Practical, efficient, stereoselective, formal synthesis of (2R,3R,4R)-3-hydroxy-4-methylproline

Article abstract of DOI:10.1016/j.tetlet.2003.08.024

A highly efficient and stereoselective synthesis of (2R,3R,4R)-HMP is disclosed employing the sulfinyl group as an internal nucleophile to functionalize an olefin in the key step of the reaction sequence. The proline ring is elaborated by a (4C+N) cycliza

Full text of DOI:10.1016/j.tetlet.2003.08.024

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7459–7462
Practical, efficient, stereoselective, formal synthesis of
(2R,3R,4R)-3-hydroxy-4-methylprolineꢀ
Sadagopan Raghavan* and S. Ramakrishna Reddy
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 1 July 2003; revised 7 August 2003; accepted 8 August 2003
Abstract—A highly efficient and stereoselective synthesis of (2R,3R,4R)-HMP is disclosed employing the sulfinyl group as an
internal nucleophile to functionalize an olefin in the key step of the reaction sequence. The proline ring is elaborated by a (4C+N)
cyclization.
© 2003 Elsevier Ltd. All rights reserved.
Antimicrobial cyclic peptides, echinocandins (1),1
pnuemocandins, sporiofungin A and mulundocandin2
have in common, an unusual amino acid, (2S,3S,4S)-3-
hydroxy-4-methylproline (HMP) (2) as one of their
constituents. An efficient route to HMP3 would be
useful in the preparation of analogs of the antifungal
lipopeptides.4 In connection with our interest in elabo-
rating key intermediates by heterofunctionalization of
olefins exploiting the sulfinyl moiety as the internal
nucleophile,5 we detail herein an efficient and stereose-
lective synthesis of (2R,3R,4R)-HMP (3).
sis), which in turn can be derived from the
bromohydrin (5), readily obtained from olefin (6).
The synthesis of 6 (P1=TBDPS) began with the ester
(7).6 Reduction of 7 with alane, generated in situ,
afforded allyl alcohol (8) which on oxidation by treat-
ment with NaIO4 afforded an equimolar mixture of
sulfoxides (9). Protection of the primary hydroxy group
as its t-butyldiphenylsilyl ether afforded 6 which could
be separated as individual diastereomers. Since we had
earlier demonstrated that the sulfoxide configuration
had no influence on the stereoselectivity of bromohy-
dration,5b no efforts were made to separate the
diastereomers. Treatment of the allyl ether (6) with
The synthesis of 3 was envisaged by a (4C+N) cycliza-
tion of the retron (4) (Scheme 1, retrosynthetic analy-
Keywords: sulfoxide; hydroxymethyl proline; bromohydrin; stereoselective.
ꢀ IICT Communication No. 030122
* Corresponding author. E-mail: purush101@yahoo.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.024

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S. Ragha6an, S. Ramakrishna Reddy / Tetrahedron Letters 44 (2003) 7459–7462
Scheme 1.
N-bromosuccinimide7 (NBS) in toluene in the presence
of water afforded bromohydrin (5) (Scheme 2).
reaction conditions10 by treatment with excess tri-
fluroacetic anhydride (TFAA) and triethylamine (Et3N)
in acetonitrile as the solvent followed by in situ hydroly-
sis and reduction of the intermediate (11) with satu-
rated aq. NaHCO3 and NaBH4 afforded the primary
alcohol (12) (Scheme 3). It is pertinent to mention that
Pummerer reaction on the substrate wherein the sec-
ondary hydroxy group was protected as its acetate,
afforded after hydrolysis and reduction, a mixture of
products resulting from acetyl migration to the primary
hydroxy group.
The regio- and stereoselectivity of bromohydration can
be rationalized by invoking the intermediates I and II,
formed by 5-exo nucleophilic attack of the sulfinyl
moiety on the olefin, p complexed to the bromonium
ion,8 and subsequent hydrolysis by attack of water at
sulfur9 (Fig. 1).
The required carbon framework was thus assembled
highly stereoselectively. The next step in the synthesis
called for the transformation of the sulfinyl moiety in 5
into a suitable leaving group. This was achieved as
follows. The secondary hydroxy group was protected as
a benzoate ester (10) by treatment with benzoic acid
and DCC. Attempted protection of 5 with benzoyl
chloride in the presence of a suitable base afforded a
complex mixture of products, probably arising from the
reaction of the reagent with the sulfinyl group in a
Pummerer type reaction. Subjecting 10 to Pummerer
Tosylation of the primary hydroxy group by treatment
with p-toluenesulfonyl chloride (Ts-Cl) in the presence
of Et3N yielded 13. The crucial (4C+N) cyclization
proceeded without incident by warming 13 with excess
benzylamine in DMF as the solvent to afford pyrro-
lidine (14). Elaboration of 14 to 3 required deprotection
of N-Bn, silyl groups and oxidation of the resulting
primary hydroxy group. Thus hydrogenolysis of 14 by
treatment with Pd/C in the presence of (Boc)2O under
Scheme 2. Reaction conditions: (a) AlH3, Et2O, 0°C, 2 h, 93%. (b) NaIO4, MeOH, H2O, rt, 16 h, 95%. (c) TBDPS-Cl, imidazole,
DCM, rt, 3 h, 78%. (d) NBS, H2O, toluene, rt, 4 h, 75%.
Figure 1.

S. Ragha6an, S. Ramakrishna Reddy / Tetrahedron Letters 44 (2003) 7459–7462
7461
Scheme 3. Reaction conditions: (a) PhCOOH, DCC, DMAP, DCM, rt, 12 h, 90%. (b) TFAA, Et3N, CH3CN, rt, NaBH4,
NaHCO3, 70%. (c) TsCl, Et3N, DCM, rt, 12 h, 85%. (d) PhCH2NH2, DMF, 60°C, 4 h, 70%. (e) H2, Pd/C, (Boc)2O, rt, 12 h, 90%.
(f) CSA, MeOH, DCM, rt, 24 h, 78%. (g) PhI(OAc)2, Tempo, CH3CN, H2O, rt, 1 h, 91%.
an atmosphere of hydrogen in methanol as the solvent
afforded carbamate (15) as a mixture of rotamers.
Deprotection of the silyl group was realized by treat-
ment of 15 with catalytic amounts of camphor-10-sul-
fonic acid (CSA)11 to afford alcohol (16). The primary
hydroxy group was oxidized readily with PhI(OAc)2/
Tempo12 to afford the acid (17), which was found to be
identical (except for the sign of rotation of plane polar-
ized light) to the sample synthesized by Langlois and
co-workers,3 who have further transformed it to HMP.
References
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Thus we have completed
a formal synthesis of
(2R,3R,4R)-HMP. Beginning with the enantiomer of
the ester (7), (2S,3S,4S)-HMP can be elaborated fol-
lowing the sequence of reactions detailed above.
In conclusion, we have disclosed a practical, efficient
and a stereoselective route to (2R,3R,4R)-HMP. The
key steps include (a) the regio- and stereoselective elab-
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Acknowledgements
S.R is thankful to Dr. J. S. Yadav, Head, Organic Div.
I and Dr. K. V. Raghavan, Director, I.I.C.T for con-
stant support and encouragement, Dr. A. C. Kunwar
for NMR spectra and Dr. Vairamani for the mass
spectra. S.R.K is thankful to CSIR (New Delhi) for the
senior research fellowship. Financial assistance from
DST is gratefully acknowledged.

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