Synthesis of Enantiopure 4-Hydroxypipecolate and 4-Hydroxylysine Derivatives from a Common 4,6-Dioxopiperidinecarboxylate Precursor

Article abstract of DOI:10.1021/jo0353886

tert-Butyl 2-substituted 4,6-dioxo-1-piperidinecarboxylates 4 have been prepared in good yield starting from Boc-Asp-O^tBu and other β-amino acids. By analogy with chiral tetramic acids, their reduction by NaBH₄ in CH₂Cl₂/AcOH afforded the corresponding cis-4-hydroxy δ-lactams in good yield and stereoselectivity (68-98% de). In the absence of the A(1,3) strain (reduction of 6-substituted 2,4-dioxo-1-piperidines 7), the cis-4-hydroxy isomer was still obtained as the major product but the de values were consistently lower. 4-Hydroxy-6-oxo- 1,2-piperidinedicarboxylate 2a, readily accessible from Boc-Asp-O^tBu (three steps, 63% overall yield), has proven to be an excellent building block for the synthesis of cis- and trans-4-hydroxypipecolates 17 and 24 (52 and 36% overall yield, respectively) and for the synthesis of a protected 4-hydroxylysine derivative 29 (41% overall yield).

Full text of DOI:10.1021/jo0353886

Syn th esis of En a n tiop u r e 4-Hyd r oxyp ip ecola te a n d
4-Hyd r oxylysin e Der iva tives fr om a Com m on
4,6-Dioxop ip er id in eca r boxyla te P r ecu r sor
J . Marin,†,‡ C. Didierjean,§ A. Aubry,§ J .-R. Casimir,†,¶ J .-P. Briand,† and G. Guichard*,†
UPR 9021 CNRS, Immunologie et Chimie The´rapeutiques, Institut de Biologie Mole´culaire et Cellulaire,
15 rue Rene´ Descartes, F-67084 Strasbourg Cedex, France, Neosystem, 7 rue de Boulogne,
F-67100 Strasbourg, France, and ESA 7036 CNRS, LCM3B, Universite´ Henri Poincare´,
BP239, F-54509 Vandoeuvre, France
g.guichard@ibmc.u-strasbg.fr
Received September 23, 2003
tert-Butyl 2-substituted 4,6-dioxo-1-piperidinecarboxylates 4 have been prepared in good yield
starting from Boc-Asp-OtBu and other â-amino acids. By analogy with chiral tetramic acids, their
reduction by NaBH4 in CH2Cl2/AcOH afforded the corresponding cis-4-hydroxy δ-lactams in good
yield and stereoselectivity (68-98% de). In the absence of the A(1,3) strain (reduction of 6-substituted
2,4-dioxo-1-piperidines 7), the cis-4-hydroxy isomer was still obtained as the major product but
the de values were consistently lower. 4-Hydroxy-6-oxo-1,2-piperidinedicarboxylate 2a , readily
accessible from Boc-Asp-OtBu (three steps, 63% overall yield), has proven to be an excellent building
block for the synthesis of cis- and trans-4-hydroxypipecolates 17 and 24 (52 and 36% overall yield,
respectively) and for the synthesis of a protected 4-hydroxylysine derivative 29 (41% overall yield).
In tr od u ction
idines,8 quinolizidine,9 and isoquinolizidine10 skeletons
as well as δ-amino acids.11 Therefore, a number of
The piperidin-2-one ring structure is a common struc-
tural feature in many natural products,1 in synthetic
molecules of biological interest2 (e.g., HIV protease
inhibitors,2a glycosidase inhibitors,2b thrombin inhibitors,2c
antagonists of the neurokinin-2 receptor,2d and fibrinogen
receptor antagonists2e), as well as in dipeptide surrogates
and various constrained peptidomimetics.3,4 In addition,
functionalized piperidin-2-ones are useful and versatile
building blocks in organic synthesis. They serve as
precursors in the synthesis of key constituents of bioac-
tive molecules such as higher membered lactams,5 enan-
tiopure substituted piperidines,6 pipecolic acids,7 indoliz-
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† Institut de Biologie Mole´culaire et Cellulaire.
‡ Neosystem.
§ Universite´ Henri Poincare´.
¶
Present address: Theraptosis, Pasteur BioTop, Institut Pasteur,
25-28 rue du Dr. Roux, 75724 Paris, France.
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Chan, F. Y.; Gaspar, C. H.; Marlier, M.; Braekman, J . C.; Daloze, D.;
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Williams, P. G.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J . J . Nat. Prod.
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10.1021/jo0353886 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/10/2003
130
J . Org. Chem. 2004, 69, 130-141

Synthesis of Enantiopure Derivatives
approaches have been investigated for the preparation
of substituted δ-lactams in enantiomerically pure form.12
Although chiral auxiliaries have been utilized with great
success,13 amino acids proved to be particularly useful
precursors for the asymmetric synthesis of substituted
piperidin-2-ones.
As part of a program dedicated to the synthesis of
enantiopure natural and unnatural hydroxylysine de-
rivatives for incorporation into biologically relevant pep-
tides (e.g., glycosylated peptides derived from type II
collagen), we became interested in the stereocontrolled
synthesis of N-acylated δ-lactams 1 and 2 (R1 ) COOR,
R2 ) H), monohydroxylated at the R and â positions, and
in their use as possible and flexible intermediates for the
synthesis of 5- and 4-hydroxylysine derivatives, respec-
tively. This group of lactams has not received much
orientation, thus providing a high diastereofacial bias for
further asymmetric transformation. Second, the ring can
be opened smoothly by hydrolysis16 or under reductive
conditions14 to afford substituted δ-amino acids and
ꢀ-amino alcohols, respectively. We have now investigated
2,4-dioxo-1-piperidinecarboxylates 4 as novel chiral educts
for the asymmetric synthesis of enantiopure 4-hydroxy-
2-oxo-1-piperidinecarboxylates 2. Although the corre-
sponding five-membered-ring 2,4-dioxo-1-pyrrolidinecar-
boxylates (chiral tetramic acid)17 obtained from Meldrum’s
acid and N-protected R-amino acids have received con-
siderable attention as precursors in the synthesis of
statine [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic
acid] derivatives (their stereocontrolled reduction leading
exclusively to the cis-4-hydroxy derivative), few reports
have been made of the synthesis and reactivity of their
six-membered counterparts.18 Two syntheses of 4-hydrox-
ypiperidin-2-ones as a novel entry to compounds incor-
porating a 4-hydroxypiperidine unit have been published
recently.6h,7a The approach reported by Davis and co-
workers is based on the selective reduction of enantiopure
6-phenylpiperidin-2,4-diones prepared from the corre-
sponding N-sulfinyl δ-amino â-keto esters and has been
applied to the synthesis of alkaloid SS20846 as well as
to the naturally occurring cis- and trans-4-hydroxypipe-
colic acids.7a Although flexible, this method suffers from
the need of a chiral N-sulfinyl imine as a chiral auxiliary
to generate the starting optically pure δ-amino â-keto
ester. Herein, we report the practical synthesis of tert-
butyl 2-substituted 4,6-dioxo-1-piperidinecarboxylates 4
starting from Asp and various â-amino acids as well as
their stereoselective reduction to the corresponding 4-hy-
droxy derivatives. The reduction of the corresponding
6-substituted 2,4-dioxo-1-piperidine 7 was also studied
to determine what the facial selectivity would be in the
absence of the A(1,3) strain. 4-Hydroxy-6-oxo-1,2-pip-
eridinedicarboxylate 2a (R1 ) COOtBu, R2 ) H), readily
accessible in high yield from Boc-Asp-OtBu, was a useful
precursor for the synthesis of 4-hydroxylysine derivatives.
In view of the importance of 4-hydroxypipecolic acids as
constituents of antibiotics and a number of potential
therapeutic agents such as NMDA agonists, HIV protease
inhibitors (palinavir), as well as TNF-R-converting en-
zyme (TACE) inhibitors,19 we also report an expedient
synthesis of enantiopure cis-4-hydroxypipecolic acid20
starting from the same lactam precursor.
attention so far. Starting from aspartic acid (Asp) as a
cheap and commercially available chiral building block,
we recently reported a convenient synthesis of enan-
tiopure (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxy-
late, a key intermediate in the synthesis of (2S,5R)-5-
hydroxylysine.14 Asymmetricoxidation ofenolates generated
from enantiopure 6-oxo-1-piperidinecarboxylate 3 was
used to introduce the hydroxyl group at the 5 position.14
N-acylated δ-lactams such as 3 are particularly useful
for two reasons: first, as a consequence of the minimiza-
tion of pseudoallylic A(1,3) strain,15 the ring substituent
at the δ position is believed to adopt a pseudoaxial
(10) For selected examples, see: (a) Casamitjana, N.; Amat, M.; Llor,
N.; Carreras, M.; Pujol, X.; Ferna´ndez, M. M.; Lo´pez, V.; Molins, E.;
Miravitlles, C.; Bosch, J . Tetrahedron: Asymmetry 2003, 14, 2033-
2039. (b) Dias, L. C.; Fernandes, A. M. A. P.; Zukerman-Schpector, J .
Synlett 2002, 1, 100-104. (c) Allin, S. M.; Vaidya, D. G.; J ames, S. L.;
Allard, J . E.; Smith, T. A. D.; McKee, V.; Martin, W. P. Tetrahedron
Lett. 2002, 43, 3661-3663. (d) Roussi, F.; Quirion, J .-C.; Tomas, A.;
Husson, H.-P. Tetrahedron 1998, 54, 10363-10378. (e) Torisawa, Y.;
Nakagawa, M.; Hosaka, T.; Tanabe, K.; Lai, Z.; Ogata, K.; Nakata, T.;
Oishi, T.; Hino, T. J . Org. Chem. 1992, 57, 5741-5747.
(11) Kende, A. S.; Dong, H.-Q.; Mazur, A. W.; Ebetino, F. H.
Tetrahedron Lett. 2001, 42, 6015-6018. (b) Casimir, J . R.; Didierjean,
C.; Aubry, A.; Rodriguez, M.; Briand, J .-P.; Guichard, G. Org. Lett.
2000, 2, 895-897. (c) Muller, M.; Schoenfelder, A.; Didier, B.; Mann,
A.; Wermuth, C.-G. Chem. Commun. 1999, 683-684. (d) Karla, R.;
Ebert, B.; Thorkildsen, C.; Herdeis, C.; J ohansen, T. N.; Nielsen, B.;
Krogsgaard-Larsen, P. J . Med. Chem. 1999, 42, 2053-2059. (e)
Rodriguez, M.; Aumelas, A.; Martinez, J . Tetrahedron Lett. 1990, 31,
5153-5156.
Resu lts a n d Discu ssion
Syn th esis of N-Acyla ted 4,6-Dioxop ip er id in es. By
analogy with the synthesis of chiral tetramic acids from
(15) For reviews on the allylic A(1,3) strain, see: (a) Hoffmann, R.
H. Angew. Chem., Int. Ed. Engl. 1992, 31, 1124-1134. (b) Hoffmann,
R. H. Chem. Rev. 1989, 89, 1841-1860.
(16) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983, 48,
2424-2426.
(17) For representative examples, see: (a) J ouin, P.; Castro, B. J .
Chem. Soc., Perkin Trans. 1 1987, 1177-1182. (b) Fehrentz, J .-A.;
Bourdel, E.; Califano, J .-C.; Chaloin, O.; Devin, C.; Garrouste, P.; Lima-
Leite, A.-C.; Llinares, M.; Rieunier, F.; Vizavonna, J .; Winternitz, F.;
Loffet, A.; Martinez, J . Tetrahedron Lett. 1994, 35, 1557-1560. (c)
Galeotti, N.; Poncet, J .; Chiche, L.; J ouin, P. J . Org. Chem. 1993, 58,
5370-5376. (d) Decicco, C. P.; Grover, P. J . Org. Chem. 1996, 61, 3534-
3541. (d) Ma, D.; Ma, J .; Ding, W.; Dai, L. Tetrahedron: Asymmetry
1996, 7, 2365-2370.
(12) For a recent review, see: Weintraub, P. M.; Sabol, J . S.; Kane,
J . M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989.
(13) Meyers, A. I.; Brengel, G. P. J . Chem. Soc., Chem. Commun.
1997, 1-7. (b) Micouin, L.; J ullian, V.; Quirion, J .-C.; Husson, H.-P.
Tetrahedron: Asymmetry 1996, 7, 2839-2846. (c) Enders, D.; Bartzen,
D. Liebigs Ann./ Recl. 1997, 1115-1123. (d) Enders, D.; Gro¨bner, R.;
Raabe, G.; Runsink, J . Synthesis 1996, 941-948.
(14) Marin, J .; Didierjean, C.; Aubry, A.; Briand, J .-P.; Guichard,
G. J . Org. Chem. 2002, 67, 8440-8449.
(18) Murray, P. J .; Starkey, I. D. Tetrahedron Lett. 1996, 37, 1875-
1878.
J . Org. Chem, Vol. 69, No. 1, 2004 131

Marin et al.
TABLE 1 a
compound
R1
R2
purified yield (%)
F IGURE 1. Keto and enol tautomers 4a and 6a with the
crystal structure of 6a .
4a
4b
4c
4d
4e
4f
COOtBu
COOBn
H
H
77
85
68
87
63
93
H
H
H
H
iBu
Bn
iPr
Me
The C2-C12 bond (carboxylate side chain) forms an
angle of 5.4(2)° with the normal to the mean plane of the
ring atoms in 6a , confirming the expected axial orienta-
tion of the C2 ring substituent because of the minimiza-
tion of the allylic A(1,3) strain. The piperidine ring in 6a
assumes a sofalike conformation, with the C2 atom
deviating by 0.599(3) Å from the least-squares plane
defined by the five other atoms. The hydroxyl group at
the 4 position, the unique potential strong proton donor
of 6a , is involved in the crystal packing as previously
described for 6e.22 Strong hydrogen bonds involving this
hydroxyl group at C4 and the carbonyl oxygen at position
C6 [d(O‚‚‚O): 2.625(2) Å] as a proton acceptor link the
molecules in infinite C(6)23 chains running along the b
axis.
Dia ster eoselective Red u ction Stu d ies. N-acylated
chiral tetramic acids can be reduced stereoselectively to
the corresponding cis-4-hydroxy derivatives either by
treatment with NaBH4 in CH2Cl2/AcOH17a-c or by hy-
drogenation with PtO2 (Adam’s catalyst) in EtOAc.17d
Herein, both procedures have been evaluated for the
reduction of N-acylated 4,6-dioxopiperidines 4. Treatment
of 4 with NaBH4 in CH2Cl2/AcOH (9:1) for 72 h resulted
in a quantitative reduction of the keto functionality24 and
gave the expected 4-hydroxylated adduct 2 with de values
in the range of 68-98% as determined by HPLC of the
crude products (Table 2).
The selectivity of the reaction is significantly influ-
enced by the bulk of the side chain at C2, with the lowest
and highest selectivities being observed for the methyl
and isopropyl groups, respectively. In the case of the
carboxylate side chains, the tert-butyl ester group in 4a
exerts a stronger stereodirecting effect than the corre-
sponding benzyl ester. Compounds 2a and 2c were
obtained in diastereomerically pure form (>99% de)
following a single recrystallizaton step (Table 2), and
their absolute configuration at C4 was confirmed by X-ray
crystal structure determination. Compound 2a (Figure
2) adopts a chair conformation with atoms N1 and C4
displaced on opposite sides of the C2, C3, C5, and C6
mean plane by -0.355(4) and 0.657(1) Å, respectively.
The hydroxyl- and tert-butylcarboxylate groups in the 4
and 6 positions of the piperidine ring assume an axial
orientation, as can be seen from the angles [5.7(2)° and
16.8(1)°] between the normal to the mean plane of the
ring atoms and the bonds C4-O1 and C2-C12, respec-
tively.25 The rules governing the crystal packing of 6a
a
(a) Meldrum’s acid, EDC, DMAP, CH2Cl2; (b) AcOEt, reflux.
R-amino acids,17 condensation of N-protected 3-amino-
propanoic acids with Meldrum’s acid in the presence of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDC) and DMAP, followed by cyclization at 80
°C in ethyl acetate, provides a convenient and short entry
to enantiopure N-acylated 4,6-dioxopiperidines 4. Diox-
opiperidines 4a -f were prepared in good to excellent
yields starting from the protected Asp derivatives 5a ,b
and â3-amino acids 5c-f (Table 1). While purification of
4b required chromatography on silica gel,21 all other
compounds (4a and 4c-f) were recovered in an analyti-
cally pure form by simple crystallization from CH2Cl2/
pentane.
Dioxopiperidines 4 exist in equilibrium with the ther-
modynamically stable enol form 6 (Figure 1). Very similar
to what is observed with other 1,3-dicarbonyl compounds
and N-protected chiral tetramic acids in particular, the
1
keto form 4 exclusively is populated in CDCl3 , while H
and 13C NMR in DMSO-d6 show only the enol form 6.
X-ray diffraction studies on crystals of 4a and 4e grown
from AcOEt/hexane reveal the enol tautomers 6a (Figure
1) and 6e.22 Both structures share very similar structural
features.
(19) (a) Mannaioni, G.; Alesiani, M.; Carla`, V.; Natalini, B.; Marinozzi,
M.; Pellicciari, R.; Moroni, F. Eur. J . Pharmacol. 1994, 251, 201-207.
(b) Lamarre, D.; Croteau, G.; Wardrop, E.; Bourgon, L.; Thibeault, D.;
Clouette, C.; Vaillancourt, M.; Cohen, E.; Pargellis, C.; Yoakim, C.;
Anderson, P. C. Antimicrob. Agents Chemother. 1997, 41, 965-971.
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2002, 12, 1387-1390
(20) For previous syntheses of cis-4-hydroxypipecolates, see: (a)
Reference 7a. (b) Lloyd, R. C.; Smith, M. E. B.; Brick, D.; Taylor, S. J .
C.; Chaplin, D. A.; McCague, R. Org. Process Res. Dev. 2002, 6, 762-
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(24) No reduction took place when 4a was treated with NaBH4 in
the absence of AcOH.
(21) For an earlier synthesis of compound 4b, see ref 18.
(22) Didierjean, C.; Marin, J .; Wenger, E.; Briand, J . P.; Aubry, A.;
Guichard, G. Acta Crystallogr. 2003, in press.
(25) In contrast, the hydroxyl and isobutyl groups in the crystal
structure of 2c assume an equatorial orientation (ref 22).
132 J . Org. Chem., Vol. 69, No. 1, 2004

Synthesis of Enantiopure Derivatives
TABLE 2. Red u ction of N-Acyla ted
4,6-Dioxop ip er id in es 4
TABLE 3. Red u ction of 6-Su bstitu ted
2,4-Dioxop ip er id in e 7
yieldb
(%)
dioxopiperidine
R1
R2
R3
R4 dra of 8 yieldb (%)
dioxopiperidine
R1
R2 R3 R4
dra of 2
7b
7c
7d
7e
7f
COOBn
H
OH
H
H
H
H
H
21:79
82:18
84:16
84:16
80:20
89
62
86
49
37
COOtBu
COOBn
H
H
OH
OH
H
H
H
7:93 (0:100)c 89 (82)c
15:85 85
H
H
H
H
iBu
Bn
iPr
Me
OH
OH
OH
OH
4a
4b
4c
4d
4e
4f
H
H
H
H
iBu
Bn
iPr
Me
OH 90:10 (100:0)d 93 (71)d
H
OH 91:9
91
95
87
H
H
OH >99:1
OH 84:16
a
(2S,4R)-8/(2S,4S)-8; ratio determined by analytical C18 RP-
b
HPLC of the crude product. Mixture of (2S,4R)-8 and (2S,4S)-8
a
obtained after purification of the crude product by a flash column
chromatography.
(2S,4R)-2/(2S,4S)-2; ratio determined by analytical C18 RP-
b
HPLC of the crude product. Mixture of (2S,4R)-2 and (2S,4S)-2
obtained after purification of the crude product by a flash column
chromatography. c Values in parentheses are for (2S,4S)-2a iso-
lated by recrystallization. Values in parentheses are for (2S,4R)-
SCHEME 1 a
d
2c isolated by recrystallization.
a
(a) PtO2, H2, AcOEt, 1 atm.
of the side chain at C6 (Table 3). A similar selectivity
(85:15 cis/trans) was reported by Davis and co-workers
in the reduction of the related enantiopure (R)-6-phen-
ylpiperidine-2,4-dione.7a
In contrast to N-acylated chiral tetramic acids,17d
hydrogenation of N-acylated 4,6-dioxopiperidines 4 with
Adam’s catalyst in EtOAc failed to yield the expected
4-hydroxylated derivatives. Hydrogenation of 4a and 4f
resulted in the quantitative formation of the fully reduced
N-acylated piperidin-2-ones 927 and 10 (Scheme 1).
Changing the solvent (THF, CHCl3) or the amount of
catalyst (5-15%) did not improve the selectivity of the
reaction, and the yields of 2a and 2f were consistently
below 10%. Monitoring the progression of the reaction
by C18 RP-HPLC revealed that 9 starts to form im-
mediately. Its amount increased as the starting material
was consumed, with the amount of 2a remaining low.
No reaction took place when Adam’s catalyst was re-
placed by Pd on C or by Pearlman’s catalyst.
F IGURE 2. ORTEP-3 view of 2a with the atom numbering
scheme and 25% probability displacement ellipsoids. H atoms
except those of the piperidine ring are omitted for clarity.
and 2a are similar to those of the hydrogen-bonded
molecules of 2a forming zigzag C(7) chains.
The reduction of the corresponding 7 in a fashion
similar to substituted cyclohexanones26 is believed to be
driven by the torsional effects that favor attack of the
hydride reagent across the axial face of the CdO.
Dioxopiperidines 7 were prepared in quantitative yield
by the treatment of 4 with trifluoroacetic acid, and their
reduction was studied under the same conditions for
comparison (Table 3). Overall, yields of 4-hydroxylated
product 8 were lower. In the absence of the A(1,3) strain,
the cis-4-hydroxyl isomer is still obtained as the major
product, thus confirming attack across the axial face of
the CdO, but the de values were lower (58-68%). The
stereoselectivity is essentially independent of the bulk
In an attempt to further improve the selectivity of the
reduction of 4a to 2a with a view to synthesize 4-hy-
droxypipecolate and 4-hydroxylysine derivatives, other
reducing agents (Table 4) were examined. Of all the other
borohydride reagents considered, NaBH4 gave the best
results. Substituting NaBH(OAc)3 for NaBH4 (entry 2)
(26) Hutchins, R. O.; Su, W. Y.; Sivakumar, R.; Cistone, F.; Stercho,
Y. P. J . Org. Chem. 1983, 48, 3412-3422.
(27) For another route to δ-lactam 9 from 5a in 74% yield, see ref
14.
J . Org. Chem, Vol. 69, No. 1, 2004 133

Marin et al.
SCHEME 2 a
TABLE 4. Effect of th e Bor oh yd r id e Rea gen t a n d th e
Ca r boxylic Acid on th e Red u ction of 4a
carboxylic time
yieldb
(%)
entry reducing agent
acid
(h)
dra of 2a
1
2
3
4
NaBH4
aceticc
aceticc
aceticc
aceticc
72 7:93 (>99)d 89 (82)d
NaBH(OAc)3
Me4NBH(OAc)3
NaBH3CN
72 4:96
16
61
0e
16 25:75
93
a
(2S,4R)-2a /(2S,4S)-2a ; ratio determined by analytical C18 RP-
a
(a) TBSCl, imidazole, CH2Cl2; (b) LiEt3BH, THF, -78 °C; (c)
Et3SiH, Et2O‚BF3, CH2Cl2, -78 °C.
b
HPLC of the crude product. Mixture of (2S,4R)-2a and (2S,4S)-
2a obtained after purification of the crude product by a flash
column chromatography. c A total of 10% v/v of acetic acid.
SCHEME 3 a
d
Values in parentheses are for (2S,4S)-2a isolated by recrystal-
lization. e Degradation of the starting material.
improved the stereoselectivity, but the reaction never
reached completion. It is worth mentioning that replacing
Na+ with the bulkier Me4N+ countercation28 resulted in
complete degradation of 4a , and no hydroxylated product
was obtained (entry 3).29 When NaBH3CN was used, the
reduction was completed within 16 h, but the de was only
50% (entry 4).
The nature of the carboxylic acid exerts a moderate
effect on the stereoselectivity of the reaction (in the
Supporting Information). However, pivalic acid gave
slightly better results than AcOH (dr 95:5, yield 93%).
(2S,4R)-4-Hyd r oxyp ip ecola te a n d (2S,4S)-4-Hy-
d r oxyp ip ecola te Syn th eses. With (2S,4S)-4-hydroxy-
6-oxo-1,2-piperidinedicarboxylate 2a in hand, we first
envisioned its two-step conversion into 4-hydroxypipe-
colate 17 via the corresponding hemiaminal. This method
had previously been reported for the reduction of pyro-
glutamates to proline derivatives30 and N-Boc-protected
piperidin-2-ones to pipecolates18,30c in high yields. How-
ever, partial reduction of 2a with LiEt3BH (super hy-
dride) did not provide the desired hemiaminal but gave
the degradation byproducts. Protection of the secondary
alcohol prior to the reduction was mandatory. The
resulting hemiaminal 12 was isolated in 75% and char-
a
(a) BH3‚SMe2, THF, rt; (b) HCl, dioxane; (c) FmocOSu, K2CO3,
acetone/H2O.
Alternatively, direct reduction of 2a with BH3‚SMe2
was considered.31 Although this reagent achieves com-
plete reduction of the lactam functionality in one single
step, it has not often been used. The possible reasons
could be the need for heating and the long reaction times.
Nevertheless, in our hands, lactam 2a was cleanly
reduced in 16 h at room temperature and yielded pure
15 in quantitative yield after workup (Scheme 3).
Simultaneous deprotection of the Boc and tert-butyl
ester functional groups yielded the (2S,4R)-4-hydroxy-
pipecolic acid (16). Protection of the secondary amine by
a (fluorenylmethoxy)carbonyl (Fmoc) group afforded the
cis-hydroxypipecolate 17 in an overall yield of 52%,
starting from the Asp derivative 5a . Although the
synthesis of 17 described in the experimental part is on
a relatively small scale (ca. 250 mg), the procedure was
also found to be suitable for a larger batch synthesis (10-
50 g).
1
acterized by H and 13C NMR. The reduction of crude 12
with Et3SiH/Et2O‚BF3 proved to be difficult because of
the partial removal of the TBS group. The desired
hydroxypipecolate 13 was finally recovered in low yield
together with the pipecolate 14 (Scheme 2). Compound
14 was unambiguously characterized by COSY NMR
experiments. Because compounds 13 and 14 are ex-
tremely close on TLC and almost inseparable by chro-
matography, this route was not investigated further.
For the preparation of the corresponding trans-(2S,4S)-
4-hydroxypipecolate, we initially tried to invert the C4
stereocenter directly on 2a under Mitsunobu conditions.32
(28) Me4NBH(OAc)3 has been described as an excellent reagent for
the reduction of â-hydroxy ketones. Evans, D. A.; Chapman, K. T.;
Carreira, E. M. J . Am. Chem. Soc. 1988, 110, 3560-3578.
(29) In contrast, the reduction of 4c with Me4NBH(OAc)3 resulted
in a clean deprotection of the Boc group to give 4,6-dioxopiperidine 8c
in 84% yield. Didierjean, C.; Marin, J .; Wenger, E.; Briand, J . P.; Aubry,
A.; Guichard, G. Acta Crystallogr. 2003, in press.
(30) For recent examples, see: (a) Oba, M.; Miyakawa, A.; Nish-
iyama, K. J . Org. Chem. 1999, 64, 9275-9278. (b) Oba, M.; Terauchi,
T.; Miyakawa, A.; Nishiyama, K. Tetrahedron: Asymmetry 1999, 10,
937-945. (c) Escribano, A.; Carren˜o, C.; Garc`ıa Ruano, J . L. Tetra-
hedron Lett. 1994, 35, 2053-2056.
(31) For examples of a lactam ring reduction with BH3‚SMe2, see:
(a) Courcambeck, J .; Bihel, F.; De Michelis, C.; Que´ve´ler, G.; Kraus,
J .-L. J . Chem. Soc., Perkin Trans. 1 2001, 1421-1430. (b) Moody, C.
M.; Young, D. W. J . Chem. Soc., Perkin Trans. 1 1997, 3519-3530. (c)
Herdeis, C.; Hubmann, H. P. Tetrahedron: Asymmetry 1994, 5, 351-
354. (d) Moody, C. M.; Young, D. W. Tetrahedron Lett. 1994, 35, 7277-
7280. (e) Moody, C. M.; Starkmann, B. A.; Young, D. W. Tetrahedron
Lett. 1994, 35, 5485-5488. (f) Heffner, R. J .; J oullie´, M. M. Tetrahedron
Lett. 1989, 30, 7021-7024.
(32) Mitsunobu, O. Synthesis 1981, 1-28.
134 J . Org. Chem., Vol. 69, No. 1, 2004

Synthesis of Enantiopure Derivatives
SCHEME 4 a
SCHEME 6 a
a
(a) PNBOH, DIAD, PPh3, THF.
SCHEME 5 a
a
(a) TPSCl, imidazole, CH2Cl2; (b) NaBH4, EtOH; (c) MsCl,
Et3N, CH2Cl2; (d) NaN3, DMF; (e) TFA/CH2Cl2 (1:1); (f) FmocOSu,
K2CO3, acetone/H2O.
oxo-1,2-piperidinedicarboxylate (1) (R1 ) COOR, R2 ) H),
which could be opened directly using sodium borohydride
in ethanol to give the corresponding 1,2-diol in high yield,
the ring opening of 2a under the same conditions failed
to give the desired 1,3-diol derivative. Instead, triol 25,
a
(a) CH2ClCOOH, DIAD, PPh3, THF; (b) 1 N NaOH, dioxane/
H2O; (c) HCl, dioxane; (d) FmocOSu, K2CO3, acetone/H2O.
1
unambiguously characterized by H and 13C NMR, was
isolated as the major side product in 32% yield.
Unfortunately, all of our attempts resulted in â elimina-
tion and yielded R,â-unsaturated lactam 1833 as the sole
product. Starting from cis-hydroxypipecolate, the inver-
sion reaction has already been mentioned, but not fully
described.34 Herein, treatment of 15 with p-nitrobenzoic
acid under Mitsunobu conditions gave the desired pipe-
colate 19 with an inverted configuration at C4 in 53%
yield, together with the 3,4-unsaturated pipecolate 20.
Both pipecolates 19 and 20 were unambiguously char-
acterized by X-ray diffraction studies (Scheme 4 and the
Supporting Information).
Chloroacetic acid was subsequently found to be the best
acid to promote inversion at C4.35 The Mitsunobu reac-
tion of 15 with chloroacetic acid afforded chloroacetate
21, which was immediately cleaved under basic condi-
tions to give the corresponding trans-4-hydroxypipecolate
22 in 70% yield (two steps). Deprotection of the N-Boc
and tert-butyl ester functional groups yielded (2S,4S)-4-
hydroxypipecolic acid 23, which was reprotected in 24
with a yield of 57% from 15 (Scheme 5).
However, upon protection of the secondary alcohol by
a TPS prior to the reduction, the O-protected 1,3-diol 27
could be obtained in 85% yield from 2a . After purification
by filtration through a short plug of silica, the primary
alcohol was converted to the corresponding azide by
mesylation followed by nucleophilic substitution with
NaN3. The azide can serve as a temporary protection for
the amino group of 4-hydroxylysine; the reduction of the
azide function being quantitatively and cleanly performed
on the solid support at the end of the elongation of the
peptidic chain.36 Selective deprotection of N-Boc and tert-
butyl ester protecting groups in the presence of tert-
butyldiphenylsilyl directly followed by protection of the
primary amine with a Fmoc functionality gave (2S,4R)-
4-hydroxylysine 29, which was ready for use in a peptide
synthesis in 41% overall yield from 5a (Scheme 6).
(2S,4R)-4-Hyd r oxylysin e a n d (2S,4S)-4-Hyd r oxy-
lysin e Syn th eses. In contrast to (2S,5R)-5-hydroxy-6-
Con clu sion
Enantiopure N-acylated δ-lactams 1 (R1 ) COOtBu,
R2 ) H)14 and 2a (this paper), monohydroxylated at the
R and â positions, respectively, represent attractive
(33) Enantiopure N-acylated 2-substituted 4,5-unsaturated 6-ox-
opiperidines are useful building blocks, which can be further trans-
formed in a stereocontrolled manner to give the corresponding 4-sub-
stituted derivatives. For the conjugate addition of organocuprate
reagents, see refs 6h and 11c. For the conjugate addition of nitro-
alkanes, see: (a) Hanessian, S.; Seid, M.; Nilsson, I. Tetrahedron Lett.
2002, 43, 1991-1994.
(35) The inversion reaction in the presence of formic acid (ref 34)
gave a lower yield of the corresponding trans-hydroxypipecolate.
(36) (a) Meldal, M.; J uliano, M. A.; J ansson, A. M. Tetrahedron Lett.
1997, 38, 2531-2534. (b) Lundquist, J . T.; Pelletier, J . C. Org. Lett.
2001, 3, 781-783.
(34) Bellier, B.; Da Nascimento, S.; Meudal, H.; Gincel, E.; Roques,
B. P.; Garbay, C. Bioorg. Med. Chem. Lett. 1998, 8, 1419-1424.
J . Org. Chem, Vol. 69, No. 1, 2004 135

Marin et al.
2-Ben zyl 1-ter t-Bu tyl (2S)-4,6-Dioxo-1,2-p ip er id in ed i-
ca r boxyla te (4b). Purification of the crude product by flash
column chromatography [AcOEt/Hex/AcOH (5:5:0.1)] gave 4b
(2.19 g, yield ) 85%): HPLC tR 9.05 (linear gradient, 30-100%
building blocks for the synthesis of 5- and 4-hydroxy-
lysine derivatives, conveniently protected for a solid-
phase peptide synthesis or for further transformations
(e.g., glycosylation). Their direct precursors 3 (R1
)
1
B, 20 min); colorless oil; [R]D +76.1 (c 1.0, CHCl3); H NMR
COOtBu, R2 ) H) and 4a are easily prepared [3 (R1 )
COOtBu, R2 ) H), 74% yield (three steps);14 4a , 77% yield
(two steps)] following a divergent approach starting from
the readily available Boc-Asp-OtBu, which is first con-
densed with Meldrum’s acid. X-ray analyses confirmed
that in lactams 3 and 4 the carboxylate side chain at the
δ position adopts a quasi-axial orientation (because of the
minimization of the pseudoallylic A(1,3) strain), which
is useful to differentiate both faces of the molecule in view
of subsequent asymmetric transformations. Herein, we
found that di-tert-butyl (2S)-4,6-dioxo-1,2-piperidinedi-
carboxylate (4a ) was reduced by NaBH4 in CH2Cl2/AcOH
in a manner similar to those of the five-membered-ring
tetramic acids to afford the corresponding cis-4-hydroxy-
lated derivatives 2a in good yield and selectivity. The ring
opening under reductive conditions (NaBH4, EtOH) fol-
lowing protection of the hydroxyl group gave the 1,3-diol
27, which was further transformed to the 4-hydroxylysine
derivative 29. Alternatively, by treatment with BH3‚
SMe2, 2a was quantitatively transformed to the enan-
tiopure cis-4-hydroxypipecolic acid 16, an amino acid
constituent of natural antibiotics and several drug can-
didates.
(300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.24 (dd, J ) 6.9, 2.0
Hz, 1H), 5.19 (s, 2H), 3.45 (d, J ) 19.4, Hz, 1H), 3.31 (d, J )
19.4 Hz, 1H), 3.04 (dd, J ) 17.9, 2.0 Hz, 1H), 2.84 (dd, J )
17.9, 6.9 Hz, 1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
199.8 (C), 169.9 (C), 165.1 (C), 151.1 (C), 134.5 (C), 128.8 (CH),
128.7 (CH), 128.5 (CH), 128.4 (CH), 128.0 (CH), 84.9 (C), 68.3
(CH2), 53.9 (CH), 50.5 (CH2), 40.5 (CH2), 27.8 (3CH3). Anal.
Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C,
62.32; H, 6.07; N, 4.19.
ter t-Bu t yl (2S)-2-Isob u t yl-4,6-d ioxo-1-p ip er id in eca r -
boxyla te (4c). Recrystallization of the crude product from
CH2Cl2/pentane gave 4c (2.69 g, yield ) 68%): HPLC tR 8.61
(linear gradient, 30-100% B, 20 min); colorless crystals; [R]D
-78.9 (c 1.0, CHCl3); mp 116-119 °C; 1H NMR (300 MHz,
CDCl3) δ 4.69-4.63 (m, 1H), 3.45 (d, J ) 20.7 Hz, 1H), 3.35
(d, J ) 20.7 Hz, 1H), 2.75 (dd, J ) 16.8, 5.3 Hz, 1H), 2.65 (dd,
J ) 16.8, 2.6 Hz, 1H), 1.63-1.51 (m, 2H), 1.53 (s, 9H), 1.39-
1.30 (m, 1H), 0.92 (d, J ) 6.2 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 202.4 (C), 166.2 (C), 151.5 (C), 84.1 (C), 50.2 (CH),
49.1 (CH2), 43.7 (CH2), 43.0 (CH2), 27.9 (3CH3), 25.1 (CH), 23.1
(CH3), 21.5 (CH3). Anal. Calcd for C14H25NO4: C, 62.43; H,
8.61; N, 5.20. Found: C, 62.80; H, 8.67; N, 5.08.
ter t-Bu tyl (2S)-2-Ben zyl-4,6-d ioxo-1-p ip er id in eca r box-
yla te (4d ). Recrystallization of the crude product from CH2-
Cl2/pentane gave 4d (567 mg, yield ) 87%): HPLC tR 9.12
(linear gradient, 30-100% B, 20 min); yellowish crystals; [R]D
-92.6 (c 1.0, CHCl3); mp 130-132 °C; 1H NMR (300 MHz,
CDCl3) δ 7.30-7.24 (m, 3H), 7.16-7.13 (m, 2H), 4.79-4.73 (m,
1H), 3.37 (d, J ) 20.7 Hz, 1H), 3.26 (d, J ) 20.8 Hz, 1H), 3.07
(dd, J ) 13.3, 5.1 Hz, 1H), 2.69 (dd, J ) 13.3, 9.5 Hz, 1H),
2.64 (m, 2H), 1.53 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 202.2
(C), 166.1 (C), 151.5 (C), 135.9 (C), 129.5 (2CH), 128.9 (2CH),
127.3 (CH), 84.2 (C), 53.5 (CH), 49.1 (CH2), 42.1 (CH2), 41.0
(CH2), 27.9 (3CH3). Anal. Calcd for C17H21NO4: C, 67.31; H,
6.98; N, 4.62. Found: C, 67.57; H, 7.09; N, 4.51.
ter t-Bu tyl (2S)-2-Isop r op yl-4,6-d ioxo-1-p ip er id in eca r -
boxyla te (4e). Recrystallization of the crude product from
CH2Cl2/pentane gave 4e (645 mg, yield ) 63%): HPLC tR 7.32
(linear gradient, 30-100% B, 20 min); white crystals; [R]D
-67.7 (c 1.0, CHCl3); mp 101-103 °C; 1H NMR (300 MHz,
CDCl3) δ 4.41-4.35 (m, 1H), 3.44 (d, J ) 20.7 Hz, 1H), 3.33
(d, J ) 20.7 Hz, 1H), 2.82 (dd, J ) 17.0, 2.4 Hz, 1H), 2.67 (dd,
J ) 17.0, 5.7 Hz, 1H), 1.80-1.68 (m, 1H), 1.53 (s, 9H), 0.98 (d,
J ) 6.7 Hz, 3H), 0.94 (d, J ) 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 202.7 (C), 166.2 (C), 152.3 (C), 84.0 (C), 57.1 (CH),
49.2 (CH2), 41.9 (CH2), 33.0 (CH), 27.9 (3CH3), 19.6 (CH3), 19.5
(CH3). Anal. Calcd for C13H21NO4: C, 61.16; H, 8.29; N, 5.49.
Found: C, 61.00; H, 8.52; N, 5.37.
Exp er im en ta l Section
Ma ter ia ls. Boc-Asp-OtBu (5a )37 was prepared starting from
the commercially available Boc-Asp(Bn)-OH. â-Amino acid
derivatives 5d -g were prepared by Arndt-Eister homologa-
tion of the Boc-protected R-amino acids.38
P r ep a r a tion of 4,6-Dioxop ip er id in es 4a -f. EDC (1.5
equiv), DMAP (1.5 equiv), and Meldrum’s acid (1.0 equiv) were
added to a 0.25 M solution of acid 5 in CH2Cl2 at 0 °C. The
mixture was allowed to reach room temperature, stirred for 3
h, and then washed with 1 N KHSO4. The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was dissolved in AcOEt to afford a 0.1 M solution,
which was refluxed for 5 h. After being allowed to cool to room
temperature, the mixture was washed with 1 N KHSO4 and
brine. Drying over Na2SO4 and evaporation of the filtrate
afforded crude 4, which was purified by recrystallization or
flash chromatography.
Di-ter t-b u t yl-(2S)-4,6-d ioxo-1,2-p ip er id in ed ica r b oxy-
la te (4a ). Recrystallization of the crude product from CH2Cl2/
pentane gave 4a (5.82 g, yield ) 77%): HPLC tR 8.14 (linear
gradient, 30-100% B, 20 min); yellowish crystals; [R]D +98.0
(c 1.0, CHCl3); mp 124-126 °C; 1H NMR (300 MHz, CDCl3) δ
5.04 (dd, J ) 6.8, 2.2 Hz, 1H), 3.50 (d, J ) 19.5 Hz, 1H), 3.34
(d, J ) 19.5 Hz, 1H), 2.99 (dd, J ) 17.5, 2.2 Hz, 1H), 2.81 (dd,
J ) 17.6, 6.8 Hz, 1H), 1.52 (s, 9H), 1.43 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 200.1 (C), 168.9 (C), 165.4 (C), 151.2 (C), 84.6
(C), 83.9 (C), 54.6 (CH), 50.3 (CH2), 40.9 (CH2), 27.9 (3CH3),
27.8 (3CH3). Anal. Calcd for C15H23NO6: C, 57.50; H, 7.40; N,
4.47. Found: C, 57.36; H, 7.48; N, 4.38.
ter t-Bu tyl (2S)-2-Meth yl-4,6-d ioxo-1-p ip er id in eca r box-
yla te (4f). Recrystallization of the crude product from CH2-
Cl2/pentane gave 4f (625 mg, yield ) 93%): HPLC tR 13.17
(linear gradient, 30-100% B, 20 min); white crystals; [R]D
1
-108.5 (c 1.0, CHCl3); mp 127-129 °C; H NMR (300 MHz,
CDCl3) δ 4.71-4.65 (m, 1H), 3.45 (d, J ) 20.7 Hz, 1H), 3.33
(d, J ) 20.7 Hz, 1H), 2.81 (dd, J ) 16.7, 5.9 Hz, 1H), 2.55 (dd,
J ) 16.6, 2.2 Hz, 1H), 1.53 (s, 9H), 1.31 (d, J ) 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 202.2 (C), 165.9 (C), 151.5 (C),
84.1 (C), 49.0 (CH2), 48.0 (CH), 45.3 (CH2), 27.9 (3CH3), 20.5
(CH3). Anal. Calcd for C11H17NO4: C, 58.14; H, 7.54; N, 6.16.
Found: C, 57.96; H, 7.51; N, 6.38.
Di-ter t-bu tyl (2S)-4-Hydr oxy-6-oxo-3,6-dih ydr o-1,2(2H)-
p yr id in ed ica r boxyla te (6a ): 1H NMR (300 MHz, (CD3)2SO)
δ 4.92 (d, J ) 1.8 Hz, 1H), 4.81 (dd, J ) 6.9, 1.7 Hz, 1H), 3.34
(bs, 1H), 3.00 (ddd, J ) 17.7, 6.9, 1.8 Hz, 1H), 2.59 (dd, J )
17.7, 1.7 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.0 (C), 169.3 (C), 164.5 (C), 152.4 (C), 96.7 (CH),
82.0 (C), 81.8 (C), 55.4 (CH), 30.7 (CH2), 28.1 (3CH3), 27.9
(3CH3).
Gen er a l P r oced u r e for 4,6-Dioxop ip er id in e Red u c-
tion . The desired dioxopiperidine was placed in an argon-filled
round-bottom flask, dissolved in distilled CH2Cl2 to give a ca.
0.15 M solution, and cooled to 0 °C. The indicated carboxylic
acid was introduced via a hypodermic syringe, and the mixture
was stirred for 5 min. The indicated amount of reducing agent
was added portionwise, and the mixture was allowed to reach
(37) Mathias, L. J . Synthesis 1979, 561-576. (b) Bergmeier, S. C.;
Cobas, A. A.; Rapoport, H. J . Org. Chem. 1993, 58, 2369-2376.
(38) Podlech, J .; Seebach, D. Liebigs Ann. 1995, 1217-1228.
136 J . Org. Chem., Vol. 69, No. 1, 2004

Synthesis of Enantiopure Derivatives
room temperature. The reaction time was specific to each
experiment. The reaction was quenched by the addition of
water and stirred for 10 min. CH2Cl2 was evaporated and
replaced by AcOEt, and the organic layer was washed with a
saturated NaHCO3 solution, water, and brine. The organic
layer was dried over Na2SO4, concentrated, and purified by
recrystallization or flash chromatography.
0.89 (d, J ) 3.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1
(C), 153.2 (C), 83.6 (C), 64.0 (CH), 58.6 (CH), 43.2 (CH2), 31.2
(CH2), 30.7 (CH), 27.8 (3CH3), 18.9 (CH3), 16.0 (CH3). Anal.
Calcd for C13H23NO4: C, 60.68; H, 9.01; N, 5.44. Found: C,
60.96; H, 9.21; N, 5.35.
ter t-Bu t yl (2S,4R)-2-Met h yl-4-h yd r oxy-6-oxo-1-p ip e-
r id in eca r boxyla te (2f). Purification of the crude product by
flash column chromatography [AcOEt/Hex (8:2)] gave 2f (83
mg, yield ) 87%): HPLC tR 11.56 (linear gradient, 5-65% B,
20 min); colorless oil; [R]D +35.3 (c 1.0, CHCl3); 1H NMR (300
MHz, CDCl3) δ 4.12-4.05 (m, 2H), 2.79 (ddd, J ) 16.4, 7.3,
2.0 Hz, 1H), 2.46 (dd, J ) 16.6, 9.0 Hz, 1H), 2.28-2.19 (m,
1H), 2.25 (bs, 1H), 1.72-1.60 (m, 1H), 1.51 (s, 9H), 1.34 (d, J
) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.6 (C), 152.9
(C), 83.6 (C), 64.0 (CH), 50.1 (CH), 43.0 (CH2), 38.7 (CH2), 27.8
(3CH3), 21.8 (CH3). Anal. Calcd for C11H19NO4: C, 57.62; H,
8.35; N, 6.11. Found: C, 57.51; H, 8.51; N, 6.05.
P r ep a r a tion of 4,6-Dioxop ip er id in es 7b -f. The desired
dioxopiperidine was placed in an argon-filled round-bottom
flask and dissolved in distilled CH2Cl2 to give a ca. 0.15 M
solution. The same volume of trifluoroacetic acid was intro-
duced via a hypodermic syringe, and the mixture was stirred
for 2 h at room temperature. The solvents were evaporated,
and the residue was purified by filtration through a plug of
silica.
Ben zyl (2S)-4,6-Dioxo-2-p ip er id in eca r b oxyla t e (7b ).
Purification of the crude product by filtration on silica (AcOEt)
gave 7b (106 mg, yield ) 99%): TLC Rf 0.22 (AcOEt); white
solid; [R]D +50.2 (c 1.1, MeOH); mp 102-103 °C; 1H NMR (300
MHz, CDCl3) δ 7.42 (bs, 1H), 7.41-7.29 (m, 5H), 5.19 (m, 2H),
4.41-4.36 (m, 1H), 3.33 (d, J ) 20.0 Hz, 1H), 3.24 (d, J ) 20.0
Hz, 1H), 2.88 (dd, J ) 16.9, 5.7 Hz, 1H), 2.72 (dd, J ) 16.9,
10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 200.9 (C), 169.8
(C), 168.8 (C), 134.4 (C), 128.9 (CH), 128.8 (2CH), 128.5 (2CH),
68.2 (CH2), 50.7 (CH), 47.5 (CH2), 40.7 (CH2). Anal. Calcd for
Di-ter t-bu tyl (2S,4S)-4-Hyd r oxy-6-oxo-1,2-piper idin ed i-
ca r boxyla te (2a ). Recrystallization of the crude product from
CH2Cl2/diisopropyl ether gave 2a (820 mg, yield ) 82%, de >
99%): HPLC tR 6.19 (linear gradient, 30-100% B, 20 min);
colorless crystals; [R]D -18.0 (c 1.0, CHCl3); mp 132-134 °C;
1H NMR (300 MHz, CDCl3) δ 4.61 (dd, J ) 6.5, 4.1 Hz, 1H),
4.23 (m, 1H), 2.74 (dd, J ) 17.4, 4.8 Hz, 1H), 2.69 (bs, 1H),
2.60 (ddd, J ) 17.4, 4.6, 1.6 Hz, 1H), 2.41-2.33 (m, 1H), 2.20
(ddd, J ) 14.1, 6.6, 2.9 Hz, 1H), 1.48 (s, 9H), 1.44 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 171.0 (C), 168.9 (C), 151.8 (C), 83.4
(C), 82.4 (C), 63.9 (CH), 56.2 (CH), 43.2 (CH2), 32.9 (CH2), 27.9
(3CH3), 27.8 (3CH3). Anal. Calcd for C15H25NO6: C, 57.13; H,
7.99; N, 4.44. Found: C, 56.85; H, 7.95; N, 4.44.
2-Ben zyl 1-ter t-Bu tyl (2S,4S)-4-Hyd r oxy-6-oxo-1,2-p i-
p er id in ed ica r boxyla te (2b). Purification of the crude prod-
uct by flash column chromatography [AcOEt/AcOH (10:0.1)]
gave 2b (86 mg, yield ) 85%): HPLC tR 7.87 (linear gradient,
30-100% B, 20 min); colorless oil; [R]D -19.8 (c 1.2, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.34-7.30 (m, 5H), 5.19 (d, J )
12.3 Hz, 1H), 5.10 (d, J ) 12.3 Hz, 1H), 4.78 (dd, J ) 6.6, 3.7
Hz, 1H), 4.28-4.23 (m, 1H), 2.75 (dd, J ) 17.4, 4.8 Hz, 1H),
2.63 (ddd, J ) 17.5, 3.8, 1.8 Hz, 1H), 2.53-2.44 (m, 1H), 2.22
(ddd, J ) 14.2, 6.4, 2.5 Hz, 1H), 1.41 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 171.8 (C), 169.0 (C), 151.7 (C), 135.3 (C), 128.5
(2CH), 128.3 (CH), 128.3 (2CH), 83.7 (C), 67.4 (CH2), 63.5 (CH),
55.5 (CH), 43.0 (CH2), 32.9 (CH2), 27.8 (3CH3). Anal. Calcd
for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.76;
H, 6.67; N, 3.99.
C
13H13NO4: C, 63.15; H, 5.30; N, 5.67. Found: C, 63.16; H,
ter t-Bu tyl (2S,4R)-4-Hyd r oxy-2-isobu tyl-6-oxo-1-p ip e-
r id in eca r boxyla te (2c). Recrystallization of the crude prod-
uct from CH2Cl2/pentane gave 2c (572 mg, yield ) 71%, de >
99%): HPLC tR 7.51 (linear gradient, 30-100% B, 20 min);
colorless crystals; [R]D +66.3 (c 1.0, CHCl3); mp 94-95 °C; 1H
NMR (300 MHz, CDCl3) δ 4.18-4.09 (m, 2H), 2.82 (ddd, J )
16.6, 5.7, 1.8 Hz, 1H), 2.59 (m, 1H), 2.48 (dd, J ) 16.6, 8.7 Hz,
1H), 2.30-2.21 (m, 1H), 1.71-1.57 (m, 3H), 1.51 (s, 9H), 0.92
(d, J ) 4.2 Hz, 3H), 0.90 (d, J ) 4.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) 170.0 (C), 152.4 (C), 83.4 (C), 64.1 (CH), 52.6
(CH), 44.8 (CH2), 43.3 (CH2), 35.5 (CH2), 27.9 (3 CH3), 24.8
(CH), 23.8 (CH3), 21.2 (CH3). Anal. Calcd for C14H25NO4: C,
61.97; H, 9.29; N, 5.16. Found: C, 62.10; H, 9.48; N, 5.22.
5.47; N, 5.64.
(2S)-2-Isobu tyl-4,6-d ioxop ip er id in e (7c). Purification of
the crude product by filtration on silica [CH2Cl2/MeOH (9:1)]
gave 7c (645 mg, yield ) 100%): TLC Rf 0.52 [CH2Cl2/MeOH
(9:1)]; white solid; [R]D +30.6 (c 1.0, MeOH); mp 122-124 °C;
1H NMR (300 MHz, CDCl3) δ 7.55 (bs, 1H), 3.75 (m, 1H), 3.29
(m, 2H), 2.70 (dd, J ) 16.3, 4.2 Hz, 1H), 2.34 (dd, J ) 16.3,
8.8 Hz, 1H), 1.77-1.68 (m, 1H), 1.56-1.47 (m, 1H), 1.42-1.34
(m, 1H), 0.95 (d, J ) 2.7 Hz, 3H), 0.93 (d, J ) 2.7 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 202.5 (C), 170.6 (C), 47.1 (CH), 46.7
(CH2), 44.5 (CH2), 44.4 (CH2), 24.3 (CH), 22.4 (CH3), 22.1 (CH3).
Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found:
C, 64.16; H, 9.00; N, 8.24.
ter t-Bu t yl (2S,4R)-2-Ben zyl-4-h yd r oxy-6-oxo-1-p ip e-
r id in eca r boxyla te (2d ). Purification of the crude product by
flash column chromatography [AcOEt/Hex (6:4)] gave 2d (92
mg, yield ) 91%): HPLC tR 8.51 (linear gradient, 30-100%
(2S)-2-Ben zyl-4,6-d ioxop ip er id in e (7d ). Purification of
the crude product by filtration on silica (AcOEt) gave 7d (67
mg, yield ) 100%): TLC Rf 0.24 (AcOEt); white solid; [R]D +9.2
(c 1.0, MeOH); mp 156-158 °C; 1H NMR (300 MHz, CDCl3) δ
7.35-7.26 (m, 3H), 7.18-7.15 (m, 2H), 7.06 (bs, 1H), 3.95-
3.88 (m, 1H), 3.24 (d, J ) 20.1 Hz, 1H), 3.12 (dd, J ) 20.1, 0.6
Hz, 1H), 2.87-2.84 (m, 2H), 2.66 (dd, J ) 16.2, 4.5 Hz, 1H),
2.43 (ddd, J ) 16.1, 8.5, 0.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 202.8 (C), 169.1 (C), 135.4 (C), 129.3 (2CH), 129.0
(2CH), 127.5 (CH), 49.8 (CH), 47.1 (CH2), 44.0 (CH2), 42.0
(CH2). Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89.
Found: C, 70.96; H, 6.36; N, 6.62.
1
B, 20 min); colorless oil; [R]D +32.4 (c 1.0, CHCl3); H NMR
(300 MHz, CDCl3) δ 7.30-7.22 (m, 5H), 4.37-4.28 (m, 1H),
4.19-4.11 (m, 1H), 3.13 (dd, J ) 13.0, 4.2 Hz, 1H), 2.95 (dd, J
) 13.0, 10.0 Hz, 1H), 2.82 (ddd, J ) 16.6, 5.5, 1.5 Hz, 1H),
2.51 (dd, J ) 16.6, 7.7 Hz, 1H), 2.33 (bs, 1H), 2.02-1.94 (m,
1H), 1.76-1.67 (m, 1H), 1.54 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 169.9 (C), 152.5 (C), 137.5 (C), 129.6 (2CH), 128.6
(2CH), 126.7 (CH), 83.6 (C), 64.3 (CH), 55.8 (CH), 43.5 (CH2),
41.3 (CH2), 33.8 (CH2), 28.0 (3CH3). Anal. Calcd for C17H23
-
NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 67.12; H, 7.71; N,
4.50.
(2S)-2-Isop r op yl-4,6-d ioxop ip er id in e (7e). Purification
of the crude product by filtration on silica [CH2Cl2/MeOH (9:
1)] gave 7e (548 mg, yield ) 100%): TLC Rf 0.40 [CH2Cl2/
MeOH (9:1)]; white solid; [R]D +35.3 (c 1.0, MeOH); mp 88-
ter t-Bu tyl (2S,4R)-2-Isop r op yl-4-h yd r oxy-6-oxo-1-p ip -
er id in eca r boxyla te (2e). Purification of the crude product
by flash column chromatography [AcOEt/Hex (7:3)] gave 2e
(94 mg, yield ) 95%): HPLC tR 6.00 (linear gradient, 30-100%
B, 20 min); white crystals; [R]D +68.5 (c 0.8, CHCl3); mp 56-
1
90 °C; H NMR (300 MHz, CDCl3) δ 7.52 (bs, 1H), 3.53-3.48
(m, 1H), 3.27 (m, 2H), 2.62 (dd, J ) 16.1, 4.6 Hz, 1H), 2.45
(dd, J ) 16.1, 8.7 Hz, 1H), 1.87-1.78 (m, 1H), 0.99 (d, J ) 6.1
Hz, 3H), 0.97 (d, J ) 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 202.9 (C), 170.6 (C), 54.4 (CH), 46.6 (CH2), 41.1 (CH2), 32.2
(CH), 18.0 (CH3), 17.7 (CH3). Anal. Calcd for C8H13NO2: C,
61.91; H, 8.44; N, 9.03. Found: C, 61.61; H, 8.46; N, 8.75.
1
58 °C; H NMR (300 MHz, CDCl3) δ 4.11-4.01 (m, 1H), 3.95
(dt, J ) 9.0, 5.8 Hz, 1H), 2.80 (ddd, J ) 16.3, 5.5, 2.4 Hz, 1H),
2.60 (bs, 1H), 2.39 (dd, J ) 16.2, 10.4 Hz, 1H), 2.17-2.04 (m,
2H), 1.68-1.57 (m, 1H), 1.50 (s, 9H), 0.91 (d, J ) 3.3 Hz, 3H),
J . Org. Chem, Vol. 69, No. 1, 2004 137

Marin et al.
(2S)-2-Meth yl-4,6-d ioxop ip er id in e (7f). Purification of
the crude product by filtration on silica [CH2Cl2/MeOH (9:1)]
gave 7f (56 mg, yield ) 100%): TLC Rf 0.20 [CH2Cl2/MeOH
(9:1)]; white solid; [R]D +83.8 (c 1.0, MeOH); mp 124-127 °C;
1H NMR (300 MHz, CDCl3) δ 7.78 (bs, 1H), 3.81-3.75 (m, 1H),
3.22 (m, 2H), 2.64 (dd, J ) 16.3, 3.7 Hz, 1H), 2.29 (dd, J )
16.3, 9.7 Hz, 1H), 1.30 (d, J ) 6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 203.4 (C), 169.5 (C), 47.1 (CH2), 46.2 (CH2), 44.4 (CH),
21.3 (CH3). Anal. Calcd for C6H9NO2: C, 56.68; H, 7.13; N,
11.02. Found: C, 56.95; H, 7.11; N, 10.98.
Red u ction of 7 in to 8. The desired dioxopiperidine 7 was
placed in an argon-filled round-bottom flask and dissolved in
distilled CH2Cl2 to give a ca. 0.15 M solution. A total of 10%
v/v of acetic acid was introduced via a hypodermic syringe,
and the mixture was cooled to 0 °C. NaBH4 (3 equiv) was added
portionwise, and the mixture was allowed to reach room
temperature. The reaction was stirred for 72 h and monitored
by RP-HPLC. The reaction was quenched by the addition of
water and stirred for 10 min. CH2Cl2 was evaporated and
replaced by AcOEt, and the organic layer was washed with
saturated NaHCO3 solution, water, and brine. The organic
layer was dried over Na2SO4, concentrated, and purified by
flash chromatography.
(2S,4R)-4-Hyd r oxy-2-m eth yl-6-oxop ip er id in e (8f). Pu-
rification of the crude product by flash column chromatography
[CH2Cl2/MeOH (9:1)] gave 8f (67 mg, yield ) 37%): TLC Rf
0.14 [CH2Cl2/MeOH (9:1)]; white solid; [R]D +83.8 (c 1.0,
MeOH); mp 181-183 °C; 1H NMR (300 MHz, CD3OD) δ 4.02-
3.92 (m, 1H), 3.53-3.41 (m, 1H), 2.59 (ddd, J ) 17.2, 5.7, 2.0
Hz, 1H), 2.18-2.09 (m, 2H), 1.37-1.25 (m, 1H), 1.21 (d, J )
6.4 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 172.3 (C), 63.9
(CH), 45.7 (CH), 39.6 (CH2), 39.4 (CH2), 20.9 (CH3). Anal. Calcd
for C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 56.05;
H, 8.64; N, 10.77.
Di-ter t-bu tyl (2S,4S)-4-[(ter t-Bu tyld im eth ylsilyl)oxy]-
6-oxo-1,2-p ip er id in ed ica r boxyla te (11). Imidazole (430 mg,
6.32 mmol) and TBSCl (476 mg, 3.16 mmol) were added to a
solution of 500 mg (1.58 mmol) of 2a in 5.0 mL of CH2Cl2 at 0
°C. The mixture was allowed to reach room temperature and
stirred overnight. After evaporation of the solvent, the residue
was dissolved in AcOEt. The solution was washed with 1 N
KHSO4, brine, and water, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by
filtration through a plug of silica [AcOEt/Hex (2:8)] to yield
11 (650 mg, yield ) 95%): HPLC tR 18.16 (linear gradient,
30-100% B, 20 min); [R]D -29.4 (c 1.1, CHCl3); colorless oil;
1H NMR (300 MHz, CDCl3) δ 4.48 (dd, J ) 7.6, 6.7 Hz, 1H),
4.12-4.03 (m, 1H), 2.74 (ddd, J ) 16.6, 5.3, 1.8 Hz, 1H), 2.49
(dd, J ) 16.6, 8.5 Hz, 1H), 2.37-2.28 (m, 1H), 2.08-1.96 (m,
1H), 1.50 (s, 9H), 1.46 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0 (C), 168.9 (C),
152.0 (C), 83.5 (C), 82.2 (C), 64.4 (CH), 56.6 (CH), 44.4 (CH2),
34.9 (CH2), 27.9 (3CH3), 27.9 (3CH3), 25.8 (3CH3), 18.1 (C),
-4.7 (CH3), -4.8 (CH3). Anal. Calcd for C21H39NO6Si: C, 58.71;
H, 9.15; N, 3.26. Found: C, 59.01; H, 9.14; N, 3.46.
Ben zyl (2S,4S)-4-Hyd r oxy-6-oxo-2-p ip er id in eca r boxy-
la te (8b). Purification of the crude product by flash column
chromatography [AcOEt/AcOH (10:0.1)] gave 8b (90 mg, yield
) 89%): TLC Rf 0.19 [AcOEt/AcOH (10:0.1)]; colorless oil; [R]D
1
-1.1 (c 1.0, MeOH); H NMR (300 MHz, CDCl3) δ 7.35-7.26
(m, 5H), 6.84 (bs, 1H), 5.17 (m, 2H), 4.17-4.13 (m, 1H), 4.09-
4.05 (m, 1H), 3.86 (bs, 1H), 2.58 (dd, J ) 17.6, 4.6 Hz, 1H),
2.44-2.38 (m, 1H), 2.31-2.23 (m, 1H), 2.18-2.09 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 171.4 (C), 170.8 (C), 135.0 (C), 128.6
(2CH), 128.5 (CH), 128.3 (2CH), 67.5 (CH2), 63.6 (CH), 51.8
(CH), 39.8 (CH2), 32.4 (CH2). Anal. Calcd for C13H15NO4: C,
62.64; H, 6.07; N, 5.62. Found: C, 62.84; H, 6.05; N, 5.47.
Di-ter t-bu tyl (2S,4R)-4-[(ter t-Bu tyld im eth ylsilyl)oxy]-
1,2-p ip er id in ed ica r boxyla te (13). A total of 307 µL of 1 M
LiEt3BH in THF (0.307 mmol) was added to a solution of 110
mg (0.256 mmol) of 13 in 2.0 mL of THF at -78 °C, and the
mixture was stirred for 30 min. The reaction was quenched
with 0.6 mL of saturated NaHCO3 and allowed to reach 0 °C.
H2O2 was added via a hypodermic syringe (5 drops), and the
mixture was stirred for 30 min at 0 °C. The solvents were
evaporated and replaced by CH2Cl2. The organic phase was
washed with water, dried over Na2SO4, filtered, and concen-
trated in vacuo to give the intermediate 12. Crude 12 and Et3-
SiH (30 mg, 0.256 mmol) were dissolved in 5.0 mL of CH2Cl2
and cooled to -78 °C. BF3‚Et2O (40 mg, 0.282 mmol) was
introduced by dropwise addition, and the mixture was stirred
for 30 min. Et3SiH (30 mg, 0.256 mmol) and BF3‚Et2O (40 mg,
0.282 mmol) were consecutively added via a hypodermic
syringe, and the mixture was stirred for an additional 2 h.
The reaction was quenched by 0.6 mL of a saturated NaHCO3
solution and allowed to reach room temperature. After the
addition of a large volume of a saturated NaHCO3 solution,
the mixture was extracted with CH2Cl2. The organic phases
were dried over Na2SO4, filtered, and concentrated in vacuo.
Purification of the crude product by flash column chromatog-
raphy [AcOEt/Hex (1:9)] gave 13 (yield < 50%): TLC Rf 0.36
[AcOEt/Hex (1:9)]; white solid; [R]D -31.4 (c 1.0, CHCl3);
(2S,4R)-4-H yd r oxy-2-isob u t yl-6-oxop ip er id in e
(8c).
Purification of the crude product by flash column chromatog-
raphy [CH2Cl2/MeOH (9:1)] gave 8c (63 mg, yield ) 62%): TLC
Rf 0.36 [CH2Cl2/MeOH (9:1)]; white solid; [R]D +31.4 (c 0.8,
MeOH); mp 179-180 °C; 1H NMR (300 MHz, CD3OD) δ 4.01-
3.92 (m, 1H), 3.49-3.40 (m, 1H), 2.64-2.56 (m, 1H), 2.20-
2.15 (m, 2H), 1.80-1.70 (m, 1H), 1.46-1.26 (m, 3H), 0.94 (d,
J ) 3.9 Hz, 3H), 0.92 (d, J ) 3.9 Hz, 3H); 13C NMR (100 MHz,
CD3OD) δ 172.3 (C), 64.0 (CH), 48.1 (CH), 45.4 (CH2), 40.0
(CH2), 37.4 (CH2), 23.8 (CH), 22.0 (CH3), 21.2 (CH3). Anal.
Calcd for C9H17NO2: C, 63.13; H, 10.01; N, 8.18. Found: C,
62.83; H, 10.05; N, 8.14.
(2S,4R)-4-H yd r oxy-2-b en zyl-6-oxop ip er id in e
(8d ).
Purification of the crude product by flash column chromatog-
raphy [CH2Cl2/MeOH (9:1)] gave 8d (78 mg, yield ) 86%): TLC
Rf 0.32 [CH2Cl2/MeOH (9:1)]; white solid; [R]D +57.3 (c 1.0,
MeOH); mp 133-134 °C; 1H NMR (300 MHz, CDCl3) δ 7.35-
7.25 (m, 3H), 7.19-7.15 (m, 2H), 5.84 (bs, 1H), 4.06-3.97 (m,
1H), 3.63-3.54 (m, 1H), 2.88 (dd, J ) 13.5, 5.4 Hz, 1H), 2.74-
2.63 (m, 2H), 2.27 (dd, J ) 17.0, 10.2 Hz, 1H), 2.20-2.15 (m,
1H), 2.55-1.43 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 171.0
(C), 136.3 (C), 129.2 (2CH), 129.0 (2CH), 127.2 (CH), 64.8 (CH),
51.3 (CH), 43.0 (CH2), 40.8 (CH2), 38.0 (CH2). Anal. Calcd for
1
appeared as a mixture of two conformers H NMR (300 MHz,
CDCl3) δ 4.61-4.52 (m, 0.5H) and 4.47-4.38 (m,0.5H), 4.07-
4.03 (m, 1H), 3.88-3.68 (m, 1H), 3.40-3.19 (m, 1H), 2.35-
2.32 (m, 0.5H) and 2.30-2.26 (m, 0.5H), 1.85-1.77 (m, 1H),
1.61-1.53 (m, 2H), 1.44 (s, 18H), 0.87 (s, 9H), 0.04 (s, 3H),
0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0 (C), 155.7
(C), 80.7 (C), 79.5 (C), 64.1 (CH), 52.4 (CH), 34.9 (CH2), 33.1
(CH2), 32.2 (CH2), 28.3 (3CH3), 28.2 (3CH3), 26.0 (3CH3), 18.5
(C), -4.8 (CH3), -4.9 (CH3). Anal. Calcd for C21H41NO5Si: C,
60.68; H, 9.94; N, 3.37. Found: C, 60.83; H, 10.03; N, 3.37.
Di-ter t-bu tyl (2S)-3,6-Dih yd r o-1,2(2H)-p yr id in ed ica r -
boxyla te (14). Pure 14 was isolated in low yield (<20%) after
flash column chromatography [AcOEt/Hex (1:9)] from the
crude product obtained for the preparation of 13: TLC Rf 0.33
[AcOEt/Hex (9:1)]; colorless oil; [R]D -9.3 (c 1.0, CHCl3);
C
12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.20; H,
7.57; N, 6.76.
(2S,4R)-4-H yd r oxy-2-isop r op yl-6-oxop ip er id in e (8e).
Purification of the crude product by flash column chromatog-
raphy [CH2Cl2/MeOH (9:1)] gave 8e (99 mg, yield ) 49%): TLC
Rf 0.18 [CH2Cl2/MeOH (9:1)]; white solid; [R]D +35.3 (c 1.0,
MeOH); mp 149-152 °C; 1H NMR (300 MHz, CD3OD) δ 4.01-
3.90 (m, 1H), 3.32-3.28 (m, 1H), 2.60 (ddd, J ) 17.0, 5.7, 2.2
Hz, 1H), 2.13 (ddd, J ) 17.0, 10.6, 0.7 Hz, 1H), 2.06-1.98 (m,
1H), 1.88-1.77 (m, 1H), 1.40-1.28 (m, 1H), 0.95 (d, J ) 6.9
Hz, 3H), 0.92 (d, J ) 6.9 Hz, 3H); 13C NMR (100 MHz, CD3-
OD) δ 172.8 (C), 64.2 (CH), 55.1 (CH), 40.1 (CH2), 32.4 (CH2),
31.5 (CH), 16.9 (CH3), 15.5 (CH3). Anal. Calcd for C8H15NO2:
C, 61.12; H, 9.62; N, 8.91. Found: C, 61.34; H, 9.77; N, 8.85.
138 J . Org. Chem., Vol. 69, No. 1, 2004

Synthesis of Enantiopure Derivatives
1
appeared as a mixture of two conformers H NMR (300 MHz,
CDCl3) δ 5.77-5.71 (m, 1.5H) and 5.64-5.59 (m, 0.5H), 4.94-
4.91 (m, 0.5H) and 4.74-4.71 (m, 0.5H), 4.09-3.99 (m, 1H),
3.91-3.66 (m, 1H), 2.66-2.56 (m, 1H), 2.47-2.37 (m, 1H), 1.48
(s, 4.5 H) and 1.46 (s, 4.5H), 1.42 (s, 4.5H) and 1.41 (s, 4.5H);
13C NMR (100 MHz, CDCl3) δ 170.7 (C), 155.8 and 155.3 (C),
124.2 and 123.9 (CH), 122.5 and 121.9 (CH), 81.4 and 81.3
(C), 80.0 (C), 53.0 and 51.6 (CH), 42.2 and 41.7 (CH2), 28.4
(3CH3), 28.0 (3CH3), 26.6 (CH2).
by AcOEt. The solution was washed with saturated NaHCO3,
dried over Na2SO4, filtered, and evaporated in vacuo. The
crude product was purified by flash column chromatography
[AcOEt/Hex (3:7)] to yield pure 18 (243 mg, yield ) 86%):
HPLC tR 9.30 (linear gradient, 30-100% B, 20 min); colorless
1
crystals; [R]D +11.6 (c 1.0, CHCl3); mp 99-102 °C; H NMR
(300 MHz, CDCl3) δ 6.55-6.50 (m, 1H), 5.88-5.84 (m, 1H),
4.82-4.79 (m, 1H), 2.82-2.73 (m, 1H), 2.71-2.61 (m, 1H), 1.45
(s, 9H), 1.34 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.5 (C),
162.5 (C), 152.1 (C), 139.7 (CH), 126.5 (CH), 83.1 (C), 82.5 (C),
56.2 (CH), 27.9 (3CH3), 27.7 (3CH3), 27.2 (CH2). Anal. Calcd
for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.13;
H, 7.82; N, 4.77.
Di-ter t-bu tyl (2S,4R)-4-Hyd r oxy-1,2-p ip er id in ed ica r -
boxyla te (15). 2a (200 mg, 0.634 mmol) was dissolved in 4.0
mL of anhydrous THF and cooled to 0 °C. BH3‚SMe2 (301 µL,
3.17 mmol) was introduced via a hypodermic syringe. The
mixture was allowed to reach room temperature and stirred
overnight. After being cooled to 0 °C, the reaction was
quenched by the addition of 1.0 mL of MeOH and stirred for
a further 10 min. Evaporation of the solvent gave a residue,
which was dissolved in AcOEt. The solution was washed with
saturated NaHCO3, water, 1 N KHSO4, and brine. The organic
layer was dried over Na2SO4 and concentrated in vacuo. The
residue was placed under high vacuum to eliminate the
dimethyl sulfide derivatives and gave pure 15 (yield ) 100%):
TLC Rf 0.30 [AcOEt/Hex (1:1)]; white crystals; [R]D -54.6 (c
0.9, CHCl3); mp 91-93 °C; appeared as a mixture of conform-
ers 1H NMR (300 MHz, CDCl3) δ 4.68-4.62 (m, 0.5H) and
4.50-4.43 (m, 0.5H), 4.10-4.06 (m, 1H), 3.85-3.68 (m, 1H),
3.36-3.17 (m, 1H), 2.36-2.31 (m, 1H), 2.10 (bs, 1H), 1.85-
1.77 (m, 1H), 1.73-1.54 (m, 2H), 1.42 (bs, 18H); 13C NMR (100
MHz, CDCl3) δ 172.0 (C), 155.6 (C), 81.3 (C), 79.7 (C), 63.1
(CH), 52.2 and 51.1 (CH), 35.9 and 34.9 (CH2), 33.1 (CH2), 31.0
(CH2), 28.3 (3CH3), 27.9 (3CH3). Anal. Calcd for C15H27NO5:
C, 59.78; H, 9.03; N, 4.65. Found: C, 59.50; H, 9.14; N, 4.67.
Di-ter t-bu tyl (2S,4S)-4-[(4-Nitr oben zoyl)oxy]-1,2-p ip -
er id in ed ica r boxyla te (19). p-Nitrobenzoic acid (83 mg, 0.497
mmol) and PPh3 (130 mg, 0.496 mmol) were added to a solution
of 15 (100 mg, 0.332 mmol) in 5.0 mL of distilled THF. The
mixture was cooled to 0 °C prior to the dropwise addition of a
solution of DIAD (101 mg, 0.499 mmol) in 1.0 mL of dry THF.
The solution was protected from light and stirred overnight
with a slow increase of temperature from 0 °C to room
temperature. THF was evaporated and replaced by AcOEt. The
solution was washed with saturated NaHCO3, dried over Na2-
SO4, filtered, and evaporated in vacuo. The crude product was
purified by flash column chromatography [AcOEt/Hex (1:9)]
to yield pure 19 (80 mg, yield ) 53%): HPLC tR 17.08 (linear
gradient, 30-100% B, 20 min); white crystals; [R]D -20.5 (c
1.0, CHCl3); mp 165-167 °C; appeared as a mixture of two
1
conformers H NMR (300 MHz, CDCl3) δ 8.25 (d, J ) 8.9 Hz,
2H), 8.16 (d, J ) 8.8 Hz, 2H), 5.04-4.93 (m, 1H) and 4.77-
4.71 (m, 1H), 4.19-4.00 (m, 1H), 3.21-3.03 (m, 1H), 2.64-
2.53 (m, 1H), 2.16-2.04 (m, 1H), 1.89-1.76 (m, 1H), 1.71-
1.57 (m, 1H), 1.48 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.0 (C), 163.8 (C), 155.1 (C), 150.5 (C), 135.6 (C),
130.7 (2CH), 123.5 (2CH), 82.2 (C), 80.4 (C), 70.3 (CH), 55.0
and 54.0 (CH), 40.1 and 39.5 (CH2), 31.9 (CH2), 30.5 and 30.4
(CH2), 28.3 (3CH3), 28.0 (3CH3). Anal. Calcd for C22H30N2O8:
C, 58.66; H, 6.71; N, 6.22. Found: C, 58.75; H, 6.96; N, 6.22.
(2S,4R)-1-[(9H -F lu or en -9-ylm et h oxy)ca r b on yl]-4-h y-
d r oxy-2-p ip er id in eca r boxylic Acid (17). 15 (250 mg, 0.829
mmol) was placed in a round-bottom flask and dissolved in
2.0 mL of trifluoroacetic acid. The solution was stirred for 2 h
at room temperature and checked by TLC. Trifluoroacetic acid
was coevaporated with hexane, and the residue was dried
under vacuum. Crude 16 was dissolved in 3.0 mL of water.
K2CO3 (344 mg, 2.49 mmol) and FmocOSu (280 mg, 0.829
mmol) dissolved in 3.0 mL of acetone were consecutively added.
After the pH (>9) of the resulting solution had been checked,
the mixture was stirred overnight. Acetone was evaporated,
and the residual solution was diluted with water. The aqueous
solution was acidified with solid KHSO4 prior to the extraction
with AcOEt. The organic phase was washed with 1 N KHSO4,
dried over Na2SO4, and concentrated in vacuo to yield a
yellowish oil. Purification of the crude product by flash column
chromatography [AcOEt/AcOH (10:0.1)] gave 17 (253 mg, yield
) 83%): HPLC tR 8.77 (linear gradient, 30-100% B, 20 min);
white solid; [R]D -9.5 (c 1.0, MeOH); mp 200-201 °C; appeared
Di-ter t-bu tyl (2S)-5,6-Dih yd r o-1,2(2H)-p yr id in ed ica r -
boxyla te (20). Pure 20 was isolated in 32% yield after flash
column chromatography [AcOEt/Hex (1:9)] of the crude product
obtained for the preparation of 19: TLC Rf 0.52 [AcOEt/Hex
(1:9)]; colorless oil; [R]D -207.9 (c 1.1, CHCl3); appeared as a
1
mixture of two conformers H NMR (300 MHz, CDCl3) δ 5.96-
5.87 (m, 1H), 5.82-5.69 (m, 1H), 4.82-4.77 (m, 0.5H) and
4.67-4.62 (m, 0.5H), 4.18-4.12 (m, 0.5H) and 4.03-3.97 (m,
0.5H), 3.11-3.02 (m, 0.5H) and 2.99-2.89 (m, 0.5H), 2.25-
2.14 (m, 1H), 2.07-1.93 (m, 1H), 1.44 (s, 9H), 1.42 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 169.7 (C), 155.0 (C), 127.6 and 127.2
(CH), 122.9 and 122.1 (CH), 81.4 (C), 79.9 (C), 56.4 and 55.5
(CH), 38.9 and 37.6 (CH2), 28.3 (3CH3), 28.0 (3CH3), 24.8 and
24.6 (CH2). Anal. Calcd for C15H25NO4: C, 63.58; H, 8.89; N,
4.94. Found: C, 63.79; H, 9.16; N, 4.88.
1
as a mixture of conformers H NMR (300 MHz, CD3OD) δ 7.82
(d, J ) 7.3 Hz, 2H), 7.68-7.58 (m, 2H), 7.41 (t, J ) 7.3 Hz,
2H), 7.33 (t, J ) 7.3 Hz, 2H), 4.68 (d, J ) 5.8 Hz, 0.5H) and
4.53 (d, J ) 6.7 Hz, 0.5H), 4.47-4.39 (m, 2H), 4.31-4.22 (m,
1H), 4.08-4.03 (m, 1H), 3.87-3.74 (m, 1H), 3.60-3.43 (m, 1H),
Di-ter t-b u t yl (2S,4S)-4-Hyd r oxy-1,2-p ip er id in ed ica r -
boxyla te (22). Chloroacetic acid (141 mg, 1.49 mmol) and
PPh3 (392 mg, 1.49 mmol) were added to a solution of 15 (300
mg, 0.995 mmol) in 10.0 mL of distilled THF. The mixture was
cooled to 0 °C prior to the dropwise addition of a solution of
DIAD (302 mg, 1.49 mmol) in 5.0 mL of dry THF. The solution
was protected from light and stirred overnight with a slow
increase of temperature from 0 °C to room temperature. THF
was evaporated and replaced by AcOEt. The solution was
washed with saturated NaHCO3, dried over Na2SO4, filtered,
and evaporated in vacuo to give 21. The crude product was
dissolved in 1.0 mL of dioxane, and the same volume of water
was added. A 1 N NaOH solution was added drop by drop until
the pH reached 9. The mixture was stirred for 30 min and
checked by TLC. The reaction was quenched by the addition
of a large volume of 1 N KHSO4 before extraction with AcOEt.
The organic phases were dried over Na2SO4, filtered, and
evaporated in vacuo. The crude product was purified by flash
column chromatography [AcOEt/Hex (1:1)] to yield 22 (211 mg,
2.47-2.38 (m, 1H), 1.92-1.81 (m, 1H), 1.77-1.58 (m, 2H); 13
C
NMR (100 MHz, CD3OD) δ 175.2 (C), 158.1 and 157.8 (C),
145.3 (C), 145.2 (C), 145.1 (C), 142.6 (C), 128.8 (2CH), 128.1
(2CH), 126.1 (2CH), 120.9 (2CH), 68.8 (CH2), 63.7 (CH), 52.5
and 52.2 (CH), 48.4 (CH), 37.1 and 36.8 (CH2), 34.2 (CH2), 32.0
and 31.9 (CH2). Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76;
N, 3.81. Found: C, 68.47; H, 6.09; N, 3.63.
Di-ter t-bu tyl (2S)-6-Oxo-3,6-dih ydr o-1,2(2H)-pyr idin edi-
ca r boxyla te (18). p-Nitrobenzoic acid (239 mg, 1.43 mmol)
and PPh3 (374 mg, 1.43 mmol) were added to a solution of 2a
(300 mg, 0.951 mmol) in 15.0 mL of distilled THF. The mixture
was cooled to 0 °C prior to the dropwise addition of a solution
of diisopropylazodicarboxylate (DIAD) (288 mg, 1.42 mmol) in
4.0 mL of dry THF. The solution was protected from light and
stirred overnight with a slow increase of temperature from 0
°C to room temperature. THF was evaporated and replaced
J . Org. Chem, Vol. 69, No. 1, 2004 139

Marin et al.
yield ) 70%): TLC Rf 0.44 [AcOEt/Hex (1:1)]; colorless oil; [R]D
26 (770 mg, yield ) 88%): HPLC tR 17.30 (linear gradient,
50-100% B, 20 min); [R]D -19.5 (c 1.0, CHCl3); colorless oil;
1H NMR (300 MHz, CDCl3) δ 7.66-7.60 (m, 4H), 7.44-7.38
(m, 6H), 4.30 (dd, J ) 8.3, 6.6 Hz, 1H), 4.06-3.97 (m, 1H),
2.65 (ddd, J ) 16.6, 5.5, 2.0 Hz, 1H), 2.53 (dd, J ) 16.6, 9.0
Hz, 1H), 2.30-2.21 (m, 1H), 2.07-1.97 (m, 1H), 1.47 (s, 9H),
1.45 (s, 9H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.0
(C), 168.7 (C), 151.9 (C), 135.6 (4 CH), 133.4 (C), 133.1 (C),
130.0 (2 CH), 127.8 (4 CH), 83.6 (C), 82.2 (C), 65.0 (CH), 56.6
(CH), 44.0 (CH2), 34.7 (CH2), 27.9 (3CH3), 27.8 (3CH3), 26.9
(3CH3), 19.0 (C).
1
-38.7 (c 1.1, CHCl3); appeared as a mixture of conformers H
NMR (300 MHz, CDCl3) δ 4.78 (bd, J ) 4.9 Hz, 0.5H) and 4.60
(bd, J ) 5.5 Hz, 0.5H), 4.03-3.88 (m, 1H), 3.61-3.50 (m, 1H),
2.99-2.84 (m, 1H), 2.69 (bs, 1H), 2.39-2.32 (m, 1H), 1.89-
1.80 (m, 1H), 1.60-1.48 (m, 1H), 1.44-1.26 (m, 1H), 1.39 (s,
9H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.7 and 170.5
(C), 155.4 (C), 81.7 (C), 80.1 (C), 65.9 and 65.7 (CH), 55.2 and
54.2 (CH), 40.5 and 39.9 (CH2), 35.3 and 35.2 (CH2), 34.0 and
33.8 (CH2), 28.2 (3CH3), 27.9 (3CH3). Anal. Calcd for C15H27
-
NO5: C, 59.78; H, 9.03; N, 4.65. Found: C, 59.98; H, 9.22; N,
4.63.
ter t-Bu tyl (2S,4S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-4-
[(ter t-bu tyld ip h en ylsilyl)oxy]-6-h yd r oxyh exa n oa te (27).
26 (710 mg, 1.28 mmol) was dissolved in 10.0 mL of EtOH
and cooled to 0 °C. After the portionwise addition of NaBH4
(242 mg, 6.40 mmol), the mixture was allowed to reach room
temperature and stirred overnight. After being quenched by
water, the mixture was stirred for a further 10 min. Evapora-
tion of the solvent gave an oil, which was dissolved in AcOEt.
The solution was washed with water and dried over Na2SO4.
Evaporation of the filtrate afforded an oil, which was subjected
to filtration through a silica pad [AcOEt/Hex (4:6)]. Pure 27
was recovered (690 mg, yield ) 97%): HPLC tR 15.66 (linear
gradient, 50-100% B, 20 min); colorless oil; [R]D +4.8 (c 1.1,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.71-7.68 (m, 4H), 7.44-
7.37 (m, 6H), 5.30 (bd, J ) 7.9 Hz, 1H), 4.14-4.04 (m, 2H),
3.63-3.49 (m, 2H), 1.96-1.92 (m, 1H), 1.75-1.71 (m, 1H), 1.57
(m, 2H), 1.42 (s, 9H), 1.36 (s, 9H), 1.06 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 171.7 (C), 155.3 (C), 135.9 (2CH), 135.8 (2CH),
133.6 (C), 133.2 (C), 129.9 (CH), 129.8 (CH), 127.8 (2CH), 127.7
(2CH), 81.6 (C), 79.5 (C), 69.6 (CH), 50.0 (CH2), 52.0 (CH), 38.4
(CH2), 38.3 (CH2), 28.3 (3CH3), 27.9 (3CH3), 26.9 (3CH3), 19.3
(C). Anal. Calcd for C31H47NO6Si: C, 66.75; H, 8.49; N, 2.51.
Found: C, 66.88; H, 8.65; N, 2.56.
ter t-Bu t yl (2S,4R)-6-Azid o-2-[(ter t-b u t oxyca r b on yl)-
a m in o]-4-[(ter t-bu tyld ip h en ylsilyl)oxy]h exa n oa te (28). A
total of 307 µL (1.80 mmol) of DIEA was added to a solution
of 670 mg (1.20 mmol) of 27 in 20.0 mL of CH2Cl2 at ambient
temperature. The solution was cooled to 0 °C, and 139 µL (1.80
mmol) of MsCl was added via a hypodermic syringe. The
mixture was allowed to reach room temperature and stirred
for 3 h. The reaction was quenched with water, and CH2Cl2
was evaporated and replaced by AcOEt. The organic phase was
washed with 1 N KHSO4, brine, saturated NaHCO3, and
water, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was dissolved in 10.0 mL of DMF. A total of 234
mg (3.60 mmol) of NaN3 was added to the solution, which was
heated to 80 °C for 8 h. After being cooled to room temperature,
water was added to the solution, which was extracted twice
with AcOEt. The combined organic layers were washed with
water, dried over Na2SO4, filtered, and evaporated in vacuo.
The crude product was purified by flash column chromatog-
raphy [AcOEt/Hex (1:9)] to yield pure 27 (560 mg, 80%): HPLC
tR 18.55 (linear gradient, 50-100% B, 20 min); [R]D -10.7 (c
1.0, CHCl3); colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.71-
7.67 (m, 4H), 7.44-7.35 (m, 6H), 5.21 (bd, J ) 7.6 Hz, 1H),
4.15-4.08 (m, 1H), 3.96-3.92 (m, 1H), 3.16 (t, J ) 7.1 Hz, 2H),
1.97-1.83 (m, 2H), 1.75-1.68 (m, 2H); 1.43 (s, 9H), 1.37 (s,
9H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.6 (C), 155.3
(C), 135.8 (4CH), 133.6 (C), 133.0 (C), 129.9 (2CH), 127.8
(4CH), 81.7 (C), 79.5 (C), 69.0 (CH), 51.8 (CH), 47.5 (CH2), 38.6
(CH2), 35.2 (CH2), 28.3 (3CH3), 27.9 (3CH3), 26.9 (3CH3), 19.3
(C). Anal. Calcd for C31H46N4O5Si: C, 63.89; H, 7.96; N, 9.61.
Found: C, 63.72; H, 8.11; N, 9.79.
(2S,4S)-1-[(9H -F lu or en -9-ylm et h oxy)ca r b on yl]-4-h y-
d r oxy-2-p ip er id in eca r boxylic Acid (24). 22 (110 mg, 0.365
mmol) was placed in a round-bottom flask and dissolved in
2.0 mL of trifluoroacetic acid. The solution was stirred for 2 h
at room temperature and checked by TLC. Trifluoroacetic acid
was coevaporated with hexane, and the residue was dried
under vacuum. Crude 23 was dissolved in 1.5 mL of water.
K2CO3 (151 mg, 1.09 mmol) and FmocOSu (123 mg, 0.365
mmol) dissolved in 1.5 mL of acetone were consecutively added.
After the pH of the resulting solution was checked, the mixture
was stirred overnight. Acetone was evaporated, and the
residual solution was diluted with water. The aqueous solution
was acidified with solid KHSO4 prior to the extraction with
AcOEt. The organic phase was washed with 1 N KHSO4, dried
over Na2SO4, and concentrated in vacuo to yield a yellowish
oil. Purification of the crude product by flash column chroma-
tography [AcOEt/AcOH (10:0.1)] gave 24 (109 mg, yield )
81%): HPLC tR 8.28 (linear gradient, 30-100% B, 20 min);
white solid; [R]D -8.2 (c 1.0, MeOH); mp 65-67 °C; appeared
as a mixture of conformers 1H NMR (300 MHz, CD3OD) δ
7.82-7.80 (m, 2H), 7.65-7.57 (m, 2H), 7.43-7.38 (m, 2H),
7.34-7.29 (m, 2H), 4.91 (d, J ) 5.7 Hz, 0.5H) and 4.74 (d, J )
5.7 Hz, 0.5H), 4.48-4.37 (m, 2H), 4.28-4.20 (m, 1H), 4.13-
4.05 (m, 0.5H), 4.00-3.91 (m, 0.5H), 3.65-3.56 (m, 1H), 3.16-
3.00 (m, 1H), 2.50-2.40 (m, 1H), 1.95-1.83 (m, 1H), 1.60-
1.47 (m, 1H), 1.38-1.23 (m, 1H); 13C NMR (100 MHz, CD3OD)
δ 174.0 (C), 157.8 and 157.4 (C), 145.3 and 145.2 (C), 145.1
and 145.0 (C), 142.6 (2C), 128.8 (2CH), 128.1 (2CH), 126.1 and
126.0 (2CH), 120.9 (2CH), 69.0 and 68.9 (CH2), 66.4 (CH), 55.5
and 55.4 (CH), 48.3 (CH), 41.5 (CH2), 36.2 and 36.1 (CH2), 34.8
and 34.7 (CH2). Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76;
N, 3.81. Found: C, 68.83; H, 6.08; N, 3.61.
ter t-Bu tyl N-[(1S,3S)-3,5-Dih yd r oxy-1-(h yd r oxym eth -
yl)p en tyl]ca r ba m a te (25). NaBH4 (48 mg, 1.27 mmol) was
added to a solution of 2a (80 mg, 0.254 mmol) in 2.0 mL of
EtOH at 0 °C. The mixture was allowed to reach room
temperature and stirred for 6 h. After being quenched with
water, the mixture was stirred for a further 10 min. Evapora-
tion of the solvent gave an oil, which was dissolved in AcOEt.
The solution was washed with water and dried over Na2SO4.
Evaporation of the filtrate afforded an oil, which was subjected
to filtration through a silica pad [CH2Cl2/MeOH (9:1)]. Pure
25 was recovered (20 mg, yield ) 32%): TLC Rf 0.42 [CH2Cl2/
MeOH (9:1)]; colorless oil; [R]D -11.4 (c 0.8, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 5.15 (bd, J ) 8.8 Hz, 1H), 4.64 (m, 1H),
3.91-3.80 (m, 3H), 3.72 (dd, J ) 10.9, 4.0 Hz, 1H), 3.62 (dd, J
) 10.9, 4.6 Hz, 1H), 3.32 (bs, 1H), 2.76 (bs, 1H), 1.96 (bs, 1H),
1.81-1.64 (m, 2H), 1.62-1.55 (m, 2H), 1.44 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 157.4 (C), 80.2 (C), 68.5 (CH), 65.3 (CH2),
61.8 (CH2), 49.1 (CH), 40.4 (CH2), 38.0 (CH2), 28.3 (3CH3).
Di-ter t-bu tyl (2S,4S)-4-[(ter t-Bu tyld ip h en ylsilyl)oxy]-
6-oxo-1,2-p ip er id in ed ica r boxyla te (26). Imidazole (432 mg,
6.34 mmol) and TPSCl (872 mg, 3.17 mmol) were added to a
solution of 500 mg (1.58 mmol) of 2a in 20.0 mL of CH2Cl2 at
0 °C. The mixture was allowed to reach room temperature and
stirred overnight. After evaporation of the solvent, the residue
was dissolved in AcOEt. The solution was washed with 1 N
KHSO4, brine, and water, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by
filtration through a plug of silica [AcOEt/Hex (2:8)] to yield
(2S,4R)-6-Azido-4-[(ter t-bu tyldiph en ylsilyl)oxy]-2-{[(9H-
flu or en -9-ylm eth oxy)car bon yl]am in o}h exan oic Acid (29).
28 (200 mg, 0.343 mmol) was dissolved in 2.0 mL of CH2Cl2
and cooled to 0 °C. A total of 2.0 mL of TFA was slowly added
via a hypodermic syringe, and the solution was stirred for 3
h. The mixture was allowed to reach room temperature and
stirred for an additional 3 h. The reaction was checked by TLC
[AcOET/pyridine/acetic acid/water (8:2:0.5:1)] and stirred at
140 J . Org. Chem., Vol. 69, No. 1, 2004

Synthesis of Enantiopure Derivatives
room temperature until 28 disappeared. The solution was
cooled to 0 °C and quenched with the addition of 50.0 mL of a
1 N NH4OH solution. The solution was extracted twice with
CH2Cl2, and the combined organic layers were dried over Na2-
SO4, filtered, and evaporated in vacuo. The residue was
dissolved in 5.0 mL of acetone, and the same volume of water
was added to the solution. A total of 142 mg (1.03 mmol) of
K2CO3 and 139 mg (0.412 mmol) of FmocOSu dissolved in 1.0
mL of acetone were added to the solution. The mixture was
stirred overnight. Acetone was evaporated and replaced by
AcOEt prior to washing the solution with 1 N KHSO4, brine,
and water. The crude product was purified by flash column
chromatography [AcOEt/Hex/AcOH (3:7:0.1)] to yield 29 (210
mg, 94%): HPLC tR 15.58 (linear gradient, 50-100% B, 20
min); [R]D +2.5 (c 1.0, MeOH); colorless oil; 1H NMR (300 MHz,
CDCl3) δ 7.80-7.70 (m, 6H), 7.63-7.58 (m, 2H), 7.46-7.29 (m,
10H), 5.57 (bd, J ) 6.9 Hz, 1H), 4.51-4.45 (m, 1H), 4.41-4.35
(m, 2H), 4.24-4.20 (m, 1H), 4.07-3.98 (m, 1H), 3.22-3.17 (m,
2H), 2.12-1.94 (m, 2H), 1.81-1.75 (m, 2H), 1.10 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 177.4 (C), 156.1 (C), 143.8 (C), 143.7
(C), 141.3 (2C), 135.9 (2CH), 135.8 (2CH), 133.4 (C), 132.7 (C),
130.1 (CH), 130.0 (CH), 127.9 (2CH), 127.8 (2CH), 127.7 (2CH),
127.1 (2CH), 125.2 (CH), 125.1 (CH), 120.0 (2CH), 68.6 (CH),
67.1 (CH2), 51.5 (CH), 47.4 (CH2), 47.1 (CH), 37.4 (CH2), 35.3
(CH2), 27.0 (3CH3), 14.2 (C). Anal. Calcd for C37H40N4O5Si: C,
68.49; H, 6.21; N, 8.64. Found: C, 68.57; H, 6.06; N, 8.40.
Ack n ow led gm en t. J .M. thanks the CNRS and
Neosystem for a predoctoral fellowship as well as the
Fondation pour la Recherche Me´dicale for its support.
Su p p or tin g In for m a tion Ava ila ble: Effect of the nature
of the carboxylic acid on the reduction of 4a , 1H and 13C NMR
data for all compounds, view of the crystal packing of 6a and
2a , ORTEP plot of compounds 18 and 19, and X-ray crystal-
lographic data of 2a , 6a , 18, and 19 as CIF files. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O0353886
J . Org. Chem, Vol. 69, No. 1, 2004 141