Total synthesis of (-)-epothilone B

Article abstract of DOI:10.1039/a802947d

The sixteen-membered ring macrolide (-)-epothilone B 1 has been synthesized by a route which features stereospecific methylation of an (E)-γ,δ-epoxy acrylate, the use of a double asymmetric reaction employing (R,R)-diisopropyltartrate and (E)-crotylboronate, and ring closure by means of an olefin metathesis reaction.

Full text of DOI:10.1039/a802947d

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Total synthesis of (2)-epothilone B
Scott A. May and Paul A. Grieco*†
Department of Chemistry and Biochemistry, Montana State Univeristy, Bozeman, Montana 59717, USA
The sixteen-membered ring macrolide (2)-epothilone B 1
BnO
BnO
OH
BnO
OH
has been synthesized by a route which features stereospecific
methylation of an (E)-g,d-epoxy acrylate, the use of a double
asymmetric reaction employing (R,R)-diisopropyltartrate
and (E)-crotylboronate, and ring closure by means of an
olefin metathesis reaction.
O
4
5
BnO
COOEt
COOEt
6
O
OR
6
7
(–)-Epothilone B 1, isolated by Höfle and co-workers1 from the
myxobacteria Sorangium cellulosum strain 90, has been the
object of intense synthetic activity.2,3 The excitement surround-
ing the epothilones stems, in part, from research conducted at
the Merck Research Laboratories by Bollag4 and co-workers
who demonstrated that the epothilones function via a paclitaxel-
like mode of action by binding to and stabilizing cell
microtubule assemblies. Particularly significant has been the
finding4 that (2)-epothilone B appears to be effective against a
number of drug-resistant tumor cell lines. We detail below an
intramolecular olefin metathesis strategy for the construction of
(2)-epothilone B which features preparation of the C(3)-C(12)
fragment 2 and its elaboration into 3, and subsequent conversion
of 3 into 1.
[TESOTf, 2,6-lutidine, CH2Cl2, 45 min, then OsO4 (catalytic),
NMO, acetone–water–ButOH (2:5:1), 7 h, followed by
NaHSO3, 14 h, then Pb(OAc)4, C6H6, 15 min]. Exposure of 8 to
(R,R)-diisopropyltartrate and (E)-crotylboronate8 in toluene
[278 °C (3 h) ? room temp. (12 h)] in the presence of 4 Å
25
molecular sieves gave rise to 9, [a]D 28.6 (c 2.1, CHCl3), as
the sole product in 93% yield, thus establishing the required
syn,anti arrangement about C(6)–C(7) and C(7)–C(8). Prior to
9,10
functionalization of the D
terminal olefin, the triethylsilyl
ether was cleaved (TBAF, THF, 30 min) and the resulting
1,3-anti diol was converted, upon exposure (15 min) to
2,2-dimethoxypropane and catalytic TsOH, into the 1,3-anti
acetonide 10, [a]D25 +11.6 (c 1.7, CHCl3), in 93% overall yield.
The stereochemical assignment for the anti acetonide follows
from the 13C NMR spectrum of 10. The observed chemical
shifts for the acetonide carbons (d 23.4, 25.7 and 100.1) in 10
are in excellent agreement with previous data from independent
studies on 1,3-anti acetonides by Rychnovsky9 and Evans.10
O
12
S
8
OH
N
7
1
O
3
6
O
OH O
12
1
OTBDMS
S
BnO
7
BnO
CHO
OTES
6
8
TESO
OH
OTBDMS
OHC
8
N
9
3
OPMB
O
2
BnO
O
O
O
O
OTBDMS
PMB = p-MeC6H4CH2
3
TES = Et3Si
10
Synthesis of the chiral C(3)-C(12) fragment 2 commenced
25
with the optically active epoxide 5, [a]D 210.1 (c 2.5,
Completion of the synthesis of the C(3)-C(12) fragment 2
was realized as follows. Hydroboration [catecholborane,
(PPh3)3RhCl (catalytic), THF, 45 min; NaOH, H2O2]11 of 10
followed by oxidation (Swern conditions) and subsequent
Horner–Wadsworth–Emmons condensation (THF, 4 h) of the
resulting aldehyde with the sodium anion derived from diethyl
(2-oxopropyl)phosphonate gave rise, in 55% overall yield, to
CHCl3), which was prepared from allylic alcohol 45 via a
Sharpless epoxidation6 [diethyl
-tartrate (0.26 equiv.), Ti(O-
L
Pri)4 (0.2 equiv.), ButOOH (3.0 equiv.), CH2Cl2, 4 Å mol
sieves, 240 °C (8 h) ? 210 °C (8 h)]. With the ready
availability of 5, efforts were focused on introduction of the
C(6) methyl group. Toward this end, 5 was transformed, in 87%
overall yield, into the (E)-g,d-epoxy acrylate 6 via a Swern
oxidation [DMSO, (COCl)2, CH2Cl2, 278 °C, 1 h, then Et3N,
0 °C, 1 h] and an (E)-selective Horner–Wadsworth–Emmons
reaction [NaH, THF, (EtO)2POCH2CO2Et, 0 °C, 1 h, then
25
11, [a]D +26.0 (c 1.05, CHCl3). Enone 11 was transformed
(77% overall) into triol 12 via a three step sequence [H2, 10%
Pd/C, EtOH–EtOAc (1:1), 5 h, then Ph3P†CH2, THF, 3 h, then
1.0
M
HCl–THF (1:1), 50 °C, 3 h] which set the stage for
RCHO, THF, 0 °C, 30 min]. Treatment of a 0.07
M
solution of
selective protection of the C(5) and C(7) hydroxy groups, which
proved critical for completion of the total synthesis of
epothilone B since the 1,3-diol acetonide present in 11 was not
compatible with the olefin metathesis reaction in the late stages
of the synthesis.
Exposure (30 min) of 12 to p-anisaldehyde dimethylacetal in
benzene containing catalytic TsOH gave rise (90%) to 13 (R =
H) which, upon silylation [TBDMSOTf, 2,6-lutidine, CH2Cl2,
278 °C, 4 h], provided (94%) 13 (R = TBDMS), [a]D25 +19.7
(c 3.9, CHCl3). Protection of the C(5) hydroxy group as its
4-methoxybenzyl (PMB) ether was realized via regioselective
6 in 1,2-dichloroethane in the presence of 6.0 equiv. of water
cooled to 230 °C with 10.0 equiv. of Me3Al (2.0
M
in hexane)
gave rise to 7 (R = H), [a]D25 +11.7 (c 2.5, CHCl3), as the sole
product in 87% yield.7 The methylation of 6 is stereospecific,
proceeding with net inversion of configuration about C(6). Note
that, in the absence of water, the transformation of 6 into 7 (R
= H) does not proceed to any appreciable extent.
Elaboration of the remaining two stereocenters at C(7) and
C(8) necessitated conversion of substrate 7 into aldehyde 8
which was realized (95% overall yield) via a three step protocol
Chem. Commun., 1998
1597

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17 in benzene (heated to 55 °C) to 20 mol% of the molybdenum-
BnO
HO
[Mo(CHMe2Ph){N(2,6-Pri2C6H3)}{OC-
O
based
catalyst
O
5
O
7
Me(CF3)2}2] of Schrock13 afforded in 55% yield a 1: 1 mixture
of Z and E isomers (cf. 18) which could be separated by
preparative TLC. Upon treatment of the enantiomerically pure
Z-isomer with HF·pyridine (THF, 3 h), a 60% yield of pre-
epothilone B 19 was obtained. Epoxidation (dimethyldioxir-
ane,15 CH2Cl2, 250 °C, 4 h) of 19 provided crystalline 1, mp
11
OH OH
12
25
93–94 °C (lit.,2 93.6–94.7 °C), [a]D 232.2 (c 0.09, CHCl3)
1
[lit.,2 231.0 (c 0.045, CHCl3)] in 86% yield. The H NMR
reductive ring cleavage12 of the 1,3-dioxane ring of the
4-methoxybenzylidene acetal 13 (R = TBDMS). Thus, a 0.04
solution of 13 (R = TBDMS) in CH2Cl2 , cooled to 278 °C,
was treated with 10.0 equiv. of a 1.0 solution of DIBAL-H in
spectrum of synthetic 1 was identical in all respects with a
spectrum of natural (-)-epothilone B.
M
We thank Professor S. Danishefsky for helpful discussions
and the 1H NMR spectra of natural (2)-1 and synthetic (2)-17.
This research was supported by a grant from the U.S. NIH (CA
28865).
M
CH2Cl2. After warming to 215 °C (1.5 h), a 75% yield of
primary alcohol 14 was isolated. Oxidation (Swern conditions)
25
of 14 provided the intact C(3)-C(12) fragment 2, [a]D 27.6 (c
4.6, CHCl3), in 98% yield.
S
OH
N
O
O
O
OR
O
OH O
19
OMe
13
Notes and References
HO
† E-mail: grieco@chemistry.montana.edu
PMBO
OTBDMS
14
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Reichenbach, Angew. Chem., Int. Ed. Engl., 1996, 35, 1567.
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and references cited therein.
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J. Org. Chem., 1989, 54, 2817.
In order to complete the total synthesis of 1, the ester enolate
derived (LDA, THF, 278 °C) from the known acetate 152 was
condensed with 2 giving rise (83%) to a readily separable
25
mixture (1.7 : 1) of diastereomers favoring 16, [a]D 228.6 (c
1.4, CHCl3), possessing the correct configuration at C(3).
Protection [TBDMSOTf, 2,6-lutidine, CH2Cl2, 250 °C, 4 h] of
the C(3) hydroxy group, followed by cleavage [DDQ, CH2Cl2–
H2O (18 : 1), 0 °C, 3 h] of the C(5) 4-methoxybenzyl ether and
25
subsequent Dess–Martin oxidation gave rise to 17, [a]D
244.0 (c 2.4, CHCl3), in 65% overall yield.
6 T. Katsuki and K. B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974.
7 M. Miyashita, M. Hoshino and A. Yoshikoshi, J. Org. Chem., 1991, 56,
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P. A. Grieco, J. D. Speake, S. K. Yeo and M. Miyashita, Tetrahedron
Lett., 1998, 39, 1125.
S
S
OTBDMS
N
N
O
O
OH OPMB
OAc
15
16
8 W. R. Roush, K. Ando, D. B. Powers, A. D. Palkowitz and R. L.
Halterman, J. Am. Chem. Soc., 1990, 112, 6339; W. R. Roush, A. D.
Palkowitz and K. Ando, J. Am. Chem. Soc., 1990, 112, 6348.
9 S. D. Rychnovsky and D. J. Skalitzky, Tetrahedron Lett., 1990, 31,
945.
S
N
OTBDMS
O
10 D. A. Evans, D. L. Rieger and J. R. Gage, Tetrahedron Lett., 1990, 31,
7099.
O
O
O
11 D. Männig and H. Nöth, Angew. Chem., Int. Ed. Engl., 1985, 24, 878;
D. A. Evans, G. C. Fu and A. H. Hoveyda, J. Am. Chem. Soc., 1992, 114,
6671.
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1593.
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Int. Ed. Engl., 1995, 34, 2039. Also See: A. Houri, Z. Xu, D. A. Cogan
and A. H. Hoveyda, J. Am. Chem. Soc., 1995, 117, 2943.
15 R. W. Murray and R. Jeyaraman, J. Org. Chem., 1985, 50, 2847.
OTBDMS
17
18
S
N
OTBDMS
O
O
O
O
OTBDMS
Ring closure to complete the formation of the sixteen-
membered ring of 1 was realized by an intramolecular olefin
metathesis reaction.13,14 Exposure (4 h) of a 0.001
M
solution of
Received in Corvallis, OR, USA, 20th April 1998; 8/02947D
1598
Chem. Commun., 1998