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CH2Cl2, RT) afforded tetrahydropyran [D]-10c (81%), in
which 65% of the pro-(S) diastereotopic allylic proton in 10c
has been stereoselectively replaced by a deuterium atom
(Scheme 6). Conversely, under the same conditions, cyclo-
propenylcarbinol [D2]-9c, dideuterated at the benzylic posi-
tion, led to the dideuterated tetrahydropyran 11 (d.r. > 95:5,
68%), in which the pro-(R) diastereotopic allylic proton has
of boat and chair conformations, respectively,[22] in which the
hydroxy group lies in the axial position and the substituent at
C7 preferentially occupies an equatorial position, could be
initially considered. However, only the boat transition-state
model TS1 can account for the observed 1,4-anti relative
orientation between the hydroxy group and the Y substituent
in the resulting six-membered products (Scheme 7).[23]
By considering the transition-state model TS1, we sur-
been exchanged to a deuterium.[18] Thus, C H insertions
ꢀ
ꢀ
mediated by donor rhodium carbenoids derived from
3,3-dimethylcyclopropenes, involve a stereospecific process
at the carbenoid carbon atom, in agreement with a concerted
mechanism.[19,20]
mised that 1,6-C H insertions should proceed at significantly
different rates for diastereomeric substrates bearing one
substituent at C5 (R or R’ ¼ H), owing to the eclipsed
ꢀ
conformation around the C4 C5 bond and the axial orienta-
tion of the hydroxy group at C4. To verify this experimentally,
the epimeric cyclopropenylcarbinols 13 and 13ꢀ were synthe-
sized from a-alkoxyaldehyde 12 (Scheme 8). Addition of
3,3-dimethylcyclopropenyllithium led to a 73:27 mixture of
the (separable) diastereomeric alcohols 13 and 13’, as a result
of a moderate Felkin–Anh stereocontrol.[24a] As expected,
addition of the Grignard reagent (generated by transmetala-
tion with MgBr2·OEt2) reversed the diastereoselectivity in
favor of 13’ (13/13’ = 14:86) owing to a chelation-controlled
nucleophilic addition.[24] Upon treatment with [Rh2(OAc)4]
(0.5 mol%) under standard conditions (CH2Cl2, RT), only
cyclopropenylcarbinol 13 underwent a smooth and highly
diastereoselective conversion to tetrahydropyran 14 (d.r. >
95:5), which was isolated in 83% yield. Ozonolysis of 14
provided the trisubstituted pyranone 15 (61%) without
epimerization.[18] By contrast, in agreement with our hypoth-
esis, the epimeric alcohol 13’ did not react even if a higher
catalyst loading or harsher conditions (reflux) were used but
underwent decomposition (Scheme 8).
Scheme 6. Deuterium labeling experiments.
ꢀ
For C H insertions mediated by dirhodium carbenoids
generated from a-diazocarbonyl compounds, computational
studies revealed that a concerted nonsynchronous process
with a significant hydride transfer component was involved
and that the more stabilized donor/acceptor carbenoids led to
relatively late transition states.[19] By analogy with these
results, in the absence of computational studies at this stage,
we have devised empirical models to rationalize the dia-
ꢀ
stereoselectivities observed in C H insertions mediated by
rhodium carbenoids generated from 3,3-dimethylcyclo-
propenylcarbinols. Although in the initially generated dirho-
ꢀ
dium carbenoids, the C2 C3 alkene bond should be parallel
ꢀ
to the C1 Rh1 bond, this may no longer be the case in the
ꢀ
transition state, if formation of the C1 H7 bond (hydride
transfer component) is well-advanced (Scheme 7). Moreover,
ꢀ
ꢀ
the conformation around the C2 C1 and C2 C4 bonds
should result from minimization of A1,3 strain (1,3-allylic
strain).[21] If the forming C1 H7 bond is orthogonal to the
C1 Rh1 bond, then the four atoms H7, C1, C2, and C4
should be almost coplanar. Thus, for 1,6-C H insertions, two
seven-membered cyclic transition-state models TS1 and TS2
ꢀ
[19]
ꢀ
ꢀ
Scheme 8. Different behavior of epimeric cyclopropenylcarbinols 13
and 13’. PMB=p-methoxybenzyl, PMP=p-methoxyphenyl.
The different behavior of the epimers 13 and 13’ suggested
ꢀ
ꢀ
that in C H insertions it may be possible to differentiate C H
bonds belonging to two diastereotopic methylene groups. An
interesting illustration is the rhodium-catalyzed reaction of
cyclopropenylcarbinol 16; of the four possible diastereomers
this reaction selectively afforded 17 (72%), which is one of
the two diastereomers (17 and 17’) that possess a 1,4-anti
relative orientation between the hydroxy and the silyloxy
groups (Scheme 9).[18]
Differentiation between two diastereotopic methylene
units was also exploited to devise a straightforward access to
bicyclic compounds, by using 3,3-dimethylcyclopropenyl-
ꢀ
Scheme 7. Empirical transition-state models for 1,6-C H insertions
(ligands on rhodium are omitted for the sake of clarity).
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 11540 –11544