Enantioselective synthesis of (S)-homocitric acid lactone and (R)-per-homocitric acid lactone involving organocatalysis

Article abstract of DOI:10.1016/j.tetasy.2010.04.050

A concise enantioselective synthesis of (S)-homocitric acid lactone and its homolog, via an organocatalytic vinylogous Mukaiyama-Michael reaction of a silyloxy furan derivative and acrolein, is described.

Full text of DOI:10.1016/j.tetasy.2010.04.050

Tetrahedron: Asymmetry 21 (2010) 771–773
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of (S)-homocitric acid lactone
and (R)-per-homocitric acid lactone involving organocatalysis
*
Sunil V. Pansare , Shubhangi V. Adsool, Rajendar Dyapa
Department of Chemistry, Memorial University, St. John’s, Newfoundland, Canada A1B 3X7
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise enantioselective synthesis of (S)-homocitric acid lactone and its homolog, via an organocatalyt-
ic vinylogous Mukaiyama–Michael reaction of a silyloxy furan derivative and acrolein, is described.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 April 2010
Accepted 23 April 2010
Available online 2 June 2010
1. Introduction
2. Results and discussion
(R)-Homocitric acid 1 (Fig. 1) is a key intermediate in the bio-
synthesis of -lysine, an essential amino acid in some yeast and
Our approach to homocitric acid lactone is based on the
Mukaiyama–Michael reaction9 of silyloxy furans and
,b-unsatu-
L
a
fungi,1 and it is also a component of the Fe–Mo cofactor in nitroge-
nase.2 The unique biological profile of homocitric acid is of interest
in the development of antifungal therapies3 and in the elucidation
of the details of nitrogen fixation.4 Studies toward these objectives
require access to enantiomerically enriched (R)-homocitric acid
and its analogs,5 neither of which are commercially available in
significant amounts. Consequently, the enantioselective synthesis
rated aldehydes and ketones, which is a useful method for the con-
struction of butenolides. The iminium ion-catalyzed version of this
reaction was pioneered by MacMillan10a,b and other organocatalyt-
ic variants have since been developed.10e–g We reasoned that the
use of acrolein as the Michael acceptor in a conjugate addition
reaction with an appropriately substituted furan would lead di-
rectly to the homocitrate lactone motif (Fig. 2).
of homocitric acid, invariably isolated as its c-lactone, has been ac-
tively investigated in recent years.6 Syntheses of racemic homocit-
rate7 and per-homocitrate7a have also been reported. Close
congeners of homocitrate such as the alkyl citrate, isocitrate, and
CO2R
CHO
TIPSO
O
+
CO2R
CHO
CO2H
CO2H
O
a
-alkyl malate motifs are key pharmacophoric units in several bio-
active alkaloids, glycosides, and antifungal agents.8 This has added
to the interest in substituted -hydroxy di- and tricarboxylic acid
O
O
O
n = 1,2
a
derivatives in recent years. Herein, we report an expeditious syn-
thesis of (S)-homocitric acid lactone 2 as well as its homolog, (R)-
per-homocitric acid lactone 3.
Figure 2. Vinylogous Mukaiyama–Michael approach to homocitrates.
With this objective in mind, the furans 411a and 5 were readily
prepared from crotonolactone by adapting the literature proce-
dure.11b Amines 6–9 were chosen as potential catalysts for the
organocatalytic conjugate addition reaction of 4 and 5 with acro-
lein. Orienting experiments were conducted with furan 4 and acro-
lein in the presence of the MacMillan first generation catalyst 6
(Table 1). Although the required product was not obtained in ethe-
real solvents, the use of halogenated solvents was beneficial and 10
was obtained in modest yield and in 73% ee in chloroform, with
water as an additive (Table 1, entry 5). The enantioselectivity with
the MacMillan catalyst 7 was low. Interestingly, a change in the
ester alkyl group had a beneficial effect on enantioselection. Thus,
the use of furan 512 (benzyl ester) as the nucleophile in CHCl3/H2O
provided the Michael adduct 1112 in 80% ee and 38% yield. Increas-
ing the amount of acrolein (20 equiv, entry 9) was not beneficial
and provided only 19% of 11 with significantly lower enantiomeric
HO
HO
O
OH
CO2H
O
CO2H
O
n
OH
O
2
3
(n = 1)
(n = 2)
O
1
Figure 1. (R)-Homocitric acid 1, (S)-homocitric acid lactone 2, and (R)-per-
homocitric acid lactone 3.
* Corresponding author. Tel.: +1 709 737 8535; fax: +1 709 737 3702.
E-mail address: spansare@mun.ca (S.V. Pansare).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.050

772
S. V. Pansare et al. / Tetrahedron: Asymmetry 21 (2010) 771–773
Table 1
dation protocol (Scheme 1). Acetalization of 11 with trimethylor-
thoformate followed by treatment of the crude acetal with
Hunig’s base provided the enol ether 1212 as a mixture of stereoiso-
mers (trans/cis = 2/1).13 Oxidative cleavage of the enol ether (OsO4/
NaIO4) provided the acid 13.12 Hydrogenation of 13 was antici-
pated to proceed with concomitant debenzylation. However, the
benzyl ester in 13 was resistant to hydrogenolysis (Pd/C, 2 atm.
H2) which invariably led to mixtures containing a trace of 2 and
the dihydro analog of 13. Nonetheless, selective reduction of the
double bond in 13 was possible (1 atm. H2), which was followed
by base hydrolysis of the ester and subsequent acidification to pro-
vide (S)-homocitric acid lactone 2 (90% from 13, Scheme 1).
CHO
CO2R
O
TIPSO
CO2R
O
O
6-9 (20 mol%)
CHO
10 (R = CH3)
room temp.
4 (R = CH3)
5 (R = CH2Ph)
11 (R = CH2Ph)
F3C
CF3
O
O
CF3
H3CO
OCH3
N
N
Ph
Ph
N
H
N
N
N
H
.
H
H
HCl
6
7
8
9
OTMS
CF3
Entry
Cat.
Solvent
Add.
Time (h)
Yield (%)
eea (%)
10
11
CO2Bn
CO2Bn
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
6
6
6
6
6
7
7
6
6
6
7
7
7
7
7
8
8
8
9
9
THF
H2Ob
H2O
H2O
H2O
H2O
TFAc
TFA
H2O
H2O
H2O
H2O
TFA
TFA
TFA
TFA
H2O
—
16
16
156
156
72
—
—
—
—
1) In(OTf)3, HC(OMe)3
O
O
Dioxane
CH2Cl2
CHCl3
CHCl3
THF
CH2Cl2
CHCl3
CHCl3
THF
CHCl3
CHCl3
CHCl3
THF
CH2Cl2
CHCl3
THF
O
O
2) DIPEA, TMSOTf
(51%)
OMe
18
12
24
21
9
52
45
73
13
20
80
69
1
CHO
12
11
1) OsO4, NaIO4
2) NaClO2, NaH2PO4
(72%)
72
3d
1) H2, Pd/C
72
20
20
38
19e,f
16
—
CO2H
CO2H
CO2Bn
O
O
O
O
CO2H
2) NaOH, HCl
(90%)
13
2
144
48
—
33e
47
50
41
36
74
33
27
35
39
72
59
41
50
35
44
1
72f
50
Scheme 1.
48f
120
91
The lactone 2 obtained in this study is dextrorotatory and is
therefore assigned the (S) configuration (½a D23
¼ þ30 (c 1, H2O);
ꢀ
lit.6c
½
a 2D3
ꢀ
¼ ꢁ48:9 (c 0.38, H2O) for the (R) enantiomer). This
CH2Cl2
CHCl3
CHCl3
—
H2O
MeOH
120
168
192
assignment also establishes the sense of asymmetric induction in
the organocatalytic Michael addition reaction leading to 11.14
Given the recent interest in the higher homolog of homocitric
acid (per-homocitric acid5d,6a), we converted lactone 11 to a homo-
log of 2. Thus, oxidation of aldehyde 11 provided the corresponding
acid which was hydrogenated to provide the target (R)-per-homoci-
tric acid lactone 1412 in good yield (85%, Scheme 2). It may be noted
that 14 is a desymmetrized derivative of the parent achiral triacid.
3
a
Chiral HPLC analysis of 11 and of the acetal with (2R,3R) butanediol for 10.
2 equiv water.
0.2 equiv TFA.
Reaction at ꢁ40 °C.
20 equiv acrolein.
Reaction at 0 °C.
b
c
d
e
f
excess (69% ee). As with 4, changing the solvent to THF was
detrimental (1% ee). This observation suggests that the reaction
is sensitive to changes in the solvent. Ethereal solvents, in particu-
lar, are detrimental to enantioselection. Reactions of 5 in the pres-
ence of amines 7–9 also provided the butenolide 11 (Table 1,
entries 10–18). When 7 was used under the conditions optimized
for 6 (CHCl3/H2O as the solvent) 11 was not obtained. The use of
TFA as an additive (instead of water) had a pronounced effect
and 11 was obtained, but with low ee (39%, entry 12). In summary,
the best conditions for the synthesis of 11 employ the ester 5 with
an excess (3 equiv) of acrolein and catalyst 6 in CHCl3/H2O as the
solvent.
Among the remaining catalysts, the imidazolidinone 7 was
superior. Reactions with the prolinol derivative 8 were found to
be very capricious in terms of enantioselectivity, and the C2-sym-
metric pyrrolidine 9 was not especially effective as a catalyst.
Overall, the higher efficiency of 6 over 7 is notable in this study.
It may be noted that the facial selectivity for the reaction of 4 with
b-substituted acroleins is known to depend on the nature of the
b-substituent and this substituent is often necessary for good
stereoselectivity.10a,d Since these studies10a were conducted with
catalyst 7, an unambiguous stereochemical assignment for adducts
10 and 11 was not possible by analogy to the reported results.
However, subsequent reactions of 11 were useful in determining
the sense of asymmetric induction in the Mukaiyama–Michael
reaction.
CO2H
CO2H
CO2Bn
CHO
1) NaClO2, NaH2PO4
O
O
O
O
2) H2, Pd/C, 50 psi
(85%)
14
11
Scheme 2.
3. Conclusion
In conclusion, expedient, organocatalysis-based, enantioselec-
tive syntheses of (S)-homocitric acid lactone and its homolog have
been developed. Notably, the methodology also provides several
butenolide intermediates that offer opportunities for chemoselec-
tive functionalization. Such reactions may find applications in the
synthesis of functionalized oxygen and nitrogen heterocycles. Cur-
rent efforts focus on these as well as other applications of the
intermediates.15
Acknowledgments
These investigations were supported by the Natural Sciences
and Engineering Research Council of Canada and the Canada Foun-
dation for Innovation.
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