preparation of C-glycosyl amino acids, providing a rapid
entry into analogues in which the intervening carbon chain
contains three or more methylenes, Figure 1. Dondoni made
Figure 2. Retrosynthetic plan.
for this methodology has been demonstrated by Nicotra on
the heptenitol 4 for the production of R-C-methyl glyco-
sides.11
Figure 1. Summary of previous CM approaches to C-glycosyl
amino acids.
We have prepared the known gluco-heptenitol 4 in one
step by addition of divinylzinc to 2,3,5-tri-O-benzyl arabi-
nose.11 The divinylzinc addition is remarkably stereoselective
for the gluco isomer due to chelation control. The CM
partner, allyl glycine 6, is available via the Williams enolate12
or by protection of the commercially available allyl glycine.
A preliminary attempt at cross-metathesis using the Grubbs
generation 1 catalyst G1 [(Cy3P)2(Cl2)RudCHPh] gave
unceremoniously no CM product but rather 55% yield of
813 by olefin transposition to the enol and subsequent acetal
formation.
Successful cross-metathesis of 4 and 6 was accomplished
using the second-generation Grubbs initiator G2; this pro-
vided 9 with the appropriate carbon chain length (C10) for
C-glycosyl serines. A significant amount of self-metathesis
byproducts, 10 and 11, was observed. Considering that a
completely nondiscriminant metathesis reaction (i.e., rate
constants for all metathesis reactions being equal) would
yield only 50% of the desired product,14 we modified the
reactivity of 4 to enhance the selectivity. Using the diacetate
or the bis-TMS ether of 4 gave a more selective CM reaction,
but the yield did not compensate for the material loss during
protection and eventual deprotection. Curiously, when the
allylic hydroxyl of 4 was protected as the benzyl ether, no
CM reaction was observed. This is in contrast to the
structurally similar allylic pMB ether reported by Basu,
which successfully undergoes CM reactions.15 Subtle elec-
tronic and steric effects have been noted for allylic alcohols
and ethers in the literature.16
use of benzyl-protected C-alkenyl glycosides and affected
cross-metathesis with a vinyl oxazolidine, derived from
Garner’s aldehyde.5 McGarvey has described the success of
the cross-metathesis approach between C-alkenyl glycosides
and L-allyl glycine,6 and we have communicated the olefin
cross-metathesis between C-allyl glycosides and L-vinyl
glycines for C-glycosyl amino acid synthesis.7 In each of
these reports, the Grubbs’ second-generation catalyst G28
was employed for the olefin cross-metathesis (CM). In our
hands and in accordance with others, the linking carbon chain
between the C-glycoside and the amino acid cannot be made
shorter than three carbons without seriously diminishing the
yield, yet serine mimics require only two linking methylenes.
This represents a severe limitation for the preparation of
C-linked glycosyl amino acids by this straightforward
methodology.9 Recognizing this limitation, Ben employed a
CM strategy for several C-linked galactosyl analogues, with
the exception of serine.10
To circumvent this limitation we considered opening the
sugar to vary the reactivity for CM olefination. Specifically,
as shown in Figure 2, we sought to employ the cross-
metathesis methodology on the readily available gluco-
heptenitol 4 and the manno stereoisomer 5 with allyl or vinyl
glycine, 6 or 7, respectively, to produce acyclic glyco-amino
acid alkenes, which upon electrophilic cyclization would
yield the desired C-glycosyl serine or alanine. Precedence
(5) Dondoni, A.; Giovannini, P. P.; Marra, A. J. Chem. Soc., Perkin
Trans. 1 2001, 2380-2388.
(6) McGarvey, G. J.; Benedum, T. E.; Schmidtmann, F. W. Org. Lett.
2002, 4, 3591-3594.
(11) Boschetti, A.; Nicotra, F.; Panza, L.; Russo, G. J. Org. Chem. 1988,
53, 4181-4185.
(7) Nolen, E. G.; Kurish, A. J.; Wong, K. A.; Orlando, M. D. Tetrahedron
Lett. 2003, 44, 2449-2453.
(12) Williams, R. M.; Sinclair, P. J.; DeMong, D. E. Org. Synth. 2003,
80, 31-37.
(8) (a) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder,
R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58-
71. (b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(13) Sharma, G. V. M.; Chander, A. S.; Krishnudu, K.; Krishna, P. R.
Tetrahedron Lett. 1997, 38, 9051-9054.
(14) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360-11370.
(9) Recently, a successful ethylene-promoted olefin cross-metathesis on
C-vinyl carbohydrates was reported: Chen, G.; Schmieg, J.; Tsuji, M.;
Franck, R. W. Org. Lett. 2004, 6, 4077-4080.
(15) Rai, A. N.; Basu, A. Org. Lett. 2004, 6, 2861-2863.
(16) Maishal, T. K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar, A.
Tetrahedron Lett. 2002, 43, 2263-2267.
(10) Liu, S.; Ben, R. N. Org. Lett. 2005, 7, 2385-2388.
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