Stereocontrolled synthesis of enantiopure cis- and trans-3,4,4a,5,8,8a-hexahydro-1H-quinolin-2-ones

Article abstract of DOI:10.1016/j.tetasy.2008.10.007

Starting from the 8-allyl substituted oxazolopiperidone lactam 2b, which is easily accessible from (R)-phenylglycinol and racemic δ-oxoester 1a, two-step sequences involving a stereoselective α-amidoalkylation reaction, either with inversion or retention of configuration, followed by a ring-closing metathesis, provide diastereodivergent routes to enantiopure cis- and trans-3,4,4a,5,8,8a-hexahydro-1H-quinolin-2-ones.

Full text of DOI:10.1016/j.tetasy.2008.10.007

Tetrahedron: Asymmetry 19 (2008) 2406–2410
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereocontrolled synthesis of enantiopure cis- and
trans-3,4,4a,5,8,8a-hexahydro-1H-quinolin-2-ones
a
a
b
a,
*
Mercedes Amat a, , Maria Pérez , Annamaria T. Minaglia , Daniele Passarella , Joan Bosch
*
a Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona, 08028-Barcelona, Spain
b Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from the 8-allyl substituted oxazolopiperidone lactam 2b, which is easily accessible from (R)-
phenylglycinol and racemic d-oxoester 1a, two-step sequences involving a stereoselective -amidoalkyl-
ation reaction, either with inversion or retention of configuration, followed by a ring-closing metathesis,
Received 19 September 2008
Accepted 10 October 2008
Available online 7 November 2008
a
provide diastereodivergent routes to enantiopure cis- and trans-3,4,4a,5,8,8a-hexahydro-1H-quinolin-
2-ones.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
In this context, starting from easily accessible unsaturated lac-
tams bearing an appropriate alkenyl substituent, a stereoselective
Previous work has illustrated that phenylglycinol-derived oxa-
zolopiperidone lactams are extremely useful building blocks that
allow the preparation of a wide range of enantiopure piperidine
derivatives bearing virtually any type of substitution pattern,
including indolizidines, quinolizidines, decahydroquinolines, per-
hydroisoquinolines, and complex piperidine-containing indole
alkaloids.1–3
conjugate addition–ring-closing metathesis sequence has provided
efficient and versatile routes to enantiopure piperidines cis-3,4-
fused and cis-2,4-bridged to five-, six-, and seven-membered
carbocyclic rings4 (Scheme 1). A crucial aspect of the above
approaches is the control of the cis relative stereochemistry of the
substituents at the 3- (or 2-) and 4-positions of the piperidine ring,
which is ensured by a stereoselective conjugate addition reaction.
C6H5
C6H5
H
N
Ring-closing
metathesis
Stereoselective
conjugate
O
O
N
O
O
O
N
addition
H
BnO2C
BnO2C
H
n = 0,1,2
n
n
a
series
C6H5
OH
cis
1. Stereoselective
NH2
MeO2C
cyclocondensation
O
R1
R2
2. Generation of an activated
unsaturated lactam
1
C6H5
Boc
N
C6H5
O
H
O
Ring-closing
metathesis
b
O
N
Stereoselective
conjugate
series
O
N
R1
R2
m
m
addition
m
a
b
H
CH2CH=CH2
H
BnO2C
H
BnO2C
alkenyl
m = 1,2
(or precursor)
cis
Scheme 1. Enantioselective synthesis of cis-3,4-fused and cis-2,4-bridged piperidines.
* Corresponding authors. Tel.: +34 93 402 45 38; fax: +34 93 402 45 39.
E-mail addresses: amat@ub.edu (M. Amat), joanbosch@ub.edu (J. Bosch).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.007

M. Amat et al. / Tetrahedron: Asymmetry 19 (2008) 2406–2410
2407
C6H5
C6H5
O
R
H
N
Ring-closing
metathesis
Stereoselective
OH
n
Stereoselective
O
H
O
8a
8
O
MeO2C
n
O
N
cyclocondensation
α-amidoalkylation
N
*
*
*
*
*
*
m
BnO2C
m
m
m
cis/trans
Scheme 2. Synthetic strategy for the enantioselective synthesis of cis- and trans-2,3-fused piperidines.
diastereodivergent synthesis of cis- and trans-hexahydroquinoline
derivatives (Scheme 2; m = n = 1).
2. Results and discussion
The known4a 8-allyl lactam 2a might seem a priori as the suitable
starting material for our purpose. This lactam can be prepared in
A similar ring-closing metathesis process from a piperidine
bearing alkenyl substituents at the 2- and 3-positions would
provide enantiopure piperidines 2,3-fused to a carbocyclic ring.
Taking into account that phenylglycinol-derived oxazolopiperi-
done lactams allow the stereocontrolled introduction of substitu-
71% yield by cyclocondensation of the c-allyl-d-oxoester 1a with
(R)-phenylglycinol, in a process that involves a dynamic kinetic res-
olution of the racemic substrate.6 However, taking into account that
earlier studies from related phenylglycinol-derived lactams indi-
ents at the
asymmetric
a-position of the piperidine ring (C-8a) by
cate that the success of a-amidoalkylation reactions depends upon
a
-amidoalkylation, either with retention or inversion
of configuration of this stereocenter,5 this approach could open
access to fused bicyclic systems in both the cis and trans series
starting from an appropriate 8-alkenyl lactam (Scheme 2).
Herein, we report the application of the above stereoselective
the H3–H8a relative stereochemistry, with the trans H3–H8a isomers
being more efficient than the cis isomers in terms of chemical yield
and stereoselectivity,5c,d we decided to use the isomeric H3–H8a
trans lactam 2b, which was prepared in 73% yield by equilibration
of 2a under acidic conditions. Minor amounts (4%) of lactam 2c
a-amidoalkylation–ring-closing metathesis sequence to the
C6H5
R
C6H5
OH
O
C6H5
O
C6H5
O
C6H5
O
3
OH
OH
OH
NH2
7.6 M HCl
+
N
O
8a
+
N
N
O
N
25 ºC, 96 h.
H
MeO2C
2a: 15%
2b: 80%
2c: 5%
2a: 71%
2b: 10%
2a
1a
racemate
C6H5
C6H5
3
O
8a
O
O
N
O
N
2c
2b
Scheme 3. Equilibration of lactam 2a.
C6H5
C6H5
O
Ti
H
N
C6H5
H
OH
OH
2nd Gen.
Grubbs cat.
H
H
O
H
H
O
O
N
H
O
N
SiMe3
Na, liq. NH3
81%
N
TiCl4
89%
C6H5
O
cis-6
Nu
cis-5
cis-3
O
N
A
MgBr
C6H5
O
C6H5
O
2b
H
N
X
OH
OH
2nd Gen.
Grubbs cat.
H
R
O
H
Mg
O
N
N
H
H
Na, liq. NH3
85%
N
C6H5
O
C6H5
87%
H
trans-
OH
H
H
6
trans-3
N
trans-5
B
4
Scheme 4. Diastereodivergent synthesis of enantiopure cis- and trans-hexahydroquinolones 6.

2408
M. Amat et al. / Tetrahedron: Asymmetry 19 (2008) 2406–2410
were also formed. This isomerization to the most stable trans H3–
H8a lactam 2b can be rationalized as depicted in Scheme 3.7
4.2. Epimerization of 2a
The introduction of an allyl substituent at the piperidine
sition was accomplished in good yield (78%) using allyltrimethylsi-
lane in the presence of TiCl4. Under these conditions,
amidoalkylation occurred with inversion of the configuration at
the C-8a position to give the cis-2,3-derivative cis-3 as the major
product (cis-3/trans-3 ratio, 4:1; Scheme 4).
a
-po-
4.2.1. (3R,8S,8aS)-8-Allyl-5-oxo-3-phenyl-2,3,6,7,8,8a-
hexahydro-5H-oxazolo[3,2-a]pyridine 2b
a
-
A solution of pure lactam 2a4a (500 mg, 1.95 mmol) in MeOH–
HCl (7.6 M, 12.5 mL) was stirred at 25 °C for 96 h. The resulting
acidic solution was neutralized with saturated aqueous NaHCO3
and extracted with CH2Cl2. The combined organic extracts were
dried and concentrated, and the resulting residue was chromato-
graphed (1:1 EtOAc/hexane) to give pure 2b (365 mg, 73%), 2a
(70 mg, 14%), and 2c (20 mg, 4%). Compound 2b: IR (NaCl)
The stereoselectivity of the
a-amidoalkylation was reversed
using allylmagnesium bromide as the nucleophile (cis-3/trans-3
ratio, 1:4), although in this case the chemical yield was low
(30%) due to the formation of the polyallylated piperidine 4 as
the major product (34%), even at ꢀ78 °C. The different stereoselec-
1658 cmꢀ1 1H NMR (300 MHz, CDCl3, COSY, HETCOR) d 1.53 (m,
;
1H, H-7), 1.66 (m, 1H, H-8), 1.96 (m, 1H, H-7), 2.07 (dt, J = 16.5,
8.4, 8.4 Hz, 1H, CH2 allyl), 2.35 (ddd, J = 18.6, 12.0, 6.6 Hz, 1H, H-
6), 2.56 (m, 2H, H-6, CH2 allyl), 3.76 (dd, J = 9.0, 7.8 Hz, 1H, H-2),
4.48 (dd, J = 9.0, 8.1 Hz, 1H, H-2), 4.71 (d, J = 8.4 Hz, 1H, H-8a),
5.13 (m, 2H, CH2@), 5.25 (t, J = 7.8 Hz, 1H, H-3), 5.83 (dddd,
J = 16.5, 10.2, 8.1, 6.0 Hz, 1H, CH@), 7.25–7.34 (m, 5H, ArH); 13C
NMR (75.4 MHz, CDCl3) d 22.8 (C-7), 31.4 (CH2 allyl), 35.9 (C-6),
39.6 (C-8), 58.3 (C-3), 72.4 (C-2), 92.0 (C-8a), 117.4 (CH2@),
126.0, 128.6 (C-o, m), 127.5 (C-p), 134.6 (CH@), 139.4 (C-i), 168.6
tivity of the above
a-amidoalkylation reactions can be explained
by considering either an attack of the nucleophile upon the less
hindered face of an acyl iminium cation8 A (inversion of configura-
tion), or the intramolecular delivery of the nucleophile from the
Grignard reagent, as depicted in B (retention of configuration).
The ring-closing metathesis of diallylpiperidones cis-3 and
trans-3 catalyzed by a second generation Grubbs catalyst9 resulted
in the closure of the carbocyclic ring to give the respective hydro-
quinolones cis-5 and trans-5 in excellent yields.10
Finally, removal of the phenylethanol moiety from lactams 5
was accomplished with sodium in liquid ammonia to lead to the
target enantiopure hexahydroquinolones cis-6 and trans-6, also in
good yields.
(NCO); ½a 2D2
¼ ꢀ59:9 (c 1.06, EtOH). Anal. Calcd for C16H19NO2ꢂ
ꢁ
1/4H2O: C, 73.40; H, 7.51; N, 5.35. Found: C, 73.27; H, 7.25; N,
5.51. Compound 2c: IR (NaCl) 1657 cmꢀ1 1H NMR (300 MHz,
;
CDCl3, COSY, HETCOR) d 1.72–1.96 (m, 3H, 2H-7, H-6), 2.32–2.48
(m, 4H, 2CH2 allyl, H-8, H-6), 3.79 (dd, J = 12.0, 10.0 Hz, 1H, H-2),
4.42 (dd, J = 12.0, 10.8 Hz, 1H, H-2), 5.05–5.09 (m, 2H, CH2@),
5.13 (d, J = 5.2 Hz, 1H, H-8a), 5.26 (t, J = 10.4 Hz, 1H, H-3), 5.26
(m 1H, CH@), 7.20–7.38 (m, 5H, ArH); 13C NMR (75.4 MHz, CDCl3)
d 20.2 (C-7), 27.5 (CH2 allyl), 28.6 (C-6), 34.7 (C-8), 58.1 (C-3), 72.1
(C-2), 89.6 (C-8a), 116.9 (CH2@), 126.0, 128.6 (C-o, m), 127.5 (C-p),
3. Conclusion
Through
a two-step sequence involving a stereoselective
a-amidoalkylation reaction and a ring-closing metathesis, phenyl-
135.5 (CH@), 139.5 (C-i), 168.6 (NCO); ½a D22
¼ ꢀ118:9 (c 1.0, CHCl3).
ꢁ
glycinol-derived oxazolopiperidone lactams open up short diaste-
reodivergent routes to enantiopure cis- and trans-hydroquinolone
derivatives. By an appropriate selection of the alkenyl substituents
at the piperidine 2- and 3-positions, the above methodology could
provide general access to enantiopure piperidines cis- and trans-
2,3-fused to carbocyclic rings of different sizes. Taking into account
that both enantiomers of phenylglycinol are commercially avail-
able, access to 2,3-fused piperidines in both enantiomeric series
is assured.
Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C,
74.60; H, 7.52; N, 5.40.
4.3.
a-Amidoalkylation reactions
4.3.1. (5S,6R)-5,6-Diallyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-
piperidone cis-3
Allyltrimethylsilane (2.5 mL, 16.3 mmol) and TiCl4 (0.6 mL,
5.4 mmol) were added to a solution of 2b (700 mg, 2.7 mmol) in
CH2Cl2 (22 mL). The resulting mixture was heated at reflux for
18 h. The reaction was quenched by the addition of saturated aque-
ous Na2CO3, and the mixture extracted with CH2Cl2. The combined
organic extracts were dried and concentrated, and the resulting
residue was chromatographed (1:3 EtOAc/hexane to EtOAc) to give
a mixture of compounds cis-3/trans-3 (635 mg, 78% yield, ratio
4:1). cis-3 (data from the above mixture): IR (NaCl) 1620,
4. Experimental
4.1. General procedures
All non-aqueous reactions were performed under an argon or
nitrogen atmosphere with dry, freshly distilled solvents using stan-
dard procedures. Drying of organic extracts during the work-up of
reactions was performed over anhydrous Na2SO4 or MgSO4. Evap-
oration of solvents was accomplished with a rotatory evaporator.
Thin-layer chromatography was done on SiO2 (silica gel 60 F254),
and the spots were located by UV and by either a 1% KMnO4 solu-
tion or iodine. Chromatography refers to flash column chromato-
graphy and was carried out on SiO2 (silica gel 60, 230–400
mesh). Melting points were determined in a capillary tube and
are uncorrected. NMR spectra were recorded at 300 or 400 MHz
(1H) and 75.4 or 100.6 MHz (13C), and chemical shifts are reported
in d values downfield from TMS or relative to residual chloroform
(7.26, 77.0 ppm) as an internal standard. Data are reported in the
following manner: chemical shift, multiplicity, coupling constant
(J) in hertz (Hz), integrated intensity, and assignment (when possi-
ble). Multiplicities are reported using the following abbreviations:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
ap, apparent. Only noteworthy IR absorptions (cmꢀ1) are listed.
Mass spectra (MS) data are reported as m/z (%).
; d 1.65 (tt,
3376 cmꢀ1 1H NMR (400 MHz, CDCl3, HETCOR)
J = 13.0, 8.5 Hz, 1H, H-4), 1.80–1.96 (m, 2H, H-4, H-5), 2.03 (m,
2H, CH2 allyl), 2.17 (q, J = 7.6 Hz, 1H, CH2 allyl), 2.36 (m, 1H, CH2
allyl), 2.56–2.62 (m, 2H, H-3), 3.27 (dd, J = 9.2, 5.2 Hz, 1H, H-6),
4.04 (dd, J = 12.0, 3.3 Hz, 1H, H-20), 4.17 (dd, J = 12.0, 7.2 Hz, 1H,
H-20), 4.66 (dd, J = 7.2, 3.3 Hz, 1H, H-10), 4.95–5.09 (m, 4H, CH2@),
5.60 (td, J = 17.1, 6,8 Hz, 1H, CH@), 5.73 (dddd, J = 16.8, 10.0, 6.8,
6.8 Hz, 1H, CH@), 7.21–7.40 (m, 5H, ArH); 13C NMR (100.6 MHz,
CDCl3) d 22.0 (C-4), 31.0 (C-3), 34.3 (CH2 allyl), 36.9 (CH2 allyl),
38.9 (C-5), 60.9 (C-6), 64.2 (C-20), 68.0 (C-10), 116.9, 117.8
(CH2@), 126.4–128.6 (C-o, m, p), 135.2, 135.5 (CH@), 137.3 (C-i),
172.2 (NCO); HMRS calcd for [C19H25NO2 + H]: 300.1958, found:
300.1955.
4.3.2. (5S,6S)-5,6-Diallyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-
piperidone trans-3
Allylmagnesium bromide (1 M in Et2O, 23.3 mL) was added to a
cooled (0 °C) solution of 2b (1.1 g, 4.2 mmol) in THF (10 mL), and

M. Amat et al. / Tetrahedron: Asymmetry 19 (2008) 2406–2410
2409
the mixture was stirred at this temperature for 18 h. The reaction
was quenched by the addition of saturated aqueous NaCl, and
the mixture extracted with EtOAc. The organic extracts were dried
and concentrated. Purification by column chromatography (1:3
EtOAc/hexane to EtOAc) gave compound 4 (516 mg, 34% yield)
and a mixture of compounds cis-3/trans-3 (378 mg, 30% yield, ratio
1:4). trans-3 (data from the above mixture): 1H NMR (400 MHz,
CDCl3, HETCOR) d 1.53 (ddd, J = 14.0, 9.6, 5.2 Hz, 1H, H-4), 1.78
(m, 1H, CH2 allyl), 1.85 (m, 1H, H-5), 1.90 (m, 1H, CH2 allyl), 1.98
(ddd, J = 14.0, 8.8, 4.8 Hz, 1H, H-4), 2.27 (ddd, J = 14.4, 10.4,
8.4 Hz, 1H, CH2 allyl), 2.44 (m, 3H, CH2 allyl, 2H-3), 3.09 (d,
J = 10.4 Hz, 1H, H-6), 4.14 (dd, J = 11.6, 4.8 Hz, 1H, H-20), 4.26 (dd,
J = 11.6, 8.4 Hz, 1H, H-20), 5.00 (m, 4H, CH2@), 4.28 (dd, J = 8.4,
4.8 Hz, 1H, H-10), 5.50 (dddd, J = 16.8, 13.6, 6.8, 6.8 Hz, 1H, CH@),
5.57 (m, 1H, CH@), 7.20–7.35 (m, 5H, ArH); 13C NMR (100.6 MHz,
CDCl3) d 20.2 (C-4), 28.4 (C-3), 33.4 (CH2 allyl), 36.0 (CH2 allyl),
39.3 (C-5), 59.6 (C-6), 63.6 (C-10), 63.9 (C-20), 116.9, 118.0
(CH2@), 127.6–128.5 (C-o, m, p), 133.8, 135.7 (CH@), 136.9 (C-i),
5.1, 1.8 Hz, 1H, H-3), 3.23 (td, J = 10.2, 10.2, 4.5 Hz, 1H, H-8a),
4.11 (dd, J = 11.8, 3.0 Hz, 1H, H-20), 4.29 (m, 1H, H-20), 4.90 (br,
1H, H-10), 5.45 (m, 1H, CH@), 5.60 (m, 1H, CH@), 7.23–7.35 (m,
5H, ArH); 13C NMR (100.6 MHz, CDCl3) d 26.3 (C-4), 32.4 (C-5),
33.9 (C-8), 33.5 (C-3), 37.4 (C-4a), 61.7 (C-8a), 64.0 (C-20), 64.7
(C-10), 124.4 (CH@), 126.0 (CH@), 125.9–128.2 (C-o, m, p), 137.9
(C-i), 172.8 (COO); ½a D22
¼ þ256:0 (c 0.8, CHCl3); HMRS calcd for
ꢁ
[C17H21NO2 + H]: 272.1645, found: 272.1635.
4.5. Removal of the chiral inductor
4.5.1. (4aS,8aR)-3,4,4a,5,8,8a-Hexahydro-1H-quinolin-2-one
cis-6
Into a three-necked, 100 mL round-bottomed flask equipped
with a coldfinger condenser charged with dry ice–acetone was
condensed 10 mL of NH3 at ꢀ78 °C, and a solution of cis-5
(50 mg, 0.15 mmol) in THF (4 mL) was added. The temperature
was raised to ꢀ33 °C, and then sodium metal was added in small
portions until the blue color persisted. The mixture was stirred at
ꢀ33 °C for 1 min. The reaction was quenched by addition of solid
NH4Cl until the blue color disappeared, and then the mixture
was stirred at rt for 4 h. The resulting residue was digested at rt
with CH2Cl2, and the suspension was filtered through CeliteÒ and
concentrated. Flash chromatography (EtOAc to 95:5 EtOAc/MeOH)
172.5 (NCO). Compound 4: IR (NaCl) 3397 cmꢀ1
;
1H NMR
(400 MHz, CDCl3, HETCOR) d 0.94 (td, J = 12.0, 12.0, 3.2 Hz, 1H, H-
3), 1.14 (m, 1H, H-4), 1.20 (br, 1H, H-3), 1.25 (m, 1H, H-4), 1.33
(m, 1H, H-5), 1.93-2.25 (3m, 8H, CH2 allyl), 2.58 (m, 1H, H-6),
3.50 (dd, J = 10.8, 8.8 Hz, 1H, H-20), 3.63 (dd, J = 10.8, 4.6 Hz, 1H,
H-20), 3.78 (dd, J = 8.8, 4.8 Hz, 1H, H-10), 4.94–5.11 (m, 8H, CH2@),
5.58–5.82 (m, 4H, CH@), 5.57 (m, 1H, CH@), 7.10–7.20 (m, 5H,
ArH); 13C NMR (100.6 MHz, CDCl3) d 22.8 (C-4), 34.5 (CH2 allyl),
35.1 (CH2 allyl), 37.0 (C-3), 41.0 (C-5), 43.4 (CH2 allyl), 43.6 (CH2
allyl), 56.7 (C-6), 62.6 (C-10), 66.7 (C-20), 73.3 (C-2), 115.8, 117.0,
118.4, 118.5 (CH2@), 127.5–128.5 (C-o, m, p), 133.7, 136.2, 137.7
afforded cis-6 (22 mg, 81% yield): IR (NaCl) 1663, 3205 cmꢀ1 1H
;
NMR (400 MHz, CDCl3, COSY, HETCOR) d 1.69–1.76 (m, 1H, H-4),
1.85 (tt, J = 14.0, 8.0 Hz, 1H, H-4), 1.98–2.08 (m, 2H, H-8, H-5),
2.15 (ddd, J = 12.8, 9.2, 4.0 Hz, 1H, H-4a), 2.25 (dm, J = 17.6 Hz,
1H, H-5), 2.36–2.50 (m, 3H, 2H-3, H-8), 3.59 (m, 1H, H-8), 5.55,
5.64 (2m, 2H, 2CH@), 6.49 (br, 1H, NH); 13C NMR (100.6 MHz,
CDCl3) d 23.7 (C-4), 27.4 (C-5), 29.2 (C-3), 30.0 (C-4a), 31.0 (C-8),
49.3 (C-8a), 122.2 (CH@), 125.4 (CH@), 172.5 (NCO);
(CH@), 141.5 (C-i); ½a D22
¼ þ33:7 (c 1.5, CHCl3); HMRS calcd for
ꢁ
[C25H35NO + H]: 366.2791, found: 366.2777.
4.4. Ring-closing metathesis reactions
½
a 2D2
ꢁ
¼ ꢀ33:9 (c 0.9, CHCl3); HMRS calcd for C9H13NO: 174.0889,
found: 174.0884.
4.4.1. (4aS,8aR)-1-[(1R)-2-Hydroxy-1-phenylethyl]-3,4,
4a,5,8,8a-hexahydro-1H-quinolin-2-one cis-5
4.5.2. (4aS,8aS)-3,4,4a,5,8,8a-Hexahydro-1H-quinolin-2-one
trans-6
Second-generation Grubbs catalyst (71 mg) was added to a
solution of lactams cis-3/trans-3 (ratio 4:1, 343 mg, 1.1 mmol) in
CH2Cl2 (163 mL). The mixture was stirred at rt for 3 h and concen-
trated. The resulting residue was purified by flash column chroma-
tography (1:4 EtOAc/hexane to EtOAc and then 95:5 EtOAc/MeOH)
to yield bicyclic lactams cis-5 (220 mg) and trans-5 (48 mg) (89%
Operating as described above in the preparation of cis-6, from
trans-5 (120 mg, 0.4 mmol) in THF (5 mL), sodium, and liquid
NH3 (15 mL), at ꢀ33 °C for 60 s, compound trans-6 was obtained
(52 mg, 85%) after flash chromatography (EtOAc to 95:5 EtOAc/
MeOH): IR (NaCl) 1680, 3189 cmꢀ1 1H NMR (400 MHz, CDCl3,
;
overall yield). cis-5: IR (NaCl) 1616, 3358 cmꢀ1
;
1H NMR
COSY, HETCOR) d 1.52 (ddd, J = 17.9, 12.1, 6.3 Hz, 1H, H-4), 1.59–
1.69 (m, 1H, H-4a), 1.79–1.93 (m, 2H, H-4, H-5), 2.05 (m, 1H, H-
8), 2.24 (m, 1H, H-5), 2.32 (m, 1H, H-8), 2.42 (dt, J = 18.0, 6.4,
6.4 Hz, 1H, H-3), 2.48 (ddd, J = 18.0, 6.3, 2.0 Hz, 1H, H-3), 3.25
(td, J = 10.5, 10.5, 5.3 Hz, 1H, H-8a), 5.61–5.71 (2m, 2H, 2CH@),
6.65 (br, 1H, NH); 13C NMR (100.6 MHz, CDCl3) d 27.5 (C-4), 31.1
(C-5), 31.5 (C-3), 33.2 (C-8), 35.3 (C-4a), 54.1 (C-8a), 123.9
(400 MHz, CDCl3, HETCOR) d 1.61 (ddd, J = 9.2, 7.2, 3.2 Hz, 1H, H-
4), 1.86–2.08 (m, 4H, H-4, H-8, 2H-5), 2.16 (ddd, J = 12.8, 9.2,
3.6 Hz, 1H, H-4a), 2.39 (dm, J = 18.0 Hz, 1H, H-8), 2.61 (m, 2H, H-
3), 3.39 (q, J = 4.8 Hz, 1H, H-8a), 3.98 (m, 1H, OH), 4.07 (dd,
J = 11.6, 2.8 Hz, 1H, H-20), 4.25 (m,1H, H-20), 4.93 (dd, J = 7.6,
3.6 Hz, 1H, H-10), 5.45 (m, 1H, CH@), 5.53 (m, 1H, CH@), 7.28–
7.38 (m, 5H, ArH); 13C NMR (100.6 MHz, CDCl3) d 21.9 (C-4), 28.7
(C-5), 30.9 (C-3), 31.4 (C-8), 32.2 (C-4a), 55.3 (C-8a), 63.9 (C-20),
64.9 (C-10), 123.0 (CH@), 124.6 (CH@), 127.7–128.6 (C-o, m, p),
(CH@), 126.7 (CH@), 172.3 (NCO); ½a D22
¼ þ186:5 (c 1.7, CHCl3);
ꢁ
HMRS calcd for C9H13NO: 174.0889, found: 174.0882.
137.4 (C-i), 171.6 (COO); ½a D22
ꢁ
¼ ꢀ39:6 (c 1.2, CHCl3); HMRS calcd
Acknowledgments
for [C17H21NO2 + H]: 272.1645, found: 272.1638.
Financial support from the Ministry of Science and Technology
(Spain)-FEDER (project CTQ2006-02390/BQU) and the DURSI, Gen-
eralitat de Catalunya (Grant 2005-SGR-0603) is gratefully
acknowledged. Thanks are also due to the Ministry of Science
and Technology (Spain) for a fellowship to A.T.M.
4.4.2. (4aS,8aS)-1-[(1R)-2-Hydroxy-1-phenylethyl]-3,4,
4a,5,8,8a-hexahydro-1H-quinolin-2-one trans-5
Operating as above, from the mixture cis-3/trans-3 (ratio 1:4,
53 mg, 0.17 mmol) and second generation Grubbs catalyst
(11 mg) in CH2Cl2 (25 mL), bicyclic lactams cis-5 (6 mg) and
trans-5 (34 mg) (87% overall yield) were obtained after column
chromatography (3:7 EtOAc/hexane). trans-5: IR (NaCl) 1621,
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