The sulfinyl moiety as an internal nucleophile. Part 8: Efficient, stereospecific synthesis of (+)-polyoxamic acid

Article abstract of DOI:10.1016/S0040-4039(03)01650-2

A straightforward and stereospecific synthesis of (+)-polyoxamic acid is disclosed. The key step of the synthesis involves the regio- and stereospecific bromohydration of an olefin via intramolecular participation by the sulfinyl group.

Full text of DOI:10.1016/S0040-4039(03)01650-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6713–6715
The sulfinyl moiety as an internal nucleophile. Part 8:
Efficient, stereospecific synthesis of (+)-polyoxamic acidꢀ
Sadagopan Raghavan* and Suju C. Joseph
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 May 2003; revised 23 June 2003; accepted 27 June 2003
Abstract—A straightforward and stereospecific synthesis of (+)-polyoxamic acid is disclosed. The key step of the synthesis involves
the regio- and stereospecific bromohydration of an olefin via intramolecular participation by the sulfinyl group.
© 2003 Elsevier Ltd. All rights reserved.
Polyoxins,1 isolated from Streptomyces cacoi var.
asoensis, are peptidonucleosides comprising a nucleo-
sidic amino acid and a hydroxylated amino acid, 5-O-
carbamoyl polyoxamic acid, linked by an amide bond.
The polyoxins are important agricultural antibiotics
that exhibit marked and selective activity against phyto-
pathogenic fungi by inhibiting chitin synthase.2 They
are also therapeutically useful against Candida albicans,
a fungal pathogen that affects humans.3 Polyoxamic
acid has been the subject of many synthetic studies4
which have employed carbohydrates or amino acids as
building blocks except for that reported by Kim et al.,4b
Baltas et al.,4c and Trost et al.4i There however remains
the need for a more general, efficient and a stereoselec-
tive approach to polyoxamic acid. By way of demon-
strating the potential of our methodology, of taking
advantage of the sulfinyl moiety as an intramolecular
nucleophile to functionalize olefins complexed to elec-
trophiles,5 we report herein a novel, concise and a
highly stereoselective synthesis of polyoxamic acid (1).
group and bromine at C3 and C4 respectively is
expected from an overall anti addition across the dou-
ble bond. The bromodiol (4) was transformed into
acetonide (5) by reaction with 2,2-dimethoxypropane
catalyzed by CSA. The 13C spectrum of 5 revealed
signals for the methyl groups of the acetonide at l 27.0,
27.4 and for the quaternary carbon at l 110.5 proving
beyond doubt the syn disposition8 of the hydroxy
groups in bromodiol (4). The observed stereo- and
regioselectivity can be rationalized through the interme-
diacy of a sulfoxonium salt (I) (Scheme 1). The 5-exo
nucleophilic attack by the sulfinyl group onto the olefin
p-complexed9 to the bromonium ion would result in the
formation of the sulfoxonium salt (I), which upon
hydrolysis by attack of water on sulfur in a SN2 fash-
ion,10 would yield the bromohydrin (4), with inversion
of sulfur configuration.
Subjecting acetonide (5) to treatment with excess
sodium azide in DMF afforded cleanly the azido ace-
tonide (6), which has all the three stereogenic centers
disposed as in (+)-polyoxamic acid, both in a relative
and absolute sense.
The synthesis commenced from the b-hydroxy sulfoxide
(3) obtained by diastereoselective reduction (>95% d.e.)
of b-keto sulfoxide (2)6 with DIBAL/ZnCl2.7 Treatment
of 3 with NBS in toluene in the presence of water
afforded the bromohydrin (4) regio- and stereospecifi-
cally. The orientation as indicated for the hydroxy
The acetonide (6) was transformed to the alcohol (8) in
a one pot operation by subjecting it to Pummerer
rearrangement11 to yield the intermediate (7) which was
Keywords: (+)-polyoxamic acid; sulfinyl group; bromohydrin; stereospecific.
ꢀ IICT Communication No. 030303.
* Corresponding author. E-mail: purush101@yahoo.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01650-2

6714
S. Ragha6an, S. C. Joseph / Tetrahedron Letters 44 (2003) 6713–6715
Scheme 1. Reaction conditions: (a) DIBAH, ZnCl2, THF, −78°C, 30 min, 91%; (b) NBS, H2O, toluene, rt, 15 min, 88%; (c)
2,2-DMP, cat. CSA, acetone, rt, 2 h, 86%; (d) NaN3, DMF, 85°C, 5 h, 75%.
Scheme 2. Reaction conditions: (a) TFAA, Et3N, CH2Cl2, 0°C, 15 min then aq. NaHCO3, NaBH4, 0°C, 20 min, 73%; (b)
TBDPS-Cl, imidazole, DCM, rt, 2 h, 94%; (c) 10% Pd(OH)2/C, H2, (Boc)2O, EtOAc, rt, 8 h, 76%; (d) TEMPO, PhI(OAc)2,
H2O/CH3CN (1:1), 6 h, rt, 82%; (e) TFA, H2O (9:1), rt, 16 h, 93%; (f) Ac2O, MeOH, rt, 16 h, 60%.
further hydrolyzed and reduced by treatment with aq.
saturated NaHCO3 and NaBH4. Treatment of alcohol
(8) with t-butyldiphenylsilyl chloride and imidazole
afforded the silyl ether (9), which upon treatment with
Pd(OH)2 under an atmosphere of hydrogen in the
presence of (Boc)2O afforded the aminoalcohol deriva-
tive (10). Oxidation of the primary hydroxy group in 10
by treatment with PhI(OAc)2 and Tempo12 afforded the
acid (11) which was characterized as its methyl ester
(12) by treatment of a small portion with excess ethe-
real diazomethane. Removal of the protecting groups in
11 by treatment with aq. TFA yielded polyoxamic acid
(1) after purification by passing through Dowex ion
exchange resin (Scheme 2). The physical characteristics
of 1 were in full agreement with the reported values in
the literature.4s (+)-Polyoxamic acid (1) was further
transformed by treatment with Ac2O to afford the
known lactone 13.4s
sulfoxide (2) to the b-hydroxy sulfoxide (3), stereo- and
regiospecific synthesis of the bromodiol (4) by sulfinyl
group participation and one-pot multistep transforma-
tion of 9 to 10. The route disclosed herein is to be
contrasted with other approaches based on dihydroxyl-
ation of unsaturated substrates possessing the requisite
carbon skeleton that afford products with poor stereo-
control.4i,4t Finally, it is worthwhile to note that start-
ing from the diastereomer of hydroxy sulfoxide (3) that
differs at the hydroxy center and following the same
sequence of reactions, (−)-polyoxamic acid can be
elaborated.
Acknowledgements
S.R. is thankful to Dr. J. S. Yadav, Head, Org. Div. I
and Dr. K. V. Raghavan, Director, IICT for constant
support and encouragement. S.C.J. is thankful to
CSIR, New Delhi for a fellowship. Financial assistance
from DST (New Delhi) is gratefully acknowledged. We
thank Dr. A. C. Kunwar for the NMR spectra.
In summary, we have disclosed a concise and a highly
stereospecific synthesis of (+)-polyoxamic acid. The key
step of the route include efficient transfer of chirality
from sulfur to carbon in the transformation of b-keto-

S. Ragha6an, S. C. Joseph / Tetrahedron Letters 44 (2003) 6713–6715
6715
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