Stereoselective synthesis of enantiopure analogues of (-)-cephalotaxine

Article abstract of DOI:10.1016/j.tetasy.2010.01.004

The asymmetric total synthesis of three analogues of (-)-cephalotaxine with structural modification of the aromatic ring was achieved in 16 steps and acceptable overall yields. The procedure used was quite similar to that reported by our group for the tot

Full text of DOI:10.1016/j.tetasy.2010.01.004

Tetrahedron: Asymmetry 21 (2010) 325–332
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of enantiopure analogues of (ꢀ)-cephalotaxine
*
Farouk Berhal, Joëlle Pérard-Viret, Jacques Royer
UMR 8638 CNRS-Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric total synthesis of three analogues of (ꢀ)-cephalotaxine with structural modification of
the aromatic ring was achieved in 16 steps and acceptable overall yields. The procedure used was quite
similar to that reported by our group for the total synthesis of (ꢀ)-cephalotaxine in 2004. The enantio-
pure spiranic compound 4 is a common intermediate on which various aromatic groups can be intro-
duced. Unexpected and interesting different chemical behaviors were observed during these syntheses.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 18 December 2009
Accepted 13 January 2010
Available online 10 February 2010
1. Introduction
(obtained from an a,b-unsaturated-c-lactam). The end of the syn-
thesis was based on the Kuehne synthesis of cephalotaxine5
(Scheme 1).
Cephalotaxine 1 is the most abundant alkaloid extracted from
several types of Cephalotaxus, evergreen conifers and shrubs native
from South-East Asia. This natural compound, first isolated in
1963,1 does not exhibit any pronounced biological activity. Never-
theless, cephalotaxine is very attractive because it is the precursor
of homoharringtonine 2 and harringtonine 3 two other alkaloids
extracted from the same plants, which exhibit a strong antileukae-
mic activity, particularly against chronic myeloid leukemia
(Fig. 1).2 Homoharringtonine is currently in phases II–III of clinical
trials.3
The availability of natural or synthetic cephalotaxine has led to
several groups investigating the preparation of analogues of homo-
harringtonine by modification of the side chain moiety through
hemisynthesis. Despite the numerous analogues which have been
prepared, until now none of them have shown an improvement
of the antileukemic activity.6
We have noticed that very few analogues of homoharringtonine
and cephalotaxine with molecular modification of the cephalotax-
ane core existed. The only analogues of cephalotaxine with this
type of modification were recently prepared by Tietze et al.7 and
represented simplified structures of cephalotaxine and deoxyhar-
ringtonine in a racemic form, while we reported some original
alkylated cephalotaxine derivatives.5
Numerous groups have been interested in the total synthesis of
cephalotaxine,4 particularly our laboratory whose strategy con-
sisted of the formation of the rings (C and D) first by the prepara-
tion of an enantioselective 1-azaspiro[4,4]nonane compound
In this context and with a future objective to prepare analogues
of homoharringtonine for biological evaluation, we herein report
the asymmetric synthesis of the first non-natural analogues of
cephalotaxine with modification at the aromatic ring.
The preparation of these analogues was accomplished by apply-
ing the total synthesis of cephalotaxine as described by our group
in 2004.5 The strategy consisted of the alkylation of the common
spiranic compound 4 with different aromatic chains and then com-
pleting the sequence (Scheme 2).
O
O
O
N
N
O
H
O
H
O
OH
HO
HO
OMe
OMe
n
CO2Me
2. Results and discussion
For the synthesis of the desired analogues it was necessary first
to prepare the enantiopure spiranic compound 4. Indeed this prod-
uct represented the common intermediate in our strategy. It was
easily synthesized in six steps from the commercially available
1 : (-)-cephalotaxine
2 : n = 1 homoharringtonine
3 : n = 0 harringtonine
Figure 1. Structures of (ꢀ)-cephalotaxine, homoharringtonine, and harringtonine.
(S)-1-(1-naphthyl)ethylamine8 and by using the chemistry of
a,b-
unsaturated-
c-lactams that has been developed for some years
* Corresponding author. Tel.: +33 153739749; fax: +33 143291403.
E-mail address: jacques.royer@parisdescartes.fr (J. Royer).
(Scheme 3).9
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.01.004

326
F. Berhal et al. / Tetrahedron: Asymmetry 21 (2010) 325–332
O
R
N
R
O
A
B
N
O
5 steps
10 steps
C
O
N
C
O
O
H
D
D
HO
OMe
1 : (-)-cephalotaxine
Scheme 1. Strategy for the total synthesis of (ꢀ)-cephalotaxine.
Ar
N
Ar
O
O
O
H
O
H
N
N
O
O
HO
OMe
4
Ar : Aromatic ring
Scheme 2. Cephalotaxine analogues retrosynthetic sequence.
This spiranic compound 4 was thus obtained in 36% overall
After the formation of the polycyclic core, the functionalization
of the ring D was performed. A first difference of reactivity was ob-
served during the dihydroxylation reaction of 9 to 10 (Scheme 5).
In the synthesis of cephalotaxine,5 the reaction led to only one dia-
stereomer. The dihydroxylation took place on the rear face of ring
D of the cephalotaxane core (cf. Scheme 5) and in a good yield. This
reaction showed that the configuration adopted by the polycyclic
ring of cephalotaxine allowed the dihydroxylation to occur only
on this face. When the same reaction was reproduced for analogue
9a (Ar = Ph), diol 10a was obtained in a good 88% yield but as a 9:1
mixture of two diastereomers. While this reaction was still highly
diastereoselective it is noteworthy that the absence of the methyl-
enedioxy group rendered the attack on the two faces of the ring D
possible (even as a minor event).
The same conditions were then applied for the naphthyl aro-
matic group analogue 9b. In this case, the same selectivity as in
the cephalotaxine series was observed. In other words, only one
diastereomer was formed and in high yield. These observations
indicate that the substitution of the aromatic ring plays an impor-
tant role on the geometry adopted by the cephalotaxane ring.
The separation of the two diastereomers 10a and 10a0 in the
phenyl analogue series was possible but did not need to be carried
out since the next step is the oxidation of the diols (Scheme 6). This
yield over six steps and with an enantiomeric excess of about
99%. The analogues were then synthesized following the sequence
we already used for the total synthesis of cephalotaxine, with only
minor changes.
Two analogues were first envisaged: one with a phenyl aro-
matic group and another one with a naphthyl aromatic group in
place of the methylenedioxyphenyl group present in cephlotaxine.
We observed some differences of reactivity according to the aro-
matic rings. The procedure used for the synthesis of cephalotaxine
was reproduced in the phenyl and naphthyl series up to the cycli-
zation leading to compound 9 (Scheme 4) and did not show impor-
tant differences in their reactivities. The spiranic compound 4
reacted first with the appropriate aromatic ethyl tosylate and so-
dium hydride in refluxing benzene and gave the N-alkylated com-
pounds 6a (74% yield) and 6b (56% yield). The keto group was
deprotected to give 7, which was oxidized to enone 8.10 The latter
was selectively reduced11 to allylic alcohol prior to Friedel–Craft
cyclization (Scheme 4). The two last steps were conducted without
the isolation of the allylic alcohols and gave 9a (Ar = Ph) and 9b
(Ar = Naphth) in 71% and 54% yields, respectively. This showed that
the cyclization does not require activation through electrodonating
groups on the aromatic ring.
α-Naphth
O
O
α-Naphth
H
N
5 steps
1 step
N
O
CH3
H2N
O
5
4
Yield (6 steps) = 36% e.e = 99%
Scheme 3. Preparation of the spiranic compound.

F. Berhal et al. / Tetrahedron: Asymmetry 21 (2010) 325–332
327
OH
Ar
TsCl
NEt3, DMAP
DCM
Ar
O
O
H
N
OTs
O
O
NaH
O
N
Ar
C
+
O
Benzene
Reflux
18 h
D
Yield
4
6a : Ar = Ph
74%
6b : Ar = 2-Naphth 56%
AcOH 1M
Reflux
24h
Ar
1) TMSOTf
NEt3
Ar
DCM
O
18 h
O
N
O
O
N
2) Pd(OAc)2
CH3CN
18 h
1) Al(iPrO)3
iPrOH
140 ºC
3 h
Yield
Yield
81%
8a : Ar = Ph
7a : Ar = Ph
7b : Ar = 2-Naphth
100%
94%
2) SnCl4
CH2Cl2/CH3NO2
-78 ºC to r.t
4 h
8b : Ar = 2-Naphth 78%
O
N
C
B
Ar
D
H
Yield
71%
9a : Ar = Ph
9b : Ar = 2-Naphth 54%
Scheme 4. General procedure for the analogues’ synthesis.
reaction was straightforward and gave diones 11a and 11b in good
yields only limited by the difficulty of the elimination of succini-
mide from the reaction mixture.
The further selective monomethylation to 12 showed several
differences in the reactivity of diones 11 according to the aromatic
ring (Scheme 6).
method, the desired product was not obtained and the starting
material was totally decomposed.
After several attempts it was possible to achieve this transfor-
mation using the Mori conditions4t with minor modifications
(Scheme 7).
When the reaction was performed with the phenyl analogue
11a, the target molecule 12a was obtained with an optimized yield
of 68%. Over the course of the optimization of the reaction condi-
tions, it was found that by increasing the amount of reactants,
the regioisomer 13 was also formed in up to 38% yield.
The reaction was then applied to the naphthyl analogue 11b. The
conditions still needed to be optimized and the target molecule 12b
was eventually obtained as a unique regioisomer in 60% yield.
Kuehne’s procedure4f which was applied with success in the
synthesis of cephalotaxine (MeOSiMe3, TfOH, and DCM) did not
lead to the desired compound when applied to 11a or 11b.
We then investigated other conditions. Several groups
described this type of reaction in the total synthesis of cephalotax-
ine. We tried the conditions reported first by Weinreb4d and then
modified by Fuchs.4e Unfortunately by using the Weinreb–Fuchs

328
F. Berhal et al. / Tetrahedron: Asymmetry 21 (2010) 325–332
O
O
O
Ar
N
Ar
Ar
N
N
OsO4
B
C
+
NMO
THF/H2O
24 h
H
H
H
D
HO
HO
OH
OH
10
10'
9
a Ar = Ph
b Ar = Naphth
c Ar = 3,4-methylenedioxyphenyl
90
:
10
(88%)
100
100
:
:
0
0
(93%)
(81%)
Scheme 5. Reactivity for the dihydroxylation reaction.
is concerned with the aromatic moiety and gives structures very
close to the natural compound.
O
Me2S
NCS
NEt3
O
Ar
N
Ar
N
4. Experimental
4.1. General
H
DCM
-40ºC to r.t
4 h
HO
HO
O
OH
Reagents were commercially obtained at highest commercial
quality and used without further purification. All reactions were
carried out under anhydrous conditions within an argon or nitro-
gen atmosphere in dry freshly distilled solvents. Reactions were
monitored by thin-layer chromatography Merck 60F-254 pre-
coated silica (0.2 mm) on aluminum. Flash chromatography was
Yield
10
11a : Ar = Ph
11b : Ar = 2-Naphth
76%
70%
Scheme 6. Oxidation reactions.
performed with SDS Silica Gel 60 (35–70 lm). Melting points were
determined on a Kofler apparatus and were not corrected. Specific
rotations were measured at 25 °C on a Perkin–Elmer 341 polarim-
eter with sodium (589 nm) lamp. IR spectra were recorded using
NaCl pellets on a Nicolet 205 spectrometer. Only noteworthy IR
absorptions are listed. 1H NMR and 13C NMR spectra were recorded
on a Bruker Avance-300 apparatus operating at 300 and 75 MHz,
respectively. Chemical shifts were reported in d (ppm).
Compounds 12a, 12b, and 13 could now be reduced to the tar-
get analogues via the reduction of the lactam and the ketone func-
tions. This was achieved in a unique step using AlH3 in THF at low
temperature (Scheme 8).
Finally, three analogues of cephalotaxine 14a, 14b, and 15 were
prepared in 16 steps in good overall yields of 7%, 3%, and 4%,
respectively (Fig. 2).
4.2. Preparation of (6R)-7-phenethyl-1,4-dioxa-7-aza-dispiro
[4.0.4.3]tridecan-8-one (6a) and (6R)-7-(2-naphthalen-2-yl-ethyl)-
1,4-dioxa-7-aza-dispiro [4.0.4.3]tridecan-8-one (6b)
3. Conclusion
We were successful in the asymmetric synthesis of three ana-
logues of cephalotaxine by using the same synthetic sequence as
we had established for the natural product. The molecular diversity
To a stirred solution of spiranic compound 4 (1 equiv) in an
anhydrous benzene (c 0.29 M) was added in one portion sodium
O
O
O
Ar
N
Ar
N
Ar
N
Conditions
H
O
+
MeO
HO
O
OMe
O
11
12
13
Ar
conditions
i
product (Yield *)
a Ar = Ph
b Ar = 2-Naphth
12a (68%)
Phenyl
Phenyl
ii
12a (55%) / 13 (38%)
12b (60%)
2-Naphthyl
iii
Scheme 7. Selective methylation reaction. Reagents and conditions: (i) trimethylorthoformate (60 equiv), PTSA (10 equiv), CH2Cl2, 18 h, rt; (ii) trimethylorthoformate
(80 equiv), PTSA (20 equiv), CH2Cl2, 18 h, rt; (iii) trimethylorthoformate (60 equiv), PTSA (10 equiv), CH2Cl2; reflux 48 h. *Isolated yields.

F. Berhal et al. / Tetrahedron: Asymmetry 21 (2010) 325–332
329
(ppm) 16.6, 30.3, 31.4, 32.6, 33.3, 35.0, 43.7, 64.6, 65.7, 71.2,
118.4, 126.3, 128.4, 129.0, 139.6, 176.5; MS (ESI) m/z 324
([M+Na]+), 340 ([M+K]+); HRMS (ESI) calcd for C18H23NO3
([M+Na]+): 324.1570; found: 324.1584.
O
Ar
N
Ar
N
AlH3
H
H
O
THF
0ºC
2h30
Compound 6b: mp 116–118 °C; ½a D23
¼ ꢀ29:9 (c 0.835, CHCl3);
ꢁ
m
(cmꢀ1) 3050, 2968, 2942, 2890, 1675, 1402; 1H NMR
HO
IR (film)
(300 MHz, CDCl3): d (ppm) 1.22–1.30 (m, 1H), 1.63–1.83 (m, 4H),
1.85–2.00 (m, 1H), 2.08–2.21 (m, 1H), 2.22–2.40 (m, 2H), 2.58–
2.70 (m, 1H), 2.94 (ddd, J = 6.8, 10.0, 12.7 Hz, 1H), 3.09 (ddd,
J = 4.8, 10.1, 12.9 Hz, 1H), 3.53 (ddd, J = 6.9, 9.9, 13.9 Hz, 1H);
3.75–3.95 (m, 5H), 7.39–7.52 (m, 3H), 7.68 (s, 1H), 7.76–7.90 (m,
3H); 13C NMR (75 MHz, CDCl3): d (ppm) 16.6, 30.3, 31.4, 32.6,
33.5, 35.3, 43.6, 64.6, 65.7, 71.0, 118.3, 125.3, 126.0, 127.2, 127.5,
127.6, 127.7, 128.0, 132.1, 133.6, 137.0, 176.6; MS (ESI) m/z 374
([M+Na]+), 390 ([M+K]+); HRMS (ESI) calcd for C22H25NO3
([M+Na]+): 374.1726; found: 374.171.
OMe
OMe
12
14
Ar
Yield
14a
14b
Phenyl
95%
2-Naphthyl
80%
4.3. Preparation of (5R)-1-phenethyl-1-aza-spiro[4.4] nonane-2,6-
dione 7a and (5R)-1-(2-naphthalen-2-yl-ethyl)-1-aza-spiro[4.4]
nonane-2,6-dione 7b
O
In a round-bottomed flask was placed compound 6a or 6b
(1 equiv) in 1 M acetic acid in water (c 0.20 M). The homogeneous
solution was stirred for 18 h at reflux, then cooled to rt and
quenched with a saturated solution of sodium hydrogencarbonate
and extracted three times with dichloromethane. The organic lay-
ers were combined, dried on magnesium sulfate, evaporated under
reduced pressure and the obtained residue was purified by flash
chromatography on silica gel with pure AcOEt as eluent to give
the compound 7a (100%) as a clear oil or 7b (94%) as a white solid.
N
N
O
AlH3
THF
0ºC
2.5h
MeO
MeO
OH
13
15 (91%)
Compound 7a: ½a 2D3
ꢁ
¼ ꢀ16:5 (c 0.945, CHCl3); IR (NaCl)
m )
(cmꢀ1
Scheme 8. Reduction steps.
3058, 3027, 2961, 2938, 1750, 1688; 1H NMR (300 MHz, CDCl3): d
(ppm) 1.72–2.23 (m, 7H), 2.35–2.56 (m, 3H), 2.83 (ddd, J = 5.3, 10.1,
13.3 Hz, 1H), 2.89 (ddd, J = 6.4, 10.0, 13.3 Hz, 1H), 3.11 (ddd, J = 6.6,
10.1, 13.8 Hz, 1H), 3.47 (ddd, J = 5.3, 10.0, 13.8 Hz, 1H), 7.19–7.33
(m, 5H); 13C NMR (75 MHz, CDCl3): d (ppm) 17.2, 28.9, 29.6, 33.2,
34.9, 34.9, 43.3, 72.1, 126.4, 128.5, 128.9, 139.0, 175.8, 216.5; MS
(ESI) m/z 280 ([M+Na]+), 296 ([M+K]+); HRMS (ESI) calcd for
C16H19NO2 ([M+Na]+): 280.1313; found: 280.1316.
hydride (1.60 equiv). The suspension was stirred for 1 h at reflux
then cooled to rt and the appropriate tosylate (1.80 equiv) was
added in one portion. The suspension was stirred for 18 h at reflux,
then cooled to rt and quenched with a saturated aqueous solution
of ammonium chloride and the aqueous layer was extracted three
times with dichloromethane. The organic layers were combined,
dried on magnesium sulfate, evaporated under reduced pressure
and the obtained residue was purified by flash chromatography
on silica gel with AcOEt/cyclohexane (80/20 v/v) or DCM/MeOH
(95/5 v/v) as eluent to give the alkylated compound 6a (74%) as
a white solid or 6b (56%) as a white solid.
Compound 7b: mp 130 °C; ½a D23
¼ ꢀ18:5 (c 0.920, CHCl3); IR
ꢁ
(film)
m
(cmꢀ1) 3054, 2961, 1747, 1692; 1H NMR (300 MHz, CDCl3):
d (ppm) 1.68–1.94 (m, 3H), 1.98–2.26 (m, 4H), 2.36–2.59 (m, 3H),
2.90–3.14 (m, 2H), 3.23 (ddd, J = 6.3, 10.2, 13.2 Hz, 2H), 3.54
(ddd, J = 5.2, 10.2, 15.8 Hz, 2H), 7.35 (dd, J = 8.4, 1.5 Hz, 1H),
7.41–7.52 (m, 2H), 7.65 (s, 1H), 7.74–7.87 (m, 3H); 13C NMR
(75 MHz, CDCl3): d (ppm) 17.2, 28.9, 29.6, 33.3, 34.9, 35.0, 43.1,
72.1, 125.4, 126.0, 127.1, 127.4, 127.4, 127.6, 128.1, 132.2, 133.6,
136.5, 175.8, 216.4; MS (ESI) m/z 330 ([M+Na]+), 346 ([M+K]+);
HRMS (ESI) calcd for C20H21NO2 ([M+Na]+): 330.1465; found:
330.1473.
Compound 6a: mp 84–86 °C; ½a D23
¼ ꢀ52:6 (c 1.125, CHCl3); IR
ꢁ
(film)
m
(cmꢀ1) 3019, 2938, 2875, 1677; 1H NMR (300 MHz, CDCl3):
d (ppm) 1.17–1.31 (m, 1H), 1.59–1.83 (m, 4H), 1.87–2.01 (m, 1H),
2.03–2.16 (m, 1H), 2.23–2.39 (m, 2H), 2.62 (ddd, J = 9.3, 11.0,
16.8 Hz, 1H), 2.79 (ddd, J = 7.0, 10.0, 12.8 Hz, 1H), 2.93 (ddd,
J = 4.8, 9.8, 13.0 Hz, 1H), 3.43 (ddd, J = 4.7, 9.8, 12.9 Hz, 1H), 3.74–
3.90 (m, 5H), 7.18–7.34 (m, 5H); 13C NMR (75 MHz, CDCl3): d
N
N
N
H
HO
H
MeO
HO
OMe
OH
OMe
14b
3%
15
14a
Overall Yield
(16 Steps)
4%
7%
Figure 2. Cephalotaxine analogues prepared.

330
F. Berhal et al. / Tetrahedron: Asymmetry 21 (2010) 325–332
4.4. Preparation of (5S)-1-phenethyl-1-aza-spiro[4.4] non-7-
ene-2,6-dione 8a and (5S)-1-(2-naphthalen-2-yl-ethyl)-1-aza-
spiro[4.4]non-7-ene-2,6-dione 8b
layers were combined, dried on magnesium sulfate, evaporated
under reduced pressure and the obtained residue was purified by
flash chromatography on silica gel with CH2Cl2/MeOH (95/5 v/v)
as eluent to give compound 9a (71% two steps) as a white solid
or 9b (54% two steps) as a white solid.
To a stirred solution of compound 7a or 7b (1 equiv) in an anhy-
drous dichloromethane (c 0.10 M) at 0 °C was added triethylamine
Compound 9a: mp 100–106 °C; ½a D23
¼ ꢀ108:7 (c 0.965, CHCl3);
ꢁ
(1.60 equiv)
and
trimethylsilyltrifluoromethane
sulfonate
IR (film) m
(cmꢀ1) 3054, 3043, 2941, 2868, 1680; 1H NMR
(1.50 equiv). The clear solution was stirred for 2 h at 0 °C and then
for 16 h at room temperature. The solution was then quenched
rapidly with cold distilled water and the aqueous phase was ex-
tracted three times with dichloromethane. The organic layers were
combined, dried on magnesium sulfate, and evaporated under re-
duced pressure. The crude residue was then placed in a round-bot-
tomed flask under argon, anhydrous acetonitrile (c 0.10 M) and
molecular sieves 4 Å were added. The suspension was stirred for
few minutes at room temperature and palladium diacetate
(1.10 equiv for compound 7a and 1.63 equiv for compound 7b)
was added. The brown suspension was stirred at room tempera-
ture for 18 h, then filtered on CeliteÒ and the solids were washed
with dichloromethane. The filtrate was evaporated under reduced
pressure and the black obtained residue was purified by flash chro-
matography on silica gel with AcOEt/Cyclohexane (80/20 v/v) as
eluent to give compound 8a (81% two steps) as a pale yellow oil
or 8b (78% two steps) as a clear oil.
(300 MHz, CDCl3): d (ppm) 2.06–2.30 (m, 4H), 2.54–2.72 (m, 2H,),
2.92–3.11 (m, 2H), 3.39 (ddd, J = 8.2, 11.2, 14.4 Hz, 1H), 3.89–3.96
(m, 1H), 4.17 (ddd, J = 7.9, 11.3, 13.5 Hz, 1H), 5.65–5.70 (m, 1H),
5.87–5.93 (m, 1H), 7.08–7.23 (m, 4H); 13C NMR (75 MHz, CDCl3):
d (ppm) 30.0, 30.2, 35.3, 37.4, 44.1, 63.8, 69.7, 127.0, 128.3,
130.1, 130.2, 128.0, 132.1, 137.1, 137.7, 174.9; MS (ESI) m/z 240
([M+H]+), 262 ([M+Na]+), 278 ([M+K]+); HRMS (ESI) calcd for
C16H17NO ([M+Na]+): 262.1204; found: 262.1204.
Compound 9b: mp 184–190 °C; ½a D23
¼ þ128:5 (c 0.755, CHCl3);
ꢁ
IR (film)
m
(cmꢀ1) 3043, 2918, 1684; 1H NMR (300 MHz, CDCl3): d
(ppm) 1.84–2.00 (m, 1H), 2.11–2.40 (m, 3H), 2.67–2.84 (m, 2H),
3.04–3.25 (m, 2H), 3.67 (ddd, J = 8.0, 11.8, 15.2 Hz, 1H), 4.20
(ddd, J = 7.5, 11.7, 13.4 Hz, 1H), 5.05–5.11 (m, 1H), 5.67–5.75 (m,
1H), 5.96–6.05 (m, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.43–7.61 (m,
2H), 7.73 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 1.4, 8.0 Hz, 1H), 8.22 (d,
J = 8.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d (ppm) 30.1, 30.6,
36.0, 37.6, 44.0, 54.7, 69.8, 122.3, 124.8, 126.5, 128.2, 128.3,
129.1, 129.2, 131.8, 132.4, 133.2, 135.9, 174.8; MS (ESI) m/z 290
([M+H]+), 312 ([M+Na]+); HRMS (ESI) calcd for C20H19NO
([M+Na]+): 312.1364; found: 312.1351.
Compound 8a: ½a 2D3
ꢁ
¼ ꢀ293:6 (c 0.93, CHCl3); IR (NaCl)
m )
(cmꢀ1
3062, 3027, 2934, 1715, 1684; 1H NMR (300 MHz, CDCl3): d (ppm)
1.90 (ddd, J = 6.6, 9.3, 12.7 Hz, 1H), 2.25 (ddd, J = 6.2, 9.6, 12.7 Hz,
1H), 2.51 (ddd, J = 6.3, 9.3, 15.9 Hz, 1H), 2.59–2.81 (m, 4H), 2.94–
3.17 (m, 1H), 3.16–3.26 (m, 2H), 6.30 (dt, J = 2.2, 6.1 Hz, 1H),
7.15–7.38 (m, 5H), 7.71 (dt, J = 2.7, 5.7 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d (ppm) 29.5, 31.2, 34.4, 40.6, 43.4, 68.6, 126.5,
128.5, 128.8, 126.5, 132.5, 139.1, 176.0, 207.9; MS (ESI) m/z 278
([M+Na]+), 294 ([M+K]+); HRMS (ESI) calcd for C16H17NO2
([M+Na]+): 278.1157; found: 278.1166.
4.6. Preparation of (2S,3R,4S,5S)-2,3-dihydroxy-15,16-desmeth-
ylenedioxy-cephalotaxan-8-one 10a and (2R,3S,4S,5S)-2,3-
dihydroxy-15,16-desmethylenedioxy-cephalotaxan-8-one 10a0
and (2S,3R,4S,5S)-2,3-dihydroxy-19,20-desmethylenedioxy-
14,19-benzocephalotaxan-8-one 10b
Compound 8b: ½a 2D3
ꢁ
¼ ꢀ138:6 (c 0.350, CHCl3); IR (NaCl)
m
To a stirred solution of compound 9a or 9b (1 equiv) in a mix-
ture of THF/H2O (9/1) (c 0.20 M) was added N-methylmorpho-
line-N-oxide (1.50 equiv). The solution was stirred for few
minutes and osmium tetroxyde (0.05 equiv) was added. The solu-
tion was stirred at room temperature for 24 h, and then an aqueous
3 M HCl solution and a solution of sodium hydrogen sulfite (15%)
were added. The mixture was stirred at rt for 1 h. The aqueous
layer was extracted five times with dichloromethane and five
times with ethyl acetate. The organic layers were combined, dried
over magnesium sulfate, evaporated under reduced pressure, and
the obtained residue was purified by flash chromatography on sil-
ica gel with CH2Cl2/MeOH (95/5 v/v) as eluent to give compounds
10a and 10a0 (88% diastereomeric ratio: 90/10) as a white solid or
compound 10b (93%) as a white solid.
(cmꢀ1) 3050, 3019, 2930, 1712, 1684, 1408, 1346; 1H NMR
(300 MHz, CDCl3): d (ppm) 1.82 (ddd, J = 6.7, 9.2, 12.7 Hz, 1H),
2.15 (ddd, J = 6.2, 9.5, 12.7 Hz, 1H), 2.36–2.50 (m, 1H), 2.52–2.68
(m, 3H), 2.80–2.93 (m, 1H), 3.04–3.35 (m, 3H), 6.23 (dt, J = 2.1,
6.1, 1H), 7.27 (dd, J = 1.7, 8.4 Hz, 1H), 7.35–7.46 (m, 2H), 7.58 (s,
1H), 7.61–7.65 (m, 1H), 7.71–7.81 (m, 3H); 13C NMR (75 MHz,
CDCl3): d (ppm) 29.6, 31.2, 34.5, 40.5, 43.2, 68.5, 125.5, 126.1,
127.1, 127.3, 127.4, 127.6, 128.1, 132.1, 133.5, 136.5, 132.4,
162.7, 176.0, 207.8; MS (ESI) m/z 328 ([M+Na]+), 344 ([M+K]+);
HRMS (ESI) calcd for C20H19NO2 ([M+Na]+): 328.1313; found:
328.131.
4.5. Preparationof(4S,5S)-2,3-dehydro-15,16-desmethylen edioxy-
cephalotaxan-8-one 9a and (4S,5S)-2,3-dehydro-19,20-desmethy-
lenedioxy-14,19-benzo-cephalotaxan-8-one 9b
Compound 10a0: 1H NMR (300 MHz, CDCl3): d (ppm) 1.81 (dt,
J = 12.8, 9.7 Hz, 1H), 2.20–2.50 (m, 3H), 2.20–2.50 (m, 2H), 2.78
(dd, J = 7.8, 15.9, 1H), 3.02–3.25 (m, 2H), 3.38 (dd, J = 3.8, 11.5 Hz,
1H), 3.76 (d, J = 4.0 Hz, 1H), 4.30 (sl, 1H), 4.68 (dd, 1H, J = 8.5,
14.8 Hz), 7.02–7.38 (m, 4H).
To a stirred solution of compound 8a or 8b (1 equiv) in isopro-
panol (c 0.20 M) was added aluminum isopropo-xyde (30 equiv).
The suspension was stirred at 140 °C for 2 h with elimination of
the solvent. The mixture was cooled to rt and an aqueous 1 M
HCl solution was added and the black suspension was stirred at
room temperature for 15 min. The aqueous phase was extracted
three times with dichloromethane. The organic layers were com-
bined, dried on magnesium sulfate, and evaporated under reduced
pressure. The crude residue was then placed in a round-bottomed
flask under argon, anhydrous dichloromethane and nitromethane
(1:1 mixture, c 0.050 M) were added. The solution was cooled at
ꢀ78 °C and tin chloride (7.60 equiv) was slowly added. The pale
yellow solution was stirred at ꢀ78 °C for 1.5 h and at rt for 2.5 h,
then an aqueous 1 M HCl solution was added and the aqueous
layer was extracted two times with dichloromethane. The organic
Compound 10a: mp 220 °C; ½a D23
¼ þ53:4 (c 0.955, CHCl3); IR
ꢁ
(film)
m
(cmꢀ1): 3478, 3194, 3062, 2918, 2883, 1657; 1H NMR
(300 MHz, CDCl3): d (ppm) 2.04–2.46 (m, 7H), 2.66 (s, 1H), 2.74–
2.85 (m, 1H), 3.05–3.24 (m, 3H), 4.07–4.20 (m, 1H), 4.32 (t,
J = 4.1 Hz, 1H), 4.45–4.53 (m, 1H), 7.10–7.25 (m, 4H); 13C NMR
(75 MHz, CDCl3): d (ppm) 29.7, 30.5, 38.4, 39.3, 40.1, 62.3, 68.0,
72.1, 78.2, 127.4, 128.2, 130.6, 131.4, 136.4, 137.2, 175.6; MS
(ESI) m/z 274 ([M+H]+), 296 ([M+Na]+), 310 ([M+K]+); HRMS (ESI)
calcd for C16H19NO3 ([M+Na]+): 296.1258; found: 296.1267.
Compound 10b: mp 246–248 °C; ½a D20
¼ þ177:9 (c 1.06, CHCl3);
ꢁ
IR (film)
m )
(cmꢀ1 3420, 3030, 2930, 2868, 1649; 1H NMR
(300 MHz, CDCl3): d (ppm) 1.83–1.98 (m, 1H), 2.04–2.18 (m, 2H),
2.24–2.50 (m, 3H), 2.63 (d, J = 5.2 Hz, 1H), 2.81 (dd, J = 7.3,

F. Berhal et al. / Tetrahedron: Asymmetry 21 (2010) 325–332
331
14.4 Hz, 1H), 2.97 (s, 1H), 3.10–3.31 (m, 2H), 3.90–4.15 (m, 1H);
4.27–4.34 (m, 1H), 4.44 (d, J = 9.7 Hz, 1H), 4.55–4.65 (m, 1H),
7.26 (d, J = 8.3 Hz, 1H), 7.43–7.61 (m, 2H), 7.73 (d, J = 8.3 Hz, 1H),
7.84 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d (ppm) 29.5, 30.8, 38.4, 39.3, 40.5, 52.8, 68.1, 72.1, 79.3,
122.8, 125.2, 126.8, 128.3, 128.8, 128.9, 133.1, 133.2, 133.4,
134.5, 175.7; MS (ESI) m/z 346 ([M+Na]+), 362 ([M+K]+); HRMS
(ESI) calcd for C20H21NO3 ([M+Na]+): 346.1414; found: 346.1418.
Compound 13: 1H NMR (300 MHz, CDCl3): d (ppm) 1.86–2.10
(m, 2H), 2.23 (ddd, J = 1.4, 8.8, 16.5 Hz, 1H), 2.44–2.58 (m, 1H),
2.70 (AB, J = 17.6 Hz
Dd=1 ppm, 2H), 3.08–3.24 (m, 2H), 3.25–
3.37 (m, 1H), 3.88 (s, 3H), 4.06–4.18 (m, 1H), 7.22–7.38 (m, 4H);
13C NMR (75 MHz, CDCl3): d (ppm) 30.0, 33.2, 35.4, 45.6, 58.9,
66.9, 126.1, 129.4, 130.0, 130.8, 129.7, 136.3, 147.8, 151.6, 174.0,
198.3.
Compound 12a: ½a D23
ꢁ
¼ ꢀ78:7 (c 0.915, CHCl3); IR (film)
m
(cmꢀ1) 3085, 3015, 2965, 2871, 1723, 1680, 1637, 1412; 1H NMR
(300 MHz, CDCl3): d (ppm) 2.11–2.39 (m, 4H), 2.50–2.73 (m, 2H),
3.00 (dd, J = 7.0, 13.3 Hz, 1H), 3.64 (s, 1H), 3.86 (s, 3H), 4.15 (ddd,
J = 8.2, 11.9, 13.4 Hz, 1H), 6.11 (s, 1H), 7.10–7.30 (m, 4H); 13C
NMR (75 MHz, CDCl3): d (ppm) 29.7, 31.1, 34.6, 38.0, 57.8, 63.2,
66.2, 123.5, 127.5, 129.1, 130.2, 131.9, 134.3, 135.8, 159.3, 174.3,
198.0; MS (ESI) m/z 284 ([M+H]+), 306 ([M+Na]+); HRMS (ESI) calcd
for C17H17NO3 ([M+Na]+): 306.1106; found: 306.1105.
4.7. Preparation of (5S)-3,4-dehydro-3-hydroxy-15,16-desme-
thylenedioxy-cephalotaxan-2,8-dione 11a and (5S)-3,4-dehydro-
3-hydroxy-19,20-desmethylenedioxy-14,19-benzocephalotaxan-
2,8-dione 11b
In a round-bottomed flask was placed under argon N-chlorosuc-
cinimide (5 equiv) in anhydrous dichloromethane (c 0.83 M). The
solution was cooled at 0 °C and dimethylsulfide (5 equiv) was
added. The white suspension obtained was stirred for 30 min at
0 °C, then cooled at ꢀ40 °C and a solution of compounds 10a and
10a0 or 10b (1 equiv) in an anhydrous dichloromethane (c 0.04 M)
was added dropwise. The suspension was stirred at ꢀ40 °C for 1 h
and triethylamine (8 equiv) was added in one portion. The clear
solution was placed at rt and stirred for 1.5 h. A solution of satu-
rated sodium chloride was added and the aqueous phase was ex-
tracted two times with dichloromethane. The organic layers were
combined, dried over magnesium sulfate, evaporated under re-
duced pressure and the obtained residue was purified by recrystal-
lization in toluene (three times) and in water (two times) to give
compound 11a (76%) as a white solid or 11b (70%) as a white solid.
4.9. Preparation of (4S,5S)-1,2-dehydro-2-methoxy-19,20-
desmethylenedioxy-14,19-benzocephalota xan-8-one 12b
To a stirred solution of compound 11b (1 equiv) in anhydrous
dichloromethane (c 0.07 M) and under argon were added trim-
ethylorthoformate (60 equiv) and para-toluene sulfonic acid
(10 equiv). The pale yellow solution was stirred at reflux for
48 h. After cooled at room temperature, a solution of saturated
sodium hydrogencarbonate was added and the phases were sep-
arated. The aqueous layer was extracted twice with dichloro-
methane. The organic layers were combined, dried over
magnesium sulfate, evaporated under reduce pressure and the
residue obtained was purified by flash chromatography on silica
gel with AcOEt/MeOH (95/5 v/v) as eluent to give the compound
Compound 11a: mp 268 °C (dec.); IR (film)
m
(cmꢀ1) 3401, 3070,
2938, 2922, 1719, 1661, 1388; 1H NMR (300 MHz, DMSO): d (ppm)
1.71–1.84 (m, 1H), 1.86–1.97 (m, 1H), 2.2 (dd, J = 8.6, 16.2 Hz, 1H);
12b (61%) as a white solid. Compound 12b: ½a D23
¼ þ59:0 (c 1.0,
ꢁ
CHCl3); 1H NMR (300 MHz, CDCl3): d (ppm) 1.88–1.97 (m, 1H),
2.20–2.40 (m, 3H), 2.76–2.82 (m, 2H), 3.07–3.11 (m, 1H), 3.92
(s, 3H), 4.13–4.25 (m, 1H), 4.75 (s, 1H), 6.18 (s, 1H), 7.3 (d,
J = 8.3 Hz, 1H), 7.44–7.59 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.87
(dd, J = 1.4, 8.0 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H);. 13C NMR
(75 MHz, CDCl3): d (ppm) 29.5, 31.8, 34.5, 37.9, 55.8, 57.8,
66.4, 121.5, 125.3, 127.2, 128.3, 129.3, 129.5, 123.1, 129.8,
133.1, 133.2, 134.5, 159.5, 174.4, 199.3; MS (ESI) m/z 356
([M+Na]+), 372 ([M+K]+); HRMS (ESI) calcd for C21H19NO3
([M+Na]+): 356.1263; found: 356.1266.
2.39–2.50 (m, 1H), 2.72 (AB, J = 17.6 Hz
Dd = 0.23 ppm, 2H), 2.95–
3.25 (m, 3H), 3.72–3.86 (m, 1H,), 7.20–7.40 (m, 4H); 13C NMR
(75 MHz, DMSO): d (ppm) 30.0, 33.5, 33.7, 35.3, 44.8, 67.4, 126.2,
129.0, 130.5, 131.0, 136.7, 142.1, 150.4, 173.4, 199.5; MS (ESI) m/
z 270 ([M+H]+), 292 ([M+Na]+); HRMS (ESI) calcd for C16H15NO3
([M+Na]+): 292.0950; found: 292.0944.
Compound 11b: 1H NMR (300 MHz, DMSO): d (ppm) 1.90–2.08
(m, 1H), 2.10–2.15 (m, 1H), 2.20–2.50 (m, 2H), 2.72 (AB, J = 18 Hz
D
d=0.18 ppm, 2H), 3.15–3.45 (m, 3H), 4.05–4.25 (m, 1H), 7.20–
7.40 (m, 1H), 7.42–7.57 (m, 2H), 7.60–7.68 (m, 1H), 7.75–7.95 (m,
2H); 13C NMR (75 MHz, DMSO): d (ppm) 30.0, 32.8, 33.1, 35.1,
44.3, 66.7, 125.9, 126.0, 127.1, 128.5, 128.7, 129.0, 131.0, 132.1,
134.8, 139.9, 150.8, 173.7, 199.5; MS (ESI) m/z 342 ([M+Na]+); HRMS
(ESI) calcd for C20H17NO3 ([M+H]+): 320.1282; found: 320.1276.
4.10. Preparation of (3S,4S,5S)-1,2-dehydro-2-methoxy-3-hydro-
xy-15,16-desmethylenedioxy cephalotaxane 14a and (3S,4S,5S)-
1,2-dehydro-2-methoxy-3-hydroxy-19,20-desmethylenedioxy-
14,19-benzo-cephalotaxane 14b
4.8. Preparation of (4S,5S)-1,2-dehydro-2-methoxy-15,16-des m
ethylenedioxy-cephalotaxan-8-one 12a and (5S)-3,4-dehydro-3-
methoxy-15,16-desmethylenedioxy-cephalotaxan-2,8-dione 13
To a stirred solution of AlH3 1 M in anhydrous THF (48 equiv)
(previously prepared from LiAlH4 and AlCl3) was added dropwise
at 0 °C a solution of compound 12a or 12b (1 equiv) in anhydrous
THF (c 0.065 M) and stirred at 0 °C for 2.5 h. The solution was then
warmed to rt and a 2 M solution of Rochelle’s salt was added and
stirred for 15 min. The aqueous phase was extracted twice with
dichloromethane. The organic layers were combined, dried over
magnesium sulfate, evaporated under reduce pressure and the res-
idue obtained was purified by flash chromatography on silica gel
with AcOEt/MeOH/NH4OH (95/5/0.5 v/v) as eluent to give the com-
pound 14a (95%) as a colorless oil or compound 14b (80%) as a col-
orless oil.
To a stirred solution of compound 11a (1 equiv) in anhydrous
dichloromethane (c 0.05 M) and under argon were added trimeth-
ylorthoformate (60 equiv) and para-toluene sulfonic acid
(10 equiv). The pale yellow solution was stirred at room tempera-
ture for 18 h, then distilled water was added and the phases were
separated. The aqueous layer was extracted with dichloromethane,
the organic layers were combined, washed three times with dis-
tilled water then dried over magnesium sulfate, evaporated under
reduce pressure and the residue obtained was purified by flash
chromatography on silica gel with AcOEt/MeOH (95/5 v/v) as elu-
ent to give compound 12a (68%) as a white solid. When the same
reaction was made using trimethylorthoformate (80 equiv) and
para-toluene sulfonic acid (20 equiv) at rt and for 18 h compound
12a was isolated with 55% yield and compound 13 with 38% yield
as a white solid.
Compound 14a:
½
a 2D3
ꢁ
¼ ꢀ150:4 (c 0.75, CHCl3); 1H NMR
(300 MHz, CDCl3): d (ppm) 1.63 (s, 1H), 1.69–1.83 (m, 2H), 1.85–
1.98 (m, 1H), 1.99–2.12 (m, 1H), 2.49 (dd, J = 7.1, 14.2 Hz, 1H),
2.55–2.78 (m, 2H), 2.89–3.10 (m, 2H), 3.46 (ddd, J = 8.2, 12.1,
13.8 Hz, 1H), 3.74–3.80 (m, 4H), 4.80 (d, J = 9.3 Hz, 1H), 4.97 (s,
1H), 7.10–7.30 (m, 4H); 13C NMR (75 MHz, CDCl3): d (ppm) 20.4,

332
F. Berhal et al. / Tetrahedron: Asymmetry 21 (2010) 325–332
Reed, J. W.. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego,
1998; Vol. 51, pp 199–264.
31.9, 43.5, 48.4, 53.9, 57.3, 58.3, 70.9, 73.6, 97.9, 126.5, 127.9,
129.5, 131.9, 135.5, 140.9, 160.5; MS (ESI) m/z 272 ([M+H]+), 294
([M+Na]+); HRMS (ESI) calcd for C17H21NO2 ([M+H]+): 272.1651;
found: 272.1600.
3. For recent papers on clinical trials of homoharringtonine, see: (a) Kantarjian, H.
M.; Talpaz, M.; Santini, V.; Murgo, A.; Cheson, B.; O’Brien, S. M. Cancer 2001, 92,
1591–1605; (b) O’Brien, S. M.; Talpaz, M.; Cortes, J.; Shan, J.; Giles, F. J.; Faderl,
S.; Thomas, D.; Garcia-Manero, G.; Mallard, S.; Rios, M. B.; Koller, C.; Kornblau,
S.; Andreeff, M.; Murgo, A.; Keating, M.; Kantarjian, H. M. Cancer 2002, 94,
2024–2032; (c) Scappini, B.; Onida, F.; Kantarjian, H. M.; Dong, L.; Verstovsek,
S.; Keating, M. J.; Beran, M. Cancer 2002, 94, 2653–2662; (d) Hitt, E. Lancet
Oncol. 2002, 3, 259; (e) Quintas-Cardama, A.; Cortes, J. Expert Opin.
Pharmacother. 2008, 9, 1029–1037; (f) Zhang, W. G.; Wang, F. X.; Chen, Y. X.;
Cao, X. M.; He, A. L.; Liu, J.; Ma, X. R.; Zhao, W. H.; Liu, S. H.; Wang, J. L. Am. J.
Hematol. 2008, 83, 185–188; (g) Quintás-Cardama, A.; Kantarjian, H.; Cortes, J.
Cancer 2009, 115, 5382–5393.
Compound 14b:
½
a 2D3
ꢁ
¼ ꢀ90:4 (c 0.24, CHCl3); 1H NMR
(300 MHz, CDCl3): d (ppm) 1.60–1.85 (m, 3H), 1.99–2.15 (m, 2H),
2.58–2.85 (m, 3H), 2.99–3.12 (m, 2H), 3.62–3.78 (m, 1H), 3.80 (s,
3H), 4.90 (d, J = 9.3 Hz, 1H), 4.98 (d, J = 9.3 Hz, 1H), 5.07 (s, 1H),
7.38 (d, J = 8.3 Hz, 1H), 7.40–7.60 (m, 2H), 7.78 (d, J = 8.2 Hz, 1H),
7.86 (d, 1H, J = 8.0 Hz), 8.18 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d (ppm) 20.1, 32.6, 44.1, 48.1, 49.9, 53.7, 57.3, 71.2, 73.1,
98.3, 122.6, 124.5, 126.4, 128.2, 128.8, 129.1, 129.9, 133.2, 133.8,
139.2, 160.7; HRMS (ESI) calcd for C21H23NO2 ([M+H]+):
322.1807; found: 322.1812.
4. Racemic total syntheses: (a) Auerbach, J.; Weinreb, S. M. J. Am. Chem. Soc. 1972,
94, 7172–7173; (b) Semmelhack, M. F.; Chong, B. P.; Jones, L. D. J. Am.Chem. Soc.
1972, 94, 8629–8630; (c) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.;
Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507–2516; (d)
Weinreb, S. M.; Auerbach, J. J. Am. Chem. Soc. 1975, 97, 2503–2506; (e)
Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1988, 110, 2341–2342; (f)
Kuehne, M. E.; Bornmann, W. G.; Parsons, W. H.; Spitzer, T. D.; Blount, J. F.;
Zubieta, J. J. Org. Chem. 1988, 53, 3439–3450; (g) Burkholder, T. P.; Fuchs, P. L. J.
Am.Chem. Soc. 1990, 112, 9601–9613; (h) Ishibashi, H.; Okano, M.; Tamaki, H.;
Maruyama, K.; Yakura, T.; Ikeda, M. J. Chem. Soc., Chem. Commun. 1990, 1436–
1437; (i) Ikeda, M.; Okano, M.; Kosaka, K.; Kido, M.; Ishibashi, H. Chem. Pharm.
Bull. 1993, 41, 276–281; (j) Lin, X.; Kavash, R. W.; Mariano, P. S. J. Am. Chem. Soc.
1994, 116, 9791–9792; (k) Lin, X.; Kavash, R. W.; Mariano, P. S. J. Org. Chem.
1996, 61, 7335–7347; (l) Tietze, L. F.; Schirok, H. Angew. Chem., Int. Ed. 1997, 36,
1124–1125; (m) Koseki, Y.; Sato, H.; Watanabe, Y.; Nagasaka, T. Org. Lett. 2002,
4, 885–888; (n) Suga, S.; Watanabe, M.; Yoshida, J. J. Am. Chem.Soc. 2002, 124,
14824–14825; (o) Li, W.-D. Z.; Wang, Y.-Q. Org. Lett. 2003, 5, 2931–2934; (p) Li,
W.-D. Z.; Ma, B.-C. J. Org. Chem. 2005, 70, 3277–3280; (q) Ma, B.-C.; Wang, Y.-Q.;
Li, W.-D. Z. J. Org. Chem. 2005, 70, 4528–4530; (r) Li, W.-D. Z.; Wang, X.-W. Org.
Lett. 2007, 9, 1211–1214; Enantioselective total syntheses: (s) Zhong, S.; Liu,
W.; Ling, Y.; Li, R. Zhongguo Yaowu Huaxue Zazhi 1994, 4, 84; (t) Isono, N.; Mori,
M. J. Org.Chem. 1995, 60, 115–119; (u) Nagasaka, T.; Sato, H.; Saeki, S.-I.
Tetrahedron: Asymmetry 1997, 8, 191–194; (v) Ikeda, M.; El Bialy, S. A. A.;
Hirose, K.-I.; Kotake, M.; Sato, T.; Bayomi, S. M. M.; Shehata, I. A.; Abdelal, A. M.;
Gad, L. M.; Yakura, T. Chem. Pharm. Bull. 1999, 47, 983–987; (w) Tietze, L. F.;
Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264–10269; (x) El Bialy, S. A. A.;
Ismail, M. A.; Gad, L. M.; Abdelal, A. M. M. Med. Chem. Res. 2002, 11, 293; (y)
Eckelbarger, J. D.; Wilmot, J. T.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370–
10371; (aa) Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J. Org. Chem. 2007, 72, 7352–
7358; (bb) Esmieu, W. R.; Worden, S. W.; Catterick, D.; Wilson, C.; Hayes, C. J.
Org. Lett. 2008, 10, 3045–3048; (cc) Taniguchi, T.; Ishibashi, H. Org. Lett. 2008,
10, 4129–4131.
4.11. Preparation of (2R,5S)-2-hydroxy-3,4-dehydro-3-
methoxy-15,16-desmethylenedioxycephalotaxane 15
To a stirred 1 M solution of AlH3 in anhydrous THF (31 equiv)
(previously prepared from LiAlH4 and AlCl3) was added dropwise
at 0 °C a 0.070 M solution of compound 13 (1 equiv) in anhydrous
THF and the mixture was stirred at 0 °C for 2.5 h. The solution was
then warmed to rt, quenched with a 2 M solution of Rochelle’s salt
and stirred for 15 min. The aqueous phase was extracted twice
with dichloromethane. The organic layers were combined, dried
on magnesium sulfate, evaporated under reduce pressure and the
residue obtained was purified by flash chromatography on silica
gel with AcOEt/MeOH/NH4OH (95/5/0.5 v/v) as eluent to give com-
pound 15 (91%) as a colorless oil. Compound 15: 1H NMR
(300 MHz, CDCl3): d (ppm) 1.48–1.68 (m, 2H), 1.70–1.82 (m, 3H),
1.85–1.98 (m,1H), 2.25 (dd, J = 7.26, 13.07 Hz, 1H), 2.70–2.82 (m,
1H), 2.85–2.94 (m, 1H), 2.95–3.03 (m, 1H), 3.05–3.12 (m, 2H),
3.32–3.48 (m, 1H), 3.70 (s, 3H), 4.72 (dd, J = 4.62, 7.22 Hz, 1H),
7.10–7.25 (m, 4H); 13C NMR (75 MHz, CDCl3): d (ppm) 23.1, 33.0,
35.6, 46.1, 46.2, 50.5, 58.1, 71.2, 72.8, 119.0, 125.4, 127.1, 129.2,
130.8, 133.5, 138.7, 155.1; MS (ESI) m/z 272 ([M+H]+), 294
([M+Na]+); HRMS (ESI) calcd for C17H21NO2 ([M+H]+): 272.1651;
found: 272.1660.
5. Planas, L.; Pérard-Viret, J.; Royer, J. J. Org. Chem. 2004, 69, 3087–3092.
6. Mikolajczak, K. L.; Smith, C. R.; Weisleder, D. J. Med. Chem. 1977, 20, 328–332.
See also Ref. 2b.
7. Tietze, L. F.; Braun, H.; Steck, P. L.; El Bialy, S. A. A.; Tölle, N.; Düfert, A.
Tetrahedron 2007, 63, 6437–6445.
8. Planas, L.; Pérard-Viret, J.; Royer, J.; Selkti, M.; Thomas, A. Synlett 2002, 10,
1629–1632.
Acknowledgments
9. (a) Baussanne, I.; Royer, J. Tetrahedron Lett. 1996, 37, 1213–1216; (b)
Baussanne, I.; Schwardt, O.; Royer, J.; Pichon, M.; Figadère, B.; Cave, A.
Tetrahedron Lett. 1997, 38, 2259–2262; (c) Baussanne, I.; Travers, C.; Royer, J.
Tetrahedron: Asymmetry 1998, 9, 797–804.
The CNRS and the French Ministry of Education and Research
are acknowledged for funding.
10. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–1013.
11. Wilds, A. L. Org. Reaction 1944, 2, 178.
References
1. Paudler, W. W.; Kerley, G. I.; McKay, J. J. Org. Chem. 1963, 28, 2194–2197.
2. (a) Powell, R. G.; Weisleder, D.; Smith, C. R., Jr; Rohwedder, W. K.
Tetrahedron Lett. 1970, 11, 815–818; (b) Jilal Miah, M. A.; Hudlicky, T.;