Angewandte
Chemie
Table 2: Michael addition catalyzed by Lewis acid/N,N’-dioxide com-
[
a]
plexes.
Scheme 5. Construction of ring B/D in the tricyclic synthon. m-CPBA=
meta-chloroperoxybenzoic acid, TBAF=tetra-n-butylammonium fluo-
ride.
[b]
[c]
Entry
Lewis acid
Ligand
Solvent
CH Cl
Yield [%]
ee [%]
1
2
3
4
5
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
13a
13b
13c
13c
13c
13c
n.r.
n.r.
10
33
85
85
–
–
42
38
93
94
2
2
2
2
CH Cl
2
successfully afforded the 3,4-fused benzofuran 12 in 89%
yield. Removal of the TES group in 12 with TBAF (95%),
and subsequent oxidation with m-CPBA, afforded 5 in 56%
yield.
CH Cl
2
EtOH
EtOH
EtOH
[
d]
6
Sc(OTf)
3
After successful construction of the ABD ring system, we
turned our attention to the construction of the chiral all-
carbon quaternary stereocenter in 1 and 2. Although a few
catalytic enantioselective conjugate additions of 3-substituted
benzofuranones were reported, to the best of our knowl-
edge, the catalytic enantioselective conjugate addition of 3-
alkyl-substituted benzofuranone to MVK has not been
reported.
[
a] Reaction conditions: 5 (0.1 mmol), MVK (0.15 mmol), solvent
(0.3 mL). [b] Yield of isolated product. [c] Determined by HPLC using
a chiral stationary phase. [d] The reaction was run at 108C. n.r. =no
reaction, Tf=trifluoromethanesulfonyl.
[
21]
[
a]
Table 3: Substrate scope of the asymmetric Michael reaction.
Initially, various amine-thiourea or urea bifunctional
organocatalysts were screened for the conjugate addition of
5
to MVK. However, the highest enantioselectivity obtained
was 55% ee (see the Supporting Information). These results
prompted us to investigate alternative catalytic reaction
systems. Inspired by the recent work of Feng and co-work-
[
22]
ers, we turned our attention to examining an asymmetric
Michael addition using the chiral metal/N,N’-dioxide com-
plexes. As described in Table 2, we initially investigated the
[
a] Reaction conditions: 14 (0.1 mmol), MVK (0.15 mmol), EtOH
Michael addition, in CH Cl at room temperature, catalyzed
2
2
(0.3 mL). Yields are those of the isolated products. Enantiomeric excess
was determined by HPLC using a chiral stationary phase.
by Yb(OTf) /13 complexes (entries 1–3). But only Yb(OTf) /
3
3
1
3c gave the desired product 4 in 10% yield with 42% ee
(
entry 3). When the solvent was changed to ethanol, 4 was
obtained in higher yield (33%) with similar ee value (entry 4).
vided the known ketone 18, the key intermediate in Fanꢀs
total synthesis of 1, in 75% yield over three steps. The
physical properties ( H and C NMR spectra, MS data, and
However, when Sc(OTf) was used instead of Yb(OTf) at
3
3
1
13
room temperature, the reaction proceeded smoothly to afford
in 85% yield with 93% ee (entry 5). Additionally, when the
reaction was run at 108C, 4 was obtained in 85% yield with
4% ee (entry 6). Under the aforementioned reaction con-
4
[a] ) of 18 are consistent with those described in the
D
[
13]
literature.
Treatment of 18 with TMSOTf and Et N
3
9
provided the corresponding silyl enol ether, which was
oxidized under Saegusa conditions to give the enone 19 in
67% yield. Finally, 19 was readily converted into 1 in a two-
ditions, conjugate additions of several 3-alkyl-substituted
benzofuranones to MVK were investigated. The results
showed that both the yield and the ee values were excellent
[
13]
step sequence.
(
Table 3).
With 4 in hand, we proceeded with the total synthesis of
(Scheme 6). Treatment of 4 with LDA yielded the cycliza-
After completion of the synthesis of 1, we turned our
attention to the synthesis of 2 (Scheme 7). Considering the
lower yield in the conversion of 3 into 17 (Scheme 6), we tried
to develop a more efficient approach. Thus, stereoselective
reduction of 3 with L-selectride gave the sole a-alcohol 20 in
1
tion product 3 in 95% yield. Subsequent direct reduction of
the 3 with Et SiH provided the b-alcohol 16 in 73% yield and
3
a-alcohol 17 in 12% yield, with the simultaneous reduction of
91% yield. Reduction of 20 with Et SiH provided 17 in 88%
yield. Reaction of 17 and formaldehyde under standard
3
[23]
ketone and removal of the Boc group. Selective protection
of the amine in 16 and 17 with methyl chloroformate and
subsequent oxidiation with Dess–Martin periodinane pro-
reaction conditions [NaBH , NaBH CN or NaBH(OAc) ]
4
3
3
gave 2 in only 30–40% yield. Methylation of 17 under
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
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