Synthesis of monoterpene piperidines from the iridoid glucoside antirrhinoside

Article abstract of DOI:10.1021/np9702648

Synthesis of five novel piperidine monoterpene alkaloids (17-21) using the iridoid glucoside antirrhinoside (4) as a synthon is described. Two strategies for their preparation were investigated: the first possible pathway involved an intermediate diol, 13, from which the piperidine ring was expected to be constructed via reaction of its ditosylate with an amine; the second strategy involved a double reductive amination as the key step to the piperidine ring, which proved successful. The stereochemistry of C-5 and C-9 in the obtained piperidine monoterpenes was the same as that reported for α- skytanthine (3), a known isolate from Skytanthus acutus (Apocynaceae).

Full text of DOI:10.1021/np9702648

1012
J . Nat. Prod. 1997, 60, 1012-1016
Syn th esis of Mon oter p en e P ip er id in es fr om th e Ir id oid Glu cosid e
An tir r h in osid e
Henrik Franzyk,* Signe M. Frederiksen, and Søren Rosendal J ensen
Department of Organic Chemistry, The Technical University of Denmark, DK-2800 Lyngby, Denmark
Received May 27, 1997X
Synthesis of five novel piperidine monoterpene alkaloids (17-21) using the iridoid glucoside
antirrhinoside (4) as a synthon is described. Two strategies for their preparation were
investigated: the first possible pathway involved an intermediate diol, 13, from which the
piperidine ring was expected to be constructed via reaction of its ditosylate with an amine; the
second strategy involved a double reductive amination as the key step to the piperidine ring,
which proved successful. The stereochemistry of C-5 and C-9 in the obtained piperidine
monoterpenes was the same as that reported for R-skytanthine (3), a known isolate from
Skytanthus acutus (Apocynaceae).
Monoterpene alkaloids have been the subject of much
interest because they often exhibit pharmacological
activity.1 The piperidine alkaloids especially, from
Skytanthus acutus and Tecoma stans2 have been studied
intensively, and tecomanine (1) has been shown to have
hypoglycemic activity.3-5 Also, incarvilline (2) and
related compounds from Incarvillea sinensis6-9sused in
the Chinese traditional medicine to treat rheumatism
and to relieve painshave been investigated.
aceae). The commercial varieties “White Wonder” and
“Bright Eyes” are preferred because of their high content
(1.5% of fresh wt) of 4 and the presence of only small
amounts of the closely eluting antirrhide (6) and 5-glu-
cosylantirrhinoside (7). Isolation was performed by
reversed-phase chromatography of the H2O-soluble part
of the crude EtOH extract as earlier described.21
Advanced synthetic pathways to such compounds
have been reported; for example, (+)-1 has been syn-
thesized enantioselectively.10,11 Moreover, (+)-R-skytan-
thine (3) has been prepared by cyclization of an inter-
mediate cyclopentanoid ditosylate with methylamine,12
and a hydroxylated 3-azabicyclo[4.3.0]nonane, racemic
isooxyskytanthine, has been prepared using a photocy-
clization step.13 Recently, a Mitsunobu-type cyclization
has been employed for the formation of the piperidine
ring in 3.14 Finally, there have been several reports15-19
on the synthesis of simple 3-azabicyclo[4.3.0]nonanes.
In the present work utilizing 4 as a synthon for
cyclopentanoids, our first goal was to make a syntheti-
cally useful intermediate. Since our primary aim was
piperidines, tosylation22 or mesylation23 of the diol 13
(see Scheme 1) and subsequent treatment with an
appropriate amine seemed the most straightforward
method for achieving this.
The biological activity known for some natural pip-
eridine monoterpenes encouraged us to synthesize
enantiomerically pure analogues. Utilizing the chirality
already present in the iridoid aglucone, steps involving
expensive chiral catalysts or reagents, as well as
separations of racemates, may be avoided. Previously,
one of us has reported20 on the conversion of antirrhi-
noside (4) into the pyridine 5. As a part of our current
investigation of 4 as a synthon for cyclopentanoids, we
have synthesized five novel piperidine monoterpenes
with the same stereochemistry at C-5 and C-9 as 2 and
3, but lacking the methyl group at C-4.
Previously, a SnCl2-catalyzed reaction of 4 has been
reported24 to yield the 5,6-monoisopropylidene deriva-
tive 10 directly in 49% yield. However, in our hands
this reaction gave a complex mixture of products.
Attempts with mild ketalization methods25-27 (as 4
degraded under conditions using strong acids) showed
that the sugar 4′,6′-diol moiety was reacting faster (with
8 as an isolable intermediate) than the aglucone 5,6-
diol. This problem was overcome by first preparing the
diisopropylidene derivative (9) using pyridinium p-
toluenesulfonate (PPTS) and 2,2-dimethoxypropane in
Me2CO27 and subsequently removing the 4′,6′-isopro-
pylidene group by heating at 60 °C in dilute HOAc.
Thus, a 72% overall yield of 10 was obtained. Now, to
avoid the inherent problem of cyclobutane formation28
during NaBH4 reduction of the aglucone of 5,6-isopro-
pylidene antirrhinoside (10), hydrogenation of 11 was
performed prior to enzymatic cleavage by â-glucosidase,
Resu lts a n d Discu ssion
Multigram amounts of antirrhinoside (4) can readily
be obtained from Antirrhinum majus L. (Scrophulari-
* Author to whom correspondence should be addressed. Phone: +45
45252103. Fax: +45 45933968. E-mail: okhf@pop.dtu.dk.
X Abstract published in Advance ACS Abstracts, October 1, 1997.
S0163-3864(97)00264-4 CCC: $14.00
© 1997 American Chemical Society and American Society of Pharmacognosy

Piperidine Synthesis
J ournal of Natural Products, 1997, Vol. 60, No. 10 1013
Sch em e 1. Preparation of a Precursor (13) of
Sch em e 2. Piperidine Synthesis via Double Reductive
Piperidines
Amination
lamine itself. Even though the yield of N-benzylated
piperidine 17 was modest (37%) the route was attractive
because of its few steps. No significant improvements
were achieved by changing: (a) the amount of reductant,
(b) the amount of benzylamine hydrochloride, or (c) the
reaction time; however, it was found that slow addition
of the reductant was important.
which next afforded the crystalline hemiacetal 12 in
85% overall yield. Reduction of 12 with NaBH4 (in
MeOH or dioxane-H2O) was anticipated to furnish the
intermediate diol 13. However, in addition to the
expected diol 13, a less polar by-product, 14, was
isolated in varying amounts, and it was occasionally the
1
main product. Analysis of the H-NMR spectrum of 14
The piperidine (17) was modified by opening of the
epoxide in two different ways. First a LiAlH4 reduc-
tion32 yielded selectively the 8-OH compound, 19, in
reasonable yield. In addition, an azide functionality
could be introduced by azidolysis33 of the epoxide to give
the azido derivative, 21. Both the original piperidine
17 and the modifications 19 and 21 were hydrogenated
under Pd/C catalysis to remove the N-benzyl protective
group. However, only the two former gave pure deben-
zylated products (i.e., 18 and 20), whereas the azido
compound 21 gave a mixture of partially reduced
products in low yield. (See Scheme 2.)
Thus, we have shown that an iridoid aglucone of the
decarboxylated type may be converted smoothly into a
piperidine compound in only two steps. This was
substantiated by an additional small-scale experiment
in which the aglucone of another iridoid, catalpol, was
shown to be able to undergo a similar reaction to give a
piperidine. The intermediate hemiacetal 12 may also
prove useful for synthesis of, for example, prostaglandin
analogues. Furthermore, we are currently investigating
the synthesis of the corresponding pyrrolidines (i.e.,
after loss of C-3) from 10.
showed that the epoxide had been opened (H-7 at δ 3.16
with J 6,7 ) 1.5 Hz in 13 was shifted downfield to δ 3.92
with J 6,7 ) 6 Hz in 14), and usual acetylation conditions
gave only a diacetate with H-7 shifted further downfield
to δ 4.78 (J 6,7 ) 6 Hz). Together, these facts were taken
as evidence for the tricyclic structure 14 proposed for
the by-product; cyclization had proceeded via attack of
the primary 3-OH group (iridoid numbering is preserved
for aglucone derivatives) at the more hindered position
of the epoxide. Thus, it was possible to obtain the
desired product 13, but, due to the disadvantage of its
lability towards weakly basic conditions, for example,
acylation (benzoylation and tosylation) in pyridine as
well as weak acids (dilute HOAc), we decided to abandon
the above synthetic scheme and try another strategy for
piperidine synthesis from 4.
Because antirrhinoside aglucone (15) in principle is
in equilibrium with the dialdehyde form 16 (although
not observable by NMR spectroscopy), a double reduc-
tive amination29-31 seemed a promising alternate path-
way to piperidines. Thus, after enzymatic removal of
the sugar moiety, almost pure antirrhinoside aglucone
was obtained in reasonable yield (74%) using continuous
extraction, and the crystalline compound could be
obtained after reversed-phase chromatography (58%
overall). The reductive amination of 15 was performed
with NaCNBH3 and benzylamine hydrochloride in
MeOH solution. Benzylamine was chosen as the amine
because the benzyl group was expected to confer suf-
ficient hydrophobicity on the resulting piperidine to
facilitate purification of the reaction mixture. Indeed,
it was found that the only major apolar impurity present
in the crude product was the readily separable benzy-
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. Antirrhino-
side (4) was isolated21 from Antirrhinum majus. The
â-glucosidase was purchased from Sigma Chemical Co.
THF was distilled from sodium and stored over molec-
ular (4 Å) sieves until use. Elemental analyses were
performed by the Microanalytical Department at the
H.C. Ørsted Institute (University of Copenhagen). Op-
tical rotations (10-1 deg cm2 g-1) were measured on a

1014 J ournal of Natural Products, 1997, Vol. 60, No. 10
Ta ble 1. 13C NMR of Antirrhinoside Derivatives (in Me2CO-d6)
Franzyk et al.
monoacetonide, respectively). The reaction mixture was
made alkaline with Et3N (0.36 mL) and concentrated.
The residue was purified by MPLC to yield 10 (830 mg,
carbon
4a
8
9
10
11
1
3
4
5
6
7
8
9
95.01
143.04
106.99
74.36
76.74
66.29
65.09
51.99
16.98
95.52
141.71
107.86
73.84
75.42b
65.81
63.20
53.06
17.74
95.38
143.05
109.22
87.66
86.22
63.68
67.36
53.26
18.03
113.99
28.02
29.58
99.82c
75.43
74.31d
74.52d
68.38
62.64
99.82c
19.33
29.48
95.17
142.88
109.18
87.78
86.33
63.73
67.56
53.41
18.07
114.02
28.06
29.60
99.25
74.60
77.77
71.62
77.94
62.98
95.86
60.53
33.41
89.50
85.03
64.45
67.25
53.78
17.33
113.47
28.24
30.33
98.71
74.53
78.07
71.59
77.59
62.86
93%) as a hygroscopic foam; [R]23 -100° (c 0.48,
D
MeOH); 1H NMR (Me2CO-d6, 500 MHz) δ 6.42 (1H, d, J
) 6 Hz, H-3), 5.31 (1H, d, J ) 7 Hz, H-1), 5.08 (1H, d,
J ) 6 Hz, H-4), 4.72 (1H, d, J ) 7.5 Hz, H-1′), 4.44 (1H,
d, J ) 1.5 Hz, H-6), 3.86 (1H, m, H-6a′), 3.62 (1H, m,
H-6b′), 3.43 (1H, m, H-3′), 3.36 (2H, m, H-4′ and H-5′),
3.28 (1H, d, J ) 1.5 Hz, H-7), 3.25 (1H, m, H-2′), 1.46
(3H, s, isopropylidene), 1.43 (3H, s, H-10), 1.33 (3H, s,
isopropylidene); 13C NMR, see Table 1; anal. C 52.14%,
H 6.50%, calcd for C18H26O10‚1/2H2O, C 52.54%, H 6.63%.
10
(CH3)2C<
(CH3)2C<
1′
2′
3′
4′
5′
6′
99.29
73.41
77.08
70.41
76.38
61.49
99.98
75.42b
74.32
74.32
68.38
62.65
99.90
19.33
29.46
3,4-Dih yd r o-5,6-O-isop r op ylid en e An t ir r h in o-
sid e (11). To 10 (4.39 g, 10.92 mmol) in MeOH (50 mL)
was added Pt/C (5%, 440 mg). The suspension was
stirred vigorously under hydrogen (1 atm). When the
consumption of H2 had subsided, the mixture was
filtered through activated charcoal over Celite and
(CH3)2C<
(CH3)2C<
concentrated to yield 11 (4.09 g, 93%) as a hygroscopic
a
d
In D2O. b,c Double intensity. Signals interchangeable.
foam; [R]23 -101° (c 0.65, MeOH); H NMR (Me2CO-
1
D
d6, 500 MHz) δ 5.19 (1H, d, J ) 3 Hz, H-1), 4.64 (1H, d,
J ) 1.5 Hz, H-6), 4.64 (1H, d, J ) 8.5 Hz, H-1′), 4.01
(1H, ddd, J ) 11.5, 7, 1.5 Hz, H-3a), 3.85 (1H, dd, J )
11.5, 2.5 Hz, H-6a′), 3.68 (1H, m, J ) 13, 11.5, 5 Hz,
H-3b), 3.67 (1H, m, J ) 11.5, 5.5 Hz, H-6b′), 3.45 (1H,
t, J ) 8.5 Hz, H-3′), 3.37 (1H, t, J ) 8.5 Hz, H-4′), 3.34
(1H, m, H-5′), 3.30 (1H, d, J ) 1.5 Hz, H-7), 3.28 (1H, t,
J ) 8.5 Hz, H-2′), 2.42 (1H, dt, J ) 13, 13, 7 Hz, H-4a),
3.29 (1H, d, J ) 3 Hz, H-9), 1.84 (1H, ddd, J ) 13, 5,
1.5 Hz, H-4b), 1.46 (3H, s, isopropylidene), 1.39 (3H, s,
H-10), 1.31 (3H, s, isopropylidene); 13C NMR, see Table
1; anal. C 52.45%, H 6.83%, calcd for C18H28O10‚1/2H2O,
C 52.29%, H 7.07%.
Perkin-Elmer 241 polarimeter. Melting points are
uncorrected. TLC was performed on Merck Si gel 60
F254 aluminium sheets with detection by charring with
H2SO4, or by UV light when applicable. Medium-
pressure Liquid chromatography (MPLC) was per-
formed on a Merck Lobar Lichroprep RP-18 C-column.
VLC (vacuum liquid chromatography) was performed
on predried (120 °C; >24 h) Merck Si gel 60H (0.04-
0.06 mm); the column size is given as height × diameter
(cm). NMR spectra were recorded on a Bruker AM-500
or HX-250 spectrometer. Chemical shifts are given in
parts per million, using the solvent peaks as internal
standards (Me2CO-d6: δ 2.05, MeOH-d4: δ 3.31, D2O:
δ 4.75, CDCl3: δ 7.27). J values are given in Hertz.
For all compounds assignments of 1H-NMR spectra were
based on 1D homonuclear decoupling experiments,
while 13C-NMR spectra were assigned using carbon-
proton shift-correlation spectra. Mass spectra (positive
mode electron impact) were obtained on a VG Trio-2
apparatus.
3,4-Dih yd r o-5,6-O-isop r op ylid en e An t ir r h in o-
sid e Aglu con e (12). Compound 11 (4.09 g, 10.1 mmol)
was dissolved in H2O (50 mL) and â-glucosidase (212
mg; Sigma) was added. The mixture was stirred at
room temperature for 3 days. The volume was reduced
to 20 mL and extracted with EtOAc (6 × 100 mL).
Drying (Na2SO4), filtration, and concentration of the
organic layers yielded 12 (2.22 g, 91%) as a crystalline
residue, which was recrystallized (Me2CO-hexane) to
give white needles, mp 104-106 °C; [R]23D +53° initially,
changing to +13° due to mutarotation (c 0.73, MeOH);
1H NMR (Me2CO-d6, 500 MHz) δ 5.28 (1H, m, H-1), 4.46
(1H, d, J ) 1.5 Hz, H-6), 3.86 (1H, ddd, J ) 10.5, 4.5, 6
Hz, H-3a), 3.67 (1H, ddd, J ) 10.5, 9.5, 4 Hz, H-3b),
3.21 (1H, d, J ) 1.5 Hz, H-7), 2.43 (1H, ddd, J ) 14,
9.5, 4.5 Hz, H-4a), 2.35 (1H, br d, J ) 4 Hz, H-9), 1.82
(1H, ddd, J ) 14, 6, 4 Hz, H-4b), 1.41 (3H, s, H-10), 1.47,
1.32 (each 3H, s, isopropylidene), only very slow mu-
tarotation was seen in Me2CO; 13C NMR, see Table 1;
anal. C 59.58%, H 7.47%, calcd for C12H18O5, C 59.48%,
H 7.49%.
5,6:4′,6′-Di-O-Isop r op ylid en e An tir r h in osid e (9).
To 4 (1.50 g, 4.14 mmol) in MeCO (35 mL) was added
2,2-dimethoxypropane (10.2 mL, 82.8 mmol) and PPTS
(2.07 g, 8.28 mmol). Stirring at room temperature for
1 h was followed by 30 min at 40 °C, then Et3N (1.72
mL, 12.4 mmol) was added and the reaction mixture
concentrated. The oily residue was purified by MPLC
(two runs) to yield 9 (1.45 g, 77%) as a hygroscopic foam;
1
[R]23 -107° (c 0.44, MeOH); H NMR (Me2CO-d6, 500
D
MHz,) δ 6.42 (1H, d, J ) 6 Hz, H-3), 5.17 (1H, d, J ) 8
Hz, H-1), 5.09 (1H, d, J ) 6 Hz, H-4), 4.79 (1H, d, J )
8 Hz, H-1′), 4.46 (1H, d, J ) 2 Hz, H-6), 3.84 (1H, dd, J
) 10.5, 5 Hz, H-6a′), 3.73 (1H, t, J ) 10.5 Hz, H-6b′),
3.53 (2H, m, H-3′ and H-4′), 3.34 (1H, m, H-2′), 3.29 (1H,
d, J ) 2 Hz, H-7), 3.28 (1H, m, H-5′), 2.51 (1H, d, J ) 8
Hz, H-9), 1.47, 1.45 (each 3H, s, isopropylidene), 1.40
(3H, s, H-10), 1.33 (6H, br s, isopropylidene); 13C NMR,
see Table 1; anal. C 55.86%, H 6.74%, calcd for
C21H30O10‚1/2H2O, C 55.87%, H 6.92%.
Red u ction of 3,4-Dih yd r o-5,6-isop r op ylid en e An -
tir r h in osid e Aglu con e (12). The aglucone 12 (183 mg,
0.76 mmol) was dissolved in MeOH-H2O (10:1, 27.5
mL) and NaBH4 (29 mg, 0.76 mmol) was added. The
reaction mixture was stirred at room temperature for
4 h. Neutralization with 10% HOAc was followed by
addition of H2O (5 mL). The MeOH was evaporated and
the residue diluted with H2O to 30 mL. Activated
charcoal (3 g) was added, and after being stirred for 30
min, the mixture was filtered through a layer of Celite
5,6-O-Isop r op ylid en e An tir r h in osid e (10). Diac-
etonide 9 (980 mg, 2.22 mmol) was heated in 1%
aqueous HOAc (10 mL) at 60 °C for 5 h, at which point
no more starting material could be detected by TLC
(CHCl3-MeOH 9:1, Rf 0.70 and 0.19 for diacetonide and

Piperidine Synthesis
J ournal of Natural Products, 1997, Vol. 60, No. 10 1015
Ta ble 3. 13C NMR Data for Piperidine Derivatives
Ta ble 2. 13C NMR of Iridoid Aglucone Derivatives (in
Me2CO-d6)
carbon
17a
18b
19a
20b
21c
carbon
12
13
14
R-15
â-15
C-1
C-3
C-4
C-5
C-6
C-7
C-8
C-9
54.11
50.15
30.56
74.07
72.14
64.77
64.65
47.66
15.12
62.53
137.89
128.79
128.33
127.21
47.75
44.14
32.98
76.34
74.25
67.31
67.58
49.84
16.49
52.91
50.03
44.17
42.05
31.15
80.15e
72.53
46.44
79.88e
54.18
23.55
52.20f
50.82f
33.63
1
3
4
5
6
7
8
9
91.00
58.36
35.96
87.68
87.31
64.56
66.96
51.61
16.50
112.91
28.47
30.38
59.10a
59.67a
38.53
92.29
87.57
63.48
67.17
51.45
17.22
112.26
28.46
30.40
58.11
61.78
28.75
88.16
80.82
74.25
86.72
49.45
18.88
114.89
28.72
27.44
91.80
140.41
105.88
70.90
78.58
67.14
63.77
52.11
15.62
95.17
142.37
106.86
74.22
78.94
65.97
63.30
54.98
18.11
31.87
80.35d
72.55
76.81g
79.62h
79.50h
80.69g
54.85f
19.73
47.95
80.03d
54.60
C-10
Ph-CH2
P h -CH2
23.84
62.69
138.06
128.84
128.26
127.12
10
63.78
(CH3)2C<
(CH3)2C<
138.96
130.38
129.32
128.34
a
Signals interchangeable.
a
b
In CDCl3. In D2O. c Due to a general low solubility no CH-
d-h
correlated spectrum was obtained; in CD3OD.
interchanged.
Signals may be
on a glass filter, washing with additional H2O. The cake
was eluted with MeOH, and concentration gave crude
13 (161 mg, 88%), which was unstable towards further
purification (partial cyclization to 14); 1H NMR (MeCO-
d6, 500 MHz) δ 4.27 (1H, d, J ) 1.5 Hz, H-6), 3.96 (1H,
dd, J ) 11, 2.5 Hz, H-1a), 3.80 (1H, dd, J ) 11, 3 Hz,
H-1b), 3.77 (1H, m, H-3a), 3.70 (1H, ddd, J ) 11, 9, 6
Hz, H-3b), 3.16 (1H, d, J ) 1.5 Hz, H-7), 2.31 (1H, ddd,
J ) 14.5, 8, 6 Hz, H-4a), 2.24 (1H, br t, J ) 2.5 Hz,
H-9), 1.93 (1H, ddd, J ) 14.5, 9, 6 Hz, H-4b), 1.48 (3H,
s, isopropylidene), 1.44 (3H, s, H-10), 1.35 (3H, s,
isopropylidene); 13C NMR, see Table 2.
dried (Na2SO4), filtered, and concentrated to yield crude
15 (4.37 g, 74%), which was purified by MPLC to yield
crystalline 15 (3.44 g, 58% overall); mp 117-119 °C;
[R]23 +130° (c 0.62, Me2CO); 1H NMR (Me2CO-d6, 500
D
MHz), major anomer (R-) δ 6.17 (1H, d, J ) 6.5 Hz, H-3),
5.94 (1H, br s, 1-OH), 5.50 (1H, t, J ) 3.5 Hz, H-1), 4.86
(1H, d, J ) 6.5 Hz, H-4), 4.20 (1H, d, J ) 9 Hz, H-6),
3.73 (1H, d, J ) 9 Hz, 6-OH), 3.34 (1H, br s, H-7), 3.28
(1H, s, 5-OH), 2.40 (1H, d, J ) 4 Hz, H-9), 1.45 (3H, s,
H-10); minor anomer (â-) δ 6.29 (1H, d, J ) 6.5 Hz, H-3),
6.18 (1H, obscured by H-3 of the major anomer, 1-OH),
4.97 (1H, dd, J ) 9.5, 6.5 Hz, H-1), 4.82 (1H, d, J ) 6.5
Hz, H-4), 4.03 (1H, d, J ) 8.5 Hz, H-6), 3.85 (1H, d, J )
8.5 Hz, 6-OH), 3.39 (1H, br s, H-7), 3.36 (1H, s, 5-OH),
2.23 (1H, d, J ) 9.5 Hz, H-9), 1.50 (3H, s, H-10); 13C
NMR, see Table 2; anal. C 52.02%, H 6.09%, calcd for
C9H12O5‚1/2H2O, C 51.67%, H 6.26%.
The aglucone 12 (106 mg, 0.438 mmol) in dioxane-
H2O (5.5 mL) was cooled to 0 °C, and NaBH4 (17 mg,
0.438 mmol) was added under stirring. The mixture
was allowed to reach 15 °C. The reaction was followed
by TLC (CHCl3-MeOH 9:1, Rf 0.58, 0.50, and 0.40 for
12, 14 and 13, respectively). After 150 min no starting
material was left, and the reaction was neutralized with
10% HOAc. Then EtOAc (25 mL) and H2O (5 mL) were
added. After separation, the organic layer was dried
(Na2SO4), filtered, and concentrated (at 30 °C) to yield
crude 14 (67 mg, 63%); TLC showed that ring-closure
only occurred during concentration; crystallization (Me2-
Dou ble Red u ctive Am in a tion of Aglu con e 15.
Aglucone 15 (8.01 g, 40 mmol) was dissolved in MeOH
(50 mL) and BnNH3Cl (5.74 g, 40 mmol) was added. The
mixture was stirred at room temperature for 3 h.
Addition of NaCNBH3 (2.52 g, 40 mmol) in MeOH (40
mL) was performed with an automatic syringe pump
(0.17 mL h-1). After 3 days the reaction mixture was
concentrated, and the residue was dissolved in CH2Cl2
(5 mL) and loaded onto a VLC column (6.5 × 5 cm).
Gradient elution with hexane (150 mL), hexane-EtOAc
4:1 to 1:1 yielded piperidine 17 (4.05 g, 37%) as a
crystalline residue. Recrystallization (Me2CO-hexane
1:10) gave needles, mp 134-136 °C; [R]23D -54° (c 0.45,
CO) gave needles, mp 144-146 °C; [R]23 -23° (c 0.53,
MeOH); H NMR (Me2CO-d6, 500 MHz) δ 4.33 (1H, d,
D
1
J ) 6 Hz, H-6), 3.98 (1H, dd, J ) 11, 8 Hz, H-1a), 3.97
(1H, dd, J ) 12, 6.6 Hz, H-3a), 3.92 (1H, d, J ) 6 Hz,
H-7), 3.88 (1H, dd, J ) 11, 5.7 Hz, H-1b), 3.55 (1H, dt,
J ) 12, 12, 4.5 Hz, H-3b), 2.38 (1H, dt, J ) 12, 12, 7
Hz, H-4a), 2.11 (1H, ddd, J ) 8, 5.7, 2 Hz, H-9), 1.59
(3H, s, isopropylidene), 1.46 (1H, ddd, J ) 12, 4.5, 2 Hz,
H-4b), 1.43 (3H, s, isopropylidene), 1.23 (3H, s, H-10);
13C NMR, see Table 2; anal. C 58.94%, H 8.15%, calcd
for C12H20O5, C 58.98%, H 8.26%.
Acetylation (pyr-Ac2O 2:1, 2 h at room temperature)
of 14 gave a crude diacetate, 1H NMR (CDCl3, 500 MHz)
δ 4.78 (1H, d, J ) 6 Hz, H-7), 4.38 (1H, dd, J ) 11.5,
7.5 Hz, H-1a), 4.35 (1H, d, J ) 6 Hz, H-6), 4.24 (1H, dd,
J ) 11.5, 6 Hz, H-1b), 3.98 (1H, dd, J ) 12.5, 7 Hz,
H-3a), 3.57 (1H, dt, J ) 2 × 12.5, 4.5 Hz, H-3b), 2.33
(1H, ddd, J ) 7.5, 6, 1.5 Hz, H-9), 2.19 (1H, dt, J ) 2 ×
12.5, 7 Hz, H-4a), 2.10, 2.03 (each 3H, s, AcO), 1.46, 1.32
(each 3H, s, isopropylidene), 1.41 (1H, ddd, J ) 12.5,
4.5, 1.5 Hz, H-4b), 1.17 (3H, s, H-10).
1
MeOH); H MNR (CDCl3, 500 MHz) δ 7.35-7.25 (5H,
m, Ph-CH2), 4.09 (1H, br s, H-6), 3.52 (2H, higher order
coupling, Ph-CH2), 3.45 (1H, br s, H-7), 2.94 (1H, ddd,
J ) 12, 7, 2 Hz, H-1a), 2.83 (1H, ddt, J ) 13, 5, 2 × 2.5
Hz, H-3a), 2.34 (1H, br dd, J ) 12, 7 Hz, H-9), 1.94 (1H,
dt, J ) 2 × 13, 2.5 Hz, H-3b), 1.81 (1H, dt, J ) 13, 2 ×
2.5 Hz, H-4a), 1.69 (1H, dt, 2 × 13, 5 Hz, H-4b), 1.63
(1H, dt, J ) 2 × 12, 3 Hz, H-1b), 1.33 (3H, s, H-10); 13
C
NMR, see Table 3; anal. C 69.98%, H 7.65%, N 5.09%,
calcd for C16H21O3N, C 69.78%, H 7.69%, N 5.09%.
LiAlH4 Red u ction of P ip er id in e 17. Compound 17
(390 mg, 1.42 mmol) was dissolved in dry THF (10 mL)
and added to a suspension of LiAlH4 (160 mg, 4.24
mmol) in dry THF (10 mL). The mixture was refluxed
(80 °C) for 2.5 h. Excess LiAlH4 was quenched with
EtOAc (10 mL). Upon addition of H2O (50 mL), the
mixture was neutralized by passing CO2 through the
solution. The volume was increased to 200 mL with
An tir r h in osid e Aglu con e (15). To 4 (10.7 g, 30
mmol) in H2O (100 mL) was added â-glucosidase (200
mg), and the mixture was stirred at 38 °C in an ether-
extractor under continuous extraction with EtOAc (1
drop/sec). After 24 h the EtOAc extracts (∼3 L) were

1016 J ournal of Natural Products, 1997, Vol. 60, No. 10
Franzyk et al.
H2O. The filtrate was extracted with EtOAc (3 × 200
mL), and the aqueous layer was made alkaline (pH 10)
with 1 M NaOH and extracted once more with EtOAc
(2 × 200 mL). Drying and concentration of the com-
bined organic layers yielded a crude product (370 mg),
which was purified on a VLC column (4 × 2 cm).
Gradient elution with hexane (50 mL), hexane-EtOAc
3:2 to 1:1 afforded crystalline 19 (290 mg, 74%); mp
2.77 (1H, dt, J ) 2 × 12.5, 3.5 Hz, H-3b), 2.48 (1H, dd,
J ) 15, 9.5 Hz, H-7a), 2.40 (1H, t, J ) 13, H-1b), 2.06
(1H, dd, J ) 12, 6.5 Hz, H-9), 1.98 (1H, overlapped,
H-4a), 1.96 (1H, overlapped, H-7b), 1.74 (1H, ddd, J )
14, 12.5, 5 Hz, H-4b), 1.28 (3H, s, H-10); 13C NMR, see
Table 3; EIMS m/z 187 [M]+, 170, calcd for C9H17O3N,
187.24.
121-124 °C; [R]23 -17° (c 0.38, MeOH); 1H NMR
Ack n ow led gm en t. We thank the Danish National
Research Councils for financial support (grant no.
9501145).
D
(CDCl3, 500 MHz) δ 7.34-7.23 (5H, m, Ph-CH2), 4.18
(1H, dd, J ) 9.5, 5 Hz, H-6), 3.55, 3.48 (each 1H, d, J )
13.5 Hz, Ph-CH2), 2.78 (2H, m, H-1a, H-3a), 2.30 (1H,
dd, J ) 15.5, 9.5, H-7a), 2.15 (1H, ddd, J ) 12, 6, 2 Hz,
H-9), 2.05 (1H, ddd, J ) 12, 8.5, 6.5 Hz, H-3b), 1.88 (1H,
ddd, J ) 15.5, 5, 2, H-7b), 1.79 (2H, m, H-4), 1.63 (1H,
t, J ) 12, H-1b), 1.15 (3H, s, H-10); 13C NMR, see Table
3; anal. C 69.34%, H 8.37%, N 5.03%, calcd for
C16H23O3N, C 69.27%, H 8.36%, N 5.05%.
Azid olysis of P ip er id in e 17. A solution of 17 (300
mg, 1.09 mmol) in 80% aqueous MeOH (5 mL) was
treated with NaN3 (355 mg, 5.45 mmol) and NH4Cl (128
mg, 2.40 mmol) at 80 °C for 21 h. The reaction mixture
was diluted with EtOAc (50 mL) and washed with an
alkaline aqueous solution (50 mL saturated aqueous
NaHCO3 and 10 mL of 1 M NaOH) and H2O (50 mL).
Drying (Na2SO4) and concentration of the organic layer
yielded crystalline 21 (310 mg, 89%). Recrystallization
Refer en ces a n d Notes
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S. Phytochemistry 1992, 31, 2930-2932.
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istry 1995, 39, 1485-1487.
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(MeOH) yielded an analytical sample of 21; mp 171-
1
174 °C; [R]23 -37° (c 0.35, MeOH); H NMR (MeOH-
(11) Miyashita, M.; Tanaka, D.; Shiratani, T.; Irie, H. Chem. Pharm.
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D
d4, 500 MHz) δ 7.33-7.22 (5H, m, Ph-CH2), 3.85 (1H,
d, J ) 7 Hz, H-6), 3.78 (1H, dd, J ) 7, 1.5 Hz, H-7),
3.52, 3.49 (each 1H, d, J ) 13 Hz, Ph-CH2), 2.69 (2H,
m, H-1a, H-3a), 2.13 (1H, dt, J ) 2 × 11.5, 3.5 Hz, H-3b),
2.02 (1H, ddd, J ) 11, 6.5, 1.5 Hz, H-9), 1.88 (1H, dd, J
) 12, 11 Hz, H-1b), 1.82 (1H, dt, J ) 13.5, 2 × 4 Hz,
H-4a), 1.73 (1H, ddd, J ) 13.5, 11, 4.5 Hz, H-4b), 1.15
(3H, s, H-10); 13C NMR, see Table 3; anal. C 60.29%,
H 7.04%, N 17.40%, calcd for C16H22O3N4, C 60.35%, H
6.97%, N 17.60%.
(12) Oppolzer, W.; J acobsen, E. J . Tetrahedron Lett. 1986, 27, 1141-
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Hyd r ogen olysis of N-Ben zyla ted P ip er id in e 17.
Compound 17 (336 mg, 1.22 mmol) was dissolved in
MeOH (5 mL). Pd/C 5% (10 mg) was added and H2 was
introduced to the mixture under vigorous stirring.
When the H2 consumption had subsided the mixture
was filtered through activated C and Celite and con-
centrated to give pure crystalline 18 (188 mg, 83%); mp
140-142 °C; [R]23D -57° (c 0.46, MeOH); 1H NMR (D2O,
500 MHz) δ 4.38 (1H, br s, H-6), 3.66 (1H, br s, H-7),
3.21 (1H, dd, J ) 19, 13 Hz, H-1a), 3.04 (1H, br dd, J )
13.5, 5 Hz, H-3a), 2.52 (1H, dt, J ) 2 × 13.5, 3 Hz, H-3b),
2.23 (2H, m, H-1b, H-9), 1.86 (1H, br dd, J ) 13.5, 3
Hz, H-4a), 1.45 (1H, dt, J ) 2 × 13.5, 5 Hz, H-4b), 1.40
(3H, s, H-10); 13C NMR, see Table 3; anal. C 58.04%,
H 8.09%, N 7.20%, calcd for C9H15O3N, C 58.36%, H
8.16%, N 7.56%.
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2219-2222.
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C. Tetrahedron 1979, 35, 1121-1123.
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Hyd r ogen olysis of N-Ben zyla ted P ip er id in e 19.
Compound 19 (155 mg, 0.560 mmol) was treated as
(31) Furneaux, R. H.; Gainsford, G. J .; Lynch, G. P.; Yorke, S. C.
Tetrahedron 1993, 49, 9605-9612.
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described for 17. This gave 20 (89 mg, 85%) as an
1
amorphous solid; [R]23 -17° (c 0.49, MeOH); H NMR
(33) Chini, M.; Crotti, P.; Gardelli, C.; Macchia, F. J . Org. Chem.
1994, 59, 4131-4137.
D
(D2O, 500 MHz) δ 4.40 (1H, dd, J ) 9.5, 6.5 Hz, H-6),
3.19 (1H, dd, J ) 13, 6.5 Hz, H-1a), 3.16 (1H, m, H-3b),
NP9702648