Synthesis of epothilones B and D from D-glucose

Article abstract of DOI:10.1016/S0040-4039(02)00457-4

An enantiospecific total synthesis of epothilones B and D from D-glucose is reported.

Full text of DOI:10.1016/S0040-4039(02)00457-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2895–2898
Synthesis of epothilones B and D from
D-glucose
Mikhail S. Ermolenko* and Pierre Potier
Institut de Chimie des Substances Naturelles du CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 22 January 2002; revised 7 February 2002; accepted 5 March 2002
Abstract—An enantiospecific total synthesis of epothilones B and D from D-glucose is reported. © 2002 Elsevier Science Ltd. All
rights reserved.
Ever since the discovery of taxol-like tubulin binding
properties of epothilones,1 some 30 research groups
worldwide have embarked on the synthesis of this
group of natural products (1–6) and hundreds of their
synthetic analogs.2 A large amount of total3,4 or partial
syntheses of the epothilones has established four differ-
ent modes for installation of the C12ꢀC13 epoxide,
three distinct macrocyclization strategies, and the skele-
ton assembly along all but one (C7ꢀC8) carbonꢀcarbon
bonds. Nevertheless, the continuous stream of publica-
tions proves that there is still enough room here for
inspiration and practical improvements with regards to
the yield, stereoselectivity or industrial application com-
presence of a number of palladium catalysts afforded
the inseparable mixture of the tri-substituted alkene 9
and its di-substituted regiomer 10 in varying, sometimes
for no apparent reason, ratio (3:2–7:1) and yield. A
close investigation of the reaction mechanism and
extensive screening and optimization for numerous
reaction parameters brought about the conditions for
highly regioselective transformation (9:10=41:1); the
residual trace amount of 10 was easily removed in the
next step. The product 9, bearing the crucial 15S and Z
alkene functionality of epothilone D, was then for-
warded to the methyl ketone 12. It should be noted that
an intermediate aldehyde is very volatile and unstable,
and only the one–step Swern oxidation/Grignard addi-
tion procedure6 afforded the alcohol 11 in high yield.
The olefination of the methyl ketone 12 with the
lithium reagents of the known phosphonate 14a7 or the
corresponding phosphine oxide 14b9 afforded the diene
15 in disappointingly low yield and selectivity (40–45%;
Z,E:Z,Z=5–7:1), while some highly polar adduct per-
sisted. Further studies revealed that of two
diastereomeric primary adducts, b-hydroxyphospho-
nates, the major one, giving rise to the undesired Z,Z
diene, requires more drastic conditions to eliminate.
Considering the ability of b-hydroxyphosphonates to
equilibrate, the olefination of 12 with the potassium
phosphonate 14a was attempted to give, in very mild
pliance. In this paper we wish to disclose some results
culminating in the total synthesis of epothilones D and
B.
Considering the common functionality pattern present,
the epothilone molecules might be dissected for two
large chiral fragments, C5ꢀC9 and C11ꢀC16, covering,
respectively, the crucial polypropionate and Z homoal-
lylic alcohol regions, as shown below. The stereochem-
istry present therein could be conveniently secured by
stereospecific transformations on
template.
a
carbohydrate
As applied to our synthesis of epothilones D and B,
both the fragments were synthesized from a common
key intermediate, the branched-chain carbohydrate
derivative 7,5 easily available in three steps and 52–55%
overall yield from methyl-a-D-glucopyranoside (Scheme
1). Thus, an improved procedure over the existing
method5 allowed preparation of the unsaturated
pyranoside diacetate 8 in high yield. A borohydride
deoxygenation of the allylic acetate function of 8 in the
* Corresponding author. Fax: +33-1 69 07 72 47; e-mail:
mikhail.ermolenko@icsn.cnrs-gif.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00457-4

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M. S. Ermolenko, P. Potier / Tetrahedron Letters 43 (2002) 2895–2898
Scheme 1. Reagents and conditions: (a) Me2CuLi·LiCN/Et2O–THF, rt, 1 h (cf. Ref. 4); (b) NaH, ImH (cat.), CS2, MeI/THF; then
Ph–Ph, 240°C, 1 h; then TsOH, 0.01 M in CH2Cl2–MeOH (3:1); (c) Ac2O, Et3N, DMAP (cat.)/CH2Cl2; (d) 8, Pd(OAc)2 (0.1
equiv.), DPPP (0.2 equiv.), Bu4NOAc (0.1 equiv.), rt, 1 h; then NaBH4 (portion-wise, 0.05 equiv. every 0.5 h; 1 equiv. total); (e)
MeONa (cat.)/MeOH; then (COCl)2, DMSO, Et3N/THF; then MeMgCl/THF; −78°C to rt; (f) (COCl)2, DMSO, Et3N/CH2Cl2;
(g) P(OEt)3 (2 equiv.), 165°C, 2 h; (h) 14a, t-BuOK/THF, then add 12, −30°C to rt for 4 h; (i) AcOH–H2O–THF (3:1:6) rt, 24
h; then NaBH4/MeOH; (j) CBr4, Ph3P/CH3CN, 0°C; then TBSOTf, 2,6-di-tert-butyl-4-methylpyridine, −40°C (one-pot); (k)
Et3N/CH2Cl2–MeOH (3:1), rt; (l) NaBH4/MeOH–DMF (1:1); (m) H2, Pd/C/AcOEt; then TBDPSCl, Py; (n) CH3C(OMe)3, TsOH
(cat.); then Et3N; AcBr/CH2Cl2; then MeONa/MeOH; (o) Me2Mg/Et2O; (p) Bu4NF/THF; (q) CBr4, Ph3P/Py; (r) TBSCl,
ImH/DMF; (s) Zn, i-PrOH–H2O (19:1), D; then NaBH4; (t) TBSCl/Py; (u) NMO, OsO4 (0.02 equiv.)/t-BuOH–H2O (9:1); then
,
H5IO6; (v) Me2CꢁCHCH2MgCl/THF; (w) NMO, TPAP (0.05 equiv.), MS 4 A/CH3CN; (x) LiCH2CO2Bu-t/THF, −78°C, 0.5 h;
(y) TBSOTf, i-Pr2NEt/CH2Cl2, −78°C; (z) PPTS/EtOH, rt; (aa) Ph3PꢁCH2 (3 equiv.)/THF, −78°C; (bb) 28+LiHMDS/THF,
−78°C; then add 26; (cc) TMSOTf, collidine/CH2Cl2, 0°C, 1 h; (dd) 2,4,6-Cl3C6H2COCl, Et3N/THF, rt, 1 h; then slow addition
to DMAP/PhCH3, 80°C; (ee) TFA/CH2Cl2, 0°C; (ff) TrisNHNH2, Et3N/Et2O, 39°C; (gg) dimethyldioxirane/CH2Cl2, −50°C.

M. S. Ermolenko, P. Potier / Tetrahedron Letters 43 (2002) 2895–2898
2897
conditions, the required Z,E diene 15 as a sole isomer
and in good yield. Mild acid hydrolysis of the acetal
function of 15 followed by borohydride reduction fur-
nished the enantiomerically pure diol 16 from which
two projected C11ꢀC16 fragments of epothilone D, the
diacetate 17 and the bromide 18, were prepared.
Guided by this observation, an one-pot, three-compo-
nent coupling between Ph3PCH3Br, the C11ꢀC16 bro-
mide 18 and the C1ꢀC9 aldehyde 26 was attempted to
give the desired seco-acid (30) in only low yield (16%).†
Several one-carbon homologations to C11ꢀC16 frag-
ment with ICH2ZnI16 (as an entry to a Wittig reagent)
or MeSO2PT17 (for a Julia olefination) were made but
finally ceased in favor of a simple two-step Wittig
approach.4g The C10ꢀC16 phosphonium bromide 29,
prepared in a separate step, was coupled with the
C1ꢀC9 aldehyde 26 to give the protected seco-acid of
On the other hand, the thermodynamically driven iso-
merization of 7 into 1910 followed by hydrogenolysis
and selective silylation afforded the diol 20 which was
converted into the epoxide 21 by an orthoester
method.11 Oxirane ring opening of 21 with Me2Mg12
proceeded regio- and stereospecifically in high yield
(91%). The following usual functional group manipula-
tion afforded the bromide 22 which was subjected to a
reductive fragmentation13 to give, after borohydride
reduction of a resulting aldehyde and silylation, the
crucial polypropionate C5ꢀC9 fragment of epothilones
23. The double bond in 23 was split, and the resulting
aldehyde was converted into the C3ꢀC9 alkene 24 via a
Grignard reagent addition. The procedure of alkene
cleavage was repeated, and the C3ꢀC9 aldehyde
obtained was treated with a-lithio tert-butyl acetate to
give a mixture of b-hydroxyesters (3S:3R ca. 7:3) from
which the required isomer was easily isolated as the
hydroxyester 25. Its further transformations provided
the C1ꢀC9 aldehyde 26 and C1ꢀC10 alkene 27.
9,10(Z)-dehydroepothilone
D 30 which, however,
resisted the hydrogenation on the BER–Ni2B catalyst,
apparently due to steric hindrance from both 8-CH3
and 7-OTBS groups. In expectation of more favorable
steric situation later on, the tert-butyl ester and 15-O-
TBS groups were clearly removed, and the seco-acid 31
thus obtained was macrolactonized to give 32. Unfortu-
nately, both the protected (32) and the deprotected (33)
9,10-dehydroepothilone D resisted the hydrogenation in
the above-mentioned conditions as well. Eventually, the
hydrogenation of 33 into epothilone D 6 was achieved
in acceptable yield by diimide generated from 2,4,6-tri-
isopropylbenzenesulfonyl hydrazide (TrisNHNH2)18 in
ether, though large excess of the reagent was required
for full conversion of the starting product. Note, the
functionality of 33 tolerated the reaction conditions.
Finally, epoxidation of epothilone D 6 with dimethyl
dioxirane19 led to epothilone B 2.20
Considerable effort was devoted to the problem of the
epothilone seco-acid skeleton assembly that required
one-carbon homologation to one of the fragments syn-
thesized. Thus, our early modeling studies have shown
that the diacetate 17 undergoes clear SN2 substitution
at the allylic position with retention of configuration of
the double bond under treatment with alkyl cuprates
(Scheme 2).
In conclusion, we have completed an enantiospecific
total synthesis of epothilones D and B from
D-glucose.
Further efforts directed to circumvent the bottle-neck
partial hydrogenation step, as well as an adaptation of
the strategy to the synthesis of the other members of
the epothilone family, are considered.
Consequently, the hydrozirconation of the derived
olefin fragment 27 followed by transmetallation to cop-
per was attempted.14 Under numerous conditions tried
the coupling of the alkene 27 and the diacetate 17
fragments failed, apparently due to lack of the Zr-to-Cu
transmetallation. Also, it was demonstrated that the
hydrogenation of the model triene 28 on the borohy-
dride exchange resin–nickel boride (BER–Ni2B)15 pro-
ceeded selectively at the di-substituted double bond.
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Scheme 2.

2898
M. S. Ermolenko, P. Potier / Tetrahedron Letters 43 (2002) 2895–2898
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(300 MHz, CDCl3): l 6.95 (s, 1H), 6.58 (s, 1H), 5.21 (dd,
J=9.7, 1.6 Hz, 1H), 5.14 (dd, J=10.1, 4.8 Hz, 1H), 4.29
(dd, J=10.9, 2.4 Hz, 1H), 3.73 (dd, J=4.2, 2.2 Hz, 1H),
3.41 (br s, 1H), 3.16 (dq, J=6.9, 2.5 Hz, 1H), 3.02 (br s,
1H), 2.68 (s, 3H), 2.63 (dt, J=15.1, 10.1 Hz, 1H), 2.45
(dd, J=15.0, 11.0 Hz, 1H), 2.38–2.30 (m, 1H), 2.2 (dd,
J=14.7, 2.7 Hz, 1H), 2.2 (br.d, J=15.7 Hz, 1H), 2.06 (d,
J=0.9 Hz, 3H), 1.93–1.82 (m, 1H), 1.8–1.7 (m, 2H), 1.66
(s, 3H), 1.34 (s, 3H), 1.32–1.22 (m, 4H), 1.20 (d, J=6.8
Hz, 3H), 1.08 (s, 3H), 1.02 (d, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): l 220.6, 170.4, 165.6, 152.0, 139.2,
138.5, 120.9, 119.4, 115.6, 79.0, 74.2, 72.4, 53.5, 41.7,
39.7, 38.5, 32.6, 31.9, 31.8, 31.6, 25.4, 22.9, 19.1, 18.2,
15.9, 15.8, 13.4. Epothilone B 2: [h]2D5 −36.0 (c 0.06,
CHCl3); 1H NMR (300 MHz, CDCl3): l 6.98 (s, 1H),
6.60 (s, 1H), 5.41 (dd, J=7.9, 2.4 Hz, 1H), 4.23 (br, 2H),
3.77 (t, J=4.1 Hz, 1H), 3.41 (br s, 1H), 3.31 (dq, J=6.8,
4.0 Hz, 1H), 2.80 (dd, J=7.6, 4.4, 1H), 2.70 (s, 3H), 2.63
(br.s, 1H), 2.55 (dd, J=14.0, 10.4 Hz, 1H), 2.35 (dd,
J=14.3, 1.8 Hz, 1H), 2.16–2.07 (m, 1H), 2.09 (s, 3H),
1.90 (dt, J=15.2, 8.1, 1H), 1.8–1.7 (m, 2H), 1.60–1.45 (m,
2H), 1.45–1.34 (m, 3H), 1.39 (s, 3H), 1.28 (s, 3H), 1.17 (d,
J=7.0 Hz, 3H), 1.08 (s, 3H), 1.00 (d, J=7.0 Hz, 3H).
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