First stereoselective synthesis of the C(1)-C(13) fragment of dolabelides using ruthenium-SYNPHOS-catalyzed asymmetric hydrogenation reactions

Article abstract of DOI:10.1055/s-2005-862351

The first stereocontrolled synthesis of the C(1)-C(13) fragment of cytotoxic macrolides dolabelides is reported. The C(3), C(7), C(9) and C(11) hydroxyl-bearing stereocenters were installed using ruthenium-mediated asymmetric hydrogenation reactions of the adequate β-keto esters and β-hydroxy ketone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-862351

LETTER
429
First Stereoselective Synthesis of the C(1)-C(13) Fragment of Dolabelides
Using Ruthenium-SYNPHOS®-Catalyzed Asymmetric Hydrogenation
Reactions
Stereoselective
S
é
m
the C(1)-C(13) Frag
i
ment of
D
ola
L
belides e Roux, Nicolas Desroy, Phannarath Phansavath,* Jean-Pierre Genêt*
Laboratoire de Synthèse Sélective Organique et Produits Naturels, UMR 7573 CNRS, Ecole Nationale Supérieure de Chimie de Paris,
11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax +33(1)44071062; E-mail: genet@ext.jussieu.fr
Received 10 November 2004
OAc OAc
OH
Abstract: The first stereocontrolled synthesis of the C(1)-C(13)
fragment of cytotoxic macrolides dolabelides is reported. The C(3),
C(7), C(9) and C(11) hydroxyl-bearing stereocenters were installed
using ruthenium-mediated asymmetric hydrogenation reactions of
the adequate b-keto esters and b-hydroxy ketone.
Dolabelide A: R = Ac
Dolabelide B: R = H
3
1
O
9
7
11
14
O
OR
15
OH
OH
OAc
30
OH
21
23
Key words: asymmetric catalysis, hydrogenation, ruthenium, total
synthesis, natural products
OAc OR
OH
3
Dolabelide C: R = Ac
Dolabelide D: R = H
9
7
1
11
14
O
OH
OR
15
O
OAc
30
Dolabelides A and B were isolated in 1995 from Japanese
sea hare Dolabella auricularia. Two other similar marine
macrolides dolabelides C and D were isolated from the
same source in 1997 (Scheme 1).1,2 These macrolides ex-
hibit cytotoxicity against HeLa-S3 cells with IC50 values
of 6.3, 1.3, 1.9 and 1.5 mg/mL, respectively. The dolabe-
lides contain a 22- or 24-membered ring, including eleven
stereogenic centers. Eight of them are hydroxyl or acetyl
functions. Those challenging molecules and especially
their syn- and anti-1,3-diol sequences constitute an ex-
cellent target for our ongoing program on the use of ru-
thenium-mediated asymmetric hydrogenation for the
preparation of biologically relevant natural products.3–5
Moreover, this would allow us to valorize the
SYNPHOS® ligand, a chiral atropisomeric diphosphine
recently developed by our group.6
21
23
Scheme 1 Structures of dolabelides A, B, C and D.
The C(1)-C(14) fragment would result from a Horner–
Wadsworth–Emmons reaction between a b-keto phospho-
nate [C(6)-C(13) fragment] and an aldehyde [C(1)-C(5)
fragment] to create the C(5)-C(6) bond. A homologation
reaction at the C(13) carbon would then deliver either the
sulfonyl benzothiazole or the phosphonate at C(14).
Dolabelides
Our retrosynthetic analysis is based on a logical discon-
nection of dolabelides into two fragments corresponding
to C(1)-C(14) and C(15)-C(30) of the natural product
(Scheme 2).
OH OH OH
OH
15
14
30
HO
X
21
23
C(15)-C(30) fragment
+
The construction of the C(14)-C(15) trisubstituted alkene
could be achieved by either a ‘one-pot’ Julia olefination
between an aldehyde at C(15) and a sulfonyl benzothiaz-
ole at C(14) or a Horner–Wadsworth–Emmons reaction
between an aldehyde at C(15) and a phosphonate at C(14).
A subsequent macrolactonization reaction between the
carboxylic acid at C(1) and the appropriate hydroxyl
function either at C(21) or C(23) would then furnish the
dolabelide skeletons. The reverse sequence would also
deliver the desired macrocyclic structures.
OH OH OH
OH
O
OH
1
C(1)-C(14) fragment
OH
O
1
5
OH OH
O
O
13
+
P(OEt)2
OH
O
HO
6
C(6)-C(13) fragment
C(1)-C(5) fragment
Scheme 2 Retrosynthetic analysis of dolabelides. X = phosphonate
or sulfonyl benzothiazole function.
SYNLETT 2005, No. 3, pp 0429–0432
1
6.
0
2.
2
0
0
5
Advanced online publication: 17.01.2005
DOI: 10.1055/s-2005-862351; Art ID: G42704ST
© Georg Thieme Verlag Stuttgart · New York

430
R. Le Roux et al.
LETTER
To our knowledge, although one synthetic approach of the The C(1)-C(5) fragment 6 was thus synthesized in seven
C(16)-C(24) fragment of dolabelides7 and two synthetic steps from 1 in 33% overall yield with excellent dia-
approaches of the C(15)-C(30) fragment8,9 have been steroselectivity in the construction of the C(2) and C(3)
described, including one from our group, no synthesis of stereocenters.
the C(1)-C(14) portion of dolabelides has been reported so
far. We describe herein a highly stereoselective synthesis
The synthesis of the C(6)-C(13) subunit started with b-
keto ester 7 required for the first asymmetric hydrogena-
of the C(1)-C(13) fragment of dolabelides using catalytic
tion reaction (Scheme 4). This compound is readily avail-
asymmetric hydrogenation10,11 of b-keto esters and b-hy-
droxy ketone as a key step to install the C(3), C(7), C(9)
and C(11) hydroxyl-bearing stereocenters iteratively.
able from propan-1,3-diol in 3 steps.18,19 For the
asymmetric hydrogenation, we used again the chiral ru-
thenium complex {Ru[(S)-SYNPHOS]Br2}. The reaction
The commercially available Roche ester 1 was used as was carried out in ethanol at 80 °C under a low pressure
starting material for the synthesis of the C(1)-C(5) portion of hydrogen (11 bar) with 1 mol% of ruthenium complex.
which provided in two steps the b-keto ester 2 required for Under these conditions b-hydroxy ester 8 was obtained in
the asymmetric hydrogenation reaction (Scheme 3). Pro- 82% yield and with excellent enantiomeric excess
tection of 1 with p-methoxybenzyl trichloroacetimidate12 (ee = 97%, determined by HPLC analysis, Chiralcel OD-
followed by subsequent side chain extension with lithio H column, hexane–propan-2-ol = 90:10, flow rate: 0.8
tert-butyl acetate13 afforded the desired compound 2 in mL/min).
64% overall yield. Asymmetric hydrogenation of 2 was
performed using the chiral ruthenium complex {Ru[(S)-
SYNPHOS]Br2}6 prepared in situ from commercially
available (COD)Ru(2-methylallyl)2.14,15 The reaction pro-
ceeded in 94% yield and with excellent diastereoselectiv-
O
O
OH O
a
b, c
BnO
BnO
OEt
O
OEt
2
2
7
8 ee = 97%
1
ity (de >95%, determined by H NMR), affording b-
hydroxy ester 3. Diastereoselective methylation16,17 of 3
delivered compound 4 in 72% yield (de >95%, deter-
MOMO
BnO
O
MOMO
OH
O
O
d
BnO
2
Ot-Bu
Ot-Bu
2
1
mined by H NMR). Conversion of the primary alcohol
11 de = 98%
9
into the corresponding aldehyde was then achieved
smoothly using the following sequence: protection of the
secondary alcohol with triisopropylsilyl triflate followed
by deprotection of the primary alcohol with DDQ and ox-
idation of the resulting hydroxy ester 5 with Dess–Martin
periodinane furnished 6 in 76% overall yield.
TBS
TBS
e, f
g,h
MOMO
O
O
MOMO
O
O
BnO
BnO
P(OEt)2
2
2
12
13
Cl
Cl
Cl
Cl
Ph2
P
Ph2
P
O
O
O
O
O
Ru
Ru
a, b
c
PMBO
Ot-Bu
HO
OMe
OH
PPh2
Cl
NH2
Ph2P
O
O
O
O
2
1
O
O
OH
O
O
d
Ikariya–Mashima's catalyst with (S)-SYNPHOS® 10
PMBO
e, f
Ot-Bu
PMBO
Ot-Bu
Scheme 4 Synthesis of the C(6)-C(13) subunit. Reagents and con-
ditions: a) {Ru[(S)-SYNPHOS]Br2} (1 mol%), H2 (11 bar), EtOH,
80 °C, 14 h, 82% (ee = 97%); b) (CH3O)2CH2, P2O5, CHCl3, 0 °C, 15
min, 86%; c) LDA, t-BuOAc, THF, –40 °C, 4.5 h, 84%; d) 10 (2.2
mol%), H2 (80 bar), MeOH, r.t., 8 h, 93%, (de = 98%); e) TBSOTf,
2,6-lutidine, CH2Cl2, –30 °C, 30 min, 92%; f) DIBALH, toluene,
–78 °C, 25 min, 85%; g) n-BuLi, MeP(O)(OEt)2, THF, –78 °C, 25
min, 87%; h) Dess–Martin periodinane, CH2Cl2, 0 °C to r.t., 2.5 h,
91%.
3 de >95%
4 de >95%
TIPSO
TIPSO
O
O
g
HO
OtBu
Ot-Bu
O
5
6
O
O
O
PPh2
PPh2
O
Compound 8 was then converted into the MOM protected
b-hydroxy ester and subsequent side chain extension with
lithio tert-butyl acetate12 furnished b-keto ester 9 in 72%
overall yield. This compound was suitable for ruthenium-
mediated asymmetric hydrogenation of the ketone func-
tion to install the second stereogenic center of the frag-
ment.
(S)-SYNPHOS®
Scheme 3 Synthesis of the C(1)-C(5) fragment. Reagents and con-
ditions: a) PMBOC(NH)CCl3, CSA, CH2Cl2, r.t., 24 h, 75%; b) LDA,
t-BuOAc, THF, –40 °C, 3 h, 85%; c) {Ru[(S)-SYNPHOS]Br2} (2
mol%), H2 (75 bar), t-BuOH–MeOH (4:1), 50 °C, 23 h, 94% (de
>95%); d) (i) LDA, THF, –40 °C; (ii) HMPA, MeI, THF, –40 °C to
–10 °C, 6 h, 72% (de >95%); e) TIPSOTf, 2,6-lutidine, CH2Cl2,
–15 °C, 2.5 h, 92%; f) DDQ, CH2Cl2, H2O, 0 °C to r.t., 1 h, 85%;
g) Dess–Martin periodinane, CH2Cl2, 0 °C to r.t., 4.5 h, 97%.
Synlett 2005, No. 3, 429–432 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of the C(1)-C(13) Fragment of Dolabelides
431
As the use of chiral ruthenium complex {Ru[(S)-
SYNPHOS]Br2} resulted in deprotection of the MOM
protecting group, we envisaged to employ Ikariya–
Mashima’s catalyst which is more suitable for acid-sensi-
tive compounds. This catalyst was first synthesized with
the chiral diphosphine BINAP by Ikariya and Saburi in
1985.20 Mashima afterwards correctly described this
catalyst using p-MeO-BINAP as the chiral diphosphine.21
The (S)-SYNPHOS complex 10 was synthesized in our
laboratory using the new and efficient procedure pub-
lished in 2000 by Mashima et al.22 Thus, the reaction was
carried out with 2.2 mol% of catalyst 1023 in methanol at
room temperature and under a high pressure of hydrogen
(80 bar).24 Under these conditions, syn-b,d-dihydroxy
ester 11 was obtained in 93% yield with excellent dia-
stereoselectivity (de = 98%, determined by HPLC analy-
sis, Chiralcel OD-H column, hexane–propan-2-ol = 99:1,
flow rate: 1.0 mL/min).
TBS
MOMO
BnO
TIPSO
O
O
O
O
P(OEt)2
+
Ot-Bu
O
2
13
6
a
TBS
MOMO
BnO
O
O
TIPSO
O
Ot-Bu
2
14
b, c
MOMO
OH OH TIPSO
O
BnO
Ot-Bu
2
15 de >95%
d
MOMO
O
O
TIPSO
O
Protection of the hydroxyl function followed by hydride
reduction of the ester then afforded aldehyde 12 in 79%
overall yield. Finally, this compound was converted into
the corresponding b-keto phosphonate 13 via addition of
lithio diethyl methyl phosphonate followed by oxidation
of the resulting b-hydroxy phosphonate. Thus, the synthe-
sis of C(6)-C(13) fragment of dolabelides was achieved in
eight steps and 34% overall yield with a high level of
enantio- and diastereoselectivity in the iterative construc-
tion of the syn-1,3-diol moiety.
BnO
Ot-Bu
2
16
Scheme 5 Synthesis of the C(1)-C(13) fragment of dolabelides.
Reagents and conditions: a) LiCl, DIPEA, MeCN, r.t., 26 h, 38%; b)
1% HCl in EtOH, r.t., 3 h, 70%; c) 10 (2 mol%), H2 (80 bar), t-BuOH–
MeOH (4:1), 50 °C, 23 h, 79% (de >95%); d) 2,2-dimethoxypropane,
PPTS, acetone, r.t., 30 min, quant.
homologation of the resulting b-hydroxy ester into a new
b-keto ester for further hydrogenation. This versatile
methodology should allow the preparation of analogues of
dolabelides in view of structure–activity relationship
studies. The achievement of the total synthesis of dolabe-
lides is currently underway and will be reported in due
course.
Once the syntheses of C(1)-C(5) and C(6)-C(13) frag-
ments were achieved, we could address the Horner–
Wadsworth–Emmons reaction to create the C(5)-C(6)
bond (Scheme 5).
This reaction was carried out under Masamune–Roush
conditions,25 suitable for the base-sensitive aldehyde 6,
and afforded stereoselectively compound (E)-14 in 38%
yield (78% yield based on recovered starting material).
The TBS protecting group was then removed selectively
to furnish in 70% yield the b-hydroxy ketone required for
the last asymmetric hydrogenation reaction to simulta-
neously install the C(7) stereogenic center and reduce the
alkene. The reaction was carried out in a mixture of tert-
butanol–methanol (4:1) at 50 °C and under high pressure
of hydrogen (80 bar) with 2 mol% of Ikariya–Mashima’s
catalyst 10. Under these conditions, compound 15 was ob-
tained in 79% yield and with excellent diastereomeric ex-
Acknowledgment
R. L. R. and N. D. are grateful to the Ministère de l’Education
Nationale et de la Recherche for a grant (2004–2006) and (2001–
2004), respectively.
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1
cess (de >95%, determined by H NMR). Conversion of
15 into the corresponding acetonide 16 then proceeded
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the anti-relationship between the C(7) and C(9) hydroxyl
groups.26
In conclusion, a stereoselective synthesis of the C(1)-
C(13) fragment of dolabelides was performed for the first
time using catalytic asymmetric hydrogenation of b-keto
esters and b-hydroxy ketone to install the hydroxyl groups
at C(3), C(7), C(9) and C(11) stereocenters. This flexible
strategy is based on an iterative process: catalyst-con-
trolled asymmetric hydrogenation of a b-keto ester and
Synlett 2005, No. 3, 429–432 © Thieme Stuttgart · New York

432
R. Le Roux et al.
LETTER
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Mashima’s Catalyst with (S)-SYNPHOS® 10.
A mixture of [RuCl2(h6-benzene)]2 (25 mg, 0.05 mmol), (S)-
SYNPHOS® (64 mg, 0.1 mmol) and dimethylammonium
chloride (8 mg, 0.1 mmol) were introduced in a 50 mL round
bottom tube equipped with a magnetic stirring bar and a
condenser. The mixture was degassed by three vacuum/
argon cycles at r.t. Degassed anhyd THF (6 mL) was added.
The orange mixture was refluxed overnight and then cooled
to r.t. The solvents were evaporated under vacuum and the
brown solid 10 was used as crude catalyst for the
hydrogenation reaction without further purification.
Typical Procedure for the Hydrogenation Reaction with
Ikariya–Mashima’s Catalyst 10.
A solution of b-keto ester 9 (110 mg, 0.30 mmol) in
degassed MeOH (2.0 mL) was added to Ikariya–Mashima’s
catalyst 10 (6.0 mg, 0.004 mmol) in a round bottom tube via
cannula. The reaction vessel was placed in a stainless steel
autoclave, which was purged with hydrogen and pressurized
to 80 bar. After stirring for 8 h at r.t., hydrogen was vented
and the reaction mixture was concentrated in vacuo. The
residue was purified by flash chromatography (C6H12–
EtOAc = 8.5:1.5) to give 11 (102 mg, 0.28 mmol, 93%, de =
98%) as a pale yellow oil.
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Synlett 2005, No. 3, 429–432 © Thieme Stuttgart · New York