Stereoselective synthesis of C15-C24 and C25-C30 fragments of dolabelides

Article abstract of DOI:10.1016/S0040-4039(03)00110-2

The stereocontrolled synthesis of a C15-C24 fragment of dolabelides is reported. The C19 and C21 hydroxyl-bearing stereocenters were installed using ruthenium-mediated asymmetric hydrogenations of cyclic hemiketal 4 and β-keto ester 7. The C25-C30 portion

Full text of DOI:10.1016/S0040-4039(03)00110-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1763–1766
Stereoselective synthesis of C15ꢀC24 and C25ꢀC30 fragments
of dolabelides
Nicolas Desroy,a Re´mi Le Roux,a Phannarath Phansavath,a Lucia Chiummiento,b Carlo Boninib,*
and Jean-Pierre Geneˆta,*
aLaboratoire de Synthe`se Se´lective Organique et Produits Naturels, UMR CNRS 7573,
Ecole Nationale Supe´rieure de Chimie de Paris, 11, rue Pierre et Marie Curie, 75231 Paris cedex 05, France
bDipartimento di Chimica, Universita` degli Studi della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Received 12 December 2002; accepted 13 January 2003
Abstract—The stereocontrolled synthesis of a C15ꢀC24 fragment of dolabelides is reported. The C19 and C21 hydroxyl-bearing
stereocenters were installed using ruthenium-mediated asymmetric hydrogenations of cyclic hemiketal 4 and b-keto ester 7. The
C25ꢀC30 portion of dolabelides was prepared as well by ring opening of chiral epoxy alcohol 12 to set up the C27 stereogenic
center. © 2003 Elsevier Science Ltd. All rights reserved.
Dolabelide A, a new 22-membered macrolide, and its
deacetyl derivative, dolabelide B, were isolated from the
Japanese sea hare Dolabella auricularia and their struc-
tures elucidated in 1995.1
subsequent macrolactonization reaction between the
carboxylic acid at C1 and the appropriate hydroxyl
function at either C21 or C23 would then furnish the
dolabelide structures. The reverse sequence would also
deliver the desired macrocyclic structures. An alterna-
tive route would involve a ring closing metathesis
between the appropriate alkenes derived from the cor-
responding alcohols at C14 and C15. The C15ꢀC30
fragment would be obtained via a Horner–Wadsworth–
Emmons reaction between b-keto phosphonate 1 and
ketone 2 to create the C24ꢀC25 trisubstituted double
Two 24-membered analogs of these compounds, dola-
belides C and D were also isolated in 1997 from the
same marine source (Scheme 1).2
These macrolides exhibit cytotoxicity against HeLa-S3
cells with IC50 values of 6.3, 1.3, 1.9 and 1.5 mg/mL,
respectively. Their structures include eleven stereogenic
centers, essentially hydroxyl or derivated functions.
As part of our ongoing program on the use of ruthe-
nium-mediated asymmetric hydrogenation for the
preparation of biologically relevant natural products3–5
as well as of our biocatalytic approach to the synthesis
of skipped polyols,6,7 we decided to undertake the
synthesis of these macrolides. Using a logical skeletal
disconnection, dolabelides were divided into two frag-
ments corresponding to C1ꢀC14 and C15ꢀC30 of the
natural products (Scheme 2). The construction of the
C14ꢀC15 junction would be achieved by a Julia one-pot
olefination between an aldehyde at C15 and a sulfonyl
benzothiazole at C14 or a Wittig reaction between a
ketone at C14 and a phosphonium salt at C15. A
* Corresponding authors. Tel.: +33-1-44-27-67-43; fax: +33-1-44-27-
10-62 (J.P.G.); Tel.: +39-971-20-22-54; fax: +39-971-20-22-23 (C.B.);
e-mail: bonini@unibas.it; genet@ext.jussieu.fr
Scheme 1. Structures of dolabelides A, B, C and D.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00110-2

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N. Desroy et al. / Tetrahedron Letters 44 (2003) 1763–1766
tert-butyl acetate15 furnished b-keto ester 7 required for
the second asymmetric hydrogenation reaction. We
used the chiral ruthenium complex (S)-(MeO-
BIPHEP)RuBr2 prepared in situ from commercially
available (COD)Ru(2-methylallyl)2.16,17
The reaction was carried out in a mixture of tert-
butanol/dichloromethane (8/2) as we have observed not
surprisingly that use of methanol as the solvent led to
deprotection of the primary alcohol. However the
hydrogenation proceeded much slower in the tert-
butanol/dichloromethane mixture than in methanol,
hence high pressure of hydrogen (100 bar) and long
reaction time (68 h) were required. Under these condi-
tions, the ligand-controlled asymmetric reduction of 7
provided b-hydroxy ester 8 in 80% yield and excellent
diastereomeric excess (d.e.=96%, determined by HPLC
Scheme 2.
bond, followed by stereoselective reduction of the
ketone function to set the hydroxyl group at C23.
To our knowledge only one preparation of the
C16ꢀC24 portion of dolabelides has been reported to
date.8 However, in this synthetic approach, the creation
of the C21 and C22 stereogenic centers by homoaldol
reaction resulted in a 1:1 mixture of diastereomers
which were separated in a subsequent step. We describe
herein a highly stereoselective synthesis of a C15ꢀC24
fragment of dolabelides using catalytic asymmetric
hydrogenation9,10 of b-keto esters to install the C19 and
C21 hydroxyl-bearing stereocenters. The preparation of
the C25ꢀC30 fragment is also reported using ring open-
ing of a chiral epoxy alcohol11 to deliver the C27
stereocenter.
1. Synthesis of the C15ꢀC24 fragment
Synthesis of the C15ꢀC24 subunit started with d-valero-
lactone 3 (Scheme 3). Addition of one equivalent of
lithio ethyl acetate to 3 at low temperature resulted in
the formation of the cyclic hemiketal 4 in 74% yield.12,13
This compound is in equilibrium with b-keto ester 4%
which is suitable for ruthenium-mediated asymmetric
hydrogenation of the ketone function. For this reac-
tion, we used our recently reported simple procedure
for the in situ preparation of chiral ruthenium–diphos-
phine complexes starting directly from anhydrous
RuCl3.14 Thus hydrogenation of 4 was carried out in
ethanol at 80°C and low pressure of hydrogen (10 bar)
with 1 mol% of the ruthenium complex using (R)-MeO-
BIPHEP as the ligand. Under these conditions b-
hydroxy ester 5 was obtained in 86% yield and excellent
enantiomeric excess (e.e. >95%, determined by 1H
NMR with Eu(tfc)3). To our knowledge, this is the first
example of asymmetric hydrogenation of a hemiketal to
the corresponding b-hydroxy ester. This methodology
should provide a rapid access to variously substituted
enantiomerically pure v,b-dihydroxy esters. Compound
5 was then converted into the protected diol 6 in 80%
overall yield and subsequent chain extension with lithio
Scheme 3. Reagents and conditions: (a) AcOEt, LDA, THF,
−78°C, 2 h, 74%; (b) RuCl3 (1 mol%), (R)-MeO-BIPHEP (1
mol%), EtOH, H2 (10 bar), 80°C, 25 h, 86%, e.e. >95%; (c)
TBDPSCl, NEt3, 4-DMAP cat., CH2Cl2, rt, 20 h, 98%; (d)
PMBOC(NH)CCl3, CSA cat., CH2Cl2, rt, 82%; (e) AcOtBu,
LDA, THF, −65 to −30°C,
5 h, 91%; (f) (S)-(MeO-
BIPHEP)RuBr2 (2 mol%), t-BuOH/CH2Cl2 (4/1), H2 (100
bar), 50°C, 68 h, 80%, d.e.=96%; (g) LDA, MeI, HMPA,
THF, −55°C to rt, 3.5 h, 74%; (h) TBSOTf, 2,6-lutidine,
CH2Cl2, −20°C, 97%; (i) DIBAL, toluene, −78°C, 3.5 h; (j)
Dess–Martin periodinane, CH2Cl2, 0°C to rt, 4 h, 72% from
9; (k) n-BuLi, diethyl methylphosphonate, THF, −78°C, 2.5
,
h, 69%; (l) PDC, 4 A molecular sieves, DMF, rt, 3 h, 86%.

N. Desroy et al. / Tetrahedron Letters 44 (2003) 1763–1766
1765
methods (NaH, THF). However, under these condi-
tions, competing b-elimination in compound 16 leading
to 3-hepten-2-one was a major drawback. We are cur-
rently trying various conditions suitable for the base-
sensitive ketone 16 as well as different protecting
groups on the C25ꢀC30 subunit for this HWE reaction.
In summary, a stereoselective synthesis of a C15ꢀC24
fragment of dolabelides was achieved using catalytic
asymmetric hydrogenation of b-keto esters to install the
hydroxyl groups at C19 and C21 stereocenters. A
C25ꢀC30 fragment was also prepared by regioselective
ring opening of a chiral epoxy alcohol to set the C27
stereocenter. This flexible approach should allow the
preparation of all stereomers in order to synthesize
analogs of dolabelides for structure–activity relation-
ship studies. The completion of the synthesis is cur-
rently underway in our laboratory and will be reported
in due course.
Scheme 4. Reagents and conditions: (a) (i) MgI2, toluene,
−60°C, 1 h; (ii) Bu3SnH, AIBN, toluene, reflux, 1 h, 80%; (b)
TBSOTf, 2,6-lutidine, CH2Cl2, −50°C to rt, 48 h, 90%; (c)
NaI, acetone, D, 5 days, 95%; (d) 2-methyl-1,3-dithiane, n-
BuLi, HMPA, −78°C, 10 min, 86%; (e) I2, NaHCO3, acetone/
H2O, rt, 45 min, 81%.
analysis, Chiralcel OD-H column, hexane/propan-2-ol:
99/1, flow rate:
1
mL/min). Diastereoselective
methylation18,19 of the b-hydroxy ester (d.e.=98%,
determined by HPLC analysis, Chiralcel OD-H
column, hexane/propan-2-ol: 99/1, flow rate: 1 mL/min)
followed by protection of the alcohol function then
afforded 9 in 70% overall yield. This compound was
then converted into the corresponding aldehyde 10 via
a hydride reduction/Dess–Martin oxidation sequence.
Finally, addition of lithio diethyl methyl phosphonate
to 10 followed by oxidation of the resulting b-hydroxy
phosphonate provided b-keto phosphonate 11, required
for the Horner–Wadsworth–Emmons reaction. Thus,
synthesis of C15ꢀC24 fragment of dolabelides was
achieved in twelve steps and 11% overall yield with a
high level of enantio- and diastereoselectivity in the
construction of the C19, C21 and C22 stereocenters.
Acknowledgements
We thank Dr. R. Schmid (Hoffmann La Roche) for
samples of (R)- and (S)-MeO-BIPHEP: (R)-(+)- or
(S)-(−)-6,6%-dimethoxy-2,2%-bis(diphenylphosphinoyl)-
1,1%-biphenyl, respectively. N.D. is grateful to the Min-
iste`re de l’Education et de la Recherche for a grant
(2001–2004).
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