Enantioselective monoreduction of 2-alkyl 1,3-diketones using chiral ruthenium catalysts. Synthesis of the C14-C25 fragment of bafilomycin A 1

Article abstract of DOI:10.1016/j.tetlet.2003.09.192

The enantioselective monoreduction of 2-alkyl 1,3-diketones by dynamic kinetic resolution using optically active ruthenium catalysts allowed the preparation of the C14-C25 fragment of bafilomycin A₁.

Full text of DOI:10.1016/j.tetlet.2003.09.192

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8823–8826
Enantioselective monoreduction of 2-alkyl 1,3-diketones using
chiral ruthenium catalysts. Synthesis of the C14ꢀC25 fragment
of bafilomycin A1
Florence Eustache, Peter I. Dalko and Janine Cossy*
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 31 July 2003; revised 18 September 2003; accepted 23 September 2003
Abstract—The enantioselective monoreduction of 2-alkyl 1,3-diketones by dynamic kinetic resolution using optically active
ruthenium catalysts allowed the preparation of the C14–C25 fragment of bafilomycin A1.
© 2003 Elsevier Ltd. All rights reserved.
Bafilomycin A1 is a polyketide isolated from the fer-
mentation broth of Streptomyces griseus in 19831
(Scheme 1). The natural product is a member of the
plecomacrolide family of macrolide antibiotics that
includes the hygrolidins,2,3 the concanamycins4 and
formamicin.5,6
development of efficient syntheses of bafilomycin A1
and its analogues.7b,12,13
Recently, we reported that the enantioselective monore-
duction of 2-alkyl 1,3-diketones by dynamic kinetic
resolution mediated by chiral ruthenium catalysts
(R,R)-I and (S,S)-I afforded, respectively, and selec-
tively 2-alkyl 3-hydroxyketones of type A and B in high
diastereo- and enantioselectivity14 (Scheme 2). As an
extension of this work, we report herein the application
of this enantioselective monoreduction of diketones to
the synthesis of the C14ꢀC25 fragment of bafilomycin
A1.
Scheme 1. Bafilomycin A1.
Bafilomycin A1 is a potent and specific inhibitor of
vacuolar ATPases (V-ATPases) in vitro and in vivo7
and displays broad antibacterial and antifungal activ-
ity.8 The stereochemistry of bafilomycin A1 was initially
assigned on the basis of molecular modelling and con-
formational analysis of published NMR data,9 and was
confirmed by X-ray analysis.10,11
The natural compound contains twelve stereogenic cen-
ters, two diene units, an acid- and base-sensitive six-
membered hemiketal unit, which participates in the
hydrogen-bonding network with the C17 hydroxyl
group and the 16-membered lactone carbonyl. By virtue
of the challenging chemical structure and biological
properties, considerable effort has been devoted to the
Scheme 2. Enantioselective monoreduction of 2-alkyl 1,3-
diketones.
The retrosynthetic analysis of bafilomycin A1 was envis-
aged by assembling fragments C and D using a Stille
coupling reaction followed by a macrolactonization.
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.192

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F. Eustache et al. / Tetrahedron Letters 44 (2003) 8823–8826
The C12ꢀC25 fragment (fragment C) could be synthe-
sized by alkylation of dithiane 18 with iodide 8. The
stereotriad 8 and the stereotetrad 18 could be obtained
by enantioselective monoreduction of diketones 3 and
10, using the optically active ruthenium catalysts (S,S)-I
and (R,R)-I, respectively (Scheme 3).
The synthesis of the C20ꢀC25 segment of bafilomycin
A1, iodide 8, began with the preparation of diketone 3.
This compound was obtained by condensation of the
kinetic enolate of 2-methylpentan-3-one 1 (LDA, THF,
−78°C) with acylbenzotriazole 2 (72% yield). The enan-
tioselective monoreduction of 3, accomplished using
ruthenium complex (S,S)-I in the presence of Et3N and
HCO2H in refluxing CH2Cl2, afforded the b-hydroxyke-
tone 4 in 60% yield14 and 94% ee.15 Hydroxyketone 4
was reduced with Me4NBH(OAc)3 in acetic acid16 to
give the syn,anti-stereotriad 5. Under these conditions,
a mixture of two isomers 5 and 5%17 was obtained in a
ratio of 90/10 in 76% yield. The separation of the two
isomers was tedious and, in order to overcome this
difficulty, the mixture of the two isomers was converted
to the corresponding acetonides18
6
and 6%
(dimethoxypropane, CSA in acetone, 74% yield) which
were then separated. As the ketal protecting group
proved to be troublesome for further operations, com-
pound 6 was transformed to the bis-t-butyldimethylsilyl
(TBDMS) ether 7 in a two-step sequence in quantitative
yield (HCl 1N, THF then TBDMSOTf, 2,6-lutidine,
CH2Cl2). The conversion of 7 into iodide 8 was
achieved in 64% yield after selective cleavage of the
benzyl protecting group [H2, Pd/C (10%), K2CO3,
AcOEt, 71% yield] followed by iodination (I2, PPh3,
imidazole in refluxing toluene).19 Iodide 8 was obtained
in eight steps from 2-methylpentan-3-one 1 with an
overall yield of 15.5% (Scheme 4).
Scheme 4. Synthesis of the C20ꢀC25 fragment.
acylbenzotriazole 2. The enantioselective monoreduc-
tion of 10, with ruthenium complex (R,R)-I, under the
previously developed conditions14 led to b-hydroxy-
ketone 11 in 93% ee.14
The synthesis of dithiane 18, which represents the
C14ꢀC19 fragment, was realized from diketone 10.
Diketone 10 was prepared in 72% yield by condensa-
tion of the lithium enolate of propiophenone 9 with
For the construction of the syn,anti,syn-stereotetrad,
the b-hydroxyketone 11 was transformed to alde-
hyde 14 via ester 12 using a regioselective Baeyer–
Villiger oxidation. The Baeyer–Villiger oxidation of the
unprotected b-hydroxyketone 11 was achieved with
bis(trimethylsilyl) peroxide in the presence of SnCl4 and
( )-1,2-bis(tosylamido)cyclohexane E in CH2Cl2 at rt.20
After treatment with NaHCO3 followed by acidic treat-
ment for 24 h, the b-hydroxy ester 12 was isolated in
78% yield, and transformed into the desired aldehyde
14 in a three-step sequence. The hydroxy group in 12
was protected as a TBDMS ether and, after reduction
with DIBAL-H (toluene, −78°C), alcohol 13 was oxi-
dized to aldehyde 14 (Swern oxidation) with a 90%
yield for the overall process (Scheme 5).
The required configuration at C17 and C18 was set
with an anti-Felkin–anti-selective aldol reaction.21
Addition of (Z)-oxazolidinone boron enolate 15 to
aldehyde 14 led to 16 in 80% yield as a single
diastereomer. The relative stereochemistry in 16 was
confirmed by transformation of 16 into lactone 19 via
1
amide 17 (cf. vide infra). The value of the H NMR
coupling constants in 19 (JH15-H16=3.9 Hz, JH16-H17=
Scheme 3. Retrosynthetic analysis of bafilomycin A1.

F. Eustache et al. / Tetrahedron Letters 44 (2003) 8823–8826
8825
3.9 Hz and JH17-H18=7.3 Hz) were in accordance with
the syn,anti,syn relative stereochemistry in stereotetrad
16 (Scheme 6).
Transformation of 16 to dithiane 18 was achieved in a
four-step sequence via amide 17. After conversion of
oxazolidinone 16 to amide 17 using N,O-dimethylhy-
droxylamine hydrochloride in the presence of trimethyl-
22
aluminium (3 equiv.) in CH2Cl2 (97% yield), the
Scheme 7. Synthesis of the C14ꢀC25 unit.
hydroxy group at C17 was protected as a TBDMS
ether, and the amide was reduced with DIBAL-H
(THF, −78°C). The resulting aldehyde was directly
treated with propane-1,3-dithiol in the presence of
TiCl4 to produce dithiane 18 in 87% overall yield. The
C14–C19 fragment, dithiane 18, was obtained in 11
steps from propiophenone with a 20.5% overall yield
(Scheme 5).
Finally, the assembly of the C14–C19 and C20–C25
fragments of bafilomycin A1 was realized by alkylation
of the lithiated dithiane 18 (t-BuLi, HMPA, THF) with
iodide 8,12c which led to the formation of compound 20
in a 28% non-optimized yield (Scheme 7).
In summary, a convergent route to prepare the
C14ꢀC25 fragment of bafilomycin A1 was achieved.
The sequence involves two dynamic kinetic resolution
steps of 2-alkyl 1,3-diketones using optically active
ruthenium complexes, which set the correct configura-
tion at C15, C16, C21 and C22. To control the C23
stereogenic center, an anti-selective directed reduction
of a b-hydroxyketone was used. The introduction of the
C17 and the C18 stereogenic centers was realized by
an anti-Felkin–anti-aldol reaction. With fragment
C14ꢀC25 in hand, progress toward the total synthesis
of bafilomycin A1 continues and will be reported in due
course.
Acknowledgements
Scheme 5. Synthesis of the C14ꢀC19 fragment.
We thank Rhodia for financial support and F.E. thanks
the CNRS and Rhodia for a grant.
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