Synthesis of non-natural l-alanine derivatives using the aza-Cope-Mannich reaction

Article abstract of DOI:10.1016/j.tetasy.2014.01.011

Non-natural l-alanine derived trans-octahydrocyclohepta[b]pyrroles were synthesized with high enantiomeric purity using the aza-Cope-Mannich reaction. The study showed that the conditions of the aza-Cope-Mannich reaction and metal catalysed cyclization ar

Full text of DOI:10.1016/j.tetasy.2014.01.011

Tetrahedron: Asymmetry 25 (2014) 468–472
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of non-natural L-alanine derivatives
using the aza-Cope–Mannich reaction
⇑
Nina K. Ratmanova, Dmitry S. Belov, Ivan A. Andreev, Alexander V. Kurkin
Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninskie Gory, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 January 2014
Accepted 22 January 2014
Non-natural L-alanine derived trans-octahydrocyclohepta[b]pyrroles were synthesized with high enan-
tiomeric purity using the aza-Cope–Mannich reaction. The study showed that the conditions of the
aza-Cope–Mannich reaction and metal catalysed cyclization are mild enough to be applied to the synthe-
sis of molecules with stereocenters, which are prone to racemization. We believe that these compounds
will be of interest to medicinal chemists.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
Non-natural
a-amino acids have attracted significant interest
H
H
NH
from synthetic chemists; they are widely used as components of
medicinally active molecules1–3 and in chiral catalysis.4,5 Various
O
H
O
N
methods to access chiral, non-racemic, non-natural a-amino acids
O
have been developed including chemoenzymatic methods,6 the
synthesis of racemates followed by resolution, asymmetric synthe-
sis7 and chiral pool synthesis.8 Previously we have reported that
several privileged9 heterocyclic systems, such as indoles,10–12 isa-
tins,13–15 pyrroles16,17 and imidazoles18,19 can be easily equipped
with an enantiopure alanine residue.
N
O
NH2
1
H
OH
perindopril
Figure 1. Examples of related biologically active compounds.
We have recently disclosed a highly stereoselective and scalable
(up to 1 mole) method to obtain natural-like compounds contain-
ing an octahydrocyclohepta[b]pyrrole core based on the aza-
Cope–Mannich rearrangement.20,21 Herein we report an extension
of this method for the preparation of non-natural amino acid deriv-
atives. The octahydrocyclohepta[b]pyrrole core and closely related
scaffolds (e.g. octahydroindole) are represented in several biologi-
cally active compounds and alkaloids (e.g. perindopril, an ACE
inhibitor and compound 1, an agent for reversing amnesia,22
Fig. 1). Herein we have chosen compound 2 as the model system
(Scheme 1), because it contains an amino acid residue, which can
be useful for medicinal chemistry applications. Furthermore, the
alanine (the simplest chiral amino acid) moiety was used to gain
a better understanding of the configurational stability of a new
class of unnatural amino acids.
2. Results and discussion
Two distinct routes were envisioned to obtain target compound
2. Both include the ring opening of enantiopure epoxide 5 with an
N-nucleophile, the partial reduction of a triple bond and the aza-
Cope–Mannich rearrangement (Scheme 1). In retrosynthesis A,
the CAN bond could be formed by the alkylation of 3 with acti-
vated
had found that the direct alkylation results in significant epimer-
ization of the resulting
-amino acids.12,13 The alternative route
L-lactate derivatives. However, in our previous work, we
a
(retrosynthesis B) was more attractive since the aza-Cope–
Mannich rearrangement of the compound 4 proceeds under mild
conditions (ambient temperature, effectively neutral pH), thus
minimizing any possible epimerization of the substrate.23 In
addition, there is no need to refunctionalize the intermediates
(i.e. debenzylation/alkylation).
Based on our experience21 as well as Nicolaou et al.,24–26 we
assumed that the reaction between racemic epoxide 5 and an
⇑
Corresponding author. Tel.: +7 495 939 1714; fax: +7 495 939 2288.
E-mail address: kurkin@direction.chem.msu.ru (A.V. Kurkin).
L-amino acid ester would lead to a separable diastereomeric
http://dx.doi.org/10.1016/j.tetasy.2014.01.011
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

N. K. Ratmanova et al. / Tetrahedron: Asymmetry 25 (2014) 468–472
469
O
O
HO
H
H
B
A
aza-Cope-
Mannich
NH
N-alkylation
N
N
H
H
H
Me
CO2R
CO2R
Me
4
3
2
aza-Cope-
Mannich
H
H
H
HO
HO
Me
O
NH
NH
Ph
CO2R
5
Scheme 1. Retrosynthetic analysis for a single enantiomer of 2.
H
NH2
CO2R
H
H
a
400000
350000
300000
250000
200000
HO
Me
HO
Me
Me
O
+
LiClO4, MeCN
NH
NH
Δ
( )-5
CO2R
CO2R
R=Et: 6a (26%)
R=Bn: 7a (10%)
6b (19%) er=76:24
7b (18%) er=60:40
R=t-Bu:
complex mixture
150000
100000
50000
0
Scheme 2. Ring-opening of the racemic epoxide 5.
mixture of aminoalcohols (both enantiopure). It was thought that
such a transformation could provide convenient access to both
trans-fused (1S)-diastereomers of 2 simultaneously.
10
15
Our synthesis commenced with ring-opening of the commer-
b
cially available racemic epoxide 5 with
L-alanine ethyl ester
250000
200000
150000
100000
50000
0
(Scheme 2). The reaction afforded amino alcohols 6a and 6b as a
chromatographically separable (on 2 g scale) 1:1 mixture in a com-
bined 45% yield. To verify the enantiomeric purity of 6a and 6b, we
used chiral HPLC. Since the reference compounds are not easily
available in a pure form, we decided to use a diastereomeric
mixture, which was obtained from the reaction of racemic 5 and
DL-alanine ethyl ester. The analysis showed the significant erosion
of the enantiomeric purity (er = 76:24). These results are in an
agreement with the fact that, in general, N-alkyl
a-amino acids,
such as 6, are more prone to epimerization in basic reaction media
than N-unsubstituted analogues.27,28
10
12.5
15
17.5
In order to improve the efficiency of the transformation we
investigated other L-alanine esters. Epoxide opening with L-alanine
benzyl ester29 furnished amino alcohols 7a and 7b with low
enantiopurity (er = 60:40, Scheme 2). Due to concomitant partial
cleavage of the benzyl group compound 7a was isolated as an
inseparable mixture with benzyl alcohol. The reaction of 5 with
200000
175000
150000
125000
c
L
-alanine tert-butyl ester30 produced an inseparable and complex
100000
75000
50000
25000
mixture. This is probably due to LiClO4-assisted t-Bu partial
cleavage. In addition to its accessibility, the -alanine ethyl ester
was found to be the only nucleophile, that gave satisfactory yields
of the amino alcohol products.
L
Having demonstrated that the preparation and separation of
amino propargylic alcohols 6a and 6b was possible, we modified
our strategy. We used enantiopure compound (+)-5 instead of
the racemic epoxide 5. Compound (+)-5 was prepared according
to the literature from commercially available alcohol 8 by applying
Shi’s epoxidation protocol (Scheme 3).31–33 The LiClO4-meditated
0
12.5
15
17.5
Figure 2. Chiral HPLC of the reference mixture (a), 6a (b) and ent-6b (c).
ethyl ester17 gave amino ethanol 6a and a stereoisomeric product
ent-6b. After chromatographic purification, compounds 6a and
epoxide ring-opening of (+)-5 with two equivalents of L-alanine

470
N. K. Ratmanova et al. / Tetrahedron: Asymmetry 25 (2014) 468–472
H
NH2
H
H
HO
HO
H
HO
Me
CO2Et
Ref. 31-33
O
+
LiClO4, MeCN
NH
NH
Δ
Me
CO2Et
Me
CO2Et
8
5
6a
(39%) ee=99%
(+)-
6b
ent- (8%)
ee=86%
Lindlar's cat.
H2, EtOH
O
H
HO
Me
CSA, CH2O
CH2Cl2, Na2SO4
Mannich
[3,3]
OH
OH
R
N+
+
N+
N
N
R
NH
H
H
H
CO2Et
CO2Et
Me
Me
CO2Et
11
(52%)
9 (66%)
(-)-10 (33%)
ee=99%
O
HO
Me
H
CSA, CH2O
Lindlar cat.
H2, EtOH
6b
ent-
(+)-10 (38%)
+
NH
CH2Cl2, Na2SO4
N
H
CO2Et
CO2Et
Me
12 (61%)
Scheme 3. Synthesis of compounds 11 and 13.
13
(68%)
p-NO2C6H4I,
ent-6b were obtained in yields of 39% and 8%, respectively. Chiral
HPLC showed the presence of only one enantiomer for 6a (Fig. 2).
The hydrogenation of 6a on Lindlar’s catalyst gave a 3:2 mixture
of alkene 9 and pyrrole (ꢀ)-10 (ee = 99%, chiral HPLC) in quantita-
tive yield. The formation of 10 is probably due to Pd-catalysed
5-endo-dig cyclization on the surface of the Lindlar’s catalyst.34–36
It is well known that enantiomerically pure 1-alkenyl-2-amino-
cycloalkanols rearrange to enantiomerically pure pyrrolidines due
to the conformational constraints of the medium-sized ring.23,37–39
Thus, carrying out the aza-Cope–Mannich reaction under the pre-
viously optimized conditions21 gave target product 11 as a single
isomer in 52% yield (Scheme 3).
Amino alcohol ent-6b (ee = 85%) was transformed into the dia-
stereomeric ketone 13 by the same sequence in 41% yield over
two steps. The moderate yields of the rearrangement can be attrib-
uted to the fact that amino alcohols 9 and 12 contain varying
amounts of inseparable impurities (5–10%).
Pd(dba)2
NO2
6a 6b
+
(1:1)
CuI, Ph3P
Et2NH
N
CO2Et
Me
ee = 52%
14, ee=32%, (71%)
H
HO
Me
p-NO2C6H4I,
Pd(dba)2
NO2
N
NH
CuI, Ph3P
Et2NH
CO2Et
Me
CO2Et
6a, ee = 99 %
14, ee=39 %, (71%)
Scheme 4. The Pd-mediated cyclization of the diastereomeric mixture of 6a and 6b
and enantiopure 6a.
The high enantiomeric excess of pyrrole 10 deserves additional
comments. In our previous work,17,35 we have shown that a two-
3. Conclusion
step sequence involving the reaction of L-amino acid esters with
We have synthesized two diastereomeric non-natural L-alanine
racemic alkynyl epoxides and subsequent Sonogashira coupling/
5-endo-dig cyclization of the resulting 1:1 diastereomeric mixture
6a and 6b led to 2-aryl-4,5,6,7-tetrahydroindoles with moderate
ee values (32–70%, Schemes 2 and 4). It was not clear whether
racemization occurred during the epoxide ring-opening or the
Sonogashira coupling/Pd-mediated 5-endo-dig cyclization. We
chose 1-iodo-4-nitrobenzene from a series of aryl halides as a sub-
strate for test reactions, since pyrrole 14 showed the lowest ee va-
lue when a mixture 6a and 6b was used as the starting material.35
Performing the experiment with pure 6a led to pyrrole 10 with
almost the same ee value (39%, Scheme 4). According to the data
analogues in 5 steps from commercially available materials.
Despite the difficulties associated with the preparation of the
amino alcohols 9 and 12, we have shown that the conditions of
the aza-Cope–Mannich reaction are mild enough to be applied in
complex settings, that is in the synthesis of molecules with stereo-
centers which are prone to racemization. The formation of pyrrole
10 in enantiopure form was observed as a side reaction during the
Lindlar reduction step.
4. Experimental
4.1. General
obtained, we concluded that the
a-alanine residue of amino
propargylic alcohols 6a, 6b and analogues epimerize easily when
exposed to weak bases (e.g. Et2NH). It should be emphasized that
pyrroles with the
a-amino acid residue are much more stable
1H and 13C NMR spectra were recorded on 400 MHz Bruker
Avance spectrometers. Spectra were referenced to residual chloro-
towards racemization.35,40–42

N. K. Ratmanova et al. / Tetrahedron: Asymmetry 25 (2014) 468–472
471
form (d 7.26 ppm, 1H; d 77.16 ppm, 13C). IR spectra were recorded
on Thermo Nicolet IR-200 in KBr or film. High resolution mass
spectra (HRMS) were measured on a Bruker maXis instrument
using electrospray ionization (ESI). The specific rotation was
measured on Perkin–Elmer 241 and Jasco DIP-360 polarimeters
at 589 nm in cells with path length 5 and 10 cm. Enantiomeric
purities were measured using HPLC with a chiral stationary phase:
Chiralpak OD-RH 4.6⁄150 mm, 5 mkm, 1 mL/min, eluent: 80%
10 mMol Ammonium acetate buffer, 20% MeCN. Reagents were
purchased at the highest commercial quality and used without fur-
ther purification, unless otherwise stated. 1-Ethynyl-7-oxabicy-
clo[4.1.0]heptane 5 was kindly provided by EDASA Scientific.
Concentration under reduced pressure was performed by rotary
evaporation at 30 °C (unless otherwise specified) at the appropri-
ate pressure.
Compounds 7a and 7b were separated by column chromatography,
but their absolute stereochemistry was not assigned
unambiguously.
4.2.3.1. Diastereomer 1.
Yield 10%, m = 0.51 g. Physical state:
yellow oil. Rf = 0.43 (silica gel, 3:1 hexanes/AcOEt). ½a D23
¼ þ6:9 (c
ꢂ
1, CHCl3). tmajor = 12.4 min, tminor = 13.5 min. 1H NMR (400 MHz,
CDCl3): d = 1.12–1.28 (m, 2H), 1.35 (d, J = 6.9 Hz, 3H), 1.47 (td,
J = 12.6, 3.9 Hz, 1H), 1.53–1.81 (m, 3H), 2.10–2.17 (m, 1H), 2.19–
2.39 (m, 2H), 2.49 (s, 1H), 3.45 (q, J = 6.8 Hz, 1H), 4.24 (br s, 1H),
5.19 (s, 2H), 7.29–7.43 (m, 5H). 13C NMR (400 MHz, CDCl3):
d = 20.1, 23.0, 25.2, 29.8, 37.8, 55.0, 65.1, 66.8, 71.8, 74.3, 84.8,
128.4 (2C), 128.5, 128.7 (2C), 135.6, 176.2. IR: mmax (film/KBr) =
3447 (br), 3299, 2935, 2862, 1735, 1452, 1370, 1194, 1166, 1147,
1066, 1039, 872, 851, 806 cmꢀ1
.
HRMS (m/z): calcd for
C
18H24NO3 [M+H]+ 302.1751; found 302.1745.
4.2. The ring-opening of epoxide 5
4.2.3.2. Diastereomer 2.
Yield 18%, m = 0.99 g. Physical state:
L-Alanine ethyl ester was prepared from its HCl salt by treating
yellow oil. Rf = 0.33 (silica gel, 3:1 hexanes/AcOEt). ½a D23
¼ ꢀ15:4 (c
ꢂ
it with 1 equiv of 10% aqueous K2CO3, extraction with DCM and
evaporation under reduced pressure at 30 °C.
1, CHCl3). tmajor = 11.1 min, tminor = 9.9 min. 1H NMR (400 MHz,
CDCl3): d = 1.12–1.50 (d+m, J = 7.1 Hz, 7H), 1.51–1.77 (m, 3H),
1.88–1.97 (m, 1H), 2.09–2.16 (m, 1H), 2.25 (dd, J = 11.5, 3.7 Hz,
1H), 2.47 (s, 1H), 3.63 (q, J = 7.0 Hz, 1H), 4.64 (br s, 1H), 5.15–
5.19 (m, 2H), 7.29–7.42 (m, 5H). 13C NMR (400 MHz, CDCl3):
d = 19.6, 23.1, 25.1, 30.0, 38.3, 54.2, 64.3, 66.8, 71.9, 73.9, 85.3,
128.4 (3C), 128.7 (2C), 135.8, 175.5. IR: mmax (film/KBr) = 3447
(br), 3289 (br), 3299, 2937, 2861, 1736, 1450, 1379, 1173, 1149,
To
a
vigorously stirred solution of epoxide (+)-5 (2.50 g,
20.4 mmol, 1 equiv) and freshly prepared
L
-alanine ethyl ester
(7.18 g, 61.4 mmol, 3 equiv) in MeCN (10 mL) LiClO4 (3.24 g,
30.6 mmol, 1.5 equiv) was added in one portion. The mixture
was stirred for 12 h at reflux. The reaction mixture was then al-
lowed to cool to ambient temperature, poured into water
(50 mL) and extracted with CH2Cl2 (3 ꢁ 50 mL). The combined ex-
tracts were dried over Na2SO4 and concentrated. The residue was
purified by flash column chromatography (20:1 hexanes/EtOAc)
to give 6a and ent-6b.
1079, 1023, 871, 850, 752 cmꢀ1
18H24NO3 [M+H]+ 302.1751; found 302.1747.
. HRMS (m/z): calcd for
C
4.3. Alkyne reduction
4.2.1. (S)-Ethyl 2-((1S,2R)-2-ethynyl-2-hydroxycyclohexylamino)-
propanoate 6a
To an ethanolic solution of 6a (0.97 g, 4.1 mmol), Lindlar’s cat-
alyst was added (0.50 g) and the resulting mixture was degassed
and stirred under 1 atm of hydrogen until complete consumption
of the starting material occurred (the reaction was monitored by
TLC, hexanes/EtOAc 1:1, typically overnight). The catalyst was then
removed by filtration, and the filtrate was concentrated under
reduced pressure to give a mixture of 9 and (ꢀ)-10 (3:2). The
residue was purified by flash column chromatography (30:1
hexanes/EtOAc) to give 9 and (ꢀ)-10. Due to decomposition of
(ꢀ)-10 on silica, it was isolated only partially.
Yield 39%, m = 1.91 g. Physical state: yellow oil. Rf = 0.48 (silica
gel, 3:1 hexanes/AcOEt). ½a D23
ꢂ
¼ þ37 (c 1, CHCl3). tr = 14.4 min. 1H
NMR (400 MHz, CDCl3): d = 1.17–1.24 (m, 1H), 1.28 (t, J = 7.2 Hz,
3H), 1.30 (d, J = 6.9 Hz, 3H), 1.32–1.39 (m, 1H), 1.46 (dd, J = 12.5,
4.2 Hz, 1H), 1.58 (dt, J = 12.7, 3.9 Hz, 1H), 1.63–1.75 (m, 2H),
1.77–1.86 (m, 2H), 2.11 (dq, J = 12.2, 2.7 Hz, 1H), 2.31 (ddd,
J = 6.7, 5.0, 3.8 Hz, 1H), 2.48 (s, 1H), 3.35 (q, J = 6.9 Hz, 1H), 4.18
(qd, J = 7.1, 1.6 Hz, 2H), 4.25 (br s, 1H). 13C NMR (400 MHz, CDCl3):
d = 14.3, 20.2, 23.1, 25.3, 29.8, 37.8, 55.0, 61.1, 65.3, 71.8, 74.3, 84.9,
176.4. IR:
m
max (KBr) = 3473 (br), 3305 (br), 2980, 2937, 2862, 1734,
4.3.1. (S)-Ethyl 2-((1S,2R)-2-hydroxy-2-vinylcyclohexylamino)-
propanoate 9
1448, 1373, 1300, 1261, 1198, 1176, 1147, 1066 cmꢀ1. HRMS (m/
z): calcd for C13H22NO3 [M+H]+ 240.1594; found 240.1592.
Yield 66%, m = 0.64 g. Physical state: yellow oil. Rf = 0.38 (silica
gel, 3:1 hexanes/AcOEt). ½a D23
ꢂ
¼ þ39:7 (c 0.5, CHCl3). 1H NMR
4.2.2. (R)-Ethyl 2-((1S,2R)-2-ethynyl-2-hydroxycyclohexylamino)-
propanoate ent-6b
(400 MHz, CDCl3): d = 1.21–1.30 (d+t, 3+3H), 1.33–1.88 (m, 9H),
2.41 (dd, J = 11.8, 3.6 Hz, 1H), 3.32 (q, J = 6.9 Hz, 1H), 3.56 (br s,
1H), 4.15 (qd, J = 21.3, 7.1 Hz, 2H), 5.24 (dd, J = 10.9, 1.7 Hz, 1H),
5.45 (dd, J = 17.1, 1.9 Hz, 1H), 6.20 (dd, J = 17.1, 10.9 Hz, 1H). 13C
NMR (400 MHz, CDCl3): d = 14.2, 20.0, 22.7, 25.4, 29.3, 38.2, 54.9,
60.9, 64.8, 73.9, 115.6, 138.7, 175.6. IR: mmax (film) = 3487 (br),
3332 (br), 2978, 2931, 2862, 1734, 1450, 1373, 1302, 1196, 1176,
1149, 1020, 928, 868, 762, 490 cmꢀ1. HRMS (m/z): calcd for
Yield 8%, m = 0.40 g. Physical state: yellow oil. Rf = 0.15 (silica
gel, 3:1 hexanes/AcOEt). ½a D23
¼ þ41 (c 1, CHCl3). tmajor = 13.6 min,
ꢂ
tminor = 12.5 min. 1H NMR (400 MHz, CDCl3): d = 1.22–1.25 (m, 1H),
1.30 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 6.9 Hz, 3H), 1.47 (dd, J = 12.5,
4.2 Hz, 1H), 1.59 (dt, J = 12.7, 3.4 Hz, 1H), 1.64–1.78 (m, 2H),
1.91–2.00 (m, 1H), 2.15 (dq, J = 12.2, 3.0 Hz, 1H), 2.21–2.26 (m,
1H), 2.27–2.31 (m, 1H), 2.32–2.36 (m, 1H), 2.48 (s, 1H), 3.58 (q,
J = 6.9 Hz, 1H), 4.13–4.27 (m, 2H), 4.79 (br s., 1H). 13C NMR
(400 MHz, CDCl3): d = 14.3, 19.8, 23.2, 25.3, 30.1, 38.4, 54.3, 61.2,
64.5, 71.9, 74.0, 85.3, 175.8. IR: mmax (KBr) = 3450 (br), 3305 (br),
2979, 2937, 2862, 1734, 1448, 1375, 1298, 1255, 1201, 1151,
C
13H24NO3 [M+H]+ 242.1751; found 242.1755.
4.3.2. (S)-Ethyl 2-(4,5,6,7-tetrahydro-1H-indol-1-yl)propanoate
10
Yield 9%, m = 0.08 g. Physical state: brown oil. Rf = 0.62 (silica
1080, 1034 cmꢀ1
240.1594; found 240.1594.
.
HRMS (m/z): calcd for C13H22NO3 [M+H]+
gel, 3:1 hexanes/AcOEt). tr = 12.0 min. ½a D23
¼ ꢀ26:8 (c 1, CHCl3).
ꢂ
1H NMR (400 MHz, CDCl3): d = 1.29 (t, J = 7.1 Hz, 3H), 1.72 (d,
J = 7.2 Hz, 3H), 1.74–1.81 (m, 2H), 1.82–1.92 (m, 2H), 2.48–2.60
(m, 4H), 4.17–4.28 (m, 2H), 4.71 (q, J = 7.2 Hz, 1H), 6.02 (d,
J = 2.9 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H). 13C NMR (400 MHz, CDCl3):
d = 14.2, 18.0, 21.9, 23.2, 23.4, 23.7, 53.3, 61.4, 107.2, 116.2, 117.6,
4.2.3. Synthesis of compounds 7a and 7b
Compounds 7a and 7b were prepared in the same manner as 6a
and 6b using L-alanine benzyl ester instead of L-alanine ethyl ester.

472
N. K. Ratmanova et al. / Tetrahedron: Asymmetry 25 (2014) 468–472
127.9, 171.6. IR: mmax (film) = 2995, 2948 (br), 2867, 1745, 1487,
1450, 1378, 1305, 1208, 1180, 1079, 1100, 1038, 706 cmꢀ1. HRMS
(m/z): calcd for C13H20NO2 [M+H]+ 222.1489; found 222.1475.
1172, 1094, 1057, 1020, 860, 823 cmꢀ1. HRMS (m/z): calcd for
C14H24NO3 [M+H]+ 254.1751; found 254.1754.
Acknowledgments
4.3.3. (R)-Ethyl 2-((1S,2R)-2-hydroxy-2-vinylcyclohexylamino)-
propanoate 12
High resolution mass spectra were recorded in the Department
of Structural Studies of Zelinsky Institute of Organic Chemistry,
Moscow. This study was supported by the Russian Foundation for
Basic Research (RFBR), Russia (Projects No. 14-03-31685, 14-03-
31709, 14-03-01114).
Alkene 12 was prepared in the same manner as 9. Pyrrole 10
was also isolated as a side product (yield 13%, m = 0.0424 g). Yield
61%, m = 0.2095 g. Physical state: yellow oil. Rf = 0.35 (silica gel, 3:1
hexanes/AcOEt). ½a D23
ꢂ
¼ þ27:6 (c 2, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 1.24–1.33 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H), 1.30 (d,
J = 7.0, 3H), 1.40–1.55 (m, 3H), 1.60–1.68 (m, 1H), 1.73–1.81 (m,
1H), 1.85–1.94 (m, 2H), 2.34 (dd, J = 11.3, 4.1 Hz, 1H), 3.49 (q,
J = 6.9 Hz, 1H), 3.68 (br s, 1H), 4.19 (t, J = 7.0 Hz, 2H), 5.26 (dd,
J = 10.9, 1.9 Hz, 1H), 5.52 (dd, J = 17.0, 2.0 Hz, 1H), 6.20 (dd,
J = 17.1, 10.9 Hz, 1H). 13C NMR (400 MHz, CDCl3): d = 14.3, 19.7,
23.0, 25.2, 29.6, 38.8, 54.3, 61.0, 64.2, 74.1, 115.6, 138.6, 176.3.
IR: mmax (film) = 3473 (br), 2979, 2933, 2862, 1734, 1450, 1373,
1331, 1300, 1252, 1184, 1155, 1047, 1009, 926, 862, 692,
References
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To a vigorously stirred mixture of 9 (0.20 g, 0.82 mmol, 1 equiv),
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4.4.1. (S)-Ethyl 2-((3aR,8aS)-4-oxooctahydrocyclohepta[b]pyrrol-
1(2H)-yl)propanoate 11
Yield 52%, m = 0.11 g. Physical state: yellow oil. Rf = 0.20 (silica
gel, 3:1 hexanes/AcOEt).
½
a 2D3
ꢂ
¼ þ2:8 (c 1, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 1.11 (d, J = 6.9 Hz, 3H), 1.19 (t+m,
J = 7.1 Hz, 3+1H), 1.35–1.47 (m, 1H), 1.61–1.76 (m, 2H), 1.77–
1.88 (m, 1H), 1.92–2.02 (m, 1H), 2.03–2.12 (m, 1H), 2.14–2.33
(m, 3H), 2.41–2.56 (m, 2H), 2.97 (td, J = 8.7, 3.5 Hz, 1H), 3.13
(ddd, J = 6.9, 9.5, 9.8 Hz, 1H), 3.49 (q, J = 6.9 Hz, 1H), 4.10 (q,
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23.0, 26.7, 34.5, 43.6, 47.0, 55.8, 56.9, 60.6, 64.7, 173.6, 211.3. IR:
mmax (film) = 2978, 2931, 2858, 1734, 1703, 1450, 1375, 1201,
1161, 1113, 1093, 1055, 1024, 862 cmꢀ1. HRMS (m/z): calcd for
C
14H24NO3 [M+H]+ 254.1751; found 254.1734.
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1(2H)-yl)propanoate 13
Ketone 13 was prepared in the same manner as 11. Yield 68%,
m = 0.1143 g. Physical state: colourless oil. Rf = 0.15 (silica gel,
3:1 hexanes/AcOEt), Rf = 0.68 (silica gel, 7:1 CHCl3/MeOH).
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½
a 2D3
ꢂ
¼ þ18:2 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.22 (t,
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J = 7.2 Hz, 3H), 1.23–1.30 (m, 2H), 1.32 (d, J = 7.3 Hz, 3H), 1.64–
1.78 (m, 2H), 1.84–1.94 (m, 1H), 2.00–2.08 (m, 1H), 2.24–2.37
(m, 3H), 2.37–2.45 (m, 1H), 2.52–2.61 (m, 1H), 2.69 (td, J = 9.1,
7.5 Hz, 1H), 3.00–3.11 (m, 2H), 3.64 (q, J = 7.0 Hz, 1H), 4.03–4.21
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26.8, 34.4, 43.9, 45.6, 55.0, 56.4, 60.1, 63.8, 172.4, 211.5. IR: mmax
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