2-Piperidone type of chiral building block for 3-piperidinol alkaloid synthesis

Article abstract of DOI:10.1021/jo990397t

An enantiomeric pair of a new 2-piperidone type of chiral building block (1) has been prepared by bakers' yeast reduction of β-keto ester (2) or lipase-mediated transesterification of hydroxy ester (±)-(1), derived from NaBH₄ reduction of 2, in enantiopure form. The absolute stereochemistry of (-)-1 was verified by its conversion to known piperidine (-)-3, an intermediate for the synthesis of (-)-spectaline. The 2-piperidone (-)-1 was converted to all four diastereomers of 2,6-disubstituted 3-piperidinol chiral building blocks on the basis of homologation of (-)-1 at the lactam carbonyl using the Eschenmoser method via corresponding thiolactams (-)-9, (-)-20, (- )-25, (-)-27, and (-)-34, followed by stereocontrolled reduction of the resulting vinylogous urethanes (+)-10, (+)15, (+)-23, (+)-28, and (+)-32, respectively, and epimerization of the hydroxyls at the 3-position [(-)-16 via (+)-17 to (-)-18 and (+)-29 via (+)-30 to (+)-31]. The versatility of these chiral building blocks has been demonstrated by the chiral synthesis of the 3-piperidinol alkaloids (+)-prosafrinine, (-)-iso-6-cassine, (-)- prosophylline, and (-)-prosopinine from (-)-37, (-)-14, (+)-36, and (-)-26, respectively.

Full text of DOI:10.1021/jo990397t

4914
J . Org. Chem. 1999, 64, 4914-4919
2-P ip er id on e Typ e of Ch ir a l Bu ild in g Block for 3-P ip er id in ol
Alk a loid Syn th esis
Naoki Toyooka,* Yasuko Yoshida, Yasuhito Yotsui, and Takefumi Momose
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630,
Toyama 930-0194, J apan
Received March 4, 1999
An enantiomeric pair of a new 2-piperidone type of chiral building block (1) has been prepared by
bakers’ yeast reduction of â-keto ester (2) or lipase-mediated transesterification of hydroxy ester
(()-(1), derived from NaBH4 reduction of 2, in enantiopure form. The absolute stereochemistry of
(-)-1 was verified by its conversion to known piperidine (-)-3, an intermediate for the synthesis of
(-)-spectaline. The 2-piperidone (-)-1 was converted to all four diastereomers of 2,6-disubstituted
3-piperidinol chiral building blocks on the basis of homologation of (-)-1 at the lactam carbonyl
using the Eschenmoser method via corresponding thiolactams (-)-9, (-)-20, (-)-25, (-)-27, and
(-)-34, followed by stereocontrolled reduction of the resulting vinylogous urethanes (+)-10, (+)-
15, (+)-23, (+)-28, and (+)-32, respectively, and epimerization of the hydroxyls at the 3-position
[(-)-16 via (+)-17 to (-)-18 and (+)-29 via (+)-30 to (+)-31]. The versatility of these chiral buliding
blocks has been demonstrated by the chiral synthesis of the 3-piperidinol alkaloids (+)-prosafrinine,
(-)-iso-6-cassine, (-)-prosophylline, and (-)-prosopinine from (-)-37, (-)-14, (+)-36, and (-)-26,
respectively.
In tr od u ction
Functionalized piperidines are very important hetero-
cycles because of their presence in numerous alkaloids,
pharmaceuticals, and synthetic intermediates. As a
result, a large number of synthetic designs for this ring
system have been developed to date.1 In particular, many
R,R′-disubstituted 3-piperidinol alkaloids have been iso-
lated, and many of them have shown important biological
activities.2
Among the recent efforts in this area, we have exhib-
ited a design for the chiral construction of both enant-
iomers of the cis-(2,3,6)-trisubstituted 3-piperidinol chiral
building block3a,4 and its utility for the chiral synthesis
of the 3-piperidinol alkaloids (-)-cassine and (+)-
spectaline3b,4 and some 5,8-disubstituted indolizidine or
1,4-disubstituted quinolizidine types of Dendrobates al-
kaloids.5
F igu r e 1.
In this paper, we describe a method for the construction
of both enantiomers of a new 2-piperidone type of chiral
building block (1)6 leading to all four diastereomers (I-
IV) needed for the synthesis of the above 3-piperidinol
alkaloids in enantiomerically pure form.7
The basic strategy we used to prepare the building
blocks (I-IV) from (-)-1 is presented in Figure 1. The
attachment of the C-6 side chain was installed by using
the lactam functionality with stereochemical control.8 In
addition, the hydroxyl at the 3-position was readily
epimerized to the desired configuration for the synthesis
of corresponding alkaloids.
(1) For reviews, see: Wang, C.-L. J .; Wuorola, M. A. Org. Prep.
Proced. Int. 1992, 24, 585-621. Takahata, H.; Momose, T. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1993; Vol.
44, pp 189-256. Michael, J . P. Nat. Prod. Rep. 1995, 12, 535-552.
Nadin, A. J . Chem. Soc., Perkin Trans. 1 1998, 3493-3513. Daly, J .
W. In The Alkaloids, Cordell, G. A., Ed.; Academic Press: San Diego,
1998; Vol. 50, pp 141-169.
(2) Strunz, G. M.; Findlay, J . A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1985; Vol. 26, pp 89-183. Aguinaldo, A.
M.; Read, R. W. Phytochemistry 1990, 29, 2309-2313. Bolzani, V. da
S.; Gunatilaka, A. A. L.; Kingston, D. G. I. Tetrahedron 1995, 51, 5929-
5934. Astudillo, S. L.; J u¨rgens, S. K.; SchmedaHirschmann, G.; Griffith,
G. A.; Holt, D. H.; J enkins, P. R. Planta Med. 1999, 65, 161-162 and
references therein. For recent synthesis of this type of alkaloids, see:
Bayquen, A. V.; Read, R. W. Tetrahedron 1996, 52, 13467-13482.
Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y. Tetrahedron:
Asymmetry 1997, 8, 3887-3893. Agami, C.; County, F.; Mathieu, H.
Tetrahedron Lett. 1998, 39, 3505-3508. Agami, C.; County, F.; Lam,
H.; Mathieu, H. Tetrahedron 1998, 54, 8783-8796. Yang, C.-F.; Xu,
Y.-M.; Liao, L.-X.; Zhou, W.-S. Tetrahedron Lett. 1998, 39, 9227-9228.
Pahl, A.; Wartchow, R.; Meyer, H. H. Tetrahedron Lett. 1998, 39, 2095-
2096. Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T.
Tetrahedron 1998, 54, 15589-15606 and references therein.
(3) (a) Momose, T.; Toyooka, N.; J in, M. Tetrahedron Lett. 1992, 33,
5389-5390. (b) Momose, T.; Toyooka, N. Tetrahedron Lett. 1993, 34,
5785-5786.
(5) Momose, T.; Toyooka, N. J . Org. Chem. 1994, 59, 943-945;
Toyooka, N.; Tanaka, K.; Momose, T.; Daly, J . W.; Garraffo, H. M.
Tetrahedron 1997, 53, 9553-9574.
(6) It was worthwhile noting Comins’ work in the field of enant-
ioselective synthesis of various alkaloids using chiral nonracemic 2,3-
dihydro-4-pyridones (5,6-didehydro-4-piperidones); see: Comins, D. L.;
Kuethe, J . T.; Hong, H.; Lakner, F. J .; Concolino, T. E.; Rheingold, A.
L. J . Am. Chem. Soc. 1999, 121, 2651-2652. Comins, D. L.; Zhang,
Y.-M.; Zheng, X. J . Chem. Soc., Chem. Commun. 1998, 2509-2510.
Comins, D. L.; Chen, X.; Morgan, L. A. J . Org. Chem. 1997, 62, 7435-
7438. Comins, D. L.; LaMunyon, D. H.; Chen, X. J . Org. Chem. 1997,
62, 8182-8187. Comins, D. L.; J oseph, S. P. In Advances in Nitrogen
Heterocycle; J AI Press Inc., 1996; Vol. 2, pp 251-294 and references
therein.
(4) Momose, T.; Toyooka, N.; J in, M. J . Chem. Soc., Perkin Trans. 1
1997, 2005-2013.
(7) For preliminary accounts, see: Toyooka, N.; Yoshida, Y.; Mo-
mose, T. Tetrahedron Lett. 1995, 36, 3715-3718.
10.1021/jo990397t CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/10/1999

2-Piperidone Type of Chiral Building Block
J . Org. Chem., Vol. 64, No. 13, 1999 4915
Sch em e 1
To verify the utility of the above 3-piperidinols as chiral
building blocks for alkaloid synthesis, we planned the
diastereodivergent synthesis of the 3-piperidinol alkaloids
(+)-prosafrinine,9 (-)-iso-6-cassine,10 (-)-prosophylline,11
and (-)-prosopinine.12
Herein, we wish to document the potential for a general
use of 1 in alkaloid synthesis via the above 3-piperidinol
building blocks (I-IV).
Relative stereochemistry of (-)-1 was verified with an
X-ray analysis.
With the enantiomeric pair of scalemic 1 in hand, we
next examined the determination of the absolute stere-
ochemistry of (-)-1 by its conversion to known piperidine
(-)-3.4 Protection of the hydroxyl in (-)-1 with MOMCl
afforded ether (-)-4, which was reduced with Super-
Hydride15 to yield alcohol (-)-5. Treatment of (-)-5 with
(PhS)2 and Ph3P in pyridine provided phenylthioether
(-)-6 which was desulfurized with Raney Ni (W-4) to give
piperidone (-)-7. Conversion of (-)-7 to benzyl ether (-)-
8, which was subjected to homologation at the lactam
carbonyl by Eschenmoser’s sulfide-contraction reaction
via thiolactam (-)-9 to provide vinylogous urethane (+)-
10. Catalytic hydrogenation of (+)-10 over Pd(OH)2
followed by protection of the resulting amine with ClCO2-
Me afforded the desired cis-(2,6)-piperidine (-)-11, which
was converted to MOM ether (-)-12 in the usual manner.
This stereoselectivity may be attributed to the steric
hindrance, by which the catalytic hydrogenation occurs
from the less hindered site (R-face) of (+)-10. This will
fix the conformation not in B but in as a result of A A(1,2)
strain16 between N-benzyl and R-methyl groups, to afford
(-)-11.
Resu lts a n d Discu ssion
First, we examined the preparation of both enant-
iomers of 2-piperidone (1). To obtain 1 in an optically pure
state, we investigated the lipase-mediated kinetic resolu-
tion of (()-1, prepared from the NaBH4 reduction of
â-keto ester (2).13 Kinetic resolution of (()-1 under the
condition of treatment with lipase AK and vinyl acetate
in i-Pr2O proceeded nicely to afford the acetate of (+)-1
in 47% yield (>99% ee) and alcohol (-)-1 in 52% yield
(91% ee), respectively. Hydrolysis of the acetate with K2-
CO3 gave enantiopure (+)-1. The enantiomer (-)-1 was
found to be prepared more effectively from bakers’ yeast
reduction of 2 under nonfermenting conditions14 in high
optical yield (98% ee), and direct recrystallization of the
crude reduction product resulted in obtaining enan-
tiopure (-)-1 in 88% isolated yield (Scheme 1).
(8) Cook, G. R.; Beholz, L. G.; Stille, J . R. Tetrahedron Lett. 1994,
35, 1669-1672; J . Org. Chem. 1994, 59, 3575-3584.
(9) Isolation: (a) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel,
R. Bull. Soc. Chim. Belg. 1972, 81, 443-458. Nonchiral synthesis: (b)
Paterne, M.; Dhal, R.; Brown, E. Bull. Chem. Soc. J pn. 1989, 62, 1321-
1324.
(10) Isolation: Christofidis, I.; Welter, A.; J adot, J . Tetrahedron
1977, 33, 977-979.
Reduction of (-)-12 with Super-Hydride gave alcohol
(-)-3, an intermediate for the chiral synthesis of (+)-
spectaline.3b,4 Thus, the absolute stereochemistry of (-)-1
was verified to be 2R,3S, and the preparation of a chiral
building block of type I was completed (Scheme 2).
Next, we examined the transformation of (-)-1 to the
other three diastereomers (type II, III, and IV) to
establish the process for the diastereodivergent synthesis
of 2,6-disubstituted 3-piperidinol alkaloids. The trans-
(2,6)-piperidines of types II and III were prepared by
hydride reduction of iminium ions generated from the
corresponding vinylogous urethanes in a highly stereo-
selective manner. Thus, reduction of (+)-10 with NaBH3-
CN in the presence of trifluoroacetic acid (TFA) provided
a 14:1 mixture of trans-(2,6)- and cis-(2,6)-piperidines.
Because it was difficult to isolate the major, desired
trans-(2,6)-piperidine in a pure state, the epimeric mix-
(11) Isolation: ref 7a. Nonchiral stereoselective synthesis: (a)
Natume, M.; Ogawa, M. Heterocycles 1981, 16, 973. Chiral syntheses
of desoxoprosophylline: (b) Saitoh, Y.; Moriyama, Y.; Takahashi, T.;
Khuong-Huu, Q. Tetrahedron Lett. 1980, 75. (c) Saitoh, Y.; Moriyama,
Y.; Hirota, H.; Takahashi, T.; Khuong-Huu, Q. Bull. Chem. Soc. J pn.
1981, 54, 488. (d) Tadano, K.; Takao, K.; Nigawara, Y.; Nishio, E.;
Takagi, I.; Maeda, K.; Ogawa, S. Synlett 1993, 565-567; (e) Tetrahe-
dron 1994, 50, 5681-5704. (f) Kadota, I.; Kawada, M.; Muramatsu,
Y.; Yamamoto, Y. Tetrahedron: Asymmetry 1997, 8, 3887-3893. (g)
Yang, C.-F.; Xu, Y.-M.; Liao, L.-X.; Zhou, W.-S. Tetrahedron Lett. 1998,
39, 9227-9228. (h) Ojima, I.; Vidal, E. S. J . Org. Chem. 1998, 63,
7999-8003.
(12) Isolation: Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel,
R. Bull. Soc. Chim. Belg. 1972, 81, 425-442. Chiral syntheses of
prosopinine: Hirai, Y.; Watanabe, J .; Nozaki, T.; Yokoyama, H.;
Yamaguchi, S. J . Org. Chem. 1997, 62, 776-777 and ref 9h. Chiral
syntheses of desoxoprosopinine: Ciufolini, M. A.; Hermann, C. W.;
Whitmire, K. H.; Byrne, N. E. J . Am. Chem. Soc. 1989, 111, 3473-
3475 and refs 8d and 8e. Yuasa, Y.; Ando, J .; Shibuya, S. Tetrahe-
dron: Asymmetry 1995, 6, 1525-1526; J . Chem. Soc., Perkin Trans. 1
1996, 793-802. Reference 9f. Agami, C.; County, F.; Mathieu, H.
Tetrahedron Lett. 1998, 39, 3505-3508. Agami, C.; County, F.; Lam,
H.; Mathieu, H. Tetrahedron 1998, 54, 8783-8796. Nonchiral stereo-
selective synthesis of desoxoprosopinine: Holmes, A. B.; Thompson,
J .; Baxter, A. J . G.; Dixon, J . J . Chem. Soc., Chem. Commun. 1985,
37-39. Cook, G. R.; Beholz, L. G.; Stille, J . R. Tetrahedron Lett. 1994,
35, 1669-1672. Luker, T.; Hiemstra, H.; Speckamp, W. N. J . Org.
Chem. 1997, 62, 3592-3596.
(15) Use of Super-Hydride was extremely effective for reduction of
this sterically hindered ester functional group. For example, no
reduction proceeded with LiAlH4 at room temperature for 14 h, and
the starting material was recovered. Reduction with LiBH4 (6 equiv)
at room temperature for 23 h gave a 1:1 mixture of (-)-4 and (-)-5.
Reduction with DIBAL (2.2 equiv) at 0 °C for 1 h resulted in the
formation of a complex mixture not including the desired alcohol (-)-
5.
(13) Bonjoch, J .; Serret, I.; Bosch, J . Tetrahedron 1984, 40, 2505-
2511.
(14) Seebach, D.; Roggo, S.; Maetzke, T.; Braunschweiger, H.;
Cercus, J .; Krieger, M. Helv. Chim. Acta 1987, 70, 1605-1615.
(16) J ohnson, F. Chem. Rev. 1968, 68, 375-413.

4916 J . Org. Chem., Vol. 64, No. 13, 1999
Toyooka et al.
Sch em e 2a
Sch em e 3a
treatment of the resulting amine with ClCO2Me gave
diastereopure trans-piperidine (-)-13 in 68% isolated
yield (Scheme 3). Reduction of (-)-13 with Super-Hydride
afforded alcohol (-)-14 (type II) in 92% yield (Scheme
3).
The trans-selectivity observed in the above reduction
is explained by the following factors. Conformer C for the
iminium salt, generated from (+)-10 under acidic condi-
tions, is favored relative to D because of A(1,2) strain16
between the N-benzyl and the methyl at the R-position,
so the hydride reacts from the preferred â-axial site,17
leading to a chairlike transition state to give trans-(2,6)-
piperidine.
Another trans-(2,6)-piperidine of type III was synthe-
sized in a similar iminium reduction of the corresponding
vinylogous urethane of trans-(2,3)-congener (+)-15. Pro-
ture was used for subsequent transformation. Hydroge-
nation of the above mixture over Pd(OH)2 followed by
Sch em e 4a

2-Piperidone Type of Chiral Building Block
J . Org. Chem., Vol. 64, No. 13, 1999 4917
Sch em e 5a
Sch em e 6a
Sch em e 7a
dibenzyl ether (-)-19,19 which was subjected to Eschen-
moser’s contraction-sulfide extrusion reaction, after
conversion to thiolactam (-)-20, to provide vinylogous
urethane (+)-15. Reduction of (+)-15 with NaBH3CN
afforded piperidine (trans:cis ) 8:1, 89% combined yield),
which was purified with fractionation by repeated chro-
matography to provide pure trans-piperidine (-)-21 in
53% isolated yield. Reduction of (-)-21 with LiAlH4
furnished alcohol (-)-22 (type III), whose application in
its racemic form to the stereoselective synthesis of
prosopinine was reported.8 However, iminium reduction
of vinylogous urethane (+)-23, prepared from (-)-18 via
diacetate (-)-24 and thiolactam (-)-25, resulted in the
formation of a 11:1 mixture of trans-(2,6)- and cis-(2,6)-
piperidines in 84% combined yield. The mixture was
reduced to the triol with LiAlH4 in refluxing THF, and
protection of the 1,3-glycol system in the resulting triol
tection of the hydroxyl in (-)-5 with BnBr gave benzyl
ether (-)-16, which was deprotected with concentrated
HCl in MeOH. Oxidation with pyridinium chlorochro-
mate (PCC) of the resulting alcohol in the presence of
NaOAc afforded ketone (+)-17 in 95% ee,18 which was
recrystallized from i-Pr2O to give an enantiopure com-
pound18 in 83% isolated yield. When the oxidation was
performed under Swern conditions, complete racemiza-
tion occurred. Reduction of the keto alcohol obtained from
hydrogenolysis of (+)-17 with NaB(OAc)3H provided diol
(-)-18 with complete stereochemical control. Both hy-
droxyls in (-)-18 were protected with BnBr to give
(17) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon: New York, 1983; pp 209-290.
(18) The enantiomeric excess was determined by HPLC analysis;
see the Experimental Section in the Supporting Information.
(19) Campbell, J . A.; Lee, W. K.; Rapoport, H. J . Org. Chem. 1995,
60, 4602-4616.

4918 J . Org. Chem., Vol. 64, No. 13, 1999
Toyooka et al.
Sch em e 8a
with 2,2-dimethoxypropane afforded acetonide, which
was purified with column chromatography to give dias-
tereomerically pure trans-piperidine (-)-26 (type III) in
75% isolated yield in two steps (Scheme 4).
Next, we examined the chiral synthesis of all-cis-
trisubstituted alkaloid (+)-prosafrinine. Vinylogous ure-
thane (+)-10 was converted stereoselectively to piperidine
(-)-37 via catalytic hydrogenation followed by protection
of the resulting amine with benzyl chloroformate (CbzCl).
Reduction of (-)-37 with Super-Hydride afforded alcohol
(-)-38 in 92% yield, which was transformed to olefin (-)-
39 via Swern oxidation followed by Wittig olefination
using the Wittig reagent 40. Finally, hydrogenation of
(-)-39 over Pd(OH)2, cleavage of benzyl ether of resulting
amine under the Birch condition and subsequent depro-
tection of the acetal moiety with acid provided (+)-
prosafrinine in 60% overall yield (Scheme 6). 1H and 13C
NMR spectra of our synthetic alkaloid were identical with
those of the literature.9
Finally, the type IV chiral building block was synthe-
sized as follows. Benzyl ether (-)-16 was subjected, after
its conversion to thiolactam (-)-27, to the Eschenmoser
method to give vinylogous urethane (+)-28 along with
the MOM ether of (+)-28 (ca. 1.7:1). Catalytic hydrogena-
tion of (+)-28 over Pd(OH)2 followed by protection of the
resulting amine with ClCO2Me afforded urethane (+)-
29. Finally, epimerization of the hydroxyl at the 3-posi-
tion was achieved in a three-step sequence as follows.20
PCC oxidation of alcohol (+)-29 provided ketone (+)-30,
which was hydrogenated over Pd(OH)2, followed by
reduction of the resulting keto alcohol with NaB(OAc)3H
in AcOH to furnish a piperidine of type IV [(+)-31]. As
an alternative route to the type IV chiral building block,
we investigated the iminium reduction of vinylogous
urethane (+)-32. Protection of the glycol in (-)-18 with
2,2-dimethoxypropane afforded acetonide (-)-33, which
was transformed to (+)-32 via thiolactam (-)-34. Reduc-
tion of (+)-32 with NaBH3CN in the presence of TFA
provided cis-(2,6)-piperidine (+)-35 exclusively, which
was reduced to alcohol (+)-36 with LiAlH4 in 99% yield
(Scheme 5). The absence of formation of trans-(2,6)-
piperidine corresponding to (+)-35 in the above reduction
was proven by comparison of (+)-36, prepared from
LiAlH4 reduction of (+)-35, with (-)-26 on the basis of
1H NMR spectra.
In addition, we examined the chiral synthesis of the
2,3(cis)-2,6(trans)-trisubstituted 3-piperidinol iso-6-cass-
ine. Swern oxidation of (-)-14 and subsequent Wittig
olefination of the resulting aldehyde gave diene 41 in 80%
yield in two steps. Wacker oxidation of 41 afforded the
methyl ketone 42 (Scheme 7), which was hydrogenated
over Pd(OH)2 in MeOH to provide the saturated ketone,
whose methoxycarbonyl protecting group was cleaved by
treatment with trimethylsilyl iodide (TMSI)21 in refluxing
1
CHCl3 to furnish iso-6-cassine. H and 13C NMR spectra
of the synthetic alkaloid were in agreement with the
reported values.10
The alkaloids prosophylline and prosopinine were
synthesized from the building blocks III and IV, respec-
tively, in the same manner. Swern oxidation of (+)-36
and subsequent Wittig reaction of the resulting aldehyde
afforded olefin (-)-43, which was subjected to hydrogena-
tion over Pd(OH)2 followed by acid treatment to give (-)-
prosophylline. 1H and 13C NMR spectra of synthetic
alkaloid were identical with those of the literature.9a
Similarly, the acetonide (-)-26 was transformed to (-)-
(20) Direct inversion of the hydroxyl in 45 under the Mitsunobu
reaction conditions afforded the enamine derivative 46 (eq 1).
This result was a contrast to the Mitsunobu inversion of the 2,3(trans)-
to the 2,3(cis)-piperidinol derivative; see: Lu, Z.-H.; Zhou, W.-S.
Tetrahedron 1993, 49, 4659-4664.
(21) J ung, M. E.; Lyster, M. A. J . Am. Chem. Soc. 1977, 99, 968-
969.

2-Piperidone Type of Chiral Building Block
J . Org. Chem., Vol. 64, No. 13, 1999 4919
prosopinine via the olefin 44 (Scheme 8). 1H and 13C NMR
spectra of synthetic alkaloid were identical with those
of the literature.12
that the stereoisomers of 2,6-disubstituted 3-piperidinol
building blocks can be prepared arbitrarily in an optically
pure state. Furthermore, we achieved the chiral synthesis
of (+)-prosafrinine, (-)-iso-6-cassine, (-)-prosophylline,
and (-)-prosopinine by the present methodology and also
demonstrated that 3-piperidinols (types I-IV) prepared
in this process were powerful chiral building blocks for
the synthesis of the aforementioned alkaloids.
Con clu sion
We have established the diastereodivergent chiral
synthesis of all four diastereomers of 2,6-disubstituted
3-piperidinols (types I-IV) via the 2-piperidone type of
chiral building block (-)-(1), which was readily obtained
by bakers’ yeast reduction of 2 in an optically pure state.
In addition, the enantiomer (+)-1 has also been prepared
by lipase-mediated kinetic resolution of (()-1. This means
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O990397T