Chapter 5
Stereocontrolled Glycosylation: Recent Advances: β-D-Rhamnosides and β-D-Mannans David Crich Downloaded by UNIV OF ARIZONA on August 6, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch005
Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607
A stereocontrolled synthesis of β-D-rhamnopyranoisdes is reported in which a modified 4,6-O-benzylidene group, employed to set the stereochemistry in the glycosidic bond forming step, functions as a precursor to the rhamnoside. A comparison of linear and convergent syntheses of an alternatingβ-(1-->3)-P-(1-->4)-mannanis also presented along with the development of propargyl ethers as protecting groups for improved stereoselectivity in β-mannosylation reactions.
60
© 2007 American Chemical Society In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
61
Downloaded by UNIV OF ARIZONA on August 6, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch005
Working initially with 4,6-0-benzylidene protected mannopyranosyl sulfoxides, activated with trifluoromethanesulfonic anhydride, and subsequently with the corresponding thioglycosides, and activating with the combination of 1benzenesulfinyl piperidine and trifluoromethanesulfonic anhydride, we have developed a facile, highly stereocontrolled synthesis of the p-mannopyranosidic linkage (1-4). The key to success in this chemistry is the presence of the 4,6-0benzylidene acetal which serves to destabilize the mannosyl oxacarbenium ion relative to the covalent a-mannosyl triflate intermediate, thereby ensuring rapid P-selective quenching of a transient contact ion pair by the incoming glycosyl acceptor (Fig. 1) (5, 6). 0
•I
Ph
Ph^vq
BSP
Bn? SPh
Tf 0, CH CI -60 °C 2
2
V
2
A
o' CF, a-mannosyl triflate
Tf20, ^—covalent
^4
CH CI , -78 °C 2
2
ROH Ph^VQ BIT
Bnl
00
o
p-mannoside a-deuterium KIE = 1.3 (-78 °C) a-deuterium KIE = 1.2 (25 °C)
transient contact ion pair
Figure I. The p-mannosylation reaction Having completed numerous syntheses of P-mannoside containing oligosaccharides and other glycoconjugates using this methodology (7-70), we turned out attention to the p-L-rhamnopyranosides (77-75), and Drhamnopyranosides. This type of linkage, which occurs widely in Nature, presents the same stereochemical challenge as the p-mannosides but raises the bar to a higher level by virtue of the 6-deoxy functionality. We hypothesized that the p-D-rhamnopyranosides might be accessed via the 4,6-O-benzylidene protected p-mannosylation, followed by a Hanessian-Hullar type fragmentation of the benzylidene acetal to the 6-bromo-4-0-benzoate-P-D-rhamnoside (14-18), with a final reductive debromination providing the target structure. Alternatively, the purely radical fragmentation of 4,6-O-benzylidene acetals,
In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
Downloaded by UNIV OF ARIZONA on August 6, 2012 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch005
62 involving simple heating with a thiol and a radical initiator (19-21) could take us directly from a benzylidene protected mannoside to a 4-0-benzoyl rhamnoside in a single step, avoiding the 6-bromo intermediate. Unfortunately, despite isolated reports the literature to the contrary, neither of these chemistries are compatible with the presence of benzyl ethers in our hands. We note, however, a very interesting large-scale NBS cleavage of a benzylidene acetal of a 1,2-diol in the presence of multiple benzyl ethers which, presumably, is possible because of the greater lability of dioxolane C-H bonds as compared to those in dioxanes (22). We turned therefore to alternative sources of the benzylidene radical, compatible with both the BSP activation protocol and the presence of multiple benzyl ethers. A system was designed based the tributyltin hydride mediated generation of acyl radicals from 2-(2-iodophenyl)ethyl thiolesters (23) and decarbonylation such as we had previously employed in our laboratory to obtain nucleotide C4' radicals (24, 25) After a control experiment to establish the stability of the thiolester function to the BSP/trifluoromethanesulfonic anhydride glycosylation conditions, diol 1 was converted to the acetal 2 by means of a transacetalization reaction. Conversion of the methyl ester to the requiste thiol ester 3 then was achieved with 2-(2-iodophenyl)ethanethiol and trimethylaluminum. A series of coupling reactions were then conducted to a range of standard primary and secondary carbohydrate alcohols as well as to 1-adamantanol. In each case exquisite selectivity for the p-anomer 4 was obtained, independent of the isomer employed at the remote benzylidene stereogenic center. Finally, a cascade of radical reactions was initiated by exposure of the glycosides to tributyltin hydride and a radical initiator in benzene at reflux, resulting in the formation of the 6-deoxy-P-D-mannosides 5, or P-D-rhamnosides, in high yield (Figures 2 and 3) (26). As anticipated on the basis of the precedent from Roberts' work (20, 27) these benzylidene radical fragmentations were highly regioselective for formation the 6-deoxy in preference to the 4-deoxy system.
H O ^ OBn
OBn
CSA.85%
In,
i) BSP, TTBP, Tf 0 2
li)ROH
7
MeOflM.
CO
^
.CO
0
