Remote Stereocenter Discrimination in the Enzymatic Resolution of Piperidine-2-ethanol. Short Enantioselective Synthesis of Sedamine and Allosedamine

Article abstract of DOI:10.1021/jo035215g

Kinetic resolution of N-Boc-piperidine-2-ethanol (2), a case of remote stereocenter discrimination, was accomplished by sequential transesterification mediated by two enzymes, Lipase PS and porcine pancreatic lipase, showing opposite enantioselectivity. The gram-scale availability of the two enantiomeric N-Boc alcohols 2a (R) and 2c (S) enlarges their synthetic exploitation for the enantioselective preparation of piperidine alkaloids. As an example, the convenient three-step synthesis of both the enantiomers of sedamine and allosedamine is described.

Full text of DOI:10.1021/jo035215g

as a chiral auxiliary7 in a seven-step procedure.3a The
corresponding N-Cbz aldehydes were obtained by inter-
molecular 1,3-dipolar cycloaddition of 2,3,4,5-tetrahydro-
pyridine 1-oxide with a chiral allyl ether followed by a
three-step synthetic elaboration.8
On the contrary, despite the fact that enzymatic kinetic
resolutions of racemates have been widely exploited in
the past years for the preparation of enantiopure syn-
thons,9 to our knowledge a biocatalyzed approach to (R)-
and (S)-1 has never been described.
Rem ote Ster eocen ter Discr im in a tion in th e
En zym a tic Resolu tion of
P ip er id in e-2-eth a n ol. Sh or t
En a n tioselective Syn th esis of Sed a m in e
a n d Allosed a m in e
Marco Angoli,† Alessio Barilli,† Giordano Lesma,†
Daniele Passarella,*,† Sergio Riva,*,‡
Alessandra Silvani,† and Bruno Danieli†
Dipartimento di Chimica Organica e Industriale e Centro
Interdisciplinare Studi Biomolecolari e Applicazioni
Industriali (CISI), Universita` degli Studi di Milano, Via
Venezian 21, 20133 Milano, Italy, and Istituto di Chimica
del Riconoscimento Molecolare, CNR, Via Mario Bianco 9,
20131 Milano, Italy
The amino alcohol 1 is a bifunctional compound and
therefore, desiring to apply an enzymatic methodology
for its resolution, the amine moiety was blocked with a
protective group in order to avoid possible effects related
to enzyme chemoselectivity. Thus, the enantioselective
acylation of the residual primary alcohol by a set of
hydrolases could be investigated in various organic
solvents.10 This was not an easy task even for enzymes,
as we were dealing with a conformationally flexible
primary alcohol located two carbons away from the
molecule stereocenter. Nevertheless, literature reports on
the ability of proteases11 and lipases12 to discriminate
remote stereocenters. More specifically, a paper on the
lipase-catalyzed kinetic resolution of a chromanethanol
(en route to the synthesis of an R-tocopherol analogue)13
prompted us to start a systematic study on the perfor-
mances of a set of commercially available lipases.
The amino group of 1 was protected to give the related
N-Boc (2), N-Cbz (3), and N-Fmoc (4) derivatives (Scheme
1). Methyl tert-butyl ether and vinyl acetate were chosen
as solvent and acylating agent, respectively. Over 20
different lipase preparations were tested by shaking the
reaction mixture at 45 °C, and Table 1 shows the best
results obtained. This preliminary screening pointed out
that enantioselectivity (E) values14 were quite low, as it
might be expected, but also that the crude porcine
pancreatic preparation possessed an opposite enantiose-
lectivity compared to all the other lipases. The N-Boc
derivative 2 was a slightly better substrate, and Lipase
PS was the more selective enzyme among the “(R)-
lipases”.
daniele.passarella@unimi.it; sergio.riva@icrm.cnr.it
Received August 19, 2003
Abstr a ct: Kinetic resolution of N-Boc-piperidine-2-ethanol
(2), a case of remote stereocenter discrimination, was ac-
complished by sequential transesterification mediated by
two enzymes, Lipase PS and porcine pancreatic lipase,
showing opposite enantioselectivity. The gram-scale avail-
ability of the two enantiomeric N-Boc alcohols 2a (R) and
2c (S) enlarges their synthetic exploitation for the enanti-
oselective preparation of piperidine alkaloids. As an ex-
ample, the convenient three-step synthesis of both the
enantiomers of sedamine and allosedamine is described.
Several multistep synthetic procedures describe the
use of racemic1 or enantiopure2,3 piperidine-2-ethanol 1
for the total synthesis of natural products2 and for the
preparation of pharmacologically active compounds.1,3
Continuing our efforts in the total synthesis of piperi-
dine alkaloids, we have recently reported on the elabora-
tion of racemic 1 for the total synthesis of the C15 lupinine
alkaloid aloperine.4 As a logical further step in the
exploitation of this synthon, we became interested in a
convenient method for the production of enantiopure
piperidine-2-ethanol in gram scale. Different synthetic
approaches to the single stereoisomers of 1 are described
in the literature. Initially, the careful diastereoselective
crystallization of the corresponding d-10-camphorsul-
fonate salt has been reported.5 More recently, (S)-1 has
been prepared from the expensive N-Boc-protected (S)-
pipecolic acid by a two-step reaction sequence.6 In turn,
Kibayashi prepared (R)-1 using 2-(1-aminoethyl)phenol
(6) De Vita, R. J .; Goulet, M. T.; Wyvratt, M. J .; Fisher, M. H.; Lo,
J .-L.; Yang, Y. T.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett.
1999, 9, 2621.
(7) (a) Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett. 1999,
40, 739. (b) Yamazaki, N.; Ito, T.; Kibayashi, C. Org. Lett. 2000, 2,
465.
(8) Ito, M.; Maeda, M.; Kibayashi, C. Tetrahedron Lett. 1992, 33,
3765.
(9) (a) Koeller, K. M.; Wong C.-H. Nature 2001, 409, 232-. (b) Carrea,
G.; Riva, S. Angew. Chem., Int. Ed. 2000, 39, 2226. (c) Pogorevc, M.;
Faber, K. J . Mol. Catal. B: Enzym. 2000, 10, 357. (d) Santaniello, E.;
Ferraboschi, P. Grisenti, P., Manzocchi, A. Chem. Rev. 1992, 92, 1071.
(10) Klibanov, A. M. Nature 2000, 409, 241.
† Universita` degli Studi di Milano.
‡ Istituto di Chimica del Riconoscimento Molecolare.
(1) Montgomery, J .; Qi, X. J . Org. Chem. 1999, 64, 9310.
(2) (a) Danilewicz, J . C.; Abel, S. M.; Brown, A. D.; Fish, P. V.;
Hawkeswood, E.; Holland, S. J .; J ames, K.; McElroy, A. B.; Overington,
J .; Powling, M. J .; Rance, D. J . J . Med. Chem. 2002, 45, 2432. (b) De
Vita, R. J .; Goulet, M. T.; Wyvratt, M. J .; Fisher, M. H.; Lo, J .-L.; Yang,
Y. T.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. 1999, 2621.
(3) (a) Yamazaki, N.; Dokoshi, W.; Kibayashi, C. Org. Lett. 2001, 3,
193. (b) Morley, C.; Knight, D. W.; Share, A. C. J . Chem. Soc., Perkin
Trans. 1 1994, 2903. (c) Reference 1d.
(11) (a) Lee, T.; J ones, J . B. J . Am. Chem. Soc. 1997, 119, 10260.
(b) Lee, T.; J ones, J . B. J . Am. Chem. Soc. 1996, 118, 502.
(12) (a) Hedenstrom, E.; Nguyen, B.-V.; Silks, L. A. Tetrahedron:
Asymmetry 2002, 13, 835. (b) Fadnavis, N. W.; Koteshwar, K. Tetra-
hedron: Asymmetry 1997, 8, 337. (c) Lovey, R. G.; Saksena, A. K.
Girljavallabhan, V. M. Tetrahedron Lett. 1994, 35, 6047. (d) Hughes,
D. L.; Bergan, J . J .; Amato, J . S.; Bhuphaty, J . L.; Leazer, J . L.;
McNamara, J . M.; Sidler, D. R.; Reidere, P. J .; Grabowski, E. J . J . J .
Org. Chem. 1990, 55, 6252.
(4) Passarella, D.; Angoli, M.; Giardini, A.; Lesma, G.; Silvani, A.;
Danieli, B. Org. Lett. 2002, 4, 2925.
(5) Toy, M. S.; Price, C. C. J . Am. Chem. Soc. 1960, 82, 3.
(13) Mizuguchi, E.; Suzuki, T.; Achiwa, K. Synlett 1994, 929.
(14) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294.
10.1021/jo035215g CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/07/2003
J . Org. Chem. 2003, 68, 9525-9527
9525

SCHEME 1
SCHEME 2 a
TABLE 1. Eva lu a tion of Lip a se En a n tioselectivity in
th e Acetyla tion of Su bstr a tes 2, 3, a n d 4a
E valuese
preferred
lipase
enantiomer
2
3
4
pancreatic lipaseb
Lipase PSc
S
6.0
5.3
2.6
2.1
1.5
1.4
1.2
1.1
1.1
3.6
2.6
2.2
1.3
1.5
1.6
1.8
1.6
1.0
4.4
6.4
2.5
4.2
2.6
1.6
2.9
1.1
1.4
R
R
R
R
R
R
R
R
Lipase Rc
Lipozymed
Lipase Gc
Candida rugosa lipaseb
Novozyme 435d
Lipase F-AP 15c
Lipase CE-5c
a
b
E ) ln[1 - c(1 + eeP)]/ln[1 - c(1 - eeP)]. Sigma. c Amano.
Novozymes. e The enantiomeric excesses (eeP) and the ratios of
d
conversion (c) were evaluated by HPLC analysis (Chiralcel OD).
It is well-known that the reaction medium can signifi-
cantly effect the enzymatic performances (activity and
selectivity).15 Accordingly, the E values of the acetylation
reactions catalyzed by Lipase PS and porcine pancreatic
lipase were evaluted in different solvents. It was found
that hexane was a slightly better solvent for Lipase PS
(E ) 8.1) (see the Supporting Information), while methyl
tert-butyl ether remained the solvent of choice for the
pancreatic enzyme. In fact, by changing the reaction
medium, small improvements in terms of selectivity were
accompanied by significant decreases of the activity of
this lipase.
In spite of the low E values of the two enzymes, the
observed complementary enantioselectivity was the basis
of an optimized protocol for the preparation of the
enantiomers 2a (R) and 2c (S) (Scheme 2). Racemic 2
was dissolved in hexane and acetylated by Lipase PS to
give 2b with 63% ee at 45% conversion. The enzyme was
filtered, the solvent and the unreacted vinyl acetate were
evaporated, and the crude mixture was dissolved in
methyl tert-butyl ether. The residual alcohol, enriched
in the (S)-enantiomer, was butanoylated by the pancre-
atic lipases to give the corresponding ester with 85% ee.
The crude reaction mixturescontaining the acetate 2b,
the butanoate 2e, and the unreacted almost racemic 2
(2a + 2c)s was easily purified by flash chromatography.
Compounds 2b and 2e were chemically hydrolyzed to
the corresponding enriched alcohols (2a and 2c, respec-
tively) and submitted to a second round of acetylation
with the respective enzymes. In this way, the low
selectivity of the two lipases was enhanced, and the two
enantiomers 2a and 2c could be isolated in 90 and 95%
ee, respectively.16
a
Reagents and conditions: (a) AcOCHdCH2, hexane, 20 °C, 190
min (45%); (b) PrCOOCHdCH2, MTBE, 20 °C, 11.5 h (30%), flash
chromatography (AcOEt-hexane 1:9); (c) CH3OH, Na2CO3; (d)
AcOCHdCH2, MTBE, 20 °C, 46 h (48%).
Having the enantiomeric enriched compounds 2a and
2c in hand, we started to explore new approaches to
optically active piperidine alkaloids bearing a stereogenic
carbon at the C-2 position.17 As a first example, we faced
the stereoselective preparation of sedamine (8 and 13)
and allosedamine (9 and 14).18 Both levorotatory sedamine
(8) and its dextrorotatory enantiomer (13) were found in
a number of Sedum species.19 (-)-Allosedamine (9) has
been isolated from Lobelia inflata,20 which furnished a
crude extract useful for the treatment of respiratory
illnesses such as asthma, bronchitis, and pneumonia.21
Numerous syntheses of sedamine, either in racemic
form22 or as a single enantiomer,23 have been reported,
(17) For
a general review about the asymmetric synthesis of
substituted piperidines, see: Bailey, P. D.; Millwood, P. A.; Smith, P.
D. Chem. Commun. 1998, 633.
(18) For a recent review about the syntheses of sedum and related
alkaloids, see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
(19) (a) Marion, L.; Lavigne, R.; Lemay, L. Can. J . Chem. 1951, 29,
347. (b) Franck, B. Chem. Ber. 1958, 91, 2803. (c) Logar, S.; Mesicek,
M.; Perpar, M.; Seles, E. Farm. Vestn. 1974, 21; Chem. Abstr. 1975,
82, 82916h. (d) Krasnov, E. A.; Petrova, L. V.; Bekker, E. F. Khim.
Prir. Soedin. 1977, 585; Chem. Abstr. 1977, 87, 164249k.
(20) Schopf, C.; Kauffmann, T.; Berth, P.; Bundschuh, W.; Dummer,
G.; Fett, H.; Habermehl, G.; Wieters, E.; Wust, W. Liebigs. Ann. Chem.
1957, 608, 88.
(21) Gershwin, M. E.; Terr, A. Clin. Rev. Allergy Immunol. 1996,
14, 241.
(22) Synthesis of (()-sedamine: (a) Tufariello, J . J .; Ali, S. A.
Tetrahedron Lett. 1978, 47, 4647. (b) Shono T.; Matsumura, Y.;
Tsubata, K. J . Am. Chem. Soc. 1981, 103, 1172. (c) Hootele’, C.;
Ibebeke-Bomangwa, W.; Driessens, F.; Sabil, S. Bull. Soc. Chim. Belg.
1987, 96, 57. (d) Tirel, P. J .; Vaultier, M.; Carrie, R. Tetrahedron Lett.
1989, 30, 1947-1950 (e) Driessens, F.; Hootele’, C. Can. J . Chem. 1991,
69, 211. (f) Ozawa, N.; Nakajima, S.; Zaoya, K.; Hamaguchi, F.;
Nagasaka, T. Heterocycles 1991, 32, 889-894. (g) Pilli, R. A.; Dias, L.
C. Synth. Commun. 1991, 21 2213. (h) Ghiaci, M.; Adibi, M. Org. Prep.
Proced. Int. 1996, 28, 474.
(15) (a) Carrea, G.; Ottolina, G.; Riva, S. Trends Biotechnol. 1995,
13, 63. (b) Wescott, C. R.; Klibanov, A. M. Biochim. Biophys. Acta 1994,
1206, 1.
(16) This protocol was highly reproducible and easily scaled-up:
approximately 2.5 g of 2a and 1.8 g of 2c were produced from 10 g of
racemic 2.
9526 J . Org. Chem., Vol. 68, No. 24, 2003

SCHEME 3 a
SCHEME 4
tion of 2c to give a stable compound in 80% yield ([R]20
D
) -50.6, c ) 0.85, CHCl3). The subsequent stepsthe
introduction of the phenyl group with the generation of
the hydroxyl functionswas made possible by reaction
with phenylmagnesium bromide in THF at -20 °C. A
quantitative conversion to a 2:3 mixture of compounds 6
and 7 was obtained after 3 h. The structural assignments
of the absolute configuration of the alcohols could not be
assessed a priori and ultimately rested with their conver-
sion into sedamine and allosedamine. The enantiomeric
excess of compounds 6 and 7 (95%), evaluated by HPLC
analysis (Chiralcel OD), was in accord with that of the
corresponding starting material.
a
Reagents and conditions: (a) (COCl)2, DMSO, Et3N; (b)
PhMgBr, THF, -20 °C; (c) LiAlH4, THF, reflux.
After separation of 6 and 7 by column chromatography,
reduction of the Boc group with LiAlH4 in refluxing THF
for 6 h gave (-)-sedamine (8, 70% yield, ee 95%) and (-)-
allosedamine (9, 71% yield, ee 95%), respectively. Analo-
while the synthesis of allosedamine received minor
attention.24 To the best of our knowledge, allosedamine
has been prepared only as the (-)-enantiomer 9.25 The
reported stereoselective syntheses of sedamine, al-
losedamine and related alkaloids were based on elabo-
rated construction of the piperidine ring or on the
introduction of the chain at the C-2 piperidine carbon,
obtaining interesting results by applying noteworthy
chemical procedures.
gously (Scheme 4), the aldehyde 10 ([R]20 ) 48, c ) 1,
D
CHCl3) was obtained by Swern oxidation of 2a . In turn,
the reaction with phenylmagnesium bromide gave the
quantitative conversion to a 2:3 mixture of compounds
11 and 12. Reduction of the Boc group gave (+)-sedamine
(13) from (+)-11 and (+)-allosedamine (13) from (+)-12,
both showing 90% ee.
In our plan, compounds 2a and 2c represented an
attractive and convenient starting material offering the
opportunity to introduce diverse appendages at C-8 while
retaining the configuration at the stereogenic C-2. Specif-
ically, we envisaged the corresponding aldehyde 526
(Scheme 3) and its enantiomer 10 as the appropriate
synthons for the target- and diversity-oriented synthe-
sis.27 The preparation of 5 was secured by Swern oxida-
In conclusion, we have demonstrated that the enzy-
matic resolution of N-Boc-piperidine-2-ethanol could be
accomplished by the sequential use of Lipase PS and
porcine pancreatic lipase exploiting their opposite enan-
tioselectivity. The gram scale availability of the two
enantiomers 2a and 2c enlarges their synthetic applica-
tion, as these chiral building blocks are expected to
provide general access to enantiopure piperidine alka-
loids. The corresponding aldehydes 5 and 10 are also
suitable synthons for diversity-oriented synthesis, and
their requisite configurational stability has been dem-
onstrated in the enantioselective synthesis of both the
enantiomers of sedamine and allosedamine. Incidentally,
the present report describes the first enantioselective
synthesis of (+)-allosedamine (14).
(23) Synthesis of (+)- and (-)-sedamine: (a) Beyerman, H. C.;
Eveleens, W.; Muller, Y. M. F. Recl. Trav. Chim. Pays-Bas 1956, 75,
63. (b) Beyerman, H. C.; Eenshuistra, J .; Eveleens, W.; Zweistra, A.
Recl. Trav. Chim. Pays-Bas 1959, 78, 43. (c) Schopf, C.; Dummer. G.;
Wust, W. Liebigs Ann. Chem. 1959, 626, 134. (d) Wakabayashi, T.;
Watanabe, K.; Kato, Y.; Saito, M. Chem. Lett. 1977, 223. (e) Irie, K.;
Aoe, K.; Tanaka, T.; Saito, S. J . Chem. Soc., Chem. Commun. 1985,
633. (f) Wanner, K. T.; Kartner, A. Heterocycles 1987, 26, 921. (g)
Wanner, K. T.; Kartner, A. Arch. Pharm. 1987, 320, 1253. (h) Pyne, S.
G.; Bloem, P.; Chapman, S. L.; Dixon, C. E.; Griffith, R. J . Org. Chem.
1990, 55, 1086. (i) Kiguchi, T.; Nakazono, Y.; Kotera, S.; Ninomiya, I.;
Naito, T. Heterocycles 1990, 31, 1525. (j) Comins, D. L.; Hong, H. J .
Org. Chem. 1993, 58, 5035. (k) Poerwono, H.; Higashiyama, K.;
Takahashi, H. Heterocycles 1998, 47, 263. (l) Yu, C.-Y.; Meth-Cohn,
O. Tetrahedron Lett. 1999, 40, 6665. (n) Meth-Cohn, O.; Yau, C. C.;
Yu, C.-Y. J . Heterocycl. Chem. 1999, 36, 1549. (o) Cossy, J .; Willis, C.;
Bellosta, V.; Bouzbouz, S. Synlett 2000, 1461. (p) Cossy, J .; Willis, C.;
Bellosta, V.; Bouzbouz, S. J . Org. Chem. 2002, 67, 1982. (q) Felpin,
F.-X.; Lebreton, J . J . Org. Chem. 2002, 67, 9192.
Ack n ow led gm en t. The authors express their grati-
tude to Francesca Belinghieri for her precious collabora-
tion in the collection of the preliminary results regarding
the synthesis of sedamine and allosedamine. Financial
support by Ministero dell’Istruzione dell’Universita` e
della Ricerca (Italy) is gratefully acknowledged. The
work was also partially supported by DGICYT, Spain
(BQU2000-0651).
(24) Synthesis of (()-allosedamine: (a) Ozawa, N.; Nakajima, K.;
Zaoya, K.; Hamaguchi, F.; Nagasaka, T. Heterocycles 1991, 32, 989.
(b) Liguori, A.; Ottana, R.; Romeo, G.; Sindona, S.; Uccella, N. Chem.
Ber. 1989, 12, 2089 and references therein.
(25) Synthesis of (-)-allosedamine: (a) Felpin, F.-X.; Lebreton, J .
Tetrahedron Lett. 2002, 43, 225. (b) Oppolzer, W.; Deeberg, J .; Tamura,
O. Helv. Chim. Acta 1994, 77, 554.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and characterization for all new compounds. H and
13C NMR spectra for compounds. Tables regarding the medium
engineering for the pancreatic lipase- and Lipase PS-mediated
acylation of 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
(26) We previously used the racemic aldehyde for the introduction
of the ethynyl fragment by reaction with Grignard reagent to achieve
the total synthesis of (()-aloperine (see ref 4).
(27) Schreiber, S. L. Science 2000, 287, 1964.
J O035215G
J . Org. Chem, Vol. 68, No. 24, 2003 9527