Diastereodivergent synthesis of the C8-C18 precursor and C1'-C11' subunit of pamamycin 607 induced by a chiral sulfoxide group

Article abstract of DOI:10.1016/S0040-4039(00)00251-3

A key step in obtaining the C8-C18 and C1'-C11' fragments of pamamycin 607, which differ by the syn- and anti-configuration of one chiral center α to the tetrahydrofuran ring, was the chelation controlled E-Z-isomerization of the substituted vinyl tetrahydrofuran intermediate 3a which has so far been obtained only in the more stable E-configuration. (C) 2000 Elsevier science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00251-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2737–2740
Diastereodivergent synthesis of the C8–C18 precursor and
C10–C110 subunit of pamamycin 607 induced by a chiral
sulfoxide group
Guy Solladié,∗ Xavier J. Salom-Roig and Gilles Hanquet
Laboratoire de Stéréochimie associé au CNRS, Université Louis Pasteur, ECPM, 25 Rue Becqurel, 67087 Strasbourg Cedex 2,
France
Received 16 December 1999; accepted 9 February 2000
Abstract
A key step in obtaining the C8–C18 and C10–C110 fragments of pamamycin 607, which differ by the syn-
and anti-configuration of one chiral center α to the tetrahydrofuran ring, was the chelation controlled E–Z-
isomerization of the substituted vinyl tetrahydrofuran intermediate 3a which has so far been obtained only in
the more stable E-configuration. © 2000 Elsevier Science Ltd. All rights reserved.
Pamamycin 607 is a member of a group of molecules isolated from streptomyces1 which has a
remarkable range of biological activities including autoregulatory activity, antibiotic properties and
anionophoric behavior.2 Structure elucidation of pamamycin 6073 showed three cis 2,5-disubstituted
tetrahydrofuran units bearing syn- and anti-stereocenters α to the ring.
Several groups are involved in the total synthesis of pamamycin 607 but only syntheses of the
C10–C110,2b,4 C1–C145 and recently the C8–C184e subunits have been published so far.
We have very recently reported6 a stereoselective synthesis of a precursor of the C8–C18 moiety 1
with a syn-stereocenter α to the ring from the β-ketosulfoxide 4 via the intermediate 3a-(E) (Scheme 1).
The C10–C110 fragment 2, which is epimeric at C20 (an anti-configuration α to the ring) should be
obtained, by analogy with the synthesis of 1, from 3a-(Z) (Scheme 1).
In a previous report,6 we described the synthesis of the enantiomerically pure 3a-(E) from lactone 6
readily made from enantiomerically pure β-hydroxy epoxide 5, obtained from the β-ketosulfoxide 4-(S)
(Scheme 2).
The transformation of the more stable E-isomer 3 into the Z-isomer was then investigated and we now
report the results of the isomerization of 3a-(E) to 3a-(Z), the key step of our strategy. The idea was to
equilibrate these two isomers and displace the equilibrium in favor of 3-(Z) by chelation of a Lewis acid
between the furanic and ester oxygens.
∗
Corresponding author. Fax: (33) 3 88 13 69 49; e-mail: solladie@chimie.u-strasbg.fr (G. Solladié)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00251-3
tetl 16531

2738
Scheme 1.
Scheme 2.
This study was first carried out on racemic analogues of 3 easily prepared by the sequence described
in Scheme 3, from racemic 4-hydroxypent-1-ene 7 by epoxidation of the double bond giving epoxide 8,
which was opened with ethyl malonate anion, followed by intramolecular lactonization and decarboxyla-
tion in the presence of magnesium chloride. Finally, aldol condensation of t-butyl propionate enolate with
the lactone 9 followed by acidic dehydration gave 10-(E). The E double bond in 10 was formed during
Scheme 3.

2739
the cationic acidic dehydration of the hemi-ketal formed in the aldol condensation of t-butyl propionate
to the lactone.7
After several attempts with different Lewis acids which gave mixtures of 10-(E) and 10-(Z), the
equilibration in favor of the Z-isomer was successful with LDA (2 equiv.) at −78°C in ether alone or
in the presence of lithium chloride (3 equiv.) through ester enolization (Scheme 4). The reaction mixture
was then quenched at −78°C by adding ethanol. The results are listed in Table 1.
Scheme 4.
Table 1
Isomerization of 3-(E) to 3-(Z) and analogues with LDA/ether at −78°C
In the case of the silylated ether 10a the addition of LiCl was necessary to get a complete conversion.
Finally, when these last conditions were applied to the enantiomerically pure 3a-(E), the Z-isomer was
obtained in 70% yield.
Then (Scheme 5) the pure Z-isomer8 of 3a was deprotected with tetrabutylammonium fluoride and
stereoselectively hydrogenated on the less hindered face with rhodium on alumina; a known process for
this type of furan derivative.9 The target molecule 2 was obtained in 73% yield.10 Direct hydrogenation of
silylated 3a led only to starting material even under more drastic conditions. In the case of the benzyl ether
of 3, we observed competitive hydrogenation of the aromatic ring giving a cyclohexylmethyl ether.11
The absolute configuration of 2 was confirmed by correlation to the known product 11 by ester
reduction with LiAlH4 and acylation with p-bromobenzoyl chloride. All the characteristics of 11 are
in agreement with those described by Marumo et al.12
In conclusion, it has been demonstrated that the two important intermediates 1 and 2 for the total
synthesis of pamamycin 607 can be obtained in high ees in 14 and 15 steps and in 17 and 11% overall
yield, respectively, from a common intermediate readily made from ethyl butyryl acetate and with only
(−)-(S)-methyl-p-tolylsulfoxide as chiral auxiliary.

2740
Scheme 5.
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9H), 1.73 (t, J=1.3 Hz, 3H), 1.10–1.80 (m, 7H), 1.99–2.21 (m, 1H), 2.74–2.91 (m, 1H), 3.02–3.16 (m, 1H), 3.96–4.04 (m,
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0.6 acetone); 1H NMR (CDCl3, 200 MHz): δ=0.74 (t, J=7.0 Hz, 3H), 1.06 (s, 9H), 1.22–1.44 (m, 4H), 1.45 (s, 9H), 1.70 (s,
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7.67–7.73 (m, 4H); 13C NMR (CDCl3, 50 MHz): δ=167.1, 165.6, 136.0, 134.7, 134.5, 129.6, 127.6, 96.3, 82.5, 79.0, 71.1,
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(m, 1H), 2.82 (broad s, 1H), 3.78–3.98 (m, 2H), 4.06–4.19 (m, 1H); 13C NMR (CDCl3, 50 MHz): δ=173.9, 80.9, 80.5, 77.3,
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