Angewandte
Communications
Chemie
Scheme 1. Preparation of the diazo 21. Reagents and conditions:
a) (Boc)2O, DMAP, DCM, RT, 15 min, 96%; b) LiHMDS, THF, À788C,
30 min, then allyl carbonochloridate, À788C to RT, 1.5 h, 83%; c) 3-
bromo-5-(bromomethyl) isoxazole, K2CO3, acetone, reflux, 16 h, 86%;
d) [Pd2(dba)3] 25, PhMe, RT, 30 min, then reflux, 3 h, 91%, 94% ee;
e) benzo[d][1,3,2]dioxaborole, [RhCl(PPh3)3], THF, RT, 30 min, then
NaBO3·H2O, THF/H2O (v/v 4:1), 858C 92%; f) MsCl, TEA, DCM, 08C,
15 min; g) NaN3, DMF, 608C, 3 h, 95% over two steps; h) PPh3, THF/
H2O (V/V 5:1), reflux, 3 h, 91%; i) NaBH4, EtOH/THF (V/V 3:1), RT,
16 h, 27 (85%), 28 (5%); j) TrocCl, Na2CO3, DCM/H2O (V/V 1:1), RT,
1 h, 94%; k) FeCl2, CH3CN, reflux, 20 min, (l) 1H-imidazole-1-sulfonyl
azide, pyridine, RT, 3 h, 91% over two steps. dba=dibenzylideneace-
tone, DCM=dichloromethane, DMAP=4-(N,N-dimethylamino)pyri-
dine, DMF=N,N-dimethylformamide, HMDS=hexamethyldisilazide,
Ms=methanesulfonyl, TEA=triethylamine, THF=tetrahydrofuran.
Figure 2. Retrosynthetic analysis of kopsine-related alkaloids. Boc=
tert-butoxycarbonyl, Troc=2,2,2-trichloroethoxycarbonyl.
ring with FeCl2 in 29 and diazotation of the resultant b-
ketone-a-diazo intermediate furnished 21 in 86% yield.
With diazo 21 available, we then evaluated the efficiency
of various metal salts as catalysts for the intramolecular
cyclopropanation reaction (Table 1). Initial experiments on
the diazo decomposition of 21 in CH2Cl2 with [Rh(OAc)2],
Rh(C3F7CO2)2, CuOTf, Cu(OTf)2, and Cu(TBS)2 as catalysts
generate the cyclopropyl ring in 20 by a metal-salt-catalyzed
diazo decomposition of 21, a strategy that we used to
efficiently construct the quaternary carbon centers at C2
and C7 in previous indole alkaloid syntheses.[10] The diazo 21
could be generated from 22 by opening the isoxazole ring and
diazotation. The first quaternary carbon center at C20 could
be constructed from 23 by an asymmetric Tsuji–Trost
rearrangement.[11,12] The intermediate 23 could be pre-
pared from the commercially available tetrahydrocarbazo-
lone 24.
As depicted in Scheme 1, we started our synthesis with 24.
Installation of a Boc group on the indole nitrogen atom,
followed by two steps, a-acylation and a-alkylation, yielded
23 in 69% yield. Application of an asymmetric Tsuji–Trost
rearrangement[11,12] with the oxazole (S)-25 as a catalyst
provided 22 in 91% yield and 94% ee. This rearrangement
was readily implemented on a 50 gram scale without loss of
either the yield or the enantioselectivity. Three steps of
converting the terminal olefin into an azide group were
realized to afford 26 in 87% yield by subsequent borohydra-
tion, mesylation, and azide replacement. Transformation of
the azide in 26 into an amine with Ph3P in aqueous THF at
608C concomitantly resulted in formation of an imine group
at C21, which was then diastereoselectively reduced with
NaBH4 in a mixture of EtOH/THF (3:1) to give 27 and 28 in
82% combined yield and a 17:1 ratio over two steps.
Protection of the amine in 27 with Troc under basic
conditions, followed by two steps of opening of the isoxazole
À
gave very disappointing results. In these cases, only the C H
insertion byproduct 30 was obtained in low yields rather than
the desired product 20 (entries 1–5). The absolute configu-
ration of 30 was determined by its X-ray crystallographic
analysis. To our delight, diazo decomposition of 21 with
20 mol% of either [Cu(acac)2], [Cu(tfacac)2], or [Cu-
(hfacac)2] in 1,2-dichloroethane (DCE) at 808C provided 20
in 10–22% yields and 30 in 12–15% yields (entries 6–8).
Using [Cu(hfacac)2] afforded 20 with the highest yield of 22%
(entry 8). To improve the yield of 20, [Cu(hfacac)2] was then
used as the catalyst in further screening of the solvent and
temperature. The yield of 20 was enhanced to 38% when
microwave irradiation conditions (1208C) were applied in
DCE (entry 9). Further screening revealed that chloroben-
zene was the best solvent for the cyclopropanation reaction
when heating at 1208C for 30 minutes (entries 10–14). Diazo
decomposition of 21 on a 5 gram scale with 20 mol% of
[Cu(hfacac)2] provided 20 in an acceptable 52% yield and 30
in 13% yield (entry 12). Successful preparation of 20 by
cyclopropanation allowed us to build up two other quaternary
carbon centers at C2 and C7, thus propelling us forward
toward the target alkaloids.
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ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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