Enantioselective synthesis of α,α'-disubstituted piperidines via ruthenium-catalyzed ring rearrangement

Article abstract of DOI:10.1055/s-2000-6267

A new method for the enantioselective synthesis of α,α'-disubstituted piperidines is described. Easily available cyclopentenones 5a,b rearrange via Ru-catalyzed RCM-ROM to heterocycles. Compound 6a is converted to the indolizidine 13.

Full text of DOI:10.1055/s-2000-6267

SPECIAL TOPIC
893
Enantioselective Synthesis of a,a’-Disubstituted Piperidines via Ruthenium-
Catalyzed Ring Rearrangement
Ulrike Voigtmann, Siegfried Blechert*
Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 135, D-10623 Berlin, Germany
Fax+49(30)31423619; E-mail: blechert@chem.tu-berlin.de
Received 23 March 2000
PCy3
Ph
Abstract: A new method for the enantioselective synthesis of a,a’-
Cl
R
Ru
Cl
disubstituted piperidines is described. Easily available cyclopenten-
*
[Ru]
PCy3
ones 5a,b rearrange via Ru-catalyzed RCM-ROM to heterocycles.
Compound 6a is converted to the indolizidine 13.
R
*
*
X
Key words: metathesis, rearrangements, piperidines, indolizidines,
X
azasugars, ruthenium, osmium, dihydroxylations
I
IV
Transition metal-catalyzed olefin metathesis is a very
powerful tool in organic synthesis. Variations of this valu-
able transformation like ring closing metathesis (RCM),
ring opening metathesis (ROM) and cross metathesis
(CM) have been investigated during recent years.1 RCM
has found many applications. Its efficiency has been prov-
en in the synthesis of various carbo- and heterocycles and
especially in the synthesis of natural products.2 The less
frequently applied ROM is mainly known as partial step
in the polymerization (ROMP) of strained rings like nor-
bornene and cyclooctene.3 However, in the presence of
acyclic olefins it is possible to combine the ROM with a
selective cross metathesis and, thus, to suppress the poly-
merization.4 Such ROM can also be combined with RCM
and CM to domino processes.5 Unstrained rings can be
opened using a RCM-ROM-RCM sequence.6 Reactions
are driven by a loss of ring strain or by the release of a vol-
atile olefin like ethylene. Currently, we are interested in
+ I
+ [Ru]
-
- II
Ph
R
X
R
[Ru]
[Ru]
X
II
III
Scheme 1
The equilibrium in this novel reaction sequence should
depend on the relative thermodynamic stabilities of sub-
strate and product. Recently, we have applied this concept
to the synthesis of the piperidine alkaloid (-)-halosalin.8
←
RCM-ROM combinations of type I → IV, which offer in-
Now, we report about the extension of this concept to-
wards the synthesis of a,a’-disubstituted piperidines and
subsequent products, which are interesting as azasugars.
As shown in the case 1Æ2 (Scheme 2) the application
of metathesis ring rearrangement IÆIV to heterocycles
with an olefinic side chain should lead to cis- or
trans- a,a’-disubstituted derivatives of defined configura-
tion depending on the chiral centre highlighted. Besides
the equilibrium problem we were also interested in rela-
tive rearrangement rates of the two diastereomers of 1.
teresting opportunities for ring rearrangements. A special
aspect of this reaction is the catalytic transfer of stereo-
centers from easily available carbocyclic olefins to het-
erocycles with substituted side chains. Based on earlier
work, we assume, that Grubbs’ pre-catalyst [Ru]7 first re-
acts with the better accessible terminal double bond of cy-
clopentene derivative I forming ruthenium carbene
complex II (Scheme 1). Subsequent reaction between I
and II would lead to dimeric products. As we did not ob-
serve any dimerization, it has to be assumed, that an in-
tramolecular [2+2] cycloaddition reaction with the cyclic
double bond and subsequent cycloreversion proceeds
much faster.
.
[Ru]
The resulting metal carbene-complex III reacts in a cross
metathesis reaction with another molecule of I under for-
mation of product IV. In principle, the dimerization is also
possible at this stage. However, NMR-analyses of the re-
action did not reveal the formation of any dimerization
products.
*
*
*
R
N
N
Pg
Pg
*
R
1
2
Scheme 2
Synthesis 2000, No. 6, 893–898 ISSN 0039-7881 © Thieme Stuttgart · New York

894
U. Voigtmann, S. Blechert
SPECIAL TOPIC
OAc
OAc
NTs
Pd(OAc)2, PPh3,
NaH, DMF
TsHN
CO2Me
OAc
5 mol% [Ru]
+
R1
CH2Cl2, RT, 95 %
RT-40°C, 71 %
N
R2
H
OBz-p-NO2
Ts
R1 R2
R1
R2
6a,b
3
4
5a,b
a
b
CO2Me
H
H
CO2Me
Scheme 3
An ester function, i.e. an allylglycine derivative, was cho- form cis- or trans-a,a’-disubstituted N-heterocycles
sen as a substituent offering a high flexibility for subse- starting from enantiomerically pure D- or L- allylglycine
quent reactions. Allylglycine derivatives have been used ester. As a proof, (+)-4 or (-)-4 was treated with 3 and we
in metathesis reactions several times.1,9 Racemization is exclusively obtained the cis-ester 6a or the thermodynam-
not to be expected under the mild, neutral conditions of ically more labile trans-ester 6b in the same yield.
metathesis. As a starting material for the synthesis of a
suitable precursor we used p-nitrobenzoate 3, which is
In the next step, we wanted to apply this new procedure to
the preparation of polyhydroxypiperidine derivatives,
representing azasugar analogs. As inhibitors of glycosi-
dases and glycosyltransferases and consequently, as po-
easily available in high overall yield by enzymatic
hydrolysis10 and Mitsunobu reaction of cis-1,3 diacetoxy-
cyclopentadiene. A Pd(0)-catalyzed allylation of rac-al-
lylglycine ester 4 with 3 gives rise to the desired 1:1
mixture of diastereomers 5a and 5b, which should be in-
tential antibacterial, antiviral, antimetastatic and
antidiabetic agents polyhydroxylated indolizidines have
drawn considerable attention.11
vestigated and compared in their ability to react as met-
We have used the new concept of ring rearrangement for
athesis precursors.
the synthesis of the novel indolizidine 13. The transforma-
Different rates of rearrangement of 5a and 5b could lead
tion of alkenyl-substituted piperidines of type 6 into an in-
to kinetic separation of diastereomers. Therefore, the mix-
dolizidine requires a cyclization to a five-membered ring.
ture (0.1 mol/L in CH2Cl2) was treated with 5 mol% of
It was planned to cleave oxidatively the terminal double
bond and to cyclize the resulting aldehyde in a reductive
amination with the deprotected secondary amine. During
the synthesis of the required enantiomerically pure cis-
disubstituted piperidine it is not necessary to start from the
expensive D-allylglycine. Instead, we treated the 1:1 dia-
stereomeric mixture of 6a and 6b, obtained from the race-
mic amino acid ester, with a catalytic amount of NaOMe
[Ru]. At room temperature both compounds are rear-
ranged equally fast. After 15 hours the transformation has
reached the equilibrium, which is characterized by the
practically complete formation of pipecolic acid deriva-
tive 6a and 6b. After filtration on silica gel 6a,b was ob-
tained almost quantitatively and in pure form. Since
racemization can be excluded under the reaction condi-
tions, it should be feasible to obtain stereochemically uni-
Na,
naphthalene
THF, 63%
7 R=Ts
8 R=H
OH
8
NaOMe
6 a,b
N
R
MeO2C
MeOH,
RT, 51%
H
Boc2O,
(C3H7)2NEt
CH2Cl2, 94%
8 R=H
9 R=Boc
7
OR
OR
OsO4, NMO
OR
10 R=H
Ac2O, NEt3
CH2Cl2, 98%
Acetone/H2O,
RT, 67%
11 R=Ac
MeO2C
N
H
Boc
10
OAc
OAc
OsO4,
OAc
OAc
1. TFA, CH2Cl2
2. K2CO3, pH 7
NaCNBH3,
MeOH, RT, 87%
NaIO4
AcO
OAc
Acetone/H2O
RT, 69%
O
N
CO2Me
13
MeO2C
N
H
Boc
12
Scheme 4
Synthesis 2000, No. 6, 893–898 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Synthesis of a,a’-Disubstituted Piperidines
895
p-Nitrobenzoic Acid (1R,4R)-4-Acetoxycyclopent-2-en-1-yl Es-
ter (3)
in methanol. After workup and chromatography on silica
gel the completely isomerized, thermodynamically more
stable compound 7 was isolated. Under the isomerization
conditions the acetyl group at C-8 was cleaved.
To an ice-cooled solution of (1R,3S)-(+)-cis-4-cyclopentene-1,3-
diol-1-acetate (700 mg, 4.9 mmol), Ph3P (5.1 g, 19.5 mmol) and p-
nitrobenzoic acid (3.3 g, 20 mmol) in anhyd THF (25 mL) under N2
was slowly added diethyl azodicarboxylate (3.5 g, 20 mmol) via a
syringe. The mixture was stirred overnight at r.t., concentrated in
vacuum, diluted with Et2O (50 mL) and stirred again for 18 h at r.t.
A white precipitate appeared. The precipitation was completed by
addition of hexane (10 mL). It was filtered off and washed with a
mixture of hexane/Et2O (1:1, 50 mL). The solvent was removed un-
der vacuum and the residue was chromatographed on silica gel
[10:1 hexane/methyl tert-butyl ether (MTBE)] to give 3 as a yellow
solid (1.30 g, 90%); mp 47 °C; [a]D25 +257.0 (c = 1.445, CHCl3).
During the preparation of precursor 5 a tosyl group proved
favourable with regard to the Pd(0)-catalyzed step. Unfor-
tunately, the deprotection conditions are not compatible
with the functional groups required for the reductive ami-
nation. Therefore, in the next step the sulfonyl group was
reductively removed using sodium naphthalide and the re-
sulting free amine 8 was protected with a Boc-group
cleavable under acidic conditions. Moreover, the intro-
duction of this group in contrast to the tosyl group enables
IR (KBr): n = 3112 (w), 3081 (w), 2954 (w), 1723 (s), 1528 (s),
a highly selective oxidation of the cyclic olefin. cis-Dihy- 1274 (s), 1238 (s), 1103 (m), 1027 (m), 719 (m) cm-1.
1H NMR (500 MHz, CDCl3) d = 8.30 (d, J = 9 Hz, 2 H, Ar-H), 8.18
(d, J = 9 Hz, 2 H, Ar-H), 6.24 (m, 2 H, C2-H, C3-H), 6.10 (m, 1 H,
C1-H), 5.90 (m, 1 H, C4-H), 2.45 (ddd, J = 15, 7, 4 Hz, 1 H, C5-H),
2.38 (ddd, J = 15, 6, 4 Hz, 1 H, C5-H), 2.08 (s, 3 H, COCH3).
13C NMR (100.6 MHz, CDCl3): d = 170.8, 164.4, 150.5, 136.4,
134.6, 135.3, 130.6, 123.5, 79.9, 78.1, 37.4, 21.0.
droxylation of 9 using a catalytic amount of OsO4 and 1.0
equivalent of NMO (N-methylmorpholine N-oxide) sur-
prisingly resulted in the formation of the triol 10, which
was obtained in 67% yield after chromatography. Besides
19% of starting material only traces of completely hy-
droxylated product were isolated.
MS (EI): m/z (%) = 232 ([M - OAc]+, 24), 150 (100), 82 (48).
The free hydroxyl groups in 10 were acetylated to give tri-
acetate 11. Oxidative double bond cleavage using catalyt- HRMS: m/z calcd for C12H10NO4 (M - OAc)+ 232.0609; found
232.0608.
ic amounts of OsO4 and 5.0 equivalents of NaIO4 yielded
aldehyde 12 suitable for planned cyclization. The Boc
group was carefully removed using trifluoroacetic acid
(TLC control) and the resulting imine was reduced with
NaBH3CN at pH 7. The reductive amination afforded the
desired indolizidine 13 in 7% overall yield over 10 steps.
Anal. calcd for C14H13NO6: C, 57.76; H, 4.46; N, 4.81; found C,
57.37; H, 4.72; N, 5.06.
2-(Toluene-4-sulfonylamino)pent-4-enoic Acid Methyl Ester (4)
To a solution of allylglycine methyl ester (2.0 g, 15.4 mmol) in
CH2Cl2 (20 mL) was added sat. aq NaHCO3 (15 mL) and p-toluene-
sulfonyl chloride (3.0 g,16.9 mmol, 1.1 equiv). After stirring strong-
ly overnight the organic layer was separated, washed with brine (2
× 25 mL), dried (MgSO4) and concentrated in vacuum. The result-
ing oil was chromatographed on silica gel (10:1 hexane/MTBE) to
give 4 as a colourless solid (3.2 g, 73%) after recrystallization from
MTBE.
In conclusion, we have presented a domino ring opening-
ring closing metathesis terminated by a methylene trans-
fer. This concept enables the preparation of enantiomeri-
cally pure cis- or trans- a,a’-disubstituted piperidines,
which can be transformed into indolizidines using easily
available racemic or enantiomerically pure starting mate-
rials. This synthetic principle is applicable to other mem-
bers of the indolizidine family by simple modifications of
the route described above. Further studies in this direction
are currently being performed in our group.
IR (KBr): n = 3277 (w), 3080, 3029 (w), 2982,2954 (w), 1741 (s),
1343 (s), 1163 (s), 1092 (m), 815 (m), 665 (m) cm-1.
1H NMR (400 MHz, CDCl3): d = 7.72 (d, J = 8 Hz, 2 H, Ar-H), 7.30
(d, J = 8 Hz, 2 H, Ar-H), 5.62 (m, 1 H, C4-H), 5.12 (d, J = 10 Hz, 1
H, C5-H), 5.08 (d, J = 17 Hz, 1 H, C5-H), 4.04 (m, 1 H, C2-H), 3.53
(s, 3 H, CO2CH3), 2.48 (dd, J = 6.5, 6.5 Hz, 2 H, C3-H), 2.44 (s, 3
H, Ar-CH3).
1H NMR spectra (400 MHz) and 13C NMR spectra (100.6 MHz)
were recorded on a Bruker AM 400 spectrometer using the indicat-
ed solvents. 1H NMR spectra (500 MHz) were recorded on a Bruker
DRX 500 spectrometer. 13C NMR spectra (67.5 MHz) were record-
ed on a Bruker AM 270 spectrometer. NMR chemical shifts are ex-
pressed in ppm upfield, relative to the internal solvent peak. HRMS
were recorded on a Finnigan MAT 95 SQ and IR spectra on a Nico-
let FT-IR 750 spectrometer. Optical rotations were measured on a
Perkin-Elmer 141 polarimeter. Melting points were determined on
a Leica Galen III heater tablemicroscope and are uncorrected. Ele-
mental analyses were recorded on a Elementar Vario El Fa. Analy-
tik Jena. Analytical TLC was performed using silica gel 60 F254
precoated plates Merck, 0.25 mm thickness with a fluorescent indi-
cator. Flash column chromatography was performed on Merck sili-
ca gel 60 (0.040-0.063 mm) using the indicated solvent. Chemicals
were purchased from Aldrich or Merck and used without further pu-
rification. Metathesis reactions were performed in a Braun MB
150B-G glove box under N2. Solvents were distilled under N2 from
sodium/benzophenone (THF) or CaH2 (CH2Cl2, DMF).
13C NMR (67.5 MHz, CDCl3) d = 171.2, 143.5, 136.7, 131.2, 129.4,
127.0, 119.4, 55.1, 52.2, 37.3, 21.3.
MS (EI): m/z (%) = 283 ([M]+, 1), 242 (60), 155 (100), 91 (84).
HRMS: m/z calcd for C13H17NO4S (M)+ 283.0878; found 283.0877.
Anal. calcd for C12H14N2O6S (nosyl-protected derivative): C, 45.86;
H, 4.46; N, 8.92; found C, 45.62; H, 4.55; N, 8.92.
(R) and (S) -2-{[(1R,4R)-4-Acetoxycyclopent-2-enyl](toluene-4-
sulfonyl)amino}pent-4-enoic Acid Methyl Ester (5a,b)
To an ice-cooled solution of racemic 4 (486 mg, 1.72 mmol) in
DMF (20 mL) was added NaH (75 mg as a 60% dispersion in oil,
1.87 mmol). The mixture was stirred for 20 min at 0 °C and 20 min
at r.t. A mixture of Pd(OAc)2 (22 mg, 0.1 mmol), Ph3P (131 mg, 0.4
mmol) and 3 (488 mg, 1.75 mmol) in anhyd DMF (20 mL) was
added in two portions. After 15 h the mixture was concentrated in
vacuum, diluted with MTBE (30 mL), washed with aq sat. NH4Cl
(50 mL), dried (MgSO4) and concentrated. The resulting oil
was chromatographed on Al2O3 (1:1 hexane/MTBE) to give 5 as a
Synthesis 2000, No. 6, 893–898 ISSN 0039-7881 © Thieme Stuttgart · New York

896
U. Voigtmann, S. Blechert
SPECIAL TOPIC
colourless oil (1:1 mixture of two inseparable diastereomers; 496
mg, 71%).
(2R, 6R)-6-[(R)-2-Acetoxybut-3-enyl]-1-(toluene-4-sulfonyl)-
1,2,3,6-tetrahydropyridine-2-carboxylic Acid Methyl Ester (6a)
Transformation of 5a (180 mg, 0.44 mmol) in CH2Cl2 (5 mL) with
[Ru] (18 mg, 0.021 mmol) was carried out analogous to the synthe-
sis of 6a,b as above and worked up to give 6a as a colourless solid
(173 mg, 96%).
1H NMR (500 MHz, CDCl3): d = 7.69 (d, J = 8 Hz, 2 H, Ar-H), 7.28
(d, J = 8 Hz, 2 H, Ar-H), 5.80 (ddd, J = 17, 10, 6 Hz, 1 H, C3’-H),
5.65 (m, 1 H, C4-H), 5.60 (m, 1 H, C5-H), 5.40 (m, 1 H, C2’-H), 5.30
(d, J = 17 Hz, 1 H, C4’-H), 5.22 (d, J = 10 Hz, 1 H, C4’-H), 4.72 (d,
J = 7 Hz, 1 H, C2-H), 4.41 (m, 1 H, C6-H), 3.70 (s, 3 H, CO2CH3),
2.48 (dd, J = 17, 6 Hz, 1H, C3-H), 2.42 (s, 3 H, Ar-CH3), 2.08 (s, 3
H, COCH3), 1.85 (m, 3 H, C3-H, C1’-H).
IR (film): n = 3075 (w), 2953 (w), 2924 (w), 1736 (s), 1341 (m),
1241 (s), 1157 (s), 664 (m) cm-1.
MS (EI): m/z (%) = 347 ([M - C2H4O]+, 8), 192 (22), 155 (68), 125
(100), 91 (100).
HRMS: m/z calcd for C18H21O4NS (M - C2H4O)+ 347.1191; found
347.1192.
Anal. calcd for C20H25NO6S: C, 58.97; H, 6.14; N, 3.44; found C,
58.63; H, 6.30; N, 3.57.
(R)-2-{[(1R,4R)-4-Acetoxycyclopent-2-enyl](toluene-4-sulfon-
yl)amino}pent-4-enoic Acid Methyl Ester (5a)
13C NMR (100.6 MHz, CDCl3): d = 171.3, 169.9, 143.5, 136.7,
136.0, 129.5, 126.9, 126.2, 122.8, 116.9, 71.8, 52.4, 51.3, 49.8,
39.5, 26.7, 22.9, 21.3.
Reaction of (+)-4 (200 mg, 0.75 mmol) with 3 (216.5 mg, 0.63
mmol) was carried out analogous to the synthesis of 5a,b as above
[NaH (37 mg as a 60% dispersion in oil, 0.93 mmol); Pd(OAc)2 (11
mg, 0.05 mmol), Ph3P (65.5 mg, 0.2 mmol), DMF (20 mL)] and
worked up to give 5a as a colourless oil (198 mg, 69%).
1H NMR (500 MHz, CDCl3): d = 7.68 (d, J = 9 Hz, 2 H, Ar-H), 7.27
(d, J = 9 Hz, 2 H, Ar-H), 5.98 (m, 2 H, C2’-H, C3’-H), 5.78 (m, 2 H,
C4-H, C4’-H), 5.13 (d, J = 10 Hz, 1 H, C5-H), 5.11 (d, J = 17 Hz, 1
H, C5-H), 4.84 (m, 1 H, C1’-H), 4.22 (dd, J = 8, 6 Hz, 1 H, C2-H),
3.64 (s, 3 H, CO2CH3), 2.88 (m, 1 H, C3-H), 2.52 (m, 1 H, C3-H),
2.42 (s, 3 H, Ar-CH3), 2.39 (m, 1 H, C5’-H), 2.06 (ddd, J = 15, 8, 2
Hz, 1H, C5’-H), 2.01 (s, 3 H, COCH3).
(2S, 6R)-6-[(R)-2-Acetoxybut-3-enyl]-1-(toluene-4-sulfonyl)-
1,2,3,6-tetrahydropyridine-2-carboxylic Acid Methyl Ester (6b)
Transformation of 5b (180 mg, 0.44 mmol) in CH2Cl2 (5 mL) with
[Ru] (18 mg, 0.021 mmol) was carried out analogous to the synthe-
sis of 6a,b as above and worked up to give 6b as a colourless solid
(166 mg, 92%).
1H NMR (500 MHz, CDCl3): d = 7.76 (d, J = 8 Hz, 2 H, Ar-H), 7.26
(d, J = 8 Hz, 2 H, Ar-H), 5.75 (ddd, J = 17, 11, 6 Hz, 1H, C3’-H),
5.70 (m, 1 H, C4-H), 5.65 (m, 1 H, C5-H), 5.22 (d, J = 17 Hz, 1 H,
C4’-H), 5.18 (d, J = 10 Hz, 1 H, C4’-H), 5.12 (m, 1 H, C2’-H), 4.37
(m, 1 H, C6-H), 4.10 (dd, J = 10, 5 Hz, 1 H, C2-H), 3.80 (s, 3 H,
CO2CH3), 2.58 (ddd, J = 18, 10, 2 Hz, 1 H, C3-H), 2.43 (s, 3 H, Ar-
CH3), 2.24 (ddd, J = 18, 5, 5 Hz, 1 H, C3-H), 1.98 (s, 3 H, COCH3),
1.90 (m, 2 H, C1’-H).
13C NMR (100.6 MHz, CDCl3): d = 171.1, 170.7, 143.2, 138.3,
136.9, 133.7, 132.8, 129.3, 127.4, 118.4, 78.6, 63.1, 59.4, 52.2,
37.1, 35.8, 21.4, 21.0.
(S)-2-{[(1R,4R)-4-Acetoxycyclopent-2-enyl](toluene-4-sulfon-
yl)amino}pent-4-enoic Acid Methyl Ester (5b)
13C NMR (100.6 MHz, CDCl3): d = 170.5, 169.7, 143.8, 137.4,
136.0, 129.4, 128.3, 127.7, 124.9, 117.0, 71.5, 54.1, 53.0, 52.4,
38.8, 26.1, 21.5, 21.0.
Reaction of (-)-4 (200 mg, 0.75 mmol) with 3 (216.5 mg, 0.63
mmol) was carried out analogous to the synthesis of 5a,b as above
[NaH (37 mg as a 60% dispersion in oil, 0.93 mmol); Pd(OAc)2 (11
mg, 0.05 mmol), Ph3P (65.5 mg, 0.2 mmol), DMF (20 mL)] and
worked up to give 5b as a colourless oil (209 mg, 73%).
1H NMR (500 MHz, CDCl3): d = 7.76 (d, J = 8 Hz, 2 H, Ar-H); 7.29
(d, J = 8 Hz, 2 H, Ar-H), 6.02 (m, 1 H, C3’-H), 5.88 (m,1 H, C2’-H),
5.70 (m, 2 H, C4-H, C4’-H), 5.05 (d, J = 10 Hz, 1 H, C5-H), 5.02 (d,
J = 17 Hz, 1 H, C5-H), 4.98 (m, 1 H, C1’-H), 3.85 (dd, J = 7, 7 Hz,
1 H, C2-H), 3.74 (s, 3 H, CO2CH3), 2.86 (m, 1 H, C3-H), 2.48 (m, 2
H, C3-H, C5’-H), 2.43 (s, 3 H, Ar-CH3), 2.11 (ddd, J = 16, 8, 3 Hz,
1H, C5’-H), 2.01 (s, 3 H, COCH3).
(2R,6R)-6-[(R)-2-Hydroxybut-3-enyl]-1-(toluene-4-sulfonyl)-
1,2,3,6-tetrahydropyridine-2-carboxylic Acid Methyl Ester (7)
To a solution of 6 (40mg, 0.1 mmol) in anhyd MeOH (3 mL) was
added NaOMe (2 mg, 0.037 mmol). The mixture was stirred over-
night, diluted with brine (5 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried (MgSO4) and con-
centrated in vacuum. The resulting oil was chromatographed on sil-
ica gel (1:1 hexane/MTBE) to give 7 (18 mg, 51%) as a colourless
oil; [a]D25 -27.3 (c = 0.3, CHCl3).
13C NMR (100.6 MHz, CDCl3): d = 170.9, 170.4, 143.3, 138.3,
136.6, 134.1, 133.6, 129.3, 127.3, 117.8, 78.0, 63.1, 58.1, 52.2,
35.6, 35.4, 21.2, 20.8.
IR (film): n = 3532 (w), 3036 (w), 2954 (w), 2926 (w), 1741 (s),
1332 (m), 1162 (s), 659 (m) cm-1.
1H NMR (400 MHz, CDCl3): d = 7.69 (d, J = 8 Hz, 2 H, Ar-H), 7.28
(d, J = 8 Hz, 2 H, Ar-H), 5.88 (ddd, J = 17, 11, 6 Hz, 1 H, C3’-H),
5.59 (m, 1 H, C4-H), 5.50 (m, 1 H, C5-H), 5.34 (d, J = 17 Hz, 1 H,
C4’-H), 5.12 (d, J = 10 Hz, 1 H, C4’-H), 4.75 (d, J = 7 Hz, 1 H, C2-
H), 4.62 (m, 1 H, C2’-H), 4.53 (m, 1 H, C6-H), 3.72 (s, 3 H,
CO2CH3), 2.48 (dd, J = 18, 6 Hz, 1 H, C3-H), 2.43 (s, 3H, Ar-CH3),
1.76 (ddd, J = 18, 8, 2 Hz, 1 H, C3-H), 1.52 (m, 2 H, C1’-H).
13C NMR (67.5 MHz, CDCl3): d = 171.4, 144.1, 140.0, 136.5,
129.4, 126.9, 126.7, 122.7, 114.3, 67.8, 52.8, 51.6, 50.7, 42.1, 22.3,
21.6.
(R)-6-[(R)-2-Acetoxybut-3-enyl]-1-(toluene-4-sulfonyl)-1,2,3,6-
tetrahydropyridine-2-carboxylic Acid Methyl Ester (6)
Compound 5a,b (360 mg, 0.88 mmol) was dissolved in anhyd
CH2Cl2 (10 mL). [Ru] (36 mg, 0.043 mmol) was added and the mix-
ture was stirred for 20 h at r.t. in a glovebox. The solvent was re-
moved under vacuum and the residue was chromatographed on
silica gel (1:1 hexane/MTBE) to give 6a,b as a colourless solid (1:1
mixture of two inseparable diasteromers; 340 mg, 95%); mp 58 °C.
IR (KBr): n = 3034 (w), 2951 (w), 2925 (w), 1740 (s), 1346 (m),
1235 (s), 1161 (s), 717 (m), 659 (m) cm-1.
MS (EI): m/z (%) = 306 ([M- C2H3O2]+, 4), 294 (84), 155 (36), 138
(100), 91 (60), 80 (82). HRMS: m/z calcd for C16H20O3NS (M -
C2H3O2)+ 306.1163; found 306.1166.
MS (EI): m/z (%) = 407 ([M]+, 1), 294 (48), 234 (42), 192 (44), 155
(28), 138 (44), 91 (84), 80 (100).
HRMS: m/z calcd for C20H25NO6S (M)+ 407.1402; found 407.1411.
Anal. calcd for C18H23NSO5•H2O: C, 56.40; H, 6.53; N, 3.65; found
C, 56.51; H, 6.23; N, 3.82.
Anal. calcd for C20H25NO6S: C, 58.97; H, 6.14; N, 3.44; found C,
59.02; H, 6.10; N, 3.63.
Synthesis 2000, No. 6, 893–898 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Synthesis of a,a’-Disubstituted Piperidines
897
(2R,6R)-6-[(R)-2-Hydroxybut-3-enyl]-1,2,3,6-tetrahydropyri-
dine-2-carboxylic Acid Methyl Ester (8)
1H NMR (400 MHz, MeOD, 60 °C): d = 5.85 (ddd, J = 17, 11, 6 Hz,
1H, C3’-H), 5.23 (d, J = 17 Hz, 1 H, C4’-H), 5.05 (d, J = 11 Hz, 1 H,
C4’-H), 4.96 (dd, J = 6, 4 Hz, 1 H, C2-H), 4.44 (ddd, J = 9, 6, 2 Hz,
1 H, C4-H), 4.18 (m, 1 H, C2’-H), 3.84 (ddd, J = 10, 6, 2 Hz, 1 H, C5-
H), 3.80 (m, 1 H, C6-H), 3.68 (s, 3 H, CO2CH3), 2.12 (m, 2 H, C3-
H), 1.66 (ddd, J = 14, 10, 4 Hz, 1 H, C1’-H), 1.48 (s, 9 H, C4H9), 1.40
(m, 1 H, C1’-H).
13C NMR (100.6 MHz, MeOD, 60 °C): d = 173.6, 157.5, 141.0,
114.0, 81.5, 71.0, 69.5, 64.0, 56.2, 53.6, 52.2, 39.1, 27.8, 26.8.
MS (EI): m/z (%) = 289 ([M - C4H8]+, 1), 186 (84), 174 (52), 168
(24), 150 (16), 57 (100).
To a solution of 7 (200 mg, 0.55 mmol) in THF (5 mL) was added
a 0.8 M solution of sodium naphthalide in DME until complete
cleavage of the tosyl group (TLC control). The mixture was diluted
with MTBE (50 mL) and extracted with 0.1 M HCl (2 × 30 mL).
The aqueous layer was neutralized and concentrated in vacuum.
The residue was chromatographed on silica gel (8:1 EtOAc/MeOH)
to give 9 as a colourless solid (73 mg, 63%); [a]D25 -40.8 (c = 1.08,
CHCl3).
IR (KBr): n = 3316 (m), 2951 (m), 2928 (m), 1740 (s), 1436 (m),
1219 (s), 997 (m), 921 (m) cm-1.
HRMS: m/z calcd for C12H19O7N (M - C4H8)+ 289.1161; found
289.1167.
1H NMR (400 MHz, MeOD): d = 5.88 (dd, J = 17, 11, 6 Hz, 1 H,
C3’-H), 5.82 (ddd, J = 10, 3, 3 Hz, 1 H, C4-H), 5.62 (m, 1 H, C5-H),
5.23 (d, J = 17 Hz, 1 H, C4’-H), 5.05 (d, J = 10 Hz, 1 H, C4’-H), 4.27
(m, 1 H, C2’-H), 3.74 (s, 3 H, CO2CH3), 3.69 (m, 1 H, C6-H), 3.58
(dd, J = 11, 4 Hz, 1 H, C2-H), 2.34 (m, 1 H, C3-H), 2.20 (m, 1 H, C3-
H), 1.66 (m, 2 H, C1’-H).
13C NMR (67.5 MHz, MeOD): d = 139.8, 128.3, 123.0, 111.9, 68.2,
53.7, 50.6, 50.0, 39.9, 26.4.
MS (EI): m/z (%) = 211 ([M]+, 4), 152 (52), 140 (72), 80 (100).
HRMS: m/z calcd for C11H17NO3 (M)+ 211.1208; found 211.1209.
(2R,4S,5R,6R)-4,5-Diacetoxy-6-[(R)-2-acetoxybut-3-enyl]pipe-
ridine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester
(11)
To a solution of 10 (60 mg, 0.17 mmol) in CH2Cl2 (5 mL) was added
Ac2O (100 mg, 1.0 mmol), Et3N (200 mg, 2.0 mmol) and 4-dimeth-
ylaminopyridine (5 mg, 0.045 mmol). After 30 min, the mixture
was concentrated in vacuum, diluted with MTBE (10 mL) and the
organic layer was washed with aq satd NH4Cl solution. The organic
layer was dried (MgSO4), concentrated in vacuum and the resulting
oil was chromatographed on silica gel (1:1 hexane/MTBE) to give
11 as a colourless oil (81 mg, 98%); [a]D25 -6.9 (c = 0.91, CHCl3).
(2R,6R)-6-[(R)-2-Hydroxybut-3-enyl]-3,6-dihydro-2H-pyri-
dine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester (9)
To a solution of 8 (300 mg, 1.42 mmol) in CH2Cl2 (10 mL) were
added di-tert-butyl dicarbonate (372 mg, 1.7 mmol) and diisopro-
pylethylamine (920 mg, 7.1 mmol). The mixture was stirred over-
night at r.t., diluted with CH2Cl2 (20 mL), washed with aq sat.
NH4Cl solution, dried (MgSO4) and concentrated. The residue was
chromatographed on silica gel (MTBE) to give 9 as a colourless oil
(423 mg, 94%); [a]D25 -40.0 (c = 0.66, CHCl3).
IR (film): n = 2954 (m), 2925 (m), 1742 (s), 1697 (s), 1368 (m),
1231 (s), 1215 (s), 1025 (m) cm-1.
1H NMR (400 MHz, CDCl3, 70 °C): d = 5.80 (ddd, J = 17, 11, 6 Hz,
1 H, C3’-H); 5.32-5.10 (m, 6 H, C2-H, C4-H, C5-H, C2’-H, C4’-
Ha,b), 4.50 (m, 1 H, C6-H), 3.74 (s, 3 H, CO2CH3), 2.30 (dd, J = 12,
4 Hz, 1 H, C3-H), 2.20 (ddd, J = 12, 12, 7 Hz, 1 H, C3-H), 2.05 (s, 6
H, COCH3), 2.00 (s, 3 H, COCH3), 1.86 (m, 2 H, C1’-Ha,b), 1.47 (s,
9 H, C4H9).
13C NMR (100.6 MHz, MeOD): d = 172.4, 170.2, 170.0, 169.9,
155.5, 135.7, 117.4, 81.4, 72.2, 69.5, 65.0, 53.9, 52.6, 51.4, 35.2,
28.2, 24.6, 21.3, 20.9.
MS (EI): m/z (%) = 412 ([M - C2H3O2]+, 4), 312 (24), 252 (100),
192 (52), 132 (38); 57 (90).
HRMS: m/z calcd for C20H30NO8 (M - C2H3O2)+ 412.1971; found
412.1977.
IR (film): n = 3447 (m), 2978 (m), 2953 (m), 1745 (s), 1678 (s),
1409 (s), 1366 (m), 1205 (m), 1170 (s), 1034 (m) cm-1.
1H NMR (400 MHz, CDCl3): d = 5.88 (dd, J = 17, 11, 5 Hz, 1 H,
C3’-H), 5.79 (m, 1 H, C4-H), 5.71 (m, 1 H, C5-H), 5.28 (d, J = 17 Hz,
1 H, C4’-H), 5.06 (d, J = 10 Hz, 1 H, C4’-H), 4.93 (m, 1 H, C2-H),
4.61 (m, 1 H, C6-H), 4.26 (m, 1 H, C2’-H), 3.67 (s, 3 H, CO2CH3),
2.61 (m, 1 H, C3-H), 2.38 (m, 1 H, C3-H), 1.66 (m, 1 H, C1’-H), 1.56
(dd, J = 10, 5 Hz, 1 H, C1’-H), 1.48 (s, 9 H, C4H9).
13C NMR (100.6 MHz, CDCl3): d = 172.5, 156.3, 140.2, 128.7,
122.4, 113.8, 81.8, 68.0, 52.3, 51.3, 48.4, 42.5, 28.4, 24.8.
MS (EI): m/z (%) = 211 ([M - C4H8]+, 1), 240 (16), 152 (12), 140
(100), 80 (62), 57 (58).
(2R,4S,5R,6R)-4,5-Diacetoxy-6-[(R)-2-acetoxy-3-oxopropyl]pi-
peridine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Es-
ter (12)
To an ice-cooled solution of 11 (18 mg, 0.038 mmol) in acetone/
phosphate puffer pH 7 (3:1 v/v, 2 mL) was added OsO4 (1 mg,
0.0039 mmol). After 10 min NaIO4 (42 mg, 0.19 mmol) was added
to the brown solution in two portions. The mixture was allowed to
warm up to r.t. and stirred overnight. EtOAc (15 mL) and brine (10
mL) were added and the aqueous layer was extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuum. The resulting dark brown oil was chro-
matographed on silica gel (EtOAc) to give 12 as a colourless oil
(12.4 mg, 69%).
HRMS: m/z calcd for C12H17NO5 (M - C4H8)+ 255.1106; found
255.1109.
(2R,4S,5R,6R)-4,5-Dihydroxy-6-[(R)-2-hydroxybut-3-enyl]pip-
eridine-1,2-dicarboxylic Acid 1-tert-Butyl Ester 2-Methyl Ester
(10)
To an ice-cooled solution of 9 (100 mg, 0.32 mmol) in acetone/H2O
(2:1 v/v; 3 mL) was added OsO4 (2 mg, 0.0078 mmol). After 5 min,
N-methylmorpholine N-oxide (43 mg, 0.32 mmol) was added to the
brown solution in two portions. The mixture was allowed to warm
up to r.t. and stirred overnight. EtOAc (15 mL) and brine (10 mL)
was added and the aqueous layer was extracted with EtOAc (3 × 10
mL). The combined organic layers were dried (MgSO4) and con-
centrated in vacuum. The resulting dark brown oil was chromato-
graphed on silica gel (EtOAc) to give 10 as a colourless oil (60 mg,
67% based on 81% of conversion);[a]D25 +27.5 (c = 1.26, CHCl3).
IR (film): n = 2976 (m), 2935 (m), 1744 (s), 1699 (s), 1369 (m),
1244 (s), 1219 (s), 1047 (m) cm-1.
1H NMR (400 MHz, CDCl3, 70 °C): d = 9.50 (s, 1 H, CHO), 5.15-
5.09 (m, 4 H, C2-H, C4-H, C5-H, C2’-H), 4.60 (m, 1 H, C6-H), 3.77
(s, 3 H, CO2CH3), 2.34 (dd, J = 13, 4 Hz, 1 H, C3-H), 2.26 (dd,
J = 13, 7 Hz, 1 H, C3-H), 2.20 (s, 3 H, COCH3), 2.12 (dd, J = 15, 10
Hz, 1 H, C1’-H), 2.07 (s, 3 H, COCH3), 2.00 (s, 3 H, COCH3), 1.78
(ddd, J = 15, 11, 5 Hz, 1 H, C1’-H), 1.46 (s, 9 H, C4H9).
IR (film): n = 3407 (m), 2976 (m), 2952 (m), 2929 (m), 1741 (s),
1668 (s), 1406 (s), 1366 (s), 1203 (m), 1166 (s), 1085 (m), 1020 (m)
cm-1.
Synthesis 2000, No. 6, 893–898 ISSN 0039-7881 © Thieme Stuttgart · New York

898
U. Voigtmann, S. Blechert
SPECIAL TOPIC
13C NMR (100.6 MHz, CDCl3): d = 197.0, 172.3, 169.9, 81.6, 75.5,
69.5, 65.1, 53.0, 52.6, 52.0, 29.6, 28.1, 24.5, 20.8.
References
(1) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Schuster, M., Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036.
(c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(d) Fürstner, A. Top. Organomet. Chem. 1998, 1, 37.
(2) (a) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou,
K. C. Angew. Chem., Int. Ed. Engl. 1997,
MS (EI): m/z (%) = 353 ([M - 2 × C2H4O2]+, 16), 201 (100), 133
(42), 113 (42), 89 (80), 81 (68), 59 (40).
HRMS: m/z calcd for C17H23NO7 (M - 2 × C2H4O2)+ 353.1474;
found 353.1477.
(2R,5R,7S,8R,8aR)-2,7,8-Triacetoxyoctahydroindolizine-5-car-
boxylic Acid Methyl Ester (13)
36, 166.
(b) Crimmins, M. T.; Choy, A. L. J. Am. Chem.Soc. 1999, 121,
5653.
To a solution of 12 (10 mg, 0.021 mmol) in CH2Cl2 (1mL) was add-
ed trifluoroacetic acid (0.1 mL) until complete cleavage of the tert-
butoxycarbonyl group, monitored by TLC. The mixture was diluted
with MeOH (1 mL) and neutralized with solid K2CO3 and then
NaBH3CN (3 mg, 0.047 mmol) was added. After stirring overnight,
trifluoroacetic acid was added until pH 2 was reached and then the
mixture was stirred for further 2 h. The solution was neutralized,
concentrated in vacuum and the residue was chromatographed on
silica gel (MTBE) to give 13 (6.5 mg, 87%) as a colourless oil;
[a]D25 +24.6 (c = 1.20, MeOH).
(c) Fürstner, A.; Müller, T. J. Org. Chem. 1998, 63, 424.
(d) Ziegler, F. E.; Wang, Y. J. Org. Chem. 1998, 63, 426.
(3) (a) Grubbs, R. H. J. Macromol. Sci. Chem. 1994, A31,1829.
(b) Schrock, R. R. Pure Appl. Chem. 1994, 66, 1447.
(4) (a) Schneider, M. F.; Lucas, N., Velder, J.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 257.
(b) Schneider, M. F.; Blechert, S. Angew. Chem., Int. Ed.
Engl. 1996, 35, 410.
(5) Stragies, R.; Blechert, S. Synlett 1998, 169.
(6) (a) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 6634.
IR (film): n = 2926, 2853 (m), 1740 (s), 1242 (s), 1221(s), 1053 (m)
cm-1.
1H NMR (400 MHz, CDCl3): d = 5.45 (m, 1 H, C7-H), 5.12 (m, 1 H,
C2-H), 4.86 (dd, J = 10, 3 Hz, 1 H, C8-H), 3.74 (s, 3 H, CO2CH3),
3.34 (d, J = 11 Hz, 1 H, C3-H), 3.16 (dd, J = 11, 4 Hz, 1 H, C5-H),
2.60 (ddd, J = 10, 10, 6 Hz, 1 H, C8a-H), 2.48 (m, 2 H, C1-H, C3-H),
2.12 (m, 2 H, C6-H), 2.12, 2.07, 2.02 (3 s, 9 H, COCH3), 1.67 (ddd,
J = 16, 10, 6 Hz, 1 H, C1-H).
13C NMR (100.6 MHz, CDCl3): d = 73.4, 71.4, 67.2, 60.3, 59.6,
58.7, 52.4, 36.1, 33.4, 21.2, 21.0, 20.8.
MS (EI): m/z (%) = 358 ([M + H]+, 1), 297 (20), 238 (100), 178 (80),
118 (72).
(b) Burke, S. D.; Quinn, K. J.; Chen, V. J. J. Org. Chem 1998,
63, 8626.
(7) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
(8) Stragies, R.; Blechert, S. Tetrahedron 1999, 55, 8179.
(9) For example Rutjes, F. P. J. T.; Schoemaker, H. E.
Tetrahedron Lett. 1997, 38, 677.
(10) (a) Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis 1974, 876.
(b) Johnson, C. R.; Bis, S. J., Tetrahedron Lett. 1992, 33,
7287.
(11) Iminosugars as Glucosidaseinhibitors, Stütz, A. E., Ed.;
Wiley-VCH: Weinheim, 1998.
HRMS: m/z calcd for C16H24O8N (M + H)+ 358.1501; found
358.1523.
NOE (500 MHz, CDCl3): 5.45 ppm (C7-H) with 4.86 ppm (C8-H)
4%; 3.16 ppm (C5-H) with 2.60 ppm (C8a-H) 3%; no NOE between
(C8-H) and (C8a-H).
Article Identifier:
1437-210X,E;2000,0,06,0893,0898,ftx,en;C02600SS.pdf
Synthesis 2000, No. 6, 893–898 ISSN 0039-7881 © Thieme Stuttgart · New York