Asymmetric synthesis of syn and anti methyl 2,3-diamino-3-phenylpropanoate derivatives from N-substituted imines and Sch?llkopf's bislactim ether

Article abstract of DOI:10.1016/j.tet.2014.01.040

Abstract The reaction between differently N-substituted benzaldimines and (2R)-Sch?llkopf's bislactim ether was studied: the azaenolate addition to imines followed by hydrolysis of the resulting adducts gave syn-(2S,3R) and anti-(2S,3S)-methyl 2,3-diamino-3-phenylpropanoate derivatives in good yields. The configurations of the newly formed stereocenters of α,β-diamino acids were assigned on the basis of the ¹H NMR analysis and by comparison with known products. The diastereoisomeric ratios were explained taking into account the effect of the substituent present on the imine nitrogen on the transition state stability. This method represents a new approach for stereoselective synthesis of α,β-diamino acids.

Full text of DOI:10.1016/j.tet.2014.01.040

Tetrahedron 70 (2014) 2054e2058
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of syn and anti methyl 2,3-diamino-3-
phenylpropanoate derivatives from N-substituted imines and
€
Schollkopf’s bislactim ether
y
z
*
Giuseppe Cremonesi , Piero Dalla Croce, Maddalena Gallanti , Concetta La Rosa
ꢀ
Universita degli Studi di Milano, DISFARM, Sezione di Chimica Generale e Organica “A. Marchesini”, V. Venezian 21, I-20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
€
The reaction between differently N-substituted benzaldimines and (2R)-Schollkopf’s bislactim ether was
studied: the azaenolate addition to imines followed by hydrolysis of the resulting adducts gave syn-
(2S,3R) and anti-(2S,3S)-methyl 2,3-diamino-3-phenylpropanoate derivatives in good yields. The con-
Received 6 November 2013
Received in revised form 7 January 2014
Accepted 20 January 2014
Available online 5 February 2014
figurations of the newly formed stereocenters of a,b
-diamino acids were assigned on the basis of the 1H
NMR analysis and by comparison with known products. The diastereoisomeric ratios were explained
taking into account the effect of the substituent present on the imine nitrogen on the transition state
Keywords:
2,3-Diamino propanoates
a,b-Diamino acids
stability. This method represents a new approach for stereoselective synthesis of a,b-diamino acids.
Ó 2014 Elsevier Ltd. All rights reserved.
Imines
€
Schollkopf bislactim ether
1. Introduction
it has proved to be highly diastereoselective in aldol-type reactions
and is commercially available in both (R) and (S)-forms. For many
years our research group has studied the stereoselective synthesis
Non-proteinogenic, optically active 2,3-diamino acids are key
structural units of numerous natural products, and they present
important biological properties and can be versatile building blocks
in organic synthesis. For example, (S)-2,3-diaminopropanoic acid is
present in several natural antibiotic cyclopeptides,1 and (2S,3R)-
2,3-diamino-3-phenylpropanoic acid has been utilized as an ana-
logue of the Taxol side chain improving the water solubility of this
antitumour compound.2 2,3-Diamino acids have also been in-
corporated into peptides, which are used to modulate secondary
and tertiary structural conformations.3 For these reasons they have
received a growing interest through the years.4 Accordingly, the
development of efficient and general methods in their preparation
has received considerable attention, especially as regards the syn-
thesis of enantiopure compounds.5 Among the various methods of
synthesis one of the most useful was the nucleophilic addition of
of new
a-amino acids by means of the reaction between the
€
Schollkopf’s bislactim ether and various electrophiles, such as alkyl
halides,8 heterocyclic-carbaldehydes,9 or ketones.10 In these two
latter cases,
b-hydroxy-a-amino acids were obtained, with an
asymmetric, enantiomerically pure quaternary carbon in the
b po-
sition when ketones were used.10
So we were interested in the possibility of obtaining enantio-
€
pure
a
,
b
-diamino acids derivatives by reacting Schollkopf’s bislac-
tim ether with the electrophilic carbon of imines. An analysis of the
literature revealed that this reagent has been used with different
types of electrophiles, especially aldehydes, but it had never been
€
added to imines. Only in a publication of 1986, Schollkopf reported
that the anion of the (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-
5-methylpyrazine initially reacted with the azomethine double
bond of 2-(benzylideneamino)ethylbromide affording, after an
intramolecular cyclization, an aziridine compound.11 The synthesis
of 2,3-diamino acids by ‘the bislactim ether method’ was also ac-
complished in 1991 by Mittendorf reacting the lithium azaenolate
of (2S)-5-alkyl-2,5-dihydro-3,6-dimethoxy-2-isopropyl-pyrazine
with dibromomethane followed by nucleophilic substitution of
bromide with sodium azide and final hydrolysis.12
chiral glycinate derivatives to imines.6 Schollkopf’s bislactim ether,
€
(i.e., (2R)- or (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyra
zine),7 is a particularly attractive chiral glycine equivalent because
* Corresponding author. Tel.: þ39 02 503 14473; fax: þ39 02 503 14476; e-mail
address: concetta.larosa@unimi.it (C. La Rosa).
y
Present address: Sifavitor S.r.l., Via Livelli 1, I-26852 Mairano di Casaletto
Our interest in the stereoselective synthesis of enantiopure
amino acids, led us to report a novel and efficient method to obtain
enantiopure -diamino acids by means of the reaction between
a-
Lodigiano (LO), Italy.
z
Present address: Abcam Biochemicals, Unit 3 Victoria Rd, Bristol BS11 9DB,
a,b
United Kingdom.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.01.040

G. Cremonesi et al. / Tetrahedron 70 (2014) 2054e2058
2055
the lithium enolate of (2R)-2,5-dihydro-3,6-dimethoxy-2-
isopropylpyrazine 1 and N-substituted imines. In order to obtain
differently N-protected diamino acids and also to evaluate the steric
and electronic effects of the nitrogen substituent on the diaster-
eoselectivity of the addition, we decided to conduct our in-
vestigation using variously N-substituted benzaldimines (E)-2aef,
bearing both electron withdrawing and electron donating groups.
This should enable us to obtain, after acid hydrolysis, differently Nb-
integration of the H-2 (4.35/4.56
d
) or H-5 (3.59/3.10
d
) signals in
the 1H NMR spectra of the crude reaction mixtures (Scheme 1).
The observed diastereoselectivity was generally poor, similarly
to that found in the case of ketones.10 Under experimental condi-
tions providing the best yield, the two adducts were formed in
almost the same amount (Table 1, entry 1). It was observed that
when conducted at higher temperatures (T¼ꢀ20 ꢁC or þ4 ꢁC rather
than ꢀ78 ꢁC) the ratio between the two diastereoisomers was
inverted and the yield decreased (Table 1, entries 2e4). This was not
due to the reversibility of the addition as the two adducts were
found to be stable under the reaction conditions. In fact, after
having separated them, they were treated with nBuLi at tempera-
tures between ꢀ78 and þ4 ꢁC for 24 h but they were recovered
unaffected. Generally, the observed diastereoselectivity could also
be influenced by the nature of the counter-ion. To assess this, the
lithium azaenolate was treated with ZnCl2, TiCl(OiPr)313 or SnCl4 to
give the corresponding transmetalated azaenolates before the ad-
dition of the imine (Table 1, entries 5e7): only in the last case did
the reaction afforded a mixture of 3a/4a at almost the same ratio
but in a lower yield.
protected a,b-diamino acids (Fig. 1).
R
H
NHR
COOMe
N
N
MeO
+
C=N
Ph
Ph
OMe
NH2
(2R)-1
2a-f
2a : R=Ph 2d : R=Boc
2b : R=Bn 2e : R=Cbz
2f : R=SO2Ph
2c : R=tBu
Fig. 1. Synthetic pathway for Nb-protected
a
,
b
-diamino acids.
The best experimental conditions reported in Table 1 entry 1,
were then applied to the reaction of (2R)-1 with imines 2bef. In the
case of imines 2b, c the reaction led to unreacted reagents and
traces of products (Table 1, entries 8, 9). In particular, the treatment
of imine 2b with the anion of (2R)-1, produced an intense pink
colour due to the deprotonation of the benzylic carbon14 and ex-
tensive delocalization of the corresponding anion prevented the
addition.15 In the case of imine 1c, failure to obtain the products has
been attributed to the steric hindrance generated by the bulky tert-
butyl group, as already observed.16 On the contrary, the reaction of
the imines 2d, e afforded mixtures of the two diastereoisomeric
adducts 3d/4d and 3e/4e in good yields and, with imine 2e, also
with a better diastereoselectivity (Table 1, entries 10, 11). Only with
imine 2f the formation of all the four possible diastereoisomers was
observed but with a preference for adduct 4f (Table 1, entry 12).
Diastereoisomers 3a, d, e and 4a, def were easily isolated by
means of flash chromatography on silica gel, and their structures
were confirmed on the basis of analytical and spectroscopic data
(HSQC, COSY and NOESY experiments). The (2S)-configuration was
2. Results and discussion
Various experimental conditions and counter-ions were exam-
ined to optimize yields and evaluate the diastereoselectivity of the
reaction. In these experiments imine 2a was taken as reference. A
THF solution of imine was added to the anion of the bislactim ether
(2R)-1 generated by the addition of nBuLi in THF at T¼ꢀ78 ꢁC. The
reaction mixture was then maintained at variable temperatures
and times (representative conditions are listed in Table 1, entries
1e4). In all cases the reaction gave mixtures of two di-
astereoisomeric adducts 3a/4a whose ratio was determined from
Table 1
Total yields and ratios of compounds 3/4
Entry Imine
R
Counter-ion T (ꢁC) t (h) Total
yield (%)
72
3 (%) 4 (%)
5
established using the JH2/H5 coupling constant value of approxi-
Liþ
ꢀ78
ꢀ20
þ4
8
6
53
45
33
42
47
55
67
58
d
d
60
d
d
59
87
62
mately 3.5 Hz, which corresponds to a trans relationship between
the H-2 and H-5 protons of the pyrazine ring.17 The (R)- and (S)-
configuration were assigned to the C-10 of the adducts 3 and 4,
respectively, by means of comparison with each other and using the
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
tBu
Boc
Cbz
Liþ
56
51
55
d
Liþ
4
16
6
6
6
Liþ
þ4
Zn2þ
Ti4þ
Sn4þ
Liþ
ꢀ20
ꢀ20
ꢀ20
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
d
data reported in the literature for the corresponding
acids obtained after hydrolysis (see below).
a,b-diamino
d
d
34
40
The reactions of (2R)-1 with aldehydes9,7b or ketones10,18 always
afforded mixtures of the two (2S)-epimers arising from the attack
of the azaenolateepyrazine from the less hindered side opposite
the isopropyl group, according to the ZimmermaneTraxler six-
membered ring model,19 and our present results confirm the 2,5-
trans-relationship in the adducts 3/4.
8
Trace
Trace
65
d
9
Liþ
8
8
8
d
10
11
12
Liþ
41
Liþa
75
70
13
SO2Ph Liþ
8
38b
a
The reported results were obtained using 2 equiv of LDA as base.
Total ratio of three inseparable diastereoisomers.
b
Li
N
NHR
NHR
1'
H
OMe
N
OMe
R
MeO
N
1'
nBuLi
MeO
C=N
Ph
Ph
Ph
+
N
H
2
2
H
H
H
THF
-78°C
5
5
N
OMe
N
N
N
OMe
2a-f
(2R)-1
OMe
OMe
4a,d,e,f
3a,d,e
2,3,4a : R=Ph
2b : R=Bn
2,3,4d : R=Boc
2,3,4e : R=Cbz
2,4f : R=SO2Ph
2c : R=tBu
Scheme 1.

2056
G. Cremonesi et al. / Tetrahedron 70 (2014) 2054e2058
Transition state models TS1 and TS2 can be proposed to ratio-
NHBoc
COOMe
NHBoc
OMe
HCl 0.1N
nalize the observed diastereoisomeric ratio for the reaction of (2R)-
1 with imine (E)-2a (Fig. 2). As in the case of aldehydes,3 in TS1 the
anion of (2R)-1 approaches the Si face of E-imine leading to (R)
configuration of the benzylic carbon, and this approach should be
the preferred one because the C-phenyl group is far from the
methoxy group. Owing to the E geometry of the imine, the co-
ordination of the metal with the nitrogen-imine lone pair is pre-
vented, but a stabilization of the TS1 could arise from an interaction
Ph
Ph
Ph
Ph
N
CH3CN
25°C
H
H
H
NH2
N
OMe
3d
5d (59%)
NHR
OMe
N
NHR
H
HCl 0.1N
COOMe
H
with the
p
system of the N-phenyl group. Actually, when R¼Ph,
H
N
CH3CN
25°C
both transition states seem to have approximately the same sta-
bility leading to a mixture about 50:50 of the two diastereoisomers.
On the contrary, when R¼Boc, Cbz or SO2Ph approach like TS2
becomes the predominant one leading to adducts 4. In this case the
coordination of the imine nitrogen lone pair with the metal allows
a more stable six-membered ring transition state.12
NH2
OMe
6d,e,f - 7
4d,e,f
4d,6d : R=Boc
4e,6e : R=Cbz
(42% 6d + 18% 7 R=H)
(58% 6e)
4f, 6f : R=SO2Ph
(60% 6f)
Scheme 2.
TS1
TS2
configuration was assigned to compound 6e according to the
analogy between the NMR spectra of adducts 3e/4e and 3d/4d. In
fact all NMR spectra of products 3aef are similar to each other
likewise for the all NMR spectra of compounds 4aef (see
Experimental).
N
N
M
M
H
H
3. Conclusions
H
H
N
H
N
H
OCH
OCH3
CH3O
CH3O
A new methodology has been introduced for the asymmetric
synthesis of Nb-protected a,b-diamino acids, key structural units of
N
N
natural products. Our procedure involves addition of the anion of
€
the Schollkopf’s reagent to imines followed by mild acidic hydro-
lysis. With electron-withdrawing imine-substituted the reaction
proceeds with good diastereoselectivity mainly providing the anti
isomers of enantiomerically pure Nb-protected 2,3-diamino esters.
The observed ratios seem to be influenced by the stereoelectronic
effects of the substituents of the imine nitrogen atom.
NH
NH
OCH3
OCH3
(S)
(R)
H
H
H
(S)
(S)
N
N
(R)
(R)
H
N
N
H
H
OCH3
OCH3
3a (53%)
4a (47%)
4. Experimental section
4.1. General
Fig. 2. Proposed transition states.
€
Melting points were determined on a Buchi B-540 apparatus.
Finally, the adducts 3a, 4a, 3d, 4d, 4e and 4f were hydrolysed
under controlled acidic conditions: they were treated with 3 equiv
of 0.1 N HCl in acetonitrile at room temperature for 54e72 h. In the
case of the N-phenyl derivatives 3a/4a the removal of the valine
chiral auxiliary lead to a complete degradation of the correspond-
Elemental analyses were performed by the Microanalytical Labo-
ratory of the Department. 1H and 13C NMR spectra were recorded
using a Varian-Gemini 200 MHz spectrometer. Chemical shifts (d)
are given in parts per million in relation to TMS; the solvent was
CDCl3 unless otherwise specified. All of the coupling constants (J)
are in Hertz. The MS spectra were recorded with a Thermo-Finnigan
LCQ advantage AP electrospray/ion trap equipped instrument us-
ing a syringe pump device to directly inject sample solutions. The
optical rotation values were measured at 25 ꢁC. The bislactim ether
(2R)-1 and imines 2a, b, f were commercially available, imines
2c,24 2d,25 and 2e26 were prepared following the reported
methods.
ing
hydrolysis of the adduct 3d led to the
yield while with 4d the reaction afforded a mixture, separable by
chromatography, of the Nb-Boc- -diamino acid 6d together with
the deprotected methyl 2,3-diamino-3-phenylpropanoate 7 with
a total yield of 60%. With similar yields the -diamino acids 6e, f
a,b
-diamino acids,20a as already noted by other authors.20b The
a,b-diamino acid 5d in good
a,b
a,b
were obtained from the corresponding compounds 4e,
f
(Scheme 2).
By comparison with the data reported in the literature for
methyl (2R,3S)-2-amino-3-[(tert-butoxycarbonyl)amino]-3-phenyl
propanoate21 and for methyl (2S,3S)-2-amino-3-[(tert-butox-
ycarbonyl)amino]-3-phenylpropanoate21 it was possible to assign
the (3R) configuration to 5d and the (3S) configuration to the C-3 of
compounds 6d and 7. Moreover, the latter shows a great analogy
with its ethyl ester.22 Similarly, the same (3S) configuration has
4.2. General procedure for the addition of bislactim ether
(2R)-1 azaenolate to imines
Butyl lithium (1.6 N solution in hexane, 1.05 equiv) was added to
a solution of (2R)-1 (1 equiv) in anhydrous THF (5 mL) cooled to
ꢀ78 ꢁC, and the mixture was stirred for 45 min. Imine 2aef
(1 equiv) in THF (4 mL) was added, and the mixture was stirred at
ꢀ78 ꢁC for 8 h. The reaction mixture was allowed to warm to
ꢀ10 ꢁC, after which a pH¼7 phosphate buffer solution (10 mL) was
been attributed to the Nb-phenylsulfonyl-a,b-diamino acid 6f
showing a 1H NMR spectrum in accordance with that of the en-
antiomer of the Nb-tosyl derivative.23 Finally, the same (3S)

G. Cremonesi et al. / Tetrahedron 70 (2014) 2054e2058
2057
added, and the mixture was extracted with ethyl acetate (3ꢂ10 mL).
The organic phase was separated and dried with Na2SO4, and the
solvent was evaporated in vacuo. Compounds 3, 4 were purified by
means of flash chromatography (SiO2, CH2Cl2/hexane¼40/60 for 3a
(Rf 0.2) and 4a (Rf 0.4); CH2Cl2/ethyl acetate¼95/5 for 3d (Rf 0.4) and
4d (Rf 0.5), 3e (Rf 0.5) and 4e (Rf 0.6); CH2Cl2/ethyl acetate¼98/2 for
4f (Rf 0.6)).
system, J¼12.1, 25.3, 2H, CH2); 5.55 (dd, J¼3.3, 9.5, 1H, H-10); 5.38
(d, J¼9.5, 1H, NH); 7.25e7.41 (m, 10H, Ph). MS-ESIþ (m/z): 424
[MþH]þ.
4.2.6. Benzyl (S)-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-yl](phenyl)methylcarbamate
(4e). Amorphous
solid (275.0 mg, 65%). [
a
]
20 þ19.8 (c 0.3, CHCl3). 1H NMR:
d 0.59, 0.91
D
(2d, J¼6.7, 6H, CH(CH3)2); 2.11 (m, 1H, CH(CH3)2); 3.24 (t, J¼3.3, 1H,
H-5); 3.68 (s, 3H, OCH3); 3.74 (s, 3H, OCH3); 4.42 (t, J¼3.6, 1H, H-2);
5.1 (AB system, J¼12.1, 25.3, 2H, CH2); 5.38 (dd, J¼3.6, 9.2, 1H, H-10);
4.2.1. N-{(R)-[(2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-
2-yl](phenyl)methyl}-N-phenylamine (3a). Colourless solid (138.7
mg, 38%); mp 89e91 ꢁC (hexane). [
a]
D
20 þ92.3 (c 1.9, CHCl3). 1H NMR:
6.31 (broad d, J¼9.2,1H, NH); 7.05e7.45 (m,10H, Ph).13C NMR:
d 16.7,
d
0.66, 0.98 (2d, J¼6.8, 6H, CH(CH3)2); 2.18 (m, 1H, CH(CH3)2); 3.59 (t,
19.1 (CH(CH3)2); 31.6 (CH(CH3)2); 52.3, 52.8 (3- and 6-OCH3); 56.2 (C-
10); 59.8, 60.5 (C-2 and C-5); 67.1 (CH2); 127.6e129.9 (Ph); 136.7 (Ph);
138.1 (Ph); 155.8 (CO); 160.2, 165.5 (C-3 and C-6). Anal. Calcd for
J¼3.5, 1H, H-5); 3.71 (s, 3H, OCH3); 3.73 (s, 3H, OCH3); 4.35 (t, J¼3.5,
1H, H-2); 4.55 (broad s, 1H, NH); 5.01 (d, J¼2.2, 1H, H-10); 6.54e6.66
(m, 3H, Ph); 7.05e7.35 (m, 7H, Ph). 13C NMR:
d
16.7, 19.0 (CH(CH3)2);
C24H29N3O4: C, 68.06; H, 6.90; N, 9.92. Found: C, 67.89; H 6.85; N,
31.7 (CH(CH3)2); 52.6 (3- and 6-OCH3); 59.1 (C-10); 60.6, 60.7 (C-2
and C-5); 113.8e129.0 (Ph); 140.4, 146.9 (Ph); 161.3, 165.9 (C-3 and C-
6). IR (Nujol): 3453 (vNH, NH), 1693 (vC]N, C]N). Anal. Calcd for
9.78. MS-ESIþ (m/z): 424 [MþH]þ.
4.2.7. N-[(R)-[(2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-
C
22H27N3O2: C, 72.30; H, 7.45; N, 11.50. Found: C, 72.25; H 7.36; N,
2-yl](phenyl)methyl]benzenesulfonamide (4f). Colourless solid (184.5
20
11.33. MS-ESIþ (m/z): 366 [MþH]þ.
mg, 43%); mp 180e181 ꢁC (ethanol). [
a]
D
þ79.9 (c 0.4, CHCl3). 1H
NMR:
d
0.60, 0.90 (2d, J¼6.9, 6H, CH(CH3)2); 2.10 (m, 1H, CH(CH3)2);
4.2.2. N-{(S)-[(2S,5R)-5-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-
2-yl](phenyl)methyl}-N-phenylamine (4a). Amorphous solid (124.1
mg, 34%). [
3.28 (t, J¼3.5,1H, H-5); 3.65 (s, 3H, OCH3); 3.77 (s, 3H, OCH3); 4.36 (t,
J¼3.9, 1H, H-2); 5.12 (dd, J¼3.9, 9.5, 1H, H-10); 6.21 (broad d, J¼9.5,
1H, NH); 6.91e7.44 (m, 8H, Ph); 7.72 (d, J¼7.6, 2H, Ph). 13C NMR:
a]
D
20 þ61.8 (c 1.0, CHCl3). 1H NMR:
d
0.60, 0.91 (2d, J¼6.9,
6H, CH(CH3)2); 2.11 (m,1H, CH(CH3)2); 3.10 (t, J¼3.5,1H, H-5); 3.73 (s,
3H, OCH3); 3.78 (s, 3H, OCH3); 4.56 (t, J¼3.5, 1H, H-2); 5.04 (d, J¼3.7,
1H, H-10); 6.58e6.64 (m, 3H, Ph); 7.06e7.25 (m, 7H, Ph); 7.55 (broad
d 16.4, 18.8 (CH(CH3)2); 31.5 (CH(CH3)2); 52.0, 52.8 (3- and 6-OCH3);
58.0 (C-10); 59.8, 60.4 (C-2 and C-5); 126.8e132.0 (Ph); 135.9 (Ph);
140.9 (Ph); 159.5,165.5 (C-3 and C-6). Anal. Calcd for C22H27N3O4S: C,
61.52; H, 6.34; N, 9.78. Found: C, 61.47; H 6.27; N, 9.64. MS-ESIþ (m/
z): 430 [MþH]þ.
s, 1H, NH). 13C NMR:
d 16.7, 19.4 (CH(CH3)2); 31.2 (CH(CH3)2); 52.1,
52.5 (3- and 6-OCH3); 58.4 (C-10); 59.8, 60.0 (C-2 and C-5);
113.5e131.3 (Ph); 138.2, 146.7 (Ph); 160.3, 164.9 (C-3 and C-6). IR
(Nujol): 3428 (vNH, NH), 1696 (vC]N, C]N). Anal. Calcd for
4.3. General procedure for the hydrolysis of adducts 3, 4
C
22H27N3O2: C, 72.30; H, 7.45; N, 11.50. Found: C, 72.20; H 7.33; N,
11.42. MS-ESIþ (m/z): 366 [MþH]þ.
Aqueous HCl 0.1 N (4.5 mL, 3 equiv) was added to a solution of
adduct 3, 4 (0.15 mmol,1 equiv) in CH3CN (1.5 mL). The mixture was
stirred for 54e72 h at room temperature and then extracted with
diethyl ether in order to remove non-basic organic compounds. It
was then treated with 25% ammonia solution under stirring until
pH¼8e10, and extracted with AcOEt (4ꢂ5 mL). The combined or-
ganic layers were dried with Na2SO4, and the solvent was removed
in vacuo. Compounds 6d and 7 were separated by means of flash
chromatography (SiO2, toluene/ethanol¼2/1, developer: ninhy-
drin). Compounds 5d, 6e and f were purified by means of column
chromatography (SiO2, toluene/ethanol¼2/1 for 5d, AcOEt/meth-
anol¼95/5 for 6e and AcOEt/methanol¼98/2 for 6f, developer:
ninhydrin).
4.2.3. tert-Butyl (R)-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-
dihydropyrazin-2-yl](phenyl)methylcarbamate
(3d). Amorphous
20
solid (105.0 mg, 27%). [
a]
þ20.5 (c 0.4, CHCl3). 1H NMR:
d 0.63,
D
0.96 (2d, J¼6.8, 6H, CH(CH3)2); 1.41 (s, 9H, C(CH3)3); 2.17 (m, 1H,
CH(CH3)2); 3.64 (t, J¼3.3, 1H, H-5); 3.69 (s, 3H, OCH3); 3.75 (s, 3H,
OCH3); 4.29 (broad s, 1H, H-2); 5.22e5.35 (broad m, 2H, H-10, NH);
7.24e7.53 (m, 5H, Ph). 13C NMR:
d 16.9, 19.2 (CH(CH3)2); 28.5
(C(CH3)3); 31.9 (CH(CH3)2); 52.9 (3- and 6-OCH3); 56.4 (C-10); 60.5,
60.9 (C-2 and C-5); 79.7 (C(CH3)3); 127.3e130.0 (Ph); 140.3 (Ph);
155.1 (CO); 161.5, 163.2 (C-3 and C-6). Anal. Calcd for C21H31N3O4: C,
64.76; H, 8.02; N, 10.79. Found: C, 64.55; H 7.87; N, 10.65. MS-ESIþ
(m/z): 390 [MþH]þ.
4.3.1. Methyl (2S,3R)-2-amino-3-[(tert-butoxycarbonyl)amino]-3-
20
4.2.4. tert-Butyl (S)-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-
phenylpropanoate (5d). Amorphous solid (26.0 mg, 59%). [a]
D
20
dihydropyrazin-2-yl](phenyl)methylcarbamate
(4d). Amorphous
þ22.5 (c 0.2, CHCl3). Lit.21 for (2R,3S) derivate: [
a
]
D
ꢀ23.7 (c 1,
20
solid (147.8 mg, 38%). [
a
]
þ20.8 (c 0.5, CHCl3). 1H NMR:
d
0.58,
CHCl3). 1H NMR:
d 1.40 (s, 9H, C(CH3)3); 2.55 (broad s, 2H, NH2);
D
0.89 (2d, J¼7.0, 6H, CH(CH3)2); 1.45 (s, 9H, C(CH3)3); 2.11 (m,
1H, CH(CH3)2); 3.19 (t, J¼3.3, 1H, H-5); 3.67 (s, 3H, OCH3); 3.76 (s,
3H, OCH3); 4.39 (t, J¼3.6, 1H, H-2); 5.32 (dd, J¼3.6, 8.8, 1H, H-10);
6.00 (broad d, J¼8.8, 1H, NH); 7.05e7.37 (m, 5H, Ph). 13C NMR:
3.76 (s, 3H, OCH3); 3.92 (d, J¼2.9, 1H, H-3); 5.23 (m, 1H, H-2); 5.81
(broad d, J¼8.8, 1H, NH); 7.22e7.35 (m, 5H, Ph). 13C NMR:
d 28.5
(C(CH3)3); 52.7 (OCH3); 56.6 (C-3); 58.7 (C-2); 79.9 (C(CH3)3);
126.6e139.9 (Ph); 155.3 (CO); 173.0 (CO). IR (Nujol): 3415 (vNH
,
d
16.6, 19.1 (CH(CH3)2); 28.5 (C(CH3)3); 31.6 (CH(CH3)2); 52.3, 52.8
NH2), 1734 (vC]O, C]O), 1692 (vC]O, C]O). Anal. Calcd for
(3- and 6-OCH3); 55.8 (C-10); 60.0, 60.4 (C-2 and C-5); 79.7
(C(CH3)3); 127.5e127.9 (Ph); 138.4 (Ph); 155.3 (CO); 160.4, 165.3
(C-3 and C-6). Anal. Calcd for C21H31N3O4: C, 64.76; H, 8.02; N,
10.79. Found: C, 64.61; H 7.92; N, 10.70. MS-ESIþ (m/z): 390
[MþH]þ.
C15H22N2O4: C, 61.21; H, 7.53; N, 9.52. Found: C, 61.05; H 7.48; N,
9.38. MS-ESIþ (m/z): 295 [MþH]þ.
4.3.2. Methyl (2S,3S)-2-amino-3-[(tert-butoxycarbonyl)amino]-3-
20
phenylpropanoate (6d). Amorphous solid (18.5 mg, 42%). [a]
D
þ24.9 (c 0.4, CHCl3). Lit.21
[
a
]
D
20 þ26.7 (c 1, CHCl3). 1H NMR:
d 1.40 (s,
4.2.5. Benzyl (R)-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-
9H, C(CH3)3); 1.55 (broad s, 2H, NH2); 3.68 (s, 3H, OCH3); 3.85 (d,
dihydropyrazin-2-yl](phenyl)methylcarbamate
(3e). Amorphous
J¼4.3, 1H, H-3); 5.11 (broad s, 1H, H-2); 5.86 (broad d, J¼7.2, 1H,
solid (42.3 mg, 10%). 1H NMR:
d
0.63, 0.96 (2d, J¼6.9, 6H,
NH); 7.20e7.40 (m, 5H, Ph). 13C NMR:
d 28.6 (C(CH3)3); 52.3 (OCH3);
CH(CH3)2); 2.13 (m, 1H, CH(CH3)2); 3.61 (t, J¼3.7, 1H, H-5); 3.68 (s,
3H, OCH3); 3.74 (s, 3H, OCH3); 4.29 (t, J¼3.3, 1H, H-2); 5.1 (AB
56.4 (C-3); 58.8 (C-2); 80.0 (C(CH3)3); 126.9e138.0 (Ph); 155.4 (CO);
173.8 (CO). IR (Nujol): 3376 (vNH, NH2), 1726 (vC]O, C]O), 1698

2058
G. Cremonesi et al. / Tetrahedron 70 (2014) 2054e2058
ꢁ
4. For reviews on
a
,
b
-diamino acids, see: (a) Viso, A.; Fernandez de la Pradilla, R.;
(vC]O, C]O). Anal. Calcd for C15H22N2O4: C, 61.21; H, 7.53; N, 9.52.
Found: C, 61.11; H 7.46; N, 9.44. MS-ESIþ (m/z): 295 [MþH]þ.
ꢁ
García, A.; Flores, A. Chem. Rev. 2005, 105, 3167e3196; (b) Viso, A.; Fernandez de
la Pradilla, R.; Tortosa, M.; García, A.; Flores, A. Chem. Rev. 2011, 111, PR1ePR42.
5. For a review on synthesis of a,b-diamino acids, see: Wang, J.; Zhang, L.; Jiang,
H.; Liu, H. Curr. Pharm. Des. 2010, 16, 1252e1259.
6. For a recent example see: Zhang, H.; Hu, X.; Wang, X.; Luo, Y.; Xu, P. J. Org. Chem.
4.3.3. Methyl (2S,3S)-2,3-diamino-3-phenylpropanoate
20
(7). Amorphous solid (5.5 mg, 18%). [
a]
þ20.6 (c 0.1, CHCl3). 1H
D
2008, 73, 3634e3637 and references therein.
NMR:
d
1.95 (broad s, 4H, NH2); 3.68 (s, 3H, OCH3); 3.70 (d, J¼5.9,
€
€
7. (a) Schollkopf, U. Top. Curr. Chem. 1983, 109, 65e84; (b) Grauert, M.; Schollkopf,
U. Liebigs Ann. Chem. 1985, 1817e1824; (c) Undheim, K. Amino Acids 2008, 34,
357e402.
1H, H-3); 4.24 (d, J¼5.9, 1H, H-2); 7.20e7.40 (m, 5H, Ph). 13C NMR:
d
52.1 (OCH3); 58.9 (C-3); 60.8 (C-2); 126.9e128.7 (Ph); 141.6 (Ph);
8. (a) Dalla Croce, P.; La Rosa, C.; Pizzatti, E. Tetrahedron: Asymmetry 2000, 11,
2635e2642; (b) Cremonesi, G.; Dalla Croce, P.; La Rosa, C.; Pizzatti, E. Hetero-
cycles 2003, 61, 563e567.
174.5 (CO). Anal. Calcd for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42.
Found: C, 61.79; H 7.18; N, 14.35. MS-ESIþ (m/z): 195 [MþH]þ.
9. (a) Dalla Croce, P.; Ferraccioli, R.; La Rosa, C.; Pizzatti, E. Heterocycles 2000, 52,
1337e1344; (b) Cremonesi, G.; Dalla Croce, P.; Fontana, F.; La Rosa, C. Tetra-
hedron: Asymmetry 2006, 17, 2637e2641; (c) Cremonesi, G.; Dalla Croce, P.;
Fontana, F.; Forni, A.; La Rosa, C. Tetrahedron: Asymmetry 2007, 18, 1667e1675;
(d) Cremonesi, G.; Dalla Croce, P.; Fontana, F.; Fiorelli, C.; La Rosa, C. Tetrahe-
dron: Asymmetry 2008, 19, 2850e2855; (e) Cremonesi, G.; Dalla Croce, P.; Forni,
A.; Gallanti, M.; Gandolfi, R.; La Rosa, C. Tetrahedron: Asymmetry 2009, 20,
1940e1947.
4.3.4. Methyl (2S,3S)-2-amino-3-{[(benzyloxy)carbonyl]amino}3-
20
phenylpropanoate (6e). Amorphous solid (28.5 mg, 58%). [a]
D
þ10.1 (c 1.4, CHCl3). 1H NMR:
d 1.58 (broad s, 2H, NH2); 3.69 (s, 3H,
OCH3); 3.83 (d, J¼4.4, 1H, H-3); 5.08 (AB system, J¼12.1, 18.8, 2H,
CH2); 5.21 (broad dd, J¼4.4, 8.6 1H, H-2); 6.18 (broad d, J¼8.6, 1H,
NH); 7.18e7.40 (m, 10H, Ph). 13C NMR:
d 52.6 (OCH3); 56.8 (C-3);
10. Cremonesi, G.; Dalla Croce, P.; Forni, A.; Gallanti, M.; La Rosa, C. Tetrahedron
2011, 67, 2925e2933.
58.6 (C-2); 67.1 (CH2); 126.6e128.9 (Ph); 136.7 (Ph); 137.9 (Ph);
155.8 (CO); 173.6 (CO). Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14;
N, 8.53. Found: C, 65.76; H 6.04; N, 8.45. MS-ESIþ (m/z): 329
[MþH]þ.
€
11. Schollkopf, U.; Busse, U.; Lonsky, R.; Hinrichs, R. Liebigs Ann. Chem. 1986,
2150e2163.
12. Hartwig, W.; Mittendorf, J. Synthesis 1991, 939e941.
13. Reetz, M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek, R.;
Maus, S. Chem. Ber. 1985, 118, 1421e1440.
14. (a) O’Donnell, M. J.; Bennet, W. D.; Bruder, W. A.; Jacobsen, W. N.; Knuth, K.;
LeClef, B.; Polt, R. L.; Bordwell, F. G.; Mrozack, S. R.; Cripe, T. A. J. Am. Chem. Soc.
1988, 110, 8520e8525; (b) Malkhasyan, A. T. S.; Asatryan, E. M.; Mirakyan, S. M.;
MartiroSyan, G. T.; Beletskava, I. P. Zh. Org. Khim. 1981, 17, 467e470.
15. The addition was unsuccessful even using 2 equiv of the anion of (2R)-1 or
using LDA as the base.
4.3.5. Methyl (2S,3S)-2-amino-3-phenyl-3-[(phenylsulfonyl)amino]
propanoate (6f). Amorphous solid (30.1 mg, 60%). [
a
]
20 þ28.6 (c 0.8,
D
CHCl3). 1H NMR:
d
1.61 (broad s, 2H, NH2); 3.61 (s, 3H, OCH3); 3.76
(d, J¼4.4, 1H, H-3); 4.90 (broad s, 1H, H-2); 6.20 (broad s, 1H, NH);
6.93e7.41 (m, 8H, Ph); 7.63 (d, J¼7.3, 2H, Ph). 13C NMR:
d 52.3
16. (a) Cliffe, I. A.; Crossley, R.; Shephed, R. G. Synthesis 1985, 1138e1140; (b)
Emling, B. L.; Horvath, R. J.; Saraceno, A. J.; Ellermeyer, E. F.; Haile, L.; Hudac, L.
D. J. Org. Chem. 1959, 24, 657e660.
(OCH3); 58.7 (C-3); 59.0 (C-2); 125.5e132.4 (Ph); 135.8 (Ph); 140.9
(Ph); 173.0 (CO). Anal. Calcd for C16H18N2O4S: C, 57.47; H, 5.43; N,
8.38. Found: C, 57.39; H 5.38; N, 8.30. MS-ESIþ (m/z): 335 [MþH]þ.
€
€
17. (a) Busch, K.; Groth, U. M.; Kuhnle, W.; Schollkopf, U. Tetrahedron 1992, 48,
5607e5618; (b) Efskind, J.; Hope, H.; Undheim, K. Eur. J. Org. Chem. 2002,
464e467.
€
18. (a) Schollkopf, U.; Groth, U. Angew. Chem., Int. Ed. Engl. 1981, 20, 977e978; (b)
Acknowledgements
€
€
Schollkopf, U.; Nozulak, J.; Groth, U. Synthesis 1982, 864e866; (c) Schollkopf, U.;
Groth, U.; Gull, M.; Nozulak, J. Liebigs Ann. Chem. 1983, 1133e1151; (d) Neu-
€
bauer, H.; Baeza, J.; Freer, J.; Schollkopf, U. Liebigs Ann. Chem. 1985, 1508e1511;
The authors thank Dr. Marta Brambilla for helpful assistance.
References and notes
(e) Kim, S.; Kim, E.; Ko, H.; Jung, Y. H. Synthesis 2003, 2194e2198.
19. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920e1923.
20. (a) Despite the mild conditions used, the NMR analysis of the crude reaction
mixture showed the absence of the signals due to the phenyl group. (b) Ta-
sheva, D.; Angelova, O.; Dryanska, V. J. Chem. Res., Synop. 1998, 428e429.
21. Lee, S.; Yoon, J.; Chung, S.; Lee, Y. Tetrahedron 2001, 57, 2139e2145.
22. Davis, F. A.; Deng, J. Org. Lett. 2004, 6, 2789e2792.
€
1. Kleinkauf, H.; von Dohren, H. Eur. J. Biochem. 1990, 192, 1e15.
2. Rossi, F. M.; Powers, E. T.; Yoon, R.; Rosenberg, L.; Meinwald, J. Tetrahedron 1996,
52, 10279e10286.
23. Zhou, X.; Lin, Y.; Dai, L. Tetrahedron: Asymmetry 1999, 10, 855e862.
3. (a) Groebke, K.; Renold, P.; Tsang, K. Y.; Allen, T. J.; McClure, K. F.; Kemp, D. S.
Proc. Natl. Acad. Sci. 1996, 93, 4025e4029; (b) Battiste, J. L.; Mao, H.; Rao, N. S.;
Tan, R.; Mahandiram, D. R.; Kay, L. E.; Frankel, A. D.; Williamson, J. R. Science
1996, 273, 1547e1551; (c) Kretsinger, J. K.; Schneider, J. P. J. Am. Chem. Soc. 2003,
125, 7907e7913.
ꢀ
ꢁ
24. Boudou, C.; Berges, M.; Sagnes, C.; Sopkova-de Oliveira Santos, J.; Perrio, S.;
Metznert, P. J. Org. Chem. 2007, 72, 5403e5406.
25. Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964e12965.
26. Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191e1193.