Synthesis of enantiopure functionalized pipecolic acids via amino acid derived N-acyliminium ions

Article abstract of DOI:10.1002/(SICI)1099-0690(199905)1999:5<1127::AID-EJOC1127>3.0.CO;2-A

The synthesis and enzymatic resolution of a novel vinylsilane-containing amino acid is described. Derivatization of this and other olefinic amino acids followed by subjection to standard N-acyliminium ion cyclization conditions provides the corresponding pipecolic acid derivatives with - in most cases - complete conservation of enantiopurity. In addition to studying the scope of this reaction, details of the N-acyliminium ion cyclization including an aza Cope equilibrium are highlighted.

Full text of DOI:10.1002/(SICI)1099-0690(199905)1999:5<1127::AID-EJOC1127>3.0.CO;2-A

FULL PAPER
Synthesis of Enantiopure Functionalized Pipecolic Acids via Amino Acid
Derived N-Acyliminium Ions
Floris P. J. T. Rutjes,*[a] Johan J. N. Veerman,[a] Wim J. N. Meester,[a] Henk Hiemstra,[a] and
Hans E. Schoemaker[b]
Keywords: Non-natural amino acids / N-Acyliminium ions / Enzymatic resolution / Pipecolic acid derivatives /
Rearrangements
The synthesis and enzymatic resolution of
a
novel
derivatives with – in most cases – complete conservation of
enantiopurity. In addition to studying the scope of this
reaction, details of the N-acyliminium ion cyclization
including an aza Cope equilibrium are highlighted.
vinylsilane-containing amino acid is described. Derivati-
zation of this and other olefinic amino acids followed by
subjection to standard N-acyliminium ion cyclization
conditions provides the corresponding pipecolic acid
Pipecolic acids (hexahydropyridine-2-carboxylic acids) amino acids 8 as starting materials for the construction of
are cyclic α-amino acids that are frequently encountered in different pipecolic acid derivatives 6. The non-natural
nature and often display interesting and potent biological amino acids 8 Ϫ available in enantiopure form by enzymatic
activity.[1] Some examples of natural products are shown resolution of the corresponding amino acid amides Ϫ
such as (S)-pipecolic acid (1),[2] baikiain (2),[3] the cis- and should after functionalization lead to the desired hetero-
trans-4-hydroxypipecolic acids (3[4] and 4[5]) and the 4-oxo cycles 6 via the N-acyliminium intermediates 7.[13]
derivative 5, which is found in the virginiamycins.[6] Pipe-
colic acids that are functionalized at the 4-position form the
major focus of this article. These types of heterocycles have
been applied as building blocks in biologically active com-
pounds[7] and may also function as rigid scaffolds for the
introduction of functional group diversity in combinatorial
chemistry approaches.[8]
Scheme 1. Retrosynthetic approach
This work was inspired by previous research in the
Hiemstra/Speckamp group on cationic cyclization reactions
of the glyoxylate adducts of the homoallylic carbamates 9
(Scheme 2).[12aϪ12c] These molecules smoothly cyclized
upon treatment with Lewis acids[12b] or protic acids[12c] to
give the cyclic products 12 as an approximately 1:1 mixture
of the cis/trans isomers. This reaction proceeds via the achi-
The general interest in these types of heterocycles has
aroused a great deal of research focused on the synthesis
of a wide range of differently functionalized pipecolic acid
ral chair-like N-acyliminium ion 10, which can undergo a
[3,3]-sigmatropic rearrangement (aza Cope rearrangement)
to the chiral isomeric N-acyliminium ion 11. Nucleophilic
attack of the olefin at the cation, followed by trapping of a
formate ion then leads to the mixture of products 12. The
existence of the aza Cope rearrangement was proven by a
trapping experiment: TFA-mediated generation of the cat-
ionic species in the presence of the hydride donor Et3SiH
gave the N-methylated allylglycine derivative 13 as the only
reaction product, showing that the rearrangement must
have taken place.[14]
The purpose of this research was to investigate whether
the enantiomerically pure amino acids 8, despite the pos-
sibility of the aza Cope rearrangement, would lead to en-
antiopure pipecolic acids. To the best of our knowledge,
there is no literature precedent for this type of cyclization
derivatives both in racemic[9] and enantiopure form.[10]
A
particular pathway that has frequently been applied consists
of the use of cationic cyclization reactions via iminium[11]
and N-acyliminium ion intermediates.[12] The latter type of
transformation is the subject of this research. As a part of
our program to utilize non-natural amino acids for syn-
thetic purposes, we set out to investigate the possibility of
using the enantiomerically pure, nucleophile-containing
[a]
Laboratory of Organic Chemistry, Institute of Molecular
Chemistry, University of Amsterdam,
Nieuwe Achtergracht 129, NL-1018 WS Amsterdam, The
Netherlands
Fax: (internat.) ϩ 31-20/525-5670
E-mail: florisr@org.chem.uva.nl
[b]
DSM Research, Department of Organic Chemistry and Biotech-
nology,
P. O. Box 18, NL-6160 MD Geleen, The Netherlands
Eur. J. Org. Chem. 1999, 1127Ϫ1135
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0505Ϫ1127 $ 17.50ϩ.50/0
1127

F. P. J. T. Rutjes et al.
FULL PAPER
(8, R ϭ H, R1 ϭ Me) and the novel vinylsilane-containing
amino acid 21.
Scheme 2. Proof for the aza Cope rearrangement
with ester-substituted N-acyliminium ions and olefins as the
nucleophiles. Similar reactions with alkyl-substituted imi-
nium ions have been carried out by Overman and co-work-
ers to arrive at enantiomerically pure α-Me-substituted
tetrahydropyridines (15) by a vinylsilane-terminated cycliza-
tion of precursor 14 (Scheme 3). Initially, this reaction was
reported to yield racemic products,[15a] but in a later publi-
cation complete retention of enantiopurity was claimed.[15b]
An N-acyliminium version of this reaction was more re-
cently pursued by Veenstra et al. at Novartis,[16] with the
aim of preparing enantiopure 2-benzyl-substituted 4-ami-
nopiperidines. Application of this method with the enantio-
merically pure olefinic precursor 16 led to a 73% yield of
the desired acetamido-substituted piperidine 17, but in a
low ee of 42%, which must be a result of the aza Cope equi-
librium.
a
b
Scheme 4. Based on a maximum theoretical yield of 50%; ee
determined by chiral HPLC [Crownpak CR(ϩ)]
Enantiopure (R)-allylglycine was prepared according
to a literature procedure by an enzymatic resolution
(aminopeptidase from Pseudomonas putida) of racemic al-
lylglycine amide,[17] while (S)-α-Me-allylglycine was access-
ible by a related resolution (aminopeptidase from Mycobac-
terium neoaurum).[18] The novel amino acid 21 was synthe-
sized in enantiomerically pure form by a similar resolution
of the racemic vinylsilane-containing amino acid amide 20
(Scheme 4). The sequence commenced with the glycine-de-
rived ketimine 18 developed by OЈDonnell.[19] Alkylation
with (Z)-3-bromo-1-trimethylsilyl-1-propene (19)[20] fol-
lowed by acid hydrolysis of the ketimine provided the corre-
sponding methyl ester. The crude ester was treated with
aqueous ammonia to give the amino acid amide, which was
purified by formation of the Schiff base (PhCHO, H2O,
pH ഠ 9), extraction from the water layer and precipitation
by acid hydrolysis in acetone. Thus, the racemic amide 20
was efficiently synthesized on a multigram scale in 72%
overall yield without using column chromatography.
The racemic amino acid amide 20 was then subjected to
the enzymatic resolution conditions (amidase produced by
Pseudomonas putida ATCC 12633)[21][22] to give a mixture
of the (S)-acid 21 and the corresponding (R)-amide. Sepa-
ration occurred by the addition of benzaldehyde, followed
by extraction of the resulting amide-derived Schiff base
with CH2Cl2. The water layer was then concentrated and
the residue purified by ion-exchange chromatography to
yield the pure (S)-acid 21. The Schiff base was hydrolyzed
to give the (R)-amide 20. As shown in Scheme 4, the amide
was hydrolyzed with good enantioselectivity: This pro-
cedure afforded the amino acid (S)-21 in an excellent ee of
99%,[25] while the (R)-amide 20 was shown to be slightly
less pure (ee: 88%).
Scheme 3. Literature examples
We reasoned that with an α-ester instead of an α-benzyl
substituent racemization would be more difficult: The
strong electron-withdrawing effect of the ester relative to
that of the benzyl function causes a large electronic differ-
ence between the two possible cations, thus preventing the
aza Cope equilibrium to take place. As a result, the stereo-
chemistry at the α-center will be retained. This reasoning is
in agreement with the fact that in the trapping experiment
starting from compound 9 a single product was obtained,
despite the stronger electrophilic character of the N-acylimi-
nium ion 10.
With these enantiopure amino acids in hand, the cycliza-
tion precursors 22؊26 were obtained by standard method-
ology in good yields (shown in Table 1) and without detect-
able racemization according to chiral HPLC analysis (Chir-
Results and Discussion
In order to verify this hypothesis, three enantiomerically alcel OD). In most cases (all except 23) the amino acids
pure amino acids with different nucleophilic side chains were esterified, followed by reaction with methyl chloro-
were used: allylglycine (8, R ϭ R1 ϭ H), α-Me-allylglycine formate or tosyl chloride. The Fmoc-protected precursor 23
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Eur. J. Org. Chem. 1999, 1127Ϫ1135

Enantiopure Functionalized Pipecolic Acids via Amino Acid Derived N-Acyliminium Ions
FULL PAPER
was obtained by reaction of the amino acid with FmocOSu, alcohols 32 and 33. Again, despite the higher reaction tem-
followed by esterification. In addition to these monosubsti- perature, the cyclization did not lead to any loss of enantio-
tuted amino acids, the disubstituted amino acid α-Me-allyl- purity as was proven by chiral HPLC.
glycine was used to prepare precursor 27 by a similar pro-
Having thus established the validity of this approach, dif-
cedure. Although the sulfonyl substituent will be more diffi- ferent cyclization conditions were investigated to introduce
cult to be removed in a later stage, this protecting group other functionalities into the piperidine ring. For example,
was deliberately chosen for the majority of the reactions treatment of 24 with a formaldehyde equivalent and SnCl4
since the absence of rotamers in the NMR spectra signifi- should provide the corresponding chloride.[12b] Because pa-
cantly simplified the interpretation of the results.
raformaldehyde itself is not compatible with such Lewis
Table 1 . Precursors, conditions and products of the cyclization reactions
a
b
c
d
Yields starting from the amino acids. Ϫ ee > 98% (Chiralcel OD), unless stated otherwise. Ϫ ee > 95% (1H NMR). Ϫ After
e
f
g
treatment with NH3/MeOH. Ϫ ee not determined. Ϫ ee ϭ 88% ϭ (Chiralcel OD). Ϫ After treatment with NH3/MeOH, heating in
toluene with catalytic pTSA.
The results of the cyclization reactions are depicted in acids, s-trioxane was used as the source of the required C1
Table 1. The carbamate-protected amino esters 22 and 23 moiety (entry 4). Surprisingly, reaction with s-trioxane and
readily cyclized with the standard cyclization conditions SnCl4 yielded the desired chloride 34 only as a by-product
(1.5 or 10 equiv of paraformaldehyde, HCO2H, room (14% yield). Instead, the enantiopure axial alcohol 32 was
temp.) to give approximately 1:1 mixtures of cis and trans obtained as the major product (73% yield), regardless of
products in comparable overall yields (entries 1 and 2). any modification in the reaction conditions. Other tempera-
Both reactions proceeded with complete retention of stereo- tures or amounts of Lewis acid did not lead to an improve-
chemistry at the C-2 center. This was proven for 28 and 29 ment of this ratio. Alternatively, this reaction was carried
by conversion of the corresponding alcohols (NH3/MeOH, out in MeCN with the aim of introducing an N substituent
0°C) into the camphanic esters [(1S)-camphanic chloride, at the 4-position by a Ritter-type reaction. This time, the
DMAP, pyridine, CH2Cl2] and analysis by 1H NMR (> reaction did not proceed at room temp., but at 50°C a
95% de). The enantiopurity of 30 and 31 was unambigu- reasonable yield (46%) of the enantiopure acetamide 35 was
ously established by analysis with chiral HPLC (Chiralcel obtained together with a small amount of the axial alcohol
OD), which was also the method of choice for analysis of 32 (11%), which could be readily separated by chromatogra-
the other cyclization products. The tosyl-protected amino phy (entry 5). Once again, also in these Lewis acid mediated
ester 24 reacted more sluggishly at room temp., which is cyclizations, no racemization could be detected.
probably due to the more strongly electron-withdrawing ef-
The (Z)-vinylsilane-substituted amino acids 25 and 26 cy-
fect of the tosyl group. At 50°C, however, the reaction was clized upon subjection to HCO2H to afford the anticipated
completed in 18 h, leading to a mixture of cis and trans baikiain derivatives 36 and 37, albeit in somewhat lower
products, which prior to purification were hydrolyzed to the yields (entries 6 and 7). Apparently, the vinylsilane group
Eur. J. Org. Chem. 1999, 1127Ϫ1135
1129

F. P. J. T. Rutjes et al.
FULL PAPER
is not as good a nucleophile as the unsubstituted olefin. tion can form the achiral allylsilane-containing intermedi-
Unfortunately, the ee of the protected unsaturated pipecolic ate 49. (E)/(Z) Isomerization of the iminium double bond
acid derivative 36 could not be determined, while the tosyl- (viz. intermediates 49 and 50) then can cause some epime-
ated analog 37 was shown to be partly racemized (88% ee). rization at the C-2 carbon atom.[24] As expected, the disub-
The disubstituted amino acid derivative 27 cyclized stituted precursor 27 behaved similarly to the monosubsti-
smoothly under the previously optimized conditions to give tuted precursors, where equilibria as shown in Scheme 5 ap-
the expected mixture of cis/trans isomers, which could not ply.
be separated by chromatography (entry 8). Therefore, the
formate esters were hydrolyzed and the resulting alcohols
subjected to lactonization conditions to give lactone 38 and
alcohol 39. Separation by chromatography now led to the
pure products, both of which were shown to be of more
than 98% enantiopurity by chiral HPLC.
The results of entries 1Ϫ5 can be largely explained by
Finally, it was shown that the Fmoc moiety is a suitable
invoking the mechanism shown in Scheme 5. Upon subjec- protecting group to arrive at the free pipecolic acids. The
tion to the cyclization conditions, precursor 40 will initially Fmoc-protected cyclization products 30 and 31 were Ϫ
lead to the chairlike N-acyl- or N-tosyliminium intermedi- after separation by column chromatography Ϫ further con-
ate 41, which according to these results does not convert verted into the corresponding cis- and trans-4-hydroxypipe-
into the achiral ester-substituted iminium ion 42. Cycliza- colic acids 51 and 52, respectively. The sequence involved
tion of 41 then leads to the secondary cation 43, which on subsequent (i) hydrolysis of the formyl ester, (ii) deprotec-
the one hand can be trapped from the least hindered equa- tion of the nitrogen and (iii) hydrolysis of the methyl ester.
torial side by a nucleophile (formate, chloride or aceto- The crude amino acids were then purified by using a
nitrile) to eventually give the trans product 44. On the other strongly acidic ion-exchange column (Dowex 50 Wϫ4) to
hand, stabilization by the ester carbonyl group might take yield the unnatural (R)-pipecolic acids 51 and 52 in 59 and
place, giving rise to the dioxycarbenium ion 45. The latter 61% yield, respectively, over three steps. Thus, starting from
intermediate can then be hydrolyzed under the reaction (R)-allylglycine, the enantiomers of these natural products
conditions (HCO2H reactions) or during the workup (SnCl4 were obtained in an efficient sequence in eight steps.
reactions) to give the axial formate 47 or alcohol 46, respec-
tively.[12b,12c]
Conclusions
In summary, we have shown that a novel vinylsilane-con-
taining amino acid can be readily obtained in enantiopure
form by an enzymatic resolution of the corresponding
amino acid amide. This and two other olefinic amino acids
served as versatile precursors in N-acyliminium ion cycliza-
tions to arrive at the corresponding pipecolic acid deriva-
tives without loss of optical activity in most cases. Thus,
differently functionalized pipecolic acids such as baikiain
and other natural products were synthesized in protected
Scheme 5. Proposed mechanism of the cyclizations
form. By applying the readily removable Fmoc protecting
group, the unnatural enantiomers of cis- and trans-4-
Comparing these results with the cyclization described by
hydroxypipecolic acid were obtained.
Veenstra,[16] one can conclude that the ester substituent has
a significant beneficial effect on the conservation of the en-
antiopurity. As stated before, this is probably the result of
an electronic effect due to the electron-withdrawing proper-
Experimental Section
General: All reactions were carried out under dry nitrogen, unless
ties of the ester function, thus preventing the aza Cope re-
described otherwise. Standard syringe techniques were applied for
arrangement to take place. In the case of the precursors 25
transfer of dry solvents and air- or moisture-sensitive reagents. Ϫ
and 26, the reaction is slightly different. The equilibrium
IR: Bruker IFS 28. Ϫ NMR: Bruker AC 200, Bruker WM 250,
Bruker ARX 400 (200, 250 or 400 MHz for 1H; 50, 63 or 100 MHz
now involves the (compared to the olefin) moderately nucle-
ophilic vinylsilane 48, which due to the low rate of cycliza- for 13C, respectively). Ϫ HRMS: JEOL JMS SX/SX102A, coupled
1130
Eur. J. Org. Chem. 1999, 1127Ϫ1135

Enantiopure Functionalized Pipecolic Acids via Amino Acid Derived N-Acyliminium Ions
FULL PAPER
to a JEOL MS-MP7000. Ϫ Elemental analyses: Vario EL. Ϫ Op-
tical rotations: PerkinϪElmer 241 (at ambient temperature). Ϫ
Melting points and boiling points are uncorrected. Ϫ Ethyl acetate
and petroleum ether (boiling range 60Ϫ80°C) were distilled prior
to use. THF and Et2O were freshly distilled from sodium benzo-
phenone ketyl prior to use. CH2Cl2 and MeCN were dried and
140.6 (d, SiCHϭCH), 171.6 (s, CO). Ϫ C8H19ClN2OSi (222.79):
calcd. C 43.13, N 12.57, H 8.60; found C 43.02, N 13.06, H 8.61.
(S)-(Z)-2-Amino-5-(trimethylsilyl)-4-pentenoic Acid [(S)-21] and
(R)-(Z)-2-Amino-5-(trimethylsilyl)-4-pentenamide [(R)-20]: A mix-
ture of racemic 20 (5.00 g, 22.5 mmol) and MnSO4 (ca. 10 mass-
% of an 8 m solution) in H2O (50 mL) was adjusted to pH ഠ
8.5 with aqueous 1  NaOH. Then a crude enzyme paste from
Pseudomonas putida ATCC 12633 (ca. 1 g) was added and the mix-
ture was shaken at 37°C for 72 h. The reaction was monitored by
˚
distilled from CaH2 and stored over 4-A molecular sieves under
nitrogen. Paraformaldehyde was converted to the monomer prior
to use by heating for 1 min in HCO2H. Purification of the amino
acids by ion-exchange chromatography using a strongly acidic
Dowex 50 Wϫ4 resin involved the following sequence: The resin
was treated with the HCl salt and washed with water until no more
HCl was detected. Then the resin was eluted with 2  NH4OH, the
ninhydrin-positive fractions were collected and concentrated to give
the free amino acid. The ee values of the free amino acids were
determined by HPLC on a Crownpak CR(ϩ) column (aqueous
HClO4, at 0Ϫ7°C).[23] The ee values of compounds 22Ϫ39 (except
for 28, 29 and 36) were determined by HPLC on a Chiralcel OD
column (10Ϫ20% iPrOH in heptane).
1
analyzing small samples of the reaction mixture with H NMR in
D2O. After a conversion of approximately 50%, the enzyme resi-
dues were removed by centrifugation. The resulting solution was
treated with benzaldehyde (1.15 mL, 11.3 mmol) and vigorously
stirred for 5 h, after which the Schiff base of the remaining amide
was extracted with CH2Cl2 (3 ϫ 100 mL). The water layer was
concentrated and the residue was purified on a strongly acidic ion-
exchange column (Dowex 50 Wϫ4) to give the amino acid (S)-21
(1.11 g, 5.93 mmol, 26%) as a white solid. The combined organic
layers were dried (MgSO4), concentrated, dissolved in acetone,
treated with 10  HCl (1.13 mL, 11.3 mmol) and after stirring for
5 h filtered to give (R)-20 (1.73 g, 7.79 mmol, 35%) as a white solid.
Ϫ (S)-21: Rf ϭ 0.77 (CHCl3/MeOH/25% NH4OH, 60:45:20). Ϫ
[α]D ϭ ϩ10.1 (c ϭ 1, 1  HCl). Ϫ ee: 99%. Ϫ Mp. 210°C (dec.).
Ϫ IR (KBr): ν˜ ϭ 3450 cmϪ1 (NH), 3300Ϫ2900 (CO2 H) 1591 (Cϭ
O), 1248, 837 (CϪSi). Ϫ 1H NMR (CD3OD) δ ϭ 0.15 (s, 9 H,
SiMe3), 2.62Ϫ2.80 (m, 2 H, CH2), 3.57 (dd, J ϭ 7.1, 5.6 Hz, 1 H,
NCH), 5.73 (d, J ϭ 14.2 Hz, 1 H, SiCH) 6.33 (dt, J ϭ 14.2, 6.9
Hz, 1 H, SiCHϭCH). Ϫ 13C NMR (CD3OD) δ ϭ 0.13 (q, SiMe3),
35.8 (t, CH2), 56.1 (d, NCH), 134.6 (d, SiCH), 142.8 (d, SiCHϭ
CH), 173.9 (s, CϭO). Ϫ HRMS (EI); C8H18NO2Si (188.1107):
(Z)-2-Amino-5-(trimethylsilyl)-4-pentenamide · Hydrochloride (20):
A mixture of the glycine-derived imine 18[19] (25.2 g, 99.6 mmol),
LiI (1.33 g, 9.96 mmol), NaH (4.32 g, 108 mmol of a 60% disper-
sion in mineral oil) and 3-bromo-1-(trimethylsilyl)-1-propene
(19,[20] 23.0 g, 119 mmol) in THF (500 mL) was refluxed for 26 h.
It was cooled down to room temp., poured into saturated aqueous
NH4Cl (500 mL) and the organic layer was separated. The aqueous
layer was extracted with diethyl ether (3 ϫ 400 mL) and the com-
bined organic layers were washed with H2O (300 mL). The solution
was dried (MgSO4) and concentrated to give the crude alkylated
product as a light yellow oil (40.4 g, 111 mmol), which was directly
used for the next step. Ϫ Rf ϭ 0.58 (50% diethyl ether in petroleum
ether). Ϫ IR (film): ν˜ ϭ 2952 cmϪ1, 1741 (CϭO), 1248 (CϪSi), 838
(CϪSi). Ϫ 1H NMR (CDCl3): δ ϭ 0.10 (s, 9 H, SiMe3), 2.75Ϫ2.79
(m, 2 H, CH2), 3.73 (s, 3 H, CO2Me), 4.20 (dd, J ϭ 7.3, 5.8 Hz, 1
H, NCH), 5.58 (d, J ϭ 14.1 Hz, 1 H, SiCH), 6.17 (dt, J ϭ 14.1,
7.3 Hz, 1 H, SiCHϭCH), 7.18Ϫ7.83 (m, 10 H, ArH). Ϫ A solution
of the crude imine (40.4 g, 111 mmol) in Et2O (500 mL) was treated
at 0°C with 1  HCl (120 mL, 120 mmol) and the reaction mixture
was stirred for 3 h at room temp. Separation of the two layers and
concentration of the water layer provided the crude amino ester
(24.0 g, 100 mmol) as the hydrochloride salt. Ϫ Rf ϭ 0.13 (70%
diethyl ether in petroleum ether). Ϫ IR (KBr): ν˜ ϭ 3405 cmϪ1
found 188.1111.
Ϫ (R)Ϫ20: Rf ϭ 0.93 (CHCl3/MeOH/25%
NH4OH, 60:45:20). Ϫ [α]D ϭ Ϫ9.4 (c ϭ 1, H2O). Ϫ ee: 88% (deter-
mined by conversion into (R)-allylglycine (6  HCl, 90°C, 4 h).
Methyl (R)-2-(Methoxycarbonyl)amino-4-pentenoate (22): A solu-
tion of (R)-allylglycine (200 mg, 1.74 mmol) in MeOH (3 mL) was
treated dropwise at 0°C with SOCl2 (253 µL, 3.48 mmol) and re-
fluxed for 4 h. The mixture was concentrated to give the crude
methyl ester hydrochloride (ca. 1.74 mmol) as a dark yellow oil. A
solution of the crude residue (1.74 mmol) in CH2Cl2 (3 mL) was
treated at 0°C with Et3N (485 µL, 3.48 mmol) and methyl chloro-
formate (161 µL, 2.09 mmol). After stirring at room temp. for 1 h,
the mixture was poured into saturated aqueous NH4Cl (10 mL)
and extracted with CH2Cl2 (3 ϫ 10 mL). The combined organic
layers were dried (MgSO4), concentrated and purified by flash
chromatography (50% diethyl ether in petroleum ether) to give 22
(260 mg, 1.39 mmol, 80%) as a colorless oil. Ϫ Rf ϭ 0.35 (50%
diethyl ether in petroleum ether). Ϫ [α]D ϭ ϩ19.5 (c ϭ 1.9,
CH2Cl2). Ϫ IR (film): ν˜ ϭ 3310 cmϪ1 (NH), 2955, 1737 (CO), 1698
1
(NH), 2955, 1749 (CϭO), 1248 (CϪSi), 839 (CϪSi). Ϫ H NMR
(CD3OD) δ ϭ 0.15 (s, 9 H, SiMe3), 2.78Ϫ2.82 (m, 2 H, CH2), 3.82
(s, 3 H, CO2Me), 4.15 (t, J ϭ 6.5 Hz, 1 H, NCH), 5.78 (dt, J ϭ
14.1, 1.5 Hz, 1 H, SiCH), 6.29 (dt, J ϭ 14.1, 7.1 Hz, 1 H, SiCHϭ
CH). Ϫ A solution of the crude methyl ester (24.0 g, 100 mmol)
was stirred in 25% aqueous NH3 (200 mL) for 18 h. After concen-
tration, the residue was dissolved in aqueous NaOH (200 mL), ben-
zaldehyde (11.7 g, 110 mmol) was added and the mixture was vigor-
ously stirred for 3 h. Extraction with CH2Cl2 (3 ϫ 300 mL), drying
(MgSO4) and concentration provided the corresponding Schiff
base. The latter was dissolved in acetone and 10  HCl (10 mL,
100 mmol) was added. After stirring for 10 h, the resulting suspen-
sion was filtered to give pure 20 as the HCl salt (16.1 g, 72 mmol,
1
(CO), 1267, 1221, 779. Ϫ H NMR (CDCl3): δ ϭ 2.42Ϫ2.57 (m, 2
H, CH2), 3.64 (s, 3 H, NCO2Me), 3.71 (s, 3 H, CO2Me), 4.40 (q,
J ϭ 6.4 Hz, 1 H, NCH), 5.08Ϫ5.12 (m, 2 H, ϭCH2), 5.29 (br d,
J ϭ 6.4 Hz, 1 H, NH), 5.60Ϫ5.71 (m, 1 H, ϭCH). Ϫ 13C NMR
(CDCl3): δ ϭ 36.5 (t, CH2), 52.2, 53.1 (d, NCH, 2 ϫ q, CO2Me),
119.1 (t, ϭCH2), 132.0 (d, ϭCH), 156.2 (s, NCO), 172.1 (s, CO).
Ϫ HRMS (EI); C8H13NO4 (187.0845): found 187.0847.
72%) as a white solid. Ϫ Rf ϭ 0.93 (CHCl3/MeOH/25% NH4OH, Methyl
(R)-2-(9-Fluorenylmethoxycarbonyl)amino-4-pentenoate
60:45:20). Ϫ Mp. 180°C (subl.). Ϫ IR (KBr) ν˜ ϭ 3390, 3272, 3189
(23): A mixture of (R)-allylglycine (500 mg, 4.35 mmol) and Et3N
cmϪ1 (NH), 2956, 1702 (CϭO), 1249, 840 (CϪSi). Ϫ 1H NMR (0.61 mL, 4.35 mmol) in H2O (4 mL) was treated with a solution
(CD3OD) δ ϭ 0.15 (s, 9 H, SiMe3), 2.71Ϫ2.75 (m, 2 H, CH2), 3.98 of Fmoc-OSu (1.42 g, 4.35 mmol) in MeCN (4 mL). The mixture
(t, J ϭ 6.2 Hz, 1 H, NCH), 5.79 (dt, J ϭ 14.2, 1.5 Hz, 1 H, SiCH),
was vigorously stirred for 2 h and concentrated to yield the crude
6.30 (dt, J ϭ 14.2, 6.9 Hz, 1 H, SiCHϭCH). Ϫ 13C NMR (CD3OD) acid (1.19 g, 3.53 mmol, 82%) as a white solid. A portion of the
δ ϭ 0.13 (q, SiMe3), 36.0 (t, CH2), 53.9 (d, NCH), 135.9 (d, SiCH),
Eur. J. Org. Chem. 1999, 1127Ϫ1135
crude acid (250 mg, 0.74 mmol) was dissolved in MeOH (2 mL),
1131

F. P. J. T. Rutjes et al.
treated at 0°C with SOCl2 (108 µL, 1.48 mmol) and refluxed for 3 140.8 (d, SiCHϭCH), 156.0 (NCO) 171.5 (CO). Ϫ HRMS (EI);
FULL PAPER
h. The mixture was concentrated and purified by flash chromatog-
raphy (30% ethyl acetate in petroleum ether) to yield 23 (270 mg,
0.74 mmol, 100%) as a white solid. Ϫ Rf ϭ 0.56 (50% ethyl acetate
in petroleum ether). Ϫ [α]D ϭ Ϫ7.7 (c ϭ 0.65, CH2Cl2). Ϫ Mp.
99Ϫ100°C. Ϫ IR (film): ν˜ ϭ 3320 (NH) cmϪ1, 2947, 1742 (CϭO),
1699 (CϭO), 1537, 1225. Ϫ 1H NMR (CDCl3): δ ϭ 2.42Ϫ2.62 (m,
2 H, CH2), 3.76 (s, 3 H, CO2Me), 4.32 (t, J ϭ 7.0 Hz, 1 H, ArCH),
4.39 (d, J ϭ 6.9 Hz, 2 H, OCH2), 4.45Ϫ4.48 (m, 1 H, NCH),
5.13Ϫ5.17 (m, 2 H, ϭCH2), 5.32 (d, J ϭ 7.2 Hz, 1 H, NH),
5.65Ϫ5.73 (m, 1 H, ϭCH), 7.25Ϫ7.77 (m, 8 H, ArH). Ϫ 13C NMR
(CDCl3): δ ϭ 36.8 (t, CH2), 47.2 (d, CHCH2O), 52.4, 53.3 (2 ϫ d,
NCH, CO2Me), 67.1 (t, CH2O), 119.4 (t, ϭCH2), 120.0, 125.1,
127.1, 127.7 (d, ArCH), 132.0 (d, ϭCH), 143.8, 143.9 (s, ArC),
156.0 (s, NCO), 172.2 (s, CO). Ϫ HRMS (EI); C21H21NO4
(351.1471): found 351.1464.
C11H21NO4Si (259.1239): found 259.1258.
Methyl (S)-(Z)-2-(Toluenesulfonylamino)-5-(trimethylsilyl)-4-pen-
tenoate (26): A portion of the crude methyl ester hydrochloride
derived from (S)-21 (144 mg, 0.62 mmol) in pyridine (6 mL) was
treated with tosyl chloride (142 mg, 0.74 mmol). After stirring for
18 h, the mixture was concentrated and purified by flash chroma-
tography (20 Ǟ 50% diethyl ether in petroleum ether) to give the
tosylamide 26 (124 mg, 0.37 mmol, 59%) as a colorless oil. Ϫ Rf ϭ
0.23 (50% diethyl ether in petroleum ether). Ϫ [α]D ϭ ϩ12.8 (c ϭ
1, CH2Cl2). Ϫ IR (film): ν˜ ϭ 3274 cmϪ1 (NH), 2953, 1743 (CϭO),
1
1248 (CϪSi), 1163, 839 (CϪSi). Ϫ H NMR (CDCl3): δ ϭ 0.09 (s,
9 H, SiMe3), 2.41 (s, 3 H, ArMe), 2.49Ϫ2.58 (m, 2 H, CH2), 3.50
(s, 3 H, CO2Me), 4.00 (dt, J ϭ 9.1, 6.1 Hz, 1 H, NCH), 5.13 (d,
J ϭ 9.1 Hz, 1 H, NH), 5.66 (d, J ϭ 14.5 Hz, 1 H, SiCH), 6.10 (dt,
J ϭ 14.2, 7.1 Hz, 1 H, SiCHϭCH), 7.28 (d, J ϭ 8.1 Hz, 2 H, ArH),
7.71 (d, J ϭ 8.3 Hz, 2 H, ArH). Ϫ 13C NMR (CDCl3): δ ϭ Ϫ0.10
(q, SiMe3), 21.3 (q, ArMe), 36.5 (t, CH2), 52.3 (q, CO2Me), 55.1
(NCH), 127.1 (d, ArC), 129.4 (d, ArC), 134.3 (d, SiCH), 136.6 (s,
ArC), 140.0 (d, SiCHϭCH), 143.5 (s, ArC), 171.3 (s, CϭO). Ϫ
HRMS (EI); C16H25NO4SSi (355.1274): found 355.1260.
Methyl (R)-2-(Toluenesulfonylamino)-4-pentenoate (24): A solution
of (R)-allylglycine (608 mg, 5.29 mmol) in MeOH (25 mL) was
treated at 0°C with SOCl2 (0.77 mL, 10.6 mmol). The mixture was
refluxed for 4 h and concentrated to give the crude methyl ester
(1.01 g) as a viscous oil. The product was dissolved in pyridine (25
mL), TsCl (3.02 g, 15.9 mmol) was added and the mixture was
heated at 40°C for 24 h. The mixture was concentrated, dissolved
in EtOAc (50 mL) and washed with aqueous CuSO4 (2 ϫ 25 mL)
and H2O (25 mL). The organic layer was dried, concentrated and
purified by flash chromatography (50 Ǟ 70% ethyl acetate in petro-
leum ether) to give 24 (1.13 g, 4.01 mmol, 76%) as a white solid.
Ϫ Rf ϭ 0.33 (30% ethyl acetate in petroleum ether). Ϫ Mp.
68Ϫ69°C. Ϫ [α]D ϭ Ϫ15.5 (c ϭ 1, CH2Cl2). Ϫ IR (film): ν˜ ϭ 3278
cmϪ1 (NH), 2953, 1742 (CϭO). Ϫ 1H NMR (CDCl3): δ ϭ 2.40 (s,
3 H, ArMe), 2.45 (t, J ϭ 6.6 Hz, 2 H, CH2), 3.51 (s, 3 H, CO2Me),
4.02 (dt, J ϭ 9.0, 5.9 Hz, 1 H, NCH), 5.04Ϫ5.10 (m, 2 H, ϭCH2),
5.22 (d, J ϭ 8.9 Hz, 1 H, NH), 5.69 (m, 1 H, ϭCH), 7.28 (d, J ϭ
8.0 Hz, 2 H, ArH), 7.71 (d, J ϭ 8.0 Hz, 2 H, ArH). Ϫ 13C NMR
(CDCl3): δ ϭ 21.4 (q, ArMe), 37.4 (t, CH2), 52.3 (q, CO2Me), 55.1
(d, NCH), 119.6 (t, ϭCH2), 127.1, 129.5 (d, ArH), 131.2 (d, ϭCH),
136.7, 143.5 (s, ArC), 171.2 (s, CO). Ϫ C13H18NO4S (284.1): calcd.
C 55.11, H 6.05, N 4.94; found C 55.10, H 6.11, N 4.91.
Methyl (S)-2-Methyl-2-(toluenesulfonylamino)-4-pentenoate (27): A
solution of (S)-α-methylallylglycine[25] (97 mg, 678 µmol) in MeOH
(5 mL) was treated at 0°C with SOCl2 (100 µL, 1.37 mmol). The
mixture was refluxed for 16 h and concentrated to give the crude
methyl ester (128 mg) as a viscous oil. The product was dissolved
in pyridine (5 mL), TsCl (381 mg, 2.0 mmol) was added and the
mixture was heated at 40°C for 70 h. The mixture was concen-
trated, dissolved in EtOAc (25 mL) and washed with aqueous
CuSO4 (2 ϫ 25 mL) and H2O (25 mL). The organic layer was
dried, concentrated and purified by flash chromatography (30%
ethyl acetate in petroleum ether) to give 27 (154 mg, 0.52 mmol,
76%) as a light yellow oil. Ϫ Rf ϭ 0.35 (30% ethyl acetate in petro-
leum ether). Ϫ [α]D ϭ ϩ2.4 (c ϭ 1.05, CH2Cl2). Ϫ IR (film): ν˜ ϭ
1
3274 cmϪ1 (NH), 1738 (CϭO). Ϫ H NMR (CDCl3): δ ϭ 1.41 (s,
3 H, Me), 2.40 (s, 3 H, ArMe), 2.46 (dd, 1 H, J ϭ 7.2, 13.8 Hz,
CH2), 2.58 (dd, 1 H, J ϭ 7.5, 13.9 Hz, CH2), 3.64 (s, 3 H, CO2Me),
5.06Ϫ5.13 (m, 2 H, ϭCH2), 5.35 (s, 1 H, NH), 5.60 (ddt, 1 H, J ϭ
7.0, 7.4, 10.2 Hz, ϭCH), 7.27 (d, 2 H, J ϭ 8.3 Hz, ArH), 7.75 (d,
2 H, J ϭ 8.3 Hz, ArH). Ϫ 13C NMR (CDCl3): δ ϭ 21.4 (q, ArMe),
22.0 (q, Me), 44.1 (t, CH2), 52.6 (q, CO2Me), 61.9 (s, NC), 120.1
(t, ϭCH2), 126.9, 129.4 (d, ArCH), 131.2 (d, ϭCH), 139.4, 143.1
(s, ArC), 173.3 (s, CO). Ϫ HRMS (EI); C14H20NO4S (298.1113):
found 298.1107.
Methyl (S)-(Z)-2-(Methoxycarbonylamino)-5-(trimethylsilyl)-4-pen-
tenoate (25): A solution of (S)-21 (300 mg, 1.69 mmol) in MeOH
(20 mL) was treated with diazomethane (freshly prepared from
Diazald [5.0 mmol in diethyl ether (15 mL) and KOH (31.5 mmol
dissolved in EtOH (45 mL)][25] at 0°C until the solution became
slightly yellow. The solution was acidified with 1  HCl and con-
centrated to afford the methyl ester hydrochloride (250 mg, 1.24
Dimethyl (2R,4S)-4-Formyloxy-1,2-piperidinedicarboxylate (28) and
mmol) as a yellow solid. A portion of the crude methyl ester (106 Dimethyl (2R,4R)-4-Formyloxy-1,2-piperidinedicarboxylate (29): A
mg, 0.53 mmol) in CH2Cl2 (10 mL) was treated at 0°C with Et3N solution of carbamate 22 (75 mg, 400 µmol) and paraformaldehyde
(180 µL, 1.28 mmol) and methyl chloroformate (50 µL, 0.64 mmol).
After stirring at room temp. for 3 h, the solution was poured into
aqueous saturated NH4Cl (10 mL) and extracted with CH2Cl2 (3
ϫ 10 mL). The combined organic layers were dried (MgSO4), con-
(18 mg, 600 µmol) in HCO2H (2 mL) was stirred at room temp.
for 16 h. The reaction mixture was concentrated and purified by
flash chromatography (30 Ǟ 70% diethyl ether in petroleum ether)
to give 28 (36 mg, 147 µmol, 37%) and 29 (40 mg, 160 µmol, 40%)
centrated and purified by flash chromatography (20 Ǟ 50% diethyl as colorless oils. Ϫ 28: Rf ϭ 0.32 (70% diethyl ether in petroleum
ether in petroleum ether) to give methyl carbamate 25 (93 mg, 0.36 ether). Ϫ [α]D ϭ ϩ7.2 (c ϭ 1, CH2Cl2). Ϫ IR (film): ν˜ ϭ 2956
mmol, 68%) as a colorless oil. Ϫ Rf ϭ 0.29 (50% diethyl ether in cmϪ1, 1746 (CϭO), 1713 (CϭO). Ϫ 1H NMR (CDCl3): δ ϭ
petroleum ether). Ϫ [α]D ϭ ϩ12.2 (c ϭ 1, CH2Cl2). Ϫ IR (film):
1.68Ϫ1.90 (m, 2 H, 2 ϫ 5-H), 1.95 (ddd, J ϭ 1.9, 6.9, 14.8 Hz, 1 H,
ν˜ ϭ 3341 cmϪ1 (NH), 2954, 1729 (CϭO), 1249 and 850 (CϪSi). Ϫ 3-Hax), 2.58 (br. d, J ϭ 14.8 Hz, 1 H, 3-Heq), 3.27, 3.36 (rotamers, t,
1H NMR (CDCl3): δ ϭ 0.10 (s, 9 H, SiMe3), 2.54Ϫ2.65 (m, 2 H, J ϭ 13.2 Hz, 1 H, 6-Hax), 3.67, 3.70, 3.72 (rotamers, s, 6 H, 2 ϫ
CH2), 3.67 (s, 3 H, CO2Me), 3.74 (s, 3 H, CO2Me), 4.44 (q, J ϭ
7.1 Hz, 1 H, NCH), 5.23 (br. d, J ϭ 6.6 Hz, 1 H, NH), 5.69 (d,
J ϭ 14.1 Hz, 1 H, SiCH), 6.14 (dt, J ϭ 14.1, 7.2 Hz, 1 H, SiCHϭ
CO2Me), 3.92, 4.05 (rotamers, br. d, J ϭ 10.9 Hz, 1 H, 6-Heq),
4.74, 4.89 (rotamers, m, 1 H, 2-H), 5.21(t, J ϭ 2.7 Hz, 1 H, 4-H),
7.92 (s, 1 H, CHO). Ϫ 13C NMR (CDCl3): δ ϭ 28.5, 30.1 (t, C-3
CH). Ϫ 13C NMR (CDCl3): δ ϭ Ϫ0.10 (q, SiMe3), 35.7 (t, CH2), and C-5), 35.9, 36.1 (rotamers, t, C-6), 50.7, 51.0, 52.1, 52.9 (rota-
52.1 and 52.2 (2 ϫ q, CO2Me), 53.1 (d, NCH), 134.1 (d, SiCH), mers, C-2 and 2 ϫ CO2Me), 66.1 (d, C-4), 156.0 (s, NCO), 159.6
1132
Eur. J. Org. Chem. 1999, 1127Ϫ1135

Enantiopure Functionalized Pipecolic Acids via Amino Acid Derived N-Acyliminium Ions
FULL PAPER
(s, HCO), 171.4 (s, CO). Ϫ HRMS (EI); C10H15NO6 (245.0899): δ ϭ 1.66Ϫ1.70 (m, 2 H, 5-Hax and 5-Heq), 1.93 (ddd, 1 H, J ϭ 2.5,
found 245.0875. Ϫ 29: Rf ϭ 0.35 (70% diethyl ether in petroleum 6.6, 14.3 Hz, 3-Hax), 2.36 (br. d, 1 H, J ϭ 14.4 Hz, 3-Heq), 2.41 (s,
ether). Ϫ [α]D ϭ Ϫ17.7 (c ϭ 1, CH2Cl2). Ϫ IR (film): ν˜ ϭ 2956 3 H, ArMe), 3.48Ϫ3.55 (m, 1 H, 6-Hax), 3.53 (s, 3 H, CO2Me),
1
cmϪ1, 1743 (CϭO), 1709 (CϭO). Ϫ H NMR (CDCl3): δ ϭ 1.52
(dq, J ϭ 4.8. 12.5 Hz, 1 H, 5-Hax), 1.78 (dt, J ϭ 6.3, 12.5 Hz, 1 H, 4-H), 4.68 (d, 1 H, J ϭ 6.4 Hz, 2-H), 7.27 (d, 2 H, J ϭ 8.3 Hz,
3-Hax), 1.97Ϫ2.05 (m, 1 H, 5-Heq), 2.51 (br. d, J ϭ 12.2 Hz, 1 H,
ArH), 7.68 (d, 2 H, J ϭ 8.3 Hz, ArH). Ϫ 13C NMR (CDCl3): δ ϭ
3-Heq), 3.07, 3.15 (rotamers, br. t, J ϭ 13.3 Hz, 1 H, 6-Hax), 3.72 21.37 (q, ArMe), 31.2, 34.1 (t, C.3 and C.5), 37.0 (t, C.6), 51.8 (d,
3.62 (ddd, 1 H, J ϭ 2.9, 3.9, 13.3 Hz, 6-Heq), 4.09Ϫ4.11 (m, 1 H,
(s, 3 H, CO2Me), 3.75 (s, 3 H, CO2Me), 4.09, 4.22 (rotamers, br.
C.2), 52.1 (q, CO2Me), 62.9 (d, C.4), 127.1, 129.3 (d, ArCH), 137.2,
d, J ϭ 13.2 Hz, 1 H, 6-Heq), 4.86 (tt, J ϭ 4.4, 11.5 Hz, 1 H, 4-
143.0 (s, ArC), 172.14 (s, CO). Ϫ HRMS (EI); C14H20NO5S
Hax), 4.92, 5.08 (rotamers, br. s, 1 H, 2-H), 7.95 (s, 1 H, CHO). Ϫ (314.1062): found 314.1057. ؊ 33: R f ϭ 0.38 (75% ethyl acetate in
13C NMR (CDCl3): δ ϭ 30.2, 31.5 (t, C-3 and C-5), 39.7 (t, C-6), petroleum ether). Ϫ [α]D ϭ ϩ30.6 (c ϭ 0.5, CH2Cl2). Ϫ IR (film):
52.5, 53.0, 53.7 (q, 2 ϫ CO2Me and d, C-2), 67.9 (d, C-4), 155.9 (s,
NCO), 160.0 (s, HCO), 170.9 (s, CO). Ϫ HRMS (EI); C10H15NO6 (ddt, 1 H, J ϭ 5.0, 10.9, 12.7 Hz, 5-Hax), 1.64 (ddd, 1 H, J ϭ 6.1,
ν˜ ϭ 3516 cmϪ1 (OH), 1740 (CϭO). Ϫ 1H NMR (CDCl3): δ ϭ 1.44
(245.0899): found 245.0904.
11.6, 12.9 Hz, 3-Hax), 1.9 (ddd, 1 H, J ϭ 2.2, 4.4, 12.4 Hz, 5-Heq),
2.36 (dquint, 1 H, J ϭ 2.2, 12.9 Hz, 3-Heq), 2.42 (s, 3 H, ArMe),
3.26 (dt, 1 H, J ϭ 2.8, 13.1 Hz, 6-Hax), 3.58 (s, 3 H, CO2Me),
3.66Ϫ3.71 (tt, 1 H, 4-H), 3.84Ϫ3.89 (dquint, 1 H, 6-Heq), 4.86 (d,
1 H, J ϭ 6.0 Hz, 2-H), 7.29 (d, 2 H, J ϭ 8.3 Hz, ArH), 7.67 (d, 2
H, J ϭ 8.3 Hz, ArH). Ϫ 13C NMR (CDCl3): δ ϭ 21.4 (q, ArMe),
33.7, 35.9 (t, C-3 and C-5), 41.3 (t, C-6), 52.1 (q, CO2Me), 54.9 (d,
C-2), 65.2 (d, C-6), 127.0, 129.4 (d, ArCH), 136.8, 143.3 (s, ArC),
170.7 (s, CO). Ϫ HRMS (EI); C14H20NO5S (314.1062): found
314.1078.
1-(9-Fluorenylmethyl) 2-Methyl (2R,4S)-4-Formyloxy-1,2-piper-
idinedicarboxylate (30) and 1-(9-Fluorenylmethyl) 2-Methyl
(2R,4R)-4-Formyloxy-1,2-piperidinedicarboxylate (31): A solution
of carbamate 23 (130 mg, 0.37 mmol) and paraformaldehyde (111
mg, 3.70 mmol) in HCO2H (3 mL) was stirred at room temp. for
16 h. The reaction mixture was concentrated and purified by flash
chromatography (30 Ǟ 50% ethyl acetate in petroleum ether) to
give 30 (67 mg, 0.16 mmol, 43%) and 31 (61 mg, 0.15 mmol, 41%)
as colorless oils. Ϫ 30: Rf ϭ 0.37 (50% ethyl acetate in petroleum
ether). Ϫ [α]D ϭ ϩ2.0 (c ϭ 1, CH2Cl2). Ϫ Mp. 51Ϫ52°C. Ϫ IR Methyl (2R,4R)-4-Chloro-1-toluenesulfonyl-2-piperidinecarboxylate
(film): ν˜ ϭ 2952 cmϪ1, 1715 (CϭO), 1704 (CϭO). Ϫ 1H NMR (34): A solution of s-trioxane (20 mg, 222 µmol) and SnCl4 (0.9
(CDCl3): δ ϭ 1.64Ϫ2.00 (m, 3 H, 2 ϫ 5-H and 3-Hax), 2.57, 2.63 mL of a 1.0  solution in CH2Cl2, 0.9 mmol) in CH2Cl2 (4 mL)
(rotamers, br. d, J ϭ 14.4 Hz, 1 H, 3-Heq), 3.29, 3.46 (rotamers, t,
J ϭ 13.4 Hz, 1 H, 6-Hax), 3.69, 3.73 (rotamers, s, 3 H, CO2Me),
was stirred at room temp. for 15 min. Then, tosylamide 24 (65 mg,
224 µmol) was added and the mixture was stirred at room temp.
3.96, 4.09 (rotamers, dd, J ϭ 13.6, 4.0 Hz, 1 H, 6-Heq), 4.22Ϫ4.55 for 20 h. The reaction mixture was poured into aqueous saturated
(m, 3 H, OCH2CH), 4.62, 4.94 (rotamers, d, J ϭ 5.9 Hz, 1 H, 2- NaHCO3 (10 mL) and extracted with CH2Cl2 (3 ϫ 10 mL). The
H), 5.24 (br. s, 1 H, 4-H), 7.28Ϫ7.78 (m, 8 H, ArH), 7.93, 7.96 combined organic layers were dried (MgSO4), concentrated and
(rotamers, s, 1 H, CHO). Ϫ 13C NMR (CDCl3): δ ϭ 28.3, 28.5,
purified by flash chromatography (25 Ǟ 100% ethyl acetate in
30.1 (rotamers, t, C-3 and C-5), 35.9, 36.3 (rotamers, t, C-6), 47.1 petroleum ether) to give 32 (71 mg, 162 µmol, 73%) and 34 (11 mg,
(d, ArCH), 50.8, 51.0, 52.1 (rotamers, d, C-2 and q, CO2Me), 66.0, 34 µmol, 14%) as colorless oils. Ϫ 34: 6:1 mixture of eq/ax chloride,
66.1 (rotamers, d, C-4), 67.5, 67.7 (rotamers, t, CH2O), 119.9, data of the eq chloride; Rf ϭ 0.34 (25% ethyl acetate in petroleum
1
124.8, 127.0, 127.6 (d, ArC), 141.2, 143.0 (s, ArC), 156.0 (s, NCO),
ether). Ϫ IR (film): ν˜ ϭ 1738 cmϪ1 (CϭO). Ϫ H NMR (CDCl3):
159.6 (s, HCO), 171.3 (s, CO). Ϫ HRMS (EI); C23H23NO6 δ ϭ 1.77 (ddd, 1 H, J ϭ 5.0, 12.8, 24.8 Hz, 5-Hax), 1.99 (ddd, 1 H,
(409.1525): found 409.1547. Ϫ 31: Rf ϭ 0.44 (50% ethyl acetate in J ϭ 6.1, 12.4, 18.5 Hz, 3-Hax), 2.10Ϫ2.16 (m, 1 H, 5-Heq), 2.43 (s,
petroleum ether). Ϫ [α]D ϭ ϩ12.5 (c ϭ 1, CH2Cl2). Ϫ Mp.
3 H, ArMe), 2.55 (dq, 1 H, J ϭ 2.1, 13.3 Hz, 3-Heq), 3.27 (dt, 1
H, J ϭ 2.8, 13.0 Hz, 6-Hax), 3.58 (s, 3 H, CO2Me), 3.83Ϫ3.92 (m,
47Ϫ48°C. Ϫ IR (film): ν˜ ϭ 2952 cmϪ1, 1742 (CϭO), 1707 (CϭO).
1
Ϫ H NMR (CDCl3): δ ϭ 1.47Ϫ1.58 (m, 1 H, 5-Hax), 1.65Ϫ1.82 2 H, 4-H and 6-Heq), 4.83 (dd, 1 H, J ϭ 1.7, 4.2 Hz, 2-H), 7.30 (d,
(m, 1 H, 3-Hax), 2.04 (br. d, J ϭ 6.7 Hz, 1 H, 5-Heq), 2.46, 2.53 2 H, J ϭ 8.0 Hz, ArH), 7.66 (d, 2 H, J ϭ 8.0 Hz, ArH). Ϫ 13C
(rotamers, br. d, J ϭ 12.3 Hz, 1 H, 3-Heq), 3.08, 3.22 (rotamers, br.
t, J ϭ 12.9 Hz, 1 H, 6-Hax), 3.73, 3.77 (rotamers, s, 3 H, CO2Me), 42.1 (t, C-6), 52.2 (q, CO2Me), 52.4 (d, C-2), 55.3 (d, C-4), 127.1,
4.06Ϫ4.52 (m, 4 H, CH2O, ArCH, 6-Heq), 4.80, 5.10 (rotamers, d, 129.5 (d, ArCH), 136.4, 143.5 (ArC, s), 170.8 (s, CO). ؊ HRMS
NMR (CDCl3): δ ϭ 21.4 (q, ArMe), 35.2, 37.2 (t, C-3 and C-5),
J ϭ 4.7 Hz, 1 H, 2-H), 4.84Ϫ4.93 (m, 1 H, 4-Hax), 7.25Ϫ7.42 (m, (EI); C14H19ClNO4S (332.0723): found 332.0708.
4 H, ArH), 7.47Ϫ7.61 (m, 2 H, ArH), 7.74Ϫ7.77 (m, 2 H, ArH),
Methyl (2R,4R)-4-(N-Acetylamino)-1-toluenesulfonyl-2-piperidine-
8.02 (s, 1 H, CHO). Ϫ 13C NMR (CDCl3): δ ϭ 30.3, 31.5 (t, C-3
and C-5), 39.8 (t, C-6), 47.1 (d, ArCH), 52.5, 53.8 (q, CO2Me and
d, C-2), 67.7 (t, CH2O), 67.9 (d, C-4), 119.9, 124.8, 127.0, 127.6 (d,
ArC), 141.2, 143.6 (s, ArC), 155.1 (s, NCO), 160.0 (s, HCO), 171.2
(s, CO). Ϫ HRMS (EI); C23H23NO6 (409.1525): found 409.1518.
carboxylate (35): A solution of s-trioxane (8.5 mg, 94 µmol) and
SnCl4 (0.30 mL of a 1.0  solution in CH2Cl2, 0.30 mmol) in
MeCN (5 mL) was stirred at room temp. for 30 min. Then, tosyl-
amide 24 (26 mg, 90 µmol) was added and the mixture was stirred
at 50°C for 18 h. The reaction mixture was poured into aqueous
saturated NaHCO3 (15 mL) and extracted with CH2Cl2 (3 ϫ 15
Methyl
(2R,4S)-4-Hydroxy-1-toluenesulfonyl-2-piperidinecar-
boxylate (32) and Methyl (2R,4R)-4-Hydroxy-1-toluenesulfonyl-2- mL). The combined organic layers were dried (MgSO4), concen-
piperidinecarboxylate (33): A solution of tosylamide 24 (52 mg, 183 trated and purified by flash chromatography (25 Ǟ 100% ethyl
µmol) and paraformaldehyde (55 mg, 1.83 mmol) in HCO2H (2 acetate in petroleum ether) to give 35 (16 mg, 41 µmol, 46%) and
mL) was stirred at 50°C for 18 h. The reaction mixture was concen- 32 (3.3 mg, 10 µmol, 11%) as colorless oils. Ϫ 35: Rf ϭ 0.20
trated and treated with 2  NH3/MeOH at 0°C for 30 min. Concen-
tration and purification by flash chromatography (75% ethyl ace-
tate in petroleum ether) afforded 32 (31 mg, 99 µmol, 54%) and 33
(21 mg, 66 µmol, 36%) as colorless oils. Ϫ 32: Rf ϭ 0.38 (75% ethyl
acetate in petroleum ether). Ϫ [α]D ϭ ϩ24.1 (c ϭ 1, CH2Cl2). Ϫ
(EtOAc). Ϫ [α]D ϭ ϩ12.0 (c ϭ 1, CH2Cl2). Ϫ IR (film): ν˜ ϭ 3382
cmϪ1 (NH), 3286 (NH), 1741 (CϭO), 1652 (CϭO). Ϫ 1H NMR
(CDCl3, data of the major of a 9:1 mixture of rotamers): δ ϭ 1.36
(ddt, 1 H, J ϭ 4.8, 12.4, 12.6 Hz, 5-Hax), 1.61 (dt, 1 H, J ϭ 6.1,
12.7 Hz, 3-Hax), 1.94 [s, 3 H, C(O)Me], 1.97Ϫ2.01 (m, 1 H, 5-Heq),
IR (film): ν˜ ϭ 3519 cmϪ1 (OH), 1738 (CϭO). Ϫ 1H NMR (CDCl3): 2.37Ϫ2.43 (m, 1 H, 3-Heq), 2.42 (s, 3 H, ArMe), 3.29 (dt, 1 H, J ϭ
Eur. J. Org. Chem. 1999, 1127Ϫ1135 1133

F. P. J. T. Rutjes et al.
FULL PAPER
2.8, 13.0 Hz, 6-Hax), 3.55 (s, 3 H, CO2Me), 3.83Ϫ3.88 (m, 2 H, 4-
(d, ArCH), 137.7, 143.5 (s, ArC), 173.7 (s, CO). Ϫ HRMS (EI);
H and 6-Heq), 4.87 (d, 1 H, J ϭ 5.9 Hz, 2-H), 5.24 (d, 1 H, J ϭ C15H22NO5S (328.1219): found 328.1199. Ϫ 39: Rf ϭ 0.14 (50%
7.2 Hz, NH), 7.29 (d, 2 H, J ϭ 8.0 Hz, ArH), 7.67 (d, 2 H, J ϭ ethyl acetate in petroleum ether). Ϫ [α]D ϭ Ϫ14.5 (c ϭ 0.91,
8.0 Hz, ArH). Ϫ 13C NMR (CDCl3, data of the major of a 9:1 CH2Cl2). Ϫ IR (film): ν˜ ϭ 3515 cmϪ1 (OH), 1738 (CϭO). Ϫ 1H
mixture of rotamers): δ ϭ 21.5 (q, ArMe), 23.3 [q, C(O)Me], 31.6, NMR (CDCl3): δ ϭ 1.54Ϫ1.62 (m, 1 H, 5-Hax), 1.66 (dd, 1 H, J ϭ
33.7 (t, C-3 and C-5), 41.6 (t, C-6), 43.4 (d, C-4), 52.3 (q, CO2Me), 8.6, 13.4 Hz, 3-Hax), 1.71 (s, 3 H, Me), 1.88Ϫ1.93 (m, 1 H, 5-Heq),
54.8 (d, C-2), 127.2, 129.6 (d, ArCH), 136.6, 143.5 (s, ArC), 169.4
(s, NCO), 170.3 (s, CO). Ϫ HRMS (EI); C13H16NO4S (355.1328):
found 355.1292.
2.28 (ddd, 1 H, J ϭ 1.4, 4.0, 13.4 Hz, 3-Heq), 2.41 (s, 3 H, ArMe),
3.09Ϫ3.15 (m, 1 H, 6-Hax), 3.68 (s, 3 H, CO2Me), 3.84Ϫ3.90 (m, 2
H, 4-H and 6-Heq), 7.27 (d, 2 H, J ϭ 8.1 Hz, ArH), 7.75 (d, 2 H,
J ϭ 8.1 Hz, ArH). Ϫ 13C NMR (CDCl3): δ ϭ 21.4 (q, ArMe), 24.6
(q, Me), 29.6, 42.1, 44.9 (t, C-3, C-5 and C-6), 52.4 (q, CO2Me),
63.4 (s, C-2), 64.7 (d, C-4), 127.2, 129.3 (d, ArCH), 138.6, 143.1
(s, ArC), 173.9 (s, CO). Ϫ HRMS (EI); C14H18NO4S (296.0956):
found 296.0942.
Dimethyl (2S)-1,2,3,6-Tetrahydropyridine-1,2-dicarboxylate (36): A
solution of 25 (36.0 mg, 0.14 mmol) and paraformaldehyde (6.3
mg, 0.21 mmol) in HCO2H (3 mL) was stirred at room temp. for
24 h. The mixture was concentrated and purified by flash chroma-
tography (50% diethyl ether in petroleum ether) to give 36 (11.0
mg, 0.06 mmol, 40%) as a colorless oil. Ϫ Rf ϭ 0.20 (50% diethyl
ether in petroleum ether). Ϫ [α]D ϭ ϩ2.8 (c ϭ 1, CH2Cl2). Ϫ IR
(film): ν˜ ϭ 2955 cmϪ1, 1743 (CϭO), 1705 (CϭO). Ϫ 1H NMR
(CDCl3): δ ϭ 2.48Ϫ2.67 (m, 2 H, 2 ϫ 3-H), 3.70, 3.72, 3.74, 3.75
(2 rotamers, s, 3 H, 2 ϫ CO2Me), 3.82Ϫ4.15 (m, 2 H, 2 ϫ 6-H),
4.92 and 5.09 (2 rotamers, d, J ϭ 6.3 Hz, 1 H, 2-H), 5.62Ϫ5.75 (m,
2 H, 4-H and 5-H). Ϫ 13C NMR (CDCl3): δ ϭ 26.3, 26.6 (rotamers,
t, C-3), 41.7, 41.8 (rotamers, t, C-6), 51.4, 51.9, 52.2, 52.8 (rotamers,
q, 2 ϫ CO2Me and C-2), 121.7, 122.2, 123.7, 124.1 (rotamers, C-4
and C-5), 157.0 (NCO), 171.8 (CϭO). Ϫ HRMS (EI); C9H13NO4
(199.0845): found 199.0844.
(2R,4S)-4-Hydroxy-2-piperidinecarboxylic Acid (51): Formate 30
(30 mg, 0.07 mmol) was stirred in a saturated NH3/MeOH solution
(3 mL) for 2 h and concentrated. The residue was dissolved in a
20% piperidine/MeOH (v/v) solution (3 mL), stirred for 2 h at room
temp. and concentrated. The residue was dissolved in THF (3 mL),
treated with 0.15  aqueous LiOH (1 mL) and stirred vigorously
for 3 h at room temp. The mixture was acidified with 2  HCl and
purified on a strongly acidic Dowex 50 Wϫ4 ion-exchange column
to yield 51 (6.5 mg, 0.04 mmol, 59%) as a thick gum. All spectro-
scopic data are in good agreement with those previously report-
ed.[6a]
(2R,4R)-4-Hydroxy-2-piperidinecarboxylic Acid (52): In a similar
procedure as described for 30, formate 31 (35 mg, 0.09 mmol) was
deprotected to afford the free pipecolic acid 52 (8 mg, 0.06 mmol,
61%) as a thick gum. All spectroscopic data are in good agreement
with those previously reported.[6a]
Methyl
(2S)-1-Toluenesulfonyl-1,2,3,6-tetrahydropyridine-2-car-
boxylate (37): A solution of 26 (57 mg, 0.16 mmol) and paraformal-
dehyde (7.3 mg, 0.24 mmol) in HCO2H (3 mL) was stirred at room
temp. for 60 h. The mixture was concentrated and purified by flash
chromatography (50% diethyl ether in petroleum ether) to give 37
(28 mg, 0.10 mmol, 60%) as a colorless oil. Ϫ ee: 87%. Ϫ Rf ϭ
0.23 (50% diethyl ether in petroleum ether). Ϫ [α]D ϭ ϩ2.2 (c ϭ 1,
CH2Cl2). Ϫ IR (film): ν˜ ϭ 2921 cmϪ1, 1732 (CϭO). Ϫ H NMR
1
Acknowledgments
(CDCl3) δ ϭ 2.41 (s, 3 H, ArMe), 2.54 (br. s, 2 H, 2 ϫ 3-H), 3.49
(s, 3 H, CO2Me), 3.81 (d, J ϭ 16.9 Hz, 1 H, 6-H), 4.07 (d J ϭ 17.0
Hz, 1 H, 6-H), 4.86 (t, J ϭ 4.6 Hz, 1 H, 2-H), 5.47Ϫ5.71 (m, 2 H,
4-H and 5-H), 7.28 (d, J ϭ 8.0 Hz, 2 H, ArH), 7.66 (d, J ϭ 8.1
Hz, 2 H, ArH). Ϫ 13C NMR (CDCl3) δ ϭ 21.4 (q, ArMe), 27.6 (t,
C-3), 42.0 (t, C-6), 51.9, 52.5 (C-2 and CO2Me), 122.1, 123.2 (d,
C-4 and C-5), 127.1, 129.3 (d, ArC), 136.1, 143.1 (s, ArC), 170.8
(CϭO). Ϫ HRMS (EI); C14H17NO4S (295.0878): found 295.0866.
Mr. J. J. M. Boesten is kindly acknowledged for determining the
ee values of the amino acids. Dr. B. Kaptein (DSM Research) is
gratefully acknowledged for a gift of enantiopure (S)-α-methylal-
lylglycine.
[1]
[1a]
See for example:
M. G. Moloney, Nat. Prod. Rep. 1998,
[1b]
205Ϫ219. Ϫ
B. Ho, T. M. Zabriskie, Bioorg. Med. Chem.
Lett. 1998, 8, 739Ϫ744.
[2]
(2S,4S)-1-Methyl-6-oxo-2-toluenesulfonyl-7-oxa-2-azabicyclo[3.2.1]-
octane (38) and Methyl (2S,4R)-4-Formyloxy-2-methyl-1-toluenesul-
fonyl-2-piperidinecarboxylate (39): A solution of tosylamide 27 (65
mg, 217 µmol) and paraformaldehyde (65 mg, 2.17 mmol) in
HCO2H (3 mL) was stirred at 50°C for 22 h. The reaction mixture
was concentrated and dissolved in a 2  NH3/MeOH solution at
0°C. After stirring for 30 min, the mixture was concentrated, dis-
solved in toluene and heated at reflux in the presence of cat. pTSA
under azeotropic removal of MeOH. The mixture was concentrated
and purified by flash chromatography (50% ethyl acetate in petro-
leum ether) to give the lactone 38 (24 mg, 93 µmol, 50%) and al-
cohol 39 (18 mg, 60 µmol, 32%) as colorless oils. Ϫ 38: Rf ϭ 0.40
(50% ethyl acetate in petroleum ether). Ϫ [α]D ϭ Ϫ47.7 (c ϭ 1,
CH2Cl2). Ϫ IR (film): ν˜ ϭ 1773 cmϪ1 (CϭO). Ϫ 1H NMR
(CDCl3): δ ϭ 1.61 (s, 3 H, CH3), 2.00Ϫ2.04 (m, 2 H, 5-Hax and 5-
Heq), 2.08 (dd, 1 H, J ϭ 6.0, 12.9 Hz, 3-Hax), 2.40Ϫ2.44 (m, 1 H,
3-Heq), 2.41 (s, 3 H, ArMe), 3.17Ϫ3.25 (m, 1 H, 6-Hax), 4.30 (ddd,
1 H, J ϭ 2.5, 5.5, 14.0 Hz, 6-Heq), 4.89 (q, 1 H, J ϭ 2.8 Hz, 4-H),
7.30 (d, 2 H, J ϭ 8.2 Hz, ArH), 7.68 (d, 2 H, J ϭ 8.2 Hz, ArH).
S. J. Mihalik, W. J. Rhead, J. Biol. Chem. 1989, 264, 2509.
[3] [3a]
F. E. King, T. J. King, A. J. Warwick, J. Chem. Soc. 1950,
[3b]
3590Ϫ3597. Ϫ
Agric. Biol. Chem. 1980, 44, 2725Ϫ2728. Ϫ
R. A. Raphael, J. Chem. Soc. 1985, 3642Ϫ3647. Ϫ
Y. Hasegawa, H. Hashimoto, M. Maeda,
[3c]
N. A. Dobson,
[3d]
A. W.
Burgstahler, C. E. Aiman, J. Org. Chem. 1960, 25, 489Ϫ492.
[4] [4a]
J. T. Romeo, L. A. Swain, A. B. Bleecker, Phytochemistry
1983, 22, 1615. Ϫ [4b] H. Vanderhaeghe, G. Janssen, F. Comper-
nolle, Tetrahedron Lett. 1971, 28, 268.
[5]
J. W. Clark-Lewis, P. I. Mortimer, J. Chem. Soc. 1961, 189.
[6] [6a]
A. S. Golubev, N. Sewald, K. Burger, Tetrahedron 1996, 47,
14757Ϫ14776. Ϫ [6b] H. Kessler, M. Kühn, T. Löschner, Liebigs
[6c]
Ann. Chem. 1986, 1Ϫ20. Ϫ
J. W. Reed, M. B. Purvis, D. G.
´
I. Kingston, A. Biot, F. Gossele, J. Org. Chem. 1989, 54,
1161Ϫ1165.
[7]
[8]
See e.g.: A. J. Hutchison, M. Williams, C. Angst, R. de Jesus,
L. Blanchard, R. H. Jackson, E. J. Wilusz, D. E. Murphy, P. S.
Bernard, J. Schneider, T. Campbell, W. Guida, M. A. Sills, J.
Med. Chem. 1989, 32, 2171.
P. L. Ornstein, D. D. Schoepp, M. B. Arnold, J. D. Leander, J.
W. Paschal, T. Elzey, J. Med. Chem. 1991, 34, 90.
[9] [9a]
C. Herdeis, W. Engel, Arch. Pharm. (Weinheim, Ger.) 1993,
[9b]
326, 297Ϫ301. Ϫ
C. S. R. Angle, D. O. Arnaiz, Tetrahedron
Lett. 1989, 30, 515Ϫ518. Ϫ [9c] J. J. N. Veerman, J. H. van Maar-
seveen, G. M. Visser, C. G. Kruse, H. E. Schoemaker, H.
Hiemstra, F. P. J. T. Rutjes, Eur. J. Org. Chem., in press.
Ϫ
13C NMR (CDCl3): δ ϭ 20.2 (q, Me), 21.3 (q, ArMe), 29.6, 43.0,
43.5 (t, C-3, C-5 and C-6), 62.3 (s, C-2), 75.1 (d, C-4), 126.9, 129.5
1134
Eur. J. Org. Chem. 1999, 1127Ϫ1135

Enantiopure Functionalized Pipecolic Acids via Amino Acid Derived N-Acyliminium Ions
FULL PAPER
[10] [10a]
R. E. A. Callens, M. J. O. Anteunis, F. Reyniers, Bull. Soc.
(Ed.: Atta-ur-Rahman), Elsevier, Amsterdam, 1993, pp.
473Ϫ518.
[14]
[10b]
Chim. Belg. 1982, 91, 713Ϫ723. Ϫ
M. de Lederkremer Tetrahedron 1993, 49, 9459. Ϫ
Hanson, M. A. Russell, Tetrahedron Lett. 1989, 30, 5751Ϫ5754.
A. P. Nin, O. Varela, R.
[10c]
G. J.
For similar trapping experiments, see: D. J. Hart, Y.-M. Tsai,
Tetrahedron Lett. 1981, 22, 1567.
[15] [15a]
[10d]
Ϫ
A. Golubev, N. Sewald, K. Burger, Tetrahedron Lett.
G. W. Daub, D. A. Heerding, L. E. Overman, Tetrahedron
[15b]
[10e]
1995, 3, 33. Ϫ
Y. Bousquet, P. C. Anderson, T. Bogri, J.-S.
1988, 44, 3919Ϫ3930. Ϫ
P. Castro, L. E. Overman, X.
Duceppe, L. Grenier, I. Guse, Tetrahedron 1997, 53,
Zhang, P. S. Mariano, Tetrahedron Lett. 1993, 34, 5243Ϫ5246.
S. J. Veenstra, K. Hauser, W. Schilling, C. Betschart, S. Ofner,
Bioorg. Med. Chem. Lett. 1996, 6, 3029Ϫ3034.
Q. B. Broxterman, B. Kaptein, J. Kamphuis, H. E. Schoemaker,
J. Org. Chem. 1992, 57, 6286.
15671Ϫ15680. Ϫ [10f] F. P. J. T. Rutjes, H. E. Schoemaker, Tetra-
[16]
[17]
[18]
[10g]
hedron Lett. 1997, 38, 677Ϫ680. Ϫ
P. D. Bailey, G. R.
Brown, F. Korber, A. Reed, R. D. Wilson, Tetrahedron: Asym-
[10h]
metry 1991, 2, 1263Ϫ1282. Ϫ
R. F. W. Jackson, L. J. Gra-
ham, A. B. Rettie, Tetrahedron Lett. 1994, 35, 4417Ϫ4418. Ϫ
B. Kaptein, W. H. J. Boesten, Q. B. Broxterman, P. J. H. Peters,
H. E. Schoemaker, J. Kamphuis, Tetrahedron: Asymmetry 1993,
4, 1113Ϫ1116.
[10i]
R. Pellicciari, B. Natalini, R. Luneia, M. Marinozzi, M.
Roberti, G. C. Rosato, B. M. Sadeghpour, J. P. Snyder, J. B.
[19] [19a]
Monahan, F. Moroni, Med. Chem. Res. 1992, 2, 491. Ϫ
M. J. OЈDonnell, R. L. Polt, J. Org. Chem. 1982, 47,
[10j]
[19b]
Y. Fujita, J. Kollonitsch, B. Witkop, J. Am. Chem. Soc.
2663Ϫ2666. Ϫ
M. J. OЈDonnell, K. Wojciechowski, L.
1965, 87, 2030.
Ghosez, M. Navarro, F. Sainte, J.-P. Antoine, Synthesis 1984,
313Ϫ315.
[11]
For a racemic route, see: [11a] S. J. Hays, T. C. Malone, G. John-
[20] [20a]
son, J. Org. Chem. 1991, 56, 4084. Ϫ For enantiopure ap-
H. Hiemstra, W. J. Klaver, W. N. Speckamp, Recl. Trav.
[11b]
[20b]
proaches, see:
C. Agami, F. Couty, M. Poursoulis, J. Vais-
Chim. Pays-Bas 1986, 105, 299Ϫ306. Ϫ
T. K. Jones, S. E.
sermann, Tetrahedron 1992, 48, 431. Ϫ [11c] J. Gillard, A. Abra-
Denmark, Org. Synth. 1986, 64, 182Ϫ188. Ϫ
C. A. Brown,
[20c]
ham, P. C. Anderson, P. L. Beaulieu, T. Bogri, Y. Bousquet, L.
V. K. Ahuja, J. Org. Chem. 1973, 38, 2226Ϫ2230.
[21]
[22]
´
Grenier, I. Guse, P. Lavallee, J. Org. Chem. 1996, 61,
Obtained from DSM Research.
[11d]
[22a]
2226Ϫ2231. Ϫ
J. W. Skiles, P. P. Giannousis, K. R. Fales,
For reviews on this type of resolution, see:
V. H. M. Elfer-
Bioorg. Med. Chem. Lett. 1996, 6, 963Ϫ966.
ink, D. Breitgoff, M. Kloosterman, J. Kamphuis, W. J. J. van
den Tweel, E. M. Meijer, Recl. Trav. Chim. Pays-Bas 1991, 110,
63Ϫ74. Ϫ [22b] H. E. Schoemaker, W. H. J. Boesten, B. Kaptein,
H. F. M. Hermes, T. Sonke, Q. B. Broxterman, W. J. J. van den
Tweel, J. Kamphuis, Pure Appl. Chem. 1992, 64, 1171Ϫ1175. Ϫ
[12]
[12a]
For racemic routes, see:
P. M. Esch, I. M. Boska, H.
Hiemstra, W. N. Speckamp, Synlett 1989, 38. Ϫ [12b] P. M. Esch,
I. M. Boska, H. Hiemstra, R. F. de Boer, W. N. Speckamp,
[12c]
Tetrahedron 1991, 47, 4039Ϫ4062. Ϫ
P. M. Esch, R. F. de
[22c]
Boer, H. Hiemstra, I. M. Boska, W. N. Speckamp, Tetrahedron
H. E. Schoemaker, W. H. J. Boesten, B. Kaptein, E. C.
[12d]
1991, 47, 4063Ϫ4076. Ϫ For enantiopure routes, see:
C.
Roos, Q. B. Broxterman, W. J. J. van den Tweel, J. Kamphuis,
Acta Chem. Scand. 1996, 50, 225Ϫ233.
Agami, C. Kadouri-Puchot, V. Le Guen, J. Vaissermann, Tetra-
[12e]
[23]
hedron Lett. 1995, 36, 1657. Ϫ
C. Agami, D. Bihan, L.
The ee values were determined by chiral HPLC analysis with
a Crownpak (CRϩ) column according to a known procedure:
Miyazawa, T.; Iwanaga, H.; Yamada, T.; Kuwata, S. Chem. Ex-
press 1991, 6, 887.
For a similar discussion with oxygen-stabilized cations, see: C.
Semeyn, R. H. Blaauw, H. Hiemstra, W. N. Speckamp, J. Org.
Chem. 1997, 62, 3426Ϫ3427 and references cited therein.
A. I. Vogel, A Textbook of Practical Organic Chemistry, 3rd ed.,
London, Longman, 1956, p. 971.
Hamon, C. Kadouri-Puchot, M. Lusinchi, Eur. J. Org. Chem.
1998, 2461Ϫ2465.
[13]
[13a]
For reviews on N-acyliminium ions, see:
H. Hiemstra, W.
[24]
[25]
N. Speckamp, in Comprehensive Organic Synthesis (Eds.: B. M.
Trost, I. Fleming), Pergamon, Oxford, 1991, vol. 2, p. 1047.
[13b]
Ϫ
H. de Koning, W. N. Speckamp, Methoden Org. Chem.
[13c]
(Houben-Weyl) 1995, vol. E 21b, p. 1953Ϫ2009. Ϫ
H.
Hiemstra, W. N. Speckamp in The Alkaloids, vol. 32 (Ed.: A.
Brossi), Academic Press, Inc., San Diego, 1988, pp. 271Ϫ239.
Received October 22, 1998
[13d]
Ϫ
H. de Koning, M. J. Moolenaar, H. Hiemstra, W. N.
[O98466]
Speckamp in Studies in Natural Products Chemistry, vol. 13
Eur. J. Org. Chem. 1999, 1127Ϫ1135
1135