Stereoselective synthesis towards the C8-C18 subunit of pamamycin-607 induced by a chiral sulfoxide group

Article abstract of DOI:10.1016/S0040-4039(99)02117-6

A close precursor of the C8-C18 subunit of pamamycin-607 was prepared by asymmetric synthesis from ethyl butyryl acetate via a chiral β,δ- diketosulfoxide.

Full text of DOI:10.1016/S0040-4039(99)02117-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 551–554
Stereoselective synthesis towards the C8–C18 subunit of
pamamycin-607 induced by a chiral sulfoxide group
Guy Solladié,∗ Xavier J. Salom-Roig and Gilles Hanquet
University Louis Pasteur, ECPM, Laboratoire de Stéréochimie Associé avec le CNRS, 25 Rue Becquerel,
67087- Strasbourg Cedex 2, France
Received 30 September 1999; accepted 10 November 1999
Abstract
A close precursor of the C8–C18 subunit of pamamycin-607 was prepared by asymmetric synthesis from ethyl
butyryl acetate via a chiral β,δ-diketosulfoxide. © 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.
Scheme 1.
Several groups are involved in the total synthesis of pamamycin-607 but only the synthesis of the
C10–C1102b,4 and C1–C145 subunits have been published so far. The group of Walkup has already
reported the synthesis of the C10–C110 fragment in racemic4a and optically active form4b,2b as well as the
synthesis of the C1–C14 portion5 from an enzymatically resolved allene derivative. The group of Perl-
mutter has recently reported the synthesis of the enantiomerically enriched 80-epi C10-C110fragment4c
from an optically active α-hydroxyacid. Finally the group of Bloch4d published a synthesis of the
C10–C110 part from an enantiomerically pure 7-oxabicyclo[2,2,1] hept-5-ene derivative also obtained
∗
Corresponding author. Fax: 33 3 88 13 6949; 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(99)02117-6
tetl 16045

552
by enzymatic resolution. Very recently Bloch4e reported the synthesis of the C8–C18 fragment by the
same method. This publication prompted us to report our own results and describe a novel, efficient,
stereocontrolled approach to a close precursor 1 of the subunit C8–C18 starting from the intermediate 2
readily made by asymmetric synthesis from the chiral β,δ-diketosulfoxide 3 (Scheme 1).
Scheme 2.
The β-ketosulfoxide 3 was obtained from ethyl butyryl acetate 4 after carbonyl protection and
condensation with two equivalents of (−)-(S)-methyl-p-tolylsulfoxide anion6 in 60% isolated yield.
DIBAL-H reduction afforded, as expected from our previous results,7 the corresponding [S(S),2(R)]-β-
hydroxysulfoxide 5a8a (de>95%). We purified only an analytical sample for identification and hydrolyzed

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the remaining crude reduction product with oxalic acid to give 5b in an overall yield after the two steps of
80%. Only one diastereomer was observed in the 200 MHz 1H NMR. The other diastereomer [S(S),2(S)]-
5c8b was prepared by reduction with ZnI2/DIBAL-H to confirm the absolute configuration and the
diastereoselectivity.7 The protection of the δ-carbonyl group as a dioxolane9 avoided side-reactions in
the reduction of β,δ-diketosulfoxides,7 improved yields (33% yield for the direct reduction of the β,δ-
diketosulfoxides because of product decompositon) and made the purification easier. After deketalization,
the resulting [S(S),2(R)]-β-hydroxy-δ-keto-sulfoxide 5b was reduced using Evans’ method10 giving anti-
[S(S),2(R),4(S)]-β,δ-dihydroxy-sulfoxide 6 (de>95%), isolated by crystallization in 97%. Stereochem-
ical assignment of the anti configuration was confirmed by 13C NMR of the corresponding acetonide
7.11 Sulfoxide reduction to the corresponding sulfide, methylation at sulfur and intramolecular sulfonium
elimination afforded in 75% yield the [2(R),4(S)]-β-hydroxy epoxide 8.12 Protection of the alcohol as
its t-butyldiphenylsilyl ether, regioselective nucleophilic epoxide opening with ethyl malonate anion
followed by smooth decarboxylation with magnesium chloride hexahydrate led to the butyrolactone 9
(73% yield). Finally reaction of 9 with t-butyl propionate enolate gave a hemiketal which, after acidic
dehydration, provided the expected intermediate 2 in 75% yield in the more stable E configuration.13
Then compound 2 was deprotected with tetrabutylammonium fluoride and stereoselectively hydro-
genated on the less hindered face with rhodium on alumina; a known process for this type of furan
derivative (Scheme 2).14 The target molecule 1 was obtained pure in 73% yield15 after chromatography.
Direct hydrogenation of silylated 2 led only to starting material even under more drastic conditions. In
the case of the benzyl ether of 2, we observed competitive hydrogenation of the aromatic ring giving a
cyclohexylmethyl ether.16
The configuration of product 1 was confirmed by chemical correlation with the known compound 10
by ester reduction with lithium aluminum hydride followed by acylation with p-bromobenzoyl chloride
(Scheme 2). All the characteristics of 10 are in agreement with those described by Walkup. 4a
In conclusion, it has been demonstrated that the important intermediate 1 for the total synthesis of
pamamycin-607 can be obtained in high ee in 14 steps and in 11% overall yield from ethyl butyryl
acetate using (−)-(S)-methyl-p-tolylsulfoxide as the chiral auxiliary.
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1
8. H NMR (200 MHz, CDCl3): (a) [S(S),2(R)]-5b: δ 0.89 (t, 3H, J=7 Hz, H-7); 1.57 (sext.; 2H, J=7 Hz, H-6); 2.39 (t, 2H,
J=7 Hz, H-5); 2.43 (s, 3H, benzylic CH3); 2.64 (d, 2H, H-3, J=6 Hz); 2.86 (AB of ABX, 2H, H-1, JAX=9.5 Hz, JBX=2.5 Hz,
JAB=13.5 Hz); 4.10 (b s, 1H, OH); 4.69–4.57 (m, 1H, H-2, X of ABX); 7.35 (B of (AB)2, 2H, arom.; JAB=8 Hz, ∆ν=36

554
Hz); 7.53 (A of (AB)2, 2H, arom.; JAB=8 Hz, ∆ν=36 Hz); (b) [S(S),2(S)]-5c: 0.90 (t, 3H, H-7, J=7.3 Hz); 1.58 (sext, 2H,
H-6, J=7.3 Hz); 2.40 (t, 2H, H-5, J=7.3 Hz); 2.41 (s, 3H, CH3 arom.); 2.78 (AB of ABX, 2H, H-3, JAX=7.3 Hz, JBX=4.9 Hz,
JAB=17.5 Hz, ∆ν=37.7 Hz); 2.93 (AB of ABX, 2H, H-1, JAX=7.5 Hz, JBX=4.4 Hz, JAB=12.9 Hz, ∆ν=24 Hz); 3.98 (d, 1H,
OH, J=2.7 Hz); 4.55–4.50 (m, 1H, H-2, X of ABX); 7.32 (B of (AB)2, 2H, H arom.; JAB=8.22 Hz, ∆ν=41.5 Hz); 7.53 (A
of (AB)2, 2H, H arom.; JAB=8.22 Hz, ∆ν=41.5 Hz); (c) (2E,6S,8S)-2: δ 0.67 (t, J=7 Hz, 3H); 1.06 (s, 9H); 1.52 (s, 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, 1H);
4.41–4.54 (m, 1H); 7.32–7.48 (m, 6H); 7.66–7.73 (m, 4H); 13C NMR: δ 169.0, 136.0, 134.7, 134.2, 129.6, 127.6, 98.8, 79.8,
79.1, 70.7, 42.5, 39.6, 31.2, 30.6, 28.6, 27.2, 19.6, 17.7, 14.0, 11.8; (d) (2R,3R,6S,8S)-1: δ 0.92 (t, 3H, H-11, J=7 Hz), 1.06
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3.87–3.77 (m, 1H), 4.02–3.88 (m, 1H), 4. 23–4.08 (m, 1H); 13C NMR: δ 167.1, 165.3, 97.2, 82.3, 79.6, 68.6, 41.2, 39.4,
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