The Total Synthesis of Epothilone D as a Yardstick for Probing New Methodologies

Article abstract of DOI:10.1002/chem.201605011

Here, a concise and highly convergent synthesis of epothilone D was investigated, relying on fragments of equal complexity that could be prepared in gram scale quantities. The strategy to construct the fragments includes the use of a previously reported enantiospecific zinc-catalyzed cross-coupling of an α-hydroxy ester triflate with a Grignard reagent, the application of a hydroboration/boron–magnesium exchange sequence for the rapid construction of the Z-substituted trisubstituted double bond present in the natural product, and a Noyori-type hydrogenation to install the β-hydroxy ester moiety of the southern part. The key to success is the diastereoselective head-to-tail macrolactonization by an intramolecular addition of the corresponding ω-alkynyl-substituted carboxylic acids to construct a new stereocenter in the macrocyclic core structure in one single step.

Full text of DOI:10.1002/chem.201605011

A Journal of
Accepted Article
Title: All for One and One for All: The Total Synthesis of Epothilone D
Authors: Bernhard Breit and Alexander Haydl
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Chemistry - A European Journal
10.1002/chem.201605011
COMMUNICATION
The Total Synthesis of Epothilone D as a Yardstick for Probing
New Methodologies
Alexander M. Haydl and Bernhard Breit*
Abstract: Herein, we report on a concise and highly convergent
synthesis of epothilone D, relying on fragments of equal complexity
which could be prepared in gram scale quantities. The strategy to
construct the fragments comprises the use of our reported
enantiospecific zinc-catalyzed cross-coupling of an α-hydroxy ester
triflate with
a
Grignard reagent, the application of our
hydroboration/boron-magnesium exchange sequence for the rapid
construction of the Z-substituted trisubstituted double bond present
in the natural product and on a Noyori-type hydrogenation to install
the β-hydroxy ester moiety of the southern part. The key to success
is our diastereoselective “head-to-tail” macrolactonization by an
intramolecular addition of the corresponding ω-alkinyl-substituted
carboxylic acids to construct a new stereocenter in the macrocyclic
core structure in just a single step.
Figure 2. The polyketides epothilone A-D as representative examples of
macrolactone-based and highly bioactive natural products.
[14a]
macrolactones
could be obtained and furthermore this
approach proved successful in a number of total synthesis
[15]
reported by us in the recent past.
The use of ω-alkinyl-
substituted carboxylic acids also brought the same type of
Polyketides prevail in a large variety of natural products and hold
an up to five times higher chance to possess biological activity,
valuable macrocycles into reach, however to date only in a
[14b]
racemic fashion.
Driven by our curiosity as to whether this
[
1,2]
compared to any other class of natural products.
Aside from a
initial methodology would allow therefore a diastereoselective
approach of macrocycles just by substrate control in natural
high level of molecular complexity, natural products holding
macrocyclic lactones in particular exhibit a broad spectrum of
[16]
product syntheses, we targeted epothilone D (4, Figure 1).
[
3]
[4a,b]
biological activitiy,
such as antineurodegenerative,
Due to its enhanced antiproliferative activity against several
[
4c]
[4d]
[4e]
[4f]
anticancer, antibiotic, olfactory, and various others.
human cancer cell lines, the natural product family of the
Many different strategic approaches for the synthesis of
macrocyclic core structures, besides the classical lactonization
conditions by anhydride-type activation of the corresponding ω-
[17]
epothilones
has already garned significant attention from
organic chemists in the recent past, although from a medicinical
[18]
point of view their importance has waned.
[
5]
seco-acids have been reported in the recent past, including
Given the 16-membered macrolactone core, epothilone D (4)
was retrosynthetically dismantled as outlined in Scheme 1.
Hence, we envisioned that an intramolecular diastereoselective
hydrooxycarbonylation of the corresponding ω-alkinyl-
substituted carboxylic acid 5 might provide straightforward
[
6a,b]
[6c]
ring-closing metathesis,
Diels-Alder macrocyclization,
[
6d,e]
intramolecular cross-coupling reactions,
metal-catalyzed
[
6f-h]
coupling reactions,
or Horner-Wadsworth-Emmons-type
[
6i]
olefinations. However, the development of improved strategic
approaches facing modern demands for resource efficiency in
organic chemistry in order to construct macrolactones remains a
highly active and challenging field of research. Our research
[
7]
group developed a rhodium catalyzed atom-economical and
regioselective addition of pronucleophiles to allenes and
[
8]
alkynes, a method which could be seen as an alternative to
[
9]
[10]
metal-catalyzed allylic substitution and oxidation to generate
[
11]
branched allylic esters. Particularly the hydrooxycarbonylation
[
12,13]
reaction using carboxylic acids
as suitable pronucleophiles,
hence representing a C-O bond-forming addition reaction to
form branched allylic esters emerged as a suitable concept to
construct macrolactones. Emanating from ω-allenyl-substituted
carboxylic acids, a broad range of enantiopure branched allylic
[
*]
Dr. A. M. Haydl, Prof. Dr. B. Breit
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Envisioned retrosynthetic disconnection of epothilone D.
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Chemistry - A European Journal
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COMMUNICATION
Scheme 2. Preparation of the northern fragment. Reagents and conditions: a)
ZnCl
1 % ee; b) LiAlH
10 mol%), CH Cl , room temperature, 24 h, 86 %; d) [{Rh(CO)(PPh
1.0 mol%), HBpin, THF, room temperature, 6 h, 93 %;
,4-di(chloromagnesium)butane, ZnBr [{Pd(PPh Cl
toluene/THF, 0 °C then room temperature, 24 h, 91 %; f) aq. NaOH, I
room temperature, 2.5 h, 97 %; g) 16, tBuli, ZnBr , [{Pd(PPh Cl }] (5.0 mol%),
THF, -78 °C then room temperature, 18 h, 90 %; h) TBAF, THF, 18 h, room
temperature, 98 %; i) (COCl) , DMSO, CH Cl , -78 °C then room temperature,
h, 94 %. Bpin=pinacolboronate, DMSO=dimethylsulfoxide, TBAF=tetra-N-
2
(10 mol%), allylmagnesium chloride, THF, -10 °C the 0 °C, 3 h, 68 %,
9
4
. Et O, 0 °C, 2 h, 90 %; c) TBSCl, imidazole, 4-DMAP
2
(
(
2
2
3
)
2
Cl}]
e)
1
2
,
3
)
2
2
}] (5.0 mol%), 14,
, THF,
2
Scheme 3. Preparation of the southern fragment. Reagents and conditions: a)
(S)-18 (5.0 mol%), H2 (30 bar), EtOH, 75 °C, 12 h, 99 %, 92 % ee (94 %,
>99% ee after crystallization from cyclohexane); b) 2,6-lutidine, TBSOTf,
CH Cl , -78 °C then room temperature, 7 h; c) aq. NaHCO , THF, room
2
3
)
2
2
2
2
2
2
2
3
1
temperature, 16 h, 99 % (2 steps); d) EtMgBr, THF, 40 °C, 24 h, 89 %; e) (S)-
18 (5.0 mol%), H2 (80 bar), MeOH, 10 °C, 36 h, 99 %, 86 % ee; f) TFA, CH Cl ,
butylammonium fluoride, TBS=tert-butyldimethylsilyl, Tf=trifluoromethane-
sulfonyl,ꢀTMS=trimethylsilyl.
2
2
0 °C then room temperature, 18 h, quant. (88 %, 96 % ee after crystallization
from pentane/Et O); g) 2,6-lutidine, TBSOTf, CH Cl , -78 °C then room temp-
erature, 7 h; h) aq. NaHCO , THF, room temperature, 16 h, quant. (2 steps).
2
2
2
access in order to obtain the core of 4. At the same time, the
interim structure should bring a valuable allylester moiety into
reach, which could then be further elaborated to its parental
compound epothilone D (4) by a subsequent Wacker-type
oxidation, followed by a Wittig olefination to introduce the
thiazole-based heterocycle and a final overall deprotection.
Similar as in earlier total syntheses of epothilone B or D, our
retrosynthetic approach could be traced back to the use of the
literature known southern fragment 8 to be connected with the
3
[
24]
literature known C3-linchpin 14,
which was prepared highly
stereoselectively from propyne within just one step. Emphasizing
that palladium-catalyzed coupling reactions of alkenylboranes
with alkyl halides in general tend to be less satisfactory than
those of their corresponding iodoalkenyl counterparts, the
vinylboronic acid ester 15 was converted to its vinyliodide
analogue in excellent yield and subsequently subjected to the
indicated cross-coupling conditions reported earlier for similar
[
19]
northern fragment 6 by an aldol addition reaction.
The
[
25]
transformations, leading to 17 in excellent yield which carried
the desired trisubstituted Z-configurated double bond motif
synthetic plan for the synthesis of the southern fragment 8
involves a Noyori-type asymmetric hydrogenation of either 3-
[
26]
[
20a]
[20b]
exclusively.
To this end, global TBS-deprotection was
oxoglutaric acid derivative
9
or β,γ-diketoester 10.
accomplished by treatment with TBAF and a subsequent Swern
oxidation of the corresponding alcohol delivered the northern
fragment 6 in overall 9 linear steps starting from 11.
Simultaneously, the construction of the northern fragment 6
relies on two methodologies reported earlier by our group. A
reaction sequence emanating from commercially available L-(+)-
lactic acid ester 7 and including the enantiospecific zinc-
catalyzed cross-coupling of α-hydroxy ester triflates with
Hence, the next assignment concentrated on the preparation of
[
19]
the desired literature known southern fragment 8 (Scheme 3).
[
21]
Although a step efficient and atom-economic synthesis of 8
seemed straightforward, we were surprised to find hardly any
precedent. Instead, step lasting solutions using stoichiometric
amounts of reagents, premetalated C-nucleophiles, chiral
auxiliaries to install the required stereocenter prevail in literature.
To circumvent this issue, we redesigned the approach to 8 by
either starting from the 3-oxoglutaric acid derivative 9 or the β,γ-
diketoester 10, respectively, which both were exposed to Noyori
hydrogenation conditions. Earlier investigations in the fields of
selective asymmetrical hydrogenation of these types of
Grignard reagents
and a subsequent hydroboration/boron-
[
22]
magnesium exchange sequence for the rapid construction of
the Z-substituted trisubstituted double bond was envisioned in
this respect.
The synthesis of the northern fragment 6 commenced by starting
[
21,23]
from the enantiopure literature known triflate 11 (>99 % ee),
itself derived from (-)-tert-butyl L-lactate and directly subjected to
[
21]
our earlier reported alkylation conditions
allylmagnesium chloride in presence of catalytic amounts of
ZnCl (Scheme 2). The corresponding α-methyl substituted γ,δ-
unsaturated tert-butyl ester was furnished highly enantiospecific
91 % ee) with only a slight erosion in terms of enantioselectivity
upon exposure to
2
[
20a]
[20b]
substrates by Zhang
and Carpentier
resulted either in only
to the
moderate enantioselectivities,
overreduction
(
corresponding diol in terms of starting from 10, the use of non-
commercially available catalysts and an unspecified absolute
configuration of the corresponding products. With this
perspective, both pathways in order to obtain the southern
fragment 8 either starting from 9 or 10 were reinvestigated.
long in good yield. Reduction of latter mediated by lithium
aluminium hydride and successive TBS-protection resulted in
the silylated alcohol 12. Next, the installation of the Z-
configurated trisubstituted double bond present in 17 could be
tackled by first catalytic hydroboration of 13, followed by a
subsequent boron-magnesium exchange reaction recently
[
20]
Following on from prior studies we carried out initial reactivity
[
22]
assays with 9 in presence of catalytic amounts of (R)-18
developed
,4-di(chloromagnesium)butane to form the corresponding alkyl
Grignard reagent and second by a Negishi coupling with the
in
our
group
upon
treatment
with
(
5.0 mol%) as described in literature in EtOH at elevated
1
temperatures (75 °C). We were pleased to discover that the
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Chemistry - A European Journal
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COMMUNICATION
Table 1. Conditions for the enantioselective Noyori-type hydrogenation of the
[
a]
3
-oxoglutaric acid derivative 9 and the β,γ-dieketoester 10 (see Scheme 3).
[
b]
[c]
[f]
92 (99)
84
Entry
Substrate
Product T [°C] Yield [%]
ee [%]
Scheme 4. Completition of epothilone D. Reagents and conditions: a) LDA,
[
d]
8,THF, -78 °C to -40 °C, 1 h, quant., d.r. 1:1; b) 2,6-lutidine, TBSOTf, CH
8 °C then room temperature, 6 h; c) aq. NaHCO , THF, room temperature,
5 h, 97 % (2 steps; 49 % for 5); d) [{Rh(cod)Cl} ] (50 mol%), DPEPhos
100 mol%), benzoic acid (100 mol%), DCE, 70 °C, 72 h, 43 %, d.r. 4:1; e)
PdCl (50 mol%), 1,4-benzoquinone, DMF/H O (7:1), room temperature, 5 h,
2 2
Cl , -
1
2
9
(R)-19
(S)-19
21
75 °C
75 °C
RT
89
99 (94)
98
92
7
3
[
e]
[f]
2
9
(
2
2
3
4
5
6
10
10
10
10
7
7
1 %; f) KHMDS, THF, -78 °C to -20 °C, 2 h, 74 %; g) TFA, CH
4 % (39 % over 3 steps).
2 2
Cl , 0 °C, 1 h,
21
10
99
86
further be enriched by recrystallization of the β-hydroxyacid to
6 % ee and in addition to this, the structure of 22 could be
secured at this point by X-ray crystallographic analysis (Scheme
21
0
74
89
9
21
-10
17
95
[
23]
3
). A concluding TBS-protection paved the way to access the
[
3
a] Reaction conditions: 10 (5.0 mmol), (S)-18 (5.0 mol%) in 25 ml of MeOH,
6 h. [b] Cited yields are those isolated after silica gel chromatography. [c] The
ee values were determined by HPLC analysis using a chiral stationary phase.
d] Reaction conditions: 9 (5.0 mmol), (R)-18 (5.0 mol%) in 25 ml of EtOH,
2 h. [e] Reaction conditions: 9 (5.0 mmol), (S)-18 (5.0 mol%) in 25 ml of
southern fragment 8 in less than five steps starting from 9 or 10.
At this juncture, we contemplated an aldol addition reaction to
[
26]
[
fuse both fragments 6 and 8. Conditions developed by Lin and
[
19a]
1
co-workers
in a similar approach of epothilone D to grant a
EtOH, 12 h. [f] After a single recrystallization.
highly diastereoselective addition reaction proved to be
incompatible with the alkyne 6, thus resulting in a complex
product mixture. The price to pay in this particular application
was the use of LDA-mediated conditions on the way to the
reaction of 9 furnished the desired β-hydroxy ester both in good
yield and highly enantioselective (92 % ee), albeit (R)-19
possessing the opposite absolute configuration as determined
[
19e]
[
23]
ω-alkinyl-substituted carboxylic acid 5,
resulting in the
by X-ray crystallographic analysis (Table 1, entry 1).
Hence,
corresponding addition product to be forged in an excellent
overall yield, but unfortunately in analogy to previous syntheses
the product possessing the correct absolute configuration could
be successfully obtained in gram-scale amounts and an
excellent yield (99 %) by using equal reaction conditions but in
presence of (S)-18 (Table 1, entry 2). Gratifyingly, a single
recrystallization of (S)-19 furnished essentially enantiopure
product in gram-scale quantities, which could then be
transposed with only little extra synthetic efforts to the literature
known southern fragment (8) first by TBS protection of the
alcohol, alongside with a parallel deprotection and silylation of
the carboxylic acid moiety, before being saponificated to the
corresponding free carboxylic acid and next C2-elongated upon
treatment with EtMgBr at slightly elevated temperatures
[
18,19]
of epothilone A-D
with a lack in the diastereoselectivity of
the reaction (d.r. 1:1). After TBS-protection of the corresponding
alcohol, both diastereomers could be separated accessing 5 in
4
9 % yield, along with its undesired diastereoisomer in 48 %
yield. Next, after the lactonization precursor 5 was prepared for
our intramolecular macrolactonization reaction, first reactivity
assays encouraged us to screen numerous conditions and we
were pleased to discover that the valuable interim structure 23
[
27]
could be obtained in amendable 43 % yield
diastereoselectivity (d.r. 4:1) in the presence of [{Rh(cod)Cl}
50 mol%), DPEphos (100 mol%) and benzoic acid (100 mol%)
with good
2
]
(
(
Scheme 3). Perpendicular to this when emanating from 10,
in DCE at 70 °C. Noteworthy is at this point that the newly
generated stereocenter was selectively installed without the aid
of a chiral ligand starting from alkynes, just by substrate control.
For the further synthesis of epothilone D (4), a Tsuji-Wacker
type oxidation reaction was elected to install the required ketone
in the allylic side. Using reaction conditions recently reported by
being already fully equipped in terms of the number of carbon
atoms present in the skeleton, the Noyori hydrogenation of the
posterior proved to be a challenging exercise. After screening
numerous chiral bidentate binap-type bidentate diphosphine
ligands, the reaction temperature was found to be most crucial
for the outcome of this process in terms of obtained yields and
enantioselectivites (Table 1; entries 3-6). To our delight, we
were pleased to discover that the reaction worked well at lower
temperatures (10 °C) using simple (S)-binap as the privileged
ligand to afford the desired product 21 in both high yield (99 %)
and decent enantioselectivities (86 % ee; Table 1, entry 4). After
deprotection of the tert-butyl ester, the enantioselectivity could
[
15b]
our group,
ketone in presence of PdCl
Wittig olefination conditions reported by Altmann and co-
23 was smoothly oxidized to the corresponding
2
and benzoquinone. Subsequent
[
28]
workers
for the synthesis of related compounds and a final
overall deprotection finally led to epothilone D (4), exhibiting
spectral properties identical in all respects to those reported for
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Chemistry - A European Journal
10.1002/chem.201605011
COMMUNICATION
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Overall, we have accomplished the total synthesis of epothilone
D by an interaction of methodologies developed by our group,
including a diastereoselective macrolactonization strategy, the
use of our reported zinc-catalyzed cross-coupling of α-hydroxy
ester triflates with Grignard reagents and furthermore the
application of our hydroboration/boron-magnesium exchange
sequence. The conclusion drawn from this ultimately successful
total synthesis project, invigorates our parallel efforts to
elaborate a general enantioselective approach to macrocycles
by starting from ω-alkinyl-substituted carboxylic acids as well as
its further application in complex target molecule synthesis.
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Acknowledgements
[
[
This work was supported by the DFG. We thank Umicore, BASF,
and Wacker for generous gifts of chemicals. Dr. Daniel Kratzert
is acknowledged for highly qualified X-Ray structure analysis,
Monika Lutterbeck, Jürgen “Leo” Leonhardt and Dr. Raffael
Schrof for their preliminary experimental work on this project.
[
Keywords: alkynes • rhodium • macrocycles • total synthesis •
natural products
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This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201605011
COMMUNICATION
COMMUNICATION
Alexander M. Haydl and Bernhard Breit*
Page No. – Page No.
The Total Synthesis of
Epothilone D as a Yardstick for
Probing New Methodologies
The natural product family of the epothilones are one of
countless natural products holding macrolactones in their
often very complex structural motif. An interaction of
methodologies developed by our group, including
a
diastereoselective macrolactonization, the use of our
reported zinc-catalyzed cross-coupling of α-hydroxy ester
triflates with Grignard reagents and the application of our
hydroboration/boron-magnesium exchange sequence
allows for rapid access to this fascinating natural product.
This article is protected by copyright. All rights reserved.