Enantioselective Synthesis of Substituted Pipecolic Acid Derivatives

Article abstract of DOI:10.1021/jo9722414

Enantiomerically pure 4-piperidones, prepared by asymmetric [4 + 2] Diels-Alder cycloadditon of chiral 2-aminodienes with imines, have been used as starting materials for the synthesis of several derivatives of pipecolic acid. The α-amino acid moiety is obtained after the oxidation of a hydroxy group or a furan ring of a conveniently protected 2-aryl-6-(hydroxymethyl)-4-piperidone. Depending on the starting piperidone and the synthetic strategy, it is possible to obtain D- or L-functionalized pipecolic acid derivatives by a short synthetic procedure. Moreover, a stereoselective epimerization of the α-carbon atom of a particular pipecolate allows for the preparation of both cis- and trans-6-(hydroxymethyl)pipecolic acids, structures related with dipeptide isosteres.

Full text of DOI:10.1021/jo9722414

3918
J . Org. Chem. 1998, 63, 3918-3924
En a n tioselective Syn th esis of Su bstitu ted P ip ecolic Acid
Der iva tives
J ose´ Barluenga,* Fernando Aznar, Carlos Valde´s, and Cristina Ribas
Instituto Universitario de Quı´mica Organometa´lica Enrique Moles, Unidad Asociada al CSIC,
Universidad de Oviedo, 33071 Oviedo, Spain
Received December 10, 1997
Enantiomerically pure 4-piperidones, prepared by asymmetric [4 + 2] Diels-Alder cycloadditon of
chiral 2-aminodienes with imines, have been used as starting materials for the synthesis of several
derivatives of pipecolic acid. The R-amino acid moiety is obtained after the oxidation of a hydroxy
group or a furan ring of a conveniently protected 2-aryl-6-(hydroxymethyl)-4-piperidone. Depending
on the starting piperidone and the synthetic strategy, it is possible to obtain D- or L-functionalized
pipecolic acid derivatives by a short synthetic procedure. Moreover, a stereoselective epimerization
of the R-carbon atom of a particular pipecolate allows for the preparation of both cis- and trans-
6-(hydroxymethyl)pipecolic acids, structures related with dipeptide isosteres.
Sch em e 1
Molecules with rigid frameworks containing the R-ami-
no acid moiety are attractive synthetic targets since they
can be used as conformationally restricted modules in the
design of new peptidomimetic structures with biological
activity.1 In this context, a naturally occurring example
is found in the piperidine-based structure of pipecolic
acid,2 a nonproteinogenic R-amino acid, and its deriva-
tives, which are present in a number of natural and
synthetic compounds with biological activity.3 Moreover,
substituted pipecolic acids have been employed as key
intermediates in the synthesis of different types of other
piperidine natural products.4 In particular, enantiomeri-
cally pure pipecolates have been used as synthetic
precursors of indolizidine alkaloids.4c For these reasons,
the asymmetric synthesis of substituted pipecolic acid
derivatives constitutes an interesting synthetic objective
that has attracted significant attention in recent years.5
We have recently reported the enantioselective syn-
thesis of functionalized 4-piperidones 3 by [4 + 2]
cycloaddition of N-silylaldimines 2 with chiral 2-amino-
1,3-butadienes 1 (Scheme 1),6 a reaction that proceeds
with good yields and very high enantiomeric excesses.
Due to the high functionalization of the resulting pip-
eridones 3, we envisioned them as potential precursors
of different families of enantiomerically pure pipecolic
acid derivatives I and II. These compounds are confor-
mationally restricted R-amino acids which have the
R-amino acid structure included not only in a six-
membered ring but also in a sterically demanding
environment. These compounds offer further interest as
synthetic precursors of natural products. For instance,
a structure closely related with these amino acids is
found in the piperidine A-ring of the marine hepatotoxin
cylindrospermopsin.7 In fact, pipecolates with the same
sterochemistry and similar functionality as some of the
* Corresponding author. Fax: (34)
barluenga@sauron.quimica.uniovi.es.
8 510 34 50. E-mail:
(1) (a) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993,
32, 1244. (b) Gante, J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(2) For some examples of biologically active substances containing
the structure of pipecolic acid, see: (a) Flynn, G. A.; Giroux, E. L.;
Dage, R. C. J . Am. Chem. Soc. 1987, 109, 7914. (b) J ones, J . K.; Mills,
S. G.; Reamer, R. A.; Askin, D.; Desmond, R.; Volante, R. P.; Shinkai,
I. J . Am. Chem. Soc. 1989, 111, 1157. (c) Sehgal, S. N.; Baker, H.;
Eng, C. P.; Singh, K.; Ve´niza C. J . Antibiot. 1983, 36, 351.
(3) (a) Wagner, I.; Musso H. Angew. Chem., Int. Ed. Engl. 1983, 22,
816. (b) Manning, K. S.; Lynn, D. G.; Shabanowitz, J .; Fellows, L. E.;
Winchester, B. J . Chem. Soc., Chem. Commun. 1985, 127. (c) Reed,
J . W.; Purvis, M. B.; Kingston, D. G. I.; Biot, A.; Gossele, F. J . Org.
Chem. 1989, 54, 1161. (d) Hays, S. J .; Malone, T. C.; J ohnson, G. J .
Org. Chem. 1991, 56, 4084. (e) Ornstein, P. L.; Schoepp, D. D.; Arnold,
M. D.; Leander, J . D.; Lodge, D.; Paschal, J . W.; Elzey, T. J . Med. Chem.
1991, 34, 90. (f) Gillard, J .; Abraham, A.; Anderson, P. C.; Beaulieu,
P. L.; Bogri, T.; Bousquet, Y.; Greinier, L.; Guse, I.; Lavalle, P. J . Org.
Chem. 1996, 61, 2226.
(5) (a) Christie, B. D.; Rapoport, H. J . Org. Chem. 1985, 50, 1239.
(b) Bashyal, B. P.; Chow, H.-F.; Fleet, G. W. J . Tetrahedron Lett. 1986,
27, 3205. (c) Bailey, P. D.; Bryans, J . S. Tetrahedron Lett. 1988, 29,
2231. (d) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30, 515.
(e) Agami, C.; Couty, F. Synlett 1990, 731. (f) Bailey, P. D.; Brown, G.
R.; Korber, F.; Reed, A.; Wilson, R. D. Tetrahedron: Asymmetry 1991,
2, 1263. (g) Berrien, J .-F.; Royer, J .; Husson, H.-P. J . Org. Chem. 1994,
59, 3769. (h) Goluveb, A.; Sewald, N.; Burger, K. Tetrahedron Lett.
1995, 36, 2037. (i) Adams, D. R.; Bailey, P. D.; Collier, I. D.; Heffernan,
J . D.; Stokes, S. J . Chem. Soc., Chem. Commun. 1996, 349.
(6) (a) Barluenga, J .; Aznar, F.; Valde´s, C.; Mart´ın, J . A.; Garc´ıa-
Granda, S.; Mart´ın, E. J . Am. Chem. Soc. 1993, 115, 4403. (b)
Barluenga, J .; Aznar, F.; Ribas, C.; Valde´s, C.; Ferna´ndez, M.; Cabal,
M. P.; Trujillo, J . T. Chem. Eur. J . 1996, 2, 805.
(4) (a) Holmes, A. B.; Swithenbank, C.; Williams, S. F. J . Chem.
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cycles 1983, 20, 2163. (c) Angle, S. R.; Henry, R. M. J . Org. Chem.
1997, 62, 8549 and references therein.
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1992, 114, 7941.
S0022-3263(97)02241-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/23/1998

Enantioselective Synthesis of Pipecolic Derivatives
J . Org. Chem., Vol. 63, No. 12, 1998 3919
Sch em e 2
Sch em e 3
However, in the presence of traces of base it undergoes
cyclization to yield the undesired bicyclic carbamate 7.10
Oxidation of 6 with J ones reagent, followed by esterifi-
cation with diazomethane, yielded fully protected pipe-
colate 8. Finally, cleavage of the Troc protective group
was performed in quantitative yield by treatment with
zinc dust in AcOH to furnish the first compound of these
series, D-methyl ketopipecolate 9 (Scheme 2).
compounds described in the present paper have been
proposed by Weinreb et al. as key compounds in the
synthesis of this marine alkaloid.8 In this paper we
report our efforts regarding the synthesis of these classes
of pipecolates.
As depicted in Scheme 1, the selection of the proper
subtituents in the starting piperidone and the subsequent
synthetic pathway can allow for the preparation of both
families of pipecolic acids. Thus, oxidation of the hydroxy
group in 3 will lead to derivatives of type I, while
oxidative degradation of an aromatic ring, typically a
furan, will furnish type II amino acids. Moreover, amino
acids I and II, obtained from 4-piperidones, will have
opposite absolute configurations (D or L) on the R-carbon
atom.
A key step in the conversion of piperidones 3 into
pipecolates is the orthogonal protection of both hydroxy
and amino functionalities. The hydroxy group was
selectively protected as TBDMS ether (tert-butyldimeth-
ylsilyl chloride, imidazole, CH3CN, rt, overnight). Pro-
tection of the amino group, however, was not trivial,
probably due to the steric hindrance around the N-H
functionality, and reaction with classic protecting re-
agents did not proceed (Boc2O) or proceeded with very
low conversion and only under harsh conditions (CbzCl).
Nevertheless, excellent results were obtained by treat-
ment of piperidones 4 with 2,2,2-trichloroethyloxycarbo-
nyl chloride (TrocCl) in pyridine to furnish fully protected
derivatives 5,9 which were used in the synthesis of both
types of amino esters (Schemes 2 and 3).
For a type II amino acid, we decided to use a furan
ring as a masked carboxylate group. The required
4-piperidone 3b was obtained in ee > 98%. After the
same protective group strategy, the furan ring of com-
pound 5b was transformed into a carboxylic acid by
oxidation with RuCl3‚H2O/NaIO4 using the Sharpless
procedure.11 The crude acid was converted into carboxy-
lic ester 10 by treatment with diazomethane in diethyl
ether. Deprotection of the amino group was again
performed by treatment with zinc dust in acetic acid to
obtain ketopipecolic ester 11, and cleavage of the TBDMS
group was carried out by treatment with aqueous HCl
to yield methyl L-(hydroxymethyl)ketopipecolate 12
(Scheme 3).
As an alternative method, we believed the synthesis
of hydroxyamino acid derivatives such as 12 might be
approached in a more straightforward way by simulta-
neously protecting the amino and hydroxy groups as a
cyclic carbamate. In fact, this transformation was carried
out in nearly quantitative yield by treatment of 4b with
triphosgene and triethylamine in THF to yield the
bicyclic carbamate 13 (Scheme 4). To avoid undesired
epimerizations on the stereocenter bearing the methyl
group, the carbonyl functionality was stereoselectively
reduced with K-Selectride (THF, -80 °C, 90 min) to give
hydroxy compound 14, which was alkylated with BnBr
(NaH, DMF, reflux) to give bicyclic carbamate 15.12
The furan ring was then transformed into a carboxylic
acid by oxidation. This time the transformation was
carried out by ozonolysis in the presence of H2O2, which
turned out to be much more convenient than the RuCl3
oxidation. Esterification of the crude acid was carried
out either by treatment with diazomethane in ether to
furnish methyl ester 16a or by formation of the corre-
sponding acid chloride (oxalyl chloride, CH2Cl2, reflux, 4
We approached type I compounds from piperidone 3a ,
available in 95% ee, as starting material. After the
protection described above, the tert-butyldimethylsilyl
ether is selectively cleaved by treatment of a solution of
5a in CH3CN with aqueous 3 N HCl (rt, 3 h). Hydroxy
compound 6 is stable in organic solvents or acidic media.
(10) Beak, P.; Lee, W. F. J . Org. Chem. 1993, 58, 1109.
(11) Carlson, P. T. H.; Katsuki, T.; Mart´ın, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(8) (a) Heintzelman, G. R.; Parvez, M.; Weinreb, S. M. Synlett 1993,
5. (b) Snider, B. B.; Harvey, T. C. Tetrahedron Lett. 1995, 36, 4587.
(c) Heintzelman, G. R.; Weinreb, S. M. J . Org. Chem. 1996, 61, 4594.
(9) Windholz, T. B.; J ohnston, D. B. R. Tetrahedron Lett. 1967, 27,
2555.
(12) A detailed NMR study of the configuration of the new stereo-
center created in the reduction step can be found in
publication (see ref 6b).
a previous

3920 J . Org. Chem., Vol. 63, No. 12, 1998
Barluenga et al.
Sch em e 4
Sch em e 5
NaOH or KOH solutions).14 When this procedure was
examined for our system (6 N NaOH, MeOH, reflux
overnight) we obtained, as expected, the desired hy-
droxyamino acid, but as a 1:1 mixture of the C-2 epimers
18 and 19 (Scheme 5). In this case, equilibration of the
stereocenter at C-2 had taken place. Better results were
obtained with tBuOK, but in refluxing THF. Thus,
t
refluxing a solution of 17a ,b and BuOK in THF for 1 h
afforded a 6:1 mixture of epimeric amino acids 18 and
19 (Scheme 5). As expected, an identical mixture was
obtained when 16a ,b were treated under the same
conditions. Clearly, under strongly basic conditions both
the ester and carbamate functionalities are cleaved, but
an unselective epimerization at C-2 simultaneously oc-
curs.
Ch a r t 1
It seemed that in order to obtain amino acids 18 or 19
as pure stereoisomers it was crucial to avoid or control
the epimerization process. To this purpose we decided
to perform the same reaction on the carboxylic acid
instead of the ester. The lower acidity of the R-hydrogen
in the carboxylic salt compared with the ester should
prevent the epimerization induced by bases. To carry
out this reaction it was a prerequisite to obtain the
carboxylic acid as a pure compound, which could be easily
attained by purification of ester 16 and further depro-
tection of the carboxylic ester. Initial attempts at basic
hydrolysis of the methyl ester 16a led to mixtures of
epimers, and therefore we prepared the benzyl ester 16c,
cleavable under neutral conditions by hydrogenolysis. In
fact, after chromatography purification of 16c, the ester
functionality was cleanly cleaved by hydrogenation in
EtOH in the presence of Pd/C to obtain pure carboxylic
acid 20 as a single stereoisomer (Scheme 6). To our
delight, when acid 20 was refluxed in THF in the
presence of tBuOK, (hydroxymethyl)pipecolic acid 19 was
obtained as a single diastereoisomer. No epimerization
had occurred. Moreover, interestingly, when ester 17c
(coming from the epimerization of 16c) was subjected to
the same sequenceshydrogenation to obtain acid 21 and
cleavage of the carbamates(hydroxymethyl)pipecolic acid
h) followed by treatment with a primary alcohol to yield
esters 16b,c.
In our synthetic strategy we had planned to open the
t
cyclic carbamate by treatment with BuOK in anhydrous
THF at 0 °C, a method that had proven useful previously
for similar systems.13 However, when esters 16 were
subjected to these conditions, the bicyclic system was not
cleaved. Instead, epimerization of the amino ester oc-
curred affording new bicyclic ester 17 as a single dias-
tereoisomer. The stereochemical configuration of these
new compounds was established based on the values of
the coupling constants in the 1H NMR spectra for
compounds 17 and by comparison with the corresponding
couplings of compounds 16. For example, for ester 16b
(Chart 1) the equatorial arrangement of the ester group
at C-2 is indicated by the large axial-axial coupling
constant between H2 and H3ax (J H2-H3 ) 12.2 Hz). On
the other hand, for 17b no axial-axial coupling constants
were observed between H2 and the hydrogens at C-3
(J H2-H3a ) 6.8 Hz, J H2-H3b ) 1.6 Hz), which suggests that
the ester group must be in the axial position. Moreover,
the large coupling constant between H5 and H6 (J H5-H6
) 10.1 Hz) confirms the equatorial-equatorial cis rela-
tionship of the substituents at C-5 and C-6.
18 was obtained, also as a single stereoisomer.
A
method, therefore, has been developed that allows for the
diastereo- and enantioselective syntheses of both cis- and
trans-D and L-6-(hydroxymethyl)pipecolic acids 18 and 19
from the same starting material.
In conclusion, we have described the diastereo- and
enantioselective syntheses of a variety of pipecolic acid
derivatives from easily available optically active 4-pip-
The ring opening of cyclic carbamates such as 16
usually requires harsh conditions (typically concentrated
(14) (a) Takao, K.; Nigawara, Y.; Nishino, E.; Takagi, I.; Maeda, K.;
Tadano, K.; Ogawa, S. Tetrahedron 1994, 50, 5681. (b) Cheˆnevert,
R.; Dickman, M. J . Org. Chem. 1996, 61, 3332.
(13) Valde´s, C., Ph.D. Thesis, Oviedo, Spain, 1992.

Enantioselective Synthesis of Pipecolic Derivatives
J . Org. Chem., Vol. 63, No. 12, 1998 3921
anhydrous Na2SO4, and concentrated under reduced pressure.
Column chromatography was carried out using 230-400 mesh
silica gel. TLC analyses were performed on silica gel 60 F254
plates, and compounds were visualized with UV light and by
spraying with acidic Mo7O24(NH4)6‚4H2O/Ce(SO4)2 solution. 1H
NMR spectra were recorded at 200 or 300 MHz at room
temperature employing CDCl3 as solvent. Chemical shifts are
reported in parts per million (ppm) relative to residual CHCl3
peak; J values are given in Hz. 13C NMR spectra were
performed at 50 or 75 MHz. 4-Piperidones 3 were prepared
as described in ref 6.
Sch em e 6
Syn th esis of Am in od ien e 1. This procedure is an opti-
mization of the methodology that we have reported previously.
Mercury(II) acetate (9.56 g, 30 mmol) was placed in a Schlenck
flask containing a magnetic stirring bar and was heated to
100 °C under vacuum (10-3 Torr) for 4 h. The heat was
removed, and the flask was allowed to cool to room tempera-
ture and filled with dry nitrogen. Dry THF (90 mL) and
3-methyl-5-[(trimethylsilyl)oxy]-3-penten-1-yne (5.05 g, 30 mmol)
were added to the flask successively, and the mixture was
stirred for 5 min. Dry diisopropylamine (10.5 g, 75 mmol) was
added to the mixture, and the stirring was continued for 15
min. Dry 2-(methoxymethyl)pyrrolidine was added to the
solution, and the reaction was stirred at room temperature
overnight. The reaction mixture was concentrated under
vacuum (do not use water aspirator!) until the solid formed
made stirring difficult. The flask was filled with dry nitrogen,
and 60 mL of dry hexanes was added to the mixture. After
the suspension was stirred and shaken for 30 min, the solution
was filtered under a dry atmosphere and the solid was washed
with additional dry hexanes (2 × 50 mL). The filtrates were
combined and concentrated to 40 mL of solution. The resulting
mixture was kept under a dry atmosphere at -20 °C for 10 h.
The clear solution was separated from the solid by cannula
and concentrated under vacuum. The oily liquid so obtained
is essentially pure aminodiene that can be further purified by
bulb-to-bulb distillation under vacuum (10-3 Torr, preheated
oil bath 130 °C, bp 75-85 °C) to give 5.6 g (67%) of aminodiene
1.
Ch a r t 2
Syn th esis of P ip er id on es 3. Compounds 3 were prepared
as described in ref 6b.
Silyla tion of th e Hyd r oxy Gr ou p of 4-P ip er id on es 3.
Syn th esis of P ip er id on es 4. To a solution of 4-piperidone
3 (3.0 mmol) in acetonitrile (20 mL) at room temperature were
added imidazole (9.0 mmol, 613 mg) and tert-butyldimethyl-
chlorosilane (9.0 mmol, 1.36 g). The resulting solution was
stirred overnight, and the reaction was quenched with H2O
(7 mL) and EtOAc (7 mL). The aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic layers were
washed with brine (5 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting orange
oil was purified by column chromatography.
eridones. It is worth pointing out that hydroxyamino
acids 18 and 19 and also hydroxyamino ester 12 are
conformationally constrained dipeptide isosteres15 in
which the R group and a carbonyl group in the original
dipeptide are replaced by the six-membered ring (Chart
2). On the other hand, structure 9 features the amino
acid moiety in a sterically crowded environment. We are
currently pursuing the synthesis of new compounds of
these families, to study their potential application in the
design of peptidomimetics with defined and predictable
conformations. Moreover, hydroxyamino acid 19 and
ester 16 have the same substitution and sterochemistry
as the A-ring of cylindrospermopsin and can therefore
be used as intermediates in developing a total synthesis
of this marine hepatotoxin. Finally, it should be noted
that the absolute configuration of the compounds de-
scribed in this paper derives from the chiral auxiliary
((S)-prolinol) used in the cycloaddition step (Scheme 1).
Since (R)-prolinol, although more expensive, is also
commercially available, the enantiomers of those com-
pounds are also accessible by these synthetic routes.
(-)-(2R,3S,6S)-2-[[(ter t-Bu tyldim eth ylsilyl)oxy]m eth yl]-
3-m eth yl-6-p h en yl-4-p ip er id on e, 4a . Piperidone 3a (658
mg) was employed as starting material. The silylated com-
pound 4a was isolated in 65% yield (650 mg). For spectro-
scopic data, see ref 6b; ee ) 95%; [R]18 ) -78 (c 0.8, CHCl3).
D
(-)-(2R,3S,6S)-2-[[(ter t-Bu tyldim eth ylsilyl)oxy]m eth yl]-
6-(3-fu r yl)-3-m eth yl-4-p ip er id on e, 4b. Piperidone 3b (628
mg) was employed as starting material. The silylated com-
pound 4b was isolated in 69% yield (670 mg). For spectro-
scopic data, see ref 6b; ee > 98%; [R]18 ) -33 (c 0.5, CHCl3).
D
P r otection of th e Am in o Gr ou p of 4-P ip er id on es 4.
Syn th esis of N-Tr oc-P r otected P ip er id on es 5. To a
solution of the corresponding silylated 4-piperidone 4 (1.8
mmol) in pyridine (15 mL) cooled to 0 °C was added 2,2,2-
trichloroethyl chloroformate (5.4 mmol, 0.74 mL) dropwise. The
resulting mixture was vigorously stirred at room temperature
for 2 h. The reaction was quenched by careful addition of H2O
(5 mL) and EtOAc (10 mL). The aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic layers were
Exp er im en ta l Section
Gen er a l. All reactions were carried out under N2 employ-
ing solvents dried following standard procedures.16 For isola-
tion, organic layers were washed with brine, dried over
(15) For similar dipeptide isosteres based on sugars, see: Graf von
Roerden, E.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 687.
(16) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988.

3922 J . Org. Chem., Vol. 63, No. 12, 1998
Barluenga et al.
washed with brine (2 × 5 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The resulting
orange oil was purified by column chromatography.
mL). The combined organic layers were washed with brine
(2 × 5 mL), dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The resulting yellow oil was purified
by column chromatography. The ester 8 was isolated in 89%
yield (195 mg) as a colorless oil: Rf ) 0.26 (SiO2, hexane/
EtOAc, 4:1); [R]20D ) +12.0 (c 0.9, CH2Cl2); 1H NMR (200 MHz,
DMSO-d6) δ 7.67-7.31 (m, 5H), 5.70 (t, 1H, J ) 5.0 Hz), 4.99
(s, 2H), 4.82 (d, 1H, J ) 8.2 Hz), 3.74 (s, 3H), 3.24 (dd, 1H, J
) 17.1, 5.1 Hz), 3.10 (dd, 1H, J ) 17.1, 4.9 Hz), 2.70-2.55 (m,
1H), 1.10 (d, 3H, J ) 6.9 Hz); 13C NMR (50.3 MHz, DMSO-d6)
δ 206.5, 171.1, 154.1, 141.0, 128.3, 127.1, 126.0, 95.3, 74.6, 59.9,
54.3, 52.2, 44.8, 43.4, 12.1 (br); HRMS (EI) calcd for
(-)-(2R,3S,6S)-2-[[(ter t-Bu tyldim eth ylsilyl)oxy]m eth yl]-
N-[(2,2,2-t r ich lor oet h oxy)ca r b on yl]-3-m et h yl-6-p h en yl-
4-p ip er id on e, 5a . Piperidone 4a (600 mg) was employed as
starting material. The protected compound 5a was isolated
in 93% yield (850 mg) as a yellow oil: Rf ) 0.32 (SiO2, hexane/
EtOAc, 8:1); [R]18D ) -32.3 (c 0.7, CH2Cl2); 1H NMR (200 MHz,
C6D6, 75 °C) δ 7.59-7.22 (m, 5H), 5.76 (t, 1H, J ) 7.0 Hz),
4.83 (s, 2H), 4.79 (td, 1H, J ) 6.0, 2.9 Hz), 3.84-3.70 (m, 2H),
3.01 (dd, 1H, J ) 16.5, 7.0 Hz), 2.88 (qd, 1H, J ) 7.3, 2.9 Hz),
2.86 (dd, 1H, J ) 16.5, 7.0 Hz), 1.39 (d, 3H, J ) 7.3 Hz), 1.09
(s, 9H), 0.19 (s, 3H), 0.18 (s, 3H); 13C NMR (75 MHz, CD2Cl2)
δ 209.5, 155.7, 143.7, 129.4, 128.1, 126.8, 96.4, 75.9, 66.1, 61.8,
56.4, 44.6, 43.3 (br), 26.5, 18.9, 17.5 (br), -5.0; HRMS (EI) calcd
for C21H29Cl3NO4Si (M - CH3) 492.0931, found 492.0937.
(-)-(2R,3S,6S)-2-[[(ter t-Bu tyldim eth ylsilyl)oxy]m eth yl]-
N-[(2,2,2-tr ich lor oeth oxy)ca r bon yl]-6-(3-fu r yl)-3-m eth yl-
4-p ip er id on e, 5b. Piperidone 4b (582 mg) was employed as
starting material. The protected compound 5b was isolated
in 70% yield (629 mg) as a yellow oil: Rf ) 0.24 (SiO2, hexane/
C
17H18Cl3NO5 421.0251, found 421.0261.
Dep r otection of Tr oc Gr ou p of Ester 8. Syn th esis of
(-)-Met h yl (2R,3S,6S)-3-Met h yl-6-p h en yl-4-oxop ip eco-
la te, 9. Zinc dust (900 mg) was added at room temperature
to a solution of 90 mg of 8 (0.21 mmol) in 9 mL of acetic acid.
The suspension was stirred for 1 h and then filtered through
Celite, and the Celite was thoroughly washed with EtOAc. The
combined filtrates were concentrated under reduced pressure.
The residue was dissolved in 10 mL of EtOAc, and the solution
was washed with a saturated aqueous NaHCO3 solution, dried
over Na2SO4, concentrated under reduced pressure, and dried
EtOAc, 8:1); [R]20 ) -9.7 (c 1.1, CHCl3); 1H NMR (200 MHz,
D
CDCl3) δ 7.37-7.34 (m, 2H), 6.37 (s, br, 1H), 5.82 (s, br, 1H),
4.94 (d, 1H, J ) 12.1 Hz), 4.82 (d, 1H, J ) 12.1 Hz), 4.40 (td,
1H, J ) 5.7, 2.9 Hz), 3.38-3.28 (m, 2H), 3.14-3.03 (m, 1H),
2.79-2.72 (m, 2H), 1.32 (d, 3H, J ) 7.0 Hz), 0.81 (s, 9H), -0.05
(s, 6H); 13C NMR (50.3 MHz, CDCl3) δ 209.5, 154.4 + 154.0
(due to rotamers), 143.1, 139.5, 126.6, 109.5, 95.2, 74.9, 63.5
(br), 61.4, 48.3 (br), 43.4, 40.1 + 39.2 (due to rotamers), 25.4,
17.8, 17.1 + 16.3 (due to rotamers), -4.1; HRMS (EI) calcd
for C20H30Cl3NO5Si 497.0959, found 497.0960.
under vacuum to afford 51 mg of pure pipecolate 9: 96% yield;
1
[R]20 ) -23.0 (c 0.3, CH2Cl2); H NMR (CDCl3, 300 MHz) δ
D
7.70 (m, 5H), 4.01 (dd, 1H, J ) 10.7, 3.8 Hz), 3.78 (s, 3H), 3.45
(d, 1H, J ) 10.7 Hz), 2.71 (dq, 1H, J ) 10.8, 6.5 Hz), 2.65 (m,
2H), 1.15 (d, 3H, J ) 6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ
208.0, 171.5, 141.2, 128.7, 128.0, 126.4, 65.6, 60.9, 52.3, 49.9,
47.7, 10.3; HRMS (EI) calcd for C14H17NO3 247.1208, found
247.1213.
Oxid a t ion of F u r a n 5b . Syn t h esis of (-)-Met h yl
(2S,5S,6R)-N-[(2,2,2-Tr ich lor oeth oxy)ca r bon yl]-6-[[(ter t-
b u t yld im et h ylsilyl)oxy]m et h yl]-5-m et h yl-4-oxop ip eco-
la te, 10. To a solution of furan 5b (350 mg, 0.7 mmol) in a
biphasic mixture of 10 mL of acetonitrile, 10 mL of water, and
7 mL of carbon tetrachloride was added 613 mg (2.87 mmol)
of sodium metaperiodate (NaIO4). Then RuCl3‚xH2O (5 mg)
was added, and the mixture was stirred until no starting
material could be detected by TLC (typically 2 h). EtOAc (20
mL) was added to the reaction mixture, and the layers were
separated. The aqueous layer was extracted with additional
EtOAc (2 × 20 mL). The combined organic layers were treated
with Na2SO4 and charcoal and filtered through Celite, and the
solvent was evaporated under reduced pressure to afford the
crude acid that was not further purified. The residue was
dissolved in 15 mL of Et2O and treated with a solution of
freshly prepared diazomethane in ether (3 mmol). After 1 h
the reaction was quenched with 0.5 mL of acetic acid and
neutralized with a saturated aqueous solution of NaHCO3. The
aqueous layer was extracted with EtOAc (2 × 20 mL). The
combined organic layers were dried over Na2SO4, filtered, and
evaporated under reduced pressure. The resulting oily residue
was purified by column chromatography (SiO2, hexane/EtOAc,
8:1) to afford 240 mg (73%) of ester 10 as a yellow oil: Rf )
Desilyla tion of th e Hyd r oxy Gr ou p of 5a . Syn th esis
of (-)-(2R,3S,6S)-N-[(2,2,2-Tr ich lor oeth oxy)ca r bon yl]-2-
(h yd r oxym eth yl)-3-m eth yl-6-p h en yl-4-p ip er id on e, 6. To
a solution of 5a (610 mg, 1.2 mmol) in acetonitrile (15 mL)
cooled to 0 °C was added 10 mL of a 3 N HCl aqueous solution.
The resulting mixture was stirred at room temperature for 2
h. The reaction mixture was diluted with H2O (5 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The
resulting yellow oil was purified by column chromatography.
The desilylated piperidone 6 was isolated in 87% yield (415
mg) as a yellow oil: Rf ) 0.28 (SiO2, hexane/EtOAc, 2:1); [R]18
D
1
) -24.6 (c 1.0, CH2Cl2); H NMR (200 MHz, CDCl3) δ 7.44-
7.26 (m, 5H), 5.81 (t, 1H, J ) 6.0 Hz), 4.82 (s, 2H), 4.43 (dd,
1H, J ) 11.4, 5.6 Hz), 3.65-3.41 (m, 2H), 3.09 (dd, 1H, J )
17.2, 5.4 Hz), 2.93 (dd, 1H, J ) 17.2, 7.0 Hz), 2.64 (qd, 1H, J
) 7.0, 5.0 Hz), 1.27 (d, 3H, J ) 7.0 Hz); 13C NMR (50.3 MHz,
CDCl3) δ 209.4, 155.1, 141.5, 128.8, 127.7, 125.8, 95.0, 75.1,
64.3, 61.0, 54.5, 43.4, 41.5 (br), 15.7; HRMS (EI) calcd for
C
15H15Cl3NO3 (M - CH3O) 362.0118, found 362.0104.
J on es Oxid a tion of th e Hyd r oxy Gr ou p of 6 a n d
Ester ifica tion . Syn th esis of (+)-Meth yl (2R,3S,6S)-N-
[(2,2,2-Tr ich lor oet h oxy)ca r b on yl]-3-m et h yl-6-p h en yl-4-
oxop ip ecola te, 8. J ones reagent was added dropwise to a
yellow solution of 2-(hydroxymethyl)-4-piperidone 6 (200 mg,
0.5 mmol) in acetone (6 mL) at 0 °C until the color of the
reaction mixture remained deep orange. Stirring was contin-
ued for 2 h, and the reaction was quenched by careful addition
of EtOH to destroy the excess of the oxidizing reagent. The
green solid was filtered through Celite and washed with
acetone (2 × 5 mL). The colorless solution was concentrated
under reduced pressure, and the resulting oil was disolved in
H2O (5 mL) and EtOAc (5 mL). The aqueous layer was
extracted with EtOAc (2 × 5 mL). The combined organic
layers were washed with brine (2 × 5 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The foam obtained was redissolved in Et2O and cooled to 0
°C, and a large excess of freshly prepared diazomethane in
Et2O solution was added. After 15 min of stirring, AcOH was
added dropwise to the yellow solution in order to destroy the
excess of diazomethane, followed by brine (5 mL) and EtOAc
(5 mL). The aqueous layer was extracted with EtOAc (2 × 5
0.54 (SiO2, hexane/EtOAc, 4:1); [R]20 ) -1.7 (c 1.0, CHCl3);
D
1H NMR (200 MHz, CDCl3) δ 5.05 (quint, 1H, J ) 4.6 Hz),
4.98-4.66 (m, 2H), 4.43-4.36 (m, 1H), 3.92 (ddd, 1H, J ) 10.5,
4.5, 2.2 Hz), 3.79 (dd, 1H, J ) 5.7, 3.8 Hz), 3.72 (s, 3H), 3.01
(dd, 1H, J ) 17.5, 5.5 Hz), 2.78 (dd, 1H, J ) 17.5, 9.0 Hz),
2.61 (qd, 1H, J ) 7.3, 1.9 Hz), 1.21 (dd, 3H, J ) 7.3, 2.6 Hz),
0.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H); 13C NMR (50.3 MHz,
CDCl3) δ 206.8 + 206.7 (due to rotamers), 170.6 + 170.4 (due
to rotamers), 154.4 + 154.3 (due to rotamers), 95.1 + 94.9 (due
to rotamers), 75.4 + 75.1 (due to rotamers), 65.5 + 65.4 (due
to rotamers), 59.7, 53.6 + 53.3 (due to rotamers), 52.6 + 52.5
(due to rotamers), 44.1 + 44.0 (due to rotamers), 36.1, 25.8,
18.4, 16.5 + 16.3 (due to rotamers), -4.8, -4.9; HRMS (EI)
calcd for C17H27Cl3NO6Si (M - CH3) 474.0673, found 474.0677.
Dep r otection of Tr oc Gr ou p of P ip ecola te 10. Syn -
th esis of (-)-Meth yl (2S,5S,6R)-6-[[(ter t-Bu tyld im eth yl-
silyl)oxy]m et h yl]-5-m et h yl-4-oxop ip ecola t e, 11. The
method is identical to that described above for 9. Compound
10 (180 mg, 0.36 mmol) afforded 112 mg (99%) of pipecolate
11: [R]20D ) -42.1 (c 0.3, CH2Cl2); 1H NMR (CDCl3, 300 MHz)

Enantioselective Synthesis of Pipecolic Derivatives
J . Org. Chem., Vol. 63, No. 12, 1998 3923
δ 3.87 (dd, 1H, J ) 9.9, 2.6 Hz), 3.77 (s, 3H), 3.68 (m, 2H),
2.73 (dd, 1H, J ) 13.8, 3.5 Hz), 2.62 (ddd, J ) 10.4, 6.5, 2.6
Hz), 2.46 (dd, 1H, J ) 13.8, 12.4 Hz), 2.35 (dq, 1H, J ) 10.4,
mL of dry DMF under dry atmosphere was slowly added 300
mg of NaH. The mixture was stirred at 120 °C for 4 h, allowed
to reach rt, and carefully quenched with 20 mL of saturated
aqueous NaHCO3 solution. The organics were extracted with
EtOAc (3 × 40 mL), and the aqueous layer was washed with
brine (3 × 25 mL), dried over Na2SO4, and concentrated under
reduced pressure. Bicyclic carbamate 15 was purified by
column chromatography (SiO2, hexane/EtOAc, 1:1) to obtain
6.5 Hz), 1.05 (d, 3H, J ) 6.5 Hz), 0.92 (s, 9H), 0.10 (s, 6H); 13
C
NMR (CDCl3, 75 MHz) δ 208.6, 171.7, 64.3, 62.8, 57.8, 52.3,
47.0, 44.7, 25.8, 18.2, 9.5; HRMS (EI) calcd for C15H29NO4Si
315.1866, found 315.1867.
Dep r otection of th e TBDMS Gr ou p of P ip ecola te 11.
Syn th esis of (-)-Meth yl (2S,5S,6R)-6-(Hyd r oxym eth yl)-
5-m eth yl-4-oxop ip ecola te, 12. A solution of pipecolate 11
(100 mg, 0.31 mmol) in 15 mL of CH3CN and 15 mL of aqueous
3 N HCl was vigorously stirred for 3 h at room temperature
and neutralized with a saturated NaHCO3 solution. The
organics were extracted with EtOAc (3 × 25 mL), dried over
Na2SO4, and concentrated in a vacuum. The crude residue
was filtered through a short silica gel column (5% MeOH in
530 mg (yield 83%): Rf ) 0.45 (SiO2, hexane/EtOAc, 1:1); [R]20
D
1
) -64 (c 0.3, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.41 (m,
7H), 6.47 (s, 1H), 4.67 (d, 1H, J ) 11.6 Hz), 4.50 (dd, 1H, J )
12.0, 3.0 Hz) 4.47 (d, 1H, J ) 11.6 Hz), 4.31 (m, 1H), 3.82 (m,
2H), 3.70 (m, 1H), 2.22 (dt, 1H, J ) 14.2, 3.5 Hz), 1.85-1.70
(m, 2H), 1.02 (d, 3H, J ) 6.7 Hz); 13C NMR (CDCl3, 75 MHz)
δ 155.9, 142.3, 139.3, 137.9, 127.9, 127.3, 127.1, 123.3, 109.7,
75.0, 70.7, 66.0, 56.9, 44.7, 38.7, 36.2, 12.7; HRMS (EI) calcd
for C19H21NO4 327.1470, found 327.1461.
CH2Cl2) to afford 61 mg (99% yield) of pipecolate 12: [R]20
)
D
-22 (c 0.5, CH2Cl2); 1H NMR (CDCl3, 200 MHz) δ 3.91 (dd,
1H, J ) 10.5, 2.9 Hz), 3.75 (s, 3H), 3.80-3.60 (m, 2H), 2.76
(dd, 1H, J ) 14.1, 3.5 Hz), 2.49 (ddd, 1H, J ) 10.5, 5.5, 2.9
Hz), 2.6-2.4 (m, 2H), 1.05 (d, 3H, J ) 6.5 Hz); 13C NMR
(CDCl3, 75 MHz) δ 208.2, 171.8, 63.9, 62.7, 57.9, 52.6, 46.8,
44.5, 29.7, 9.6; HRMS (EI) calcd for C8H12NO3 (M - CH2OH)
170.0817, found 170.0824.
Ozon olysis of th e F u r a n Rin g. Syn th esis of (-)-
Met h yl (2S,4R,5S,6R)-1-Aza -4-(b en zyloxy)-5-m et h yl-8-
oxa -9-oxobicyclo[4.3.0]n on a n e-2-ca r boxyla te, 16a . Furan
15 (450 mg, 1.37 mmol) was dissolved in a mixture of 60 mL
of CH2Cl2, 10 mL of methanol, 4.5 mL of H2O2 (30% v/v), and
400 mg of NaOH. The solution was stirred for 10 min and
cooled to -78 °C. Then a stream of O3/O2 (300 L/h, 2.5 g of
O3) was bubbled through the solution using a gas diffusion
tube. The ozone stream was mantained until complete disap-
pearance of the starting material was observed by TLC (40
min). The ozonizer was turned off, and the oxygen stream was
maintained for 15 min. The mixture was stirred at room
temperature for 1 h, and the reaction was quenched with 1 N
HCl (30 mL). After addition of 60 mL of CH2Cl2, the aqueous
layer was extracted with CH2Cl2 (3 × 40 mL). The combined
organic layers were dried over Na2SO4, and the solvent was
evaporated under reduced pressure. The crude acid obtained
was dissolved in 40 mL of THF, and a large excess of a freshly
prepared solution of diazomethane (4 mmol) in ether (15 mL)
was added. After 15 min at room temperature 3 mL of AcOH
and 25 mL of water were added successively. The aqueous
layer was extracted with EtOAc (2 × 40 mL). The organic
layers were combined and dried, and the solvent was evapo-
rated to afford a colorless oil that was purified by column
chromatography (SiO2, hexane/EtOAc, 3:1) to afford 288 mg
of ester 16a (67% yield): Rf ) 0.40 (SiO2, hexane/EtOAc, 1:1);
[R]20D ) -52 (c 0.2, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.4-
7.2 (m, 5H), 4.65 (d, 1H, J ) 11.6 Hz), 4.45 (d, 1H, J ) 11.6
Hz), 4.39 (dd, 1H, J ) 8.2, 7.0 Hz), 4.08 (dd, 1H, J ) 11.9, 3.6
Hz) 3.95 (dd, 1H, J ) 8.2, 7.9 Hz), 3.81 (s, 3H), 3.79 (m, 2H),
2.33 (dt, 1H, J ) 14.0, 3.6 Hz), 1.79 (ddd, 1H, J ) 14.0, 11.9,
2.1 Hz), 1.72 (dqd, 1H, J ) 10.6, 6.7, 2.4 Hz), 1.05 (d, 3H, J )
6.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 170.3, 156.4, 137.7, 128.3,
127.8, 127.5, 74.5, 71.2, 67.5, 56.2, 52.5, 51.2, 38.3, 30.7, 13.0;
HRMS (FAB) calcd for C17H22NO5 (M + 1) 320.1497, found
320.1482.
F or m a tion of th e Bicyclic Ca r ba m a te. Syn th esis of
(+)-(2S ,5S ,6R )-1-Aza -2-(3-fu r y l)-5-m e t h y l-8-o x a -4,9-
d ioxobicyclo[4.3.0]n on a n e, 13. Triphosgene (980 mg, 3.3
mmol) was slowly added to an ice-cooled solution of hydrox-
ypiperidone 3b (700 mg, 3.3 mmol) in 40 mL of THF. Then, a
solution of triethylamine (0.93 mL, 6.6 mmol) in 15 mL of THF
was added dropwise. After 30 min of stirring, the reaction
was quenched with water (20 mL) and extracted with EtOAc
(3 × 40 mL). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The result-
ing residue was purified by column chromatography (SiO2,
CH2Cl2/EtOAc, 8:1) to give rise to 736 mg of carbamate 13
(yield 95%): Rf ) 0.45 (SiO2, CH2Cl2/EtOAc, 4:1), [R]20D ) +18
(c 0.9, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.37 (m, 2H),
6.41 (s, 1H), 4.95 (dd, 1H, J ) 5.8, 4.9 Hz), 4.4 (m, 1H), 4.00
(m, 2H), 2.94 (dd, 1H, J ) 15.6, 5.8 Hz), 2.80 (dd, 1H, J )
15.6, 4.9 Hz), 2.48 (m, 1H), 1.06 (d, 3H, J ) 7.8 Hz); 13C NMR
(CDCl3, 75 MHz) δ 206.5, 156.0, 143.5, 139.5, 124.9, 109.0,
67.3, 58.4, 48.0, 46.3, 44.0, 10.0; HRMS (EI) calcd for C12H13NO4
235.0844, found 235.0840.
Red u ction of th e Ca r bon yl Gr ou p . Syn th esis of (-)-
(2S,4R,5S,6R)-1-Aza-2-(3-fu r yl)-4-h ydr oxy-5-m eth yl-8-oxa-
9-oxobicyclo[4.3.0]n on a n e, 14. A solution of ketone 13 (730
mg, 3.1 mmol) in 25 mL of dry THF was cooled to -80 °C. A
solution of K-Selectride (1 M) in THF (5 mmol, 5 mL) was
added dropwise, and the mixture stirred for 60-90 min (the
reaction can be monitored by TLC and quenched when the spot
of the starting material has disappeared). The reaction was
quenched with 5 mL of water, and the cold bath was removed.
Once the reaction mixture reached rt, EtOH (3 mL) and 3 N
NaOH (4 mL) were added. After 5 min, the mixture was
treated with 5 mL of H2O2 (30% vol), and the stirring continued
for 20 min. The mixture was then treated with 10 mL of
saturated aqueous Na2CO3 solution, and the organics were
extracted with EtOAc (3 × 40 mL). The organic layers were
dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography (SiO2,
Ester ifica tion of th e Cr u d e Acid via F or m a tion of th e
Acid Ch lor id e: Syn th esis of (-)-Eth yl (2S,4R,5S,6R)-1-
Az a -4 -(b e n z y l o x y )-5 -m e t h y l -8 -o x a -9 -o x o b i c y c l o -
[4.3.0]n on a n e-2-ca r boxyla te, 16b. After the ozonolysis
described above, the crude acid was dissolved in 30 mL of dry
CH2Cl2, treated with 0.5 mL of oxalyl chloride, and refluxed
for 4 h. The hot bath was removed, and the volatiles were
evaporated under vacuum. The resulting residue was redis-
solved in 20 mL of CH2Cl2, and 5 mL of dry ethanol were added
to the solution. After 2 h of stirring at room temperature, the
reaction was quenched with saturated NaHCO3, and the
organics were extracted with CH2Cl2, dried over Na2SO4, and
concentrated in a vacuum. The carboxylic ester was then
purified by column chromatography (SiO2, hexane/EtOAc, 3:1)
to afford 283 mg of ester 16b: 62% yield; Rf ) 0.43 (SiO2,
CH2Cl2/EtOAc, 4:1) to obtain 721 mg (98%) of 14: Rf ) 0.1
1
(SiO2, hexane/EtOAc, 1:1); [R]20 ) -58.9 (c 0.4, CH2Cl2); H
D
NMR (CDCl3, 300 MHz) δ 7.40 (s, 2H), 6.43 (s, 1H), 4.58 (dd,
1H, J ) 10.3, 4.8 Hz), 4.35 (t, 1H, J ) 7.3 Hz), 4.01 (td, 1H, J
) 2.6, 2.1 Hz), 3.85 (m, 2H), 1.95 (m, 2H), 1.71 (qdd, 1H, J )
10.3, 6.7, 2.1 Hz), 1.01 (d, 3H, J ) 6.7 Hz); 13C NMR (CDCl3,
75 MHz) δ 156.5, 142.6, 139.7, 123.4, 109.9, 67.9, 66.4, 56.5,
44.6, 40.9, 39.0, 12.8; HRMS (EI) calcd for C12H15NO4 237.1001,
found 237.0994. Anal. Calcd for C12H15NO4: C, 61.27; H, 5.57;
N, 5.95. Found: C, 61.07; H, 5.60; N, 5.89.
hexane/EtOAc, 1:1); [R]20 ) -38.3 (c 0.12, CH2Cl2); 1H NMR
D
(CDCl3, 300 MHz) δ 7.37-7.31 (m, 5H), 4.68 (d, 1H, J ) 12.0
Hz), 4.43 (d, 1H, J ) 12.0 Hz), 4.39 (dd, 1H, J ) 8.2, 7.3 Hz),
4.33-4.22 (m, 3H), 4.05 (dd, 1H, J ) 12.2, 3.4 Hz), 3.95 (t,
1H, J ) 8.2 Hz), 3.80-3.70 (m, 2H), 2.32 (dt, 1H, J ) 14.2, 3.4
Hz), 1.78 (ddd, 1H, J ) 14.2, 12.2, 2.1 Hz), 1.75-1.63 (m, 1H),
1.31 (t, 3H, J ) 7.3 Hz), 0.99 (d, 3H, J ) 6.9 Hz); 13C NMR
Alk yla tion of 14. Syn th esis of (-)-(2S,4R,5S,6R)-1-Aza -
4 -( b e n z y l o x y ) -2 -( 3 -f u r y l ) -5 -m e t h y l -8 -o x a -9 -o x o -
bicyclo[4.3.0]n on a n e, 15. To a solution of alcohol 14 (475
mg, 1.95 mmol) and benzyl bromide (5.7 mmol, 0.7 mL) in 25

3924 J . Org. Chem., Vol. 63, No. 12, 1998
Barluenga et al.
(CDCl3, 75 MHz) δ 169.8, 156.9, 137.8, 128.3, 127.8, 127.5,
74.6, 71.2, 67.5, 61.6, 56.3, 51.4, 38.0, 13.9, 13.1; HRMS (EI)
calcd for C18H23NO5 333.1576, found 333.1567.
(-)-(2S,4R,5S,6R)-1-Aza -4-(ben zyloxy)-5-m eth yl-8-oxa -
9-oxobicyclo[4.3.0]n on a n e-2-ca r boxylic a cid , 20: [R]20
)
D
-46 (c 0.4, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.34 (m,
5H), 4.68 (d, 1H, J ) 11.6 Hz), 4.42 (m, 2H), 4.09 (dd, 1H, J )
12.0, 3.0 Hz), 3.95 (t, 1H, J ) 8.6 Hz), 3.77 (m, 1H), 3.72 (m,
1H), 2.40 (dt, 1H, J ) 13.8, 3.0 Hz), 1.79 (m, 1H), 1.70 (m,
1H), 0.96 (d, 3H, J ) 6.8 Hz); 13C NMR (CDCl3, 75 MHz) δ
173.4, 157.2, 137.7, 128.4, 127.8, 127.6, 74.4, 71.2, 67.9, 56.4,
51.3, 38.2, 30.9, 13.0; HRMS (FAB) calcd for C16H20NO5
306.1341, found 306.1352.
Syn th esis of (-)-Ben zyl (2S,4R,5S,6R)-1-Aza -4-(ben zyl-
oxy)-5-m eth yl-8-oxa -9-oxobicyclo[4.3.0]n on a n e-2-ca r box-
yla te, 16c. The procedure is identical to that described for
the ethyl ester 16b. Once the acid chloride had been redis-
solved in CH2Cl2, 2 mL of benzyl alcohol was added to the
solution. After 2 h of stirring at room temperature, the
reaction was quenched with 15 mL of a saturated aqueous
NaHCO3 solution, and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The combined organic layers were dried
over Na2SO4, filtered, and evaporated under reduced pressure.
The excess of benzyl alcohol was eliminated by Kugelro¨hr
distillation (10-3 Torr, 100 °C). The ester was purified by
column chromatography (SiO2, hexane/EtOAc, 4:1) to afford
(-)-(2R,4R,5S,6R)-1-Aza -4-(ben zyloxy)-5-m eth yl-8-oxa -
9-oxobicyclo[4.3.0]n on a n e-2-ca r boxylic a cid , 21: [R]20
)
D
-48 (c 0.4, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.4 (m, 5H),
4.62 (d, 1H, J ) 12 Hz), 4.50 (m, 2H), 4.29 (d, 1H, J ) 12 Hz),
4.00 (m, 1H), 3.92 (m, 1H), 3.58 (m, 1H), 2.78 (m, 1H), 1.75
(m, 1H), 1.53 (m, 1H), 0.95 (d, 3H, J ) 6.7 Hz); 13C NMR
(CDCl3, 75 MHz) δ 175.9, 157.1, 136.6, 128.4, 127.6, 127.2,
74.2, 70.8, 67.7, 52.6, 48.8, 39.6, 28.9, 13.2; HRMS (FAB) calcd
for C16H20NO5 (M + 1) 306.1341, found 306.1348.
330 mg (61%) of 16c: Rf ) 0.15 (SiO2, hexane/EtOAc, 4:1);
1
[R]20 ) -43.7 (c 0.5, CH2Cl2); H NMR (CDCl3, 300 MHz) δ
D
7.5-7.3 (m, 10H), 5.25 (s, 2H), 4.65 (d, 1H, J ) 11.9 Hz), 4.43
(d, 1H, J ) 11.9 Hz), 4.39 (dd, 1H, J ) 8.2, 7.0 Hz), 4.13 (dd,
1H, J ) 12.2, 3.0 Hz), 3.95 (dd, 1H, J ) 8.2, 8.0 Hz), 3.8-3.7
(m, 2H), 2.33 (dt, 1H, J ) 14.3, 3.6 Hz), 1.82 (ddd, 1H, J )
14.3, 12.2, 2.1 Hz), 1.72 (dqd, 1H, J ) 10.6, 6.8, 2.1 Hz), 0.99
(d, 3H, J ) 6.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 169.7, 156.5,
137.7, 135.3, 128.5, 128.4, 128.3, 128.2, 127.7, 127.4, 74.6, 71.2,
67.4, 67.3, 56.2, 51.3, 38.2, 30.7, 12.9; HRMS (EI) calcd for
Clea va ge of th e Cyclic Ca r ba m a te. Syn th esis of Hy-
d r oxya m in o Acid s 18 a n d 19. Carboxylic acid 20 or 21 (80
mg, 0.26 mmol) was dissolved in 8 mL of dry THF under N2
t
atmosphere. A sonicated solution of BuOK in 2 mL of dry
THF was added dropwise, and the mixture refluxed for 60 min.
The solution was poured into a mixture of 3 N HCl aqueous
solution (10 mL) and ether (5 mL). The organic layer was
discarded. The aqueous layer was evaporated to dryness
under vacuum, and the organic material was extracted with
methanol (10 mL). The methanol solution was filtered through
Celite and concentrated to afford the hydrochloric salt of the
hydroxyamino acid, which was desalted by ion-exchange
chromatography as follows: A column was loaded with Dowex
50Wx8-100 ion-exchange resin and washed with water until
neutral pH. Then the hydrochloric salt was dissolved in 1 mL
of water and loaded into the column. The column was eluted
with water until the pH of the eluent coming out of the column
was neutral. Then, the column was eluted with 20% am-
monium hydroxide aqueous solution. The basic fractions were
collected and concentrated under vacuum to afford 54 mg of
the hydroxyamino acid 18 or 19 (yield 75%). By this procedure
were prepared the following.
C
23H25NO5 395.1733, found 395.1739.
Ep im er iza tion of 16. Syn th esis of Ca r boxylic Ester s
17. A solution of ester 16 (0.24 mmol) in 15 mL of THF was
cooled to 0 °C with an ice bath. Then a sonicated solution of
tBuOK (108 mg, 0.96 mmol) in 5 mL of dry THF was added
dropwise, and the solution was stirred for 30 min and poured
into a 3 N HCl aqueous solution (10 mL). The organics were
extracted with EtOAc (3 × 15 mL) and the combined organic
layers washed with brine, dried over Na2SO4, and concentrated
in a vacuum to afford essentially pure ester 17, which can be
further purified by filtration through a short chromatographic
column (SiO2). By this method were prepared the following.
E t h yl (2R,4R,5S,6R)-1-Aza -4-(b en zyloxy)-5-m et h yl-8-
oxa -9-oxobicyclo[4.3.0]n on a n e-2-ca r boxyla te, 17b. Com-
pound 16b (50 mg) afforded 48 mg of 17b (yield 96%): Rf )
0.32 (SiO2, hexane/EtOAc, 1:1); 1H NMR (CDCl3, 300 MHz) δ
7.36-7.23 (m, 5H), 4.62 (d, 1H, J ) 11.8 Hz), 4.51 (t, 1H, J )
7.3 Hz), 4.48 (dd, 1H, J ) 6.8, 1.6 Hz), 4.31 (d, 1H, J ) 11.8
Hz), 4.07-3.85 (m, 4H), 3.62-3.57 (m, 1H), 2.85 (ddd, 1H, J
) 14.6, 3.4, 1.6 Hz), 1.76 (ddd, J ) 14.6, 6.8, 1.3 Hz), 1.56 (dqd,
1H, J ) 10.1, 6.9, 1.4 Hz), 1.12 (t, 3H, J ) 7.3 Hz), 0.95 (d,
3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 170.3, 156.9, 137.8, 128.4,
128.1, 127.4, 74.4, 70.8, 67.8, 61.4, 52.6, 49.1, 39.7, 29.6, 13.8,
13.3; HRMS (EI) calcd for C18H23NO5 333.1576, found 333.1578.
(-)-Ben zyl (2R,4R,5S,6R)-1-Aza -4-(ben zyloxy)-5-m eth -
yl-8-oxa -9-oxob icyclo[4.3.0]n on a n e-2-ca r b oxyla t e, 17c.
Compound 16c (65 mg) afforded 63 mg (97%) of 17c: Rf )
(-)-(2S,4R,5S,6R)-4-[(Ben zyloxy)m et h yl]-6-(h yd r oxy-
m eth yl)-5-m eth ylp ip ecolic a cid , 19: [R]20 ) -23 (c 0.5,
D
H2O); 1H NMR (D2O, 300 MHz) δ 7.4 (m, 5H), 4.94 (d, 1H, J )
12.0 Hz), 4.68 (d, 1H, J ) 12.0 Hz), 4.2-4.0 (m, 3H), 3.89 (dd,
1H, J ) 12.4, 5.6 Hz), 3.45 (m, 1H), 2.85 (m, 1H), 2.2-1.9 (m,
2H), 1.18 (d, 3H, J ) 6.7 Hz); 13C NMR (D2O, 75 MHz) δ 174.3,
138.4, 129.2, 129.1, 128.6, 74.3, 71.1, 59.9, 55.0, 53.4, 34.0, 27.2,
13.9; HRMS (FAB) calcd for C15H22NO4 (M + 1) 280.1549,
found 280.1549.
(-)-(2R,4R,5S,6R)-4-[(Ben zyloxy)m et h yl]-6-(h yd r oxy-
m eth yl)-5-m eth ylp ip ecolic a cid , 18: [R]20 ) -12 (c 0.2,
D
0.29 (SiO2, hexane/EtOAc, 1:1); [R]20 ) -43 (c 0.5, CH2Cl2);
D
H2O); 1H NMR (D2O, 300 MHz) δ 7.5 (m, 5H), 4.85 (d, 1H, J )
11.6 Hz), 4.48 (d, 1H, J ) 11.6 Hz), 4.2-3.8 (m, 5H), 3.03 (m,
1H), 2.2-2.0 (m, 2H), 1.11 (d, 3H, J ) 7.0 Hz); 13C NMR (D2O,
75 MHz) δ 173.0, 137.2, 128.0, 127.9, 127.4, 73.1, 69.8, 58.7,
53.7, 52.1, 32.7, 26.0, 12.7; HRMS (EI) calcd for C14H18NO3
(M - CH2OH) 248.1286, found 248.1273.
1H NMR (CDCl3, 300 MHz) δ 7.4-7.1 (m, 10H), 4.98 (d, 1H, J
) 12.2 Hz), 4.83 (d, 1H, J ) 12.2 Hz), 4.6-4.45 (m, 3H), 4.29
(dd, 1H, J ) 9.1 Hz), 4.1-3.9 (m, 2H), 3.60 (m, 1H), 2.83 (ddd,
1H, J ) 14.5, 3.6, 1.5 Hz), 1.78 (dd, 1H, J ) 14.5, 7.0, 1.8 Hz),
1.55 (m, 1H), 0.95 (d, 3H, J ) 6.7 Hz); 13C NMR (CDCl3, 75
MHz) δ 170.3, 156.9, 137.8, 135.1, 128.4, 128.3, 128.2, 128.0,
127.6, 127.4, 74.2, 70.7, 67.9, 67.1, 52.6, 49.2, 39.6, 29.2, 13.2;
HRMS (EI) calcd for C23H25NO5 395.1733, found 395.1742.
Clea va ge of Ben zyl Ester s. Syn th esis of Ca r boxylic
Acid s 20 a n d 21. A flask containing the benzyl ester 16c or
17c (120 mg, 0.30 mmol) and 10% Pd/C (50 mg) and capped
with a rubber septum was evacuated with the aid of a needdle
and filled with hydrogen with a balloon. After the operation
was repeated twice, 10 mL of EtOH was added to the flask
through the septum with a syringe and a needle. The mixture
was stirred at room temperature for 90 min when the balloon
and the septum were removed. The solution was filtered
through Celite, the Celite was washed with 15 mL of ethanol,
and the combined filtrates were concentrated under vacuum
to afford 92 mg (99% yield) of pure carboxylic acid 20 or 21,
respectively. Using this procedure were prepared the follow-
ing.
Ack n ow led gm en t. Financial support of this work
was provided by Comisio´n Asesora de Investigacio´n
Cient´ıfica y Te´cnica DGICYT of Spain (PB-92 1005). A
FICYT predoctoral fellowship to C.R. from the regional
government of Asturias is gratefully acknowledged.
Su p p or t in g In for m a t ion Ava ila b le: Copies of the 13C
NMR spectra of all the compounds described (20 pages). This
material is contained in libraries on microfiche, inmediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O9722414