A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones: Application to the asymmetric syntheses of neurokinin substance P receptor antagonist (-)-L-733,061 and (-)-deoxocassine

Article abstract of DOI:10.1021/jo049166z

A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones based on the regio- and diastereoselective reductive alkylation of (S)-3- benzyloxyglutarimide 7 is described. This method opens an entrance to chiral nonracemic substituted 3-piperidinols.

Full text of DOI:10.1021/jo049166z

A Gen er a l Ap p r oa ch to
(5S,6R)-6-Alk yl-5-ben zyloxy-2-p ip er id in on es: Ap p lica tion to th e
Asym m etr ic Syn th eses of Neu r ok in in Su bsta n ce P Recep tor
An ta gon ist (-)-L-733,061 a n d (-)-Deoxoca ssin e†
Liang-Xian Liu, Yuan-Ping Ruan, Zheng-Qing Guo, and Pei-Qiang Huang*
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
Xiamen University, Xiamen, Fujian 361005, P. R. China
pqhuang@xmu.edu.cn
Received May 17, 2004
A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones based on the regio- and
diastereoselective reductive alkylation of (S)-3-benzyloxyglutarimide 7 is described. This method
opens an entrance to chiral nonracemic substituted 3-piperidinols. The versatility of the method is
illustrated by the asymmetric syntheses of neurokinin substance P receptor antagonist L-733,061
(ent-1), (-)-deoxocassine (4), and an inhibitor of HIV proteases (5a ).
CHART 1. Som e Bioa ctive P ip er id in es a n d
2-P ip er id in on es
Selectivity, versatility, and flexibility are among the
major concern in organic synthesis. Development of
multifunctional chiral nonracemic building blocks or
synthons has been proven to be a powerful strategy to
meet the needs of both the versatility and flexibility.1
2-Alkyl-3-hydroxypiperidines, 2,6-dialkyl-3-hydroxypip-
eridines, and the corresponding 5-hydroxy-2-piperidino-
nes are structural units found in a number of bioactive
natural products, drugs, and drug candidates. For ex-
ample, (+)-L-733,060 (1)2 and (2S,3S)-CP-99,994 (2) are
selective and potent neurokinin substance P receptor
antagonists, which have been shown to possess potent
antiemetic activity (Chart 1); febrifugine and isofebri-
fugine are well-known antimalarial alkaloids;3 (-)-cass-
ine (3)4 is a representative of a number of bioactive 2,6-
dialkyl-3-piperidinol based alkaloids,5 and 1,3,6-tri-
substituted 5-hydroxy-2-piperidinones such as 5 are
potential candidates as inhibitors of HIV proteases.6
The important bioactivities, common structural fea-
tures, and stereochemistry and substituent diversities
associated with these piperidines and 2-piperidinones
have stimulated the development of 3-piperidinol syn-
thon-based versatile synthetic approaches.7
† Dedicated to Professor Li-Xin Dai on the occasion of his 80th
birthday.
Recently, we have embarked on a program aimed at
the development of the protected 3-hydroxyglutarimide
(S)-6 as a versatile multifunctional chiral nonracemic
3-piperidinol synthon.8 The studies have culminated in
the asymmetric syntheses of neurokinin substance P
(1) For notable examples, see: (a) Groaning M, D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843. (b) Husson, H.-P.; Royer, J . Chem. Soc.
Rev. 1999, 28, 383. (c) Comins, D. L.; J oseph, S. P. In Advances in
Nitrogen Heterocycles; Moody, E. J ., Ed.; J AI Press: Greenwich, CT,
1996; Vol. 2, p 251.
(2) (a) Baker, R.; Harrison, T.; Hollingworth, G. J .; Swain, C. J .;
Williams, B. J . EP 0528,495A1, 1993. (b) Harrison, T.; Williams, B.
J .; Swain, C. J .; Ball, R. G. Bioorg. Med. Chem. Lett. 1994, 4,
2545.
(3) For a leading reference on the syntheses and bioactivities of
febrifugine and isofebrfugine, see: Kobayashi, S.; Ueno, M.; Suzuki,
R.; Ishitani, H.; Kim, H.-S.; Wataya, Y. J . Org. Chem. 1999, 64,
6833.
(4) (a) Makabe, H.; Kong, L.-K.; Hirota, M. Org. Lett. 2003, 5, 27.
(b) Bonte, A. Bull. Soc. Chim. Fr. 1981, 11. (c) Hasserberg, H.-A.;
Gerlach, H. Ann. Chem. 1989, 255.
(6) (a) Humphries, M. E.; Murphy, J .; Phillips, A. J .; Abell, A. D. J .
Org. Chem. 2003, 68, 2432. (b) Battistini, L.; Rassu, G.; Pinna, L.;
Zanardi, F.; Casiraghi, G. Tetrahedron: Asymmetry 1999, 10, 765. (c)
De Lucca, G. V. Bioorg. Med. Chem. Lett. 1997, 7, 501.
(7) For recent reviews on the syntheses of 3-piperidinols and related
compounds, see: (a) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.;
Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 105. (b) Zhou, W.
S.; Lu, Z. H.; Xu, Y. M.; Liao, L. X.; Wang, Z. M. Tetrahedron 1999,
55, 11959. (c) Laschat, S.; Dickner, T. Synthesis 2000, 1781. (d)
Toyooka, N.; Nemoto, H. Drugs Future 2002, 27, 143. (e) Weintraub,
P. M.; Sabol, J . S.; Kane, J . M.; Borcherding, D. R. Tetrahedron 2003,
59, 2953.
(5) For a review on the piperidine alkaloids, see: Schneider, M.
Pyridine and Piperidine Alkaloids: An Uupdate. In Alkaloids: Chemi-
cal And Biochemical Perspectives; Pelletier, S. W., Ed.; Elsevier
Science: Oxford, 1996; Vol. 10, pp 155-299.
10.1021/jo049166z CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/31/2004
J . Org. Chem. 2004, 69, 6001-6009
6001

Liu et al.
SCHEME 1
SCHEME 2
receptor antagonists (2S,3S)-L-733,060 (1) and (2S,3S)-
CP-99,994 (2)8a as well as antimalarial alkaloids (+)-
febrifugine and isofebrifugine.8b The key point of our
method is the regioselective and cis-diastereoselective
introduction of a phenyl or allyl group at the C-6 of the
N,O-acetal derived from O-silyl group protected gluta-
rimide 6 via R-amidoalkylation (6 to 8, Scheme 1, path
a). To develop a more flexible approach allowing the
introduction of various alkyl groups at the C-2 of 6,
required for the syntheses of a variety of piperidine
alkaloids and related bioactive compounds, we decided
to explore the regio- and stereoselective reductive alkyl-
ation approach (7 to 8, Scheme 1, path b).9 The study
opens a new access to trans-6-alkyl-5-benzyloxy-2-pip-
eridinones 12, which are valuable precursors for a
number of bioactive substituted 5-hydroxy-2-piperidino-
nes6,10 and substituted 3-piperidinols,5,7,10 for example,
compounds 3 and 4.
TABLE 1. Resu lts of Red u ctive Alk yla tion of 7a
Accor d in g to P r oced u r e Sh ow n in Sch em e 2
selectivitiesb
entry
R
yield (%)a
C2/C6
trans:cis
1
2
3
4
5
6
7
8
CH3
C2H5
12a (80)
12b (79)
12c (80)
12d (73)
12e (81)
12f (77)
12g (80)
12h (70)
86:14
88:12
93:7
97:3
97:3
92:8
92:8
95:5
92:8
95:5
95:5
98:2
97:3
96:4
94:6
96:4
n-C4H9
Bn
n-C5H11
n-C8H17
Ph
4-MeOC6H4
a
b
Isolated yield of 12 starting from 7a . Ratio based on chro-
matography separation.
Multigram quantities of (S)-3-hydroxyglutarimide 6a
are readily available from (S)-glutamic acid as described
previously.8 Protection of the hydroxy group under stan-
dard conditions (BnBr, Ag2O, Et2O, rt) provided the
desired protected (S)-glutarimide 7a {white crystals, mp
SCHEME 3
74.5-75.0 °C, [R]20 -53.6 (c 1.0, CHCl3)} in 90% yield
D
(Scheme 1). With enantioenriched 7a easily available in
quantity, we then proceeded to study its reaction with
Grignard reagents. Addition of methylmagnesium iodide
(3 molar equiv) to (S)-3-benzyloxy-1-(4-methoxybenzyl)-
glutarimide 7a (THF, -78 °C) yielded 9a (Scheme 2) as
a separable diastereomeric mixture (combined yield 84%).
Although the determination of both regio- and diaste-
reoselectivities and tentative attribution of regio- versus
diastereoisomers can be made at this stage, only after
the subsequent reductive deoxygenation step could we
conclude that the methylmagnesium iodide addition to
7a proceeded in 86:14 regioselectivity (Table 1, entry 1)
in favor of the C-2 addition. The major regioisomer 9a
consisted of two diastereomers in 80:20 ratio. The stereo-
chemistries of diastereomeric 9a were not assigned (vide
infra).
Because the subsequent Lewis acid mediated reductive
deoxygenation11 was considered to proceed via the inter-
mediacy of N-acyliminium12 11 (Scheme 2), in which the
stereochemistry at the C-6 will be destroyed, the dia-
stereomeric mixture 9 was used without separation in
the next step. Indeed, in the presence of 3 molar equiv
of boron trifluoride etherate, the diastereomers of 9a were
reduced with an excess of triethylsilane (CH2Cl2, -78
°C-rt) to yield predominantly trans-12a (Scheme 2) in a
combined yield of 95%. The trans/cis diastereoselectivity
observed in this reaction was 92:8 according to chroma-
tography separation (Table 1, entry 1). The stereochem-
istry of the major diastereomer 12a was assigned to trans
by its conversion into known 1310d (Scheme 3), which was
further confirmed by converting 12g and 12a to (-)-1
(L-733,061) and (-)-deoxocassine 4, respectively (vide
infra). The ee of 12a was determined to be 96.0% on the
basis of HPLC analysis on a chiral column.
(8) (a) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett.
2003, 5, 1927. (b) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003,
1663.
(9) (a) Huang, P.-Q.; Wang, S. L.; Ye, J . L.; Ruan, Y. P.; Huang, Y.
Q.; Zheng, H.; Gao, J . X. Tetrahedron 1998, 54, 12547. (b) Huang, P.-
Q.; Wang, S. L.; Ruan, Y. P.; Gao, J . X. Nat. Prod. Lett. 1998, 11, 101.
(c) Huang, P. -Q.; Chen, Q. F.; Chen, C.-L.; Zhang, H.-K. Tetrahedron:
Asymmetry 1999, 10, 3827. (d) Huang, P.-Q.; Zheng, X. Arkivoc 2003,
(II) 7, at www.arkat-usa.org. (e) Wu, T.-J .; Ye, J .-L.; Huang, P.-Q. Chin.
J . Chem. 2003, 21, 723. (f) He, B.-Y.; Wu, T.-J .; Yu, X.-Y.; Huang, P.-
Q. Tetrahedron: Asymmetry 2003, 14, 2101. (g) Huang, P.-Q.; Meng,
W.-H. Lett. Org. Chem. 2004, 1, 99. (h) Chen, M. D.; Zhou, X.; He, M.
Z.; Ruan, Y. P.; Huang, P.-Q. Tetrahedron 2004, 60, 1651.
(10) For some approaches to chiral nonracemic 6-alkyl-5-hydroxy-
2-piperidinones, see: (a) Lee, H. K.; Chun, J . S.; Pak, C. S. J . Org.
Chem. 2003, 68, 2471. (b) Koulocheri, S. D.; Magiatis, P.; Skaltsounis,
A. L.; Haroutounian, S. A. Tetrahedron 2002, 58, 6665. (c) Barros, M.
T.; J anuario-Charmier, M. A.; Maycock, C. D.; Michaud, T. Tetrahedron
2002, 58, 1519. (d) Ha, J . D.; Cha, J . K. J . Am. Chem. Soc. 1999, 121,
10012. (e) Folmer, J . J .; Acero, C.; Thai, D. L.; Rapoport, H. J . Org.
Chem. 1998, 63, 8170. (f) Toyooka, N.; Yoshida, Y.; Momose, T.
Tetrahedron Lett. 1995, 36, 3715. (g) Oishi, T.; Iwakuma, T.; Hirama,
M.; Ito, S. Synlett 1995, 404.
Encouraged by these results, the reductive alkylations
of 7a with other Grignard reagents were investigated,
(11) (a) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974,
633. (b) Nagai, Y. Org. Prep. Proc. Int. 1980, 12, 13. (c) Hart, D. J .;
Yang, T.-K. J . Org. Chem. 1985, 50, 235. (d) Rolf, D.; Gray, G. R. J .
Am. Chem. Soc. 1982, 104, 3539.
(12) For recent reviews on the chemistry of N-acyliminium, see: (a)
Speckamp, W. N.; Moolenaar, M. J . Tetrahedron 2000, 56, 3817. (b)
Maryanoff, B. E.; Zhang, H.-C.; Cohen, J . H.; Turchi, I. J .; Maryanoff,
C. A. Chem. Rev. 2004, 104, 1431.
6002 J . Org. Chem., Vol. 69, No. 18, 2004

(5S,6R)-6-Alkyl-5-benzyloxy-2-piperidinones
SCHEME 4
SCHEME 5
dinol 162a {[R]20 -66.1 (c 0.9, CHCl3)} in 83% yield.
D
Swern oxidation15 [(COCl)2, DMSO, CH2Cl2, -78 ∼ -20
°C; i-Pr2NEt] afforded known tert-Boc-protected (R)-2-
phenyl-3-piperidinone 17,16 which was reduced immedi-
ately with L-Selectride17 to provide cis-(2R,3R)-182 {col-
orless oil, [R]20 -51.1 (c 1.0, CHCl3); lit.8a [R]15 +53.8
and the results are reported in Table 1. Thus, all of the
addition reactions proceed with similar or better C-2
regioselectivity. It is important to note that in a number
of cases, substantial amounts of tautomeric ring-opening
keto amides products 10 were obtained. Taking into
account that tautomers 9 and 10 are interconvertible
under acidic conditions, an experimentally expedient
protocol for their conversion into 12 would reside on the
direct use of the above-mentioned tautomeric mixture in
the subsequent reaction. This turned out to be fruitful.
In practice, after the Grignard reagent addition to 7a ,
the crude was subjected to a short column chromato-
graphy to eliminate the C-6 regioisomers and other side
products, and all diastereomeric and tautomeric isomers
of 9 were collected in one fraction, which without further
separation was treated with Et3SiH/BF3‚OEt2 to give the
desired 6-alkyl-5-benzyloxy-2-piperidinones 12 in high
diastereoselectivities and in good chemical yields (Table
1, entries 2-8).
Although the addition of Grignard reagents to gluta-
rimides13 has been reported as early as 1936,13a most of
them dealt with symmetric glutarimides, avoiding regio-
selectivity or stereoselectivity problems. However, in one
case, the addition of both phenyllithium and 2-furyl-
lithium to racemic 3-methylglutarimide and its N-methyl
derivative was reported to give the C-6 addition pro-
ducts.13d In the present study, the observed high C-2
regioselectivity (86-97%) of Grignard reagent addition
to 7a could be attributed to both the inductive effect14 of
the C-3 substituent and the (C-3) O-Mg-O (C-2 carbonyl)
chelation-induced activating effects.
So far, we have demonstrated that starting from (S)-
3-hydroxyglutarimide (6a ), one can access a series of
2-alkyl-3-piperidinols with either (2S,3S)8 or (2R,3S) (vide
infra, Scheme 4) stereochemistries. To illustrate the
synthetic utility of the method in establishing (2R,3R)
stereochemistry (numbering based on 6a ), we decided to
undertake the synthesis of (2R,3R)-L-733,061 (ent-1),2 the
antipode of (2S,3S)-L-733,060 (+)-1.2 It has been dem-
onstrated that cis-2,3-substitution is essential for high-
affinity binding to the human NK1 (hNK1) receptor.2b
Thus, as shown in Scheme 4, lithium aluminum
hydride reduction of 12g (yield 90%), followed by one-
pot carbamative debenzylation [H2, l atm, 20% Pd(OH)2/
C, (Boc)2O] led directly to N-tert-Boc-2-phenyl-3-piperi-
D
D
(c 1.0, CHCl3) for (2S,3S)-18} as the only diastereomer.
The overall yield from 16 to 18 was 74%.
Etherification (NaH, 3,5-(CF3)2C6H3CH2Br, DMF, rt,
yield 77%) of (-)-18 gave (-)-192 {[R]28 -35.6 (c 1.0,
D
CHCl3); lit.8a [R]28D +36.9 (c 1.0, CHCl3) for the antipode},
which was then deprotected to afford (-)-L-733,061 (ent-
1)2,18 {ent-1‚HCl mp 213-215 °C. [R]28 -79.6 (c 1.0,
D
MeOH); lit.2a mp 215-216 °C. [R]23 +87.3 (c 1, MeOH)
D
for (+)-1}(Scheme 5).
The synthesis of (-)-L-733,061 (ent-1) served to dem-
onstrate that the method presented here not only allowed
preparation of a series of trans-(5S,6R)-6-alkyl-5-hydroxy-
2-piperidinones but also opened a flexible entrance to
both trans-(2R,3S)- and cis-(2R,3R)-2-alkyl-3-piperidinols,
which are key structural features found in a number of
bioactive natural or designed piperidines.4,8,18-20 For
example, (R)-2-phenyl-3-piperidinone 17 has been used
as the key intermediate in the asymmetric synthesis of
the antipode of another NK-1 receptor antagonist,16 and
the antipode of 15 has been used as an advanced
intermediate in the asymmetric synthesis of natural
product trans-(2R,3S)-3-hydroxypipecolic acid,19 which
has also been transformed into (-)-swainsonine,20 an
indolizidine alkaloid possessing potent and specific R-D-
mannosidase inhibitory activity.
Next, we turned attention to the synthesis of deoxo-
cassine (4)21 to demonstrate the synthetic versatility of
the building block 7a in introducing the C-6 substituent
(numbering based on 6a ). Thus, as shown in Scheme 6,
lithium aluminum hydride reduction of 12a (yield, 84%),
followed by one-pot carbamation-debenzylation of 20 [H2,
l atm, 20% Pd(OH)2/C, (Boc)2O, EtOH] led directly to
N-tert-Boc-2-methyl-3-piperidinol 21 in 79% yield. Fi-
(15) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(16) Maligres. P. E.; Waters, M. M.; Lee, J .; Reamer, R. A.; Askin,
D. J . Org. Chem. 2002, 67, 1093.
(17) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40, 7099.
(18) For the syntheses of (+)-1, see: (a) Calvez, O.; Langlois, N.
Tetrahedron Lett. 1999, 40, 7099. (b) Stadler, H.; Bos, M. Heterocycles
1999, 51, 1067. (c) Tomooka, K.; Nakazaki, A.; Nakai, T. J . Am. Chem.
Soc. 2000, 122, 408. (d) Lee, J .; Hoang, T.; Lewis, S.; Weissman, S. A.;
Askin, D.; Volante, R. P.; Reider, P. J . Tetrahedron Lett. 2001, 42, 6223.
(e) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915. (f) Bodas,
M. S.; Upadhyay, P. K.; Kumar, P. Tetrahedron Lett. 2004, 45, 987.
(19) Haddad, M.; Larcheveˆque, M. Tetrahedron Lett. 2001, 42, 5223.
(20) Ferreira, F.; Greck, C.; Geneˆt, J . P. Bull. Soc. Chim. Fr. 1997,
134, 615.
(13) (a) Lukes, R.; Gorocholinsky, J . Collect. Czech. Chem. Commun.
1936, 8, 223. (b) Lukes, R.; Blahe, K.; Blahe, K. Chem. Listy 1952, 46,
726. (c) Lukes, R.; Cerny, M. Collect. Czech. Chem. Commun. 1959,
24, 3596. (d) Wrobel, J . T.; Cybulski, J .; Dabrowski, Z. Synthesis 1977,
686. (e) Evans, D. A.; Thomas, E. W.; Cherpeck, R. J . Am. Chem. Soc.
1982, 104, 3695.
(21) For the syntheses of deoxocassine, see: (a) Kurihara, K.;
Sujimoto, T.; Saitoh, Y.; Igarashi, Y.; Hirota, H.; Moriyama, Y.;
Tsuyuki, T.; Takahashi, T.; Khuong-Huu, Q. Bull. Chem. Soc. J pn.
1985, 58, 3337. (b) Ma, D.-W.; Ma, N. Tetrahedron Lett. 2003, 44, 3963.
(14) Link, J . T.; Danishefsky, S. J . Tetrahedron Lett. 1994, 35, 9135.
J . Org. Chem, Vol. 69, No. 18, 2004 6003

Liu et al.
SCHEME 6
SCHEME 8
SCHEME 7
SCHEME 9
nally, TBDMS ether derivative 22 was obtained upon
treatment of 21 with TBDMSCl and imidazole at room
temperature.22
To introduce the C-6 side chain of deoxocassine, Beak’s
methodology23 was employed. Thus treatment of 22 with
sec-butyllithium (1.2 molar equiv) and TMEDA (-30 °C,
1.5 molar equiv) generated in situ the dipole stabilized
C-6 carbanion, which was allowed to react with DMF
(-78 °C, 10 min). In this way, the desired formylated
product 23 was obtained in 94:6 diastereoselectivity and
in a combined yield of 72% (Scheme 7). The stereochem-
istry of the major diastereomer 23 was tentatively
assigned as trans by analogy with the literature reports.23
This assignment was confirmed by its epimerization to
thermodynamically more stable C2/C6 cis-diastereomer23
24 (vide infra). Treatment of the diastereomeric mixture
of 23 with SiO2 and triethylamine (rt, 72 h) led to an 11:
89 diastereomeric mixture of 23 and 24 in favor of C2/C6
cis-epimer 24.
To illustrate the potential nucleophilic reactivity at the
C-5 of 7, the synthesis of 5a , a compound belonging to a
class of inhibitors of HIV proteases as represented by 5,6
was undertaken (Scheme 9). Prepared similarly as
described for 12 from (R)-3-hydroxyglutarimide (R)-6b,8b
31 was deprotonated with sec-butyllithium at -78 °C,
and addition of benzyl bromide (-78 to -30 °C, 6 h)
afforded a separable diastereomeric mixture 32/33 in 9:1
ratio (combined yield, 79%). Both diastereomers 32 and
33 were subjected to hydrogenolysis conditions (H2, l atm,
10% Pd/C, rt, 3 days) to yield, respectively, 5a and 5c in
excellent yield. Comparison of 1H and 13C NMR spectral
data of 5a and 5c with those reported6c allowed conclu-
sion that the major diastereomer obtained during the C-3
benzylation of 31 was 32.
In summary, we have demonstrated that N-protected-
3-benzyloxyglutarimide (S)-7 is a versatile 3-piperidinol
synthon equivalent; the multiple reactivities possessed
by 7 allowed the flexible introduction of a variety of
substituents at the N-1, C-2, C-5, and C-6 positions of
glutarimide 7 in regio- and diastereoselective fashion.
Application of the present methodology to the asymmetric
syntheses of other bioactive substituted 5-hydroxy-2-
piperidinones and 3-piperidinols is under current inves-
tigation.
Treatment of aldehyde 24 with the Wittig reagent
generated in situ from 25 and n-butyllithium gave olefin
26 (Scheme 8). Hydrogenation of 26 (H2, 10% Pd/C, rt,
EtOH; yield 100%) followed by deprotection (TBAF, THF,
rt, 15 h) provided alcohol 28 in quantitative yield.
Inversion of the configuration at the C-3 by Swern
oxidation15 (yield 63%, recovered starting material 30%),
followed by L-Selectride reduction17 provided 30 (yield
100%) as the only diastereomer. Finally, deprotection of
30 under acidic conditions (HCl, MeOH, rt, 15 h) afforded
the desired (2R,3R,6S)-deoxocassine (4) {mp 47-48 °C;
lit.21a mp 47.5-48.5 °C. [R]25D -11.8 (c 0.9, CHCl3); lit.21a
[R]18 -12.3 (c 0.19, CHCl3); lit.21b [R]20 -12.4 (c 0.8,
D
D
CHCl3)} in 96% yield.
(22) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(23) (a) Beak, P.; Basu, A.; Gallagher, D. J .; Park, Y. S.; Thayu-
manavan, S. Acc. Chem. Res. 1996, 29, 552. (b) Beak, P.; Lee, W. K. J .
Org. Chem. 1990, 55, 2578. (c) Beak, P.; Lee, W. K. J . Org. Chem. 1993,
58, 1109. (d) Wilkinson, T. J .; Stehle, N. W.; Beak, P. Org. Lett. 2000,
2, 155.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Optical
rotations were recorded on an automatic polarimeter. IR
6004 J . Org. Chem., Vol. 69, No. 18, 2004

(5S,6R)-6-Alkyl-5-benzyloxy-2-piperidinones
spectra were recorded on a FT-IR spectrophotometer. NMR
spectra were recorded in CDCl3 (1H at 500 MHz and 13C at
125 MHz), and chemical shifts are expressed in parts per
million (δ) relative to internal Me4Si. HRFABMS spectra were
recorded on a FTMS apparatus. Silica gel (300-400 mesh) was
used for column chromatography, eluting (unless otherwise
stated) with an ethyl acetate/petroleum ether (PE) (60-90 °C)
mixture. Dichloromethane, DMF, and diisopropylethylamine
were distilled over calcium hydride under N2. Ether and THF
were distilled over sodium benzophenone ketyl under N2.
equiv) and BF3‚OEt2 (3 molar equiv) successively. The mixture
was stirred at -78 °C for 6 h, then allowed to warm up slowly,
and stirred at room temperature overnight. A saturated
aqueous NaHCO3 was added, and the aqueous layer was
separated and extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (eluent
EtOAc/PE ) 1:2) to yield 12.
(5S,6R)-5-Ben zyloxy-1-(4-m eth oxyben zyl)-6-m eth yl-2-
p ip er id in on e (12a ). Following the general reductive alkyl-
ation procedure, 12a and its diastereomer were obtained in
92:8 diastereomeric ratio and in a combined yield of 80%.
(5S,6R)-12a (major diastereomer): Rf 0.35 (EtOAc/PE ) 1:1).
(S)-3-H yd r oxy-1-(4-m et h oxyb en zyl)-2,6-p ip er id in ed i-
on e (6a ). To a tetrahydrofuran solution (90 mL) of (S)-N-(4-
methoxybenzyl)-tetrahydro-5-oxo-2-furancarboxamide (16.00
mmol), prepared from L-glutamic acid as described previously,8a
was added a cooled suspension of potassium tert-butoxide (7.20
mmol) in anhydrous THF (30 mL) at -78 °C and under
nitrogen atmosphere. After 10 min of stirring at -78 °C, the
temperature was allowed to arise to -65 °C over 25 min and
then adjusted to -50 to -45 °C in 5 min. The reaction was
quenched with saturated NH4Cl at -78 °C. The residue was
extracted with EtOAc (3 × 30 mL). The EtOAc extracts were
washed with brine (15 mL), dried over anhydrous Na2SO4, and
concentrated to give compound 6a (yield 70-80%) as white
Colorless oil. [R]20 +96.9 (c 1.3, CHCl3); IR (film) 2990, 2832,
D
1637, 1470, 1454, 1246, 1176, 1102 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.30-6.78 (m, 9H), 5.41 (d, J ) 15.0 Hz, 1H), 4.39
(d, J ) 11.9 Hz, 1H), 4.30 (d, J ) 11.9 Hz, 1H), 3.83 (d, J )
15.0 Hz, 1H), 3.78 (s, 3H), 3.60 (dq, J ) 6.6, 1.5 Hz, 1H), 3.52
(m, 1H), 2.73 (ddd, J ) 18.5, 10.7, 8.4 Hz, 1H), 2.42 (ddd, J )
18.5, 6.0, 3.1 Hz, 1H), 2.05 (m, 2H), 1.19 (d, J ) 6.6 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 169.6, 158.7, 138.0, 129.2, 129.0
(2C), 128.2 (2C), 127.5, 127.1 (2C), 113.8 (2C), 75.0, 69.8, 55.17,
53.7, 46.6, 27.1, 21.3, 18.3; HRESIMS calcd for [C21H25NO3 +
H]+ 340.1907, found 340.1908. The enantiomeric excess of 12a
is 96.0% as determined by chiral HPLC [100:7:0.3 hexane/
dichloroethane/ethanol, λ ) 270 nm, tR 10.9 min for (5S,6R)-
12a , 19.0 min for (5S,6S)-12a ].
crystals. Mp 98-99 °C (EtOAc); [R]20 -70.0 (c 1.2, CHCl3);
D
IR (film) 3465, 2960, 1730, 1677, 1514, 1338, 1305, 1249, 1177,
1
1112 cm-1; H NMR (500 MHz, CDCl3) δ 7.32 (d, J ) 8.6 Hz,
2H), 6.80 (d, J ) 8.6 Hz, 2H), 4.90 (s, 2H), 4.22 (ddd, J ) 12.9,
5.4, 1.4 Hz, 1H), 3.78 (s, 3H), 3.55 (dd, J ) 2.6, 1.4 Hz, 1H),
2.88 (ddd, J ) 18.1, 4.8, 2.6 Hz, 1H), 2.66 (ddd, J ) 18.1, 12.9,
5.4 Hz, 1H), 2.34 (dddd, J ) 12.9, 5.4, 5.4, 2.6 Hz, 1H), 1.88
(dddd, J ) 12.9, 12.9, 12.9, 4.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 175.1, 171.1, 159.1, 130.5 (2C), 128.7, 113.8 (2C), 68.4,
55.2, 43.0, 30.9, 25.2; MS (EI) m/z 249 (M+, 100), 203 (28), 121
(20); HRESIMS calcd for [C13H15NO4 + Na]+ 272.0893, found
272.0897. Anal. Calcd for C13H15NO4: C, 62.65; H, 6.02; N, 5.62.
Found: C, 62.58; H, 5.98; N, 5.41.
(5S,6R)-5-Ben zyloxy-6-eth yl-1-(4-m eth oxyben zyl)-2-p i-
p er id in on e (12b). Following the general reductive alkylation
procedure, 12b and its diastereomer were obtained in 95:5
diastereomeric ratio and in a combined yield of 79%. (5S,6R)-
12b (major diastereomer): Rf 0.35 (EtOAc/PE ) 1:1). Colorless
oil. [R]20D +89.2 (c 0.9, CHCl3); IR (film) 2935, 2879, 1644, 1512,
1463, 1245, 1176, 1091, 1031 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.36-6.75 (m, 9H), 5.44 (d, J ) 14.9 Hz, 1H), 4.36 (d, J )
11.7 Hz, 1H), 4.27 (d, J ) 11.7 Hz, 1H), 3.76 (d, J ) 14.9 Hz,
1H), 3.74 (s, 3H), 3.67 (m, 1H), 3.32 (m, 1H), 2.69 (ddd, J )
17.1, 8.6, 8.6 Hz, 1H), 2.42 (m, 1H), 2.02 (m, 2H), 1.82 (m, 1H),
1.43 (m, 1H), 0.86 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.6, 158.7, 138.1, 129.3, 129.1 (2C), 128.2 (2C),
127.5, 127.2 (2C), 113.8 (2C), 71.8, 69.7, 59.8, 55.2, 46.8, 27.2,
24.9, 21.5, 10.7; HRESIMS calcd for [C22H27NO3 + H]+
354.2064, found 354.2069. Anal. Calcd for C22H27NO3: C, 74.79;
H, 7.65; N, 3.97. Found: C, 74.58; H, 7.96; N, 3.93.
(S)-3-Ben zyloxy-1-(4-m eth oxyben zyl)-2,6-p ip er id in ed i-
on e (7a ). To a mixture of (S)-6a (3.500 g, 14.06 mmol) and
silver oxide (9.783 g, 42.17 mmol) in dry ether (200 mL) was
added benzyl bromide (5.02 mL, 42.13 mmol). The mixture was
stirred at room temperature for 10 days. After filtration
through silica gel, the solvent was removed under reduced
pressure. Flash chromatographic purification on silica gel
(eluent EtOAc/PE ) 1:8) provided 7a (4.288 g, 90%) as a waxy
solid, which was crystallized from ether to yield 7a as white
crystals. Mp 74.5-75.0 °C; [R]20D -53.6 (c 1.0, CHCl3); IR (film)
2931, 1680, 1513, 1378, 1503, 1248, 1161, 1015 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.40-6.82 (m, 9H), 4.91 (d, J ) 14.5 Hz,
1H), 4.88 (d, J ) 14.5 Hz, 1H), 4.83 (d, J ) 11.8 Hz, 1H), 4.66
(d, J ) 11.8 Hz, 1H), 4.08 (dd, J ) 5.9, 5.2 Hz, 1H), 3.78 (s,
3H), 2.93 (ddd, J ) 17.7, 7.7, 6.4 Hz, 1H), 2.60 (ddd, J ) 17.7,
6.2, 6.2 Hz, 1H), 2.08 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
171.6, 171.5, 159.0, 137.2, 130.4 (2C), 129.3, 128.5 (2C), 128.0
(3C), 113.8 (2C), 73.9, 72.5, 55.2, 42.4, 29.1, 24.1; MS (EI) m/z
339 (M+, 4), 248 (M+ - Bn, 12), 121 (100), 91 (18); HRESIMS
calcd for [C20H21NO4 + Na]+ 362.1363, found 362.1360. Anal.
Calcd for C20H21NO4 C, 70.80; H, 6.19; N, 4.13. Found: C,
70.98; H, 6.29; N, 4.10.
Gen er a l P r oced u r e for Red u ctive Alk yla tion of (S)-
7a . To a cooled (-78 °C) solution of (S)-7a (1 molar equiv) in
THF (0.1 M) was added dropwise a solution of RMgX in Et2O
(3 molar equiv). The mixture was stirred at -78 °C for 3 h (in
the cases of entries 4 and 6-8, the reactions were allowed to
slowly warm to -10 °C). The reaction was quenched with
saturated NH4Cl. After extraction with CH2Cl2, the combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica
gel (eluent EtOAc/PE ) 1:2) to yield 9 and 10, which were
used in the next step without further separation.
(5S,6R)-5-Ben zyloxy-6-(n -bu tyl)-1-(4-m eth oxyben zyl)-
2-p ip er id in on e (12c). Following the general reductive alkyl-
ation procedure, 12c and its diastereomer were obtained in
95:5 diastereomeric ratio and in a combined yield of 80%.
(5S,6R)-12c (major diastereomer): Rf 0.40 (EtOAc/PE ) 1:1).
Colorless oil. [R]20 +63.7 (c 1.0, CHCl3); IR (film) 2954, 2933,
D
2871, 1643, 1512, 1464, 1246, 1175, 1030 cm-1; 1H NMR (500
MHz, CDCl3) δ 7.36-6.70 (m, 9H), 5.45 (d, J ) 14.9 Hz, 1H),
4.34 (d, J ) 11.7 Hz, 1H), 4.25 (d, J ) 11.7 Hz, 1H), 3.78 (s,
3H), 3.73 (d, J ) 14.9 Hz, 1H), 3.64 (m, 1H), 3.38 (m, 1H),
2.68 (ddd, J ) 18.4, 9.9, 8.6 Hz, 1H), 2.41 (m, 1H), 2.20 (m,
2H), 1.72 (m, 1H), 1.40 (m, 1H), 1.32-1.10 (m, 4H), 0.88 (t, J
) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.6, 158.7,
138.1, 129.4, 129.2 (2C), 128.3 (2C), 127.5, 127.2 (2C), 113.8
(2C), 72.3, 69.8, 58.3, 55.2, 46.8, 31.9, 28.5, 27.2, 22.6, 21.6,
13.9; HRESIMS calcd for [C24H31NO3 + H]+ 382.2377, found
382.2373.
(5S,6R)-6-Ben zyl-5-ben zyloxy-1-(4-m et h oxyb en zyl)-2-
p ip er id in on e (12d ). Following the general reductive alkyla-
tion procedure, 12d and its diastereomer were obtained in 98:2
diastereomeric ratio and in a combined yield of 73%. (5S,6R)-
12d (major diastereomer): Rf 0.30 (EtOAc/PE ) 1:2). Colorless
oil. [R]20D +79.5 (c 1.1, CHCl3); IR (film) 3024, 2937, 1642, 1512,
1455, 1246, 1175, 1100, 1073, 1030 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.26-6.70 (m, 14H), 5.45 (d, J ) 15.0 Hz, 1H), 4.04
(d, J ) 11.8 Hz, 1H), 4.00 (d, J ) 11.8 Hz, 1H), 3.71 (d, J )
15.0 Hz, 1H), 3.69 (s, 3H), 3.64 (m, 1H), 3.44 (m, 1H), 3.05
To a cooled (-78 °C) solution of a mixture of 9 and 10 (1
molar equiv) in CH2Cl2 were added dropwise Et3SiH (10 molar
J . Org. Chem, Vol. 69, No. 18, 2004 6005

Liu et al.
(dd, J ) 13.9, 4.6 Hz, 1H), 2.66 (ddd, J ) 18.1, 11.6, 7.7 Hz,
1H), 2.54 (dd, J ) 13.9, 9.9 Hz, 1H), 2.40 (ddd, J ) 18.1, 7.7,
2.1 Hz, 1H), 2.05 (m, 1H), 1.95 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 169.7, 158.8, 137.9, 137.4, 129.3 (2C), 129.2, 128.8
(2C), 128.7 (2C), 128.1 (2C), 127.3, 127.2 (2C), 126.8, 113.9 (2C),
71.3, 69.5, 59.5, 55.1, 46.9, 38.8, 27.0, 21.5; HRESIMS calcd
for [C27H29NO3 + H]+ 416.2220, found 416.2221. Anal. Calcd
for C27H29NO3: C, 78.07; H, 6.99; N, 3.37. Found: C, 78.36;
H, 6.99; N, 3.37.
11.7 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.65 (m, 1H), 3.33 (d,
J ) 15.0 Hz, 1H), 2.81 (ddd, J ) 18.6, 11.7, 7.2 Hz, 1H), 2.54
(ddd, J ) 18.6, 6.4, 4.6 Hz, 1H), 1.93-1.80 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 170.3, 159.2, 158.8, 137.9, 130.6, 129.3
(2C), 129.0, 128.3 (2C), 128.0 (2C), 127.6, 127.3 (2C), 114.3 (2C),
113.9 (2C), 76.3, 70.2, 62.2, 55.4, 55.2, 46.9, 27.3, 20.6; MS
(ESI) m/z 432 (M + H+, 100). Anal. Calcd for C27H29NO4: C,
75.17; H, 6.73; N, 3.25. Found: C, 74.82; H, 6.89; N, 2.92.
(5S,6R)-5-Hyd r oxy-6-m eth yl-2-p ip er id in on e (13). To a
solution of 12a (0.70 g, 2.06 mmol) in CH3CN (49 mL) and
H2O (14 mL) was added CAN (4.53 g, 8.26 mmol). The
resultant mixture was stirred at room temperature for 30 min.
H2O (60 mL) was added, and the aqueous phase was extracted
with EtOAc (5 × 20 mL). The combined organic layers were
washed successively with saturated aqueous sodium bicarbon-
ate (5 × 5 mL) and brine (5 mL), then dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
The residue and a catalytic amount of TsOH were resolved in
CH2Cl2 (20 mL), and the mixture was stirred at room tem-
perature overnight. The mixture was basified with a saturated
sodium bicarbonate solution to reach pH 7. The mixture was
extracted with CH2Cl2 (2 × 15 mL), and the organic layers
were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (eluent EtOAc/PE/NH3/H2O/
MeOH ) 100:100:1:5) to yield the N-deprotected piperidinone
(270 mg, 60%) as a waxy solid.
(5S,6R)-5-Ben zyloxy-1-(4-m eth oxyben zyl)-6-(n -p en tyl)-
2-p ip er id in on e (12e). Following the general reductive alkyl-
ation procedure, 12e and its diastereomer were obtained in
97:3 diastereomeric ratio and in a combined yield of 81%.
(5S,6R)-12e (major diastereomer): Rf 0.40 (EtOAc/PE ) 1:1).
Colorless oil. [R]20 +57.9 (c 1.1, CHCl3); IR (film) 2930, 2859,
D
1644, 1513, 1463, 1246, 1175, 1073 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.32-6.78 (m, 9H), 5.45 (d, J ) 14.9 Hz, 1H), 4.34
(d, J ) 11.8 Hz, 1H), 4.25 (d, J ) 11.8 Hz, 1H), 3.74 (s, 3H),
3.73 (d, J ) 14.9 Hz, 1H), 3.64 (m, 1H), 3.38 (m, 1H), 2.69
(ddd, J ) 18.6, 9.8, 8.8 Hz, 1H), 2.42 (ddd, J ) 18.6, 5.3, 4.3
Hz, 1H), 2.02 (m, 2H), 1.71 (m, 1H), 1.39 (m, 1H), 1.32-1.12
(m, 6H), 0.87 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 169.6, 158.7, 138.2, 129.3, 129.1 (2C), 128.2 (2C), 127.4, 127.2
(2C), 113.8 (2C), 72.2, 69.7, 58.3, 55.1, 46.8, 32.2, 31.6, 27.1,
26.0, 22.4, 21.5, 13.9; HRESIMS calcd for [C25H33NO3 + H]+
396.2533, found 396.2530. Anal. Calcd for C25H33NO3: C, 75.95;
H, 8.35; N, 3.54. Found: C, 75.46; H, 8.50; N, 3.41.
(5S,6R)-5-Ben zyloxy-1-(4-m et h oxyb en zyl)-6-(n -oct yl)-
2-p ip er id in on e (12f). Following the general reductive alkyl-
ation procedure, 12f and its diastereomer were obtained in 96:4
diastereomeric ratio and in a combined yield of 77%. (5S,6R)-
12f (major diastereomer): Rf 0.35 (EtOAc/PE ) 1:2). Colorless
oil. [R]20D +55.7 (c 0.5, CHCl3); IR (film) 2927, 2855, 1644, 1512,
1463, 1246, 1175, 1098, 1035 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.35-6.76 (m, 9H), 5.45 (d, J ) 15.0 Hz, 1H), 4.34 (d, J )
11.8 Hz, 1H), 4.25 (d, J ) 11.8 Hz, 1H), 3.75 (d, J ) 15.0 Hz,
1H), 3.73 (s, 3H), 3.64 (m, 1H), 3.37 (m, 1H), 2.68 (ddd, J )
18.5, 10.3, 8.2 Hz, 1H), 2.40 (ddd, J ) 18.5, 9.0, 4.6 Hz, 1H),
2.05 (m, 2H), 1.70 (m, 1H), 1.42-1.00 (m, 13H), 0.89 (t, J )
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.6, 158.8, 138.2,
129.2 (2C), 128.3 (2C), 127.5 (2C), 127.2 (2C), 113.8 (2C), 72.3,
69.8, 58.4, 55.2, 46.9, 32.2, 31.8, 29.4 (3C), 27.2, 26.4, 22.7,
21.6, 14.1; MS (ESI) m/z 438 (M + H+, 100), 460 (M + Na+,
30); HRESIMS calcd for [C28H39NO3 + H]+ 437.6289, found
437.6280.
(5S,6R)-5-Ben zyloxy-1-(4-m eth oxyben zyl)-6-p h en yl-2-
p ip er id in on e (12g). Following the general reductive alkyla-
tion procedure, 12g and its diastereomer were obtained in 94:6
diastereomeric ratio and in a combined yield of 80%. (5S,6R)-
12g (major diastereomer): Rf 0.40 (EtOAc/PE ) 1:2). Colorless
oil. [R]20D +73.1 (c 1.2, CHCl3); IR (film) 3061, 3029, 3003, 1644,
1512, 1464, 1451, 1246, 1174 cm-1; 1H NMR (500 MHz, CDCl3)
δ 7.40-6.76 (m, 14H), 5.65 (d, J ) 14.9 Hz, 1H), 4.64 (br s,
1H), 4.44 (d, J ) 11.8 Hz, 1H), 4.38 (d, J ) 11.8 Hz, 1H), 3.78
(s, 3H), 3.68 (m, 1H), 3.33 (d, J ) 14.9 Hz, 1H), 2.82 (ddd, J )
18.5, 11.5, 7.5 Hz, 1H), 2.55 (ddd, J ) 18.5, 6.1, 4.1 Hz, 1H),
1.86 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 170.1, 158.8, 138.7,
137.8, 129.2, 128.9 (2C), 128.7 (2C), 128.3 (2C), 127.8, 127.6,
127.3 (2C), 126.8 (2C), 113.8 (2C), 76.2, 70.1, 62.6, 55.2, 46.9,
27.2, 20.6. MS (EI) m/z 401 (M+, 50), 262 (100), 121 (35), 91
(36), 77 (10); HRESIMS calcd for [C26H27NO3 + H]+ 402.2064,
found 402.2069. Anal. Calcd for C26H27NO3: C, 77.80; H, 6.73;
N, 3.49. Found: C, 77.17; H, 6.67; N, 3.74.
A suspension of the N-deprotected piperidinone (80 mg, 0.37
mmol) and Pd/C (50 mg, 10% Pd) in ethanol (5 mL) was stirred
at room temperature and under atmosphere of H2 for 72 h.
The mixture was filtered through Celite, and the solvent was
removed under reduced pressure. Flash chromatographic
purification on silica gel (eluent CH2Cl2/EtOH/NH3‚H2O ) 100:
10:1) provided 13 (36 mg, 76%) as colorless crystals. Mp 130-
131 °C (EtOAc) (lit.10d mp 130-131 °C). [R]26 +48.5 (c 1.0,
D
CH2Cl2) [lit.10d [R]20 -49.1 (c 1.0, CH2Cl2)]; IR (film) 3292,
D
3196, 2923, 2848, 1652, 1558, 1540, 1457, 1418, 1262, 1075
cm-1; 1H NMR (500 MHz, CDCl3) δ 5.72 (br s, 1H), 3.64 (ddd,
J ) 8.4, 6.3, 1.0 Hz, 1H), 3.38 (apparent dquint, J ) 6.5, 1.0
Hz, 1H), 2.53 (dt, J ) 18.1, 6.0 Hz, 1H), 2.38 (ddd, J ) 18.1,
9.2, 6.5 Hz, 1H), 2.04 (m, 2H), 1.86 (dddd, J ) 13.4, 9.2, 9.2,
6.3 Hz, 1H), 1.26 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz,
CD3CN) δ 172.0, 69.4, 54.6, 28.1, 27.0, 20.4; MS (ESI) m/z 130
(M + H+, 100).
(2R,3S)-3-Ben zyloxy-1-(4-m eth oxyben zyl)-2-p h en ylp i-
p er id in e (14). To a cooled (0-5 °C) suspension of lithium
aluminum hydride (520 mg, 13.68 mmol) in anhydrous THF
(25 mL) was added, under N2 atmosphere, a solution of 12g
(1.830 g, 4.56 mmol) in THF (5 mL). The mixture was stirred
at room temperature for 3 h, then warmed to 40 °C, and stirred
at that temperature for 1 h. The mixture was chilled with an
ice bath. To the mixture were added successively ether (5 mL),
a 10% solution of sodium hydroxide (0.4 mL), and H2O (0.1
mL). The resultant mixture was stirred at room temperature
for 30 min and then filtered through Celite. The filtrate was
concentrated at reduced pressure, and the residue was purified
by flash chromatography on silica gel (CH2Cl2/CH3COCH3
)
150:1) to afford 14 (1.580 g, 90%) as a waxy solid. [R]25D +26.5
(c 1.1, CHCl3); IR (neat) 2934, 2858, 2785, 1511, 1453, 1246,
1098 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.56-6.78 (m, 14H),
4.15 (d, J ) 11.5 Hz, 1H), 3.90 (d, J ) 11.5 Hz, 1H), 3.77 (s,
3H), 3.67 (d, J ) 13.3 Hz, 1H), 3.38 (ddd, J ) 11.2, 8.6, 4.4
Hz, 1H), 3.06 (d, J ) 8.6 Hz, 1H), 2.88 (m, 1H), 2.79 (d, J )
13.3 Hz, 1H), 2.20 (m, 1H), 1.90 (ddd, J ) 13.4, 11.2, 1.7 Hz,
1H), 1.66 (m, 1H), 1.55 (m, 1H), 1.38 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 158.5, 142.5, 138.6, 131.6, 129.7 (2C), 129.1
(2C), 128.2 (2C), 128.0 (2C), 127.6 (2C), 127.2 (2C), 113.5 (2C),
81.4, 74.0, 71.6, 58.5, 55.2, 52.1, 31.1, 23.5; MS (ESI) m/z 388
(M + H+, 100); HRESIMS calcd for [C26H29NO2 + H]+
388.2271, found 388.2267.
(5S,6R)-5-Ben zyloxy-1-(4-m et h oxyb en zyl)-6-(4-m et h -
oxyp h en yl)-2-p ip er id in on e (12h ). Following the general
reductive alkylation procedure, 12h and its diastereomer were
obtained in 96:4 diastereomeric ratio and in a combined yield
of 70%. (5S,6R)-12h (major diastereomer): Rf 0.35 (EtOAc/
PE ) 1:2). Colorless oil. [R]20 +38.5 (c 1.0, CHCl3); IR (film)
D
2934, 1642, 1612, 1512, 1463, 1248, 1175, 1033 cm-1; 1H NMR
(500 MHz, CDCl3) δ 7.35-6.76 (m, 13H), 5.63 (d, J ) 15.0 Hz,
1H), 4.58 (br s, 1H), 4.43 (d, J ) 11.7 Hz, 1H), 4.38 (d, J )
(2R,3S)-1-(ter t-Bu tyloxycar bon yl)-3-h ydr oxy-2-ph en ylpi-
p er id in e (16). To a mixture of 14 (1.200 g, 3.10 mmol) and
6006 J . Org. Chem., Vol. 69, No. 18, 2004

(5S,6R)-6-Alkyl-5-benzyloxy-2-piperidinones
20% Pd(OH)2/C (500 mg) were added ethanol (30 mL) and di-
tert-butyl dicarbonate (2.13 mL, 9.28 mmol). The mixture was
stirred at room temperature and under an atmosphere of H2
for 72 h. The resultant mixture was filtered through Celite
and concentrated under reduced pressure. Flash chromato-
graphic purification on silica gel (eluent EtOAc/PE ) 1:4)
provided 16 (710 mg, 83%) as a colorless waxy solid, which
was crystallized from Et2O to provide 162a as white crystals.
Mp 67-68 °C. [R]20D -66.1 (c 0.9, CHCl3); IR (neat) 3446, 2931,
1693, 1668, 1417, 1366, 1169, 1128 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.38-7.17 (m, 5H), 5.38 (br s, 1H), 4.52 (m, 1H), 4.10
(m, 1H), 2.86 (ddd, J ) 13.2, 13.2, 3.2 Hz, 1H), 2.14 (d, J )
6.3 Hz, 1H), 1.92 (qt, J ) 13.2, 4.5 Hz, 1H), 1.76 (m, 1H), 1.65-
1.57 (m, 1H), 1.45 (s, 9H), 1.43-1.36 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 156.7, 138.3, 128.7 (2C), 126.9, 126.4 (2C), 80.1,
67.5, 60.3, 40.0, 28.4, 26.0, 18.9; MS (ESI) m/z 555 (2M + H+,
100), 278 (M + H+, 45). Anal. Calcd for C16H23NO3: C, 69.31;
H, 8.30; N, 5.05. Found: C, 69.66; H, 8.51; N, 4.95.
values.2a HRESIMS calcd for [C20H19NOF6 + H]+ 404.1444,
found 404.1470.
(2R,3S)-3-Ben zyloxy-1-(4-m eth oxyben zyl)-2-m eth ylp i-
p er id in e (20). To a cooled (0-5 °C) suspension of lithium
aluminum hydride (813 mg, 21.39 mmol) in anhydrous THF
(25 mL) was added, under N2 atmosphere, a solution of 12a
(1.45 g, 4.28 mmol) in THF (5 mL). The mixture was stirred
at room temperature for 3 h, then warmed to 45 °C, and stirred
at that temperature for 1 h. The mixture was chilled with an
ice bath. To the mixture were added successively ether (15
mL), a 10% solution of sodium hydroxide (0.8 mL), and H2O
(0.1 mL). The resultant mixture was allowed to attain room
temperature and stirred for 30 min before being filtered
through Celite. After being concentrated at reduced pressure,
the residue was purified by flash chromatography on silica gel
(EtOAc/PE ) 1:1) to afford 20 (1.17 g, 84%) as a pale yellow
oil. [R]25D -22.0 (c 0.9, CHCl3); IR (film) 2860, 1511, 1244, 1115,
1103, 1036 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.38-6.82 (m,
9H), 4.62 (d, J ) 11.6 Hz, 1H), 4.47 (d, J ) 11.6 Hz, 1H), 3.96
(d, J ) 13.5 Hz, 1H), 3.78 (s, 3H), 3.22 (d, J ) 13.5 Hz, 1H),
3.13 (ddd, J ) 8.0, 4.2, 1.6 Hz, 1H), 2.69 (ddd, J ) 11.2, 3.5,
3.5 Hz, 1H), 2.32 (dq, J ) 6.2, 1.6 Hz, 1H), 2.11 (ddd, J ) 16.5,
8.0, 3.7 Hz, 1H), 1.96 (ddd, J ) 11.2, 11.2, 2.8 Hz, 1H), 1.65
(ddd, J ) 16.5, 7.6, 4.2 Hz, 1H), 1.43 (m, 1H), 1.32 (d, J ) 6.2
Hz, 3H), 1.28 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 158.5,
138.8, 131.0, 130.2 (2C), 128.3 (2C), 127.8 (2C), 127.4, 113.5
(2C), 80.1, 71.0, 60.8, 57.1, 55.2, 51.1, 29.1, 22.8, 15.5; MS (ESI)
m/z 326 (M + H+, 100); HRESIMS calcd for [C21H27NO2 + H]+
326.2114, found 326.2120.
(2R,3R)-1-(ter t-Bu t yloxyca r b on yl)-3-h yd r oxy-2-p h en -
ylp ip er id in e (18). Dimethyl sulfoxide (0.25 mL, 3.53 mmol)
was added dropwise to a cooled (-78 °C) solution of oxalyl
chloride (0.15 mL, 1.71 mmol) in CH2Cl2 (6 mL). The mixture
was stirred at -78 °C for 5 min, and a solution of 16 (320 mg,
1.16 mmol) in CH2Cl2 (4 mL) was added dropwise. After being
stirred at the same temperature for 1 h, i-Pr2NEt (0.60 mL,
3.45 mmol) was added, and the mixture was allowed to warm
slowly to -25 °C. The resultant mixture was recooled to -78
°C, and a buffer solution of NaOAc-HOAc (2 mL) and water
(10 mL) were added successively. After CH2Cl2 extraction (3
× 10 mL), the combined organic layers were washed with brine
(5 mL), dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was chromato-
graphed (eluent EtOAc/PE ) 1:4) to yield known 1716 as a
colorless oil (253 mg, yield 80%), which was used in the next
step immediately. IR (neat) 2975, 2933, 1722, 1698, 1450, 1410,
(2R,3S)-1-(ter t-Bu t yloxyca r b on yl)-3-h yd r oxy-2-m et h -
ylp ip er id in e (21). To a mixture of 20 (1.10 g, 3.38 mmol) and
20% Pd(OH)2/C (560 mg) were added ethanol (10 mL) and di-
tert-butyl dicarbonate (1.60 mL, 6.97 mmol). The mixture was
stirred at room temperature under an atmosphere of H2 for
72 h. The mixture was filtered over Celite and concentrated
under reduced pressure to afford a crude, which was resub-
jected to hydrogenolysis conditions (10% Pd/C, 300 mg, EtOH,
rt, H2, 1 atm, 10 h). The mixture was filtered through Celite
again and concentrated under reduced pressure. Flash chro-
matographic purification on silica gel (eluent EtOAc/PE ) 1:4)
1392, 1366, 1167, 1107 cm-1 1H NMR (500 MHz, CDCl3) δ
;
7.40-7.20 (m, 5H), 5.65 (br s, 1H), 4.10 (br s, 1H), 3.30 (m,
1H), 2.51-2.40 (m, 2H), 2.01-1.88 (m, 2H), 1.43 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 205.6, 155.0, 135.7, 129.0 (2C),
127.7, 125.4 (2C), 80.8, 66.4, 40.2, 37.4, 28.3 (3C), 22.9; MS
(EI) m/z 275 (M+, 5), 219 (72), 191 (25), 174 (36), 146 (100), 91
(25).
provided 21 (580 mg, 79%) as a colorless oil. [R]30 -25.9 (c
D
0.9, CHCl3); IR (film) 3434, 2976, 2939, 2869, 1691, 1664, 1414,
1
1366, 1152 cm-1; H NMR (500 MHz, CDCl3) δ 4.30 (m, 1H),
To a cooled (-78 °C) solution of 17 (190 mg, 0.69 mmol) in
anhydrous THF (6 mL) was added dropwise, under N2 atmo-
sphere, a solution of L-Selectride (1 M in THF, 1.00 mL, 1.00
mmol), and the mixture was stirred at -78 °C for 2 h. The
reaction was quenched by successive addition of a saturated
aqueous ammonium chloride (1 mL) and water (6 mL). After
extracted with CH2Cl2 (3 × 10 mL), the combined organic
layers were washed with brine (5 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
Flash chromatography (eluent EtOAc/PE ) 1:4) of the crude
then yielded known (2R,3R)-182 as a colorless oil (177 mg, yield
93%). [R]20 -51.1 (c 1.0, CHCl3) {lit.4 [R]15 +53.8 (c 1.0,
3.95 (m, 1H), 3.72 (m, 1H), 2.85 (ddd, J ) 13.2, 13.2, 2.6 Hz,
1H), 1.95 (br s, 1H), 1.83 (m, 1H), 1.72 (m, 2H), 1.45 (s, 9H),
1.40 (m, 1H), 1.12 (d, J ) 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 156.1, 79.6, 68.7, 53.0, 38.3, 28.4 (3C), 25.5, 19.1, 14.5;
MS (ESI) m/z 216 (M + H+, 100); HRESIMS calcd for [C11H21
-
NO3 + H]+ 216.1594, found 216.1592.
(2R,3S)-1-(ter t-Bu toxyca r bon yl)-3-[(ter t-bu tyld im eth -
ylsilyl)oxy]-2-m eth ylp ip er id in e (22). A mixture of 21 (580
mg, 2.70 mmol), imidazole (370 mg, 5.44 mmol), TBDMSCl
(815 mg, 5.40 mmol), and a catalytic amount of DMAP in DMF
(18 mL) was stirred at room temperature overnight. Water
(60 mL) was added, and the aqueous phase was extracted with
Et2O (5 × 10 mL). The combine organic phases were washed
with brine (5 mL), dried over anhydrous Na2SO4, filtered, and
concentrated. Flash chromatographic purification (eluent EtOAc/
PE ) 1:15) of the crude provided 22 (866 mg, 98%) as a
D
D
CHCl3) for (2S,3S)-18}. The spectral data are identical with
those of (2S,3S)-18.4 HRESIMS calcd for [C16H23NO3 + Na]+
300.1570, found 300.1560.
(2R,3R)-1-(ter t-Bu tyloxyca r bon yl)-2-p h en yl-3-[(3,5-bis-
(tr iflu or om eth yl)ben zyl)oxy]p ip er id in e (19). Compound
(2R,3R)-192 was prepared from (2R,3R)-18 by a procedure
analogue to that used for the preparation of (2S,3S)-19.2 Yield
77%. Colorless oil. [R]28D -35.6 (c 1.0, CHCl3) {lit.8a [R]28D +36.9
(c 1.0, CHCl3) for (+)-19}. The spectral data of (2R,3R)-19 are
identical with those of (2S,3S)-19.8a HRESIMS calcd for
[C25H27NO3F6 + Na]+ 526.1787, found 526.1812.
(2R,3R)-2-P h en yl-3-[(3,5-bis(t r iflu or om et h yl)b en zyl)-
oxy]p ip er id in e (-)-(1). (-)-(2R,3R)-12 was prepared from
(2R,3R)-19 by a procedure analogue to that used for the
preparation of (2S,3S)-12. Yield 88%. Colorless oil. [R]28D -79.6
(c 1.0, MeOH, hydrochloride) {lit.2a [R]23D +87.3 (c 1.0, MeOH)}.
The spectral data of (-)-(2R,3R)-1 are identical to the reported
colorless oil. [R]30 -11.2 (c 1.0, CHCl3); IR (neat) 2930, 2885,
D
2857, 1693, 1418, 1365, 1254, 1182, 1086, 1057 cm-1; 1H NMR
(500 MHz, CDCl3) δ 4.20 (m, 1H), 3.98 (m, 1H), 3.62 (m, 1H),
2.78 (ddd, J ) 13.4, 13.4, 2.6 Hz, 1H), 1.90 (dddd, J ) 13.6,
13.6, 8.6, 4.2 Hz, 1H), 1.66 (dddd, J ) 13.6, 13.6, 3.7, 2.2 Hz,
1H), 1.55 (m, 1H), 1.44 (s, 9H), 1.30 (m, 1H), 1.07 (d, J ) 7.2
Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.01 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 155.3, 78.8, 69.0, 53.0, 38.0, 28.4 (3C), 26.7,
25.7 (3C), 19.3, 18.0, 14.7, -5.0, -5.1; MS (ESI) m/z 330 (M +
H+, 100), 352 (M + Na+, 15); HRESIMS calcd for [C17H35NO3-
Si + H]+ 330.2459, found 330.2463.
(2R,3S,6R)-1-(ter t-Bu t oxyca r b on yl)-5-[(ter t-b u t yld i-
m eth ylsilyl)oxy]-6-m eth ylp ip er id in e-2-ca r boxya ld eh yd e
J . Org. Chem, Vol. 69, No. 18, 2004 6007

Liu et al.
(23). To a cooled (-78 °C) solution of 22 (600 mg, 1.83 mmol)
in dry ether (10 mL) were added TMEDA (0.41 mL, 2.74 mmol)
and s-BuLi (1.3 M in heptane, 1.7 mL, 2.21 mmol). The mixture
was slowly warmed to -30 °C, stirred at that temperature for
30 min, and then recooled to -78 °C again. To the resulting
mixture was added dropwise DMF (0.28 mL, 3.61 mmol) in
dry ether (1 mL). The resultant mixture was stirred for 10
min at -78 °C and then quenched with saturated aqueous
NH4Cl (2 mL). The organic layer was separated. The aqueous
layer was extracted with Et2O (5 × 5 mL), and the combined
organic phases were washed with brine (5 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. Flash chromatographic purification (eluent EtOAc/
PE ) 1:15) provided 23 (465 mg, 72%; diastereoselectivity )
temperature and under an atmosphere of H2 for 24 h. The
mixture was filtered through Celite. After being concentrated
under reduced pressure, the residue was chromatographed on
silica gel column (EtOAc/PE ) 1:40) to yield 27 as a colorless
oil (75 mg, 100%). [R]30 +10.7 (c 0.9, CHCl3); IR (neat) 2927,
D
2855, 1690, 1364, 1178, 1063 cm-1; 1H NMR (500 MHz, CDCl3)
δ 4.10 (m, 2H), 3.66 (m, 1H), 2.09 (dddd, J ) 13.5, 13.5, 6.2,
3.8 Hz), 1.79 (dddd, J ) 13.5, 13.5, 3.4, 2.3 Hz, 1H), 1.48 (m,
2H), 1.43 (s, 9H), 1.25 (s, 22H), 1.10 (d, J ) 7.3 Hz, 3H), 0.88
(m, 3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 155.7, 78.7, 69.1, 53.2, 49.7, 35.4, 31.9, 29.7,
29.7 (5C), 29.3, 28.5 (3C), 27.3, 25.7 (3C), 22.7, 22.1, 20.5, 19.2,
18.0, 14.1, -4.9, -5.0; MS (ESI) m/z 498 (M + H+, 100);
HRESIMS calcd for [C29H59NO3Si + Na]+ 520.4156, found
520.4149.
94:6) as a colorless oil. [R]30 -70.6 (c 1.1, CHCl3); IR (neat)
D
2954, 2931, 2707, 1733, 1685, 1395, 1366, 1173 cm-1; 1H NMR
(500 MHz, CDCl3) δ 9.36 (s, 1H), 4.06 (m, 1H), 3.75 (m, 1H),
3.70 (m, 1H), 2.02 (m, 1H), 1.76 (m, 1H), 1.60 (m, 2H), 1.45 (s,
9H), 1.09 (d, J ) 6.8 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 197.9, 155.3, 80.9, 68.8, 58.3, 53.7,
28.3 (3C), 25.7 (3C), 23.9, 18.7, 18.0, 16.2, -5.0 (2C); MS (ESI)-
m/z 358 (M + H+, 100), 380 (M + Na+, 20); HRESIMS calcd
for [C18H35NO4Si + H]+ 358.2408, found 358.2405.
(2R,3S,6S)-1-(ter t-Bu toxyca r bon yl)-3-h yd r oxy-2-m eth -
yl-6-u n d eca n ylp ip er id in e (28). To a solution of 27 (62 mg,
0.12 mmol) in dry THF (2 mL) was added TBAF (1 M in THF,
0.24 mL, 0.24 mmol) at room temperature. The solution was
allowed to stir overnight, and then an aqueous NH4Cl solution
(1 mL) and water (5 mL) were added successively. The mixture
was extracted with CH2Cl2 (3 × 6 mL), and the combined
organic layers were washed with brine (3 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was chromatographed (EtOAc/PE ) 1:4)
(2R ,3S ,6S )-1-(t er t -Bu t oxyca r b on yl)-5-[(t er t -b u t yld i-
m eth ylsilyl)oxy]-6-m eth yl p ip er id in e-2-ca r boxya ld eh yde
(24). A mixture of 23 (330 mg, 0.92 mmol), silica gel (500 mg,
300-400 mesh), Et3N (0.09 mL, 0.06 mmol), EtOAc (1 mL),
and petroleum ether (9 mL) was stirred at room temperature
and under N2 atmosphere for 72 h. After filtration, the solvent
was evaporated. The residue was chromatographed on silica
gel (eluent EtOAc/PE ) 1:15) to provide 24 (251 mg, 76%,
to yield 28 (48 mg, 100%) as a colorless oil. [R]30 -4.6 (c 0.6,
D
CHCl3); IR (neat) 3440, 2925, 2854, 1689, 1667, 1407, 1366,
1
1177 cm-1; H NMR (500 MHz, CDCl3) δ 4.20 (m, 1H), 4.08
(dq, J ) 7.1, 6.3 Hz, 1H), 3.75 (m, 1H), 1.96 (m, 1H), 1.85 (m,
2H), 1.58 (m, 1H), 1.45 (s, 9H), 1.40 (m, 2H), 1.26 (m, 20H),
1.16 (d, J ) 7.1 Hz, 3H), 0.87 (t, J ) 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 156.0, 79.3, 68.6, 53.1, 50.1, 35.2, 31.9,
29.7, 29.6 (5C), 29.3, 28.5 (3C), 27.5, 22.7, 21.1, 20.2, 19.2, 14.1;
MS (ESI) m/z 384 (M + H+, 100), 406 (M + Na+, 10);
HRESIMS calcd for [C23H45NO3 + H]+ 384.3472, found
384.3471.
diastereoselectivity ) 89:11) as a colorless oil. [R]30 +95.6 (c
D
1
0.5, CHCl3); H NMR (500 MHz, CDCl3) δ 9.60 (s, 1H), 4.65
(m, 1H), 4.21 (m, 1H), 3.60 (m, 1H), 2.02 (m, 2H), 1.52 (m,
1H), 1.47 (s, 9H), 1.42 (m, 1H), 0.99 (d, J ) 7.2 Hz, 3H), 0.87
(s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 203.1, 155.3, 80.3, 68.22, 58.5, 53.3, 28.3 (3C), 25.7 (3C), 22.9,
18.0, 17.8, 15.6, -4.9, -5.1; MS (ESI) m/z 358 (M + H+, 100),
380 (M + Na+, 20); HRESIMS calcd for [C18H35NO4Si + H]+
358.2408, found 358.2407.
(2R,3R,6S)-1-(ter t-Bu toxyca r bon yl)-3-h yd r oxy-2-m eth -
yl-6-u n d eca n ylp ip er id in e (30). Dimethyl sulfoxide (0.036
mL, 0.51 mmol) was added dropwise to a cooled (-78 °C)
solution of oxalyl chloride (0.02 mL, 0.25 mmol) in CH2Cl2 (0.5
mL). After the mixture was stirred at -78 °C for 5 min, a
solution of 28 (48 mg, 0.13 mmol) in CH2Cl2 (1.5 mL) was
added dropwise and the stirring was continued for 1 h. To the
resultant mixture was added i-Pr2NEt (0.087 mL, 0.50 mmol),
and the mixture was allowed to warm slowly to -10 °C. The
mixture was recooled to -78 °C, and a buffer solution of
NaOAc-HOAc (0.5 mL) and water (5 mL) were added succes-
sively. After CH2Cl2 extraction (3 × 10 mL), the combined
organic layers were washed with brine (3 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was chromatographed (eluent EtOAc/
PE ) 1:4) to yield 29 (colorless oil, 30 mg, yield 63%) and the
recovered starting material (30%). Compound 29 was used in
the next step immediately.
To a cooled (-78 °C) solution of 29 (30 mg, 0.079 mmol) in
anhydrous THF (1 mL) was added dropwise, under N2 atmo-
sphere, a solution of L-Selectride (1 M in THF, 0.16 mL, 0.16
mmol), and the mixture was stirred at -78 °C for 2 h. The
reaction was quenched by successive addition of a saturated
aqueous ammonium chloride solution (0.5 mL) and water (5
mL). After being extracted with CH2Cl2 (3 × 5 mL), the
combined organic layers were washed with brine (3 mL), dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. Flash chromatography (eluent EtOAc/PE )
1:4) of the crude then yielded (2R,3R,6S)-30 as a colorless oil
(30 mg, 100%). [R]28D +6.1 (c 1.9, CHCl3); IR (neat) 3434, 2925,
2854, 1690, 1665, 1406, 1366, 1175 cm-1; 1H NMR (500 MHz,
CDCl3) δ 4.41 (m, 1H), 3.95 (m, 1H), 3.75 (dq, J ) 7.1, 2.0 Hz,
1H), 1.95 (br s, 1H), 1.75-1.56 (m, 4H), 1.49 (m, 2H), 1.46 (s,
9H), 1.26 (m, 20H), 1.14 (d, J ) 7.1 Hz, 3H), 0.87 (t, J ) 7.0
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 155.3, 79.4, 69.9, 50.4,
49.6, 35.0, 31.9, 29.6, 29.6 (5C), 29.3, 28.5 (3C), 27.6, 26.4, 22.9,
(2R ,3S ,6S )-1-(t er t -Bu t oxyca r b on yl)-3-[(t er t -b u t yld i-
m et h ylsilyl)oxy]-2-m et h yl-6-u n d eca n -1′-en ylp ip er id in e
(26). To a cooled (0 °C) solution of 25 (235 mg, 0.47 mmol) in
dry THF (3 mL) was added dropwise n-BuLi (2.5 M, 0.19 mL,
0.48 mmol) under N2 atmosphere. After being stirred at room
temperature for 10 min, the mixture was cooled to -78 °C and
stirred for 15 min. To the resultant mixture was added
aldehyde 24 (110 mg, 0.31 mmol) in THF (2 mL). The solution
was stirred for 1 h at -78 °C and warmed slowly to room
temperature. The reaction was partitioned between water (5
mL) and CH2Cl2 (8 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 5 mL), and the combined organic phases were
washed with brine (5 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. Flash
chromatographic purification (eluent EtOAc/PE ) 1:40) af-
forded 26 (120 mg, 75%) as a colorless oil. [R]25 -20.6 (c 0.5,
D
CHCl3); IR (neat) 2955, 2927, 2855, 1691, 1364, 1178, 1069
cm-1; 1H NMR (500 MHz, CDCl3) δ 5.60 (dd, J ) 10.9, 9.1 Hz,
1H), 5.34 (ddd, J ) 10.9, 8.4, 7.2 Hz, 1H), 5.01 (ddd, J ) 7.2,
6.1, 2.3 Hz, 1H), 4.17 (dq, J ) 7.4, 7.2 Hz, 1H), 3.69 (m, 1H),
2.23 (dddd, J ) 13.5, 13.5, 6.1, 3.7 Hz, 1H), 2.15 (m, 2H), 1.87
(dddd, J ) 13.5, 13.5, 3.4, 2.3 Hz, 1H), 1.45 (s, 9H), 1.40-1.20
(m, 18H), 1.15 (d, J ) 7.4 Hz, 3H), 0.90 (m, 3H), 0.87 (s, 9H),
0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 155.3,
131.3, 131.2, 78.9, 69.0, 53.5, 46.9, 31.9, 29.8, 29.6 (2C), 29.4
(2C), 29.3, 28.5 (3C), 27.4, 25.7 (3C), 23.6, 22.7, 22.6, 19.6, 18.0,
14.1, -4.9, -5.0; MS (ESI) m/z 496 (M + H+, 100); HRESIMS
calcd for [C29H57NO3Si + Na]+ 518.4000, found 518.4002.
(2R ,3S ,6S )-1-(t er t -Bu t oxyca r b on yl)-3-[(t er t -b u t yld i-
m eth ylsilyl)oxy]-2-m eth yl-6-u n d eca n ylp ip er id in e (27).
To a suspension of Pd/C (50 mg, 10% Pd) in ethanol was added
26 (75 mg, 0.15 mmol). The mixture was stirred at room
6008 J . Org. Chem., Vol. 69, No. 18, 2004

(5S,6R)-6-Alkyl-5-benzyloxy-2-piperidinones
22.7, 14.1, 13.5; MS (ESI) m/z 406 (M + Na+, 5), 384 (M + H+,
100); HRESIMS calcd for [C23H45NO3 + H]+ 384.3472, found
384.3476.
anhydrous ether (2.5 mL) was added s-BuLi (1.3 M in heptane,
0.20 mL, 0.26 mmol) under nitrogen atmosphere, and the
mixture was stirred for 30 min. To the resulting mixture was
added dropwise BnBr (0.06 mL, 0.52 mmol), and the stirring
was continued at the same temperature for 2 h and then at
-35 °C for 3 h. Saturated aqueous ammonium chloride (1 mL)
and water (5 mL) were added successively. The mixture was
extracted with ether (3 × 8 mL), and the combined organic
layers were washed with brine (3 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
Flash chromatograph (eluent EtOAc/PE ) 1:3) of the crude
yielded 32 and 33 (97 mg, diastereomeric ratio ) 90:10,
combined yield 79%). Major diastereomer (32): colorless oil.
(2R ,3R ,6S )-3-H yd r oxy-2-m e t h yl-6-u n d e ca n ylp ip e r i-
d in e (Deoxoca ssin e, 4). A 0.5 M solution of HCl in MeOH
(1 mL) was added to 30 (30 mg, 0.079 mmol), and the resulting
solution was stirred under N2 atmosphere and at room
temperature overnight. The solvent was removed under re-
duced pressure. To the resultant residue was added water (2
mL). The mixture was basified with 5% NaHCO3 and extracted
with CH2Cl2 (3 × 3 mL). The combined organic layers were
washed with brine (1 mL), dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (eluent CH2Cl2/MeOH/
NH3‚H2O ) 100:5:1) gave (2R,3R,6S)-deoxocassine 4 (21 mg,
96%) as a white solid. Mp 47-48 °C (lit.21a mp 47.5-48.5 °C).
[R]25D -11.8 (c 0.9, CHCl3) {lit.21a [R]18D -12.3 (c 0.19, CHCl3);
[R]15 -32.7 (c 0.5, CHCl3); IR (film) 3027, 2928, 1637, 1453,
D
1073 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.40-6.90 (m, 20H),
5.50 (d, J ) 14.8 Hz, 1H), 4.04 (d, J ) 12.6 Hz, 1H), 4.01 (d,
J ) 12.6 Hz, 1H), 3.88 (d, J ) 14.8 Hz, 1H), 3.68 (m, 1H), 3.54
(dd, J ) 13.7, 3.9 Hz, 1H), 3.48 (m, 1H), 2.97 (dd, J ) 13.7,
4.8 Hz, 1H), 2.83 (dd, J ) 13.9, 11.2 Hz, 1H), 2.67 (dd, J )
13.9, 8.9 Hz, 1H), 2.56 (m, 1H), 2.02 (ddd, J ) 14.2, 7.3, 4.6
Hz, 1H), 1.72 (ddd, J ) 14.2, 5.5, 5.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 172.5, 140.4, 137.9, 137.2, 129.4, 129.0 (3C),
128.8 (3C), 128.6, 128.3, 128.2, 128.1 (3C), 127.5, 127.4 (3C),
127.3 (2C), 126.9, 126.1, 113.8, 73.1, 70.1, 60.6, 48.2, 38.8, 38.5,
26.7, 22.6; MS (ESI) m/z 476 (M + H+, 100), 498 (M + Na+,
30); HRESIMS calcd for [C33H33NO2 + H]+ 476.2584, found
476.2586.
lit.21b [R]20 -12.4 (c 0.8, CHCl3)}; IR (neat) 3390, 2924, 2853,
D
1562, 1466, 1404, 1014 cm-1
;
1H NMR (500 MHz, CDCl3) δ
3.63 (m, 1H), 3.40-2.96 (br s, 1H), 2.88 (dq, J ) 6.4, 1.4 Hz,
1H), 2.65 (m, 1H), 1.95 (m, 1H, NH), 1.58-1.38 (m, 4H), 1.26
(s, 22H), 1.21 (d, J ) 6.4 Hz, 3H), 0.88 (t, J ) 6.7 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 67.5, 57.5, 56.1, 35.9, 31.9, 31.7,
29.7, 29.6 (5C), 29.6, 29.3, 25.7, 25.0, 22.7, 17.9, 14.1; MS (ESI)
m/z 284 (M + H+, 100); HRESIMS calcd for [C18H37NO + H]+
284.2948, found 284.2952.
(R)-1-Ben zyl-3-ben zyloxy-2,6-p ip er id in ed ion e ((R)-7b).
Following the procedure described for (S)-7a , this compound
was prepared from (R)-6b in a yield of 90%. (R)-7b: waxy solid.
(3R,5R,6S)-1,3,6-Tr ib en zyl-5-h yd r oxy-2-p ip er id in on e
(5a ). To a mixture of 32 (92 mg, 0.19 mmol) and Pd/C (60 mg,
20% Pd) was added methanol (2 mL) and formic acid (0.2 mL),
and the mixture was stirred for 10 h. The mixture was filtered
through Celite and concentrated. The residue was purified by
flash chromatography on silica gel (eluent EtOAc/PE ) 1:3)
to provide 5a (56 mg, 75%) as white crystals. Mp 145-146 °C
(EtOAc/PE). [R]15 +23.1 (c 1.6, CHCl3) {lit.6a [R]15 +10.9
[R]20 +51 (c 1.0, CHCl3); IR (film) 2927, 1728, 1678, 1343,
D
1158, 1018; 1H NMR (500 MHz, CDCl3) δ 7.29-7.15 (m, 10H),
4.88 (d, J ) 13.5 Hz, 1H), 4.82 (d, J ) 13.5 Hz, 1H), 4.73 (d,
J ) 11.5 Hz, 1H), 4.56 (d, J ) 11.5 Hz, 1H), 4.00 (t, J ) 5.2
Hz, 1H), 2.86 (ddd, J ) 18.0, 7.5, 7.5 Hz, 1H), 2.53 (ddd, J )
18.0, 6.0, 6.0 Hz, 1H), 2.03 (m, 2H); 13C NMR (125 MHz, CDCl3)
δ 171.6, 171.4, 137.1, 137.0, 128.6 (2C), 128.5 (2C), 128.4 (2C),
128.0 (2C), 127.4 (2C), 73.8, 72.4, 42.9, 29.0, 24.0; MS (ESI)
310 (M + H+, 80), 332 (M + Na+, 100); HRESIMS calcd for
[C19H19NO3 + H]+ 310.1438, found 310.1439.
D
D
(c 2, CHCl3)}; IR (film) 3386, 2924, 1607, 1493, 1452, 1080
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.20-7.00 (m, 15H), 5.39
(d, J ) 14.9 Hz, 1H), 3.74 (d, J ) 14.9 Hz, 1H), 3.72 (m, 1H),
3.42 (dd, J ) 13.7, 4.3 Hz, 1H), 3.38 (m, 1H), 2.90 (dd, J )
14.0, 5.4 Hz, 1H), 2.79 (dd, J ) 13.7, 10.4 Hz, 1H), 2.65 (dd, J
) 14.0, 8.2 Hz, 1H), 2.49 (m, 1H), 1.95 (ddd, J ) 14.3, 7.5, 4.6
Hz, 1H), 1.55 (ddd, J ) 14.3, 6.8, 6.8 Hz, 1H), 1.62-1.50 (br s,
1H); 13C NMR (125 MHz, CDCl3) δ 172.3, 140.1, 137.2, 137.1,
129.5 (2C), 129.1 (2C), 128.8 (2C), 128.7 (2C), 128.4 (2C), 128.2
(2C), 127.5, 127.0, 126.2, 66.8, 64.1, 48.3, 39.4, 38.6, 38.4, 30.0;
MS (ESI) m/z 386 (M + H+, 90), 408 (M + Na+, 100);
HRESIMS calcd for [C26H27NO2 + H]+ 386.2114, found
386.2109.
(5R,6S)-5-Ben zyloxy-1,6-d iben zyl-2-p ip er id in on e (31).
Following the general reductive alkylation procedure as
described for 7a , the reductive alkylation of (R)-7b led to 31
and its diastereomer in 96:4 diastereomeric ratio and in a
combined yield of 54%. (5R,6S)-31: colorless oil. [R]15 -86.1
D
(c 1.1, CHCl3); IR (film) 3023, 2941, 1642, 1495, 1453, 1073
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.26-7.00 (m, 15H), 5.56
(d, J ) 15.3 Hz, 1H), 4.12 (d, J ) 12.3 Hz, 1H), 4.09 (d, J )
12.3 Hz, 1H), 3.86 (d, J ) 15.3 Hz, 1H), 3.70 (ddd, J ) 9.8,
4.6, 1.9 Hz, 1H), 3.51 (m, 1H), 3.12 (dd, J ) 14.0, 4.6 Hz, 1H),
2.75 (ddd, J ) 18.1, 11.6, 7.5 Hz, 1H), 2.61 (dd, J ) 14.0, 9.8
Hz, 1H), 2.47 (ddd, J ) 18.1, 5.5, 1.5 Hz, 1H), 2.12 (m, 1H),
2.02 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 169.8, 137.8, 137.4,
137.2, 128.9 (2C), 128.8 (2C), 128.5 (2C), 128.2 (2C), 128.0 (2C),
127.4 (2C), 127.30, 127.2, 126.9, 71.3, 69.6, 60.0, 47.6, 38.8,
27.1, 21.5; MS (ESI) m/z 386 (M + H+, 100), 408 (M + Na+,
10); HRESIMS calcd for [C26H27NO2 + H]+ 386.2114, found
386.2107.
Ack n ow led gm en t. The authors are grateful to the
National Science Fund for Distinguished Young Inves-
tigators, the NNSF of China (20272048; 203900505),
and the Ministry of Education (Key Project 104201) for
financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 1, 4, 5a , 7a , 7b, 12a -h , 13, 14, 16, 18-
24, 26-28, and 30-32. This material is available free of charge
via the Internet at http://pubs.acs.org.
(3R,5R,6S)-5-Ben zyloxy-1,3,6-t r ib en zyl-2-p ip er id in o-
n e (32) a n d (3S,5R,6S)-5-Ben zyloxy-1,3,6-tr iben zyl-2-p i-
p er id in on e (33). To a cooled (-78 °C) solution of (5R,6S)-31
(100 mg, 0.26 mmol) and HMPA (0.09 mL, 0.52 mmol) in
J O049166Z
J . Org. Chem, Vol. 69, No. 18, 2004 6009