An enantioselective synthetic route to cis-2,4-disubstituted and 2,4-bridged piperidines

Article abstract of DOI:10.1021/jo801172b

(Chemical Equation Presented) A synthetic route to enantiopure cis-2,4-disubstituted and 2,4-bridged piperidines is reported, the key step being a stereoselective conjugate addition of an organocuprate to a phenylglycinol-derived unsaturated lactam bearing a substituent at the 8a-position.

Full text of DOI:10.1021/jo801172b

SCHEME 1. Synthetic Strategy
An Enantioselective Synthetic Route to
cis-2,4-Disubstituted and 2,4-Bridged Piperidines
Mercedes Amat,* Maria Pe´rez, Annamaria T. Minaglia, and
Joan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, and
Institute of Biomedicine (IBUB), UniVersity of Barcelona,
08028 Barcelona, Spain
amat@ub.edu; joanbosch@ub.edu
ReceiVed May 30, 2008
derivatives, including the antidepressant drug (-)-paroxetine,3
cis-fused perhydrocycloalka[c]pyridines,4 and the indole alkaloid
(+)-uleine.5
To further expand the potential of these lactams, we decided
to explore a synthetic route to enantiopure 2,4-bridged piperidine
derivatives, as outlined in Scheme 1. The key step would be
the stereocontrolled introduction of an appropriate unsaturated
chain at the 4-position of the piperidine ring by conjugated
addition of an organocuprate to an unsaturated lactam A bearing
an unsaturated substituent at the 2-position. A subsequent ring-
closing metathesis from the resulting cis-2,4-disubstituted pi-
peridine derivative would lead to the target bridged azabicyclo.
A synthetic route to enantiopure cis-2,4-disubstituted and 2,4-
bridged piperidines is reported, the key step being a
stereoselective conjugate addition of an organocuprate to a
phenylglycinol-derived unsaturated lactam bearing a sub-
stituent at the 8a-position.
Aminoalcohol-derived oxazolopiperidone lactams are excep-
tionally versatile building blocks for the enantioselective
construction of structurally diverse piperidine-containing natural
products and bioactive compounds.1 These lactams allow the
substituents to be introduced at the different ring positions in a
regio- and stereocontrolled manner, providing easy access to
enantiopure polysubstituted piperidines bearing virtually any
type of substitution pattern.2 In particular, the conjugate addition
to R,ꢀ-unsaturated oxazolopiperidone lactams allows the ste-
reocontrolled formation of a C-C bond at the piperidine
4-position and has successfully been used to generate either cis
or trans 3,4-disubstituted enantiopure piperidine-containing
FIGURE 1. Stereoelectronic control in the conjugate addition.
It has previously been established6 that the conjugate
addition of organocuprates to unsaturated oxazolopiperidone
lactams B (when R ) H) is highly stereoselective as a
consequence of the conformational rigidity of the bicyclic
system. The nucleophilic attack occurs under stereoelectronic
control7 on the exo face, axial to the electrophilic carbon of
the conjugate double bond (Figure 1).8 However, it could be
expected9 a priori that the presence of a substituent at the
angular position (R * H) could alter the stereochemical
(1) For reviews, 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. Eur. J. 2006, 12, 8198–8207. For more recent
work, see: (e) Amat, M.; Santo, M. M. M.; Go´mez, A. M.; Jokic, D.; Molins,
E.; Bosch, J. Org. Lett. 2007, 9, 2907-2910. (f) Allin, S. M.; Duffy, L. J.; Page,
P. C. B.; Mckee, V.; McKenzie, M. J. Tetrahedron Lett. 2007, 48, 4711–4714.
(g) Amat, M.; Griera, R.; Fabregat, R.; Molins, E.; Bosch, J. Angew. Chem.,
Int. Ed. 2008, 47, 3348–3351.
(2) For recent reviews on the synthesis of piperidines, see: (a) Laschat, S.;
Dickner, T. Synthesis 2000, 13, 1781–1813. (b) Weintraub, P. M.; Sabol, J. S.;
Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989. (c) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701–1729. For a recent review on the synthesis
of pharmaceutically active compounds containing a disubstituted piperidine
framework, see: (d) Ka¨llstro¨m, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601–
635.
(3) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez, M.; Llor, N.; Molins,
E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074–3084.
(4) Amat, M.; Pe´rez, M.; Minaglia, A. T.; Peretto, B.; Bosch, J. Tetrahedron
2007, 63, 5839–5848.
(5) Amat, M.; Pe´rez, M.; Llor, N.; Escolano, C.; Luque, F. J.; Molins, E.;
Bosch, J. J. Org. Chem. 2004, 69, 8681–8693.
(6) (a) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins, E. Org.
Lett. 2001, 3, 611–614. (b) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J. Org. Lett.
2002, 4, 2787–2790. See also refs 3 and 5.
(7) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: Oxford, 1983, p 221. (b) Perlmutter, P. Conjugate Addition
Reactions in Organic Synthesis; Pergamon Press: Oxford, 1992, p 25.
(8) For recent related examples, see: (a) Brewster, A. G.; Broady, S.; Hughes,
M.; Moloney, M. G.; Woods, G. A. Org. Biomol. Chem. 2004, 2, 1800–1810.
(b) Allin, S. M.; Khera, J. S.; Thomas, C. I.; Witherington, J.; Doyle, K.;
Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2006, 47, 1961–1964.
6920 J. Org. Chem. 2008, 73, 6920–6923
10.1021/jo801172b CCC: $40.75 2008 American Chemical Society
Published on Web 07/31/2008

TABLE 1. Conjugate Addition Reactions from Unsaturated
Lactams 3
SCHEME 2. Conjugate Addition to 8a-Substituted
Unsaturated Oxazolopiperidone Lactams
unsaturated lactam
product
yield (%)a
R1/R2 cis:trans ratiob
3a
3a
3a
3b
3b
3b
4a
5a
6a
4b
5b
6b
62
70
74
61
91
72
93:7
78:22
85:16
94:6
85:15
92:8
a Overall yield from selenides 2. b Calculated by NMR after
debenzyloxycarbonylation
SCHEME 3. Synthesis of Enantiopure cis-2,4-Disubstituted
Piperidines
outcome of the conjugate addition as a consequence of the
1,3-syn diaxial interactions between this substituent and
the incoming nucleophile. For this reason, to evaluate the
viability of our synthetic plan, we decided to carry out a
preliminary study on the stereoselectivity of similar conjugate
addition reactions from the model, more easily accessible,
unsaturated lactams 3a and 3b. These lactams were pre-
pared,10 via the corresponding selenides 2 (diastereomeric
mixtures), from the known lactams 1a and 1b11 (Scheme 2).
The easily removable benzyloxy-carbonyl electron-withdraw-
ing group was used to enhance the reactivity of the conjugated
system.12
The conjugate addition of a vinyl group to lactam 3a was
satisfactorily accomplished (62% overall yield from 2a) with
vinylmagnesium bromide in the presence of LiCl, CuI, and
trimethylsilyl chloride13 in THF. The high exo facial stereose-
lectivity of the conjugate addition was confirmed after removal
of the benzyloxycarbonyl substituent present in 4a by hydro-
genolysis, which took place with simultaneous hydrogenation
of the vinyl group, followed by thermal decarboxylation. Under
these conditions, a 93:7 mixture (calculated by NMR) of lactam
7a and its C-7 epimer was obtained (see Table 1).
Similar conjugate additions of allylmagnesium chloride to
unsaturated lactams 3a and 3b took place with lower stereose-
lectivity, and after removal of the benzyloxycarbonyl group as
in the above series, lactams 8a and 8b were obtained along with
the corresponding C-7 epimers (78:22 and 85:15 ratio, respec-
tively) in acceptable overall yield (50% from 2a; 65% from
2b).
A moderate stereoselectivity was also observed in the
conjugate addition of the organocuprate derived from phenyl-
magnesium chloride to 3a: a 84:16 mixture of lactam 9a and
its C-7 epimer was isolated in 51% overall yield from 2a.
In contrast, somewhat surprisingly, the conjugate addition
of this organocuprate to the 8a-phenyl-substituted lactam 3b
took place in excellent yield and very high exo stereoselec-
tivity (Table 1), ultimately leading to lactam 9b in 60%
overall yield (from 2b). A π-stacking interaction between
the incoming- and 8a-phenyl groups could account for the
high stereoselectivity.
To illustrate the synthetic usefulness of the above meth-
odology, the phenyl-substituted lactams 9a and 9b were
converted to enantiopure cis-2,4-disubstituted piperidines as
shown in Scheme 3. Thus, treatment of lactams 9 with LiAlH4
brought about both the reduction of the amide carbonyl group
and the reductive opening of the oxazolidine ring, which took
place with complete retention of configuration,14 to give
piperidines 10a and 10b. The cis-relationship of the piperidine
substituents at C-2 and C-4 in 10 was evident from the
multiplicity of the axial 2 and 4 protons in the NMR spectra
(see Supporting Information), thus confirming the stereo-
chemical outcome of the above conjugate additions. A
subsequent debenzylation in the presence of (Boc)2O gave
enantiopure piperidines 11a and 11b.
Under the same conditions the sterically more demanding 8a-
phenyl-substituted lactam 3b gave a similar result: the conjugate
addition of a vinyl residue took place in 61% yield (from 2b)
and the subsequent debenzyloxycarbonylation afforded (73%)
a 94:6 diastereomeric mixture of 7b and its C-7 epimer.
(9) (a) Muller, M.; Schoenfelder, A.; Didier, B.; Mann, A.; Wermuth, C.-G.
Chem. Commun. 1999, 683–684. (b) Hanessian, S.; van Otterlo, W. A. L.;
Nilsson, I.; Bauer, U. Tetrahedron Lett. 2002, 43, 1995–1998. (c) Garc´ıa, E.;
Lete, E.; Sotomayor, N. J. Org. Chem. 2006, 71, 6776–6784.
(10) Unsaturated lactams 3 and 14 are acid- and base-sensitive and must be
prepared immediately before the next reaction and used without further
purification.
(11) The starting lactams 1a and 1b were prepared by cyclocondensation of
(R)-phenylglycinol with 5-oxohexanoic acid11a and 5-oxo-6-phenylpentanoic
acid,11b respectively. (a) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995,
60, 7084–7085. (b) Amat, M.; Bassas, O; Llor, N.; Canto´, M.; Pe´rez, M.; Molins,
E.; Bosch, J. Chem. Eur. J. 2006, 12, 7872–7881.
(12) (a) Overman, L. E.; Robichaud, A. J. J. Am. Chem. Soc. 1989, 111,
300–308. (b) Amat, M.; Llor, N.; Bosch, J.; Solans, X. Tetrahedron 1997, 53,
719–730. (c) Cossy, J.; Mirguet, O.; Gomez Pardo, D.; Desmurs, J.-R New
J. Chem. 2003, 27, 475–482. (d) Deiters, A.; Pettersson, M.; Martin, S. F. J.
Org. Chem. 2006, 71, 6547–6561, and references therein.
The above results made evident that the presence of a
substituent at the angular 8a-position has little effect on the
(13) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019–6022.
(b) Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett. 1986, 27, 1047–1050.
(c) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett.
1986, 27, 4029–4032.
(14) For a discussion on the stereochemical outcome in the reduction of 8a-
substituted oxazolopiperidone lactams, see ref 11b and references therein.
J. Org. Chem. Vol. 73, No. 17, 2008 6921

SCHEME 4. Synthesis of Enantiopure
2-Azabicyclo[3.3.1]nonanes and 7-Azabicyclo[4.3.1]decanes
(58% overall yield) by alane reduction followed by hydro-
genolysis in the presence of (Boc)2O.18 However, in 17a the
reductive cleavage of the C-O bond of the oxazolidine ring
was more difficult, probably because the process involves the
bridgehead carbon of a 6,6-bridged system. In this series, alane
reduction of 17a caused only the reduction of the lactam
carbonyl. A subsequent prolonged (48 h) treatment of the
resulting tricyclic amine with Et3SiH-TiCl4 led to bicyclic amine
18a (48% overall yield from 17a), which was then converted
to the enantiopure 2-azabicyclo[3.3.1]nonane (morphan) 19a as
in the above 6,7-bridged series.19 Alternatively, in the B-
homomorphan series, tricyclic lactam 17b was converted to
lactam 21 in two steps (65% overall yield) as depicted in Scheme
4.
In summary, the exo facial stereoselectivity observed in
the conjugate addition of organocuprates to 8a-unsubstituted
unsaturated oxazolopiperidone lactams B (R ) H) is main-
tained in the 8a-substituted derivatives, in particular when
the incoming group is vinyl. By choosing the appropriate
substituent at the 8a position in the starting oxazolopiperidone
and the appropriate organocuprate in the conjugate addition
step, the reported methodology provides a versatile route to
enantiopure cis-2,4-disubstituted and 2,4-bridged pipe-
ridines.20
Experimental Section
General Procedure for the Conjugate Addition to
Unsaturated Lactams (with 4a as an Example). LiCl (189 mg,
4.5 mmol) was heated at 80 °C for 1 h under vacuum (10-15
mmHg) in a three-necked, 500-mL round-bottomed flask. Then,
CuI (357 mg, 4.5 mmol) and THF (5 mL) were added at room
temperature, and the mixture was stirred at room temperature for
5 min. The suspension was cooled at -78 °C, and vinylmagnesium
bromide (1 M in THF, 4.5 mL), TMSCl (0.57 mL, 4.5 mmol), and
the crude of unsaturated lactam 3a (1.8 mmol) in THF (8 mL) were
successively added. The resulting mixture was stirred at -78 °C
for 20 h. The reaction was quenched with saturated aqueous NH4Cl,
and the organic layer was extracted with EtOAc. The combined
organic extracts were dried and concentrated. Flash chromatography
(1:4 EtOAc/hexane) gave lactams 4a (major) and 7-epi-4a as
mixtures of C-6 epimers (508 mg, 62% overall yield from 2a). 4a
stereoselectivity of the conjugate addition. However, to access
bridged piperidine derivatives following the strategy outlined
in Scheme 1, we decided to take advantage of the higher
stereoselectivity of the vinyl conjugate additions and chose
starting lactams A bearing an allyl or 3-butenyl substituent at
the 8a-position, which should ultimately lead to 6,6- and 6,7-
bridged azabicyclic systems, respectively.
The synthetic sequence is outlined in Scheme 4. The required
unsaturated lactams 1410 were prepared from lactams 12a15 and
12b16 via the corresponding selenides 13. As could be expected
from the above model experiments, the conjugate addition of
the organocuprate derived from vinylmagnesium bromide to
crude lactams 14 took place in good yield (∼60% from 13)
and excellent facial diastereoselectivity to give the exo com-
pounds 15 as C-6 epimeric mixtures (only trace amounts of C-7
endo epimers were detected by NMR), which were directly
cyclized (∼80% yield) in the presence of the second generation
Grubbs catalyst.17 A subsequent catalytic hydrogenation of the
resulting bridged derivatives 16 brought about both the reduction
of the C-C double bond and debenzylation to lead, after thermal
decarboxylation, to tricyclic lactams 17a (78%) and 17b (83%).
In the 6,7-bridged series, lactam 17b was converted to the
enantiopure 7-azabicyclo[4.3.1]decane (B-homomorphan) 19b
1
(major C-6 epimer): IR (NaCl) 1665, 1744 cm-1; H NMR (400
MHz, CDCl3, COSY, HETCOR) δ 1.54 (s, 3H, CH3), 1.94 (dd, J
) 14.4, 8.4 Hz, 1H, H-8), 2.38 (dd, J ) 14.4, 7.2 Hz, 1H, H-8),
3.15 (m, 1H, H-7), 3.40 (d, J ) 10.8 Hz, 1H, H-6), 4.03 (dd, J )
9.2, 6.8 Hz, 1H, H-2), 4.41 (t, J ) 8.4 Hz, 1H, H-2), 5.09 (m, 2H,
CH2d), 5.17 (d, J ) 12.4 Hz, 1H, CH2 benzyl), 5.24 (d, J ) 12.4
Hz, 1H, CH2 benzyl), 5.42 (t, J ) 7.2 Hz, 1H, H-3), 5.74 (ddd, J
) 17.2, 10.4, 7.2 Hz, 1H, CHd), 7.25-7.36 (m, 10H ArH); 13C
NMR (100.6 MHz, CDCl3) δ 26.7 (CH3), 36.0 (C-7), 39.5 (C-8),
53.7 (C-6), 59.1 (C-3), 67.0 (CH2 benzyl), 69.2 (C-2), 93.2 (C-8a),
116.5 (CH2d), 124.5-128.5 (C-o, m, p), 135.6, 139.7 (C-i), 138.1
(CHd), 166.7 (NCO), 168.7 (COO). Anal. Calcd for C24H25NO4:
C, 73.64; H, 6.44; N, 3.58. Found: C, 73.30; H, 6.58; N,
3.51.
(18) To our knowlewdge this is the first synthetic route to enantiopure
7-azabicyclo[4.3.1]decanes.
(15) Lactam 12a was prepared in three steps [(1) H2, Pd/C; (2) n-Bu3P,
o-NO2(C6H4)SeCN; (3) H2O2, Pyr.; 40% overall yield] from the known11a 8a-
benzyloxypropyl-substituted lactam.
(16) Lactam 12b was prepared in 57% yield by cyclocondensation of (R)-
phenylglycinol with the known 5-oxo-8-nonenoic acid: Mazur, P.; Nakanishi,
K. J. Org. Chem. 1992, 57, 1047–1051.
(17) (a) Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
2003; Vols. 1-3. (b) Felpin, F.-X.; Lebreton, J Eur. J. Org. Chem. 2003, 3693–
3712. (c) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199–2238.
(19) The synthesis of enantiopure 2-azabicyclo[3.3.1]nonanes has been little
explored: (a) Quirante, J.; Torra, M.; Diaba, F.; Escolano, C.; Bonjoch, J.
Tetrahedron: Asymmetry 1999, 10, 2399–2410. (b) Karig, G.; Fuchs, A.; Bu¨sing,
A.; Brandstetter, T.; Scherer, S.; Bats, J. W.; Eschenmoser, A.; Quinkert, G.
HelV. Chim. Acta 2000, 83, 1049–1078.
(20) For previous syntheses of cis-2,4-disubstituted piperidines, see: (a) Beak,
P.; Lee, W.-K. J. Org. Chem. 1990, 55, 2578–2590. (b) Dwyer, M. P.; Lamar,
J. E.; Meyers, A. I. Tetrahedron Lett. 1999, 40, 8965–8968. (c) Watson, P. S.;
Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–3681.
6922 J. Org. Chem. Vol. 73, No. 17, 2008

General Procedure for the Ring-Closing Metathesis
Reaction (with 16a as an Example). Second-generation Grubbs
catalyst (3 mg) was added to a solution of lactams 15a (20 mg,
0.05 mmol) in CH2Cl2 (7 mL). The mixture was stirred at room
temperature for 2 h, concentrated, and purified by flash column
chromatography (1:9 to 1:4 EtOAc/hexane) to yield tricyclic lactam
16a as a mixture of C-6 epimers (ratio 2:1, 16 mg, 80% yield).
1H, H-2), 4.57 (t, J ) 8.8 Hz, 1H, H-2), 5.45 (t, J ) 7.6 Hz, 1H,
H-3), 5.76 (m, 1H, CHd), 5.90 (m, 1H, CHd); 13C NMR (100.6
MHz, CDCl3, selected resonances) δ 30.9 (C-10), 33.3 (C-7), 36.2
(CH2), 53.5 (C-6), 57.9 (C-3), 67.0 (CH2 benzyl), 70.1 (C-2), 92.4
(C-11), 164.5 (NCO), 168.9 (COO); HMRS calcd for [C24H23NO4
+ H] 390.1699, found 390.1704.
Acknowledgment. Financial support from the Ministry of
Science and Technology (Spain)-FEDER (project CTQ2006-
02390/BQU) and the DURSI, Generalitat de Catalunya (Grant
2005-SGR-0603) is gratefully acknowledged. Thanks are also
due to the Ministry of Science and Technology (Spain) for a
fellowship to A.T.M. and Dr. Daniele Passarella, University
degli Studi di Milano, for helpful collaboration.
1
16a (major): IR (NaCl) 1659, 1734 cm-1; H NMR (400 MHz,
CDCl3, HETCOR) δ 2.30-2.45 (m, 3H, 2H-10, CH2), 2.35 (dd, J
) 12.0, 4.0 Hz, 1H, CH2), 3.24 (d, J ) 4.0 Hz, 1H, H-7), 3.67 (d,
J ) 6.4 Hz, 1H, H-6), 4.00 (t, J ) 8.8 Hz, 1H, H-2), 4.61 (t, J )
8.4 Hz, 1H, H-2), 5.18 (d, J ) 12.4 Hz, 1H, CH2 benzyl), 5.22 (d,
J ) 12.4 Hz, 1H, CH2 benzyl), 5.48 (t, J ) 8.0 Hz, 1H, H-3), 5.64
(m, 1H, CHd), 5.76 (m, 1H, CHd), 7.05-7.20 (m, 10H, ArH);
13C NMR (100.6 MHz, CDCl3) δ 31.8 (C-10), 34.4 (C-7), 36.1
(CH2), 52.0 (C-6), 58.7 (C-3), 67.2 (CH2 benzyl), 70.1 (C-2), 92.3
(C-11), 125.0-129.9 (C-o, m, p, CHd), 135.4, 139.2 (C-i), 164.2
Supporting Information Available: Experimental proce-
dures and full spectroscopic data for all compounds, and copies
of 1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
(NCO), 169.7 (COO). 16a (minor): H NMR (400 MHz, CDCl3,
selected resonances) δ 2.19 (ddd, J ) 12.4, 4.4, 1.6 Hz, 1H, H-10),
3.05 (br, 1H, H-7), 3.53 (s, 1H, H-6), 4.02 (dd, J ) 9.2, 7.6 Hz,
JO801172B
J. Org. Chem. Vol. 73, No. 17, 2008 6923