Enzymatic route to chiral, nonracemic cis-2,6- and cis,cis-2,4,6-substituted piperidines. Synthesis of (+)-dihydropinidine and dendrobate alkaloid (+)-241D

Article abstract of DOI:10.1021/jo9519569

Piperidine-based compounds are an important class of natural alkaloids found in plants, insects, and amphibians. A general asymmetric synthesis of 2-alkyl-6-methylpiperidines is presented via the enzymatic desymmetrization of meso cis-2,6- and cis,cis-2,4,6-substituted piperidines with Aspergillus niger lipase (ANL). The enzymatic reaction proceeds in excellent chemical yield and high enantiotopic selectivity (ee ≥ 98%). The general method is used to effect the synthesis of (±)-dihydropinidine-HCl as well as the first asymmetric synthesis of dendrobate alkaloid (+)-241D.

Full text of DOI:10.1021/jo9519569

3332
J . Org. Chem. 1996, 61, 3332-3341
En zym a tic Rou te to Ch ir a l, Non r a cem ic cis-2,6- a n d
cis,cis-2,4,6-Su bstitu ted P ip er id in es. Syn th esis of
(+)-Dih yd r op in id in e a n d Den d r oba te Alk a loid (+)-241D
Robert Cheˆnevert* and Michael Dickman
De´partement de chimie, Faculte´ des sciences et de ge´nie, Universite´ Laval, Que´bec, QC G1K 7P4, Canada
Received November 3, 1995X
Piperidine-based compounds are an important class of natural alkaloids found in plants, insects,
and amphibians. A general asymmetric synthesis of 2-alkyl-6-methylpiperidines is presented via
the enzymatic desymmetrization of meso cis-2,6- and cis,cis-2,4,6-substituted piperidines with
Aspergillus niger lipase (ANL). The enzymatic reaction proceeds in excellent chemical yield and
high enantiotopic selectivity (ee g 98%). The general method is used to effect the synthesis of
(+)-dihydropinidine-HCl as well as the first asymmetric synthesis of dendrobate alkaloid (+)-
241D.
Piperidine compounds constitute an important class of
naturally occurring alkaloids found in plants and insects.1
In addition, a handful of monocyclic, piperidine-based
alkaloids as well as numerous bicyclic ones have been
identified in dendrobate frogs.2 What is remarkable
about these alkaloids is the preponderance of 2,6-disub-
stitution, many times in the cis configuration, on the
piperidine ring. Pinidine (1) is a well-known cis-piperi-
dine compound found in several species of the family
Pinaceae.3 An often associated compound, dihydropini-
dine (2) has recently been isolated from the Mexican bean
beetle, Epilachna varivestis, as a minor constituent.4
Many cis-2,6-piperidine alkaloids 3 have been found in
the venom of fire ants of the genus Solenopsis.5 The four
monocyclic piperidines isolated from the skins of poison-
dart, dendrobate frogs all contain 2,6-disubstitution. The
most well-known of these, cis,cis-2-n-nonyl-6-methyl-4-
hydroxypiperidine 241D (4), has recently been synthe-
sized in its racemic form.6 Among the many bicyclic
alkaloids containing a piperidine ring, the indolizidine,
monomorine I (5), and decahydroquinoline cis-195A (6)
are representative2c,7 (Figure 1).
F igu r e 1.
been found to block the action of acetylcholine by a
noncompetitive blockade of the nicotinic receptor-channel
complex as well as blocking the binding of [3H]perhydro-
histrionicotoxin.8 The bicyclic indolizidines and decahy-
droquinolines show extensive physiological activities.2c,7
The interest in these compounds is well displayed by
the wealth of published material detailing their sources,
biological activities, and syntheses. Pinidine has been
shown to be a powerful teratogen.3 Numerous studies
have outlined the wide range of activities (necrotoxic,
hemolytic, phytotoxic, insecticidal, antibacterial, and
antifungal) that the 2-alkyl-6-methylpiperidines of fire
ant venom possess.1b Racemic piperidine 241D (4) has
These alkaloids have been the object of intensive
synthetic efforts resulting in a variety of racemic and
asymmetric syntheses.1b,6,7,9 We report here the first
total, asymmetric synthesis of (+)-241D (4). Building on
previous work,10 the enzymatic desymmetrization of meso
cis-2,6-disubstituted piperidines with Aspergillus niger
lipase (ANL) was extended to meso cis,cis-2,4,6-trisub-
stituted piperidines, thus opening the way to the syn-
thesis of enantiopure (+)-piperidine 241D ((+)-4). In
addition, the synthesis of (+)-dihydropinidine hydrochlo-
ride ((+)-2-HCl) by the same chemoenzymatic method
displays the generality of this technique.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) (a) Strunz, G. M.; Findlay, J . A. Pyridine and Piperidine
Alkaloids. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York,
1985; Vol. 26, pp 89-174. (b) Numata, A.; Ibuka, I. Alkaloids from
Ants and Other Insects. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1987; Vol. 31, pp 193-315.
(2) (a) Daly, J . W.; Edwards, M. W.; Myers, C. W. J . Nat. Prod. 1988,
51, 1188. (b) Daly, J . W.; Myers, C. W.; Whittaker, N. Toxicon. 1987,
25, 1023. (c) Daly, J . W.; Garraffo, H. M.; Spande, T. F. Amphibian
Alkaloids. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 1993; Vol. 43, pp 185-298.
(3) Stermitz, F. R.; Tawara, J . N.; Biokhin, A.; Foderaro, T. A.; Hope,
H. J . Org. Chem. 1993, 58, 4813.
(4) Attygalle, A. B.; Xu, S. C.; McCormick, K. D.; Meinwald, J .;
Blankespoor, C. L.; Eisner, T. Tetrahedron 1993, 49, 9333.
(5) Blum, M. S.; J ones, T. H.; Fales, H. S. Tetrahedron 1982, 38,
1949.
(6) Daly, J . W.; Edwards, M. W.; Garraffo, H. M. Synthesis 1994,
1167.
(7) Takahata, H.; Momose, T. Simple Indolizidine Alkaloids. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1993; Vol.
44, pp 189-256.
(8) Daly, J . W.; Nishizawa, Y.; Edwards, M. W.; Waters, J . A.;
Aronstam, R. S. Neurochemical Res. 1991, 16, 489.
(9) (a) Theodorakis, E.; Royer, J .; Husson, H. P. Synthetic Commun.
1991, 21, 521. (b) Comins, D. L.; Weglarz, M. A. J . Org. Chem. 1991,
56, 2506. (c) Higashiyama, K.; Nakahata, K.; Takahashi, H. Hetero-
cycles 1992, 33, 17. (d) Takahata, H.; Bandoh, H.; Hanayama, M.;
Momose, T. Tetrahedron: Asymm. 1992, 3, 607. (e) Lu, Z. H.; Zhou,
W. S. J . Chem. Soc., Perkin Trans. 1 1993, 593. (f) Comins, D. L.;
Dehghani, A. J . Chem. Soc., Chem. Commun. 1993, 1838. (g) Meyers,
A. I.; Munchhof, M. J . J . Am. Chem. Soc. 1995, 117, 5399.
(10) Cheˆnevert, R.; Dickman, M. Tetrahedron: Asymm. 1992, 3,
1021.
S0022-3263(95)01956-6 CCC: $12.00 © 1996 American Chemical Society

Synthesis of (+)-Dihydropinidine
J . Org. Chem., Vol. 61, No. 10, 1996 3333
Sch em e 1a
diester 14. Hydrogenation of the crude amine hydro-
chloride in H2O over rhodium on alumina11 followed by
liberation of the amine with K2CO3 gave the amino
alcohol 15 which was recrystallized before further use
to ensure cis,cis purity. The yield of 15 was moderate
(54% from 13) because of losses due to hydrogenolysis of
the C-O bond at position 4, but no attempt was made to
improve the yield, since Dreiding’s study reported that
the above hydrogenation conditions were the best pos-
sible.11 Protection of the amine with the appropriate
carboalkoxy chloride gave 16, and protection of the
alcohol as the MOM ether yielded the diester 17. Reduc-
tion of this diester with LiBH4 gave the diol 18 which
was acetylated to afford the diacetate 19.
a
Reaction conditions: (a) MeOH, 2,2-dimethoxypropane, 12 N
En zym a tic Desym m etr iza tion . Initially, a wide
range of lipases and proteases were screened for activity
with the meso cis-piperidine substrates. All tested
enzymes in a variety of aqueous reaction conditions
showed no or very little hydrolytic activity in the presence
of diesters 10 and 17. The enzymatic acetylation of diols
11 and 18 in organic solvent was more successful, but
poor yields of monoacetate and competitive conversion
to diacetate rendered this technique of little value.
However, the reverse reaction, enzymatic hydrolysis of
the diacetates 12 and 19, gave good to excellent results
in terms of both chemical yield and enantioselectivity
(Table 1). Three enzymes consistently hydrolyzed the
four acetates. Pig liver esterase (PLE) hydrolyzed the
acetates relatively quickly, but the chemical yields of
monoacetates 20 and 21 were negligible to poor. Hy-
drolysis in the presence of wheat germ lipase (WGL)
provided monoacetates of good enantiomeric purity (71-
93%) but only moderate chemical yield (30-58%). As-
pergillus niger lipase (ANL) in the presence of 7% CH3CN
gave very high enantiomeric excess values (ee g 98%)
and good to excellent chemical yields (76-92%).
HCl; (b) (i) H2, (ii) K2CO3; (c) BnO2CCl or EtO2CCl; (d) LiBH4; (e)
Ac2O.
Sch em e 2a
a
Reaction conditions: (a) MeOH, 2,2-dimethoxypropane, 12 N
HCl; (b) (i) H2, (ii) K2CO3; (c) BnO2CCl or EtO2CCl; (d) MOM-Cl;
(e) LiBH4; (f) Ac2O.
The first set of experiments with ANL were conducted
in pure phosphate buffer at pH 7. However, within 18-
24 h the growth of a bacillus in the medium (observed
by microscopic analysis) made the reaction difficult to
monitor and necessitated the addition of more enzyme
to complete the reaction. It was found that by adding
7% CH3CN to the reaction, the growth of the bacillus
(probably a spore contaminant in the bought enzyme) was
suppressed. This had the effect of slowing the reaction,
but both chemical yield and enantioselectivity were
improved. The enantiopurities of all the monoacetates
were determined by formation of Mosher’s ester and
analysis of the diastereomeric composition with 19F NMR.
Absolu te Con figu r a tion . Since the absolute config-
uration of the monoacetate 20a produced by the action
of ANL on 12a is known,10 the absolute configuration of
20b from ANL hydrolysis was not difficult to ascertain.
The N-carbobenzoxy monoacetate 20a was mesylated
under standard conditions to give the unstable acetate
22a (Scheme 3). Addition of 0.5 N NaOH to a solution
of 22a in THF and MeOH hydrolyzed the acetate and
provoked concomitant, intramolecular attack on the
carbonyl of the carbamate by the newly formed hydroxy
group to form the oxazolidinone 23 in 73% yield. The
moderate yield of 23 was due to an interesting secondary
reaction. The alcohol was found to also attack the
methylene carbon of the 2-substituent, thereby displacing
the mesylate to give a meso N-carbobenzoxy bicyclic ether
in 20% yield. This sequence of reactions was repeated
Resu lts a n d Discu ssion
Su bstr a te P r ep a r a tion . In a previous paper, we
outlined a simple and rapid method for the preparation
of meso cis-2,6-piperidines.10 Unfortunately, we have
since discovered that this method leads to a mixture of
cis:trans isomers (∼8:1) which are inseparable by stan-
dard chromatographic techniques. This forced the de-
velopment of a different route to the required meso
piperidines. Though this new method is longer by one
step, the overall yield of the substrates is significantly
higher than for the former preparation.
Esterification of pyridine-2,6-dicarboxylic acid (7) in
absolute MeOH, 2,2-dimethoxypropane and 12 N HCl
gave the diester hydrochloride 8 (Scheme 1). The crude
pyridine salt was hydrogenated in H2O over palladium
on carbon, and after filtration of the catalyst, the free
piperidine 9 was generated by the addition of solid
K2CO3. This amino diester was recrystallized in hexane
before further use to ensure the complete absence of any
contamination by the trans isomer. Protection of the
amine with the appropriate carboalkoxy chloride yielded
10, which was reduced with LiBH4 to give the diol 11.
Acetylation with acetic anhydride afforded the diacetate
12.
The synthesis of the meso cis,cis-2,4,6-piperidine sub-
strates followed a route similar to that of the 2,6-
piperidines (Scheme 2). Esterification of chelidamic acid
(13) under the same conditions as for 7 produced the
(11) Dreiding, A. S.; Hermann, K. Helv. Chim. Acta 1976, 59, 626.

3334 J . Org. Chem., Vol. 61, No. 10, 1996
Ta ble 1. En zym a tic Desym m etr iza tion of Dia ceta tes 12 a n d 19
Cheˆnevert and Dickman
time (h) (1 equiv, hydrolysis)
12 19
yield (% monoOAc)
20 21
sign of optical rotation, % ee (Mosher ester)
20
21
a
b
a
b
a
b
a
b
a
b
a
b
enzyme
R ) Bn R ) Et R ) Bn R ) Et R ) Bn R ) Et R ) Bn R ) Et
R ) Bn
R ) Et
R ) Bn
R ) Et
PLE
WGL
ANL
1.5
40
50
3
9
24
72
2
31
46
16
24
39
95
<5
43
73
82
38
58
85
92
19
30
71
76
46
55
74
82
(+) 25
(-) 71
(-) 92
(-) g98
(-) 83
(-) 93
(-) 91
(-) g98
(-) 77
(-) 89
(-) 92
(-) g98
(+) 81
(+) 95
(+) g98
ANL (7% CH3CN) 108
102
Sch em e 3a
Sch em e 4a
a
Reaction conditions: (a) Ms-Cl; (b) 0.5 N NaOH; (c) NaBH4.
for the N-carbethoxy monoacetate 20b, obtained from
ANL hydrolysis, to yield 23 which was identical to 23
(from 20a ) in all respects including the same sign for
their optical rotations. Therefore, the monoacetate 20b
was found to have the same absolute configuration as
20a , 2(R)-(acetoxymethyl)-6(S)-(hydroxymethyl).
The absolute configurations of the monoacetates 21a ,b
were more difficult to determine, because of the absence
of cis,cis-2,4,6-piperidines of known configuration. How-
ever, it was realized that if the relative positions of the
acetate and alcohol could be discovered then the absolute
configuration of the compound would be known, since the
4-substituent is cis.11 Thus, the reduction of the methoxy
methyloxy group to hydrogen was deemed necessary in
order to relate the reduced compound to a known cis-
2,6-piperidine. After much effort directed toward reduc-
ing the -OMOM group without affecting the rest of the
molecule, it was decided to follow the cyclization tenden-
cies of these N-carboalkoxy monoacetates.
The hydroxy group of monoacetate 21a was protected
with methyl chloromethyl ether to give 25a , which was
hydrolyzed and cyclized to afford 26 (Scheme 4). Regen-
eration of the two MOM-protected alcohols gave 27,
which was reacted with methanesulfonyl chloride to yield
the dimesylate 28. Reduction of 28 with NaBH4 in
DMSO at 120 °C gave the desired oxazolidinone 24. This
compound was found to be identical in all respects to the
product obtained by the NaBH4 reduction of monomes-
ylate 23 in DMSO at 80 °C (Scheme 3). Therefore, the
absolute configuration of 21a from ANL hydrolysis was
determined to be 2(R)-(acetoxymethyl)-4(S)-[(methoxy-
methyl)oxy]-6(S)-(hydroxymethyl). The absolute config-
uration of 21b was found to be the same by synthesizing
a
Reaction conditions: (a) MOM-Cl; (b) 0.5 N NaOH; (c) MeOH,
12 N HCl; (d) Ms-Cl; (e) NaBH4.
25b and then 26 and relating its optical rotation to that
of 26 (from 21a ).
Syn th esis of P ip er id in e Alk a loid s (+)-2-HCl a n d
(+)-4. In order to demonstrate the utility of the enzy-
matic desymmetrization of meso piperidines, the synthe-
sis of natural piperidine alkaloids was begun using
monoacetates 20 and 21. Initially, much experimenta-
tion was conducted in the hope of either reducing the
6-(hydroxymethyl) group to 6-methyl and transforming
the acetoxy group to a long-chain alkyl or the opposite
sequence of hydroxymethyl to long-chain alkyl and ac-
etoxymethyl to methyl. However, it was found that most
such efforts led to cyclization and the formation of
oxazolidinones. Two cases in point are demonstrative:
Any basic, protic solvent system will effect cyclization to
the oxazolidinone of a N-carbalkoxy 2- or 6-(hydroxy(or
acetoxy-)methyl) piperidine.12 Also, any N-carbalkoxypi-
peridine with a 2- or 6-substituent in the form of -CH2R,
where R is a leaving group, is inherently unstable. This
is due to carbamate carbonyl attack on the aforemen-
tioned CH2 to give a resonance-stabilized oxonium ion
which will degrade to the oxazolidinone on addition of
any relatively acid substance (e.g., H2O). Alternatively,
Momose et al.13 reported the reduction of a N-car-
bomethoxy-2-(hydroxymethyl)piperidine to 2-methylpi-
peridine by Swern oxidation of the alcohol to give the
aldehyde which was transformed to a dithiane and then
(12) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.
(13) Momose, T.; Toyooka, N.; Hirai, Y. Chem. Lett. 1990, 1319.

Synthesis of (+)-Dihydropinidine
J . Org. Chem., Vol. 61, No. 10, 1996 3335
Sch em e 6a
F igu r e 2.
Sch em e 5a
a
Reaction conditions: (a) Ms-Cl; (b) 0.5 N NaOH; (c) NaBH4;
(d) 1 N KOH; (e) PhCH2Br; (f) Swern; (g) Wittig; (h) (i) H2, (ii)
K2CO3.
a
Reaction conditions: (a) 1 N KOH; (b) PhCH2Br; (c) Swern;
(d) Wittig; (e) H2.
to yield (+)-2-HCl quantitatively from 35. An analytical
sample of (+)-2-HCl was prepared by recrystallization
from absolute EtOH/EtOAc, and its spectral data (1H and
13C NMR) were found to be identical to literature values
[[R]25D ) +13.3 (c 1.14, EtOH) (lit.14 [R]25D ) +12.8 (c 1.07,
EtOH))]. Thus, enantiopure (+)-dihydropinidine-HCl
was synthesized from pyridine-2,6-dicarboxylic acid (7)
in 14 steps with an overall yield of 21%.
desulfurized with Raney nickel. Unfortunately, our
attempts to repeat this synthetic sequence with 20b met
with limited success.
As a result of these problems, a brief study was
undertaken of the effect other N-protecting groups on the
enzymatic desymmetrization of cis-2,6-piperidines.
Substrates 29, 30 and 31 (Figure 2) were prepared
following standard procedures and subjected to enzymatic
hydrolysis with ANL in phosphate buffer/7% CH3CN.
Activity was observed with all three substrates, but the
results were disappointing. The chemical yields of the
monoacetates were moderate (47%-62%), and more
seriously, the best ee was only 22%. Thus, returning to
the monoacetates 20 and 21, the syntheses of (+)-
dihydropinidine hydrochloride and (+)-241D were pur-
sued via the oxazolidinone.
From the monoacetate 20b, (+)-2-HCl was obtained
in eight steps. The N-carbethoxy monoacetate 20b was
chosen for this synthesis over the N-carbobenzoxy analog
20a because of the higher overall yield of 20b from 7 (61%
versus 47% for 20a ) and the need for only two flash-
chromatographic columns during the synthetic sequence
7 to 20b. Thus, 20b was transformed to 24 in three steps
as already described earlier. The oxazolidinone ring of
24 was opened by the action of 1 N KOH in MeOH at
reflux to give the amino alcohol 32 which was trans-
formed without purification to the N-benzylamino alcohol
33 (Scheme 5). In order to verify that no racemization
had occured from 20b to 33, the Mosher esters of
enantiopure 33 and racemic 33 were prepared and
compared using 1H NMR. (The CH2 group R to the ester
showed excellent diastereotopicity.) The ee of enantiopure
33 was found to be g98%. Swern oxidation of 33 gave
the highly unstable aldehyde 34, which, after workup,
was immediately added to the already prepared ethyl
Wittig ylide to afford the olefin 35 in a mixture of cis:
trans isomers (∼9:1). No special effort was made to
completely isolate the two isomers, since the next step
was the hydrogenation of the olefin and removal of the
N-benzyl group using Pearlman’s catalyst in acidic EtOH
The synthesis of (+)-4 from the monoacetate 21a was
completed in eight steps via a similar synthetic pathway
(Scheme 6). Methanesulfonyl chloride was reacted with
monoacetate 21a to give mesylate 36. Because of its
instability, 36 was immediately cyclized to the oxazoli-
dinone 37. This reaction proceeded in high yield without
the formation of the meso ether analogous to those
observed during the reactions of 22a and 22b . Steric
hindrance by the cis-4-methoxy methyl ether was evoked
to explain this effect. The mesylate 37 was reduced by
nucleophilic substitution with NaBH4 in DMSO at 80 °C
to yield the oxazolidinone 38 which was opened by 1 N
KOH in refluxing MeOH to afford the amino alcohol 39.
This was followed by benzylation of crude 39 to give the
alcohol 40. In order to verify the enantiopurity of 40,
the Mosher esters of enantiopure 40 and racemic 40 were
prepared and compared using 1H NMR. (Once again, the
CH2 group R to the ester showed excellent diastereotop-
icity.) The ee of enantiopure 40 was found to be g98%.
Swern oxidation of 40 gave the highly unstable aldehyde
41, which was added to the n-octyl Wittig ylide im-
mediately after workup, and olefin 42 was obtained as a
mixture of cis:trans isomers (∼10:1) in 87% yield from
40. The final synthetic step was accomplished by hy-
drogenation of olefin 42 in acidic EtOH with Pearlman’s
catalyst. This reaction removed both O- and N-protecting
groups as well as hydrogenating the double bond in near-
quantitative yield to afford (+)-4-HCl. Recrystallization
from absolute EtOH/EtOAc gave a pure analytical sample
of (+)-4-HCl as white needles [[R]25 ) +15.8 (c 1.30,
D
EtOH)]. Liberation of the amine with Na2CO3 yielded
(14) Hill, R. K.; Yuri, T. Tetrahedron 1977, 33, 1569.

3336 J . Org. Chem., Vol. 61, No. 10, 1996
Cheˆnevert and Dickman
for C9H9NO4: C, 55.38; H, 4.65; N, 7.18. Found: C, 55.49; H,
4.66; N, 7.19.
(+)-4 which was recrystallized from EtOAc. The spectral
data for (+)-4 (1H NMR and mass spectrum) were found
to be identical to the literature,2a but our value for the
optical rotation of (+)-4 [[R]25D ) +6.5 (c 2.0, MeOH)] was
cis-2,6-Bis(m eth oxyca r bon yl)p ip er id in e (9). To a sus-
pension of crude 8 (23.08 g, 99.64 mmol) in freshly degassed
H2O (125 mL) was added 460 mg of 10% Pd/C. Hydrogenation
was performed at 45 psi for 15 h at rt. After filtration of the
mixture through a pad of Celite, Na2CO3 (15.8 g, 149.5 mmol)
and 300 mL of EtOAc were added, and the mixture was stirred
at 0 °C for 10 min. Saturation of the H2O with NaCl was
followed by three extractions with EtOAc which on drying and
evaporation yielded 19.2 g of crude 9. Recrystallization of 9
from hexane to eliminate any trace of contamination by the
trans isomer gave 17.8 g (74% from 7) of pure cis-9: mp 91.5-
much lower than the literature value [lit.2a [R]25 ) +39
D
(c 0.2, MeOH)]. This can be attributed to the fact that
Edwards et al. measured their optical rotation with less
than 1 mg of column-purified product,2a whereas we used
40 mg of recrystallized (+)-4. Therefore, enantiopure
piperidine alkaloid (+)-241D was synthesized from che-
lidamic acid 13 in an overall yield of 14%.
Two naturally-occurring piperidine alkaloids have been
asymmetrically synthesized from nonracemic, commer-
cially available compounds. One of these alkaloids, (+)-
241D [(+)-4], has been synthesized in enantiopure form
for the first time. The key reaction step, the enzymatic
desymmetrization of meso piperidines, has opened the
way to a general synthesis of any cis-2,6-dialkyl- or cis-
2,6-dialkyl-cis-4-hydroxypiperidine. The synthesis of
other monocyclic and bicyclic piperidine-based alkaloids
via this enzymatic step is currently in progress.
92.5 °C; IR (KBr) υ 3338, 3010, 2978-2800, 1760 cm-1 1H
;
NMR (CDCl3) δ 3.55 (s, 6H), 3.21 (dd, J 1 ) 11.3 Hz, J 2 ) 2.56
Hz, 2H), 2.25 (br s, 1H), 1.86-1.77 (m, 3H), 1.40-1.15 (m, 3H);
13C NMR (CDCl3) δ 172.5, 58.0, 51.6, 28.3, 23.8. Anal. Calcd
for C9H15NO4: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.82;
H, 7.67; N, 7.01.
Gen er a l P r oced u r e for N-P r otection of Am in o Diester
9. Dry THF (100 mL) was freshly distilled into a round-
bottomed flask containing 40 mmol of 9, and a dry N2
atmosphere was established. After the solution was cooled to
0 °C, 1.3 equiv of DiPEA followed by 1.2 equiv of the
appropriate carboalkoxy chloride were added. The ice bath
was immediately removed, and the reaction was stirred for 4
h at rt. The mixture was then poured into 200 mL of ether/
50 mL of 3 N HCl and extracted two times with ether. The
solvents were dried and evaporated.
Exp er im en ta l Section
Gen er a l. Type I lipase from wheat germ (WGL) and
esterase from porcine liver (PLE) were purchased from Sigma
Chemical Co. Lipase from Aspergillus niger (ANL) was
obtained from Fluka Chemical Corp. (catalogue no. 62301). All
enzymes were used without further purification. All enzymatic
hydrolytic desymmetrizations were carried out in phosphate
buffer at pH 7 prepared by mixing 50 mL of 0.1 M potassium
dihydrogen phosphate, 29.1 mL of 0.1 M sodium hydroxide
(NaOH), and 20.9 mL of distilled water. The enzymatic
reactions were followed by measurement of the pH with a glass
electrode and titration with 0.1 M NaOH to maintain the pH
at 7.
N-Ca r boben zoxy-cis-2,6-bis(m eth oxyca r bon yl)p ip er i-
d in e (10a ). Purification of the crude product by FC (10%
EtOAc/90% PE to 25% EtOAc/75% PE) gave a 95% yield of
10a as an oil: IR (neat) υ 3080-3020, 2942-2840, 1735, 1700
1
cm-1; H NMR (CDCl3) δ 7.37-7.29 (m, 5H), 5.20 (br d, 2H),
4.90 (br s, 2H), 3.67 (s, 6H), 2.16 (br d, 2H), 1.85-1.54 (m,
4H); 13C NMR (CDCl3) δ 171.5, 155.9, 136.2, 128.3, 127.9,
127.7, 67.8, 52.4, 52.1, 25.6, 16.5.
N -Ca r b e t h oxy-cis-2,6-b is(m e t h oxyca r b on yl)p ip e r i-
d in e (10b). Purification of the crude product by crystallization
from pentane provided a 98% yield of 10b as white cubes: mp
All extractions were done with undistilled, reagent grade
solvents and dried with MgSO4. Evaporations were performed
with a rotary evaporator. Column purifications were con-
ducted by flash chromatography (FC) on silica gel 60 (230-
400 mesh), and the FC solvents, petroleum ether 35-60 (PE)
and ethyl acetate (EtOAc), were distilled before use. Anhy-
drous solvents were distilled under nitrogen:THF and benzene
from sodium wire/benzophenone and CH2Cl2 and CH3CN from
CaH2. Anhydrous DMSO was distilled under vacuum from
CaH2 and stored over 4 Å molecular sieves. Diisopropylethyl-
amine (DiPEA), Et3N, and pyridine were distilled from KOH
and stored over KOH in brown bottles.
47.5-48.5 °C; IR (KBr) υ 2960-2825, 1745, 1705 cm-1 1H
;
NMR (CDCl3) δ 4.92-4.75 (br d, 2H), 4.17 (br s, 2H), 3.65 (s,
6H), 2.17-2.10 (m, 2H), 1.77-1.50 (m, 4H), 1.23 (t, J ) 7.15
Hz, 3H); 13C NMR (CDCl3) δ 171.8, 156.2, 62.1, 52.2, 51.9, 25.6,
16.5, 14.5. Anal. Calcd for C12H19NO6: C, 52.74; H, 7.01; N,
5.13. Found: C, 53.12; H, 7.14; N, 5.34.
Gen er a l P r oced u r e for Red u ction of Ca r ba m a te Di-
ester s 10 a n d 17. To a 0 °C solution of 10 or 17 (30-40 mmol)
in 200 mL of anhydrous THF under a N2 atmosphere was
added 4 equiv of LIBH4. The ice bath was immediately
removed, and the reaction was stirred for 5 h. On completion
of the reaction, the solution was poured into a stirred mixture
of 300 mL of EtOAc/100 mL of 5% NaHCO3/solid NaHCO3
(attention: violent foaming) and stirred vigorously for 5 min.
After saturation of the aqueous phase with NaCl, the mixture
was extracted four times with EtOAc and the organic solvents
were dried.
N-Ca r b ob e n zoxy-cis-2,6-b is(h yd r oxym e t h yl)p ip e r i-
d in e (11a ). FC beginning with 50% EtOAc/50% PE and
progressing to pure EtOAc gave the diol 11a in 84% yield. An
analytical sample was prepared by crystallization from ether
to give 11a as white plates: mp 85.0-86.5 °C; IR (KBr) υ 3400,
3060-3040, 2980-2835, 1650 cm-1; 1H NMR (CDCl3) δ 7.36-
7.30 (m, 5H), 5.16 (s, 2H), 4.50-4.42 (m, 2H), 3.62 (d, J ) 7.98
Hz, 4H), 3.43 (s, 2H), 1.63-1.45 (m, 6H); 13C NMR (CDCl3) δ
158.2, 136.7, 128.5, 127.9, 127.7, 67.5, 64.5, 51.2, 24.5, 15.1.
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01.
Found: C, 64.57; H, 7.69; N, 5.01.
Proton (300 and 400 MHz), 13C (75.47 and 100.61 MHz), and
19F (282.41 MHz) magnetic resonance experiments were
performed in CDCl3 or CD3OD.
2,6-Bis(m eth oxyca r bon yl)p yr id in e Hyd r och lor id e (8).
To a suspension of 2,6-pyridinedicarboxylic acid (7, 19.9 g,
119.08 mmol) in 400 mL of absolute MeOH was added 160
mL of 2,2-dimethoxypropane (1.301 mol) and 15 mL of
concentrated HCl (180 mmol HCl). The mixture was refluxed
for 4 h under a CaCl2 drying tube. Following reflux, the
temperature was allowed to go to rt, and the reaction was
stirred overnight. After evaporation of the solvents and the
addition of anhydrous ether (100 mL), the insoluble hydro-
chloride was filtered to give 23.25 g of crude 8. The crude
product could be used “as is” for the next step. An analytical
sample of the free pyridine of 8 was obtained as follows: 150
mg of crude 8 was suspended in 50 mL of CH2Cl2/20 mL of 5%
NaHCO3 solution and stirred for 10 min. The free pyridine
was extracted three times with CH2Cl2, and the CH2Cl2 was
dried and evaporated. FC was performed using 25% EtOAc/
75% PE to 50% EtOAc/50% PE to yield 122 mg of the free
pyridine of 8 which was recrystallized from hexane to give 98
mg of pure 8 as the free pyridine: mp 120.5-121.0 °C; IR (KBr)
N-Ca r b et h oxy-cis-2,6-b is(h yd r oxym et h yl)p ip er id in e
(11b). FC of the crude diol with 75% EtOAc/25% PE to pure
EtOAc afforded 11b in 96% yield as a viscous oil: IR (neat) υ
3410, 2945-2880, 1665 cm-1 1H NMR (CDCl3) δ 4.44-4.37
;
1
υ 3420, 3055, 2960, 1735 cm-1; H NMR (CDCl3) δ 8.22 (d, J
(m, 2H), 4.13 (q, J ) 7.11, 2H), 3.64-3.59 (m, 4H), 3.50 (br s,
2H), 1.65-1.40 (m, 6H), 1.24 (t, J ) 7.11 Hz, 3H); 13C NMR
(CDCl3) δ 158.6, 64.6, 61.8, 51.0, 24.5, 15.1, 14.6.
) 7.81 Hz, 2H), 7.96 (t, J ) 7.81 Hz, 1H), 3.93 (s, 6H); 13C
NMR (CDCl3) δ 165.0, 148.2, 138.3, 128.0, 53.1. Anal. Calcd

Synthesis of (+)-Dihydropinidine
J . Org. Chem., Vol. 61, No. 10, 1996 3337
N -Ca r b ob e n zoxy-cis,cis-2,6-b is(h yd r oxym e t h yl)-4-
[(m eth yloxy)m eth oxy]p ip er id in e (18a ). FC of the crude
diol with pure EtOAc afforded 18a in 93% yield as a viscous
(CI, NH3) calcd for C16H27NO8 (M+ + H) 362.1815, found
362.1807 ( 0.0011.
Ch elid a m ic Acid Dim eth yl Ester Hyd r och lor id e (14).
The title compound was synthesized by following the same
protocol as that for 8, except the starting material was
chelidamic acid (13, 12.37 g, 61.50 mmol). In this way, 14.62
g of crude 14 was obtained which could be used “as is” for the
next step. An analytical sample of the free amine of 14 was
obtained as follows: 141 mg of crude 14 was suspended in 50
mL of CH2Cl2/10 mL of 5% Na2CO3 solution and stirred for 10
min. The free amine was extracted three times with CH2Cl2,
and the extract was dried and evaporated. FC was done with
50% EtOAc/50% PE progressing to 75% EtOAc/25% PE to give
108 mg of the free amine of 14, which was recrystallized from
EtOAc: mp 169.5-170.5 °C; IR (KBr) υ 3220, 2960, 2700, 2455,
1
oil: IR (neat) υ 3425, 3070-3040, 2950-2830, 1687 cm-1; H
NMR (CDCl3) δ 7.29-7.24 (m, 5H), 5.18 (s, 2H), 4.63 (s, 2H),
4.57-4.45 (m, 2H), 3.95-3.84 (m, 3H), 3.80-3.72 (m, 2H), 3.37
(s, 3H), 2.91 (br s, 2H), 1.93-1.71 (m, 4H); 13C NMR (CDCl3)
δ 157.2, 136.3, 128.2, 127.7, 127.5, 94.7, 69.0, 67.3, 64.9, 55.2,
51.3, 29.0; MS (CI, NH3) m/ z 340 (MH+).
N -C a r b e t h o x y -c i s ,c i s -2,6-b i s (h y d r o x y m e t h y l)-4-
[(m eth yloxy)m eth oxy]p ip er id in e (18b). FC of the crude
diol with 1% MeOH/99% EtOAc gave 18b in 94% yield as a
viscous oil: IR (neat) υ 3400, 2970-2815, 1665 cm-1; 1H NMR
(CDCl3) δ 4.61 (s, 2H), 4.47-4.36 (m, 2H), 4.13 (q, J ) 6.74
Hz, 2H), 3.90-3.69 (m, 5H), 3.34 (s, 3H), 3.28 (br s, 2H), 1.95-
1.77 (m, 4H), 1.24 (t, J ) 6.74 Hz, 3H); 13C NMR (CDCl3) δ
157.9, 95.0, 69.1, 65.4, 61.7, 55.4, 51.0, 29.1, 14.4.
Gen er a l P r oced u r e for Acetyla tion of Diols 11 a n d 18.
A solution of 11 or 18 (30 mmol) in 10 equiv of anhydrous
pyridine was acetylated by the addition of 0.05 equiv of DMAP
as catalyst and 4 equiv of Ac2O. The solution was heated with
stirring to about 100 °C with a heat gun and left to cool for 30
min. The solvents were evaporated to near dryness, and 200
mL of ether and 50 mL of 3 N HCl were added. After transfer
to a separatory funnel, the ether portion was removed, and
the aqueous phase was extracted two more times with ether.
The combined ether fractions were dried and evaporated. In
the case of diol 18, a minimum of 1 N HCl was used for the
neutralization of the remaining pyridine, and the combined
ether fractions were washed with 5% NaHCO3 solution before
drying and evaporating.
N -Ca r b ob e n zoxy-cis-2,6-b is(a ce t oxym e t h yl)p ip e r i-
d in e (12a ). FC was performed using 10% EtOAc/90% PE to
20% EtOAc/80% PE to give the diOAc 12a in 97% yield as a
viscous oil: IR (neat) υ 3082-3026, 2943-2860, 1740, 1695
cm-1; 1H NMR (CDCl3) δ 7.40-7.25 (m, 5H), 5.15 (s, 2H), 4.51
(br s, 2H), 4.21 (dd, J 1 ) 10.79 Hz, J 2 ) 7.91 Hz, 2H), 3.94
(dd, J 1 ) 10.79 Hz, J 2 ) 6.48 Hz, 2H), 1.97 (s, 6H), 1.81-1.50
(m, 6H); 13C NMR (CDCl3) δ 170.4, 155.9, 136.3, 128.3, 127.8,
127.7, 67.1, 64.2, 48.1, 24.7, 20.5, 14.4; HRMS (CI, NH3) calcd
for C19H25NO6 (M+ + H) 364.1760, found 364.1753 ( 0.0011.
1
1725, 1680, 1600, 1575 cm-1; H NMR (CDCl3) δ 10.15 (br s,
1H), 7.49 (s, 2H), 3.97 (s, 6H); 13C NMR (CDCl3) δ 174.5, 163.3,
142.8, 118.5, 53.6. Anal. Calcd for C9H9NO5: C, 51.19; H,
4.30; N, 6.63. Found: C, 51.21; H, 4.20; N, 6.58.
cis,cis-2,6-Bis(m e t h oxyca r b on yl)-4-h yd r oxyp ip e r i-
d in e (15). The same procedure was employed for the syn-
thesis of 15 as that used for 9, except Rh on alumina powder-
Degussa type (479 mg) was the catalyst for this hydrogenation.
Also, considering the high solubility of 15 in H2O, five
extractions with EtOAc were performed. Thus, 14.45 g of
crude 14 gave 10.47 g of a white solid on evaporation of the
dried EtOAc fractions. All of this white solid was ground up
and suspended in 100 mL of hexane, and the mixture was
refluxed for 30 min. After hot filtration through a Buchner
funnel, the filtrate was evaporated to give 3.09 g (25% from
13) of crude 9. The hexane-insoluble solid was taken up in a
minimum of CHCl3 and precipitated with hexane to give 7.347
g (54% from 13) of pure cis,cis-15. An analytical sample of 15
was obtained by recrystallization from EtOAc: mp 139.0-
1
140.0 °C; IR (KBr) υ 3300, 3150, 2960-2760, 1735 cm-1; H
NMR (CDCl3) δ 3.75 (m, 1H), 3.73 (s, 6H), 3.38 (dd, J 1 ) 11.85
Hz, J 2 ) 2.40 Hz, 2H), 2.36-2.27 (m, 4H), 1.32 (ddd, J 1 ∼ J 2
∼ J 3 ) 11.9 Hz, 2H); 13C NMR (CDCl3) δ 172.2, 68.3, 56.4,
52.3, 37.8. Anal. Calcd for C9H15NO5: C, 49.76; H, 6.96; N,
6.45. Found: C, 49.79; H, 7.07; N, 6.47.
Gen er a l P r oced u r e for N-P r otection of Am in o Alcoh ol
15. To a mixture of 20 mmol of 15 and 2 equiv of NaHCO3 in
100 mL of CH2Cl2/20 mL of H2O at rt was added 1.5 equiv of
the appropriate carboalkoxy chloride, and the reaction was
stirred vigorously for 4 h. Brine was added, and the mixture
was extracted four times with CH2Cl2.
N-Ca r b ob en zoxy-cis,cis-2,6-b is(m et h oxyca r b on yl)-4-
h yd r oxyp ip er id in e (16a ). After the CH2Cl2 fractions were
dried and evaporated, FC was performed with 25% EtOAc/
75% PE to 40% EtOAc/60% PE to give the carbamate 16a in
90% yield. An analytical sample of 16a was prepared by
crystallization from ether: mp 71.5-72.5 °C; IR (KBr) υ 3468,
3082-3015, 2951-2865, 1730, 1695 cm-1; 1H NMR (CDCl3) δ
7.38-7.30 (m, 5H), 5.20 (s, 2H), 4.99 (br s, 2H), 4.11 (m, 1H),
3.80 (d, J ) 3.18 Hz, 1H), 3.72 (s, 6H), 2.50-2.39 (m, 2H),
1.89-1.76 (m, 2H); 13C NMR (CDCl3) δ 173.2, 155.4, 135.9,
128.2, 127.8, 127.6, 67.8, 61.3, 52.3, 50.1, 31.6. Anal. Calcd
for C17H21NO7: C, 58.11; H, 6.02; N, 3.99. Found: C, 58.24;
H, 6.00; N, 3.87.
N-Ca r b et h oxy-cis-2,6-b is(a cet oxym et h yl)p ip er id in e
(12b). Crystallization of the crude diOAc from hexane afforded
12b in 96% yield as white cubes: mp 60.5-62.0 °C; IR (KBr)
υ 2960-2880, 1747, 1695 cm-1; 1H NMR (CDCl3) δ 4.40 (br s,
2H), 4.15 (dd, J 1 ) 10.80 Hz, J 2 ) 8.26 Hz, 2H), 4.08 (q, J )
7.00 Hz, 2H), 3.85 (dd, J 1 ) 10.80 Hz, J 2 ) 6.36 Hz, 2H), 2.00
(s, 6H), 1.72-1.65 (m, 2H), 1.59-1.44 (m, 4H), 1.21 (t, J )
7.00 Hz, 3H); 13C NMR (CDCl3) δ 170.5, 156.2, 64.3, 61.6, 48.0,
24.7, 20.8, 14.5; HRMS (CI, NH3) calcd for C14H23NO6 (M+
+
H) 302.1603, found 302.1601 ( 0.0009. Anal. Calcd for
C14H23NO6: C, 55.80; H, 7.69; N, 4.65. Found: C, 55.98; H,
7.85; N, 4.71.
N -C a r b o b e n zoxy -ci s,ci s-2,6-b is(a c e t o x ym e t h yl)-4-
[(m et h yloxy)m et h oxy]p ip er id in e (19a ). FC was done
beginning with 10% EtOAc/90% PE to 25% EtOAc/75% PE to
give the diOAc (19a ) in 93% yield as a viscous oil: IR (neat) υ
3085-3030, 2950-2820, 1745, 1700 cm-1; 1H NMR (CDCl3) δ
7.38-7.28 (m, 5H), 5.12 (s, 2H), 4.66-4.51 (m, 2H), 4.58 (s,
N-Ca r b et h oxy-cis,cis-2,6-b is(m et h oxyca r b on yl)-4-h y-
d r oxyp ip er id in e (16b). After the CH2Cl2 fractions were
dried and evaporated, FC was performed with 40% EtOAc/
60% PE to 60% EtOAc/40% PE to give the carbamate 16b as
a viscous oil in 92% yield: IR (neat) υ 3458, 2980-2840, 1740,
2H), 4.31 (dd, J 1 ) 10.92 Hz, J 2 ) 7.02 Hz, 2H), 4.15 (dd, J 1
)
10.92 Hz, J 2 ) 7.85 Hz, 2H), 3.94 (m, 1H), 3.31 (s, 3H), 2.03-
1.73 (m, 4H), 1.90 (s, 6H); 13C NMR (CDCl3) δ 170.4, 156.0,
136.4, 128.3, 127.9, 127.9, 94.5, 67.9, 67.3, 66.0, 55.3, 47.6, 29.1,
20.6; HRMS (CI, NH3) calcd for C21H29NO8 (M+ + H) 424.1971,
found 424.1974 ( 0.0012.
1
1700 cm-1; H NMR (CDCl3) δ 5.02-4.88 (br s, 2H), 4.21 (br
s, 2H), 4.12 (m, 1H), 3.84 (d, J ) 3.59 Hz, 1H), 3.74 (s, 6H),
2.47-2.38 (m, 2H), 1.86-1.78 (m, 2H), 1.26 (t, J ) 7.12 Hz,
3H); 13C NMR (CDCl3) δ 173.9, 155.9, 62.4, 61.6, 52.6, 50.0,
31.8, 14.5.
N -C a r b e t h o x y -c i s ,c i s -2,6-b i s (a c e t o x y m e t h y l)-4-
[(m et h yloxy)m et h oxy]p ip er id in e (19b ). FC was per-
formed using 20% EtOAc/80% PE to 40% EtOAc/60% PE to
give the diOAc (19b) in 94% yield as a viscous oil: IR (neat) υ
2980-2805, 1737, 1690 cm-1; 1H NMR (CDCl3) δ 4.55 (s, 2H),
4.52-4.46 (m, 2H), 4.28 (dd, J 1 ) 10.76 Hz, J 2 ) 7.30, 2H),
4.09 (dd, J 1 ) 10.76 Hz, J 2 ) 7.71 Hz, 2H), 4.07 (q, J ) 7.13
Hz, 2H), 3.90 (m, 1H), 3.28 (s, 3H), 1.98 (s, 6H), 1.91-1.72
(m, 4H), 1.20 (t, J ) 7.13 Hz, 3H); 13C NMR (CDCl3) δ 170.4,
156.1, 94.4, 67.9, 66.0, 61.5, 55.3, 47.3, 28.9, 20.7, 14.4; HRMS
Gen er a l P r oced u r e for O-P r otection of Alcoh ols 16
a n d 21. To a solution of 16 or 21 (20 mmol) and 3.5 equiv of
DiPEA in 50 mL of anhydrous CH2Cl2 at 0 °C under N2 was
added 3 equiv of MOM-Cl dropwise with stirring. After 30
min, the ice bath was removed, and the reaction was stirred
for 15 h. The reaction mixture was then poured into 200 mL
of EtOAc/50 g of ice/50 mL of 3 N HCl with stirring at 0 °C,

3338 J . Org. Chem., Vol. 61, No. 10, 1996
Cheˆnevert and Dickman
and the aqueous phase was extracted three times with EtOAc.
The combined EtOAc fractions were washed with 5% NaHCO3
solution, dried with MgSO4, and then evaporated.
127.9, 67.5, 51.9, 48.6, 25.0, 24.6, 20.7, 14.7; HRMS (CI, NH3)
calcd for C17H23NO5 (M+ + H) 322.1654, found 322.1651 (
0.0009.
N -C a r b e t h o x y -ci s-2(R )-(a c e t o x y m e t h y l)-6(S )-(h y -
d r oxym eth yl)p ip er id in e (20b). When ANL in 7% CH3CN/
93% phosphate buffer was used, the monoacetate 20b was
isolated in 92% yield as a colorless oil with an ee g98% as
N-Ca r b ob en zoxy-cis,cis-2,6-b is(m et h oxyca r b on yl)-4-
[(m eth yloxy)m eth oxy]piper idin e (17a). FC beginning with
15% EtOAc/85% PE and finishing with 30% EtOAc/70% PE
afforded 17a in 94% yield as a colorless oil: IR (neat) υ 3080-
measured by 19F NMR of Mosher’s ester made from 20b: [R]25
1
3020, 2980-2810, 1760, 1735, 1700 cm-1; H NMR (CDCl3) δ
D
) -6.1 (c 2.6, CHCl3); IR (neat) υ 3460, 2950-2880, 1745, 1692
7.31-7.22 (m, 5H), 5.12 (s, 2H), 4.71 (br s, 2H), 4.49 (s, 2H),
3.87 (m, 1H), 3.61 (s, 6H), 3.24 (s, 3H), 2.41-2.30 (m, 2H),
1.98-1.86 (m, 2H); 13C NMR (CDCl3) δ 171.3, 155.6, 135.9,
128.1, 127.8, 127.6, 93.8, 67.5, 65.8, 54.9, 51.7, 51.3, 29.5; MS
(CI, NH3) m/ z 396 (MH+).
cm-1 1H NMR (CDCl3) δ 4.45 (m, 1H), 4.34 (m, 1H), 4.17-
;
4.11 (m, 3H), 3.97 (dd, J 1 ) 10.92 Hz, J 2 ) 6.88 Hz, 1H), 3.58
(d, J ) 7.42 Hz, 2H), 2.35 (br s, 1H), 2.03 (s, 3H), 1.82-1.44
(m, 6H), 1.25 (t, J ) 7.15 Hz, 3H); 13C NMR (CDCl3) δ 170.7,
157.4, 64.8, 64.5, 61.7, 51.6, 48.4, 24.9, 24.6, 20.8, 14.8, 14.6;
HRMS (CI, NH3) calcd for C12H21NO5 (M+ + H) 260.1498,
found 260.1496 ( 0.0008.
N -Ca r b e t h oxy-cis,cis-2,6-b is(m e t h oxyca r b on yl)-4-
[(m et h yloxy)m et h oxy]p ip er id in e (17b ). FC beginning
with 30% EtOAc/70% PE and finishing with 50% EtOAc/50%
PE gave 17b as a colorless oil in 90% yield: IR (neat) υ 2980-
2810, 1735, 1695 cm-1; 1H NMR (CDCl3) δ 4.68 (br s, 2H), 4.50
(s, 2H), 4.12 (q, J ) 7.08 Hz, 2H), 3.87 (m, 1H), 3.65 (s,6H),
3.25 (s, 3H), 2.37-2.29 (m, 2H), 1.98-1.90 (m, 2H), 1.18 (t, J
) 7.08 Hz); 13C NMR (CDCl3) δ 171.8, 156.1, 94.0, 66.1, 62.2,
55.2, 52.0, 51.5, 29.9, 14.5.
N -Ca r b ob e n zoxy-cis,cis-2(R )-(a ce t oxym e t h yl)-4(S )-
[(m e t h ylo xy )m e t h o xy]-6(S )-(h y d r o xy m e t h yl)p ip e r i-
d in e (21a ). After the reaction with ANL in 7% CH3CN/93%
phosphate buffer, the monoacetate 21a was isolated in 76%
yield as a colorless oil with an ee g98% as measured by 19F
NMR of Mosher’s ester made from 21a : [R]25 ) -2.0 (c 3.2,
D
CHCl3); IR (neat) υ 3450, 3080-3020, 2940-2820, 1735, 1687
cm-1; 1H NMR (CDCl3) δ 7.35-7.29 (m, 5H), 5.18 (AB system,
2H), 4.67-4.58 (m, 3H), 4.45 (m, 1H), 4.28 (AB system, 2H),
3.94 (m, 1H), 3.82 (m, 1H), 3.77 (m, 1H), 3.39 (s, 3H), 2.70 (br
s, 1H), 2.02-1.81 (m, 4H), 1.92 (s, 3H); 13C NMR (CDCl3) δ
170.8, 156.9, 136.5, 128.6, 128.1, 128.0, 95.1, 68.7, 67.6, 66.6,
65.8, 55.6, 51.4, 48.1, 29.6, 29.0, 20.8; HRMS (CI, NH3) calcd
for C19H27NO7 (M+ + H) 382.1866, found 382.1875 ( 0.0011.
N -C a r b e t h o x y -ci s,ci s-2(R )-(a c e t o x y m e t h y l)-4(S )-
[(m e t h ylo xy )m e t h o xy ]-6(S )-(h y d r o xy m e t h yl)p ip e r i-
d in e (21b). After the reaction with ANL in 7% CH3CN/93%
phosphate buffer, the monoacetate 21b was isolated in 82%
yield as a colorless oil with an ee g98% as measured by 19F
N -Ca r b ob e n zoxy-cis,cis-2(R )-(a ce t oxym e t h yl)-4(S )-
[(m eth yloxy)m eth oxy]-6(S)-[[(m eth yloxy)m eth oxy]m eth -
yl]p ip er id in e (25a ). FC was done with 25% EtOAc/75% PE
to afford 25a in 92% yield as a colorless oil: [R]25 ) -6.2 (c
D
4.4, CHCl3); IR (neat) υ 3100-3040, 2950-2825, 1745, 1700
cm-1; 1H NMR (CDCl3) δ 7.40-7.29 (m, 5H), 5.16 (AB system,
2H), 4.66-4.55 (m, 5H), 4.46 (br s, 1H), 4.30 (dd, J 1 ) 10.38
Hz, J 2 ) 7.11 Hz, 1H), 4.12 (dd, J 1 ) 10.38 Hz, J 2 ) 7.65 Hz,
1H), 3.96 (m, 1H), 3.76 (dd, J 1 ∼ J 2 ) 9.1 Hz, 1H), 3.62 (dd, J 1
) 9.14 Hz, J 2 ) 5.45 Hz, 1H), 3.36 (s, 3H), 3.33 (s, 3H), 2.08
(m, 1H), 1.96 (s, 3H), 1.98-1.77 (m, 3H); 13C NMR (CDCl3) δ
170.7, 156.0, 136.7, 128.5, 128.1, 128.0, 96.5, 94.5, 69.9, 68.1,
67.4, 66.5, 55.4, 55.3, 49.0, 47.8, 29.4, 28.7, 20.8.
NMR of Mosher’s ester made from 21b: [R]25 ) -15.2 (c 2.0,
D
CHCl3); IR (neat) υ 3450, 2975-2820, 1735, 1685 cm-1
;
1H
N -C a r b e t h o x y -ci s,ci s-2(R )-(a c e t o x y m e t h y l)-4(S )-
[(m eth yloxy)m eth oxy]-6(S)-[[(m eth yloxy)m eth oxy]m eth -
yl]p ip er id in e (25b). FC with 35% EtOAc/65% PE gave 25b
in 94% yield as a colorless oil: [R]25D ) -9.9 (c 2.2, CHCl3); IR
(neat) υ 2980-2820, 1740, 1690 cm-1; 1H NMR (CDCl3) δ 4.62-
4.55 (m, 4H), 4.48 (m, 1H), 4.36 (m, 1H), 4.25 (dd, J 1 ) 10.76
Hz, J 2 ) 7.31 Hz, 1H), 4.16-4.03 (m, 3H), 3.92 (m, 1H), 3.62
(dd, J 1 ∼ J 2 ) 9.4 Hz, 1H), 3.54 (dd, J 1 ) 9.41 Hz, J 2 ) 4.45
Hz, 1H), 3.33 (s, 3H), 3.30 (s, 3H), 2.03 (m, 1H), 1.99 (s, 3H),
1.86-1.70 (m, 3H), 1.22 (t, J ) 6.92 Hz, 3H); 13C NMR (CDCl3)
δ 170.7, 156.2, 96.4, 94.3, 69.8, 68.1, 66.4, 61.6, 55.4, 55.2, 48.6,
47.5, 29.2, 28.5, 20.9, 14.6; MS (CI, CH4) m/ z 364 (MH+).
NMR (CDCl3) δ 4.59 (AB system, 2H), 4.50 (m, 1H), 4.34 (m,
1H), 4.23-4.18 (m, 2H), 4.16-4.05 (m, 2H), 3.87 (m, 1H), 3.79-
3.64 (m, 2H), 3.32 (s, 3H), 2.81 (br s, 1H), 1.99 (s, 3H), 1.97-
1.78 (m, 4H), 1.21 (t, J ) 7.56 Hz, 3H); 13C NMR (CDCl3) δ
170.6, 156.9, 94.8, 68.5, 66.3, 65.6, 61.6, 55.3, 51.0, 47.7, 29.3,
28.8, 20.7, 14.4; HRMS (CI, NH3) calcd for C14H25NO7 (M+
H) 320.1709, found 320.1712 ( 0.0009.
+
Gen er a l P r oced u r e for Mesyla tion of Mon oa ceta tes 20
a n d 21 a n d Diol 27. To a stirred solution of 1 mmol of
monoacetate 20 or 21 (obtained from ANL hydrolysis in 7%
CH3CN/93% phosphate buffer) or 1 mmol of diol 27 and 2 equiv
of Et3N in 6 mL of anhydrous THF under dry N2 at -10 °C
was added dropwise 1.5 equiv of methanesulfonyl chloride (4
equiv of Et3N and 3 equiv of MeSO2Cl for 27). The mixture
was stirred for 4 h between -5 and -10 °C and then poured
into 40 mL of EtOAc/20 g of ice/10 mL of 3 N H2SO4 and stirred
for 5 min. (For the monoacetate 21a , 5% NaHCO3 solution
was substituted for 3 N H2SO4 in the workup.) The aqueous
phase was extracted three times with EtOAc, and the organic
fractions were dried and evaporated. (Mesylates 22 and 36
are relatively unstable, and so they were made as needed and
then converted to the subsequent product.)
Gen er a l P r oced u r e for En zym a tic Hyd r olysis of Di-
a ceta tes 12 a n d 19. The diOAc (1.0-1.5 mmol) was sus-
pended in 30 mL of phosphate buffer at pH 7.0. To this
mixture was added the appropriate enzyme (100 µL of PLE
suspension, 50 mg of WGL, or 60 mg of ANL), and the reaction
was stirred at 350 rpm at rt. When 7% CH3CN was used with
ANL, the diOAc was first dissolved in 2.0 mL of CH3CN, and
then 28.0 mL of phosphate buffer at pH 7.0 was added with
stirring. Once 1 equiv of the diOAc was hydrolyzed, the
aqueous mixture was saturated with NaCl and extracted three
times with EtOAc. The combined EtOAc fractions were dried
and evaporated. The monoacetate, diol, and any remaining
diOAc were separated by FC beginning with 20% EtOAc/80%
PE and finishing with pure EtOAc. (See Table 1 for the
various yields and enantiomeric purities of monoacetates 20
and 21 with each enzyme.)
N-Ca r boben zoxy-cis-2(S)-[[(m eth ylsu lfon yl)oxy]m eth -
yl]-6(R)-(a cetoxym eth yl)p ip er id in e (22a ). FC was per-
formed with 20% EtOAc/80% PE progressing quickly to 40%
EtOAc/60% PE to give 22a in 91% yield as a colorless oil: [R]25
D
) -11.3 (c 1.5, CHCl3); IR (neat) υ 3100- 3020, 2940-2850,
1
1735, 1685 cm-1; H NMR (CDCl3) δ 7.40-7.35 (m, 5H), 5.15
N-Ca r b ob en zoxy-cis-2(R)-(a cet oxym et h yl)-6(S)-(h y-
d r oxym eth yl)p ip er id in e (20a ). When ANL in 7% CH3CN/
93% phosphate buffer was used, pure 20a was isolated in 82%
yield as a colorless oil with an ee g98% as measured by 19F
(AB system, 2H), 4.48 (br s, 2H), 4.23-4.08 (m, 3H), 3.90 (dd,
J 1 ) 11.19 Hz, J 2 ) 6.91 Hz, 1H), 2.96 (s, 3H), 1.98 (s, 3H),
1.88 (m, 1H), 1.79-1.54 (m, 5H); 13C NMR (CDCl3) δ 170.4,
155.7, 136.0, 128.4, 128.0, 127.9, 68.2, 67.3, 64.4, 48.5, 48.1,
37.1, 24.6, 24.1, 20.5, 14.2.
NMR of Mosher’s ester made from 20a : [R]25 ) +5.2 (c 3.8,
D
CHCl3); IR (neat) υ 3450, 3020-3080, 2860-2930, 1745, 1690
N-Ca r beth oxy-cis-2(S)-[[(m eth ylsu lfon yl)oxy]m eth yl]-
6(R)-(a cetoxym eth yl)p ip er id in e (22b). FC beginning with
25% EtOAc/75% PE and progressing quickly to 50% EtOAc/
cm-1; 1H NMR (CDCl3) δ 7.27-7.37 (m, 5H), 5.13 (AB system,
2H), 4.49 (m, 1H), 4.35 (m, 1H), 4.14 (dd, J 1 ) 10.77 Hz, J 2
)
50% PE afforded 22b in 96% yield as a colorless oil: [R]25
)
7.82 Hz, 1H), 3.98 (dd, J 1 ) 10.77 Hz, J 2 ) 7.01 Hz, 1H), 3.59
(d, J ) 7.39 Hz, 2H), 2.39 (br s, 1H), 1.94 (s, 3H), 1.44-1.81
(m, 6H); 13C NMR (CDCl3) δ 170.7, 157.0, 136.6, 128.5, 128.1,
D
-15.7 (c 2.8, CHCl3); IR (neat) υ 3030, 2960-2870, 1740, 1695
1
cm-1; H NMR (CDCl3) δ 4.42 (br s, 2H), 4.21-4.05 (m, 5H),

Synthesis of (+)-Dihydropinidine
J . Org. Chem., Vol. 61, No. 10, 1996 3339
CHCl3); IR (neat) υ 3020, 2960-2780, 1745 cm-1 1H NMR
3.86 (dd, J 1 ) 11.00 Hz, J 2 ) 6.58 Hz, 1H), 3.03 (s, 3H), 2.03
(s, 3H), 1.87 (m, 1H), 1.75-1.52 (m, 5H), 1.25 (t, J ) 7.12 Hz,
3H); 13C NMR (CDCl3) δ 170.5, 156.0, 68.3, 64.5, 61.8, 48.4,
47.9, 37.3, 24.6, 24.1, 20.7, 14.4, 14.2.
;
(CDCl3) δ 4.79 (2 dd’s, AB system, 2H), 4.65 (AB system, 2H),
4.37 (dd, J 1 ∼ J 2 ) 8.3 Hz, 1H), 3.92 (dd, J 1 ) 8.30 Hz, J 2
)
6.31 Hz, 1H), 3.78-3.63 (m, 2H), 3.46 (m, 1H), 3.35 (s, 3H),
3.06 (s, 3H), 2.20-2.07 (m, 2H), 1.54 (ddd, J 1 ∼ J 2 ∼ J 3 ) 11.5
Hz, 1H), 1.43 (ddd, J 1 ∼ J 2 ∼ J 3 ) 11.8 Hz, 1H); 13C NMR
(CDCl3) δ 156.1, 94.8, 72.0, 68.1, 67.2, 55.4, 55.0, 52.4, 37.1,
35.9, 34.1; MS (CI, CH4) m/ z 310 (MH+).
N-Ca r b ob en zoxy-cis,cis-2(S)-[[(m et h ylsu lfon yl)oxy]-
m eth yl]-4(R)-[(m eth yloxy)m eth oxy]-6(R)-(a cetoxym eth -
yl)p ip er id in e (36). FC was begun with 25% EtOAc/75% PE
and went quickly to 50% EtOAc/50% PE to give 36 in 97%
yield as a colorless oil: [R]25D ) -13.7 (c 2.2, CHCl3); IR (neat)
υ 3090-3020, 2960-2820, 1740, 1695 cm-1; 1H NMR (CDCl3)
δ 7.39-7.27 (m, 5H), 5.15 (AB system, 2H), 4.62-4.56 (m, 4H),
cis,cis-1,2(R)-(1-Oxooxazolidin o)-4(S)-h ydr oxy-6(S)-(h y-
d r oxym eth yl)p ip er id in e (27). To a solution of 26 (183 mg,
0.665 mmol) in 7 mL of absolute MeOH at rt was added 3 drops
of 12 N HCl. The stirred solution was heated to 60 °C for 4 h
and then cooled to rt. Solid NaHCO3 (200 mg) was added, and
the MeOH was evaporated. The nonvolatile components were
dissolved in EtOAc, and the EtOAc was dried. FC was begun
with pure EtOAc and finished with 5% MeOH/95% EtOAc to
4.46 (dd, J 1 ∼ J 2 ) 9.1 Hz, 1H), 4.26 (dd, J 1 ) 10.33 Hz, J 2
)
5.89 Hz, 2H), 4.14 (dd, J 1 ) 10.33 Hz, J 2 ) 7.50 Hz, 1H), 4.01
(m, 1H), 3.35 (s, 3H), 2.93 (s, 3H), 2.05 (br d, J ) 14. 9 Hz,
1H), 1.95 (br d, 1H), 1.93 (s, 3H), 1.84-1.75 (m, 2H); 13C NMR
(CDCl3) δ 170.5, 155.8, 136.1, 128.4, 128.1, 128.0, 94.5, 70.3,
67.6, 67.4, 66.1, 55.5, 47.8, 47.4, 37.1, 28.7, 28.2, 20.6.
yield 121 mg (97%) of the diol 27 as a viscous oil: [R]25
)
D
-3.4 (c 4.8, CHCl3); IR (neat) υ 3390, 2960-2860, 1725 cm-1
;
cis,cis-1,2(R )-(1-Oxooxa zolid in o)-4(S )-[(m e t h ylsu l-
fon yl)oxy]-6(S )-[[(m e t h ylsu lfon yl)oxy]m e t h yl]p ip e r i-
d in e (28). FC was performed beginning with 50% EtOAc/50%
PE and progressing to 75% EtOAc/25% PE to afford the
1H NMR (CDCl3) δ 4.65 (dd, J 1 ) 8.25 Hz, J 2 ) 6.74 Hz, 1H),
4.47 (dd, J 1 ∼ J 2 ) 8.5 Hz, 1H), 3.98 (dd, J 1 ) 8.49 Hz, J 2
)
7.30 Hz, 1H), 3.94-3.72 (m, 4H), 3.25 (m, 1H), 3.05 (br s, 1H),
2.24 (br d, J ) 12.01 Hz, 1H), 1.99 (br d, J ) 12.63 Hz, 1H),
1.55-1.40 (m, 2H); 13C NMR (CDCl3) δ 157.4, 68.0, 67.2, 63.1,
56.6, 55.4, 39.0, 36.9; MS (CI, CH4) m/ z 188 (MH+).
dimesylate 28 in 96% yield as a viscous oil: [R]25 ) -13.5 (c
D
4.5, CHCl3); IR (neat) υ 3030, 2980-2870, 1750 cm-1; 1H NMR
(CDCl3) δ 4.88-4.81 (m, 3H), 4.43 (dd, J 1 ) 8.54 Hz, J 2 ) 7.53
Hz, 1H), 3.98 (dd, J 1 ) 8.54 Hz, J 2 ) 6.12 Hz, 1H), 3.78 (m,
1H), 3.58 (m, 1H), 3.09 (s, 3H), 3.07 (s, 3H), 2.38 (m, 1H), 2.28
(m,1H), 1.82 (ddd, J 1 ∼ J 2 ∼ J 3 ) 11.9 Hz, 1H), 1.70 (ddd, J 1
∼ J 2 ∼ J 3 ) 11.8 Hz, 1H); 13C NMR (CDCl3) δ 156.0, 75.1,
67.7, 67.1, 54.7, 52.2, 39.0, 37.4, 36.0, 34.1; MS (CI, CH4) m/ z
344 (MH+).
Gen er a l P r oced u r e for Red u ction of Mesyla tes 23, 28,
a n d 37. To a stirred solution of the mesylate (10 mmol) in 30
mL of anhydrous DMSO under N2 at rt was added 4 equiv of
NaBH4, and the temperature was increased to 80-90 °C with
an oil bath (120 °C for the dimesylate 28). After being stirred
for 8 h, the solution was cooled by replacing the oil bath with
a rt H2O bath, and 5 mL of H2O was carefully added with
stirring. After 5 min, the mixture was carefully poured into
a stirred 1 L flask of 300 mL of ether/100 mL of 5% NaHCO3
solution and again stirred for 5 min. The aqueous phase was
extracted four times with ether, and the combined ether
fractions were dried and evaporated.
Gen er a l P r oced u r e for Hyd r olysis a n d Cycliza tion of
Aceta tes 22, 25, a n d 36. A quantity of acetate (15 mmol)
was dissolved in 100 mL of THF and 40 mL of MeOH at rt. To
this solution was added 40 mL (20 mmol) of 0.5 N NaOH, and
the mixture was stirred for 1 h. After the addition of solid
NaHCO3 to saturate the aqueous phase and separate it from
the organic solvents, the mixture was extracted three times
with EtOAc. The combined organic fractions were then dried
and evaporated.
cis-1,2(R)-(1-Oxooxa zolid in o)-6(S)-m et h ylp ip er id in e
(24). (This oxazolidinone, whether from mesylate 23 or
dimesylate 28, was identical in all respects.) FC was done
beginning with 10% EtOAc/90% PE and progressing to 25%
EtOAc/75% PE to give 24 in 72% yield (from 23) or 42% yield
(from 28). An analytical sample was crystallized from diiso-
cis-1,2(R)-(1-Oxooxa zolid in o)-6(S)-[[(m eth ylsu lfon yl)-
oxy]m eth yl]p ip er id in e (23). (This mesylate, whether from
22a or 22b, was identical in all respects.) FC was performed
beginning with 10% EtOAc/90% PE and finishing with 60%
EtOAc/40% PE to give 23 in 73% yield. (The secondary
product, the meso ether mentioned in the text, was isolated
in 20% yield.) An analytical sample of mesylate 23 was
obtained by crystallization from EtOAc: mp 59.0-60.0 °C; 23
propyl ether: mp 41.0-42.5 °C; 24 (from 23), [R]25 ) -58.8
D
(c 2.4, CHCl3); 24 (from 28), [R]25 ) -57.2 (c 1.3, CHCl3); IR
D
1
(KBr) υ 2980-2860, 1750 cm-1; H NMR (CDCl3) δ 4.31 (dd,
J 1
∼ J 2 ) 8.3 Hz, 1H), 3.76 (dd, J 1 ∼ J 2 ) 8.3 Hz, 1H), 3.53
(m, 1H), 3.18 (m, 1H), 1.92-1.79 (m, 2H), 1.71-1.63 (m, 1H),
1.58 (d, J ) 6.72 Hz, 3H), 1.50-1.21 (m, 3H); 13C NMR (CDCl3)
δ 156.6, 67.2, 57.1, 51.8, 34.0, 29.5, 23.0, 18.7. Anal. Calcd
for C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C, 61.66;
H, 8.62; N, 9.06.
(from 22a ), [R]25D ) -26.7 (c 2.2, CHCl3); 23 (from 22b), [R]25
D
) -26.4 (c 1.8, CHCl3); IR (KBr) υ 3030, 2950-2870, 1745
1
cm-1; H NMR (CDCl3) δ 4.79 (d, J ) 5.20 Hz, 2H), 4.35 (dd,
J 1 ∼ J 2 ) 8.3 Hz, 1H), 3.85 (dd, J 1 ) 8.30 Hz, J 2 ) 6.94 Hz,
1H), 3.61 (m, 1H), 3.41 (m, 1H), 3.04 (s, 3H), 1.98 (m, 1H),
1.83-1.75 (m, 2H), 1.60-1.32 (m, 3H); 13C NMR (CDCl3) δ
156.5, 68.8, 67.9, 56.9, 54.7, 37.2, 29.2, 27.6, 22.7. Anal. Calcd
for C9H15NO5S: C, 43.36; H, 6.06; N, 5.62. Found: C, 43.36;
H, 6.25; N, 5.55.
cis,cis-1,2(R)-(1-Oxooxa zolid in o)-4(S)-[(m et h yloxy)-
m eth oxy]-6(S)-m eth ylp ip er id in e (38). FC of the reaction
residue with 25% EtOAc/75% PE to 50% EtOAc/50% PE
afforded 38 in 74% yield. An analytical sample was prepared
by crystallization from diisopropyl ether: mp 44.0-45.5 °C;
cis,cis-1,2(R)-(1-Oxooxa zolid in o)-4(S)-[(m et h yloxy)-
m e t h oxy]-6(S )-[[(m e t h yloxy)m e t h oxy]m e t h yl]p ip e r i-
d in e (26). (This oxazolidinone, whether from 25a or 25b, was
identical in all respects.) FC was done beginning with 25%
EtOAc/75% PE and progressing to 50% EtOAc/50% PE to
[R]25 ) -35.3 (c 1.2, CHCl3); IR (KBr) υ 2940-2780, 1745
D
1
cm-1; H NMR (CDCl3) δ 4.65 (s, 2H), 4.30 (dd, J 1 ∼ J 2 ) 8.0
Hz, 1H), 3.82 (dd, J 1 ∼ J 2 ) 8.0 Hz, 1H), 3.71-3.55 (m, 2H),
3.34 (s, 3H), 3.24 (m, 1H), 2.15 (br d, J ) 12.06 Hz, 1H), 1.99
(br d, J ) 12.84 Hz, 1H), 1.60 (d, J ) 6.59 Hz, 3H), 1.35 (ddd,
J 1 ∼ J 2 ∼ J 3 ) 11.8 Hz, 2H); 13C NMR (CDCl3) δ 156.3, 94.6,
72.4, 66.5, 55.4, 55.2, 49.6, 40.5, 36.1, 18.3. Anal. Calcd for
C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.84; H,
7.62; N, 6.50.
afford 26 as a colorless oil in 95% yield: 26 (from 25a ), [R]25
D
) -13 (c 3.2, CHCl3); 26 (from 25b), [R]25 ) -13 (c 3.2,
D
1
CHCl3); IR (neat) υ 2960-2790, 1755 cm-1; H NMR (CDCl3)
δ 4.70-4.64 (m, 4H), 4.34(dd, J 1 ) 8.31 Hz, J 2 ) 7.70 Hz, 1H),
4.25 (dd, J 1 ) 10.26 Hz, J 2 ) 5.54 Hz, 1H), 4.04 (dd, J 1 ) 10.26
Hz, J 2 ) 6.36 Hz, 1H), 3.91 (dd, J 1 ) 8.31 Hz, J 2 ) 6.05 Hz,
1H), 3.75-3.61 (m, 2H), 3.37 (s, 3H), 3.36 (s, 3H), 3.32 (m, 1H),
2.14 (m,2H), 1.46 (m, 2H); 13C NMR (CDCl3) δ 156.1, 96.9, 94.8,
72.6, 67.1, 66.9, 55.5, 55.4, 53.9, 36.3, 35.1; MS (CI, CH4) m/ z
276 (MH+).
Gen er a l P r oced u r e for Hyd r olysis of Oxa zolid in on es
24 (fr om 20b) a n d 38. A solution of the oxazolidinone (6
mmol) in 50 mL of absolute MeOH was mixed with 30 mL (30
mmol) of 1 N KOH and refluxed for 40 h. The reaction was
then cooled to rt, and the MeOH was evaporated. After
partition between 80 mL of CH2Cl2 and 20 mL of brine, the
aqueous phase was extracted three times with CH2Cl2, and
the combined CH2Cl2 fractions were dried and evaporated to
give the crude, crystalline amino alcohol in quantitative yield.
In both cases, the crude product was sufficiently pure to
proceed to the next synthetic step without purification.
cis,cis-1,2(R)-(1-Oxooxa zolid in o)-4(S)-[(m et h yloxy)-
m e t h oxy]-6(S )-[[(m e t h ylsu lfon yl)oxy]m e t h yl]p ip e r i-
d in e (37). The pure mesylate 37 was recovered in 93% yield
as a viscous oil after FC beginning with 50% EtOAc/50% PE
and ending with 66% EtOAc/34% PE: [R]25 ) -7.6 (c 1.4,
D

3340 J . Org. Chem., Vol. 61, No. 10, 1996
Cheˆnevert and Dickman
cis-2(R)-(Hyd r oxym eth yl)-6(R)-m eth ylp ip er id in e (32).
(Attention: This amino alcohol (32) sublimes very readily.) An
analytical sample of amino alcohol 32 was obtained by recrys-
N -Be n zyl-cis-2(R )-(1-p r op e n yl)-6(S )-m e t h ylp ip e r i-
d in e (35). Anhydrous benzene (30 mL) and 628 mg (5.60
mmol) of t-BuOK were mixed at rt under N2, and 2.23 g (6.00
mmol) of Ph3P(Et)(Br) was added to the mixture. After the
mixture was stirred for 1.5 h, the crude aldehyde 34 (4.00
mmol, assuming 100% yield from Swern oxidation of 33) was
added with 15 mL of anhydrous benzene to the reaction
mixture, and it was refluxed for 1 h. The reaction mixture
was then partitioned between 100 mL of EtOAc/50 mL of 10%
Na2S2O3 solution, and the aqueous phase was extracted two
times with EtOAc. The organic fractions were dried and
evaporated, and the residue was dissolved in 50 mL of PE and
filtered. FC beginning with pure PE and progressing to 3%
EtOAc/97% PE was performed to yield 761 mg (83% from 33)
tallization from diisopropyl ether: mp 93.0-94.0 °C; [R]25
)
D
-22.4 (c 1.02, CHCl3); IR (KBr) υ 3245, 3110, 2950-2600 cm-1
;
1H NMR (CDCl3) δ 4.11 (br s, 2H), 3.55 (dd, J 1 ) 10.98 Hz, J 2
) 3.64 Hz, 1H), 3.40 (dd, J 1 ) 10.98 Hz, J 2 ) 8.10 Hz, 1H),
2.74-2.60 (m, 2H), 1.75 (m, 1H), 1.59 (m, 1H), 1.50 (m, 1H),
1.32 (m, 1H), 1.19-1.04 (m, 2H), 1.08 (d, J ) 6.18 Hz, 3H);
13C NMR (CDCl3) δ 65.4, 58.3, 52.1, 33.5, 27.3, 23.9, 22.2. Anal.
Calcd for C7H15NO: C, 65.07; H, 11.70; N, 10.84. Found: C,
65.11; H, 12.08; N, 10.80.
c i s,c i s-2(R )-(H y d r o x y m e t h y l)-4(S )-[(m e t h y lo x y )-
m eth oxy]-6(S)-m eth ylpiper idin e (39). An analytical sample
of amino alcohol 39 was prepared by recrystallization from
of 35 (cis:trans 9:1) as a colorless oil: [R]25 (cis) ) -5.9 (c
D
EtOAc: mp 88.5-89.5 °C; [R]25 ) -16.9 (c 1.05, CHCl3); IR
1.7, CHCl3); IR (neat) υ (cis) 3080-3020, 2965-2780, 2580,
1600 cm-1; 1H NMR (CDCl3) (cis) δ 7.36-7.18 (m, 5H), 5.58-
5.41 (m, 2H), 4.02 (d, J ) 15.81 Hz, 1H), 3.65 (d, J ) 15.81
Hz, 1H), 3.17 (m, 1H), 2.41 (m, 1H), 1.68-1.54 (m, 3H), 1.63
(d, J ) 5.37 Hz, 3H), 1.45-1.28 (m, 3H), 1.07 (d, J ) 5.99 Hz,
3H); 13C NMR (CDCl3) (cis) δ 140.9, 135.8, 128.6, 127.8, 126.2,
123.7, 59.2, 57.2, 55.2, 35.6, 33.3, 24.2, 22.5, 13.4; HRMS (EI,
70 eV) calcd for C16H23N (M+) 229.1830, found 229.1835 (
0.0006.
D
(KBr) υ 3250, 3120, 2960-2600 cm-1; 1H NMR (CDCl3) δ 4.63
(br s, 2H), 3.64-3.53 (m, 2H), 3.42 (dd, J 1 ) 11.04 Hz, J 2
)
7.49 Hz, 1H), 3.33 (s, 3H), 2.78-2.65 (m, 2H), 1.96 (br d, J )
12.22 Hz, 1H), 1.87 (br d, J ) 11.82 Hz, 1H), 1.10 (d, J ) 5.52
Hz, 3H), 1.13-1.00 (m, 2H); 13C NMR (CDCl3) δ 94.4, 73.9,
65.8, 56.0, 55.1, 49.8, 40.8, 34.6, 22.2. Anal. Calcd for
C9H19NO3: C, 57.12; H, 10.12; N, 7.40 Found: C, 57.05; H,
10.30; N, 7.35.
Gen er a l P r oced u r e for N-Ben zyla tion of Am in o Alco-
h ols 32 a n d 39. The crude amino alcohol (5 mmol) and 1.5
equiv of DiPEA were dissolved in 10 mL of anhydrous CH3CN,
and 1.2 equiv of BnBr was added to the solution which was
then refluxed for 3 h under a CaCl2 drying tube. After being
cooled to rt, the reaction mixture was poured into 50 mL of
CH2Cl2/10 mL of 1N NaOH and stirred for 10 min. The
aqueous phase was extracted three times with CH2Cl2, and
the combined organic fractions were dried and evaporated.
N-Ben zyl-cis-2(R)-(h yd r oxym eth yl)-6(S)-m eth ylp ip er i-
d in e (33). FC was performed beginning with 10% EtOAc/90%
PE (to eliminate any trace of 24) and then progressing quickly
to 50% EtOAc/50% PE to give 33 as a colorless oil in 81% yield
N-Ben zyl-cis,cis-2(R)-(1-n on en yl)-4(S)-[(m et h yloxy)-
m eth oxy]-6(S)-m eth ylp ip er id in e (42). This olefin was
prepared according to the procedure for 35, except Ph3P(n-
octyl)(Br) was used as the Wittig reagent. [Triphenyl-n-
octylphosphonium bromide was prepared by reacting Ph3P
with n-octylBr in refluxing anhydrous benzene overnight. No
precipitate was observed so the benzene was evaporated, and
the resulting viscous oil was triturated repeatedly with
anhydrous ether to remove the slight excess of n-octylBr. The
crude Ph3P(n-octyl)(Br) was dried under vacuum over P2O5 and
used “as is”.] Thus, the crude aldehyde (41, 4.00 mmol,
assuming 100% yield from Swern oxidation of 40) was reacted
to afford, after FC beginning with pure PE and progressing to
5% EtOAc/95% PE, 1.31 g (87% from 40) of 42 (cis:trans 10:1)
(from 24): [R]25 ) -27.1 (c 1.4, CHCl3); IR (neat) υ 3360,
D
as a colorless oil: [R]25 (cis) ) 9.40 (c 1.50, CHCl3); IR (neat)
3080-3020, 2960-2780 cm-1; H NMR (CDCl3) δ 7.40-7.21
1
D
1
υ (cis) 3080-1010, 2980-2740, 1600 cm-1; H NMR (CDCl3)
(m, 5H), 3.69 (AB system, 2H), 3.65 (dd, J 1 ) 11.24 Hz, J 2
)
(cis) δ 7.34-7.18 (m, 5H), 5.40 (m, 2H), 4.65 (s, 2H), 4.01 (d, J
) 15.79 Hz, 1H), 3.58 (d, J ) 15.79 Hz, 1H), 3.54 (m, 1H),
3.37 (s, 3H), 3.22 (m, 1H), 2.47 (m, 1H), 2.10-2.01 (m, 2H),
1.98-1.83 (m, 2H), 1.50-1.26 (m, 12H), 1.06 (d, J ) 5.69 Hz,
3H), 0.90 (t, J ) 6.32 Hz, 3H); 13C NMR (CDCl3) (cis) δ 140.8,
133.4, 130.5, 128.1, 127.7, 126.1, 94.3, 72.8, 57.9, 55.5, 55.0,
54.5, 41.5, 39.5, 31.7, 29.4, 29.3, 29.1, 27.8, 22.5, 22.3, 14.0;
HRMS (EI, 70 eV) calcd for C24H39NO2 (M+) 373.2981, found
373.2979 ( 0.0011.
4.06 Hz, 1H), 3.32 (dd, J 1 ) 11.24 Hz, J 2 ) 3.87 Hz, 1H), 2.71-
2.57 (m, 2H), 2.32 (br s, 1H), 1.90-1.54 (m, 4H), 1.44-1.25
(m, 2H), 1.18 (d, J ) 6.33 Hz, 3H); 13C NMR (CDCl3) δ 141.1,
128.3, 127.4, 126.5, 63.6, 63.2, 56.7, 53.8, 32.8, 27.2, 22.9, 22.1;
MS (CI, NH3) m/ z 220 (MH+).
N-Ben zyl-cis,cis-2(R)-(h yd r oxym eth yl)-4(S)-[(m eth yl-
oxy)m eth oxy]-6(S)-m eth ylp ip er id in e (40). FC was done
with 25% EtOAc/75% PE and progressing to 50% EtOAc/50%
PE to afford 40 as a colorless oil in 90% yield (from 38): [R]25
D
(+)-2(R),6(S)-Dih yd r op in id in e Hyd r och lor id e [(+)-2-
HCl]. A quantity of olefin (35, 646 mg, 2.816 mmol) and 3.0
mL (9.0 mmol HCl) of 3 N HCl were dissolved in 15 mL of
freshly, degassed absolute EtOH. Pearlman’s catalyst (Pd(OH)2
on carbon, 94 mg) was suspended in the solution, and the
mixture was hydrogenated at 40 psi at 40 °C for 15 h. After
filtration of the mixture through a pad of Celite, the EtOH
and H2O were evaporated. Toluene (50 mL) was added and
evaporated to dryness in order to remove any trace of H2O.
The crude (+)-2-HCl (pure by 1H and 13C NMR) was obtained
in near-quantitative yield (496 mg). Recrystallization from
absolute EtOH/EtOAc gave 422 mg (84% from 35) of (+)-2-
HCl as white needles: mp 242.0-243.0 °C (lit.9e mp 245.0-
246.2 °C); [R]25 ) +13.3 (c 1.14, EtOH) (lit.14 [R]25 ) +12.8
) -22.8 (c 2.0, CHCl3); IR (neat) υ 3440, 3090-3020, 2970-
2790 cm-1; 1H NMR (CDCl3) δ 7.39-7.20 (m, 5H), 4.68 (s, 2H),
3.73 (AB system, 2H), 3.65-3.54 (m, 2H), 3.36 (s, 3H), 3.34
(m, 1H), 2.76-2.62 (m, 2H), 1.95-1.82 (m, 3H), 1.64 (ddd, J 1
∼ J 2 ∼ J 3 ) 11.8 Hz, 1H), 1.35 (ddd, J 1 ∼ J 2 ∼ J 3 ) 11.8 Hz,
1H), 1.20 (d, J ) 6.15 Hz, 3H); 13C NMR (CDCl3) δ 141.1, 128.4,
127.3, 126.7, 94.4, 73.1, 63.7, 62.3, 55.6, 55.1, 51.9, 39.4, 33.6,
21.9; HRMS (CI, NH3) calcd for C16H25NO3 (M+ + H) 280.1913,
found 280.1917 ( 0.0008.
Gen er a l P r oced u r e for Sw er n Oxid a tion of Alcoh ols
33 a n d 40. To a stirred solution of 2 equiv of oxalyl chloride
in 12 mL of anhydrous CH2Cl2 at -78 °C under N2 was added
3 equiv of anhydrous DMSO in 4 mL of anhydrous CH2Cl2
dropwise and the mixture allowed to react for 5 min at -78
°C. The alcohol (4 mmol) in 4 mL of anhydrous CH2Cl2 was
added, and the reaction mixture was stirred for 1 h at -78
°C. On addition of 4 equiv of anhydrous Et3N, the dry ice/
acetone bath was removed, and the reaction temperature was
left to go to rt. The reaction was diluted with 20 mL of CH2Cl2
and then poured into 50 mL of CH2Cl2/20 mL of 10% NH4OH
solution. The aqueous phase was extracted twice with CH2Cl2,
and the combined CH2Cl2 fractions were dried and evaporated.
The residue was dissolved in ether and filtered through a
MgSO4 pad and the ether evaporated. The crude aldehyde (34
or 41) was used immediately in the next step of the synthesis
(Wittig reaction). All attempts to purify or analyze the
aldehyde resulted in its degradation.
D
D
(c 1.07, EtOH)); IR (KBr) υ 3180, 2960-2370, 2075, 1600, 1585
1
cm-1; H NMR (CDCl3) δ 9.41 (br s, 1H), 9.03 (br s, 1H), 3.06
(m, 1H), 2.89 (m, 1H), 2.16-2.05 (m, 1H), 1.95-1.23 (m, 9H),
1.55 (d, J ) 6.50 Hz, 3H), 0.88 (t, J ) 7.32 Hz, 3H); 13C NMR
(CDCl3) δ 58.1, 54.3, 35.0, 30.4, 27.2, 22.7, 19.3, 18.6, 13.6.
(+)-cis,cis-2(R)-n -Non yl-4(S)-h yd r oxy-6(S)-m eth ylp ip -
er id in e Hyd r och lor id e [(+)-241D-HCl] [(+)-4-HCl]. The
synthesis of (+)-4-HCl was conducted in the same manner
as that for (+)-2-HCl. The acidic hydrogenation conditions
successfully removed both the N-benzyl group and the meth-
oxymethyl ether as well as reduced the olefin. Thus, 330 mg
(0.883 mmol) of 42 was converted to crude (+)-4-HCl (243
mg) in near-quantitative yield. An analytical sample was

Synthesis of (+)-Dihydropinidine
J . Org. Chem., Vol. 61, No. 10, 1996 3341
obtained by recrystallization from absolute EtOH/EtOAc to
36.7, 31.7, 29.6, 29.4, 29.2, 25.9, 22.5, 22.3, 13.9; HRMS (EI,
70 eV) calcd for C15H31NO (M+) 241.2406, found 241.2395 (
0.0007.
afford (+)-4-HCl as white needles: mp 228 °C dec; [R]25
)
D
+15.8 (c 1.30, EtOH); IR (KBr) υ 3320, 2960-2640, 2485, 2440,
2100 cm-1 1H NMR (CD3OD) δ 3.82 (m, 1H), 3.27 (m, 1H),
;
3.16 (m, 1H), 2.23 (m, 1H), 2.14 (m, 1H), 1.76 (m, 1H), 1.61
(m, 1H), 1.47-1.28 (m, 16 H), 1.39 (d, J ) 7.30 Hz, 3H), 0.90
(t, J ) 6.44 Hz, 3H); 13C NMR (CD3OD) δ 68.9, 59.3, 55.3, 43.0,
40.5, 36.8, 35.4, 33.0, 32.9, 32.8, 28.6, 26.1, 21.6, 16.9.
Ack n ow led gm en t. This work was supported by
grant funding from NSERC. M.D. was the holder of a
NSERC postgraduate scholarship. The authors thank
Dr. Henri Veschambre and Pascale Besse at Universite´
Blaise Pascal, Aubie`re, France, for their help during this
synthesis. M.D. would like to extend his warm thanks
to everyone at Universite´ Blaise Pascal for making his
stay a memorable experience.
(+)-cis,cis-2(R)-n -Non yl-4(S)-h yd r oxy-6(S)-m eth ylp ip -
er id in e [(+)-241D] [(+)-4]. The free piperidine ((+)-4) was
prepared by dissolving 134 mg (0.482 mmol) of crude (+)-4-
HCl in 10 mL of H2O and adding 102 mg (0.962 mmol) of
Na2CO3. Extraction of the precipitated amino alcohol with
EtOAc (2 × 30 mL) was followed by drying and evaporation
of the solvent to give 111 mg (95%) of crude (+)-4. Recrys-
tallization from EtOAc afforded 96 mg of pure (+)-4 as white
flakes: mp 108.0-109.0 °C; [R]25D ) +6.5 (c 2.0, MeOH) (lit.2a
Su p p or tin g In for m a tion Ava ila ble: Spectrometric in-
formation (1H or 13C NMR) for new compounds (28 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
[R]25 ) +39 (c 0.2, MeOH)); IR (KBr) υ 3250, 3145, 2945-
D
2550 cm-1; 1H NMR (CDCl3) δ 3.63 (m, 1H), 2.66 (m, 1H), 2.53
(m, 1H), 2.00-1.89 (m, 2H), 1.58 (br s, 2H), 1.42-1.21 (m,
16H), 1.11 (d, J ) 6.09 Hz, 3H), 1.07-0.90 (m, 2H), 0.88 (t, J
) 6.57 Hz, 3H); 13C NMR (CDCl3) δ 69.2, 54.7, 50.0, 43.8, 41.7,
J O9519569