Enhanced rate and selectivity by carboxylate salt as a basic cocatalyst in chiral N-heterocyclic carbene-catalyzed asymmetric acylation of secondary alcohols

Article abstract of DOI:10.1021/ja4055838

The rate and enantioselectivity of chiral NHC-catalyzed asymmetric acylation of alcohols with an adjacent H-bond donor functionality are remarkably enhanced in the presence of a carboxylate cocatalyst. The degree of the enhancement is correlated with the basicity of the carboxylate. With a cocatalyst and a newly developed electron-deficient chiral NHC, kinetic resolution and desymmetrization of cyclic diols and amino alcohols were achieved with extremely high selectivity (up to s = 218 and 99% ee, respectively) at a low catalyst loading (0.5 mol %). This asymmetric acylation is characterized by a unique preference for alcohols over amines, which are not converted into amides under the reaction conditions.

Full text of DOI:10.1021/ja4055838

Communication
pubs.acs.org/JACS
Enhanced Rate and Selectivity by Carboxylate Salt as a Basic
Cocatalyst in Chiral N‑Heterocyclic Carbene-Catalyzed Asymmetric
Acylation of Secondary Alcohols
Satoru Kuwano, Shingo Harada, Bubwoong Kang, Raphael Oriez, Yousuke Yamaoka, Kiyosei Takasu,*
̈
and Ken-ichi Yamada*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
the mixture. After 8 h, ester (+)-4b was produced in 46% yield
ABSTRACT: The rate and enantioselectivity of chiral
with 80% ee, and enantiomerically enriched (−)-2b (68% ee)
was recovered in 54% yield [selectivity factor (s)16 = 18] (Table
NHC-catalyzed asymmetric acylation of alcohols with an
adjacent H-bond donor functionality are remarkably
enhanced in the presence of a carboxylate cocatalyst.
The degree of the enhancement is correlated with the
basicity of the carboxylate. With a cocatalyst and a newly
developed electron-deficient chiral NHC, kinetic resolu-
tion and desymmetrization of cyclic diols and amino
alcohols were achieved with extremely high selectivity (up
to s = 218 and 99% ee, respectively) at a low catalyst
loading (0.5 mol %). This asymmetric acylation is
characterized by a unique preference for alcohols over
amines, which are not converted into amides under the
reaction conditions.
1, entry 1). The independence of the s value from the conversion
guaranteed its relevance in evaluating the selectivity [see the
Supporting Information (SI)]. When α-bromo aldehyde 3b was
used in lieu of 3a, the reaction proceeded slightly faster (54%
conv. after 6 h) with a similar level of selectivity (s = 20) (entry
2). Surprisingly, using α-benzoyloxy aldehyde 3c accelerated the
reaction (51% conv. after 3 h) despite the inferior leaving-group
ability of benzoate, and to our delight, the selectivity was also
improved (s = 29) (entry 3).
We speculated that the liberated benzoate might be
responsible for the observed improvement and therefore
conducted the reaction with 3b in the presence of potassium
benzoate. The reaction was markedly accelerated. The selectivity
was the same (s = 29), but the conversion reached 43% after only
15 min (entry 4). The same result was obtained when potassium
benzoate was generated in situ from 1:1 benzoic acid/K3PO4
(entry 5). Consequently, benzoates with different basicities were
tested with the in situ generation protocol. As shown in entries
5−7, the more basic the utilized benzoate,17 the more enhanced
the rate and selectivity. After only 2 min, 47% conversion was
accomplished with high selectivity (s = 39) using 4-
dimethylaminobenzoate (entry 7). These results indicate that
the in situ-generated carboxylate acts as a base.
Modification of the chiral NHC further improved the
selectivity. After screening NHCs (see the SI), we found that a
new NHC derived from precursor 1b bearing a Br atom on the
indane moiety gave better results (40% conv. after 1 min, s = 62;
entry 8). Finally, the NHC derived from 1c bearing a nitro group
gave the best result, and ( )-2b was resolved with a much higher
selectivity (s = 85; entry 9). Although it is known that the steric
and electronic properties of the N-aryl groups significantly
influence the catalytic ability of NHCs,18 to the best of our
knowledge, this is the first example showing that the catalytic
ability of chiral triazolylidene-type NHCs can be tuned by
modifying the remote indane moiety.19
nzymes are biological catalysts that promote chemical
Etransformations in living organisms under mild conditions.
These transformations are achieved by cooperative functions of
amino acid residues, which may be acidic, basic, or nucleophilic,
located in proper positions. In artificial catalysis, achiral additives
occasionally serve as cocatalysts that cooperatively function to
assist the asymmetric catalysts and increase the efficiency.1 N-
Heterocyclic carbenes (NHCs) have recently emerged as useful
organocatalysts. NHCs have been utilized in various trans-
formations2 as catalysts for umpolung of aldehydes,3 generation
of activated esters via redox of aldehydes,4 and activation of
alcohols as a general base.5 Herein we report that carboxylate
salts work as a Brønsted base cocatalyst and enhance the rate and
selectivity of NHC-catalyzed asymmetric acylation of alcohols.
Kinetic resolution of racemic secondary alcohols via
enantioselective acylation is an important process in synthetic
chemistry.6 Many artificial catalysts7 and enzymatic methods8
have been developed for this purpose. Although numerous
methods to kinetically resolve alcohols via enantioselective
acylation are already available, when we initiated this study, an
efficient example of NHC-catalyzed redox acylation had yet to be
reported.9−12 To further extend our previous study,13 we
investigated the kinetic resolution of relatively unexplored
important chiral building blocks, trans-cycloalkane-1,2-diols.14,15
A mixture of chiral NHC precursor 1a (10 mol %), racemic
trans-1,2-diol ( )-2b, and K3PO4 (1.1 equiv) in chloroform was
stirred for 10 min at room temperature to generate the chiral
NHC, and then α-chloro aldehyde 3a (0.8 equiv) was added to
Among the tested bases (see the SI), 1,8-bis(dimethylamino)-
naphthalene (proton sponge) was the best, providing sufficient
selectivity (s = 115) with only 0.1 mol % 1c and 0.1 equiv of the
carboxylate additive (entry 10). Lowering the temperature
Received: June 4, 2013
Published: July 17, 2013
© 2013 American Chemical Society
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Communication
Table 1. Optimization of the Reaction Conditions
further improved the selectivity (s = 193 at 0 °C, s = 239 at −20
°C) at the cost of the catalyst loading (entries 11 and 12).
Nevertheless, this high turnover number is a remarkable contrast
to those of already-known organocatalyses, which typically
require >1 mol % and sometimes 10−20 mol % catalyst.20
Next, other cyclic diols were applied to the reaction (Table 2).
Six- to eight-membered cycloalkanediols ( )-2b−d were
acylated with high selectivities (s = 149−218; entries 2−4). It
is noteworthy that the highest selectivity to date (s = 18),
although lower than for the other substrates, was observed in the
resolution of cyclopentanediol ( )-2a (entry 1).14f Cyclohexene
derivative ( )-2e was also resolved with high selectivity (s = 136;
entry 5). Almost optically pure diols (−)-2b−e (>99% ee) were
easily obtained when the reaction exceeded 50% conversion
(entries 6−9). Because of the high selectivity, in addition to the
alcohols, the esters (+)-4, which could be hydrolyzed to the
antipodes of the recovered alcohols, were obtained with high
optical purities (97−98% ee) in lower conversion (41−43%). It
is noteworthy that the reaction quantitatively gave 2 and 4
without the formation of byproducts.
Table 2. Kinetic Resolution of Diols 2
The utility of the reaction was highlighted by the multigram-
scale availability of optically pure (−)-2e, which could be
converted into 5, a known intermediate21 of antiflu drug
oseltamivir (Scheme 1). The two hydroxy groups were replaced
by azide groups through a triflate in 72% yield with inversion of
the stereochemistry. Reduction of the azides followed by
protection with Boc groups gave 5 in 69% yield without
racemization.
It was reported that acylazoliums, the acylating intermediate in
this reaction, strongly prefer acyl transfer to alcohols rather than
amines, resulting in selective O-acylation in the presence of free
amine.13,22 To see whether the reaction can enjoy the benefits of
this interesting selectivity, it was tested in the presence of
dibenzylamine (Scheme 2). Although the pKa values of the
indicated that the amine should mainly exist as the free amine, the
reaction of ( )-2b proceeded without interference of the amine
to give almost the same results (42% conv. after 8 h, s = 203) as in
the absence of the amine (43% conv. after 8 h, s = 218; Table 2,
entry 2) along with quantitative recovery of the amine.
The following observations suggested that the carboxylate
additive is involved in the stereodetermining transition state.
23
+
conjugate acids (Bn2NH2 , 7.7; proton sponge·H+, 12.1)
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Communication
On the basis of the above speculation, we hypothesized that
the reaction would work well with alcohols bearing an adjacent
hydrogen-bond donor other than a hydroxyl group. Indeed, 2-
aminocycloalkanols 7 were also good substrates.25,26 The six- and
seven-membered-ring substrates ( )-7b and -7c gave good
yields (46−48%) of the corresponding esters (+)-8b and -8c
with high selectivities (94−95% ee) and optically pure amino
alcohols (−)-7b and (+)-7c (>99% ee), respectively, by
modulation of the conversion (Table 3). Moreover, this
methodology was applicable to the desymmetrization of meso-
diol 9 to give optically pure 10 (>99% ee) in 98% yield even at
ambient temperature (Scheme 4).
Scheme 1. Formal Synthesis of Oseltamivir from (−)-2e
Scheme 2. Enantio- and Chemoselective O-Acylation in the
Presence of Free Amine
Table 3. Kinetic Resolution of Amino Alcohols 7
When the reaction of Table 2, entry 2 was conducted without the
addition of the carboxylic acid, both the rate and selectivity
dramatically decreased (conv. after 8 h from 42% to 23%; s from
218 to 55). Furthermore, the absolute configuration of the chiral
carboxylate additive influenced the enantioselectivity of the
acylation. Relative to the reaction without an additive (s = 20;
Table 1, entry 2), when potassium (R)- or (S)-O-methylmande-
late was used in lieu of benzoate, the S enantiomer improved the
selectivity (s = 26) while the antipode did not (s = 18).
On the basis of these results, the geometry of the possible
transition state was calculated at the B3LYP/6-31G** level of
theory (Figure 1). The carboxylate additive serves as a general
Scheme 4. Desymmetrization of meso-Amino Diol
Figure 1. Perspective view of the calculated transition state for the fast-
reacting enantiomer of 2b (H atoms of the C−H bonds have been
omitted for clarity).
In conclusion, we have developed highly enantioselective
kinetic resolution and desymmetrization of secondary alcohols
possessing an adjacent hydrogen-bond donor using a newly
developed NHC bearing a nitro group on the indane moiety. The
rate and selectivity are markedly enhanced by the presence of a
carboxylate cocatalyst, which likely works as a base to facilitate
the C−O bond-forming step. The compatibility with a free
amino functionality is an amazing characteristic that distin-
guishes this asymmetric acylation from other methods. Details of
the carboxylate effects are currently under investigation in our
laboratory.
base to deprotonate the hydroxyl group, creating a C−O bond.
The other hydroxy group of the diol stabilizes the transition state
by hydrogen bonding with the carboxylate (O···H−O = 1.853
Å). The acylation of racemic monomethyl ether ( )-6 without
an additional hydrogen-bond donor did not proceed, and ( )-6
was recovered in 82% yield after 24 h (Scheme 3). The
Scheme 3. Importance of the Adjacent H-Bond Donor
ASSOCIATED CONTENT
■
S
* Supporting Information
Procedures and additional data. This material is available free of
charge via the Internet at http://pubs.acs.org.
plausibility of this model was also supported by the reasonable
free energy difference between the transition states of the fast-
and slow-reacting enantiomers of 2b (ΔΔG⧧ = 2.55 kcal/mol,
corresponding to s = 73 at 25 °C). To the best of our knowledge,
this is the first report where a carboxylate anion works as a
Brønsted base cocatalyst to enhance the selectivity of asymmetric
NHC catalysis.24
AUTHOR INFORMATION
■
Corresponding Author
kay-t@pharm.kyoto-u.ac.jp; yamak@pharm.kyoto-u.ac.jp
Notes
The authors declare no competing financial interest.
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Journal of the American Chemical Society
Communication
diacylation). (b) Naemura, K.; Fukuda, R.; Murata, M.; Konishi, M.;
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ACKNOWLEDGMENTS
■
We thank JSPS [Grant-in-Aid for Young Scientist (B)], MEXT
(Platform for Drug Design, Discovery and Development),
Uehara Memorial Foundation, and Takeda Science Foundation
for financial support.
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