Unusual temperature dependence of enantioselectivity in asymmetric reductions by chiral NADH models

Article abstract of DOI:10.1021/ol060475g

Unusual stereoselectivity changes, i.e., enhancement and inversion of enantioselectivity with increasing temperature, were observed in the asymmetric reduction of methyl benzoylformate with chiral 1,4-dihydropyridines possessing amino acid residues as lig

Full text of DOI:10.1021/ol060475g

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2067-2070
Unusual Temperature Dependence of
Enantioselectivity in Asymmetric
Reductions by Chiral NADH Models
Ryota Saito,*,† Shoichiro Naruse,† Koji Takano,† Keiko Fukuda,†
Akira Katoh,† and Yoshihisa Inoue*,‡,§
Department of Materials and Life Science, Seikei UniVersity, 3-3-1 Kichijoji-kitamachi,
Musashino 180-8633, Japan, Entropy Control Project, ICORP, JST, Kamishinden,
Toyonaka 560-0085, Japan, and Department of Applied Chemistry, Osaka UniVersity,
2-1 Yamada-oka, Suita 565-0871, Japan
rsaito@st.seikei.ac.jp
Received February 24, 2006
ABSTRACT
Unusual stereoselectivity changes, i.e., enhancement and inversion of enantioselectivity with increasing temperature, were observed in the
asymmetric reduction of methyl benzoylformate with chiral 1,4-dihydropyridines possessing amino acid residues as ligating chiral auxiliaries.
q
q
The differential activation parameters, ∆∆
H
and ∆∆
S
R, obtained from the Eyring plots demonstrate that the entropy term controls the
S-
S
-R
enantiodifferentiating step, accounting for the observed unique temperature dependencies.
1,4-Dihydropyridines are known to be the active part of the
reduced form of the nicotinamide adenine dinucleotide
(NADH), which plays a vital role in many biological
reductions through the transfer of a hydride or two electrons
plus one proton to a substrate bound to an enzyme in living
systems.1 Since the first demonstration of the stereoselective
reduction of ethyl benzoylformate with an NADH model
possessing a chiral carboxamide at C3,2 a variety of 1,4-
dihydropyridine derivatives have been synthesized and
examined as chiral reducing agents for activated carbonyl
compounds (such as R-ketoesters) to mimic the highly
stereoselective bioreductions and consequently apply them
to synthetic organic chemistry.3-13
These studies demonstrated that a magnesium ion plays a
major role in the reduction of activated ketones with NADH
models through the formation of a transient “ternary”
complex with an NADH model and a substrate (Figure 1)4,5
and that the enantiomeric excess of the reduction product
can be enhanced by blocking one of the two enantiotopic
hydrogens at C4 or by locking the dihydropyridine confor-
mation by bridging its C2 and C3,10,11 C3 and C5,3 or N1
and C312 positions. Earlier studies also revealed that the
simple alteration of an achiral moiety of the chiral 1,4-
dihydropyridines, possessing a natural amino acid or amino
alcohol residue, can switch the chiral sense of the product.3,8
Similarly, a 1,3-cyclic NADH model and the corresponding
† Seikei University.
‡ Entropy Control Project.
§ Osaka University.
(1) Stryer, L. Biochemistry, 3rd ed.; Freeman: New York, 1988; Chapters
15-18.
(2) Ohnishi, Y.; Kagami, M.; Ohno, A. J. Am. Chem. Soc. 1975, 97,
4766-4768.
10.1021/ol060475g CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/21/2006

Figure 1. Schematic illustration of the proposed ternary complexes (or the transition states) involved in the asymmetric reduction of
R-ketoesters with chiral 1,4-dihydronicotinamides.
open-chain analogue afford (R)- and (S)-products, respec-
tively, upon reduction of methyl benzoylformate.12 Clearly,
the conformational changes, caused by varying the achiral
moiety or disconnecting the bridge, are suspected to be
responsible for such switching of the product’s chirality.
However, its origin and the factors and mechanism control-
ling this intriguing and potentially useful phenomenon remain
unanswered. We wish now to report the results of our
examinations of the temperature effect on the enantiodiffer-
entiating reduction of methyl benzoylformate with simple
NADH models, 1a-d, containing amino acid residues as
chiral auxiliaries (Table 1). This study will reveal the origin
of the chirality inversion and the role of entropy in this
biomimetic enantiodifferentiating process and will propose
the possibility of enantioselectivity manipulation by reaction
temperature.
We performed the asymmetric reduction of methyl ben-
zoylformate (0.2 mmol) with 1a-d (0.2 mmol) under an
argon atmosphere in the presence of anhydrous magnesium
perchlorate (0.2 mmol)12,13 in dehydrated acetonitrile (4.0
mL) over a temperature range of -35 to 72 °C. Gas
chromatographic (GC) analysis of the reaction mixture after
workup showed that only the reduction of the ketoester
proceeded to give chiral methyl mandelate in moderate to
excellent chemical yields, which were not completely
Table 1. Results and Activation Parameters for the
Asymmetric Reduction of Methyl Benzoylformate with the
Enantiopure NADH Models 1a-e in Acetonitrile in the
Presence of Magnesium Ions at Various Temperatures
1,4-Dihydronicotinamides (1) possessing an amino acid
residue (i.e., methyl esters of L-alanine, L-valine, L-pheny-
lalanine, L-proline, and (S)-phenylglycine) were synthesized
by reduction of the corresponding pyridinium salts, which
were synthesized by reacting nicotinyl chloride hydrochloride
with the corresponding amino acid methyl esters in the
presence of triethylamine and the subsequent N-methylation
with iodomethane.12
(3) Endo, T.; Hayashi, Y.; Okawara, M. Chem. Lett. 1977, 6, 391-394.
(4) Ohno, A.; Nakai, J.; Nakamura, K.; Goto, T.; Oka, S. Bull. Chem.
Soc. Jpn. 1981, 54, 3482-3485
(5) Ohno, A.; Kobayashi, H.; Goto, T.; Oka, S. Bull. Chem. Soc. Jpn.
1984, 57, 1279-1282.
(6) Talma, A. G.; Jouin, P.; De Vries, J. G.; Troostwijk, C. B.; Werumeus
Buning, G. H.; Waninge, J. K.; Visscher, J.; Kellogg, R. M. J. Am. Chem.
Soc. 1985, 107, 3981-3997.
(7) Yasui, S.; Ohno, A. Bioorg. Chem. 1986, 14, 70-96.
(8) Binay, P.; Dupas, G.; Bourguignon, J.; Que´guiner, G. Tetrahedron
Lett. 1988, 29, 931-932.
(9) Almarsson, O.; Bruice, T. C. J. Am. Chem. Soc. 1993, 115, 2125-
2138.
(10) Combret, Y.; Duflos, J.; Dupas, G.; Bourguignon, J.; Que´guiner,
G. Tetrahedron: Asymmetry 1993, 4, 1635-1644.
(11) Combert, Y.; Duflos, J.; Dupas, G.; Bourguingnon, J.; Que´guiner
Tetrahedron 1993, 49, 5237-5246.
a The positive sign of the ee indicates the predominant formation of the
(12) Katoh, A.; Naruse, S.; Ohkanda, J.; Yamamto, H. Heterocycles 1997,
45, 1441-1446.
S-(+)-isomer. b From eqs 1 and 2. ∆∆HqS-R given in kcal mol-1; ∆∆Sq
S-R
given in cal mol-1
.
(13) Okamura, M.; Mikata, Y.; Yamazaki, N.; Tsutsumi, A.; Ohno, A.
Bull. Chem. Soc. Jpn. 1993, 66, 1191-1196.
2068
Org. Lett., Vol. 8, No. 10, 2006

optimized. The enantiomeric excess (ee) of the product was
determined by chiral HPLC analysis.12 Control experiments
revealed that the enantiomeric methyl mandelate does not
racemize under the employed reaction conditions even at 72
°C.
ln(kS/kR) ) ln[(100 + % ee)/(100 - % ee)]
ln(kS/kR) ) ∆∆SqS-R/R - ∆∆HqS-R/RT
(1)
(2)
As can be seen from the differential Eyring equation (eq
2),14-16 the enantioselectivity in an asymmetric reaction is
determined in general by a balance of the enthalpy and
entropy terms. The unique temperature dependence profiles
obtained with 1c and 1d (and anticipated for the other NADH
models) imply that not only the enthalpic but also the
entropic contributions are significant in the enantiodifferen-
tiating reduction step of this reaction, as was the case with
the other photochemical and catalytic asymmetric reactions
reported previously.14-17
The temperature effects on the product’s ee are illustrated
in Figure 2, where the natural logarithm of the relative rate
To understand the nature of the present temperature effect,
the differential activation enthalpy (∆∆Hq
) ∆∆Hq
-
S-R
S
∆∆Hq ) and entropy (∆∆Sq
) ∆∆Sq - ∆∆Sq ) values
R
S-R
S
R
were calculated by applying eq 2 to the plots in Figure 2.
As shown in Table 1, the ∆∆Sq
values are not equal to
S-R
zero. Especially, the ∆∆SqS-R values for 1c (-3.75 cal/mol)
and 1d (+1.89 cal/mol) are comparably large to those
observed in the enantiodifferentiating photoisomerization of
cyclooctene.17 These large ∆∆Sq
values are thought to
S-R
be due to large activation volume variations caused by the
broader movement sphere of the benzyl group (for 1c) and
the flipping action of the pyrrolidine ring (for 1d). Moreover,
Figure 2. Temperature dependence of the enantioselectivity in the
asymmetric reduction of methyl benzoylformate with 1a (closed
circle; r (correlation coefficient) ) 0.983), 1b (closed square; r )
0.973), 1c (closed triangle; r ) 0.989), 1d (open circle; r ) 0.980),
and 1e (open square; r ) 0.990).
the ∆∆Hq
and ∆∆Sq
values were found to have the
S-R
S-R
same sign. These factors are jointly responsible for the unique
temperature-dependent ee changes, i.e., the switching of the
product’s chirality at certain temperatures and the ee
enhancement at higher temperatures.14,17
Ohno et al. previously proved the significant contribution
made by the entropy term in the asymmetric reduction with
simple NADH models.18 However, they employed inherently
chiral 4-substituted NADH models possessing a methyl at
C4, and the asymmetric reduction of benzoquinones was
conducted in the absence of the magnesium ion. Our present
study provides the first example of the entropy-controlled
asymmetric reduction with NADH models, which do not
carry a stereogenic center at the C4 but form a ternary
complex with the substrate organized by the magnesium ion,
thus constituting one of the simplest biomimetic asymmetric
reduction systems using 1,4-dihydronicotinamides. Moreover,
the present study provides the first example of chirality
inversion instigated by the reaction temperature in a biomi-
metic reduction. Product-chirality switching phenomena
caused by temperature have recently been reported for chiral
photochemical reactions14,16,19 and less frequently for thermal
reactions, such as desymmetrization with chiral organotin
catalysts15 and the enzymatic kinetic resolution of racemic
secondary alcohols,20 but the same phenomenon has never
been observed in a biomimetic reduction.
constant for the formation of (S)-(+)- and (R)-(-)-methyl
mandelate, i.e., the ln(kS/kR) value calculated by eq 1,14 is
plotted as a function of the reciprocal temperature to give a
good straight line in each case. When the reduction was
conducted with 1a (R ) Ala-OMe), (S)-methyl mandelate
was predominantly obtained, whereas the reduction with 1b
(Val-OMe) and 1e (PhG-OMe) gave the (R)-enantiomer (at
least in the temperature range employed). This clearly
demonstrates that the achiral substituent at the stereogenic
center significantly affects the stereochemical outcome of
the asymmetric reduction and can cause the inversion of the
product’s chirality, as revealed by simply replacing the
methyl in 1a with isopropyl (1b) or phenyl (1e) which leads
to the inversion of the product’s chirality. It is also
noteworthy that the product’s ee is improved not by lowering
but by raising the temperature, as can be seen with 1c (Phe-
OMe) in the temperature range employed. Of particular
interest is the discovery that the major enantiomer produced
with 1d (Pro-OMe) is switched from (R)- to (S)-methyl
mandelate at around 0 °C, and thereafter, the ee continues
to increase as the temperature is further elevated. It should
be emphasized that the enantiodifferentiation mechanism is
unchanged over the whole temperature range in the present
system because, in each case, all the plots fit to a single
straight line over the temperature range.15
(15) Otera, J.; Sakamoto, K.; Tsukamoto, T.; Orita, A. Tetrahedron Lett.
1998, 39, 3201-3204.
(16) Poon, T.; Sivaguru, J.; Franz, R.; Jockusch, S.; Martinez, C.;
Washington, I.; Adam, W.; Inoue, Y.; Turro, N. J. J. Am. Chem. Soc. 2004,
126, 10498-10499
(17) Inoue, Y.; Ikeda, H.; Kaneda, M.; Sumiura, T.; Everitt, S. R. L.;
Wada, T. J. Am. Chem. Soc. 2000, 122, 406-407.
(18) Ohno, A.; Goto, M.; Mitaka, Y.; Kashiwagi, T.; Murayama, T. Bull.
Chem. Soc. Jpn. 1991, 64, 87-90.
(14) (a) Inoue, Y. Chem. ReV. 1992, 92, 741-770. (b) Inoue, Y.;
Ramamurthy, V. Chiral Photochemistry; Marcel Dekker: New York, 2004.
Org. Lett., Vol. 8, No. 10, 2006
2069

For a global view of the present asymmetric reduction
system, we examined whether the enthalpy-entropy com-
pensation relationship holds. In Figure 3, the obtained
interactions are involved to retain the structural integrity of
the diastereomeric exciplex structure.14,19 In the present
system, the ternary complex composed of the NADH model,
the magnesium ion, and the substrate is in a very similar
situation, involving weak ligation of multiple carbonyls to
the magnesium ion. As a consequence of the conformational
flexibility of the ternary complex, arising from the weak
interactions, the enantiodifferentiating hydride transfer is
thought to be sensitive to the temperature changes.
In conclusion, we have shown that the product chirality
can be inverted by simply changing the reaction temperature
and further that the product’s ee increases with increasing
temperature. These apparently unusual phenomena were
analyzed by the differential Eyring equation (eq 2) to show
the crucial contributions of the same-sign enthalpic and
entropic terms, which are balanced depending on the reaction
temperature. Thus, the product’s chirality is determined by
the enthalpy term at low temperatures. As the temperature
increases, the relative contribution of the enthalpy to the
differential activation free energy, or the product’s ee,
decreases as it reaches the critical racemic point, where
∆∆SqS-R/R ) ∆∆HqS-R/RT in eq 2, and thereafter, the
product’s chirality is dominated by the entropy term to give
the product with the opposite ee increasing with increasing
temperature. Judging from the similar phenomena found
already for several asymmetric reactions in the ground and
excited states, we may conclude that the origin of such
dramatic switching behavior is the difference in conforma-
tional flexibility of the diastereomeric transition states
involved. We may further propose a new general strategy
for controlling chiral reactions utilizing conformational
flexibility and other entropy-related factors, which is an
alternative approach to the conventional strategy of con-
structing a rather rigid, structured framework around the
reaction center.
Figure 3. Enthalpy-entropy compensation plot for the differential
activation parameters obtained in the asymmetric reduction of
methyl benzoylformate with 1,4-dihydropyridines (1a-e).
∆∆Sq
values are plotted against the ∆∆Hq
values.
S-R
S-R
Interestingly, all of the data points fit well to a single straight
line with a correlation coefficient of 0.983. The slope of this
line gives an isokinetic, or isoenantiodifferentiating, tem-
perature of -27 °C. These results confirm that the enan-
tiodifferentiating mechanism is not altered by changing the
chiral auxiliary, even though a chirality switching by
temperature variation is observed.
According to mechanistic investigations of the enantiod-
ifferentiating photoreactions, the chirality inversion phenom-
enon is associated with the intervention of a conformationally
flexible excited-state complex (exciplex), where several weak
Acknowledgment. Financial support by MEXT to R.S.
is gratefully appreciated. We would like to thank Dr. Guy
A. Hembury for assistance in the preparation of this
manuscript.
(19) (a) Inoue, Y.; Yamasaki, N.; Yokoyama, T.; Tai, A. J. Org. Chem.
1992, 57, 1332-1345. (b) Inoue, Y.; Matsushima, E.; Wada, T. J. Am.
Chem. Soc. 1998, 120, 10687-10696. (c) Hoffmann, R.; Inoue, Y. J. Am.
Chem. Soc. 1999, 121, 10702-10710. (d) Asaoka, S.; Wada, T.; Inoue, Y.
J. Am. Chem. Soc. 2003, 125, 3008-3027.
(20) (a) Pham, V. T.; Phillips, R. S.; Ljungdahl, L. G. J. Am. Chem.
Soc. 1989, 111, 1935-1936. (b) Tripp, A. E.; Burdette, D. S.; Zeikus, J.
G.; Phillips, R. S. J. Am. Chem. Soc. 1998, 120, 5137-5141. (c) Pham, V.
T.; Phillips, R. S. J. Am. Chem. Soc. 1990, 112, 3629-3632. (d) Heiss, C.;
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Supporting Information Available: Experimental pro-
cedures and spectroscopic data for the NADH models. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060475G
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Org. Lett., Vol. 8, No. 10, 2006