synthesized in turn, from the P-ketoester 6. For the synthesis of 6 we started with
enone 1, readily prepared following a known procedure.6 The analysis of the IH NMR spectrum of the
reaction product of its reduction revealed the presence of a 2: 1 mixture of allylic alcohols and also that the
acetal moiety had been hydrolyzed, presumably during the work-up, giving directly 8.
- 4 5
0 I JJ
684 J. A. BACIGALUPPO eta/.
We have found no precedent in the literature for the hydrolysis of acetals under these conditions.
sterically congested enamides 14.
3. P-Hydroxy Esters
Enantiomerically pure P-hydroxy esters have served extensively as valuable chiral building
blocks in synthetic organic and natural product chemistry.17 One of the most direct routes to
enantiomerically-enriched P-hydroxy esters is through asymmetric hydrogenation of the corresponding
P-ketoesters, and several highly enantioselective catalyst systems have been developed for this
transformation. For example, Ru-BINAP catalysts have been shown to provide a wide range of P-
hydroxy esters with very high selectivity
2 SYNTHESIS OF KEY INTERMEDIATE (4 ) FROM THE SEVEN-MEMBERED
p-KETOESTER ( 5 )
2.1 Model test of the formation of hydroazulene by pinacol coupling
A Michael addition of compound (10) to acrolein gave keto-
aldehyde (ll), which was subjected to pinacol coupling to afford
the diol (12). Diol (12) was oxidized to the hydroxy-ketone (13)
with DMSO and trifluoroacetic anhydride. However, oxidation of
(12) with PPC gave (13) in very poor yield, the major product
being the open-ring compound (11). Compound (13) proved to be a
mixture of trans and cis isomers
16 (67%) as the
monohydrate. Reaction of 16 with the phenethylamine derivative 17 afforded the keto-imine 18 (61%). This
reaction appeared to take place by initial formation of a Schiff base at the central carbonyl, followed by a Pictet-
Spengler cyclization and rapid oxidative decarboxylation of the resulting p-keto-ester. Methylation (SO%), and
subsequent hydride reduction (72%) led directly to the cordrastines (diastereomeric ratio of 1 2 in favor of 20).
&olBu P O I B U ' PPh,
Me0 C02Et Me0 ' CO,Et PPh3
Me0 2 equiv. Me0
1 4 1 5
segments, we made a decision to embark on the development of a general strategy for the synthesis of these
molecules.To initiate the synthesis of batzelladine A (lo), we first investigated a synthetic protocol for the
0 1998 IUPAC, Pure and Applied Chemistry70,303-306
Anti-HIV compounds 305
left hand bicyclic guanidine segment (11) starting from ethylacetoacetate (scheme 5). It was first converted
into the a-alkylidene-p-ketoester derivative (12) and then subjected to conjugate addition with concomitant
cyclisation using 0-methylisourea to give 13
followed by immediate protection of the unstable alcohol gave ethoxyethyl ether 12 (Scheme 3). Diazo
transfer reaction of the p-ketoester 12 under standard conditions furnished diazo compound 13, which was
subjected to copper-mediated cyclopropanation to give the bicyclic ketone 14. Reduction of ketone 14 with
sodium borohydride, acetylation of the resultant alcohol, hydrolysis of the ethoxyethyl ether, and
subsequent ozonolysis of the olefin furnished the aldehyde 11.
a (a) NaH, THF, 0 "C, then BuLi; sorbic aldehyde, 0 to
agents constitute a versatile entrke to
fbnctionalized amino acid derivatives. The synthesis of W-azirine-2-carboxylic esters
fiom aziridine-2-carboxylic esters by an eliminative reaction is reported. An alternative
preparation of 2H-azirine-2-carboxylic esters involves an alkaloid mediated synthesis
from the oxime tosylates of p-ketoesters by a modified Neber reaction.
Aziridine-2-carboxylic esters are of interest in view of their structural relationship with a- as well as p-amino
acids and the intrinsic high reactivity of the three-membered ring. Little
-t-BuOH mixture is excellent for
p-ketoester reductions. **NB-Enantrane gives 86%. Therefore *.
Fig. 25. Optimum reagents for asymmetric reduction
of representative ketones.
It is noteworthy that with two exceptions, Bind-H and Terashima's reagent, all of the most favorable reagents are
ALLYL- AND CROTYLBORATION
Simple organoboranes, such as triethylborane do not add to the carbonyl group. However, as was first pointed out
by Mikhailov, allylboron derivatives undergo a fast addition, which proceeds with allylic rearrangement (Fig. 26,
(ref. 63). The same aldehyde has been expediently produced from the asymmetric hydrogenation of
the corresponding P-ketoester in high enantiomeric purity (ref. 58,62). In spite of the relatively high
overall yield, the L-malic acid template route is impractical on an industrial scale in view of the number of
steps needed to elaborate the relatively simple target aldehyde. As in many other instances where several
reactive functional groups are present (C@H, OH), temporary protection and deprotection are inevitable,
hence the number of extra steps. However, the