Conversion of the iridoid glucoside antirrhinoside into 3- azabicyclo[3.3.0]octane building blocks

Article abstract of DOI:10.1021/np9905517

The iridoid glucoside antirrhinoside (1) was transformed into polysubstituted 3-azabicyclo[3.3.0]octanes 3, 12, and 13 in 4 to 5 steps. Ozonolysis of the diacetonide of 1 and of its 7-deoxy-derivative 8 afforded cyclopentanoids 2 and 10, respectively. Conditions for the selective conversion of 2 and 10 into the corresponding ditosylates 4 and 11 were investigated. Cyclization of 4 and 11 was achieved with benzylamine and 2- methoxybenzylamine to yield bicyclic pyrrolidines 3, 12, and 13. Additional building blocks 14 and 15 were obtained by selective deprotection of the N- benzyl and isopropylidene moieties in 12 and 13, respectively.

Full text of DOI:10.1021/np9905517

592
J . Nat. Prod. 2000, 63, 592-595
Con ver sion of th e Ir id oid Glu cosid e An tir r h in osid e in to
3-Aza bicyclo[3.3.0]octa n e Bu ild in g Block s
Henrik Franzyk,* Signe M. Frederiksen, and Søren Rosendal J ensen
Department of Organic Chemistry, The Technical University of Denmark, Building 201, DK-2800, Lyngby, Denmark
Received November 5, 1999
The iridoid glucoside antirrhinoside (1) was transformed into polysubstituted 3-azabicyclo[3.3.0]octanes
3, 12, and 13 in 4 to 5 steps. Ozonolysis of the diacetonide of 1 and of its 7-deoxy-derivative 8 afforded
cyclopentanoids 2 and 10, respectively. Conditions for the selective conversion of 2 and 10 into the
corresponding ditosylates 4 and 11 were investigated. Cyclization of 4 and 11 was achieved with
benzylamine and 2-methoxybenzylamine to yield bicyclic pyrrolidines 3, 12, and 13. Additional building
blocks 14 and 15 were obtained by selective deprotection of the N-benzyl and isopropylidene moieties in
12 and 13, respectively.
The 3-azabicyclo[3.3.0]octane framework is only known
from a few synthetic analogues of biologically active
compounds. For example, it is found in analogues of
prostacyclin (PGI2),1,2 a potential non-peptide substance P
antagonist,3 and in the antidiabetic gliclazide.4 Usually,
3-azabicyclo[3.3.0]octanes are obtained by desymmetriza-
tion of a meso-intermediate, and three different approaches
have been developed by Flynn et al.5-7
Previously, the iridoid glucoside antirrhinoside (1) has
been converted into a monoterpene pyridine alkaloid,8
bicyclic piperidine building blocks,9 chiral cyclopentane
building blocks10 for the preparation of carbocyclic nucleo-
side analogues,11 and a natural bicyclic lactone.12 In the
present work, we wish to report on the synthesis of
3-azabicyclo[3.3.0]octane building blocks from 1.
Resu lts a n d Discu ssion
In previous papers9,10 it was shown that antirrhinoside
(1) readily could be converted into the corresponding 5,6:
4′,6′-diacetonide, which, upon ozonolysis with a reductive
workup procedure, was transformed into the partially
protected cyclopentane 2. Here, we intended first to employ
2 for the preparation of the derived pyrrolidine 3 via its
ditosylate, but unexpectedly, the tosylation of diol 2 proved
sluggish even with a large excess of tosyl chloride at room
temperature. The desired ditosylate 4 was obtained only
in low yield, together with monotosylate 5 and tetrahydro-
furan 6. To diminish the apparent competing cyclization
of 5 to 6, tosylation at low temperature (-10 °C) with a
prolonged reaction time was attempted; however, after 3
days only monotosylate 5 had formed. Therefore, the excess
of tosyl chloride was increased, and the reaction temper-
ature was kept at 4 °C for an additional 3 days. The
mixture was then allowed to reach room temperature, and
ditosylate 4 prevailed in the reaction mixture, although
with smaller amounts of 5 and 6.
Benzylamines were chosen for the cyclization of ditosy-
lates into 3-azabicyclo[3.3.0]octanes to facilitate purification
and to allow subsequent modification into pyrrolidines with
an unprotected nitrogen. Conversion of ditosylate 4 into
N-benzylpyrrolidine 3 went smoothly with an excess of
benzylamine in hot tetrahydrofuran. Because it was an-
ticipated that the low reactivity of 2 might be due to the
presence of the 7,8-epoxy functionality, its removal prior
to ditosylation was considered a feasible alternative ap-
proach. Nevertheless, reduction of 2 with LiAlH4 afforded
only an undesired product (triol 7) corresponding to a
hydride attack at the most hindered position. This unusual
regioselectivity may be caused by coordination of the
aluminum reagent with the hydroxyl group at C-1 in 2.
Consequently, a strategy with epoxide reduction before the
ozonolysis step seemed more promising. Hence, the 5,6:
4′,6′-diacetonide of 1 was subjected to LiAlH4 reduction,
and this led to an approximately 10:1 mixture of ring-
opened products 8 and 9. This mixture was inseparable
on normal-phase chromatography, but analytical samples
of each product were obtained by reversed phase chroma-
tography. In large-scale work it proved most facile to carry
out the ozonolysis on the mixture of 8 and 9, and this
afforded the separable triols 10 and 7 in an approximately
∼10:1 ratio. In the case of 10, tosylation at low temperature
(-10 °C) gave exclusively ditosylate 11 in almost quantita-
tive yield. Cyclization of 11 was performed with both
benzylamine and 2-methoxybenzylamine, and this provided
pyrrolidines 12 and 13, respectively, in good to moderate
yield. The reactivity of ditosylate 11 was markedly lower
* To whom correspondence should be addressed. Tel.: +45 4525 2111.
Fax: +45 4593 3968. E-mail: okhf@pop.dtu.dk.
10.1021/np9905517 CCC: $19.00
© 2000 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/14/2000

Antirrhinoside Conversion
J ournal of Natural Products, 2000, Vol. 63, No. 5 593
respectively, in methylene groups. 1H NMR signals were
assigned by COSY experiments, while 13C NMR signals were
assigned from HSQC spectra. Primes denote signals arising
from the sugar moiety.
than that of ditosylate 4; that is, the former required both
a higher reaction temperature and an extended reaction
time to ensure complete cyclization. The rate-limiting factor
in the cyclization of 4 as well as of 11 appears to be the
initial monosubstitution inasmuch as no intermediary
N-benzylamino-substituted tosylates could be detected by
analytical TLC during the progress of the reaction.
To enable its possible further elaboration into N-acylated
derivatives, pyrrolidine 12 was subjected to hydrogenation
in the presence of palladium on carbon catalyst, which gave
the pure crystalline unprotected pyrrolidine 14 in high
yield. Also, the isopropylidene-protecting group in N-(2-
methoxybenzyl)pyrrolidine 13 was removed by treatment
with p-toluenesulfonic acid in CHCl3-MeOH to yield
trihydroxy-pyrrolidine 15 in good yield.
Tosyla tion of Diol 2 a t Room Tem p er a tu r e. Diol 2 (100
mg, 0.435 mmol) was dissolved in CH2Cl2 (2 mL), and pyridine
(0.28 mL, 8 × 0.435 mmol) and TsCl (332 mg, 4 × 0.435 mmol)
were added. The mixture was stirred at room temperature for
24 h, and then excess reagent was quenched with ice. The
reaction mixture was diluted with CH2Cl2 (15 mL) and washed
successively with 0.5 M H2SO4, H2O, aqueous saturated
NaHCO3, and H2O (each 15 mL). The organic layer was dried
(Na2SO4) and concentrated. The residue was purified on a VLC
column (3 × 3 cm). Elution with hexane and then hexane-
EtOAc (10:1 to 3:1) yielded successively 6 (20 mg, 22%), 4 (44
mg, 19%), and 5 (45 mg, 27%).
Tetr a h yd r ofu r a n 6: mp 39-40 °C (hexane-EtOAc); [R]22
D
+21.7° (c 0.42, CHCl3); 1H NMR (CDCl3, 250 MHz) δ 4.60 (1H,
d, J 6,7 ) 1.5 Hz, H-6), 3.90 (2H, m, H-1a and H-4a), 3.78 (1H,
dd, J a,b ) 10 Hz, J 1b,9 ) 4.5 Hz, H-1b), 3.63 (1H, d, J a,b ) 9.5
Hz, H-4b), 3.42 (1H, d, J 6,7 ) 1.5 Hz, H-7), 2.79 (1H, dd, J 1a,9
) 8.5 Hz, J 1b,9 ) 4.5 Hz, H-9), 1.52, 1.27 (each 3H, s,
isopropylidene), 1.40 (3H, s, H-10); 13C NMR (CDCl3, 75 MHz)
δ 113.9 (isopropylidene), 97.5 (C-5), 86.7 (C-6), 76.9 (C-4), 69.0
(C-1), 67.5 (C-8), 65.0 (C-7), 53.5 (C-9), 28.1, 26.7 (isopropyl-
idene), 16.5 (C-10); anal. C 62.01%, H 7.90%, calcd for
C
11H16O4, C 62.25%, H 7.60%.
Ditosyla te 4: mp 154-156 °C (hexane-EtOAc); [R]22
D
-12.5° (c 0.56, CHCl3); 1H NMR (CDCl3, 250 MHz) δ 7.84-
7.30 (8H, 2 × Ts), 4.38 (1H, d, J 6,7 ) 1.5 Hz, H-6), 4.26 (1H,
dd, J a,b ) 10.5 Hz, J 1a,9 ) 3 Hz, H-1a), 4.16 (1H, dd, J a,b
)
10.5 Hz, J 1b,9 ) 3 Hz, H-1b), 4.09 (1H, d, J a,b ) 10.5 Hz, H-4a),
3.98 (1H, d, J a,b ) 10.5 Hz, H-4b), 3.34 (1H, d, J 6,7 ) 1.5 Hz,
H-7), 2.61 (1H, t, J 1a,9 ) J 1b,9 ) 3 Hz, H-9), 2.48, 2.45 (each
3H, s, 2 × Ts), 1.50, 1.02 (each 3H, s, isopropylidene), 1.36
(3H, s, H-10); 13C NMR (CDCl3, 75 MHz) δ 145.7, 145.1, 132.3,
131.6, 130.3, 129.9, 128.1, 127.9 (2 × CH3-Ph-SO3), 114.7
(isopropylidene), 90.2 (C-5), 82.7 (C-6), 70.2 (C-4), 67.1 (C-1),
66.0 (C-8), 63.4 (C-7), 49.0 (C-9), 29.3, 27.8 (isopropylidene),
21.7, 21.6 (2 × CH3-Ph-SO3), 16.0 (C-10); anal. C 55.46%, H
5.84%, calcd for C25H30O9S2, C 55.75%, H 5.61%.
Mon otosyla te 5: mp 105-106 °C (hexane-EtOAc); [R]22
D
-4.0° (c 0.60, CHCl3); 1H NMR (CDCl3, 250 MHz) δ 7.94-7.34
(4H, m, Ts), 4.58 (1H, d, J a,b ) 10 Hz, H-4a), 4.44 (1H, d,
J 6,7 ) 1.5 Hz, H-6), 4.06 (2H, m, H-1a and H-4b), 3.87 (1H,
dd, J a,b ) 11 Hz, J 1b,9 ) 3.5 Hz, H-1b), 3.37 (1H, d, J 6,7 ) 1.5
Hz, H-7), 2.50 (4H, m, H-9 and Ts), 1.59, 1.12 (each 3H, s,
isopropylidene), 1.52 (3H, s, H-10); 13C NMR (CDCl3, 75 MHz)
δ 145.1, 132.4, 129.8, 128.1 (CH3-Ph-SO3), 114.1 (isopropyl-
idene), 90.6 (C-5), 83.2 (C-6), 70.9 (C-4), 66.9 (C-8), 63.6 (C-7),
59.2 (C-1), 50.8 (C-9), 29.6, 28.0 (isopropylidene), 21.6 (CH3-
Ph-SO3), 16.5 (C-10); anal. C 56.11%, H 6.26%, calcd for
In conclusion, the inherent chirality of antirrhinoside (1)
was utilized (4-5 steps) to prepare enantiopure 3-azabi-
cyclo[3.3.0]octane building blocks 3 and 12-15. The present
protocol is devoid of expensive chiral catalysts or reagents,
and no resolution of racemates is required.
C
18H24O7S, C 56.24%, H 6.29%.
Exp er im en ta l Section
Tosyla tion of Diol 2 a t Low Tem p er a tu r e. To diol 2 (343
mg, 1.49 mmol) in CH2Cl2-pyridine (2:1, 6 mL) was added
TsCl (1.28 g, 4.5 × 1.49 mmol). The mixture was kept at -10
°C for 3 days, at which point only 4-monotosylate 5 had formed.
More TsCl (427 mg, 1.5 × 1.49 mmol) was added, and the
mixture was kept at 4 °C for an additional 3 days, followed by
3 h at room temperature. Workup and purification, as de-
scribed above, afforded 6 (15 mg, 4%), 4 (400 mg, 50%), and 5
(88 mg, 15%).
Gen er a l Exp er im en ta l P r oced u r es. THF was freshly
distilled from sodium. All concentrations were performed in
vacuo. Elemental analyses were performed by the Microana-
lytical Department at the H. C. Ørsted Institute (University
of Copenhagen) or by Microanalytical Laboratory, Institute of
Physical Chemistry, Vienna. Optical rotations (10-1 deg cm2
g-1) were measured on a Perkin-Elmer 241 polarimeter.
Melting points are uncorrected. TLC was performed on Merck
Si gel 60 F254 aluminum sheets with detection by charring with
H2SO4, or by UV light when applicable. MPLC was performed
N-Ben zylp yr r olid in e 3. Ditosylate 4 (363 mg, 0.674 mmol)
was dissolved in dry THF (5 mL), and BnNH2 (0.44 mL, 6 ×
0.674 mmol) was added. The mixture was heated to 55-60 °C
for 24 h. After the reaction mixture had cooled to room
temperature, saturated aqueous NaHCO3 (30 mL) was added.
Then the mixture was extracted with EtOAc (3 × 50 mL). The
organic layers were dried (Na2SO4) and concentrated to yield
a residue that was purified on a VLC column (4 × 2 cm).
Elution with hexane and then hexane-EtOAc (10:1 to 5:1)
on
a Merck Lobar Lichroprep RP18 C-column. VLC was
performed on predried (120 °C; >24 h) Merck Si gel 60H; the
column size is given as height × diameter. NMR spectra were
recorded on Bruker HX-250 and Varian Inova 500 or Mercury
300 spectrometers. Chemical shifts are given in parts per
million, using the solvent peaks as internal standards
(CDCl3: δH ) 7.27, δC ) 77.0, CD3OD: δH ) 3.31, δC ) 49.0).
Coupling constants (J values) are given in hertz. The sub-
scripts a and b indicate the low field and high field protons,
yielded pure 3 as an oil: (183 mg, 90%), [R]22 -4.5° (c 0.60,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.34-7.22 (5H, m, Ph-
CH2), 4.57 (1H, d, J 6,7 ) 1.5 Hz, H-6), 3.59, 3.54 (each 1H, d,

594 J ournal of Natural Products, 2000, Vol. 63, No. 5
Franzyk et al.
J ) 13 Hz, Ph-CH2), 3.41 (1H, d, J 6,7 ) 1.5 Hz, H-7), 2.92
Hz, H-9), 1.87 (1H, ddq, J 8,9 ) 12.5 Hz, J 8,10 ) 7 Hz, J 7,8 ) 5
Hz, H-8), 1.56, 1.51, 1.48, 1.39 (each 3H, s, 2 × isopropylidene),
1.10 (3H, d, J 8,10 ) 7 Hz, H-10); 13C NMR (CD3OD, 75 MHz) δ
142.7 (C-3), 115.9 (isopropylidene), 107.2 (C-4), 100.7 (isopro-
pylidene), 100.4 (C-1′), 93.8 (C-1), 87.9 (C-6), 83.0 (C-5), 75.2
(C-2′), 74.9 (C-4′), 74.4 (C-3′), 72.1 (C-7), 68.8 (C-5′), 63.1 (C-
6′), 52.8 (C-9), 41.6 (C-8), 29.4, 28.3, 28.0, 19.3 (2 × isopropyl-
idene), 12.4 (C-10); anal. C 55.29%, H 7.21%, calcd for
(1H, d, J a,b ) 9.5 Hz, H-4a), 2.69 (1H, dd, J a,b ) 9 Hz, J 1a,9
)
3 Hz, H-1a), 2.65 (1H, dd, J 1b,9 ) 9 Hz, J 1a,9 ) 3 Hz, H-9), 2.40
(1H, d, J a,b ) 9.5 Hz, H-4b), 2.47 (1H, t, J a,b ) J 1b,9 ) 9 Hz,
H-1b), 1.54, 1.29 (each 3H, s, isopropylidene), 1.38 (s, 3H,
H-10); 13C NMR (CDCl3, 75 MHz) δ 138.2, 128.4, 128.2, 127.1
(Ph-CH2), 113.6 (isopropylidene), 96.6 (C-5), 87.5 (C-6), 68.2
(C-8), 65.3 (C-7), 65.2 (C-4), 59.7 (Ph-CH2), 54.4 (C-1), 52.8
(C-9), 28.2, 27.0 (isopropylidene), 16.5 (C-10); anal. C 71.96%,
H 7.97%, N 4.61%, calcd for C18H23NO3, C 71.73%, H 7.69%,
N 4.65%.
C
21H32O10•1/2H2O, C 55.61%, H 7.13%.
Ozon olysis of Dia ceton id es 8 a n d 9. A 10:1 mixture of 8
and 9 (2.89 g, 6.51 mmol) was dissolved in CH2Cl2-MeOH (3:
1, 80 mL). Upon cooling to -78 °C, the mixture was treated
with ozone for 30 min. Then Ar was passed through the
solution for 30 min, at which point EtOH (40 mL) and NaBH4
(0.74 g, 3 × 6.51 mmol) were added. The mixture was stirred
below -65 °C for an additional 2 h, when another portion of
NaBH4 (0.74 g) was added. The reaction mixture was stirred
at room temperature for the next 12 h and was then neutral-
ized with HOAc (2 mL) and concentrated. The residue was
partitioned between EtOAc (250 mL) and brine-saturated
NaHCO3 (2:1, 150 mL). The aqueous layer was extracted with
more EtOAc (5 × 250 mL). The EtOAc phases were dried
(Na2SO4 and NaHCO3) and concentrated. The crude product
(1.40 g) was purified on a VLC column (4 × 4.5 cm). Elution
with hexane and then hexane-Me2CO (5:1 to 2:1) afforded
successively 7 (89 mg, 6%) and 10 (1.02 g, 67.5%).
LiAlH4-Red u ction of Diol 2. To diol 2 (212 mg, 0.923
mmol) in THF (4 mL) was added LiAlH4 (97 mg, 2.8 × 0.923
mmol), and the mixture was heated to reflux for 9 h. Excess
reagent was quenched with EtOAc (2 mL), H2O (5 mL) was
added, and then the mixture was neutralized using CO2.
Again, H2O (10 mL) was added, and the mixture was filtered.
The filtrate was extracted with EtOAc (3 × 20 mL). The
organic layers were dried (Na2SO4) and concentrated. The
crude product was crystallized (Me2CO-hexane) to give triol
7 (102 mg, 48%); mp 118-120 °C; [R]23 +31° (c 0.57, MeOH);
D
1H NMR (CD3OD, 250 MHz) δ 4.42 (1H, d, J 6,7 ) 5 Hz, H-6),
3.94 (1H, t, J 6,7 ) J 7,8 ) 5 Hz, H-7), 3.76 (1H, dd, J a,b ) 11.5
Hz, J 1a,9 ) 4 Hz, H-1a), 3.76 (1H, d, J a,b ) 12 Hz, H-4a), 3.69
(1H, d, J a,b ) 12 Hz, H-4b), 3.68 (1H, dd, J a,b ) 11.5 Hz,
J 1b,9 ) 6.5 Hz, H-1b), 2.11 (1H, ddd, J 8,9 ) 12 Hz, J 1b,9 ) 6.5
Hz, J 1a,9 ) 4 Hz, H-9), 1.94 (1H, ddq, J 8,9 ) 12 Hz, J 8,10 ) 6.5
Hz, J 7,8 ) 5 Hz, H-8), 1.51, 1.40 (each 3H, s, isopropylidene),
1.06 (3H, d, J 8,10 ) 6.5 Hz, H-10); 13C NMR (CD3OD, 75 MHz)
δ 115.9 (isopropylidene), 93.3 (C-5), 85.7 (C-6), 72.8 (C-7), 64.8
(C-1), 60.1 (C-4), 55.7 (C-9), 41.0 (C-8), 28.8, 28.6 (isopropyl-
idene), 13.1 (C-10); anal. C 56.62%, H 8.51%, calcd for
Tr iol 10: mp 116-118 °C (hexane-Me2CO); [R]23 +7.9°
D
1
(c 0.63, MeOH); H NMR (CD3OD, 300 MHz) δ 4.39 (1H, dd,
J 6,7a ) 6.5 Hz, J 6,7b ) 5.5 Hz, H-6), 3.79 (2H, d, J 1,9 ) 7 Hz,
H-1), 3.75 (1H, d, J a,b ) 11.5 Hz, H-4a), 3.67 (1H, d,
J a,b ) 11.5 Hz, H-4b), 2.48 (1H, t, J 1,9 ) 7 Hz, H-9), 2.11 (1H,
dd, J a,b ) 13.5 Hz, J 6,7a ) 6.5 Hz, H-7a), 2.04 (1H, dd, J a,b
)
C
11H20O5, C 56.88%, H 8.68%.
13.5 Hz, J 6,7b ) 5.5 Hz, H-7b), 1.53, 1.38, (each 3H, s,
isopropylidene), 1.16 (3H, s, H-10); 13C NMR (CD3OD, 75 MHz)
δ 113.6 (isopropylidene), 93.3 (C-5), 82.5 (C-6), 80.1 (C-8), 64.5
(C-4), 62.2 (C-9), 59.3 (C-1), 48.0 (C-7), 29.6, 28.4 (isopropy-
lidene), 24.7 (C-10); anal. C 56.70%, H 8.50%, calcd for
LiAlH4-Red u ction of 5,6:4′,6′-Di-O-isop r op ylid en e-a n -
tir r h in osid e. To a stirred suspension of LiAlH4 (2.62 g, 69.0
mmol) in THF (50 mL) under Ar, was added a solution of
antirrhinoside diacetonide9 (9.38 g, 21.2 mmol) in THF (50
mL). The mixture was heated to reflux for 4 h. After the
reaction mixture had cooled to room temperature, excess
reagent was slowly quenched with EtOAc (50 mL). The
mixture was neutralized with CO2 (pH 7-8). Then pH was
adjusted to 9 by adding saturated aqueous NaHCO3 (50 mL).
Then, H2O (50 mL) was added, and the resulting solution was
extracted with EtOAc (6 × 250 mL). The EtOAc layers were
washed with brine (25 mL). The combined organic layers were
dried (Na2SO4) and concentrated to yield a foam that was
purified on a VLC column (5.5 × 5 cm). Gradient elution with
hexane to hexane-Me2CO (2:1) yielded a 10:1 mixture of 8
and 9 (8.12 g, 87%). Analytical samples of each compound were
obtained after rechromatography by MPLC.
C
11H20O5, C 56.88%, H 8.68%.
Ditosyla tion of Tr iol 10. Triol 10 (0.36 g, 1.55 mmol) was
dissolved in CH2Cl2-pyridine (3:1, 8 mL), then the mixture was
cooled to -78 °C, and TsCl (1.03 g, 3.5 × 1.55 mmol) was
added. The mixture was allowed slowly to warm to -10 °C,
and was then kept at -10 °C for 5 days. The reaction mixture
was diluted with CH2Cl2 (50 mL) and was then washed
successively with 0.5 M H2SO4, H2O, aqueous saturated
NaHCO3, and H2O (each 50 mL). The organic phase was dried
(MgSO4), filtered, and concentrated. The residue was purified
on a VLC column (4 × 3 cm). Elution with hexane and then
hexane-EtOAc (5:1 to 2:1) gave ditosylate 11 (0.83 g, 99%):
mp 95-97 °C (hexane-EtOAc); [R]22 + 2.3° (c 0.43, CHCl3);
D
Dia cet on id e 8: mp 114-116 °C (MeOH); [R]23 -160°
1H NMR (CDCl3, 500 MHz) δ 7.80-7.74 (4H, m, Ts), 7.39-
7.35 (4H, m, Ts), 4.45 (1H, dd, J 6,7b ) 5.5 Hz, J 6,7a ) 2 Hz,
H-6), 4.14 (1H, dd, J a,b ) 10.5 Hz, J 1a,9 ) 5.5 Hz, H-1a), 4.13
(1H, d, J a,b ) 11 Hz, H-4a), 4.10 (1H, dd, J a,b ) 10.5 Hz,
J 1b,9 ) 5.5 Hz, H-1b), 4.08 (1H, d, J a,b ) 11 Hz, H-4b), 2.54
(1H, dt, J 1a,9 ) J 1b,9 ) 5.5 Hz, J 7a,9 ) 1.5 Hz, H-9), 2.46 (6H, s,
2 × Ts), 2.10 (1H, ddd, J a,b ) 15 Hz, J 6,7a ) 2 Hz, J 7a,9 ) 1.5
Hz, H-7a), 1.97 (1H, dd, J a,b ) 15 Hz, J 6,7b ) 5.5 Hz, H-7b),
D
(c 0.44, MeOH); 1H NMR (CD3OD, 300 MHz) δ 6.39 (1H, d,
J 3,4 ) 6.5 Hz, H-3), 5.55 (1H, br s, H-1), 5.08 (1H, dd, J 3,4
)
6.5 Hz, J 4,9 ) 1.5 Hz, H-4), 4.67 (1H, d, J 1′,2′ ) 8 Hz, H-1′),
4.31 (1H, dd, J 6,7a ) 7 Hz, J 6,7b ) 5 Hz, H-6), 3.89 (1H, dd,
J a′,b′ ) 10.5 Hz, J 5′,6a′ ) 5.3 Hz, H-6a′), 3.77 (1H, t, J a′,b′
)
J 5′,6b′ ) 10.5 Hz, H-6b′), 3.52, 3.49 (each 1H, br t, J ) 9 Hz,
H-3′ and H-4′), 3.29 (2H, m, H-2′ and H-5′), 2.63 (1H, br s,
H-9), 2.19 (1H, dd, J a,b ) 14 Hz, J 6,7a ) 7 Hz, H-7a), 2.05 (1H,
dd, J a,b ) 14 Hz, J 6,7b ) 5 Hz, H-7b), 1.54, 1.51, 1.42, 1.39 (each
3H, s, 2 × isopropylidene), 1.22 (3H, s, H-10); 13C NMR
(CD3OD, 75 MHz) δ 144.0 (C-3), 113.7 (isopropylidene), 106.2
(C-4), 100.8 (isopropylidene), 100.3 (C-1′), 92.9 (C-1), 84.7 (C-
6), 81.4 (C-5), 79.5 (C-8), 75.3 (C-2′), 74.9 (C-4′), 74.4 (C-3′),
68.8 (C-5′), 63.1 (C-6′), 59.1 (C-9), 48.3 (C-7), 29.4, 28.8, 27.6,
19.3 (2 × isopropylidene), 25.2 (C-10); anal. C 56.48%, H 7.06%,
calcd for C21H32O10, C 56.75%, H 7.26%.
1.45, 1.21 (each 3H, s, isopropylidene), 1.15 (3H, s, H-10); 13
C
NMR (CDCl3, 75 MHz) δ 145.3, 145.2, 132.3, 132.1, 130.1,
130.0, 128.0, 127.9 (CH3-Ph-SO3), 112.3 (isopropylidene), 90.4
(C-5), 82.5 (C-6), 80.4 (C-8), 69.1 (C-4), 66.5 (C-1), 58.9 (C-9),
45.5 (C-7), 28.2, 26.4 (isopropylidene), 23.9 (C-10), 21.7 (CH3-
Ph-SO3); anal. C 55.55%, H 6.05%, calcd for C25H32O9S2, C
55.54%, H 5.97%.
N-Ben zylp yr r olid in e 12. Ditosylate 11 (797 mg, 1.47
mmol) was dissolved in THF (20 mL), and BnNH2 (1.28 mL,
8 × 1.47 mmol) was added. The mixture was heated to 60 °C
for 24 h and then to reflux for 3 days. Workup, as described
above for 3, gave a residue, which was purified on a VLC
column (3 × 3 cm). Elution with hexane, and then hexane-
EtOAc (20:1 to 10:1) afforded 12 as a colorless syrup (371 mg,
83%): [R]22D + 9.2° (c 0.60, CHCl3); 1H NMR (CDCl3, 250 MHz)
δ 7.35-7.20 (5H, m, Ph-CH2), 4.40 (1H, d, J 6,7b ) 4 Hz, H-6),
3.56, 3.47 (each 1H, d, J ) 13 Hz, Ph-CH2), 2.88 (1H, d,
Dia ceton id e 9: [R]25 -136° (c 0.58, MeOH); 1H NMR
D
(CD3OD, 300 MHz) δ 6.33 (1H, d, J 3,4 ) 6.5 Hz, H-3), 5.36 (1H,
br s, H-1), 5.08 (1H, dd, J 3,4 ) 6.5 Hz, J 4,9 ) 1.5 Hz, H-4), 4.64
(1H, d, J 1′,2′ ) 8 Hz, H-1′), 4.31 (1H, d, J 6,7 ) 5 Hz, H-6), 3.98
(1H, br t, J 6,7 ) J 7,8 ) 5 Hz, H-7), 3.90 (1H, dd, J a′,b′ ) 10.5
Hz, J 5′,6a′ ) 5.5 Hz, H-6a′), 3.79 (1H, t, J a′,b′ ) J 5′,6b′ ) 10.5 Hz,
H-6b′), 3.53, 3.48 (each 1H, br t, J ) 9 Hz, H-3′ and H-4′),
3.30-3.25 (2H, m, H-2′ and H-5′), 2.30 (1H, br d, J 8,9 ) 12.5

Antirrhinoside Conversion
J ournal of Natural Products, 2000, Vol. 63, No. 5 595
J a,b ) 10 Hz, H-4a), 2.71 (1H, dd, J a,b ) 10 Hz, J 1a,9 ) 8 Hz,
110.3 (2-MeO-Ph-CH2), 110.2 (isopropylidene), 97.5 (C-5),
86.9 (C-6), 81.5 (C-8), 63.3 (C-4), 61.6 (C-9), 56.5 (C-1), 55.3
(Ar-OCH3), 52.9 (2-MeO-Ph-CH2), 43.8 (C-7), 27.2, 24.8
(isopropylidene), 23.3 (C-10); anal. C 68.34%, H 8.05%, N
4.28%, calcd for C19H27NO4, C 68.43%, H 8.17%, N 4.20%.
H-1a), 2.64 (1H, d, J a,b ) 10 Hz, H-4b), 2.54 (1H, ddd, J 1a,9
)
8 Hz, J 1b,9 ) 6 Hz, J 7a,9 ) 2 Hz, H-9), 2.25 (1H, dd, J a,b ) 10
Hz, J 1b,9 ) 6 Hz, H-1b), 2.18 (1H, dd, J a,b ) 15 Hz, J 7a,9 ) 2
Hz, H-7a), 2.02 (1H, dd, J a,b ) 15 Hz, J 6,7b ) 4 Hz, H-7b), 1.52,
1.30 (each 3H, s, isopropylidene), 1.20 (3H, s, H-10); 13C NMR
(CDCl3, 75 MHz) δ 138.5, 128.4, 128.2, 127.0 (Ph-CH2), 110.3
(isopropylidene), 97.3 (C-5), 86.8 (C-6), 81.5 (C-8), 63.3 (C-4),
61.5 (C-9), 60.0 (Ph-CH2), 56.5 (C-1), 43.8 (C-7), 27.2, 24.7
(isopropylidene), 23.3 (C-10); anal. C 70.97%, H 8.06%, N
4.55%, calcd for C18H25NO3, C 71.26%, H 8.31%, N 4.62%.
Hyd r ogen a tion of N-Ben zylp yr r olid in e 12. Compound
12 (371 mg) was hydrogenated for 4 days in MeOH (5 mL) in
the presence of 5% Pd/C (40 mg). The catalyst was filtered off
on activated C over Celite, which then was washed with more
Dep r otection of N-(2′-Meth oxyben zyl)p yr r olid in e 13.
Acetonide 13 (54 mg, 0.16 mmol) was dissolved in CHCl3-
MeOH (3:1, 6.5 mL), and then p-TsOH‚H2O (30 mg, 0.16 mmol)
was added. The mixture was heated to reflux for 12 h. The
solvent was removed in vacuo, and Et3N (10 µL) was added to
the residue, which was purified on a VLC column (4 × 2 cm).
Elution with hexane, CHCl3, and then CHCl3-EtOH (25:1)
yielded deprotected pyrrolidine 15 (40 mg, 85%): [R]25 +18°
D
(c 0.48, MeOH); 1H NMR (CD3OD, 300 MHz) δ 7.28-7.18,
6.95-6.85 (each 2H, m, Ar-CH2), 3.79 (3H, s, 2′-OMe), 3.77
(1H, dd, J 6,7a ) 4.5 Hz, J 6,7b ) 3 Hz, H-6), 3.59, 3.54 (each 1H,
J ) 13 Hz, Ph-CH2), 2.71 (1H, dd, J a,b ) 10 Hz, J 1a,9 ) 7.5
MeOH. Concentration of the filtrate yielded 14 (237 mg,
1
91%): mp 64-65 °C (MeOH); [R]25 +27° (c 0.55, MeOH); H
D
NMR (CD3OD, 300 MHz) δ 4.45 (1H, d, J 6,7b ) 4.5 Hz, H-6),
3.20 (1H, br d, J a,b ) 12.5 Hz, H-4a), 3.13 (1H, br dd, J a,b
Hz, H-1a), 2.55 (1H, d, J a,b ) 10 Hz, H-4a), 2.49 (1H, d, J a,b
)
)
10 Hz, H-4b), 2.44 (1H, dd, J a,b ) 10 Hz, J 1b,9 ) 5 Hz, H-1b),
2.23 (1H, ddd, J 1a,9 ) 7.5 Hz, J 1b,9 ) 5 Hz, J 7b,9 ) 2 Hz, H-9),
1.95 (1H, dd, J a,b ) 13.5 Hz, J 6,7a ) 4.5 Hz, H-7a), 1.87 (1H,
ddd, J a,b ) 13.5 Hz, J 6,7b ) 3 Hz, J 7b,9 ) 2 Hz, H-7b), 1.20 (3H,
s, H-10); 13C NMR (CD3OD, 75 MHz) δ 159.1, 131.5, 129.4,
127.4, 121.2, 111.6 (2-MeO-Ph-CH2), 89.9 (C-5), 80.9 (C-8),
78.1 (C-6), 66.8 (C-4), 62.7 (C-9), 57.4 (C-1), 55.8 (Ar-OCH3),
54.1 (2-MeO-Ph-CH2), 46.6 (C-7), 23.7 (C-10); anal. C 65.49%,
H 7.88%, N 4.70%, calcd for C16H23NO4, C 65.51%, H, 7.90%,
N 4.77%.
10.5 Hz, J 1a,9 ) 8.5 Hz, H-1a), 2.96 (1H, d, J a,b ) 12.5 Hz, H-4b),
2.45 (1H, dt, J 1a,9 ) J 1b,9 ) 8.5 Hz, J 7a,9 ) 1.5 Hz, H-9), 2.37
(1H, dd, J a,b ) 10.5 Hz, J 1b,9 ) 8.5, H-1b), 2.10 (1H, br d,
J a,b ) 15 Hz, H-7a), 2.01 (1H, br dd, J a,b ) 15 Hz, J 6,7b ) 4.5
Hz, H-7b), 1.46, 1.30 (each 3H, s, isopropylidene), 1.19 (3H, s,
H-10); 13C NMR (CD3OD, 75 MHz) δ 111.8 (isopropylidene),
101.4 (C-5), 87.4 (C-6), 81.7 (C-8), 64.7 (C-9), 58.4 (C-4), 50.3
(C-1), 44.3 (C-7), 27.2, 25.1 (isopropylidene), 24.1 (C-10); anal.
C 61.73%, H 9.17%, N 6.44%, calcd for C11H19NO3, C 61.95%,
H 8.98%, N 6.57%.
N-(2′-Meth oxyben zyl)p yr r olid in e 13. Ditosylate 11 (2.07
g, 3.83 mmol) was dissolved in THF (15 mL), and 2-methoxy-
benzylamine (1.50 mL, 3.1 × 3.83 mmol) was added. The
mixture was heated to reflux for 2 days. The solvent was
removed in vacuo, and the residue was purified on a VLC
column (4.5 × 4 cm). Elution with hexane, and then hexane-
EtOAc (6:1) yielded successive fractions of almost pure 13 (453
mg, 36%) and pure N-(2′-methoxybenzyl)pyrrolidine 13 (229
Refer en ces a n d Notes
(1) Miyajima, K.; Takemoto, M.; Achiwa, K. Chem. Pharm. Bull. 1991,
39, 3175-3179.
(2) Nakai, H.; Arai, Y.; Hamanaka, N.; Hayashi, M. Tetrahedron Lett.
1979, 805-808.
(3) Malleron, J .-L.; Peyronel, J .-F.; Desmazeau, P.; M’Houmadi, C.;
Planiol, C. Tetrahedron Lett. 1995, 36, 543-546.
(4) Taylor, A. R.; Brownsill, R. D.; Grandon, H.; Lefoulon, F.; Petit, A.;
Luijten, W.; Kopelman, P. G.; Walther, B. Drug Metab. Dispos. 1996,
24, 55-64.
mg, 18%) as syrups: [R]24 +9.0° (c 1.0, CHCl3); 1H NMR
D
(CDCl3, 500 MHz) δ 7.35 (1H, dd, J o ) 8, J m ) 2 Hz, Ar-CH2),
(5) Becker, D. P.; Nosal, R.; Zabrowski, D. L.; Flynn, D. L. Tetrahedron
1997, 53, 1- -20.
7.23 (1H, dt, J o ) 8, J m ) 2 Hz, Ar-CH2), 6.94 (1H, br t, J o
)
(6) Flynn, D. L.; Zabrowski, D. L. J . Org. Chem. 1990, 55, 3673-3674.
(7) Becker, D. P.; Flynn, D. L. Tetrahedron 1993, 49, 5047-5054.
(8) Frederiksen, S. M.; Stermitz, F. R. J . Nat. Prod. 1996, 59, 41-46.
(9) Franzyk, H.; Frederiksen, S. M.; J ensen, S. R. J . Nat. Prod. 1997,
60, 1012-1016.
8 Hz, Ar-CH2), 6.87 (1H, br d, J o ) 8 Hz, Ar-CH2), 4.45 (1H,
d, J 6,7b ) 4.5 Hz, H-6), 3.82 (3H, s, 2′-OMe), 3.64 (1H, s, 8-OH),
3.60, 3.56 (each 1H, d, J ) 14 Hz, Ar-CH2), 2.94 (1H, d,
J a,b ) 10 Hz, H-4a), 2.77 (1H, dd, J a,b )10 Hz J 1a,9 ) 8 Hz,
(10) Franzyk, H.; J ensen S. R.; Rasmussen, J . H. Eur. J . Org. Chem. 1998,
365-370.
H-1a), 2.68 (1H, d, J a,b ) 10 Hz, H-4b), 2.54 (1H, ddd, J 1a,9
)
8 Hz, J 1b,9 ) 6 Hz, J 7a,9 ) 2 Hz, H-9), 2.30 (1H, dd, J a,b ) 10
Hz, J 1b,9 ) 6 Hz, H-1b), 2.17 (1H, dd, J a,b ) 15 Hz, J 7a,9 ) 2
Hz, H-7a), 2.03 (1H, dd, J a,b ) 15 Hz, J 6,7b ) 4.5 Hz, H-7b),
(11) Franzyk, H.; Rasmussen, J . H.; Mazzei, R. A.; J ensen, S. R. Eur. J .
Org. Chem. 1998, 2931-2935.
(12) Franzyk, H.; Frederiksen S. M., J ensen S. R. Eur. J . Org. Chem. 1998,
1665-1667.
1.53, 1.32, (each 3H, s, isopropylidene), 1.22 (3H, s, H-10); 13
C
NMR (CDCl3, 75 MHz) δ 157.3, 129.6, 127.8, 126.6, 120.4,
NP9905517