Gold(I)-catalyzed enantioselective polycyclization reactions

Article abstract of DOI:10.1021/ja103544p

A series of enantioselective polycyclization reactions, catalyzed by a cationic bisphosphine gold complexes, are described. The polycyclization reactions, which employ an alkyne as an initiating group, begin with a gold-promoted 6-exo-dig cyclization and can be terminated with a variety of nucleophiles including carboxylic acids, phenols, sulfonamides, and electron-rich aryl groups. This method allows for the preparation of up to four bonds in a single operation with excellent diastereo- and enantioselectivity.

Full text of DOI:10.1021/ja103544p

Published on Web 06/02/2010
Gold(I)-Catalyzed Enantioselective Polycyclization Reactions
Steven G. Sethofer, Timo Mayer, and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received April 26, 2010; E-mail: fdtoste@berkeley.edu
Polycyclization reactions of unsaturated molecules allow for the
only trace amounts of 3 (eq 1).14 Under these conditions, gold(I)-
catalyzed cyclization of 1a, in the presence of an electrophilic iodine
source, afforded diastereomerically pure vinyl iodide 2c in 96%
ee. The observation that the enantioselectivity obtained in the
formation of 2c was identical with that of 2a is in agreement with
iodination occurring subsequent to the cyclization event.15 Internal
alkyne 1b also underwent the gold(I)-catalyzed cyclization to afford
2b as a single alkene isomer in 86% yield and 92% ee (eq 1),
although longer reaction times were required, even at rt, for full
conversion.
rapid construction of complex structures in a single operation.1
Thus, numerous methods that proceed with excellent diastereose-
lectivity have been developed over the past 50 years.2 In contrast,
enantioselective variants are rare and the majority of reported examples
involve cyclization cascades that are promoted by reactions of alkenes
with electrophillic reagents.3,4 Given that the substrates contain mul-
tiple alkenes, initiating polycyclization reactions through selective
activation of an alkyne5,6 offers the potential advantage of circumvent-
ing unwanted reactions resulting from nonselective alkene activation;
however, an example of an enantioselective polycyclization reaction
of alkynes has yet to be reported.
Table 1. Optimization of Reaction Conditions
Given that the majority of polycyclization reactions have been
induced by an endocyclic process, we first evaluated the use of
chiral phosphinegold(I) complexes in a 6-endo-dig initiated poly-
cyclization of 1,5-enynes;7 however, only poor enantioselectivity
was obtained (up to 33% ee). While gold(I)-catalyzed enantiose-
lective reactions of alkynes remain rare, the majority of reports
involve 5-exo-dig additions;8 however, we have recently reported
an example of an enantioselective rearrangement initiated by a
6-exo-dig cyclization.9 Therefore we hypothesized that a related
process might be employed to induce enantioselective polycycliza-
tion reactions.
% yielda
2a (3)
ee
(%)
entry
ligand (L)
solvent
1
2
3
4
5
6
7
8
9
(S)-BINAP
(R)-tolyl-BINAP
(R)-xylyl-BINAP
(R)-DTBM-Segphos
(R)-MeO-DTBM-BIPHEP
(R)-MeO-DTBM-BIPHEP
(R)-MeO-DTBM-BIPHEP
(R)-MeO-DTBM-BIPHEP
(R)-MeO-DTB-BIPHEP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
benzene
toluene
m-xylene
m-xylene
83 (7)
72 (8)
70 (10)
81 (8)
71 (7)
76 (8)
77 (9)
76 (12)
86 (11)
-17
23
40
2
46
83
85
87
92
a Yield determined by 1H NMR versus an internal standard
(9-bromophenanthrene).
We next evaluated various nucleophiles as terminating groups
for the gold-catalyzed polycyclization. We were pleased to find
that the catalyst and conditions developed for lactonization of 1
were fairly insensitive to the nature of the terminating group. For
example, gold-catalyzed sulfonamide-terminated cyclization of
enyne 4 produced decahydroquinoline 5 in 75% yield and 92% ee
(eq 2).
Accordingly, we began a systematic evaluation of ligand effects
in the bicyclization of carboxylic acid 1a (Table 1).10 Reaction of
1a, catalyzed by a series of monocationic (BINAP)gold(I) com-
plexes, produced lactone 2a with 17-40% ee along with small
amounts of 3 (entries 1-3). Given the notable improvements in
enantioselectivity previously observed in the gold-catalyzed reaction
employing sterically encumbered phosphines,8,11 we examined tert-
butyl-substituted phosphines as ligands. While the Segphos-based
ligand gave poorer enantioselectivity (entry 4), we were pleased to
find that the use of MeO-DTBM-BIPHEP resulted in the formation
of 2a in 48% ee (entry 5). The reaction showed a dramatic solvent
effect, with nonpolar aromatic solvents providing the desired lactone
2a in up 87% ee.12 Switching the ligand to MeO-DTB-BIPHEP
furnished fused bicyclic compound 2a as a single diastereomer13
in 87% yield and 92% ee (entry 9). A further improvement in
enantioselectivity was achieved by conducting the reaction at -40
°C, thereby furnishing 2a in 96% ee, as a single diastereomer and
9
8276 J. AM. CHEM. SOC. 2010, 132, 8276–8277
10.1021/ja103544p  2010 American Chemical Society

C O M M U N I C A T I O N S
Cyclization of phenoxy-substituted phenyl alkynes also afforded
products consistent with a cation-initiated polycyclization reaction.
For example, gold-catalyzed reaction of 6a-c produced hexahy-
droxanthene derivatives 7a-c in excellent yield and enantioselec-
tivity (eq 3). Additionally, the use of an electron-rich aryl group
as a nucleophile allowed for the enantioselective formation of 9,
which contains a benzylic quaternary center, in 98% yield and 94%
ee (eq 4). The generality of the reaction conditions is noteworthy,
allowing a diverse range of nucleophilic terminating groups to
participate in the gold-catalyzed polycyclization reaction with
excellent chemo-, diastereo-, and enantioselectivity.
In contrast, gold-catalyzed reaction of tert-butyl ester 10 afforded
only 18% of lactone 2a along with 27% of 3 and 18% of
cycloheptadiene 11, in xylene at room temperature. Moreover, gold-
catalyzed reaction of 10 in methylene chloride generated 11 as the
major product (eq 5). These products are consistent with a
mechanism in which gold, rather than the trapping nucleophile,
stabilizes the developing positive charge in the cyclization.16 This
observation supports the hypothesis that the nature of the nucleo-
phile, and even the solvent, can impact the nature of the gold
intermediate in these cyclization reactions.17,18
Solvias and Takasago for the generous donation of phosphine
ligands, and Johnson Matthey for a gift of AuCl3.
Supporting Information Available: Experimental procedures,
compound characterization data, and crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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Acknowledgment. We gratefully acknowledge NIHGMS (RO1
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