A novel highly stereoselective total synthesis of epothilone B and of its (12R, 13R) acetonide

Article abstract of DOI:10.1016/S0040-4039(00)01318-6

Stereoselective syntheses of epothilone B (1) and its novel derivative 2 are described. Key steps are the formation of intermediate 3 via Sharpless AD-reaction and Davis-Evans-hydroxylation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01318-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7635–7638
A novel highly stereoselective total synthesis of epothilone B
and of its (12R,13R) acetonide
Johann Mulzer,* Gunter Karig and Peter Pojarliev
Institut fu¨r Organische Chemie der Universita¨t Wien, Wa¨hringer Strasse 38, A-1090 Vienna, Austria
Received 13 July 2000; accepted 31 July 2000
Abstract
Stereoselective syntheses of epothilone B (1) and its novel derivative 2 are described. Key steps are the
formation of intermediate 3 via Sharpless AD-reaction and Davis–Evans-hydroxylation. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; antitumor compounds; oxazolidinone; hydroxylation.
Epothilone B (1)1 shows outstanding microtubule binding affinities and cytotoxity against tumor
cells and multiple drug resistant tumor cell lines.2 The role of 1 as a potential paclitaxel successor
has initiated intense interest in its synthesis, resulting in several total syntheses of 1 and numerous
derivatives thereof.2b In this respect, variations of the 12,13-section have proven particularly
fruitful, resulting in the exchange of the epoxide, among others, for a Z double bond (epothilone
D) or a cyclopropane moiety.3 It occurred to us to bridge the 12,13-bond by a larger
heterosubstituted ring, which should allow more conformational flexibility. In this paper we
present a stereoselective synthesis of the novel trans-12,13-acetonide analogue 2 of epothilone B.
* Corresponding author. Fax: +431-4277-52189; e-mail: johann.mulzer@univie.ac.at
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01318-6

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Additionally we report a highly stereoselective synthesis of epothilone B (1) itself. Both
syntheses make use of aldehyde 3. In the synthesis of 2, aldehyde 3 is directly coupled with the
known ketone 4a,4, whereas in the synthesis of 1, aldehyde 3 is first converted into the epoxy
derivative 5, which is then coupled with the known ketone 4b4 following our previous route.5
The key fragments for the synthesis of 3 are the phosphonium salt 9 (containing C7–C10) and
the aldehyde 13 (containing C11–C16) (Scheme 1). Known oxazolidinone 76 was converted into
the TBS–ether 8, which was converted into phosphonium salt 9. The key step in the synthesis
of aldehyde 13 was the Sharpless AD-reaction7 of enoate 11, which was obtained from the
protected butanediol 10 as shown.
Scheme 1. Reagents and conditions: (a) 1.1 equiv. NaHMDS, THF, then cinnamyl bromide, −78°C to rt, 4 h, 76%
(>96:4 dr). (b) 1.2 equiv. LiBH4, 1.1 equiv. H2O, Et2O, 0°C to rt, 2 h, 90%. (c) TBSCl, imidazole, DMF, rt, 3 h, 99%.
(d) O3, CH2Cl2/EtOH (9:1), −78°C, 2 min, then 3.7 equiv. NaBH4, −78°C to rt, 5 h, 97%. (e) i. 3 equiv. imidazole,
1.5 equiv. PPh3, 1.5 equiv. I2, Et2O/MeCN (3:1), 0°C, 30 min, ii. 1.5 equiv. PPh3, neat, 90°C, 5 h, 76%. (f) i. DMSO,
oxalyl chloride, triethylamine, ii. 1.1 equiv. ethyl-2-(triphenylphosphoranyliden)-propionate, THF, 80°C, 4 h, 84%. (g)
AD-mix b, MeSO2NH2, tBuOH/H2O (1:1), rt, 12 h, 96% (>98% ee). (h) (MeO)2CMe2, CSA, rt, 12 h, 99%. (i) 3 equiv.
DIBAH, THF, 0°C to rt, 12 h, 94%. (j) Dess–Martin-periodinane, pyridine, CH2Cl2, 0°C, 4 h, 97%
The synthesis of the key aldehydes 3 and 5 (Scheme 2) was started with a Wittig reaction
between 9 and 13, which furnished olefin 14 as a mixture of E/Z isomers, which was converted
into the oxazolidinone 15. Asymmetric hydroxylation of the sodium enolate of 15 was achieved
with Davis’ oxaziridine8 to form 16 with 92% de at C15. The oxazolidinone moiety in 16 was
replaced by the Weinreb-amide, and after protecting the 15-hydroxy group as a TBS ether,
addition of MeLi furnished methyl ketone 17. E selective Wittig reaction (E/Z 30:1), selective
monodesilylation of the 7-TBS ether and Dess–Martin-oxidation furnished key intermediate 3.
To form the epoxide 5, aldehyde 3 was converted into olefin 18 by Wittig reaction, global
O-deprotection and selective protection of the 15-OH with 3 equivalents of TESCl. Selective
mesylation of the 13-OH was achieved to generate intermediate 19. On treatment with
potassium carbonate the desired epoxide was formed and, via dihydroxylation and ensuing
glycol cleavage, the 7-olefin was selectively oxidized to aldehyde 5.9
The aldol reaction of 3 with ketone 4a gave adduct 20 (Scheme 3). The main diastereomer was
separated by chromatography and converted via seco acid 21 into 29 via the methodology
developed earlier.4 Similarly, ketone 4b and aldehyde 5 were coupled to generate 1 as described
previously.5
In conclusion, we have presented efficient syntheses of 1 and 2, which establish the stereogenic
centers at C3, 6, 12, 13, and 15 independently with high diastereoselectivity by using external
sources of chirality. Only centers C6 and 7 are determined during the aldol addition by internal

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Scheme 2. Reagents and conditions: (a) 1.1 equiv. NaHMDS, THF, 0°C, 30 min, then 13, 0°C to rt, 30 min, 87% over
two steps. (b) H2, Pd/Al2O3 cat., EtOH, 3 bar, rt, 36 h, 91%. (c) 4 equiv. NaIO4, 0.05 equiv. RuCl3–H2O,
CCl4/MeCN/H2O (2:2:3), rt, 80 min, 88%. (d) 1.1 equiv. NEt3, 1.0 equiv. PivCl, Et2O, −78 to 0°C, 1 h, then Li-salt
of (4S,5R)-4-methyl-5-phenyl-1,3-oxazolidinone, THF, −78 to 0°C, 1 h, 80%. (e) 1.4 equiv. NaHMDS, THF, −78°C,
1 h, then 1.8 equiv. Davis oxaziridine, −84°C, 5 min, then CSA, −84°C to rt, 10 min, 66% (>96:4 dr). (f) 4 equiv.
H2N(OMe)MeCl, 8 equiv. iPrMgCl, THF, −10 to 0°C, 1 h, 94%. (g) TBSOTf, 2,6-lutidine, CH2Cl2, 0°C, 1 h, 97%.
(h) 1.1 equiv. MeLi, THF, −78°C, 90 min, 91%. (i) 5 equiv. (2%-methyl thiazol-4%-yl)-methyl-tri-n-butyl-phosphonium
chloride, 5 equiv. KHMDS, THF, −78 to 45°C, 1 h, 98% (E/Z 30:1). (j) 1 equiv. CSA, CH2Cl2/MeOH (1:1), 0°C, 7
h, 97%. (k) 1.3 equiv. Dess–Martin-periodinane, pyridine, CH2Cl2, 0°C, 4 h, 97%. (l) triphenylmethylphosphonium
iodide, nBuLi, hexane–THF, then EtOH, 1 M HCl, 75%. (m) NEt3, triethylchlorosilane, 25°C, 3 h. (n) NEt3,
methanesulfonylchloride, −15°C, 4 h, 81%. (o) methanol, potassium carbonate, 25°C, 1 h, 90%. (p) osmium tetroxide,
NMO, THF, tert-BuOH, 0°C, 16 h, then sodium periodate, EtOH, H2O, 25°C, 1 h, 62%
stereoinduction. In the synthesis of 2, this induction is 6:1, and in the case of 1 it is >95:5.5 Our
introduction of the 12,13-epoxide is also highly stereocontrolled and in this respect more reliable
than the direct epoxidation of epothilone D, which gives varying diastereomeric ratios between
5:1 and 20:1.2b Hence we have achieved the first totally stereoselective synthesis of 1.
Scheme 3. Reagents and conditions: (a) LDA, THF, −78°C, 45 min, then 3, 20 min, 70% (6:1). (b) TBSOTf,
2,6-lutidine, CH2Cl2, 0°C, 12 h, 93%. (c) CSA, CH2Cl2/MeOH (1:1), 0°C, 8 h, 84%. (d) i. 1.3 equiv. Dess–Martin-peri-
odinane, pyridine, CH2Cl2, 0°C, 2 h, ii. 5 equiv. NaClO2, NaHPO4, 2,3-dimethyl-but-2-ene, tBuOH/H2), rt, 50 min,
93%. (e) 4 equiv. TBAF, THF, rt, 12 h. (f) 1.2 equiv. 2,4,6-trichlorobenzoyl chloride, 2 equiv. NEt3, toluene, rt, 2 h,
then add to a solution of 10 equiv. DMAP in toluene, 110°C, 3 h, 50% over two steps. (g) 15% CF3CO2H in CH2Cl2,
−18 to 0°C, 6 h, 80%

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Acknowledgements
Financial support by the FWF (Austrian Science Foundation) and the Schering AG, Berlin,
is gratefully acknowledged.
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8
Am. Chem. Soc. 1997, 119, 7974. Novel asymmetric preparation of 4a: Mulzer, J.; Mantoulidis, A.; Ohler, E.
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1
9. Analytical data: 2: H NMR (400 MHz, CHCl3): l=0.98 (d, J=7.1 Hz, 3H), 1.08 (s, 3H), 1.10 (s, 3H), 1.12 (s,
3H), 1.14 (d, J=6.8 Hz, 3H), 1.18–1.42 (m, 4H), 1.34 (s, 3H), 1.55–1.67 (m, 3H), 1.91 (ddd, J=15.7, 3.3, 1.8 Hz,
1H), 1.99 (s, 3H), 2.10 (ddd, J=15.7, 7.8, 4.0 Hz, 1H), 2.45–2.59 (m, 3H), 2.8 (s, 3H), 3.28 (dq, J=6.8, 5.8 Hz,
1H), 3.57 (br, 1H), 3.72 (t, J=4.0 Hz, 1H), 3.99 (dd, J=7.8, 1.5 Hz, 1H), 4.15 (dd, J=10.7, 2.6 Hz, 1H), 5.47 (br,
1H), 6.57 (s, 1H), 6.92 (s, 1H), 13C NMR (100 MHz, CHCl3): l=13.58, 16.73, 16.92, 18.97, 19.07, 20.83, 21.17,
21.58, 26.48, 28.55, 31.16, 32.77, 36.05, 38.88, 40.30, 43.41, 53.15, 71.74, 74.14, 75.33, 76.21, 77.21, 106.14, 114.94,
117.43, 137.00, 152.24, 164.55, 169.69, 219.76. [h]2D0=−37.6 (c=0.6, CHCl3). HRMS calcd for C30H47NO7S:
1
565.3073, found 565.3081. 5: H NMR (400 MHz, CHCl3): l=0.61 (q, J=7.8 Hz, 6H), 0.94 (t, J=7.8 Hz, 9H),
1.09 (d, J=7.0 Hz, 1H); 1.27 (s, 3H); 1.32–1.53 (m, 5H), 1.60 (ddd, J=14.0, 7.0, 4.0 Hz, 1H); 1.66–174 (m, 1H);
1.89 (ddd, J=14.0, 9.0, 4.5 Hz, 1H), 2.02 (s, 3H), 2.33 (m, 1H), 2.70 (s, 3H), 2.89 (dd, J=7.0, 4.5 Hz, 1H), 4.34
(dd, J=9.0, 4.0 Hz, 1H); 6.93 (s, 1H), 9.91 (d, J=2.0 Hz, 1H). 13C NMR (100 MHz, CHCl3): l=5.2, 7.2, 13.7,
14.2, 19.6, 22.6, 23.2, 31.0, 33.3, 36.4, 46.7, 61.1, 62.4, 76.5, 115.8, 119.2, 142.6, 153.4, 164.9, 205.2. [h]2D0=−10.6
(c=1.0, CHCl3). HRMS calcd for C24H41NO3SSi: 451.2576, found 451.2559.
.