Toward the synthesis of pamamycin-607

Article abstract of DOI:10.1016/S0040-4039(00)00022-8

Using sultone chemistry, a short and highly enantioselective synthesis of an advanced precursor for the larger hydroxy acid moiety and of the complete smaller hydroxy acid portion of the macrodiolide antibiotic pamamycin-607 has been accomplished. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00022-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1721–1724
Toward the synthesis of pamamycin-607
Heiko Bernsmann,a Benno Hungerhoff,a Regina Fechner,a Roland Fröhlich b and Peter Metz a,∗
aInstitut für Organische Chemie, Technische Universität Dresden, Mommsenstr. 13, D-01062 Dresden, Germany
bOrganisch-Chemisches Institut, Universität Münster, Corrensstraße 40, D-48149 Münster, Germany
Received 16 November 1999; accepted 15 December 1999
Abstract
Using sultone chemistry, a short and highly enantioselective synthesis of an advanced precursor for the larger
hydroxy acid moiety and of the complete smaller hydroxy acid portion of the macrodiolide antibiotic pamamycin-
607 has been accomplished. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: antibiotics; Diels–Alder reactions; sultones; desulfurization.
Sultones derived from vinylsulfonates of hydroxyalkyl substituted 1,3-dienes via intramolecular
Diels–Alder reaction have proven to be versatile intermediates for organic synthesis.1 Using sultone
chemistry, we have recently developed a highly stereoselective and flexible synthesis of actic acids 1
that is not only applicable to the naturally occurring macrotetrolide subunits2 with R1=Me, Et, i-Pr and
R2=Me, but allows a further variation of the substituents R1 and R2 in a straightforward manner. Scheme
1 illustrates how the hydroxy acids 1 can be assembled from four simple building blocks: furan, an
epoxide, vinylsulfonyl chloride, and an organolithium reagent. Moreover, an enantioselective synthesis
is at hand, since a large variety of the requisite enantiomerically pure epoxides is readily available in
both enantiomeric forms.3 Our sultone route to 1 was first exemplified for racemic nonactic acid (R1,
R2=Me). Due to the extensive application of sequential transformations, only six steps were needed to
secure methyl nonactate from furan.4
Here, we report a related approach toward pamamycin-607 (2).5,6 The pamamycins are a group of
16-membered macrodiolides isolated from Streptomyces alboniger and Streptomyces aurantiacus, which
display pronounced autoregulatory, antibiotic, and anionophoric activities.7 Pamamycin-607 is especially
interesting for its potent activity against Gram-positive bacteria including multiple antibiotic-resistant
strains of Mycobacterium tuberculosis7 as well as against some phytopathogenic fungi.5b,7 Due to these
biological properties and challenged by its unique structure, several groups have developed routes to
different moieties of pamamycin-607,8 while a total synthesis of 2 has not been reported yet.
∗
Corresponding author. Tel: (+49) 351-463-7006; fax: (+49) 351-463-3162; e-mail: metz@coch01.chm.tu-dresden.de (P.
Metz)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00022-8
tetl 16302

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Scheme 1.
The macrocycle 2 is composed of two hydroxy acids, a larger fragment 3 and a smaller fragment 4
(Scheme 2). We view the larger fragment 3 as a substituted actic acid analog, which should be available
by our general route to actic acids from hydroxyalkylfuran 5. This precursor itself is disconnected
retrosynthetically to the methyl ester 6 of yet another actic acid analog. Following the building block
assembly depicted in Scheme 1, we have recently prepared the enantiomerically pure methyl ester 6
(Scheme 3).
Scheme 2.
Alcohol 7, readily available from furan and (S)-1,2-epoxypentane9 reacted with vinylsulfonyl chloride
to give sultone 8 by a tandem esterification/cycloaddition with complete diastereoselectivity. Subsequent
treatment of 8 with 2 equivalents of methyllithium induced a tandem elimination/alkoxide-directed 1,6-
addition10 to yield the bicyclic compounds 9a–c. Ozonolysis of this mixture, followed by eliminative
workup afforded two diastereomeric hemi-acetals 10. Only the trisubstituted olefins 9a and 9b are
attacked by ozone, while the vinylic sultone 9c can easily be separated. A Lewis acid-catalyzed exchange
of the hydroxyl group in 10 against a phenylthio group in 11 then set the stage for a tandem reductive
elimination/hydrogenation with Raney nickel to give 6 ([α]25D=−23.5 (c 1.43, CH2Cl2)) via a single

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Scheme 3. (a) (i) n-BuLi, THF, −78°C to −15°C, (ii) (S)-1,2-epoxypentane, −15°C to 25°C, 77%; (b) CH2_CHSO2Cl, NEt3,
THF, 0°C to 25°C, 81%; (c) (i) MeLi, THF, −78°C to 0°C; (ii) NH4Cl, H2O, −78°C to 25°C, 66%; (d) (i) O3, NaHCO3, CH2Cl2,
MeOH, −78°C; (ii) Ac2O, pyridine, CH2Cl2, 25°C, 61%; (e) PhSH, BF3·Et2O, CH2Cl2, 25°C, 82%; (f) Raney Ni (W2), 50 bar
H2, EtOH, 25°C, 54%
2,3-dihydrofuran. The conversion of 11 to 6 proceeds without adding hydrogen gas, too.4 However, we
recently found that conducting these desulfurizations under hydrogen pressure is superior in terms of
reproducibility,11 while the diastereoselectivity (6:6-epi-6=18:1) is not affected at all.
Using a similar strategy, we prepared the complete C-2 epimeric smaller fragment 4 as well (Scheme
4). To this end, sultone 14 was efficiently generated with complete diastereoselectivity from 2-bromo-4-
methylfuran (12)12 via intramolecular Diels–Alder reaction of the vinylsulfonate derived from alcohol
13. The configuration of 14 was unambiguously established by X-ray diffraction analysis.13 Upon
subjecting 14 to a tandem elimination/alkoxide-directed 1,6-hydride addition,14 the bicyclic compounds
15a–c with the required trans relationship of the hydroxyl and the methyl substituent were isolated in
good yield. Application of the reaction sequence tandem ozonolysis/cyclization, Lewis acid-catalyzed
hydroxyl/phenylthio exchange, and tandem reductive elimination/hydrogenation already used for the
synthesis of 6 finally led to 18 ([α]25D=+29.5 (c 1.23, CHCl3)), the methyl ester of the smaller fragment
4 with high diastereoselectivity (18:6-epi-18=17:1) for the final step. Further elaboration of ester 6 to the
larger fragment 3 of pamamycin-607 (2) via hydroxyalkylfuran 5 is currently being investigated and will
be reported in due course.
Acknowledgements
Financial support of this work by the Deutsche Forschungsgemeinschaft and the Fonds der Chem-
ischen Industrie is gratefully acknowledged. We thank the BASF AG and the ASTA Medica AG for
generous gifts of chemicals.

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Scheme 4. (i) t-BuLi, THF, −78°C to −15°C, (ii) (S)-1,2-epoxypentane, −15°C to 25°C; 92%; (b) CH2_CHSO2Cl, NEt3, THF,
0°C to 25°C, 94%; (c) (i) Red-Al®, toluene, 25°C; (ii) NH4Cl, H2O, 25°C, 59%; (d) (i) O3, NaHCO3, CH2Cl2, MeOH, −78°C;
(ii) Ac2O, pyridine, CH2Cl2, 25°C, 57%; (e) PhSH, BF3·Et2O, CH2Cl2, 25°C, 84%; (f) Raney Ni (W2), 50 bar H2, EtOH, 25°C,
51%
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