Stereoselective synthesis of 1,4-dideoxy-1,4-imino-D-allitol and formal synthesis of (2S,3R,4S)-3,4-dihydroxyproline

Article abstract of DOI:10.1016/S0040-4039(03)01366-2

A stereoselective synthesis of 1,4-dideoxy-1,4-imino-D-allitol 1 and formal synthesis of (2S,3R,4S)-3,4-dihydroxyproline was achieved via the addition of vinylmagnesium bromide to the benzylimine derived from (R)-2,3-O-isopropylidene glyceraldehyde followed by N-allylation, ring-closing metathesis (RCM), and dihydroxylation.

Full text of DOI:10.1016/S0040-4039(03)01366-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5641–5643
Stereoselective synthesis of 1,4-dideoxy-1,4-imino-
D-allitol and
formal synthesis of (2S,3R,4S)-3,4-dihydroxyprolineꢀ
A. Madhan and B. Venkateswara Rao*
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 29 April 2003; revised 22 May 2003; accepted 30 May 2003
Abstract—A stereoselective synthesis of 1,4-dideoxy-1,4-imino-D-allitol 1 and formal synthesis of (2S,3R,4S)-3,4-dihydroxyproline
was achieved via the addition of vinylmagnesium bromide to the benzylimine derived from (R)-2,3-O-isopropylidene glyceralde-
hyde followed by N-allylation, ring-closing metathesis (RCM), and dihydroxylation.
© 2003 Elsevier Ltd. All rights reserved.
Many natural and unnatural polyhydroxylated pyrro-
lidines and polyhydroxylated piperidines commonly
referred to as azasugars or iminocyclitols are potent
glycosidase inhibitors.1 These azasugars represent an
important class of transition state analogue inhibitors
of glycosidase and glycotransferases, and they have
been found to be chemotherapeutic agents for the treat-
ment of diseases such as diabetes, cancer, inflammation
and viral infections including HIV (Fig. 1).
tives.5 Herein we wish to report a highly efficient
stereoselective synthesis of 1,4-dideoxy-1,4-imino- -alli-
D
tol 1 via the stereoselective addition of vinyl magnesium
bromide to the N-benzylimine derived from (R)-2,3-O-
isopropylidene glyceraldehyde6 based on the highly
diastereoselective approach developed by Cativiela et
al.,7 followed by N-allylation, ring-closing metathesis
and dihydroxylation. Recently this approach was
utilised in our laboratory for the synthesis of (−)-
cytoxazone.8
The asymmetric inducing properties of hydroxylated
pyrrolidine derivatives as chiral auxiliaries in alkyla-
tion,2 acylation3 and aldolisation4 have also been
demonstrated. Among these azasugars, imino fura-
noses, i.e. 1,4-dideoxy-1,4-imino alditols have attracted
considerable attention because of their potential biolog-
ical activity and structural features.
Compound 5 was prepared in one-pot from 3 as
described by Cativiela et al.,9 (Scheme 1) as a single
diastereomer. Compound 5, on treatment with (Boc)2O
afforded 6 which under Li/liq. NH3/THF conditions
gave compound 7 as a white solid. Further treatment
with allyl bromide in the presence of NaH and DMF
resulted in diene 8, [h]2D5=−6.5 (c 0.9, CHCl3). Treat-
ment of 8 with 10 mol% Grubbs’ catalyst10 in DCM at
rt afforded 9, [h]2D5=−26.4 (c 0.6, CHCl3). Reaction of
Several syntheses of these compounds have been devel-
oped, mostly based on transformation of sugar deriva-
Figure 1.
Keywords: imine; Grignard reaction; N-allylation; ring-closing metathesis; dihydroxylation; azasugars.
ꢀ IICT Communication Number: 030416.
* Corresponding author. Fax: +91-40-27160512; e-mail: venky@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01366-2

5642
A. Madhan, B. Venkateswara Rao / Tetrahedron Letters 44 (2003) 5641–5643
Scheme 1. Reagents and conditions: (a) BnNH2, anhy.MgSO4, dry ether, 0°C–rt, 2 h; (b) CH2ꢀCHꢁMgBr, dry ether, 0°C–rt, 15
h, 76% (overall yield for two steps); (c) (Boc)2O, Et3N, dry DCM, 0°C–rt, 24 h, 72%; (d) Li, liq NH3, THF, −50°C, 1 h, 81%;
(e) Allyl bromide, NaH (60%), DMF, 0°C–rt, 12 h, 75%; (f) 10 mol% Grubbs’ catalyst [Cl2(Pcy3)2RuꢀCHPh], DCM, rt, 12 h, 75%;
(g) OsO4 (10 mol%), NMO monohydrate, acetone:H2O (3:1), 12 h, 80%; (h) methanol–HCl, rt, 10 h, 82%.
Scheme 2. Reagents and conditions: (a) 2,2-DMP, cat. PTSA, dry acetone, rt, 12 h, 71%; (b) 60% AcOH, 48 h, 73%.
11
9 with OsO4 (10 mol%), and NMO in acetone:H2O
resulted in compound 10, [h]2D5=−36.4 (c 0.5, CHCl3) as
a single isomer. Compound 10 on treatment with
MeOH–HCl12 finally afforded the target molecule 1, as
its HCl salt, [h]D25=+25.0 (c 1, H2O) [lit.5j [h]2D5=+25.6
(c 0.9, H2O)] whose NMR spectral data were in good
agreement with the literature.5i,j
References
1. For a review, see: Asano, N.; Nash, R. J.; Molyneux, R.
J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645.
2. (a) Enomoto, M.; Ito, Y.; Katuski, T.; Yamaguchi, M.
Tetrahedron Lett. 1985, 26, 1343; (b) Evans, D. A.; McGee,
I. R. J. Am. Chem. Soc. 1981, 103, 2876.
3. Ito, Y.;Katuski, T.;Yamaguchi, M. TetrahedronLett. 1984,
25, 6015.
4. Katuski, T.; Yamaguchi, M. Tetrahedron Lett. 1985, 26,
5807.
The synthesis of (2S,3R,4S)-3,4-dihydroxyproline was
achieved as follows: Treatment of 10 with 2,2-DMP
(cat. PTSA, acetone) under anhydrous conditions gave
11 which on selective hydrolysis of the side-chain ace-
tonide gave compound 12 [h]2D5=−34.9 (c 0.9, CHCl3)
[lit.5i [h]D25=−33.5 (c 0.17, CHCl3)] (Scheme 2). The
NMR spectral data of 12 were in agreement with those
reported.5i Compound 12 has been converted to
(2S,3R,4S)-3,4-dihydroxyproline 2 in three steps by
Fleet et al.,5i so providing the formal synthesis of 2.
5. (a) Pham-Huu, D. P.; Gizaw, Y.; BeMiller, J. N.; Petrus,
L. Tetrahedron Lett. 2002, 43, 383; (b) Lee, E. R.; Smith,
D. M.; Nash, J. R.; Griffiths, C. R.; McNeil, M.; Grewal,
K. R.; Yan, W.; Besra, S. G.; Brennan, J. P.; Fleet, G. W.
J. Tetrahedron Lett. 1997, 38, 6733; (c) Bernotas, C. R.
Tetrahedron Lett. 1990, 39, 469; (d) Lundt, I.; Madsen, R.
Synthesis 1993, 720; (e) Paulsen, H.; Steinert, K.; Henys,
K. Chem. Ber. 1970, 103, 1599; (f) Lombardo, M.; Fab-
broni, S.; Trombini, C. J. Org. Chem. 2001, 66, 1264; (g)
Ayad, T.; Genisson, Y.; Baltas, M.; Gorrichon, L. Synlett
2001, 866; (h) Kuszman, J.; Kiss, L. Carbohydr. Res. 1986,
53, 45; (i) Fleet, G. W. J.; Son, J. C. Tetrahedron 1988, 44,
2637; (j) Buchnnan, J. G.; Lumbard, K. W.; Sturgeon, R.
J.; Thompson, D. K. J. Chem. Soc., Perkin Trans. 1 1990,
699; (k) Long, D. D.; Stetz, R. J. E.; Nash, R. J.; Marquess,
D. G.; Lloyd, J. D.; Winters, A. L.; Asano, N.; Fleet, G.
W. J. Chem. Soc., Perkin Trans. 1 1999, 901; (l) Appel, R.;
Kleinstuck, R. Chem. Ber. 1974, 107, 5; (m) Lundt, I.;
Madsen, R. Synthesis 1993, 714 and references cited therein.
6. Badorrey, R.; Cativiela, C.; Diaz-de-villegas, M. D.;
Galvez, J. A. Tetrahedron 1997, 53, 1411.
In conclusion, a highly efficient stereoselective synthesis
of 1,4-dideoxy-1,4-imino- -allitol 1 has been achieved
D
via a strategy which may be useful for the synthesis of
analogues of 1.
Acknowledgements
One of the authors (A.M.) thanks the CSIR, New
Delhi, for a research fellowship. We also thank Dr. J. S.
Yadav and Dr. G. V. M. Sharma for their support and
encouragement.

A. Madhan, B. Venkateswara Rao / Tetrahedron Letters 44 (2003) 5641–5643
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7. (a) Kierstead, R. W.; Faraone, A.; Mennona, F.; Mullin,
J.; Guthrie, R. W.; Crowley, H.; Simko, B.; Blaber, L. C.
J. Med. Chem. 1983, 26, 1561; (b) Schmid, C. R.; Bryant,
J. D. Org. Synth (Coll.) 1993, 72, 6.
10. (a) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36,
1621; (b) Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001,
66, 7155; (c) Bhasker, G.; Venkateswara Rao, B. Tetra-
hedron Lett. 2003, 44, 915.
11. Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1989, 37, 1087.
12. Okada, T.; Sato, H.; Tsuji, T.; Tsushima, T.; Nakai, H.;
Yoshida, T.; Matsuura, S. Chem. Pharm. Bull. 1993, 41,
132.
8. Madhan, A.; Ravi Kumar, A.; Venkateswara Rao, B.
Tetrahedron: Asymmetry 2001, 12, 2009.
9. Badorrey, R.; Cativiela, C.; Diaz-de-villegas, M. D.;
Galvez, J. A. Synthesis 1997, 747.