Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis

Article abstract of DOI:10.1021/ja002024b

An enantioselective total synthesis of epothilones A (1) and B (2) using multifunctional asymmetric catalysis such as a cyanosilylation of an aldehyde, an aldol reaction of an unmodified ketone with an aldehyde, and a protonation in the conjugate addition of a thiol to an α,β-unsaturated thioester has been achieved. We divided 1 and 2 into fragment A, fragment B, and fragment C. A catalytic asymmetric synthesis of fragments A and B was accomplished using a catalytic asymmetric cyanosilylation as a key step. An enantiocontrolled synthesis of fragment C was achieved in two ways. One is the use of a direct catalytic asymmetric aldol reaction of an unmodified ketone with an aldehyde as a key step, and the other utilizes a catalytic asymmetric protonation in the conjugate addition of a thiol to an α,β-unsaturated thioester as a key step. Suzuki cross-coupling of fragment A with fragment C followed by Yamaguchi lactonization as key steps led to an enantiocontrolled synthesis of epothilone A (1). On the other hand, Suzuki cross-coupling of fragment B with fragment C followed by Yamaguchi lactonization accomplished an enantiocontrolled synthesis of epothilone B (2).

Full text of DOI:10.1021/ja002024b

J. Am. Chem. Soc. 2000, 122, 10521-10532
10521
Enantioselective Total Synthesis of Epothilones A and B Using
Multifunctional Asymmetric Catalysis
Daisuke Sawada, Motomu Kanai, and Masakatsu Shibasaki*
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
ReceiVed June 6, 2000
Abstract: An enantioselective total synthesis of epothilones A (1) and B (2) using multifunctional asymmetric
catalysis such as a cyanosilylation of an aldehyde, an aldol reaction of an unmodified ketone with an aldehyde,
and a protonation in the conjugate addition of a thiol to an R,â-unsaturated thioester has been achieved. We
divided 1 and 2 into fragment A, fragment B, and fragment C. A catalytic asymmetric synthesis of fragments
A and B was accomplished using a catalytic asymmetric cyanosilylation as a key step. An enantiocontrolled
synthesis of fragment C was achieved in two ways. One is the use of a direct catalytic asymmetric aldol
reaction of an unmodified ketone with an aldehyde as a key step, and the other utilizes a catalytic asymmetric
protonation in the conjugate addition of a thiol to an R,â-unsaturated thioester as a key step. Suzuki cross-
coupling of fragment A with fragment C followed by Yamaguchi lactonization as key steps led to an
enantiocontrolled synthesis of epothilone A (1). On the other hand, Suzuki cross-coupling of fragment B with
fragment C followed by Yamaguchi lactonization accomplished an enantiocontrolled synthesis of epothilone
B (2).
Introduction
Synthesis of Fragments A and B. The requisite R,â-
unsaturated aldehyde 7 for the catalytic asymmetric cyanosi-
lylation was first synthesized according to reported procedures.2h
With large amounts of 7 in hand, a catalytic asymmetric
cyanosilylation was carefully examined, and the results are
summarized in Table 1. The Lewis acid-Lewis base bifunc-
tional asymmetric catalyst was prepared starting from Et2AlCl
Epothilones (see Scheme 1 for epothilones A (1) and B (2))
show potent antitumor activity by binding and stabilizing
microtubles in the same way as taxol, and they are promising
drug candidates. Epothilones A (1) and B (2) were isolated from
the myxobacteria of the genus Sorangium, and their structures
were determined by Ho¨fle et al.1 Highly efficient total syntheses
were disclosed by the research groups of Danishefsky, Nicolaou,
Schinzer, and others,2 making possible structure-activity
relationships of epothilones. An enantioselective total synthesis,
however, using simple asymmetric catalysts has not been
achieved, although an enantioselective total synthesis of epothilone
A (1) has been accomplished using antibody catalysts2k or an
enzyme.2t Herein we report a full account of an enantioselective
total synthesis of epothilones A (1) and B (2) using multifunc-
tional asymmetric catalysts for a direct aldol reaction, a
cyanosilylation, and a conjugate addition/enantioselective pro-
tonation, demonstrating the usefulness of these reactions for the
catalytic asymmetric synthesis of complex molecules.
Retrosynthetic Analysis. Scheme 1 shows our retrosynthetic
analysis of 1 and 2 using multifunctional asymmetric catalysis
to control all the chiral centers included in 1 and 2. The 16-
membered rings of 1 and 2 were expected to be constructed by
Suzuki coupling of fragments A and C and/or fragments B and
C followed by Yamaguchi lactonization. Fragments A and B
could be obtained by a catalytic asymmetric cyanosilylation of
aldehyde 7 controlled by the Lewis acid-Lewis base bifunc-
tional catalyst as a key step.3 Fragment C could be synthesized
by a catalytic asymmetric epoxidation and aldol reaction as key
steps.4,5 Alternatively, aldehyde 9 was expected to be constructed
using a catalytic asymmetric protonation in the conjugate
addition of thiol 17 to 18 as the key step.6
(2) (a) Balog, A.; Meng, D.; Kamenecka, T.; Bertinato, P.; Su, D.-S.;
Sorensen, E. J.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1996, 35,
2801-2803. (b) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou,
K. C. Angew. Chem., Int. Ed. Engl. 1997, 36, 166-168. (c) Schinzer, D.;
Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M. Angew. Chem., Int. Ed.
Engl. 1997, 36, 523-524. (d) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.;
Yang, Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 525-527. (e) Su, D.-S.;
Meng, D.; Bertinato, P.; Balog, A.; Sorensen, E. J.; Danishefsky, S. J.;
Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. Angew. Chem., Int. Ed.
Engl. 1997, 36, 757-759. (f) Nicolaou, K. C.; Winssinger, N.; Pastor, J.;
Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.;
Giannakakou, P.; Hamel, E. Nature 1997, 387, 268-272. (g) Nicolaou, K.
C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.;
Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960-
7973. (h) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He,
Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z. J. Am. Chem. Soc. 1997, 119,
7974-7991. (i) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka,
T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073-
10092. (j) Harris, C. R.; Kuduk, S. D.; Balog, A.; Savin, K.; Glunz, P. W.;
Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 1, 7050-7062. (k) Sinha,
S. C.; Barbas III, C. F.; Lerner, R. A. Proc. Natl. Acad. Sci. U.S.A. 1998,
14603-14608. (l) For a review, see: Nicolaou, K. C.; Roschangar, F.;
Vourloumis, D. Angew. Chem., Int. Ed. 1998, 37, 2014-2045. (m) Mulzer,
J.; Mantoulaidis, A.; Ohler, E. Tetrahedron Lett. 1998, 39, 8633-8636.
(n) May, S. A.; Grieco, P. A. J. Chem. Soc., Chem. Commun. 1998, 1597-
1598. (o) Schinzer, D.; Bauer, A.; Schieber, J. Synlett 1998, 861-864. (p)
White, J. D.; Carter, R. G.; Sundermann, K. F. J. Org. Chem. 1999, 64,
684-685. (q) Schinzer, D.; Bauer, A.; Bo¨hm, O. M.; Limberg, A.; Cordes,
M. Chem. Eur. J. 1999, 5, 2483-2491. (r) Schinzer, D.; Bauer, A.; Schieber,
J. Chem. Eur. J. 1999, 5, 2492-2500. (s) Balog, A.; Harris, C.; Savin, K.;
Zhang, X.-G.; Chou, T. C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998,
37, 2675-2678. (t) Machajewski, T. D.; Wong, C.-H. Synthesis 1999,
1469-1472. (u) Sawada, D.; Shibasaki, M. Angew. Chem., Int. Ed. 2000,
39, 209-213. (v) Martin. H. J.; Drescher, M.; Mulzer, J. Angew. Chem.,
Int. Ed. 2000, 39, 581-583.
(1) Ho¨fle, G.; Bedolf, N.; Steinmetz, H.; Schomburg, D.; Gerth, K.;
Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567-1569.
10.1021/ja002024b CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/18/2000

10522 J. Am. Chem. Soc., Vol. 122, No. 43, 2000
Sawada et al.
Scheme 1. Molecular Structure and Retrosynthetic Analysis
of Epothilone A (1) and B (2)
Figure 1. Proposed transition state for the catalytic asymmetric
cyanosilylation.
Scheme 2. Catalytic Asymmetric Cyanosilylation
1, finally we were pleased to find that the desired cyanohydrin
6 was obtained in 97% and in 99% ee in the presence of 5 mol
% of catalyst by adding 1.2 equiv of TMSCN over 48 h. This
result shows that the ratio of the catalyst and TMSCN is quite
important to promote the reaction effectively. This tendency is
very unusual in our catalytic asymmetric cyanosilylation of
aldehydes, strongly indicating the following fact. It seems that
the thiazole functional group activates TMSCN by the coordina-
tion to Si of TMSCN, allowing the substitution of Cl in the
catalyst with CN. The asymmetric catalyst generated from Et2-
AlCN and the ligand 19 was shown to be rather unreactive for
a catalytic asymmetric cyanosilylation of aldehydes in our
group.7 On the basis of the mechanistic studies,3 the reaction
should proceed through the proposed transition state shown in
Figure 1. At present, however, the possibility that the actual
reagent structure is TMSNC cannot be excluded. With large
quantities of 6 in hand, the synthesis of fragments A and B
was pursued. Direct conversion of 6 to the aldehyde 5 using
DIBAL was first attempted (Scheme 3). The yield, however,
was moderate, giving 5 only in about 40%. On the other hand,
ethanolysis using HCl in ethyl alcohol followed by hydrolysis
gave rise to the ester 20 in good yield accompanied by a small
Table 1. Catalytic Asymmetric Synthesis of 6
concn
cat.
TMSCN slow addition of time yield ee
entry (M) (mol %) (equiv)
TMSCN (h)
(h) (%) (%)
1
2
3
4
5
6
0.3
0.3
0.6
0.6
0.3
0.3
20
20
20
20
10
5
3
10
10
10
10
24
48
86
51
90
74
84
50
83 98
97 99
70 97
97 99
95 99
97 99
1.8
1.8
1.2
1.2
1.2
and the chiral ligand 19 according to the established procedure
in our group (Scheme 2).3
The reaction was first carried out using 20 mol % of catalyst
in the presence of n-Bu3PdO (80 mol %) and TMSCN (3 equiv,
slow addition over 10 h) at -40 °C, giving the corresponding
cyanohydrin 6 in 83% and 98% ee after acidic workup. The
absolute configuration of 6 is already known,3 and the ee was
unequivocally determined by HPLC analysis after converting
6 to the TBS ether (DAICEL CHIRALPAK AD, hexane/2-
propanol (100:1, v/v), flow rate 1.0 mL/min, retention times
7.5 min (R) isomer and 8.0 min (S) isomer, detection at 254
nm). In an attempt to improve the reactivity of the above-
mentioned catalytic asymmetric cyanosilylation, further reactions
using different conditions were examined. As shown in Table
(3) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 1999, 121, 2641-2642.
(4) (a) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M.
J. Am. Chem. Soc. 1997, 119, 2329-2330. (b) Watanabe, S.; Kobayashi,
Y.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett.
1998, 39, 7353-7356. (c) Watanabe, S.; Arai, T.; Sasai, H.; Bougauchi,
M.; Shibasaki, M. J. Org. Chem. 1998, 63, 8090-8091.
(5) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871-1873. (b) Yoshikawa, N.;
Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1999, 121, 4168-4178.
(6) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998,
120, 4043-4044.
(7) Hamashima, Y.; Kanai, M.; Shibasaki, M. Unpublished results.

EnantioselectiVe Synthesis of Epothilones A and B
Scheme 3. Synthesis of Compound 23a
J. Am. Chem. Soc., Vol. 122, No. 43, 2000 10523
Scheme 5. Synthesis of Fragment Ba
a (a) Ph3P+CH2OMeCl-, LHMDS, THF, 68%; (b) Hg(OAc)2 n-Bu4NI,
THF, H2O, 60%; (c) Ph3P+CH2CH3I-, n-BuLi, THF then I2, then
NaHMDS, 50%; (d) HF‚pyridine, THF, 100%; (e) Ac2O Et3N, DMAP,
CH2Cl2, 96%.
a (a) HCl, EtOH, H2O, 90 °C, 83%; (b) TBSCl, imidazole, DMF,
99%; (c) DIBAL, toluene, -78 °C, 94%; (d) TMSCtCLi, THF, -78
°C; then ClCO2Me, 79%; (e) Pd(OAc)2, n-Bu3P, HCO2NH4, benzene,
50 °C 51%.
Scheme 6. Synthesis of Compound 34a
Scheme 4. Synthesis of Fragment Aa
a (a) Ti(OiPr)4, iPrMgBr, Et2O, -78 to -50 °C, 69% for 24, 29%
for 25; (b) i. I2, CH2Cl2; ii. HF‚pyridine, THF, 75% (for two steps);
(c) I2, CH2Cl2, 59%; (d) Ac2O, Et3N, DMAP, CH2Cl2, 100%.
amont of the corresponding carboxylic acid. Since racemization
was observed when the above reaction was carried out at g
100 °C, the actual ethanolysis was performed at 90 °C. After
protection of the alcohol as a TBS ether, the resulting ester 21
was reduced with DIBAL to give the desired aldehyde 5 in 77%
overall yield from 6. Reaction of 5 with the lithium acetylide
followed by treatment with ClCO2Me afforded 22 in a mixture
of diastereomers (79%), which underwent reduction with a
catalytic amount of Pd(OAc)2, n-Bu3P, and HCO2NH4, giving
23 in 51% yield.8 Then conversion of 23 to fragment A was
first examined. In contrast to our expectation, hydroalumination
of 23 using DIBAL did not afford the desired product under a
variety of reaction conditions. On the other hand, hydrotitana-
tion9 proceeded well, giving 24 (69%) and 25 (26%) after acidic
workup (Scheme 4). This successful transformation might be
ascribed to lower Lewis acidity of low-valent titanium than
DIBAL, thereby making the undesired coordination of the
thiazole moiety to low-valent titanium unlikely. The silylalkene
a (a) i. PhCHO, TsOH‚H2O, benzene, reflux, ii. DIBAL, CH2Cl2 85%;
(b) SO3‚Py, DMSO, Et3N, 96%; (c) LDA, butanone, THF, -78 °C,
81%; (d) trifluoroacetic anhydride, CH2Cl2, then DBU 100%; (e) H2O2,
NaOH aq, MeOH, 66%; (f) NH2OMe‚HCl AcONa, MeOH, 83%; (g)
CuCN, MeLi, Et2O, -78 °C, 60%; (h) Raney nickel (W2), H2, H3BO3,
acetone, THF, MeOH, H2O 78%.
24 was successively treated with I2 and HF‚pyridine to give
the cis-iodoalkene 26 (75%). Similarly, 25 was treated with I2,
furnishing 26 (59%). The resulting alcohol 26 was then protected
as an acetate to provide fragment A (99% ee). The stereochem-
istry of the carbon-carbon double bond was confirmed by the
1H NMR coupling constant (7.5 Hz). Transformation to fragment
B was attempted next. Conversion of 23 to fragment B was
first attempted under a variety of reaction conditions. However,
this attempt was found to be unfruitful.
Thus, 5 was transformed into the aldehyde 27 using the Wittig
reaction followed by hydrolysis in 41% overall yield,10 which
was further treated with iodophosphorane, giving 28 exclusively
(8) (a) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. Tetrahedron
Lett. 1993, 34, 2161-2164. (b) Tsuji, J.; Sugiura, T.; Minami, I. Synthesis
1987, 603-606.
(10) Corey, E. J.; Narasaka, K.; Shibasaki, M. J. Am. Chem. Soc. 1976,
98, 6417-6418.
(9) Sato, F.; Ishikawa, H.; Sato, M. Tetrahedron Lett. 1981, 22, 85-88.

10524 J. Am. Chem. Soc., Vol. 122, No. 43, 2000
Sawada et al.
Table 2. Epoxide Opening of cis Epoxy-oximes by Cuprate
Reagents
entry
R1
R2
R3
yield (%)
1
2
3
4
5
6
7
Me
propyl
phenethyl
phenethyl
phenethyl
phenethyl
pentyl
pentyl
pentyl
pentyl
pentyl
pentyl
pentyl
phenethyl
Me
Me
Me
Bu
Ph
vinyl
Me
77
72
85
80
80
50
81
Figure 2. NOE results for (()-35 and (()-36.
Scheme 7. Conversion of (()-34 to Acetonides (()-35 and
(()-36
Figure 3. Formation of the (Z)-O enolate followed by alkylation.
Scheme 8. Synthesis of Compound (()-40 and (()-41a
in 50% yield (Scheme 5).11 Removal of the protecting group
followed by acetylation gave rise to fragment B (99% ee) in
96% overall yield. The stereochemistry of the trisubstituted
carbon-carbon double bond was determined by precedent.2i
Synthesis of Fragment C. According to the retrosynthetic
analysis shown in Scheme 1, the synthesis of optically active
fragment C was investigated. The requisite R,â-unsaturated
ketone 11 was first synthesized starting from neopentyl glycol
(12) as shown in Scheme 6. A catalytic asymmetric epoxidation
of 11 was examined using the lanthanoid-containing asymmetric
catalysts developed in our group.4 Unfortunately, however,
because of the steric hindrance of the quaternary carbon atom
in the R-position to the double bond, only small amounts of
the epoxide were obtained with low ee values. This unfortunate
result led us to another strategy for the synthesis of optically
active 8. We envisioned that a direct aldol reaction of acetophe-
none with (()-9 (see Scheme 1) promoted by the heteropoly-
metallic asymmetric catalyst would give desired 8 by an
effective catalyst control. Toward this aim 11 was oxidized with
H2O2 to the epoxy ketone (()-10 which was then converted
into the methyloxime (()-32. The epoxide opening to give the
anti-aldol (()-34 was achieved by using the cuprate reagent
(f (()-33) and subsequent reduction with Raney nickel
followed by hydrolysis.12 To the best of our knowledge, this is
a new method to prepare an anti-aldol).13 The relative stereo-
chemistry of (()-34 was determined by NOE experiments
(Scheme 7) of the corresponding acetonides (()-35 and (()-
36 obtained by NaBH4 reduction followed by treatment with
2,2-dimethoxypropane and PPTS as shown in Figure 2.
a (a) LHMDS, allyl bromide, DMPU, THF, -78 °C, 48% (recovery
of 34, 52%); (b) Me4NBH(OAc)3, AcOH, MeCN, 79% for 38, 11%
for 39; (c) methoxypropene, TsOH, DMF, 96% for 40, 73% for 41.
Toward the synthesis of fragment C, the next step was the
stereocontrolled allylation of (()-34. After protection of the
hydroxyl group of (()-34 as a TBS ether, the allylation was
examined. Unfortunately, however, although the reaction pro-
ceeded well, only a low stereoselectivity was observed. In
striking contrast to this result, when the allylation was carried
out using nonprotected (()-34 in the presence of 1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), only the de-
sired product was formed albeit in modest yield (48%, conver-
sion yield 100%). This highly stereoselective allylation seems
to proceed through the (Z)-O enolate shown in Figure 3. The
reason the chemical yield is just modest might be ascribed to
the generation of LiBr, which prevents the reaction from
proceeding effectively. When alkali metals other than lithium
(11) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827-
2828.
(12) For the related reaction, see: Corey, E. J.; Melvin, L. S., Jr.;
Haslanger, M. F. Tetrahedron Lett. 1975, 3117-3120.
(13) It is also possible to prepare syn aldols from cis enones by this
method (Table 2).

EnantioselectiVe Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 122, No. 43, 2000 10525
Scheme 11. Catalytic Asymmetric Aldol Reaction and
Subsequent Conversion to Fragment Ca
Figure 4. NOE results for (()-40 and (()-41.
Scheme 9. Determination of the Stereochemistry of the
Allylation
Scheme 10. Synthesis of (()-9a
a (a) Li, liquid NH3, t-BuOH, THF, 100%; (b) TPAP, NMO, MS
4A, CH2Cl2, 89%.
were utilized, a lower stereoselectivity was observed. Stereo-
selective reduction of (()-37 with Me4NBH(OAc)314 (Scheme
8) resulted in the formation of the desired alcohol 38 (79%)
together with the undesired alcohol 39 (11%). The stereochem-
istry of the resulting secondary alcohol was unequivocally
determined by NOE experiments of the corresponding ac-
etonides (()-40 and (()-41 (Figure 4). At this stage, the
stereochemistry of the allylation was determined as follows.
Hydroboration of (()-40 followed by oxidative workup and
further oxidation with PDC gave the corresponding carboxylic
acid. Treatment of this carboxylic acid with HCl resulted in
the removal of the protecting group and the subsequent
lactonization, giving the lactone (()-42. The coupling constant
between Ha and Hb of (()-42 was shown to be 10.2 Hz,
confirming the stereochemistry of the allylation (Scheme 9).
Birch reduction of (()-40 and subsequent oxidation with TPAP
gave rise to the requisite (()-aldehyde 9 in 89% overall yield
(Scheme 10).
a (a) Acetophenone, (R)-LLB, KHMDS, H2O, THF, -20 °C, 30%
(89% ee) for 8, 29% (88% ee) for 44 (recovery of 9 36%); (b) BTSP,
SnCl4, MS 4A, ligand 45, K2CO3, CH2Cl2, 69%; (c) BCl3 CH2Cl2, -78
°C, 87%; (d) TBSOTf, iPr2NEt, CH2Cl2; (e) Dess-Martin periodinane,
CH2Cl2, 65% (for two steps).
(LLB) (20 mol %), KHMDS (18 mol %), and H2O (40 mol
%)5 at -20 °C for 168 h gave the desired aldol product 8 in
30% and in 89% ee together with the diastereomer 44 in 29%
and in 88% ee. Under these reaction conditions, 36% of (()-9
was recoverd and the excess acetophenone was also completely
recovered. It appeared that the reaction became sluggish as the
aldol reaction proceeded. In addition, when the reaction was
worked up, a trace amount of the dehydrated product was
observed. The stereochemistry of the newly formed secondary
alcohol in both 8 and 44 was determined to be S by the Mosher
method.15 As far as we know, this is the first example of a
catalytic resolution of a racemic compound in an aldol reaction
using a simple asymmetric catalyst.2k,t The desired diastereomer
8 underwent Baeyer-Villiger oxidation with bis(trimethylsilyl)
peroxide (BTSP), SnCl4, and ligand (()-45 to give the ester 46
in 69% yield (conversion yield 88%).16 Treatment of the ester
46 with BCl3 (87%) followed by selective protection as a TBS
In the next step, the direct catalytic asymmetric aldol reaction
with acetophenone was carefully examined (Scheme 11). After
several attempts, it was found that treatment of (()-9 with 8
equiv of acetophenone in the presence of the heteropolymetallic
asymmetric catalyst generated from (R)-LaLi3tris(binaphthoxide)
(14) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(15) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.

10526 J. Am. Chem. Soc., Vol. 122, No. 43, 2000
Sawada et al.
Scheme 12. Determination of the Stereochemistry of Aldol
Products 8 and 44
Figure 5. Proposed transition state of the catalytic asymmetric aldol
reaction.
Scheme 13. Synthesis of Optically Active 40 Using
Catalytic Aymmetric Protonation in the Conjugate Addition
of a Thiol to a Conjugated Thioestera
ether furnished 48, and subsequent oxidation with Dess-Martin
periodinane gave fragment C in 65% overall yield. The
stereochemistry of 8 and the diastereomer 44 was determined
as follows (Scheme 12). Treatment of 48 and/or 49 with acid
afforded the lactones 50 and 51, respectively, and NOE
experiments of the lactones resulted in the determination of the
stereochemistry of 8 and 44. It should be mentioned that a
strategy of this type would be useful for exploring the diversity
of epothilones in terms of medicinal chemistry. On the basis of
the mechanistic studies,5 the transition model for this aldol
reaction is proposed to be as shown in Figure 5.
As shown above, we have succeeded in synthesizing fragment
C in 89% ee. Unfortunately, however, the above synthesis is
not effective due to the necessity of a catalytic resolution,
although we believe that the synthesis is quite interesting in
terms of an asymmetric synthesis of the requisite compound.
Therefore, we further investigated the feasibility of a catalytic
asymmetric synthesis of the aldehyde 9. As already mentioned
in the retrosynthetic analysis of fragment C, we envisioned that
a catalytic asymmetric protonation in the conjugate addition of
a thiol to an R,â-unsaturated thioester6 would lead to a catalytic
asymmetric synthesis of 9. Reaction of 17 with 18 in the
presence of 5 mol % of (S)-SmNa3tris(binaphthoxide) (SmSB)
gave 16 in 92% yield and 88% ee, which was then reduced
with LiAlH4 followed by protection of the resulting primary
alcohol as a MPM ether, furnishing 53 in 93% overall yield
(Scheme 13). The absolute configuration of 16 is already
known,6 and the ee was determined by HPLC analysis (see the
Experimental Section). The transition state model is proposed
to be as shown in Figure 6. The sulfide 53 was oxidized with
mCPBA, and the subsequent Pummerer rearrangement17 gave
rise to the corresponding aldehyde 54, which was reduced with
NaBH4 to afford the alcohol 55. The primary alcohol of 55 was
brominated, and the resulting bromide 56 was reacted with
lithium divinylcuprate to yield the alkene 57. Deprotection of
the MPM group in 57 with DDQ and subsequent oxidation gave
the very volatile aldehyde 14. Carefully handling, the aldol
reaction of 14 with the ketone 15 successfully procceeded to
give the desired aldol product 13 (60%, 4:1 ratio).2s After
protection of the secondary alcohol as a TBS ether, reduction
using DIBAL afforded the alcohol with the desired stereochem-
istry, which was converted to the opticlly active acetonide 40.
As already discussed, 40 was transformed into the aldehyde
9. During the synthetic route mentioned above (16 f 9), no
a (a) (S)-SmSB (5 mol %), 4-t-BuPhSH (17), CH2Cl2, 92%, 88%
ee; (b) LAH, Et2O, 95%; (c) MPMCl, NaH, DMF, 98%; (d) i. mCPBA,
CH2Cl2, -20 °C, ii. trifluoroacetic anhydride, pyridine CH2Cl2, 78%;
(e) NaBH4, MeOH, 100%; (f) CBr4, PPh3, CH2Cl2, 100%; (g) CuCN,
MeLi, tetravinyltin, THF, -78 °C f rt 88%; (h) i. DDQ, H2O, CH2Cl2,
ii. TPAP, NMO, MS 4A CH2Cl2; (i) LDA 15, THF, -78 °C, 60% for
three steps (4:1); (j) TBSOTf, iPr2NEt, CH2Cl2, 100%; (k) i. DIBAL,
toluene -78 °C, ii. methoxypropene, TsOH, DMF, 91%.
racemization was observed. Thus, although the synthesis
involves relatively many steps, we have succeeded in synthesiz-
ing optically active 9 in a catalytic asymmetric manner using
multifunctional asymmetric catalysis.
Total Synthesis of Epothilones A and B. Having synthesized
the requisite fragments A, B and C, first of all, the synthesis of
epothilone A (1) was examined (Scheme 14). Following mainly
the synthesis achieved by Danishefsky et al.,2a,i however, it was
found that, in our case, hydroboration of fragment C (89% ee)
(16) Go¨ttlich, R.; Yamakoshi, K.; Sasai, H.; Shibasaki, M. Synlett 1997,
971-973.
(17) Konno, K.; Hashimoto, K.; Shirahama, H.; Matsumoto, T. Tetra-
hedron Lett. 1986, 27, 3865-3868.

EnantioselectiVe Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 122, No. 43, 2000 10527
Scheme 15. Total Synthesis of Epothilone B (2)a
Figure 6. Proposed transition state of the catalytic asymmetric
protonation in the conjugate addition of a thiol to a conjugated thioester.
Scheme 14. Total Synthesis of Epothilone A (1)a
a (a) 9-BBN (2 molar equiv), ultrasound, THF, then PdCl2(dppf) (20
mol %), K3PO4, DMF, H2O 60 °C, 50%; (b) NaOH, MeOH H2O, 93%;
(c) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP, toluene,
90%; (d) HF‚pyridine, THF, 92%; (e) 3,3-dimethyldioxirane, CH2Cl2,
-35 °C 97%.
Hydrolysis of 61 followed by Yamaguchi lactonization and the
subsequent removal of the silyl group gave epothilone D (4) in
84% overall yield. Finally, we were pleased to obtain epothilone
B (2) by treatment with 3,3-dimethyldioxirane in 97% yield,
which was identified by comparison with an authentic sample
(1H and 13C NMR spactra) kindly provided by Prof. K. C.
Nicolaou.
Conclusions
We have achieved an enantioselective total synthesis of
epothilones A (1) and B (2) by controlling all the chiral centers
using multifunctional asymmetric catalysis. These syntheses
have succeeded in demonstrating the usefulness of multifunc-
tional asymmetric catalysis such as a cyanosilylation, an aldol
reaction, and a conjugate addition/protonation for the synthesis
of complex molecules. Although the practicability of the shown
synthesis is still unsatisfactory, we would like to emphasize that
this is the first step of enantiocontrolled syntheses of complex
molecules using multifunctional asymmetric catalysis. To
improve the practicability of the total synthesis, further inves-
tigations are currently under way.
a (a) 9-BBN (2 molar equiv), ultrasound, THF, then PdCl2(dppf) (50
mol %), K3PO4, DMF, H2O, 60 °C, 50%; (b) NaOH, MeOH, H2O,
84%; (c) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP,
toluene, 88%; (d) HF‚pyridine, THF, 99%; (e) 3,3-dimethyldioxirane,
CH2Cl2, -35 °C, 49%.
using 9-BBN did not proceed well. Fortunately this reaction
proceeded well with ultrasound,18 and the subsequent coupling
reaction with fragment A in the presence of PdCl2(dppf) gave
the desired product 59 (99% ee) in 50% yield together with a
trace amount of the diastereomer (less polar). Hydrolysis of 59
with NaOH in MeOH furnished the hydroxy acid in 84%, which
was followed by Yamaguchi lactonization, affording the lactone
60 (88%). Finally, treatment of 60 with HF‚pyridine followed
by epoxidation gave rise to epothilone A (1) in 99% ee [4
(desired):1 (undesired) ratio]. The structure of 1 was unequivo-
cally confirmed (1H and 13C NMR spectra) by comparison with
the spectral data kindly provided by Prof. K. C. Nicolaou.
Experimental Section
(2R,3E)-2-Hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-
butenenitrile (6). In a flame-dried flask 19 (64 mg, 0.0895 mmol)
was placed and dried at 50 °C for 2 h under the reduced pressure.
Then 3 mL of dichloromethane was added, followed by the addition
of diethylaluminum chloride (93 µL, 0.089 mmol, 0.96 M in hexane)
under an argon atmosphere. After stirring for 10 min, tributylphosphine
oxide (78 mg, 0.358 mmol) in dichloromethane (1.2 mL) was added at
room temperature. The resulting mixture was stirred at the same
temperature for 1 h to give a clear solution. To this stirred solution of
the catalyst was added aldehyde 7 (300 mg, 1.79 mmol) in dichlo-
romethane (1.4 mL) at -40 °C. After 30 min, TMSCN (287 µL, 2.15
mmol) was slowly added over 48 h using a syringe pump. (CAUTION!
TMSCN should be added dropwise from the top of the flask, where
the temperature may be above 15 °C, because the melting point of
Similarly, the total synthesis of epothilone B (2) was achieved.
Suzuki cross-coupling of fragment B with fragment C gave 61
(99% ee) in 50% yield (Scheme 15), again accompanied by the
formation of a trace amount of the diastereomer (less polar).
(18) Brown, H. C.; Racherla, U. S. Tetrahedron Lett. 1985, 26, 2187-
2190.

10528 J. Am. Chem. Soc., Vol. 122, No. 43, 2000
Sawada et al.
TMSCN is 11-12 °C.) The reaction mixture was allowed to stir for
39 h at the same temperature. Trifluoroacetic acid (2.0 mL) was added
at -40 °C, and the mixture was stirred vigorously at room temperature
for 1 h to hydrolyze the trimethylsilyl ether of the product. After the
addition of ethyl acetate (30 mL), the mixture was stirred for a further
30 min. The organic layer was separated and washed with water. The
aqueous layer was extracted with ethyl acetate (30 mL × 2). The
combined organic layers were washed with brine and dried over Na2-
SO4. The crude product was further purified by flash chromatography
CHCl3) (99% ee); IR (neat) 2929, 2857, 2360, 1732, 1471, 1254, 1109,
839, 780, 669 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.37 (d, J ) 1.37
Hz, 1H), 6.99 (s, 1H), 6.71 (s, 1H), 4.42 (m, 1H), 2.71 (s, 3H), 2.05
(m, 3H), 0.94 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 199.7, 165.2, 152.8, 134.6, 121.9, 117.0, 83.3, 26.1, 19.6,
18.6, 15.3, -4.5, -4.6; EI-MS m/z 311 (M+); EI-HRMS calcd for
C15H25NO2SiS (M+) 311.1375, found 311.1378.
(1E,3S)-3-(tert-Butyldimethylsilyloxy)-2-methyl-6-trimethylsilyl-
1-(2-methyl-1,3-thiazol-4-yl)-1-hexen-5-yne (23). (Trimethylsilyl)-
acetylene (198 µL, 1.4 mmol) was dissolved in THF (5 mL) and cooled
to -78 °C. Butyllithium (903 µL, 1.55 M hexane solution, 1.4 mmol)
was added, and the reaction mixture was stirred at the same temperature
for 20 min. Then aldehyde 5 (218 mg, 0.7 mmol) in THF (1 mL) was
added to the reaction mixture. After 40 min methyl chloroformate (216
µL, 2.8 mmol) was added and the whole mixture was stirred for
additional 30 min. A saturated aqueous NaHCO3 (30 mL) was added
to the mixture followed by the addition of AcOEt (30 mL). The organic
layer was separated, and the aqueous phase was further extracted twice
with AcOEt (30 mL). The combined organic layers were washed with
brine, dried (Na2SO4), and concentrated to give a residue which was
purified by silica gel flash chromatography (AcOEt/hexane, 1:10) to
give a diastereomixture of carbonate 22 (259 mg, 0.55 mmol; 79%) as
a colorless oil. To a solution of carbonate 22 (65 mg, 0.14 mmol),
palladium acetate (6.2 mg, 0.028 mmol), and ammonium formate (35
mg, 0.56 mmol) in benzene (2 mL) was added tributylphosphine, and
the mixture was heated at 50 °C. After 24 h the mixture was evaporated
under reduced pressure and the residue was purified by silica gel flash
chromatography (AcOEt/hexane, 1:100) to give alkyne 23 (28 mg, 0.07
mmol; 51%) as a colorless oil: [R]24D +31.3 (c 0.5, CHCl3) (99% ee);
IR (neat) 2956, 2856, 2177, 1730, 1471, 1249, 1083, 933, 843, 777,
(ethyl acetate/hexane 1:3) to give cyanohydrin 6 (337 mg, 97%): [R]25
D
+16.5 (c 0.7, CHCl3) (99% ee); IR (neat) 3039, 2821, 2694, 2361,
1508, 1450, 1381, 1277, 1197, 1166, 1091, 980, 901, 813, 743 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.06 (s, 1H), 6.74 (m, 1H), 4.98 (m,
1H), 2.73 (s, 3H), 2.19 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 166.7,
151.3, 134.8, 122.0, 118.8, 117.9, 66.7, 19.3, 15.3; EI-MS m/z 194
(M+); EI-HRMS calcd for C9H10N2OS (M+).
(2R,3E)-Ethyl 2-Hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-
3-butanoate (20). Cyanohydrin 6 (348 mg, 1.79 mmol) was dissolved
in a ca. 5.6 M HCl ethanol solution (10 mL) containing concentrated
HCl aq (5 mL). The reaction mixture was heated at 90 °C for 5 h and
then poured into saturated aqueous NaHCO3 (100 mL) at 0 °C. The
mixtire was extracted with AcOEt (100 mL) three times, and the
combined organic layers were washed with brine and dried over Na2-
SO4 and concentrated to give a residue which was purified by silica
gel flash chromatography (AcOEt/hexane, 1:1) to give ester 20 (359
mg, 1.486 mmol; 83%) as a solid: [R]23D -116 (c 0.72, CHCl3) (99%
ee); IR (neat) 3465, 2980, 2925, 1733, 1444, 1192, 1080, 1024, 879,
1
738 cm-1; H NMR (500 MHz, CDCl3) δ 7.00 (s, 1H), 6.63 (s, 1H),
4.64 (d, J ) 5.6 Hz, 1H), 4.27 (dq, J ) 3.5, 7.0 Hz, 1H), 4.25 (dq, J
) 3.5, 7.0 Hz, 1H), 3.29 (d, J ) 5.6 Hz, 1H), 2.71 (s, 3H), 2.07 (m,
3H), 1.27 (dd, J ) 7.0, 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
173.9, 165.1, 152.8, 136.2, 123.1, 117.1, 77.0, 62.6, 19.6, 14.5, 14.5;
EI-MS m/z 241 (M+); EI-HRMS calcd for C11H15NO3S (M+) 241.0772,
found 241.0771.
1
642 cm-1; H NMR (500 MHz, CDCl3) δ 6.92 (s, 1H), 6.45 (s, 1H),
4.32 (dd, J ) 5.0, 7.2 Hz, 1H), 2.71 (s, 3H), 2.50 (dd, J ) 7.2, 16.7
Hz, 1H), 2.43 (dd, J ) 5.0, 16.7 Hz, 1H), 2.01 (m, 3H), 0.91 (s, 9H),
0.12 (s, 3H), 0.12 (s, 9H), 0.05 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 164.5, 153.1, 141.2, 119.4, 115.6, 104.8, 86.2, 76.9, 29.0, 25.9, 19.3,
18.4, 13.8, 0.14, -4.6, -4.8; EI-MS m/z 393 (M+); EI-HRMS calcd
for C20H35NOSi2S (M+) 393.1978, found 393.1984.
(2R,3E)-Ethyl 2-(tert-Butyldimethylsilyloxy)-3-methyl-4-(2-meth-
yl-1,3-thiazol-4-yl)-3-butenoate (21). To a solution of ester 20 (309
mg, 1.28 mmol) in DMF (2 mL) were added imidazole (262 mg, 3.84
mmol) and TBSCl (290 mg, 1.92 mmol) at 0 °C. The reaction mixture
was stirred for 3 h at room temperature. A saturated aqueous NaHCO3
(20 mL) was added to the mixture followed by the addition of AcOEt
(20 mL). The organic layer was separated, and the aqueous phase was
further extracted twice with AcOEt (20 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated to
give a residue that was purified by silica gel flash chromatography
(AcOEt/hexane, 1:10) to give the silyl ether 21 (451 mg, 1.27 mmol;
99%) in 99% ee as a colorless oil: [R]22D -41.8 (c 0.85, CHCl3) (99%
ee); IR (neat) 2929, 2857, 1752, 1472, 1252, 1115, 1030, 893, 838,
(1E,3S,5Z)-3-(tert-Butyldimethylsilyloxy)-2-methyl-6-trimethyl-
silyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadiene (24) and (1E,3S,5Z)-
2-Methyl-6-trimethylsilyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-
3-ol (25). Alkyne 23 (60 mg, 0.15 mmol) was dissolved in Et2O (3
mL) and cooled to -78 °C. Ti(O-i-Pr)4 (225 µL, 0.76 mmol)and then
i-PrMgCl (762 µL, 2.0 M Et2O solution, 1.52 mmol) were added, and
the mixture was warmed to -50 °C and stirred for 1 h. A saturated
aqueous NH4Cl solution (20 mL) was added to the mixture followed
by the addition of AcOEt (20 mL). The organic layer was separated,
and the aqueous phase was further extracted twice with AcOEt (20
mL). The combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated to give a residue which was purified by silica
gel flash chromatography (AcOEt/hexane, 1:20 f 1:2) to give alkene
24 (42 mg, 0.105 mmol; 69%) and 25 (11 mg, 0.04 mmol; 26%). 24:
1
779 cm-1; H NMR (500 MHz, CDCl3) δ 6.98 (s, 1H), 6.63 (s, 1H),
4.67 (m, 1H), 4.17 (q, J ) 7.0 Hz, 2H), 2.71 (s, 3H), 2.09 (m, 3H),
1.26 (t, J ) 7.0 Hz, 3H), 0.92 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 172.0, 164.9, 153.1, 137.4, 121.6, 116.7,
78.5, 61.3, 26.1, 19.6, 18.7, 14.6, 14.5, -4.7, -4.7; EI-MS m/z 355
(M+); EI-HRMS calcd for C17H29NO3SiS (M+) 355.1637, found
355.1636. The enantiomeric excess was determined by chiral stationary
phase HPLC analysis [DAICEL CHIRALPAK AD, hexane/2-propanol
(250:1, v/v), flow rate 1.0 mL/min, retention time 9.5 min (S)-isomer
and 11.5 min (R)-isomer, detection at 254 nm].
[R]25 +12.5 (c 0.45, CHCl3) (99% ee); IR (neat) 2927, 2855, 1731,
D
1461, 1249, 1078, 837, 776 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.93
(s, 1H), 6.47 (s, 1H), 6.30 (m, 1H), 5.56 (m, 1H), 4.17 (dd, J ) 5.2,
7.3 Hz, 1H), 2.71 (s, 3H), 2.44 (m, 1H), 2.35 (m, 1H), 2.01 (m, 3H),
0.89 (s, 9H), 0.11 (s, 3H), 0.06 (s, 9H), 0.01 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 165.0, 153.7, 145.9, 142.8, 131.3, 119.5, 115.7, 79.4,
41.1, 26.5, 19.8, 18.9, 14.5, 0.85, -4.0, -4.3; EI-MS m/z 395 (M+);
EI-HRMS calcd for C20H37NOSi2S (M+) 395.2134, found 395.2134.
25: [R]22D -7.8 (c 0.23, CHCl3) (99% ee); IR (neat) 3388, 2955, 2855,
(2R,3E)-2-(tert-Butyldimethylsilyloxy)-3-methyl-4-(2-methyl-1,3-
thiazol-4-yl)-3-butenal (5). Ester 21 (105 mg, 0.3 mmol) was dissolved
in toluene (20 mL) and cooled to -78 °C. DIBAL (325 µL, 1 M
solution in toluene, 0.32 mmol) was added dropwise to maintain the
temperature at -78 °C. After the addition was complete, the reaction
mixture was stirred at the same temperature for 1 h. A saturated aqueous
Rochelle salt solution (40 mL) and AcOEt (30 mL) were successively
added, and the quenched mixture was allowed to warm to room
temperature and stirred for 2 h. The organic layer was separated, and
the aqueous phase was further extracted twice with AcOEt (30 mL).
The combined organic layers were washed with brine, dried (Na2SO4),
and concentrated to give a residue which was purified by silica gel
flash chromatography (AcOEt/hexane, 1:10) to give the aldehyde 5
1
1725, 1600, 1443, 1248, 1074, 838, 764 cm-1; H NMR (500 MHz,
CDCl3) δ 6.89 (s, 1H), 6.51 (s, 1H), 6.26 (m, 1H), 5.63 (m, 1H), 4.15
(m, 1H), 2.65 (s, 3H), 2.42 (m, 2H), 2.00 (m, 3H), 0.08 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 154.2, 147.6, 144.0, 141.5, 128.6, 119.2,
115.8, 100.7, 39.3, 19.3, 14.5, 0.34; EI-MS m/z 281 (M+); EI-HRMS
calcd for C14H23NOSiS (M+) 281.1270, found 281.1275.
(1E,3S,5Z)-2-Methyl-6-iodo-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexa-
dien-3-ol (26). To a solution of alkene 24 (9 mg, 0.023 mmol) in CH2-
Cl2 (1.5 mL) was added iodine (17 mg, 0.068 mmol), and the mixture
was stirred at room temperature for 12 h. The mixture was evaporated
under reduced pressure, and the residue was purified by silica gel flash
(86 mg, 0.28 mmol; 94%) as a colorless oil: [R]20 +148.9 (c 0.75,
D

EnantioselectiVe Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 122, No. 43, 2000 10529
chromatography (CH2Cl2) to give a mixture of iodoalkenes which was
directly used for the next step. To a mixture of iodoalkenes in THF (1
mL) was added HF‚Py (0.5 mL) at 0 °C, and the mixture was stirred
at room temperature for 12 h. Then the mixture was poured into
saturated aqueous NaHCO3 (20 mL) at 0 °C and extracted with AcOEt
(20 mL) three times. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated to give a residue that was
successively purified by silica gel flash chromatography (AcOEt/hexane,
1:1) and preparative thin-layer chromatography (silica gel, AcOEt/
hexane, 1:1.5) to give hydroxyalkene 26 (5.7 mg, 0.017 mmol; 75% in
aldehyde 27 (52 mg, 0.16 mmol; 60%) as a colorless oil: [R]19D -21.8
(c 2.4, CHCl3) (99% ee); IR (neat) 2928, 2856, 1726, 1389, 1254, 1083,
1
838, 777 cm-1; H NMR (500 MHz, CDCl3) δ 9.79 (dd, J ) 2.9, 2.9
Hz, 1H), 6.94 (s, 1H), 6.56 (s, 1H), 4.69 (dd, J ) 3.9, 8.1 Hz, 1H),
2.73 (ddd, J ) 2.9, 8.1, 10.1 Hz, 1H) 2.70 (s, 3H), 2.50 (ddd, J ) 2.9,
3.9, 10.1 Hz, 1H), 2.04 (m, 3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.03 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 201.8, 165.0, 153.0, 140.7, 119.6,
116.2, 74.3, 50.4, 26.0, 19.5, 18.4, 14.4, -4.3, -4.9; EI-MS m/z 325
(M+); EI-HRMS calcd for C16H27NO2SiS (M+) 325.1532, found
325.1630.
two steps): [R]26 -11.0 (c 0.25, CHCl3) (99% ee); IR (neat) 3388,
D
(1E,3S,5Z)-3-(tert-Butyldimethylsilyloxy)-6-iodo-2-methyl-1-(2-
methyl-1,3-thiazol-4-yl)-1,5-heptadiene (28). To a suspension of
(ethyl)triphenylphosphonium iodide (200 mg, 0.48 mmol) in THF (1
mL) was added butyllithium (315 µL, 1.52 M hexane solution, 0.48
mmol) at 0 °C, and the mixture was stirred at room temperature for 30
min. Then the mixture was added to a solution of iodine (122 mg,
0.48 mmol) in THF (2 mL) at -78 °C, and the whole mixture was
allowed to warm to -20 °C. NaHMDS (463 µL, 1 M THF solution,
0.46 mmol) was then added to the mixture. After 15 min the mixture
was cooled to -78 °C again and aldehyde 27 (52 mg, 0.16 mmol) in
THF (1 mL) was added to the mixture, which was then warmed to
-20 °C gradually. After 1.5 h saturated aqueous NH4Cl (30 mL) was
added to the mixture followed by the addition of AcOEt (30 mL). The
organic layer was separated, and the aqueous phase was further extracted
twice with AcOEt (30 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated to give a residue which
was purified by silica gel flash chromatography (CH2Cl2) followed by
a second silica gel flash chromatography (AcOEt/hexane, 1:50) to give
iodoalkene 28 (37 mg, 0.08 mmol; 50%) as a colorless oil: [R]21D +14.2
(c 1.63, CHCl3) (99% ee); IR (neat) 2954,2927, 2855, 2360, 1733, 1653,
1506, 1471, 1387, 1360, 1251, 1183, 1068, 951, 884, 835, 776, 727,
2922, 1653, 1507, 1439, 1290, 1189, 1041 cm-1; 1H NMR (500 MHz,
CDCl3) δ 6.87 (s, 1H), 6.57 (s, 1H), 6.35 (dt, J ) 1.4, 7.5 Hz, 1H),
6.28 (dt, J ) 6.3, 7.5 Hz, 1H), 4.33 (t, J ) 6.5 Hz, 1H), 2.71 (s, 3H),
2.51 (m, 2H), 2.08 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 164.8,
152.7, 141.2, 137.5, 119.5, 116.0, 84.8, 76.2, 40.6, 19.3, 14.5; EI-MS
m/z 335 (M+); EI-HRMS calcd for C11H14NOSI (M+) 334.9841, found
334.9839.
(1E,3S,5Z)-2-Methyl-6-trimethylsilyl-1-(2-methyl-1,3-thiazol-4-
yl)-1,5-hexadien-3-yl acetate (Fragment A). To a solution of alkene
26 (4.5 mg, 0.013 mmol) in CH2Cl2 (1.5 mL) were added triethylamine
(7.5 µL, 0.054 mmol), acetic anhydride (2.5 µL, 0.027 mmol), and
then small amounts of DMAP. The mixture was stirred at room
temperature for 6 h, and then a saturated aqueous NH4Cl solution (20
mL) was added to the mixture followed by the addition of AcOEt (20
mL). The organic layer was separated, and the aqueous phase was
further extracted twice with AcOEt (20 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated to
give a residue which was purified by silica gel flash chromatography
(AcOEt/hexane, 1:4) to give fragment A (5.1 mg, 0.013 mmol; quant):
[R]26 -27.7 (c 0.5, CHCl3) (99% ee); IR (neat) 2923, 1737, 1369,
D
1234, 1019 cm-1; 1H NMR (500 MHz, CDCl3) δ 6.97 (s, 1H), 6.53 (s,
1H), 6.35 (dt, J ) 1.3, 7.5 Hz, 1H), 6.18 (dt, J ) 6.5, 7.5 Hz, 1H),
5.40 (t, J ) 6.4 Hz, 1H), 2.71 (s, 3H), 2.60 (m, 2H), 2.10 (m, 3H),
2.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.3, 165.1, 152.7, 137.0,
136.6, 121.2, 116.8, 85.5, 77.2, 38.8, 21.5, 19.6, 15.3; EI-MS m/z 377
(M+); EI-HRMS calcd for C13H16NO2SI (M+) 376.9947, found
376.9949.
1
457 cm-1; H NMR (500 MHz, CDCl3) δ 6.93 (s, 1H), 6.49 (s, 1H),
5.46 (dt, J ) 1.3, 6.6 Hz, 1H), 4.22 (t, J ) 6.2 Hz, 1H), 2.71 (s, 3H),
2.48 (d, J ) 1.3 Hz, 3H), 2.36 (m, 2H), 2.02 (m, 3H), 0.90 (s, 9H),
0.06 (s, 3H), 0.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.7, 153.4,
142.1, 132.5, 119.3, 115.6, 102.7, 77.6, 44.1, 34.0, 26.2, 19.6, 18.6,
14.5, -4.3, -4.6; EI-MS m/z 448 (M+ - CH3), 406 (M+ - t-Bu);
EI-HRMS calcd for C14H21NOSiSI (M+ - t-Bu) 406.0158, found
406.0166.
(1E,3S,5Z)-2-Methyl-6-iodo-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexa-
dien-3-ol (26). To a solution of alkene 25 (11 mg, 0.039 mmol) in
CH2Cl2 (1 mL) was added iodine (50 mg, 0.2 mmol), and the mixture
was stirred at room temperature for 12 h. The mixture was evaporated
under reduced pressure, and the residue was successively purified by
silica gel flash chromatography (CH2Cl2) and then preparative thin-
layer chromatography (silica gel, AcOEt/hexane, 1:1.5) to give iodo-
alkene 26 (7.7 mg, 0.023 mmol; 59%).
(3S,4E)-3-(tert-Butyldimethylsilyloxy)-4-methyl-5-(2-methyl-1,3-
thiazol-4-yl)-4-pentenal (27). To a suspension of (methoxymethyl)-
triphenylphosphonium chloride (216 mg, 0.63 mmol) in THF (4 mL)
was added LHMDS (630 µL, 1.0 M THF solution, 0.63 mmol) at 0
°C, and the mixture was stirred at room temperature for 20 min. Then
the mixture was cooled to -78 °C, aldehyde 5 (131 mg, 0.42 mmol)
in THF (1 mL) was added to the mixture, which was then allowed to
warm to room temperature gradually and stirred for 2 h. H2O (20 mL)
was added to the mixture followed by the addition of AcOEt (20 mL).
The organic layer was separated, and the aqueous phase was further
extracted twice with AcOEt (20 mL). The combined organic layers
were washed with brine, dried (Na2SO4), and concentrated to give a
residue which was purified by alumina flash chromatography (AcOEt/
hexane, 1:30) to give the enol ether (91 mg, 0.27 mmol; 68%) which
was immediately used in the next step.
To a solution of the enol ether (91 mg, 0.27 mmol) in THF (4 mL)
and H2O (0.4 mL) was added mercury acetate (402 mg, 1.26 mmol),
and the mixture was stirred for 2.5 h. Tetrabutylammonium iodide (1.55
g, 4.2 mmol) was added to the solution, and the whole was stirred for
an additional 2 h. Saturated aqueous NH4Cl (20 mL) was added to the
mixture followed by the addition of AcOEt (20 mL). The organic layer
was separated, and the aqueous phase was further extracted twice with
AcOEt (20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated to give a residue which was purified
by silica gel flash chromatography (AcOEt/hexane, 1:6) to give
(1E,3S,5Z)-3-Hydroxy-6-iodo-2-methyl-1-(2-methyl-1,3-thiazol-
4-yl)-1,5-heptadiene (29). To a solution of iodoalkene 28 (34 mg, 0.073
mmol) in THF (2 mL) was added HF‚Py (1 mL) at 0 °C, and the
mixture was stirred at room temperature for 12 h. Then the mixture
was poured into saturated aqueous NaHCO3 (30 mL) at 0 °C and
extracted with AcOEt (30 mL) three times. The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated to give
a residue which was purified by silica gel flash chromatography (AcOEt/
hexane, 1:2) to give hydroxyalkene 29 (26 mg, 0.073 mmol; quant):
[R]21 -8.4 (c 0.85, CHCl3) (99% ee); IR (neat) 3370, 2951, 2919,
D
2848, 1725, 1654, 1508, 1427, 1375, 1288, 1188, 1150, 1096, 1053,
1
1021, 965, 881, 813, 728, 450 cm-1; H NMR (500 MHz, CDCl3) δ
6.95 (s, 1H), 6.57 (s, 1H), 5.53 (dt, J ) 1.3, 6.5 Hz, 1H), 4.27 (t, J )
6.2 Hz, 1H), 2.71 (s, 3H), 2.51 (d, J ) 1.3 Hz, 3H), 2.45 (m, 2H), 2.17
(brs, 1H), 2.05 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.0, 153.0,
141.8, 131.8, 119.5, 116.1, 103.7, 76.8, 42.8, 34.1, 19.5, 14.8; EI-MS
m/z 349 (M+); EI-HRMS calcd for C12H16NOSI (M+) 348.9998, found
348.9988.
(1E,3S,5Z)-6-Iodo-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hep-
tadien-3-yl Acetate (Fragment B). To a solution of alkene 29 (23
mg, 0.066 mmol) in CH2Cl2 (1.5 mL) were added triethylamine (12
µL, 0.13 mmol), acetic anhydride (37 µL, 0.26 mmol), and then small
amounts of DMAP. The mixture was stirred at room temperature for
6 h, and saturated aqueous NH4Cl (20 mL) was added to the mixture
followed by the addition of AcOEt (20 mL). The organic layer was
separated, and the aqueous phase was further extracted twice with
AcOEt (20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated to give a residue which was purified
by silica gel flash chromatography (AcOEt/hexane, 1:4) to give
fragment B (25 mg, 0.063 mmol; 96%): [R]24 -24.6 (c 1.2, CHCl3)
D
(99% ee); IR (neat) 3454, 3110, 2958, 2916, 2855, 1736, 1655, 1503,
1428, 1369, 1295, 1234, 1184, 1130, 1105, 1019, 964, 872, 730 cm-1
;

10530 J. Am. Chem. Soc., Vol. 122, No. 43, 2000
Sawada et al.
1H NMR (500 MHz, CDCl3) δ 6.97 (s, 1H), 6.52 (s, 1H), 5.41 (dt, J
) 1.5, 6.5 Hz, 1H), 5.34 (t, J ) 6.4 Hz, 1H), 2.71 (s, 3H), 2.54 (m,
2H), 2.49 (d, J ) 1.5 Hz, 3H), 2.09 (m, 3H), 2.08 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.4, 165.0, 152.8, 137.3, 130.7, 121.0, 116.7,
104.0, 77.7, 40.7, 34.1, 21.6, 19.6, 15.3; EI-MS m/z 391 (M+); EI-
HRMS calcd for C14H18NO2SI (M+) 391.0103, found 391.0102.
Benzyloxy-3-hydroxy-2,2,4,6-tetramethyl-8-nonen-5-one, a Mix-
ture of (3R,4S,6S) and (3S,4R,6R) Isomers (37). To a solution of
hydroxy ketone 34 (1.073 g, 3.85 mmol) in THF (5.5 mL) and DMPU
(2 mL) was added LHMDS (8.48 mL, 1.0 M THF solution, 8.48 mmol)
at -78 °C followed by the addition of DMPU (9.5 mL) again. After
40 min, allyl bromide (1.67 mL, 19.3 mmol) was added to the mixture,
which was stirred at the same temperature for 1.5 h. Saturated aqueous
NH4Cl (50 mL) was added to the mixture followed by the addition of
AcOEt (50 mL). The organic layer was separated, and the aqueous
phase was further extracted twice with AcOEt (50 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and concen-
trated to give a residue which was purified by silica gel flash
chromatography (AcOEt/hexane/CH2Cl2, 1:20:10) to give allyl ketone
37 (589 mg, 1.85 mmol; 48%) as a colorless oil and the starting material
34 (558 mg, 2.0 mmol). 37: IR (neat) 3743, 2971, 2929, 2876, 1691,
1H), 3.30 (dd, J ) 3.0, 9.9 Hz, 1H), 3.13 (dd, J ) 8.6, 15.3 Hz, 1H),
3.08 (dd, J ) 2.9, 15.3 Hz, 1H), 2.49 (m, 1H), 1.97 (m, 1H), 1.77 (m,
1H), 1.61 (m, 1H), 1.36 (s, 3H), 1.29 (s, 3H), 1.04 (s, 3H), 0.97 (d, J
) 6.1 Hz, 3H), 0.88 (s, 3H), 0.81 (d, J ) 6.3 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 201.3, 137.7, 137.4, 133.5, 128.9, 128.6, 116.5, 100.7,
81.5, 74.9, 73.8, 41.7, 40.9, 37.8, 33.3, 32.8, 26.4, 24.0, 20.2, 16.6,
14.7, 14.0; EI-MS m/z 388 (M+); EI-HRMS calcd for C24H36O4 (M+)
388.2613, found 388.2622. 44: [R]24 -62.0 (c 0.97, CHCl3) (88%
D
ee); IR (neat) 3511, 2972, 2934, 2878, 1682, 1598, 1449, 1378, 1290,
1
1221, 996, 753, 690 cm-1; H NMR (500 MHz, CDCl3) δ 7.99 (m,
2H), 7.56 (m, 1H), 7.46 (m, 2H), 5.77 (m, 1H), 5.02 (m, 2H), 4.33
(ddd, J ) 2.4, 4.2, 9.6 Hz, 1H), 3.67 (d, J ) 4.2 Hz), 3.50 (d, J ) 6.1
Hz, 1H), 3.34 (dd, J ) 3.3, 10.3 Hz, 1H), 3.16 (dd, J ) 9.6, 15.9 Hz,
1H), 2.98 (dd, J ) 2.4, 15.9 Hz, 1H), 2.50 (m, 1H), 2.03 (m, 1H), 1.77
(m, 1H), 1.63 (m, 1H), 1.40 (s, 3H), 1.30 (s, 3H), 0.99 (s, 3H), 0.95 (s,
3H), 0.95 (d, J ) 6.3 Hz, 3H), 0.83 (d, J ) 6.6 Hz, 3H); 13C NMR
(125 MHz,CDCl3) δ 200.7, 137.9, 137.4, 133.4, 128.9, 128.5, 116.5,
100.9, 81.1, 73.9, 73.5, 41.2, 41.2, 37.8, 33.0, 32.8, 26.3, 23.8, 20.1,
20.0, 14.7, 14.1; EI-MS m/z 389 (M+ + 1); EI-HRMS calcd for
C24H37O4 (M++1) 389.2692, found 389.2695. The enantiomeric
excesses were determined by chiral stationary phase HPLC analysis
[DAICEL CHIRALPAK AD, hexane/2-propanol (100:1, v/v), flow rate
1.0 mL/min, retention time 11 min (S)-isomer and 12.5 min (R)-isomer,
detection at 254 nm for 8; DAICEL CHIRALPAK AD, hexane/2-
propanol (100:1, v/v), flow rate 1.0 mL/min, retention time 10 min
(S)-isomer and 12 min (R)-isomer, detection at 254 nm for 44].
1
1455, 1379, 1097, 1002, 916, 737, 698 cm-1; H NMR (500 MHz,
CDCl3) δ 7.26 (m, 5H), 5.60 (m, 1H), 4.95 (m, 2H), 4.44 (d, J ) 12.2
Hz, 1H), 4.38 (d, J ) 12.2 Hz, 1H), 4.04 (brs, 1H), 3.49 (d, J ) 3.6
Hz, 1H), 3.27 (d, J ) 9.0 Hz, 1H), 3.13 (d, J ) 9.0 Hz, 1H), 2.91 (dq,
J ) 3.6, 7.0 Hz, 1H), 2.64 (m, 1H), 2.34 (m, 1H), 1.96 (m, 1H), 1.16
(d, J ) 6.8 Hz), 0.96 (d, J ) 7.0 Hz, 3H), 0.84 (s, 3H), 0.83 (s, 3H);
13C NMR (125 MHz, CDCl3) δ; EI-MS m/z 318 (M+); EI-HRMS calcd
for C20H30O3 (M+) 318.2195, found 318.2193.
Procedure for the Preparation of (R)-LLB Complex (Which Was
Used for (R)-Heteropolymetallic Asymmetric Catalyst). To a stirred
solution of (R)-binaphthol (3.50 g, 12.2 mmol), in THF (39.7 mL) at
0 °C, was added a solution of La(O-i-Pr)3 (20.4 mL, 4.07 mmol, 0.2
M in THF, freshly prepared from the powder of La(O-i-Pr)3 purchased
from Kojundo Chemical Co., Ltd., 5-1-28, Chiyoda, Sakato, Saitama,
350-02, Japan (Fax: +81-492-84-1351) and dry THF). The solution
was stirred for 30 min at room temperature, and then the solvent was
evaporated under reduced pressure. The resulting residue was dried
for 1 h under reduced pressure (ca. 5 mmHg) and dissolved in THF
(60.5 mL). The solution was cooled to 0 °C, and n-BuLi (7.45 mL,
12.2 mmol, 1.64 M in hexane) was added. The mixture was stirred for
12 h at room temperature to give a 0.06 M (R)-LLB solution, which
was used for the preparation of (R)-heteropolymetallic asymmetric
catalyst. This catalyst solution can be stored for several months under
an atmosphere of argon. (CAUTION: The powder of La(O-i-Pr)3 should
be used immediately after opening the ampule.)
(3S,4′R,5′R,6′S,4′′S)-Phenyl-3-hydroxy-4-methyl-4-[2,2,5-trimethyl-
6-(1-pente-4-yl)-1,3-dioxan-4-yl]pentanoate (46). In a flame-dried
flask MS4A (11 mg) was added and dried at 180 °C for 12 h under
reduced pressure. Ligand 45 (5.7 mg, 0.0135 mmol) and K2CO3 (15
mg, 0.108 mmol) were added, followed by CH2Cl2 (400 µL) under an
argon atmosphere. To the suspension were added SnCl4 (14 µL, 0.0135
mmol, 1 M in CH2Cl2) and BTSP (230 µL, 0.216 mmol, 0.94 M in
CH2Cl2) at 0 °C. After 10 min aldol 8 (21 mg, 0.054 mmol) in CH2Cl2
(600 µL) was added to the mixture and the whole mixture was stirred
for 10 h at the same temperature. Saturated aqueous Na2S2O3 (30 mL)
was added to the mixture followed by the addition of AcOEt (30 mL).
The organic layer was separated, and the aqueous phase was further
extracted twice with AcOEt (30 mL). The combined organic layers
were washed with brine, dried (Na2SO4), and concentrated to give a
residue which was purified by preparative thin-layer chromatography
(silica gel, AcOEt/hexane, 1:10) to give ester 46 (15 mg, 0.0373 mmol;
69%) as a colorless oil and starting material 8 (4.6 mg, 0.0119 mmol;
22%). 46: [R]30D +2.7 (c 1.55, CHCl3) (89% ee); IR (neat) 3493, 2975,
2934, 2883, 1759, 1594, 1493, 1378, 1198, 1138, 688 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.70 (m, 2H), 7.20 (m, 1H), 7.10 (m, 2H), 5.77
(m, 1H), 5.03 (m, 2H), 4.16 (dd, J ) 3.0, 9.8 Hz, 1H), 3.39 (d, J ) 6.1
Hz), 3.31 (dd, J ) 2.9, 10.2 Hz, 1H), 2.75 (dd, J ) 3.0, 14.7 Hz, 1H),
2.64 (dd, J ) 9.8, 14.7 Hz, 1H), 2.51 (m, 1H), 1.97 (m, 1H), 1.77 (m,
1H), 1.63 (m, 1H), 1.40 (s, 3H), 1.32 (s, 3H), 1.01 (s, 3H), 0.95 (d, J
) 6.7 Hz, 3H), 0.86 (s, 3H), 0.82 (d, J ) 6.5 Hz, 3H); 13C NMR (125
MHz, C6D6) δ 172.4, 152.4, 138.2, 130.6, 126.6, 122.8, 117.1, 101.2,
81.8, 75.5, 74.5, 42.2, 38.6, 38.6, 34.1, 33.7, 26.8, 24.3, 20.3, 17.2,
15.2, 14.5; EI-MS m/z 389 (M+ - Me), 405 (M+ + 1); EI-HRMS
calcd for C23H33O5 (M+ - Me) 389.2328, found 389.2320.
(3S,5R,6R,7S,8S)-Phenyl-3,5,7-trihydroxy-4,4,6,8-tetramethyl-10-
undecenoate (47). Ester 46 (80 mg, 0.2 mmol) was dissolved in CH2-
Cl2 (3 mL), and the solution was cooled to -78 °C. BCl3 (990 µL,
0.989 mmol, 1 M in xylene) was added to the solution, which was
stirred at the same temperature for 20 min. Saturated aqueous NaHCO3
(30 mL) was added to the mixture followed by the addition of AcOEt
(30 mL). The organic layer was separated, and the aqueous phase was
further extracted twice with AcOEt (30 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated to
give a residue which was purified by silica gel flash chromatography
(AcOEt/hexane, 1:2) to give triol 47 (63 mg, 0.172 mmol; 87%) as a
colorless oil: [R]30D -10.0 (c 1.05, CHCl3) (89% ee); IR (neat) 3432,
2925, 2854, 1730, 1381, 1195, 1136, 1070 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.40 (m, 2H), 7.26 (m, 1H), 7.10 (m, 2H), 5.85 (m, 1H),
5.06 (m, 2H), 4.09 (dd, J ) 2.4, 10.3 Hz, 1H), 3.76 (dd, J ) 1.5, 9.6
Hz), 3.69 (d, J ) 2.7 Hz, 1H), 2.83 (dd, J ) 2.4, 16.3 Hz, 1H), 2.72
(3S,4′R,5′R,6′S,4′′S)-3-Hydroxy-4-methyl-4-[2,2,5-trimethyl-6-(1-
pente-4-yl)-1,3-dioxan-4-yl]pentophenone (8) and (3S,4′S,5′S,6′R,4′′R)-
3-Hydroxy-4-methyl-4-[2,2,5-trimethyl-6-(1-pente-4-yl)-1,3-dioxan-
4-yl]pentophenone (44). To a stirred solution of potassium bis(trimeth-
ylsilyl)amide (KHMDS, 532 µL, 0.266 mmol, 0.5 M in toluene) at 0
°C was added a solution of water (590 µL, 0.59 mmol, 1.0 M in THF).
The resulting solution was stirred for 20 min at 0 °C, and then (R)-
LLB (2.95 mL, 0.295 mmol, 0.1 M in THF) was added and the mixture
was stirred at 0 °C for 30 min. The pale yellow solution thus obtained
was then cooled to -20 °C, and acetophenone (1.38 mL, 11.8 mmol)
was added. The solution was stirred for 20 min at this temperature,
and then aldehyde 9 (397 mg, 1.48 mmol) was added and the reaction
mixture was stirred for 168 h at -20 °C. The mixture was quenched
by addition of 1 N HCl (4 mL), and the aqueous layer was extracted
with ethyl acetate (3 × 30 mL). The combined organic layers were
washed with brine and dried over Na2SO4. The solvent was removed
under reduced pressure, and the residue was purified by flash chro-
matography (SiO2, ethyl acetate/hexane 1/30) to give 8 (172 mg, 0.177
mmol; 30%) in 89% ee as a colorless oil, 44 (166 mg, 0.171 mmol;
29%) in 88% ee as a colorless oil, and starting material 9 (143 mg,
0.532 mmol; 36%). 8: [R]29 -16.0 (c 0.895, CHCl3) (89% ee); IR
D
(neat) 3500, 2974, 2936, 2876, 1681, 1598, 1449, 1378, 1221, 1024,
1
997, 753, 690 cm-1; H NMR (500 MHz, CDCl3) δ 7.99 (m, 2H),
7.57 (m, 1H), 7.47 (m, 2H), 5.77 (m, 1H), 5.02 (m, 2H), 4.23 (ddd, J
) 1.7, 2.9, 8.6 Hz, 1H), 3.70 (d, J ) 1.7 Hz, 1H), 3.42 (d, J ) 6.1 Hz,

EnantioselectiVe Synthesis of Epothilones A and B
J. Am. Chem. Soc., Vol. 122, No. 43, 2000 10531
(dd, J ) 10.3, 16.3 Hz, 1H), 2.50 (m, 1H), 2.03 (m, 1H), 1.95 (m,
1H), 1.70 (m, 1H), 1.09 (s, 3H), 1.07 (d, J ) 6.8 Hz, 3H), 0.88 (s,
3H), 0.84 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, C6D6) δ 172.6,
151.9, 138.4, 130.2, 126.6, 122.5, 117.0, 85.3, 78.0, 76.6, 42.2, 38.7,
37.8, 37.0, 35.1, 21.8, 16.1, 16.1, 14.0; EI-MS m/z 364 (M+); EI-HRMS
calcd for C21H32O5 (M+) 364.2250, found 364.2247.
quenched with 1 N HCl (2 mL) and then extracted with AcOEt (30
mL). The combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated to give a residue which was purified by silica
gel flash chromatography (AcOEt/hexane, 1:1) to give 16 (1.15 g, 3.88
mmol; 92%): [R]24D -102 (c 0.87, CHCl3) (93% ee); IR (neat) 2964,
1
1686, 964 cm-1; H NMR (500 MHz, CDCl3) δ 7.31 (s, 4H), 3.26-
3.32 (m, 1H), 2.80-2.92 (m, 1H),1.31 (s 9H), 1.28 (d, J ) 6.7 Hz,
3H), 1.25 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 202.2,
149.8, 132.0, 130.2, 126.0, 48.1, 37.8, 34.5, 31.2, 23.3, 17.3, 14.6; EI-
MS m/z 296 (M+). Anal. Calcd for C16H24OS2: C, 64.81; H, 8.16.
Found: C, 64.52; H, 8.20.
(3S,6R,7S,8S)-Phenyl 3,7-Di-tert-butyldimethylsilyloxy-4,4,6,8-tet-
ramethyl-5-oxo-10-undecenoate (Fragment C) and (3R,5S,2′R,3′S,4′S)-
5-(tert-Butyldimethylsilyloxy)-4,4-dimethyl-3-[3-(tert-butyldimeth-
ylsilyloxy)-4-methyl-6-hepten-2-yl]tetrahydro-2-pyrone (50). To a
solution of triol 47 (63 mg, 0.172 mmol) in CH2Cl2 (3 mL) were added
diisopropylethylamine (150 µL, 0.86 mmol) and tert-butyldimethylsilyl
trifluoromethanesulfonate (120 µL, 0.86 mmol), and the mixture was
stirred for 30 min. AcOEt (30 mL) was added to the mixture followed
by the addition of saturated aqueous NH4Cl (30 mL). The organic layer
was separated, and the aqueous phase was further extracted twice with
AcOEt (30 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated to give a residue which was purified
by silica gel flash chromatography (AcOEt/hexane, 1:10) to give silyl
ether 48 as a colorless oil which was used for the next step quickly.
To a solution of silyl ether 48 in CH2Cl2 (3 mL) was added Dess-
Martin periodinane (220 mg, 0.516 mmol) at 0 °C, and the mixture
was stirred at room temperature for 2 h. Saturated aqueous NaHCO3
(30 mL) and saturated aqueous Na2S2O3 (30 mL) were added to the
mixture. Then AcOEt (30 mL) was added and the organic layer was
separated, and the aqueous phase was further extracted twice with
AcOEt (30 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated to give a residue which was purified
by silica gel flash chromatography (AcOEt/hexane, 1:5) to give the
mixture. Further preparative thin-layer chromatography (silica gel,
AcOEt/hexane, 1:30) furnished fragment C (66 mg, 0.112 mmol; 65%
in two steps) and lactone 50 (4 mg, 0.0086 mmol; 5% in 2 steps).
Fragment C: [R]29D -23.8 (c 0.77, CHCl3) (89% ee); IR (neat) 2930,
2857, 1762, 1693, 1472, 1377, 1255, 1197, 1144, 1089, 989, 837, 776
(4R,5S,6S)-1-Benzyloxy-5-hydroxy-2,2,4,6-tetramethyl-8-nonen-
3-one (13). To a solution of 57 (336 mg, 1.53 mmol) in CH2Cl2 (3
mL) was added DDQ (380 mg, 1.68 mmol) at 0 °C, and the mixture
was stirred for 2 h at room temperature. Saturated aqueous NaHCO3
(30 mL) was added to the mixture followed by Et2O (30 mL). The
organic layer was separated, and the aqueous phase was further extracted
twice by the addition by the addition of Et2O (30 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and concen-
trated by distillaiton to a final volume of 10 mL, which was purified
by silica gel flash chromatography (Et2O/pentane, 1:8 f 1:3) to give
alcohol in Et2O/pentane solution. Then the solution was diluted by CH2-
Cl2 (3 mL) and cooled to 0 °C. To the solution of alcohol were added
NMO (250 mg, 2.13 mmol), MS4A (710 mg), and then TPAP (32 mg,
0.071 mmol), and the mixture was allowed to stir for 1 h at room
temperature. The mixture was filtered through MgSO4, Celite, and silica
gel; then the mixture was concentrated by distillaiton to a final volume
of 10 mL, which was added to the next reaction.
To a solution of N,N-diisopropylamine (232 µL, 1.66 mmol) in THF
(20 mL) was added butyllithium (1.04 mL, 1.52 M hexane solution,
1.6 mmol) at -78 °C. The mixture was allowed to warm to 0 °C and
stirred for 40 min and then cooled to -78 °C again, and ketone 15
(332 µL, 1.51 mmol) in THF (2 mL) was added to the mixture. After
1 h aldehyde 14 in Et2O/CH2Cl2 solution (2 mL) was added to the
mixture and the whole mixture was stirred for 1 h. Saturated aqueous
NH4Cl (40 mL) was added to the mixture followed with AcOEt (40
mL). The organic layer was separated, and the aqueous phase was
further extracted twice with AcOEt (40 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated to
give a residue which was purified by silica gel flash chromatography
(AcOEt/hexane, 1:20) to give aldol 13 (289 mg, 0.906 mmol; 60%) as
a colorless oil: [R]24D -27.5 (c 0.22, CHCl3) (87% ee); IR (neat) 3500,
2969, 1689, 1455, 1381, 1099, 1029, 910, 737, 698, 506 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.34 (m, 2H), 7.28 (m, 3H), 5.76 (m, 1H), 5.00
(m, 2H), 4.48 (s, 2H), 3.54 (m, 1H), 3.47 (s, 2H), 3.39 (m, 1H), 3.24
(dq, J ) 1.5, 6.8 Hz, 1H), 2.51 (m, 1H), 1.86 (m, 1H), 1.62 (m, 1H),
1.20 (s, 3H), 1.17 (s, 3H), 1.04 (d, J ) 6.8 Hz, 3H), 0.77 (d, J ) 6.6
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 221.9, 138.2, 137.4, 128.7,
128.0, 127.9, 116.6, 77.5, 74.5, 73.8, 49.9, 40.5, 37.6, 35.4, 22.2, 22.1,
15.4, 10.0; EI-MS m/z 318 (M+), 303 (M+ - Me); EI-HRMS calcd
for C19H23O3 (M+ - Me) 303.196, found 303.196.
1
cm-1; H NMR (500 MHz, C6D6) δ 7.19 (m, 2H), 7.10 (m, 1H), 6.95
(m, 2H), 5.84 (m, 1H), 5.10 (m, 2H), 4.79 (dd, J ) 3.3, 6.0 Hz, 1H),
4.06 (dd, J ) 1.8, 6.8 Hz), 3.22 (m, 1H), 2.87 (dd, J ) 3.5, 16.7 Hz,
1H), 2.65 (dd, J ) 6.3, 16.7 Hz, 1H), 2.43 (m, 1H), 2.04 (m, 1H), 1.65
(m, 1H), 1.19 (s, 3H), 1.18 (d, J ) 7.5 Hz, 3H), 1.16 (s, 3H), 1.06 (m,
12H), 1.00 (s, 9H), 0.23 (s, 3H) 0.18 (s, 3H), 0.16 (s, 3H),0.15 (s,
3H);13C NMR(125 MHz,C6D6) δ 217.7, 171.1, 152.3, 138.8, 130.3,
126.6, 122.7, 116.9, 78.7, 74.8, 54.5, 46.5, 41.6, 39.6, 36.8, 27.3, 27.1,
24.5, 20.2, 19.6, 19.3, 18.9, 16.6, -2.6, -2.7, -3.2, -3.8; EI-MS m/z
533 (M+ - t-Bu), 521 (M+ - C5H9); EI-HRMS calcd for C28H49O5Si2
(M+) 521.3118, found 521.3119. 50: [R]29D +20.5 (c 0.1, CHCl3) (89%
ee); IR (neat) 2929, 2857, 1379, 1471, 1362, 1256, 1088, 1038, 836,
1
775 cm-1; H NMR (500 MHz, C6D6) δ 5.90 (m, 1H), 5.14 (m, 2H),
4.47 (d, J ) 9.1 Hz, 1H), 4.34 (dd, J ) 0.9, 6.9 Hz, 1H), 3.16 (dd, J
) 3.0, 3.4 Hz, 1H), 2.66 (m, 1H), 2.40 (m, 2H), 2.00 (m, 1H), 1.82
(m, 1H), 1.77 (m, 1H), 1.10 (s, 9H), 1.00 (d, J ) 6.5 Hz, 3H), 0.96 (d,
J ) 6.6 Hz, 3H), 0.95 (s, 9H), 0.93 (s, 3H), 0.61 (s, 3H), 0.39 (s, 3H),
0.33 (s, 3H), -0.03 (s, 6H); 13C NMR(125 MHz,C6D6) δ 168.7, 139.1,
116.9, 84.1, 77.3, 75.3, 39.7, 39.2, 38.4, 38.0, 37.9, 28.4, 27.4, 26.7,
26.0, 19.5, 18.9, 16.9, 13.5, -2.3, -3.1, -3.7, -4.1; EI-MS m/z 429
(M+ - t-Bu); EI-HRMS calcd for C26H54O4Si2 (M+ - t-Bu) 429.2856,
found 429.2856.
Preparation of CH2Cl2 Solution of (S)-SmNa3tris(binaphthoxide)
Complex (SmSB). To a stirred solution of (S)-BINOL (43 mg, 0.15
mmol) in THF were added a solution of Sm(O-i-Pr)3 (0.05 mmol;
purchased from Kojundo Chemical Co., Ltd., 5-1-28, Chiyoda, Sakato,
Saitama 350-02, Japan (Fax: +81-492-84-1351)) in THF (0.5 mL) and
a solution of NaO-t-Bu (0.15 mmol) in THF (0.3 mL) at 0 °C. After
being stirred for 2 h at room temperature, the THF solution of (S)-
SmSB was concentrated under reduced pressure. The resulting (S)-
SmSB powder was redissolved in CH2Cl2 (3 mL). This solution was
directly used as a catalyst.
(3S,6R,7S,8S,12Z,15S,16E)-Phenyl 3,7-Di-tert-butyldimethylsil-
yloxy-15-methoxycarbonyl-4,4,6,8,16-pentamethyl-17-(2-methyl-
1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate (59). To a solution
of fragment C (10 mg, 0.0169 mmol) in THF (0.5 mL) was added
9-BBN (69 µL, 0.5 M solution in THF, 0.0338 mmol) at 0 °C, and the
mixture was stirred in the ultrasonic bath cleaner (28 °C) for 50 min.
H2O (50 µL) was added to the mixture at 0 °C followed by the addition
of fragment A (10.1 mg, 0.0266 mmol) in DMF (1 mL), PdCl2(dppf)
(7 mg, 0.00846 mmol), and K3PO4‚3H2O (14 mg, 0.0508 mmol). After
degassing (FPTmethod), the mixture was stirred for 5 h at 60 °C. A
saturated aqueous NH4Cl (30 mL) was added to the mixture followed
by the addition of AcOEt (30 mL). The organic layer was separated,
and the aqueous phase was further extracted twice with AcOEt (30
mL). The combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated to give a residue which was purified by silica
gel flash chromatography (AcOEt/hexane, 1:1) and then preparative
thin-layer chromatography (silica gel, AcOEt/hexane, 1:2) to give
S-Ethyl (S)-3-(4-tert-Butylphenylthio)-2-methylpropanethioate
(16). To a solution of (S)-SmSB (0.2 mmol) in CH2Cl2 (3 mL) were
successivery added ethylthio methacrylate (18) (527 mg, 4 mmol) and
4-tert-butylthiophenol (17) (680 µL, 4 mmol) at -78 °C. After being
stirred for 7 h at the same temperature, the reaction mixture was
coupled product 59 (7.1 mg, 0.00846 mmol; 50%): [R]21 -38.9 (c
D
0.325, CHCl3); IR (neat) 2929, 2856, 1739, 1693, 1472, 1370, 1237,
1
1196, 1144, 1088, 988, 837, 776 cm-1; H NMR (500 MHz, C6D6) δ

10532 J. Am. Chem. Soc., Vol. 122, No. 43, 2000
Sawada et al.
7.21 (m, 2H), 7.11 (m, 1H), 6.94 (m, 2H), 6.69 (s, 1H), 6.54 (s, 1H),
5.59 (m, 2H), 5.53 (m, 1H), 4.79 (dd, J ) 3.5, 6.1 Hz, 1H), 4.07 (dd,
J ) 2.2, 6.3 Hz, 1H), 3.27 (dq, J ) 2.2, 6.6 Hz, 1H), 2.92 (dd, J )
3.4, 16.8 Hz, 1H), 2.68 (m, 1H), 2.54 (m, 1H), 2.35 (m, 3H), 2.31 (s,
3H), 2.17 (m, 2H), 1.78 (s, 3H), 1.60 (m, 3H), 1.35 (m, 2H), 1.24 (s,
3H), 1.23 (s, 3H), 1.22 (d, J ) 6.6 Hz, 3H), 1.09 (s, 9H), 1.06 (d, J )
6.6 Hz, 3H), 1.01 (s, 9H), 0.24 (s, 3H), 0.22 (s, 3H), 0.20 (s, 3H), 0.18
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 218.3, 170.9, 170.5, 165.0,
152.9, 151.1, 137.7, 133.0, 129.7, 126.1, 124.4, 121.9, 121.0, 116.5,
78.9, 78.0, 74.0, 53.9, 45.6, 40.9, 39.2, 31.4, 31.0, 28.3, 28.2, 27.5,
27.4, 24.0, 21.6, 19.8, 19.6, 18.9, 18.6, 18.1, 15.9, 15.2, -3.3, -3.3,
-3.9, -4.3. Anal. Calcd for C46H75NO7Si2S: C, 65.59; H, 8.97; N,
1.66. Found: C, 65.38; H, 8.94; N, 1.68.
(4S,7R,8S,9S,13Z,16S,1′E)-4,8-Di-tert-butyldimethylsilyloxy-5,5,7,9-
tetramethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)-1-ethenyl]-
1-oxa-13-cyclohexadecene-2,6-dione (60). To a solution of coupled
product 59 (7.1 mg, 0.00846 mmol) in MeOH (1 mL) was added 3 N
aqueous NaOH (1 mL), and the mixture was stirred at 50 °C for 36 h.
Saturated aqueous NH4Cl (20 mL) was added to the mixture followed
by the addition of AcOEt (20 mL). The organic layer was separated,
and the aqueous phase was further extracted twice with AcOEt (20
mL). The combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated to give a residue which was purified by silica
gel flash chromatography (AcOEt/hexane, 1:1) to give hydroxy acid
(5.1 mg, 0.00708 mmol; 84%).
To a solution of hydroxy acid (5.1 mg, 0.00708 mmol) in THF (500
µL) were added Et3N (12 µL, 0.0845 mmol) and 2,4,6-trichlorobenzoyl
chloride (11 µL, 0.0704). The mixture was stirred at room temperature
for 20 min, diluted with toluene (500 µL), and added dropwise over a
period of 3 h to a solution of DMAP (17 mg, 0.141 mmol) in toluene
(6 mL). After complete addition, the mixture was stirred for an
additional 1 h and concentrated in vacuo. Purification of the residue
by silica gel flash chromatography (AcOEt/hexane, 1:10) gave lactone
60 (4.4 mg, 0.0062 mmol; 88%). The spectral data of 60 thus obtained
were identical with those of an authentic sample.2h,i
(3S,6R,7S,8S,12Z,15S,16E)-Phenyl 3,7-Di-tert-butyldimethylsil-
yloxy-15-methoxycarbonyl-4,4,6,8,12,16-hexamethyl-17-(2-meth-
yl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate (61). To a solu-
tion of fragment C (10.6 mg, 0.0179 mmol) in THF (0.5 mL) was added
9-BBN (72 µL, 0.5 M solution in THF, 0.0359 mmol) at 0 °C, and the
mixture was stirred in the ultrasonic bath cleaner (28 °C) for 1.5 h.
H2O (50 µL) was added to the mixture at 0 °C followed by the addition
of fragment B (9.8 mg, 0.0251 mmol) in DMF (1 mL), PdCl2(dppf) (3
mg, 0.00359 mmol), and K3PO4‚3H2O (14 mg, 0.0538 mmol). After
degassing (FPTmethod), the mixture was stirred for 1 h at 60 °C. A
saturated aqueous NH4Cl (30 mL) was added to the mixture followed
by the addition of AcOEt (30 mL). The organic layer was separated,
and the aqueous phase was further extracted twice with AcOEt (30
mL). The combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated to give a residue which was purified by silica
gel flash chromatography (AcOEt/hexane, 1:1) and then preparative
thin-layer chromatography (silica gel, AcOEt/hexane, 1:2) to give
coupled product 61 (5.7 mg, 0.00664 mmol; 37%): [R]22 -32.3 (c
D
0.45, CHCl3); IR (neat) 2930, 2856, 1739, 1693, 1472, 1370, 1239,
1
1197, 1145, 1088, 989, 836, 776 cm-1); H NMR (500 MHz, CDCl3)
δ 7.36 (m, 2H), 7.21 (m, 1H), 7.14 (m, 2H), 6.69 (s, 1H), 6.51 (s, 1H),
5.23 (m, 1H), 5.07 (m, 1H), 4.46 (dd, J ) 3.6, 5.8 Hz, 1H), 3.79 (dd,
J ) 1.8, 6.9 Hz, 1H), 3.18 (m, 1H), 2.74 (dd, J ) 3.5, 16.5 Hz, 1H),
2.70 (s, 3H), 2.53 (dd, J ) 6.0, 16.5 Hz, 1H), 2.40 (m, 2H), 2.06 (s,
3H), 2.05 (s, 3H), 2.00 (m, 1H), 1.66 (s, 3H), 1.40 (m, 6H), 1.30 (s,
3H), 1.12 (s, 3H), 1.09 (d, J ) 6.5 Hz, 3H), 0.91 (m, 12H), 0.90 (s,
9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.07 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 218.3, 170.9, 170.5, 164.9, 153.0, 151.1, 138.7, 137.9, 129.7,
126.1, 121.9, 120.9, 119.8, 116.5, 79.3, 78.0, 74.1, 53.9, 45.6, 40.9,
39.2, 32.9, 32.0, 31.2, 26.6, 26.5, 26.4, 24.0, 23.8, 21.6, 19.9, 19.6,
18.9, 18.6, 18.1, 15.9, 15.2, -3.3, -3.4, -3.9, -4.3. Anal. Calcd for
C47H77NO7Si2S: C, 65.92; H, 9.06; N, 1.64. Found: C, 65.66; H, 8.80;
N, 1.61.
(4S,7R,8S,9S,13Z,16S,1′E)-4,8-Di-tert-butyldimethylsilyloxy-
5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-1,3-thiazol-4-yl)-1-
ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione (62). To a solution of
coupled product 61 (5 mg, 0.00584 mmol) in MeOH (1 mL) was added
3 N aqueous NaOH (1 mL), and the mixture was stirred at 50 °C for
36 h. Saturated aqueous NH4Cl (20 mL) was added to the mixture
followed by the addition of AcOEt (20 mL). The organic layer was
separated, and the aqueous phase was further extracted twice with
AcOEt (20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated to give a residue which was purified
by silica gel flash chromatography (AcOEt/hexane, 1:1) to give hydroxy
acid (4 mg, 0.00543 mmol; 93%).
To a solution of hydroxy acid (3.9 mg, 0.00528 mmol) in THF (200
µL) were added Et3N (8.3 µL, 0.0528 mmol) and 2,4,6-trichlorobenzoyl
chloride (8.8 µL, 0.0634). The mixture was stirred at room temperature
for 20 min, diluted with toluene (700 µL), and added dropwise over a
period of 3 h to a solution of DMAP (32 mg, 0.264 mmol) in toluene
(5.1 mL). After complete addition, the mixture was stirred for an
additional 1 h and concentrated in vacuo. Purification of the residue
by silica gel flash chromatography (AcOEt/hexane, 1:5) and then
preparative thin-layer chromatography (silica gel, AcOEt/hexane, 1:6)
gave lactone 62 (3.4 mg, 0.00475 mmol; 90%). The spectral data of
62 thus obtained were identical with those of an authentic sample.2h
Acknowledgment. Financial support was provided by
CREST, The Japan Science and Technology Corporation (JST),
and RFTF of Japan Society for the Promotion of Science. We
thank Prof. K. C. Nicolaou for sending us spectral data of
epothilones A and B.
Supporting Information Available: 1H NMR and 13C NMR
spectra of products and experimental procedures not described
in the Experimental Section. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA002024B