Diastereoselective total synthesis of 3,6-disubstituted piperidine alkaloids, (3R,6S)-epi-pseudoconhydrine and (3R,6R)-pseudoconhydrine in memory of Dr. K. Anji Reddy, the founder of Dr. Reddy's Laboratories Ltd.

Article abstract of DOI:10.1016/j.tetlet.2013.03.051

Diastereoselective total synthesis of 3,6-disubstituted piperidine alkaloids, epi-pseudoconhydrine (1) and pseudoconhydrine (2) has been developed starting from enantiopure (S)-epichlorohydrin. The key steps in the synthesis of these alkaloids involved α-aminobutyrolactone ring opening with N,O-dimethyhydroxyl amine followed by a Grignard reaction and cascade debenzylation-reductive aminative cyclization under hydrogenation conditions. High de was obtained in the synthesis of epi-pseudoconhydrine (1).

Full text of DOI:10.1016/j.tetlet.2013.03.051

Tetrahedron Letters 54 (2013) 2909–2912
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective total synthesis of 3,6-disubstituted piperidine alkaloids,
(3R,6S)-epi-pseudoconhydrine and (3R,6R)-pseudoconhydrine
Sandip R. Khobare a,b, Vikas S. Gajare a, Subbarao Jammula a, U. K. Syam Kumar a, , Y. L. N. Murthy b
⇑
a Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India
b Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Diastereoselective total synthesis of 3,6-disubstituted piperidine alkaloids, epi-pseudoconhydrine (1) and
pseudoconhydrine (2) has been developed starting from enantiopure (S)-epichlorohydrin. The key steps
in the synthesis of these alkaloids involved a-aminobutyrolactone ring opening with N,O-dimethyhydr-
oxyl amine followed by a Grignard reaction and cascade debenzylation-reductive aminative cyclization
under hydrogenation conditions. High de was obtained in the synthesis of epi-pseudoconhydrine (1).
Ó 2013 Elsevier Ltd. All rights reserved.
Received 1 December 2012
Revised 8 March 2013
Accepted 12 March 2013
Available online 28 March 2013
In memory of Dr. K. Anji Reddy, the founder
of Dr. Reddy’s Laboratories Ltd.
Keywords:
Alkaloids
epi-Pseudoconhydrine
Pseudoconhydrine
Diastereoselective
Weinreb amide
Grignard reaction
Development of new synthetic methodologies for the enantiose-
lectiveanddiastereoselective synthesisoffunctionalizedchiralpiper-
idines has achieved significant importance in the recent past, because
oftheirwidespreadpresenceinseveralbiologically active natural and
unnatural products.1 Cassine (3),2 spectaline (4),3 deoxocassine (5),
azimic acid (6), carpamic acid (7), 5-hydroxy sedamine (8), and pros-
opinine (9) are few of the biologically active piperidine based natural
products(Fig. 1) with varied biologicalactivities. Thesesix membered
nitrogen heterocyclic natural products exhibit antibiotic and anes-
thetic properties.4 Pseudoconhydrine (2) is one of the difunctional-
ized piperidine based alkaloids, isolated from poison Hemlock,
OH
OH
OH
OH
N
H
1
N
H
2
H3C
H3C
OH
R
N
H
Ph
N
CH3
8
Conium maculatum L.,5 along with coniine, N-methylconiine,
c-con-
3: R= (CH2)10COCH3
4: R =(CH2)12COCH3
5: R =(CH2)11CH3
6: R =(CH2)5COOH
7: R =(CH2)7COOH
OH
iceine, and conhydrine. The (ꢀ) pseudoconhydrine (2) is (3R,6R)-6-
propylpiperidin-3-ol with trans stereochemical relationship between
the substituents on a piperidine frame work, whereas (+)-epi-pseud-
oconhydrine (1) has a cis (3R,6S) stereochemical relationship. Similar
toepi-pseudoconhydrine(1),cisstereochemicalrelationshipbetween
3,6-disubstitution on piperidine ring has also been found in a number
of natural products such as 5-hydroxy sedamine (8), azimic acid (6),
carpamic acid (7), and cassine (3).6
O
OH
H3C
N
H
9
9
Figure 1. Natural products containing piperdin-3-ol framework.
thesis of challenging cis isomer, that is, epi-pseudoconhydrine (1)
has limited precedence in the literature.8 The racemic pseud-
oconhydrine synthesis is reported way back in 1949 by Leo Marion
and W. F. Cockburn et al. starting from appropriately substituted
pyridine derivative.9 Diastereoselective synthesis of pseudoconhy-
drine is developed from homochiral N-alkenylurethane7b and also
from N-Boc-2-acyloxazolidines.7k The ring expansion strategy of
Though thermodynamically favored 3,6-trans-diastereoselec-
tive synthesis of pseudoconhydrine (2) is well reported,7 the syn-
⇑
Corresponding author. Fax: +91 40 23045439.
E-mail address: syam_kmr@yahoo.com (U.K. Syam Kumar).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.051

2910
S. R. Khobare et al. / Tetrahedron Letters 54 (2013) 2909–2912
appropriately substituted dihydrofuranone derivatives has been
utilized in the synthesis of pseudoconhydrine and epi-pseud-
oconhydrine.8b Harrity and co-workers reported the cycloaddition
reaction of substituted aziridines with Pd–trimethylenemethane
complexes for the synthesis of pseudoconhydrine.10 Other note-
worthy syntheses of pseudoconhydrine and epi-pseudoconhydrine
includes tandem hydroformylation–condensation reaction,7t ring
expansion of the substituted proline derivatives7h, and also the
metal-free regioselective aminotrifluoroacetoxylation of alkenes.11
Most of these epi-pseudoconhydrine (1) and pseudoconhydrine
(2) syntheses gave the product in high yields and de and in some
cases with high ee, the use of complex reagents, and unstable inter-
mediates makes some of these syntheses quite difficult to perform
on higher scales. Some of these reported syntheses although began
with chirally pure starting materials, the final products were iso-
lated as diastereomeric mixtures.
O
b
a
N
H
N
10
O
12
O
O
O
Bn
d
Bn
c
N
N
Bn
Bn
COOEt
14
15
CH3
N
HO
HO
Bn
Bn
e
As part of our continued efforts to develop new methodologies
for the synthesis of biologically active natural and unnatural prod-
ucts,12 herein we report our successful efforts toward the total syn-
thesis of (+)-epi-pseudoconhydrine (1) and (ꢀ)-pseudoconhydrine
(2) starting with enantiomerically pure (S)-epichlorohydrin. The
retrosynthetic analysis of pseudoconhydrine (2) is provided in
CH3
N
N
OMe
Bn
Bn
O
O
17
16
CH3
HO
Bn
N
CH3
Scheme 1. Pseudoconhydrine (2) could be obtained from chiral
hydroxyketone 17 by a cascade debenzylation-stereocontrolled
reductive amination process. The ring opening of chiral -amin-
obutyrolactone 15 with N,O-dimethylhydroxylamine followed by
Grignard reaction would provide a direct access to -hydroxyke-
tone 17. Chiral -aminobutyrolactone 15 in turn could be obtained
from dihydrofuranone-3-carboxylate (14) formed by the reaction
of -aminoepoxide (12) and diethyl malonate (13).
c-
Bn
OH
a
18
Scheme 2. (a) S-Epichlorohydrin (11), NaOH, 65–70 °C, 95% (b) Na, EtOH, Diethyl
malonate (13), RT (c) LiCl, DMSO, 120–130 °C (d) HCl.HN(OMe)Me, i-PrMgCl, THF,
ꢀ5 °C (e) n-PrMgBr, THF, 0–10 °C.
c
a
a
We initiated the synthesis of (ꢀ)-pseudoconhydrine (2) from
magnesium chloride, which was then used for the ring opening
of 15 and the corresponding Weinreb amide 16 was isolated in
75% yield.14 The Weinreb amide 16 was then reacted with excess
n-propyl magnesium bromide and the product c-hydroxyl ketone
17 was obtained in 70% yield after column chromatographic
enantiomerically pure (S)-epichlorohydrin 11, and dibenzylamine
10. Thus dibenzylamine 10 was reacted with (S)-epichlorohydrin
11 in the presence of sodium hydroxide at 65–70 °C under neat
reaction conditions and the required product
a-aminoepoxide
12 was isolated in 95% yield with SOR, +6.5°. The oxirane ring
in 12 was opened with diethyl malonate 13 in THF, in the pres-
ence of freshly prepared sodium ethoxide to yield (5R)-ethyl 5-
((dibenzylamino)methyl)-2-oxotetrahydrofuran-3-carboxylate 14,
which was then subjected to in situ hydrolysis and decarboxyl-
ation under Krapcho conditions.13 The product (R)-5-((dibenzyla-
mino)methyl)dihydrofuran-2(3H)-one 15 was isolated in 51% of
purifications.
A one pot three-step cascade reaction which involves debenzy-
lation, cyclization, and reductive amination was then investigated
on 17 to get the required natural product 2.15 Thus
c-hydroxy ke-
tone 17 was subjected for hydrogenation reaction with 10% Pd/C in
ethanol at room temperature under 30 psi hydrogen pressure
(Scheme 3). The debenzylation, concomitant reductive amination
reaction on 17 resulted the epi-pseudoconhydrine (1) and pseud-
oconhydrine (2), in 1.7:1 cis:trans diastereoselectivity. Our subse-
quent efforts to improve the diastereoselectivity during the
reductive amination reaction under these conditions were not
successful.
overall yield. Though ring opening of
a-aminobutyrolactone 15
with n-propyl magnesium bromide was attempted, the reaction
did not yield the expected product (R)-8-(dibenzylamino)-7-
hydroxyoctan-4-one (17), and unwanted tertiary alcohol 18 was
isolated as the major product (Scheme 2). Thus to synthesis
c-
hydroxyketone 17, a stepwise approach was explored. The mag-
nesium N,O-dimethylhydroxylamine was generated from Me(M-
eO)NH under Bodrouxs reaction conditions using isopropyl
HO
Bn
N
OH
CH3
a
Bn
HO
OH
Bn
N
O
H3C
H3C
N
CH3
19
17
Bn
N
H
H3C
O
OH
OH
17
N
b,c
2
N
H3C
N
H
20
OH
OMe
N
Bn
N
Cbz
Bn
O
21
O
CH3
Bn
Bn
d
O
16
15
OH
OH
H3C
OH
d
O
EtOOC
Bn
O
H3C
N
H3C
N
H
N
H
Bn
N
N
Bn
O
Cbz
Bn
12
EtOOC
13
22
1
2
COOEt
14
Scheme 3. (a) 10% Pd/C, EtOH, RT (b) CbzCl, Na2CO3, THF–H2O, RT (c) Separation by
Scheme 1. Retrosynthesis.
column chromatography (d) 10% Pd/C, EtOH.

S. R. Khobare et al. / Tetrahedron Letters 54 (2013) 2909–2912
2911
Our efforts toward the separation of the diastereomers (20) by
crystallization or by column chromatography were not successful,
and thus decided to separate these diastereomers by protection–
deprotection protocols. The N-Cbz protection was performed on
the diastereomeric pair (20)7j and individual N-Cbz protected
piperidines 21 and 22 were separated by column chromatography.
N-Cbz deprotection16 was then carried on 21 and 22 to yield the
pseudoconhydrine (2) and epi-pseudoconhydrine (1). The epi-
pseudoconhydrine (1)19, and (ꢀ)-pseudoconhydrine (2)17, thus ob-
tained were confirmed by spectral and analytical data and found to
be identical with the reported literature values. [(ꢀ)-Pseudoconhy-
drine (2): mp 184.48 °C (water); lit.7t mp 185–185.5 °C], specific
H H
H
N
Pd/C/ H2
OTBDMS
O
CH3
CH3
CH3
N
Si
cis product
25
H3C
H3C
H3C
24
H3C
H3C
H
N
Pd/C/ H2
trans product
O
CH3
OTBDMS
N
Si
CH3
CH3
H3C
H3C
H3C
H3C
26
H
H
24
H
N
H3C
OH
Pd/C/ H2
OH
N
optical rotation, ½a D25
ꢁ
= ꢀ5.5° {c 0.26, EtOH (free base)}; lit.7h
diastereoisomeric
mixture
a 2D5
ꢁ
= ꢀ6° (c 1.05, MeOH, HCl salt), lit.,10
½
a 2D5
ꢁ
= ꢀ11.4° (c 0.99,
20
19
½
CH2Cl2, free base). {epi-Pseudoconhydrine (1) ½a D25
ꢁ
= +9.4° (c 1.0,
MeOH, HCl salt)}; lit.7b, ½a D25
ꢁ
= +9.24°, MeOH. {lit. data for the (ꢀ)
Figure 2. Plausible mechanism for stereoselectivity.
enantiomer,7r
½
a 2D5
ꢁ
= ꢀ11.1° (c 1.0, EtOH)}.
To increase the diastereoselectivity during the hydrogenation
reaction, which involves debenzylation and reductive aminative
cyclization, we decided to protect the –OH group in c-hydroxyke-
In summary, a highly diastereoselective synthesis of (3R,6S)-
epi-pseudoconhydrine (1) and (3R,6R)-pseudoconhydrine (2) has
been developed, with good yields. The three-step cascade reaction
involving debenzylation, cyclization, and reductive amination was
performed in a one pot process. The stereochemical outcome of the
hydrogenation reaction can be rationalized by the steric bulkiness
of the protecting groups. The developed routes for these alkaloids
utilize fairly inexpensive reagents, and an operational friendly pro-
cess. This strategy opens a new way for the enantioselective con-
struction of disubstituted and polysubstituted piperidine
tone 17 with a bulky protecting group (Scheme 4). The hydroxyl
group in 17 was protected with TBDMS using TBDMSCl/imidazole
in the presence of a catalytic amount of DMAP and the product 23
was isolated in 82% yield as viscous liquid. The cascade debenzyla-
tion-reductive aminative cyclization on 23 with 10% Pd/C under
hydrogenation conditions yielded a mixture of TBDMS protected
epi-pseudoconhydrine 25, and TBDMS protected pseudoconhy-
drine 26 in 9:1 diastereomeric ratio in 91% yield. The deprotection
of TBDMS group in 25 and 2618 and further purification by column
chromatography afforded (+)-epi-pseudoconhydrine (1) as a single
diastereomer in 76% yield. The spectral data19 of our synthetic (+)-
epi-pseudoconhydrine (1) are in accordance with the reported
values.7b
alkaloids in good yield and highlights the usefulness of
a-amin-
obutyrolactones in asymmetric synthesis. The application of this
methodology for the synthesis of other biologically active complex
piperidine alkaloids is currently underway.
The diastereoselectivity in the cascade debenzylation-reductive
aminative cyclization is probably due to the increased steric bulk-
iness of O-TBDMS group, which directs the hydrogenation from its
anti phase as shown in Fig. 2. The hydrogenation of imine in 24 will
occur from less hindered b-face, and yields cis (3R,6S) isomer 25 as
the major distereomer,20 whereas the hydrogenation from the
same face of bulky O-TBDMS group results the trans (3R,6R) isomer
26 as the minor isomer. The unprotected –OH group in 19 does not
have the ability to direct the imine hydrogenation under these con-
ditions, hence resulted in poor diastereoselectivity in pseud-
oconhydrine synthesis.
Acknowledgments
The authors would like to thank Dr. Vilas Dahanukar of Dr. Red-
dy’s Laboratories for useful discussions. We also thank the Analyt-
ical Department, Dr. Reddy’s Laboratories, for providing the
analytical support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
051.
References and notes
HO
Bn OTBDMS
N
Bn
N
CH3
1. (a) Strunzand, G. M.; Finlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic Press:
San Diego, 1986; Vol. 26, p 89; (b) Jones, T. H.; Blum, M. S.; Robertson, H. G. J.
Nat. Prod. 1990, 53, 429; (c) Davies, F. A.; Santhanaram, M. J. Org. Chem. 2006,
71, 4222; (d) Voituriez, A.; Ferreira, F.; Perez-Luna, A.; Chemla, F. Org. Lett.
2007, 9, 4705.
CH3
a
Bn
Bn
O
O
17
23
2. (a) Christofidis, I.; Welter, A.; Jadot, J. Tetrahedron 1977, 33, 977; (b) Hasseberg,
H.-A.; Gerlach, H. Liebigs Ann. Chem. 1989, 255.
OTBDMS
OTBDMS
b
3. (a) Rice, W. Y.; Coke, J. L. J. Org. Chem. 1966, 31, 1010; (b) Highet, R. J. J. Org.
Chem. 1964, 29, 471; (c) Highet, R. J.; Highet, P. F. J. Org. Chem. 1966, 31, 1275;
(d) Hill, R. K. In Chemistry of the Alkaloids; Pelletier, S. W., Ed.; New York, 1970;
p 385.; (e) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T. J. Org. Chem. 1999,
64, 4914.
N
H
25
H3C
H3C
N
24
4. Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull. Soc. Chim. Belg. 1972,
81, 425.
5. Ladenburg, A.; Adam, G. Chem Ber. 1891, 24, 1671.
OTBDMS
OH
c
6. For a recent review of piperidine natural product synthesis, see: Koulocheri, S.
D.; Pitsinos, E. N.; Haroutounian, S. A. Curr. Org. Synth. 2008, 12, 1454.
7. For recent syntheses of pseudoconhydrine, see: (a) Plehiers, M.; Hootelé, C.
Tetrahedron Lett. 1993, 34, 7569; (b) Takahata, H.; Inose, K.; Momose, T.
Heterocycles 1994, 38, 269; (c) Oppolzer, W.; Bochet, C. G. Tetrahedron Lett.
1995, 36, 2959; (d) Sakagami, H.; Kamikubo, T.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1996, 1433; (e) Fry, D. F.; Brown, M.; McDonald, J. C.; Dieter, R.
K. Tetrahedron Lett. 1996, 37, 6227; (f) Plehiers, M.; Hootelé, C. Can. J. Chem.
N
H
26
H3C
N
H3C
H
1
(3 ,6S)-6-propylpiperidin-3-ol
R
Scheme 4. (a) TBDMSCl, imidazole, DMAP, DCM (b) 10% Pd/C, EtOH (c) EtOH,
IPA.HCl.

2912
S. R. Khobare et al. / Tetrahedron Letters 54 (2013) 2909–2912
1996, 74, 2444; (g) Hirai, Y.; Shibuya, K.; Fukuda, Y.; Yokoyama, H.; Yamaguchi,
removed by extraction with DCM) the aqueous layer was concentrated
completely under vacuum to afford crystalline pseudoconhydrine
hydrochloride salt which was further recrystallized from MeOH–ether (1:10)
to give a crystalline title compound (0.6 g, 85%). For determining the SOR, free
base was generated as follows. Treatment of the salt with 2 M NaOH (1 ml) and
extraction with ether (3 ꢂ 1.5 ml) followed by concentration of ether layer
afforded the product as a solid, which was used for comparing the SOR.
S. Chem. Lett. 1997, 221; (h) Cossy, J.; Dumas, C.; Pardo, D. G. Synlett 1997, 905;
(i) Dockner, M.; Sasaki, N. A.; Riche, C.; Potier, P. Liebigs Ann. Recl. 1997, 1267;
(j) Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. J. Org. Chem. 1997, 62, 746; (k)
Agami, C.; Couty, F.; Lam, H.; Mathieu, H. Tetrahedron 1998, 54, 8783; (l)
Löfstedt, J.; Pettersson-Fasth, H.; Bäckvall, J.-E. Tetrahedron 2000, 56, 2225–
2230; For syntheses of N-methylpseudoconhydrine, see: (m) Shono, T.;
Matsumura, M.; Onomura, O.; Sato, M. J. Org. Chem. 1988, 53, 4118; (n)
Herdeis, C.; Held, W. A.; Kirfel, A.; Schwabenlander, F. Liebigs Ann. 1995, 1295;
(o) Bartels, M.; Zapico, J.; Gallagher, T. Synlett 2004, 2636; (p) Gang, L.; Jie, M.;
Chen-Guo, F.; Pei-Qiang, H. Tetrahedron: Asymmetry 2008, 19, 1297; (q)
Marloes, W.; Floris, L. Delft; Floris, R. Tetrahedron 2010, 66, 5623; (r)
Gandham, S.; Suneel, K.; Shinde, B.; Das, B. Tetrahedron: Asymmetry 2011, 22,
1000; (s) Helena, L.; Forrest, M. J. Am. Chem. Soc. 2010, 132, 1249; (t) Roderick,
B.; Sivarajan, K.; Straub, B. J. Org. Chem. 2011, 76, 6844.
17. Spectral data of (2):Yield: 0.6 g, 84.6%; mp: 184.48 °C, HCl salt, ½a D20
= ꢀ5.5° (c
ꢁ
0.26, EtOH, free base) lit.7h
½
a 2D0
ꢁ
= ꢀ6° (c 1.05, MeOH, HCl salt), lit.10
½ ꢁ = ꢀ11.4° (c 0.99, CH2Cl2, free base).; IR 3378, 2965, 2941, 2801, 1610,
a 2D0
1433, 1104, 1075; 1HNMR (400 MHz, D2O) d 3.89 (m, 1H), 3.40 (dd, J = 3.4 &
12.2 Hz, 1H), 3.12 (m, 1H), 2.74 (t, J = 11.2 Hz, 1H), 2.08–2.1 (m, 2H) 1.3–1.63
(m, 6H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (400 MHz, D2O) d 66.531, 58.594, 50.9,
36.9, 32.9, 28.7, 20.9, 15.7; HRMS calcd m/z for C8H18NO+H: 144.1381, found:
144.1388.
8. (a) For syntheses of 3-epi-pseudoconhydrine see: Ref. 7b.; (b) Herdeis, C.;
Schiffer, T. Synthesis 1997, 1405; (c) Ref. 7g.; (d) Ref. 7l.; (e) Ref. 7p.; (f) Ref. 7t.
9. Marion, L.; Cockburn, W. F. J. Am. Chem. Soc. 1949, 71, 3402.
10. Hedley, S. J.; Wesley, J.; Alexander, H.; David, A.; Harrity, J. P. A. Synlett 2001,
1596.
18. 3R,6S)-6-Propylpiperidin-3-ol hydrochloride ((+)-epi-pseudoconhydrine) (1):
(3R,6S)-5-((tert-butyldimethylsilyl) oxy)-2-propylpiperidine (24 and 25, 9:1
ratio) (1.9 g, 0.0074 mol) was stirred for 20 h in 30 mL of ethanol: IPAꢃHCl (3:1)
and then concentrated to obtain a crude hydrochloride salt. Crude salt was
stirred with 19 mL, 1 N HCl for 15 min and washed with 3 ꢂ 19 mL
dichloromethane and discarded the organic layer. pH of the aqueous layer
was adjusted to 14 using NaOH and the aqueous layer was extracted with
19 mL dichloromethane (three times). Concentration of organic layer gave
desired product with 9:1 cis:trans selectivity. This product was further purified
by flash chromatography (SiO2, DCM/methanol, 93:7) to afford only cis product
(3R,6S-epi-pseudoconhydrine).Treatment of epi-pseudoconhydrine free amine
with 1 N HCl for 10 min followed by extraction with dichloromethane,
concentration of aqueous layer completely under vacuum afforded the epi-
pseudoconhydrine hydrochloride salt (1.0 g, 76%).
11. Helena, M.; Forrest, E. M. J. Am. Chem. Soc. 2010, 132, 1249.
12. (a) Shanmugapriya, D.; Shankar, R.; Satyanarayana, G.; Dahanukar, V. H.; Syam
Kumar, U. K.; Vembu, N. Synlett 2008, 2945; (b) Suresh Babu, M.; Anil Kumar,
N.; Raghunath, A.; Vasudev, R.; Syam Kumar, U. K. J. Heterocycl. Chem. 2011, 48,
540; (c) Wagh, M. B.; Shankar, R.; Syam Kumar, U. K. Synlett 2011, 88; (d)
Shankar, R.; Wagh, M. B.; Madhubabu, M. V.; Vembu, N.; Syam Kumar, U. K.
Synlett 2011, 844; (e) Raghunadh, A.; Suresh, Babu M.; Anil Kumar, N.; Santosh,
G.; Vaikunta Rao, L.; Syam Kumar, U. K. Synthesis 2012, 44, 281.
13. Hiromi, U.; Ryo, K.; Yuuki, A.; Miki, H.; Yu, K. Org. Lett. 2011, 23, 6268.
14. Michael, W.; Ronald, B.; Nobuyoshi, Y.; George, M.; Ulf-H, D.; Edward, G.
Tetrahedron Lett. 1995, 36, 5461.
19. Spectral data of (1): Yield: 0.9 g, 85.0% (free base); mp: 130.69 °C, ½a D20
= +9.4° (c
ꢁ
1.0, MeOH). lit.,7b a D20 = +9.24°, MeOH.; IR 3397, 2960, 1623, 1445, 982; 1H
½ ꢁ
15. Subba Rao, V.; Pradeep, Kumar Tetrahedron 2006, 62, 9942.
NMR (400 MHz, D2O): d 4.22 (s, 1H), 3.14–3.31 (m, 3H), 1.39–1.95 (m, 8H), 0.92
(t, J = 7.3 Hz, 3H); 13C NMR (400 MHz, D2O): d 64.254, 59.335, 51.296, 37.818,
30.414, 25.505, 20.578, 15.727; HRMS calcd m/z for C8H18NO+H:144.1387,
found: 144.1388.
16. (3R,6R)-6-Propylpiperidin-3-ol
hydrochloride
(ꢀ)-Pseudoconhydrine
(2):
Palladium on charcoal (0.275 g, 20 mol%, 10% Pd on charcoal) was added to a
solution of (3R,6R)-benzyl 5-hydroxy-2-propylpiperidine-1-carboxylate, (21)
(1.1 g, 0.004 mol) in ethanol (11 mL), and the mixture was hydrogenated using
H2 balloon pressure for 1 h. The solution was filtered through Celite bed and
the filtrate evaporated to give the title compound. The free amine was
converted to HCl salt by treating with 2 N HCl for 10 min, (impurities were
20. (a) Gosselin, F.; Lubell, W. D. J. Org. Chem. 1998, 63, 7463; (b) Swarbrick, M. E.;
Gosselin, F.; Lubell, W. D. J. Org. Chem. 1993, 1999, 64; (c) Gosselin, F.; Lubell,
W. D. J. Org. Chem. 2000, 65, 2163.