A recyclable chiral auxiliary for the asymmetric syntheses of α-aminonitriles and α-aminophosphinic derivatives

Article abstract of DOI:10.1016/j.tetasy.2008.03.013

Optically active α-aminonitriles and α-aminophosphinic derivatives have been prepared in high yield and high ee using an easy route by extending our previously developed method involving the following sequence: (i) stereoselective Strecker condensation of

Full text of DOI:10.1016/j.tetasy.2008.03.013

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 876–883
A recyclable chiral auxiliary for the asymmetric syntheses
of a-aminonitriles and a-aminophosphinic derivatives
Jean-Christophe Rossi,a,* Marc Marull,b Nicolas Larcher,a Jacques Taillades,a
Robert Pascal,a Arie van der Leec and Phillipe Gerbierd
aInstitut des Biomole´cules Max Mousseron (IBMM), UMR 5247, CNRS, Universite´ Montpellier 1,
Universite´ Montpellier 2, CC1706, Place E. Bataillon, 34095 Montpellier Cedex 5, France
bDepartment Pharmazie, Zentrum fu¨r Pharmaforschung, Ludwig-Maximilians-Universita¨t Mu¨nchen,
Butenandtstraße 7, D-81377 Mu¨nchen, Germany
cInstitut Europe´en des Membranes, UMR 5635, Universite´ Montpellier 2, CC047, Place E. Bataillon 34095 Montpellier Cedex, France
dInstitut Charles Gerhardt, UMR 5253, Universite Montpellier 2, CC007, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France
Received 19 February 2008; accepted 13 March 2008
Available online 15 April 2008
Abstract—Optically active a-aminonitriles and a-aminophosphinic derivatives have been prepared in high yield and high ee using an easy
route by extending our previously developed method involving the following sequence: (i) stereoselective Strecker condensation of a
chiral ketone with HCN and NH3 followed by (ii) condensation with RCHO, an HCN donor or a phosphinate and (iii) regioselective
decomposition of the intermediate to release the target compound. The third step enables the easy regeneration of the initial chiral
ketonic auxiliary.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
on the control of chirality of both C and P centres starting
from a chiral phoshinate. The latter was obtained by the
resolution of two diastereoisomers. The originality of this
concept is based on the use of a chiral phosphorus auxil-
iary. However, this process implies the separation of
diastereoisomers at an intermediary stage and many subse-
quent steps to afford the a-aminophosphinate product.
The Strecker reaction1 represents one of the simplest and
most economical methods for the preparation of a-amino
acids on a laboratory scale as well as on a larger scale.
There has also been considerable interest in extending the
scope of this reaction to asymmetric processes for the syn-
thesis of optically active amino acids and in particular of
non-proteinogenic a-amino acids.2 a-Aminophosphonic
and a-aminophosphinic acids, in which the carboxyl group
of the a-amino acids is replaced by a phosphorus-derived
functionality, have attracted significant attention because
of their structural analogy allowing some of their deriva-
tives to behave as transition state analogues in hydrolytic
reactions. The corresponding enzyme inhibitor properties
have been exploited in the design of herbicides, neuroactive
agents, HIV protease antagonists, etc.3 Although numer-
ous examples of the stereoselective syntheses of a-amino-
acids and a-aminophosphonic4 derivatives can be found
in the literature, there are only few examples dealing with
the stereoselective synthesis of a-aminophosphinic deriva-
tives. Recently, Haruki et al.5 proposed a synthesis based
A popular asymmetric concept in stereoselective synthesis
is the use of a preformed N-substituted chiral imine and
the subsequent addition of a nucleophile HX (X = CN,
PO3H, PO2H, PO2Et, etc.) in the absence or presence of
a catalyst.6 It is also possible to add a chiral nucleophile
such as 2-hydrogeno-2oxo-1,4,2-oxazaphosphinane onto a
prochiral imine as recently described by Pirat et al.7 The le-
vel of asymmetric induction at the a-carbon depends both
on the nature of the substituents (steric hindrance, hydro-
philic/hydrophobic interactions) and/or the possible inter-
action of the nucleophile with the substrate that could be
otherwise enhanced in the organocatalytic versions of these
reactions.2
According to Harada’s principle,8 and following our previ-
ous investigations on the Strecker reaction, we have
already outlined a promising synthesis involving a tertiary
*
Corresponding author. E-mail: j-christ.rossi@univ-montp2.fr
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.013

J.-C. Rossi et al. / Tetrahedron: Asymmetry 19 (2008) 876–883
877
a-aminonitrile 2 derived from the Strecker reaction
between a chiral ketone 1 with HCN and NH3 . The sub-
O
9
O
H2SO4
O
HCN
CN
CN
OH
sequent condensation of this tertiary a-aminonitrile with
an aldehyde affords the N-substituted chiral imine 3. Imi-
nes 3 with a cyano group closely attached to the nitrogen
atom display an increased stability as shown, for example,
by a good resistance to the hydrolysis that make the use of
stabilizing aromatic substituents useless in these cases. The
subsequent addition of HCN leads to iminodinitrile 4. The
selective decomposition of 4 (X = CN) gave the enantio-
merically enriched aminonitrile 5 with the recovery of the
starting chiral ketone 1. In this synthesis, the chirality of
product 5 is the result of two consecutive 1–3 transfer of
chirality in the steps of formation of aminonitrile 2 and
of iminodinitrile 4 (Scheme 1).
*
1a
1b
Scheme 2.
quent step consisted of the selective reaction of the major
diastereoisomer of a-aminonitriles 2a and 2b from the dia-
stereoisomeric mixture with RCHO. As described previ-
ously, chiral imines 3a and 3b are obtained with a
preferential anti configuration.14 The corresponding imines
3a and 3b, are obtained in good yields (89% in the case of
R = Bn).
2.1. a-Aminonitrile synthesis
*
O
CN
*
CN
O
R'
NH3
*
*
R
R'
HCN
R'
R
N
*
H2N *
R"
Hydrogen cyanide can be generated directly in the reaction
mixture by neutralization of cyanide salts, or obtained
from a donor such as acetone cyanohydrin. The addition
of hydrogen cyanide to imines 3a and 3b leads to a-imino-
dinitriles, 4a and 4b, respectively. The (R)-configuration
observed on the formed tetrahedral centre corresponds to
an attack on the less bulky Si side of the imine. In the case
of the precursor of the valine, R = Pri, prepared either by
the addition of HCN or by using (CH3)2C(CN)OH as a
HCN donor, the observed diastereoselectivities (R/S) were
quite similar (about 70:30, Table 1). This result is in agree-
ment with a dissociation of the acetone cyanohydrin lead-
ing to the formation of trace amounts of HCN in
methanol. However, it should be noted that these yields
and diastereoselectivities are considerably higher than
those obtained by the one pot reaction between aminoni-
trile 2 and aldehyde 10 in the form of cyanohydrin
RCH(CN)OH (R = Pri, yield 10%, R/S = 55:45).
R"
R"
1
3
2
HX
1
R
CN
R
*
R'
*
X
N
H
X
NH2
*
(retro-
R"
Strecker)
4 (X=CN)
4' (X=OP(OR)Ph)
5 (X=CN)
5'(X=OP(OR)Ph)
Scheme 1.
We have already demonstrated that the immobilization of
the ketonic auxiliary offers opportunities in the synthesis
of chiral amino acids on solid supports.10 Taking into
account the availability of various hydrocyanating agents,
such as cyanohydrins Me2C(CN)OH, diethyl aluminium
cyanide (C2H5)2AlCN,11 or trimethylsilyl cyanide
(TMSCN),12,13 we decided to investigate the effects of
hydrocyanating agents on the stereoselectivity of the asym-
metric synthesis of a-aminonitriles. Herein, we report the
generalization of this synthetic methodology to the asym-
metric synthesis of a-aminophosphinate 50 via a N-substi-
tuted a-aminophosphinate 40 (X = OP(OR)Ph). This
methodology allows in principle chiral auxiliary 2 to be
regenerated from the recycled ketone 1.
In Table 1 are shown the main results obtained using di-
ethylaluminium cyanide or trimethylsilyl cyanide as hydro-
cyanating reagents. With diethylaluminium cyanide, the
diastereoselectivity (R/S = 70:30) remains unchanged when
compared to the direct hydrocyanation in spite of the fact
that a complexation of the alkoxide EtAl(OPri)CN (gener-
ated by previous treatment of Et2AlCN with 2-PrOH) on
the Si face of the chiral imine is highly probable. With tri-
methylsilyl cyanide, the experimental conditions proposed
by Kunz et al.13 (2-PrOH/20 °C/ZnCl2 or THF/ꢀ40 °C/
SnCl4) led to a strong increase in the reaction rate for the
hydrocyanation of imine 3a although the diastereoselectiv-
ity is often reduced when compared with the direct use of
HCN.
2. Results and discussion
The chiral ketonic precursors 1a and 1b were prepared
from enantiopure (ꢀ)-carvone.10 (1R,2R,3R,5R)-(ꢀ)-3-
Cyanodihydrocarvone 1a was obtained by the straight-
forward stereoselective hydrocyanation of the cyclic
double bond. Subsequent hydroxylation of 1a afforded
(ꢀ)-(1R,2R,5R)-2-methyl-5-(1-hydroxy-1-methylethenyl)-3-
oxocyclohexane carbonitrile 1b (Scheme 2).
In a less dissociating solvent, such as chloroform and in the
presence of zinc chloride, the same diastereoselectivity (R/
S = 75:25) was observed using chiral auxiliary 1a, whereas
1b induces a significant improvement (R/S = 85:15). These
results suggest that the presence of the 1-hydroxy-1-methyl-
ethyl group in the chiral auxiliary 1b allows the complexa-
tion of ZnCl2 on the Si face of the imine and then facilitates
the cyanide attack generated by the interaction of
Me3SiCN with the Lewis acid.
Starting from compounds 1a or 1b, a-aminonitriles 2a and
2b (Scheme 3) were prepared according to a procedure pre-
viously described by us10 in convenient yields. The 1–3
asymmetric induction from the initial stereogenic centre
of carvone gives high diastereoselectivity (up to 90%) and
good yield starting from (R)-cyanocarvone. The subse-

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J.-C. Rossi et al. / Tetrahedron: Asymmetry 19 (2008) 876–883
CN
R1
NC
R
CN
N
H
CN
CN
HCN
R1
R1
RCHO
4a,b
CN
CN
CN
N
H2N
NC
R
CN
R1
HCN/NH3
H2O
O
3a,b
H
P
OEt
Ph
O
NH2
1a,b
R1
O
P
CN
R1
CN
EtO
Ph
a: R1 = -C(CH2)CH3
b: R1 = -C(CH3)2OH
N
H
R
2a,b
4'a,b
Scheme 3.
Table 1. Yields and diastereoselectivities of the synthesis of a-aminodinitriles 4a and 4b (R = Pri) by hydrocyanation of the imines 3a and 3b (R = Pri)
HCN donor
Conditions
Chiral auxiliary
Yield (%)
Diastereoisomers 4 (R = Pri) ratio (R/S)
Me2C(OH)CN
MeOH/reflux
1a
1b
1a
1b
1a
1a
1a
1a
1a
1a
1b
68
75
54
50
85
0
75
54
63
70:30
75:25
75:25
75:25
70:30
HCN
MeOH/20 °C
Et2AlCN/2-PrOH (1.5:1)
Me3SiCN
THF/ꢀ78 °C
(1) HCCl3/20 °C
(2) HCCl3/20 °C/ZnCl2
(3) 2-PrOH/20 °C/ZnCl2
(4) THF/ꢀ40 °C/SnCl4
(5) THF/20 °C/SnCl4
(6) HCCl3/20 °C/ZnCl2
70:30
60:40
70:30
60:40
85:15
73
For the hydrocyanation by Me3SiCN, the experimental conditions are given below: (imine weight g, solvent volume mL, Me3SiCN volume mL, Lewis acid
weight g, reaction time h.) 1 (1, 20, 0.5, 0, 2); 2 (0.5, 20, 0.5, 0.53, 2); 3 (1, 40, 1, 0.5, 6); 4 (1, 20, 1, 0.6, 6); 5 (1, 20, 1, 0.6, 4); 6 (0.3, 20, 0.3, 0.15, 4).
As we have shown previously,10 the formation of the chiral
a-aminonitrile 5 can be achieved by the treatment of a-
aminodinitrile 4 with silver nitrate in nitric acid, without
racemization. This regioselective decomposition in high
yield and high ee of the tertiary aminonitrile present in 4
leads to an acceptable recovery of the chiral ketone 1.
obtained starting from 3b, when the reaction was per-
formed in CHCl3. The diastereoisomeric ratios were almost
independent of changes in the experimental conditions
used.
Suitable crystals of one of the major diastereoisomers of 40b
(d 40.4 ppm, 31P NMR) were obtained by repeated crystal-
lization from ethyl acetate. Figure 1 shows the molecular
structure as determined by X-ray diffraction analysis
performed on a single crystal. All NMR data could be
assigned and are in good agreement with the chair-like con-
formation characteristic of the crystal. Coupling constants
are given in Section 4.
2.2. a-Aminophosphinate synthesis
Chiral imines 3a and 3b obtained by the addition of benz-
aldehyde (R = Ph) onto a-aminonitriles 2a and 2b, were
chosen as substrates for the hydrophosphinylation reaction
using ethyl phenyl phosphinate as a model compound.
Chiral imines 3a and 3b were heated with 1.2 equiv of race-
mic ethylphenylphosphinate at 60–70 °C either in chloro-
form or without solvent according to the classical
procedure15 and the reaction was run until the imine was
entirely consumed. The diastereoisomeric ratios for N-pro-
tected a-aminophosphinates 40a and 40b were determined
by 31P NMR in the reaction mixture. From a stereochem-
ical point of view, the addition step induces the formation
of two new stereogenic centres (the reactive carbon atom
and the phosphorus atom) leading, in principle, to four dia-
stereoisomers, which could be detected by 31P NMR. The
results are reported in Table 2. Elimination of the solvent
followed by crystallization in EtOAc afforded the two ma-
jor diasteroisomers of 40b. The best yields (Table 2) were
The major diastereoisomer 40b has an (S)-configuration at
Ca indicating that the diastereoselectivity of this first step
is clearly under kinetic control. The (S)-configuration at
the a-carbon is the result of the preferential formation of
Table 2. Diastereoisomeric ratio and the yield of N-protected amin-
ophosphinate 40a and 40b with or without solvent
N-Protected
aminophosphinate
Solvent
Diastereoisomeric ratio Yield (%)
(%) 31P NMR
40b
40b
40a
40a
CHCl3
No solvent
CHCl3
8:46:3:43
9:51:8:32
7:51:5:37
9:47:6:38
96
55
80
71
No solvent

J.-C. Rossi et al. / Tetrahedron: Asymmetry 19 (2008) 876–883
879
obtained in high yield (90%) and with a P(R)/P(S) ratio
equal to 78:22. Treatment of 50b with HBr in glacial acetic
acid according the Belov16 procedure afforded pure (S)-a-
aminobenzyl phenylphosphinic acid. The specific rotation
{[a]20 (k, nm) = +29 (589)} was opposite to that of the
known compound16 thus confirming our hypothesis and
indicating that the diastereoisomeric excess exceeds 9:1 in
the hydrophosphinylation step. The starting ketone was
also recovered in good yield (89%) and without substantial
racemization.
3. Conclusion
In conclusion, we have developed a concise five step enan-
tioselective synthesis of a-aminophosphinic acids by
extending our original asymmetric synthetic route to a-
aminonitriles or aminoacids using a chiral recyclable auxil-
iary. This synthetic pathway corresponds to 1–5 chirality
transfer. The specific structure of the cyclanic starting
chiral ketone allows the easy regeneration of the chiral aux-
iliary. The key step of the process involves the addition of
HX (X = CN or PO(OEt)(Ph)) onto the Si face of a pro-
chiral imine. In the first case (HCN), we showed that the
stereoselectivity could be enhanced by the use of ZnCl2.
Excellent stereoselectivity is observed for the hydrophosph-
inylation reaction. C(S)-a-aminophosphinates are obtained
in good yield through an easy work-up. Application of the
synthesis of chiral a,a0-diaminophosphinate is currently on
going.
Figure 1. The X-ray structure of a molecule of 40b showing displacement
ellipsoids drawn at the 30% probability level. Hydrogen atom spheres are
drawn with an arbitrary radius.
4. Experimental
a transition state corresponding to the addition of ethyl-
phenylphosphinate onto the Si face of the imine 3b in an
anti-configuration, as shown in Scheme 4.
1H NMR spectra were recorded with a Bruker AC200
(200 MHz) or a Bruker AM400 (400 MHz) spectrometer.
Chemical shifts are expressed in parts per million downfield
from TMS, which was used as an internal standard. 31P
NMR spectra were recorded with a Bruker AC200
(81.01 MHz). Chemical shifts are expressed in parts per
million downfield from H3PO4 85%. 13C NMR spectra
Attack on Re side
Attack on Si side
OH
O
OH
CN
-
P
H
CN
CN
EtO
Ph
C
N
H
CN
Ph
C
N
were recorded with
a Bruker AM400 spectrometer
O
Ph
-
(100.61 MHz) using broadband decoupling. Chemical
shifts are expressed in parts per million downfield from
TMS, using the middle resonance of CDCl3 (d 77 ppm)
as an internal standard. Infrared spectra were recorded
with a Thermo Nicolet Avatar 320 FT-IR spectrophoto-
meter. Mass spectra were obtained with a Jeol SX 102
spectrometer and on Micromass Q-Tof by electrospray
ionization. Elemental analyses were performed with a
Perkin–Elmer 2400 CHN recorder.
P
EtO
Ph
OH
OH
CN
CN
H
R
R
R
H
CN
S
CN
EtO
Ph
(R or S)
C
N
H
C
N
Ph
O
P
H
P
O
Ph
OEt
Ph
(R or S)
4'b minor
4'b major
The collection of the diffraction data was performed at
173 K on an Oxford-Diffraction GEMINI-S single crystal
diffractometer using graphite-monochromatized Cu-Ka
Scheme 4. Possible explanation for the preferential (S)-configuration at
the a-carbon by attack on the anti-conformer of imines 3a and 3b.
˚
In order to confirm our hypothesis and to validate the
recovery of the ketonic auxiliary, the deprotection of 40b
(Scheme 5) was achieved by using aqueous AgNO3/
HNO3 as previously described.9
radiation (k = 1.5418 A) in order to maximize the differ-
ence between Friedel intensities as to facilitate the determi-
nation of the absolute configuration. A total of 9367
frames were collected using x and / scans mode. The
three-dimensional structure was solved in the monoclinic
space group C2 (no. 5) by using ab initio methods with
the recently discovered charge-flipping algorithm.17 The
The resulting a-aminophosphinate 50b [two majors diaste-
reoisomers were identified as C(S)P(R) and C(S)P(S)] was

880
J.-C. Rossi et al. / Tetrahedron: Asymmetry 19 (2008) 876–883
O
P
CN
O
P
CN
AgNO3/HNO3
R1
R1
CN
EtO
Ph
CN
EtO
Ph
N
H
N
CN
O
R1
1b
4'b
H2O
H
H
HBr/AcOH
NH2
P
O
Ph
OEt
NH2
P
O
Ph
OH
5'b
Scheme 5.
absence of the inversion centre was established by an anal-
ysis of the resulting electron density map yielding
Rsym = 0.62, where Rsym is the normalized averaged
weighted square phase error between symmetry equivalent
structure factor phases. The final Flack parameter,
0.015(18), shows that the right absolute configuration was
chosen. The hydrogen atoms were found from difference
Fourier maps, and their positions were optimized using
an initial refinement with soft restraints on the bonds and
angles to regularize their geometry. The H2O molecule
was found to be disordered with respect to its protons over
two positions with equal occupation probabilities. The
structural refinements were performed with the CRYSTALS
package18 on Fobs using reflections with I > 2r(I). CCDC
677069 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
cmꢀ1) m 3603 (OH), 3391 (NH2), 2304 (CN), 1389–1372
(gem dimethyl); H NMR (400 MHz, CDCl3) d 1.17 (6H,
1
d, CH3, JH–H = 8.52 Hz), 1.31 (3H, d, CH3, JH-2ax
=
6.82 Hz,), 1.30 (1H, t, H-6ax, J6ax–6eq = 12.88 Hz,), 1.41
(1H, td, H-4ax, J4ax–4eq = 13.42 Hz, J4ax–5ax = 4.85 Hz,),
1.63 (1H, m, H-2ax), 1.80 (1H, br s, OH), 1.94 (1H,
m, H-5ax), 2 (2H, br s, NH2), 2.18 (1H, m, H-4eq,
J4eq–4ax = 13.52 Hz, J4eq–3eq = 2.57 Hz,), 2.26 (1H, m,
H-6eq, J6eq–6ax = 13.08 Hz, J6eq–5ax = 2.51 Hz,), 3.04 (1H,
m, H-3eq, J3eq–2ax = 4.97 Hz, J3eq–4eq = 2.62 Hz,); 13C
NMR (CDCl3, 100.62 MHz) d 14.7 (CH3), 26.86 (CH3),
27.4 (C-4), 29.8 (C-3), 40.12 (C-6), 42.44 (C-2), 53.93
(C-1), 71.4 (C–OH), 118.71 (CN–C-3), 121.63 (CN–C-1).
4.2. (1R,2R,3R,5R)-1-Benzylideneamino-2-methyl-5-
(1-hydroxy-1-methyl-ethyl)cyclohexane-1,3-dicarbonitrile
3b (R = Ph)
A mixture of a-aminonitrile 2b (3.92 g, 17.73 mmol), benz-
aldehyde (2.80 g, 26.38 mmol) and anhydrous Na2SO4 in
35 mL of anhydrous chloroform was refluxed with a
water-separative funnel. During the reaction, the mixture
was filtered twice after which more anhydrous Na2SO4
was added. After 18 h, the mixture was cooled to room
temperature and filtered. The filtrate was concentrated
under vacuum to give the crude iminodinitrile. Yield:
89%. The residue was purified by chromatography (silica
Optical rotations were measured at 589 nm (Na) and 365,
436, 546, 578 nm (Hg) with a digital polarimeter Perkin–El-
mer 341 using a 1 mL cell. Melting points (uncorrected)
were measured with a Totoli instrument. TLC were per-
formed with Silica 60 F254 (Merck) plates and revealed
with iodine and/or UV-ray.
(ꢀ)-(1R,2R,5R)-2-Methyl-5-(1-methylethenyl)-3-oxocyclo-
hexane carbonitrile 2a and (1R,2R,3R,5R)-1-isobutylidene-
amino-2-methyl-5-(1-methylethenyl)cyclohexane-1,3-dicar-
bonitrile 3a (R = Pri) were prepared according to our pre-
viously described procedures.9,10
gel column) by using diethyl ether/methanol (98:2) as elu-
20
ent. Yield: 47%. Mp = 72.4–76.8 °C; ½aꢁD ¼ ꢀ32:0 (c
0.11, CH3OH); IR (KBr, cmꢀ1) m 3395 (N–H), 2251
(CN), 1707 (C@N), 1646 (C@Caromatic), 1384, 1368 (gem
dimethyl), 1225 (C–O); 1H NMR (CDCl3, 400 MHz) d
1.11 (3H, d, JH-2ax = 6.9 Hz, CH3), 1.17 (6H, m, CH3),
1.55 (1H, m, H4ax), 1.73 (1H, m, H6ax), 2.02 (1H, m,
H6eq), 2.11 (1H, m, H2ax), 2.29 (1H, m, H4eq), 2.49 (1H,
m, H5ax), 3.16 (1H, m, H-3eq), 7.43–7.74 (5H, m, Haromatic),
8.55 (1H, s, Himine).
4.1. (1R,2R,3R,5R)-1-Amino-2-methyl-5-(1-hydroxy-1-
methyl-ethyl)cyclohexane-1,3-dicarbonitrile 2b
A solution of sodium cyanide (5.98 g, 122.04 mmol) and
ammonium chloride (7.75 g, 144.86 mmol) in 96 mL of
28% ammonia solution was added dropwise to a solution
of 2b (10 g, 51.21 mmol) in methanol (7 mL). The reaction
mixture was then stirred at room temperature. After 24 h,
ammonia was removed in vacuo. The solution was satu-
rated with sodium chloride and extracted with dichloro-
methane. The organic layers were dried over Na2SO4 and
4.3. (1R,2R,3R,5R)-1-Isobutylidene-amino-2-methyl-5-
(1-hydroxy-1-methylethyl)cyclohexane-1,3-dicarbonitrile
3b (R = Pri)
A mixture of a-aminonitrile 2b (1.6 g, 7.24 mmol), isobu-
tyraldehyde (7.78 g, 10.86 mmol) and anhydrous Na2SO4
in 35 mL of anhydrous chloroform was heated at reflux
the solvent was removed in vacuo. Yield: 80%. mp =
20
121.4–122 °C; ½aꢁD ¼ ꢀ14:9 (c 0.32, CH3OH); IR (CH2Cl2,

J.-C. Rossi et al. / Tetrahedron: Asymmetry 19 (2008) 876–883
881
in the presence of a water-separative funnel. During the
reaction, wet sulfate was removed by filtration and a new
amount of anhydrous Na2SO4 was introduced in the reac-
tion medium. After 6 h, the mixture was cooled to room
temperature and filtered. Evaporation of the solvent in
vacuo afforded slightly yellow crystals. Yield: 90%. IR
(CHCl3, cmꢀ1) m 3600, 3400–3500 (br) (O–H), 2240 (CN),
1660 (C@N), 1390, 1370 (gem dimethyl); 1H NMR (CDCl3,
60 MHz) d 1.1–1.26 (15H, CH3, Pri), 3.16 (1H, m, H-3eq),
7.9 (1H, s, Himine).
J = 6.8 Hz), 1.38 (t, 1H, H-6ax), 1.44 (m, 1H, H-4ax),
1.70 (m, 1H, H-2ax), 1.95 (m, 1H), 2.21 (m, 1H, H-4eq),
2.67 (m, 1H, H-6eq), 3.09 (m, 1H, H-3eq), 3.65 (t, 1H).
Compound (R)-4a (R = Pri): IR (CHCl3, cmꢀ1) m 3600
(OH), 3300–3500 (NH), 2240 (CN), 1370–1390 (CH3gem);
NMR 1H (250 MHz, CDCl3) d 1.05 (d, 6H, CH3gem
,
J = 6.7 Hz), 1.2 (s, 3H, CH3b), 1.34 (d, 3H, CH3a,
J = 6.8 Hz), 1.38 (t, 1H, H6ax), 1.44 (m, 1H, H4ax), 1.70
(m, 1H, H2ax), 1.95 (m, 1H), 2.21 (m, 1H, H4eq), 2.5 (m,
1H, H6eq), 3.09 (m, 1H, H3eq), 3.57 (m, 1H).
4.4. Hydrocyanation of (1R,2R,3R,5R)-1-isobutylidene-
amino-2-methyl-5-(1-methylethenyl)cyclohexane-1,3-dicar-
bonitrile 3a (R = Pri) by acetone cyanohydrin
4.6. Hydrocyanation of (1R,2R,3R,5R)-1-isobutylidene-
amino-2-methyl-5-(1-methylethenyl)cyclohexane-1,3-di-
carbonitriles 3a and 3b (R = Pri) by hydrogen cyanide
Acetone cyanohydrin (7.5 mL, 79 mmol) was added to 3a
(R = Pri) (1.9 g, 7.4 mmol) in methanol (50 mL). After
4 h at reflux, methanol was eliminated in vacuo. The
remaining acetone cyanohydrin was distilled in vacuo
(0.1 mm Hg) to afford a mixture of (R)-4a and (S)-4a. Dia-
stereoisomeric excess (de) (R/S) = 7:3 was determined by
1H NMR 250 MHz. Silica gel chromatography (acetone/
CHCl3: 3:97) of the mixture gave the two iminodinitriles
Potassium cyanide (0.252 g, 3.9 mmol) in 15 mL of methyl
alcohol was added dropwise to 5 mL of an HCl solution
(0.79 M) in methyl alcohol in a 100 mL flask equipped with
a condenser thermostated at 0 °C. A solution of 3a (1 g,
3.9 mmol) in 10 mL of methyl alcohol was then added
dropwise at room temperature. After 4 h, the mixture
was filtered and the solvent was evaporated in vacuo.
The reaction mixture was treated by chloroform. Salts were
eliminated by filtration and the solvent was removed.
Yield: 54%. de (R/S) = 7.5:2.5 by 1H NMR 250 MHz.
The same protocol was used for 3b (R = Pri); Yield: 50%.
de (R/S) = 7.5:2.5.
(R)-4a (R = Pri) and (S)-4a, (R = Pri) Yield: 68%. Com-
20
pound (R)-4a, (R = Pri) mp = 163 °C; ½aꢁD ¼ þ60:8 (c 1,
CHCl3); IR (CHCl3, cmꢀ1) m 3305–3340 (NH), 3080
1
(CH2@CH), 2240 (CN), 1640 (C@C); NMR H (CDCl3,
250 MHz) d 1.13 (d, 6H, Pri, J = 6.78 Hz), 1.3 (m, 1H,
H-6ax), 1.43 (d, 3H, CH3, J = 6.78 Hz), 1.55 (m, 1H,
H4ax), 1.79 (m, 4H, CH3, H2ax), 2.04 (m, 1H), 2.20 (m,
1H, H4eq), 2.53 (m, 2H, H6eq, H5ax), 3.15 (m, 1H, H3eq),
3.65 (t, 1H), 4.85 (d, 2H, CH2).
4.7. Hydrocyanation of (1R,2R,3R,5R)-1-isobutylidene-
amino-2-methyl-5-(1-methylethenyl)cyclohexane-1,3-dicar-
bonitriles 3a and 3b (R = Pri) by diethylaluminium cyanide
20
Compound (S)-4a (R = Pri): Mp = 185 °C; ½aꢁD ¼ ꢀ102:2
(c 1, CHCl3); IR (CHCl3, cmꢀ1) m 3305–3340 (NH), 3080
(CH2@CH), 2240 (CN), 1640 (C@C); NMR 1H
(250 MHz, CDCl3) d 1.03 (d, 6H, Pri), 1.23 (m, 1H,
H-6ax), 1.37 (d, 3H, CH3, J = 6.78 Hz), 1.50 (m, 1H,
H-4ax), 1.73 (m, 4H, CH3, H-2ax), 1.90 (m, 1H, H), 2.14
(m, 1H, H-4eq), 2.26 (m, 1H, H-6eq), 2.69 (m, 1H,
H-5ax), 3.08 (m, 1H, H-3eq), 3.45 (t, 1H, H), 4.76 (d,
2H, CH2).
Under nitrogen, propan-2-ol (0.06 g, 1 mmol) was added to
a toluene (1.5 mL, 1.5 mmol) solution (1 M) of diethyl-
aluminium cyanide. This mixture was added quickly to a
solution of 3a (0.257 g, 1 mmol) in 2.5 mL of THF at
ꢀ78 °C. The mixture was allowed to return to room tem-
perature and stirred for 2 h, cooled to ꢀ78 °C, neutralized
by 1 mL of HCl (0.05 M) and diluted by 5 mL of EtOAc.
After elimination of the aluminium salts by filtration on
Celite, the solvent was evaporated in vacuo to afford a crys-
4.5. Hydrocyanation of (1R,2R,3R,5R)-1-isobutylidene-
amino-2-methyl-5-(1-hydroxy-1-methylethyl)cyclohexane-
1,3-dicarbonitrile 3b (R = Pri) by acetone cyanohydrin
1
talline white product. Yield: 85%. de (R/S) = 7:3 by H
NMR 250 MHz. Compound 3b (R = Pri) Yield: 75%; de
(R/S) = 7:3.
Acetone cyanohydrin (6.9 mL, 76 mmol) was added to 3b
(R = Pri) (2.1 g, 7.6 mmol) in methanol (50 mL). The mix-
ture is heated at reflux for 5 h. Methanol was then evapo-
rated in vacuo. The remaining acetone cyanohydrin was
distilled in vacuo (0.1 mm Hg) to afford a mixture of (R)-
4b and (S)-4b. Yield: 75%. de (R/S) = 7.5:2.5 by 1H
NMR 250 MHz. The two iminodinitriles (R)-4b (R = Pri)
and (S)-4b (R = Pri) were separated by silica gel chromato-
graphy (MeOH/CHCl3 1:9).
4.8. Hydrocyanation of (1R,2R,3R,5R)-1-isobutylidene-
amino-2-methyl-5-(1-methylethenyl)cyclohexane-1,3-di-
carbonitrile 3a (R = Pri) by trimethylsilylcyanide
The hydrocyanation was performed under nitrogen and the
solutions of trimethylsilylcyanide and imine were mixed
under the conditions described in Table 1. At the end of
the reaction, the remaining trimethylcyanide was hydro-
lyzed by the addition of water (ca 50 mL). The reaction
medium was washed with CH2Cl2. The organic layer was
dried over anhydrous Na2SO4 and the solvent was evapo-
rated in vacuo. The yield and de (R/S) of the reaction were
reported in Table 1.
20
Compound (R)-4b (R = Pri): mp = 168–170 °C; ½aꢁD
¼
þ57:2 (c 1, MeOH); IR (CHCl3, cmꢀ1) m 3600 (OH),
3300–3500 (NH), 2240 (CN), 1370–1390 (CH3gem); NMR
1H (250 MHz, CDCl3)
d
1.05 (d, 6H, CH3gem
,
J = 6.7 Hz), 1.2 (s, 3H, CH3b), 1.34 (d, 3H, CH3a,

882
J.-C. Rossi et al. / Tetrahedron: Asymmetry 19 (2008) 876–883
4.9. Hydrocyanation of (1R,2R,3R,5R)-1-isobutylidene-
amino-2-methyl-5-(1-hydroxy-1-methylethyl)cyclohexane-
1,3-dicarbonitrile 3b (R = Pri) by trimethylsilylcyanide
4.12. Ethyl{[(1R,2R,3R,5R)-1,3-dicyano-5-(1-methyl-
ethenyl)-2-methyl-cyclohexylamino]-phenyl-methyl}-
phenylphosphinate 40a (R = Ph) in chloroform
Under nitrogen,
a
solution of trimethylsilylcyanide
A mixture of imine 3a (R = Ph) (237 mg, 0.81 mmol) and
ethylphenylphosphinate (166 mg, 0.98 mmol) in 2.5 mL of
chloroform was refluxed (50–70 °C) for 18 h. The removal
of the solvent in vacuo gave a mixture of four diastereoiso-
mers. Yield: 85%. Diastereoisomeric ratio determined by
31P NMR 81.01 MHz: 7:51:5:37.
(0.29 mL, 2.2 mmol) in CHCl3 (10 mL) and anhydrous
NiCl2 (0.15 g, 1.1 mmol) were added to 3b (0.3 g,
1.1 mmol) in CHCl3 (10 mL). The mixture was stirred
during 4 h at room temperature. At this time, the
trimethylsilylcyanide excess was hydrolyzed by the addition
of 40 mL of water. The aqueous layer was extracted twice
with CHCl3. Organic layers were joined, dried over
Na2SO4 and the solvent was removed in vacuo. Yield:
4.13. Ethyl{[(1R,2R,3R,5R)-1,3-dicyano-5-(1-methyl-
ethenyl)-2-methyl-cyclohexylamino]-phenyl-methyl}-
phenylphosphinate 40a (R = Ph) solvent free
1
73%. De (R/S) = 8.5:1.5 by H NMR 250 MHz.
A mixture of imine 3a (R = Ph) (243 mg, 0.83 mmol) and
ethylphenylphosphinate (170 mg, 1 mmol) was refluxed
(50–70 °C) for 20 h to gave a mixture of four diastereoiso-
mers. Yield: 96%. Diastereoisomeric ratio determined by
31P NMR 81.01 MHz: 9:47:6:38.
4.10. Ethyl{[(1R,2R,3R,5R)-1,3-dicyano-5-(1-hydroxy-1-
methylethyl)-2-methylcyclohexylamino]-phenyl-methyl}-
phenylphosphinate 40b (R = Ph)
A mixture of imine 3b (R = Ph) (352 mg, 1.14 mmol) and
ethylphenylphosphinate (242 mg, 1.42 mmol) in chloro-
form (5 mL) was refluxed (50–70 °C) for 18 h. After com-
pletion (monitored by 31P NMR 81.01 MHz) the removal
of the solvent in vacuo gave a mixture of four diastereoiso-
mers in an 8:46:3:43 ratio. The addition of 10 mL of hot
ethyl acetate and crystallization at room temperature af-
fords white crystals of 40b as two major isomers [31P
4.14. Cleavage of ethyl{[(1R,2R,3R,5R)-1,3-dicyano-5-(1-
hydroxy-1-methylethyl)-2-methyl-cyclohexylamino]-phenyl-
methyl}-phenylphosphinate 40b (R = Ph) by AgNO3
In a 50 mL flask containing 40b (111 mg, 0.231 mmol) in
3 mL of methanol was added 4.6 mL of AgNO3 0.1 M.
The pH of the solution was adjusted to 1 with dilute nitric
acid. The mixture was stirred at 50 °C. After completion of
the reaction (monitored by 31P NMR), silver cyanide salts
were removed by filtration. The NaCl was added to the fil-
trate to precipitate the excess Ag+ and the suspension was
filtered. The reaction medium was extracted with 5 mL of
CH2Cl2. The organic layer was dried over anhydrous
sodium sulfate. Starting chiral ketone 1b was recovered
NMR (CDCl3, 81.01 MHz) d 40.4, 37.9; de = 6:4]. Yield:
20
96%. mp = 165–170 °C; ½aꢁD ¼ ꢀ7:7 (c 0.013, CH3OH);
31P NMR (CDCl3, 81.01 MHz) d 40.9, 40.4, 38.5, 37.9;
1H NMR (CDCl3, 400 MHz) d 1 (3H, d, JH–H-2ax
=
7.04 Hz, CH3), 1.09 (6H, d, JH–H = 8.96 Hz, CH3), 1.26
(3H, t, JH–H = 7.03 Hz, CH3(EtO)), 1.30 (1H, m, H-6ax),
1.54 (1H, m, H-4ax), 1.68 (1H, m, H-2ax), 1.88 (1H, m,
H-5ax), 2 (1H, m, H-4eq), 2.12 (1H, m, H-6eq), 2.5 (2H,
br s, NH, OH), 3 (1H, m, H-3eq), 4.05 (2H, m, CH2),
4.18 (1H, d, JH–P = 15.02 Hz, CH minor), 4.31 (1H, d,
JH–P = 18.74 Hz, CH major), 7.11–7.39 (10H, m,
Haromatic); 13C NMR (CDCl3, 100.62 MHz) d 15.17 (O–
CH2–CH3), 16.59 (CH–CH3), 26.83, 27.58 (CH3–C–OH),
29.52 (C-4), 33.03 (C-3), 37.71 (C-6), 38.93 (C-2), 41.98
(C-5), 57.85 and 58.94 (CH–P), 61.90 (O-CH2–CH3), 71.39
(C-1), 76.72 (CH3–C–OH), 118.38 and 118.57 (CN),
after removal of the solvent in vacuo. Yield = 89% and
20
½aꢁD ¼ ꢀ17:5 (c 1, EtOH 100) The aqueous layer was neu-
tralized by NaOH 0.1 M and extracted with CH2Cl2. The
organic layer was dried over anhydrous sodium sulfate.
Crude ethyl a-aminobenzylphenylphosphinate 50b was ob-
tained after removal of the solvent (yield: 63%, 2 diastere-
oisomers). Diastereoisomeric ratio: 78:22 (by 31P NMR,
20
81.01 MHz). ½aꢁD ¼ þ36:5 (c 0.02, CH3OH); 31P NMR
127.53–132.60 (CHaromatic@CHaromatic), 135.57 (Caromatic
P and Caromatic–CH).
–
1
(DMSO-d6, 81.01 MHz), d 37.6, 35.9; H NMR (DMSO-
d6, 200 MHz) d 1.1 (3H, t, JH–H = 7.11 Hz, CH3 minor),
1.28 (3H, t, JH–H = 6.99 Hz, CH3 major), 3.26 (2H, br s,
NH2), 3.83 (2H, q, JH–H = 7,14 Hz, CH2 minor), 4.06
(2H, q, JH–H = 6.99 Hz, CH2 major), 4.95 (1H, d,
Repeated crystallization from ethyl acetate afforded one of
the two major diastereoisomers (31P NMR (CDCl3,
20
81.01 MHz) d 40.4). Mp = 165 °C. ½aꢁD ¼ ꢀ30:6 (c 0.01,
JH–P = 11.96 Hz, CH minor), 5.06 (1H, d, JH–P
=
CH3OH). HRMS: (MH+) calcd for C27H35N3O3P,
480.2403; found, 480.2416.
12.33 Hz, CH major), 7.47 (10H, m, Haromatic); FAB-MS:
m/z 276 [M+1]+ (calcd 275.3).
4.11. Ethyl{[(1R,2R,3R,5R)-1,3-dicyano-5-(1-hydroxy-1-
methylethyl)-2-methyl-cyclohexylamino]-phenyl-methyl}-
phenylphosphinate 40b (R = Ph) solvent free
4.15. Hydrolysis of ethyl a-aminobenzylphenylphosphinate
50b
Compound 50b (40 mg, 0.146 mmol) was treated with 33%
HBr in glacial acetic acid (0.7 mL) at room temperature
according to Belov’s procedure.16 After completion of the
reaction (monitored by TLC) the volatile products were
removed in vacuo. The residue was dissolved in 1 mL of
methanol and propylene oxide was added to eliminate the
A mixture of imine 3b (R = Ph) (130 mg, 0.43 mmol) and
ethylphenylphosphinate (89.6 mg, 0.53 mmol) was refluxed
(50–70 °C) for 20 h to give a mixture of 4 diastereoisomers.
NMR yield: 55%. Diastereoisomeric ratio determined by
31P NMR 81.01 MHz: 9:51:8:32.

J.-C. Rossi et al. / Tetrahedron: Asymmetry 19 (2008) 876–883
883
excess of Brꢀ. Diethyl ether (5 mL) was added to initiate
the precipitation and the mixture was placed in the refri-
gerator. Filtration and washing with Et2O gave the desired
compound 60b. Mp = 205 °C; [a]20 (k, nm) = +29 (589),
+30 (578), +34 (546), +67 (436), +121 (365), (c 0.02,
7. (a) Pirat, J. L.; Monbrun, J.; Virieux, D.; Volle, J. N.; Tillard,
M.; Cristau, H. J. J. Org. Chem. 2005, 70, 7035–7041; (b)
Pirat, J. L.; Monbrun, J.; Virieux, D.; Volle, J. N.; Cristau, H.
J. Tetrahedron 2005, 61, 7029–7036.
8. Harada, K. Nature 1963, 200, 1201.
9. Rossi, J. C.; Marull, M.; Boiteau, L.; Taillades, J. Eur. J. Org.
Chem. 2007, 662–668.
10. (a) Taillades, J.; Garrel, L.; Lagriffoul, P. H.; Commeyras, A.
Bull. Soc. Chim. Fr. 1992, 129, 191–198; (b) Tadros, Z.;
Lagriffoul, P. H.; Mion, L.; Taillades, J.; Commeyras, A. J.
Chem. Soc., Chem. Commun. 1991, 19, 1373–1375.
11. Davis, F. A.; Portonovo, P. S.; Reddy, R. E.; Chiu, Y. J. Org.
Chem. 1996, 61, 440–441.
1
HCl/EtOH 1:1); 31P NMR (D2O, 81.01 MHz) d 35.7; H
NMR (D2O, 200 MHz) d 3.6 (1H, d, JH–P = 11.96 Hz,
CH), 7.47 (10H, m, Haromatic).
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