September 1998
SYNLETT
963
N-Acyl 'Quat' Pyrrolidinone Auxiliary as a Chiral Amide Equivalent via Direct Aminolysis
Stephen G. Davies* and Darren J. Dixon
Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK.
Received 29 June 1998
Abstract: A novel route into chiral amides is achieved through the
efficient, non-racemising, cleavage of N-acyl side chains from a ‘Quat’
pyrrolidinone chiral auxiliary using a range of N-nucleophiles.
The majority of naturally occurring substances containing the amide
bond invariably carry a stereogenic centre adjacent to the amidic
carbonyl. This, combined with the vast number of naturally occurring
peptides and pseudopeptides eliciting interesting biological and
pharmacological properties, highlights the need for more efficient
desired primary amide 4 as a colourless solid in 68% yield. Inspection of
asymmetric routes to such important compounds.
1
the H nmr spectrum (300 MHz, CDCl ) of the triturand indicated the
3
The chiral auxiliary has played a regular role in the synthesis of the key,
homochiral fragments contained within many of these pseudopeptides
and related compounds. Invariably, the chiral auxiliaries are cleaved
hydrolytically to afford the carboxylic acid which is then sequentially
activated and coupled to an amine or a suitably protected α-amino acid
through standard procedures.
presence of the pyrrolidinone 1 as the major component and methyl
ester 5 as the minor, Scheme 3.
Herein, we wish to report a conceptually more simple route to such
chiral amides and pseudopeptides via direct aminolysis of the ‘Quat’
pyrrolidinone auxiliary
Scheme 1.
1
from attached chiral acyl side chains,
The specific rotation, [α] 24 +55.4 (c 0.675, EtOH); [Lit., [α]
8
21
+53.1
D
D
8
The pyrrolidinone auxiliary 11 has been shown to induce high
(c 2.5, EtOH)] and melting point, mp 114-115 °C [Lit., 113-114 °C] of
4 were in good agreement with the reported data. A H nmr (300 MHz,
CDCl ) chiral shift experiment with Eu(hfc) showed the ee of amide 4
1
2
3
diastereoselectivities in both enolate alkylation and aldol reactions of
attached acyl side chains. This combined with the exceptional
propensity for exocyclic- over endocyclic-cleavage with O-centred
nucleophiles, through steric block of the ring carbonyl by the geminal
9
3
3
to be >98%. Clearly, this higher than expected enantiomeric excess had
arisen through the trituration process and gave no indication of the
amount, if any, of racemisation occurring during the cleavage process.
1
dimethyl groups, made pyrrolidinone 1 ideally suited to be a precursor
to chiral amides through direct aminolysis pathways.
Encouraged by the preliminary result, 3 was then treated with an excess
(
6 eq.) of neat allylamine and the progress of the reaction monitored by
Interestingly, there have been only a few reports of the direct cleavage
TLC. After 36 hours, simple work up and purification afforded pure
allylamide 6 and pyrrolidinone 1 both in near quantitative yields. A H
nmr (300 MHz, CDCl ) chiral shift experiment with Eu(hfc) showed
the ee of allylamide 6 to be >96%. This value was in excellent
agreement with the diastereomeric excess of the starting material 3 and
confirmed that direct aminolysis was occurring without racemisation,
Scheme 4.
from other chiral auxiliaries of chiral N-acyl side chains with either
1
4
ammonia or amines. The majority of these involve chiral auxiliaries
9
with a high sulphur content which have been synthesised and utilised
for, amongst other qualities, their lability towards nucleophilic
3
3
5
,6,7
reagents.
However, chiral auxiliaries of this type are severely
restricted in terms of the number of types of asymmetric transformations
which attached N-acyl side chains can undergo, with tin (II) mediated
aldol reactions being the most common.
The benzylated propionyl pyrrolidinone 3 was chosen as the model
system for our preliminary studies. This material was efficiently
3
prepared via a modification of the literature procedure. Hence,
acylation of the pyrrolidinone 1 with BuLi and propionyl chloride gave
the N-propionyl pyrrolidinone
2 in excellent yield. Subsequent
treatment with LDA at -78 °C followed by benzyl bromide afforded the
desired material 3 in good yield and with high diastereoselectivity (>
96% de), Scheme 2.
In the first aminolysis, 3 was treated with a saturated solution of
ammonia in methanol for 2 hours at 0°C. Removal of volatiles in vacuo
and trituration of the resulting material with pentane afforded the
In an analogous fashion, treatment of 3 with benzylamine led to the
efficient generation of benzylamide 7 (96%). Although the enantiomeric
excess of 7 was not measured directly it was assumed to be >96% on the