Journal of the American Chemical Society
Article
the chemoselective reduction of the CC double bond of the
α,β-unsaturated ester moiety could be readily achieved under
the conditions of PtO2/H2. For example, 3l was hydrogenated
to give the desired product in 90% yield. Then, the ester
hydrolysis with LiOH successfully afforded corresponding acid
10, which was further converted to 3,4-dihydronaphthalen-
1(2H)-one 11 through the intramolecular Friedel−Crafts
reaction without eroding the enantioselectivity. In the other
example, the hydrogenation of 3t followed by aminolysis led to
the formation of amide 12 in 82% overall yield. This amide was
subsequently transformed to valuable benzo-fused lactam
1,3,4,5-tetrahydro-benzo[b]azepin-2-one 13 containing a chiral
stereocenter in 96% yield with no ee erosion via an efficient
palladium-catalyzed C−N coupling. We also explored the
possibility of accessing benzo-fused oxygen-containing seven-
membered-ring heterocycles. The subjection of 3u to a tandem
LiAH4 and PtO2/H2 sequence, followed by the Mitsunobu
reaction, furnished chiral 2,3,4,5-tetrahydrobenzo[b]oxepine
15 in good yield with the complete retention of enantiopurity.
It is noteworthy that these derivation products bearing gem-
diaryl chirality would be difficult to access using other synthesis
strategies. In addition, the partial reduction of α,β-unsaturated
esters to form the corresponding allylic alcohols (e.g., 16)
without a loss of enantioselectivity can be efficiently achieved
with DIBAL-H. Moreover, α,β-unsaturated ester product 3a
was subjected to conjugate addition with Grignard reagent
EtMgBr under the copper/BINAP catalyst system. Interest-
ingly, this reaction proceeded cleanly and was found to
produce 5-substituted 3-heptanone compound 17 as the only
product (84% yield) with good diastereoselectivity (∼9/1 dr)
and excellent enantioselectivity (94% ee). The stereochemistry
of the newly formed carbon center was determined by X-ray
diffraction analysis of the single crystal of its derivative N-Ts
hydrazone. (See the SI for details.) Thus, both intramolecular
and intermolecular addition of the alkene moiety of the α,β-
unsaturated ester products can be achieved.
Scheme 7. Calculated Relative Free Energies of Several
Isomers of the Rh(I)-Vinylcarbenoid Intermediate in
Solution by the SMD B3LYP-D3 Method
Subsequently, the practicality of this catalytic method was
evaluated by conducting the reaction of 2,6-dichlorophenyl
styryldiazoacetate 1a with 1-(3-methoxyphenyl)pyrrolidine 2a
on a 4.0 mmol scale (1.33 g) under the standard conditions.
To our delight, this gram-scale reaction smoothly furnished
desired insertion product 3a in a comparable yield (95%) and
with maintained enantioselectivity (93% ee). (See the SI for
details.)
To gain some insight into the reaction mechanism, a
combined experimental and computational study was then
performed. A set of deuterium-labeling experiments were
carried out. First, 3a was obtained with no deuterium
incorporated in the presence of D2O or CDCl3, indicating
that the α-hydrogen does not come from solvent or residue
water (Scheme 5a). To exclude the possible reaction pathway
through a π-allyl-rhodium intermediate, deuterated phenyl-
vinyldiazoacetate 1a was prepared and subjected to the
reaction conditions. Indeed, no migration of the deuterium
atom to the α-carbon was observed (Scheme 5b). When 2
equiv of the aniline 2a/2a-d (0.43:0.57) mixture was employed
in the reaction, the product was obtained with 39% hydrogen
at the α-position of the α,β-unsaturated ester (Scheme 5c).
This result clearly indicates that the α-hydrogen atom is
derived exclusively from the C4 position of aniline derivative.
Furthermore, the proton transfer should not be the rate-
determining step of the reaction because an inverse kinetic
Figure 2. Calculated LUMO, Hirshfeld charge, and electrophilicity (f
+, in blue color) for the two reacting carbon sites of the three key
Rh(I)-vinylcarbenoid intermediates (C1cd, C1cp, and C2cp) as well as
the related carbene intermediate in the absence of the Rh(I)-ligand
part (Non-Rh) in solution by the SMD B3LYP-D3 method.
are present in many biologically active compounds.16 This
procedure offers a convenient method for the construction of
chiral 2,3-dihydrobenzofurans bearing two contiguous carbon
stereocenters.
To further demonstrate the synthesis value of this method, a
series of product transformations were conducted (Scheme 4).
Compound 3a was easily converted to alcohol 6 via successive
reduction with LiAlH4 and hydrogenation with PtO2/H2.
Then, the hydroxyl of alcohol 6 was protected by using TBSCl.
The deamination of product 7 with CH3I and Na/NH3,
followed by deprotection of the TBS group of 8 under the
TBAF conditions, provided gem-diaryl-substituted chiral
butanol 9 in 88% yield with 91% ee over two steps. Notably,
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J. Am. Chem. Soc. 2021, 143, 2608−2619