Highly regio- and stereoselective synthesis of alkylidenecyclopropanes via Ru(II)-pheox catalyzed asymmetric inter- and intramolecular cyclopropanation of allenes

Article abstract of DOI:10.1021/ol5014944

An efficient protocol for the synthesis of optically active alkylidenecyclopropanes (ACPs) via the Ru(II)-Pheox catalyzed asymmetric cyclopropanation of allenes has been established. This catalytic system proceeded with high regioselectivity to give the A

Full text of DOI:10.1021/ol5014944

Letter
pubs.acs.org/OrgLett
Highly Regio- and Stereoselective Synthesis of
Alkylidenecyclopropanes via Ru(II)-Pheox Catalyzed Asymmetric
Inter- and Intramolecular Cyclopropanation of Allenes
Soda Chanthamath, Hao Wei Chua, Seiya Kimura, Kazutaka Shibatomi, and Seiji Iwasa*
Department of Environmental, Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi
441-8580, Japan
S
* Supporting Information
ABSTRACT: An efficient protocol for the synthesis of optically active alkylidenecyclopropanes (ACPs) via the Ru(II)-Pheox
catalyzed asymmetric cyclopropanation of allenes has been established. This catalytic system proceeded with high regioselectivity
to give the ACP products in high yield with high diastereoselectivity (up to 99/1) and enantioselectivity (up to 99% ee).
lkylidenecyclopropanes (ACPs) are useful structural
Amotifs that can serve as key intermediates in organic
synthesis.1 Many reports in the literature describe the use of
alkylidenecyclopropanes as useful intermediates for the syn-
thesis of biologically important compounds such as 3-
methylenecyclobutyl esters,2 3-azabicyclo[3.1.0]hexanes,3 tetra-
hydropyrans,4 and 3-ozabicyclo[3.1.0]hexane-2-ones.5
Although numerous synthetic methods to access ACPs have
been developed over the past few decades,6 methods to access
optically active ACPs are rare.7 Achiral rhodium-catalyzed
cyclopropanation of allenes with diazoesters is often employed
for the synthesis of ACPs; however, this method poses
difficulties regarding control of the regio- and stereochemistry
of the product.8 The most efficient asymmetric catalytic
methods for the formation of ACPs has been reported by
Frost7b,c and Charette.7d Their work involved the reaction of
disubstituted diazoacetates with allenes using a chiral rhodium-
(II) catalyst. However, bulky disubstituted diazoacetate was
found to be important in providing high regio- and stereo-
control; therefore the reaction of monosubstituted diazoacetate
still remains a challenge. Herein, we describe the first
asymmetric catalytic inter- and intramolecular cyclopropanation
of monosubstituted diazoacetates in the presence of a Ru(II)-
Pheox catalyst. Furthermore, the development of the first
enantioselective method for the synthesis of cis-cyclopropanes
via reduction of the ACP products is also disclosed.
acetates 2 catalyzed by Ru(II)-Pheox (Table 1). Using ethyl
diazoacetate (EDA), the E/Z ratio of product 3 was low;
however, high regio- and enantioselectivity were obtained
(Table 1, entry 1). tert-Butyl diazoacetate provided an increase
in the E/Z ratio to 95:5 and excellent regioselectivity of product
a
Table 1. Screening of Various Diazoacetates
a
Diazo compound diluted in CH2Cl2 was slowly added (11 h) by
b
c
using a syringe pump. Isolated yield. Determined by NMR.
Recently, we reported the efficient use of functionalized
diazoacetates as the carbene source for the asymmetric
cyclopropanation of alkenes using a chiral Ru(II)-Pheox
catalyst.9 Therefore, we began our study by examining the
cyclopropanation of cyclohexylallene 1a with various diazo-
d
Determined by chiral HPLC. Cy = cyclohexyl.
Received: May 25, 2014
Published: June 11, 2014
© 2014 American Chemical Society
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3, albeit in lower yield (Table 1, entry 2). Employing methyl
(diazoacetoxy)acetate (MDA) failed to improve the yield of
product (Table 1, entry 3). Pleasingly, when succinimidyl
diazoacetate was used as the carbene source, the desired
product 3 was obtained in high yield (82%) with excellent
diastereoselectivity (97:3) and enantioselectivity (92% ee)
(Table 1, entry 4).
Table 3. Cyclopropanation of Various Allenes
Next, we optimized the reaction conditions as shown in
Table 2. Surprisingly, the reaction without the slow addition of
Table 2. Optimization of Reaction Conditions
a
b
c
c
entry temp (°C)
time
12 h
yield (%) E/Z
E ee (%) Z ee (%)
d
1
2
3
4
5
6
rt
82
86
86
90
81
87
97:3
92
85
91
96
97
98
99
99
99
99
99
99
rt
1 min
5 min
10 min
3 h
97:3
97:3
98:2
98:2
98:2
0
−10
−20
−30
70 h
a
b
c
Isolated yield. Determined by NMR. Determined by chiral HPLC
analysis. 2d was slowly added over 11 h.
d
the diazo compound afforded the desired product 3d in good
yield (86%); however, the enantioselectivity fell to 85% ee
(Table 2, entry 2). The effect of the reaction temperature was
also investigated (Table 2, entries 2−6). The enantioselectivity
of 3d was improved to 98% ee by decreasing the reaction
temperature to −30 °C (entry 6); however, a longer reaction
time was required. From these results, it was concluded that
carrying out the reaction at −10 °C without slow addition of
the diazo compound was optimal for this catalytic system.
Under the optimized reaction conditions, a variety of allenes
derivatives were examined for reaction with succinimidyl
diazoacetate using the Ru(II)-Pheox catalyst (Table 3). It was
observed that monosubstituted aliphatic allenes reacted
smoothly with high regioselectivity and excellent enantiose-
lectivity to give the desired product 3 in moderate to high yield
(Table 3, entries 1−5). Unfortunately, the diastereoselectivity
decreased for the less hindered allene substrates. It is worth
noting that the cyclopropanation of 1,2-pentadiene only gave a
moderate yield of desired product due to the formation of
dimer byproducts (Table 3, entry 3). As a result, we decided to
use slow addition of the diazo compound in the presence of 5
mol % catalyst to suppress any dimer formation. Pleasingly, the
yield could be improved to 68% without detrimental effects to
the diastereo- or enantioselectivity (Table 3, entry 4).
Disubstituted allenes also underwent cyclopropanation to give
the alkylidenecyclopropane product in high yield and high
enantioselectivity; however, the regioselectivity was lower than
that for the monosubstituted allenes (Table 3, entries 6 and 7).
This may be due to the increase in electron density on the
internal carbon−carbon double bond of the allenes. Next, we
investigated the cyclopropanation of aromatic allenes: propa-
1,2-dien-1-ylbenzene, 2-(propa-1,2-dien-1-yl)naphthalene, and
1-methyl-4-(propa-1,2-dien-1-yl)benzene (Table 3, entries 8−
11). The cyclopropanation of propa-1,2-dien-1-ylbenzene
proceeded with excellent diastereoselectivity (99:1) and
enantioselectivity (97% ee) but in only moderate yield (Table
a
b
e
c
d
Isolated yield. Determined by NMR. Determined by chiral HPLC.
2d was slowly added for 4 h at −10 °C by using 5 mol % of catalyst.
5 mol % of catalyst was used.
3, entry 8). The yield could be improved to 85% by slow
addition of the diazo compound with only a slight decrease in
regioselectivity (Table 3, entry 9). Cyclopropanations of the
other aromatic allenes were carried out under the same
conditions as mentioned above, to give the corresponding
alkylidenecyclopropanes in high yield with high diastereo- and
enantioselectivity (Table 3, entries 10 and 11). Disappointingly,
the regioselectivities were lower compared to the monosub-
stituted aliphatic allenes. In contrast, the less hindered aromatic
allenes gave high regio- and enantioselectivity, while the
diastereoselectivity was reduced (Table 3, entries 12 and 13).
In addition, we also examined the cyclopropanation of
functionalized allenes such as methoxyallene and ethyl 2,3-
butadienoate; however, no cyclopropane products were
observed due to the decomposition of allene substrates and
the formation of a dimer from the diazo compound.
Encouraged by the results from the intermolecular cyclo-
propanation of allenes with succinimidyl diazoacetate, we
decided to investigate the intramolecular cyclopropanation of
allenic diazoacetates using the Ru(II)-Pheox catalyst (Table 4).
The cyclization of various symmetric allenic diazoacetates (R1 =
R2 = H, CH3, and cyclohexyl) proceeded smoothly under mild
reaction conditions to afford the bicyclic cyclopropane fused γ-
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the corresponding cis-cyclopropane 7 in high yield with
excellent cis-selectivity (>99:1) and enantioselectivity (99%
ee) (Scheme 1a). This is the first example for the
Table 4. Cyclopropanation of Various Allenic Diazoacetates
Scheme 1. Stereoselective Hydrogenation and Nucleophilic
Substitution of Alkylidenecyclopropanes (ACPs)
enantioselective synthesis of cis-cyclopropanes via reduction
of alkylidenecyclopropanes. The cis-isomer was confirmed by
1
comparing the H NMR spectral data of 7 with those of the
cyclopropane product synthesized from the direct reaction of
allylbenzene with succinimidyl diazoacetate 2d in the presence
of the Ru(II)-Pheox catalyst. The absolute configuration of 7
was determined by comparing the optical rotation of the
corresponding (+)-2-benzylcyclopropylmethanol obtained from
the LiAlH4 reduction of cis-cyclopropane 7 with the literature
data.11 Inspired by this result, we also carried out the
hydrogenation of bicyclic alkylidenecyclopropane fused γ-
lactone 6d (50:50 E:Z ratio) under the same reaction
conditions as mentioned above to afford bicyclic product 8 in
high yield (88%) with excellent enantioselectivity (98% ee)
(Scheme 1b). The (1S,5R,6S) configuration of 6-ethyl-3-
oxabicyclo[3.1.0]hexan-2-one 8 was confirmed by the compar-
ison of its optical rotation with literature data.12 By association,
the absolute configuration of 6-ethylidene-3-oxabicyclo[3.1.0]-
hexan-2-one 6d was confirmed to be (1R,5S). Being able to use
succinimidyl diazoacetate for cyclopropanation is very useful, as
the resulting product 3d can easily react with benzylamine and
benzyl alcohol to form other functionalized alkylidenecyclo-
propanes (9 and 10) in good yield and with high stereo-
selectivity (Scheme 1c).
a
b
c
Isolated yield. Determined by NMR. Determined by chiral HPLC
d
analysis. Allenic diazoacetate was slowly added over 4 h.
lactones in high yield (up to 91%) and excellent enantiose-
lectivity (99% ee for all substrates) (Table 4, entries 1−3). To
the best of our knowledge this is the first example of
asymmetric catalytic intramolecular cyclopropanation of allenic
diazoacetates. Racemic allenic diazoacetates (R1 = CH3, R2 = H
and R1 = C5H11, R2 = H) also underwent intramolecular
cyclopropanation to give the corresponding E and Z bicyclic
products in high yield and high enantioselectivity (Table 4,
entries 4 and 5). Following this, we also investigated using
substrates bearing larger R1 substituents such as phenyl and tert-
butyl. It is worth noting that although the cyclopropanation of
these substrates had improved diastereoselectivity (E/Z = 81/
19), the enantioselectivity of the E isomer fell to 48% ee and
slow addition was also required (Table 4, entries 6 and 7).
Interestingly, the reaction of allenic diazoacetate bearing a small
R3 (CH3) substituent proceeded smoothly to give the
corresponding bicyclic product in high yield and high
enantioselectivity; however, a low yield and enantioselectivity
were obtained with a large R3 (Ph) substituent (Table 4, entries
8 and 9).10
In conclusion, we have successfully developed an efficient
protocol for the synthesis of optically active ACP derivatives via
a Ru(II)-Pheox catalyzed asymmetric intermolecular cyclo-
propanation of allenes with succinimidyl diazoacetate. This
catalytic system gives direct access to ACPs in high yield with
high regioselectivity, diastereoselectivity (up to 99/1), and
enantioselectivity (up to 98% ee). Additionally, we have
successfully carried out the intramolecular cyclopropanation
The cyclopropanation product succinimidyl 2-benzylidene-
cyclopropanecarboxylate 3j was readily hydrogenated to give
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(10) The transition state geometries for the asymmetric intra-
molecular cyclopropanation were also described: See the Supporting
Information.
(11) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J.
Am. Chem. Soc. 1991, 113, 726−728. (b) Doyle, M. P.; Forbes, D. C.
Chem. Rev. 1998, 98, 911−935. (c) Lo, M. M.-C; Fu, G. C. J. Am.
Chem. Soc. 1998, 120, 10270−10271. (d) Hu, S.; Dordick, J. S. J. Org.
Chem. 2002, 67, 314−317.
(12) For the determination of the absolute configuration of 6-ethyl-3-
oxabicyclo[3.1.0]hexan-2-one 8, see: (a) Muller, P.; Lacrampe, F. Hel.
Chim. Acta 2004, 87, 2848−2859. (b) Ghanem, A.; Lacrampe, F.;
Schuring, V. Hel. Chim. Acta. 2005, 88, 216−239.
of various symmetric and racemic allenic diazoacetates to afford
the corresponding bicyclic alkylidenecyclopropane fused γ-
lactones in high yield with high enantioselectivity. Furthermore,
the utility of the present asymmetric cyclopropanation is
highlighted in the stereoselective synthesis of enantioenriched
cis-cyclopropanes via reduction of the ACP products.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data of all the
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: iwasa@ens.tut.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (C) (No. 23550179) from the Japan Society for the
Promotion of Science.
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