A general synthetic route to enantiopure 5-substituted cis- decahydroquinolines

Full text of DOI:10.1021/jo802587h

SCHEME 1. Synthetic Strategy
A General Synthetic Route to Enantiopure
5-Substituted cis-Decahydroquinolines
Mercedes Amat,* Robert Fabregat, Rosa Griera, and
Joan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, and
Institute of Biomedicine (IBUB), UniVersity of Barcelona,
AV. Joan XXIII s/n, 08028 Barcelona, Spain
TABLE 1. Synthesis of 2-Substituted 6-Oxocyclohexene-
propionates
amat@ub.edu; joanbosch@ub.edu
ReceiVed NoVember 21, 2008
entry series
R1
methoda product yield (%)
1
2
3
4
5
6
a
b
c
d
e
f
CH3
(CH2)3CH3
C6H4-p-OCH3
(CH2)2CH(O2C2H4)
(CH2)5OTBDMS
(CH2)5OTBDPS
A
A
B
C
C
C
2a
2b
2c
2d
2e
2f
70
54
58
88
88
89
a Method A: R1Li, (C6H5)SCu. Method B: R1MgBr, CuI. Method C:
9-R1-(9-BBN), PdCl2(PPh3)2, K3PO4, DMF.
A practical synthetic route to enantiopure 5-substituted cis-
decahydroquinolines has been developed, the key steps being
a stereoselective cyclocondensation of 2-substituted 6-oxo-
cyclohexenepropionates 2 with (R)-phenylglycinol, the ste-
reoselective hydrogenation of the resulting unsaturated
tricyclic lactams, and the stereoselective reductive cleavage
of the oxazolidine ring.
Crucial for the implementation of this route is to have
available a practical method for the preparation of the starting
unsaturated δ-oxo esters 2 that allows a variety of R1 substituents
present in natural products to be introduced at the ꢀ position of
the cyclohexenone ring. For this purpose, 1,3-cyclohexanedione
was converted to bromo enone 1 in two steps, by alkylation
with methyl acrylate4 and subsequent bromination of the
resulting diketo ester with (Ph3P)Br2.5
The decahydroquinoline ring system is the central structure
of many naturally occurring biologically active alkaloids,
isolated not only from plants but mainly from other terrestrial
(amphibians, arthropods)1 and marine (tunicates, flatworms)2
organisms. A common structural feature of these alkaloids is
the presence of a carbon side chain, of variable length, at the
C-5 position. Although decahydroquinoline alkaloids have
received considerable synthetic attention,3 the enantioselective
synthesis of 5-substituted cis-decahydroquinolines has not been
explored so far.
We present herein a general synthetic route to enantiopure
5-substituted cis-decahydroquinolines, the key steps being a
stereoselective cyclocondensation of (R)-phenylglycinol with a
2-substituted 6-oxocyclohexenepropionate (2) and the stereo-
selective reduction of the resulting tricyclic lactam 3 (Scheme
1).
The introduction of an alkyl substituent into bromo enone 1
to give ꢀ-alkyl R,ꢀ-unsaturated cyclohexenones 2a and 2b was
effected by reaction of 1 with the corresponding lithium
phenylthio(alkyl)cuprates6 (Table 1, entries 1 and 2). In the butyl
series, minor amounts of the ketone resulting from the attack
of the butyl residue on the ester carbonyl group were also
formed. To evaluate the versatility of the procedure we also
studied the introduction of an aryl substituent. In this case, the
organocuprate was generated by treatment of the corresponding
Grignard reagent with CuI7 (entry 3). Finally, functionalized
carbon chains incorporating a protected aldehyde or hydroxy
group were introduced in excellent yield via a Suzuki coupling.8
Thus, regioselective hydroboration of 4-vinyl-1,3-dioxolane
(entry 4) or silyl-protected (TBDMS or TBDPS) 4-penten-1-
ols (entries 5 and 6) with 9-BBN, followed by a cross-coupling
reaction of the resulting 9-R1-9-BBN derivatives with bromo
enone 1 in the presence of a catalytic amount of PdCl2(PPh3)2
gave the respective substitution products 2d-f.
(1) (a) Spande, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh, H. J. C.;
Daly, J. W.; Fukumoto, S.; Imamura, K.; Tokuyama, T.; Torres, J. A.; Snelling,
R. R.; Jones, T. H. J. Nat. Prod. 1999, 62, 5–21. (b) Jones, T. H.; Gorman,
J. S. T.; Snelling, R. R.; Delabie, J. H. C.; Blum, M. S.; Garraffo, H. M.; Jain,
P.; Daly, J. W.; Spande, T. F. J. Chem. Ecol. 1999, 25, 1179–1193. (c) Daly,
J. W.; Garraffo, H. M.; Jain, P.; Spande, T. F.; Snelling, R. R.; Jaramillo, C.;
Rand, A. S. J. Chem. Ecol 2000, 26, 73–85. For a recent review, see: (d) Daly,
J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575.
(2) (a) Steffan, B. Tetrahedron 1991, 47, 8729–8732. (b) Kubanek, J.;
Williams, D. E.; Dilip de Silva, E.; Allen, T.; Andersen, R. J. Tetrahedron Lett.
1995, 36, 6189–6192. (c) Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod.
2002, 65, 454–457.
(4) Konno, M.; Nakae, T.; Sakuyama, S.; Imaki, K.; Nakai, H.; Hamanaka,
N. Synlett 1997, 1472–1474.
(5) Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I. Can. J. Chem. 1982,
60, 210–223.
(6) (a) Piers, E.; Nagakura, I. J. Org. Chem. 1975, 40, 2694–2696. (b) Piers,
E.; Cheng, K. F.; Nagakura, I. Can. J. Chem. 1982, 60, 1256–1263.
(7) Organocopper Reagents. A Practical Approach; Taylor, R. J. K., Ed.;
Oxford University Press: New York, 1994.
(8) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki,
A. J. Am. Chem. Soc. 1989, 111, 314–321.
(3) For a review, see: Kibayashi, C.; Aoyagi, S. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1997; Vol. 19, pp 3-
88.
1794 J. Org. Chem. 2009, 74, 1794–1797
10.1021/jo802587h CCC: $40.75 2009 American Chemical Society
Published on Web 01/02/2009

TABLE 2. Cyclocondensation Reactions of δ-Oxo Esters 2 with
(R)-Phenylglycinol
TABLE 3. Alane Reductions of Tricyclic Lactams 3
a
entry
series
R1
product
yield (%)
entry
δ-oxo ester
R1
producta
yield (%)a
1
2
3
4
5
6
a
b
c
d
f
CH3
(CH2)3CH3
C6H4-p-OCH3
(CH2)2CH(O2C2H4)
(CH2)5OTBDPS
(CH2)3CO2Me
4a
4b
4c
4d
4f
54
59
55
64
52
55
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
1
CH3
3a
3b
3c
3d
3e
3f
3g
3h
3i
89
76
77
77
43
51
77
42
15
(CH2)3CH3
C6H4-p-OCH3
(CH2)2CH(O2C2H4)
(CH2)5OTBDMS
(CH2)5OTBDPS
(CH2)3CO2Me
H
g
4g′
a The g′ series: R1 ) (CH2)4OH.
Br
at the hydroquinoline ring fusion carbons were also formed.
The absolute configuration of the hydroquinoline ring fusion
carbons in tricyclic lactams 3 was confirmed when lactam 3h
was reduced to the known lactam 6h (see below).
The stereoselective formation of lactams 3 involves the initial
generation of an imine A, which is in equilibrium via dienamine
B with two diastereoisomeric imines C and four diastereoiso-
meric oxazolidines D (Scheme 2). A final irreversible lactam-
ization occurs most rapidly from oxazolidine D1 through a
chairlike six-membered transition state in which the propionate
chain avoids repulsive interactions with R1 (A1,2 strain) and C6H5
groups.12
a Compound 3 and the diastereoisomer at the hydroquinoline ring
fusion carbons in a ratio of ∼4:1.
SCHEME 2. Proposed Mechanistic Pathway
An alternative route to lactams 3 involving an initial
cyclocondensation of bromo enone 1 with (R)-phenylglycinol
and a subsequent cross-coupling reaction from the resulting
tricyclic alkenyl bromide 3i was not further explored due to
the low yield of the cyclocondensation step (Table 2, entry 9).
The conversion of tricyclic lactams 3 to the target cis-
decahydroquinolines required the stereoselective reductive
cleavage of the C-O oxazolidine bond, reduction of the lactam
carbonyl group, debenzylation of the phenylethanol moiety, and
the stereoselective hydrogenation of the hydroquinoline carbon-
carbon double bond. The first two transformations were
satisfactorily accomplished by alane reduction, which took place
with retention of the configuration13 at the 8a stereocenter,
leading to cis-octahydroquinolines 4a-g′ in the yields indicated
in Table 3. Minor amounts (5-10%) of the corresponding 8a
epimers were also formed. Under the reaction conditions, the
butyrate chain of 3g underwent reduction to hydroxybutyl
(compound 4g′).
With a versatile method in hand for the preparation of the
required δ-oxo esters 2,9 we next studied their cyclocondensation
with (R)-phenylglycinol.10 The reactions were performed in a
Dean-Stark apparatus, in refluxing benzene containing a
catalytic amount of AcOH. Under these conditions, δ-oxo esters
2a-f led to the corresponding tricyclic cis-hydroquinolones
3a-f, in which the migration of the carbon-carbon double bond
has occurred, in the yields indicated in Table 2 (entries 1-6).
Similarly, the known oxo esters 2g9 and 2h11 were converted
to the respective cyclocondensation products 3g and 3h (entries
7 and 8). These transformations result in the generation of two
stereogenic centers with a well-defined absolute configuration
in a single synthetic step from an achiral precursor. In all cases,
minor amounts (approximate ratio 4:1) of the diastereoisomers
However, catalytic hydrogenation of 4a, 4f, and 4g′ under a
variety of conditions [Pd-C or Pd(OH)2, MeOH, Boc2O; PtO2,
MeOH, then Pd-C or Pd(OH)2, Boc2O] was not stereoselective
as C-5 epimeric mixtures of the respective decahydroquinolines
5a, 5f, and 5g′ (Figure 1) were obtained. In the 5-aryl series,
all attempts to hydrogenate the conjugated carbon-carbon
double bond of 4c were unsuccessful.
(9) For the preparation of 2a and 2g (ethyl ester) by a less general procedure,
namely an aldol cyclocondensation of 1,5-polycarbonyl derivatives, see: Amat,
M.; Griera, R.; Fabregat, R.; Molins, E.; Bosch, J. Angew. Chem., Int. Ed. 2008,
47, 3348–3351.
(10) For reviews on the use of phenylglycinol-derived lactams as chiral
building blocks for the enantioselective synthesis of piperidine-containing
derivatives, see: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503–9569.
(b) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1–8. (c) Groaning,
M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–9873. (d) Escolano, C.; Amat,
M.; Bosch, J. Chem.sEur. J. 2006, 12, 8198–8207. For more recent work, see:
(e) Amat, M.; Pe´rez, M.; Minaglia, A. T.; Peretto, B.; Bosch, J. Tetrahedron
2007, 63, 5839–5848. (f) Amat, M.; Lozano, O.; Escolano, C.; Molins, E.; Bosch,
J. J. Org. Chem. 2007, 72, 4431–4439. (g) Amat, M.; Pe´rez, M.; Minaglia, A. T.;
Bosch, J. J. Org. Chem. 2008, 73, 6920–6923. (h) Soteras, I.; Lozano, O.;
Escolano, C.; Orozco, M.; Amat, M.; Bosch, J.; Luque, F. J. J. Org. Chem.
2008, 73, 7756–7763.
As could be expected, taking into account the conformational
rigidity of tricyclic lactams 3, this inconvenience was overcome
by reversing the order of the above transformations. Thus,
hydrogenation of 3a using PtO2 as the catalyst took place in
(12) For the stereochemical outcome of related cyclocondensation reactions
from γ-substituted δ-keto esters, see: (a) Amat, M.; Canto´, M.; Llor, N.; Escolano,
C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343–5351. (b)
Amat, M.; Bassas, O.; Llor, N.; Canto´, M.; Pe´rez, M.; Molins, E.; Bosch, J.
Chem.sEur. J. 2006, 12, 7872–7881.
(13) Fre´ville, S. Ce´le´rier, J. P. Thuy, V. M. Lhommet, G. Tetrahedron
Asymmetry 1995, 6, 2651–2654. See also ref 12a.
(11) Hwu, J. R.; Hakimelahi, G. H.; Chou, C.-T. Tetrahedron Lett. 1992,
33, 6469–6472.
J. Org. Chem. Vol. 74, No. 4, 2009 1795

SCHEME 4. A General Synthetic Route to Enantiopure
5-Substituted cis-Decahydroquinolines
FIGURE 1. Decahydroquinolines resulting from the hydrogenation of
hexahydroquinolines 4.
TABLE 4. Catalytic Hydrogenation of Tricyclic Lactams 3
entry
series
R1
catalyst
product
yield (%)
1
2
3
4
5
6
7
a
b
c
e
f
g
h
CH3
(CH2)3CH3
A
B
A
B
A
A
B
6a
6b
6c
6e
6f
6g
6h
98
96
In summary, we have developed an expeditious practical route
to enantiopure 5-substituted cis-decahydroquinolines from achiral
δ-oxo esters 2, which are easily accessible from 1,3-cyclohex-
anedione. A stereoselective cyclocondensation reaction with (R)-
phenylglycinol results in the straightforward construction of the
hydroquinoline system. Two subsequent stereoselective reduc-
tive processes complete the synthesis (Scheme 4).
C6H4-p-OCH3
(CH2)5OTBDMS
(CH2)5OTBDPS
(CH2)3CO2Me
H
84
85
97
95
SCHEME 3. Synthesis of Enantiopure 5-Substituted
cis-Decahydroquinolines
Experimental Section
General Procedure for the Synthesis of 2-Substituted 6-Oxo-
cyclohexenepropionates. Method A (with 2a as an Example).
MeLi (32 mL, 1.6 M in Et2O) was added to a suspension of
C6H5SCu (8.6 g, 50 mmol) in anhydrous THF (260 mL) at -20
°C, and the mixture was stirred at this temperature for 15 min.
After cooling at -78 °C, bromo enone 1 (6.5 g, 25 mmol) in
anhydrous THF (50 mL) was added, and the mixture was allowed
to reach 0 °C, stirred for 2.5 h, and poured into saturated aqueous
NH4Cl. The aqueous layer was extracted with EtOAc, and the
organic extracts were dried and concentrated. The residue was
chromatographed (9:1 hexane-EtOAc) to give 2a (3.4 g, 70%):
1H NMR (300 MHz) δ 1.88-1.96 (m, 2H), 1.97 (s, 3H), 2.33-2.40
(m, 6H), 2.59-2.64 (m, 2H), 3.65 (s, 3H); 13C NMR (75.4 MHz)
δ 21.0 (CH2), 21.1 (CH3), 22.1 (CH2), 32.8 (CH2), 33.0 (CH2), 37.7
(CH2), 51.4 (CH3), 133.6 (C), 156.5 (C), 173.5 (C), 198.2 (C);
HMRS calcd for [C11H16O3 + Na]: 219.100, found: 219.099.
Method B (with 2c as an Example). CuI (340 mg, 1.78 mmol)
was added to a solution of bromo enone 1 (300 mg, 1.15 mmol) in
anhydrous THF (6 mL), and the resulting suspension was vigorously
stirred at -10 °C. p-Methoxyphenylmagnesium bromide (6.8 mL,
0.5 M in THF) was slowly added, and the mixture was stirred at
-10 °C for 16 h, poured into saturated aqueous NH4Cl (5 mL)
and Et2O (5 mL), and stirred for 1 h. The aqueous layer was
extracted with Et2O, and the organic extracts were dried and
concentrated. The residue was chromatographed (3:2 hexane-
nearly quantitative yield and complete stereoselectivity to give
saturated lactam 6a (Table 4, entry 1). The absolute configu-
ration of 6a was unambiguously established by X-ray crystal-
lographic analysis.14 Similarly, hydrogenation of 3b,e-g using
either Pd-C or PtO2 as the catalyst took place in excellent yield
and stereoselectivity to give the respective decahydroquinoline
derivatives 6b,e-g. However, as in the above reduction of 4c,
the conjugated carbon-carbon double bond of the aryl-
substituted derivative 3c was reluctant to undergo reduction
(entry 3). On the other hand, hydrogenation of the unsubstituted
derivative 3h led to lactam 6h (entry 7), which was identical
(NMR, specific rotation) to that previously prepared by direct
cyclocondensation of 2-oxocyclohexanepropionic acid with (R)-
phenylglycinol, whose absolute configuration had been unam-
biguously determined by X-ray crystallography.12b
1
Et2O) to give 2c (192 mg, 58%) as a yellow oil: H NMR (300
MHz) δ 2.04-2.11 (m, 2H), 2.31-2.37 (m, 2H), 2.47-2.56
(m, 4H), 2.58-2.62 (m, 2H), 3.58 (s, 3H), 3.83 (s, 3H), 6.90-6.94
(m, 2H), 7.08-7.12 (m, 2H); 13C NMR (75.4 MHz) δ 22.3 (CH2),
22.5 (CH2), 33.5 (CH2), 33.6 (CH2), 37.9 (CH2), 51.3 (CH3), 55.2
(CH3), 113.9 (CH), 128.0 (CH), 133.1 (C), 134.3 (C), 158.3 (C),
159.3 (C), 163.2 (C), 173.3 (C), 199.2 (C); HMRS calcd for
[C17H20O4 + H]: 289.1434, found: 289.1428. Anal. Calcd for
C17H20O4 ·1/2H2O: C, 68.67; H, 7.12. Found: C, 68.85; H, 7.00.
Method C (with 2d as an Example). 2-Vinyl-1,3-dioxolane (0.29
mL, 2.9 mmol) was added to a solution of 9-BBN (5.8 mL, 0.5 M
in THF) at 0 °C, and the mixture was stirred at rt for 3 h. Then,
To complete the synthesis, removal of the chiral auxiliary
was performed in two steps. Thus, reduction of 6a, 6f, and
6g with alane brought about both the reductive opening of
the oxazolidine ring, with retention of the configuration,13and
the reduction of the lactam and ester carbonyl groups to give
the respective cis-decahydroquinolines 7a, 7f, and 7g′ (Scheme
3). A final hydrogenation in the presence of Pd(OH)2 and
(Boc)2O led to the enantiopure N-protected derivatives 8a, 8f,
and 8g′. Alternatively, hydrogenation of 7a in the absence of
(Boc)2O gave the N-unsubstituted cis-decahydroquinoline 9a.15
(15) The 1H and 13C NMR data of 9a were coincident with those reported in
the racemic series: Meyers, A. I.; Milot, G. J. Am. Chem. Soc. 1993, 115, 6652–
6660.
(14) For a preliminary report on the preparation of 3a and its reduction to
6a, see ref 9.
1796 J. Org. Chem. Vol. 74, No. 4, 2009

DMF (12 mL), K3PO4 (407 mg, 1.92 mmol), PdCl2(PPh3)2 (42 mg,
0.06 mmol), and bromo enone 1 (500 mg, 1.92 mmol) were added,
and the mixture was heated at 60 °C for 16 h. H2O (12 mL) was
added, and stirring was continued for 30 min. The aqueous layer
was extracted with EtOAc, and the combined organic extracts were
washed with H2O, dried, and concentrated. The residue was
chromatographed (1:1 hexane-EtOAc) to give 2d (475 mg, 88%)
as a yellow oil: 1H NMR (300 MHz) δ 1.76-1.84 (m, 2H),
1.89-1.97 (m, 2H), 2.28-2.32 (m, 8H), 2.56-2.64 (m, 2H),
3.62 (s, 3H), 3.82-3.91 (m, 2H), 3.92-3.99 (m, 2H), 4.83-4.90
(m, 1H); 13C NMR (75.4 MHz) δ 21.5 (CH2), 22.4 (CH2), 29.3
(CH2), 31.0 (CH2), 32.3 (CH2), 33.9 (CH2), 38.5 (CH2), 51.8
(CH3), 65.7 (2CH2), 104.0 (CH), 134.2 (C), 159.8 (C), 173.8
(C), 198.3 (C); HMRS calcd for [C15H22O5 + H]: 283.1540,
found: 283.1533. Anal. Calcd for C15H22O5 · 1/2H2O: C, 61.84;
H, 7.96. Found: C, 61.98; H, 7.98.
General Procedure for Cyclocondensation Reactions (with
3g as an Example). (R)-Phenylglycinol (5.8 g, 42.6 mol) was added
to a solution of keto ester 2g (4 g, 14.2 mol) and AcOH (1.2 mL,
21.3 mol) in benzene (200 mL). The mixture was heated at reflux
for 48 h with azeotropic elimination of H2O produced by a
Dean-Stark apparatus. The resulting mixture was cooled and
concentrated to give an oil. Flash chromatography (from 3:2 to 1:1
hexane-EtOAc) afforded lactam 3g (3.2 g, 61%) and its C-7a,
C-11a diastereoisomer (0.8 g, 16%). 3g (higher Rf): 1H NMR (300
MHz) δ 1.58-1.91 (m, 6H), 1.99-2.12 (m, 4H), 2.17-2.25
(m, 1H), 2.28-2.40 (m, 2H), 2.42-2.55 (m, 1H), 2.68 (dd, J )
18.6, 6 Hz, 1H), 3.67 (s, 3H), 3.81 (t, J ) 8.4 Hz, 1H), 4.55 (t, J
) 8.4 Hz, 1H), 5.28-5.47 (m, 2H), 7.17-7.35 (m, 5H); 13C NMR
(75.4 MHz) δ 22.9 (CH2), 23.0 (CH2), 25.0 (CH2), 25.9 (CH2),
31.3 (CH2), 33.3 (CH2), 33.5 (CH2), 43.2 (CH), 51.4 (CH3), 58.4
(CH), 69.4 (CH2), 94.2 (C), 120.9 (CH), 125.2 (2CH), 127.0 (CH),
128.4 (2CH), 136.2 (C), 140.2 (C), 169.4 (C), 173.7 (C); mp 90-94
°C; [R]22D -101.3 (c 1.1, MeOH). Anal. Calcd for C22H27NO4: C,
71.52; H, 7.37; N, 3.79. Found: C, 71.50; H, 7.42; N, 3.84.
General Procedure for Alane Reductions of Tricyclic Lac-
tams 3 and 6 (with 4g′ as an Example). To a suspension of AlCl3
(362 mg, 2.71 mmol) in anhydrous THF (50 mL) at 0 °C was slowly
added LiAlH4 (340 mg, 8.94 mmol). After the mixture was stirred
at 25 °C for 30 min and cooled to -78 °C, a solution of lactam 3g
(500 mg, 1.35 mmol) in anhydrous THF (5 mL) was slowly added.
The stirring was continued for 90 min at -78 °C and for 90 min
at 25 °C. Then, the mixture was cooled to 0 °C, and the reaction
was quenched with H2O. The aqueous layer was extracted with
CH2Cl2, and the combined organic extracts were dried and
concentrated. Column chromatography (from 8:2 to 1:1 hexane-
EtOAc) afforded a mixture of 4g′ (245 mg, 55%) and its C-8a
epimer (22 mg, 5%). 4g′ (lower Rf): 1H NMR (400 MHz) δ
1.26-1.73 (m, 10H), 1.86-2.15 (m, 5H), 2.5 (m, 1H), 2.69-2.79
(m, 2H), 3.61 (t, J ) 6.4 Hz, 2H), 3.79 (dd, J ) 10.6, 5.4 Hz, 1H),
3.85 (dd, J ) 10.6, 6.2 Hz, 1H), 3.92 (t, J ) 6.0 Hz, 1H), 5.24
(s, 1H), 7.26-7.33 (m, 5H); 13C NMR (100.6 MHz) δ 18.9 (CH2),
24.1 (2CH2), 24.9 (CH2), 26.4 (CH2), 32.5 (CH2), 34.4 (CH2), 38.8
(CH), 44.0 (CH2), 55.0 (CH), 61.9 (CH2), 62.8 (CH2), 65.0 (CH2),
120.5 (CH), 127.5 (2CH), 128.3 (CH), 128.4 (2CH), 139.0 (C),
140.3 (C); [R]22 -27.4 (c 1.2, MeOH); HMRS calcd for
D
[C21H31NO2 + H] 330.2428, found 330.2426.
General Procedure for Catalytic Hydrogenation of Tricyclic
Lactams 3 (with 6g as an Example). A solution of lactam 3g
(500 mg, 1.35 mmol) in MeOH (40 mL) containing 40% PtO2 (200
mg) was stirred under hydrogen at rt for 24 h. The catalyst was
removed by filtration and washed with MeOH. The combined
organic solutions were concentrated affording pure compound 6g
(486 mg, 97%) as an oil: 1H NMR (300 MHz) δ 1.39-1.86
(m, 13H), 2.05-2.21 (m, 1H), 2.30-2.35 (m, 2H), 2.40-2.53 (dd,
J ) 11.1, 6.9 Hz, 1H), 2.60-2.68 (dd, J ) 18.2, 6.9 Hz, 1H), 3.67
(s, 3H), 3.82 (dd, J ) 8.8, 8.1 Hz, 1H), 4.49 (t, J ) 8.8 Hz, 1H),
5.29 (t, J ) 8.8 Hz, 1H), 7.15-7.34 (m, 5H); 13C NMR (75.4 MHz)
δ 17.9 (CH2), 23.6 (CH2), 24.1 (CH2), 24.6 (CH2), 30.4 (CH2), 31.2
(CH2), 32.6 (CH2), 34.1 (CH2), 39.6 (CH), 43.4 (CH), 51.4 (CH3),
58.0 (CH), 69.6 (CH2), 95.3 (C), 125.3 (2CH), 127.0 (CH), 128.4
(2CH), 140.2 (C), 169.3 (C), 174.1 (C); [R]22 -67.7 (c 1.0,
D
MeOH); HMRS calcd for [C22H29NO4 +H] 372.2169, found
372.2163. Anal. Calcd for C22H29NO4: C, 71.13; H, 7.87; N, 3.77.
Found: C, 70.84; H, 7.81; N, 3.69.
Acknowledgment. Financial support from the Ministry of
Science and Technology (Spain)-FEDER (Project CTQ2006-
02390/BQU) and the DURSI, Generalitat de Catalunya (Grant
2005SGR-0603) is gratefully acknowledged.
Supporting Information Available: Complete experimental
1
procedures and copies of the H and 13C NMR spectra of all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO802587H
J. Org. Chem. Vol. 74, No. 4, 2009 1797