Enantioselective synthesis of the C1-C15 fragment of dolabelide C

Article abstract of DOI:10.1055/s-2006-949614

A synthesis of the C1-C15 fragment of dolabelide C is reported. The key step is a diastereoselective Mukaiyama aldol reaction to form the C6-C7 bond, followed by reduction and deoxygenation of the carbonyl group at C5. The trisubstituted vinyl iodide is i

Full text of DOI:10.1055/s-2006-949614

LETTER
2269
Enantioselective Synthesis of the C1–C15 Fragment of Dolabelide C
Enantioselective
S
u
ynthesis of
t
r
é
15 Fragmen
l
t
of
D
o
labelid
e
e
C
Vincent, Joëlle Prunet*
Laboratoire de Synthèse Organique, UMR CNRS 7652, Ecole Polytechnique, DCSO, 91128 Palaiseau, France
Fax +33(1)69333851; E-mail: joelle.prunet@polytechnique.fr
Received 18 May 2006
Ph
Abstract: A synthesis of the C1–C15 fragment of dolabelide C is
reported. The key step is a diastereoselective Mukaiyama aldol
reaction to form the C6–C7 bond, followed by reduction and
deoxygenation of the carbonyl group at C5. The trisubstituted vinyl
iodide is introduced via the corresponding vinyl boronate by cross
metathesis.
OH
11
O
7
O
O
9
O
7
O
5
OP OP
11
1
R
OMe
R
H
6
5
3
4
Key words: stereoselective synthesis, aldol reactions, metathesis,
Michael additions, acetals
OP OP OP
7
OP
O
1
15
I
OH
30
6
C1-C15
1
In 1995, Yamada and co-workers isolated dolabelides A
and B, two 22-membered ring lactones, from the sea hare
Dolabella auricularia (family Aplysiidae).1 In 1997, two
similar 24-membered ring lactones, dolabelides C and D,
were also extracted from the same source.2 These com-
pounds were shown to exhibit cytotoxicity against
HeLa-S3 cell lines with IC50 values of 6.3, 1.3, 1.9, and 1.5
mg/mL, respectively. Their structures were determined by
FAB high resolution mass spectroscopy and 2D NMR;
their absolute configuration was determined by the modi-
fied Mosher method.3 Several groups have reported syn-
theses of dolabelide fragments,4 and the total synthesis of
dolabelide D was very recently completed by Leighton
and co-workers.5
OP OP OH
OP
16
C16-C30
2
OAc OAc
OH
O
OAc
15
O
OAc
OH
OH
23
30
16
Dolabelide C
Scheme 1
We chose dolabelide C as a potential target, but the strat-
egy we designed could be applied to the other members of
the family. The retrosynthesis we envisaged is illustrated
in Scheme 1. Opening of the macrolactone, followed by
disconnection through the C15–C16 bond furnishes com-
pounds 1 and 2 of roughly equal complexity. These two
fragments would be joined by a Suzuki coupling between
the vinyl iodide at C15 and a borane derived from the
alkene at C16. A macrolactonization would then close the
ring.
The known epoxide 67 with a benzyloxy group at C14 was
chosen as a precursor for the C7–C14 portion of the target
molecule (Scheme 2). The C15 carbon would be added at
a late stage of the synthesis. Jacobsen’s HKR8 of this ep-
oxide, catalyzed by salen complex 7, furnished the corre-
sponding homochiral epoxide 8 in 47% yield (94%
theoretical) with an excellent ee. Opening of the epoxide
moiety with vinylmagnesium bromide in the presence of
a catalytic amount of CuI gave homoallylic alcohol 9 in
96% yield. Cross metathesis of this compound with meth-
yl acrylate and second generation Grubbs’ catalyst9 in
dichloromethane at reflux led to unsaturated ester 10 as
the E isomer exclusively in excellent yield. Benzylidene
acetal 11 was obtained by treatment of homoallylic
alcohol 10 with benzaldehyde and t-BuOK, and the ester
function was reduced with DIBAL-H at –95 °C to give
aldehyde 12 in excellent yield.
We report here the synthesis of the C1–C15 fragment of
dolabelide C. Compound 1 could be assembled by a dia-
stereoselective aldol reaction between aldehyde 3 and ke-
tone 4 (Scheme 1), and the extra carbonyl group at C5
would be reduced in later steps. The protected syn-1,3-
diol functional group at C9 and C11 would be installed by
an intramolecular conjugate addition of a hemiacetal an-
ion made in situ from homoallylic alcohol 5 and benzalde-
hyde under basic conditions.6
The C1–C6 ketone 14 (Scheme 3) was prepared by the
addition of MeLi to the corresponding Weinreb amide 13,
which was reported by Heathcock and co-workers during
their study towards the synthesis of discodermolide.10 The
corresponding trimethylsilyl enol ether 15 was formed in
quantitative yield.
SYNLETT 2006, No. 14, pp 2269–2271
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949614; Art ID: D14406ST
© Georg Thieme Verlag Stuttgart · New York

2270
A. Vincent, J. Prunet
LETTER
7
catalyzed carboalumination to introduce the methyl group
and the terminal iodide.16 Unfortunately, all our attempts
to obtain compound 23 were unsuccessful. No reaction
occurred at low temperature even in the presence of a
small amount of water,17 and decomposition was observed
at higher temperatures.
O
O
BnO
BnO
14
0.6 equiv H2O
6
8 ee > 98%
47% (94% theoretical)
MgBr
CuI
96%
OH
O
OH
Grubbs' II
We also tried to prepare a vinyl silane derivative which
could be easily converted to 23, but silylcupration fol-
lowed by quenching with MeI18 was not regioselective for
compound 21, and the methyl group was not incorporated.
Use of MeMgSnBu3/MeI did not lead either to the corre-
sponding vinyl stannane.19
R
OMe
R
COOMe
94%
9
10 E/Z > 99:1
R = BnO(CH2)3
74%
Ph
PhCHO, t-BuOK
Ph
O
O
O
O
O
O
7
DIBAL-H
BnO
Ph
R
OMe
H
14
94%
11 dr > 98:2
12
O
O
O
7
TMSO
OPMB
C7–C14 fragment
1
BnO
H
OTBS
14
6
12
15
93%
BF3·OEt2
Ph
MesN
NMes
Ph
N
O
N
M
Cl
Cl
t-Bu
O
t-Bu
Ru
O
O
OH
7
O
5
OPMB
t-Bu
t-Bu
PCy3
BnO
OTBS
14
7 M = Co(OAc)
Grubbs' II
16 dr = 82:18
98%
99%
1) TBSOTf, Et3N
2) NaBH4
Scheme 2
Ph
O
O
OTBS
OH OPMB
5
O
R
OPMB
TMSO
6
OPMB
1
TMSCl, Et3N
BnO
OTBS
OTBS
OTBS
LiHMDS
quant.
17 dr = 70:30
15
91%
92%
1) NaH, CS2, MeI
2) AIBN, Bu3SnH
13 R = N(Me)OMe
14 R = Me
MeLi
97%
Ph
O
O
OTBS
OPMB
Scheme 3
BnO
5
OTBS
18
The Mukaiyama aldol reaction between silyl enol ether 15
and aldehyde 12 is controlled by the aldehyde, furnishing
the 1,3-anti product 16 as the major diastereomer (82:18
ratio) in 93% yield (Scheme 4).11 The major diastereomer
was isolated in 75% yield after further chromatography.
After protection of alcohol 16 as its TBS ether, the next
operation involved complete reduction of the C5 ketone,
which is not present in the natural product. This carbonyl
group was first reduced with NaBH4, and the resulting al-
cohols 17 were converted into the corresponding xan-
thates. Deoxygenation proceeded smoothly with Bu3SnH
and AIBN in toluene at reflux12 to give compound 18 in
81% overall yield (four steps) from 16.
86%
93%
1) H2, Raney Ni
2) IBX
Ph
O
O
OTBS
OPMB
H
OTBS
19
O
O
O
K2CO3, MeOH
P(OMe)2
93%
Ph
N2
20
O
O
OTBS
OPMB
OTBS
1
21
To complete the synthesis of the C1–C15 portion of dola-
belide C, a vinyl iodide moiety had to be appended to C14.
For this purpose, the primary benzyloxy group was selec-
tively hydrogenolyzed in the presence of the PMB ether
and the benzylidene acetal with Raney nickel.13 The
resulting alcohol was oxidized with iodoxybenzoic acid
(IBX)14 to furnish aldehyde 19. This aldehyde was then
converted into the terminal alkyne 21 with Ohira’s reagent
2015 in good yield. We had planned to use Negishi’s Zr-
Scheme 4
Aldehyde 19 was then homologated to the corresponding
ketone in 2 steps (Scheme 5), but conversion of this
intermediate into the vinyl iodide using the Takai
method20 was not possible. Finally, this ketone was trans-
formed into the gem-disubstituted olefin 22 (65% yield
along with 26% recovered ketone),21 and cross metathesis
Synlett 2006, No. 14, 2269–2271 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of the C1–C15 Fragment of Dolabelide C
2271
(5) Park, P. K.; O’Malley, S. J.; Schmidt, D. R.; Leighton, J. L.
J. Am. Chem. Soc. 2006, 128, 2796.
(6) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58,
2446.
(7) Lowik, D. W. P. M.; Liskamp, R. M. J. Eur. J. Org. Chem.
2000, 1219.
(8) (a) Chow, S.; Kitching, W. Tetrahedron: Asymmetry 2002,
13, 779. (b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
(9) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (b) Chatterjee, A. K.; Grubbs, R. H. Angew.
Chem. Int. Ed. 2002, 41, 3172.
with the required boronate followed by boron–iodine ex-
change furnished 23 as a 2:1 mixture of E/Z isomers.22
The pure E olefin23 could be isolated in 55% yield by pre-
parative HPLC.
In conclusion, we have synthesized the C1–C15 fragment
of dolabelide C in a convergent manner in 17 steps for the
longest linear sequence (11.4% overall yield from 6). The
key step is a diastereoselective Mukaiyama aldol to form
the C6–C7 bond and establish the C7 stereocenter.
(10) The key step of the synthesis of amide 13 is an Evans aldol
reaction with an aldehyde derived from the Roche ester:
Clark, D. L.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5878.
(11) Evans, D. A.; Coleman, P. J.; Côté, B. J. Org. Chem. 1997,
62, 788.
(12) (a) Ozawa, T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem.
2001, 66, 3338. (b) Barton, D. H. R.; Dorchak, J.;
Jaszberenyi, J. Cs. Tetrahedron 1992, 48, 7435.
(13) Vincent, A.; Prunet, J. Tetrahedron Lett. 2006, 47, 4075.
(14) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537.
Ph
O
O
OTBS
OPMB
H
OTBS
19
O
1) MeMgBr
2) IBX
52% (3 steps)
Ph
3) CH3PPh3+Br–, BuLi
O
O
OTBS
OPMB
(15) (a) Ohira, S. Synth. Commun. 1989, 19, 561. (b) Müller, S.;
Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
(c) Davies, H. M. L.; Cantrell, W. R.; Romines, K. R.; Baum,
J. S. Org. Synth. 1992, 70, 93.
(16) Negishi, E.-i.; Van Horn, D. E.; Yoshida, T. J. Am. Chem.
Soc. 1985, 107, 6639.
OTBS
22
1)
O
B
O
Grubbs' II
55% (2 steps)
Ph
(17) Wipf, P.; Lim, S. Angew. Chem. Int. Ed. 1993, 32, 1068.
(18) (a) Barbero, A.; Cuadrado, P.; Fleming, I.; Gonzalez, A. M.;
Pulido, F. J.; Sanchez, A. J. Chem. Soc., Perkin Trans. 1
1995, 1525. (b) Fleming, I.; Newton, T.; Roessler, F. J.
Chem. Soc., Perkin Trans. 1 1981, 2527.
(19) Uenishi, J.; Kawahama, R.; Yonemitsu, O. J. Org. Chem.
1997, 62, 1691; this reaction was performed on a model
compound.
2) I2, NaOH
OTBS
O
O
OPMB
1
15
I
OTBS
23
C1–C15 fragment
(20) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408.
Scheme 5
(21) This reaction has not been optimized.
Acknowledgment
(22) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031.
(23) Spectroscopic data for compound 23: 1H NMR (400 MHz,
CDCl3): d = 7.51 (dd, J = 7.9, 1.5 Hz, 2 H, Ph), 7.35–7.40
(m, 3 H, Ph), 7.27 (d, J = 8.6 Hz, 2 H, PMB), 6.86 (d, J =
8.6 Hz, 2 H, PMB), 5.94 (dd, J = 2.1, 1.3 Hz, 1 H, CH-15),
5.48 (s, 1 H, CHPh), 4.53 (d, J = 10.8 Hz, 1 H, CHHPh),
4.49 (d, J = 11.0 Hz, 1 H, CHHPh), 3.98–4.18 (m, 2 H, CH-
7, CH-9), 3.78–3.82 (m, 1 H, CH-11), 3.79 (s, 3 H, OCH3),
3.72 (dd, J = 9.6, 5.2 Hz, 1 H, CH-1), 3.63 (dd, J = 9.6, 3.0
Hz, 1 H, CH-1), 3.27 (dd, J = 8.7, 2.2 Hz, 1 H, CH-3), 2.35–
2.48 (m, 2 H, CH2-13), 1.87 (d, J = 1.2 Hz, 3 H, CH3-14),
1.78–1.84 (m, 2 H, CH-2, CH-12), 1.30–1.75 (m, 10 H, CH-
4, CH2-5, CH2-6, CH2-8, CH2-10, CH-12), 0.89–0.97 [m, 24
H, SiC(CH3)3, CH3-2, CH3-4], 0.09, 0.08, 0.06 [s, 12 H,
Si(CH3)2]. 13C NMR (100 MHz, CDCl3): d = 147.6 (C-14),
158.9, 138.9, 131.6, 129.1, 128.5, 128.1, 126.0, 113.7 (Ar),
100.2 (CHPh), 83.6 (C-3), 75.9 (C-11), 74.9 (C-15), 74.5
(CH2Ph), 73.0 (C-9), 67.9 (C-7), 65.0 (C-1), 55.3 (OCH3),
43.3 (C-6), 38.6 (C-2), 37.5 (C-10), 36.3 (C-8), 35.6 (C-4),
35.1 (C-13), 33.9 (C-12), 29.6 (C-5), 26.0 [SiC(CH3)3], 24.0
(CH3-14), 18.3, 18.1 (SiC), 14.7 (CH3-2), 13.5 (CH3-4),
–4.1, –4.5, –5.3, –5.4 [Si(CH3)2]. HRMS (EI): m/z calcd for
C45H75O6I1Si2: 894.4147; found: 894.4155.
Financial support was provided by the CNRS and the Ecole
Polytechnique. A.V. acknowledges the Délégation Générale pour
l’Armement (DGA) for a fellowship. We thank Jean-Pierre Pulicani
for HPLC purification of compound 23.
References and Notes
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36, 7491.
(2) Suenaga, K.; Nagoya, T.; Shibata, T.; Kigoshi, H.; Yamada,
K. J. Nat. Prod. 1997, 60, 155.
(3) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
(4) (a) C16–C24: Grimaud, L.; de Mesmay, R.; Prunet, J. Org.
Lett. 2002, 4, 419. (b) C15–C24 and C25–C30: Desroy, N.;
Le Roux, R.; Phansavath, P.; Chiummiento, L.; Bonini, C.;
Genêt, J.-P. Tetrahedron Lett. 2003, 44, 1763. (c) C1–C13:
Le Roux, R.; Desroy, N.; Phansavath, P.; Genêt, J.-P. Synlett
2005, 429. (d) C15–C30: Schmidt, D. R.; Park, P. K.;
Leighton, J. L. Org. Lett. 2003, 5, 3535. (e) C1–C13: Keck,
G. E.; McLaws, M. D. Tetrahedron Lett. 2005, 46, 4911.
Synlett 2006, No. 14, 2269–2271 © Thieme Stuttgart · New York