Highly enantioselective synthesis of cyclopropylamine derivatives via Ru(II)-pheox-catalyzed direct asymmetric cyclopropanation of vinylcarbamates

Article abstract of DOI:10.1021/ol303404c

The Ru(II)-Pheox-catalyzed asymmetric cyclopropanation of vinylcarbamates with diazoesters resulted in the corresponding cyclopropylamine derivatives in high yield and excellent diastereoselectivity (up to 96:4) and enantioselectivity (up to 99% ee).

Full text of DOI:10.1021/ol303404c

ORGANIC
LETTERS
2013
Vol. 15, No. 4
772–775
Highly Enantioselective Synthesis
of Cyclopropylamine Derivatives via
Ru(II)-Pheox-Catalyzed Direct Asymmetric
Cyclopropanation of Vinylcarbamates
Soda Chanthamath, Dao Thi Nguyen, Kazutaka Shibatomi, and Seiji Iwasa*
Department of Environmental and Life Sciences, Toyohashi University of Technology,
1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan
iwasa@ens.tut.ac.jp
Received December 13, 2012
ABSTRACT
The Ru(II)-Pheox-catalyzed asymmetric cyclopropanation of vinylcarbamates with diazoesters resulted in the corresponding cyclopropylamine
derivatives in high yield and excellent diastereoselectivity (up to 96:4) and enantioselectivity (up to 99% ee).
Optically active cyclopropylamines have beenrecognized
as useful building blocks for biologically active com-
pounds such as belactosin A,1 coronamic acid,2 tcprPNA,3
tranylcypromine,4 and trovafloxacin.5 Several studiesin the
literature have reported the synthesis of cyclopropylamine
derivatives via alkaline hydrolysis of optically active cyclo-
propanecarboxylic acid esters or cyclopropanecarboxa-
mides and subsequent Curtius rearrangement.1c,d,3,6 For
example, Miyata and co-workers recently applied this
procedure to prepare cyclopropylamine 2, which is a
useful intermediate in the synthesis of (1R,2S)-NCL-1
(see Scheme 1a).7 In 2003, Nguyen and co-workers8 devel-
oped a synthesis of cyclopropylamine derivative 4 via
(4) (a) Riley, T. N.; Brier, C. G. J. Med. Chem. 1972, 15, 1187–1188.
(b) Arvidsson, L.-E.; Johansson, A. M.; Hacksell, U.; Nilsson, J. L. G.;
Svensson, K.; Hjorth, S.; Magnusson, T.; Carlsson, A.; Lindberg, P.;
€
Andersson, B.; Sanchez, D.; Wirkstrom, H.; Sundell, S. J. Med. Chem.
1988, 31, 92–99. (c) Csuk, R.; Schabel, M. J.; Von Scholz, Y. Tetrahedron:
Asymmetry 1996, 7, 3505–3512. (d) Moreau, B.; Charette, A. B. J. Am.
Chem. Soc. 2005, 127, 18014–18015. (e) Binda, C.; Valente, S.; Romaneghi,
M.; Pilotto, S.; Cirilli, R.; Karytinos, A.; Ciossani, G.; Botrugno, O. A.;
Forneris, F.; Tardugno, M.; Edmondson, D. E.; Minucci, S.; Mattevi, A.;
Mai, A. J. Am. Chem. Soc. 2010, 132, 6827–6833.
(1) (a) Asai, A.; Hasegawa, A.; Ochiai, K.; Yamashita, Y.; Mizukami,
T. J. Antibiot. 2000, 53, 81–83. (b) Brandl, M.; Kozhushkov, S. I.; Loscha,
K.; Kokoreva, O. V.; Yufit, D. S.; Howard, J. A. K.; de Meijere, A. Synlett
2000, 12, 1741–1744. (c) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5,
2331–2334. (d) Armstrong, A.; Scutt, J. N. Chem. Commun. 2004, 510–
511. (e) Larionov, O. V.; de Meijere, A. Org. Lett. 2004, 6, 2153–2156.
(f) Asai, A.; Tsujita, T.; Sharma, S. V.; Yamashita, Y.; Akinaga, S.;
Funakoshi, M.; Kobayashi, H.; Mizukami, T. Biochem. Pharmacol. 2004,
67, 227–234. (g) Yoshida, K.; Yamaguchi, K.; Arisawa, M.; Matsuda, A.;
Shuto, S. Pept. Sci 2006, 184–185. (h) Vanier, S. F.; Larouche, G.; Wurz,
R. P.; Charette, A. B. Org. Lett. 2010, 12, 672–675.
(5) (a) Gootz, T. D.; Zaniewski, R.; Haskell, S.; Schmieder, B.;
Tankovic, J.; Girard, D.; Courvalin, P.; Polzer, R. J. Antimicrob. Agents
€
Chemother. 1996, 40, 2691–2697. (b) Salaun, J. Top. Curr. Chem. 2000,
207, 1–67. (c) Pannu, H. K.; Gottlieb, L.; Fishman, E. K. Emerg. Radiol.
2001, 8, 108–110. (d) Peterson, M. L.; Hovde, L. B.; Wrigdt, D. H.; Brown,
G. H.; Hoang, A. D.; Rotschafer, J. C. Antimicrob. Agents Chemother.
2002, 46, 203–210. (e) Waring, J. F.; Liguori, M. J.; Luyendyk, J. P.;
Maddox, J. F.; Ganey, P. E.; Stachlewitz, R. F.; North, C.; Blomme,
E. A. G.; Roth, R. A. J. Pharmacol. Exp. Ther. 2006, 316, 1080–1087.
(6) (a) Feng, G.-Q.; Wang, D.-X.; Zheng, Q.-Y.; Wang, M.-X.
Tetrahedron: Asymmetry 2006, 17, 2775–2780. (b) Yoshida, K.; Yamaguchi,
K.; Mizuno, A.; Unno, Y.; Asai, A.; Sone, T.; Yokosawa, H.; Matsuda, A.;
Arisawa, M.; Shuto, S. Org. Biomol. Chem. 2009, 7, 1868–1877. (c)
Benelkebir, H.; Hodgkinson, C.; Duriez, P. J.; Hayden, A. L.; Bulleid,
R. A.; Crabb, S. J.; Packham, G.; Ganesan, A. Bioorg. Med. Chem. 2011, 19,
3709–3716.
(2) (a) Hiyama, T.; Kai, M. Tetrahedron Lett. 1982, 23, 2103–2104.
(b) Pirrung, M. C.; Brown, W. L. J. Am. Chem. Soc. 1990, 112, 6388–
6389. (c) Calmes, M.; Daunis, J.; Escale, F. Tetrahedron: Asymmetry
ꢀ
ꢀ
~
1996, 7, 395–396. (d) Jimenez, J. M.; Rife, J.; Ortuno, R. M. Tetrahe-
dron: Asymmetry 1996, 7, 537–558. (e) Antoine, F.; Aballache, K.
Tetrahedron: Asymmetry 1998, 9, 305–320.
(3) Pokorski, J. K.; Myers, M. C.; Appella, D. H. Tetrahedron Lett.
2005, 46, 915–917.
r
10.1021/ol303404c
Published on Web 01/29/2013
2013 American Chemical Society

Sharpless oxidative degradation of the phenyl group of
optically active cyclopropanecarboxylic acid ester 3 and
subsequent Curtius rearrangement (Scheme 1b).
In initial investigations, we investigated the cyclopropa-
nation of benzyl vinylcarbamate 5a with diazoester 6a,
catalyzed by commonly used catalysts such as Rh2(OAc)4
and Cu(CH3CN)4PF6 (Table 1). The desired product was
obtained in good yield with low trans-diastereoselectivity
(65:35) when using either Rh2(OAc)4 or Cu(CH3CN)4PF6
(Table 1, entries 2 and 3). Encouraged by the results ob-
tained with Rh2(OAc)4, we chose the chiral complex Rh2-
(S-TBPTTL)4, which was recently reported by Hashimoto
and co-workers to be useful in cyclopropanations,10
and used it as the catalyst in the asymmetric cyclopropana-
tion of benzyl vinylcarbamate. Indeed, Rh2(S-TBPTTL)4
gave the desired product in good yield (71%), yet both
the diastereoselectivity and enantioselectivity were low
(46:54 dr, 0% trans ee and 7% cis ee) (Table 1, entry 4).
Although the diastereoselectivity and enantioselectivity
were slightly improved by decreasing the temperature to
À30 °C, the yield decreased accordingly (Table 1, entry 5).
To our delight, RuCl2(pybox-ip)(C2H4) catalyst, which
was synthesized by Nishiyama’s group and is broadly used
in cyclopropanation reactions,11 afforded protected cyclo-
propylamine 7a in high yield (90%) with good trans-
diastereoselectivity (77:23) and enantioselectivity (79%
ee) in the presence of 2 mol % of the catalyst (Table 1,
entry 6). With the good results obtained with RuCl2-
(pybox-ip)(C2H4) in hand, the Ru(II)-Pheox complex,12
a catalystsystemrecently developedby our researchgroup,
was also tested in the cyclopropanation reaction (Table 1,
entry 7). Surprisingly, the Ru(II)-Pheox catalyst readily
catalyzed the cyclopropanation of benzyl vinylcarbamate
5a with diazoester 6a, to give the corresponding protected
cyclopropylamine 7a in excellent yield (99%) and high
enantioselectivity (90% ee). To the best of our knowledge,
this is the first report of the successful enantioselective
carbene transfer cyclopropanation of diazoester into
vinylcarbamate.
The same authors also reported the asymmetric cyclo-
propanation of vinylcarbamates with diazoesters using
chiral ruthenium(salen) and Doyle’s dirhodium catalysts
to afford the corresponding protected cyclopropylamines
in good yields.8 Unfortunately, poor diastereoselectivities
and no enantioselectivity were obtained. In 2009, a cyclo-
propanation of N-vinyl phthalimide with R-aryl diazoke-
tone was reported by Davies and co-workers.9 Although
the corresponding protected cyclopropylamine was ob-
tained in high yield with excellent diastereoselectivity and
enantioselectivity, the removal of phthalimide is not al-
ways straightforward and a potentially hazardous hydra-
zine is commonly used. In summary, the currently
available asymmetric cyclopropanation methods present
certain drawbacks, and a straightforward route to cyclo-
propylamines needs to be developed. This prompted us to
search for a highly efficient catalytic system that promotes
the cyclopropanation of vinylcarbamate derivatives with
diazoesters, to give the corresponding cyclopropylamines
in high yields with excellent diastereoselectivity and ex-
cellent enantioselectivity (Scheme 1c).
Scheme 1. Currently Used Strategies for the Preparation of
Optically Active Cyclopropylamines
To improve the diastereoselectivity and enantioselectiv-
ity of this catalytic system further, we conducted the
cyclopropanation in various solvents (Table 2, entries
1À4). For all tested solvents, cyclopropanation proceeded
smoothly in high yield but with differing diastereoselec-
tivities and enantioselectivities. Toluene led to a significant
increase in terms of trans-selectivity (trans/cis = 86:14),
although enantioselectivity decreased (83% trans ee).
Dichloromethane was found to be the solvent of choice.
The effect of temperature on the reaction was also inves-
tigated (Table 2, entries 5À8), showing that enantioselec-
tivity could be improved to 92% ee at a temperature
(10) Goto, T.; Takeda, K.; Anada, M.; Ando, K.; Hashimoto, S.
Tetrahedron Lett. 2011, 52, 4200–4203.
(11) (a) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh,
K. J. Am. Chem. Soc. 1994, 116, 2223–2224. (b) Simpson, J. H.; Godfrey,
J.; Fox, R.; Kotnis, A.; Kacsur, D.; Hamm, J.; Totelben, M.; Rosso, V.;
Mueller, R.; Delaney, E.; Deshpande, R. P. Tetrahedron: Asymmetry
2003, 14, 3569–3574. (c) Charette, A. B.; Bouchard, J.-E. Can. J. Chem.
2005, 83, 533–542. (d) Marcin, L. R.; Denhart, D. J.; Mattson, R. J. Org.
Lett. 2005, 83, 2651–2654.
(12) (a) Abu-Elfotoh, A.-M.; Phomkeona, K.; Shibatomi, K.; Iwasa,
S. Angew. Chem., Int. Ed. 2010, 49, 8439–8443. (b) Chanthamath, S.;
Phomkeona, K.; Shibatomi, K.; Iwasa, S. Chem. Commun. 2012, 48,
7750–7752.
(7) Ogasawara, D.; Suzuki, T.; Mino, K.; Ueda, R.; Khan, M. N. A.;
Matsubara, T.; Koseki, K.; Hasegawa, M.; Sasaki, R.; Nakagawa, H.;
Mizukami, T.; Miyata, N. Bioorg. Med. Chem. 2011, 19, 3702–3708.
(8) Miller, J. A.; Hennessy, E. J.; Marshall, W. J.; Scialdone, M. A.;
Nguyen, S. T. J. Org. Chem. 2003, 68, 7884–7886.
(9) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787–790.
Org. Lett., Vol. 15, No. 4, 2013
773

Underthese optimized conditions, the cyclopropanation
of a series of vinylcarbamates and diazoesters was exam-
ined (Table 3). Reaction of benzyl vinylcarbamate with
the bulky tert-butyl diazoester gave the corresponding
protected cyclopropylamine product in high yield with
excellent enantioselectivity (97% trans ee). However,
diastereoselectivity was low (Table 3, entry 2). In contrast
to the successful use of succinimidyl diazoacetate in the
cyclopropanation of styrene derivatives,12b low diastereo-
selectivity and enantioselectivity were obtained in the
cyclopropanation of benzyl vinylcarbamate (Table 3, entry 3).
tert-Butyl vinylcarbamate was also readily cyclopropa-
nated with diazoesters to afford the desired products in
high yields (Table 3, entries 4 and 5), where it should be
noted that, in particular, the reaction involving the bulky
tert-butyl diazoester displayed higher diastereoselectivity
(trans/cis = 72:28) and enantioselectivity (93% ee) than
the reaction of ethyl diazoester.
In addition, the cyclopropanation of diprotected vinyl-
amines such as benzyl carbobenzyloxy(vinyl)carbamate
and tert-butyl-tert-butoxycarbonyl(vinyl)carbamate was
investigated (Table 3, entries 6À9). Interestingly, both
diastereoselectivity and enantioselectivity were signifi-
cantly improved (up to 91:9 dr and up to 97% ee) with a
negligible effect on yield. Inspired by these results, we also
carried out the experiments using larger R2 (Bz) and
smaller R2 (Me) substituents (Table 3, entries 10À12).
Surprisingly, high diastereoselectivity and enantioselectiv-
ity were obtained using a smaller R2 substituent (R2 = Me,
93:7 dr and 99% ee), indicating that disubstituted vinylamines
Table 1. Screening of Various Metal Catalystsa
eed (%)
time yieldb trans/
entry
catalyst
Pd(OAc)2
(h)
(%)
cisc
trans cis
1
72
8
0
76
70
71
24
90
99
2
Rh2(OAc)4
65:35
65:35
46:54
35:65
77:23
70:30
3
Cu(CH3CN)4PF6
Rh2(S-TBPTTL)4
Rh2(S-TBPTTL)4
RuCl2(pybox-ip)(C2H4)
Ru(II)-Pheox
6
4
5
0
4
7
5e
6f
7
72
8
10
79 80
5
90 94
a Reaction conditions: benzyl vinylcarbamate (1 mmol) and ethyl
diazoester (0.2 mmol) in the presence of catalyst (1 mol %) under Ar.
b Isolated yield. c Determined by NMR. d Determined by chiral HPLC
analysis. e The reaction was carried out at À30 °C. f 2 mol % of catalyst
was used. Cbz = benzyloxycarbonyl.
of À30 °C, with diastereoselectivity decreasing to 57:43
(Table 2, entry 8). As such, room temperature was found to
be the optimal temperature for this catalytic system.
Table 3. Ru(II)-Pheox-Catalyzed AsymmetricCyclopropanation
of Various Vinylcarbamates with Diazoestersa
Table 2. Optimization of Reaction Conditionsa
5
eed (%)
6
entry R1
R2
R
7 yieldb (%)
trans/cisc trans cis
1
2
Cbz
Cbz
Cbz
Boc
Boc
H
Et
99
91
90
89
82
91
77
88
72
90
77
97
7a
7b
7c
7d
7e
7f
70:30
52:48
43:57
60:40
72:28
90:10
86:14
91:9
90
97
49
89
93
96
97
96
95
97
97
99
94
96
31
99
91
88
99
84
eed (%)
H
H
H
H
tBu
Su
Et
3
entry solvent temp (°C) yieldb (%) trans/cisc trans cis
4
1
2
3
4
5
6
7
8
THF
rt
97
95
99
99
97
96
98
99
75:25
86:14
80:20
70:30
62:38
61:39
60:40
57:43
85
83
87
90
90
91
91
92
92
78
95
94
95
97
97
97
5
tBu
toluene
acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
6
Cbz Cbz Et
Cbz Cbz tBu
Boc Boc Et
Boc Boc tBu
7
7g
7h
7i
rt
rt
8
9
90:10
92:8
0
À10
À20
À30
10
11
12
Cbz Bz
Cbz Bz
Et
tBu
7j
7k
7l
94:6
Cbz Me Et
93:7
a Reaction conditions: benzyl vinylcarbamate (1 mmol) and ethyl
diazoester(0.2mmol) in the presenceofRu(II)-Pheox(1mol%) underAr.
b Isolated yield. c Determined by NMR. d Determined by chiral HPLC
analysis.
a Reaction conditions: vinylcarbamate 5 (1 mmol) and diazoester 6
(0.2 mmol) in the presence of catalyst (1 mol %) under Ar. b Isolated
yield. c Determined by NMR. d Determined by chiral HPLC analysis.
Su = succinimidyl, Boc = tert-butoxycarbonyl, Bz = benzoyl.
774
Org. Lett., Vol. 15, No. 4, 2013

Scheme 2. Plausible Transition State Leading to a cis-Selective
Approach of the Reactants
Scheme 3. Preparation of (1R,2R)-2-((tert-Butoxycarbonyl)-
amino)cyclopropylmethanol 8, a Key Intermediate in the
Synthesis of Belactosin A
gave much higher diastereoselectivity and enantioselectivity
(Table 3, entries 6À12) as compared with monosubstituted
vinylamines (Table 3, entries 1À5). This may result from a
hydrogen bond that forms between the N-hydrogen of the
vinylcarbamate and the carbonyl oxygen of the carbenoid
intermediate, leading to a cis-selective approach of the
reactants, as shown in Scheme 2.
the (1R,2R) configuration was confirmed by comparison
of the optical rotation.13
Finally, to demonstrate the utility of our direct enan-
tioselective cyclopropylamine synthesis, we prepared a
key intermediate in the reported synthesis of belactosin
A from cyclopropylamine7h(Table3, entry 8), asshown in
Scheme 3. The optically active 2-((tert-butoxycarbonyl)-
amino)cyclopropylmethanol intermediate 8 was readily
synthesized by the reduction of cyclopropylamine 7h with
DIBAL in 60% yield withhigh enantioselectivity(96% ee).
Even though the configuration of belactosin A at both
chiral carbon centers in the cyclopropane motif is opposite
to the configuration of our cyclopropane product 7h, the
desired configuration should, in principle, straightfor-
wardly be obtained using the R-enantiomer of Ru(II)-
Pheox as a catalyst. Apart from this, we employed this
intermediate 8 to determine the absolute configuration
of 7h by reacting it with benzyl chloride in the presence
of NaH, to give the corresponding (R,R)-tert-butyl-(2-
((benzyloxy)methyl)cyclopropyl) carbamate 9, of which
In conclusion, we succeeded in the development of the
first highly enantioselective cyclopropanation of vinylcar-
bamate derivatives with diazoesters, using the Ru(II)-Pheox
complex as a catalyst. The reaction proceeds smoothly
under mild conditions, giving the corresponding protected
cyclopropylamine products in high yield, with excellent
diastereoselectivity (up to 96:4) and enantioselectivity (up
to 99% ee). Furthermore, the utility of the present asym-
metric cyclopropanation is highlighted in the stereoselective
and straighforward synthesis of enantioenriched 2-((tert-
butoxycarbonyl)amino)cyclopropylmethanol 8, which is a
key intermediate in the synthesis of the antitumor antibiotic
belactosin A. We hope that this efficient procedure will
contribute to the progress of synthetic organic chemistry.
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (C) (No. 20550137)
from Japan Society for the Promotion of Science.
(13) Absolute configuration of 9 was determined to be (1R,2R) by
comparing the reported specific optical rotation: [R]2D5 À40.0 (c 0.40,
CHCl3), lit.1c [R]D22 À30.0 (c 0.40, CHCl3) for 1R,2R-isomer.
Supporting Information Available. Experimental pro-
cedures, characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
775