Synthesis of bicyclic cyclopropylamines from amino acid derivatives

Article abstract of DOI:10.3987/COM-05-S(T)52

The synthesis of novel [3.1.0] bicyclic cyclopropylamines from differently substituted amino acids using Ti(II)-mediated coupling and the extension of this methodology to provide [4.1.0] systems is described.

Full text of DOI:10.3987/COM-05-S(T)52

HETEROCYCLES, Vol. 67, No. 2, 2006
519
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 519 - 522. © The Japan Institute of Heterocyclic Chemistry
Received, 29th July, 2005, Accepted, 29th September, 2005, Published online, 30th September, 2005. COM-05-S(T)52
SYNTHESIS OF BICYCLIC CYCLOPROPYLAMINES FROM AMINO
ACID DERIVATIVES✝
Catherine A. Faler, Bin Cao, and Madeleine M. Joullié*
Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104-
6323, USA; Email: mjoullie@sas.upenn.edu
Abstract – The synthesis of novel [3.1.0] bicyclic cyclopropylamines from
differently substituted amino acids using Ti(II)-mediated coupling and the
extension of this methodology to provide [4.1.0] systems is described.
Cyclopropylamines and substituted cyclopropylamines are important structural elements in a variety of
biologically active compounds. We have previously reported the Ti(II)-mediated coupling of a terminal
olefin and the N,N'-dimethyl carboxamide moiety of aromatic amino acid derivatives to synthesize a
series of N, N'-dimethylcyclopropylamines, by applying the Kulinkovich reaction to modified amino
acids, and found that a tyrosine derivative was a weak dopamine receptor antagonist.1 Here, we present
an extension of our previous approach to the formation of bicyclic [4.1.0] cyclopropylamines, and to the
synthesis of additional [3.1.0] systems using differently substituted amino acids.
The [4.1.0] systems, obtained from a homoallylated amine, displayed greater diastereomeric selectivity
than the [3.1.0] systems with an approximate 9:1 ratio of diastereomers (Scheme 1).2
O
O
O
TFA, HCHO,
allyltributyl tin
PhCHO, Na(OAc) BH
SOCl
3
2
OH
OMe
OMe
NH
NH
2
NH
2
MeOH, quant.
1,2-dichloroethane
CHCl /MeOH
R
R
R
3
Bn
2a. R = -H
2b. R = -OH
1a. R = -H
1b. R = -OH
3a. R = -H, 98%
3b. R = -OTBDMS,
53% from 2b
TBDMSCl,
Et N, DBU
3
2c. R = -OTBDMS
O
O
Me N
Me N
2
2
ClTi(O-i-Pr) ,
3
NMe
2
OMe
Me N•HCl, Me Al
c-C H MgCl
2
3
5 9
+
N
N
N
N
R
Bn
R
Bn
R
Bn
R
Bn
THF
benzene
6a. R = -H, 60%
6b. R = -OTBDMS, 37%
5a. R = -H, 90%
5b. R = -OTBDMS, 35%
4a. R = -H, 80%
4b. R = -OTBDMS, 73%
major
diastereomer
TBAF, THF
6c. R = -OH, 89%
Scheme 1. Nitrogen-containing [4.1.0] bicycles from L-tyrosine and L-phenylalanine.
-------------------------------------
✝ Dedicated to Professor Barry M. Trost on the occasion of his 65th birthday.

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HETEROCYCLES, Vol. 67, No. 2, 2006
In an effort to modify the substituents on the exocyclic amino group, and thereby extend the application
of the bicycles, we explored alternate amidation procedures. We used a very efficient reaction developed
by Liskamp et al. to produce benzyl amides directly from unprotected amino acids.3 Though the yield
suffered on a larger scale, dichlorodimethylsilane was highly successful in generating benzyl amides from
all the amino acids we used, including proline, which was expected to be difficult for steric reasons. The
benzyl amide (8) was then converted to an appropriately substituted compound for cyclization (Scheme
2). It should be noted that when 10 was exposed to hydrogenation conditions, only the more labile
benzylmethylamine was deprotected. We assumed that the resulting free amine poisoned the palladium
catalyst preventing further reaction.
O
O
O
O
Et N, PhCHO, MeOH;
3
KBH , MeOH
Me SiCl
2
benzylamine
2
Bn
4
Bn
N
O
OH
N
H
H
HN
N
pyridine
Si
NH
NH
HN
2
2
55% from phenylalanine
Bn
7
8
O
Bn
NH
1) allyl bromide, Et N,
3
THF, 75%
N
Bn
H , 10% Pd/C
2
ClTi(O-i-Pr)
3,
N
N
MeOH/EtOH, 98%
2) NaH, MeI, THF, 75%
c-C H MgCl
Bn
5
THF, 85%
9
Bn
N
Bn
11
10
9
Scheme 2. Synthesis of dibenzyl-substituted aminocyclopropane.
In addition to benzyl-substitution, it was desirable to synthesize aromatic substituted aminocyclopropanes
to alter the electronic properties of the exocyclic amine. Because of their weak nucleophilicity, the
coupling of aniline or anisidine to an N, N'-allylbenzylphenylalanine acid failed to yield an amide. An
aromatic bislithium amide was, therefore, chosen for aminolysis.4 As shown in Scheme 3, the addition of
a bislithium amide produced from anisidine gave the desired product which was then methylated and
cyclized. Compound (13) can also be protected with a benzyl group in excellent yield. Although other
substrates gave diastereomeric mixtures, in this case only a single diastereomer could be isolated.5 We
attribute the selectivity to greater steric hindrance in the presumed intermediate A.
OMe
OMe
OMe
O
O
O
ClTi(O-i-Pr)
Li N
2
OMe
MeI, NaH
3
N
H
N
N
N
N
Bn
Bn
13
THF, 80%
c-C H MgCl
5 11
Bn
14
THF, 78%
THF, 68%
12
OMe
OMe
OMe
OMe
N
N
N
N
O i-Pr
O i-Pr
O
Ti
O
H
Ti
O i-Pr
O i-Pr
O i-Pr
O i-Pr
O
Bn N
Ti
N
N
Bn
H
N
Bn
A
B
15
Bn
Scheme 3. Installation of a p-methoxyphenyl group.

HETEROCYCLES, Vol. 67, No. 2, 2006
521
We also attempted to synthesize similar bicycles containing a heteroatom. This modification was
accomplished with serine and cystine, the dimer of cysteine. We envisioned protecting serine and cysteine
as an oxazole and thiazolidine, respectively. This approach would negate the need for the benzyl
protecting group, thus shortening the synthesis. Unfortunately, neither of these heterocycles survived the
conditions for amidation. Serine, therefore, was protected as a TBDMS ether and carried through the
described sequence of steps to cyclization and deprotected to give azabicyclo[3.1.0]hexyl methanol (20)
as well as azabicyclo[4.1.0]heptyl methanol (22).6 In the former example, it was found that the bislithium
amidolysis gave higher yields than the conventional Weinreb approach.7
R
1) SOCl , MeOH, quant.
2
O
2) TBDMSCl, imidazole,
MeCN, quant.
O
O
allyl bromide,
K CO , TBAI
Li N
2
2
3
TBDMSO
OMe
TBDMSO
OMe
HO
OH
N
3) TEA, PhCHO, MeOH;
THF
MeCN, 81%
NH
NH
2
Bn
Bn
KBH , MeOH, 60%
4
16
R
17
R
O
R
O
1) ClTi(O-i-Pr)
c-C H MgCl, THF
3,
N
NaH, MeI
THF
TBDMSO
N
5
9
TBDMSO
N
H
HO
N
Bn
N
2) TBAF, THF
N
Bn
Bn
19a. R = -H, quant.
19b. R = -OMe, 61%
18a. R = -H, 56%
18b. R = -OMe, 40%
20a. R = -H, 30% 2 steps
20b. R = -OMe, 28% 2 steps
O
1) TFA, HCHO,
allyltributyl tin,
CHCl /MeOH, 75%
3
1)ClTi(O-i-Pr)
3,
c-C H MgCl,
THF, 61%
Me N
2
Me N
2
O
5
9
TBDMSO
NMe
2
HO
Bn
HO
Bn
TBDMSO
OMe
+
N
N
N
NH
Bn
21
2) TBAF, THF, quant.
2) Me N•HCl, Me Al,
2
benzene, 60%
Bn
3
16
22a
22b
Scheme 4. L-Serine-derived [3.1.0] and [4.1.0] bicycles.
The protection of the sulfur in cysteine proved difficult, thus, the bicycle was synthesized as a dimer from
cystine. A milder reducing agent, sodium cyanoborohydride, was needed in the benzylation step to
prevent cleavage of the sulfur-sulfur bond. Compound (23) was then suitably modified to give disulfide
(25).
1) PhCHO, Et N,
3
MgSO , THF
O
OMe
1) allyl Br, K2CO3,
Bu NI, MeCN, 82%
O
OMe
O
O
4
4
S
S
MeO
Bn
S
NH
Bn
MeO
S
NH
2
2) Me N•HCl, Me3Al
2
benzene, 81%
2) NaBH3CN, MeCN,
50%, 2 steps
NH
NH
O
2
23
Bn
O
NMe
2
N
NMe
2
ClTi(O i-Pr)
3
S
S
S
Me N
2
S
N
c-C H MgCl
5
THF, 40%
9
Me N
2
N
N
Bn
Bn
Bn
24
25
Scheme 5. L-Cystine-derived bicycle.

522
HETEROCYCLES, Vol. 67, No. 2, 2006
In summary, a number of novel bicyclic cyclopropylamines have been synthesized from amino acid
derivatives. Innovative amidation routes were successfully applied to achieve various amino substitutions
of the cyclopropylamines. We are investigating the biological activity as well as the ring opening
reactions of these interesting molecules.
ACKNOWLEDGEMENTS
We thank the NSF (CHEM-1030958) and the University of Pennsylvania for financial support. We are
also grateful to Dr. George Furst, Dr. Patrick Carroll, and Dr. Rakesh Kohli for technical assistance.
REFERENCES AND NOTES
1. (a) B. Cao, D. Xiao, and M. Joullié, Org. Lett., 1999, 1, 1799; (b) B. Cao, Ph.D. Thesis, University
of Pennsylvania, Philadelphia, PA, 2002.
2.
3.
Stereochemical assignment made by 2D 1H-1H NOESY spectral experiment.
S. H. Leeuwen, P. J. L. M. Quaedflieg, Q. B. Broxterman, and R. M. J. Liskamp, Tetrahedron Lett.,
2002, 43, 9203.
4.
5.
6.
T. Ooi, E. Tayama, M. Yamada, and K. Maruoka, Synlett, 1999, 6, 729.
Stereochemistry was determined by X-Ray crystallography.
M. Gensini, S. Kozhushkov, D. Yufit, J. Howard, M. Es-Sayed, and A. de Meijere, Eur. J. Org.
Chem., 2002, 15, 2499. de Meijere et al. were unable to make bicycles from serine and glycine
under our previously reported conditions and used instead methyltitanium triisopropoxide and
cyclohexylmagnesium bromide. We were successful with both chloro- and methyltitanium
triisopropoxide on multiple serine and glycine derivatives.
7. J. Levin, E. Turos, and S. Weinreb, Synth. Commun., 1982, 12, 989. Conversion of 17 to the
corresponding dimethyl amide occurred in 6% isolated yield.