The 12,13-diol cyclization approach for a truly stereocontrolled total synthesis of epothilone B and the synthesis of a conformationally restrained analogue

Article abstract of DOI:10.1002/1521-3765(20010518)7:10<2261::AID-CHEM2261>3.0.CO;2-F

A highly convergent and stereocontrolled synthesis of epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mesylation and base treatment of the 12,13-diol 30 which was formed by a chelate Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragments were synthesized from the chiral carbon pool precursors (S)-citronellol and (S)-lactic acid, respectively. A highly diastereoselective aldol additon of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivered the full carbon skeleton, containing all the stereogenic centers of 1. Functional group manipulation, macrolactonization and removal of two protecting groups then yielded 1. The spatial closeness of the C4-β-methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them through a methylene bridge to give a cyclohexanone derivative. Thus, the Northern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 47. Further manipulations and macrolactonization delivered the conformationally restrained epothilone derivative 42.

Full text of DOI:10.1002/1521-3765(20010518)7:10<2261::AID-CHEM2261>3.0.CO;2-F

FULL PAPER
The 12,13-Diol Cyclization Approach for a Truly Stereocontrolled
Total Synthesis of Epothilone B and the Synthesis of a
Conformationally Restrained Analogue
Harry J. Martin,* Peter Pojarliev, Hanspeter Kählig, and Johann Mulzer*[a]
Abstract: A highly convergent and ster-
eocontrolled synthesis of epothilone B
(1) has been developed. The epoxide
moiety in 1 was generated by regiose-
lective mesylation and base treatment of
the 12,13-diol 30 which was formed by a
chelate Cram controlled Grignard addi-
tion of 14 and methyl ketone 13. Both
fragments were synthesized from the
chiral carbon pool precursors (S)-citro-
nellol and (S)-lactic acid, respectively. A
highly diastereoselective aldol additon
of epoxy-aldehyde 7 and the known
Southern hemisphere ketone 8 delivered
the full carbon skeleton, containing all
the stereogenic centers of 1. Functional
group manipulation, macrolactonization
and removal of two protecting groups
then yielded 1. The spatial closeness of
the C4-b-methyl and C6-methyl group in
the crystal structure of 1 inspired us to
connect them through
a methylene
bridge to give a cyclohexanone deriva-
tive. Thus, the Northern hemisphere
aldehyde 7 was added to the enolate of
the cyclohexanone 47. Further manipu-
lations and macrolactonization deliv-
ered the conformationally restrained
epothilone derivative 42.
Keywords: carbonyl addition ´ epo-
thilones ´ epoxidation ´ stereoselec-
tive synthesis ´ total synthesis
spent on developing stereocontrolled approaches to 1/2 it is
more than surprising that the stereoproblem of introducing
the 12,13-epoxide in pure (12R,13S) configuration still awaits
a satisfactory solution. (Scheme 1). Usually the epoxide is
generated through epoxidation of the corresponding 12,13-
olefins (epothilone D, 3, and epothilone C, 4) either with
mCPBA or dimethyl or trifluorodimethyl dioxirane. The high
stereocontrol initially reported by Danishefsky[3a,c] could not
be reproduced by Nicolaou, who found a virtually reagent
independent ratio of 4:1 instead.[3b] Additionally, the two
epoxide diastereomers are difficult to separate (TLC) and the
application of peroxidic epoxidizing agents does not appear
acceptable for the industrial scale. Recently Nicolaou report-
ed a solution of the problem by using a 12-hydroxymethylene
substituent in a stereocontrolled Sharpless epoxidation, how-
ever, this methodology requires several additional steps and
does not appear satisfactory.[4e]
Though to a lesser degree the introduction of C6/C7 in the
correct (6R,7S)-configuration still poses a problem. Usually,
the C-6,7-bond is formed by an aldol addition of ketone 6 to
the 12,13-unsaturated aldehyde 5 (or shorter fragments
thereof). The diastereomeric ratio of 6R,7S:6S,7R-diastereom-
ers routinely is about 3 ± 4:1. Only Schinzer[3e] and White[3h]
reported stereoselectivities of >90:10. This degree of selec-
tivity was also recently achieved in Nicolaouꢀs synthesis of
some epothilone B derivatives.[4e] Remarkably, on reviewing
the various syntheses of 1 there is not one synthesis so far, in
which all stereogenic units are introduced with a selectivity of
Introduction
Epothilone B (1)[1] shows outstanding microtubule binding
affinities and cytotoxity against tumor cells and multiple drug
resistant tumor cell lines.[2] The role of 1 as a potential
paclitaxel successor has initiated intense interest in its syn-
thesis, resulting in several total syntheses of 1 and numerous
derivatives thereof.[3, 4]
Apart from the objective to procure material for biological
tests these syntheses were increasingly carried out in the
intention to use 1 and the simpler epothilone A (2) as a
testbed for the application of novel methodology. Thus, ring
closing metathesis was used to generate the 12,13-olefin,[5] and
ring closing aldol addition to form the 2,3-bond.[6] For the
formation of the C-11,12-bond an interesting sp2 ± sp3-con-
necting Suzuki coupling was employed.[3a,c,e] Another issue
was the introduction of stereogenic centers through chiral
catalysis. For instance in the synthesis of 2 Shibasaki applied
multifunctional catalysis for the construction of C15 (hydro-
cyanation) and C3 (aldol addition),[7] and the Lerner group
prepared non-racemic fragments of 2 with the aid of catalytic
antibodies.[8] In view of the extensive efforts which have been
[a] Dr. H. J. Martin, Prof. Dr. J. Mulzer, Dr. P. Pojarliev, Dr. H. Kählig
Institut für Organische Chemie der Universität Wien
Währinger Strasse 38, 1090 Wien (Austria)
Fax : (‡43)1-4277-52189
E-mail: harry.martin@univie.ac.at
johann.mulzer@univie.ac.at
Chem. Eur. J. 2001, 7, No. 10
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2261

H. J. Martin, J. Mulzer et al.
FULL PAPER
showed that ketone acetonides 15 underwent highly selective
additions with various Grignard reagents to form the syn-
triols 16 in about 90% isolated yields (Scheme 2).[10] The
mechanistic interpretation implies a chelate Cram intermedi-
ate 17 which is attacked at the carbonyl group from the less
hindered face. In this way the trajectory is antiperiplanar to
the endocyclic C O-bond to give syn-triol 18.
R
R
O
S
S
N
7
7
6
OH
OH
N
O
O
6
O
OH
O
O
OH O
R = Me, epothilone B (1)
R = H, epothilone A (2)
R = Me, epothilone D (3)
R = H, epothilone C (4)
S
HO
13
HO
Me
HO
15
O
12
S
N
N
12
S
N
13
15
13
15
7
3
6
O
7
H
+
R
OTES
OTBS
O
O
11
12
5
C1-C6 fragment (6)
BrMg
15
O
13
O
12
PMBO
O
+
O
12
S
N
13
1
6
15
7
H
+
13
14
O
OTBS
OTES
O
7
8
HO
O
RMgBr
R = Et, iPr, Ph, vinyl
O
R
O
O
O
HO
HO
12
CO2Et
13
15
AD mix β
9 steps
15
16, ds > 95 : 5
O
CO2Et
7
O
OTBS
OTES
R
R
Me
OH
Me
9
10 (12R/13S : 12S/13R = 3:1)
O
O
Me
Me
O
O
Scheme 1. Retrosynthetic analysis I for the synthesis of epothilone B.
'R
O
Mg
X
Me
Me
R'MgX
17
18
>95:5, which would be desirable for any up-to-date-method-
ology.
Scheme 2. Retrosynthetic analysis II for the convergent synthesis of the
Northern hemisphere aldehyde.
Recently we reported a novel approach to the introduction
of the epoxide function in 1 (Scheme 1). The key step of the
synthesis was the highly stereoselective (ds >95:5) aldol
addition of ketone 8 to the epoxy aldehyde 7.[3j] The epoxide
moiety in 7 was prepared through a regiocontrolled cycliza-
tion of diol 10, which was readily available from the olefinic
ester 9 by Sharpless AD reaction. In this way the epoxide was
introduced very early in the synthesis and turned out to be
surprisingly stable over a variety of synthetic operations.
However, there were two flaws in this synthesis: the
introduction of the 12,13-diol through Sharpless AD reaction
of olefin 9 to form diol 10 was not stereoselective and the 15-
O-protective group had to be changed from TBS to TES later
in the synthesis to allow the final 15-O-deprotection under
mild conditions.
We now report a new synthesis of 7 which eliminates the
previous drawbacks and makes use of simple and reliable
reactions which are applicable on the larger scale without
problems, and most gratifyingly, create all stereogenic units
with the required >95% stereoselectivity. The synthesis of 7
was centered around the 13,15-syn diol acetonide moiety
represented in intermediate 12, which, in the synthetic
direction, had to be transformed into 7 via the 15-O-silylated
triol 11. Acetonide 12, in turn, was prepared from ketone 13
through a chelate Cram controlled addition of the Grignard
reagent 14.[9] The high stereocontrol of this addition was to be
expected from previous experiments in our group which
Results and Discussion
Our synthesis started with the known addition of allyltrime-
thylsilane to aldehyde 19 (Scheme 3), which furnishes the syn-
adduct 20 with >95:5 diastereoselectivity.[11] Subsequent
O-silylation of 20 gave 21 which was treated with ozone
followed by addition of isopropenyl magnesium bromide to
form the triol 22 as a 3:2-mixture of diastereomers which was
converted into the acetonide 24. After oxidation of 24 to the
ketone, the epimeric mixture was treated with mild base to
achieve complete equilibration to the syn-diastereomer 13.[12]
The addition of the Grignard reagent 14 (readily available
from the known alcohol via the bromide)[13] to ketone 13
proceeded with high chelate Cram selectivity as expected to
furnish the tertiary alcohol 25. After PMB deprotection and
oxidation, ketone 27 was transferred into the thiazolyl olefin
12 by an E-selective Wittig reaction.[3g] Global O-deprotection
led to the triol 29 which, much to our surprise, underwent
completely regioselective O-silylation at the 15-position to
generate 30, even when 3 mol equivalents of TESCl had to be
applied for a complete conversion! Subsequent 13-O-mesy-
lation also proceeded with perfect regiocontrol to convert 30
into 31. The stage was now set for the base catalyzed
formation of the 12,13-epoxide 32 under inversion at C13
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Chem. Eur. J. 2001, 7, No. 10

Total Synthesis of Epothilone B
2261±2271
PMBO
PMBO
PMBO
PMBO
PMBO
c,d
H
a
f
g
O
O
O
O
OR
OR OH
O
O
19
20: R = H
22: R = TBS
23: R = H
e
b
24
21: R = TBS
13
(28)
PBu3 Cl
S
N
RO
HO
O
HO
j
O
h
12
O
O
O
k
27 (ds > 97:3)
25: R = PMB
26: R = H
i
O
S
N
S
R3O
13
o
l
15
N
OR1 OR2
OTES
X
29: R1 = R2 = R3 = H
30: R1 = TES, R2 = R3 = H
31: R1 = TES, R2 = Ms, R3 = H
32: X = CH2
7: X = O
m
n
p
Scheme 3. a) See ref. [11]; b) TBSCl, imidazole, DMF, 228C, 24 h, 97% c) O3, CH2Cl2/MeOH, 788C, then PPh3, 98%; d) isopropenyl magnesium
bromide, THF, 108C, 45 min, 89% as a 3:2-mixture of diastereomers; e) 1.2 equiv TBAF, THF, 1 h, 258C, 99%; f) 2,2-dimethoxypropane, cat. TsOH, 99%;
g) O3/PPh3, CH2Cl2, 788C, then 2.0 equiv K2CO3, MeOH, 1 h, 258C, (94% in two steps); h) MgBr2, CH2Cl2, 788C, 3.0 equiv 14, 3 h, (78%, ds ˆ 96:4);
i) 1.2 equiv DDQ, CH2Cl2, 45 min, 258C, (98%); j) 1.5equiv Dess ± Martin-periodinane, CH2Cl2, 2 h, 258C, 95%; k) 5.0 equiv 28, KHMDS, 08C, 40 min, then
27, 458C, 20 min, THF, 80%; l) 15% HCl, MeOH, 12 h, 258C, 99%; m) 3.0 equiv TESCl, Et3N, CH2Cl2, 12 h, 258C, 90%; n) MsCl, Et3N, 92%; o) K2CO3,
MeOH, 1 h, 258C, 90%; p) NMO, OsO4, NaIO4, (62% in two steps). TBS ˆ tert-butyldimethylsilyl; TBAF ˆ tetrabutylammonium fluoride; Ts ˆ 4-
toluenesulfonyl; DDQ ˆ 2,3-dichloro-3,4-dicyanobenzoquinone; KHMDS ˆ potassium hexamethyldisilazide; TES ˆ triethylsilyl; Ms ˆ methanesulfonyl,
NMO ˆ 4-methylmorpholine-N-oxide.
and retention at C12. Regioselective dihydroxylation of the
terminal olefin followed by glycol cleavage delivered the
desired aldehyde 7.
and hence could be connected by a one carbon bridge to form
a cyclohexane analogue 42 in which the ªSouth Eastº
(C3 C7) fragment can be expected to underly a significant
conformational restriction. (Figure 1).
Next we set about a stereocontrolled synthesis of ketone 8
(see Scheme 4). This compound had been made by a Brown
allylation of aldehyde 34 with moderate enantioselectivity (ee
ꢀ84%).[3b] We applied Duthalerꢀs allylation protocol[14] and
to our delight we found that reagent 33 converted aldehyde 34
into adduct 35 with an ee >98%. Additionally we found the
workup much more convenient than for Brownꢀs method
which implied repeated and tedious column chromatography
to remove the boron containing side products. Aldol addition
of the lithium enolate of ketone 8 to aldehyde 7 proceeded
with excellent diastereoselectivity (>95:5) to form the adduct
36 which was protected to give the 7-OTroc derivative 37. The
further success of the synthesis crucially depended on the
handling of the O-protective groups. Thus, 37 was first
converted into the aldehyde and then 15-O-desilylated to
give hydroxy aldehyde 38 which was oxidized to the acid 39
with Pinnickꢀs reagent.[15] Yamaguchi macrolactonization[16]
furnished lactone 40 which was first deprotected at 7-O to give
41 and after removal of the 3-TBS group, epothilone B (1)
which was identical in all pertinent analytical data with the
natural compound described. In effect we have thus achieved
a truly stereocontrolled synthesis of 1, in addition to the one
reported earlier.[3m]
Figure 1. Design of a conformationally restrained epothilone analogue.
The synthesis of 42 started from the cyclohexane derivative
43, which was provided by the Schering (ZK 204027, ee
>98%) (Scheme 5). Reduction with LAH furnished alcohol
44, which was oxidized to aldehyde 45 and then subjected to
an asymmetric Brown allylation followed by acetal hydrolysis
to furnish 46 with a ds ˆ 6:1. This value is much lower than the
one observed for the acyclic analogue 34 (92:8), so that the
allylation of 45 may be assumed to be a mismatched case.
After TBS protection of the hydroxyl group the ketone 46 was
used in the aldol condensation with aldehyde 7 to form the
diastereomeric adducts 48 in a ratio of 4:1. After protection,
7-OTroc derivative 49 was oxidized to the aldehyde 50 with
OsO4/NMO followed by glycol cleavage with NaIO4. Depro-
Encouraged by this result we turned to the synthesis of a
conformationally restricted analogue. On inspecting the
crystal structure of 1 and on the basis of the conformational
analysis of epothilone A in solution[17] it occurred to us that
the (pro-R)-4- and the 6-methyl groups are closely together,
Chem. Eur. J. 2001, 7, No. 10
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2263

H. J. Martin, J. Mulzer et al.
FULL PAPER
O
S
N
O
O
MgCl
a
OR2
c
b
Ph
Ph
Ph
Ph
8
O
OH
35
O
O
Cl
TESO
aldol addition
Ti
of 7
OR1
O
O
O
34
33
36: R1 = TBS, R2 = H
37: R1 = TBS, R2 = Troc
d
O
O
S
N
S
OR2
OTroc
N
e, f
h
HO
O
R2C
O
OR1
O
OR1
O
O
40: R1 = TBS, R2 = Troc
41: R1 = TBS, R2 = H
1: R1 = R2 = H
38: R1 = TBS, R2 = H
39: R1 = TBS, R2 = OH
i
j
g
Scheme 4. a) 33, allylmagnesium chloride, THF, 08C, 90 min, then add 34, 748C, 3 h, 61%; b) TBSOTf, 2,6-lutidine, CH2Cl2, 788C, 1 h, 87%;
c) diisopropylamine, nBuLi (1.6m in hexanes), THF, 08C, 20 min, then add 8 (in THF), 788C to 408C, 30 min, then add 7 (in THF), 788C, 15 min, 92%;
d) TrocCl, CH2Cl2, pyridine, 208C, 30 min, 91%; e) NMO, OsO4 (5 mol%), THF/tBuOH/H2O 10:10:1, 258C, 16 h, workup with Na2S2O3; crude diol in
EtOH/H2O, NaIO4, 258C, 1 h, 78% over two steps; f) HF/pyridine, THF, 228C, 20 min, 91%; g) NaClO2, 2,3-dimethyl-2-butene, NaH2PO4, tBuOH, H2O,
228C, 45 min, 92%; h) 38, 2,4,6-trichlorobenzoyl chloride, triethylamine, DMAP, 0.02m solution in toluene, 228C, 90 min, 65% i) Zn, ammonium chloride,
EtOH, reflux, 20 min, 92%; j) HF/pyridine, 358C, 7d, 67%. Tf ˆ trifluormethanesulfonyl; TrocCl ˆ 2,2,2-trichloroethyl chloroformate; DMAP ˆ 4-
dimethylaminopyridine.
tection of O-15 and Pinnick oxidation of the resulting
O
MeO2C
aldehyde 51 led to the seco acid which was converted without
purification into the macrolactone 52 through Yamaguchi
lactonization. Sequential deprotection furnished 53 and,
eventually, the desired epothilone B analogue 42. Careful
analysis by two-dimensional NMR spectroscopy revealed the
(R) configuration at C6 which established a cis-relationship of
the two carbon appendages around the cyclohexane ring.
However, the configuration of C7 could not be assigned with
certainty. We did not insist on this point, as no biological
activity of 42 towards tumor cell line MCF-7 was observed.
In conclusion, we have established a fully stereocontrolled
synthesis of epothilone B, essentially based on well estab-
lished methodology which starts from inexpensive materials.
This methodology has also been successfully applied to the
synthesis of a conformationally restricted epothilone ana-
logue.
a
b
c
HO
O
O
O
O
O
O
OR O
43
46: R = H
44
45
d
47: R = TBS
O
S
e
ratio at C7 = ca. 4 : 1
7 OR
47
N
TESO
X
OR O
48: R1 = H, R2 = TBS, X = CH2
49: R1 = Troc, R2 = TBS, X = CH2
50: R1 = Troc, R2 = TBS, X = O
f
g
O
O
S
S
N
OR1
OR1
N
h
i
O
50
HO
Experimental Section
OR2
51
O
O
OR2
O
O
52: R1 = H, R2 = TBS, X = CH2
53: R1 = Troc, R2 = TBS, X = CH2
42: R1 = H, R2 = H
j
Unless otherwise stated, solvents were dried by distillation under argon,
from Na (toluene), Na/K (Et2O, abbreviated as ether), potassium (THF),
CaH2 (Et3N, DMF), P2O5 (CH2Cl2), KOH (pyridine) and Mg (MeOH,
EtOH). All other commercially available reagents were used without
further purification unless specified otherwise. All reactions were per-
formed in oven-dried glassware under argon. Chromatography refers to
flash column chromatography on silica gel 60 (230 ± 400 mesh). Thin-layer
chromatography (TLC) was performed on Al-backed plates (Merck silica
gel 60 F254) and visualised by using either a UV lamp, phosphomolybdic
acid, sulphuric acidic/anisaldehyde or potassium permanganate solutions.
Melting points (m.p.) are uncorrected. Optical rotations are reported in g
per 100 mL. Infrared spectra (IR) were measured as evaporated films on
single crystal silica plates and reported in wave numbers (cm 1) with broad
signals denoted by (br). High resolution mass spectra were obtained using
electron ionisation (EI), field ionisation (FI) or fast atom bombardment
k
Scheme 5. a) LAH, Et2O, 25 8C, 3 h, 97%; b) oxalylchloride, DMSO,
CH2Cl2, 788C, 15 min, then NEt2iPr, 08C, 1 h, 90%; c) ( )-Ipc2B(allyl),
allylmagnesium bromide, Et2O, THF, 788C, 3 h, workup with H2O2,
NaOH, ds ˆ 6:1, 50%; d) TBSOTf, 2,6-lutidine, CH2Cl2, 96%; e) LDA,
THF, 788C, 10 min, then 7, 788C, 10 min, 78%; f) TrocCl, pyridine,
CH2Cl2, 258C, 40 min, 98%; g) OsO4, NMO, tBuOH, THF, 258C, 16 h,
then NaIO4, H2O, EtOH, 258C, 1 h, 64%; h) HF, pyridine, THF, 258C,
20 min, 88%; i) NaClO2, butanol, 2,3-dimethyl-but-2-ene, H2O, NaH2PO4,
258C, 2 h, then 2,4,6-trichlorobenzoyl chloride, NEt3, toluene, DMAP,
258C, 30 min, 36%; j) Zn, EtOH, NH4Cl, reflux, 30 min, 95%; k) HF,
pyridine, 408C, 4 d, 50%. Ipc ˆ isopinocampheyl; LDA ˆ lithium diisopro-
pylamide.
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Chem. Eur. J. 2001, 7, No. 10

Total Synthesis of Epothilone B
2261±2271
1
(FAB). H and 13C NMR were recorded on a Bruker AC 250 (250 MHz),
(brs, 0.6  OH), 2.93 (d, J ˆ 5 Hz, 0.4  OH), 2.87 (d, J ˆ 3 Hz, 1  OH),
1.72 ± 1.53 (m, 2H), 1.70 (s, 3H), 1.21 (d, J ˆ 6.2 Hz, 1.8H), 1.15 (d, J ˆ
6.2 Hz, 1.2H); 13C NMR (62.5 MHz, CDCl3): d ˆ 159.4, 147.3, 130.3, 129.4,
114.0, 113.9, 110.8, 110.3, 77.9, 77.8, 75.6, 75.4, 72.5, 72.4, 70.7, 70.3, 55.3,
55.3, 37.6, 36.9, 18.7, 17.8, 15.4, 15.2; EI HRMS: m/z: 280.1682 [M] , calcd
for C16H24O4: 280.1675.
AM 400 (400 MHz) or AM 600 (600 MHz) spectrometer. Chemical shifts
are reported using the solvent resonance internal standard (chloroform,
d ˆ 7.26 and 77.0).
‡
Silyl ether 21, silylation of alcohol 20: A solution of alcohol 20 (8.95 g,
38.0 mmol) in dry DMF (180 mL) was treated with imidazole (15.5 g,
227 mmol) and TBS chloride (8.00 g, 53.0 mmol). After stirring over a
period of 16 h at room temperature, the reaction mixture was added to
hexane/ether (1:1 mixture, 400 mL) and washed with saturated aqueous
NaHCO3 solution (2 Â 100 mL), water (100 mL) and brine (100 mL). The
organic layer was dried (MgSO4) and concentrated under reduced pressure.
Purification by column chromatography (silica gel, hexane/EtOAc 50:1 !
Acetonide 24: A solution of diol 23 (1.75 g, 6.25 mmol) in 2,2-dimethoxy-
propane (50 mL) and catalytic amount of p-TsOH ´ H2O (50 mg) was
stirred for 3 h at 258C. The reaction mixture was diluted with ice-water
(50 mL) and ether (50 mL) and washed with saturated aqueous NaHCO3
solution (50 mL). The aqueous phase was extracted with ether (3 Â 50 mL)
and the combined organic phases were washed with brine (40 mL), dried
(MgSO4), and concentrated. The crude mixture was purified by flash
column chromatography (hexane/EtOAc 15:1) to provide acetonide 24
20:1) afforded silyl ether 21 as a colorless oil (12.94 g, 97%). [a]D20
ˆ
0.4
(c ˆ 2.40, CHCl3); IR (thin film): nÄmax ˆ2955, 2857, 1642, 1613, 1587, 1514,
1464, 1249, 1098, 1039 cm 1; H NMR (400 MHz, CDCl3): d ˆ 7.26 (d, J ˆ
(2.0 g, 99%) as a colorless oil. IR (thin film): nÄmax ˆ2989, 2937, 2870, 2836,
1
1
8.5 Hz, 2H), 6.87 (d, J ˆ 8.5 Hz, 2H), 5.83 (ddt, J ˆ 17.0, 10.0, 7.3 Hz, 1H),
5.04 (d, J ˆ 17.0 Hz, 1H), 5.01 (d, J ˆ 10.0 Hz, 1H), 4.52 (d, J ˆ 12.0 Hz,
1H), 4.44 (d, J ˆ 12.0 Hz, 1H), 3.80 (s, 3H), 3.72 (qn, J ˆ 4.0 Hz, 1H), 3.47
(dq, J ˆ 4.0, 6.5 Hz, 1H), 2.42 ± 2.34 (m, 1H), 2.17 ± 2.08 (m, 1H), 1.12 (d,
J ˆ 6.5 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): d ˆ 159.5, 136.6, 131.5, 129.5, 116.8, 114.1, 77.4, 74.2,
71.1, 55.7, 36.7, 26.3, 18.5, 14.4, 4.1 (two signals); EI HRMS: m/z: 293.1581
1613, 1248 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 7.29 ± 7.22 (m, 2H),
6.89 ± 6.81 (m, 2H), 4.95 (brs, 0.4H), 4.91 (brs, 0.6H), 4.81 (brs, 0.4H), 4.77
(brs, 0.6H), 4.61 ± 4.48 (m, 2H), 4.28 ± 4.24 (m, 0.4H), 4.23 ± 4.18 (m, 0.6H),
3.98 ± 3.81(m, 1H), 3.78 (s, 3H), 3.57 ± 3.44 (m, 1H), 1.9 ± 1.56 (m, 2H), 1.73
(s, 3H), 1.45 (s, 0.9H), 1.43 (s, 0.9H), 1.38 (s, 1.2H), 1.13 (d, J ˆ 6.4 Hz,
1.2H), 1.11 (d, J ˆ 6.4 Hz, 1.8H); 13C NMR (62.5 MHz, CDCl3): d ˆ 159.0,
145.2, 129.2, 113,7, 110,3, 100.5, 75.9, 71.3, 70.0, 69.7, 55.2, 32.4, 25.0, 24.5,
‡
‡
[M C4H9] , calcd for C20H34O3Si: 350.2277.
18.6, 15.3; EI HRMS: m/z: 320.1977 [M] , calcd for C19H28O4: 320.1988.
Alcohol 22, ozonolysis of alkene 21 and Grignard reaction: Ozone was
passed through a solution of alkene 21 (8.02 g, 25 mmol) in CH2Cl2
(200 mL) and methanol (10 mL) at 788C until a blue color appeared.
Excess ozone was removed by purging with air (2 min), then PPh3 (19.7 g,
75 mmol) was added and the mixture was allowed to warm to room
temperature. The solvents were removed under reduced pressure and the
residue was purified by column chromatography (silica gel, hexanes/
EtOAc/CH2Cl2 40:1:10, then hexanes/EtOAc 20:1 ! 10:1) to give aldehyde
(7.90 g, 98%) as a colorless liquid. [a]2D0 ˆ ‡2.8 (c ˆ 2.20, CHCl3); IR (thin
Ketone 13, ozonolysis of alkene 24: Alkene 24 (2.0 g, 6.25 mmol) was
dissolved in a mixture of CH2Cl2 and MeOH (8:1, 65 mL), and the solution
was cooled to 788C. Oxygen was bubbled through the solution for 2 min,
after which ozone was passed through until the reaction mixture had a pale
blue color (ca. 15 min). The solution was then purged with air for 2 min at
788C (until disappearance of blue color) and PPh3 (2.46 g, 9.38 mmol)
was added. The reaction mixture was allowed to warm to room temper-
ature and stirred for 12 h at 258C. The solvent was removed under reduced
pressure, and the residue was purified by flash column chromatography
(hexane/EtOAc 40:1 to 10:1) to provide a 1:1 epimeric mixture of ketone
13. The mixture of epimers were dissolved in dry MeOH (100 mL) and
treated with dry K2CO3 (1.73 g, 12.5 mmol) at 258C. After stirring for 1 h at
258C, a mixture of ether (50 mL) and ice-water (50 mL) was added and the
reaction mixture was neutralised with saturated aqueous NH4Cl solution.
The organic phases were separated and the aqueous phase was extracted
with ether (3 Â 50 mL). The combined organic phases were washed with
brine (40 mL), dried (MgSO4) and concentrated under reduced pressure.
Flash column chromatography (hexane/EtOAc 10:1) furnished the pure
ketone 13 (1.9 g, 94% for two steps) as a single diastereomer. [a]2D0 ˆ ‡23.8
(c ˆ 2.1, CHCl3); IR (thin film): nÄmax ˆ2993, 2939, 2837, 1718, 1613, 1514,
1380, 1107, 973 cm 1; 1H NMR (CDCl3, 250 MHz): d ˆ 7.27 ± 7.20 (m, 2H),
6.88 ± 6.80 (m, 2H), 4.56 (d, J ˆ 11.6 Hz, 1H), 4.49 (d, J ˆ 11.6 Hz, 1H), 4.21
(dd, J ˆ 12.0, 3.0 Hz, 1H), 3.93 (ddd, J ˆ 11.7, 5.5, 2.5 Hz, 1H), 3.77 (s, 3H),
3.53 ± 3.41 (m, 1H), 2.17 (s, 3H), 1.66 (dt, J ˆ 13.0, 2.7 Hz, 1H), 1.45 (s, 3H),
1.43 (s, 3H), 1.36 (dd, J ˆ 13.0, 1.0 Hz, 1H), 1.15 (d, J ˆ 7.0 Hz, 3H);
13C NMR (62.5 MHz, CDCl3): d ˆ 208.9, 159.1, 130.9, 129.2, 113.7, 98.9, 76.1,
74.8, 72.0, 71.3, 55.3, 29.9, 27.7, 25.4, 19.5, 15.0; EI HRMS: m/z: 322.1776
1
film): nÄmax ˆ2934, 1728, 1612, 1514, 1466, 1250, 1101, 1037 cm 1; H NMR
(400 MHz, CDCl3): d ˆ 9.75 (s, 1H), 7.25 ± 7.17 (m, 2H), 6.88 ± 6.82 (m, 2H),
4.50 (d, J ˆ 11.5 Hz, 1H), 4.38 (d, J ˆ 11.5 Hz, 1H), 4.32 ± 4.25 (m, 1H), 3.78
(s, 3H), 3.56 ± 3.48 (m, 1H), 2.68 ± 2.60 (m, 1H), 2.50 ± 2.41 (m, 1H), 1.11 (d,
J ˆ 6.5 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H); 13C NMR (100.6 MHz, CDCl3):
d ˆ 202.2, 159.6, 130.9, 129.6, 114.2, 76.6, 71.0, 69.4, 55.7, 46.4, 26.1, 18.3,
‡
13.9,
4.2,
4.5; EI HRMS: m/z: 295.1366 [M C4H9] , calcd for
C19H32O4Si: 352.2070.
A solution of the above aldehyde (7.82 g, 22.2 mmol) in dry THF (20 mL)
was slowly added at 108C to a solution of isopropenyl magnesium
bromide (0.5m solution in THF, 53.0 mL, 26.5 mmol). The mixture was
allowed to warm to 08C and was quenched by addition to a saturated
aqueous NH4Cl solution (100 mL) and ether (100 mL). The aqueous layer
was extracted with ether (2 Â 40 mL), the combined organic phases were
dried and concentrated. Purification by flash column chromatography
(silica gel, hexanes/EtOAc 10:1) furnished allylic alcohol 22 (7.79 g, 89%,
mixture of diastereomers ca. 3:2) as a colorless oil. IR (thin film): nÄmax
ˆ
1
3438 (br), 2955, 1650, 1613, 1514, 1463, 1250, 1086 cm
;
1H NMR
‡
[M] , calcd for C18H26O5: 322.1780.
(400 MHz, CDCl3): d ˆ 7.28 ± 7.21 (m, 2H), 6.90 ± 6.84 (m, 2H), 4.99 (s,
1H), 4.84 (s, 0.6H), 4.81 (s, 0.4H), 4.56 ± 4.44 (m, 2H), 4.23 ± 4.15 (m, 1H),
4.00 (dt, J ˆ 7.0, 4.5 Hz, 0.4H), 3.95 (dt, J ˆ 8.5, 4.5 Hz, 0.6H), 3.80 (s, 3H),
3.62 ± 3.50 (m, 1H), 3.10 (d, J ˆ 2.5 Hz, 0.6H), 2.81 (d, J ˆ 3.5 Hz, 0.4H),
1.95 ± 1.76 (m, 1H), 1.73 (s, 3H), 1.68 ± 1.58 (m, 1H), 1.16 (d, J ˆ 6.5 Hz,
1.8H), 1.14 (d, J ˆ 6.5 Hz, 1.2H), 0.88 (s, 9H), 0.07 (s, 1.8H), 0.06 (s, 1.2H),
Alcohol 25, Grignard reaction of ketone 13: Mg cuttings (365 mg, 15 mmol)
were moistened with dry THF (0.2 mL). (3S)-6-Bromo-3-methyl-hex-1-ene
(2.21 g, 12.5 mmol), dissolved in dry THF (12.5 mL), was slowly added at
258C under argon atmosphere. After the exothermic reaction was
complete, the solution was stirred for 30 min at 258C. The dark-brown
solution of 14 was separated from the mixture via syringe and used in the
next step.
‡
0.00 (s, 3H); EI HRMS: m/z: 337.1849 [M C4H9] , calcd for C22H38O4Si:
394.2539.
Diol 23, desilylation of 22: A solution of silyl ether 22 (2.5 g, 6.3 mmol) in
dry THF (60 mL) at 08C was treated with TBAF (1m solution in THF,
7.6 mL, 7.6 mmol). After stirring for 1 h at 258C, the reaction mixture was
diluted with ether (60 mL) and washed with saturated aqueous NH4Cl
solution (60 mL). The aqueous phase was extracted with ether (3 Â 50 mL),
and the combined organic phases were washed with brine (40 mL), dried
(MgSO4), and concentrated. The crude mixture was purified by flash
column chromatography (hexane/EtOAc 4:1) to provide diol 23 (1.75 g,
MgBr2 ´ Et2O (1.48 g, 5.4 mmol) was added in portions to a cooled ( 788C)
solution of ketone 13 (1.45 g, 4.5 mmol) in dry CH2Cl2 (30 mL). After
stirring for 30 min, the homogeneous mixture was treated dropwise with
Grignard compound 14 (1m in THF, 13.5 mL, 13.5 mmol) at 788C and
stirred for 1 h at this temperature. The mixture was allowed to warm to
258C and stirred for 1 h. Ice-water (30 mL) was added and the solution was
treated with saturated aqueous NH4Cl solution (30 mL). The aqueous
phase was extracted with CH2Cl2 (3 Â 25 mL) and the combined organic
phases were washed with brine (30 mL), dried (MgSO4), and concentrated.
The crude mixture was purified by flash column chromatography (hexane/
EtOAc 8:1) to give a mixture of diastereomers (syn:anti ˆ 24:1 by HPLC
analysis). Separation of these diastereomers was carried out by HPLC
99%) as a colorless liquid. IR (thin film): nÄmax ˆ3418 (br), 2969, 2934, 2868,
1
1612, 1513, 1248, 1106 cm
;
1H NMR (CDCl3, 250 MHz): d ˆ 7.28 ± 7.18
(m, 2H), 6.90 ± 6.81 (m, 2H), 5.03 (brs, 0.4H), 4.98 (brs, 0.6H), 4.85 (brs,
0.4H), 4.80 (s, 0.6H), 4.58 (d, J ˆ 11.2 Hz, 1H), 4.35 (d, J ˆ 11.2 Hz, 1H),
4.36 ± 4.23 (m, 1H), 3.79 (s, 3H), 3.81 ± 3.63 (m, 1H), 3.50 ± 3.33 (m, 1H), 3.1
(Nucleosil 50 ± 5, 237 Â 32 mm, 15% EtOAc in hexane, 80 mLmin 1, UV254
,
Chem. Eur. J. 2001, 7, No. 10
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0710-2265 $ 17.50+.50/0
2265

H. J. Martin, J. Mulzer et al.
FULL PAPER
10.0 min for the syn-product) to yield pure 25 (1.48 g, 78%) as a colorless
purified by flash column chromatography (hexane/EtOAc 1:2) to provide
oil. [a]2D0
ˆ
7.5 (c ˆ 2.1, CHCl3); IR (thin film): nÄmax ˆ3572 (br), 2939,
triol 29 (168 mg, 99%) as a colorless oil. [a]2D0 ˆ ‡8.1 (c ˆ 1.6, CHCl3); IR
1
1
1639, 1613, 1513, 1379 cm
;
1H NMR (CDCl3, 250 MHz): d ˆ 7.30 ± 7.21
(thin film): nÄmax ˆ 3384 (br), 2955, 2865, 1452, 1374, 910 cm
;
1H NMR
(m, 2H), 6.91 ± 6.88 (m, 2H), 5.75 ± 5.59 (m, 1H), 4.99 ± 4.85 (m, 2H), 4.57
(d, J ˆ 11.7 Hz, 1H), 4.50 (d, J ˆ 11.7 Hz, 1H), 3.88 (dq, J ˆ 11.2, 3.0 Hz,
1H), 3.78 (s, 3H), 3.64 (dd, J ˆ 11.2, 3.0 Hz), 3.54 ± 3.42 (m, 1H), 2.24 (brs,
1 Â OH), 2.17 ± 2.04 (m, 1H), 1.45 ± 1.22 (m, 8H), 1.40 (s, 3H), 1.38 (s, 3H),
1.11 (d, J ˆ 6.4 Hz, 3H), 1.04 (s, 3H), 0.96 (d, J ˆ 6.6 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3): d ˆ 144.7, 131.1, 129.2, 113.7, 112.4, 98.6, 73.4, 73,2, 72.0,
71.3, 55.2, 38.9, 37.6, 37.2, 30.0, 25.3, 21.1, 21.1, 20.2, 19.8, 15.0; EI HRMS:
(CDCl3, 250 MHz): d ˆ 6.90 (s, 1H), 6.54 (brs, 1H), 5.74 ± 5.57 (m, 1H),
4.97 ± 4.83 (m, 2H), 4.41 ± 4.31 (m, 1H), 3.72 ± 3.63 (m, 1H), 2.64 (s, 3H),
2.17 ± 2.03 (m, 1H), 1.98 (d, J ˆ 0.9 Hz, 3H), 1.74 ± 1.64 (m, 2H), 1.50 ± 1.20
(m, 6H), 1.07 (s, 3H), 0.95 (d, J ˆ 6.7 Hz, 3H); 13C NMR (62.5 MHz,
CDCl3): d ˆ 165.0, 152.5, 144.8, 142.3, 118.7, 115.6, 112.5, 77.9, 77.2, 74.4,
38.9, 37.7, 37.2, 35.8, 21.4, 21.1, 20.2, 19.0, 14.4; EI HRMS: m/z: 353.2032
‡
[M] , calcd for C19H31NO3S: 353.2025.
‡
m/z: 420.2866 [M] , calcd for C25H40O5: 420.287.
Silyl ether 30, monosilylation of 29: Dry triethylamine (212 mg, 1.8 mmol)
followed by triethylchlorosilane (68 mg, 0.45 mmol) was added to a cooled
(08C) solution of triol 29 (160 mg, 0.45 mmol) in dry CH2Cl2 (25 mL). After
stirring for 3 h at 258C, the reaction mixture was treated with additional
TESCl (136 mg, 0.90 mmol) and the reaction mixture was stirred for an
additional 16 h at 258C. The reaction was quenched by the addition of
saturated aqueous NH4Cl solution (10 mL). The aqueous phase was
extracted with CH2Cl2 (3 Â 15 mL) and the combined organic phases were
washed with brine (20 mL), dried (MgSO4) and concentrated. The crude
mixture was purified by flash column chromatography (hexane/EtOAc 3:1)
Compound 26, PMB-deprotection of 25: DDQ (926 mg, 4.08 mmol) was
added in small portions at 08C within 5 min to a solution of PMB-ether 25
(1.43 g, 3.4 mmol) in a mixture of CH2Cl2 and H2O (10:1, 55 mL). After
stirring for 45 min at 258C, the reaction mixture was diluted with saturated
aqueous NaHCO3 solution (50 mL) and aqueous Na2S2O3 solution (1m,
10 mL). The aqueous phase was extracted with CH2Cl2 (3 Â 30 mL) and the
combined organic phases were washed with brine (30 mL), dried (MgSO4)
and concentrated. The crude mixture was purified by flash column
chromatography (hexane/EtOAc 4:1) to provide 26 (1.0 g, 98%) as a
colorless oil. [a]2D0 ˆ ‡1.74 (c ˆ 1.0, CHCl3); IR (thin film): nÄmax ˆ3453 (br),
to provide pure silyl ether 30 (192 mg, 90%) as a colorless oil. [a]D20
ˆ
4.7
;
1
1
3075, 2971, 1640, 1461, 1379, 911 cm
;
1H NMR (CDCl3, 250 MHz): d ˆ
(c ˆ 1.5, CHCl3); IR (thin film): nÄmax ˆ3451 (br), 2956, 2910, 909 cm
5.78 ± 5.62 (m, 1H), 5.03 ± 4.92 (m, 2H), 3.75 ± 3.55 (m, 3H), 2.60 (brs, 1 Â
OH), 2.25 (brs, 1 Â OH), 2.23 ± 2.07 (m, 8H), 1.42 (s, 3H), 1.39 (s, 3H), 1.18
(d, J ˆ 6 Hz, 3H), 1.08 (s, 3H), 1.01 (d, J ˆ 7 Hz, 3H); 13C NMR (62.5 MHz,
CDCl3): d ˆ 144.7, 112.5, 98.9, 73.7, 73.2, 73.1, 70.7, 38.9, 37.7, 37.2, 30.0, 26.4,
1H NMR (CDCl3, 250 MHz): d ˆ 6.93 (s, 1H), 6.48 (brs, 1H), 5.73 ± 5.57 (m,
1H), 4.96 ± 4.82 (m, 2H), 4.41 (dd, J ˆ 8.5, 4.8 Hz, 1H), 3.71 (brs, 1  OH),
3.58 (dd, J ˆ 9.0, 0.9 Hz, 1H), 2.68 (s, 3H); 2.15 ± 2.02 (m, 1H), 1.99 (d, J ˆ
0.9 Hz, 3H), 1.75 ± 1.62 (m, 2H), 1.50 ± 1.20 (m, 6H), 1.05 (s, 3H), 0.98 ± 0.87
(m, 12H), 0.68 ± 0.55 (m, 6H); 13C NMR (62.5 MHz, CDCl3): d ˆ 164.5,
152.6, 144.7, 141.5, 119.6, 115.6, 112.3, 79.9, 76.2, 74.0, 38.7, 37.7, 37.2, 37.1,
‡
21.2, 21.1, 20.2, 20.0, 17.7; EI HRMS: m/z: 285.2057 [M] , calcd for
C16H29O4: 285.2066.
‡
21.4, 21.0, 20.1, 19.1, 13.8, 6.7, 4.7; EI HRMS: m/z: 467.2896 [M] , calcd for
Ketone 27, Dess ± Martin oxidation of 26: Dry pyridine (1.0 mL) and Dess ±
Martin periodinane (445 mg, 1.0 mmol) were added at 08C to a solution of
26 (200 mg, 0.67 mmol) in dry CH2Cl2 (15 mL). After stirring for 2 h at
258C, the reaction was quenched with a 1:1 mixture of aqueous Na2S2O3
solution (1m) and saturated aqueous NaHCO3 solution (20 mL). The
aqueous phase was extracted with CH2Cl2 (3 Â 15 mL) and the combined
organic phases were washed with brine (10 mL), dried (MgSO4) and
concentrated. The crude mixture was purified by flash column chromatog-
raphy (hexane/EtOAc 6:1) to provide ketone 28 (190 mg, 95%) as a
C25H45NO3SSi: 467.2889.
Mesylate 31, monomesylation of 30: Dry triethylamine (46 mg, 0.45 mmol)
followed by methanesulfonyl chloride (44 mg, 0.38 mmol) was added to a
cooled ( 208C) solution of diol 31 (70 mg, 0.15 mmol) in dry CH2Cl2
(6 mL). After stirring for 3.5 h at 208C the reaction was quenched by
addition of ice-water (10 mL) and saturated aqueous NaHCO3 solution
(10 mL). The aqueous phase was extracted with CH2Cl2 (3 Â 10 mL) and
the combined organic phases were washed with brine (20 mL), dried
(MgSO4) and concentrated. The crude mixture was purified by flash
column chromatography (hexane/EtOAc 4:1 to 3:1) to provide unstable
colorless foam. [a]D20
ˆ
24.2 (c ˆ 1.0, CHCl3); IR (thin film): nÄmax ˆ 3508
(br), 2942, 1720, 1381 cm 1; 1H NMR (CDCl3, 250 MHz): d ˆ 5.74 ± 5.56 (m,
1H), 4.88 ± 4.83 (m, 2H), 4.21 (dd, J ˆ 11.7, 3.2 Hz, 1H), 2.19 (s, 3H), 2.18 ±
2.04 (m, 1H), 1.68 (dt, J ˆ 13.0, 2.7 Hz, 1H), 1.50 ± 1.20 (m, 8H), 1.44 (s,
3H), 1.41 (s, 3H), 1.04 (s, 3H), 0.96 (d, J ˆ 6.6 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3): d ˆ 209.1, 144.7, 112.5, 99.1, 74.9, 73.4, 73.3, 38.8, 37.7,
37.2, 29.9, 26.7, 25.4, 21.2, 21.1, 20.2, 19.6.
1
mesylate 32 (75 mg, 92%) as a colorless oil. H NMR (CDCl3, 250 MHz):
d ˆ 6.95 (s, 1H), 6.56 (brs, 1H), 5.70 ± 5.53 (m, 1H), 4.91 ± 4.80 (m, 2H),
4.54 (dd, J ˆ 8.0, 3.0 Hz, 1H), 4.36 (dd, J ˆ 8.5, 5.0 Hz, 1H), 3.1 (s, 3H), 2.68
(s, 3H), 2.1 (brs, 1  OH), 2.09 ± 1.96 (m, 1H), 2.02 (d, J ˆ 1.1 Hz, 3H), 1.81
(ddd, J ˆ 13.0, 8.0, 5.0 Hz, 1H), 1.46 ± 1.17 (m, 7H), 1.25 (s, 3H), 1.0 ± 0.80
(m, 3 Â TES-CH3, 1 Â Me, 12H), 0.67 ± 0.52 (m, 6H); 13C NMR (62.5 MHz,
CDCl3): d ˆ 164.5, 152.4, 144.5, 141.6, 119.8, 116.4, 112.6, 86.2, 75.6, 74.1,
39.1, 38.9, 37.8, 37.8, 37.7, 37.1, 21.6, 20.4, 20.1, 13.0, 6.8, 4.7; EI HRMS: m/z:
Thiazolyl olefin 12, Wittig reaction of 27: A solution of Wittig salt 28
(1.12 g, 3.2 mmol) in dry THF (10 mL) was cooled to 788C and treated
dropwise with KHMDS (0.5m in toluene, 6.4 mL, 3.2 mmol). After stirring
for 45 min at 788C ketone 27 (190 mg, 0.64 mmol), dissolved in dry THF
(1.0 mL), was added to the reaction mixture at 788C. The cooling bath
was removed and the reaction mixture was stirred for 45 min at 408C. Ether
(20 mL) was added and the reaction was quenched by the addition of a
cooled solution (08C) of saturated aqueous NH4Cl (20 mL). The aqueous
phase was extracted with ether (3 Â 15 mL) and the combined organic
phases were washed with brine (20 mL), dried (MgSO4) and concentrated.
The crude mixture (E/Z ˆ 28:1, by 1H NMR analysis) was purified by flash
column chromatography (hexane/EtOAc 6:1) to provide pure compound
12 (202 mg, 80%) as a colorless oil. [a]2D0 ˆ ‡5.2 (c ˆ 1.5, CHCl3); 1H NMR
(CDCl3, 250 MHz): d ˆ 6.93 (s, 1H), 6.58 (brs, 1H), 5.78 ± 5.55 (m, 1H),
5.04 ± 4.88 (m, 2H), 4.35 (dd, J ˆ 4.5, 3.5 Hz, 1H), 3.78 (dd, J ˆ 5.5, J ˆ
4.5 Hz, 1H), 2.71 (s, 3H), 2.28 (brs, 1 Â OH), 2.22 ± 2.08 (m, 1H), 2.08 (dd,
J ˆ 0.9 Hz, 3H), 1.62 ± 1.25 (m, 8H), 1.52 (s, 3H), 1.49 (s, 3H), 1.09 (s, 3H),
‡
545.2672 [M] , calcd for C26H47O5NS2Si: 545.2665.
Oxirane 32: Dry K2CO3 (36 mg, 0.26 mmol, 2.0 equiv) was added in
portions at 258C to a solution of mesylate 31 (70 mg, 0.13 mmol) in dry
MeOH (5 mL) and the mixture was stirred for 1 h at 258C. The reaction
was quenched by the addition of ice-water (10 mL), ether (10 mL) and
saturated aqueous NH4Cl solution (10 mL). The aqueous phase was
extracted with ether (3 Â 10 mL) and the combined organic phases were
washed with brine (15 mL), dried (MgSO4) and concentrated. The crude
mixture was purified by flash column chromatography (hexane/EtOAc
10:1) to provide pure oxirane 32 (53 mg, 90%) as a colorless oil. [a]D20
ˆ
7.6 (c ˆ 0.25, CHCl3); IR (thin film): nÄmax ˆ2956, 2876, 1455, 1377, 1261,
1182, 1082, 1006, 962, 908, 739 cm 1; 1H NMR (250 MHz, CDCl3): d ˆ 6.91
(s, 1H), 6.50 (brs, 1H), 5.74 ± 5.58 (m, 1H), 4.99 ± 4.85 (m, 2H), 4.32 (dd,
J ˆ 8.9, 3.7 Hz, 1H), 2.86 (dd, J ˆ 7.5, 4.3 Hz, 1H), 2.68 (s, 3H), 2.17 ± 2.02
(m, 1H), 2.01 (d, J ˆ 1.1 Hz, 3H), 1.88 (ddd, J ˆ 13.9, 8.9, 4.3 Hz, 1H), 1.59
(ddd, J ˆ 14.0, 7.8, 4.3 Hz, 1H), 1.52 ± 1.20 (m, 6H), 1.25 (s, 3H), 0.99 ± 0.82
(m, 3 Â TES-CH3, 1 Â Me, 12H), 0.66 ± 0.55 (m, 6H); 13C NMR (62.5 MHz,
CDCl3): d ˆ 164.8, 153.1, 144.6, 142.3, 118.7, 115.3, 112.6, 76.2, 62.0, 61.7,
37.8, 36.8, 36.1, 33.1, 23.1, 20.1, 19.2, 14.1, 14.0, 6.8, 4.8; EI HRMS: m/z:
‡
1.01 (d, J ˆ 6.7 Hz, 3H); EI HRMS: m/z: 393.2336 [M] , calcd for
C22H35NO3S: 393.2338.
Triol 29, global O-deprotection of 12: A 15% aqueous HCl solution
(10 mL) was added to a solution of acetonide 12 (190 mg 0.48 mmol) in
ethanol (20 mL) and the reaction mixture was stirred for 12 h at 258C. The
reaction was quenched by the addition of ice-water (20 mL) and
neutralised by the addition of saturated aqueous NaHCO3 solution
(20 mL). The aqueous phase was extracted with EtOAc (2 Â 20 mL) and
ether (2 Â 20 mL). The combined organic phases were then washed with
brine (20 mL), dried (MgSO4) and concentrated. The crude mixture was
‡
449.2784 [M] , calcd for C25H43NO2SSi: 449.2774.
Aldehyde 7, glycolization and cleavage of alkene 32: N-Methylmorpholine-
N-oxide (0.7m aqueous solution, 0.14 mL) followed by osmium tetroxide
[0.13 mL, 0.04m solution (10 mgmL 1) in tBuOH, ca. 5 mol%] was added
at 08C to a cooled (08C) solution of alkene 33 (45 mg, 0.1 mmol) in a
2266
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Chem. Eur. J. 2001, 7, No. 10

Total Synthesis of Epothilone B
2261±2271
mixture of THFand tBuOH (1:1, 1.5 mL). After stirring for 16 h at 258C the
reaction was quenched by the addition of ice-water (5 mL), Na2S2O3
(74 mg) and CH2Cl2 (5 mL). The aqueous phase was extracted with CH2Cl2
(3 Â 10 mL) and the combined organic phases were washed with brine
(15 mL), dried (MgSO4) and concentrated. The crude mixture was filtered
through silica gel (hexane/EtOAc 1:1), concentrated and redissolved in a
5:1 mixture of ethanol and water (6 mL). NaIO4 (42 mg, 0.2 mmol) was
added at 258C. After stirring for 1 h at 258C, the reaction was quenched
with the addition of ice-water (5 mL), saturated aqueous NaHCO3 solution
(5 mL) and ether (10 mL). The aqueous phase was extracted with ether
(3 Â 10 mL) and the combined organic phases were washed with brine
(15 mL), dried (MgSO4), concentrated and purified by flash column
chromatography (hexane/EtOAc 4:1) to provide pure aldehyde 7 (28 mg,
concentrated. Purification by column chromatography (silica gel, hexane/
EtOAc 5:1) provided aldol product 36 (582 mg, 92%, ds >95:5, by 1H NMR
analysis) as a colorless oil. [a]D20
nÄmax ˆ3502, 2956, 2877, 1683, 1472, 1082, 1003, 837, 776 cm
ˆ
17.0 (c ˆ 1.05, CHCl3); IR (thin film):
1
;
1H NMR
(600 MHz, CDCl3): d ˆ 6.93 (s, 1H), 6,52 (s, 1H), 5.78 (ddt, J ˆ 17.0, 10.0,
7.0 Hz, 1H), 5.05 ± 4.98 (m, 2H), 4.34 (dd, J ˆ 9.0, 4.0 Hz, 1H), 3.93 (dd, J ˆ
6.5, 4.5 Hz, 1H), 3.50 (s, 1H, OH), 3.31 (d, J ˆ 9.0 Hz, 1H), 3.25 (q, J ˆ
7.0 Hz, 1H), 2.89 (dd, J ˆ 7.5, 4.5 Hz, 1H), 2.70 (s, 3H), 2.22 ± 2.16 (m, 1H),
2.14 ± 2.08 (m, 1H), 2.02 (s, 3H), 1.90 (ddd, J ˆ 14.0, 9.0, 4.5 Hz, 1H), 1.81 ±
1.74 (m, 1H), 1.61 (ddd, J ˆ 14.0, 7.5, 4.0 Hz, 1H), 1.57 ± 1.44 (m, 4H), 1.40 ±
1.32 (m, 1H), 1.28 (s, 3H), 1.18 (s, 3H), 1.13 (s, 3H), 1.03 (d, J ˆ 7.0 Hz, 1H,
0.95 (t, J ˆ 7.8 Hz, 9H), 0.90 (s, 9H), 0.83 (d, J ˆ 6.5 Hz, 3H), 0.62 (q, J ˆ
7.8 Hz, 6H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (100.6 MHz, CDCl3): d ˆ
222.9, 164.8, 153.5, 142.7, 136.7, 119.1, 117.1, 115.7, 76.9, 76.5, 75.3, 62.5, 61.4,
54.7, 41.5, 40.0, 36.4, 36.0, 33.8, 33.5, 26.4, 23.8, 23.1, 22.7, 19.8, 19.6, 18.6,
62% in two steps) as a colorless oil. [a]D20
ˆ
10.6 (c ˆ 1.0, CHCl3); IR (thin
1
film): nÄmax ˆ2956, 2876, 1726, 1459, 1378, 1183, 1079, 1006, 745 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 9.61 (d, J ˆ 2.0 Hz, 1H), 6.93 (s, 1H), 6.52
(s, 1H), 4.34 (dd, J ˆ 9.0, 4.0 Hz, 1H), 2.89 (dd, J ˆ 7.0, 4.5 Hz, 1H), 2.70 (s,
3H), 2.33 ± 2.25 (m, 1H), 2.02 (s, 3H), 1.89 (ddd, J ˆ 14.0, 9.0, 4.5 Hz, 1H),
1.74 ± 1.66 (m, 1H), 1.60 (ddd, J ˆ 14.0, 7.0, 4.0 Hz, 1H), 1.53 ± 1.32 (m, 5H),
1.27 (s, 3H), 1.09 (d, J ˆ 7.0 Hz, 1H), 0.94 (t, J ˆ 7.8 Hz, 9H), 0.61
(q, J ˆ 7.8 Hz, 6H); 13C NMR (100.6 MHz, CDCl3): d ˆ 205.2, 164.9,
153.4, 142.6, 119.2, 115.8, 76.5, 62.4, 61.1, 46.7, 36.4, 33.3, 31.0, 23.2, 22.6,
15.7, 14.4, 10.1, 7.2, 5.2, 3.1, 3.7; EI HRMS: m/z: 735.4773 [M] , calcd
‡
for C40H73NO5SSi2: 735.4748.
Trichloroethyl carbonate 37, protection of alcohol 36: A well stirred
solution of aldol 36 (516 mg, 0.70 mmol) in dry CH2Cl2 (25 mL) and
pyridine (1 mL) at 158C was treated with 2,2,2-trichloroethyl chlorofor-
mate (0.57 mL, 4.2 mmol). After stirring at 208C for 0.5 h, saturated
aqueous NaHCO3 solution (50 mL) was added. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (2 Â 30 mL).
The combined organic phases were dried (MgSO4) and concentrated under
reduced pressure. Purification by column chromatography (silica gel,
hexanes/EtOAc 10:1) provided 37 (580 mg, 91%) as a pale yellow oil.
‡
19.6, 14.2, 13.7, 7.2, 5.2; EI HRMS: m/z: 451.2559 [M] , calcd for
C24H41NO3SSi: 451.2576.
Hydroxy ketone 35, Hafner± Duthaler allylation: A solution of allylmag-
nesium chloride (2.0m solution in 5.5 mL THF, 11.0 mmol) was added
slowly at 08C to a solution of titanium reagent 33 (7.36 g, 12.0 mmol) in dry
ether (100 mL) and the mixture was stirred at 08C for 1.5 h. The reaction
mixture then was cooled to 788C and keto aldehyde 34 (1.41 g, 11.0 mol),
dissolved in ether (10 mL), was added. The mixture was stirred for
additional 3 h at 788C, then ammonium fluoride (45% solution in water,
50 mL) was added and the mixture was stirred at room temperature
overnight. After filtration through celite and extraction with ether (2 Â
50 mL), the combined organic phases were washed with brine (50 mL)
dried and concentrated. The solid residue was stirred with pentane
(50 mL), filtered and concentrated. Purification by flash column chroma-
tography (silica gel, hexane/EtOAc/CH2Cl2 9:1:5) afforded hydroxy ketone
35 (1.14 g, 61%) as a colorless oil, containing traces of chiral ligand (ee
[a]2D0
ˆ
34.6 (c ˆ 2.0, CHCl3); IR (thin film): nÄmax ˆ2956, 2878, 1760, 1699,
1464, 1383, 1251, 1082, 992, 928, 837, 776 cm 1; 1H NMR (400 MHz, CDCl3):
d ˆ 6.93 (s, 1H), 6.52 (s, 1H), 5.77 (ddt, J ˆ 17.0, 10.0, 7.0 Hz, 1H), 5.03 ±
4.95 (m, 2H), 4.84 (d, J ˆ 12.0 Hz, 1H), 4.81 (dd, J ˆ 7.5, 4.5 Hz, 1H), 4.68
(d, J ˆ 12.0 Hz, 1H), 4.33 (dd, J ˆ 9.0, 3.5 Hz, 1H), 3.75 (dd, J ˆ 6.3, 4.3 Hz,
1H), 3.44 (dq J ˆ 4.5, 7.0 Hz, 1H), 2.88 (dd, J ˆ 7.5, 4.5 Hz, 1H), 2.70 (s,
3H), 2.28 ± 2.19 (m, 1H), 2.05 ± 1.95 (m, 1H), 2.01 (d, J ˆ 1.0 Hz, 3H), 1.87
(ddd, J ˆ 14.0, 9.0, 4.5 Hz, 1H), 1.75 ± 1.66 (m, 1H), 1.56 (ddd, J ˆ 14.0, 7.5,
3.5 Hz, 1H), 1.54 ± 1.38 (m, 4H), 1.30 (s, 3H), 1.28 ± 1.22 (m, 1H), 1.26 (s,
3H), 1.20 ± 1.10 (m, 1H), 1.07 (d, J ˆ 7.0 Hz, 3H), 0.97 ± 0.91 (t, J ˆ 8.0 Hz,
9H‡3H), 0.89 (s, 9H), 0.61 (q, J ˆ 8.0 Hz, 6H), 0.06 (s, 6H); 13C NMR
(100.6 MHz, CDCl3): d ˆ 216.0, 164.8, 154.6, 153.4, 142.6, 136.8, 119.2, 117.0,
115.7, 95.2, 83.2, 78.5, 77.0, 76.5, 62.5, 61.1, 54.4, 42.7, 39.8, 36.4, 35.4, 33.7,
32.2, 26.5, 24.3, 23.1, 22.7, 20.4, 19.6, 18.6, 16.5, 14.4, 11.9, 7.2, 5.2, 3.3,
1
>98%, by chiral HPLC). H NMR (400 MHz, CDCl3): d ˆ 5.85 ± 5.79 (m,
1H), 5.10 ± 5.06 (m, 2H), 3.73 (dd, J ˆ 10.0, 2.5 Hz, 1H), 2.54 ± 2.38 (m,
3H), 2.24 ± 2.17 (m, 1H), 2.03 ± 1.95 (m, 1H), 1.14 (s, 3H), 1.10 (s, 3H), 0.98
(t, J ˆ 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): d ˆ 217.2, 135.6, 117.7,
75.5, 51.2, 36.3, 31.3, 21.7, 19.5, 7.8.
‡
3.5; FAB HRMS: m/z: 1042.2865 [M‡Cs] , calcd for C43H74Cl3NO7SSi2:
909.3790.
Hydroxy aldehyde 38, glycolization and cleavage of alkene 37: OsO4
Silyl ether 8, silylation of hydroxy ketone 35: 2,6-Lutidine (0.70 mL,
6.0 mmol) and TBS triflate (1.15 mL, 5.0 mmol) were added at 788C to a
solution of alcohol 35 (425 mg, 2.5 mmol) in dry CH2Cl2 (15 mL). After 1 h,
saturated aqueous NH4Cl solution (10 mL) was added and the mixture was
allowed to warm to room temperature. The aqueous layer was extracted
with CH2Cl2 (2 Â 5 mL), dried (MgSO4) and concentrated. Purification by
flash column chromatography (silica gel, hexane/EtOAc 40:1) afforded
1
(0.43 mL, 10 mgmL in tBuOH, ꢀ5 mol%) and NMO (1.7 mL, 0.2m in
H2O, 0.34 mmol) were added to
a solution of alkene 37 (311 mg,
0.34 mmol) in THF (7.5 mL) and tBuOH (7.5 mL). The mixture was stirred
for 16 h at room temperature, then Na2S2O3 (0.25 g), water (25 mL) and
CH2Cl2 (25 mL) were added. The aqueous layer was extracted with CH2Cl2
(2 Â 15 mL) and the combined organic phases were dried (MgSO4) and
concentrated. The residue was dissoved in hexane/ethyl acetate 1:1 and
filtered through silica gel to give crude diol (302 mg), which was used
without further purification. A solution of crude diol (302 mg) in ethanol
(15 mL) and water (3 mL) was treated with sodium periodate (214 mg,
1.0 mmol) and stirred for 1 h at room temperature. The mixture was poured
into saturated aqueous NaHCO3 solution (25 mL), diluted with water
(25 mL) and extracted with ether (3 Â 25 mL). The combined organic
phases were washed with brine (20 mL), dried (MgSO4) and concentrated.
Purification by flash column chromatography (silica gel, hexanes/EtOAc
silyl ether 8 (616 mg, 87%) as a colorless oil. [a]2D0 ˆ ‡3.6 (c ˆ 2.08, CHCl3);
1
IR (thin film): nÄmax ˆ2957, 2886, 1706, 1472, 1090, 1024 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 5.74 (m, 1H), 5.02 ± 4.94 (m, 2H), 3.96 (dd, J ˆ 6.5,
5.0 Hz), 2.48 (dq, J ˆ 11.3, 7.0 Hz, 2H), 2.19 ± 2.08 (m, 2H), 1.09 (s, 3H), 1.06
(s, 3H), 0.96 (t, J ˆ 7.0 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H);
13C NMR (100.6 MHz, CDCl3): d ˆ 215.8, 136.2, 116.5, 76.7, 52.9, 39.0, 31.9,
‡
26.0, 22.4, 20.2, 7.7, 3.6, 4.4; FI MS: m/z: 227 [M C4H9] , 185, 83, 57;
elemental analysis calcd for C16H32O2Si (284): C 67.54, H 11.34; found: C
67.78, H 11.24.
10:1 ! 5:1) afforded aldehyde 38 (242 mg, 78%) as a colorless oil. [a]D20
ˆ
Hydroxy ketone 36, aldol addition of ketone 8 and aldehyde 7: Diisopro-
pylamine (0.19 mL, 1.36 mmol) in dry THF (3.5 mL) was treated with
nBuLi (0.84 mL, 1.6m in hexane, 1.36 mmol) at 408C. After 20 min at
08C, the solution was cooled to 788C and ketone 8 (382 mg, 1.34 mmol),
dissolved in THF (0.5 mL), was added dropwise (3 min). After stirring for
15 min at 788C and the mixture was allowed to warm to 408C over a
period of 0.5 h. The mixture was cooled to 788C and aldehyde 7 (390 mg,
0.86 mmol), dissolved in THF (0.5 mL), was added dropwise (3 min). After
15 min at 788C, the reaction was quenched by addition of saturated
aqueous NH4Cl solution and ether (5 mL), the cooling bath was removed
and water (5 mL) was added. The aqueous layer was extracted with ether
(2 Â 10 mL) and the combined organic phases were dried (MgSO4) and
43.4 (c ˆ 1.00, CHCl3); IR (thin film): nÄmax ˆ2956, 1759, 1726, 1698, 1464,
1383, 1252, 1083, 1003, 838, 778 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.74
(s, 1H), 6.93 (s, 1H), 6.52 (s, 1H), 4.83 (d, J ˆ 12.0 Hz, 1H), 4.74 (dd, J ˆ 7.5,
4.0 Hz, 1H), 4.67 (d, J ˆ 12.0 Hz, 1H), 4.36 ± 4.31 (m, 2H), 3.44 (dq, J ˆ 4.5,
6.5 Hz, 1H), 2.88 (dd, J ˆ 7.5, 4.5 Hz, 1H), 2.70 (s, 3H), 2.67 (ddd, J ˆ 18.0,
4.5, 1.0 Hz, 1H), 2.39 (ddd, J ˆ 18.0, 5.0, 2.0 Hz, 1H), 2.02 (s, 3H), 1.86 (ddd,
J ˆ 14.0, 9.0, 4.5 Hz, 1H), 1.77 ± 1.67 (m, 1H), 1.60 ± 1.10 (m, 6H), 1.56 (ddd,
J ˆ 14.0, 7.5, 4.0 Hz, 1H), 1.33 (s, 3H), 1.26 (s, 3H), 1.06 (d, J ˆ 6.5 Hz, 3H),
1.03 (s, 3H), 0.96 (d, J ˆ 6.5 Hz, 3H), 0.94 (t, J ˆ 8.0 Hz, 9H), 0.87 (s, 9H),
0.62 (q, J ˆ 8.0 Hz, 6H), 0.11 (s, 3H), 0.03 (s, 3H); 13C NMR (100.6 MHz,
CDCl3): d ˆ 215.8, 200.8, 164.8, 154.6, 153.4, 142.6, 119.2, 115.8, 95.1, 82.7,
77.1, 76.5, 72.7, 62.5, 61.1, 53.8, 49.7, 42.6, 36.4, 35.3, 33.7, 32.3, 26.3, 23.4, 23.0,
Chem. Eur. J. 2001, 7, No. 10
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0710-2267 $ 17.50+.50/0
2267

H. J. Martin, J. Mulzer et al.
FULL PAPER
22.5, 20.4, 19.6, 18.5, 16.4, 14.9, 11.6, 4.0, 4.1; EI HRMS: m/z: 854.2844
[M C4H9] , calcd for C42H72Cl3NO8SSi2: 911.3583.
raphy (silica gel, hexane/EtOAc 2:1 ! 1:1) to give 41 (23 mg, 92%) as a
‡
colorless oil. [a]D20
ˆ
38.2 (c ˆ 1.02, CHCl3); IR (thin film): nÄmax ˆ3524,
2935, 1745, 1695, 1463, 1380, 1256, 1196, 1158, 1100, 1068, 978, 837, 777,
Hydroxy aldehyde 38, monodesilylation of 37: In a polypropylene flask, a
solution of the aldehyde 37 (204 mg, 0.22 mmol) in dry THF (4 mL) was
treated with an HF/py stock solution (6 mL; prepared from 5 mL HF/
pyridine complex, 15 mL pyridine and 10 mL THF). After stirring over a
period of 20 min at room temperature, the reaction mixture was carefully
added to a well stirred mixture of saturated aqueous NaHCO3 solution
(100 mL) and ether (20 mL). The layers were separated and the aqueous
phase was extracted with ether (3 Â 20 mL). The combined organic phases
were dried (MgSO4) and concentrated. The residue was purified by column
chromatography (deactivated silica gel, hexanes/EtOAc 2:1 ! 1:1) to give
1
757 cm 1; H NMR (400 MHz, CDCl3): d ˆ 6.98 (s, 1H), 6.55 (s, 1H), 5.17
(brd, J ˆ 10.0 Hz, 1H), 4.07 (dd, J ˆ 10.0, 2.0 Hz, 1H), 3.88 (dd, J ˆ 6.0,
2.5 Hz, 1H), 3.07 (qn, J ˆ 6.7 Hz, 1H), 2.82 ± 2.75 (m, 2H), 2.70 (s, 3H), 2.66
(dd, J ˆ 16.0, 10.0 Hz, 1H), 2.37 (brs, 1H), 2.20 (ddd, J ˆ 15.0, 3.0, 2.0 Hz,
1H), 2.10 (s, 3H), 1.87 (dt, J ˆ 15.0, 10.0 Hz, 1H), 1.80 ± 1.70 (m, 2H), 1.52 ±
1.20 (m, 5H), 1.28 (s, 3H), 1.20 (s, 3H), 1.15 (s, 3H), 1.14 (d, J ˆ 6.5 Hz, 3H),
1.03 (d, J ˆ 7.0 Hz, 3H), 0.86 (s, 9H), 0.14 (s, 3H), 0.03 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): d ˆ 216.8, 171.3, 165.2, 152.6, 137.8, 120.9, 117.0, 77.8,
76.4, 75.3, 63.3, 62.3, 53.8, 45.3, 39.8, 37.5, 34.3, 32.3, 32.1, 26.4, 25.0, 24.4,
23.6, 22.9, 19.6, 19.0, 18.7, 15.4, 15.1, 3.2, 5.2; EI HRMS: m/z: 621.3531
compound 38 (204 mg, 91%) as a pale yellow oil. [a]D20
ˆ
57.6 (c ˆ 0.50,
‡
[M] , calcd for C33H35NO6SSi: 621.3519.
CHCl3); IR (thin film): nÄmax ˆ2957, 1758, 1725, 1698, 1471, 1384, 1252, 1090,
992, 928, 838, 778 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.74 (s, 1H), 6.95
(s, 1H), 5.70 (s, 1H), 4.84 (d, J ˆ 12.0 Hz, 1H), 4.75 (dd, J ˆ 7.8, 4.3 Hz, 1H),
4.68 (d, J ˆ 12.0 Hz, 1H), 4.41 ± 4.32 (m, 2H), 3.44 (dq, J ˆ 4.0, 7.0 Hz, 1H),
2.96 (dd, J ˆ 8.0, 4.0 Hz, 1H), 2.70 (s, 3H), 2.67 (dd, J ˆ 17.5, 4.0 Hz, 1H),
2.40 (ddd, J ˆ 17.5, 5.5, 2.0 Hz, 1H), 2.09 (d, J ˆ 3.5 Hz, 1H), 2.06 (s, 3H),
1.94 (ddd, J ˆ 14.0, 9.0, 4.0 Hz, 1H), 1.78 ± 1.70 (m, 1H), 1.67 (ddd, J ˆ 14.0,
8.0, 4.0 Hz, 1H), 1.58 ± 1.42 (m, 4H), 1.38 ± 1.15 (m, 2H), 1.34 (s, 3H), 1.28
(s, 3H), 1.07 (d, J ˆ 6.5 Hz, 1H), 1.04 (s, 3H), 0.98 (d, J ˆ 7.0 Hz, 1H), 0.87
(s, 9H), 0.11 (s, 3H), 0.03 (s, 3H); 13C NMR (100.6 MHz, CDCl3): d ˆ 215.8,
200.9, 165.0, 154.6, 153.1, 142.1, 119.3, 116.2, 95.1, 82.7, 77.1, 75.8, 72.6, 62.2,
61.1, 53.8, 49.7, 42.6, 35.3, 34.5, 33.6, 32.3, 26.3, 23.4, 23.0, 22.5, 20.4, 19.6,
Epothilone B (1): In a polypropylene flask, a solution of 41 (10.5 mg,
0.017 mmol) was dissolved in dry pyridine (1.6 mL) and treated with HF/
pyridine complex (0.4 mL). After stirring over a period of 7 d at 358C, the
reaction mixture was carefully added to a well stirred mixture of saturated
aqueous NaHCO3 solution (25 mL) and ether (15 mL). The layers were
separated and the aqueous phase was extracted with ether (3 Â 10 mL). The
combined organic phases were dried (MgSO4) and concentrated. The
residue was purified by column chromatography (silica gel, hexanes/EtOAc
2:1 ! 1:1) to give epothilone B (5.8 mg, 67%) as a colorless oil, which
crystallized upon standing (m.p. 90 ± 928C). [a]D20
ˆ
35.5 (c ˆ 0.20,
1
MeOH); H NMR (600 MHz, CDCl3): d ˆ 6.97 (s, 1H), 6.59 (s, 1H), 5.41
(dd, J ˆ 7.8, 2.8 Hz, 1H), 4.26 ± 4.21 (m, 1H), 4.18 (brd, J ˆ 6.0 Hz, 1H;
OH), 3.77 (dd, J ˆ 5.5, 3.5 Hz, 1H), 3.30 (dq, J ˆ 4.2, 6.8 Hz, 1H), 2.81 (dd,
J ˆ 7.5, 4.5 Hz, 1H), 2.70 (s, 3H), 2.65 (brs, 1H, OH), 2.54 (dd, J ˆ 14.0,
10.2 Hz, 1H), 2.37 (dd, J ˆ 14.0, 3.0 Hz, 1H), 2.11 (dd, J ˆ 3.5, 4.5 Hz), 2.09
(s, 3H), 1.92 (ddd, J ˆ 15.6, 7.8, 7.6 Hz, 1H), 1.77 ± 1.68 (m, 2H), 1.54 ± 1.46
(m, 2H), 1.45 ± 1.37 (m, 3H), 1.37 (s, 3H), 1.28 (s, 3H), 1.25 (s, 3H), 1.16 (d,
J ˆ 6.8 Hz, 3H), 1.08 (s, 3H), 1.00 (d, J ˆ 7.0 Hz, 3H); 13C NMR (150 MHz,
CDCl3): d ˆ 220.6, 170.6, 165.1, 151.8, 137.5, 119.7, 116.1, 76.7, 74.1, 72.9,
61.6, 61.3, 53.1, 42.9, 39.2, 36.4, 32.3, 32.0, 30.8, 22.7, 22.3, 21.4, 19.7, 19.1, 17.0,
15.8, 13.6.
18.5, 16.4, 14.9, 11.6, 4.0,
[M‡Cs] , calcd for C36H58Cl3NO8SSi: 797.2718.
4.1; FAB HRMS (CsI): m/z: 930.1764
‡
Hydroxy acid 39, Pinnick oxidation of aldehyde 38: A solution of sodium
chlorite (55 mg, 0.51 mmol) and NaH2PO4 (55 mg) in water (1 mL) was
added to a solution of aldehyde 38 (151 mg, 0.188 mmol) in tBuOH (5 mL)
and 2,3-dimethyl-2-butene. The mixture was stirred at room temperature
for 45 min and quenched by addition of saturated aqueous NH4Cl solution
(10 mL) and water (10 mL). After extraction with CH2Cl2 (3 Â 10 mL), the
combined organic phases were dried (MgSO4) and concentrated to give
crude seco-acid 39 (148 mg) which was used without further purification.
1H NMR (400 MHz, CDCl3): d ˆ 6.97 (s, 1H), 6.75 (s, 1H), 4.91 (d, J ˆ
12.0 Hz, 1H), 4.77 (dd, J ˆ 8.5, 4.0 Hz, 1H), 4.67 (d, J ˆ 12.0 Hz, 1H), 4.47
(dd, J ˆ 7.5, 2.0 Hz, 1H), 4.32 (t, J ˆ 7.0 Hz, 1H), 3.46 ± 3.38 (m, 1H), 2.85 (t,
J ˆ 6.0 Hz, 1H), 2.70 (s, 3H), 2.59 (dd, J ˆ 17.0, 2.0 Hz,1H), 2.35 (dd, J ˆ
17.0, 7.5 Hz, 1H), 2.00 (s, 3H), 1.82 ± 1.20 (m, 9H), 1.26 (s, 3H), 1.17 (s, 3H),
1.12 (d, J ˆ 6.5 Hz, 3H), 1.11 (s, 3H), 1.04 (d, J ˆ 7.0 Hz, 1H), 0.89 (s, 9H),
0.13 (s, 3H), 0.08 (s, 3H).
Alcohol 44, reduction of 43: A cooled (08C) solution of methyl ester 43
(Schering, ZK 204027, 3.0 g, 14 mmol) in ether (200 mL) was treated
portionwise with LiAlH4 (531 mg, 14 mmol). The reaction mixture was
stirred for 3.5 h at 258C and then quenched by dropwise addition of ice-
water (50 mL) and saturated aqueous NH4Cl solution (50 mL). The phases
were separated, the aqueous phase was extracted twice with ether, and the
combined organic phases were washed with brine (30 mL) and dried over
MgSO4. Purification by flash column chromatography (hexane/EtOAc 5:1)
Lactone 40, Yamaguchi cyclization of hydroxy acid 39: Dry triethylamine
(0.06 mL, 0.42 mmol) and 2,4,6-trichlorobenzoyl chloride (0.053 mL,
0.28 mmol) were added at 08C to a solution of crude seco-acid 39
(140 mg, 0.170 mmol) in dry toluene (1.5 mL). After stirring the mixture at
room temperature for one hour, it was diluted with dry toluene (3.5 mL)
and slowly added to a solution of DMAP (208 mg, 1.70 mmol) in toluene
(95 mL) via syringe pump over a period of 1 h. After addition was
completed, stirring was continued for 0.5 h, then the reaction mixture was
concentrated to a ꢀ20 mL volume and filtered through silica gel. The
solution was concentrated and purified by column chromatography (silica
gel, hexane/EtOAc 4:1) to provide lactone 40 (88 mg, 65%) as a colorless
gave the alcohol 44 (2.53 g, 97%) as a colorless liquid. [a]D20
ˆ
13.7 (c ˆ
6.1, CHCl3); IR (thin film): nÄmax ˆ3453 (br), 2937, 1464, 1415, 1332, 1276,
1178, 1095, 1031, 949 cm 1; 1H NMR (250 MHz, CDCl3): d ˆ 3.97 ± 3.91 (m,
4H), 3.59 (dd, J ˆ 11.2, 5.3 Hz, 1H), 3.44 (dd, J ˆ 11.2, 6.2 Hz, 1H), 2.87
(dd, J ˆ 5.9, 5.5 Hz, 1H), 1.75 ± 1.28 (m, 8H), 0.98 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d ˆ 113.8, 68.8, 64.5, 64.3, 41.9, 33.3, 30.5, 23.5, 20.5,
18.7; elemental analysis calcd for C10H18O3 (186): C 64.49; H 9.74; found: C
64.26, H 9.87.
Aldehyde 45, Swern oxidation of 44: DMSO (3.25 mL, 42.9 mmol,
3.75 equiv) was added dropwise at 788C to a solution of oxalyl chloride
(1.3 mL, 14.3 mmol) in CH2Cl2 (40 mL). After stirring for 15 min at 788C,
a solution of the above alcohol 44 (2.13 g, 11.44 mmol), dissolved in dry
CH2Cl2 (20 mL), was added dropwise at 788C. The solution was stirred
for 15 min, then DIPEA (13 mL, 75.6 mmol) was added. After 10 min the
mixture was allowed to warm to 08C over a 1 h. The mixture was diluted
with CH2Cl2 (60 mL) and quenched by addition of ice-water (60 mL) and
saturated aqueous NH4Cl solution (30 mL). The phases were separated, the
aqueous phase was extracted twice with CH2Cl2, and the combined organic
phases were washed with brine (30 mL) and dried over MgSO4. After
filtration through a short pad of silica gel (hexane/EtOAc 10:1), the solvent
was removed under reduced pressure and the unstable crude aldehyde 45
(1.9 g, 90%) was subjected to the next reaction without further purification.
IR (thin film): nÄmax ˆ3262 (br), 2939, 1722, 1461, 1353, 1277, 1182, 1044,
1018, 991 cm 1; 1H NMR (250 MHz, CDCl3): d ˆ 9.7 (s, 1H), 4.05 ± 3.90 (m,
4H), 2.05 ± 1.90 (m, 1H), 1.80 ± 1.40 (m, 8H), 1.1 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): dˆ 205.7, 110.8, 65.1, 64.7, 53.7, 32.2, 31.2, 23.3, 20.8, 16.3.
oil. [a]2D0 ˆ ‡4.8 (c ˆ 1.00, CHCl3); IR (thin film): nÄmax ˆ2958, 2934, 1760,
1
1698, 1464, 1380, 1248, 1158, 1100, 1067, 930, 827, 778 cm
;
1H NMR
(600 MHz, CDCl3): d ˆ 6.99 (s, 1H), 6.56 (s, 1H), 5.21 ± 5.14 (m, 2H), 4.87
(d, J ˆ 12.0 Hz, 1H), 4.75 (d, J ˆ 12 Hz, 1H), 4.05 (d, J ˆ 9.8 Hz, 1H), 3.30
(dq, J ˆ 10.2, 6.3 Hz, 1H), 2.82 (dd, J ˆ 10.3, 4.0 Hz, 1H), 2.79 (dd, J ˆ 16.5,
1.5 Hz, 1H), 2.71 (s, 3H), 2.64 (dd, J ˆ 16.5, 10.0 Hz, 1H), 2.25 ± 2.21 (m,
1H), 2.11 (s, 3H), 1.93 ± 1.64 (m, 4H), 1.55 ± 1.42 (m, 2H), 1.32 ± 1.24 (m,
1H), 1.28 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H), 1.16 ± 1.08 (m, 1H), 1.12 (d, J ˆ
6.7 Hz, 3H), 1.03 (d, J ˆ 6.7 Hz, 3H), 0.88 (s, 9H), 0.16 (s, 3H), 0.03 (s,
3H); 13C NMR (150.1 MHz, CDCl3): d ˆ 212.8, 171.2, 165.2, 155.0, 95.2,
86.7, 77.9, 77.0, 76.5, 63.1, 62.3, 53.8, 46.1, 39.6, 35.5, 34.5, 31.9, 31.6, 26.5,
25.5, 24.5, 24.2, 23.0, 19.6, 19.5, 19.0, 16.7, 14.7, 3.1, 5.3; EI HRMS: m/z:
‡
795.2541 [M] , calcd for C36H56Cl3NO8SSi: 795.2562.
Hydroxy lactone 41: Zinc powder (200 mg) and NH4Cl (200 mg) were
added to a solution of lactone 40 (32 mg, 0.040 mmol) in dry ethanol
(3 mL). After refluxing over a period of 20 min, the mixture was cooled to
room temperature, diluted with EtOAc (10 mL) and filtered through celite.
The solution was concentrated and purified by flash column chromatog-
Alcohol 46, Brown allylation: A solution of MgBr2 ´ Et2O (3.1 mL, 1m
solution in ether, 3.1 mmol) was added to a cooled solution ( 788C) of
2268
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0710-2268 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 10

Total Synthesis of Epothilone B
2261±2271
(
)-DIPCl (Aldrich No. 31,702 ± 0, 988 mg, 3.08 mmol) in dry ether
for (6R,7R)-isomer 48 and 12.2 min for its isomer] gave pure 48 (201 mg),
52 mg of its isomer and 50 mg unreacted aldehyde 7.
(20 mL). The reaction mixture was stirred for 30 min, and then warmed
to room temperature without removing the precipitated magnesium salts.
The suspension was cooled to 788C and the above aldehyde 45 (474 mg,
2.57 mmol), dissolved in dry THF (3 mL), was added dropwise with stirring
over a period of 3 h. The magnesium salts were removed, the mixture was
treated with 3n NaOH (3 mL, 9 mmol) and 30% H2O2 (1.2 mL) and then
stirred at 508C overnight. The organic layer was separated and washed with
saturated aqueous NH4Cl solution (50 mL) and brine (20 mL), and dried
over MgSO4. After filtration and removal of the solvent under reduced
pressure, the residue was purified by flash column chromatography
(hexane/EtOAc 10:1) to give 283 mg a mixture of epimers in ca. 6:1 ration
(by 1H NMR analysis). The mixture was dissolved in acetone/water 3:2
(30 mL) and treated with p-TsOH ´ H2O (30 mg) at 258C. The reaction
mixture was stirred overnight and quenched by addition of saturated
aqueous NaHCO3 solution (10 mL) and ether (20 mL). The organic layer
was separated and the aqueous phase was extracted with ether (5 Â 20 mL).
The combined organic phases were dried over MgSO4, concentrated under
reduced pressure, and the crude mixture was purified by flash column
chromatography (hexane/EtOAc 5:1). The mixture of epimers was
separated by HPLC (Supersphere Si60, 241 Â 16 mm, 15% EtOAc in
hexane, 20 mLmin 1, UV254, 10.0 min for 46 and 11.0 min for epi-46) to give
pure 202 mg 46 und 33 mg epi-46 (50% yield in two steps).
(6R,7R)-Hydroxy ketone 48: [a]D20 ˆ ‡19.0 (c ˆ 0.7, CHCl3); IR (thin film):
1
nÄmax ˆ3105 (br), 2957, 2757, 2708, 1726, 1505, 1459, 1378, 1240, 1005 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 6.90 (s, 1H), 6.5 (brs, 1H), 5.82 ± 5.63 (m,
1H), 5.04 ± 4.92 (m, 2H), 4.31 (dd, J ˆ 8.7, 3.7 Hz, 1H), 4.19 (dd, J ˆ 6.6,
4.8 Hz, 1H), 3.76 ± 3.65 (m, 1H), 3.16 (d, J ˆ 3.2 Hz, 1  OH), 2.85 (dd, J ˆ
7.3, 4.3 Hz, 1H), 2.67 (s, 3H), 2.55 ± 2.41 (m, 1H), 2.30 ± 1.78 (m, 6H), 1.99
(d, J ˆ 1.4 Hz, 3H), 1.65 ± 1.20 (m, 11H), 1.25 (s, 3H), 0.90 ± 0.79 (m, (1 Â
TBS-tBu, 3 Â TES-CH3, 2 Â Me, 24H), 0.65 ± 0.52 (m, 6H), 0.08 (s, 3H),
0.06 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d ˆ 219.1, 164.4, 153.1, 142.3,
135.4, 118.7, 117.7, 115.3, 76.1, 73.0, 72.8, 62.1, 61.0, 56.2, 51.6, 38.6, 37.2, 36.1,
34.4, 33.6, 33.2, 30.7, 26.0, 23.2, 22.3, 20.1, 19.2, 18.3, 16.7, 14.0, 12.5, 6.8, 4.8,
‡
3.4, 4.2; EI HRMS: m/z: 747.4722 [M] , calcd for C41H73NO5SSi2:
747.4748.
Trichloroethyl carbonate 49, protection of alcohol 48: A solution of alcohol
48 (106 mg, 0.14 mmol) in dry CH2Cl2 (5 mL) was treated with dry pyridine
(0.25 mL) and TrocCl (0.1 mL, 0.74 mmol) at 08C. After stirring for 40 min
at 258C, the reaction mixture was quenched by addition of ice-water
(10 mL), saturated aqueous NaHCO3 solution (5 mL) and CH2Cl2 (10 mL).
The organic layer was separated, and the aqueous phase was extracted with
CH2Cl2 (3 Â 10 mL). The combined organic phases were dried over MgSO4
and concentrated. Purification by flash column chromatography (hexane/
EtOAc/CH2Cl2 5:0.3:2) gave pure 49 (127 mg, 98%) as a colorless oil:
(S,R)-Isomer 46: [a]D20
(br), 2938, 1699, 1452, 1054, 910, 610 cm
ˆ
10.2 (c ˆ 1.1, CHCl3); IR (thin film): nÄmax ˆ3483
1
;
1H NMR (250 MHz, CDCl3):
[a]2D0 ˆ ‡35.64 (c ˆ 0.55, CHCl3); IR (thin film): nÄmax ˆ 2954, 1765, 1711,
1
d ˆ 5.98 ± 5.78 (m, 1H), 5.18 ± 5.01 (m, 2H), 3.91 (ddd, J ˆ 9.8, 4.6, 3.2 Hz,
1H), 2.55 ± 1.50 (m, 10 H, 1 Â OH), 1.11 (s, 3H); 13C NMR (62.5 MHz,
CDCl3): d ˆ 216.9, 136.2, 116.9, 73.8, 53.0, 39.2, 35.0, 32.7, 26.6, 20.7, 20.0; EI
1461, 1378 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 6.9 (s, 1H), 6.49 (brs,
1H), 5.82 ± 5.64 (m, 1H), 5.18 (dd, J ˆ 9.1, 1.8 Hz, 1H), 5.10 ± 4.97 (m, 2H),
4.72 (s, 2H), 4.31 (dd, J ˆ 9.1, 3.4 Hz, 1H), 4.20 (dd, J ˆ 6.6, 5.0 Hz, 1H),
2.86 (dd, J ˆ 7.5, 4.1 Hz, 1H), 2.82 ± 2.69 (m, 1H), 2.67 (s, 3H), 2.30 ± 1.74
(m, 6H), 2.00 (d, J ˆ 1.1 Hz, 3H), 1.68 ± 1.12 (m, 11H), 1.25 (s, 3H), 0.97 ±
0.83 (m, (1 Â TBS-tBu, 3 Â TES-CH3, 2 Â Me, 24H), 0.66 ± 0.53 (m, 6H),
0.11 (s, 3H), 0.09 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d ˆ 212.8, 164.4,
153.9, 153.1, 142.3, 135.2, 118.7, 117.9, 115.3, 94.9, 79.2, 76.5, 76.2, 72.9, 62.1,
60.9, 56.2, 50.0, 38.7, 37.9, 36.0, 33.7, 33.1, 30.9, 29.7, 25.9, 23.2, 22.3, 20.5,
19.2, 18.3, 16.4, 14.0, 12.8, 6.8, 4.8, 3.4, 4.2; EI HRMS: m/z: 921.3813
‡
HRMS: m/z: 182.1312 [M] , calcd for C11H18O2: 182.1307.
(R,R)-Isomer epi-46: [a]D20
3483 (br), 2938, 1699, 1452, 1054, 910, 610 cm
ˆ
55.4 (c ˆ 1.1, CHCl3); IR (thin film): nÄmax
ˆ
1
;
1H NMR (250 MHz,
CDCl3): d ˆ 5.99 ± 5.80 (m, 1H), 5.14 ± 5.02 (m, 2H), 3.83 (dt, J ˆ 10.0,
3.0 Hz, 1H), 3.18 (d, J ˆ 3.0 Hz, 1  OH), 2.58 ± 2.42 (m, 1H), 2.37 ± 2.50
(m, 1H), 2.24 ± 1.50 (m, 8H), 1.16 (s, 3H); 13C NMR (62.5 MHz, CDCl3):
d ˆ 218.3, 136.1, 116.8, 74.7, 52.2, 38.9, 36.2, 34.9, 27.2, 20.8, 16.8; EI HRMS:
‡
[M] , calcd for C44H74Cl3NO7SSi2: 921.3790.
‡
m/z: 182.1313 [M] , calcd for C11H18O2: 182.1307.
Aldehyde 50, glycolization and cleavage of alkene 49: N-Methylmorpho-
line-N-oxide (0.7m aqueous solution, 0.3 mL) followed by osmium
tetroxide [0.26 mL, 0.04m solution (10 mgmL 1) in tBuOH, ca. 5 mol%]
was added at 08C to a cooled (08C) solution of alkene 49 (190 mg,
0.206 mmol) in a mixture of THF and tBuOH (1:1, 4 mL). After stirring for
16 h at 258C the reaction was quenched by the addition of ice-water
(10 mL), Na2S2O3 (148 mg) and CH2Cl2 (10 mL). The aqueous phase was
extracted with CH2Cl2 (3 Â 10 mL) and the combined organic phases were
washed with brine (20 mL), dried (MgSO4) and concentrated. The crude
mixture was filtered through silica gel (hexane/EtOAc 1:1), concentrated
and redissolved in a 5:1 mixture of ethanol and water (15 mL). NaIO4
(84 mg, ꢀ0.2 mmol) was added at 258C. After stirring for 1 h at 258C the
reaction was quenched with the addition of ice-water (10 mL), saturated
aqueous NaHCO3 solution (10 mL) and ether (20 mL). The aqueous phase
was extracted with ether (3 Â 20 mL) and the combined organic phases
were washed with brine (20 mL), dried (MgSO4), concentrated and purified
by flash column chromatography (hexane/EtOAc 9:1) to provide pure
Silyl ether 47: 2,6-Lutidine (1.0 mL, ca. 8.7 mmol) and TBS triflate
(1.35 mL, 5.86 mmol) were added sequentially to a cooled (08C) solution
of 46 (534 mg, 2.93 mmol) in dry CH2Cl2 (30 mL). After stirring for 1 h, the
reaction mixture was quenched with saturated aqueous NH4Cl solution
(10 mL) and the aqueous phase was extracted with CH2Cl2 (3 Â 20 mL).
The combined organic phases were washed with brine (20 mL) and dried
over MgSO4. After filtration and removal of the solvent under reduced
pressure, the residue was purified by flash column chromatography
(hexane/EtOAc 30:1) to give 47 as colorless liquid (834 mg, 96%).
[a]2D0 ˆ ‡99.5 (c ˆ 2.3, CHCl3); IR (thin film): nÄmax ˆ2934, 2857,1707,
1
1471, 1462, 1252, 1094, 911 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 5.87 ±
5.69 (m, 1H), 5.04 ± 4.93 (m, 2H), 4.22 (dd, J ˆ 6.4, 5.0 Hz, 1H), 2.36 ± 2.27
(m, 2H), 2.20 ± 2.07 (m, 3H), 1.93 ± 1.55 (m, 4H), 1.47 ± 1.35 (m, 1H), 0.98 (s,
3H), 0.85 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR (62.5 MHz, CDCl3):
d ˆ 214.9, 136.3, 116.9, 73.5, 54.8, 40.0, 38.0, 34.8, 26.9, 26.0, 20.8, 18.6, 18.3,
‡
3.6, 4.3; EI HRMS: m/z: 296.2161 [M] , calcd for C17H32O2Si: 296.2172.
aldehyde 50 (120 mg, 64% in two steps) as a colorless oil. [a]2D0 ˆ ‡33.0
Hydroxy ketones 48, aldol addition of ketone 47 and aldehyde 7: A solution
of ketone 47 (241 mg, 0.81 mmol) in dry THF (0.5 mL) was added dropwise
to a freshly prepared solution of LDA [2.7 mL, 0.81 mmol; nBuLi (1.55 mL,
1.6 m solution in hexanes, 2.5 mmol) was added to diisopropylamine
(0.35 mL, 2.5 mmol) in 6.1 mL dry THF at 08C] at 788C. After stirring
for 10 min, the solution was allowed to warm to 408C, and after 30 min at
that temperature, it was recooled to 788C. A solution of aldehyde 7
(244 mg, 0.54 mmol) in dry THF (0.5 mL) was added dropwise. The
resulting mixture was stirred for 10 min at 788C and then quenched by
slow addition of saturated aqueous NH4Cl solution (3 mL). The reaction
mixture was warmed to 08C, and ether (5 mL) was added, followed by
addition of ice-water (5 mL). The organic layer was separated, and the
aqueous phase was extracted with ether (3 Â 10 mL). The combined
organic phases was dried over MgSO4 and concentrated under reduce
pressure to afford a mixture of aldol products (6R,7R)-isomer 48 and one
isomer in a ca. 4:1 ratio (78%, by 1H NMR analysis). Purification by flash
column chromatography (hexane/EtOAc 10:1) and HPLC [Supersphere
Si60-4, 241 Â 16 mm, 13% EtOAc in hexane, 20 mLmin 1, UV254, 8.0 min
1
(c ˆ 1.3, CHCl3); IR (thin film): nÄmax ˆ2954, 1765, 1711, 1461, 1378 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 9.71 (d, J ˆ 0.9 Hz, 1  CHO), 6.91 (s,
1H), 6.50 (brs, 1H), 5.12 (dd, J ˆ 9.4, 2.3 Hz, 1H), 4.93 (dd, J ˆ 5.5, 3.7 Hz,
1H), 4.81 (d, J ˆ 12.1 Hz, 1H), 4.61 (d, J ˆ 11.9 Hz, 1H), 4.31 (dd, J ˆ 8.9,
3.7 Hz, 1H), 2.86 (dd, J ˆ 7.5, 4.1 Hz, 1H), 2.8 ± 2.69 (m, 1H), 2.67 (s, 3H),
2.57 (dd, J ˆ 5.7, 1.4 Hz, 0.3H), 2.49 (dd, J ˆ 5.7, 1.4 Hz, 0.7H), 2.36 (d, J ˆ
3.7 Hz, 0.7H), 2.28 (d, J ˆ 3.7, 0.3H), 2.28 ± 2.16 (m, 1H), 2.07 ± 1.83 (m,
3H), 2.00 (d, J ˆ 1.4 Hz, 3H), 1.74 ± 1.12 (m, 11H), 1.25 (s, 3H), 0.98 ± 0.79
(m, 1 Â TBS-tBu, 3 Â TES-CH3, 2 Â Me, 24H), 0.65 ± 0.53 (m, 6H), 0.14 (s,
3H), 0.01 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d ˆ 213.0, 199.9, 164.4,
153.8, 153.1, 142.3, 118.7, 115.3, 94.9, 79.5, 76.5, 76.2, 65.2, 62.1, 60.9, 55.9,
50.3, 48.5, 36.8, 36.0, 33.6, 33.1, 30.2, 29.7, 25.8, 23.1, 22.3, 20.6, 19.2, 18.1,
‡
16.5, 14.0, 12.8, 6.8, 4.8, 4.6, 4.8; EI HRMS: m/z: 923.3554 [M] , calcd
for C43H72Cl3NO8SSi2: 923.3583.
Hydroxy aldehyde 51, monodesilylation of 50: A solution of 50 (90 mg,
0.097 mmol) in dry THF (4 mL) was treated with a stock solution of HF/py
(3 mL) [prepared from HF/pyridine complex (5 mL), dry pyridine (15 mL)
Chem. Eur. J. 2001, 7, No. 10
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0710-2269 $ 17.50+.50/0
2269

H. J. Martin, J. Mulzer et al.
FULL PAPER
and dry THF (10 mL)]. After stirring for 20 min at 258C, the reaction
mixture was cooled at 08C and quenched by addition of saturated aqueous
NaHCO3 solution (50 mL) and ether (10 mL). The aqueous phase was
extracted with ether (3 Â 20 mL) and the combined organic phases were
washed with brine (20 mL), dried (MgSO4) and concentrated. The crude
mixture was filtered through silica gel (hexane/EtOAc 2:1) and gave
compound 51 (68 mg, 88%) as a colorless oil. [a]2D0 ˆ ‡33.9 (c ˆ 1.25,
CHCl3); Rf ˆ 0.23 (2.5% MeOH in CH2Cl2); IR (thin film): nÄmax ˆ3396(br),
2955, 2932, 2857, 1765, 1711, 1507, 1379 cm 1; 1H NMR (250 MHz, CDCl3):
d ˆ 9.71 (d, J ˆ 0.9 Hz, 1  CHO), 6.93 (s, 1H), 6.58 (brs, 1H), 5.14 (dd, J ˆ
9.1, 2.1 Hz, 1H), 4.92 (dd, J ˆ 5.5, 3.2 Hz, 1H), 4.79 (d, J ˆ 11.9 Hz, 1H),
4.61 (d, J ˆ 11.9 Hz, 1H), 4.40 ± 4.30 (m, 1H), 2.93 (dd, J ˆ 7.8, 4.3 Hz, 1H),
2.80 ± 2.69 (m, 1H), 2.67 (s, 3H), 2.57 (dd, J ˆ 5.7, 1.4 Hz, 0.3H), 2.49 (dd,
J ˆ 5.7, 1.4 Hz, 0.7 Hz), 2.36 (d, J ˆ 3.4 Hz, 0.7H), 2.28 (d, J ˆ 3.4, 0.3H),
2.26 ± 2.15 (m, 1H, 1  OH), 2.05 (d, J ˆ 1.1 Hz, 3H), 2.03 ± 1.89 (m, 3H),
1.74 ± 1.12 (m, 11H), 1.25 (s, 3H), 0.95 ± 0.80 (m, 1 Â TBS-tBu, 2 Â Me,
15H), 0.13 (s, 3H), 0.02 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d ˆ 213.0,
199.9, 164.6, 153.9, 152.8, 141.8, 118.8, 115.7, 94.6, 79.3, 76.5, 75.4, 65.2, 61.9,
60.9, 55.9, 50.3, 48.6, 36.8, 36.1, 33.7, 33.7, 33.2, 30.3, 25.8, 23.3, 22.1, 20.6,
was cooled at 08C and quenched by addition of saturated aqueous NaHCO3
solution (10 mL) and ether (5 mL). The aqueous phase was extracted with
ether (3 Â 10 mL) and the combined organic phases were dried (MgSO4)
and concentrated. Purification by flash column chromatography (hexane/
EtOAc 1:1 ! 1:2) and HPLC (Supersphere Si60-4, 250 Â 4 mm, 10%
iPrOH in hexane, 2 mLmin 1, UV254, 8.0 min) furnished lactone 42 (1.9 mg,
50%) as a colorless wax. [a]D20 ˆ ‡8.1 (c ˆ 0.25, CHCl3); Rf ˆ 0.44 (hexane/
EtOAc 1:2); 1H NMR (250 MHz, CDCl3): d ˆ 6.94, (s, 1H), 6.58 (brs, 1H),
5.28 (d, J ˆ 3.2 Hz, 1H), 4.83 ± 4.76 (m, 1H), 3.97 (d, J ˆ 5.5 Hz, 1H), 3.17
(d, J ˆ 3.0 Hz, 1H), 2.95 ± 2.83 (m, 1H), 2.79 (dd, J ˆ 9.7, 2.2 Hz, 1H), 2.65
(s, 3H), 2.38 (dd, J ˆ 9.0, 2.3 Hz, 1H), 2.20 (dd, J ˆ 9.0, 4.4 Hz, 1H), 2.12 ±
1.90 (m, 2H), 2.03 (d, J ˆ 1.1 Hz, 3H), 1.80 ± 1.40 (m, 14H), 1.25 (s, 3H),
1.07 (d, J ˆ 6.6 Hz, 3H), 0.9 (s, 3H); 13C NMR (150 MHz, CDCl3): d ˆ
218.5, 170.5, 165.6, 153.0, 139.6, 119.0, 115.4, 78.7, 76.1, 68.4, 63.0, 62.0, 56.0,
49.2, 38.9, 38.7, 38.0, 36.3, 34.3, 32.9, 32.7, 25.1, 22.1, 20.7, 18.9, 17.7, 16.0, 15.3;
‡
EI HRMS: m/z: 519.2667 [M] , calcd for C28H41NO6S: 519.2655.
Acknowledgement
‡
19.2, 18.1, 16.5, 14.6, 13.0, 4.3, 4.8; EI HRMS: m/z: 809.2685 [M] , calcd
for C37H58Cl3NO8SSi: 809.2718.
Financial support by the Austrian Science Foundation (FWF) (Project
P-12677-CHE) and by the Schering AG, Berlin is gratefully acknowledged.
We also thank Prof. W. Skuballa, Schering AG for providing us with the
compound ZK 204027, Dr. U. Klar, Schering AG for performing the
biological tests with compound 42 and Sabine Schneider for HPLC support.
Lactone 52, Pinnick oxidation and Yamaguchi macrolactonization: A
solution of NaClO2 (21 mg, 0.23 mmol) and NaH2PO4 (21 mg) in water
(0.5 mL) was added to
a solution of hydroxy aldehyde 51 (57 mg,
0.07 mmol) in tBuOH/2,3-dimethyl-but-2-ene (1:1, 4.4 mL) and the reac-
tion was stirred for 2 h at 258C. The solution was concentrated under
reduced pressure and subjected to flash column chromatography (silica gel,
2.5% MeOH in CH2Cl2) to give seco-acid (28 mg, 48%) as a colorless oil:
Rf ˆ 0.12 (2.5% MeOH in CH2Cl2). A solution of the above seco-acid
(28 mg, 0.034 mmol) in dry toluene (1 mL) was treated at 08C with dry
Et3N (0.14 mmol) and 2,4,6-trichlorobenzoyl chloride (0.07 mmol). The
reaction mixture was stirred at 08C for 1 h and then added (over 3 h) to a
solution of DMAP (50 mg, 0.3 mmol) in dry toluene (100 mL) at 258C and
stirred at that temperature for 30 min. The reaction mixture was
concentrated under reduced pressure to a small volume and filtered
through silica gel. The residue was washed with 40% EtOAc in hexane
(20 mL), and the resulting solution was concentrated. Purification by flash
column chromatography (hexane/EtOAc 5:1) furnished lactone 52 (10 mg,
36%) as a colorless oil. [a]D20 ˆ ‡7.2 (c ˆ 0.5, CHCl3); Rf ˆ 0.43 (hexane/
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EtOAc 4:1); IR (thin film): nÄmax ˆ2925, 2854, 1755, 1709, 1656, 1379, 1250,
1
1111 cm
;
1H NMR (250 MHz, CDCl3): d ˆ 6.99 (s, 1H), 6.55 (brs, 1H),
5.31 (t, J ˆ 7.0 Hz, 1H), 4.85 (d, J ˆ 12.1 Hz, 1H), 4.68 (d, J ˆ 12.0 Hz, 1H),
4.61 (t, J ˆ 5.5 Hz, 1H), 4.44 (dd, J ˆ 10.3, 2.3 Hz, 1H), 3.18 ± 3.07 (m, 1H),
2.75 ± 2.67 (m, 1H), 2.69 (s, 3H), 2.48 ± 2.00 (m, 4H), 2.39 (dd, J ˆ 5.3,
3.7 Hz, 2H), 2.16 (d, J ˆ 1.4 Hz, 3H), 1.96 ± 1.12 (m, 11H), 1.25 (s, 3H),
0.98 ± 0.80 (m, 1 Â TBS-tBu, 2 Â Me, 15H), 0.01 (s, 3H), 0.02 (s, 3H);
13C NMR (62.5 MHz, CDCl3): d ˆ 210.2, 170.7, 164.8, 155.2, 152.1, 135.8,
122.6, 117.1, 94.9, 85.2, 79.0, 76.7, 68.7, 61.8, 61.0, 56.0, 48.1, 39.5, 37.1, 36.2,
33.8, 32.2, 31.9, 29.4, 25.8, 25.5, 22.7, 22.0, 19.3, 18.2, 16.3, 14.8, 14.1, 4.0,
‡
4.6; EI HRMS: m/z: 807.2587 [M] , calcd for C37H56Cl3NO8SSi: 807.2561.
Hydroxy lactone 53, Troc-deprotection of 52: A solution of 52 (8.0 mg,
0.01 mmol) in dry EtOH (2 mL) was treated with Zn powder (40 mg) and
NH4Cl (40 mg) at a rate sufficient to maintain a gentle reflux for 30 min.
EtOAc (5 mL) was added at 08C and the mixture was filtered through silica
gel. The resulting solution was concentrated under reduced pressure.
Purification by flash column chromatography (hexane/EtOAc 3:1 ! 2:1)
gave pure product 53 (6 mg, 95%). [a]2D0 ˆ ‡22.0 (c ˆ 0.7, CHCl3); Rf ˆ 0.14
(hexane/EtOAc 4:1); 1H NMR (250 MHz, CDCl3): d ˆ 6.99 (s, 1H), 6.56
(brs, 1H), 5.38 (t, J ˆ 7.0 Hz, 1H), 4.66 (t, J ˆ 5.5 Hz, 1H), 3.03 ± 2.89 (m,
1H), 2.84 (dd, J ˆ 7.0, 2.2 Hz, 1H), 2.78 (brs, 1  OH), 2.76 ± 2.71 (m, 1H),
2.70 (s, 3H), 2.35 (t, J ˆ 5.7 Hz, 2H), 2.31 ± 2.10 (m, 2H), 2.16 (d, J ˆ 1.2 Hz,
3H), 2.09 ± 1.99 (m, 2H), 1.93 ± 1.18 (m, 11H), 1.25 (s, 3H), 1.04 (d, J ˆ
6.4 Hz, 3H), 0.93 (s, 3H), 0.89 ± 0.78 (s, 9H), 0.00 (s, 3H), 0.03 (s, 3H);
13C NMR (62.5 MHz, CDCl3): d ˆ 217.3, 170.5, 164.8, 152.1, 136.0, 122.5,
117.0, 79.5, 78.7, 69.1, 62.1, 61.1, 56.6, 49.2, 39.7, 38.5, 38.3, 33.2, 32.5, 31.9,
29.4, 25.9, 25.6, 22.7, 22.0, 19.2, 18.3, 16.0, 14.7, 14.1, 3.9, 4.6; EI HRMS:
‡
m/z: 633.3536 [M] , calcd for C34H55NO8SSi: 633.3519.
Epothilone B analogue 42, desilylation of 53: A solution of silyl ether 53
(5 mg, 0.008 mmol) in dry pyridine (1 mL) was treated with 0.5 mL of a
stock solution of HF/py [prepared from HF/pyridine complex (0.4 mL) and
dry pyridine (0.6 mL)]. After stirring for 4 d at 408C, the reaction mixture
2270
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Chem. Eur. J. 2001, 7, No. 10

Total Synthesis of Epothilone B
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Received: November 20, 2000 [F2878]
Chem. Eur. J. 2001, 7, No. 10
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