Highly efficient formal synthesis of cephalotaxine, using the stevens rearrangement-acid lactonization sequence as a key transformation

Article abstract of DOI:10.1021/jo8025252

Cephalotaxine (1), the major alkaloid isolated from Cephalotaxus species, has attracted considerable attention due to the promising antitumor activity of several of its derivatives and its unique structural features. Herein we describe a highly efficient formal synthesis of 1 employing the [2,3]-Stevens rearrangement-acid lactonization sequence as a key transformation from readily available (3,4-dimethoxyphenyl)acetic acid, methyl prolinate, and allyl bromide.

Full text of DOI:10.1021/jo8025252

Highly Efficient Formal Synthesis of
Cephalotaxine, Using the Stevens
Rearrangement-Acid Lactonization Sequence as
A Key Transformation
Mo-ran Sun, Hong-tao Lu, Yan-zhi Wang, Hua Yang,* and
Hong-min Liu*
New Drug Research & DeVelopment Center, School of
Pharmaceutical Science, Zhengzhou UniVersity,
Zhengzhou 450001, China
yanghua@zzu.edu.cn
ReceiVed NoVember 13, 2008
FIGURE 1. Retrosynthesis analysis of cephalotaxine.
spirolactone 4. The precursor 4 could be derived either from
the acid-lactonization of γ-en-carboxylate 5 (path A, X ) H2)
or from the condensation of 3,4-dimethoxyphenacetyl chloride
with spirolactone 6 (path B, X ) O). In path A and path B,
(3,4-dimethoxyphenyl) acetic acid, methyl prolinate, and allyl
bromide were the starting materials. These materials are
commercially available.
Cephalotaxine (1), the major alkaloid isolated from Cepha-
lotaxus species, has attracted considerable attention due to
the promising antitumor activity of several of its derivatives
and its unique structural features. Herein we describe a highly
efficient formal synthesis of 1 employing the [2,3]-Stevens
rearrangement-acid lactonization sequence as a key trans-
formation from readily available (3,4-dimethoxyphenyl)acetic
acid, methyl prolinate, and allyl bromide.
As shown in Scheme 1, the synthesis of 3a commenced from
3,4-dimethoxyphenyl acetic acid 7, which was converted to
iodide 8 with 82% overall yield.6 Reaction of iodide 8 with
methyl prolinate in CH3CN at room temperature for 8 h yielded
the nitrogen alkylation product 9 in 87% yield. Workup of 9
with allyl bromide in the presence of K2CO3 in CH3CN
furnished the γ-en-carboxylate 5 via a facile [2,3]-Stevens
rearrangement of the resulting allyl quaternary ammonium salt
10 in 85% yield. The Stevens rearrangement that we modified
(K2CO3 in CH3CN) was superior to the technique reported in
the literature (KOBut-DMSO-THF).7 Thus, the quaternary
carbon center R to the nitrogen of the pyrrolidine, which was
key in the total synthesis of cephalotaxine, was successfully
produced8 in one pot at the outset of our synthesis. With 5 in
hand, we turned our attention to the synthesis of spiroenone
3a. 3a, or its derivatives, can be prepared by using a Wacker
oxidation as the key transformation. However, a stoichiometric
amount of PdCl2 is required. Using this method, our observed
Cephalotaxine (1, CET), the parent member of the Cepha-
lotaxus alkaloids,1 has a unique ring skeleton containing an
unusual 1-azaspiro[4,4]nonane moiety fused to a benzazepine
moiety. The structural characteristics of CET and the clinically
proven yet intriguing antitumor therapeutic potentials of its
naturally occurring ester derivatives (harringtonine and homo-
harringtonine) have attracted a long-standing interest in their
chemical synthesis.2 Herein we describe a highly efficient
synthesis of CET (1) employing the [2,3]-Stevens rearrange-
ment-acid lactonization sequence as a key transformation.
Our retrosynthesis of 1 led to the tetracyclic core 2 and
spiroenone 3 (Figure 1). The transformation of 2b f 1 and 3
f 23 has been demonstrated by Hanaoka et al.4 and Li et al.,5
respectively. We assumed that 3 should be available by a
combination of lactone reduction, swern oxidation, and intramo-
lecular keto-aldehyde aldol condensation starting from the
(3) For possible transformation from 3 to 1 via an alternative pathway, see
relevant total synthesis of cephalotaxine: (a) Kuehne, M. E.; Bornmann, W. G.;
Parsons, W. H.; Spitzer, T. D.; Blount, J. F.; Zubieta, J. J. Org. Chem. 1988,
53, 3439. (b) Planas, L.; Perard-Viret, J.; Royer, J. J. Org. Chem. 2004, 69,
3087. (c) Sha, C. K.; Young, J. J.; Yeh, C. P.; Chang, S. C.; Wang, S. L. J. Org.
Chem. 1991, 56, 2694. (d) Isono, N.; Mori, M. J. Org. Chem. 1995, 60, 115. (e)
Tieze, L. F.; Shirok, H. J. Am. Chem. Soc. 1999, 121, 10264. (f) Ikeda, M.;
Hirose, K.; El, Bialy, S. A. A.; Sato, T.; Yakura, T.; Bayoma, S. M. M. Chem.
Pharm. Bull. 1998, 46, 1084. (g) Suga, S.; Watanabe, M.; Yoshida, J. I. J. Am.
Chem. Soc. 2002, 124, 14824. (h) Semmelhack, M. F.; Chong, B. P.; Stauffer,
R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97,
2507.
(1) For reviews see: (a) Huang, L.; Xue, Z. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1984; Vol. 23, pp 157-226. (b) Hudlicky, T.;
Kwart, L. D.; Reed, J. W. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; John Wiley and Sons: New York, 1987; Vol. 5, pp 639-
690. (c) Jalil Miah, M. A.; Hudlicky, T.; Reed, J. W. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1998; Vol. 51, pp 199-269.
(4) Yasuda, S.; Yamada, T.; Hanoka, M. Tetrahedron Lett. 1986, 27, 2023.
(5) Li, W.-D. Z.; Wang, X.-W. Org. Lett. 2007, 9, 1211.
(6) (a) Molander, G. A.; Hiersemann, M. Tetrahedron Lett. 1997, 25, 4347.
(b) Shiina, I.; Oshiumi, H.; Hashizume, M.; Yama, Y.-S.; Ibuka, R. Tetrahdron
Lett. 2004, 45, 543.
(2) For a recent total synthesis, see: Hameed, A.; Blake, A. J.; Hayes, C. J.
J. Org. Chem. 2008, 78, 8045, and references cited therein.
(7) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931.
10.1021/jo8025252 CCC: $40.75
Published on Web 01/26/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2213–2216 2213

SCHEME 1. Preparation of Enone 3a
yield was low.9 Thus, we attempted to obtain spiroenone 3a
via acid-lactonization of 5. To our surprise, although iodo-
lactonization of γ-en-carboxylic acid was widely applied in the
total synthesis of natural products, the acid-lactonization of γ-en-
carboxylate has seldom been reported.10 Among various acidic
systems (HCl, H2SO4, PPA, MsOH, TFA, TsOH), triflic acid
(5 equiv, DCM, rt, 5-7 min) gave the highest yield (95%). It
also requires the simplest experimental scheme for transforming
5 to amino spirolactone 4a. The direct iodolactonization of 5
led to a slow decomposition of the substrate. This is presumably
due to the existence of nitrogen atom. The unstable keto-
aldehyde intermediate is produced by subjecting 4a to LiAlH4
reduction11 and subsequent Swern oxidation12 of the resulting
diol 13. An attempt to oxidize diol 13 with PCC and PDC failed
because the R-amino aldehyde was sensitive to decomposition
under an acid environment. For this reason, the crude product
was condensed, without purification by column chromatography
with KOtBu-THF, to afford spirocyclopentenone 3a.13
the key transformation steps. The instability of the keto-aldehyde
intermediate was responsible for the low overall yields (30%)
of Swern oxidation and Aldol condensation. So we developed
a modified synthesis route (path B), which employed amido
spirocyclopentenone 3b as a precursor for CET synthesis.
Following a procedure analogous to the one mentioned above,
we first synthesized the spirolactone 6 from readily available
methyl prolinate 14 by the following sequence (Scheme 2): (1)
N-allylation of methyl prolinate 14 (allyl bromide, K2CO3,
DMF), (2) [2,3]-Stevens rearrangement of the resulting quater-
nary ammonium by the reaction of 15 with benzyl bromide in
CH3CN, and (3) acid-lactonization of 16 (5 equiv of TfOH,
DCM, rt) followed by debenzylation through catalytic hydro-
genation (Pd/C, H2).14 Condensation of spirolactone 6 with 3,4-
dimethoxyphenacetyl chloride produced the amide spirolactone
4b, which was subjected to selective reduction with LiBH4 to
give diol 18.15 To our delight, Swern oxidation of diol 18
produced the stabilized amido keto-aldehyde 19 in almost
quantitative yield. The treatment of 19 with K2CO3, under
MeOH-H2O16 conditions, produced the amido spirocyclopen-
tenone 3b. According to Li et al.’s procedure,5 triflic acid
mediated Friedel-Crafts cyclization of amido spirocyclopen-
tenone 3b furnished 2b, whose spectra (1H NMR, 13C NMR,
IR) were in full accord with those reported by Hanaoka et al.4
The modified sequence outlined in Scheme 2 constitutes a highly
efficient formal synthesis of CET. The overall yield from methyl
prolinate 14 to 3b, through eight-stage operations, is ca. 51%.
In summary, sequential application of the [2,3]-Stevens
rearrangement and acid-lactonization reaction provides a rapid
entry to the synthetically challenging tetracyclic core 2b (2a)
of cephalotaxine. This process should have general application
in bioactive alkaloid synthesis. The efficiency and practicality
of the synthesis follows from its brevity. The availability of
starting materials, the operationally simple reaction with inex-
pensive reagents, and high overall yield make it especially
suitable for large-scale production. The 10-50 g scale of 2b
was easily available in our laboratory.
Thus we have accomplished a formal synthesis of CET, using
a facile [2,3- Stevens rearrangement and acid-lactonization as
(8) Preparation of the allyl quaternary ammonium 10, via the following path,
was unsuccessful under mild or forcing solvents conditions (CH3CN, DMSO, rt
f reflux).
(9) The unsuccessful transformation of 5 f 12, 11 f 13 was probably
attributed to the stronger coordination of the nitrogen atom to PdCl2 and CuCl2.
Viscous brown jelly was produced during the course of the following
reaction:
(10) For reported acid-lactonization reaction of γ-en-carboxylate, see: (a)
Amonkar, C. P.; Tilve, S. G.; Parameswaran, P. S. Synthesis 2005, 14, 2341.
(b) Guo, M.; Varady, L. Tetrahedron Lett. 2002, 43, 3677. (c) Ila Hiriyakkan-
avar, A.-D.; Junjappa, H. Tetrahedron 1987, 43, 5367. (d) Tiecco, M.; Tingoli,
M.; Testaferri, L.; Bartoli, D. Synth. Commun. 1989, 19, 2817.
(11) Jung, M. E.; Min, S.-J. Tetrahedron 2007, 63, 3682.
Currently, we are exploring various conditions to transform
2b to cephalotaxine via simpler methods than those used by
(12) Demark, M. E.; Fu, J. Org. Lett. 2002, 4, 1951.
(13) Considerable difficulty was encountered in finding conditions suitable
for the base-catalyzed aldol condensation of keto-aldehyde intermediate. Among
the conditions (K2CO3/MeOH, KOH/MeOH, proline/EtOH, proline/DMSO)
examined, the only effective one was the KOtBu/THF system, which furnished
the amino spirocyclopentenone 3a. For information on this system, see: Freiria,
M.; Whitehead, A. J.; Tocher, D. A.; Motherwell, W. B. Tetrahedron 2004, 60,
2673.
(14) Wright, S. W.; Ammirati, M. J.; Andrews, K. M.; Brodeur, A. M.; et
al. J. Med. Chem. 2006, 49, 3068.
(15) Ahn, J.-B.; Yun, C.-S.; Kim, K. H.; Ha, D.-C. J. Org. Chem. 2000, 65,
9249.
(16) Pandolfi, E.; Comas, H. Tetrahedron Lett. 2003, 44, 4631.
2214 J. Org. Chem. Vol. 74, No. 5, 2009

SCHEME 2. Modified Highly Efficient Synthesis of 3b
Hanaoka.3 An application of this method to the synthesis of
optically active cephalotaxine and its analogues is now in
progress.
bromide (0.90 g, 8.8mmol), and dry K2CO3 (1.60 g, 12 mmol) in
dry CH3CN (20.0 mL) was stirred for 6 h at room temperature.
The solvent was evaporated in vacuo and then water (20 mL) and
ethyl acetate (100 mL) were added. The aqueous phase was
extracted with ethyl acetate (30.0 mL), combined with the organic
phase, and dried over anhydrous MgSO4. Evaporation of the solvent
invacuofollowedbycolumnchromatography(petroleumether-EtOAc,
5/1) gave 5 as a colorless oil (1.97 g, 85%). IR (KBr) νmax 3071,
Experimental Section
4-(2-Iodoethyl)-1,2-dimethoxybenzene (8). To a solution of
LiAlH4 (0.39 g, 10 mmol) suspended in dry THF (20 mL) was
added 3,4-dimethoxyphenyl acetic acid 7 (0.98 g, 5 mmol) at room
temperature. The mixture was stirred for 30 min and then H2O (0.39
mL), 15% aqueous NaOH (0.39 mL), and H2O (1.17 mL) were
added successively. After the mixture was stirring for 5 min, the
produced aggregates were filtered out and the solvent was removed
in vacuo to give the alcohol (0.86 g, 93%) as a colorless oil. To a
cooled (0 °C) solution of alcohol (0.86 g, 4.73 mmol) in dry CH2Cl2
(8.0 mL) were added Et3N (0.81 mL, 5.68 mmol) and tosyl chloride
(1.10 g, 5.68 mmol). After the reaction mixture was stirred at room
temperature for 30 min, CH2Cl2 (30 mL) was added and the mixture
was washed with a saturated aqueous solution of Na2CO3 and brine
successively. The organic phase was dried, concentrated, and
subjected to column chromatography to give tosylate (1.51 g, 95%)
as a colorless oil. A mixture of tosylate (1.50 g, 4.50 mmol) and
sodium iodide (6.73 g, 44 mmol) in acetone (5.0 mL) was refluxed
for 6 h. The resulting mixture was cooled to room temperature and
the solvent was evaporated. The residue was taken up in water (10
mL) and extracted with ethyl acetate and the combined organic
layers were washed with water, dried over Na2SO4, and concen-
trated. Silica gel column chromatography of crude product eluting
with petroleum ether-EtOAc (10/1) gave 8 as a colorless oil (1.20
g, 93%). 1H NMR (400 MHz, CDCl3) δ 3.07 (t, J ) 15.5 Hz, 2H),
3.28 (t, J ) 15.5 Hz, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 6.67-6.70
(m, 2H), 6.76 (d, J ) 8.0 Hz, 1H).
1
1725 cm-1; H NMR (400 MHz, CDCl3) δ 1.70-1.89 (m, 3H),
2.04-2.10 (m, 1H), 2.20-2.38 (m, 1H), 2.47-2.75 (m, 5H),
2.87-2.94 (m, 1H), 3.17-3.26 (m, 1H), 3.64 (s, 3H), 3.86 (s, 6H),
5.00-5.07 (m, 2H), 5.65-5.75 (m, 1H), 6.70-6.73 (m, 2H),
6.77-6.79 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 174.6, 148.7,
147.3, 134.3, 133.1, 120.6, 117.7, 112.1, 111.2, 77.4, 77.9, 70.5,
55.9, 51.4, 39.1, 35.7, 33.8, 29.7, 21.7; HRMS (ESI) m/z obsd
334.2011 ([M + H]+, calcd 334.2018 for C19H28NO4).
Spirolactone (4a). To a solution of compound 5 (2.41 g, 7.3
mmol) in dry CH2Cl2 (10.0 mL) was added triflic acid (5.50 g,
36.5 mmol). After the solution was stirred for 7 min at room
temperature, CH2Cl2 (100 mL) was added and the resulting mixture
was washed with a saturated aqueous solution of Na2CO3 and brine.
The organic phase was separated, dried, and concentrated. The crude
residue was purified by flash column chromatogramphy on silica
gel (petroleum ether-EtOAc 4/1) to give 4a as a colorless oil (2.20
g, 95%). IR (KBr) νmax 1763 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.37 (d, J ) 6.1 Hz, 3H), 1.87-2.08 (m, 5H), 2.17-2.22 (m, 1H),
2.69-2.89 (m, 4H), 3.06-3.87 (m, 2H), 3.85 (s, 3H), 3.88 (s, 3H),
4.40-4.50 (m,1H), 6.7-6.8 (m, 3H); 13C NMR (100 MHz, CDCl3)
δ 178.2, 148.8, 147.4, 132.8, 120.6, 112.1, 111.2, 77.1, 73.4, 70.5,
55.9, 51.3, 39.8, 36.1, 35.6, 22.6, 21.8, 21.1; HRMS (ESI) m/z obsd
320.1867 ([M + H]+, calcd 320.1862 for C18H26NO4).
Diol (13). To a solution of LiAlH4 (0.39 g, 10 mmol) suspended
in dry THF (20.0 mL) was added spirolactone 4a (2.22 g, 6.96
mmol) in dry THF (5.0 mL) under refluxing conditions. The
resulting mixture was cooled to room temperature after refluxing
for 30 min and then H2O (0.39 mL), 15% aqueous NaOH (0.39
mL), and H2O (1.17 mL) were added successively. After 5 min of
stirring, the produced aggregates were filtered out and the solvent
was evaporated in vacuum to give 13 as a colorless oil (2.04 g,
Methyl 1-(3,4-Dimethoxyphenethyl)pyrrolidine-2-carboxy-
late (9). A mixture of methyl prolinate (1.29 g, 10 mmol),
compound 8 (2.92 g, 10 mmol), and K2CO3 (2.76 g, 20 mmol) in
CH3CN (15 mL) was brought to reflux for 5 h. The resulting mixture
was cooled and diluted with EtOAc (150 mL). The organic layer
was washed with water (3 × 10 mL) and brine (2 × 10 mL), then
dried over anhydrous MgSO4. After evaporation of the solvent in
vacuo, the crude residue was purified by silica gel column
chromatography eluting with petroleum ether-EtOAc (4/1) to give
1
92%). IR (KBr) νmax 3373 cm-1; H NMR (400 MHz, CDCl3) δ
1.20 (d, J ) 6.2 Hz, 3H), 1.46 (d, J ) 16.2 Hz, 1H), 1.53-1.65
(m, 1H), 1.72-1.81 (m, 3H), 1.87-1.92 (m, 1H), 2.67-2.82 (m,
5H), 3.06-3.11 (m, 1H), 3.40 (d, J ) 11.1 Hz, 1H), 3.55 (d, J )
11.1 Hz, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 3.84-3.92 (m, 1H),
6.72-6.74 (m, 2H), 6.78-6.80 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 148.8, 147.4, 132.7, 120.1, 112.3, 77.3, 76.9, 66.7, 64.9,
55.9, 51.3, 50.4, 41.4, 35.6, 32.3, 25.7, 21.7; HRMS (ESI) m/z obsd
324.2170 ([M + H]+, calcd 324.2175 for C18H30NO4).
1
9 as a colorless oil (2.55 g, 87%). IR (KBr) νmax 1725 cm-1; H
NMR (400 MHz, CDCl3) δ 1.78-1.99 (m, 3H), 2.04-2.19 (m,
1H), 2.55-2.65 (m, 1H), 2.67-2.88 (m, 2H), 2.84-2.87 (m, 1H),
3.18-3.23 (m, 2H), 3.67 (s, 3H), 3.79 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.6, 148.7, 147.2, 132.3, 120.3, 111.8, 111.1, 77.0,
65.9, 56.9, 55.7, 53.5, 51.8, 34.8, 29.3, 23.1; HRMS (ESI) m/z obsd.
294.1700 ([M + H]+, calcd 294.1705 for C16H24NO4).
Methyl 1-(3,4-Dimethoxyphenethyl)-2-allylpyrrolidine-2-car-
boxylate (5). A mixture of compound 9 (2.00 g, 6.8 mmol), allyl
Amino Spirocyclopentenone (3a). To a cooled (-78 °C)
solution of DMSO (3.74 g, 48 mmol) in dry CH2Cl2 (8.0 mL) was
J. Org. Chem. Vol. 74, No. 5, 2009 2215

added a solution of oxalyl chloride (2.86 g, 22.4 mmol) in dry
CH2Cl2 (8.0 mL) over a period of 6 min then the mixture was stirred
for 10 min. Next a solution of diol (3.38 g, 10 mmol) in dry CH2Cl2
(10.0 mL) was added to the mixture at -78 °C. After 15 min at
the same temperature, Et3N (5.06 g, 50.0 mmol) was added and
the solution was allowed to warm to room temperature. The mixture
was quenched by addition of water (10 mL) and the organic layer
was washed with a saturated aqueous solution of NaHCO3 and brine,
then dried and concentrated. The residue without further purification
(400 MHz, CDCl3) δ 1.79-2.04 (m, 4H), 2.07 (d, J ) 18.4 Hz,
1H), 2.42-2.52 (m, 3H), 2.61-2.79 (m, 3H), 3.10-3.26 (m, 1H),
3.84 (s, 3H), 3.86 (s, 3H), 6.12 (d, J ) 5.6 Hz, 1H), 6.67-6.70
(m, 3H), 7.33 (d, J ) 5.6 Hz, 1H); HRMS (ESI) m/z obsd 302.1757
([M + H]+, calcd 302.1756 for C18H24NO3).
Acknowledgment. We thank the National Nature Science
Foundation (20502023) for financial support.
t
Supporting Information Available: Experimental proce-
dures and spectral data of compounds 15-17, 6, 18, 19, and
2b-4b, and 1H and 13C NMR spectra for all compounds
characterized in this work. This material is available free of
charge via the Internet at http://pubs.acs.org.
was solved in dry THF (10 mL) and KOBu (1.12 g, 10 mmol)
was added. After 20 min of stirring at room temperature, the solvent
was evaporated under vacuum. The residue was taken up in water
(15.0 mL) and extracted with ethyl acetate (3 × 50.0 mL). The
combined organic phase was dried, concentrated, and subjected to
column chromatography (petroleum ether-EtOAc 1/1) to give 3a
as a colorless oil (0.91 g, 30%). IR (KBr) νmax 1713 cm-1; 1H NMR
JO8025252
2216 J. Org. Chem. Vol. 74, No. 5, 2009