Kinetic resolution of secondary alcohols using amidine-based catalysts

Article abstract of DOI:10.1021/jo202220x

Kinetic resolution of racemic alcohols has been traditionally achieved via enzymatic enantioselective esterification and ester hydrolysis. However, there has long been considerable interest in devising nonenzymatic alternative methods for this transformation. Amidine-based catalysts (ABCs), a new class of enantioselective acyl transfer catalysts developed in our group, have demonstrated, inter alia, high efficacy in the kinetic resolution of benzylic, allylic, and propargylic secondary alcohols and 2-substituted cycloalkanols, and thus provide a viable alternative to enzymes.

Full text of DOI:10.1021/jo202220x

Article
pubs.acs.org/joc
Kinetic Resolution of Secondary Alcohols Using
Amidine-Based Catalysts
Ximin Li, Hui Jiang, Eric W. Uffman, Lei Guo, Yuhua Zhang, Xing Yang, and Vladimir B. Birman*
Department of Chemistry, Washington University, One Brookings Drive, St. Louis, Missouri 63130, United States
S
* Supporting Information
ABSTRACT: Kinetic resolution of racemic alcohols has been traditionally achieved
via enzymatic enantioselective esterification and ester hydrolysis. However, there has
long been considerable interest in devising nonenzymatic alternative methods for this
transformation. Amidine-based catalysts (ABCs), a new class of enantioselective acyl
transfer catalysts developed in our group, have demonstrated, inter alia, high efficacy
in the kinetic resolution of benzylic, allylic, and propargylic secondary alcohols and
2-substituted cycloalkanols, and thus provide a viable alternative to enzymes.
transfer catalysts. The most successful of these amidine-based
catalysts (ABCs) developed thus far are shown in Figure 1.
KR of secondary alcohols provided both the initial impetus
for the design of this class of catalysts and a convenient context
for their development and exploration of their mechanism of
action.6 In addition to our own efforts in this area, several other
groups have subsequently explored the use of ABCs in this
transformation and made important contributions by broaden-
ing their known substrate scope, establishing new reaction
protocols, and exploring additional variations of the catalyst
design.7−11 Furthermore, we and others have demonstrated the
utility of ABCs in other types of transformations as well, such as
desymmetrization of meso-diols,6g KR of oxazolidinones and
β-lactams via enantioselective N-acylation,12 intramolecular
ketene [2 + 2] and [2 + 4] cycloadditions,13 Steglich re-
arrangement,14,15 KR and DKR of chiral acyl donors via enantio-
selective alcoholysis,16,17 epoxide opening,18 O-silylation,19 and
Michael addition.20
INTRODUCTION
■
Chiral secondary alcohols can be encountered in virtually all
areas of organic chemistry. They are especially broadly repre-
sented among natural products, pharmaceuticals, and synthetic
intermediates. Despite great advances in their enantioselective
synthesis,1 kinetic resolution (KR) of racemates2 remains a
widely used method for their preparation in optically pure form.
Traditionally, this transformation has been accomplished by us-
ing two enantioselective enzymatic methods: esterification and
hydrolysis of the corresponding esters (Scheme 1).3
Scheme 1. Enzymatic Kinetic Resolution of Alcohols
The primary objective of this paper is to provide an overview
of ABC-catalyzed KR of the four main classes of secondary
alcohols explored by our group to date: benzylic, allylic, pro-
pargylic, and β-substituted cycloalkanols. We shall focus on the
key structure−selectivity trends noted in the course of our work
and thereby hopefully give the reader an accurate idea of the
currently known scope and limitations of this methodology.
With this in mind, we have excluded the details of our studies
on the optimization of catalyst design and reaction protocol
and shall concentrate on the results obtained with the most
successful and well-studied catalysts developed in our group
(1−5a) under optimal reaction conditions.
Although both of these methods have been applied suc-
cessfully to many structural classes of alcohols and often exhibit
excellent enantioselectivity, enzymes are less than ideal as
catalysts. One of their most obvious limitations is their
availability in only one enantiomeric form, which requires
identification of a different enzyme and reoptimization of
reaction conditions whenever the enantioselectivity of a given
enzymatic process needs to be reversed. Apart from purely
practical considerations, exclusive dependence on enzymes for
achieving a synthetic transformation is intellectually unsatisfy-
ing. As a result, over the last one and a half decades, many
research groups have been engaged in the development of low
molecular weight enantioselective acylation catalysts that would
be able to serve, inter alia, as an alternative to enzymes in KR of
alcohols.4,5
RESULTS AND DISCUSSION
■
Benzylic Alcohols. Many nonenzymatic enantioselective
acyl transfer catalysts have proved to be effective in the KR of
secondary benzylic alcohols.21 As a result, this transformation
In 2003, our group initiated a research program aimed at
developing a new class of easily accessible enantioselective acyl
Received: November 4, 2011
Published: January 20, 2012
© 2012 American Chemical Society
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Figure 1. Most successful amidine-based catalysts.
has been widely used to test the enantioselectivity of newly de-
signed catalysts. ABCs were no exception. The first successful
catalyst of this class, CF3-PIP 1, demonstrated good to excellent
levels of enantioselectivity with this type of substrates (Scheme 2).6a
or less additive.23 Tetrahydropyrimidine-based catalysts 4 and 5a
were less enantioselective than 2 or 3 when tested in KR of sub-
strates 7 and 12 at room temperature (entries 2e and 6e). Fortu-
nately, they are considerably more active than the latter at low
temperatures, which allows them to achieve quite respectable
results in these cases (entries 2f and 7f). Although we have not
explored systematically the structure−selectivity trends exhibited by
tetrahydropyrimidine-based catalysts 4 and 5a for this class of
substrates, recent studies by Smith et al.9 using catalyst 5b suggest
that they should be largely similar to those noted above.
Scheme 2. Kinetic Resolution of Benzylic Alcohols Using
CF3−PIP 1
Electronic effects of substitution on the aromatic ring have
been explored most systematically using CF3-PIP 1 (Table 2,
entries 1−5). Electron-rich meta-substituents lead to increased
enantioselectivities, while electron-withdrawing groups have the
opposite effect, which is consistent with the expected enhance-
ment of cation−π interactions. Apart from this study, 3,5-
disubstituted alcohol 21, which is valuable as a precursor to
antiemetic drug aprepitant (Emend, Merck & Co.), was resolved
with BTM 3. The lower enantioselectivity obtained in this case,
relative to the unsubstituted alcohol 6 (Table 2, entry 6 vs Table 1,
entry 1c), is also in accord with the trend noted above.
Ortho-substitution has a more dramatic effect on the out-
come of KR. Thus, 1-(o-tolyl)ethanol 22 is resolved with 2−3-fold
higher selectivity factors than the unsubstituted alcohol 6 using
catalysts 1−3 (Table 3, entry 1, vs Table 1, entry 1). Other groups
have also reported that this substrate produces superior results
with other classes of catalysts.24 Increased enantioselectivity is also
observed when the ortho-substituent is a methoxy group, especially
when using catalyst 2 (entry 2a). Consistent with this trend,
another ortho-substituted alcohol, 1-(1-naphthyl)ethanol 10, is
also resolved with higher enantioselectivities than 6, as observed in
our studies (Table 1, entries 5 vs 1) and those by others.24
In sharp contrast to 22, substitution of both ortho-positions
with methyl groups is highly detrimental: 1-mesitylethanol 24 is
resolved with rather low enantioselectivities by all ABCs tested,
particularly BTM 3 (Table 3, entry 3). It is noteworthy that the
very same substrate was resolved with a record selectivity factor
(s = 390) with Vedejs’ phosphine-based asymmetric acylation
catalyst.5n Furthermore, 1-(2,6-dimethoxyphenyl)ethanol 25
cannot be acylated at all using catalysts 2 and 3 (entry 4).
Nevertheless, 1-(9-anthryl)ethanol 26, in which both ortho-
positions are occupied by fused benzene rings, turns out to be
an excellent substrate for both Cl-PIQ 2 and BTM 3 (entry 5).
In fact, the latter result is twice as high as the only one pre-
viously obtained for this compound.5i,26 Its trifluoromethyl
analog 27, developed by Pirkle et al. as a chiral NMR shift
reagent,27 is also resolved with outstanding enantioselectivity
and unusually short reaction time (entry 6).
The most significant structure−selectivity trends noted with this
catalyst were as follows:
(a) increasing the steric bulk of the alkyl group resulted in higher
selectivity factors22 (cf. Table 1, entries 1a, 2a, 3a, and 4a)
(b) replacing the phenyl group with an aryl containing an
extended π-system led to better enantioselectivities and
higher reaction rates (entries 1a vs 5a and 7a)
(c) cyclic benzylic alcohol 14 reacted very slowly and
without any detectable asymmetric induction (entry 9a)
(d) sterically similar, but fully saturated, substrate 15 failed to
react under the standard conditions (entry 10a)
These observations led us to propose that in the transition
state the benzene ring of the substrate is stacked above the
pyridinium ring of the N-acylated catalyst due to π−π and/or
cation−π interactions. Subsequently, this simplistic transition
state model was analyzed and refined by computational studies
in collaboration with the Houk group6i (Figure 2).
Figure 2. Proposed transition state. Predictive model and geometry
optimized by DFT calculations.
Second-generation catalyst Cl-PIQ 2 developed in the course
of our subsequent studies6b exhibits higher enantioselectivity
and reaction rates than CF3-PIP 1 (Table 1, entries 1−6, b vs a).
The third-generation catalyst BTM 36d is even more
enantioselective, although less active, than 2 (entries 1−6, c,d
vs b). All three imidazoline-based catalysts 1−3, however, usually
display qualitatively similar trends in the KR of benzylic alcohols.
Entries 7 and 8 (vs 5c,d and 6c,d) demonstrate that a combination
of a bulky alkyl group and a polarizable aryl group leads to very
high selectivity factors, suggesting that these two factors are more
Although the effects of polar substituents in the alkyl chain
have not been studied systematically in our group, several
examples provided in Table 4 illustrate that these too can have
a profound influence on reactivity and enantioselectivity. KR
of chlorinated alcohol 28, the key intermediate en route to
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Table 1. KR of Secondary Benzylic Alcohols: Basic Variations
a
b
Conditions: 1.0 equiv of ( )-substrate, 0.75 equiv of (EtCO)2O, 0.75 equiv of i-Pr2NEt, catalyst, CDCl3, unless specified otherwise. Absolute
c
configuration shown refers to the fast-reacting enantiomer of the substrate in reactions catalyzed by (R)-1, 2, 3, or (S)-4 and 5a. (i-PrCO)2O was
used instead of (EtCO)2O. The reaction was carried out in toluene. The reaction was carried out in tert-amyl alcohol/toluene mixture.
d
e
fluoxetine (Prozac, Eli Lilly & Co.) proceeds with lower
enantioselectivity (Table 3, entry 1) than that of the des-chloro
compound 7 (Table 1, entry 2d). Not entirely unexpectedly, a
problem was encountered in the KR of 3-amino alcohols, which
we investigated in the context of a model study leading up to an
asymmetric synthesis of (+) and (−)-lobeline.6g The simplest
member of this series, 29, turned out to undergo rather rapid
uncatalyzed reaction even at 0 °C (Table 4, entry 2a), which,
obviously, reduced the efficacy of BTM, even at a high catalyst
loading (entry 2b). Diastereomeric substrates ( )-sedamine 30
and ( )-allo-sedamine 31, in which the tertiary amino group
forms part of a piperidine ring, also underwent significant
background acylation (entries 3a and 4a). Most intriguingly,
however, a synthetically useful selectivity factor was obtained
in the former case (entry 3b), but not the latter (entry 4b),
despite the fact that the background reaction was, in fact, faster
for 30 than for 31. We attribute these observations to the pres-
ence of a hydrogen bond between the tertiary nitrogen and the
hydroxyl group, which increases the nucleophilicity of the latter.
The geometry of this interaction is obviously important in both
the catalyzed and the uncatalyzed acylations, as suggested by
the significant differences between 29 and its two constrained
analogs 30 and 31. (Figure 3). Substrate 32 is resolved with
Figure 3. Hydrogen bonding in 3-amino alcohols 29−31.
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Table 2. KR of Secondary Benzylic Alcohols: Effects of Meta-
Substituents
Table 3. KR of Secondary Benzylic Alcohols: Effects of
Ortho-Substituents
a,b
See Table 1.
only modest enantioselectivity (entry 5) despite the absence of
a significant background reaction.28 Of course, the limitations
posed by the presence of a tertiary amino group may often be
circumvented synthetically, i.e., by keeping the nitrogen in the
form of amide. Both diastereomeric carbamates 33 and 34
underwent fairly effective KR at room temperature (entries 6
and 7) and could be subsequently reduced to sedamine and
allo-sedamine, respectively.6g However, a more straightforward
solution to this problem would also be desirable. As we dem-
onstrated recently, the use of HBTM-2 5a is advantageous in the
KR of amino alcohol 29 simply because the low temperature at
which this highly active catalyst can operate allows the
uncatalyzed acylation to be effectively suppressed (entries
2c vs 2b).
The KR of heteroaryl alcohols 35 and 36 was investigated
only briefly. The results obtained with Cl-PIQ 2 and BTM 3
were rather modest (entries 8 and 9). While we have made no
attempt at optimization in these cases, a recent study by Shiina
et al.7c has demonstrated that good to excellent enantiose-
lectivities can be obtained in BTM-catalyzed KR of similar
substrates using mixed diphenylacetic−pivalic anhydride as the
acylating agent.
a,b
See Table 1.
successful. The lower rate and enantioselectivity observed in
this case (Table 5, entry 1a), compared with the analogous
reaction of its benzylic analogue 6 (Table 1, entry 1a), was not
surprising. We speculated that, although the new substrate
featured an extended π-system, in the proposed transition state,
most of it was too far away from the pyridinium ring to con-
tribute much to the π-interaction. In an effort to improve the
enantioselectivity in the KR of this class of substrates, we de-
cided to extend the π-system of the catalyst itself and developed
the second-generation catalyst, Cl-PIQ 2 (Figure 4).
Allylic Alcohols. Enantioselective acylation of allylic
alcohols has received much less attention than that of the
benzylic alcohols discussed above.29 Prior to our work, only two
systematic studies in this area were published by Fu30 and by
Vedejs.31,32 Our interest in this class of substrates stemmed
from the realization that π-interactions likely played the key
role in the chiral recognition of benzylic alcohols by CF3-PIP 1.
We were curious whether a double bond adjacent to the
hydroxyl group would also be able to direct chiral recognition.
However, our attempt to achieve KR of the simplest trans-
cinnamyl alcohol 37 using CF3-PIP 1 was only moderately
Figure 4. Rationale for the second-generation catalyst design.
As we had hoped, the new catalyst achieved uniformly higher
reaction rates and enantioselectivities, compared to CF3-PIP 1,
in the KR of all trans-cinnamyl alcohols examined (Table 5).
Available data suggest that increasing the steric bulk of the alkyl
substituent in this category of substrates is not as clearly bene-
ficial for the enantioselectivity as it was in the benzylic series,
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Table 4. KR of Secondary Benzylic Alcohols: Effect of
Heteroatoms in the Ring and on the Alkyl Chain
Table 5. KR of Secondary trans-Cinnamyl Alcohols
a,b
c
See Table 1. The reaction was carried out in toluene.
of alcohol 37 and able to afford the same enantioselectivity at
−40 °C (Table 5, entry 1d).
Later studies also demonstrated that the phenyl substituent
can be replaced with an additional double bond without sig-
nificant loss of enantioselectivity provided that effective con-
jugation is maintained. Thus, the results obtained in the
Cl-PIQ-catalyzed KR of dienyl alcohol 43 are comparable to
those achieved with its cinnamyl analogue 37 (Table 6, entry 1a
vs Table 5, entry 1b), whereas in the case of β-ionol 44 the
enantioselectivity is drastically reduced (Table 6, entry 2a).
Presumably, the steric interactions imposed by the three methyl
groups in 44 force the cyclohexene ring to twist out of
conjugation with the β−γ double bond and interfere with its
approach to the N-acylated catalyst. Unconjugated allylic
alcohols 45 and 46 can also be resolved using Cl-PIQ, although
the selectivity factors are only modest and larger catalyst
loadings are required due to reduced reaction rates (entries 3a
and 4b). Still, π-interactions between the single double bond
and the catalyst evidently play a critical role in the chiral
recognition of these substrates because the fully saturated alco-
hol 15 (Table 1, entries 10b and c) reacts much more slowly
than 46 and displays greatly reduced enantioselectivity.
Interestingly, the beneficial influence of a β-phenyl substituent
is observed in the KR of cis-cinnamyl alcohol 47, even though
it can hardly attain coplanarity with the double bond. In fact,
the selectivity factors obtained with cis-alcohols 47 and 48
(Table 6, entries 5 and 6) are comparable with those obtained
with their trans-counterparts 37 (Table 5, entries 1b and c) and
45 (Table 6, entry 3). The presence of a cis-methyl group in
substrates 49 and 50 apparently slows their acylation, but does
a-c
See Table 1.
and may depend on the substitution on the double bond
(entries 2 vs 1 and 4 vs 3). Overall, it appears that coplanarity
of the benzene ring and the double bond plays an important
role. This is particularly evident in the comparison of selectivity
factors achieved for substrate 41 and its conformationally
restricted analogue 42 (entries 5 and 6). The lower rates and/
or enantioselectivities obtained with alcohols bearing a methyl
group cis- to the phenyl (cf. entries 3 vs 1 and 4 vs 2) may also
be attributed to the same factor.
Contrary to our expectations, the third-generation catalyst
BTM 3, which had displayed far better selectivity factors in the
KR of most types of benzylic alcohols, turned out to be less
suitable for KR of allylic alcohols than Cl-PIQ 2. Not only did it
produce a somewhat lower selectivity factor in the KR of 37
(Table 5, entries 1c vs 1b) but also required extended reaction
time and additional catalyst loading due to the apparent catalyst
deactivation by this substrate (vide infra). Results obtained with
other allylic alcohols are consistent with these observations
(Table 6, entries 1−8, b). On the other hand, the analogous
ring-expanded catalyst HBTM-2 5a is quite active in the KR
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Table 6. KR of Miscellaneous Secondary Allylic Alcohols
Table 7. KR of Propargylic Alcohols
a,b
See Table 1.
not have much effect on the enantioselectivity (cf. entries 7 vs 3
and 8 vs 4).
Propargylic Alcohols. Apart from Fu’s seminal study,33 the
nonenzymatic KR of propargylic alcohols had not been ex-
plored in detail. In 2006, we examined this class of substrates
with the aim of testing the ability of ABCs to “recognize” a
triple bond. BTM proved to be superior to Cl-PIQ and was
adopted for the systematic study of the structure−selectivity
trends. In sharp contrast to the benzylic series (Table 1), in-
creasing the size of the alkyl group α- to the hydroxyl leads to
a decrease in enantioselectivity (Table 7, entries 1−4).
Conjugated propargylic alcohols wherein the alkyne moiety is
substituted with an aryl, alkenyl, alkynyl, or acyl group are
acylated with higher enantioselectivity than their unconjugated
counterparts (cf. entries 1b and 5−7 vs entries 8−10; entry 2 vs
entries 11 and 12). Within the latter category, the enantio-
selectivity drops off with increased steric bulk of the alkyl (or
silyl) substituent, presumably because the latter interferes with
the π-interaction between the substrate and the N-acylated
catalyst in the transition state. All these trends are qualitatively
in line with Fu’s earlier observations. However, the selectivity
factors are uniformly higher than those obtained in his study.
Tetrahydropyrimidine-based catalyst 5a produced a respectable
first result (entry 1c). Its isopropyl analogue 5b was recently
reported by Smith et al. to exhibit even higher enantioselectivity
in the KR of the same substrate.9
a,b
See Table 1, except that the reaction was carried out without adding
c
i-Pr2NEt. The reaction was carried out in toluene.
2-Substituted Cycloalkanols. The structures of the first
three series of substrates examined in this study share a com-
mon pattern: all of them bear an unsaturated moiety, such as an
aryl, alkenyl, or alkynyl group, α- to the hydroxyl group.
Although some structure−selectivity trends and relative perfor-
mance of ABCs varied from series to series, we had every
reason to believe that in all these cases the mechanism of chiral
recognition remained substantially the same and in accord with
our π-interaction hypothesis (Figure 2). Naturally, we wished
to explore the efficacy of ABCs in the KR of structurally
different substrates. With this in mind, we examined the KR of
( )-trans-2-phenylcyclohexanol 63,34 hoping that the aryl ring
at the β-position relative to the hydroxyl might still serve as a
viable recognition element. Imidazoline-based catalysts 2 and
especially 3 produced encouraging selectivity factors in the first
trial, although the reactions were rather slow and required high
catalyst loadings (Table 8, entries 1a and 1b). Under the same
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conditions, tetrahydropyrimidine-based HBTM 4 displayed
much higher reaction rate and somewhat better enantioselec-
tivity (entry 1c). Thankfully, its catalytic activity decreased only
moderately at low temperatures, while the enantioselectivity
increased manifold (entry 1d). Ultimately, this catalyst and its
more active analogue 5a proved to be particularly suitable for
substrate 63 and other 2-arylcycloalkanols (entries 2−5). They
also display modest enantioselectivities in the KR of cyclo-
hexanols bearing an ester or azide moiety at the β-position
(entries 6−8) but are virtually ineffective when the substituent
is an isopropyl group (entry 9). This evidence suggests that
π-interactions are critical for chiral recognition of 2-substituted
cycloalkanols,35 although the geometry of such interactions
would be somewhat different from that of the previously
studied substrates (Figure 5). In addition, rigidity of the sub-
strate appears to play an important role, since acyclic alcohol 72
is resolved with much lower enantioselectivity (entry 10b) than
either diastereomer of 2-phenylcyclohexanol (entries 1d and 4).
Table 8. KR of 2-Substituted Cycloalkanols
Figure 5. Transition-state models of the HBTM-catalyzed KR of
alcohols 63 and 7.
Deactivation of BTM. Shortly after discovering the
remarkable enantioselectivity of BTM in the KR of benzylic
alcohols, we became aware of its sensitivity to the presence of
moisture during the reaction. When BTM-catalyzed acylations
were carried out in an ice bath, we often observed that the
reaction slowed or stopped at low conversions until additional
catalyst was introduced. A control experiment revealed the
origin of the problem: when a solution of BTM and excess
acetic anhydride in CDCl3 was kept for several days at room
temperature, a new compound was gradually formed (Scheme 3).
Scheme 3. Deactivation of BTM 3 in the Presence of
Moisture
a,b
c
See Table 1. The reaction was carried out in tert-amyl alcohol/
d
e
toluene mixture. The reaction was carried out in toluene. The
reaction was carried out in tert-amyl alcohol.
chloroform as the reaction media and adding a drying agent, such
as anhydrous sodium sulfate or carbonate.
Later, we also observed seemingly similar behavior in BTM-
catalyzed KR of allylic alcohols, despite the usual precautions to
exclude and absorb moisture. However, the catalyst was largely
recovered unchanged by chromatography, and no appreciable
amounts of 78b or any other degradation product could be
isolated. We surmised that the catalyst in this case might be
inhibited by the alcohol substrate itself via formation of a hypo-
thetical inactive species that later reverts to BTM during
chromatography. To test this possibility, we devised the fol-
lowing experiment.
Its formation was accelerated considerably when small amounts of
water were added intentionally to the solution. The structure of
this degradation product, 78a, indicated that it probably arose
from the attack of water on the isothiouronium carbon of the
N-acylated intermediate 75a followed by the opening of the
thiazole ring and, finally, acylation of the thiol group. Fortunately,
the formation of 78 could be effectively suppressed by utilizing dry
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As expected, BTM-catalyzed acylation of the primary
benzylic alcohol (2-naphthyl)methanol 79 was found to occur
at a much faster rate than that of typical secondary alcohols.
We reasoned that replacing pure BTM in this reaction with an
aliquot of a KR reaction mixture containing an equivalent
amount of the catalyst should result in significantly reduced
reaction rates only if the KR substrate has already inhibited it.
The results obtained with several representative secondary
alcohols are summarized in Table 9.
column 4) catalyzed acylation of 79 to essentially the same
extent as did pure BTM (entry 2, column 4). After 2 h,
however, the same mixture, despite the absence of any observ-
able reaction of 25, produced a markedly lower catalytic effect
(columns 5 and 6), indicating that the inhibition had already
taken place.
Racemic allylic alcohol 37 displayed an interesting combina-
tion of these two modes of behavior. The first aliquot, in which
the conversion had already reached nearly the same level as in
the case of ( )-7, nevertheless produced clear signs of catalyst
inhibition (entry 5, column 4). After 2 h, the conversion of 37
had reached a plateau at 60% (column 5). The inhibitory
activity was comparable to that of 25, which accounted for the
lack of further reaction progress.
Table 9. Substrate Inhibition Test
These results led us to hypothesize that the inhibitory activity
of substrate 37 might reside primarily in the (R)-enantiomer,
which undergoes O-acylation only slowly in the presence of
(S)-BTM and therefore continues to be available for the
putative side reaction diverting BTM from the catalytic cycle.
Indeed, the fast-reacting (S)-37 produced little catalyst
inhibition and, accordingly, was completely acylated within
2 h (entry 6). At the same time, enantioenriched (R)-37 inhib-
ited acylation of 79 even more strongly than did its racemate
(entry 7 vs 5).
Taken together, these results provide evidence that the
slow-reacting enantiomer of the allylic alcohol substrate in
BTM-catalyzed KR is not an innocent bystander but, often, an
unwelcome source of interference. The same may be true for
other classes of alcohols, albeit to a lesser extent. The cor-
relation between an alcohol’s structure and inhibitory activity
remains unclear at this point, as does the nature of the putative
inactive form of the catalyst. We surmise, however, by analogy
with the water-induced catalyst degradation discussed above,
that alcohols in general may react with the isothiouronium
Scheme 4. Proposed Mechanism of Substrate Inhibition of
BTM
a
0% after 4 h.
carbon of N-acylated BTM (75b) to produce a species like 81
(Scheme 4). The rate of its formation relative to the desired
attack at the acyl carbonyl and the ease of the reverse reaction
likely determine the degree of inhibition. This hypothesis, if
correct, would also account for the surprisingly low catalytic
activity of BTM (and tetramisole) in acetylation of methanol
noted in our earlier work.6f
( )-1-Phenylpropanol 7 was chosen as a typical “non-
problematic” substrate. When its KR was carried out in the
presence of 20 mol % of (S)-BTM, the conversion reached 49%
after only 1.5 min (entry 3, column 4). An aliquot withdrawn at
this point and added to a solution of 79 produced only slightly
lower catalytic effect than the same amount of pure BTM
(t1/2 = 45 vs 28 min, respectively, cf. entries 3 and 2), indicating
that the catalyst inhibition was not significant. Repetition of the
same experiment after 2 h, when the conversion of 7 reached
over 80%, produced essentially the same results.
CONCLUSION
■
As we have seen, the five generations of ABCs developed thus
far do not simply differ in their overall activity and enantio-
selectivity but exhibit different enantioselectivity profiles toward
various classes of substrates and thus can be subdivided into
three groups, which are somewhat complementary to one an-
other in their practical utility. Although the details of our opti-
mization studies are beyond the scope of this article, some
On the other hand, benzylic alcohol 25, notable for its total
lack of reactivity under BTM catalysis, produced a strikingly
different outcome under identical conditions. An aliquot of
its reaction mixture taken shortly after mixing (entry 4,
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Article
prepared as previously described.6a,b,d,h Substrate alcohols were either
obtained commercially or synthesized using known procedures.
Solvents used for chromatography were ACS or HPLC grade, as
appropriate. Reactions were monitored by thin-layer chromatography
general recommendation regarding their use are provided be-
low, as they would be of interest to the synthetic practitioner.
(1) CF3-PIP 1 and Cl-PIQ 2. These catalysts work best in
chloroform at 0 °C, at least in the context of KR of alcohols.
Propionic anhydride is the optimal acylating agent, while acetic
and isobutyric anhydrides produce lower enantioselectivities.
For all substrates examined, 1 and 2 produce qualitatively
similar results, with the latter being uniformly superior to the
former in terms of both enantioselectivity and reaction rates.
Therefore, apart from its sentimental value as the first effective
ABC, there appears to be little to recommend CF3-PIP 1 for
future studies, while Cl-PIQ 2 still remains our catalyst of
choice for the KR of allylic alcohols.
1
(TLC) and by H NMR. EM Science 60F silica gel plates were used
for TLC analyses. Flash column chromatography was performed over
ICN Ecochrom silica gel (32−63 mm). HPLC analyses were per-
formed using Chiralcel OD-H and Chiralpak AS-H analytical chiral
stationary-phase columns (4.6 × 250 mm, Chiral Technologies, Inc.)
1
at 1 mL/min flow rate, unless specified otherwise. H and 13C NMR
spectra were recorded on a 300 MHz spectrometer. The chemical
shifts are reported as δ values (ppm) relative to TMS using residual
CHCl3 peak (7.26 ppm) as the reference. High-resolution mass
spectral analyses were performed on using the electrospray ionization
(ESI) method.
(2) BTM 3. This catalyst is less active than Cl-PIQ 2 and,
therefore, is typically used in higher catalyst loadings. In addition, it
is relatively more prone to deactivation in the presence of moisture,
as discussed above. Therefore, it is advisible to protect the reaction
mixture from atmospheric moisture and to add a drying agent,
such as anhydrous sodium sulfate or carbonate. Chloroform is
the preferred reaction medium. In contrast to the other ABCs,
BTM 3 often produces higher enantioselectivities when used in
combination with isobutyric rather than propionic anhydride.
More elaborate acylating agents have not been studied systemat-
ically in our group due to their higher cost. However, recent
studies by Shiina7b,c indicate that the use of diphenylacetic-pivalic
anhydride often results in dramatically increased selectivity factors.
Overall, BTM 3 is the most enantioselective of all ABCs developed
to date in the KR of benzylic and propargylic alcohols, as well as
several other applications described elsewhere.12a,17b,e
(3) HBTM 4, HBTM-2 5a, and HBTM-2.1 5b. Tetrahy-
dropyrimidine-based catalysts 4 and 5a are considerably more
active than imidazoline-based catalysts 1−3 and have been
typically used at −40 °C, which produces greatly improved
selectivity factors compared to 0 °C while allowing reaction
times to be kept reasonably short. In addition, 4 and 5a are
more tolerant of solvent variation than 1−3 and demonstrate
good performance in toluene, tert-amyl alcohol, and chloro-
form, the former currently being our first choice. HBTM 4 and
HBTM-2 5a are both more active and more enantioselective
than Cl-PIQ 2 and BTM 3 in the KR of cycloalkanols, as well
as some other applications.13,15b,17a,c,d Although they are less
enantioselective than the latter two toward benzylic, allylic, and
propargylic alcohols at room temperature, they can still be quite
useful in their KR of these substrates at low temperatures. The
higher catalytic activity and easier synthesis of HBTM-2 5a lead
us to favor it relative to the parent catalyst 4. As might be
expected, its isopropyl homologue HBTM-2.1 5b is even more
active and enantioselective than 5a,9 although its synthesis is
somewhat more involved.15b
2. Kinetic Resolution Data. Tables 10−13 summarize previously
unpublished data grouped by the catalyst used. Detailed descriptions
of experimental conditions can be found in the previous publications
(CF3-PIP 1,6a Cl-PIQ 2,6b BTM 3,6d and HBTM 4,6h respectively).
Selectivity factors and conversions were calculated from the
enantiomeric excess values of the ester products and the recovered
unreacted alcohol substrates according to Kagan’s equations.2,22 The
ee's of alcohols were determined by chiral stationary-phase HPLC
either directly or after appropriate derivatization, as specified in section
3. All esters were hydrolyzed to the corresponding alcohols prior to
HPLC analysis.
3. HPLC Properties and Characterization Data. Unless
specified otherwise, absolute configurations were determined by com-
paring the sign of optical rotation with the literature data. In those
cases when the method of establishing the absolute configuration is
not specified, the assignment of HPLC peaks is by analogy.
Indan-1-ol (14). Alcohol: Commercially available. HPLC (OD-H,
3% i-PrOH/hexane): 17.8 min, 20.8 min. Propionate ester: Previously
reported.36
1-cyclohexylethan-1-ol (15). Alcohol: Commercially available. (−)-
(R)-enantiomer37 recovered after KR using (S)-2 and -3. HPLC:
Separation achieved using the corresponding benzoate (see
below). Propionate ester: Previously reported.36 Benzoate ester: Pre-
viously reported.38 HPLC (OD-H, 100% hexane): 10.6 min (R),
11.5 min (S).
1-[3-(Dimethylamino)phenyl]ethan-1-ol (16). Alcohol: Commer-
cially available. HPLC (OD-H, 10% i-PrOH/hexane): 9.4 min (R),
1
16.0 min (S). Propionate ester: H NMR (300 MHz, CDCl3): δ 7.25
(t, J = 8.1 Hz, 1H), 6.75−6.65 (m, 3H), 5.86 (q, J = 6.6 Hz, 1H), 2.98
(s, 6H), 2.36 (q, J = 7.5 Hz, 1H), 1.54 (d, J = 6.6 Hz, 3H), 1.14 (t, J =
7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 174.0, 150.9, 143.0,
129.4, 114.4, 112.2, 110.5, 72.9, 40.8, 28.2, 22.6, 9.4; IR: 2980, 2939,
1735, 1606, 1502, 1355, 1187, 1064, 994, 776, 697. MS HR-ESI: calcd
+
for C13H20NO2 (M + H+) 222.1489, found 222.1487.
1-(3-Methoxyphenyl)ethan-1-ol (17). Alcohol: Synthesized by
1
borohydride reduction of the corresponding ketone. H NMR data
(see the Supporting Information) are in agreement with those
previously reported.39 HPLC (OD-H, 5% i-PrOH/hexane): 9.4 min
1
(R), 11.5 min (S). Propionate ester: H NMR (300 MHz, CDCl3): δ
In summary, we have demonstrated that ABCs exhibit good
to excellent performance in the KR of several classes of alcohols
bearing a π-system adjacent to the hydroxyl group. Their broad
substrate scope, coupled with easy availability in both enantio-
meric forms and generally high enantioselectivity, suggest that
they can indeed provide a practical alternative to enzymes. The
absolute configurations of the products observed in all cases
studied are consistent with our proposed general TS model,6a,i
which underscores its value as a predictive tool and a guide to
further development of new applications of ABCs.
7.26 (t, J = 7.8 Hz, 1H), 6.59−6.81 (m, 4H), 5.87 (q, J = 6.6 Hz, 1H),
2.40−2.32 (m, 2H), 1.52 (d, J = 6.6 Hz, 3H), 1.15 (t, J = 7.5 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 173.8, 159.9, 143.8, 129.8, 118.5,
113.2, 112.0, 72.2, 55.4, 28.1, 22.5, 9.3. IR (KBr, cm−1) 2981, 1736,
1186, 699; MS HR-ESI:: calcd for C12H16NaO3+ (M + Na+) 231.0992,
found 231.0993.
1-(3-Methylphenyl)ethan-1-ol (18). Alcohol: Synthesized by
1
borohydride reduction of the corresponding ketone. H NMR data
(see the Supporting Information) are in agreement with those pre-
viously reported.39,40 HPLC (OD-H, 5% i-PrOH/hexane): 16.7 min
1
(R), 20.0 min (S). Propionate ester: H NMR (300 MHz, CDCl3):
δ 7.15−6.98 (m, 4H), 5.75 (q, J = 6.6 Hz, 1H), 2.28−2.20 (m, 5H),
1.41 (d, J = 6.6 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 173.8, 141.9, 138.2, 128.7, 128.5, 126.9, 123.2, 72.2, 28.0,
22.4, 21.6, 9.2. IR (KBr, cm−1) 3027, 2981, 1737, 1188, 1065, 786, 703.
EXPERIMENTAL SECTION
1. General Methods. All reagents were obtained commercially
and used as received unless otherwise specified. Catalysts 1−4 were
■
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a
Table 10. KR Catalyzed by CF3-PIP (1)
entry
1
substrate
time (h)
8
no.
eePR (%)
eeSM (%)
CHPLC (%)
s
CAVG (%)
sAVG
16
1
2
1
2
1
2
3
1
2
3
1
2
1
2
1
2
90.0
89.7
90.3
88.3
90.2
90.1
89.6
78.6
79.7
75.2
78.1
32.3
94.2
94.4
64.7
65.0
65.7
69.7
50.1
74.3
21.9
24.7
27.2
67.1
72.3
72.5
38.8
77.0
48.0
50.3
62.0
64.0
42.2
43.7
35.7
46.3
19.5
21.5
23.3
46.1
47.5
49.1
33.2
30.0
33.8
34.8
48.9
49.6
37.4
38.5
32.1
36.7
24.1
24.3
23.7
16.7
19.0
15.2
11.8
10.5
53.9
57.1
8.6
43
38
2
3
17
18
8
8
41
21
34
24
b
4
19
8
48
17
5
20
22
24
8
8
32
34
49
11
56
8.8
c
6
b,d
7
25
9.0
a
General conditions: 1.0 M substrate, 0.75 M (EtCO)2O, 0.75 M i-Pr2NEt, 2 mol % (S)-CF3-PIP, CDCl3, 0 °C. (S)-Enantiomer of the product is
b
c
d
favored. The selectivity factor is lower than previously reported (ref 6a. The selectivity factor is higher than previously reported (ref 6a). (R)-CF3-
PIP was used.
a
Table 11. KR Catalyzed by Cl-PIQ (2)
entry
1
substrate
catalyst (mol %)
20
time (h)
53
no.
eePR (%)
eeSM (%)
CHPLC (%)
s
CAVG (%)
sAVG
15
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
21.4
21.5
91.6
91.3
94.1
94.4
74.0
70.1
13.6
13.9
84.8
84.7
92.2
92.3
66.8
67.2
38.9
39.2
48.1
48.1
49.5
49.4
47.5
48.7
0
1.8
1.8
39
1.8
2
3
4
5
22
23
24
25
26
35
36
43
44
45
47
48
49
50
2
5
6
5
61.3
59.3
48
49
48
0
60
112
12
109
115
13.3
2
6.5
47
5
11.6
5
0
b
6
2
83.4
82.3
72.7
74.4
78.2
78.0
78.2
77.8
29.2
31.8
67.6
67.6
83.4
83.3
68.4
67.6
69.1
67.8
78.5
79.8
97.3
97.1
62.0
66.6
63.1
62.4
82.5
83.7
26.6
27.7
46.6
51.7
65.5
65.4
60.6
59.9
58.8
56.1
45.5
42.6
53.8
54.1
46.0
47.2
44.6
44.5
51.4
51.8
47.7
46.6
40.8
43.3
44.0
44.0
47.0
47.0
46.0
45.3
36.7
34.8
46.8
43.0
11.8
13.5
15.5
15.3
20.7
20.8
2.3
54
47
45
52
47
42
44
47
46
36
45
13
15
21
2.4
8.3
22
9.6
9.4
13
7
5
35
6
8
2
9
5
7
10
11
12
13
14
15
5
23
12
23
6
2.5
10
5
8.1
8.6
21.7
21.5
9.8
10
10
10
9.4
24
45
9.8
9.0
13.0
13.5
a
General conditions: 1.0 M substrate, 0.75 M (EtCO)2O, 0.75 M i-Pr2NEt, 2 mol % of (S)-Cl-PIQ, CDCl3, 0 °C, anhydrous Na2CO3. (S)-
b
enantiomer of the product is favored. (R)-Cl-PIQ was used.
MS HR-ESI: calcd for C12H16NaO2+ (M + Na+) 215.1043, found
215.1043.
reported.40 HPLC (OD-H, 5% i-PrOH/hexane): 8.9 min (S), 9.8 min
(R). Propionate ester: 1H NMR (300 MHz, CDCl3): δ 7.49 (s, 1H), 7.40
(d, J = 7.8 Hz, 1H), 7.28−7.17 (m, 2H), 5.83 (q, J = 6.6 Hz, 1H), 2.35 (q,
1-(3-Bromophenyl)ethan-1-ol (19). Alcohol: Synthesized by boro-
1
hydride reduction of the corresponding ketone. H NMR data (see the
J = 7.8 Hz, 2H), 1.50 (d, J = 6.6 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13
C
Supporting Information) are in agreement with those previously
NMR (75 MHz, CDCl3): δ 173.7, 144.4, 131.1, 130.3, 129.3, 124.9, 122.8,
1731
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a
Table 12. KR Catalyzed by BTM (3)
entry
substrate
catalyst mol %
8
time (h)
22
no.
eePR (%)
eeSM (%)
CHPLC (%)
s
CAVG (%)
sAVG
b
1
14
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
1
2
9.96
11.6
23.3
23.1
91.0
90.8
90.4
90.8
1.7
1.6
14.9
12.3
59.0
59.4
45.1
45.3
52.2
52.1
0
1.2
1.3
14
1.3
b
2
15
21
23
25
26
27
28
32
32
33
33
34
35
36
43
44
45
46
47
48
49
50
72
20
4
52
24
19.5
47
24
1.0
24
10
22
14
18
24
30
30
120
47
30
47
35
24
35
35
8
33.5
33.9
74.7
75.2
98.7
98.8
2.2
59
45
52
0
2.2
47
2.2
c
3
47.8
47.1
98.3
4
5
5
102
105
5
0
d
6
4
97.4
97.5
97.2
96.7
91.5
92.0
68.4
67.6
85.0
85.5
90.7
90.1
93.7
93.6
87.9
89.4
83.1
83.9
83.7
83.9
75.7
77.0
34.4
33.7
62.9
63.1
78.2
77.6
58.1
57.4
51.8
56.5
31.7
33.9
24.7
26.5
79.3
79.2
83.4
82.6
93.5
88.9
88.0
85.5
87.0
87.2
71.0
70.3
81.3
80.1
82.4
81.5
84.9
80.6
63.6
61.3
52.0
50.1
36.2
42.1
14.8
13.6
30.3
29.3
25.4
25.9
9.9
46.1
45.9
49.0
47.9
49.0
48.2
56.0
56.3
45.5
45.1
47.3
47.1
46.8
46.5
49.1
47.4
43.4
42.2
38.3
37.5
32.4
35.4
30.0
28.7
32.5
31.7
24.5
25.0
14.6
13.8
42.8
42.3
36.6
39.5
23.4
19.0
15.3
14.6
197.0
206.7
243.0
176.7
65.8
65.6
14.7
14.3
26.1
26.8
51.8
47.4
79.2
76.5
41.8
44.3
20.7
21.3
18.8
18.5
10.3
11.6
2.4
46
48
49
56
45
47
47
48
43
38
34
29
32
25
14
43
38
21
15
202
210
66
d
7
4
c
8
4
9
8
15
c
10
8 + 8
8
26
b
11
50
b
,c
12
13
14
15
16
17
18
19
20
21
22
23
24
8
78
b
8 + 8
10
10
10
10
10
10
10
10
10
10
8
43
21
19
11
2.3
5.9
10
2.3
b
5.9
5.9
10.5
10.2
4.2
b
b
b
b
4.1
4.9
2.4
1.8
9.9
9.2
4.1
38.7
41.4
18.3
22.1
7.6
4.5
5.3
2.3
2.5
1.8
6.2
1.8
14.3
13.5
9.9
9.8
a
General conditions: 0.25 M substrate, 0.75 M (EtCO)2O, 0.75 M i-Pr2NEt, 4 mol % of (S)-BTM, CDCl3, 0 °C, anhydrous Na2SO4. (S)-enantiomer
b
c
d
of the product is favored. Reaction performed at room temperature. (i-PrCO)2O is used instead of (EtCO)2O. (R)-BTM was used.
a
Table 13. KR Catalyzed by HBTM (4)
entry
1
substrate
catalyst
2
time (h)
1.7
no.
eePR (%)
eeSM (%)
CHPLC (%)
s
CAVG (%)
sAVG
14
1
2
3.1
3.1
5.4
4.7
63.7
60.5
1.1
1.1
62
1.1
a
Conditions: 0.25 M ( )-14, 0.75 M (EtCO)2O, 0.75 M i-Pr2NEt, 2 mol % of (S)-HBTM, CDCl3, rt, anhydrous Na2SO4.
71.5, 28.0, 22.5, 9.3. IR (KBr, cm−1) 3063, 2981, 1739, 1182, 784, 695.
MS HR-ESI: calcd for C11H13BrNaO2+ (M + Na+) 278.9991, found
278.9993.
1-(3-Nitrophenyl)ethan-1-ol (20). Alcohol: Synthesized by borohy-
dride reduction of the corresponding ketone. H NMR data (see the
Supporting Information) are in agreement with those previously
1
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reported.39 HPLC (OD-H, 1% i-PrOH/hexane): 54.7 min (S), 58.4
min (R). Propionate ester: H NMR (300 MHz, CDCl3): δ 8.22 (s,
2986, 1758, 1271, 1178, 1086, 730. MS HR-ESI: calcd for
+
C19H15F3NaO2 (M + Na+) 355.0916, found 355.0917.
1
3-Chloro-1-phenylpropan-1-ol (28). Alcohol: Synthesized by
borohydride reduction of the corresponding ketone. H NMR data
1H), 8.14 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.52 (t, J =
7.8 Hz, 1H), 5.93 (q, J = 6.6 Hz, 1H), 2.43−2.34(m, 1H). 13C NMR
(75 MHz, CDCl3): δ 173.8, 148.7, 144.3, 132.5, 129.8, 123.0, 121.2,
71.1, 28.0, 9.2; IR: 2983, 2941, 1739, 1532, 1351, 1182, 1082, 1065,
738, 688. MS HR-ESI: calcd for C11H13NNaO4+ (M + Na+) 246.0737,
found 246.0736.
1
(see the Supporting Information) are in agreement with those
previously reported.42 HPLC (AS-H, 1% i-PrOH/hexane): 22.5 min
1
(R), 26.0 min (S). Propionate ester: H NMR (300 MHz, CDCl3): δ
7.36−7.26 (m, 5H), 5.95 (dd, J1 = 8.4 Hz, J2 = 5.4 Hz, 1H), 3.61−3.41
(m, 2H), 2.45−2.16 (m, 4H), 1.14 (t, J = 7.5 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 173.6, 139.9, 128.9, 128.4, 126.6, 73.2, 40.9, 39.4,
27.9, 9.3. IR (KBr, cm−1): 3033, 2979, 1740, 1183, 699. MS HR-ESI:
1-[3,5-Bis(trifluoromethyl)phenyl]ethan-1-ol (21). Alcohol: Com-
mercially available. HPLC (OD-H, 2% i-PrOH/hexane): 9.2 min (R);
1
10.4 min (S). Propionate ester: H NMR (300 MHz, CDCl3): δ 7.81
+
calcd for C12H15ClNaO2 (M + Na+) 249.0653, found 249.0652.
(s, 1H), 7.79 (s, 2H), 5.96 (q, J = 6.6 Hz, 1H), 2.41 (q, J = 7.8 Hz,
2H), 1.57 (d, J = 6.6 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 173.6, 144.8, 132.4, 131.9, 126.4, 122.0, 70.9, 27.9,
22.5, 9.2. IR (KBr, cm−1) 2988, 1745, 1280, 1175, 1134, 899, 683; MS
1-Phenyl-2-(pyridin-2-yl)ethan-1-ol (32). Alcohol: Synthesized
from 2-picoline and benzaldehyde as previously described.6g,43 1H
NMR data (see the Supporting Information) are in agreement with
those previously reported.43 HPLC (OD-H, 10% i-PrOH/hexane): 9.0
min (R), 15.4 min (S). Propionate ester: 1H NMR (300 MHz, CDCl3):
δ 8.54 (m, 1H), 7.56 (td, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H), 7.38−7.26 (m,
5H), 7.14−7.09 (m, 2H), 6.20 (dd, J1 = 9.0 Hz, J2 = 5.4 Hz, 1H),
3.41−3.20 (m, 2H), 2.25 (q, J = 7.8 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H).
13C NMR (75 MHz, CDCl3): δ 173.5, 157.7, 149.6, 140.6, 136.4,
128.7, 128.2, 126.7, 124.1, 121.9, 75.5, 45.6, 27.9, 9.2. IR (KBr, cm−1)
3033, 2980, 2941, 1737, 1182, 763, 700. MS HR-ESI: calcd for
+
HR-ESI: calcd for C13H12F6NaO2 (M + Na+) 337.0633, found
337.0649.
1-(2-Methoxyphenyl)ethan-1-ol (23). Alcohol: Synthesized by
1
borohydride reduction of the corresponding ketone. H NMR data
(see the Supporting Information) are in agreement with those pre-
viously reported.40 (+)-(R) enantiomer37 recovered after KR using
(S)-2 and -3. HPLC (OD-H, 2% i-PrOH/hexane): 18.3 min (S),
19.8 min (R).
+
C16H17NNaO2 (M + Na+) 278.1151, found 278.1152. Isobutyrate
1
Propionate Ester. H NMR (300 MHz, CDCl3): δ 7.36 (dd; J1 =
ester: 1H NMR (300 MHz, CDCl3): δ 8.45 (m, 1H), 7.56 (td, J1 = 7.8
Hz, J2 = 1.8 Hz, 1H), 7.38−7.24 (m, 5H), 7.14−7.10 (m, 2H), 6.19
(dd, J1 = 9.0 Hz, J2 = 5.4 Hz, 1H), 3.40−3.21 (m, 2H), 2.51−2.42
(m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 176.1, 157.7, 149.6, 140.7, 136.4, 128.7, 128.1,
126.6, 124.1, 121.9, 75.4, 45.7, 34.2, 19.1, 18.9. IR (KBr, cm−1): 3033,
2973, 1734, 1190, 1153, 762, 699. MS HR-ESI: calcd for
7.4 Hz, J2 = 1.6 Hz; 1H), 7.26 (td; J1 = 7.4 Hz, J2 = 1.6 Hz; 1H), 6.96
(td; J1 = 7.4 Hz, J2 = 0.8 Hz; 1H), 6.87 (dd; J1 = 7.4 Hz, J2 = 0.8 Hz;
1H), 6.26 (q; J = 6.5 Hz; 1H), 3.84 (s; 3H), 2.37 (q; J = 7.7 Hz; 2H),
1.48 (d; J = 6.5 Hz; 3H), 1.16 (t; J = 7.7 Hz; 3H). 13C NMR (75 MHz,
CDCl3) δ 173.5, 156.0, 130.6, 128.5, 125.7, 120.6, 110.5, 66.9, 55.4,
27.9, 21.2, 9.2. IR (KBr, cm−1): 2981.8, 2940.5, 1737.9, 1187.3. MS
HR-ESI: calcd for C12H16O3Na (M + Na+) m/z 231.0997, found
231.0986;
+
C17H19NNaO2 (M + Na+) 292.1308, found 292.1308.
1-(2,6-Dimethoxyphenyl)ethan-1-ol (25). Previously reported41
without characterization. Synthesized as described below.
tert-Butyl (2R)-2-[(2R)-2-Hydroxy-2-phenylethyl]piperidine-1-
carboxylate (33). Alcohol: Synthesized from 1-phenyl-2-(pyridin-2-
yl)ethan-1-ol 32 (see above) as previously described.6g 1H NMR data
(see the Supporting Information) are in agreement with those
previously reported.44 HPLC (OD-H, 2% i-PrOH/hexane): 12.6 min
1
(R); 26.2 min (S). Propionate ester: H NMR (300 MHz, CDCl3): δ
7.35−7.24 (m, 5H), 5.72 (dd, J1 = 8.4 Hz, J2 = 5.7 Hz, 1H), 4.26 (br,
1H), 3.99 (d, J = 12.6 Hz, 1H), 2.85 (t, J = 12.6 Hz, 1H), 2.41−2.24
(m, 3H), 1.97−1.88 (m, 1H), 1.60−1.49 (m, 5H), 1.43−1.33 (m,
10H), 1.11 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 173.9,
155.0, 140.9, 128.7, 128.2, 126.9, 79.5, 74.1, 36.4, 28.7, 28.1, 27.9, 25.7,
19.2, 9.2. IR (KBr, cm−1) 2975, 2935, 1739, 1689, 1164, 699; MS HR-
A solution of 1,3-dimethoxybenzene (786 mg, 5.69 mmol) in 20 mL
of THF was cooled to −78 °C and treated with 1.96 M n-BuLi in
hexanes (3.8 mL, 7.5 mmol). The reaction mixture was allowed to
warm to rt, stirred for 2 h, and then cooled to −78 °C and treated with
acetaldehyde (0.5 mL, 9 mmol). The mixture was allowed to warm to
rt and worked up as usual with water and Et2O. The organic phase was
dried over MgSO4, concentrated, and subjected to flash chromatog-
raphy (15→20% EtOAc/hexanes) to afford a pale-yellow solid (608 mg,
59% yield). Mp: 54−55 °C (from hexanes). 1H NMR (300 MHz,
CDCl3): δ 7.26 (t, J = 8.1 Hz, 1H), 6.56 (d, J = 8.1 Hz, 2H), 5.38−5.27
(m, 1H), 3.88 (br, 1H), 3.84 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 157.4, 128.1, 120.9, 104.3, 64.0, 55.7, 23.6. IR: 2967,
1596, 1477, 1234, 1108. MS HR-ESI: calcd for C10H14O3Na+ (M + Na+)
205.0835, found 205.0844.
+
ESI: calcd for C21H31NNaO4 (M + Na+) 384.2145, found 384.2143.
Isobutyrate ester: 1H NMR (300 MHz, CDCl3): δ 7.34−7.24 (m, 5H),
5.69 (dd, J1 = 8.4 Hz, J2 = 6.0 Hz, 1H), 4.27 (br, 1H), 3.99 (d, J = 12.6
Hz, 1H), 2.85 (t, J = 12.6 Hz, 1H), 2.61−2.51 (m, 1H), 2.32−2.22 (m,
1H), 1.98−1.90 (m, 1H), 1.60−1.49 (m, 5H), 1.43−1.33 (m, 10H),
1.16 (d, J = 7.2 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 176.4, 155.0, 141.0, 128.7, 128.1, 126.7, 79.5, 74.0, 36.4,
34.3, 28.7, 27.9, 25.7, 19.2, 19.1, 19.0. IR (KBr, cm−1) 2973, 2933,
+
1734, 1689, 1162, 761, 699. MS HR-ESI: calcd for C22H33NNaO4
(M + Na+) 398.2302, found 398.2297.
1-(Anthracen-9-yl)ethan-1-ol (26). Alcohol: Commercially avail-
able. HPLC (OD-H, 10% i-PrOH/hexane): 10.4 min (S), 21.5 min
(R). Propionate ester: 1H NMR (300 MHz, CDCl3): δ 8.63 (d, J = 8.7 Hz,
2H), 8.43 (s, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.57−7.44 (m, 5H), 2.49−2.29
(m, 2H), 1.95 (d, J = 6.6 Hz, 3H), 1.11 (t, J = 7.5 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 174.1, 132.6, 131.9, 129.6, 129.6, 128.7, 126.1, 125.0, 69.0,
28.0, 21.8, 9.2. IR: 3052, 2981, 1939, 1736, 1670, 1183, 732, 698. MS HR-
ESI:: calcd for C19H18NaO2+ (M + Na+) 301.1199, found 301.1195.
1-(Anthracen-9-yl)-2,2,2-trifluoroethan-1-ol (27). Alcohol: Com-
mercially available. HPLC (OD-H, 10% i-PrOH/hexane): 12.1 min
tert-Butyl (2S)-2-[(2R)-2-Hydroxy-2-phenylethyl]piperidine-1-car-
boxylate (34). Alcohol: Synthesized from 1-phenyl-2-(pyridin-2-
yl)ethan-1-ol 32 (see above) as previously described.6g 1H NMR
data (see the Supporting Information) are in agreement with those
previously reported.44 HPLC (AD-H, 8% i-PrOH/hexane): 9.4 min
1
(R); 19.9 min (S). Propionate ester: H NMR (300 MHz, CDCl3): δ
7.33−7.24 (m, 5H), 5.58(t, J = 6.9 Hz, 1H), 5.60−3.98 (br, 2H), 2.73
(t, J = 12.6 Hz, 1H), 2.42−2.04 (m, 4H), 1.58−1.41 (m, 16H), 1.01
(t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 173.7, 155.0,
141.3, 128.7, 128.1, 126.6, 79.5, 73.2, 39.1, 36.8, 28.9, 28.6, 27.9, 25.8,
19.3, 9.1. IR (KBr, cm−1) 2977, 2936, 1743, 1689, 1166, 699. MS HR-
1
(S), 29.2 min (R). Propionate ester: H NMR (300 MHz, CDCl3): δ
+
ESI: calcd for C21H31NNaO4 (M + Na+) 384.2145, found 384.2146.
8.79 (d, J = 9.07 Hz, 1H), 8.57 (s, 1H), 8.39 (d, J = 9.3 Hz, 1H), 8.04
(d, J = 8.4 Hz, 2H), 7.89 (q, J = 8.1 Hz, 1H), 7.68−7.51 (m, 4H),
2.63−2.43 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 172.6, 132.0, 131.7, 131.5, 131.3, 131.1, 129.8, 129.5, 127.9,
126.6, 125.2, 122.8, 121.6, 69.0(q, J = 137.7 Hz), 27.5, 9.0; IR: 3055,
1-(Pyridin-2-yl)ethan-1-ol (35). Alcohol: Synthesized by borohy-
1
dride reduction of the corresponding ketone. H NMR data (see the
Supporting Information) are in agreement with those previously
reported.40 (+)-(R)-Enantiomer45 recovered after KR using (S)-2 and
1733
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Article
-3. HPLC (OD-H, 1% i-PrOH/hexane): 25.8 min (R), 30.2 min (S).
Propionate ester: H NMR (300 MHz, CDCl3): δ 8.54 (d, J = 4.5 Hz,
for C19H21NO2Na (M + Na+) m/z 318.1464, measured m/z 318.1465.
HPLC (OD-H, 20% i-PrOH/hexane): 27.4 min (R), 33.9 min (S).
(3Z)-4-Phenylbut-3-en-2-ol (47). Alcohol: Synthesized by partial
hydrogenation of 4-phenyl-3-butyn-2-ol as previously described.50 1H
NMR data (see the Supporting Information) are in agreement with
those previously reported.51 (−)-(S) enantiomer52 recovered after KR
using (R)-2. HPLC (OD-H, 5% i-PrOH/hexane): 6.1 min (S), 12.1
min (R). Absolute configuration was additionally confirmed by
hydrogenation to 4-phenylbutan-2-ol and HPLC comparison with a
sample obtained by hydrogenation of resolved trans-isomer 37 (see
1
1H), 7.67−7.61 (m, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.18−7.13
(m, 1H), 5.88 (q, J = 6.6 Hz, 1H), 2.37 (q, J = 6.6 Hz, 2H), 1.55 (d,
J = 6.9 Hz, 3H), 1.12 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 173.9, 160.7, 149.5, 136.9, 122.8, 120.5, 73.0, 28.0, 20.9, 9.3.
IR (KBr, cm−1) 3056, 2982, 1739, 1186, 1070, 749. MS HR-ESI: calcd
for C10H14NO2 (M + H+) 180.1019, found 180.1018.
1-(Thiophene-2-yl)ethan-1-ol (36). Alcohol: Synthesized by
1
borohydride reduction of the corresponding ketone. H NMR data
1
(see the Supporting Information) are in agreement with those
previously reported.37 (+)-(R) Enantiomer37 recovered after KR using
(S)-2 and -3. GC (20 m of cyclodextin-β analytical column,
temperature increased from 105 to 125 °C, 0.5 °C/min): 11.8 min
below). Propionate ester: H NMR (300 MHz, CDCl3) δ 7.42−7.30
(m; 5H), 6.58 (d; J = 11.6 Hz; 1H), 5.88 (dq; J1 = 9.0 Hz, J2 = 6.3 Hz;
1H), 5.71 (dd; J1 = 11.6 Hz, J2 = 9.0 Hz; 1H), 2.34 (q; J = 7.6 Hz;
2H), 1.42 (d; J = 6.3 Hz; 3H), 1.17 (t; J = 7.6 Hz; 3H). 13C NMR (75
MHz, CDCl3) δ 173.5, 136.3, 131.4, 130.8, 128.5, 128.3, 127.3, 67.6,
27.8, 20.8, 9.0. IR (KBr, cm−1) 2980, 2940, 1733, 1190. MS HR-ESI
calcd for C13H16O2Na (M + Na+) m/z 227.1043, measured m/z
227.1048. 4-Phenylbutan-2-ol: HPLC (OD-H, 10% i-PrOH/hexane,
0.5 mL/min): 12.8 min (R), 18.0 min (S).
1
(S), 12.3 min (R). Propionate ester: H NMR (300 MHz, CDCl3): δ
7.25 (m; 1H), 7.05 (m; 1H), 6.96 (m; 1H), 6.19 (q; J = 6.6 Hz; 1H),
2.33 (q; J = 7.7 Hz; 2H), 1.64 (d; J = 6.6 Hz; 3H), 1.14 (t; J = 7.7 Hz;
3H). 13C NMR (75 MHz, CDCl3): δ 173.4, 144.6, 126.4, 125.0, 67.3,
27.7, 21.9, 8.9. IR (KBr, cm−1): 2983, 2941, 1738, 1183. MS HR-ESI:
calcd for C9H12O2SNa (M + Na+) m/z 207.0456, measured m/z
207.0453.
(3Z)-3-Dodecen-2-ol (48) Alcohol. Synthesized from 1-decyne as
described below.
(3E,5E)-Hepta-3,5-dien-2-ol (43). Alcohol: Synthesized by addition
of methylmagnesium chloride to the corresponding aldehyde.46 1H
NMR data (see the Supporting Information) are in agreement with
those previously reported.46 The enantiomer recovered after KR using
(S)-2 and -3 was assigned the (R)-configuration using Mosher ester
analysis.47 HPLC (OD-H, 2% i-PrOH/hexane): 8.9 min (R), 10.6 min
(a) Preparation of 3-Dodecyn-2-ol.52 A solution of 1-decyne (996
mg, 7.23 mmol) in 9 mL of THF was cooled to −78 °C, treated
with n-BuLi (2.9 mL, 2.5 M), and allowed to warm to 0 °C.
After 15 min, the reaction mixture was cooled to −78 °C, and a
solution of acetaldehyde (0.45 mL, 8.0 mmol) in 3 mL of THF
was added dropwise. The mixture was again allowed to warm to
0 °C, stirred at that temperature for 2 h, quenched with
saturated aqueous NH4Cl, and extracted with Et2O. The extract
was dried over Na2SO4, concentrated, and subjected to flash
chromatography (10→15% EtOAc/hexane) to afford 1.16 g of
the expected alcohol (88% yield). (a) Preparation of 3-Dodecen-
2-ol 48.52 Performed analogously to the literature procedure
referenced above.50 A solution of NaBH4 (53 mg, 1.4 mmol) in
2 mL of EtOH was added to a solution of Ni(OAc)2·4H2O
(342 mg, 1.37 mmol) in 60 mL of EtOH. To the resulting black
suspension were added ethylenediamine (172 mg, 2.86 mmol)
and 3-dodecyn-2-ol (1.935 g, 10.6 mmol). The flask with
purged with hydrogen, and the reaction mixture was stirred at rt
for 2 h until completion (1H NMR). The hydrogen atmosphere
was removed, activated charcoal was added, and the reaction
mixture was filtered through a plug of Celite and extracted with
Et2O. The extract was washed with water and brine, dried over
Na2SO4, and concentrated. Flash chromatography (5→10%
EtOAc/hexane) afforded 1.740 g of the pure Z-allylic alcohol
1H NMR data (see the Supporting Information) are in agreement
with those previously reported.52 (−)-(S)-Enantiomer52 was
recovered after KR using (R)-2. HPLC separation achieved
using the corresponding phenylcarbamate (see be-
1
(S). Propionate ester: H NMR (300 MHz, CDCl3) δ 6.20 (dd; J1 =
15.1 Hz, J2 = 10.5 Hz; 1H), 6.01 (m; 1H), 5.67 (m; 1H), 5.52 (dd; J1 =
15.1 Hz; J2 = 7.7 Hz; 1H), 5.37 (quintet; J = 7.7 Hz; 1H), 2.30 (q; J =
7.4 Hz; 2H), 1.75 (d; J = 7.7 Hz; 1H), 1.43 (d; J = 6.3 Hz; 3H), 1.13
(t; J = 7.4 Hz; 3H). 13C NMR (75 MHz, CDCl3) δ 173.7, 131.9, 130.8,
130.6, 129.7, 70.6, 27.9, 20.3, 18.1, 9.1. IR (KBr, cm−1) 2928, 2853,
1735, 1187. MS HR-ESI calcd for C10H16O2Na (M + Na+) m/z
191.1043, measured m/z 191.1057.
(3E)-4-(2,6,6-Trimethylcyclohex-1-en-1-yl)but-3-en-2-ol (44). Al-
cohol: Synthesized by borohydride reduction of the corresponding
ketone. 1H NMR data (see the Supporting Information) are in
agreement with those previously reported48 (+)-(R) enantiomer48
recovered after KR using (S)-2 and -3. HPLC (OD-H, 100% hexane):
1
33.3 min (S), 38.1 min (R). Propionate ester: H NMR (300 MHz,
CDCl3) δ 6.06 (m; 1H), 5.42−5.36 (m; 2H), 2.30 (q; J = 7.6 Hz; 2H),
1.95 (m; 2H), 1.63 (s; 3H), 1.62−1.56 (m; 2H), 1.44−1.40 (m; 2H),
1.33 (d; J = 6.1 Hz, 3H), 1.12 (t; J = 7.6 Hz; 3H), 0.96 (s; 3H), 0.95
(s; 3H). 13C NMR (75 MHz, CDCl3) δ 173.7, 136.5, 132.9, 129.9,
71.3, 39.3, 33.8, 32.6, 28.6, 28.0, 21.2, 20.5, 19.2, 9.2. MS HR-ESI:
calcd for C16H26O2Na (M + Na+) m/z 273.1825, measured m/z
273.1833. IR (KBr, cm−1): 2964, 2929, 2866, 1738, 1187.
(3E)-6-Phenylhex-3-en-2-ol (45). Alcohol: Synthesized from 3-
phenylpropanal as previously described.49 1H NMR data (see the
Supporting Information) are in agreement with those previously
reported.49 (+)-(R)-Enantiomer49 recovered after KR using (S)-2 and
-3. Absolute configuration confirmed using Mosher ester analysis.47
HPLC separation achieved using the corresponding phenylcarbamate
1
(see below). Propionate: H NMR (300 MHz, CDCl3) δ 7.34−7.29
(m; 2H), 7.24−7.19 (m; 3H), 5.76 (dt; J1 = 15.2 Hz, J2 = 6.6 Hz; 1H),
5.51 (dd; J1 = 15.2, J2 = 6.5 Hz; 1H), 5.36 (quintet; J = 6.5 Hz; 1H),
2.73 (t; J = 7.6 Hz; 2H), 2.42−2.36 (m; 2H), 2.34 (q; J = 7.6 Hz; 2H),
1.31 (d; J = 6.5 Hz; 3H), 1.17 (t; J = 7.6 Hz; 3H). 13C NMR (75 MHz,
CDCl3) δ 173.7, 141.6, 132.0, 130.3, 128.4, 128.2, 125.8, 70.7, 35.4,
33.9, 27.9, 20.3, 9.1. MS HR-ESI calcd for C15H21O2Na (M + Na+)
m/z 255.1356, measured m/z 255.1358. IR (KBr, cm−1): 2980, 2932,
1
low). Propionate ester: H NMR (300 MHz, CDCl3): δ 5.64
(m; 1H), 5.52−5.44 (m; 1H), 5.35 (m; 1H), 2.28 (q; J = 7.5 Hz;
2H), 2.14 (m; 2H), 1.4−1.2 (m; 15 H), 1.14 (t; J = 7.5 Hz; 3H),
0.87 (m; 3H). 13C NMR (75 MHz, CDCl3): δ 173.7, 133.1, 129.3,
66.9, 31.8, 29.5, 29.4, 29.3, 27.9, 27.3, 22.6, 20.9, 14.1, 9.1. IR (KBr,
cm−1): 2925.9, 2855.1, 1737.7, 1188.3. MS HR-ESI: calcd for
C15H28O2Na (M + Na+) m/z 263.1987, measured m/z 263.1984.
1
1736, 1189. N-Phenylcarbamate: H NMR (300 MHz, CDCl3): δ 7.46
(m; 2H), 7.36 (m; 4H), 7.25 (m; 3H), 7.13 (m; 1H), 6.76 (s; 1H),
5.88 (dt; J1 = 15.4 Hz, J2 = 6.6 Hz; 1H), 5.59 (dd; J1 = 15.4 Hz, J2 = 6.6
Hz; 1H), 5.41 (quintet; J = 6.6 Hz; 1H), 2.77 (t; J = 6.6 Hz; 2H), 2.43
(q; J = 6.6 Hz; 2H), 1.41 (d; J = 6.6 Hz; 3H). 13C NMR (75 MHz,
CDCl3) δ 152.9, 141.5, 138.0, 132.3, 130.2, 128.9, 128.4, 128.2, 125.8,
123.2, 118.6, 71.9, 35.3, 33.9, 20.5. IR (KBr, cm−1) 3321, 3027, 2979,
2931, 1704, 1600, 1539, 1444, 1313, 1223, 1049.0. MS HR-ESI: calcd
1
N-Phenylcarbamate: H NMR (300 MHz, CDCl3): δ 7.38 (m;
2H), 7.29 (m; 2H), 7.04 (m; 2H), 6.55 (s; 1H), 5.66 (m; 1H),
5.51 (m; 1H), 5.41 (m; 1H), 2.17 (m; 2H), 1.34 (d; J = 6.3 Hz;
3H), 1.26 (m; 12H), 0.87 (t; J = 6.7 Hz; 3H). 13C NMR
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The Journal of Organic Chemistry
Article
(75 MHz, CDCl3): δ 152.9, 138.0, 133.4, 129.2, 129.0, 123.2,
118.6, 68.0, 31.9, 29.53, 29.45, 29.26, 29.25, 27.8, 22.6, 21.2, 14.1.
IR (KBr, cm−1): 3323, 2926, 2854, 1704, 1603, 1538, 1443, 1312,
1221, 1051. MS HR-ESI: calcd for C19H30NO2Na (M + Na+) m/z
326.2091, measured m/z 326.2100. HPLC (OD-H, 6% i-PrOH/
hexane): 6.8 min (S), 20.3 min (R).
1H), 2.02−1.97 (m; 4H), 1.73 (s; 3H), 1.62−1.52 (m; 4H),
1.32 (d; J = 6.6 Hz; 3H). 13C NMR (75 MHz, CDCl3): δ 153.1,
138.2, 129.9, 129.3, 129.0, 123.2, 118.5, 71.1, 32.1, 23.1, 22.83,
22.82, 18.9,18.7; IR (KBr, cm−1): 3310, 2929, 1698, 1601, 1538,
1443, 1225, 1050. MS HR-ESI: calcd for C16H22NO2 (M + H+)
m/z 260.1645, measured m/z 260.1642. HPLC (OD-H, 10% i-
PrOH/hexane): (R)-enantiomer: 11.6 min; (S)-enantiomer:
5.0 min.
4-Methylpent-3-en-2-ol (49). Alcohol: Synthesized by borohydride
reduction of the corresponding ketone. 1H NMR data (see the
Supporting Information) are in agreement with those previously
reported.39 (S)-Enantiomer recovered after KR using (R)-2. HPLC
separation achieved using the corresponding phenylcarbamate (see
below). The absolute configuration was established by hydrogenation
to 4-methyl-2-pentanol and HPLC comparison of the corresponding
p-nitrobenzoate with a sample derived from commercially available
Naphthalen-2-ylmethyl Propanoate (80). Alcohol: Commercially
available. Propionate: Previously reported without characterization.55
1H NMR (300 MHz, CDCl3): δ 7.87−7.83 (m, 4H), 7.52−7.46 (m,
3H), 5.30 (s, 2H), 2.53−2.39 (m, 2H), 1.20 (t, J = 6.6 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 174.3, 133.5, 133.2, 133.1, 128.4, 128.0,
127.7, 127.3, 126.3, 126.2, 126.2, 125.9, 66.3, 27.6, 9.1. IR: 2923, 1732,
1176. MS HR-ESI: calcd for C14H14O2Na+ (M + Na+) m/z 237.0886,
measured m/z 237.0890.
1
(R)-4-methyl-2-pentanol (see below). Propionate ester: H NMR (300
MHz, CDCl3): δ 5.58 (m; 1H), 5.15 (m; 1H), 2.28 (q; J = 7.7 Hz;
2H), 1.71 (s; 6H), 1.24 (d; J = 6.3 Hz; 3H), 1.11 (t; J = 7.7 Hz; 3H).
13C NMR (75 MHz, CDCl3): δ 173.9, 136.1, 125.0, 68.0, 27.9, 25.7,
20.9, 18.2, 9.1. IR (KBr, cm−1): 2923, 2853, 1735, 1191. MS HR-EI:
calcd for C9H16O2 (M+) m/z 156.1150, measured m/z 156.1146.
4. Deactivation of BTM in the Presence of Moisture: A
Control Experiment.
1
N-Phenylcarbamate: H NMR (300 MHz, CDCl3): δ 7.37 (m; 2H),
7.29 (m; 2H), 7.04 (m; 1H), 6.60 (s; 1H), 5.65 (m; 1H), 5.24 (m;
1H), 1.81 (s; 3H), 1.79 (s; 3H), 1.39 (d; J = 6.3 Hz; 3H). 13C NMR
(75 MHz, CDCl3): δ 153.0, 138.1, 136.6, 129.0, 124.9, 123.2, 118.5,
69.1, 25.7, 21.2, 18.3. IR (KBr, cm−1): 3320, 2975, 2931, 1701, 1600,
1539, 1444, 1230, 1063, 1046, 1026. MS HR-EI: calcd for C13H18NO2
(M + H+) m/z 220.1332, measured m/z 220.1330. HPLC (OD-H,
12% i-PrOH/hexane): 5.2 min (S), 20.2 min (R). 4-Methylpentan-
2-yl 4-nitrobenzoate:53 HPLC (OD-H, 100% hexane): 18.7 min (S),
20.4 min (R).
To a solution of BTM (30 mg, 0.12 mmol) and Ac2O (50 μL,
0.53 mmol) in 1 mL of CDCl3 in an NMR tube was added 5 μL
of water. The reaction progress was monitored by H NMR.
1
The color of the solution slowly changed to brown. After one
week, 31 mg (74% yield) of the product (1-acetyl-2-oxo-3-[2-
(acetylthio)phenyl]-4-phenyl-2,3,4,5-tetrahydroimidazole, 78a)
was isolated by flash chromatography (EtOAc/hexanes 1:2). 1H
NMR (300 MHz, CDCl3): δ 7.56−7.26 (m, 9H), 5.46 (dd, J1 =
9.3 Hz, J2 = 2.9 Hz, 1H), 4.22 (t, J = 9.3 Hz, 1H), 3.56 (dd,
1-(2-Methylcyclohex-1-en-1-yl)ethan-1-ol (50). Alcohol: Synthe-
sized as described below.
J1 = 8.7 Hz, J2 = 2.9 Hz, 1H), 2.57 (s, 3H), 2.26 (s, 3H). 13
C
NMR (75 MHz, CDCl3): δ 193.3, 170.3, 153.9, 140.8, 139.7,
137.5, 131.3, 129.0, 128.9, 128.1, 127.8, 127.4, 125.6, 54.6,
52.9, 30.2, 24.0. IR (film, cm−1): 1729, 1692, 1376. MS FAB:
calcd for C19H18O3N2S, (M + Na+) m/z 377.0935, found
Acylation of 1-methylcyclohexene followed by acid-catalyzed
isomerization was carried out as described in the literature54 to
afford a mixture of isomeric ketones A and B, which could be
separated completely only by flash chromatography on silica gel
impregnated with 10% AgNO3 (0→2% EtOAc/hexane). Pure
ketone B (92 mg, 0.666 mmol) and CeCl3·7H2O (248 mg,
0.666 mmol) were dissolved in 2 mL of MeOH. Solid NaBH4
(50 mg, 1.32 mmol) was added at rt. After being stirred for 1 h,
the reaction mixture was quenched with aqueous NH4Cl and
extracted three times with Et2O. Drying the extract over
MgSO41 gave 78 mg of 50 (84% yield), which was pure by
NMR. H NMR (300 MHz, CDCl3): δ 4.84 (q; J = 6.3 Hz;
1H), 1.94 (m; 3H), 1.65 (s; 3H), 1.67−1.5 (m; 5H), 1.21 (d;
J = 6.3 Hz; 3H). 13C NMR (75 MHz, CDCl3): δ 132.8, 128.1,
66.7, 32.3, 22.99, 22.98, 22.2, 20.8, 18.6. IR (KBr, cm−1): 2924,
1727, 1284. MS HR-ESI: calcd for C9H17O (M + H+)
141.1274, found 141.1274. (−)-(R)-Enantiomer recovered after
KR using using (S)-2 and -3. Absolute configuration assigned
using Mosher ester analysis.47 HPLC separation achieved using
the corresponding N-phenylcarbamate (see below). Propionate
ester: 1H NMR (300 MHz, CDCl3): δ 5.79 (q; J = 6.6 Hz; 1H),
2.28 (q; J = 7.5 Hz; 2H), 1.95 (m; 4H), 1.68 (s; 3H), 1.60−
1.45 (m; 4H), 1.24 (d; J = 6.6 Hz; 3H), 1.11 (t; J = 7.5 Hz;
3H). 13C NMR (75 MHz, CDCl3): δ 173.8, 129.4, 69.9, 32.1,
27.8, 23.0, 22.84, 22.80, 18.9, 18.5, 9.2. IR (KBr, cm−1): 2924,
2854, 1737, 1462. MS HR-ESI: calcd for C12H20O2Na (M +
Na+) m/z 219.1356, measured m/z 219.1355. N-Phenyl-
377.0930.
6. Inhibition of BTM by Alcohol Substrates. 6a. Comparison
of the Reaction Rates of (2-Naphthyl)methanol and ( )-1-
Phenylethanol. (2-Naphthyl)methanol 79 (79 mg, 0.50 mmol),
racemic 1-phenylethanol ( )-7 (68 mg, 0.50 mmol), (S)-BTM ent-3
(10 mg, 0.040 mmol), and i-Pr2NEt (174 μL, 1.0 mmol) were
dissolved in CDCl3 in a 1 mL volumetric tube (final concentration:
0.50 M (2-naphthyl)methanol, 0.50 M 1-phenylethanol, 0.040 M
BTM, 1.0 M i-Pr2NEt). The mixture was transferred into an NMR
tube, neat propionic anhydride (128 μL, 1 mmol) was added at room
1
temperature, and the reaction progress was monitored by H NMR.
In 10 min, the conversion of (2-naphthyl)methanol into the
corresponding propionate ester 80 reached ca. 30%, while that of 1-pheny-
lethanol was ca. 3%. Thus, the consumption of propionic anhydride by the
latter was not expected to provide much interference when monitoring the
acylation of the former. The CH-O peaks of the alcohols and the esters did
not overlap and could be integrated with fair accuracy.
All subsequent experiments were performed at room temperature
using the stock solutions listed below (in deuterated chloroform). The
reaction progress was monitored by comparing the integration of the
CH-O peaks of the reactant alcohols and the corresponding esters in
the 1H NMR spectra of the reaction mixtures: Stock solution A: 1.0 M
(2-naphthyl)methanol, 1.0 M i-Pr2NEt. Stock solution B: 0.20 M (S)-
BTM, 1.0 M i-Pr2NEt. Stock solution C-1−C-5: 1.0 M 1 [( )-7,
( )-25, ( )-37, (S)-37 (97% ee), (R)-37 (93% ee), respectively],
0.20 M (S)-BTM, 1.0 M i-Pr2NEt.
1
carbamate: H NMR (300 MHz, CDCl3): δ 7.38 (m; 2H),
7.29 (m; 2H), 7.04 (m; 1H), 6.52 (s; 1H), 5.83 (q; J = 6.6 Hz;
6b. Background Reaction Check. Propionic anhydride (64 μL,
0.50 mmol, 1.0 equiv) was added to 0.50 mL of stock solution A. After
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The Journal of Organic Chemistry
Article
4 h, no acylation of (2-naphthyl)methanol was detected by NMR
(Table 9, entry 1).
(5) For leading references to asymmetric catalyst designs that
demonstrated competence in the KR of alcohols (s > 10), see: 4-
Aminopyridines: (a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(b) Kawabata, T.; Yamamoto, K.; Momose, Y.; Yoshida, H.; Nagaoka,
Y.; Fuji, K. Chem. Commun. 2001, 2700. (c) Spivey, A. C.; Zhu, F.;
Mitchell, M. B.; Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68,
7379. (d) Naraku, G.; Shimomoto, N.; Hanamoto, T.; Inanaga, J.
Enantiomer 2000, 5, 135. (e) Priem, B.; Pelotier, B.; Macdonald,
S. J. F.; Anson, M. S.; Campbell, I. B. J. Org. Chem. 2003, 68, 3844.
(f) Jeong, K.-S.; Kim, S.-H.; Park, H.-J.; Chang, K.-J.; Kim, K. S. Chem.
Lett. 2002, 1114. (g) Yamada, S.; Misono, T.; Iwai, Y.; Masumizu, A.;
6c. Catalyzed Acylation of (2-Naphthyl)methanol in the Absence
of Other Alcohols. To stock solution A (0.40 mL) was added stock
solution B (0.10 mL) followed by propionic anhydride (64 μL,
0.50 mmol), resulting in a reaction mixture with the following initial
concentrations of the reactants: 0.80 M (2-naphthyl)methanol 79,
0.040 M (S)-BTM, 1.0 M (EtCO)2O, 1.0 M i-Pr2NEt. Conversion of
(2-naphthyl)methanol reached 50% in 28 min (Table 9, entry 2).
6d. Catalyzed Acylation of (2-Naphthyl)methanol 79 in the
Presence of Other Alcohols. Typical Procedure. One milliliter
aliquots of Stock Solutions A and C-1 were each treated with
propionic anhydride (128 μL, 1.0 mmol, 1 equiv). Within 1.5−2 min
of mixing, a 0.1 mL aliquot of reaction mixture C-1 was added to a
0.4 mL aliquot of reaction mixture A resulting in the following initial
concentrations of the reactants: 0.80 M (2-naphthyl)methanol 79, 0.20 M
( )-1-phenylethanol 7, 0.04 M (S)-BTM, 1.0 M i-Pr2NEt, 1.0 M
(EtCO)2O. At that time, the conversion of 7 into its ester was
estimated to be 49%. Monitoring by NMR continued. The conversion
of 7 did not change substantially over time, while that of 79 reached
50% after 45 min (Table 9, entry 3, column 4).
́
Akiyama, Y. J. Org. Chem. 2006, 71, 6872. (h) O'Dalaigh, C.; Connon,
S. J. J. Org. Chem. 2007, 72, 7066. (i) Crittall, M. R.; Rzepa, H. S.;
Carbery, D. R. Org. Lett. 2011, 13, 1250. Imidazoles: (j) Miller, S. J.
Acc. Chem. Res. 2004, 37, 601. (k) Ishihara, K.; Sakakura, A.; Hatano,
M. Synlett 2007, 686. (l) Geng, X.-L.; Wang, J.; Li, G.-X.; Chen, P.;
Tian, S.-F.; Qu, J. J. Org. Chem. 2008, 73, 8558. (m) Hrdina, R.;
Muller, C. E.; Schreiner, P. R. Chem. Commun. 2010, 46, 2689.
Phosphines and phosphinites: (n) Vedejs, E.; Daugulis, O. J. Am.
Chem. Soc. 2003, 125, 4166. (o) Mizuta, S.; Ohtsubo, Y.; Tsuzuki, T.;
Fujimoto, T.; Yamamoto, I. Tetrahedron Lett. 2006, 47, 8227. Vicinal
diamines: (p) Oriyama, T.; Taguchi, H.; Terakado, D.; Sano, T. Chem.
Lett. 2002, 26. N-Heterocyclic carbenes: (q) Kano, T.; Sasaki, K.;
Maruoka, K. Org. Lett. 2005, 7, 1347. Lewis acids: (r) Mitsuda, M.;
Tanaka, T.; Tanaka, T.; Demizu, Y.; Onomura, O.; Matsumura, Y.
Tetrahedron Lett. 2006, 47, 8073. (s) Gissibl, A.; Finn, M. G.; Reiser,
After aging reaction mixture C-1 for 2 h at room temperature, a new
0.1 mL aliquot was withdrawn from it and added to 0.4 mL of freshly
prepared reaction mixture A (stock solution A + (EtCO)2O). The
conversion of 7 at that point was 82%. The half-life of 79 in the re-
sulting mixture was 51 min (Table 9, entry 3, column 5). The
procedure described above was repeated with stock solutions C-2−
C-5. The results are summarized in Table 9, entries 4−7.
O. Org. Lett. 2005, 7, 2325. (t) Mazet, C.; Roseblade, S.; Kohler, V.;
̈
Pfaltz, A. Org. Lett. 2006, 8, 1879.
(6) (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J.
J. Am. Chem. Soc. 2004, 126, 12226. (b) Birman, V. B.; Jiang, H. Org.
Lett. 2005, 7, 3445. (c) Birman, V. B.; Li, X.; Jiang, H.; Uffman, E. W.
Tetrahedron 2006, 62, 285. (d) Birman, V. B.; Li, X. Org. Lett. 2006, 8,
1351. (e) Birman, V. B.; Guo, L. Org. Lett. 2006, 8, 4859. (f) Birman,
V. B.; Li, X.; Han, Z. Org. Lett. 2007, 9, 37. (g) Birman, V. B.; Jiang,
H.; Li, X. Org. Lett. 2007, 9, 3237. (h) Birman, V. B.; Li, X. Org. Lett.
2008, 10, 1115. (i) Li, X.; Liu, P.; Houk, K. N.; Birman, V. B. J. Am.
Chem. Soc. 2008, 130, 13836. (j) Zhang, Y.; Birman, V. B. Adv. Synth.
Catal. 2009, 351, 2525.
(7) (a) Shiina, I.; Nakata, K. Tetrahedron Lett. 2007, 48, 8314.
(b) Shiina, I.; Nakata, K.; Ono, K.; Sugimoto, M.; Sekiguchi, A.
Chem.Eur. J. 2010, 16, 167. (c) Shiina, I.; Ono, K.; Nakata, K. Chem.
Lett. 2011, 40, 147.
(8) (a) Zhou, H.; Xu, Q.; Chen, P. Tetrahedron 2008, 64, 6494.
(b) Xu, Q.; Zhou, H.; Geng, X.; Chen, P. Tetrahedron 2009, 65, 2232.
(c) Chen, P.; Zhang, Y.; Zhou, H.; Xu, Q. Acta Chim. Sin. 2010, 68,
1431.
(9) Belmessieri, D.; Joannesse, C.; Woods, P. A.; MacGregor, C.;
Jones, C.; Campbell, C. D.; Johnston, C. P.; Duguet, N.; Concellon,
C.; Bragg, R. A.; Smith, A. D. Org. Biomol. Chem. 2011, 9, 559.
(10) Kobayashi, M.; Okamoto, S. Tetrahedron Lett. 2006, 47, 4347.
(11) (a) Hu, B.; Meng, M.; Wang, Z.; Du, W. T.; Fossey, J. S.; Hu,
X. Q.; Deng, W. P. J. Am. Chem. Soc. 2010, 132, 17041. (b) Hu, B.;
Meng, M.; Fossey, J. S.; Mo, W. M.; Hu, X. Q.; Deng, W. P. Chem.
Commun. 2011, 47, 10632.
(12) (a) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W.
J. Am. Chem. Soc. 2006, 128, 6536. (b) Yang, X.; Bumbu, V. D.;
Birman, V. B. Org. Lett. 2011, 13, 4755.
(13) (a) Purohit, V. C.; Matla, A. S.; Romo, D. J. Am. Chem. Soc.
2008, 130, 10478. (b) Leverett, C. A.; Purohit, V. C.; Romo, D. Angew.
Chem., Int. Ed. 2010, 49, 9479. (c) Belmessieri, D.; Morrill, L. C.;
Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011, 133,
2714.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: birman@wustl.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Washington University in Saint Louis, the National
Institute of General Medical Sciences (R01 GM072682), and
the National Science Foundation (CHE 1012979) for support
of these studies.
REFERENCES
■
(1) For selected catalytic, enantioselective approaches to secondary
alcohols, see: Hydride reduction of ketones: (a) Cho, B. T. Chem. Soc.
Rev. 2009, 38, 443. (b) Cho, B. T. Tetrahedron 2006, 62, 7621.
Hydrogenation of ketones: (c) Wang, C.; Wu, X.; Xiao, J. Chem. Asian
J. 2008, 3, 1750. (d) Sandoval, C. A.; Ohkuma, T.; Muniz, K.; Noyori,
R. J. Am. Chem. Soc. 2003, 125, 13490. Addition of carbon
nucleophiles to aldehydes: (e) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101,
757. Ring opening of epoxides: (f) Jacobsen, E. N. Acc. Chem. Res.
2000, 33, 421. (g) Pineschi, M. Eur. J. Org. Chem. 2006, 22, 4979.
(2) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(3) Williams, J. M. J.; Parker, R. J.; Neri, C. Enzymatic Kinetic
Resolution. In Enzyme Catalysis in Organic Synthesis, 2nd ed.; Drauz,
K., Waldmann, H., Eds.; Wiley-VCH: New York, 2002;Vol. 1, pp 287−
312.
(14) (a) Dietz, F. R.; Groger, H. Synlett 2008, 663. (b) Dietz, F. R.;
̈
Groger, H. Synthesis 2009, 4208.
̈
(4) For reviews summarizing advances in this field, see: (a) Vedejs,
E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44, 3974. (b) Denmark, S. E.;
Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560. (c) Spivey, A. C.;
Arseniyadis, S. Top. Curr. Chem. 2010, 291, 233. (d) Muller, C. E.;
Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50, 6012. (e) Pellissier, H.
(15) (a) Joannesse, C.; Simal, C.; Concellon, C.; Thomson, J. E.;
Campbell, C. D.; Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem.
2008, 6, 2900. (b) Joannesse, C.; Johnston, C. P.; Concellon, C.;
Simal, C.; Philp, D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48,
8914.
̈
Adv. Synth.Catal. 2011, 353, 1613.
1736
dx.doi.org/10.1021/jo202220x | J. Org. Chem. 2012, 77, 1722−1737

The Journal of Organic Chemistry
Article
(16) (a) Shiina, I.; Nakata, K.; Onda, Y. Eur. J. Org. Chem. 2008,
5887. (b) Shiina, I.; Nakata, K.; Ono, K.; Onda, Y.; Itagaki, M. J. Am.
Chem. Soc. 2010, 132, 11629.
(17) (a) Yang, X.; Birman, V. B. Adv. Synth. Catal. 2009, 351, 2301.
(b) Yang, X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892. (c) Yang, X.;
Birman, V. B. Angew. Chem., Int. Ed. 2011, 50, 553. (d) Yang, X.;
Birman, V. B. Chem.Eur. J. 2011, 17, 11296. (e) Bumbu, V. D.;
Birman, V. B. J. Am. Chem. Soc. 2011, 133, 13902.
(18) (a) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268.
(b) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2011, 133, 16001.
(19) Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Org. Lett. 2011, 13,
3794.
(20) (a) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.; Fossey, J. S.;
Deng, W.-P. Angew. Chem., Int. Ed. 2011, 50, 4897. (b) Shi, Y. H.;
Wang, Z.; Hu, B.; Wang, M.; Fossey, J. S.; Deng, W. P. Org. Lett. 2011,
13, 6010.
(21) Several other classes of catalysts are particularly effective in the
KR of secondary benzylic alcohols: See ref 5a,c,g,i,n,q.
(22) Enantioselectivity in kinetic resolutions is usually expressed in
terms of a selectivity factor (s) defined as the ratio of reaction rates of
the fast- and the slow-reacting enantiomers of the starting material: s =
kfast/kslow. If the starting material is racemic, both the conversion (C)
and the selectivity factor s can be calculated from the ee values of the
product and the recovered substrate according to Kagan’s equations
(ref 2) as follows: C = eeSM/(eeSM + eePR); s = ln[(1 − C)(1 −
eeSM)]/ln[(1 − C)(1 + eeSM)].
(23) It should be noted in this context that the calculation of high
selectivity factors (s > 100) from the ee values (refs 2 and 22), is prone
to significant error. Therefore, these values should be treated as
approximate.
(24) See, e.g. (a) Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem.
1998, 63, 2794. (b) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 1999,
121, 5813. (c) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000,
65, 3154 and ref 5i.
(36) Janssen, A. J. M.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron
1991, 47, 7645.
(37) Matharu, D. S.; Morris, D. J.; Clarkson, G. J.; Wills, M. Chem.
Commun. 2006, 3232.
(38) Evans, D. A.; Anderson, J. C.; Taylor, M. K. Tetrahedron Lett.
1993, 34, 5563.
(39) Hatzakis, N. S.; Smonou, I. Bioorg. Chem. 2005, 33, 325.
(40) Kantam, M. L.; Yadav, J.; Laha, S.; Srinivas, P.; Sreedhar, B.;
Figueras, F. J. Org. Chem. 2009, 74, 4608.
(41) Ramachandran, P. V.; Gong, B.; Brown, H. C. Tetrahedron Lett.
1994, 35, 2141.
(42) (a) Fronza, G.; Fuganti, C.; Grasselli, P.; Mele, A. J. Org. Chem.
1991, 56, 6019. (b) Silvestri, R.; Artico, M.; Regina, G. L.; Pasquali,
A. D.; Martino, G. D.; D’Auria, F. D.; Nencioni, L.; Palamara, A. T.
J. Med. Chem. 2004, 49, 3924.
(43) Solladie-Cavallo, A.; Roje, M.; Isarno, T.; Sunjic, V.; Vinkovic, V.
Eur. J. Org. Chem. 2000, 6, 1077.
(44) (a) Pilli, R. A.; Dias, L. C. Synth. Commun. 1991, 21, 2213.
(b) Angoli, M.; Barilli, A.; Lesma, G.; Passarella, D.; Riva, S.; Silvani,
A.; Danieli, B. J. Org. Chem. 2003, 68, 9525.
(45) (a) Seemayer, R.; Schneider, M. P. Tetrahedron: Asymmetry
1992, 3, 827. (b) Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem.
2006, 71, 7035.
(46) Martelli, J.; Gree
Tetrahedron 1989, 45, 4213.
́ ́
, D.; Kessabi, J.; Gree, R.; Toupet, L.
(47) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(48) Akai, S.; Hanada, R.; Fujiwara, N.; Kita, Y.; Egi, M. Org. Lett.
2010, 12, 4900.
(49) Li, D. R.; He, A.; Falck, J. R. Org. Lett. 2010, 12, 1756.
(50) Blackmond, D. G.; Hodnett, N. S.; Lloyd-Jones, G. C. J. Am.
Chem. Soc. 2006, 128, 7450.
(51) Adam, W.; Humpf, H.-U.; Roschmann, K. J.; Saha-Moller, C. R.
̈
J. Org. Chem. 2001, 66, 5796.
(52) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129.
(53) Kawanami, Y.; Mikami, Y.; Hoshino, K.; Suzue, M.; Kajihara, I.
Chem. Lett. 2009, 38, 722.
(25) These results deviate from those reported in our original
study.6a During repetition of the KR under uniform conditions,
substrates 17−19 and 24 produced lower selectivity factors, and
substrate 22 a higher selectivity factor than those found earlier.
(26) Enantiomeric enrichment of nonracemic 26 using BTM-
catalyzed KR has been reported recently: Ball, J. C.; Brennan, P.;
Elsunaki, T. M.; Jaunet, A.; Jones, S. Tetrahedron: Asymmetry 2011, 22,
253.
(54) Stanetty, P.; Mihovilovic, M. D.; Mereiter, K.; Vollenkle, H.
̈
Tetrahedron 1998, 54, 875.
(55) Kashoulis, A.; Gilbert, A.; Ellis-Davies, G. Tetrahedron Lett.
1984, 25, 2905.
(27) Pirkle, W. H.; Sikkenga, D. L.; Pavlin, M. S. J. Org. Chem. 1977,
42, 384.
(28) In this case, the low enantioselectivity may arise from the
competition between the phenyl and the pyridyl groups in the
transition state. See Table 8 for examples of a β-aryl group directing
chiral recognition.
(29) Nonenzymatic KR of this class of alcohols can be accomplished
with high enantioselectivity via asymmetric epoxidation: Martin, V. S.;
Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B.
J. Am. Chem. Soc. 1981, 103, 6237.
(30) Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F. M.;
Fu, G. C. Chem. Commun. 2000, 1009.
(31) Vedejs, E.; MacKay, J. A. Org. Lett. 2001, 3, 535.
(32) Individual examples of allylic alcohols can also be found in ref 5g
and 5q.
(33) Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc.
1999, 121, 5091.
(34) Previously, 63 had been resolved successfully (s > 20) by several
other nonenzymatic catalysts: (a) Sano, T.; Imai, K.; Ohashi, K.;
Oriyama, T. Chem. Lett. 1999, 265. (b) Copeland, G. T.; Miller, S. J.
J. Am. Chem. Soc. 2001, 123, 6496. (c) Jeong, K. S.; Kim, S. H.; Park,
H. J.; Chang, K. J.; Kim, K. S. Chem. Lett. 2002, 1114. (d) Dalaigh,
C. O.; Hynes, S. J.; O’Brien, J. E.; McCabe, T.; Maher, D. J.; Watson,
G. W.; Connon, S. J. Org. Biomol. Chem. 2006, 4, 2785.
(35) Besides 2-aryl derivatives, several other types of 2-substituted
cycloalkanols have been resolved: (a) Kawamata, Y.; Oriyama, T.
Chem. Lett. 2010, 39, 382. (b) References 5k and 34a,b.
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