COMMUNICATION
Highly enantioselective dynamic kinetic resolution and
desymmetrization processes by cyclocondensation of chiral
aminoalcohols with racemic or prochiral d-oxoacid derivatives{
Mercedes Amat,*a Oriol Bassas,a Miquel A. Perica`s,b Mireia Pasto´b and Joan Bosch*a
Received (in Cambridge, UK) 10th September 2004, Accepted 1st December 2004
First published as an Advance Article on the web 20th January 2005
DOI: 10.1039/b413937b
In this communication we report highly enantioselective
cyclocondensation reactions involving DKR and/or differentiation
of enantiotopic or diastereotopic ester groups using a variety of
d-oxoacid derivatives including simple racemic aldehydes (1) and
ketones (2, 3), prochiral aldehydo-diesters bearing enantiotopic
ester groups (4 and 6), and racemic aldehydo-diesters bearing
diastereotopic ester groups (5; Fig. 1).
Cyclocondensation reactions of aminoalcohols 7 and 8 with
racemic or prochiral d-oxoacid derivatives provide poly-
substituted lactams with high enantioselectivity in a process
that involves dynamic kinetic resolution and/or desymmetriza-
tion of enantiotopic or diastereotopic ester groups.
The development of new and practical methodologies for the
generation of two or more stereogenic centers with high diastereo-
and enantioselectivity in a single synthetic step is one of the most
challenging subjects in organic synthesis. Since the piperidine ring
is the central structure of many biologically active alkaloid natural
products and therapeutic agents, with thousands of piperidine
compounds mentioned as drug candidates in clinical and
preclinical studies,1 much effort has been devoted to the develop-
ment of general methods for the synthesis of enantiopure
piperidine derivatives.2
Preliminary studies using 3-amino-3-phenyl-1-propanol or 2-(1-
aminoethyl)phenol were disappointing because cyclocondensation
reactions with aldehyde 1 and ketones 2 and 3 took place with low
stereoselectivity and/or chemical yield.
More successful results, in particular with ketones, were
obtained using cis-1-amino-2-indanol (7), a conformationally rigid
analog of phenylglycinol (Table 1). Thus, although cyclocondensa-
tion with aldehyde 4 took place in good chemical yield with a
stereoselectivity similar to that previously observed when using
phenylglycinol4 giving lactam 10a as the major product, no DKR
was observed from racemic aldehyde 1. Interestingly, the
generation of enantiopure lactam 10a (isolated in 60% yield)
involves the enantioselective desymmetrization of two enantiotopic
ester groups. In contrast, cyclocondensation of 7 with racemic
ketones 2 and 3 took place in excellent chemical yield and with
better stereoselectivity than when using phenylglycinol.
Enantiopure tetracyclic lactams 11b and 12b were isolated in
61% and 77% yield, respectively, thus making evident that DKR of
the isomerizable stereocenter a to the ketone carbonyl had
occurred to a considerable extent.
In this context, in previous work we have demonstrated that
simplephenylglycinol-derivedbicycliclactamsA(R15R25R35H;
Scheme 1) are versatile synthons that provide easy access to a
variety of enantiopure substituted piperidines by successive
introduction of the substituents on the lactam ring.3 More
recently, we envisaged a procedure for the direct generation of
bicyclic lactams A that already incorporate the carbon substituents
on the heterocyclic ring.4 It involves the dynamic kinetic resolution
(DKR)5 of racemic d-oxoacid derivatives or the desymmetrization6
of prochiral d-oxodiesters in cyclocondensation processes using
(R)- or (S)-phenylglycinol. However, the moderate diastereo-
selectivity (4 : 1) of most of the above phenylglycinol-induced
cyclocondensations was a synthetic drawback that had to be
overcome.
The best results in terms of chemical yield and stereoselectivity
in cyclocondensation reactions with aldehydes were obtained when
using aminoalcohol 8.7 Thus, 8 reacted with racemic aldehyde 1 to
give a 9 : 1 stereoisomeric mixture of lactams 13 in 78% yield.8
Similarly, prochiral aldehydo-diesters 4 and 6 underwent highly
enantioselective desymmetrizations during cyclocondensation with
8 since 14 : 1 and 24 : 1 stereoisomeric mixtures of the respective
lactam esters 14 and 16 were formed in excellent yield. The major
Scheme 1
{ Electronic supplementary information (ESI) available: Typical experi-
mental procedure and 1H and 13C NMR spectra for all new compounds.
*amat@ub.edu (Mercedes Amat)
Fig. 1
joanbosch@ub.edu (Joan Bosch)
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 1327–1329 | 1327
Amat, Mercedes
