Alkyl substituent effects on pipecolyl amide isomer equilibrium: Efficient methodology for synthesizing enantiopure 6-alkylpipecolic acids and conformational analysis of their N-acetyl N'-methylamides

Article abstract of DOI:10.1021/jo982181h

Enantiopure 6-alkylpipecolic acid hydrochlorides 1a-e were synthesized in five steps and 15-59% overall yields from α-tert-butyl β-methyl N- (PhF)aspartate (3) via an approach featuring selective hydride reduction to the corresponding aspartate β-aldehyde 2, aldol condensations with the enolates of various methyl alkyl ketones, and diastereoselective intramolecular reductive aminations. The influence of the 6-position substituent on the equilibrium and the energy barrier for isomerization of the amide N-terminal to pipecolate was then explored via the synthesis of N- acetyl N'-methylpipecolinamide (16) and its (2S,6R)-6-tert- butylpipecolinamide counterpart 17, and their conformational analysis by proton NMR spectroscopy and coalescence experiments. The presence of the tert-butyl substituent augmented the population of the amide cis-isomer and lowered the barrier for pipecolyl amide isomerization in water. Compared with the results from our previous examination of N-acetyl-5-tert-butylproline N'- methylamides (Beausoleil, E.; Lubell, W. D. J. Am. Chem. Soc. 1996, 118, 12902), the consequences of the bulky 6-alkyl substituent on the acetamide geometry and isomerization barrier were less pronounced in the pipecolate series relative to the respective proline amides.

Full text of DOI:10.1021/jo982181h

J . Org. Chem. 1999, 64, 1993-2002
1993
Alk yl Su bstitu en t Effects on P ip ecolyl Am id e Isom er Equ ilibr iu m :
Efficien t Meth od ology for Syn th esizin g En a n tiop u r e
6-Alk ylp ip ecolic Acid s a n d Con for m a tion a l An a lysis of Th eir
N-Acetyl N′-Meth yla m id es
Martin E. Swarbrick, Francis Gosselin, and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al C. P. 6128, Succursale Centre Ville, Montre´al,
Que´bec, Canada H3C 3J 7
Received October 30, 1998
Enantiopure 6-alkylpipecolic acid hydrochlorides 1a -e were synthesized in five steps and 15-
59% overall yields from R-tert-butyl â-methyl N-(PhF)aspartate (3) via an approach featuring
selective hydride reduction to the corresponding aspartate â-aldehyde 2, aldol condensations with
the enolates of various methyl alkyl ketones, and diastereoselective intramolecular reductive
aminations. The influence of the 6-position substituent on the equilibrium and the energy barrier
for isomerization of the amide N-terminal to pipecolate was then explored via the synthesis of
N-acetyl N′-methylpipecolinamide (16) and its (2S,6R)-6-tert-butylpipecolinamide counterpart 17,
and their conformational analysis by proton NMR spectroscopy and coalescence experiments. The
presence of the tert-butyl substituent augmented the population of the amide cis-isomer and lowered
the barrier for pipecolyl amide isomerization in water. Compared with the results from our previous
examination of N-acetyl-5-tert-butylproline N′-methylamides (Beausoleil, E.; Lubell, W. D. J . Am.
Chem. Soc. 1996, 118, 12902), the consequences of the bulky 6-alkyl substituent on the acetamide
geometry and isomerization barrier were less pronounced in the pipecolate series relative to the
respective proline amides.
In tr od u ction
antagonists.11 In addition, alkylpipecolates have served
as starting materials for synthesizing biologically active
piperidine alkaloids.12,13 For example, N-(methoxycarbo-
nyl)-6-n-propylpipecolate was used in the synthesis of the
N-methyl derivative of coniine,13 the principal toxic
constituent of hemlock.
Pipecolic acid (piperidine-2-carboxylic acid) is a wide-
spread, naturally occurring nonproteinogenic amino acid
found in many biologically interesting compounds. For
example, pipecolate residues are components of the
immunosuppressive drugs FK5061 and rapamycin,2 an-
tibiotic peptides such as the virginiamycins3 and the
efrapeptins,4 the antiprotozoal agent apicidin5, and in-
hibitors of HIV protease.6 Pipecolates have also served
as proline substitutes in structure-activity studies of
biologically relevant peptides.7,8 Furthermore, alkyl-
substituted pipecolic acids have been employed as dihy-
dropicolinic acid (DHDPA) synthase inhibitors9 and
N-methyl-D-aspartic acid (NMDA) receptor agonists10 and
Concurrent with our research on employing alkylpro-
lines in conformationally rigid mimics of peptide second-
ary structures,14,15 we became interested in the effects
of azacycloalkane amino acids of larger ring-size. We
initiated a program to synthesize and study alkylpipe-
colates in peptide structures in order to examine the
influence of ring-size, alkyl-substituent, and stereochem-
istry on peptide conformation.16 Since 5-alkylprolines
exhibited steric effects that greatly enhanced the cis-
isomer of the amide N-terminal to prolyl residues in
peptides,14 6-alkylpipecolates were chosen as our first
targets in order to study the influence of bulky 6-position
substituents on the equilibrium of pipecolyl amides.
The synthesis of alkylpipecolic acid derivatives17 has
received considerable attention;18-22 however, few meth-
ods offer the potential for selective and stereocontrolled
(1) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.;
Goto, T.; Hashimoto, M. J . Am. Chem. Soc. 1987, 109, 5031.
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1978, 56, 2491.
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Biochem. 1975, 58, 259.
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Brinen, L. S.; Clardy, J . J . Org. Chem. 1992, 57, 2306. (b) Gupta, S.;
Krasnof, S. B.; Roberts, D. W.; Renwick, J . A. A.; Brinen, L. S.; Clardy,
J . J . Am. Chem. Soc. 1991, 113, 707.
(5) Darkin-Rattray, S. J .; Gurnett, A. M.; Myers, R. W.; Dulski, P.
M.; Crumley, T. M.; Allocco, J . J .; Cannova, C.; Meinke, P. T.; Colletti,
S. L.; Bednarek, M. A.; Singh, S. B.; Goetz, M. A.; Dombrowski, A. W.;
Polishook, J . D.; Schmatz, D. M. Proc. Natl. Acad. Sci. U.S.A. 1996,
93, 13143.
(6) (a) Liard, F.; Ghiro, E.; Paris, W.; Yoakim, C. J . Pharm. Biomed.
Anal. 1995, 14, 151. (b) Copeland, T. D.; Wondrak, E. M.; Tozser, J .;
Roberts, M. M.; Oroszlan, S. Biochem. Biophys. Res. Commun. 1990,
169, 310.
(10) Mannaioni, G.; Alesiani, M.; Carla`, V.; Natalini, B.; Marinozzi,
M.; Pelliciari, R.; Moroni, F. Eur. J . Pharmacol. 1994, 251, 201.
(11) Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.; J ones, N. D.;
Deeter, J . B.; Lodge, D.; Leander, J . D. J . Med. Chem. 1992, 35, 3111.
(12) Reviewed in: O′Hagan, D. Nat. Prod. Rep. 1997, 14, 637.
(13) Ohtani, B.; Tsuru, S.; Nishimoto, S.-i.; Kagiya, T.; Izawa, K. J .
Org. Chem. 1990, 55, 5551.
(14) Beausoleil, E.; Lubell, W. D. J . Am. Chem. Soc. 1996, 118,
12902.
(7) (a) Kern, D.; Schutkowski, M.; Drakenberg, T. J . Am. Chem. Soc.
1997, 119, 8403. (b) Ando, S.; Ikuhara, T.; Kamata, T.; Sasaki, Y.;
Hisanga, S.-i.; Kishimoto, T.; Ito, H.; Inagaki, M. J . Biochem. 1997,
122, 409.
(8) Wu, W.-J .; Raleigh, D. P. J . Org. Chem. 1998, 63, 6689.
(9) Couper, L.; McKendrick, J . E.; Robins, D. J .; Chrystal, E. J . T.
Bioorg. Med. Chem. Lett. 1994, 4, 2267.
(15) Lombart, H.-G.; Lubell, W. D. J . Org. Chem. 1996, 61, 9437.
(16) Preliminary results have been reported in part in Gosselin, F.;
Swarbrick, M. E.; Lubell, W. D. In Peptides 1998 (Proceedings of the
25th European Peptide Symposium); Bajusz, S., Hudecz, F., Eds;
Akade´mia Kiado´: Budapest, Hungary, 1999, in press.
(17) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633.
10.1021/jo982181h CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/27/1999

1994 J . Org. Chem., Vol. 64, No. 6, 1999
Swarbrick et al.
Sch em e 2. Syn th esis of N-(P h F )Asp a r ta te
Sch em e 1. Gen er a l Str a tegy for Alk ylp ip ecola te
Syn th esis
â-Ald eh yd e 2
acids. In principle, this route offers access to pipecolates
with alkyl substituents at four of the five ring carbons
by employment of â-alkyl-branched aspartates24 and
alkyl-substituted enolates, as well as by conjugate addi-
tions to the R,â-unsaturated ketone intermediate.25 We
report now the employment of this route for synthesizing
enantiopure pipecolates with primary, secondary, and
tertiary alkyl as well as aryl 6-position substituents.16,26
The influence of the 6-position substituent on the
pipecolyl amide isomer equilibrium was studied via the
synthesis and conformational analysis of N-acetyl N′-
methylpipecolinamide (16) and its (2S,6R)-6-tert-bu-
tylpipecolinamide counterpart 17. Using NMR spectro-
scopy and coalescence experiments, we observed that the
consequences of the presence of the bulky (6R)-substitu-
ent on the pipecolyl amide isomer equilibrium in water
were similar to those previously observed in our com-
parison of N-acetylproline N′-methylamide 18 with its
(2S, 5R)-5-tert-butyl analogue 19.14 Steric interactions
between the N-acetyl and 6-position substituents disfa-
vored the amide trans-isomer and augmented the cis-
amide population. In addition, the presence of the (6R)-
tert-butyl substituent lowered the energy barrier for
amide isomerization in 16 relative to 17. On the other
hand, the effects of the tert-butyl substituent were less
pronounced in the pipecolate series relative to the respec-
tive proline amides. By elucidating their substituent
effects on pipecolinamide conformation and by providing
effective methodology for synthesizing 6-alkylpipecolates,
our report is intended to further the employment of
alkylpipecolates as tools for studying the structure-
activity relationships of biologically relevant peptides.
introduction of alkyl substituents at each of the ring
carbons. We are exploring a biomimetic entry into this
ring system in order to provide pipecolates with substit-
uents at the 3-, 4-, 5-, and 6-positions (Scheme 1, PhF )
9-phenylfluoren-9-yl). In analogy to the diaminopimelate
pathway for L-lysine biosynthesis, which features the
enzyme catalyzed aldol condensation between pyruvate
and aspartate â-aldehyde with subsequent cyclization to
provide L-dihydropicolinic acid,23 our route employs an
aldol condensation/reductive amination sequence to trans-
form N-(PhF)aspartate â-aldehyde 2 into alkylpipecolic
(18) Syntheses of 3-substituted pipecolates include the following: (a)
Agami, C.; Bihan, D.; Hamon, L.; Puchot-Kadouri, C. Tetrahedron
1998, 54, 10309. (b) Lorthiois, E.; Marek, I.; Normant, J . F. J . Org.
Chem. 1998, 63, 566. (c) Battistini L.; Zanardi F.; Rassu G.; Spanu P.;
Pelosi G.; Fava G. G.; Ferrari M. B.; Casiraghi G. Tetrahedron:
Asymmetry 1997, 8, 2975. (d) Makara, G. M.; Marshall, G. R.
Tetrahedron Lett. 1997, 38, 5069. (e) Agami, C.; Couty, F.; Mathieu,
H. Tetrahedron Lett. 1996, 37, 4001. (f) Subramanyam, C.; Chatterjee,
S.; Mallamo, J . P. Tetrahedron Lett. 1996, 37, 459. (g) Greck, C.;
Ferreira, F.; Geneˆt, J . P. Tetrahedron Lett. 1996, 37, 2031.
(19) Syntheses of 4-substituted pipecolates include the following: (a)
Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39, 5887. (b)
Bousquet, Y.; Anderson, P. C.; Bogri, T.; Duceppe, J .-S.; Grenier, L.;
Guse, I. Tetrahedron 1997, 53, 15671. (c) Golubev, A. S.; Sewald, N.;
Burger, K. Tetrahedron 1996, 52, 14757. (d) Machetti, F.; Cordero, F.
M.; De Sarlo, F.; Guarna, A.; Brandi, A. Tetrahedron Lett. 1996, 37,
4205. (e) Gillard, J .; Abraham, A.; Anderson, P. C.; Beaulieu, P. L.;
Bogri, T.; Bousquet, Y.; Grenier, L.; Guse, I.; Lavalle´e, P. J . Org. Chem.
1996, 61, 2226. (f) Skiles, J . W.; Giannousis, P. P.; Fales, K. R. Bioorg.
Med. Chem. Lett. 1996, 6, 963.
Resu lts a n d Discu ssion
(20) Syntheses of 5-substituted pipecolates include the following: (a)
Murray, P. J .; Starkey, I. D. Tetrahedron Lett. 1996, 37, 1875. (b)
Hoarau, S.; Fauche`re, J . L.; Pappalardo, L.; Roumestant, M. L.;
Viallefont, P. Tetrahedron: Asymmetry 1996, 7, 2585. (c) Adams, D.
R.; Bailey, P. D.; Collier, I. D.; Heffernan, J . D.; Stokes, S. Chem.
Commun. 1996, 349. (d) Ezquerra, J .; Pedregal, C.; Escribano, A.;
Carren˜o, M. C.; Ruano, J . L. G. Tetrahedron Lett. 1995, 36, 3247.
(21) Syntheses of optically active 6-substituted pipecolates include
the following: enzymatic desymmetrisation (a) Cheˆnevert, R.; Morin,
M.-P. Tetrahedron: Asymmetry 1996, 9, 2161; diastereoselective
additions to chiral iminium ions (b) Ojima, I.; Tzamarioudaki, M.;
Eguchi, M. J . Org. Chem. 1995, 60, 7078. (c) Berrien, J .-F.; Royer, J .;
Husson, H.-P. J . Org. Chem. 1994, 59, 3769. (d) Ludwig, C.; Wistrand,
L.-G. Acta Chem. Scand. 1994, 48, 367. For a racemic synthesis see
ref 9.
(22) Syntheses of multi-substituted pipecolates include the following:
(a) Barluenga, J .; Aznar, F.; Valde´s, C.; Ribas, C. J . Org. Chem. 1998,
63, 3918. (b) Klumpe, M.; Do¨tz, K. H. Tetrahedron Lett. 1998, 39, 3683.
(c) Grandel, R.; Kazmaier, U.; Rominger, F. J . Org. Chem. 1998, 63,
4524. (d) Ho, B.; Zabriskie, T. M. Bioorg. Med. Chem. Lett. 1998, 8,
739. (e) Herdeis, C.; Heller, E. Tetrahedron: Asymmetry 1997, 8, 1115.
(f) Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997, 38, 8009. (g)
J ackson, R. F. W.; Turner, D.; Block, M. H. Synlett 1997, 789. (h)
Hanessian, S.; Reinhold: U.; Gentile, G. Angew. Chem., Int. Ed. Engl.
1997, 36, 1881.
Syn th esis a n d Rea r r a n gem en t of Asp a r ta te â-Al-
d eh yd e. 6-Alkylpipecolic acids 1 were synthesized from
aspartic acid via a route featuring aldol condensation on
R-tert-butyl N-(PhF)aspartate â-aldehyde 2, dehydration,
and subsequent diastereoselective reductive amination
of ꢀ-oxo R-N-(PhF)amino esters 7 (Scheme 4). We reported
previously on the Wittig and Horner-Wadsworth-Em-
mons olefination chemistry of (2S)-tert-butyl 2-[N-(PhF)-
amino]-4-oxobutanoate (2),27 and its synthesis from R-tert-
butyl â-methyl N-(PhF)aspartate (3)24b by selective â-ester
(23) Cox, R. J . Nat. Prod. Rep. 1996, 13, 29.
(24) (a) Humphrey, J . M.; Bridges, R. J .; Hart, J . A.; Chamberlin,
A. R. J . Org. Chem. 1994, 59, 2467. (b) Gmeiner, P.; Feldman, P. L.;
Chu-Moyer, M. Y.; Rapoport, H. J . Org. Chem. 1990, 55, 3068. (c) Dunn,
P. J .; Ha¨ner, R.; Rapoport, H. J . Org. Chem. 1990, 55, 5017. (d) Wolf,
J .-P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164.
(25) Paz, M. M.; Sardina, J . F. J . Org. Chem. 1993, 58, 6990.
(26) 5,6-Dialkylpipecolates have also been prepared using this
methodology: Swarbrick, M. E.; Lubell, W. D. manuscript in prepara-
tion.

Alkyl Substituent Effects on Pipecolyl Amide Isomer Equilibrium
J . Org. Chem., Vol. 64, No. 6, 1999 1995
Sch em e 3. P r op osed Mech a n ism for th e
Rea r r a n gem en t of Ald eh yd e 2 in to Aza d ien e 5
kinetically controlled conditions prior to the addition of
aldehyde 2.29 Enones 7 were synthesized by dehydration
of alcohols 6 using two different conditions. Initially, we
subjected â-hydroxy ketones 6 to diisopropylcarbodiimide
and catalytic copper(I) chloride in THF which furnished
enones 7 in 62-87% yields.30 Improved yields of enones
7b-f were obtained via the elimination of the correspond-
ing methanesulfonates using methanesulfonyl chloride
and triethylamine in dichloromethane. Treatment of 6a
under the latter conditions provided enone 7a in 64%
yield accompanied by 32% yield of a single diastereomeric
methanesulfonate, which suggested that steric crowding
prevented this diastereomer from attaining the confor-
mation required for elimination. In all cases, formation
of olefin having only the (E)-configuration was indicated
by the large (15.2-16.0 Hz) vicinal coupling constants
between the vinyl protons.
Hydrogenations of enones 7 were originally performed
using 10% palladium-on-carbon as catalyst in a solution
of 10:1 methanol:acetic acid under 3 atm of hydrogen.31
Under these conditions, concurrent hydrogenation of the
double bond and cleavage of the PhF protecting group
were followed by iminium ion formation and subsequent
reduction from the side opposite the tert-butyl ester to
selectively furnish the cis-6-alkylpipecolate tert-butyl
esters 8. The relative stereochemistry of the pipecolate
6-position substituent was assigned initially based on
analogy with our studies on the hydrogenation of R-tert-
butyl δ-oxo-R-N-(PhF)amino esters which produced 5-alkyl-
prolines with high selectivity in favor of the cis-diaste-
reomer.31 Using similar hydrogenation conditions to
prepare related fused-pipecolate analogues, we later
confirmed the assignment of the 6-position stereochem-
istry by crystallization of the (2S,6R,8S)-methyl 9-oxo-
8-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-2-carboxyl-
ate and analysis by X-ray diffraction.27
6-tert-Butylpipecolate 8a could be purified by chroma-
tography after filtration and concentration; however,
isolation of pure 6-alkylpipecolates 8b-d was less straight-
forward, due largely to their volatility. Although chro-
matographic purification could be circumvented by par-
titioning the 9-phenylfluorene hydrocarbon into hexanes,
subsequent concentration of the methanolic acetic acid
solution under vacuum was accompanied by loss of
material due to the volatility of the acetate salts of 8b-
d . Direct conversion of tert-butyl esters 8b-d into amino
acids 1b-d was accomplished by treatment of the crude
hydrogenation product with 1:1 trifluoroacetic acid:
dichloromethane, extraction of the pipecolate trifluoro-
acetates into water, concentration, and ion-exchange
chromatography which furnished zwitterionic 6-alkyl-
pipecolates 1b-d in respective yields of 59%, 61%, and
81%. Although amino acids 1b-d were of adequate
purity for subsequent use, their hygroscopic nature
thwarted recrystallization. Hydrogenation of enones
7a -d in the absence of acetic acid proved the most
effective means for isolating 6-alkylpipecolates 8a -d .
Treatment of enones 7a -d in methanol with palladium-
on-carbon and 3 atm of hydrogen furnished tert-butyl
6-alkylpipecolates 8a -d in 86-91% respective yields
after chromatography with diethyl ether in dichlo-
reduction using DIBAL-H in THF at -40 °C to furnish
N-(PhF)homoserine tert-butyl ester (4), followed by oxi-
dation of the primary alcohol using DMSO and oxalyl
chloride in dichloromethane. We report now that alde-
hyde 2 can be synthesized in one transformation and
>95% yield from diester 3 by selective reduction with
DIBAL-H in toluene at -78 °C for 5 min (Scheme 2).
As previously reported,27 aldehyde 2 can be stored for
several months at -20 °C without decomposition; how-
ever, when dissolved in CDCl3, 2 was transformed into a
new product 5 within a few hours as judged by the
disappearance of the signals for the aldehyde, R- and
â-protons, respectively, at 9.52, 3.04, and 2.40 ppm in
the NMR spectrum. In the FT-IR spectrum of 5, we
observed bands at 1610 and 1714 cm-1 corresponding,
respectively, to the stretches for an R,â-unsaturated
imine and ester. Mass spectrometric analysis of 5 by fast
atom bombardment gave a peak with m/z ) 396, indicat-
ing loss of water from aldehyde 2 when nitrobenzyl
alcohol was used as the matrix, and with thioglycerol as
the matrix, a peak was obtained with m/z ) 504 which
indicated loss of water from 2 and formation of a
thioglycerol adduct. Crystals of 5 were later grown from
EtOAc-hexanes. Crystallographic analysis by X-ray dif-
fraction demonstrated the product from decomposition
of 2 to be tert-butyl N-(PhF)-5-azapenta-2,4-dienoate (5,
Figure 1).28 This conjugated imine is presumed to form
by a process that commences with intramolecular attack
of the N-(PhF)amine onto the â-aldehyde (Scheme 3). In
the presence of trace amounts of acid in chloroform, the
resulting aminol may lose water to provide a strained
dehydroazetidine carboxylate that ring opens by elimina-
tion of the iminium ion nitrogen to furnish azadiene 5.
The thioglycerol adduct obtained in the mass spectral
analysis of 5 may have thus resulted from 1,4- or 1,2-
additions of this thiol to 5-azapenta-2,4-dienoate 5.
Syn th esis of 6-Alk ylp ip ecola tes. Aldol condensa-
tions with aldehyde 2 and the lithium enolates of a
variety of methyl alkyl ketones furnished the respective
ꢀ-oxo γ-hydroxy R-N-(PhF)amino esters 6 in 61-93%
yields (Scheme 4, Table 1). In the cases of 3-methylbutan-
2-one and pentan-2-one, the enolate was generated under
(27) Gosselin, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463.
(28) The structure of 5 was solved at l′Universite´ de Montre´al X-ray
facility using direct methods (SHELXS96) and refined with NRCVAX
and SHELXL96:
C27H25NO2; Mr ) 395.480; monoclinic, colorless
crystal; space group P21; unit cell dimensions (Å) a ) 10.616(3), b )
8.537(2), c ) 13.146(7); â ) 110.15(3)°; volume of unit cell (Å3) ) 1118.5-
(7); Z ) 2; R1 ) 0.0343 for I > 2 σ(I), wR2 ) 0.0584 for all data; GOF
) 0.990. The author has deposited the atomic coordinates for the
structure of 5 with the Cambridge Crystallographic Data Center. The
coordinates can be obtained, on request, from the Cambridge Crystal-
lographic Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK.
(29) For a review, see d’Angelo, J . Tetrahedron 1976, 32, 2979.
(30) Miller, M. J . J . Org. Chem. 1980, 45, 3131.
(31) (a) Beausoleil, E.; L′Archeveˆque, B.; Be´lec, L.; Atfani, M.; Lubell,
W. D. J . Org. Chem. 1996, 61, 9447. (b) Ibrahim, H. H.; Lubell, W. D.
J . Org. Chem. 1993, 58, 6438.

1996 J . Org. Chem., Vol. 64, No. 6, 1999
Swarbrick et al.
Sch em e 4. Syn th esis of 6-Alk ylp ip ecolic Acid Hyd r och lor id e Sa lts 1
examine the competition between PhF group hydro-
genolysis and aryl ketone reduction (Table 2).34
The rates of ketone hydrogenation and N-PhF bond
hydrogenolysis were competitive using palladium and
platinum catalysts such that tert-butyl 6-phenylpipeco-
late 8e was isolated in low yield. The best yield (20%) of
8e was obtained on hydrogenation of 7e over palladium-
on-carbon in methanol under 1 atm of hydrogen. Selective
reduction of the double bond and aryl ketone without loss
of the phenylfluorenyl group was achieved on hydrogena-
tion of 7e with Raney nickel as catalyst to give N-(PhF)-
amino alcohol 11. As previously noted,35 selective olefin
hydrogenation without PhF removal was accomplished
with a platinum catalyst and gave (2S)-tert-butyl 6-oxo-
6-phenyl-2-N-(PhF)aminohexanoate (12) from 7e. At-
tempts to convert 12 to 6-arylpipecolate 8e gave similar
product distributions as those obtained from hydrogena-
tions of 7e under identical conditions. In summary, the
reductive amination route proved more effective for
preparing 6-alkyl rather than 6-arylpipecolates due to
competitive aryl ketone reductions.
En a n tiom er ic P u r ity. Determination of the enan-
tiomeric purity of 6-alkylpipecolate 1 by the preparation
and analysis of diastereomeric derivatives proved more
difficult than purity studies we had previously conducted
on related 5-alkylprolines.31 As noted in a failed attempt
to determine the enantiomeric purity of an alkylpiperi-
dine,36 although amides and ureas could be synthesized
by acylation of the piperidine nitrogen, analysis by proton
NMR spectroscopy did not indicate sufficiently distinct
diastereomeric signals for ascertaining the limits of
detection of the minor isomer. Furthermore, these dia-
stereomeric derivatives eluted with similar retention
times in cursory examinations by reverse-phase HPLC.
F igu r e 1. ORTEP view of tert-butyl N-(PhF)-5-azapenta-2,4-
dienoate (5). Ellipsoids drawn at 40% probability level. Hy-
drogens represented by spheres of arbitrary size.27
romethane as eluant. The 6-alkylpipecolate hydrochlo-
rides were then quantitatively obtained by exposure of
tert-butyl esters 8 to HCl in dichloromethane.
The 9-phenylfluorene hydrocarbon was quantitatively
recovered from the hydrogenation of ꢀ-oxo-R-N-(PhF)-
amino esters 7. Endeavoring to recycle this hydrocarbon
back to the protecting group precursor, 9-bromo-9-phen-
ylfluorene, we found that simply heating 9-phenylfluo-
rene with N-bromosuccinimide in carbon tetrachloride32
provided the corresponding bromide in 96% yield after
evaporation of the volatiles, digestion of the residue with
hexanes, and filtration of the insoluble succinimide
(Scheme 5). This efficient recycle of 9-phenylfluorene to
9-bromo-9-phenylfluorene has thus provided an economic
means for extending the duration of utility of the 9-phen-
ylfluorenyl protecting group.33
Syn th esis of 6-Ar ylp ip ecola tes. Hydrogenation of
(2S,4E)-tert-butyl 6-oxo-6-phenyl-2-N-(PhF)-aminohex-4-
enoate (7e) in the presence of acetic acid under the
conditions described above for the synthesis of 6-alkyl-
pipecolate did not furnish the desired 6-arylpipecolate 8e;
instead, (2S,6RS)-tert-butyl 2-amino-6-hydroxy-6-phen-
ylhexanoate (9) was isolated as a 1:1 mixture of diaster-
eomers in 46% yield (Scheme 6). Furthermore, no cleav-
age of the PhF protecting group was observed on hydro-
genation of (2S,4E)-tert-butyl 6-oxo-6-(2′-pyridyl)-2-N-
(PhF)aminohex-4-enoate (7f) under similar conditions;
instead, (2S,6RS)-tert-butyl 2-[N-(PhF)amino]-6-hydroxy-
6-(2′-pyridyl)hexanoate (10) was obtained as a 1:1 mix-
ture of diastereomers in 58% yield. These results prompted
The enantiomeric purity of 6-alkylpipecolate 1 was
successfully determined after conversion to the respective
N-benzylpipecolate and subsequent coupling to a chiral
amine (Scheme 7). (2S,6S)-6-Methylpipecolate tert-butyl
ester (1d ) was treated with benzyl bromide and potas-
sium carbonate in DMF to provide N-(benzyl)pipecolate
14 in 95% yield. Dipeptides 15 were synthesized by tert-
butyl ester solvolysis on exposure of 14 to HCl gas in
dichloromethane, followed by coupling to D- and L-
phenylalanine methyl ester hydrochloride using benzo-
triazol-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate
(TBTU)37 and DIEA in acetonitrile. Measurement of the
(32) Buu-Ho¨i, Ng. Ph. J ustus Liebigs Ann. Chem. 1944, 556, 1.
(33) Although it is listed in the Aldrich Chemical Co. 1996-97
catalogue for $40.70 Canadian per gram, we synthesize >250 g batches
of 9-bromo-9-phenylfluorene from inexpensive fluorenone, bromoben-
zene, butyllithium and HBr in >80% yield using the convenient
protocol described in: J amison, T. F.; Lubell, W. D.; Dener, J . M.;
Krische´, M. J .; Rapoport, H. Org. Synth. 1992, 71, 220.
(34) Monographs include the following: (a) Rylander, P. N. Catalytic
Hydrogenation In Organic Synthesis; Academic Press: New York, 1979.
(b) Rylander, P. N. Catalytic Hydrogenation Over Platinum Metals;
Academic Press: New York, 1967.
(35) (a) Lubell, W.; Rapoport, H. J . Org. Chem. 1989, 54, 3824. (b)
Park, K. H.; Rapoport, H. J . Org. Chem. 1994, 59, 394.
(36) Davis, F. A.; Szewczyk, J . M. Tetrahedron Lett. 1998, 39, 5951.
an investigation of the hydrogenation of 7e in order to

Alkyl Substituent Effects on Pipecolyl Amide Isomer Equilibrium
J . Org. Chem., Vol. 64, No. 6, 1999 1997
Ta ble 1. Isola ted Yield s in th e Syn th esis of 6-Alk ylp ip ecola tes
Sch em e 5. Recycle of 9-P h en ylflu or en e to
9-Br om o-9-p h en ylflu or en e
purity. Hence 6-alkylpipecolic acids 1 are presumed to
be of >99% enantiomeric purity.
Con for m a tion a l An a lysis of N-Acetyl N′-Meth yl
P ip ecolin a m id es. N-Acetyl N′-methyl pipecolinamide
16 and its (2S,6R)-6-tert-butyl counterpart 17 were
synthesized in order to examine the influence of the bulky
6-position substituent on the amide isomer equilibrium
and the rate of amide isomerization N-terminal to the
pipecolyl residue. Pipecolic acid was N-protected with di-
tert-butyl dicarbonate in an aqueous dioxane solution
containing sodium hydroxide, and the resulting N-(BOC)-
pipecolate was coupled to methylamine using TBTU in
acetonitrile. Pipecolinamide 16 was then obtained after
solvolysis of the BOC group with gaseous HCl in dichlo-
romethane, followed by acetylation on heating in the
presence of acetic anhydride and triethylamine in dichlo-
romethane. (2S,6R)-N-Acetyl N′-methyl 6-tert-butylpipe-
colinamide was synthesized without N-protection by
coupling to methylamine using TBTU in acetonitrile,
followed by N-acetylation on heating with acetic anhy-
dride, sodium acetate, and triethylamine in toluene at
reflux.
Sch em e 6. Hyd r ogen a tion of En on e 7E
The pipecolinamide isomer equilibrium and the energy
barrier for amide isomerization were determined in water
(D2O) because of its physiological importance and for
comparison with literature examples.14 In comparison to
reaction rates in nonprotic and nonpolar solvents, amide
isomerization N-terminal to proline has been shown to
proceed slower in water, which stabilizes the polar amide
ground states relative to the less polar transition state.38
The cis-isomer geometry was assigned based on the cross-
peak arising from the nuclear Overhauser effect between
the N-acetyl and prolyl R-hydrogens in the NOESY and
ROESY spectra of 16 and 17 in water. The populations
of the amide isomers were measured by integration of
their isomeric acetyl methyl singlets in the 1H NMR
spectra. The energy barriers (∆Gq) for amide isomeriza-
tion in 16 and 17 were determined by recording a series
of 1H NMR spectra at 400 MHz with increasing temper-
atures until the resonances for the two isomer popula-
tions were observed to coalesce. The energy barriers for
amide isomerization in 16 and 17 were then calculated
to, respectively, be 17.8 and 17.0 kcal/mol in D2O.39 For
comparison, the isomer populations and the energy
barriers for isomerization of 16 and 17 are listed next to
the values for N-(acetyl)proline N′-methylamide (18) and
its (2S,5R)-5-tert-butyl counterpart 19 in Table 3.14
Ta ble 2. Ca ta lytic Hyd r ogen a tion of En on e 7e
Sch em e 7. En a n tiom er ic P u r ity of (2S,
6S)-6-Meth ylp ip ecola te 8d
(37) (a) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D.
Tetrahedron Lett. 1989, 30, 1927. The crystal structure of HBTU, the
corresponding PF6 salt, substantiates a guanidinium-1-N-oxide salt for
TBTU: (b) Abdelmoty, I.; Albericio, F.; Carpino, L. A.; Foxman, B.;
Kates, S. A. Lett. Peptide Sci. 1994, 1, 57.
(38) Stein, R. L. Adv. Protein Chem. 1993, 44, 1.
(39) Sandstro¨m, J . Dynamic NMR Spectroscopy, Academic Press:
London, 1982, ch. 6, p 79.
methyl ester singlets at 3.68 and 3.52 ppm in CDCl3 by
400 MHz H NMR spectroscopy and incremental addi-
tions of diastereomeric (2S,6R,2′S)-15 demonstrated
(2S,6R,2′R)-dipeptide 15 to be of >99% diastereomeric
1

1998 J . Org. Chem., Vol. 64, No. 6, 1999
Swarbrick et al.
Ta ble 3. P r olin e14 a n d P ip ecola te N-Acetyl-N′-Meth yl
tion substituent augmented the pipecolyl amide cis-
isomer population and lowered the barrier for amide
isomerization in a manner similar to albeit less pro-
nounced than the influence of a 5-tert-butyl substituent
on the amide of the corresponding proline series.14 This
approach has thus expanded our capacity for synthesizing
and employing azacycloalkane carboxylates as tools for
the exploration of conformation-activity relationships of
biologically active peptides.
Am id e Equ ilibr iu m
Exp er im en ta l Section
Gen er a l. Unless stated otherwise, solvents and reagents
were used as supplied, and all reactions were carried out under
nitrogen. Toluene was distilled from sodium, tetrahydrofuran
from sodium/benzophenone, dichloromethane from P2O5, and
the methyl ketones from CaSO4, immediately prior to use.
Diisopropylamine, DIEA, and triethylamine were distilled from
CaH2. Diisopropylcarbodiimide was distilled from KMnO4.
Copper(I) chloride was purified by precipitation from hydro-
chloric acid.41 Methanesulfonyl chloride was passed through
a pad of basic alumina immediately prior to use. n-Butyl-
lithium was titrated using menthol in THF containing fluorene
as indicator. Final reaction solutions were dried over Na2SO4.
Flash-column chromatography42 was performed on 230-400
mesh silica gel; TLC was performed on aluminum-backed silica
plates with visualization by UV-light, iodine, or ninhydrin.
Mass spectral data, and HRMS (FAB and ES) data, were
obtained by the Universite´ de Montre´al Mass Spectroscopy
facility. 1H NMR and 13C NMR spectra were, respectively,
recorded at 400 and 100 MHz in CDCl3. Chemical shifts are
in ppm (δ units) relative to internal (CH3)4Si or residual
solvent for 1H NMR spectra, and relative to solvant signals
for 13C NMR spectra. Chemical shifts for aromatic and vinyl
carbons are not reported for PhF-containing compounds.
Catalytic hydrogenation was conducted at 1 atm in a round-
bottomed flask equipped with a balloon and at 3 atm in a high-
pressure hydrogenation apparatus.
As observed in our comparison of N-acetyl N′-methyl-
amides of proline and (2S,5R)-5-tert-butylproline, the
bulky substituent caused steric interactions that disfa-
vored the trans-isomer and increased the cis-amide
isomer population. Furthermore, a lower barrier for
amide isomerization was observed for the (6R)-tert-
butylpipecolinamide 17 relative to the simple pipecolyl
amide 16 (Table 3). The influences of the tert-butyl
substituent were less pronounced in the pipecolinamides
relative to their proline counterparts.
The 2.6 kcal/mol lower barrier for isomerization of
pipecolinamide 16 relative to N-(acetyl)proline N′-me-
thylamide (18) compared well with the 2.8 kcal/mol lower
barrier for isomerization of N-acetyl 2-methylpyrrolidine
(15.3 kcal/mol) relative to N-acetyl 2-methylpiperidine
(18.1 kcal/mol).40 The barrier for amide isomerization was
also observed to be lower for pipecolyl than prolyl
residues in peptides.8 A tendency for greater amide cis-
isomer populations N-terminal to pipecolyl versus prolyl
residues has been recorded in peptides and attributed
to increased steric interaction between the N-terminal
amino acid and the bulkier piperidine ring.8 Since the
amount of cis-isomer exhibited by N-acetyl N′-meth-
ylpipecolinamide (16) is similar to that of N-(acetyl)-
proline N′-methylamide (18) in water, the N-acetyl
residue does not appear to have sufficient bulk to
discriminate between the piperidine and pyrrolidine ring-
sizes. The greater conformational liberty of the six- versus
five-member ring may also account for the lower aceta-
mide cis-isomer population for 6-tert-butylpipecolinamide
17 relative to 5-tert-butylproline amide 19.
(2S)-ter t-Bu tyl 2-[N-(P h F )a m in o]-4-oxobu ta n oa te (2).
Diisobutylaluminum hydride (46.6 mL of a 1.0 M solution in
toluene, 0.047 mol) was added dropwise over 10 min to a
stirred solution of (2S)-R-tert-butyl â-methyl-N-(PhF)aspartate
(3, 18.8 g, 0.042 mol, prepared according to ref 26) in toluene
(420 mL) at -78 °C. Upon complete addition, the reaction was
stirred for an additional 5 min and quenched by the addition
of acetone (10 mL) followed by water (10 mL). Sodium
bicarbonate (approximately 45 g) was added to the mixture
which was allowed to warm to room temperature with vigorous
stirring and filtered through a pad of sodium bicarbonate on
Celite. The filter cake was washed thoroughly with ethyl
acetate, and the filtrate was concentrated in vacuo to furnish
the title compound26 in >95% yield as a viscous colorless oil
which was subsequently used without further purification:
1
TLC Rf ) 0.44 (20% ethyl acetate in hexanes); H NMR (300
MHz) δ 1.21 (s, 9 H), 2.40 (m, 2 H), 3.03 (dd, 1 H, J ) 7.4,
5.5), 3.34 (br s, 1 H), 7.15-7.72 (m, 13 H), 9.48 (dd, 1 H, J )
2.8, 2.2).
Con clu sion
Our investigation has provided effective means for
preparing novel alkylpipecolates and better understand-
ing of their conformational effects in peptide structures.
Enantiopure 6-alkylpipecolates were synthesized by em-
ployment of R-tert-butyl N-(PhF)aspartate â-aldehyde 2
in an aldol condensation, dehydration, reductive amina-
tion sequence. Primary, secondary, and tertiary alkyl as
well as aromatic groups all were stereoselectively intro-
duced at the 6-position of pipecolic acid. Furthermore,
extension of this methodology offers potential to provide
pipecolates with other substitution patterns. Comparison
of N-acetyl N′-methyl pipecolinamide 16 and its (2S,6R)-
6-tert-butyl counterpart 17 demonstrated that the 6-posi-
ter t-Bu tyl N-(P h F )-5-a za p en ta -2,4-d ien oa te (5) was iso-
lated, after stirring 3 in CDCl3, by chromatography using a
gradient of 0-5% EtOAc in hexanes as eluant. Evaporation
of the collected fractions and recrystallization from EtOAc and
hexanes gave colorless needles: mp ) 148-149 °C; TLC Rf )
0.57 (20% EtOAc in hexanes); 1H NMR δ 7.83-7.74 (m, 3 H),
7.39-7.22 (m, 13 H), 6.04 (d, 1 H, J ) 15.8), 1.49 (s, 9 H); 13
C
NMR δ 28.0, 80.2, 81.1, 158.1, 164.9; FT-IR (Nujol, cm-1) 1714,
1610; m/z (nitrobenzyl alcohol): 396 (MH+); m/z (thiogly-
cerol): 504 (M + 109).
Gen er a l P r oced u r e for Ald ol Con d en sa tion of Asp a r -
ta te â-Ald eh yd e 2 w ith 3-Meth ylbu ta n -2-on e a n d P en ta n -
2-on e. A solution of n-butyllithium (1.2 mmol) in hexanes was
(41) Keller, R. N.; Wycoff, H. D. Inorg. Synth. 1946, 2, 1.
(42) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(40) Paulsen, H.; Todt, K. Chem. Ber. 1967, 100, 3385.

Alkyl Substituent Effects on Pipecolyl Amide Isomer Equilibrium
J . Org. Chem., Vol. 64, No. 6, 1999 1999
added dropwise to a stirred solution of diisopropylamine (164
µL, 1.2 mmol) in THF (1 mL) at -10 °C to 0 °C. Upon complete
addition, the solution was cooled to -78 °C, stirred for 15 min,
and treated with the ketone (1.1 mmol, 110 mol %). After
stirring an additional 15 min, the reaction mixture was treated
dropwise via cannula with a solution of aldehyde 2 (414 mg, 1
mmol) in THF (1 mL) and stirred at -78 °C until analysis by
TLC indicated the complete consumption of aldehyde 2 (1-2
h). The reaction was quenched by the addition of a solution of
saturated aqueous sodium bicarbonate (0.5 mL), allowed to
warm to room temperature, and treated with additional
saturated aqueous sodium bicarbonate (10 mL). The mixture
was separated, and the aqueous phase was extracted with
diethyl ether (3 × 10 mL). The combined organic layers were
dried and concentrated in vacuo to a crude product which was
purified by flash-column chromatography, eluting with an
ethyl acetate:hexanes system of appropriate polarity.
Gen er a l P r oced u r e for Ald ol Con d en sa tion of Asp a r -
ta te â-Ald eh yd e 2 w ith Aceton e, P in a colon e, Acetop h e-
n on e, a n d 2-Acetylp yr id in e. A solution of n-butyllithium
(1.4 mmol) in hexanes was added dropwise to a stirred solution
of diisopropylamine (273 µL, 2.0 mmol) in THF (1 mL)
maintaining the temperature between -10 °C and 0 °C. Upon
complete addition, the solution was cooled to -78 °C, stirred
for 15 min, treated with the ketone (1.4 mmol, 140 mol %),
stirred 30 min, and treated dropwise via cannula with a
solution of aldehyde 2 (414 mg, 1 mmol) in THF (1 mL).
Stirring was continued at -78 °C until TLC analysis indicated
complete consumption of aldehyde (1-2 h). Quench, workup,
and purification all were performed in the same manner as
described above.
7.15-7.80 (m, 13H); 13C NMR (major isomer) δ 13.6, 16.9, 27.7,
39.8, 45.4, 49.9, 55.9, 67.4, 72.9, 81.1, 173.9, 209.7; 13C NMR
(minor isomer) 13.6, 16.9, 27.7, 39.6, 45.5, 49.7, 54.0, 65.5, 72.9,
81.4, 174.2, 209.8; HRMS calcd for C32H38NO4 (MH+) 500.2801,
found 500.2815.
(2S,4RS)-ter t-Bu tyl 4-h yd r oxy-6-oxo-2-[N-(P h F)a m in o]-
h ep ta n oa te (6d ) was prepared as described above using
acetone and isolated as a white solid containing an inseparable
2:1 mixture of diastereomers (68% from 2): TLC Rf ) 0.26
(30% ethyl acetate in hexanes); 1H NMR (major isomer) δ 1.14
(s, 9 H), 1.47-1.52 (m, 2 H), 2.15 (s, 3 H), 2.29 (dd, 1 H, J )
16.0, 4.7), 2.51 (dd, 1 H, J ) 16.0, 8.0), 2.69-2.73 (m, 1 H),
3.98-4.05 (m, 1 H), 7.14-7.73 (m, 13 H); 1H NMR (minor
isomer) δ 1.24 (s, 9 H), 1.47-1.52 (m, 2 H), 2.13 (s, 3 H), 2.34
(dd, 1 H, J ) 16.5, 4.8), 2.54 (dd, 1 H, J ) 16.0, 8.0), 2.69-
2.73 (m, 1 H), 4.20-4.30 (1 H, m), 7.14-7.73 (m, 13 H); 13C
NMR (major isomer) δ 27.7, 30.5, 39.7, 50.8, 55.9, 67.4, 72.9,
81.2, 173.9, 207.6; 13C NMR (minor isomer) δ 27.7, 30.7, 39.5,
50.7, 54.1, 65.4, 72.9, 81.4, 174.1, 207.5; HRMS calcd for C30H34
-
-
NO4 (MH+) 472.2488, found 472.2505. Anal. Calcd for C30H34
NO4: C, 76.41; H, 7.05; N, 2.97. Found C, 76.28; H, 7.15; N,
3.01.
(2S,4RS)-ter t-Bu t yl 4-h yd r oxy-6-oxo-6-p h en yl-2-[N-
(P h F )a m in o]h exa n oa te (6e) was prepared as described
above using acetophenone and isolated as a white solid
containing an inseparable 2:1 mixture of diastereomers (93%
from 2): TLC Rf ) 0.28 (20% ethyl acetate in hexanes); 1H
NMR (major isomer) δ 1.16 (s, 9 H), 1.60-1.70 (m, 2 H), 2.77
(dd, 1 H, J ) 9.4, 5.4), 2.84 (dd, 1 H, J ) 16.4, 5.4), 3.32 (t, 1
H, J ) 7.1), 4.24-4.31 (m, 1 H), 7.12-7.96 (m, 18 H); 1H NMR
(minor isomer) δ 1.23 (s, 9 H), 1.60-1.70 (m, 2 H), 2.78 (m, 1
H), 2.92 (dd, 1 H, J ) 16.6, 5.5), 3.36 (t, 1 H, J ) 7.1), 4.46-
4.54 (m, 1 H), 7.12-7.96 (m, 18 H); 13C NMR (major isomer) δ
27.8, 40.1, 45.7, 55.8, 67.4, 73.0, 81.1, 174.1, 198.8; 13C NMR
(minor isomer) δ 27.7, 39.7, 45.8, 54.1, 65.8, 73.0, 81.4, 174.2,
198.7; HRMS calcd for C35H36NO4 (MH+) 534.2644, found
534.2662.
(2S,4RS)-ter t-Bu tyl 4-h yd r oxy-6-oxo-6-(2-p yr id yl)-2-[N-
(P h F )a m in o]h exa n oa te (6f) was prepared as described
above using 2-acetylpyridine and isolated as a white solid
containing an inseparable 3:1 mixture of diastereomers (61%
from 2): TLC Rf ) 0.33 (30% ethyl acetate in hexanes); 1H
NMR (major isomer) δ 1.15 (s, 9H), 1.57-1.68 (m, 2H), 2.75
(dd, 1H, J ) 9.8, 4.8), 3.09 (dd, 1H, J ) 16.1, 4.4), 3.30 (dd,
1H, J ) 16.1, 8.1), 4.26-4.33 (m, 1H), 7.10-8.70 (m, 17H); 1H
NMR (minor isomer) δ 1.22 (s, 9H), 1.57-1.68 (m, 2H), 2.78-
2.82 (m, 1H), 3.21 (dd, 1H, J ) 16.5, 4.6), 3.30-3.35 (m, 1H),
4.48-4.56 (m, 1H), 7.10-8.70 (m, 17H); 13C NMR (major
isomer) δ 27.7, 40.2, 45.1, 55.8, 67.4, 73.0, 81.0, 174.1, 200.2;
13C NMR (minor isomer) δ 27.7, 40.0, 45.5, 54.1, 65.7, 73.0,
81.2, 174.4, 200.2; HRMS calcd for C34H35N2O4 (MH+) 535.2597,
found 535.2612.
Gen er a l P r oced u r e A for th e Deh yd r a tion of â-Hy-
d r oxy Keton es 6a -e. A solution of â-hydroxy ketone 6 (1
mmol, 100 mol %) in THF (8 mL) was treated with copper(I)
chloride (40 mg, 0.4 mmol) and diisopropylcarbodiimide (470
µL, 3 mmol), and the suspension was heated at a reflux for 14
h. After cooling to room temperature, the solvent was removed
in vacuo, and the residue was purified by flash-column
chromatography, eluting with an ethyl acetate:hexanes system
of appropriate polarity.
Gen er a l P r oced u r e B for th e Deh yd r a tion of â-Hy-
d r oxy Keton es 6a -f. Methanesulfonyl chloride (85 µL, 1.1
mmol) was added dropwise to a stirred solution of â-hydroxy
ketone 6 (1 mmol) and triethylamine (418 µL, 3 mmol) in
dichloromethane (2.5 mL) at 0 °C. Upon complete addition,
the reaction was stirred for 30 min at 0 °C, allowed to warm
to room temperature, and stirred until TLC analysis indicated
the consumption of the starting material (1-2 h). The reaction
was diluted with dichloromethane (10 mL) and washed with
water (10 mL). The aqueous phase was extracted with dichlo-
romethane (3 × 5 mL), and the combined organic layer was
dried and concentrated in vacuo to a crude oil that was purified
by flash-column chromatography eluting with an ethyl acetate:
hexanes system of appropriate polarity to furnish enones 7.
(2S,4RS)-ter t-Bu tyl 4-h yd r oxy-6-oxo-7,7-d im eth yl-2-[N-
(P h F )a m in o]octa n oa te (6a ) was prepared as described
above using pinacolone and isolated as a white foam containing
an inseparable 2:1 mixture of diastereomers (84% from 2):
TLC Rf ) 0.24 (20% ethyl acetate in hexanes); 1H NMR (major
isomer) δ 1.11 (s, 9 H), 1.15 (s, 9 H), 1.50-1.56 (m, 2 H), 2.36
(dd, 1 H, J ) 17.2, 5.4), 2.70 (dd, 1 H, J ) 17.2, 6.8), 2.71-
2.75 (m, 1 H), 4.04-4.15 (m, 1 H), 7.18-7.38 (m, 10 H), 7.46-
1
7.52 (m, 1 H), 7.67-7.72 (m, 2 H); H NMR (minor isomer) δ
1.09 (s, 9 H), 1.23 (s, 9 H), 1.50-1.56 (m, 2 H), 2.44 (dd, 1 H,
J ) 17.4, 5.5), 2.63 (dd, 1 H, J ) 17.4, 7.2), 2.71-2.75 (m, 1
H), 4.31-4.38 (m, 1 H), 7.18-7.38 (m, 10 H), 7.46-7.52 (m, 1
H), 7.67-7.72 (m, 2 H); 13C NMR (major isomer) δ 26.1, 27.7,
40.0, 43.6, 55.8, 67.0, 72.9, 81.0, 174.1, 214.4; 13C NMR (minor
isomer) δ 26.1, 27.7, 39.7, 44.1, 53.8, 65.3, 72.9, 81.1, 174.5,
214.7; HRMS calcd for C33H40NO4 (MH+) 514.2957, found
514.2973.
(2S,4RS)-ter t-Bu t yl 4-h yd r oxy-7-m et h yl-6-oxo-2-[N-
(P h F )a m in o]octa n oa te (6b) was prepared as described
above using 3-methylbutan-2-one and isolated as a pale-yellow,
glassy solid containing an inseparable 2:1 mixture of diaster-
eomers (77% from 2): TLC Rf ) 0.48 (30% ethyl acetate in
hexanes); 1H NMR (major isomer) δ 1.07 (d, 3H, J ) 6.9), 1.08
(d, 3H, J ) 6.9), 1.15 (s, 9H), 1.50-1.55 (m, 2H), 2.33 (dd, 1H,
J ) 16.3, 5.0), 2.51-2.64 (m, 2H), 2.70-2.74 (m, 1H), 4.02-
1
4.08 (m, 1H), 7.20-7.75 (m, 13H); H NMR (minor isomer) δ
1.06 (d, 3H, J ) 6.9), 1.07 (d, 3H, J ) 6.9), 1.24 (s, 9H), 1.50-
1.55 (m, 2H), 2.39 (dd, 1H, J ) 16.1, 4.9), 2.51-2.64 (m, 2H),
2.70-2.74 (m, 1H), 4.26-4.34 (m, 1H), 7.20-7.75 (m, 13H);
13C NMR (major isomer) δ 17.8, 27.7, 39.9, 41.1, 47.5, 55.9,
67.2, 72.9, 81.0, 174.0, 213.2; 13C NMR (minor isomer) δ 17.9,
27.7, 39.7, 41.3, 47.3, 53.9, 65.4, 72.9, 81.3, 174.3, 213.4; HRMS
calcd for C32H38NO4 (MH+) 500.2801, found 500.2774. Anal.
Calcd for C32H37NO4: C, 76.92; H, 7.46; N, 2.80. Found C,
76.84; H, 7.55; N, 2.80.
(2S,4RS)-ter t-Bu tyl 4-h yd r oxy-6-oxo-2-[N-(P h F)a m in o]-
n on a n oa te (6c) was prepared as described above using
pentan-2-one and isolated as an off-white solid containing an
inseparable 2:1 mixture of diastereomers (72% from 2): TLC
Rf ) 0.30 (20% ethyl acetate in hexanes); 1H NMR (major
isomer) δ 0.91 (t, 3H, J ) 7.4), 1.14 (s, 9H), 1.47-1.63 (m, 4H),
2.23-2.73 (m, 5H), 3.99-4.05 (m, 1H), 7.15-7.80 (m, 13H);
1H NMR (minor isomer) δ 0.89 (t, 3H, J ) 7.4), 1.23 (s, 9H),
1.47-1.63 (m, 4H), 2.23-2.73 (m, 5H), 4.25-4.30 (m, 1H),

2000 J . Org. Chem., Vol. 64, No. 6, 1999
Swarbrick et al.
(2S,4E)-ter t-Bu tyl 6-oxo-7,7-d im eth yl-2-[N-(P h F )a m i-
n o]oct-4-en oa te (7a ) was isolated as an oil from 6a in 87%
yield with method A and 62% with method B: TLC Rf ) 0.57
(20% EtOAc in hexanes); [R]20D -144.5 (c 1.0, CHCl3); 1H NMR
δ 1.19 (s, 9 H), 1.23 (s, 9 H), 2.28-2.41 (m, 2 H), 2.73 (m, 1 H),
3.19 (d, 1 H, J ) 8.1), 6.50 (d, 1 H, J ) 15.2), 6.97 (dt, 1 H, J
) 15.1, 7.6), 7.16-7.40 (m, 10 H), 7.45-7.48 (m, 2 H), 7.67-
7.72 (m, 2 H); 13C NMR δ 26.0, 27.7, 38.7, 42.6, 55.5, 72.8,
80.8, 173.8, 203.24; HRMS calcd. for C33H38NO3 (MH+) 496.2852,
found 496.2836. Anal. Calcd for C33H37NO3: C, 79.97; H, 7.52;
N, 2.83. Found C, 80.21; H, 7.90; N, 2.96.
washing with dichloromethane provided an additional crop of
9-phenylfluorene hydrocarbon.
(2S,6R)-ter t-Bu tyl 6-(1,1-d im eth yleth yl)-2-p ip er id in e-
ca r boxyla te (8a ) was isolated as a colorless oil in 86% yield
from 7a : TLC Rf ) 0.24 (5% Et2O in CH2Cl2); [R]20 -19.9 (c
D
1
0.6, CHCl3); H NMR (CD3OD) δ 0.93 (s, 9 H), 1.13-1.02 (m,
1 H), 1.22-1.44 (m, 2 H), 1.47 (s, 9 H), 1.65 (m, 1 H), 1.92 (m,
2 H), 2.23 (dd, 1 H, J ) 2.2, 11.3), 3.17 (dd, 1 H, J ) 2.6, 11.5);
13C NMR (CD3OD) δ 25.9, 27.0, 27.1, 28.4, 29.8, 34.3, 61.5,
67.2, 82.1, 173.8; HRMS calcd for C14H28NO2 (MH+) 242.21201,
found 242.21130.
(2S,4E)-ter t-Bu t yl 7-m et h yl-6-oxo-2-[N-(P h F )a m in o]-
oct-4-en oa te (7b) was isolated as a white solid from 6b in
62% yield with method A and 87% yield with method B: TLC
(2S,6R)-ter t-Bu tyl 6-(1-m eth yleth yl)-2-p ip er id in eca r -
boxyla te (8b) was isolated as a colorless oil in 91% yield from
7b: TLC Rf ) 0.22 (10% diethyl ether in dichloromethane);
Rf ) 0.69 (30% ethyl acetate in hexanes); mp 94-96 °C; [R]20
[R]20 -19.5 (c 1.0, CHCl3); H NMR δ 0.88 (d, 3H, J ) 6.7),
1
D
D
1
-145.4 (c 1.5, CHCl3); H NMR δ 1.11 (d, 3 H, J ) 7.0), 1.12
0.91 (d, 3H, J ) 6.7), 1.00 (dtd, 1H, J ) 11.1, 8.8, 4.0), 1.21-
1.39 (m, 2H), 1.42 (s, 9H), 1.58 (sept, 1H, J ) 6.7), 1.59-1.65
(m, 1H), 1.82-1.99 (m, 3H), 2.19 (ddd, 1H, J ) 11.1, 6.5, 2.5),
3.15 (dd, 1H, J ) 11.3, 2.8); 13C NMR δ 18.7, 19.1, 24.7, 28.0,
(d, 3 H, J ) 6.9), 1.18 (s, 9 H), 2.22-2.36 (m, 2 H), 2.67 (t, 1
H, J ) 6.2), 2.84 (sept., 1 H, J ) 6.9), 3.16 (br s, 1 H), 6.09 (d,
1 H, J ) 15.7), 6.80 (dt, 1 H, J ) 15.7, 7.4), 7.15-7.73 (m, 13
H); 13C NMR δ 18.4, 27.8, 38.0, 38.8, 55.5, 72.9, 81.1, 173.8,
203.5; HRMS calcd for C32H36NO3 (MH+) 482.2695, found
482.2686.
28.4, 29.3, 33.1, 60.0, 62.3, 80.7, 172.7; HRMS calcd for C13H26
-
NO2 (MH+): 228.1964, found 228.1957.
(2S,6S)-ter t-Bu tyl 6-pr opyl-2-piper idin ecar boxylate (8c)
was isolated as a colorless oil in 90% yield from 7c: TLC Rf )
(2S,4E)-ter t-Bu tyl 6-oxo-2-[N-(P h F)am in o]n on -4-en oate
(7c) was isolated as a white solid from 6c in 63% yield with
method A and 91% yield with method B: TLC Rf ) 0.50 (20%
0.20 (20% diethyl ether in dichloromethane); [R]20 -13.7 (c
D
1.0, CHCl3); 1H NMR 0.89 (t, 3H, J ) 7.0), 0.98-1.09 (m, 1H),
1.23-1.44 (m, 6H), 1.45 (s, 9H), 1.61-1.67 (m, 1H), 1.84-1.90
(m, 1H), 1.95-2.00 (m, 1H), 2.51 (dtd, 1H, J ) 11.0, 5.9, 2.6),
3.22 (dd, 1H, J ) 11.3, 2.9); 13C NMR δ 14.2, 19.0, 24.6, 28.0,
ethyl acetate in hexanes); mp 88-89 °C; [R]20 -135.1 (c 1.5,
D
1
CHCl3); H NMR δ 0.97 (t, 3 H, J ) 7.4), 1.18 (s, 9 H), 1.67
(sex., 2 H, J ) 7.4), 2.22-2.36 (m, 2 H), 2.52 (td, 2 H, J ) 7.4,
1.2), 2.68 (t, 1 H, J ) 6.5), 3.19 (br. s, 1 H), 6.03 (dt, 1 H, J )
16.0, 1.4), 6.74 (dt, 1 H, J ) 16.0, 7.4), 7.15-7.70 (m, 13 H);
13C NMR δ 13.8, 17.6, 27.8, 38.8, 41.6, 55.5, 72.9, 81.1, 173.8,
200.2; HRMS calcd for C32H36NO3 (MH+) 482.2695, found
482.2681.
29.3, 31.9, 39.3, 56.1, 59.7, 80.8, 172.6; HRMS calcd for C13H26
-
NO2 (MH+) 228.1957, found 228.1964.
(2S,6S)-ter t-Bu tyl 6-m eth yl-2-piper idin ecar boxylate (8d)
was isolated as a colorless oil in 86% yield from 7d : TLC Rf )
0.28 (10% diethyl ether in dichloromethane); [R]20D -7.4 (c 1.04,
1
(2S,4E)-ter t-Bu tyl 6-oxo-2-[N-(P h F)am in o]h ept-4-en oate
(7d ) was isolated as a white solid from 6d in 62% yield with
method A and 86% yield with method B: TLC Rf ) 0.37 (20%
CHCl3); H NMR δ 0.94-1.06 (m, 1H), 1.08 (t, 3H, J ) 6.2),
1.21-1.45 (m, 2H), 1.43 (s, 9H), 1.53-1.59 (m, 1H), 1.78-1.85
(m, 2H), 1.90-1.96 (1H, m), 2.61 (dqd, 1H, J ) 10.9, 5.7, 2.6),
3.21 (dd, 1H, J ) 11.3, 2.8); 13C NMR δ 22.7, 24.6, 28.0, 28.9,
33.7, 51.7, 59.7, 80.7, 172.5; HRMS calcd for C11H22NO2 (MH+)
200.1651, found 200.1644.
ethyl acetate in hexanes); mp 81-82 °C; [R]20 -148.0 (c 1.3,
D
1
CHCl3); H NMR δ 1.19 (s, 9 H), 2.25 (s, 3 H), 2.31 (m, 2 H),
2.66 (t, 1 H, J ) 6.1), 3.19 (br. s, 1 H), 6.00 (d, 1 H, J ) 15.9),
6.70 (dt, 1 H, J ) 15.9, 7.4), 7.15-7.73 (m, 13 H); 13C NMR δ
26.5, 27.8, 38.8, 55.4, 72.9, 81.1, 173.8, 198.3; HRMS calcd for
(2S,6R)-ter t-Bu t yl 6-p h en yl-2-p ip er id in eca r b oxyla t e
(8e) was isolated as a white solid: mp ) 74-75 °C; TLC Rf )
0.57 (20% ethyl acetate in hexanes); [R]20D -28.0 (c 1.3, CHCl3);
1H NMR δ 1.40 (s, 9H), 1.38-1.52 (m, 3H), 1.68-1.74 (m, 1H),
1.89-2.00 (m, 2H), 2.18 (br. s, 1H), 3.31 (dd, 1H, J ) 11.1,
2.7), 3.57 (dd, 1H, J ) 10.8, 2.3), 7.19-7.45 (m, 5H); 13C NMR
δ 25.1, 28.0, 28.5, 34.2, 60.3, 61.7, 76.7, 126.7, 127.1, 128.3,
144.6, 172.2; HRMS calcd for C16H24NO2 (MH+) 262.1807,
found 262.1813.
C
30H32NO3 (MH+) 454.2382, found 454.2391.
(2S,4E)-ter t-Bu t yl 6-oxo-7-p h en yl-2-[N-(P h F )a m in o]-
h ep t-4-en oa te (7e) was isolated as a white solid from 6e in
81% yield with method A and 92% yield with method B: TLC
Rf ) 0.44 (20% ethyl acetate in hexanes); mp 43-45 °C; [R]20
D
1
-108.5 (c 1.1, CHCl3); H NMR δ 1.18 (s, 9H), 2.32-2.46 (m,
2H), 2.71 (t, 1H, J ) 6.4), 3.20 (br.s, 1H), 6.79 (dt, 1H, J )
15.4, 1.2), 6.95 (dt, 1H, J ) 15.4, 7.5), 7.15-7.95 (m, 18H); 13
C
(2S,6RS)-ter t-Bu tyl 2-a m in o-6-h yd r oxy-6-p h en ylh ex-
a n oa te (9) was isolated as a viscous colorless oil containing
an inseparable 1:1 mixture of diastereomers (46% from 7e):
NMR δ 27.8, 39.1, 55.7, 73.0, 81.1, 173.9, 190.6; HRMS calcd
for C35H33NO3 (MH+) 454.2382, found 454.2391.
1
(2S,4E)-ter t-Bu tyl 6-oxo-7-(2′-p yr id yl)-2-[N-(P h F )a m i-
n o]h ep t-4-en oa te (7f) was isolated as an off-white solid from
6f in 65-80% yield with method B: TLC Rf ) 0.53 (30% ethyl
TLC Rf ) 0.33 (10% Et3N in Et2O); H NMR δ 1.34-1.58 (m,
3H), 1.41 (s, 9H), 1.63-1.81 (m, 3H), 2.15 (br.s, 3H), 3.24-
3.29 (m, 1H), 4.62-4.68 (m, 1H), 7.21-7.36 (m, 5H); 13C NMR
(second diastereomer in parentheses where resolved) δ 21.7,
(21.8), 27.9, 29.6, 34.3, (34.5), 38.7, 54.6, (54.7), 73.9, 81.0,
125.8, 127.3, 128.3, 144.8, (144.9), 175.2; HRMS calcd for
acetate in hexanes); mp 118 °C (dec); [R]20 -91.7 (c 1.0,
D
CHCl3); 1H NMR δ 1.18 (s, 9 H), 2.36-2.51 (m, 2 H), 2.72 (dd,
1 H, J ) 6.9, 5.9), 3.21 (br s, 1 H), 7.14-7.70 (m, 14 H), 7.86
(m, 1 H), 8.14 (m, 1 H), 8.70 (m, 1 H); 13C NMR δ 27.7, 39.1,
55.7, 72.9, 81.0, 173.9, 189.0; HRMS calcd for C34H33N2O3
(MH+) 517.2492, found 517.2500.
C
16H26NO3 (MH+) 280.1913, found 280.1905.
(2S,6RS)-ter t-Bu tyl 6-h yd r oxy-2-[N-(P h F )a m in o]-6-(2′-
p yr id yl)h exa n oa te (10) was isolated as a viscous colorless
oil containing an inseparable 1:1 mixture of diastereomers
(67% from 7f): TLC Rf ) 0.37 (40% EtOAc in hexanes); 1H
NMR (second diastereomer in brackets where resolved) δ 1.10
(s, 9H), [1.11 (s, 9H)], 1.25-1.70 (m, 6H), 2.44-2.49 (m, 1H),
4.64-4.70 (m, 1H), 7.15-7.80 (m, 16H), 8.51-8.56 (m, 1H);
13C NMR (second diastereomer in parentheses where resolved)
δ 21.0, (21.1), 27.8, 35.6, 38.1, 55.8, 72.4, (72.5), 73.0, 80.3,
175.4; HRMS calcd for C34H37N2O3 (MH+) 521.2804, found
521.2795.
Gen er a l P r oced u r e for th e Hyd r ogen a tion of E-Oxo-
r-N-(P h F )a m in o Acid An a logu es 7a -f over P a lla d iu m
a n d P la tin u m Ca ta lysts. A solution of enone 7 (1 mmol) in
either ethyl acetate (20 mL), methanol (20 mL), or 10:1
methanol/acetic acid (22 mL) was treated with either pal-
ladium-on-carbon (10 wt %, 100 mg) or platinum-on-carbon
(5 wt %, 200 mg). The reaction vessel (see general experimental
details) was filled, vented, and refilled with hydrogen three
times, and the suspension was stirred under hydrogen at room
temperature for 14 h. The catalyst was filtered onto Celite and
washed thoroughly with methanol (7e and 7f) or dichlo-
romethane (7a -d ). The filtrate was concentrated in vacuo, and
the residue was purified by flash-column chromatography with
9-phenylfluorene as the first product to elute. In cases where
the filter cake had been washed with methanol, subsequent
(2S)-ter t-Bu tyl 6-oxo-6-p h en yl-2-[N-(P h F )a m in o]h ex-
a n oa te (12) was isolated as a white solid in 84% yield from
7e: mp ) 91-92 °C; TLC Rf ) 0.44 (20% EtOAc in hexane);
[R]20 -159.4 (c 1.2, CHCl3); 1H NMR δ 1.19 (s, 9H), 1.40-
D
1.57 (m, 2H), 1.76-1.88 (m, 2H), 2.54 (br. s, 1H), 2.71 (ddd,
1H, J ) 17.0, 7.0, 6.6), 2.79 (ddd, 1H, J ) 17.0, 8.3, 6.7); 13C

Alkyl Substituent Effects on Pipecolyl Amide Isomer Equilibrium
J . Org. Chem., Vol. 64, No. 6, 1999 2001
NMR δ 19.9, 27.6, 34.9, 38.0, 55.3, 72.9, 80.4, 175.2, 199.9;
HRMS calcd for C35H36NO3 (MH+) 518.2695, found 518.2686.
(2S,6RS)-ter t-Bu t yl 6-h yd r oxy-6-p h en yl-2-[N-(P h F )-
a m in o]h exa n oa te (11). To a stirred suspension of Raney
nickel (ca.. 10 mg of a 50% slurry in water, pore size 50 µm,
surface area 80-100 m2/g, washed three times with ethanol)
in ethanol (4 mL) was added a solution of (2S,4E)-tert-butyl
6-oxo-7-phenyl-2-[N-(PhF)amino]hept-4-enoate (7e, 445 mg,
0.86 mmol) in ethanol (5 mL). The resulting suspension was
stirred under 3 atm of hydrogen at room temperature for 14
h. Careful filtration followed by concentration furnished 11
(425 mg, 95%) as a white foam containing an inseparable 1:1
mixture of diastereomers: TLC Rf ) 0.18 (10% EtOAc in
hexanes): 1H NMR δ 1.15 (s, 9 H), 1.32-2.07 (m, 6 H), 2.46-
2.50 (m, 1 H), 3.05 (br. s, 1 H), 4.59-4.65 (m, 1 H), 7.15-7.71
(m, 18 H); 13C NMR (second diastereomer in parentheses
where resolved) δ 21.6, (21.7), 27.8, 35.5, 38.7, 55.9, 73.0, 74.3,
80.4, 175.4; HRMS calcd for C35H38NO3 (MH+) 520.2852, found
520.2834.
and brine (5 mL), dried, and concentrated in vacuo to give a
pale yellow oil (79 mg). Purification by flash-column chroma-
tography (dichloromethane followed by 5% diethyl ether in
dichloromethane) furnished (2S,6S)-tert-butyl N-benzyl-6-me-
thylpiperidine-2-carboxylate (14, 66 mg, 95%) as a colorless
oil: TLC Rf ) 0.64 (10% diethyl ether in dichloromethane);
1
[R]20 -24.8 (c 0.5, CHCl3); H NMR δ 1.00 (d, 3H, J ) 6.3),
D
1.21-1.36 (m, 1H), 1.38 (s, 9H), 1.49-1.55 (m, 1H), 1.60-1.69
(m, 2H), 1.74-1.81 (m, 1H), 2.36 (dqd, 1H, J ) 9.6, 6.2, 2.9),
3.01 (dd, 1H, J ) 10.5, 3.3), 3.65 (d, 1H, J ) 15.9), 3.84 (d,
1H, J ) 15.9), 7.15-7.38 (m, 5H); 13C NMR δ 21.2, 23.0, 27.8,
30.2, 34.1, 56.2, 56.4, 66.5, 80.5, 126.3, 127.7, 128.7, 139.5,
173.5; HRMS calcd for C18H28NO2 (MH+) 290.2120, found
290.2130.
En a n tiom er ic P u r ity of (2S,6S)-ter t-Bu tyl N-Ben zyl-
6-m eth ylp ip er id in e-2-ca r boxyla te (14). Dry HCl gas was
bubbled through a stirred solution of (2S,6S)-tert-butyl N-ben-
zyl-6-methylpiperidine-2-carboxylate (14, 36 mg) in dichlo-
romethane at 0 °C for 2 h. Evaporation of the volatiles in vacuo
gave a white solid from which portions (10 mg, 0.04 mmol)
were dissolved in acetonitrile (0.5 mL) and treated with D- or
L-phenylalanine methyl ester hydrochloride (11 mg, 0.05 mmol,
120 mol %), TBTU (16 mg, 0.05 mmol, 120 mol %), and
diisopropylethylamine (35 µL, 0.20 mmol, 500 mol %) at room
temperature. After stirring for 1 h, the yellow solution was
diluted with ethyl acetate (5 mL), washed sequentially with
water (2 × 5 mL) and brine (5 mL), dried, and concentrated
in vacuo to a crude viscous yellow oil which was directly
examined by 1H NMR spectroscopy. The limits of detection
were determined by measuring the diastereomeric methyl
ester singlets at 3.52 and 3.68 ppm in CDCl3 in the 400 MHz
1H NMR spectra. Less than 1% of (2′S)-15 was detected in the
spectrum of (2′R)-15. Purification by chromatography using a
gradient of 0-5% diethyl ether in dichloromethane as eluant
gave dipeptides having the following spectra.
(2S,6S)-N-Ben zyl-6-m et h ylp ip ecolyl-D-p h en yla la n in e
m eth yl ester ((2′R)-15): 1H NMR δ 1.11 (d, 3 H, J ) 6.1),
1.15-1.36 (m, 2 H), 1.53-1.67 (m, 4 H), 1.83-1.87 (m, 1 H),
2.36-2.45 (m, 1 H), 2.81 (dd, 1 H, J ) 13.9, 7.6), 2.96 (dd, 1
H, J ) 13.9, 6.2), 3.01 (dd, 1 H, J ) 9.9, 3.7), 3.47 (d, 1 H, J )
15.4), 3.67 (d, 1 H, J ) 15.4), 3.68 (s, 3H), 4.78 (td, 1 H, J )
8.0, 6.2), 7.00-7.31 (m, 10 H).
(2S,6S)-N-Ben zyl-6-m et h ylp ip ecolyl-l-p h en yla la n in e
m eth yl ester ((2′S)-15): 1H NMR δ 1.05 (d, 3 H, J ) 6.1),
1.15-1.39 (m, 3 H), 1.55-1.68 (m, 3 H), 1.83-1.90 (m, 1 H),
2.32-2.41 (m, 1H), 3.01 (dd, 1 H, J ) 10.6, 3.4), 3.06 (dd, 1 H,
J ) 13.9, 6.7), 3.14 (dd, 1 H, J ) 13.9, 6.7), 3.52 (s, 3 H), 3.67
(d, 1H, J ) 15.5), 3.85 (d, 1 H, J ) 15.5), 4.79 (dt, 1 H, J )
8.1, 6.2), 7.11-7.53 (m, 10 H).
Recycle of 9-p h en ylflu or en e to 9-br om o-9-p h en ylflu o-
r en e was accomplished by heating a mixture of 9-phenylfluo-
rene (969 mg, 4.00 mmol) and N-bromosuccinimide (711 mg,
4.00 mmol) in CCl4 (4 mL) at a reflux for 1 h. After cooling,
the reaction was concentrated in vacuo, and the residue was
successively digested with volumes of hexanes until TLC
analysis showed that no UV-active material was contained in
the hexanes. Concentration of the combined hexane volumes
gave 9-bromo-9-phenylfluorene as a yellow solid (1.23 g,
96%): mp 98-100 °C (lit.43 mp 99 °C).
N-Acetyl N′-Meth ylp ip ecolin a m id e (16). A solution of
pipecolic acid (1.0 g, 7.7 mmol) in dioxane (15 mL) and water
(8 mL) was treated with NaOH (12 mL, 1 M) followed by di-
tert-butyl dicarbonate (4.06 g, 18.6 mmol, 240 mol %), stirred
for 48 h at room temperature, and evaporated to a 5 mL
volume that was diluted with EtOAc (20 mL) and acidified
with 5% HCl to pH 2-3. The aqueous layer was saturated with
solid NaCl and extracted with EtOAc until TLC of the organic
layer showed no ninhydrin-active material. The combined
organic layers were washed with brine (5 mL), dried, and
evaporated to a solid residue that was dried for 48 h in a drying
pistol. N-(BOC)-Pipecolic acid (1.62 g, 91%) was obtained as a
white powder: mp 125 °C; HRMS calcd for C11H20NO4 (MH+)
230.1392, found 230.1388.
Gen er a l Meth od for th e Dep r otection of ter t-Bu tyl
6-Alk ylp ip ecola tes 8. Dry HCl gas was bubbled through a
solution of 6-alkylpipecolate tert-butyl ester 8 (0.5 mmol) in
dichloromethane (2-3 mL) at 0 °C until complete disappear-
1
ance of the tert-butyl ester singlet was observed by H NMR
analysis (2-4 h). Removal of the solvent in vacuo furnished
pipecolate hydrochlorides 1‚HCl.
(2S,6R)-6-(1,1-Dim eth yleth yl)-2-p ip er id in eca r boxylic
a cid h yd r och lor id e (1a ‚HCl) was isolated as a white powder
in 98% yield from 8a : mp > 220 °C dec; [R]20 -25.4 (c 0.7,
D
1
0.1 N HCl); H NMR (CD3OD) δ 1.08 (s, 9H), 1.44-1.57 (m,
1H), 1.63-1.82 (m, 2H), 1.99-2.06 (m, 2H), 2.28-2.34 (m, 1H),
3.02 (dd, 1H, J ) 12.5, 2.5), 3.97 (dd, 1H, J ) 12.7, 3.3); 13C
NMR (CD3OD) δ 23.9, 24.7, 26.9, 27.0, 34.5, 60.7, 68.0, 171.2;
HRMS calcd for C10H20NO2 (MH+) 186.1494, found 186.1499.
(2S,6R)-6-(1-Meth yleth yl)-2-p ip er id in eca r boxylic a cid
h yd r och lor id e (1b‚HCl) was isolated as a white powder in
100% yield from 8b: mp > 215 °C dec; [R]20 -18.8 (c 0.6, 0.1
D
N HCl); 1H NMR (CD3OD) δ 0.88 (d, 3H, J ) 6.7), 0.91 (d, 3H,
J ) 6.7), 1.00 (dtd, 1H, J ) 11.1, 8.8, 4.0), 1.21-1.39 (m, 2H),
1.42 (s, 9H), 1.58 (sept., 1H, J ) 6.7), 1.59-1.65 (m, 1H), 1.82-
1.99 (m, 3H), 2.19 (ddd, 1H, J ) 11.1, 6.5, 2.5), 3.15 (dd, 1H,
J ) 11.3, 2.8); 13C NMR (CD3OD) δ 18.0, 19.7, 23.6, 25.5, 27.2,
32.3, 59.6, 64.1, 171.3; HRMS calcd for C9H18NO2 (MH+)
172.1338, found 172.1330.
(2S,6S)-6-P r op yl-2-p ip er id in eca r boxylic a cid h yd r o-
ch lor id e (1c‚HCl) was isolated as a white powder in 97%
yield from 8c: mp > 209 °C dec; [R]20D -13.0 (c 1.0, 0.1 N HCl);
1H NMR (CD3OD) δ 0.99 (t, 3H, J ) 7.3), 1.34-1.78 (m, 7H),
1.95-2.07 (m, 2H), 2.30-2.39 (m, 1H), 3.11-3.19 (m, 1H), 3.94
(dd, 1H, J ) 12.4, 3.2); 13C NMR (CD3OD) δ 14.2, 19.6, 23.5,
27.4, 28.8, 36.7, 58.2, 58.9, 171.3; HRMS calcd for C9H18NO2
(MH+) 172.1338, found 172.1343.
(2S,6S)-6-Meth yl-2-p ip er id in eca r boxylic a cid h yd r o-
ch lor id e (1d ‚HCl) was isolated as a white powder in 98%
yield from 8d : mp > 212 °C dec; [R]20 -11.7 (c 1.1, 0.1 N
D
HCl); 1H NMR (CD3OD) δ 1.37 (d, 3H, J ) 6.6), 1.41-1.50 (m,
1H), 1.58-1.74 (m, 2H), 1.89-1.99 (m, 2H), 2.29-2.36 (m, 1H),
3.22-3.29 (m, 1H), 3.94 (dd, 1H, J ) 12.4, 3.3); 13C NMR (CD3-
OD) δ 19.4, 23.6, 27.1, 31.1, 54.4, 58.7, 171.3; HRMS calcd for
C7H14NO2 (MH+) 144.1025, found 144.1020.
(2S,6R)-6-P h en yl-2-p ip er id in eca r boxylic a cid h yd r o-
ch lor id e (1e‚HCl) was isolated as a white powder in 96%
yield from 8e: mp >230 °C dec; [R]20D -17.0 (c 0.4, 0.1 N HCl);
1H NMR (CD3OD) δ 1.81-2.14 (m, 5H), 2.38-2.45 (m, 1H),
4.18 (dd, 1H, J ) 12.4, 3.4), 4.35 (dd, 1H, J ) 11.6, 3.0), 7.41-
7.57 (m, 5H); 13C NMR (CD3OD) δ 24.1, 26.9, 30.9, 59.7, 62.4,
128.6, 130.5, 130.7, 137.9. 171.0; HRMS calcd for C12H16NO2
(MH+) 206.1181, found 206.1171.
(2S,6S)-ter t-Bu tyl N-Ben zyl-6-m eth ylp ip er id in e-2-ca r -
boxyla te (14). Benzyl bromide (34 µL, 0.29 mmol, 120 mol
%) and potassium carbonate (66 mg, 0.48 mmol, 200 mol %)
were added to a solution of (2S,6S)-tert-butyl 6-methylpiperi-
dine-2-carboxylate (8d , 48 mg, 0.24 mmol) in DMF (0.2 mL).
After stirring for 36 h, the suspension was diluted with ethyl
acetate (5 mL), washed successively with water (3 × 5 mL)
(43) Kliegl, A. Chem. Ber. 1905, 38, 284.

2002 J . Org. Chem., Vol. 64, No. 6, 1999
Swarbrick et al.
A solution of N-(BOC)-pipecolic acid (500 mg, 2.18 mmol),
TBTU (1.05 g, 3.3 mmol, 150 mol %), and methylamine
hydrochloride (295 mg, 4.36 mmol, 200 mol %) in acetonitrile
(20 mL) was then treated with DIEA (1.33 mL, 7.6 mmol, 350
mol %), stirred for 24 h at room temperature, and evaporated
to a residue that was dissolved in EtOAc (40 mL), washed with
5% HCl (2 × 5 mL), H2O (5 mL), NaHCO3 (2 × 5 mL, saturated
solution), H2O (2 × 5 mL), and brine (5 mL), dried, and
evaporated to give N-(BOC)-pipecolate N′-methylamide (393
mg, 74%) as a clear crystalline solid: mp ) 86-88 °C; 1H NMR
(CD3OD) δ 4.61 (bs, 1 H), 3.94 (m, 1 H), 2.99 (t, 1 H, J ) 13),
2.72 (s, 3H), 2.12 (d, 1 H, J ) 13), 1.60 (m, 3 H), 1.43 (s, 9 H),
resin (3 g, Dowex SBR) in H2O (20 mL) to remove excess
methylamine hydrochloride. The resin was filtered, and the
solution was evaporated to dryness. The crude amide product
was heated for 1 week in the presence of acetic anhydride (5
mL) and sodium acetate (82 mg, 1 mmol) in toluene (5 mL).
Evaporation of the volatiles and chromatography of the residue
using a gradient of 0-5% MeOH in CHCl3 as eluant gave 17
(36 mg, 28%) as a viscous oil: 1H NMR (D2O, trans-isomer) δ
0.96 (s, 9 H), 1.23-1.40 (m, 1 H), 1.69-1.84 (m, 2 H), 1.86-
2.09 (m, 3 H), 2.33 (s, 3 H), 2.76 (s, 3 H), 4.01 (m, 1H), 5.04
(dd, 1 H, J ) 8.4, 8.2); (cis-isomer) δ 0.91 (s, 9 H), 1.23-1.40
(m, 1 H), 1.69-1.84 (m, 2 H), 1.86-2.09 (m, 3 H), 2.22 (s, 3
H), 2.79 (s, 3 H), 4.57 (m, 1 H), 4.71 (dd, 1 H, J ) 7.6, 7.3); 13
C
1.48-1.31 (m, 3 H); HRMS calcd for
C
12H23N2O3 (MH+)
243.1709, found 243.1701.
NMR (D2O, trans-isomer,) δ 17.7, 23.8, 24.0, 25.0, 26.2, 27.2,
36.7, 54.9, 61.9, 175.2, 177.9; (cis-isomer) δ 17.9, 22.6, 23.5,
25.2, 26.4, 27.1, 36.3, 56.7, 58.1, 174.2, 177.5; HRMS calcd for
N-(BOC)-Pipecolate N′-methylamide (390 mg, 1.6 mmol) was
dissolved in CH2Cl2 (10 mL), cooled to 0 °C, treated with
gaseous HCl bubbles for 5 min, stirred for 1 h at room
temperature, and evaporated to a residue that was dissolved
in CH2Cl2 (8 mL) and treated with Et3N (444 µL, 3.2 mmol,
200 mol %) and acetic anhydride (302 µL, 3.2 mmol, 200 mol
C
13H25N2O2 (MH+) 241.1916, found 241.1907.
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council (NSERC) of Canada, and the Ministe`re de
l′EÄ ducation du Que´bec. The crystal structure analysis
of compound 5 was performed by Francine Be´langer-
Garie´py at l′Universite´ de Montre´al X-ray facility. We
thank Sylvie Bilodeau, Robert Mayer, and Dr. M. T.
Phan Viet of the Regional High-Field NMR Laboratory
for their assistance. Nabil Masri is thanked for work to
optimize reaction conditions. F.G. thanks NSERC for a
PGSB Scholarship (97-99) and FCAR for a M. Sc.
Scholarship (96-97). M.E.S. thanks Glaxo-Wellcome for
the award of a Postdoctoral Fellowship. We are grateful
for a loan of Pd/C from J ohnson Matthey PLC.
%). The mixture was heated at
a reflux overnight and
evaporated to dryness. Chromatography of the residue using
a gradient of 0-5% MeOH in CHCl3 as eluant gave 16 (128
1
mg, 65%) as a white crystalline solid: mp ) 99-100 °C; H
NMR (D2O, trans-isomer) δ 1.38-1.46 (m, 1H), 1.51-1.66 (m,
1H), 1.68-1.71 (m, 4H), 2.22 (s, 3H), 2.78 (s, 3H), 3.21 (m, 1H),
3.87 (bd, 1H, J ) 14.7), 5.09 (bd, 1H, J ) 2.2); (cis-isomer) δ
1.38-1.46 (m, 1H), 1.51-1.66 (m, 1H), 1.68-1.71 (m, 4H), 2.13
(s, 3H), 2.18 (bm, 1H), 2.28 (bm, 1H), 2.71 (bm, 1H), 2.81 (s,
3H), 4.30 (bd, 1H, J ) 13.7), 4.65 (bd, 1H); 13C NMR (D2O,
trans-isomer) δ 20.0, 21.2, 24.6, 26.2, 26.8, 45.1, 53.8, 173.8,
174.6; (cis-isomer) δ 20.2, 21.0, 24.3, 26.3, 26.4, 40.4, 58.5,
173.2, 174.4; HRMS calcd for C9H17N2O2 (MH+) 185.1290,
found 185.1285.
(2S,6R)-N-Acet yl N′-Met h yl 6-ter t-Bu t ylp ip ecolin a -
m id e (17). To a solution of acid 1a (100 mg, 0.33 mmol), TBTU
(159 mg, 0.495 mmol, 150 mol %), and methylamine hydro-
chloride (44.6 mg, 0.66 mmol, 200 mol %) in acetonitrile (2.3
mL) was added Et3N (229 µL, 1.65 mmol, 500 mol %). The clear
solution was stirred for 24 h at room temperature and then
evaporated to a residue that was treated with an ion-exchange
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1a -e, 7b-f, and 8a -e; crystallographic data for 5.
This material is available free of charge via the Internet at
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