Enantioselective synthesis of 3,3-disubstituted piperidine derivatives by enolate dialkylation of phenylglycinol-derived oxazolopiperidone lactams

Article abstract of DOI:10.1021/jo070397q

(Chemical Equation Presented) The stereochemical outcome of the enolate dialkylation of simple phenylglycinol-derived oxazolopiperidone lactams is studied. High stereoselectivities in the generation of the quaternary stereocenter are obtained by the appropriate choice of both the configuration of the starting lactam and the order of introduction of the substituents. The usefulness of the methodology is illustrated by the conversion of some of the dialkylated lactams into known synthetic precursors of alkaloids and by the total synthesis of (-)-quebrachamine.

Full text of DOI:10.1021/jo070397q

Enantioselective Synthesis of 3,3-Disubstituted Piperidine
Derivatives by Enolate Dialkylation of Phenylglycinol-Derived
Oxazolopiperidone Lactams
Mercedes Amat,*,† Oscar Lozano,† Carmen Escolano,† Elies Molins,‡ and Joan Bosch†
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona, 08028-Barcelona, Spain,
and Institut de Cie`ncia de Materials (CSIC), Campus UAB, 08193-Cerdanyola, Spain
amat@ub.edu
ReceiVed February 27, 2007
The stereochemical outcome of the enolate dialkylation of simple phenylglycinol-derived oxazolopiperidone
lactams is studied. High stereoselectivities in the generation of the quaternary stereocenter are obtained
by the appropriate choice of both the configuration of the starting lactam and the order of introduction
of the substituents. The usefulness of the methodology is illustrated by the conversion of some of the
dialkylated lactams into known synthetic precursors of alkaloids and by the total synthesis of
(-)-quebrachamine.
SCHEME 1. Enolate Dialkylations of Bicyclic Lactams
Introduction
Chiral nonracemic bicyclic lactams have proven to be
extremely useful and versatile building blocks for the enanti-
oselective preparation of a wide variety of natural and unnatural
products. The first studies in this field were reported by A. I.
Meyers, who described highly diastereoselective dialkylation
reactions of chiral lactam enolates and demonstrated the
synthetic utility of this transformation with the asymmetric
construction of a variety of cyclopentenones, cyclohexenones,
and carboxylic acids containing quaternary carbon centers.1
More recent work on the use of chiral bicyclic lactams in
asymmetric synthesis has shown that they are also excellent
precursors for the synthesis of optically active pyrrolidine and
piperidine derivatives.2
place endo with respect to the substituent R1 at the angular
position, although when this substituent is hydrogen the ste-
reoselectivities are poor.3 The presence of an alkyl or aryl
substituent on the 2 position oriented toward the endo concave
face (R2 * H) provokes a reversal in the facial stereoselectivity,
resulting in an exclusive alkylation on the exo face.3c On the
other hand, although there are no systematic studies about the
influence of the aminoalcohol moiety substituents on the
stereoselectivity of enolate dialkylations of chiral oxazolopip-
eridone lactams (Scheme 1, n ) 2), in the reported examples
of such dialkylations, all of them from lactams bearing an alkyl
or aryl substituent at the angular position, the reaction always
takes place with endo selectivity, even when R2 ) C6H5.4 No
The numerous examples described by Meyers of the dialky-
lation of enolates generated from a wide structural variety of
chiral oxazolopyrrolidone lactams (Scheme 1, n ) 1) make
evident that the second alkylation step almost invariably takes
† University of Barcelona.
‡ Institut de Cie`ncia de Materials.
(1) For reviews, see: (a) Romo, D.; Meyers, A. I. Tetrahedron 1991,
47, 9503. (b) Meyers, A. I. In Stereocontrolled Organic Synthesis; Trost,
B. M., Ed.; Blackwell Scientific Publications: Oxford, 1994; pp 145-175.
(2) For reviews, see: (a) Meyers, A. I.; Brengel, G. P. Chem. Commun.
1997, 1. (b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843.
(c) Escolano, C.; Amat, M.; Bosch, J. Chem. Eur. J. 2006, 12, 8198.
(3) (a) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A. J. Org. Chem. 1996,
61, 5712. (b) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F. J.
Am. Chem. Soc. 1997, 119, 4565. (c) Meyers, A. I.; Seefeld, M. A.; Lefker,
B. A.; Blake, J. F.; Williard, P. G. J. Am. Chem. Soc. 1998, 120, 7429.
10.1021/jo070397q CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/09/2007
J. Org. Chem. 2007, 72, 4431-4439
4431

Amat et al.
SCHEME 2. Monoalkylation of Oxazolopiperidone Lactams
FIGURE 1. Alkaloids embodying a 3,3-disubstituted piperidine moiety.
dialkylation reactions of oxazolopiperidone lactams unsubsti-
tuted at the angular position have been described so far.
In a previous paper we reported the enolate monoalkylation
of a variety of phenylglycinol-derived oxazolopiperidone lac-
tams5 and discussed the influence of the configuration at C-8a
and the effect of substituents at the C-8 and C-8a positions on
the stereoselectivity of the reaction.6 Herein, we report our
results on the sequential dialkylation of the enolate of simple
phenylglycinol-derived oxazolopiperidone lactams 1a and 1b,
lactams, bearing a benzyl, ethyl, or allyl substituent, were
initially prepared from each of the C-8a isomeric lactams 1a
and 1b following our previously described procedure.5 Thus,
treatment of a THF solution of lactams 1a and 1b with LiHMDS
at -78 °C, followed by addition of benzyl bromide, ethyl iodide,
or allyl bromide at the same temperature, afforded the corre-
sponding alkylated products 2-4 and 5-7, respectively, as
epimeric mixtures at the new stereogenic center (Scheme 2). In
all cases the exo isomer was predominant except in the
alkylation of lactam 1a with ethyl iodide. The stereoselectivity
of these reactions ranged from excellent (6b was isolated as a
single isomer) to very low (as in 4). However, this was not a
drawback since the C-6 isomeric mixtures of lactams 2-7 could
be used in the subsequent alkylation as the stereochemical
outcome of this process is irrespective of the configuration of
the C-6 stereocenter in the starting material.
The introduction of the second substituent from the above
monoalkylated lactams was initially attempted under the reaction
conditions we had successfully used to perform monoalkylation
reactions from 1a and 1b. Surprisingly, all attempts to alkylate
the 6-benzyl-substituted lactam 2 at -78 °C by treatment of a
THF solution of the lactam with LiHMDS (3 equiv) for 2 h,
followed by addition of an excess (3 equiv) of ethyl iodide were
unfruitful. A similar result was observed when the reaction was
carried out at 0 °C, whereas treatment of 2 with LiHMDS at
room temperature for 2 h, followed by addition of ethyl iodide
at this temperature afforded an equimolecular mixture of isomers
8a and 8b (see Scheme 3). An increase of the stereoselectivity
was observed upon cooling the enolate solution to -78 °C
before the addition of an excess of ethyl iodide: under these
conditions a 33:67 isomeric mixture of the endo and exo
alkylation products (8a and 8b, respectively) was obtained in
76% yield. More satisfactorily, alkylation of the enolate
(generated at 25 °C) of the 6-ethyl-substituted lactam 3 with
benzyl bromide at -78 °C afforded with very high stereose-
lectivity the disubstituted lactam 8a, resulting from an exo
diastereofacial alkylation of the enolate. This result makes
evident that the order in which the substituents are incorporated
dramatically affects the stereochemical outcome of the dialky-
lation.
unsubstituted at the angular position, and the subsequent
elaboration of the resulting dialkylated lactams into enantiopure
piperidine derivatives with two different substituents at the
3-position. As target compounds we selected piperidines bearing
an ethyl and either a benzyl or an allyl substituent at the
quaternary stereocenter. The ethyl substituent is a common
structural unit present in many alkaloids, whereas the allyl
substituent can be further elaborated by known oxidative
procedures to give synthetic precursors of complex natural
products such as (-)-rhazinilam, (+)-eburnamonine, (+)-
aspidospermidine, or (-)-quebrachamine (Figure 1).
Results and Discussion
To establish the most convenient protocol for the stereose-
lective generation of a quaternary stereocenter at the 3 position
of the piperidine ring by dialkylation of oxazolopiperidone
lactams we investigated the influence on the stereoselectivity
of (i) the order of incorporation of the substituents and (ii) the
configuration of the C-8a stereocenter. Three monoalkylated
(4) (a) Meyers, A. I.; Hanreich, R.; Wanner, K. T. J. Am. Chem. Soc.
1985, 107, 7776. (b) Meyers, A. I.; Lefker, B. A.; Wanner, K. T.; Aitken,
R. A. J. Org. Chem. 1986, 51, 1936. (c) Meyers, A. I.; Lefker, B. A.
Tetrahedron 1987, 43, 5663. (d) Meyers, A. I.; Berney, D. J. Org. Chem.
1989, 54, 4673. (e) Resek, J. E.; Meyers, A. I. Synlett 1995, 145. (f) Reeder,
M. R.; Meyers, A. I. Tetrahedron Lett. 1999, 40, 3115. (g) Watson, D. J.;
Meyers, A. I. Tetrahedron Lett. 2000, 41 1519. (h) Hughes, R. C.; Dvorak,
C. A.; Meyers, A. I. J. Org. Chem. 2001, 66, 5545. See also, (i) Schwarz,
J. B.; Meyers, A. I. J. Org. Chem. 1998, 63, 1619.
(5) Amat, M.; Escolano, C.; Lozano, O.; Go´mez-Esque´, A.; Griera, R.;
Molins, E.; Bosch, J. J. Org. Chem. 2006, 71, 3804.
(6) Soteras, I.; Lozano, O.; Go´mez-Esque´, A.; Escolano, C.; Orozco, M.;
Amat, M.; Bosch, J.; Luque, F. J. J. Am. Chem. Soc. 2006, 128, 6581.
In contrast with what we had observed from the above cis
H-3/H-8a lactams 2 and 3, the enolate of the C-8a epimeric
lactam 5 (H-3/H-8a trans) could be efficiently generated at
-78 °C by using LiHMDS as the base (Scheme 4). A
4432 J. Org. Chem., Vol. 72, No. 12, 2007

Synthesis of 3,3-Disubstituted Piperidine DeriVatiVes
SCHEME 3. Alkylation of 6-Substituted Cis H-3/H-8a
Oxazolopiperidone Lactams: Benzyl and Ethyl Substituents
SCHEME 5. Alkylation of 6-Substituted Cis H-3/H-8a
Oxazolopiperidone Lactams: Allyl and Ethyl Substituents
SCHEME 6. Alkylation of 6-Substituted Trans H-3/H-8a
Oxazolopiperidone Lactams: Allyl and Ethyl Substituents
SCHEME 4. Alkylation of 6-Substituted Trans H-3/H-8a
Oxazolopiperidone Lactams: Benzyl and Ethyl Substituents
TABLE 1. Alkylation of Oxazolopiperidone 7
subsequent addition of ethyl iodide afforded the corresponding
exo isomer 9a7 with excellent stereoselectivity (9a:9b 96:4). A
higher temperature (25 °C) in the enolate ethylation resulted in
a poorer stereoselectivity (9a:9b 60:40). In this trans H-3/H-8a
series, the ethyl-substituted lactam 6 underwent enolate alkyl-
ation with benzyl bromide in poor stereoselectivity, even at
-78 °C, leading to a 33:67 mixture of isomers 9a and 9b. Again,
the order of introduction of the substituents has a crucial
influence on the stereoselectivity of the dialkylation.
T, °C
enolate
T, °C
yield,
%
entry
base
solvent formation alkylation
11a:11b
1
2
3
4
5
6
LiHMDS
LiHMDS
LiHMDS
NaHMDS THF
KHMDS
KHMDS
THF
THF
THF
-78
25
25
-78
-78
-78
-78
-78
25
-78
-78
-78
71
72
67
50
62
56
91:9
91:9
77:23
93:7
95:5
98:2
THF
toluene
We next investigated the preparation of lactams bearing an
allyl and ethyl substituent at the 3 position of the piperidine
ring. As already observed when operating from lactams 2 and
3, generation of the enolate of the cis H-3/H-8a configurated
lactam 4 (LiHMDS, THF) required working at room tempera-
ture. A subsequent addition of ethyl iodide at -78 °C yielded
an equimolecular mixture of dialkylated compounds 10a7 and
10b (Scheme 5). Alternatively, addition of allyl bromide to the
enolate of ethyl-substituted lactam 3 occurred with only
moderate stereoselectivity, leading to a mixture of isomers 10a
and 10b, in which the exo-allylated product predominated (71:
29).
Better stereochemical results in the preparation of allyl-ethyl-
substituted lactams were obtained from the trans H-3/H-8a
6-allyl lactam 7. Thus, treatment of the lithium enolate of 7
with ethyl iodide at -78 °C afforded isomer 11a, resulting from
alkylation on the exo face of the enolate, with good stereose-
lectivity (Scheme 6 and Table 1, entries 1 and 2; 11a:11b 91:
9). As expected, the stereoselectivity decreased when the
temperature of the alkylation step was raised to 25 °C (entry
3). The use of NaHMDS or KHMDS as the base, instead of
LiHMDS (entries 4 and 5), resulted in a slight increase in
stereoselectivity. Finally, changing the solvent from THF to
toluene (entry 6), when using KHMDS, resulted in the stereo-
selective formation of lactam 11a. The order in which the
(7) The absolute configuration of the dialkylated lactams 9a and 10a
was unambiguously confirmed by X-ray crystallographic analysis.
J. Org. Chem, Vol. 72, No. 12, 2007 4433

Amat et al.
SCHEME 7. Synthesis of Enantiopure 3,3-Disubstituted
alkylating agents are added again modifies the stereochemical
outcome of the dialkylation since allylation of the ethyl-
substituted lactam 6 with allyl bromide at -78 °C took place
with only a modest exo facial selectivity to give a 30:70 mixture
of isomers 11a and 11b, respectively.
Piperidine Derivatives
The above results deserve some comments. In contrast with
the endo diastereofacial selectivity observed by Meyers for the
enolate dialkylation of oxazolopiperidone lactams bearing a
substitutent at the C-8a angular position, C-8a unsubstituted
lactams 2-7 preferently undergo the second alkylation on the
exo face of the enolate. On the other hand, for a given cis or
trans H-3/H-8a relationship, the best stereoselectivities in the
introduction of the second substituent parallel those observed
in the monoalkylation reactions from lactams 1a (cis) and 1b
(trans) when the same alkylating reagent is used. Thus, in the
cis H-3/H-8a series, starting from unsubstituted lactam 1a the
best stereoselectivity was observed in the benzylation reaction
leading to the exo isomer 2b.5 Similarly, only the exo benzyl-
ation of the ethyl-substituted cis H-3/H-8a lactam 3 was highly
stereoselective, whereas the ethylation of 2 and 4 or the
allylation of 3 were not. In turn, in the trans H-3/H-8a series
the best stereoselectivity from the unsubstituted lactam 1b was
observed in the ethylation reaction leading to the exo isomer
6b.5 Again, the exo ethylation of the benzyl- and allyl-substituted
trans H-3/H-8a lactams 5 and 7, respectively, was highly
stereoselective, whereas the benzylation or the allylation of 6
took place with moderate stereoselectivity.
SCHEME 8. Synthesis of Methyl
(R)-3-Ethyl-3-piperidineacetate
Thus, from a stereochemical point of view, the best sequences
for the preparation of lactams with benzyl and ethyl substituents
at the quaternary stereocenter involve either the ethylation of
1a followed by benzylation of the resulting monoalkylated
lactam 3 to give 8a or the benzylation of lactam 1b followed
by ethylation of the resulting lactam 5 to give 9a. Since in both
cases the second alkylation step takes place with exo diaste-
reofacial selectivity, the two sequences afford dialkylated
lactams with the same absolute configuration at the quaternary
stereocenter. On the other hand, the best sequence for the
stereoselective preparation of a bicyclic lactam bearing allyl and
ethyl substituents involves the allylation of the enolate of 1b
followed by stereoselective exo ethylation of the monoalkylated
lactam 7 to give 11a.
The conversion of the dialkylated lactams into 3,3-disubsti-
tuted piperidine derivatives simply requires the removal of the
phenylethanol moiety of the chiral inductor by reductive
cleavage of the C8a-O and benzylic C3-N bonds of the
oxazolidine ring. Starting from lactam 9a this was accomplished
by treatment with Et3SiH and TiCl4 followed by removal of
the benzylic substituent from the resulting piperidone 12 with
sodium in liquid ammonia (Scheme 7). In this way, (S)-3-benzyl-
3-ethyl-2-piperidone (13) was obtained in 80% overall yield.
By selection of the appropriate R or S enantiomer of
phenylglycinol, both commercially available, both enantiomers
of a target 3,3-substituted-2-piperidone are accessible through
the above methodology. This was illustrated with the synthesis
of (R)-3-allyl-3-ethyl-2-piperidone (15),8 which possesses the
absolute configuration required for the synthesis of the indole
alkaloids depicted in Figure 1. Thus, sequential enolate dialkyl-
ation of (S)-phenylglycinol-derived lactam ent-1b with allyl
bromide and ethyl iodide, as described above for its enantiomer,
afforded disubstituted lactam ent-11a, which was converted as
in the above benzyl-ethyl series to piperidone 15 in 65% overall
yield. In both series, the configuration of the quaternary
stereogenic center was unequivocally established by X-ray
crystallographic analysis of the intermediate phenyglycinol-
derived piperidones 12 and 14. Taking into account that racemic
15 has previously been used in the synthesis of rhazinilam9 (see
Figure 1), chiral piperidone 15 can be considered a precursor
for the enantioselective synthesis of this natural product.
To further illustrate the usefulness of the above 3,3-disub-
stituted piperidines for the enantioselective synthesis of natural
products, bicyclic lactam ent-11a was converted to methyl (R)-
3-ethyl-3-piperidineacetate (19). This was accomplished in good
overall yield by ruthenium oxidation of the carbon-carbon
double bond of ent-11a, followed by LiAlH4 reduction of the
resulting acid 16, hydrogenolysis, and subsequent conventional
functional group interconversions, as outlined in Scheme 8. In
the racemic series, amino ester 19 has been used as a platform
for the synthesis of several indole alkaloids such as (()-
eburnamonine, (()-aspidospermidine, or (()-quebrachamine.10
The synthesis of the Aspidosperma indole alkaloid (-)-
quebrachamine from 19 requires the introduction of the 2-(3-
indolyl)ethyl chain on the piperidine nitrogen, the closure of
the nine-membered ring by electrophilic cyclization on the
indole 2-position, and finally, the adjustment of the oxidation
level in the resulting tetracyclic keto lactam. Following a route
(9) Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647.
(10) (a) Ziegler, F. E.; Kloek, J. A.; Zoretic, P. A. J. Am. Chem. Soc.
1969, 91, 2342. (b) Irie, K.; Ban, Y. Heterocycles 1981, 15, 201. (c)
Imanishi, T.; Miyashita, K.; Nakai, A.; Inoue, M.; Hanaoka, M. Chem.
Pharm. Bull 1983, 31, 1191. (d) Wenkert, E.; Hudlicky, T. J. Org. Chem.
1988, 53, 1953.
(8) For the synthesis of enantioenriched (ee ) 42%) lactam 15 by
asymmetric dialkylation of a chiral N-(dialkylamino)lactam, see: Enders,
D.; Teschner, P.; Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2001, 4463.
4434 J. Org. Chem., Vol. 72, No. 12, 2007

Synthesis of 3,3-Disubstituted Piperidine DeriVatiVes
chamine.16 The NMR data15e and [R]D value17 of our synthetic
quebrachamine were coincident with those reported in the
literature for the natural product.
SCHEME 9. Enantioselective Synthesis of
(-)-Quebrachamine
Conclusion. By the appropriate choice of both the configu-
ration of the starting lactam (H-3/H-8a, either cis or trans) and
the order of introduction of the substituents, the enolate
dialkylation of phenylglycinol-derived oxazolopiperidone lac-
tams allows the stereoselective introduction of substituents at
the â-position of the piperidine ring, with generation of a
quaternary sterocenter, to ultimately lead to enantiopure 3,3-
disubstituted piperidine derivatives. Taking into account that
both enantiomers of phenylglycinol are commercially available,
the procedure provides access to 3,3-disubstituted piperidines
in both enantiomeric series.
Experimental Section
General Procedure for the Alkylation of Lactams 2-6. A
solution of the lactam (1 mmol) in THF was added to a solution of
LiHMDS (1 M in THF, 1.5 or 3.0 mmol) in THF at 25 °C for
lactams 2-4 and at -78 °C for lactams 5-7. After the solution
was stirred at the same temperature for 2 h, the alkylating reagent
(2.6 mmol) was added at -78 °C, and stirring was continued at
this temperature for an additional 3 h. The reaction was quenched
by the addition of saturated aqueous NaCl, and the resulting mixture
was extracted with EtOAc and CH2Cl2. The combined organic
extracts were dried and concentrated, and the resulting residue was
chromatographed.
that parallels the one used in our previous synthesis of (20R)-
and (20S)-dihydrocleavamine,5 piperidine 19 was acylated with
the mixed anhydride of indole-3-acetic acid and pivalic acid11
to give amido ester 20, which was converted to the correspond-
ing carboxylic acid 21 and then cyclized10a by treatment with
polyphosphoric acid to give the desired tetracyclic keto lactam
22 in good overall yield (Scheme 9). Although 22 could be
partially reduced in excellent yield to alcohols 24 and 25 by
treatment with NaBH4 (MeOH, rt) and LiAlH4 (THF, rt),
respectively, the complete reduction of 22 to (-)-quebrachamine
proved to be more difficult. This conversion was accomplished
in only moderate yield (30%) with LiAlH4 in refluxing
N-methylmorpholine (NMM),12 which nevertheless represents
a significant improvement of the reported yield (6%) for this
reduction (from rac-22) in refluxing dioxane.10a Under the latter
conditions, reduction of 22 led to the known indoloindolizidine
23,13,14 which, taking into account previous correlations,13,15
constitutes an alternative formal synthesis of (-)-quebra-
[3R,6S(and 6R),8aR]-6-Benzyl-6-ethyl-5-oxo-3-phenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[3,2-a]pyridine (8a and 8b). From
lactam 2: Following the general procedure, lactam 2 (200 mg, 0.65
mmol) in THF (8 mL), LiHMDS (1.95 mL, 1.95 mmol) in THF
(2 mL), and ethyl iodide (0.14 mL, 1.69 mmol) afforded a 33:67
(calculated by GC/MS) mixture of epimers 8a and 8b (168 mg,
76%), which were separated by flash chromatography (7:3 hexane-
Et2O). From lactam 3: Following the general procedure, lactam 3
(372 mg, 1.52 mmol) in THF (15 mL), LiHMDS (4.6 mL, 4.6
mmol) in THF (5 mL), and benzyl bromide (0.50 mL, 4.00 mmol)
afforded a 95:5 (calculated by GC/MS) mixture of epimers 8a and
8b (290 mg, 60%), which were separated by flash chromatography
(7:3 hexane-Et2O). 8a: IR (film) 1650 cm-1; 1H NMR (400 MHz)
δ 0.77 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.47 (m, 1H, CH3CH2), 1.72-
1.85 (m, 4H, H-7, H-8, CH3CH2), 2.13 (m, 1H, H-8), 2.41 and
3.19 (2d, J ) 13.2 Hz, 2H, CH2Ph), 3.92 (dd, J ) 9.0, 2.0 Hz, 1H,
H-2), 3.96 (dd, J ) 9.0, 6.5 Hz, 1H, H-2), 4.10 (m, 1H, H-8a),
4.80 (dd, J ) 6.5, 2.0 Hz, 1H, H-3), 7.18-7.34 (m, 10H, ArH);
13C NMR (100 MHz) δ 9.1 (CH3CH2), 25.9 (C-7), 26.8 (C-8), 33.6
(CH3CH2), 44.2 (CH2Ph), 46.8 (C-6), 59.2 (C-3), 73.9 (C-2), 88.3
(C-8a), 126.4 (CH), 126.6 (2CH), 127.4 (CH), 128.0 (2CH), 128.4
(2CH), 130.7 (2CH), 138.2 (C i), 142.1 (C i), 171.2 (NCO); MS-
EI m/z 335 (M+, 13), 91 (80), 104 (100), 243 (36); HRMS calcd
for C22H25NO2, 335.1885; found, 335.1897. 8b: IR (film) 1647
(11) Sza´ntay, C.; Bo¨lcskei, H.; Ga´cs-Baitz, E.; Keve, T. Tetrahedron
1990, 46, 1687.
(12) (-)-Quebrachamine was also obtained, although in poorer yield
(5%), when the reduction was carried out with BH3 in THF at reflux,
following the conditions reported for the complete reduction of related seven-
membered keto lactams: Khandelwal, Y.; Jain, P. C.; Anand, N. Indian J.
Chem. B 1989, 28B, 475.
(13) (a) Takano, S.; Sato, M.; Hatakeyama, S.; Hirama, M.; Ogasawara,
K. Heterocycles 1976, 5, 221. (b) Takano, S.; Hatakeyama, S.; Ogasawara,
K. J. Am. Chem. Soc. 1979, 101, 6414.
(14) For the formation of similar allylindoloindolizidines in the LiAlH4
reduction of related tetracyclic nine-membered 16-oxolactams, see: (a)
Narisada, M.; Watanabe, F.; Nagata, W. Tetrahedron Lett. 1971, 39, 3681.
(b) Ziegler, F. E.; Bennett, G. B. J. Am. Chem. Soc. 1973, 95, 7458. See
also ref 5.
(15) (a) Kutney, J. P.; Abdurahman, N.; Gletsos, C.; Le Quesne, P.; Piers,
E.; Vlattas, I. J. Am. Chem. Soc. 1970, 92, 1727. (b) Kutney, J. P.; Chan,
K. K.; Failli, A.; Fromson, J. M.; Gletsos, C.; Leutwiler, A.; Nelson, V.
R.; de Souza, J. P. HelV. Chim. Acta 1975, 58, 1648. (c) Takano, S.; Yonaga,
M.; Ogasawara, K. J. Chem. Soc. Chem. Commun. 1981, 1153. (d) Node,
M.; Nagasawa, H.; Fuji, K. J. Org. Chem. 1990, 55, 517. (e) Temme, O.;
Taj, S.-A.; Anderson, P. G. J. Org. Chem. 1998, 63, 6007.
1
cm-1; H NMR (400 MHz) δ 0.88 (t, J ) 7.5 Hz, 3H, CH3CH2),
1.13 (dddd, J ) 14.0, 12.0, 10.0, 4.0 Hz, 1H, H-8), 1.28 (m, 1H
CH3CH2), 1.69 (ddd, J ) 14.4, 14.0, 4.0 Hz, 1H, H-7), 1.80-1.89
(m, 2H, CH3CH2, H-7), 2.01 (ddd, J ) 12.0, 6.8, 4.0 Hz, 1H, H-8),
2.40 and 3.11 (2d, J ) 13.5 Hz, 2H, CH2Ph), 4.03 (dd, J ) 9.0,
1.2 Hz, 1H, H-2), 4.12 (dd, J ) 9.0, 6.8 Hz, 1H, H-2), 4.72 (dd,
J ) 10.0, 4.0 Hz, 1H, H-8a), 4.87 (dd, J ) 6.8, 1.2 Hz, 1H, H-3),
(16) For previous enantioselective syntheses of the alkaloids (+)- and
(-)-quebrachamine, see: (a) Takano, S.; Chiba, K.; Yonaga, M.; Ogasawara,
K. J. Chem. Soc., Chem. Commun. 1980, 616. (b) Asaoka, M.; Takei, H.
Heterocycles 1989, 29, 243. (c) Kozmin, S. A.; Iwama, T.; Huang, Y.;
Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628. (d) Fujimura, T.;
Nakashima, H.; Sakagami, H.; Taniguchi, T.; Ogasawara, K. Tetrahedron
Lett. 2002, 43, 97. See also refs 15c, d, e.
(17) Southon, I. W.; Buckingham, J. Dictionary of Alkaloids; Chapman
and Hall: London, 1989; p 901.
J. Org. Chem, Vol. 72, No. 12, 2007 4435

Amat et al.
6.83-6.85 (m, 2H, ArH), 7.11-7.37 (m, 8H, ArH); 13C NMR
(100 MHz) δ 8.8 (CH3CH2), 25.8 (C-7), 26.3 (C-8), 32.7 (CH3CH2),
45.3 (CH2Ph), 46.5 (C-6), 59.3 (C-3), 74.1 (C-2), 88.8 (C-8a), 126.3
(CH), 127.4 (2CH), 127.5 (CH), 128.1 (2CH), 128.3 (2CH), 130.4
(2CH), 137.7 (C i), 141.7 (C i), 171.6 (NCO); MS-EI m/z 335
(M+, 5), 91 (58), 104 (32), 232 (100); HRMS calcd for C22H25-
NO2, 335.1885; found, 335.1895.
42.6 (CH2CHd), 44.5 (C-6), 59.0 (C-3), 73.8 (C-2), 88.5 (C-8a),
118.2 (CH2d), 126.4 (2CH), 127.2 (CH), 128.2 (2CH), 134.4
(CH2CHd), 141.8 (C i), 171.3 (NCO); mp 132-134 °C (Et2O-
hexane); [R]2D2 -158 (c 0.5, MeOH); MS-EI m/z 285 (M+, 3), 104
(100), 243 (56), 257 (53). Anal. calcd for C18H23NO2: C, 75.76;
H, 8.12; N, 4.91. Found: C, 75.69; H, 8.19; N, 5.12. 10b: IR (film)
1646 cm-1 1H NMR (300 MHz) δ 0.86 (t, J ) 7.5 Hz, 3H, CH3-
:
[3R,6S(and 6R),8aS]-6-Benzyl-6-ethyl-5-oxo-3-phenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[ 3,2-a]pyridine (9a and 9b). From
lactam 5: Following the general procedure, lactam 5 (330 mg,
1.07 mmol) in THF (8 mL), LiHMDS (3.2 mL, 3.20 mmol) in THF
(10 mL), and ethyl iodide (0.2 mL, 2.78 mmol) afforded an 96:4
(calculated by GC/MS) mixture of epimers 9a and 9b (231 mg,
64%), which were separated by flash chromatography (1:4 Et2-
hexane). From lactam 6: Following the general procedure, lactam
6 (150 mg, 0.61 mmol) in THF (6 mL), LiHMDS (1.83 mL,
1.83 mmol) in THF (2 mL), and benzyl bromide (0.2 mL, 1.6 mmol)
afforded an 33:67 (calculated by GC/MS) mixture of epimers 9a
and 9b (124 mg, 57%), which were separated by flash chroma-
CH2), 1.33 (m, 1H, CH3CH2), 1.72 (m, 1H, CH3CH2), 1.75-1.80
(m, 2H, H-7), 1.87-2.00 (m, 1H, H-8), 2.05 (dd, J ) 13.5, 7.5
Hz, 1H, CH2CHd), 2.24 (ddd, J ) 12.0, 7.0, 3.3 Hz, 1H, H-8),
2.34 (dd, J ) 13.5, 7.2 Hz, 1H, CH2CHd), 4.03 (dd, J ) 9.0,
0.9 Hz, 1H, H-2), 4.16 (dd, J ) 9.0, 6.6 Hz, 1H, H-2), 4.81 (dd,
J ) 9.9, 3.3 Hz, 1H, H-8a), 4.87 (dm, J ) 6.6 Hz, 1H, H-3), 4.93
(m, 1H, CH2d), 4.97 (m, 1H, CH2d), 5.53 (m, 1H, CH2CHd),
7.23-7.36 (m, 5H, ArH); 13C NMR (75.4 MHz) δ 8.7 (CH3CH2),
26.2 and 26.3 (C-7 and C-8), 31.0 (CH3CH2), 44.1 CH2CHd), 45.1
(C-6), 59.0 (C-3), 73.8 (C-2), 88.6 (C-8a), 117.6 (CH2d), 126.5
(2CH), 127.2 (CH), 128.2 (2CH), 134.1 (CH2CHd), 141.7 (C i),
171.7 (NCO); mp 131-133 °C (Et2O-hexane); [R]2D2 -45 (c 0.5,
MeOH); MS-EI m/z 285 (M+, 5), 104 (100), 243 (42). Anal. calcd
for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.67; H,
8.21; N, 4.94.
1
tography (1:4 Et2O-hexane). 9a: IR (film) 1647 cm-1; H NMR
(300 MHz) δ 0.78 (t, J ) 7.5 Hz, 3H, CH3CH2), 0.98 (m, 1H,
H-8), 1.30 (m, 1H, CH3CH2), 1.71 (dd, J ) 6.0, 4.0 Hz, 1H, H-7),
1.74 (d, J ) 4.0 Hz, 1H, H-7), 1.86 (m, 1H, CH3CH2), 1.98 (ddd,
J ) 12.6, 7.8, 4.3 Hz, 1H, H-8), 2.65 and 3.23 (2d, J ) 13.2 Hz,
2H, CH2Ph), 3.70 (dd, J ) 8.7, 8.1 Hz, 1H, H-2), 4.39 (dd, J )
8.7, 8.1 Hz, 1H, H-2), 4.95 (dd, J ) 9.3, 4.3 Hz, 1H, H-8a), 5.22
(t, J ) 8.1 Hz, 1H, H-3), 7.10-7.33 (m, 10H, ArH); 13C NMR
(75.4 MHz) δ 8.6 (CH3CH2), 24.2 (C-7), 25.7 (C-8), 32.9 (CH3CH2),
44.4 (CH2Ph), 46.6 (C-6), 58.9 (C-3), 72.8 (C-2), 88.9 (C-8a), 126.0
(2CH), 126.4 (CH), 127.3 (CH), 128.0 (2CH), 128.5 (2CH), 130.1
(2CH), 138.0 (C i), 139.6 (C i), 173.0 (NCO); mp 111-113 °C
(Et2O-EtOAc); [R]22 -208 (c 1.0, MeOH); MS-EI m/z 335 (M+,
31), 91 (100), 306 (D93). Anal. calcd for C22H25NO2: C, 78.77; H,
7.51; N, 4.18. Found: C, 78.55; H, 7.46; N, 4.15. 9b: IR (film)
1648 cm-1; 1H NMR (300 MHz) δ 1.00 (t, J ) 7.2 Hz, 3H, CH3-
CH2), 1.62 (m, 1H, H-8), 1.70-1.74 (m, 2H, H-7), 1.81 (m, 2H,
CH2CH3), 2.10 (dddd, J ) 11.6, 4.4, 4.4, 3.2 Hz, 1H, H-8), 2.45
and 3.22 (2d, J ) 13.2 Hz, 2H, CH2Ph), 3.62 (dd, J ) 8.8, 8.0 Hz,
1H, H-2), 4.39 (dd, J ) 8.8, 8.0 Hz, 1H, H-2), 4.60 (dd, J ) 8.8,
4.8 Hz, 1H, H-8a), 5.18 (t, J ) 8.8 Hz, 1H, H-3), 6.94 (dd, J )
8.5, 6.8 Hz, 2H, ArH), 7.05 (dd, J ) 8.0, 1.6 Hz, 2H, ArH), 7.11
(tm, J ) 7.0 Hz, 2H, ArH), 7.17 (m, 1H, ArH), 7.25-7.33 (m, 3H,
ArH); 13C NMR (75.4 MHz) δ 8.9 (CH3CH2), 23.6 (C-7), 25.4
(C-8), 31.5 (CH3CH2), 43.2 (CH2Ph), 46.5 (C-6), 58.7 (C-3), 72.9
(C-2), 88.5 (C-8a), 126.1 (CH, Ar), 126.6 (2CH), 127.5 (CH), 128.0
(2CH), 128.5 (2CH), 130.7 (2CH), 137.7 (C i), 139.5 (C i), 172.8
(NCO); MS-EI m/z 335 (M+, 25), 104 (100), 91 (90).
[3R,6S(and 6R),8aR]-6-Allyl-6-ethyl-5-oxo-3-phenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[3, 2-a]pyridine (10a and 10b). From
lactam 4: Following the general procedure, lactam 4 (200 mg, 0.78
mmol) in THF (8 mL), LiHMDS (2.3 mL, 2.3 mmol) in THF
(2 mL), and ethyl iodide (0.16 mL, 2.00 mmol) afforded an 50:50
(calculated by GC/MS) mixture of epimers 10a and 10b (137 mg,
62%), which were separated by flash chromatography (1:1 Et2O-
hexane). From lactam 3: Following the general procedure, lactam
3 (200 mg, 0.82 mmol) in THF (8 mL), LiHMDS (2.5 mL,
2.5 mmol) in THF (2 mL), and allyl bromide (0.18 mL, 2.12 mmol)
afforded an 71:29 (calculated by GC/MS) mixture of epimers 10a
and 10b (160 mg, 69%), which were separated by flash chroma-
tography (1:1 Et2O-hexane). 10a: IR (film) 1647 cm-1; 1H NMR
(300 MHz) δ 0.71 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.42 (m, 1H,
CH3CH2), 1.64 (m, 1H, CH3CH2), 1.70-1.92 (m, 3H, H-7, H-8),
1.99 (dd, J ) 13.2, 8.7 Hz, 1H, CH2CHd), 2.26 (m, 1H, H-8),
2.45 (dddd, J ) 13.2, 6.0, 1.5, 1.5 Hz, 1H, CH2CHd), 4.00 (dd,
J ) 9.0, 1.2 Hz, 1H, H-2), 4.14 (dd, J ) 9.0, 6.6 Hz, 1H, H-2),
4.76 (dd, J ) 9.3, 3.6 Hz, 1H, H-8a), 4.87 (dd, J ) 6.6, 1.2 Hz,
1H, H-3), 5.04 (dm, J ) 7.8 Hz, 1H, CH2d), 5.08 (m, 1H, CH2d),
5.72 (m, 1H, CH2CHd), 7.20-7.35 (m, 5H, ArH); 13C NMR
(75.4 MHz) δ 8.8 (CH3CH2), 26.4 (C-7 and C-8), 32.3 (CH3CH2),
[3R,6S(and 6R),8aS]-6-Allyl-6-ethyl-5-oxo-3-phenyl-2,3,6,7,8,-
8a-hexahydro-5H-oxazolo[3, 2-a]pyridine (11a and 11b). From
lactam 7: Following the general procedure, lactam 7 (970 mg, 3.77
mmol) in THF (10 mL), LiHMDS (11.0 mL, 11.0 mmol) in THF
(42 mL), and ethyl iodide (0.8 mL, 9.81 mmol) afforded a 91:9
(calculated by GC/MS) mixture of epimers 11a and 11b (768 mg,
71%), which were separated by flash chromatography (1:4 Et2O-
hexane). From lactam 6: Following the general procedure, lactam
6 (250 mg, 1.02 mmol) in THF (10 mL), LiHMDS (3.1 mL,
3.1 mmol) in THF (3 mL), and allyl bromide (0.23 mL, 2.65 mmol)
afforded a 30:70 (calculated by GC/MS) mixture of epimers 11a
and 11b (188 mg, 65%), which were separated by flash chroma-
tography (1:4 Et2O-hexane). 11a: IR (film) 1640 cm-1; 1H NMR
(300 MHz) δ 0.78 (t, J ) 7.5 Hz, 3H, CH2CH3), 1.40 (m, 1H,
CH2CH3), 1.59-1.78 (m, 4H, H-7, H-8, CH2CH3), 2.20 (m, 1H,
H-8), 2.29 (dd, J ) 14.0, 7.0 Hz, 1H, CH2CHd), 2.47 (dd, J )
14.0, 7.0 Hz, 1H, CH2CHd), 3.73 (dd, J ) 9.0, 8.1 Hz, 1H, H-2),
4.47 (dd, J ) 9.0, 8.1 Hz, 1H, H-2), 5.01 (t, J ) 4.5 Hz, 1H, H-8a),
5.05 (m, 1H, CH2d), 5.09 (dm, J ) 6.6 Hz, 1H, CH2d), 5.20 (t,
J ) 8.1 Hz, 1H, H-3), 5.80 (m, 1H, CH2dCH), 7.24-7.34 (m,
5H, ArH); 13C NMR (75.4 MHz) δ 8.6 (CH2CH3), 24.8 (C-7), 26.0
(C-8), 32.0 (CH2CH3), 42.8 (CH2CHd), 45.3 (C-6), 58.8 (C-3),
73.0 (C-2), 89.1 (C-8a), 117.9 (CH2d), 126.1 (2CH), 127.4 (CH),
128.6 (2CH), 134.4 (CH2dCH), 139.7 (C i), 170.1 (NCO); mp 90-
96 °C (Et2O-hexane); MS-EI m/z 285 (M+, 8), 104 (100), 243
(71), 257 (66). Anal. calcd for C18H23NO2: C, 75.76; H, 8.12; N,
4.91. Found: C, 75.45; H, 8.45; N, 4.99. 11b: IR (film) 1643 cm-1
;
1H NMR (300 MHz) δ 0.92 (t, J ) 7.5 Hz, 3H, CH2CH3), 1.55-
1.88 (m, 5H, H-7, H-8, CH2CH3), 2.03 (dd, J ) 13.5, 8.7 Hz, 1H,
CH2CHd), 2.21 (dddd, J ) 16.6, 4.5, 4.5, 3.0 Hz, 1H, H-8), 2.43
(dddd, J ) 13.5, 6.0, 1.5, 1.5 Hz, 1H, CH2CHd), 3.72 (dd, J )
9.0, 8.0 Hz, 1H, H-2), 4.47 (dd, J ) 9.0, 8.0 Hz, 1H, H-2), 4.97
(dd, J ) 9.0, 4.5 Hz, 1H, H-8a), 5.03-5.07 (m, 2H, CH2d), 5.20
(t, J ) 8.0 Hz, 1H, H-3), 5.52-5.66 (m, 1H, CH2dCH), 7.15-
7.35 (m, 5H, ArH); 13C NMR (75.4 MHz) δ 8.9 (CH2CH3), 24.6
(C-7), 26.0 (C-8), 30.8 (CH2CH3), 43.2 (CH2-CHd), 44.8 (C-6),
58.6 (C-3), 72.9 (C-2), 88.7 (C-8a), 118.3 (CH2d), 126.0 (2CH),
127.2 (CH), 128.4 (2CH), 134.0 (CH2dCH), 139.6 (C i), 173.0
(NCO); mp 71-75 °C (Et2O-hexane); MS-EI m/z 285 (M+, 5),
104 (92), 244 (47), 257 (100); HRMS calcd for C18H23NO2,
285.1728; found, 285.1721.
Following the general procedure, from lactam ent-7 were
obtained lactams ent-11a ([R]2D2 -154 (c 0.5, MeOH)) and ent-11b
([R]2D2 +61 (c 1.1, MeOH)).
(3S)-3-Benzyl-3-ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]-2-pi-
peridone (12). Triethylsilane (0.08 mL, 0.48 mmol) and TiCl4
4436 J. Org. Chem., Vol. 72, No. 12, 2007

Synthesis of 3,3-Disubstituted Piperidine DeriVatiVes
(0.10 mL, 0.72 mmol) were added to a cooled (-78 °C) solution
of lactam 9a (160 mg, 0.48 mmol) in CH2Cl2 (10 mL). The mixture
was stirred at room temperature for 6 h, quenched by the addition
of saturated aqueous NH4Cl, and extracted with CH2Cl2. The
combined organic extracts were dried and concentrated, and the
resulting residue was chromatographed (1:1 EtOAc-hexane) to
(R)-3-Allyl-3-ethyl-2-piperidone (15). Following the procedure
described for the preparation of 13, lactam 14 (100 mg, 0.35 mmol)
in NH3 (15 mL) gave piperidone 15 (51 mg, 88%) after flash
1
chromatography (1:1 EtOAc-hexane): IR (film) 1658 cm-1; H
NMR (300 MHz) δ 0.89 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.51 (m,
1H, CH3CH2), 1.67-1.83 (m, 5H, H-4, H-5, CH3CH2), 2.18 (dd,
J ) 13.5, 7.8 Hz, 1H, CH2CHd), 2.49 (dddd, J ) 13.5, 6.6, 1.2,
1.2 Hz, 1H, CH2CHd), 3.23-3.28 (m, 2H, H-6), 5.05 and 5.10
(2 m, 2H, CH2d), 5.79 (m, 1H, CH2CHd), 6.35 (br s, 1H, NH);
13C NMR (75.4 MHz) δ 8.6 (CH3CH2), 19.6 (C-5), 28.5 (C-5),
31.0 (CH3CH2), 42.4 (C-6), 42.7 (CH2CHd), 44.6 (C-3), 117.5
afford piperidone 12 (145 mg, 90%): IR (film) 1606, 3401 cm-1
;
1H NMR (300 MHz) δ 0.92 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.22-
1.34 (m, 2H, H-5), 1.48 (m, 1H, CH3CH2), 1.56 (m, 1H, H-4), 1.63
(dd, J ) 9.6, 4.0 Hz, 1H, H-5) 1.73 (m, 1H, H-4), 1.97 (m, 1H,
CH3CH2), 2.59 and 3.34 (2d, J ) 13.0 Hz, 2H, CH2Ph), 2.73 (ddd,
J ) 12.6, 8.5, 4.0 Hz, 1H, H-6), 2.85 (m, 1H, H-6), 4.00 (dd, J )
11.5, 8.5 Hz, 1H, H-2′), 4.07 (dd, J ) 11.5, 5.4 Hz, 1H, H-2′),
5.85 (dd, J ) 8.5, 5.4 Hz, 1H, H-1′), 7.21-7.32 (m, 10H, ArH);
13C NMR (75.4 MHz) δ 8.9 (CH3CH2), 20.2 (C-5), 28.2 (C-4),
33.3 (CH3CH2), 44.3 (C-6), 45.2 (CH2Ph), 47.6 (C-3), 58.9 (C-1′),
61.6 (C-2′), 126.3 (CH), 127.5 (CH), 127.8 (2CH), 127.9 (2CH),
128.5 (2CH), 130.4 (2CH), 136.9 (C i), 138.3 (C i), 175.8 (NCO);
mp 115-116 °C (EtOAc); [R]2D2 -107 (c 0.5, MeOH); MS-EI m/z
338 [(M+ + 1), 2), 91 (100), 228 (52), 278 (30), 306 (72). Anal.
calcd for C22H27NO2: C, 78.30; H, 8.06; N, 4.15. Found: C, 77.95;
H, 7.99; N, 4.02.
(S)-3-Benzyl-3-ethyl-2-piperidone (13). Into a three-necked,
100 mL round-bottomed flask equipped with a coldfinger condenser
charged with dry ice-acetone was condensed NH3 (15 mL) at
-78 °C. The temperature was raised to -33 °C, and a solution of
lactam 12 (68 mg, 0.20 mmol) in THF (2 mL) was added. Then
sodium metal was added in small portions until a blue color
persisted, and the reaction was stirred at the same temperature for
90 s. The reaction was quenched by addition of solid NH4Cl until
the blue color disappeared, and the mixture was stirred at room
temperature for an additional 4 h. The resulting residue was diluted
with water and extracted with Et2O. The combined organic extracts
were dried, filtered, and concentrated, and the crude residue was
chromatographed (1:1 EtOAc-hexane) to afford piperidone 13
(39 mg, 89%): IR (film) 1656 cm-1; 1H NMR (300 MHz) δ 0.93
(t, J ) 7.5 Hz, 3H, CH3CH2), 1.45 (m, 1H, CH3CH2), 1.60-1.70
(m, 4H, H-4, H-5), 1.89 (m, 1H, CH3CH2), 2.25 and 2.58 (2d, J )
13.2 Hz, 2H, CH2Ph), 3.04 (m. 1H, H-6), 3.15 (m, 1H, H-6), 5.18
(br s, 1H, NH), 7.19-7.26 (m, 5H, ArH); 13C NMR (75.4 MHz) δ
8.7 (CH3CH2), 19.8 (C-5), 28.0 (C-4), 29.7 (C-3), 32.1 (CH3CH2),
42.6 (C-6), 44.2 (CH2Ph), 46.7 (C-3), 126.3 (CH), 128.0 (2CH),
130.5 (2CH), 138.2 (C i), 176.5 (NCO); [R]2D2 -23 (c 0.67,
MeOH); MS-EI m/z 217 (M+, 18), 55 (34), 91 (73), 188 (100);
HRMS calcd for C14H19NO, 217.1466; found, 217.1467. Anal. calcd
for C14H19NO‚1/4H2O: C, 75.81; H, 8.86; N, 6.31. Found: C, 75.87;
H, 8.63; N, 6.21.
(CH2d), 134.5 (CH2CHd), 176.8 (NCO); [R]22 + 11 (c 0.5,
D
MeOH); MS-EI m/z 167 (M+, 5), 55 (100), 138 (95); HRMS calcd
for C10H17NO, 167.1310; found, 167.1312.
[(3S,6R,8aR)-6-Ethyl-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-
5H-oxazolo[3, 2-a]pyridine-6-acetic Acid (16). A suspension of
the lactam ent-11a (4.28 g, 15.02 mmol), NaIO4 (12.8 g, 60.0
mmol), and RuCl3 (150 mg, 0.72 mmol) in a mixture of CCl4
(64 mL), acetonitrile (64 mL), and water (93 mL) was vigorously
stirred at room temperature for 24 h. The mixture was extracted
with CH2Cl2, and the combined organic extracts were dried and
concentrated. The resulting dark residue was digested with Et2O.
The solution was filtered through Celite and concentrated to yield
16 (4.27 g, 94%): IR (film) 1650, 1730 cm-1; 1H NMR (300 MHz)
δ 0.86 (t, J ) 7.5 Hz, 3H, CH3CH2), 1.65-1.82 (m, 4H, CH3CH2,
H-8, H-7), 1.90 (dd, J ) 10.5, 3.6 Hz, 1H, H-7), 2.30 (m, 1H,
H-8), 2.65 (d, J ) 15.6 Hz, 1H, CH2COO), 2.75 (d, J ) 15.6 Hz,
1H, CH2COO), 3.76 (t, J ) 8.1 Hz, 1H, H-2), 4.51 (dd, J ) 9.3,
8.4 Hz, 1H, H-2), 5.06 (dd, J ) 8.4, 4.5 Hz, 1H, H-8a), 5.22 (t,
J ) 8.1 Hz, 1H, H-3), 7.23-7.38 (m, 5H, ArH); 13C NMR
(75.4 MHz) δ 8.3 (CH3CH2), 25.6 (C-8), 26.7 (C-7), 31.5 (CH3CH2),
42.7 (CH2COO), 43.7 (C-6), 59.0 (C-3), 72.7 (C-2), 88.8 (C-8a),
126.0 (2CH), 127.6 (CH), 128.6 (2CH), 138.7 (C i), 173.7 (NCO),
174.4 (COO); mp 94-100 °C (CH2Cl2); [R]22 +95 (c 0.87,
MeOH); MS-EI m/z 303 (M+, 46), 104 (100), 120D(61). Anal. calcd
for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.16; H,
6.98; N, 4.49.
(3R)-3-Ethyl-3-(2-hydroxyethyl)-1-[(1S)-2-hydroxy-1-phenyl-
ethyl]piperidine (17). LiAlH4 (3.0 g, 80.86 mmol) was added to a
solution of 16 (2.45 g, 8.09 mmol) in THF (150 mL), and the
mixture was stirred at room temperature for 28 h. The reaction
was quenched by the addition of cool brine, and the resulting
extracts were dried and concentrated to give 17 (1.95 g, 88%): IR
(film) 2932, 3376 cm-1 1H NMR (300 MHz) δ 0.81 (t, J )
;
7.5 Hz, 3H, CH3CH2), 1.36 (m, 1H, CH3CH2), 1.24-1.40 (m, 3H,
CH3CH2, H-4), 1.52-1.78 (m, 4H, CH2CH2OH, H-5), 2.02 (dddm,
J ) 9.5, 9.5, 2.0 Hz, 1H, H-6), 2.10 (d, J ) 11.0 Hz, 1H, CH2-
OH), 2.41 (d, J ) 11.0 Hz, 1H, CH2OH), 2.66 (ddd, J ) 9.5, 4.5,
4.5 Hz, 1H, H-6), 3.02 (br s, 1H, OH), 3.55 (dd, J ) 8.5, 5.0 Hz,
1H, H-1′), 3.68 (ddd ap, J ) 7.0, 7.0, 1.2 Hz, 2H, H-2), 3.74 (dd,
J ) 11.0, 5.0 Hz, 1H, H-2′), 3.97 (dd, J ) 11.0, 8.5 Hz, 1H, H-2′),
7.17-7.30 (m, 2H, ArH), 7.31-7.35 (m, 3H, ArH); 13C NMR
(75.4 MHz) δ 7.3 (CH3CH2), 22.2 (C-5), 31.1 (C-4), 33.7 (CH3CH2),
35.6 (C-3), 38.3 (CH2CH2OH), 50.0 (C-6), 58.7 (C-2), 60.1 (CH2-
OH), 61.2 (C-2′), 70.8 (C-1′), 127.5 (CH), 128.0 (2CH), 128.7
(2CH), 136.3 (C i); [R]2D2 +18 (c 1.15, MeOH); MS-EI m/z 278
[(M+ + 1), 100], 246 (47), 260 (34); HRMS calcd for C17H27NO2,
277.2041; found, 277.2032. Anal. calcd for C17H27NO2‚1/3H2O: C,
72.06; H, 9.81; N, 4.94. Found: C, 71.75; H, 9.64; N, 4.81.
(3R)-3-Allyl-3-ethyl-1-[(1S)-2-hydroxy-1-phenylethyl]-2-pip-
eridone (14). Following the procedure described for the preparation
of 12, triethylsilane (0.17 mL, 1.05 mmol), TiCl4 (0.22 mL, 1.58
mmol), and a solution of lactam ent-11a (300 mg, 1.05 mmol) in
CH2Cl2 (18 mL) afforded piperidone 14 (259 mg, 86%) after
column chromatography (1:1 EtOAc-hexane): IR (film)
1608 cm-1; 1H NMR (300 MHz) δ 0.90 (t, J ) 7.5 Hz, 3H, CH3-
CH2), 1.47 (m, 1H, CH3CH2), 1.63-1.73 (m, 4H, H-4, H-5), 1.86
(m, 1H, CH3CH2), 2.19 (dd, J ) 13.5, 8.0 Hz, 1H, CH2CHd), 2.55
(ddt, J ) 13.5, 8.0, 1.2 Hz, 1H, CH2CHd), 2.90 (m, 1H, H-6),
3.15 (m, 1H, H-6), 3.59 (br s, 1H, OH), 4.03 (m, 1H, H-2′), 4.14
(m, 1H, H-2′), 5.04-5.10 (m, 2H, CH2d), 5.76 (m, 1H, CH2CHd
), 5.91 (dd, J ) 9.5, 5.0 Hz, 1H, H-1′), 7.21-7.34 (m, 5H, ArH);
13C NMR (75.4 MHz) δ 8.9 (CH3CH2), 20.3 (C-5), 28.7 (C-4),
32.0 (CH3CH2), 43.9 (C-6), 44.1 (CH2CHd), 46.0 (C-3), 58.4 (C-
1′), 61.5 (C-2′), 117.8 (CH2d), 127.4 (CH), 127.6 (2CH), 128.4
(2CH), 134.6 (CH2CHd), 137.2 (C i), 176.0 (NCO); mp 79-80
(R)-1-(tert-Butoxycarbonyl)-3-ethyl-3-(2-hydroxyethyl)piperi-
dine (18). A solution of 17 (2.75 g, 9.93 mmol) and di-tert-
butyldicarbonate (4.3 g, 19.86 mmol) in EtOH (400 mL) containing
10% Pd(OH)2/C was hydrogenated at room temperature and
atmospheric pressure for 65 h. The catalyst was removed by
filtration, the solvent was evaporated, and the resulting residue was
chromatographed (1:4 EtOAc-hexane) to give 18 (1.75 g, 69%):
°C (Et2O-hexane); [R]22 +148 (c 0.5, MeOH); MS-EI m/z 287
D
(M+, 3), 91 (82), 256 (100). Anal. calcd for C18H25NO2: C, 75.23;
H, 8.77; N, 4.87. Found: C, 74.99; H, 8.89; N, 4.89.
1
IR (film) 1692, 3444 cm-1; H NMR (300 MHz) δ 0.84 (t, J )
7.5 Hz, 3H, CH2CH3), 1.25 (m, 1H), 1.30-1.66 (m, 13H), 3.65
J. Org. Chem, Vol. 72, No. 12, 2007 4437

Amat et al.
(m, 2H, CH2OH); 13C NMR (75.4 MHz) δ 7.2 (CH2CH3), 21.0
(CH2), 27.1 (CH2), 28.2 [C(CH3)3], 34.2 (CH2), 35.1 (C-3), 36.4
(CH2), 44.1 (CH2), 52.3 (C-2), 58.0 (CH2OH), 79.1 [C(CH3)3], 154.8
(NCO); [R]2D2 +73 (c 1.07, MeOH); MS-EI m/z 257 (M, 1), 57
(100), 113 (14), 156 (15); HRMS calcd for C14H27NO3, 257.1991;
found, 257.1979. Anal. calcd for C14H27NO3‚1/4H2O: C, 64.21 H,
10.58; N, 5.35. Found: C, 64.48; H, 10.36; N, 5.25.
3.50 (d, J ) 13.6 Hz), 3.66 (m), 3.80 (d, J ) 17.2 Hz), 3.86-3.93
(m)] (6H), 6.93-7.31 (m, 4H), 7.60 (d, J ) 8 Hz), [8.35 (d, J )
17.6 Hz) and 8.46 (br s)] (1H); 13C NMR (75.4 MHz) δ Minor
rotamer 7.3 (CH3), 20.6 (CH2), 27.2 (CH2), 30.8 (CH2), 33.4 (CH2),
36.3 (C), 38.2 (CH2), 42.5 (CH2), 50.8 (CH2), 108.0 (C), 111.3
(CH), 118.3 (CH), 119.2 (CH), 121.7 (CH), 122.8 (CH), 126.6 (C),
136.1 (C), 171.8 (C), 174.0 (C); Major rotamer 7.3 (CH3), 21.7
(CH2), 29.6 (CH2), 31.2 (CH2), 33.6 (CH2), 36.6 (C), 38.9 (CH2),
47.3 (CH2), 54.4 (CH2), 108.4 (C), 111.4 (CH), 118.6 (CH), 119.3
(CH), 122.0 (CH), 123.2 (CH), 127.0 (C), 136.1 (C), 172.0 (C),
176.0 (C); MS-EI m/z 328 [(M+, -23), 7], 77 (1), 130 (100); HRMS
calcd for C19H24N2NaO3, 351.1685; found, 351.1679.
Methyl (R)-3-Ethylpiperidine-3-acetate (19). Piridinium dichro-
mate (2.60 g, 7.00 mmol) was added to a solution of 18 (300 mg,
1.17 mmol) in DMF (12 mL), and the mixture was stirred at room
temperature for 24 h. Cooled 1 N aqueous HCl was added, and the
mixture was extracted with Et2O. The combined organic extracts
were washed with saturated aqueous NaCl, dried, and concentrated
to give crude (3R)-1-(tert-butoxycarbonyl)-3-ethylpiperidine-3-
acetic acid (289 mg, 92%), which was used in the next reaction
without further purification: 1H NMR (300 MHz) δ 0.86 (t, J )
7.5 Hz, 3H), 1.42-1.51 (m, 5H), 1.47 (br s, 9H), 2.07 (d ap, J )
10.5 Hz, 2H), 3.11-3.55 (m, 2H), 4.09 (t, J ) 7.5 Hz, 2H); 13C
NMR (100 MHz) δ 7.4 (CH3), 20.1 (CH2), 27.6 (C), 28.2 (CH3),
33.7 (CH2), 36.1 (CH2), 38.5 (CH2), 43.6 (CH2), 52.1 (CH2), 79.5
(C), 155.1 (C), 177.0 (C). A solution of the above acid (134 mg,
0.49 mmol) and chlorotrimethylsilane (0.14 mL, 1.09 mmol) in
MeOH (2 mL) was stirred at room temperature for 24 h. The solvent
was evaporated, and the residue was dissolved in Et2O and washed
with 5% aqueous NaHCO3 and brine. The combined organic
extracts were dried and concentrated to afford 19 (70 mg, 77%):
(-)-5,16-Dioxoquebrachamine (22). A stirred suspension of 21
(301 mg, 0.92 mmol) in PPA (30 g) was heated at 90 °C for 30
min. The mixture was poured into ice and extracted with CH2Cl2.
The dried combined organic extracts were concentrated to afford
22 (243 mg, 85%): IR (KBr) 1633, 3440 cm-1 1H NMR
;
(300 MHz) δ: 1.00 (t, J ) 7.5 Hz, 3H, H-18), 1.20 (m, 1H, H-19),
1.33 (m, 1H, H-19), 1.46 (dd, J ) 13.0, 8.4 Hz, 1H, H-15), 1.55
(m, 1H, H-14), 1.73-1.85 (m, 2H, H-14 and H-15), 2.34 (dd, J )
12.6, 1.5 Hz, 1H, H-17), 2.61 (ddd, J ) 13.0, 13.0, 3.8 Hz, 1H,
H-3), 2.98 (dd, J ) 13.5, 1.2 Hz, 1H, H-21), 3.30 (d, J ) 12.6 Hz,
1H, H-17), 3.89 (d, J ) 13.5 Hz, 1H, H-21), 4.04 (d, J ) 16.8 Hz,
1H, H-6), 4.30 (d, J ) 16.8 Hz, 1H, H-6), 4.69 (ddd, J ) 13.0,
3.0, 1.5 Hz, 1H, H-3), 7.13 (m, 1H, H-10), 7.34 (dd, J ) 3.0,
0.9 Hz, 2H, H-9, H-11), 7.35 (d, J ) 0.9 Hz, 1H, H-12), 7.63 (d,
J ) 8.0 Hz, H-9), 9.33 (br s, 1H, NH); 13C NMR (75.4 MHz) δ
7.1 (C-18), 19.6 (C-14), 30.4 (C-19), 34.9 (C-6), 35.4 (C-15), 40.3
(C-20), 44.1 (C-3), 44.3 (C-17), 55.2 (C-21), 111.7 (C-12), 115.2
(C-7), 120.5 (C-10), 121.0 (C-9), 126.8 (C-11), 128.7 (C-8), 132.4
(C-13), 135.4 (C-2), 170.1 (NCO), 192.8 (CO); mp 140-144 °C
(CH2Cl2); [R]22 -365 (c 0.55, MeOH); MS-EI m/z 310 (M+, 100),
129 (91), 14D3 (91), 226 (36); HRMS calcd for C19H22N2O2,
310.1681; found, 310.1676. Anal. calcd for C19H22N2O2‚1/3H2O:
C, 72.14; H, 7.22; N, 8.86. Found: C, 71.88; H, 7.12; N, 8.37.
1
IR (film) 1734, 2929 cm-1; H NMR (400 MHz) δ 0.94 (t, J )
7.5 Hz, 3H), 1.49 (q, J ) 7.5 Hz, 2H), 1.49 (m, 1H), 1.58-1.65
(m, 3H), 2.02 (br s, 1H), 2.43 and 2.50 (2d, J ) 14.0 Hz, 2H),
2.60 and 2.82 (2d, J ) 13.0 Hz, 2H), 2.77 (m, 1H), 2.92 (m, 1H),
3.73 (s, 3H); 13C H NMR (100 MHz) δ 7.1 (CH3), 22.2 (CH2),
28.7 (CH2), 33.9 (CH2), 35.4 (C), 38.8 (CH2), 46.7 (CH2), 51.0
(CH3), 55.0 (CH2), 172.6 (C); [R]22 -37 (c 1.0 MeOH); MS-EI
D
m/z 184 [(M+ - 1), 9], 58 (8), 111 (100), 154 (60); HRMS calcd
for C10H19NO2, 185.1416; found, 185.1411.
(2R,11bS)-2-Allyl-2-ethyl-2,3,5,6,11,11b-hexahydro-1H-in-
dolizino[8,7-b]indole (23). A solution of 22 (100 mg, 0.32 mmol)
in dioxane (10 mL) was added to a suspension of LiAlH4
(159 mg, 4.20 mmol) in dioxane (20 mL), and the mixture was
heated at reflux for 3 h. The mixture was cooled (0 °C), and water
was added until the suspension turned colorless. The mixture was
filtered, the filtrate was concentrated, and the resulting residue was
chromatographed (1:4 EtOAc-hexane to 9:1 EtOAc-hexane) to
give 23 (59 mg, 66%): 1H NMR (400 MHz) δ 0.74 (t, J ) 7.5 Hz,
3H, CH3CH2), 1.22-1.28 (m, 2H, CH3CH2), 1.61 (dd, J ) 12.8,
5.6 Hz, 1H, H-1), 2.11 (dd, J ) 12.8, 8.0 Hz, 1H, H-1), 2.23-2.30
(m, 2H, H-1′), 2.60 (m, 1H, H-5), 2.64 (d, J ) 9.2 Hz, 1H, H-3),
2.73 (d, J ) 9.2 Hz, 1H, H-3), 2.90 (m, 1H, H-6), 2.97 (ddd, J )
11.2, 11.2, 4.0 Hz, 1H, H-5), 3.25 (m, 1H, H-6), 4.21 (t ap, 1H,
H-11), 5.07-5.13 (m, 2H, CH2)), 5.80 (m, 1H, CH2dCH), 7.05-
7.12 (m, 2H, H-7 and H-8), 7.28 (d, J ) 7.2 Hz, 1H, H-10), 7.46
(d, J ) 7.6 Hz, 1H, H-9), 8.0 (br s, 1H, NH); 13C NMR (100.6
MHz) δ 8.9 (CH3CH2), 17.6 (C-5), 31.6 (CH3CH2), 41.2 (C-1),
42.1 (CH2CHd), 44.6 (C-2), 46.0 (C-6), 56.9 (C-11), 60.0 (C-3),
107.3 (C-6a), 110.7 (C-10), 117.2 (CH2d), 118.0 (C-9), 119.2 (C-
7), 121.2 (C-8), 127.4 (C-6b), 135.4 (CH2CHd), 135.7 (C), 136.0
(C); MS-EI m/z 279 [(M+ - 1), 74], 156 (32), 184 (30), 208 (36),
237 (100); [R]D22 -14 (c 1.05, CHCl3); HRMS calcd for C19H24N2,
(M+ + 1) 281.1939; found, 281.2012.
Methyl (R)-3-Ethyl-1-(3-indolylacetyl)piperidine-3-acetate (20).
The mixed anhydride of pivalic acid and indole-3-acetic acid11
(4.30 g, 24.5 mmol) was added to a suspension of piperidine 19
(1.26 g, 6.84 mmol) in THF (10 mL), and the mixture was stirred
at room temperature for 3 days. The solvent was evaporated, and
the resulting residue was chromatographed (3:7 EtOAc-hexane to
EtOAc) to give 20 (2.02 g, 86%): IR (film) 1625, 1729, 3406 cm-1
;
1H NMR (300 MHz) δ 0.97 and 1.02 (t, J ) 7.5 Hz, 3H), 1.45-
1.56 (m, 4H), 1.68-1.72 (m, 2H), 2.35-2.45 (m, 2H), 3.30 and
3.52 (2d, J ) 13.0 Hz, 2H), 3.50 (m, 1H), 3.74 (dd, J ) 12.6,
10.2 Hz, 1H), 3.78 and 3.79 (s, 3H, OCH3), 3.85-4.13 (m, 2H),
7.08 (d, J ) 15.3 Hz, 1H), 7.23-7.34 (m, 2H), 7.44 (d, J )
8.1 Hz, 1H), 7.80 (t, J ) 7.5 Hz, 1H), 9.11 (br s, 1H); 13C NMR
(75.4 MHz) δ Minor rotamer 7.3 (CH3), 20.6 (C-5), 27.6 (CH2),
30.7 (CH2), 33.1 (CH2), 36.4 (C-3), 38.0 (CH2), 42.2 (C-6), 50.0
(C-2), 51.2 (CH3), 108.5 (CH), 111.2 (C), 118.4 (CH), 119.0 (CH),
121.5 (CH), 122.6 (CH), 126.7 (C), 136.1 (C), 170.5 (C), 172.0
(C); Major rotamer:7.5 (CH3), 21.4 (C-5), 28.0 (CH2), 31.5 (CH2),
33.5 (CH2), 36.5 (C-3), 38.5 (CH2), 46.7 (C-6), 51.1 (CH3), 54.3
(C-2), 108.6 (CH), 111.2 (C), 118.5 (CH), 119.0 (CH), 121.6 (CH),
122.8 (CH), 126.9 (C), 136.1 (C), 171.1 (C), 172.1 (C); MS-EI
m/z 342 [(M+ -23), 6], 130 (100), 212 (1); HRMS calcd for
C20H26N2NaO3, 365.1841; found, 365.1836.
(R)-3-Ethyl-1-(3-indolylacetyl)piperidine-3-acetic Acid (21).
A solution of 20 (150 mg, 0.44 mmol) in MeOH (4 mL) and 5%
aqueous NaOH (4.8 mL) was heated at reflux temperature for 2.5
h. The solvent was evaporated, and the resulting residue was
dissolved in 2 N aqueous HCl and extracted with CH2Cl2. The
combined organic extracts were dried and concentrated to give 21
(106 mg, 74%): IR (film) 1624, 1702, 3410 cm-1; 1H NMR (300
MHz) δ 0.73 and 1.13 (t, J ) 7.5 Hz, 3H), 1.22-1.53 (m, 6H),
2.08 and 2.21 (2d, J ) 13.6 Hz, 2H), [2.93 (d, J ) 13.6 Hz), 3.11
(ddd, J ) 13.2, 10.0, 3.2 Hz), 3.20 (d, J ) 13.6 Hz), 3.55 (m),
(-)-16-Hydroxy-5-oxoquebrachamine (24). NaBH4 (183 mg,
4.84 mmol) was added to a solution of 22 (150 mg, 0.48 mmol) in
MeOH (5 mL), and the suspension was stirred at room temperature
for 1.5 h. The solvent was evaporated, water was added to the
resulting residue, and the mixture was extracted with CH2Cl2. The
combined organic extracts were dried, filtered, and concentrated
to yield 24 (130 mg, 86%): IR (film) 1654, 3207 cm-1; 1H NMR
(400 MHz) δ 0.60 (t, J ) 7.5 Hz, 3H, H-18), 0.93-1.02 (m, 2H,
H-19), 1.31 (m, 1H, H-15), 1.53 (m, 1H, H-14), 1.64 (m, 1H, H-15),
4438 J. Org. Chem., Vol. 72, No. 12, 2007

Synthesis of 3,3-Disubstituted Piperidine DeriVatiVes
1.73 (m, 1H, H-14), 1.80 (d, J ) 14.0 Hz, 1H, H-17), 1.88 (dd,
J ) 14.0, 10.0 Hz, 1H, H-17), 2.52 (td, J ) 12.6, 3.2 Hz, 1H,
H-3), 2.60 (d, J ) 13.6 Hz, 1H, H-21), 3.54 (d, J ) 16.0 Hz, 1H,
H-6), 3.68 (d, J ) 16.0 Hz, 1H, H-6), 3.77 (d, J ) 13.6 Hz, 1H,
H-21), 4.62 (dm, J ) 12.6 Hz, 1H, H-3), 5.33 (d, J ) 10.0 Hz,
1H, H-16), 6.98 (t, J ) 7.2 Hz, 1H, H-10), 7.05-7.16 (m, 2H,
suspension turned colorless. Then, the mixture was filtrated through
Celite, the filtrate was evaporated, and the resulting residue was
chromatographed (1:4 EtOAc-hexane to EtOAc) to give (-)-
quebrachamine (44 mg, 30%) and indoloindolizidine 23 (79 mg,
52%). (-)-Quebrachamine: 1H NMR (500 MHz) δ 0.84 (t, J )
7.5 Hz, 3H, H-18), 1.01-1.11 (m, 2H, H-17, H-19), 1.13-1.26
(m, 3H, H-14, H-17, H-19), 1.48 (d, J ) 12.0 Hz, 1H, H-21), 1.50-
1.60 (m, 2H, H-14, H-15), 1.90 (ddd, J ) 14.0, 7.0, 1.5 Hz, 1H,
H-15), 2.21 (td, J ) 11.5, 3.5 Hz, 1H, H-3), 2.30 (td, J ) 11.5,
4.5 Hz, 1H, H-5), 2.40 (ddd, J ) 11.5, 4.5, 3.0 Hz, 1H, H-5), 2.43
(m, 1H, H-3), 2.63 (ddd, J ) 15.0, 7.5, 1.5 Hz, 1H, H-6), 2.70
(ddd, J ) 15.0, 10.0, 1.5 Hz, 1H, H-6), 2.80 (ddd, J ) 14.5, 4.5,
3.0 Hz, 1H, H-16), 2.90 (ddd, J ) 14.5, 12.0, 5.0 Hz, 1H, H-16),
3.25 (dm, J ) 12.0 Hz, 1H, H-21), 7.05 (m, 2H, H-10, H-11), 7.25
(m, 1H, H-12), 7.43 (m, 1H, H-9), 7.68 (br s, 1H, NH); 13C NMR
(100 MHz) δ 7.8 (C-18), 22.0 (C-6), 22.4 (C-16), 22.7 (C-14), 32.0
(C-19), 33.4 (C-15), 34.7 (C-17), 37.0 (C-20), 53.2 (C-5), 55.0 (C-
3), 56.6 (C-21), 108.7 (C-7), 110.0 (C-12), 117.4 (C-9), 118.6 (C-
10), 120.2 (C-11), 129.0 (C-8), 134.8 (C-13), 140.0 (C-2); [R]D22
-99 (c 0.27, CHCl3) (lit.17 [R]D -100 (CHCl3)).
H-9, H-11), 7.23 (d, J ) 8.0 Hz, 1H, H-12), 8.90 (s, 1H, NH); 13
C
NMR (100.6 MHz) δ 7.0 (C-18), 20.5 (C-14), 33.2 (C-6), 34.7
(C-20), 35.6 (C-19), 38.5 (C-15), 42.5 (C-3), 47.2 (C-17), 51.9 (C-
21), 63.9 (C-16), 103.0 (C-7), 110.8 (C-12), 117.8 (C-9), 119.2
(C-10), 121.8 (C-11), 127.8 (C-8), 134.8 (C-13), 138.2 (C-2), 169.9
(NCO); MS-EI m/z 312 (M+, 100), 130 (69), 156 (47), 296 (37);
HRMS calcd for C19H24N2O2, (M+ + 1) 313.1910; found, 313.1910.
(-)-16-Hydroxyquebrachamine (25). A solution of 22 (80 mg,
0.26 mmol) in THF (3 mL) was added to a suspension of LiAlH4
(137 mg, 3.61 mmol) in THF (5 mL), and the mixture was stirred
at room temperature for 5 h. After the mixture was cooled (0 °C),
and water was added until the suspension turned colorless. After
filtration of the mixture, the filtrate was concentrated to give 25
(67 mg, 87%): 1H NMR (400 MHz) δ 0.66 (t, J ) 7.5 Hz, 3H,
H-18), 0.77-0.85 (m, 2H, H-19), 0.96 (m, 1H, H-15), 1.52 (m,
1H, H-14), 1.61 (m, 1H, H-15), 1.70-1.93 (2d, J ) 12 Hz, H-21),
1.81-1.98 (m, 2H, H-14, H-17), 2.14 (ddd, J ) 13.0, 13.0, 1.2
Hz, 1H, H-5), 2.65 (m, 1H, H-17), 2.41 (m, 1H, H-3), 2.56 (dm,
J ) 13.0 Hz, 1H, H-5), 2.65 (ddd, J ) 13.0, 13.0, 4.0 Hz, 1H,
H-6), 2.80 (dm, J ) 13.0 Hz, 1H, H-6), 2.91 (m, 1H, H-3), 4.10
(br s, 1H, OH), 6.23 (dd, J ) 11.2, 2.4 Hz, 1H, H-16), 7.02-7.15
(m, 2H, H-9, H-10), 7.31 (d, J ) 8.0 Hz, 1H, H-12), 7.48 (d, J )
8.0 Hz, 1H, H-11), 9.10 (br s 1H, NH); 13C NMR (100.6 MHz) δ
7.4 (C-18), 24.0 (C-14), 26.1 (C-6), 35.7 (C-20), 35.8 (CH3CH2),
38.2 (C-15), 47.2 (C-17), 54.0 (C-3 and C-5), 66.1 (C-16), 109.6
(C-7), 110.8 (C-12), 118.2 (C-11), 118.6 (C-9), 121.2 (C-10), 127.7
(C-8), 135.7 (C-13), 140 (C-2).
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. Thanks are also
due to the Ministry of Science and Technology (Spain) for a
fellowship to O.L.
Supporting Information Available: Table with 13C NMR
1
assignments for lactams 8-11, copies of the H and 13C NMR
spectra of compounds 8-25 and (-)-quebrachamine, and X-ray
crystallographic data for compounds 9a, 10a, 12, and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(-)-Quebrachamine. LiAlH4 (627 mg, 16.5 mmol) was added
to a solution of 22 (170 mg, 0.55 mmol) in N-methylmorpholine
(NMM) (40 mL), and the mixture was heated at reflux for 7 h.
After the mixture (0 °C) cooled, water was added until the
JO070397Q
J. Org. Chem, Vol. 72, No. 12, 2007 4439