Enantioselective synthesis of piperidine, indolizidine, and quinolizidine alkaloids from a phenylglycinol-derived δ-lactam

Article abstract of DOI:10.1021/jo0266083

Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.

Full text of DOI:10.1021/jo0266083

En a n tioselective Syn th esis of P ip er id in e, In d olizid in e, a n d
Qu in olizid in e Alk a loid s fr om a P h en ylglycin ol-Der ived δ-La cta m
Mercedes Amat,* Nu´ria Llor, J ose´ Hidalgo, Carmen Escolano, and J oan Bosch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain
amat@farmacia.far.ub.es
Received October 25, 2002
Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-
a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and
trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis
of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-
solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine
I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.
The piperidine ring is found in one of the simplest
alkaloids, coniine, in other diversely substituted piperi-
dine alkaloids, mainly cis- and trans-2,6-dialkyl substi-
tuted (e.g. pinidine, lupetidine, solenopsins),1 in bicyclic
indolizidine (e.g. monomorine I), perhydroquinoline (e.g.
pumiliotoxin C), and quinolizidine (e.g. lupinine) alka-
loids,2 as well as in many of the most complex polycyclic
alkaloids (e.g. morphine, strychnine).3 These nitrogen
derivatives occur not only in plants but also in insects4
and amphibians.2b-d Most of these natural products
exhibit notable biological activities, and many piperidine-
containing entities are under pharmaceutical research.5
For these reasons, and because the structural diversity
of these alkaloids makes them a good vehicle for the
testing of synthetic methodology, the synthesis of enan-
tiopure piperidine derivatives has attracted considerable
synthetic attention over the last years.6 In this context,
the development of chiral nonracemic piperidine building
blocks, with the final aim of synthesizing diversely
substituted enantiopure piperidine derivatives, consti-
tutes an area of current interest.7 In particular, chiral
bicyclic lactams derived from R- or S-phenylglycinol have
emerged as powerful tools as they allow the stereoselec-
tive incorporation of substituents at the different carbon
atom positions of the piperidine ring.8
In this paper we report the enantioselective synthe-
sis of 2-alkylpiperidines and stereocontrolled routes to
enantiopure cis- and trans-2,6-dialkylpiperidines, the
former also providing access to substituted indolizidines
and quinolizidines, starting from a common bicyclic
lactam 1. The interest and usefulness of this approach
(6) (a) Kibayashi C. In Studies in Natural Products Chemistry.
Stereoselective Synthesis, Part G; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, The Netherlands, 1992; Vol. 11, pp 229-275. (b) Wang,
C.-L. J .; Wuonola, M. A. Org. Prep. Proced. Int. 1992, 24, 585-621. (c)
Cossy, J .; Vogel, P. In Studies in Natural Products Chemistry.
Stereoselective Synthesis, Part H; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, The Netherlands, 1993; Vol. 12, pp 275-363. (d) Angle,
S. R.; Breitenbucher, J . G. In Studies in Natural Products Chemistry.
Stereoselective Synthesis, Part J ; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, The Netherlands, 1995; Vol. 16, pp 453-502. (e) Bailey,
P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 633-640.
(f) Laschat, S.; Dickner, T. Synthesis 2000, 1781-1813.
(7) (a) Rubiralta, M.; Giralt, E.; D´ıez, A. Piperidine. Structure,
Preparation, Reactivity, and Synthetic Applications of Piperidine and
its Derivatives; Elsevier: Amsterdam, The Netherlands, 1991. (b)
Oppolzer, W. Pure Appl. Chem. 1994, 66, 2127-2130. (c) Husson, H.-
P.; Royer, J . Chem. Soc. Rev. 1999, 28, 383-394. (d) Comins, D. L. J .
Heterocycl. Chem. 1999, 36, 1491-1500. (e) Guilloteau-Bertin, B.;
Compe`re, D.; Gil, L.; Marazano, C.; Das, B. C. Eur. J . Org. Chem. 2000,
1391-1399. For a chemoenzymatic approach to enantiopure piperidine
derivatives, see: (f) Danieli, B.; Lesma, G.; Passarella, D.; Silvani, A.
Curr. Org. Chem. 2000, 4, 231-261.
(1) (a) Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985;
Vol. 3, pp 1-90. (b) Strunz, G. M.; Findlay, J . A. In The Alkaloids;
Brossi, A., Ed.; Academic Press: London, 1985; Vol. 26, pp 89-183.
(c) Schneider, M. J . In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon: Oxford, UK, 1996; Vol. 10, pp 155-
299.
(2) (a) Kinghorn, A. D.; Balandrin M. F. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1984;
Vol. 2, pp 105-148. (b) Daly, J . W.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1986; Vol.4, pp 1-274. (c) Daly, J . W.; Garraffo, H. M.; Spande,
T. F. In The Alkaloids; Cordell G. A., Ed.; Academic Press: London,
UK, 1993; Vol. 43, pp 185-288. (d) Takahata, H.; Momose, T. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1993;
Vol. 44, pp 189-256. (e) Ohmiya, S.; Saito, K.; Murakoshi, I. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1995;
Vol. 47, pp 1-114. (f) Michael, J . P. Nat. Prod. Rep. 2001, 18, 520-
542.
(3) (a) Saxton, J . E., Ed. Monoterpenoid Indole Alkaloids. In The
Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley:
Chichester, UK, 1994; Vol. 25, Supplement to Part 4. (b) Casy, A. F.;
Parfitt, R. T. Opioid Analgesics. Chemistry and Receptors; Plenum
Press: New York, 1986.
(4) (a) Numata, A.; Ibuka, I. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 31, pp 193-315. (b) Braekman,
J . C.; Daloze, D. In Studies in Natural Products Chemistry. Stereo-
selective Synthesis, Part D; Atta-ur-Rahman, Ed.; Elsevier: Amster-
dam, The Netherlands, 1990; Vol. 6, pp 421-466. (c) See also ref 2c.
(5) Watson, P. S.; J iang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681.
(8) 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. For more recent work, see: (d) Amat, M.; Pe´rez, M.; Llor, N.;
Bosch, J .; Lago, E.; Molins, E. Org. Lett. 2001, 3, 611-614. (e) Amat,
M.; Canto´, M.; Llor, N.; Bosch, J . Chem. Commun. 2002, 526-527. (f)
Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.; Pe´rez, M.; Bosch, J . Angew.
Chem., Int. Ed. 2002, 41, 335-338. (g) Amat, M.; Canto´, M.; Llor, N.;
Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J . J . Org. Chem. 2002,
67, 5343-5351. (h) Amat, M.; Pe´rez, M.; Llor, N.; Bosch, J . Org. Lett.
2002, 4, 2787-2790.
10.1021/jo0266083 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/07/2003
J . Org. Chem. 2003, 68, 1919-1928
1919

Amat et al.
SCHEME 1. En a n tioselective Syn th esis of
(R)-Con iin e
SCHEME 2. Syn th esis of En a n tiop u r e
2-Alk ylp ip er id in es
TABLE 1. Dia gn ostic NMR Ch em ica l Sh ifts for
6-Su bstitu ted La cta m sa
is illustrated by the synthesis of several alkaloids with
the above-mentioned structural types.
R
lactam
C-1′
C-6
H-1′
(R)-CH3
(S)-CH3
(R)-n-Pr
(S)-n-Pr
(R)-n-Bu
(S)-C6H5
(R)-C6H5
(S)-3-indolyle
(R)-3-indolyle
4a b
4bc
5a
64.6
62.6
66.1
63.4
66.3
67.9
60.4
68.0
59.7
52.8
51.8
57.7
56.4
58.0
62.6
58.2
57.0
50.5
4.60
5.21
4.54
5.24
4.59
4.21
5.90
4.40
5.97
Resu lts a n d Discu ssion
5bd
6a
The starting bicyclic lactam 1 was prepared in 74%
overall yield by our previously reported procedure, by
cyclocondensation of R-phenylglycinol with methyl 5-oxo-
pentanoate in refluxing toluene, followed by equilibration
of the initially formed cis/trans mixture of lactams with
TFA/CH2Cl2 at room temperature.9,10 The enantioselec-
tive synthesis of 2-alkylpiperidines required the stereo-
controlled introduction of substituents at the piperidine
R position by asymmetric R-amidoalkylation.11 Interac-
tion of 1 with a Lewis acid would generate an acyl
iminium ion A (Scheme 1), which would undergo nucleo-
philic attack upon the less hindered Re face, thus
producing a new stereocenter with a well-defined con-
figuration. The application of this concept with TiCl4 and
allyltrimethylsilane as the nucleophile led to the allylated
piperidones 2a and 2b in good yield and diastereoselec-
tivity (9:1).12 LiAlH4 reduction of the lactam carbonyl,
followed by separation of the resulting diastereomeric
piperidines 3 and, finally, simultaneous hydrogenation
of the carbon-carbon double bond and debenzylation
from the major isomer 3a completed the enantioselective
synthesis of (R)-coniine.13,14 The absolute configuration
7a
7b
a
b
δ values in ppm from TMS. Data also reported in ref 16b.
c Data from ref 16c. Data from ref 10c. e Data from ref 12a.
d
of the stereogenic center was confirmed to be R from the
sign of the specific rotation of the hydrochloride.
Similarly, the addition of higher order cyanocuprates15
to lactam 1 in the presence of BF3‚Et2O took place to give
the corresponding alkylated (4-6) or arylated (7) prod-
ucts (Scheme 2) in good yields and high diastereoselec-
tivities (approximate a :b ratios: 95:5 for 4 and 5; 9:1 for
6 and 7). The absolute configuration of the new stereo-
genic center was assigned from the 1H and 13C NMR data
(Table 1)16 and by conversion of the allyl derivative 2a
into 5a by catalytic hydrogenation. The procedure con-
stitutes an alternative and general method for the
synthesis of enantiopure 2-substituted piperidines.17
Thus, LiAlH4 reduction of 4a followed by catalytic hy-
(9) (a) Amat, M.; Llor, N.; Bosch, J . Tetrahedron Lett. 1994, 35,
2223-2226. (b) 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.
(14) For recent enantioselective syntheses, see: (a) Wilkinson, T.
J .; Stehle, N. W.; Beak, P. Org. Lett. 2000, 2, 155-158. (b) Andre´s, J .
M.; Herra´iz-Sierra, I.; Pedrosa, R.; Pe´rez-Encabo, A. Eur. J . Org. Chem.
2000, 1719-1726. (c) Bois, F.; Gardette, D.; Gramain, J .-C. Tetrahedron
Lett. 2000, 41, 8769-8772. (d) Hunt, J . C. A.; Laurent, P.; Moody, C.
J . Chem. Commun. 2000, 1771-1772. (e) Eskici, M.; Gallagher, T.
Synlett 2000, 1360-1362. (f) Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martel, J . J . Am. Chem. Soc. 2001, 123, 11829-11830.
(g) Pachamuthu, K.; Vankar, Y. D. J . Organomet. Chem. 2001, 624,
359-363.
(15) (a) Lipshutz, B. H. In Organocopper Reagents. A Practical
Approach; Taylor, R. J . K., Ed.; Oxford University Press: New York,
1994; pp 105-128. (b) For the use of organocopper derivatives in
intermolecular R-amidoalkylation reactions, see: Ludwig, C.; Wistrand,
L.-G. Acta Chem. Scand. 1994, 48, 367-371.
(16) (a) In the major isomers a the methine benzylic proton appears
more shielded, and both the benzylic and C-6 carbons more deshielded,
than in the minor isomers b. (b) Fre´ville, S.; Bonin, M.; Ce´le´rier, J .-
P.; Husson, H.-P.; Lhommet, G.; Quirion, J .-C.; Thuy, V. M. Tetra-
hedron 1997, 53, 8447-8456. (c) Lienard, P.; Varea, T.; Quirion, J .-
C.; Husson, H.-P. Synlett 1994, 143-144.
(17) For related approaches, involving the reductive ring-opening
of phenylglycinol-derived 8a-substituted bicyclic δ-lactams, see: (a)
Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995, 60, 7084-7085.
(b) Fre´ville, S.; Ce´le´rier, J . P.; Thuy, V. M.; Lhommet, G. Tetra-
hedron: Asymmetry 1995, 6, 2651-2654. See also ref 8e.
(10) Lactam
1 (or its enantiomer) has also been prepared by
alternative procedures: (a) Royer, J .; Husson, H.-P. Heterocycles 1993,
36, 1493-1496. (b) Micouin, L.; Quirion, J .-C.; Husson, H.-P. Synth.
Commun. 1996, 26, 1605-1611. (c) Tera´n, J . L.; Gnecco, D.; Galindo,
A.; J ua´rez, J .; Bernes, S.; Enr´ıquez, R. G. Tetrahedron: Asymmetry
2001, 12, 357-360. However, in this article the authors misleadingly
report that they have prepared the 8a-epimer of 1.
(11) Hiemstra, H.; Speckamp, W. N.; In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
UK, 1991; Vol. 2, Heathcock, C. H., Ed., pp 1047-1082.
(12) (a) A similar stereoselectivity was observed in the reaction of
1 with indole in the presence of TiCl4: Amat, M.; Llor, N.; Bosch, J .;
Solans, X. Tetrahedron 1997, 53, 719-730. For a disscusion on the
stereoselectivity of allyltrimethylsilane R-amidoalkylations to related
(R)-phenylglycinol- or (S)-1-phenylethylamine-derived δ- and γ-lac-
tams, see: (b) Polniaszek, R. P.; Belmont, S. E.; Alvarez, R. J . Org.
Chem. 1990, 55, 215-223. (c) Kiguchi, T.; Nakazono, Y.; Kotera, S.;
Ninomiya, I.; Naito, T. Heterocycles 1990, 31, 1525-1535. (d) Burgess,
L. E.; Meyers, A. I. J . Am. Chem. Soc. 1991, 113, 9858-9859. (e)
Interestingly, the reaction of 1 with PrMgBr takes place with opposite
diastereoselectivity to give piperidone 5b as the major product: see
ref 10c.
(13) For a preliminary account of this part of the work, see ref 9a.
1920 J . Org. Chem., Vol. 68, No. 5, 2003

Enantioselective Synthesis of Piperidine Alkaloids
SCHEME 3. Syn th esis of En a n tiop u r e cis- a n d
tr a n s-2,6-Dia lk ylp ip er id in es
SCHEME 4. Syn th esis of En a n tiop u r e
cis-2,6-Dia lk ylp ip er id in es: (-)-Dih yd r op in id in e
benzylation completed the enantioselective synthesis of
the piperidine alkaloid dihydropinidine,23 which was
isolated as the hydrochloride. Our dihydropinidine‚HCl
was dextrorotatory, thus indicating a natural 2R,6S24
absolute configuration.25
The above methodology can be extended to the syn-
thesis of bicyclic quinolizidine derivatives bearing a cis-
2,6-dialkylpiperidine moiety. In this case, the alkylation
of the masked iminium ion 11 had to be effected with a
four-carbon Grignard reagent incorporating a protected
aldehyde group (Scheme 5). Thus, reaction of oxazolo-
piperidine 11 with the Grignard reagent derived from
2-(3-bromopropyl)-1,3-dioxolane stereoselectively gave
cis-2,6-disubstituted piperidine 13. Catalytic hydrogena-
tion of 13 under slightly acidic hydrolytic conditions
brought about debenzylation, deprotection of the carbonyl
group, and closure of the second piperidine ring by a
reductive amination process to give enantiopure cis-4-
methylquinolizidine 14.
drogenolysis of the resulting 2-methylpiperidine 8 in the
presence of (Boc)2O gave (R)-N-Boc-2-methylpiperidine
(9).18 Alternatively, debenzylation of 4a with Na in liquid
NH3 gave enantiopure 6-methyl-2-piperidone (10).
The 6-alkyl-2-pyridones resulting from the alkylation
of bicyclic lactam 1 were envisaged as synthetic precur-
sors of both cis- and trans-2,6-dialkylpiperidines. Thus,
partial reduction of the lactam carbonyl group followed
by nucleophilic alkylation of the resulting iminium cation
B with a Grignard reagent would lead to enantiopure cis-
2,6-dialkylpiperidines (Scheme 3). Reversal of this se-
quence, i.e. nucleophilic alkylation with an organo-
metallic reagent followed by hydride reduction of the
resulting iminium species C, should afford enantiopure
trans-2,6-dialkylpiperidines. In both cases, the stereo-
selectivity of the second step would be a consequence of
the stereoelectronically preferred axial approach19 of the
nucleophile to the iminium intermediate, in a half-chair
conformation with the 6-alkyl substituent in a pseudo-
axial disposition to relieve the A(1,2) strain.7c The attack
of either the organometal derivative R2 on B or the
hydride ion on C would occur cis with respect to the
substituent R1 via a chairlike transition state.
In accordance with these expectations, Red-Al reduc-
tion of piperidone 4a gave oxazolopiperidone 11 (a 2:1
mixture of epimers at C-8a), which is, in fact, a single
masked iminium ion D (Scheme 4).20 A subsequent reac-
tion with propylmagnesium bromide led to the enantio-
pure cis-dialkylpiperidine 12 as the only isomer detect-
able from the reaction mixture.21 The cis relationship
between the methyl and propyl substituents in 12 was
deduced from the difference between the 13C NMR
chemical shifts corresponding to the methine and meth-
ylene carbons of the chiral auxiliary.22 A catalytic de-
Operating in a similar manner, but using a three-
carbon Grignard reagent bearing a protected aldehyde
group, the above approach leads to enantiopure indol-
izidines embodying a cis-2,6-dialkylpiperidine moiety.
Scheme 6 outlines the reaction sequences leading to
(21) For the opening of hexahydrooxazolo[3,2-a]pyridines with Grig-
nard reagents, see: (a) Guerrier, L.; Royer, J .; Grierson, D. S.; Husson,
H.-P. J . Am. Chem. Soc. 1983, 105, 7754-7755. (b) Katritzky, A. R.;
Qiu, G.; Yang, B.; Steel, P. J . J . Org. Chem. 1998, 63, 6699-6703. For
a study on the stereoselectivity of the reaction, see: (c) Poerwono, H.;
Higashiyama, K.; Yamauchi, T.; Kubo, H.; Ohmiya, S.; Takahashi, H.
Tetrahedron 1998, 54, 13955-13970.
(22) A positive value of ∆(δCH - δCH2) is indicative of a 2,6-cis
relationship, whereas the trans isomers show a slightly negative
value: Yue, C.; Nicolay, J .-F.; Royer, J .; Husson, H.-P. Tetrahedron
1994, 50, 3139-3148.
(23) Although dihydropinidine was first isolated as the hydrogena-
tion product of the alkaloid pinidine,23a-c it has also been isolated from
the Mexican Bean Beetle, Epilachna varivestis:23d (a) Tallent, W. H.;
Stromberg, V. L.; Horning, E. C. J . Am. Chem. Soc. 1955, 77, 6361-
6364. (b) Tallent, W. H.; Horning, E. C. J . Am. Chem. Soc. 1956, 78,
4467-4469. (c) Absolute configuration: Hill, R. K.; Chan, T. H.; J oule,
J . A. Tetrahedron 1965, 21, 147-161. (d) Attygalle, A. B.; Xu, S.-C.;
McCormick, K. D.; Meinwald, J .; Blankespoor, C. L.; Eisner, T.
Tetrahedron 1993, 49, 9333-9342.
(24) (a) To avoid confusion with other reports, it must be noted that,
according to the IUPAC recommendations, we assign the lower locant
(i.e., 2) to the chain that should be cited first in the name (i.e., methyl).
(b) It must also be noted that the [R]D value for the base has been
reported to be -1.2 (c 1.62, EtOH)23a,b and that, therefore, dihydro-
pinidine is levorotatory. There is also a confusion in the literature in
this respect.
(18) For the preparation of both enantiomers of 9, which are valuable
synthetic intermediates, see: Doller, D.; Davies, R.; Chackalamannil,
S. Tetrahedron: Asymmetry 1997, 8, 1275-1278.
(19) (a) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983; Chapter 6. (b) For related
highly stereoselective approaches to R- and â-C-glycopyranosides,
see: Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982, 104,
4976-4978.
(25) For recent enantioselective syntheses of dihydropinidine, see:
(a) Ciblat, S.; Besse, P.; Papastergiou, V.; Veschambre, H.; Canet, J .-
L.; Troin, Y. Tetrahedron: Asymmetry 2000, 11, 2221-2229. (b) Fre´ville,
S.; Delbecq, P.; Thuy, V. M.; Petit, H.; Ce´le´rier, J . P.; Lhommet, G.
Tetrahedron Lett. 2001, 42, 4609-4611. See also ref 14a and references
cited therein.
(20) For a preliminary account of this part of the work, see: Amat,
M.; Llor, N.; Hidalgo, J .; Herna´ndez, A.; Bosch, J . Tetrahedron:
Asymmetry 1996, 7, 977-980.
J . Org. Chem, Vol. 68, No. 5, 2003 1921

Amat et al.
SCHEME 5. Syn th esis of En a n tiop u r e
4-Su bstitu ted Qu in olizid in es
SCHEME 7. Syn th esis of th e In d olizid in e Alk a loid
Mon om or in e I
SCHEME 6. Syn th esis of En a n tiop u r e
5-Su bstitu ted In d olizid in es: In d olizid in e 167B
enantiomers of lactam 4a and oxazolopiperidine 11
(Scheme 7). In this series, the introduction of the second
chain on the piperidine ring of ent-11 was effected by
using the functionalized acetylide 20, which already
incorporates the four-carbon chain present at C-3 in
monomorine I.30 The reaction between ent-11 and 20
furnished the cis-2,6-disubstituted piperidine 21 in 75%
yield, again as a single stereoisomer. Catalytic hydro-
genation of 21 under acidic conditions led to the N-
unsubstituted piperidine ketone 22 in excellent yield,
in a one-pot reaction involving hydrogenation of the
triple bond, debenzylation, and hydrolysis of the acetal
group. Closure of the pyrrolidine ring, with generation
of the third stereogenic center, was accomplished in a
subsequent step by reductive amination, using hydro-
gen in MeOH solution in the absence of acid.31 Mono-
morine I was obtained as a single stereoisomer in 90%
yield.32
As we have depicted in Scheme 3, we expected that
reversing the reduction and nucleophilic alkylation steps
from the starting phenylglycinol-derived 6-alkyl-2-
piperidones would result in the preparation of the trans-
2,6 isomers. However, attempts to prepare trans-2,6-
dialkylpiperidines by treating lactam 4a with Grignard,
organolithium, or organocerium reagents, followed by a
hydride reduction, resulted in failure.33 For this reason,
we used the synthetically equivalent, but more reactive
thioimidate salt 25, which was prepared in 75% overall
yield from 4a , by silylation of the hydroxy group, followed
by treatment with Lawesson’s reagent and subsequent
methylation of the resulting thioamide 24 (Scheme 8).
5-methyl- and 5-propylindolizidine (18 and 19, respec-
tively), the latter being indolizidine 167B (gephyrotoxin
167B), a minor alkaloid isolated from the skin secretions
of neotropical frogs.26 The syntheses proceed via oxazolo-
piperidines 11 and 15 (a mixture of C-8a epimers),
respectively, the latter prepared by Red-Al reduction of
propyl lactam 5a . In this case, minor amounts of the
corresponding fully reduced piperidine (deoxo-5a ) were
isolated from the reaction mixture. Reaction of the
masked iminium ions 11 and 15 with the Grignard
reagent derived from 2-(2-bromoethyl)-1,3-dioxane gave
the respective cis-2,6-disubstituted piperidines 16 and 17.
Finally, hydrogenation in the presence of Pd/C under
acidic hydroalcoholic conditions led to the enantiopure
cis-5-alkylindolizidines 1827 and 19,28 with an R config-
uration at both piperidine R-carbons.
As the S isomer of phenylglycinol is also commercially
available, the enantiomer of lactam 1 is also easily
accessible, thus expanding the potential of the methodol-
ogy, as it provides access to cis-5-alkylindolizidine alka-
loids with an S configuration at both piperidine R
carbons, for instance monomorine I, the trail pheromone
of the Pharaoh ant.29 The synthesis proceeds via the
(29) (a) Isolation: Ritter, F. J .; Rotgans, I. E. M.; Talman, E.;
Verwiel, P. E. J .; Stein, F. Experientia 1973, 29, 530-531. (b) Absolute
configuration: Royer, J .; Husson, H.-P. J . Org. Chem. 1985, 50, 670-
673.
(30) Attempts to generate a Grignard reagent from several 1-halo-
3-heptanone acetals were unsuccessful.
(26) Daly, J . W. Prog. Chem. Nat. Prod. 1982, 41, 205-340.
(27) Fora previous enantioselective synthesis, see: Polniaszek, R.
P.; Belmont, S. E. J . Org. Chem. 1990, 55, 4688-4693.
(28) For recent enantioselective syntheses of indolizidine 167B,
see: (a) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2, 465-
467. (b) Back, T. G.; Nakajima, K. J . Org. Chem. 2000, 65, 4543-4552.
(c) Kim, G.; Lee, E. Tetrahedron: Asymmetry 2001, 12, 2073-2076.
(d) Zaminer, J .; Stapper, C.; Blechert, S. Tetrahedron Lett. 2002, 43,
6739-6741.
(31) This stereoselective cyclization has previously been reported:
Yamaguchi, R.; Hata, E.; Matsuki, T.; Kawanisi, M. J . Org. Chem.
1987, 52, 2094-2096. See also ref 29b.
(32) For previous enantioselective syntheses of monomorine I, see:
Riesinger, S. W.; Lo¨fstedt, J .; Pettersson-Fasth, H.; Ba¨ckvall, J .-E. Eur.
J . Org. Chem. 1999, 3277-3280 and references cited therein.
(33) It has been reported recently that the sodium salt of lactam
4a satisfactorily reacts with CH3MgCl to give, after hydride reduction,
trans-2,6-dimethylpiperidine 26 (R ) H): see ref 16b.
1922 J . Org. Chem., Vol. 68, No. 5, 2003

Enantioselective Synthesis of Piperidine Alkaloids
SCHEME 8. Syn th esis of En a n tiop u r e
tr a n s-2,6-Dia lk ylp ip er id in es: Lu p etid in e a n d
Solen op sin A
dimethylcuprate, followed by NaBH4 reduction of the
resulting iminium species E, stereoselectively afforded
the desired trans-2,6-dimethylpiperidine 26.34 Only trace
amounts (<5%) of the cis isomer were detected by NMR.
Piperidine 8 (as the O-TBDMS derivative) was also
isolated in ∼15% yield. Finally, hydrogenolysis of the
benzylic substituent of 26 gave trans-2R,6R-dimethyl-
piperidine, whose hydrochloride showed an [R] value
(dextrorotatory) and spectroscopic data in agreement
with those reported for the hydrochloride of the alkaloid
lupetidine.35 The above methodology provides a general
synthetic entry to enantiopure trans-2,6-dialkylpiperi-
dines. This was illustrated by the synthesis of solenopsin
A, an alkaloid isolated from the venom secreted by fire
ants.36 Introduction of the undecyl chain via a copper
reagent on the same thioimidate 25, followed by reduc-
tion with NaBH4, afforded trans-piperidine 27, although
in this case with moderate stereoselectivity (cis/trans
ratio 3:7).37 After desilylation, the resulting alcohols 28
were separated by column chromatography, and the
major trans-isomer was debenzylated to give solenopsin
A,38 which was isolated as the hydrochloride. The NMR
spectral data and [R] value of our synthetic material
agreed with those reported for the natural product.
SCHEME 9. Syn th etic Ap p lica tion s of Ch ir a l
Non r a cem ic Bicyclic La cta m 1
In conclusion, bicyclic lactam 1 (and its enantiomer)
has proven to be a versatile chiral building block for the
enantioselective synthesis of diversely substituted piperi-
dine derivatives as it allows the stereocontrolled forma-
tion of C-C bonds at the different carbon atom positions
of the nitrogen heterocycle. Scheme 8 outlines the most
important synthetic goals achieved from 1. In addition
to the 2-alkyl- and cis- and trans-2,6-dialkylpiperidines
reported here, alkylation at the R position of the carbonyl
group of lactam 1 provides access to enantiopure 3-alkyl-
piperidines,39 whereas conjugate addition to R,â-unsat-
urated lactams derived from 1 ultimately leads to enan-
tiopure trans-3,4-disubstituted piperidines, such as the
antidepressive drug paroxetine.9b
(34) For a preliminary account of this part of the work, see: Amat,
M.; Hidalgo, J .; Llor, N.; Bosch, J . Tetrahedron: Asymmetry 1998, 9,
2419-2422.
(35) (a) Isolation: Kuzovkov, A. D.; Menshikov, G. P. Zh. Obshch.
Khim. 1950, 20, 1524-1527; Chem. Abstr. 1951, 45, 2485g. (b) Absolute
configuration: Hill, R. K.; Morgan, J . W. J . Org. Chem. 1966, 31, 3451-
3452. (c) It must be noted that lupetidine base is levorotatory. (d) For
previous enantioselective syntheses, see: Najdi, S.; Kurth, M. J .
Tetrahedron Lett. 1990, 31, 3279-3282. See also ref 16b. (e) For the
synthesis of ent-lupetidine (2S,6S), see: Adamo, M. F. A.; Aggarwal,
V. K.; Sage, M. A. Synth. Commun. 1999, 29, 1747-1756. See also ref
7e.
(36) (a) Isolation: MacConnell, J . G.; Blum, M. S.; Fales, H. M.
Tetrahedron 1971, 26, 1129-1139. (b) Absolute configuration: Leclercq,
S.; Thirionet, I.; Broeders, F.; Daloze, D.; Vander Meer, R.; Braekman,
J . C. Tetrahedron 1994, 50, 8465-8478.
(37) The lower stereoselectivity in the hydride reduction of the CdN
bond in related 1-piperidinium salts when R is an alkyl group larger
than methyl has previously been reported: (a) Maruoka, K.; Miyazaki,
T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H.
J . Am. Chem. Soc. 1983, 105, 2831-2843. (b) Ukaji, Y.; Watai, T.; Sumi,
T.; Fujisawa, T. Chem. Lett. 1991, 1555-1558.
We expected that the addition of an organometallic
reagent to the iminium moiety of 25, followed by elimina-
tion of the methylsulfanyl group, would lead to the
required iminium cation, for instance E. However, se-
quential treatment of 25 with MeLi or MeMgBr, and then
with NaBH4, afforded the 2-substituted piperidine 8 (as
O-TBDMS derivative) as the only identifiable product.
This result was attributed to the basicity of the above
organometallic reagents, which deprotonate the R posi-
tion of thioimidate 25 yielding an enamine; the subse-
quent addition of a hydride ion under protic conditions
(MeOH) affords the reduced product. In accordance with
the above interpretation, the use of the less basic lithium
(38) (a) For previous enantioselective syntheses, see ref 14a and
references cited therein. See also: (b) Takahata, H.; Ouchi, H.; Ichinose,
M.; Nemoto, H. Org. Lett. 2002, 4, 3459-3462. (c) For a review, see:
Leclercq, S.; Daloze, D.; Braekman, J .-C. Org. Prep. Proc. Int. 1996,
28, 499-543. (d) For the synthesis of the 2S,6S-enantiomer, see:
Grierson, D. S.; Royer, J .; Guerrier, L.; Husson, H.-P. J . Org. Chem.
1986, 51, 4475-4477.
(39) Amat, M.; Pshenichnyi, G.; Bosch, J .; Molins, E.; Miravitlles,
C. Tetrahedron: Asymmetry 1996, 7, 3091-3094.
J . Org. Chem, Vol. 68, No. 5, 2003 1923

Amat et al.
The residue was dissolved in water and washed with Et2O,
and the aqueous phase was evaporated. The resulting residue
was purified by crystallization (Et2O-EtOH) to give pure (R)-
coniine hydrochloride (195 mg, 73%) as a white solid: 1H NMR
(CDCl3, 500 MHz) δ 0.91 (t, J ) 7.5 Hz, 3 H), 1.35-1.41 (m, 3
H), 1.57-1.63 (m, 1 H), 1.65-1.73 (m, 1 H), 1.76-1.80 (m, 1
H), 1.84-2.00 (m, 4 H), 2.75-2.82 (m, 1 H), 2.84-2.93 (m, 1
H), 3.41 (dm, J ) 12.5 Hz, 1 H), 9.17 (br s, 1 H), 9.43 (br s, 1
H); 13C NMR (CDCl3, 50.3 MHz) δ 13.6 (CH3), 18.4 (CH2), 22.0
(CH2), 22.2 (CH2), 27.9 (CH2), 35.2 (CH2), 44.6 (CH2), 56.9 (CH);
[R]22 -7.1 (c 1.0, EtOH) {lit.14b [R]23 -7.3 (c 0.33, EtOH)}.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined in
a capillary tube and are uncorrected. Unless otherwise indi-
cated, NMR spectra were recorded at 200 or 300 MHz (1H)
and 50.3 or 75 MHz (13C) and are reported downfield from
TMS. Only noteworthy IR absorptions are listed. Thin-layer
chromatography was done on SiO2 (silica gel 60 F254), and the
spots were located with aqueous potassium permanganate
solution or with iodoplatinate reagent. All nonaqueous reac-
tions were performed under an inert atmosphere. Solvents for
chromatography and reactions were distilled at atmospheric
pressure prior to use and dried using standard procedures.
Drying of the organic extracts during the workup of reactions
was performed over anhydrous Na2SO4 or MgSO4. Evaporation
of solvents was accomplished with a rotatory evaporator.
Microanalyses and HRMS were performed by Centre
d’Investigacio´ i Desenvolupament (CSIC), Barcelona.
D
D
(6R )-1-[(1R )-2-H yd r oxy-1-p h e n yle t h yl]-6-m e t h yl-2-
p ip er id on e (4a ). MeLi (17.3 mL of a 1.5 M solution in Et2O,
26.0 mmol) was added to a suspension of CuCN (1.16 g, 13.0
mmol) in anhydrous THF (40 mL) at -78 °C, and the mixture
was stirred under nitrogen for 2 h. The resulting suspension
was added via cannula to a solution of lactam 1 (945 mg, 4.35
mmol) and BF3‚Et2O (1.65 mL, 13.0 mmol) in anhydrous THF
(5 mL) at - 78 °C, and the stirring was continued for 2 h. The
crude mixture was poured into saturated aqueous NH4Cl, the
organic layer was extracted with AcOEt, and the combined
organic extracts were dried, filtered, and concentrated to give
an oil (1.6 g). Flash chromatography (AcOEt) afforded com-
pound 4 (710 mg, 70%) as a 97:3 mixture of epimers 4a and
4b, respectively. Pure 4a was obtained by crystallization from
(6S)-6-Allyl-1-[(1R)-2-h yd r oxy-1-p h en yleth yl]-2-p ip er i-
d on e (2a ). Allyltrimethylsilane (2.0 mL, 12.6 mmol) was
added at room temperature to a solution of bicyclic lactam 1
(880 mg, 4.05 mmol) in anhydrous CH2Cl2 (15 mL). Then, a
solution of TiCl4 (0.45 mL, 4.1 mmol) in CH2Cl2 (15 mL) was
added, and the dark mixture was stirred at room temperature
for 4 h and poured into an aqueous NaHCO3 solution. The
aqueous layer was extracted with CH2Cl2, and the combined
organic solutions were dried, filtered, and concentrated to give
compound 2 (956 mg, 91%) as a 9:1 mixture of C-6 isomers 2a
and 2b, respectively. 2a : IR (film) 3367, 1616 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 1.60-1.78 (m, 2 H), 1.80-1.90 (m, 2 H),
2.20-2.23 (m, 2 H), 2.40-2.55 (m, 2 H), 3.31 (dddd, J ) 8.5,
5.5, 5.5, 3.0 Hz, 1 H), 4.00 (dd, J ) 12.0, 3.5 Hz, 1 H), 4.23
(dd, J ) 12.0, 7.5 Hz, 1 H), 4.67 (dd, J ) 7.5, 3.5 Hz, 1 H),
4.95-5.03 (m, 2 H), 5.55 (m, 1H), 7.20-7.35 (m, 5 H); 13C NMR
(CDCl3, 50.3 MHz) δ 15.6 (CH2), 25.3 (CH2), 31.7 (CH2), 37.0
(CH2), 57.3 (CH), 64.1 (CH2), 65.9 (CH), 118.3 (CH2), 127.6
(CH), 127.8 (CH), 128.7 (CH), 134.0 (CH), 137.3 (C), 172.3 (C).
(2S )-2-Allyl-[(1R )-2-h yd r oxy-1-p h e n yle t h yl]p ip e r i-
d in e (3a ). A solution of the above mixture of epimers 2a and
2b (900 mg, 3.46 mmol) in anhydrous Et2O (10 mL) was slowly
added to a suspension of LiAlH4 (530 mg, 14.0 mmol) in
anhydrous Et2O (300 mL). The mixture was heated at reflux
for 1 h and cooled to 0 °C. The excess of hydride was destroyed
by successive dropwise addition of 15% aqueous NaOH (10 mL)
and H2O (10 mL). The suspension was filtered through a Celite
pad and the aqueous layer was extracted with Et2O. The
combined organic layers were dried, filtered, and concentrated
to give a yellow oil (635 mg). Flash chromatography (3:2 Et2O-
hexane) afforded isomers 3b (77 mg, 9%) and 3a (622 mg,
1
Et2O: IR (film) 3550, 1616 cm-1; H NMR (CDCl3, 500 MHz)
δ 1.20 (d, J ) 7.0 Hz, 3 H), 1.60-2.00 (m, 4 H), 2.48 (ddd, J )
17.0, 10.0, 7.5 Hz, 1 H), 2.54 (dddd, J ) 17.0, 8.0, 3.5, 1.0 Hz,
1 H), 3.48-3.54 (m, 1 H), 4.04 (ddd, J ) 12.0, 4.0, 3.5 Hz, 1
H), 4.28 (ddd, J ) 12.0, 9.0, 7.0 Hz, 1H), 4.46 (dd, J ) 9.0, 4.0
Hz, 1 H), 4.60 (dd, J ) 7.0, 3.5 Hz, 1 H), 7.20-7.40 (m, 5 H);
13C NMR (CDCl3, 75 MHz) δ 16.0 (CH2), 19.6 (CH3), 29.3 (CH2),
31.8 (CH2), 52.8 (CH), 63.4 (CH2), 64.5 (CH), 127.2 (CH), 127.3
(CH), 128.2 (CH), 137.4 (C), 171.6 (C); mp 81-83 °C (lit.16b
mp 82 °C); [R]22 -19 (c 1.0, EtOH) {lit.16b [R]20 -12.2 (c 1.3,
D
D
MeOH)}. Anal. Calcd for C14H19NO2: C, 72.07; H, 8.20; N, 6.00.
Found: C, 71.78; H, 8.27; N, 5.84.
(6R )-1-[(1R )-2-H yd r oxy-1-p h e n yle t h yl]-6-p r op yl-2-
p ip er id on e (5a ). Operating as above, starting from lactam
1 (1.44 g, 6.63 mmol) and n-PrLi (49.5 mL of a 0.8 M solution
in Et2O, 39.6 mmol), compound 5 (1.1 g, 65%) was obtained
as a 93:7 mixture of epimers 5a and 5b, respectively, after
purification of the crude mixture by flash chromatography
(AcOEt). Crystallization from Et2O afforded pure 5a : IR (film)
3403, 1645 cm-1; 1H NMR (CDCl3, 200 MHz) δ 0.88 (t, J ) 7.0
Hz, 3 H), 1.00-2.00 (m, 8 H), 2.46-2.54 (m, 2 H), 3.20-3.26
(m, 1 H), 4.00 (dd, J ) 11.8, 3.2 Hz, 1 H), 4.18-4.29 (m, 1 H),
4.54 (dd, J ) 7.0, 3.2 Hz, 1 H), 4.67 (br s, 1 H), 7.27-7.34 (m,
5 H); 13C NMR (CDCl3, 50.3 MHz) δ 13.7 (CH3), 15.8 (CH2),
19.5 (CH2), 25.3 (CH2), 31.7 (CH2), 34.4 (CH2), 57.7 (CH), 64.1
(CH2), 66.1 (CH), 127.4 (CH), 127.5 (CH), 128.4 (CH), 137.3
73%). 3a : IR (film) 3390 cm-1; H NMR (CDCl3, 200 MHz) δ
1
1.00-1.70 (m, 6 H), 1.82 (td, J ) 11.0, 2.6 Hz, 1 H), 2.42-2.53
(m, 3 H), 2.90 (ddd, J ) 11.0, 3.5, 3.5 Hz, 1 H), 3.58 (dd, J )
10.3, 5.3 Hz, 1 H), 4.00 (t, J ) 10.3 Hz, 1 H), 4.33 (dd, J )
10.3, 5.3 Hz, 1 H), 5.03-5.20 (m, 2 H), 5.76-5.98 (m, 1 H),
7.10-7.45 (m, 5 H); 13C NMR (CDCl3, 50.3 MHz) δ 23.8 (CH2),
26.1 (CH2), 31.6 (CH2), 37.0 (CH2), 45.3 (CH2), 56.7 (CH), 59.6
(CH2), 60.8 (CH), 117.2 (CH2), 127.5 (CH), 128.0 (CH), 128.8
(C), 171.8 (C); [R]22D -32 (c 2.0, MeOH). Anal. Calcd for C16H23
-
NO2‚1/3H2O: C, 71.87; H, 8.92; N, 5.24. Found: C, 71.73; H,
8.91; N, 5.24.
(6R )-6-B u t y l-1-[(1R )-2-h y d r o x y -1-p h e n y le t h y l]-2-
p ip er id on e (6a ). Operating as above, starting from lactam
1 (250 mg, 1.15 mmol) and n-BuLi (4.4 mL of a 1.6 M solution
in hexane, 7.0 mmol), compound 6 (205 mg, 65%) was obtained
as a 91:9 mixture of epimers 6a and 6b, respectively, after
purification of the crude mixture by flash chromatography
(CH), 134.6 (CH), 135.8 (C); [R]22 -61 (c 1.0, EtOH). Anal.
D
Calcd for C16H23NO: C, 78.32; H, 9.45; N, 5.71. Found: C,
77.95; H, 9.53; N, 5.67. 3b: IR (film) 3400 cm-1 1H NMR
;
(CDCl3, 200 MHz) δ 1.43-1.60 (m, 6 H), 2.14-2.38 (m, 1 H),
2.45-2.68 (m, 2 H), 2.97-3.05 (m, 1 H), 3.66-3.85 (m, 2 H),
3.76 (t, J ) 10.0 Hz, 1 H), 4.93-5.03 (m, 2 H), 5.61-5.82 (m,
5 H), 7.10-7.50 (m, 5 H); 13C NMR (CDCl3, 50.3 MHz) δ 19.4
(CH2), 25.9 (CH2), 28.0 (CH2), 30.9 (CH2), 43.1 (CH2), 57.2 (CH),
61.8 (CH2), 67.7 (CH), 116.1 (CH2), 127.5 (CH), 128.3 (CH),
128.6 (CH), 136.6 (CH), 140.4 (C).
(R)-2-P r op ylp ip er id in e [(R)-Con iin e]. Pd-C (10%, 68
mg) was added to a solution of piperidine 3a (400 mg, 1.62
mmol) in MeOH (100 mL), and the resulting suspension was
hydrogenated at atmospheric pressure for 24 h. The catalyst
was removed by filtration, and the solution was acidified by
addition of a few drops of methanolic HCl and concentrated.
1
(Et2O). 6a : IR (film) 3480, 1593 cm-1; H NMR (CDCl3, 500
MHz) δ 0.86 (t, J ) 7.5 Hz, 3 H), 1.00-1.15 (m, 1 H), 1.20-
1.35 (m, 3 H), 1.45-1.60 (m, 2 H), 1.60-1.80 (m, 2 H), 1.82-
1.90 (m, 2 H), 2.47-2.52 (m, 2 H), 3.18-3.22 (m, 1 H), 4.02
(ddd, J ) 11.0, 3.0, 3.0 Hz, 1 H), 4.24-4.30 (m, 1 H), 4.53 (dd,
J ) 7.0, 3.5 Hz, 1 H), 4.59 (dd, J ) 8.5, 3.0 Hz, 1 H), 7.20-
7.40 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ 13.8 (CH3), 16.0
(CH2), 22.4 (CH2), 25.4 (CH2), 28.5 (CH2), 31.9 (CH2), 32.0
(CH2), 58.0 (CH), 64.3 (CH2), 66.3 (CH), 127.4 (CH), 127.5 (CH),
128.4 (CH), 137.4 (C), 171.8 (C); [R]22D -37 (c 1.0, EtOH). Anal.
Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.08. Found: C,
73.96; H, 9.14; N, 5.08.
1924 J . Org. Chem., Vol. 68, No. 5, 2003

Enantioselective Synthesis of Piperidine Alkaloids
(6S )-[(1R )-2-H y d r o x y -1-p h e n y le t h y l]-6-p h e n y l-2-
p ip er id on e (7a ). Operating as above, starting from lactam
1 (200 mg, 0.92 mmol) and PhLi (3.0 mL of a 1.8 M solution
in 7:3 cyclohexanes-Et2O, 5.5 mmol), epimeric compounds 7a
(182 mg, 67%) and 7b (22 mg, 8%) were obtained after flash
chromatography (99:1 CHCl3-EtOH). 7a : IR (KBr) 3500-
3300, 1613 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.65-1.80 (m,
2 H), 1.82-1.92 (m, 1 H), 2.00-2.14 (m, 1 H), 2.62 (ddd, J )
17.0, 10.0, 7.0 Hz, 1 H), 2.73 (m, 1 H), 4.02 (dd, J ) 12.4, 3.0
Hz, 1 H), 4.10 (dd, J ) 12.4, 6.4 Hz, 1 H), 4.21 (dd, J ) 6.4,
3.0 Hz, 1 H), 4.51 (dd, J ) 5.3, 4.5 Hz, 1 H), 7.20-7.40 (m, 10
H); 13C NMR (CDCl3, 75 MHz) δ 15.9 (CH2), 31.5 (CH2), 32.8
(CH2), 62.6 (CH), 64.4 (CH2), 67.9 (CH), 126.5 (CH), 127.4 (CH),
127.4 (CH), 127.6 (CH), 128.4 (CH), 128.7 (CH), 137.1 (C),
ammonia was evaporated by allowing the reaction mixture to
warm to room temperature, and the resulting mixture was
poured into water and extracted with CHCl3. The organic layer
was dried, filtered, and concentrated to give a residue, which
was chromatographed (AcOEt) affording piperidone 10 (108
mg, 74%): IR (KBr) 1660 cm-1; 1H NMR (CDCl3, 300 MHz) δ
1.20 (d, J ) 6.6 Hz, 3 H), 1.21-1.40 (m, 1 H), 1.60-1.80 (m, 1
H), 1.87-1.91 (m, 2 H), 2.27-2.30 (m, 1 H), 2.37 (dm, J ) 18.0
Hz, 1 H), 3.51 (m, 1 H), 6.45 (br s, 1 H);13C NMR (CDCl3, 75
MHz) δ 19.8 (CH2), 22.7 (CH3), 30.4 (CH2), 30.9 (CH2), 48.7
(CH), 172.4 (C); [R]22 - 24 (c 2.5, CH2Cl2) {lit.41 [R]22 - 21.9
D
D
(c 1.92, H2O)}.
(2R,5R)-5-Meth yl-3-p h en yl-2,3,6,7,8,8a -h exa h yd r o-5H-
oxa zolo[3,2-a ]p yr id in e (11). A solution of lactam 4a (1.69
g, 7.24 mmol) in anhydrous THF (100 mL) was cooled to - 78
°C, and then an excess of Red-Al (6.53 mL of a 65% solution
in toluene 21.7 mmol) was added in three portions at intervals
of 40 min. The resulting solution was stirred at - 78 °C for 24
h, and a 25% aqueous KOH solution (25 mL) was slowly added.
The aqueous layer was extracted with AcOEt, and the com-
bined organic extracts were dried, filtered, and concentrated
to give an oil. Flash chromatography (7:2 AcOEt-hexane)
afforded compound 11 (1.1 g, 70%) as a mixture of epimers,
which could not be separated, and minor amounts of piperidine
8. 11: IR (film) 2934 cm-1; MS m/z (rel intensity) 217 (M, 22),
216 (M - 1, 71), 202 (100). Major epimer: 1H NMR (CDCl3,
300 MHz) δ 0.90 (d, J ) 7.0 Hz, 3 H), 1.20-1.80 (m, 5 H),
2.00-2.04 (m, 1 H), 3.14 (m, 1 H), 3.57 (t, J ) 7.5 Hz, 1 H),
3.92 (t, J ) 7.5 Hz, 1 H), 4.10 (t, J ) 7.5 Hz, 1 H), 4.23 (dd, J
) 9.5, 3.0 Hz, 1 H), 7.26-7.39 (m, 5 H); 13C NMR (CDCl3, 75
MHz) δ 9.6 (CH3), 18.4 (CH2), 31.3 (CH2), 32.2 (CH2), 47.7 (CH),
62.3 (CH), 73.7 (CH2), 87.6 (CH), 128.7 (CH), 129.0 (CH), 129.5
(CH), 139.0 (C). Minor epimer: 1H NMR (CDCl3, 300 MHz) δ
1.08 (d, J ) 6.0 Hz, 3H), 1.20-1.80 (m, 5 H), 2.21-2.26 (m, 1
H), 3.10-3.20 (m, 1 H), 4.00 (dd, J ) 8.0, 2.0 Hz, 1 H), 4.33
(dd, J ) 9.5, 3.0 Hz, 1 H), 4.38 (dd, J ) 8.0, 6.5 Hz, 1 H), 4.53
(dd, J ) 6.5, 2.0 Hz, 1 H), 7.26-7.39 (m, 5 H); 13C NMR (CDCl3,
75 MHz) δ 20.9 (CH3), 22.3 (CH2), 31.3 (CH2), 34.3 (CH2), 50.8
(CH), 62.0 (CH), 73.0 (CH2), 90.7 (CH), 127.8 (CH), 128.1 (CH),
128.4 (CH), 140.9 (C).
140.7 (C), 172.6 (C); mp 124-125 °C (Et2O); [R]22 +10.8 (c
D
0.54, EtOH). Anal. Calcd for C19H21NO2: C, 77.25; H, 7.16; N,
4.74. Found: C, 77.29; H, 7.20; N, 4.73. 7b: IR (KBr) 3400-
3200, 1612 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.60-1.90 (m,
4 H), 2.58 (ddd, J ) 17.2, 9.7, 7.4 Hz, 1 H), 2.72 (dm, J ) 17.2
Hz, 1 H), 3.73 (dd, J ) 11.3, 8.5 Hz, 1 H), 3.79 (dd, J ) 11.3,
6.0 Hz, 1 H), 4.36 (dd, J ) 4.4, 3.6 Hz, 1 H), 5.90 (dd, J ) 8.5,
6.0 Hz, 1 H), 7.11-7.30 (m, 10 H); 13C NMR (CDCl3, 75 MHz)
δ 16.0 (CH2), 31.8 (CH2), 32.0 (CH2), 58.2 (CH), 60.4 (CH), 63.0
(CH2), 126.7 (CH), 128.4 (CH), 128.6 (CH), 127.6 (CH), 128.0
(CH), 136.6 (C), 141.9 (C), 172.7 (C); mp 144-146 °C (Et2O);
[R]22D -26 (c 0.32, EtOH). Anal. Calcd for C19H21NO2: C, 77.25;
H, 7.16; N, 4.74. Found: C, 77.24; H, 7.20; N, 4.76.
(2R)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-2-m eth ylp ip er i-
d in e (8). Piperidone 4a (100 mg, 0.43 mmol) was added to a
suspension of LiAlH4 (82 mg, 2.2 mmol) in anhydrous THF
(30 mL), and the resulting mixture was stirred for 1 h at 0 °C.
Then, a 15% aqueous NaOH solution (15 mL) was slowly
added, and the crude mixture was filtered through a Celite
pad. The solution was washed with brine, and the aqueous
layer was extracted with Et2O. The organic extracts were
dried, filtered, and concentrated to give a yellow oil (103 mg),
which was purified by flash chromatography (AcOEt) affording
compound 8 (80 mg, 85%) as an oil: IR (film) 3400-3200 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.08-1.20 (m, 1 H), 1.28 (d, J )
5.8 Hz, 3 H), 1.32-1.50 (m, 2 H), 1.57-1.62 (m, 3 H), 1.70 (td,
J ) 11.5, 2.5 Hz, 1 H), 2.42 (m, 1 H), 2.88 (dm, J ) 11.5 Hz,
1 H), 3.54 (dd, J ) 10.5, 5.2 Hz, 1 H), 3.98 (t, J ) 10.5 Hz, 1
H), 4.31 (dd, J ) 10.5, 5.2 Hz, 1 H), 7.16-7.34 (m, 5 H); 13C
NMR (CDCl3, 75 MHz) δ 21.1 (CH3), 24.5 (CH2), 26.5 (CH2),
36.0 (CH2), 45.5 (CH2), 53.5 (CH), 59.0 (CH2), 60.8 (CH), 127.6
(2R,6S)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-2-m eth yl-6-
p r op ylp ip er id in e (12). A solution of compound 11 (500 mg,
2.30 mmol) in anhydrous Et2O (8 mL) was slowly added to a
cooled (-60 °C) solution of propylmagnesium bromide [pre-
pared from magnesium turnings (559 mg) and 1-bromopropane
(2.1 mL, 23 mmol) in anhydrous THF (5 mL)], and the
resulting mixture was stirred at -60 °C for 20 h and poured
into brine. The aqueous layer was extracted with AcOEt, and
the organic extracts were dried, filtered, and concentrated to
give an oil, which was purified by flash chromatography
(AcOEt) affording piperidine 12 (480 mg, 80%): IR (film)
(CH), 128.0 (CH), 128.2 (CH), 135.6 (C); [R]22 -59 (c 0.5,
D
EtOH) {lit.40 [R]20 - 83.3 (c 1.16, CHCl3)}. Anal. Calcd for
D
C14H21NO: C, 76.66; H, 9.65; N, 6.38. Found: C, 76.81; H, 9.74;
N, 6.10.
(R)-N-(ter t-Bu toxyca r bon yl)-2-m eth ylp ip er id in e (9). A
solution of compound 8 (273 mg, 1.24 mmol) and di-tert-butyl
dicarbonate (470 mg, 2.15 mmol) in AcOEt (40 mL) containing
10% Pd(OH)2-C (100 mg) was hydrogenated at 25 °C for 48
h. The catalyst was removed by filtration, and the solvent was
evaporated to give an oil. Flash chromatography (9:1 hexanes-
Et2O) afforded carbamate 9 (220 mg, 89%): IR (film) 1693
1
3400-3200 cm-1; H NMR (CDCl3, 300 MHz) δ 0.91 (t, J )
7.2 Hz, 3 H), 1.06 (d, J ) 6.6 Hz, 3 H), 1.10-1.65 (m, 10 H),
2.83-2.89 (m, 1 H), 2.88-3.20 (m, 1 H), 3.69 (dd, J ) 10.3,
5.5 Hz, 1 H), 3.80 (dd, J ) 10.3, 7.6 Hz, 1 H), 4.00 (dd, J )
7.6, 5.5 Hz, 1 H), 7.31-7.33 (m, 5 H); 13C NMR (CDCl3, 75
MHz) δ 14.3 (CH3), 15.5 (CH2), 20.0 (CH3), 21.1 (CH2), 26.1
(CH2), 31.1 (CH2), 36.5 (CH2), 50.4 (CH), 52.5 (CH), 61.7 (CH2),
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.12 (d, J ) 7.0 Hz, 3 H),
1.20-1.70 (m, 6 H), 1.46 (s, 9 H), 2.81 (td, J ) 12.7, 2.3 Hz, 1
H), 3.92 (dm, J ) 13.4 Hz, 1 H), 4.38 (m, 1 H); 13C NMR (CDCl3,
75 MHz) δ 15.6 (CH3), 18.6 (CH2), 25.6 (CH2), 28.4 (CH3), 30.0
(CH2), 38.6 (CH2), 45.9 (CH), 78.9 (C), 154.9 (C); [R]22D - 47 (c
65.0 (CH), 127.4 (CH), 128.2 (CH), 128.3 (CH), 139.9 (C); [R]22
D
- 3.4 (c 1.0, CH2Cl2). Anal. Calcd for C17H27NO: C, 78.11; H,
10.41; N, 5.35. Found: C, 78.16; H, 10.50; N, 5.27.
1.5, CHCl3) {lit.18 [R]20 - 46.4 (c 0.83, CHCl3)}.
D
(2R,6S)-2-Met h yl-6-p r op ylp ip er id in e [(2R,6S)-Dih y-
d r op in id in e]. A solution of piperidine 12 (410 mg, 1.57 mmol)
in MeOH (20 mL) containing 10% Pd(OH)2-C (246 mg) was
hydrogenated for 4 h at room temperature. The catalyst was
removed by filtration, and the resulting solution was acidified
by addition of methanolic HCl. The solvent was removed under
reduced pressure, and the residue was dissolved in water. The
aqueous solution was washed with Et2O and concentrated, and
(R)-6-Meth yl-2-p ip er id on e (10). A solution of lactam 4a
(300 mg, 1.29 mmol) in THF (15 mL) was cooled to - 78 °C
and then ammonia was bubbled through the flask until
approximately 40 mL was collected. The reaction mixture was
allowed to warm to -33 °C, and small pieces of sodium were
added until the blue color persisted. After 30 s of stirring, the
mixture was quenched by slow addition of solid NH4Cl. The
(40) Poerwono, H.; Higashiyama, K.; Yamauchi, T.; Takahashi, H.
Heterocycles 1997, 46, 385-400.
(41) Kunz, F.; Re´tey, J .; Arigoni, D.; Tsai, L.; Stadtman, T. C. Helv.
Chim. Acta 1978, 61, 1139-1145.
J . Org. Chem, Vol. 68, No. 5, 2003 1925

Amat et al.
the residue was purified by crystallization (2:1 EtOH-AcOEt)
to give pure (2R,6S)-dihydropinidine hydrochloride (182 mg,
(CDCl3, 300 MHz) δ 0.77 (t, J ) 7.2 Hz, 3 H), 0.90-2.10 (m,
10 H), 2.14-2.25 (m, 1 H), 4.00 (dd, J ) 8.1, 2.7 Hz, 1 H), 4.34
(dd, J ) 9.6, 3.0 Hz, 1 H), 4.38 (dd, J ) 8.1, 6.9 Hz, 1 H), 4.55
(dd, J ) 6.9, 2.7 Hz, 1 H), 7.20-7.50 (m, 5 H); 13C NMR (CDCl3,
75 MHz) δ 14.2 (CH3), 18.5 (CH2), 21.7 (CH2), 30.3 (CH2), 30.7
(CH2), 36.0 (CH2), 54.8 (CH), 61.0 (CH), 72.6 (CH2), 90.4 (CH),
127.3 (CH), 128.2 (CH), 128.9 (CH), 140.1 (C). Deoxo-5a : IR
(film) 3595 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.85-1.80 (m,
10 H), 0.95 (t, J ) 7.5 Hz, 3 H), 1.80 (td, J 11.3, 2.3 Hz, 1 H),
2.39 (m, 1 H), 2.89 (dm, J ) 11.5 Hz, 1 H), 3.58 (dd, J ) 10.4,
5.2 Hz, 1 H), 3.99 (t, J ) 10.4 Hz, 1 H), 4.32 (dd, J ) 10.4, 5.2
Hz, 1 H), 7.10-7.50 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ
14.7 (CH3), 17.7 (CH2), 24.0 (CH2), 26.2 (CH2), 31.4 (CH2), 34.8
(CH2), 45.6 (CH2), 57.3 (CH), 59.5 (CH2), 60.5 (CH), 127.6 (CH),
128.5 (CH), 128.9 (CH), 135.8 (C); [R]22D -58.4 (c 0.83, EtOH).
Anal. Calcd for C16H25NO: C, 77.68; H, 10.19; N, 5.66. Found:
C, 77.67; H, 10.12; N, 5.74.
1
65%) as a white solid: IR (film) 2937 cm-1; H NMR (CDCl3,
500 MHz) δ 0.90 (t, J ) 7.5 Hz, 3 H), 1.26-1.36 (m, 1 H), 1.38-
1.50 (m, 2 H), 1.57 (d, J ) 6.5 Hz, 3 H), 1.58-1.66 (m, 1 H),
1.70-1.84 (m, 3 H), 1.86-1.98 (m, 2 H), 2.08-2.18 (m, 1 H),
2.84-2.94 (m, 1 H), 3.02-3.12 (m, 1 H), 9.05 (br s, 1 H), 9.43
(br s, 1 H); 13C NMR (CDCl3, 75 MHz) δ 13.6 (CH3), 18.6 (CH2),
19.2 (CH3), 22.7 (CH2), 27.2 (CH2), 30.4 (CH2), 35.0 (CH2), 54.2
(CH), 58.1 (CH); mp 247-249 °C (lit.25a mp 242-243 °C); [R]22
D
+12 (c 1.0, EtOH) {lit.21a [R]22 +12.5 (c 1.0, EtOH)}.
D
(2R ,6R )-2-[3-(1,3-D io x o la n -2-y l)p r o p y l]-1-[(1R )-2-
h yd r oxy-1-p h en yleth yl]-6-m eth ylp ip er id in e (13). A solu-
tion of 3-(ethylenedioxy)-1-propylmagnesium bromide [pre-
pared from 2-(3-bromopropyl)-1,3-dioxane (2.24 g, 11.5 mmol)
and magnesium turnings (280 mg) in anhydrous THF (9 mL)]
was slowly added to a solution of compound 11 (634 mg, 2.92
mmol) in THF (48 mL) at 0 °C, and the resulting solution was
stirred for 30 min. The ice bath was removed and the mixture
was stirred at room temperature for 72 h. The crude mixture
was poured into brine, the aqueous layer was extracted with
Et2O, and the combined organic extracts were dried, filtered,
and concentrated. Flash chromatography (gradient from 1:1
hexane-AcOEt to AcOEt) of the residue afforded compound
(2R,6R)-2-[2-(1,3-Dioxa n -2-yl)eth yl]-1-[(1R)-2-h yd r oxy-
1-p h en yleth yl-6-m eth ylp ip er id in e (16). A solution of 2-[2-
(bromomagnesio)ethyl]-1,3-dioxane [prepared from 2-(2-bromo-
ethyl)-1,3-dioxane (0.35 mL, 3.0 mmol) and magnesium turn-
ings (73 mg) in anhydrous THF (6 mL)] was slowly added at
0 °C to a solution of compound 11 (160 mg, 0.74 mmol) in THF
(4 mL), and the resulting solution was stirred for 20 h. The
crude mixture was poured into brine and extracted with
AcOEt. The organic extracts were dried, filtered, and concen-
trated. Flash chromatography (gradient from hexane to AcOEt)
of the residue afforded compound 16 (174 mg, 71%): IR (film)
1
13 (670 mg, 69%): IR (film) 3453 cm-1; H NMR (CDCl3, 300
MHz) δ 1.06 (d, J ) 6.6 Hz, 3 H), 1.00-1.75 (m, 12 H), 2.84-
2.89 (m, 1 H), 2.90-3.04 (m, 1 H), 3.69 (dd, J ) 10.0, 5.5 Hz,
1 H), 3.80 (dd, J ) 10.0, 8.0 Hz, 1 H), 3.84 (m, 1 H), 3.85 (dd,
J ) 5.0, 3.0 Hz, 1 H), 3.95 (dd, J ) 5.0, 3.0 Hz, 1 H), 3.97 (m,
1 H), 4.00 (dd, J ) 8.0, 5.5 Hz, 1 H), 4.84 (t, J ) 4.7 Hz, 1 H),
7.25-7.40 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ 15.5 (CH2),
20.2 (CH3), 22.3 (CH2), 25.9 (CH2), 31.0 (CH2), 33.9 (CH2), 34.3
(CH2), 50.3 (CH), 52.7 (CH), 61.6 (CH2), 64.8 (CH2), 65.0 (CH),
104.3 (CH), 127.4 (CH), 128.2 (CH), 128.3 (CH), 140.0 (C).
Anal. Calcd for C20H32ClNO3: C, 64.93; H, 8.72; N, 3.79.
Found: C, 64.58; H, 8.73; N, 3.77.
1
3439 cm-1; H NMR (CDCl3, 300 MHz) δ 1.07 (d, J ) 6.7 Hz,
3 H), 1.10-1.80 (m, 11 H), 2.00-2.20 (m, 1 H), 2.84-2.94 (m,
1 H), 2.96-3.10 (m, 1 H), 3.71 (dd, J ) 10.5, 5.5 Hz, 1 H), 3.78
(t, J ) 11.0 Hz, 1 H), 3.79 (m, 1 H), 3.82 (dd, J ) 10.5, 7.5 Hz,
1 H), 4.02 (dd, J ) 7.3, 5.3 Hz, 1 H), 4.13 (m, 2 H), 4.53 (t, J
) 4.6 Hz, 1 H), 7.20-7.50 (m, 5 H); 13C NMR (CDCl3, 75 MHz)
δ 15.3 (CH2), 20.1 (CH3), 25.8 (CH2), 28.3 (CH2), 30.9 (CH2),
33.4 (CH2), 50.0 (CH), 52.4 (CH), 61.8 (CH2), 65.1 (CH), 66.8
(2 CH2), 102.3 (CH), 127.4 (CH), 128.2 (CH), 128.4 (CH), 140.0
(C). Anal. Calcd for C20H31NO3: C, 72.04; H, 9.37; N, 4.20.
Found: C, 72.12; H, 9.38; N, 4.17.
(4R,9a S)-4-Meth ylqu in olizid in e (14). Piperidine 13 (150
mg, 0.45 mmol) was dissolved in a 0.06 M aqueous HCl
solution (10 mL) and hydrogenated at atmospheric pressure
and room temperature for 72 h in the presence of 10% Pd-C
(35 mg). The mixture was filtered, washed with Et2O, basified
by addition of solid Na2CO3, and extracted with CH2Cl2. The
organic solution was concentrated to give 14 as an oil, which
was taken up with an ethereal HCl solution. Elimination of
the solvent under reduced pressure afforded the hydrochloride
of compound 14 (56 mg, 66%) as a white solid: 1H NMR
(CDCl3, 300 MHz) δ 1.56 (d, J ) 6.3 Hz, 3 H), 1.40-1.68 (m,
8 H), 1.75-1.92 (m, 6 H), 2.06-2.60 (m, 5 H), 2.76 (m, 1 H),
2.88 (m, 1 H), 3.82 (dm, J ) 11.6 Hz, 1 H); 13C NMR (CDCl3,
75 MHz) δ 17.5 (CH3), 22.5 (CH2), 22.7 (CH2), 23.0 (CH2), 30.3
(CH2), 30.4 (CH2), 31.7 (CH2), 51.1 (CH2), 62.2 (CH), 65.3 (CH);
(2R,6R)-2-[2-(1,3-Dioxa n -2-yl)eth yl]-1-[(1R)-2-h yd r oxy-
1-ph en yleth yl]-6-pr opylpiper idin e (17). Operating as above,
starting from compound 15 (433 mg, 1.76 mmol) piperidine
17 (492 mg, 77%) was obtained after purification by flash chro-
matography (gradient from 1:1 hexane-AcOEt to AcOEt): IR
(film) 3590 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.83 (t, J ) 7.4
Hz, 3 H), 0.90-1.80 (m, 15 H), 2.08 (m, 1 H), 2.75-2.82 (m, 1
H), 2.91-3.01 (m, 1 H), 3.70 (dd, J ) 10.5, 5.0, 1 H), 3.74-
3.83 (m, 2 H), 3.84 (dd, J ) 10.7, 7.5 Hz, 1 H), 3.98 (dd, J )
7.4, 5.2 Hz, 1 H), 4.10-4.15 (m, 2 H), 4.54 (t, J ) 4.6 Hz, 1 H),
7.25-7.45 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ 14.2 (CH3),
14.7 (CH2), 20.8 (CH2), 25.8 (2 CH2), 27.2 (CH2), 27.9 (CH2),
33.5 (CH2), 35.6 (CH2), 52.3 (CH), 56.0 (CH), 62.0 (CH2), 66.9
(2 CH2), 67.2 (CH), 102.3 (CH), 127.6 (CH), 128.3 (CH), 128.6
(CH).
[R]22 - 23 (c 0.5, CHCl3). Anal. Calcd for C10H20ClN‚H2O: C,
D
61.01; H, 10.65; N, 7.11. Found: C, 61.01; H, 10.54; N, 7.14.
For the base: 1H NMR (CDCl3, 300 MHz) δ 1.09 (d, J ) 6.0
Hz, 3 H), 1.15-2.00 (m, 15 H), 3.26 (dm, J ) 10.5 Hz, 1 H);
13C NMR (CDCl3, 75 MHz) δ 20.7 (CH3), 24.5 (CH2), 24.6 (CH2),
26.3 (CH2), 33.8 (CH2), 34.0 (CH2), 35.3 (CH2), 51.7 (CH2), 59.0
(CH), 63.0 (CH).
(5R,8a R)-5-Meth ylin d olizin e (18). A solution of compound
16 (200 mg, 0.60 mmol) in EtOH (10 mL) and 1.0 M aqueous
HCl (1 mL) containing 10% Pd-C (30 mg) was hydrogenated
under vigorous stirring at room temperature and atmospheric
pressure for 18 h. The catalyst was removed by filtration, and
the solution was concentrated under vacuum. The residue was
taken-up with 1.0 N aqueous HCl (10 mL) and extracted with
Et2O. The aqueous layer was basified by addition of solid
Na2CO3 and extracted with Et2O. The ethereal solution was
acidified by addition of a few drops of ethereal HCl and
concentrated under vacuum to give the hydrochloride of 18
(3R,5R)-3-P h en yl-5-p r op yl-2,3,6,7,8,8a -h exa h yd r o-5H-
oxa zolo[3,2-a ]p yr id in e (15). Operating as described for 11,
starting from lactam 5a (400 mg, 1.53 mmol), compound 15
(mixture of epimers, 255 mg, 68%) and (2R)-1-[(1R)-2-hydroxy-
1-phenylethyl]-2-propylpiperidine (deoxo-5a ; 61 mg, 16%) were
obtained after purification of the crude mixture by flash
chromatography (7:3 AcOEt-hexane). Major epimer: 1H NMR
(CDCl3, 300 MHz) δ 0.81 (t, J ) 7.2 Hz, 3 H), 0.88-2.10 (m,
10 H), 2.86 (m, 1 H), 3.58 (t, J ) 7.2 Hz, 1 H), 4.02 (t, J ) 7.2
Hz, 1 H), 4.10 (dd, J ) 7.8, 6.9 Hz, 1 H), 4.23 (dd, J ) 9.3, 3.3
Hz, 1 H), 7.20-7.45 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ
14.2 (CH3), 17.9 (CH2), 20.6 (CH2), 24.7 (CH2), 27.4 (CH2), 31.6
(CH2), 52.2 (CH), 61.3 (CH), 73.3 (CH2), 87.7 (CH), 127.5 (CH),
127.9 (CH), 128.4 (CH), 139.5 (C). Minor epimer: 1H NMR
1
(86 mg, 82%) as a white solid: IR (film) 3398 cm-1; H NMR
(CDCl3, 300 MHz, assigned by 1H-1H correlation NMR experi-
ments) δ 1.45 (qd, J ) 13.5, 4.5 Hz, 1 H, H-7), 1.47 (d, J ) 6.5
Hz, 3H, CH3), 1.79 (dm, J ) 14.5 Hz, 1 H, H-6), 1.87-2.00 (m,
4 H, H-1, H-2, H-6, H-8), 2.05-2.26 (m, 4 H, H-1, H-2, H-6,
H-8), 2.65 (m, 1 H, H-3), 2.72-2.80 (m, 1 H, H-8a), 2.80-2.84
(m, 1 H, H-5), 3.78-3.82 (m, 1 H, H-3), 11.6 (br s, 1H, NH);
1926 J . Org. Chem., Vol. 68, No. 5, 2003

Enantioselective Synthesis of Piperidine Alkaloids
1
13C NMR (CDCl3, 75 MHz, assigned by H-13C NMR correla-
Hz, 3 H), 1.13 (d, J ) 6.5 Hz, 3 H), 1.05-1.95 (m, 16 H), 2.02-
2.09 (m, 1 H), 2.18-2.24 (m, 1 H), 2.42-2.50 (m, 1 H); 13C NMR
(CDCl3, 50 MHz) δ 14.2 (CH3), 22.9 (CH3), 22.9 (CH2), 24.9
(CH2), 29.4 (CH2), 29.8 (CH2), 30.3 (CH2), 30.9 (CH2), 35.8
tion experiments) δ 18.0 (CH3), 19.1 (C-2), 23.0 (C-7), 27.0 (C-
1), 28.4 (C-8), 30.8 (C-6), 50.2 (C-3), 61.0 (C-5), 67.6 (C-8a);
[R]22 -96 (c 1.0, EtOH). Anal. Calcd for C9H18ClN: C, 61.52;
D
H, 10.33; N, 7.97. Found: C, 61.29; H, 10.29; N, 7.76. For the
(CH2), 39.7 (CH2), 60.3 (CH), 62.9 (CH), 67.1 (CH); [R]22 +33
D
base: IR (film) 2810 cm-1; H NMR (CDCl3, 300 MHz) δ 1.04
1
(c 0.6, hexane) {lit.32 [R]22 +34.7 (c 1.02, hexane)}.
D
(d, J ) 6.7 Hz, 3 H), 1.10-1.80 (m, 11 H), 1.91 (m, 1 H), 1.95
(m, 1 H), 3.13 (tm, J ) 9.0 Hz, 1 H); 13C NMR (CDCl3, 75 MHz)
δ 20.2 (CH3), 21.0 (CH2), 24.6 (CH2), 29.9 (CH2), 30.4 (CH2),,
34.0 (CH2), 51.5 (CH2), 58.8 (CH), 64.6 (CH).
(6R)-1-[(1R)-2-(ter t-Bu t yld im et h ylsilyloxy)-1-p h en yl-
eth yl]-6-m eth yl-2-p ip er id on e (23). To a solution of alcohol
4a (685 mg, 2.94 mmol) in anhydrous CH2Cl2 (11 mL) were
added TBDMSCl (904 mg, 6.0 mmol), Et3N (0.84 mL, 6.0
mmol), and imidazole (204 mg, 3.0 mmol), and the resulting
mixture was stirred under argon at room temperature for 36
h. The crude reaction mixture was poured into saturated
aqueous NH4Cl, and the aqueous layer was extracted with
CH2Cl2. The combined organic extracts were dried, filtered,
and concentrated to give a yellow oil (1.9 g) which, after flash
chromatography (1:1 AcOEt-hexane), afforded compound 23
(5R,8a R)-5-P r op ylin d olizid in e (19) [Gep h yr ot oxin
167B]. Operating as described for 18, starting from 17 (321
mg, 0.89 mmol), the hydrochloride of compound 19 (164 mg,
1
90%) was obtained as a white solid: IR (film) 3350 cm-1; H
NMR (CDCl3, 500 MHz) δ 0.91 (t, J ) 7.0 Hz, 3 H), 1.15-1.25
(m, 1 H), 1.26-1.45 (m, 2 H), 1.60.1.80 (m, 1 H), 1.85-2.05
(m, 6 H), 2.06-2.25 (m, 4 H), 2.50-2.65 (m, 2H), 2.66-2.68
(m, 1 H), 3.80-3.90 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.7
(CH3), 18.9 (CH2), 19.4 (CH2), 23.2 (CH2), 27.1 (CH2), 27.8
(CH2), 28.5 (CH2), 33.5 (CH2), 50.4 (CH2), 65.5 (CH), 68.3 (CH).
For the base: 1H NMR (CDCl3, 300 MHz) δ 0.94 (t, J ) 6.9
Hz, 3 H), 1.21-2.10 (m, 17 H), 3.32 (td, J ) 8.8, 2.0 Hz, 1 H);
13C NMR (CDCl3, 75 MHz) δ 14.5 (CH3), 19.1 (CH2), 20.3 (CH2),
24.6 (CH2), 30.4 (CH2), 30.7 (CH2), 30.8 (CH2), 36.7 (CH2), 51.5
(CH2), 63.8 (CH), 65.1 (CH); [R]22D -109 (c 1.32, CH2Cl2) {lit.28b
1
(931 mg, 91%) as a transparent oil: IR (KBr) 1626 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.03 (s, 3 H), 0.04 (s, 3 H), 0.87 (s,
9 H), 0.96 (d, J ) 6.5 Hz, 3 H), 1.58-1.64 (m, 1 H), 1.67-2.00
(m, 3 H), 2.33-2.51 (m, 2 H), 3.66-3.70 (m, 1 H), 4.22 (dd, J
) 10.4, 6.5 Hz, 1 H), 4.27 (dd, J ) 10.4, 6.5 Hz, 1 H), 5.06 (t,
J ) 6.5 Hz, 1 H), 7.20-7.45 (m, 5 H); 13C NMR (CDCl3, 75
MHz) δ -5.6 (CH3), -5.5 (CH3), 16.2 (CH3), 18.0 (C), 20.2
(CH2), 25.7 (CH3), 29.8 (CH2), 31.8 (CH2), 51.2 (CH), 61.6 (CH),
63.4 (CH2), 127.2 (CH), 128.1 (CH), 128.2 (CH), 139.0 (C), 170.2
(C); mp 50-52 °C (Et2O); [R]22D -19 (c 1.0, EtOH). Anal. Calcd
for C20H33NO2Si: C, 69.11; H, 9.57; N, 4.03. Found: C, 69.06;
H, 9.67; N, 3.97.
[R]20 -106.9 (c 1.1, CH2Cl2)}.
D
(2S,6S)-2[(2-Bu tyl-1,3-d ioxola n -2-yl)eth yn yl]-1-[(1S)-2-
h yd r oxy-1-p h en yleth yl]-6-m eth ylp ip er id in e (21). A 1.0 M
solution of ethylmagnesium bromide (3.7 mL, 3.7 mmol) in
THF was slowly added to a solution of 2-butyl-2-ethynyl-1,3-
dioxolane (567 mg, 3.68 mmol) in anhydrous THF (15 mL) at
0 °C. After 30 min of stirring, the solution was added via
cannula to a solution of en t-11 (200 mg, 0.92 mmol) in
anhydrous THF (2 mL) at 0 °C. The resulting mixture was
warmed to room temperature, stirred for 14 h, poured into
brine, and extracted with AcOEt. The organic extracts were
dried, filtered, and concentrated to give a residue, which was
purified by flash chromatography (98:2 hexanes-Et2NH)
affording piperidine 21 (256 mg, 75%): IR (film) 3460, 2222
(6R)-1-[(1R)-2-(ter t-Bu t yld im et h ylsilyloxy)-1-p h en yl-
eth yl]-6-m eth yl-2-p ip er id in eth ion e (24). Lawesson’s re-
agent (1.82 g, 4.50 mmol) was added to a solution of lactam
23 (2.60 g, 7.50 mmol) in anhydrous toluene (135 mL) heated
at 75 °C, and the resulting solution was stirred for 40 min.
The mixture was cooled to room temperature and concentrated
under reduced pressure, and the resulting residue was purified
by flash chromatography (4:1 hexanes-Et2O) affording thio-
lactam 24 (2.24 g, 82%) as a brown solid: IR (film) 1470 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.11 (s, 3 H), 0.12 (s, 3 H), 0.60
(d, J ) 6.8 Hz, 3 H), 0.90 (s, 9 H), 1.60-1.95 (m, 5 H), 3.04
(ddd, J ) 18.2, 8.9, 5.5 Hz, 1 H), 3.33 (ddd, J ) 18.2, 8.5, 5.4
Hz, 1 H), 4.06-4.10 (m, 1 H), 4.19 (dd, J ) 10.7, 5.5 Hz, 1 H),
4.30 (dd, J ) 10.7, 5.5 Hz, 1 H), 7.19 (t, J ) 5.5 Hz, 1 H), 7.35
(m, 3 H), 7.57 (m, 2 H); 13C NMR (CDCl3, 75 MHz) δ -5.7
(CH3), -5.5 (CH3), 16.2 (CH2), 18.0 (C), 19.3 (CH3), 25.7 (CH3),
28.6 (CH2), 39.9 (CH2), 51.9 (CH), 61.4 (CH2), 63.3 (CH), 127.9
(CH), 128.3 (CH), 129.2 (CH), 136.8 (C), 200.9 (C); mp 58-61
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.96 (t, J ) 7.3 Hz, 3 H),
1.12 (d, J ) 6.8 Hz, 3 H), 1.35-1.45 (m, 4 H), 1.53-1.63 (m, 3
H), 1.80-1.94 (m, 5 H), 2.18 (m, 1 H), 2.86-2.91 (m, 1 H),
3.85-3.95 (m, 3 H), 4.00-4.13 (m, 5 H), 7.25-7.50 (m, 5 H);
13C NMR (CDCl3, 75 MHz) δ 14.0 (CH3), 14.4 (CH3), 16.6 (CH2),
22.6 (CH2), 26.2 (CH2), 32.2 (2 CH2), 38.8 (CH2), 44.9 (CH),
49.7 (CH), 63.7 (CH2), 64.5 (2 CH2), 64.8 (CH), 82.5 (C), 85.7
(C), 103.4 (C), 127.5 (CH), 128.4 (CH), 128.5 (CH), 139.9 (C).
Anal. Calcd for C23H33NO3: C, 74.37; H, 8.95; N, 3.77. Found:
C, 73.98; H, 9.11; N, 3.52.
°C; [R]22 -169 (c 0.29, EtOH).
D
(2R,6R)-[(1R)-2-(ter t-Bu tyld im eth ylsilyloxy)-1-p h en yl-
eth yl]-2,6-d im eth ylp ip er id in e (26). Iodomethane (1.2 mL,
19 mmol) was added to a solution of thiolactam 24 (700 mg,
1.93 mmol) in anhydrous Et2O (1 mL), and the mixture was
stirred at room temperature for 14 h. Evaporation of the
solvent and excess of iodomethane under nitrogen at reduced
pressure afforded iminium salt 25 as an orange foam: 1H NMR
(CDCl3, 300 MHz) δ 0.02 (s, 6 H), 0.68 (d, J ) 6.6 Hz, 3 H),
0.76 (s, 9 H), 1.65-2.15 (m, 4 H), 2.92 (s, 3 H), 3.11 (dt, J )
20.5, 7.5 Hz, 1 H), 3.90 (ddd, J ) 20.5, 8.7, 1.3 Hz, 1 H), 4.18
(dd, J ) 11.2, 5.0 Hz, 1 H), 4.33 (dd, J ) 11.2, 8.0 Hz, 1 H),
5.78 (dd, J ) 8.0, 5.0 Hz, 1 H), 7.25-7.48 (m, 5 H); 13C NMR
(CDCl3, 75 MHz) δ -4.0 (2 CH3), 14.1 (CH2), 18.0 (CH3), 20.0
(CH3), 25.5 (3 CH3), 27.6 (CH2), 32.8 (CH2), 55.4 (CH), 61.0
(CH2), 69.2 (CH), 129.0 (2 CH), 129.3 (2 CH), 130.0 (CH), 131.1
(C), 193.5 (C). Compound 25 was dissolved in anhydrous THF
(7 mL), cooled to 0 °C, and added via cannula to a 0.2 M
solution of Me2CuLi‚LiI (19 mL) in THF-Et2O. The mixture
was stirred at - 5 °C for 30 min and then NaBH4 (154 mg,
4.07 mmol) was added. The resulting suspension was stirred
at 0 °C for 10 min, glacial AcOH (3.5 mL) was slowly added,
and the stirring was continued for 1 h at room temperature.
The crude reaction mixture was poured into water (15 mL)
and solid Na2CO3 was added till alkaline pH. The aqueous
(2S,6S)-2-Meth yl-6-(3-oxoh ep tyl)p ip er id in e (22). A solu-
tion of acetal 21 (256 mg, 0.69 mmol) in 0.2 N aqueous HCl
(10 mL) containing 10% Pd-C (90 mg) was hydrogenated for
72 h at room temperature and atmospheric pressure. The
catalyst was removed by filtration, and the solution was
diluted with 2 N aqueous HCl (5 mL) and extracted with Et2O.
The aqueous layer was basified by addition of solid Na2CO3
and extracted with CH2Cl2. The combined organic extracts
were dried, filtered, and concentrated to give ketone 22 (122
mg, 84%). For the hydrochloride: 1H NMR (CDCl3, 200 MHz,
most significant signals) δ 0.87 (t, J ) 7.5 Hz, 3 H), 1.54 (d, J
) 4.6 Hz, 3 H), 3.00 (m, 1 H), 3.10 (m, 1 H), 9.00 (br s, 1 H),
9.15 (br s, 1 H); 13C NMR (CDCl3, 50.3 MHz) δ 13.7 (CH3),
19.2 (CH3), 22.1 (CH2), 22.7 (CH2), 25.6 (CH2), 27.1 (CH2), 27.7
(CH2), 30.1 (CH2), 38.3 (CH2), 42.3 (CH2), 54.0 (CH), 57.4 (CH)
209.3 (C).
(3R,5S,8a S)-3-Bu t yl-5-m et h ylin d olizid in e
(Mon o-
m or in e I). A solution of ketone 22 (100 mg, 0.47 mmol) in
MeOH (15 mL) containing 10% Pd-C was hydrogenated for
14 h at room temperature and atmospheric pressure. The
suspension was filtered, and the solution was concentrated to
give an oil (83 mg, 90%), which was identified as the alkaloid
monomorine: 1H NMR (CDCl3, 300 MHz) δ 0.89 (t, J ) 6.8
J . Org. Chem, Vol. 68, No. 5, 2003 1927

Amat et al.
layer was extracted with Et2O, and the combined organic
extracts were dried, filtered, and concentrated to give a yellow
oil (632 mg) which, after flash chromatography (1:1 Et2O-
hexane), afforded compound 26 (368 mg, 55%) and (2R)-
1-[(1R)-2-(ter t-bu t yld im et h ylsilyloxy)-1-p h en ylet h yl]-2-
m eth ylp ip er id in e (O-TBDMS-8, 96 mg, 15%). 26: IR (film)
2928 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.03 (s, 3 H), 0.05 (s,
3 H), 0.85-0.87 (m, 15 H), 1.25-1.32 (m, 2 H), 1.50-1.60 (m,
4 H), 3.18 (m, 2 H), 3.97 (dd, J ) 10.0, 6.0 Hz, 1 H), 4.03 (dd,
J ) 10.0, 7.0 Hz, 1 H), 4.14 (t, J ) 6.3 Hz, 1 H), 7.10-7.50 (m,
5 H); 13C NMR (CDCl3, 75 MHz) δ -5.3 (2 CH3), 18.3 (2 CH3),
18.6 (C), 19.8 (CH2), 25.9 (3 CH3), 34.0 (2 CH2), 48.5 (2 CH),
61.9 (CH), 64.6 (CH2), 125.9 (CH), 127.6 (2 CH), 128.2 (2 CH),
isomers) in anhydrous THF (5 mL), and the mixture was
stirred at room temperature for 4 h. The mixture was poured
into brine (10 mL), and the aqueous layer was extracted with
Et2O. The combined organic extracts were dried, filtered, and
concentrated to give an oil (560 mg), which, after flash
chromatography (95:5 CH2Cl2-Et2NH), afforded trans-28 (229
mg, 58%) and cis-28 (98 mg, 25%). trans-28: IR (film) 3425
cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.53 (m, 1 H), 0.90 (t, J )
6.9 Hz, 3 H), 1.06 (d, J ) 6.3 Hz, 3 H), 0.80-1.80 (m, 25 H),
2.93-2.98 (m, 1 H), 3.20-3.25 (m, 1 H), 3.57 (dd, J ) 9.7, 4.7
Hz, 1 H), 4.02 (t, J ) 10.4 Hz, 1 H), 4.35 (dd, J ) 10.4, 5.1 Hz,
1 H), 7.20-7.40 (m, 5 H); 13C NMR (CDCl3, 75 MHz) δ 14.1
(CH3), 19.4 (CH2), 20.0 (CH3), 22.7 (CH2), 27.1 (CH2), 28.4
(CH2), 29.3 (3 CH2), 29.4 (CH2), 29.6 (CH2), 29.7 (CH2), 29.9
(CH2), 30.2 (CH2), 31.9 (CH2), 36.4 (CH2), 47.2 (CH), 51.4 (CH),
58.4 (CH), 58.6 (CH2), 127.4 (CH), 127.9 (CH), 128.4 (CH),
144.0 (C); [R]22 -40 (c 1.8, EtOH). Anal. Calcd for C21H37
-
D
NOSi: C, 72.56; H, 10.73; N, 4.03. Found: C, 72.56; H, 10.71;
1
N, 4.04. O-TBDMS-8: IR (film) 2954 cm-1; H MNR (CDCl3,
300 MHz) δ -0.07 (s, 3 H), -0.04 (s, 3 H), 0.78 (s, 9 H), 1.13
(d, J ) 6.2 Hz, 3 H), 1.05-1.19 (m, 1 H), 1.20-1.35 (m, 1 H),
1.47-1.59 (m, 4 H), 2.16-2.24 (m, 1 H), 2.37-2.42 (m, 1 H),
2.72-2.78 (m, 1 H), 3.85-4.03 (m, 3 H), 7.24-7.28 (m, 5 H);
13C NMR (CDCl3, 75 MHz) δ -5.5 (CH3), -5.4 (CH3), 17.2
(CH3), 22.8 (CH2), 25.7 (CH3), 26.5 (CH2), 34.6 (CH2), 46.6
(CH2), 52.4 (CH), 64.6 (CH), 65.4 (CH2), 126.6 (CH), 127.5 (CH),
129.1 (CH), 138.5 (C). Anal. Calcd for C20H35NOSi: C, 72.01;
H, 10.57; N, 4.19. Found: C, 71.86; H, 10.50; N, 4.11.
140.5 (C); [R]22D -32 (c 1.1, MeOH). cis-28: IR (film) 3418 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 0.89 (t, J ) 6.9 Hz, 3 H), 1.13 (d,
J ) 6.5 Hz, 3 H), 1.17-1.80 (m, 26 H), 2.89-2.93 (m, 1 H),
3.08-3.11 (m, 1 H), 3.78 (dd, J ) 10.9, 5.1 Hz, 1 H), 3.87-
3.93 (m, 1 H), 4.07-4.11 (m, 1 H), 7.25-7.45 (m, 5 H); 13C NMR
(CDCl3, 75 MHz, most significant signals) δ 14.1 (CH3), 15.7
(CH2), 19.8 (CH3), 22.7 (CH2), 26.1 (CH2), 28.1 (CH2), 29.3
(CH2), 29.8 (CH2), 31.0 (CH2), 32.0 (CH2), 33.8 (CH2), 51.3 (CH),
53.8 (CH), 61.8 (CH2), 65.5 (CH), 127.7 (CH), 128.4 (CH), 128.6
(CH), 140.0 (C).
(2R,6R)-2,6-Dim et h ylp ip er id in e (Lu p et id in e). Pd-
(OH)2-C (20%, 60 mg) was added to a solution of compound
26 (594 mg, 1.71 mmol) in a 0.5 M ethanolic HCl solution (5
mL), and the mixture was hydrogenated at 75 psi for 13 h.
The catalyst was removed by filtration, and the solution was
concentrated under vacuum to give a brown gum, which was
taken up with water. The aqueous solution was washed with
Et2O and concentrated to dryness. The residue was crystallized
from Et2O-EtOH to give the hydrochloride of the alkaloid
lupetidine (199 mg, 78%): 1H NMR (CDCl3, 300 MHz) δ 1.48
(d, J ) 6.8 Hz, 6 H), 1.58 (dd, J ) 15.0, 6.0 Hz, 1 H), 1.62-
1.71 (m, 3 H), 1.96-2.00 (m, 2 H), 3.53-3.56 (m, 2 H), 9.40
(br s, 2 H); 13C NMR (CDCl3, 75 MHz) δ 16.8 (2 CH3), 17.2
(CH2), 28.7 (2 CH2), 47.3 (2 CH); mp 243-245 °C (lit.35d mp
(2R,6R)-2-Meth yl-6-u n d ecylp ip er id in e (Solen op sin A).
A solution of trans-28 (151 mg, 0.40 mmol) in MeOH (20 mL)
containing 20% Pd(OH)2-C (15 mg) was hydrogenated at
atmospheric pressure overnight under vigorous stirring. The
suspension was filtered, and the solution was acidified by
addition of a few drops of ethereal HCl and concentrated. The
residue was dissolved in water, and the resulting aqueous
solution was washed with Et2O and then concentrated to
dryness. Purification of the resulting residue by crystallization
from EtOH-Et2O afforded a white solid (87 mg, 74%), which
was identified as the hydrochloride of the alkaloid solenopsin
A: 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, J ) 6.5 Hz, 3 H),
1.16-1.40 (m, 18 H), 1.47 (d, J ) 6.8 Hz, 3 H), 1.54-1.80 (m,
5 H), 1.86-2.08 (m, 3 H), 3.24-3.29 (m, 1 H), 3.50-3.55 (m, 1
H), 9.40 (br s, 2 H); 13C NMR (CDCl3, 75 MHz) δ 14.1 (CH3),
16.8 (CH3), 17.3 (CH2), 22.6 (CH2), 25.8 (CH2), 26.1 (CH2), 29.0
(CH2), 29.3 (2 CH2), 29.4 (CH2), 29.5 (3 CH2), 30.7 (CH2), 31.8
(CH2), 47.9 (CH), 51.7 (CH); mp 143-144 °C (lit.42 mp 141-
142 °C); [R]22 -7.0 (c 1.3, CHCl3) {lit.42 [R]22 -7.6 (c 0.5,
247-249 °C); [R]22 +12.4 (c 3.04, EtOH) {lit.35d [R]D +12.8 (c
D
3.06, EtOH)}.
(2R,6R)-1-[(1R)-2-(ter t-Bu tyld im eth ylsilyloxy)-1-p h en -
yleth yl]-2-m eth yl-6-u n d ecylp ip er id in e (27). To a cooled (0
°C) solution of undecylmagnesium bromide [prepared from
undecyl bromide (1.75 mL, 7.86 mmol) and magnesium turn-
ings (191 mg)] in anhydrous THF (15 mL) was added CuI (748
mg, 3.93 mmol), and the mixture was stirred at 0 °C for 10
min. Then, a solution of salt 25 [prepared from thioamide 24
(700 mg, 1.93 mmol) as described above] in anhydrous THF
(7 mL) was added, and the mixture was stirred at 0 °C for 30
min. The temperature was lowered to -20 °C, NaBH4 (154
mg, 4.07 mmol) was added, and the stirring was continued
for 10 min. Then, glacial AcOH (2.1 mL) was added, the cooling
bath was removed and, after 1 h of stirring, the solution was
poured into water (15 mL), made alkaline by addition of solid
Na2CO3, and extracted with Et2O. The combined organic
extracts were dried, filtered, and concentrated to give an oil
(750 mg). Flash chromatography (9:1 hexanes-Et2O) afforded
compound 27 (516 mg, 55%) as a 7:3 mixture of trans-cis
isomers, respectively. trans-27: 1H NMR (CDCl3, 300 MHz) δ
0.01 (s, 3 H), 0.03 (s, 3 H), 0.86 (s, 9 H), 0.88 (t, J ) 7.0 Hz, 3
H), 0.98 (d, J ) 6.7 Hz, 3 H), 1.00-1.70 (m, 26 H), 2.96 (m, 1
H), 3.15 (m, 1 H), 3.94-4.00 (m, 2 H), 4.15 (t, J ) 6.5 Hz, 1
H), 7.10-7.50 (m, 5 H); 13C NMR (CDCl3, 75 MHz, most
significant signals) δ -5.3 (CH3), 14.6 (CH3), 20.3 (CH3), 20.3
(CH2), 25.9 (CH3), 48.5 (CH), 52.9 (CH), 61.2 (CH), 64.9 (CH2),
125.8 (CH), 127.4 (CH), 128.5 (CH), 144.4 (C).
D
D
CHCl3)}.
Ack n ow led gm en t . This work was supported by
the DGICYT, Spain (BQU2000-0651). Thanks are
also due to the DURSI, Generalitat de Catalunya, for
Grant 2001SGR-0084, to the “Ministerio de Educacio´n
y Ciencia” for a fellowship to J .H., and to the SCT of
the University of Barcelona. We thank DSM Deretil
(Almer´ıa, Spain) for the generous gift of (R)-phenyl-
glycine.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
compounds 2a -7a ,b, 9-19, 21, 22, 26, cis-28, trans-28,
coniine-HCl, dihydropinidine-HCl, monomorine I, lupetidine-
HCl, and solenopsin A-HCl. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0266083
(2R,6R)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-2-m eth yl-6-
u n d ecylp ip er id in e (28). A 1.0 M solution of tetra-n-butyl-
ammonium fluoride (2.0 mL, 2.0 mmol) in THF was added to
a solution of compound 27 (516 mg, 1.06 mmol, mixture of
(42) Comins, D. L.; Benjelloun, N. R. Tetrahedron Lett. 1994, 35,
829-832.
1928 J . Org. Chem., Vol. 68, No. 5, 2003