Syntheses of (-)-epothilone B

Article abstract of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2492::AID-CHEM2492>3.0.CO;2-R

Two efficient routes for the total synthesis of (-)-epothilone B are reported. One strategy is based on ring-closing metathesis, and a second synthesis on a macrolactonization. The key fragments are available on large scale to provide sufficient material for biological tests. Thiazole fragment 4 was obtained by an improved route starting from (S)-malic acid. The first synthesis is based on our preceding paper. The critical trisubstituted double bond C12-13 in our second approach was constructed by a highly efficient Pd- mediated coupling reaction. Ring closure was achieved by macrolactonization.

Full text of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2492::AID-CHEM2492>3.0.CO;2-R

FULL PAPER
Syntheses of ( )-Epothilone B
Dieter Schinzer,* Armin Bauer, and Jennifer Schieber[a]
Abstract: Two efficient routes for the total synthesis of ( )-epothilone B are
reported. One strategy is based on ring-closing metathesis, and a second synthesis on
a macrolactonization. The key fragments are available on large scale to provide
sufficient material for biological tests. Thiazole fragment 4 was obtained by an
improved route starting from (S)-malic acid. The first synthesis is based on our
preceding paper. The critical trisubstituted double bond C12 ± 13 in our second
approach was constructed by a highly efficient Pd-mediated coupling reaction. Ring
closure was achieved by macrolactonization.
Keywords: cytotoxic
epothilones ´ macrolides ´ natural
products
agents
´
alternative, selective access to this series of compounds based
on highly efficient aldol and transition-metal mediated
coupling reactions leading to a seco acid precursor of
Nicolaouꢀs macrolactonization route[3g, 4d] to ( )-epothi-
lone B.
Introduction
The discovery that the bacterial macrolides epothilone A and
epothilone B[1] act as biological analogues of paclitaxel has
induced intense research activity,[2] resulting in several total
syntheses of epothilone A[3] and B,[4] partial syntheses,[5] and
numerous derivatives.[6] In various biochemical assays, pacli-
taxel and the epothilones were found to be almost identical in
their effect on microtubule stabilization and cytotoxic proper-
ties. However, being tested on multiple-drug resistant (MDR)
human carcinoma cell lines, the epothilones were significantly
more potent than paclitaxel. They may even prove to be more
promising anticancer drugs than paclitaxel with less undesired
side effects.[7] Recent studies with MDR cell lines indicate that
epothilone B is the most potent of the epothilones in vitro,
whereas deoxyepothilone B (epothilone D) exhibited the best
therapeutic results in vivo and is thus regarded as a lead
compound for potential clinical development.[8]
In the preceding paper,[9] we described the synthesis of
epothilone A by an approach based on ring-closing meta-
thesis. Here we report two routes to epothilone B. The first
approach proceeds along a similar path developed for
epothilone A, representing, together with the work of Dan-
ishefsky et al.,[3b] a formal total synthesis of ( )-epothilone B
(1). This olefin metathesis approach, however, suffers from
unsactisfactory stereocontrol in the ring-closure step. In view
of the importance of sufficient quantities of epothilone B and
its analogues for drug development, we have elaborated an
Results and Discussion
The metathesis approach to epothilone B: The retrosynthetic
analysis of our olefin metathesis approach to epothilone B is
outlined in Scheme 1. Building blocks 2 and 4 are identical to
the thiazole and ethyl ketone fragments employed in the
S
N
olefin metathesis,
O
OH
4
epoxidation
3
O
12
S
N
13
8
5
OH
7
6
15
aldol reaction
O
1
3
esterification
O
OH
O
epothilone B: 1
[a] Prof. Dr. D. Schinzer, Dipl.-Chem. A. Bauer, J. Schieber
Chemisches Institut der Otto-von-Guericke-Universität
Universitätsplatz 2, D-39106 Magdeburg (Germany)
Fax: (‡49)391-6712223
O
O
O
2
Scheme 1. Retrosynthetic analysis of epothilone BÐthe olefin metathesis
approach.
E-mail: Dieter.Schinzer@chemie.uni-magdeburg.de
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2492±2500
preceding epothilone A synthesis.[9] They were assembled
with the aldehyde building block 3 in the same manner to
afford the desired olefin metathesis precursor, which was first
published by Danishefsky et al.,[3b] as outlined below.
Again, an Evans asymmetric alkylation was chosen for the
introduction of the chiral center in the aldehyde building
block 3. 1,4-Addition of a homoallylcuprate derived from
commercially available 3-methyl-3-buten-1-ol[10] to the acrylo-
yl oxazolidinone 5[11] in the presence of TMSCl and LiI[12] gave
6-methylheptenoyl oxazolidinone 6 in 60% yield (Scheme 2).
a
+
O
O
O
O
O
3
2
b
O
O
OH
9
e
O
O
O
O
OR1 OR2
O
OR3
a
b
N
N
O
O
10: R1 = R2 = R3= H
5
6
c
11: R1 = R2 = R3 = TBS
12: R1 = H, R2 = R3= TBS
d
O
O
c
f
N
HO
O
OH
O
OTBS O
OTBS
8
7
13
S
N
d
O
3
O
Scheme 2. Synthesis
of
the
aldehyde
building
block
3.
14
O
OTBS O
OTBS
ˆ
a) CH2 CH(CH3)CH2CH2MgBr (1.8 equiv), CuBr´ Me2S (1.1 equiv), LiI
(1.1 equiv), TMSCl (2.07 equiv), THF, 788C, 6 h, 60%; b) NaHMDS
(1.1 equiv), THF, 788C, 30 min; then MeI (5 equiv), 788C, 11 h, 87%;
c) LAH, Et2O, RT, 24 h, 94%; d) Dess ± Martin periodinane[13] (1.2 equiv),
CH2Cl2, RT, 5 min, 80%; NaHMDS ˆ sodium hexamethyldisilazane.
g
1
Scheme 3. Assembly of the building blocks 2 and 3 and completion of the
synthesis. a) Ketone 2, LDA (0.95 equiv), THF, 788C, 1 h; then aldehyde
3, 788C, 45 min, 68%; b) PPTS (1.0 equiv), MeOH, RT, 24 h, 88%;
c) TBSOTf (1.5 equiv/OH), 2,6-lutidine (2.5 equiv/OH), CH2Cl2, 508C to
‡108C, 4 h, 99%; d) CSA (0.2 equiv), MeOH/CH2Cl2 (1:1), 08C, 5 h, 84%;
e) PDC (9 equiv), DMF, RT, 36 h, 91%; f) DCC (1.1 equiv), DMAP
(0.15 equiv), CH2Cl2, RT, 16 h, 61%; g) 1. [Mo(CHMe2Ph){N(2,6-
iPr2C6H3)}{OCMe(CF3)2}2] (ring-closing olefin metathesis); 2. separation
of E and Z isomers; 3. desilylation; 4. epoxidation, see ref. [3b]; PPTS ˆ
pyridinium p-toluenesulfonate, TBSOTf ˆ tert-butyldimethylsilyl trifluor-
omethanesulfonate, CSA ˆ camphorsulfonic acid, PDC ˆ pyridinium di-
chromate, DCC ˆ dicyclohexyl carbodiimide, DMAP ˆ 4-dimethylamino-
pyridine
Its enolate was generated by the action of NaHMDS in THF
at 788C, followed by the reaction with excess methyl iodide
to afford alkylation product 7, which was isolated in 87% yield
(diastereoselectivity of the alkylation 10:1 by 1H NMR
spectroscopy of the crude product). Reductive removal
(LAH) of the auxiliary furnished alcohol 8, which was
converted to the aldeyde 3 by Dess ± Martin oxidation (78%
over two steps).
The conditions employed for the assembly of the corre-
sponding fragments in the epothilone A synthesis proved to
be optimal for the coupling of building blocks 2 and 3
(Scheme 3). Again, the anti Cram (6R,7S) isomer 9 was
favored in this crossed aldol reaction, the diastereoselectivity
being somewhat lower (10:1) than for the epothilone A
synthesis. Transformation of the aldol product 9 to the acid 13
needed for the synthesis of the metathesis precursor required
protective group manipulations and C1 oxidation: Thus, acid
cleavage of the dioxolane and persilylation of the resulting
triol 10 yielded tris-silyl ether 11. Selective desilylation gave
alcohol 12, which was converted to acid 13 by PDC oxidation.
DMAP-catalyzed DCC coupling of 13 with the thiazole
building block 4 resulted in the formation of ester 14, whose
[14]
ˆ
the Grubbs catalyst [RuCl2( CHPh)(PCy3)] under various
conditions were unsuccessful. However, Danishefsky et al.[3b]
have shown that 14 can be transformed into epothilone B with
the Schrock catalyst [Mo(CHMe2Ph){N(2,6-iPr2C6H3)}{OC-
Me(CF3)2}2][15] followed by deprotection and epoxidation.[3b]
The macrolactonization approach to epothilone B: Scheme 4
depicts the retrosynthetic analysis that led to the macro-
lactonization-based strategy for the synthesis of epothilone B.
The key step for the formation of a seco acid needed for
cyclization to deoxy-1 by macrolactonization[3g, 4d] would be an
aldol reaction of the ethyl ketone 2 employed in the meta-
thesis approach and the Nicolaou[3g, 4d] aldehyde 15. Further
disconnection of 15 led to the thiazole fragment 17 and a
1
spectroscopical data ([a], IR, MS, H and 13C NMR) were
consistent with the olefin metathesis precursor described by
Danishefsky et al.[3b] Attempts to cyclize 14 in the presence of
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D. Schinzer et al.
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21 under standard conditions (80% yield for two steps).
Finally, the known alkyl iodide 16[17] was obtained by a one-
pot hydroboration/iodination reaction[19] in 60% yield.
S
N
I
I
+
OTBS
The thiazole building block 17 was synthesized according to
an improved sequence which was amenable to a multigram
scale-up. In the preceding synthesis,[5a, 9] the stereocenter in
this fragment had been established by a Sharpless resolution,
which gave 25 in 80% ee. In this sequence, (S)-malic acid was
chosen as the source of chirality. Its cyclohexylidene ketal
22[20] was selectively reduced with BH3 ´ Me2S (Scheme 6). The
reduction product was transformed into the known lactone
OTBS
16
17
Pd coupling
S
O
H
N
15
OTBS
O
epoxidation
S
N
O
OR
HO
OH
c
a
O
O
aldol reaction
O
O
O
TBSO
OTBS
O
O
O
macrolactonization
25
22
23: R = H
OH
O
b
24: R = TBS
epothilone B: 1
S
OH
O
S
N
d
e
P(OEt)2
N
O
O
O
26
OTBS
27
2
Scheme 4. Retrosynthetic analysis of epothilone BÐthe macrolactoniza-
tion approach.
O
S
S
I
f
N
N
C7 ± C11 building block 16. An efficient palladium-mediated
Negishi-type coupling reaction[16] was envisioned for the
assembly of 16 and 17 to a precursor of aldehyde 15.
OTBS
OTBS
28
17
Scheme 6. Synthesis of the thiazole building block 17. a) 1. BH3 ´ Me2S
(2.85 equiv), B(OMe)3 (2.85 equiv), THF, 24 h; 2. pTsOH ´ H2O (0.1 equiv),
CH2Cl2, RT, 24 h, 72% over two steps; b) TBSCl (1.1 equiv), imidazole
(2.2 equiv), DMF, RT, 24 h, 93%; c) 1. MeLi (1.1 equiv), THF, 788C, 3 h;
2. TBSCl (1.1 equiv), imidazole (2.2 equiv), DMF, RT, 24 h, 73% over two
steps; d) 1. nBuLi, THF, 788C, then 25; 2. HF, MeCN/Et2O, glass, 69%
over two steps, see preceding paper; e) Swern oxidation, 82%;
An approach to the C7 ± C11 fragment 16 was originally
developed by Evans et al. for a synthesis of the polyether
antibiotic X-206 using diastereoselective alkylation and
hydrozirconation as the key steps.[17a] The phenylalanine-
derived oxazolidinone 18[18] is the starting material for our
synthesis of 16 which furnishes this compound in multigram
quantities. Alkylation of the Na enolate of 18 with 3-iodo-
propene (allyl iodide) gave crystalline amide 19 in 61% yield
ˆ
f) Ph3P C(H)I (1.8 equiv), THF, 308C, 20 min, 54%.
23[21] by acid catalysis. Protection of compound 23 afforded
silyl ether 24 in 93% yield. Addition of MeLi[22] gave a lactol
which opened under standard TBS protection conditions to
the enantiomerically pure ketone 25 (49% from 22). Alcohol
27 was obtained following the Horner± Emmons reaction and
desilylation protocol from our synthesis of epothilone A.[9]
Oxidation of 27 to the aldehyde 28 was performed under
Swern conditions (82%). A Z-selective Wittig reaction of 28
with iodomethyltriphenylphosphorane[23] then led to the
desired vinyl iodide 17 as the only stereoisomer in 54% yield.
An efficient palladium-mediated coupling[16a] of vinyl
iodide 17 with the organozinc species[24] derived from 16 led
to the bis-silyl ether 29 in 84% yield (Scheme 7). Selective
deprotection to the alcohol 30 was achieved by CSA in
MeOH/CH2Cl2 (82%). Reaction of 30 with Dess ± Martin
periodinane as the reagent of choice provided aldehyde 15
needed for the aldol reaction with ketone 2 in 97% yield.
In contrast to our metathesis approach to the epothilones,
the conditions for the aldol reaction of ethyl ketone 2 and the
aldehyde 15 had to be slightly changed (Scheme 8). In order to
ensure complete conversion of the aldehyde to the desired
1
(Scheme 5); only one stereoisomer was detected by H and
13C NMR spectroscopy. Action of LAH resulted in the
formation of alcohol 20 which was protected as its TBS ether
O
O
O
O
a
b
N
N
O
O
19
18
Bn
Bn
I
d
TBSO
OR
16
20: R = H
c
21: R = TBS
Scheme 5. Synthesis of the C7 ± C11 fragment 16. a) NaHMDS
(1.05 equiv), THF, 788C, 1 h; then 3-iodopropene (1.5 equiv), 788C,
4 h, 61%; b) LAH (7 equiv), Et2O, RT, 5 h; c) TBSCl (1.3 equiv), imidazole
(2.6 equiv), DMF, RT, 24 h, 80% over two steps; d) BH3 ´ THF (1.2 equiv),
THF, 08C, 1 h; then MeOH, NaOAc (1.0 equiv), ICl (1.0m solution in
CH2Cl2, 1.0 equiv), 08C, 30 min, 60%.
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Epothilone B
2492±2500
Conclusions
S
N
a
I
In summary, we have presented two formal total syntheses of
epothilone B and D. Especially our aldol reaction offers the
best and efficient method to date for the acyclic stereocontrol
of the configurations at C6 and C7, which represents the major
stereochemical issue in the field of epothilones. In addition,
we have presented a straightforward synthesis to construct the
tricyclic double bond at C12 C13 by a palladium-mediated
coupling. Finally, our methods allow the synthesis of designed
analogues for in vitro and in vivo testing.
OR
TBSO
16
OTBS
29: R = TBS
30: R = H
b
S
N
c
O
OTBS
15
Scheme 7. Pd coupling of building blocks 16 and 17 and transformation to
the aldehyde 15. a) Zn (1.5 equiv), benzene/DMAc (7:1), 608C, 2.5 h; then
17 (0.67 equiv), [Pd(PPh3)4] (4 mol%), 608C, 30 min, 84%; b) CSA
(1.05 equiv), MeOH/CH2Cl2 (1:1), 08C, 30 min, RT, 30 h, 82%; c) Dess ±
Martin periodinane (1.3 equiv), pyridine (1.3 equiv), CH2Cl2, 97%;
DMAc ˆ N,N-dimethyl acetamide.
Experimental Section
General techniques: See preceding article.[9]
(4S)-4-Isopropyl-3-(6-methyl-6-heptenoyl)-oxazolidin-2-one (6): 4-Bromo-
2-methyl-1-butene[10] (997 mg, 0.2 equiv) was added to a suspension of Mg
(76.0 mmol, 2.0 equiv) in THF (5 mL). After the reaction had started a
solution of 4-bromo-2-methyl-1-butene (8.973 g, 1.8 equiv) in THF (45 mL)
was added at such a rate that the mixture gently refluxed. Refluxing was
continued for 20 min after the addition of the alkyl bromide was complete.
The mixture was cooled to room temperature and added dropwise to a
solution of CuBr´ Me2S (7.561 g, 36.8 mmol, 1.1 equiv) and LiI (4.923 g,
36.8 mmol, 1.1 equiv) in THF (60 mL) at 608C. The resulting brown
cuprate suspension was stirred for 15 min at 608C, and TMSCl (9.6 mL,
76.0 mmol, 2.07 equiv) was added dropwise. Stirring was continued for
10 min at 608C. A solution of (S)-3-acryloyl-4-isopropyl-1,3-oxazolidin-2-
one (5)[11] (6.126 g, 33.4 mmol) in THF (50 mL) was added at 788C within
1 h. The reaction mixture was stirred at 788C for 5 h. NEt3 (13.9 mL,
100.3 mmol, 3 equiv) was added dropwise and stirring was continued for 3 h
at 788C. Saturated aqueous NH4Cl solution (40 mL) was added and the
mixture was warmed to room temperature. The organic phase was
separated and the aqueous layer was extracted with Et2O (4 Â 200 mL).
The combined organic extracts were dried over MgSO4 and concentrated in
vacuo. Purification of the residue by flash chromatography (pentane/Et2O
a
S
N
+
O
O
O
O
15
OTBS
2
b
S
N
OH
O
O
O
31
OTBS
d
S
1
5:1) gave oxazolidinone 6 (5.068 g, 60%) as a colorless oil. [a]2D0 ˆ ‡64.3,
OR
O
OR OR
N
20
[a] ˆ ‡75.7 (c ˆ 1.15, CHCl3); IR (film): nÄmax ˆ 3543, 3074, 2966, 1782,
546
OTBS
1
1701, 1650, 1464, 1387, 1302, 1206, 1073, 888 cm
;
1H NMR (400 MHz,
32: R = H
33: R = TBS
c
CDCl3): d ˆ 4.72 ± 4.66 (m, 2H; H-7'), 4.47 ± 4.41 (m, 1H; H-4), 4.27 (t, 2J ˆ
8.7 Hz, 1H; H-5), 4.21 (dd, 2J ˆ 9.2 Hz, 3J ˆ 3.1 Hz, 1H; H-5), 3.05 ± 2.82
Scheme 8. Final steps of the macrolactonization approach to epothi-
lone BÐsynthesis of a seco acid precursor. a) Ketone 2 (1.0 equiv), LDA
(0.98 equiv), THF, 788C, 1 h; then aldehyde 15 (0.5 equiv), 788C,
15 min, 85%; b) PPTS (1.0 equiv), MeOH, RT, 72 h, 86%; c) TBSOTf
(1.5 equiv/OH), 2,6-lutidine (2.5 equiv/OH), CH2Cl2, 508C to 08C, then
08C, 2 h, 95%; d) 1. C1-OH deprotection; 2. C1 oxidation to carboxylic
acid; 3. C15-OH deprotection; 4. Yamaguchi macrolactonization; 5.
desilylation; 6. epoxidation, see ref. [3g].
3
(m, 2H; H-2'), 2.42 ± 2.33 (m, 1H; C4-CH), 2.05 (t, J ˆ 7.5 Hz, 2H; H-5'),
1.71 (s, 3H; C6'-CH3), 1.70 ± 1.61 (m, 2H), 1.55 ± 1.46 (m, 2H)(H-3', H-4'),
0.92 (d, 3J ˆ 7.0 Hz, 3H; C4-CHCH3), 0.87 (d, 3J ˆ 6.9 Hz, 3H; C4-CHCH3);
13C NMR (100 MHz, CDCl3): d ˆ 173.2, 154.0, 145.5, 109.9, 63.3, 58.3, 37.4,
35.3, 28.3, 26.9, 24.0, 22.3, 17.9, 14.6; MS (70 eV, EI): m/z (%): 253 (14)
‡
[M] , 198 (4), 184 (21), 171 (74), 130 (100), 125 (26), 99 (36), 97 (29), 85
(42), 83 (63), 69 (38), 68 (39), 55 (88); HRMS (EI): calcd for C14H23NO3
253.1678, found 253.167; C14H23NO3 (253.3) calcd C 66.37, H 9.15, N 5.53;
found C 66.41, H 9.24, N 5.19.
aldol product 31, two equivalents of the lithium enolate
generated from ketone 2 had to be employed in the reaction.
The product ratio anti Cram (6R,7S) to Cram (6S,7R) was
determined as 9:1 by HPLC. The aldol product 31 was isolated
in 85% yield from the reaction mixture. Transformation of
intermediate 31 into the known seco acid precursor 33[3g]
required cleavage of the ketal protecting group by the action
of PPTS in MeOH, leading to the triol 32. Finally, silylation of
compound 32 with TBSOTf and 2,6-lutidine led to the known
tetrakis-silyl ether 33 identical ([a], IR, MS, 1H and 13C NMR)
to an intermediate from Nicolaouꢀs synthesis of epothilone B.
Nicolaou et al.[3g] have shown that this precursor can be
converted to ( )-epothilone B by a seven-step sequence
consisting of selective deprotection steps, C1 oxidation,
Yamaguchi macrolactonization, and epoxidation.[3g]
(4S,2'S)-4-Isopropyl-3-(2,6-dimethyl-6-heptenoyl)-oxazolidin-2-one (7): A
solution of NaHMDS (1.0m in THF; 17.6 mL, 17.6 mmol, 1.1 equiv) was
cooled to 788C, and a precooled (08C) solution of 6 (4.059 g, 16.0 mmol)
in THF (17 mL) was added. The reaction mixture was stirred for 30 min at
788C, and a solution of MeI (5 mL, 80.0 mmol, 5 equiv) in THF (2 mL)
was added. After 11 h of stirring at 788C, the mixture was quenched with
saturated NH4Cl solution (20 mL), and extracted with Et2O (4 Â 200 mL).
The combined organic extracts were dried over MgSO4, and concentrated
in vacuo. Purification of the crude product (10:1 ratio of diastereomers by
1H NMR) by flash chromatography (pentane/Et2O 7:1) furnished
7
20
(3.739 g, 87%) as a colorless oil. [a]2D0 ˆ ‡88.8, [a] ˆ ‡105.0 (c ˆ 1.04,
546
CHCl3); IR (film): nÄmax ˆ 2967, 1782, 1700, 1460, 1386, 1301, 1205, 1058,
888 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 4.72 ± 4.66 (m, 2H; H-7'), 4.48 ±
4.42 (m, 1H; H-4), 4.27 (t, 2J ˆ 8.7 Hz, 1H; H-5), 4.20 (dd, 2J ˆ 9.1 Hz, 3J ˆ
3.1 Hz, 1H; H-5), 3.80 ± 3.70 (m, 1H; H-2'), 2.41 ± 2.30 (m, 1H; C4-CH),
2.01 (t, 3J ˆ 7.3 Hz, 2H; H-5'), 1.70 (s, 3H; C6'-CH3), 1.60 ± 1.32 (m, 4H;
H-3', H-4'), 1.21 (d, 3J ˆ 6.9 Hz, 3H; C2'-CH3), 0.92 (d, 3J ˆ 7.0 Hz, 3H; C4-
CHCH3), 0.87 (d, 3J ˆ 6.9 Hz, 3H; C4-CHCH3); 13C NMR (100 MHz,
Chem. Eur. J. 1999, 5, No. 9
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D. Schinzer et al.
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CDCl3): d ˆ 177.2, 153.7, 145.6, 110.0, 63.2, 58.4, 37.7, 37.6, 32.6, 28.4, 25.2,
(312 mg, 0.4 equiv) was added and stirring was continued for 10 h. Water
(4.5 mL) and saturated aqueous NaHCO3 solution (4.5 mL) were added,
and the mixture was concentrated under reduced pressure. The residue was
dissolved in Et2O (300 mL) and the resulting solution was washed with
brine (20 mL). The organic layer was separated and dried over MgSO4.
After removal of the solvent in vacuo and flash chromatography (Et2O) of
‡
22.3, 17.9, 17.8, 14.7; MS (70 eV, EI): m/z (%): 267 (0.6) [M] , 198 (10), 185
(100), 156 (6), 139 (109, 130 (44), 110 (10), 95 (209, 85 (20), 69 (36), 55 (28),
43 (11); C15H25NO3 (267.4) calcd C 67.38, H 9.42, N 5.24; found C 67.53, H
9.46, N 5.06.
(S)-2,6-Dimethyl-6-hepten-1-ol (8): LAH (850 mg, 22.4 mmol, 3.4 equiv)
was added in small portions to a solution of oxazolidinone 7 (3.517 g,
13.15 mmol) in Et2O (85 mL) within a period of 3 h. The reaction mixture
was stirred for 24 h at room temperature, quenched by dropwise addition of
water (0.85 mL), 15% aqueous NaOH (0.85 mL), and water (2.25 mL). The
mixture was stirred for 4 h at room temperature until a white precipitate
formed, which was filtered off by suction through a small plug of celite. The
precipitate was washed with Et2O (4 Â 40 mL). The filtrate and washings
were combined, and concentrated in vacuo. Purification of the residue by
flash chromatography (pentane/Et2O 5:1) afforded alcohol 8 (1.753 g,
the residue, triol 10 (863 mg, 88%) was obtained as a colorless oil. [a]D20
ˆ
20
40.3, [a]
ˆ
49.7 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3402, 2937, 1685,
546
1
1649, 1467, 1376, 1329, 1055, 979, 885 cm
;
1H NMR (400 MHz, CDCl3):
d ˆ 4.72 ± 4.66 (m, 2H; H-13), 4.08 ± 4.01 (m, 1H; H-3), 3.94 ± 3.83 (m, 2H;
H-1), 3.35 (d, 3J ˆ 9.0 Hz, 1H; H-7), 3.34 (s, 1H; C7-OH), 3.27 (dq, 3J ˆ
6.9 Hz, 3J ˆ 1.6 Hz, 1H; H-6), 2.58 (brs, 1H; OH), 2.09 ± 1.93 (m, 2H;
H-11), 1.79 ± 1.48 (m, 5H; H-2, H-8, H-9, H-10), 1.71 (s, 3H; C12-CH3),
1.42 ± 1.30 (m, 1H; H-10), 1.21, 1.12 (2s, 2 Â 3H; C4-CH3), 1.14 ± 1.04 (m,
3
3
1H; H-9), 1.07 (d, J ˆ 6.9 Hz, 3H; C6-CH3), 0.86 (d, J ˆ 6.8 Hz, 3H; C8-
CH3); 13C NMR (100 MHz, CDCl3): d ˆ 223.8, 146.2, 109.7, 76.4, 74.7, 62.2,
52.6, 40.9, 38.2, 35.5, 32.5, 32.4, 24.8, 22.4, 21.5, 18.5, 15.5, 10.1; MS (70 eV,
20
94%) as a colorless liquid. [a]D20
ˆ
11.8, [a]
ˆ
13.6 (c ˆ 1.0, CHCl3);
546
1
IR (film): nÄmax ˆ 3334, 2934, 1650, 1455, 1375, 1042, 886 cm
;
1H NMR
‡
‡
EI): m/z (%): 314.0 (1) [M] , 297.6 (100) [M‡H H2O] , 279.1 (35), 239.9
(17), 222.9 (33), 214.9 (21), 197.0 (36), 184.9 (29), 173.9 (24), 156.7 (78),
141.0 (52), 122.6 (44), 99.9 (50), 81.9 (48), 69.0 (43); HRMS (EI) calcd for
C18H34O4 296.2351, found 296.235.
(400 MHz, CDCl3): d ˆ 4.73 ± 4.65 (m, 2H; H-7), 3.52 ± 3.38 (m, 2H; H-1),
2.05 ± 1.97 (m, 2H; H-5), 1.71 (s, 3H; C6-CH3), 1.69 ± 1.35 (m, 5H), 1.16 ±
1.05 (m, 1H)(H-2, H-3, H-4, OH), 0.93 (d, 3J ˆ 6.7 Hz, 3H; C2-CH3);
13C NMR (100 MHz, CDCl3): d ˆ 146.0, 109.8, 68.3, 38.0, 35.7, 32.7, 24.9,
‡
‡
22.3, 16.5; MS (70 eV, EI): m/z (%): 142 (18) [M] , 124 (12) [M H2O] ,
109 (60), 95 (40), 82 (71), 69 (97), 68 (100), 56 (92); HRMS (EI): calcd for
C9H18O 142.1358, found 142.135.
(3S,6R,7S,8S)-1,3,7-Tri-(tert-butyldimethylsilyloxy)-4,4,6,8,12-pentameth-
yl-12-tridecen-5-one (11): 2,6-Lutidine (2.39 mL, 20.6 mmol, 7.5 equiv) and
TBSOTf (2.83 mL, 7.5 mmol, 4.5 equiv) were added dropwise at 508C to
a solution of triol 10 (863 mg, 2.74 mmol) in CH2Cl2 (8.2 mL). The mixture
was allowed to warm to 108C within 4 h. Flash chromatography (pentane/
(S)-2,6-Dimethyl-6-heptenal (3): Dess ± Martin periodinane[13] (4.581 g,
10.8 mmol, 1.2 equiv) was added to a solution of alcohol 8 (1.280 g,
9.0 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 5 min. Flash
Et2O 20:1) of the reaction mixture gave tris-silyl ether 11 (1.783 g, 99%) as
20
chromatography (pentane/Et2O 10:1) of the reaction mixture provided
a colorless oil. [a]D20
ˆ
31, [a]
ˆ
38 (c ˆ 1.0, CHCl3); IR (film): nÄmax
ˆ
546
20
1
aldehyde 3 (1.000 g, 80%) as a colorless liquid. [a]2D0 ‡12.9, [a] ˆ ‡16.2
3075, 2955, 1698, 1652, 1473, 1388, 1361, 1255, 1104, 986, 838, 775, 669 cm
1H NMR (400 MHz, CDCl3): d ˆ 4.71 ± 4.64 (m, 2H; H-13), 3.89 (dd, J ˆ
;
546
3
(c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 2937, 2815, 1728, 1650, 1458, 1376,
1
3
3
3
3
888 cm 1; H NMR (400 MHz, CDCl3): d ˆ 9.62 (d, J ˆ 2.0 Hz, 1H; H-1),
4.73 ± 4.65 (m, 2H; H-7), 2.40 ± 2.30 (m, 1H; H-2), 2.03 (t, 3J ˆ 7.4 Hz, 2H;
H-5), 1.71 (s, 3H; C6-CH3), 1.53 ± 1.18 (m, 4H; H-3, H-4), 1.10 (d, 3J ˆ
7.0 Hz, 3H; C2-CH3); 13C NMR (100 MHz, CDCl3): d ˆ 205.2, 145.3, 110.2,
7.5 Hz, J ˆ 2.8 Hz, 1H; H-3), 3.77 (dd, J ˆ 6.6 Hz, J ˆ 2.2 Hz, 1H; H-7),
3.67 (dt, 2J ˆ 9.4 Hz, 3J ˆ 5.0 Hz, 1H; H-1), 3.62 ± 3.54 (m, 1H; H-1), 3.14
(dq, 3J ˆ 9.4 Hz, 3J ˆ 5.0 Hz, 1H; H-6), 2.05 ± 1.92 (m, 2H; H-11), 1.70 (s,
3H; C12-CH3) 1.64 ± 1.01 (m, 7H; H-2, H-8, H-9, H-10), 1.22 (s, 3H; C4-
CH3), 1.05 (d, 3J ˆ 6.9 Hz, 3H; C6-CH3), 1.03 (s, 3H; C4-CH3), 0.92 (d, 3J ˆ
6.9 Hz, 3H; C8-CH3), 0.91, 0.90, 0.88 (3s, 9H; OSiC(CH3)3), 0.09, 0.07, 0.06,
0.06, 0.03, 0.02 (6s, 6  3H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ
218.2, 145.9, 109.8, 77.4, 74.04, 61.0, 53.7, 45.0, 38.9, 38.4, 38.1, 30.7, 26.2, 26.1,
26.0, 25.7, 24.5, 22.4, 19.4, 18.5, 18.4, 18.3, 17.5, 15.2, 3.7, 3.7, 3.8, 4.0,
‡
46.2, 37.6, 30.0, 24.8, 22.2, 13.3; MS (70 eV, EI): m/z (%): 140 (0.6) [M] , 122
(4) [M H2O] , 107 (14), 93 (16), 82 (100), 69 (40), 67 (41), 55 (61), 43 (50);
‡
HRMS (EI): calcd for C9H16O 140.1201, found 140.119.
(4R,5S,6S,4'S)-2-(2,2-Dimethyl-1,3-dioxan-4-yl)-5-hydroxy-2,4,6,10-tetra-
methylundec-10-en-3-one (9): A solution of ethyl ketone 2 (1.179 g,
5.5 mmol) in THF (5.0 mL) was added dropwise at 788C to a freshly
prepared solution of LDA [nBuLi (3.27 mL, 1.6m solution in hexanes,
5.23 mmol, 0.95 equiv) was added to a solution of diisopropylamine
(741 mL, 5.23 mmol) in THF (5.5 mL) at 08C]. The mixture was stirred
for 1 h at 788C. Aldehyde 3 (772 mg, 5.5 mmol, 1.0 equiv) was added
dropwise and stirring was continued for 45 min at 788C. The reaction
mixture was quenched by dropwise addition of saturated aqueous NH4Cl
solution at 788C. The organic layer was separated and the aqueous layer
was extracted with Et2O. The combined extracts were dried over MgSO4
and concentrated in vacuo. Flash chromatography (pentane/Et2O 10:1) of
the residue afforded anti Cram aldol product 9 (1.326 g, 68%) and Cram
‡
5.2, 5.3 ; MS (PCI, CH4): m/z (%): 657.2 (50) [M‡H] , 641.5 (5) [M
‡
CH3] , 545.2 (2), 403.3 (4), 373.3 (13), 311.2 (14), 303.8 (100), 255.1 (52),
‡
123.2 (37); HRMS (EI): calcd for C32H67O4Si3 [M tBu] 599.4347, found
599.432.
(3S,6R,7S,8S)-3,7-Di-(tert-butyldimethylsilyloxy)-1-hydroxy-4,4,6,8,12-
penta-methyl-12-tridecen-5-one (12):
A solution of CSA (121 mg,
0.52 mmol, 0.2 equiv) in MeOH (20 mL) was added at 08C to a solution
of tris-silyl ether 11 (1.696 g, 2.58 mmol) in MeOH (70 mL) and CH2Cl2
(50 mL). The reaction mixture was stirred for 5 h at 08C and quenched with
saturated aqueous NaHCO3 solution (20 mL). Precipitated solid NaHCO3
was filtered off. The filtrate was concentrated under reduced pressure,
diluted with Et2O (200 mL) and washed with brine (20 mL). The phases
were separated and the aqueous layer was extracted with Et2O (2 Â 40 mL).
The combined organic phases were dried over MgSO4 and the solvents
were removed in vacuo. The residue was purified by flash chromatography
(pentane/Et2O 5:1) to give alcohol 12 (1.175 g, 84%) as a colorless oil.
aldol product (136 mg, 7%) as colorless oils. anti Cram diastereomer:
20
[a]2D0
ˆ
23.3, [a]
ˆ
28.1 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3508, 2969,
546
2361, 1685, 1458, 1373, 1273, 1197, 1107, 971, 882 cm 1; 1H NMR (400 MHz,
CDCl3): d ˆ 4.72 ± 4.64 (m, 2H; H-11), 4.06 (dd, 3J ˆ 11.8 Hz, 3J ˆ 2.5 Hz,
1H; H-4'), 3.96 (dt, 2J ˆ 11.9 Hz, 3J ˆ 2.7 Hz, 1H; H-6'), 3.86 (ddd, 3J ˆ
11.7 Hz, J ˆ 5.4 Hz, 3J ˆ 1.6 Hz, 1H; H-6'), 3.50 (s, 1H; OH), 3.37 (d, 3J ˆ
20
3
[a]2D0
ˆ
19.4, [a]
ˆ
22.8 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3449, 2931,
546
9.3 Hz, 1H; H-5), 3.29 (dq, 3J ˆ 7.0 Hz, 3J ˆ 1.2 Hz, 1H; H-4), 2.09 ± 1.94 (m,
2H; H-9), 1.82 ± 1.48 (m, 4H; H-6, H-7, H-8, H-5'), 1.71 (s, 3H; C10-CH3),
1.41 (s, 3H; C2'-CH3), 1.40 ± 1.31 (m, 2H; H-8, H-5'), 1.33 (s, 3H; C2'-CH3),
1.21 (s, 3H; H-1), 1.16 ± 1.05 (m, 1H; H-7), 1.09 (s, 3H; C2-CH3), 1.02
(d, 3J ˆ 7.0 Hz, 3H; C4-CH3), 0.84 (d, 3J ˆ 7.0 Hz, 3H; C6-CH3);
13C NMR (100 MHz, CDCl3): d ˆ 222.9, 146.2, 109.5, 98.4, 74.7, 74.3,
59.8, 51.5, 41.2, 38.2, 35.3, 32.6, 29.7, 25.1, 24.7, 22.3, 21.5, 19.0, 18.5,
1
1691, 1473, 1388, 1255, 1103, 987, 837, 775, 670 cm 1; H NMR (400 MHz,
CDCl3): d ˆ 4.71 ± 4.64 (m, 2H; H-13), 4.07 (dd, 3J ˆ 6.1 Hz, 3J ˆ 4.1 Hz,
3
3
1H; H-3), 3.80 (dd, J ˆ 7.3 Hz, J ˆ 1.7 Hz, 1H; H-7), 3.66 ± 3.57 (m, 2H;
H-1), 3.13 (dq, 3J ˆ 7.1 Hz, 3J ˆ 7.1 Hz, 1H; H-6), 2.05 ± 1.91 (m, 2H; H-11),
1.87 (t, 3J ˆ 5.4 Hz, 1H; OH), 1.70 (s, 3H; C12-CH3), 1.66 ± 0.96 (m, 7H;
3
H-2, H-8, H-9, H-10), 1.22 (s, 3H; C4-CH3), 1.06 (d, J ˆ 6.9 Hz, 3H; C6-
CH3), 1.06 (s, 3H; C4-CH3), 0.93 (d, 3J ˆ 6.9 Hz, 3H; C8-CH3), 0.90 (2s, 2 Â
9H; OSiC(CH3)3), 0.11, 0.07, 0.06, 0.06 (4s, 4 Â 6H; OSi(CH3)2); 13C NMR
(100 MHz, CDCl3): d ˆ 219.6, 145.9, 109.9, 77.6, 73.1, 60.3, 53.8, 45.1, 38.7,
38.4, 38.3, 30.4, 26.2, 26.1, 25.7, 24.9, 22.4, 18.5, 18.3, 17.7, 17.6, 15.7, 3.6,
‡
15.3, 9.2; MS (70 eV, EI): m/z (%): 354 (3) [M] , 339 (6), 296 (9),
278 (5), 214 (6), 197 (10), 185 (26), 156 (84), 141 (28), 127 (26), 123 (65), 115
(78), 82 (100); C21H38O4 (354.5): calcd C 71.15, H 10.80; found C 71.21,
H 10.88.
‡
3.8, 3.9; MS (70 eV, EI): m/z (%): 542.1 (<0.5) [M] , 525.1 (51)
‡
‡
(3S,6R,7S,8S)-1,3,7-Trihydroxy-4,4,6,8,12-pentamethyl-12-tridecen-5-one
(10): A solution of aldol product 9 (1.102 g, 3.11 mmol) in MeOH (20 mL)
was added to a solution of PPTS (469 mg, 1.87 mmol, 0.6 equiv) in MeOH
(130 mL). The mixture was stirred at room temperature for 14 h. PPTS
[M‡H H2O] , 485.0 (28) [M tBu] , 412.9 (11), 393.0 (5), 373.0 (11),
353.0 (27), 345.0 (100), 311.0 (66), 303.0 (12), 271.0 (87), 255.0 (72), 212.9
(18), 190.1 (74), 172.8 (46), 145.0 (60), 130.9 (92); C30H62O4Si2 (543.0) calcd
C 66.36, H 11.51; found C 66.22, H 11.42.
2496
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2496 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Epothilone B
2492±2500
(3S,6R,7S,8S)-3,7-Di-(tert-butyldimethylsilyloxy)-4,4,6,8,12-pentamethyl-
5-oxo-12-tridecenoic acid (13): A solution of PDC (5.886 g, 15.65 mmol,
9.0 equiv) in DMF (15 mL) was added to a solution of alcohol 12 (944 mg,
1.74 mmol) in DMF (10 mL). The reaction mixture was stirred for 36 h at
room temperature, mixed with brine (100 mL), diluted with water
(100 mL), and extracted with CH2Cl2 (6 Â 100 mL). The combined extracts
were dried over MgSO4 and concentrated in vacuo. The residue was
2.57 ± 2.49 (m, 1H; H-3'), 2.29 ± 2.20 (m, 1H; H-3'), 1.19 (d, 3J ˆ 6.8 Hz, 3H;
C2'-CH3); 13C NMR (100 MHz, CDCl3): d ˆ 176.5, 153.1, 135.4, 135.3,
129.4, 128.9, 127.3, 117.2, 66.0, 55.4, 38.1, 38.0, 37.1, 16.4; MS (70 eV, EI): m/z
(%): 273.1 (10) [M] , 244.1 (1), 117.0 (4), 97.0 (12), 91.0 (17), 69.1 (100), 67.0
(36), 53.0 (29); C16H19NO3 (241.3): calcd C 70.31, H 7.01, N 5.12; found C
70.64, H 7.09, N 5.21.
‡
(2S)-2-Methyl-4-penten-1-ol (20): LAH (3.343 g, 88.1 mmol, 7 equiv) was
added in small portions to a solution of oxazolidinone 19 (6.967 g,
25.5 mmol) in Et2O (120 mL) within a period of 4 h. The reaction mixture
was stirred for 1 h at room temperature and quenched by dropwise addition
of water (3.34 mL), 15% aqueous NaOH (3.34 mL), and water (8.35 mL) at
08C. The mixture was stirred for 4 h at room temperature until a white
precipitate formed, which was filtered off by suction through a small plug of
celite. The precipitate was washed with Et2O (200 mL) and CH2Cl2
(200 mL). The filtrate and the washings were combined and concentrated
in vacuo. (4R)-4-benzyl-1,3-oxazolidin-2-one (2.639 g, 58%) precipitated as
colorless needles. The solid was filtered off by suction and washed with
Et2O (5 mL) and pentane (5 mL). The filtrate and the washings were
combined. After evaporation of the solvent crude alcohol 20[17a] (2.922 g)
was obtained as a colorless liquid, which was used for the preparation of
silyl ether 21 without further purification. An analytical sample was
purified by flash chromatography (pentane/Et2O 2:1) to afford acid 13
20
(885 mg, 91%) as a viscous, colorless oil. [a]D20
ˆ
28.6, [a]
ˆ
33.4 (c ˆ
546
1.0, CHCl3); IR (film): nÄmax ˆ 2936, 2710, 1719, 1460, 1389, 1303, 1255, 1099,
1
986, 843, 774, 670 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 4.70 ± 4.58 (m,
2H; H-13), 4.38 (dd, 3J ˆ 6.8 Hz, 3J ˆ 3.0 Hz, 1H; H-3), 3.79 (dd, 3J ˆ
7.2 Hz, 3J ˆ 1.7 Hz, 1H; H-7), 3.14 (dq, 3J ˆ 7.0 Hz, 3J ˆ 7.0 Hz, 1H; H-6),
2.49 (dd, 2J ˆ 16.4 Hz, 3J ˆ 3.1 Hz, 1H; H-2), 2.30 (dd, 2J ˆ 16.4 Hz, 3J ˆ
6.8 Hz, 1H; H-2), 2.04 ± 1.91 (m, 2H; H-11), 1.69 (s, 3H; C12-CH3), 1.57 ±
0.96 (m, 5H; H-8, H-9, H-10), 1.23, 1.09 (2s, 2  3H; C4-CH3), 1.05 (d, 3J ˆ
6.9 Hz, 3H; C6-CH3), 0.92 (d, 3J ˆ 7.1 Hz, 3H; C8-CH3), 0.90, 0.88 (2s, 2 Â
9H; OSiC(CH3)3), 0.09, 0.05, 0.05, 0.04 (4s, 4 Â 3H; OSi(CH3)2); 13C NMR
(100 MHz, CDCl3): d ˆ 218.1, 178.2, 145.9, 109.8, 77.6, 73.5, 53.5, 45.2, 40.2,
38.7, 38.3, 30.4, 26.2, 26.0, 25.7, 23.7, 22.3, 19.1, 18.5, 18.2, 17.7, 15.7, 3.6,
‡
3.8, 4.3, 4.6; MS (PCI, CH4): m/z (%): 557.5 (46) [M‡H] , 541.5 (89)
‡
‡
[M CH3] , 499.4 (100) [M tBu] , 453.4 (7), 445.4 (9), 425.4 (48), 417.4
(68), 409.4 (22), 401.4 (44); C30H60O5Si2 (557.0) calcd C 64.69, H 10.86;
found C 64.89, H 10.96.
obtained by flash chromatography (pentane/Et2O 5:1). [a]D20
ˆ
2.1,
20
[a]
ˆ
2.5 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 3337, 2916, 1641, 1457,
546
1
1044, 993, 912 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 5.86 ± 5.75 (m, 1H;
H-4), 5.17 ± 4.99 (m, 2H; H-5), 3.53 ± 3.40 (m, 2H; H-1), 2.22 ± 2.14 (m, 1H;
H-3), 2.04 (brs, 1H; OH), 1.97 ± 1.89 (m, 1H; H-3), 1.78 ± 1.66 (m, 1H; H-2),
0.92 (d, 3J ˆ 6.8 Hz, 3H; C2-CH3); 13C NMR (100 MHz, CDCl3): d ˆ 136.9,
(1S)-1-[(E)-1-Methyl-2-(2-methyl-1,3-thiazol-4-yl)-1-ethenyl-3-butenyl
(3S,6R,7S,8S)-3,7-di-[tert-butyldimethylsilyloxy]-4,4,6,8,12-pentamethyl-
5-oxo-12-tridecenoate (14): DCC (91 mg, 0.44 mmol, 1.1 equiv) was added
at 08C to a solution of acid 13 (223 mg, 0.40 mmol), thiazole alcohol 4
(84 mg, 0.40 mmol) and DMAP (7.3 mg, 0.06 mmol, 0.15 equiv) in CH2Cl2
(5 mL). The mixture was stirred for 10 min at 08C and for 16 h at room
temperature The solvent was removed in vacuo and the residue was
‡
116.0, 67.7, 37.8, 35.5, 16.3; MS (PCI, CH4): m/z (%): 101 (21) [M‡H] , 99
‡
(32), 83 (100) [M‡H H2O] , 81 (34), 71 (11), 55 (12).
tert-Butyldimethyl-{[(2S)-2-methyl-4-pentenyl]oxy}silane (21): Imidazole
(4.121 g, 60.5 mmol, 2.6 equiv) and TBSCl (30.3 mmol, 1.3 equiv) were
added to a solution of the crude alcohol 20 (2.669 g ꢀ 23.3 mmol) in DMF
(15 mL). The mixture was stirred for 24 h at room temperature. Flash
chromatography of the reaction mixture (pentane/Et2O 20:1) gave silyl
purified by flash chromatography (pentane/Et2O 20:1) to afford ester 14
20
(183 mg, 61%) as a colorless oil. [a]D20
ˆ
38.8, [a]
ˆ
46.9 (c ˆ 0.1,
546
CHCl3) [Lit.:[3b] [a]D
ˆ
55.1 (c ˆ 0.85, CHCl3)]; IR (film): nÄmax ˆ 2930,
1
1737, 1697, 1472, 1377, 1254, 1179, 1085, 989, 836, 776 cm
;
1H NMR
ether[17a] 22 (3.991 g, 80% over two steps) as a colorless oil. [a]2D0
ˆ
1.0,
20
(400 MHz, CDCl3): d ˆ 6.94 (s, 1H; thiazole H-5), 6.49 (s, 1H; H-2''), 5.78 ±
5.65 (m, 2H; H-3'), 5.30 (t, 3J ˆ 6.7 Hz, 1H; H-1'), 5.13 ± 5.00 (m, 2H; H-4'),
4.70 ± 4.62 (m, 2H; H-13), 4.34 (dd, 3J ˆ 6.0 Hz, 3J ˆ 3.6 Hz, 1H; H-3), 3.73
(dd, 3J ˆ 6.8 Hz, 3J ˆ 2.0 Hz, 1H; H-7), 3.19 ± 3.11 (m, 1H; H-6), 2.70 (s,
3H; thiazole CH3), 2.53 (dd, 2J ˆ 17.0 Hz, 3J ˆ 3.6 Hz, 1H; H-2), 2.53 ± 2.40
(m, 2H; H-2'), 2.29 (dd, 2J ˆ 17.0 Hz, 3J ˆ 6.1 Hz, 1H; H-2), 2.07 (d, 4J ˆ
1.2 Hz, 3H; C1''-CH3), 2.01 ± 1.94 (m, 2H; H-11), 1.69 (s, 3H; C12-CH3),
1.61±0.94 (m, 5H; H-8, H-9, H-10), 1.23 (s, 3H; C4-CH3), 1.04 (d, 3J ˆ
6.8 Hz, 3H; C6-CH3), 1.03 (s, 3H; C4-CH3), 0.89 (d, 3J ˆ 7.1 Hz, 3H; C8-
CH3), 0.89, 0.88 (2s, 2 Â 9H; OSiC(CH3)3), 0.10, 0.05, 0.03, 0.03 (4s, 4 Â 3H;
OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 217.7, 171.2, 164.5, 152.6,
146.0, 136.8, 133.4, 121.1, 117.8, 116.4, 109.8, 78.7, 77.6, 74.1, 53.3, 45.2, 40.3,
38.8, 38.3, 37.5, 30.6, 26.2, 26.0, 25.7, 23.2, 22.3, 20.4, 19.2, 18.5, 18.2, 17.6,
15.4, 14.6, 3.6, 3.8, 4.3, 4.7; MS (PCI, NH3): m/z (%): 748 (85)
[a]
ˆ
1.2 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 2957, 2858, 1472, 1256, 1095,
546
1
911, 838, 775 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 5.85 ± 5.73 (m, 1H,
H-4), 5.04 ± 4.96 (m, 2H; H-5), 3.44 (dd, 2J ˆ 9.8 Hz, 3J ˆ 6.2 Hz, 1H; H-1),
3.40 (dd, 2J ˆ 9.8 Hz, 3J ˆ 6.2 Hz, 1H; H-1), 2.23 ± 2.15 (m, 1H; H-3), 1.90 ±
1.81 (m, 1H; H-3), 1.73 ± 1.61 (m, 1H; H-2), 0.90 (s, 9H, OSiC(CH3)3), 0.87
(d, 3J ˆ 6.7 Hz, 3H; C2-CH3), 0.04 (s, 6H, OSi(CH3)2); 13C NMR (100 MHz,
CDCl3): d ˆ 137.4, 115.6, 67.8, 37.7, 35.7, 26.0, 18.3, 16.4, 5.4; MS (PCI,
‡
CH4): m/z (%): 215.2 (22) [M‡H] , 213.1 (72), 208.9 (100), 199.1 (34) [M
‡
‡
CH3] , 157.0 (21) [M tBu] , 145.0 (14), 133.0 (38), 82.8 (32).
1-(tert-Butyldimethylsilyl) [(2S)-5-iodo-2-methylpentyl] ether (16): BH3 ´
THF (1.0m solution in THF, 5.94 mL, 1.2 equiv) was added dropwise at 08C
to a solution of silyl ether 21 (3.184 g, 14.85 mmol) in THF (5 mL) was
added. The mixture was stirred for 1 h at room temperature. MeOH
(0.5 mL) and NaOAc (1.0m solution in MeOH, 14.85 mL, 1 equiv) were
added at 08C, followed by the addition of ICl (1.0m solution in CH2Cl2,
14.85 mL, 1 equiv) within 30 min at 08C. The reaction mixture was stirred
for 30 min at room temperature, quenched with Na2S2O3 (1.0m aqueous
solution, 40 mL), and extracted with pentane/Et2O (20:1, 3 Â 100 mL). The
combined organic extracts were dried over MgSO4 and concentrated in
vacuo. Purification of the crude product by flash chromatography (pentane/
‡
[M‡H] , 520 (12), 447 (75), 419 (51), 391 (57), 363 (12), 192 (100), 123 (11);
C41H73NO5SSi2 (748.3) calcd C 65.81, H 9.83, N 1.87, S 3.93; found C 66.30,
H 10.06, N 1.92, S 3.91.
(4R)-4-Benzyl-3-[(2S)-2-methyl-4-pentenoyl]-1,3-oxazolidin-2-one (19): A
solution of NaHMDS (1.0m in THF, 47.25 mL, 47.25 mmol, 1.05 equiv) was
added dropwise to a solution of (4R)-4-benzyl-3-propionyl-1,3-oxazolidin-
2-one (18)[18] (10.50 g, 45.0 mmol) in THF (120 mL) at 788C. The reaction
Et2O 20:1) gave known[17a] alkyl iodide 16 (3.067 g, 60%) as a colorless oil.
20
[a]2D0
ˆ
5.8, [a]
ˆ
7.2 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 2956, 2857,
546
mixture was stirred for 1 h at
788C, and 3-iodopropene (6.20 mL,
1472, 1256, 1095, 837, 775 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 3.42 (dd,
2J ˆ 9.8 Hz, 3J ˆ 6.3 Hz, 1H; H-1), 3.39 (dd, 2J ˆ 9.8 Hz, 3J ˆ 6.2 Hz, 1H;
H-1), 3.23 ± 3.13 (m, 2H; H-5), 1.96 ± 1.76 (m, 2H), 1.66 ± 1.44 (m, 2H),
1.33 ± 1.12 (m, 1H)(H-2, H-3, H-4), 0.89 (s, 9H, OSiC(CH3)3), 0.88 (d, 3J ˆ
6.5 Hz, 3H; C2-CH3), 0.04 (s, 6H, OSi(CH3)2); 13C NMR (100 MHz,
CDCl3): d ˆ 68.1, 35.0, 34.3, 31.3, 25.9, 18.3, 16.7, 7.3, 5.4; MS (PCI, CH4):
67.5 mmol, 1.5 equiv) was added dropwise. The mixture was stirred for 4 h
at 788C, allowed to warm to room temperature, and quenched with
saturated NH4Cl solution (45 mL). The organic layer was separated and the
aqueous layer was extracted with Et2O (3 Â 90 mL). The combined organic
extracts were dried over MgSO4 and concentrated in vacuo. Purification of
the crude product (10:1 ratio of diastereomers by 1H NMR) by flash
chromatography (pentane/Et2O 4:1) gave oxazolidinone 19 (7.56 g, 61%)
‡
‡
m/z (%): 343.0 (100) [M‡H] , 327.0 (63) [M CH3] , 284.9 (71) [M
‡
as a colorless oil, which crystallized upon standing. M.p. 288C; [a]D20
ˆ
tBu] , 215.1 (79), 210.9 (33), 83.0 (7).
41.7 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 2982, 1782, 1699, 1381, 1243,
(3S)-3-Hydroxytetrahydrofuranone (23): A solution of (5S)-(2,2-cyclo-
hexylidene-4-oxo-1,3-dioxolan-5-yl)acetic acid 22[20] (15.04 g, 70.2 mmol) in
THF (70 mL) was added dropwise to a mixture cooled to 08C of BH3 ´ Me2S
complex (100 mL, 200.0 mmol, 2.0m) and B(OMe)3 (24.2 mL, 200.0 mmol)
in THF (175 mL). The reaction mixture was stirred for 24 h at room
temperature and cooled to 08C. MeOH (70 mL) was added dropwise. The
1
1210, 1102, 701 cm 1; H NMR (400 MHz, CDCl3): d ˆ 7.37 ± 7.20 (m, 5H;
Ar-H), 5.88 ± 5.77 (m, 1H; H-4'), 5.15 ± 5.04 (m, 2H; H-5'), 4.73 ± 4.64 (m,
1H; H-4), 4.20 (dd, 2J ˆ 9.1 Hz, 3J ˆ 0.7 Hz, 1H; H-5), 4.15 (dd, 2J ˆ 9.1 Hz,
3J ˆ 3.4 Hz, 1H; H-5), 3.91 ± 3.82 (m, 1H; H-2'), 3.29 (dd, 2J ˆ 13.3 Hz, 3J ˆ
3.3 Hz, 1H; C4-CH2), 2.70 (dd, 2J ˆ 13.3 Hz, 3J ˆ 9.8 Hz, 1H; C4-CH2),
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2497 $ 17.50+.50/0
2497

D. Schinzer et al.
FULL PAPER
mixture was stirred for 1 h at room temperature, and the solvents were
removed under reduced pressure to afford a thick oil. This process was
repeated twice with MeOH (105 mL) to afford a colorless oil. The crude
product (a mixture of lactone 23 and (5S)-(1'-hydroxyethyl)-2,2-cyclo-
hexylidene-1,3-dioxolan-4-one) was dissolved in CH2Cl2 (175 mL). pTsO-
H ´ H2O (1.335 g, 7.02 mmol, 0.1 equiv) was added and the mixture was
stirred for 24 h at room temperature. NEt3 (0.98 mL) was added and the
mixture was concentrated in vacuo. Purification of the residue by flash
tert-Butyldimethylsilyl {(1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-
thiazol-4-yl)-1-ethenyl]-3-pentenyl} ether (17): nBuLi (5.14 mL,
12.86 mmol, 1.96 equiv of a 2.5m solution in hexanes) was added at 08C
to a stirred suspension of ethyl triphenylphosphonium iodide (13.12 mmol,
2.0 equiv) in THF (60 mL). The resulting clear red ylide solution was added
dropwise to a rapidly stirred solution of iodine (3.163 g, 12.46 mmol,
1.90 equiv) in THF (90 mL) cooled to
suspension was stirred vigorously for 10 min at 788C and for 30 min at
30 to 408C. solution of NaHMDS (1.0m in THF, 11.81 mL,
788C. The resulting yellow
chromatography (Et2O) gave lactone[21] 23 (5.160 g, 72%) as a colorless oil.
A
20
[a]2D0
ˆ
60.1, [a]
ˆ
71.3 (c ˆ 0.67, CHCl3); IR (film): nÄmax ˆ 3400, 1773,
11.81 mmol, 1.80 equiv) was added dropwise within 10 min at 308C.
The mixture was stirred for 15 min at 308C. A solution of aldehyde 28
(2.137 g, 6.56 mmol) in THF (30 mL) was added dropwise within 10 min.
The mixture was stirred for 10 min at 308C and quenched with saturated
aqueous NH4Cl solution (10 mL). Pentane (150 mL) was added and the
mixture was filtered through a small plug of silica. The column was eluted
with pentane/Et2O (4:1, 400 mL). The filtrate was concentrated in vacuo.
Purification of the residue by flash chromatography (pentane/Et2O 10:1)
546
1
1378, 1221, 1185, 1128, 1015, 947, 719 cm
;
1H NMR (400 MHz, CDCl3):
d ˆ 4.54 (t, 3J ˆ 9.2 Hz, 1H; H-3), 4.43 (td, 3J ˆ 9.0 Hz, 3J ˆ 2.1 Hz, 1H;
H-5), 4.29 ± 4.22 (m, 1H; H-5), 3.90 (s, 1H, OH), 2.66 ± 2.58 (m, 1H; H-4),
2.35 ± 2.26 (m, 1H; H-4); 13C NMR (100 MHz, CDCl3): d ˆ 178.2, 67.4, 65.2,
‡
‡
30.8; MS (PCI, CH4): m/z (%): 116.9 (6) [M‡CH4] , 102.9 (100) [M] , 84.9
(3).
(3S)-3-[(tert-Butyldimethylsilyl)oxy]tetrahydrofuranone (24): Imidazole
(241 mg, 3.54 mmol, 2.2 equiv) and TBSCl (267 mg, 1.77 mmol, 1.1 equiv)
were added to a solution of lactone 23 (164 mg, 1.61 mmol) in DMF
(1.5 mL). The mixture was stirred for 24 h at room temperature. Flash
gave vinyl iodide 17 (1.640 g, 54%) as a pale yellow oil. [a]2D0 ˆ ‡14.2,
20
[a] ˆ ‡18.5 (c ˆ 1.0, CHCl3); IR (film): nÄmax ˆ 2955, 2857, 1652, 1507,
546
1472, 1252, 1184, 1067, 837, 777 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 6.91
(s, 1H; H-5''), 6.49 (s, 1H; H-2'), 5.46 (td, 3J ˆ 6.7 Hz, 4J ˆ 1.5 Hz, 1H; H-3),
chromatography (pentane/Et2O 10:1) of the reaction mixture afforded silyl
3
4
4.21 (t, J ˆ 6.3 Hz, 1H; H-1), 2.71 (s, 3H; C2''-CH3), 2.48 (d, J ˆ 1.4 Hz,
3H; H-5), 2.44 ± 2.29 (m, 2H; H-2), 2.02 (d, 4J ˆ 1.1 Hz, 3H; C1'-CH3), 0.90
(s, 9H, OSiC(CH3)3), 0.06, 0.02 (2s, 2 Â 3H; OSi(CH3)2); 13C NMR
(100 MHz, CDCl3): d ˆ 164.4, 153.1, 141.7, 132.1, 118.9, 115.2, 102.3, 77.3,
43.7, 33.7, 25.8, 19.2, 18.2, 14.1, 4.7, 5.0; MS (PCI, CH4): m/z (%): 464.4
20
ether 24 (321 mg, 93%) as a colorless oil. [a]D20
ˆ
31.7, [a]
ˆ
37.4 (c ˆ
546
0.86, CHCl3); IR (film): nÄmax ˆ 2931, 2859, 1790, 1473, 1362, 1254, 1154,
1
1022, 840, 781 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 4.43 ± 4.35 (m, 2H;
H-5, H-3), 4.22 ± 4.15 (m, 1H; H-5), 2.49 ± 2.41 (m, 1H; H-4), 2.27 ± 2.21 (m,
1H; H-4), 0.91 (s, 9H, OSiC(CH3)3), 0.17, 0.14 (2s, 2 Â 3H; OSi(CH3)2);
13C NMR (100 MHz, CDCl3): d ˆ 175.8, 68.2, 64.7, 32.3, 25.6, 18.2, 4.8,
‡
‡
‡
(100) [M‡H] , 448.3 (32) [M CH3] , 423.3 (3), 406.2 (16) [M tBu] ,
369.2 (5), 332.0 (50), 282.1 (63), 232.3 (11), 229.1 (23), 205.1 (28);
C18H30INOSSi (463.5): calcd C 46.65, H 6.52, N 3.02, S 6.92; found C
46.67, H 6.77, N 3.12, S 6.57.
‡
‡
5.3; MS (70 eV, EI): m/z (%): 217.1 (20) [M‡H] , 201.0 (81) [M CH3] ,
‡
189.0 (6), 171.0 (78), 159.2 (79) [M tBu] , 146.8 (13), 145.0 (16), 130.9
(100), 114.9 (92), 102.9 (35), 100.9 (37); HRMS (EI): calcd for C6H11O3Si
‡
[M tBu] 159.0477, found 159.047.
4-[(1E,3S,5Z,10S)-3,11-Di-(tert-butyldimethylsilyloxy)-2,6,10-trimethyl-
1,5-undecadienyl]-2-methyl-1,3-thiazole (29): 1,2-Dibromoethane (35 mL)
(3S)-3,5-Di-[(tert-butyldimethylsilyl)oxy]pentan-2-one
(25):
MeLi
was added to
a
suspension of powdered Zn/Cu couple[25] (477 mg,
(0.67 mL, 1.11 mmol, 1.1 equiv of a 1.65m solution in Et2O) was added
dropwise to a stirred solution cooled to 788C of silyl ether 24 (218 mg,
1.01 mmol) in THF (4 mL). After stirring at 788C for 3 h, the reaction
was quenched by the addition of glacial acetic acid (72 mL, 1.26 mmol,
1.25 equiv). Et2O (20 mL) and saturated aqueous NaHCO3 solution
(10 mL) were added. The organic layer was separated after stirring for
5 min, and the aqueous layer was extracted with Et2O (2 Â 20 mL). The
combined organic extracts were dried (MgSO4) and concentrated in vacuo
to give crude (3S)-3-[(tert-butyldimethylsilyl)oxy]-2-methyl-tetrahydrofur-
7.27 mmol, 2.3 equiv) in benzene (11 mL). The mixture was heated for a
few seconds under reflux. After cooling to room temperature, TMSCl
(35 mL) was added and the mixture was stirred for 5 min. DMAc (0.75 mL)
and alkyl iodide 16 (1.623 g, 4.74 mmol, 1.5 equiv) in benzene (4 mL) were
added. The mixture was stirred for 2.5 h at 608C. TESOTf (20 mL) and
DMAc (0.75 mL) were added and the mixture was heated under reflux for
1 h. After cooling to room temperature, [Pd(PPh3)4] (140 mg, 4 mol%) was
added and the mixture was stirred for 5 min. A solution of vinyl iodide 17
(1.463 g, 3.16 mmol) in benzene (3 mL) was added. The mixture was stirred
for 30 min at 608C, cooled to room temperature, and quenched with
saturated aqueous NH4Cl solution (5 mL). The organic layer was separated
and the aqueous layer was extracted with MeOtBu (3 Â 30 mL). The
combined organic extracts were dried over MgSO4 and concentrated in
vacuo. Purification of the residue by flash chromatography (pentane/Et2O
an-2-ol (235 mg, 93%) as
a colorless crystalline solid (mixture of
diastereomers), which was used for the synthesis of ketone 25 without
further purification: Imidazole (125 mg, 1.84 mmol, 2.2 equiv) and TBSCl
(139 mg, 0.92 mmol, 1.1 equiv) were added to
[(tert-butyldimethylsilyl)oxy]-2-methyl-tetrahydrofuran-2-ol
a
solution of (3S)-3-
(194 mg,
0.83 mmol) in DMF (0.80 mL). The mixture was stirred for 24 h at room
temperature. Purification of the reaction mixture by flash chromatography
(pentane/Et2O 20:1) afforded ketone 25 (226 mg, 78%) as a colorless oil.
25:1) afforded coupling product 29 (1.458 g, 84%) as a colorless oil. [a]D20
ˆ
20
‡12.2, [a] ˆ ‡9.3 (c ˆ 1.25, CHCl3); IR (film): nÄmax ˆ 2930, 2858, 1472,
546
1361, 1256, 1184, 1092, 940, 837, 776 cm 1; 1H NMR (200 MHz, CDCl3): d ˆ
20
[a]2D0
ˆ
11.8, [a]
ˆ
14.1 (c ˆ 1.0, CHCl3), identical (1H and 13C NMR,
546
6.92 (s, 1H; H-5'), 6.45 (s, 1H; H-11), 5.18 ± 5.06 (m, 1H; H-5), 4.07 ± 4.03
IR, EI-MS) with 25 obtained by the Sharpless resolution protocol described
in the preceding paper.[9] Compound 25 was transformed to thiazole
alcohol 27 by Horner± Emmons reaction and selective desilylation
according to the method applied in the preceding paper.[9]j
2
3
2
(m, 1H; H-3), 3.44 (dd, J ˆ 9.8 Hz, J ˆ 5.8 Hz, 1H; H-11), 3.34 (dd, J ˆ
3
9.7 Hz, J ˆ 6.6 Hz, 1H; H-11), 2.70 (s, 3H; C2'-CH3), 2.31 ± 2.17 (m, 2H;
H-4), 2.04 ± 1.95 (m, 2H; H-7), 1.99 (d, 4J ˆ 1.2 Hz, 3H; C2-CH3), 1.58 (s,
3H; C6-CH3), 1.66 ± 1.53 (m, 2H), 1.46 ± 0.95 (m, 3H)(H-8, H-9, H-10), 0.89
3
(s, 18H, OSiC(CH3)3), 0.87 (d, J ˆ 7.0 Hz, 3H; C10-CH3), 0.04, 0.03, 0.03,
(3S,4E)-3-[(tert-Butyldimethylsilyl)oxy]-4-methyl-5-(2-methyl-1,3-thiazol-
4-yl)-4-pentenal (28): A solution of DMSO (2.04 mL, 28.8 mmol, 2.4 equiv)
in CH2Cl2 (6 mL) was added dropwise at 788C to a stirred solution of
(COCl)2 (1.14 mL, 13.2 mmol, 1.1 equiv) in CH2Cl2 (30 mL) within 5 min.
The mixture was stirred for 10 min at 708C. A solution of thiazole alcohol
27 (3.93 g, 12.0 mmol) in CH2Cl2 (5 mL) was added dropwise within 5 min.
The mixture was stirred for 30 min at 708C. The reaction was quenched
by dropwise addition of NEt3 (8.4 mL, 60.0 mmol). The mixture was
warmed to room temperature within 45 min. Water (30 mL) was added and
the mixture was stirred for 10 min. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 Â 100 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
Purification of the residue by flash chromatography (pentane/Et2O 5:2)
0.00 (4s, 4  3H; OSi(CH3)2); 13C NMR (50 MHz, CDCl3): d ˆ 164.4, 153.3,
142.6, 136.9, 121.4, 118.6, 114.9, 79.0, 68.4, 35.8, 35.3, 33.2, 32.3, 26.0, 25.8,
25.4, 23.5, 19.2, 18.3, 18.2, 16.7, 13.9, 4.7, 4.9, 5.3; MS (70 eV, EI): m/z
‡
‡
‡
(%): 551 (0.5) [M] , 536 (1.7) [M CH3] , 494 (3.5) [M tBu] , 282 (100)
[C14H24NOSSi] , 173 (2), 91 (22), 73 (21); HRMS (EI): calcd for
‡
‡
C29H54NO2SSi2 [M CH3] 536.3414, found 536.342.
(2S,6Z,9S,10E)-9-(tert-Butyldimethylsilyloxy)-2,6,10-trimethyl-11-(2-
methyl-1,3-thiazol-4-yl)-undeca-6,10-dien-1-ol
(30): CSA
(366 mg,
1.56 mmol, 1.05 equiv) was added over a 5 min period at 08C to a solution
of the coupling product 29 (828 mg, 1.5 mmol) in a mixture of CH2Cl2
(15 mL) and MeOH (15 mL). The mixture was stirred for 30 min at 08C
and for 3 h at room temperature, quenched with NEt3 (0.22 mL, 1.56 mmol,
1.05 equiv) and concentrated in vacuo. After flash chromatography
afforded aldehyde 28 (3.21 g, 82%) as a pale yellow oil. [a]D20
ˆ
19.2,
20
[a]
ˆ
22.1 (c ˆ 1.0, CHCl3), identical (1H and 13C NMR, IR, EI-MS)
(pentane/Et2O 1:1) of the residue, alcohol 30 (582 mg, 82%) was obtained
546
20
with 28 obtained by the Dess ± Martin oxidation protocol.[9]
as a colorless oil. [a]2D0 ˆ ‡7.6, [a] ˆ ‡10.5 (c ˆ 1.0, CHCl3); IR (film):
546
2498
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2498 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Epothilone B
2492±2500
1
nÄmax ˆ 3362, 2930, 2857, 1463, 1361, 1253, 1186, 1075, 940, 837, 776 cm
;
118.6, 114.9, 98.5, 79.1, 74.7, 74.4, 59.9, 51.6, 41.3, 35.4, 35.3, 33.0, 32.4, 29.8,
25.8, 25.2, 25.1, 23.5, 21.6, 19.2, 19.0, 18.6, 18.2, 15.4, 13.9, 9.3, 4.7, 4.9;
MS (70 eV, EI): m/z (%): 650 (3) [M] , 436 (5), 282 (100) [C14H24NOSSi] ,
167 (10), 149 (21), 115 (12), 73 (25); C36H63NO5SSi (650.0): C 66.46, H 9.69,
N 2.15, S 4.99; found C 66.37, H 9.34, N 2.42, S 4.72.
1H NMR (400 MHz, CDCl3): d ˆ 6.92 (s, 1H; H-5'), 6.45 (s, 1H; H-11),
5.18 ± 5.12 (m, 1H; H-7), 4.11 ± 4.06 (m, 1H; H-9), 3.50 (dd, 2J ˆ 10.5 Hz,
3J ˆ 5.9 Hz, 1H; H-1), 3.41 (dd, 2J ˆ 10.4 Hz, 3J ˆ 6.4 Hz, 1H; H-1), 2.70 (s,
3H; C2'-CH3), 2.32 ± 2.17 (m, 2H; H-8), 2.09 ± 1.92 (m, 2H; H-5), 1.98 (d,
4J ˆ 1.2 Hz, 3H; C10-CH3), 1.67 (s, 3H; C6-CH3), 1.65 (brs, 1H; OH),
1.64 ± 1.52 (m, 2H), 1.48 ± 1.30 (m, 2H), 1.13 ± 1.03 (m, 1H)(H-2, H-3, H-4),
0.89 (s, 9H, OSiC(CH3)3), 0.89 (d, 3J ˆ 6.9 Hz, 3H; C2-CH3), 0.04, 0.00 (2s,
2  3H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 164.4, 153.1, 142.7,
136.8, 121.7, 118.7, 114.8, 79.2, 68.2, 35.7, 35.5, 33.1, 32.2, 25.8, 25.3, 23.5, 19.1,
‡
‡
(3S,6S,7S,8S,12Z,15S,16E)-1,3,7-Trihydroxy-15-[(tert-butyldimethyl-
silyl)oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-
heptadecadien-5-one (32): PPTS (6.0 mg, 24 mmol, 0.6 equiv) was added to
a solution of aldol product 31 (26 mg, 0.04 mmol) in MeOH (0.5 mL). The
mixture was stirred for 22 h at room temperature. Another portion of PPTS
(4.0 mg, 16 mmol, 0.4 equiv) was added and stirring was continued for 50 h
at room temperature. The solvent was removed in vacuo and the residue
‡
18.2, 16.6, 13.9, 4.7, 4.9; MS (70 eV, EI): m/z (%): 437.4 (0.2) [M] , 422.2
(0.4) [M CH3] , 380.2 (0.6) [M tBu] , 297.1 (2), 282.1 (100)
[C14H24NOSSi] , 240.0 (3), 165.9 (8), 73.0 (79); HRMS (EI): calcd for
‡
‡
‡
was purified by flash chromatography (Et2O) to give triol 32 (21 mg, 86%)
20
as a colorless oil. [a]D20
ˆ
7.0, [a]
ˆ
8.0 (c ˆ 0.3, CHCl3); IR (film):
C24H43NO2SSi 437.2784, found 437.275.
546
1
nÄmax ˆ 3396, 2930, 2857, 1687, 1470, 1374, 1257, 1060, 973, 836, 776 cm
;
(2S,6Z,9S,10E)-9-(tert-Butyldimethylsilyloxy)-2,6,10-trimethyl-11-(2-me-
thyl-1,3-thiazol-4-yl)-undeca-6,10-dienal (15): Pyridine (73 mL, 0.91 mmol)
was added to a stirred solution of Dess ± Martin periodinane[13] (386 mg,
0.91 mmol, 1.3 equiv) in CH2Cl2 (5 mL). The mixture was cooled to 08C
and a solution of alcohol 30 (306 mg, 0.7 mmol) in CH2Cl2 (5 mL) was
added dropwise. The mixture was stirred for 30 min at room temperature.
Et2O (30 mL), pyridine (146 mL, 1.82 mmol), and buffered aqueous
Na2S2O3 solution (10 mL, 0.5m, pH 7) were added. The organic layer was
separated and the aqueous layer was extracted with MeOtBu (2 Â 20 mL).
The combined organic layers were dried (MgSO4) and concentrated in
vacuo. Purification of the residue by flash chromatography (pentane/Et2O
1H NMR (400 MHz, CDCl3): d ˆ 6.92 (s, 1H, H-5'), 6.44 (s, 1H; H-17),
5.18 ± 5.12 (m, 1H; H-13), 4.10 ± 4.03 (m, 2H; H-15, H-3), 3.94 ± 3.91 (m,
2H; H-1), 3.51 (brd, 3J ˆ 3.7 Hz, 1H; C7-OH), 3.36 (d, 3J ˆ 8.9 Hz, 1H;
H-7), 3.30 (brs, 1H; OH), 3.28 (dq, 3J ˆ 6.9 Hz, 3J ˆ 1.8 Hz, 1H; H-6), 2.77
(brs, 1H; OH), 2.72 (s, 3H; C2'-CH3), 2.26 ± 2.15 (m, 2H; H-14), 2.05 ± 1.93
(m, 2H; H-11), 1.98 (d, 4J ˆ 1.3 Hz, 3H; C16-CH3), 1.78 ± 1.40 (m, 5H; H-2,
H-8, H-9, H-10), 1.67 (d, 4J ˆ 1.1 Hz, 3H; C12-CH3), 1.38 ± 0.91 (m, 2H;
3
H-9, H-10), 1.22, 1.13 (2s, 2  3H; C4-CH3), 1.06 (d, J ˆ 6.9 Hz, 3H; C6-
CH3), 0.89 (s, 9H; OSiC(CH3)3), 0.86 (d, 3J ˆ 6.8 Hz, 3H; C8-CH3), 0.05,
0.00 (2s, 2  3H; OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 223.3,
164.5, 153.1, 142.7, 136.8, 121.6, 118.7, 114.8, 79.2, 76.3, 74.4, 62.1, 52.7, 41.1,
35.6, 35.4, 32.8, 32.5, 32.3, 25.8, 25.1, 23.5, 21.6, 19.1, 18.5, 18.2, 15.5, 13.8,
5:1) gave aldehyde[3g] 15 (295 mg, 97%) as a pale yellow oil. [a]2D0 ˆ ‡19.9,
[a] ˆ ‡25.5 (c ˆ 1.7, CHCl3) [Lit.:[3g] [a]D ˆ ‡14.7 (c ˆ 1.7, CHCl3)]; IR
20
546
‡
10.1, 4.0, 4.3; MS (PCI, CH4): m/z (%): 610.7 (0.2) [M] , 536.5 (1.0)
[M tBu] , 464.3 (10), 420.3 (13), 378.2 (11), 304.1 (81), 282.0 (42)
[C14H24NOSSi] , 175.9 (15), 157.0 (22), 139.0 (17), 100.9 (100), 83.0 (50),
57.0 (70); HRMS (EI): calcd for C32H56NO5SSi [M CH3] 594.3649, found
(film): nÄmax ˆ 2930, 2857, 1727, 1507, 1463, 1389, 1255, 1184, 1076, 940, 837,
‡
777 cm 1; H NMR (400 MHz, CDCl3): d ˆ 9.60 (d, J ˆ 2.0 Hz, 1H; H-1),
6.91 (s, 1H; H-5'), 6.45 (s, 1H; H-11), 5.19 ± 5.13 (m, 1H; H-7), 4.11 ± 4.06
(m, 1H; H-9), 2.71 (s, 3H; C2'-CH3), 2.35 ± 2.17 (m, 3H), 2.10 ± 1.95 (m,
2H), 2.00 (d, 4J ˆ 1.1 Hz, 3H; C10-CH3), 1.66 (d, 4J ˆ 1.0 Hz, 3H; C6-CH3),
1.72 ± 1.61 (m, 1H), 1.45 ± 1.22 (m, 3H)(H-2, H-3, H-4, H-8), 1.08 (d, 3J ˆ
7.0 Hz, 3H; C2-CH3), 0.88 (s, 9H, OSiC(CH3)3), 0.04, 0.00 (2s, 2 Â 3H;
OSi(CH3)2); 13C NMR (100 MHz, CDCl3): d ˆ 205.1, 164.4, 153.2, 142.5,
136.1, 122.1, 118.7, 115.0, 78.9, 46.3, 35.4, 31.8, 30.4, 25.8, 25.2, 23.4, 19.2,
1
3
‡
‡
594.361.
(3S,6S,7S,8S,12Z,15S,16E)-1,3,7,15-Tetra[(tert-butyl-dimethylsilyl)oxy]-
4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadeca-
dien-5-one (33): 2,6-Lutidine (29 mL, 247.5 mmol, 2.5 equiv) was added to a
solution of triol 32 (20.0 mg, 33 mmol) in CH2Cl2 (0.2 mL). The mixture was
cooled to 508C and TBSOTf (34 mL, 148.5 mmol, 1.5 equiv) was added.
The mixture was allowed to warm to 08C and stirring was continued for 2 h
at 08C. The solvent was removed in vacuo and the residue was purified by
‡
18.2, 14.0, 13.3, 4.7, 4.9; MS (70 eV, EI): m/z (%): 435 (0.48) [M] , 420
(0.90) [M CH3] , 378 (0.82) [M tBu] , 303 (3), 282 (100)
[C14H24NOSSi] , 75 (8), 73 (6); HRMS (EI): calcd for C24H41NO2SSi
‡
‡
‡
flash chromatography (pentane/Et2O 20:1). The tetrakis-silyl ether[3g] 33
435.2627, found 435.263.
20
(30 mg, 95%) was obtained as a colorless oil. [a]D20
ˆ
13.7, [a]
ˆ
15.7
546
(4S,5S,6S,7S,10Z,13S,14E)-13-[(tert-Butyldimethylsilyl)oxy]-2-[(4R)-2,2-
dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6,10,14-pentamethyl-15-(1,3-thia-
zol-4-yl)-10,14-pentadecadien-3-one (31): A solution of ethyl ketone 2
(64 mg, 0.3 mmol, 1 equiv) in THF (0.5 mL) was added dropwise at 788C
to a freshly prepared solution of LDA [nBuLi (118 mL, 0.294 mmol,
0.98 equiv of a 2.5m solution in hexanes) was added to a solution of
diisopropylamine (41.6 mL, 0.294 mmol) in THF (0.5 mL) at 08C]. The
mixture was stirred for 30 min at 08C. The solution was stirred for 1 h at
788C. A solution of aldehyde 15 (65 mg, 0.15 mmol, 0.5 equiv) in THF
(0.6 mL) was added dropwise and stirring was continued for 20 min at
788C. The mixture was quenched by dropwise addition of saturated
NH4Cl solution (2 mL). The organic layer was separated and the aqueous
layer was extracted with Et2O (3 Â 5 mL). The combined organic extracts
were dried (MgSO4) and concentrated in vacuo. Purification of the residue
by flash chromatography (pentane/Et2O 10:1, then 5:1) afforded anti Cram
(6R,7S) aldol product 31 (83 mg, 85%) and its corresponding Cram (6S,7R)
(c ˆ 0.1, CHCl3) [Lit.:[3g] [a]D
ˆ
10.8 (c ˆ 0.5, CHCl3)]; IR (film): nÄmax
ˆ
1
2929, 2857, 1698, 1473, 1388, 1362, 1256, 1093, 986, 836, 775, 669 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 6.91 (s, 1H, H-5'), 6.45 (s, 1H; H-17),
3
5.17 ± 5.10 (m, 1H; H-13), 4.10 ± 4.05 (m, 1H; H-15), 3.88 (dd, J ˆ 7.5 Hz,
3J ˆ 2.7 Hz, 1H; H-3), 3.76 (dd, 3J ˆ 6.7 Hz, 3J ˆ 1.9 Hz, 1H; H-7), 3.71 ±
3.64 (m, 1H), 3.62 ± 3.54 (m, 1H; H-1), 3.18 ± 3.11 (m, 1H; H-6), 2.71 (s, 3H;
C2'-CH3), 2.31 ± 2.17 (m, 2H; H-14), 2.01 ± 1.93 (m, 2H; H-11), 1.99 (d, 4J ˆ
1.1 Hz, 3H; C16-CH3), 1.66 (s, 3H; C12-CH3), 1.64 ± 1.01 (m, 7H; H-2, H-8,
H-9, H-10), 1.22 (s, 3H; C4-CH3), 1.04 (d, 3J ˆ 6.9 Hz, 3H; C6-CH3), 1.02 (s,
3H; C4-CH3), 0.93 ± 0.86 (m, 39H; C8-CH3, 4 Â OSiC(CH3)3), 0.09, 0.07,
0.06, 0.04, 0.03, 0.02 (6s, 6 Â 3H; OSi(CH3)3), 0.00 (s, 6H; OSi(CH3)2);
13C NMR (100 MHz, CDCl3): d ˆ 218.3, 164.3, 153.3, 142.5, 136.8, 121.6,
118.7, 114.9, 79.0, 77.5, 74.0, 61.0. 53.7, 45.0, 39.0, 38.1, 35.3, 32.6, 31.0, 29.7,
26.2, 26.1, 26.0, 25.9, 24.5, 23.5, 19.4, 19.2, 18.5, 18.3, 18.2, 18.1, 17.6, 15.2,
13.9, 3.6, 3.7, 3.8, 4.0, 4.6, 4.9, 5.2, 5.3; MS (PCI, CH4): m/z
‡
‡
‡
(%): 952.7 (27) [M‡H] , 936.7 (14) [M CH3] , 894.6 (5) [M tBu] ,
diastereomer (9 mg, 9.5%) (ratio 9:1 by HPLC) as colorless oils. (6R,7S)
820.6 (16), 634.4 (16), 624.4 (9), 550.4 (100), 435.6 (16), 303.1 (67), 282.0
20
Isomer: [a]2D0
ˆ
25, [a]
ˆ
27 (c ˆ 0.1, CHCl3); IR (film): nÄmax ˆ 3505,
546
‡
(95) [C14H24NOSSi] , 231.0 (10), 188.9 (16), 132.9 (22); HRMS (EI): calcd
2931, 2858, 1686, 1472, 1373, 1255, 1197, 1098, 971, 837, 777 cm 1; 1H NMR
(400 MHz, CDCl3): d ˆ 6.91 (s, 1H, H-5''), 6.45 (s, 1H; H-15), 5.17 ± 5.09
(m, 1H; H-11), 4.10 ± 4.06 (m, 1H; H-13), 4.04 (dd, 3J ˆ 11.8 Hz, 3J ˆ
for C47H92NO5SSi4 894.5773, found 894.577.
2
3
2.5 Hz, 1H; H-4'), 3.96 (dt, J ˆ 11.9 Hz, J ˆ 2.7 Hz, 1H; H-6'), 3.86 (ddd,
2J ˆ 11.7 Hz, 3J ˆ 5.4 Hz, 3J ˆ 1.7 Hz, 1H; H-6'), 3.50 (brs, 1H; OH), 3.36
3
3
3
(d, J ˆ 9.3 Hz, 1H; H-5), 3.27 (dq, J ˆ 7.0 Hz, J ˆ 1.4 Hz, 1H; H-4), 2.71
(s, 3H; C2''-CH3), 2.34 ± 2.14 (m, 2H; H-12), 2.06 ± 1.93 (m, 2H; H-9), 1.99
(d, 4J ˆ 1.2 Hz, 3H; C14-CH3), 1.82 ± 1.71 (m, 1H; H-7), 1.67 (d, 4J ˆ 1.1 Hz,
3H; C10-CH3), 1.66 ± 1.22 (m, 5H; H-6, H-8, H-5'), 1.40 (s, 3H; C2'-CH3),
1.33 (s, 3H; C2'-CH3), 1.20 (s, 3H; H-1), 1.16 ± 1.05 (m, 1H; H-7), 1.09 (s,
3H; C2-CH3), 1.02 (d, 3J ˆ 7.0 Hz, 3H; C4-CH3), 0.88 (s, 9H; OSiC(CH3)3),
0.82 (d, 3J ˆ 6.8 Hz, 3H; C6-CH3), 0.04, 0.00 (2s, 2  3H; OSi(CH3)2);
13C NMR (100 MHz, CDCl3): d ˆ 222.8, 164.3, 153.3, 142.6, 136.9, 121.4,
Acknowledgment
We thank Prof. Dr. G. Höfle for authentic samples of the natural
epothilones B and D. We are grateful to S. Lange, Universität Hannover
(Germany) for recording high resolution mass spectra. This work was
supported by the Fonds der Chemischen Industrie. We thank the Novartis
Pharma AG (Basel) for financial support and generous gifts of chemicals.
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2499 $ 17.50+.50/0
2499

D. Schinzer et al.
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Received: March 4, 1999 [F 1649]
2500
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2500 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9