Total synthesis of taxane terpenes: Cyclase phase Dedicated to Professor Melanie S. Sanford on the occasion of her receipt of the Tetrahedron Young Investigator Award

Article abstract of DOI:10.1016/j.tet.2013.04.028

A full account of synthetic efforts toward a lowly oxidized taxane framework is presented. A non-natural taxane, dubbed 'taxadienone', was synthesized as our first entry into the taxane family of diterpenes. The final synthetic sequence illustrates a seven-step, gram-scale, and enantioselective route to this tricyclic compound in 18% overall yield. This product was then modified further to give (+)-taxadiene, the lowest oxidized member of the taxane family of natural products.

Full text of DOI:10.1016/j.tet.2013.04.028

Tetrahedron xxx (2013) 1e17
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of taxane terpenes: cyclase phase
y
y
*
Yoshihiro Ishihara , Abraham Mendoza , Phil S. Baran
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A full account of synthetic efforts toward a lowly oxidized taxane framework is presented. A non-natural
taxane, dubbed ‘taxadienone’, was synthesized as our first entry into the taxane family of diterpenes. The
final synthetic sequence illustrates a seven-step, gram-scale, and enantioselective route to this tricyclic
compound in 18% overall yield. This product was then modified further to give (þ)-taxadiene, the lowest
oxidized member of the taxane family of natural products.
Received 20 January 2013
Received in revised form 6 April 2013
Accepted 8 April 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated to Professor Melanie S. Sanford
on the occasion of her receipt of the Tetra-
hedron Young Investigator Award
Keywords:
Total synthesis
Terpene
Taxane
Taxadiene
Cyclase phase
1. Introduction
eudesmantetraol (2) most likely arise from CeH oxidation9 of 3 or
4, which in turn arise from farnesyl pyrophosphate (5). In a sim-
Taxanes represent a large family of terpenes comprising over
350 natural products, of which many exhibit cytotoxic activity
against various types of cancer and also display interesting neu-
rological and antibacterial properties.1 The most celebrated exam-
ple of these diterpenoids, from both medicinal and structural
standpoints, is TaxolÒ (1; Fig. 1).1a,d,e Its success as an anti-cancer
drug, its densely functionalized and complex structure, and its
unique mechanism of action involving the stabilization of micro-
tubules2 have fascinated medicinal chemists, synthetic chemists,
and biologists alike. While chemical synthesis seems to be no
longer needed to solve a supply problem for this particular drug,
synthetic chemistry is able to modify biologically active structures
in ways that synthetic biology cannot.3 Coupled with the oppor-
tunity to invent new methods using a complex framework, this
natural product appeared to us as an ideal target for an endeavor in
organic synthesis.4e7
ilar vein, a laboratory two-phase approach allowed for the sim-
plification of target 2 into a lowly oxidized eudesmane framework
such as dihydrojunenol (6), followed by retrosynthetic discon-
nections into simple starting materials such as methyl vinyl ke-
tone and isovaleradehyde.10 Our next objective is to target TaxolÒ
(1) while retaining the same line of logic. Since TaxolÒ (1) is one of
the most highly oxidized taxanes, a two-phase terpene synthesis
strategy that targets TaxolÒ (1) would also generate other taxanes
that are lower in oxidation level.11 The ultimate goal is to di-
vergently access as many ‘pre-TaxolÒ’ compounds as possible
(both natural and unnatural) and to learn about the innate re-
activity of the taxane framework through various CeH oxidation
strategies.
Structurally, TaxolÒ (1) and other taxanes are highly function-
alized diterpenes with a captivating 6e8e6 tricyclic skeleton and
a bridgehead olefin. It is adorned with many acetyl and benzoyl
groups, as well as a signature side chain at the C13 oxygen atom
(see carbon numbering on 1). For retrosynthetic analysis purposes,
1 is treated as if it was devoid of acyl groups and is substituted with
oxygenated hydrocarbon 7. Many oxidized taxanes have in com-
mon a C2-hydroxyl group and can be envisioned to arise from taxa-
4(5),11(12)-dien-2-one, or ‘taxadienone’ (10; quotation marks in
the text are removed hereinafter for brevity). This ketone repre-
sents a key intermediate for a comprehensive access to the taxane
A general two-phase design for the construction of terpenes
was recently formulated using eudesmane sesquiterpenes as
a proof of concept.8 In Nature, oxidized eudesmanes such as
* Corresponding author. Tel.: þ1 858 784 7373; fax: þ1 858 784 7375; e-mail
address: pbaran@scripps.edu (P.S. Baran).
y
These authors contributed equally to this manuscript.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.028
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
Fig. 1. A two-phase biosynthesis versus terpene synthesis in the eudesmane and taxane families of natural products. [O]¼oxidation.
family because it would allow for both the natural C2
a-alcohol
series and the unnatural C2 -alcohol series. Furthermore, if tax-
b
adiene (8), the least oxidized natural product1c in the taxane family,
was to be desired, one could simply deoxygenate 10. Thus, tax-
adienone (10) became the target of our cyclase phase endpoint,
which would serve as the diverging starting point toward poly-
hydroxylated taxanes. The synthesis of both taxadienone (10) and
taxadiene (8) has been reported in an earlier communication12 and
is described herein as a full account.
Fig. 2. Early retrosynthetic disconnections for taxadienone (10).
2. Results and discussion
Nicolaou’s A-ring synthesis,4c employed a trimethylated butadiene
component for their DielseAlder reactions. The most commonly
used diene fragments, along with the number of steps it takes to
make them, are shown in Fig 3A. Regarding the taxane C-ring, cy-
clohexane starting materials13 that were deemed useful are listed
in Fig. 3B.
With a collection of A-ring precursors and C-ring frameworks
ready to use, potentially useful A-ring/C-ring coupled compounds
were synthesized (Fig. 4). Many of these were generated as a mix-
ture of inseparable diastereomers (38, 40, 41, 45e48, 50), pre-
senting early problems in the designed routes. Furthermore, many
of these steps were only feasible in low yields and were not
scalable.
2.1. Initial strategies and failed approaches
Considering the wealth of chemical knowledge surrounding the
synthesis of the taxane framework,4e7 there were so many retro-
synthetic routes that could be followed toward the synthesis of
taxadienone (10). While each synthesis has its strengths and
weaknesses, we were particularly drawn to Nicolaou’s route,4c
which involved a DielseAlder reaction to set the A-ring (see ring
numbering on 1 in Fig. 1). For the C-ring, judging from the absence
of functional groups in 10, a simple cyclohexane-based starting
material was deemed best. Numerous experimental explorations
and strategy revisions then came from the synthesis of the B-ring
(Fig. 2).
Despite the drawbacks in yield and diastereoselectivity in
forming many of the compounds presented in Fig. 4, these in-
termediates were used in a number of approaches toward the B-ring,
and a snapshot of many of the evaluated strategies toward tax-
adienone (10) is illustrated in Fig. 5. For example, the known
Many other previous attempts at making the taxane skeleton
employed a DielseAlder route for the A-ring,6,7 possibly because of
its isohypsic and atom-economical nature. These studies, as well as
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
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Fig. 3. (A) Dienes that have been used in various taxane core syntheses.4c,7aes (B) Potentially useful cyclohexane starting materials to serve as the taxane C-ring.13 The reported
minimum number of steps to make these dienes and cyclohexanes are listed for comparison. Note: aDiene 12 can be made in one step from tetramethylallene and formaldehyde
using a thermal ene reaction,7a but tetramethylallene is prohibitively expensive at >$200/g (SigmaeAldrich, April 2013). bCommercially available as of April 2013.
Fig. 4. Selected examples of A-ring/C-ring coupled compounds in initial studies.
difficulties in forming the taxane skeleton4 led us to consider a ring-
closing metathesis (RCM) strategy to forge the central eight-mem-
bered ring since olefin metathesis is a robust method to synthesize
medium-sized rings (Fig. 5, disconnection A). However, the fact that
the required substrate 54 would take many steps to build and that
the stereocenters at C1 and C8 would have to be formed with two
separate enantioselective reactions dissuaded us from this route. An
aldol route was then conceived, partly because the required
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
Fig. 5. Initial synthetic investigations toward the synthesis of taxadienone (10). Disconnection A: a ring-closing metathesis (RCM) approach would require many steps to even reach
the key intermediate 54. Disconnection B: the required aldol closure from 55 simply did not proceed. Disconnection C: the required reductive aldol closure from 47 or 48 did not
proceed. Disconnection D: without a suitable dienophile (i.e., using an electronically neutral olefin), the DielseAlder reaction did not proceed under thermal or radical cation
conditions. Disconnection E: with sp2 carbons at C3 and C8, the DielseAlder reaction did not proceed even under radical cation conditions, and conjugate addition at C8 to install
the methyl unit did not proceed because only the undesired conjugate addition onto C14 occurred. Disconnection F: a Shapiro reaction with an acrolein trap, followed by oxidation
and DielseAlder reaction, would not lead to an enantioselective synthesis of 10 because the stereochemistry at C8 could not be set selectively.
diketone 55 can be easily synthesized from ketone 43 (disconnec-
tion B). However, despite a plethora of attempted experiments using
various Lewis and Brønsted acids and bases, the desired cyclization
from 55 did not proceed. Similar failures were met when attempting
Reformatsky-type cyclizations from 47 or 48 using reducing agents
such as Zn,14a,b SmI2,14c CrCl2,14d Co(PPh3)414e or Et3B14f (disconnec-
tion C). Thereafter, closure of the AB ring by a DielseAlder reaction
was envisioned. While allylated ketone 50 does not contain a suit-
able dienophile for a normal-demand DielseAlder reaction, it was
Fig. 6. A scalable 1,6-addition reaction resulting in a compound bearing both an A-ring
precursor and a C-ring, which then became the focal point of this research project.
hoped that a proximity-induced DielseAlder reaction15 of an elec-
tronically neutral dienophile would take place (disconnection D).
However, thermal conditions or radical cation conditions using tri-
arylamine hexachloroantimonate16 did not allow closure of the B-
2.2. Revised strategy and further failures, followed by com-
pletion of racemic taxadienone (10)
ring. In a similar vein, DielseAlder reaction of substrates 52 and 53
was attempted under thermal or radical-based conditions (discon-
nection E). These intermediates did not undergo [4þ2] cyclization,
likely due to the conformation engendered by the sp2 carbons at C3
and C8. Furthermore, a methyl 1,4-addition at C8 was not possible,
since reaction first occurred at the less hindered C14, even with
a large tert-butyldiphenylsilyl group appended at C14. Lastly, ketone
41 was considered a viable intermediate toward the formation of
taxadienone (10), since a Shapiro reaction with acrolein trap, oxi-
dation, and DielseAlder reaction could potentially form an isomer of
10 (disconnection F). However, ketone 41 already required six steps
to construct (see Fig. 4), and the stereocenter at C8 was thought to be
challenging to control despite existing methods in asymmetric
enolate alkylation.17
During these initial studies, a convenient 1,6-addition of diene
11 onto known vinylcyclohexenone 5618 was found to take place in
good (72%) yield on gram-scale (resulting in 1.7 g of product in one
run), resulting in a dieneecyclohexane coupled compound (42)
that was previously only feasible in six steps (Fig. 6). This reaction
was initially optimized using BF3$OEt2, but was later optimized
with TMSCl (vide infra). As the objective of this research project
was a scalable and enantioselective synthesis of the taxane skele-
ton, this reaction was highly suitable unlike many of the reactions
shown in Fig. 4. Efforts hereafter were therefore focused around
enone 42.
With many grams of enone 42 in hand, the synthetic route was
then revised and centered around a single strategy: methylation of
the cyclohexenone, followed by a three-carbon appendage and
a key DielseAlder reaction (Fig. 7). The first methylation step was
restricted to two methods, a methyl 1,4-addition19 or a cyclo-
propanation,20 because these reactions were the most likely to be
amenable to enantioselective synthesis. From transient in-
termediate 58, a three-carbon appendage could then take place via
an SN2 onto an allyl halide or via a 1,2-addition onto acrolein or an
acryloyl halide. This three-carbon unit would then have to be oxi-
dized accordingly, by CeH activation or otherwise, to furnish the
ketone oxidation state in 60. Finally, the key DielseAlder reaction
from 60 to 61 had good literature precedent through the work of
Jenkins7u and Williams6,21 whose intermediates only differed from
60 at the C4 position. The advantage of this sequence over many
other possible routes was that the asymmetric construction of the
6e8e6 tricyclic skeleton would only rely on one enantioselective
reaction, after which the resulting stereochemical information
could be propagated to set all the other stereocenters
diastereoselectively.
Based on this plan, the most efficient synthesis of 60 from 42
would be a one-step reaction: a methyl conjugate addition followed
by trapping with an acryloyl halide. While the methyl 1,4-addition
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
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Fig. 7. Revised strategy for the synthesis of the taxane tricyclic framework. [O]¼oxidation, [H]¼reduction.
Fig. 8. Limited utility of kinetic enolate 58, rearrangement to thermodynamic enolate 62, and failure to allylate at C3.
step proceeded smoothly and was quenched with acid to give 43 or
trapped with TMSCl to give 44, it could not be trapped with a three-
carbon unit to give 50, 59 or 60; only ketone 43 would result
(Fig. 8). In fact, intermediate 58 was completely unreactive at C3
toward carbon-based electrophiles; while it could be trapped with
deuterium oxide or halonium ions at C3 (e.g., to form 45 and 46 in
Fig. 4), it would only give C5-allylated product 63 and a small
amount of C5-bis-allylated product 64 when forced to react with
allyl iodide. This most likely occurs because kinetic enolate 58
rearranges to thermodynamic enolate 62 at ‘high’ temperatures
(>4 ꢀC), and because the C5 position is less hindered than the C3
position, thus reacting more easily.
Lewis acidic conditions, only to return 44 or result in hydrolyzed
ketone 43 (Fig. 10). Thinking that perhaps the lability of the tri-
methylsilyl group in 44 is the root of the problem in the failure of
Mukaiyama-type reactions, a more robust TBS enol ether 65 was
synthesized and subjected to the same set of Lewis acidic condi-
tions. The only outcome was that the reaction of 65 was much
slower than that of 44; when submitted to a larger amount of Lewis
acid for a longer period of time, 65 resulted in ketone 43 as well.
Believing that trace amounts of water were hydrolyzing 44, 58, and
65 whenever a reaction was run, water was excluded with utmost
rigor but 43 would always form.
The only successful albeit inefficient and stereochemically non-
selective way to place an allyl group onto the C3 position to make
50 was via Pd-catalyzed methods (see Fig. 4, 44 to 50). However,
not only did the DielseAlder cyclization of 50 not occur (see Fig. 5),
but allylic CeH oxidation also did not proceed, only resulting in
decomposed material likely due to the lability of the diene moiety
(Fig. 9). This result demanded that the revised strategy in Fig. 7
avoid the formation of 50, and go through 59 or 60 instead.
In order to synthesize 59 or 60, much effort was spent on trying
to functionalize kinetic enolate 58. Since 58 must be stored in the
fridge or freezer and is not stable for much longer than a day, TMS
enol ether 44 was stored in large batches to serve as a direct sur-
rogate for 58. Both 44 and 58 were reacted with acrolein, acryloyl
chloride, and benzaldehyde (as a test substrate) under a variety of
Fig. 9. Failure to oxidize allylated ketone 50 at the C2 position via allylic CeH oxidation
methods.
With many failures en route to the taxane framework, the one
compound that never failed to form was hydrolyzed ketone 43. The
accumulation of this compound in this project prompted an at-
tempt at regenerating the potentially useful TMS enol ether 44.
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
cyclopropane epoxide 70, which results from over-methylenation;
since the less reactive ketone moiety seemingly competes with
the enone olefin for reaction with the CoreyeChaykovsky reagent,
this suggests that access to the sterically hindered C3eC8 olefin is
difficult. As for a three-carbon appendage onto ketone 57, it was
hoped that the increased s-character of the CeH bond in a cyclo-
propane would aid in deprotonation and functionalization.22
However, treatment with an unhindered strong base only led to
C5 deprotonation and functionalization, resulting in 73 and 74 upon
allylation and 75 upon acrolein addition (Fig. 12C).
With the cyclopropane strategy now also a dead-end, it was
again time to reevaluate all the synthesis routes that had been
examined and to revisit failed reactions that seemingly should have
worked. Since the synthesis plan laid out in Fig. 7 was still very
attractive, we analyzed every failed reaction and concluded that the
reaction that should have worked is the aldol reaction of 44 with
acrolein to give aldol product 59. While we had always assumed
that the hydrolysis of TMS enol ether 44 to ketone 43 involved
water, this time we asked ourselves the question: what would
happen if we deliberately added water? Perhaps 44 actually reacts
with acrolein to give 59 but suffers a fast retro-aldol reaction, whose
rate can be slowed down by the addition of water? Thus, a bold
move was made to include water in the reaction conditions, this
time employing aldol conditions that only works well with water23
(Fig. 13). This reaction of 44 to 59, to our surprise and delight,
resulted in an extension of three carbons at C3 while retaining
a functional group at C2. This represented a turning point in this
project, as all the ‘dead ends and detours’ seemed to finally give
way to a successful total synthesis.24
With aldol product 59 in hand, a first-generation synthesis of
racemic taxadienone (10) was not far out of reach (Fig. 14). Oxida-
tion of the allylic alcohol under Swern conditions gave uncyclized
diketone 60, which was an inseparable mixture of diastereomers at
C3 (dr w3:2). Hoping that a Lewis acidic reaction would funnel both
isomers of this mixture toward the desired diastereomer, the key
DielseAlder cyclization to 61 was accomplished using previously
described acidic conditions,6,7f,u,21 generating a 6e8e6 tricyclic
framework for the first time in this project. Although the reaction
yield was low and the diastereomeric ratio did not appear to im-
prove during the cyclization, 61 was carried onward, with optimi-
zations performed at a later time (vide infra).
Fig. 10. Failure to functionalize the C3 position of 44, 58, and 65 using acrolein,
acryloyl chloride or benzaldehyde.
However, ketone 43, while bearing a carbonyl group at C4, would
not allow selective functionalization at C3 because it would always
deprotonate at C5 first. For example, generation of a TMS enol ether
from 43 resulted in
greater than 10:1 over the desired
D
4,5 enol ether 66, with a diastereoselectivity of
D
3,4 enol ether 44: unfortunately,
66 and 44 were inseparable and therefore this attempt at material
recovery proved to be fruitless (Fig. 11). Another try at making use
of ketone 43 was the formation of enone 67, to possibly allow for
C3-deprotonation. While the formation of 67 was possible through
IBX oxidation of 43 or ItoeSaegusa oxidation of 66, the resulting
enone could not be deprotonated and functionalized at C3.
Although diketone 61 appears to have two reactive carbonyl
groups, the C2 carbonyl is quite hindered due to the nearby gem-
dimethyl group, and thus addition of MeMgBr onto 61 in PhMe
occurred selectively at the C4 position to give 76 as a single di-
astereomer. It is of note that this reaction does not occur when
conducted in THF or in Et2O. Finally, keto-alcohol 76 was dehy-
drated using Burgess reagent or Martin sulfurane to give the de-
sired taxadienone (10) as a major product and its isomer exo-
taxadienone (77) as a significant but still a minor product. Most
fortunately, taxadienone (10) turned out to be crystalline, and an X-
ray structure confirmed the connectivity and relative stereochem-
istry of the molecule.
Fig. 11. Attempting to make use of hydrolyzed ketone 43: synthesis of a TMS enol ether
from 43 resulting primarily in D4,5 enol ether 66, as well as formation of enone 67.
Due to the accumulated failures when using intermediates 44
and 58, a methyl conjugate addition strategy was temporarily sus-
pended and a plan to synthesize cyclopropane 57 was put into ac-
tion instead (Fig. 12A). The goal here was to append a three-carbon
unit to the cyclopropane C3 position to make 68 and open the cy-
clopropane thereafter. After all, this method of introducing the C19
methyl group was featured in Kuwajima’s successful syntheses of
taxusin (8)5b,c and TaxolÒ(1).4n,o While Kuwajima performed
a SimmonseSmith cyclopropanation on an allylic alcohol substrate,
an enone moiety was present in 42 and thus a CoreyeChaykovsky
cyclopropanation was carried out (Fig. 12B). As a result, cyclo-
propanated ketone 57 did form in low yield (w30%), but it was
accompanied by side products 69, 71, and 72 (in a combined yield of
w30%). Aldehyde 71 and allylic alcohol 72 most likely arise from
Although each step in this reaction sequence was modest at
best, a first-generation synthesis of the taxane framework was
now complete (Fig. 15). Many more hurdles remained, however, to
reach our goal of a scalable and enantioselective synthesis of
taxadienone (10). Possible areas of improvement are noted, in-
cluding the known two-step synthesis from 78 to 11 that could be
t
shortened, the use of pyrophoric BuLi, the asymmetry-inducing
step, the use of toxic HMPA, the two-step synthesis from 44 to
60 that could be shortened and rendered scalable, the low di-
astereomeric ratio when forming 60, the low yield and scalability
of the DielseAlder cyclization step, and the two-step synthesis
from 61 to 10 that could be shortened, rendered scalable, and
made regioselective.
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
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Fig. 12. (A) A cyclopropanation strategy that was (B) inefficient during the cyclopropane synthesis step and that (C) failed at cyclopropane C3 functionalization.
2.3. Enantioselective route to taxadienone (10), total synthe-
sis of taxadiene (8), and reaction optimizations from the
vantage point of scalability
One of the advantages of the first route to taxadienone (10)
described in Fig. 15 is that only one asymmetric reaction would be
needed to generate enantiomerically enriched taxadienone (10);
another is that the C8 stereocenter, once formed, is not epimeriz-
able. Although asymmetric conjugate additions using alkyl nucle-
ophiles are well-known,19 early developments only involved the
formation of chiral tertiary carbon centers from disubstituted
enones.19aee Only recently (since 2005) has there been a method-
ology that allows for the construction of chiral quaternary stereo-
centers, with only two major research groups studying the addition
Fig. 13. The elusive aldol reaction at C3, requiring the unexpected additive: water.
of methyl nucleophiles, those of Alexakis19feh and Hoveyda.19iek
A
decision was then made to employ Alexakis’ chemistry simply
based on the ease of preparation of both enantiomeric series of the
chiral catalyst.19h
The plan was then to test the enantioselectivity and absolute
configuration of the asymmetric addition at three stages (Fig. 16):
(1) after generation of the first achiral intermediate 44, hydrolysis
would form an enantioenriched sample of 43 that could be tested
against the previously synthesized racemic 43, using chiral HPLC to
obtain the enantiomeric ratio; (2) enantioenriched 44 could then
be elaborated onto taxadienone (10), for which an attempt could be
made at determining the absolute configuration using X-ray crys-
tallography despite the absence of heavy atoms;25 (3) enantioen-
riched taxadiene (8) could be synthesized from 10 and the sign of
the optical rotation could be compared to that of the bioengineered
sample of 8 (which was found to be of positive optical rotation).26
Fig. 14. Completion of racemic taxadienone (10).
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
Fig. 15. A summary of the nine-step, first-generation racemic synthesis of taxadienone (10), with possible areas of improvement marked with *.
Fig. 16. Plan of action for testing the enantioselectivity and absolute configuration of the asymmetric addition step. Note: the desired enantiomeric series of products are displayed.
The absolute configuration of the asymmetric synthesis needed to
be verified at two distinct stages because taxadiene (8), while being
a natural product,1c was never isolated in large enough amounts for
sufficient purification and analysis, and thus its optical rotation had
never been recorded.
crystallographic analysis resulted in a small enough uncertainty in
the Flack parameter to allow for absolute configuration de-
termination;25 however, (ꢁ)-61 turned out to have the wrong
configuration. For further verification, (ꢁ)-61 was elaborated into
(ꢁ)-10, whereby determination of the absolute configuration by X-
ray analysis again established the wrong configuration of this
molecule. Having enough confidence after these two assignments,
the correct enantiomeric series was then targeted, using chiral
catalyst (þ)-79.
At the outset, one enantiomer of chiral ligand 79 was chosen at
random, and it was decided that studies would be conducted on
(ꢁ)-79. The first asymmetric reaction that was performed using
Alexakis’ conditions (2 equiv Me3Al, 5 mol % CuTC, 10 mol % (ꢁ)-79,
Et2O, ꢁ30 ꢀC, 18 h)19h was successful, resulting in 88% yield and 93%
ee of (ꢁ)-43 (Fig. 17). However, since Alexakis was unsuccessful in
trapping the enolate intermediate with a silyl group,19h the syn-
thesis and isolation of 44 indeed proved to be difficult. After some
experimentation, it was found that the enolate intermediate after
the conjugate addition can be silylated after dilution with THF then
adding TMSCl and Et3N, and that (þ)-44 can be isolated after high
dilution with hexanes and quenching with basic alumina. After
three steps from (þ)-44, diketone (ꢁ)-61 was obtained; un-
expectedly, this compound was found to crystallize on one occasion
and thus an X-ray structure was obtained. A high-precision X-ray
Restarting the synthesis with (þ)-79, TMS enol ether (ꢁ)-44 was
formed, from which (þ)-43, (þ)-61, and (þ)-10 were generated (i.e.,
Fig. 17 but with all the stereocenters inverted). While (þ)-61 could
not be crystallized on this occasion, (þ)-10 reproducibly yielded
crystals (from Et2O/MeOH) and the absolute configuration was
confirmed to be the desired one by X-ray crystallography (see
Fig. 18). However, another method of confirmation of absolute
configuration was still desired. To this end, deoxygenation studies
were conducted on (þ)-10 to generate taxadiene (8), which was
used to verify that the synthetic route also generated a sample with
a positive optical rotation.26
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
9
Fig. 17. Synthesis of (þ)-44, (ꢁ)-43, (ꢁ)-61, and (ꢁ)-10, with X-ray structures of the latter two compounds displaying the wrong absolute configuration.
Fig. 18. X-ray structure of enantiomerically enriched (þ)-taxadienone (10) with the correct absolute configuration and deoxygenation from (þ)-taxadienone (10) to taxadiene (8).
The final stages of the synthesis of a natural taxane, taxadiene
(8), were not simple: classic methods of ketone deoxygenation such
as Clemmensen and WolffeKishner reductions failed (including
methodology in recent reports such as Myers’ method27), largely
due to the failure of forming the requisite hydrazone (Fig. 18). The
led to taxadiene (8) was the acetylationeNa/tBuOH/HMPA strat-
egy.28b Thus, (þ)-80 was treated with KH and AcCl in refluxing THF
(reactions using Ac2O did not work, and KH led to a faster reaction
than KHMDS or NaH) to give (þ)-82, and Na/tBuOH/HMPA in Et2O
led to taxadiene (8). While this synthetic sample of taxadiene (8)
was found to have an optical rotation of þ170ꢀ, that of the bio-
engineered sample26 was þ135ꢀ. Despite the discrepancy in the
absolute value of these optical rotations,12 the sign of the optical
rotation of these two samples matched, thereby lending further
support for the use of ligand (þ)-79 to synthesize the correct en-
antiomeric series of the taxane skeleton.
With the enantioselective synthesis of taxadienone (10) and
taxadiene (8) now complete, it was time to revisit the entire syn-
thesis from the vantage point of reaction scalability (Fig.19). Almost
every single step of this sequence was optimized, on one occasion
even resulting in a different synthetic intermediate than what was
originally carried out. As a result, the nine-step synthesis of tax-
adienone (10) was reduced to a seven-step sequence, with the
overall yield increasing from 1.5% to 18%. Extensive optimizations of
all reactions (except for the reaction from 28 to 5618) from the
starting alkene 78 to enantiomerically enriched (þ)-taxadienone
(10) are shown in Fig. 20.
C2 carbonyl group is quite hindered at the
b face due to the C16 and
C19 methyl groups, which can be seen in the X-ray structure of
(þ)-10. This effect had also been observed in the inertness of the C2
carbonyl to undergo attack by a Grignard reagent in diketone 61
(see Fig. 14). It is therefore difficult for any functional group to leave
from the
(10) at its
face, and as this is too energetically prohibited, the hydrazinohy-
drin intermediate expels hydrazine back from the face to simply
b
face as well: even if hydrazine could attack taxadienone
a
face, a molecule of water needs to depart from the
b
-
a
return the starting material 10. Thus, we resorted to a three-step
deoxygenation procedure. LiAlH4 reduction of (þ)-10 proceeded
smoothly to give (þ)-80, and xanthate formation, while requiring
the use of KOtBu as base, occurred in moderate yield to give xan-
thate (þ)-81. However, standard BartoneMcCombie deoxygenation
never provided the desired taxadiene (8; for which authentic NMR
spectra were available),1c,6 as evidenced by NMR analysis of the
crude product. At this juncture, unusual deoxygenation methods
were attempted: acetylation followed by Li/EtNH2,28a K/tBuNH2,28a
or Na/HMPA;28b SO3/pyridine followed by NaH/LiAlH4;28c and
Ph2SiHCl/InCl3.28d Out of these methods, the one that eventually
While the contents of Fig. 20 will not be reiterated, it is im-
portant to note that these optimization efforts have resulted in an
enantioselective and scalable synthesis of a laboratory cyclase
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10
Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
Fig. 19. The nine-step, first-generation racemic synthesis of taxadienone (10; shown in black) as well as its seven-step, second-generation enantioselective synthesis (shown in blue).
Fig. 20. Optimization of most of the steps in the enantioselective synthesis of (þ)-taxadienone (10), resulting in more efficient reaction conditions and even going through
a different synthetic intermediate.29
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
11
Fig. 20. (continued)
phase endpoint that enables future efforts to elaborate the taxane
pyramid. In summary, the synthesis of enantiomerically enriched
(þ)-taxadienone (10) was achieved in a total of eight steps, with
a longest linear sequence of seven steps. A few grams of (þ)-10
could be synthesized by one chemist over the course of seven days,
with an overall yield of 18% from 78 or 20% from 28. Furthermore,
the last three steps leading to enantiomerically enriched (þ)-tax-
adiene (8) were also carried out on gram-scale, providing a scalable
access to Nature’s cyclase phase endpoint1c as well (Fig. 21). It is of
note that this 10-step synthesis of (þ)-taxadiene (8) compares fa-
vorably with the only total synthesis of (ꢂ)-8 thus far, in 26 steps,
back in 1995.6
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12
Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
where enzymes can oxidize substrates virtually anywhere they
want (for the assumed order of CeH oxidation on the taxane
skeleton in Nature,31 see 8), long-range CeH oxidations are very
limited in the laboratory. Furthermore, taxadienone (10) has an
oxygen atom at C2, which is strategic because in principle, it would
allow for the generation of a series of natural taxanes with a C2
hydroxyl group (89) and a series of unnatural taxanes with a C2
hydroxyl group (90) for medicinal chemistry research (Fig. 24).
a
b
-
-
Fig. 21. Gram-scale synthesis of (þ)-taxadiene (8) from (þ)-taxadienone (10).
A dauntingly complex, yet intriguing system on which to im-
plement the two-phase strategy is that of the taxanes, and the value
of this project lies in building upon the formidable efforts of other
researchers that have spearheaded Csp3 eH oxidation strategies.11
Ultimately, we hope that future endeavors in pursuing a two-
phase terpene total synthesis (on taxanes or on other terpene
families) will aid in identifying gaps in current methodology and
provide numerous opportunities for invention. Our laboratory is
currently proceeding onward with the taxane oxidase phase and
these studies will be reported in due course.
3. Conclusion, strategic perspective, and future outlook
The efficiency with which the synthesis of (þ)-taxadienone (10)
was completed is partly due to the low oxidation state of the target,
which was an intended objective of this study (Fig. 22). With only
one heteroatom present in target 10, protecting group chemistry
was minimized,30 side reactions were reduced, and the use of
versatile but harsh organometallic reagents was enabled. The
generation of ample quantities of this tricyclic terpene should en-
able subsequent use as a starting material in a creative exploration
of CeH oxidation chemistry.
4. Experimental section
4.1. General
All reactions were carried out under an inert nitrogen atmo-
sphere with dry solvents under anhydrous conditions unless oth-
erwise stated. Dry acetonitrile (MeCN), dichloromethane (DCM),
diethyl ether (Et2O), tetrahydrofuran (THF), toluene (PhMe), and
triethylamine (Et3N) were obtained by passing the previously
degassed solvents through activated alumina columns. Reagents
were purchased at the highest commercial quality and used with-
out further purification, unless otherwise stated. Yields refer to
chromatographically and spectroscopically (1H NMR) homoge-
neous material, unless otherwise stated. Reactions were monitored
by thin layer chromatography (TLC) carried out on 0.25 mm E.
Merck silica plates (60F-254), using UV light as the visualizing
agent and an acidic solution of p-anisaldehyde and heat, ceric
ammonium molybdate and heat, or KMnO4 and heat as developing
Fig. 22. Summary of the taxane cyclase phase.
With the completion of a successful cyclase phase in the labo-
ratory, an oxidase phase can then be planned based on oxidations of
olefins and CeH bonds. In this project, one functional group has
been placed strategically on each of the A, B, and C rings of the
taxane skeleton in taxadienone (10)done heteroatom and two
olefinsdto propagate oxidative information in the most efficient
manner (Fig. 23). This was designed because unlike in Nature,
Fig. 23. Nature’s presumed oxidation sequence31 from taxadiene (8) and a planned propagation of oxidative information from the three functional groups of taxadienone (10). [O]¼
oxidation.
Fig. 24. Strategic advantage of having an over-oxidized functional group at C2: generating a series of natural and unnatural taxanes. [O]¼oxidation.
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Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
13
agents. Flash silica gel chromatography was performed using E.
Merck silica gel (60, particle size 0.043e0.063 mm), flash alumina
chromatography was performed using Brockmann Grade 1 alumi-
2H), 4.88 (dq, J¼2.9, 1.5 Hz, 1H), 4.51 (dq, J¼2.7, 0.9 Hz, 1H), 2.48
(dddt, J¼14.7, 6.7, 5.5, 1.4 Hz, 1H), 2.32e2.22 (m, 1H), 2.22 (dd,
J¼13.2, 2.0 Hz, 1H), 2.15 (dd, J¼13.0, 0.8 Hz, 1H), 2.06e1.86 (m, 4H),
1.77e1.69 (m, 1H), 1.73 (dd, J¼1.4, 0.9 Hz, 3H), 1.63 (s, 3H), 1.63 (s,
3H), 1.59e1.41 (m, 2H), 1.17 (m, 2H), 0.99 (s, 3H) ppm. 13C NMR
ꢀ
num oxide (activated, basic, 58 A, 60 mesh powder), and flash
FlorisilÒ chromatography was conducted using Acros magnesium
silicate (activated, 60e100 mesh). Chiral HPLC was performed using
a Hitachi LaChrom Elite HPLC system. NMR spectra were recorded
on Bruker DRX-600 and AMX-400 instruments and were calibrated
using residual undeuterated solvent as an internal reference (CHCl3
at 7.26 ppm 1H NMR, 77.2 ppm 13C NMR). The following abbrevi-
ations were used to explain NMR peak multiplicities: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad. High-
resolution mass spectra (HRMS) were recorded on an Agilent LC/
MSD TOF mass spectrometer by electrospray ionization time-of-
flight (ESI-TOF) reflectron experiments. IR experiments were
recorded on a PerkineElmer Spectrum 100 FT-IR spectrometer.
Optical rotations were obtained on a PerkineElmer 341 polarime-
ter. Melting points were recorded on a Fisher-Johns 12-144 melting
point apparatus and are uncorrected.
(151 MHz, CDCl3):
54.0, 49.2, 39.2, 36.3, 35.4, 33.8, 28.3, 27.5, 25.1, 22.9, 21.9, 19.6 ppm.
IR (neat):
¼3075, 2928, 2855, 1709, 1640, 1459, 1444, 1373, 1283,
d 212.3, 146.5, 136.5, 136.3, 125.2, 116.4, 113.3,
n
1228, 1193, 1075, 999, 909, 893 cmꢁ1. HRMS (ESI-TOF): calcd for
C
19H30O [MþHþ] 275.2369, found 275.2374.
4.2.1.3. Data for (ꢂ)-64. Appearance: slightly yellow oil. TLC:
Rf¼0.77e0.79 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3):
d
5.76e5.56 (m, 2H), 5.10e5.00 (m, 4H), 4.90 (dq, J¼2.9,
1.4 Hz, 1H), 4.53 (dq, J¼2.7, 0.9 Hz, 1H), 2.38e2.23 (m, 4H), 2.24 (d,
J¼14.0 Hz, 1H), 2.14 (dd, J¼14.0, 1.2 Hz, 1H), 2.00 (m, 2H), 1.74 (dd,
J¼1.4, 0.9 Hz, 3H), 1.73e1.66 (m, 3H), 1.65 (s, 3H), 1.64 (s, 3H),
1.28e1.18 (m, 3H), 0.90 (s, 3H) ppm. 13C NMR (151 MHz, CDCl3):
d
214.2, 146.5, 136.3, 133.9, 133.7, 125.2, 118.3, 118.3, 113.3, 51.2, 50.6,
40.0, 39.7, 39.6, 38.7, 31.9, 31.4, 25.1, 25.1, 22.9, 21.9, 19.6 ppm. IR
4.2. Experimental procedures and data of synthetic
intermediates
(neat):
n
¼3075, 2925, 2857,1703,1638,1444,1372,1328,1286,1201,
1160, 1082, 993, 910, 893 cmꢁ1. HRMS (ESI-TOF): calcd for C22H34
O
[MþHþ] 315.2682, found 315.2689.
Note: Procedures and data for bromodiene 11, vinyl-
cyclohexenone 56, enone 42, TMS enol ether 44, ketone 43, aldol
product 59, uncyclized diketone 60, cyclized diketone 61, di-
astereomeric diketone 86, enol triflate 87, taxadienone (10), tax-
adienol 80, acetoxytaxadiene 82, and taxadiene (8) have been
reported in the Supplementary data of Ref. 12 and will not be re-
iterated below.
4.2.2. TBS enol ether 65. To a flame-dried 20 mL microwave vial
equipped with a stir bar was added TMS enol ether (ꢂ)-44
(65.0 mg, 0.212 mmol, 1.00 equiv) in THF (3 mL) and cooled to 0 ꢀC.
A solution of MeLi in Et2O (1.6 M; 150 mL, 0.24 mmol,1.13 equiv) was
added dropwise and this mixture was stirred at 0 ꢀC for 1 h. A so-
lution of freshly distilled TBSCl (distilled over CaH2; 200.0 mg,
1.327 mmol, 6.26 equiv) in THF (3 mL) was added and this reaction
mixture was stirred at 0 ꢀC for 1 h. The reaction was quenched at
4.2.1. C5-Allylated ketone 63 and bis-allylated ketone 64. To a flame-
dried 10 mL microwave vial equipped with a stir bar was added TMS
0
ꢀC with 1:1 MeOH/Et3N (3 mL), diluted with H2O (5 mL), and
enol ether (ꢂ)-44 (31.4 mg, 0.102 mmol, 1.00 equiv) in THF (500
m
m
L)
L,
extracted with EtOAc (3ꢃ7 mL). The combined organic layers were
washed with H2O (10 mL) then brine (10 mL), dried over Na2SO4,
and then evaporated to dryness in vacuo. Although TMS enol ether
44 is unstable on silica gel, TBS enol ether 120 is stable and can be
purified by silica gel. Thus, purification by silica gel flash chroma-
tography (hexanes) yielded (ꢂ)-65 (40.7 mg, 55% yield). Appear-
ance: colorless oil. TLC: Rf¼0.37e0.40 (silica gel, hexanes). 1H NMR
and cooled to 0 ꢀC. A solution of MeLi in Et2O (1.6 M; 70
0.112 mmol, 1.10 equiv) was added dropwise and this mixture was
stirred at 0 ꢀC for 1 h. A solution of freshly prepared allyl iodide
(40 mL, 0.437 mmol, 4.29 equiv) in THF (400 mL) was added and this
reaction mixture was warmed to room temperature overnight. The
reactionwas quenched with saturated aqueous NH4Cl (1 mL), diluted
with H2O (3 mL), and extracted with EtOAc (3ꢃ3 mL). The combined
organic layers were washed with H2O (5 mL) then brine (5 mL), dried
over MgSO4, and then evaporated to dryness in vacuo. Purification by
silica gel flash chromatography (gradient of EtOAc/hexanes) yielded
three separate compounds (in order of decreasing Rf), (ꢂ)-64 (3.0 mg,
9% yield), (ꢂ)-63a (8.5 mg, 30% yield), and (ꢂ)-63b (11.5 mg, 39%
yield). While 63a and 63b are C5-epimers of one another, the relative
stereochemistry at C5 for 63a and 63b is unknown.
(400 MHz, CDCl3):
d
4.89 (dq, J¼2.9 and 1.4 Hz,1H), 4.66 (s,1H), 4.53
(dq, J¼2.7, 0.9 Hz, 1H), 2.02 (m, 2H), 1.95 (m, 2H), 1.75 (dd, J¼1.4,
0.9 Hz, 3H), 1.67 (m, 2H), 1.66 (s, 6H), 1.42 (m, 1H), 1.35e1.20 (m,
3H), 0.96 (s, 3H), 0.92 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H) ppm. 13C NMR
(151 MHz, CDCl3):
d 149.7, 146.9, 137.3, 124.5, 114.4, 112.9, 42.0, 34.7
(two carbons), 30.1, 28.0, 26.2, 25.9, 23.0, 21.9, 19.8, 19.6, 18.2, e4.1,
ꢁ4.3 ppm. IR (neat): ¼3074, 2933, 2866, 1660, 1444, 1366, 1263,
n
1250, 1203, 1137, 963, 938, 894, 840, 752 cmꢁ1. HRMS (ESI-TOF):
calcd for C22H40OSi [MþHþ] 349.2921, found 349.2924.
4.2.1.1. Data for (ꢂ)-63a. Appearance: slightly yellow oil. TLC:
Rf¼0.74e0.77 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
4.2.3.
D
4,5-TMS enol ether 66 (>90% pure, contains some 44). To
CDCl3):
d
5.78 (dddd, J¼17.0, 10.1, 7.8, 6.4 Hz, 1H), 5.06e4.96 (m,
a flame-dried 10 mL microwave vial equipped with a stir bar was
2H), 4.91 (dq, J¼3.0, 1.5 Hz, 1H), 4.53 (dq, J¼2.7, 0.8 Hz, 1H), 2.52
(dddt, J¼14.4, 6.7, 5.4, 1.4 Hz, 1H), 2.34e2.24 (m, 1H), 2.22 (d,
J¼12.8 Hz, 1H), 2.12 (dd, J¼12.8, 1.6 Hz, 1H), 2.08e1.93 (m, 4H), 1.75
(dd, J¼1.5, 0.9 Hz, 3H), 1.65 (s, 3H), 1.65 (s, 3H), 1.64e1.58 (m, 2H),
1.48 (m, 1H), 1.32 (m, 2H), 0.85 (s, 3H) ppm. 13C NMR (151 MHz,
added lithium diethylamide (2.0 M, synthesized by adding nBuLi to
diethylamine; 250
m
L, 0.500 mmol, 1.52 equiv) and this was cooled
to 0 ꢀC. Freshly distilled TMSCl (distilled over CaH2; 200
mL,
1.58 mmol, 4.80 equiv) was added, followed by a solution of ketone
(ꢂ)-43 (77.0 mg, 0.329 mmol, 1.0 equiv) in THF (1 mL). The reaction
mixture was stirred at 0 ꢀC for 30 min and then warmed to room
temperature over 1 h. It was then cooled to 0 ꢀC, 1:1 MeOH/Et3N
(1 mL) was added, and this reaction mixture was warmed to room
temperature over 1 h. The reaction mixture was diluted with H2O
(3 mL) and extracted with EtOAc (3ꢃ2 mL). The combined organic
layers were washed with H2O (4 mL) then brine (4 mL), dried over
Na2SO4, and then evaporated to dryness in vacuo. Purification by
Et3N-treated silica gel chromatography (2% Et3N in hexanes) yiel-
ded >90% pure (ꢂ)-66 with <10% of (ꢂ)-44 (combined: 69.0 mg,
CDCl3):
d 212.5, 146.5, 136.6, 136.4, 125.1, 116.4, 113.3, 53.5, 49.6,
43.0, 39.7, 36.1, 33.7, 28.9, 25.2, 22.9, 22.8, 21.9, 19.6 ppm. IR (neat):
n
¼3075, 2915, 2854, 1710, 1640, 1443, 1380, 1371, 1285, 1201, 1190,
1072, 993, 910, 893 cmꢁ1. HRMS (ESI-TOF): calcd for C19H30
O
[MþHþ] 275.2369, found 275.2367.
4.2.1.2. Data for (ꢂ)-63b. Appearance: slightly yellow oil. TLC:
Rf¼0.71e0.74 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3):
d
5.76 (dddd, J¼16.8, 10.1, 7.6, 6.5 Hz, 1H), 5.06e4.96 (m,
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14
Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
57% yield), along with recovered (ꢂ)-43 (27.2 mg, 35% yield). Ap-
pearance: colorless oil. TLC: Rf¼0.00e0.20 (silica gel, hexanes,
streaks due to decomposition when without Et3N). 1H NMR
146.3, 135.9, 125.4, 113.4, 37.8, 36.3, 33.8, 28.6, 27.9, 25.6, 22.8, 21.8,
19.6, 18.4, 17.4 ppm. IR (neat):
n
¼3074, 2914, 2855, 1688, 1631, 1444,
1372, 1323, 1243, 1216, 1170, 1076, 935, 891, 871 cmꢁ1. HRMS (ESI-
(400 MHz, CDCl3):
d
4.89 (dq, J¼2.9, 1.5 Hz, 1H), 4.82 (tt, J¼3.7,
TOF): calcd for C16H24O [MþHþ] 233.1900, found 233.1904.
1.3 Hz, 1H), 4.53 (dq, J¼2.7, 1.0 Hz, 1H), 2.08e1.98 (m, 4H), 1.86 (m,
1H),1.75 (dd, J¼1.5,1.0 Hz, 3H),1.70 (m,1H),1.66 (s, 3H),1.65 (s, 3H),
1.27 (m, 4H), 0.91 (s, 3H), 0.17 (s, 9H) ppm. 13C NMR (151 MHz,
4.2.5.2. Data for (ꢂ)-69. Appearance: slightly yellow oil. TLC:
Rf¼0.74e0.77 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3):
d
149.3,146.8,137.0,124.6,113.0,103.2, 42.5, 40.4, 33.0, 32.9,
CDCl3):
d
5.50 (br s, 1H), 4.91 (dq, J¼3.0, 1.5 Hz, 1H), 4.54 (dq,
25.3, 24.0, 23.0, 21.9, 21.2, 19.6, 0.5 ppm. IR (neat):
n
¼3074, 2933,
J¼2.7, 0.9 Hz, 1H), 2.69 (s, 2H), 2.30 (m, 1H), 2.23e2.13 (m, 4H),
2.11e1.92 (m, 3H), 1.75 (dd, J¼1.5, 0.9 Hz, 3H), 1.68e1.58 (m, 2H),
2866, 1660, 1444, 1366, 1263, 1250, 1203, 1137, 963, 938, 894, 840,
752 cmꢁ1. HRMS (ESI-TOF): calcd for C22H40OSi [MþHþ] 349.2921,
found 349.2924.
1.66 (s, 6H) ppm. 13C NMR (151 MHz, CDCl3):
d 146.6, 136.7,
136.3, 125.4, 120.5, 113.3, 57.7, 54.4, 36.3, 36.1, 29.6, 29.5, 24.2,
22.9, 21.9, 19.7 ppm. IR (neat):
¼3074, 3034, 2915, 2855, 1631,
n
4.2.4. Methylated enone 67. This compound can be prepared in
w20% yield using one of two ways: from ketone 43 or TMS enol
ether 66. From ketone 43: To a flame-dried 20 mL microwave vial
was added IBX (611.0 mg, 2.182 mmol, 4.87 equiv), followed by
a solution of ketone 43 (105.0 mg, 0.4480 mmol, 1.00 equiv) in
DMSO (4 mL). This mixture was heated to 80 ꢀC for 8 h. The reaction
mixture was cooled to room temperature, upon which it was par-
titioned using saturated aqueous NaHCO3 (5 mL) and EtOAc (5 mL).
The aqueous layer was extracted with EtOAc (2ꢃ3 mL). The com-
bined organic layers were washed with H2O (5 mL) then brine
(5 mL), dried over MgSO4, and then evaporated to dryness in vacuo.
Purification by flash silica gel chromatography afforded 67 (21.0 mg,
20% yield). From TMS enol ether 66: To a flame-dried 5 mL micro-
wave vial were added TMS enol ether 66 (42.0 mg, 0.115 mmol,
1.00 equiv), MeCN (1 mL), and Pd(OAc)2 (30.0 mg, 0.134 mmol,
1.17 equiv), in that order, and this dark reaction mixture was stirred
at room temperature for 16 h. This mixture was directly filtered on
Celite (eluting with EtOAc). The obtained solution was evaporated
in vacuo and purified by flash silica gel chromatography to afford 67
(5.4 mg, 20% yield) and ketone 43 (9.9 mg, 37%). Appearance: Yel-
low oil. TLC: Rf¼0.57e0.59 (silica gel, 1:3 EtOAc/hexanes). 1H NMR
1442, 1399, 1371, 1291, 1175, 1040, 931, 891, 826, 790 cmꢁ1
.
HRMS (ESI-TOF): calcd for C16H24O [MþHþ] 233.1900, found
233.1910.
4.2.5.3. Data for (ꢂ)-71 as a 3:2 mixture of inseparable diaster-
eomers. Appearance: slightly yellow oil. TLC: Rf¼0.79e0.82 (silica
gel, 1:3 EtOAc/hexanes). Major diastereomer, 1H NMR (400 MHz,
CDCl3):
d
9.72 (d, J¼1.3 Hz, 1H), 4.88 (m, 1H), 4.50 (m, 1H), 2.47 (m,
1H), 2.12 (m, 2H), 1.79 (m, 1H), 1.74 (dd, J¼1.5, 0.9 Hz, 3H), 1.69 (m,
1H), 1.65 (s, 3H), 1.64 (s, 3H), 1.58 (m, 1H), 1.52e1.44 (m, 1H),
1.44e1.34 (m, 1H), 1.34e1.07 (m, 3H), 1.02 (ddd, J¼9.4, 5.2, 1.7 Hz,
1H), 0.53 (dd, J¼9.3, 4.5 Hz, 1H), 0.28 (t, J¼4.9 Hz, 1H) ppm. Minor
diastereomer, 1H NMR (400 MHz, CDCl3):
d
9.66 (d, J¼1.5 Hz, 1H),
4.88 (m, 1H), 4.50 (m, 1H), 2.74 (m, 1H), 2.12 (m, 2H), 1.79 (m, 1H),
1.75 (dd, J¼1.5, 0.9 Hz, 3H), 1.69 (m, 1H), 1.66 (s, 3H), 1.65 (s, 3H),
1.58 (m, 1H), 1.52e1.44 (m, 1H), 1.44e1.34 (m, 1H), 1.34e1.07 (m,
3H), 0.93 (ddd, J¼9.0, 6.7, 5.6 Hz, 1H), 0.48 (dd, J¼8.8, 4.8 Hz, 1H),
0.20 (t, J¼5.2 Hz, 1H) ppm. Major diastereomer, 13C NMR (151 MHz,
CDCl3):
d 204.1, 146.8, 136.6, 124.8, 113.0, 48.7, 40.3, 28.1, 27.6, 22.9,
22.9, 21.9, 20.3, 19.6, 19.6, 16.7, 16.4 ppm. Minor diastereomer, 13C
NMR (151 MHz, CDCl3): 204.3, 146.8, 136.4, 124.9, 113.1, 45.6, 40.3,
28.2, 27.9, 22.9, 21.9, 20.4, 20.1, 19.6, 18.9, 16.5, 14.4 ppm. IR (neat):
d
(400 MHz, CDCl3):
d
6.86 (ddd, J¼10.1, 4.6, 3.7 Hz, 1H), 6.03 (dt,
J¼10.1, 1.9 Hz, 1H), 4.90 (dq, J¼3.0, 1.5 Hz, 1H), 4.52 (dq, J¼2.7,
0.9 Hz, 1H), 2.33 (dt, J¼17.8, 3.0 Hz, 1H), 2.30 (AB quartet, 2H), 2.18
(dddd, J¼18.8, 4.6, 1.8, 1.1 Hz, 1H), 2.03 (m, 2H), 1.74 (dd, J¼1.5,
0.9 Hz, 3H), 1.65 (s, 3H), 1.63 (s, 3H), 1.37 (m, 2H), 1.02 (s, 3H) ppm.
n
¼3073, 2925, 2855, 2712, 1726, 1631, 1447, 1371, 1301, 1172, 1123,
1076, 1021, 892, 833 cmꢁ1. HRMS (ESI-TOF): calcd for C17H26
O
[MþHþ] 247.2056, found 247.2048.
13C NMR (151 MHz, CDCl3):
d
200.1, 148.4, 146.4, 136.1, 129.2, 125.4,
4.2.5.4. Data for (ꢂ)-72. Appearance: slightly yellow oil. TLC:
Rf¼0.50e0.53 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
113.4, 50.3, 40.1, 38.2, 36.6, 25.3, 24.7, 22.8, 21.9, 19.6 ppm. IR (neat):
n
¼3074, 2960, 2915, 2871, 1679, 1631, 1444, 1386, 1343, 1284, 1246,
CDCl3):
d
5.39 (d, J¼6.5 Hz,1H), 4.89 (dq, J¼3.0,1.5 Hz, 1H), 4.51 (dq,
1168, 1124, 893, 733 cmꢁ1. HRMS (ESI-TOF): calcd for C16H24
O
J¼2.7, 0.8 Hz, 1H), 4.13 (br s, 2H), 2.17 (dtd, J¼26.2, 13.3, 5.3 Hz, 2H),
2.03 (dt, J¼17.1, 6.5 Hz, 1H), 1.90 (dd, J¼12.8, 7.2 Hz, 1H), 1.87e1.76
(m, 1H), 1.75 (dd, J¼1.5, 0.9 Hz, 3H), 1.66 (s, 3H), 1.65 (s, 3H), 1.50
(td, J¼12.6, 5.4 Hz, 1H), 1.45 (td, J¼12.5, 6.1 Hz, 1H), 1.32 (br s, 1H),
1.26 (m, 1H), 1.00 (dd, J¼8.4, 4.2 Hz, 1H), 0.80 (t, J¼4.2 Hz, 1H), 0.64
[MþHþ] 233.1900, found 233.1902.
4.2.5. CoreyeChaykovsky products 57, 69, 71, and 72. To a flame-
dried 20 mL microwave vial were added trimethylsulfoxonium
iodide (58.0 mg, 0.264 mmol, 1.00 equiv), DMSO (200
m
L), and NaH
(dd, J¼8.4, 4.2 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3):
d 146.7,
(60% dispersion in mineral oil, w11 mg, w0.28 mmol, w1.0 equiv).
After stirring for 30 min at room temperature, enone 42 (57.5 mg,
0.263 mmol, 1.00 equiv) was added and the reaction mixture was
stirred overnight. H2O (1 mL) was added and then this reaction
mixture was extracted with Et2O (3ꢃ1 mL). The combined organic
layers were washed with H2O (2 mL) then brine (2 mL), dried over
MgSO4, and then evaporated to dryness in vacuo. Purification by
flash silica gel chromatography afforded 57 (18.3 mg, 30% yield),
69 (6.2 mg, 10% yield), 71 (6.1 mg, 10% yield), 72 (6.2 mg, 10%
yield).
140.6, 136.7,124.9, 117.5,113.0, 67.4, 38.8, 28.5, 24.2, 23.2, 22.9, 21.9,
21.6, 19.6, 19.2, 16.7 ppm. IR (neat):
n
¼3347 (br), 3072, 2913, 2853,
1661, 1631, 1442, 1371, 1168, 1069, 1050, 1005, 931, 892, 813 cmꢁ1
.
HRMS (ESI-TOF): calcd for C17H26O [MþHþ] 247.2056, found
247.2053.
4.2.6. Allylated cyclopropane ketone 73. To a flame-dried 10 mL
microwave vial equipped with a stir bar was added ketone (ꢂ)-57
(18.0 mg, 0.0775 mmol, 1.0 equiv) in THF (500 mL) and cooled to
0
ꢀC. Lithium diethylamide (2.0 M, synthesized by adding nBuLi to
diethylamine; 40 mL, 0.080 mmol, 1.0 equiv) was added and was
4.2.5.1. Data for (ꢂ)-57. Appearance: slightly yellow oil. TLC:
Rf¼0.56e0.60 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
stirred at 0 ꢀC for 30 min. A solution of freshly prepared allyl iodide
(30 mL, 0.33 mmol, 4.2 equiv) in THF (200 mL) was added and this
reaction mixture was warmed to room temperature overnight. The
reaction was quenched with saturated aqueous NH4Cl (1 mL), di-
luted with H2O (1 mL), and extracted with EtOAc (3ꢃ1 mL). The
combined organic layers were washed with H2O (2 mL) then brine
(2 mL), dried over MgSO4, and then evaporated to dryness in vacuo.
CDCl3):
d
4.89 (dq, J¼2.9, 1.5 Hz, 1H), 4.50 (dq, J¼2.7, 0.9 Hz, 1H),
2.27 (ddd, J¼18.4, 5.6, 3.1 Hz, 1H), 2.14 (t, J¼8.5 Hz, 2H), 2.08e1.92
(m, 2H), 1.82e1.67 (m, 2H), 1.73 (dd, J¼1.5, 0.9 Hz, 3H), 1.64 (s, 6H),
1.62 (m, 1H), 1.59 (dd, J¼10.0, 4.5 Hz, 1H), 1.49e1.30 (m, 3H), 0.92
(dd, J¼10.0, 5.2 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3):
d 209.7,
Please cite this article in press as: Ishihara, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.028

Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
15
Purification by PTLC (gradient of EtOAc/hexanes) yielded four
separate compounds (in order of decreasing Rf), (ꢂ)-74 (1.4 mg, 5%
yield, w90% pure), (ꢂ)-73a (3.6 mg,17% yield), (ꢂ)-73b (2.6 mg,12%
yield) and recovered (ꢂ)-57 (8.9 mg, 49%). While 73a and 73b are
C5-epimers of one another, the relative stereochemistry at C5 for
73a and 73b is unknown.
875 cmꢁ1. HRMS (ESI-TOF): calcd for C19H26O [MþHþ] 271.2056,
found 271.2055.
4.2.8. Methylated alcohol 76. To a flame-dried 5 ml microwave vial
was added a solution of (ꢂ)-61 (40.0 mg, 0.139 mmol, 1.00 equiv) in
PhMe (900
200
m
L) and this was cooled to 0 ꢀC. MeMgBr solution (2.8 M;
L, 0.560 mmol, 4.03 equiv) was then added dropwise, and the
m
4.2.6.1. Data for (ꢂ)-74. The full compound characterization has
not been obtained. Its structure has been assigned solely by its mass
analysis and an analogy to the formation of allylated products 63
and 64 (see Fig. 8). Appearance: slightly yellow oil. TLC:
Rf¼0.80e0.83 (silica gel, 1:3 EtOAc/hexanes). HRMS (ESI-TOF):
calcd for C22H32O [MþHþ] 313.2526, found 313.2520.
reaction mixture was stirred at 0 ꢀC for 10 min. The reaction was
quenched with saturated aqueous NH4Cl (0.5 mL), diluted with H2O
(1 mL), and extracted with EtOAc (3ꢃ1 mL). The combined organic
layers were washed with H2O (2 mL) then brine (2 mL), dried over
Na2SO4, and then evaporated to dryness in vacuo. Purification by
silica gel flash chromatography (gradient of EtOAc/hexanes) yielded
(ꢂ)-76 (25.3 mg, 60%). Appearance: slightly yellow oil. TLC:
Rf¼0.64e0.68 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
4.2.6.2. Data for (ꢂ)-73a. Appearance: slightly yellow oil. TLC:
Rf¼0.77e0.80 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3):
d 4.00 (s, 1 H, D2O exchangeable), 2.87 (s, 1H), 2.74 (ddd,
CDCl3):
d
5.67 (ddt, J¼17.3, 10.2, 7.2 Hz, 1H), 5.06e4.99 (m, 2H), 4.90
J¼14.5, 11.5, 5.2 Hz, 1H), 2.49 (m, 1H), 2.44 (t, J¼12.2 Hz, 1H), 2.14
(m, 1H), 2.05e1.85 (m, 1H), 1.79 (m, 1H), 1.78 (s, 3H), 1.66 (dddd,
J¼14.0, 4.1, 2.9, 1.5 Hz, 1H), 1.51 (td, J¼13.2, 3.7 Hz, 1H), 1.39 (m, 1H),
1.29 (dt, J¼15.2, 5.3 Hz, 1H), 1.25 (s, 3H), 1.24 (dtd, J¼13.2, 3.5, 1.5,
1H), 1.14 (s, 3H), 1.11 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H) ppm. 13C NMR
(dq, J¼3.0,1.5 Hz,1H), 4.51 (dq, J¼2.7, 0.9 Hz,1H), 2.50 (dddt, J¼13.6,
6.7, 3.9, 1.2 Hz, 1H), 2.23 (m, 1H), 2.14 (t, J¼8.4 Hz, 2H), 2.02 (m, 1H),
1.95 (m, 1H), 1.85e1.70 (m, 2H), 1.74 (dd, J¼1.5, 0.9 Hz, 3H), 1.65 (s,
6H), 1.61 (d, J¼10.2, 4.5 Hz, 1H), 1.50e1.30 (m, 4H), 0.85 (dd, J¼10.2,
5.2 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3):
d
209.9, 146.4, 136.0,
(151 MHz, CDCl3):
40.4, 39.5, 38.0, 32.7, 30.2, 28.4, 26.9, 25.1, 24.7, 21.9, 18.7, 18.6 ppm.
IR (neat):
¼3504, 2962, 2900, 1661, 1460, 1380, 1369, 1327, 1176,
d 223.6, 137.3, 129.9, 72.2, 64.8, 57.1, 42.8, 40.7,
135.9, 125.5, 117.1, 113.4, 46.0, 37.6, 35.6, 33.7, 27.9, 27.7, 25.6, 22.9,
22.9, 21.9, 19.7, 15.8 ppm. IR (neat):
n
¼3075, 2916, 2855, 1684, 1640,
n
1442, 1371, 1335, 1263, 1213, 1171, 1073, 997, 910, 892 cmꢁ1. HRMS
1137, 1093, 1044, 949, 896, 732 cmꢁ1. HRMS (ESI-TOF): calcd for
(ESI-TOF): calcd for C19H28O [MþHþ] 273.2213, found 273.2210.
C
20H32O2 [MþHþ] 305.2475, found 305.2466.
4.2.6.3. Data for (ꢂ)-73b. Appearance: slightly yellow oil. TLC:
Rf¼0.74e0.77 (silica gel, 1:3 EtOAc/hexanes). 1H NMR (400 MHz,
4.2.9. Taxadienyl xanthate (þ)-81. To a flame-dried 10 mL micro-
wave vial equipped with a stir bar were added KOtBu (15.0 mg,
0.134 mmol, 2.0 equiv) and THF (1 mL). This was cooled to 0 ꢀC,
upon which taxadienol (þ)-80 (19.5 mg, 0.0676 mmol, 1.0 equiv)
was added as a solution in THF (0.5 mL), and warmed to room
temperature over 2 h. The reaction mixture was cooled to 0 ꢀC,
CDCl3):
d
5.79e5.68 (m, 1H), 5.06e5.03 (m, 1H), 5.01 (t, J¼1.2 Hz,
1H), 4.90 (dq, J¼3.0, 1.5 Hz, 1H), 4.53e4.50 (m, 1H), 2.50e2.42 (m,
1H), 2.17e1.98 (m, 4H), 1.92e1.76 (m, 3H), 1.74 (dd, J¼1.5, 0.9 Hz,
3H), 1.65 (s, 6H), 1.61e1.56 (m, 2H),1.38e1.32 (m, 2H),1.27e1.24 (m,
1H), 1.02 (dd, J¼10.0, 5.2 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3):
upon which freshly distilled CS2 (100
mL, 1.66 mmol, 24 equiv) was
d
211.2, 146.4, 136.5, 135.9, 125.5, 116.9, 113.4, 43.2, 38.5, 34.8, 33.2,
added and stirred for 1 h at 0 ꢀC. Finally, MeI (50
mL, 0.803 mmol,
30.4, 28.1, 26.2, 24.9, 22.9, 21.9, 21.6, 19.7 ppm. IR (neat):
n
¼3074,
12 equiv) was added and the reaction mixture was warmed to room
temperature over 1 h. The reaction was quenched with saturated
aqueous NH4Cl (0.5 mL), diluted with H2O (1 mL), and extracted
with EtOAc (3ꢃ1 mL). The combined organic layers were washed
with H2O (2 mL) then brine (2 mL), dried over Na2SO4, and then
evaporated to dryness in vacuo. Purification by silica gel flash
chromatography (gradient of EtOAc/hexanes) yielded (þ)-81
(13.1 mg, 51%). Appearance: yellow oil. TLC: Rf¼0.42e0.44 (silica
2918, 2856,1684,1639,1443,1371,1320,1265,1228,1205,1167, 996,
909, 892 cmꢁ1. HRMS (ESI-TOF): calcd for C19H28O [MþHþ]
273.2213, found 273.2213.
4.2.7. Acroleinated cyclopropane ketone 75. To a flame-dried 10 mL
microwave vial equipped with a stir bar was added ketone (ꢂ)-57
(18.0 mg, 0.0775 mmol, 1.0 equiv) in THF (500 mL) and cooled to
0
ꢀC. Lithium diethylamide (2.0 M, synthesized by adding nBuLi to
gel, hexanes). 1H NMR (400 MHz, CDCl3):
d
6.39 (d, J¼4.1 Hz, 1H),
diethylamine; 40
m
L, 0.080 mmol, 1.0 equiv) was added and was
5.32 (s, 1H), 3.22 (s, 1H), 2.81 (td, J¼13.6, 5.2 Hz, 1H), 2.69 (td,
J¼14.2, 5.2 Hz, 1H), 2.60 (s, 3H), 2.34 (dd, J¼9.3, 3.9 Hz, 1H), 2.30 (d,
J¼9.6 Hz, 1H), 2.22 (d, J¼8.8 Hz, 1H), 2.20e2.06 (m, 2H), 2.05e1.94
(m, 2H), 1.85 (ddd, J¼18.6, 10.5, 3.6 Hz, 1H), 1.80 (s, 3H), 1.71 (s, 3H),
1.46 (s, 3H), 1.42 (ddd, J¼15.3, 5.0, 3.0 Hz, 1H), 1.37 (ddd, J¼14.8,
10.6, 4.1 Hz, 1H), 1.15 (m, 1H), 1.03 (s, 3H), 0.99 (s, 3H) ppm. 13C NMR
stirred at 0 ꢀC for 30 min. A solution of freshly distilled acrolein
(distilled over CaSO4; 20 mL, 0.30 mmol, 3.9 equiv) in THF (200 mL)
was added and this reaction mixture was warmed to room tem-
perature overnight. The reaction was quenched with saturated
aqueous NH4Cl (1 mL), diluted with H2O (1 mL), and extracted with
EtOAc (3ꢃ1 mL). The combined organic layers were washed with
H2O (2 mL) then brine (2 mL), dried over MgSO4, and then evapo-
rated to dryness in vacuo. Purification by PTLC (gradient of EtOAc/
hexanes) yielded (ꢂ)-75 (6.0 mg, 29%). Appearance: slightly yellow
oil. TLC: Rf¼0.71e0.73 (silica gel, 1:3 EtOAc/hexanes). 1H NMR
(151 MHz, CDCl3):
d 215.2, 137.8, 136.7, 128.9, 122.4, 90.2, 46.4, 41.8,
40.3, 38.2, 38.2, 38.2, 32.4, 28.9, 26.2, 25.4, 24.8, 24.6, 23.9, 22.1,
21.4, 19.6 ppm. IR (neat):
n
¼3048, 3004, 2919, 2882, 2857, 1459,
1376, 1250, 1212, 1079, 1052, 963, 895, 821, 784 cmꢁ1. HRMS (ESI-
TOF): calcd for C22H34OS2 [MþHþ] 379.2124, found 379.2140. Op-
20
(400 MHz, CDCl3):
d
7.12 (d, J¼11.6 Hz, 1H), 6.56 (ddd, J¼16.7, 11.6,
tical rotation: [
a
]
þ1.4 (c 5.0, CHCl3), taken on a 91% ee sample.
D
10.1 Hz,1H), 5.63 (d, J¼16.8 Hz,1H), 5.51 (d, J¼10.0 Hz,1H), 4.91 (dq,
J¼3.0, 1.5 Hz, 1H), 4.52 (dq, J¼2.7, 0.9 Hz, 1H), 2.76 (dd, J¼17.2,
5.3 Hz, 1H), 2.25 (m, 1H), 2.15 (t, J¼8.4 Hz, 2H), 2.05 (ddd, J¼13.3,
5.6, 1.8 Hz, 1H), 1.82 (td, J¼13.6, 5.6 Hz, 1H), 1.79 (dd, J¼9.4, 4.1 Hz,
1H), 1.74 (dd, J¼1.4, 0.9 Hz, 3H), 1.65 (s, 6H), 1.53e1.36 (m, 3H), 1.00
4.2.10. Dimered enone 85. During the formation of enone 42 from
bromodiene 11 and vinylcyclohexenone 56, varying amounts of
a bis-addition product have been observed, sometimes not at all,
sometimes in large quantities of w20% yield. This product has been
characterized and was found to have the structure shown in Fig. 20.
Appearance: yellow oil. TLC: Rf¼0.28e0.31 (silica gel, 1:1 EtOAc/
(dd, J¼9.5, 5.0 Hz, 1H) ppm. 13C NMR (151 MHz, CDCl3):
d 199.1,
146.4, 136.0, 135.1, 132.2, 131.4, 125.9, 125.5, 113.4, 37.7, 33.6, 30.1,
27.9, 24.5, 22.9, 22.1, 21.9, 19.7, 17.6 ppm. IR (neat):
2856, 1670, 1630, 1611, 1580, 1444, 1372, 1319, 1264, 1228, 989, 892,
n
¼3075, 2917,
hexanes). 1H NMR (400 MHz, CDCl3):
d 5.85 (s, 1H), 5.82 (s,1H), 4.99
(dq, J¼2.9, 1.4 Hz, 1H), 4.54 (dq, J¼2.7, 0.9 Hz, 1H), 2.40e2.30 (m,
4H), 2.30e2.20 (m, 7H), 2.10e2.00 (m, 2H), 2.00e1.90 (m, 4H), 1.73
Please cite this article in press as: Ishihara, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.028

16
Y. Ishihara et al. / Tetrahedron xxx (2013) 1e17
McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E.
(dd, J¼1.4, 0.9 Hz, 3H), 1.68 (s, 3H), 1.66 (s, 3H), 1.65 (m, 1H), 1.57 (m,
1H) ppm. 13C NMR (151 MHz, CDCl3):
199.9, 199.8, 168.4, 165.7,
145.3, 133.9, 128.0, 127.0, 125.7, 114.9, 46.2, 37.8, 37.4, 36.0, 34.6,
30.0, 29.1, 27.2, 23.0, 22.8, 22.6, 22.2, 20.4 ppm. IR (neat):
2931, 2866, 1663, 1621, 1453, 1427, 1372, 1345, 1324, 1252, 1190,
1132, 964, 886 cmꢁ1. HRMS (ESI-TOF): calcd for C23H32O2 [MþHþ]
341.2475, found 341.2485.
J. Am. Chem. Soc. 1997, 119, 2757e2758; Total synthesis by T. Mukaiyama: (l)
d
ꢁ
Shiina, I.; Saitoh, K.; Frechard-Ortuno, I.; Mukaiyama, T. Chem. Lett. 1998, 27,
3e4; (m) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.;
Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.-i; Hasegawa, M.; Yamada, K.;
Saitoh, K. Chem.dEur. J. 1999, 5, 121e161; Total synthesis by I. Kuwajima: (n)
Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.;
Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980e12981; (o) Kusama, H.; Hara, R.;
Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima,
I. J. Am. Chem. Soc. 2000, 122, 3811e3820; Total synthesis by Y. Kishi, only
described in a Ph.D. Thesis by his graduate student: (p) Lim, J. Ph.D. Dissertation;
Harvard University: 2000; Formal synthesis by T. Doi: (q) Doi, T.; Fuse, S.;
Miyamoto, S.; Nakai, K.; Sasuga, D.; Takahashi, T. Chem. Asian J. 2006, 1,
370e383.
5. The total synthesis of a less oxidized taxane, taxusin, has been accomplished
three times. Total synthesis by R. A. Holton: (a) Holton, R. A.; Juo, R. R.; Kim, H.
B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J. Am. Chem. Soc.
1988, 110, 6558e6560; Total synthesis by I. Kuwajima: (b) Hara, R.; Furukawa,
T.; Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186e9187; (c) Hara,
R.; Furukawa, T.; Kashima, H.; Kusama, H.; Horiguchi, Y.; Kuwajima, I. J. Am.
Chem. Soc. 1999, 121, 3072e3082; Total synthesis by L. A. Paquette: (d) Paquette,
L. A.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5203e5212; (e) Paquette, L. A.; Wang,
H.-L.; Su, Z.; Zhao, M. J. Am. Chem. Soc. 1998, 120, 5213e5225.
n
¼3073,
4.3. X-ray crystallographic data
Crystallographic data for (þ)-10, (ꢁ)-10, (ꢁ)-61, and (ꢁ)-86 have
been deposited with the Cambridge Crystallographic Data Centre.
Copies of the data can be obtained free of charge from http://
www.ccdc.cam.ac.uk/products/csd/request/ with CCDC # 837815
for (þ)-10, # 932623 for (ꢁ)-10, # 932622 for (ꢁ)-61, and # 840165
for (ꢁ)-86.
Acknowledgements
6. The total synthesis of the least oxidized natural taxane, taxadiene (8), has only
been reported once prior to our own work in Ref. 12: Rubenstein, S. M.; Wil-
liams, R. M. J. Org. Chem. 1995, 60, 7215e7223.
We thank D.-H. Huang and L. Pasternack for assistance in NMR
spectroscopy, G. Siuzdak for assistance in mass spectrometry, A.
Rheingold (UCSD) for assistance in X-ray crystallography, and M.
Wasa and J.-Q. Yu for chiral HPLC assistance. We thank N. Wilde for
valuable technical assistance. We particularly thank G. Stephano-
poulos (MIT) for providing a bioengineered sample of taxadiene.
Financial support for this work was provided by the NIH/NIGMS
(GM-097444), NSERC (doctoral fellowship for Y.I.), MEC-Fulbright
Program (postdoctoral fellowship for A.M.), and BristoleMyers
Squibb (unrestricted research support).
7. Many syntheses of the taxane skeleton have been reported, and selected reports
are shown here. Synthesis efforts by K. J. Shea: (a) Shea, K. J.; Davis, P. D. Angew.
Chem., Int. Ed. Engl. 1983, 22, 419e420; (b) Shea, K. J.; Gilman, J. W.; Haffner, C. D.;
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C. D. Tetrahedron Lett. 1988, 29, 1367e1370; (d) Jackson, R. W.; Higby, R. G.;
Gilman, J. W.; Shea, K. J. Tetrahedron 1992, 48, 7013e7032; (e) Jackson, R. W.;
Shea, K. J. Tetrahedron Lett. 1994, 35, 1317e1320; Synthesis efforts by J. D.
Winkler: (f) Winkler, J. D.; Kim, H. S.; Kim, S. Tetrahedron Lett. 1995, 36, 687e690;
(g) Winkler, J. D.; Holland, J. M.; Peters, D. A. J. Org. Chem. 1996, 61, 9074e9075;
(h) Winkler, J. D.; Kim, H. S.; Kim, S.; Ando, K.; Houk, K. N. J. Org. Chem. 1997, 62,
2957e2962; Synthesis efforts by A. G. Fallis: (i) Tjepkema, M. W.; Wilson, P. D.;
Wong, T.; Romero, M. A.; Audrain, H.; Fallis, A. G. Tetrahedron Lett. 1995, 36,
6039e6042; (j) Fallis, A. G. Pure Appl. Chem. 1997, 69, 495e500; (k) Tjepkema,
M. W.; Wilson, P. D.; Audrain, H.; Fallis, A. G. Can. J. Chem. 1997, 75, 1215e1224;
(l) Forgione, P.; Wilson, P. D.; Yap, G. P. A.; Fallis, A. G. Synthesis 2000, 921e924;
(m) Villalva-Servín, N. P.; Laurent, A.; Yap, G. P. A.; Fallis, A. G. Synlett 2003,
1263e1266; (n) Laurent, A.; Villalva-Servín, N. P.; Forgione, P.; Wilson, P. D.;
Smil, D. V.; Fallis, A. G. Can. J. Chem. 2004, 82, 215e226; (o) Villalva-Servín, N. P.;
Laurent, A.; Fallis, A. G. Can. J. Chem. 2004, 82, 227e239; Synthesis efforts by P.
Magnus: (p) Frost, C.; Linnane, P.; Magnus, P.; Spyvee, M. Tetrahedron Lett. 1996,
37, 9139e9142; (q) Magnus, P.; Westwood, N.; Spyvee, M.; Frost, C.; Linnane, P.;
Tavares, F.; Lynch, V. Tetrahedron 1999, 55, 6435e6452; Synthesis efforts by G.
Pattenden: (r) Hitchcock, S. A.; Houldsworth, S. J.; Pattenden, G.; Pryde, D. C.;
Thomson, N. M.; Blake, A. J. J. Chem. Soc., Perkin Trans. 1 1998, 3181e3206;
Synthesis efforts by A. J. Phillips: (s) Phillips, A. J.; Morris, J. C.; Abell, A. D. Tet-
rahedron Lett. 2000, 41, 2723e2727; Synthesis efforts by P. R. Jenkins: (t) Brown,
P. A.; Jenkins, P. R. J. Chem. Soc., Perkin Trans. 1 1986, 1303e1309; (u) Bonnert, R.
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