Enantioselective synthesis of the larger fragment of pamamycin-607

Article abstract of DOI:10.1016/S0040-4039(00)01308-3

The enantiomerically pure methyl ester of the complete larger hydroxy acid (C(1)-C(18)) of the macrodiolide antibiotic pamamycin-607 has been synthesized using a general sultone route to actic acids and analogs. The requisite N,N-dimethylamino moiety was introduced by Mitsunobu inversion with hydrazoic acid followed by a reaction cascade involving hydrogenation and double reductive methylation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01308-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7629–7633
Enantioselective synthesis of the larger fragment of
pamamycin-607†
Heiko Bernsmann, Margit Gruner and Peter Metz*
Institut fu¨r Organische Chemie, Technische Universita¨t Dresden, Mommsenstr. 13, D-01062 Dresden, Germany
Received 20 July 2000; accepted 29 July 2000
Abstract
The enantiomerically pure methyl ester of the complete larger hydroxy acid (C(1)ꢀC(18)) of the
macrodiolide antibiotic pamamycin-607 has been synthesized using a general sultone route to actic acids
and analogs. The requisite N,N-dimethylamino moiety was introduced by Mitsunobu inversion with
hydrazoic acid followed by a reaction cascade involving hydrogenation and double reductive methylation.
© 2000 Elsevier Science Ltd. All rights reserved.
Keywords: antibiotics; sultones; desulfurization; Mitsunobu reaction.
Pamamycin-607 (1)1,2 is a member of a group of 16-membered macrodiolides that have been
isolated from Streptomyces alboniger and Streptomyces aurantiacus. Next to displaying autoreg-
ulatory and anionophoric activities,3 the macrocycle 1 composed of the two hydroxy acids 2 and
3 (Scheme 1) is especially interesting for its potent antibiotic activity against Gram-positive
Scheme 1.
* Corresponding author. Tel: (+49) 351-463-7006; fax: (+49) 351-463-3162; e-mail: metz@coch01.chm.tu-dresden.de
† Dedicated to Professor A. Kleemann on the occasion of his 60th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01308-3

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bacteria including multiple antibiotic-resistant strains of Mycobacterium tuberculosis3a as well as
against phytopathogenic fungi.1b,3a
Whereas several groups have disclosed synthetic routes to different moieties of pamamycin-
607 (1),4–6 a total synthesis of 1 has not been published yet. Our approach to 1 relies on an
iterative application of a methodology7 developed for the synthesis of actic acids and analogs.
Along these lines, we recently reported an efficient access to sultone 55b as a highly advanced
intermediate for the larger fragment 2 via methyl ester 4 (Scheme 2) as well as to the methyl
ester of the smaller fragment 3.5a Here we communicate the straightforward conversion of
sultone 5 to the methyl ester of the complete larger fragment 2 that is a building block of the
pamamycin homologs 621A and 635B too.3b
Scheme 2.
Treatment of sultone 5 with two equivalents of methyllithium cleanly introduced a methyl
group only syn to the hydroxyl substituent via tandem elimination/alkoxide-directed 1,6-
addition8 (Scheme 3). In the resultant epimeric trisubstituted olefins 6a and 6b, all carbon atoms
of the larger fragment’s backbone had now been assembled. While only trace amounts of a
tetrasubstituted alkene isomer5a were detected, a small quantity of the benzene derivative 7 could
be isolated as a byproduct. The crude mixture was easily separated by flash chromatography to
give the pure components in the yields listed in Scheme 3, and the two allylic sultones 6a and
6b were then separately subjected to an oxidative olefin cleavage (Scheme 4).
Scheme 3.

7631
Scheme 4.
Ozonolysis of the major sultone 6a followed by eliminative workup5a delivered the expected
hemi-acetal 8 as a single stereoisomer in excellent yield (Scheme 4). Crucial to the successful
execution of this transformation was to keep the ozonation time as short as possible and to
conduct the acetylation/elimination of the intermediate peroxy hemi-acetal at reflux tempera-
ture. Remarkably, only the same stereoisomer 8 was obtained from the minor sultone 6b under
these conditions as well. This result is readily rationalized through an equilibration of the
corresponding g-hydroxy ketone 10, which should be very prone to epimerization at C(5)
(pamamycin numbering) due to the presence of two adjacent electron-withdrawing groups. Once
an (S) configuration is set up at C(5), recyclization indeed should lead to hemi-acetal 8 with a
cis fusion between five- and six-membered ring. In the diastereomer 8 isolated, all carbon
substituents can occupy an equatorial position on a chair d-sultone, whereas at least one carbon
substituent would have to be axial in the alternative diastereomer 9. While the relative
configuration at C(5) and C(6) (pamamycin numbering) was irrelevant in view of the further
synthetic elaboration, formation of a single product made characterization easier. Treatment of
hemi-acetal 8 with thiophenol in the presence of trifluoroborane not only effected lactol
S,O-acetal interchange, but simultaneously cleaved the silyl ether on the side chain9 to give
alcohol 11.
In order to find suitable conditions for the introduction of the requisite dimethylamino moiety
with inversion of configuration that might be coupled in a tandem fashion with the reductive
sultone cleavage, a model experiment was performed (Scheme 5). To this end, methyl ester 45a
was first subjected to a Mitsunobu reaction10 with either hydrazoic acid or zinc azide. Using
hydrazoic acid as azide source turned out to be superior with respect to both yield and reaction
time (1 h versus 2 days with zinc azide). Upon application of our standard conditions for

7632
reductive sultone desulfurization5a to the resultant product 12 followed by addition of a 35%
aqueous formaldehyde solution to the reaction mixture, a smooth azide reduction and subse-
quent double reductive alkylation11 of the intermediate primary amine took place to deliver the
dimethylamino product 13.4h
Scheme 5.
Similarly, a Mitsunobu reaction of S,O-acetal 11 with hydrazoic acid efficiently introduced
the nitrogen function of 14 with clean inversion of configuration (Scheme 6). Gratifyingly,
treatment of azide 14 under the conditions used for 12 indeed directly provided the desired
methyl ester 161e,2b,12 ([h]3D0=−33.4 (c 0.99, CH2Cl2)) of the larger fragment of pamamycin-607
(1) as a single stereoisomer. Further optimization of this reaction cascade as well as coupling of
fragments 2 and 3 to give pamamycin-607 (1) is currently being investigated and will be reported
in due course.
Scheme 6.
Acknowledgements
Financial support of this work by the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank the BASF AG and the ASTA
Medica AG for generous gifts of chemicals, Prof. U. Gra¨fe, Hans-Kno¨ll-Institut fu¨r Naturstoff-
Forschung, Jena, for a sample of natural pamamycin-607 and Professor M. Natsume, Tokyo
1
University of Agriculture and Technology, for H NMR and mass spectra of 16.

7633
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