A versatile approach to pyrrolidine azasugars and homoazasugars based on a highly diastereoselective reductive benzyloxymethylation of protected tartarimide

doi:10.1016/j.tet.2007.02.087

Tetrahedron

Volume 63, Issue 27, 2 July 2007, Pages 6346-6357

https://doi.org/10.1016/j.tet.2007.02.087 Get rights and content

Abstract

A highly diastereoselective synthesis of enantio-enriched all trans-3,4-dibenzyloxyl-5-benzyloxymethyl-2-pyrrolidinone 13a was developed based on SmI₂-mediated benzyloxymethylation of O,O′-dibenzyltartarimide. The versatility of 13a and its antipode as the key building blocks for the asymmetric synthesis of pyrrolidine azasugars and homoazasugars has been demonstrated by elaborating them into naturally occurring DAB 1 (1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-DMDP 7, and 5-epi-radicamine B 36 as well as the reductive ring-opening product 35.

Graphical abstract

Introduction

Many pyranoses and furanoses with the ring oxygen replaced by an amino group, known as imino sugars or azasugars,1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f) are sugar mimics, which have been found to inhibit specific enzymes such as glycosidases.1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f) Because glycosidases are involved in several important biological processes, these polyhydroxylated alkaloids have stimulated interest in the development of specific glycosidase inhibitors for studying and treating metabolic disorders such as diabetes, or as antiviral, antibacterial, and anticancer agents or as immunomodulators, and are providing biochemists with molecular tools for probing several important processes, such as the metastasis of some cancers, the immune response, and virus replication. In particular, α-glucosidase inhibitors have shown potential as therapeutic agents for type II diabetes2, 2(a) and HIV-1 infection.^2b

1,4-Dideoxy-1,4-imino-d-arabinitol (1, known as DAB 1) was isolated from two types of leguminose plants Arachniodes standishii3, 3(a), 4, 4(a) and Angylocalyx boutiqueanus.^3b The antipode of DAB 1 is a synthetic product.4, 4(a), 4(b) LAB 1 was shown to be a potent inhibitor of the α-l-arabinofuranosidase III of Monilinia fructigena,5, 5(a) and a much more powerful inhibitor of sucrase and some mouse gut α-glucosidases than DAB 1.^5b It is also a promising candidate for treatment of type II diabetes,^5c and was one of the most powerful anti-HIV agents among 47 aminosugar derivatives screened.5(c), 5(d), 5(e) Structurally related nectrisine (FR 900483) (3) is a fungal metabolite isolated from Nectria lucida.6, 6(a), 6(b) DAB 1 and nectrisine exhibit extremely potent yeast α-glucosidase inhibitory activities [IC₅₀=1.8×10⁻⁷ M^4b and 4.8×10⁻⁸ M,⁷ respectively]. The N-hydroxyethylated derivative of DAB 1, namely, N-hydroxyethyl-DAB 1⁸ (4) was isolated from the seeds of African legume Angylocalyx pynaertii, while the oxidation product of DAB 1, l-2,3-trans-3,4-trans-dihydroxyproline (DHP) (5), was isolated from the acid hydrolyzates of the toxic mushroom Amanita virosa.9, 9(a), 9(b)

Moreover, many C-5 carbon-substituted derivatives of DAB 1, known as homoazasugars or aza-C-glycosides are either natural products or sugar mimics showing enhanced bioactivities and at the same time exhibiting higher stability toward chemical and enzyme degradation.¹⁰ For example, 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) 6 occurs in many disparate species of plants,^11a and was also isolated from Streptomyces;^11b the 6-deoxy analog of DMDP (6-deoxy-DMDP)12, 12(a), 12(b), 8 7, a unique molecule in inhibiting β-mannosidase,11, 11(a), 11(b) was isolated from the seeds of African legume A. pynaertii; radicamine B (8) and broussonetine W (9) are two structurally related compounds recently isolated from Lobelia chinensis Lour (Campanulaceae), which also show α-glucosidase inhibitory activity.13, 13(a), 13(b), 13(c)

Consequently, the synthesis of polyhydroxylated pyrrolidine alkaloids/azasugars has attracted much attention, and a number of methods have been developed.4, 4(a), 4(b), 14, 14(a), 14(b), 14(c), 15, 15(a), 15(b), 15(c), 15(d), 15(e), 15(f), 15(g), 15(h), 15(j), 15(k), 15(l), 15(m), 15(n), 15(o), 15(p), 15(q), 15(r), 15(s), 16, 16(a), 16(b), 16(c), 16(d), 16(e), 16(f), 16(g), 17, 17(a), 17(b), 17(c), 17(d) In view of the presence of α-hydroxymethyl-dihydroxypyrrolidine^1a 1 as the common structural feature in many azasugars, an attractive approach to these compounds would be that allowing installation of the α-hydroxymethyl group in a straightforward manner. Although optically active tartaric acid has been used to synthesize this class of compounds,15(i), 15(s), 16(d) such as DAB 1 (1), LAB 115(i), 15(s) (2), nectrisine (3),^16d and broussonetine C,¹⁸ methods for the introduction of the hydroxymethyl group into the α-position of a pyrrolidine or a piperidine ring have generally been accomplished by indirect and multi-step procedures.15(s), 18, 19, 19(a), 19(b), 19(c), 19(d), 19(e) In some of these approaches, low diastereoselectivities have been observed.15(g), 16(d) As a part of our ongoing project aimed at the development of malimide/3-hydroxyglutarimide-based synthetic methodologies,20, 20(a), 20(b) and in continuation of our studies on the asymmetric synthesis of azasugars and related compounds,21, 21(a), 21(b), 21(c), 21(d) we report herein a short and highly diastereoselective approach for the enantioselective synthesis of DAB 1 (1), LAB 1 (2), N-hydroxyethyl-DAB 1 (4), 6-deoxy-DMDP 7, and 5-epi-radicamine B 36 as well as the reduced-ring-opening product 35 based on the direct introduction of a benzyloxymethyl group via the reductive benzyloxymethylation of tartarimide 14 or ent-14.

Section snippets

Results and discussion

In our recent efforts to develop a flexible method for the synthesis of 2-benzyloxymethyl-2-piperidinone by the stepwise reductive 2-benzyloxymethylation of the protected 3-hydroxyglutarimides (Scheme 1),^21b several abnormal phenomena have been observed. For example, the 2-benzyloxymethylation of the O-benzyl protected 3-hydroxyglutarimide 10a led, unexpectedly, to two regioisomeric carbinols in a 1:1 ratio; while although the 2-benzyloxymethylation of the O-tert-butyldimethylsilyl protected

Conclusion

In summary, we have demonstrated that all trans-5-benzyloxymethyl-3,4-dibenzyloxyl-2-pyrrolidinone 13a can be synthesized by direct reductive benzyloxymethylation of O,O′-dibenzyltartarimide in highly diastereoselective manner, and 13a is a versatile building block for the asymmetric synthesis of pyrrolidine type azasugars and homoazasugars. In addition, the possibility to perform a selective oxidation of a primary alcohol, in the presence of secondary alcohol,39, 40, 40(a), 40(b) to a

General

Melting points were determined on an X-4 digital micro melting point apparatus and were uncorrected. Infrared spectra were measured with a Nicolet Avatar 330 FT-IR spectrometer using film KBr pellet technique. ¹H NMR spectra were recorded in CDCl₃ on a Bruker AV400 or a Varian unity +500 spectrometer with tetramethylsilane as an internal standard. Chemical shifts are expressed in δ (ppm) units downfield from TMS. Mass spectra were recorded by Bruker Dalton Esquire 3000 plus LC–MS apparatus.⁴¹

Acknowledgements

The authors are grateful to the NSF of China (20390050; 20572088), Qiu Shi Science & Technologies Foundation (Hong Kong), and the program for Innovative Research Team in Science & Technology (University) in Fujian Province for financial support.

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A versatile approach to pyrrolidine azasugars and homoazasugars based on a highly diastereoselective reductive benzyloxymethylation of protected tartarimide

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

General

Acknowledgements

Tetrahedron Lett.

Tetrahedron Lett.

J. Org. Chem.

J. Nat. Prod.

Eur. J. Biochem.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

Org. Lett.

Carbohydr. Res.

Curr. Org. Chem.

Tetrahedron Lett.

Org. Lett.

Chem.—Eur. J.

Synlett

J. Am. Chem. Soc.

Synthesis

J. Heterocycl. Chem.

J. Org. Chem.

J. Am. Chem. Soc.

Tetrahedron

Tetrahedron Lett.

Synlett

Acc. Chem. Res.

Acc. Chem. Res.

Phytochemistry

Monatsh. Chem.

Tetrahedron: Asymmetry

J. Med. Chem.

J. Virol.

Phytochemistry

Phytochemistry

Life Sci.

Biochem. J.

Diabetes Obes. Metab.

FEBS Lett.

Proc. Natl. Acad. Sci. U.S.A.

J. Antibiot.

Tetrahedron Lett.

Biochem. Biophys. Res. Commun.

J. Nat. Prod.

Proc. Natl. Acad. Sci. U.S.A.

Biochemistry

Phytochemistry