A convenient route to optically active γ-substituted γ-lactones

Article abstract of DOI:10.1039/b409061f

Sodium borohydride reduction of 4-substituted (-)-menthyl/ (-)-bornyl-4-oxobutanoates followed by simple trituration in acidic medium at low temperature resulted in the formation of optically active γ-substituted γ-lactones.

Full text of DOI:10.1039/b409061f

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L E T T E R
A convenient route to optically active c-substituted c-lactones
Anil V. Karnik,*a Sudhir T. Patil,a Subodh S. Patnekara and Abha Semwalb
a Department of Chemistry, University of Mumbai, Vidyanagari, Kalina, Mumbai, 400 098
India. E-mail: avkarnik@hotmail.com; Fax: +91-022-26528547; Tel: +91-022-26526091
b Bio-Organic Division, Bhabha Atomic Research Center, Mumbai, 400085 India
Received (in Montpellier, France) 14th June 2004, Accepted 8th September 2004
First published as an Advance Article on the web 9th November 2004
Sodium borohydride reduction of 4-substituted (ꢀ)-menthyl/
(ꢀ)-bornyl-4-oxobutanoates followed by simple trituration in
acidic medium at low temperature resulted in the formation of
optically active c-substituted c-lactones.
optically active g-substituted g-lactones 7a–e with recovery of
the chiral auxiliary in an optically pure form.
The secondary carbinol 2 formed by the reduction of 4-
oxobutanoates 1 with sodium borohydride is capable of gen-
erating an enantiotopic carbocation 3 in acidic medium
(Fig. 1). The carbocation so-formed can undergo further
reaction with an internal nucleophile if available. If the for-
mation of a stable enantiotopic carbocation is considered as a
possibility then its attack in an enantioselective manner by a
chiral auxiliary could occur. Based on these considerations, an
asymmetric synthesis of g-substituted g-lactones 7 was envi-
saged by using 4-oxobutanoates 1 together with a chiral
alcohol auxiliary.
When 4-substituted 4-oxobutanoates 1a–e in the presence of
chiral alcohol auxiliaries were reacted with sodium boro-
hydride and the subsequent acidification was carried out under
cold conditions, the formation of optically active lactones was
observed. When the reaction was further investigated it was
observed that the reaction time required for complete conver-
sion into the lactone varied from 1 to 4.5 h depending on the
substitution pattern. In the NaBH4 reduction of 1, when the
reaction mixtures were extracted immediately after acidifica-
tion, the corresponding g-hydroxybutanoates 2 were isolated
and none (or small amounts, in the case of aryl substituents) of
the lactone 7 could be detected. Clearly, lactonization is a
slow process occurring during the trituration period in acidic
medium.
Substituted g-lactones are the basic structural units of many
complex and challenging biologically active natural pro-
ducts.1–3 Optically pure substituted g-lactones have been
employed as synthons/intermediates for acquiring many bio-
logically important compounds such as antitumor antibiotic
(+)-hitachimycin,4 an aggregation pheromone R-(ꢀ)-sulca-
tol,5 antileukaemic liganans (+)-trans-burseran and (ꢀ)-iso-
stegane,6 a natural product dihydromevinolin,7 etc. Therefore,
it is not surprising that various biological and chemical meth-
ods have been described in the literature to access these
important ring systems in optically active forms.8–13 The use
of chiral reducing agents such as BINAP-Ru(II)-catalyzed
hydrogenation,14,15 hydrosilylation catalyzed by rhodium com-
plexes with chiral phosphine ligands16 and enzymatic hydro-
lysis of hydroxy esters17 are some of the methods that have
given satisfactory results. Optically pure g-substituted g-lac-
tones have also been obtained from optically pure glutamic
acid18–20 with retention of configuration. However the use of
an optically pure alcohol as a chiral auxiliary for the reduction
of 4-oxobutanoates 1 using sodium borohydride, followed by
hydrolysis, resulted in optically inactive g-lactones.21 We de-
scribe herein a novel, short and efficient methodology that
employs readily available and inexpensive chiral auxiliaries and
very mild reaction conditions to achieve the synthesis of
The overall chemical sequence resembles that of transester-
ification and hence it is essential, by similarity, to look for the
presence of AAL1; AAC1 and AAC2 type mechanisms. The fact
Fig. 1 Proposed mechanism for lactonization via a cyclic oxocarbenium ion.
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
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N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 2 0 – 1 4 2 2

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Fig. 2 Mechanism of addition of the hydroxyl group to the ester carbonyl.
that an optically active compound is obtained rules out AAC1,
where the chiral auxiliary is not a part of the transition state
leading to cyclization. The hydroxy ester formed after reduc-
tion of the keto carbonyl group can also exhibit addition of the
hydroxyl group to the ester carbonyl group as shown in Fig. 2,
in a mechanism close to an AAC2 type. It is not impertinent to
consider the formation of lactone via this route. But this route
is likely to give racemic lactones if the two diastereomeric
hydroxy esters are formed in equimolar proportions. A pre-
vious literature report21 indicates that the optical induction
does not occur at the reduction stage, which we further
confirmed by isolating the hydroxyesters before cyclization
and subjecting them to cyclization at the solvent reflux tem-
perature, leading to the formation of racemic lactones. Relative
reaction times required for the formation of g-lactones 7
should not have been much different in case of AAC2 type
reactions for 7a and 7b–e. Experimental findings show that
levulinic acid is 3 to 4 times less reactive. This accounts for the
difference in stability of methyl alkyl carbocation 3a and aryl
alkyl carbocations as in the case of 3b–e, if the formation of a
carbocation is to be considered as the rate-determining step.
Based on these premises we favour the possibility of the
formation of a diastereotopic carbocation followed by enantio-
selective attack on the carbonyl of the ester group under the
influence of the nearby chiral alcohol moiety of the ester. The
use of aq. HCl during the second stage (cyclization) favours
SN1 type reactions more strongly. This mechanism is close to
the AAL1 type mechanism.
In a typical reaction (Scheme 1) 1 was dissolved in methanol
and reduction with NaBH4 was carried out as usual. The
solution was acidified under cold conditions. The mixture
was stirred until the formation of the lactone was complete
as monitored by TLC. Extraction followed by column chro-
matography gave the g-substituted g-lactones (7a–e; Table 1).
The chiral auxiliary, (ꢀ)-menthol/(ꢀ)-borneol, was also recov-
ered as optically pure by chromatography. The enantiomeric
excess for compounds 7a–e was calculated on the basis of
comparison of the optical rotation and chiral HPLC for some
of the samples. When (ꢀ)-menthol was used as the chiral
auxiliary, ee values were found to be in the range from 25%
to 63%. The enantioselectivity was enhanced to 61–95% when
(ꢀ)-borneol was employed as the chiral auxiliary. The config-
urational outcome depends on the difference in the two dia-
stereomeric transition states involved and incidentally S
enantiomers were obtained as major products in all cases. In
compounds 7b–e the relative configurations remain the same,
however, in 7a the relative configuration is opposite even
though the configuration remains as S due to the change in
priority order of the ligands. Assignments of configurational
descriptors have been done according to comparison with
literature reports5,11,13 for 7a and 7b but configurational
assignments for compounds 7c, 7d and 7e have not been
reported in the literature. These compounds have structural
similarities with compound 7b, the substituents are at the para
position of the phenyl ring and by comparison to the sign of
optical rotation with 7b they are considered to have similar
configurations, though this has not been established. Spectral
details for 7a–e are found to be in good agreement with the
literature.22
The proposed mechanism, shown in Fig. 1, involving the for-
mation of a diastereomerically enriched cyclic oxocarbenium
intermediate 4, finds support in the following observations: (a)
sodium borohydride reduction of (ꢀ)-menthyl/(ꢀ)-bornyl-4-
oxobutanoates 1 followed by acidification and immediate
extraction gave g-hydroxy esters 2 and not the corresponding
lactones 7; (b) g-hydroxy esters 2 on trituration in an ice-cold
HCl mixture gave optically active lactones 7; (c) g-hydroxy
esters 2 on refluxing in aqueous HCl gave racemic lactones;21
(d) (ꢀ)-menthyl/(ꢀ)-bornyl-4-aryl-4-oxobutanoates 1b–e gave
faster formation of lactones (Table 1) compared to (ꢀ)-
menthyl/(ꢀ)-bornyl levulinates 1a, which indicates the facile
formation of a benzyl carbocation from 4-aryl substituted
substrates; (e) the g-substituted g-lactones formed were config-
urationally stable and there was no loss of optical activity after
standing in aq. HCl (15 ml of 1 : 1 HCl for 10 mmol of product)
for a prolonged period (448 h).
The present asymmetric synthesis of g-substituted g-lactones is
more convenient relative to other chemical and biological ap-
proaches. The easy recovery of the chiral auxiliary in an optically
pure form is achieved. The level of enantioselectivity is satisfac-
tory and, moreover, it utilizes readily available and inexpensive
chiral auxiliaries. The operation is simple and adaptable to large-
scale production. The methodology offers an opportunity for the
use of any available chiral alcohol. The methodology is simple
enough to be employed for polysubstituted g-lactones and
consequently should open an easier route to many other biolo-
gically important compounds and natural products accessible
through the intermediacy of substituted g-lactones. Further
work to optimize the chiral induction is in progress.
Experimental
Typical reaction procedure for the synthesis of c-substituted
c-lactones 7a–e
In a typical experiment (ꢀ)-menthyl/(ꢀ)-bornyl-4-oxobutano-
ate (10 mmol) and methanol (15 ml) were placed into a round
bottom flask and cooled externally. Sodium borohydride (5
mmol) was added slowly with constant stirring within half an
hour. The reaction was monitored by TLC and was complete
after 90 min. Then methanol was removed by vacuum distilla-
tion. A mixture of ice and HCl (1 : 1, 15 ml) was added to the
Scheme 1 Conversion of 4-oxobutanoates 1 to g-substituted g-lactones 7a–e. R = CH3 (a), C6H5 (b), 40-CH3C6H4 (c), 40-OCH3C6H4 (d), 40-
BrC6H4 (e); R*OH = (ꢀ)-menthol, (ꢀ)-borneol. Conditions: i NaBH4, MeOH, RT; ii dilute HCl, ꢀ5 to 0 1C, stirring 1–5 h.
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 2 0 – 1 4 2 2
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Table 1 Formation of g-substituted g-lactones 7a–e from (ꢀ)-menthyl/(ꢀ)-bornyl-4-oxobutanoates 1a
(ꢀ)-Menthol
Stirrring
time/h
(ꢀ)-Borneol
Stirrring
time/h
R
Mp/1C
% Yield
[a]25
% ee
Mp/1C
% Yield
[a]25
% ee
D
D
7a
7b
7c
7d
7e
a
CH3
C6H5
4.5
1.25
1
Oil
Oil
64
45
61
66
62
56
ꢀ7.84
ꢀ8.00
ꢀ5.24
ꢀ3.47
ꢀ5.02
27b
25c
45c
63c
33c
4.5
1.5
Oil
Oil
64
50
70
69
64
63
ꢀ17.94
ꢀ23.27
ꢀ12.08
ꢀ05.29
ꢀ10.48
61b
72c
94c
95c
69c
4-CH3C6H4
4-OCH3C6H4
4-BrC6H4
1.25
2.5
2
49
85
49
85
2
2.25
7a and 7b have S configuration; compounds 7c, 7d and 7e are structurally similar to 7b (the change in structure is away from the chiral center) and
b
have the same sign of optical rotation, hence are considered to be S configured, though the configuration has not been established. The ee was
calculated on the basis of the optical rotation for 7a reported in ref. 13 (i.e ꢀ29.6). The ee for 7b–e was also calculated by chiral HPLC.23
c
residue and the mixture was stirred continuously until lactone
formation was confirmed by comparison with authentic lac-
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Acknowledgements
23 The enantiomeric excess for 7b–e was calculated by chiral HPLC
using a Bruker HPLC V5.205 with a (R,R) Whelc-01 5 mM (Merck
Germany) chiral column. The injection volume is 20 ml, the elution
mixture 93 : 7 n-hexane : 2-propanol and elution flow rate of
The authors wish to thank Prof. S. H. Mashraqui, from the
University of Mumbai, for fruitful discussions regarding this
work and Dr S. Chattopadyay, Head of the Bio-organic
Division, BARC, Mumbai, for chiral HPLC analyses.
2 ml minꢀ1
.
1422
N e w J . C h e m . , 2 0 0 4 , 2 8 , 1 4 2 0 – 1 4 2 2