Formal nucleophilic substitution of bromocyclopropanes with amides en route to conformationally constrained β-amino acid derivatives

Article abstract of DOI:10.1021/ol101228k

A chemo- and diastereoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides with secondary amides is described. This method allows for convergent and highly selective synthesis of trans-β-aminocyclopropane carboxylic acid derivatives.

Full text of DOI:10.1021/ol101228k

ORGANIC
LETTERS
2010
Vol. 12, No. 18
3968-3971
Formal Nucleophilic Substitution of
Bromocyclopropanes with Amides en
route to Conformationally Constrained
ꢀ-Amino Acid Derivatives
Anthony R. Prosser, Joseph E. Banning, Marina Rubina, and Michael Rubin*
Department of Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045-75832
mrubin@ku.edu
Received May 27, 2010
ABSTRACT
A chemo- and diastereoselective protocol for the formal nucleophilic substitution of 2-bromocyclopropylcarboxamides with secondary amides
is described. This method allows for convergent and highly selective synthesis of trans-ꢀ-aminocyclopropane carboxylic acid derivatives.
Designing small molecules that bind to therapeutically
important biological targets with high affinity and selectivity
is one of the major goals of contemporary bioorganic and
medicinal chemistry. In this respect, cyclopropane-based
peptide mimics are attractive and versatile targets due to their
innate rigidity, unusual geometry, compact size, and meta-
bolic stability.1 Natural and synthetic analogs of R-aminocy-
clopropanecarboxylic acid (R-ACC) are ubiquitous; they have
been extensively explored and find a widespread application
in medicinal, chemical and agricultural research.2 ꢀ-ACC
derivatives3 are emerging as important tools for investigation
of conformational preferences in peptides,1,4 key elements
of muliple natural products,5 organocatalysts6 and prospective
drug candidates.1,7
We have recently reported an efficient and selective
approach to functionalized cyclopropyl ethers via a formal
inter- and intramolecular substitution in bromocyclopropanes
with oxygen-based nucleophiles.8,9 This method allows for
installation of nucleophilic entities in the three-membered
ring via the strain-driven addition to the cyclopropene double
bond,10 while bypassing the isolation of the cyclopropene
species, which permits employment of even the most unstable
strained olefins (eq 1).
(5) For reviews, see: (a) Chemistry and Biochemistry of the Amino Acids;
Barrett, G. C., Ed.; Chapman and Hall: New York, 1985. (b) Hoekstra,
W. J. Chemistry and Biology of ꢀ-Amino Acids. Curr. Med. Chem. 1999,
6, 905. (c) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 25, 117.
(6) D’Elia, V.; Zwicknagl, H.; Reiser, O. J. Org. Chem. 2008, 73, 3262.
(7) (a) Ott, G. R.; Chen, X.; Duan, J.; Voss, M. E. WO 2002074738.
(b) Duan, J.; Ott, G.; Chen, L.; Lu, Z.; Maduskuie, T. P., Jr.; Voss, M. E.;
Xue, C.-B. WO 2001070673. (c) Behling, J. R.; Boys, M. L.; Cain-Janicki,
K. J.; Colson, P.-J.; Doubleday, W. W.; Duran, J. E.; Farid, P. N.; Knable,
C. M.; Muellner, F. W.; Nugent, S. T.; Topgi, R. S. WO 9802410. See also
refs 3a,b.
(1) See, for example: (a) Benfield, A. P.; Teresk, M. G.; Plake, H. R.;
DeLorbe, J. E.; Millspaugh, L. E.; Martin, S. F. Angew. Chem., Int. Ed.
2006, 45, 6830. (b) DeLorbe, J. E.; Clements, J. H.; Teresk, M. G.; Benfield,
A. P.; Plake, H. R.; Millspaugh, L. E.; Martin, S. F. J. Am. Chem. Soc.
2009, 131, 16758.
(2) For leading reviews, see: (a) Salau¨n, J.; Baird, M. S. Curr. Med.
Chem. 1995, 2, 511. (b) Salau¨n, J. Top. Curr. Chem. 2000, 207, 1.
(3) See, for recent examples: (a) Urman, S.; Gaus, K.; Yang, Y.;
Strijowski, U.; Sewald, N.; De Pol, S.; Reiser, O. Angew. Chem., Int. Ed.
2007, 46, 3976. (b) Koglin, N.; Zorn, C.; Beumer, R.; Cabrele, C.; Bubert,
C.; Sewald, N.; Reiser, O.; Beck-Sickinger, A. G. Angew. Chem., Int. Ed.
2003, 42, 202. See also: (c) Beumer, R.; Bubert, C.; Carbele, C.; Vielhauer,
O.; Pietzsch, M.; Reiser, O. J. Org. Chem. 2000, 65, 8960, and references
cited therein.
(8) Alnasleh, B. K.; Sherrill, W. M.; Rubina, M.; Banning, J.; Rubin,
M. J. Am. Chem. Soc. 2009, 131, 6906
.
(9) Banning, J. E.; Prosser, A. R.; Rubin, M. Org. Lett. 2010, 12, 1488
.
(10) For our recent reports on preparative synthesis of isolable cyclo-
propenes, see: (a) Sherrill, W. M.; Kim, R.; Rubin, M. Synthesis 2009, 1477.
(b) Kim, R.; Sherrill, W. M.; Rubin, M. Tetrahedron 2010, 66, 4947.
(4) De Pol, S.; Zorn, C.; Klein, C. D.; Zerbe, O.; Reiser, O. Angew.
Chem., Int. Ed. 2004, 43, 511
.
10.1021/ol101228k  2010 American Chemical Society
Published on Web 08/20/2010

tions used previously for addition of O-nucleophiles.9 As it
was shown previously, dehydrohalogenation of 5a produces
a highly unstable conjugate cyclopropene i, which decom-
poses rapidly unless intercepted with a nucleophile.19 To our
delight, trapping of i with NMA proceeded efficiently
affording high yield of trans-diamide 6aa (eq 3).
As a part of an ongoing program aimed at expanding the
range of nucleophilic entities pertinent to this transformation,
we herein report a method for incorporation of a nitrogen
moiety in the three-membered ring, which allows for direct
access to ꢀ-ACC derivatives. While diastereoselective trans-
fer of transition metal carbenoids generated from diazocom-
pounds to enamines remains a challenging task,11 ꢀ-ACC
cores are usually accessed via Michael-initiated ring closure
reactions12 or [2 + 1]-cyclopropanation of acrylates with
R-nitrodiazoacetates,13 followed by appropriate functional
group transformations. At the same time, approaches that
allow direct and efficient installation of amine function in a
pre-existing three-membered ring remain scarce.14,15 Several
previously reported attempts on the addition of such nucleo-
philes to cyclopropenes resulted in cleavage of the small
ring.16
We started by probing a series of different amines as
N-pronucleophiles; however, our attempts to induce addition
of diethylamine, diphenylamine, N-ethylaniline, N-tosylbu-
tylamine, and phthalimide met with no success.17 In contrast,
nucleophilic attack by N-methylacetamide (NMA, 4a) on the
generated in situ but isolable 3-methyl-3-phenylcyclopropene
(2a) afforded trans-cyclopropylamine derivative 3aa in good
yield and high diastereoselectivity, which was controlled by
steric factors (eq 2).8,18 Encouraged by these results, we
tested 1,2-elimination of bromocyclopropane 5a under condi-
Further screening of various N-alkyl alkylcarboxamides
against bromocyclopropylcarboxamide 5a revealed an ad-
verse steric effect. Thus, introduction of a primary alkyl
substituent in both N- and C-termini of an amide 4b resulted
in a notable yield drop (Table 1, entry 2). Pronucleophiles
(11) For discussion, see: (a) Miller, J. A.; Hennessy, E. J.; Marshall,
W. J.; Scialdone, M. A.; Nguyen, S. T. J. Org. Chem. 2003, 68, 7884. For
development of diastereoselective protocols, see: (b) Sladojevich, F.;
Trabocchi, A.; Guarna, A. Org. Biomol. Chem. 2008, 6, 332. (c) Denton,
J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787. (d) Bonge, H. T.; Pintea,
B.; Hansen, T. Org. Biomol. Chem. 2008, 6, 3670.
Table 1. Steric Effect in the Formal Substitution of
Bromocyclopropane 5a with Secondary Amides
(12) See for example: (a) Inokuma, T.; Sakamoto, S.; Takemoto, Y.
Synlett 2009, 1627. (b) Fan, R.; Ye, Y.; Li, W.; Wang, L. AdV. Synth. Catal.
2008, 350, 2488. (c) Zhang, J.; Hu, Z.; Dong, L.; Xuan, Y.; Lou, C.-L.;
Yan, M. Tetrahedron: Asymmetry 2009, 20, 355. (d) Lv, J.; Zhang, J.; Lin,
Z.; Wang, Y. Chem.sEur. J. 2009, 15, 972.
(13) See for example Zhu, S.; Perman, J. A.; Zhang, X. P. Angew. Chem.,
Int. Ed. 2008, 47, 8460.
(14) For ring-retentive nucleophilic addition of amines to cyclopropenes,
see: (a) Gritsenko, E. I.; Khaliullin, R. R.; Plemenkov, V. V.; Faizullin,
E. M. Zh. Obshch. Khim. 1988, 58, 2733. (b) Franck-Neumann, M.; Miesch,
M.; Kempf, H. Tetrahedron 1988, 44, 2933. For nucleophilic displacement
of halogen in cyclopropyl halides with N-heterocycles, amides, and
sulfamides, see: (c) Kang, S. Y.; Lee, S.-H.; Seo, H. J.; Jung, M. E.; Ahn,
K.; Kim, J.; Lee, J. Bioorg. Med. Chem. Lett. 2008, 18, 2385. (d) Basle,
E.; Jean, M.; Gouault, N.; Renault, J.; Uriac, P. Tetrahedron Lett. 2007,
48, 8138. (e) Liang, G.-B.; Qian, X.; Feng, D.; Biftu, T.; Eiermann, G.;
He, H.; Leiting, B.; Lyons, K.; Petrov, A.; Sinha-Roy, R.; Zhang, B.; Wu,
J.; Zhang, X.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett.
no.
R1
R2
NuH
producta
yield, %b
drc
1
2
3
4
5
6
7
8
Me
Me
n-Bu
i-Pr
n-Bu
t-Bu
n-Bu
Me
4a
4b
4c
4d
4e
4f
6aa
6ab
6ac
6ad
6ae
6af
88
51
11:1
25:1
25:1
17:1
-
-
>25:1
>25:1
n-Pr
n-Pr
i-Pr
n-Bu
t-Bu
Ph
28d
31d
NR
NR
75
2007, 17, 1903
.
4g
4h
6ag
6ah
(15) For ring retentive installation of phosphorous-based nucleophilic
moiety into pre-existing three-membered cycle, see: Alnasleh, B. K.; Sherrill,
Ph
n-Bu
72
a Reactions performed in 0.5 mmol. b Isolated yields of diastereomeric
mixtures unless specified otherwise. c dr (trans:cis) determined by GC or
1H NMR analysis of crude reaction mixtures. d NMR yields determined by
analysis of a crude reaction mixture. Bromocyclopropane 5a was consumed
completely.
W. M.; Rubin, M. Org. Lett. 2008, 10, 3231
.
(16) (a) Yang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew.
Chem., Int. Ed. 2008, 47, 7350. (b) Ma, S. Pur. Appl. Chem. 2008, 80,
695. (c) Chen, J.; Maz, S. J. Org. Chem. 2009, 74, 5595. (d) Ma, S.; Zhang,
J.; Lu, L.; Jin, X.; Cai, Y.; Hou, H. Chem. Commun. 2005, 909. (e) Ma, S.;
Zhang, J.; Cai, Y.; Lu, L. J. Am. Chem. Soc. 2003, 125, 13954. (f)
Nakamura, I.; Bajracharya, G. B.; Yamamoto, Y. J. Org. Chem. 2003, 68,
2297.
(17) It is believed that a fine balance between acidity and nucleofilicity
of the pronucleophile is essential for the successful transformation. See ref
9 for discussion.
bearing a secondary alkyl substituent at either terminus (2c,d)
provided poor yields (entries 3,4), whereas t-Bu-substituted
Org. Lett., Vol. 12, No. 18, 2010
3969

pronucleophiles 4e,f gave no reaction (entries 5,6). We
rationalized that the effective nucleophilicity of the sterically
hindered amide species can be enhanced by varying their
electronic properties. To test this idea, we substituted an alkyl
group at the C-terminus of the pronucleophile with a phenyl
ring. Gratifyingly, the reaction between bromocyclopropane
5a and benzamide 4g afforded good yield of diamide 6ag.
Likewise, N-butyl amide 4h produced 6ah with comparably
high yield and excellent diastereoselectivity (Table 1, entries
7, 8). Next, we tested 5a with a series of differently
substituted N-butyl benzamides 4i-o to further explore the
effect of electronic factors on the reactivity (Table 2).
mationaly constrained trans-cyclopropyl amino acid deriva-
tives, with the possibility for a three-dimensional diversifi-
cation (Scheme 1). Thus, readily available acyl chloride 7
can be converted into an array of amides 5 by varying
primary or secondary amines 8. At the same time, a variety
of pronucleophiles 4 can be obtained from primary amines
10 and different carboxylic acids 9. Amides 4 derived from
linear aliphatic and electron-defficient benzoic acids 9 usually
provide highest yields in this transformation (Tables 1 and
2, Scheme 1). Notably, installation of the CF3-groups in the
benzamide derivatives 4n,o significantly facilitated isolation
and purification of the corresponding products 6an and 6ao
due to their improved solubility in organic solvents compared
to other N-butyl benzamide derivatives (6ah, 6aj-am, Table
2). The presence of fluorine-containing groups also allowed
for accurate assessment of the selectivity by 19F NMR, as
severe line broadening in proton spectra resulting from slow
conformational rotation made 1H NMR data inapplicable for
the analysis. Accordingly, CF3-substituted benzamides were
used for more detailed investigations of the scope and
limitation of this reaction. It was found that p-CF3-substituted
benzamides possessing primary N-alkyl groups rendered
efficient nucleophilic addition to give n-octyl- (6ap), benzyl-
(6aq), and 2-phenethyl benzamides (6ar) in high yields and
perfect diastereoselectivites (Scheme 1). At the same time,
nucleophilic addition of a more sterically hindered N-
cyclohexyl 4-(trifluoromethyl)benzamide (2s) proceeded
sluggishly, resulting in marginal yield of the corresponding
diamide 6as (Scheme 1). In contrast, amides 4o, 4t-w
derived from 3,5-bis(trifluoromethyl)benzoic acid reacted
with bromocyclopropane 5a much more readily. Superior
product yields were obtained not only for the less sterically
hindered derivative 6aw, but also for more challenging bulky
products 6at, 6av, 6au, bearing secondary N-alkyl substit-
uents. However, very bulky N-tert-butylamide 4y (R1 ) 3,5-
(CF3)2C6H3, R2 ) t-Bu) did not provide any product in the
reaction with 5a.
Table 2. Electronic Effect in the Formal Substitution of
Bromocyclopropane 5a with Secondary Amides
no.
R1
NuH
producta
yield, %b
drc
1
2
3
4
5
6
7
8
Ph
4h
4i
4j
4k
4l
4m
4n
4o
6ah
6ai
6aj
6ak
6al
6am
6an
6ao
72
NR
80d
81
80
80
85
87
>25:1
-
p-MeOC6H4
o-ClC6H4
p-ClC6H4
p-CNC6H4
p-NO2C6H4
p-CF3C6H4
3,5-(CF3)2C6H3
>25:1
>25:1
>25:1
>25:1
>25:1e
>25:1e
a Typical reaction conditions: bromocyclopopane 5a (0.5 mmol), amide
4 (1.0 mmol), powdered KOH (1.75 mmol), 18-crown-6 (0.05 mmol), THF
(5 mL) - stirred at 85 °C for 12 h. b Isolated yields of trans-diamide. c dr
(trans:cis) determined by GC or 1H NMR analysis of crude reaction
mixtures. The notation >25:1 is used when no minor diastereomer was
detected. d NMR yields determined by analysis of a crude reaction mixture.
e dr (trans:cis) determined by 19F NMR analysis of crude reaction mixtures.
The scope of the cyclopropylcarboxamides 5 was also
investigated. Bromocyclopropylcarboxamide derivatives of
morpholine (5b), piperidine (5c), and cyclohexylamine (4d),
afforded diamides 6bo, 6bw, 6cw, 6cx, and 6dt in good to
high yields (Scheme 1). Weinreb amide 5e was also tested
in this reaction; however, the corresponding product 6ex was
obtained in 31% yield only, presumably, due to a decreased
stability of the intermediate cyclopropene species (Scheme
1).
Interestingly, introduction of an electron-donating p-MeO
group completely shut down the reaction (Table 2, entry 2).
On the other hand, incorporation of an electron-withdrawing
groups in the ortho- (entry 3) or para- (entries 4-7) position
of the aromatic ring in the benzamide pronucleophile allowed
for improved reactivity. The best results were achieved with
p-CF3-(entry 7) and 3,5-bis(CF3)-substituted aryl groups
(entry 8). It should be mentioned that no diamide product
was observed in the reaction with primary amide (p-
CF3C6H4CONH2) despite complete consumption of the
bromocyclopropane 5a.20
Similarly to the previously reported formal nucleophilic
substitution reaction with alkoxides and phenoxides,9 the
diastereoselectivity in the described transformation was
governed by a base-assisted epimerization. However, ad-
ditional treatment of the reaction mixture with t-BuOK was
unnecessary in this case,9 as the thermodynamically more
favored trans-diastereomer was produced exclusively under
the standard reaction conditions. It should be mentioned that
accurate assignment of the product configuration by 1H NMR
We envisioned that the described methodology can be
efficiently applied toward convergent synthesis of confor-
(18) We have also previously demonstrated a single example of a formal
nucleophilic substitution of 1a with pyrrole. Studies on incorporation of
other heterocyclic moieties in the three-membered ring via this approach
are currently underway and will be reported in due course.
(19) Although never observed directly, intermediate i was proved in the
reaction of 5a with phenoxides. See ref 9.
3
based on the analysis of JHH coupling constants of the
cyclopropyl proton signals was impeded by severe broaden-
ing of the corresponding resonance lines. Careful optimiza-
(20) We failed to detect any cyclopropane-containing products in this
reaction.
3970
Org. Lett., Vol. 12, No. 18, 2010

Scheme 1. Convergent Approach to Conformationally Constrained trans-Cyclopropyl Amino Acid Derivatives
tion of the sample temperature provided acceptable resolution
for measuring the coupling constants in 6ab in DMSO-d6.
As an additional evidence, trans-configuration of diamide
6bw was unambigously assigned by X-ray crystallography
(Figure 1). These data were used to assign the structures of
all other products by analogy.
In conclusion, we have developed an efficient and highly
diastereoselective formal substitution of 2-bromocyclopro-
pane carboxamides with secondary amides leading to con-
formationally constrained trans-cyclopropyl ꢀ-amino acid
derivatives. Strong influence of the steric and electronic
factors on the efficiency of the formal substitution reaction
has been demonstrated. The trans-selectivity in this reaction
is effectively controlled by a base-assisted epimerization.
Development of a nonracemic version of this reaction and
work on further transformations of ꢀ-diamides is currently
underway in our laboratories.
Acknowledgment. We thank the University of Kansas,
the National Science Foundation (EEC-0310689) and the
McNair Scholars Program (ARP) for financial support. We
thank Dr. Victor W. Day (KU X-ray Crystallography Lab)
for solving crystal structure of compound 6bw.
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. ORTEP drawing of diamide 6bw showing 50% prob-
ability amplitude displacements ellipsoids.
OL101228K
Org. Lett., Vol. 12, No. 18, 2010
3971