Scalable enantioselective total synthesis of taxanes

Article abstract of DOI:10.1038/nchem.1196

Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via a concise preparation of (+)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more oxidized members of its family. This route enables a gram-scale preparation of the 'parent' taxane-taxadiene-which is the largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels-Alder strategy. Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre, from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.

Full text of DOI:10.1038/nchem.1196

ARTICLES
PUBLISHED ONLINE: 6 NOVEMBER 2011 | DOI: 10.1038/NCHEM.1196
Scalable enantioselective total synthesis of taxanes
Abraham Mendoza†, Yoshihiro Ishihara† and Phil S. Baran
*
Taxanes form a large family of terpenes comprising over 350 members, the most famous of which is Taxol (paclitaxel), a
billion-dollar anticancer drug. Here, we describe the first practical and scalable synthetic entry to these natural products via
a concise preparation of (1)-taxa-4(5),11(12)-dien-2-one, which has a suitable functional handle with which to access more
oxidized members of its family. This route enables a gram-scale preparation of the ‘parent’ taxane—taxadiene—which is the
largest quantity of this naturally occurring terpene ever isolated or prepared in pure form. The characteristic 6-8-6 tricyclic
system of the taxane family, containing a bridgehead alkene, is forged via a vicinal difunctionalization/Diels–Alder strategy.
Asymmetry is introduced by means of an enantioselective conjugate addition that forms an all-carbon quaternary centre,
from which all other stereocentres are fixed through substrate control. This study lays a critical foundation for a planned
access to minimally oxidized taxane analogues and a scalable laboratory preparation of Taxol itself.
erpenes are omnipresent natural products that are found the less-oxidized taxane members such as taxadiene (7)22.
predominantly as constituents of plant oils and have long Although not necessarily a means of supplanting its current tonne-
T
held importance as flavours and fragrances, and as poisons scale production, a reexamination of Taxol (1) over 15 years after
and medicines1–3. Isolation, structural elucidation and synthetic its first total syntheses could be of academic and medicinal merit.
studies on this vast family of natural products were already being In this Article, we present the first scalable synthetic entry to the
conducted over 100 years ago1, providing constant challenges to taxane family, setting the stage for rapid access to minimally
chemists and thus resulting in continuous development of the oxidized taxane analogues and a scalable laboratory preparation of
field. Taxol (1), a successful anticancer drug, is one example that Taxol (1) itself.
has societal and scientific merit, being one of the most famous ter-
Inspired by nature’s efficiency in creating vast numbers of
penes from a medicinal standpoint and one of the most densely complex terpene natural products, a research programme was
functionalized and complex molecules from a structural standpoint. initiated in 200723 to mimic the essence of the two-phase biosyn-
Its unique mechanism of action, involving the stabilization of thesis of terpenes24. In the first biogenetic phase (the cyclase
microtubules4, has also held fascination for biologists, so extensive phase), linear hydrocarbon building blocks are brought together
research efforts have been carried out around the globe by both che- and cyclized efficiently, and in the second phase (the oxidase
mists and biologists.
phase), C¼C and C–H bonds are oxidized in a divergent manner,
Taxol (1) is a potent anticancer drug that was originally used as a thus generating structural diversity. The taxanes represent a large
treatment for ovarian and breast cancer5, but its versatile effects now family of terpenes comprising over 350 natural products25–32, for
extend to treatments of lung, liver and other types of cancer6. Initially which this two-phase terpene synthesis strategy, if realized in a
isolated from the bark of the yew tree7, substantial work in the 1980s laboratory setting, could target not only Taxol (1) itself, but also
and 1990s led to a semisynthetic route to Taxol (1) that reduced the related taxanes that differ in oxidation levels (Fig. 1)23,33. As such,
accompanying detrimental effects to the yew tree population8–10
.
this research programme has been designed to recapitulate the
Currently, its commercial supply relies on cell-culture production, way that nature builds taxanes. The goal is to divergently access
and it is now manufactured with plant cell-culture technology all ‘pre-taxol’ compounds (both natural and unnatural) and to
through a collaboration of Bristol-Myers Squibb and Phyton unveil new insights into their chemical reactivity during an
Biotech, Inc., a DFB Pharmaceuticals company. This diterpene is ‘oxidative ascent’ of the taxane pyramid. This Article outlines the
one of the few natural products that continues to draw worldwide completion of our artificial ‘cyclase phase’ for the taxane terpene
attention, and tremendous efforts have already culminated in seven family, as a prelude to a total synthesis of Taxol (1). Thus, the logic
total syntheses11–19 and one formal synthesis20. However, the inven- (including strategic and tactical concerns)21 and execution of
tory of man-made Taxol (1) produced by total synthesis is still less a concise and scalable synthesis of minimally oxidized taxanes,
than 30 mg (refs 11–20), even when including the most recent including nature’s putative cyclase phase endpoint, taxadiene (7)34,
approach by Takahashi in which an automated synthesis was used are reported.
for the majority of the synthetic steps20. In contrast, the current
Structurally, Taxol (1) is a highly oxygenated diterpene adorned
industrial output of 1 through the use of biological machinery is with acetyl and benzoyl groups, as well as a signature taxol side
on the scale of tonnes (109 mg), clearly indicating the magnitudes chain at the C13 oxygen atom (see carbon numbering on 1,
of difference between chemical and biological scales and efficiency. Fig. 1a). For retrosynthetic discussion purposes, 1 is treated as if it
Closing this huge gap is not simply a matter of engineering, but were devoid of acyl groups, and this target is substituted with oxyge-
rather a learning objective through which to guide chemical inno- nated hydrocarbon 2 (ref. 33). Placing 2 at the apex of an ‘oxidase
vation in the tactics, strategies21 and methods of synthesis (for a phase pyramid’, the number of C–O bonds decreases as one moves
discussion of the different definitions of the terms ‘strategy’ and down the pyramid, with taxanes 3, 4 and 5 corresponding to the
‘tactics’, see ref. 21). Until the pioneering bioengineering work of oxidation pattern of 2-acetoxybrevifoliol25, taxinines E and J26 and
Stephanopoulos in 2010, there was no access to large quantities of yunnanxane27, respectively (Fig. 1b). These highly oxidized taxanes
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California, 92037, USA; †These authors contributed
equally to this manuscript. e-mail: pbaran@scripps.edu
*
NATURE CHEMISTRY | VOL 4 | JANUARY 2012 | www.nature.com/naturechemistry
21
© 2011 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1196
ARTICLES
allowing for a gram-scale access to 6 in only seven steps, as well as a
gram-scale synthesis of (þ)-taxadiene (7).
a
Retrosynthetic analysis of Taxol by an 'oxidase phase pyramid'
Higher [O] state
AcO
O
Me
HO
O
OH
OH
Me
Me
13
Me
Same
[O] state
2
10
Me
B
Me
Me
8
'Level 11'
Results
RO
HO
A
C
5
4
Me
1
3
In the forward direction, known compounds 10 (refs 35,40,41; made
from 8 in a modified one-pot procedure; see Supplementary
Information) and 11 (ref. 45; made from 9 using a one-step pro-
cedure) were combined to generate enone 12 by means of a Lewis
acid-modified organocopper 1,6-addition (Fig. 2). This convergent
synthesis of 12 is operationally simple and provides decagram quan-
tities per reaction batch (86%; over 50 g of this material has been
synthesized to date). This enone was deemed to be a suitable sub-
strate for the enantioselective conjugate addition of Alexakis43 to
establish the quaternary centre (C8). However, this strategy was con-
tingent on the feasibility of trapping the resulting aluminium
enolate by trimethylsilyl chloride (TMSCl). Although Alexakis
noted that isolation of such silyl enol ethers is difficult due to
facile desilylation43, a modified quenching procedure involving
dilution with tetrahydrofuran (THF), addition of TMSCl, followed
by addition onto Florisil in 1:10 Et3N:hexanes, allowed the isolation
of trimethylsilyl (TMS) enol ether 14 in 89% yield and in 93% e.e.
(1.0 g scale; enantioselectivity measured for desilylated ketone 15
on chiral high-performance liquid chromatography (HPLC); see
Supplementary Information). Only 2 mol% of CuTC and 4 mol%
of chiral phosphoramidite ligand 13 were required43, and this asym-
metric reaction was routinely conducted on a gram scale (over 20 g
of this material has been synthesized to date). TMS enol ether 14
was indeed quite prone to desilylation, and formation of undesired
ketone 15 was often the sole reaction pathway when attempting
Mukaiyama aldol reactions46 with commonly used Lewis acids
O
O
H
H
2
HO
HO
'Level 9'
AcO
HO
OH
BzO
1
4
2
'Level 7'
Taxol
BzHN
Taxol [O] state
(= 'level 11')
O
5
'Level 6'
R =
Ph
'Oxidase phase pyramid'
OH
b
Representative taxanes of varying [O] state
HO
OH
HO
H
OH
HO
OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
HO
HO
OH
HO
OH
OH
H
H
H
HO
H
OH
OH
OH
5
4
3
Taxinine E or J [O] state
Yunnanxane [O] state
2-acetoxybrevifoliol [O] state
(= 'level 7')
(= 'level 6')
(= 'level 9')
c
Disconnection of 'taxadienone' (6)
Me3Al
Br
Me
Me
Me
Me
Me
H
[H]
Me
Me
Me
Me
Me
Me
H
O
H
H
Me
Me
O
Me2Zn
O
(+)-6
(+)-7
•
•
•
•
Three-component coupling
Scalable
'Taxadienone'
(= 'level 4')
Taxadiene
(= 'level 2')
Enantioselective
Minimizes concession steps
Figure 1 | Retrosynthetic analysis of Taxol (1) and other members of the
taxane family. a, Partial ‘oxidase phase pyramid’ for the retrosynthetic
planning of the taxane family, including its key member, Taxol (1).
b, Representative taxanes of varying oxidation states, sharing a C2-hydroxyl
group. c, Synthetic design for ‘taxadienone’ (6) and reduction to generate
taxadiene (7). Sites of oxidation installed onto taxadiene (7) are indicated in
red. The ‘oxidation level’ of taxanes is defined as the number of C¼C and
C–O bonds installed onto the taxane carbon skeleton33.
.
(such as TiCl4, SnCl4, Sn(OTf)2, Sc(OTf)3, BF3 OEt2, TMSOTf,
.
ZnCl2 or MgBr2 OEt2) or other catalysts (such as LiClO4,
Zr(OtBu)4, Bi(OTf)3, AgOTf or SiCl4), even when performed
under strictly anhydrous conditions. Surprisingly, water was
found to be the enabling additive that allowed for an aldol
reaction with acrolein. Gratifyingly, Kobayashi conditions47 with
Gd(OTf)3 in 1:10:4 H2O:EtOH:PhMe generated the corresponding
aldol product smoothly as a 2:1 mixture of diastereomers that are
isomeric at C3. This aldol product was then oxidized in the same
all feature a C2-hydroxyl group and can be further simplified to reaction pot with Jones’ reagent to generate keto-enone 16 in 85%
taxa-4(5),11(12)-dien-2-one (6), dubbed ‘taxadienone’, which over two steps (3.2 g scale, 2:1 ratio of diastereomers at C3; this inse-
represents a benchmark intermediate for comprehensive access parable mixture of stereoisomers was carried onwards for the
to the taxane family. Furthermore, if taxadiene (7) were desired, ensuing step). A Diels–Alder reaction to generate the 6-8-6 tricyclic
one could simply deoxygenate 6 to generate the least oxidized skeleton has previously been demonstrated on similar systems35–37
natural product in the taxane family (Fig. 1c). A full scholarly and mixture 16 reacted predictably with BF3 OEt2 to furnish
analysis of the taxane pyramid has been described previously, tricyclic compound 17 (2.3 g scale). The desired diketone 17 was
together with the merits in choosing a C2-oxidized taxane such obtained in 47% yield, together with its diastereomer (see
,
.
as 6 (ref. 33).
Supplementary Information) in 29% yield, with complete diaster-
Strategic disconnections of 6 were built upon the landmark eoselectivity at C1. These cyclized diketones displayed very different
syntheses of 1 (refs 11–20) and the many studies geared towards polarities and were thus easily separated by silica gel chromato-
the taxane framework35–41. Of the many possible disconnections of graphy at this stage. Only one more carbon remained to be installed
the 6-8-6 tricyclic backbone, one was chosen such that (i) the to complete the taxane framework: this was achieved via enol triflate
forward synthesis would be short, convergent and scalable42 and formation followed by Negishi coupling to generate taxadienone (6)
(ii) its asymmetric synthesis would only rely on one enantioselective in 84% over two steps (2.4 g scale). This material solidified
reaction, after which the resulting stereochemical information could quite readily, and single-crystal X-ray analysis confirmed both the
be propagated to set all other stereocentres diastereoselectively. A absolute and relative stereochemistry of the synthesized ABC
vicinal difunctionalization/Diels–Alder strategy to forge the taxane ring system. This lowly oxidized core is the key intermediate for
AB ring system (see ring numbering in 2, Fig. 1a) seemed to fulfil our future research efforts to elaborate the taxane pyramid. In
most of the above criteria. The Diels–Alder strategy has been used summary, the total synthesis of (þ)-taxadienone (6) was achieved
previously in the context of taxane synthesis by Shea35, Jenkins36 in a total of 8 steps, with a longest linear sequence of 7 steps. A
and Williams37, as well as others38–41. In fact, Williams reported few grams of taxadienone (6) could be synthesized by one chemist
the only total synthesis of (+)-taxadiene (7), in 26 steps, as long over the course of 7 days, with an overall yield of 18% from 8 or
ago as 1995 (ref. 37). Furthermore, the decision to implement a 20% from 9.
vicinal difunctionalization strategy was underpinned by recent devel-
With the key taxane 6 secured in gram quantities, taxadiene (7)
opments in the asymmetric formation of all-carbon quaternary was then targeted, primarily as a means of spectroscopic comparison
centres43,44. Thus, a concise, enantioselective strategy was conceived, to previously reported data, but also to demonstrate the feasibility
22
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© 2011 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1196
ARTICLES
Me
Me
Me
Ph
N
Me
Me
Me
a. CHBr3, tBuOK; then
Me
Me
O
P
O
Me
Me
Me
Me
Me
Br
PhNMe2, 150 ºC
Me
Me
(67%)
Ph
O
Me
Me
8 (commercial)
10 (known)
(+)-13
(+)-15
b. sBuLi, TMSCl,
c. Me3Al (1.4 equiv.),
CuTC (2 mol%),
CuBr2•SMe2
Me
Me
Me
O
ligand 13 (4 mol%),
a'. vinylmagnesium
8
then THF, TMSCl
bromide (see ref. 45)
Me
Me
Me
Me
(75%)
(89%, 93% e.e.)
[gram scale]
(86%)
[decagram scale]
OEt
O
O
OTMS
12
(–)-14
9 (commercial)
11 (known)
d. Acrolein (20 equiv.),
Gd(OTf)3 (10 mol%),
1:10:4 H2O/EtOH/PhMe;
then Jones' reagent (85%)
[gram scale]
Me
Me
Me
Me
Me
Me
Me
e. BF3•OEt2,
CH2Cl2
f. PhNTf2, KHMDS;
Me
Me
Me
Me
g. Me2Zn, Pd(PPh3)4
3
3
Me
1
2
(47% (+)-17
+ 29% undesired
diastereomer)
[gram scale]
(84%, two steps)
[gram scale]
H
H
H
H
H
Me
O
O
O
O
O
16 (2:1 d.r., mixture of
isomers, major
diastereomer shown)
(+)-6
(+)-17 (>99:1 d.r. at C1)
'Taxadienone'
Figure 2 | Enantioselective synthesis of key taxane 6. Conditions: a. 2,3-dimethyl-2-butene, CHBr3, potassium tert-butoxide, hexanes, 2 h; evaporate volatile
materials, then N,N-dimethylaniline, 150 8C, 30 min (67%); a′. 3-ethoxy-2-cyclohexen-1-one, vinylmagnesium bromide, Et2O, 16 h (75%)45
;
.
b. 10, sec-butyllithium, Et2O, –78 8C, 15 min; then CuBrSMe2, 30 min; then TMSCl, 5 min; then 11, 2 h; warm to room temperature, 8 h; then AcOH, 30 min;
then 3 M HCl, 30 min (86%); c. CuTC (2 mol%), phosphoramidite 13 (4 mol%), Et2O, room temperature, 30 min; then 2.0 M Me3Al, enone 12, –30 8C,
24 h; then THF, TMSCl, 0 8C to room temperature, 8 h; then Et3N, Florisil, 2 h (89%, 93% e.e.); d. Gd(OTf)3 (10 mol%), acrolein, 1:10:4 H2O:EtOH:PhMe,
4 8C, 24 h; then evaporate volatiles, then Jones’ reagent, acetone, 10 min (85% over two steps, 2:1 d.r. at C3, inseparable mixture of diastereomers); e.
.
BF3 OEt2, CH2Cl2, 0 8C, 6 h (47% 17 þ 29% undesired diketone); f. 0.4 M KHMDS, PhNTf2, THF, 0 8C, 1 h; g. 1.2 M Me2Zn, Pd(PPh3)4 (5 mol %), THF, 0 8C
to room temperature, 5 h (84% over two steps). TMSCl, trimethylsilyl chloride; CuTC, copper(I) thiophene-2-carboxylate; PhNTf2, N-phenylbis(trifluoro
methanesulfonimide); KHMDS, potassium hexamethyldisilazide; Pd(PPh3)4, tetrakis(triphenylphosphine)palladium.
of a large-scale laboratory production of enantioenriched 7. epimerize the C1 stereocentre into the desired configuration.
Furthermore, taxadiene (7) is produced in negligible amounts in However, despite a plethora of attempted experiments, the desired
nature (less than 1 mg can be obtained from 750 kg of tree bark cyclization from 19 did not proceed. Thereafter, strategies involving
from T. brevifolia)34 and therefore its optical rotation has never been closure of the AB ring by a Diels–Alder reaction were envisioned.
recorded. To this end, a three-step deoxygenation sequence48 was One attempt involved the formation of ketone 20 by a sequence
performed in 52% yield overall on a gram scale (Fig. 3), to generate involving a coupling of the enolate of 2,6-dimethylcyclohexanone
(þ)-7, which was spectroscopically indistinguishable from natural and a primary alkyl bromide, a Shapiro reaction onto acrolein,
7 (ref. 34), previously synthesized (+)-7 (ref. 37) and bioengineered oxidation and Diels–Alder (disconnection C), much akin to the
(þ)-7 (ref. 22). The optical rotation of [a]D (CHCl3) ¼ þ1658 (c ¼ 1.0) transformation from 14 to 17 (Fig. 2). However, ketone 20
is reported herein for the first time and is comparable to that already required many steps to construct, and the stereocentre at
obtained for a bioengineered sample of (þ)-7 (see Supplementary C8 was challenging to control, despite existing methods in asym-
Information). This represents the largest quantity of pure (þ)-7 metric enolate alkylation49. Finally, enones 21 were considered as
isolated to date.
viable intermediates in the formation of 6 (disconnection D) due
to our initial difficulties in forging the C2–C3 bond via the
Mukaiyama aldol reaction (vide supra). Although enones 21 were
formed in short order and already contained all but one carbon of
the taxane framework, they did not undergo [4 þ 2] cyclization,
probably due to the rigidity of the sp2 carbons at C3 and C8.
Furthermore, a methyl 1,4-addition at C8 was not possible,
Discussion
In retrospect, the forward synthesis of (þ)-taxadienone (6) appears
to be rather simple and perhaps intuitive; however, in practice, this
optimized approach required many rounds of strategic and tactical
revision21. Strategically, the retrosynthesis designed in Fig. 1c was
one of many that were considered at the outset. A small snapshot
of the many evaluated blueprints is presented in Fig. 4. For
example, the known difficulties in forming the 6-8-6 tricyclic frame-
work of taxanes11–20 led us to first consider a ring-closing metathesis
(RCM) strategy to close the central 8-membered ring (disconnec-
tion A). However, the realization that the required substrate 18
would take many steps to build, and the fact that the stereocentres
at C1 and C8 would have to be formed with two separate enantio-
a. LiAlH4, Et2O (72%)
Me
Me
Me
Me
b. KH, AcCl (89%)
c. Na, tBuOH (82%)
Me
Me
Me
Me
[gram scale]
H
H
H
H
Me
Me
O
>1 g of (+)-7
has been
prepared to date
(+)-6
(+)-7
'Taxadienone'
Taxadiene
selective reactions, dissuaded us from pursuing this route. An Figure 3 | Elaboration of (1)-taxadienone (6) to (1)-taxadiene (7) by a
aldol route was then conceived, partly due to the facile formation three-step reduction–deoxygenation sequence. Conditions: a. LiAlH4
of 19 via ketone 15 (disconnection B). Although installation of (3.0 equiv.), Et2O, –78 8C to room temperature, 12 h (72 %); b. KH
the stereocentres at C1 and C8 might still require two independent (7 equiv.), acetyl chloride (4 equiv.), THF, 60 8C, 18 h (89%); c. Na
enantioselective transformations, the hope was that the reaction (18 equiv.), Et2O, HMPA, tBuOH, room temperature, 40 min (82%)48. Sites
conditions used for the aldol cyclization would concomitantly of oxidation installed onto taxadiene (7) are indicated in red.
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© 2011 Macmillan Publishers Limited. All rights reserved.
23

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1196
ARTICLES
Me
Me
Me
oligomers and polymers. This problem was solved using high
dilution conditions (running the reaction at ꢀ0.01 M) and by
the slow addition of substrate 16 to the Lewis acid solution (see
Supplementary Information).
Developing a scalable route to the taxane core involved the study
and modification of fundamental aspects of the described chemistry,
rather than a mere exercise in scaling up. The conciseness of the
synthetic route is a direct result of trying to achieve a scalable
synthesis, and the reliability of the yields attests to the small
variability of reactions run on a larger scale50.
Me
8
C: Shapiro/aldol/
Diels–Alder
Me
Me
Me
Me
8
A: RCM
1
Me
O
H
Me
H
H
O
Me
O
Me
Me
18
20
D: later-stage
1,4-addition at
C8
Me
Me
X
Me
8
H
8
3
B: aldol
Me
O
(+)-6
Me
Me
Me
Me
1
2
'Taxadienone'
14
H
O
O
O
21
19
X = H or R3Si
Despite the efficiency of the described approach, there are two
obvious limitations in the synthesis of taxadienone (6): (i) the
single functional group manipulation from cyclized diketone 17 to
the corresponding enol triflate (rendering the route 85% rather
than 100% ideal)42 and (ii) the 2:1 diastereoselectivity in the aldol
reaction of 14 and acrolein. These issues are currently being
addressed by (i) developing a scalable, one-step enol triflation/
methyl coupling reaction and (ii) generating creative acrolein
equivalents and/or reaction conditions with various additives to
increase the diastereoselectivity of the aldol step.
Figure 4 | Initial synthetic investigations towards the synthesis of
taxadienone (6). Disconnection A: an RCM approach would require many
more steps in building the taxane framework. Disconnection B: the required
aldol closure simply did not proceed. Disconnection C: a Shapiro reaction,
followed by aldol and Diels–Alder reactions, is strategically similar to the
successful synthetic route, but the stereochemistry at C8 could not be set
stereoselectively. Disconnection D: conjugate addition at C8 to install the
methyl unit did not proceed, because only the undesired conjugate addition
onto C14 occurred.
In summary, a scalable, enantioselective entry to the taxane
family of natural products was achieved in only seven steps from
commercially available starting material (18–20% overall yield).
This triply convergent approach to taxa-4(5),11(12)-dien-2-one
(6) allowed for a minimization of concession steps, in which 6 of
7 steps formed skeletal (C–C) bonds. Every one of these steps
was performed on a gram scale, attesting to the scalability and
robustness of the sequence. Furthermore, (þ)-taxadiene (7) was
because reaction first occurred at the less hindered C14, even when a
large tert-butyldiphenylsilyl group was appended at C14. After
many more strategic revisions and success in forming the required
C2–C3 bond from TMS enol ether 14 using Gd(OTf)3, the final
synthetic strategy depicted in Fig. 2 was realized.
Tactically, although quite efficient at present, most steps shown
in Fig. 2 were initially difficult to scale and suffered from low and synthesized, enabling further structural confirmation, as well as
inconsistent yields. Even the first transformation from 8 to 10 the first optical rotation determination of this natural product.
(Fig. 2) was not trivial, despite it being a known two-step transform- The simple chemical route to (þ)-7 nicely complements the
ation35,40,41. Modifying the reaction stoichiometry and reaction recent pioneering studies of Stephanopoulos and co-workers22
,
whose bioengineering strategy also delivers gram-scale quantities
of (þ)-7, albeit as a 9:1 mixture of olefin isomers (taxa-
4(5),11(12)-diene (7) and taxa-4(20),11(12)-diene) (see
Supplementary Information). Studies are currently under way to
make use of the existing functional group handles in 6 to oxidize
various sites on the taxane skeleton and to create a pyramid-like
library of unnatural and natural taxanes en route to Taxol (1).
times was necessary to coax this process into giving good yields
consistently on a decagram scale, with eventual success as a one-
pot operation. The second transformation, a merging of the two
similar-sized fragments 10 and 11, can be conducted in good
yields (86%) on a decagram scale, but initially this reaction was
plagued with inconsistent yields due to side-product formation:
.
the original reaction conditions of tert-butyllithium, BF3 OEt2 and
CuI resulted in 1,6-addition of tert-butyllithium (whereas sec-butyl-
lithium is not a very competent nucleophile for this reaction), iodi-
nation of 12 (whereas the use of CuBr SMe2 circumvents this
Received 22 August 2011; accepted 10 October 2011;
published online 6 November 2011
.
problem), and deconjugation of 12 to give a b,g-unsaturated
ketone (this problem was rectified by optimizing the work-up
procedure; see Supplementary Information). The third, asymme-
try-inducing step43 from 12 to 14 was straightforward when run
on a small scale (,100 mg) and delivered high enantioselectivity
with 0.5 mol% CuTC and 1 mol% ligand loading. However, on
increasing the reaction scale to a gram scale, the reaction conversion
suffered significantly. Eventually, a higher catalyst loading (2 mol%
CuTC and 4 mol% ligand) and precise temperature control allowed
this reaction to give reliable yields and consistent enantioselectivity
on a gram scale. Also worth mentioning is a modified quenching
procedure that was developed to address the troublesome TMS
trapping of the aluminium enolate43 (vide supra).
The fourth and the most difficult reaction was the aldol reaction
of 14 and acrolein, which only returned desilylated ketone 15 under
most reaction conditions. Avariety of Lewis acid-mediated reactions
(vide supra), as well as anionic silicon–metal exchange reactions,
never led to the desired product. This aldol reaction only proceeded
when lanthanide triflates such as Yb(OTf)3 or Gd(OTf)3 and very
specific solvent systems were used. The final challenge was a scalable
Diels–Alder reaction from 16 to 17, which has been known to
proceed in moderate yields on similar substrates35–37. Although
efficient on a small scale, the yield decreased when the reaction
was conducted on a gram scale, possibly due to the formation of
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to P.S.B.
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