Enantioselective cycloisomerization of 1,6-enynes to bicyclo[3.1.0]hexanes catalyzed by rhodium and benzoic acid

Article abstract of DOI:10.1021/ja504048u

It has been established that a cationic Rh(I)/(S)-Segphos or (S)-DTBM-Segphos complex and benzoic acid catalyze the enantioselective cycloisomerization of 1,6-enynes, possessing carbonyl groups at the enyne linkage, to 2-alkylidenebicyclo[3.1.0]hexanes. The present cycloisomerization may involve site selective γ-hydrogen elimination. The one-pot enantioselective cycloisomerization and lactonization of 1,6-enynes, leading to bicyclic lactones, has also been accomplished.

Full text of DOI:10.1021/ja504048u

Communication
pubs.acs.org/JACS
Enantioselective Cycloisomerization of 1,6-Enynes to
Bicyclo[3.1.0]hexanes Catalyzed by Rhodium and Benzoic Acid
Koji Masutomi,‡ Keiichi Noguchi,§ and Ken Tanaka*,†,‡,∥
†Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, Ookayama,
Meguro-ku, Tokyo 152-8550, Japan
‡Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei,
Tokyo 184-8588, Japan
§Instrumentation Analysis Center, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
∥Japan Science and Technology Agency, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
S
* Supporting Information
Scheme 1
ABSTRACT: It has been established that a cationic
Rh(I)/(S)-Segphos or (S)-DTBM-Segphos complex and
benzoic acid catalyze the enantioselective cycloisomeriza-
tion of 1,6-enynes, possessing carbonyl groups at the
enyne linkage, to 2-alkylidenebicyclo[3.1.0]hexanes. The
present cycloisomerization may involve site selective γ-
hydrogen elimination. The one-pot enantioselective cyclo-
isomerization and lactonization of 1,6-enynes, leading to
bicyclic lactones, has also been accomplished.
ransition-metal-catalyzed cycloisomerization reactions are
Thighly efficient methods for the construction of complex
cyclic frameworks.1,2 Among them, the transition-metal-
catalyzed cycloisomerization of 1,6-enynes is one of the most
actively studied transformations.2 For example, a number of
catalytic cycloisomerization reactions of the 1,6-enynes, leading
to bicyclic cyclopropanes (bicyclo[4.1.0]hept-2-enes3 and 1-
vinylbicyclo[3.1.0]hexanes4), have been reported to date
(Scheme 1, top). These reactions are initiated by activation of
alkynes with π-electrophilic transition-metal complexes.3,4
However, the transition-metal-catalyzed cycloisomerization of
1,6-enynes, leading to the bicyclic cyclopropanes, that proceeds
through the formation of metallacycle intermediates has not been
reported. Recently, Sato and Oonishi reported the novel
cycloisomerization of 1,6-allenynes, leading to none-fused
cyclopropanes, via the formation of metallacycles followed by
γ-hydrogen elimination by using a cationic Rh(I)/N-heterocyclic
carbene (NHC) complex as a catalyst (Scheme 1, middle).5−8 In
this paper, we disclose the unprecedented enantioselective
cycloisomerization of 1,6-enynes, leading to bicyclo[3.1.0]-
hexanes, catalyzed by a cationic Rh(I)/chiral bisphosphine
complex and benzoic acid, which may proceed via the
enantioselective formation of metallacycles followed by metal-
lacycle ring-opening and site selective γ-elimination of the
methylene hydrogen (Scheme 1, bottom).
Recently, our research group reported the sequential cyclo-
isomerization/hetero Diels−Alder reaction of 1,6-enynes,
possessing the monosubstituted alkene moiety, with aldehydes
catalyzed by a cationic Rh(I)/BINAP complex and benzoic
acid.9−11 The first step (cycloisomerization of 1,6-enynes to 1,3-
dienes) proceeds through the formation of rhodacyclopentene A
followed by protonation with benzoic acid and β-hydrogen
elimination (Scheme 2). In this reaction, the protonation of the
bicyclic intermediate A with benzoic acid to produce monocyclic
intermediate B may facilitate the β-hydrogen elimination.9
Indeed, not the β-hydrogen elimination but the aldehyde
insertion to the rhodacyclopentene A proceeded in the absence
of benzoic acid.12
The above result prompted our investigation into the rhodium
and benzoic acid-catalyzed reaction of a 1,6-enyne, possessing no
β-hydrogen in intermediates A and B. Thus, the reaction of 1,6-
enyne 1a, possessing the 1,1-disubstituted alkene moiety, in the
Received: April 23, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
Scheme 2
presence of the cationic Rh(I)/BINAP complex and benzoic acid
was attempted. We were pleased to find that 2-
alkylidenebicyclo[3.1.0]hexane 2a was obtained in high yield
with high enantioselectivity using 10 mol % of the rhodium
catalyst and 40 mol % of benzoic acid at 80 °C (Table 1, entry
Figure 1. Structures of chiral bisphosphine ligands.
Table 1. Optimization of Reaction Conditions for
Enantioselective Cycloisomerization of 1,6-Enyne 1a
a
mol % without significant decrease of the product yield (entry
12).
With the optimized reaction conditions in hand, we explored
the scope of the cationic Rh(I)/(S)-Segphos complex and
benzoic acid-catalyzed cycloisomerization of 1,6-enynes 1 to 2-
alkylidenebicyclo[3.1.0]hexanes 2 as shown in Table 2. With
respect to the substituent at the alkyne terminus (R1), not only
phenyl-substituted enyne 1a but also 4-methyl-, 4-bromo-, and 4-
trifluoromethylphenyl-substituted enynes 1b−d furnished the
desired cycloisomerization products 2b−d with high yields and
ee values. Meta- or ortho-substituted phenyl derivatives 1e−g
were also suitable substrates for this process, although higher
reaction temperature (95 °C) was required for 3-trifluorome-
thylphenyl derivative 1f in order to complete the reaction.
Additionally, the reactions of alkyl-substituted enynes 1h and 1i
proceeded with high yields and ee values, although higher
reaction temperature and catalyst loading (85 °C, 20 mol % Rh)
were required for n-butyl-substituted enyne 1i. With respect to
the substituent at the alkene moiety (R2), not only methyl-
substituted enyne 1a but also sterically more demanding ethyl-
substituted enyne 1j afforded the desired product 2j with high
yield and ee value at 95 °C. With respect to the substituent at the
quaternary carbon center [C(C(O)R3)2], not only dibenzyl
malonate-linked enyne 1a but also dimethyl malonate- and 1,3-
diphenylpropane-1,3-dione-linked enynes 1k and 1l afforded the
desired products 2k and 2l with moderate to good yields and ee
values at 95 °C. Although the yields were low to moderate, the
use of 30 mol % of the cationic Rh(I)/(S)-DTBM-Segphos
catalyst for phenyl- and methyl-substituted enynes 1a and 1h
afforded the corresponding cycloisomerization products 2a and
2h with excellent ee values. The relative and absolute
configurations of (+)-2c were unambiguously determined to be
1S,5R by an X-ray crystallographic analysis.15
Interestingly, 1,6-enynes 1m−o that do not possess carbonyl
groups at the enyne linkage did not afford the corresponding 2-
alkylidenebicyclo[3.1.0]hexanes 2m−o at all, although tosyla-
mide-linked 1,6-enyne 1o afforded the well-known cyclo-
isomerization product 3o3c,e shown in Scheme 1 in low yield
(Scheme 3).
A possible mechanism for the present rhodium and benzoic
acid-catalyzed cycloisomerization reaction of 1,6-enyne 1a to 2-
alkylidenebicyclo[3.1.0]hexane 2a is shown in Scheme 4. 1,6-
Enyne 1a reacts with a cationic Rh(I) complex to generate
rhodacyclopentene intermediate C. Protonation of this rhoda-
cycle C with benzoic acid affords rhodium benzoate intermediate
D.9 Coordination of the carbonyl group to rhodium forms
intermediate D′, which forces rhodium to approach γ-hydrogen
Rh/ligand
(mol %)
convn
b
yield
c
entry
ligand
(%)
(%)
ee (%)
1
2
3
4
(S)-BINAP
10
10
10
10
10
10
10
10
10
10
10
100
83
100
83
43
0
89
77
96
68
28
0
81 (+)
78 (+)
81 (+)
3 (+)
(S)-H8-BINAP
(S)-Segphos
(S,S)-DIOP
d
5
(S,S)-Chiraphos
(R,R)-Me-Duphos
(S)-tol-BINAP
(S)-xyl-BINAP
(S)-tol-Segphos
(S)-xyl-Segphos
36 (+)
−
83 (+)
82 (+)
83 (+)
81 (+)
95 (+)
d
6
7
8
77
60
64
100
29
65
45
45
88
25
9
10
11
(S)-DTBM-
Segphos
e
12
(S)-Segphos
5
100
93
81 (+)
a
[Rh(cod)2]BF4 (0.010 mmol), ligand (0.010 mmol), 1a (0.10 mmol),
BzOH (0.040 mmol), and (CH2Cl)2 (1.5 mL) were used.
b
c
d
Determined by recovery of 1a. Isolated yield. [Rh(nbd)2]BF4 was
e
used in place of [Rh(cod)2]BF4. [Rh(cod)2]BF4 (0.010 mmol), ligand
(0.010 mmol), 1a (0.20 mmol), BzOH (0.080 mmol), and (CH2Cl)2
(1.5 mL) were used.
1).13 Importantly, bicyclo[3.1.0]hexane skeletons are found as
core structures of natural products.14 Therefore, the develop-
ment of a new method for the catalytic enantioselective synthesis
of bicyclo[3.1.0]hexane derivatives that would enable facile
access to new analogues of this class of compounds in
enantiomerically enriched form is an important topic.
The optimization of reaction conditions for the enantiose-
lective cycloisomerization of 1a to 2a is shown in Table 1.
Screening of chiral bisphosphine ligands (Figure 1, entries 1−6)
revealed that biaryl bisphosphine ligands (entries 1−3) showed
higher catalytic activity and enantioselectivity than nonbiaryl
bisphosphine ligands (entries 4−6). Among biaryl bisphosphine
ligands examined, (S)-Segphos showed the best result (entry 3).
The use of sterically demanding biaryl bisphosphine ligands
(entries 7−11) decreased the catalytic activity, although
significantly improved enantioselectivity was observed by using
(S)-DTBM-Segphos as a ligand (entry 11). When using (S)-
Segphos as a ligand, the catalyst loading could be reduced to 5
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Communication
Table 2. Enantioselective Cycloisomerization of 1,6-Enynes
1a−l
Scheme 4
a
Scheme 5
acid. We were pleased to find that the present cycloisomerization
products, bicyclic 3-cyclopropylpropionic esters 2, could also be
converted to the corresponding bicyclic lactones 4. Conven-
iently, the one-pot enantioselective cycloisomerization and
lactonization of 1,6-enynes 1 were succeeded upon addition of
a (CH2Cl)2 solution of TsOH·H2O to the crude mixture of the
cycloisomerization reaction followed by heating at 80 °C. As
shown in Table 3, a variety of bicyclic lactones 4 were obtained
from 1,6-enynes 1 in one-pot with good yields and ee values.
Table 3. One-Pot Enantioselective Cycloisomerization and
a
Lactonization of 1,6-Enynes 1
a
[Rh(cod)2]BF4 (0.010 mmol), (S)-Segphos (0.010 mmol), 1 (0.20
mmol), BzOH (0.080 mmol), and (CH2Cl)2 or CH3(CHCl)CH2Cl
(1.5 mL) were used. The cited yields are of the isolated products.
b
[Rh(cod)2]BF4 (0.060 mmol), (S)-DTBM-Segphos (0.060 mmol), 1
(0.20 mmol), BzOH (0.080 mmol), and (CH2Cl)2 (1.5 mL) were
c
used. [Rh(cod)2]BF4 (0.040 mmol), (S)-Segphos (0.040 mmol), 1
(0.20 mmol), BzOH (0.080 mmol), and CH3(CHCl)CH2Cl (1.5 mL)
were used.
Scheme 3
a
[Rh(cod)2]BF4 (0.010 mmol), (S)-Segphos (0.010 mmol), 1 (0.20
mmol), BzOH (0.080 mmol), and (CH2Cl)2 or CH3(CHCl)CH2Cl,
(1.5 mL) were used in the cycloisomerization. Then a (CH2Cl)2 (0.5
mL) solution of TsOH·H2O (0.20 mmol) was added. The cited yields
are of the isolated products.
on not the methyl but on the methylene group. Thus, the site
selective γ-elimination of the methylene hydrogen proceeds to
give 2a and regenerates the Rh(I) complex and benzoic acid.16
This proposed mechanism was consistent with the fact that 1,6-
enynes 1m−o without carbonyl groups at the enyne linkage
failed to furnish 2m−o (Scheme 3).
The present lactonization reaction may proceed through a
similar mechanism of the previously reported lactonization of 3-
cyclopropylpropionic esters, leading to monocyclic lactones,
although the formation of bicyclic lactones has not been
reported.18 As shown in Scheme 6, the ring opening of the
cyclopropane moiety of 2a and elimination of benzyl tosylate
may afford bicyclic lactone 4a.
Consistent with the above reaction pathway, the reaction of
enyne 1k-d2 possessing the dideuterated allylic methylene group
furnished monodeuterated product 2k-d (Scheme 5).
3-Cyclopropylpropionic acids17 and esters18 were known for
being able to convert to monocyclic lactones with a Brønsted
In conclusion, we have established that a cationic Rh(I)/(S)-
Segphos or (S)-DTBM-Segphos complex and benzoic acid
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Scheme 6
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catalyze the enantioselective cycloisomerization of 1,6-enynes,
possessing carbonyl groups at the enyne linkage, to 2-
alkylidenebicyclo[3.1.0]hexanes. The present cycloisomerization
may involve the site selective γ-hydrogen elimination by
coordination of the carbonyl group to rhodium. The one-pot
enantioselective cycloisomerization and lactonization of 1,6-
enynes to produce bicyclic lactones proceeded in good yields by
the addition of TsOH·H2O after the rhodium-catalyzed
cycloisomerization.
(7) For other examples of the transition-metal-catalyzed cyclopropane
ring formation presumably through γ-hydrogen elimination: (a) Mao, J.;
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
ktanaka@apc.titech.ac.jp
Notes
■
(9) Ishida, M.; Tanaka, K. Org. Lett. 2013, 15, 2120.
(10) For the cationic rhodium(I)/bisphosphine complex-catalyzed
cyclization of 1,6-diynes with carboxylic acids: Tanaka, K.; Saito, S.;
Hara, H.; Shibata, Y. Org. Biomol. Chem. 2009, 7, 4817.
(11) For the cycloisomerization of 1,6-enynes, leading to exocyclic 1,3-
dienes, by using a neutral iridium(I) complex and acetic acid:
(a) Chatani, N.; Inoue, H.; Morimoto, T.; Muto, T.; Murai, S. J. Org.
Chem. 2001, 66, 4433. (b) Yamamoto, Y.; Hayashi, H.; Saigoku, T.;
Nishiyama, H. J. Am. Chem. Soc. 2005, 127, 10804.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported partly by a Grant-in-Aid for Scientific
Research (No. 25105714) from the Ministry of Education,
Culture, Sports, Science and Technology (Japan) and ACT-C
from the Japan Science and Technology Agency (Japan). We are
grateful to Takasago International Corporation for the gift of
Segphos, BINAP, and H8-BINAP derivatives and Umicore for
generous support in supplying rhodium complexes.
(12) Ishida, M.; Shibata, Y.; Noguchi, K.; Tanaka, K. Chem.Eur. J.
2011, 17, 12578.
(13) Lowering the amount of benzoic acid and reaction temperature
decreased the product yields.
(14) (a) Bhasker, R. A.; Qi, C.; Eugene, A. M. Tetrahedron: Asymmetry
2000, 11, 4681. (b) Ichiba, T.; Higa, T. J. Org. Chem. 1986, 51, 3364.
(15) See the Supporting Information.
(16) A rhodium carboxylate is probably needed to promote the present
C−H bond activation. For the effect of rhodium and iridium
carboxylates to promote σ-bond metathesis by way of a 6-centered
(rather than 4-centered) transition state: (a) Kong, J.-R.; Ngai, M.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718. (b) Ngai, M.-Y.; Barchuk,
A.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 280.
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