Entropy-controlled asymmetric synthesis. How differential activation entropy is induced in chiral tethered reactions

Article abstract of DOI:10.1021/ol006741m

(equation presented) Kinetic measurements to determine effective molarities of intramolecular reactions using 2,4-pentanediol and related tethers showed that methyl groups on the tether accelerate the major diastereomeric process but decelerate the minor process. The efficient promotion of stereocontrol is suggested to be due to chiral perturbation of the reaction rate through the entropy term. The conformation of the encounter complex of the reagent and reactant moieties was deduced by stereochemical analysis of the intramolecular adducts.

Full text of DOI:10.1021/ol006741m

ORGANIC
LETTERS
2001
Vol. 3, No. 1
37-40
Entropy-Controlled Asymmetric
Synthesis. How Differential Activation
Entropy Is Induced in Chiral Tethered
Reactions
Takashi Sugimura,* Kazutake Hagiya, Yasuhiro Sato, Takahiro Tei, Akira Tai, and
Tadashi Okuyama
Faculty of Science, Himeji Institute of Technology, Kohto, Kamigori,
Ako-gun, Hyogo 678-1297, Japan
sugimura@sci.himeji-tech.ac.jp
Received November 27, 2000
ABSTRACT
Kinetic measurements to determine effective molarities of intramolecular reactions using 2,4-pentanediol and related tethers showed that
methyl groups on the tether accelerate the major diastereomeric process but decelerate the minor process. The efficient promotion of stereocontrol
is suggested to be due to chiral perturbation of the reaction rate through the entropy term. The conformation of the encounter complex of the
reagent and reactant moieties was deduced by stereochemical analysis of the intramolecular adducts.
The reaction using a chiral 2,4-pentanediol tether between
prochiral reactant and reagent moieties (PD-tethered reaction)
is a versatile and practical method for asymmetric syntheses.1
The stereochemistries of the products are strictly controlled
by only the two small methyl groups (and even by a single
methyl group in some cases1c,2) on the flexible tether
irrespective of the reaction type, rate, or conditions. Recently,
we have shown that one of the PD-tethered reactions
maintains its stereoselectivity over a wide range of reaction
temperatures (185-423 K) and concluded that the differential
activation free energy (∆∆G‡) of the two diastereomeric
processes controlled by the PD tether consists mostly of the
differential activation entropy (∆∆S‡).2 Thus, entropy-
controlled asymmetric synthesis (ECAS) has been proposed
to have high potential for stereocontrol with a simple reaction
design. In this communication, we report kinetic and stereo-
chemical studies on a PD-tethered reaction to clarify how
the chiralities on the tether induce sufficient stereochemical
control.
(1) (a) Sugimura, T.; Yoshikawa, M.; Futagawa, T.; Tai, A. Tetrahedron
1990, 46, 5955-5966. Sugimura, T.; Yoshikawa, M.; Mizuguchi, M.; Tai,
A. Chem. Lett. 1999, 831-832. (b) Underiner, T. L.; Paquette, L. A. J.
Org. Chem. 1992, 57, 5438-5446. Sugimura, T.; Iguchi, H.; Tsuchida, R.;
Tai, A.; Nishiyama, N.; Hakushi, T. Tetrahedron: Asymmetry 1998, 9,
1007-1013. (c) Sugimura, T.; Nishiyama, N.; Tai, A. Tetrahedron:
Asymmetry 1993, 4, 43-44. (d) Sugimura, T.; Yamada, H.; Inoue, S.; Tai,
A. Tetrahedron: Asymmetry 1997, 8, 649-655. Sugimura, T.; Inoue, S.;
Tai, A. Tetrahedron Lett. 1998, 39, 6487-6490. (e) Mori, A.; Sugimura,
T.; Tai, A. Tetrahedron: Asymmetry 1997, 8, 661-664. (f) Sugimura, T.;
Nagano, S.; Tai, A. Chem. Lett. 1998, 45-46. (g) Yamaguchi, K.; Sugimura,
T.; Nishida, F.; Tai, A. Tetrahedron Lett. 1998, 39, 4521-4524.
(2) Sugimura, T.; Tei, T.; Mori, A.; Okuyama, T.; Tai, A. J. Am. Chem.
Soc. 2000, 122, 2128-2129.
Alkyl substitution as the chiral origin to control asym-
metric synthesis usually affects the reaction by differential
retardation between the two diastereomeric processes by
steric repulsion or structural strain in the two transition states.
However, when the perturbation of the reaction rate by the
alkyl substituent is induced in an entropy term, an increase
in the reaction rate is also possible through an increase in
the frequency factor of the reaction. Thus, we determined
the effect of the methyl groups on the PD tether upon the
intramolecular reaction rate.
10.1021/ol006741m CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/07/2000

The reaction employed for the present study is the Rh2-
(OAc)4-catalyzed reaction of the diazo ester and the phenyl
group tethered by PD (1 in Scheme 1), where two pairs of
(>90%) was observed with m-tolyl derivatives 6 and 7 in
addition to the stereocontrol (>99.6% de) with chiral 6. The
reactions of o-tolyl derivatives 8 and 9 were sluggish. The
achiral substrate 9 was converted to a mixture of products
which mostly retained the o-tolyl group, while 8 gave an
unexpected adduct at the 4,5-position by using Rh2(OAc)4
Scheme 1
7
(>80% de). When 8 was treated with Rh2(OCOCF3)4, the
product was sharply switched to the regular adduct at the
1,2-position (>99.6% de).
The relative rates for the intramolecular and the intermo-
lecular additions of the rhodium carbenoids produced in situ
were determined by the reaction of the substrate in the
presence of benzene (at 20 ( 1 °C). The reaction resulted
in both the intra- and intermolecular additions to give the
corresponding cycloheptatrienes, the ratio of which was
1
determined by H NMR. The relative rates calculated from
the ratios at various concentrations of benzene were con-
verted to the effective molarities compared with isopropoxy-
benzene as a reference substrate (Table 1).8
Table 1. Effective Molarities of the Reaction of 1-8 with
Rh2(OAc)4 and Perturbation Factors R for the Major Isomers
substrate
effective molarity/M
R6aS
130
62
8.8
9.8
1a
129
1a
1.4b
R6aS/R6aR
1
2
3
4
5
6
7
8
0.64 ( 0.06
0.31 ( 0.03
0.044 ( 0.001
0.049 ( 0.011
0.010 ( 0.001
1.23 ( 0.15
>500
24
4.2
70
>500
>9b
0.019 ( 0.002
0.013 (0.003
a The reactions of 5 and 7 were used as the standard achiral reactions
b
(k6aS ) k6aR) for 1-4 and 6 and 8, respectively. R1S and R1S/R1R for 8.
adjacent reaction sites of the 1,2-positions in the phenyl group
are differentiated by the carbenoid to result in a diastereo-
merically pure cycloheptatriene via the norcaradiene inter-
mediate.1f The high diastereomeric excess (de) of the product
was further shown in the present study to be over 99.6% de
(at room temperature).3 With substrates 2-4 having a
different tether, the reaction selectivities were moderate to
very high (see Scheme 1), and the major products had the
same 6aS stereochemistry as that of 1.4,5,6 Good regiocontrol
The reactions of the PD-tethered substrates, 1 and 2, are
faster than those of 3 and 4 having a singly methylated tether,
which are faster than that of the achiral substrate 5 having
no methyl group. That is, each methyl substitution on the
tether enhances the reaction rate by 1 order of magnitude.
The low effective molarity of 5 is ascribed to the entropy
loss during the formation of an eight-membered ring from
the flexible tether.9 Acceleration of the intramolecular
reaction to give the major 6aS-stereoisomer by methyl
(3) The high de was maintained in the temperature range between -15
and 60 °C (CHCl3).
(4) Structures of the minor products were not identified in all reactions.
Values of the de of the major products were determined by GLC with achiral
and chiral columns after treatments of the reaction mixtures with lithium
aluminum hydride and acetic anhydride/pyridine. Reference samples were
prepared through epimerization of the isolated major products followed by
the above conversion. The selectivities shown in Table 1 might be
underestimated because of intermolecular reactions. See the Supporting
Information for the experimental details.
(5) For reviews, see the following: (a) Doyle, M. P. Chem. ReV. 1986,
86, 919-939. (b) Davis, H. M. In ComprehensiVe Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Oxford, 1991; pp 1031-1067. (c) Doyle, M.
P.; Forbes, D. C. Chem. ReV. 1998, 98, 911-935.
(6) For the intramolecular reactions, see the following: (a) Padwa, A.;
Krumpe, K. E. Tetrahedron 1992, 48, 5385-5453. (b) Clark, J. S.
Tetrahedron Lett. 1992, 33, 6193-6196. (c) Martin, S. F.; Spaller, M. R.;
Liras, S.; Hartmann, B. J. Am. Chem. Soc. 1994, 116, 4493-4494. (d) Taber,
D. F.; Malcolm, S. C. J. Org. Chem. 1998, 63, 3717-3721.
(7) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M.
P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc.
1993, 115, 8669-8680. Padwa, A.; Austin, D. J.; Hornbuckle, S. F. J. Org.
Chem. 1996, 61, 63-72.
(8) The reactivity ratio of isopropoxybenzene and benzene was inde-
pendently determined from the reaction with ethyl diazoacetate (9.3 ( 0.9).
(9) (a) Issacs, N. Physical Organic Chemistry; Longman Scientific &
Technical: Essex, 1995; pp 643-677. (b) Winnik, M. A. Chem. ReV. 1981,
81, 491-524.
(10) Entropy-driving acceleration of the intramolecular reaction by the
methyl substitution is known as the Thorpe-Ingold effect. See the
following: (a) Kirby, A. J. In AdVances in Physical Organic Chemistry;
Gold, V., Bethell, D., Eds.; Academic Press: London, 1980; Vol. 17, pp
183-278. (b) De Tar, D. F.; Luthra, N. P. J. Am. Chem. Soc. 1980, 102,
4505-4512. (c) Jager, J.; Graafland, T.; Schenk, H.; Kirby, A. J.; Engberts,
J. B. F. J. Am. Chem. Soc. 1984, 106, 139-143. (d) Sternbach, D. D.;
Rossana, D. M.; Ohan, K. D. Tetrahedron Lett. 1985, 26, 591-594.
38
Org. Lett., Vol. 3, No. 1, 2001

substitution on the tether is characteristic of chiral perturba-
tion through the entropy term.10 Reactions with m-tolyl
substrates being faster than those with phenyl substrates (6
vs 1 and 7 vs 5) indicates that the rate-determining step of
each overall reaction is the addition step following the
conformational change of the tether part to achieve the
encounter complex both for the chiral and achiral tethers;
the more electron-rich tolyl group should have a higher
activity toward rhodium carbenoid addition.
Selected possible structures of the encounter complex in
the reaction of 5 are illustrated in Figure 1. Since the free
The role of the methyl groups as the chiral source becomes
clearer by the introduction of a chiral perturbation factor, R.
The two diastereomeric reaction rates, k6aS and k6aR, can be
expressed by the unperturbed achiral reaction rate k of 5 (or
7) and chiral perturbation factors, R6aS and R6aR. That is, k6aS
) R6aSk/2, k6aR ) R6aRk/2, and the stereoselectivity k6aS/k6aR
) R6aS/R6aR. In energy terms, R corresponds to δ∆G‡
comprising δ∆H‡ and δ∆S‡ terms.11
Figure 1. Possible encounter complexes to give the intramolecular
adducts. Arrows indicate steric interactions (X or X' ) methyl).
energy differences among them caused by methyl substitution
on the tether should be due to the entropy term, simple MO
calculations cannot provide useful information. For example,
the two methyl groups of the substrate 2 take the axial and
equatorial positions both in A and ent-A. However, analysis
of the regio- and stereochemical outcomes indicates the
encounter complex in the present reaction to be A.
The stereochemical outcomes of 1-4 exclude processes
through encounter complexes such as ent-A and C. The
carbenoids having s-cis conformations,13 D and E, can also
be excluded because the lactone ring in the adduct has a
trans fusion. The regioselectivity of m-tolyl substrates, 6 and
7, can be explained by steric repulsion during the ensuing
addition from both A and B.
The encounter complex B is finally excluded by the results
with o-tolyl substrates, 8 and 9. The methyl group at the
X′-position causes steric repulsion with the tether proton in
both A and B. Then, the rhodium carbenoid is forced to
approach the sterically congested position (X ) Me) in A,
whereas there is no steric barrier in B. Since the reactions
of 8 and 9 were both sluggish, B can be ruled out. The
anomalous and selective reaction of 8 is also rationalized
with A. The addition of the carbenoid generated with Rh2-
(OAc)4 occurs at the 4,5-position avoiding the steric barrier,
The chiral perturbation factors R6aS for 1-4, 6, and 8 are
given in Table 1. In the reaction of 1, R6aS corresponds to a
130-fold acceleration, which translates to an increase in
activation entropy δ∆S‡6aS of 10 cal mol-1K-1. Considering
the magnitude of the stereoselectivity (R6aS/R6aR > 500), the
R
6aR value must be less than unity. That is, the methyl group
reduces the production rate of the 6aR-adduct through the
minor diastereomeric process, in contrast to its acceleration
of the major process.
Since δ∆S‡6aS for the chiral tethered reactions is expected
to be induced during the formation of the cyclic conformation
of a medium ring, the chiral fate of the reactions should be
determined at this stage prior to the start of the addition
reaction. That is, the chiralities on the tether control the
preequilibrium constants, K6aS and K6aR, for the formation
of the encounter complexes of the rhodium carbenoid and
the reaction site of the aromatic group. The chiral perturba-
tion in entropy brings about a sufficient difference in K6aS
and K6aR, and the difference is carried over to the product
ratio through the rate-determining steps.12
(11) The concept of the chiral perturbation factor is useful for under-
standing of the stereocontrol mechanism of other asymmetric syntheses.
For example, the linear relationship between the differential activation
enthalpy (∆∆H‡) and entropy (∆∆S‡) could not be understood simply as
difference in the activation parameters, ∆H‡ - ∆H‡ and ∆S‡ - ∆S‡ .
R
S
R
S
By introduction of the chiral perturbations factors, RR and RS, they are
translated to δ∆H‡R - δ∆H‡S and δ∆S‡R - δ∆S‡ , respectively. When the
S
‡
chiral perturbation mechanism is similar among the reactions, δ∆S and
δ∆H‡ show the isokinetic relation, and thus those differences, ∆∆H‡ and
∆∆S‡, should have a linear relationship. For the recent experimental
examples, see the following: (a) Gallicchio, E.; Kubo, M. M.; Lecy, R. M.
J. Am. Chem. Soc. 1998, 120, 4526-4527. (b) Inoue, Y.; Ikeda, H.; Kaneda,
M.; Sumimura, T.; Everitt, S. R. L.; Wada, T. J. Am. Chem. Soc. 2000,
122, 406-407.
(12) A similar explanation for the reaction rate using “critical distance”
in nonstereoselective reactions was also reported. Menger, F. M. Acc. Chem.
Res. 1985, 18, 128-134.
(13) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. Organo-
metallics 1984, 3, 53-61.
Org. Lett., Vol. 3, No. 1, 2001
39

whereas the more reactive carbenoid prepared with Rh2-
(OCOCF3)4 adds to the stereocongested 1,2-position in
conformation A. Thus, A is implicated as the predominant
conformation of the encounter complex giving the intramo-
lecular adducts in all the reaction systems employed in the
present study.
In conclusion, the opposite effects of the chiral source on
the reaction rates of the two diastereomeric processes are
found to be an explanation of strict stereocontrol by small
methyl groups. This efficient stereocontrol is considered to
be the most notable characteristic of ECAS. In biological
reactions and template reactions,14 selectivities controlled by
differential activation entropy are rather common. However,
most of those reactions differentiate the substrate or its
reaction site at the adsorption or incorporation step of the
substrate, and a particular combination of the substrate and
the “reactor” is necessary. The PD-tethered reaction has a
different stereocontrol mechanism, which should be called
an “intramolecular enantio-differentiating reaction”.15 This
mechanism makes the PD-tethered reaction widely ap-
plicable.
So far, we have learned from the PD-tethered reactions
that requirements for designing ECAS with versatile ap-
plicability are (1) large negative ∆S‡ before chiral perturba-
tion, (2) minimum chiral perturbation, and (3) a relatively
fast intrinsic reaction. The chiral fate of such a reaction is
determined in the encounter complex, which results in
versatile stereocontrol irrespective of the transition state of
the intrinsic reaction.
Acknowledgment. The authors thank Professor Howard
Maskill (Newscastle upon Tyne) for critically reading the
manuscript and invaluable comments.
Supporting Information Available: Experimental details
including spectral data, determination of stereochemical
purity, and kinetics determinations. This information is
available free of charge via the Internet at http://pubs.acs.org.
(14) Diederich, F.; Stang, P. J. Templated Organic Synthesis; Wiley &
Sons: Weinheim, 2000.
(15) Izumi, I.; Tai, A. Stereo-differentiating Reactions; Academic
Press: New York, 1977.
OL006741M
40
Org. Lett., Vol. 3, No. 1, 2001