Efficient syntheses of oncinotine and neooncinotine

Article abstract of DOI:10.1021/jo049526i

We have synthesized two natural alkaloids, oncinotine (1) and neooncinotine (2), by means of efficient ring-closing metathesis (RCM) reactions. The required dienes for RCM were assembled from three basic components: 2-allylpiperidine (5), 9-decenoic acid (6), and diamines 7. We developed two different methods to achieve the linkage: the Michael addition of acrylamide and two amidations of succinic anhydride. The Grubbs catalyst was used to form the 17- and 18-membered lactams in 50% and 68% yields, respectively.

Full text of DOI:10.1021/jo049526i

Efficien t Syn th eses of On cin otin e a n d Neoon cin otin e
Duen-Ren Hou,*,† Hsiu-Yi Cheng,‡ and Eng-Chi Wang‡
Department of Chemistry, National Central University, J ung-Li City, Taoyuan, Taiwan 320, ROC,
and Graduate Institute of Pharmaceutical Science, Kaohsiung Medical University,
Kaohsiung, Taiwan 807, ROC
drhou@cc.ncu.edu.tw
Received March 23, 2004
We have synthesized two natural alkaloids, oncinotine (1) and neooncinotine (2), by means of
efficient ring-closing metathesis (RCM) reactions. The required dienes for RCM were assembled
from three basic components: 2-allylpiperidine (5), 9-decenoic acid (6), and diamines 7. We developed
two different methods to achieve the linkage: the Michael addition of acrylamide and two amidations
of succinic anhydride. The Grubbs catalyst was used to form the 17- and 18-membered lactams in
50% and 68% yields, respectively.
In tr od u ction
Polyamines, such as spermidine and spermine, are
present in a wide range of organisms from bacteria to
plants and animals, and interest in these compounds is
increasing because of their important role in cell growth.1
Oncinotine (1) and neooncinotine (2), which can be
isolated from the stem bark of Oncinotisnitida (Apocyn-
aceae), belong to the spermidine group.2,3 Both com-
pounds are macrocyclic lactams fused with a piperidine
unit and they differ only by the relative orientation of
the spermidine moiety incorporated into the macrocyclic
ring, i.e., oncinotine contains a 17-membered ring and a
4-aminobutyl side chain; on the other hand, neooncino-
tine has an 18-membered ring and a 3-aminopropyl side
chain.
macrocyclic rings were achieved through the formation
of the amide bonds4 or by reductive amination,5 which
meant that the preparation of lengthy carbon chains was
inevitable and laborious. Multiple protections and depro-
tections were required, even though the final products
contain only the functional groups associated with amines
and lactams.
The Hesse and Schmid groups have both reported
syntheses of these alkaloids, and Kibayashi’s group has
developed an enantioselective synthesis to (-)-oncino-
tine.4,5 In these syntheses, the constructions of the
Recently, ring-closing metathesis (RCM) has evolved
as a powerful tool for forming medium and large rings,
which are rather difficult to prepare with more-conven-
tional methods.6 Applying RCM to the synthesis of the
oncinotines provides a new route to the formation of the
macrolactams in which the problems of the previous
syntheses can be circumvented. Herein, we report our
results regarding the use of ring-closing metathesis to
prepare oncinotine and neooncinotine.
* Address correspondence to this author.
† National Central University.
‡ Kaohsiung Medical University.
(1) (a) Walters, D. R. Phytochemistry 2003, 64, 97-107. (b) Wallace,
H. M.; Fraser, A. V.; Hughes, A. Biochem. J . 2003, 376, 1-14. (c)
Bergeron, R. J .; McManis, J . S.; Weimar, W. R.; Schreier, K.; Gao, F.;
Wu, Q.; Ortiz-Ocasio, J .; Luchetta, G. R.; Porter, C.; Vinson, J . R. T.
J . Med. Chem. 1995, 38, 2278-2285. (d) Pegg, A. Biochem. J . 1986,
234, 249-262. (e) Tabor, C. W.; Tabor, H. Annu. Rev. Biochem. 1984,
53, 749-790. (f) J a¨nne, J .; Po¨so¨, H.; Raina, A. Biochim. Biophys. Acta
1978, 473, 241-293.
(2) (a) Badawi, M. M.; Guggisberg, A.; van den Broek, P.; Hesse,
M.; Schmid, H. Helv. Chim. Acta 1968, 51, 1813-1817. (b) Guggisberg,
A.; Badawi, M. M.; Hesse, M.; Schmid, H. Helv. Chim. Acta 1974, 57,
414-434.
(3) For a review of marcrocyclic spermidine alkaloids, see: Guggis-
berg, A.; Hesse, M. In The Alkaloids; Cordell, G. A., Ed.: Academic
Press: San Diego, CA, 1998; Vol. 50, Chapter 6, pp 210-256.
(4) (a) Schneider, F.; Bernauer, K.; Guggisberg, A.; van den Broek,
P.; Hesse, M.; Schmid, H. Helv. Chim. Acta 1974, 57, 434-440. (b)
Guggisberg, A.; van den Broek, A.; Hesse, M.; Schmid, H.; Schneider,
F.; Bernauer, K. Helv. Chim. Acta 1976, 59, 3013-3025. (c) Bienz, S.;
Guggisberg, A.; Walchli, R.; Hesse, M. Helv. Chim. Acta 1988, 71,
1708-1718. (d) Doll, M. K.-H.; Guggisberg, A.; Hesse, M. Helv. Chim.
Acta 1996, 79, 973-981.
Scheme 1 displays our strategy toward these macro-
cyclic compounds. With the aim of using ring-closing
(5) (a) Ina, H.; Ito, M.; Kibayashi, C. J . Org. Chem.1996, 61, 1023-
1029. (b) Ina, H.; Ito, M.; Kibayashi, C. J . Chem. Soc., Chem. Commun.
1995, 10, 1015-1016.
(6) For recent reviews on the use of ring-closing metathesis in
synthesis, see: (a) Alkene Metathesis in Organic Synthesis; Fu¨rstner,
A., Ed., Springer-Verlag: Berlin, Germany, 1998. (b) Fu¨rstner, A.
Angew. Chem., Int. Ed. Engl. 2000, 39, 3012-3043. (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29. (d) Naota, T.; Takaya,
H.; Murahashi, S.-I. Chem. Rev. 1998, 98, 2599-2660. (e) Yet, L. Chem.
Rev. 2000, 100, 2963-3008 and references therein.
10.1021/jo049526i CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/10/2004
6094
J . Org. Chem. 2004, 69, 6094-6099

Syntheses of Oncinotine and Neooncinotine
SCHEME 1. Retr osyn th etic An a lysis of 1 a n d 2
SCHEME 2. P r ep a r a tion of 5a
a
Reagents and conditions: (a) ref 11a; (b) TFA, CH2Cl2, 99%.
SCHEME 3. P r ep a r a tion of 7a
metathesis, the retrosyntheses of the oncinotines led to
the alkenes 3 and their precursors, the dienes 4. In fact,
there are several possible combinations of dienes 4 that,
in theory, can be used for RCM reactions, but we chose
dienes 4a and 4b after taking the following points into
consideration. It is known that the metathesis reaction
is sensitive to the groups surrounding the olefins; for
example, vicinal polar groups7 and sterically hindered
carbon atoms attached to the olefinic units usually retard
metathesis reactions.8 Therefore, a piperidine bearing a
remote olefin side chain is preferred. Recent studies in
ring-closing metathesis have shown that the Grubbs
catalyst can tolerate homoallylic amines, such as those
in 4a and 4b.9 The accessibility of the substrates to form
the dienes 4 is also an important factor. Since the length
of the carbon chain in 3 is fixed (x + y ) 8), the
availability of both converging alkenes, the piperidine 5
and the alkenoic acid 6, must be considered. After
searching the literature, we found that methods for
preparing 2-substituted alkenyl piperidines are rarer for
molecules in which the terminal olefin is more distant
from the piperidine unit.10-13 In addition, commercial
supplies of 8-nonenoic acid/alcohol and 7-octenoic acid/
a
Reagents and conditions: (a) K2CO3, BnNEt3Cl, acetone, rt
(8a : 75%; 8b: 80%); (b) Bn2NH, xylene, reflux, (7a : 75%; 7b:
80%); (c) H2NNH2, EtOH, reflux (7a : 56%; 7b: 54%).
alcohol are very limited. In contrast, the key components
of 4a and 4b are more easily obtained: the 2-allylpip-
eridine 5 has been reported by several groups,11 and its
counterpart alkene is derived from 9-decenoic acid (6).
Connecting diamines 7 and piperidine 5 with proper
linkers leads to the spermidine moiety of these alkaloids,
at which point the dienes 4a and 4b are ready for ring
closure.
Resu lts a n d Discu ssion
2-Allylpiperidine 5 was prepared from the commer-
cially available 2-piperidineethanol by using a procedure
based on that reported by Ikeda’s group; the product was
stored as its trifluoroacetate salt for further reactions
(Scheme 2).11a The required decenoic acid 6 was prepared
from the oxidation of 9-decenol.14 We applied the Gabriel
synthesis to form diamines 7, as depicted in Scheme 3.
After alkylating dibenzylamine with N-4-bromobutyl- and
N-3-bromopropylphthalimides (8a and 8b), we depro-
tected 9a ,b using hydrazine to give diamines 7a ,b.
With the three components in handsthe piperidine 5,
the diamines 7, and the acid 6sthe next step was to
connect these moieties with suitable methylene linkers
to form dienes 4a ,b. Although synthetic methods to
prepare linear polyamines such as spermidines have been
developed,15 we have found them difficult to apply when
piperidine 5 and diamines 7 are present as subunits. We
attempted several approaches, of which the following two
routes proved to be effective (Schemes 4 and 5). The
Michael addition of diamine 7a to acrylamide 10 was the
central step in the preparation of the precursor of
oncinotine, diene 4a . Thus, acrylamide 10, prepared from
piperidine 5 and acryloyl chloride, was heated under
reflux with diamine 7a to give the Michael adduct 11.
Amide 11 was then reduced with lithium aluminum
hydride and coupled with acid 6 to give diene 4a .
(7) Fu¨rstner, A.; Thiel, O. R.; Lehmann, C. W. Organometallics 2002,
21, 331-335. (b) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-
803. (c) Fu¨rstner, A.; J eanjean, F.; Razon, P. Angew. Chem., Int. Ed.
2002, 41, 2097-2101.
(8) Kirkland, T. A.; Grubbs, R. H. J . Org. Chem. 1997, 62, 7310-
7318.
(9) The ring-closing metathesis of allylic and homoallylic amines is
known. See: (a) Salim, S. S.; Bellingham, R. K.; Satcharoen, V.; Brown,
R. C. D. Org. Lett. 2003, 5, 3403-3406. (b) Edwards, A. S.; Wybrow,
R. A.; J ohnstone, C.; Adams, H.; Harrity, J . P. A. Chem. Commun.
2002, 1542-1543. (c) Wright, D. L.; Schulte, J . P.; Page, M. A. Org.
Lett. 2000, 2, 1847-1850.
(10) For selected syntheses of 2-vinylpiperidine, see: (a) Cohen, H.
L.; Minsk, L. M. J . Am. Chem. Soc. 1957, 79, 1759-1762. (b) Hassner,
A.; Maurya, R.; Padwa, A.; Bullock, W. H. J . Org. Chem. 1991, 56,
2775-2781. (c) Mori, M.; Kanda, N.; Oda, I.; Ban, Y. Tetrahedron 1985,
41, 5465-5474. (d) Yang, S.-C.; Shea, F.-R.; Chung, W.-H. J . Chin.
Chem. Soc. 1998, 45, 293-296. (e) Brosius, A. D.; Overman, L. E.;
Schwink, L. J . Am. Chem. Soc. 1999, 121, 700-709.
(11) For selected syntheses of 2-allylpiperidine, see: (a) Ikeda, M.;
Kugo, Y.; Sato, T. J . Chem. Soc., Perkin Trans. 1 1996, 1819-1824.
(b) Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J . Am. Chem. Soc. 2003,
125, 14133-14139. (c) Takahata, H.; Kubota, M.; Takahashi, S.;
Momose, T. Tetrahedron: Asymmetry 1996, 7, 3047-3054. (d) Arm-
strong, S. K.; Collington, E. W.; Stonehouse, J .; Warren, S. J . Chem.
Soc., Perkin Trans. 1 1994, 2825-2831. (e) Wanner, K. T.; Waden-
storfer, E.; Kaertner, A. Synlett 1991, 11, 797-799. (f) Meyers, A. I.;
Edwards, P. D.; Rieker, W. F.; Bailey, T. R. J . Am. Chem. Soc. 1984,
106, 3270-3276.
(12) For the synthesis of 2-(3-butenyl)piperidine, see: Szychowski,
J .; Wrobel, J . T.; Leniewski, A. Bull. Acad. Pol. Sci., Ser. Sci. Chim.
1980, 28, 9-17.
(14) Yates, P.; Wong, J .; McLean, S. Tetrahedron 1981, 37, 3357-
3363.
(13) (4-Penten-1-yl)piperidine has been reported; see: J ones, T. H.;
Blum, M. S.; Fales, H. M. Tetrahedron 1982, 38, 1949-1958. To the
best of our knowledge, other piperidines having longer terminal alkene
units substituted in the 2-position have not been reported.
(15) For reviews on polyamine synthesis, see: (a) Karigiannis, G.;
Papaioannou, D. Eur. J . Org. Chem. 2000, 1841-1863. (b) Pak, J . K.;
Guggisberg, A.; Hesse, M. Tetrahedron 1998, 54, 8035-8046. (c)
Bergeron, R. J . Acc. Chem. Res. 1986, 19, 105-113.
J . Org. Chem, Vol. 69, No. 18, 2004 6095

Hou et al.
SCHEME 4. Syn th esis of 4a a
SCHEME 6. Rin g-Closin g Meta th eses To F or m 1
a n d 2a
a
Reagents and conditions: (a) acryloyl chloride, Et3N, CH2Cl2,
0 °C, 99%; (b) 7a , toluene, reflux, 80%; (c) LiAlH4, THF, reflux,
95%; (d) (i) 6, SOCl2, reflux; (ii) 12, Et3N, CH2Cl2, 0 °C, 86%.
SCHEME 5. Syn th esis of 4ba
a
Reagents and conditions: (a) Grubbs catalyst 16, HCl(aq)
,
CH2Cl2, reflux (3a : 50%; 3b: 68%); (b) H2, Pd/C (17a : 87%; 17b:
99%); (c) NH4CO2H, Pd(OH)2/C, ethanol, reflux (1: 74%; 2: 70%).
17b with H2/Pd/C occurred only at elevated tempera-
tures.4b 1H NMR spectroscopy indicated that deprotection
of 17a ,b over Pd/C did not reach completion, even after
4 h at 60 °C, and the concentrations of the impurities
grew gradually as the reaction continued. Fortunately,
debenzylation with Pearlman’s catalyst, Pd(OH)2/C, and
ammonium formate gave cleaner products (1 and 2).18
We also found that direct hydrogenations of alkenes 3a ,b
using Pearlman’s catalyst were not as clean as the
products from the stepwise reactions.
a
Reagents and conditions: (a) succinic anhydride, K2CO3, DMF,
rt, 91%; (b) 7b, N,N’-diisopropylcarbodiimide, CH2Cl2, 82%; (c)
LiAlH4, THF, reflux, 96%; (d) (i) 6, SOCl2, reflux; (ii) 15, Et3N,
CH2Cl2, 0 °C, 85%.
In summary, we have developed efficient methods for
the syntheses of oncinotine and neooncinotine. Only the
preparations of diamines 7 and piperidine 5 involve
protection/deprotection steps, and just six further steps
were required to form these macrocyclic alkaloids once
the three components 5, 6, and 7 were obtained. The total
yields of oncinotine and neooncinotine from 2-pipe-
ridineethanol were 10% and 14%, respectively. These
concise syntheses clearly show the merits of ring-closing
metathesis for preparing macrocyclic compounds. Asym-
metric versions of these syntheses should be feasible by
incorporating the known chiral 2-(2-hydroxyethyl)pip-
eridine as a starting material.19
In contrast, we used succinic anhydride to provide the
four bridging methylene units of 4b, the precursor of
neooncinotine. The acylation of piperidine 5 with succinic
anhydride was achieved in high yield. The resulting
carboxylic acid (13) was coupled with diamine 7b by
using N,N’-diisopropylcarbodiimide (DIC). The product
diamide (14) was reduced to triamine 15, which was
coupled with 6 to form diene 4b. Each of these transfor-
mations was accomplished in good yield.
In preparing the two precursors 4a ,b, we observed also
the rotational isomers of amides 10, 11, 13, 14, 4a , and
4b in their NMR spectra.
The Grubbs’ second-generation catalyst was used to
achieve the ring closures.16 Brown’s group recently
reported that ring-closing metatheses of amines can be
performed under neutral or basic conditions,9a but we
obtained the cyclized products 3a and 3b only under
acidic conditions and heating under reflux in dichlo-
romethane. These results are similar to those reported
by the Grubbs and Wright groups.9c,17 Both dienes 4a and
4b gave similar yields in their cyclizations, so it appears
that the size of the ring, 17- or 18-membered, is not a
critical issue here.
Exp er im en ta l Section
2-Allylp ip er id in e (5). Trifluoroacetic acid (3 mL) was
added to a solution of tert-butyl 2-allylpiperidine-1-carboxylate
(2.0 g, 8.87 mmol) in CH2Cl2 (3 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 2 h. The excess trifluoroacetic
acid and solvent were removed under vacuum to give the
trifluoroacetate salt of 5 (2.13 g, 8.87 mmol, 99%). 1H NMR
(CDCl3, 200 MHz) δ 1.45-1.57 (m, 2H), 1.71-1.92 (m, 4H),
2.26-2.48 (m, 2H), 2.60-3.05 (m, 2H), 3.29-3.36 (d, J ) 13.3
Hz, 1H), 5.07-5.16 (m, 2H), 5.62-5.76 (m, 1H), 8.89 (br, 1H),
9.34 (br, 1H). 13C NMR (CDCl3, 50 MHz) δ 130.3, 121.1, 57.3,
45.6, 37.8, 28.4, 22.2, 21.0. MS (CI) m/z 126 (C8H16N) [M +
H]+.
Hydrogenation of the lactams 3a and 3b at room
temperature provided compounds 17a and 17b. As
reported by Hesse and co-workers, the debenzylation of
(18) (a) Wang, Y.; Dong, X.; Larock, R. C. J . Org. Chem. 2003, 68,
3090-3098. (b) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry
1996, 7, 1919-1922. (c) Pearlman, W. M. Tetrahedron Lett. 1967, 1663.
(19) Toy, M. S.; Price, C. C. J . Am. Chem. Soc. 1960, 82, 2613-
2616.
(16) Scholl, S.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956.
(17) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc. 1993,
115, 9856-9857.
6096 J . Org. Chem., Vol. 69, No. 18, 2004

Syntheses of Oncinotine and Neooncinotine
N-(4-Br om obu tyl)p h th a lim id e (8a ). Phthalimide (5.88 g,
39.9 mmol), potassium carbonate (16.58 g, 120 mmol), and
benzyltriethylammonium chloride (1.0 g, 4.4 mmol) were
suspended in acetone (100 mL). 1,4-Dibromobutane (25.9 g,
14.5 mL, 120 mmol) was added to the suspension and then
the reaction mixture was stirred at room temperature for 24
h. The solvent was evaporated under vacuum and the residue
was dissolved in water (70 mL) and CH2Cl2 (40 mL). The
organic layer was separated and the aqueous solution was
further extracted with CH2Cl2 (2 × 40 mL). The combined
organic solution was dried over Na2SO4, filtered, and concen-
trated. The crude product was purified by column chromatog-
raphy (SiO2; EtOAc/hexanes, 1:3; Rf 0.44) to provide 8a (10.63
g, 37.6 mmol, 94%) as a colorless solid. Mp 72.5-74.0 °C. IR
(neat) 2941, 1772, 1710, 1464, 1439, 718 cm-1. 1H NMR (CDCl3,
200 MHz) δ 1.77-1.99 (m, 4H), 3.36-3.42 (t, J ) 6.3 Hz, 2H),
3.64-3.70 (t, J ) 6.6 Hz, 2H), 7.64-7.71 (m, 2H), 7.75-7.82
(m, 2H). 13C NMR (CDCl3, 50 MHz) δ 27.1, 29.7, 32.7, 36.8,
123.1, 131.9, 133.8, 168.2. HRMS (FAB) calcd for [M + H]+
(C12H13BrNO2) 282.0130, found 282.0125. The spectroscopic
data are consistent with those reported previously.20
solid.22 Mp 107.5-110.0 °C. IR (neat) 3374, 3293, 3072, 2941,
1
2790, 1491, 1455, 740, 698 cm-1. H NMR (CDCl3, 200 MHz)
δ 1.84-1.91 (m, 2H), 2.49 (t, J ) 6.8 Hz, 2H), 3.56 (s, 4H),
3.67 (t, J ) 7.5 Hz, 2H), 7.14-7.31 (m, 10H), 7.64-7.69 (m,
2H), 7.75-7.81 (m, 2H). 13C NMR (CDCl3, 50 MHz) δ 25.7,
36.1, 50.2, 58.0, 122.9, 126.7, 128.0, 128.7, 132.0, 133.6, 139.2,
168.2. HRMS (FAB) calcd for [M + H]+ (C25H25N2O2) 385.1916,
found 385.1913. A mixture of hydrazine monohydrate (0.76 g,
15.7 mmol) and 9b (5.03 g, 13.1 mmol) in ethanol (30 mL) was
heated under reflux for 3.5 h. After the reaction mixture was
cooled to room temperature, concentrated HCl (1.4 mL) was
added, and the solution was heated under reflux for another
1 h. The solvent was evaporated under vacuum and then
saturated aqueous K2CO3 (200 mL) and diethyl ether (200 mL)
were added to the mixture. The insoluble material was
removed and the organic layer was separated. The aqueous
solution was extracted with diethyl ether (2 × 60 mL) and the
combined organic phases were washed with saturated aqueous
NaCl (50 mL), dried over Na2SO4, filtered, and concentrated.
The crude product was purified by column chromatography
(SiO2: CHCl3/MeOH, 9:1; Rf 0.45) to provide 7b (1.81 g, 7.1
mmol, 54%) as a colorless oil.21 1H NMR (CDCl3, 500 MHz) δ
1.65-1.70 (m, 2H), 1.97 (br, 2H), 2.49 (t, J ) 6.7 Hz, 2H), 2.73
(t, J ) 6.7 Hz, 2H), 3.7 (s, 4H), 7.25-7.29 (m, 2H), 7.30-7.39
(m, 8H). 13C NMR (CDCl3, 125 MHz) δ 30.4, 40.0, 50.7, 58.4,
126.9, 128.2, 128.9, 139.7. HRMS (FAB) calcd for [M + H]+
(C17H23N2) 255.1861, found 255.1858.
N,N-Diben zylbu ta n e-1,4-d ia m in e (7a ). A solution of ph-
thalimide 8a (3.0 g, 10.6 mmol) in xylene (30 mL) was added
dropwise to a solution of dibenzylamine (4.6 g, 23.4 mmol) in
xylene (30 mL) at 70 °C. After the addition was complete, the
reaction mixture was heated under reflux for 20 h. The
precipitated salt was filtered and the filtrate was concentrated.
The crude oily product was purified by column chromatography
(SiO2: EtOAc/hexanes, 1:3; Rf 0.61) to provide N-(4-dibenzyl-
aminobutyl)phthalimide (9a , 3.17 g, 7.9 mmol, 75%) as a light-
yellow oil. 1H NMR (CDCl3, 200 MHz) δ 1.37-1.75 (m, 4H),
2.44 (t, J ) 6.2 Hz, 2H), 3.52 (s, 4H), 3.59 (t, J ) 7.0 Hz, 2H),
7.18-7.35 (m, 10H), 7.65-7.70 (m, 2H), 7.79-7.83 (m, 2H).
13C NMR (CDCl3, 50 MHz) δ 24.4, 26.3, 37.8, 52.8, 58.3 (CH2
× 5), 123.1, 126.7, 128.1, 128.7, 132.1, 133.8, 139.7, 168.4.
HRMS (FAB) calcd for [M + H]+ (C26H27N2O2) 399.2073, found
399.2079. A mixture of hydrazine monohydrate (0.40 g, 8.0
mmol) and 9a (3.17 g, 8.0 mmol) in ethanol (30 mL) was heated
under reflux for 3.5 h. After the mixture was cooled to room
temperature, concentrated HCl (0.8 mL) was added, and the
solution was then heated under reflux for another 1 h. The
solvent was evaporated under vacuum and then saturated
aqueous K2CO3 (100 mL) and diethyl ether (120 mL) were
added to the residue. The insoluble material was removed and
the organic layer was separated. The aqueous solution was
extracted with diethyl ether (2 × 60 mL) and the combined
organic phases were washed with saturated aqueous NaCl (50
mL), dried over Na2SO4, filtered, and concentrated. The crude
product was purified by column chromatography (SiO2: CHCl3/
MeOH, 9:1; Rf 0.17) to provide 7a (1.21 g, 4.5 mmol, 56%) as
a colorless oil.21 1H NMR (CDCl3, 200 MHz) δ 1.37-1.50 (m,
4H), 1.81 (br, 2H), 2.40 (t, J ) 6.8 Hz, 2H), 2.57 (t, J ) 6.7 Hz,
2H), 3.52 (s, 4H), 7.16-7.37 (m, 10H). 13C NMR (CDCl3, 50
MHz) δ 24.2, 30.9, 41.7, 52.9, 58.1, 126.6, 127.9, 128.6, 139.7.
HRMS (FAB) calcd for [M + H]+ (C18H25N2) 269.2018, found
269.2016.
N-Acr yloyl-2-a llylp ip er id in e (10). Triethylamine (260 µL,
1.84 mmol) and acryloyl chloride (35 µL, 0.44 mmol) were
added sequentially to a solution of piperidine 5 (46 mg, 0.37
mmol) in CH2Cl2 (2 mL) at 0 °C. The reaction mixture was
stirred for another 30 min at 0 °C and then warmed to room
temperature. The mixture was diluted with CH2Cl2 (20 mL),
washed with 1 N HCl (2 × 10 mL) and saturated aqueous NaCl
(10 mL), dried over Na2SO4, filtered, and concentrated. The
crude product was purified by column chromatography (SiO2:
EtOAc; Rf 0.66) to provide 10 (65 mg, 0.37 mmol, 99%) as a
1
light-yellow oil. H NMR (CDCl3, 500 MHz) δ 1.32-1.34 (br,
1H), 1.54-1.62 (m, 5H), 2.08 (m, 1H), 2.21-2.26 (br, 1H), 2.61
and 3.03 (br, 1H), 3.70 and 4.47 (br, 1H), 4.02 and 4.82 (br,
1H), 4.96 (br, 2H), 5.54 (d, J ) 10.8 Hz, 1H), 5.63 (br, 1H),
6.12 (d, J ) 16.5 Hz, 1H), 6.45-6.47 (br, 1H). 13C NMR (CDCl3,
125 MHz) δ (rotamers) 18.8, 25.2, 26.1, 27.1, 28.7, 34.2, 34.8,
36.9, 41.4, 47.8, 53.0, 116.7, 117.9, 126.8 (COCHdCH2), 128.6
(COCHdCH2), 134.2, 135.2, 165.9. HRMS (FAB) calcd for [M
+ H]+ (C11H18NO) 180.1388, found 180.1385.
1-{3-[4-(Dib e n zyla m in ob u t yl)a m in o]p r op ion yl}-2-
a llylp ip er id in e (11). A mixture of diamine 7a (265 mg, 0.98
mg) and piperidine 10 (117 mg, 0.98 mmol) in toluene (5 mL)
was heated under reflux for 32 h. The solvent was evaporated
under vacuum and the crude product was purified by column
chromatography (SiO2: CHCl3/MeOH, 9:1; Rf 0.23) to provide
the title compound 11 (348 mg, 0.77 mmol, 79%) as a light-
yellow oil. IR (neat) 2930, 2860, 2797, 1637, 1458, 915, 741,
1
698 cm-1. H NMR (CDCl3, 500 MHz) δ 1.27 (br, 1H), 1.56-
1.69 (m, 9H), 2.29-2.36 (m, 2H), 2.37-2.46 (m, 3H), 2.55-
2.65 (m, 4H), 2.89 (br, 1H), 3.55 (s, 4H), 2.80 and 3.05 (br,
1H), 3.61 and 4.55 (br, 1H), 3.90 (br, 1H, NH), 5.00-5.12 (m,
2H), 5.71-5.74 (m, 1H), 7.21-7.24 (m, 2H), 7.30-7.33 (m, 4H),
7.36-7.37 (m, 4H). 13C NMR (CDCl3, 125 MHz) δ (rotamers)
170.2, 170.3, 139.8, 135.2, 134.2, 128.8, 128.2, 126.8, 118.1,
116.8, 58.3, 52.9, 52.6, 49.4, 47.5, 45.4, 45.3, 41.0, 36.5, 34.6,
34.2, 32.5,32.3, 28.4, 27.2, 26.8, 26.0, 25.3, 24.7, 18.8. HRMS
(FAB) calcd for [M + H]+ (C29H42N3O) 448.3328, found
448.3328.
N,N-Diben zylp r op a n e-1,3-d ia m in e (7b). N-(3-Bromopro-
pyl)phthalimide (2.84 g, 10.6 mmol) dissolved in xylene (30
mL) was added dropwise to a solution of dibenzylamine (4.6
g, 23.4 mmol) in xylene (30 mL) at 70 °C. After the addition
was complete, the reaction mixture was heated under reflux
for 20 h. The precipitated salt was filtered and the filtrate was
concentrated. The crude product was purified by recrystalli-
zation from EtOAc/hexanes to provide N-(3-dibenzylamino-
propyl)phthalimide (9b, 3.26 g, 8.4 mmol, 80%) as a colorless
1-{3-[4-(Dib en zyla m in ob u t yl)a m in o]p r op yl}-2-a llyl-
p ip er id in e (12). LiAlH4 (50 mg, 1.2 mmol) was added to a
solution of compound 11 (54 mg, 0.12 mmol) in THF, which
was then heated under reflux for 3 h. The reaction mixture
(20) Crabb, T. A.; Patel, A.; Newton, R. F.; Cholerton, T. J . J . Chem.
Soc., Perkin Trans. 1 1985, 191-196.
(21) Hoffmann, K. J .; Stenberg, P.; Ljunggren, C.; Svensson, U.;
Nilsson, J . L. G.; Eriksson, O.; Hartkoorn, A.; Lunden, R. J . Med. Chem.
1975, 18, 278-284.
(22) Zaragoza, F.; Stephensen, H. J . Org. Chem. 2001, 66, 2518-
2521.
J . Org. Chem, Vol. 69, No. 18, 2004 6097

Hou et al.
was diluted with diethyl ether (30 mL) and quenched with
water (0.5 mL) and saturted aqueous Na2CO3 (1 mL). The
organic solution was decanted and concentrated to give the
product 12 (47 mg, 0.11 mmol, 90%) as a colorless oil. IR (neat)
60.0, 116.4, 126.9, 128.1, 128.2, 128.4, 128.8, 136.0, 139.8.
HRMS (FAB) calcd for [M + H]+ (C29H44N3) 434.3535, found
434.3546.
Dien e 4a . A mixture of 9-decenoic acid (115 mg, 0.68 mmol)
and thionyl chloride (0.5 mL, 6.85 mmol) was heated under
reflux in a 25-mL flask at 60 °C for 30 min. The excess thionyl
chloride was evaporated under vacuum and additional CH2-
Cl2 (2 mL) was added. The solution of 9-decenoyl chloride was
added by syringe to a solution of 12 (250 mg, 0.56 mmol) and
triethylamine (120 µL, 0.85 mmol) in CH2Cl2 (10 mL) at 0 °C.
After being stirred at 0 °C for another 1 h, the reaction mixture
was warmed to room temperature, diluted with CH2Cl2 (20
mL), washed with water (2 × 10 mL) and saturated aqueous
NaCl (10 mL), dried over Na2SO4, filtered, and concentrated.
The crude product was purified by column chromatography
(SiO2: CHCl3/MeOH, 9:1; Rf 0.50) to provide 4a (228 mg, 0.39
mmol, 70%) as a light-yellow oil. IR (neat) 3028, 2928, 2855,
1643, 1456, 994, 911,740, 698 cm-1. 1H NMR (CDCl3, 500 MHz)
δ 1.27-1.31 (m, 8H), 1.37-1.38 (m, 3H), 1.49-1.50 (m, 3H),
1.60-1.62 (m, 4H), 1.74 (br, 2H), 1.87 (br, 2H), 2.04 (m, 3H),
2.21-2.27 (m, 4H), 2.35-2.65 (m, 3H), 2.65-3.14 (br, 3H),
3.14-3.29 (m, 4H), 3.56 (s, 4H), 4.93-5.14 (m, 4H), 5.79-5.84
(m, 2H), 7.23-7.26 (m, 2H), 7.29-7.37 (m, 8H). 13C NMR
(CDCl3, 125 MHz) δ (rotamers) 178.4, 173.3, 172.8, 139.8,
139.6, 139.2, 139.1, 135.1, 133.8, 128.8, 128.7, 128.2, 128.1,
126.9, 126.8, 118.3, 117.2, 114.2, 114.1, 59.78, 59.5, 58.5, 58.3,
53.2, 53.0, 50.6, 50.2, 49.8, 49.4, 47.9, 45.8, 45.6, 43.5, 35.8,
34.3, 33.8, 33.6, 33.2, 33.1, 29.7, 29.5, 29.4, 29.3, 29.0, 28.9,
27.1, 26.6, 25.6, 25.5, 25.4, 24.9, 25.5, 24.4, 22.8, 22.7, 22.1,
21.2. HRMS (FAB) calcd for [M + H]+ (C39H60N3O) 586.4736,
found 586.4734.
Dien e 4b. A mixture of 9-decenoic acid (156 mg, 0.92 mmol)
and thionyl chloride (0.15 mL, 2.06 mmol) was heated under
reflux in a 25-mL flask at 60 °C for 30 min. The excess thionyl
chloride was evaporated under vacuum and additional CH2-
Cl2 (2 mL) was added. The solution of 9-decenoyl chloride was
added by syringe to a solution of 15 (266 mg, 0.61 mmol) and
triethylamine (250 µL, 1.82 mmol) in CH2Cl2 (10 mL) at 0 °C.
After being stirred at 0 °C for another 1 h, the reaction mixture
was warmed to room temperature, diluted with CH2Cl2 (20
mL), washed with water (2 × 10 mL) and saturated aqueous
NaCl (10 mL), dried over Na2SO4, filtered, and concentrated.
The crude product was purified by column chromatography
(SiO2: CHCl3/MeOH, 9:1; Rf 0.55) to provide 4b (245 mg, 0.42
mmol, 85%) as a light-yellow oil. IR (neat) 3029, 2928, 2854,
1642, 1457, 994, 911,740, 698 cm-1. 1H NMR (CDCl3, 500 MHz)
δ 1.28-1.36 (br, 11H), 1.46 (m, 3H), 1.50-1.82 (br, 8H), 2.03-
2.04 (m, 2H), 2.21-2.40 (m, 4H), 2.40-2.61 (m, 4H), 2.61-
3.02 (m, 3H), 3.02-3.20 (m, 2H), 3.20-3.32 (m, 2H), 3.57 (s,
4H), 4.93-5.09 (m, 4H), 5.78-5.82 (m, 2H), 7.22-7.36 (m,
10H). 13C NMR (CDCl3, 125 MHz) δ (rotamers) 172.9, 172.7,
139.7, 139.3, 139.2, 139.1, 135.4, 134.6, 128.8, 128.7, 128.3,
128.2, 127.1, 126.8, 117.6, 117.0, 114.2, 114.1, 59.6, 59.5, 58.7,
58.4, 52.7, 52.2, 51.2, 51.0, 50.9, 48.3, 47.9, 46.1, 45.1, 44.3,
41.3, 36.8, 36.4, 35.0, 34.6, 33.8, 33.7, 33.2, 31.9, 29.5, 29.4,
29.3, 29.1, 28.9, 28.8, 27.2, 25.9, 25.7, 25.5, 25.4, 25.3, 22.7,
21.8. HRMS (FAB) calcd for [M + H]+ (C39H60N3O) 586.4736,
found 586.4732.
3026, 2927, 2854, 2792, 1454, 1025, 910, 740, 698 cm-1 1H
.
NMR (CDCl3, 500 MHz) δ 1.24 (m, 1H), 1.30-1.45 (m, 7H),
1.45-1.74 (m, 4H), 2.10-2.24 (m, 2H), 2.24-2.39 (m, 4H), 2.40
(m, 2H), 2.48 (m, 2H), 2.54 (m, 2H), 2.70 (m, 1H), 2.82 (m,
1H), 3.51 (s, 4H), 4.99-5.04 (m, 2H), 5.73-5.79 (m, 1H), 7.17-
7.20 (m, 2H), 7.24-7.28 (m, 4H), 7.33-7.34 (m, 4H). 13C NMR
(CDCl3, 125 MHz) δ 23.3, 24.9, 25.6, 25.7, 27.5, 30.4, 35.6, 49.0,
50.0, 51.5, 52.1, 53.2, 58.4, 59.8, 116.5, 126.8, 128.2, 128.8,
135.9, 140.0. HRMS (FAB) calcd for [M + H]+ (C29H44N3)
434.3535, found 434.3537.
4-Oxo-4-(2-a llylp ip er id in o)bu tyr ic Acid (13). Anhydrous
K2CO3 (380 mg, 2.76 mmol) was added to a solution of
piperidine 5 (23 mg, 0.18 mmol) and succinic anhydride (55
mg, 0.55 mmol) in DMF (2 mL). After the mixture was stirred
at room temperature for 24 h, diethyl ether (20 mL) and water
(5 mL) were added to the suspension. The organic layer was
separated and the aqueous solution was further extracted with
diethyl ether (2 × 10 mL). The combined ether phases were
washed with 1 N HCl (2 × 10 mL) and saturated aqueous NaCl
(10 mL), dried over Na2SO4, filtered, and concentrated to
provide the acid 13 (37 mg, 0.17 mmol, 91%) as a light-yellow
oil. 1H NMR (CDCl3, 500 MHz) δ (rotamer) 1.17 (br, 1H), 1.48-
1.72 (m, 5H), 2.18-2.40 and 2.40-2.52 (m, 2H), 2.62 (m, 4H),
2.62 (m) and 3.07 (dt, J ) 13.5, Hz, J ) 2.4 Hz, 1H), 3.62 (d,
J ) 13.2 Hz) and 4.49 (d, J ) 13.4 Hz, 1H), 3.97 (br) and 4.80
(dd, J ) 12.9, Hz, J ) 6.9 Hz,1H), 4.96-5.10 (m, 2H), 5.64-
5.70 (m, 1H), 8.94 (br, 1H). 13C NMR (CDCl3, 125 MHz) δ
(rotamer) 18.7, 18.8, 25.3, 25.9, 27.2, 28.3, 28.4, 28.5, 28.8, 30.0,
34.2, 34.6, 37.1, 41.1, 48.1, 52.9, 116.9, 118.3, 134.0, 135.0,
170.7, 170.8, 176.5, 176.6. HRMS (FAB) calcd for [M + H]+
(C12H20NO3) 226.1443, found 226.1461.
N-(3-Diben zylam in opr opyl)-4-oxo-4-(2-allylpiper idin yl)-
bu tyr a m id e (14). 1,3-Diisopropylcarbodiimide (410 µL, 2.63
mmol) was added to a solution of acid 13 (456 mg, 2.02 mmol)
and diamine 7b (515 mg, 2.02 mmol) in CH2Cl2 (30 mL). After
the solution was stirred at room temperature for 24 h, the
solvent was evaporated and the crude product was purified
by column chromatography (SiO2: EtOAc; Rf 0.56) to provide
the diamide 14 (76 mg, 0.16 mmol, 82%) as a light-yellow oil.
1H NMR (CDCl3, 500 MHz) δ 1.40 (m, 1H), 1.63-1.70 (m, 8H),
2.22-2.42 (m, 3H), 2.42-2.52 (m, 3H), 2.55-2.64 (m, 2H), 2.48
(m) and 3.10 (t, J ) 13.4 Hz, 1H), 3.68 (d, J ) 12.9 Hz) and
4.52 (d, J ) 13.5 Hz, 1H), 4.03 (m) and 4.85 (m, 1H), 5.00-
5.14 (m, 2H), 5.72 (m, 1H), 6.0 (br, 1H), 7.28-7.38 (m, 10H).
13C NMR (CDCl3, 125 MHz) δ (rotamer) 18.8, 25.4, 26.0, 26.2,
26.3, 27.2, 28.4, 28.9, 29.2, 31.6, 34.2, 34.6, 36.7, 37.5, 37.6,
40.9, 47.6, 50.3, 50.4, 52.4, 58.5, 116.7, 118.0, 127.1, 127.2,
128.3, 128.4, 129.0, 134.3, 135.3, 139.5, 170.4, 170.5, 171.9,
172.4. HRMS (FAB) calcd for [M + H]+ (C29H40N3O2) 462.3121,
found 462.3128.
1-{3-[4-(Dib en zyla m in op r op yl)a m in o]b u t yl}-2-a llyl-
p ip er id in e (15). LiAlH4 (1.53 g, 38.2 mmol) was added to a
solution of diamide 14 (1.76 g, 3.8 mmol) in THF (30 mL). After
the solution was heated under reflux for 3 h, diethyl ether (50
mL) was added to the reaction mixture, which was quenched
with water (5 mL) and saturated aqueous Na2CO3 (5 mL). The
white precipitate was filtered and the filtrate was concentrated
to give triamine 15 (1.42 g, 3.3 mmol, 87%) as a light-yellow
oil. IR (neat) 3302, 3072, 3028, 2944, 2791, 1498, 1449, 1124,
La cta m 3a . Concentrated HCl (10 drops) was added to a
solution of diene 4a (177 mg, 0.30 mmol) and Grubbs catalyst
15 (25.6 mg, 0.03 mmol) in CH2Cl2 (70 mL). Nitrogen was
bubbled through the solution for 10 min before the reaction
mixture was heated under reflux for 24 h. The solution was
poured into a separation funnel and washed with saturated
aqueous NaHCO3 (2 × 10 mL) and saturated aqueous NaCl
(10 mL). The organic layer was collected, dried over Na2SO4,
filtered, and concentrated. The crude product was purified by
column chromatography (SiO2: CHCl3/MeOH, 9:1; Rf 0.48) to
provide 3a (84 mg, 0.15 mmol, 50%) as a brown oil. IR (neat)
991, 966, 911, 740, 697 cm-1 1H NMR (CDCl3, 500 MHz) δ
.
1.24 (br, 1H), 1.38-1.55 (m, 7H), 1.55-1.62 (m, 2H), 1.62-
1.72 (m, 2H), 2.11-2.25 (m, 2H), 2.25-2.40 (m, 4H), 2.43 (m,
2H), 2.49 (m, 2H), 2.52-2.69 (m, 3H), 2.78 (br, 1H), 3.51 (s,
4H), 5.00-5.03 (m, 2H), 5.73-5.80 (m, 1H), 7.18-7.21 (m, 2H),
7.24-7.38 (m, 8H). 13C NMR (CDCl3, 125 MHz) δ 23.3, 23.5,
25.7, 26.9, 28.2, 30.4, 35.7, 48.0, 50.0, 51.3, 51.8, 53.6, 58.4,
3028, 2930, 2855, 1642, 1459, 970, 741, 698 cm-1 1H NMR
.
(CDCl3, 500 MHz) δ 1.15-1.35 (m, 11H), 1.35-1.50 (br, 3H),
1.50-1.70 (m, 8H), 1.78-2.05 (m, 4H), 2.05-2.51 (m, 7H),
6098 J . Org. Chem., Vol. 69, No. 18, 2004

Syntheses of Oncinotine and Neooncinotine
2.51-2.98 (br, 2H), 3.11-3.20 (m, 4H), 3.52 (s, 4H), 5.41-5.43
(m, 2H), 7.18-7.86 (m, 10H). 13C NMR (CDCl3, 125 MHz) δ
(rotamer) 173.6, 173.0, 172.9, 139.6, 139.2, 129.1, 129.0, 128.8,
128.3, 128.2, 127.1, 127.0, 58.8, 58.5, 53.2, 53.1, 52.7, 51.9, 51.1,
51.0, 50.9, 48.4, 48.3, 46.2, 45.8, 44.2, 35.5, 35.1, 33.1, 32.8,
32.7, 31.8, 29.7, 28.8, 28.5, 28.1, 27.9, 27.6, 27.4, 27.3, 27.2,
27.0, 26.9, 26.2, 26.3, 26.1, 25.5, 25.4, 25.0, 22.5. HRMS (FAB)
calcd for [M + H]+ (C37H56N3O) 558.4423, found 558.4426.
La cta m 3b. Concentrated HCl (10 drops) was added to a
solution of diene 4b (240 mg, 0.41 mmol) and Grubbs catalyst
16 (35 mg, 0.04 mmol) in CH2Cl2 (100 mL) and then N2 gas
was bubbled through the solution for 10 min. The reaction
mixture was then heated under reflux for 24 h. The solution
was poured into a separation funnel and washed with satu-
rated aqueous NaHCO3 (10 mL × 2) and saturated aqueous
NaCl (10 mL). The organic layer was collected, dried over Na2-
SO4, filtered, and concentrated. The crude product was purified
by column chromatography (SiO2: CHCl3/MeOH, 9:1; Rf 0.55)
to provide 3b (156 mg, 0.3 mmol, 68%) as a brown oil. IR (neat)
mL), washed with saturated aqueous NaHCO3 (10 mL) and
saturated aqueous NaCl (10 mL), dried over Na2SO4, filtered,
and concentrated to give oily 17b (12.1 mg, 0.02 mmol, 99%).
1H NMR (CDCl3, 500 MHz) δ 1.22-1.50 (m, 14H), 1.50-1.75
(m, 6H), 1.75-1.95 (m, 4H), 1.95-2.13 (br, 2H), 2.13-2.35 (m,
4H), 2.39 (m, 3H), 2.48-2.98 (br, 2H), 2.98-3.25 (br, 4H), 3.50
(s, 4H), 5.34-5.47 (m, 2H), 7.16-7.22 (m, 2H), 7.24-7.49 (m,
8H). 13C NMR (CDCl3, 125 MHz) δ (rotamer) 173.6, 172.9,
172.6, 139.8, 139.6, 128.6, 128.1, 128.0, 126.7, 126.6, 58.4, 58.2,
53.1, 52.9, 52.2, 51.9, 51.1, 50.2, 47.7, 47.2, 46.5, 46.1, 45.5,
45.3, 35.4, 34.9, 33.1, 32.8, 32.6, 31.3, 29.4, 28.7, 27.9, 27.8,
27.5, 27.4, 27.0, 26.9, 28.8, 26.7, 26.5, 26.2, 26.0, 25.4, 24.4,
23.4. HRMS (FAB) calcd for [M + H]+ (C37H56N3O) 558.4423,
found 558.4436.
On cin otin e (1). A mixture of lactam 17a (20.1 mg, 0.036
mmol), Pd(OH)2/C (20% w/w, 6 mg), and ammonium formate
(22.6 mg, 0.36 mmol) in ethanol (3 mL) was heated under
reflux for 18 h. The ethanol was evaporated under vacuum
then CH2Cl2 (10 mL) was added to the residue. The palladium
catalyst was filtered off and the filtrate was concentrated. The
crude product was purified by column chromatography (SiO2:
CHCl3/MeOH/concentrated NH4OH, 40:9:1; Rf 0.63) to provide
1 (10.0 mg, 0.026 mmol, 74%) as a light-yellow oil. IR (neat)
3027, 2928, 2853, 1639, 1455, 969, 740, 698 cm-1 1H NMR
.
(CDCl3, 500 MHz) δ 1.15-1.35 (m, 11H), 1.35-1.50 (br, 3H),
1.50-1.70 (m, 8H), 1.78-2.05 (m, 4H), 2.05-2.51 (m, 7H),
2.51-2.98 (br, 2H), 3.11-3.20 (m, 4H), 3.52 (s, 4H), 5.41-5.43
(m, 2H), 7.18-7.86 (m, 10H). 13C NMR (CDCl3, 125 MHz) δ
(rotamer) 173.6, 173.0, 172.9, 139.6, 139.2, 129.1, 129.0, 128.8,
128.3, 128.2, 127.1, 127.0, 58.8, 58.5, 53.2, 53.1, 52.7, 51.9, 51.1,
51.0, 50.9, 48.4, 48.3, 46.2, 45.8, 44.2, 35.5, 35.1, 33.1, 32.8,
32.7, 31.8, 29.7, 28.8, 28.5, 28.1, 27.9, 27.6, 27.4, 27.3, 27.2,
27.0, 26.9, 26.2, 26.3, 26.1, 25.5, 25.4, 25.0, 22.5. HRMS (FAB)
calcd for [M + H]+ (C37H56N3O) 558.4423, found 558.4426.
La cta m 17a . Concentrated HCl (1 drop) was added to a
mixture of lactam 3a (12.9 mg, 0.02 mmol) and Pd/C (5% w/w,
4 mg) in MeOH (1 mL). The flask was placed into an autoclave
and the mixture was reacted under H2 (20 atm) for 5 h. The
Pd/C and methanol were removed by filtration and under
vacuum, respectively. The residue was dissolved in CH2Cl2 (20
mL), washed with saturated aqueous NaHCO3 (10 mL) and
saturated aqueous NaCl (10 mL), dried over Na2SO4, filtered,
and concentrated to give oily 17a (11.2 mg, 0.02 mmol, 87%).
1H NMR (CDCl3, 500 MHz) δ 1.23-1.46 (m, 20H), 1.23-1.95
(m, 10H), 2.15-2.34 (m, 4H), 2.42 (br, 3H), 2.50-2.69 (br, 1H),
2.80-2.95 (br, 1H), 2.95-3.38 (m, 4H), 3.53 (s, 4H), 7.14-7.33
(m, 10H). 13C NMR (CDCl3, 125 MHz) δ (rotamer) 173.6, 173.0,
172.9, 139.8, 139.2, 129.1, 129.0, 128.8, 128.3, 128.2, 127.0,
126.8, 58.8, 58.5, 53.2, 53.1, 52.7, 51.9, 51.1, 51.0, 50.9, 48.4,
48.3, 46.2, 45.8, 44.2, 35.5, 35.1, 33.1, 32.8, 32.7, 31.8, 29.7,
28.8, 28.6, 28.1, 27.9, 27.6, 27.4, 27.3, 27.2, 27.0, 26.9, 26.6,
26.3, 26.1, 25.5, 25.4, 25.0, 25.5. HRMS (FAB) calcd for [M +
H]+ (C37H58NO3) 560.4580, found 560.4578.
1
2929, 2855, 1642, 1461, 731 cm-1. H NMR (CDCl3, 500 MHz)
δ 1.23-1.35 (m, 17H), 1.47-1.75 (m, 10H), 1.75-2.0 (br, 3H),
2.20-2.29 (m, 3H), 2.30-3.01 (m, 8H), 3.01-3.28 (m, 4H).5a
HRMS (FAB) calcd for [M + H]+ (C23H46N3O) 380.3641, found
380.3653.
Neoon cin otin e (2). A mixture of lactam 17b (14.8 mg,
0.026 mmol), Pd(OH)2/C (20% w/w, 5 mg), and ammonium
formate (16.4 mg, 0.26 mmol) in ethanol (3 mL) was heated
under reflux for 19 h. The ethanol was evaporated under
vacuum and then CH2Cl2 (10 mL) was added to the residue.
The palladium catalyst was filtered off and the filtrate was
concentrated. The crude product was purified by column
chromatography (SiO2: CHCl3/MeOH/concentrated NH4OH,
40:9:1; Rf 0.65) to provide 2 (7.0 mg, 0.018 mmol, 70%) as a
light-yellow oil. IR (neat) 2928, 2855, 1641, 1461, 733 cm-1
.
1H NMR (CDCl3, 500 MHz) δ 1.23 (m, 6H), 1.29-1.45 (m, 10H),
1.45-1.78 (m, 10H), 1.81 (m, 1H), 1.85-2.02 (m, 1H), 2.02-
2.50 (br, 5H), 2.50-3.00 (br, 6H), 3.01-0.345 (br, 4H). HRMS
(FAB) calcd for [M + H]+ (C23H46N3O) 380.3641, found
380.3640.
Ack n ow led gm en t. This work was supported (NSC
92-2113-M008-015) by the National Science Council,
Taiwan, ROC.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 1-4, 7-15, and 17, 13C NMR spectra for com-
pounds 1, 3, 4, 7-15, and 17, and1H-1H COSY spectra of
compounds 10 and 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
La cta m 17b. Concentrated HCl (1 drop) was added to a
mixture of lactam 3b (12.7 mg, 0.02 mmol) and Pd/C (5% w/w,
4 mg) in MeOH (1 mL). The flask was placed into an autoclave
and then the mixture was reacted under H2 (20 atm) for 5 h.
The Pd/C and methanol were removed by filtration and under
vacuum, respectively. The residue was dissolved in CH2Cl2 (20
J O049526I
J . Org. Chem, Vol. 69, No. 18, 2004 6099