Highly convergent stereoselective synthesis of chiral key intermediates in the synthesis of Palinavir from imines derived from L-glyceraldehyde

Article abstract of DOI:10.1016/S0040-4020(01)01152-8

Imines derived from O-protected (S)-glyceraldehyde are valuable intermediates in the synthesis of different kinds of amino acids. We have developed a highly convergent and stereoselective method to obtain (2S,3S)-N-tert-butoxycarbonyl-1-phenyl-3,4-epoxy-2-butylamine and (2S,4R)-N-tert-butoxycarbonyl-4-hydroxypipecolic acid tert-butylamide, which are key intermediates in the synthesis of Palinavir, that consist in the treatment of the appropriate imine with benzylmagnesium bromide and Danishefsky's diene, respectively, and subsequent transformation of the obtained adducts into the desired compounds. The reaction of N-benzylimine derived from (S)-2,3-di-O-benzylglyceraldehyde with benzylmagnesium bromide is completely diastereoselective at low temperature. Hetero Diels-Alder reaction of imine derived from (S)-2,3-di-O-benzylglyceraldehyde and (R)-N-α-methylbenzylamine is completely diastereoselective at low temperature in the presence of ZnI₂.

Full text of DOI:10.1016/S0040-4020(01)01152-8

TETRAHEDRON
Pergamon
Tetrahedron 58 -2002) 341±354
Highly convergent stereoselective synthesis of chiral key
intermediates in the synthesis of Palinavir from imines
derived from l-glyceraldehyde
p
Ramon Badorrey, Carlos Cativiela, Marõa D. Dõaz-de-Villegas and Jose A. Galvez
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Departamento de Quõmica Organica, Facultad de Ciencias-Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza-CSIC,
E-50009 Zaragoza, Spain
Received 12 March 2001; revised 5 June 2001; accepted 14 November 2001
AbstractÐImines derived from O-protected -S)-glyceraldehyde are valuable intermediates in the synthesis of different kinds of amino acids.
We have developed a highly convergent and stereoselective method to obtain -2S,3S)-N-tert-butoxycarbonyl-1-phenyl-3,4-epoxy-2-butyl-
amine and -2S,4R)-N-tert-butoxycarbonyl-4-hydroxypipecolic acid tert-butylamide, which are key intermediates in the synthesis of
Palinavir, that consist in the treatment of the appropriate imine with benzylmagnesium bromide and Danishefsky's diene, respectively,
and subsequent transformation of the obtained adducts into the desired compounds. The reaction of N-benzylimine derived from -S)-2,3-di-
O-benzylglyceraldehyde with benzylmagnesium bromide is completely diastereoselective at low temperature. Hetero Diels±Alder reaction
of imine derived from -S)-2,3-di-O-benzylglyceraldehyde and -R)-N-a-methylbenzylamine is completely diastereoselective at low
temperature in the presence of ZnI2. q 2002 Published by Elsevier Science Ltd.
1. Introduction
CvN bond, and pipecolic acid derivatives6 by hetero
Diels±Alder cycloaddition with activated dienes.
The synthesis of enantiomerically pure chiral compounds
represents a major challenge in organic chemistry. Among
the different approaches developed to this end, the use of
naturally occurring compounds provides an enormous range
and diversity of possible starting materials. To be of use in
asymmetric synthesis these compounds should be cheap and
readily available, preferably in both enantiomeric forms. In
this context carbohydrates,1 sugars and polyhydroxylated
compounds, in general, and -R)- and -S)-glyceraldehyde
derivatives, which are easily available from d-mannitol
and l-ascorbic acid or l-mannonic g-lactone, respectively,
are particularly important building blocks.1a,2
Palinavir -1) -Fig. 1) is a highly potent peptidomimetic-
based inhibitor of human immunode®ciency virus
protease -HIVPr) inhibitor and viral replication in vitro
with a favourable pharmacological pro®le.7 Whereas the
3-amino-2-propanol-hydroxypipecolic acid segment of this
compound seems to be fundamental to mimic the transition
state for the cleavage of the phenylalanine±proline peptide
bond and modulate the overall physicochemical properties
of this inhibitor while maintaining antiviral properties,
substitution of the quinaldic-valine fragment leads to
structurally simpler hydroxyethylamine-based HIV protease
inhibitors.8
The synthesis of amino acids in their enantiomerically pure
form has been a major subject of study in our group for
many years. In the course of our work aimed at the develop-
ment of new versatile synthetic methodologies for the asym-
metric synthesis of different kinds of amino acids, we have
shown that imines derived from O-protected d-glyceralde-
hyde can act as synthetic precursors in the synthesis of
amino acids,3 a-amino-b-hydroxy acids4 and a-hydroxy-
b-amino acids5 through the addition of nucleophiles to the
In the synthesis of the right-hand side of this compound
developed by Beaulieu et al.9 compound 4 was prepared
by coupling the chiral a-amino epoxide 2, obtained in
28±35% overall yield from N,N-dibenzylalaninol on a kg
scale,9c with enantiomerically pure 4-hydroxypipecolic acid
Keywords: asymmetric synthesis; addition reactions; cycloadditions;
Grignard reagents.
p
Corresponding authors. Tel.: 134-76762274; fax: 134-76761210;
e-mail: loladiaz@posta.unizar.es; jagl@posta.unizar.es
Figure 1. Structure of Palinavir.
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020-01)01152-8

342
R. Badorrey et al. / Tetrahedron 58 02002) 341±354
Scheme 1. Beaulieu synthesis of the right-handed segment of Palinavir: -a) Al2O3; -b) HCl; -c) NaOH.
amide 3, obtained in ca. 20% overall yield on a kg scale
from 3-buten-1-ol9c,10 or aspartic acid derivatives11
-Scheme 1).
reagents asymmetrically,26 the addition of organometallic
reagents to the C±N double bond of a chiral imine has
proven to be a useful strategy to the stereoselective
synthesis of amines.27 On the other hand the aza-Diels±
Alder reaction between a chiral imine and an activated
diene is one of the most powerful methodologies for the
construction of piperidine derivatives.28
A variety of approaches towards the stereoselective
synthesis of syn and anti a-amino epoxides have been
reported. The synthesis of syn derivatives can be performed
by epoxidation of N-protected-a-amino aldehydes by
sulfoxonium ylides,12 reduction of a-N,N-dibenzylamino-
a0-chloroketones followed by cyclisation13 or epoxidation
of allylamines.14 Epoxidation of N,N-diprotected-a-amino
aldehydes by sulfoxonium ylides,15 stereoselective reduc-
tion of a-N-acylamino-a0-chloroketones and subsequent
cyclisation,14d,16 condensation of dihalomethanes with
N,N-dibenzylamino-a-amino aldehydes7a,9c,13,17 or reduc-
tive amination of ketoepoxides18 allows the synthesis of
anti epoxides. Finally, the appropriate regioselective activa-
tion of one hydroxy group in 3-amino-1,2-diols allows the
synthesis of epoxides of syn and anti con®guration.4c,19
Taking into account that glyceraldimines add organo-
metallic reagents3,4c,5,26,29 and behave as dienophiles in the
aza-Diels±Alder reaction6 in this paper we have studied the
stereoselective synthesis of both chiral fragments of chiral
intermediate 4, using imines derived from glyceraldehyde as
synthetic precursors.
2. Results and discussion
2.1. Retrosynthetic analysis
Asymmetric syntheses of pipecolic acid and derivatives
have recently been reviewed.20 Enantiomerically pure cis
and trans 4-hydroxypipecolic acid derivatives have been
obtained by different procedures. Apart from chemical or
enzymatic resolution of compounds obtained by hydrogena-
tion of pyridine derivatives21 or resolution of the racemic
lactone obtained by intramolecular iminium ion cyclisation
of homoallylic amines,9c,10 several asymmetric syntheses of
these compounds have been described. In this context dia-
stereoselective reduction of 4-oxopipecolic acid derivatives
with the appropriate reducing agent usually affords the
corresponding 4-hydroxy derivative of cis or trans con-
®guration.11,22 From cis 4-hydroxypipecolic acid derivatives
trans compounds have been obtained by Mitsunobu
inversion.22b,d N-Acyliminium ions have proven to be appro-
priate precursors of 4-hydroxypipecolic acid derivatives,23
and both enantiomers of cis-4-hydroxypipecolic acid have
been prepared using l-lysine, d-glucosamine, d-glucono-
heptono-1,4-lactone, or -R)- or -S)-glycidol as the chiral
source.24 Finally, d-amino b-keto esters have been recently
used as chiral building blocks for the synthesis of the four
stereoisomers of 4-hydroxypipecolic acid.25
The retrosynthetic analysis of compounds 2 and 3 suggested
that both chiral fragments could be obtained in enantio-
merically pure form starting from imines derived from
glyceraldehyde with the appropriate con®guration at C2,
as shown in Scheme 2.
Fragment 2 could be obtained from the N-benzylimines
derived from O-protected glyceraldehyde by nucleophilic
addition of a benzylmagnesium halide and subsequent
cyclisation of the amino alcohol. According to our
previously described results on the addition of methyl-
magnesium,5 phenylmagnesium3a,4c and vinylmagnesium3b
bromides to imines derived from O-protected glyceralde-
hyde, organometallic addition to N-benzylimines derived
from -R)-2,3-di-O-isopropylideneglyceraldehyde would
afford the corresponding aminodiols with S con®guration
at the newly formed stereogenic carbon, whereas organo-
metallic addition to N-benzylimines derived from -R)-2,3-
di-O-benzylglyceraldehyde would provide aminodiols of R
con®guration at the same stereogenic carbon. In order to
obtain -2S,3S)-N-tert-butoxycarbonyl-1-phenyl-3,4-epoxy-
2-butylamine -2), the anti aminoepoxide with the desired
absolute con®guration, -R)-2,3-di-O-isopropylideneglycer-
aldehyde or -S)-2,3-di-O-benzylglyceraldehyde could be
used as starting materials. Nevertheless, when we tested
Since Sato et al. ®rst reported that N-substituted 2,3-O-
isopropylidene-d-glyceraldimines add organometallic

R. Badorrey et al. / Tetrahedron 58 02002) 341±354
343
Scheme 2. Retrosynthetic steps to epoxide 2 and 4-hydroxypipecolic acid derivative 3 from glyceraldehyde derivatives.
the addition of commercially available benzylmagnesium
chloride with the imine 5, derived from -R)-2,3-di-O-iso-
propylideneglyceraldehyde, under the usual conditions, the
corresponding amine 10 of R con®guration at the newly
formed stereogenic carbon was obtained -Scheme 3). This
result is in contrast to our previously described ®ndings
regarding the reversal of the stereochemical course of the
addition of phenylmagnesium and vinylmagnesium
bromides to N-benzylimines derived from glyceraldehyde
depending on the O-protecting group.3,4c The absolute
con®guration of the newly formed stereogenic carbon was
unambiguously established after N-debenzylation/Boc-
protection of compound 10 to afford Boc derivative 11
and X-ray analysis of this product. For this reason imine 5
was de®nitively rejected as a starting material for our
synthetic proposal.
benzylglyceraldehyde is used as the starting material. More-
over, when the imine derived from a-methylbenzylamine of
the appropriate con®guration is combined with the di-O-
benzylderivative of glyceraldehyde, the subsequent
cycloaddition reaction occurs with complete diastereo-
stereoselectivity.6b In this case -S)-2,3-di-O-benzylglyceral-
dehyde and -R)-a-methylbenzylamine must be chosen in
order to construct the skeleton of the 4-hydroxypipecolic
acid of S con®guration at C2.
Taking into account these considerations we decided to use
-S)-2,3-di-O-benzylglyceraldehyde as the starting material
to develop a convergent stereoselective synthesis for both
key intermediates in the synthesis of compound 4.
2.2. Synthesis of $S)-2,3-di-O-benzylglyceraldehyde
The 4-hydroxypipecolic acid derivative would be the result
of a hetero Diels±Alder reaction between Danishefsky's
diene and N-benzylimines derived from 2,3-di-O-benzyl-
glyceraldehyde or 2,3-di-O-isopropylideneglyceraldehyde
followed by subsequent manipulation of the substituents
on the piperidone ring. In a previous paper we described
that hetero Diels±Alder reactions of N-benzylimines
derived from O-protected -R)-glyceraldehyde preferentially
provide the corresponding piperidones of 2R con®guration
and that the best results are obtained when -R)-2,3-di-O-
-S)-2,3-Di-O-benzylglyceraldehyde was obtained from
commercially available l-mannonic g-lactone -12) by the
route shown in Scheme 4. Reduction of l-mannonic
g-lactone -12) with lithium borohydride in dry methanol
gave l-mannitol, which was converted into the correspond-
ing triacetonide using 2,2-dimethoxypropane in dry acetone
containing camphorsulfonic acid. The product of this
reaction was then partially hydrolysed to the monoacetonide
13 according to a recently described procedure.30
From compound 13 -S)-2,3-di-O-benzylglyceraldehyde -8)
was obtained by similar procedures to those described for
the synthesis of enantiomeric -R)-2,3-di-O-benzylglyceral-
dehyde.31 Benzylation of 3,4-O-isopropylidene-l-mannitol
-13) with benzyl bromide in the presence of sodium hydride
and tetrabutylammonium iodide afforded 1,2,5,6-tetra-O-
benzyl-3,4-O-isopropylidene-l-mannitol -14), which was
hydrolysed in an acidic medium to give 1,2,5,6-tetra-O-
benzyl-l-mannitol -15). Heterogeneous sodium periodate
glycol cleavage of 15 gave the desired product -S)-2,3-di-
O-benzylglyceraldehyde -8), from which N-benzylimines 7
and 9 were obtained according to our previously described
procedures for ent-75 and ent-9,6b respectively.
Scheme 3. Asymmetric benzylmagnesiumchloride addition to imine 5.

344
R. Badorrey et al. / Tetrahedron 58 02002) 341±354
Scheme 4. Synthesis of -S)-2,3-di-O-benzyl-l-glyceraldehyde.
2.3. Synthesis of $2S,3S)-N-tert-butoxycarbonyl-1-
phenyl-3,4-epoxy-2-butylamine
procedure19g for the synthesis of this compound, i.e. the
primary alcohol group in compound 19 was selectively
protected in 95% yield by treatment with tert-butyl-
dimethylsilyl chloride/imidazole in DMF, which allowed
the mesylation of the secondary hydroxyl group by the
action of methanesulfonyl chloride in a basic medium to
give compound 21. Subsequent treatment of compound 21
with TBAF in THF led to the corresponding alkoxide, which
immediately cyclised in situ with concomitant stereo-
chemical inversion to afford the desired epoxide 2 in 67%
yield -Scheme 6).
Addition of imine 7 to commercially available benzyl-
magnesium chloride under standard conditions,3,4c,5 gave
the corresponding amine 16 of 1S,2R con®guration together
with a large amount of a by-product that was isolated and
fully characterised as ole®n 17 on the basis of its analytical
and spectroscopic data -Scheme 5). The formation of this
by-product clearly results from an elimination/nucleophilic
addition process that competes with the pure imine
nucleophilic addition.
In this way the required intermediate 2 to the synthesis of
Palinavir was obtained stereoselectively from chiral imine 8
in six steps and ca. 26% overall yield.
On using benzylmagnesium bromide as the organometallic
reagent and carrying out the reaction at low temperature
-2308C), the elimination reaction was avoided and amine
16 was obtained as a single diastereoisomer in 68% isolated
yield. Attempts to perform a one-step synthesis of N-Boc
amino diol 19 by hydrogenolysis of amine 16 in the
presence of di-tert-butyldicarbonate at atmospheric pressure
afforded a mixture of compounds. From this mixture the
N-Boc derivative of the starting compound, which is inert
to hydrogenation even at high pressure and temperature, and
compound 18 were isolated. On the other hand, hydro-
genolysis of the N-debenzylated intermediate was
extremely dif®cult unless N-Boc protection had previously
been performed. We therefore performed a three-step
procedure involving selective benzylamine hydrogenolysis
of compound 16 by hydrogenation, catalysed by palladium
hydroxide on charcoal, at atmospheric pressure for 12h.
This step was followed by N-Boc protection with di-tert-
butyldicarbonate and extensive hydrogenolysis of the
resulting compound for 2h.
The excellent agreement of the speci®c rotation measured
for compound 2, [a]D ˆ16.6 -c 1.1, CHCl3) or,
25
[a]D ˆ29.0 -c 1.1, CH3OH), with the previously described
25
values7a for the same compound allowed us to further
con®rm the stereochemistry and enantiomeric purity of the
compound obtained.
2.4. Synthesis of $2S,4R)-N-tert-butoxycarbonyl-4-
hydroxypipecolic acid tert-butylamide
In a previous detailed study we assessed the reactions of
imines obtained from -R)-2,3-di-O-benzylglyceraldehyde
and benzylamines with 1-methoxy-3-trimethylsilyloxy-
buta-1,3-diene -Danishefsky's diene) in the presence of a
Lewis acid. We concluded that at low temperature using
acetonitrile as solvent, ZnI2 as the Lewis acid and -S)-a-
methylbenzylamine as the chiral auxiliary to achieve double
stereodifferentiation, the reaction takes place with complete
control of stereochemistry to give enaminone ent-22, which
is a potential scaffold for useful synthetic transformations.
From compound 19 epoxide 2 has been obtained according
to a slight modi®caton of Samuelsson previously described
Scheme 5. Asymmetric benzylmagnesiumchloride addition to imine 7.

R. Badorrey et al. / Tetrahedron 58 02002) 341±354
345
Scheme 6. Synthesis of chiral epoxide 2.
The synthetic scheme designed for the synthesis of -2S,4R)-
N-tert-butoxycarbonyl-4-hydroxypipecolic acid thus started
with the reaction between imine 9, derived from -S)-2,3-di-
O-benzylglyceraldehyde and -R)-a-methylbenzylamine
-matched pair), and Danishefsky's diene. On using aceto-
nitrile as the solvent at 2208C and in the presence of ZnI2,
the reaction afforded enaminone 22 of S con®guration at C2
as a single diasteroisomer in 73% yield. Selective reduction
of enaminone 22 with l-selectridew in THF at 2788C gave
the 4-piperidinone 23. Although in some cases it has been
reported11,22c that 4-oxopipecolic acid derivatives are
reduced to cis 4-hydroxypipecolic acid derivatives using
l- or k-selectridew as reducing agents, the reaction of
4-piperidinone 23 with l-selectridew afforded the corre-
sponding 4-hydroxy compound 24 of trans con®guration
as a single diastereoisomer. This behaviour is in accordance
with previously reported studies on the reduction of 2,6-
disubstituted-4-oxo-piperidines.32 Alternatively, upon
treatment of 4-piperidinone 23 with sodium borohydride
cis 4-hydroxy derivative 25 was obtained with total
diastereoselectivity -Scheme 7).
Once the stereochemistry of the carbonyl reduction step had
been determined, the one-step reduction of enamidone 22 to
cis 4-hydroxy derivative 25 with sodium borohydride was
tested. The simultaneous reduction of the double bond
moiety and the carbonyl group was successfully achieved
to yield the desired compound in 98% yield.
Compound 25 was then acetylated and converted into
the N-Boc derivative 27 by selective hydrogenolytic
N-debenzylation in the presence of di-tert-butyldicarbonate.
Scheme 7. Reaction of chiral imine 9 with Danishefsky's diene and subsequent reduction of cycloadduct 22.

346
R. Badorrey et al. / Tetrahedron 58 02002) 341±354
Scheme 8. Synthesis of 4-hydroxypipecolic acid derivative 31.
Subsequent removal of the O-benzyl groups by hydro-
genolysis using palladium hydroxide as a catalyst gave the
corresponding diol 28. Oxidative cleavage of the 1,2-diol
moiety by treatment with excess sodium periodate in the
presence of ruthenium trichloride afforded orthogonally
protected -2S,4R)-4-hydroxypipecolic acid 29, which was
coupled ef®ciently with tert-butylamine using the
coupling reagent BOP to yield the corresponding tert-butyl-
amide 30. Finally, basic hydrolysis of the acetyl group
cleanly afforded -2S,4R)-N-tert-butoxycarbonyl-4-hydroxy-
pipecolic acid tert-butylamide -31) according to Scheme 8.
and of the relative con®guration at C4 with respect to the
known con®guration at C2 is possible by nOe difference
experiments. Intraresidue Nuclear Overhauser enhance-
ments are observed between proton Ha at about 2.75 ppm
and Hd at about 3.51 ppm which indicate the proximity of
these nuclei and its 1,3-diaxial disposition proving the cis
stereochemistry of compound 25.
The assignment of the trans con®guration for diastereomeric
compound 24 follows by elimination and it is also consistent
with the nuclear Overhauser enhancements observed for the
acetylated compound 32. Acetilation was necessary to
1
In this way the required intermediate 32 for the synthesis of
Palinavir was constructed stereoselectively from chiral
imine 8 in eight steps and about 31% overall yield.
obtain and H NMR spectrum in which the signal due to
Hd appeared well resolved as a lone multiplet. Representa-
tive nuclear Overhauser enhancements are collected in
Fig. 2.
Comparison of the speci®c rotation of compound 31,
[a]D ˆ264.4 -c 1.03, CH3OH), with the known value20
25
for
-2S,4R)-N-tert-butoxycarbonyl-4-hydroxypipecolic
acid tert-butylamide allowed us to further con®rm the
stereochemistry and enantiomeric purity of the compound
obtained.
Although this route can be judged unsuitable for scale-up it
should be amenable to the preparation of other substituted
pipecolic acids as stereoisomeric compounds of 32.
2.5. Structural assignments
A detailed study of the 1H NMR spectral data of compounds
24 and 25, produced in the reduction of 4-piperidinone 23
with l-selectridew or sodium borohydride, respectively,
allowed complete structural assignments to be made.
1
The signals of the H NMR spectrum of compound 25 can
be assigned by a DQF-COSY spectrum. The complete
assignment of the diastereotopic protons -axial vs equatorial)
Figure 2. Determination of the relative con®guration of products 25 and 32
derived from reduction of piperidone 23 by means of nOe measurements.

R. Badorrey et al. / Tetrahedron 58 02002) 341±354
347
3. Conclusion
anisaldehyde/sulphuric acid/ethanol -2:1:100). Column
chromatography was performed using silica gel -Kiesegel
60). Chemicals for reactions were used as purchased from
The Aldrich Chemical Co. Compounds 7 and 9 were syn-
thesised from -S)-2,3-di-O-benzylglyceraldehyde according
to our previously described procedures for ent-75 and ent-
9,4c respectively. 3,4-O-Isopropylidene-l-mannitol -13) was
obtained from l-manonic-g-lactone according to the litera-
ture procedure.30 Benzylmagnesium bromide -ca. 0.8 M
solution in diethyl ether) was prepared according to
Brown's procedure.34
We have designed convenient and completely stereo-
selective processes for the synthesis of -2S,3S)-N-tert-
butoxycarbonyl-1-phenyl-3,4-epoxy-2-butylamine
and
-2S,4R)-4-hydroxypipecolic acid tert-butylamide, key inter-
mediates in the synthesis of the right-handed segment of
Palinavir, from the common starting material -S)-2,3-di-O-
benzylglyceraldehyde. The stereoselective synthesis of
-2S,3S)-N-tert-butoxycarbonyl-1-phenyl-3,4-epoxy-2-butyl-
amine is based on a low temperature benzylmagnesium
bromide addition to the N-benzylimine derived from
O-protected -S)-glyceraldehyde which confers a high versa-
tility to this methodology as the use of the imine with the
appropriate absolute con®guration and the right choice of
the conditions to perform the cyclisation would allow the
synthesis of any diastereoisomer of the epoxide. Moreover
by changing the organometallic reagent it would be possible
to obtain key intermediates to the synthesis of new
analogues of hydroxyethylamine-based HIV protease
inhibitors with different side chains which is important to
optimise the aqueous solubility and antiviral activity.33
4.2.1. $2S,3R)-3-Benzylamino-1,2-di-O-isopropylidene-4-
phenyl-1,2-butanediol $10). A solution of chiral imine 5
-1.1 g, 5 mmol) in diethyl ether -20 mL) was added drop-
wise over 30 min to a stirred solution of benzylmagnesium
chloride -1 M solution in diethyl ether, 10.5 mL,
10.5 mmol) at 2208C under argon. After being stirred for
15 h at room temperature, the reaction mixture was poured
into saturated aqueous NH4Cl -30 mL), the organic layer
separated and the aqueous layer extracted with diethyl
ether -3£10 mL). The combined organic layers were dried
over anhydrous MgSO4, ®ltered and concentrated in vacuo.
Puri®cation of the residue by ¯ash chromatography eluting
with diethyl ether/hexane 1:1 afforded 1.17 g -75%) of
-2S,3R)-3-benzylamino-1,2-di-O-isopropylidene-4-phenyl-
4. Experimental
1,2-butanediol -10) as a yellowish oil. [a]D ˆ10.8 -c 1,
4.1. General procedures
25
CHCl3); IR -neat) 3405 cm21; 1H NMR -300 MHz, CDCl3)
d 1.32 -s, 3H), 1.39 -s, 3H), 1.90 -brs, 1H), 2.68±2.78 -m,
2H), 2.81±2.88 -m, 1H), 3.67 -dd, Jˆ8, 7 Hz, 1H), 3.75 -d,
Jˆ13.2Hz, 1H), 3.83 -dd, Jˆ8, 6.5 Hz, 1H), 3.86 -d,
Jˆ13.2Hz, 1H), 4.04±4.11 -m, 1H), 7.15±7.30 -m, 10H);
13C NMR -75 MHz, CDCl3) d 25.2, 26.6, 37.3, 51.6, 60.0,
66.5, 77.6, 108.8, 126.3, 126.8, 128.1, 128.3, 128.5, 129.3,
138.7, 140.4; HRMS -FAB1): m/zˆ312.1970 -MH1 calcd
for C20H26NO2: 312.1963).
Melting points were determined in open capillaries using a
BuÈchi capillary melting point apparatus and are not
corrected. Infrared spectra were recorded on a Perkin±
Elmer 1600FT spectrophotometer as neat liquids or as
nujol dispersions, and prominent peaks are expressed in
cm21. NMR spectra were recorded on Varian Unity-300
or Bruker ARX-300 instruments operating at 300 MHz for
1H NMR and at 75 MHz for 13C NMR. The chemical shifts
-d) are reported in parts per million and the coupling
constants -J) in Hertz. The following abbreviations are
used: s, singlet; d, doublet; t, triplet; m, multiplet; bs,
broad signal; bd, broad doublet; dd, doublet of doublets,
4.2.2. $2S,3R)-3-tert-Butoxycarbonylamino-1,2-di-O-iso-
propylidene-4-phenyl-1,2-butanediol $11). To a stirred
suspension of 20% Pd-OH)2/C -250 mg) in absolute ethanol
-10 mL) under H2 at 1 atm, was added a solution of -2S,3R)-
3-benzylamino-1,2-di-O-isopropylidene-4-phenyl-1,2-
butanediol -10) -935 mg, 3 mmol) in absolute ethanol
-10 mL). The reaction was vigorously stirred at room
temperature overnight, ®ltered and the solvent evaporated
in vacuo. The obtained residue, diisopropylethylamine
-45 mg, 0.35 mmol) and di-tert-butyl dicarbonate -1.31 g,
6 mmol) were dissolved in dry THF -25 mL). After being
stirred at 608C for 2h the reaction mixture was concentrated
in vacuo to afford a crude product, which was puri®ed by
¯ash chromatography eluting ®rst with diethyl ether/hexane
-1:7) and then with diethyl ether/hexane -1:5) to give
-2S,3R)-3-tert-butoxycarbonylamino-1,2-di-O-isopropyl-
idene-4-phenyl-1,2-butanediol -11) -491 mg, 51%) as a
ddd, doublet of doublet of doublets. The H and 13C NMR
1
spectra of N-Boc protected compounds were not conclusive
at room temperature due to the presence of a dynamic equi-
librium between rotamers caused by the restricted rotation
of the nitrogen±carbon bond of the urethane group. In order
to overcome this problem NMR spectra of these compounds
were acquired at 333 K. Optical rotations were measured on
a Perkin±Elmer 241-C polarimeter at 258C with concentra-
tions given in g 100 mL21. Elemental analyses were
performed using a Perkin±Elmer 200 C,H,N,S elemental
analyser. Electron impact mass spectra were obtained on a
high resolution VG-autospec spectrometer.
4.2. Materials
white solid. Mpˆ918C -lit.35 mp 89±908C); [a]D ˆ138.3
25
-c 1, CHCl3) {lit.35 [a]D ˆ135.8 -c 1.5, CHCl3)}; IR
Tetrahydrofuran -THF) and diethyl ether were distilled from
sodium benzophenone ketyl. Chloroform and dichloro-
methane were distilled from P2O5. Dimethylformamide
20
1
-Nujol) 3400, 1695 cm21; H NMR -300 MHz, CDCl3) d
1.31 -s, 3H), 1.39 -s, 9H), 1.44 -s, 3H), 2.82 -dd, Jˆ13.8,
8.1 Hz, 1H), 2.89 -dd, Jˆ13.8, 7 Hz, 1H), 3.64 -dd, Jˆ8.1,
6.9 Hz, 1H), 3.80±3.90 -m, 1H), 3.87 -dd, Jˆ8.1, 6.9 Hz,
1H), 4.07 -ddd, Jˆ6.9, 6.9, 2.1 Hz, 1H), 4.68 -bd, Jˆ7.8 Hz,
1H), 7.15±7.30 -m, 5H); 13C NMR -75 MHz, CDCl3) d
25.0, 26.4, 28.4, 39.7, 52.5, 66.4, 75.7, 79.4, 109.1, 126.5,
Ê
was dried for two days with 3 A molecular sieves. Aceto-
nitrile was distilled from anhydrous CaCl2. Whenever
possible the reactions were monitored by TLC. TLC was
performed on precoated silica gel polyester plates and
products were visualised using UV light -254 nm) and

348
R. Badorrey et al. / Tetrahedron 58 02002) 341±354
128.5, 129.5, 138.2, 155.8; Elemental analysis calcd -%) for
C18H27NO4: C, 67.26; H, 8.47; N, 4.35; found: C, 67.56; H,
8.53; N, 4.41.
residue by ¯ash chromatography -diethyl ether/hexanes,
1:1). [a]D ˆ237.6 -c 1.10, CHCl3); IR -neat) 1734 cm21
;
25
1H NMR -300 MHz, CDCl3) d 3.76 -dd, Jˆ10.8, 5.2Hz,
1H), 3.78 -dd, Jˆ10.8, 4.5 Hz, 1H), 3.97 -ddd, Jˆ5.2, 4.5,
0.6 Hz, 1H), 4.52-d, Jˆ12.3 Hz, 1H), 4.56 -d, Jˆ12.3 Hz,
1H), 4.68 -d, Jˆ11.7 Hz, 1H), 4.73 -d, Jˆ11.7 Hz, 1H),
7.20±7.40 -m, 10H), 9.70 -d, Jˆ0.6 Hz, 1H); 13C NMR
-75 MHz, CDCl3) d 69.1, 72.7, 73.6, 82.7, 127.7, 127.8,
128.0, 128.1, 128.4, 128.5, 137.1, 137.5, 202.1; HRMS
-FAB1): m/zˆ271.1340 -MH1 calcd for C17H19O3:
271.1334).
4.2.3.
1,2,5,6-Tetra-O-benzyl-3,4-O-isopropylidene-l-
mannitol $14). To a cooled -08C) solution of 3,4-O-iso-
propylidene-l-mannitol -13) -7.75 g, 35 mmol) in dry
THF -100 mL) under an atmosphere of argon was added
NaH -60% dispersion in mineral oil, 7.37 g, 175 mmol),
tetrabutylammonium iodide -12.95 g, 35 mmol) and benzyl
bromide -59.85 g, 350 mmol). After stirring at room
temperature overnight, the reaction mixture was partitioned
between water -50 mL) and diethyl ether -100 mL). The
organic layer was separated and the aqueous layer extracted
with diethyl ether -3£30 mL). The combined organic layers
were dried over anhydrous MgSO4, ®ltered and concen-
trated in vacuo. The residue was puri®ed by ¯ash chromato-
graphy on a silica gel column. Elution ®rst with hexanes and
then with diethyl ether/hexanes -1:4) gave 18.7 g -92%
yield) of 1,2,5,6-tetra-O-benzyl-3,4-O-isopropylidene-l-
4.2.6.
$1S,2R)-N-Benzyl-2,3-dibenzyloxy-1-benzyl-1-
propylamine $16). A solution of chiral imine 7 -1.25 g,
3.5 mmol) in diethyl ether -5 mL) was added dropwise
over 30 min to a stirred solution of benzylmagnesium
bromide -0.8 M solution in diethyl ether, 9.14 mL,
7.3 mmol) in diethyl ether -60 mL) at 2308C under argon.
After being stirred overnight at 2308C, the reaction mixture
was poured into saturated aqueous NH4Cl -30 mL), the
organic layer was separated and the aqueous layer extracted
with diethyl ether -2£30 mL). The combined organic layers
were dried over anhydrous MgSO4, ®ltered and concen-
trated in vacuo. Puri®cation of the residue by ¯ash chroma-
tography, eluting with diethyl ether, afforded 1.1 g -68%) of
-1S,2R)-N-benzyl-2,3-dibenzyloxy-1-benzyl-1-propylamine
mannitol -14) as a colourless oil. [a]D ˆ212.2 -c 0.95,
25
CHCl3); IR -neat) 1096 cm21
;
1H NMR -300 MHz,
CDCl3) d 1.33 -s, 3H), 3.56±3.63 -m, 1H), 3.70±3.78 -m,
2H), 4.15±4.17 -m, 1H), 4.45 -s, 2H), 4.55 -d, Jˆ11.7 Hz,
1H), 4.71 -d, Jˆ11.7 Hz, 1H), 7.24±7.29 -m, 10H); 13C
NMR -75 MHz, CDCl3) d 27.1, 70.6, 72.7, 73.3, 78.5,
79.2, 109.7, 127.5, 127.5, 127.5, 127.8, 128.2, 128.3,
138.3, 138.5; HRMS -FAB1): m/zˆ583.3041 -MH1 calcd
for C37H43O6: 583.3059).
-16) as a yellowish oil. [a]D ˆ16.0 -c 1, CHCl3); IR -neat)
25
1
3083 cm21; H NMR -300 MHz, CDCl3) d 2.75±2.92 -m,
2H), 2.94±3.02 -m, 1H), 3.60±3.68 -m, 1H), 3.70±3.80 -m,
4H), 4.44 -d, Jˆ11.9 Hz, 1H), 4.49 -d, Jˆ11.9 Hz, 1H), 4.54
-d, Jˆ11.8 Hz, 1H), 4.77 -d, Jˆ11.8 Hz, 1H), 7.05±7.40 -m,
20H); 13C NMR -75 MHz, CDCl3) d 36.9, 51.8, 59.9, 71.6,
72.7, 73.4, 78.7, 126.0, 126.8, 127.5, 127.7, 127.8, 128.2,
128.2, 128.3, 128.4, 129.2, 138.4, 139.0, 139.8, 140.7;
HRMS -FAB1): m/zˆ452.2596 -MH1 calcd for
C31H34NO2: 452.2589).
4.2.4. 1,2,5,6-Tetra-O-benzyl-l-mannitol $15). 1,2,5,6-
Tetra-O-benzyl-3,4-O-isopropylidene-l-mannitol -14) -17.5 g,
30 mmol) was dissolved in 70% acetic acid -80 mL) and the
resulting solution stirred at 1008C for 2h. The solution was
carefully concentrated in vacuo and the residue obtained
was dissolved in diethyl ether -60 mL) and washed with
saturated aqueous NaHCO3 -30 mL). The organic layer
was separated, dried over MgSO4 and the solvent evapo-
rated in vacuo. Puri®cation of the residue by ®ltration
through a silica gel pad, eluting with diethyl ether/hexanes
-1:1), gave 13.7 g -84% yield) of 1,2,5,6-tetra-O-benzyl-l-
4.2.7. $1S,2R)-N-tert-Butoxycarbonyl-2,3-dibenzyloxy-1-
benzyl-1-propylamine $18). To a stirred suspension of
20% Pd-OH)2/C -150 mg) in absolute ethanol -10 mL)
under H2 at 1 atm, was added a solution of -1S,2R)-N-
benzyl-2,3-dibenzyloxy-1-benzyl-1-propylamine -16) -780 mg,
1.75 mmol) in absolute ethanol -6 mL). The reaction was
vigorously stirred at room temperature overnight, ®ltered
and the solvent evaporated in vacuo. The obtained residue,
diisopropylethylamine -26 mg, 0.2 mmol) and di-tert-butyl
dicarbonate -765 mg, 3.5 mmol) were dissolved in dry THF
-15 mL). After being stirred at 608C for 2h the reaction
mixture was concentrated in vacuo to afford a crude
product, which was puri®ed by ¯ash chromatography elut-
ing ®rst with diethyl ether/hexane -1:7) and then with
diethyl ether/hexane -1:5) to give -1S,2R)-N-tert-butoxy-
carbonyl-2,3-dibenzyloxy-1-benzyl-1-propylamine -18) -525
mannitol -15) as a colourless oil. [a]D ˆ112.7 -c 1.02,
25
CHCl3) {lit.36 for enantiomer of 15 [a]D ˆ212.4 -c 0.83,
20
1
CHCl3)}; IR -neat) 3450, 1092cm 21; H NMR -300 MHz,
CDCl3) d 3.02-d, Jˆ6 Hz, 1H), 3.62±3.79 -m, 3H), 3.95 -d,
Jˆ6 Hz, 1H), 4.53 -s, 2H), 4.57 -d, Jˆ11.7 Hz, 1H), 4.71 -d,
Jˆ11.7 Hz, 1H), 7.24±7.29 -m, 10H); 13C NMR -75 MHz,
CDCl3) d 69.9, 70.2, 73.0, 73.5, 79.2, 127.6, 127.7, 127.7,
127.9, 128.4, 138.0, 138.1; HRMS -FAB1): m/zˆ543.2762
-MH1 calcd for C34H39O6: 543.2746).
4.2.5. $S)-2,3-Di-O-benzyl-l-glyceraldehyde $8). To a
solution of 1,2,5,6-tetra-O-benzyl-l-mannitol -15) -2.9 g,
5.35 mmol) in methanol -30 mL) was added solid NaIO4
-1.37 g, 6.4 mmol) with vigorous stirring. After being stir-
red at room temperature for 24 h the reaction mixture was
®ltered and the solid washed with diethyl ether -3£30 mL).
The combined organic ®ltrates were evaporated in vacuo
and the residue was dissolved in diethyl ether, ®ltered and
evaporated in vacuo to afford 1.37 g -95% yield) of -S)-2,3-
di-O-benzyl-l-glyceraldehyde -8) as a thick oil, which was
used without further puri®cation. An analytically pure
sample of the aldehyde was obtained by puri®cation of the
mg, 66%) as a colourless oil. [a]D ˆ29.9 -c 1, CHCl3); IR
25
-neat) 3440, 1713 cm21; 1H NMR -300 MHz, CDCl3) d 1.37
-s, 9H), 2.78±2.86 -m, 2H), 3.50±3.67 -m, 3H), 4.01±4.08
-m, 1H), 4.42-d, Jˆ12Hz, 1H), 4.50 -d, Jˆ12Hz, 1H),
4.53 -d, Jˆ11.7 Hz, 1H), 4.74 -d, Jˆ11.7 Hz, 1H), 4.85
-brs, 1H), 7.10±7.40 -m, 15H); 13C NMR -75 MHz,
CDCl3) d 28.4, 39.0, 53.5, 71.6, 73.1, 73.6, 77.5, 79.1,
126.3, 127.6, 127.7, 127.8, 128.0, 128.4, 128.4, 129.4,
138.4, 138.6, 155.6; HRMS -FAB1): m/zˆ461.2559 -M1
calcd for C29H35NO4: 461.2566).

R. Badorrey et al. / Tetrahedron 58 02002) 341±354
349
4.2.8. $2R,3S)-3-tert-Butoxycarbonylamino-4-phenyl-1,2-
butanediol $19). A solution of -1S,2R)-N-tert-butoxycar-
bonyl-2,3-dibenzyloxy-1-benzyl-1-propylamine -18) -230
mg, 0.5 mmol) in methanol -5 mL) was hydrogenated with
20 wt% Pd-OH)2 -75 mg) catalyst at room temperature and
hydrogen at atmospheric pressure for 5 h. When the reaction
was complete the catalyst was removed by ®ltration and the
®ltrate evaporated to dryness. The resulting crude material
was puri®ed by ®ltration through a silica gel pad, eluting
with diethyl ether, to give 132mg -94% yield) of -2 R,3S)-3-
tert-butoxycarbonylamino-4-phenyl-1,2-butanediol -19) as
were dried over anhydrous MgSO4, ®ltered and concen-
trated in vacuo. The residue was puri®ed by ¯ash chromato-
graphy on a silica gel column. Elution with diethyl ether/
hexanes -1:1) gave 575 mg -96% yield) of -2S,3R)-N-tert-
butoxycarbonyl-4-tert-butyldimethylsilyloxy-3-mesyloxy-
1-phenyl-2-butylamine -21) as an oil. [a]D ˆ235.0 -c 1,
25
1
CHCl3); IR -neat) 3378, 1710 cm21; H NMR -300 MHz,
CDCl3) d 0.03 -s, 3H), 0.05 -s, 3H), 0.88 -s, 9H), 1.35 -s,
9H), 2.83 -dd, Jˆ14.1, 7.8 Hz, 1H), 2.93 -dd, Jˆ14.1,
6.7 Hz, 1H), 3.06 -s, 3H), 3.80 -dd, Jˆ11.5, 5.3 Hz, 1H),
3.84 -dd, Jˆ11.5, 6.5 Hz, 1H), 4.09±4.18 -m, 1H), 4.64 -bs,
1H), 4.66±4.71 -m, 1H), 7.15±7.30 -m, 5H); 13C NMR
-75 MHz, CDCl3) d 25.6, 25.5, 18.3, 25.9, 28.3, 38.6,
38.9, 52.6, 63.4, 79.8, 83.6, 126.7, 128.4, 129.4, 137.4,
155.3; HRMS -FAB1): m/zˆ473.2278 -M1 calcd for
C22H39NO6SSi: 473.2267).
a
white solid. Mp 808C -lit.37 mp 88.5±90.58C);
[a]D ˆ236.0 -c 1, CHCl3) {lit.37 [a]D ˆ236.8 -c 1,
25
20
CHCl3)}; IR -Nujol) 3370, 1691 cm21
;
1H NMR
-300 MHz, CDCl3) d 1.38 -s, 9H), 2.89 -d, Jˆ7.8 Hz,
2H), 3.46±3.61 -m, 2H), 3.62±3.70 -m, 1H), 3.83±3.95
-m, 1H), 4.76 -bd, Jˆ8.7 Hz, 1H), 7.15±7.30 -m, 5H); 13C
NMR -75 MHz, CDCl3) d 28.3, 38.5, 53.0, 64.3, 72.0, 80.0,
126.5, 128.6, 129.2, 138.1, 156.7; Elemental analysis calcd
-%) for C15H23NO4: C, 64.04; H, 8.24; N, 4.98; found: C,
64.12; H, 8.27; N, 5.03.
4.2.11.
$2S,3S)-N-tert-Butoxycarbonyl-1-phenyl-3,4-
epoxy-2-butylamine $2). A 1 M solution of tetrabutyl-
ammonium ¯uoride in THF -1.3 mL, 1.3 mmol) was
added dropwise to a solution of -2S,3R)-N-tert-butoxy-
carbonyl-4-tert-butyldimethylsilyloxy-3-mesyloxy-1-phenyl-
2-butylamine -21) -310 mg, 0.65 mmol) in dry THF -6 mL)
at 08C. The solution was then warmed up to room tempera-
ture and stirred overnight. The reaction mixture was par-
titioned between water -3 mL) and diethyl ether -5 mL). The
organic layer was separated and the aqueous layer extracted
with diethyl ether -3£10 mL). The combined organic layers
were dried over anhydrous MgSO4, ®ltered and concen-
trated in vacuo. The residue was puri®ed by ¯ash chromato-
graphy on a silica gel column. Elution ®rst with diethyl
ether/hexanes -1:5) and then with diethyl ether/hexanes
-1:1) gave 115 mg -67% yield) of -2S,3S)-N-tert-butoxy-
carbonyl-1-phenyl-3,4-epoxy-2-butylamine -2) as a pale
yellow solid. Mp 1238C -lit.7a mp 122±124.58C);
4.2.9. $2R,3S)-3-tert-Butoxycarbonylamino-1-tert-butyl-
dimethylsilyloxy-4-phenyl-2-butanol $20). A solution of
-2R,3S)-3-tert-butoxycarbonylamino-4-phenyl-1,2-butane-
diol -19) -380 mg, 1.35 mmol), tert-butyldimethyl-
silylchloride -225 mg, 1.5 mmol) and imidazole -204 mg,
3 mmol) in dry dimethylformamide -7 mL) was stirred at
room temperature for 24 h. The mixture was diluted with
diethyl ether -25 mL) and washed with saturated aqueous
NH4Cl -12mL). The organic layer was treated with water,
the organic layer separated and the aqueous layer extracted
with diethyl ether -3£15 mL). The combined organic layers
were dried over anhydrous MgSO4, ®ltered and concen-
trated in vacuo. The crude product was puri®ed by ¯ash
chromatography on a silica gel column. Successive elution
with diethyl ether/hexanes -1:5), diethyl ether/hexanes -1:3)
and diethyl ether/hexanes -1:1) gave 507 mg -95% yield) of
-2R,3S)-3-tert-butoxycarbonylamino-1-tert-butyldimethyl-
silyloxy-4-phenyl-2-butanol -20) as a white solid. Mp 838C;
[a]D ˆ16.6 -c 1.1, CHCl3) {lit.7a [a]Dˆ16.9 -c 1,
25
CHCl3)}; [a]D ˆ29.0 -c 1.1, CH3OH) {lit.7a [a]Dˆ28.6
25
1
-c 1, CH3OH)}; IR -nujol) 3374, 1677 cm21; H NMR
-300 MHz, CDCl3) d 1.37 -s, 9H), 2.70 -dd, Jˆ4.9,
2.6 Hz, 1H), 2.74 -dd, Jˆ4.9, 3.9 Hz, 1H), 2.83 -dd,
Jˆ14.1, 7.5 Hz, 1H), 2.86±2.94 -m, 1H), 2.96 -dd,
Jˆ14.1, 5.2Hz, 1H), 3.58±3.76 -m, 1H), 4.36 -brs, 1H),
7.18±7.30 -m, 5H); 13C NMR -75 MHz, CDCl3) d 28.2,
37.7, 46.4, 52.9, 53.2, 79.6, 126.6, 128.4, 129.3, 136.9,
155.2; Elemental analysis calcd -%) for C15H21NO3: C,
68.41; H, 8.04; N, 5.32; found: C, 68.38; H, 8.09; N, 5.21.
[a]D ˆ224.0 -c 1, CHCl3); IR -nujol) 3357, 1668 cm21
;
25
1H NMR -300 MHz, CDCl3) d 0.02-s, 3H), 0.03 -s, 3H),
0.87 -s, 9H), 1.38 -s, 9H), 2.56 -bs, 1H), 2.90 -d, Jˆ8 Hz,
1H), 3.47±3.59 -m, 2H), 3.60±3.65 -m, 1H), 3.72±3.80 -m,
1H), 4.96 -bd, Jˆ9 Hz, 1H), 7.15±7.25 -m, 5H); 13C NMR
-75 MHz, CDCl3) d 25.5, 25.4, 18.3, 25.9, 28.4, 39.0, 53.8,
65.1, 71.4, 79.3, 126.3, 128.4, 129.5, 138.6, 155.9; Elemen-
tal analysis calcd -%) for C21H37NO4Si: C, 63.76; H, 9.43;
N, 3.54; found: C, 63.82; H, 9.37; N, 3.51.
4.2.12. $S)-N-[$R)-a-Methylbenzyl]-2-[$R)-1,2-dibenzyl-
oxyethyl]-5,6-dihydro-4-pyridone $22). To a suspension
of ZnI2 -2.25 g, 7 mmol) in dry acetonitrile -30 mL), cooled
under argon at 2208C, was added a solution of the crude
imine 9 -2.60 g, 7 mmol) in dry acetonitrile -6 mL) and the
mixture was stirred for 10 min. Danishefsky's diene -1.8 g,
2mL, 10.5 mmol) was then added in one portion by syringe
and the reaction was stirred overnight at 2208C. The result-
ing dark yellow solution was partitioned between saturated
aqueous NaHCO3 -30 mL) and dichloromethane -30 mL).
The organic layer was separated and the aqueous layer
extracted with dichloromethane -3£20 mL). The combined
organic phases were washed with 1N HCl and brine, dried
over MgSO4 and the solvent evaporated in vacuo. The
resulting dark-coloured oil was puri®ed by ®ltration through
a silica gel pad -diethyl ether followed by ethyl acetate as
4.2.10.
$2S,3R)-N-tert-Butoxycarbonyl-4-tert-butyl-
dimethylsilyloxy-3-mesyloxy-1-phenyl-2-butylamine
$21). A solution of methanesulfonyl chloride -170 mg,
1.5 mmol) in dry dichloromethane -1 mL) was added drop-
wise to a solution of -2R,3S)-3-tert-butoxycarbonylamino-
1-tert-butyldimethylsilyloxy-4-phenyl-2-butanol -20) -500
mg, 1.27 mmol) and triethylamine -150 mg, 1.5 mmol) in
dry dichloromethane -10 mL) at 08C under argon. The solu-
tion was allowed to warm up to room temperature and, after
stirring for 1 h, the reaction mixture was partitioned
between water -5 mL) and dichloromethane -5 mL). The
organic layer was separated and the aqueous layer extracted
with diethyl ether -3£15 mL). The combined organic layers

350
R. Badorrey et al. / Tetrahedron 58 02002) 341±354
eluents) to yield 2.4 g -78% yield) of -S)-N-[-R)-a-methyl-
benzyl]-2-[-R)-1,2-dibenzyloxyethyl]-5,6-dihydro-4-pyri-
puri®ed by ®ltration through a silica gel pad, eluting ®rst
with diethyl ether/hexanes -1:1) and then with diethyl ether/
hexanes -3:1) to yield 250 mg -86% yield) of -2S,4S)-N-
[-R)-a-methylbenzyl]-2-[-R)-1,2-dibenzyloxyethyl]-4-
done -22) as a yellowish oil. [a]D ˆ296.0 -c 1, CHCl3)
25
{lit.6b for the enantiomer of 22 [a]D ˆ184.0 -c 1,
20
1
CHCl3)}; IR -neat) 1640, 1584 cm21; H NMR -300 MHz,
hydroxypiperidine -24) as a pale yellow oil. [a]D ˆ18.7 -c
25
1, CHCl3); IR -neat) 3400 cm21 1H NMR -300 MHz,
;
CDCl3) d 1.57 -d, Jˆ6.9 Hz, 3H), 2.36 -bd, Jˆ17.1 Hz,
1H), 2.73 -dd, Jˆ16.8, 6.6 Hz, 1H), 3.50 -dd, Jˆ11.1,
3.3 Hz, 1H), 3.73 -dd, Jˆ11.1, 1.8 Hz, 1H), 3.98±4.10 -m,
2H), 4.47 -d, Jˆ11.7 Hz, 1H), 4.48 -d, Jˆ12Hz, 1H), 4.54
-d, Jˆ12Hz, 1H), 4.65 -d, Jˆ11.7 Hz, 1H), 4.72-q,
Jˆ6.9 Hz, 1H), 4.77 -dd, Jˆ7.4, 1.2Hz, 1H), 6.71 -d,
Jˆ7.4 Hz, 1H), 7.20±7.40 -m, 15H); 13C NMR -75 MHz,
CDCl3) d 20.2, 37.3, 56.7, 62.7, 67.7, 72.2, 73.5, 76.4,
97.5, 127.8, 127.8, 127.8, 127.9, 128.0, 128.3, 128.4,
128.8, 137.8, 138.0, 139.2, 149.8, 190.4; HRMS -EI):
m/zˆ441.2291 -M1 calcd for C29H31NO3: 441.2303).
CDCl3) d 1.25 -d, Jˆ6.6 Hz, 3H), 1.38±1.61 -m, 3H),
1.85±1.94 -m, 1H), 2.40 -ddd, Jˆ12.3, 6, 3.9 Hz, 1H),
2.62 -ddd, Jˆ12.3, 9, 3.6 Hz, 1H), 3.11±3.20 -m, 1H),
3.62-dd, Jˆ10.5, 6.9 Hz, 1H), 3.85 -dd, Jˆ10.5, 2.1 Hz,
1H), 3.95±4.15 -m, 3H), 4.47 -d, Jˆ12Hz, 1H), 4.55 -d,
Jˆ12Hz, 1H), 4.66 -d, Jˆ11.7 Hz, 1H), 4.79 -d,
Jˆ11.7 Hz, 1H), 7.16±7.40 -m, 15H); 13C NMR -75 MHz,
CDCl3) d 13.5, 32.2, 33.4, 40.1, 54.2, 56.2, 65.4, 71.5, 72.8,
73.4, 78.6, 126.5, 127.5, 127.5, 127.6, 127.7, 128.0, 128.3,
128.3, 128.4, 138.4, 139.0, 145.0; HRMS -FAB1):
m/zˆ446.2682 -MH1 calcd for C29H36NO3: 446.2695).
4.2.13. $S)-N-[$R)-a-Methylbenzyl]-2-[$R)-1,2-dibenzyl-
oxyethyl]-4-piperidone $23). l-Selectridew -1 M, 6 mL,
6 mmol) was added dropwise to a solution of -S)-N-[-R)-
a-methylbenzyl]-2-[-R)-1,2-dibenzyloxyethyl]-5,6-dihydro-
4-pyridone -22) -2.3 g, 5.2 mmol) in dry THF -35 mL) at
2788C under an argon atmosphere. After being stirred for
72h at that temperature, the reaction mixture was quenched
with saturated aqueous NH4Cl -15 mL) and partitioned
between water -30 mL) and diethyl ether -30 mL). The
organic layer was separated and the aqueous layer extracted
with diethyl ether -3£20 mL). The combined organic phases
were washed with brine, dried over MgSO4 and the solvent
evaporated in vacuo. The crude product was puri®ed by
silica gel column chromatography eluting ®rst with diethyl
ether/hexanes -1:3) and then with diethyl ether/hexanes
-3:2) to yield 1.98 g -85% yield) of -S)-N-[-R)-a-methyl-
benzyl]-2-[-R)-1,2-dibenzyloxyethyl]-4-piperidone -23) as
4.2.15.
$2S,4R)-N-[$R)-a-Methylbenzyl]-2-[$R)-1,2-di-
benzyloxyethyl]-4-hydroxypiperidine $25). Method A. A
solution of sodium borohydride -160 mg, 4.2mmol) in 4%
aqueous sodium hydroxide -35 mL) was added dropwise to
a solution of -S)-N-[-R)-a-methylbenzyl]-2-[-R)-1,2-di-
benzyloxyethyl]-4-piperidone -23) -1.55 g, 3.5 mmol) in
THF -35 mL) at 08C. After being stirred for 30 min at that
temperature, the reaction mixture was extracted with
dichloromethane -3£15 mL). The combined organic phases
were washed with brine, dried over MgSO4 and the solvent
evaporated in vacuo. The crude product was puri®ed by
®ltration through a silica gel pad, eluting with diethyl
ether/hexanes -3:1) to yield 1.34 g -86% yield) of -2S,4R)-
N-[-R)-a-methylbenzyl]-2-[-R)-1,2-dibenzyloxyethyl]-4-
hydroxypiperidine -25) as a colourless oil.
a colourless oil. [a]D ˆ21.0 -c 1, CHCl3) {lit.6b for the
Method B. Sodium borohydride -1.73 g, 45.5 mmol) was
added to a solution of -S)-N-[-R)-a-methylbenzyl]-2-[-R)-
1,2-dibenzyloxyethyl]-5,6-dihydro-4-pyridone -22) -2 g,
4.55 mmol) in ethanol -100 mL). After being stirred for
16 h at room temperature, the reaction mixture was
neutralised with 1N hydrochloric acid and concentrated in
vacuo. The resulting solution was extracted with dichloro-
methane -3£25 mL), the combined organic phases were
dried over MgSO4 and the solvent evaporated in vacuo.
The crude product was puri®ed by ®ltration through a
silica gel pad, eluting with ethyl acetate to yield 1.98 g
-98% yield) of -2S,4R)-N-[-R)-a-methylbenzyl]-2-[-R)-
25
enantiomer of 23 [a]D ˆ10.8 -c 1, CHCl3)}; IR -neat)
20
1712cm 21
;
1H NMR -300 MHz, CDCl3) d 1.35 -d,
Jˆ6.6 Hz, 3H), 2.10±2.19 -m, 2H), 2.33 -ddd, Jˆ16.6,
9.9, 6.6 Hz, 1H), 2.60 -dd, Jˆ15, 6.6 Hz, 1H), 3.08±3.18
-m, 1H), 3.23±3.28 -m, 1H), 3.35 -ddd, Jˆ13.8, 9.9, 4.2Hz,
1H), 3.54±3.62-m, 1H), 3.65±3.70 -m, H2), 4.00 -q,
Jˆ6.6 Hz, 1H), 4.45 -d, Jˆ12Hz, 1H), 4.50 -d, Jˆ12Hz,
1H), 4.55 -d, Jˆ11.4 Hz, 1H), 4.63 -d, Jˆ11.4 Hz,
1H), 7.10±7.40 -m, 15H); 13C NMR -75 MHz, CDCl3)
d 19.2, 38.0, 40.1, 43.4, 58.5, 58.7, 71.8, 73.4, 73.5,
81.2, 127.1, 127.2, 127.4, 127.5, 127.6, 128.1, 128.2,
128.3, 128.4, 138.2, 138.3, 145.2, 209.0; HRMS
-FAB1): m/zˆ444.2551 -MH1 calcd for C29H34NO3:
444.2538).
1,2-dibenzyloxyethyl]-4-hydroxypiperidine -25) as
colourless oil.
a
[a]D ˆ20.7 -c 0.95, CHCl3); IR -neat) 3403 cm21; H
1
25
4.2.14.
$2S,4S)-N-[$R)-a-Methylbenzyl]-2-[$R)-1,2-di-
NMR -300 MHz, CDCl3) d 1.11±1.30 -m, 2H), 1.16 -d,
Jˆ6.9 Hz, 3H), 1.57±1.75 -m, 1H), 2.08 -ddd, Jˆ11.7,
11.7, 2.4 Hz, 1H), 2.30 -dddd, Jˆ12, 4.5, 2.4, 2.4 Hz, 1H),
2.43 -ddd, Jˆ11.7, 3.9, 3.9 Hz, 1H), 2.75 -ddd, Jˆ10.5, 4.5,
2.7 Hz, 1H), 3.45±3.60 -m, 1H), 3.68 -dd, Jˆ10.5, 7.5 Hz,
1H), 3.99 -dd, Jˆ10.5, 1.2Hz, 1H), 4.03±4.14 -m, 2H), 4.47
-d, Jˆ12Hz, 1H), 4.60 -d, Jˆ12Hz, 1H), 4.70 -d,
Jˆ11.7 Hz, 1H), 4.84 -d, Jˆ11.7 Hz, 1H), 7.18±7.40 -m,
15H); 13C NMR -75 MHz, CDCl3) d 9.1, 34.5, 35.1, 42.6,
54.1, 57.3, 69.4, 71.3, 72.7, 73.5, 77.7, 126.5, 127.4, 127.5,
127.6, 127.6, 127.7, 128.0, 128.3, 128.3, 128.4, 138.2,
138.8, 143.9; HRMS -FAB1): m/zˆ446.2687 -MH1 calcd
for C29H36NO3: 446.2695).
benzyloxyethyl]-4-hydroxypiperidine $24). l-Selectridew
-1 M, 0.75 mL, 0.75 mmol) was added dropwise to a
solution of -S)-N-[-R)-a-methylbenzyl]-2-[-R)-1,2-dibenzyl-
oxyethyl]-4-piperidone -23) -288 mg, 0.65 mmol) in dry
THF -10 mL) at 2788C under an argon atmosphere. After
being stirred for 1 h at that temperature, the reaction mixture
was quenched with saturated aqueous NH4Cl -5 mL) and
partitioned between water -5 mL) and diethyl ether
-15 mL). The organic layer was separated and the aqueous
layer extracted with diethyl ether -3£15 mL). The combined
organic phases were washed with brine, dried over MgSO4
and the solvent evaporated in vacuo. The crude product was

R. Badorrey et al. / Tetrahedron 58 02002) 341±354
351
4.2.16.
$2S,4R)-N-[$R)-a-Methylbenzyl]-2-[$R)-1,2-di-
pressure for 2h. When the reaction was complete the
catalyst was removed by ®ltration and the solid washed
with ethyl acetate -3£20 mL). The combined organic
extracts were evaporated to dryness and the resulting
crude material was puri®ed by ®ltration through a silica
gel pad, eluting with ethyl acetate to give -2S,4R)-N-tert-
butoxycarbonyl-2-[-R)-1,2-dihydroxyethyl]-4-acetyloxy-
piperidine -28) -515 mg, 85%) as a colourless oil.
benzyloxyethyl]-4-acetyloxypiperidine $26). A solution
of -2S,4R)-N-[-R)-a-methylbenzyl]-2-[-R)-1,2-dibenzyloxy-
ethyl]-4-hydroxypiperidine -25), -1.35 g, 3 mmol) triethyl-
amine -365 mg, 3.6 mmol), dimethylaminopyridine -20 mg,
0.16 mmol) and acetic anhydride -335 mg, 3.3 mmol) in dry
dichloromethane -45 mL) was stirred at room temperature
for 2h under an argon atmosphere. The reaction mixture
was then concentrated in vacuo and the residue puri®ed
by ®ltration through a silica gel pad, eluting with diethyl
ether/hexanes -1:2) to yield 1.36 g -92% yield) of -2S,4R)-
N-[-R)-a-methylbenzyl]-2-[-R)-1,2-dibenzyloxyethyl]-4-
[a]D ˆ245.0 -c 0.93, CHCl3); IR -neat) 3465, 1735,
25
1
1663 cm21; H NMR -300 MHz, CDCl3) d 1.46 -s, 9H),
1.71±1.80 -m, 2H), 1.86±1.92 -m, 2H), 2.03 -s, 3H), 2.41
-bs, 1H), 2.91 -bs, 1H), 3.24 -ddd, Jˆ14.1, 10.2, 5.4 Hz,
1H), 3.52-ddd, Jˆ10.8, 5.6, 5.6 Hz, 1H), 3.67 -ddd,
Jˆ10.8, 6.6, 4.2Hz, 1H), 3.89 -ddd, Jˆ13.5, 3.9, 3.9 Hz,
1H), 4.01±4.10 -m, 1H), 4.42-ddd, Jˆ8.7, 4.5, 4.5 Hz, 1H),
5.06±5.10 -m, 1H); 13C NMR -75 MHz, CDCl3) d 21.1,
28.4, 29.3, 29.9, 36.3, 51.9, 64.1, 67.3, 72.6, 80.8, 156.7,
169.7; HRMS -FAB1): m/zˆ304.1753 -MH1 calcd for
C14H26NO6: 304.1760).
acetyloxypiperidine -26) as a colourless oil. [a]D ˆ24.8 -c
25
1, CHCl3); IR -neat) 1733 cm21 1H NMR -300 MHz,
;
CDCl3) d 1.15 -d, Jˆ6.9 Hz, 3H), 1.18±1.32-m, H2 ),
1.71±1.77 -m, 1H), 1.98 -s, 3H), 2.08 -ddd, Jˆ12, 12,
2.4 Hz, 1H), 2.30 -dddd, Jˆ12, 4.5, 2.4, 2.4 Hz, 1H), 2.39
-ddd, Jˆ12, 3.9, 3.9 Hz, 1H), 2.81 -ddd, Jˆ11.4, 4.5,
2.4 Hz, 1H), 3.66 -dd, Jˆ10.5, 7.8 Hz, 1H), 4.00±4.14 -m,
3H), 4.49 -d, Jˆ12.3 Hz, 1H), 4.55±4.67 -m, 1H), 4.60 -d,
Jˆ12.3 Hz, 1H), 4.70 -d, Jˆ12Hz, 1H), 4.80 -d, Jˆ12Hz,
1H), 7.18±7.40 -m, 15H); 13C NMR -75 MHz, CDCl3)
d 8.2, 21.3, 31.5, 31.7, 42.7, 53.7, 57.3, 71.0, 72.0,
72.7, 73.5, 77.2, 126.5, 127.4, 127.5, 127.5, 127.6, 127.8,
128.0, 128.3, 128.4, 138.3, 138.8, 143.5, 170.4; HRMS
-FAB1): m/zˆ488.2805 -MH1 calcd for C31H38NO4:
488.2800).
4.2.19. $2S,4R)-N-tert-Butoxycarbonyl-4-acetyloxypipe-
colic acid $29). Small portions of NaIO4 -1.5 g, 7 mmol)
were added to a stirred solution of -2S,4R)-N-tert-butoxy-
carbonyl-2-[-R)-1,2-dihydroxyethyl]-4-acetyloxypiperidine
-28) -532mg, 1.75 mmol) in acetonitrile/carbon tetra-
chloride/water -2:2:3, 50 mL). After being vigorously
stirred for 5 min following completion of the addition, the
mixture was treated with RuCl3´H2O -16.6 mg, 0.08 mmol)
and stirring was continued for 2h. Dichloromethane
-20 mL) was then added, the organic phase was separated
and the aqueous phase extracted with dichloromethane
-3£10 mL). The combined organic extracts were dried
over MgSO4 and the solvent evaporated to dryness. The
resulting crude material was puri®ed by silica gel column
chromatography eluting with diethyl ether/hexanes -2:1) to
give -2S,4R)-N-tert-butoxycarbonyl-4-acetyloxypipecolic
4.2.17.
benzyloxyethyl]-4-acetyloxypiperidine $27). A solution
of -2S,4R)-N-[-R)-a-methylbenzyl]-2-[-R)-1,2-dibenzyl-
$2S,4R)-N-tert-Butoxycarbonyl-2-[$R)-1,2-di-
oxyethyl]-4-acetyloxypiperidine -26) -1.2g, 2.5 mmol)
and di-tert-butyl dicarbonate -1.66 g, 7.6 mmol) in absolute
ethanol -15 mL) was added to a stirred suspension of 20%
Pd-OH)2/C -300 mg) in absolute ethanol -5 mL) and the
mixture was hydrogenated with H2 at 1 atm by shaking at
room temperature for 2h. After completion the reaction
mixture was ®ltered and concentrated in vacuo to afford a
crude product which was puri®ed by ¯ash chromatography
eluting ®rst with diethyl ether/hexane -1:4) and then with
diethyl ether/hexane -1:1) to give -2S,4R)-N-tert-butoxycar-
bonyl-2-[-R)-1,2-dibenzyloxyethyl]-4-acetyloxypiperidine
-27) -1.07 g, 89%) as a colourless oil. [a]D ˆ114.1 -c
acid -29) -443 mg, 88%) as a pale yellow oil.
[a]D ˆ28.9 -c 1, CHCl3); IR -neat) 3500±2800, 1742,
25
1
1695 cm21; H NMR -300 MHz, CDCl3) d 1.44 -s, 9H),
1.68 -dddd, Jˆ12.6, 11.7, 4.6, 2.2 Hz, 1H), 1.78±1.85
-m, 1H), 1.90 -ddd, Jˆ14.3, 7.2, 2.7 Hz, 1H), 1.95 -s,
3H), 2.55 -dddd, Jˆ14.3, 3.8, 2.1, 2.1 Hz, 1H), 3.25±3.35
-m, 1H), 3.85±3.92-m, 1H), 4.75±4.93 -m, 1H), 5.04±5.09
-m, 1H); 13C NMR -75 MHz, CDCl3) d 20.8, 28.4, 28.8,
30.5, 36.3, 51.0, 66.2, 80.5, 155.6, 169.8, 175.8; HRMS
-FAB1): m/zˆ288.1453 -MH1 calcd for C13H22NO6:
288.1447).
0.76, CHCl3); IR -neat) 1735, 1693 cm2125
;
1H NMR
-300 MHz, CDCl3) d 1.41 -s, 9H), 1.61±1.22 -m, 2H),
1.80 -ddd, Jˆ15, 6.6, 3.3 Hz, 1H), 1.91 -s, 3H), 1.89±1.94
-m, 1H), 2.78 -ddd, Jˆ15, 10.4, 3.9 Hz, 1H), 3.56 -dd,
Jˆ10.8, 4.8 Hz, 1H), 3.64 -dd, Jˆ10.8, 3.3 Hz, 1H),
3.83±3.94 -m, 1H), 4.03 -ddd, Jˆ9.6, 4.8. 3.3 Hz, 1H),
4.42-ddd, Jˆ9.6, 6.6, 2.4 Hz, 1H), 4.50 -d, Jˆ12Hz,
1H), 4.53 -d, Jˆ12Hz, 1H), 4.55 -d, Jˆ12Hz, 1H), 4.70
-d, Jˆ12Hz, 1H), 4.98±5.06 -m, 1H), 7.18±7.35 -m, 10H);
13C NMR -75 MHz, CDCl3) d 21.2, 28.5, 29.3, 29.7, 34.8,
51.3, 67.6, 71.3, 72.3, 73.6, 79.5, 127.5, 127.6, 127.7, 128.2,
128.2, 128.4, 138.4, 138.9, 155.4, 169.8; HRMS -FAB1):
m/zˆ484.2689 -MH1 calcd for C28H38NO6: 484.2699).
4.2.20. $2S,4R)-N-tert-Butoxycarbonyl-4-acetyloxypipe-
colic acid tert-butylamide $30). To a stirred solution of
-2S,4R)-N-tert-butoxycarbonyl-4-acetyloxypipecolic acid
-29) -496 mg, 1.72mmol) in acetonitrile/dimethylforma-
mide -10:1, 5.5 mL) at 08C under an argon atmosphere
was added tert-butylamine -190 mg, 2.6 mmol), benzo-
triazol-1-yl-oxy-tridimethylamino)phosphonium hexa¯uoro-
phosphate -BOP reagent) -840 mg, 1.9 mmol) and
diisopropylethylamine -665 mg, 5.15 mmol). After addi-
tional stirring at room temperature for 1.5 h, the reaction
mixture was ®ltered and the solvent evaporated in vacuo.
The resulting crude material was puri®ed by silica gel
column chromatography eluting with ethyl acetate to give
-2S,4R)-N-tert-butoxycarbonyl-4-acetyloxypipecolic acid
tert-butylamide -30) -535 mg, 90%) as a white solid. Mp
4.2.18.
$2S,4R)-N-tert-Butoxycarbonyl-2-[$R)-1,2-di-
hydroxyethyl]-4-acetyloxypiperidine $28). A solution of
-2S,4R)-N-tert-butoxycarbonyl-2-[-R)-1,2-dibenzyloxyethyl]-
4-acetyloxypiperidine -27) -965 mg, 2mmol) in ethanol
-20 mL) was hydrogenated with 20 wt% Pd-OH)2
-300 mg) as catalyst at room temperature and atmospheric

352
R. Badorrey et al. / Tetrahedron 58 02002) 341±354
112±1158C; [a]D ˆ27.5 -c 0.91, CH3OH); IR -nujol)
Acknowledgements
25
1
3422, 3323, 1742, 1688, 1677 cm21; H NMR -300 MHz,
CDCl3) d 1.18 -s, 9H), 1.41 -s, 9H), 1.56±1.78 -m, 3H), 1.91
-s, 3H), 2.66 -dddd, Jˆ14.7, 3.6, 1.8, 1.8 Hz, 1H), 3.08 -ddd,
Jˆ13.8, 10.7, 4.8 Hz, 1H), 3.85±3.95 -m, 1H), 4.45±4.53
-m, 1H), 4.95 -dddd, Jˆ3.6, 3.4, 3.4, 3.4 Hz, 1H), 5.67 -brs,
1H); 13C NMR -75 MHz, CDCl3) d 21.1, 28.1, 28.2, 28.8,
28.9, 36.3, 50.9, 53.3, 66.0, 80.8, 155.1, 169.3, 170.1;
Elemental analysis calcd -%) for C17H30N2O5: C, 59.63;
H, 8.83; N, 8.18; found: C, 59.38; H, 8.95; N, 8.08.
We thank DGES -PB97-0998) and DGA -P22/98) for
®nancial support of this research.
References
1. -a) Hanessian, S. Total Synthesis of Natural Products: the
Chiron Approach; Pergamon: Oxford, 1983. -b) Jurczak, J.;
Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447±488.
-c) Cintas, P. Tetrahedron 1991, 47, 6079±6111. -d) Kunz,
H.; Ruck, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 336±358.
-e) Ferrier, R. J.; Middlenton, S. Chem. Rev. 1993, 93, 2779±
2831. -f) Monneret, C.; Florent, J. C. Synlett 1994, 305±318.
-g) Collins, P.; Ferrier, R. J. Monosaccharides. Their
Chemistry and Their Roles in Natural Products; Wiley: New
York, 1995. -h) Bols, M. Carbohydrate Building Blocks;
Wiley: New York, 1966. -i) Lichtenthaler, F. W.; Mondel,
S. Pure Appl. Chem. 1997, 69, 1853±1866.
4.2.21. $2S,4R)-N-tert-Butoxycarbonyl-4-hydroxypipeco-
lic acid tert-butylamide $31). To a stirred solution of
-2S,4R)-N-tert-butoxycarbonyl-4-acetyloxypipecolic acid
-30) -531 mg, 1.55 mmol) in methanol -10 mL) was added
a 1 M aqueous solution of K2CO3 -4.65 mL). After stirring
at room temperature for 2h, the reaction mixture was
concentrated in vacuo and extracted with ethyl acetate
-3£10 mL). The combined organic extracts were dried
over MgSO4 and the solvent evaporated to dryness. The
resulting crude material was puri®ed by silica gel column
chromatography eluting with ethyl acetate/hexanes -1:1) to
2. -a) Patrocinio, V. L.; Costa, P. R. R.; Correira, C. R. D.
Synthesis 1994, 474±476. -b) Morikawa, T.; Sasaki, H.;
Hanai, R.; Shibuya, A.; Taguchi, T. J. Org. Chem. 1994, 59,
97±103. -c) Leonard, J.; Mohialdin, S.; Reed, D.; Ryan, G.;
Swain, P. A. Tetrahedron 1995, 51, 12843±12858. -d) Dubois,
L.; Dorey, G.; Potier, P.; Dood, R. H. Tetrahedron: Asymmetry
1995, 6, 455±462. -e) Handa, S.; Hawes, J. E.; Pryce, R. J.
Synth. Commun. 1995, 25, 2837±2845. -f) Chattopaghyay, A.;
Mamdapur, V. R. J. Org. Chem. 1995, 60, 585±587.
-g) Massing, U.; Eibl, H. Chem. Phys. Lipids 1995, 76,
211±224. -h) Junquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. Tetrahedron 1996, 52, 7045±7052. -i) Enders, D.;
Reinhold, U. Liebigs Ann. 1996, 11±26. -j) Niu, C. S.;
Petterson, T.; Miller, M. J. J. Org. Chem. 1996, 61, 1014±
1022. -k) Yamashita, K.; Urabe, H.; Sato, F. Tetrahedron Lett.
1997, 38, 4619±4622. -l) Sanz, J. M. B.; Sastre, J. A. L.;
Molina, R. P.; Garcia, C. R. A. J. Carbohydr. Chem. 1998,
17, 1331±1350.
give -2S,4R)-N-tert-butoxycarbonyl-4-hydroxypipecolic
acid tert-butylamide -31) -340 mg, 73%) as a white solid.
Mp 131±1328C -lit.10 mp 131±1338C); [a]D ˆ264.4 -c
25
1.03, CH3OH) {lit.10 [a]D ˆ264.9 -c 1.03, CH3OH)}; IR
25
-nujol) 3343, 1673, 1646 cm21
;
1H NMR -300 MHz,
CDCl3) d 1.31 -s, 9H), 1.47 -s, 9H), 1.56 -dddd, Jˆ13.5,
13.1, 5.3, 3.2Hz, 1H), 1.67±1.76 -m, 1H), 1.79 -ddd, Jˆ15,
6.9, 3.6 Hz, 1H), 2.20±2.28 -m, 1H), 3.14 -ddd, Jˆ13.1,
13.1, 2.7 Hz, 1H), 3.76±3.85 -m, 1H), 3.96±4.33 -m, 1H),
4.64±4.69 -m, 1H), 5.42-brs, 1H), 6.52-brs, 1H); 13C NMR
-75 MHz, CDCl3) d 28.4, 28.7, 30.8, 32.5, 35.9, 51.4, 53.9,
61.7, 80.9, 156.2, 172.7; Elemental analysis calcd -%) for
C15H28N2O4: C, 59.98; H, 9.40; N, 9.33; found: C, 59.88; H,
9.35; N, 9.26.
4.2.22.
benzyloxyethyl]-4-acetyloxypiperidine $32). A solution
of -2S,4S)-N-[-R)-a-methylbenzyl]-2-[-R)-1,2-dibenzyl-
$2S,4S)-N-[$R)-a-Methylbenzyl]-2-[$R)-1,2-di-
Â
3. -a) Badorrey, R.; Cativiela, C.; Dõaz de Villegas, M. D.;
Â
Galvez, J. A. Tetrahedron 1997, 53, 1411±1416. -b) Badorrey,
 Â
R.; Cativiela, C.; Dõaz de Villegas, M. D.; Galvez, J. A.
oxyethyl]-4-hydroxypiperidine -24) -225 mg, 0.5 mmol),
triethylamine -61 mg, 0.6 mmol), dimethylaminopyridine
-3.3 mg, 0.026 mmol) and acetic anhydride -56 mg,
0.55 mmol) in dry dichloromethane -7.5 mL) was stirred
at room temperature for 2h under an argon atmosphere.
Then the reaction mixture was concentrated in vacuo and
the residue puri®ed by ®ltration through a silica gel pad,
eluting with diethyl ether/hexanes -1:2), to yield 235 mg
-96% yield) of -2S,4S)-N-[-R)-a-methylbenzyl]-2-[-R)-1,2-
Synthesis 1997, 747±749.
 Â
4. -a) Cativiela, C.; Dõaz de Villegas, M. D.; Galvez, J. A. Tetra-
Â
hedron Lett. 1995, 36, 2859±2860. -b) Cativiela, C.; Dõaz de
Â
Villegas, M. D.; Galvez, J. A.; Garcõa, J. I. Tetrahedron 1996,
Â
Â
52, 9563±9574. -c) Badorrey, R.; Cativiela, C.; Dõaz de Ville-
Â
gas, M. D.; Galvez, J. A. Tetrahedron 1999, 55, 14145±
Â
14160. -d) Badorrey, R.; Cativiela, C.; Dõaz de Villegas,
Â
M. D.; Galvez, J. A. Tetrahedron: Asymmetry 2000, 11,
dibenzyloxyethyl]-4-acetyloxypiperidine
-32)
as
a
1015±1025.
5. Cativiela, C.; Dõaz de Villegas, M. D.; Galvez, J. A.
Tetrahedron: Asymmetry 1996, 7, 529±536.
yellowish oil. [a]D ˆ17.5 -c 1, CHCl3); IR -neat)
Â
Â
25
1735 cm21
;
1H NMR -300 MHz, CDCl3) d 1.24 -d,
Jˆ6.6 Hz, 3H), 1.49±1.60 -m, 2H), 1.96±2.07 -m, 2H),
2.03 -s, 3H), 2.40±2.57 -m, 2H), 3.08±3.17 -m, 1H), 3.62
-dd, Jˆ10.8, 6.9 Hz, 1H), 3.87 -dd, Jˆ10.8, 1.8 Hz, 1H),
3.92±4.10 -m, 2H), 4.47 -d, Jˆ12Hz, 1H), 4.55 -d,
Jˆ12Hz, 1H), 4.70 -d, Jˆ12Hz, 1H), 4.79 -d, Jˆ12Hz,
1H), 5.02±5.10 -m, 1H), 7.18±7.40 -m, 15H); 13C NMR
-75 MHz, CDCl3) d 8.2, 21.4, 29.2, 30.3, 40.5, 54.7, 56.3,
68.8, 71.2, 72.8, 73.4, 78.5, 126.5, 127.4, 127.5, 127.6,
127.8, 128.0, 128.2, 128.3, 128.3, 138.3, 138.9, 145.0,
170.4; HRMS -FAB1): m/zˆ488.2815 -MH1 calcd for
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