Total synthesis of 26-hydroxyepothilone B and related analogues

Article abstract of DOI:10.1039/a705845d

A series of 26-substituted epothilones B (3, 22, 23a-n and 24a-h,j-l,o) have been constructed by total synthesis involving a selective Wittig olefination, an aldol reaction and a macrolactonization as key steps.

Full text of DOI:10.1039/a705845d

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Total synthesis of 26-hydroxyepothilone B and related analogues
K. C. Nicolaou,* Sacha Ninkovic, M. Ray V. Finlay, Francisco Sarabia and Tianhu Li
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey
Pines Road,, La Jolla, California 92037, USA and Department of Chemistry and Biochemistry, University of California, San
Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
A series of 26-substituted epothilones B (3, 22, 23a–n and
24a–h,j–l,o) have been constructed by total synthesis involv-
ing a selective Wittig olefination, an aldol reaction and a
macrolactonization as key steps.
derivative, with 7 led to 9. The transformation of 9 to 10
proceeded under the influence of MMPP7 (91%), and reduction
of the latter with DIBAL-H provided aldehyde 11 (97%).
The coupling of the C1–C6 ketone fragment 127,15 with 11
via a syn-selective aldol reaction (Scheme 2) furnished 13 along
with its (6S,7R) diastereoisomer 14 (85% total yield, ca. 3:1).
Chromatographic purification followed by silylation gave 15.
The use of buffered HF·pyridine in THF permitted selective
desilylation of 15 giving 16 (74%), which was sequentially
oxidized to 17, and thence to carboxylic acid 18. Selective
desilylation at C15 was achieved by the use of Bu4NF in THF,
providing 19 (89%). The latter compound was in turn subjected
to the Yamaguchi macrolactonization forming 20 (75%).
Exposure of 20 to HF·pyridine in THF promoted concomitant
removal of both the silyl groups and the trityl moiety, leading to
3 (78%). Alternatively, treatment of 20 with camphorsulfonic
acid in MeOH–CH2Cl2 resulted in the selective removal of the
trityl group, giving 21 (70%). Sharpless asymmetric epoxida-
tion of 3 then gave 26-hydroxyepothilone B 22 (76%).
The availability of 3, 21 and 22 facilitated access to a number
of 26-substituted epothilones. As indicated in Scheme 3, 21 was
converted to 23a–c by reaction with the corresponding acid
anhydride or chloride under basic conditions followed by
desilylation. MnO2 oxidation of 3 proved highly efficient,
providing a,b-unsaturated aldehyde 23d (85%). Further oxida-
tion of 23d with NaClO2 led to carboxylic acid 23e (98%),
which was converted to 23f by treatment with CH2N2 (80%).
Methylation and benzylation of 21 followed by desilylation
afforded 23h (58% overall) and 23i (35% overall), respectively.
Halogenation of 21 followed by desilylation led to chloride 23g
(73% overall) or fluoride 23j (51% overall). Alternatively,
treatment of 21 with MnO2 and reaction of the resulting
aldehyde with the anion derived from Me3SiCHN2 followed by
The novel molecular structures and impressive antitumour
properties of the epothilones1 have captured the imagination of
synthetic chemists, biologists2,3 and clinicians. Isolated1 from
myxobacterium Sorangium cellulosum, these substances ex-
hibit tubulin polymerization properties2 similar to Taxol4 and
show potent cytotoxicity against Taxol-resistant tumour cells.3
Research in this field has resulted in the total synthesis of the
naturally occurring epothilones B 15–7 and A 2,5,7–11 and a
plethora of analogues.5–17 Owing to the higher antitumour
potency of the 12-methyl bearing epothilone B 2 as compared to
epothilone A 1, this substituent (the C26 methyl group) was
considered a prime candidate for modification. An expedient
entry into this series of compounds was sought. Here we report
such a strategy which culminated in the total synthesis of
26-hydroxydesoxyepothilone B 3, 26-hydroxyepothilone B 22
and a series of related analogues 23a–n and 24a–h,j–l,o.
The approach to the C26-modified epothilones B followed a
similar path to that developed in these laboratories5,7 for
epothilone B 1, and involved (i) stereoselective Wittig olefina-
tion, (ii) aldol condensation and (iii) macrolactonization
(Fig. 1).
Protection of 4 (Scheme 1) as a trityl (CPh3) ether furnished
5† in 99%. Hydroboration of 5 led to 6 (94%), which was
converted to 7 by the action of PPh3, I2 and imidazole (90%).
Stereoselective alkylation of SAMP hydrazone 8,18 via its lithio
Wittig
R
HO
12
olefination
O
26
S
N
S
N
HO
7
6
HO
Table 1 Biological activities of epothilone analogues
IC50/nm (relative resistance)b
O
O
3
O
OH
O
Aldol
condensation
O
OH
O
1 R = Me epothilone B
2 R = H epothilone A
Macrolactonization
Induction
of tubulin
assemblya (%)
Taxol-resistant
3
Parental
1A9
Fig. 1 Structures of 1 and 2 and retrosynthetic analysis of 3
Compound
PTX10
PTX22
23g
23j
23k
23l
24d
24g
24j
24k
24l
24o
Taxol
Epothilone A
Epothilone B
88
83
95
66
87
69
93
94
79
41
50
72
100
90
> 100
6
30
> 100
24
0.50
0.55
4.7
8.5
55
> 100
4
14
93
3.1
0.55
0.15
0.95
0.45
20
43
4.2
0.045
RO
Ph3CO
0.65
8.7
60
X
iv
S
N
S
N
Y
N
R
5
8
OSiMe2But
OSiMe2But
0.25
0.15
0.63
0.27
25
9 R = CH2=N–Y
10 R = CN
4 R = H, X = CH=CH2
i
v
vi
5 R = CPh3, X = CH=CH2
6 R = CPh3, X = (CH2)2OH
7 R = CPh3, X = (CH2)2I
N
ii
Y =
11 R = CHO
iii
MeO
2
2
50
19
0.035
Scheme 1 Reagents and conditions: i, Ph3CCl, DMAP, DMF, 70 °C, 1 h; ii,
9-borabicyclo[3.3.1]nonane, THF, 0 °C, 2 h, then aq. NaOH (3 m), then 30%
H2O2; iii, I2, imidazole, PPh3, Et2O–MeCN (3:1), 0 °C, 0.5 h; iv, 8, LDA,
0.040
THF, 0 °C, 14 h, then 7, THF, 2100
?
220 °C, 10 h; v,
a Assays performed as in ref. 4. b Inhibition of human ovarian carcinoma cell
growth. Assays performed as in ref. 7. Each IC50 value shown is an average
value obtained from three independent assays.
monoperoxyphthalic acid (Mg salt) (MMPP), MeOH–phosphate buffer (pH
7) (1:1), 0 °C, 1 h; vi, DIBAL-H, toluene, 278 °C, 1 h
Chem. Commun., 1997
2343

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Ph3CO
latter was then exposed to Ac2O in CH2Cl2 providing the
corresponding acetamide 23m (39%, 4 steps). Similar chem-
istry was employed for the preparation of epothilones 24a–c,
e–h (Scheme 2). Compound 24d was synthesized by selective
oxidation of 22 with TEMPO–bleach (90%), and subsequent
hydroxy protection, Wittig methylenation and deprotection
allowed access to 24k (49%, 3 steps). Iodide 24o was prepared
by selective tosylation of the primary hydroxy moiety of 22 and
subsequent displacement with NaI (72%). Alternatively, treat-
ment of 22 with DAST furnished fluoride 24j. Reaction of 23h
and 23l with methyl(trifluoromethyl)dioxirane provided, re-
spectively, the epoxy methyl ether 24h (20%) and the ethyl
analogue 24l (55%).
S
N
OSiMe2But
+
O
OSiMe2But
12
O
OSiMe2But
11
i
Ph3CO
Ph3CO
S
N
S
N
R1O
HO
+
(ca. 3:1)
OSiMe2But
OR3
R4
R4
OR2
14 R2 = SiMe2But, R4 = CH2OSiMe2But
O
OR2
O
Table 1 shows the tubulin binding5 and cytotoxicity proper-
ties of a selected number of the synthesized epothilones.
We thank Dr E. Hamel for a gift of purified tubulin and Dr P.
Giannakakou for the cell lines. This work was supported by
Novartis, the NIH, The Skaggs Institute for Chemical Biology,
the CaP CURE Foundation, and the Fulbright Commission
(M. R. V. F.).
13 R1 = H, R2 = R3 = SiMe2But, R4 = CH2OSiMe2But
15 R1 = R2 = R3 = SiMe2But, R4 = CH2OSiMe2But
16 R1 = R2 = R3 = SiMe2But, R4 = CH2OH
17 R1 = R2 = R3 = SiMe2But, R4 = CHO
ii
iii
iv
v
18 R1 = R2 = R3 = SiMe2But, R4 = CO2H
vi
19 R1 = R2 = SiMe2But, R3 = H, R4 = CO2H
vii
R1
R1
O
O
S
S
N
HO
HO
N
Footnotes and References
O
O
* E-mail: kcn@scripps.edu
† All new compounds exhibited satisfactory spectral and exact mass data.
O
OR2
20
3
O
O
OH
R
1 = CH2OCPh3, R3 = SiMe2But
viii
ix
xi
R1 = CH2OH, R2 = H
22
R
1 = CH2OH
1 G. Ho¨fle, N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth and H.
Reichenbach, Angew. Chem., Int. Ed. Engl., 1996, 35, 1567.
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272, 2534.
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5 K. C. Nicolaou, N. Winssinger, J. A. Pastor, S. Ninkovic, F. Sarabia, Y.
He, D. Vourloumis, Z. Yang, T. Li, P. Giannakakou and E. Hamel,
Nature, 1997, 387, 268.
6 D.-S. Su, D. Meng, P. Bertinato, A. Balog, E. J. Sorensen, S. J.
Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He and S. B. Horwitz,
Angew. Chem., Int. Ed. Engl., 1997, 36, 757.
7 K. C. Nicolaou, S. Ninkovic, F. Sarabia, D. Vourloumis, Y. He, H.
Vallberg, M. R. V. Finlay and Z. Yang, J. Am. Chem. Soc., 1997, 119,
7974.
x
21 R1 = CH2OH, R3 = SiMe2But
23a R1 = CH2OAc, R2 = H
24a R1 = CH2OAc
xi,viii
xii,viii
xiii,viii
xiv
xii
24b R1 = CH2OC(O)But
24c R1 = CH2OBz
24d R1 = CHO
xiii
23b
23c R1 = CH2OBz, R2 = H
23d
1 = CHO,R2 = H
R
1 = CH2OC(O)But, R2 = H
xv
v
24e
R
1 = CO2H
R
v
xv
23e R1 = CO2H, R2 = H
23f R1 = CO2Me, R2 = H
24f R1 = CO2Me
24g R1 = CH2Cl
xv
xxvii
xxviii
xix
xvi,viii
1 = CH2Cl, R2 = H
1 = CH2OMe, R2 = H
24h
24j
R
R
1 = CH2OMe
1 = CH2F
23g
23h
R
xvii,viii
R
xviii,viii
xxvi,xx,iii
23i R1 = CH2OBn, R2 = H
23j
1 = CH2F, R2 = H
24k R1 = CH=CH2
24l R1 = Et
xxviii
xix,viii
R
xiv,xx,viii
xiv,xx,xxi,viii
xxii,xxix
23k R1 = CH=CH2, R2 = H
23l R1 = Et, R2 = H
24o R1 = CH2I
xxii,xxiii,viii
xiv,xxiv,viii
23m R1 = CH2NHAc, R2 = H
23n R1 = CH≡CH, R2 = H
8 A. Balog, D. Meng, T. Kamenecka, P. Bertinato, D.-S. Su, E. J.
Sorensen and S. J. Danishefsky, Angew. Chem., Int. Ed. Engl., 1996, 35,
2801; D. Meng, D.-S. Su, A. Balog, P. Bertinato, E. J. Sorensen, S. J.
Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He and S. B. Horwitz, J. Am.
Chem. Soc., 1997, 119, 2733.
9 Z. Yang, Y. He, D. Vourloumis, H. Vallberg and K. C. Nicolaou,
Angew. Chem., Int. Ed. Engl., 1997, 36, 166; K. C. Nicolaou, F. Sarabia,
S. Ninkovic and Z. Yang, Angew. Chem., Int. Ed. Engl., 1997, 36,
525.
10 D. Schinzer, A. Limberg, A. Bauer, O. M. Bo¨hm, M. Cordes, Angew.
Chem., Int. Ed. Engl., 1997, 36, 523.
11 K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, F. Roschangar, F.
Sarabia, S. Ninkovic, Z. Yang and J. I. Trujillo, J. Am. Chem. Soc., 1997,
119, 7960.
Scheme 2 Reagents and conditions: i, LDA, THF, 0 °C, 15 min, then 12,
THF, 278 ? 260 °C, 1 h, then 11, THF, 278 °C; ii, ButMe2SiOSO2CF3,
2,6-lutidine, CH2Cl2, 0 °C, 2 h; iii, HF·pyridine, pyridine, THF, 0 ? 25 °C,
4 h; iv, (COCl)2, DMSO, Et3N, CH2Cl2, 278 ? 0 °C, 1.5 h; v, NaClO2,
Me2CNCHMe, NaH2PO4, ButOH–H2O (5:1), 25 °C, 2 h; vi, Bu4NF, THF,
25 °C, 8 h; vii, 2,4,6-Cl3C6H2COCl, Et3N, THF, 0 °C, 1 h, then add to
DMAP in toluene, 75 °C, 1 h; viii, 30% HF·pyridine (v/v), THF, 0 ? 25 °C,
24 h; ix, (+)-diethyl l-tartrate, Ti(OPri)4, ButOOH, 230 °C, 2 h; x,
camphorosulfonic acid, MeOH–CH2Cl2 (1:1), 0 ? 25 °C, 3 h; xi, Ac2O,
DMAP, EtOAc, 0 °C, 0.5 h; xii, ButCOCl, Et3N, DMAP, CH2Cl2, 0 °C, 0.5
h; xiii, BzCl, Et3N, DMAP, CH2Cl2, 0 °C, 0.5 h; xiv, MnO2, Et2O, 25 °C,
3 h; xv, CH2N2, Et2O, 0 °C; xvi, PPh3, CCl4, 75 °C, 24 h; xvii, NaH, MeI,
DMF, 0 °C, 1 h; xviii, NaH, BnBr, DMF, 0 ? 25 °C, 1 h; xix, DAST,
CH2Cl2, 278 ? 25 °C, 1 h; xx, Ph3P+CH3Br2, (Me3Si)2NLi, THF, 0 °C;
xxi, H2, Lindlar catalyst, EtOAc, room temp., 15 min.; xxii, TsCl, Et3N,
DMAP, CH2Cl2, 0 °C, 1 h; xxiii, NaN3, DMF, 25 °C, 10 h, then PPh3, THF,
60 °C, 8 h, then Ac2O, CH2Cl2, 10 min; xxiv, Me3SiCHN2, then BunLi,
THF, 278 ? 0 °C, 1 h; xxv, TEMPO (0.008 m, CH2Cl2), NaOCl (0.035 m,
5% aq. NaHCO3), aq. KBr (0.2 m), CH2Cl2, 0 °C, 0.5 h; xxvi, Me3SiCl,
Et3N, CH2Cl2, 0 ? 25 °C, 10 h; xxvii, PPh3, MeCN–CCl4 (1:3), 25 °C, 1
h; xxviii, methyl(trifluoromethyl)dioxirane, MeCN, 0 °C; xxix, NaI,
acetone, 25 °C, 10 h
12 Isolation and structure elucidation: G. Ho¨fle, personal communi-
cation.
13 K. C. Nicolaou, Y. He, F. Roschangar, N. P. King and D. Vourloumis,
Angew. Chem., in the press.
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Vourloumis and C. G. Nicolaou, Chem. Eur. J., in the press.
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Vourloumis and Y. He, Chem. Eur. J., in the press.
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the usual desilylation conditions gave 23n (68%). The aldehyde
obtained from MnO2 oxidation of 21 (90%) was also subjected
to Wittig methylenation (85%) furnishing, after desilylation,
alkene 23k (85%). A similar sequence of reactions with this
aldehyde (Wittig methylation and hydrogenation followed by
desilylation) provided 23l. Conversion of 3 to the corresponding
tosylate, followed by displacement with NaN3 in DMF and
reduction with PPh3, furnished the required primary amine. The
18 D. Enders, A. Plant, D. Backhaus and U. Reinhold, Tetrahedron, 1995,
51, 10 699.
Received in Corvallis, OR, USA, 11th August 1997; 7/05845D
2344
Chem. Commun., 1997