Asymmetric synthesis of trans-2,3-piperidinedicarboxylic acid and trans-3,4-piperidinedicarboxylic acid derivatives

Article abstract of DOI:10.1021/jo016086b

Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz protected analogues 8a,b and 17a,b are described. Enantiomerically pure 1b has been synthesized in five steps starting from L-aspartic acid β-tert-butyl ester. Tribenzylation of the starting material followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1 diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde 7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%. Optically pure 2b has been synthesized beginning with N-Cbz-β-alanine. The synthesis involves the induction of the first stereogenic center using Evans's chemistry and sequential LDA-promoted alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and reductive amination affords 2b in an overall yield of 28%.

Full text of DOI:10.1021/jo016086b

J . Org. Chem. 2002, 67, 865-870
865
Asym m etr ic Syn th esis of tr a n s-2,3-P ip er id in ed ica r boxylic Acid
a n d tr a n s-3,4-P ip er id in ed ica r boxylic Acid Der iva tives
Chu-Biao Xue,* Xiaohua He, J ohn Roderick, Ronald L. Corbett, and Carl P. Decicco
Chemical and Physical Sciences,
DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880
chu-biao.xue@dupontpharma.com
Received September 4, 2001
Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-
4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz
protected analogues 8a ,b and 17a ,b are described. Enantiomerically pure 1b has been synthesized
in five steps starting from L-aspartic acid â-tert-butyl ester. Tribenzylation of the starting material
followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1
diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde
7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%.
Optically pure 2b has been synthesized beginning with N-Cbz-â-alanine. The synthesis involves
the induction of the first stereogenic center using Evans’s chemistry and sequential LDA-promoted
alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and
reductive amination affords 2b in an overall yield of 28%.
Conformationally constrained amino acids are useful
structural components for peptidomimetics and nonpep-
tide small molecules in drug discovery.1 Incorporation of
unnatural, nonproteinogenic amino acids into small
peptides is expected to provide more druglike peptido-
mimetics with improved physiological and physiochemi-
cal properties such as binding affinity and metabolic
stability.2 In addition, cyclic amino acids may serve as a
chemical platform for manipulation through the amino
and carboxylic acid functionalities of hydrophobic and/
or hydrophilic pendant substituents required for binding
interactions with biological targets, making them ideal
building blocks for the preparation of potential nonpep-
tide therapeutic agents using parallel synthesis or com-
binatorial chemistry methodologies.
acid (1b) and (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidi-
necarboxylic acid (2b). The need for large quantities of
enantiomerically pure 1b and 2b for structure-activity
relationship (SAR) studies has led us to devise efficient
synthetic methods to prepare these intermediates using
readily accessible starting materials. Herein, we report
asymmetric syntheses of 1b, 2b and their corresponding
N-Boc and N-Cbz protected analogues starting from
L-aspartic acid â-tert-butyl ester and N-Cbz-â-alanine,
respectively.
2,3-Piperidinedicarboxylic acid and 3,4-piperidinedi-
carboxylic acid are structurally rigidified aspartic acid
and aminomethyl-succinic acid derivatives, respectively.
These heterocycles possess multiple functional groups for
structural diversification and could be useful as scaffolds
for construction of biologically active peptidomimetics or
nonpeptide small molecule ligands. For example, (2S,3S)-
2,3-piperidinedicarboxylic acid (1a ) and (3R,4S)-3,4-pi-
peridinedicarboxylic acid (2a ) have been employed in our
laboratory as templates for a series of protease inhibitors
of therapeutic interest.3 The common intermediates used
are (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic
(2S,3S)-2,3-P ip er id in ed ica r boxylic Acid Der iva -
tives. The synthesis of (2S,3S)-3-(methoxycarbonyl)-2-
piperidinecarboxylic acid, the 3-methyl ester of 1a , has
been reported from (S)-2-phenylglycinol and dimethyl
acetylenedicarboxylate involving an aza-annulation reac-
tion.4 In addition, 2-tert-butyl 3-methyl (2S,3S)-1-(9-
phenylfluoren-9-yl)-2,3-piperidinedicarboxylate, another
intermediate of 1a , has been synthesized from L-aspar-
tate.5 For our purposes, tert-butyl protection at the
3-carboxylic acid is required for the target compound 1b,
which prompted us to consider an alternative synthetic
route starting from the commercially available L-aspartic
acid â-tert-butyl ester. Our plan was to introduce an allyl
group at the â-carbon (C-3) of the L-aspartate followed
by hydroboration of the olefin, oxidation of the resulting
alcohol, and cyclization via reductive amination (Scheme
1). In this strategy, a suitable protecting group is required
(1) For reviews on conformationally constrained amino acids, see:
(a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789. (b) Sardina, F. J .; Rapoport, H. Chem.
Rev. 1996, 96, 1825. (c) Ohfune, Y. Acc. Chem. Res. 1992, 25, 360.
(2) (a) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699. (b)
Adang, A. E. P.; Hermkens, P. H. H.; Linders, J . T. M.; Ottenheijm,
H. C. J .; van Staveren, C. J . Rec. Trav. Chim. Pays Bas 1994, 113, 63.
(c) Olson, G. L.; Bolin, D. R.; Bonner, M. P.; Bos, M.; Cook, C. M.; Fry,
D. C.; Graves, B. J .; Hatada, M.; Hill, D. E.; Kahn, M.; Madison, V. S.;
Rusiecki, V. K.; Sarabu, R.; Sepinwall, J .; Vincent, G. P.; Voss, M. E.
J . Med. Chem. 1993, 36, 3039. Marshall, G. R. Tetrahedron 1993, 49,
3547.
(4) Agami, C.; Hamon, L.; Kadouri-Puchot, C.; Le Guen, V. J . Org.
Chem. 1996, 61, 5736.
(5) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H. J .
Org. Chem. 1990, 55, 3068.
(3) Xue, C.-B. et al. Manuscript in preparation.
10.1021/jo016086b CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/10/2002

866 J . Org. Chem., Vol. 67, No. 3, 2002
Xue et al.
Sch em e 1
Sch em e 2a
to block alkylation at the R-carbon (C-2) of the aspartate
and to influence the diastereomeric selectivity at C-3.
Although Cbz has been shown to be able to block C-2
alkylation by deprotonation at the monoprotected R-
amino, alkylation of NR-Cbz-L-aspartate with an allyl
halide produces the anti diastereomer as the major
diastereomer with an R-configuration at C-3,6 which is
the opposite configuration in compound 1b. Rapoport’s
9-phenylfluoren-9-yl residue7 is another amino protecting
group that effectively suppresses R-deprotonation of
R-amino acid derivatives and allows selective deproto-
nation at other acidic sites in the molecule. When the
amino group of an L-aspartate was doubly protected with
benzyl and 9-phenylfluoren-9-yl, alkylation of the aspar-
tate derivative with allyl iodide using potassium hexa-
methyldisilazide (KHMDS) gives rise to the syn diaste-
reomer as the major diastereomer (syn:anti ) 10:1) with
an S-configuration at C-3,8 which is the desired config-
uration in compound 1b. While extremely efficient on
laboratory scale, however, 9-bromo-9-phenylfluorene is
an expensive reagent unsuitable for large scale synthesis.
We provide here an attractive procedure that employs
dibenzyl protection for the R-amino of the aspartate.9
As depicted in Scheme 2, L-aspartic acid â-tert-butyl
ester (3) was subjected to K2CO3-mediated benzylation
with benzyl bromide in a mixed solvent system of DMF/
DMSO (4:1) at 50 °C to produce the tribenzylated product
4 in 90% yield in one step. In this reaction, DMSO was
required to enhance the solubility of the starting material
3. Addition of 1.1 equiv of lithium hexamethyldisilazide
(LHMDS) to a solution of 4 in THF at -78 °C followed
by quenching with 1.2 equiv of allyl bromide at -30 °C
gave rise to the syn (5a ) and anti (5b) allylated products
in a ratio of 1.5:1, the former being the desired diaste-
reomer. Compounds 5a and 5b were inseparable by silica
gel chromatography, and a mixture of 5a and 5b was
obtained in 90% yield. Switching the electrophile from
allyl bromide to allyl iodide had little effect on the
diastereoselectivity. Significant improvement in diaste-
reoselectivity was achieved when enolate formation was
conducted using 1.2 equiv of KHMDS and 1.5 equiv of
allyl iodide was employed as the electrophile. Under these
conditions, a mixture of 5a and 5b was obtained in a 6:1
a
Conditions: BnBr, K2CO3, DMF/DMSO (4:1), 50 °C, 90%; (b)
KHMDS, allyl iodide, THF, 75%; (c) 9-BBN, THF, 78%; (d) PDC,
CH2Cl2, 75%; (e) H2, Pd-C, MeOH, 95%; (f) (Boc)2O, NaOH/
NaHCO3, THF, H2O, 85%; (g) CbzOSu, NMM, DMF, 82%.
excess of 5a over 5b. No diallylated product was formed
under these conditions. However, use of 1.5 equiv of
KHMDS and 1.5 equiv of allyl iodide resulted in forma-
tion of a significant amount (∼20%) of diallylated product,
which was derived from another alkylation of 5a and 5b
at the C-3 center. These results reveal that the dibenzyl
protected amino is sterically hindered enough to prevent
alkylation at the C-2 center even in the presence of excess
base. The difference in diastereofacial selectivity between
the potassium enolate and lithium enolate can be ex-
plained by the hypothesis proposed by Chamberlin et al.8
With the potassium enolate, formation of a seven-
membered K-chelated cyclic enolate results in the pref-
erential attack of the electrophile opposite to the bulky
N,N-dibenzylamino residue to form 5a as the major
diastereomer. In contrast, the lithium enolate cannot
form cyclic chelation because of its (E)-geometry and
assumes a hydrogen-in-plane conformation. Conse-
quently, electrophile attack is equally accessible from
each side of the plane leading to formation of 5a and 5b
in roughly similar amounts.
Hydroboration of the mixture of 5a and 5b produced
the corresponding alcohols, which were easily separated
by silica gel chromatography to provide the desired
diastereomer 6a in 78% yield. To convert the alcohol 6a
to an aldehyde, we examined several oxidation conditions
including pyridinium dichromate (PDC),10 Swern oxida-
tion, sulfur trioxide pyridine complex11 and Dess-Martin
periodinane.12 PDC was found to be superior to other
conditions examined, providing the aldehyde 7 in 75%
yield. When the aldehyde 7 was subjected to high-
pressure hydrogenation in methanol using 10% Pd-C (29
wt %) as the catalyst, (2S,3S)-3-(tert-butoxycarbonyl)-2-
piperidinecarboxylic acid (1b) was obtained in 95% yield
(6) (a) Cotton, R.; J ohnstone, A. N. C.; North, M. Tetrahedron 1995,
51, 8525. (b) Parr, I. B.; Boehlein, S. K.; Dribben, A. B.; Schuster, S.
M.; Richards, N. G. J . J . Med. Chem. 1996, 39, 2367. (c) Hanessian,
S.; Margarita, R.; Hall, A.; Luo, X. Tetrahedron Lett. 1998, 39, 5883.
(7) (a) Christie, B. D.; Rapoport, H. J . Org. Chem. 1985, 50, 1239.
(b) Feldman, P.; Rapoport, H. J . Org. Chem. 1986, 51, 3882. (c) Dunn,
P. J .; Haner, R.; Rapoport, H. J . Org. Chem. 1990, 55, 5017. (d) Wolf,
J . P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164.
(8) Humphrey, J . M.; Bridges, R. J .; Hart, J . A.; Chamberlin, A. R.
J . Org. Chem. 1994, 59, 2467.
(9) N,N-Dibenzyl protection for the R-amino of amino acids has been
widely used in the preparation of R-amino aldehydes. For review see:
Reetz, M. Chem. Rev. 1999, 99, 1121.
(10) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
(11) Parikh, J . R.; Doering, W. E. J . Am. Chem. Soc. 1967, 89, 5505.
(12) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.

Synthesis of trans-2,3-Piperidinedicarboxylic Acid
J . Org. Chem., Vol. 67, No. 3, 2002 867
Sch em e 3
Sch em e 4a
after overnight reaction. Longer reaction time was re-
quired to complete the reaction if less catalyst was used.
The proton NMR spectrum of 1b exhibits a large coupling
constant between the C-2 and C-3 protons (8.5 Hz in CD3-
OD and 10.3 Hz in DMSO), clearly indicating an axial
position for both hydrogens and in agreement with the
trans stereochemistry reported previously.4 Reaction of
1b with di-tert-butyl dicarbonate [(Boc)2O] or N-(benzyl-
oxycarbonyloxy)succinimide (CbzOSu) afforded the N-Boc
and N-Cbz protected analogues 8a and 8b, respectively.
(3R,4S)-3,4-P ip er id in ed ica r boxylic Acid Der iva -
tives. To our knowledge, an asymmetric synthesis of
trans-3,4-piperidinedicarboxylate has not been previously
reported in the literature. Compound 2b contains an
embedded â-amino acid moiety, which immediately sug-
gested the use of â-alanine as a starting point for
sequential alkylations with tert-butyl bromoacetate and
then with an allyl halide (Scheme 3). We planned to use
Evans’s chemistry13 to introduce the first stereogenic
center. The second stereogenic center could be then
inducted during the dianion alkylation with an allyl
eletrophile, the stereochemistry of which has been well
established in the literature.14 To avoid intramolecular
cyclization, the â-amino group was doubly protected using
benzyl and Cbz groups which could be later removed
during piperidine ring formation by reductive amination.
Dibenzyl protection for the â-amino was not feasible
based on the consideration that the tertiary basic amino
residue would not survive the ozonolysis conditions
required to generate the aldehyde from the olefin moiety.
The synthesis started with commercially available
N-Cbz-â-alanine (9), which was subjected to a benzylation
in a mixed solvent of THF/DMF (4:1) to provide product
10 in 90% yield (Scheme 4). In the absence of DMF, the
reaction was sluggish, requiring several days of reaction
time to reach completion. In contrast, when DMF was
used as the only solvent, N,O-dibenzylated product was
obtained exclusively. Coupling of 10 with Evans’s chiral
auxiliary (R)-4-benzyl-2-oxazolidinone using pivaloyl chlo-
ride as the carboxyl activating agent15 produced the
alkylation precursor 11 in 88% yield. LDA-mediated
alkylation of 11 with tert-butyl bromoacetate followed by
LiOH/H2O2 hydrolysis gave rise to the succinic acid
a
Conditions: (a) BnBr, NaH, THF/DMF (4:1), 90%; (b) (1)
pivaloyl chloride, DIEA, THF, (2) (R)-4-benzyl-2-oxazolidinone,
LiCl, 88%; (c) LDA, tert-butyl bromoacetate, THF, 75%; (d) LiOH,
H2O2, THF, 90%; (e) LDA, allyl iodide, THF, 80%; (f) BnBr, DBU,
benzene, 87%; (g) O3, CH2Cl2, P(PPh3)3, 78%; (h) H2, Pd-C, MeOH,
95%; (i) (Boc)2O, NMM, THF, H2O, 88%; (j) CbzOSu, NMM, DMF,
83%.
monoester 13 with an R-configuration. Intermediate 13
was subjected to enolate formation using 2.2 equiv of
LDA followed by quenching with 1.5 equiv of allyl iodide,
providing exclusively the desired syn diastereomer 14 in
80% yield after chromatography. The high diastereose-
lectivity is consistent with previous reports on alkylation
of related succinic acid monoesters.14,16 For comparison,
the alkylation was found to be sluggish when allyl
bromide was used as the electrophile. After conversion
of the carboxylic acid 14 to a benzyl ester 15, ozonolysis
provided the aldehyde 16 in 85% yield. Reductive ami-
nation afforded the cyclized product 2b as a TFA salt.
The stereochemistry of 2b was thoroughly investigated
using 2D NMR experiments and clearly indicated the anti
orientation of the C-3 and C-4 hydrogens, both adopting
an axial position. Reaction of 2b with (Boc)2O or CbzOSu
furnished the N-Boc and N-Cbz protected analogues 17a
and 17b, respectively.
In summary, enantiomerically pure (2S,3S)-3-(tert-
butoxycarbonyl)-2-piperidinecarboxylic acid (1b) has been
synthesized in five steps in an overall yield of 38%
starting from L-aspartic acid â-tert-butyl ester. Dibenzyl
protection employed for the R-amino of the aspartate has
proved to be able to direct regioselective alkylation at the
C-3 center. Although this protection results in slightly
(16) Xue, C.-B.; Voss, M.; Nelson, D.; Duan, J .; Cherney, R.;
J acobson, I.; He, X.; Roderick, J .; Chen, L.; Corbett, R.; Wang, L.;
Meyer, D.; Kennedy, K.; DeGrado, W.; Hardman, K.; Teleha, C.; J affee,
B.; Liu, R.; Copeland, R.; Covington, M.; Christ, D.; Trzaskos, J .;
Newton, R.; Magolda, R.; Wexler, R.; Decicco, C. J . Med. Chem. 2001,
44, 2636-2660.
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J . Am. Chem. Soc. 1982,
104, 1737.
(14) Becket, R. P.; Crimmins, M. J .; Davis, M. H.; Spavold, Z. Synlett
1993, 137.
(15) Ho, G.-J .; Mathre, D. J . J . Org. Chem. 1995, 60, 2271.

868 J . Org. Chem., Vol. 67, No. 3, 2002
Xue et al.
mixture of 5a and 5b (21 g, 42 mmol) in THF (50 mL) cooled
in an ice bath was added a 0.5 M solution of 9-BBN (168 mL,
84 mmol). The mixture was allowed to stir at room-tempera-
ture overnight. After being cooled in an ice bath, a solution of
NaOAc (69 g) in water (50 mL) was added followed by a
solution of 33% H2O2 (68.5 mL). The mixture was stirred at
room temperature for 3 h and extracted with EtOAc three
times. The combined extracts were washed with brine, dried
(MgSO4), and concentrated. The residue was chromatographed
on silica gel, eluting with 30% EtOAc/hexanes to provide 16.9
g (78%) of the fast-moving isomer 6a and 2.6 g (12%) of the
slow-moving isomer 6b. 6a : 1H NMR (CDCl3) δ 7.5-7.2 (m,
15H), 5.24 (dd, J ) 24.5,12.5 Hz, 2H), 3.82 (m, 2H), 3.80 (d, J
) 13.5 Hz, 2H), 3.54 (d, J ) 11.4 Hz, 1H), 3.47 (t, J ) 6.6 Hz,
1H), 3.30 (d, J ) 13.5 Hz, 2H), 2.85 (m, 1H), 1.9-1.4 (m, 4H),
1.34 (s, 9H). MS (ESI) m/z 518.1 (M + H)+. Anal. Calcd for
lower diastereomeric excess (6:1) in allylation as com-
pared with N-benzyl-N-9-phenylfluoren-9-yl protection
(10:1 diastereomeric excess), it significantly shortens our
synthetic sequence (one step from starting material 3 to
the alkylation precursor 4) and avoids the use of the
expensive 9-bromo-9-phenylfluorene reagent. Beginning
with N-Cbz-â-alanine, optically pure (3R,4S)-4-(tert-bu-
toxycarbonyl)-3-piperidinecarboxylic acid (2b) has been
synthesized in eight steps in an overall yield of 28%.
Compounds 1b, 2b, and their corresponding N-Boc and
N-Cbz protected analogues 8a ,b and 17a ,b are novel
conformationally rigidified amino acid derivatives which
represent a useful source of chiral building blocks suit-
able for further synthetic elaboration in drug discovery.
C
32H39NO5: C, 74.25; H, 7.59; N, 2.71. Found: C, 73.96; H,
7.85; N, 2.48. 6b: 1H NMR (CDCl3) δ 7.5-7.2 (m, 15H), 5.22
(dd, J ) 24.3 & 12.4 Hz, 2H), 4.00 (d, J ) 13.2 Hz, 2H), 3.83
(m, 2H), 3.64 (d, J ) 11.6 Hz, 1H), 3.47 (t, J ) 6.6 Hz, 1H),
3.22 (d, J ) 13.4 Hz, 2H), 2.84 (m, 1H), 1.9-1.4 (m, 4H), 1.41
(s, 9H). MS (ESI) m/z 518.1 (M + H)+.
Exp er im en ta l Section
1H NMR data were obtained at 300 MHz using a Varian
VXR400 spectrometer and were referenced to TMS. 2D NMR
experiments were operated at 399.735 MHz at 30 °C on a
Varian Inova 400 spectrometer. Mass spectral data were
obtained on either VG 70-VSE or Finnigan MAT 8230 mass
spectrometers. Optical rotations were taken at 25 °C on a
Perkin-Elmer 341 Polarimeter. Combustion analyses were
performed by Quantitative Technologies, Inc, Bound Brook,
NJ . Dry THF was distilled from calcium hydride. KHMDS and
LHMDS (0.5 M in toluene and 1.0 M in THF, respectively)
were used from fresh bottles purchased from Aldrich Chemical
Co. Other solvents and reagents were used as purchased from
commercial suppliers unless otherwise indicated. Yields quoted
herein were isolated yields.
1-Ben zyl 4-ter t-Bu tyl (2S)-2-(Diben zyla m in o)bu ta n e-
d ioa te (4). To a suspension of L-aspartic acid â-tert-butyl ester
(25 g, 132 mmol) in DMF (200 mL) and DMSO (50 mL) was
added benzyl bromide (79 mL, 462 mmol) followed by K2CO3
(55 g, 396 mmol). The mixture was mechanically stirred at 50
°C overnight. After being cooled to room temperature, in-
solubles were filtered off, and the filtrate was reduced to a
small volume by evaporation under reduced pressure. The
residue was diluted with water (500 mL), and the resulting
solution was extracted with EtOAc three times. The combined
organic phase was washed with brine three times, dried
(MgSO4), and concentrated. The residue was purified on silica
gel, eluting with 10% EtOAc/hexanes to provide 54.5 g (90%)
of the tribenzylated product 4. 1H NMR (CDCl3) δ 7.43 (m,
5H), 7.30 (m, 10H), 5.32 (d, J ) 12.4 Hz, 1H), 5.20 (d, J )
12.1 Hz, 1H), 3.95 (m, 1H), 3.80 (d, J ) 13.9 Hz, 2H), 3.60 (d,
J ) 13.5 Hz, 2H), 2.87 (dd, J ) 15.9 and 8.4 Hz, 1H), 2.62 (dd,
J ) 15.4 and 8.2 Hz, 1H), 1.40 (s, 9H). MS (ESI) m/z 460.1 (M
+ H)+. Anal. Calcd for C29H33NO4): C, 75.79; H, 7.24; N, 3.05.
Found: C, 75.63; H, 7.20; N, 2.97.
4-Ben zyl 1-ter t-Bu tyl (3S)-2-Allyl-3-(d iben zyla m in o)-
bu ta n ed ioa te (5). To a solution of 4 (30 g, 65.35 mmol) in
freshly distilled dry THF (300 mL) at -78 °C was added a 0.5
M solution of KHMDS in toluene (157 mL). After stirring at
-78 °C for 1 h, allyl iodide (9 mL, 98 mmol) was added. The
temperature was raised to -30 °C and stirring was continued
at -30 °C for 3 h. The reaction was quenched with 10% citric
acid solution followed by dilution with brine. The resulting
solution was extracted with ethyl acetate three times. The
combined extracts were washed with brine, dried (MgSO4), and
concentrated. Chromatography on silica gel eluting with 20%
EtOAc/hexanes provided 24.4 g (75%) of a mixture of 5a and
5b (6:1). 1H NMR (CDCl3) δ 7.6-7.2 (m, 15H), 5.4-5.1 (m, 3H),
4.90 (m, 2H), 4.00 (d, J ) 13.8 Hz, 1/6 × 2H), 3.85 (d, J ) 13.9
Hz, 5/6 × 2H), 3.61 (d, J ) 11.1 Hz, 1/6 × 1H), 3.58 (d, J )
11.3 Hz, 5/6 × 1H), 3.36 (d, J ) 13.6 Hz, 5/6 × 2H), 3.24 (d, J
) 11.8 Hz, 1/6 × 2H), 2.95 (m, 1H), 2.65 (m, 1H), 2.20 (m, 1H),
1.42 (s, 1/6 × 9H), 1,31 (s, 5/6 × 9H). MS (ESI) m/z 500.1 (M
+ H)+. Anal. Calcd for C32H37NO4: C, 76.92; H, 7.46; N, 2.80.
Found: C, 76.69; H, 7.32; N, 2.73.
1-Ben zyl 4-ter t-Bu tyl (2S,3S)-2-(Diben zyla m in o)-3-(3-
oxop r op yl)bu ta n ed ioa te (7). To a solution of 6a (14.1 g, 27.3
mmol) in CH2Cl2 (400 mL) was added pyridinium dichromate
(20.5 g, 54.5 mmol). The mixture was stirred at room temper-
ature for 2 days and filtered through a pad of silica gel. The
silica gel was thoroughly rinsed with CH2Cl2 and then CHCl3.
The combined filtrate was concentrated under reduced pres-
sure. The residue was purified on silica gel eluting with 40%
1
EtOAc/hexanes to provide 10.5 g (75%) of the aldehyde 7. H
NMR (CDCl3) δ 9.50 (s, 1H), 7.5-7.2 (m, 15H), 5.26 (dd, J )
24.5 and 12.5 Hz, 2H), 3.80 (d, J ) 13.6 Hz, 2H), 3.52 (d, J )
11.3 Hz, 1H), 3.30 (d, J ) 13.1 Hz, 2H), 2.95 (m, 1H), 2.45 (m,
2H), 2.2-1.6 (m, 2H), 1.35 (s, 9H). MS (ESI) m/z 516.3 (M +
H)+. Anal. Calcd for C32H37NO5: C, 74.54; H, 7.23; N, 2.72.
Found: C, 74.82; H, 7.07; N, 2.61.
(2S,3S)-3-(ter t-Bu toxyca r bon yl)-2-p ip er id in eca r boxy-
lic Acid (1b). To a solution of the aldehyde 7 (5.15 g, 10 mmol)
in methanol (100 mL) in a Parr bottle was added 10% Pd-C
(1.5 g). The mixture was stirred under H2 at 50 psi overnight.
The catalyst was filtered off, and the solution was concentrated
under reduced pressure. The residue was washed with EtOAc
to provide 2.2 g (95%) of the cyclized product 1b. [R]D +14.0°
1
(c 0.35, MeOH). H NMR (CD3OD) δ 3.73 (d, J ) 8.5 Hz, 1H),
3.32 (m, 1H), 3.02 (m, 1H), 2.83 (m, 1H), 1.93 (m, 1H), 1.83-
1.72 (m, 2H), 1.67 (m, 1H), 1.48 (s, 9H). MS (ESI) m/z 230.1
(M + H)+. Anal. Calcd for C11H19NO4: C, 57.63; H, 8.35; N,
6.11. Found: C, 57.74; H, 8.74; N, 5.92.
(2S,3S)-1,3-Bis(ter t-bu toxyca r bon yl)-2-p ip er id in eca r -
boxylic Acid (8a ). To a solution of 1b (1.15 g, 5 mmol) in
THF (5 mL) and water (5 mL) cooled in an ice bath was added
NaHCO3 (0.84 g, 10 mmol) followed by di-tert-butyl dicarbonate
(1.37 g, 6 mmol). The mixture was allowed to stir at room
temperature overnight. After being cooled in an ice bath, a
solution of 1 N HCl (12 mL) was slowly added with stirring.
EtOAc was added. The separated organic phase was washed
with brine three times, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel eluting with 5%
MeOH/CH2Cl2 to provide 1.4 g (85%) of the N-Boc derivative
8a . [R]D +8.5° (c 0.40, MeOH). 1H NMR (CDCl3) δ 5.55 (bs,
1H), 5.12 (d, J ) 10.4 Hz, 1H), 5.18 (m, 2H), 3.90 (m, 1H),
3.20 (m, 1H), 3.0-2.5 (m, 2H), 2.10 (m, 1H), 1.55 (m, 2H), 1.40
(s, 18H). MS (ESI) m/z 330.2 (M + H)+. Anal. Calcd for C16H27
-
NO6: C, 58.36; H, 8.21; N, 4.26. Found: C, 58.55; H, 8.42; N,
4.55.
(2S,3S)-1-[(Ben zyloxy)ca r b on yl]-3-(ter t-b u t oxyca r b o-
n yl)-2-p ip er id in eca r boxylic Acid (8b). To a solution of 1b
(1.15 g, 5 mmol) in DMF (10 mL) was added N-(benzyloxy-
carbonyloxy)succinimide (1.25 g, 5 mmol) followed by NMM
(1.5 mL, 15 mmol). The mixture was stirred at room-temper-
ature overnight. EtOAc was added. The solution was acidified
with a solution of 1 N HCl and washed with brine three times,
dried (MgSO4), and concentrated. The residue was purified on
silica gel eluting with 5% MeOH/CH2Cl2 to give 1.5 g (82%) of
1-Ben zyl 4-ter t-Bu tyl (2S,3S)-2-(Diben zyla m in o)-3-(3-
h yd r oxyp r op yl)bu ta n ed ioa te (6a ). To a solution of the

Synthesis of trans-2,3-Piperidinedicarboxylic Acid
J . Org. Chem., Vol. 67, No. 3, 2002 869
1
the N-Cbz derivative 8b. [R]D +1.2° (c 0.40, MeOH). H NMR
2H), 1.40 (s, 9H). MS (ESI) m/z 428.3 (M + H)+. Anal. Calcd
for C24H29NO6: C, 67.42; H, 6.79; N, 3.27. Found: C, 67.15;
H, 6.71; N, 3.09.
(CDCl3) δ 7.65 (bs, 1H), 7.35 (m, 5H), 5.50 (d, J ) 15.4 Hz,
1H), 5.18 (m, 2H), 4.10 (m, 1H), 3.20 (m, 1H), 3.1-2.5 (m, 2H),
2.20 (m, 1H), 1.55 (m, 2H), 1.40 (s, 9H). MS (ESI) m/z 364.2
(M + H)+. Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N,
3.85. Found: C, 62.77; H, 7.14; N, 3.86.
(2R,3S)-2-({Ben zyl[(ben zyloxy)car bon yl]am in o}m eth yl)-
3-(ter t-bu toxyca r bon yl)-5-h exen oic Acid (14). To a solu-
tion of diisopropylamine (4.6 mL, 32.9 mmol) in THF (18 mL)
at -78 °C was added a solution of 2.5 M n-butyllithium (12.8
mL, 32.2 mmol). The solution was stirred at 0 °C for 30 min.
After the mixture was cooled back to -78 °C, a solution of 13
(6.2 g, 14.6 mmol) in THF (30 mL) was added. The mixture
was stirred at -78 °C for 60 min at which time allyl iodide
(1.7 mL, 19 mmol) was added. After being stirred at -30 °C
for 5 h, the solution was poured into a cold solution of 0.5 N
HCl with vigorous stirring. EtOAc was added. The organic
phase was separated, and the water layer was extracted with
EtOAc twice. The combined organic phase was washed with
brine, dried (MgSO4), and concentrated. The residue was
purified on silica gel eluting with EtOAc/hexanes to give 5.45
g (80%) of the allylated product 14. 1H NMR (CDCl3) δ 8.3
(bs, 1H), 7.30 (m, 10H), 5.65 (m, 1H), 5.22 (d, J ) 12.4 Hz,
1H), 5.16 (m, 2H), 5.00 (d, J ) 12.4 Hz, 1H), 4.72 (d, J ) 14.7
Hz, 1H), 4.25 (d, J ) 14.7 Hz, 1H), 3.70 (m, 1H), 3.40 (m, 1H),
3.15 (m, 1H), 2.67 (m, 1H), 2.00 (m, 2H), 1.25 (s, 9H). MS (ESI)
m/z 468.3 (M + H)+. Anal. Calcd for C27H33NO6: C, 69.36; H,
7.06; N, 2.99. Found: C, 69.70; H, 7.04; N, 2.96.
3-{Ben zyl[(ben zyloxy)ca r bon yl]a m in o}p r op a n oic Acid
(10). To a solution of N-benzyloxycarbonyl-â-alanine (33.5 g,
150 mmol) in THF (400 mL) and DMF (100 mL) cooled in an
ice bath was slowly added NaH (21.6 g, 60% in oil, 450 mmol).
After stirring for 15 min, benzyl bromide (26.8 mL, 225 mmol)
was added. The reaction was allowed to stir at room temper-
ature overnight and quenched slowly by addition of water
followed by 1 N HCl (pH ) 3). The solution was extracted with
EtOAc three times. The combined organic phase was washed
with brine three times, dried (MgSO4), and concentrated.
Purification on silica gel eluting with 40% EtOAc/hexanes gave
42.2 g (90%) of the N-benzylated product 10. 1H NMR (CDCl3)
δ 7.4-7.1 (m, 10H), 5.18 (d, J ) 5.4 Hz, 2H), 4.50 (s, 2H), 3.50
(m, 2H), 2.52 (m, 2H). MS (ESI) m/z 314.1 (M + H)+. Anal.
Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.67; H, 6.17; N, 4.41.
Ben zyl Ben zyl{3-[(4R)-4-b en zyl-2-oxo-1,3-oxa zolid in -
3-yl]-3-oxop r op yl}ca r ba m a te (11). To a solution of the
carboxylic acid 10 (41.8 g, 133.5 mmol) and NEt3 (40.5 mL,
400 mmol) in THF (500 mL) cooled at -30 °C was slowly added
pivaloyl chloride (17.7 mL, 147 mmol). The mixture was stirred
at -30 °C for 1 h at which time LiCl (6.22 g, 147 mmol) was
added followed by (R)-(+)-4-benzyl-2-oxazolidinone (26 g, 147
mmol). The mixture was allowed to stir at room-temperature
overnight. The volatiles were removed under reduced pressure.
Water and EtOAc were added. The organic phase was sepa-
rated, washed with brine, dried (MgSO4), and concentrated.
Purification on silica gel eluting with 40% EtOAc/hexanes gave
4-Ben zyl 1-ter t-Bu tyl (2S,3R)-2-Allyl-3-({ben zyl[(ben zyl-
oxy)ca r bon yl]a m in o}m eth yl)bu ta n ed ioa te (15). A mix-
ture of 14 (8.4 g, 18 mmol), benzyl bromide (4.3 mL, 35 mmol),
and DBU (4.1 g, 27 mmol) in benzene (60 mL) was stirred at
60 ïC for 2 h. After cooling to room temperature, insoluble
materials were filtered off. The filtrate was concentrated under
reduced pressure. The residue was purified on silica gel,
eluting with 15% EtOAc/hexanes to give 8.7 g (87%) of the
1
ester 15. H NMR (CDCl3) δ 7.4-7.0 (m, 15H), 5.60 (m, 1H),
1
55.4 g (88%) of 11. H NMR (CDCl3) δ 7.4-7.1 (m, 15H), 5.20
5.2-4.8 (m, 6H), 4.60 (m, 1H), 4,25 (m, 1H), 3.50 (m, 2H), 3.10
(m, 1H), 2.80 (m, 1H), 2.20 (m, 2H). MS (ESI) m/z 558.2 (M +
H)+. Anal. Calcd for C34H39NO6: C, 73.16; H, 6.99; N, 2.51.
Found: C, 72.78; H, 7.04; N, 2.50.
(d, J ) 13.6 Hz, 2H), 4.55 (m, 3H), 4.10 (m, 2H), 3.60 (m, 2H),
3.20 (m, 3H), 2.70 (m, 1H). MS (ESI) m/z 473.4 (M + H)+. Anal.
Calcd for C28H28N2O5: C, 71.17; H, 5.97; N, 5.93. Found: C,
70.86; H, 6.05; N, 5.79.
1-Ben zyl 4-ter t-Bu tyl (2R,3S)-2-({Ben zyl[(ben zyloxy)-
car bon yl]am in o}m eth yl)-3-(2-oxoeth yl)bu tan edioate (16).
Into a solution of 15 (4.3 g, 7.72 mmol) in CH2Cl2 (130 mL) at
-78 °C was bubbled O2 for 10 min, followed by O3. The solution
turned blue in 10 min and bubbling continued for additional
15 min. Nitrogen was then bubbled into the mixture until the
blue color disappeared. Triphenylphosphine (1.91 g, 15.4 mmol)
was added, and the solution was allowed to stir at room-
temperature overnight. The reaction was quenched by addition
of aqueous 1 N HCl solution. The organic layer was separated,
washed with brine, dried (MgSO4), and concentrated. Chro-
matography on silica gel eluting with 20% EtOAc/hexanes gave
3.3 g (78%) of the aldehyde 16. 1H NMR (CDCl3) δ 9.65 (s,
1H), 7.4-7.0 (m, 15H), 5.10 (m, 4H), 4.60 (m, 1H), 4.30 (m,
1H), 3.60 (m, 2H), 3.3-2.8 (m, 3H), 2.60 (m, 1H), 1.36 (s, 9H).
MS (ESI) m/z 560.2 (M + H)+. Anal. Calcd for C33H37NO7: C,
70.84; H, 6.62; N, 2.50. Found: C, 70.56; H, 6.56; N, 2.48.
(3R,4S)-4-(ter t-Bu toxyca r bon yl)-3-p ip er id in eca r boxy-
lic Acid (2b). To a solution of 16 (4.5 g, 8.0 mmol) in methanol
(50 mL) was added TFA (0.7 mL) followed by 10% palladium
on carbon (1.3 g). The mixture was stirred under hydrogen at
50 psi overnight. The catalyst was removed by filtration, and
the solution was concentrated. The residue was washed with
ether to give 1.7 g (95%) of the cyclized product 2b. [R]D +15.7°
ter t-Bu tyl (3R)-3-({Ben zyl[(ben zyloxy)car bon yl]am in o}-
m eth yl)-4-[(4R)-4-ben zyl-2-oxo-1,3-oxa zolid in -3-yl]-4-oxo-
bu ta n oa te (12). To a solution of diisopropylamine (5.33 mL,
52.8 mmol) in THF (75 mL) at -78 °C was added a solution of
2.5 M n-butyllithium (21.1 mL, 52.8 mmol). The solution was
stirred at 0 °C for 30 min and after cooling back to -78 °C, a
solution of 11 (22.7 g, 48 mmol) in THF (100 mL) was added.
The mixture was stirred at -78 °C for 1 h at which time tert-
butyl bromoacetate (7.8 mL, 52.8 mmol) was added. The
solution was allowed to stir at -30 °C for 5 h and quenched
by addition of an aqueous solution of citric acid. Following
addition of EtOAc, the organic phase was separated, and the
water layer was extracted with EtOAc three times. The
combined organic phase was washed with 10% citric acid and
brine, dried (MgSO4), and concentrated. Silica gel chromatog-
raphy eluting with 20% EtOAc/hexanes gave 21 g (75%) of the
desired product 12. 1H NMR (CDCl3) δ 7.4-7.1 (m, 15H), 5.12
(m, 2H), 4.50 (m, 4H), 4.00 (m, 2H), 3.50 (m, 2H), 3.2.5 (m,
1H), 2.95 (m, 1H), 2.70 (m, 1H), 2.40 (m, 1H), 1.35 (s, 9H). MS
(ESI) m/z 587.1 (M + H)+. Anal. Calcd for C34H38N2O7: C,
69.61; H, 6.53; N, 4.78. Found: C, 69.86; H, 6.52; N, 4.64.
(2R)-2-({Ben zyl[(ben zyloxy)ca r bon yl]a m in o}m eth yl)-
4-ter t-bu toxy-4-oxobu ta n oic Acid (13). To a solution of 12
(40.9 g, 69.8 mmol) in THF (150 mL)/water (120 mL) cooled
in an ice bath was added a solution of 30% hydrogen peroxide
(28.5 mL, 279 mmol). After the mixture was stirred for 5 min,
a solution of LiOH (4.4 g, 105 mmol) in water (30 mL) was
added. The mixture was allowed to stir at 0 ïC for 2 h at which
time sodium sulfite (35 g) was added. Stirring was continued
for 30 min, The solution was acidified with 10% citric acid (pH
) 3) and extracted with EtOAc three times. The combined
organic phase was washed with brine, dried (MgSO4), and
concentrated. Purification on silica gel eluting with 10% CH3-
CN/CH2Cl2 followed with 10% MeOH/CH2Cl2 gave 26.8 g (90%)
of the carboxylic acid 13. 1H NMR (CDCl3) δ 7.4-7.1 (m, 10H),
5.18 (s, 2H), 4.50 (m, 2H), 3.50 (m, 2H), 3.16 (m, 1H), 2.50 (m,
1
(c 0.236, MeOH). H NMR (CD3OD) δ 3.58 (m, 1H), 3.38 (m,
1H), 3.15-2.98 (m, 3H), 2.80 (m, 1H), 2.17 (m, 1H), 1.81 (m,
1H), 1.42 (s, 9H). MS (ESI) m/z 230.3 (M + H)+. Anal. Calcd
for C11H19NO4‚CF3CO2H: C, 45.48; H, 5.87; N, 4.08. Found:
C, 45.70; H, 5.67; N, 4.03.
(3R,4S)-1,4-Bis(ter t-bu toxyca r bon yl)-3-p ip er id in eca r -
boxylic Acid (17a ). To a suspension of 2b (2.29 g, 10 mmol)
in THF (10 mL) cooled in an ice bath was added a solution of
1 N NaOH (10 mL) followed by NaHCO3 (1.68 g, 20 mmol)
and di-tert-butyl dicarbonate (2.4 g, 11 mmol). After being
stirred at room temperature for 5 h, the solution was cooled
in an ice bath and acidified with 1 N HCl. EtOAc was added,
and the separated organic phase was washed with brine three

870 J . Org. Chem., Vol. 67, No. 3, 2002
Xue et al.
times, dried (MgSO4), and concentrated. Chromatography on
silica gel eluting with 5% MeOH/CH2Cl2 provided 2.9 g (88%)
of the N-Boc derivative 17a . [R]D -17.2° (c 0.40, MeOH). 1H
NMR (CDCl3) δ 7.1 (bs, 1H), 4.25 (m, 1H), 4.02 (m, 1H), 2.8-
2.6 (m, 4H), 1.96 (m, 1H), 1.46 (m, 1H), 1.44 (s, 9H), 1.41 (s,
1 N HCl, washed with brine three times, dried (MgSO4), and
concentrated. Purification on silica gel eluting with 5% MeOH/
CH2Cl2 gave 1.4 g (83%) of the N-Cbz derivative 17b. [R]D
1
-21.8° (c 0.30, MeOH). H NMR (CDCl3) δ 7.37 (m, 5H), 5.12
(m, 2H), 4.35 (m, 1H), 4.15 (m, 1H), 3.0-2.6 (m, 4H), 1.95 (m,
1H), 1.58 (m, 1H), 1.41 (s, 9H). MS (ESI) m/z 364.4 (M + H)+.
Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N, 3.85. Found:
C, 62.89; H, 6.86; N, 3.85.
9H). MS (ESI) m/z 330.2 (M + H)+. Anal. Calcd for C16H27
-
NO6: C, 58.35; H, 8.20; N, 4.25. Found: C, 58.56; H, 8.28; N,
4.36.
(3R,4S)-1-[(Ben zyloxy)ca r bon yl]-4-(ter t-bu toxyca r bo-
n yl)-3-p ip er id in eca r boxylic Acid (17b). To a solution of 2b
(1.45 g, 4.22 mmol) in DMF (10 mL) was added N-(benzyloxy-
carbonyloxy)succinimide (1.16 g, 4.65 mmol) followed by NMM
(1.72 mL, 17 mmol). After being stirred at room-temperature
overnight, EtOAc was added. The solution was acidified with
Ack n ow led gm en t. We thank Thomas H. Scholz for
performing 2D NMR studies and Pete Crawford for
measuring optical rotations.
J O016086B