acetal could eventually be deprotected via acid-catalyzed
hydrolysis,10 a Zn-mediated reduction protocol (TCE),11 or
a selective oxidation or reduction (benzyl group). Toward
this end, glucal 5 was separately reacted with TCE and
benzyl alcohol under a variety of conditions9,12 to give
glycosides 7a-b (Scheme 2). These experiments led to
optimized reaction conditions allowing moderate yields of
both glycosides (Table 1). Of note was the isolation of a
methodology. The allylic nature of the activated alcohol
provided the possibility of forming either the desired four-
membered or an undesired six-membered heterocycle. While
our group has shown that open chain allylic alcohols can be
successfully used as â-lactam precursors,6 the cyclic nature
of allylic alcohols 8a-b imposes additional steric demands
on the proposed cyclization reaction. For example, to allow
the formation of the â-lactam ring via an SN process requires
the reactive intermediate to adopt a 5HO conformation
(Scheme 2) in which the ester and alcohol functionalities
are in pseudo-axial positions and the aglycon is in a pseudo-
equitorial position preventing anomeric and allylic stabiliza-
tion.14 One would expect that such a conformation would
be higher in energy than the corresponding OH5 conformation
(Scheme 2). This hypothesis is supported by NMR studies
of 2,3-unsaturated pyranosides.14,15 These studies have found
that R-erythro-2,3-unsaturated glycosides prefer the OH5
conformation displaying J4,5 coupling constants of ∼9 Hz,
while the corresponding â-anomers display J4,5 coupling
Table 1. Conditions for Ferrier Reaction of Glucal 5
entry ROH Lewis acid
temp./time
R/âa
yieldb
1
2
3
4
TCEc
TCE
BnOH InCl3
BF3‚OEt2
BF3‚OEt2
0 °C/4 h
-78 °C/12 h
room temp./30 min
-10 °C/4 days
5:1 53%
5:1 69%
4:1 39%
BnOH BF3‚OEt2
>99:1 53%
1
a Determined by H NMR. b Isolated. c TCE ) Trichloroethanol.
5
constants of ∼2-3 Hz indicating the adoption of a HO
conformation.14,15 The observation of a J4,5 coupling constant
of 9.50 Hz for R-7b suggests the preference for this system
single anomer of the benzyl glycoside using a catalytic
amount of BF3‚OEt2 at -10 °C (entry 4, Table 1). This
procedure proved to be especially appealing since the product
could be isolated directly from the reaction mixture via
recrystallization!
O
to also adopt a H5 conformation.
Given these considerations, our success in this endeavor
seemed far from certain. Therefore, we were delighted to
find that subjection of hydroxamates 8a-b to Mitsunobu
reaction conditions5 provided the desired novel bicyclic
â-lactams 9a-b as stable crystalline solids in good yields.
This result serves to further underscore the robustness of our
N1-C4 ring closure strategy toward the construction of
â-lactams. The structure and absolute stereochemistry of
â-lactam 9b were confirmed by X-ray diffraction.
With the successful preparation of â-lactams 9a-b, we
targeted the selective deprotection of the acetal moiety as
the next synthetic goal. For â-lactam 9a, we were disap-
pointed to find that a number of conditions failed to provide
the desired hemiacetal10,11,16 or lactone.17 However, we
hypothesized that the two benzyl moieties of â-lactam 9b
should have differing reactivities. We were encouraged by
a report in which a benzyl aglycon had been successfully
oxidized to a benzoate ester using in situ generated Collin’s
reagent.18 Model studies using diester 7b showed that these
conditions did indeed provide the targeted benzoyl aglycon
product 10 (Scheme 3). Further, treatment of a model N1-
O-benzyl-â-lactam under the same conditions showed that
no oxidation occurred at the hydroxamate benzyl group.
Encouraged by these results, we subjected â-lactam 9b to
the same conditions hoping to receive the benzoyl aglycon.
To our surprise, under these conditions, â-lactam 9b showed
With the two glycosides in hand, we set out to determine
the set of conditions necessary for the formation of the
requisite â-hydroxy hydroxamates 8a-b. While the trans-
formation of esters 7a-b to the hydroxamates 8a-b would
seem to be straightforward, we discovered that it was actually
quite challenging and required the development of a novel
strategy. For instance, after removal of the acetate group,
attempts to saponify the methyl ester with LiOH followed
by an aqueous EDAC‚HCl coupling with O-benzylhydroxy-
lamine hydrochloride (OBHA‚HCl)5 proved to be disastrous
and provided only decomposition products. This and related
attempts showed that these glycosides appear to be highly
sensitive to the reaction conditions. We were, therefore,
pressed to develop a strategy to access hydroxamates 8a-b
using neutral or near-neutral reaction conditions. To our
delight, we found that deprotection of the methyl ester could
be carried out effectively using KOTMS in THF.13 After
removal of the solvent and dissolution of the salt in dry DMF,
a mixture of EDAC‚HCl and OBHA‚HCl was added result-
ing in the formation of the hydroxamates 8a-b, which in
the case of 8b could be isolated directly from the reaction
mixture by recrystallization.
We next focused our attention on the formation of the
â-lactam ring. As mentioned earlier, this transformation
represented an interesting test of our N1-C4 ring closure
(14) Angerbauer, R.; Schmidt, R. R. Carbohydr. Res. 1981, 89, 193-
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Marko´, I. E. Tetrahedron Lett. 1999, 40, 1799-1802. (b) Nair, V.; Nair,
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