Total syntheses of epothilones B and D: Applications of allylstannanes in organic synthesis

Article abstract of DOI:10.1016/S0040-4039(01)01795-6

Following exploratory studies which culminated in syntheses of the alcohol 16, a total synthesis of epothilones B and D is reported in which the trisubstituted 12,13-double-bond is introduced stereoselectively using the tin(IV) bromide-promoted reaction between the allylstannane 22 and the aldehyde 17. A Barton deoxygenation then gave the C(7)-C(15) fragment 25. After development of the thiazole containing side-chain, an aldol condensation with the ethyl ketone 36 gave the adduct 37 which was taken through to epothilone D 2 and then to epothilone B 1.

Full text of DOI:10.1016/S0040-4039(01)01795-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8373–8377
Total syntheses of epothilones B and D: applications of
allylstannanes in organic synthesis
Nathaniel Martin and Eric J. Thomas*
The Department of Chemistry, The University of Manchester, Manchester M13 9PL, UK
Received 15 June 2001; revised 1 September 2001; accepted 10 September 2001
Abstract—Following exploratory studies which culminated in syntheses of the alcohol 16, a total synthesis of epothilones B and
D is reported in which the trisubstituted 12,13-double-bond is introduced stereoselectively using the tin(IV) bromide-promoted
reaction between the allylstannane 22 and the aldehyde 17. A Barton deoxygenation then gave the C(7)ꢀC(15) fragment 25. After
development of the thiazole containing side-chain, an aldol condensation with the ethyl ketone 36 gave the adduct 37 which was
taken through to epothilone D 2 and then to epothilone B 1. © 2001 Elsevier Science Ltd. All rights reserved.
The epothilones,1 e.g. epothilones B 1 and D 2, are of
considerable interest at present because of their potent
cytotoxic activity with modes of action closely related
to that of taxol.2 Several total syntheses of epothilones
have been reported together with extensive studies of
the synthesis of analogues for biological evaluation.3
One well established strategy for epothilone synthesis
involves an aldol condensation between an aldehyde 3
and an ethyl ketone, e.g. 4, to form the C(6)ꢀC(7) bond,
followed by functional group manipulation and
macrocyclisation.4
The aldehydes 3 contain two stereogenic centres and a
trisubstituted double-bond. We now report two
allylstannane5 based approaches to this fragment evalu-
ated by syntheses of the model alcohol 16. In one
sequence, the tin chemistry was coupled with an Ire-
land–Claisen rearrangement6 so that the stereogenic
centre at C(15) has controlled the introduction of that
at C(8) providing an example of 1,8-stereocontrol, a
strategy rarely used in the synthesis of aliphatic com-
pounds.7 In the second, more convergent, synthesis of
16 the allyltin chemistry was used to introduce the
trisubstituted double-bond with excellent stereoselectiv-
ity. This second synthesis of 16 was then modified by
the use of a differently protected stannane 22 to prepare
the triol derivative 25 which was incorporated into a
total synthesis of epothilones B and D.
Me
O
S
Me
Me
OH
N
Me
Me
Me
O
O
Me
The allylstannane 9 required for the model work was
prepared as outlined in Scheme 1. Alkylation of 2-
methylpropenyl phenyl sulfone8 using the iodide 59 gave
the alkylated sulfone 6 as a mixture of diastereoiso-
mers. These were not separated, but were hydrolysed to
give the diol 7 which was monosilylated and the silyl
ether converted into the 5-hydroxyhex-2-enylstannane 9
as a 50:50 mixture of (E)- and (Z)-isomers using trib-
utyltin hydride.10
O
OH
1
Me
S
N
Me
Me
7
OH
Me
Me
Me
Me
O
6
O
OH
O
2
Me
12
Me
Me
O
The first synthesis of the alcohol 16 is outlined in
Scheme 2. Transmetallation of the stannane 9 using
tin(IV) bromide generated an allyltin tribromide which
reacted with (E)-crotonaldehyde with modest 1,6-
stereocontrol11 to give a mixture of the diol 10 and its
epimer at C(7), ratio 80:20, in favour of the required
isomer 10. It may be that formation of the minor
isomer is due to competing co-ordination of the tert-
13
15
Me
8
OP
OP
Me
CHO
OP
3
4
(P = protecting groups)
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01795-6

8374
N. Martin, E. J. Thomas / Tetrahedron Letters 42 (2001) 8373–8377
The disubstituted double-bond in the ester 13 was
Me
reduced selectively by a three-step sequence involving
protection of the 7,8-double-bond as its epoxide, cata-
lytic hydrogenation of the 4,5-double-bond, and
stereospecific regeneration of the (Z)-7,8-double-bond
using potassium selenocyanate13 to give the alkene 14.
Oxidative deprotection followed by reduction then gave
the diol 15 which was taken through to the alcohol 16
by cleavage using sodium periodate followed by reduc-
tion with sodium borohydride. The alcohol 16, a possi-
ble precursor of aldehydes 3, corresponds to the
C(7)ꢀC(16) fragment of epothilone D.
I
O
O
i
O
O
S(O)2Ph
Me
Me
Me
Me
5
6
ii, iii
Me
OSiMe2But Me
SnBu3
iv
RO
OH
S(O)2Ph
OH
9
7 R = H
(E : Z = 50 : 50)
The second synthesis of the alcohol 16 is outlined in
Scheme 3. Reaction of the chiral aldehyde 1714 with the
8 R = tBuMe2Si
Scheme 1. Reagents and conditions: i, DMPU, nBuLi,
PhS(O)2CH2C(CH3)ꢁCH2 (86%); ii, Amberlyst 15; iii,
tBuMe2SiCl, imid. (86% from 6); iv, Bu3SnH (62%).
Me
OH
7
O
i, ii
H
RO
Me
Me
butyldimethylsilyloxy substituent with the tin bro-
mide5,11 but this was not investigated any further.
Instead, deprotection gave the triol 11 together with its
epimer which were separated by recrystallisation to give
the diastereomerically pure triol 11. After protection of
the vicinal diol unit as an acetonide, the remaining
secondary alcohol was esterified to give the (p-methoxy-
benzyloxy)acetate 12. This was subjected to an Ireland–
Claisen rearrangement to give the methyl ester 13 after
a hydrolytic work-up and treatment with trimethyl-
silyldiazomethane.
OH
OPMB
OPMB
17
18 R = tBuMe2Si
19 R = H
iii, iv
Me
OR
v
16
Me
O
O
OPMB
The structure of the rearrangement product 13 was
assigned on the basis that the (Z)-ketene acetal had
been formed from ester 12 via the co-ordinated lithium
enolate,7,12 and that this ketene acetal had rearranged
via a chair-like transition state.6 This assignment was
confirmed by the second synthesis of the C(8)ꢀC(15)
alcohol 16, vide infra.
20 R = H
21 R = C(S)OPh
Scheme 3. Reagents and conditions: i, 9·SnBr4, −78°C (72%;
80:20); ii, nBu4NF; iii, Me2C(OMe)2 (79% from 18); iv,
PhOCS·Cl, py (84%); v, (a) Bu3SnH, AIBN (90%), (b) DDQ
(79%).
Me
7
Me
O
4
CO2Me
OPMB
8
OPMB
Me
Me
OH
7
5
Me
O
iv
i, ii
iii
Me
9
O
O
RO
Me
O
Me
10 R = tBuMe2Si
11 R = H
12
13
OH
O
Me
Me
v
Me
Me
Me
vi
vii
OH
OH
OPMB
CO2Me
Me
OH
Me
O
Me
O
O
O
O
O
Me
Me
Me
Me
Me
Me
16
15
14
n
Scheme 2. Reagents and conditions: i, SnBr4, −78°C, (E)-MeCHꢁCH·CHO [73%, 80:20 at C(7)]; ii, Bu4NF (98%) then separate
diastereoisomers (ca. 60% of 11); iii, (a) 2,2-dimethoxypropane (81%), (b) PMBOCH2CO2H, DIC, DMAP (82%); iv, LiN(SiMe3)2,
−78°C, Me3SiCl, 30 min, then rt 4 h followed by Me3SiCHN2 (78%); v, (a) MCPBA (88%), (b) H2, PtO2 (98%), (c) KSeCN (79%);
vi, (a) DDQ (80%), (b) LiAlH4 (78%); vii, NaIO4 then NaBH4 (74%).

N. Martin, E. J. Thomas / Tetrahedron Letters 42 (2001) 8373–8377
8375
stannane 9 gave a mixture of the diol 18 and its epimer
at C(7), ratio 80:20 in favour of the diol 18. Desilyla-
tion gave the triol 19, which was converted into the
acetonide 20. A Barton deoxygenation followed by
oxidative cleavage of the p-methoxybenzyl ether then
gave the alcohol 16 identical to a sample prepared by
the first route (Mosher’s derivatives).
gested that difficulties would be encountered in
removing it later in the synthesis.16 Oxidative cleavage
gave the corresponding alcohol which was reprotected
as its pivalate ester 26. Selective removal of the tert-
butyldimethylsilyl group followed by Dess–Martin oxi-
dation led to the aldehyde 27 which was taken through
to the ketone 28 by addition of methyl magnesium
bromide followed by further oxidation. Condensation
of this ketone with the phosphonate 3117 gave the diene
29 together with ca. 10% of its (Z)-isomer. Reductive
removal of the pivalate ester followed by a Dess–Mar-
tin oxidation provided the aldehyde 30.
These two syntheses of alcohol 16 use allyltin chemistry
for the stereoselective and regiospecific introduction of
the C(12)ꢀC(13) double-bond. The first synthesis also
incorporates a procedure for 1,8-stereocontrol. How-
ever, the second approach is more convergent and
efficient.15
The C(1)ꢀC(6) fragment, the ethyl ketone 36 was pre-
pared from (R)-pantolactone 32 (Scheme 5). Thus pro-
tection of pantolactone as its tert-butyldimethylsilyl
ether followed by reduction gave the lactols 33 which
were converted into the alkenol 34 using an excess of
the Tebbe reagent.18 Dess–Martin oxidation and addi-
tion of ethylmagnesium bromide gave the alcohol 35 as
At this point it was decided to attempt to complete a
total synthesis of epothilones using the approach used
in the second, more convergent, synthesis of alcohol 16.
However, it was decided to modify this approach by
using a different allylstannane so that protecting group
interconversions would be reduced.
X
Me
Me
RO
ii
OH
A synthesis of the intact C(7)ꢀC(17) fragment of the
epothilones using the convergent allylstannane strategy
is outlined in Scheme 4. In this synthesis a bis-protected
dihydroxyalkeneylstannane 22 was used. This stannane,
prepared from the allylic sulfone 8, was transmetallated
using tin(IV) bromide to generate an allyltin tribromide
which reacted with the aldehyde 17 to give the alcohols
O
Me
tBuMe2SiO
Me
32 R = H, X = O
33 R = TBS, X = H,OH
34
iii
i
23. As expected for a (5-alkoxyhexenyl)stannane,5,11
a
Me
Me
O
Me
Me
iv
50:50 mixture of the C(7)-epimers was obtained but the
control of the geometry of the trisubstituted double-
bond was excellent, less than 2% of any isomeric (E)-
alkene being obtained.
DMTO
Me
Me
tBuMe2SiO
tBuMe2SiO
OH
36
35
t
The 7-hydroxyl group was removed by reduction of the
thionocarbonate 24 using tributyltin hydride to give the
differentially protected triol 25. It was necessary at this
point to replace the p-methoxybenzyl group by a differ-
ent protecting group since literature precedent sug-
Scheme 5. Reagents and conditions: i, (a) BuMe2SiCl, imid.,
(b) DIBAL-H (75% from 32); ii, Tebbe reagent (88%); iii, (a)
Dess–Martin, (b) EtMgBr, CeCl3 (76% from 34); iv, (a)
BH3·THF then H2O2, (b) DMTCl, EtNiPr2, DMAP (52%
from 35), (c) Dess–Martin (89%).
Me
OR
7
Me
OSiMe2But Me
ii, iii
iv, v
i
SnBu3
8
tBuMe2SiO
Me
tBuMe2SiO
Me
OSEM
OSEM
23 R = H
OPMB
OSEM
OR
22
25 R = PMB
26 R = Piv
S
N
24 R = C(S)OPh
Me
P(O)(OEt)2
vi
Me
Me
Me
31
S
N
Me
Me
viii, ix
vii
Me
OHC
Me
O
Me
Me
R
OSEM
OPiv
OSEM
OPiv
OSEM
29 R = CH2OPiv
30 R = CHO
28
27
Scheme 4. Reagents and conditions: i, (a) SEMCl, EtNiPr2 (78%), (b) Bu3SnH, AIBN (59%); ii, SnBr4, −78°C, 17 (62%); iii,
PhOCS·Cl, py. (80%); iv, Bu3SnH, AIBN (59%); v, (a) DDQ (91%), (b) PivCl (96%); vi, (a) Bu4NF (97%), (b) Dess–Martin; vii,
n
(a) MeMgBr (85% over the two steps), (b) Dess–Martin (99%); viii, 31, BuLi (74%); ix, (a) DIBAL-H, (b) Dess–Martin (89%
from 29).

8376
N. Martin, E. J. Thomas / Tetrahedron Letters 42 (2001) 8373–8377
Me
Me
S
N
S
Me
Me
Me
Me
ii
i
OH
Me
OP
Me
Me
Me
30
N
Me
Me
O
Me
Me
O
SEMO
DMTO
SEMO
OP
Me
OH
Me
OP
38
37
iii
S
S
N
Me
Me
iv, v
vi
Me
Me
1
OR
Me
OP
Me
Me
Me
N
Me
Me
O
Me
Me
O
O
OH
HO2C
O
OR
OP
40 R = SiMe2But
2 R = H
39
(P = SiMe2But)
t
Scheme 6. Reagents and conditions: i, 36·LiNiPr2, −78°C (67%); ii, (a) BuMe2SiOTf (99%), (b) Cl2CHCO2H (79%); iii, (a)
n
Dess–Martin, (b) NaClO2, (c) MgBr2, BuSH, K2CO3 (62% from 38); iv, 2,4,6-trichlorobenzoyl chloride, then DMAP (62%); v,
F3CCO2H, DCM (91%); vi, DMDO, −50°C (82%, facial selectivity 4.2:1 in favour of epothilone B 1).
studentship (to N.M.) under the CASE scheme, and Dr.
D. Rawson of Pfizer for many helpful discussions.
a mixture of diastereoisomers which were not sepa-
rated. Instead regioselective hydroboration–oxidation
followed by selective protection of the primary alcohol
as its dimethoxytrityl ether and Dess–Martin oxidation
of the secondary alcohol provided the required ethyl
ketone 36.
References
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The aldol condensation between the aldehyde 30 and
the ethyl ketone 36 using lithium diisopropylamide as
base gave the required product 37 with excellent
stereoselectivity (Scheme 6). The configuration assigned
to the aldol product was based initially on literature
precedent4 and was confirmed by the completion of a
synthesis of the natural products 1 and 2.
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The 7-hydroxyl group was protected as its tert-
butyldimethylsilyl ether and selective removal of the
dimethoxytrityl group gave the primary alcohol 38.
This was oxidised to the corresponding carboxylic acid
and the 15-hydroxyl group deprotected to give the
hydroxy-acid 39. Cyclisation using the modified
Yamaguchi procedure followed by desilylation gave
epothilone D 2 which had spectroscopic data (NMR,
MS, IR) identical to those reported for the natural
product. Regio- and stereoselective oxidation of the
12,13-double-bond using dimethyl dioxirane following
the literature procedure3 then gave epothilone B 1,
again with spectroscopic data identical to those
published.
This work includes the completion of a total synthesis
of epothilones B and D. Of interest is the use of allyltin
chemistry for the convergent and stereoselective forma-
tion of the trisubstituted C(12)ꢀC(13) double-bond. The
exploratory work also exemplified a procedure for 1,8-
stereocontrol.
Acknowledgements
We thank the EPSRC and Pfizer Global Research for a

N. Martin, E. J. Thomas / Tetrahedron Letters 42 (2001) 8373–8377
8377
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Me
Me
Me
Me
ii
i
CH2OPiv
13
O
OH
O
O
O
O
Me
Me
i
ii
Me
Me
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