Organic Letters
Letter
nation) but also by kinetic resolution of the resulting 2 (the
second hydrodebromination).12
Scheme 3. Conversion of 2a to Methaqualone 4a
Indeed, when racemic mebroqualone rac-2a was treated with
1.0 equiv of NaBH4 in the presence of (R)-DTBM-
SEGPHOS−Pd(OAc)2 catalyst, 38% ee of (+)-2a was
recovered (recovery yield 22%) together with reduction
product 3a (54%, Scheme 2), and the major enantiomer of
the recovered (+)-2a had the same absolute configuration as
product 2a described in Table 2 (entries 1 and 2).
Scheme 2. Kinetic Resolution with rac-2a
In conclusion, we succeeded in the catalytic enantioselective
synthesis of mebroqualone and its derivatives through chiral
Pd-catalyzed reductive asymmetric desymmetrization of 3-(2,6-
dibromoaryl)quinazolin-4-ones followed by kinetic resolution
of the resulting monobromo products. Furthermore, the
absolute stereochemistry of the mebroqualone product was
determined to have the (P)-configuration.
Since the absolute stereochemistry of mebroqualone 2a has
yet to be determined, the stereochemical assignment of 2a was
investigated next. We observed significant self-disproportiona-
tion of enantiomers (SDE) during MPLC purification of
optically active 2a (66% ee) and could obtain 99% ee of 2a by
the SDE (Figure 2).13,14 Subsequently, X-ray crystal structural
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
Experimental details and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was partly supported by a Grant-in-Aid for Scientific
Research.
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Figure 2. SDE observed in MPLC of 2a (66% ee) and X-ray crystal
structure of (+)-(P)-2a.
REFERENCES
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analysis of (+)-2a (99% ee) was performed, and the major
enantiomer was determined to have the (P)-configuration
(Figure 2).15 The stereochemistries of other mebroqualone
derivatives 2b−h, which have a large positive [α]D value as in
2a, were also predicted to have the (P)-configuration.
(1) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am.
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We also attempted to convert mebroqualone 2a to
methaqualone 4a. Miller et al. mentioned that Suzuki−Miyaura
coupling of optically active mebroqualone analogue VI
(Scheme 1) with organoboronic acid brings about a significant
decrease in the ee in the coupling product.5 After a detailed
survey, they found the reaction conditions which proceed
without a decrease in the original ee, while the reaction is
limited to arylboronic acid and the reaction with alkyl boronic
acid was not described. We investigated Suzuki−Miyaura
coupling of optically active mebroqualone 2a with methyl
boronic acid in the presence of Pd(OAc)2 and various
phosphine ligands.16 The reaction of (P)-2a (94% ee) with
DPPP ligand gave 42% ee of methaqualone product (P)-4a in
40% yield (Scheme 3). Although reactions in the presence of
other phosphine ligands [Ph3P, (o-Tol)3P, t-Bu3P, John-Phos]
were also conducted, unfortunately, no better result than that of
DPPP was obtained. Since the 2a and 4a have high rotational
barriers (more than 31 kcal/mol), the significant decrease in
the ee is most probably due to the lower rotational barrier
around the chiral axis in aryl-Pd intermediates 2A and 2A′.
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