Chemistry of allylsulfones: A new preparation of N-diphenylmethylene-2- vinyl-substituted cyclopropylamines

Article abstract of DOI:10.1055/s-2004-835663

A new methodology for the synthesis of N-diphenylmethylene-2-vinyl- substituted cyclopropylamines, starting from the allylsulfone 11, is described. The starting material 11 can be obtained in both enantiomeric forms. The stereoselectivity of the cyclopropane formation has been studied by molecular modeling.

Full text of DOI:10.1055/s-2004-835663

158
LETTER
Chemistry of Allylsulfones: A New Preparation of N-Diphenylmethylene-2-
Vinyl-Substituted Cyclopropylamines
Chemistry of
A
llyl
a
sulfones vid Díez,*a P. García,a P. Fernández,a Isidro S. Marcos,a N. M. Garrido,a P. Basabe,a Howard B. Broughton,b
Julio G. Uronesa
a
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5,
37008 Salamanca, Spain
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain
b
Fax +34(923)294574; E-mail: ddm@usal.es
Received 30 July 2004
OR
SO2Ph
OR
OR
Abstract: A new methodology for the synthesis of N-diphenyl-
methylene-2-vinyl-substituted cyclopropylamines, starting from
the allylsulfone 11, is described. The starting material 11 can be
obtained in both enantiomeric forms. The stereoselectivity of the
cyclopropane formation has been studied by molecular modeling
SO2Ph
I
I
2
1
Base
OR
Key words: cyclopropylamines, vinylsulfones, allylsulfones, cy-
clopropanes, Garner’s aldehyde
+
SO2Ph
SO2Ph
4
3
COOH
OH
The importance of the cyclopropylamine function in
drugs such as ciprofloxacin (Ciprobay®) and moxifloxa-
cin (Avalox®) and natural products as belactosin A,1 to-
gether with increasing awareness of the importance of
chirality in biological activity, make the asymmetric
synthesis of cyclopropylamines an important area for
research. In spite of this interest there are not many pro-
cedures for the synthesis of 2-substituted cyclopropyl-
amines, the most widely used being the Curtius
rearrangement,2 cyclopropanation of N-protected
enamines3 or a Kulinkovich type reaction with dialkyl-
amides.4 Less exemplified is cyclopropanation with imine
carbene complexes.5 Our completely different approach
to 2-vinyl-substituted amino-cyclopropanes is based upon
the synthesis of cyclopropanols from allylsulfones which
we have described previously (Scheme 1).6 The vinylsul-
fone unit reactivity was exploited further and led to the
synthesis of 5, an amino acid analogue of glutamic acid.10
H2N
5
Scheme 1
The allylsulfones 12 and 13 were obtained by the proce-
dure developed by our group10 for the synthesis of allyl
sulfones such as 1 or 2, starting in this case from the pre-
viously described compounds 6 and 7 (Scheme 2).11
R
Boc
Boc
N
N
R
O
O
R
6
R
7
a
87%
OH
a
85%
OH
OMs
SO2Ph
8
OMs
SO2Ph
9
b
b
83%
80%
The methodology for cyclopropane formation consists of
the treatment of allyl sulfones such as 1 or 2 with base, to
give trans:cis cyclopropanols 3 and 4 diastereoselec-
tively, in a ratio of 70:30 or 30:70 (depending upon the
protecting groups) from 2, and 95:5 independent of the
protecting group from 1 (Scheme 1).
10
11
c, 85%
c, 77%
SO2Ph
NH2
NH2
SO2Ph
HO
HO
12
13
Due to the synthetic utility of 1,2-amino alcohols8 and es-
pecially the use of Garner’s aldehyde in the synthesis of
natural and unnatural compounds with biological activity9
we decided to apply our methodology to the synthesis of
enantiomerically pure cyclopropylamines.
Scheme 2 Reaction conditions: a) MsCl, Et3N, CH2Cl2, 0 °C;
b) NaSO2Ph, DMF, r.t.; c) MeOH, 2 N HCl, 40 °C, 12 h.
In order to apply our cyclopropane formation methodolo-
gy it was necessary to protect the nitrogen with at least one
electron-withdrawing group, due to the donor–acceptor
character of the anticipated vinylcyclopropane products.12
Deprotection of the acetonides of 10 and 11 under the
usual conditions gave, in good yield, amino alcohols 12
and 13. The nitrogen was protected with the standard
protecting groups (Tosyl, Boc, Moc, alone or together
SYNLETT 2005, No. 1, pp 0158–0160
0
5.
0
1.
2
0
0
5
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-835663; Art ID: D21704ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chemistry of Allylsulfones
159
with a benzyl group) and the hydroxyl group converted to either 0° (for cyclization of 17) or 180° (for cyclization of
various leaving groups, but in no case did treatment with 16), and performing a stochastic conformational17 search
base lead to the desired cyclopropanes. With all these fail- including energy minimization of each conformer found
ures to produce the cyclopropane ring, we chose to protect with the MMFF94s forcefield.
the nitrogen as its diphenylmethylene derivative,13 as used
With a torsional constraint of 400 kJ/mol, the models for
the transition states for the cyclization of 16 to the cis- and
trans-cyclopropane showed only a 1.4 kJ/mol difference
in MMFF94s strain energy, while the transition state mod-
previously in the synthesis of the amino-cyclopropane
moiety of belactosin by Armstrong et al.1f and in the syn-
thesis of 1-amino-cyclopropane carboxylic acid in the
preparation of azepines by Salaün et al.14
el for the cyclization of 17 to 19 was 5.4 kJ/mol lower in
Compound 12 was protected as the diphenylmethylene energy than that for cyclization of 17 to 18. Very similar
derivative 14, which was transformed without isolation trends were observed with other values of the torsional
(by reaction with iodide, PPh3 and imidazole in dichlo- constraint, suggesting that this effect is genuine, and it is
romethane) into the iodide 16,15 which in turn and without easy to see in Figure 1 that the transition state model for
purification, was treated with HMDSNa to give the ami- cyclization of the cis-olefin 17 to the cis-cyclopropane 18
no-cyclopropanes 18 and 19 stereoselectively in a 1:4 ra- (upper right) is notably more crowded than the other three,
tio. In order to increase the selectivity as we have done in with a particularly severe interaction between the vinylic
the synthesis of cyclopropanols, compound 13 was syn- proton and the imine nitrogen. It thus seems reasonable to
thesized analogously as for 12, and transformed similarly propose that the reaction proceeds via a product-like tran-
into the iodide 17. When this compound was submitted to sition state and that this poor steric interaction reduces
the same conditions, only compound 19 was detected,16 in practically to zero the amount of 17 that is converted to
good yield, and its structure and stereochemistry were de- 18, explaining the observed difference in stereoselectivity
termined by extensive NMR studies (Scheme 3).
between cyclization of the cis precursor 17 and the trans-
analogue 16.
SO2Ph
NH2
NH2
SO2Ph
HO
HO
12
13
a
a
Ph
Ph
Ph
Ph
N
SO2Ph
R
N
SO2Ph
R
R
R
OH
14
OH
15
17
b
b
I
I
16
c
c
Ph
Ph
Figure 1
Ph
N
Ph
N
In conclusion, we have obtained chiral amino-cyclo-
propanes substituted with a vinyl sulfone, with high dia-
stereoselectivity, which we attribute to a product-like
transition state in which unfavorable interactions between
C1 and the protected secondary amine are minimized. To
the best of our knowledge this is the first time that amino-
cyclopropanes have been synthesized in this way. The im-
portance of 1,2-amino alcohols, the accessibility of both
enantiomers of Garner’s aldehyde and the versatility of
the vinylsulfone group attached to the cyclopropane prod-
ucts make this procedure an excellent entry to the synthe-
sis of this class of compound as building blocks for the
synthesis of conformationally restricted amino acids.
SO2Ph
SO2Ph
19
18
Scheme 3 Reaction conditions: a) i. 2 M HCl; ii. Ph2C=NH,
CH2Cl2; b) I2, PPh3, imidazole, CH2Cl2; c) HMDSNa, THF, –78 °C,
38%, for the three steps.
We undertook a molecular modeling study to try to under-
stand why the stereoselectivity was so much better for the
(Z)-allylsulfone (such as 17) than it had been for (E)-allyl-
sulfones (such as 16). Applying the same reasoning as we
had previously found to work for the cyclopropanol for-
mation,7 we considered models for a late transition state
for each of four possible reactions: formation of the cis- or
trans-cyclopropane from either the Z or E precursor. The
late transition state models were obtained by constraining
the C1-C2-C3-C4 torsion in the products 18 and 19 to
Acknowledgment
The authors thank the CICYT (BQU 2001-1034), and Universidad
de Salamanca for a doctoral fellowship to P. G.
Synlett 2005, No. 1, 158–160 © Thieme Stuttgart · New York

160
D. Díez et al.
LETTER
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Synlett 2005, No. 1, 158–160 © Thieme Stuttgart · New York