Asymmetric strecker reaction with chiral amines: A catalyst-free protocol using acetone cyanohydrin in water

Article abstract of DOI:10.1002/ejoc.201201533

The synthesis of a series of new chiral α-aminonitriles was achieved in a diastereoselective Strecker reaction in a one-pot procedure with aldehydes, enantiopure amines, and acetone cyanohydrin in water. Primary and secondary amines derived from L-α-amino acids were used as sources of chirality. The reactions proceeded efficiently without any catalyst at room temperature. The diastereoselectivity of the process, and the configurational stability of new chiral α-aminonitriles were investigated. The identification of labile intermediates by NMR analysis, and a proposed mechanism and a model for the asymmetric induction are reported. The chemical transformation of proline-derived chiral α-amino-nitriles into chiral amino-diacids, aminols, and amides is reported. A series of new chiral α-aminonitriles was obtained in a diastereoselective Strecker reaction. Aldehydes were coupled with enantiopure amines derived from L-proline, L-phenylglycine, L-phenyl alanine, and L-tryptophan, in a one-pot procedure using acetone cyanohydrin in water. Copyright

Full text of DOI:10.1002/ejoc.201201533

FULL PAPER
DOI: 10.1002/ejoc.201201533
Asymmetric Strecker Reaction with Chiral Amines: a Catalyst-Free Protocol
Using Acetone Cyanohydrin in Water
Matteo Pori,[a] Paola Galletti,*[a] Roberto Soldati,[a] and Daria Giacomini*[a]
Dedicated to Professor Gianfranco Cainelli on the occasion of his 80th birthday
Keywords: Asymmetric synthesis / Multicomponent reactions / Cyanides / Aldehydes / Amines / Strecker reaction
The synthesis of a series of new chiral α-aminonitriles was
achieved in a diastereoselective Strecker reaction in a one-
pot procedure with aldehydes, enantiopure amines, and ace-
tone cyanohydrin in water. Primary and secondary amines
derived from L-α-amino acids were used as sources of chiral-
ity. The reactions proceeded efficiently without any catalyst
at room temperature. The diastereoselectivity of the process,
and the configurational stability of new chiral α-aminonitriles
were investigated. The identification of labile intermediates
by NMR analysis, and a proposed mechanism and a model
for the asymmetric induction are reported. The chemical
transformation of proline-derived chiral α-amino-nitriles into
chiral amino-diacids, aminols, and amides is reported.
to chiral imines, where the source of chirality was the O-
protected (2S)-lactic aldehyde.[5] The optimal reaction con-
ditions (Lewis acid catalysts and organic solvent[6]) varied
for imines with different N-protecting groups. Interestingly,
we observed that a preformed N-trimethylsilylimine was
capable of reacting with TMSCN in dichloromethane with-
out any catalyst to give chiral N-unprotected α-amino-
nitriles in good yields and with good diastereoselectivities.
The first example of a diastereoselective Strecker reac-
tion assisted by a chiral auxiliary on the amine component
was reported by Harada, who used (S)-1-phenyl-ethylamine
as the chiral auxiliary to obtain chiral (S)-α-amino acids
after acid hydrolysis of the nitrile and cleavage and recovery
of the N-alkyl group.[7,8] As a result of this approach, exten-
sive studies involving other chiral amines, including amino
acids, amino amides, amino alcohols, sulfinamides, glyc-
osylamines, hydrazines, and others, were carried out with
good results in terms of yields and diastereoselectivities.[9]
A diastereoselective Strecker reaction leading to enantio-
pure α-aryl glicines was recently reported by James and co-
workers.[10]
Recently, we reported a simple, convenient, and practical
method for the synthesis of α-aminonitriles through a cata-
lyst-free Strecker reaction of a carbonyl compound, amine,
and acetone cyanohydrin in water.[11] We used acetone
cyanohydrin as the cyanide source, exploiting its “in situ”
dissociation into HCN and acetone. In water, the dissoci-
ation process was quite slow, but the addition of a small
amount of basic compounds dramatically increased the de-
composition rate. The one-pot reactions proceeded very ef-
ficiently without any catalyst at room temperature and with
Introduction
α-Aminonitrile compounds play a significant role in or-
ganic chemistry. Because of their bifunctional nature, they
are versatile intermediates for the synthesis of natural and
bioactive compounds, and they can be precursors to impor-
tant building blocks such as naturally and non-naturally oc-
curring α-amino acids.[1] One of the earliest procedures to
obtain α-aminonitriles was the Strecker reaction, a three-
component reaction between a carbonyl compound, an
amine, and cyanide ion.[2]
Spurred on by the ever-increasing demand for non-natu-
ral enantioenriched α-amino acids for proteomic sciences
and medicinal chemistry, one of the hottest topics in recent
years has been the asymmetric Strecker reaction leading to
enantiopure α-aminonitriles, precursors of enantiopure α-
amino acids,[3] amines, and amine derivatives. In general,
two approaches have been used to achieve successful asym-
metric Strecker reactions: the addition of cyanide to chiral
non-racemic imines, and the catalytic enantioselective cyan-
ation of achiral imines.[4] As an example, we dealt some
years ago with diastereoselective Strecker reactions in a
study on the addition of trimethylsilyl cyanide (TMSCN)
[a] Department of Chemistry “G. Ciamician”, University of
Bologna,
Via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-209-9456
E-mail: daria.giacomini@unibo.it
paola.galletti@unibo.it
Homepage: http://www.unibo.it/SitoWebDocente/
default.htm?UPN = daria.giacomini%40unibo.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201533.
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high chemoselectivity. α-Aminonitriles were generally ob- 15,[15] and 16[13,16] are known compounds, and the absolute
tained in good to excellent yields and, it is noteworthy that configuration of the major diastereoisomers 13a–16a were
in some cases, the expected pure α-aminonitrile directly sep- assigned as (S,S; i.e., 1,3-“syn”), by comparison with litera-
1
arated from water.
ture H NMR spectroscopic data.
The next aim of the project is now to extend the protocol
(S)-Phenylglycinol 6 gave a general enhancement of the
to the asymmetric variant. In this paper, we report the syn- diastereomeric ratios with all the aldehydes (Table 1, en-
thesis of chiral α-aminonitriles obtained by a diastereoselec- tries 5–7, compounds 17–19) up to a value of 83:17, which
tive Strecker reaction in water using enantiopure amines. was obtained with compounds 19a–b. The absolute configu-
We screened primary and secondary amines derived from rations of the major diastereoisomers 17a and 19a were as-
1
l-proline, l-phenylglycine, l-phenylalanine, and l-trypto- signed as (S,R) by comparison with the H NMR spectro-
phan in a one-pot procedure with aldehydes and acetone scopic data for the same compounds reported in the litera-
cyanohydrin in water and obtained α-aminonitriles incor- ture.[17,18] For compounds 18a–b, the configuration was as-
porating the chiral amine skeleton. We investigated the dia- signed by comparison with 1H NMR spectra of amino-
stereoselectivities and the configurational stabilities of the nitriles 17a–b and 19a–b. In particular, we observed a con-
new chiral α-aminonitriles. Furthermore, we evaluated the stant and similar trend in the chemical shift of the proton
l-proline-derived aminonitriles as chiral precursors of un- on the carbon α to the CN group. The CHCN signal in the
usual α-amino acids and their derivatives. As there are still major diastereoisomers (i.e., 17a and 19a) was more
only a few reports[12] dealing with the asymmetric Strecker shielded than the corresponding signal in the minor dia-
reaction with acetone cyanohydrin as the cyanide source, a stereomers (i.e., 17b and 19b). The same trend was observed
contribution to this area was highly desirable.
for 18a and 18b, and this allowed an assignment of the con-
figuration. Notwithstanding the difference in stereochemi-
cal descriptors of the major diastereoisomers, i.e., (S,S) for
aminonitriles 13a–16a, and (S,R) for 17a–19a, the stereoin-
duction exerted by amine 6 was of the same sense as for
Harada’s amine 5, giving predominantly the 1,3-“syn”
stereoisomers in all cases.
Results and Discussion
Primary Chiral Amines
The study of the asymmetric variant of the one-pot
The key role of the OH group in l-phenylalaninol (6) as
Strecker reaction in water using acetone cyanohydrin as the an enhancer of dr was confirmed by using the correspond-
cyanide source started with some enantiopure primary ing O-methyl ether (i.e., 7) as starting amine. In this case,
amines in combination with achiral aromatic or aliphatic lower dr values for the product aminonitriles (i.e., 20a–b
aldehydes (Table 1). As model aldehydes, benzaldehyde (1), and 21a–b) were obtained: 64:36 and 71:29, respectively.
butanal (2), isobutyraldehyde (3), and pivaldehyde (4) were
The configurations of 20a and 21a were assigned as (S,R)
evaluated. As chiral amines, we tested the Harada’s source on the basis of the same trend of CHCN chemical shifts
of chirality (S)-1-phenylethylamine (5), β-aminols, β-amino- observed for compounds 17 and 19, as discussed above. To
ethers, such as (S)-2-amino-2-phenylethanol (6), (S)-2- confirm the assignment, compound 17a was directly trans-
methoxy-1-phenylethanamine (7), (S)-2-amino-3-phen- formed into 20a through simple O-methylation (see Sup-
ylpropan-1-ol (10), (S)-2-amino-3-(1H-indol-2-yl)propan-1- porting Information for experimental details and NMR
ol (11), and methyl esters of l-phenylglycine (i.e., 8), of l- spectroscopic data).
phenylalanine (i.e., 9), and of l-tryptophan (i.e., 12). Free
When methyl esters of amino acids were used as sources
α-amino acids were also tested, but they did not give results. of chirality (Table 1, entries 10–13 and 16–17), the dia-
The experimental protocol consisted of pre-mixing the stereomeric ratios were not outstanding, and a highest dr
aldehyde and the chiral amine in a closed vial without any value of 77:23 was seen for 23a–b, obtained from l-phenyl-
solvent at room temperature, followed by the addition of glycine methyl ester (8) and butanal (2). The configuration
water and of one equivalent of acetone cyanohydrin, con- of compounds 22a–b was established to be (S,R) by chemi-
secutively. The reaction mixture was subjected to orbital cal transformation of a 2:1 mixture of 22a/22b into 17a/17b
shaking overnight at room temperature. The reactions pro- by reducing the methyl ester with NaBH4. The configura-
ceeded smoothly, and gave the products in good to excellent tions of aminonitriles 23a–b, 24a–b, 25a–b, 26a–b, and 27a–
yields. The best results in terms of yield were obtained with b were assigned on the basis of the 1H NMR chemical shift
amine 5 and β-aminols 6 and 10, which gave the aminoni- trends of the whole series, as described above (Supporting
triles in almost quantitative yields. Using amino acid methyl Information). Aminonitriles 28a–b are known compounds,
esters 8, 9, and 12, the yields were lower, and we could and their configurations were assigned by comparison with
detect in the crude mixture the presence of by-products NMR literature data.[19]
such as aldehyde cyanohydrins; in these cases the isolation
of the aminonitriles required solvent extraction followed by carbon, as is the case for amines 10 and 11, the diastereo-
chromatographic purifucation. selectivity dropped completely (Table 1, entries 12 and 17).
Whenever the chiral amine was more flexible on the β-
As regards the diastereomeric outcome, amine 5 gave 2:1 α-Substituents on the aldehyde seem to have little influence
mixtures of the two diastereoisomers a and b (Table 1, en- on diastereomeric ratio, with a slight increase of dr being
tries 1–4, products 13–16). Aminonitriles 13,[13] 14,[13,14] seen for aliphatic and α-branched aldehydes compared to
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Asymmetric Strecker Reaction with Chiral Amines
Table 1. One-pot Strecker reaction in water with 1 equiv. of acetone cyanohydrin and primary chiral amines.
[a] Combined yields of both isomers. [b] Amine used as hydrochloride and treated in situ with Et3N (1 equiv.; see Exp. Sect.).
benzaldehyde (Table 1, entries 2, 7, 9, and 11), with a few
exceptions (Table 1, entries 2 and 13).
The reaction of diphenylprolinol (34) with butanal (2)
gave the corresponding aminonitriles (i.e., 45a–b) in quanti-
tative yield, and in all other cases, variable amounts of alde-
hyde cyanohydrins and starting materials could be detected
in the crude reaction mixtures, and the products had to be
purified by flash chromatography, thus lowering the yields.
When l-proline esters 30, 31, and 32 were used as the
sources of chirality, quite similar diastereomeric ratios were
observed (average value 75:25), irrespective of the nature of
the ester group (methyl, tert-butyl, or benzyl) or the alde-
hyde used (Table 2, entries 1–5, 10, and 11). Better dia-
stereoselectivities were obtained with (S)-prolinol (33),
Secondary Chiral Amines
One major feature of our Strecker protocol is that it
works well with secondary amines.[11] Thus, we decided to
test secondary chiral amines, including l-proline esters 30–
32, l-prolinol derivatives 33–34, the (4R)-hydroxy-l-proline
ester 35, and (4R)-hydroxy-l-prolinol (36), with 1 and 2 as
model aldehydes (Table 2).
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Table 2. One-pot Strecker reaction in water with 1 equiv. of acetone cyanohydrin and secondary chiral amines.
[a] Combined yields of both isomers. [b] Amine used as hydrochloride and treated in situ with Et3N (1 equiv.; see Exp. Sect.).
which gave 42 and 43 with a dr of 82:18 using benzaldehyde shielded than that of the minor diastereomer for the whole
or butanal (Table 2, entries 6 and 7). (S)-α,α-Diphenylprol- series of compounds (see Supporting Information). Com-
inol 34 gave the best result, generating a single diastereoiso- pound 45a was analyzed by single-crystal X-ray diffraction,
mer with either benzaldehyde (1) or butanal (2) (Table 2, and the absolute structure is shown in Figure 1. To assign
entries 8 and 9). Notably, the enantiomerically pure amino- the absolute configuration of compound 46a, we had to
nitrile (i.e., 45a) was obtained directly from the crude mate- transform it into iodo derivative 50a by a Mitsunobu reac-
rial in quantitative yield without any purification. The abso- tion,[20] thus obtaining a crystalline product suitable for X-
lute configuration of the major or exclusive diastereoiso- ray diffraction analysis (Figure 1). The X-ray diffraction
mers of the proline-derived α-aminonitriles were assigned data of the two structures unequivocally confirmed the S
as (S,S) by X-ray single crystal analysis and 1H NMR spec- configurations of the newly-formed stereocenters.
troscopy. Products 37–43 and 46–49 showed the same trend
in the H NMR chemical shift of the CHCN proton, with trends was confirmed by several chemical transformations.
the proton of the major diastereoisomer always more de- Thus, compound 46a was transformed into 48a by methyl
The stereochemical assignment using 1H NMR signal
1
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Asymmetric Strecker Reaction with Chiral Amines
good yields.[22] Computational studies on the effect of the
structure of the amine on the formation of iminium inter-
mediates with aldehydes in water showed that aminol and
iminum species were intermediates with high barriers, espe-
cially for secondary cyclic amines such as proline methyl
ester and pyrrolidine.[23] In case of l-prolinols, because of
the presence of a primary alcohol in the side chain, the
formation of bicyclic 1,3-oxazolidines, as well as imine/im-
onium and aminol intermediates, could be possible (Fig-
ure 2).[24]
To obtain some evidence about the intermediates in-
volved in our catalyst-free one-pot reaction in water, NMR
analysis was performed with benzaldehyde (1), butanal (2),
l-prolinol (33), and l-diphenylprolinol (34). An equimolar
mixture of the aldehyde and the amine was pre-mixed at
room temperature, and aliquots were diluted in NMR tubes
in two solvents, D2O or CDCl3, and quickly analyzed. We
obtained resolvable spectra that indicated the presence of
several species in solution (see Supporting Information for
details and spectra). When l-prolinol (33) was mixed with
benzaldehyde (1) in CDCl3 and D2O, two new distinct spe-
cies with specific signals in the range 5.4–5.5 ppm were ob-
served, together with some remaining starting materials.
The spectra of butanal (2) and prolinol (33) showed similar
species with signals at 4.0–4.5 ppm; in D2O, traces of the
aldehyde hydrate and an imonium species appeared. Upon
addition of acetone cyanohydrin, the resonances of the two
new species disappeared, and those of the corresponding
aminonitriles appeared.
Figure 1. X-ray structures for compounds 45a and 50a.
ester reduction with NaBH4, and in the same way, 47a was
transformed into 49a, and 37a into 42a. Finally, compound
37a was converted into 44a by Grignard addition (see Sup-
porting Information).
For the one-pot Strecker reaction, two mechanisms have
been proposed: one going via an imine (or iminium ion)
intermediate, the other via an aminol intermediate.[21] The
imine route is more plausible in those cases where the
Strecker reaction is carried out in organic solvents and in
the presence of a dehydrating agent that could force the
elimination of water. However, Tanaka et al. demonstrated
that imines could be efficiently formed also in water by mix-
ing aromatic aldehydes and amines; the Schiff bases sepa-
The rapid consumption of the intermediate species
rated from the aqueous medium as crystalline products in agreed with our previously reported observation that acet-
Figure 2. Reaction intermediates and models for the asymmetric induction.
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one cyanohydrin decomposes quickly in H2O in the pres-
ence of traces of amine or imine species to give acetone and
HCN.[11]
1
Careful analysis of H and 13C NMR spectra and com-
parison with authentic spectra of 1,3-oxazolidines reported
in the literature[25] allowed us to assign a bicyclic 1,3-oxaz-
olidine structure to the two diastereomeric intermediates.
However, the diastereomeric ratio of the 1,3-oxazolidines
(7:3) observed in the NMR analysis did not strictly corre-
spond to the dr of the final aminonitrile products (for in-
stance 42a/42b 82:18, see Table 2), because of epimerization
phenomena (see below).
Scheme 1. Reduction of some chiral α-aminonitriles.
Interestingly, the 1H NMR analysis of the reaction of
diphenylprolinol (34) with aldehydes 1 or 2 in CDCl3 re-
vealed, as well as large amounts of starting materials re-
maining, the presence of only one isomer of 1,3-oxazolid-
ine,[26] and this corresponds to the fact that a single dia-
stereomer of aminonitrile was obtained in the Strecker reac-
tion with both aldehydes (Table 2, entries 8 and 9).
Even alcoholysis procedures with HCl in methanol de-
signed to transform the cyanide group into a methyl ester[29]
did not succeed.
The presence of bicyclic intermediates could provide in-
direct evidence for a high reactivity of the iminium species,
which presumably have a very short lifetime in aqueous
solution and undergo a rapid intramolecular cyclization.
However, despite the presence of several reactive intermedi-
ates, upon the addition of acetone cyanohydrin to the aque-
ous solution, all of the productive equilibria shifted to form
the aminonitrile products. As a tentative model for the
asymmetric induction exerted by the l-prolinols, the pre-
dominant or exclusive formation of (S,S)-aminonitriles
could derive from addition to the Re face of the iminium, or
from bimolecular nucleophilic substitution from the bottom
face of the 1,3-oxazolidine (Figure 2).
All of the proline-derived α-aminonitriles were new com-
pounds, and bearing in mind the importance and the utility
of proline derivatives in organocatalysis and metal catalysis,
the preservation of l-proline and (4R)-4-hydroxy-(S)-prol-
ine scaffolds in the target molecules allowed the formation
of very interesting bifunctional compounds suitable for the
design and synthesis of new chiral ligands. Thus, we investi-
gated the reactivity of some of the proline-derived amino-
nitriles in reduction and hydrolysis, just to explore their
Scheme 2. Hydrolysis of some chiral α-aminonitriles.
On the other hand, good results were obtained in the
transformation into new chiral aminols and amino acids. hydrolysis of the nitrile to an amide. Using a stoichiometric
We treated aminonitriles 37a and 38a with LiAlH4, and ob- amount of TiCl4 in acetic acid and 4 equiv. of water,[30] pure
tained chiral 1,5-aminols 51a and 52a, respectively, by con- 37a was converted into amide 54a in quantitative yield
comitant reduction of the ester and nitrile groups without any epimerization. It is interesting that when the
(Scheme 1).
same procedure was used with 4-hydroxy-prolinol 48a, bicy-
According to the literature, hydrolysis of the nitrile group clic lactone 55a was formed, due to an intramolecular cycli-
should be a routine transformation. We found, however, zation.
that the hydrolysis of pure aminonitrile 37a occurred under
This result on the epimerization phenomena in the hy-
drastic conditions with an excess of aqueous HCl (37%) for drolysis reaction, as well as the observation of unexpected
24 h at reflux, and gave a 75:25 mixture of two diastereoiso- spontaneous epimerization in stored samples, prompted us
mers 53a and 53b in 88% total yield (Scheme 2). To avoid to face the problem of configurational stability of α-amino-
the epimerization, we tried several milder conditions re- nitriles. For example, we observed that isolated minor dia-
ported in the literature, such as HCl (5% in dioxane),[27] stereoisomer 37b partially converted into the major dia-
sulfuric acid in CH2Cl2 at 0 °C, or NaHCO3 (1 m aque- stereomer (i.e., 37a) over time, whereas major diastereomer
ous).[28] None of these reactions resulted in the formation 37a did not epimerize. Also, in a 86:14 mixture of com-
of dicarboxylic acids, only epimerization of the starting pounds 48a–b, minor diastereoisomer 48b completely iso-
aminonitriles and retro-Strecker products were observed. merized into 48a within a month.
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Asymmetric Strecker Reaction with Chiral Amines
The epimerization of aryl-α-aminonitriles has already
been reported in the literature. Sakurai, for instance, ob-
served isomerization of diastereomeric α-aryl aminonitriles
when the compounds were dissolved in DMSO, or after
heating.[31] We then prepared [D6]DMSO solutions of iso-
lated pure diastereoisomers 37a and 37b, and heated them
Experimental Section
General Remarks: Commercial reagents were used as received with-
out additional purification. 1H and 13C NMR spectra were re-
corded with an INOVA 400 or a GEMINI 200 instrument with a
5 mm probe. All chemical shifts were calibrated to deuterated sol-
vent signals; δ values are quoted in ppm units, and J values are
quoted in Hz. Polarimetric Analyses were conducted with a Unipol
L 1000 “Schmidt–Haensch” Polarimeter at 598 nm. FTIR spectra:
Thermo Nicolet 380 instrument, measured as films between NaCl
plates; wavenumbers are reported in cm–1. TLC: Merck 60 F254
plates. Column chromatography: Merck silica gel 200–300 mesh.
GC–MS: Agilent Technologies MSD1100 single-quadrupole mass
spectrometer, EI voltage 70 eV, gradient from 50 to 280 °C in
30 min, column HP5 5% Ph-Me Silicone. HPLC–MS: Agilent
Technologies HP1100 instrument, equipped with a ZOBRAX-
Eclipse XDB-C8 Agilent Technologies column; mobile phase: H2O/
CH3CN, 0.4 mL/min, gradient from 30 to 80% of CH3CN in 8 min,
80% CH3CN until 25 min, coupled with an Agilent Technologies
MSD1100 single-quadrupole mass spectrometer, full scan mode
from m/z = 50 to 2600, scan time 0.1 s in positive-ion mode, ESI
spray voltage 4500 V, nitrogen gas 35 psi, drying gas flow 11.5 mL/
min, fragmentor voltage 20 V. Elemental analyses: Thermo Flash
2000 CHNS/O Analyzer. Single-crystal X-ray diffraction data were
collected at room temperature with an Oxford Diffraction Xcalibur
diffractometer equipped with a Mo-Kα radiation source (λ =
0.71073 Å) and a Sapphire3 CCD detector. The structure was
solved using SHELXS-97 (altro) or SIR-92 (iodioderiv) programs;
SHELXL-97 was used for structural refinement.[33]
1
at 80 °C for 24 h. H NMR spectra of both of the samples
showed the formation of traces of benzaldehyde and l-pro-
line methyl ester, and also of epimerization products with a
final diastereomeric ratio of 68:32 (37a/37b) starting from
37a, and 65:35 (37a/37b) starting from 37b. Moreover, the
two separated diastereoisomeric aminonitriles, 46a and 46b,
after being heated without solvent for 24 h at 80 °C, gave
1
identical H NMR spectra recorded in CDCl3 that showed
epimerization products in both samples with a convergent
diastereomeric ratio 46a/46b of 72:28. Even in those cases,
we observed traces of starting materials, benzaldehyde and
trans 4-hydroxy-(S)-proline methyl ester, together with two
further diastereoisomers derived from the partial racemiza-
tion (about 15%) of the carbon α to the ester group. In the
case of butanal derivatives 47a–b, the same experiment gave
a complex product mixture, and the spectra were not resolv-
able.
The presence of starting materials, and the observation
that final diastereomeric ratios obtained in the isomeriza-
tion experiments were consistent with the diastereomeric ra-
tios obtained in the Strecker protocol (Table 2, entries 1 and
10), suggest that epimerization takes place by a retro-
Strecker dehydrocyanation/cyanation mechanism.[32]
Crystal Data for 45a: C22H26N2O, M = 334.45, space group: C2
(monoclinic), a = 19.665(4), b = 6.4176(13), c = 16.037(5) Å, β =
102.86°(3), V = 1973.2(8) Å3, Z = 4, Dc = 1.126 gcm–3, λ (Mo-Kα)
= 0.069 mm–1, T = 293(2) K, 6912 reflections collected, 1914
unique (Rint = 0.0757), 1010 reflections with I Ͼ 2s(I), 231 param-
eters, R1 = 0.0575, wR2 (all data) = 0.1721. CCDC reference
number: 894335.
Conclusions
Crystal Data for 50a: C14H15IN2O2, M = 370.18, space group: P21
(monoclinic), a = 5.7970(15), b = 15.367(5), c = 8.313(3) Å, β =
90.950°(3), V = 740.4(4) Å3, Z = 2, Dc = 1.660 gcm–3, λ (Mo-Kα)
= 2.162 mm–1, T = 293(2) K, 2682 reflections collected, 1885
unique (Rint = 0.0312), 1597 reflections with I Ͼ 2s(I), 161 param-
eters, R1 = 0.0505, wR2 (all data) = 0.1378. CCDC reference
number: 894334.
In summary, we have developed the synthesis of a series
of chiral α-aminonitriles obtained by a diastereoselective
Strecker reaction in a one-pot procedure with aldehydes
and acetone cyanohydrin in water, using enantiopure
amines. Primary and secondary amines derived from l-pro-
line, l-phenylglycine, l-phenylalanine, and l-tryptophan
were used as sources of chirality. Reactions proceeded ef-
ficiently without any catalyst at room temperature, and in
some cases, chiral α-aminonitriles were obtained pure after
simple extraction from water. To obtain some evidence
about the intermediates involved with the best-performing
amines (l-prolinol and l-diphenylprolinol), NMR analysis
Amines 5, 6, 8, 9, 10, 12, 30, 31, 32, 33, 34, and 35 were purchased
from Sigma Aldrich and used without purification,
Amines 7,[34] 11,[35] and 36[36] were synthesized following published
procedures.
with two model aldehydes, benzaldehyde and butanal, was
General Procedure for the Synthesis of α-Aminonitriles 13–29, 37–
1
performed. H and 13C NMR spectra indicated the pres- 49: The chosen aldehyde (1 mmol) and amine (1 mmol) were mixed
in an orbital shaker at room temp. in a 5 mL vial equipped with a
screw cap. After 10 min, water (4 mL) and acetone cyanohydrin
(1 mmol) were added, and the cap was closed. If the amine was
used as its hydrochloride, triethylamine (1 mmol) was added prior
to the addition of the aldehyde. The mixture was stirred in an or-
bital shaker for 20 h. The reaction mixture was poured into brine
(5 mL) and extracted with CH2Cl2 (2ϫ 10 mL), then the combined
extracts were dried with Na2SO4 and concentrated. If necessary,
the products were purified by flash chromatography. Dia-
stereomeric ratios were determined from 1H NMR spectra or
HPLC data of the crude material.
ence of bicyclic 1,3-oxazolidines as reactive intermediates,
and a model for the asymmetric induction was proposed.
Chemical transformation of proline-derived α-aminonitriles
into chiral amino-diacids, aminols, and amides is reported.
All of the proline-derived chiral α-aminonitriles are unprec-
edented, and bearing in mind the importance and utility of
proline derivatives, the preservation of the proline scaffolds
in the target molecules allowed us to obtain very interesting
bifunctional compounds suitable for the design and synthe-
sis of new proline-based chiral ligands.
Eur. J. Org. Chem. 2013, 1683–1695
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1689

M. Pori, P. Galletti, R. Soldati, D. Giacomini
FULL PAPER
Compounds 13, 14, 15, 16, 17, 19, and 28 were known, and gave
spectroscopic data consistent with the published data.
52.7, 63.2, 118.2, 127.3, 128.1, 128.8, 128.9, 129.0, 129.2, 134.2,
136.1, 171.7 ppm. IR: ν = 3327, 2252, 1739, 1453 cm–1. HPLC–
˜
MS: Rt = 9.00 min; m/z = 254 [M – CN]+, 276 [M – HCN + Na]
[2-(2-Hydroxy-1-phenylethyl)amino]pentanenitrile (18): The major
diastereoisomer was separated by flash chromatography, the minor
isomer was characterized in the crude mixture. Data for major iso-
mer 18a (2R,2ЈS): yellow syrup. [α]2D5 = +157.37 (c = 0.64, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H, CH3),
1.48–1.58 (m, 2 H, CH3CH2CH2), 1.74–1.79 (dt, J = 7.2, 7.2 Hz, 2
H, CH3CH2CH2), 2.34 (br. s, 2 H, OH and NH), 3.30 (t, J =
7.2 Hz, 1 H, CHCN), 3.61 (dd, J = 9.6, 11.2 Hz, 1 H, CHHOH),
3.80 (dd, J = 4.0, 11.2 Hz, 1 H, CHHOH), 4.13 (dd, J = 4.0, 9.6 Hz,
1 H, CHPh), 7.28–7.39 (m, 5 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.4, 18.9, 35.6, 47.7, 63.1, 67.2, 120.1, 127.7, 128.3,
+, 281 [M + H]+, 303 [M + Na]+, 319 [M + K]+. Data for minor
1
isomer 22b (2S,S): H NMR (400 MHz, CDCl3): δ = 2.54 (dd, J =
6.4, 6.8 Hz, 1 H, NH), 3.74 (s, 3 H, CH3), 4.62 (d, J = 6.8 Hz, 1
H, PhCHCO2), 4.87 (d, J = 6.8 Hz, 1 H, CHCN), 7.35–7.55 (m, 5
H, ArH) ppm. IR: ν = 3327, 2252, 1453 cm–1. HPLC–MS: R =
˜
t
8.83 min; m/z = 254 [M – CN]+, 276 [M – HCN + Na]+, 281 [M
+ H]+, 303 [M + Na]+, 319 [M + K]+.
Methyl 2-[(1-Cyanobutyl)amino]-2-phenylacetate (23): Charac-
terized as a diastereomeric mixture, yellow oil. Data for major iso-
mer 23a (2R,S): 1H NMR (400 MHz, CDCl3): δ = 0.91 (t, J =
7.2 Hz, 3 H, CH3CH2), 1.47–1.62 (m, 2 H, CH3CH2CH2), 1.74–
1.80 (m, 2 H, CH3CH2CH2), 2.45 (d, J = 11.6 Hz, 1 H, NH), 3.25
(dt, J = 6.8, 11.6 Hz, 1 H, CHCN), 3.71 (s, 3 H, CO2CH3), 4.64 (s,
1 H, CHPh), 7.33–7.43 (m, 5 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.3, 18.8, 35.4, 47.4, 52.7, 63.2, 119.7, 128.1, 128.8,
128.8, 138.1 ppm. IR: ν = 3415, 3325, 2962, 2932, 2227, 1065 cm–1.
˜
C13H18N2O (218.29): calcd. C 71.53, H 8.31, N 12.83; found C
71.99, H 8.45, N 12.72. HPLC–MS: Rt = 7.35 min; m/z = 219 [M
+ H]+, 241 [M + Na]+. Data for minor isomer 18b (2S,2ЈS): yellow
syrup. 1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.2 Hz, 3
H, CH3), 1.48–1.58 (m, 2 H, CH3CH2CH2), 1.69–1.78 (m, 2 H,
CH3CH2CH2), 2.46 (br. s, 2 H, OH and NH), 3.55–3.88 (m, 3 H,
CHCN, CH2OH), 3.99 (dd, J = 4.4, 7.6 Hz, 1 H, CHPh), 7.28–7.39
(m, 5 H, ArH) ppm. HPLC–MS: Rt = 6.51 min; m/z = 219 [M +
H]+, 241 [M + Na]+.
128.9, 137.1, 171.9 ppm. IR: ν = 3331, 3031, 2960, 2875, 2253,
˜
2226, 1739, 1455, 1436 cm–1. HPLC–MS: Rt = 8.62 min; m/z = 220
[M – CN]+, 247 [M + 1]+, 269 [M + Na]+, 285 [M + K]+. Data for
1
minor isomer 23b (2R,S): H NMR (400 MHz, CDCl3): δ = 0.97
(t, J = 7.2 Hz, 3 H, CH3CH2), 1.47–1.62 (m, 2 H, CH3CH2CH2),
1.74–1.80 (m, 2 H, CH3CH2CH2), 2.04 (br. s, 1 H, NH, minor),
3.72 (s, 3 H, CO2CH3), 3.68–3.76 (m, 1 H, CHCN), 4.65 (s, 1 H,
PhCH), 7.33–7.43 (m, 5 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.4, 18.8, 35.5, 48.8, 52.7, 63.3, 119.8, 127.6, 128.6,
128.7, 136.3, 172.3 ppm. HPLC–MS: Rt = 8.32 min; m/z = 220 [M –
CN]+, 247 [M + H]+, 269 [M + Na]+, 285 [M + K]+.
2-[(2-Methoxy-1-phenylethyl)amino]-2-phenylacetonitrile
(20):
Characterized as a diastereomeric mixture, signals refer to the
major diastereosiomer, only the main signals of the minor dia-
stereomer are reported. Data for major isomer 20a (2R,2ЈS) and
minor isomer 20b (2S,2ЈS): orange oil. 1H NMR (400 MHz,
CDCl3): δ = 3.33 (s, 3 H, OCH3 minor), 3.40 (s, 3 H, OCH3), 3.46–
3.54 (m, 2 H, CH2OMe), 3.96 (dd, J = 3.2, 8.8 Hz, 1 H,
PhCHCH2O, minor), 4.40 (dd, J = 5.6, 8.0 Hz, 1 H, PhCHCH2O),
4.49 (s, 1 H, CHCN), 4.71 (s, 1 H, CHCN, minor), 7.27–7.43 (m,
6 H, ArH), 7.50–7.54 (m, 4 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 51.8, 58.6, 60.6, 76.9, 118.6, 127.2, 127.8, 128.4, 128.7,
Methyl 2-{[Cyano(phenyl)methyl]amino}-3-phenylpropanoate (24):
Characterized as a diastereomeric mixture, pale yellow oil. HPLC–
MS: Rt = 9.40 min (major + minor); m/z 268 [M – CN]+, 290, 295
[M + H]+, 317 [M + Na]+, 333 [M + K]+. Data for major isomer
24a (2R,S): 1H NMR (400 MHz, CDCl3): δ = 2.42 (br. s, 1 H, NH),
2.96 (dd, J = 8.4, 13.6 Hz, 1 H, PhCHHCH), 3.12 (dd, J = 5.2,
13.6 Hz, 1 H, PhCHHCH), 3.70 (dd, J = 5.2, 8.4 Hz, 1 H,
CHCH2Ph), 3.75 (s, 3 H, CH3), 4.58 (s, 1 H, CHCN), 7.19–7.56
(m, 10 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 39.7, 52.2,
52.9, 60.4, 118.6, 126.9, 127.4, 128.5, 128.9, 129.1, 129.3, 134.3,
128.8, 128.9, 135.1, 138.1 ppm. IR:
ν = 3325, 2890, 2228,
˜
1108 cm–1. HPLC–MS: Rt = 9.68 min, minor isomer; m/z = 240
[M – CN]+, 267 [M + 1]+; Rt = 10.19 min, major isomer; m/z =
240 [M – CN]+, 267 [M + 1]+.
Compound 20a was also obtained starting from 17a (see Support-
ing Information for details).
136.8, 173.6 ppm. IR: ν = 3328, 2952, 2925, 2293, 2229, 1736 cm–1.
˜
Data for minor isomer 24b (2S,S): 1H NMR (400 MHz, CDCl3): δ
= 2.10 (br. s, 1 H, NH), 2.93–3.00 (m, 1 H, PhCHH), 3.14 (dd, J
= 5.6, 14.0 Hz, 1 H, PhCHH), 3.79 (s, 3 H, CH3), 3.88 (dd, J =
5.6, 8.0 Hz, 1 H, CHCH2), 4.88 (s, 1 H, CHCN), 7.19–7.56 (m, 10
H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 39.4, 52.1, 53.3,
59.6, 118.4, 127.1, 127.5, 128.6, 129.0, 129.1, 129.2, 134.2, 136.2,
173.6 ppm.
2-[(2-Methoxy-1-phenylethyl)amino]pentanenitrile (21): Charac-
terized as a diastereomeric mixture, signals refer to the major dia-
stereosiomer, only the main signals of the minor diastereomer are
reported. Data for major isomer 21a (2R,2ЈS) and minor isomer
1
21b (2S,2ЈS): orange oil H NMR (400 MHz, CDCl3): δ = 0.91 (t,
J = 7.2 Hz, 3 H, CH3), 0.93 (t, J = 7.2 Hz, 3 H, CH3 minor), 1.49–
1.55 (m, 2 H, CH3CH2CH2), 1.63–1.69 (m, 2 H, CH3CH2 CH2,
minor), 1.71–1.78 (m, 2 H, CH3CH2 CH2), 3.25 (t, J = 7.2 Hz, 1
H, CHCN), 3.36–3.44 (m, 2 H, CH2OMe), 3.41 (s, 3 H, OCH3),
3.76 (t, J = 6.8 Hz, 1 H, CHCN), 4.13 (dd, J = 3.6, 7.6 Hz, 1 H,
CHPh), 4.25 (dd, J = 5.2, 8.0 Hz, 1 H, CHPh), 7.28–7.39 (m, 5 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.5, 18.9, 35.8,
Methyl 2-[(1-Cyanobutyl)amino]-3-phenylpropanoate (25): Dia-
stereoisomers separated by flash chromatography. Data for major
isomer 25a (1ЈR,S): pale yellow oil; [α]2D0 = +292.6 (c = 1.25,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.8 Hz, 1
H, CH3CH2CH2), 1.40–1.49 (m, 2 H, CH2), 1.57–1.69 (m, 2 H,
CH2), 2.03 (dd, J = 7.7, 10.4 Hz, 1 H, NH), 2.86 (dd, J = 7.6,
13.6 Hz, 1 H, CHHPh), 3.02 (dd, J = 5.6, 13.6 Hz, 1 H, CHHPh),
3.27 (dt, J = 7.2, 10.4 Hz, 1 H, CHCN), 3.62 (ddd, J = 5.6, 7.6,
7.7 Hz, 1 H, CH2CHNHCO2Me), 3.74 (s, 3 H, CH3), 7.17–7.31 (m,
47.5, 58.6, 60.2, 77.0, 120.3, 127.7, 128.2, 128.7, 138.4 ppm. IR: ν
˜
= 3326, 2962, 2930, 2225, 1689, 1455, 1118 cm–1. HPLC–MS: Rt =
9.13 min, minor isomer; m/z = 233 [M + H]+, 438 [2M – CN]+; Rt
= 9.68 min, major isomer; m/z = 233 [M + H]+, 438 [2M – CN]+.
Methyl 2-{[Cyano(phenyl)methyl]amino}-2-phenylacetate (22a): 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.3, 18.7, 35.7,
Characterized as a diastereomeric mixture, yellow oil. Data for 39.8, 49.4, 52.1, 61.2, 119.9, 126.8, 128.4, 129.3, 136.9, 173.7 ppm.
major isomer 22a (2R,S): H NMR (400 MHz, CDCl3): δ = 2.78 IR: ν = 3328, 3002, 2874, 2225, 1956, 1888, 1737, 1205 cm–1.
1
˜
(dd, J = 3.6, 10.4 Hz, 1 H, NH), 3.71 (s, 3 H, CH3), 4.50 (d, J =
10.4 Hz, 1 H, PhCHCO2), 4.77 (d, J = 3.6 Hz, 1 H, CHCN), 7.35– 69.25, H 7.81, N 10.68. HPLC–MS: Rt = 9.16 min; m/z = 261 [M
7.55 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 51.7, + 1]+, 283 [M + Na]+. Data for minor isomer 25b (1ЈS,S): 1H NMR
C15H20N2O2 (260.33): calcd. C 69.20, H 7.74, N 10.76; found C
1690
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1683–1695

Asymmetric Strecker Reaction with Chiral Amines
(400 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 1 H, CH3CH2CH2),
1.40–1.49 (m, 2 H, CH2), 1.57–1.69 (m, 2 H, CH2), 21.81 (br. s, 1
H, NH), 2.92 (dd, J = 8.0, 14.0 Hz, 1 H, CHHPh), 3.12 (dd, J =
5.6, 14.0 Hz, 1 H, CHHPh), 3.70–3.76 (m, 1 H, CHCN), 3.72 (s, 3
IndCHHCH), 3.21 (ddd, J = 0.8, 5.2, 14.8 Hz, 1 H, IndCHHCH),
3.41 (t, J = 8.0 Hz, 1 H, CH2CHCN), 3.71–3.76 (m, 1 H,
CH2CHCOMe), 3.71 (s, 3 H, CO2Me), 7.07–7.24 (m, 3 H, ArH),
7.35–7.39 (m, 1 H, ArH), 7.61–7.64 (m, 1 H, ArH), 8.08 (br. s, 1
H, CH3), 3.81–3.86 (m, 1 H, CH2CHNHCO2Me), 7.17–7.31 (m, 5 H, NHInd) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.2, 18.6,
H, ArH) ppm. HPLC–MS: Rt = 8.90 min; m/z = 261 [M + 1]+, 283
28.9, 35.3, 48.9, 52.1, 60.5, 110.8, 111.1, 118.6, 119.6, 119.9, 122.1,
[M + Na]+.
122.8, 127.3, 136.0, 174.1 ppm. IR: ν = 3445, 2977, 2227, 1736,
˜
1494, 1155 cm–1. HPLC–MS: Rt = 8.78 min; m/z = 273 [M –
CN]+, 300 [M + H]+, 322 [M + Na]+. Data for minor isomer 29b
(1ЈR,S): 1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.2 Hz, 3
H, CH3CH2CH2), 1.39–1.53 (m, 2 H, CH3CH2CH2), 1.64–1.70 (m,
2 H, CH3 CH2CH2CH), 2.09 (br. s, 1 H, CHNHCHCN), 3.15 (ddd,
J = 0.8, 8.4, 14.4 Hz, 1 H, IndCHHCH), 3.31 (ddd, J = 0.8, 4.8,
14.8 Hz, 1 H, IndCHHCH), 3.66 (t, J = 6.8 Hz, 1 H, CH2CHCN),
3.73 (s, 3 H, CO 2 M e) , 3 . 9 6 ( dd , J = 5.2, 8.4 Hz, 1 H,
CH2CHCOMe), 7.07–7.24 (m, 3 H, ArH), 7.35–7.39 (m, 1 H,
2-[(1-Hydroxy-3-phenylpropan-2-yl)amino]-3-methylbutanenitrile
(26): Characterized as a diastereomeric mixture enriched in the
minor stereoisomer after flash chromatography, pale yellow oil.
Data for major isomer 26a (2R,1ЈS): 1H NMR (400 MHz, CDCl3):
δ = 0.98–1.03 [m, 6 H, CH(CH3)2], 1.90–1.96 [m, 1 H, CH(CH3)2],
2.65 (dd, J = 7.2, 13.2 Hz, 1 H, CHCHHPh), 2.77 (dd, J = 6.0,
13.2 Hz, 1 H, CHCHHPh), 3.09–3.16 (m, 1 H, CH2CHCH2), 3.30
(d, J = 5.6 Hz, 1 H, CHCHCN), 3.42 (dd, J = 7.2, 11.2 Hz, 1 H,
CHCHHOH), 3.74 (dd, J = 4.0, 11.2 Hz, 1 H, CHCHHOH), 7.24–
7.39 (m, 5 H, ArH) ppm. HPLC–MS: Rt = 7.22 min, major isomer;
m/z = 206 [M – CN]+, 233 [M + H]+, 255 [M + Na]+. Data for
ArH), 7.61–7.64 (m, 1 H, ArH), 8.12 (br. s, 1 H, NHInd) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 13.3, 18.7, 29.2, 35.7, 49.3, 52.1,
59.4, 110.3, 111.2, 118.6, 119.5, 119.9, 122.3, 122.7, 127.3, 136.2,
173.8 ppm. HPLC–MS: Rt = 8.63 min; m/z = 273 [M – CN]+, 300
[M + H]+, 322 [M + Na]+.
1
minor isomer 26b (2S,1ЈS): H NMR (400 MHz, CDCl3): δ = 1.00
(d, J = 6.8 Hz, 3 H, CH3CHCH3), 1.05 (d, J = 6.8 Hz, 3 H,
CH3 CHCH3 ), 1.61 (br. s, 1 H, OH), 1.88–1.99 [m, 1 H,
CHCH(CH3)2], 2.14 (br. s, 1 H, NH), 2.80 (dd, J = 8.4, 13.6 Hz, 1
H, CHCHHPh), 2.94 (dd, J = 6.0, 13.6 Hz, 1 H, CHCHHPh),
3.17–3.22 (m, 1 H, CH2CHCH2), 3.43–3.47 (m, 2 H, CHCHHOH,
CHCHCN), 3.66 (dd, J = 3.2, 11.2 Hz, 1 H, CHCHHOH), 7.24–
7.39 (m, 5 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.9,
19.1, 31.7, 38.0, 54.9, 58.1, 61.9, 119.1, 126.9, 128.8, 129.2,
Methyl 1-[Cyano(phenyl)methyl]pyrrolidine-2-carboxylate (37): Dia-
stereoisomers separated by flash chromatography. Data for major
isomer 37a (S,1S): yellow oil; [α]2D0 = –94.06 (c = 0.64, CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 1.79–1.87 (m, 2 H, CH2CH2CH2),
2.06–2.14 (m, 1 H, CHHCHCO2Me), 2.21–2.31 (m, 1 H,
CHHCHCO2Me), 2.55 (dt, J = 8.8, 8.8 Hz, 1 H, CH2CHHN),
2.72–2.76 (m, 1 H, CH2CHHN), 3.61 (dd, J = 7.2, 9.2 Hz, 1 H,
CHHCHCO2Me), 3.80 (s, 3 H, CH3), 5.37 (s, 1 H, CHCN), 7.35–
7.43 (m, 3 H, ArH), 7.57–7.60 (m, 2 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.8, 28.8, 48.2, 52.1, 58.1, 63.0, 116.0,
137.2 ppm. IR: ν = 3442, 3338.7, 2963, 2929, 2227, 1120 cm–1
.
˜
HPLC–MS: Rt = 6.87 min; m/z = 206 [M – CN]+, 233 [M + H]+,
255 [M + Na]+.
2-{[1-Hydroxy-3-(1H-indol-2-yl)propan-2-yl]amino}-3-methyl-
butanenitrile (27): Characterized as a diastereomeric mixture, pale
yellow oil. Data for major isomer 27a (2R,1ЈS): 1H NMR
(400 MHz, CDCl3): δ = 0.98–1.00 [m, 6 H, CH(CH3)2], 1.68–2.04
(br. s, 2 H, OH, NHCHCN), 1.86–1.97 [m, 1 H, CHCH(CH3)2],
3.01 (ddd, J = 0.8, 8.0, 14.4 Hz, 1 H, IndCHHCH), 3.07 (ddd, J =
0.8, 8.4, 14.4 Hz, 1 H, IndCHHCH), 3.28–3.34 (m, 1 H,
CH2CHCH2), 3.46–3.53 (m, 2 H, CHCHCN, CHCHHOH), 3.70
(dd, J = 3.6, 10.8 Hz, 1 H, CHCHHOH), 7.06–7.25 (m, 3 H, ArH),
7.37–7.40 (m, 1 H, ArH), 7.62–7.66 (m, 1 H, ArH), 8.09 (br. s, 1
H, NHInd, minor), 8.14 (br. s, 1 H, NHInd) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.8, 19.1, 26.8, 31.8, 55.2, 57.6, 62.4,
111.2, 111.4, 118.7, 119.5, 119.6, 122.2, 122.5, 127.4, 136.2 ppm.
127.6, 128.7, 128.8, 133.8, 173.3 ppm. IR: ν = 2953, 2227, 1743,
˜
1206 cm–1. C14H16N2O2 (244.29): calcd. C 68.83, H 6.60, N 11.47;
found C 69.02, H 6.71, N 11.57. HPLC–MS: Rt = 8.37 min; m/z =
245 [M + H]+, 267 [M + Na]+. Data for minor isomer 37b (S,1R):
yellow oil. 1H NMR (400 MHz, CDCl3): δ = 1.58–1.98 (m, 2 H,
CH2CH2CH2), 2.00–2.09 (m, 1 H, CHHCHCO2Me), 2.12–2.22 (m,
1 H, CHHCHCO2Me), 2.91–2.99 (m, 1 H, CHHN), 3.32 (s, 3 H,
CH3), 3.33–3.38 (m, 1 H, CH2CHHN), 3.48 (dd, J = 4.0, 9.2 Hz,
1 H,CH2CHCO2Me), 5.17 (s, 1 H, CHCN), 7.35–7.41 (m, 3 H,
ArH), 7.45–7.52 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 23.9, 30.4, 51.6, 53.1, 58.7, 61.0, 116.6, 128.3, 128.6,
129.1, 132.9, 174.0 ppm. HPLC–MS: Rt = 7.27 min; m/z = 245 [M
+ 1]+, 267 [M + Na]+.
IR: ν = 3412, 3057, 2228, 1457, 1031 cm–1. HPLC–MS: Rt =
˜
Benzyl 1-(1-Cyanobutyl)methylpyrrolidine-2-carboxylate (38): The
major diastereoisomer was separated by flash chromatography, the
minor isomer was characterized in the crude mixture. Data for
major isomer 38a (S,1S): pale yellow oil; [α]2D0 = –64.37 (c = 1.4,
7.66 min; m/z = 245 [M – CN]+, 294 [M + Na]+. Data for minor
isomer 27b (2S,1ЈS): 1H NMR (400 MHz, CDCl3): δ = 0.98–1.00
[m, 6 H, CH(CH3)2], 1.68–2.04 (br. s, 2 H, OH, NHCHCN), 1.86–
1.97 [m, 1 H, CHCH(CH3)2], 2.81 (ddd, J = 0.8, 3.6, 14.4 Hz, 1 H,
IndCHHCH), 2.96 (ddd, J = 0.8, 6.0, 14.4 Hz, 1 H, IndCHHCH),
3.23–3.29 (m, 1 H, CH2CHCH2), 3.46–3.53 (m, 2 H, CHCHCN,
CHCHHOH), 3.77 (dd, J = 3.6, 10.8 Hz, 1 H, CHCHHOH), 7.06–
7.25 (m, 3 H, ArH), 7.37–7.40 (m, 1 H, ArH), 7.62–7.66 (m, 1 H,
ArH), 8.09 (br. s, 1 H, NHInd) ppm. 13C NMR (100 MHz, CDCl3):
δ = 17.9, 19.2, 27.4, 31.7, 55.3, 58.4, 64.3, 111.2, 111.8, 118.7, 119.5,
119.8, 122.3, 122.6, 127.6, 136.3 ppm. HPLC–MS: Rt = 7.35 min;
m/z = 245 [M – CN]+, 294 [M + Na]+.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.97 (t, J = 7.2 Hz, 3
H, CH3CH2CH2), 1.43–1.60 (m, 2 H, CH3CH2), 1.70–1.82 (m, 2
H, CH2CH2CH2), 1.87–1.94 (m, 2 H, CH3CH2CH2), 1.99–2.07 (m,
1 H, CHHCHCO2Me), 2.12–2.22 (m, 1 H, CHHCHCO2Me), 2.59
(dt, J = 8.8, 8.4 Hz, 1 H, CHHN), 3.11 (ddd, J = 4.4, 6.4, 8.8 Hz,
1 H, CHHN), 3.43 (dd, J = 6.4, 8.4 Hz, 1 H, CHCO2Me), 3.73 (s,
3 H, CH3), 3.97 (t, J = 7.6 Hz, 1 H, CHCN) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.3, 19.2, 23.0, 28.6, 34.4, 47.9, 52.0, 54.0,
63.5, 117.8, 173.3 ppm. IR: ν = 2960, 2876, 2223, 1747, 1175 cm–1.
˜
Methyl 2-(1-Cyanobutyl)amino-3-(1H-indol-2-yl)propanoate (29): C11H18N2O2 (210.14): calcd. C 62.83, H 8.63, N 13.32; found C
Characterized as a diastereomeric mixture, pale yellow oil. Data
62.78, H 8.71, N 13.48. HPLC–MS: Rt = 7.49 min; m/z = 130 [M –
for major isomer 29a (1ЈR,S): 1H NMR (400 MHz, CDCl3): δ =
CH3(CH2)2CHCN + 2]+, 211 [M + 1]+. Data for minor isomer 38b
1
0.87 (t, J = 7.2 Hz, 3 H, CH3CH2CH2), 1.39–1.53 (m, 2 H, (S,1R): H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 8.0 Hz, 3 H,
CH3CH2CH2), 1.64–1.70 (m, 2 H, CH3 CH2CH2CH), 1.74 (br. s, CH3CH2CH2), 1.43–1.60 (m, 2 H, CH3CH2), 1.70–1.82 (m, 2 H,
1 H, CHNHCHCN), 3.10 (ddd, J = 0.8, 7.2, 14.8 Hz, 1 H,
CH2CH2CH2), 1.87–1.94 (m, 2 H, CH3CH2CH2), 1.99–2.07 (m, 1
Eur. J. Org. Chem. 2013, 1683–1695
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1691

M. Pori, P. Galletti, R. Soldati, D. Giacomini
FULL PAPER
H, CHHCHCO2Me), 2.12–2.22 (m, 1 H, CHHCHCO2Me), 2.80–
2.87 (m, 1 H, CHHN), 3.19–3.24 (m, 1 H, CHHN), 3.56 (dd, J =
CDCl3): δ = 22.8, 28.6, 48.1, 58.0, 62.9, 66.6, 115.9, 127.4, 128.2,
128.3, 128.5, 128.6, 128.7, 133.7, 135.5, 172.4 ppm. IR: ν = 3064,
˜
4.0, 12.0 Hz, 1 H, CHCO2Me), 3.76–3.81 (m, 1 H, CHCN), 3.82 3033, 2926, 2850, 2227, 1956, 1888, 1743, 1175 cm–1. C20H20N2O2
(s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.4, 19.3,
24.1, 29.2, 34.7, 47.9, 51.9, 3.7, 63.5, 118.2, 175.0 ppm. HPLC–MS:
Rt = 6.92 min; m/z = 211 [M + H]+.
(320.38): calcd. C 74.98, H 6.29, N 8.74; found C 75.07, H 6.34, N
8.69. HPLC–MS: Rt = 10.86 min; m/z = 321 [M + H]+, 343 [M +
Na]+. Data for minor isomer 41b (S,1R): pale yellow oil; [α]2D0
=
1
–17.93 (c = 0.99, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.88–
1.99 (m, 2 H, CH2CH2CH2), 2.01–2.08 (m, 1 H, CHHCHCO2Bn),
2.10–2.22 (m, 1 H, CHHCHCO2Bn), 2.98 (dt, J = 6.8, 8.8 Hz, 1
H, CH2CHHN), 3.37 (dt, J = 2.8, 8.8 Hz, 1 H, CHHN), 3.52 (dd,
J = 4.0, 9.6 Hz, 1 H, CHHCHCO2Bn), 4.71 (d, JAB = 12.0 Hz, 1
H, CHHPh), 4.80 (d, JAB = 12.4 Hz, 1 H, CHHPh), 5.17 (s, 1 H,
CHCN), 7.18–7.20 (m, 2 H, ArH), 7.31–7.39 (m, 6 H, ArH), 7.46–
7.51 (m, 2 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 23.8,
30.4, 52.8, 58.4, 60.9, 66.1, 116.7, 128.0, 128.1, 128.2, 128.3, 128.5,
tert-Butyl 1-[Cyano(phenyl)methyl]pyrrolidine-2-carboxylate (39).
Diastereoisomers separated by flash chromatography. Data for
major isomer 39a (S,1S): pale yellow oil; [α]2D0 = –54.53 (c = 0.27,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.52 [s, 9 H, C(CH3)3],
1.78–1. 84 (m, 2 H, CH2 CH2 CH2 ), 2. 02–2.10 (m, 1 H,
CHHCHCO2Me), 2.16–2.25 (m, 1 H, CHHCHCO2Me), 2.54 (dt,
J = 7.6, 9.2 Hz, 1 H, CH2CHHN), 2.71 (ddd, J = 4.4, 6.0, 9.2 Hz,
1 H, CHHN), 3.48 (dd, J = 6.8, 8.8 Hz, 1 H, CHCO2tBu), 5.39 (s,
1 H, CHCN), 7.34–7.43 (m, 3 H, ArH), 7.58–7.61 (m, 2 H, ArH)
ppm. 13C NMR (50 MHz, CDCl3): δ = 22.7, 28.1, 28.8, 48.2, 58.2,
128.9, 132.9, 135.4, 173.3 ppm. IR: ν = 3064, 3033, 2952, 2828,
˜
2226, 1743, 1166 cm–1. C20H20N2O2 (320.38): calcd. C 74.98, H
6.29, N 8.74; found C 75.21, H 6.44, N 8.61. HPLC–MS: Rt =
9.98 min; m/z = 321 [M + H]+, 343 [M + Na]+, 359 [M + K]+.
63.6, 81.4, 116.2, 127.6, 128.7 (2 C), 134.1, 171.9 ppm. IR: ν =
˜
2959, 2874, 2227, 1735, 1010 cm–1. C17H22N2O2 (286.37): calcd. C
71.30, H 7.74, N 9.78; found C 71.53, H 7.86, N 9.84. HPLC–MS:
Rt = 10.88 min; m/z = 172 [M – tBu – CN + 3]+, 260 [M – CN]+,
287 [M + 1]+, 309 [M + Na]+, 325 [M + K]+. Data for minor isomer
2-[2-(Hydroxymethyl)pyrrolidin-1-yl]-2-phenylacetonitrile (42):
Characterized as a diastereomeric mixture. Signals refer to the
major diastereosiomer, only the main signals of the minor dia-
stereomer are reported, pale yellow oil. Data for major isomer 42a
(2S,2ЈS) and minor isomer 42b (2R,2ЈS): 1H NMR (400 MHz,
CDCl3): δ = 1.67–1.74 (m, 1 H, NCH2CH2CHHCH), 1.76–1.87
(m, 2 H, CH2CHHCH2, NCH2CH2CHHCH), 1.99–2.04 (m, 1 H,
CH2CHHCH2), 2.15 (br. s, 1 H, OH), 2.62 (dt, J = 8.8, 9.6 Hz, 1
H, CH2CHHN), 2.68–2.73 (m, 1 H, CHHN), 2.88–2.95 (m, 1 H,
minor), 3.00–3.04 (m, 1 H, minor), 3.11–3.16 (m, 1 H,
CHCH2OH), 3.61 (dd, J = 3.6, 11.2 Hz, 1 H, CHCHHOH), 3.82
(dd, J = 3.2, 11.2 Hz, 1 H, CHCHHOH), 5.11, (s, 1 H, CHCN
minor), 5.27 (s, 1 H, CHCN), 7.37–7.42 (m, 3 H, ArH), 7.43–7.52
(m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.1, 27.5,
1
39b (S,1R): pale yellow oil. H NMR (400 MHz, CDCl3): δ = 1.57
[s, 9 H, C(CH3)3], 1.82–1.89 (m, 1 H, CH2CHHCH2), 1.92–1.98
(m, 1 H, CH2CHHCH2), 1.99–2.07 (m, 1 H, CHHCHCO2Me),
2.09–2.18 (m, 1 H, CHHCHCO2Me), 2.54 (dt, J = 6.4, 9.2 Hz, 1
H, CH2CHHN), 3.35–3.40 (m, 2 H, CHHN, CHCO2tBu), 5.16 (s,
1 H, CHCN), 7.35–7.39 (m, 3 H, ArH), 7.52–7.54 (m, 2 H, ArH)
ppm. HPLC–MS: Rt = 10.09 min; m/z = 172 [M – tBu – CN +
3]+, 260 [M – CN]+, 287 [M + 1]+, 309 [M + Na]+, 325 [M + K]+.
tert-Butyl 1-(1-Cyanobutyl)pyrrolidine-2-carboxylate (40): Charac-
terized as a diastereomeric mixture, pale yellow oil. IR: ν = 2964,
˜
2933, 2223, 1739, 1150, 1100 cm–1. Data for major isomer 40a
1
(S,1S): H NMR (400 MHz, CDCl3): δ = 0.98 (t, J = 7.6 Hz, 3 H,
49.2, 57.9, 62.6, 63.2, 116.3, 127.5, 128.7, 128.8, 134.1 ppm. IR: ν
˜
= 3424, 3063, 3033, 2924, 2875, 2227, 1602, 1452, 1077 cm–1
.
CH3CH2CH), 1.47 [s, 9 H, C(CH3)3], 1.49–1.59 (m, 4 H,
CH2CH2CH3), 1.74–1.81 (m, 1 H, CHHCH2N), 1.82–1.91 (m, 1
H, CHHCH2N), 1.94–2.02 (m, 1 H, CHHCHCOOCH3), 2.07–2.15
(m, 1 H, CHHCHCO2Me), 2.57 (dt, J = 8.0, 8.8 Hz, 1 H, CHHN),
3.07–3.12 (m, 1 H, CHHN), 3.29 (dd, J = 6.8, 8.8 Hz, 1 H,
CHCO2CH3), 3.99 (t, J = 7.6 Hz, 1 H, CHCN) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.4, 19.3, 22.9, 28.1, 28.6, 34.5, 47.9, 54.1,
64.2, 81.2, 118.1, 171.9 ppm. HPLC–MS: Rt = 10.26 min; m/z =
275 [M + Na]+. Data for minor isomer 40b (S,1R): 1H NMR
(400 MHz, CDCl3): δ = 0.94 (t, J = 7.2 Hz, 3 H, CH3CH2CH),
1.46 [s, 9 H, C(CH3)3], 1.49–1.59 (m, 4 H, CH2CH2CH3), 1.74–1.81
(m, 1 H, CHHCH2N), 1.82–1.91 (m, 1 H, CHHCH2N), 1.94–2.02
( m , 1 H , C H H C H C O O C H 3 ) , 2 . 0 7 – 2 . 1 5 ( m , 1 H ,
CHHCHCO2CH3), 2.77–2.83 (m, J = 8.8 Hz, 1 H, CHHN), 3.18–
3.22 (m, 1 H, CHHN), 3.39 (dd, J = 3.2, 9.6 Hz, 1 H, CHCO2CH3),
3.78 (dd, J = 6.4, 9.6 Hz, 1 H, CHCN) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.4, 19.4, 24.3, 27.9, 29.7, 35.0, 47.9, 55.7, 64.2, 80.8,
118.5, 174.0 ppm. HPLC–MS: Rt = 9.68 min; m/z = 275
[M + Na]+.
HPLC–MS: Rt = 5.36 min, minor isomer; m/z = 190 [M – CN]+;
Rt = 6.38 min, major isomer; m/z = 217 [M + H]+, 190 [2M –
CN]+.
Compound 42a was also obtained starting from 37a by reduction
of the ester functionality with NaBH4 (see Supporting Information
for details).
2-[2-(Hydroxymethyl)pyrrolidin-1-yl]pentanenitrile (43): Charac-
terized as a diastereomeric mixture. Signals refer to the major dia-
stereosiomer, only the main signals of the minor diastereomer are
reported, pale yellow oil. Data for major isomer 43a (2S,2ЈS) and
minor isomer 43b (2R,2ЈS): 1H NMR (400 MHz, CDCl3): δ = 0.98
(t, J = 7.2 Hz, 3 H, CH3 CH2 CH2 ), 1.46–1.56 (m, 2 H,
CH3CH2CH2), 1.71–1.87 (m, 4 H, CH3CH2CH2, CH2CH2CH2),
1.92–1.98 (m, 2 H, CH2CH2CH2CH), 2.63 (dt, J = 6.8, 8.8 Hz,
1 H, CH2CHHN), 2.7–2.83 (m, 1 H, minor), 2.92–2.97 (m, 1 H,
CHCH2OH), 3.03–3.08 (m, 1 H, CH2CHHN), 3.11–3.17 (m, 1 H,
minor), 3.46 (ddd, J = 3.6, 8.8, 12.0 Hz, 1 H, CHCHHOH), 3.63
(ddd, J = 2.8, 2.8, 12.0 Hz, 1 H, CHCHHOH), 3.72 (dd, J = 6.0,
9.2 Hz, 1 H, CHCN minor), 3.83 (dd, J = 7.6, 8.0 Hz, 1 H, CHCN)
ppm. 13C NMR (100 MHz, CDCl3): δ = 13.4, 19.3, 23.4, 27.2, 34.7,
Benzyl 1-[Cyano(phenyl)methyl]pyrrolidine-2-carboxylate (41): Dia-
stereoisomers separated by flash chromatography. Data for major
isomer 41a (S,1S): pale yellow oil; [α]2D0 = –65.20 (c = 1.19, CHCl3).
1 H NMR (400 MHz, CDCl 3 ) : δ = 1 . 5 8 – 1 . 8 7 ( m , 2 H ,
CH2CH2CH2), 2.09–2.18 (m, 1 H, CHHCHCO2Bn), 2.21–2.31 (m,
1 H, CHHCHCO2Me), 2.59 (dt, J = 8.0, 8.4 Hz, 1 H, CH2CHHN),
2.70–2.75 (m, 1 H, CH2CHHN), 3.65 (dd, J = 6.8, 8.8 Hz, 1 H,
48.7, 53.5, 62.5, 62.8, 118.0 ppm. IR: ν = 3423, 2962, 2960, 2875,
˜
2224, 1640, 1043 cm–1.
(S)-2-[(S)-2-(Hydroxydiphenylmethyl)pyrrolidin-1-yl]-2-phenylaceto-
nitrile (44a): White solid, m.p. 105–112 °C. [α]2D0 = +21.39 (c = 0.38,
CHHCHCO2Bn), 5.21 (d, JAB = 12.4 Hz, 1 H, CHHPh), 5.26 (d, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.55–1.79 (m, 2 H,
JAB = 12.4 Hz, 1 H, CHHPh), 5.35 (s, 1 H, CHCN), 7.35–7.41 (m,
CH2CH2CH2), 1.84–1.91 [m, 1 H, CH2CHHCHC(Ph)2OH], 2.04–
8 H, ArH), 7.50–7.52 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, 2.14 [m, 1 H, CH2CHHCHC(Ph)2OH], 2.67–2.76 (m, 2 H,
1692
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1683–1695

Asymmetric Strecker Reaction with Chiral Amines
CH2CH2N), 4.03 (s, 1 H, CHCN), 4.15 (br. s, 1 H, OH), 4.33 [dd, 10.4 Hz, 1 H, CHHCHHN), 3.73–3.78 (m, 1 H, CHHCHCO2Me),
J = 4.4, 9.2 Hz, 1 H, CHHCHC(Ph)2OH], 7.17–7.23 (m, 3 H,
ArH), 7.29–7.38 (m, 8 H, ArH), 7.60–7.62 (m, 2 H, ArH), 7.78–
7.80 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.8,
29.4, 50.7, 59.1, 68.9, 78.2, 116.6, 125.2, 125.4, 126.7, 127.1, 127.4,
3.75 (s, 3 H, CH3), 3.99 (t, J = 7.6 Hz, 1 H, CHHCHCN), 4.45–
4.51 (m, 1 H, CHOH) ppm. 13C NMR (50 MHz, CDCl3): δ = 12.9,
18.7, 34.0, 38.1, 51.8, 53.5, 56.0, 61.7, 68.6, 117.5, 172.7 ppm. IR:
ν = 3450, 2959, 2874, 2226, 1743, 1438, 1090 cm–1. C H N O
˜
11 18
2
3
128.3, 128.7, 128.8, 128.9, 133.9, 145.5, 147.1 ppm. IR: ν = 3500,
(226.27): calcd. C 58.39, H 8.02, N 12.38; found C 58.48, H 8.11,
N 12.21. HPLC–MS: Rt = 3.99 min; m/z = 200 [M – CN]+, 227 [M
+ H]+, 249 [M + Na]+. Data for minor isomer 47b (2S,4R,1ЈR): 1H
NMR (400 MHz, CDCl3 ): δ = 0.94 (t, J = 7.2 Hz, 1 H,
CH3CH2CH2), 1.42–1.57 (m, 2 H, CH3CH2CH2), 1.59–1.72 (m, 2
H, CH3CH2CH2), 1.87 (br. s, 1 H, OH), 2.14 (dddd, J = 0.8, 5.6,
8.4, 14.0 Hz, 1 H, CHCHHCHCO2Me), 2.22–2.28 (m, 1 H,
CHCHHCHCO2Me), 2.82 (ddd, J = 0.8, 4.4, 10.0 Hz, 1 H,
CHCHHN), 3.42 (dd, J = 5.6, 10 Hz, 1 H, CHCHHN), 3.75 (s, 3
H, CH3), 3.76–3.82 (m, 2 H, CHCO2Me, CHCN), 4.52–4.58 [m, 1
H, CH2CH(OH)CH2]. HPLC–MS: Rt = 3.31 min; m/z = 200 [M –
CN]+, 227 [M + H]+, 249 [M + Na]+.
˜
2970, 1682, 1596 cm–1. C25H24N2O (368.47): calcd. C 81.49, H 6.57,
N 7.60; found C 81.62, H 6.68, N 7.51 HPLC–MS: Rt = 12.07 min;
m/z = 342 [M – CN]+, 369 [M + H]+, 391 [M + Na]+.
Compound 44a was also obtained in 41% yield starting from 37a
by Grignard addition (see Supporting Information for details).
(S)-2-[(S)-2-(Hydroxydiphenylmethyl)pyrrolidin-1-yl]pentanenitrile
(45a): White solid, m.p. 107–114 °C. [α]2D0 = –36.21 (c = 0.62,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.66 (t, J = 6.8 Hz, 1
H, CH3CH2CH2), 1.06–1.16 (m, 2 H, CH3CH2CH2), 1.37–1.46 (m,
1 H, CH3CH2CHH), 1.48–1.58 (m, 1 H, CH3CH2CHH), 1.73–1.84
[m, 3 H, CHHCHHCHC(CPh2 OH)], 1.93–2.06 [m, 1 H,
CH2CHHCH(CPh2OH)], 2.71–2.79 (m, 2 H, CHCN, CH2CHHN),
3.09–3.14 (m, 1 H, CH2CHHN), 3.96 (br. s, 1 H, OH), 4.10 [dd, J
= 3.6, 9.2 Hz, CH(CPh2OH)], 7.16–7.21 (m, 2 H, ArH), 7.27–7.34
(m, 4 H, ArH), 7.53–7.56 (m, 2 H, ArH), 7.61–7.63 (m, 2 H, ArH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 13.0, 18.9, 24.0, 28.9, 34.5,
50.1, 54.7, 69.6, 77.9, 118.4, 125.1, 125.4, 126.5, 126.8, 128.1, 128.5,
2-[4-Hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]-2-phenylacetonitrile
(48): Compound 48a (2S, 4R, 1ЈS), the major isomer, was obtained
pure and characterized after spontaneous isomerization of a 48a/
48b mixture, pale yellow solid, m.p. 105.2–107.1 °C. [α]2D0 = –110.91
1
(c = 0.66, MeOH). H NMR (400 MHz, CDCl3): δ = 1.95 (ddd, J
= 4.4, 8.0 and 13.0 Hz, 1 H, CHCHHCH), 1.92–2.11 (br. s, 2 H,
OH), 2.06 (ddd, J = 6.8, 8.4 and 13.0 Hz, 1 H, CHCHHCH), 2.59
(dd, J = 4.8, 10.0 Hz, 1 H, CHCHHN), 3.01 (dd, J = 6.0, 10.0 Hz,
1 H, CHCHHN), 3.39–3.45 (m, 1 H, CHHCHCH2OH), 3.62 (dd,
J = 4.0, 12.0 Hz, 1 H, CHCHHOH), 3.85 (dd, J = 3.2, 12.0 Hz, 1
H, CHCHHOH), 4.31–4.36 (m, 1 H, CHOH), 5.32 (s, 1 H,
CHCN), 7.37–7.42 (m, 3 H, ArH), 7.48–7.51 (m, 2 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 37.1, 57.4, 57.7, 61.5, 62.7, 69.4,
145.4, 147.1 ppm. IR: ν = 3411, 3066, 3023, 2923, 2224, 1141 cm–1.
˜
C
22H26N2O (334.45): calcd. C 79.00, H 7.84, N 8.38; found C
79.28, H 7.92, N 8.44. HPLC–MS: Rt = 11.78 min; m/z = 308 [M –
CN]+, 335 [M + H]+.
Methyl 1-[Cyano(phenyl)methyl]-4-hydroxypyrrolidine-2-carboxyl-
ate (46): Diastereoisomers separated by flash chromatography.
Data for major isomer 46a (2S,4R,1ЈS): white solid, m.p. 88–92 °C.
116.4, 127.4, 128.9 (2 C), 133.7 ppm. IR (nujol): ν = 3334,
˜
[α]2D0 = –74.20 (c = 1.5, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
2229 cm–1. C13H16N2O2 (232.28): calcd. C 67.22, H 6.94, N 12.06;
found C 66.89, H 6.98, N 11.99. HPLC–MS: Rt = 2.49 min (major
+ minor); m/z = 206 [M – CN]+, 233 [M + H]+, 255 [M + Na]+,
487 [2M + Na]+. Data for minor isomer 48b (2S,4R,1ЈR): obtained
only as a diastereomeric mixture, only the main signals are re-
ported. 1H NMR (400 MHz, CDCl3): δ = 3.85 (dd, J = 5.2,
11.6 Hz, 1 H, CHCHHOH), 4.40–4.50 (m, 1 H, CHOH), 5.16 (s,
1 H, CHCN) ppm.
1.77 (br. s, 1 H, OH), 2.23–2.27 (m, 2 H, CH2CHCO2Me), 2.57
(dd, J = 4.0, 10.4 Hz, 1 H, CHCHHN), 3.08 (dd, J = 5.2, 10.4 Hz,
1 H, CHCHHN), 3.80 (s, 3 H, CH3), 3.92 (dd, J = 7.6, 8.8 Hz, 1
H, CHHCHCO2Me), 4.37–4.42 (m, 1 H, CHOH), 5.38 (s, 1 H,
CHCN), 7.37–7.43 (m, 3 H, ArH), 7.57–7.59 (m, 2 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): δ = 38.7, 52.2, 56.7, 57.9, 61.6, 69.2,
116.2, 127.5, 128.8, 128.9, 133.5, 172.8 ppm. IR: ν = 3178, 2227,
˜
1740, 1207 cm–1. C14H16N2O3 (260.29): calcd. C 64.60, H 6.20, N
10.76; found C 65.02, H 6.18, N 10.68. HPLC–MS: Rt = 5.41 min;
m/z = 234 [M – CN]+, 261 [M + H]+, 283 [M + Na]+. Data for
minor isomer 46b (2S,4R,1ЈR): white solid, m.p. 103–104 °C.
Compound 48a was also obtained starting from 46a by reduction
of the ester functionality with NaBH4 (see Supporting Information
for details).
1
[α]2D0 = –13.10 (c = 1.5, CHCl3). H NMR (400 MHz, CDCl3): δ =
2-[4-Hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]pentanenitrile (49):
Characterized as a diastereomeric mixture, signals refer to the
major diastereosiomer, only the main signals of the minor dia-
stereomer are reported. Data for major isomer 49a (2S,4R,2ЈS) and
minor isomer 49b (2S,4R,2ЈS): pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 0.97 (t, J = 7.2 Hz, 3 H, CH3CH2CH2), 0.98 (t, J =
7.6 Hz, 3 H, CH3 CH2 CH2 , minor), 1.45–1.68 (m, 2 H,
CH3CH2CH2), 1.66–1.79 (m, 2 H, CH3CH2CH2), 1.89 (ddd, J =
4.0, 7.6 and 13.0 Hz, 1 H, CHCHHCH), 1.96–2.07 (m, 1 H,
CHCHHCH), 2.63 (dd, J = 4.0, 9.6 Hz, 1 H, CHCHHN), 2.77
(dd, J = 5.6, 9.6 Hz, 1 H, CHCHHN, minor), 3.20–3.26 (m, 1 H,
CHCHCH2OH), 3.34 (dd, J = 5.6, 10.0 Hz, 1 H, CHCHHN), 3.48
(dd, J = 3.2, 12.0 Hz, 1 H, CHCHHOH), 3.55–3.59 (m, 1 H,
1.99 (br. s, 1 H, OH), 2.11 (dddd, J = 0.8, 4.8, 8.4, 9.2 Hz, 1 H,
CHCHHCHCO2Me), 2.18–2.25 (m, 1 H, CHCHHCHCO2Me),
2.89 (ddd, J = 0.8, 4.0, 9.6 Hz, 1 H, CHCHHN), 3.38 (s, 3 H,
CH3), 3.55 (dd, J = 4.8, 9.6 Hz, 1 H, CHCHHN), 3.75 (dd, J =
6.4, 8.4 Hz, 1 H, CHHCHCO2Me), 4.55–4.60 (m, 1 H, CHOH),
5.16 (s, 1 H, CHCN), 7.37–7.41 (m, 3 H, ArH), 7.47–7.50 (m, 2 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 39.4, 51.7, 57.9,
59.6, 60.6, 69.8, 116.6, 128.3, 128.7, 129.2, 132.4, 173.2 ppm. IR: ν
˜
= 3377, 2943, 2230, 1739, 1207 cm–1. C14H16N2O3 (260.29): calcd.
C 64.60, H 6.20, N 10.76; found C 64.81, H 6.29, N 10.64. HPLC–
MS: Rt = 3.99 min; m/z = 234 [M – CN]+, 261 [M + H]+, 283 [M
+ Na]+, 543 [2M + Na]+.
Methyl 1-(1-Cyanobutyl)-4-hydroxypyrrolidine-2-carboxylate (47): CHCHHOH minor), 3.68 (dd, J = 3.2, 12.0 Hz, 1 H, CHCHHOH),
Diastereoisomers separated by flash chromatography. Data for
3.77 (dd, J = 6.4, 10.0 Hz, 1 H, CHCN, minor), 3.87 (t, J = 8.0 Hz,
major isomer 47a (2S,4R,1ЈS): pale yellow oil; [α]2D0 = –103.90 (c =
1 H, CHCN), 4.40 (m, 1 H, CHOH) ppm. 13C NMR (100 MHz,
0.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.97 (t, J = 7.6 Hz, CDCl3): δ = 13.3, 19.2, 34.6, 36.9, 53.2, 57.0, 61.5, 61.7, 69.7,
3 H, CH3CH2CH2), 1.48–1.60 (m, 2 H, CH3CH2CH2), 1.73–1.79 118.1 ppm. IR: ν = 3406, 2961, 2874, 2226, 1097 cm–1. HPLC–MS:
˜
(m, 3 H, CH3CH2CH2, OH), 2.12–2.24 (m, 2 H, CH2CHCO2Me), Rt = 1.79 min (major + minor); m/z = 172 [M – CN]+, 199 [M +
2.63 (dd, J = 3.6, 10.4 Hz, 1 H, CHHCHHN), 3.43 (dd, J = 5.2, 1]+, 221 [M + Na]+.
Eur. J. Org. Chem. 2013, 1683–1695
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1693

M. Pori, P. Galletti, R. Soldati, D. Giacomini
FULL PAPER
Product 49a was also obtained starting from 42a by reduction of
the ester functionality with NaBH4 (see Supporting Information
for details).
with CH2Cl2 to obtain 692 mg of 53 (88%) as a mixture of dia-
stereoisomers (de 78:22).
Characterized as a diastereomeric mixture. Signals refer to the
Methyl (2S,4S)-1-[(S)-Cyano(phenyl)methyl]-4-iodopyrrolidine-2- major diastereosiomer, only the main signals of the minor dia-
carboxylate (50a): DEAD (40 % solution in toluene; 107 mg,
0.61 mmol) was added dropwise to a stirred solution of 46a
(134 mg, 0.51 mmol) and triphenylphosphane (161 mg, 0.61 mmol)
in THF (1.5 mL) at 0 °C, and then methyl iodide (38 μL,
0.61 mmol) was added. After 20 min, the solution was warmed to
room temperature and stirred for 5 h until TLC showed that the
reaction was complete. The reaction mixture was concentrated to
dryness under reduced pressure, and the residue was purified by
flash chromatography to give 50a (153 mg, 0.41 mmol, 81%) as a
white solid, m.p. 80–85 °C. [α]2D0 = –28.55 (c = 0.20, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 2.66 (ddd, J = 6.0, 6.4, 14.4 Hz, 1
H, CHICHHCHCO2Me), 2.91 (ddd, J = 6.8, 9.2, 14.4 Hz, 1 H,
CHICHHCHCO2 Me), 2.99 (dd, J = 4.0, 11.2 Hz, 1 H,
NCHHCHI), 3.05 (dd, J = 6.0, 11.2 Hz, 1 H, NCHHCHI), 3.76
(dd, J = 6.8, 8.8 Hz, CH2CHCO2Me), 3.84 (s, 3 H, CH3), 4.32 (m,
1 H, CHI), 5.49 (s, 1 H, CHCN), 7.37–7.46 (m, 3 H, ArH), 7.64–
7.66 (m, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.3,
41.8, 52.5, 57.8, 59.1, 62.2, 116.4, 127.3, 128.9, 129.0, 133.2,
stereomer (white solid) are reported. Data for major isomer 53a
(2S,S) and minor isomer 53b (2S,R): 1H NMR (400 MHz,
C D 3 O D ) : δ = 2 . 0 2 – 2 . 3 1 ( m , 3 H , C H 2 C H 2 C H 2
,
CH2CHHCHCO2H), 2.39–2.46 (m, 1 H, CH2CHHCHCO2H),
2.54–2.64 (m, 1 H, CH2CHHCHCO2H, minor), 3.36–3.46 (m, 1 H,
NCHHCH2, minor), 3.56–3.62 (m, 1 H, NCHHCH2), 3.59–3.67
(m, 1 H, CH2CHHN, minor), 3.95–4.01 (m, 1 H, NCHHCH2),
4.39–4.43 (m, 1 H, CH2CHCO2H, minor), 4.49 (dd, J = 6.4, 9.2 Hz,
1 H, CH2CHCO2H), 5.45 (s, 1 H, PhCH), 5.55 (s, 1 H, PhCH,
minor), 7.51–7.62 (m, 5 H, Ph) ppm. Data for major diastereomer
53a: 13C NMR (100 MHz, CD3OD): δ = 25.2, 31.4, 57.9, 67.7,
72.3, 131.3, 131.5, 132.2, 132.9, 170.7, 171.8 ppm. HPLC–MS: Rt
= 1.48 min; m/z = 250.
Methyl (2S)-1-[(S)-2-Amino-2-oxo-1-phenylethyl]pyrrolidine-2-carb-
oxylate (54a): Methyl ester 37a (1.64 mmol, 400 mg), acetic acid
(9.84 mmol, 637 μL), water (6.56 mmol, 118 μL), TiCl4 (3.28 mmol,
360 μL), and CH2Cl2 (1 mL) were added in that order to a 5 mL
vial equipped with a screw cap. The solution was stirred overnight
on an orbital shaker, and the reaction was monitored by TLC.
When the reaction was complete, CH2Cl2 was added, and the or-
ganic phase was separated and discarded. The aqueous solution
was treated with saturated NaHCO3 until basic pH was reached,
and then it was extracted with CH2Cl2 (3ϫ). The combined organic
extracts were dried with Na2SO4 and concentrated in vacuo to give
429 mg of 54a in quantitative yield, white solid, m.p. 149.2–
153.9 °C. [α]2D0 = +2.83 (c = 1.20, CHCl3). 1H NMR (400 MHz,
171.8 ppm. IR: ν = 3028, 2950, 2230, 1746, 1493, 1130 cm–1
.
˜
C14H15IN2O2 (370.19): calcd. C 45.52, H 4.08, N 7.57; found C
45.62, H 4.11, N 7.42. HPLC–MS, Rt = 9.93 min; m/z 371 [M +
H]+, 393 [M + Na]+.
{(S)-1-[(S)-2-Amino-1-phenylethyl]pyrrolidin-2-yl}methanol (51a): A
solution of LiAlH4 (2 m in diethyl ether; 500 μL) was added drop-
wise to a stirred solution of cyanoester 37a (0.2 mmol) in THF
(1.7 mL) at 0 °C under an inert atmosphere. After 15 min, the solu-
tion was warmed to room temperature. The progress of the reaction
was monitored by TLC, and at completion after 4 h, Na-K tartrate
salt (saturated aqueous) was added with vigorous stirring to favor
phase separation. The separated organic phase was dried (Na2SO4)
and concentrated, and the residue was purified by flash chromatog-
raphy (eluent CHCl3/MeOH/NH4OH, 60:30:1) to yield 17 mg of
product 51a (39%). [α]2D0 = +1.68 (c = 0.31, CH2Cl2). 1H NMR
C D C l 3 ) : δ = 1 . 8 1 – 1 . 9 6 ( m , 3 H , C H 2 C H 2 C H 2
,
CH2CHHCHCO2Me), 2.00–2.08 (m, 1 H,CH2CHHCHCO2Me),
2.71–2.77 (m, 1 H, CH2CHHN), 3.27–3.32 (m, 1 H, CH2CHHN),
3.36 (dd, J = 4.0, 9.6 Hz, 1 H, CH2CHCO2Me), 3.50 (s, 3 H, CH3),
4.24 (s, 1 H, PhCHCONH2), 5.73 (br. s, 1 H, CONHH), 7.29–7.33
(m, 5 H, ArH), 7.66 (br. s, 1 H, CONHH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.2, 30.6, 51.7, 54.4, 61.7, 73.2, 128.5,
(D2O, 400 MHz): δ = 1.62–1.71 (m, 2 H, NCH2CH2CH2), 1.78– 128.6, 129.2, 136.5, 174.8, 175.9 ppm. IR: ν = 3397, 2919, 1725,
˜
1.87 (m, 2 H, NCH2CH2CH2), 2.66 (m, 1 H, NCHHCH2CH2), 1667, 1129 cm–1. C14H18N2O3 (262.30): calcd. C 64.10, H 6.92, N
2.91 (m, 1 H, NCHHCH2CH2), 3.02 (m, 2 H, CH2NH2), 3.15 (m,
10.68; found C 63.99, H 6.94, N 10.72. HPLC–MS: Rt = 3.41 min;
2 H, CHN, CH2OH), 3.35 (dd, J = 4.4, 12.4 Hz; 1 H, CH2OH), m/z = 263 [M + H]+, 285 [M + Na]+, 547 [2M + Na]+.
3.74 (dd, J = 4.8, 10.8 Hz, 1 H, PhCHN), 7.40–7.53 (m, 5 H, Ph)
(4S,7R,8aS)-7-Hydroxy-4-phenyltetrahydro-1H-pyrrolo[2,1-c][1,4]-
ppm. 13C NMR (D2O, 50.3 MHz): δ = 24.4, 28.7, 43.6, 52.9, 60.6,
oxazin-3(4H)-one (55a): The product was obtained in 40% yield
64.9, 68.0, 127.7, 127.9, 128.3, 128.6, 128.8, 139.2 ppm. IR (neat):
after flash chromatography following the same procedure reported
ν = 3358, 2924, 1599, 1493, 1453, 1379, 1074, 1040, 766, 735,
˜
for the synthesis of amide 54a from aminol 48a. Pale yellow oil.
704 cm–1. HPLC–MS: Rt = 1.26 min; m/z = 221 [M + H]+.
1
[α]2D0 = –2.47 (c = 0.15, CHCl3). H NMR (400 MHz, CDCl3): δ =
{(S)-1-[(S)-1-Aminopentan-2-yl]pyrrolidin-2-yl}methanol (52a): Fol-
lowing the same procedure as above, starting from 38a. Yield 36%,
1.92 (ddd, J = 4.8, 9.6, 14.0 Hz, 1 H, CHOHCHHCH), 2.09–2.17
(m, 1 H, CHOHCHHCH), 2.91 (dd, J = 3.6, 10.0 Hz, 1 H,
NCHHCHOH), 3.12–1.15 (d, J = 10.0 Hz, 1 H, NCHHCHOH),
3.84–3.92 (m, 1 H, CH2CHCH2OCO), 4.14 (dd, J = 4.8, 11.6 Hz,
1
orange oil; [α]2D0 = +68.0 (c = 1.50, CHCl3). H NMR (400 MHz,
CDCl3): δ = 0.93 (t, J = 6.4 Hz, 3 H, CH3CH2CH2), 1.31–1.46 (m,
4 H, CH3CH2CH2), 1.63–1.82 (m, 4 H, NCH2CH2CH2), 2.61–2.82 CHCHHOCO), 4.17 (dd, J = 4.4, 11.6 Hz, CHCHHOCO), 4.49–
(m, 4 H,CHCH2NH2, N CH2CH2CH2), 2.97–3.13 (m, 5 H, 4.51 (m, 1 H, CH2CHOHCH2), 4.60 (s, 1 H, CHPh), 7.37–7.40 (m,
NCHCH2NH2, CH2CHCH2OH, OH, NH2), 3.30 (dd, J = 4.8,
10.8 Hz, 1 H, CHHOH), 3.48 (dd, J = 3.6, 10.8 Hz, 1 H, CHHOH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.3, 20.4, 24.5, 29.0, 31.7,
3 H, ArH), 7.64–7.66 (m, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 37.6, 52.9, 62.2, 65.8, 68.4, 71.3, 127.1, 128.2, 128.7,
135.5, 170.9 ppm. IR: ν = 3362, 2924, 2853, 1737, 1042 cm–1
.
˜
42.4, 50.0, 58.8, 60.9, 64.4 ppm. IR: ν = 3280, 2957, 2927, 2870,
C13H15NO3 (233.26): calcd. C 66.94, H 6.48, N 6.00; found C
66.88, H 6.53, N 6.09. HPLC–MS, Rt = 2.44 min; m/z = 234 [M +
H]+, 256 [M + Na]+, 272 [M + K]+, 489 [2M + Na]+.
˜
1660, 1106 cm–1. C10H22N2O (186.29): calcd. C 64.47, H 11.90, N
15.04; found C 64.58, H 11.99, N 14.78.
2-Carboxy-1-[carboxy(phenyl)methyl]pyrrolidin-1-ium Hydrogen
Chloride (53): A solution of 37a (2.75 mmol, 670 mg) in HCl (37%;
12 mL) was heated at reflux for 24 h, and after completion of the
reaction, the water was removed. The crude material was washed
Supporting Information (see footnote on the first page of this arti-
cle): determination of absolute configuration; schemes and experi-
mental details for the chemical correlation between α-aminonitriles,
and table of 1H NMR and HPLC data of isomers; experimental
1694
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1683–1695

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Published Online: February 8, 2013
Eur. J. Org. Chem. 2013, 1683–1695
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1695