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Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 1870
www.rsc.org/obc PAPER
Enantioselective synthesis of the carbocyclic nucleoside (−)-abacavir†
Grant A. Boyle,a Christopher D. Edlin,a Yongfeng Li,b Dennis C. Liotta,b Garreth L. Morgans*a and
Chitalu C. Musondaa
Published on 07 December 2011 on http://pubs.rsc.org | doi:10.1039/C2OB06775G

Received 21st October 2011, Accepted 5th December 2011

DOI: 10.1039/c2ob06775g

An enantiopure β-lactam with a suitably disposed electron withdrawing group on nitrogen, participated in
a π-allylpalladium mediated reaction with 2,6-dichloropurine tetrabutylammonium salt to afford an
advanced cis-1,4-substituted cyclopentenoid with both high regio- and stereoselectivity. This advanced
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intermediate was successfully manipulated to the total synthesis of (−)-Abacavir.

Introduction the furanose ring has been replaced by an isoteric methylene or

ethylene group (vida infra).
Acquired immune deficiency syndrome (AIDS) has rapidly The construction of carbocyclic nucleosides, more specifically
become one of the major causes of death in the world.1 It is esti- the putting together of a heterocyclic base with a 1,4-substituted
mated that over 60 million people have been infected with the carbocyclic sugar analogue is generally carried out in one of
human immunodeficiency virus (HIV), which is the causative three ways. Firstly, by direct substitution of the hydroxyl group
agent of AIDS. Since the discovery of HIV in the 1980s, remark- by a Mitsunobu coupling reaction on the general carbocyclic
able progress has been made in the development of novel anti- ring 3 with a heterocyclic base (Scheme 1).6 These reactions
viral drugs.2 Entecavir 1, Carbovir 2a, and Abacavir 2b are some result in a net inversion of hydroxyl stereochemistry.
well known examples of carbocyclic nucleosides that have arisen A second approach is to use Trost palladium catalysed allylic
from this extraordinary effort (Fig. 1). Carbocyclic nucleosides alkylation chemistry of activated esters such as 4. This protocol
have been the subject of extensive investigation into their poten- follows a double displacement/inversion and a resultant net
tial uses as antiviral agents for example as therapeutic agents to retention of configuration. This is a particularly useful method
address hepatitis and herpes virus and HIV.3,4 The antiviral prop- for the convergent synthesis of carbocyclic nucleosides and can
erties exhibited by these carbocyclic nucleosides are due, in part, be achieved directly from a chiral sugar or from desymmetriza-
to their metabolic and chemical stability towards phosphorylases tion of a meso intermediate, amongst others.7–11
and phosphotransferases.5 These compounds are structural ana- A final general approach to this class of molecules follows the
logues of endogenous nucleosides in which the oxygen atom in synthesis of the carbocyclic nucleoside by linear construction of
the heterocyclic fragment from an amino group of the cyclopen-
tyl moiety 5.12–14 Also, Jung reported the use of an activated
amine as a leaving group in a palladium catalysed substitution
reaction.15
The utilization of functionalized cyclopentene as the source
of the sugar fragment is a common approach to the synthesis
of carbocyclic nucleosides, particularly in conjunction with

Fig. 1 Some examples of relevant carbocyclic nucleosides.

a
iThemba Pharmaceuticals PTY (Ltd.), PO BOX 21Modderfontein, 1645
Gauteng, South Africa. E-mail: gmorgans@ithembapharma.com;
Fax: +27 (0)11 372-4518; Tel: +27 (0)11 372-4500
b
Emory University, Department of Chemistry, 1521 Dickey Dr Emerson
403, Atlanta, GA, USA, 30322. Tel: 404-727-8130
† Electronic supplementary information (ESI) available: Copies of 1H
NMR and 13C NMR spectra of new compounds. See DOI: 10.1039/
c2ob06775g Scheme 1 General approaches to carbocyclic nucleosides.

1870 | Org. Biomol. Chem., 2012, 10, 1870–1876 This journal is © The Royal Society of Chemistry 2012
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asymmetric synthesis, chiral pool and enzymatic resolution

approaches.16,17
Among these, the enantioselective construction of the cyclo-
pentenoids has involved two discreet stages, an initial [4 + 2]
cycloaddition reaction of cyclopentadiene with either CvN,
NvO and O2 dienophiles, followed by enzymatic hydrolysis.
An example of a CvN dienophile-enzymatic hydrolysis
approach has made use of 2-azabicyclo[2.2.1]hept-5-en-3-one
(±) 6, which is readily prepared from the [4 + 2] cycloaddition
between cyclopentadiene and tosylcyanide, followed by aqueous
hydrolysis.18 The resultant lactam can be enzymatically resolved
to either enantiomer 6 (Scheme 2).19 Similarly, an NvO dieno-
Published on 07 December 2011 on http://pubs.rsc.org | doi:10.1039/C2OB06775G

phile-enzymatic hydrolysis approach has made use of 4-acetami-

docyclopent-2-en-1-yl acetate 8 which is readily synthesized
from the [4 + 2] cycloaddition of cyclopentadiene and nitroso-
carbamate, generated in situ, to afford adduct 7.20 Compound 8
is conveniently resolved via an enzymatic hydrolysis that utilizes Scheme 3 Proposed use of π-allylpalladium chemistry for the syn-
thesis of advanced intermediate 15 from lactam 16.
electric eel acetyl cholinesterase to afford enantiomerically pure
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9. Finally, di-acetate 11 can formally be regarded as the reduction

and acetylation product of the [4 + 2] cycloaddition product 10 of the π-allylpalladium complex would be facilitated by the
of cyclopentadiene and singlet oxygen.21 The bis-acetate 11 can relief of the four membered ring strain25 and the formation of the
be resolved by enantioselective enzymatic hydrolysis with elec- requisite cis-1,4-substituted cyclopentenoid moiety would
tric eel acetyl cholinesterase22 or with porcine pancreas lipase to proceed with a net retention of configuration as a consequence of
afford enantiomerically pure 12.23 the well established double inversion that is operative in these
reactions. Finally, further manipulation of intermediate 15 might
then result in the formation of the carbocyclic nucleoside Abaca-
vir 2b.
While there have been many reported methods for the syn-
thesis of various substituted carbocyclic nucleosides, particularly
Abacavir,26–35 overall yields of the reported synthetic routes are
generally low and the synthetic schemes often require extensive
manipulations of the [4 + 2] cycloadduct being utilized. Because
Abacavir has proven to be an important component of many
HIV combination regimens, particularly paediatrics, there is a
need for improved methods for producing Abacavir that require
fewer synthetic steps and higher overall yields.

Results and discussion

With this in mind, the starting material for the synthesis was the
known β-lactam 13, which was prepared in two steps and in high
Scheme 2 Some relevant [4 + 2]–enzymatic hydrolysis approaches to
chiral sugar building blocks.
enantiomeric purity.24 To facilitate the novel π-allylpalladium
complex formation an anion stabilizing electron withdrawing
group needed to be installed onto the nitrogen of lactam 13, and
We hypothesized that carbocyclic nucleosides could be pre- cheap readily available sulfonyl chlorides, sulfonyl anhydrides
pared using a complementary approach involving a [2 + 2] and carbamates were initially screened (Scheme 4). An initial
cycloaddition of cyclopentadiene with chlorososulfonyl isocya- screen of alkyl and aromatic sulfonylchlorides (entries 1–3)
nate (CSI), followed by enzymatic resolution and nucleobase proved disappointing as complex reaction mixtures were
addition by way of a π-allylpalladium intermediate. Specifically, obtained. However after further optimization, treatment of the
racemic lactam 13, readily prepared from cyclopentadiene and resolved lactam 13 with n-butyllithium, followed by quenching
CSI after reductive workup, can be efficiently resolved by with p-toluenesulfonyl chloride gave the desired product 18d in
enzyme catalyzed hydrolysis (Scheme 3).24 We envisioned that a 60% yield (entry 4) after conventional workup. Initially, these
suitably activated derivative 16 might be an attractive precursor compounds exhibited poor shelf stability. However, subsequent
of a π- allylpalladium intermediate 17 that could be captured studies showed that the compounds were indefinitely stable as
directly by an intact nucleobase. Based on the chemistry devel- long as they were pure, dry and free of residual acid. Sub-
oped by Trost, we thought it likely that the reaction of the sequently, a more reliable process was developed, i.e., lactam 13
nucleobase with a π-allylpalladium intermediate would be both was allowed to react with 4-methylbenzenesulfonic anhydride in
regioselective and stereoselective (see Scheme 3). The formation the presence of triethylamine and catalytic DMAP to afford 18d

This journal is © The Royal Society of Chemistry 2012 Org. Biomol. Chem., 2012, 10, 1870–1876 | 1871
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Published on 07 December 2011 on http://pubs.rsc.org | doi:10.1039/C2OB06775G

Scheme 4 Summary of attempts at installing an electron withdrawing

group onto lactam 13.

in reproducible yields of 75–81% (entry 6). Presumably, this

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increase in yield observed when sulfonyl anhydrides are used in

place of the corresponding sulfonyl chlorides is a consequence
of the relatively low reactivity of the conjugate base, p-toluene-
sulfonate, relative to chloride, as well as the absence of a Lewis
acid. Finally, reaction with di-tert-butyl dicarbonate afforded the
known compound 18e36 in 71% yield (entry 7).
With the N-sulfonylamido and Boc derivatives in hand, we
were in a position to attempt the key reaction in our sequence,
i.e., the formation of a nucleoside intermediate through the direct
introduction of 2,6-dichloropurine37 tetrabutylammonium salt by
way of a π-allylpalladium complex. Reaction of 18d with 2,6-
dichloropurine tetrabutylammonium salt using either Pd(OAc)2
or Pd2(dba)3 in the presence of P(i-OPr)3 as the phosphine Scheme 5 Synthesis of Abacavir 2b.
ligand in tetrahydrofuran at ambient temperature afforded 19 in
75% yield (Scheme 5). Moreover, analysis of the crude reaction
sample of 19 by 1H NMR indicated ca. 7% of the N7 regio-
isomer, attesting to the high regioselectivity of the reaction proto-
col. Also, reaction of the 2,6-dichloropurine salt with 18e, using
identical conditions to those described above, failed to give the
desired product, suggesting that the Boc group was not suffi-
ciently electron-withdrawing to facilitate the ring-opening
reaction.
Next, the transformation of 19 to 21 was carried out. That is,
N-methylation of 19 which can be achieved using methyl iodide
(74%), dimethylsulfate (70%) or under Mitsunobu conditions
(94%) to afford 20 in good to excellent yields. Smooth reductive Scheme 6 Use of 4-methoxybenzylamine as an ammonia surrogate.
amido bond cleavage of 20 with sodium borohydride followed
by heterocyclic amination with cyclopropylamine in refluxing
ethanol finally afforded 21 in 63% over the two steps. 4-methoxybenzylamine in hot DMSO afforded compound 23 in
The synthesis of Abacavir 2b was completed by reaction of 21 90% isolated yield. This compound when warmed in DMSO in
with hydrazine hydrate in warm methanol/water mixture fol- the presence of HCl resulted in full decomposition of starting
lowed by treatment with sodium nitrite to afford the putative material as assessed by TLC analysis. However, when 23 was
intermediate 22. The product was not characterized but immedi- exposed to neat TFA at 50 °C for 72 h, (−)-Abacavir 2b was
ately subjected to stannous chloride mediated reduction to afford obtained in 73% yield.
Abacavir 2b in 70% yield over the three steps. In summary, an efficient enantioselective synthesis of the car-
Finally, a more direct approach to introduce the NH2 function- bocyclic nucleoside, (−)-Abacavir 2b has been accomplished by
ality at the 6-position of the purine base was investigated using exploiting an enzymatic resolution sequence for the rapid asym-
4-methoxybenzylamine as an ammonia surrogate (Scheme 6). metric construction of the sugar fragment of the nucleoside. In
This route appeared attractive as it avoids the use of potentially addition, a direct palladium catalyzed coupling of the sugar frag-
explosive and toxic reagents as exhibited in the closing synthetic ment to the purine base allowed for the highly convergent
sequences in Scheme 5. Thus, reaction of 21 with an excess of assembly of the nucleoside analogue 19 which was seamlessly

1872 | Org. Biomol. Chem., 2012, 10, 1870–1876 This journal is © The Royal Society of Chemistry 2012
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converted to (−)-Abacavir 2b. Lastly, introduction of the amine D −35.0 (c 0.2 in CHCl3); δH (400 MHz,
CHCl3), lit.,36 [α]25
functional group at the 6-position of the purine base was CDCl3, Me4Si) 2.40–2.50 (m, 1H), 2.65–2.75 (m, 1H),
approached in a more direct manner from 21 using 4-methoxy- 3.75–3.85 (m, 1H), 4.5 (s, 1H), 5.90–5.95 (m, 1H), 6.00–6.05
benzylamine as an ammonia surrogate. This allowed for one less (m, 1H), 6.4 (br s, 1H); δC (100 MHz, CDCl3) 172.5, 136.7,
step as well as avoiding potentially explosive intermediates 130.6, 59.1, 53.0, 30.6
(azide 22) and toxic reagents (SnCl2) en route to (−)-Abacavir
2b.
(1S,5R)-6-Tosyl-6-azabicyclo[3.2.0]hept-3-en-7-one 18d

Method 1. Compound 13 (15.0 g, 137 mmol) was added to

Experimental dichloromethane (160 mL) and cooled to 0 °C under nitrogen.
All the reactions dealing with air or moisture sensitive com- DMAP (1.68 g, 13.8 mmol) and triethylamine (16.7 g,
Published on 07 December 2011 on http://pubs.rsc.org | doi:10.1039/C2OB06775G

pounds were carried out in a dry reaction vessel under a positive 165 mmol) were added and the mixture stirred for 2 min to com-
pressure of nitrogen. Analytical thin-layer chromatography was pletely dissolve the solids. 4-Methylbenzenesulfonic anhydride
performed on an aluminium backed plates coated with 0.25 mm (55.0 g, 169 mmol) was added portion wise to the reaction
230–400 mesh silica gel containing a fluorescent indicator. Thin mixture over 5 min. The reaction mixture went to a dark brown
layer chromatography plates were visualized by exposure to red colour and was allowed to warm to room temperature and
ultraviolet light (254 nm) and/or by immersion in basic KMnO4 stirred at ambient temperature for an additional 24 h. The reac-
followed by heating. Organic solutions were concentrated by tion mixture was washed with brine (2 × 100 mL) and water (2 ×
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rotary evaporation at c.a. 30 mmHg. Flash column chromato- 100 mL). The organic extract was dried over sodium sulfate,
graphy was performed on Silica gel 60 (230–400 mesh, ASTM). filtered and evaporated to afford a brown residue. The residue
IR spectra were recorded as neat liquids or KBr pellets and was dissolved into a minimum amount of dichloromethane and
absorptions are reported in cm−1. NMR spectra were measured filtered through a silica gel pad with dichloromethane as the
on a Bruker 400 MHz Avance instrument at 400 MHz for 1H eluent. The washings were monitored by TLC to ensure all the
and 100 MHz for 13C NMR, using tetramethylsilane as an product had eluted. The residue was recrystallized from ethyl
internal reference and CDCl3 or d6-DMSO as a solvent. Chemi- acetate–hexane mixtures to afford 18d (27.0 g, 75%) as a crystal-
cal shift values for protons are reported in parts per million line white solid. mp: 93–95 °C (ethyl acetate–hexane); [α]20 D

( ppm, δ scale) downfield from tetramethylsilane and are refer- −125.3 (c 0.50 in CHCl3); νmax/cm−1 3068, 2921, 1781, 1348,
enced to residual proton of CDCl3 (δ 7.26) or residual protons of 119; δH (400 MHz, CDCl3, Me4Si) 7.86 (d, J = 8.4 Hz, 2H),
d6-DMSO (δ 2.50). Carbon nuclear magnetic resonance spectra 7.34 (d, J = 8.0 Hz, 2H), 6.04–6.02 (m, 2H), 5.02–4.99 (m, 1H),
(13C NMR) were recorded at 100 MHz: chemical shifts for 3.85–3.81 (m, 1H), 2.71–2.66 (m, 1H), 2.54–2.45 (m, 1H), 2.44
carbons are reported in parts per million ( ppm, δ scale) (s, 3H); δC (100 MHz, CDCl3) 167.0, 145.0, 138.7, 136.4,
downfield from tetramethylsilane and are referenced to the 129.9, 128.3, 127.3, 66.0, 51.8, 31.0, 21.6; m/z 264.0651 (MH+,
carbon resonance of CDCl3 (δ 77.0) or the carbon resonance of C13H14NO3S requires 264.0694).
d6-DMSO (δ 39.51). Data are presented as follows: chemical Method 2. A solution of 13 (2.00 g, 18.32 mmol) in dry THF
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = (33 mL) was added drop wise to a stirred mixture of 1.6 M n-
quartet, quint = quintet, sext = sextet, sept = septet, m = multi- BuLi in hexane (19.5 mL, 31.21 mmol) in dry THF (33 mL) at
plet and/or multiplet resonances, br = broad), coupling constant −78 °C under Argon. The mixture was stirred at −78 °C for 1 h
in hertz (Hz), and signal area integration in natural numbers. and p- toluenesulfonyl chloride (4.65 g, 24.40 mmol) was
High resolution mass spectra were measured using a Waters API added. The reaction mixture was gradually warmed to ambient
Q-TOF Ultima instrument. Optical rotations were recorded on a temperature. The solvent was evaporated in vacuo, and the
Jasco DIP-370 Polarimeter at 20 °C or 25 °C. residue was purified by flash chromatography (SiO2, hexane–
All reagents were purchased from commercial sources unless ethyl acetate, 4 : 1) to give 18d (2.90 g, 60%) as a white solid.
otherwise noted. Analytical data were identical to those reported above.

(1S,5R)-6-Azabicyclo[3.2.0]hept-3-en-7-one 13 (1S,5R)-tert-Butyl-7-oxo-6-azabicyclo[3.2.0]hept-3-ene-6-
carboxylate 18e
6-Azabicyclo[3.2.0]hept-3-en-7-one38 (55.0 g, 504 mmol) was
added to diisopropyl ether (1000 mL) and filtered through a por- To a solution of 13 (1.00 g, 9.16 mmol), DMAP (0.22 g,
osity 3 glass sintered funnel to give a yellow homogeneous sol- 1.8 mmol) and Et3N (3.80 mL, 27.3 mmol) in tetrahydrofuran
ution. Novozyme® 435 (53.0 g, 53 mg mL−1) and distilled (20 mL), Boc2O (2.00 g, 9.16 mmol) was added in several por-
water (9.10 mL, 1.00 equiv.) was added. The reaction mixture tions at 0 °C. The mixture was stirred at ambient temperature
was heated, without stirring, to 70 °C over 1 h and maintained at over the weekend. The reaction mixture was diluted with ethyl
that temperature for 11 h. The reaction mixture was allowed to acetate (60 mL) and washed with water (3 × 20 mL). The
cool overnight and the enzyme filtered off. The enzyme was organic extract was dried over sodium sulfate, filtered and con-
washed with diisopropyl ether (5 × 75 mL) and the combined centrated under vacuum. The crude product was purified by flash
organic fractions were evaporated to give an orange solid. The chromatography (SiO2, hexane–ethyl acetate, 4 : 1) to afford 18e
solid was recrystallized from diisopropyl ether (75 mL) to afford (1.44 g, 75%) as an orange oil. The spectral and analytical prop-
D −42.0 (c 0.5 in
13 (23.0 g, 42%) as a crystalline tan solid. [α]20 erties matched those reported in the literature.36

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(1S,4R)-4-(2,6-Dichloro-9H-purin-9-yl)-N-tosylcyclopent-2- to afford 19 (12.8 g, 75%) as a white solid. The solid was iso-
enecarboxamide 19 lated as a tenacious acetone adduct which could not be removed
after extended high vacuum drying at 60 °C. This adduct had no
Small scale. To a stirred solution of tetrabutylammonium salt consequence in the next step though.
of 2,6-dichloropurine (0.67 g, 1.5 mmol) in anhydrous THF
(20 mL) was added DMF (10 mL). Pd(OAc)2 (34 mg,
0.15 mmol) and triisopropyl phosphite (0.21 mL, 0.91 mmol) Routes to (1S,4R)-4-(2,6-dichloro-9H-purin-9-yl)-N-methyl-N-
were added and stirred under argon at ambient temperature for tosylcyclopent-2-enecarboxamide 20
1 h. A solution of 18d (0.40 g, 1.5 mmol) in dry THF (5 mL)
was added drop wise to the resultant mixture, which was then Iodomethane as the electrophile. Compound 19 (5.00 g,
stirred for a further 2 h. The solvent was evaporated in vacuo, 11.05 mmol) in acetone (50 mL) was reacted with methyl iodide
and the residue was purified by flash chromatography (SiO2, (6.81 g, 48.0 mmol) in the presence of K2CO3 (4.58 g,
Published on 07 December 2011 on http://pubs.rsc.org | doi:10.1039/C2OB06775G

dichloromethane–methanol, 19 : 1) to give 19 (0.33 g, 49%) as a 33.2 mmol) at reflux temperature for 4 h. The reaction mixture
was filtered through Celite and the Celite pad was washed with
yellow solid. mp 214–215 °C (from MeOH); [α]25 D −81.6 (c 0.50
in MeOH); νmax/cm−1 3256, 2966, 1686, 1683, 1609, 1503; δH additional acetone (50 mL). The solvent was evaporated and the
(400 MHz, CDCl3, Me4Si) 12.35 (brs, 1H), 7.80 (d, J = 8.0 Hz, residue was taken into ethyl acetate (50 mL), and washed with
2H), 7.39 (d, J = 8.0 Hz, 2H) 6.22–6.18 (m, 1H), 6.12–6.07 (m, water (25 mL) and brine (25 mL). The organic extract was dried
1H), 5.7.–5.63 (m, 1H), 3.76–3.68 (m, 1H), 2.80–2.70 (m,1H), over sodium sulfate, filtered and evaporated. The residue was tri-
2.38 (s, 3H), 2.00–2.05 (m, 1H); δC (100 MHz, CDCl3) 171.1, D −73.3
turated with diethyl ether to afford 20 (3.80 g, 74%). [α]20
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152.9, 150.8, 149.5, 146.1, 144.3, 136.2, 135.1, 130.9, 130.6, (c 0.5 in MeOH); νmax/cm−1 3256, 2966, 1686, 1683, 1609,
129.5, 127.5, 59.6, 50.7, 32.8, 21.0; m/z 452.0342 (MH+, 1503; δH (400 MHz, CDCl3, Me4Si) 8.33 (s, 1H), 7.76 (d, J =
C18H16Cl2N5O3S requires 452.0351). 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.21–6.78 (m, 1H),
6.01–5.99 (m, 1H), 5.87–5.83 (m, 1H), 4.60–4.57 (m, 1H), 3.27
(s, 3H), 2.93–2.85 (m, 1H), 2.47 (s, 3H), 2.20–2.14 (m, 1H); δC
Large scale preparation. 2,6-Dichloropurine (15.0 g, (100 MHz, CDCl3) 173.7, 152.7, 152.6, 151.5, 145.5, 145.3,
79.0 mmol) was partially dissolved into tetrahydrofuran 136.8, 135.8, 130.8, 130.5, 130.2, 127.2, 59.4, 50.9, 35.5, 33.4,
(50 mL). A freshly prepared solution of tetrabutylammonium 21.6; m/z 466.0524 (MH+, C19H18Cl2N5O3S requires 466.0507).
hydroxide hydrate (Sigma-Aldrich, 63.5 g, 79.0 mmol) in deio-
nised water (200 mL) was added to the reaction mixture. The Dimethylsulfate as the electrophile. Compound 19 (1.00 g,
mixture solubilised and after 2 h the solvents were evaporated. 2.21 mmol) in acetone (50 mL) was reacted with dimethylsulfate
Toluene (50 mL) was added and evaporated to dryness again. (0.73 g, 5.7 mmol) in the presence of K2CO3 (0.76 g,
This process was repeated twice more. The semi-solid residue 5.53 mmol) at ambient temperature overnight. The reaction
was triturated with diethyl ether (300 mL) under rapid stirring mixture was filtered through Celite and the Celite pad was
for 3 h. The solids were filtered and dried under high vacuum to washed with additional acetone (50 mL). The solvent was evap-
afford tetrabutylammonium 2,6-dichloropurin-9-ide (32.2 g, orated and the residue was taken into ethyl acetate (50 mL), and
94%) as a white free-flowing solid. The solid was stored in a washed with water (25 mL) and brine (25 mL). The organic
well sealed desiccator and away from light when not in use. extract was dried over sodium sulfate, filtered and evaporated.
Pd2(dba)3 (1.74 g, 1.90 mmol) and triisopropylphosphite The residue was triturated with diethyl ether to afford 20 (0.72 g,
(2.00 mL, 7.70 mmol) were added to dry tetrahydrofuran 70%). The analytical data matched those reported above.
(100 mL), degassed and purged with nitrogen 5 times, and
allowed to stir for 30 min during which time the solution Mitsunobu reaction. To a stirring solution of 19 (0.65 g,
changed from purple to dark green. Tetrabutylammonium 2,6- 1.44 mmol) in THF–CH2Cl2 (1 : 1, 20 mL) was added methanol
dichloropurin-9-ide (16.4 g, 38.0 mmol) was added and allowed (0.2 mL), PPh3 (1.33 g, 5.76 mmol), and diisopropyl azodicar-
to stir until all the solids had dissolved. Finally, 18d (10.0 g, boxylate (0.98 mL, 5.74 mmol). After stirring for 30 min under
38.4 mmol) was added and the reaction mixture was degassed argon, the solvent was evaporated in vacuo to give a residue,
and purged with nitrogen 5 times. The reaction mixture was which was purified by flash chromatography (SiO2 hexane–ethyl
allowed to stir for 90 min. The reaction mixture was filtered acetate, 1 : 2) to afford 20 (0.63 g, 1.35 mmol, 94%) as a solid.
through Celite and the Celite pad was washed with additional The analytical data matched those reported above.
tetrahydrofuran (3 × 50 mL). The solvent was evaporated to give
a red oil. Analysis by proton NMR suggested that the N7 vs. N9 ((1S,4R)-4-(2-Chloro-6-(cyclopropylamino)-9H-purin-9-yl)
substitution ratio as 7% and 93% respectively. The oil was taken cyclopent-2-en-1-yl)methanol 21
up into ethyl acetate (500 mL) and washed with 10% HCl (4 ×
50 mL) and brine (50 mL). The organic extract was dried over A solution of 20 (2.80 g, 6.00 mmol) in isopropyl alcohol
magnesium sulfate, filtered and evaporated to dryness to afford a (8 mL) and tetrahydrofuran (32 mL) was cooled to 0 °C. Sodium
red glass. The glass was rapidly stirred in hexane (50 mL) and borohydride (0.227 g, 6.00 mmol) was added portion wise over
acetone (75 mL) was added until solids started to crash out of 1 min, and stirring was continued until TLC analysis indicated a
solution. The heterogeneous solution was stirred at 0 °C for complete reaction. This took 60 min. The reaction was quenched
30 min and filtered. The solids were washed with chilled with water (20 mL) at 0 °C and allowed to warm to ambient
acetone–hexane mixtures (1 : 1, 3 × 15 mL), and air-dried on the temperature for 2 h. The reaction mixture was taken into ethyl
filter for 5 min. The solids were further dried under high vacuum acetate (100 mL) and washed with water (50 mL) and brine

1874 | Org. Biomol. Chem., 2012, 10, 1870–1876 This journal is © The Royal Society of Chemistry 2012
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(2 × 50 mL). The aqueous layer was re-extracted with ethyl overnight. The reaction mixture was diluted with ethyl acetate
acetate (2 × 50 mL). The pooled organic extract was dried over (50 mL) and washed with water (3 × 25 mL) and brine (20 mL).
magnesium sulfate, filtered and evaporated to give a brown The organic extract was dried over sodium sulfate, filtered and
residue. Flash chromatography (SiO2, hexane–ethyl acetate, evaporated to give an oil that was chromatographed (SiO2, ethyl
1 : 2) afforded ((1S,4R)-4-(2,6-dichloro-9H-purin-9-yl)cyclopent- acetate–methanol, 98 : 2) twice by way of preparative TLC to
2-en-1-yl)methanol (1.48 g, 86%) as a viscous oil. δH afford ((1S,4R)-4-(6-(cyclopropylamino)-2-((4-methoxybenzyl)
(400 MHz, CDCl3, Me4Si) 8.52 (s, 1H), 6.25–6.23 (m, 1H), amino)-9H-purin-9-yl)cyclopent-2-en-1-yl)methanol 23 (0.21 g,
5.88–5.85 (m, 1H), 5.80–5.77 (m, 1H), 3.90 (dd, J = 10.5, 3.7, 90%) as an orange gum. [α]20 D −2.7 (c 0.50 in CHCl3); δH
1H), 3.75 (dd, J = 10.5, 3.7, 1H), 3.50 (brs, 1H), 3.12–3.10 (m, (400 MHz, CDCl3, Me4Si) 7.41 (s, 1H), 7.30 (d, J = 8.7, 2H),
1H), 2.93–2.84 (m, 1H), 1.92–1.86 (m, 1H); δC (100 MHz, 6.81 (d, J = 8.7, 2H), 6.09–6.03 (m, 1H), 5.90 (brs, 1H),
CDCl3) 152.7, 152.6, 151.2, 145.7, 140.3, 130.6, 128.8, 64.0, 5.79–5.73 (m, 1H), 5.46–5.37 (m, 1H), 5.24–5.16 (m, 1H), 4.56
60.6, 47.5, 34.0. The data matched those in the literature.35 Dry (brs, 1H), 4.54 (brs, 1H), 3.83–3.77 (m, 1H), 3.76 (s, 3H),
Published on 07 December 2011 on http://pubs.rsc.org | doi:10.1039/C2OB06775G

ethanol (10 mL) was added to the above oil (1.48 g, 5.19 mmol) 3.74–6.37 (m, 1H), 3.05 (brs, 1H), 2.94 (brs, 1H), 2.82–2.64 (m,
and stirred until the oil dissolved completely. Cyclopropylamine 1H), 2.21 (brs, 1H), 2.08–1.97 (m, 1H), 0.83–0.72 (m, 2H),
(2.00 mL, 28. 4 mmol) was added and the reaction mixture was 0.62–0.49 (m, 2H); δC (100 MHz, CDCl3) 159.0, 158.6, 156.0,
warmed to 50 °C and maintained at that temperature for 5 h. The 137.7, 136.2, 132.5, 130.6, 129.1, 114.9, 113.7, 65.2, 60.8, 55.2,
solvent was evaporated and the residue taken up into acetone 47.7, 45.4, 32.7, 23.6, 7.2; m/z 407.2208 (MH+, C22H27N6O2
(25 mL) and stirred with sodium bicarbonate (500 mg) for requires 407.2195).
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30 min. The organic layer was filtered and evaporated to give a Compound 23 (0.16 g, 0.38 mmol) was dissolved into chloro-
residue that was purified by flash chromatography (SiO2, ethyl form (5 mL) and stirred under nitrogen. TFA (1.5 mL) was
acetate) to afford 21 (1.15 g, 3.76 mmol, 73%) as a white foam added and the reaction mixture was heated at 50 °C for 18 h.
that collapsed into a gum over time. [α]20 D = 23.3 (c 0.50 in More TFA (2.5 mL) was added and stirring was continued an
CHCl3) νmax/cm−1 3322, 3256, 1686, 1683, 1503; δH additional 18 h at 50 °C. Finally, an additional aliquot of TFA
(400 MHz, CDCl3, Me4Si) 7.81 (s, 1H), 6.80 (brs, 1H), 6.14 (m, (2.5 mL) was added and stirring was continued for 18 h at
1H), 5.81 (m, 1H), 5.62 (m, 1H), 3.77 (m, 1H), 3.66 (m, 1H), 50 °C. The solvent was evaporated and the residue was neutral-
2.97 (m, 3H), 2.81 (m, 1H), 1.81 (m, 1H), 0.87 (m, 2H), 0.6 (m, ized with saturated sodium carbonate solution (20 mL) and
2H); δC (100 MHz, CDCl3) 156.2, 154.1, 138.9, 138.8, 129.6, extracted with chloroform (4 × 10 mL) and dried over mag-
118.6, 64.5, 60.0, 47.5, 34.0, 7.2; m/z 306.1122 (MH+, nesium sulfate. Preparative TLC (SiO2, chloroform–methanol,
C14H17ClN5O requires 306.1122). 97 : 3) afforded 2b (0.080 g, 73%) as a solid. The analytical data
matched those given earlier for 2b above.
Routes to Abacavir 2b

Azide route. Compound 21 (0.20 g, 0.66 mmol) was dis- References

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