Asymmetric synthesis of α,β-diamino acid derivates via Mannich-type reactions of a chiral Ni(ii) complex of glycine with N-tosyl imines

Article abstract of DOI:10.1039/c1ob05848g

A practical procedure composed of an asymmetric Mannich-type reaction between N-tosyl imine and a Ni(ii) complex of glycine with (R)-o-[N-(N- benzylprolyl)amino]bezaophenone (BPB) as a chiral auxiliary catalyzed by Et ₃N in DMF to (R,2R,3S)-com

Full text of DOI:10.1039/c1ob05848g

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PAPER
Asymmetric synthesis of a,b-diamino acid derivates via Mannich-type
reactions of a chiral Ni(II) complex of glycine with N-tosyl imines†
Guowei Song, Meihong Jin, Zhenjiang Li* and Pingkai Ouyang
Received 28th May 2011, Accepted 7th July 2011
DOI: 10.1039/c1ob05848g
A practical procedure composed of an asymmetric Mannich-type reaction between N-tosyl imine and a
Ni(II) complex of glycine with (R)-o-[N-(N-benzylprolyl)amino]bezaophenone (BPB) as a chiral
auxiliary catalyzed by Et3N in DMF to (R,2R,3S)-complexes, and decomposition of products with HCl
to offer syn-(2R,3S)-a,b-diamino acids, was developed. Stereochemical mechanism of the Mannich
reaction was proposed and supported by determining the absolute configuration of the product of the
Mannich reaction relying on X-ray analysis. This two-step approach to amino acids was a general
method and adapted to large-scale preparation.
Introduction
a,b-Diaminoacidsareimportantnon-codedaminoacids andhave
presented various biological significance.1 These diamino acids
have attracted a great deal of attention due mainly to the following
Scheme 1 Four strategies for the synthesis of a,b-diamino acids through
the Mannich-type reactions.
features: 1) free a,b-diamino acids were detected as biologically
active ingredients in natural products such as b-N-oxalyl-L-a,b-
diaminopropionic acid2 and L-b-methylaminoalanine3 in plants
leading to the Guam disease;4 2) a,b-diamino acids were found
as key structural fragments in natural peptidic antibiotics from
bacteria or marine organisms;5 3) a,b-diamino acids also were
used to synthesize peptidomimetics6 and other useful drugs;7 4)
a,b-diamino acids were found in the Murchison meteorite fell
in Australia in 1969 and considered to be essential materials for
peptide nucleic acids as evolutionary substance before life.8
In the past decades, a number of synthetic routes toward
a,b-diamino acids have been reported.1 Generally speaking, the
strategy by forming the basic carbon skeleton was an important
one, in which the Mannich reaction was significant to the synthesis
of a,b-diamino acids or their derivates. In the direct-type Mannich
reaction of three-component including an aldehyde, an amine
and an a-acidic carbonyl compound, a-amino acid ester was
seldom used as carbonyl donor to prepare a,b-diamino acids
due to the inadequate acidity of the a-proton.9 Instead, the
Mannich-type reactions focusing on utilizing preformed imines
and enolate equivalents attracted our attention.10 In Scheme
1, four strategies for the asymmetric synthesis of a,b-diamino
acids through the Mannich-type reactions between chiral or
achiral imines and chiral or achiral glycine ester derivatives were
illustrated. Catalytic asymmetric Mannich-type reactions were
widely investigated recently to prepare a,b-diamino acids (Scheme
1, strategy a).11 Organocatalytic methods12 and metal- catalyzed
methods13 with high diastereo- or enantiocontrol were applied
but limited in large scale enantiomeric synthesis for the aim of
medicine. Long reaction time and high loading of chiral catalyst
were required unless more efficient catalysts were developed. Other
methods to synthesize a,b-diamino acids through the Mannich-
type reaction using chiral auxiliary were applied in some case. The
imines with chiral directing group linking to nitrogen atom such as
sulfinimines were employed to prepare a,b-diamino acids (Scheme
1, strategy b).14 However, the limited categories of chiral imines
hindered general methods from developing. On the other hand,
glycine equivalents with chiral auxiliaries were plentiful and used
successfully in the large scale preparation of enantiopure amino
acids.15 To our surprise, the potential strategy by using glycine
equivalent with a chiral auxiliary in the Mannich-type reactions
with imines (Scheme 1, strategy c), was not well developed to
prepare a,b-diamino acids. Chiral Ni(II) complex of the Schiff
base of glycine 1 displayed unique reactivity and stereoselectivity
has been widely used to synthesize enantiopure tailor-made amino
acids successfully.15f,g Another focus of the Mannich-type reaction
is on searching for stable and activated imines due mainly to
pool reactivity and unstability of ordinary imines. Soloshonok
reported an asymmetric Mannich reaction of chiral Ni(II) complex
of glycine with the imine activated by CF3 group to synthesize
State Key Laboratory of Materials-Oriented Chemical Engineering, College
of Biotechnology and Pharmaceutical Engineering, Nanjing University of
Technology, 5 Xinmofan Road, Nanjing, 210009, China. E-mail: zjli@
njut.edu.cn; Fax: +86(25)83172083; Tel: +86(25)83172083
† Electronic supplementary information (ESI) available: Characterization
data (1H, 13C NMR and mass spectrometry) for all compounds, ratio of
diastereomers of kye intermediate products by 1H NMR analysis. CCDC
reference numbers 777524. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob05848g
7144 | Org. Biomol. Chem., 2011, 9, 7144–7150
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a,b-diamino acids (Scheme 2).16 Unfortunately, this fluorinated
imine run short of alterable structures. Liu and co-workers used
N-Boc-a-amido sulfones to replace imines.17 Strong base such
as NaH, t-BuOK and DBU et al. and long reaction time were
required due to the poor reactivity of these amido sulfones.
Especially, the a-amido sulfones derived from aliphatic aldehydes
gave low yields in the reactions. Thus, we were eager to search
for activated imines. As one of the few types of electron-deficient
imines, N-sulfonylimines with strong electron withdrawing group
at nitrogen atom were stable enough to be isolated but reactive
enough to undergo reactions.18
Scheme 3 The system of preparing a,b-diamino acids via the Mannich–
type reactions of a chiral Ni(II) complex of glycine with N-tosyl imines.
Table 1 The optimizing for the reaction conditions in the asymmetric
Mannich reaction between Ni(II) complex of glycine and N-tosyl imine
derived from benzaldehyde
Scheme 2 The strategies for the synthesis of a,b-diamino acids with
N-sulfonylimines in this work compared with previous work.
(R,2R,3S)-3/
Entry Basea
Solvent
DMF
t/h T/◦C (R,2R,3R)-3b
Yield (%)c
Herein, we reported a two-step approach to prepare a,b-
diamino acids via the Mannich-type reactions between N-
sulfonylimines 2 and (R)-Ni(II) complex of glycine 1 with (R)-o-[N-
(N-benzylprolyl)amino]benzophenone (BPB) as a chiral auxiliary
mediated by base (Scheme 3), which would be a general method
with high stereoselectivity.
1
2
3
NEt3
0.3
2
30
30
30
30
30
30
30
30
-60
60
90/10
74/26
—
81/19
—
—
—
—
89/11
—
81
56
Trace
51
Trace
—
—
Trace
83
NaOH DMF
NaH DMF
KOtBu DMF
12
2
4
5
6
7
8
9
10
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
THF
Acetone 24
CH2Cl2
MeCN
DMF
24
24
24
0.5
1
Results and discussion
DMF
—
The Ni(II)-complex 1 was synthesized in three steps based on an
improved method.19 N-Tosyl imines were produced as described
in the literature reported by us previously.20 A notable merit of
Ni(II) complex of glycine 1 was high acidity of the a-protons of
glycine part. The acidity of a-H1 (labeled in Scheme 3) of complex
1 (The pKa was about 17–19 in DMSO or 11–12 in water21) was
equal to phenol (The pKa was about 18 in DMSO). Thus, it could
use both inorganic base (even Na2CO3) and organic bases that can
lead to a mild condition of reaction to convert complex 1 into an
enolate form. Therefore, a wider range of bases can be selected to
catalyze the asymmetric Mannich reaction between Ni(II) complex
of glycine 1 and N-tosyl imines 2. Another consideration about
this reaction was about the solution which should be propitious
to the stabilization of enolate depending on the intermolecular
hydrogen bond. Also, complex 1 is a strong polar molecule
and the solvent should be able to dissolve the complex well.
Polar aprotic solvents would be good choices to this kind of
reaction.
a The reactions were carried out at 30 ◦C under N2. Ratio of complex
(R)-1/imine 2/base = 1/1.3–1.5/1–1.3; 10 mmol. b Determined by 1H
NMR analysis of crude reaction mixtures. c Chemical yield of (R,2R,3S)-
3 determined after their separation from unreacted substrate by column
chromatography.
(Table 1). First, we chose NEt3 to catalyze the asymmetric
Mannich-type reaction in DMF. The reaction proceeded smoothly
and an excellent yield was got within 20 min. Ratio of diastere-
omers of (R,2R,3S)-3 and (R,2R,3R)-3 was about 90/10 which was
determined by 1H NMR analysis of crude reaction mixtures. Then,
NaOH, NaH and t-BuOK were used to catalyze the reactions
(entry 2–4). Modest yield and lower diastereoselectivity were
obtained in the reactions when NaOH and t-BuOK were used
(entry 2 and 4). NaH was not a good choice for the reaction (entry
3). Further, we selected different solvents (entry 5–8) to investigate
the reactivity of the reaction and there were almost no reaction
products that were detected by TLC. At last, the temperature was
changed. The yield and diastereoselectivity had no conspicuous
changes at -60 ◦C (entry 9). At a higher temperature (60 ◦C),
Initially, we selected chiral (R)-Ni(II) complex of glycine 1
and N-tosyl imine derived from benzaldehyde as model reaction
for optimizing reaction conditions about bases and solvents
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a significant decomposition of the Ni(II)complex was observed
(entry 10).
Encouraged by the good reactivity of this asymmetric
Mannich-type reaction with NEt3 in DMF, we investigated the
stereoselectivity of the reaction further using the same model
above. The temperature of the inter-conversion about E, Z of C,N
double bound was about 50 ◦C (theDG# value was about 16 kcal
mol-1).22 So N-tosyl imines existed mainly in the way of E-isomer
at 30 ◦C. The enolate of chiral complex 1 was attacked at the
position of a-C of glycine by E-N-benzylidene-4-methylbenzene-
sulfonimide which worked as electrophilic reagent. In the light of
the chiroptical properties of complex 1, a-C of glycine generated
to be the second chiral center which was determined to be (R)-
configuration.16,17,23 The configuration of b-C came from the car-
bon of C,N double bound was first deduced from the steric effect
of complex 3 (Fig. 1). In the mixture of products, (R,2R,3S)-3 was
predominantly isomer. A serious nonbonded repulsion between
the substituting group at b-C and the neighboring phenyl group
was responsible for this preference. The steric repulsion in isomer
(R,2R,3R)-3 was much stronger than that in (R,2R,3S)-3 (Fig. 2).
The largest group kept away from the Ni(II)-complex plane and
the neighboring phenyl group to avoid the most serious repulsion.
In order to prove our inference, we got the absolute configuration
Fig. 2 (R,2R,3S)-3: the absolute configuration of the main product of the
Mannich reaction determined by X-ray analysis.
of the major product by single crystal X-ray diffraction (Figure
2). The major product was (R,2R,3S)-3 as we presumed above.
Having determined the absolute configuration of (R,2R,3S)-3,
the scope of the reaction was investigated. First, serial N-tosyl
imines derived from adipic, aromatic and heterocyclic aldehydes
were prepared. Then the asymmetric Mannich-type reactions of
chiral Ni(II) complex of glycine 1 with N-sulfonyl imines were
checked. As summarized in Table 2, we established that both
aromatic (Table 2, entries 1–5) and heterocyclic (entry 6) N-tosyl
imines had a good yield and diastereoselectivity. Excitingly, adipic
imine (entry 7) also had a satisfactory yield and diastereose-
lectivity. The aromatic imines with electron-withdrawing groups
in substituent (entries 4–5) had better reactivity than that with
electron-donating groups (entries 2–3).
Fig. 1 The probable products of the asymmetric Mannich-type reactions.
Table 2 Asymmetric Mannich-type reactions of chiral Ni(II) complex of glycine with N-sulfonyl imines, using NEt3 in DMFa
Entry
R
3
T/min
Ratio of diastereomers (R,2R,3S)-3/(R,2R,3R)-3b
Yield (%)c
1
2
3
4
5
6
7
Phenyl
3a
3b
3c
3d
3e
3f
20
38
35
18
15
30
25
90/10
91/9
89/11
86/14
89/11
87/13
78/22
81
76
79
82
85
86
74
4-Methoxyphenyl
4-Methyphenyl
3-Nitrophenyl
2-Chlorophenyl
2-Furyl
Isobutyl
3g
a The reactions were carried out at 30 ◦C under N2. Ratio of complex (R)-1/imine 2/base = 1/1.5/1–1.3; 10 mmol scale. b Determined by 1H NMR analysis
of crude reaction mixtures. c Chemical yield of (R,2R,3S)-3 determined after their separation from unreacted substrate by column chromatography.
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Table 3 The preparation of (2R,3S)-diamino acids derivates by hydrolyzing the main products (R,2R,3S)-3 of the Mannich-type reactionsa
Entry
R
4
Yield (%)b
Syn-(2R,3S)-4:Anti-(2R,3S)-4c
1
2
3
4
5
6
7
Phenyl
4a
4b
4c
4d
4e
4f
84
80
81
87
84
86
82
95 : 5
4-Methoxyphenyl
4-Methyphenyl
3-Nitrophenyl
2-Chlorophenyl
2-Furyl
> 99 : 1
> 99 : 1
99 : 1
> 99 : 1
> 99 : 1
> 99 : 1
Isobutyl
4g
a 20 mmol of the complex 3 was decomposed in 50 mL MeOH with 20 mL 6 N HCl at 70 ◦C. b Isolated yield of (2R,3R)-4 determined after their from
reaction mixture by column chromatography. c Determined by 1H NMR of amino acids 4 after recrystallization from alcohol.
a,b-Diamino acids were generated by hydrolyzing the Ni(II)-
complex 3 at 70 ◦C with 6 N HCl in MeOH. The chiral auxiliary
(R)-BPB was recovered in 90% yield which can be used in the
regeneration of Ni(II)-complex of glycine 1. The target amino acids
were then obtained by separation from a H+ form ion exchange
resin column in aqueous phase. The result had showed in Table
3. The amino acids (2R,3S)-4 were got with excellent yield and
syn-selectivity, which can be prepared on multi-gram scales (over
20 g).
internal standard. Mass spectra were recorded on an ABI Mariner
ESI-TOF instrument. X-ray diffraction data were collected in a
D/Max-RA automatic diffractometer.
General procedures for the synthesis of (R,2R,3S)-3
To a solution of complex 1 (5.0 g, 10 mmol) and DMF (20 mL)
was added imine (15 mmol) and NEt3 (1.4–1.8 mL, 10–13 mmol)
in one portion with vigorous stirring under inert gas at 30 ◦C.
The reaction was monitored by TLC (EtOAc : CH2Cl2 = 5 : 1).
The reaction mixture was stirred for 0.5 h and then quenched
with 5% aqueous acetic acid (500 mL). The crystals formed in
refrigerator at 0–5 ◦C overnight. The crystals were filtered off,
washed with H2O and dried in vacuum at 50 ◦C. Products 3
were obtained by the purification of crude products with silica gel
(column 25 ¥ 4 cm, EtOAc : CH2Cl2 = 3 : 1), and further purified
by the recrystallization from EtOH.
Conclusion
In summary, we have successfully developed a general method
to synthesize a,b-diamino acids via the asymmetric Mannich-
type reactions between Ni(II) complex of glycine with N-tosyl
imines including aryl-, heteroaryl- and alkyl-derived imines. All
the reactions had good reactivity and stereoselectivity within one
hour catalyzed by Et3N in DMF. The absolute configuration of
the main products of Mannich reactions was determined to be
(R,2R,3S)-configuration by X-ray analysis and syn-(2R,3S)-a,b-
diamino acids were obtained in excellent yield. This asymmetric
Mannich-type reaction was a general, mild and high performance
method to prepare a,b-diamino acids on multi-gram scale.
(R,2R,3S)-3a. Yield red solid (6.1 g, 81%), mp 177–180 ◦C,
dH (500 MHz; CDCl3) 1.41–1.44 (1H, m, Pro-H), 1.73–1.76 (1H,
m, Pro-H), 1.85–1.86 (1H, m, Pro-H), 1.91–2.09 (1H, m, Pro-H),
2.10–2.24 (1H, m, Pro-H), 2.30 (3H, s, -CH3), 2.83–2.84 (1H, m,
Pro-H), 3.16–3.20 (1H, m, Pro-H), 3.36 (1H, d, J 12.5 Hz, CH2Ph),
4.11 (1H, d, J 12.5 Hz, CH2Ph), 4.38 (1H, d, J 4.8 Hz, a-CH),
4.51–4.52 (1H, dd, J 4.8 Hz, J 9.2 Hz, b-CH), 6.66–6.70 (2H,
m, ArH), 6.86 (1H, d, J 9.2 Hz, ArH), 6.95 (2H, d, J 8.0 Hz,
ArH), 7.09 (2H, d, J 7.4 Hz, ArH), 7.12–7.21 (4H, m, ArH), 7.26–
7.33 (5H, m, ArH), 7.37–7.40 (1H, t, ArH), 7.56–7.63 (3H, m,
ArH), 7.95 (2H, d, J 7.3 Hz, ArH), 8.26 (1H, d, J 8.6 Hz, ArH);
dC (125 MHz; CDCl3; Me4Si) 21.25, 22.78, 30.39, 57.06, 57.18,
63.61, 70.30, 72.57, 120.55, 123.13, 125.66, 126.32, 126.43, 127.63,
128.22, 128.43, 128.67, 128.74, 129.39, 129.56, 130.30, 131.32,
132.89, 133.18, 133.57, 133.86, 136.18, 138.35, 142.28, 143.24,
173.45, 177.38, 180.13; MS (ESI+) m/z 757.2 [M+H]+.
Experimental
All air or moisture-sensitive reactions were carried out under
nitrogen or argon atmosphere and glassware was dried at high
temperature and cooled under nitrogen before use. Solvents were
purified and stored according to standard procedures. Thin layer
chromatography was performed using silica gel plates coated with
GF254 silica. Plates were visualised using UV light (254 nm).
Column chromatography was performed in glass columns with
G60 silica (100–200 mesh). Melting points were recorded on a
XRC-1 and were uncorrected. H NMR (300 or 500 MHz) and
(R,2R,3S)-3b. Yield red solid (6.0 g, 76%), mp 183–185 ◦C,
dH (500 MHz; CDCl3; Me4Si) 1.46–1.48 (1H, m, Pro-H), 1.88–
1.91 (H, m, Pro-H), 2.05–2.08 (1H, m, Pro-H), 2.16–2.18 (1H, m,
1
13C NMR (125 MHz) were recorded on a Bruker DRX 300 or
Varian 500 spectrometer. J values are reported in Hz and TMS as
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Pro-H), 2.32 (3H, s, -CH3), 2.90–2.92 (1H, m, Pro-H), 3.19–3.21
(1H, m, Pro-H), 3.36 (1H, d, J 12.6 Hz, CH2Ph), 3.80 (3H, s,
-OCH3), 4.13 (1H, d, J 12.6 Hz, CH2Ph), 4.34 (1H, d, J 4.7 Hz, a-
CH), 4.45–4.48 (1H, dd, J 4.7 Hz, J 9.1 Hz, b-CH), 6.67–6.68 (2H,
m, ArH), 6.78 (1H, d, J 9.2 Hz, ArH), 6.84 (2H, d, J 8.7 Hz, ArH),
6.97 (2H, d, J 8.0 Hz, ArH), 7.00 (2H, d, J 8.6 Hz, ArH), 7.12–
7.16 (3H, m, ArH), 7.21 (2H, d, J 8.6 Hz, ArH), 7.26–7.29 (3H, m,
ArH), 7.57–7.58 (3H, m, ArH), 7.97 (2H, d, J 7.1 Hz, ArH), 8.25
(1H, d, J 8.6 Hz, ArH); dC (125 MHz; CDCl3) 21.27, 22.70, 30.38,
55.26, 56.68, 57.34, 63.69, 70.35, 72.68, 76.75, 77.00, 77.26, 114.00,
120.55, 123.12, 125.68, 126.35, 126.50, 127.61, 128.10, 128.68,
129.36, 129.50, 129.53, 130.27, 131.33, 132.84, 133.22, 133.57,
133.83, 138.47, 142.20, 143.20, 159.86, 173.31, 177.48, 180.13; MS
(ESI+) m/z 787.2 [M+H]+.
(1H, m, ArH), 6.87–6.89 (1H, m, ArH), 6.91–6.97 (4H, m, ArH),
6.98–7.00 (1H, m, ArH), 7.05–7.09 (1H, m, ArH), 7.09–7.14 (3H,
m, ArH), 7.25–7.29 (2H, m, ArH), 7.35–7.45 (2H, m, ArH), 7.54
(2H, d, J 7.1 Hz, ArH), 8.05 (2H, d, J 7.2 Hz, ArH), 8.30 (1H, d,
J 8.6 Hz, ArH). dC(125 MHz; CDCl3) 21.25, 23.85, 30.77, 57.36,
63.46, 70.78, 72.08, 76.74, 77.00, 77.25, 120.32, 123.20, 125.84,
126.89, 127.24, 127.47, 128.52, 128.66, 128.79, 128.83, 128.91,
128.98, 129.26, 129.50, 130.11, 131.40, 132.76, 132.98, 133.18,
133.34, 133.64, 133.97, 136.49, 143.17, 143.21, 172.32, 179.92,
180.15; MS (ESI+) m/z 791.1 [M+H]+.
(R,2R,3S)-3f. Yield red solid (6.3 g, 86%) mp 185–188 ◦C,
dH (500 MHz; CDCl3) 1.64–1.67 (1H, m, Pro-H), 1.87–1.93 (1H,
m, Pro-H), 2.21–2.26 (1H, m, Pro-H), 2.28 (3H, s, -CH3), 2.31–
2.33 (1H, m, Pro-H), 2.43–2.46 (1H, m, Pro-H), 3,12–3.16 (1H,
m, Pro-H), 3.19–3.23 (1H, m, Pro-H), 3.44 (1H, d, J 12.7 Hz,
CH2Ph), 4.16 (1H, d, J 12.6 Hz, CH2Ph), 4.18 (1H, d, J 5.1 Hz,
a-CH), 4.48–4.51 (1H, dd, J 5.5 Hz, J 9.1 Hz, b-CH), 6.21 (1H,
d, J 3.2 Hz, Furan-H), 6.33–6.34 (1H, m, Furan-H), 6.54–6.60
(2H, m, ArH), 6.77 (1H, d, J 9.1 Hz, Furan-H), 7.00 (2H, d, J
8.2 Hz, ArH), 7.04 (1H, d, J 7.0 Hz, ArH), 7.06–7.09 (2H, m,
ArH), 7.16 (1H, d, J 7.2 Hz, ArH), 7.20 (1H, d, J 5.2 Hz, ArH),
7.22–7.24 (3H, m, ArH), 7.33–7.34 (1H, m, ArH), 7.43–7.52(3H,
m, ArH), 7.90 (2H, d, J 7.7 Hz, ArH), 8.18 (1H, d, J 8.7 Hz,
ArH). dC(125 MHz; CDCl3) 21.34, 22.86, 30.43, 51,25, 57.00,
63.59, 70.40, 70.65, 76.75, 77.00, 77.25, 109.49, 110.89, 120.56,
123.15, 125.88, 126.15, 126.46,127.82, 128.73, 128.80, 129.07,
129.30, 129.52, 130.31, 131.39, 132.83, 133.09, 133.59, 133.81,
138.00, 142.46, 142.83, 142.84, 143.09, 150.38, 173.76, 177.47,
180.06; MS (ESI+) m/z 747.2 [M+H]+.
(R,2R,3S)-3c. Yield red solid (6.1 g, 79%), mp 183–185 ◦C,
dH (500 MHz; CDCl3) 1.43–1.45 (1H, m, Pro-H), 1.76–1.78(1H,
m, Pro-H), 1.85–1.89 (1H, m, Pro-H), 2.01–2.03 (1H, m, Pro-H),
2.15–2.20 (1H, m, Pro-H), 2.32 (3H, s, -CH3), 2.37 (3H, s, -CH3),
2.86–2.90 (1H, m, Pro-H), 3.17–3.21 (1H, m, Pro-H), 3.37 (1H, d,
J 12.6 Hz, CH2Ph), 4.13 (1H, d, J 12.6 Hz, CH2Ph), 4.34 (1H, d,
J 4.8 Hz, a-CH), 4.45–4.48 (1H, dd, J 4.8 Hz, J 9.1 Hz, b-CH),
6.67–6.68 (2H, m, ArH), 6.79 (1H, d, J 9.2 Hz, ArH), 6.95–6.98
(4H, m, ArH), 7.11–7.17 (5H, m, ArH), 7.20 (2H, d, J 8.3 Hz,
ArH), 7.25–7.28 (3H, m, ArH), 7.55–7.61 (3H, m, ArH), 7.96
(2H, d, J 7.1 Hz, ArH), 8.26 (1H, d, J 8.6 Hz, ArH). dC(125 MHz;
CDCl3) 21.08, 21.29, 22.55, 30.27, 56.90, 57.24, 63.66, 70.35, 72.56,
76.74, 76.99, 77.25, 120.55, 123.14, 125.69, 126.35, 126.51, 127.65,
128.35, 128.69, 128.76, 128.83, 129.30, 129.36, 129.54, 130.28,
131.34, 132.86, 133.16, 133.20, 133.59, 133.85, 138.06, 138.44,
142.23, 143.22, 173.33, 177.45, 180.07; MS (ESI+) m/z 771.2
[M+H]+.
(R,2R,3S)-3g. Yield red solid (6.1 g, 74%), mp 213–215 ◦C. dH
(300 MHz; CDCl3) 1.24–1.28 (1H, m, Pro-H), 1.40–1.44 (1H, m,
Pro-H), 1.58 (6H, s, -CH3), 1.67–1.87 (2H, m, Pro-H), 2.02–2.05
(1H, m, -CH), 2.14–2.19 (2H, m, -CH2), 2.31 (3H, s, -PhCH3),
2.79–2.86 (1H, m, Pro-H), 3.15–3.21 (1H, m, Pro-H), 3.38 (1H, d,
J 12.0 Hz, -CH2Ph), 4.10 (1H, d, J 12.0 Hz, -CH2Ph), 4.38 (1H,
d, J 4.8 Hz, a-CH), 4.49–4.54 (1H, dd, J 4.9 Hz, J 4.8 Hz, b-CH),
6.69–6.70 (2H, m, ArH), 6.83(1H, d, J 6.3 Hz, ArH), 6.94–6.97
(2H, m, ArH), 7.08–7.10 (2H, m, ArH), 7.14–7.21 (4H, m, ArH),
7.28–7.31 (3H, m, ArH), 7.58–7.61 (2H, m, ArH), 7.95 (2H, d, J
8.4 Hz, ArH), 8.26 (1H, d, J 9.0 Hz, ArH). dC (125 MHz; CDCl3)
21.41, 23.64, 30.70, 57.53, 61.25, 63.15, 69.92, 76.75, 77.00, 77.25,
120.80, 124.22, 125.14, 126.23, 126.35, 128.87, 129.07, 129.15,
129.30, 129.52, 129.56, 129.68, 132.69, 132.16, 133.13, 133.34,
134.61, 142.54, 171.62, 177.27, 181.37. MS (ESI+) m/z 737.23
[M+H]+; HRMS (ESI+) m/z: Calc. for C39H42N4NiO5S: 737.2297
[M+H]+. Found 737.2316.
(R,2R,3S)-3d. Yield red solid (6.6 g, 82%), mp 194–196 ◦C,
dH (500 MHz; CDCl3; Me4Si) 1.45–1.47 (1H, m, Pro-H), 1.63–
1.67 (2H, m, Pro-H), 1.78–1.80 (1H, m, Pro-H), 1.89–1.91 (1H,
m, Pro-H), 2.16 (3H, s, Pro-H), 2.27 (3H, s, -CH3), 2.81–2.82 (1H,
m, Pro-H), 3.17–3.21 (1H, m, Pro-H), 3.38 (1H, d, J 12.7 Hz,
CH2Ph), 4.12 (1H, d, J 12.7 Hz, CH2Ph), 4.40 (1H, d, J 4.9 Hz,
a-CH), 4.58–4.61 (1H, dd, J 4.9 Hz, J 8.8 Hz, b-CH), 6.69–6.75
(2H, m, ArH), 6.94–6.96 (3H, m, ArH), 7.12–7.15 (1H, m, ArH),
7.17–7.22 (4H, m, ArH), 7.26–7.29 (1H, m, ArH), 7.32–7.33 (1H,
m, ArH), 7.39 (1H, d, J 7.6 Hz, ArH), 7.57–7.60 (1H, m, ArH),
7.62–7.67 (3H, m, ArH), 7.81 (1H, s, ArH), 7.92 (2H, d, J 7.3 Hz,
ArH), 8.23 (1H, d, J 8.7 Hz, ArH), 8.30 (1H, d, J 8.7 Hz, ArH);
dC (125 MHz; CDCl3) 21.20, 22.61, 30.45, 56.67, 57.05, 63.67,
70.13, 71.86, 76.74, 77.00, 77.25, 120.81, 123.06, 123.13, 123.23,
125.36, 126.35, 127.53, 128.83, 129.18, 129.41, 129.72, 129.75,
130.65, 131.30, 133.10, 133.44, 134.06, 134.98, 138.12, 138.46,
142.95, 143.40, 148.81, 174.25, 176.82, 180.08; MS (ESI+) m/z
802.2 [M+H]+.
X-Ray crystal structure determination for 3a
The crystalline sample of 3a recrystallised from ethanol. Data were
collected using a D/Max-RA automatic diffractometer with Mo-
Ka graphite monochromated radiation using standard procedures
at 293 K. The structure was solved and refined using SHELXS-97.
(R,2R,3S)-3e. Yield red solid (6.7 g, 85%), mp 179–182 ◦C,
dH (500 MHz; CDCl3) 2.10–2.14 (1H, m, Pro-H), 2.16–2.19 (1H,
m, Pro-H), 2.20 (3H, s, -CH3), 2.57–2.62 (1H, m, Pro-H), 2.94–
2.98 (1H, m, Pro-H), 3.45–3.49 (2H, m, Pro-H), 3.53 (1H, d,
J 12.7 Hz, CH2Ph), 3.66–3.69 (1H, m, Pro-H), 4.23 (1H, d, J
7.4 Hz, CH2Ph), 4.36–4.38 (1H, d, J 12.7 Hz, a-CH), 5.67–5.68
(1H, m, -NH), 5.75 (1H, d, J 7.5 Hz, b-CH), 6.36–6.38 (1H, dd,
J 1.6 Hz, J 8.3 Hz, ArH), 6.55–6.56 (1H, m, ArH), 6.57–6.58
X-Ray crystal structure data for 3a. Empirical formula:
C41H38N4NiO5S C2H5OH; formula weight: 803.09; crystal dimen-
sions = 0.40 ¥ 0.30 ¥ 0.10 mm; crystal colour: red; crystal system:
monoclinic; space group: P21; lattice parameters: a = 9.859(2),
3
˚
˚
b = 17.767(2), c = 12.361(3) A, b = 91.25(3), V = 2164.7(8) A ;
7148 | Org. Biomol. Chem., 2011, 9, 7144–7150
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Z = 2; m = 0.546 mm-1, Dc = 1.415 Mg m-3; R1 = 0.1003, wR2 (I
> 2s(I)) = 0.1919, R2 = 0.0678, wR2 (all data) = 0.1661; CCDC
number: 777524.
(2R,3S)-4f. Yield white solid (5.6 g, 86%), mp 185–188 ◦C,
[a]3D0 -12.6 (c 1, H2O). dH (500 MHz; DMSO-d6) 2.35 (3H, s,
-CH3), 3.29 (1H, d, J 4.9 Hz, a-CH), 4.81 (1H, d, J 4.9 Hz, b-CH),
6.12–6.14 (1H, m, Furan-H), 6.22 (1H, s, Furan-H), 7.29 (2H, d,
J 8.0 Hz, ArH), 7.38 (1H, d, J 7.1 Hz, Furan-H), 7.58 (2H, d,
J 8.1 Hz, ArH). dC (125 MHz; DMSO-d6) 20.82, 51.29, 54.32,
108.25, 110.08, 126.23, 129.23, 129.28, 138.27, 142.37, 142.44,
150.28, 168.65. MS (ESI+) m/z 324.1 [M+H]+.
General procedures for the synthesis of (2R,3S)-4
Complex 3 (15.0–16.0 g, 20 mmol) was decomposed by refluxing
with methanolic solution of 6 N HCl (20 mL) until the solution
was clean. Then the solution was evaporated to dryness. Water
(50 mL) was added to the residue and the insoluble material was
filtered, washed with water and dried to afford (R)-BPB·HCl. To
the aqueous layer a solution of aq. NH3 was added to pH 6 and
the solution was extracted with CHCl3 several times. Amino acid
4 was recovered from the solution by the ion-exchange technique
(H+ form).
(2R,3S)-4g. Yield white solid (5.2 g, 82%), mp 213–215 ◦C,
[a]3D0 -19.8 (c 1, H2O). dH (300 MHz; D2O + HCl) 0.11–0.13 (3H,
d, J 10.0 Hz, -CH3), 0.34–0.36 (3H, d, J 10.0 Hz, -CH3), 0.83–0.87
(1H, m, -CH), 1.00–1.08 (2H, m, -CH2), 2.08 (3H, s, -PhCH3),
3.46–3.48 (1H, m, b-CH), 3.82–3.83 (1H, d, J 5.0 Hz, a-CH), 7.09–
7.12 (2H, d, J 15.0 Hz, ArH), 7.45–7.47 (2H, d, J 10.0 Hz, ArH).
dC (125 MHz; D2O + HCl) 23.23, 23.48, 24.37, 26.46, 43.00, 54.24,
59.20, 129.83, 132.86, 137.87, 148.22, 172.28; HRMS (ESI+) m/z:
Calc. for C14H22N2O4S: 337.1198 [M+Na]+. Found 337.1193.
(2R,3S)-4a. Yield white solid (5.6 g, 84%), mp 187–190 ◦C,
[a]3D0 -12.9 (c 1, H2O). dH (500 MHz; DMSO-d6) 2.32 (3H, s, -CH3),
3.21 (1H, d, J 5.3 Hz, a-CH), 4.61–4.62 (1H, d, J 5.3 Hz, b-CH),
7.17–7.19 (5H, m, ArH), 7.22 (2H, d, J 8.1 Hz, ArH), 7.47–7.52
(2H, m, ArH). dC (125 MHz; DMSO) 20.74, 55.67, 56.85, 126.16,
127.32, 127.77, 127.84, 129.17, 136.96, 138.29, 142.22, 168.59; MS
(ESI+) m/z 357.1 [M+Na]+.
Acknowledgements
We are grateful to the Major Science and Technology Research
Program of Ministry of Education of China (Grant No. 208049)
and the Major Basic Research and Development Program of
China (Grant No. 2009CB724700) for financial support.
(2R,3S)-4b. Yield white solid (5.8 g, 80%), mp 186–188 ◦C,
[a]3D0 -23.4 (c 1, H2O). dH (500 MHz; DMSO-d6) 2.33 (3H, S,
-CH3), 3.16–3.17 (1H, d, J 5.0 Hz, a-CH), 3.69 (3H, s, -OCH3),
4.55–4.56 (1H, d, J 5.0 Hz, b-CH), 6.70–6.72 (2H, m, ArH), 7.05–
7.07 (2H, m, ArH), 7.22–7.24 (2H, m, ArH), 7.48–7.50 (2H, m,
ArH). dC (125 MHz; DMSO) 20.85, 55.01, 55.22, 56.01, 113.44,
126.26, 128.61, 129.15, 129.29, 138.37, 142.27, 158.80, 168.27; MS
(ESI+) m/z 365.1 [M+H]+.
Notes and references
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[a]3D0 -15.5 (c 1, H2O). dH (500 MHz; D2O + HCl) 2.23 (s, 3H,
-PhCH3), 2.33 (s, 3H, -CH3), 3.14–3.15 (1H, d, J 5.0 Hz, a-CH),
4.54–4.55 (1H, d, J 5.0 Hz, b-CH), 6.96–6.97 (2H, d, J 5.0 Hz,
ArH), 7.02–7.04 (2H, d, J 10.0 Hz, ArH), 7.23–7.24 (2H, d, J
5.0 Hz, ArH), 7.49–7.51 (2H, d, J 10.0 Hz, ArH). dC (125 MHz;
DMSO-d6) 20.58, 20.85, 55.22, 56.31, 126.26, 127.86, 128.53,
129.30, 133.74, 136.71, 138.32, 142.35, 168.27. MS (ESI+) m/z
349.1 [M+H]+.
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(2R,3S)-4d. Yield white solid (6.6 g, 87%), mp 194–196 ◦C,
[a]3D0 -38.0 (c 1, H2O). dH (500 MHz; DMSO-d6) 2.25 (3H, s,
-CH3), 3.38 (1H, d, J 5.3 Hz, a-CH), 4.82 (1H, d, J 5.3 Hz, b-CH),
7.13 (2H, d, J 8.1 Hz, ArH), 7.41–7.46 (3H, m, ArH), 7.60 (1H, d,
J 7.6 Hz, ArH), 7.90 (1H, s, ArH), 8.00 (1H, d, J 8.1 Hz, ArH). dC
(125 MHz; DMSO-d6) 20.70, 55.87, 56.50, 122.30, 122.88, 126.17,
129.20, 134.84, 137.99, 138.69, 142.40, 147.30, 168.17. MS (ESI+)
m/z 380.1 [M+H]+.
(2R,3S)-4e. Yield white solid (6.3 g, 84%), mp 179–182 ◦C,
[a]3D0 -9.8 (c 1, H2O). dH (500 MHz; DMSO-d6) 2.25–2.27 (3H,
d, J 10.0 Hz, -CH3), 3.37–3.38 (2H, d, J 5 Hz, a-CH), 4.77–4.78
(1H, d, J 5.0 Hz, b-CH), 7.12–7.14 (2H, d, J 10.0 Hz, ArH),
7.40–7.47 (3H, m, ArH), 7.57–7.59 (1H, d, J 5.0 Hz, ArH), 7.88
(1H, m, ArH), 8.00–8.02 (1H, m, ArH). dC (125 MHz; DMSO-
d6) 20.67, 56.00, 56.61, 122.25, 122.85, 126.16, 129.43, 134.78,
138.78, 138.01, 138.80, 142.37, 147.31, 168.32; MS (ESI+) m/z
369.1 [M+H]+.
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7150 | Org. Biomol. Chem., 2011, 9, 7144–7150
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