Two-Phase Synthesis of Taxol

Article abstract of DOI:10.1021/jacs.0c03592

Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.

Full text of DOI:10.1021/jacs.0c03592

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Article
Two-Phase Synthesis of Taxol®
Yuzuru Kanda, Hugh Nakamura, Shigenobu Umemiya, Ravi Kumar Puthukanoori, Venkata
Ramana Murthy Appala, Gopi Krishna Gaddamanugu, Bheema Rao Paraselli, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03592 • Publication Date (Web): 14 May 2020
Downloaded from pubs.acs.org on May 14, 2020
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Two-Phase Synthesis of Taxol®
Yuzuru Kanda†, Hugh Nakamura†, Shigenobu Umemiya†, Ravi Kumar Puthukanoori‡, Venkata
Ramana Murthy Appala‡, Gopi Krishna Gaddamanugu‡, Bheema Rao Paraselli§, Phil S. Baran†*
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†Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
‡Chemveda Life Sciences, Pvt. Ltd., Plot No. B – 11/1, IDA Uppal, Hyderabad, Telangana 500039, India.
§Chemveda Life Sciences, Inc., 9920 Pacific Heights Blvd, Suite 150, San Diego, CA 92121, United States.
ABSTRACT: Taxol® is widely regarded as amongst the most famed natural isolates ever discovered, and has been the
subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled
with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its
preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically-guided access to
synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and
eventual commercialization have relied upon natural- (plant material) or biosynthetically-derived (synthetic biology)
supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of
biosynthetic machinery for terpene synthesis can be used to arrive at Taxol®.
secondary alcohols creates a chemoselectivity puzzle of
the highest magnitude. In the early 1990’s, at least 30
teams18 competed for finishing the synthesis first, and all
completed syntheses, regardless of date, have been
deservingly heralded as major (even “herculean”)1
accomplishments in the annals of organic chemistry. A
relatively concise totally synthetic approach to 1 has been
widely viewed as impossible, with one textbook
(published in 2007) declaring that “…even an academic-
type synthesis of 1 poses a major challenge, unlikely to be
solved by a preparation under 30 or 40 steps in length”.9
This prediction had so far proven true, as ten distinct
syntheses have been disclosed (from 1994 to 2015).19-31 Of
those, seven have reported totally synthetic approaches
and three have described formal syntheses that
Introduction
Taxol® (1, Figure 1) stands as amongst the most famous
terpene-based natural products to be used in a clinical
setting.1 Registering >$9 billion in sales between 1993 and
20022 for use as an anticancer agent, Taxol is still
prescribed today in generic form, and alternative
formulations such as Abraxane® (albumin-bound) have
generated >$5.5 billion in revenue as of January 2020.3
Numerous other taxanes have either been approved by the
FDA, or are in various stages of clinical development.4–6
The storied history of Taxol in society began in ancient
times and has been narrated in numerous books and
reviews.1,7–10 After the molecule’s iconic structure was
fully elucidated in 1971,11 and clarity regarding its unique
mechanism of action was revealed in 1979,12 numbers of
clinicians, formulations experts, biologists, and chemists
contributed to its eventual use as a life-saving medicine in
1992.13 Taxol has stimulated research in nearly all
branches of chemical science, including medicinal,
natural product, engineering, chemical biology,
biochemistry, and last but not least, synthetic organic.
Historically, the clinical use of 1 relied exclusively on
semisynthesis,14,15 both for the preparation of analogs
(from 2), and as the initial commercial source before the
advent of a synthetic biology-based route using plant-cell
cultures.16,17
intercepted known intermediates. From
a strategic
perspective, three of these syntheses used naturally-
occurring terpene starting materials (e.g. 3),19,20, 23,24,27 six
of them fused two chemically synthesized six-membered
ring systems to form the central eight-membered ring (e.g.
4),21,22, 25,27–31 and one built out by double annulation onto
an already-constructed eight-membered ring (e.g. 5).26
Previous approaches to 1 showed that it was feasible to
create such a molecule in the lab and paved a foundation
for future approaches to taxanes. However, these
pioneering studies remained within the realm of academic
research as they did not form a basis for scalable chemical
production of 1 or a viable medicinal chemistry campaign
to explore taxane bioactivity. Obviously, the quantity of
chemically synthesized 1 by these efforts (or ours) can
never match the metric ton quantities prepared yearly
through plant-derived sources. Aside from efficiency,
another salient feature of taxane biosynthesis is its
inherent divergency and the formation of hundreds of
differentially oxidized analogs. It is this feature of
biosynthesis that we sought to mimic in the two-phase
Structurally, this heavily-oxygenated polycyclic
diterpenoid presents a monumental challenge for total
synthesis due to the dense orientation of functionality that
render precise and predictable manipulations difficult.
Any route to such a molecule must address the issue of a
conformationally flexible central eight-membered ring
system, which makes the neighboring reactivity of various
functional groups unpredictable and substrate-dependent.
In addition, the congested array of similarly reactive
1
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retrosynthetic approach. Since prior approaches followed
the canonical rules of retrosynthetic analysis (e.g.
maximizing convergency) to establish the feasibility of
accessing specifically 1, actual taxanes (compounds
containing the full carbon skeleton) are not accessed in
those syntheses until late in the sequence.
Page 2 of 9
known as an “oxidase-phase”. This ingenious synthetic
plan, despite being linear rather than convergent, benefits
strategically from near-perfect redox economy and
ideality. Divergent access to analogs is encoded into this
logic, as each oxidative event during the oxidase-phase
potentially gives rise to different bioactivity; thus, the
oxidase-phase represents a superb medicinal chemistry
machinery from an evolutionary standpoint. It therefore
stands to reason that designing a chemical synthesis
patterned off this biosynthetic route for structures as
complex as 1 could harbor similar divergence, in contrast
to conventional abiotic approaches to 1 that have been
reported to date.
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In 2009, we disclosed a proof-of-concept to efficiently
access highly oxidized terpenes that holistically mimics
this underlying logic of biosynthesis.34 Two-phase terpene
synthesis logic, despite lacking convergency, could be
applied to concise syntheses of complex systems such as
ingenol,35 phorbol,36 thapsigargin,37 and others.38,39
Application of this strategy to the non-skeletally
rearranged taxanes,40 of which 1 resides at the apex of
structural complexity, remained aspirational for the past
decade. This can be visualized in Figure 1, with a
hypothetical retrosynthetic pyramid for the two-phase
synthesis of 1 requiring a chemist to navigate no less than
nine different C–O bond forming steps from a minimally
oxidized taxane precursor such as taxadienone (9). Initial
progress towards this goal was registered in 2012 with the
scalable synthesis of enantiopure 9 and taxadiene (6)
through
a
concise
cyclase-phase.41
Although
bioengineering approaches to
6
are known,42 our
laboratory has been a primary supplier of this molecule to
numerous groups around the world (nine as of this
writing). Extensive studies were then performed to
decipher the innate reactivity of 6 towards allylic
oxidation (installation of C–5, 10, and 13) culminating in
the total synthesis of taxuyunnanine D (8).43 Translating
those lessons to the total synthesis of taxabaccatin III (7)
via 9 was successful.44 As aforementioned, the vexing
arrangement of oxygenation required more than a
consideration of chemo-, regio-, and stereoselectivity
which Nature mastered using eons of evolution with
enzymes. Scheme 1 outlines a route to 1 that overcomes
such challenges.
Figure 1. Approaches to the synthesis of Taxol (1): Semi-
synthesis, canonical total synthesis, biosynthesis, and two-
phase synthesis (this work).
The goal of this study, initiated in 2007, was to answer
to a fundamental question of whether an approach to
terpene synthesis loosely patterned on the logic of
biosynthesis, would enable a hypothetical medicinal
chemistry approach to taxanes in the absence of a viable
semisynthetic option. Herein we present the realization of
Two-phase synthesis of Taxol®
Starting from simple feedstock-derived building blocks
10-13, the cyclase-phase published in 201241 underwent
significant optimization and was initially accomplished
using flow chemistry by Albany Molecular Research Inc.
(AMRI) to deliver multigram quantities of 14.45
Subsequently, our collaborators (Chemveda) devised a
semi-process scale 2nd generation cyclase-phase route
through the following modifications (see SI for full
summary and graphical procedure): (i) use of alternative
solvents for extracting volatile intermediates to simplify
workup; (ii) replacement of s-BuLi with less expensive n-
our ultimate goal: a two-phase synthesis of Taxol®(1).
Nature’s route to complex terpenes is well-documented
and enlists two conceptually different types of
enzymes32,33. The first class of enzymes (cyclases) forges
C–C bonds to generate complex hydrocarbon-based
frameworks in what is known as a “cyclase-phase”. These
minimally oxidized terpenes are then processed by a
second set of enzymes that install C–O bonds in what is
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Journal of the American Chemical Society
Me
Me
Me
H
Me
H
O
Me
Me
Me
Me
a. Cr(V)
b. CuBr2
1
2
3
4
5
6
7
8
Me
Me
Me
Me
O
13
[gram scale]
(55%, 2 steps)
[gram scale]
2
• simple workup
• no s-BuLi • short
10
12
H
H
OEt
O
O
O
O
14
O
15
5
reaction time
13
CHBr3
11
17
O
Na
O
• simple ligand [>100 g prepared]
O
13
Cr
Cr(V): Et
O
c. NBS, BPO then
• recrystalization (96% ee)
(68%)
[gram scale]
O
O
Me
(see ref. 40 for 1st gen)
Me
O
DTBMP, Ag(I), TESOH
Et
e. MeMgBr
then DIBAL
then LiAlD4
(74%)
16
TESO
TESO
TESO
TESO
Me
Me
13
Me
18 Me
O
10
10
d. LiBr,
Li2CO3
Me
H
Me
H 4
Me
Me
6
9
g. DMDO
6
5
Me
Me
Me
Me
Me
Me
Me
Me
R1O
O
R1O
O
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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50
51
52
53
54
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57
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60
5
(49%)
[gram scale]
(88%)
[gram scale]
f. NaHMDS,
TBSCl
(94%)
[gram scale]
Br
H
1
H
2
Me
2
Me
OH
HO
H
H
H
OH
O
O
D
D
HO
21
HO
20
O
19
O
18
R1 = TBS
h. TPAP, NMO
[gram scale]
(81%)
TESO
j. TBAI,
BF3•OEt2
then
Me TES
O
TESO
TESO
Me
HO
Me
Me
Me
then
triphosgene
Me
H
Me
7
Me
Me
i. Na,
i-PrOH
X
6
2-Fpyr
2
Me
Me
Me
Me
Me
Me
R1O
O
R1O
R1O
O
HO
4
H
5
OH
then
TMSimid
then
(51%, 2 steps)
[gram scale]
OR2
1
Me
4
H
2
H
Me
Me
2
Me
OH
Me
R1O
O
O
HO
OH
OH
O
24
O
O
22
O
(R2, X)
H, I
TMS, I
TMS, I=O
DMDO
23
25a
25b
25c
O
O
TESO
TESO
TESO
TESO
m. Burgess
reagent
OBOM
5
OBOM
7
Me
Me
Me
Me
k. Ti(III)
(67%)
Me
Me
H
Me
H
Me 7
O
then
DMDO
7
6
then HF
Me
Me
6
Me
Me
Me
Me
Me
Me
R1O
R1O
R1O
R1O
5
l. BOMCl
(84%)
[gram scale]
(43%)
(32%)
OR2
Me
OH
4
20
OR2
OR2
H
H
Me
Me
O
O
O
O
O
O
O
OH
HO
HO
O
O
O
O
29
28
27
26
O
n. MsCl
then OsO4
(68%)
q. KOt-Bu
then
triphosgene
then Ac2O
TESO
O
10
O
AcO
10
OH
Me
O
Me
OBOM
Me
OBOM
OBOM
OBOM
9
9
Me
Me
Me
Me
p. KOt-Bu,
(PhSeO)2O
o. DIPEA
Me
then IBX
Me
Me
Me
Me
Me
Me
Me
Me
R1O
R1O
R1O
R1O
5
(60%)
(62%)
(73%)
OMs
OH
O
O
O
4
H
H
H
H
OH20
OH
OAc
O
O
HO
O
O
20
O
O
OH
32
O
OH
30
31
33
O
O
s.
O
OBn
r. TASF
then PhLi
(48%)
BzN
Oxidation Choreography
early
Ph
35
TESO
AcO
HO
AcO
Me
O
Me
O
Me
OH
7
OBOM
middle
late
Me
Me
13
LHMDS then
H2, Pd/C
10
Me
H 4
NHBzO
7
5, 10/13 9, 7, 2 1/4/20
2, 13, 5 10, 1, 7 4/20, 9
• PG guided C1 oxidation
• masked oxidations
• steric controlled C1 oxidation
and C2 reduction
Biosynthesis
Two-Phase
Me
Me
Me
Me
Me
Me
6
R1O
Ph
O
HO
13
13
5
(85%)
OH
Taxol® (1)
O
O
1
2
H
H
Me
2
H
HO
OH
OAc
OAc
D
HO
OBz
OBz
34
step a
Solvent
step c
step g
step j
step k
BF3 quencher
Yield [%]
(C5,C6)
Solvent [M]
Yield [%]
Yield [%]
C4
C10:C18
1:1
Result
Additive
trace
20
trace
trace
50
20-25
29
25a + 24
25b + 24
25a
42
low conv.
low conv.
ca. 35
PhCF3
MeCN
HFIP
β-OH, α-Me
β-OH, α-Me
ketone
olefin
CH2, CH2
olefin
CH2, CH2
Br, CH2
acetone (0.09)
DCM (0.21)
CHCl3 (0.19)
BSA
none
collidine, TMSCl
H2O
trace product
pyridine
2,6-lutidine
DTBP
1:1
1:1
1:0
34
22
49
ketone
ketone
25a
25b
TMSOH
HFIP, TMSOH
acetone:CHCl3 = 1:1 (0.05)
CHCl3 (0.30)
i-PrOH
Et3SiH
2-Fpyridine
67
Scheme 1. Two-phase synthesis of 1. Reagents and conditions are as follows. (a) Cr(V) (16), HFIP, TMSOH, t-BuOH, 80
ºC. (b) CuBr2, THF, rt, 55%, over 2 steps. (c) NBS, BPO, CCl4, then DTBMP, AgOTf, TESOH, 4Å MS, PhMe, rt, 68%. (d) LiBr,
Li2CO3, DMF, 100ºC, 88%. (e) MeMgBr, DCM, 0 ºC to rt, then DIBAL, -78 ºC, DCM, then LiAlD4, THF, 60 ºC, 74%. (f) NaHMDS,
TBSCl, THF, 0 ºC to rt, 94%. (g) DMDO, 0 ºC, 49%. (h) TPAP, NMO, DCM, rt, 81%. (h) Na, i-PrOH, Et2O, rt, then triphosgene,
pyr, DMAP, DCM, -78 to 0 ºC. (j) TBAI, BF3•OEt2, DCM, -78 ºC, then 2-Fpyr, -78 ºC, then TMSIm, rt, then DMDO, -78 ºC to
rt, 43%. (k) Cp2TiCl, Et3SiH, THF, -78 ºC to rt, 67%. (l) BOMCl, TBAI, DIPEA, DCE, 45 ºC, 84%. (m) Burgess reagent, PhMe,
dioxane, then HF, H2O, pyr, MeCN, rt, 32%. (n) MsCl, pyr, 0 ºC to rt, then OsO4, THF, pyr, 0 ºC to rt, 68%. (o) DIPEA, PhMe,
then IBX, DMSO, H2O, 80 ºC, 62%. (p) KOt-Bu, (PhSeO)2O, THF, H2O, -78 to 0 ºC, 73%. (q) KOt-Bu, THF, then triphosgene,
pyr, DMAP, DCM, -78 to 0 ºC, then Ac2O, DMAP, pyr, rt, 60%. (r) TASF, THF, rt, then PhLi, THF, -78 °C, 48%. (s) -lactam
(35), LHMDS, THF, -78 ºC to rt, then Pd/C, H2, EtOH, 80 ºC, 85%.; HFIP, hexafluoroisopropanol; TMSOH, trimethylsilanol;
3
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NBS, N-bromosuccinimide; BPO, benzoyl peroxide; DTBMP, 2,6-di-tert-butyl-4-methylpyridine; TESOH, triethylsilanol;
DIBAL, diisobutylaluminium hydride; HMDS, hexamethyldisilazane; TBSCl, t-butyldimethylsilyl chloride; DMDO,
dimethyldioxirane; TPAP, tetrapropylammonium perruthenate; NMO, N-methylmorpholine N-oxide; pyr, pyridine; DMAP, 4-
dimethylaminopyridine; TBAI, tetra-n-butylammonium iodide; 2-Fpyr, 2-fluoropyridine; TMSIm, N-(trimethylsilyl)imidazole;
Cp2TiCl, bis(cyclopentadienyl)titanium(III) chloride; BOMCl, benzyl chloromethyl ether; DIPEA, N,N-diisopropylethylamine;
DCE, 1,2-dichloroethane; MsCl, methanesulfonyl chloride; IBX, 2-iodoxybenzoic acid; TASF, tris(dimethylamino)sulfonium
difluorotrimethylsilicate.
1
2
3
4
5
6
7
8
9
BuLi; (iii) use of a more easily-accessible ligand to set the
stereochemistry; (iv) development of an operationally-
convenient and reproducible enolate trapping sequence;
(v) shorter reaction time; and (vi) development of a
simple recrystallization protocol for purification. In this
way, ca. 110 grams of 14 were prepared in a simple batch
protocol. Lessons from previous studies on the selective
C–H functionalization of allylic C–H bonds in the taxane
core suggested that oxidation at C–13 would be feasible.
It was found that the solvent played a decisive role in
controlling the regioselectivity (as three allylic positions
can be oxidized) and conversion to enone 15 using the
Cr(V)-based oxidant 16.43,46 As shown in the inset table
for step a, a unique protic and non-nucleophilic mixture
of HFIP/TMSOH (2:1) exhibited critical synergy to
achieve the high C–13 selectivity over C–11 to afford 15,
which could be carried on directly to the next reaction
with minimal purification. It has been speculated that the
mechanism of this oxidation putatively involves a cationic
intermediate.47 This tri-carbonyl-bearing scaffold was
selectively brominated at C–5 rather than C–1, C–3, C–10,
or C–14 using CuBr2, delivering 17 (whose structure was
undoubtably confirmed by X-ray crystallography) in 55%
isolated yield (19-gram scale). This high selectivity
stemmed from the fact C–1 and 2 are virtually non-
enolizable, and the C–14 enolate would form a strained
bridgehead diene. Bromination at this stage was essential,
as it served as a placeholder for the eventual C–5 and C–
7 oxidations and also drove subtle conformational shifts
that enabled complete selectivity in the ensuing C–H
allylic oxidation at C–10 (see inset table for step c, and SI
for discussion). Radical-based oxidation of C–10 took
place smoothly following our 2014 protocol,43 proceeding
through a dibromide (C–5/10) that could be selectively
displaced at C–10 with TESOH in the presence of Ag(I) to
deliver 18 in 68% isolated yield (gram-scale). Elimination
of the C–5 bromide under standard conditions
(LiBr/Li2CO3) afforded di-enone 19 in 88% isolated yield
on gram-scale. To set the stage for the pivotal C–1
oxidation, the last carbon atom of the taxane core was
installed, the C–13 stereochemistry was set, and a
deuterium atom was strategically placed onto C–2; that is,
taxane 20 was produced from 19 by sequential addition
of MeMgBr and DIBAL, and then LiAlD4 (relative
reactivity dictated by C–19, 11 and 20 methyl groups,
respectively) followed by TBS installation in 67% yield
over two transformations (gram-scale). The remarkable
site-selectivity in functionalizing 19 was enabled by
exploiting the unique steric and electronic features
associated with each carbonyl group. A complex matrix of
experiments across multiple taxanes (see SI) revealed
substrate 20 to be ideally suited to chemo- and
stereoselective oxidation events using DMDO in step g to
diastereomer (gram-scale).48 The Δ11,12-olefin remained
intact because of the steric shielding by C–10 and 13
substituents as well as the nature of this hyperstable
olefin.49,50 The stereoselectivity of the Δ5,6-olefin
epoxidation was guided by the C–19 methyl group. The
solvent (CHCl3, which presumably enhances the reactivity
of DMDO through H-bonding) and concentration choice
were essential (see inset table for step g)51,52 as was the
precise functionality expressed in taxane 20. Thus, if C–2
bearing alcohol did not have the -stereochemistry
(presumably prevents C–2 from directing oxidation
elsewhere)53 and -deuterium incorporation (9% with C–
2 α–H, see SI),54–57 or if C–4 did not bear full substitution,
rapid oxidation back to the C–2 ketone took place with
little to no observable hydroxylation at C–1 (see SI).
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11
12
13
14
15
16
17
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19
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25
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60
The second half of the synthesis began with TPAP-
mediated58 oxidation of C–2 (22, 85% isolated yield,
gram-scale). Thermodynamic reduction of the ketone
using Na/i-PrOH59 followed by addition of triphosgene to
epoxy-triol 23 furnished carbonate 24 in 51% isolated
yield (gram-scale) with the C–5/6 epoxide left completely
unscathed. As with the oxidation in step g, the
stereochemistry and right balance of sterics at C–4 again
played an important role in enabling this outcome,
presumably due to its staggered conformation relative to
the C–2 α-keto radical intermediate during the reduction.
The stage was now set for a redox-relay event to
stereoselectively install the C–7 oxygen atom. This
maneuver was achieved without isolation of unstable
intermediates in one-flask through a carefully designed
sequence involving the addition of orthogonally reactive
and volatile reagents. In the event, taxane 24 was exposed
to TBAI/BF3•OEt2 to regioselectively (via stereoelectronic
guidance) afford the corresponding iodohydrin 25a,
followed by addition of 2-fluoropyridine to sequester
boron-salts. As indicated in the inset table, the use of
other additives and alternative bases led to low yields,
stemming from incomplete reaction (26) and/or
reformation of 24. Immediate capping at C–5 with a TMS
group (TMS-imidazole), followed by addition of DMDO,
led to iodine-oxidation and spontaneous syn-elimination
of iodoso 25c to liberate olefin 26, which could be further
stereoselectively oxidized to epoxy-taxane 27 in 43%
isolated yield.60 Regioselective elimination through 25c
was essential, as E2 elimination of the corresponding
iodide 25b did not take place due to steric hindrance
around C–7 and C–5 syn hydrogen was conformationally
less accessible. It is important to note that this sequential
addition design proved to be essential in practice, as 25a
was found to revert to 24 upon isolation. Ti-mediated,
sterically-guided, regioselective reductive lysis of the
epoxide in the presence of Et3SiH followed by BOM
installation proceeded in 56% isolated yield to furnish 28
deliver epoxy-triol 21 in 49% yield as
a single
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Journal of the American Chemical Society
(gram-scale).61 The use of triethyl silane as reductive
the sequence.26 Such issues cannot be resolved by creative
engineering solutions or sophisticated analytical
chemistry, as Takahashi has shown with the fully
automated formal synthesis of 1 that delivered 0.0001 g
of baccatin III after 44 machine-automated
transformations.27 While the current synthesis offers no
benefit in terms of overall yield, and clearly was not
developed in a vacuum and benefitted from the many
pioneering syntheses that came before, it does however
provide a conceptual blueprint for how a viable medicinal
chemistry evaluation could take place without semi-
synthetic approaches. Furthermore, since multigram
quantities of the full taxane skeleton are accessed at a very
early stage (step e), this could serve as a new platform for
further analogue synthesis combined with the known
structure-activity relationships of 1 (as demonstrated
with 6, 7, and 8).65,66 Since taxanes only exhibit useful
bioactivity when a C–13 sidechain is present, it is notable
that our route mirrors biosynthesis in that the proper
oxidation is installed at C–13 very early in the synthesis
(step a) rather than at a late-stage as in most of the past
routes (see Scheme 1 oxidation choreography for a
summary). The strategic advance of this two-phase
retrosynthesis is reinforced by the fact that all of the
methods employed to access 1 were, in principle, known
and available to past practitioners. The robust nature of
these reactions ensured that two-thirds of the
transformations in this synthesis could be conducted on a
gram-scale.
1
quenching agent in Ti-mediated epoxide reduction is, to
the best of our knowledge, without precedent, and
increased both the yield and robustness of the
transformation (see inset table for step k). At this juncture,
28 structurally resembled one of Holton’s intermediates
and the following transformations were thus heavily
inspired by their findings.20 The tertiary alcohol at C–4,
which played a pivotal role in numerous transformations,
was dismantled through Burgess dehydration, followed
by addition of HF•py to afford allylic alcohol 29 in 32%
yield, accompanied by a C–5 ketone side product (see SI,
compound SI-13). Next, the C–5 hydroxyl group was
activated with MsCl and the resulting allylic mesylate
(which could not be isolated due to its instability) was
immediately subjected to dihydroxylation using OsO4 to
deliver oxetane-precursor diol 30 in 68% isolated yield.
Oxetane formation was achieved using a hindered amine
base (DIPEA), and subsequent addition of IBX directly
oxidized the C–10 allylic -OTES group to the C–10 enone,
forming 31 in 62% isolated yield. C–9 oxidation took
place first, using a modification of Holton’s conditions
(KOt-Bu and water/(PhSeO)2O) to deliver 32 (with the
cyclic carbonate cleaved) in 73% yield. Redox-
isomerization (KOt-Bu) and quadruple acylation to
reinstall the cyclic carbonate and acetylate C–4/10
proceeded smoothly to afford taxane 33. Tandem
desilylation at C–13 and addition of PhLi gave rise to
baccatin III bearing a BOM group at C–7 (34) in 48%
isolated yield.24 The total synthesis of 1 could be
completed by Ojima-acylation62 using -lactam 35 and
the Li-alkoxide of 34, followed by hydrogenation in 85%
isolated yield. The use of 35, which has not been utilized
in the context of taxane synthesis before,63 enabled more
direct access to 1. This sequence could be performed with
high reproducibility through the isolation and
purification of 22 intermediates and has been used to
prepare 35.2 mg of 1 in multi-batch fashion.
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60
Conclusion and Outlook
It is worth recounting some of the key lessons, tactics,
and maneuvers that enabled the current route to 1. As
with the biosynthetic two-phase approach, this synthesis
focuses mostly on the oxidase-phase and thus the precise
choreography of O-installation was critical to access the
target. C–2 was chosen as the first oxygenation not only
due to the retrosynthetic simplification it enabled during
the cyclase phase but also because of its critical role in
bioactivity.66 Oxidation of C–13, 5 and 10 gave the best
material throughput in this order. These oxidations were
rapidly completed based on our previous work43,44 to set
the stage for the key C–1 oxidation. The challenge of
installing C–1 and C–7 could be addressed in unison
through careful selection of neighboring functionality and
redox-relay through a C–5/6 epoxide group. The C–7
oxidation state was installed through a carefully designed
redox relay originating from the C–4 ketone, the C–5
Discussion
It is worth contrasting the strategy employed in Nature
with the pioneering syntheses that preceded this work. As
aforementioned, the biological two-phase approach to 1 is
rather linear, requiring no fewer than 20 different
enzymes (2 in the cyclase-phase and 18 in the oxidase-
phase).32,33,64 Each transformation takes place in high
yield and intermediates are individually sequestered
leading to incredible efficiency and scalability.
Conventional retrosynthetic analysis would teach that a
more convergent approach to 1 should be a better solution
for procurement in the laboratory. Yet, as history has
proven, such designs so far did not succeed in
meaningfully adding to the supply of 1. This issue stems
from the sheer number of manipulations required by all
syntheses (including our work). A potential approach for
medicinal chemistry explorations was uncharted because
bromide, the C–5/6 epoxide, the C–6 iodide, the Δ6,7
-
olefin, the C–6/7-epoxide, and finally to the C–7 alcohol.
As the supporting information detail, multiple
generations of strategies were evaluated before finalizing
this pathway. This is clearly a weakness of the two-phase
design with regards to one of the most densely
functionalized terpenes known. In biosynthesis,
enzymatic hydroxylation events accomplished through
eons of evolution don’t necessitate protecting groups or
functional group manipulations and are largely
impervious to subtle substrate modifications. C–4 and C–
20 benefited from simple dihydroxylation of an olefin,
and the pioneering work of Holton20 guided the final C–9
oxidation (and stereochemistry thereof).
prior
retrosynthetic
designs
accessed
taxanes
(compounds bearing the complete carbon skeleton) late
into the syntheses, a challenge the present approach
overcomes. To be sure, of the 10 syntheses reported,
actual taxanes are accessed half-way21 or near the end of
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While this synthesis does employ protecting groups (C– substrate that needs to be prepared when a particular
Page 6 of 9
1
2
3
4
5
6
7
8
5, C–7, C–10, and C–13) their effect was maximized by
strategic selections and allocations so that analogous
functional groups were well differentiated throughout the
synthesis – e.g. simultaneous installation of an –OTES
group upon C–H oxidation (C–10) or tandem removal
during oxidation (C–10) in the presence of –OTBS (C–13).
The silyl groups at C–13 and C–10 did play a pivotal role
in shielding the bridgehead olefin from oxidation.
Unconventional means of protecting functionality and
directing reactivity were also employed including the use
of deuterium (kinetic isotope effect) at C–2,67 a bromine
atom at C–5, a tertiary alcohol at C–4, and an epoxide at
C–5/6. The dense functionality innates to 1 enabled
unique positionally selective reactions such as the
reactivity of a tricarbonyl (step e), the oxidation at C–1
(step g), and the stability and reactivity of epoxide
intermediates (steps h-j). Reactive intermediates (c, j, n,
and q) could also be utilized through consecutive
transformation fails.
As aforementioned, we began our campaign to access
Taxol® (1) to answer a fundamental thought-experiment:
Would a holistically-biomimetic approach enable an
unified medicinal synthetic campaign involving divergent
access to natural and non-natural taxanes at various
oxidation patterns? In one sense, if 1 were pursued by a
large pharma company in the absence of a natural supply,
this route would indeed enable such a study (where mg
quantities of each analog are needed). On the other hand,
the blueprint laid out herein, required deeply-
choreographed empirically derived manipulations unique
to each substrate’s reactivity. Thus, extensive effort would
be required and process chemists might choose a different
path to the final target. At the end of the day, chemical
synthesis to specifically access 1 will likely never be
competitive with a fully enzymatic approach. To avoid
unnecessary concession steps that beleaguer all syntheses
of 1, we predict that far more improved medicinal
chemistry-based approaches to novel taxanes could be
accomplished using a hybrid approach that employs
synthesis to generate carbon frameworks (for example
containing unnatural motifs) and enlists synthetic biology
for chemo- and site-specific oxidations.69 In the
meantime, the present synthesis demonstrates that two-
phase synthesis can open the possibility of divergent
access to taxanes, in contrast to classical synthetic
strategies.
9
10
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13
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20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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60
operations
in
order
to
achieve
challenging
transformations with minimal labor.
Through this unique opportunity of implementing the
“pyramid-climbing” approach to one of the most densely
functionalized terpenes (arguably, the most iconic
known), we could reevaluate the way one approaches
disconnections to other terpenes. The two-phase
approach is
a
synthetically high-risk/high-reward
strategy as we have demonstrated with other syntheses
(such as ingenol,35 phorbol,36 and thapsigargin37). As a
carbon skeleton of a target terpene is built in early stage,
all oxidase-phase reactions are essentially a late-stage
functionalization of a complex natural product. As the
oxidation level ascends, there are more and more
(similar) functional groups in a molecule; thereby,
protecting group manipulations and choice of substrate
compatible reagents and conditions become progressively
more challenging. However, all late-stage intermediates
can in principle be elaborated to bioactive candidates,
since a carbon skeleton is already present (akin to
Nature’s route). Such a route might pass through a low
yielding transformation, but that is typically a minor issue
when it comes to an initial medicinal chemistry campaign.
This leads to the second point that the two-phase
synthesis is a useful strategy depending on the context.
For example, the overall yield of Nicolaou’s convergent
Taxol synthesis was 0.0078%,21 while our linear two-
phase approach ended up yielding only 0.0014%.
Employing either approach for a target-oriented synthesis
(e.g. process chemistry) would be inappropriate and
result in poor material throughput. On the other hand,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Detailed experimental procedures and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Authors
*pbaran@scripps.edu
ACKNOWLEDGMENT
We are especially grateful to Yerram Reddy, V. K. R. and
Kokkirala, Y. V. of Chemveda for providing ample quantities
of compound 14. Financial support for this work was
provided by NIH (GM-118176), Funai overseas scholarship
(predoctoral fellowship to Y. K.), Honjo international
scholarship (predoctoral fellowship to Y. K.) and JSPS
(postdoctoral fellowship to H. N.). The early stages of this
program were funded in part by grants from TEVA, LEO
Pharma, Bristol-Myers Squibb, and The Scripps Research
Institute. We thank D.-H. Huang and L. Pasternack (Scripps
Research Institute) for assistance with NMR spectroscopy;
M. Gembicky (University of California, San Diego) for
assistance with X-ray crystallography; J. S. Chen, B. B.
Sanchez and E. Sturgell (Scripps Research Institute) for
assistance with LCMS analysis and HRMS analysis. We thank
the NOSAMS facility for conducting the isotopic analysis
(NSF Cooperative Agreement #OCE-1239667).
under
a circumstance where multiple non-specific
analogues were required (e.g. medicinal chemistry), the
two-phase strategy would be an extremely powerful way
of achieving maximal analog output. Lastly, we felt this
aspect was enabling for navigating the dead-ends and
detours often encountered in complex natural product
synthesis.68 Arrays of substrates possessing the same
carbon skeleton but slightly different reactivity due to
subtle differences in functional group arrangement enable
facile substrate screening. In contrast, a traditional
convergent synthesis might require
a
redesigned
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GRAPHICAL ABSTRACT
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