Angewandte
Communications
Chemie
Scheme 2. Synthesis of dendrobine (1) via Kende Intermediate 13. Reagents and Conditions: a) 3 (1.5 equiv), CuBr·SMe2 (5.0 mol%), CH2Cl2,
À788C, 1 h; b) NaN3 (1.1 equiv), DMF, 238C, 16 h, 84% for two steps; c) LiAlH4 (1.5 equiv), Et2O, À78 to 238C, 2 h; d) 7 (1.0 equiv), MgSO4
(1.0 wt. equiv), Et2O, 238C, 2 h; then NaBH4 (0.8 equiv), MeOH, 238C, 1 h; e) Et3N (0.8 equiv), DMAP (0.17 equiv), TsCl (0.8 equiv), CH2Cl2,
238C, 16 h; followed by K2CO3 (1.7 equiv), MeOH, 238C, 16 h, 40% overall yield from 5; f) see Table 1; g) BH3·THF (10 equiv), THF, 08C, 2 h;
followed by NaOH (10% aq.)/H2O2 (35% aq.) (1:1), THF, 0 to 508C, 1 h, 87%; h) (COCl)2 (10 equiv), DMSO (20 equiv), CH2Cl2, À788C, 1 h;
followed by Et3N (30 equiv), À78 to 238C, 1 h, 86%; i) LiOH (0.1 equiv), iPrOH, 238C, 24 h, 80%; j) HCHO (37% aq., 20 equiv), NaCNBH3
(10 equiv), AcOH (3.0 equiv), MeOH, À78 to 238C, 5 h, 53%. Key: acetic acid (AcOH), N,N’-(dimethylamino)pyridine (DMAP), N,N’-
dimethylformamide (DMF), dimethylsulfoxide (DMSO), isopropanol (iPrOH), para-toluenesulfonyl chloride (TsCl), trimethylsilyl (TMS).
Table 1: Transition-metal-mediated cycloisomerization of dienyne 8 and diene-assisted CH activation of
triene 9.
a one-pot tosylation (TsCl, Et3N,
DMAP) and desilylation (K2CO3,
MeOH) provided the targeted
dienyne 8 in 40% overall yield
from azide 5. In this manner,
every reaction along the estab-
lished pathway employed inexpen-
sive and easily handled reagents,
and required only two trivial chro-
matographic purifications (5 and 8)
over the entire synthetic sequence.
With dienyne 8 in hand, the
Entry
Substrate
Conditions
Yield [%][c]
1
2
3
4
5
6
7
8
8
8
8
8
8
8
8
8
8
9
9
9
9
8
Pd(OAc)2, benzene, 808C, 2 h
Pd(OAc)2, PPh3, benzene or DCE, 808C, 2 h
Pd(OAc)2, L1, benzene, 808C, 2 h
9+9a (35%), (9:9a 3:5)
9 (76% or 69%)
9+9a (24%), (9:9a 10:1)
9 (60%)
9+9a (41%), (9:9a 1:8)
9+9a (67%), (9:9a 10:1)
8 (72%)
stage was set to investigate the
proposed transition-metal-medi-
ated cascade process. To obtain
a clear picture of the individual
processes, cycloisomerization of
dienyne 8 was first examined.[13] In
this context, while the desired reac-
tion pathway involving the terminal
alkene and alkyne in 8 was antici-
pated based on both kinetic and
thermodynamic grounds, we were
conscious of potential side reac-
tions that might engage the pend-
ant trans-disubstituted alkene prior
to the desired cycloisomerization
event. Pleasingly, enyne cycloiso-
merization product 9 was obtained
from a variety of palladium cata-
lytic systems (Table 1). However,
certain conditions afforded varying
amounts of the enyne-cycloisome-
rization product 9a as a conse-
quence of alkyne moiety participa-
tion in an endo- rather than the
Pd(OAc)2(PPh3)2, benzene, 808C, 2 h
Pd2(dba)3, AcOH, benzene, RT, 12 h
Pd2(dba)3, P(o-tolyl)3, AcOH, benzene, RT, 12 h
Pd2(dba)3, P(o-tolyl)3, benzene, RT, 12 h
[Rh(COD)Cl2]2, AgSbF6, PPh3, DCE, 808C, 3 h
RhCl(PPh3)3, AgSbF6, DCE, 808C, 3 h
[Rh(COD)Cl2]2, AgSbF6, PPh3, DCE, 808C, 3 h
RhCl(PPh3)3, AgOTf, DCE, 808C, 3 h
RhCl(PPh3)3, AgSbF6, DCE, 808C, 3 h
RhCl(PPh3)3, AgSbF6, DCE, 808C, 3 h
Pd(OAc)2, PPh3, DCE, 808C, 2 h;
8 (50%)
8 (40%)
10 (43%)
10 (35%)
10 (67%)
10 (15%)
10 (60%)
9[a]
10[b]
11[b]
12[a]
13[b]
14[a]
then RhCl(PPh3)3, AgSbF6, DCE, 808C, 2 h
Pd(OAc)2, PPh3, DCE,
RhCl(PPh3)3, AgSbF6, DCE, 808C, 2 h
15[a]
8
9 (70%)
[a] Rhodium catalyst prepared by initially stirring at 808C for 1 h; [b] rhodium catalyst prepared by
initially stirring at 238C for 1 h; [c] chromatographically isolated yield and product ratio determined by
1H NMR analysis of the crude reaction mixture. Key: acetic acid (AcOH), acetate (OAc), 1,5-cyclo-
octadiene (COD), dibenzylideneacetone (dba), 1,2-dichloroethane (DCE), ortho-methylphenyl (o-tolyl).
desired
exo-mode
(Table 1,
Entries 1–6).[14] Trost had previ-
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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