6
18
S. Chandrasekhar, G. Kulkarni / Tetrahedron: Asymmetry 13 (2002) 615–619
the instability of 6 to chromatography). The simplest
congestion (the polycyclic framework and the exo face
of the camphane moiety), the large group (L) points
away from this region, and the medium group (M)
points towards a region of intermediate steric conges-
tion (the endo face of the capmphane moiety). The
reasons for the preferential reaction of the (S)-isomer in
the case of 4a are not entirely clear at this stage.
explanation for the formation of one diastereomer in
>
50% yield in the above process, appears to be a
7,8
dynamic kinetic resolution process: in this the enan-
tiomers of a derivative of the alcohol 4 along the
reaction path are equilibrated, stereoselective reaction
of one of these with the chiral acid 6 then displacing the
equilibrium. The intermediate that is best positioned
along the reaction path, and most likely to be so
equilibrated, is the activated derivative corresponding
to III (Scheme 1), presumably via dissociation to a
carbocation or the corresponding ion pair (discussed
below).
The dynamic kinetic resolutions observed in the two
cases above could occur via the initial reversible dissoci-
ation of 7b to 7c leading to the formation of the more
stable of the two possible diastereomers (indicated as
7b%, Scheme 3, corresponding to 9, Scheme 2), which
would slowly collapse to the ester 6 as discussed above.
No dynamic kinetic resolution was observed in the
other cases under the above ‘equimolar conditions’, the
corresponding diastereomeric esters being generally
formed in equal amounts by NMR. It seems very likely
that the stability of the derived benzylic cations is the
origin of the phenomenon, based on the relatively
extended conjugation possible in the cations derived
from 4d and 4f.
Scheme 3.
4
. Mechanism of enantioselection
5. Conclusions
It would appear that the generally high e.e. values
obtained indicate a rigid transition state, whether at
step 3 or at step 4 (Scheme 1). In the event that
enantioselectivity originates at step 3, a carboxylate
anion relatively tightly bound to the cationic phospho-
rus atom—perhaps making it pentavalent—is indicated.
A new process of kinetic resolution with concomitant
chirality inversion—one of the cherished goals of asym-
metric synthesis—has been designed and demonstrated.
The process defines a chiral version of the well-known
Mitsunobu reaction, employing the readily accessible
(1S)-(+)-ketopinic acid as a chiral auxiliary, and affords
various secondary alcohols in excellent yields and enan-
tiomeric excesses. Two of the benzylic alcohols also
undergo dynamic kinetic resolution during the above
Mitsunobu reaction, providing relatively high yields of
chiral alcohol. The above reactions apparently involve
3
1
(
There is indeed P NMR evidence for such intermedi-
3
ates. ) It is, in fact, likely that rigid intermediates such
as 7 are involved, in which a pentavalent phosphorus
atom is also coordinated with the ketone oxygen atom;
7
a and 7b are analogous to II and III (Scheme 1),
9,10
respectively (hexacoordinate phosphorus is known ).
The rigidity of the tricyclic framework of 7a would
confer high stereoselectivity to its reaction with the
alcohol 4 to yield 7b; interestingly, 7b may then collapse
intramolecularly—and hence stereospecifically—to 6 by
acyloxy transfer from phosphorus to carbon via the
six-membered cyclic transition state designated as [8].
a rigid phosphorane intermediate formed from Ph P,
3
the ketopinic acid and the alcohol. Additionally the
results also offer some insights into the mechanism of
the Mitsunobu reaction itself.
Acknowledgements
1
1
(This 6-endo-tet process, would be allowed by the
presence of the second row phosphorus atom. It is
assumed above that the selectivity originates in step 3,
Scheme 1, but see below.)
CSIR (New Delhi) is thanked for generous financial
support.
It can be seen in Table 1 that the (S)-alcohols generally
remain unreacted in the above Mitsunobu process
References
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9
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(
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