Improved synthesis of γ-lactones from cyclopropyl cyanoesters

Article abstract of DOI:10.1080/00397911.2010.501472

Cyclopropyl cyanoesters 2 were reliably converted to c-lactones 4 on treatment with aqueous sulfuric acid. The cyanoesters could be easily prepared from ketones or aldehydes in two steps, making this process particularly attractive from an efficiency standpoint. Copyright

Full text of DOI:10.1080/00397911.2010.501472

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Improved Synthesis of γ-Lactones from
Cyclopropyl Cyanoesters
Nandini C. Patel a , Jacob B. Schwarz a , Khondaker Islam a , Whitney
Miller a , Tuan P. Tran a & Yunjing Wei a
a Pfizer Global Research and Development, Groton, Connecticut,
USA
Version of record first published: 25 May 2011.
To cite this article: Nandini C. Patel , Jacob B. Schwarz , Khondaker Islam , Whitney Miller , Tuan P.
Tran & Yunjing Wei (2011): Improved Synthesis of γ-Lactones from Cyclopropyl Cyanoesters, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:15, 2209-2215
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Synthetic Communications1, 41: 2209–2215, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.501472
IMPROVED SYNTHESIS OF c-LACTONES FROM
CYCLOPROPYL CYANOESTERS
Nandini C. Patel, Jacob B. Schwarz, Khondaker Islam,
Whitney Miller, Tuan P. Tran, and Yunjing Wei
Pfizer Global Research and Development, Groton, Connecticut, USA
GRAPHICAL ABSTRACT
Abstract Cyclopropyl cyanoesters 2 were reliably converted to c-lactones 4 on treatment
with aqueous sulfuric acid. The cyanoesters could be easily prepared from ketones or alde-
hydes in two steps, making this process particularly attractive from an efficiency standpoint.
Keywords Condensation; cyclopropyl cyanoester; Knoevenagel; lactone; ring expansion
INTRODUCTION
c-Lactones constitute a class of naturally occurring substances that continue to
be the target of important advances in synthetic methodology.[1] During the course
of an effort directed toward the preparation and biological testing of a series of
cyclopropyl b-amino acids 3, we relied on the use of cyanoester intermediates 2.[2]
The cyanoesters were particularly valuable from an efficiency standpoint in that they
could be obtained from ketones and aldehydes 1 in two steps via a facile nitroalkane
cyclopropanation process.[3] Herein we report that the versatile cyclopropyl cyanoe-
sters 2 may also be reliably converted in a single step to c-lactones of type 4.
To illustrate this process, 6-oxa-spiro[2.5]octane cyanoester was fashioned
from ketone 5a using standard conditions.[2] Hence, Knoevenagel condensation fol-
lowed by cyclopropanation with nitromethane proceeded smoothly to afford cya-
noester 2a in 85% yield (Scheme 1). While attempting to carry out a hydrolysis
reaction of 2a with aqueous mineral acid, moderate conversion to a product that
1
no longer contained the cyclopropane ring by H NMR was observed. Analytical
data for the compound suggested the formation of lactone 4a. To confirm our
Received November 22, 2009.
Address correspondence to Nandini C. Patel, Pfizer Global Research and Development, Eastern Point
Road, Groton, CT 06340, USA. E-mail: nandini.c.patel@pfizer.com and Jacob B. Schwarz, Genentech,
1 DNA Way, South San Francisco, CA 94080-4990 (present address). E-mail: schwarz.jacob@gene.com
2209

2210
N. C. PATEL ET AL.
Figure 1. c-Lactone synthesis from cyclopropyl cyanoesters.
hypothesis, cyclohexyl derivative 4b was prepared through the same process and was
consistent with literature data.[4] With the lactone products correctly identified, we
then sought to gain some mechanistic insight and subsequently evaluate the scope
and generality of the process.
A survey of the literature led us to a report describing protolysis of cyclopro-
panes containing geminal electronegative substituents (Scheme 2).[5] They found that
treatment of gem-dimethyl cyanoester 2f with anhydrous perchloric acid afforded a-
carboxylactone 7 (23%), a-cyanolactone 8 (19%), as well as recovered starting
material (48%). In addition, treatment of 2f in neat trifluoracetic acid (TFA) at ambi-
ent temperature for 5 days resulted in no reaction, serving to underscore the stability
of cyanoesters 2 to highly acidic media. However, when they treated diester substrate
9 under the same HClO4 conditions, it was readily converted to 7. In fact, others had
=
shown that the diacid analog of 9 readily isomerized to the a-acid of 7 (X CO2H) in
H2O with t1=2 ꢀ 3 h.[6] Although decarboxylation of esters of type 7 have been shown
to proceed in excellent yield,[7] obtaining unsubstituted lactones of type 4 would
Scheme 1. Three step synthesis of lactones 4a,b from ketones 5a,b.

SYNTHESIS OF LACTONES FROM CYCLOPROPYL
2211
Scheme 2. Formation of carboethoxy- and cyano-lactones 7 and 8.
nevertheless add another step to the sequence.[8] Hence, the gain in operational
efficiency, coupled with the hazards associated with the use of perchloric acid,
implied that the sulfuric acid method outlined in Scheme 1 provides a distinct advan-
tage over the existing literature processes.
Examples of spirocyclic cyclopropyl cyanoester cleavage to the c-lactone pro-
ducts using sulfuric acid are shown in Table 1 (entries a–e). In all cases, the yield of
isolated lactone product exceeded 35%. From liquid chromatographic=mass spectro-
metric (LC=MS) analysis of the reaction progress, the final decarboxylation event
was rate limiting, and in the case of 1a the a-carboxylic acid lactone was also isolated
as a minor product (14% yield). The hydrolytic ring opening of less highly substi-
tuted cyclopropanes derived from aldehydes also proceeded to afford lactones, albeit
in reduced yield compared to the spiro systems (entries f–g). In addition to volatility,
the lower propensity to form carbocationic intermediates may have contributed to
the diminished yields obtained.
Given the efficiency with which diester 9 was converted to a-methoxycarbonyl-
lactone 7, the cyanoester and diester processes were compared holistically starting
from the ketone or aldehyde precursor 1. The Knoevenagel process with malonate
to produce the unsaturated diester is routinely promoted by a Lewis acid (e.g.,
ZnCl2=Ac2O[9] or stoichiometric TiCl4[10]), and the yields obtained are generally
lower than those for the cyanoacetate condensation performed with piperidinium
acetate.[11] Once the diester is in hand, cyclopropanation may be performed in the
same fashion as for cyanoester 6[3] or via a bromination and hydride addition
sequence.[12] Alternately, the cyclopropyl diesters may be prepared via transition-
metal-catalyzed diazomalonate addition to a terminal olefin.[13] Owing to the facts
that (1) the cyanoacetate Knoevenagel is catalytic and run in the absence of solvent,
(2) the nitromethane cyclopropanation is robust, and (3) a separate decarboxylation
step is obviated, the cyclopropyl cyanoester process is clearly more efficient (and
green) than that described previously for the diesters=diacids.
In conclusion, we have developed the protolytic cleavage of cyclopropane cya-
noesters into an efficient process that directly affords 5-substituted c-lactones in
moderate yield on treatment with aqueous sulfuric acid. Previously, this process

2212
N. C. PATEL ET AL.
Table 1. Conversion of cyanoesters 2 to c-lactones 4 with H2SO4
Entry
Cyanoester 2
Product 4
Yield (%)a
a
41
b
54
44
36
c
d
e
36
f
19
29
g
aIsolated yields. For procedures, see Experimental section.
was carried out with anhydrous perchloric acid, affording only a poor yield of the
a-ester and a-nitrile substituted lactones. Although perchloric cleavage of related
cyclopropyl diesters was shown to be a more robust process, decarboxylation of
the a-carboxylate would be required to obtain lactones unsubstituted in the
3-position. In addition, cyclopropyl cyanoesters are more efficiently prepared than

SYNTHESIS OF LACTONES FROM CYCLOPROPYL
2213
their diester counterparts, making the present process more attractive and green by
reducing the number of steps as well as eliminating solvent usage.
EXPERIMENTAL
Representative Procedure for Knoevenagel Condensation
Acetic acid (0.15 mL, 2.7 mmol), was added to a mixture of tetrahydro-pyran-
4-one (2.68 g, 26.8 mmol) and ethyl cyanoacetate (2.9 mL, 26.8 mmol) at 0 ꢁC
followed by piperidine (0.27 mL, 2.7 mmol). The ice-water bath was removed, and
2.7 mmol portions each of acetic acid and piperidine were added. The mixture was
stirred 25 min, then partitioned between EtOAc and saturated NaHCO3 (aq). The
phases were separated, and the organic phase was washed with brine, dried
(Na2SO4), and concentrated to provide 5.1 g (98%) of 1-cyano-6-oxa-spiro[2.5]
octane-1-carboxylic acid ethyl ester[15] as a colorless oil. 1H NMR (500 MHz,
CDCl3): d 4.28 (q, J ¼ 7.1 Hz, 2 H), 3.86 (t, J ¼ 5.5 Hz, 2 H), 3.78 (t, J ¼ 5.5 Hz, 2
H), 3.17 (t, J ¼ 5.5 Hz, 2 H), 2.78 (t, J ¼ 5.6 Hz, 2 H), 1.34 (q, J ¼ 7.1 Hz, 3 H).
13C NMR: d 173.66, 161.80, 115.19, 103.70, 68.50, 68.24, 62.21, 36.98, 32.66, 14.28.
Representative Procedure for Cyclopropanation
Nitromethane (3.8 mL, 70.3 mmol) and DBU (2.2 mL, 14.1 mmol) were added
to 1-cyano-6-oxa-spiro[2.5]octane-1-carboxylic acid ethyl ester (2.74 g, 14.1 mmol) in
60 mL acetonitrile and the whole was stirred 16 h at ambient temperature. The mix-
ture was partitioned between EtOAc=1 N HCl (aq). The phases were separated, the
aqueous phase was extracted with EtOAc, and the combined organics were washed
with brine, dried (Na2SO4), and concentrated. The residue was purified by flash
chromatography (20 ! 80% EtOAc=heptane) to afford 2.57 g (87%) of 1-cyano-6-
1
oxa-spiro[2.5]octane-1-carboxylic acid ethyl ester 2a as a colorless oil. H NMR
(500 MHz, CDCl3): d 4.26 (q, J ¼ 7.1 Hz, 2 H), 3.86 (dt, J ¼ 11.4, 3.4 Hz, 1 H),
3.77 (ddd, J ¼ 7.4, 3.9, 3.8 Hz, 1 H), 3.60–3.70 (m, 2 H), 1.92 (dt, J ¼ 17.0, 3.2 Hz,
1 H), 1.71–1.88 (m, 4 H), 1.53 (d, J ¼ 5.1 Hz, 1 H), 1.33 (t, J ¼ 7.2 Hz, 3 H). 13C
NMR: d 165.92, 117.86, 67.27, 67.05, 63.09, 37.08, 34.60, 29.35, 28.39, 24.38,
14.37. MS m=z 209.
Representative Procedure for Lactone Formation
A mixture of 1-cyano-6-oxa-spiro[2.5]octane-1-carboxylic acid ethyl ester 2a
(0.51 g, 2.44 mmol) in 5.0 mL 50% (v=v) aq. H2SO4 was stirred 2 days at 100 ꢁC.
The mixture was cooled and partitioned between EtOAc=water. The phases were
separated, the aqueous phase was extracted with EtOAc, and the combined organics
were dried (Na2SO4) and concentrated. The residue was purified by flash chromato-
graphy (20 ! 80% EtOAc=heptane) to afford 158 mg (41%) of 1,8-dioxa-spiro[4.5]-
decan-2-one 4a as a colorless oil. 1H NMR (400 MHz, CD3OD): d 3.71 (t, J ¼ 5.3 Hz,
4 H), 2.61 (t, J ¼ 8.3 Hz, 2 H), 2.09 (t, J ¼ 8.3 Hz, 2 H), 1.79 (t, J ¼ 5.6 Hz, 4 H). 13
C
NMR: d 177.64, 83.60, 64.26, 36.74, 32.52, 27.83. MS m=z 156. The by-product
2-oxo-1,8-dioxa-spiro[4.5]decane-3-carboxylic acid was also isolated (69 mg, 14%).

2214
N. C. PATEL ET AL.
ACKNOWLEDGMENTS
The authors thank Jennifer Davoren, Amy Dounay, Andrew Flick, Christopher
O’Donnell, and Suvi Simila for helpful suggestions.
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