Formal syntheses of (±)-stemonamine and (±)-cephalotaxine

Article abstract of DOI:10.1021/jo900113s

A short and efficient approach to aza-quaternary pyrrolo- [l,2-a]azepine 8 and aza-quaternary indolizine 23, as the crucial intermediates for syntheses of stemonamine (la) and cephalotaxine (1b), has been developed on the basis of the key intramolecular S

Full text of DOI:10.1021/jo900113s

Formal Syntheses of (()-Stemonamine and
(()-Cephalotaxine
Yu-Ming Zhao, Peiming Gu, Hai-Jun Zhang,
Qing-Wei Zhang, Chun-An Fan, Yong-Qiang Tu,* and
Fu-Min Zhang*
FIGURE 1. Selected polycyclic aza-quaternary alkaloids.
State Key Laboratory of Applied Organic Chemistry and
Department of Chemistry, Lanzhou UniVersity,
Lanzhou 730000, P. R. China
fundamental research and drug development.4 However, more
efficient and general approaches to theses alkaloids are still
desirable, especially for challenging construction of polycyclic
aza-quarternary skeletons.
tuyq@lzu.edu.cn; zhangfm@lzu.edu.cn
In connection with our previous investigations,5 we have
recently reported the first total synthesis of (()-stemonamine
(1a) based on the tandem semipinacol rearrangement/Schmidt
reaction.6 This achievement encouraged us to develop alterna-
tively more general and efficient new strategies for this type
and other kinds of complex aza-quaternary alkaloids syntheses.
Herein, we wish to present a concise tactic for formal syntheses
of (()-stemonamine (1a) and (()-cephalotaxine (1b) using the
key Schmidt reaction of the 2-quaternary-1,3-cyclodione sub-
strates.
ReceiVed January 23, 2009
As shown in Scheme 1, our synthetic plan focused on the
construction of crucial tricyclic enone 8 and tetracyclic enone
23, which could be achieved from 6 and 19 through several
transformations including oxidation and aldol cyclization. As
the key strategy level step, intramolecular Schmidt reaction7 of
symmetric azido diones 5 and 18 would provide the desired
aza-quaternary pyrrolo[1,2-a]azepine 6 and aza-quaternary in-
dolizine 19, respectively.
A short and efficient approach to aza-quaternary pyrrolo-
[1,2-a]azepine 8 and aza-quaternary indolizine 23, as the
crucial intermediates for syntheses of stemonamine (1a) and
cephalotaxine (1b), has been developed on the basis of the
key intramolecular Schmidt reaction of symmetric azido-
diones 5 and 18, respectively.
Initially, we selected stemonamine (1a) possessing the basic
structural element of interest as an optimal target to test our
methodology. As shown in Scheme 2, dione 2 was obtained
(4) For recent examples of the synthesis of (()-cephalotaxine, see: (a)
Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1990, 112, 9601. (b) Ishibashi,
H.; Okano, M.; Tamaki, H.; Maruyama, K.; Yakura, T.; Ikeda, M. J. Chem.
Soc., Chem. Commun. 1990, 1436. (c) Ikeda, M.; Okano, M.; Kosaka, K.; Kido,
M.; Ishibashi, H. Chem. Pharm. Bull. 1993, 41, 276. (d) Lin, X.; Kavash, R. W.;
Mariano, P. S. J. Am. Chem. Soc. 1994, 116, 9791. (e) Lin, X.; Kavash, R. W.;
Mariano, P. S. J. Org. Chem. 1996, 61, 7335. (f) Tietze, L. F.; Schirok, H. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1124. (g) Koseki, Y.; Sato, H.; Watanabe, Y.;
Nagasaka, T. Org. Lett. 2002, 4, 885. (h) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett.
2003, 5, 2931. (i) Li, W.-D. Z.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277. (j)
Ma, B.-C.; Wang, Y.-Q.; Li, W.-D. Z. J. Org. Chem. 2005, 70, 4528. (k) Li,
W.-D. Z.; Wang, X.-W. Org. Lett. 2007, 9, 1211. (l) Kuznetsov, N. Y.;
Kolomnikova, G. D.; Khrustalev, V. N.; Golovanov, D. G.; Bubnov, Y. N. Eur.
J. Org. Chem. 2008, 5647. For the synthesis of (-)-cephalotaxine, see: (m) Isono,
N.; Mori, M. J. Org. Chem. 1995, 60, 115. (n) Nagasaka, T.; Sato, H.; Saeki, S.
Tetrahedron: Asymmetry 1997, 8, 191. (o) Ikeda, M.; El Bialy, S. A. A.; Hirose,
K.; Kotake, M.; Sato, T.; Bayomi, S. M. M.; Shehata, I. A.; Abdelal, A. M.;
Gad, L. M.; Yakura, T. Chem. Pharm. Bull. 1999, 47, 983. (p) Tietze, L. F.;
Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264. (q) Planas, L.; Perard- Viret,
J.; Royer, J. J. Org. Chem. 2004, 69, 3087. (r) Eckelbarger, J. D.; Wilmot, J. T.;
Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370. (s) Zhao, Z.; Mariano, P. S.
Tetrahedron 2006, 62, 7266. (t) Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J. Org.
Chem. 2007, 72, 7352. (u) Esmieu, W. R.; Worden, S. W.; Catterick, D.; Wilson,
C.; Hayes, C. J. Org. Lett. 2008, 10, 3045. (v) Taniguchi, T.; Ishibashi, H. Org.
Lett. 2008, 10, 4129. (w) Hameed, A.; Blake, A. J.; Hayes, C. J. J. Org. Chem.
2008, 73, 8045.
The alkaloids stemonamine (1a)1 and cephalotaxine (1b)2
(Figure 1) represent a number of natural polycyclic aza-
quaternary alkaloids, respectively. As a potential drug, 1a and
its analogues were used in China and Japan for centuries for
the treatment of respiratory diseases and as insecticides. A
number of derivatives of 1b (i.e., harringtonine and homohar-
ringtonine) have been found to be highly effective for the
treatment of acute human leukemia and are currently undergoing
clinical trials.3 Owing to their unique structures and important
biological activities, 1a and 1b have always attracted consider-
able interest from synthetic organic and medicinal chemists.
Over the past years, a number of great efforts have been made
toward the syntheses of these alkaloids for the purpose of
(1) For reviews on stemona alkaloids, see: (a) Pilli, R. A.; Ferreira de Oliveira,
M. C. Nat. Prod. Rep. 2000, 17, 117. (b) Pilli, R. A.; Rosso, G. B.; de Oliveira,
M. C. F. In The Alkaloids; Cordell, G. A., Ed.; Elsevier: New York, 2005; Vol.
62, pp 77-173. (c) Greger, H. Planta Med. 2006, 72, 99.
(2) For reviews on the cephalotaxus alkaloids, see: (a) Weinreb, S. M.;
Semmelhack, M. F. Acc. Chem. Res. 1975, 8, 158. (b) Huang, L.; Xue, Z. The
Alkaloids; Academic Press: NewYork, 1984; Vol. 23, p 157. (c) JalilMiah, M. A.;
Hudlicky, T.; Reed, J. W. The Alkaloids; Academic Press: San Diego, 1998;
Vol. 51, p 199.
(3) (a) Levy, V.; Zohar, S.; Bardin, C.; Vekhoff, A.; Chaoui, D.; Rio, B.;
Legrand, O.; Sentenac, S.; Rousselot, P.; Raffoux, E.; Chast, F.; Chevret, S.;
Marie, J. P. Br. J. Cancer 2006, 95, 253. (b) Kantarjian, H. M.; Talpaz, M.;
Santini, V.; Murgo, A.; Cheson, B.; O’Brien, S. M. Cancer 2001, 92, 1591.
(5) Gu, P. M.; Zhao, Y.-M.; Tu, Y. Q.; Ma, Y. F.; Zhang, F. M. Org. Lett.
2006, 8, 5271.
(6) Zhao, Y.-M.; Gu, P. M.; Tu, Y.-Q.; Fan, C.-A.; Zhang, Q. W. Org. Lett.
2008, 10, 1763.
(7) Intramolecular Schmidt reaction: (a) Aube´, J.; Milligan, G. L. J. Am.
Chem. Soc. 1991, 113, 8965–8966. (b) Milligan, G. L.; Mossman, C. J.; Aube´,
J. J. Am. Chem. Soc. 1995, 117, 10449–10459.
10.1021/jo900113s CCC: $40.75
Published on Web 03/25/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3211–3213 3211

SCHEME 1
SCHEME 3
SCHEME 2
SCHEME 4
from commercially available cyclohexane-1,3-dione 1 in 62%
overall yield via two steps involving allylation and Michael
addition. Reduction of 2 with NaBH(CN)3 gave rise to the
corresponding hemiketal 3, which was converted to mesylate
-78 °C gave ꢀ-hydroxy ketone 17,12 and subsequent oxidation
of 17 with Dess-Martin reagent afforded the desired 18 in 70%
yield over two steps.
With a reliable route to 18 in hand, we turned our attention
to the key intramolecular Schmidt reaction. To our delight, we
obtained the desired product 19 in 75% yield using the same
procedure as for 5 (Scheme 4). Wacker oxidation of 19 furnished
the methyl ketone 20 in quantitative isolated yield.4h To
complete the synthesis, treatment of lactam 20 with Lawesson’s
reagent and reduction of thiolactam using W-2 Raney Ni in THF
gave the tertiary amine 22 in 85% yield over two steps. Finally
an easy aldol cyclization of 22 gave the key tetracyclic aza-
quaternary intermediate 23 in 80% yield, whose spectral
chracteristics were identical to those reported by Li and
co-worker.4h-j The intermediate 23 has been used for the total
synthesis of cephalotaxine by Li’s groups, and therefore, we
completed successfully a formal synthesis of cephalotaxine.
In summary, we have accomplished simple and efficient
formal total syntheses of stemonamine and cephalotaxine via a
facile intramolecular Schmidt reaction of symmetric azido dione
precursor. This concise Schmidt reaction may be applicable in
other alkaloids syntheses. Currently, we are carrying on an
investigation of this reaction from asymmetric vision in our
laboratory.
8
and treated with NaN3 to afford azido dione 5 in 58% yield
over three steps. With 5 in hand, the key intramolecular Schmidt
reaction was investigated. As expected, treatment of 5 with 2.05
equiv of TiCl4 in CH2Cl2 at 0 °C successfully gave the desired
aza-quaternary pyrrolo[1,2-a]azepine 6 in 93% yield, which
could conveniently convert to 1a according to our reported
6
produce.
The successful formal synthesis of 1a above encouraged us
to develop another formal synthesis of more challenging
molecular 1b. Initially, we envisioned that the key substrate 18
could be achieved through Pd-catalyzed arylation of cyclopen-
tane-1,3-dione with 10 and successive allylation according to
the Buchwald procedure;9 however, we could not obtain the
desired 2-aryl-1,3-dione product 18 under our reaction condi-
tions. Thus, we had to develop other method for preparation of
18. As depicted in Scheme 3, our project commenced with
Suzuki-Kumada coupling10 of aryl boracic acid (prepared from
10) and 2-iodocyclopentenone11 to afford enone 12 in 81%
overall yield from 10. The Grignard addition of the resulting
enone 12, followed by substitution with NaN3, epoxidation, and
protection with TMSCl, afforded siloxy epoxy azide 16 in 63%
overall yield from 12. Treatment of epoxide 16 with TiCl4 at
Experimental Section
Azido Diketone 5. The diketone 4 (6.64 g, 21.0 mmol) was
treated with NaN3 (4.1 g, 63.0 mmol) in DMF (30 mL) at room
temperature under argon. After 15 h, the mixture was diluted with
ether. The organic phase was washed with water twice, dried over
MgSO4, concentrated, and chromatographed (Rf ) 0.6, 1:1 hexane/
(8) CAUTION! Alkyl azides are potential explosion hazards in substrate
synthesis.
(9) Joseph, M. F.; Xiaohua, H.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
(10) Black, W. C.; Brideau, C.; Chan, C.-C.; Charleson, S.; Chauret, N.;
Claveau, D.; Ethier, D.; Gordon, R.; Greig, G.; Guay, J.; Hughes, G.; Jolicoeur,
P.; Leblanc, Y.; Nicoll-Griffith, D.; Ouimet, N.; Riendeau, D.; Visco, D.; Wang,
Z.; Xu, L.; Prasit, P. J. Med. Chem. 1999, 42, 1274.
(12) Here, compound 17 failed to give an N-insertion product via the Schmidt
reaction under these conditions.
(11) Krafft, M. E.; Cran, J. W. Synlett 2005, 1263.
3212 J. Org. Chem. Vol. 74, No. 8, 2009

ethyl acetate; dense liquid) to give the desired diketone 5 (5.30 g,
96% yield): H NMR (300 MHz, CDCl3) δ 0.90-1.00 (t, 3H),
Tertiary Amine Compound 22. A solution of thiolactam (60
mg, 0.18 mmol) in THF (3 mL) was treated with W2-Raney Ni at
room temperature. The reaction mixture was stirred for 1 h and
filtered. The solvent was removed under reduced pressure, and the
residue was chromatographed (Rf ) 0.2, 2:1 hexane/ethyl acetate;
1
1.20-1.40 (m, 2H), 1.75-2.10 (complex, 6H), 2.45-2.65 (m, 6H),
3.10-3.25 (t, 2H), 4.54 (s, 1H), 4.80 (s, 1H); 13C NMR (75
MHz,CDCl3) δ 12.2, 16.6, 24.6, 30.0, 33.7, 39.8, 44.1, 51.3, 68.0,
112.9, 146.3, 210.8; MS (EI) m/z 178, 164, 150, 136, 55, 41; HRMS
(ESI) calcd for C14H25N4O2 (M + NH4) 281.1972, found 281.1969.
Error: 1.1 ppm.
1
colorless dense liquid) to give 22 (46 mg, 85% yield): H NMR
(400 MHz, CDCl3) δ 1.85-1.95 (m, 1H), 2.06 (s, 3H), 2.07-2.30
(complex, 3H), 2.35-2.45 (m, 1H), 2.55-2.65 (m, 2H), 2.85-3.20
(complex, 6H), 3.30-3.40 (m, 1H), 3.55-3.60 (d, 1H), 5.85-5.90
(m, 2H), 6.55-6.60 (d, 2H); 13C NMR (100.6 MHz,CDCl3) δ 22.4,
23.0, 38.1, 45.6, 47.4, 53.3, 70.6, 100.9, 106.2, 109.5, 126.4, 127.1,
Amide Compound 6. To a solution of the azido dione 5 (363
mg, 1.38 mmol) in dry CH2Cl2 (6 mL) under argon was added TiCl4
(1.45 mL, 1 M in CH2Cl2) at -78 °C. The resulting mixture was
stirred for 15 min under these conditions. The mixture was then
warmed to room temperature and quenched with 3 mL of water.
The resulting mixture was partitioned between water and CH2Cl2.
The organic layer was collected, dried over MgSO4, filtered,
concentrated, and chromatographed (Rf ) 0.1, 1:1 hexane/ethyl
146.4, 146.8, 205.4, 207.0; IR (neat) 1038, 1235, 1483, 1706 cm-1
;
MS (EI) m/z 273, 230, 189, 115, 43; HRMS (ESI) calcd for
C17H20NO4 (M+ + H) 302.1387, found 302.1383. Error 1.3 ppm.
Pentacyclic Enone Compound 23. To a solution of 22 (30 mg,
0.1 mmol) in t-BuOH (3 mL) was added KOtBu (13.4 mg, 0.12
mmol) at 40 °C under argon. After 30 min, the solvent was removed
under reduced pressure, and the residue was taken in 50 mL of
CHCl3. The organic phase was washed with water and brine, dried
over MgSO4, concentrated, and chromatographed (Rf ) 0.05, 1:1
hexane/ethyl acetate; colorless dense liquid) to give cyclic enone
23 (23 mg, 80% yield): 1H NMR (400 MHz, CDCl3) δ 1.75-1.95
(complex, 2H), 2.05-2.18 (m, 1H), 2.40-2.58 (m, 2H), 2.65-2.90
(complex, 4H), 3.00-3.15 (m, 2H), 3.30-3.42 (m, 1H), 5.85-5.90
(m, 2H), 6.10-6.20 (d,1H), 6.37 (s,1H), 6.59 (s, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 22.2, 26.7, 27.1, 46.6, 46.9, 67.1, 100.8,
104.9, 109.3, 126.1, 129.2, 129.7, 146.6, 146.8, 178.9, 205.6; IR
(neat) 1038, 1236, 1482, 1713, 2932 cm-1; MS (EI) m/z 283, 254,
240, 226, 196, 115, 41; HRMS calcd for C17H18NO3 (M+ + H)
284.1281, found 284.1284. Error: 1.1 ppm.
1
acetate; dense liquid) to afford 6 (300 mg, 93% yield): H NMR
(300 MHz, CDCl3) δ 0.90-1.00 (m, 3H), 1.80-2.15 (complex,
9H), 2.20-2.60 (complex, 4H), 2.70-2.90 (m, 2H), 3.50-3.80 (m,
2H), 4.75-4.90 (m, 2H); 13C NMR (75 MHz,CDCl3) δ 12.1, 20.7,
22.6, 29.4, 32.8, 34.8, 37.5, 39.4, 47.1, 74.2, 114.2, 146.2, 170.8,
210.7; IR (neat) 1649, 1714 cm-1; MS (EI) m/z 235, 178, 166,
150, 138, 123; HRMS (ESI) calcd for C14H22O2N (M++ H)
236.1645, found 236.1648. Error: 1.3 ppm.
Amide Compound 19. To a solution of 18 (40 mg, 0.12 mmol)
in CH2Cl2 (3 mL) under argon was added TiCl4 (0.24 mL, 1 M in
CH2Cl2) at 0 °C. The resulting mixture was stirred for 40 min under
these conditions. The mixture was then quenched with 2 mL of
water. The resulting mixture was partitioned between water and
CH2Cl2. The organic layer was collected, dried over MgSO4, filtered,
and concentrated. Chromatography (Rf ) 0.5, ethyl acetate; dense
Acknowledgment. We gratefully acknowledge financial sup-
port from the NSFC (Nos. 20621091, 20672048, and 20732002)
and the “111” program of Chinese Education Ministry.
1
liquid) afforded 19 (27.4 mg, 75% yield): H NMR (300 MHz,
CDCl3) δ 2.40-2.80 (complex, 6H), 2.85-3.05 (m, 2H), 3.15-3.30
(m, 1H), 4.85-4.95 (m, 1H), 5.10-5.20 (m, 2H), 5.50-5.70 (m,
1H), 5.90-5.95 (m, 2H), 6.57 (s, 1H), 6.95 (m,1H); 13C NMR (75
MHz, CDCl3) δ 29.0, 29.8, 35.4, 35.7, 43.7, 71.6, 101.2, 105.9,
109.1, 121.0, 126.5, 128.3, 131.5, 146.5, 147.2, 168.9, 204.7; IR
(neat) 1235, 1406, 1485, 1655, 1728 cm-1; MS (EI) m/z 299, 258,
230, 84; HRMS (ESI) calcd for C17H18NO4 (M+ + H) 300.1230,
found 300.1229. Error: 0.3 ppm.
Supporting Information Available: General experimental
procedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO900113S
J. Org. Chem. Vol. 74, No. 8, 2009 3213