Asymmetric Total Syntheses of (-)-Antofine and (-)-Cryptopleurine Using (R)-(E)-4-(Tributylstannyl)but-3-en-2-ol

Article abstract of DOI:10.1021/jo049820a

The asymmetric total syntheses of the representative phenanthroindolizidine and phenanthroquinolizidine alkaloids, (-)-antofine and (-)-cryptopleurine, are described. An efficient synthetic pathway to the key intermediate 12, in enantiomerically pure form, was achieved by using a chiral building block (R)-9 and the Overman rearrangement with a total transfer of chirality. The problem of constructing the pyrrolidine and piperidine rings was successfully addressed, primarily by using a ring-closing metathesis reaction and a cross-metathesis reaction, respectively.

Full text of DOI:10.1021/jo049820a

Asym m etr ic Tota l Syn th eses of (-)-An tofin e a n d
(-)-Cr yp top leu r in e Usin g (R)-(E)-4-(Tr ibu tylsta n n yl)bu t-3-en -2-ol
Sanghee Kim,*,†,‡ Taeho Lee,‡ Eunjung Lee,‡ J aekwang Lee,‡ Gao-jun Fan,‡
Sang Kook Lee,§ and Deukjoon Kim†
College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Korea,
Natural Products Research Institute, College of Pharmacy, Seoul National University, 28 Yungun,
J ongro, Seoul 110-460 Korea, and College of Pharmacy, Ewha Womans University, 11-1 Daehyun,
Seodaemun, Seoul 120-750, Korea
pennkim@snu.ac.kr
Received J anuary 31, 2004
The asymmetric total syntheses of the representative phenanthroindolizidine and phenanthro-
quinolizidine alkaloids, (-)-antofine and (-)-cryptopleurine, are described. An efficient synthetic
pathway to the key intermediate 12, in enantiomerically pure form, was achieved by using a chiral
building block (R)-9 and the Overman rearrangement with a total transfer of chirality. The problem
of constructing the pyrrolidine and piperidine rings was successfully addressed, primarily by using
a ring-closing metathesis reaction and a cross-metathesis reaction, respectively.
In tr od u ction
The phenanthroindolizidine and phenanthroquinoli-
zidine alkaloids are structurally related groups of pen-
tacyclic natural products. Since the first isolation of
tylophorine (1, Figure 1) in 1935,1 more than 60 alkaloids
and their seco-analogues have been reported. These
alkaloids are well-known for their characteristic biologi-
cal properties, especially for their profound cytotoxic
activity.2 Due to their exceptional bioactivity and unusual
architecture, many unique and interesting synthetic
methodologies have been reported.3
F IGURE 1. Chemical structures of compound 1-3.
construction. As part of our ongoing research into the
preparation and biological evaluation of phenanthroin-
dolizidine natural products and their analogues, we have
since developed a new synthetic approach to these
alkaloids. Herein, we describe a new enantioselective
synthetic route to (-)-antofine (2) and a representative
phenanthroquinolizidine, (-)-cryptopleurine (3).
Recently, we described the first total synthesis of (-)-
antofine (2, Figure 1),4 whose IC50 values against drug-
sensitive and multidrug-resistant cancer cell lines are in
the low nanomolar range.5 The key step of our synthesis
was the creation of a stereogenic center by using the
enantioselective catalytic phase transfer alkylation to-
gether with a ring-closing metathesis for pyrrolidine ring
Resu lts a n d Discu ssion
* To whom correspondence should be addressed. Phone: 82-2-740-
8913. Fax: 82-2-762-8322.
The retrosynthetic analysis of 2 and 3 is shown in
Scheme 1. The pentacyclic skeleton of the target natural
products could be constructed by employing the reported
Pictet-Spengler annulation of 2-arylmethylpyrrolidine
4 and 2-arylmethylpiperidine 5, which were previously
synthesized via a different synthetic route. The cycliza-
tion precursors 4 and 5 should be accessible from the
allylamine 6 by sequential metathesis and hydrogena-
tion. The key intermediate 6 was in turn envisioned to
arise from the chiral allylic alcohol 7, via the Overman
rearrangement of the corresponding allyl imidate. Fur-
ther analysis indicated that the requisite allylic alcohol
7 could be synthesized from the readily available phenan-
thryl bromide 84 and the chiral building block (R)-9,6 for
which we recently reported an efficient enzymatic prepa-
ration method.
† College of Pharmacy, Seoul National University.
‡ Natural Products Research Institute, College of Pharmacy, Seoul
National University.
§ Ewha Womans University.
(1) Ratnagiriswaran, A. N.; Venkatachalam, K. Indian J . Med. Res.
1935, 22, 433-441.
(2) (a) Gellert, E. In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; Academic Press: New York, 1987; pp 55-
132. (b) Suffness, M.; Cordell, G. A. In The Alkaloids, Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: New York, 1985; Vol.
25, pp 3-355.
(3) For a good review with citations, see: (a) Li, Z.; J in, Z.; Huang,
R. Synthesis 2001, 2365-2378. (b) Bick, I. R. C.; Sinchai, W. In The
Alkaloids; Rodrigo, R. G. A., Ed.; Academic Press: New York, 1981;
Vol. 19, pp 193-220. (c) Gellert, E. J . Nat. Prod. 1982, 45, 50-73.
(4) Kim, S.; Lee, J .; Lee, T.; Park, H.-g.; Kim, D. Org. Lett. 2003, 5,
2703-2706.
(5) (a) Stærk, D.; Lykkeberg, A. K.; Christensen, J .; Budnik, B. A.;
Abe, F.; J aroszewski, J . W. J . Nat. Prod. 2002, 65, 1299-1302. (b) Lee,
S. K.; Nam, K.-A.; Heo, Y.-H. Plant Med. 2003, 69, 21-25.
10.1021/jo049820a CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/08/2004
3144
J . Org. Chem. 2004, 69, 3144-3149

Total Syntheses of (-)-Antofine and (-)-Cryptopleurine
SCHEME 1. Retr osyn th etic An a lysis of
SCHEME 3a
(-)-An tofin e a n d (-)-Cr yp top leu r in e
SCHEME 2a
a
Reagents and conditions: (a) (i) 5 N NaOH, EtOH/CH2Cl2,
50 °C, 1 day; (ii) Cbz-Cl, THF, rt, 1 h, 87%. (b) Allyl bromide, NaH,
THF/HMPA, rt, 3 h, 100%. (c) 15 (5 mol %), CH2Cl2, rt, 2 h, 98%.
(d) H2, 10% Pd/C, MeOH, rt, 2 h, 63%. (e) HCHO, HCl, EtOH,
reflux, 3 days, 80%, in the dark.
Of these, the Pd(CH3CN)2Cl2/DMF system was found to
be superior to other combinations. With this system,
reaction occurred at room temperature to give the desired
(E)-allylic alcohol 7 in 95% yield. Alcohol 7 was then
treated with trichloroacetonitrile and DBU to afford
trichloroacetimidate 11 in 99% yield. Since 11 is not
stable for storage, it was used directly after silica gel
chromatography. Thermal Overman rearrangement9 of
11 in boiling toluene provided the (E)-allylic trichloro-
acetamide 12 as the only identifiable product in 99% ee
and 93% yield. Chirality was conserved during the
reaction, and as a result, the stereochemistry originating
from the chiral building block (R)-9 was transferred to
the allylic amine 12.
a
Reagents and conditions: (a) CBr4, PPh3, CH3CN, 0 °C, 1 h,
98%; (b) (R)-9, Pd(CH3CN)2Cl2 (5 mol %), DMF, rt, 2 h, 95%; (c)
CCl3CN, DBU, CH2Cl2, 0 °C, 2 h, 99%; (d) toluene, reflux, 12 h,
93%.
Initially, we explored the direct N-allylation of trichlo-
roacetamide 12 (Scheme 3). Our attempts at accomplish-
ing the N-allylation of 12, using various methods,10 such
as the allyl halide/base and π-allylpalladium complex,
were not successful and provided only the recovered
starting material, presumably, at least in part, due to
the electron-deficient nature of the trichloroacetamide
nitrogen. Thus, we decided to change the trichloroacetyl
group of 12 to the benzyloxycarbonyl group. Hydrolysis
of the trichloroacetamide 12 was performed in the
presence of excess 5 N NaOH in EtOH/CH2Cl2. In the
same reaction flask, the resulting free amine was con-
The starting material for our synthesis was the known
phenanthryl alcohol 10, which was obtained from the
commercially available homoveratric acid and p-anisal-
dehyde via the conventional four-step sequence according
to the previously reported procedure.7 Treatment of 10
with CBr4 and PPh3 provided bromide 8 (Scheme 2),
which appeared to be sensitive to silica gel chromatog-
raphy. It was very important to minimize the residency
time of this compound on the chromatography column
to obtain a high isolation yield (>98%).4 With multigram
quantities of 8 in hand, we then investigated the Stille
coupling of phenanthryl bromide 8 with (R)-(E)-4-(tribu-
tylstannyl)but-3-en-2-ol ((R)-9, >99% ee) in the presence
of palladium as a catalyst.8 Different palladium sources
and solvents were examined for this coupling reaction.
(8) For the Pd-catalyzed couplings of vinylstannane and benzyl
bromide, see: Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50, 3213-
3234.
(9) Overman, L. E. J . Am. Chem. Soc. 1976, 98, 2901-2910.
(10) Several conditions: (1) allyl bromide, NaH, DMF; (2) allyl
bromide, KHMDS, THF; (3) allyl bromide, K2CO3, TBAI, acetone,
reflux; (4) allyl alcohol, DEAD, PPh3, THF; (5) allyl acetate, Pd(PPh3)4,
K2CO3, THF, 60 °C; (6) allyl methyl carbonate, [Allyl-PdCl]2, PPh3,
THF, 60 °C.
(6) Lee, T.; Kim, S. Tetrahedron: Asymmetry 2003, 14, 1951-1954.
(7) Bremmer, M. L.; Khatri, N. A.; Weinreb, S. M. J . Org. Chem.
1983, 48, 3661-3666.
J . Org. Chem, Vol. 69, No. 9, 2004 3145

Kim et al.
SCHEME 4a
verted directly to the Cbz derivative 13 in 87% yield. The
subsequent N-allylation of the Cbz-protected amine 13
with allyl bromide and NaH in THF/HMPA successfully
provided the desired bis-allylamine 14 in nearly quan-
titative yield.
The remaining main steps to (-)-antofine required the
construction of the pyrrolidine ring with a bis-allylamine
moiety and the Pictet-Spengler annulation of the 2-aryl-
methylpyrrolidine (Scheme 3). These steps were ac-
complished by employing reaction conditions analogous
to those of our previous synthesis.4 The ring-closing
metathesis11 of 14 was successfully performed with a
commercially available second-generation Grubbs’ cata-
lyst 15 in CH2Cl2 at room temperature, to produce the
desired 2,5-dihydropyrrole derivative 16 in 98% yield.
Subsequent catalytic hydrogenation effected simulta-
neous reduction of the alkene and deprotection of the
benzyloxycarbonyl protecting group to give the previously
known pyrrolidine 44,12 in 63% yield. Finally, the Pictet-
Spengler cyclomethylenation of 2-arylmethylpyrrolidine
4, using the previously reported reaction conditions4,11-13
(formaldehyde, HCl, EtOH, reflux), generated the central
piperidine ring to afford (-)-antofine (2) in 80% yield.
The spectroscopic data (1H and 13C NMR) obtained for
the synthetic material were in agreement with those
reported for the naturally occurring compound. The
a
Reagents and conditions: (a) 17 or 18, 15 (5 mol %), CH2Cl2,
reflux, 1 day, 38% with 17 or 82% with 18; (b) H2, 10% Pd/C,
MeOH, rt, 4 h, 95%; (c) 5 N NaOH, MeOH, rt, 1 day, 90%; (d)
DIAD, PPh3, CH2Cl2, rt, 15 h, 68%; (e) HCHO, HCl, EtOH, reflux,
2 days, 67%, in the dark.
optical rotation measured for the synthetic 2 {[R]19
D
-125.2 (c 1.27, CHCl3)} is within the range of values
reported for the natural antofine.14
With the key intermediate 13 in hand, we next turned
our attention to the preparation of (-)-cryptopleurine (3).
At first, we explored the direct N-homoallylation of 13
with 4-bromo-1-butene under several different conditions
(Scheme 4). However, these attempts were all unsuccess-
ful.15 In view of the failure of the direct N-homoallylation
approach, we next turned our attention to cross-metath-
esis16 for piperidine ring construction. To our delight, the
cross-metathesis coupling of the internal olefin 13 with
the terminal olefin, homoallyl acetate 17 (4 equiv),
catalyzed by the second-generation Grubbs’ catalyst 15
(5 mol %) in refluxing CH2Cl2 for 1 day, successfully gave
the desired heterodimers 19 as an inseparable E/Z
mixture (38%, 4:1 E/Z) along with the recovered starting
material (54%).17 Moreover, when the known homoallyl
acetate homodimer 1818 was employed as a coupling
partner in the same reaction conditions, the cross-
metathesis proceeded more efficiently, to give mainly 19
in 82% yield with an E/Z ratio of 8:1 (96% yield based on
the recovered starting material) along with a small
amount of recovered starting material (14%).19 We believe
that this successful homologation of the internal olefin
will broaden the utility of this cross-metathesis in natural
product synthesis.
Hydrogenation of an E/Z mixture of 19 resulted in the
reduction of the double bond and simultaneous depro-
tection of the Cbz group to give 20 (95% yield), which
was saponified in a methanolic aqueous NaOH solution
to afford amino alcohol 21 (90% yield). The obtained
amino alcohol 21 was then subjected to Mitsunobu
reaction conditions20 employing PPh3 and DIAD in CH2-
Cl2 at room temperature. This effected the necessary ring
closure and provided the previously known piperidine 512
in 68% yield. The final step toward (-)-cryptopleurine
(3), through the Pictet-Spengler annulation of 2-aryl-
methylpiperidine 5, was carried out as described above.
Treatment of 5 with formaldehyde in boiling acidic
ethanol afforded (-)-cryptopleurine (3) (67% yield), whose
(11) For a good review about the application of the ring-closing
metathesis reaction to the synthesis of piperidine and pyrrolidine,
see: Felpin, F.-X.; Lebreton, J . Eur. J . Org. Chem. 2003, 3693-3712.
(12) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetra-
hedron 1999, 55, 2659-2670.
(13) Nordlander, J . E.; Njoroge, F. G. J . Org. Chem. 1987, 52, 1627-
1630.
(14) Optical rotation values of natural antofine range from -32 to
-165°. See: (a) Cave´, A.; Leboeuf, M.; Moskowitz, H.; Ranaivo, A.; Bick,
I. R. C.; Sinchai, W.; Nieto, M.; Sevenet, T.; Cabalion, P. Aust. J . Chem.
1989, 42, 2243-2263. (b) Baumgartner, B.; Erdelmeier, C. A. J .;
Wright, A. D.; Rali, T.; Sticher, O. Phytochemistry 1990, 29, 3327-
3330. (c) Li, X.; Peng, J .; Onda, M. Heterocycles 1989, 29, 1797-1808.
(d) Herbert, R. B.; Moody, C. J . Phytochemistry 1972, 11, 1184-1184.
(e) Capo, M.; Saa, J . M. J . Nat. Prod. 1989, 52, 389-390. (f) Wiegrebe,
W.; Faber, L.; Brockmann, H., J r.; Budzikiewicz, H.; Krueger, U.
Liebigs Ann. Chem. 1969, 721, 154-162. See also refs 3-5 and 12.
(15) (a) Takahata, H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Kato, A.;
Adachi, I. J . Org. Chem. 2003, 68, 3603-3607. (b) Gille, S.; Ferry, A.;
Billard, T.; Langlois, B. R. J . Org. Chem. 2003, 68, 8932-8935.
(16) For a recent review about olefin cross-metathesis, see: Connon,
S. J .; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900-1923.
(17) Employment of the first-generation Grubbs’ catalyst in the same
reaction conditions did not provide the desired heterodimers 19.
1
[R]D value {[R]21D -108.7 (c 1.03, CHCl3)} and H and 13C
NMR spectra were in agreement with those reported in
the literature.21
In conclusion, asymmetric total syntheses of the rep-
resentative naturally occurring phenanthroindolizidine
(18) Maishal, T. K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar,
A. Tetrahedron Lett. 2002, 43, 2263-2267.
(19) For a precedent about selective cross-metathesis of internal
olefins with homodimer, see: Morgan, J . P.; Morrill, C.; Grubbs, R. H.
Org. Lett. 2002, 4, 67-70.
(20) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Balasubramanian,
T.; Hassner, A. Tetrahedron: Asymmetry 1998, 9, 2201-2205.
3146 J . Org. Chem., Vol. 69, No. 9, 2004

Total Syntheses of (-)-Antofine and (-)-Cryptopleurine
residue was purified by flash silica gel column chromatography
and phenanthroquinolizidine alkaloids, (-)-antofine and
(-)-cryptopleurine, were accomplished. We developed an
efficient synthetic pathway to the important intermediate
12 in enantiomerically pure form by using a chiral
building block (R)-9 and the Overman rearrangement
with a total transfer of chirality. Construction of the
pyrrolidine and piperidine rings was successfully ac-
complished in our approach, primarily due to the use of
a metathesis reaction. We believe that the protocol
outlined above is efficient enough to apply to the syn-
thesis of other members of this important class of natural
products, as well as to other modified analogues.
(hexane/EtOAc, 3:1) to give (E)-allylic trichloroacetamide 12
(820 mg, 93%) as a white solid: mp 145-146 °C; [R]21 -22.1
D
(c 0.95, CHCl3); the enantioselectivity was determined by chiral
HPLC analysis (CHIRALCEL OD-H, hexane/2-propanol (95:
5, v/v); flow rate, 1.0 mL/min; λ 254 nm; retention time, S
(major) 29.46 min, R (minor) 38.33 min, 99% ee); 1H NMR (300
MHz, CDCl3) δ 1.62 (d, J ) 5.1 Hz, 3H), 3.08 (dd, J ) 8.4,
13.8 Hz, 1H), 3.54 (dd, J ) 5.4, 13.8 Hz, 1H), 3.99 (s, 3H),
4.09 (s, 3H), 4.13 (s, 3H), 4.81 (m, 1H), 5.47-5.64 (m, 2H), 6.79
(br d, J ) 7.5 Hz, 1H), 7.17 (dd, J ) 2.4, 8.7 Hz, 1H), 7.36 (s,
1H), 7.64 (s, 1H), 7.69 (d, J ) 8.7 Hz, 1H), 7.81 (d, J ) 2.4 Hz,
1H), 7.88 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 17.7, 38.8, 53.2,
55.4, 55.9, 56.2, 92.7, 103.7, 103.8, 104.9, 115.4, 124.7, 125.6,
126.5, 126.6, 127.6, 128.6, 128.8, 129.6, 130.6, 148.7, 149.5,
158.0, 161.0; IR (CHCl3) υmax 3335, 3002, 2938, 1703, 1611,
1474 (cm-1); MS (EI) (m/z) 495 (M+, 3), 281 (100), 265 (3), 237
Exp er im en ta l Section
(R)-5-(3,6,7-Tr im eth oxyp h en a n th r en -9-yl)p en t-3-en -2-
ol (7). To a solution of (R)-(E)-4-(tributylstannyl)but-3-en-2-
ol ((R)-9) (799 mg, 2.21 mmol) and phenanthryl bromide 84
(667 mg, 1.85 mmol) in DMF (9 mL) was added Pd(CH3CN)2Cl2
(28 mg, 0.11 mmol, 5 mol %). The reaction mixture was stirred
at room temperature for 2 h and then quenched with 10% KF
solution. After being stirred for an additional 10 min, it was
then diluted with EtOAc, washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. The resulting residue
was purified by flash silica gel column chromatography (hex-
ane/EtOAc, 1:1) to give (E)-allylic alcohol 7 (617 mg, 95%) as
a white solid: mp 139 °C; [R]20D +4.34 (c 0.91, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.25 (d, J ) 6.3 Hz, 3H), 1.60 (s, 1H),
3.75 (d, J ) 6.3 Hz, 2H), 4.00 (s, 3H), 4.02 (s, 3H), 4.10 (s,
3H), 4.31 (ddq, J ) 0.9, 6.6, 6.3 Hz, 1H), 5.67 (tdd, J ) 1.5,
6.6, 15.3 Hz, 1H), 5.94 (dtd, J ) 0.9, 6.3, 15.3 Hz, 1H), 7.17
(dd, J ) 2.4, 8.7 Hz, 1H), 7.35 (s, 1H), 7.42 (s, 1H), 7.72 (d,
J ) 8.7 Hz, 1H), 7.82 (d, J ) 2.4 Hz, 1H), 7.89 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 23.3, 36.3, 55.3, 55.6, 55.8, 68.5,
103.6, 103.7, 104.9, 115.2, 124.5, 124.6, 125.9, 126.5, 128.5,
129.5, 130.2, 130.8, 136.0, 148.4, 149.0, 157.7; IR (CHCl3) υmax
3497, 2967, 2834, 1611, 1474, 1236 (cm-1); MS (EI) (m/z) 352
(M+, 100), 281 (23), 268 (27), 105 (21), 83 (18), 71 (26), 57 (34);
HRMS (EI) calcd for C22H24O4 (M+) 352.1674, found 352.1672.
2,2,2-Tr ich lor o-a cetim id ic Acid (R)-1-Meth yl-4-(3,6,7-
tr im eth oxyp h en a n th r en -9-yl)bu t-2-en yl Ester (11). To a
solution of (E)-allylic alcohol 7 (616 mg, 1.75 mmol) in CH2Cl2
(5 mL) was added CCl3CN (0.35 mL, 3.49 mmol) and DBU
(30 µL, 0.19 mmol) at 0 °C. The reaction mixture was stirred
at 0 °C for 2 h. The volatiles were evaporated, and the residue
was purified by flash silica gel column chromatography (hex-
ane/EtOAc, 2:1, 1% triethylamine) to give trichloroacetimidate
11 (861 mg, 99%) as a colorless oil: [R]21D +22.0 (c 0.66, CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.42 (d, J ) 6.3 Hz, 3H), 3.82 (d,
J ) 6.0 Hz, 2H), 4.017 (s, 3H), 4.023 (s, 3H), 4.12 (s, 3H), 5.52
(ddq, J ) 0.9, 6.6, 6.3 Hz, 1H), 5.71 (tdd, J ) 1.5, 6.6, 15.6 Hz,
1H), 6.15 (dtd, J ) 0.9, 6.3, 15.6 Hz, 1H), 7.19 (dd, J ) 2.7,
8.7 Hz, 1H), 7.35 (s, 1H), 7.45 (s, 1H), 7.73 (d, J ) 8.7 Hz,
(5), 165 (3), 152 (3), 71 (1), 55 (1); HRMS (EI) calcd for C24H24
-
NO4Cl3 (M+) 495.0770, found 495.0772.
(S)-[1-(3,6,7-Tr im eth oxyp h en a n th r en -9-ylm eth yl)bu t-
2-en yl]ca r ba m ic Acid Ben zyl Ester (13). To a solution of
(E)-allylic trichloroacetamide 12 (531 mg, 1.07 mmol) in CH2-
Cl2 (2 mL) and EtOH (4 mL) was added 5 N NaOH (1 mL).
The reaction mixture was stirred at 50 °C for 1 day. The
volatiles were evaporated to give allylamine intermediate. To
a solution of allylamine intermediate in THF (5 mL) was added
benzyl chloroformate (0.60 mL, 4.20 mmol) at 0 °C. The
resulting mixture was stirred at room temperature for 1 h. It
was then diluted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. Purification of the
residue by flash column chromatography on silica gel (hexane/
EtOAc, 3:1) afforded the Cbz derivative 13 (454 mg, 87%) as
a white solid: mp 164 °C; [R]18D -1.71 (c 1.25, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.59 (d, J ) 4.5 Hz, 3H), 3.03 (m, 1H),
3.50 (m, 1H), 4.02 (s, 3H), 4.12 (s, 6H), 4.63 (m, 1H), 4.89 (br
s, 1H), 5.09 (br s, 2H), 5.41-5.55 (m, 2H), 7.18 (dd, J ) 2.7,
8.7 Hz, 1H), 7.33 (br s, 5H), 7.37 (s, 1H), 7.71 (d, J ) 8.7 Hz,
1H), 7.84 (d, J ) 2.1 Hz, 1H), 7.92 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 17.6, 40.3, 52.9, 55.5, 55.9, 56.2, 66.6, 103.8, 105.3,
115.3, 124.6, 125.8, 126.4, 126.9, 127.0, 128.0, 128.4, 128.7,
129.7, 130.3, 130.5, 136.5, 148.6, 149.4, 149.5, 155.7, 157.9;
IR (CHCl3) υmax 3356, 2936, 1713, 1611, 1474 (cm-1); MS (EI)
(m/z) 485 (M+, 3), 315 (5), 281 (70), 265 (3), 237 (4), 223 (3),
204 (10), 160 (23), 91 (100), 57 (3); HRMS (EI) calcd for C30H31
-
NO5 (M+) 485.2202, found 485.2204.
(S)-Allyl-[1-(3,6,7-tr im eth oxyp h en a n th r en -9-ylm eth yl)-
bu t-2-en yl]ca r ba m ic Acid Ben zyl Ester (14). To a solution
of 13 (94 mg, 0.19 mmol) in THF (4 mL) and HMPA (0.4 mL)
were added NaH (23 mg, 0.58 mmol, 60% dispersion in mineral
oil) and allyl bromide (80 µL, 0.97 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 3 h, and then
diluted with CH2Cl2, washed with brine, and dried over Na2-
SO4. The solvent was removed, and the residue was purified
by flash silica gel column chromatography (hexane/EtOAc, 3:1)
to give bis-allylamine 14 (100 mg, 100%) as a colorless oil:
[R]19D -43.1 (c 1.55, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.62
(br d, J ) 4.2 Hz, 3H), 3.25-4.04 (m, 4H), 4.01 (s, 3H), 4.11
(s, 6H), 4.82 (dd, J ) 7.2, 14.4 Hz, 1H), 5.01-5.14 (m, 4H),
5.52 (m, 1H), 5.69-5.76 (m, 2H), 7.17 (dd, J ) 2.4, 8.7 Hz,
1H), 7.11-7.31 (m, 6H), 7.61 (br s, 1H), 7.66 (d, J ) 8.7 Hz,
1H), 7.83 (d, J ) 1.5 Hz, 1H), 7.91 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 17.8, 37.4, 48.0, 55.5, 55.9, 59.3, 66.8, 103.8, 103.9,
105.0, 115.2, 116.2, 124.6, 125.9, 126.0, 126.8, 127.7, 127.8,
128.3, 128.8, 129.2, 129.4, 129.7, 130.4, 135.3, 148.5, 149.4,
155.7, 157.9; IR (CHCl3) υmax 2938, 2834, 2361, 1694, 1611,
1455 (cm-1); MS (EI) (m/z) 525 (M+, 3), 315 (3), 281 (8), 265
(3), 244 (12), 223 (3), 200 (11), 91 (100), 65 (5), 57 (4); HRMS
(EI) calcd for C33H35NO5 (M+) 525.2515, found 525.2514.
1H), 7.85 (d, J ) 2.1 Hz, 1H), 7.92 (s, 1H), 8.28 (br s, 1H); 13
C
NMR (75 MHz, CDCl3) δ 19.7, 36.4, 55.4, 55.7, 55.9, 75.7, 91.8,
103.66, 103.71, 105.0, 115.3, 124.6, 124.7, 126.0, 126.5, 129.6,
130.3, 130.5, 130.6, 131.5, 148.5, 149.0, 157.8, 161.7; IR
(CHCl3) υmax 3337, 2936, 2832, 1659, 1611, 1474 (cm-1); MS
(EI) (m/z) 495 (M+, 2), 334 (33), 319 (12), 288 (11), 281 (100),
237 (8), 202 (8), 165 (9), 152 (11), 83 (9), 57 (17); HRMS (EI)
calcd for C24H24NO4Cl3 (M+) 495.0770, found 495.0771.
(S)-2,2,2-Tr ich lor o-N-[1-(3,6,7-tr im eth oxyph en an th r en -
9-ylm eth yl)bu t-2-en yl]a ceta m id e (12). A solution of trichlo-
roacetimidate 11 (884 mg, 1.78 mmol) in toluene (18 mL) was
heated to reflux for 12 h. The solvent was removed, and the
(21) Optical rotation values of natural cryptopleurine range from
-96.7 to -106°. See: (a) Gellert, E.; Riggs, N. V. Aust. J . Chem. 1954,
7, 113-114. (b) Suzuki, H.; Aoyagi, S.; Kibayashi, C. J . Org. Chem.
1995, 60, 6114-6122. (c) Suzuki, H.; Aoyagi, S.; Kibayashi, C.
Tetrahedron Lett. 1995, 36, 935-936. See also refs 3, 7, and 12.
(S)-2-(3,6,7-Tr im et h oxyp h en a n t h r en -9-ylm et h yl)-2,5-
d ih yd r o-p yr r ole-1-ca r boxylic Acid Ben zyl Ester (16). To
a solution of bis-allylamine 14 (153 mg, 0.29 mmol) in CH2Cl2
(3 mL) was added second-generation Grubbs’ catalyst 15 (12
J . Org. Chem, Vol. 69, No. 9, 2004 3147

Kim et al.
mg, 0.01 mmol). The reaction mixture was stirred at room
temperature for 2 h. The volatiles were removed, and the
residue was purified by flash silica gel column chromatography
(hexane/EtOAc, 3:1 to 1:2, gradient) to give 2,5-dihydropyrrole
(S)-5-Ben zyloxyca r b on yla m in o-6-(3,6,7-t r im et h oxy-
p h en a n th r en -9-yl)h ex-3-en yl Aceta te (19). To a solution
of 13 (206 mg, 0.424 mmol) and homoallyl acetate homodimer
18 (171 mg, 0.854 mmol) in CH2Cl2 (10 mL) was added second-
generation Grubbs’ catalyst 15 (19 mg, 0.022 mmol). The
reaction mixture was heated to reflux for 1 day and then cooled
to room temperature. It was concentrated to dryness. The
residue was purified by flash column chromatography on silica
gel (hexane/EtOAc, 3:1 to 1:1, gradient) to give 19 (193 mg,
82%) as a colorless oil and 13 (29 mg, 14%): 1H NMR (300
MHz, CDCl3) (E/Z mixture, ratio 8:1) (E)-isomer δ 1.93 (s, 3H),
2.25 (m, 2H), 3.01 (m, 1H), 3.54 (m, 1H), 3.89-3.96 (m, 2H),
4.02 (s, 3H), 4.12 (s, 6H), 4.65 (m, 1H), 4.90 (br s, 1H), 5.09 (s,
2H), 5.37-5.47 (m, 1H), 5.56 (dd, J ) 6.0, 15.6 Hz, 1H), 7.18
(dd, J ) 2.4, 9.0 Hz, 1H), 7.33 (br s, 6H), 7.36 (s, 1H), 7.70 (d,
J ) 8.7 Hz, 1H), 7.84 (d, J ) 2.4 Hz), 7.92 (s, 1H), (Z)-isomer
δ 1.84 (s, 3H), 2.25 (m, 2H), 3.56-3.66 (m, 2H), 3.89-3.96 (m,
2H), 4.02 (s, 3H), 4.12 (s, 6H), 4.84-4.92 (m, 2H), 5.11 (s, 2H),
5.34-5.48 (m, 2H), 7.17 (dd, J ) 2.7, 9.0 Hz, 1H), 7.33 (br s,
7H), 7.69 (d, J ) 8.7 Hz, 1H), 7.83 (br d, J ) 1.8 Hz), 7.91 (s,
1H); 13C NMR (75 MHz, CDCl3) (E)-isomer δ 20.7, 31.4, 40.2,
52.6, 55.4, 55.9, 56.1, 63.4, 66.6, 103.7, 105.1, 115.3, 124.6,
125.6, 126.3, 126.7, 127.2, 128.0, 128.4, 129.6, 130.5, 131.8,
136.4, 148.6, 149.5, 155.6, 157.9, 170.8; IR (CHCl3) υmax 3360,
2938, 1715, 1611, 1473, 1145 (cm-1); MS (EI) (m/z) 557 (M+,
8), 463 (3), 449 (5), 281 (100), 237 (7), 91 (31); HRMS (CI) calcd
for C33H36NO7 ([M + H]+) 558.2492, found 558.2491.
16 (138 mg, 98%) as a white solid: mp 184-186 °C; [R]19
D
+14.0 (c 1.41, CHCl3); 1H NMR (300 MHz, CDCl3) (two
rotamers in a 5:2 ratio) major rotamer δ 2.79 (dd, J ) 10.8,
12.9 Hz, 1H), 4.01-4.27 (m, 3H), 4.02 (s, 3H), 4.13 (s, 3H),
4.21 (s, 3H), 5.02 (m, 1H), 5.21 (d, J ) 12.3 Hz, 1H), 5.28 (d,
J ) 12.3 Hz, 1H), 5.73 (m, 2H), 7.18 (dd, J ) 2.7, 8.7 Hz, 1H),
7.34-7.44 (m, 6H), 7.73 (d, J ) 7.8 Hz, 1H), 7.86 (d, J ) 2.4
Hz, 1H), 7.93 (s, 1H), 8.15 (s, 1H), minor rotamer δ 2.93 (dd,
J ) 9.9, 13.5 Hz, 1H), 3.74 (s, 1H), 3.93-4.35 (m, 3H), 4.02 (s,
3H), 4.10 (s, 3H), 5.08 (m, 1H), 5.24 (d, J ) 12.3 Hz, 1H), 5.35
(d, J ) 12.3 Hz, 1H), 5.52 (m, 1H), 5.77 (m, 1H), 7.19 (dd, J )
2.1, 8.7 Hz, 1H), 7.31-7.46 (m, 7H), 7.70 (d, J ) 8.7 Hz, 1H),
7.84 (d, J ) 2.1 Hz, 1H), 7.91 (s, 1H); 13C NMR (75 MHz,
CDCl3) (two rotamers ratio 5:2) major rotamer δ 39.1, 53.6,
55.5, 56.0, 56.6, 64.8, 66.6, 103.5, 103.8, 106.2, 115.3, 124.7,
125.0, 125.9, 127.1, 127.88, 127.94, 128.5, 128.6, 129.5, 129.6,
130.3, 130.4, 137.0, 148.7, 149.7, 154.7, 157.9, minor rotamer
δ 39.8, 54.1, 55.6, 64.0, 67.2, 105.2, 115.5, 124.6, 126.3, 128.2,
129.7, 130.6, 149.4; IR (CHCl3) υmax 2936, 1699, 1611, 1472
(cm-1); MS (EI) (m/z) 483 (M+, 1), 316 (8), 282 (16), 237 (3),
223 (1), 202 (4), 158 (11), 152 (2), 91 (100), 65 (8), 51 (2); HRMS
(EI) calcd for C30H29NO5 (M+) 483.2045, found 483.2044.
(R)-2-(3,6,7-Tr im et h oxyp h en a n t h r en -9-ylm et h yl)p yr -
r olid in e (4). To a solution of 16 (73 mg, 0.15 mmol) in MeOH
(6 mL) was added 10% Pd/C (73 mg, 100 wt %). The reaction
mixture was hydrogenated (1 atm) with vigorous stirring at
room temperature for 2 h. It was then diluted with CH2Cl2,
filtered through Celite, and concentrated. The residue was
purified by flash silica gel column chromatography (CH2Cl2/
MeOH, 7:1, 1% NH4OH) to give 2-arylmethylpyrrolidine 4 (33
(R)-5-Am in o-6-(3,6,7-tr im eth oxyp h en a n th r en -9-yl)h ex-
yl Aceta te (20). Following the same procedure as for 4, from
E/Z mixture 19 (290 mg, 0.520 mmol) in MeOH (5 mL) and
10% Pd/C (145 mg, 50 wt %), after a reaction time of 4 h, free
amine 20 (210 mg, 95%) was obtained as a colorless oil: [R]20
D
1
-12.6 (c 1.18, CHCl3); H NMR (300 MHz, CDCl3) δ 1.43 (m,
1H), 1.64 (m, 5H), 1.99 (s, 3H), 2.68 (dd, J ) 8.1, 13.2 Hz, 1H),
3.05 (m, 1H), 3.27-3.39 (m, 2H), 3.99-4.12 (m, 2H), 4.01 (s,
3H), 4.03 (s, 3H), 4.10 (s, 3H), 7.18 (dd, J ) 2.4, 8.7, 1H), 7.37
(s, 1H), 7.48 (s, 1H), 7.75 (d, J ) 8.7 Hz, 1H), 7.83 (d, J ) 2.4
Hz, 1H), 7.91 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.6, 22.5,
28.4, 37.1, 41.7, 50.6, 55.1, 55.4, 55.5, 64.0, 103.3, 103.5, 104.4,
115.1, 124.5, 125.5, 126.1, 129.3, 129.7, 130.1, 148.3, 148.8,
157.6, 170.7; IR (CHCl3) υmax 3462, 2936, 1734, 1609, 1474,
1113 (cm-1); MS (EI) (m/z) 425 (M+, 3), 282 (100), 267 (6), 144
(26), 84 (28); HRMS (EI) calcd for C25H31NO5 (M+) 425.2202,
found 425.2205.
(R)-5-Am in o-6-(3,6,7-tr im eth oxyp h en a n th r en -9-yl)h ex-
a n -1-ol (21). To a solution of 20 (177 mg, 0.416 mmol) in
MeOH (4 mL) was added 5 N NaOH (1 mL) at room temper-
ature. The reaction mixture was stirred at room temperature
for 1 day. After the reaction mixture was cooled to room
temperature, water was added. The resulting mixture was
extracted with EtOAc twice. The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. Purification of the residue by flash column
chromatography on silica gel (CH2Cl2/MeOH, 9:1 to 4:1,
gradient) gave amino alcohol 21 (143 mg, 90%) as a milky oil:
[R]20D -46.1 (c 0.89, CHCl3); 1H NMR (300 MHz, CDCl3 + CD3-
OD) δ 1.45 (m, 6H), 2.68 (dd, J ) 8.1, 13.2 Hz, 1H), 3.12-3.20
(m, 2H), 3.46 (m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 3.94 (s, 3H),
7.05 (dd, J ) 2.4, 8.7, 1H), 7.16 (s, 1H), 7.30 (s, 1H), 7.60 (d,
J ) 8.7 Hz, 1H), 7.66 (br d, J ) 1.5 Hz, 1H), 7.74 (s, 1H); 13C
NMR (75 MHz, CDCl3 + CD3OD) δ 22.0, 32.0, 36.1, 40.8, 50.4,
55.1, 55.5, 55.6, 61.3, 103.4, 103.7, 104.4, 115.3, 124.7, 125.5,
125.7, 126.0, 129.1, 129.4, 130.2, 148.4, 148.9, 157.7; IR
(CHCl3) υmax 3351, 2934, 1609, 1474, 1113 (cm-1); MS (EI)
(m/z) 383 (M+, 3), 282 (100), 102 (43), 85 (40); HRMS (EI) calcd
for C23H29NO4 (M+) 383.2096, found 383.2095.
mg, 63%) as a white solid: mp 144-148 °C; [R]18 -5.61 (c
D
0.95, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.57 (m, 1H), 1.74
(m, 1H), 1.88 (m, 2H), 2.85-2.94 (m, 2H), 3.11 (m, 1H), 3.22
(dt, J ) 6.9, 14.1 Hz, 2H), 3.56 (dt, J ) 14.1, 6.6 Hz, 1H), 3.99
(s, 3H), 4.05 (s, 3H), 4.09 (s, 3H), 7.17 (dd, J ) 2.4, 8.7 Hz,
1H), 7.41 (s, 1H), 7.48 (s, 1H), 7.74 (d, J ) 8.7 Hz, 1H), 7.80
(d, J ) 2.4 Hz, 1H), 7.89 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
23.9, 30.9, 37.4, 45.2, 55.4, 55.9, 56.4, 59.2, 103.7, 103.8, 104.5,
115.4, 124.6, 125.2, 125.7, 126.2, 128.9, 129.8, 130.5, 148.7,
149.5, 158.0; IR (KBr) υmax 2934, 2831, 1611, 1516 (cm-1); MS
(FAB) (m/z) 352 ([M + H]+, 51), 282 (23), 154 (13), 136 (11),
70 (100); HRMS (FAB) calcd for C22H26NO3 ([M + H]+)
352.1913, found 352.1905.
(-)-An tofin e (2). To a solution of 2-arylmethylpyrrolidine
4 (33 mg, 0.09 mmol) in EtOH (2 mL) was added 37%
formaldehyde (500 µL) and concentrated HCl (50 µL). The
reaction mixture was refluxed for 3 days in the dark. The
reaction mixture was concentrated to dryness under reduced
pressure. The residue was dissolved in CH2Cl2 and treated
with 10% HCl. The aqueous layer was extracted with CH2Cl2
twice, and the combined organic extracts were washed with
water and brine, dried over MgSO4, filtered, and concentrated
in vacuo. Purification of the residue by flash column chroma-
tography on silica gel (CH2Cl2/MeOH, 10:1) afforded the
desired product (-)-antofine (2) (27 mg, 80%) as a white
solid: mp 212-214 °C (lit.14 mp 206-211 °C); [R]19D -125.2 (c
1.27, CHCl3); 1H NMR (600 MHz, CDCl3) δ 1.74 (m, 1H), 1.89
(m, 1H), 2.02 (m, 1H), 2.21 (m, 1H), 2.42 (m, 2H), 2.86 (m,
1H), 3.28 (dd, J ) 2.4, 15.6 Hz, 1H), 3.44 (dt, J ) 1.8, 8.5 Hz,
1H), 3.64 (d, J ) 14.7 Hz, 1H), 3.99 (s, 3H), 4.04 (s, 3H), 4.08
(s, 3H), 4.66 (d, J ) 14.7 Hz, 1H), 7.18 (dd, J ) 2.5, 9.0 Hz,
1H), 7.27 (s, 1H), 7.78 (d, J ) 9.0 Hz, 1H), 7.86 (d, J ) 2.5 Hz,
1H), 7.87 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 21.5, 31.2,
33.6, 53.8, 55.0, 55.4, 55.8, 55.9, 60.1, 103.8, 103.9, 104.6, 114.8,
123.5, 124.1, 124.2, 125.5, 126.6, 127.0, 130.1, 148.3, 149.3,
157.4; IR (KBr) υmax 1622, 1512 (cm-1); MS (EI) (m/z) 363
(M+, 24), 294 (100), 279 (11); HRMS (CI) calcd for C23H26NO3
([M + H]+) 364.1912, found 364.1913.
(R)-2-(3,6,7-Tr im eth oxyph en an th r en -9-ylm eth yl)piper -
id in e (5). To a solution of amino alcohol 21 (61 mg, 0.159
mmol) in CH2Cl2 (16 mL) were added DIAD (80 µL, 0.406
mmol) and PPh3 (106 mg, 0.404 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 15 h. The solvent
was removed, and the residue was purified by flash silica gel
3148 J . Org. Chem., Vol. 69, No. 9, 2004

Total Syntheses of (-)-Antofine and (-)-Cryptopleurine
column chromatography (CH2Cl2/MeOH, 10:1) to give 2-aryl-
(d, J ) 11.1 Hz, 1H), 3.63 (d, J ) 15.4 Hz, 1H), 4.01 (s, 3H),
4.06 (s, 3H), 4.10 (s, 3H), 4.44 (d, J ) 15.4 Hz, 1H), 7.19 (dd,
J ) 2.4, 9.0 Hz, 1H), 7.25 (s, 1H), 7.79 (d, J ) 9.0 Hz, 1H),
7.89 (d, J ) 2.4 Hz, 1H), 7.90 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 24.6, 26.2, 34.0, 34.9, 55.7, 56.1, 56.2, 56.5, 57.8,
104.1, 104.1, 105.0, 115.0, 123.6, 123.9, 124.3, 124.7, 125.8,
126.7, 130.3, 148.5, 149.6, 157.6; IR (CHCl3) υmax 2930, 1611,
1470, 1125 (cm-1); MS (EI) (m/z) 377 (M+, 32), 294 (100), 279
(15), 251 (17), 208 (15), 189 (14), 165 (17), 83 (10), 69 (9), 55
(27); HRMS (EI) calcd for C24H27NO3 (M+) 377.1991, found
377.1992.
methylquinolizidine 5 (39 mg, 68%) as a white solid: mp 147-
148 °C; [R]20 -18.8 (c 0.99, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.25 (m, 2H), 1.73-1.83 (m, 5H), 1.97 (m, 1H), 2.87
(dt, J ) 2.4, 12.6 Hz, 1H), 3.26-3.33 (m, 2H), 3.54 (br d, J )
12.3 Hz, 1H), 3.99 (s, 3H), 4.08 (s, 3H), 4.19 (s, 3H), 7.14 (dd,
J ) 2.4, 9.0 Hz, 1H), 7.41 (s, 1H), 7.61 (s, 1H), 7.64 (d, J ) 9.0
Hz, 1H), 7.78 (d, J ) 2.4 Hz, 1H), 7.86 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 22.6, 22.7, 28.7, 37.8, 45.1, 55.5, 55.9, 56.7,
57.1, 103.8, 103.9, 105.0, 115.4, 124.8, 125.5, 126.2, 126.8,
126.9, 129.8, 130.7, 148.8, 149.9, 158.1; IR (KBr) υmax 3400,
2938, 1611, 1474, 1113 (cm-1); MS (EI) (m/z) 365 (M+, 1), 282
(27), 84 (100); HRMS (CI) calcd for C23H28NO3 ([M + H]+)
366.2069, found 366.2066.
Ack n ow led gm en t. This study was supported by a
grant from the Korea Health 21 R&D Project, Ministry
of Health & Welfare, Republic of Korea (01-PJ 2-PG6-
01NA01-0002).
(-)-Cr yp top leu r in e (3). Following the same procedure as
for 2, from 2-arylmethylquinolizidine 5 (26 mg, 71 µmol) in
EtOH (2 mL), 37% formaldehyde (500 µL), and concentrated
HCl (40 µL), after a reaction time of 2 days, (-)-cryptopleurine
(3) (18 mg, 67%) was obtained as a white solid: mp 191-192
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
°C (lit.21 195-197 °C); [R]21 -108.7 (c 1.03, CHCl3); 1H NMR
and 13C NMR spectra of compounds 2-5, 7, 12-14, and 19
and HPLC data of compound 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
D
(500 MHz, CDCl3) δ 1.45 (m, 1H), 1.54 (m, 1H), 1.77-1.81 (m,
2H), 1.88 (d, J ) 12.2 Hz, 1H), 2.03 (d, J ) 11.5 Hz, 1H), 2.30
(dt, J ) 3.9, 11.2 Hz, 1H), 2.39 (t, J ) 10.1 Hz, 1H), 2.88 (dd,
J ) 10.7, 15.9 Hz, 1H), 3.08 (dd, J ) 3.1, 16.4 Hz, 1H), 3.27
J O049820A
J . Org. Chem, Vol. 69, No. 9, 2004 3149