Chapter 7
Downloaded by UNIV OF MINNESOTA on May 21, 2013 | http://pubs.acs.org Publication Date: December 5, 2002 | doi: 10.1021/bk-2003-0841.ch007
Iminosugars, Isoiminosugars, and Carbasugars from Activated Carbohydrate Lactones: Efficient Synthesis of Biologically Important Compounds Inge Lundt Technical University of Denmark, Department of Organic Chemistry, Building 201, DK-2800 Lyngby, Demark
The synthetic potential of selectively activated aldonolactones as building blocks for synthesis of optically pure, highly func— tionalised organic molecules is highlighted. Preparation of iminosugars from selectively brominated lactones requires only two transformations, in which the ring closure by reaction with ammonia is the key step. Stereoselective alkylation of unprotected bromodeoxylactones offers a general synthetic approach to isoiminosugars. Radical induced carbocyclisation of ω-bromoα,β-unsaturated aldonolactones yields functionalised cyclopentane /cyclohexane lactones stereospecifically, generating one or two chiral centers in the ring closing step. Stereo- and regio-selective functional group interconvertion within the bicyclic cyclopentanelactone system gives access to hydroxy/amino substituted cyclo— pentanes. Aldonolactones provide thus in few steps access to compounds of biologically importance in an optically pure state.
© 2003 American Chemical Society In Carbohydrate Synthons in Natural Products Chemistry; Witczak, Z., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2002.
117
118
Carbohydrate Lactones/Aldonolactones
Downloaded by UNIV OF MINNESOTA on May 21, 2013 | http://pubs.acs.org Publication Date: December 5, 2002 | doi: 10.1021/bk-2003-0841.ch007
Preparation and Chemical Reactivity In the past twenty years aldonolactones have found widespread application as cheap, chiral synthons for the synthesis of many biologically important compounds and natural products (7). Particularly the area of aza- and carbasugar synthesis has seen aldonolactones emerging as versatile starting materials (1,2). Aldonolactones constitute a more diverse chiral pool of compounds than aldoses. From each aldose several aldonolactones/aldonic acids are available in just one step, i.e. by anomeric oxidation of the aldose (5), by one carbon Kiliani chain elongation [4] or by one carbon oxidative degradation (5). In addition, a number of aldonolactones are available by some more special reactions including reduction, or oxidative cleavage of the double bond in vitamin C (6). As a result, aldonolactones are in many cases more readily available than the corresponding aldoses, especially in the L-series. The chemical reactivity of aldonolactones also differ remarkably from the reactivity of aldoses. For synthetic manipulation of aldoses several steps are usually required at the outset to protect and define the stereochemistry at the C-l hemiacetal function e.g. via a glycoside. The lactone group at C - l in aldonolactones, however, can be maintained through a number of transformations (7,2). The reactivity of the hydroxy groups in aldonolactones is also different from what is normally observed in aldoses. Particularly the hydroxy group a to the lactone group show similar or enhanced reactivity as compared to the primary hydroxy group. This gives rise to a number of regioselective reactions in aldonolactones and diminishes the need for many different protecting groups (7,2). Furthermore, it should be noted that aldonolactones usually prefer the 5-membered 1,4-lactone form contrary to the 6-membered pyranose form predominant in aldoses.
Preparation of Activated Aldonolactones The regioselective functionalisation of aldonolactones is possible at the position a to the lactone and at the primary (co) position. The most efficient method for this functionalisation is treatment of the aldonolactone/aldonic acid with hydrogen bromide in acetic acid (Scheme 1). In this strongly acidic medium the lactone is partly acetylated followed by formation of acetoxonium ions. These then undergo opening with bromide ions to give acetylated bromodeoxyaldonolactones (7). The formation of acetoxonium ions controls the
In Carbohydrate Synthons in Natural Products Chemistry; Witczak, Z., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2002.
119
Downloaded by UNIV OF MINNESOTA on May 21, 2013 | http://pubs.acs.org Publication Date: December 5, 2002 | doi: 10.1021/bk-2003-0841.ch007
regio- and stereo-selectivity of introduction of the bromine: bromide is always opening the acetoxonium ion at the primary position and at C-2, with inversion of the configuration. These are formed from 1,4-lactones having the OH-2 and OH-3 in a c/s-orientation. In two cases however, in glucono- and xylono-lactone having the OH-2 and OH-3 in a rraws-orientation, bromine is also introduced at C-2 with inversion of the configuration. The acetoxonium ions are here formed between two trans hydroxy groups from the open aldonic acids, which in these cases are present to a certain extend. In general, the aldonolactones adopt the 1,4-lactone form (7).
HBr AcOH
HO
Br
HO
a^-Dibromo-a,/o-hexofuranose (Scheme 17). HO
Ha1) NH (liq.) 2) H Q U - ^ ^75% 3
H
yj^o
H N-
2
W ^
- V 1 5
0
CaCl
