Synthesis of the C6-C21 fragment of epothilone analogues

Article abstract of DOI:10.1016/j.mencom.2014.11.022

(2S,4E,6Z,9S,10E)-9-[tert-Butyl(diphenyl)silyloxymethyl]-2,6,10-trimethyl-11-(2-methylthiazol-4-yl)undeca-4,6,10-trien-1-ol, a key precursor for epothilone analogues, was prepared by multi-step synthesis using the Julia-Kocienski olefination at the key step.

Full text of DOI:10.1016/j.mencom.2014.11.022

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 372–373
Synthesis of the C6–C21 fragment of epothilone analogues
Ruslan F. Valeev,* Radmir F. Bikzhanov and Mansur S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa,
Russian Federation. Fax: +7 347 235 6066; e-mail: rusl0@yandex.ru
DOI: 10.1016/j.mencom.2014.11.022
(2S,4E,6Z,9S,10E)-9-[tert-Butyl(diphenyl)silyloxymethyl]-2,6,10-trimethyl-11-(2-methylthiazol-4-yl)undeca-4,6,10-trien-1-ol, a key
precursor for epothilone analogues, was prepared by multi-step synthesis using the Julia–Kocienski olefination at the key step.
Among microtubule stabilizing natural products (taxol, disco-
dermolide, dictyostatin),1–4 the sixteen-membered epothilones
(Epo)5 are one of the most prospective candidates for drug
development (Scheme 1).6,† Many different epothilone analogues
have been synthesized and studied,6–9 thus providing a rather
comprehensive understanding of the structure–activity relation-
ship for epothilone class of compounds. We concentrated on the
synthesis of a novel type epothilone structure 3 in which the
methylene unit is isosterically displaced in the C15–C3 fragment.10
Once we obtained the northern C10–C21 fragment of an Epo
analogue 6,10 we planned to synthesize the C6–C9 chiral block,
which seemed promising to be coupled with C10–C21 carbon
chain. The Julia–Kocienski olefination11 as the coupling strategy
was chosen, therefore sulfone 5 was required. The chiral building
block 4 can be used in the total synthesis of an Epo D analogue
1 since the selective C9–C10 double bond reduction in unsaturated
analogue Epo 490 212 is possible.12
Me
4-Bromobutyryl chloride was used as a starting compound for
the synthesis of compound 5 (Scheme 2).† To introduce the chiral
center in the target molecule, the Evans asymmetric alkylation13
was chosen. The chiral auxiliary 8 was prepared from l-valine
as described.14 4-Bromobutyryl chloride reacted with lithium
derivative of 8 giving bromo amide 9. Subsequent substitution
of bromine by the action of 1-phenyl-1H-tetrazole-5-thiol in the
presence of Na2CO3 resulted in sulfide 10. Methylation of the
sodium enolate of 10 with MeI at –78°C furnished a mixture
of diastereomers in a ratio of 1:10 (according to 1H NMR) with
the predominance of the (S)-isomer 11. Reduction of 11 with
LiAlH4 provided an inseparable mixture of products (by TLC
analysis) which was subjected to oxidation with H2O2 in the
9
Me
S
10
15
OH
Me
Me
Me
N
Me Me
1
O
3
2
O
OH
O
1 C9
C10, Epo D
2 C9 C10, Epo 490
Me
9
Me
16
S
10
M2e1
OH
Me
Me
O
N
6
14
Me Me
2
O
O
O
Me
Me
Me
15
1
3
O
O
ii
i
N
HN
Me
Me
Br
OH
O
3
O
Me
Me
Me
8
9
Me
O
O
Me
Me
N
N
Me
S
iii
N
N
OH
Me
S
Me
Me
N
N
Me
O
Ph
OTBDPS
Me
4
10
Me
O
R
S
O
N
N
Me
Me
Me
Me
Me
N
N
O
N
OTBS
iv
N
+
Me
N
N
S
5
N
S
N
O
Ph
O
OTBDPS
Ph
Me
5
6 R = CH2OH
7 R = CHO
11
TBDPS = SiPh2But
TBS = SiMe2But
Scheme 2 Reagents and conditions: i, BuLi, –80°C, 40 min, then
Br(CH2)3C(O)Cl, –80°C, 2 h, 84%; ii, 1-phenyl-1H-tetrazole-5-thiol,
Na2CO3, acetone, room temperature, 12 h, 88%; iii, NaN(SiMe3)2 (NaHMDS),
–78°C, 1 h, then MeI, –70°C for 2 h, 85%; iv, LiAlH4, THF, 5°C, 30 min,
room temperature, 1 h, then (NH4)6Mo7O24·4H2O, 30% aqueous H2O2,
EtOH, room temperature, 12 h, then ButSiMe2Cl (TBSCl), imidazole, DMAP,
CH2Cl2, room temperature, 8 h (65% yield for 3 steps).
Scheme 1
†
For experimental details and characteristics of compounds obtained,
see Online Supplementary Materials.
© 2014 Mendeleev Communications. All rights reserved.
– 372 –

Mendeleev Commun., 2014, 24, 372–373
catalysis. Thus, the synthesized C6–C21 fragment as monopro-
Me
Me
tected diol 4 ‡ can be used for the further selective transformations.
O
OH
Me
Me
S
S
i
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2014.11.022.
Me
Me
N
N
OTBDPS
Me
OTBDPS
6
7
Me
References
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S
ii
iii
5
4
OTBS
Me
Me
N
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OTBDPS
12
6 J. Mulzer, K.-H. Altmann, G. Höfle, R. Müller and K. Prantz, C. R. Chim.,
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Scheme 3 Reagents and conditions: i, 2,2,6,6-tetramethylpiperidine-N-oxyl
(TEMPO), PhI(OAc)2, CH2Cl2, room temperature, 6 h, 93%; ii, KHMDS,
–78°C for 20 min, then 7, –78°C, 30 min, 86%; iii, p-TSA, MeOH–CH2Cl2
(1:1), 15°C, 12 h, 95%.
Int. Ed., 2005, 44, 7469.
presence of ammonium heptamolybdate in EtOH.15 After standard
workup the crude product was treated with TBSCl followed
by the separation of the resulting sulfone 5 and recovered
oxazolidinone 8 using column chromatography.
9 A. Rivkin, F.Yoshimura,A. E. Gabarda, T. C. Chou, H. J. Dong, W. P. Tong
and S. J. Danishefsky, J. Am. Chem. Soc., 2003, 125, 2899.
10 R. F. Valeev, R. F. Bikzhanov, N. Z. Yagafarov and M. S. Miftakhov,
Tetrahedron, 2012, 68, 6868.
11 P. R. Blakemore, W. J. Cole, P. J. Kocienski and A. Morley, Synlett.,
The careful oxidation of thiazole-containing alcohol 6 was
achieved under mild conditions by the action of PhI(OAc)2 under
TEMPO catalysis (Scheme 3).† The coupling 5 + 7 was accom-
plished using the Julia–Kocienski method. The coupling proceeds
1998, 1, 26.
12 K. Biswas, H. Lin, J. T. Njardarson, M. D. Chappell, T.-C. Chou,Y. Guan,
W. P. Tong, L. He, S. B. Horwitz and S. J. Danishefsky, J. Am. Chem. Soc.,
2002, 124, 9825.
rapidly affording E-isomer 12 exclusively (1H NMR, JC H–C
9
10H
13 D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem. Soc., 1982,
15.6 Hz). Upon analysis of the 1H and 13C NMR spectra of 12,‡
104, 1737.
14 S. D. Bull, S. G. Davies, S. Jones and H. J. Sanganee, J. Chem. Soc.,
Perkin Trans. 1, 1999, 387.
15 B. M. Trost, D. Amans, W. M. Seganish and C. K. Chung, J. Am. Chem.
Soc., 2009, 131, 17087.
none of the other isomers was detected.
Finally, the selective hydrolysis of the TBS-protecting group
in 12 has been achieved in MeOH–CH2Cl2 solution under p-TSA
‡
4-{(1E,3S,5Z,7E,10S)-11-[tert-Butyl(dimethyl)silyloxy]-3-[tert-
butyl(diphenyl)silyloxymethyl]-2,6,10-trimethylundeca-1,5,7-trien-
1-yl}-2-methyl-1,3-thiazole 12. 1.5 m solution of KHMDS in THF (1.1 ml,
1.65 mmol) was added to a stirred solution of sulfone 5 (0.34 g, 0.83 mmol)
in dry THF (15 ml) under Ar at –78°C. After stirring this mixture for
20 min, aldehyde 7 (0.32 g, 0.63 mmol) was added via cannula as a
solution in THF (5 ml). The mixture was stirred for 30 min at –78°C, then
the cooling bath was removed, and the mixture was allowed to warm to
room temperature. A saturated aqueous solution of NH4Cl (20 ml) was
added, the layers were separated, the aqueous one was extracted with ethyl
acetate (3×20 ml), the combined organic phase was dried over MgSO4,
filtered and evaporated. Purification of the residue by column chromato-
graphy (9% ethyl acetate–light petroleum) afforded 12 (0.38 g, 86%) as a
colourless liquid. Rf (20% ethyl acetate–light petroleum) 0.62; [a]D20 –1.3
(c 1.53, CH2Cl2). IR (Nujol mull, nmax/cm–1): 3428, 2956, 2929, 2857,
1462, 1112, 837, 702, 505. 1H NMR (300 MHz, CDCl3) d: 0.04 (s, 6H),
0.87 (d, 3H, J 7.0 Hz), 0.90 (s, 9H), 1.04 (s, 9H), 1.72–1.74 (m, 1H), 1.76
(s, 3H), 1.89–1.90 (m, 1H), 1.91 (s, 3H), 2.23–2.64 (m, 4H), 2.70 (s, 3H),
3.41–3.43 (m, 2H), 3.67–3.72 (m, 2H), 5.20 (t, 1H, J 7.0 Hz), 5.57–5.68
(m, 1H), 6.35 (s, 1H), 6.45 (d, 1H, J 15.6 Hz), 6.83 (s, 1H), 7.33–7.40 (m,
6H), 7.65 (d, 4H, J 6.7 Hz). 13C NMR (75 MHz, CDCl3) d: –5.4, 14.2,
16.6, 18.3, 19.1, 19.2, 20.7, 26.0, 26.9, 27.5, 36.3, 37.0, 52.3, 66.1, 67.9,
114.5, 120.6, 126.3, 127.6, 128.5, 129.0, 129.5, 132.7, 133.8, 135.7, 141.0,
153.5, 164.1. MS (APCI), m/z: 721 (66), 704 (100), 689 (24, MH+).
Found (%): C, 71.28; H, 8.76; N, 1.89; S, 4.62. Calc. for C41H61NO2SSi2
(%): C, 71.56; H, 8.93; N, 2.04; S, 4.66.
Received: 11th April 2014; Com. 14/4347
(2S,4E,6Z,9S,10E)-9-[tert-Butyl(diphenyl)silyloxymethyl]-2,6,10-
trimethyl-11-(2-methyl-1,3-thiazol-4-yl)undeca-4,6,10-trien-1-ol 4.
p-TSA (0.01 g, 0.08 mmol) was added to an ice-bath cooled solution of
compound 12 (0.26 g, 0.38 mmol) in MeOH–CH2Cl2 (1:1, 20 ml). The
mixture was stirred at 15°C for 12 h, then it was quenched with solid
NaHCO3 and filtered. The filtrate was evaporated and the residue was
purified by column chromatography (30% ethyl acetate–light petroleum) to
provide 4 (0.21 g, 95%) as a light yellow oil. Rf (20% ethyl acetate–light
petroleum) 0.21; [a]2D0 –0.7 (c 1.14, CH2Cl2). IR (Nujol mull, nmax/cm–1):
3374, 2956, 2929, 2857, 1428, 1112, 702, 505. 1H NMR (300 MHz,
CDCl3) d: 0.92 (d, 3H, J 7.0 Hz), 1.05 (s, 9H), 1.72–1.73 (m, 1H), 1.76
(s, 3H), 1.91 (s, 3H), 1.98–2.05 (m, 1H), 2.19–2.31 (m, 2H), 2.40–2.59
(m, 2H), 2.71 (s, 3H), 3.41–3.51 (m, 2H), 3.65–3.73 (m, 2H), 5.22 (t,
1H, J 7.0 Hz), 5.63–5.68 (m, 1H), 6.34 (s, 1H), 6.48 (d, 1H, J 15.6 Hz),
6.84 (s, 1H), 7.35–7.41 (m, 6H), 7.65 (d, 4H, J 6.7 Hz). 13C NMR (75 MHz,
CDCl3) d: 16.7, 16.9, 19.1, 19.3, 20.7, 26.9, 27.6, 36.1, 37.0, 52.4, 66.1,
67.7, 114.5, 120.5, 126.8, 127.6, 128.3, 128.9, 129.6, 132.6, 133.8, 135.7,
141.1, 153.4, 164.2. MS (APCI), m/z: 575 (31, MH+), 557 (100). Found
(%): C, 73.20; H, 8.05; N, 2.36; S, 5.54. Calc. for C35H47NO2SSi (%):
C, 73.25; H, 8.25; N, 2.44; S, 5.59.
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