Highly stereoselective cyclopropanation of diazo Weinreb amides catalyzed by chiral Ru(II)-: Amm -Pheox complexes

Article abstract of DOI:10.1039/c6cc02498j

The first highly stereoselective cyclopropanation of diazo Weinreb amides with olefins was accomplished using chiral Ru(ii)-Amm-Pheox complex 7a to give the corresponding chiral cyclopropyl Weinreb amides in high yields (up to 99%) with excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 96% ee).

Full text of DOI:10.1039/c6cc02498j

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DOI: 10.1039/C6CC02498J
Journal Name
COMMUNICATION
Highly Stereoselective Cyclopropanation of Diazo Weinreb Amides
Catalyzed by Chiral Ru(II)-Amm-Pheox Complexes
Received 00th January 20xx,
Accepted 00th January 20xx
Soda Chanthamath,* Hamada S. A. Mandour, Tong Thi Minh Thu, Kazutaka Shibatomi and Seiji
Iwasa*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first highly stereoselective cyclopropanation of diazo Weinreb
amides with olefins was accomplished using chiral Ru(II)-Amm-
Pheox complex 7a to give the corresponding chiral cyclopropyl
Weinreb amides in high yields (up to 99%) with excellent
diastereoselectivities (up to 99:1 dr) and enantioselectivities (up
to 96% ee).
Chiral cyclopropane derivatives are valuable structural motifs found
in numerous natural products with diverse biological activities.1
Thus, during the past two decades, the development of synthetic
methodologies toward chiral cyclopropane compounds has
attracted much attention and the transition-metal-catalyzed
asymmetric cyclopropanation of olefins with diazoacetates is widely
recognized as one of the more powerful methods in terms of highly
stereoselective synthesis.2 In contrast to the excellent results
obtained with diazoacetates,3 diazoacetamides are rarely used as a
carbene source because of the low electrophilicity and steric
hindrance of the resulting metal-carbene intermediate.4 This
prompted us to explore the asymmetric cyclopropanation of olefins
with various diazoacetamides, namely, diazo Weinreb amides,
because the resulting cyclopropanes are potentially useful synthetic
intermediates that can be easily converted to the corresponding
aldehydes, ketones, and alchohols.5 Therefore, we initially prepared
diazo
Weinreb
amides,
such
as
N-methoxy-N-methyl
diazoacetamide (MMD) 2a,6 the novel N-benzyl-N-methoxy
diazoacetamide (BMD) 2b, and N-acetoxy-N-methyl diazoacetamide
(AMD) 2c, according to the Fukuyama method.7
In our previous studies Ru(II)-Pheox complex 3a proved to be an
efficient catalyst for inter- and intramolecular cyclopropanations of
various diazoacetates.8 Hence, we decided to use 3a for the
asymmetric cyclopropanation of diazo Weinreb amides 2 (Table 1).
The reaction of simple diazo Weinreb amide MMD 2a proceeded
smoothly at room temperature to afford the desired cyclopropane
product 4a in low yield with moderate stereoselectivity (entry 1).
Investigation of the effect of temperature revealed that −30 °C is
the most efficient for the cyclopropanation reaction, giving the
corresponding product in high yield (80%) with high
enantioselectivity (90% ee), albeit with low trans/cis ratio (83:17 dr)
(entry 4). The use of bulky diazo Weinreb amide BMD 2b did not
show any improvement (entry 6). On the basis of the successful use
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of functionalized diazoacetates for highly stereoselective
cyclopropanations,9 functionalized diazo Weinreb amide 2c was
also investigated and was found to be crucial for the trans-
selectivity: the corresponding cyclopropylamide 4c was obtained in
99:1 dr, albeit with low enantioselectivity (85% ee) (entry 7).
Surprisingly, the cyclopropanation with commonly used catalysts,
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DOI: 10.1039/C6CC02498J
11
such as Rh2(OAc)4, Ru(II)-Pybox10 and Rh2(S-TBPTTL)4 proceeded
with low yields and poor enantioselectivities (products resulting
from the dimerization of the diazo compound were mainly
observed)(entries 8–12).
In order to improve the enantioselectivity, the Ru(II)-Pheox 3a
catalyst was modified in terms of electron density (catalysts 3b–d)
and bulkiness (catalysts 7a–d). An internal quaternary ammonium
unit is featured in these complexes, on account of the enhanced
reaction rate and selectivity observed by Jeffery and co-workers
upon addition of quaternary ammonium salts as additives.12
Catalyst 7a–d were prepared as shown in Scheme 1. At first, we
successfully synthesized Ru(II)-(iodomethyl)phenyl-Pheox complex 6
from (chloromethyl)phenyl-Pheox ligand 5 in 89% yield for two
steps. Treatment of 6 with appropriate tertiary amines in CH3CN
afforded the desired Ru(II)-Amm-Pheox catalysts 7a–d in moderate
yields (41–54%).
Encouraged by these results, we investigated the
cyclopropanation of diazo Weinreb amide AMD 2c with various
olefins using Ru(II)-Amm-Pheox 7a. The obtained results are
summarized in Table 3. The reaction of styrene derivatives bearing
an electron-donating group at the para position showed a higher
enantioselectivity as compared with those with an electron-
donating substituent at the ortho or meta position (entries 2–4).
Namely, the highest enantioselectivity (96% ee) was obtained for
the styrene bearing a para-methoxy substituent (entry 5). An
electron-withdrawing substituted styrene could be easily
cyclopropanated with AMD 2c without any significant loss in
catalytic activity and stereoselectivity (entry 6). On the other hand,
the cyclopropanation of α-methyl substituted styrene afforded the
desired product with moderate enantioselectivity (74% ee) but in
high yield and high trans/cis ratio (entry 7). In addition, Ru(II)-Amm-
Pheox 7a proved to be effective for the asymmetric
cyclopropanation of sterically demanding tert-butyl vinyl ether and
N-vinylcarbazole to provide the corresponding cyclopropane
products in high yields with excellent diastereo- and
Screening of various Ru(II)-Pheox 3 and Ru(II)-Amm-Pheox 7
catalysts is shown in Table 2. As a result, we found that the
enantioselectivity could be increased to 89% ee by using Ru(II)-
Pheox catalyst 3c, which bears a CF3 electron-withdrawing group
(entry 3). Surprisingly, the bulky Ru(II)-Amm-Pheox 7a exhibited
higher activity and enantioselectivity as compared with simple
Ru(II)-Pheox 3, giving the corresponding product in high yield (98%)
with excellent diastereoselectivity (98:2 dr) and high
enantioselectivity (92% ee) (entry 5). To the best of our knowledge,
this is the first report on the highly stereoselective
cyclopropanation reaction of diazo Weinreb amide derivatives. It is
noteworthy that increasing the bulkiness of the quaternary
ammonium unit on the Ru(II)-Amm-Pheox 7 had negative effects on
the yield and the enantioselectivity of the reaction (entries 6–8).
enantioselectivities (entries
8 and 9). However, moderate
enantioselectivity was obtained when N-methyl-N-vinylacetamide
was used as olefinic substrate (76% ee) (entry 10).
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To further demonstrate the utility of the obtained chiral
products, we next investigated the arylation of chiral cyclopropyl
Weinreb amide 4c with Grignard reagent PhMgBr for the formation
of chiral cyclopropyl ketone 11. Unfortunately, the desired product
was obtained in low yield and many byproducts were observed. On
the other hand, the arylation reaction of chiral cyclopropyl Weinreb
amide 4a proceeded smoothly to provide the desired chiral
cyclopropyl ketone 11 in 89% yield with high enantioselectivity
(90% trans ee) (Scheme 3).
We envisioned that the high level of diastereocontrol achieved
with this catalytic system could be attributed to the formation of a
In order to demonstrate the advantage of using diazo Weinreb bulky seven-membered ring by coordination of the acetoxy
amides as carbene source for the asymmetric cyclopropanation, we carbonyl group with the Ru metal center, which prevented a cis-
investigated the synthetic transformations of the obtained selective approach of the styrene as described in previous reports.9
cyclopropane products (Scheme 2). Chiral cyclopropyl Weinreb These results clearly indicate the importance of using a carbonyl-
amide 4c can easily undergo reduction with LiAlH4 under functionalized diazo Weinreb amide as carbene source to achieve a
appropriate conditions to form the corresponding chiral (1R,2R)- highly trans-selective cyclopropanation. On the other hand, we
aldehyde 8 and (1R,2R)-alcohol 9 in high yields with high diastereo- speculate that the high enantioselectivity achieved with this
and enantioselectivities. In addition, treatment of 4c with NaOH in catalytic system might be attributed to the bulky quaternary
THF afforded chiral cyclopropyl Weinreb amide 10 in high yield ammonium unit, which prevents a (1S,2S)-selective approach of the
(86%) and unaltered enantioselectivity (92% ee). Since the (1R,2R) styrene from the re-face (the chiral environment of the phenyl
configuration of alcohol 9 was confirmed by the comparison of its group might prevent the styrene closing in from the si-face)
optical rotation,13 the absolute configuration of cyclopropyl (Scheme 4).
Weinreb amide 4c was also determined to be (1R,2R).
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4
5
In conclusion, we successfully developed of the first highly
stereoselective cyclopropanation of diazo Wienreb amides
with olefins using chiral Ru(II)-Pheox-type catalysts. Ru(II)-
Amm-Pheox complex 7a featuring an internal quaternary
ammonium unit exhibited obviously higher activity and
enantioselectivity as compared with previously described
Ru(II)-Pheox complex 3, to afford the corresponding chiral
cyclopropyl Weinreb amides in high yields (up to 99%) with
excellent diastereoselectivities (up to 99:1 dr) and
enantioselectivities (up to 96% ee). In addition, the use of
acetoxy-functionalized diazoacetamide AMD as a carbene
source was found to be crucial for the high trans-selectivity of
the cyclopropanation reaction. Moreover, the obtained chiral
Weinreb amides were readily converted to various useful
synthetic intermediates, such as alcohols, ketones, and
aldehydes, in one step and without any loss of
enantioselectivity.
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