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Rapid Formation of Molecular

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Complexity in Organic Synthesis issue

Reviewing the latest advances in reaction development and

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complex, target-directed synthesis

Guest Editors Professors Erik J. Sorensen and Huw M. L. Davies

Please take a look at the issue 11 table of contents to access

other reviews in this themed issue
 TUTORIAL REVIEW www.rsc.org/csr | Chemical Society Reviews

The economies of synthesisw

Timothy Newhouse,a Phil S. Baran*a and Reinhard W. Hoffmann*b
Received 5th May 2009
First published as an Advance Article on the web 21st August 2009
DOI: 10.1039/b821200g

In this tutorial review the economies of synthesis are analysed from both detailed and macroscopic
perspectives, using case-studies from complex molecule synthesis. Atom, step, and redox economy
Published on 21 August 2009 on http://pubs.rsc.org | doi:10.1039/B821200G

are more than philosophical constructs, but rather guidelines, which enable the synthetic chemist
to design and execute an efficient synthesis. Students entering the field of synthesis might find this
tutorial helpful for understanding the subtle differences between these economic principles and
also see real-world situations where such principles are put into practice.
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Introduction pushed the capabilities of synthetic methodology to its limits.

One culmination point was the total synthesis of palytoxin, 1,2
Since the dawn of organic chemistry, the synthesis of complex a compound with 64 stereogenic centres (Scheme 1).
natural products has been the testing ground of methods and Palytoxin, 1, was assembled from seven building blocks in
strategies in synthesis and in doing so defines the frontiers of 39 steps. The synthesis of the seven building blocks has not
the field.1 Endeavours in complex molecule total synthesis been published yet in detail, but it can be safely guessed that
often have a way of yielding enormous dividends in the form this required more than 140 steps. Hence it is obvious what
of fundamental insight into selectivity principles and the enormous effort, manpower, and logistics were involved.
outright invention of new chemistry in order to reach the Due to economic considerations, eventually society will not
target. With increasing capabilities in the power of organic be able to support such an endeavour, unless it is of utmost
synthesis the perception of what constitutes a complex target importance such as the penicillin synthesis project during
structure has changed accordingly, be it from acetic acid to World War II. In that effort more than 1000 chemists in
adamantane to strychnine to erythronolide to maitotoxin and 39 laboratories joined forces.3a The synthetic strategies and
so on. The last century has witnessed a breathtaking development methods of the 20th century reach their limits with molecules
of synthetic methods and celebrated epochal syntheses of such as palytoxin, when the number of synthetic steps
terrifyingly complex target compounds,1 and in doing so has significantly exceeds 100. In a manufacturing setting, the
production plant synthesis of Roche’s Fuzeon with 106 steps3b
a
may well hold the record for decades to come. It must be the
Department of Chemistry, The Scripps Research Institute, 10550 N,
Torrey Pines Road, La Jolla, CA 92037, USA.
goal of the 21st century to accomplish more with less, and in
E-mail: pbaran@scripps.edu order to do so, one has to analyse the factors that are limiting
b
Fachbereich Chemie der Philipps-Universität Marburg, in traditional organic synthesis.
Hans-Meerwein-Strasse, 35032 Marburg, Germany. From the discussion above one realises that the number
E-mail: rwho@chemie.uni-marburg.de
w Part of the rapid formation of molecular complexity in organic of steps in a synthesis has a paramount influence on the
synthesis themed issue. feasibility and practicality of a synthesis project, as it determines

Timothy Newhouse received Phil S. Baran was born in New

his BA in Chemistry from Jersey in 1977 and received his
Colby College in 2005 under undergraduate education from
the supervision of Professor New York University with
Dasan M. Thamattoor. He is Professor David I. Schuster
currently a graduate student in 1997. After earning his
studying the total synthesis PhD with Professor K. C.
of indole alkaloids with Nicolaou at the Scripps
Professor Phil S. Baran at Research Institute in 2001 he
the Scripps Research Institute. pursued postdoctoral studies
with Professor E. J. Corey at
Harvard until 2003, at which
point he began his independent
career at Scripps, rising to the
Timothy Newhouse Phil S. Baran rank of Professor in 2008. His
laboratory is dedicated to the
study of fundamental organic chemistry through the auspices of
natural product total synthesis.

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Scheme 1 Palytoxin (1).

the manpower input, the material input, the logistics involved Hendrickson postulates that the skeleton forming steps
as well as the amount of waste and byproducts that are are the only essential steps in synthesis. If the skeleton
handled. It is for this very good reason that Wender et al. forming steps are executed correctly, one should be able to
emphasise the ‘‘step economy’’ of synthesis projects.4 Yet this simultaneously set up the functionality needed for the final
appeal has to be translated into clear guidance on how to target or the next step, including the requisite stereocentres.
reduce the step count, i.e. to simplify or streamline complex All other refunctionalisation steps (e.g. protecting group
target syntheses. management steps, non-strategic redox manipulations, etc.)
This leads to the fundamental question: which steps in a should be minimised in order to simplify complex target
synthesis sequence are essential and, hence, indispensable? synthesis. Indeed, the simplification of synthesis with respect
This question has been answered by Hendrickson in 1975, to reducing the number of steps and redox manipulations, as
when he addressed ‘‘the ideal synthesis:’’5 well as molecular waste, is imperative. However, one must not
‘‘The ideal synthesis creates a complex molecule. . . in a forget the overall goal of increased efficiency and should keep
sequence of only construction reactions involving no intermediary in mind the importance of molecular yield. A balance between
refunctionalisations, and leading directly to the target, not only brevity of sequence and overall yield is critically important.
its skeleton but also its correctly placed functionality.’’ To understand how far we are away from Hendrickson’s
ideal synthesis, take for example the assembly line of Kishi’s
palytoxin synthesis. It involved 11 skeleton forming steps, 15
refunctionalisation steps, and 13 protecting group management
Reinhard W. Hoffmann steps. Kishi’s palytoxin synthesis can be used as a ruler for the
studied chemistry from 1951 state of natural product synthesis at the end of the last century.
to 1958 at the University
To generalise from this single example, this reveals that roughly
of Bonn, finishing with a
doctorate under the guidance two thirds of the steps of a synthesis are ones that reflect
of Professor B. Helferich. our inability to achieve the Hendrickson ‘‘ideal.’’ This is a
Two years of postdoctoral consequence of the fact that the most sophisticated methods
studies at the Pennsylvania for many skeleton-forming reactions have not yet been developed.
State University were followed The current set of methods are not chemoselective enough to
by a second postdoctorate allow for the elimination of non-skeleton building steps.6
with Professor G. Wittig at While new methodology is enabling in the synthesis of
the University of Heidelberg. complex natural products, thinking about the logic and strat-
There he started his indepen-
egy required to reach the ‘‘ideal synthesis’’ is essential.7
dent research that led to his
The economies of synthesis are a useful conceptual frame-
Reinhard W. Hoffmann habilitation in 1964. Three
years later he was appointed work from which to design and analyse syntheses. What
as Dozent at the Technische Hochschule Darmstadt. Since 1970 follows below is a brief description of the ‘‘economic principles’’
he has held a position as professor of organic chemistry at the underlying synthesis logic and a series of synthesis vignettes,
Universität Marburg (emeritus status since 2001). which illustrate such economic considerations.

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 Step economy the Dess–Martin-mediated oxidation of an alcohol, a reagent
with a molecular weight of 424 is used to remove 2
The precepts of step economy teach organic chemists that hydrogen atoms.
minimising the number of steps leads to an efficient multistep
synthesis in terms of cost and time expended to obtain the
desired target. While designing and executing a target-oriented Illustrative syntheses
synthesis, the structure cannot be modified to accommodate the
Methyl homodaphniphyllate and proto-daphniphylline
current state of the art in organic synthesis, rather ‘‘the goal
(Heathcock)
structure is very clear and stubbornly inflexible.’’8 Thus, the
conceptual framework of step economy brings about the One of the most time-tested approaches to achieving an
conclusion that achieving a total synthesis requires innovation efficient synthesis is through employing a biomimetic strategy.13
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in the form of strategy, tactics and method invention. Alter- These strategies frequently have the natural consequence of
natively, in cases where there is not a goal structure, but rather a reducing the number of functional group interconversions
goal function, such as in some biological, medicinal or materials necessary to achieve the desired level of complexity. An
studies, the target can be chemically simplified to the extent that overwhelming example of how this can be a successful strategy
it requires a fewer number of steps to access. The judicious is in Heathcock and Piettre’ synthesis of proto-daphniphylline,
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choice and development of reactions or sequences of reactions 10. They use a purely abiotic ‘‘network analysis’’ (standard
allows for the step-economical synthesis of a given target retrosynthetic analysis) to methyl homodaphniphyllate, 6
structure.9 (Scheme 2A), and another approach draws heavily from the
presumed biosynthesis (Scheme 2B).
The first approach builds the skeleton layer by layer using
Atom economy network analysis and must address several refunctionalisation
A traditional perspective on the development of novel chemical steps of the type Hendrickson teaches us to avoid. In contrast,
transforms prioritises synthetic efficiency in terms of mole the use of a biomimetic Michael, Diels–Alder, aza-Prins
percent by the maximisation of theoretical product yield with cascade leads to the most efficient synthesis of the natural
respect to chemo-, regio-, diastereo-, and enantioselective product. In a single isohypsic cascade (7 - 10), two C–N
control. A modification of this ideological perspective came bonds, four C–C bonds, and five rings are generated, under-
with Trost’s concept of atom economy,10 which places an scoring the power of redox neutral (isohypsic) reactions in
additional restriction on synthetic methodology—that is to synthesis. This rapid generation of complexity demonstrated
maximise the mass efficiency of a reaction with respect to all of in Heathcock’s second-generation synthesis not only allows
the reactants. When viewing organic reactions with an atom for a general strategy for the synthesis of a diverse family of
economy ‘‘filter,’’ the ideal reaction incorporates all of the alkaloids, but also minimises the use of protecting groups. The
atoms of the starting materials into the desired product by the biomimetic strategy was later applied to a number of family
merger of chemical building blocks, using only catalytic members, including methyl homodaphniphyllate, 6.
quantities of reagents. For example, the Diels–Alder reaction While protecting groups cannot always be completely
proceeds with 100% atom economy. Multiple features of eliminated in the synthesis of complex molecules, minimisation
a reaction come under scrutiny, including stoichiometric of their use is advantageous from the perspectives of both step
reagents and high molecular weight byproducts. The importance and atom economy. The pros and cons of protecting group
of this perspective becomes clear given the cost of pharma- chemistry have recently been reviewed.6
ceutical and material production, as well as the increasing
importance of green chemistry within the context of sustainable Torreyanic acid (Porco)
development.11 Another broadly applicable biomimetic Diels–Alder strategy
has been employed by Porco and co-workers in their elegant
syntheses of epoxyquinoid natural products.14 One example of
Redox economy
this Diels–Alder dimerisation event is shown in Scheme 3 with
Accounting for redox manipulations over the course of a the total synthesis of torreyanic acid (17). While protecting
synthesis can be a powerful tool to shorten the pathway to a group interchanges are employed in the synthesis of the
given target molecule. The basic goal of redox economy is to monomer, 16, the final step proceeds with all of the functionality
minimise non-strategic redox manipulations in order to present in the dimeric natural product. In this convergent
achieve an isohypsic synthesis—one which has no redox steps. approach, the number of steps required is greatly diminished,
When oxidation or reduction operations are used, the oxidation relative to a hypothetical alternative strategy, as the mono-
state of the intermediates should not fluctuate, but rather meric components are identical and do not require separate
increase or decrease steadily (or exponentially) in the con- syntheses.
struction of complex molecules. The natural consequence of Typical of pericyclic reactions (sigmatropic rearrangements,
this is a step economic synthesis.12 Additionally, due to a lack electrocyclisations, group transfer reactions, and cycloadditions)
of chemoselective methodologies, the avoidance of oxidation is their atom-economical nature with all of the atoms in the
and reduction steps frequently results in a more atom starting materials typically present in the product or with
economic synthesis, as these reactions (relative to redox neutral loss of low molecular weight materials (CO2, N2, etc.). In
reactions) tend to be less atom economical. For example, in a spectacular show of atom economy, no other reactants

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Scheme 2 A dramatic cascade reaction en route to daphniphyllum alkaloids.

Scheme 3 Biomimetic Diels–Alder reaction in the synthesis of epoxyquinoid natural products.

(catalyst, solvent, etc.) are necessary to effect Porco’s Diels– oxidation strategy can be successful in the synthesis of com-
Alder cycloaddition. Also typical of pericyclic reactions is that plex molecules.
the starting materials’ oxidation state usually does not change
Hirsutene (Wender and Mehta)
(cycloadditions and ene reactions with singlet-oxygen are
obvious exceptions to this rule). Thus, striving for a redox The arene–olefin cycloaddition reaction, popularised by
neutral strategy can naturally guide a chemist to consider Wender and coworkers,16a is another example of a pericyclic
pericyclic reactions in retrosynthetic analysis. reaction, which has been used to generate complexity in target-
oriented synthesis (Scheme 5). In the synthesis of hirsutene, 29,
a photoinduced, formal [3 + 2] cycloaddition, followed by
Rugulosin (Nicolaou)
[1,3] diradical recombination, provides a useful tetracycle, 27,
Another beautiful example of biomimetic cascade reactions is after deacetylation, proceeding in 22% yield along with three
seen in Nicolaou’s total synthesis of rugulosin, 23, and related other diastereomers (9%). A second redox neutral transformation,
family members (Scheme 4).15 Nicolaou and co-workers were a cationic dehydration event, fragments the recently formed
attracted to these targets by their highly congested core cyclopropane to afford the hirsutene core, 28, in short order.
structures and were intrigued by the possibility of re-enacting In the final steps of the synthesis, a few refunctionalisations are
their biosynthesis. This was ultimately achieved by first necessary, deviating from the otherwise isohypsic synthesis. The
synthesising a suitably protected monomer, 22, which upon combined two-step strategy of an arene–olefin cycloaddition
exposure to basic, oxidative conditions underwent the desired with a strategic cyclopropane fragmentation is atom economical,
oxidative dimerisation, Michael, Michael cascade reaction. in that all three rings of the carbocyclic core of hirsutene are
As with all biomimetic dimerisation reactions, the synthetic formed with only the loss of water from the starting materials.
route is of a highly step and atom economic nature. This While there is one protecting group interchange, the sequence
synthesis also provocatively shows how a daring late-stage is highly step economic.

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Scheme 4 Biomimetic oxidative dimerisation in the synthesis of rugulosin.

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Scheme 5 Arene–olefin cycloaddition reaction in the synthesis of hirsutene.

It is also instructive to note that compound 27 might be

considered more complex than the final target. Such ‘‘overbred
skeletons’’ are only desirable when they can be generated and
converted to the target in a rapid fashion.
Mehta and co-workers16b later reported an extremely
atom-economical synthesis of the tricyclic hirsutene core, 35
(Scheme 6). A remarkable sequence of events, requiring only
heat, light, and solvent as reagents, transpired to assemble the
core structure in an isohypsic fashion. Beginning with a
benzoquinone, 30, and cyclopentadiene a thermal Diels–Alder
gives 32. This is followed by photochemical [2 + 2] to afford
33 and thermal cyclobutane fragmentation provides 34.
Finally, a double epimerisation (via olefin isomerisation) sets
the required stereochemistry to deliver the core, 35, in four
steps and 28% overall yield, in the near absence of any
reagents. To complete the synthesis, a mere six steps were
then required to adjust the functionality present to that of
hirsutene, 29.

Pentalenene (Paquette)
Paquette and co-workers have developed two syntheses17 of
pentalenene (37), separated by 20 years (Scheme 7). The first of
these is a traditional approach proceeding in over 20 steps and
involving several corrective refunctionalisations. The second- Scheme 6 Synthesis of the hirsutene core in the near absence of
generation synthesis used only two skeletal building operations reagents.
and a total of eight steps. This remarkable simplification of the
synthesis was due to a cascade process in which the complex
Methylphenidate (Matsumura and Davies)
tricyclic structure, 43, was generated in one stroke from a
monocyclic starting material, 38, in a sequence of electrocyclic In the total synthesis of methylphenidate (Ritalin), 48, Davies
reactions and an aldol addition. In this way a remarkably and co-workers demonstrate excellent atom, step and redox
rapid increase in complexity was attained. economy by the use of a C–H activation reaction (Scheme 8).19
Cascade reactions are still restricted to rather special One previous asymmetric route relied on the use of a chiral
situations, yet their application in complex target synthesis is auxiliary in an aldol reaction (46 - 47), which provided
steadily increasing,18 because they provide a truly powerful material with excellent diastereoselectivity.20 However, the
tool to rapidly generate complexity. use of this stoichiometric reagent is costly from the perspective

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 Miyakolide C6–C13 fragment (Masamune and White)
The last decade has seen major advances in the field of allylic
oxidation methodology, especially palladium catalysed oxidation
of alkenes to allylic alcohols and amines. The benefit of linear
increase of oxidation state with simultaneous functional group
installation can be illustrated by comparison of parts A and B
in Scheme 9. The original synthesis21a of the intermediate 52
starts from 1,4-butanediol, 49, and subsequent differentiation
of the hydroxyl groups requires a sequence involving a total of
four protecting group steps.
Published on 21 August 2009 on http://pubs.rsc.org | doi:10.1039/B821200G

The alternative strategy21b in Scheme 9B starts from alcohol

53, having a terminal double bond as profunctionality for the
other alcohol function. This allowed for the generation of the
allylic alcohol at the end of the reaction sequence by a
palladium catalysed oxidation (i.e. 55 - 56). Since this
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functionality was now generated after all the other steps had
been completed, the differentiation problem did not exist as
one alcohol was masked as an olefin. While desymmetrisation
of a late-stage intermediate can be a powerful tool (vide infra),
in the case of Scheme 9A the use of a symmetrical starting
material brought no advantage, because the desymmetrisation
required a large number of steps. Hence, the alternative
strategy (Scheme 9B) turned out to be more effective. Thus,
as seen in the previous section C–H functionalisation can
allow for significant shortening of synthetic sequences.

Davanone (Honda–Tsuchihashi and Vosburg)

A recent total synthesis of (+)-davanone, 61, from Vosburg
and co-workers22 achieves step, atom and redox economy
Scheme 7 Squarate ester cascade reaction enables a rapid pentale- through careful synthetic design (Scheme 10). Using Bode’s
nene synthesis. thiazolium catalyst, a redox isomerisation is first used for the
synthesis of a b-hydroxyester, 63. The resulting alcohol, 63,
of atom economy and requires a number of steps to install and then participates in a Tsuji–Trost reaction to form the desired
then later remove. An abbreviated synthesis utilised an tetrahydrofuran, 64. After conversion of the ethyl ester to a
enantioselective, rhodium(II)-catalysed intermolecular C–H Weinreb amide, reaction with prenyl magnesium chloride
insertion with phenyldiazoacetate to directly afford methyl- affords the enantiopure natural product, 61. The four successive
phenidate, 48, after Boc deprotection. While the diastereo- isohypsic transformations provide a successful strategy for
selectivity is notably lower, the direct nature of this synthesis a step economic synthesis relative to the previous enantio-
greatly enables the rapid synthesis of a diversity of analogs. selective synthesis (20 steps from commercial material).
When used strategically, the logic of C–H functionalisation Protecting groups are avoided, further simplifying the synthesis.
can dramatically shorten sequences and, in some cases, even Additionally, the reaction sequence involves two catalytic
solve seemingly insurmountable challenges. reactions, which are highly atom economical, producing only
minimal byproducts.

Platencin (Rutjes and Mulzer)

While transition-metal processes are powerful opportunities to
maximise synthesis economy, judicious reaction selection is
still necessary. This can be seen by comparing the final steps of
two formal syntheses of platencin, 70.23 In Rutjes’ synthesis in
Scheme 11A the authors chose to form the skeletal bond by a
samarium iodide reductive coupling reaction. This required
protection and later deprotection of the enone, 65, as well as
ozonolytic cleavage of both double bonds. Refunctionalisation
of diol 66 then requires an additional three steps to reach
Nicolaou’s intermediate 67 for the synthesis of platencin 70.
By opting to use ring-closing metathesis as the transition-
Scheme 8 Strategic C–H oxidation in the synthesis of methyl- metal catalysed bond-forming reaction (Scheme 11B), protecting
phenidate (48). groups are no longer necessary and the overall transformation

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Scheme 9 C–H oxidation used in the synthesis of the miyakolide C6–C13 fragment (51).

Scheme 10 Two approaches for the total synthesis of (+)-davanone (61).

Scheme 11 Ring-closing metathesis to synthesise platencin (70).

to intermediate 67 can be performed in a mere three steps as intermediate 72, which can be converted to 79, was synthesised
opposed to seven. Overall, the Mulzer synthesis of platencin by the Nakata group through an approach involving sequential
takes place in nine steps and is a profound example of step, ring formation requiring 29 steps (Scheme 12A). With the
atom, and redox economy in action. importance of this intermediate apparent, Nelson’s approach,
which proceeds via bidirectional synthesis, followed by late-stage
desymmetrisation (Scheme 12B), significantly simplified the
Hemibrevetoxin B (Nakata and Nelson)
pathway to 79. This approach relies on an acid-catalysed
Another dramatic example of step reduction is the Nelson epoxide opening to simultaneously form both tetrahydropyran
approach24 to hemibrevetoxin B, 79. The advanced key rings in 75. Net two-carbon homologation and epoxidation

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Scheme 12 Desymmetrisation of a diepoxide en route to hemibrevetoxin B (79).

furnishes the key intermediate 77. Jacobsen’s epoxide opening step, but the remaining 10 refunctionalisation steps (redox
then acts to desymmetrise 77 and after acetonide formation manipulations and protecting group interchanges) detract
affords 72. This approach results in a four-fold reduction in from the otherwise elegant approach.
the total number of steps required to synthesise this important
Spirastrellolide A methyl ester (Paterson)
intermediate, 72. The approach is guided by linearly increasing
oxidation state and a general avoidance of protecting groups, Paterson’s first approach to the C26–C40 bis-spiroacetal
leading to a highly efficient synthesis. subunit of spirastrellolide A, 97, while only 11 linear steps,
was plagued by a low yielding acetonide deprotection and
Rifamycin (Kishi and Harada–Oku)
spirocyclisation step (92 - 93) as a result of the propensity of
As demonstrated in Scheme 12, a valuable strategy to reduce the five-membered lactone, 92, to undergo elimination and
the number of skeleton forming steps in a synthesis is to find a aromatisation (Scheme 14A).26 The first generation route also
hidden symmetry in the target or a precursor intermediate: suffers from the use of high molecular weight, stoichiometric
such symmetry permits a bidirectional elaboration of the reagents (DMP, [Ph3PCuH]6, etc.). An alternative strategy was
skeleton with an attendant reduction in the skeleton building employed,26 which both avoids these problems and allows for
steps.25 This can be illustrated with regard to rifamycin S, 80, greater material throughput.
in the synthesis of a portion of its ansa chain, 82. The In Paterson’s landmark total synthesis of spirastrellolide A
pioneering synthesis by Nagaoka and Kishi25a synthesised methyl ester, 97,26 an exponential increase in oxidation state
the key intermediate 82 from the aldehyde 81 by chain via a double dihydroxylation event is accompanied by
extension (Scheme 13A). The skeleton was extended in a an exponential increase in complexity (Scheme 14B). This
sequential manner, amounting to four skeleton building steps approach allows for the rapid formation of the tricyclic
(accompanied by one strategic and eight corrective redox- bis-spiroacetal subunit, 96, from a linear carbon chain pre-
operations and eight protecting group steps). cursor, 94, containing the requisite functionality necessary for
A key to an improvement is the direct use of the synthesis of the natural product. While a mixture of isomers is
latent symmetry in the intermediate 82. This provided the obtained, the undesired isomers can be conveniently recycled
opportunity to elaborate the skeleton in a symmetrical manner to afford a predominance of the desired product. While the
from a central building block 83 (Scheme 13B). Two-fold step economy of the two routes is identical, the second-
simultaneous chain extension by addition of crotylboronate generation route leads to a dramatic increase in redox and
to 83 is the single skeleton building reaction in this novel atom economy—thus a greater supply of material can be
synthesis25b of 82. Symmetry is maintained throughout a obtained.
number of refunctionalisation steps until tetraol 86. At this
Oseltamivir phosphate (Roche, Corey and Hayashi)
point the symmetry of the prochiral compound 86 is broken by
differentiation with the aid of a chiral auxiliary (TMS-enol The synthetic challenge of the H5N1 influenza treatment,
ether of menthone, 87). The resulting monoacetal is then oseltamivir phosphate, largely relates to the development of
readily converted into the enantiomerically pure target 82. a process-friendly route, which can directly impact the current
Note that this synthesis of 82 has only one skeleton building supply problem.27 Roche has previously disclosed a highly

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Scheme 13 Desymmetrisation of a meso tetraol in the synthesis of rifamycin S (80).

Scheme 14 Double spirocyclisation in the total synthesis of spirastrellolide A methyl ester (97).

efficient process scale route (12–13 steps, 39% overall yield) Following the potential for a life-threatening influenza
shown in Scheme 15A. However, this route has the Achilles epidemic in 2005, the global supply of Tamiflu came into
heel of requiring a starting material, shikimic acid, 98, which is question due to the limited available quantities of 98. While
not readily available for manufacturing scale production. A Corey’s alternative strategy27 reported in 2006, depicted in
number of subtle features, which are generally overlooked, Scheme 15B is less efficient in terms of overall yield (22%), the
become major players in the chemistry of drug production. greater availability of the starting materials makes this route
Thus, as with most process routes to medicinal agents, the more attractive. Another fantastic route reported in 2009 by
Roche process route is a masterpiece of design, engineering, Hayashi et al.27 requires only three pots from relatively cheap
and execution. materials to afford the target in 57% overall yield. However

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Scheme 15 Addressing the supply problem of Tamiflu (110).

within the context of process chemistry, the use of an acyl natural product, 115. While the details of the one-pot trans-
azide, 109, detracts somewhat from this otherwise brilliant formation have not yet been published, the two-pot procedure
approach, as these are potentially dangerous intermediates. proceeds with excellent regio-, chemo-, and diastereoselectivity
Both of the syntheses in Schemes 15B and 15C have the clear (74% overall). The use of an isohypsic cascade with no
advantage over Scheme 15A, as they are not limited by the refunctionalisations necessary resulted in a highly efficient
availability of the starting materials. Several syntheses of increase in molecular complexity.29
Tamiflu have recently emerged and a very insightful review
of their relative merits has been published.28
Suggested further reading
Perovskone (Majetich)
As the purpose of this review is to highlight the various aspects
In a total synthesis of perovskone (115), Majetich demon- of the economies of synthesis in action, it cannot possibly be
strates atom, step and redox economy with a spectacular comprehensive. The interested reader can find several fine
biomimetic cascade (Scheme 16). After eleven steps Majetich monographs on the topic of total synthesis for more examples
obtains intermediate 111, which then undergoes a Diels–Alder that can be scrutinised through the economic ‘‘filters’’
cycloaddition with diene 112 and olefin isomerisation to arrive delineated herein. Scheme 17 features a number of other
at 113. This tetracycle then participates in an ene reaction, excellent examples of syntheses that display striking levels of
followed by two acid-catalysed etherifications to afford the step, redox, or atom economy.30–37

Scheme 16 Majetich rapidly assembles the core of perovskone.

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Scheme 17 More examples of economic total synthesis.

Conclusion D. P. O’Malley and P. S. Baran, Acc. Chem. Res., 2009, 42,

530–541.
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10 B. M. Trost, Science, 1991, 254, 1471–1477.
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