Stereoselective Synthesis of (-)-Cephalotaxine and C-7 Alkylated Analogues

Article abstract of DOI:10.1021/jo049884l

A total asymmetric synthesis of (-)-cephalotaxine is reported. The chemistry of α,β-unsaturated γ-lactams was used to access the 1-azaspiro[4.4]nonane skeleton in enantiomerically pure form via a stereocontrolled semipinacolic rearrangement of an α-hydrox

Full text of DOI:10.1021/jo049884l

Ster eoselective Syn th esis of (-)-Cep h a lota xin e a n d C-7 Alk yla ted
An a logu es
Lo¨ıc Planas, J oe¨lle Pe´rard-Viret, and J acques Royer*
UMR 8638 (CNRS-Universite´ Paris-5), Faculte´ des Sciences Pharmaceutiques et Biologiques,
4 avenue de l’Observatoire, 75270 Paris Cedex 06, France
jacques.royer@univ-paris5.fr
Received J anuary 20, 2004
A total asymmetric synthesis of (-)-cephalotaxine is reported. The chemistry of R,â-unsaturated
γ-lactams was used to access the 1-azaspiro[4.4]nonane skeleton in enantiomerically pure form
via a stereocontrolled semipinacolic rearrangement of an R-hydroxyiminium ion. This spiro
compound was transformed into (-)-cephalotaxine without any racemization or epimerization by
following the racemic synthesis reported by Kuehne. We thus performed a total synthesis of (-)-
cephalotaxine in 98.7% ee with an overall yield of 9.8% over a 16 steps sequence. This synthetic
process was adaptable to the access of some alkylated analogues.
In tr od u ction
(-)-Cephalotaxine 1 was isolated in 1963 from the
evergreen plum yews of the genus Cephalotaxus as the
most abundant alkaloid.1 Its greatest interest is the
powerful activity of its ester derivatives, harringtonine
2a and homoharringtonine 2b, against chronic myelog-
enous leukaemia (Figure 1). Homoharringtonine has thus
been extensively studied and is now in phase III clinical
trials.2 However, the natural source of this alkaloid re-
mains very limited, and some species of the Asian shrub,
from which it is extracted, are endangered.3 Furthermore,
it should be mentioned that this material is only ca.
90% ee pure.4
F IGURE 1. Cephalotaxus alkaloids.
syntheses and many approaches.6 There is still a pressing
interest for an efficient synthesis of this structurally
original alkaloid, and approaches continue to be pub-
lished.7-9
Recently, an efficient hemisynthesis of enantiopure
homoharringtonine from (-)-cephalotaxine has been
described,5 which has increased the interest in the
synthesis of this parent pentacyclic natural product.
Thus, an efficient and scalable synthesis of enantiopure
(-)-cephalotaxine should be quite interesting.
During the 1970s and the 1980s, many teams were
engaged in this challenging synthesis, the main problem
being the construction of the spiro quaternary center at
rings C and D. This led to more than 10 racemic
In the past decade, as new developments in asym-
metric organic chemistry were growing, four asymmetric
syntheses were proposed. The first one, published by Mori
in 1995, was based on the use of unnatural D-proline.10
Mori underlined and partially resolved the problem of
racemization in the last steps since (-)-cephalotaxine was
obtained with an 88% ee according to the optical rotation,
while the ee of the next to last product was carefully
examined and found to be 88% (chiral HPLC). In 1997,
Nagasaka achieved the syntheses of both (-)- and (+)-
cephalotaxine by resolution of an intermediate following
separation of diastereoisomeric ketal derivatives by
* Corresponding author. Tel: (33) 1 53 73 97 49. Fax: (33) 1 43 29
14 03.
(1) Paudler, W. W.; Kerley, G. I.; McKay, J . J . Org. Chem. 1963,
28, 2194-2197.
(6) For a review on these syntheses: J ilal Miah, M. A.; Hudlicky,
T.; Reed, J . W. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
San Diego, CA, 1998; Vol. 51.
(2) For a review on HHT clinical trials: (a) Kantarjian, H. M.;
Talpaz, M.; Santini, V.; Murgo, A.; Cheson, B.; O’Brien, S. M. Cancer
2001, 92, 1591-605. Most recent results: (b) Hitt, E. Lancet Oncol.
2002, 3, 259. (c) O’Brien, S.; Talpaz, M.; Cortes, J .; Shan, J .; Giles, F.
J .; Faderl, S.; Thomas, D.; Garcia-Manero, G.; Mallard, S.; Beth, M.;
Koller, C.; Kornblau, S.; Andreeff, M.; Murgo, A.; Keating, M.;
Kantarjian, H. M. Cancer 2002, 94, 2024-32. (d) Scappini, B.; Onida,
F.; Kantarjian, H. M.; Dong, L.; Verstovsek, S.; Keating, M. J .; Beran,
M. Cancer 2002, 94, 2653-62.
(7) For more recent syntheses: (a) Kim, S. H.; Cha, J . K. Synthesis
2000, 2113-2116. (b) Booker Milburn, K. I.; Dudin, L. F.; Anson, C. E.;
Guile, S. D. Org. Lett. 2001, 3, 3005-3008. (c) Tietze, L. F.; Steck, P.
L. Eur. J . Org. Chem. 2001, 4353-4356. (d) Worden, S. M.; Mapitse,
R.; Hayes, C. J . Tetrahedron Lett. 2002, 43, 6011-6014.
(8) (a) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T. Org. Lett.
2002, 4, 885-888. (b) Suga, S.; Watanabe, M.; Yoshida, J .-i. J . Am.
Chem. Soc. 2002, 124, 14824-14825.
(3) Farjon, A. World checklist and bibliography of conifers; The Royal
Botanic Gardens: Kew, 1998.
(4) Huang, W.; Li, Y.; Pan, X. Sci. Sin. 1980, 23, 835-846.
(5) Robin, J .-P.; Dhal, R.; Dujardin, G.; Girodier, L.; Mevellec, L.;
Poutot, S. Tetrahedron Lett. 1999, 40, 2931-2934.
(9) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931-2934. In this
paper, the resolution of the next to last intermediate furnished (-)-
cephalotaxine.
(10) Isono, N.; Mori, M. J . Org. Chem. 1995, 60, 115-119.
10.1021/jo049884l CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/02/2004
J . Org. Chem. 2004, 69, 3087-3092
3087

Planas et al.
SCHEME 1
SCHEME 2
HPLC.9 Though no details were given in this report, the
optical rotation of the target product corresponds to a
high enantiomeric purity. In 1999, Ikeda published a
synthesis from unnatural D-proline,12 while Tietze per-
formed an elegant and very efficient asymmetric synthe-
sis based on palladium chemistry.13 These syntheses were
formal syntheses, and the ee of the last described
intermediate was limited to 85-90%.
SCHEME 3
In this context, we wish to report herein a new scalable
and highly efficient asymmetric synthesis of (-)-cepha-
lotaxine in 98.7% ee. This synthesis is based on the
stereoselective spirocyclization we reported in a previous
communication.14 We will describe herein the overall
synthesis and a careful determination of the enantiomeric
purity of (-)-cephalotaxine together with some C-7-
alkylated cephalotaxine derivatives.
ment could be attained by the use of chiral auxiliary on
the nitrogen atom, and we selected (S)-1-(1-naphthyl)-
ethylamine as the most efficient chiral appendage and
starting material.
Resu lts a n d Discu ssion
The strategy we chose was focused on the achievement
of a method for the construction of the C/D ring moiety
of 1 and more precisely to develop an efficient access to
the 1-azaspiro[4.4]nonane skeleton in an asymmetric
fashion. This project was based upon the chemistry of
R,â-unsaturated γ-lactams 3 we have developed for some
years in the laboratory. These compounds were thought
to be of particular interest in the asymmetric construction
of a quaternary center R to the nitrogen of the pyrrolidine
ring and hence a spiro derivative. Indeed, depending
upon the conditions, these R,â-unsaturated γ-lactams 3
are equivalent to either the carbanion synthon I or the
carbocation synthon II as depicted in the Scheme 1.
Silyloxypyrrole 4, equivalent to carbanion synthon I,
reacts with electrophiles at C-5 to furnish 6. This last
compound possesses the R,â-unsaturated lactam function
from which a new reaction at the same center is possible
through the anionic or cationic species.
Thus, starting from (S)-1-(1-naphthyl)ethylamine, we
prepared the silyloxypyrrole 4a in 54% yield (after
purification) over two steps as described in Scheme 2.
The vinylogous Mukaiyama aldol reaction of 4a with
cyclobutanone affords the R,â-unsaturated γ-lactam 6a
with 77% yield but only 4% diastereoisomeric excess.
Acidic treatment of 6a (concentrated HCl in CH2Cl2 at 0
°C) furnished the desired spiro compound 7 in quantita-
tive yield with a good diastereoisomeric excess (80%).
Besides this good de, it was found that the two dia-
stereoisomers can be very easily separated. Indeed, the
major diastereoisomer was crystallized from ethanol fur-
nishing 69% yield of pure compound as shown from 1H
NMR analyses. Additional product could be obtained
after flash chromatography on silica gel of the mother
liquor, giving almost the totality of the major diastere-
oisomer. The spiro compound 7 exhibiting the required
configuration was then obtained in 86% yield.
Cep h a lota xin e Tota l Syn th esis Ach ievem en t. To
perform the cleavage of the chiral appendage, the ketone
function of 7 was protected as the cyclic ketal 8, using
ethylene glycol under standard conditions (Scheme 3).
Reductive cleavage of the N-benzylic bond of 8 was then
performed with lithium in liquid ammonia, and the
bispiro lactam 9 was isolated in quantitative yield over
the two steps. This material was used without purifica-
tion through the next step, which consisted of N-alkyla-
tion with the tosylate of 3,4-methylenedioxypheny-2-
ethanol11 to give 10 in 80% yield after purification.
We turned our attention to the semipinacolic rear-
rangement investigated by Paquette15 through R-hy-
droxyoxonium and applied to R-hydroxyiminium by
Dake.16 We described in a previous communication the
use of this rearrangement in the R,â-unsaturated γ-lac-
tam series.14 We showed that stereocontrolled rearrange-
(11) Nagasaka, T.; Sato, H.; Saeki, S.-I. Tetrahedron: Asymmetry
1997, 8, 191-194.
(12) Ikeda, M.; el Bialy, S. A.; Hirose, K.; Kotake, M.; Sato, T.;
Bayomi, S. M.; Shehata, I. A.; Abdelal, A. M.; Gad, L. M.; Yakura, T.
Chem. Pharm. Bull. 1999, 47, 983-7.
(13) Tietze, L. F.; Schirok, H. J . Am. Chem. Soc. 1999, 121, 10264-
10269.
(14) Planas, L.; Pe´rard-Viret, J .; Royer, J .; Selkti, M.; Tomas, A.
Synlett 2002, 1629-1632.
(15) (a) Paquette L. A.; Negri J . T.; Rogers R. D. J . Org. Chem. 1992,
57, 3947-3956. (b) Paquette L. A.; Lanter J . C.; J onhston J . N. J . Org.
Chem. 1997, 62, 1702-1712. (c) Paquette L. A.; Kiney M. J .; Dullweber
U. J . Org. Chem. 1997, 62, 1713-1722.
(16) (a) Fenster M. D. E.; Patrick B. O.; Dake G. R. Org. Lett. 2001,
3, 2109-2112. (b) Fenster M. D. E.; Dake G. R. Org. Lett. 2003, 5,
4313-4316.
3088 J . Org. Chem., Vol. 69, No. 9, 2004

Stereoselective Synthesis of (-)-Cephalotaxine
SCHEME 4
SCHEME 5
Deprotection of 10 in acidic medium finally provides 11
in a quantitative yield (Scheme 3).
Eventually, enantiopure 11 was transformed to
(-)-cephalotaxine following the procedure used by Kue-
hne for his racemic synthesis and summarized in Scheme
4. It consists of eight steps with an overall yield of 69%.
In our hands, the synthesis was achieved with an
overall yield of 32%. Only two minor changes were done.
First, we found that there is no need, in the oxidation
reaction of 12 to 13, to have benzoquinone in addition
with palladium acetate since the latter is used in a
stoichiometric amount.17 The second change was con-
cerned with the last step, which we have to perform very
carefully due to the sensitivity of cephalotaxine to race-
mization. Though no clear racemization mechanism was
proposed, cephalotaxine is known to be sensitive to acidic
conditions. That could explain why natural cephalotaxine
was not isolated as an enantiomerically pure compound.
It was reported that the methyl iodide derivative 19 (Y
) CH3, Scheme 5), prepared from natural cephalotax-
ine, was obtained in a racemic form.18 The equilibrium
between 19 and an open form like 20, having lost all
asymmetric carbons, might be responsible for this race-
mization (Scheme 5). Such a reaction may arise upon
treatment of cephalotaxine with acid (Bro¨nsted or Lewis
acid).
taxine [[R]20 -182 (CHCl3, c ) 0.21) (lit.20 [R]20 -188
D
D
(CHCl3))].
We then determined the enantiomeric purity of this
synthetic material. It could be easily analyzed by means
of chiral HPLC, but for doing so we needed both enan-
tiomers. Thus, we first studied a cephalotaxine sample
obtained from a natural source which classically con-
tained 5-10% (+)-cephalotaxine.4 This analysis (Chiral
HPLC/MS spectrometry) proved that the natural sample
has an enantiomeric purity of 83%. Using the same
HPLC conditions, we could determine that our synthetic
sample contains 0.65% of (+)-cephalotaxine and hence
(-)-cephalotaxine was prepared in 98.7% enantiomeric
purity. It is noteworthy that the enantiomeric purity of
this material corresponds to that of (S)-1-(1-naphthyl)-
ethylamine, which was used as chiral inducer and source
of nitrogen.
Thus, we decided to change the conditions described
by Kuehne (LiAlH4 in refluxing THF), and instead, we
used the more reactive aluminum hydride that allows us
achieve the reaction at 0 °C. In addition, the reduction
of γ-lactams is described to be cleaner with this reagent.19
These conditions furnished a 75% yield of (-)-cephalo-
(17) Ito, Y.; Suginome, M. In Handbook of Organopalladium Chem-
istry for Organic Synthesis; Negishi, E.-i., Ed.; J ohn Wiley & Sons:
New York, 2002; pp 2873-2879.
C-7-Alk yla ted An a logu es. The asymmetric synthesis
we performed allowed us to achieve the synthesis of some
(18) Abraham, D. J .; Rosenstein, R. D.; McGandy, E. L. Tetrahedron
Lett. 1969, 10, 4085-4086.
(19) Meyers, A. I.; Burgess, L. E. J . Org. Chem. 1991, 56, 2294-
2296.
(20) Arora, S. K.; Bates, R. B.; Grady, R. A.; Powell, R. G. J . Org.
Chem. 1974, 39, 1269-1271.
J . Org. Chem, Vol. 69, No. 9, 2004 3089

Planas et al.
SCHEME 6
lotaxines 30a -c were obtained by application of the last
three steps of the synthesis of cephalotaxine with the
same yields as for the parent compound. Minor epimer
23a was also transformed to 31a .
Con clu sion
By using an original and efficient stereoselective access
to 1-azaspiro[4.4]nonane compounds, and following the
Kuehne synthesis for the end of the sequence, we
reported an asymmetric synthesis of (-)-cephalotaxine
in 98.7% ee with an overall yield of 9.8% over a 16-step
sequence. It thus proved the relevance of the chemistry
of R,â-unsaturated γ-lactams for the synthesis of complex
alkaloids. This synthetic sequence is adaptable for access
to some alkylated analogues.
Exp er im en ta l Section
(1′S)-1-(1′-(1-Na p h th yl)eth yl)-2-ter t-bu tyld im eth ylsily-
loxy-1H-p yr r ole (4a ). To a solution of (S)-1-(1-naphthyl)-
ethylamine (3.42 g, 26.28 mmol) and 2,5-dimethoxy-2,5-
dihydrofuran (3.00 g, 17.52 mmol) in water (70 mL, 0.25 M)
was added a concentrated aqueous solution of HCl (2.32 mL,
26.28 mmol). The reaction mixture was stirred at rt for 1 h,
neutralized with solid NaHCO3, and extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4 and
concentrated under vacuum. A red oily mixture of the R,â- and
â,γ-unsaturated lactams was then obtained. To a solution of
this crude product (ca. 17.52 mmol) and NEt3 (3.50 g, 35 mmol)
in CH2Cl2 (35 mL, 0.5 M) was slowly added tert-butyldimeth-
ylsilyl triflate (4.86 g, 18.40 mmol). The reaction mixture was
stirred at rt for 1 h, and the solvent was then evaporated. The
residue was purified by filtration on a pad of alumina (heptane/
AcOEt 88/12), providing 4a (3.50 g, 57% for two steps) as a
slightly colored solid. Mp ) 97 °C (heptane-AcOEt). 1H NMR
(300 MHz, CDCl3): δ ) -0.05 (s, 3H), 0.23 (s, 3H), 0.80 (s,
9H), 1.89 (d, J ) 7.0 Hz, 3H), 5.31 (dd, J ) 3.6, 2.0 Hz, 1H),
6.01 (t, J ) 3.5 Hz, 1H), 6.16 (q, J ) 7.0 Hz, 1H), 6.35 (dd, J
) 3.4, 1.9 Hz, 1H), 7.10 (d, J ) 7.2 Hz, 1H), 7.42 (t, J ) 7.9
Hz, 1H), 7.50-7.55 (m, 2H), 7.77 (d, J ) 8.3 Hz, 1H), 7.88 (d,
J ) 7.4 Hz, 1H), 8.08 (d, J ) 8.0 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ ) -5.0, -4.6, 18.2, 21.4, 25.7, 49.5, 87.7, 105.2,
109.8, 123.2, 125.8, 126.5, 128.1, 129.1, 131.0, 134.1, 139.7,
analogues through the alkylation of the pyrrolidine ring
of the alkaloid. A few approaches to the preparation of
analogues of cephalotaxine were reported. They were
mainly concerned with modification of the aromatic A
ring (dimethoxyphenyl21 and indole22 in place of meth-
ylenedioxyphenyl group) or change of the size of the B,
C, or D ring to a six-membered ring as reported by Tietze
showing the versatility of his method.23 But, to the best
of our knowledge, only one analogue of cephalotaxine was
reported: it consists of the change to dimethoxyphenyl
instead of the methylenedioxyphenyl group.21
Cephalotaxine analogues might be useful for accessing
homoharringtonine analogues whose antitumoral activity
should be evaluated. We planned to introduce alkyl
substituents on the C ring in order to investigate what
spatial surrounding is compatible with the biological
activity. To attain several analogues, it appears necessary
to be able to introduce a substituent quite late in the
synthesis. We thus thought that alkylation of lactam 16
after protection of the diol moiety would be suitable.
The diol 16 was protected as an acetonide using
standard conditions to give 21 in 86% yield (Scheme 6).
Alkylation of 21 was achieved through deprotonation
using s-BuLi in THF at -78 °C and addition of MeI, BuI,
and PhCH2Br to provide diastereomeric alkylated lac-
tams 22 and 23 in 88-97% yield and in a 4:1 ratio. The
(S)-configuration of the new chiral center of the major
isomer 22 was determined through 1H NMR NOE
experiments and could be easily explained by the geom-
etry of the tetracyclic compound. In each series, the
diastereoisomers could be separated by flash chromatog-
raphy. Major diastereoisomers 22a -c were deprotected
to the corresponding diol, and then the alkylated cepha-
142.2. IR (KBr): ν ) 2929, 2858, 1560, 1492, 1438 cm-1. [R]25
:
D
+11.7 (c ) 0.69, CH2Cl2). HRMS (CI, NH3, [MH]+): m/z calcd
352.2097, found 352.2101.
(1′S)-5-(1-Hyd r oxycyclobu tyl)-1-(1′-(1-n a p h th yl)eth yl)-
1,5-d ih yd r op yr r ol-2-on e (6a ). To a solution of 4a (4.17 g,
11.86 mmol) in anhydrous CH2Cl2 (80 mL, 0.15 M) containing
3 Å MS was added, under argon, cyclobutanone (1.43 mL, 18.98
mmol). After 15 min at rt, the solution was cooled at -78 °C,
and BF3‚Et2O (2.25 mL, 17.79 mmol) was added over the
course of 15 min. The solution was stirred at -78 °C for 2 h,
filtered, and allowed to warm to 0 °C. The reaction was then
quenched by addition of water. An insoluble compound could
be then filtered giving 0.94 g of the pure minor diastereoiso-
mer. The aqueous phase was separated and extracted with
CH2Cl2. The crude mixture obtained after drying and evapora-
tion of the solvent was triturated with ether. A 1.48 g crop of
crystals consisting of the major diastereoisomer was thus
obtained. From the residue, 0.40 g of a diastereoisomeric
mixture was obtained after flash chromatography (CH2Cl2/
MeOH, 96/4). Finally, compound 6a was obtained in a 77%
combined yield. Ma jor Dia ster eoisom er . Mp ) 196-198 °C
(Et2O). 1H NMR (300 MHz, CDCl3): δ ) 1.36 (m, 1H), 1.8-
2.1 (m, 5H), 1.75 (s, 1H), 1.86 (d, J ) 7.0 Hz, 3H), 3.51 (t, J )
1.5 Hz, 1H), 6.07 (q, J ) 7.0 Hz, 1H), 6.28 (dd, J ) 6.0, 1.6 Hz,
1H), 6.81 (dd, J ) 6.0, 1.8 Hz, 1H), 7.47 (m, 3H), 7.63 (m, 2H),
7.84 (m, 2H). 13C NMR (75 MHz, CDCl3): δ ) 13.6, 19.1, 31.9,
36.2, 49.0, 69.6, 75.9, 123.2, 125.2, 125.8, 126.1, 127.3, 128.5,
(21) Yasuda, S.; Yamada, T.; Hanaoka, M. Tetrahedron Lett. 1986,
27, 2023-2026.
(22) Noe, E.; Seraphin, D.; Qiang, Z.; Djate, F.; Henin, J .; Laronze,
J .-Y.; Levy, J . Tetrahedron Lett. 1996, 37, 5701-5704.
(23) (a) Tietze, L. F.; Schirok, H.; Wohrmann, M. Chemistry 2000,
6, 510-518. (b) Tietze, L. F.; Schirok, H.; Wohrmann, M.; Schrader,
K. Eur. J . Org. Chem. 2000, 2433-2444.
3090 J . Org. Chem., Vol. 69, No. 9, 2004

Stereoselective Synthesis of (-)-Cephalotaxine
129.1, 129.2, 132.0, 134.0, 136.2, 145.7, 173.3. IR (KBr): ν )
organic phase was dried over Na2SO4 and concentrated under
vacuum. The crude product was purified by filtration through
a pad of silica gel (CH2Cl2/Et3N 99/1 and then CH2Cl2/MeOH/
Et3N 95/5/1), providing 9 (1.28 g, quant) as a white solid. An
analytical sample was obtained by recrystallization in EtOH.
Mp ) 75-76 °C (EtOH). 1H NMR (300 MHz, CDCl3): δ ) 1.6-
1.95 (m, 7H), 2.25-2.55 (m, 3H), 3.8-4.0 (m, 4H), 6.13 (bs,
1H). 13C NMR (75 MHz, CDCl3): δ ) 16.6, 29.9, 30.8, 32.0,
35.7, 65.3, 66.2, 68.1, 116.6, 178.2. IR (KBr): ν ) 2974, 1667,
1153 cm-1. MS(CI, NH3): m/z ) 198 ([MH]+), 215 ([M +
3382, 2977, 2934, 1658, 1394 cm-1. Anal. Calcd for C20H21
-
NO2: C, 78.15; H, 6.89; N, 4.56. Found: C, 78.03; H, 7.06; N,
4.60. MS (CI, NH3): m/z ) 308 (MH+), 238 (MH+ - C4H6O).
[R]25 -13.8 (c ) 0.97, CHCl3). Min or Dia ster eoisom er . Mp
D
) 245 °C (CH2Cl2). 1H NMR (300 MHz, CDCl3): δ ) 0.35-0.5
(m, 1H), 1.01 (s, 1H, D2O exch), 1.35-1.55 (m, 2H), 1.55-1.7
(m, 2H), 1.78 (d, J ) 7.1 Hz, 3H), 1.85-2.0 (m, 1H), 4.25 (t, J
) 1.6 Hz, 1H), 6.30 (m, 2H), 6.94 (dd, J ) 7.0, 6.0 Hz, 1H),
7.4-7.6 (m, 4H), 7.83 (d, J ) 8.1 Hz, 1H), 7.90 (d, J ) 8.3 Hz,
1H), 8.23 (d, J ) 8.4 Hz, 1H). 13C NMR (75 MHz, DMSO): δ
) 17.7, 24.4, 36.2, 40.6, 55.1, 74.8, 81.3, 128.5, 130.3, 130.8,
131.7, 132.9, 134.3, 134.5, 136.1, 139.0, 143.5, 151.3, 177.6.
IR (KBr): ν ) 3388, 2976, 2937, 1660 cm-1. MS(CI, NH3): m/z
) 308 (MH+), 238 (MH+ - C4H6O). [R]25D: -264.1 (c ) 0.52,
CHCl3).
NH4]+). [R]25D: -49.4 (c ) 1.0, CHCl3). Anal. Calcd for C10H15
-
NO3: C, 60.90; H, 7.67; N, 7.10. Found: C, 60.37; H, 7.44; N,
6.55.
(6R)-7-[2-(3,4-Meth ylen ed ioxyp h en yl)eth yl]-1,4-d ioxa -
7-a za d isp ir o[4.0.4.3]tr id eca n -8-on e (10). To a solution of
9 (0.31 g, 1.57 mmol) in anhydrous benzene (5 mL, 0.3 M) was
added NaH (60 mg, 2.50 mmol) portionwise. The mixture was
refluxed for 5 min and then cooled to rt. Solid toluene-4-
sulfonic acid 2-benzo[1,3]dioxol-5-ylethyl ester11 (0.90 g, 2.81
mmol) was added, and the mixture was heated at reflux for
16 h. The reaction mixture was poured into an aqueous
saturated solution of NH4Cl and extracted with CH2Cl2. The
organic phase was dried over Na2SO4 and concentrated under
vacuum. The crude product was purified by flash chromatog-
raphy on silica gel (CH2Cl2/MeOH/Et3N 95/5/1), providing 10
(5R )-(1′S )-1-(1′-(1-Na p h t h yl)e t h yl)-1-a za sp ir o[4.4]-
n on a n e-2,6-d ion e (7). To a solution of 6a (13.30 g, 43.27
mmol) in CH2Cl2 (930 mL, 0.05 M) at 0 °C was added
concentrated aqueous HCl (6.14 mL, 64.90 mmol). After 24 h
at 0 °C, the solution was allowed to warm to rt, and the solvent
was removed under vacuum. The crude product was redis-
solved in CH2Cl2 and reevaporated twice to eliminate trace
amount of acid and provide 7 (13.30 g, quant) as an amorphous
solid. The pure major diastereomer of 7 (9.17 g, 86%) was
obtained by crystallization in 40 mL of 95% EtOH and by flash
chromatography of the mother liquor (silica gel; AcOEt/
1
(449 mg, 80%) as a white solid. Mp ) 88 °C (i-Pr2O). H NMR
(300 MHz, CDCl3): δ ) 1.27 (m, 3H), 1.55-1.75 (m, 4H), 1.89
(m, 1H), 2.08 (m, 1H), 2.24 (dd, J ) 12.6, 9.7 Hz, 1H), 2.32
(dd, J ) 12.2, 10.0 Hz, 1H), 2.59 (m, 1H), 2.67 (m, 1H), 2.83
(ddd, J ) 13.0, 9.9, 4.7 Hz, 1H), 3.34 (ddd, J ) 13.7, 10.0, 7.0
Hz, 1H), 3.67 (m, 1H), 3.7-3.85 (m, 4H), 5.89 (s, 2H), 6.66 (d,
J ) 7.9 H, 1 Hz), 6.72 (s, 1H), 6.73 (d, J ) 7.9 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ ) 16.9, 30.5, 31.7, 32.9, 33.8, 35.1,
44.1, 64.9, 65.9, 71.2, 101.1, 108.4, 109.7, 118.6, 122.1, 133.7,
146.2, 147.8, 176.7. IR (KBr): ν ) 2945, 2884, 1682, 1491, 1444
cm-1. MS (CI, NH3): m/z ) 346 ([MH]+). [R]25D: -41.9 (c )
1.27, CHCl3). Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71;
N, 4.06. Found: C, 66.35; H, 6.68; N, 3.85.
1
cyclohexane 50/50). Mp ) 140 °C (Et2O). H NMR (400 MHz,
CDCl3): δ ) 1.07-1.17 (m, 2H), 1.34-1.55 (m, 2H), 1.62 (ddd,
J ) 12.3, 8.5, 6.5 Hz, 1H), 1.67 (d, J ) 7.0 Hz, 3H), 1.87 (ddd,
J ) 18.9, 11.6, 9.5 Hz, 1H), 1.93 (ddd, J ) 12.3, 8.9, 6.8 Hz,
1H), 2.23 (dd, J ) 18.9, 6.1 Hz, 1H), 2.43 (ddd, J ) 16.8, 8.5,
6.8 Hz, 1H), 2.53 (ddd, J ) 16.8, 8.9, 6.5 Hz, 1H), 6.25 (q, J )
7.1 Hz, 1H), 7.3-7.6 (m, 4H), 7.83 (d, J ) 9.7 Hz, 1H), 7.79 (d,
J ) 7.6 Hz, 1H), 8.00 (d, J ) 8.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ ) 7.8, 18.9, 29.0, 31.7, 32.3, 35.7, 47.5, 72.3, 124.0,
125.1, 125.9, 126.3, 127.2, 129.1, 129.3, 132.7, 133.9, 136.1,
175.7, 217.0. IR (KBr): ν ) 2968, 1750, 1679, 1380, 1347, 780
cm-1. MS(CI, NH3): m/z ) 308 (MH+). Anal. Calcd for C20H21
-
(5R)-1-[2-(3,4-Meth ylen edioxyph en yl)eth yl]-1-azaspir o-
[4.4]n on a n e-2,6-d ion e (11). A solution of 10 (3.80 g, 11.00
mmol) in a water/acetic acid 9/1 mixture (56 mL, 0.2 M) was
refluxed for 16 h and then cooled to rt. The mixture was poured
into an aqueous saturated solution of NaHCO3 and extracted
with CH2Cl2. The organic phase was washed with brine, dried
over Na2SO4, and concentrated under vacuum, providing 11
NO2: C, 78.15; H, 6.89; N, 4.56. Found: C, 77.96; H, 7.15; N,
4.41. [R]25D: -48.4 (c ) 1.04, CHCl3).
(6R)-(1′S)-7-(1′-(1-n a p h t h yl)p h en ylet h yl)-1,4-d ioxa -7-
a za d isp ir o[4.0.4.3]tr id eca n -8-on e (8). To a solution of 7
(10.63 g, 34.58 mmol) in toluene (120 mL, 0.2 M) were added
ethylene glycol (19,33 mL, 346 mmol) and PTSA (0.66 g, 3.46
mmol). The reaction mixture was refluxed in a Dean-Stark
apparatus overnight, cooled to rt, poured in a saturated
aqueous solution of NaHCO3, and extracted with CH2Cl2. The
organic phase was dried over Na2SO4 and concentrated under
vacuum, providing 8 (12.15 g, quant) as a beige solid. An
analytical sample was obtained by recrystallization in i-Pr2O.
Mp ) 99 °C (i-Pr2O). 1H NMR (300 MHz, CDCl3): δ ) 1.5-
1.65 (m, 2H), 1.65-1.85 (m, 4H), 1.90 (d, J ) 7.3 Hz, 3H), 2.13
(m, 1H), 2.35-2.5 (m, 3H), 2.67 (ddd, J ) 16.3, 10.7, 8.7 Hz,
1H), 3.0-3.2 (m, 2H), 3.48 (m, 1H), 5.70 (q, J ) 7.3 Hz, 1H),
7.35-7.5 (m, 2H), 7.52 (dt, J ) 1.3, 8.2 Hz, 1H), 7.69 (d, 1H),
7.83 (d, 1H), 7.95 (t, J ) 8.5 H, 1 Hz). 13C NMR (100 MHz,
CDCl3): δ ) 16.4, 20.4, 30.6, 30.8, 31.9, 32.2, 51.5, 63.6, 65.3,
72.7, 116.9, 123.2, 125.2, 125.3, 125.9, 126.2, 127.2, 129.2,
130.5, 133.8, 140.5, 178.5. IR (KBr): ν ) 3057, 2973, 2864,
1
(3.45 g, quant) as a yellow oil. H NMR (300 MHz, CDCl3): δ
) 1.67-1.85 (m, 3H), 1.92-2.17 (m, 4H), 2.30-2.45 (m, 3H),
2.57-2.74 (m, 2H), 3.03 (ddd, J ) 13.4, 10.3, 6.5 Hz, 1H), 3.38
(ddd, J ) 13.5, 10.0, 5.1 Hz, 1H), 5.91 (s, 2H), 6.62 (d, J ) 7.6
Hz, 1H), 6.67 (s, 1H), 6.71 (d, J ) 7.6 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ ) 17.6, 29.2, 29.9, 33.6, 34.9, 35.2, 43.8, 72.5,
101.1, 108.6, 109.6, 122.0, 133.1, 146.4, 148.0, 176.2, 217.1.
IR (film): ν ) 2963, 2888, 1745, 1685, 1503, 1491, 1443, 1403,
1247, 1037 cm-1. MS(CI, NH3): m/z ) 302 ([MH]+). [R]25
:
D
-13.6 (c ) 0.72, CHCl3). Anal. Calcd for C17H19NO4‚1/2H2O:
C, 65.79; H, 6.50; N, 4.51. Found: C, 65.63; H, 6.24; N, 4.53.
Cep h a lota xin e (1). To a cooled (0 °C) solution of 18 (62
mg, 0.19 mmol) in anhydrous THF (1 mL) was added a cooled
(0 °C) 1 M solution of AlH3 in THF (3 mL, 3 mmol, prepared
from solid AlCl3 and 1 M LiAlH4 in THF). The reaction mixture
was stirred for 2.5 h, treated at 0 °C by wet Na2SO4, and
filtered after loss of color. The solids were thoroughly washed
with distilled THF, and the filtrate was concentrated under
vacuum. The crude product was purified by flash chromatog-
raphy on silica gel (CH2Cl2/MeOH/NH4OH 95/5/0.5), providing
1690, 1361 cm-1. MS (CI, NH3): m/z ) 352 (MH+). [R]25
D
+163.0 (c ) 1.08, CHCl3). Anal. Calcd for C22H25NO3: C, 75.19;
H, 7.17; N, 3.99. Found: C, 74.44; H, 7.14; N, 3.68.
(6R)-1,4-Dioxa -7-a za d isp ir o[4.0.4.3]tr id eca n -8-on e (9).
To a cooled (-78 °C) solution of 8 (2.30 g, 6.51 mmol) in THF
(32 mL, 0.2 M), in a flask equipped with a cold trap (-78 °C),
was condensed ammonia (about 60 mL). To the mixture was
added lithium (0.60 g, 0.086 mol) portionwise until persistent
dark blue colorization of the solution occurred. The reaction
mixture was stirred for 30 min and allowed to warm to rt
(evaporating thus ammonia). It was poured into an aqueous
saturated solution of NH4Cl and extracted with CH2Cl2. The
1
1 (45 mg, 75%) as a white solid. H NMR (400 MHz, CDCl3):
δ ) 1.70 (sl, 1H), 1.72-1.80 (m, 2H), 1.88 (ddd, J ) 11.5, 8.0,
4.0 Hz, 1H), 2.01 (dd, J ) 11.5, 9.6 Hz, 1H), 2.36 (dd, J ) 14.4,
6.9 Hz, 1H), 2.53-2.66 (m, 2H), 2.92 (ddd, J ) 11.8, 11.3, 7.1
Hz, 1H), 3.07 (m, 1H), 3.36 (ddd, J ) 14.1, 12.3, 7.8 Hz, 1H),
3.68 (d, J ) 9.4 Hz, 1H), 3.73 (s, 3H), 4.76 (d, J ) 9.1 Hz, 1H),
4.93 (s, 1H), 5.91 (s, 2H), 6.65 (s, 1H), 6.68 (s, 1H). 13C NMR
J . Org. Chem, Vol. 69, No. 9, 2004 3091

Planas et al.
(75 MHz, CDCl3): δ ) 20.6, 32.0, 43.9, 48.9, 54.2, 57.5, 58.3,
70.9, 73.6, 97.9, 101.2, 110.6, 112.9, 128.3, 134.6, 146.4, 147.2,
160.8. IR (film): ν ) 3522, 2939, 2880, 2799, 1651, 1504, 1486,
1222, 1038 cm-1. [R]20D: -182 (c ) 0.21, CHCl3). HRMS (ESI+,
[MH]+): m/z calcd 316.1549, found 316.1544. HPLC (DAICEL,
Chiralpak AD, hexane/i-PrOH/Et3N 80/20/0.5): tR ) 11.4 min.
(2S,3R,4S,5S)-19,19-Dim et h yl-1,3-d ioxolocyclop en t a -
[4,5-c]cep h a lota xa n e (21). A solution of diol 16 (0.57 g; 1.80
mmol) and p-toluenesulfonic acid (17 mg, 0.09 mmol) in
acetone (9 mL) was stirred for 4 h at rt. Some product
precipitated as a white solid and was filtered, rinsed with a
small amount of acetone, and dried to give 230 mg of 21. The
solvent was removed in vacuo and the residue dissolved in
dichloromethane. The organic phase was washed with an
aqueous saturated NaHCO3 solution, dried over Na2SO4, and
filtered, and the solvent was distilled off. The crude reaction
mixture was purified by flash chromatography on silica gel
(CH2Cl2/MeOH/NH4OH 95/5/0.5), providing 319 mg of 21 as a
white solid. Then, 549 mg (86%) of 21 was obtained as a white
+85.6 (c ) 1.90, CHCl3). HRMS (ESI+, [MNa]+): m/z calcd
394.1630, found 394.1636.
(7S)-7-Meth ylcep h a lota xin e (30a ). Colorless oil (35 mg,
77%). 1H NMR (400 MHz, CDCl3): δ ) 1.00 (d, J ) 6.9 Hz,
3H), 1.61 (dd, J ) 11.5, 4.5 Hz, 1H), 1.64 (d, J ) 3.3 Hz, 1H),
2.15-2.28 (m, 3H), 2.33 (dd, J ) 14.4, 6.8 Hz, 1H), 2.66 (dd, J
) 10.8, 7.9 Hz, 1H), 2.86 (ddd, J ) 11.8, 11.4, 7.1 Hz, 1H),
3.08 (dd, J ) 7.4, 6.1 Hz, 1H), 3.32 (ddd, J ) 14.2, 12.2, 7.8
Hz, 1H), 3.63 (d, J ) 9.4 Hz, 1H), 3.74 (s, 3H), 4.74 (dd, J )
9.3, 2.8 Hz, 1H), 4.93 (s, 1H), 5.91 (s, 2H), 6.63 (s, 1H), 6.66 (s,
1H). 13C NMR (75 MHz, CDCl3): δ ) 20.7, 29.2, 32.1, 48.2,
53.1, 57.5, 60.2, 63.1, 70.7, 73.4, 99.8, 101.2, 110.7, 112.9, 128.7,
134.4, 146.4, 147.1, 160.4. IR (film): ν ) 3546, 2924, 1654,
1502, 1486, 1458, 1340, 1221, 1039 cm-1. [R]25D: -158.1 (c )
1.85, CHCl3). HRMS (ESI+, [MH]+): m/z calcd 330.1705, found
330.1719.
(7S)-7-Bu tylcep h a lota xin e (30b). Colorless oil (76 mg,
93%). 1H NMR (400 MHz, CDCl3): δ ) 0.88 (t, J ) 7.1 Hz,
3H), 1.17-1.36 (m, 6H), 1.60-1.68 (m, 2H), 2.06 (m, 1H), 2.18-
2.30 (m, 2H), 2.31 (dd, J ) 14.4, 6.9 Hz, 1H), 2.65 (dd, J )
10.7, 8.0 Hz, 1H), 2.87 (ddd, J ) 11.8, 11.3, 7.0 Hz, 1H), 3.06
(t, J ) 8.3 Hz, 1H), 3.32 (ddd, J ) 14.1, 12.4, 7.7 Hz, 1H), 3.64
(d, J ) 9.4 Hz, 1H), 3.73 (s, 3H), 4.74 (dd, J ) 9.3, 3.3 Hz,
1H), 4.92 (s, 1H), 5.90 (s, 2H), 6.63 (s, 1H), 6.66 (s, 1H). 13C
NMR (75 MHz, CDCl3): δ ) 14.4, 23.1, 30.9, 32.1, 34.8, 36.0,
48.3, 51.5, 57.6, 60.2, 61.8, 68.3, 73.4, 99.7, 101.2, 110.7, 113.0,
128.7, 134.4, 146.4, 150.5, 160.3. IR (film): ν ) 3537, 2954,
1
solid. Mp ) 188-190 °C (Et2O). H NMR (400 MHz, CDCl3):
δ ) 1.31 (s, 3H), 1.59 (s, 3H), 2.10-2.28 (m, 5H), 2.60 (dd, J )
15.5, 5.8 Hz, 1H), 2.69 (ddd, J ) 15.1, 7.0, 1.6 Hz, 1H), 2.78
(ddd, J ) 14.9, 12.0, 6.7 Hz, 1H), 3.03 (dd, J ) 13.7, 6.2 Hz,
1H), 3.16 (d, J ) 5.2 Hz, 1H), 4.08 (ddd, J ) 13.8, 11.8, 7.1
Hz, 1H), 4.67 (t, J ) 5.4 Hz, 1H), 4.79 (dt, J ) 5.6, 2.7 Hz,
1H), 5.89 (s, 2H), 6.61 (s, 1H), 6.63 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ ) 25.8, 28.4, 30.3, 30.8, 38.3, 39.3, 41.5, 65.4, 70.9,
80.1, 88.1, 101.4, 111.0, 111.4, 111.8, 129.2, 131.5, 146.9, 147.4,
175.1. IR (film): ν ) 2978, 2938, 1686, 1506, 1489, 1400, 1371,
1647, 1502, 1483, 1219, 1039 cm-1. [R]25 -157.8 (c ) 0.76,
D
CHCl3). HRMS (ESI+, [MH]+): m/z calcd 372.2175, found
372.2160.
1275, 1248, 1213 cm-1. [R]25 +69.0 (c ) 0.63, CHCl3). HRMS
D
(ESI+, [MH]+): m/z calcd 380.1474, found 380.1471.
(7S)-7-Ben zylcep h a lota xin e (30c). Colorless oil (42 mg,
76%). 1H NMR (400 MHz, CDCl3): δ ) 1.64 (d, J ) 3.7 Hz,
1H), 1.76 (dd, J ) 13.0, 6.0 Hz, 1H), 2.17 (dd, J ) 13.0, 9.3
Hz, 1H), 2.33 (dd, J ) 14.4, 6.7 Hz, 1H), 2.40-2.51 (m, 2H),
2.63-2.75 (m, 3H), 2.87 (ddd, J ) 11.8, 11.4, 7.0 Hz, 1H), 3.01
(dd, J ) 8.1, 6.7 Hz, 1H), 3.32 (ddd, J ) 14.3, 12.2, 7.9 Hz,
1H), 3.62 (d, J ) 9.4 Hz, 1H), 3.75 (s, 1H), 4.73 (dd, J ) 9.3,
3.4 Hz, 1H), 4.92 (s, 1H), 5.89 (s, 2H), 6.62 (s, 1H), 6.66 (s,
1H), 7.16 (d, J ) 6.9 Hz, 2H), 7.20 (d, J ) 7.5 Hz, 1H), 7.28 (t,
J ) 7.0 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ ) 32.1, 36.4,
41.7, 48.1, 50.9, 57.6, 60.3, 61.2, 70.5, 73.4, 99.7, 101.2, 110.7,
112.9, 126.2, 128.6, 128.7, 129.0, 134.4, 141.2, 146.4, 147.1,
160.5. IR (film): ν ) 3546, 2925, 1654, 1502, 1486, 1340, 1039
cm-1. [R]25D: -131.9 (c ) 2.10, CHCl3). HRMS (ESI+, [MH]+):
m/z calcd 406.2018, found 406.2023.
Gen er a l Alk yla tion P r oced u r e of La cta m 21. A solution
of lactam 21 (200 mg; 0.56 mmol) in dry THF (5.6 mL) was
cooled to -78 °C under an argon atmosphere. A solution of
1.4 M s-BuLi (0.60 mL, 0.84 mmol) in cyclohexane was slowly
added (via syringe) to the mixture, and stirring was continuted
for 20 min at -78 °C. Alkyl halide (3 equiv) was then slowly
added to the mixture, which was stirred for 1 h at low
temperature. The reaction was quenched by addition of brine,
the cooling bath was removed, and the mixture was allowed
to rise to room temperature. The aqueous phase was separated
and extracted with CH2Cl2, and the organic phases, joined,
were dried over Na2SO4. After evaporation of the solvent, the
oily residue was purified by flash chromatography on silica
gel using AcOEt as solvent.
(2S,3R,4S,5S,7S)-7-Meth yl-20,20-d im eth yl-1,3-d ioxolo-
cyclop en ta [4,5-c]cep h a lota xa n -8-on e (22a ). Colorless oil
(7R)-7-Meth ylcep h a lota xin e (31a ). Colorless oil (14 mg,
66%). 1H NMR (400 MHz, CDCl3): δ ) 0.99 (d, J ) 6.7 Hz,
3H), 1.61 (bs, 1H), 1.63-1.74 (m, 2H), 1.95 (dd, J ) 11.7, 7.4
Hz, 1H), 2.25 (m, 1H), 2.35 (dd, J ) 14.4, 6.7 Hz, 1H), 2.62
(dd, J ) 10.2, 8.0 Hz, 1H), 2.70-2.90 (m, 2H), 3.30 (ddd, J )
14.3, 12.0, 7.6 Hz, 1H), 3.65 (d, J ) 9.3 Hz, 1H), 3.73 (s, 3H),
4.72 (dd, J ) 9.1, 1.1 Hz, 1H), 4.95 (s, 1H), 5.92 (s, 2H), 6.64
(s, 1H), 6.67 (s, 1H). 13C NMR (75 MHz, CDCl3): δ ) 20.6,
29.3, 32.2, 49.0, 52.9, 57.5, 58.3, 61.5, 72.1, 73.4, 98.7, 101.2,
110.6, 112.9, 128.5, 134.6, 146.3, 147.1, 160.7. IR (film): ν )
1
(165 mg; 79%). H NMR (400 MHz, CDCl3): δ ) 1.09 (d, J )
3 Hz, 3H), 1.32 (s, 3H), 1.61 (s, 3H), 1.83 (t, J ) 11.7 Hz, 1H),
2.15-2.24 (m, 2H), 2.53 (dd, J ) 12.3, 7.6 Hz, 1H), 2.61 (dd, J
) 14.8, 6.4 Hz, 1H), 2.70-2.82 (m, 2H), 3.07 (dd, J ) 13.6, 6.3
Hz, 1H), 3.20 (d, J ) 4.8 Hz, 1H), 4.15 (dd, J ) 13.2, 6.7 Hz,
1H), 4.64 (t, J ) 5.0 Hz, 1H), 4.79 (dt, J ) 5.5, 2.2 Hz, 1H),
5.88 (s, 2H), 6.60 (s, 1H), 6.62 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ ) 25.8, 28.4, 31.0, 35.8, 38.3, 41.8, 49.7, 65.2, 68.5,
80.2, 88.7, 101.4, 111.0, 111.4, 111.6, 128.8, 132.5, 146.9, 147.4,
3517, 2926, 2881, 2795, 1648, 1484, 1221, 1037 cm-1. [R]25
-134.4 (c ) 0.70, CHCl3).
:
D
177.1. IR (film): ν ) 2983, 2934, 1682, 1487, 1217, 1037 cm-1
.
[R]20 +47.0 (c ) 1.35, CHCl3). HRMS (ESI+, [MNa]+): m/z
D
calcd 394.1630, found 394.1642.
Ack n ow led gm en t. This research was supported by
the CNRS and the MENRT. We thank Prof. B. Bodo
and Dr. A. J ossang from the “Museum National
d’Histoire Naturelle” (Paris) for a gift of natural (-)-
cephalotaxine.
(2S,3R,4S,5S,7R)-7-Meth yl-20,20-d im eth yl-1,3-d ioxolo-
cyclop en ta [4,5-c]cep h a lota xa n -8-on e (23a ). Colorless oil
1
(38 mg; 18%). H NMR (400 MHz, CDCl3): δ ) 1.04 (d, J ) 7
Hz, 3H), 1.32 (s, 3H), 1.59 (s, 3H), 1.70 (dd, J ) 12.2, 9.7 Hz,
1H), 2.25 (dd, J ) 15.4, 2.5 Hz, 1H), 2.37-2.45 (m, 2H), 2.54
(dd, J ) 12.3, 8.3 Hz, 1H), 2.75 (ddd, J ) 15.0, 7.2, 2.6 Hz,
1H), 2.85 (m, 1H), 3.04 (ddd, J ) 13.2, 4.6, 1.6 Hz, 1H), 3.10
(d, J ) 5.7 Hz, 1H), 3.97 (ddd, J ) 13.6, 11.4, 7.2 Hz, 1H),
4.72 (t, J ) 5.6 Hz, 1H), 4.79 (dd, J ) 5.6, 2.6 Hz, 1H), 5.89
(2s, 2H), 6.62 (s, 1H), 6.63 (s, 1H). 13C NMR (75 MHz, CDCl3):
δ ) 16.0, 25.8, 28.5, 30.6, 35.6, 38.8, 41.0, 46.5, 65.7, 69.6, 80.0,
87.4, 101.4, 111.0, 112.0, 128.7, 130.3, 146.7, 178.0. IR (film):
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal methods, detailed procedures, and analytical data for
1
compounds 12-18 and 22-29 and selected H NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ν ) 2984, 2934, 1682, 1504, 1488, 1372, 1215, 1038 cm-1. [R]20
:
J O049884L
D
3092 J . Org. Chem., Vol. 69, No. 9, 2004