Total synthesis of epothilone A

Article abstract of DOI:10.1016/S0040-4039(01)01585-4

A convergent total synthesis of epothilone A (1) is described. The key steps are diastereoselective aldol condensation of aldehyde 3 to form the C₆-C₇ bond; macrolactonization and Wadsworth-Emmons reaction of methyl ketone with phosp

Full text of DOI:10.1016/S0040-4039(01)01585-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7341–7344
Total synthesis of epothilone A
Rama M. Hindupur,a Bijoy Panicker,a Muralikrishna Valluria and Mitchell A. Averya,b,c,
*
aDepartment of Medicinal Chemistry, School of Pharmacy, University of Mississippi, PO Box 1848, University,
MS 38677-1848, USA
bDepartment of Chemistry, University of Mississippi, PO Box 1848, University, MS 38677-1848, USA
cNational Center for National Products Research, University of Mississippi, PO Box 1848, University, MS 38677-1848, USA
Received 6 August 2001; revised 20 August 2001; accepted 23 August 2001
Abstract—A convergent total synthesis of epothilone A (1) is described. The key steps are diastereoselective aldol condensation
of aldehyde 3 to form the C6ꢀC7 bond; macrolactonization and Wadsworth–Emmons reaction of methyl ketone with phosphonate
reagent 5. © 2001 Elsevier Science Ltd. All rights reserved.
The naturally occurring macrolactones, epothilone A
(1) and epothilone B (2), possess novel molecular archi-
tecture and a taxol-like antitumor mechanism of action.
They have been a popular synthetic target since their
isolation and characterization from Sorangium cellulo-
sum several years ago.1 Along with their antifungal and
microtubule binding properties, these compounds have
the advantage of better solubility than taxol, can be
obtained in multigram quantities and demonstrate
increased potency over taxol multi-drug resistant cancer
cell lines.2,3 The numbers of completed syntheses, par-
tial syntheses, and patents relating to these compounds
within the last 4 years is remarkable.4–6
1. A few aspects of this work have been published.7
Herein we wish to report our convergent total synthesis
of epothilone A 1.
The synthesis of aldehyde unit 3, the top half of
epothilone A 1 was dependent upon the ring opening of
the epoxide 7 by an alkynylalane, with the final three
carbon atoms to be introduced from a chiral propio-
nate. The synthesis was initiated by silylating the
(2S,3R)-1,2-epoxy-3-butanol 68 with TBDMSCl and
imidazole to form the epoxy silyl ether 7, as outlined in
Scheme 1. Regioselective opening of this epoxide to
afford diol 10 in excellent overall yield could be
achieved upon reaction with alane 9. The alkynylalane
9 was prepared in situ with dimethylaluminium chlo-
ride. Selective hydrogenation of the alkyne 10 using
Lindlar’s catalyst furnished the Z-olefin 11. A sequence
of simple reactions transformed 11 into iodide 12:
selective tosylation of the primary alcohol; protection
of the secondary alcohol as the TMS (trimethylsilyl)
ether with TMS triflate and 2,6-lutidine; and finally,
NaI displaced the tosylate to give the iodide 12.
Retrosynthetic analysis of the epothilones indicated to
us that synthons 3, 4 and 5 could serve as key interme-
diates once appropriately protected. With these struc-
tures in hand, a diastereoselective aldol condensation of
3 with the enolate of 4, employing double stereodiffer-
entiation to form the C6ꢀC7 bond, could be followed by
macrolactonization and Wadsworth–Emmons reaction
of 5 with a methyl ketone to complete the synthesis of
R
R
O
S
O
OH
3
N
OR
OR
O
S
N
HO
O
OH
O
PO(OR)2
O
Epothilone A, 1, R = H
Epothilone B, 2, R = Me
OTBS
O
4
5
* Corresponding author. Tel.: 1-662-915-5880; fax: 1-662-915-5638; e-mail: mavery@olemiss.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01585-4

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R. M. Hindupur et al. / Tetrahedron Letters 42 (2001) 7341–7344
a
OTBS
OH
O
O
7
6
AlR2
b
9
c
TMSO
8
TMSO
HO
HO
d
OTBS
10
11
OTBS
OH
OH
e
N
13
O
S
O
I
N
O
f
O
S
OTBS
OTBS
OTMS
12
14
O
O
OTMS
g, h
O
OTBS
OTMS
3
Scheme 1. Reagents: (a) TBDMSCl, imidazole, CH2Cl2, 0°C to rt, 91%; (b) n-BuLi, Me2AlCl, toluene, 0°C; (c) 7 in toluene, 0°C;
add 9, warm to rt, then aq. AcOH, rt, 92%; (d) H2, Lindlar’s catalyst, quinoline, EtOH, rt, quant.; (e) i. p-toluenesulfonyl
chloride, pyridine, mol% DMAP, CH2Cl2, 0°C to rt, 89%; ii. trimethylsilyltriflate, 2,6-lutidine, CH2Cl2, 0°C to rt, 98%; iii. NaI,
acetone, reflux, 94%; (f) 13, n-BuLi, THF–HMPA; −78°C, then add 12 and warm to −30°C, 68%; (g) DIBALH, CH2Cl2, −30°C;
(h) SO3-Py, DMSO, TEA, CH2Cl2, 0°C, 80% for two steps.
Alkylation of iodide 12 with the enolate of propionyl
amide 13,9 prepared from (−)-camphor sultam, afforded
the desired S homologated material 14, auxiliary intact
in 68% yield with >99% d.e. DIBALH-reduction of the
adduct resulted in the formation of the corresponding
alcohol which was then oxidized using SO3–py complex
to furnish the desired aldehyde 3. The overall process
could be accomplished in eight steps from the pentynyl
derivative 8.
This mixture was then treated with excess of TBSOTf
and 2,6-lutidine to furnish a mixture of tetra-silylated
products which was treated with aq. acetic acid to
deprotect TMS ether with simultaneous deprotection of
TBS esters. At this stage the aldol product mixture was
separated from the unreacted keto acid 4 using flash
column chromatography to obtain compounds 15 and
16 in a 1:2 diastereomeric ratio.
It is worth noting that this aldol condensation was
sensitive to a number of factors. Transmetallation of
the dilithium enolate of 4 with ZnCl2 to generate a Zn
enolate had a beneficial effect on the diastereoselective
aldol reaction providing an excess (2:1) of the required
syn,syn diastereomer 16 over the unwanted syn,anti
diastereomer 15.
For the aldol condensation outlined in retrosynthesis,
the silyl protected keto acid 4 was required. This acid
could be prepared as reported in our earlier work via
enantioselective aldol reaction based on Evans chiral
oxazolidinones.6 The optimum conditions for the ensu-
ing aldol condensation with aldehyde 3 required gener-
ation of the dilithio derivative 4 with LDA [−78 to
−40°C] followed by exchange with Zn for Li using
ZnCl2 at −78°C, and then addition of aldehyde 3
resulted in the formation of aldol products, as shown in
Scheme 2.10
In addition, choice of primary structure and/or protect-
ing groups for the aldehyde side-chain in the aldol
reaction was critical for success. An earlier reported
protecting scheme for the diol side chain of the alde-

R. M. Hindupur et al. / Tetrahedron Letters 42 (2001) 7341–7344
7343
HO
OTBS
O
O
HO
4
+
O
O
O
OTBS
OTBS
OTBS
OTMS
OTBS
a
3
OH
15
HO
OTBS
b
HO
O
O
OTBS
OTBS
O
OTBS
16
OH
O
O
OTBS
15:16 = 1:2
17
c
S
N
OTBS
OTBS
d
O
O
O
O
OTBS
O
O
OTBS
O
19
18
e
Epothilone A, 1
Scheme 2. Reagents: (a) i. 4 in THF, 2LDA, −78 to −40°C then ZnCl2, −78 to −50°C; then add 3, THF, 1 h; ii. TBDMSOTf,
2,6-lutidine, CH2Cl2, 0°C to rt, iii. aq. AcOH, rt, 72%. (b) i. 2,4,6-trichlorobenzoyl chloride, TEA, THF, DMAP, toluene, rt, 1
h; ii. H2SiF6, tert-BuOH, MeCN, CH2Cl2, rt, 24 h, 70%; (c) oxalyl chloride, DMSO, TEA, CH2Cl2, −78°C, 93%; (d) 5, n-BuLi,
THF, −78°C to rt, 60%; (e) i. 20% TFA in CH2Cl2, 0°C, 1 h, 92%; ii. methyl(trifluoromethyl)dioxirane, MeCN, 0°C, 56%.
matographic separation gave the desired alcohol 17.
Oxidation of 17 under Swern conditions provided the
methyl ketone 18, which underwent Wadsworth–
Emmons reaction with the phosphonate reagent 512 to
furnish the E-alkene 19 in good yield and with nearly
complete regioselectivity. Removal of both TBS groups
from 19 furnished the corresponding diol. Finally,
hyde 3, in which the TBS and TMS groups were
replaced with bulkier DPS and TBS groups, respec-
tively (i.e. 20),7 gave reduction product 21 upon
attempted aldol condensation. This mechanistically
obscure outcome could be alleviated as we outlined
after a number of other protecting groups were exam-
ined and discarded due to this side reaction.
treatment
of
19
with
methyl(trifluoromethyl)
dioxirane13 led cleanly to epothilone A 1, whose spec-
tral data was in accord with the reported data for
epothilone A.
20
O
ODPS
OTBS
Acknowledgements
Attempeted
Aldol Condensation
We thank the Elsa U. Pardee Foundation for partial
financial support of these efforts, and Dr. Ho¨fle for
communications regarding the stereochemistry of 1 in
December of 1995.
21
OH
ODPS
References
OTBS
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