A general synthetic route to enantiopure cis-fused perhydrocycloalka[c]pyridines from phenylglycinol-derived lactams

Article abstract of DOI:10.1016/j.tet.2007.01.072

A synthetic route to enantiopure piperidines bearing a five-, six-, or seven-membered carbocyclic ring cis-fused on the c side of the heterocycle from a common phenylglycinol-derived δ-lactam is reported. Key steps are (i) a cyclocondensation reaction of

Full text of DOI:10.1016/j.tet.2007.01.072

Tetrahedron 63 (2007) 5839–5848
A general synthetic route to enantiopure
cis-fused perhydrocycloalka[c]pyridines from phenylglycinol-
derived lactams
*
Mercedes Amat, Maria Perez, Annamaria T. Minaglia, Bruno Peretto and Joan Bosch
*
ꢀ
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain
Received 21 December 2006; accepted 31 January 2007
Available online 3 February 2007
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Abstract—A synthetic route to enantiopure piperidines bearing a five-, six-, or seven-membered carbocyclic ring cis-fused on the c side of the
heterocycle from a common phenylglycinol-derived d-lactam is reported. Key steps are (i) a cyclocondensation reaction of (R)-phenylglycinol
with a racemic g-oxoester in a process that involves a dynamic kinetic resolution; (ii) a highly stereoselective conjugate addition of an organo-
cuprate to an unsaturated d-lactam; and (iii) a ring-closing olefin metathesis.
Ó 2007 Elsevier Ltd. All rights reserved.
SC6H5
1. Introduction
Me
O
CONHt-Bu
N
HO
N
H
N
H
N
The cis-perhydroisoquinoline ring system is present in a
large number of bioactive natural and synthetic products.
Among them, of particular interest are the indole alkaloids
of the yohimbine–reserpine type1 and the marine sponge al-
kaloids of the manzamine2 and madangamine3 groups, all of
them displaying a variety of notable pharmacological activ-
ities, as well as the HIV protease inhibitors nelfinavir and
saquinavir.4 Similarly, both the lower and higher carbocyclic
ring homologs of perhydroisoquinolines are ring systems
also found in natural products. Thus, a-skytanthine,5 incar-
villine,6 tecostanine,7 and related bicyclic alkaloids are sub-
stituted cis-fused perhydrocyclopenta[c]pyridines whereas
the cis-perhydrocyclohepta[c]pyridine framework is present
in the indole alkaloids of the ervatamine group8 (Fig. 1).
H
H
H
OH
H
H
Nelfinavir
(-)-Alloyohimbane
Me
R
H
Me
N
H
N
N
Me
Me
H
O
H
(+)-α-Skytanthine
R = CO2Me (-)-Ervatamine
R = H, 19,20-didehydro (+)-Methuenine
Figure 1.
indolo[2,3-a]quinolizidines, as well as more complex indole
alkaloids.9,10
2. Results and discussion
In this paper we further illustrate the potential of phenyl-
glycinol-derived oxazolopiperidone lactams in the enantio-
selective construction of piperidine-containing heterocycles.
We present a general synthetic route to enantiopure piper-
idines bearing a cis-fused five-, six-, or seven-membered car-
bocyclic ring on the c side of the heterocycle.
In previous work we have demonstrated that phenylglycinol-
derived oxazolopiperidone lactams are exceptionally versa-
tile building blocks for the enantioselective synthesis of
structurally diverse piperidine-containing derivatives, in-
cluding polysubstituted piperidines bearing virtually any
type of substitution pattern, quinolizidines, indolizidines,
perhydroquinolines, hexahydroisoquinolines, benzo[a]- and
The key steps of the synthesis are (i) a cyclocondensation
reaction of (R)-phenylglycinol with racemic g-substituted
d-oxoester 1, in a process that involves a dynamic kinetic
resolution;11 (ii) a highly stereoselective conjugate addition
of an appropriate organocuprate to an unsaturated lactam;
(iii) the closure of the carbocyclic ring by a ring-closing
Keywords: Phenylglycinol; Oxazolopiperidone lactams; Conjugate addi-
tion; Ring-closing olefin metathesis; Dynamic kinetic resolution; Enantio-
pure cis-fused piperidines; Perhydroisoquinoline.
* Corresponding authors. Tel.: +34 93 4024538; fax: +34 93 4024539;
e-mail addresses: amat@ub.edu; joanbosch@ub.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.072

5840
M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
olefin metathesis;12 and finally (iv) the reductive removal of
the chiral inductor (Scheme 1).
Nu
CO2R
O
H
H
N
O
C6H5
Dynamic kinetic
resolution
Stereoselective
8a
C6H5
conjugate addition
OH
H
C6H5
O
C6H5
O
NH2
MeO2C
4
O
O
N
CHO
N
Figure 2. Stereoelectronic control in the conjugate addition.
BnO2C
BnO2C
oxidation of the resulting mixtures of selenides 3 with
H2O2 in the presence of pyridine, afforded 4a and 4b, respec-
tively, in good overall yield. Lactams 4 proved to be sensitive
to both mild acid and basic conditions, affording the corre-
sponding pyridones 5. Consequently, they were immediately
used in the next reaction without further purification.
1, racemate
n
Ring-closing
metathesis
C6H5
Removal of the
chiral inductor
H
N
O
O
H
O
N
H
The conjugate addition of an allyl group was accomplished
in excellent chemical yield and complete exo-facial dia-
stereoselectivity by reacting lactams 4a and 4b with allyl-
magnesium bromide in presence of CuI, LiCl, and
TMSCl.18 The observed stereoselectivity can be explained
by considering a stereoelectronically controlled19 axial at-
tack of the nucleophile on the electrophilic carbon of the con-
jugated double bond of the conformationally rigid lactams 4
(Fig. 2). The resulting cis-diallyl lactams 6a and 6b were iso-
lated as mixtures of epimers at the isomerizable stereocenter
adjacent to the ester and lactam carbonyl groups (Scheme
3).20 However, this did not represent any inconvenience
from the synthetic standpoint because the benzyloxycar-
bonyl substituent would be removed in a later synthetic step.
n = 0,1,2
BnO2C
H
H
n
n
Scheme 1. Synthetic strategy.
The starting racemic oxoester 1 was conveniently prepared
in 64% yield by reaction of the piperidine enamine of 4-pen-
tenal with methyl acrylate.13 Cyclocondensation of 1 with
(R)-phenylglycinol at 0 ꢀC in the presence of anhydrous
Na2SO4, followed by heating at 75–80 ꢀC under vacuum
(10–15 mmHg) stereoselectively afforded the enantiopure
bicyclic lactam 2 in 71% yield (Scheme 2). Minor amounts
(10%) of the (8S,8aS)-diastereoisomer were also isolated.
This result clearly indicated that a dynamic kinetic re-
solution, with epimerization of the configurationally labile
stereogenic center a to the aldehyde carbonyl group, had
occurred during the cyclocondensation reaction.
C6H5
O
C6H5
O
O
H
O
CH2=CHCH2MgBr,
CuI, LiCl, TMSCl
N
N
7a
4
R
C6H5
RO2C
C6H5
RO2C
R
OH
H
8
NH2
6
O
a R = Me
b R = Bn
O
N
8a
MeO2C
CHO
a) H2, Pd/C
b)
R
8
C6H5
O
C6H5
O
2
1, racemate
H
N
OH
H
O
H
O
N
N
LHMDS, ClCO2R
then PhSeCl
H
Et3SiH, TiCl4
Na, liq. NH3
C6H5
C6H5
O
H
H
H
O
O
O
N
N
H2O2
10
9
11
LiAlH4
AlCl3
RO2C
C6H5Se
RO2C
R
Ru
PCy3
Cl
Cl
C6H5
4
3
CO2t-Bu
N
H
C6H5
Ph
OH
H
H2, Pd/C
(Boc)2O
N
a R = Me
b R = Bn
OH
O
N
7
H
12
7a R =Mes
7b R = PCy3
N
N Mes
H
RO2C
5
13
Scheme 2. Preparation of the starting unsaturated d-lactams.
Scheme 3. Enantioselective synthesis of cis-perhydroisoquinolines.
It is known that a,b-unsaturated lactams are poor Michael
acceptors.14 The presence of an additional activating elec-
tron-withdrawing group a to the carbonyl or attached to
the nitrogen is usually necessary for the success of the con-
jugate addition of organocuprates to unsaturated d-lac-
tams.15–17 For this reason, lactam 2 was converted to the
unsaturated lactams 4, which incorporate an additional acti-
vating alkoxycarbonyl substituent in conjugation with the
double bond. Thus, sequential treatment of 2 with LHMDS,
methyl or benzyl chloroformate, and PhSeCl, followed by
The ring-closing metathesis of lactams 6a and 6b catalyzed
by the second-generation Grubbs catalyst 7a resulted in the
closure of the carbocyclic ring to give the respective hydro-
isoquinolones 8a and 8b in excellent yield (85%). The use of
the first-generation Grubbs catalyst 7b in the reaction from
6b was less satisfactory, hydroisoquinolone 8b being iso-
lated in only 66% yield after 20 h.
Catalytic hydrogenation of benzyloxycarbonyl ester 8b us-
ing Pd–C as the catalyst brought about both the reduction

M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
5841
C6H5
O
C6H5
O
C6H5
O
C6H5
O
H
N
Et3SiH
TiCl4
O
a) H2, Pd/C
b)
O
H
OH
H
O
H
N
N
N
O
N
Na, liq. NH3
7a
CH2=CHMgBr
H
H
CuI, LiCl, TMSCl
BnO2C
BnO2C
H
H
H
H
H
14
15
17
18
4b
16
C6H5
O
C6H5
C6H5
O
C6H5
O
CH2=CHCH2CH2MgBr
CuI, LiCl, TMSCl
H
N
Et3SiH
TiCl4
OH
H
O
a) H2, Pd/C
b)
O
H
O
H
N
O
N
N
N
O
Na, liq. NH3
7a
BnO2C
BnO2C
H
H
H
19
20
21
22
23
Scheme 4. Enantioselective synthesis of cis-perhydrocyclopenta[c]pyridines and cis-perhydrocyclohepta[c]pyridines.
of the carbon–carbon double bond and the debenzylation of
the benzyloxycarbonyl group to give a b-keto acid, which
was then decarboxylated by heating in refluxing toluene,
leading to a single perhydroisoquinolone 9 in 85% overall
yield.
3. Conclusion
In conclusion, starting from a common phenylglycinol-
derived unsaturated d-lactam we have developed an enantio-
selectivesyntheticroutetocis-perhydrocycloalka[c]pyridines.
By choosing the appropriate unsaturated organocuprate,
this route provides practical and efficient access to enan-
tiopure cis-perhydroisoquinolines as well as piperidines
bearing a five- or seven-membered carbocyclic ring cis-
fused on the c side of the heterocycle. The availability
of both enantiomers of phenylglycinol gives access to these
bicyclic derivatives in both enantiomeric series.
Removal of the chiral inductor was performed in two steps.
Reductive opening of the oxazolidine ring present in 9 with
triethylsilane in the presence of TiCl4 gave bicyclic lactam
10, which was then debenzylated by treatment with sodium
in liquid ammonia. The enantiopure cis-perhydroisoquino-
lin-3-one 11, an advanced intermediate in the synthesis of
(ꢁ)-alloyohimbane,21 was obtained in excellent overall
yield.
4. Experimental
Alternatively, reduction of 9 with alane brought about both
the reductive opening of the oxazolidine ring and the re-
duction of the lactam carbonyl to give the tertiary amine
12. A final hydrogenation in the presence of Pd(OH)2 and
(Boc)2O led to the enantiopure N-protected cis-perhydroiso-
quinoline 13.22
4.1. General experimental procedures
Melting points were determined in a capillary tube on
€
a Buchi apparatus 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. Only noteworthy IR absorptions are listed. Thin-
layer chromatography (TLC) was done on SiO2 (silica gel 60
F254), and the spots were located with aqueous potassium
permanganate solution. Column chromatography was car-
ried out using the flash chromatography technique. All
non-aqueous reactions were performed under an inert atmo-
sphere. Drying of the organic extracts during the workup of
reactions was performed over anhydrous Na2SO4 or MgSO4.
Evaporation of solvents was accomplished with a rotatory
evaporator. Microanalyses were performed by the Centre
The extension of the above route to the synthesis of enantio-
pure piperidines cis-fused to five- and seven-membered
carbocyclic rings simply required the use of an unsaturated
organocuprate of suitable length, either vinyl or 3-butenyl,
in the conjugate addition to the unsaturated lactam 4b
(Scheme 4). In both cases the reaction again took place
with complete exo-facial stereoselectivity, cis with respect
to the allyl substituent, leading to the corresponding lactams
14 and 19 as mixtures of epimers at the stereogenic center
adjacent to the carbonyl groups.
ꢀ
D’Investigacio i Desenvolupament (CSIC), Barcelona, and
Ring-closing metathesis of 14 led to the cis-fused cyclopenta-
[c]piperidine derivative 15, whereas a similar reaction from
19 gave the higher homolog 20, bearing a seven-membered
carbocyclic ring.23 Operating as in the above perhydroiso-
quinoline series, tricyclic lactams 15 and 20 were converted
in high overall yield to the corresponding cis-fused piperi-
dones 18 and 23. Thus, catalytic hydrogenation followed
by decarboxylation led to 16 and 21, respectively, as single
diastereoisomers. A subsequent reductive cleavage of the
C–O bond of the oxazolidine ring with Et3SiH–TiCl4, fol-
lowed by removal of the phenylethanol moiety from the
resulting derivatives 17 and 22 with sodium in liquid ammo-
nia completed the synthesis.
HRMS by the Unidade de Espectrometria de Masas, San-
tiago de Compostela.
4.2. Preparation of the starting unsaturated lactams 4
4.2.1. (3R,8R,8aR)-8-Allyl-5-oxo-3-phenyl-2,3,6,7,8,8a-
hexahydro-5H-oxazolo[3,2-a]pyridine (2). A mixture of
racemic aldehyde 113 (4.6 g, 29 mmol), (R)-phenylglycinol
(3.97 g, 29 mmol), and anhydrous Na2SO4 (17 g,
12 mmol) in Et2O (115 mL) was stirred at 0 ꢀC for 2 h.
The resulting suspension was filtered, and the filtrate was
concentrated under reduced pressure. The residue was
heated at 80 ꢀC for 18 h under vacuum (10–15 mmHg).

5842
M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
Column chromatography (SiO2 previously washed with 8:2
Et3N–EtOAc; 1:3 EtOAc–hexane to EtOAc as eluent) of the
residue afforded oxazolopiperidone 2 (5.3 g, 71%) and its
(8S,8aS)-diastereoisomer 20 (753 mg, 10%). Compound 2
(C-i), 163.3 (NCO), 170.8 (COO); [a]2D2 ꢁ99.3 (c 0.7,
CHCl3); m/z 471 (M+, 6), 390 (68), 313 (67), 254 (50),
240 (86). HRMS calcd for C24H25NO4Se: 471.0948, found:
471.0955. Compound 3a (lower Rf epimer): IR (NaCl) 1656,
1740 cmꢁ1; 1H NMR (400 MHz, CDCl3, COSY, HETCOR)
d 1.98 (m, 1H, CH2 allyl), 2.00 (dd, J¼15.2, 11.6 Hz, 1H, H-
7), 2.08 (dd, J¼15.2, 4.0 Hz, 1H, H-7), 2.32 (m, 1H, H-8),
2.52 (m, 1H, CH2 allyl), 3.73 (s, 3H, CH3), 4.10 (dd,
J¼9.2, 1.2 Hz, 1H, H-2), 4.17 (dd, J¼9.2, 6.8 Hz, 1H,
H-2), 4.63 (d, J¼9.2 Hz, 1H, H-8a), 4.97 (m, 3H, H-3,
CH2]), 5.59 (dddd, J¼16.0, 10.0, 8.0, 6.0 Hz, 1H,
CH]), 7.23–7.47 (m, 10H, ArH); 13C NMR (100.6 MHz,
CDCl3) d 33.6 (C-7), 35.0 (CH2), 36.5 (C-8), 53.3 (CH3),
55.6 (C-6), 59.6 (C-3), 73.8 (C-2), 91.6 (C-8a), 117.8
(CH2]), 126.8–138.3 (C-o, m, p), 134.0 (CH]), 140.5
(C-i), 162.8 (NCO), 171.0 (COO); [a]2D2 +18.46 (c 0.5,
CHCl3); m/z 471 (M+, 26), 390 (19), 314 (18), 282 (50),
240 (53). HRMS calcd for C24H25NO4Se: 471.0948, found:
471.0946.
(lower Rf): IR (NaCl) 1655 cmꢁ1 1H NMR (300 MHz,
;
CDCl3, COSY, HETCOR) d 1.45 (dddd, J¼13.8, 13.8,
12.0, 7.2 Hz, 1H, H-7), 2.02 (m, 3H, H-7, H-8, CH2 allyl),
2.30 (ddd, J¼18.0, 12.0, 6.6 Hz, 1H, H-6), 2.42 (ddd,
J¼18.0, 7.2, 1.8 Hz, 1H, H-6), 2.62 (m, 1H, CH2 allyl),
4.02 (dd, J¼9.0, 1.2 Hz, 1H, H-2), 4.10 (dd, J¼9.0,
6.9 Hz, 1H, H-2), 4.54 (d, J¼8.7 Hz, 1H, H-8a), 4.92 (d,
J¼6.6 Hz, 1H, H-3), 5.12 (m, 2H, CH2]), 5.86 (dddd,
J¼16.5, 10.2, 7.8, 6.0 Hz, 1H, CH]), 7.20–7.30 (m, 5H,
ArH); 13C NMR (75.4 MHz, CDCl3) d 23.5 (C-7), 31.1
(C-6), 35.3 (CH2), 38.9 (C-8), 58.8 (C-3), 73.5 (C-2),
91.7 (C-8a), 117.2 (CH2]), 126.0, 128.2 (C-o, m), 127.1
(C-p), 134.4 (CH]), 141.2 (C-i), 166.9 (NCO); [a]D22
ꢁ32.8 (c 1.0, EtOH). Anal. Calcd for C16H19NO2$1⁄4
H2O: C, 73.40; H, 7.51; N, 5.35. Found: C, 73.71; H,
7.25; N, 5.41. Compound 20 (higher Rf): IR (NaCl)
1658 cmꢁ1
;
1H NMR (300 MHz, CDCl3, COSY, HET-
4.2.3. (3R,8S,8aR)-8-Allyl-6-(benzyloxycarbonyl)-5-oxo-
3-phenyl-6-(phenylselenyl)-2,3,6,7,8,8a-hexahydro-5H-
oxazolo[3,2-a]pyridine (3b). Operating as in the above
preparation of 3a, from lactam 2 (5.39 g, 20 mmol), lithium
bis(trimethylsilyl)amide (1 M in THF, 40 mL), benzyl chloro-
formate (6.6 mL, 20 mmol), and PhSeCl (5.7 g, 30 mmol),
lactam 3b was obtained as a mixture of C-6 epimers (8.3 g,
80% overall yield) after column chromatography (1:4
EtOAc–hexane to 1:3 EtOAc–hexane). Compound 3b
COR) d 1.53 (m, 1H, H-7), 1.66 (m, 1H, H-8), 1.96 (m,
1H, H-7), 2.07 (dt, J¼16.5, 8.4, 8.4 Hz, 1H, CH2 allyl),
2.35 (ddd, J¼18.6, 12.0, 6.6 Hz, 1H, H-6), 2.56 (m, 2H,
H-6, CH2 allyl), 3.76 (dd, J¼9.0, 7.8 Hz, 1H, H-2), 4.48
(dd, J¼9.0, 8.1 Hz, 1H, H-2), 4.71 (d, J¼8.4 Hz, 1H, H-
8a), 5.13 (m, 2H, CH2]), 5.25 (t, J¼7.8 Hz, 1H, H-3),
5.83 (dddd, J¼16.5, 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), 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
(NCO); [a]2D2 ꢁ59.9 (c 1.06, EtOH). Anal. Calcd for
C16H19NO2$1⁄4 H2O: C, 73.40; H, 7.51; N, 5.35. Found:
C, 73.27; H, 7.25; N, 5.51.
1
(higher Rf epimer): IR (NaCl) 1666, 1728 cmꢁ1; H NMR
(300 MHz, CDCl3, COSY, HETCOR) d 1.85 (dd, J¼14.1,
12.6 Hz, 1H, CH2 allyl), 1.92 (dd, J¼13.5, 7.8 Hz, 1H, H-
7), 1.99 (m, 1H, H-8), 2.37 (dm, J¼14.1 Hz, 2H, CH2 allyl,
H-7), 3.93 (dd, J¼9.0, 1.2 Hz, 1H, H-2), 3.96 (d, J¼9.3 Hz,
1H, H-8a), 3.98 (dd, J¼9.0, 6.0 Hz, 1H, H-2), 4.84 (dd,
J¼6.0, 1.2 Hz, 1H, H-3), 5.00 (br t, J¼9.0 Hz, 2H,
CH2]), 5.02 (d, J¼12.3 Hz, 1H, CH2 benzyl), 5.07 (d,
J¼12.3 Hz, 1H, CH2 benzyl), 5.60 (dddd, J¼16.8, 10.5,
8.1, 6.0 Hz, 1H, CH]), 7.15–7.58 (m, 15H, ArH); 13C
NMR (75.4 MHz, CDCl3) d 34.5 (C-7), 36.7 (CH2), 37.6
(C-8), 54.7 (C-6), 59.5 (C-3), 67.6 (CH2), 73.8 (C-2), 91.4
(C-8a), 117.6 (CH2]), 126.2–129.5, 138.1 (C-o, m, p),
133.6 (CH]), 135.0, 140.3 (C-i), 163.0 (NCO), 169.8
(COO); [a]2D2 ꢁ75.3 (c 0.76, EtOH). Anal. Calcd for
C30H29NO4Se: C, 65.93; H, 5.35; N, 2.56. Found: C,
65.53; H, 5.57; N, 2.48. Compound 3b (lower Rf epimer):
4.2.2. (3R,8S,8aR)-8-Allyl-6-(methoxycarbonyl)-5-oxo-
3-phenyl-6-(phenylselenyl)-2,3,6,7,8,8a-hexahydro-5H-
oxazolo[3,2-a]pyridine (3a). Lithium bis(trimethylsilyl)-
amide (1 M in THF, 10 mL) was slowly added at ꢁ78 ꢀC
to a solution of lactam 2 (2.0 g, 1.07 mmol) in anhydrous
THF (120 mL), and the resulting mixture was stirred for
90 min. Then, methyl chloroformate (0.6 mL, 7.78 mmol)
and, after 90 min of continuous stirring at ꢁ78 ꢀC, PhSeCl
(2.08 g, 10.8 mmol) were added to the solution. The result-
ing mixture was stirred for 1 h and poured into saturated
aqueous NH4Cl. The aqueous layer was extracted with
EtOAc, and the combined organic extracts were dried and
concentrated. Flash chromatography (1:9 EtOAc–hexane
to 1:1 EtOAc–hexane) of the resulting oil afforded 3a as
a mixture of C-6 epimers (3.14 g, 86% overall yield). Com-
1
IR (NaCl) 1660, 1725 cmꢁ1; H NMR (300 MHz, CDCl3,
COSY, HETCOR) d 1.95 (m, 1H, CH2 allyl), 2.00 (dd,
J¼15.3, 4.2 Hz, 1H, H-7), 2.06 (dd, J¼15.3, 4.8 Hz, 1H,
H-7), 2.29 (m, 1H, H-8), 2.46 (m, 1H, CH2 allyl), 4.05
(dd, J¼9.0, 1.5 Hz, 1H, H-2), 4.12 (dd, J¼9.0, 6.3 Hz, 1H,
H-2), 4.54 (d, J¼9.0 Hz, 1H, H-8a), 4.93 (dd, J¼6.3,
1.5 Hz, 1H, H-3), 4.98 (m, 2H, CH2]), 5.15 (d,
J¼12.6 Hz, 1H, CH2 benzyl), 5.20 (d, J¼12.6 Hz, 1H,
CH2 benzyl), 5.56 (dddd, J¼16.8, 10.2, 8.1, 6.0 Hz, 1H,
CH]), 7.15–7.40 (m, 15H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 33.5 (C-7), 34.9 (CH2), 36.5 (C-8), 55.3 (C-6),
59.3 (C-3), 67.7 (CH2), 73.7 (C-2), 91.3 (C-8a), 117.5
(CH2]), 126.6–129.3, 138.1 (C-o, m, p), 133.9 (CH]),
135.1, 140.3 (C-i), 162.5 (NCO), 170.1 (COO); [a]D22
+23.0 (c 1.0, EtOH). Anal. Calcd for C30H29NO4Se$1⁄4
H2O: C, 65.39; H, 5.40; N, 2.54. Found: C, 65.33; H, 5.35;
N, 2.53.
pound 3a (higher Rf epimer): IR (NaCl) 1667, 1725 cmꢁ1
;
1H NMR (400 MHz, CDCl3, COSY, HETCOR) d 1.82 (dd,
J¼14.0, 12.4 Hz, 1H, CH2 allyl), 1.98 (m, 2H, H-7, H-8),
2.33 (dd, J¼14.0, 2.8 Hz, 1H, CH2 allyl), 2.41 (m, 1H, H-
7), 3.58 (s, 3H, CH3), 4.00 (dd, J¼9.2, 2.0 Hz, 1H, H-2),
4.05 (dd, J¼9.2, 6.8 Hz, 1H, H-2), 4.15 (d, J¼8.8 Hz, 1H,
H-8a), 4.87 (dd, J¼6.8, 2.0 Hz, 1H, H-3), 5.03 (m, 2H,
CH2]), 5.71 (dddd, J¼16.8, 10.4, 7.6, 6.4 Hz, 1H,
CH]), 7.26–7.66 (m, 10H, ArH); 13C NMR (100.6 MHz,
CDCl3) d 34.8 (C-7), 36.6 (CH2), 37.7 (C-8), 53.0 (CH3),
54.0 (C-6), 59.4 (C-3), 74.0 (C-2), 91.8 (C-8a), 117.7
(CH2]), 126.4–138.2 (C-o, m, p), 133.7 (CH]), 140.5

M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
5843
4.2.4. (3R,8S,8aR)-8-Allyl-6-(methoxycarbonyl)-5-oxo-3-
phenyl-2,3,8,8a-tetrahydro-5H-oxazolo[3,2-a]pyridine
(4a). Aqueous H2O2 (30%, 0.73 mL, 23.8 mmol) and pyri-
dine (0.36 mL, 4.4 mmol) were added to a solution of sele-
nides 3a (1.6 g, 2.8 mmol) in CH2Cl2 (231 mL), and the
resulting mixture was stirred at rt for 2 h. The two phases
were separated, and the organic layer was washed with water
(10ꢂ20 mL), dried, and concentrated to give crude 4a
(1.65 g) as an oil, which was kept at ꢁ30 ꢀC and used in
the next reaction without further purification: IR (NaCl)
a mixture of C-6 epimers (ratio 2:1). Compound (6S)-6a
1
(major): IR (NaCl) 1665, 1736 cmꢁ1; H NMR (300 MHz,
CDCl3, COSY, HETCOR) d 1.80 (ddd, J¼14.1, 12.0,
9.0 Hz, 1H, CH2 allyl), 2.16 (dt, J¼14.1, 9.3, 9.3 Hz, 1H,
CH2 allyl), 2.34 (dm, J¼12.0 Hz, 1H, H-7), 2.44–2.70 (m,
3H, H-8, CH2 allyl), 3.43 (d, J¼1.5 Hz, 1H, H-6), 3.60 (s,
3H, CH3), 4.02 (dd, J¼9.3, 1.8 Hz, 1H, H-2), 4.15 (dd,
J¼9.3, 7.2 Hz, 1H, H-2), 4.62 (d, J¼9.6 Hz, 1H, H-8a),
4.91 (dd, J¼7.2, 1.8 Hz, 1H, H-3), 5.14 (m, 4H, CH2]),
5.68 (dddd, J¼15.0, 10.2, 9.0, 4.8 Hz, 1H, CH]), 5.84
(dddd, J¼15.3, 9.9, 8.7, 5.1 Hz, 1H, CH]), 7.26–7.33 (m,
5H, ArH); 13C NMR (75.4 MHz, CDCl3) d 31.6, 31.8
(CH2), 36.9 (C-7), 38.5 (C-8), 51.5 (C-6), 52.3 (CH3), 59.6
(C-3), 73.9 (C-2), 89.4 (C-8a), 117.4, 118.5 (CH2]),
126.4, 128.2 (C-o, m), 127.4 (C-p), 134.4, 134.8 (CH]),
140.5 (C-i), 162.3 (NCO), 170.6 (COO); m/z 355 (M+, 1),
312 (21), 296 (13), 282 (8), 272 (8), 254 (5). Compound
(6R)-6a (minor): 13C NMR (75.4 MHz, CDCl3) d 32.8,
35.9 (CH2), 36.5 (C-7), 41.9 (C-8), 52.5 (CH3), 53.7 (C-6),
59.2 (C-3), 73.8 (C-2), 89.8 (C-8a), 118.4, 119.6 (CH2]),
126.7–128.5 (C-o, m, p), 132.8, 133.4 (CH]), 140.6 (C-i),
162.5 (NCO), 170.8 (COO); m/z 355 (M+, 2), 314 (5), 272
(8), 254 (4), 176 (6), 148 (11), 128 (7), 120 (17), 119 (12),
117 (20), 105 (13), 104 (100). HRMS calcd for
C21H25NO4: 355.1783, found: 355.1779.
1
1673, 1741 cmꢁ1; H NMR (300 MHz, CDCl3) d 2.31 (dt,
J¼14.4, 8.7 Hz, 1H, CH2 allyl), 2.70 (dm, J¼14.4 Hz, 1H,
CH2 allyl), 2.91 (m, 1H, H-8), 3.78 (s, 3H, CH3), 4.20 (dd,
J¼9.0, 2.4 Hz, 1H, H-2), 4.24 (dd, J¼9.0, 6.0 Hz, 1H,
H-2), 4.87 (d, J¼10.5 Hz, 1H, H-8a), 5.03 (dd, J¼6.0,
2.4 Hz, 1H, H-3), 5.27 (m, 2H, CH2]), 5.86 (dddd,
J¼15.3, 10.8, 8.7, 5.7 Hz, 1H, CH]), 7.20–7.36 (m, 5H,
ArH); 13C NMR (75.4 MHz, CDCl3) d 33.5 (CH2), 41.2
(C-8), 52.3 (CH3), 58.3 (C-3), 74.4 (C-2), 89.8 (C-8a),
119.0 (CH2]), 126.8, 128.5 (C-o, m), 127.7 (C-p), 129.7
(C-6), 133.3 (CH]), 140.2 (C-i), 147.6 (C-7), 157.3
(COO), 164.3 (NCO).
4.2.5. (3R,8S,8aR)-8-Allyl-6-(benzyloxycarbonyl)-5-oxo-
3-phenyl-2,3,8,8a-tetrahydro-5H-oxazolo[3,2-a]pyridine
(4b). Operating as described for the preparation of 4a, from
selenides 3b (200 mg, 0.36 mmol), 30% aqueous H2O2
(76 mL, 2.5 mmol), and pyridine (33 mL, 0.47 mmol) in
CH2Cl2 (26 mL), crude unsaturated lactam 4b was obtained,
kept at ꢁ30 ꢀC, and used in the next reaction without further
purification: 1H NMR (400 MHz, CDCl3, COSY, HETCOR)
d 2.29 (ddd, J¼14.0, 8.8, 8.0 Hz, 1H, CH2 allyl), 2.68 (dm,
J¼14.0 Hz, 1H, CH2 allyl), 2.91 (m, 1H, H-8), 4.18 (dd,
J¼9.2, 2.0 Hz, 1H, H-2), 4.22 (dd, J¼9.2, 6.4 Hz, 1H,
H-2), 4.87 (d, J¼10.8 Hz, 1H, H-8a), 5.05 (dd, J¼6.4,
2.0 Hz, 1H, H-3), 5.20 (d, J¼12.4 Hz, 1H, CH2 benzyl),
5.21 (masked, 2H, CH2]), 5.26 (d, J¼12.4 Hz, 1H, CH2
benzyl), 5.83 (dddd, J¼16.8, 10.8, 8.8, 6.0 Hz, 1H, CH]),
7.10–7.40 (m, 11H, ArH, H-7); 13C NMR (100.6 MHz,
CDCl3) d 33.6 (CH2), 41.3 (C-8), 58.3 (C-3), 67.1 (CH2),
74.5 (C-2), 89.9 (C-8a), 119.0 (CH2]), 126.8–128.6 (C-o,
m, p, C-6), 133.3 (CH]), 140.3, 135.5 (C-i), 147.6 (C-7),
157.3 (NCO), 163.7 (COO).
4.3.2. (3R,7R,8S,8aR)-7,8-Diallyl-6-(benzyloxycarbonyl)-
5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]-
pyridine (6b). Operating as in the preparation of 6a, from
the above crude lactam 4b (0.36 mmol), allylmagnesium
bromide (1 M solution in Et2O, 1.04 mL), CuI (197 mg,
1.04 mmol), LiCl (45 mg, 1.04 mmol), and TMSCl (131 mL,
1.04 mmol) in THF (3 mL), lactams (6S)-6b (123 mg) and
(6R)-6b (25 mg) (93% overall yield from 3b) were obtained
after column chromatography (1:4 EtOAc–hexane to 1:2
EtOAc–hexane). Compound (6S)-6b (lower Rf epimer): IR
(NaCl) 1666, 1736 cmꢁ1 1H NMR (300 MHz, CDCl3,
;
COSY, HETCOR) d 1.80 (ddd, J¼14.1, 12.0, 8.7 Hz, 1H,
CH2 allyl), 2.16 (ddd, J¼14.1, 9.6, 9.6 Hz, 1H, CH2 allyl),
2.32 (dm, J¼11.7 Hz, 1H, H-7), 2.50 (m, 2H, H-8, CH2 allyl),
2.62 (dm, J¼14.1 Hz, 1H, CH2 allyl), 3.47 (d, J¼0.9 Hz, 1H,
H-6), 3.99 (dd, J¼9.0, 1.8 Hz, 1H, H-2), 4.14 (dd, J¼9.0,
6.9 Hz, 1H, H-2), 4.61 (d, J¼9.6 Hz, 1H, H-8a), 4.91 (dd,
J¼6.9, 1.8 Hz, 1H, H-3), 5.02 (d, J¼12.3 Hz, 1H, CH2 ben-
zyl), 5.09 (d, J¼12.3 Hz, 1H, CH2 benzyl), 5.13 (m, 4H,
CH2]), 5.67 (m, 2H, CH]), 7.20–7.30 (m, 10H, ArH);
13C NMR (75.4 MHz, CDCl3) d 31.7 (CH2), 36.8 (C-7),
38.6 (C-8), 51.7 (C-6), 59.7 (C-3), 66.8 (CH2), 74.0 (C-2),
89.4 (C-8a), 117.4, 118.6 (CH2]), 126.4–128.4 (C-o, m,
p), 134.4, 134.8 (CH]), 135.5, 140.5 (C-i), 162.2 (NCO),
169.9 (COO); [a]2D2 ꢁ11.3 (c 0.4, CHCl3); m/z 431 (M+, 1),
388 (4), 340 (7), 296 (21), 282 (11), 268 (3), 254 (5), 240
(2). HRMS calcd for C27H29NO4: 431.2096, found:
431.2097. Compound (6R)-6b (higher Rf epimer): IR
4.3. Conjugate addition reactions from unsaturated
lactams 4
4.3.1. (3R,7R,8S,8aR)-7,8-Diallyl-6-(methoxycarbonyl)-5-
oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]-
pyridine (6a). LiCl (332 mg, 7.84 mmol) was heated
at 80 ꢀC for 1 h under vacuum (10–15 mmHg) in a two-
necked, 100 mL round-bottomed flask. Then, CuI (1.49 mg,
7.84 mmol) and THF (26 mL) were added at rt, and the mix-
ture was stirred at rt for 5 min. The suspension was cooled
at ꢁ78 ꢀC, and allylmagnesium bromide (1 M in Et2O,
7.84 mL), TMSCl (0.99 mL, 7.84 mmol), and the above
crude unsaturated lactam 4a (2.8 mmol) in THF (3 mL)
were successively added. The resulting mixture was stirred
at ꢁ78 ꢀC for 18 h. The reaction was quenched with satu-
rated aqueous NH4Cl, and the organic layer was extracted
with EtOAc. The combined organic extracts were dried and
concentrated. Flash chromatography (1:9 EtOAc–hexane to
3:7 EtOAc–hexane) gave 6a (804 mg, 81% yield from 3a) as
(NaCl) 1668, 1736 cmꢁ1 1H NMR (300 MHz, CDCl3,
;
COSY, HETCOR) d 1.84 (m, 1H, H-8), 2.16 (m, 2H, CH2
allyl), 2.36 (m, 1H, H-7), 2.44 (m, 2H, CH2 allyl), 3.35
(d, J¼7.6 Hz, 1H, H-6), 4.06 (dd, J¼9.2, 0.8 Hz, 1H, H-2),
4.14 (dd, J¼9.2, 6.4 Hz, 1H, H-2), 4.71 (d, J¼9.2 Hz, 1H,
H-8a), 4.92 (dd, J¼6.4, 0.8 Hz, 1H, H-3), 5.05 (m, 2H,
CH2]), 5.13 (masked, 2H, CH2]), 5.14 (d, J¼12.4 Hz,
1H, CH2 benzyl), 5.19 (d, J¼12.4 Hz, 1H, CH2 benzyl),
5.64 (dddd, J¼17.6, 10.4, 7.6, 7.6 Hz, 1H, CH]), 5.85

5844
M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
(dddd, J¼16.8, 10.0, 7.2, 7.2 Hz, 1H, CH]), 7.20–7.40 (m,
10H, ArH); 13C NMR (75.4 MHz, CDCl3) d 33.1, 36.1
(CH2), 36.8 (C-7), 42.0 (C-8), 53.8 (C-6), 59.2 (C-3), 67.2
(CH2), 73.9 (C-2), 89.9 (C-8a), 118.3, 119.6 (CH2]),
126.7–128.6 (C-o, m, p), 132.9, 133.5 (CH]), 135.4, 140.7
(C-i), 162.7 (NCO), 170.3 (COO); [a]2D2 ꢁ53.6 (c 0.5,
CHCl3); m/z 431 (M+, 7), 388 (6), 340 (17), 296 (13), 282
(2), 254 (7). HRMS calcd for C27H29NO4: 431.2096, found:
431.2088.
CH2), 1.71 (m, 1H, CH2), 1.98 (ddd, J¼15.6, 15.6, 8.0 Hz,
1H, CH2), 2.29–2.10 (m, 3H, CH2 allyl, H-7, CH2), 2.46
(m, 1H, H-8), 2.58 (m, 1H, CH2 allyl), 3.42 (s, 1H, H-6),
3.97 (dd, J¼9.0, 1.2 Hz, 1H, H-2), 4.11 (dd, J¼9.0,
6.8 Hz, 1H, H-2), 4.58 (d, J¼9.2 Hz, 1H, H-8a), 4.90 (dd,
J¼6.8, 1.2 Hz, 1H, H-3), 4.97 (dd, J¼10.4, 1.6 Hz, 1H,
CH2]), 5.04 (d, J¼12.4 Hz, 1H, CH2 benzyl), 5.08 (d,
J¼12.4 Hz, 1H, CH2 benzyl), 5.02–5.11 (m, 3H, CH2]),
5.61–5.76 (m, 2H, CH]), 7.34–7.21 (m, 10H, ArH); 13C
NMR (100.6 MHz, CDCl3) d 26.3 (CH2), 31.3 (CH2), 31.5
(CH2), 36.5 (C-7), 38.8 (C-8), 52.2 (C-6), 59.6 (C-3), 66.8
(CH2), 73.9 (C-2), 88.4 (C-8a), 116.0, 117.3 (CH2]),
126.3–128.4 (C-o, m, p), 134.5, 136.8 (CH]), 135.4,
140.5 (C-i), 162.3 (NCO), 169.8 (COO). Anal. Calcd for
C28H31O4N$1⁄2 H2O: C, 73.98; H, 7.10; N, 3.08. Found: C,
74.14; H, 6.95; N, 3.04. Compound (6R)-19 (minor): IR
4.3.3. (3R,7R,8S,8aR)-8-Allyl-6-(benzyloxycarbonyl)-5-
oxo-3-phenyl-7-vinyl-2,3,6,7,8,8a-hexahydro-5H-ox-
azolo[3,2-a]pyridine (14). Operating as in the preparation
of 6a, from crude lactam 4b (prepared from 1.8 mmol of
selenides 3b), vinylmagnesium bromide (1 M solution in
Et2O, 6.84 mL), CuI (1.3 g, 6.84 mmol), LiCl (290 mg,
6.84 mmol), and TMSCl (865 mL, 6.84 mmol) in THF
(40 mL), lactam 14 was obtained as a mixture of C-6 epimers
(ratio 2:1, 463 mg, 62% yield from 3b) after flash chromato-
graphy (1:4 EtOAc–hexane to 1:2 EtOAc–hexane). Com-
(NaCl) 1668, 1736 cmꢁ1 1H NMR (400 MHz, CDCl3,
;
COSY, HETCOR) d 1.56 (m, 2H, CH2), 1.83 (dddd,
J¼8.8, 8.8, 4.8, 4.8 Hz, 1H, H-8), 2.00 (m, 2H, CH2), 2.27
(dddd, J¼8.8, 8.8, 6.8, 5.2 Hz, 1H, H-7), 2.40 (t,
J¼6.4 Hz, 2H, CH2 allyl), 3.32 (d, J¼6.8 Hz, 1H, H-6),
4.06 (dd, J¼9.0, 1.5 Hz, 1H, H-2), 4.14 (dd, J¼9.0,
6.6 Hz, 1H, H-2), 4.70 (d, J¼8.7 Hz, 1H, H-8a), 4.94 (dd,
J¼6.6, 1.5 Hz, 1H, H-3), 4.90–5.18 (m, 4H, CH2]), 5.15
(d, J¼12.3 Hz, 1H, CH2 benzyl), 5.20 (d, J¼12.3 Hz, 1H,
CH2 benzyl), 5.66 (m, 1H, CH]), 5.83 (ddd, J¼14.8,
10.0, 7.6 Hz, 1H, CH]), 7.05–7.20 (m, 10H, ArH); 13C
NMR (100.6 MHz, CDCl3) 29.3 (CH2), 32.1 (CH2), 33.7
(CH2), 37.0 (C-7), 43.3 (C-8), 54.3 (C-6), 59.1 (C-3), 67.2
(CH2), 73.8 (C-2), 89.9 (C-8a), 115.3, 118.2 (CH2]),
133.8, 137.3 (CH]), 135.3, 140.7 (C-i), 163.8 (NCO),
170.2 (COO); m/z 445 (M+, 2), 355 (4), 354 (15), 310 (9),
300 (3), 268 (4), 254 (3), 214 (3), 201 (6), 148 (14), 128
(6), 120 (16), 119 (7), 117 (11), 108 (7), 104 (39), 103 (8),
92 (9), 91 (100). HRMS calcd for C28H31NNaO4:
468.2150, found: 468.2150.
1
pound (6S)-14 (major): IR (NaCl) 1666, 1736 cmꢁ1; H
NMR (400 MHz, CDCl3, HETCOR) d 2.15 (m, 1H, CH2
allyl), 2.47 (dt, J¼10.0, 4.0, 4.0 Hz, 1H, H-8), 2.54 (m, 1H,
CH2 allyl), 3.01 (dd, J¼8.0, 4.0 Hz, 1H, H-7), 3.48 (d,
J¼1.2 Hz, 1H, H-6), 4.00 (dd, J¼9.2, 1.6 Hz, 1H, H-2),
4.13 (dd, J¼9.2, 6.8 Hz, 1H, H-2), 4.56 (d, J¼9.2 Hz, 1H,
H-8a), 4.92 (dd, J¼6.8, 1.2 Hz, 1H, H-3), 5.07 (d,
J¼12.4 Hz, 1H, CH2 benzyl), 5.11 (d, J¼12.4 Hz, 1H, CH2
benzyl), 5.13–5.18 (m, 2H, CH2] allyl), 5.16 (d,
J¼17.2 Hz, 1H, CH2] vinyl), 5.26 (d, J¼10.8 Hz, 1H,
CH2] vinyl), 5.70 (m, 1H, CH] allyl), 5.82 (ddd,
J¼17.2, 10.8, 8.0 Hz, 1H, CH] vinyl), 7.25–7.32 (m,
10H, ArH); 13C NMR (CDCl3, 100.6) d 31.7 (CH2), 38.7
(C-8), 40.9 (C-7), 52.6 (C-6), 59.7 (C-3), 67.1 (CH2), 74.0
(C-2), 89.6 (C-8a), 117.5 (CH2]), 118.8 (CH2]), 126.5–
128.5 (C-o, m, p), 134.0, 134.6 (CH]), 135.4, 140.6 (C-i),
162.1 (NCO), 167.7 (COO); m/z 417 (M+, 1), 326 (3), 283
(5), 282 (10), 240 (4), 148 (9), 128 (4), 120 (8), 119 (4),
118 (3), 117 (8), 108 (5), 104 (23), 91 (100). HRMS calcd
for C26H27NNaO4: 440.1832, found: 440.1843. Compound
(6R)-14 (minor): 1H NMR (400 MHz, CDCl3, selected reso-
nances) d 2.02 (m, 1H, CH2 allyl), 3.10 (ddd, J¼10.4, 6.4,
4.0 Hz, 1H, H-7), 3.53 (d, J¼6.0 Hz, 1H, H-6), 4.07 (dd,
J¼9.2, 1.2 Hz, 1H, H-2), 4.15 (dd, J¼9.2, 6.8 Hz, 1H, H-
2), 4.68 (d, J¼9.6 Hz, 1H, H-8a), 4.94 (dd, J¼6.8, 1.2 Hz,
1H, H-3), 5.02 (d, J¼12.4 Hz, 1H, CH2 benzyl), 5.09 (d,
J¼12.4 Hz, 1H, CH2 benzyl); 13C NMR (100.6 MHz,
CDCl3, selected resonances) d 32.2 (CH2), 42.5 (C-8), 42.8
(C-7), 54.0 (C-6), 59.9 (C-3), 66.8 (CH2), 73.8 (C-2), 89.5
(C-8a), 117.8 (CH2]), 121.0 (CH2]), 141.0 (C-i).
4.4. Ring-closing metathesis reaction
4.4.1. (3R,6aR,10aS,10bR)-6-(Methoxycarbonyl)-5-oxo-
3-phenyl-2,3,6,6a,7,10,10a,10b-octahydro-5H-ox-
azolo[2,3-a]isoquinoline (8a). Second-generation Grubbs
catalyst (7a, 57 mg) was added to a solution of lactam 6a
(300 mg, 0.84 mmol) in CH2Cl2 (125 mL). The mixture
was stirred for 2 h at rt, concentrated, and purified by flash
column chromatography (1:4 EtOAc–hexane to 2:3 EtOAc–
hexane) to yield tricyclic lactam 8a as a mixture of C-6 epi-
mers (220 mg, 81% yield). Compound (6R)-8a (major): IR
(NaCl) 1667, 1738 cmꢁ1 1H NMR (300 MHz, CDCl3,
;
COSY) d 2.00 (m, 1H, H-7), 2.20 (m, 1H, H-7), 2.43 (m,
2H, H-10), 2.50 (m, 1H, H-6a), 2.70 (m, 1H, H-10a), 3.18
(s, 1H, H-6), 3.60 (s, 1H, CH3), 3.96 (dd, J¼9.0, 1.2 Hz,
1H, H-2), 4.12 (dd, J¼9.0, 6.9 Hz, 1H, H-2), 4.85 (d,
J¼9.9 Hz, 1H, H-10b), 4.92 (dd, J¼6.9, 1.2 Hz, 1H, H-3),
5.69 (m, 2H, H-8, H-9), 7.22–7.35 (m, 5H, ArH); 13C
NMR (75.4 MHz, CDCl3) d 25.1 (C-10), 28.0 (C-7), 32.6
(C-10a), 33.5 (C-6a), 52.2 (CH3), 53.9 (C-6), 59.4 (C-3),
73.6 (C-2), 87.1 (C-10b), 124.4, 124.8 (C-8, C-9), 126.8,
128.0 (C-o, m), 127.2 (C-p), 140.6 (C-i), 162.0 (NCO),
170.2 (COO). Compound (6S)-8a (minor): 13C NMR
(75.4 MHz, CDCl3, selected resonances) d 24.7 (C-10),
32.6 (C-10a), 36.7 (C-6a), 51.8 (CH3), 53.7 (C-6), 59.6
(C-3), 73.3 (C-2), 86.6 (C-10b), 140.9 (C-i), 162.4 (NCO),
4.3.4. (3R,7R,8S,8aR)-8-Allyl-6-(benzyloxycarbonyl)-7-
(3-butenyl)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-
oxazolo[3,2-a]pyridine (19). Operating as in the pre-
paration of 6a, from crude lactam 4b (prepared from
1.8 mmol of selenides 3b), 3-butenylmagnesium bromide24
(5.04 mmol), CuI (960 mg, 5.04 mmol), LiCl (214 mg,
5.04 mmol), and TMSCl (636 mL, 5.04 mmol) in THF
(15 mL), lactam 19 was obtained as a mixture of C-6 epi-
mers (ratio 9:1, 557 mg, 70% yield from 3b) after flash chro-
matography (1:4 EtOAc–hexane to 1.5:2 EtOAc–hexane).
Compound (6S)-19 (major): IR (NaCl) 1664, 1735 cmꢁ1
1H NMR (400 MHz, CDCl3, HETCOR) d 1.18 (m, 1H,
;

M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
5845
169.1 (COO). Anal. Calcd for C19H21O4N$1⁄4 H2O: C, 68.76;
H, 6.53; N, 4.22. Found: C, 68.82; H, 6.90; N, 4.20.
131.8 (HC]CH), 135.0, 140.8 (C-i), 163.4 (NCO), 169.2
(COO). Anal. Calcd for C24H23O4N$1⁄2 H2O: C, 72.35; H,
6.07; N, 3.52. Found: C, 72.10; H, 5.93; N, 3.33. HRMS
calcd for C24H23NO4: 389.1627, found: 389.1623.
4.4.2. (3R,6aR,10aS,10bR)-6-(Benzyloxycarbonyl)-5-
oxo-3-phenyl-2,3,6,6a,7,10,10a,10b-octahydro-5H-ox-
azolo[2,3-a]isoquinoline (8b). Operating as above, from
lactam 6b (575 mg, 1.33 mmol) and second-generation
Grubbs catalyst (7a, 86 mg) in CH2Cl2 (190 mL), tricyclic
lactam 8b was obtained as a mixture of C-6 epimers (ratio
85:15, 455 mg, 85% yield) after column chromatography
(1:4 EtOAc–hexane to 1.3:1 EtOAc–hexane). Compound
4.4.4. (3R,6aR,11aS,11bR)-6-(Benzyloxycarbonyl)-5-
oxo-3-phenyl-2,3,5,6,6a,7,8,11,11a,11b-decahydrocyclo-
pent[c]oxazolo[3,2-a]pyridine (20). Operating as described
for the preparation of 8a, from lactam 19 (184 mg,
0.41 mmol) and second-generation Grubbs catalyst (7a,
26 mg) in CH2Cl2 (60 mL) stirred for 4 h, tricyclic lactam
20 was obtained as a mixture of C-6 epimers (ratio 9:1,
145 mg, 85%) after column chromatography (1:3 EtOAc–
hexane). Compound (6R)-20 (major): IR (NaCl) 1675,
(6R)-8b (major): IR (NaCl) 3030, 2915, 1736, 1665 cmꢁ1
;
1H NMR (300 MHz, CDCl3, COSY, HETCOR) d 2.00 (m,
1H, H-7), 2.26 (m, 1H, H-7), 2.47 (m, 2H, H-10), 2.52 (m,
1H, H-6a), 2.73 (m, 1H, H-10a), 3.24 (s, 1H, H-6), 3.97
(dd, J¼9.0, 1.5 Hz, 1H, H-2), 4.14 (dd, J¼9.0, 6.9 Hz, 1H,
H-2), 4.86 (d, J¼9.9 Hz, 1H, H-10b), 4.94 (dd, J¼6.9,
1.5 Hz, 1H, H-3), 5.03 (d, J¼12.3 Hz, 1H, CH2 benzyl),
5.10 (d, J¼12.3 Hz, 1H, CH2 benzyl), 5.69 (m, 2H, H-8,
H-9), 7.20–7.32 (m, 10H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 25.3 (C-10), 28.3 (C-7), 32.9 (C-10a), 33.7 (C-
6a), 54.2 (C-6), 59.8 (C-3), 67.1 (CH2), 73.8 (C-2), 87.3
(C-10b), 124.5, 125.0 (C-8, C-9), 126.3–128.4 (C-o, m, p),
135.3, 140.6 (C-i), 162.0 (NCO), 169.7 (COO). Compound
(6S)-8b (minor): 1H NMR (300 MHz, CDCl3, selected reso-
nances) d 2.65 (m, 1H, H-10a), 3.58 (d, J¼5.7 Hz, 1H, H-6),
4.02 (dd, J¼9.0, 1.2 Hz, 1H, H-2), 4.12 (dd, J¼9.0, 6.0 Hz,
1H, H-2), 4.91 (d, J¼9.9 Hz, 1H, H-10b), 5.10 (d,
J¼12.3 Hz, 1H, CH2 benzyl), 5.16 (d, J¼12.3 Hz, 1H,
CH2 benzyl); 13C NMR (75.4 MHz, CDCl3) d 24.9 (C-10),
29.7 (C-7), 32.6 (C-10a), 36.7 (C-6a), 53.9 (C-6), 59.7
(C-3), 66.8 (CH2), 73.5 (C-2), 86.8 (C-10b), 124.0, 124.5
(C-8, C-9), 126.3–128.4 (C-o, m, p), 135.3, 141.0 (C-i),
162.5 (NCO), 168.6 (COO).
1739 cmꢁ1
;
1H NMR (400 MHz, CDCl3, COSY,
HETCOR) d 1.69 (m, 2H, H-11, H-8), 2.23 (m, 2H, H-8,
H-7), 2.55 (m, 2H, H-6a, H-11), 2.60 (m, 1H, H-11a), 3.23
(d, J¼5.6 Hz, 1H, H-6), 4.04 (dd, J¼8.8, 1.6 Hz, 1H, H-
2), 4.17 (dd, J¼8.8, 7.2 Hz, 1H, H-2), 4.83 (d, J¼8.4 Hz,
1H, H-11b), 4.94 (dd, J¼7.2, 1.6 Hz, 1H, H-3), 5.11 (d,
J¼12.4 Hz, 1H, CH2 benzyl), 5.15 (d, J¼12.4 Hz, 1H,
CH2 benzyl), 5.71 (m, 1H, H-9), 5.77 (m, 1H, H-10),
7.23–7.34 (m, 10H, ArH); 13C NMR (100.6 MHz,
CDCl3) d 26.2 (C-8), 28.1 (C-11), 28.5 (C-7), 39.1
(C-11a), 40.8 (C-6a), 55.2 (C-6), 59.0 (C-3), 66.9 (CH2),
74.1 (C-2), 88.4 (C-11b), 126.3–128.4, 131.7 (C-o, m, p,
C-9, C-10), 135.4, 140.4 (C-i), 163.2 (NCO), 169.6
(COO); m/z 417 (M+, 3), 326 (7), 283 (15), 282 (47),
214 (4), 148 (9), 146 (3), 128 (6), 120 (14), 119 (5), 117
(8), 105 (6), 104 (24), 103 (8), 92 (9), 91 (100). Compound
(6S)-20 (minor): 13C NMR (100.6 MHz, CDCl3, selected
resonances) d 26.3 (C-8), 27.6 (C-11), 28.6 (C-7), 40.5
(C-11a), 41.4 (C-6a), 55.6 (C-6), 58.7 (C-3), 67.0 (CH2),
73.8 (C-2), 89.6 (C-11b), 141.0 (C-i), 163.2 (NCO),
168.8 (COO). HRMS calcd for C26H27NNaO4: 440.1837,
found: 440.1832.
4.4.3. (3R,6aR,9aS,9bR)-6-(Benzyloxycarbonyl)-5-oxo-3-
phenyl-2,3,5,6,6a,9,9a,9b-octahydrocylopent[c]ox-
azolo[3,2-a]pyridine (15). Operating as described for the
preparation of 8a, from lactam 14 (443 mg, 1.06 mmol)
and second-generation Grubbs catalyst (7a, 50 mg) in
CH2Cl2 (151 mL), tricyclic lactam 15 was obtained as a mix-
ture of C-6 epimers (ratio 9:1, 366 mg, 88% yield) after
column chromatography (1:2.5 EtOAc–hexane to 1:1.5
EtOAc–hexane). Compound (6R)-15 (major): IR (NaCl)
4.5. Catalytic hydrogenation
4.5.1. (3R,6aS,10aS,10bR)-5-Oxo-3-phenylperhydroox-
azolo[2,3-a]isoquinoline (9). A solution of 8b (500 mg,
1.24 mmol) in MeOH (40 mL) containing 10% Pd–C
(56 mg) was hydrogenated at 25 ꢀC for 48 h. The catalyst
was removed by filtration, and the solvent was evaporated.
The resulting oil was dissolved in toluene (70 mL) and the
solution was heated to reflux for 12 h, cooled, and poured
into brine. The aqueous layer was extracted with EtOAc,
and the combined organic extracts were dried and con-
centrated. The residue was chromatographed (1:1 EtOAc–
hexane) to afford compound 9 (287 mg, 85%) as a white
1678, 1741 cmꢁ1 1H NMR (300 MHz, CDCl3, COSY)
;
d 2.49 (dm, J¼16.2 Hz, 1H, H-9), 2.75–2.93 (m, 2H, H-9,
H-9a), 3.14 (d, J¼11.7 Hz, 1H, H-6), 3.74 (m, 1H, H-6a),
4.17 (dd, J¼9.0, 1.5 Hz, 1H, H-2), 4.22 (dd, J¼9.0,
6.0 Hz, 1H, H-2), 4.75 (d, J¼8.1 Hz, 1H, H-9b), 5.00 (dd,
J¼6.0, 1.5 Hz, 1H, H-3), 5.19 (d, J¼12.3 Hz, 1H, CH2 ben-
zyl), 5.09 (d, J¼12.3 Hz, 1H, CH2 benzyl), 5.54 (ddd, J¼6.6,
4.5, 2.1 Hz, 1H, CH]), 5.77 (ddd, J¼5.7, 5.4, 2.1 Hz, 1H,
CH]), 7.10–7.20 (m, 10H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 35.8 (C-9), 41.7 (C-9a), 46.4 (C-6a), 53.8 (C-6),
58.5 (C-3), 67.2 (CH2), 74.7 (C-2), 91.9 (C-9b), 126.5–
128.6 (C-o, m, p), 130.8, 130.9 (HC]CH), 135.5, 140.1
(C-i), 163.9 (NCO), 168.8 (COO); mp 105–106 ꢀC; m/z
390 (M++1, 2), 389 (M+, 8), 348 (4), 298 (25), 255 (10),
254 (31), 213 (7), 148 (16), 128 (7), 120 (20), 117 (14),
108 (7), 105 (8), 104 (33), 103 (9), 92 (8), 91 (100). Com-
pound (6R)-15 (minor): 13C NMR (75.4 MHz, CDCl3,
selected resonances) d 36.3 (C-9), 41.6 (C-9a), 46.1
(C-6a), 52.9 (C-6), 58.5 (C-3), 67.2 (CH2), 74.0 (C-2),
1
solid: IR (NaCl) 1660 cmꢁ1; H NMR (300 MHz, CDCl3,
COSY, HETCOR) d 1.40–1.80 (m, 7H), 2.10 (m, 3H,
H-10a, H-6a, H-10), 2.12 (dm, J¼18.3 Hz, 1H, H-6), 2.56
(dd, J¼18.3, 7.2 Hz, 1H, H-6), 3.99 (dd, J¼9.0, 1.5 Hz,
1H, H-2), 4.16 (dd, J¼9.0, 6.9 Hz, 1H, H-2), 4.92 (d,
J¼6.0 Hz, 1H, H-3), 5.04 (d, J¼9.6 Hz, 1H, H-10b), 7.10–
7.30 (m, 5H, ArH); 13C NMR (75.4 MHz, CDCl3) d 20.6
(CH2), 25.8 (CH2), 26.0 (CH2), 29.8 (CH2), 33.2 (C-6a),
37.5 (C-10a), 38.5 (C-6), 59.1 (C-3), 73.7 (C-2), 86.7
(C-10b), 126.2, 128.3 (C-o, m), 127.3 (C-p), 141.5 (C-i),
166.9 (NCO); mp 126–128 ꢀC; [a]D22 +37.9 (c 0.64,
CHCl3). Anal. Calcd for C17H21O2N$1⁄4 H2O: C, 74.02; H,
7.86; N, 5.08. Found: C, 74.24; H, 7.82; N, 4.76.

5846
M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
4.5.2. (3R,6aS,9aS,9bR)-5-Oxo-3-phenylperhydrocyclo-
pent[c]oxazolo[3,2-a]pyridine (16). Operating as above,
from lactam 15 (146 mg, 0.37 mmol) and 10% Pd–C
(16 mg) in MeOH (13 mL), lactam 16 was obtained
(80 mg, 83%) after column chromatography (1:1.5 EtOAc–
m/z 274 (M++1, 2), 255 (28), 254 (13), 213 (29), 242
(100), 214 (11), 151 (20).
4.6.2. (4aS,7aS)-2-[(1R)-2-Hydroxy-1-phenylethyl]-3-oxo-
perhydrocyclopenta[c]pyridine (17). Operating as above,
from lactam 16 (55 mg, 0.21 mmol) in CH2Cl2 (5 mL), TiCl4
(84 mL, 0.53 mmol), and Et3SiH (94 mL, 0.85 mmol), lactam
17 was obtained (51 mg, 94%) after column chromatography
hexane): IR (NaCl) 1673 cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 1.33 (m, 1H), 1.68 (m, 3H), 2.01 (m, 1H), 2.04
(d, J¼17.1, 13.0 Hz, 1H, H-6), 2.52 (m, 1H), 2.54 (dd,
J¼17.1, 6.0 Hz, 1H, H-6), 4.12 (dd, J¼9.0, 1.2 Hz, 1H, H-
2), 4.24 (dd, J¼9.0, 6.6 Hz, 1H, H-2), 4.70 (d, J¼8.4 Hz,
1H, H-9b), 5.01 (dd, J¼6.6, 1.2 Hz, 1H, H-3), 7.10–7.17
(m, 5H, ArH); 13C NMR (CDCl3, 75.4 MHz) d 25.8 (CH2),
30.0 (CH2), 33.9 (CH2), 35.7 (C-6a), 38.3 (C-6), 44.4
(C-9a), 58.0 (C-3), 74.6 (C-2), 92.4 (C-9b), 126.3, 128.5
(C-o, m), 127.5 (C-p), 140.9 (C-i), 168.4 (NCO); [a]D22
+15.6 (c 0.5, CHCl3); m/z 258 (M+, 5), 257 (27), 256 (4),
227 (4), 189 (6), 161 (8), 149 (8), 148 (36), 147 (4), 128
(5), 120 (42), 119 (12), 118 (36), 117 (32), 105 (12), 104
(100), 103 (18), 91 (29), 90 (23). HRMS calcd for
C16H19NNaO2: 280.1308, found: 280.1309.
1
(EtOAc) as a white solid: IR (NaCl) 1632, 3379 cmꢁ1; H
NMR (300 MHz, CDCl3, COSY) d 1.25 (m, 2H), 1.44 (m,
1H), 1.66 (m, 2H), 1.86 (m, 1H), 2.07 (m, 1H, H-8a), 2.24
(dd, J¼14.1, 9.0 Hz, 1H, H-4), 2.36 (m, 1H, H-4a), 2.54
(dd, J¼14.1, 6.0 Hz, 1H, H-4), 4.90 (dd, J¼13.2, 8.7 Hz,
1H, H-1), 3.06 (dd, J¼13.2, 6.0 Hz, 1H, H-1), 3.14 (br s,
1H, OH), 4.02 (ddd, J¼11.1, 9.0, 7.2 Hz, 1H, H-20), 4.15
(dd, J¼11.1, 4.8 Hz, 1H, H-20), 5.68 (dd, J¼9.0, 4.8 Hz,
1H, H-10), 7.10–7.17 (m, 5H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 25.5 (CH2), 30.9 (CH2), 34.1 (CH2), 35.7 (C-4a),
37.9 (C-8a), 38.1 (C-4), 46.5 (C-1), 58.3 (C-10), 62.3
(C-20), 127.6, 128.6 (C-o, m), 127.7 (C-p), 137.2 (C-i),
174.4 (NCO); mp 60–62 ꢀC; [a]D22 ꢁ10.3 (c 1.0, CHCl3).
Anal. Calcd for C16H21O2N: C, 74.10; H, 8.16; N, 5.40.
Found: C, 73.99; H, 8.24; N, 5.27.
4.5.3. (3R,6aS,11aS,11bR)-5-Oxo-3-phenylperhydro-
cyclohept[c]oxazolo[3,2-a]pyridine (21). Operating as in
the preparation of 9, from lactam 20 (918 mg, 2.2 mmol)
and 10% Pd–C (103 mg) in MeOH (73 mL), lactam 21
was obtained (510 mg, 81%) after column chromatography
4.6.3. (4aS,9aS)-2-[(1R)-2-Hydroxy-1-phenylethyl]-3-oxo-
perhydrocyclohepta[c]pyridine (22). Operating as in the
preparation of 10, from lactam 21 (95 mg, 0.233 mmol) in
CH2Cl2 (7 mL), TiCl4 (0.15 mL, 1.32 mmol), and Et3SiH
(0.13 mL, 0.83 mmol), lactam 22 was obtained (70 mg,
73%) after column chromatography (7:3 EtOAc–hexane):
(7:3 EtOAc–hexane): IR (NaCl) 1673 cmꢁ1 1H NMR
;
(300 MHz, CDCl3, COSY, HETCOR) d 1.25–1.58 (m,
6H), 1.67–2.32 (m, 6H), 2.10 (dd, J¼15.6, 12.6 Hz, 1H,
H-6), 2.30 (dd, J¼15.6, 4.5 Hz, 1H, H-6), 4.10 (dd, J¼8.7,
1.2 Hz, 1H, H-2), 4.22 (dd, J¼8.7, 6.6 Hz, 1H, H-2), 4.65
(d, J¼8.1 Hz, 1H, H-11b), 5.00 (dd, J¼6.6, 1.2 Hz, 1H, H-
3), 7.26–7.32 (m, 5H, ArH); 13C NMR (75.4 MHz, CDCl3)
d 28.1 (CH2), 28.3 (CH2), 28.9 (CH2), 30.7 (CH2), 33.2
(CH2), 35.9 (C-6a), 39.6 (C-6), 44.3 (C-11a), 57.9 (C-3),
74.5 (C-2), 92.0 (C-11b), 126.2, 128.5 (C-o, m), 127.5 (C-
p), 141.0 (C-i), 168.6 (NCO); [a]2D2 ꢁ5.3 (c 0.45, CHCl3).
Anal. Calcd for C18H23O2N$3/4H2O: C, 72.33; H, 8.26; N,
4.69. Found: C, 72.46; H, 7.87; N, 4.48.
1
IR (NaCl) 3376, 1634 cmꢁ1; H NMR (400 MHz, CDCl3,
COSY, HETCOR) d 1.21–1.43 (m, 5H), 1.62 (m, 1H), 1.76
(m, 4H), 1.89 (m, 1H, H-9a), 2.11 (m, 1H, H-4a), 2.26 (dd,
J¼15.6, 10.0 Hz, 1H, H-4), 2.46 (dd, J¼15.6, 5.6 Hz, 1H,
H-4), 2.90 (dd, J¼13.2, 6.4 Hz, 1H, H-1), 2.95 (dd,
J¼13.2, 9.2 Hz, 1H, H-1), 3.05 (br s, 1H, OH), 4.05 (m,
1H, H-20), 4.14 (m, 1H, H-20), 5.61 (t, J¼4.0 Hz, 1H, H-3),
7.23–7.34 (m, 5H, ArH); 13C NMR (100.6 MHz, CDCl3)
d 27.6 (CH2), 27.8 (CH2), 29.7 (CH2), 30.2 (CH2), 32.6
(CH2), 35.5 (C-4a), 37.7 (C-9a), 39.5 (C-4), 48.3 (C-1),
59.0 (C-10), 62.4 (C-20), 127.6, 128.6 (C-o, m), 127.7
(C-p), 137.1 (C-i), 173.8 (NCO); [a]2D2 +3.3 (c 1.0,
CHCl3); m/z 288 (M+ꢁ1, 1), 269 (7), 268 (4), 257 (14),
256 (46), 228 (3), 168 (16), 144 (3), 132 (10), 131 (5), 120
(4), 119 (4), 118 (10), 117 (10), 109 (16), 107 (14), 104
(16), 103 (21), 95 (9), 92 (10), 91 (100). HRMS calcd for
C18H25NNaO2: 310.1783, found: 310.1778.
4.6. Removal of the chiral inductor
4.6.1. (4aS,8aS)-2-[(1R)-2-Hydroxy-1-phenylethyl]-3-oxo-
perhydroisoquinoline (10). TiCl4 (0.61 mL, 5.6 mmol)
and Et3SiH (0.56 mL, 3.5 mmol) were added to a solution
of lactam 9 (383 mg, 1.4 mmol) in CH2Cl2 (25 mL), and
the resulting mixture was heated at reflux for 24 h. The
mixture was poured into saturated aqueous NaHCO3 and
extracted with CH2Cl2. The combined organic extracts
were dried and concentrated, and the resulting residue was
chromatographed (7:3 EtOAc–hexane) to give 10 (320 mg,
4.6.4. (4aS,8aS)-3-Oxoperhydroisoquinoline (11). Into a
three-necked, 100 mL round-bottomed flask equipped with
a coldfinger condenser charged with dry ice–acetone were
condensed 15 mL of NH3 at ꢁ78 ꢀC. The temperature was
raised to ꢁ33 ꢀC, and a solution of 10 (208 mg,
0.76 mmol) in THF (10 mL) was added. Then, sodium metal
was added in small portions until the blue color persisted,
and the mixture was stirred at ꢁ33 ꢀC for 1 min. The reac-
tion 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
EtOAc, and the suspension was filtered and concentrated.
Flash chromatography (1:2 EtOAc–hexane to 60:1 EtOAc–
MeOH) afforded 11 (145 mg, 89%): IR (NaCl)
1666 cmꢁ1; 1H NMR (400 MHz, CDCl3, COSY, HETCOR)
1
81%): IR (NaCl) 3373, 1614 cmꢁ1; H NMR (400 MHz,
CDCl3, COSY, HETCOR) d 1.36 (m, 2H), 1.48 (m, 4H),
1.56 (m, 2H), 1.92 (m, 1H, H-8a), 2.00 (m, 1H, H-4a),
2.43 (dd, J¼18.0, 6.4 Hz, 1H, H-4), 2.53 (dd, J¼18.0,
6.8 Hz, 1H, H-4), 2.88 (dd, J¼12.4, 5.2 Hz, 1H, H-1), 3.16
(dd, J¼12.4, 7.2 Hz, 1H, H-1), 4.10 (dd, J¼11.6, 9.2 Hz,
1H, H-20), 4.14 (dd, J¼11.6, 5.2 Hz, 1H, H-20), 5.78 (dd,
J¼9.2, 5.2 Hz, 1H, H-10), 7.25–7.35 (m, 5H, ArH); 13C
NMR (100.6 MHz, CDCl3) d 22.8 (CH2), 26.5 (CH2), 28.2
(2CH2), 32.1 (C-4a), 32.8 (C-8a), 35.8 (C-4), 46.0 (C-1),
58.8 (C-10), 61.7 (C-20), 127.7 (C-p), 127.8, 128.6 (C-o,
m), 136.8 (C-i), 171.4 (NCO); [a]2D2 ꢁ39.6 (c 1.3, CHCl3);

M. Amat et al. / Tetrahedron 63 (2007) 5839–5848
5847
d 1.38–1.65 (m, 8H), 1.99 (m, 1H, H-8a), 2.07 (m, 1H, H-4a),
2.30 (dd, J¼18.0, 6.8 Hz, 1H, H-4), 2.37 (dd, J¼18.0,
6.8 Hz, 1H, H-4), 3.26 (ddd, J¼12.4, 6.4, 2.4 Hz, 1H,
H-1), 3.32 (ddd, J¼12.4, 5.6, 2.0 Hz, 1H, H-1), 6.40 (br s,
1H, NH); 13C NMR (100.6 MHz, CDCl3) d 22.6 (CH2),
23.2 (CH2), 24.3 (CH2), 28.5 (CH2), 32.1, 32.2 (C-4a,
C-8a), 34.2 (C-4), 44.7 (C-1), 172.2 (NCO); [a]2D2 ꢁ29.2
(c 0.8, MeOH) (lit.21a [a]2D2 ꢁ30.9 (c 1.02, MeOH)); m/z
153 (M+, 48), 152 (11), 136 (6), 125 (53), 110 (15).
HRMS calcd for C9H15NO: 153.1153, found: 153.1157.
(CH2), 27.1 (CH2), 27.9 (CH2), 29.9 (CH2), 34.3, 36.3
(C-4a, C-8a), 50.7, 52.6 (C-1, C-3), 60.4 (C-20), 70.2
(C-10), 127.7 (C-p), 128.0, 128.9 (C-o, m), 136.0 (C-i).
4.6.8. (4aS,8aS)-2-(tert-Butoxycarbonyl)perhydroiso-
quinoline (13). A solution of 12 (70 mg, 0.27 mmol) and
di-tert-butyl dicarbonate (67 mg, 0.3 mmol) in EtOAc
(11 mL) containing 20% Pd(OH)2–C (20 mg) was hydroge-
nated at rt for 24 h at atmospheric pressure. The catalyst was
removed by filtration, and the solvent was evaporated to give
an oil, which was chromatographed (1:2 EtOAc–hexane to
1:1 EtOAc–hexane) to afford 13 (52 mg, 81%): IR (NaCl)
4.6.5. (4aS,7aS)-3-Oxoperhydrocyclopenta[c]pyridine
(18). Operating as above, from lactam 17 (79 mg,
0.31 mmol) in THF (6 mL), sodium, and liquid NH3
(10 mL) stirred at ꢁ33 ꢀC for 1.5 min, compound 18 was ob-
tained (41 mg, 95%) after column chromatography (EtOAc):
1
1696 cmꢁ1; H NMR (300 MHz, CDCl3, 50 ꢀC) d 1.20–
1.80 (m, 21H), 2.90 (m, 1H), 3.02 (dd, J¼13.2, 3.6 Hz,
1H, H-1), 3.65 (ddd, J¼13.2, 4.5, 1.2 Hz, 1H), 3.80 (m,
13
1H); C NMR (75.4 MHz, CDCl3, 50 ꢀC) d 22.1 (CH2),
1
IR (NaCl) 3238, 1670 cmꢁ1; H NMR (400 MHz, CDCl3,
25.1 (CH2), 26.0 (CH2), 26.9 (CH2), 30.0 (CH2), 28.5
(3CH3), 34.6, 36.3 (C-4a, C-8a), 43.2, 48.6 (C-1, C-3),
78.9 [C(CH3)3], 155.2 (COO); [a]2D2 ꢁ5.4 (c 1.0, CHCl3).
HETCOR) d 1.28 (m, 1H), 1.37 (m, 1H), 1.46 (m, 1H),
1.70 (m, 1H), 1.95–1.80 (m, 2H), 2.16 (dd, J¼17.2,
8.4 Hz, 1H, H-4), 2.35 (m, 1H, H-7a), 2.43 (m, 2H), 3.01
(ddd, J¼13.2, 6.0, 4.0 Hz, 1H, H-1), 3.32 (ddd, J¼13.2,
5.6, 4.0 Hz, 1H, H-1), 5.80 (br s, 1H, NH); 13C NMR
(75.4 MHz, CDCl3) d 25.5 (CH2), 30.9 (CH2), 34.0 (CH2),
35.9 (C-4), 36.3 (C-4a), 37.4 (C-7a), 44.4 (C-1), 174.9
(NCO); [a]2D2 ꢁ25.6 (c 0.25, CHCl3); m/z 139 (M+, 100),
131 (6), 111 (20), 110 (9), 98 (10), 97 (18), 96 (30), 84
(17), 83 (24), 82 (73), 81 (14), 80 (13). HRMS calcd for
C8H13NNaO: 162.0895, found: 162.0890.
Acknowledgements
Financial support from the Ministry of Science and Technol-
ogy (Spain)-FEDER (project CTQ2006-02390/BQU) and
the DURSI, Generalitat de Catalunya (grant 2005SGR-
0603) is gratefully acknowledged. Thanks are also due to
the Ministry of Education and Science (Spain) for a Fellow-
ship to A.T.M., and to the European Science Foundation for
a COST short-term scientific mission to B.P. (working group
D28/008/03).
4.6.6. (4aS,9aS)-3-Oxoperhydrocyclohepta[c]pyridine
(23). Operating as described above in the preparation of
11, from 22 (110 mg, 0.31 mmol) in THF (8 mL), sodium,
and liquid NH3 (15 mL) stirred at ꢁ33 ꢀC for 0.5 min, com-
pound 23 was obtained (57 mg, 89%) after flash chromato-
References and notes
1
graphy (EtOAc): IR (NaCl) 3247, 1666 cmꢁ1; H NMR
ꢀ
(400 MHz, CDCl3, HETCOR) d 1.42 (m, 5H), 1.75 (m,
5H), 2.14 (m, 2H), 2.17 (dd, J¼19.2, 8.0 Hz, 1H, H-4),
2.36 (dd, J¼19.2, 9.2 Hz, 1H, H-4), 3.08 (ddd, J¼12.4,
8.0, 2.4 Hz, 1H, H-1), 3.25 (ddd, J¼12.4, 5.2, 3.2 Hz, 1H,
H-1), 6.40 (br s, 1H, NH); 13C NMR (75.4 MHz, CDCl3)
d 26.5 (CH2), 26.6 (CH2), 29.5 (CH2), 29.8 (CH2), 32.2
(CH2), 35.2, 36.6 (C-4a, C-9a), 37.9 (C-4), 46.6 (C-1),
173.8 (NCO). Anal. Calcd for C10H17NO: C, 71.81; H,
10.24; N, 8.37. Found: C, 71.42; H, 10.27; N, 8.25.
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2.87 mmol) in THF (47 mL) at 0 ꢀC. After the mixture
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1
3427 cmꢁ1; H NMR (300 MHz, CDCl3, 50 ꢀC) d 1.20–
2.00 (2m, 13H), 2.34 (td, J¼11.0, 3.0 Hz, 1H), 2.63 (dd,
J¼11.0, 3.6 Hz, 1H), 3.20 (br s, 1H), 3.60 (dd, J¼8.7,
5.1 Hz, 1H, H-20), 3.64 (dd, J¼8.7, 5.1 Hz, 1H, H-10), 3.95
(dd, J¼8.7, 7.8 Hz, 1H, H-20), 7.16–7.33 (m, 5H, ArH);
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