Synthesis of enantiopure cyclic amino acid derivatives via a sequential diastereoselective Petasis reaction/ring closing olefin metathesis process

Article abstract of DOI:10.1016/j.tetasy.2017.01.001

A novel approach to the synthesis of enantiopure cyclic amino esters is reported. The utilization of allylboronic acid together with (S)-α-methylbenzylamine as a chiral auxiliary in the Petasis/Mannich reaction led to the formation of allylglycine derivatives in good yield and with high diastereoselectivity. Subsequent esterification, N-allylation followed by ring-closing metathesis (RCM) reaction enabled the preparation of enantiomerically pure cyclic α-amino acid derivatives.

Full text of DOI:10.1016/j.tetasy.2017.01.001

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of enantiopure cyclic amino acid derivatives via a
sequential diastereoselective Petasis reaction/ring closing olefin
metathesis process
⇑
Veronika A. Morozova, Irina P. Beletskaya, Igor D. Titanyuk
Department of Chemistry, Moscow State University, Leninski gory 1, bd.3, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the synthesis of enantiopure cyclic amino esters is reported. The utilization of allyl-
Received 24 November 2016
Revised 14 December 2016
Accepted 3 January 2017
Available online xxxx
boronic acid together with (S)-a-methylbenzylamine as a chiral auxiliary in the Petasis/Mannich reaction
led to the formation of allylglycine derivatives in good yield and with high diastereoselectivity.
Subsequent esterification, N-allylation followed by ring-closing metathesis (RCM) reaction enabled the
preparation of enantiomerically pure cyclic
a
-amino acid derivatives.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
describe its use in the construction of synthetically valuable build-
ing blocks, such as heterocyclic rings containing phosphorus,6 oxy-
gen or nitrogen,7 and have found wide application in natural
product synthesis,8 pharmaceutical research and drug develop-
ment.9 In certain cases cyclic amino acids were obtained by olefin
metathesis in high yields.10 However those methods are limited by
serious problems concerning the synthesis of metathesis precur-
sors, especially when enantiomerically pure compounds are
required, and are often accompanied by complicated techniques
and non-trivial synthetic approaches.
Peptides modified by nonproteinogenic amino acids are useful
building blocks for drug discovery. In particular, cyclic amino acids
have been the subject of growing interest because their incorpora-
tion into is one of the most prominent pathways leading to confor-
mationally constrained peptides and can lead to specific biological
activities.1 For example, (R)- and (S)-pipecolic acid are frequently
used fragments in a variety of physiologically active peptides and
drugs.2
The Petasis boronic acid Mannich reaction is a versatile multi-
component reaction of boronic acids, amines, and aldehydes,
which generates highly functionalized a-amino acids and a-amino
Herein we report a novel pathway to the synthesis of
enantiopure cyclic amino acid derivatives which consists of: (i)
Petasis/Mannich reaction utilizing glyoxylic acid and allylboronic
alcohols.3 The Petasis reaction is a powerful and atom-economical
method for the construction of structurally diverse secondary or
tertiary amine derivatives, and has been widely utilized as a key
step in the synthesis of many bioactive molecules and complex
natural products.4 In general, the Petasis reaction involves the
addition of a borono nucleophile to an iminium ion, resulting in
an assortment of compounds depending on the nature of the start-
ing compounds.
acid together with (S)-a-methylbenzylamine as the chiral auxiliary
to afford, in one-step, an allylglycine derivative; (ii) subsequent
etherification and N-allylation followed by Ru-mediated
intramolecular carbocyclization via ring-closing metathesis.
Herein we propose a simple inexpensive pathway to enantiopure
cyclic amino esters. Typical applications of this methodology are
demonstrated by the preparation of (R)- or (S)-pipecolic acid
derivatives.
The ring-closing metathesis (RCM) of dienes is one of the most
important methodologies used for the assembly of cyclic organic
compounds. Olefin metathesis has risen to prominence in organic
synthesis over the past decades, largely due to the development
of easy to handle catalysts that enable controlled reactions.5 RCM
represents a key step in many synthetic sequences: recent articles
2. Results and discussion
The Petasis/Mannich reaction was used to synthesize
optically active allylglycine derivatives. In order to stimulate the
stereoselective constraction of the newly formed stereogenic
center, the following available enantiomerically pure amines and
sulfinamides were applied to the Petasis/Mannich reaction: (S)-1-
phenylethylamine 5, (S)-N-allyl-1-phenylethylamine, (S)-N-Boc-1-
⇑
Corresponding author.
E-mail address: Titanyuk@org.chem.msu.ru (I.D. Titanyuk).
http://dx.doi.org/10.1016/j.tetasy.2017.01.001
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Morozova, V. A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.001

2
V. A. Morozova et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
phenylethylamine, (S)-p-toluenesulfinamide and (R)-t-butanesulfi-
namide. The choice of these substrates has been made so that the
nitrogen atom could further be readily deprotected and the chiral
auxiliary removed via hydrogenation or acid hydrolysis. It was
found that only (S)-1-phenylethylamine 5 afforded the desired
amino acid in high yield and with good diastereoselectivity. The
three-component reaction of this amine with glyoxylic acid and
allylboronic acid was performed in dichloromethane at room tem-
perature to give allylglycine derivative 3 in 81% yield and with 93:7
dr (Scheme 1).
(S)-N-Allyl-1-phenylethylamine and (S)-N-Boc-1-phenylethy-
lamine appeared to be ineffective under same reaction conditions.
This is probably due to the steric hindrance and/or insufficient
nucleophilicity of the nitrogen atom, which prevents formation
of the iminium intermediate. Chiral sulfinamides were examined
as alternative auxiliaries, but reacted too slowly and the reaction
mixture required heating up to 50 °C. It was observed that (S)-p-
toluenesulfinamide provided the desired amino acid in low yield
(8%). (R)-t-Butanesulfinamide did not react at all.
Allylboronic acid pinacolate 4 was utilized as a starting allyl-
borono compound, which is stable and easy to handle in chemical
transformations (Scheme 1).
Unfortunately, pinacolate 4 provided worse results; 30% yield
and 37% de. The pinacol ester moiety is too bulky and thus makes
it more difficult for the allyl group to couple to the imine in com-
parison to unsubstituted allylboronic acid 2.
The application of (S)-1-phenylethylamine in the Petasis/Man-
nich reaction furnished product 3 with high diastereoselectivity
(de 86%). A similar asymmetric reaction of 2-phenylvinylboronic
acid with glyoxylic acid and (S)-1-phenylethylamine described by
Petasis and Zavialov11 gave a diastereoselectivity of only 66%.
The diastereomeric excess of 3 was determined by 1H NMR
spectroscopy and confirmed by chromatographic separation. The
spectrum of the diastereomeric mixture consisted of two sets of
signals corresponding to the major and minor isomers. Mostly
the identical signals of both isomers are overlapped but the peaks
assigned to CH3-group are distinctively different. The doublets at
1.66 and 1.60 ppm correspond to the major and minor isomer,
respectively, and their intensity can be easily integrated (Fig. 1).
(Scheme 3). Comparing the value of the specific rotation of 8 with
the literature data confirmed its (R)-configuration. Consequently,
we deduced that the (R,S)-configured amino acid 3 was predomi-
nantly obtained under Petasis/Mannich conditions.
The RCM precursors 9 and 10 were prepared via allylation of the
corresponding amino esters (R,S)-6 and (R,S)-7 by interaction with
allyl bromide (Scheme 4). This reaction failed under a variety of
conditions, which may be due to the steric hindrance caused by
the a-methylbenzyl group. It was relatively difficult to determine
the optimal solvent, base and temperature conditions to overcome
the main drawbacks: the low product yield and undesired by-prod-
ucts formation, which impeded the isolation of the amino esters.
We found that (R,S)-6 and (R,S)-7 were allylated (allyl bromide,
DMF, K2CO3, 80 °C, 12 h) to furnish compounds 9 and 10 in good
yield (60%). Unfortunately, amino esters underwent partial
epimerization during the course of reaction due to the slightly
acidic character of the hydrogen atom at the
a-carbon. Epimeriza-
tion was detected by means of NMR spectroscopy. Chromato-
graphic separation of the diastereomers for
unsuccessful.
9 and 10 was
It is well known that olefin metathesis of compounds contain-
ing a basic and nucleophilic nitrogen atom is difficult to achieve
because the Grubbs’ catalyst can be ‘poisoned’ which stops the
reaction. Our first attempt to carry out carbocyclization of amino
ester 9 using 5 mol % 1st generation Grubbs’ catalyst confirmed
this problem; the presence of an amino group resulted in a low
yield of 9 (Table 1, entry 1). Two approaches were applied to
increase the product yield: (i) the application of the more active
2nd generation Grubbs’ catalyst; (ii) the addition of the Lewis acid
Ti(OEt)4 to suppress nitrogen nucleophilicity.14
The catalyst system screening indicated that the RCM reaction
of 9 gave satisfactory result (63% isolated yield of 11) when 2nd
generation Grubbs’ catalyst was used (Table 1, entry 2). When
the reaction of 10 was catalyzed by the 1st generation Grubbs’ cat-
alyst in the presence of 0.5 equiv of Ti(OEt)4 the expected RCM pro-
duct 12 was obtained in 57% isolated yield (Table 1, entry 3). The
combination of 2nd generation Grubbs’ catalyst with 0.5 equiv of
Ti(OEt)4 gave 91% yield of 12 (Table 1, entry 4).
The major and minor diastereomers of cyclic amino esters 11
and 12 were successfully separated by conventional silica chro-
matography and each diastereomer was fully characterized by 1H
and 13C spectroscopy as well as elemental analysis.
2.1. Synthesis of enantiopure cyclic amino esters via ring-
closing metathesis
It should be noted that deprotection of the amino function
accompanied by reduction of the double bond is possible via
hydrogenation/hydrogenolysis. The optically active ethyl esters of
(R)- and (S)-pipecolic acid can be easily obtained starting from
(R,S)-12 and (S,S)-12 (Scheme 5).15
After esterification of enantiomerically enriched derivative 3
(de 86%) with methanol or ethanol, the major and minor diastere-
omers of the resulting amino esters 6 and 7 were isolated sepa-
rately by conventional silica chromatography (Scheme 2). The
pure major (R,S)-isomers were obtained in 84% yield in both
reactions.
Subsequent treatment with HCl furnished (R)- and (S)-pipecolic
acid ethyl ester hydrochlorides (R)-13 and (S)-13 in 80% overall
The assignment of the absolute configuration for the stere-
yield. Optical rotation [a]
22 of (R)-13 was +1.8 (c 0.2, H2O), whereas
D
ogenic
a
-carbon of the main isomer was achieved via an additional
the specific rotation of (S)-13 is À2.1 (c 0.15, H2O). Estimation of
the enantiomeric purity of the enantiomers was carried out by con-
verting them into free pipecolic acid by acidic hydrolysis (6 M HCl).
experiment. Subsequent hydrogenation of the major diastereomer
of 6 furnished enantiomerically pure norvaline methyl ester 8
O
81%, dr 93:7
H2N
5
Ph
Ph
B(OH)2
H
HO
HO
DCM, rt 24 h
COOH
*
O
2
1
HN
Ph
O
O
30%, dr 2:1
H2N
5
H
3
DCM, rt 24 h
B
O
O
4
1
Scheme 1. Comparison of Petasis reactions using 2 and 4.
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V. A. Morozova et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
93.00
6.93
1.60
1.75
1.70
1.65
1.55
1.50
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Chemical Shift (ppm)
Chemical Shift (ppm)
Figure 1. 1H NMR (CD3OD/D2O) spectrum of compound 3.
COOR
COOR
Ph
COOH
Ph
1) MeOH or EtOH, SOCl2
HN
Ph
HN
HN
2) major isomer separation
6 R = Me; 7 R = Et
(R,S)-6 84%
(S,S)-6 6%
3
(de 86%)
7
7
(S,S)- 6%
(R,S)- 84%
Scheme 2. Esterification of 3.
COOMe
Ph
COOMe
NH2
[α]D20 = -20.8
Scheme 3. Transformation of 3 to (R)-norvaline 8.
[α]D20 = -20.5 (ref. 12)
[α]D20 = -24.5 (ref. 13)
H2, Pd/C
HN
8
(R,S)-6
COOR
Ph
3. Conclusion
COOR
Ph
AllBr, DMF, K2CO3
90 oC, 8 h
N
HN
We have proposed for the first time a simple inexpensive path-
way to enantiopure cyclic amino esters via a sequential diastereos-
elective Petasis reaction/ring closing olefin metathesis process. The
synthetic utility of this method was demonstrated by the prepara-
9 60% (de 58%)
(R,S)-6 (de 100%)
10
60% (de 60%)
7
(R,S)- (de 100%)
COOR
Ph
COOR
tion of enantiomerically pure six-membered cyclic
a-amino acid
derivatives. We suggest that this methodology could be used to
furnish a range of amino esters with various substituents and ring
size.
N
N
Ph
6,9,11 R = Me
7,10,12
RCM
R = Et
11
(R,S)-
11
(S,S)-
total yield 63%
(R,S)-12
total yield 91%
(S,S)-11
4. Experimental
4.1. General
Scheme 4. Allylation/ring-closing metathesis.
Nuclear magnetic resonance (1H NMR, 13C NMR) spectra were
measured at 25 °C in an indicated solvent with Bruker AV-400
spectrometer or Agilent 400-MR spectrometer. 1H and 13C NMR
spectra were recorded at 400 MHz and 100 MHz respectively.
The proton chemical shifts are reported in parts per million from
The values of the specific rotations for the obtained (R)-pipecolic
acid {[
a
]
D
25 = +26.0 (c 0.2, H2O)} and (S)-pipecolic acid {À25.8 (c
0.2, H2O)} were in agreement with the published data [+26.3 (c
1, H2O) and À26.3 (c 1, H2O) respectively].16
Table 1
Results of RCM reactiona
Entry
Starting compd
Catalyst
Product
Yield
1
2
3
4
9
9
10
10
Grubbs’ 1
Grubbs’ 2
Grubbs’ 1 + Ti(OEt)4
Grubbs’ 2 + Ti(OEt)4
(R,S)-11 + (S,S)-11
(R,S)-11 + (S,S)-11
(R,S)-12 + (S,S)-12
(R,S)-12 + (S,S)-12
18
63
57
91
a
Reaction conditions: 9 or 10 (1 mmol), 5 mol % catalyst with/without 0.5 mmol Ti(OEt)4, DCM, room temperature, 24 h.
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4
V. A. Morozova et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
data, while 1H NMR indicated 86% de. No additional purification
1. H2, Pd/C, MeOH
2. HCl
(R,S)-12
was required. White powder. Yield: 1.774 g (81%). Major diastere-
omer (signals taken from mixture): 1H NMR (methanol-d4/D2O) d:
7.50–7.44 (m, 5H), 5.82 (m, 1H), 5.23 (d, J = 16.7 Hz, 1H), 5.16 (d,
J = 9.5 Hz, 1H), 4.41 (m, 1H), 3.47 (t, J = 6.0 Hz, 1H), 2.61 (m, 2H),
1.65 (d, J = 7.7 Hz, 3H); 13C NMR (methanol-d4/D2O) d: 186.6,
132.1, 129.1, 129.0, 127.4, 118.3, 60.0, 57.0, 48.2, 34.2, 17.4. Minor
diastereomer (selected signals taken from mixture): 1H NMR
(methanol-d4) d: 7.35–7.30 (m, 5H), 1.61 (d, J = 6.7 Hz, 3H); 13C
NMR (methanol-d4) d: 129.1.
N
CO2Et
H
HCl
13
(R)-
1. H2, Pd/C, MeOH
2. HCl
12
(S,S)-
N
H
CO2Et
HCl
IR (KBr) for mixture: 700, 762, 1381, 1570, 1639; [
(c 0.006, 1 M HCl, de 86%); Analysis for mixture: Calcd for
a
]
20 = À18.3
D
13
(S)-
C13H17NO2: C, 71.39; H, 7.78; N, 6.35; found: C, 71.21; H, 7.81; N,
Scheme 5. Transformation of (R,S)-12 and (S,S)-12 to pipecolic ester.
6.39. An analogous reaction with 2b instead of 2a gave product 3
(0.657 g, 30%, de 37%) as white powder.
the residual proton signal of solvent. High resolution mass spectra
(HRMS) were measured on a Bruker maXis instrument using
electrospray ionization (ESI). IR spectra were recorded with the
Specord UR-20 infrared spectrometer. Optical rotation values
recorded using VNIEKI Prodmash polarimeter. Analytical thin layer
chromatography (TLC) was performed on Silica gel 60 F254 Plates
(Merck, 0.25 mm thickness). Silica gel column chromatography
was performed using Silica 60 (Macherey-Nagel, 0.040–
0.063 mm) using indicated solvent systems. Reagents were pur-
chased from commercial supplier (Sigma–Aldrich) and were used
without further purification.
4.1.4. N-[(S)-(1-Phenylethyl)amino]pent-4-enoic acid methyl
ester 6
To a stirred solution of amino acid 3 (439 mg, 2 mmol) in
methanol (5 mL), SOCl2 (714 mg, 6 mmol) was added dropwise.
The reaction mixture was refluxed for 3 h and then stirred at room
temperature for 12 h. The pH was adjusted to ꢀ7 with aqueous
K2CO3. The excess methanol was removed in vacuum and then
the aqueous phase was extracted with 10-mL portions (3 times)
of ether. The combined extracts were dried (Na2SO4), filtered,
and concentrated in vacuum. Purification of the mixture by column
chromatography (EtOAc/petrol ether, 1:15 v/v) gave separated
diastereomers (R,S)-6 and (S,S)-6 in a combined yield 419 mg (90
%). Major diastereomer: (R)-N-[(S)-(1-phenylethyl)amino]pent-4-
enoic acid methyl ester (R,S)-6. Yellow oil. Yield 391 mg (84%).
Anhydrous dichloromethane was prepared by distillation from
calcium hydrate.
4.1.1. Allylboronic acid 2a17
20 = À22.7° (c 0.86, CHCl3); 1H NMR (CDCl3) d: 7.30–7.24 (m,
Allylmagnesium bromide (80 mL of freshly prepared 0.41 M
solution in ether, 32 mmol) and a solution of trimethyl borate
(2.78 g, 26.7 mmol) in 30 mL of ether were added simultaneously,
but separately, over a 1 h period to 25 mL of ether maintained at
À78 °C. The mixture was stirred at À78 °C for an additional 2 h
(heavy precipitate) and then was warmed to 0 °C at which point
40 mL of cold (0 °C) 2 M aqueous HC1 was added. The two-phase
mixture was stirred at room temperature for 1 h and then the
aqueous layer was extracted with 20 mL portions (3 times) of 5:l
Et2O–CH2Cl2. The combined extracts were dried (Na2SO4), filtered,
and concentrated in vacuum without removal of all the solvent
(anhydrous, concentrated allylboronic acid is unstable). TLC analy-
sis (2:1 EtOAc–hexane, I2 visualization) showed a single spot at Rf
0.57.
[
a
]
D
5H), 5.76 (m, 1H), 5.09 (m, 2H), 3.78 (q, J = 6.5 Hz, 1H), 3.58 (s,
3H), 3.38 (t, J = 6.2 Hz, 1H), 2.41 (t, J = 6.6 Hz, 2H), 1.92 (br s, NH),
1.35 (d, J = 6.5 Hz, 3H); 13C NMR (CDCl3) d: 174.9, 145.1, 133.6,
128.4, 126.8, 126.7, 118.0, 58.8, 56.2, 51.5, 37.4, 23.2; IR (KBr):
702, 762, 1198, 1603, 1641, 1738, 3330; HRMS m/z: Calcd for C14
-
H
19NO2Na [M+Na]+: 256.1313; found: 256.1304; Analysis: Calcd
for C14H19NO2: C, 72.07; H, 8.21; N, 6.00; found: C, 72.09; H,
8.31; N, 5.91. Minor diastereomer: (S)-N-[(S)-(1-phenylethyl)
amino]pent-4-enoic acid methyl ester (S,S)-6. (Signals taken from
diastereomeric mixture): 1H NMR (CDCl3) d: 7.39–7.36 (m, 5H),
5.68 (m, 1H), 5.07 (m, 2H), 3.98 (q, J = 6.8 Hz, 1H), 3.63 (s, 3H),
3.49 (t, J = 6.1 Hz, 1H), 2.45 (t, J = 6.4 Hz, 2H), 1.91 (br s, NH),
1.29 (d, J = 6.5 Hz, 3H).
4.1.2. Allylboronic acid pinacol ester 2b18
4.1.5. N-[(S)-(1-Phenylethyl)amino]pent-4-enoic acid ethyl ester
7
The crude allylboronic acid was dissolved in 50 mL of dry ether
and treated with anhydrous pinacol (2.77 g, 24 mmol, 0.75 equiv
based on allylmagnesium bromide used in the previous step).
The solution was stirred overnight (14 h) at room temperature,
and then dried over anhydrous MgSO4. Then solution was filtered,
concentrated in vacuum without removal of all solvent and dis-
tilled to afford 2b (2.822 g, 70%) as a yellow oil. Yield:. Bp 60 °-
C/25 Torr; 1H NMR (CDCl3) d: 5.87 (m, 1H), 4.98 (d, J = 17.8 Hz,
1H), 4.93 (d, J = 13.8 Hz, 1H), 1.73 (d, J = 8.1 Hz, 2H), 1.26 (s,
12H). Spectral information is consistent to published data.18
To a stirred solution of amino acid 3 (439 mg, 2 mmol) in etha-
nol (5 mL), SOCl2 (714 mg, 6 mmol) was added dropwise. Reaction
mixture was refluxed for 3 h and then stirred at room temperature
for 12 h. The pH was adjusted to ꢀ7 with aqueous K2CO3. The
excess ethanol was removed in vacuum and then the aqueous
phase was extracted with 10-mL portions (3 times) of ether. The
combined extracts were dried (Na2SO4), filtered, and concentrated
in vacuum. Purification of the mixture by column chromatography
(EtOAc/petrol ether, 1:15 v/v) gave separated diastereomers (R,S)-7
and (S,S)-7 in a combined yield of 445 mg (90%). Major diastere-
omer: (R)-N-[(S)-(1-phenylethyl)amino]pent-4-enoic acid ethyl
4.1.3. N-[(S)-1-Phenylethyl]pent-4-enoic acid 3
To a stirred solution of glyoxylic acid monohydrate (920 mg,
10 mmol) in CH2Cl2 (10 mL), (S)-a-phenylethylamine (1.212 g,
10 mmol) was added in one portion and the solution was stirred
for 5 min. Next, allylboronic acid 2a (15 mmol, 1.5 equiv based
on allylmagnesium bromide used in the previous step) was added
and the reaction mixture was stirred vigorously at room tempera-
ture for 24 h. The precipitate was isolated by filtration and washed
with ether (5 mL). The crude material gave good spectroscopic
ester (R,S)-7. Yellow oil. Yield 415 mg (84%). [
a
]
20 = À76.8 (c 0.63,
D
CHCl3); 1H NMR (CDCl3) d: 7.30–7.24 (m, 5H), 5.71 (m, 1H), 5.06
(m, 2H), 4.18 (q, J = 7.2 Hz, 1H), 3.72 (q, J = 6.6 Hz, 2H), 3.08 (t,
J = 6.6 Hz, 1H), 2.33 (t, J = 6.8 Hz, 2H), 1.85 (br s, NH), 1.34 (d,
J = 6.4 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3) d: 174.5,
145.2, 133.7, 128.4, 127.1, 126.8, 117.9, 60.5, 58.7, 56.1, 37.4,
23.2, 14.3; IR (KBr): 702, 762, 1186, 1603, 1641, 1734, 3331. Anal-
ysis: Calcd for C15H21NO2: C, 72.84; H 8.56; N 5.46; found: C, 72.77;
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V. A. Morozova et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
H, 8.73; N, 5.22. Minor diastereomer: (S)-N-[(S)-(1-phenylethyl)
amino]pent-4-enoic acid ethyl ester (S,S)-7 Yellow oil. Yield
2.30 (m, 1H), 1.37 (d, J = 7.1 Hz, 3H); 13C NMR (CDCl3) d: 145.3,
128.5, 127.3, 127.0, 126.3, 122.4, 61.8, 55.4, 50.9, 45.6, 29.1, 22.1,
carbonyl signal was not detected due to small amount of sample.
30 mg (6%). [
a
]
D
20 = À23.3 (c 0.086, CHCl3); 1H NMR (CDCl3) d:
7.30–7.24 (m, 5H), 5.71 (m, 1H), 5.06 (m, 2H), 4.05 (q, J = 7.3 Hz,
1H), 3.78 (q, J = 6.6 Hz, 2H), 3.36 (t, J = 6.2 Hz, 1H), 2.40 (t,
J = 6.8 Hz, 2H), 1.9 (br s, NH), 1.34 (d, J = 6.4 Hz, 3H), 1.20 (t,
J = 6.9 Hz, 3H); 13C NMR (CDCl3) d: 175.2, 145.0, 133.8, 128.4,
126.9, 111.7, 60.5, 58.5, 56.6, 38.2, 25.3, 23.2, 14.4; IR (KBr): 702,
762, 1186, 1603, 1641, 1734, 3331; HRMS m/z: Calcd for
4.1.9. Ethyl 1-[(S)-1-phenylethyl]-1,2,3,6-tetrahydropyridine-2-
carboxylate 12
At first, Ti(OEt)4 (50 mol %) and Grubbs’ second generation cat-
alyst (5 mol %) and were subsequently added to a magnetically
stirred solution of compound 10 (201 mg, 0.7 mmol) in anhydrous
DCM (40 ml) and the mixture stirred under argon atmosphere at
room temperature for 16 h. Concentration in vacuum afforded
the crude product as a brown oil. Purification of the mixture by col-
umn chromatography (EtOAc/petrol ether, 1:10 v/v) gave sepa-
rated diastereomers (R,S)-12 and (S,S)-12 in a combined yield
165 mg (91%). Major diastereomer: ethyl (R)-1-[(S)-1-pheny-
lethyl]-1,2,3,6-tetrahydropyridine-2-carboxylate (R,S)-12. Yield
C
15H22NO2 [M+H]+: 248.1650; found: 248, 1645.
4.1.6. Methyl 2-[(S)-allyl(1-phenylethyl)amino]pent-4-enoate 9
Compound 6 (233 mg, 1 mmol) was dissolved in 3 mL of dry
DMF. Allyl bromide (242 mg, 2 mmol) and K2CO3 (276 mg, 2 mmol)
were added and the reaction mixture was stirred at 90 °C for 8 h
(reaction control by TLC). The mixture was filtered and subjected
to column chromatography (EtOAc/petrol ether, 1:20 v/v). A mix-
ture of diastereomers was obtained (de 58%). Yield 164 mg (60%).
Major diastereomer (signals taken from mixture): 1H NMR (CDCl3)
d: 7.39–7.14 (m, 5H), 5.77 (m, 1H), 5.65 (m, 1H), 5.25–4.98 (m, 4H),
4.15 (m, 1H), 3.69 (s, 3H), 3.48 (m, 4H), 2.42 (m, 1H), 2.31 (m, 1H),
1.31 (d, J = 6,1 Hz, 3H); 13C NMR (CDCl3) d: 174.8, 144.4, 137.9,
135.1, 128.0, 127.6, 126.7, 116.7, 116.4, 59.1, 56.7, 51.2, 50.0,
35.0, 15.7. IR (KBr) for mixture: 700, 770, 1157, 1602, 1640,
1736; Analysis (mixture): Calcd for C17H23NO2: C, 74.69; H 8.48;
N 5.12; found: C, 74.80; H, 8.52; N, 5.09.
136 mg (75%). [a]
20 = +65.8 (c 0.456, CHCl3); Rf 0.4; 1H NMR (CDCl3,
D
d): 1H NMR (CDCl3) d: 7.38–7.20 (m, 5H), 5.69 (m, 1H), 5.59 (m,
1H), 4.16 (qd, J = 2.8 Hz, 7.2 Hz, 2H), 4.05 (dd, J = 2.3 Hz, 6.4 Hz,
1H), 3.96 (q, J = 6.6 Hz, 1H), 3.26 (d, J = 17.1 Hz, 1H), 2.97 (d,
J = 17.1 Hz, 1H), 2.62 (d, J = 17.3 Hz, 1H), 2.48 (d, J = 17.5 Hz, 1H),
1.35 (d, J = 6.7 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3) d:
173.5, 145.9, 128.3, 127.3, 126.3, 121.8, 62.1, 60.0, 54.2, 47.2,
29.1, 21.1, 14.4; IR (KBr): 702, 756, 1171, 1491, 1600, 1638,
1736; Analysis: Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40;
found: C, 74.23; H, 8.17; N, 5.51. Minor diastereomer: ethyl (S)-
1-[(S)-1-phenylethyl]-1,2,3,6-tetrahydropyridine-2-carboxylate (S,
4.1.7. Ethyl 2-[(S)-allyl(1-phenylethyl)amino]pent-4-enoate 10
Compound 7 (294 mg, 1 mmol) was dissolved in 3 mL of dry
DMF. Allyl bromide (242 mg, 2 mmol) and K2CO3 (276 mg, 2 mmol)
were added and reaction mixture was stirred at 90 °C for 10 h
(reaction control by TLC). The mixture was filtered and subjected
to column chromatography (EtOAc/petrol ether, 1:20 v/v). A mix-
ture of diastereomers was obtained (de 60%). Yield 172 mg (60%).
Major diastereomer (signals taken from mixture): 1H NMR (CDCl3)
d: 7.39–7.31 (m, 5H), 5.83–5.65 (m, 2H), 5.25–4.98 (m, 4H), 4.16 (q,
J = 8.1 Hz, 2H), 3.95 (m, 1H), 3.51 (m, 1H), 3.38 (m, 2H), 2.44–2.30
(m, 3H), 1.35 (d, J = 2.4 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H). IR (KBr) for
mixture: 703, 769, 1153, 1600, 1638, 1737; Analysis (mixture):
Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87; found: C, 75.14;
H, 8.73; N, 4.67.
S)-12. Yield 29 mg (16%). [
a
]
20 = À61.0 (c 0.3, CHCl3); Rf 0.2; 1H
D
NMR (CDCl3) d: 7.40–7.23 (m, 5H), 5.79 (m, 1H), 5.72 (m, 1H),
4.11 (m, 3H), 3.62 (m, 2H), 3.43 (d, J = 6.9 Hz, 1H), 2.44 (d,
J = 17.3 Hz, 1H), 2.32 (d, J = 17.3 Hz, 1H), 1.41 (d, J = 6.7 Hz, 3H),
1.24 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3) d: 173.1, 145.3, 128.5,
127.3, 127.1, 126.2, 122.4, 61.8, 59.8, 55.4, 45.7, 29.1, 22.1, 14.4.
4.2. Synthesis of enantiopure ethyl 1-piperidine-2-carboxylate
hydrochloride
4.2.1. General procedure
To a solution of compound (R,S)-12 (130 mg, 0.5 mmol) in 10 ml
of methanol, 5 mol% of palladium on carbon (5% Pd) was added.
Then a rubber ball filled with hydrogen was connected to the flask
and the mixture was stirred in the hydrogen atmosphere for 4 h at
room temperature. After the total disappearance of starting com-
pound (TLC monitoring) the reaction mixture was filtered and
3 M HCl was added to filtrate. Solvents were evaporated using
rotary evaporator. The residue was washed with ethyl acetate
and dried in high vacuum for 30 min to afford white powder in a
4.1.8. Methyl 1-[(S)-1-phenylethyl]-1,2,3,6-tetrahydropyridine-
2-carboxylate 11
Grubbs’ second generation catalyst (5 mol %) was added to a
magnetically stirred solution of compound 9 (273 mg, 1 mmol) in
anhydrous DCM (40 ml) and the mixture was stirred under an
argon atmosphere at room temperature for 16 h. Concentration
in vacuum afforded the crude product as a brown oil. Purification
of the mixture by column chromatography (EtOAc/petrol ether,
1:10 v/v) gave separated diastereomers (R,S)-11 and (S,S)-11 in a
combined yield 223 mg (82%). Major diastereomer: methyl (R)-1-
[(S)-1-phenylethyl]-1,2,3,6-tetrahydropyridine-2-carboxylate (R,
79 mg
hydrochloride (R)-13: [
(80%)
yield.
Ethyl (R)-1-piperidine-2-carboxylate
]
22 = +1.8 (c 0.2, H2O); 1H NMR (D2O) d:
D
a
4.25 (q, J = 7.0 Hz, 2H); 4.00 (d, J = 12 Hz, 1H), 3.45 (d, J = 12 Hz,
1H), 3.08 (d, J = 12 Hz, 1H), 2.50 (m, 1H), 1.8 (m,2H), 1.50–1.70
(m, 3H),1.30 (t, J = 7.1 Hz, 3H); 13C NMR (D2O) d: 169.7, 63.5,
56.9, 44.1, 25.6, 21.2, 13.2. Ethyl (S)-1-piperidine-2-carboxylate
S)-11. Yield 183 mg (67%). [
a]
20 = +22.9 (c 0.87, CHCl3); Rf 0.4; 1H
hydrochloride (S)-13: [
spectra are identical to those of compound (R)-13.
a
]
22 = À2.1 (c 0.15, H2O); 1H and 13C NMR
D
D
NMR (CDCl3) d: 7.35–7.24 (m, 5H), 5.67 (m, 1H), 5.60 (m, 1H),
4.09 (dd, J = 2.3 Hz, 6.7 Hz, 1H), 3.95 (q, J = 6.7 Hz, 1H), 3.71 (s,
3H), 3.23 (d, J = 17.3 Hz, 1H), 2.98 (d, J = 17.3 Hz, 1H,), 2.63 (m,
1H), 2.48 (m, 1H), 1.34 (d, J = 6.1 Hz, 3H); 13C NMR (CDCl3) d:
174.0, 145.9, 128.4, 127.2, 126.8, 126.3, 121.8, 62.1, 54.1, 51.2,
47.2, 29.0, 21.2; IR (KBr): 702, 756, 1171, 1491, 1600, 1638,
1736; Analysis: Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71;
found: C, 73.23; H, 7.87; N 5.50. Minor diastereomer: methyl (S)-
1-[(S)-1-phenylethyl]-1,2,3,6-tetrahydropyridine-2-carboxylate (S,
S)-11. Yield 40 mg (15%). Rf 0.2; 1H NMR (CDCl3) d: 7.36–7.20 (m,
5H), 5.78 (m, 1H), 5.69 (m, 1H), 4.07 (q, J = 6.7 Hz, 1H), 3.62 (s,
3H), 3.56 (m, 2H), 3.44 (dd, J = 6.3 Hz, 1.8 Hz, 1H), 2.44 (m, 1H),
4.3. Assignment of the absolute configuration
4.3.1. Synthesis of D-norvaline methyl ester 8
Amino ester 6a (major isomer) (233 mg, 1 mmol) was placed in
a Schlenk flask and flashed with argon. Next, 106 mg 5% Pd/C and
3 mL methanol were added and the flask was filled with hydrogen
via balloon. The slurry was stirred under a hydrogen atmosphere at
35–40 °C for 24 h. The reaction mixture was filtered and the sol-
vent was evaporated under medium vacuum (35–40 Torr) to give
8. Caution! Product 8 is volatile! Colorless oil. Yield: 90 mg
Please cite this article in press as: Morozova, V. A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.001

6
V. A. Morozova et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
20 = À20.8 (c 0.214, CHCl3); 1H NMR (CDCl3) d: 7.48 (br s,
Weinheim, Germany, 2005; (c) Kaiser, P. F.; Churches, Q. I.; Hutton, C. A.
Aust. J. Chem. 2007, 60, 799; (d) Candeias, N. R.; Montalbano, F.; Cal, P. M. S. D.;
Gois, P. M. P. Chem. Rev. 2010, 110, 6169.
(69%). [a]
D
NH2), 3.65 (s, 3H), 3.63 (m, 1H), 1.58 (m, 2H), 1.39 (m, 2H), 0.98 (t,
J = 5.5 Hz, 3H). The (R)-configuration was confirmed by comparing
the value of the specific rotation of 8 with the literature data.12,13
4. (a) Pye, P. J.; Rossen, K.; Weissman, S. A.; Maliakal, A.; Reamer, R. A.; Ball, R.;
Tsou, N. N.; Volante, R. P.; Reider, P. J. Chem. Eur. J. 2002, 8, 1372; (b) Hong, Z.;
Liu, L.; Hsu, C. C.; Wong, C. Angew. Chem., Int. Ed. 2006, 45, 7417; (c) Davis, A. S.;
Pyne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2004, 69, 3139; (d)
Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149.
5. (a) Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783; (b) Schrock, R. R. Angew.
Chem., Int. Ed. 2006, 45, 3748; (c) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45,
3760.
6. Abdelli, A.; Bourdreux, F.; Gaucher, A.; Efrit, M.; M’Rabet, H.; Prim, D.
Tetrahedron Lett. 2016, 57, 379.
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Acknowledgments
This work was supported by a Russian Science Foundation
(grant 14-23-00186). The research work was carried out using
NMR spectrometer Agilent 400-MR purchased under the program
of MSU development. High resolution mass spectra were recorded
in the Department of Structural Studies of Zelinsky Institute of
Organic Chemistry, Moscow, Russia.
8. (a) Mangold, S. L.; Grubbs, R. H. Chem. Sci. 2015, 6, 4561; (b) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490; (c) Yu, X.; Sun, D.
Molecules 2013, 18, 6230.
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A.; Stewart, G. W.; Wise, C.; Alam, M.; Song, Z. J.; Tan, L. Org. Lett. 2015, 17,
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A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.01.
001.
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Please cite this article in press as: Morozova, V. A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.001