OR2
OTr
Y
O
R1
R1
i
iii
R2
X
R1O
Th
R2
TBDMSO
Th
OR
OTBDMS
O
OTBDMS
X
6a R1 = H, R2 = Th
b R1 = Me, R2 = Th
c R1 = Me, R2 = I
15a,b,c X = TBDMSO, H; Y = CO2Me
16a,b,c X = TBDMSO, H; Y = CH2OH
17a,b,c X = TBDMSO, H; Y = CH2OTr
18b X = TBDMSO, H; Y = CH2Cl
19b X = TBDMSO, H; Y = CH3
20a,b,c X = OH, H; Y = CH2OTr
21a,b,c X = O; Y = CH2OTr
O
OTBDMS
R1O
O
O
ii
28 R1 = TBDMS; R2 = Tr
29 R1 = R2 = H
iii
25a R = TBDMS; X = CH2OTBDMS
26 R = TBDMS; X= CH2OH
27 R = H; X = CO2H
iv
v
i
iv
ii
vi
S
v
X
Th
=
viii
vii
N
O
O
R1
R1
22b X = OH, H; Y = CH3
viii
vii
HO
Th
23b X = O; Y = CH3
HO
Th
O
O
O
Scheme 3 Reagents and conditions: i, 14 (1.3 equiv. based on 12), C6H6,
reflux, 18 h, 84–93%; ii, DIBAL-H, THF, 278 °C, 3 h, 71–95%; iii, TrCl,
DMAP, DMF, 70 °C, 18 h, 82–95%; iv, CCl4, PPh3, reflux, 18 h, 80%; v,
LiEt3BH, THF, 278 °C, 1 h, 92%; vi, HF•Py.Py, THF, 25 °C, 4 h, 66–73%;
vii, CSA, MeOH, 25 °C, 1 h, 95%; viii, SO3•Py, DMSO, Et3N, THF, 0 °C,
1 h.
O
O
O
OH
OH
30 R1 = H; X = OH
31 R1 = H; X = I
32 R1 = Me; X=I
1 R1 = H
33 R1 = Me
vi
Scheme 5 Reagents and conditions: i, HF•Py.Py, THF, 25 °C, 3 h, 87%
(after 1 recycle); ii, (a) (COCl)2, DMSO, CH2Cl2, 278 °C, 30 min, then
Et3N, 278 ? 0 °C, 30 min; (b) NaClO2, Me2CNCHMe, NaH2PO4, ButOH–
H2O, 25 °C, 2 h; (c) TBAF, THF, 25 °C, 12 h, ca. 100% (3 steps); iii,
2,4,6-Cl3C6H2COCl, Et3N, THF, 0 °C, 1 h, then add to DMAP in toluene,
75 °C, 1 h, 73%; iv, HF•Py, THF, 0 ? 25 °C, 24 h, 78%; v, (+)-diethyl l-
tartrate, Ti(PriO)4, ButOOH, CH2Cl2, 4 Å MS, 230 °C, 2 h, 80%; vi, (a)
TsCl, Et3N, DMAP, CH2Cl2, 0 ? 25 °C, 1 h; (b) NaI, acetone, 25 °C, 15 h,
91% (2 steps); vii, NaBH3CN, HMPA, 45 °C, 40 h, 67–70%.
application of these conditions to aldehydes 21a–c and 23b lead
to significant amelioration of stereoselectivity which was
naturally accompanied by an improved yield of the desired aldol
stereoisomer in each case (Scheme 4, Table 1). Intermediates
25a–d were obtained in good overall yields after subsequent
TBDMS-protection. Under these closely defined conditions the
aldol reaction is highly reproducible and applicable to multi-
gram quantities. These results, in terms of diastereoselectivities
and yields, are at least as good as those obtained by Schinzer and
co-workers in their epothilone B syntheses.2b Since our
approach features a rather convenient protecting group strategy,
we believe this development renders our modified route the
most effective solution to date for epothilone B.
The TBDMS-protected aldol product 25a was processed
through to 26-hydroxy-16-desmethylepothilone B 30 in the
same fashion as our published route to 26-hydroxyepothilone B
(Scheme 5).3a As projected, the Sharpless epoxidation pro-
ceeded with complete stereo- and regio-control at the C12–C13
position. It should be noted that for this analogue series,
competitive side-chain epoxidation would likely have been
problematic upon use of conventional oxidants. In order to
complete the synthesis, removal of the C26 hydroxy group was
required. This was achieved by initial conversion to iodide 31
followed by reductive deiodination with NaBH3CN7 to provide
X
our desired analogue 1 in good overall yield. Furthermore, this
deoxygenation sequence has also been demonstrated for the
production of epothilone B (33) itself from our previously
reported iodide 32. Thus, all of the synthetic methodology
described herein is applicable to epothilone B, which renders
our approach now highly selective at every step, and sig-
nificantly increases the speed of access to this and related
structures. Work is currently underway to assess the biological
activity of 1 and related analogues of epothilone B.
We thank D.-H. Huang and Gary Siuzdak for NMR and MS
studies, respectively. This research was financially supported
by the National Institutes of Health USA and The Skaggs
Institute for Chemical Biology, from the George Hewitt
Foundation (to N. P. K.), the Deutsche Forschungsgemeinschaft
(to B. W.), and grants from CaPCURE and Novartis.
Notes and references
† All new compounds exhibited satisfactory spectral and exact mass data.
‡ The ee was shown to be !97% by chiral HPLC (Chiralcel OD-H column)
by comparison with the racemate.
R1
O
OTBDMS
OTBDMS
24
TBDMSO
R2
i, ii
§ Due to high polarity and complex NMR spectra 14 was not purified as
characterized. We observed full mass return for 12 ? 14 and used the
material crude using quantities assuming purity.
¶ The aldehydes were freshly prepared and not purified prior to use.
∑The unreacted ketone 24 is easily recovered by chromatography.
1 For a review of the literature to Feb. 1998, see: K. C. Nicolaou, F.
Roschangar and D. Vourloumis, Angew. Chem., Int. Ed., 1998, 37,
2014.
X
OTBDMS
+
O
OTBDMS
OTBDMS
R1
R2
O
OTBDMS
21a R1 = H, R2 = Th, X = OTr
25a
R
R
R
1 = H, R2 = Th, X = OTr
1 = Me, R2 = Th, X = OTr
1 = Me, R2 = I, X = OTr
R
1 = Me, R2 = Th, X = H
b
c
R
R
R
1 = Me, R2 = Th, X = OTr
1 = Me, R2 = I, X = OTr
1 = Me, R2 = Th, X = H
b
c
d
23b
2 For recent syntheses see: (a) S. A. May and P. Grieco, Chem. Commun.,
1998, 1597; (b) D. Schinzer, A. Bauer and J. Scheiber, Synlett, 1998, 861;
(c) A. Balog, C. Harris, K. Savin, X.-G. Zhang, T. C. Chou and S. J.
Danishefsky, Angew. Chem., Int. Ed., 1998, 37, 2675; (d) J. Mulzer, A.
Mantoulidis and E. Öhler, Tetrahedron Lett., 1998, 39, 8633; (e) S. C.
Sinha, C. F. Barbas III and R. A. Lerner, Proc. Natl. Acad. Sci. U.S.A.,
1998, 95, 14603.
Scheme 4 Reagents and conditions: i, LDA (2.4 equiv.), 24 (2.3 equiv.),
THF, 278 ? 240 °C, 1 h, then add 21 or 23, THF 278 °C, 2 min, then
AcOH, 278 ? 0 °C; ii, TBDMSOTf, 2,6-lutidine, THF, 278 ? 0 °C,
1 h.
Table 1 Yields and stereoselectivities for aldol reactions
3 (a) K. C. Nicolaou, M. R. V. Finlay, S. Ninkovic and F. Sarabia,
Tetrahedron, 1998, 54, 7127; (b) K. C. Nicolaou, M. R. V. Finlay, S.
Ninkovic, N. P. King, Y. He, T. Li, F. Sarabia and D. Vourloumis, Chem.
Biol., 1998, 5, 365; (c) K. C. Nicolaou, N. P. King, M. R. V. Finlay, Y.
He, F. Roschangar, D. Vourloumis, H. Vallberg, F. Sarabia, S. Ninkovic
and D. Hepworth, Bioorg. Med. Chem., 1998, in the press.
4 M. Tamura and J. Kochi, Synthesis, 1971, 303.
5 Y. Morimoto and H. Shirahama, Tetrahedron, 1996, 52, 10631.
6 C. H. Heathcock, in Comprehensive Organic Synthesis, ed. B. M. Trost
and I Fleming, Pergamon, Oxford, 1991, vol. 2, pp. 181–235.
7 R. O. Hutchins, D. Kandasamy, C. A. Maryanoff, D. Masilamani and
B. E. Maryanoff, J. Org. Chem., 1977, 42, 82.
Aldol product
Aldehyde Selectivitya (%)b
25 (%) (2 steps)c
21a
21b
21c
23b
!10:1
!15:1
!10:1
!10:1
76
77
79
71
72
73
75
67
a
Conservative estimates based upon mass recovery of the major isomer
b
relative to all other polar impurities. Often contaminated with small
c
amounts ( = 5%) of starting aldehyde. Yields are compensated. Single
stereoisomer free from traces of aldehyde and other impurities.
Communication 8/09954E
520
Chem. Commun., 1999, 519–520