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2-Azanorbornane – a versatile chiral aza-Diels–

Cite this: DOI: 10.1039/c5ob00173k
Alder cycloadduct: preparation, applications in
Published on 07 April 2015. Downloaded by Universiteit Utrecht on 24/04/2015 07:44:58.
stereoselective synthesis and biological activity

Elżbieta Wojaczyńska,*a Jacek Wojaczyński,b Karolina Kleniewska,a Mateusz Dorsza
Received 28th January 2015, and Tomasz K. Olszewskia
Accepted 7th April 2015
DOI: 10.1039/c5ob00173k The review presents the achievements in the field of preparation of chiral 2-azanorbornyl derivatives and
www.rsc.org/obc their application in various stereoselective reactions as well as in biomimetic studies.
1. Introduction
Of the three isomers of azanorbornane (azabicyclo[2.2.1]-
heptane), differing by the position of a nitrogen atom (Fig. 1),
the 2-aza-derivative is of special importance due to the intrinsic
chirality of the molecule (Fig. 2). This relatively simple bicyclic
system possesses a rigid skeleton which can serve as a versatile
platform for the synthesis of various enantiopure derivatives
which have already found a number of applications. Fig. 2 Two enantiomers of 2-azanorbornane (numbering scheme
shown for one of the isomers). Of the two typical depictions of the
2-Azanorbornane (or its unsaturated analogue, 2-azanorborn-
bicyclic skeleton shown in the figure, the first one is used throughout
ene) is easily synthetically available and can be prepared in the review. Note that for 2-azanorbonene, due to Cahn–Ingold–Prelog
priority rules, configurations of stereocenters are opposite in compar-
ison with its reduced counterpart.
both the enantiomeric forms from inexpensive starting

materials, also on a gram or even kilogram scale. The synthetic
routes to this bicyclic system will be described in section 2 of
Fig. 1 1-Azanorbornane (1), 2-azanorbornane (2, one of the enantio-
this review. The basic structure offers wide possibilities for
mers shown) and 7-azanorbornane (3).
various modifications, from simple alteration of peripheral
substituents to more elaborate transformations, in many cases
a
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of utilizing the possible chiral induction. Typically, 3-substituted
Technology, Wybrzeże Wyspiańskiego 27, 50 370 Wrocław, Poland.
derivatives are used which are isolated from the synthesis of
E-mail: elzbieta.wojaczynska@pwr.edu.pl
b
Department of Chemistry, University of Wrocław, 14 F. Joliot-Curie St., 50 383
the bicyclic system as exo (a major product in most pre-
Wrocław, Poland parations) or endo isomers (Fig. 3). This opens additional
Elżbieta Wojaczyńska received her M. Sc. Eng. degree in organic Jacek Wojaczyński graduated in chemistry from the Department of
chemistry from the Wrocław University of Technology in 1997. Her Mathematics, Physics and Chemistry of the University of Wrocław
doctoral thesis on the enantioselective synthesis and application in 1993. Five years later he defended his Ph.D. thesis on metallo-
of chiral sulfoxides was completed under the supervision of Pro- porphyrin modifications at the Department of Chemistry of the
fessor Jacek Skarżewski in 2001. Her research at the Department same university (supervisor: Prof. L. Latos-Grażyński). He is a
of Organic Chemistry of the Wrocław University of Technology member of the Metalloporphyrin Chemistry Group at this depart-
focuses on the synthesis of new chiral building blocks and of novel ment, and his research field includes oligoporphyrins, heme pro-
chiral ligands for asymmetric synthesis. teins and, primarily, degradation of oligopyrrolic macrocycles.
This journal is © The Royal Society of Chemistry 2015 Org. Biomol. Chem.
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Review Organic & Biomolecular Chemistry
reaction where the dienophile contains a nitrogen atom,8–10

was applied with great success for the synthesis of 2-azanorbor-
nyl derivatives. The reaction of cyclopentadiene with imines,
oximes and other aza-dienophiles leads to variously substi-
tuted 2-azabicyclo[2.2.1]heptenes which can be hydrogenated
Fig. 3 The two epimers of 3-substituted (1S,4R)-2-azanorbornane 4. to their saturated counterparts. Facial diastereoselectivity of
cycloaddition limits the number of possible isomeric products.
Moreover, the use of chiral dienophiles or catalysts allows
obtaining a particular enantiomer of 2-azanorbornene, which
routes for adjusting the modified compounds for particular is especially important for applications of its various deriva-
transformations. tives in stereoselective synthesis and for biomimetic studies.
The applications of 2-azanorbornane derivatives as versatile The review by Blondet and Morin published in 1982 pre-
chiral building blocks in asymmetric synthesis are presented sented the early achievements in the synthesis of 2-azabicyclo-
in section 3. The unlimited possibilities for modifications of [2.2.1]heptanes, heptenes and heptadienes.11 In this section,
the bicyclic scaffold include introduction of various donor we focus on further developments in the field, in particular on
groups and thus formation of catalytically active complexes. In the enantioselective preparative routes.
consequence, they have been employed in numerous asym- 2.1.1. The aza-DA reaction between cyclic dienes and
metric processes as chiral ligands, and also as catalysts in imines. In 1985 Larsen and Grieco reported for the first time
metal-free transformations. This practical aspect of appli- that simple inactivated iminium salts, generated in a
cations of 2-azanorbornanes is discussed in section 4. In addi- Mannich-like protocol, can combine with dienes in aza-DA
tion, these compounds have been identified as valuable rigid reaction under mild conditions and in aqueous media.12 Using
analogues of various biologically active molecules, like piper- this protocol, 2-azabicyclo[2.2.1]octene 5a and 2-azabicyclo[2.2.1]-
idine or pyrrolidine alkaloids and proline. 2-Azabicyclo[2.2.1]- heptenes 5b–e were obtained when cyclopenta- and cyclohexa-
heptane derivatives have also been applied as convenient pre- diene were reacted with various imines generated from simple
cursors in the stereoselective synthesis of monocyclic systems aldehydes and amine hydrochlorides (Scheme 1).
useful in medicinal chemistry. The biomedical applications of In an asymmetric variant of this reaction employing (1S)-1-
the title system are discussed in section 5. phenylethylamine hydrochloride as the source of chirality,
aqueous formaldehyde and cyclopentadiene a 4 : 1 mixture of
separable diastereoisomers 5d was isolated in 86% yield. This
protocol could also be performed in the presence of catalytic
2. Preparation of 2-azanorbornyl addition of lanthanide(III) triflates as reported later by Wang
derivatives and co-workers, extending the scope of that reaction to include
2.1. Synthesis of 2-azanorbornyl derivatives via the aza-Diels– higher aldehydes.13
Alder reaction
The Diels–Alder reaction (DA) is one of the most popular trans-
formations for organic chemists to efficiently create complex
molecules. Since its discovery in 1928 by Diels and Alder,1 this
pericyclic reaction involving a conjugated diene and a dieno-
phile has been used for the diastereo- and regioselective gene-
ration of six-membered rings with up to four stereogenic
centres in a single step.2–4 It is universally acknowledged for
the rapid, atom-economical build-up of complex structures of
defined geometries with minimal waste. These criteria fulfil
the requirements of a scalable chemical process; thus the
application of this transformation in chemical industry is a
feasible enterprise.5–7 The aza-DA, a variant of the Diels–Alder Scheme 1 Reaction of iminium ions with dienes.12
Karolina Kleniewska received her M.Sc. Eng. degree in organic Mateusz Dorsz received his M.Sc. Eng. degree (2014) from the
chemistry from the Wrocław University of Technology in 2014. She Wrocław University of Technology. His master’s dissertation
works on her PhD under the supervision of Dr Elżbieta Woja- involved the synthesis of novel trans-1,2-diaminocyclohexane and
czyńska in the Department of Organic Chemistry at the same uni- 2-azanorbornane derivatives. Currently he continues his PhD
versity. Her current research interests focus on the stereoselective studies in the Department of Organic Chemistry of the
synthesis and application of 2-azanorbornene analogues. Wrocław University of Technology under the supervision of Dr
E. Wojaczyńska.
Org. Biomol. Chem. This journal is © The Royal Society of Chemistry 2015
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Scheme 2 Reaction of cyclopentadiene with iminium ions derived from activated aldehydes.14
In continuation of their previous work, Grieco et al. also

showed that iminium ions derived from activated aldehydes
such as phenyl- and methylglyoxal and amine hydrochlorides
react with cyclopentadiene in water at room temperature yield-
ing the 2-azanorbornene derivatives 6a–e (Scheme 2).14
The best yield (86%) was obtained for the reaction of cyclo-
pentadiene with imine derived from phenylglyoxal and methyl-
amine, whereas the best exo/endo ratio (10 : 1) was observed for Scheme 3 Synthesis of azabicyclo[2.2.1]heptene derivatives 8 via the
the product 6d issued from the reaction of cyclopentadiene TFA/BF3·OEt2 catalyzed aza-DA reaction of chiral imine 7 with
with imine obtained from methylglyoxal and benzylamine cyclopentadiene.15–17
hydrochloride.14
After the seminal works of Grieco,12,14 in 1990 and 1991 the
groups of Stella,15 Bailey16 and Waldmann17 independently
reported an efficient stereoselective synthesis of 2-azabicyclo-
[2.2.1]heptene derivatives 8 employing the aza-DA reaction of
chiral imines 7, derived from the condensation of enantiopure
1-phenylethylamine and alkyl glyoxylate, with cyclopentadiene
and catalyzed by TFA/BF3·OEt2 (Scheme 3).
The mechanism of the reaction between chiral imine (aza-
dienophile) and cyclopentadiene was proposed by Stella and
Abraham (Scheme 4).15 The role of the catalyst is significant
due to the activation of the imine and also has an impact on
the diastereoselectivity (exo/endo ratio) of the aza-DA reaction.
The complete diastereoface selectivity was suggested by the
authors, with only products of Re addition observed. However,
further investigations by Hashimoto et al. who isolated all the
four isomers and assigned the configuration of all stereo-
centers, showed that under the original Stella conditions two
Scheme 4 Mechanism of the aza-DA reaction of an imine derived from
(1S)-1-phenylethylamine and ethyl glyoxylate with cyclopentadiene
(CpH).15,18
Tomasz K. Olszewski received his M.Sc. Eng. degree in chemistry

in 2002 from the Wrocław University of Technology. In 2006 he
obtained his PhD in chemistry (with Honours) from both the epimers differing only in the configuration on 3-C were
Wrocław University of Technology (with Professor Bogdan Bodu- obtained (Scheme 4), and the modification of reaction con-
szek) and Université de Montpellier II (with Professor Claude ditions can lead to changes in the ratio of minor products,
Grison). Shortly thereafter, as a post-doctoral fellow, he spent one with the exo-diastereomer with the configuration on 3-C oppo-
year at the National Hellenic Research Foundation in Athens site to the configuration of the imine used remaining the
(Greece), and two years at the University of Basque Country major cycloadduct (constituting ca. 80%).18 In most prep-
(Spain). Before returning to academia he worked as a project arations, only this product is isolated from the reaction and
leader at a chemical company. At present, he works in the Depart- the remaining isomers are discarded.
ment of Organic Chemistry of the Wrocław University of Techno- The advantage of the approach proposed by Stella, Bailey
logy. His research interests span the areas of organophosphorus and Waldmann lies in the use of inexpensive starting materials
chemistry, asymmetric synthesis and recently catalysis. in combination with the high selectivity observed when utiliz-
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ing (1S)- or (1R)-1-phenylethylamine as the chiral auxiliary. The

reaction is highly exo-selective; the exo/endo ratio reported
varied from 86 : 14 to 98 : 2.15–17 Bailey and co-workers have
extensively studied the asymmetric synthesis of 2-azanorborn-
ene derivatives (including 8b) using the aza-DA [4 + 2] cyclo-
addition between imines of the type Ph(R)CH–NvCHCOOEt
and dienes.19 The reaction showed extremely high regio- and
diastereoselectivity, moreover, the use of the (S)-1-phenylethyl
group as a chiral auxiliary led to high asymmetric induction. A Scheme 5 Synthesis of heterocyclic azanorbornene derivatives 9.24
significant preference for the exo adducts was observed, which

can be explained by directing the bulkier auxiliary away from
the bridging (CH2)n group into the axial endo position and highly reactive dienes under Lewis acid catalysis. A new route
forcing the ester into the considerably less hindered based on the use of non-activated imine dienophiles would
exo stereochemistry. broaden the scope of this reaction considerably. Therefore
The aza-DA reactions between cyclopentadiene and several attempts to use different imines have been described
iminium ions derived from glyoxylates have been a subject of in the literature.
theoretical studies performed in 2005 by Rodríguez-Borges Andersson et al. reported on the use of nitrogen containing
et al. using density functional theory (DFT).20 The obtained heterocyclic aldehydes in the synthesis of heterocyclic imine
results suggested a highly asynchronous concerted mechan- dienophiles and their reaction with cyclopentadiene affording
ism, which in turn may explain the preferred exo stereo- a palette of heterocyclic azanorbornene derivatives 9a–f
selectivity of the reaction and the significant effect of the (Scheme 5).24 A second nitrogen atom placed in conjugation
solvent used in the reaction. The exo/endo ratio increased with with the imine fulfilled the role of an electron-withdrawing
the solvent polarity in good agreement with the experimental group under the acidic reaction conditions and hence acti-
findings. Further theoretical studies carried out by the same vated the imine. The use of a Lewis acid such as boron trifluor-
authors in 2009, revealed that the exo/endo selectivity was pre- ide (BF3), which was beneficial in the earlier mentioned
dicted to decrease with increasing temperature in accordance cycloaddition of glyoxylate-derived imines, resulted only in a
with the experimental observations.21 In addition, DFT was used fast polymerization of the aldehyde. In turn, strong Brønsted
by Teixeira et al. to elucidate the role of the ester group of the acids such as methanesulfonic acid and trifluoroacetic acid
dienophile. The theoretical calculations confirmed that the exo proved to be very effective, and the use of these two reagents
cycloadducts (sterically less hindered) are always favored relative either alone or in a 1 : 1 combination resulted in good conver-
to the endo analogues, both for kinetic and thermodynamic sions and stereoselectivities. In all cases the exo product was
reasons. The influence of the ester group was shown to be much formed almost exclusively and the diastereoselectivities varied
more noticeable when the solvent effect was considered.22 from 75 : 25 in the case of 9e to 90 : 10 for 9c, 9d and 9f.24
In 2002 using the methodology depicted in Scheme 3, Later on the same group reported on the synthesis of 2-aza-
Andersson et al. reported the synthesis of (1R,3R,4S)-8a on a norbornene derivatives 10a–g (Scheme 6).25 The non-activated
111.5 g scale with 56% overall yield.23 Later on, Hashimoto iminodienophiles having protecting groups such as benzyl,
and co-workers reported on the preparation of (1S,3S,4R)-8a on benzyloxycarbonyl, and tosyl did not undergo the cyclo-
an industrial scale (103 kg, 32% overall yield) by replacing addition reaction, most likely due to the steric hindrance. In
fluorinated chemicals with a biphasic system TMSCl–CH3OH/ turn the iminodienophiles prepared from less bulky phthal-
toluene.18 imide and succinimide aldehyde derivatives reacted smoothly
Due to the low reactivity (or poor electrophilicity) of the with cyclopentadiene to give cycloadducts 10 (Scheme 6). The
imine functionality, [4 + 2] cycloaddition is possible only with yields varied from 70% in the case of 10g to 95% for 10c. The
Scheme 6 The aza-DA reaction of non-activated imine derivatives with cyclopentadiene and the formation of bicyclic products 10.25
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Scheme 7 Synthesis of spirocyclic 2-azanorbornene derivatives 11.27
best exo/endo selectivity (85 : 15) was observed for 10c and 10d. In 2000, in the search for alternative substrates for imine
The use of chiral aldehydes for the preparation of imines formation, Andersson’s group reported on the use of bisamido
applied in the synthesis of the two derivatives, 10a and 10e is tartrates 15.29 The oxidative cleavage of 15a–c with periodic
worth noting since in most enantioselective routes leading to acid furnished the corresponding aminoaldehydes which sub-
2-azanorbornenes various enantiopure amines have been sequently reacted with (S)-phenylethylamine to form the
applied as the source of chirality.26 desired imines used in the aza-DA reaction with cyclopenta-
It is noteworthy that apart from the possibility of using diene to yield the 2-azanorbornene derivatives 16. Compounds
different iminodienophiles modification of the diene moiety is 16a–c were further used as building blocks for the improved
also feasible. As reported by Andersson’s group the use of spiro- synthesis of enantiomerically pure diamines 17a–c30 firstly by
dienes 11a–b, prepared by the addition of dihaloalkane to cyclo- deprotection of the amine by hydrogenolysis with Pd(OH)2,
pentadiene, led to spirocyclic 2-azanorbornene derivatives 12a–b and subsequently reduction of the amide by means of LiAlH4
(Scheme 7).27 The low yields were attributed to the high ten- (Scheme 9).
dency of diene polymerization under acidic reaction conditions. In order to improve the diastereoselectivity of the aza-DA
Loh and co-workers reported a Lewis acid-mediated aza-DA reaction, chiral glyoxyloyl derived-iminodienophiles obtained
reaction of cyclopentadiene and 3-pyridinecarboxaldehyde- with the use of various enantiopure auxiliaries have been
derived imines as a new route for the preparation of 2-azabicyclo- applied, as reported in the literature. García-Mera, Rodríguez-
[2.2.1]heptene derivatives 13a–c (Scheme 8). The best results of Borges and co-workers described the effective and highly
the aza-DA reaction between deactivated imines and cyclo- enantioselective synthesis of 3-functionalized 2-azabicyclo-
pentadiene were obtained using a AlCl3/Et3N mixture in a 3 : 1 [2.2.1]heptene derivatives 21 and 22 via an aza-DA reaction
ratio under anhydrous conditions at 0 °C. Interestingly, when between cyclopentadiene and the protonated imines prepared
an imine derived from p-anisidine was used, the Povarov reac- from N-benzylamine and glyoxylates of the two diastereomers
tion product was formed resulting from the reversal of roles: of (−)-8-phenylmenthol 18a and 18b, as easily recoverable
the N-aryl-substituted, electron-poor imine acted as an aza- stereocontrolling chiral auxiliaries (Scheme 10).31–33
diene and a cyclopentadiene as a dienophile to afford the qui- The highly asymmetric (1S,3-exo) induction observed was
noline derivative 14.28 explained by considering two important factors: firstly, dieno-
Scheme 8 Preparation of heterocyclic derivatives of 2-azanorbornene 13a–c.28
Scheme 9 Synthesis of 2-azanorbornene derivatives 16, 17.29
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Scheme 10 Use of diastereomers of (−)-8-phenylmenthol 18a and 18b in the synthesis of 2-azanorbornene derivatives 21 and 22.31–33
phile in the reaction should have an E configuration, more between bulky substituents turned one of the diastereotopic
stable for stereochemical and polar reasons, secondly in the faces much less hindered than the other.
close vicinity of the CvN bond, the benzyl group exerts a Another example of the use of chiral auxiliaries was
larger steric hindrance than the ester group. In addition, to reported by Jurczak’s group who prepared a series of 2-azanor-
minimize stereochemical interactions between the methylene bornene derivatives 23 by an aza-DA cycloaddition reaction
moiety of the diene and the bulky substituent of the iminium between cyclopentadiene and N-benzyliminoacetyl derivatives
ion the approach diene–dienophile must occur in an exo of (2R)-bornane-10,2-sultam and chiral secondary alcohols as
manner. chiral auxiliaries reaching a de up to 80% (Scheme 11).35
The same authors also described the double diastereoselec- An interesting approach utilizing an enantiopure catalyst as
tion in the aza-DA cycloaddition between a chiral imine a source of chiral induction in the aza-Diels–Alder reaction
derived from glyoxylates bearing chiral auxiliaries, (−)-8-phenyl- was proposed by Jørgensen and co-workers.36 Bis-phosphine
menthyl or (+)-8-phenylneomenthyl and (1S)- or (1R)-1-phenyl- (BINAP derivative (R)-24) or phosphine-oxazoline (S)-25 and
ethylamines, with cyclopentadiene in the presence of copper(I) perchlorate as the metal source were chosen in the
BF3·OEt2/TFA.34 The presence of two chiral auxiliaries and the catalyst screening using Danishefsky’s diene and N-tosyl imino
stereochemistry of the phenylethylamine auxiliary played an ester. Their application in the aza-DA reaction of this dieno-
important role in obtaining a single adduct since the need for phile with cyclopentadiene led mainly to an exo (1S,3S,4R)-2-
coplanarity of the benzene rings and for maximum distance azanorbornene derivative in 81–88% yield and an ee up to
Scheme 11 Preparation of 2-azanorbornene derivatives 23 with the use of chiral auxiliaries.
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can also be considered as imino dienophiles in the aza-DA

reaction leading to N-hydroxyl-2-azanorbornene derivatives. In
2008, Sousa and co-workers reported the first aza-DA reaction
with non-O-functionalized oximes as the azadienophiles
(Scheme 13).40 The influence of several Lewis and/or Brønsted
acids such as TFA, BF3, AlCl3, ZnI2 or HClO4 on the [4 + 2]
heterocycloaddition between cyclopentadiene and methyl
glyoxylate oxime leading to a mixture of the corresponding
exo/endo adducts was investigated. In addition, the influence
of temperature on a product ratio and yield was examined.
The reaction yielded a mixture of the exo/endo formally
Scheme 12 Synthesis of 2-azanorbornene derivatives catalyzed by a [4 + 2] aza-DA azanorbornene cycloadducts 27 and 28, together
chiral copper(I) complex. with the product of [3 + 2] dipolar cycloaddition 29 which was
found to be the major product regardless of the conditions.
The relative yields and diastereoselectivities were found to be
83% (Scheme 12); endo diastereomer was also formed in more dependent on the catalyst rather than on the tempera-
minor quantities (7–9%). ture. Later on, further investigations concerning the influence
A similar approach was used by Maison and co-workers for of various parameters of the mechanism for the formation of
the synthesis of N-protected 2-azanorbornyl derivatives using both 1,3- and 1,4-cycloadducts were performed by the same
(R)-24 as a source of chirality.37,38 The obtained 2-azabicyclo- authors (Scheme 14).41 The type of catalyst had the major
alkane scaffolds were used as synthetic intermediates for con- impact on the course of the reaction and the ratio of the exo/
formationally constrained glutamate analogues,37 potential endo products, since it may coordinate to the oxygen or the
ligands for glutamate receptors, known to play an important nitrogen atoms in oxime and allow a competition between 1,3-
role in several neurological disorders.39 and 1,4-cycloadditions. The best overall yields of 2-azanorbor-
2.1.2. The aza-DA reaction between cyclic dienes and nenes 27 and 28 were obtained with TFA as the catalyst, while
oximes or other aza-dienophiles. N-Hydroxylimines (oximes) the use of BF3·OEt2 yielded selectively the isoxazolidine 29.
Scheme 13 Products of cycloaddition between oxime glyoxylate and cyclopentadiene.40
Scheme 14 Proposed mechanism for the cycloaddition of cyclopentadiene to oxime glyoxylate.41
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lactam in enantiomerically pure form using menthylsulfonyl

cyanides or chiral catalysts were moderately efficient; the
highest ee reported (25.6%) was obtained for a reaction cata-
lyzed by a chiral aluminum complex; instead, resolution of
racemic compound 30 and its derivatives via enzymatic kinetic
resolution with various biocatalysts was found to be the most
convenient method.43
2.2. Synthesis of 2-azanorbornyl derivatives using multistep

protocols
Scheme 15 Synthesis of Vince lactam 30.45 Apart from the very efficient aza-DA protocols leading to 2-aza-
norbornyl derivatives other methods for the synthesis of these
compounds have also been reported in the literature. These
procedures usually rely on multistep reaction sequences.
The same authors also studied the use of chiral auxiliaries Coldham et al. reported on the synthesis of 2-azanorbornane
in the cycloaddition reaction between stereoisomeric 8-phenyl- derivative 37 (Scheme 16) using a tin-lithium exchange and
menthyl and 8-phenylneomenthyl glyoxylate oximes and cyclo- anionic cyclization (carbolithiation) as the final step.47 The
pentadiene.42 The results revealed that the 1,3-cycloaddition is lactam 32, used as the starting material, was first N-alkylated
preferred over the 1,4-process. Since the overall yields were and then allylated to yield a 3 : 1 mixture of products 34 and
moderate (32–40%), the stereoselectivity of the formation of 35 separable by column chromatography. Subsequently, the
the minor Diels–Alder cycloadducts was not established. isolated trans-34 was decarbonylated to give intermediate 36
In the quest for an efficient route to 2-azabicyclo[2.2.1]- that was further reacted with nBuLi at −78 °C to form the
hepten-3-one (Vince lactam 30, a versatile synthetic building 2-azanorbornane derivative 37 in 22% overall yield. The
block for carbocyclic nucleoside analogues43), alternatives to diastereoselectivity of cyclization (only endo isomer was
the classical method based on cycloaddition of tosyl cyanide observed) was explained by a favored formation of a boat-
with cyclopentadiene44 have been developed. An interesting shaped transition state. The intramolecular carbolithiation
aza-DA reaction was reported by Griffiths and co-workers who was also applied to the synthesis of 1- and 7-azanorbornane
used methanesulfonyl cyanide as an aza-dienophile in the systems.
reaction with 20% excess of cyclopentadiene at room tempera- The synthesis of racemic derivatives of 2-azanorbornane
ture forming in situ the cycloaddition product 31. Subsequent starting from 1,2-substituted pyrrole was described by Zanardi
treatment with water resulted in formation of the desired et al., with aldol carbocyclization as a decisive step for the dia-
2-azanorbornene derivative 30 in up to 90% yield stereoselective formation of a bicyclic skeleton.48 Enantio-
(Scheme 15).45 One-pot procedure, involving regeneration of selective preparation of 2-azanorbornanes made use of
cyanide, was scaled up to give ca. 100 g L−1 of the reactor enantiopure starting materials. Grygorenko and co-workers
volume of 30. proposed a novel synthetic route to both enantiomers of 2-aza-
Also chlorosulfonyl isocyanate was used as aza-dienophile bicyclo[2.2.1]heptane-1-carboxylic acid 42, a rigid bicyclic
in the aza-DA reaction as described by Malpass and Tweedle; proline analogue, based on a tandem cyanide addition–intra-
the procedure was improved by Vince’s group by changing the molecular cyclization.49 In their approach chloromethyl-
reaction conditions to suppress the formation of β-lactam in cyclopentanone 38 and nitrile 39 were reacted in refluxing
favor of the desired γ-lactam 30.46 Attempts to obtain Vince acetonitrile for 30 h and led to a mixture of bicyclic products
Scheme 16 Preparation of 2-azanorbornane derivative endo-37.47
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Scheme 17 Synthesis of azanorbornane derivative 42.49
40, 41 in 40% overall yield (Scheme 17). Subsequent transfor- compound 42 in 22% total yield and 75% ee (Scheme 18). In a
mations of isomers of 40 led to the desired products 42 (in the key step, cyclization of a derivative of 44 promoted by KHMDS
form of hydrochlorides) in only 2% overall yield. allowed obtaining the azanorbornane derivative 45 which was
Later on Grygorenko et al. reported on an improved hydrolyzed to give hydrochloride 42.50
approach to 2-azabicyclo[2.2.1]heptane-1-carboxylic acid 42 Another application of a proline derivative for the stereo-
involving a multistep reaction sequence starting from the opti- selective preparation of a 2-azanorbornane system was
cally pure trans-4-hydroxy-L-proline 43 and yielding the desired reported by Husbands and co-workers who prepared the com-
Scheme 18 Synthesis of bicyclic proline derivative 42.50
Scheme 19 Multistep preparation of 2-azanorbornane derivative 50.51
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pound 50 (Scheme 19),51 a new analogue of meperidine, will not be discussed if they are not associated with alteration
μ-opioid agonist that displays a psychostimulant effect.52 trans- of stereochemistry of the substrate.
L-Hydroxyproline methyl ester 46, easily prepared from com-
mercially available trans-L-hydroxyproline 43, was converted to
ethyl carbamate 47 which was than subjected to reduction 3.1. Reactions retaining the 2-azanorbornyl scaffold
with lithium aluminum hydride followed by tosylation of the Several research groups concentrated on the selective introduc-
formed diol, yielding compound 48 (18% overall yield). tion of various substituents into the 2-azanobornane skeleton.
The key step in the synthesis was the alkylation of 48 with a The presence of a double bond in the product of an aza-DA
phenylacetonitrile anion using LDA (48% yield) or NaNH2 reaction, 2-azabicyclo[2.2.1]heptene, allows additions which
(37% yield) as a base. Interestingly, alkylations resulted in typically lead mainly to exo stereoisomers. In particular, aryla-
selective formation of a single diastereomer. Finally, hydrolysis tion procedures of the 5- or 6-position were described. Kasyan
of 49 followed by esterification gave the desired conformation- and co-workers prepared analogues of alkaloid epibatidine
ally restricted exo-phenyl derivative 50. modified in the bicyclic ring.53 The Boc-protected substrate 51
was subjected to the reductive Heck coupling reaction with
2.3. Summary
aryl iodide under typical conditions, which allowed obtaining
The aza-Diels–Alder reaction of cyclopentadiene and chiral the corresponding 5-aryl-2-azabicyclo[2.2.1]heptane derivatives
imines, presented in section 2.1.1, followed by double bond in a regio- and stereospecific manner (Scheme 20). The Boc
hydrogenation, remains the most convenient route to enantio- group was removed under acidic conditions to provide the
merically pure 2-azanorbornanes. The success of this approach amine 53, followed by treatment with tosyl chloride in the
is connected with the high optical purity of the product (with presence of sodium hydroxide, or trifluoromethanesulfonic
both enantiomers available) connected with a considerable anhydride and triethylamine which furnished the corres-
diastereoselectivity (the major exo diastereomer can be easily ponding crystalline derivatives 54 and 55 as single 5-exo
isolated from the minor cycloadducts), and the possibility of isomers. In contrast, the Pd-catalyzed hydroarylation reaction
scaling up. However, for derivatives with the unique substi- of Vince lactam 30 with a series of electron rich and electron
tution pattern (for example, those substituted in the 1- or/and poor aryl/heteroaryl iodides afforded mixtures of 5- and 6-sub-
4-position) protocols utilizing bridge formation in the respect- stituted isomers in moderate to good yields (59–98%).54 Also
ive 5-membered pyrrolidine or cyclopentane ring (to the best rhodium-catalyzed arylation of Vince lactam derivatives using
of our knowledge, a six-membered piperidine ring has not arylboronic acids under microwave radiation yielded a mixture
been used as the synthetic precursor), though in general of 5-exo- and 6-exo-regioisomers,55 while N-substitution of 30
associated with lower overall yields, should also be taken into was achieved with a copper catalyst,56 as described by Ishikura
account. Interestingly, 2-azabicyclo[2.2.1]heptanes were identi- and co-workers.
fied as attractive substrates in the stereoselective syntheses of Oxidations of double bonds of 2-azanorbornene leading to
these monocyclic systems exhibiting substantial biological 5,6-disubstituted derivatives were also described. Dihydroxyla-
activity, as described in sections 3 and 5 of this review. tion with osmium tetroxide and N-methylmorpholine N-oxide,
the K2OsO2(OH)4/K2CO3/K3[Fe(CN)6] system or KMnO4 in
aqueous KOH led to exo vicinal diols.57 An efficient epoxi-
3 Azanorbornyl derivatives as dation of Vince lactam 30 was performed with oxone in water
building blocks in the synthesis at pH = 6, and an exo isomer of epoxide was selectively
obtained in 80% yield.58 Dioxalane-appended derivatives,
As it was shown in the previous section, the 2-azabicyclo[2.2.1]- which were obtained via the protection of diols with a ketone
heptanes are generally easily synthetically available and can be or a corresponding dimethyl ketal, were found effective as
prepared in both enantiomeric forms from inexpensive start- chiral ligands in the ruthenium-catalyzed transfer hydrogen-
ing materials, even at a kilogram scale. This in combination ation of ketones (see section 4.4).57a,59
with the fact that these simple bicyclic systems offer a wide
range of possible modifications, including those in which
additional stereogenic centers are created, made the 2-azanor-
bornyl derivatives a versatile platform for the synthesis of
various compounds, which have already found a number of
applications in medicinal chemistry and catalysis.
From the variety of transformations of 2-azabicyclo[2.2.1]-
heptanes we have selected examples of stereoselective reac-
tions in which high asymmetric induction from the bicyclic
system have been observed: substitution or modification of
existing substituents, and ring opening (leading to valuable
monocyclic products) or its expansion. Thus, the numerous, Scheme 20 2-Azanorbornene derivative 51 as a building block in the
sometimes very sophisticated changes in substitution patterns synthesis of epibatidine analogues.53
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Scheme 21 Reaction of enolate 57 with electrophiles.60
Andersson’s group reported on the diastereoselective syn-

thesis of various 3,3-disubstituted 2-azanorbornane derivatives
via the reaction of exocyclic enolate 57 with various electro-
philes (Scheme 21).60 In the case of the treatment of enolate
57 with water as an electrophile a 70 : 30 mixture of endo/exo
diastereoisomers was obtained due to the protonation from
the less hindered exo face of the enolate, yielding an epimer of
the starting compound 56. However, enolate reacted with high
diastereoselectivity with other electrophiles to afford the bicyc- Scheme 22 Preparation of 2-azanorbornane-based phosphinooxazo-
lic products 58. For all cases the obtained regio- and chemo- lidine chiral ligand 60.61
selectivity were high (95 to >98%) albeit reactions with both

secondary halides and α,β-unsaturated ketone led to much
lower yields, 40 and 20% respectively.
In a different approach to introduce additional donor
atoms to the structure of 2-azabicyclo[2.2.1]heptane, the
derivative 59 was used by Okuyama and co-workers to prepare
a new 2-azanorbornane-based phosphinooxazolidine chiral
ligand 60, as an analogue of the known chiral phosphinoox-
azolidine, very effective in the palladium-catalyzed asymmetric
allylation reaction.61 The reaction of 59 with 2-(diphenyl-
phosphino)benzaldehyde in refluxing toluene furnished the
desired compound 60 as a single diastereomer in 65% yield
(Scheme 22). Other oxazolidine-fused enantiopure 2-azanor-
bornanes prepared by the same research group were used as
chiral ligands in the enantioselective diethylzinc addition to
aldehydes.62
Stereoselective conversions of substituents attached to the
Scheme 23 Preparation of secondary alcohols based on 2-azanor-
chiral 2-azanorbornane scaffold have also been reported.
bornane scaffold.63
Andersson’s group described the preparation of secondary
alcohols containing additional stereocenters, useful in
the enantioselective addition of dialkylzinc to imines.63,64
(S)-Epimers were obtained from aldehyde 61 ( prepared by hydride, with slightly lower yields and selectivity (dr =
Swern oxidation of the respective primary alcohol) in the reac- 80 : 20).63 Pfaltz and co-workers described an analogous reac-
tion with Grignard reagents in the presence of cerium(III) tion of two enantiomers of aldehyde 61 with 1-naphthylmagne-
chloride (Scheme 23). Two products were formed in an 85 : 15 sium bromide which provided the corresponding alcohols as
ratio, and the major isomer was isolated by flash chromato- single diastereomers.65
graphy. The selectivity of the reaction was explained by the pre- Higher asymmetric induction was observed in our labora-
ferential approach of the nucleophile from the less hindered tory in the hydrophosphonylation of aldehyde 61 with silylated
side of the substrate.63 (R)-Epimers were prepared in the dia- phosphorus esters leading to α-hydroxyphosphonic acid
stereoselective reduction of ketone 63 with lithium aluminum derivatives of 2-azanorbornane.66 When exo-aldehyde fur-
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Scheme 25 Retro-DA reaction as a tool in the synthesis of chiral

primary amines from 2-azanorbornenes.67
Scheme 24 Synthesis of α-hydroxyphosphonic acids attached to a
2-azanorbornane.66
Other reagents such as copper sulfate (CuSO4) or sulfonic

acid based ion exchange resins were also tested with success
nished exclusively the (S)-α-hydroxyphosphonic acid 65, the in this reaction.68 The methodology was used for preparation
use of aldehyde endo-61 epimer yielded the isomer with the of N-methylated amino acids, di- and tripeptides: the iminium
opposite configuration of the newly created stereogenic center ion species generated during the retro-DA reaction of the
66 (Scheme 24). appropriate 2-substituted-2-azanorbornene derivative in a 1 : 1
chloroform/trifluoroacetic acid mixture, treated with triethyl-
3.2. Modification of the 2-azanorbornyl skeleton silane at room temperature yielded the desired enantiopure
Another group of transformations of the 2-azanorbornene and products in just 0.5–2 h reaction time in good yields.69
2-azanorbornane derivatives includes the alteration of the Synthesis of pyrrolidine derivatives is typically achieved by
bicyclic skeleton: ring opening leading to derivatives of cyclo- C5–C6 bond cleavage of the appropriately substituted bicyclic
pentane or pyrrolidine and conversion to other bicyclic system. As a continuation of previously performed work,40
scaffolds. Many of these products, often obtained with high Rodríguez-Borges and co-workers used the 2-azanorbornene
enantioselectivity, found various applications in asymmetric derivatives including 27 and 56 as the starting materials in the
synthesis as chiral ligands or precursors of biologically active synthesis of polyhydroxypyrrolidines and their selective
compounds.38,43 A part of target compounds will be shown in functionalization.70,71 The dihydroxylated bicyclic compounds
section 5 of this review. In this part, selected examples of the were converted to monocyclic products using the oxidative
above mentioned transformations will be presented. cleavage with sodium periodate and in situ reduction of the
In the earliest studies on this topic and inspired by pre- obtained aldehydes, as exemplified in Scheme 26. The
viously performed studies on the reaction of cyclopentadiene obtained results showed the efficiency of the applied methodo-
with C-acyl iminium ions,14 Grieco et al. observed that the logy, allowing selective introduction of functional groups into
2-azanorbonene hydrochloride and its N-alkyl derivatives 67 polyhydroxypyrrolidine analogues.
underwent a retro-DA reaction at 50 °C or even at room temp- Formation of a cyclopentane ring requires C–N (C1–N or C3–
erature in the presence of N-methylmaleimide (used as a trap- N) or (less probable) C3–C4 bond cleavage of the 2-azabicyclo-
ping agent for cyclopentadiene), affording the chiral primary [2.2.1]heptane. Andersson et al. used the 2-azanorbornane
amines without any racemization (Scheme 25).67 High conver- derivative 72 as the starting material in the synthesis of cyclo-
sion rates and yields were observed when the process was pentylamine 75, a molecule of high importance in medicinal
carried out in aqueous solution; quaternary ammonium salts chemistry.57a After protection of the nitrogen atom with the
were suggested as intermediates in the reaction. tosyl group, the ester moiety was reduced to form the alcohol
Scheme 26 Application of dihydroxylated 2-azanorbornene derivative 69 in the synthesis of functionalized pyrrolidines.70
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Scheme 27 Preparation of cyclopentylamine 75.57a
73 which was transformed to the bromide derivative 74. Ring

opening was achieved by treatment of 74 with magnesium in
refluxing tetrahydrofuran. The reaction was facilitated by the

presence of the electron-withdrawing tosyl group, and the
desired amine 75 was formed in 90% yield (Scheme 27).
The protocol was successfully applied to the synthesis of
cyclopentylamine and cyclohexylamine bearing ketal
functionality.57a
The same group also reported on the synthesis of four types
of α-amino acid derivatives using one azabicyclic substrate 8b
as the chiral building block under different reductive reaction
conditions (Scheme 28).72
In addition, the authors demonstrated that the obtained
optically pure amino ester (R)-77 could be easily transformed
into the corresponding amino alcohol, and further into valu- Scheme 29 Synthesis of 1-azabicyclic alkaloids 80 with the use of
able chiral auxiliaries with potential for use in asymmetric Vince lactam 30 as a building block.73
synthesis.
2-Azanorbornanes and 2-azanorbornenes can also be con-
verted into other bicyclic compounds. Arjona et al. described
an application of 2-azanorbornene derivative 30 in the enantio- did not cyclize and the products of ring-opening metathesis-
selective synthesis of the azabicyclic γ-lactams 80 cross metathesis (ROM-CM) 81 were obtained, but they could
(Scheme 29).73 The synthetic pathway was based on the be converted into the desired azabicyclic γ-lactams by the inde-
N-alkylation of 30 in the first step, and followed by a domino pendent ring-closure metathesis (RCM).
olefin metathesis. The procedure allowed the preparation of Bailey et al. demonstrated the formation of two isomeric
optically pure 1-azabicyclic alkaloids 80 with different ring oxaazabicyclooctanes as a result of the brief treatment of 2-aza-
sizes. Usually, derivatives 79 underwent the metathesis norbornene derivative 8b with m-chloroperbenzoic acid
smoothly, but in some cases the 2-azanorbornene derivatives (mCPBA).74 Ring expansion of 2-aza[2.2.1]heptane was also
observed in our laboratory. A nucleophilic substitution of
2-azanorbornane-3-yl methanol 82 under Mitsunobu con-
ditions or with the use of mesyl chloride resulted in conver-
sion into derivatives containing a seven-membered ring.75 The
synthetic method was found to be versatile, and bridged chiral
azepanes (2-azabicyclo[3.2.1]octanes) 83 bearing various func-
tional groups could be prepared, including azide, sulfide, sele-
nide, esters, ethers and chloride (Scheme 30).
The ring expansion reaction was stereoselective: in each
case alcohol (1S,3R,4R)-82 (exo) was converted to a product
with a (1S,4S,5R) configuration. The process also proceeds in a
stereospecific manner: when alcohol (1S,3S,4R)-82 (endo) was
used as a substrate, azide 83a with an opposite configuration
on C-4 was formed as compared to the product obtained from
exo-isomer (Scheme 30).
2-Azabicycloalkanes were also used as key intermediates in
the synthesis of variously substituted diazabicycloalkanes with
defined (and diverse) stereochemistry.57b A number of other
Scheme 28 Synthesis of α-amino acid derivatives from 2-azanorbor- target structures available from 2-azabicyclo[2.2.1]heptene illus-
nene substrate 8b as a chiral building block.72 trate the versatility of this unsaturated heterocyclic precursor.
View Article Online
tioning. Modifications of the 2-azanorbornane scaffold may

involve ring opening or ring expansion as well.
A large family of chiral ligands based on 2-azabicyclo[2.2.1]-
heptane has been prepared and used with success in diverse
asymmetric transformations. The majority of contributions in
the field come from the group led by Pher G. Andersson. A
review by Brandt and Andersson published in 2000 showed the
variety of possible catalytic applications of these bicyclic com-
pounds.76 Since that time, a substantial development has been
observed, in particular 2-azanorbornane derivatives bearing
phosphine and oxazoline or thiazole substituents were found
efficient in the iridium-catalyzed hydrogenation of various sub-

strates containing a CvC or CvN bond. In this section, we
shall focus on the new achievements though comparisons to
the older results will be made as well.
Scheme 30 Synthesis of bridged azepanes 83 from a 2-azanorbornane
4.2. Enantioselective addition of diethylzinc to aldehydes
building block.75
and other organocatalytic transformations
2-Azanorbornanes have proved to be very potent catalysts for
asymmetric addition of dialkylzinc to aldehydes. The impor-
4. Catalytic applications of chiral tance of this reaction is connected with its synthetic utility
2-azanorbornane derivatives since it yields chiral secondary alcohols, useful building
blocks for asymmetric synthesis.77 As β-amino alcohols were
4.1. Introduction previously reported to be extremely efficient catalysts in this
The successful stereoselective synthesis of 2-azabicyclo[2.2.1]- reaction,78 Nakano et al. prepared a series of 2-azanorbornene
heptene almost immediately aroused an interest in the poss- derivatives containing a tertiary alcohol fragment in the
ible applications of this compound and its derivatives as desired position with respect to the nitrogen atom.79,80 These
ligands in asymmetric synthesis. A cycloadduct obtained in derivatives 59, 84a–g and the primary alcohol 82 were used as
the course of the aza-Diels–Alder reaction contains a rigid catalysts in the enantioselective addition of diethylzinc to
bicyclic skeleton bearing a nitrogen donor (a tertiary amine various aldehydes (Scheme 32). For most derivatives (S)-alco-
which can be converted to a secondary one by the reductive hols were formed preferentially with ee values in the range of
removal of the original substituent derived from the aza-dieno- 28–92% and 20–97% yield; only 59 and 82 led mainly to (R)
phile used), a substituent at the 3 position and a double bond product, albeit with low stereoselectivity (36% and 22% ee for
which are the three places of possible modifications the addition to benzaldehyde, respectively). The N-methylated
(Scheme 31), as described in the previous section. All changes ligand 84b was found to be the most effective (65–97% yield
of the electronic or steric properties of chiral ligands allow the and 73–92% ee for aryl aldehydes). Even better results were
adjustment of their coordination properties, and, as a conse- obtained for the thiol derivative, but the analysis of the syn-
quence, the activity and stereocontrol in the catalytic reactions. thetic route reveals that this compound in fact has a bridged
The controlled tuning of basicity of donors and possibility of azepane structure 87 instead of the expected 86 (Scheme 33). A
hydrogen bond formation are of special importance for the
potential organocatalytic applications.
In addition, the basic bicyclic compound is easily syntheti-
cally available in both enantiomeric forms. The relatively
underexplored possibility of application of the minor endo dia-
stereomer formed in the aza-DA reaction is also worth men-
Scheme 31 A general scheme of possible transformations of the aza-

DA cycloadduct (exemplified by one of isomers of 8b) as a route to the Scheme 32 Enantioselective diethylzinc addition to aldehydes cata-
family of chiral ligands. lyzed by 2-azanorbornyl-3-methanols.79,80
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Scheme 33 Ring expansion upon introduction of the thioacetate

moiety.75,80
Scheme 35 Enantioselective addition of diethylzinc to imines.63,64,81
similar rearrangement upon formation a thioacetate (enantio-

mer of 83c) was observed in our investigations on ring expan-
sion 2-azanorbornane derivatives (section 3.2).75 reaction, allowing preparation of various phosphinoyl imines
Nakano and co-workers published two articles on the appli- in 65–91% yield and 87–98% ee.64 The high enantioselectivity
cations of oxazolidines fused to the chiral 2-azanorbornanyl was only noted when stoichiometric amounts of the chiral
scaffold in the enantioselective diethylzinc addition to alde- inducer were used. For example, when 10 mol% of ligand 89d
hydes (Scheme 34).62 Among chiral ligands 88a–g tested in the was applied, the ee dropped significantly (from 91% to 68%),
conversion of benzaldehyde, the use of compound 88f was and the yield lowered from 63% to 38%.81 However, the cata-
accompanied with the highest yield (89%) and enantiomeric lyst could be recovered from the reaction and reused without
excess (83%). For other substrates, the reported enantio- significant loss of stereoselectivity.
selectivity was rather medium or low (24–63% ee). Chiral (1R,3S,4S)-2-azanorbornyl-3-methanol 59 was also
Andersson’s group concentrated on the application of alco- used by Loh and co-workers as a catalyst for enantioselective
hols derived from 2-azanorbornane in the enantioselective epoxidation of α,β-enones (Scheme 36).82 For the optimal reac-
addition of dialkylzinc to imines.63,64,81 A series of 2-azanor- tion conditions (20 mol% of catalyst, hexane used as a solvent,
bornyl-3-methanols 89a–k, including primary, secondary and room temperature, 6 days) results of trans-chalcone were found
tertiary alcohols were prepared bearing various substituents on promising (81% yield and 88% ee), and for most of the sub-
the hydroxylated carbon atom. Using the addition of Et2Zn to strates tested enantioselectivity was also high (ee for aryl-sub-
N-(diphenylphosphinoyl)benzaldimine as a model reaction, stituted ketones were in the range of 80–88%). The structure of
ligand 89h bearing an additional stereogenic center was the catalyst was not optimized in that study. The same group
selected as an optimal inducer of chirality (Scheme 35).81 The applied alcohol 59 and its derivatives 84a, 90a–b as well as
observed tendencies of the stereochemical outcome were sub- carboxylic acid 91 as chirality inducers for the stereoselective
stantiated by theoretical calculations.63 Toluene and chloro- Michael addition of vinyl malononitriles to α,β-unsaturated
benzene were identified as the most suitable solvents for the aldehydes (Scheme 37).83 N-Substituted alcohol 84a was com-
pletely ineffective, while compound 59, used in 20 mol% load,
led to the highest yield and enantioselectivity. THF solvent
and p-nitrobenzoic acid as an additive were found beneficial
for the good reaction outcome. Various maleonitriles were
reacted with crotonaldehyde in 41–86% isolated yield and
71–91% ee which was in several cases increased up to >99% by
recrystallization from 2-propanol.
Scheme 34 Enantioselective addition of diethylzinc to aldehydes cata-

lyzed by fused oxazoline derivatives.62 Scheme 36 Enantioselective epoxidation of enones.82
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Scheme 37 Organocatalytic stereoselective vinylogous Michael

addition.83
Scheme 39 Comparison of the efficiency of two chiral diamines in the

4.3. Rearrangement of epoxides to allylic alcohols rearrangement of meso-epoxides.86
Andersson’s group also exhibited an interest in the desymme-
trization of meso-epoxides or chiral, racemic epoxides via their
rearrangement to the isomeric allylic alcohols (Scheme 38). In
the best solvent, and a DBU additive showed the beneficial
the second case, nonracemic chiral epoxides can also be iso-
influence on the stereochemical outcome of the reaction by
lated due to the kinetic resolution if the reaction is stopped
preventing aggregation of lithium amides. Only 5% of the
before complete conversion. The resulting chiral allylic alco-
chiral catalyst in the presence of 1.5–2 equivalents of LDA was
hols are regarded as useful precursors in the synthesis of a
found sufficient for the stereoselective conversion of various
number of biologically active compounds.84
meso-epoxides with ee values in most cases ≥94% (17a) and
An enantioselective variant of the reaction has been develo-
even 98–99% (17d).30,86 Several examples of substrates and the
ped in which the rearrangement has been mediated by a chiral
results of the catalytic reaction are shown in Scheme 39, and
base (typically a lithium amide), in many cases used in super-
the remaining tested diamines 17 are depicted in Fig. 4.
stoichiometric amounts (1.5–3.0 equivalents), and the sub-
Since an LDA-mediated background reaction can be respon-
strate scope has been rather limited.85 In their quest for a
sible for the lowering of stereoselectivity of epoxide rearrange-
versatile, stereoselective system allowing the use of much lower
catalyst loadings, Andersson and co-workers developed a new
protocol, based on 2-azanorbornyl diamines (2-azabicyclo-
[2.2.1]heptane derivatives bearing a cyclic amine
substituent).30,86–88 These compounds are available in both
enantiomeric forms, which opened the possibility of prepa-
ration of the desired isomer of the chiral allylic alcohol.29,30
Both the structure of the catalyst and reaction conditions were
optimized. Evaluation of the chiral 2-azanorbornyl derivatives
resulted in the identification of pyrrolidine derivatives: 17a,
and, in particular, dimethylated 17d as the optimal chiral
bases, prevailing over the ones containing piperidine or benzo-
pyrrolidine substituents. Tetrahydrofuran was recognized as
Fig. 4 Structure of diamines tested in the desymmetrization of

Scheme 38 Base-mediated desymmetrization of epoxides. epoxides.30,86
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ment, Bertilsson and Andersson tested other achiral bases in 4.4. Asymmetric reduction of ketones
the catalytic process with diamine 17a as the chirality source.89 Enantioselective reduction of asymmetrical ketones yielding
No satisfactory replacement for LDA was found, however, a chiral secondary alcohols is one of the most exploited
great improvement of ees was achieved by slow addition of the methods of creation of a new stereogenic center in a molecule.
stoichiometric base thus maintaining its low concentration Catalytic transfer hydrogenation offers a cheap and operation-
during the reaction. ally simple protocol for this transformation utilizing various
The proposed reaction mechanism was confirmed by convenient sources of hydrogen, like secondary alcohols or
theoretical calculations performed by Brandt et al.90 A possible formic acid.93
dimerization of lithium amides derived from pyrrolidine-sub- Various chiral ligands based on a 2-azanorbornane skeleton
stituted 2-azanorbornanes in the absence of a DBU co-solvent were applied by Andersson’s group to the enantioselective
was taken into account. It was shown that dimers are likely to
transfer hydrogenation of ketones using isopropanol as the

form and are inactive in the catalytic reaction. A correct predic- reducing agent (Schemes 41–43).59,94–99 Among chiral promo-
tion of the enantioselectivity was achieved and allowed the ters: sulfur-containing ligands97 and oxazoline derivatives,99
explanation of differences between catalytic and stoichiometric combined with iridium(I), and alcohols,94–96,98 including those
modes of investigated ligands. The non-stereospecific back- bearing an additional ketal functionality at the remote
ground reaction was suggested to account for the observed end,59,98,100 the latter complexed with ruthenium(II), were
variation of selectivity. found to be the most efficient. Promising results (83–97% ee)
The methodology and catalysts developed by Andersson were also obtained in the Ru-catalyzed reaction (Scheme 41) of
and co-workers were successfully used by Liu and Kozmin for various ketones with the addition of 2 mol% of 2-azanorbornyl-
desymmetrization of meso-silane oxide (Scheme 40).91 A bicyc- methanol 92a (a racemic product was obtained when a tertiary
lic amine 17a was selected as an optimal chirality source, and alcohol 92b was used).94 Also secondary alcohols 92c–f yielded
10 mol% loading and addition of 2 equivalents of LDA the addition product in a relatively high ee and reasonable
resulted in an allylic alcohol obtained in 78% yield and 93% conversions in most cases (also for aryl-substituted acetophe-
ee. This compound was further used for the synthesis of nones).95,96 However, introduction of a dioxolane ring (ligands
several polyols with a complete diastereoselectivity.91 The sila- 93a–e, Scheme 42) increased the turnover frequency, and for
cyclic allylic alcohol and its enantiomer available from the 93e acetophenone was reduced within 30 minutes (97% con-
enantioselective desymmetrization of epoxide were also
applied as key precursors in the synthesis of (−)-pinolidoxin, a
potent modulator of plant pathogenesis.92
Pyrrolidine derivatives of 2-azanorbornane were also found
effective in the kinetic resolution of racemic epoxides by a
selective rearrangement of one of the enantiomers to an allylic
alcohol.30a,87,88 When the reaction was stopped shortly before
or after reaching 50% conversion, both chiral epoxides and
alcohols were isolated in up to 99% ee. Reactions were per-
formed in THF at 0 °C using an excess of LDA (1.2–2 equi-
valents) and DBU (5 equivalents). Amine 17a (10 mol%)
exhibited a limited substrate scope, yielding high stereo-
selectivity for cis-β-methylstyrene oxide, and 1-alkyl- or 2,2-di-
substituted cyclohexene oxides, while epoxides having other Scheme 41 Transfer hydrogenation of ketones with 2-azanorbonane-
substitution patterns neither reacted nor led to racemates.87 derived alcohols.59,98,100
An improvement of the stereochemical outcomes and extend-
ing of the reaction scope was made possible when 17a was
replaced by its dimethylated derivative 17d (used in 5 mol%),
though in most cases ee was rarely high for both the epoxide
and allylic alcohol.88
Scheme 42 Transfer hydrogenation of acetophenone with dioxolane-

Scheme 40 Desymmetrization of silacyclopentene oxide.91 appended ligands.59,98
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Scheme 44 Borane reduction of ketones catalyzed by

2-azanorbornylmethanols.101
Scheme 43 Transfer hydrogenation with iridium complexes of oxazo-

line-derived ligands.99
and 87% ee), though similar values were noted for the di-
naphthyl-substituted derivative. Compound 59 was then tested
in the reduction of a series of aromatic ketones; again, the
version) to (S)-alcohol of 96% ee, and for other tested aromatic
yields were excellent (>95%), and enantiomeric excess fell into
ketones the results were comparable (with the optimum for
the 47–89% range.
1-acetonaphthone: 100% conversion after 4 minutes and >99%
ee).59,98 A dioxolane-appended ligand (enantiomer of 93e) was
also found efficient in the ruthenium-catalyzed asymmetric
4.5. Enantioselective hydrogenation
transfer hydrogenation of various azirines to aziridines
(72–92% yield, up to 70% ee).100 Andersson et al. undertook asymmetric hydrogenation of
Moderate enantioselectivities (up to 79% ee) and yields various, often demanding, substrates containing double CvC
were observed in the transfer hydrogenation of acetophenone or CvN bonds as a means of introduction of chirality into
catalyzed by metal-complexed 2-azanorbornanes substituted compounds bearing a variety of functional groups, useful in
with an oxazoline fragment (94a–k, Scheme 43).99 A test with the synthesis of more complex chiral molecules.102–118 They
ligand 94a showed that, in contrast to previously studied alco- selected several chiral ligands which when complexed with
hols 92, 93, it was inactive in combination with ruthenium(II) iridium(I) led to the optimal results of the catalytic reaction.
precatalysts, and better results were obtained with rhodium(I) Among them, (N,P) and (S,P)-donating 2-azanorbornyl deriva-
(up to 18% conversion after 16 hours and 71% ee), but iridium(I) tives substituted with phosphine and oxazoline or thiazole
was found to be most efficient (32% conversion and 79% ee). rings 96, 97 (Fig. 5) were found particularly effective
Ten of the 11 newly synthesized derivatives bore an additional (Scheme 45), though their performance was found dependent
stereogenic center, constituting five epimeric pairs. For isopro- on the structure of substrates studied. The idea of such a
pyl, tert-butyl and phenyl-substituted compounds an isomer modification of a bicyclic skeleton was substantiated by the
with (S) configuration of the oxazoline carbon atom led mainly success of a Pfaltz’s chiral phosphinooxazoline-based iridium
to 1-(R)-phenylethanol, while for (R) diastereomers (S)-product catalyst with a tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
predominated. Though the outcome of ligands 94a–k was not anion ([BArF]−)119 and the performance of chiral thiazole-
excellent, further investigations conducted by Andersson’s based ligands designed in Andersson’s group.120 Iridium com-
group on oxazoline derivatives based on a 2-azanorbornane
scaffold, containing a phosphine substituent, revealed their
high efficiency in the iridium-catalyzed hydrogenation of
alkenes (vide infra).
Results comparable to those noted for compounds 94a–k
were obtained with N,S-donating ligands containing a sulfide
or sulfoxide moiety (up to 80% for one of diastereomeric sulfox-
ides).97 However, as a sulfanyl derivative was prepared from
N-protected 2-azanorbornanemethanol via a route involving
nucleophilic substitution, one should take into account the poss-
ible ring-expanded structures for these ligands (see section 3.2).
2-Azanorbornylmethanols 59, 92a, 92b and newly prepared
95a–f were also applied by Pinho et al. in the enantioselective
borane reduction of ketones (Scheme 44).101 Screening of
potential catalysts in the reaction of acetophenone allowed the Fig. 5 Phosphine–oxazoline and phosphine–thiazole ligands based on
choice of 59 as the best ligand for this purpose (>95% yield a 2-azanorbornane skeleton.102–118
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Scheme 46 Asymmetric hydrogenation of alkenes catalyzed by the

iridium complex.103
Scheme 45 Asymmetric hydrogenation of olefins catalyzed by the

iridium(I) complex with ligands 96, 97. The structure of the complex
shown for the thiazole derivative.
plexes were prepared as microcrystalline, stable solids and

characterized.103,108
The performance of 2-azarnorbornyl derivatives was com-
pared to other chiral ligands; comprehensive reviews on
iridium-catalyzed hydrogenations offer a wider perspective of Scheme 47 Asymmetric hydrogenation of fluoroalkenes.104
the field.121–124 DFT calculations were undertaken to probe the
relatively poorly understood mechanism of iridium-catalyzed
olefin hydrogenation using various chiral ligands (including
96a).107 The study revealed the utility of a simple model system imidazole moiety.105 2-Azanorbornyl derivatives 96a and 96b
which could be used, in most cases with success, to predict were also inferior to these ligands in the screening of catalysts
the configuration of the major product of the reaction. for the asymmetric hydrogenation of 1,1-diarylsubstituted
A series of ten oxazoline-phosphine (N,P)-donating ligands olefins (up to 80% ee was noted for 96b).106 A progress was
based on the chiral 2-azanorbornane scaffold 96 were prepared achieved when thiazole derivatives 97 were introduced
by Andersson et al. and their performance in the iridium-cata- (Scheme 48); in particular, compounds 97c and 97d performed
lyzed hydrogenation of various alkenes was investigated.103 significantly better for certain substrates as compared to 96i,
Part of them were found effective in the stereoselective though terminal alkenes bearing an isopropyl or ethyl group
reduction of trans-α-methylstilbene: 99% conversion within remained a challenge (up to 50% and 17% ee, respectively).108
0.5 h with ee = 73–92% was noted for 96a–d, 96f, 96g, and 96k. Both oxazoline- (96b, 96j) and thiazole-based (97d) 2-aza-
On the other hand, a hindered derivative with two phenyl sub- norbornane derivatives were found to be efficient in the
stituents on the oxazoline ring (96i) led to the highest ee value iridium-catalyzed hydrogenation of α,β-unsaturated carboxylic
of 96%, albeit accompanied by lower conversion (81%; it could esters.112 These ligands appeared to complement each other
be increased by application of a higher pressure of H2). This for the substrates of a particular structure: in the case of (E)-
compound was chosen for tests of the possible substrate scope β,β-disubstituted esters compound 97d gave optimal results,
and resulted in high yields and ee up to 99% for the part of while 96b was found to be the most effective for (Z) isomers,
examined alkenes (Scheme 46) – the notable exceptions were a and 96j was chosen as the best ligand for reduction of α,β-di-
terminal alkene and several hindered cycloalkenes which were substituted unsaturated carboxylates (Scheme 49). In all cases
unreactive.
In the case of olefins bearing a fluorine substituent in the
vinyl position, among the three 2-azanorbornane-derived
ligands (96a, 96b and 96i) derivative 96b complexed with
iridium was recognized as the best catalyst resulting in the
highest conversion and chemoselectivity (low extent of C–F
bond cleavage).104 However, the stereoselectivity was low for
the part of substrates (Scheme 47). Similarly, trifluoromethyl-
substituted alkene was hydrogenated using ligands 96b and
96i with the outcome (27% ee and 79% conversion for 96b,
47% ee and only 8% conversion for 96i) much worse than Scheme 48 Asymmetric hydrogenation of alkenes catalyzed by iridium(I)
observed for other chiral inducers containing a thiazole or complexes with oxazoline and thiazole-based ligands.108
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Scheme 52 Asymmetric hydrogenation of vinylsilanes.116

Scheme 49 Asymmetric hydrogenation of α,β-unsaturated carboxylic

esters.112
as compared to other, thiazole-based ligands which were then
used for conversion of various phosphine oxides and vinyl
phosphonates.115
quantitative conversion and very high enantioselectivities In their studies on expanding the possible substrate
(ee was in the range of 85 to >99%) were observed. The utility classes, Andersson’s group investigated iridium-catalyzed
of the described catalytic hydrogenation was demonstrated by hydrogenation of vinylsilanes.116 Only one of the two silanes
the enantioselective preparation of several intermediates used tested with oxazoline ligand 96i was transformed with high
previously in total syntheses of biologically active compounds. stereoselectivity (Scheme 52); slightly better results were noted
The iridium complex of oxazoline derivative 96b appeared for the thiazole-derived ligand (not based on the 2-azanorbor-
to be an optimal catalyst for hydrogenation of enol phosphi- nane skeleton; compounds of types 97a–d were introduced two
nates (Schemes 50 and 51).113,114 For substrates with a ter- years later) and further evaluation with various substrates was
minal double bond, high conversions (in most cases in the performed with this compound.
range from 93 to >99%) and enantioselectivities (ee between Satisfactory enantioselectivity (72–98% ee) and yield were
85 and >99%) were observed.113 The obtained products were observed when vinyl boronates bearing an aryl or cyclopentyl
transformed to the corresponding secondary alcohols or phos- substituent were hydrogenated using iridium complexes of
phines without loss of enantioselectivity. Most of the di- and ligands 96b, 96g, or 97c as catalysts (Scheme 53).117 These
trisubstituted enol phosphinates, including those bearing two derivatives were found to complement one another for
alkyl groups at the double bond were also hydrogenated with various substrates. For most boronates, the decrease of
high stereoeselectivity.114 However, catalyst screening showed pressure of hydrogen resulted in lowering or even reversal of
that 96b led to unsatisfactory results for hydrogenation of stereoselectivity.
diphenylvinylphosphine oxide (>99% conversion, but 78% ee) 2-Azanorbornane-based thiazole-phosphine ligand 97d was
chosen by the preliminary screening as the best ligand for the
iridium-catalyzed hydrogenation of cyclic and linear unsatu-
rated sulfones (Scheme 54).118 Enantioselectivity was high in
all cases, and yields were in most cases high with the exception
of ortho-tolyl seven-membered and phenyl-substituted six-
membered derivatives (23% and 43% conversion, respectively).
Hydrogenation products were further converted to chiral allylic
and homoallylic compounds using the Ramberg–Bäcklund
rearrangement.
Scheme 50 Asymmetric hydrogenation of phosphinates containing a
terminal CvC bond.113
Scheme 51 Asymmetric hydrogenation of unsaturated

phosphinates.113,114 Scheme 53 Asymmetric hydrogenation of unsaturated boronates.117
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Scheme 56 Asymmetric hydrogenation of enamines.110

Chiral secondary amines were efficiently produced by

iridium-catalyzed hydrogenation of imines with oxazoline–
phosphine ligands based on the 2-azanorbornane
scaffold.102,103 Ligand 96a was tested for a series of acyclic
N-arylimines, yielding in most cases high conversions (98–99%,
with an exception of N-benzyl and ortho-tolyl derivatives) and
enantioselectivities (80–90% ee; Scheme 57). For more complex
imines the results were less satisfactory which was explained by
Scheme 54 Asymmetric hydrogenation of unsaturated sulfones.118 the conformational strain upon coordination to iridium in the
transition state. Studies on the modification of the structures of
catalysts revealed that while the change of substituents on the
oxazoline ring resulted in the decrease of both yield and stereo-
Among ligands tested in hydrogenation of N-heterocyclic
selectivity of the catalytic reaction (ligands 96g, 96i, 96k, 96l),
olefins, compound 96h was most efficient for alkyl-substituted
an appropriate substitution of phosphine aryls retained or
substrates with a six-membered ring.109 For particular 3,4-
slightly improved the outcome as compared to 96a (ligands 96b,
unsaturated heterocycles, also the use of derivatives 96b and
96d, 96f as well as cyclohexyl-substituted 96c); conversion
97d led to optimal results, as exemplified in Scheme 55.111
dropped down to 61% only for 96e.
Asymmetric hydrogenation of enamines leading to chiral
The presented examples strongly confirm the statement
tertiary amines was also performed by Andersson’s group.110
from the 2006 paper by Andersson and co-workers that
Preliminary screening included, among others, 2-azanorbo-
“iridium-catalyzed asymmetric hydrogenation is still highly
nane derivatives 96a, 96b, 96i and 97c, and selected o-tolyl-
substrate dependent and the development of efficient chiral
substituted ligand 96b which was used in further studies on
ligands that tolerate a broader range of substrates remains a
the possible substrate scope (Scheme 56). For most enamines,
challenge”.116 Since that time a significant progress has been
moderate to high enantioselectivity (ee = 64–87%) and quanti-
made, mainly thanks to the introduction of thiazole-derived
tative conversion after 6 hours were noted, however, in the
bicyclic ligands which have been found complementary to oxa-
case of certain pyrrolidine or morpholine derivatives yields
zoline-based ones. It is thus possible that previous results
and ees were significantly lower which was attributed to the
obtained for certain substrates were not optimal. Still, very
catalyst poisoning by basic amines formed in the course of
high conversions and enantioselectivities observed for a large
reaction.
variety of substrates bearing functional groups should be
underlined.
Besides the wide use of iridium-based systems, platinum
was also tried as the catalyst for the hydrogenation of ethyl pyr-
uvate in acetic acid with 2-azanorbornane-based naphthyl-sub-
stituted aminoalcohols as chiral modifiers.65 Pfaltz and co-
workers obtained the best result (quantitative yield and 64%
Scheme 55 Asymmetric hydrogenation of heterocyclic olefins.109,111 Scheme 57 Asymmetric hydrogenation of imines.102,103
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Scheme 60 Allylic oxidation of alkenes catalyzed by copper

complexes.127
Scheme 58 Platinum-catalyzed asymmetric hydrogenation of ethyl
pyruvate.65
were Y = 63% and ee = 65%. These results were found superior

ee) for 98a compound with no substituent in the position 2 of to proline itself, however, high catalyst loadings and long reac-
the 2-azanorbornyl system, while 98b and 99 gave less than tion times were necessary (Scheme 60).
30% ee and low conversion (Scheme 58). Bertilsson and Andersson synthesized and characterized a
dinuclear rhodium complex of the sulfonylated carboxylate
4.6. Other catalytic reactions ligand 101, a bicyclic analogue of proline derivative 102.128
The obtained compound (103, Scheme 61) was applied as a
Several articles have been published in which the authors
catalyst in the asymmetric cyclopropanation of various olefins
studied other catalytic reactions, often focusing on the possi-
with vinyl- and phenyl-diazoesters.129 Trans diastereomers
bility of replacement of pyrrolidine or proline derivatives by
were formed almost exclusively (dr > 20 : 1), enantioselectivities
their more rigid 2-azanorbornane counterpart and the effect of
were rather satisfactory (ee was generally in the range of
such a modification on the yield and stereochemical outcome.
65–92%, with the exception of p-nitrophenyl derivatives), and
Interestingly, the catalytic system [Ir(COD)L*]BArF efficient
yields in most cases exceeded 50%. However, the expected
in the hydrogenation of various unsaturated compounds was
increase of the stereoselectivity in comparison with the
found useful in the enantioselective isomerization of primary
complex of the less rigid proline derivative was not observed.
allylic alcohols.125 Of the three ligands tested in the conversion
Modin et al. described the synthetic approach to phos-
of (E)-4-methyl-3-phenylpent-2-en-1-ol, compound 97a was
phines 104a–b, the bicyclic analogues of pyrrolidine derivative
almost inactive, while the other thiazole derivative 97c and
105, and their application as (O,P)-donating ligands in the
oxazoline 96e led to the desired (S)-aldehyde with >99% ee
copper(I)-catalyzed enantioselective 1,4-addition of a Grignard
(Scheme 59). Since the yield for 96e was significantly higher
reagent to 2-cyclohexenone (Scheme 62).130 The performance
(88% vs. 43% for 97c), this derivative was applied for a series
of the obtained chiral inducers was much worse than 105 at
of (E)- and (Z)-trisubstituted substrates; the stereoselectivity
was excellent (91 to >99% ee), and the yields were strongly sub-
stitution-dependent.
Södergren and Andersson described the attempted use of a
chiral 2-azanorbornyl derivative in the allylic oxidation of
olefins with a peroxy ester to give the corresponding allylic
alcohol derivative, catalyzed by copper salt (Kharasch–Sos-
novsky reaction126). Compound 91 was tested in this reaction
as a rigid analogue of proline (100).127 Cyclopentene was con-
verted into (R)-2-benzoate in yields up to 54% and ee up to
60%, while maximum values for the 2-cyclohexene derivative
Scheme 61 Cyclopropanation of alkenes catalyzed by dirhodium

Scheme 59 Enantioselective isomerization of allylic alcohols.125 complex 103.128
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pared in one step from the 2-azanorbornane-3-carbaldehyde

61.132 A striking difference between the two Schiff bases tested
(108a and 108b) shows that the change of configuration of
only one of the five stereogenic centers can be responsible for
the observed stereoselectivity. The increase of size of the
dithioacetal ring had a beneficial influence on the stereo-
chemical outcome of the reaction; 94% yield and 95% ee for
the dithiane derivative 108d were the best values in the series
(Scheme 63). Other (N,S) ligands investigated in that study per-
formed significantly worse which may be connected with the
fact that they were actually bridged azepane derivatives.132
Scheme 62 1,4-Addition of a Grignard reagent to 2-cyclohexenone.130 The application of 2-azanorbornyl derivatives in a variety of
asymmetric catalytic reactions proves the utility of this bicyclic
skeleton as a versatile basis for the synthesis of the effective
chiral ligands or organocatalysts. A significant progress has
high catalyst loadings (34% mol and 17% mol), while the best
been made, in particular, in the field of asymmetric hydroge-
results were noted for only 4.7 mol% of the bicyclic t-butyl
nation, while other catalytic processes received relatively less
derivative 104a (73% yield, 71% ee and less than 10% of the
attention which opens the area for further explorations.
1,2 addition). The methylated ligand 104b led to the desired
product with a comparable stereoselectivity, albeit with lower
yield. The simple comparison with pyrrolidine-derived phos-
phine 106 is hampered by the fact that bicyclic compounds 5. Biological activity of
presumably contain a significant amount of ring-expanded
2-azanorbornyl derivatives
isomers 106, formed under conditions of nucleophilic substi-
tution applied to the synthesis of 104 (see section 3.2). The relative ease of preparation of chiral 2-azanorbornyl
2-Azanorbornane-derived ligands were also applied in palla- derivatives aroused an interest in the possible biomedical
dium-catalyzed asymmetric allylic alkylation (Trost–Tsuji reac- applications of these bicyclic compounds. They were recog-
tion).131 Okuyama, Nakano and Hongo prepared a bicyclic nized as valuable rigid analogues of various piperidine alka-
pyrrolidynyl-phosphinooxazolidine ligand 107 and its tricyclic loids, and 2-azabicyclo[2.2.1]heptane-3-carboxylic acid was
analogue 60 and examined their effectiveness as chiral indu- used as a proline surrogate in a powerful approach to confor-
cers in the AAA reaction of 1,3-diphenyl-2-propenyl acetate and mationally constrained oligopeptides with possible therapeutic
dimethyl malonate (Scheme 63).61 The low yield and stereo- utility. On the other hand, the bicyclic chiral 2-azanorbornane
selectivity obtained for ligand 60 containing the 2-azanorbor- or 2-azanorbornene system was found useful in enantio-
nane fragment was attributed to the hindered formation of the selective construction of cyclopentanoids. In this approach,
catalytically active palladium complex. Much better results the rigid skeleton is constructed and appropriately modified
were obtained by our group for (N,S)-coordinating ligands, pre- with a complete control of stereochemistry, and stereoselective
Scheme 63 Application of 2-azanorbornyl derivatives in palladium catalyzed AAA reaction.61,132 Results for ligands 108 are given for 10 mol% of a
chiral ligand used.
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ring opening leads to the desired monocyclic derivative. In par-

ticular, 2-azabicyclo[2.2.1]hept-5-en-3-one (Vince lactam 30)
appeared to be an attractive precursor of carbocyclic
nucleoside analogues, many of which exhibited significant
antibiotic, antitumor and, first of all, antiviral activity
(Carbovir derivatives).
Fig. 8 Polar β-turn mimetics containing a 2-azanorbornane (114) or a
pyrrolidine (115) fragment.134
5.1. Bicyclic analogs of biologically active compounds
2-Azanorbornane derivatives found use as precursors of
bridged, bicyclic analogues of various natural compounds con-
In the search for nonpeptide drug candidates for neuro-

taining an appropriately substituted cyclopentane fragment (in peptide receptors, Horwell et al. used molecular modeling to
particular, cyclopentylamine derivatives), a piperidine or pyrro- design a compound with a desired conformation and dipole
lidine heterocycle, including mimetics of proline (Fig. 6). The moment to mimic a bicyclic hexapeptide exhibiting high tachy-
studies were focused on their synthesis and determination of kine affinity.134 Racemic 2-azanorbornane derivative 114 was
the impact of the modification on the exhibited biological prepared which was found to fulfill the criteria and compared
activity, e.g. affinity for specific receptors. to the previously synthesised135 pyrrolidine-based β-turn
Both piperidine and pyrrolidine structural motifs can be mimetic 115 of the peptide (Fig. 8). An additional constraint
found in a number of natural alkaloids, including piperine did not improve the performance of these compounds which
109, lobeline 110, coniine 111, nicotine 112 or hygrine 113 showed only moderate affinity for a neurokine-1 (NK-1) recep-
(Fig. 7), to name a few. Their synthetic analogs are therefore of tor and lack of affinity for NK-2.
great interest for the pharmaceutical industry. Most of these As an example of the construction of constrained piperidine
compounds are chiral and their biological activity is strongly derivatives, Portoghese et al. investigated the bridged analogs
dependent on the absolute stereochemistry. Thus, synthetic of the synthetic analgesic meperidine ( pethidine 116).136 Two
methods leading to piperidine or pyrrolidine derivatives with epimers of 117 (Fig. 9) were obtained to study the effect of con-
the defined configurations of stereogenic centers are of special formation on analgetic potency. Endo (5S) isomer was found
importance.133 The aza-Diels–Alder reaction offering the desir- more active (but also more toxic) than the exo form (5R) and
able stereocontrol was thus recognized as an interesting syn- meperidine itself, which was in part connected with better
thetic pathway which was utilized in the synthesis of bridged brain penetration due to higher lipid solubility.
pyrrolidine or piperidine derivatives. Also bicyclic rigid analogues of a nicotinic acid-derived
alkaloid arecoline 118 were prepared by Pombo-Villar et al.137
Two enantiomeric pairs 119a and 119b (Fig. 10) were obtained
to test their cholinergic activity as muscarinic agonists.
Raubo et al. prepared enantiopure 1-phenyl-2-azabicyclo-
[2.2.1]heptane derivatives 120 bearing 6-exo or endo substitu-
Fig. 6 2-Azanorbornane as a bridged analogue of cyclopentane, cyclo-

pentylamine, piperidine, pyrrolidine and proline.
Fig. 9 Meperidine and its bicyclic mimetics.136
Fig. 7 Examples of alkaloids bearing a piperidine or a pyrrolidine ring. Fig. 10 Arecoline and its bicyclic analogues.137
View Article Online
Two enantiomers of exo-2-azabicyclo[2.2.1]heptane-3-

carboxylic acid 91 (Fig. 13) were used by Mellor et al. as a
means for construction of conformationally constrained oligo-
peptides, analogues of fragments of a transforming growth
factor (TGFα).141 Eight peptides (four linear and four with a di-
sulfide bridge) were successfully synthesized containing either
prolyl (L- or D-enantiomer) or 91 (one of enantiomers) residue.
Fig. 11 NK1 receptor ligands.138 Conformational studies showed that the bridged amino acids
behaved similarly to their proline counterparts. Only the two
peptides containing both the cystyl fragment and the bicyclic
proline analogues were effective in the tests of induction of
ents as 2-phenylpiperidine mimics in neurokin NK1 receptor

DNA synthesis.142
modulators (Fig. 11).138 Ring-closing metathesis and regio-
Compound 91 was also used as a proline mimetic and
and stereoselective oxirane opening were applied as the key
appeared to be a convenient building block for the develop-
steps in the reaction sequence in which Diels–Alder cyclo-
ment of new tetrapeptides as inhibitors of the X-linked inhibi-
addition was not utilized. Only endo (6S) epimers exhibited
tor of apoptosis protein (XIAP), which exhibited activity similar
binding to the NK1 receptor comparable to the known cis-sub-
to natural ligands.143 Venkatraman and co-workers tested pep-
stituted piperidine analog 121.
tides containing 91-derived residue in their search for effective
The synthesis of ledipasvir 122 (Fig. 12), a clinical drug can-
inhibitors of hepatitis C NS3-NS4A serine protease essential
didate for oral treatment of hepatitis C virus infection was ela-
for viral replication, which could be used for the treatment of
borated.139 The compound contains a 2-azanorbornane
chronic HCV infections.144 They assumed that the confor-
fragment as a terminal heterocycle which was found to be a
mation of the rigid proline surrogate could ensure maximum
key feature for pharmacokinetic properties of the drug, sur-
contact with the surface of the enzyme. Optimization of the
passing the piperidine analog.
remaining residues, supported by the X-ray structure of one of
Bicyclic mimetics of natural amino acids, especially proline,
the inhibitors bound to the target enzyme, led to the identifi-
also received considerable attention. A racemic, dicarboxylic
cation of four most potent derivatives 124a–d (Fig. 14). The
2-azanorbornyl derivative 123 (Fig. 13) was prepared by Bunch
general idea of using bicyclic proline analogs in the construc-
and co-workers as a conformationally restricted analogue of
tion of new agents for the treatment of hepatitis was later suc-
(S)-glutamic acid.140 The authors intended to mimic the folded
cessfully applied for the design of boceprevir, telaprevir and
conformation of this amino acid which plays an important
narlaprevir.145
role as a neurotransmitter in the central nervous system.
2-Azanorbornane, perhydroindole and 2-azabicyclo[2.2.2]-
However, compound 123 did not show affinities at the native
octane fragments were used as skeletons for a series of com-
ionotropic Glu receptors.
pounds tested as inhibitors of prolyl endopeptidase.146 Carbo-
xylic acid 91 served as a starting point for the preparation of
five derivatives 125a–e (Fig. 15); 125a showed activity compar-
able with the reference proline analog and 125b was among
the most promising. However, the authors decided to perform
in vivo tests with other derivatives among which perhydroin-
dole-containing compounds provided the most potent inhi-
bition and oral availability.
Fig. 12 The structure of ledipasvir.139
Fig. 13 2-Azanorbornane derivatives used as rigid analogues of natural Fig. 14 2-Azanorbornane derivatives exhibiting activity against hepatitis
amino acids. C serine protease.144
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Fig. 15 2-Azanorbornyl derivatives tested as inhibitors of prolyl

endopeptidase.146
In a continuation of their study of proline derivatives as

effective ligands for the peptidyl-prolyl isomerase FKBP12
which could be used for the treatment of neurodegenerative
Scheme 64 Synthesis of peptides containing an exo-2-azabicyclo-
diseases, Wu and co-workers prepared a series of exo and endo [2.2.1]hept-5-ene-3-carbonyl subunit.148
2-azanorbornyl-based N-glyoxyl or sulfonamide esters and
thioesters 126a–e, 127a–d (Fig. 16).147 They observed that exo
isomers, showing more structural similarity to L-proline,
exhibited significant FKBP12 inhibitory activity. This was in
line with the molecular modeling studies which showed less
effective binding modes of endo isomers to the active site of
isomerase. In vivo tests, in which compounds exo-126a and
127a were used in a mouse model of Parkinson’s disease,
proved their efficiency in neuroregeneration.
Another approach to the stereoselective synthesis of pep-
tides 128a–c containing an exo-2-azabicyclo[2.2.1]hept-5-ene-3-
carbonyl subunit as a bicyclic proline mimetic was described
by Jäger et al.148 Instead of incorporation of a preformed 2-aza-
norbornene-derived residue, it was synthesized by the aza-
Diels–Alder cycloaddition of cyclopentadiene to dehydroglycyl-
containing peptides, which were prepared in two steps from
the corresponding seryl derivatives (Scheme 64). Exo diastereo-
mers were preferentially formed, which was substantiated by
the diene approach from the less sterically hindered face oppo-
site to valine or phenylalanine residue. The presence of a
double bond in the resulting peptide allowed further on-site
modifications.
2-Azanorbornyl derivatives were also used to mimic other Fig. 17 Epibatidine and its analogues.
bicyclic systems exhibiting biological activity. Malpass and co-

workers studied the analogues of epibatidine (129, Fig. 17), the
alkaloid isolated from the skin of the Equadorian poison tree
frog, Epipedobates Tricolor.53,149–153 This compound exhibits
high analgesic activity as an agonist at the nicotinic acetyl-
choline receptors of the nervous system; however, its thera-
peutic application is hindered by the extreme toxicity. This fact
stimulated work on analogues and isomers devoid of draw-
backs of the original alkaloid while preserving its antinocicep-
tive activity. In this line, four (6-chloro-3-pyridyl)-substituted
2-azarbornane derivatives 53, 130 (Fig. 17) preserving the rigid
bicyclic structure, were prepared by the treatment of N-pro-
tected 2-azanorbornene with 2-chloro-4-iodopyridine.53,149–151
Also 7-substituted isomers, syn- and anti-isoepibatidine (131)
Fig. 16 2-Azanorbornane derivatives tested as ligands for the peptidyl- in which the positions of the heterocycle and the amine were
prolyl isomerase.147 reversed as compared to epibatidine itself, and their methyl-
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isoaxolyl analogs (isoepiboxidines 132) were obtained.152–154 5.2. Precursors of chiral monocyclic systems
Studies on structure–activity relationships showed that com- Derivatives of 2-azanorbornane or 2-azanorbornene have been
pounds endo-53, endo-130, syn-131 and syn-132 with similar utilized as useful synthetic precursors of monocyclic systems
N–N distances to 129 (4.3–4.8 Å) retain their high affinity at exhibiting biological activity. Some of these compounds
nicotinic receptors, while exo- and anti-derivatives were inac- contain an appropriately substituted pyrrolidine ring. For
tive.151,154 However, the new compounds did not exhibit the example, neuroexcitants, α-kainic acid 138a and 3-(carboxy-
desired receptor subtype selectivity which is regarded as a key methyl)pyrrolidine-2,4-carboxylic acid 138b were obtained
factor for lower toxicity and fewer undesirable side effects.154 from a 7-azabicyclo[2.2.1]heptadiene (136) through its
Various bicyclic systems were also used to mimic the pro- rearrangement to 2-azabicyclo derivatives (137) and stereo-
perties of atropine, a potent tropane alkaloid based on an selective ring opening (Scheme 65).157
8-azabicyclo[3.2.1]octane skeleton. Azaprophen 133, a highly
More frequently, various cyclopentane or cyclopentene

potent antimuscarinic agent with a nitrogen atom in 2-posi- derivatives, including carbocyclic nucleosides exemplified by
tion of a bicyclooctane fragment was synthesized by Carroll entecavir and carbovir (Fig. 19) were prepared from 2-azanor-
and co-workers (Fig. 18).155 Its 2-azanorbornyl analogs, bornene precursors. In a typical approach, a functionalized
bearing one carbon atom less in the bicyclic system, were five-membered ring is obtained in two stages, starting with the
tested as muscarinic antagonists (2,2-diphenylpropionate
derivatives 134a, 135a) or agonists (acetoxy-substituted com-
pounds 119b, 134b, 135b–c), with the highest efficiency
observed for endo-134a and exo-119b, respectively.156 The
investigated compounds did not show the selectivity for sub-
types of muscarinic receptors.
Fig. 19 Examples of carbocyclic nucleosides of antiviral or antibiotic

activity.
Fig. 18 Azaprophen and its 2-azanorbornyl analogues.155,156 Scheme 66 The use of Vince lactam for the synthesis of inhibitors of
aminotransferase BioA.158
Scheme 65 2-Azanorbornene as a precursor of kainic acid derivatives.157
View Article Online
Scheme 67 The use of Vince lactam for the synthesis of carbocyclic adenosine derivatives.159
[4 + 2] cycloaddition of cyclopentadiene with aza-dienophiles,

followed by the ring opening; additional steps involve modifi-
cations either of the cycloadduct or the monocyclic product.
Numerous synthetic procedures have been developed, and
most of them make use of 2-azabicyclo[2.2.1]hepten-3-one
(Vince lactam 30, Scheme 66). Its chiral rigid skeleton and the
presence of lactam function and a double bond whose reactiv-
ity can be utilized, make it an ideal precursor for organic and
pharmaceutical chemistry. Vince lactam is now commercially
available, both as a racemate and in the enantiomerically pure
form. The synthetic versatility of this compound has been
thoroughly reviewed.43 As one of the recent examples, a
racemic Vince lactam was used as a precursor in the synthesis
of potential inhibitors (143, 144; Scheme 66) of aminotransfer-
ase BioA involved in biotin biosynthesis.158 The stereoselective
synthesis of 2′-fluoro-6′-methylene carbocyclic adenosine 146
starting from rac-30 (in one of the initial steps, its N-protected
derivative 145 was resolved into enantiomers) was also
reported (Scheme 67).159
Derivatives of Vince lactam 147–149 were applied in the
total synthesis of (−)-rasfonin 150, a possible selective inducer
of apoptosis (Scheme 68).160 After diastereoselective side chain
modifications, the bicyclic chiral auxiliaries were removed
from the reaction intermediate.
5.3. Elements of various systems exhibiting biological activity

In a quest for selective vasopressin receptor antagonists, which
could be used for the treatment of congestive heart failure,
hypertension, renal disease, edema, and hyponatremia
Dyatkin et al. prepared a series of benzodiazepines fused to a
chiral 2-azanorbornane 153a–f (Scheme 69).161 While exo
derivatives showed significant in vitro affinity to both human
Scheme 68 Synthesis of (−)-rasfonin.160
V1a vs. V2 receptors, isomer endo-153a was V2-selective. In vivo
tests on rats revealed modest bioavailability and plasma clear-
ance rates, and good efficacy as diuretics (compounds 153a,
153b) and the ability to reverse vasopresin-induced hyperten- lack of cytotoxicity made it a good candidate for further
sion (derivatives 153a, 153b, 153f ). investigations.
Three polysulfones based on 2-azanorbornenes 154a–c were
prepared by Gorbunova and Anikina to test their antioxidant
properties in lipid peroxidation (Fig. 20).162 N-Benzyl derivative 6. Summary
154a exhibited significant activity in mice liver homogenate
oxidation by iron(II) chloride/ascorbate and inhibited The chiral 2-azabicyclo[2.2.1]heptane (or 2-azabicyclo[2.2.1]-
mice erythrocyte hemolysis by H2O2 which, together with a heptene) system can be attained by several synthetic routes,
View Article Online

Scheme 69 Synthesis of benzodiazepines fused to a chiral 2-azanorbornane backbone.161
Scheme 70 Synthesis of the enantiopure tetracyclic compound using

(1R,2R)-1,2-diaminocyclohexane as a chirality source.163 A 2-azanorbor-
Fig. 20 Polysulfones based on 2-azanorbornene scaffold.162 nene fragment in the tetracyclic product 155 indicated.
the most important since 2-azanorbornane serves as a rigid

with the aza-Diels–Alder cycloaddition of enantiomerically
chiral scaffold and as an additional source of discrimination
pure imines to cyclopentadiene being the most important and
in the course of catalytic reactions. Certain possibilities
convenient method. Chirality multiplication due to the high
remain relatively underexplored, like the preparation of
stereoselectivity of cycloaddition is particularly worth empha-
systems containing two or more bicyclic fragments. Also cata-
sizing. The examples presented in sections 3–5 showed the ver-
lytic (in particular, organocatalytic) applications have been
satility of 2-azanorbornyl derivatives as chiral building blocks,
limited to several reactions. Thus, intrinsic chirality, the ease
their utility in the stereoselective catalysis and applications
of synthesis and various possible ways of modifications make
in biomedical studies. The investigations are now facilitated
2-azanorbornane an attractive compound for diverse and yet
by the fact that these bicyclic compounds are commercially
not completely explored applications.
available.
Still, there is room for further exploration. Novel, modified
systems can be obtained by using various substrates at the
cycloaddition stage as exemplified by our stereoselective Abbreviation list
synthesis of enantiopure tri- and tetracyclic compounds
bearing up to 5 stereogenic centers (example is shown in aza-DA aza-Diels–Alder reaction
Scheme 70).163 BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl
The known modifications of the 2-azabicyclo[2.2.1]heptane Boc tert-Butoxycarbonyl
derivatives include transformations of the bicyclic skeleton, Bpin Pinacolatoboron
stereoselective ring opening, and alteration of substituents. BSA (N,O)-Bis(trimethylsilyl)acetamide
The synthesis of bisfunctional ligands with a possible control Cbz Carboxybenzyl
of the mutual position and character of donor groups remains COD Cyclooctadiene
View Article Online
CpH Cyclopentadiene (b) H. Abraham and L. Stella, Tetrahedron, 1992, 48, 9707–
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene 9718.
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Organic &

2-Azanorbornane – a versatile chiral aza-Diels–

stereoselective synthesis and biological activity

both the enantiomeric forms from inexpensive starting

Review Organic & Biomolecular Chemistry

reaction where the dienophile contains a nitrogen atom,8–10

Organic & Biomolecular Chemistry Review

In continuation of their previous work, Grieco et al. also

Tomasz K. Olszewski received his M.Sc. Eng. degree in chemistry

Review Organic & Biomolecular Chemistry

ing (1S)- or (1R)-1-phenylethylamine as the chiral auxiliary. The

significant preference for the exo adducts was observed, which

Organic & Biomolecular Chemistry Review

Scheme 7 Synthesis of spirocyclic 2-azanorbornene derivatives 11.27

Scheme 8 Preparation of heterocyclic derivatives of 2-azanorbornene 13a–c.28

Scheme 9 Synthesis of 2-azanorbornene derivatives 16, 17.29

Review Organic & Biomolecular Chemistry

Scheme 11 Preparation of 2-azanorbornene derivatives 23 with the use of chiral auxiliaries.

Organic & Biomolecular Chemistry Review

can also be considered as imino dienophiles in the aza-DA

Scheme 13 Products of cycloaddition between oxime glyoxylate and cyclopentadiene.40

Scheme 14 Proposed mechanism for the cycloaddition of cyclopentadiene to oxime glyoxylate.41

Review Organic & Biomolecular Chemistry

lactam in enantiomerically pure form using menthylsulfonyl

2.2. Synthesis of 2-azanorbornyl derivatives using multistep

Scheme 16 Preparation of 2-azanorbornane derivative endo-37.47

Organic & Biomolecular Chemistry Review

Scheme 17 Synthesis of azanorbornane derivative 42.49

Scheme 18 Synthesis of bicyclic proline derivative 42.50

Scheme 19 Multistep preparation of 2-azanorbornane derivative 50.51

Review Organic & Biomolecular Chemistry

Organic & Biomolecular Chemistry Review

Scheme 21 Reaction of enolate 57 with electrophiles.60

Andersson’s group reported on the diastereoselective syn-

selectivity were high (95 to >98%) albeit reactions with both

Review Organic & Biomolecular Chemistry

Scheme 25 Retro-DA reaction as a tool in the synthesis of chiral

Other reagents such as copper sulfate (CuSO4) or sulfonic

Scheme 26 Application of dihydroxylated 2-azanorbornene derivative 69 in the synthesis of functionalized pyrrolidines.70

Organic & Biomolecular Chemistry Review

Scheme 27 Preparation of cyclopentylamine 75.57a

73 which was transformed to the bromide derivative 74. Ring

refluxing tetrahydrofuran. The reaction was facilitated by the

Review Organic & Biomolecular Chemistry

tioning. Modifications of the 2-azanorbornane scaﬀold may

eﬃcient in the iridium-catalyzed hydrogenation of various sub-

Scheme 31 A general scheme of possible transformations of the aza-

Organic & Biomolecular Chemistry Review

Scheme 33 Ring expansion upon introduction of the thioacetate

Scheme 35 Enantioselective addition of diethylzinc to imines.63,64,81

similar rearrangement upon formation a thioacetate (enantio-

Scheme 34 Enantioselective addition of diethylzinc to aldehydes cata-

Review Organic & Biomolecular Chemistry

Scheme 37 Organocatalytic stereoselective vinylogous Michael

Scheme 39 Comparison of the eﬃciency of two chiral diamines in the

Fig. 4 Structure of diamines tested in the desymmetrization of

Organic & Biomolecular Chemistry Review

transfer hydrogenation of ketones using isopropanol as the