Enantioselective Carbene Cascade: An Effective Approach to Cyclopentadienes and Applications in Diels–Alder Reactions

Article abstract of DOI:10.1002/adsc.201501106

An asymmetric carbene cascade reaction, which proceeds through carbene/alkyne metathesis and formal (3+2) cycloaddition and converts alkynyl-tethered enol diazoacetates to chiral bicyclic cyclopentadienes, is presented; and no catalytic asymmetric version of these carbene cascade transformations has been disclosed so far. The proton signals of the cyclopropene intermediates are observed in the mechanism study, which clearly demonstrate the reaction pathways. In addition, these products are intercepted via Diels–Alder reactions to provide bridged polycyclic structures in high yields and enantioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201501106

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DOI: 10.1002/adsc.201501106
Enantioselective Carbene Cascade: An Effective Approach to
Cyclopentadienes and Applications in Diels–Alder Reactions
Xiangbo Wang,a Yunfei Zhou,a Lihua Qiu,a Ruwei Yao,a Yang Zheng,a
Cheng Zhang,a Xiaoguang Bao,a,* and Xinfang Xua,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
E-mail: xgbao@suda.edu.cn or xinfangxu@suda.edu.cn
Received: December 4, 2015; Revised: March 1, 2016; Published online: April 15, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501106.
Abstract: An asymmetric carbene cascade reaction,
which proceeds through carbene/alkyne metathesis
and formal (3+2) cycloaddition and converts alkyn-
yl-tethered enol diazoacetates to chiral bicyclic cy-
clopentadienes, is presented; and no catalytic asym-
metric version of these carbene cascade transforma-
tions has been disclosed so far. The proton signals
of the cyclopropene intermediates are observed in
the mechanism study, which clearly demonstrate the
reaction pathways. In addition, these products are
intercepted via Diels–Alder reactions to provide
bridged polycyclic structures in high yields and
enantioselectivities.
ed with N-phenylmaleimide via Diels–Alder reactions
to provide bridged polycyclic structures in high yields
with high enantioselectivities. In addition, this bicy-
clo[2.2.1]heptene framework is the core unit in many
drug candidates,[6] including those used as potential
antidepressants[6a] and anticancer candidates.[6b,c]
Catalytically generated metal carbenes have shown
versatile reactivity and broad applications in modern
organic synthetic chemistry,[7] especially for multi-
bond formation.[8] In this context, Rh-catalyzed cas-
cade reactions with alkynyl-tethered diazo compounds
have shown powerful applications in various ring
structure formation or reconstruction, in which multi-
ple bonds were formed in one reaction.[9] The gener-
ated vinyl metal carbene intermediate was reported
to be terminated by typical metal carbene reactions,
including ylide formation,[9] cyclopropanation,[10] cy-
cloaddition[11] and Buchner reactions.[12] More recent-
Keywords: cascade reactions; cycloaddition; cyclo-
pentadienes; diazo compounds; dirhodium cata-
lysts; metal carbenes
ly, May and co-workers have reported a carbene/
[13]
À
alkyne metathesis terminated with C H insertion,
and the cyclopropene intermediate in the carbene/
Cyclopentadiene, which is a useful synthon in Diels– alkyne metathesis process was confirmed.[13b,14] Sur-
Alder reactions,[1] has offered tremendous synthetic prisingly, besides the reported versatile asymmetric
opportunities in the construction of various bicy- carbene transformations,[7,8] there has been no report-
clo[2.2.1]heptene frameworks, especially in total syn- ed catalytic asymmetric version of a carbene/alkyne
thesis.[2] Many efforts have been made toward the syn- metathesis cascade reaction. Inspired by these works
thesis of this unit, including its multisubstituted var- and our continuing interesting in this field,[15] a chiral
iants, particularly with substitution at the 5-posi- cyclopentadiene formation approach could be envi-
tion.[3–5] However, the main obstacle to the practical sioned from enol diazoacetates (Scheme 1, lower
use of this synthon is its facile [1,5]-sigmatropic shift, part), which would produce the cyclized product with
which usually generates tautomers of the cyclopenta- a chiral center at the 5-position.
dienes and gives mixtures of cycloaddition adducts in
The designed alkynyl-tethered enol diazoacetates 2
reactions with corresponding dienophiles;[4] and there were easily obtained by enolization of the corre-
have been only limited examples with chiral 5-substi- sponding a-diazo-b-keto esters 1, which were conven-
tuted cyclopentadienes that do not undergo the facile iently prepared from commercially available materials
[1,5]-sigmatropic shift.[5a,b] Herein, we report the syn- in three steps on a gram scale.[16] The corresponding
thesis of stable bicyclic 5-substituted chiral cyclopen- cyclopentadiene 3a was generated as the only product
tadienes via a catalytic asymmetric metal carbene cas- in 100% conversion when 2a was treated with
cade reaction, and these products are in situ intercept- 1.0 mol% Rh2(OAc)4 in DCM at room temperature,
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Table 1. Optimization of the reaction conditions.[a]
En-
try
Rh(II)
Solvent
T
Yield
ee
[oC]
[%][b] [%][c]
1
2
3
4
Rh2(S-DOSP)4
Rh2(S-PTA)4
DCM
DCM
DCM
DCM
DCM
TBME
r.t.
r.t.
r.t.
rt
r.t.
0
67
72
59
53
76
69
71
54
66
72
82
26
42
47
69
75
77
80
77
82
87
92
90
Rh2(S-PTPA)4
Rh2(S-NTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-TFPTTL)4
5
6[d]
7
toluene r.t.
toluene r.t.
8
9
10
Rh2(S-TCPTTL)4 toluene r.t.
Rh2(S-TBPTTL)4 toluene r.t.
11[d] Rh2(S-TBPTTL)4 toluene
0
Scheme 1. Rh-catalyzed cyclopentadiene formations.
12[d] Rh2(S-TBPTTL)4 toluene À10 78
[a]
Reactions were carried out at the indicated temperature
with 2a (0.2 mmol) in 2.0 mL solvent with 1.0 mol%
dirhodium catalyst for 2 h, then N-phenylmaleimide
(0.3 mmol) was added, and the reaction mixture was
stirred for another 36 h at room temperature.
Isolated yield after chromatography.
Enantioselectivity was determined by chiral HPLC analy-
sis, see the Supporting Information for details.
and its structure was confirmed spectroscopically.[16]
No decomposition of 3a was observed at room tem-
perature even after a week. However, decomposition
of 3a occurred during the column chromatography on
silica gel. To our delight, when the reaction mixture
was treated with 1.5 equiv. of N-phenylmaleimide,
endo-addition at the less sterically hindered side oc-
curred to give the bridged polycyclic product 4a as
a single anti-diastereoisomer in 65% isolated yield
(Scheme 2).[5e] The structure of this product was con-
[b]
[c]
[d]
The first step was carried for 12 h at the indicated tem-
perature. TBME=tert-butyl methyl ether.
firmed by single-crystal X-ray diffraction analysis of lysts in toluene (entries 8–12) revealed that Rh2(S-
its chloro-derivative 4h.[17]
TBPTTL)4 gave the best result at 08C to form 4a in
Encouraged by these results, we investigated the 82% isolated yield with 92% ee (entry 11).
asymmetric version of this cascade reaction with 2a as Using the optimal reaction conditions we evaluated
substrate (Table 1). Cyclopentadiene formation was the cycloaddition of 3a that was catalytically generat-
complete within 2 h at room temperature in the pres- ed from 2a, with N-phenylmaleimide derivatives. The
ence of 1.0 mol% chiral dirhodium catalysts (see the reactions occurred in moderate to high yields
Supporting Information, Scheme S1). Moderate to (Table 2, entries 1–6) with almost identical enantiose-
high enantioselectivity was observed for the Diels– lectivity (91–93% ee), which was consistent with enan-
Alder reaction product 4a when using phthalimide- tiocontrol originating from the chiral dirhodium-cata-
amino acid ligated dirhodium catalysts (entries 2–5), lyzed carbene cascade reaction. Substituents on the
but with Rh2(S-DOSP)4 4a was obtained with only aryl ring of the diazo compounds show minimal ef-
26% ee in 67% yield (entry 1). Evaluation of various fects on selectivity, and the bridged polycyclic prod-
solvents revealed that reaction in toluene gave higher ucts are obtained in high yield with 89–96% ee. More-
enantioselectivity without affecting the yield of 4a over, when the reaction was catalyzed by this cata-
(entries 5–7). Further screening of halogenated cata- lystꢀs enantiomer, Rh2(R-TBPTTL)4, similar reactivity
was observed, and formation of the enantiomeric
product demonstrated access to both R and S stereo-
isomers (entry 8, result in parentheses). The alkyl-sub-
stituted 2g, which was used as a mixture of Z/E iso-
mers, gave one product with moderate yield and
enantioselectivity, and the steric effect might account
for, at least partially, the low enantioselectivity
(entry 17). The reaction with terminal H or ethyl
groups gave a mess and with no starting material re-
covered. The TMS-substituted one produced the cy-
clopentadiene smoothly; however, cycloaddition did
not occur due to the steric effect. In addition, the re-
action could be carried out on a gram scale with
0.5 mol% of catalyst to give the desired product in
Scheme 2. Metal carbene cascade reactions.
58% yield with 92% ee (entry 7, result in parenthe-
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Enantioselective Carbene Cascade: An Effective Approach
Table 2. Asymmetric metal carbene cascade reaction with alkyne-tethered diazo compounds.[a]
Entry
Ar
R
R’
4
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
82
55
74
83
68
76
92
92
92
91
92
93
4-MeOC6H4
4-NO2C6H4
2-BrC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC6H4
4-ClC6H4
4-MeC6H4
3-MeC6H4
4-MeOC6H4
4-CF3C6H4
4-MeO2CC6H4
Ph
88 (58)[i]
70 (67)[j]
90
93 (92)[i]
94 (93)[j]
89
9
10
11[d]
12[e,f]
13[g]
14[e]
15[d]
16[d]
17[e,h]
82
83
55
70
95
77
85
55
89
93
90
96
89
89
92
47
Ph
4-ClC6H4
4-FC6H4
4-MeOC6H4
C2H5
Ph
Ph
Ph
Ph
[a]
Reactions were carried out at 08C on a 0.2 mmol scale.
Isolated yield.
[b]
[c]
[d]
[e]
[f]
Determined by chiral HPLC analysis.
The first step was carried out at À108C.
The reaction was carried out in TBME.
The first step was carried out at 408C for 2 h.
The first step was carried out at 258C for 2 h.
A mixture of the diazo compound 2q with Z/E=2.4:1 was used for the reaction due to its inseparability by chromatogra-
phy.
The reaction was carried out in 1.0 mmol scale with 0.5 mol% of catalyst.
The data in parentheses are for the reaction catalyzed by Rh2(R-TBPTTL)4.
[g]
[h]
[i]
[j]
ses). Interestingly, no desired product was detected
when Ar was ortho-substituted with a methyl group,
although the corresponding cyclopentadiene was ob-
served, which might arise from steric hindrance. Ef-
forts to promote the transformation by elevating the
reaction temperature gave regioisomer 5 instead of 4
(Table 3). When 2 was treated with dirhodium catalyst
at 08C and then heated with N-phenylmaleimide at
1008C, 5e was obtained (entry 5, in 44% yield with
88% ee), whose formation was probably due to a con-
certed [1,5]-hydrogen shift of the corresponding cyclo-
pentadiene under thermal conditions followed by the
Diels–Alder reaction. To see the generality of this re-
activity pattern, other substrates were tested under
these reaction conditions; they produced the isomeric
adducts in moderate to high yield with almost identi-
cal ee values compared to the results of the corre-
sponding adducts obtained at room temperature
(Table 3, 88–92% ee). Based on this result, a concerted
[1,5]-hydrogen shift that maintains the enantiopurity
Table 3. Asymmetric metal carbene cascade reaction under
thermal conditions.[a]
Entry Ar1
Ar2
5
Yield [%][b] ee [%][c]
1
Ph
4-BrC6H4
4-ClC6H4
3-MeC6H4 Ph
2-MeC6H4 Ph
Ph
Ph
Ph
Ph
5a 70
5b 65
5c 59
5d 72
5e 44
92
92
92
90
88
90
2[d]
3
4
5
6[d]
4-FC6H4 5f 67
[a]
[b]
[c]
[d]
Reactions were carried out at 08C on a 0.2 mmol scale.
Isolated yield.
Determined by chiral HPLC analysis.
The first step was carried out at À108C.
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of the cyclopentadienes could be inferred, and the ste-
reochemistry of 4 (4R,4aR,7aS,8R,9R) could be de-
duced from the corresponding structure of 5, and
these two compounds could also be distinguished by
proton NMR.[16] The absolute structure of 5 was con-
firmed by single-crystal X-ray diffraction analysis of
its bromo derivative 5b, and the configurations of
other compounds were assigned by analogy.[17] The
Diels–Alder addition with other acyclic dienophiles,
including ethyl acrylate, dimethyl maleate or dimethyl
acetylenedicarboxylate, did not occur under the cur-
rent conditions, and only slow decomposition of the
cyclopentadiene was observed. Further applications
with these cyclopentadiene products are under inves-
tigation.
Scheme 3. Proposed reaction pathways.
mediate 7ꢀ was also clearly detected after a few more
To gain insight into the mechanism of this cascade hours (Figure 1, purple part),[13] which gave the vinyl
transformation, a control reaction catalyzed with carbene 7 and was followed by intramolecular formal
Rh2(OAc)4 was carried out in an NMR tube with tol- (3+2)-cycloaddition to give the cyclopentadiene 3a
uene-d8 as the solvent (Figure 1). After 9 h, most of (Figure 1, green part).[15] According to these results,
the starting material 2a was consumed and the first we proposed the carbene/alkyne metathesis cascade
cyclopropene intermediate 6’ was observed (Figure 1, pathway (Scheme 3). Although rearrangement of 7’ to
blue part; this transformation was observed in our the final product could not be completely excluded,
previous work),[11c] which could regenerate the corre- the direct (3+2)-cycloaddition of alkyne with enol
sponding enol metal carbene 6 in the presence of metal carbene generated from 2a could be ruled
a metal catalyst (Scheme 3).[11] The following carbene/ out.[18] Further investigation on the cycloaddition part
alkyne metathesis to form another cyclopropene inter- of this cascade transformation, including control reac-
Figure 1. Proton NMR observations.
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Enantioselective Carbene Cascade: An Effective Approach
sequent cycloaddition step easier than 3a’’, both kinet-
ically and thermodynamically (Scheme 5). Therefore,
5a, instead of 5a’, was observed experimentally.
In summary, an asymmetric dirhodium-catalyzed
carbene cascade reaction with alkyne-tethered diazo
compounds has been reported for the first time. The
reaction provides a direct approach to optically active
bicyclic cyclopentadienes under mild reaction condi-
tions with high enantioselectivity. In addition, a [1,5]-
H shift only occurs at high temperature for the gener-
ated cyclopentadienes, which allows their successful
application in Diels–Alder additions for the controlla-
ble construction of different bridged polycyclic com-
Scheme 4. Control reactions.
tions and computational studies, revealed that under pounds with high yields and selectivity. Further inves-
thermal conditions 4a could convert to 5a which is the tigation of this cascade reaction with broad substrate
thermodynamically more stable product, with 100% scope is underway in our laboratory.
conversion and 62% isolated yield (Scheme 4).[16] The
same reaction of 4a with 92% ee gave optically active
5a with only a 1–2% decrease in ee, which further Experimental Section
confirmed a concerted [1,5]-H shift from 3a to 3a’
under thermal conditions. Computational studies also General Procedure
indicated that the energy barrier of the [1,5]-sigma-
In a 10-mL oven-dried vial containing a magnetic stirring
bar, Rh2(S-TBPTTL)4 (1.0 mol%, 5.0 mg) was dissolved in
anhydrous toluene (1.0 mL). Diazo compound 2 (0.2 mmol)
tropic shift for 5-substituted cyclopentadienes is
around 24 kcalmolÀ1, which is ca. 4 kcalmolÀ1 higher
than that for the unsubstituted substrate (without the
TBSO group).[16] Thus, the presence of the TBSO
group might be responsible for the sluggish rearrange-
ment, which is consistent with the reported results.[5a]
The energy barrier leading to 3a’ from 3a is 1.6 kcal
molÀ1 lower in energy than that leading to 3a’’ (Sup-
porting Information, Figure S1). Thus, the formation
of 3a’ is slightly favored kinetically. Additionally, com-
putational results indicate that 3a’ undergoes the sub-
in anhydrous toluene (1.0 mL) was added via a syringe
pump over 30 min under argon at 08C. The reaction mixture
was stirred at 08C overnight, and then the N-phenylmalei-
mide derivative (0.3 mmol, 1.5 equiv.) was added, the reac-
tion mixture was stirred for another 36 h at room tempera-
ture. The reaction mixture was directly purified by column
chromatography on silica gel without any additional treat-
ment (eluent: hexane:EtOAc=10:1 to 5:1) to give the de-
sired product 4; yield: 55–95% yield with 47–96% enantio-
selectivity.
Acknowledgements
We are grateful for grants from Soochow University and
PAPD of Jiangsu Province; XX was supported by NSFC of
Jiangsu province (BK20150315) and XB was supported by
the NSFC (21302133).
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1576
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Adv. Synth. Catal. 2016, 358, 1571 – 1576