A concise synthesis of unnatural (+)-5-epi-nojirimycin-δ-lactam via asymmetric reduction of a meso-imide

Article abstract of DOI:10.1016/S0957-4166(99)00030-0

Nojirimycin-δ-lactam skeleton was synthesized by asymmetric reduction of a cyclic triacetyloxy meso imide with a chiral β-amino thiol ligand. The resulting product was converted to unnatural (+)-5-epi-nojirimycin-δ- lactam.

Full text of DOI:10.1016/S0957-4166(99)00030-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 657–660
A concise synthesis of unnatural (+)-5-epi-nojirimycin-δ-lactam
via asymmetric reduction of a meso-imide
Jahyo Kang,a,∗ Choon Woo Lee,a Geun Jho Lim b and Byung Tae Cho c
aDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
bDong-A Pharmaceutical Research Laboratories, 47-5 Sanggal-ri, Yongin-gun, Kyunggi-do 449-900, South Korea
cDepartment of Chemistry, Hallym University, Chunchon 200-702, South Korea
Received 8 December 1998; accepted 6 January 1999
Abstract
Nojirimycin-δ-lactam skeleton was synthesized by asymmetric reduction of a cyclic triacetyloxy meso imide
with a chiral β-amino thiol ligand. The resulting product was converted to unnatural (+)-5-epi-nojirimycin-δ-
lactam. © 1999 Elsevier Science Ltd. All rights reserved.
The synthetic challenge of naturally occurring monosaccharide-like alkaloids containing a piperidine
moiety, 1a and 1b, and their analogues such as nojirimycin-δ-lactams 2a,b are significant since they are
potent and selective glycosidase inhibitors,1,2 and thus are expected to have potential chemotherapeutic
utilities such as antidiabetic agents,3 novel anticancer4,5 and anti-HIV agents.6,7 The syntheses of
nojirimycin-δ-lactams 2a,b have so far been accomplished by oxidation of nojirimycin,8 amination of
idofuranose9 and from glucose as a mixture.8 Many synthetic methods have been reported to present the
flexibility of approaches to the synthesis of the nojirimycin skeleton by the preparation of analogues.
However, they have little advantage in the synthesis of the enantiomer as well as their C-1 and C-5
derivatives.
We appreciate that another possible synthetic strategy would be the use of enantioselective reduction
in the presence of a catalytic amount of β-amino thiol ligand 710 of a six-membered cyclic meso imide
3 bearing three equatorial hydroxy groups at C-2, 3 and 4 positions. Subsequent substitution of the C-5
hydroxyl group with a hydroxymethyl group through a chiral acyliminium ion 5 would furnish the desired
product. This strategy has the advantage that the syntheses of C-5 analogues and their enantiomers could
∗
Corresponding author. E-mail: kangj@ccs.sogang.ac.kr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00030-0

658
J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 657–660
Table 1
Asymmetric reduction of cyclic imides with β-amino thiol ligand 7a
be accomplished by properly controlling chiral ligands and nucleophiles. In this communication, we wish
to disclose the use of the asymmetric reduction of a meso-imide for the enantioselective synthesis of an
unnatural nojirimycin-δ-lactam enantiomer.
In fact, chiral catalytic reduction of the meso imides by optically active ligands occupies an important
position in the field of modern organic synthesis, and nucleophilic additions to resulting chiral acylimi-
nium ion are important methods for the preparation of nitrogen containing natural products.11
Our asymmetric reduction of meso triacetyloxy imide 3a12 and tribenzyloxy imide 3b13 was carried
out with BDMPB (bis(2,6-dimethylphenoxy)borane: 6)10 as a reducing agent in toluene in the presence
of a catalytic amount (20%) of the thiazazincolidine complex 8, generated in situ from enantiomerically
pure amino thiol ligand 7 and Et2Zn.10
The corresponding hydroxy δ-lactams 4a and 4b were individually converted to a δ-lactam, (−)-9 (1:
Ac2O, Pyr, CH2Cl2; 2: Et3SiH, BF3·OEt2, CH2Cl2), and a δ-lactone, (−)-10 (1: NaBH4, EtOH; 2: 2 N
H2SO4, THF), respectively. The products were analyzed by chiral HPLC for enantioselectivity for the
reduction of meso imide, the results of which are summarized in Table 1. Although the enantioselectivity
in the reduction of meso tribenzyloxy imide 3b was relatively low, it was gratifying to find that the same
reduction of triacetyloxy meso imide 3a, using identical conditions, gave higher enantioselectivity.
The reduction product, 4a [resulting from the reaction of imide 3a with BDMPB (3 equiv.) in the

J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 657–660
659
presence of 8 (20 mol%), −10°C, 16 h; 62% yield, 85% ee] was ultimately converted to the unnatural
nojirimycin skeleton as shown in Scheme 1, which was initiated by acetylation to the corresponding
acetate 11 in 87% yield. Subsequently, substitution of lactam acetate 11 with propargyltrimethylsilane16
produced allenic compound 12 in 88% yield with a form under a mixed Lewis acid combination of
BF3·OEt2 and t-butyldimethylsilyl triflate17 to give 5-epi-compound 12. It was noteworthy that the
nucleophilic addition of propargylsilane on the resulting acyliminium ion center took place exclusively
from the axial direction.18,19 Compound 12 was transformed to hydroxymethyl product 14 by ozonolysis
followed by reduction of crude aldehyde 13 with NaBH4 in 86% yield for two steps. Attempted
base-induced epimerization of the α-carbon of crude aldehyde 13 to the corresponding C-5 equatorial
compound under various conditions20 invariably produced an elimination product 15. After acetylation
of monoalcohol 14 followed by oxidative cleavage of the p-methoxyphenyl group with CAN (58% yield
for the steps to 16), the final compound (+)-2b21 was obtained by removal of all acetyl moieties with
NaOH (81% yield) (Scheme 1).
Scheme 1. Reagent: (a) Ac2O, Py–CH2Cl2, rt, 87%. (b) Propargyltrimethylsilane, BF3·OEt2, TBSOTf (0.2 equiv.), CH3CN,
88%. (c) O3, CH2Cl2, −78°C. (d) NaBH4, EtOH, 0°C, 86% (2 steps). (e) Ac2O, Py–CH2Cl2, rt. (f) CAN, CH3CN–H2O, rt, 58%
(2 steps). (g) Et3N, i-PrOH–CH2Cl2, 28%. (h) 2 N NaOH, MeOH, 0°C, 81%
In conclusion, we have shown that enantioselective reductive differentiation of the carbonyl groups in a
meso-imide, axial addition of an organometallic to iminium ion center derived therefrom and subsequent
removal of the nitrogen protecting group can be applied to a concise and efficient synthesis of potentially
biologically active nitrogen heterocycles.
Acknowledgements
This research was supported by Organic Chemistry Research Center, Hallym University and Basic
Science Research Institute Program of Korea Ministry of Education (BSRI-98-3412).
References
1. For a review, see: Nishimura, Y. J. Synth. Org. Chem. Jpn. 1991, 49, 846–857.
2. Hughes, A. B.; Rudge, A. J. Natural Product Reports 1994, 11, 135–162.
3. Anzeveno, P. B.; Creemer, L. J.; Daniel, J. K.; King, C.-H. R.; Liu, P. S. J. Org. Chem. 1989, 54, 2539–2542.
4. Wong, C.-H.; Dumas, D. P.; Ichikawa, Y.; Koseki, K.; Danishefsky, S. J.; Westone, B. W.; Lowe, J. B. J. Am. Chem. Soc.
1992, 114, 7321–7322.

660
J. Kang et al. / Tetrahedron: Asymmetry 10 (1999) 657–660
5. Tsuruoka, T.; Fukuyasu, H.; Ishii, M.; Usui, T.; Shibahara, S.; Inouye, S. J. Antibiot. 1996, 49, 155–161.
6. Gruters, R. A.; Neefjes, J. J.; Tersmette, M.; de Goede, R. E. Y.; Tulp, A.; Huisman, H. G.; Miedema, F.; Ploegh, H. L.
Nature 1987, 330, 74–77.
7. Karpas, A.; Fleet, G. W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; Jacob, G. S.; Rademacher, T.
W. Proc. Natl. Acad. Sci. USA 1988, 85, 9229–9233.
8. Inouye, S.; Tsuruoka, T.; Ito, T.; Niida, T. Tetrahedron 1968, 23, 2125–2144.
9. Fleet, G. W. J.; Carpenter, N. M.; Petursson, S.; Ramsden, N. G. Tetrahedron Lett. 1990, 31, 409–412.
10. Kang, J.; Lee, J. W.; Kim, J. I.; Pyun, C. Tetrahedron Lett. 1995, 36, 4265–4268.
11. Luker, T.; Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem. 1998, 63, 220–221.
12. The imide 3a was prepared by the following scheme. See Cantrell, C. E.; Kiely, D. E.; Abruscato, G. J.; Riordan, J. M. J.
Org. Chem. 1977, 42, 3562–3567.
13. Compound 3b was obtained from oxidation of a related hydroxy lactam which was synthesized by the known method.
Miller, S. A.; Chamberin, A. R. J. Am. Chem. Soc. 1990, 112, 8100–8112.
14. Authentic compound (+)-9 (100% ee) was synthesized by application of the method used in Ref. 13.
15. Authentic compound (+)-10 (100% ee) was obtained by a known method. Lopez, R.; Fernandez-Mayoralas, A. J. Org.
Chem. 1994, 59, 737–745.
16. Nativi, C.; Taddei, M.; Mann, A. Tetrahedron 1989, 45, 1131–1144.
17. Nicolaou, K. C.; Hwang, C. K.; Duggan, M. E. J. Am. Chem. Soc. 1989, 111, 6682–6690.
18. Equatorial product was not detected on TLC and NMR.
19. Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. Tetrahedron Lett. 1992, 33, 737–740 and 3109–3112.
20. Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1985, 26, 1123–1126, and also see Ref. 19.
21. Compound (+)-2b: 1H NMR (D2O, 300 MHz) δ 3.87 (dd, J=8 Hz, 4.2 Hz, 1H), 3.85 (d, J=8 Hz, 1H), 3.78 (t, J=8 Hz,
1H), 3.60 (d, J=1.6 Hz, 1H), 3.57 (s, 1H), 3.48 (m, 1H); 13C NMR (D2O, 75.5 MHz) δ 173.44, 72.66, 71.39, 68.70,
59.70, 54.01; IR (KBr) 1666.6 cm−1 (C_O). The enantiomeric excess of (+)-2b was identified by HPLC analysis of the
corresponding tetraacetate 16 prepared from the synthetic (+)-2b (Ac2O, Pyr, CH2Cl2) on Daicel Chiralcel OD-H (40%
i-PrOH in hexane, flow rate: 0.7 mL/min, 230 nm UV detector). In the case of 4a with 81% ee has shown it to be 82% ee
in this analysis (tR: 25.71 min; minor, tR: 36.37 min; major).