2
Q. Zhang et al. / Tetrahedron Letters 60 (2019) 150992
Scheme 2. Cascade reaction of 6 and the proposed reaction pathway.
Fig. 1. Representative members of mexicanolide limonoids with the cyclohexane-
fused bicyclo[3.3.1]nonane ring system.
and Brønsted acids (e.g., p-TsOH, MsOH, TfOH, H2SO4, HCl, and
HClO4), solvents (e.g., THF, CH3CN, toluene, MeNO2, and MeOH),
as well as reaction temperatures, we found that the tricyclic frame-
work could be built in a straightforward one-pot reaction of 6 in
the presence of HCl in MeOH, affording tricyclic dienone 12 in
45% isolated yield (Scheme 2).
hydrolysis, two chemoselective aldol reactions, and alkene migra-
tion in one pot.
Results and discussion
To understand the reaction process of this transformation, a
plausible reaction mechanism was proposed. Firstly, acid-medi-
ated acetal hydrolysis generates d-oxo aldehyde 13. Secondly, the
first intramolecular aldol condensation of 13 produces 14 with
the formation of C ring. Thirdly, the second intramolecular aldol
reaction between the ketone and the enone chemoselectively gen-
erates tricyclic intermediate 15, which undergoes dehydration and
alkene migration to give the desired tricyclic ketone 12. To support
the proposed reaction mechanism, preliminary mechanistic stud-
ies were conducted. Bicyclic intermediate 14 was isolated as a
stable compound in 41% yield from the HCl-mediated reaction of
6 by lowering the reaction temperature and shortening the reac-
tion time. 14 could be smoothly converted to 12 under the typical
cascade reaction conditions (see the Supporting Information for
details). Those results are consistent with our proposed reaction
pathway involving enone 14 as the key intermediate.
To investigate the influence of additional substituents on this
cascade reaction, ketal 11 with a gem-dimethyl group was sub-
jected to the typical cascade reaction conditions (i.e., HCl/MeOH).
However, no desired tricyclic product was observed. Further
screening of the acids revealed that H2SO4 was an efficient acid
to promote the cascade reaction of 11, affording multi-substituted
tricyclic dienone 16 in 43% isolated yield (Scheme 3).
The cascade reaction precursors 6 and 11 were prepared from
the known compounds 2 [18] and 7 [19], respectively (Scheme 1).
Following alkylation with dimethyl malonate, Krapcho decarboxy-
lation [20] of the resulting diester gave rise to monoester 3 in a
good yield. Ammonolysis of ester 3 and subsequent Grignard reac-
tion furnished enone 4, which was subjected to Michael addition
with b-ketoester 5 under heterogeneous reaction conditions with
solid LiOH as the base and toluene as the solvent to give acetal
diketoester 6 in 74% yield [21]. Synthesis of 11 commenced with
mono-methyl addition of diamide 7. Ketal protection of the resul-
tant ketone 8 and subsequent vinyl Grignard reagent addition pro-
vided enone 9. Treatment of 9 with dimethyl b-ketoester 10 under
the same conditions for synthesis of acetal 6 afforded ketal 11 in
64% yield. It’s worth noting that compound 11 possessing two
adjacent quaternary carbon centers can be efficiently accessed
under such mild conditions.
With diketoester 6 and 11 in hand, we proceeded to investigate
one-pot construction of the tricyclic cyclohexane-fused bicyclo
[3.3.1]nonane skeleton. After extensive investigation of various
Lewis acids (e.g., ZnBr2, Sc(OTf)3, Yb(OTf)3, AlCl3, and BF3ÁOEt2)
The structures and stereochemistry of 12 and 16 were unam-
biguously determined by X-ray crystallographic analysis (Fig. 2)
[22]. It is noteworthy that the double bond locations on the C rings
of products 12 and 16 are different. Vysotskaya and co-workers
reported that the dehydration of 2-hydroxy tricyclo-[7.3.1.02,7
]
tridecan-13-one derivatives, which are saturated equivalents of
tentative intermediate 15, would lead to products with double
bonds located at different sites using different acids as the promot-
ers [23]. In our case, 12 and 16 with different double bond loca-
tions were speculated to be generated respectively as the
thermodynamic products under the conditions of heating and
strong acids. Additionally, the double bonds located on B rings of
Scheme 1. Preparation of precursors 6 and 11.
Scheme 3. Cascade reaction of 11–16.