First total synthesis of (±)-stemonamide and (±)-isostemonamide

Article abstract of DOI:10.1021/ol010106e

(Equation presentation) The total synthesis of the tetracyclic alkaloids stemonamide (1) and isostemonamide (2) is presented. The key step is the reaction between a silyloxyfuran and an N-acyliminium ion. The second quaternary center is created by an intr

Full text of DOI:10.1021/ol010106e

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2505-2508
First Total Synthesis of
(±)-Stemonamide and
(±)-Isostemonamide
Andrew S. Kende,* Jose I. Martin Hernando, and Jared B. J. Milbank
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627
kende@chem.rochester.edu
Received May 21, 2001
ABSTRACT
The total synthesis of the tetracyclic alkaloids stemonamide (1) and isostemonamide (2) is presented. The key step is the reaction between
a silyloxyfuran and an N-acyliminium ion. The second quaternary center is created by an intramolecular aldol spirocyclization. After 1,4-
addition of an appropriate side chain, the methyl and double bond are installed by Mannich reaction. The seven-membered ring is closed by
intramolecular nucleophilic displacement.
The tetracyclic alkaloids stemonamide (1) and isostemon-
amide (2) were isolated from the roots of Stemona japonica
by Xu et al. in 1994.1 The highly compact spirocyclic
structures of these compounds were elucidated through
extensive NMR analyses and by comparison with data for
stemonamine 3, for which an X-ray structure had been
obtained2 (Figure 1).
summarized,3 but no total synthesis of alkaloids having the
spirocyclic stemonamide nucleus has been reported.4 We now
report the first total synthesis of (()-stemonamide (1) and
(()-isostemonamide (2).
Our approach, retrosynthetically presented in Scheme 1,
envisioned the use of acyliminium chemistry5 to form the
C(9a) quaternary center, followed by aldol spirocyclization
to obtain the contiguous C(12) quaternary center. The four-
Scheme 1. Retrosynthetic Analysis
Figure 1.
Extensive synthetic work toward Stemona alkaloids,
culminating in a number of elegant total syntheses, has been
(1) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat. Prod. 1994, 57, 665.
(2) Iizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Uyeo, S. J. Chem. Soc.,
Chem. Commun. 1973, 125.
10.1021/ol010106e CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/12/2001

carbon alkyl chain required to build the final azepine ring
was to be introduced by conjugate Grignard addition to a
tricyclic enone intermediate.
isomer 9 was subsequently assigned the relative stereochem-
istry of stemonamide, whereas the more polar isomer 10
corresponded to the isostemonamide series as a result of the
individual X-ray analyses of their respective derived targets
1 and 2.
As depicted in Scheme 2, the synthesis began with
Grignard addition of (3-benzyloxypropyl)magnesium bro-
To effect the desired conjugate addition of the azepine
ring carbons, conversion of these saturated ketones to the
corresponding conjugated enones was required. Our initial
attempts to dehydrogenate ketones 9 and 10 using selenium
chemistry failed. Deprotonation of 9 with LDA and reaction
with PhSeCl9 or reaction of its silyl enol ether with PhSeCl10
gave the corresponding R-phenylselen derivatives in very
low yield. The desired enones 11 and 12 were ultimately
synthesized by treating the tert-butyldimethylsilyl enol
ethers11 with Pd(OAc)212 to produce the enones in 76% and
61% yields, respectively (Scheme 3).
Scheme 2a
Conjugate addition of the Grignard reagent 13 in the
presence of CuBr-Me2S occurs mainly anti to the C-N
bond (Scheme 4). In the stemonamide series, enone 11 gave
a (a) BnO(CH2)3MgBr, Et2O, reflux, 30 min; (b) PPTS, MeOH,
rt, 30 min, 90% (2 steps); (c) H2, 5% Pd/C, 3 h, 90%; (d) BF3
Et2O, CH2Cl2, rt, 40 min, 82%.
Scheme 4a
mide to succinimide 4. The resulting unstable hemiaminal
was protected as the methoxy derivative 5, which upon
hydrogenolytic debenzylation afforded the spiro compound
6 in 66% overall yield from 4.
The first quaternary center was created by addition of
silyloxyfuran 76 to the N-acyliminium ion generated from 6
with BF3‚Et2O at room temperature.7,8 Under these conditions
a 1:2 mixture of diastereomeric alcohols 8 was produced in
82% yield (Scheme 2). Swern oxidation of alcohols 8
produced the corresponding aldehydes which were cyclized
directly using DBU to yield tricyclic aldol products, con-
verted by Swern oxidation to a 1:1 mixture of tricyclic
ketones 9 and 10 (Scheme 3). These ketones were readily
separated by column chromatography; the faster eluting
a (a) PMBO(CH2)4MgBr 13, 5% CuBr-Me2S, TMSCl, HMPA,
THF, -78 °C, 30 min, 74% of 14R/14â, 57% of 15, 32% of 16.
a 6.4:1 ratio of 14R and 14â in 74% yield. In the
isostemonamide series, enone 12 gave only products of
Scheme 3a
(3) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17,
117.
(4) Narasaka et al. (Bull Chem. Soc. Jpn. 1996, 69, 2063) have
synthesized the tricyclic alkaloid (()-stemoamide, mistakenly designated
as (()-stemonamide by these authors. For a discussion, see ref 3.
(5) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter
4.1, pp 1047-1082. (b) Speckamp, W. N.; Moolenar, M. J. Tetrahedron
2000, 56, 3817.
(6) Pelter, A.; Al-Bayati, R. H. I.; Ayoub, M. T.; Lewis, W.; Pardasani,
P.; Hansel, R. J. Chem. Soc., Perkin Trans. 1 1987, 717.
(7) (a) Arai, Y.; Kontani, T.; Koizumi, T. Tetrahedron: Asymmetry 1992,
3, 535. (b) Arai, Y.; Kontani, T.; Koizumi, T. J. Chem. Soc., Perkin Trans.
1 1994, 15. (c) Louwrier, S.; Ostendorf, M.; Boom, A.; Hiemstra, H.;
Speckamp, W. N. Tetrahedron 1996, 52, 2603.
(8) Martin has used a similar addition of a silyloxyfuran to an iminium
species in his total synthesis of the Stemona alkaloid croomine. Martin, S.
F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299.
(9) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975, 97,
5434.
(10) Danishefsky, S.; Zamboni, R.; Kahn, M.; Etheredge, S. J. J. Am.
Chem. Soc. 1981, 103, 3460.
a (a) (COCl)2, DMSO, TEA, CH2Cl2; (b) DBU, CH2Cl2, over-
night, rt; (c) (COCl)2, DMSO, TEA, CH2Cl2, 70% (3 steps); (d)
TBDMSOTf, collidine, toluene, 7 h, 0 °C to room temperature,
80% (stem. series) and 68% (isostem. series); (e) Pd(OAc)2, O2,
DMSO, 80 °C, 24-48h, 93% (11) and 89% (12).
2506
Org. Lett., Vol. 3, No. 16, 2001

R-attack, 15 and 16, in yields of 57% and 32%, respectively.
The use of TMSCl and HMPA as additives was required
for any reaction to take place in acceptable yields.13 In our
case, examination of molecular models suggests that the
steric hindrance of the N-PMB group is responsible for the
observed stereoselectivity in the cuprate addition,14 although
another factor that can contribute to this anti-diastereo-
selectivity is the use of TMSCl as additive.15
unsuccessful, giving mainly products derived from depro-
tection of the O-PMB group and addition of the solvent to
the methylene group. In the case of ketones 17, RhCl3
isomerization did produce ca. 10% the desired enone system
of 19. This observation suggested the hypothesis that steric
hindrance by the large N-PMB substituent interfered with
the formation of the hypothetical σ-alkyl intermediate.20 The
isomerization requires the metal and the endocyclic hydrogen
H-9 to be syn. This hypothesis was confirmed by experiments
with pure 17R and 17â. While treatment with RhCl3 of the
R-isomer (17R) gave a complex mixture of products without
traces of isomerization, the â-isomer (17â) afforded the
expected endocyclic alkene with partial loss of the O-PMB
group in ca. 60% yield under the same conditions. This
obstacle was cleanly overcome by initial removal of the
N-PMB (and O-PMB) groups in the 17R/â mixture and in
18, using cerium(IV) ammonium nitrate.21 The resulting
unprotected lactams then underwent facile RhCl3-mediated
isomerization to yield the desired enones 19 and 20 in
acceptable yields.
A Mannich reaction was now used to install the R-methyl
group as well as to provide unsaturation (Scheme 5). In the
Scheme 5a
Azepine ring closure was then achieved by intramolecular
nucleophilic displacement of the mesylates 21 and 22
(Scheme 6).22 Reaction of the mesylate 21 with NaH in
Scheme 6a
a (a) KH, Me2NdCH2+CF3COO-, THF, overnight, 67% (17) and
85% (18); (b) CAN, CH3CN-H2O, 2 h, 80% (stem.) and 75%
(isostem.); (c) RhCl3‚xH2O, EtOH-H2O (10:1), reflux, 36h, 66%
(19) and 69% (20); (d) Me2NdCH2+CF3COO-, CH2Cl2, rt, 3 h,
96%
stemonamide series, deprotonation of the 14R/â mixture with
KH16 and treatment with dimethylmethyleneammonium
trifluoroacetate17 gave the R-methylene ketones 17 in 67%
yield. Under the same conditions, ketone substrate 16 gave
R-methylene compound 18 in 85% yield. The TMS enol
ether 15, also obtained in the 1,4-addition, was converted to
18 in 96% yield by direct treatment with the Mannich reagent
in CH2Cl2 at room temperature.18
a (a) MsCl, DMAP, py, CH2Cl2 0 °C, 1 h (stem.), 4 h (isostem.);
(b) NaH, THF, rt, 30 h (stem.), 5 h (isostem.).
Our first attempts to isomerize the exocyclic double bond
19
of 17 and 18 into the ring using RhCl3 were largely
tetrahydrofuran produced racemic stemonamide (1) in 33%
yield, along with 10% of unreacted 21. In a similar way,
isostemonamide (2) was prepared in 58% yield.
(11) Arseniyadis, S.; Rico Ferreira, M. R.; Quilez del Moral, J.; Martin
Hernando, J. I.; Potier, P.; Toupet, L. Tetrahedron: Asymmetry 1998, 9,
4055.
(12) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(b) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zeng, D.
Tetrahedron Lett. 1995, 36, 2423.
(13) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetra-
hedron Lett. 1986, 27, 4025.
(14) (a) Posner, G. H. Org. React. 1972, 19, 1. (b) Rossiter, B. E.;
Swingle, N. M. Chem. ReV. 1992, 92, 771.
(15) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 186.
(16) Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. Tetrahedron Lett.
1977, 1621.
(17) Ahond, A.; Cave, A.; Kan-Fan, C.; Husson, H.-P.; de Rostolan, J.;
Potier, P. J. Am. Chem. Soc. 1968, 90, 5622.
(18) Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. J. Am.
Chem. Soc. 1976, 98, 6715.
(19) Andrieux, J.; Barton, D. H. R.; Patin, H. J. Chem Soc., Perkin Trans.
1 1977, 359.
The structures of our synthetic stemonamide23 and iso-
stemonamide24 were corroborated by single-crystal X-ray
determinations25 of each compound and by their elemental
1
analyses and NMR, IR and mass spectra. Their H NMR
(20) Yamamoto, A. In Organotransition Metal Chemistry; Wiley-
Interscience: New York, 1986; pp 372-374. A mechanism through a π-allyl
intermediate also requires a hydrogen abstraction from the R-face of the
molecule.
(21) Yamaura, M.; Suzuki, T.; Hashimoto, H.; Yoshimura, J.; Okamoto,
T.; Shin, C.-G. Bull. Chem. Soc. Jpn. 1985, 58, 1413.
(22) (a) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett.
1994, 35, 6417. (b) Kohno, Y.; Narasaka, K. Bull Chem. Soc. Jpn. 1996,
69, 2063.
Org. Lett., Vol. 3, No. 16, 2001
2507

and 13C NMR spectra were indistinguishable from spectra
kindly provided to us by Prof. Y. Ye.26 Our route comprises
the first total syntheses of (()-stemonamide and (()-
isostemonamide in 4% and 7% yields from succinimide 4,
respectively.
Acknowledgment. We thank the University of Rochester
for partial support of this research.
Supporting Information Available: Data for 9, 10, 11,
1
12, 21, and 22. H and 13C NMR spectra of for 9, 10, 11,
(23) (()-1: colorless crystals, mp 240-241 °C (EtOAc/CH2Cl2). IR
(cm-1): 2925, 1765, 1698, 1661, 1456, 1389, 1326, 1145, 1075, 1006, 858.
1H NMR (400 MHz, CDCl3): 1.22-1.44 (2H, m); 1.81 (1H, bd, J ) 17.0);
1.84 (3H, s); 1.93 (1H, dt, J ) 8.8, 12.5); 1.99 (3H, s); 2.05-2.16 (2H, m);
2.27 (1H, dd, J ) 8.8, 16.6); 2.34 (1H, dd, J )7.8, 12.5); 2.58 (1H, ddd,
J ) 7.8, 12.5, 16.6); 2.82 (1H, bt, J ) 13.0); 2.97 (1H, bdd, J ) 5.8, 12.8);
3.97 (3H, s); 4.16 (1H, bd, J ) 14.4). 13C NMR (100 MHz, CDCl3): 8.4,
9.1, 27.3, 29.8, 30.1, 31.9, 41.2, 59.2, 74.5, 90.1, 99.6, 136.9, 168.6, 170.9,
172.9, 175.8, 196.5. APCI: 663 ([2MH]+, 10), 332 ([MH]+, 100), 207 (9),
125 (12). HRMS (DCI/NH3): calcd for C18H22NO5 m/z ) 332.1498, found
332.1507. Anal. Calcd: C, 65.24; H, 6.39. Found: C, 65.53; H, 6.58.
(24) (()-2: colorless crystals, mp 225-227 °C (EtOAc/CH2Cl2). IR
(cm-1): 2926, 2360, 1766, 1698, 1661, 1450, 1393, 1331, 1248, 1165, 1126,
1073, 1036, 1006, 963, 734. 1H NMR (400 MHz, CDCl3): 1.22-1.43 (2H,
m); 1.76 (1H, bd, J ) 14.2); 1.84 (3H, s); 1.90 (1H, dt, J ) 9.1, 13.0); 2.05
(3H, s); 2.01-2.04 (2H, m); 2.24 (1H, ddd, J ) 7.1, 13.0, 16.5); 2.33 (1H,
dd, J ) 9.1, 16.5); 2.59 (1H, dd, J ) 7.1, 13.0); 2.90-2.98 (2H, m); 4.13
(3H, s); 4.14 (1H, bd, J ) 15.0). 13C NMR (100 MHz, CDCl3): 8.3, 9.2,
12, 21, and 22. 1H and 13C NMR spectra of synthetic 1 and
2. ORTEP plots of 1 and 2. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL010106E
26.9, 27.6, 29.4, 29.7, 42.3, 59.8, 73.5, 86.4, 102.7, 136.6, 168.7, 171.7,
172.6, 174.6, 196.9. APCI: 663 ([2MH]+, 16), 332 ([MH]+, 100). HRMS
(DCI/NH3): calcd for C18H22NO5 m/z ) 332.1498, found 332.1495. Anal.
Calcd: C, 65.24; H, 6.39. Found: C, 65.36; H, 6.59.
(25) Huffman, J. C.; Molecular Structure Center, Department of Chem-
istry, Indiana University.
(26) We thank Prof. Y. Ye (Shanghai Institute of Materia Medica) for
1
sending us copies of H and 13C NMR spectra of natural 1 and 2.
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Org. Lett., Vol. 3, No. 16, 2001