Catalytic Enantio- And Diastereoselective Cyclopropanation of 2-Azadienes for the Synthesis of Aminocyclopropanes Bearing Quaternary Carbon Stereogenic Centers

Article abstract of DOI:10.1021/acs.orglett.9b02692

We report the catalytic enantio- and diastereoselective preparation of aminocyclopropanes by the cyclopropanation of terminal and (Z)-internal 2-azadienes with donor/acceptor carbenes derived from α-diazoesters. The resulting cyclopropanes bear quaternary carbon stereogenic centers vicinal to the amino-substituted carbon and are formed as a single diastereomer in up to 99:1 er and 97% yield with 0.5 mol % of Rh₂(DOSP)₄ and only 1.5 equiv of the diazo reagent. Transformations with internal azadienes afford cyclopropanes with three contiguous stereogenic centers.

Full text of DOI:10.1021/acs.orglett.9b02692

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Enantio- and Diastereoselective Cyclopropanation of
2‑Azadienes for the Synthesis of Aminocyclopropanes Bearing
Quaternary Carbon Stereogenic Centers
Xinxin Shao and Steven J. Malcolmson*
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States
S
* Supporting Information
ABSTRACT: We report the catalytic enantio- and diastereoselective preparation of aminocyclopropanes by the
cyclopropanation of terminal and (Z)-internal 2-azadienes with donor/acceptor carbenes derived from α-diazoesters. The
resulting cyclopropanes bear quaternary carbon stereogenic centers vicinal to the amino-substituted carbon and are formed as a
single diastereomer in up to 99:1 er and 97% yield with 0.5 mol % of Rh2(DOSP)4 and only 1.5 equiv of the diazo reagent.
Transformations with internal azadienes afford cyclopropanes with three contiguous stereogenic centers.
Scheme 1. Catalytic Enantioselective Methods toward
Aminocyclopropanes with Quaternary Stereogenic Centers
evelopment of new strategies for the catalytic enantiose-
lective synthesis of amino-substituted stereogenic centers
D
is critical as these chiral amines are found in numerous natural
products, pharmaceuticals, and fine chemicals. The stereo-
selective construction of enantioenriched amines comprised of
multiple contiguous stereogenic centers is particularly challeng-
ing, especially as these carbons become more substituted.
One attractive class of chiral amines for preparing bioactive
compounds are aminocyclopropanes1 due to the geometric
constraint imposed by the carbocycle and the resulting precise
orientation of the functional groups that decorate it. However,
the enantioselective synthesis of aminocyclopropanes with a
quaternary stereogenic center vicinal to the amino group is
challenging, and lack of accessibility has perhaps diminished the
exploration of molecules within this chemical space in drug
discovery. Adding further complexity to these structures are
aminocyclopropanes with a third stereogenic center.
One enantioselective approach that has emerged for
synthesizing aminocyclopropanes with quaternary carbon
stereogenic centers involves the desymmetrization of highly
strained cyclopropenes (Scheme 1). Both hydroamination2 and
carboamination3 strategies, including annulation reactions,4
have recently been disclosed. While enabling the preparation of
cyclopropanes with 2−3 stereogenic carbons, this approach
relies upon preassembly of the three-membered ring. A second
tactic utilizes nitroalkenes5 in a number of related annulations
with enolate nucleophiles (Scheme 1).6 Access to the amine
would require reduction of the nitro group; furthermore,
epimerization may occur at the nitro-substituted carbon.5b
A straightforward way to prepare aminocyclopropanes is the
enantio- and diastereoselective cyclopropanation of N-sub-
stituted olefins with disubstituted carbene precursors;7,8
however, this strategy has seen limited success, being restricted
to just a handful of examples.9,10 Most cyclopropanations of N-
alkenyl substrates have entailed reactions with ethyl diazoacetate
or related α-diazoesters while also being constrained to terminal
Received: July 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
olefins, leading to products lacking quaternary carbons or more
than two stereogenic centers.11 The expansion of this
disconnection to encompass disubstituted olefins and/or
donor/acceptor carbene12 precursors would provide access to
more highly substituted cyclopropanes, including those bearing
quaternary stereogenic centers. In 2012, Gu, Li, and co-workers
reported the enantioselective cyclopropanation of 1,1-disub-
stituted alkenyl azides with donor/acceptor carbenes (Scheme
1).13,14 The products contain vicinal fully-substituted carbons,
however, reduction of the azide is necessary for preparing the
aminocyclopropane. Compounds with a third stereogenic
carbon were not reported.
Scheme 2. Catalyst Performance in Azadiene
Cyclopropanation
In this work, we have developed enantioselective cyclo-
propanations of terminal and (Z)-internal 2-azadienes15 with
donor/acceptor carbenes. The reactions proceed efficiently with
0.5 mol % Rh2(DOSP)4 catalyst and a slight excess of the
diazoester (Scheme 1). The cyclopropane products, comprised
Scheme 3. Scope of Diazoesters for Cyclopropanation of Azadiene 1
B
DOI: 10.1021/acs.orglett.9b02692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Azadiene Cyclopropanation with Diazoesters
Derived from Natural Products and Drug Molecules
Scheme 5. Cyclopropanation of (Z)-4-Alkyl-2-azadienes
Scheme 6. Alternative Annulations with 3-Substituted
Azadienes or α-Styrenyl Diazoesters
of two to three stereogenic centers, one of which is quaternary,
are formed with excellent diastereo- and enantiocontrol with the
benzophenone imine serving as a protecting and stabilizing
group for the amine within this donor/acceptor cyclopropane.16
We initiated our studies by examining the cyclopropanation of
terminal 2-azadiene 1 with phenyl-substituted diazoester 2a
(Scheme 2).17 With several chiral Rh(II)-based catalysts in
nonpolar solvent, cyclopropane 3a is obtained in ≥80% yield as a
single diastereomer with the imino and ester groups in a trans
relationship. The highest enantioselectivity and yield of 3a is
obtained with Rh2(R-DOSP)4 (Rh-1) at −45 °C in hexanes.
With the feasibility of our approach to aminocyclopropanes
established, we next set out to investigate the range of donor/
acceptor diazo reagents that would participate in Rh-1-catalyzed
cyclopropanation of 2-azadiene 1. While the conditions shown
in Scheme 2 proved optimal for the transformation of diazo
reagent 2a, diazoesters bearing other aryl groups often require
elevated temperatures and/or alternative nonpolar solvents for
reaction efficiency (Scheme 3). In some instances, this is due to
the electronic character of the Rh−carbene and in others
because of poor solubility of the diazo reagent in hexanes or at
low temperature.
(3l), trifluoromethyl (3m), boronic ester (3n), and nitro (3o)
functionality. Several halides and pseudohalides at the para-
position afford cyclopropanes 3c−h in 88−97% yield. Halogens
at the meta- (3s, 3u) and ortho-positions (3t)18 also allow for
efficient preparation of the protected aminocyclopropanes.
Heteroarene-substituted cyclopropanes, such as indolyl 3v and
thiophenyl 3w, can be isolated from cyclopropanation of
terminal azadiene 1. In all cases, the cyclopropanes are formed
as the trans-imino ester isomer in 72−97% yield and 90:10 to
99:1 er.
A range of electronically modified arenes within the diazo
reagent are tolerated, including electron-donating methoxy
(3b), siloxymethyl (3i), naphthyl (3q), and dioxalato (3r)
groups and electron-withdrawing ester (3j), ketone (3k), nitrile
We have also investigated the cyclopropanation of azadiene 1
with diazoesters prepared from natural products and drugs
C
DOI: 10.1021/acs.orglett.9b02692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
attempted reactions of the imine, with the ester still intact,
lead to complex mixtures.17 Reduction of the ester of 3a to
alcohol 9 allows for hydrolysis to the free amine, which may be
acylated to deliver 10 (Scheme 7). This pathway to the free
amine, easily obtained under mildly acidic conditions, will
enable elaboration of the aminocyclopropane building blocks to
downstream synthesis, including providing a pathway for
incorporation of this unit into peptides.24,25
Scheme 7. Functionalization of Cyclopropane Products
Additionally, the methyl ester of 3a may be hydrolyzed under
mild conditions to furnish carboxylic acid 11 in 62−83% yield
(Scheme 7). The somewhat unstable carboxylic acid, if used
immediately, may serve as an acyl donor: conversion to the
activated N-hydroxysuccinimide ester and subsequent trans-
formation to the carboxamide enables 12 to be obtained in 86%
yield over two steps.
a
DIC = diisopropylcarbodiimide; Suc = succinyl.
2-Azadienes continue to emerge as useful chemical building
blocks for constructing chiral amines.15 Whereas we have
previously shown their utility as enamine umpolung reagents,15
here we illustrate that they may serve as a highly useful protected
form of an amino-substituted olefin. Cyclopropanations of N-
containing alkenes are an attractive strategy for accessing
aminocyclopropanes but these transformations are uncommon,
especially those that afford compounds with quaternary
stereogenic centers (donor/acceptor carbenes) or wherein
each carbon of the cyclopropane is stereogenic. In this study,
we have demonstrated that Rh2(DOSP)4-catalyzed cyclo-
propanations of 2-azadienes with donor/acceptor carbenes
proceed with exceptional levels of efficiency, diastereo-, and
enantioselectivity to afford myriad protected aminocyclopro-
panes bearing quaternary stereogenic centers.
(Scheme 4). Both clofibrate- (3x) and fenofibrate-derived (3y)
diazoesters deliver iminocyclopropanes in ca. 97:3 er. Addition-
ally, connection of chiral molecules to the diazo reagents
through an ester (menthol, 3z) or benzyl ether (vitamin E, 3ab)
linkage enables formation of N-substituted cyclopropanes in ca.
88% yield and 94.5:5.5 dr. For the estrone-derived diazoester
that affords cyclopropane 3aa, the Rh2(R-DOSP)4 catalyst (Rh-
1) is efficient but only modestly diastereoselective (86% yield,
91.5:8.5 dr). Contrastingly, the catalyst enantiomer is “matched”
and furnishes the diastereomer of 3aa (97:3 dr) in 87% yield.
Achiral Rh2(esp)2 is significantly less stereoselective (29:71 dr),
delivering only 65% yield of product.
We next turned our attention to reactions of 4-alkyl-2-
azadienes (Scheme 5). Whereas the (E)-olefin isomers fail to
undergo cyclopropanation with Rh-1-derived donor/acceptor
carbenes, instead undergoing allylic C−H insertion,12,17 the
(Z)-internal azadienes 4 deliver multisubstituted cyclopropanes
5 comprised of three contiguous stereogenic centers in good
yield as a single diastereomer. Several diazoesters participate in
cyclopropanation of phenethyl-substituted azadiene 4a, furnish-
ing imino esters 5a−d in 89:11 to 92.5:7.5 er. Variation of the
azadiene’s aryl group is permissible with cyclopropanes 5e−g
formed with good enantioselectivity. Ethereal functionality
within the azadiene alkyl chain is tolerated but leads to modest
enantioselectivity (5h−i).
We attempted a number of additional azadiene/diazoester
couplings to prepare aminocyclopropanes with other substitu-
tion patterns or bearing alternative functional groups; however,
rather than the anticipated cyclopropane, different annulation
products were formed (Scheme 6). 3-Methyl-2-azadiene 6 leads
to unsaturated pyrrolidine 7 in 75% yield and 91.5:8.5 er. The
enantioselectivity suggests that the transformation proceeds
through Rh-1-catalyzed cyclopropanation of the azadiene and
subsequent transition-metal-mediated ring expansion19,20 of the
donor/acceptor cyclopropane, similar to vinylcyclopropane to
cyclopentene rearrangements.21 Furthermore, the reaction of
terminal azadiene 1 with the styrenyl-substituted diazoester 2ad
affords unsaturated pyrrolidine 8 (96:4 er) via formal [3 + 2]-
cycloaddition. Likely the reaction proceeds through initial attack
of the azadiene nitrogen upon the donor/acceptor carbene
followed by cyclization from the resulting ammonium ylide.22,23
Once more, the high enantioselectivity indicates that Rh-1 is
intimately associated with the cyclization event that leads to 8.
The imine-protected form of the nitrogen atom within the
cyclopropane products is sufficiently deactivating to suppress
ring-opening of the donor/acceptor cyclopropane;24 however,
hydrolysis of the imine leads to ring-opening, and other
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02692.
Experimental procedures, analytical data for new
compounds, and spectral data (PDF)
Accession Codes
CCDC 1920043 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: steven.malcolmson@duke.edu.
ORCID
Steven J. Malcolmson: 0000-0003-3229-0949
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIH (GM124286) and Duke University for
financial support of this research. We thank Dr. Roger Sommer
(NC State) for assistance with X-ray crystallography.
D
DOI: 10.1021/acs.orglett.9b02692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Screening Rhodium Metallopeptide Libraries “On Bead”: Asymmetric
Cyclopropanation and a Solution to the Enantiomer Problem. Angew.
Chem., Int. Ed. 2012, 51, 8568. (c) Denton, J. R.; Davies, H. M. L.
Enantioselective Reactions of Donor/Acceptor Carbenoids Derived
from α-Aryl-α-Diazoketones. Org. Lett. 2009, 11, 787. (d) Melby, T.;
Hughes, R. A.; Hansen, T. Diastereoselective Synthesis of 1-Aryl-2-
Amino-Cyclopropane Carboxylates. Synlett 2007, 2007, 2277.
(10) For α-nitrodiazoacetate cyclopropanations of styrenes, see:
(a) Lindsay, V. N. G.; Lin, W.; Charette, A. B. Experimental Evidence
for the All-Up Reactive Conformation of Chiral Rhodium(II)
Carboxylate Catalysts: Enantioselective Synthesis of cis-Cyclopropane
α-Amino Acids. J. Am. Chem. Soc. 2009, 131, 16383. (b) Moreau, B.;
Charette, A. B. Expedient Synthesis of Cyclopropane α-Amino Acids by
the Catalytic Asymmetric Cyclopropanation of Alkenes Using
Iodonium Ylides Derived from Methyl Nitroacetate. J. Am. Chem.
Soc. 2005, 127, 18014.
(11) (a) Brandenberg, O. F.; Prier, C. K.; Chen, K.; Knight, A. M.; Wu,
Z.; Arnold, F. H. Stereoselective Enzymatic Synthesis of Heteroatom-
Substituted Cyclopropanes. ACS Catal. 2018, 8, 2629. (b) Xie, M.-S.;
Zhou, P.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Enantioselective
Intermolecular Cyclopropanations for the Synthesis of Chiral
Pyrimidine Carbocyclic Nucleosides. Org. Lett. 2016, 18, 4344.
(c) Chanthamath, S.; Nguyen, D. T.; Shibatomi, K.; Iwasa, S. Highly
Enantioselective Synthesis of Cyclopropylamine Derivatives via Ru(II)-
Pheox-Catalyzed Direct Asymmetric Cyclopropanation of Vinyl-
carbamates. Org. Lett. 2013, 15, 772. (d) Chanthamath, S.;
Phomkeona, K.; Shibatomi, K.; Iwasa, S. Highly Stereoselective
Ru(II)−Pheox Catalyzed Asymmetric Cyclopropanation of Terminal
Olefins with Succinimidyl Diazoacetate. Chem. Commun. 2012, 48,
7750. (e) Abu-Elfotoh, A.-M.; Phomkeona, K.; Shibatomi, K.; Iwasa, S.
Asymmetric Inter- and Intramolecular Cyclopropanation Reactions
Catalyzed by a Reusable Macroporous-Polymer-Supported Chiral
Ruthenium(II)/Phenyloxazoline Complex. Angew. Chem., Int. Ed.
2010, 49, 8439. For a related approach to aminocyclopropanes, see:
(f) Le, C. T. L.; Ozaki, S.; Chanthamath, S.; Shibatomi, K.; Iwasa, S.
Direct Catalytic Asymmetric Cyclopropylphosphonation Reactions of
N,N-Dialkyl Groups of Aniline Derivatives by Ru(II)-Pheox Complex.
Org. Lett. 2018, 20, 4490.
REFERENCES
■
(1) (a) Shimpia, N. A.; Prathib, S. K.; Ponnuruc, A. K.; Batharajud, R.;
Dhakea, R. B. Novel Synthesis of Ticagrelor, an Anti-Thrombotic
Agent. J. Chem. Pharm. Res. 2015, 7, 1024. (b) Kawamura, S.; Unno, Y.;
List, A.; Mizuno, A.; Tanaka, M.; Sasaki, T.; Arisawa, M.; Asai, A.; Groll,
M.; Shuto, S. Potent Proteasome Inhibitors Derived from the Unnatural
cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity,
and Mode of Action. J. Med. Chem. 2013, 56, 3689. (c) Benelkebir, H.;
Hodgkinson, C.; Duriez, P. J.; Hayden, A. L.; Bulleid, R. A.; Crabb, S. J.;
Packham, G.; Ganesan, A. Enantioselective Synthesis of Tranylcypro-
mine Analogues as Lysine Demethylase (LSD1) Inhibitors. Bioorg. Med.
Chem. 2011, 19, 3709. (d) Khan, A. A.; Araujo, F. G.; Brighty, K. E.;
Gootz, T. D.; Remington, J. S. Anti-Toxoplasma gondii Activities and
Structure-Activity Relationships of Novel Fluoroquinolones Related to
Trovafloxacin. Antimicrob. Agents Chemother. 1999, 43, 1783.
(2) (a) Li, Z.; Zhao, J.; Sun, B.; Zhou, T.; Liu, M.; Liu, S.; Zhang, M.;
Zhang, Q. Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-
Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime. J.
Am. Chem. Soc. 2017, 139, 11702. (b) Teng, H.-L.; Luo, Y.; Wang, B.;
Zhang, L.; Nishiura, M.; Hou, Z. Synthesis of Chiral Amino-
cyclopropanes by Rare-Earth_metal-Catalyzed Cyclopropene Hydro-
amination. Angew. Chem., Int. Ed. 2016, 55, 15406.
(3) Simaan, M.; Marek, I. Asymmetric Catalytic Preparation of
Polysubstituted Cyclopropanol and Cyclopropylamine Derivatives.
Angew. Chem., Int. Ed. 2018, 57, 1543.
(4) (a) Teng, H.-L.; Luo, Y.; Nishiura, M.; Hou, Z. Diastereodivergent
Asymmetric Carboamination/Annulation of Cyclopropenes with
Aminoalkenes by Chiral Lanthanum Catalysts. J. Am. Chem. Soc.
2017, 139, 16506. (b) Semakul, N.; Jackson, K. E.; Paton, R. S.; Rovis,
T. Heptamethylindenyl (Ind*) Enables Diastereoselective Benzamida-
tion of Cyclopropenes via Rh(III)-Catalyzed C−H Activation. Chem.
Sci. 2017, 8, 1015.
(5) (a) Dou, X.; Yao, W.; Zhou, B.; Lu, Y. Asymmetric Synthesis of 3-
Spirocyclopropyl-2-oxindoles via Intramolecular Trapping of Chiral
Aza-ortho-xylylene. Chem. Commun. 2013, 49, 9224. (b) Dou, X.; Lu, Y.
Diastereodivergent Synthesis of 3-Spirocyclopropyl-2-oxidindoles
through Direct Enantioselective Cyclopropanation of Oxindoles.
Chem. - Eur. J. 2012, 18, 8315.
(12) (a) Davies, H. M. L.; Morton, D. Guiding Principles for Site
Selective and Stereoselective Intermolecular C−H Functionalization by
Donor/Acceptor Rhodium Carbenes. Chem. Soc. Rev. 2011, 40, 1857.
(b) Davies, H. M. L.; Walji, A. M. Rhodium(II)-Stabilized Carbenoids
Containing Both Donor and Acceptor Substituents. Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
2005; pp 301−340.
(13) Gu, P.; Su, Y.; Wu, X.-P.; Sun, J.; Liu, W.; Xue, P.; Li, R.
Enantioselective Preparation of cis-β-Azidocyclopropane Esters by
Cyclopropanation of Azido Alkenes Using a Chiral Dirhodium Catalyst.
Org. Lett. 2012, 14, 2246.
(14) For intermolecular transformations with N-vinylpyrimidines, see:
(a) Wang, H.-X.; Guan, F.-J.; Xie, M.-S.; Qu, G.-R.; Guo, H.-M.
Construction of All-Carbon Quaternary Stereocenters via Asymmetric
Cyclopropanations: Synthesis of Chiral Carbocyclic Pyrimidine
Nucleosides. Adv. Synth. Catal. 2018, 360, 2233. For intramolecular
reactions with N-vinylpurines, see: (b) Huang, K.-X.; Xie, M.-S.; Zhao,
G.-F.; Qu, G.-R.; Guo, H.-M. Synthesis of Chiral Cyclopropyl
Carbocyclic Purine Nucleosides via Asymmetric Intramolecular
Cyclopropanations Catalyzed by a Chiral Ruthenium(II) Complex.
Adv. Synth. Catal. 2016, 358, 3627.
(15) (a) Malcolmson, S. J.; Li, K.; Shao, X. 2-Azadienes as Enamine
Umpolung Synthons for the Preparation of Chiral Amines. Synlett
2019, 30, 1253. (b) Daniel, P. E.; Onyeagusi, C. I.; Ribeiro, A. A.; Li, K.;
Malcolmson, S. J. Palladium-Catalyzed Synthesis of α-Trifluoromethyl
Benzylic Amines via Fluoroarylation of gem-Difluoro-2-azadienes
Enabled by Phosphine-Catalyzed Formation of an Azaallyl−Silver
Intermediate. ACS Catal. 2019, 9, 205. (c) Shao, X.; Li, K.;
Malcolmson, S. J. Enantioselective Synthesis of anti-1,2-Diamines by
Cu-Catalyzed Reductive Couplings of Azadienes with Aldimines and
Ketimines. J. Am. Chem. Soc. 2018, 140, 7083. (d) Li, K.; Shao, X.;
(6) For related strategies, see: (a) Li, J.-P.; Zhao, G.-F.; Wang, H.-X.;
Xie, M.-S.; Qu, G.-R.; Guo, H.-M. Highly Enantioselective Synthesis of
Chiral Cyclopropyl Nucleosides via Catalytic Asymmetric Intermo-
lecular Cyclopropanation. Org. Lett. 2017, 19, 6494. (b) Luis-Barrera,
́
́
J.; Mas-Balleste, R.; Aleman, J. One-Pot Asymmetric Syntheiss of
Cyclopropanes with Quaternary Centers Starting from Bromonitroal-
kenes under Aminocatalytic Conditions. ChemPlusChem 2015, 80,
1595. (c) Pesciaioli, F.; Righi, P.; Mazzanti, A.; Bartoli, G.; Bencivenni,
G. Organocatalytic Michael-Alkylation Cascade: The Enantioselective
Nitrocyclopropanation of Oxindoles. Chem. - Eur. J. 2011, 17, 2842.
(7) Cyclopropanation of acrylates with donor/acceptor carbenes
followed by a downstream Curtius rearrangement would also deliver
analogous aminocyclopropanes. See: (a) Pons, A.; Tognetti, V.;
Joubert, L.; Poisson, T.; Pannecoucke, X.; Charette, A. B.; Jubault, P.
Catalytic Enantioselective Cyclopropanation of α-Fluoroacrylates: An
Experimental and Theoretical Study. ACS Catal. 2019, 9, 2594.
(b) Wang, H.; Guptill, D. M.; Varela-Alvarez, A.; Musaev, D. G.; Davies,
H. M. L. Rhodium-Catalyzed Enantioselective Cyclopropanation of
Electron-Deficient Alkenes. Chem. Sci. 2013, 4, 2844. (c) Miller, J. A.;
Hennessy, E. J.; Marshall, W. J.; Scialdone, M. A.; Nguyen, S. T. trans-
Cyclopropyl β-Amino Acid Derivatives via Asymmetric Cyclopropa-
nation Using a (Salen)Ru(II) Catalyst. J. Org. Chem. 2003, 68, 7884.
(8) For an additional approach to aminocyclopropanes with a
quaternary stereogenic center, see: Valenta, P.; Carroll, P. J.; Walsh, P. J.
Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopro-
panes and 1,3-Amino Alcohols via Asymmetric Catalysis. J. Am. Chem.
Soc. 2010, 132, 14179.
(9) (a) Sambasivan, R.; Zheng, W.; Burya, S. J.; Popp, B. V.; Turro, C.;
Clementi, C.; Ball, Z. T. A Tripodal Peptide Ligand for Asymmetric
Rh(II) Catalysis Highlights Unique Features of On-Bead Catalyst
Development. Chem. Sci. 2014, 5, 1401. (b) Sambasivan, R.; Ball, Z. T.
E
DOI: 10.1021/acs.orglett.9b02692
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Tseng, L.; Malcolmson, S. J. 2-Azadienes as Reagents for Preparing
Chiral Amines: Synthesis of 1,2-Amino Tertiary Alcohols by Cu-
Catalyzed Enantioselective Reductive Couplings with Ketones. J. Am.
Chem. Soc. 2018, 140, 598.
(16) Reissig, H.-U.; Zimmer, R. Donor−Acceptor-Substituted
Cyclopropane Derivatives and Their Application in Organic Synthesis.
Chem. Rev. 2003, 103, 1151.
(17) For additional data, see the Supporting Information.
(18) The stereochemistry of the major isomer of 3t was established by
single-crystal X-ray diffraction. The absolute stereochemistry of all
other products is assigned by analogy.
(19) For a related example with a carbodiene, see: Schnaubelt, J.;
Marks, E.; Reiβig, H.-U. [4 + 1] Cycloadditions of the Rhodium
Di(methoxycarbonyl) Carbenoid to 2-Silyloxy-1,3-Dienes. Chem. Ber.
1996, 129, 73.
(20) (a) Rodriguez, K. X.; Kaltwasser, N.; Toni, T. A.; Ashfeld, B. A.
Rearrangement of an Intermediate Cyclopropyl Ketene in a RhII-
Catalyzed Formal [4 + 1]-Cycloaddition Employing Vinyl Ketenes as
1,4-Dipoles and Donor−Acceptor Metallocarbenes. Org. Lett. 2017, 19,
2482. (b) de Nanteuil, F.; Serrano, E.; Perrotta, D.; Waser, J. Dynamic
Kinetic Asymmetric [3 + 2] Annulation Reactions of Amino-
cyclopropanes. J. Am. Chem. Soc. 2014, 136, 6239. (c) de Nanteuil,
F.; Waser, J. Catalytic [3 + 2] Annulations of Aminocyclopropanes for
the Enantiospecific Synthesis of Cyclopenylamines. Angew. Chem., Int.
Ed. 2011, 50, 12075.
(21) (a) Hudlicky, T.; Koszyk, F. J.; Kutchan, T. M.; Sheth, J. P.
Cyclopentene Annulation via Intramolecular Addition of Diazoketones
to 1,3-Dienes. Applications to the Synthesis of Cyclopentanoid
Terpenes. J. Org. Chem. 1980, 45, 5020. (b) Aris, V.; Brown, J. M.;
Conneely, J. A.; Golding, B. T.; Williamson, D. H. Synthesis and
Thermolysis of Rhodium and Iridium Complexes of endo-6-
vinylbicyclo[3.1.0]hex-2-ene. A Metal-Promoted Vinylcyclopropane
to Cyclopentene Rearrangement. J. Chem. Soc., Perkin Trans. 2 1975, 2,
4.
(22) For a closely related non-enantioselective example, see: Doyle,
M. P.; Yan, M.; Hu, W.; Gronenberg, L. S. Highly Selective Catalyst-
Directed Pathways to Dihydropyrroles from Vinyldiazosacetates and
Imines. J. Am. Chem. Soc. 2003, 125, 4692.
(23) For reactions with carbodienes, resulting in a different reaction
́
pathway, see: (a) Guzman, P. E.; Lian, Y.; Davies, H. M. L. Reveral of
the Regiochemistry in the Rhodium-Catalyzed [4 + 3] Cycloaddition
between Vinyldiazoacetates and Dienes. Angew. Chem., Int. Ed. 2014,
53, 13083. (b) Parr, B. T.; Davies, H. M. L. Rhodium-Catalyzed
Tandem Cyclopropanation/Cope Rearrangement of 4-Alkenyl-1-
sulfonyl-1,2,3-triazoles with Dienes. Angew. Chem., Int. Ed. 2013, 52,
10044.
(24) Boddaert, T.; Taylor, J. E.; Bull, S. D.; Aitken, D. J. A Selective
Deprotection Strategy for the Construction of trans-2-Aminocyclopro-
panecarboxylic Acid Derived Peptides. Org. Lett. 2019, 21, 100.
́
(25) (a) Kiss, L.; Mandity, I. M.; Fulop, F. Highly Functionalized
̈
̈
Cyclic β-Amino Acid Moieties as Promising Scaffolds in Peptide
Research and Drug Design. Amino Acids 2017, 49, 1441. (b) Werner, H.
M.; Horne, W. S. Folding and Function in α/β-Peptides: Targets and
Therapeutic Applications. Curr. Opin. Chem. Biol. 2015, 28, 75.
(c) Cabrele, C.; Martinek, T. A.; Reiser, O.; Berlicki, L. Peptides
Containing β-Amino Acid Patterns: Challenges and Successes in
Medicinal Chemistry. J. Med. Chem. 2014, 57, 9718. (d) Urman, S.;
Gaus, K.; Yang, Y.; Strijowski, U.; Sewald, N.; De Pol, S.; Reiser, O. The
Constrained Amino Acid β-Acc Confers Potency and Selectivity to
Integrin Ligands. Angew. Chem., Int. Ed. 2007, 46, 3976. (e) Gnad, F.;
Reiser, O. Synthesis and Applications of β-Aminocarboxylic Acids
Containing a Cyclopropane Ring. Chem. Rev. 2003, 103, 1603.
F
DOI: 10.1021/acs.orglett.9b02692
Org. Lett. XXXX, XXX, XXX−XXX