Enantioselective synthesis of (R)-homocitric acid lactone

Article abstract of DOI:10.1016/j.tetlet.2007.08.005

An expedient enantioselective approach to (R)-homocitric acid lactone from an ephedrine-derived morpholine-dione, a cationic glycolate equivalent, is described.

Full text of DOI:10.1016/j.tetlet.2007.08.005

Tetrahedron Letters 48 (2007) 7099–7101
Enantioselective synthesis of (R)-homocitric acid lactone
*
Sunil V. Pansare and Vikrant A. Adsool
Department of Chemistry, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada A1B 3X7
Received 25 May 2007; revised 30 July 2007; accepted 1 August 2007
Available online 6 August 2007
Abstract—An expedient enantioselective approach to (R)-homocitric acid lactone from an ephedrine-derived morpholine-dione, a
cationic glycolate equivalent, is described.
Ó 2007 Elsevier Ltd. All rights reserved.
9
(
R)-Homocitric acid (1, Fig. 1) is a key intermediate in
ephedrine-derived morpholinedione 3, which functions
as a cationic glycolate equivalent. The dione 3 is easily
prepared from commercially available 1R,2S-ephedrine
and ethyloxalyl chloride in good yield (85%). Treatment
of 3 with butenylmagnesium bromide generated the
hemiacetal 4 (82%, Scheme 1). The diasteroselectivity
of the process was moderate (1/1–5/1, depending on
the reaction temperature) and the stereochemistry of
the major diastereomer was not determined. The hemi-
the biosynthesis of L-lysine, an essential amino acid in
some yeast and fungi, and it is also a component of
the Fe–Mo cofactor in nitrogenase. The unique biolog-
ical profile of homocitric acid is of interest in the devel-
opment of antifungal therapies and in the elucidation
of the intricacies of nitrogen fixation. Studies toward
these objectives require access to enantiomerically
enriched (R)-homocitric acid and its analogues, neither
1
2
3
4
5
of which are commercially available in significant
amounts. Consequently, the enantioselective synthesis
acetal in 4 was readily allylated (TiCl , allytrimethyl-
4
silane, ꢀ40 °C) to furnish the dialkylmorpholinone 5
1
0
of homocitric acid, invariably isolated as its c-lactone
(68%) as a single diastereomer (98% ee). The newly
generated stereocenter in 5 was assigned the ‘R’ config-
uration on the basis of an NOE experiment, which indi-
cated a syn orientation of the allyl group and the
benzylic hydrogen in the morpholinone ring. This result
is probably the outcome of a stereoelectronically con-
trolled axial allylation of the oxocarbenium ion in a
6
2
(Fig. 1), has been actively investigated in recent years.
Syntheses of the racemate have also been reported
7
recently. In addition, it has been observed that the alkyl
citrate, isocitrate, or a-alkyl malate motifs, which are
close congeners of homocitrates, are key pharmaco-
phoric units in several bioactive alkaloids, glycosides
8
11
and antifungal agents. This has added to the interest
boat-like transition state assembly (Scheme 1).
in substituted a-hydroxy di- and tri-carboxylic acid
derivatives in recent years.
Ph
Ph
Our approach to (R)-homocitric acid is based on the
double alkylation of a chiral oxalic acid derivative, the
N
N
N
MgBr
ether 0 oC to rt, 4 h
O
O
O
O
(
82%)
OH
O
3
HO
HO
O
OH
HO
4
SiMe3
O
O
-
40 o
C
TiCl
4
O
HO
Ph
Ph
O
O
OH
+
O
O
O
1
2
O
N
(
68%)
O
Figure 1. (R)-Homocitric acid (1) and (R)-homocitric acid lactone (2).
5
SiMe3
*
Corresponding author. Tel.: +1 709 737 8535; fax: +1 709 737
702; e-mail: spansare@mun.ca
3
Scheme 1. Diastereoselective double alkylation of morpholinone 3.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.005

7100
S. V. Pansare, V. A. Adsool / Tetrahedron Letters 48 (2007) 7099–7101
The overall conversion of the dione 3 to the dialkyl gly-
colamide 5 constitutes an asymmetric dialkylation of a
chiral oxalic acid derivative. This procedure is an alter-
native to conventional approaches to chiral a,a-dialkyl-
ated glycolic acid derivatives that are based on
tion product furnished (R)-homocitric acid c-lactone
23 20
6c
(64%, 98% ee, ½aꢁ ꢀ57.0 (c 1, H O); lit. ½aꢁ ꢀ48.9
D
2
D
(c 0.38, H O)). It may be noted that the use of labeled
2
1
5
butenyl Grignard reagents prepared from 4-bromobu-
tene deuterated at C-4 should allow the introduction of
deuterium in the lactone ring of 2. Similarly, the use of
1
2
sequential dialkylation of glycolate anions.
The
1
6
approach may be advantageous when the S 2 reactivity
deuterated allyltrimethylsilanes should provide access
to homocitrate that is deuterated in the acetate side
chain. The synthesis is therefore well suited for the prep-
N
of the electrophile is a limitation in the anion alkylation
protocol. Having constructed the required a-hydroxy
stereocenter in the target molecule, we proceeded to
remove the ephedrine portion in 5. Dissolving metal
5
a
aration of labeled homocitrates that may be of interest
in biological studies.
reduction of 5 (Na/NH , ꢀ78 °C) provided the hydroxy
3
amide 6 in good yield (81%, Scheme 2). Details of the
homobenzylic C–N bond cleavage in 5 are not known
at present. It is plausible that, at some stage in the reduc-
tion, a benzylic carbanion is generated and it undergoes
facile b-elimination of the N-acyl moiety. We next
investigated the hydrolysis of the secondary amide in
Acknowledgements
These investigations were supported by the Natural Sci-
ences and Engineering Research Council of Canada and
the Canada Foundation for Innovation.
1
3
6
. Not surprisingly, this proved to be a challenging task.
Heating 6 in aqueous acids led to multiple products,
some of which were presumably derived from intra-
molecular alcohol-alkene etherification reactions of 6.
Basic hydrolysis conditions resulted in decomposition.
Attempts to activate the amide by N-nitrosation were
unsuccessful as were the efforts to convert the amide into
an iminium species or an imidate ester. We therefore
decided to utilize a two step procedure for achieving
the required transformation. Treatment of 6 with iodine
Supplementary data
Experimental methods, spectroscopic data with assign-
1
4
1
13
ments, H and C data for all compounds. Supplemen-
tary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.08.005.
(
2.5 equiv) gave a mixture of products. These are prob-
References and notes
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acid 7 was obtained in excellent yield (91%, Scheme 2).
The efficiency of the dehalogenation reaction lends some
credence to the proposed reactions of 6 with iodine,
since the lactonization as well as the iodoetherification
products should readily generate 7 after metallation
with zinc.
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8
Scheme 2. Synthesis of (R)-homocitric acid lactone.

S. V. Pansare, V. A. Adsool / Tetrahedron Letters 48 (2007) 7099–7101
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