require extensive protecting group manipulations. For ex-
ample, the synthesis of L-oxetanocin by Gumina and Chu
required 10 steps for preparation of an intermediate similar
to 2 in 36% yield starting from L-xylose.3 Asymmetric
syntheses that start from small organic molecules are
potentially shorter and more efficient routes to highly
substituted 2-hydroxy-γ-lactones.4-6
propargylamines via an acyl-Claisen and iodolactonization
route.
Initially, we attempted to access amide 4 via the aza-
Claisen rearrangement10 of allylic amide 6. Synthesis of 6
(Scheme 2) started with the condensation of the known
aldehyde 811 with chiral hydroxylamine 1012 to give the
nitrone 11.13
Recently, we reported4 a total synthesis of 3′,5′-C-branched
uridine 1 (Base ) uracyl, TES ) triethylsilyl, TBDPS )
tert-butyldiphenylsilyl, Tr ) trityl) (Scheme 1), which we
are using as a monomer for preparation of amide-linked RNA
analogues.7 In our synthesis, we prepared γ-butyrolactone 2
from small achiral molecules (7-9) in only six steps and
29% yield using Ireland-Claisen rearrangement of 5 fol-
lowed by iodolactonization of 3 as the key steps (Scheme
1). Although the total synthesis of 2 was shorter than
analogous routes from carbohydrates,4 several problems
remained unsolved. First, the asymmetric propynylation8 of
aldehyde 8 with propargyl ether 9, which we used as the
first step to establish the absolute stereochemistry, gave a
modest yield (50%) and enantioselectivity (ee 92%) with our
substrates. The enantioselectivity was a particular concern
because multiple couplings of azido acids 1 during the
synthesis of amide-linked RNA would create complex
mixtures of diastereomeric oligoamides. Second, the iodola-
ctonization of carboxylic acid 3 was not stereoselective, and
acceptable yields were obtained only after separation and
recycling of the undesired 3,4-cis diastereomer, thus making
the procedure laborious.
Scheme 2. Aza-Claisen Route to trans-3,4-Dialkyl-γ-lactones
Addition of the trityl propargyl ether 9 to nitrone 11 under
conditions developed by Carreira and co-workers8b,14 resulted
in the formation of two diastereomers in a ratio of 88:12.
Interestingly, deprotonation of the alkyne with n-butyllithium
reversed the diastereomeric ratio, but the stereoselectivity
under these conditions was low (Scheme 2). At this point,
we decided to probe the feasibility of the aza-Claisen
rearrangement without determining the absolute stereochem-
istry at the newly established chiral center in 12. If the
planned syntheses were successful, the required absolute
stereochemistry of the final product could be ensured by
choosing the correct enantiomer of 10.
Thus, both diastereomers of 12 were separated by silica
gel column chromatography and separately converted into
(Z)-alkenes 13 using Lindlar reduction. The anti relationship
of the 2-OH and 3-alkyl substituents in 4 required the (Z)-
configuration in 13. The N-OH group was replaced by the
benzyloxy acetyl function in a two-step sequence of N-O
cleavage15 and standard acylation with 7. In contrast to our
On the other hand, iodolactonization of amide 4 (Scheme
1) was expected, on the basis of our previous work,5 to give
respectable stereoselectivity.9 Therefore, we hypothesized that
an aza-Claisen rearrangement of 6 followed by iodolacton-
ization of 4 would constitute a more efficient and general
route to trans-3,4-dialkyl-γ-butyrolactones, including the
desired intermediate 2. Moreover, we envisioned that a chiral
auxiliary (R*) bound to nitrogen in 6 or earlier intermediates
could ensure high stereochemical purity of 1, because the
diastereomeric intermediates could be separated by conven-
tional means. In this communication, we report the experi-
mental realization of this design that resulted in a novel
synthesis of trans-3,4-dialkyl-γ-butyrolactones from chiral
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