Communications
Table 1: Optimization of the reaction conditions for the intramolecular
asymmetric allylic alkylation of 1a.[a]
Entry
L/AgX
t/T [h/8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1/AgOTf
L2/AgOTf
L3/AgOTf
L4/AgOTf
L5/AgOTf
L6/AgOTf
L7/AgOTf
L8/AgOTf
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
24/RT
48/0
72
85
90
95
8
30
9
28
29
0
95
95
77
73
78
66
96
55
25
10
95
95
71
84
55
27
0
72
35
48
88
22
6
87
62
92
65
90
84
90
92
94
Figure 2. Library of chiral bidentate ligands screened in the gold-catalyzed
enantioselective alkylation of indole with allylic alcohols. (R)-tol-binap=
(R)-(+)-2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl, (R,R)-binaphane=(R,R)-
1,2-bis[(R)-4,5-dihydro-3H-binaphtho(1,2-c:2’,1’-e)phosphino]benzene, (R,R)-
chiraphos=(2R,3R)-(+)-2,3-bis(diphenylphosphino)butane,(R,R)-diop
=(4R,5R)-4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane,
(S)-xylyl-phanephos=(S)-(+)-4,12-bis[di(3,5-xylyl)phosphino]-[2.2]paracyclo-
phane(R)-xyl-sdp=(R)-(+)-7,7’-bis[di(3,5-dimethylphenyl)phosphino]-
2,2’,3,3’-tetrahydro-1,1’-spirobiindane, (R)-segphos=(R)-(+)-5,5’-bis(di-
phenylphosphino)-4,4’-bi-1,3-benzodioxole.
9
L9/AgOTf
(R)-L10/AgOTf
L11/AgOTf
10
11
12
13
14
15
16
17
18[d]
19[e]
20[f]
21[g]
L12/AgOTf
(R)-L10/AgBF4
(R)-L10/AgSbF6
(R)-L10/AgOTs
(R)-L10/AgNTf2
(R)-L10/AgOTf
(R)-L10/AgOTf
(S)-L10/AgOTf
(S)-L10/AgOTf
(R)-L10/AgOTf
64/0
48/0
48/0
48/0
[a] All the reactions were carried out in anhydrous toluene under a
nitrogen atmosphere. L/[Au]/[Ag]=10:20:20 mol%, unless otherwise
specified. The catalytic complex was synthesized in situ in CH2Cl2 with
AuCl·SMe2. [b] Yield of isolated product after purification by flash
chromatography. [c] Determined by HPLC on a chiral stationary phase.
[d] At 08C, 64 h, L10/[Au]/[Ag]=5:10:10 mol%. [e] Preformed L10-
(Au2Cl2) complex was employed. Opposite stereoinduction with respect
to entry 15 was detected. [f] In the presence of molecular sieves (4ꢁ).
[g] The reaction was carried out without any moisture restriction (reagent
grade toluene, no air exclusion).
entries 10, 13–16). By lowering the reaction temperature to
08C the enantiomeric excess increased to 90% with 95%
yield after 48 hours, (Table 1, entry 17). Preformed[16c,21] or
in situ assembled L10–(Au2Cl2) complexes furnished compa-
rable outcomes (compare Table 1, entry 17 with 19), and
rigorous moisture exclusion was required to achieve syntheti-
cally acceptable reaction rates (Table 1, entry 21). However,
the addition of activated molecular sieves did not markedly
affect the stereochemical outcome of the process (Table 1,
entry 20). Further experimental controls were carried out to
rationalize the role of silver in the reaction course. Firstly,
removal of the insoluble AgCl from the reaction mixture did
not lead to significant variations with respect to entry 17 in
Table 1, and secondly, the inertness of the L10–(Ag2OTf2)
complex in the model cyclization was proven by running the
reaction in the absence of AuCl·SMe2 (only traces of 2a were
observed). To the best of our knowledge, this is among the few
site (C2-position). In the same manner, the role of the
R group of the malonate tethering unit was analyzed (Table 2,
entries 8 and 9) by replacing the model (diethyl)indolyl
alcohol 1a with the corresponding (dimethyl) (1h) and
(ditBu) precursors (1i). Interestingly, even though the pres-
ence of bulky tert-butyl groups positively affected the
enantiomeric excess (92% ee; Table 2, entry 9), the smaller
methyl substituent caused a slight drop in enantiodifferentia-
tion (85% ee; Table 2, entry 8).
Moreover, the methodology proved to be a reliable
synthetic alternative to the intramolecular hydroarylation of
allenes,[16b,c] which have been reported by Widenhoefer and
co-workers for the synthesis of enantiomerically enriched 4-
vinyl-THCs (4). As a proof of concept, readily accessible
indolyl alcohols 3a–e (see the Supporting Information for
synthetic details) were subjected to gold-catalyzed intramo-
lecular FCA under the optimum reaction conditions leading
to the corresponding polycyclic compounds 4a–e in good to
high enantiomeric excesses (up to 86% ee, Table 3).
examples of enantioselective gold(I)-catalyzed transforma-
[22,23]
=
tions of an unactivated C C bonds.
Having established the optimal reaction conditions, we
explored the scope of the methodology by subjecting a range
of indolyl alcohols 1b–j to ring-closing Friedel–Crafts alky-
lation and the results are shown in Table 2.
Tolerance toward a wide range of functional groups
(electron-withdrawing and -donating groups) on the indolyl
unit was demonstrated by obtaining the corresponding
tetrahydrocarbazoles (2) in good yields and high enantiomer-
ic excesses (up to 96%; Table 2, entries 1–5, 10, 11). Notably,
precursor 1g (Table 2, entry 7) did not undergo ring-closing
Friedel–Crafts alkylation, probably owing to detrimental
steric hindrance of the methyl group near the cyclization
9534
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 9533 –9537