Stereoselective synthesis of the C7-C21 segment of epothilone A via asymmetric alkoxyallyl- and crotylboration

Article abstract of DOI:10.1016/S0040-4039(03)00748-2

The synthesis of the C₇-C₂₁ fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using α-pinene-derived reagents is described.

Full text of DOI:10.1016/S0040-4039(03)00748-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3745–3748
Stereoselective synthesis of the C7ꢀC21 segment of epothilone A
via asymmetric alkoxyallyl- and crotylborationꢀ
P. Veeraraghavan Ramachandran,* Bodhuri Prabhudas, Debarshi Pratihar, J. Subash Chandra and
M. Venkat Ram Reddy
Herbert C. Brown Center for Borane Research, Department of Chemistry, 560 Oval Drive, Purdue University, West Lafayette,
IN 47907-2084, USA
Received 6 February 2003; revised 21 March 2003; accepted 24 March 2003
Abstract—The synthesis of the C7ꢀC21 fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using
a-pinene-derived reagents is described. © 2003 Elsevier Science Ltd. All rights reserved.
As part of our program on the applications of pinane-
based versatile reagents1 for organic syntheses, we have
recently described the synthesis of several biologically
active molecules via asymmetric allylboration–ring-clos-
ing metathesis pathway.2 Herein we describe our
approach towards the C7ꢀC21 synthon (1) of potent
anti-cancer agent epothilone A3,4 via a-pinene-derived
asymmetric alkoxyallyl- and crotylboration. Our ret-
rosynthetic analysis of 1 is shown in Scheme 1.
pared from 1,3-dichloroacetone and thioacetamide using
a literature procedure5 and converted to the Wittig salt
2. We chose to prepare 3 starting with an alkoxyallylbora-
tion of acetaldehyde using B-(Z)-g-(2-methoxyethoxy)-
methoxyallyldiisopinocampheylborane.6 Protection of 5
with benzyl bromide, followed by a hydroboration–oxi-
dation provided the corresponding alcohol, which was
oxidized using Dess–Martin periodinane (DMP)7 to the
required aldehyde 3 (Scheme 2). Although one of the
chiral centers derived from alkoxyallylboration will be
converted to the ketone 13, the protocol does not
necessitate any additional steps to create this chiral center.
We envisaged the synthesis of 1 by the convergence of
2, 3, and 4. 4-Chloromethyl-2-methylthiazole was pre-
Scheme 1.
Keywords: epothilone; alkoxyallylboration; crotylboration; a-pinene; Wittig reaction.
ꢀ Contribution No. 23 from Herbert C. Brown Center for Borane Research.
* Corresponding author. E-mail: chandran@purdue.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00748-2

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P. V. Ramachandran et al. / Tetrahedron Letters 44 (2003) 3745–3748
Scheme 2.
The preparation of 1 was initially attempted as shown
in Scheme 3. TBS-protection of commercially avail-
able methyl (R)-3-hydroxy-2-methylpropionate 8, fol-
lowed by reduction of the methyl ester and iodination
provided 9. Nucleophilic substitution of the iodide
with allyl magnesium bromide in the presence of cata-
lytic amounts of lithium tetrachlorocuprate8 or stoi-
chiometric cuprous iodide afforded variable yields
(22–50%) of 10, which when subjected to hydrobora-
tion–oxidation, followed by iodination furnished the
1o-iodide 11. Wittig coupling of aldehyde 3 with 11
gave 58% of the olefin 12. Debenzylation under Birch
reduction conditions, followed by DMP-oxidation
provided the ketone 13. The coupling9 of Wittig salt
2 and 13 yielded 14. Silyl deprotection, followed by a
DMP-oxidation furnished the required synthon 1 for
epothilone A (Scheme 3).
olefin furnished the aldehyde 17. Wittig coupling with
3-benzyloxypropyl iodide provided the olefin 18. A
simultaneous debenzylation and reduction of the dou-
ble bond was achieved by Pd-catalyzed hydrogena-
tion. The alcohol was converted to the corresponding
iodide 19, which was utilized for a Wittig reaction
with the aldehyde 3 to provide 20. It is noteworthy
that the Z-olefin was formed selectively and in high
yields from the substrate that is prone to b-elimina-
tion. Debenzylation using lithium in liquid ammonia
achieved the formation of the 2o-alcohol without
affecting the double bond. The alcohol was oxidized
using DMP to the ketone 21, which was coupled9
with 2 to provide 22 in good yields. Selective depro-
tection of the two silyl groups using dilute HCl, fol-
lowed by Pb(OAc)4 cleavage provided the target
synthon 1 (Scheme 4).
The unreliable yields during the allyl-substitution of
the 1o-iodide 9 compelled us to modify the synthetic
scheme. We designed a protocol utilizing pinane-
based crotylboration.10 A bonus from this procedure
is the replacement of the relatively expensive chiral
ester 8.
The structures of all of the intermediates were con-
firmed by 13C and 1H NMR spectroscopy and mass
spectrometry.
Thus, we have achieved a large-scale preparation of
the C7ꢀC21 synthon 111 of epothilone A using Wittig
reaction and pinane-based alkoxyallyl- and crotylbo-
ration as key steps. Studies towards completing the
preparation of epothilone A and the synthesis of
other epothilones, particularly certain fluorinated
analogs are under way.
We began our synthesis with the Z-crotylboration of
tert-butyldimethylsiloxyacetaldehyde 15 to provide the
homoallylic alcohol 16. Silyl protection of the
hydroxyl group, followed by oxidative cleavage of the
Scheme 3.

P. V. Ramachandran et al. / Tetrahedron Letters 44 (2003) 3745–3748
3747
Scheme 4.
Acknowledgements
C.; Lehmann, C. W. Chem. Eur. J. 2001, 7, 5299; (i)
Hindupur, R. M.; Panicker, B.; Valluri, M.; Avery, M. A.
Tetrahedron Lett. 2001, 42, 7341; (j) Bode, J. W.; Car-
reira, E. M. J. Am. Chem. Soc. 2001, 123, 3611; (k) Liu,
Z.-Y.; Chen, Z.-C.; Yu, C.-Z.; Wang, R.-F.; Zhang,
R.-Z.; Huang, C.-S.; Yan, Z.; Cao, D.-R.; Sun, J.-B.; Li,
G. Chem. Eur. J. 2002, 8, 3747.
Financial support from the Herbert C. Brown Center
for Borane Research and Aldrich Chemical Company is
greatly acknowledged.
5. Hooper, F. E.; Johnson, T. B. J. Am. Chem. Soc. 1934,
56, 470.
22References
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Limberg, A.; Bauer, A.; Bohm, O. M.; Cordes, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 523; (b) Nicolaou,
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Kochi, J. Synthesis 1971, 303; (b) Fouquet, G.; Schlosser,
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1
11. Characterization of 1: H NMR: l (ppm) (CDCl3): 9.58
(d, J=1.95 Hz, 1H), 6.94 (s, 1H), 6.47 (s, 1H), 5.39–5.43
(m, 2H), 4.71 (d, J=6.84 Hz, 1H), 4.63 (d, J=6.87 Hz,
1H), 4.12 (t, J=6.75 Hz, 1H), 3.78–3.85 (m, 1H), 3.51–
3.63 (m, 3H), 3.37 (s, 3H), 2.69 (s, 3H), 2.27–2.42 (m,
3H), 1.97–2.07 (m, 5H), 1.33–1.41 (m, 4H), 1.06 (d,
J=6.99 Hz, 3H); 13C NMR l (ppm) (CDCl3): 205.14,
164.58, 152.76, 138.28, 131.11, 125.98, 121.54, 115.98,
92.78, 81.56, 71.82, 67.06, 59.06, 46.24, 31.97, 30.08,
27.38, 26.88, 19.27, 13.84, 13.34; EI-MS: m/z 256, 89
[(CH3OCH2CH2OCH2)+, 100%]; CI-MS: m/z 396 (M+
H)+, 290 [(M+H)−(HOCH2OCH2CH2OCH3), 100%], 256,
168, 89; HRMS-CI: (M+H) 396.2205 (observed),
396.2209 (calcd).
1
Characterization of 20: H NMR l (ppm) (CDCl3): 7.22–
7.43 (m, 5H), 5.36–5.51 (m, 2H), 4.79 (s, 2H), 4.62 (d,

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P. V. Ramachandran et al. / Tetrahedron Letters 44 (2003) 3745–3748
(s, 1H), 6.48 (s, 1H), 5.32–5.48 (m, 2H), 4.71 (d, J=6.87
J=11.88 Hz, 1H), 4.51 (d, J=11.82 Hz, 1H), 3.55–3.73
(m, 5H), 3.46–3.53 (m, 4H), 3.38 (s, 3H), 2.24–2.45 (m,
2H), 1.97–2.08 (m, 2H), 1.61–1.64 (m, 1H), 1.26–1.42 (m,
3H), 1.19 (d, J=5.49 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H),
0.82 (d, J=6.57 Hz, 3H), 0.05 (m, 12H); 13C NMR l
(ppm) (CDCl3): 138.85, 131.95, 128.30, 127.65, 127.45,
125.69, 95.48, 79.88, 75.87, 71.78, 71.29, 67.04, 65.36,
59.03, 35.31, 33.46, 28.13, 27.73, 26.04, 25.97, 18.39,
18.23, 15.32, 13.37, −3.93, −4.77, −5.24, −5.33; ESI: m/z
675 (Na adduct); HRMS-ESI: 675.4460 (actual), 675.4452
(calcd).
Hz, 1H), 4.63 (d, J=6.87 Hz, 1H), 4.12 (t, J=6.86 Hz,
1H), 3.79–3.86 (m, 1H), 3.44–3.63 (m, 6H), 3.37 (s, 3H),
2.69 (s, 3H), 2.31–2.45 (m, 2H), 1.99–2.10 (m, 5H),
1.59–1.64 (m, 1H), 1.07–1.44 (m, 4H), 0.87 (s, 9H), 0.86
(s, 9H), 0.79 (d, J=6.87 Hz, 3H), 0.02 (m, 12H); 13C
NMR l (ppm) (CDCl3): 164.48, 152.83, 138.41, 131.95,
125.23, 121.48, 115.88, 92.75, 81.67, 75.85, 71.83, 67.00,
65.34, 59.02, 35.24, 33.45, 31.91, 27.76, 27.69, 26.02,
25.95, 19.24, 18.36, 18.21, 13.79, 13.35, −3.95, −4.79,
−5.26, −5.35; ESI: m/z 656, 678 (Na adduct); HRMS-
ESI: 656.4202 (actual), 656.4200 (calcd).
1
Characterization of 22: H NMR l (ppm) (CDCl3): 6.92