Highly diastereoselective esterification of ketenes generated in situ from acyl chlorides with (R)-pantolactone derivatives

Article abstract of DOI:10.1002/ejoc.201301383

Our mechanistic investigations have revealed that Et₃N is a key requirement for the highly diastereoselective formation of esters from the corresponding acyl chlorides with (R)-pantolactone via ketene-derived complexes. Furthermore, we have discovered that (R)-N-benzyl-pantolactam is a more effective chiral alcohol than (R)-pantolactone for the esterification of in situ generated ketenes. Ketene esterification with (R)-pantolactone derivatives is a powerful synthetic method for the synthesis of chiral α-arylpropionic acids. Our mechanistic investigations have revealed that Et₃N is a key requirement for the predominant formation of ketenes from acyl chlorides, and (R)-N-benzylpantolactam was a much more effective chiral auxiliary.

Full text of DOI:10.1002/ejoc.201301383

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301383
Highly Diastereoselective Esterification of Ketenes Generated In Situ from
Acyl Chlorides with (R)-Pantolactone Derivatives
Takafumi Yamagami,*[a] Masanori Hatsuda,[b] Masayuki Utsugi,[a] Ryo Kobayashi,[a] and
Yasunori Moritani[a]
Keywords: Asymmetric synthesis / Chiral auxiliaries / Esterification / Hydrogen bonds / Ketenes
Our mechanistic investigations have revealed that Et3N is a
key requirement for the highly diastereoselective formation
of esters from the corresponding acyl chlorides with (R)-
pantolactone via ketene-derived complexes. Furthermore,
we have discovered that (R)-N-benzyl-pantolactam is a more
effective chiral alcohol than (R)-pantolactone for the esterifi-
cation of in situ generated ketenes.
Introduction
Optically active α-arylpropionic acids and their deriva-
tives are versatile chiral building blocks in the synthesis of
pharmaceuticals.[1] In 1989 Larsen et al. reported a synthe-
sis of an α-arylpropionic acid class of nonsteroidal anti-
inflammatory drugs (ibuprofen and naproxen) by asymmet-
ric esterification of ketenes prepared in situ from the corre-
sponding racemic carboxylic acids with (R)-pantolactone
[Equation (1)].[2,3] Since then, various methods for ketene
esterification have been reported; however, few chiral
alcohols other than (R)-pantolactone effectively undergo
asymmetric addition to ketenes.[3,4] Thus, (R)-pantolactone
is still used as a potent auxiliary for the preparation of chi-
ral α-arylpropionic acids by ketene esterification followed
by hydrolysis, with studies revealing that the stereoselecti-
vity of the process is strongly influenced by the ketene in-
volved.[3,5] Although optimization by the random screening
of Larsens’ conditions can enhance the (R)-pantolactone
selectivity, to date, the critical factor influencing the selec-
tivity of the reaction is unclear. In this context, we describe
mechanistic insights into the diastereoselective formation of
esters derived from ketenes and (R)-pantolactone, high-
lighting the fact that Et3N is a key to high diastereoselectiv-
ity. We also report an excellent approach to the asymmetric
synthesis of α-arylpropionic acids by using (R)-N-benzyl-
pantolactam.
(1)
Results and Discussion
The asymmetric synthesis of (R)-2-[4-(cyclopropylsulf-
onyl)phenyl]-3-(tetrahydropyran-4-yl)propionic acid [(R)-
1a; Scheme 1] has been achieved by ketene esterification
using (R)-pantolactone.[6,7] Our optimized conditions, in
which Et3N was used instead of Me2NEt, gave the ester
with higher diastereoselectivity (–10 °C, 91:9 dr; –40 °C,
94:6 dr; –78 °C, 97:3 dr); however, the selectivity was clearly
lower than that obtained with nonfunctionalized com-
pounds (up to Ͼ99:1 dr).[2] To elucidate the factors in-
fluencing the stereoselectivity of the synthesis of ester
(R,R)-3a, we studied the reactions of a deuterium-labeled
substrate in the presence of Et3N (Table 1).
[a] Process Chemistry Research Laboratories, CMC Division,
Mitsubishi Tanabe Pharma Corporation,
3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
E-mail: yamagami.takafumi@mk.mt-pharma.co.jp
http://www.mt-pharma.co.jp
[b] CMC Strategy & Planning Department, CMC Division,
Mitsubishi Tanabe Pharma Corporation,
3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301383.
Scheme 1. Asymmetric synthesis of (R)-1a.
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SHORT COMMUNICATION
Table 1. Deuterium-labeling experiments.[a]
showed no selectivity with rac-2b, gave the ester with signifi-
cant selectivity (Entry 4). These results indicate that the
highly selective formation of (R,R)-3b from rac-2b with
Et3N is achieved largely by the conversion of acyl chlorides
into ketenes, whereas less bulky Me2NEt and less basic,
nucleophilic pyridine tend to convert the acyl chloride into
an activated acylammonium salt, in whole or in part. Thus,
the selectivity for (R,R)-3b from rac-2b by using Me2NEt
or pyridine was lower than that achieved with isolated ket-
ene 4b (Scheme 2). Unfortunately, the use of Et3N·HCl led
to a decrease in yield and selectivity, which explains that
Et3N·HCl has little effect on the reaction progress (En-
try 5).[11,12] The formation of small amounts of ester would
have indicated that a portion of Et3N·HCl dissociates to
release the free amine, which would function as a catalyst
to promote the reaction. In contrast, treatment of (R)-pan-
tolactone with NaH and Et3N·HCl facilitated diastereo-
Entry
X
Y
T [°C] Time [h]
dr[b] (Yield [%])[b]
Y-(R,R)-3a
X-(R,R)-3a
1
2
H
H
H
D[c] –10
D[c] –80
D[c] –10
2
2
12
16
17:1 (83)
Ͼ99:1[d] (78)
6:1 (61)
3:1 (7)
3:1 (7)
2:1 (24)
2.4:1 (16)
3[e]
4[f] D[g]
H
–10
16:1 (39)
[a] Et3N was added to a rac-2a solution at –10 °C. After stirring
the mixture for 0.5 h, a solution of (R)-[D]pantolactone was added
dropwise at –10 or –80 °C. [b] Determined by 1H NMR spec-
1
troscopy. [c] 97% D. [d] (S,R)-[D]3a was not detected by H NMR
spectroscopy. [e] NaH and 15-crown-5 were added to a mixture of selective esterification, although the selectivity was lower
(Entry 6),[13] which indicates that the activation of (R)-pan-
rac-2a and Et3N in toluene. After stirring the mixture for 1 h, a
solution of (R)-[D]pantolactone was added dropwise at –10 °C. [f]
tolactone is essential for the reaction and demonstrates that
Et3N was added to a solution of rac-[D]2a and (R)-pantolactone
an alkoxide path via the enolate is not very highly selective.
at –10 °C. [g] 96% D. cPr = cyclopropyl, 4-THP = tetrahydro-2H-
The decrease observed in selectivity in Entries 4 and 6 is
likely due to a loss of hydrogen-bonding interactions be-
tween the alcohol of (R)-pantolactone and Et3N in the
pyran-4-yl.
When acyl chloride rac-2a was treated with deuterium-
labeled (R)-pantolactone (97% D) at –10 °C in toluene,
deuteriated ester (R,R)-[D]3a with higher stereoselectivity
and a small amount of protonated ester (R,R)-3a with lower
selectivity were obtained (Entry 1).[8] Thus, the pantolact-
onyl ester is formed highly stereoselectively mainly because
of selective proton transfer from the alcohol, but the degree
of selectivity is likely limited by another proton source
other than the alcohol. A lower temperature enhanced the
stereoselectivity of the protonation by the alcohol proton
and gave a small amount of (S,R)-[D]3a; however, it did not
suppress protonated ester formation (Entry 2). To suppress
the participation of another proton, that is, the one derived
by dehydrochlorination of the acyl chloride, we treated the
reaction mixture with NaH and 15-crown-5 as well as (R)-
[D]pantolactone (Entry 3). This deprotonation led to a re-
duction of the ratio of the ester protonated by (R)-pantolact-
one.[9,10] However, when the acyl chloride with deuterium
at the α-carbon atom (rac-[D]2a, 96% D) was treated with
(R)-pantolactone, the ester was protonated by the alcohol
with almost the same selectivity as observed for the forma-
tion of the deuteriated ester (Entry 1), although its yield
was lower than that of the unlabeled rac-2a (Entry 4). These
results indicate that the acidity of the α-position of rac-2a
and participation of the α-proton affect the diastereoselec-
tive formation of ester (R,R)-3a derived from acyl chloride
and (R)-pantolactone in the presence of Et3N.
Table 2. Esterification of isolated ketene with (R)-pantolactone.[a]
Entry
Additive
Yield [%][b]
dr[c]
1
2
3
none
Et3N
Me2NEt
pyridine
Et3N·HCl
Et3N·HCl
Ͻ1[c]
87 (88)[d]
90 (85)[d]
51 (83)[d]
8
1.2:1
49:1 (24:1)[d]
49:1 (1.4:1)[d]
6:1 (1:1)[d]
24:1
4
5
6[e]
64
6:1
[a] An (R)-pantolactone solution was added dropwise to a mixture
of 4b and additive in toluene at –10 °C. [b] Isolated yield based on
1
4b. [c] Determined by H NMR spectroscopy. [d] Values in paren-
theses are results obtained with 4b prepared in situ from acyl chlor-
ide rac-2b with additive (2 equiv.). [e] NaH was added to an (R)-
pantolactone solution. After stirring the mixture for 1 h, 4b and
Et3N·HCl were added stepwise at –10 °C.
Use of an isolated ketene as a substrate instead of one
generated in situ revealed the factors influencing the selec-
tivity (Table 2). Use of nonfunctionalized ketene 4b without
an amine gave only a small amount of ester (R,R)-3b with
low selectivity (Entry 1). Addition of tertiary trialkylamines
(Et3N or Me2NEt) gave the ester with high diastereoselec-
Scheme 2. Proposed mechanism for diastereoselective esterification
tivity (Entries 2 and 3). Even sp2-hybridized pyridine, which via activated species derived from acyl chloride.
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Diastereoselective Esterification of Ketenes
transition state.[14] Cannizzaro and Houk used a computa- (Scheme 3).[15] Thus, the reaction conditions promoting the
tional approach to predict that highly stereo- dissociation of hydrogen bonds in the transition state (i.e.,
selective tautomerization to an ester can be achieved the use of a less basic, nucleophilic amine, alkoxide addition
through a high rotational barrier for the conformational via an enolate, or a change in the polar solvent)[16] would
equilibrium between ketene acetals A and B derived from lower the rotational barrier energy to promote equilibration
a
ketene and an (R)-pantolactone–amine complex of the two ketene acetals, thereby resulting in decreased
selectivity. This hypothesis suggests that the low diastereo-
selectivity for ester (R,R)-3a protonated by the alcohol is
due to weak hydrogen-bonding interactions because of the
low electron density of the oxygen atoms in a ketene acetal
with an electron-withdrawing sulfone moiety on the aryl
ring.
To enhance significantly the hydrogen-bonding interac-
tions of the oxygen atoms of the ketene acetal, we prepared
(R)-N-benzylpantolactam, which has an amidic carbonyl
moiety with a stronger proton affinity than (R)-panto-
lactone, as a chiral auxiliary. This auxiliary gave the corre-
sponding ester (R,R)-5a from rac-2a with 98:2 dr in 88%
yield even at –10 °C (Table 3, Entry 1). This auxiliary also
worked well for nonfunctionalized acyl chloride rac-2b and
other functionalized acyl chlorides, (S)-2c prepared from
naproxen, ring-fused rac-2d, and rac-2e, giving the corre-
sponding esters (R,R)-5b–5e (Entries 2–5) with higher dia-
stereoselectivities than those obtained from (R)-pantolact-
one. Furthermore, ester (R,R)-5a was hydrolyzed at –10 °C
without epimerization/racemization with lithium peroxide
to give (R)-1a with a 98:2 er in 95% yield.[17,18]
Scheme 3. Proposed mechanism for stereoselective formation of
ketene acetals through hydrogen bonding.
Table 3. Diastereoselective esterification of ketenes prepared in situ.
Conclusions
We have elucidated that Et3N as base is a key for the
highly diastereoselective formation of esters from the corre-
sponding acyl chlorides with (R)-pantolactone via ketene-
derived complexes. Furthermore, we have discovered that
(R)-N-benzylpantolactam is a more effective chiral auxil-
iary for the asymmetric synthesis of α-arylpropionic acids.
Experimental Section
General Procedure for the Synthesis of Esters (R,R)-3 and (R,R)-5
Procedure a: SOCl2 (1.3 equiv.) was added to a solution of carb-
oxylic acid 1 and Et3N or DMF (3 mol-%) in toluene at 40 °C.
After stirring for 4 h, the reaction mixture was concentrated under
vacuum. The residue, acyl chloride 2, was dissolved in toluene.
Et3N (2.0 equiv.) was added to the solution, and the resulting mix-
ture was stirred at –10 °C for 0.5 h. A solution of (R)-pantolactone
(1.3 equiv.) or (R)-N-benzylpantolactam (1.0 equiv.) in toluene was
added dropwise to the yellow solution at –10 °C over 20 min. After
stirring at –10 °C for 2 h, citric acid and H2O were added to the
reaction solution. After warming to 25 °C, the resulting solution
was separated. The organic layer was washed with 10% aq. NaCl,
dried with MgSO4, filtered, and concentrated under vacuum. The
residue was purified by chromatography on silica gel with EtOAc/
n-hexane (1:3 Ǟ 3:2) to give ester (R,R)-3 or (R,R)-5.
1
[a] Determined by H NMR spectroscopy. [b] Isolated yield based
on 2. [c] Et3N was added to a solution containing 2 and (R)-pantol-
actone or (R)-N-benzylpantolactam at –10 °C. [d] Et3N was added
to a solution of 2 at –10 °C. After stirring the reaction mixture for
0.5 h, an (R)-pantolactone or (R)-N-benzylpantolactam solution
was added dropwise to a mixture of 2 and Et3N in toluene at
–10 °C. [e] (S,R)-5 was not detected by H NMR spectroscopy. [f]
THF was used as the solvent instead of toluene. Bn = benzyl.
Procedure b: SOCl2 (1.3 equiv.) was added to a solution of carbox-
ylic acid 1 and Et3N or DMF (3 mol-%) in toluene at 40 °C. After
stirring for 4 h, the reaction mixture was concentrated under vac-
uum. The residue, acyl chloride 2, and (R)-pantolactone (1.3 equiv.)
1
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T. Yamagami, M. Hatsuda, M. Utsugi, R. Kobayashi, Y. Moritani
SHORT COMMUNICATION
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or (R)-N-benzylpantolactam (1.0 equiv.) were dissolved in toluene.
Et3N (2.0 equiv.) was added to the solution, and the resulting mix-
ture was stirred at –10 °C for 2 h. Citric acid and H2O were added
to the reaction solution. After warming to 25 °C, the resulting solu-
tion was separated. The organic layer was washed with 10% aq.
NaCl, dried with MgSO4, filtered, and concentrated under vacuum.
The residue was purified by chromatography on silica gel with
EtOAc/n-hexane (1:3 Ǟ 3:2) to give ester (R,R)-3 or (R,R)-5.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and 1H and
13C NMR spectra of the products.
Acknowledgments
[8] Changing the solvent to THF or MeCN decreased the selectiv-
ity of (R,R)-[D]3a (THF: 11:1 dr, 87% yield; MeCN: 5:1 dr,
51% yield).
We are grateful to Prof. Dr. D. G. Blackmond for useful comments
and suggestions during the initial research on this mechanism.
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[10] Surprisingly, excess NaH (2 equiv.) reduced the ratio of the es-
ter (1:2 dr, 39% yield).
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[12] Use of Me3N·HCl or pyridine·HCl instead of Et3N·HCl gave
ester (R,R)-3b with lower selectivity (Me3N·HCl: 19:1 dr, 24%
yield; pyridine·HCl: 2.4:1 dr, 20% yield).
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[13] Use of free Et3N with NaH instead of Et3N·HCl gave a mix-
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[14] For a recent book on hydrogen bonding, see: P. M. Pihko, Hy-
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[16] Changing the solvent to THF slightly contributed to the selec-
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of polar CH3CN significantly decreased its selectivity (6:1 dr,
89% yield).
[17] (R)-N-Benzylpantolactam was recovered from the reaction
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[59% yield based on (R,R)-5a, unoptimized].
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Received: September 11, 2013
Published Online: October 9, 2013
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Eur. J. Org. Chem. 2013, 7467–7470