Preparation of the three C1-C7, C8-C15, and C16-N22 fragments of the Hsp90 inhibitor herbimycin A

Article abstract of DOI:10.1055/s-2005-864804

The construction of the three C16-N22 2, C1-C7 6 (as 23) and C8-C15 5 (as 32) segments of the Hsp90 inhibitor herbimycin A (1) is reported. l-Iodo-3-nitro-2,5-diphenol compound 2 was obtained in 55% yield for 3 steps from the commercially available diiodo derivative 7. Reaction between 1,1-dibromo-alkene 22 and vinyltin 17a using Pd(PPh₃)₄ or Pd(CH₃CN)₂Cl₂/CuI/diisopropylethylamine, in toluene or DMF at 85 °C, led to enyne 23 in 63% yield (19% overall yield from isopropylidene glyceraldehyde). The synthesis of the C8-C15 sub-unit 32 was performed in 3.4% overall yield for 13 steps, from the commercially available ester 24, with a Hoppe crotylation as a key step.

Full text of DOI:10.1055/s-2005-864804

LETTER
981
Preparation of the Three C1-C7, C8-C15, and C16-N22 Fragments of the
Hsp90 Inhibitor Herbimycin A
P
reparationof
y
T
hree Fragm
l
ents
o
v
f
H
erbimycin
i
A
e Centonze-Audureau,a François-Hugues Porée,b Jean-François Betzer,b Jean-Daniel Brion,*a Ange Pancrazi,*b
Janick Ardisson*b
a
CNRS-BIOCIS, Université de Châtenay-Malabry, Faculté de Pharmacie, 92296 Châtenay-Malabry, France
Fax +33(1)46835398
b
Laboratoire de Synthèse Organique Sélective et Chimie Organométallique, NRS-UCP-ESCOM, UMR 8123 ESCOM,
Bat E 13 Bd de l’Hautil, 95092 Cergy-Pontoise, France
Fax +33(1)30756186; E-mail: janick.ardisson@chim.u-cergy.fr
Received 1 February 2005
OPG
Abstract: The construction of the three C16-N22 2, C1-C7 6 (as
23) and C8-C15 5 (as 32) segments of the Hsp90 inhibitor herbimy-
22
cin A (1) is reported. 1-Iodo-3-nitro-2,5-diphenol compound 2 was
obtained in 55% yield for 3 steps from the commercially available
diiodo derivative 7. Reaction between 1,1-dibromo-alkene 22 and
vinyltin 17a using Pd(PPh3)4 or Pd(CH3CN)2Cl2/CuI/diisopropyl-
ethylamine, in toluene or DMF at 85 °C, led to enyne 23 in 63%
yield (19% overall yield from isopropylidene glyceraldehyde). The
synthesis of the C8-C15 sub-unit 32 was performed in 3.4% overall
yield for 13 steps, from the commercially available ester 24, with a
Hoppe crotylation as a key step.
16
O
I
NO2
OPG
O
MeO
1
7
2
OHC
OMe
O
16
MeO
4
1
7
N
15
Key words: herbimycin A, synthesis, Stille, enyne, 1,1-dibromo-1-
alkene, Sharpless oxidation, Hoppe aldehyde allylation
22
H
O
O
H2NOCO
MeO
OMe
1
7
8
MeO
OMe
Molecular chaperones such as heat shock protein 90
(Hsp90) assist the folding, maturation and subcellular
localization of their client proteins, and target damaged
proteins for degradation via the proteasome. Therefore,
the inhibition of Hsp90 provides a novel approach toward
regulating crucial enzymes involved in the progression of
cancer. The benzoquinoid ansamycins, such as herbimy-
cin A and geldanamycin, have recently been identified as
inhibitors of the Hsp90 folding process. Consequently,
these molecules are getting a lot of attention in the litera-
ture.1
PGO
herbimycin A 1
6
OMe
OMe
OMe
O
15
8
I
8
PGO
15
OMe
OMe
3
5
Scheme 1
Herbimycin A (1)2 was isolated from the fermentation
broth of Streptomyces hygroscopicus strain AM-3672,
and exhibits pronounced antitumor and antiangiogenic
properties. At this time, only two syntheses of herbimycin
A (1) have been reported.3
The present work describes the preparation of C16-N22
diphenol 2, C1-C7 enyne 6 and C8-C15 alcohol 5 (as pre-
cursors of compounds 4 and 3, respectively).
Northern fragment 2 was prepared in 55% overall yield
for 3 steps from the commercially available diiodo com-
pound 7. Mono-nitration of 7 under classical conditions
led to nitro-aldehyde 8 in 80% yield. In order to generate
the diphenol derivative 9, we took advantage of the alde-
hyde function to perform a Baeyer–Villiger oxidation.
This reaction cleanly delivered compound 9 in 80% yield
(Scheme 2).
Our synthetic plan developed for herbimycin A (1) in-
volved the convergent approach depicted in Scheme 1.
Our intention was to employ metal-catalyzed coupling
reactions to form both the C15-C16 bond between the
Northern C16-N22 aromatic fragment 2 and the Southern
C8-C15 side chain 3, and the C7-C8 link between the
Eastern C1-C7 dienyl sub-unit 4 and segment 3. A macro-
lactamization reaction was programmed for the final cy-
clization step at N22-C1.
The last step for the preparation of C16-N22 Northern
fragment 2 was achieved by methylation of 9 by means of
KOH/MeI in DMF at 20 °C for 4 hours, in 85% yield.4
SYNLETT 2005, No. 6, pp 0981–0985
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864804; Art ID: G05105ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
4.
2
0
0
5
For the Eastern fragment 4 synthesis, a Stille Pd(0)-
catalyzed coupling reaction was planed between vinyl

982
S. Centonze-Audureau et al.
LETTER
6
CHO
OH
CHO
CHO
O
a
b
O
13
16
I
16
I
22
I
NO2
a
OH
SnBu3
Br
7
8
Br
O
Br
OH
OMe
c
c
O
b
O
O
O
O
22
16
I
22
16
I
NO2
NO2
OH
OMe
14
16
9
2
15
Scheme 4 a) Zn (3 equiv), CBr4 (3 equiv), PPh3 (3 equiv), CH2Cl2,
20 °C 12 h, 65%; b) Bu3SnH (1.1 equiv), Pd(PPh3)4, THF, 20 °C, 20
min, 90%; c) n-BuLi (3 equiv), –40 °C, 2 h, Bu3SnCl, 20 °C, 1 h,
95%.
Scheme 2 a) NaNO2 (1 equiv), HOAc 80 °C, 15 h, 80%;
b) m-CPBA (3 equiv), CH2Cl2, 4 °C, 15 h, 80%; c) KOH, MeI,
DMF, 20 °C, 4 h, 85%.
into the corresponding 1,1-dibromo-alkene derivative 22
in 45% overall yield (Scheme 6).14 Compounds 22 and
17a under Shen’s conditions [Pd(PPh3)4 or
Pd(CH3CN)2Cl2/CuI/diisopropylethylamine, in toluene or
DMF at 85 °C] conducted to the expected enyne 23 in
63% yield.15
partners 10 and 11 (Scheme 3), or between 10 and
acetylenic compound 12. In this approach, a partial reduc-
tion of the resulting enyne 6 is required to reach the
desired compound 4.
For synthesis of compounds 11 and 12, isopropylidene
glyceraldehyde 135 was selected as an appropriate starting
material to introduce the C-6 centre (Scheme 4). Applica-
tion of the Corey–Fuchs method6 then led to dibromo
alkene 14, which is a versatile intermediate.7
The elaboration of Southern C8-C15 sub-unit 5 started
from the commercially available hydroxy-ester 24; classi-
cal transformations gave access, via ester 25, to the a,b-
unsaturated aldehyde 26 in 50% overall yield for 6 steps
(Scheme 7).
1,1-Dibromo-1-alkene 14 delivered pure (Z)-vinyl bro-
mide 15 under Bu3SnH/Pd(0) conditions, in 90% yield
(Scheme 5).8 Besides, acetylenic compounds 167 (95%
yield) was easily obtained by n-BuLi treatment of 14, fol-
lowed by Bu3SnCl trap.
THPO
THPO
Br
SnBu3
17a
However, we were disappointed to find out that Stille cou-
pling reaction9 between vinylbromide 15, vinyliodide 17b
or 17c10 and vinyltin 17a,11 or tributylstannylalkyne 16
did not lead, in sufficient yields, to expected diene or
enyne compounds 18, 19 or 2012 (Scheme 5).
O
O
O
O
a
15
18
Consequently, we turned to the Shen method.13 Com-
pound 14 was first transformed in 3 steps via alcohol 21
HO
HO
HO
b
I
17b
O
1
1
17b
MeO
PGO
10
Y
SnBu3
O
O
c
3
X
OHC
7
OHC
7
19
CO2Me
OMe
OMe
O
O
4
11
MeO2C
16
1
I
17c
PGO
O
O
c
Y
7
7
20
10
CHO
OPG
Scheme 5 a) Pd(PPh3)4 or Pd(CH3CN)2Cl2 (15 mol%), CuI (30
mol%), THF, toluene or DMF, 85 °C; b) Cp2ZrCl2 (0.25 equiv),
AlMe3 (3 equiv), CH2Cl2, 20 °C, 24 h, then I2 (1.2 equiv), 0 °C, 25%;
c) 17b or 17c, PdCl(CH3CN)2Bn (15 mol%), CuI (30 mol%), toluene,
85 °C, 12 h, 30%.
OMe
OMe
6
12
Scheme 3
Synlett 2005, No. 6, 981–985 © Thieme Stuttgart · New York

LETTER
Preparation of Three Fragments of Herbimycin A
983
Br
Br
Br
Br
8
OH
11
13
15
a
b
a
b
THPO
8
14
28
TBSO
TBSO
OMe
OH
29
21
22
OH
11
OH
11
15
15
c
12
12
THPO
THPO
O
THPO
OH
1
c
30
31
7
OTBS
OMe
11
15
23
8
OMe
12
d
THPO
OMe
Scheme 6 a) i) Amberlyst 15, MeOH, 20 °C, 12 h, 71%; ii) TBSCl,
imidazole, CH2Cl2, 20 °C, 10 h, 91%; b) MeI (excess), THF–DMF
8:1, NaH (1.3 equiv), 0 °C, 3 h, 70%; c) 17a, Pd(CH3CN)2Cl2 (15
mol%), CuI (30 mol%), DIPEA (1.5 equiv), DMF, 85 °C, 12 h, 63%.
32
Scheme 8 a) i) DIAD (1.2 equiv), PPh3 (1.2 equiv), PhCO2H (1.2
equiv), toluene, –78 °C, 10 min, 40%; ii) LiAlH4, THF, 20 °C, 80%;
b) D-(–)-diethyltartarate (1.2 equiv), Ti(Oi-Pr)4 (1.2 equiv), TBHP (2
equiv), CH2Cl2, –25 °C, 15 h, 85%; c) DIBALH (2.1 equiv), THF,
0 °C, 5 h, 60%; d) n-BuLi (3.2 equiv), MeI excess, THF, –78 °C to
20 °C, 12 h, 70%.
Elaboration of the C15-C8 skeleton was initiated by an
enantioselective Hoppe crotylation16 of aldehyde 26 to af-
ford the pure vinyl carbamate 27 in 85% yield (100% de,
Scheme 7). Further t-BuLi (3 equiv) treatment of 27 deliv-
ered the expected acetylenic derivative 28 in 70% yield.
At this stage, installation of the secondary C12 alcohol
function was envisaged in a two steps sequence. Stereo-
selective matched Sharpless epoxidation17 of 29 using D-
(–)-diethyltartarate gave epoxide 30 in 85% yield as a
pure isomer (the corresponding diastereomer was not
observed). Reduction of 30 under DIBALH/THF
conditions18 furnished the anti-1,2-diol 31 in 60% yield
(the corresponding anti-1,3-diol was isolated in 9%
yield).
Inversion of the C11 center of compound 28 was envis-
aged under Mitsunobu conditions. As a consequence of
the allylic and homopropargylic position of the C11 hy-
droxyl function, this reaction led to the inverted benzoyl
ester in a fair 40% yield when the temperature was kept at
–78 °C for 10 minutes. Generation of alcohol 29 was then
obtained by LiAlH4 reduction (80% yield, Scheme 8).
Subsequent methylation of 31 was then carried out using
3.2 equivalents of n-BuLi and an excess of MeI to furnish
dimethoxy derivative 32 in 70% yield.19
15
15
a
CO2Me
CO2Me
HO
THPO
In this sequence, and in spite of a modest yield for the
Mitsunobu reaction, preparation of Southern fragment 32
was achieved in 3.4% overall yield for 13 steps from the
commercially available ester 24.
24
25
13
11
CHO
15
b
THPO
THPO
12
26
Structural proof for 31 was obtained by NMR analysis of
lactol 33, prepared in a three-step sequence (Scheme 9);
the observed coupling constant JH11-H12 = 9.8 Hz, gave
confirmation of the C11-C12 anti configuration.20
OH
10
15
c
8
26
11
OCb
OCb = OCON(iPr)2
27
OAc
8
OH
10
H
OH
15
O
a
d
14
11
THPO
THPO
28
11
OH
b
OAc
Scheme 7 a) i) DHP, APTS, 20 °C, 12 h, 95%; ii) LAH (0.8 equiv)/
THF, 0 °C, 3 h, 85%; iii) IBX (2.2 equiv), DMSO, 20 °C, 2 h, quan-
titative; iv) (C6H5)3P=CHCO2Me/toluene, 50 °C, 10 h, 81%; b) i)
DIBALH (2.1 equiv)/THF, –78 °C, 1 h, 80%; ii) IBX (2.2 equiv),
DMSO, 20 °C, 2 h, 95%; c) (E)-crotyl (diisopropyl)carbamate (2.6
equiv), 1.6 M n-BuLi in hexane (2.4 equiv), (–)-sparteine (2.3 equiv),
–78 °C, 10 min, then –78 °C, 3 h for crystallization. Then Ti(Oi-Pr)4
(6 equiv), pentane, –50 °C and –78 °C, 30 min for transmetallation,
26 –78 °C, 2 h, 85%; d) t-BuLi (3.1 equiv)/Et2O, –78 °C, 45 min,
70%.
33
34
31
8
OMe
15
11
32
TPSO
10
OMe
Scheme 9 a) i) Amberlyst 15, MeOH, 25 °C, 15 h; ii) IBX (2.2
equiv), DMSO, 0 °C, 1.5 h; iii) Ac2O, pyridine, 63% yield for 3 steps;
b) i) Amberlyst 15, MeOH, 20 °C, 2 h, 75%; ii) TPSCl, imidazole,
DMF, 20 °C, 12 h, 85%.
Synlett 2005, No. 6, 981–985 © Thieme Stuttgart · New York

984
S. Centonze-Audureau et al.
LETTER
(10) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990,
47.
THP ether 32 was also transformed into the TPS deriva-
tive 3421 which was correlated with the same compound,
obtained by another approach based on a sequential
Sharpless dihydroxylation–Brown crotylation.22
(11) (a) Booker-Milburn, K. I.; Heffernan, G. D.; Parsons, P. J. J.
Chem. Soc., Chem. Commun. 1992, 350. (b) Barbero, A.;
Cuadrado, P.; Fleming, I.; Gonzalez, A. M.; Pulido, F. J. J.
Chem. Soc., Chem. Commun. 1992, 351.
In conclusion, preparation of Northern fragment 2 of
herbimycin A 1 was achieved in 55% yield for 3 steps.
Synthesis of the Eastern part 23, precursor of diene frag-
ment 4, was performed in 19% overall yield for 5 steps
from the known glyceraldehyde derivative 13. Finally,
elaboration of the C8-C15 chain 32, precursor of aldehyde
3, was accomplished in 3.4% overall yield for 13 steps.
(12) Compound 19: 1H NMR (270 MHz, CDCl3): d = 5.54 (wide
s, 1 H), 4.82 (dd, J = 6.4, 6.2 Hz, 1 H), 4.11 (dd, J = 7.8, 6.2
Hz, 1 H), 4.04 (s, 2 H), 3.86 (dd, J = 7.8, 6.4 Hz, 1 H), 1.81
(s, 3 H, CH3), 1.57 (s, 1 H, OH), 1.43 (s, 3 H, CH3), 1.33 (s,
3 H, CH3).
(13) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873.
(14) Compound 22: 1H NMR (270 MHz, CDCl3): d = 6.29 (d,
J = 8.0 Hz, 1 H), 3.93 (m, 1 H), 3.63 (m, 2 H), 3.29 (s, 3 H,
CH3, OCH3), 0.82 [s, 9 H, 3 CH3, SiC(CH3)3], 0.01 [s, 6 H,
2 CH3, Si(CH3)2]. 13C NMR (67.8 MHz, CDCl3): d = 137.2
(CH), 92.4 (C), 82.2 (CH), 64.4 (CH2), 57.2 (CH3, OCH3),
25.8 [3 CH3, SiC(CH3)3], 18.3 [C, SiC(CH3)3], –4.0, –4.5 [2
CH3, Si(CH3)2]. MS (CI, NH3): m/z = 392 [MH+ + NH3], 375
[MH+].
The final synthesis of the Hsp90 inhibitor, herbimycin A
(1), is under study in our laboratory.
Acknowledgment
The CNRS, UCP and ESCOM are acknowledged for financial
support. We gratefully thank Pfizer Laboratories for a doctoral
fellowship to S. C.-A.
(15) Compound 23: 1H NMR (400 MHz, CDCl3): d = 5.61 (br s,
1 H), 4.61 (t, J = 3.3 Hz, 1 H), 4.19 (d, J = 14.4 Hz, 1 H),
4.17 (m, 1 H), 3.94 (d, J = 14.4 Hz, 1 H), 3.84 (m, 1 H), 3.79
(dd, J = 10.5, 6.5 Hz, 1 H), 3.77 (dd, J = 10.5, 5.5 Hz, 1 H),
3.51 (m, 1 H), 3.45 (s, 3 H, CH3, OCH3), 1.89 (s, 3 H, CH3),
1.73–1.58 (m, 6 H, 3 CH2), 0.82 [s, 9 H, 3 CH3, SiC(CH3)3],
0.01 [s, 6 H, 2 CH3, Si(CH3)2]. 13C NMR (67.8 MHz,
CDCl3): d = 148.5 (C), 105.5 (CH), 98.1 (CH), 90.0 (C), 84.2
(C), 73.9 (CH), 70.6 (CH2), 66.7 (CH2), 62.5 (CH2), 57.3
(CH3, OCH3), 30.9 (CH2), 26.4 [3 CH3, SiC(CH3)3], 25.8
(CH2), 19.7 (CH2), 18.9 [C, SiC(CH3)3], –4.8, –4.7 [2 CH3,
Si(CH3)2]. MS (CI, NH3): m/z = 386 [MH+ + NH3], 369
[MH+]. IR (CCl4) 2929, 2856, 2360, 2341, 1578, 1463, 1129,
869 cm–1. Anal. Calcd (%) for C20H36O4Si (368.58): C,
65.17; H, 9.84. Found: C, 65.35; H, 9.97.
References
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Wickremasinghe, R. G. Blood 2004, 103, 1855.
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Int. J. Cancer 2004, 109, 643.
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Nakagawa, A.; Oiwa, H.; Hasegawa, Y.; Ikai, T. J.
Antibiotics 1979, 32, 255. (b) Omura, S.; Nakagawa, A.;
Sadakane, N. Tetrahedron Lett. 1979, 4323. (c) Furusaki,
A.; Matsumoto, T.; Nakagawa, A.; Omura, S. J. Antibiotics
1980, 33, 781. (d) Iwai, Y.; Nakagawa, A.; Sadakane, N.;
Omura, S.; Oiwa, H.; Matsumoto, S.; Takahashi, M.; Ikai,
T.; Ochiai, Y. J. Antibiotics 1980, 33, 1114. (e) Shibata, K.;
Satsumabayashi, S.; Nakagawa, A.; Omura, S. J. Antibiotics
1986, 39, 1630.
(3) (a) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.; Tamai, T.;
Tatsuta, K. Bull. Chem. Soc. Jpn. 1992, 65, 2974.
(b) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.; Tamai, T.;
Tatsuta, K. Tetrahedron Lett. 1991, 32, 6015. (c) Carter, K.
D.; Panek, J. S. Org. Lett. 2004, 6, 55. (d) Synthesis of
advanced fragments: Eshelman, J. E.; Epps, J. L.;
Kallmerten, J. Tetrahedron Lett. 1993, 34, 749. (e) Martin,
S. F.; Dodge, J. A.; Burgess, L. E.; Limberakis, C.;
Hartmann, M. Tetrahedron 1996, 52, 3229. (f) Martin, S.
F.; Limberakis, C.; Burgess, L. E.; Hartmann, M.
Tetrahedron 1996, 52, 3229.
(16) (a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932.
(b) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. Engl.
1989, 28, 69. (c) Zschage, O.; Hoppe, D. Tetrahedron 1992,
48, 5657. (d) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2282.
(17) (a) Katsuki, T.; Sharpless, K. B. Tetrahedron Lett. 1979, 20,
4733. (b) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica
Acta 1979, 12, 63. (c) Katsuki, T.; Sharpless, K. B. J. Am.
Chem. Soc. 1980, 102, 5974.
(18) (a) Hansen, R. M. Chem. Rev. 1991, 91, 437. (b) Dai, L.;
Lou, B.; Zhang, Y.; Guo, G. Tetrahedron Lett. 1986, 4343.
(c) Sharpless, B. M.; Caron, M. J. Org. Chem. 1985, 50,
1557.
(19) Compound 32: 1H NMR (270 MHz, CDCl3): d (two
diastereomers) = 4.55 (m, 1 H), 3.87 (m, 1 H), 3.60 (m, 1 H),
3.50 (m, 1 H), 3.39, 3.37 (2 s, 3 H, CH3, CH3O), 3.28, 3.26
(2 s, 3 H, CH3, CH3O), 3.25 (m, 1 H), 3.20 (m, 1 H), 3.03 (m,
1 H), 2.52 (m, 1 H), 2.03 (m, 1 H), 1.81 (s, 3 H, CH3), 1.73–
1.58 (m, 6 H, 3 CH2), 1.68 (m, 1 H), 1.32, (m, 1 H), 1.10 (d,
J = 7.0 Hz, 3 H, CH3), 0.94 (d, J = 6.9 Hz, 3 H, CH3). 13
C
NMR (67.5 MHz, CDCl3): d (two diastereomers) = 98.7,
98.5 (CH), 83.4 (CH), 80.5 (CH), 79.6 (C), 78.5 (C), 72.4,
72.3 (CH2), 62.4 (CH2), 61.5, 61.2 (CH3, CH3O), 57.9, 57.8
(CH3, CH3O), 35.1–34.8 (CH2), 30.6 (CH2), 30.4, 30.2 (CH),
29.8 (CH), 25.4, 25.3 (CH2), 19.3, 19.2 (CH2), 18.3 (CH3),
17.8 (CH3), 3.5 (CH3). Anal. Calcd for C18H32O4 (312.44):
C, 69.19; H, 10.32. Found: C, 69.03; H, 10.56.
(4) Compound 2: 1H NMR (270 MHz, CDCl3): d = 7.60 (d,
J = 2.5 Hz, 1 H), 7.50 (d, J = 2.5 Hz, 1 H), 3.85 (s, 3 H, CH3,
OMe), 3.60 (s, 3 H, CH3, OMe). MS (GC, EI): m/z = 309
[M+].
(5) Jackson, D. Y. Synth. Commun. 1988, 18, 337.
(6) Corey, E.-J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
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(8) Uenishi, J.-i.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.;
Tsuji, J. Tetrahedron Lett. 1996, 37, 6759.
(20) Compound 33: 1H NMR (270 MHz, CDCl3): d = 5.29 (d,
J = 5.0 Hz, 1 H), 4.89 (td, J = 9.8, 4.3 Hz, 1 H), 3.42 (dd,
J = 9.8, 2.9 Hz, 1 H), 2.61–2.59 (m, 1 H), 2.34–2.31 (m, 1
H), 2.14–2.04 (m, 9 H, 2 CH3CO + 2 H), 1.23 (d, J = 7.0 Hz,
3 H, CH3), 0.92 (d, J = 6.9 Hz, 3 H, CH3).
(9) The Stille Reaction; Farina, V.; Krishnamurthy, V.; Scott,
W. J., Eds.; John Wiley and Sons, Inc.: New York, 1998.
Synlett 2005, No. 6, 981–985 © Thieme Stuttgart · New York

LETTER
Preparation of Three Fragments of Herbimycin A
985
(21) Compound 34: 1H NMR (270 MHz, CDCl3): d = 7.61–7.58
(m, 4 H, arom.), 7.36–7.31 (m, 6 H, arom.), 3.54 (m, 1 H),
3.42 (m, 1 H), 3.35 (s, 3 H), 3.25 (s, 3 H), 3.15 (m, 1 H), 3.05
(dd, J = 7.0, 3.6 Hz, 1 H), 2.55 (m, 1 H), 1.86 (m, 1 H), 1.82
(s, 3 H), 1.64 (m, 1 H), 1.22 (m, 1 H), 1.11 (d, J = 7.0 Hz, 3
(22) This route used more conventional transformations to reach
the desired fragment in a 6% overall yield for 18 steps
(Scheme 10). Centonze-Audureau, S.; Porée, F-H.; Betzer,
J. F.; Brion, J.-D.; Pancrazi, A.; Ardisson, J. unpublished
results.
H), 0.98 [s, 9 H, SiC(CH3)3], 0.93 (d, J = 6.9 Hz, 3 H). 13
C
NMR (67.5 MHz, CDCl3): d = 135.6 (4 CH, arom.), 133.9 (2
C, arom.), 129.4 (2 CH, arom.), 127.5 (4 CH, arom.), 84.0
(CH), 80.2 (CH), 79.8 (C), 78.6 (C), 69.5 (CH2), 61.2, 57.0
(2 CH3, 2 CH3O), 33.2 (CH2), 30.1 (CH), 28.9 (CH), 26.9 [3
CH3, SiC(CH3)3], 19.3 [C, SiC(CH3)3], 18.5 (CH3), 16.8
(CH3), 4.0 (CH3). Anal. Calcd for C29H42O3Si (466.73): C,
74.63; H, 9.07. Found: C, 74.86; H, 9.18.
15
15
Sharpless
12
TPSO
OH
TPSO
24
14
dihydroxylation
7 steps
OH
OH
Brown crotylation
5 steps
15
9
11
12
34
TPSO
10
5 steps
OMe
Scheme 10
Synlett 2005, No. 6, 981–985 © Thieme Stuttgart · New York