Total synthesis of 14β-fluorosteroids via a transannular Diels-Alder reaction

Article abstract of DOI:10.1139/v05-259

14β-Fluorosteroids 3 and 4 were synthesized to give a new class of unnatural cardenolides. The total synthesis of racemic 14β-fluorosteroids was accomplished using a highly diastereoselective transannular Diels-Alder reaction on a trans-cis-cis macrocycli

Full text of DOI:10.1139/v05-259

29
Total synthesis of 14␤-fluorosteroids via a
transannular Diels–Alder reaction
Sylvie Beaubien and Pierre Deslongchamps
Abstract: 14β-Fluorosteroids 3 and 4 were synthesized to give a new class of unnatural cardenolides. The total synthe-
sis of racemic 14β-fluorosteroids was accomplished using a highly diastereoselective transannular Diels–Alder reaction
on a trans-cis-cis macrocyclic triene. The α-fluoro analog 4 provided a comparable inhibitory activity to natural
digitoxigenin 1.
Key words: fluorosteroid, bioisostere, cardiovascular diseases, transannular Diels–Alder reaction (TADA),
macrocyclization.
Résumé : Les 14β-fluorostéroïdes 3 et 4 ont été synthétisés en vue d’obtenir une nouvelle classe de cardénolides non-
naturels. La synthèse totale racémique des 14β-fluorostéroïdes a été accomplie en utilisant la réaction diastéréosélective
de Diels–Alder transannulaire à partir d’un triène macrocyclique trans-cis-cis. L’α fluoro-analogue 4 donne une activité
inhibitrice comparable à la digitoxigénine 1.
Mots clés : fluorostéroïde, bioisostère, maladies cardiovasculaires, réaction de Diels–Alder transannulaire (DATA), ma-
crocyclisation.
Beaubien and Deslongchamps 48
Introduction
biological activity of these analogs could then be measured
and compared with that of digitoxigenin 1.
The (+)-digitoxigenin 1 is derived from the biologically
active trisaccharide digitoxin 2, which is extracted from the
Digitalis purpura plant (1) (Fig. 1). These cardenolide ste-
roids belong to the large digitalis family, and the principal
use of this type of molecule is the treatment of cardiovascu-
lar diseases (2).
Compounds from the digitalis family are considered to be
dangerous because the therapeutic dose can correspond to up
to 60% of the lethal dose. The therapeutic dose for cardio-
vascular disease is very small (1) (0.2 mg for digitoxin 2).
For this reason, many efforts have been made to synthesize
cardenolide analogs to diminish the toxicity of this type of
compound.
To synthesize these two fluoro analogs, we used the
transannular Diels–Alder (TADA) (5) reaction to construct
the tetracyclic skeleton. Our past studies on the TADA reac-
tion (6, 7) have shown that a 13-membered ring with a trans-
cis-cis olefin geometry can lead to an A.B.C.[6.6.5] tricycle
having a trans-syn-cis (TSC) ring junction configuration (8).
In this reaction, four asymmetric centers are created simulta-
neously with high stereoselectivity. The challenging synthe-
sis of the fluorinated compound, which represents a new
class of unnatural cardenolides, is reported herein.
Results and discussion
Bioisosterism is an approach used to decrease the toxicity
of a drug (3). Based on this method, we decided to consider
fluoro analogs of digitoxigenin 1, since fluorine is a
bioisostere of the hydroxyl group. In addition, some analogs
of digitoxigenin 1 are known to possess an α,β-unsaturated
ester instead of butenolide at the C-17 position (4). We,
therefore, decided to synthesize the racemic fluoro analogs 3
and 4 of digitoxigenin 1 with a fluorine atom at the C-14 po-
sition and an α,β-unsaturated ester at the C-17 position. The
Retrosynthesis
The retrosynthetic analysis of fluoro analogs 3 and 4 is
presented in Scheme 1. These fluoro analogs can be ob-
tained by Birch reduction of the aromatic ring and by
homologation of the C-17 ketone of tetracycle 5 to form the
α,β-unsaturated esters 3 and 4. Tetracycle 5 (TSC) can be
obtained via the TADA reaction of trienic macrocycle 6 pos-
sessing an E,E-diene and an E-dienophile. Macrocycle 6 can
be formed from the β-keto ester 7 by macrocyclization. This
β-keto ester can be obtained from compound 8 by alkylation.
Homologation of diol 9 with two different Horner–Emmons
reactions can produce compound 8. Finally, the diol 9 can be
prepared from commercially available compound 10 in a few
steps.
Received 26 July 2005. Published on the NRC Research
PressWeb site at http://canjchem.nrc.ca on 25 February 2006.
S. Beaubien and P. Deslongchamps.1 Laboratoire de
synthèse organique, Département de chimie, Institut de
Pharmacologie de Sherbrooke, Université de Sherbrooke,
3001, 12e Avenue nord, Sherbrooke, QC J1H 5N4, Canada.
Synthesis of ␤-keto ester 7
The synthesis of β-keto ester 7 starts with the reduction of
the commercially available ketone 10 with lithium alu-
minium hydride to give the corresponding alcohol followed
1Corresponding author (e-mail:
Pierre.Deslongchamps@USherbrooke.ca).
Can. J. Chem. 84: 29–48 (2006)
doi:10.1139/V05-259
© 2006 NRC Canada

30
Can. J. Chem. Vol. 84, 2006
Fig. 1. Target structures.
O
CO2Me
O
Me
F
Me
OH
17
H
Me
H
H
HO
RO
1 R = H
2 R = trisaccharide
3
4
C-17β
C-17α
Scheme 1.
CO2Me
O
O
Me
F
E
Me
17
F
H
H
H
F
MeO
MeO
HO
6
E = CO2Me
3
4
C-17β
C-17α
5
OPiv
F
OTBDPS
F
OMe
MeO
MeO
CO2Et
O
O
7
8
O
OH
OH
MeO
MeO
10
9
by dehydratation to produce the olefin 11 in a quantitative
yield (Scheme 2). Ozonolysis of this olefin was performed
followed by treatment with sodium borohydride (9) to give
diol 9 in 86% yield. The selective oxidation of the benzylic
alcohol of diol 9 was accomplished with manganese dioxide
and the hydroxyaldehyde 12 was obtained in 85% yield.
This hydroxyaldehyde was protected as a TBDMS ether and
a Horner–Emmons (10) reaction was performed to produce
the α,β-unsaturated ester 13 with very good yield as a single
detectable geometrical isomer. Reduction with DIBALH of
the α,β-unsaturated ester 13 afforded the corresponding alco-
hol, which was protected as a TBDPS ether to give
disilylated compound 14. The selective deprotection of
TBDMS in the presence of the TBDPS ether was performed
with a catalytic amount of PPTS in ethanol, and alcohol 15
was obtained in 98% yield. Swern oxidation (11) then led to
aldehyde 16 in quantitative yield.
The fluorine atom, which is required at the 14β position in
the final targets 3 and 4, was introduced at this step with a
Horner–Emmons (10) reaction. The aldehyde 16 was treated
with the anion of fluorophosphonate 17 (12), and α,β-unsat-
urated ester 8 was obtained in 93% yield (Scheme 2). The
isomer with the E geometry (12) was the only compound ob-
1
served by H NMR. With this key intermediate in hand, we
could synthesize β-keto ester 7 for the macrocyclization re-
action.
To this end, α,β-unsaturated ester 8 was reduced with lith-
ium aluminium hydride to provide a quantitative yield of the
alcohol, which was converted to the allylic chloride 18 with
hexachloroacetone and triphenylphosphine (13). The intro-
duction of the β-keto ester was accomplished by treating
allylic chloride 18 with the dianion of methyl acetoacetate
(14) to afford β-keto ester 19 in 65% yield. Deprotection of
the silyl ether was carried out with TBAF, and the resulting
© 2006 NRC Canada

Beaubien and Deslongchamps
31
Scheme 2.
1) O3, MeOH, -78°C
2) NaBH4, r.t.
O
1) LiAlH4, THF, -78oC
3) NaOH, H2O2, THF
86%
2) PTSA, benz, reflux
100%
MeO
MeO
11
10
O
1) TBDMSCl, Im.
THF, 100%
MnO2, pent:CH2Cl2
H
OH
OH
OH
2) (EtO)2P(O)CH2CO2Et
NaH, THF, 97%
85%
MeO
MeO
9
12
O
1) DIBALH, CH2Cl2
0oC, 97%
OEt
OTBDPS
OR
2) TBDPSCl, Im.
THF, 93%
OTBDMS
MeO
MeO
13
14 R = TBDMS
15 R = H
PPTS
EtOH
98%
n-BuLi, THF, -78oC
OTBDPS
OTBDPS
F
Swern, 100%
MeO
(EtO)2P(O)CH(F)CO2Et 17
93%
H
MeO
CO2Et
O
16
8
alcohol was converted to a pivaloate ester to give β-keto es-
ter 7, the desired macrocyclization precursor (Scheme 3).
heating macrocycle 6 at 165 °C in the presence of
triethylamine in a sealed tube for 4 h. The TSC tetracycle 21
was obtained in 78% yield as a single isomer. In this step,
four new chiral centers were formed simultaneously with a
high degree of stereoselectivity.
The selective formation of the TSC tetracycle can be ex-
plained by considering the transition state of the TADA reac-
tion. As seen in Scheme 5, in transition state 22, the olefins
are perfectly aligned for the TADA reaction without any se-
vere steric interaction. The other possible TADA product,
CST tetracycle 21a, cannot be obtained owing to improper
orbital alignment (transition state 22a). Thus, this
transannular process allows complete control in the forma-
tion of TSC tetracycle 21 (18). The desired key 17β-fluoro
racemic intermediate was thus obtained with a very good
yield at each step.
Macrocyclization and TADA reaction
The key steps in this synthesis are the macrocyclization
and the TADA reaction. To achieve macrocyclization, the
silyl enol ether of β-keto ester 7 was prepared with N,N-
bistrimethylsilylacetamide and subsequent slow addition
(14 h) of this silyl enol ether to a solution of palladium cata-
lyst at a high dilution (2 mmol/L). This concentration is es-
sential to eliminate polymer formation. Under these reaction
conditions (8, 15), the macrocyclization took place to afford
the 13-membered ring macrocycle 20 in an excellent yield of
88% (Scheme 4). Now, we have to introduce an E-olefin to
make the necessary diene for the TADA reaction.
Macrocycle 20 was thus treated with benzeneseleninic anhy-
dride (16, 17), and the trienic macrocycle 6 was obtained in
91% yield.
Installation of the C-13 methyl group and a model
study for the homologation at the C-17 position
Having built the key intermediate 21, the next step was to
The macrocycle 6 contains the E-dienophile and E,E-
diene that are necessary to obtain the TSC tetracycle after
the TADA reaction. This key step was accomplished by
© 2006 NRC Canada

32
Can. J. Chem. Vol. 84, 2006
Scheme 3.
OTBDPS
F
OTBDPS
1) LiAlH4, THF, 0oC, 100%
2) HCA, PPh3, THF, 99%
F
MeO
CO2Et
MeO
OMe
Cl
8
18
OTBDPS
F
NaI, NaH, n-BuLi
1) TBAF, THF, 77%
MeC(O)CH2CO2Me,
THF, 65%
2) PivCl, 2.6-lut
CH2Cl2, 97%
MeO
O
O
19
OPiv
F
OMe
MeO
O
O
7
Scheme 4.
O
E
OPiv
F
Pd(PPh3)4, Ph2P(CH2)3PPh2
BSA, THF, reflux, 2 × 10–3 mol/L
F
OMe
slow add. (14 h), 88%
MeO
MeO
O
O
7
20 E = CO2Me
O
O
E
E
F
Et3N, toluene, 165oC
(PhSeO)2O, Et3N
CH2Cl2, 91%
4 h, sealed tube
78%
H
F
MeO
MeO
6
E = CO2Me
21 E = CO2Me
obtain a methyl group at the C-13 position and explore the
homologation at the C-17 position.
Oxetane 27 was also obtained as a side product in 10%
yield. This compound must come from the intramolecular
displacement of the C-17 tosylate by the β-secondary alcohol
of the minor β isomer of 25.
Hydrogenation of the olefin in tetracycle 21 (Scheme 6)
was carried out, and compound 23 was obtained in quantita-
tive yield. Reduction of the ester and ketone moieties was
performed to give diol 24 as a 9:1 mixture of α:β isomers at
C-17, which could not be separated. Selective tosylation of
the primary alcohol of this diol mixture was then achieved in
two steps (19). First, the diol 24 was treated with dibutyltin
oxide at reflux in a mixture of benzene and DMF with a
Dean–Stark trap and the corresponding ketal tin intermediate
was formed. Tosyl chloride was then added to produce a 9:1
mixture (α:β isomers) of tosylate 25 in 87% yield. This mix-
ture was reduced with sodium borohydride, and compound
26 was obtained pure in 85% yield after chromatography.
Having tetracycle 26 with the desired methyl group at the
C-13 position in hand, homologation at the C-17 position
was then investigated. Many types of reactions for C-17
homologation of steroids are known in the literature (20). In
our case, many attempts were made to add one carbon at this
position. Several homologation methods were tried (Wittig
(21), epoxidation (22, 23), SN2 reaction, etc.), but the best
results were obtained with a coupling reaction. The alcohol
was first oxidized with TPAP–NMO (24) to give ketone 5 in
87% yield (Scheme 7). This ketone was treated with KHMDS
to form the corresponding enolate. Comins reagent (25) was
© 2006 NRC Canada

Beaubien and Deslongchamps
33
Scheme 5.
F
H
H
F
TADA
CO2Me
CO2Me
O
MeO
0
MeO
0
O
22
21
O
E
TADA
CO2Me
MeO
H
0
O
X
H
F
H
F
MeO
22a
21a E = CO2Me
Scheme 6.
OH
1) Bu2Sn(O)
O
OH
E
F
benzene:DMF (3:1)
reflux
1) H2, 5% Pd/BaSO4
EtOH, 100%
H
F
H
2) TsCl, r.t., 87%
2) LiBH4:MeOH (1:1)
THF, 94%
MeO
MeO
24 (9:1 α:β )
21 E = CO2Me
OTs
OH
O
OH
Me
F
NaBH4, DMSO
80oC, 85%
MeO
+
H
F
H
H
F
MeO
MeO
25 (9:1 α:β )
27 (10%)
26
then added, and the triflic enol ether 28 was obtained in 84%
yield.
cis ring junction is by using a nitrile (28). The coupling re-
action was therefore performed on the triflic enol ether 28
with Pd(PPh3)4 and LiCN (29) from which α,β-unsaturated
nitrile 32 was obtained in 79% yield (Scheme 8). Hydroge-
nation of this α,β-unsaturated nitrile provided a mixture of
α- (33a, 37%) and β- (33b, 58%) nitriles, which were sepa-
rated by chromatography. The structure of β-nitrile 33b was
confirmed by a X-ray diffraction analysis (Fig. 2). Having
obtained the desired β-nitrile, the model study for the C-17
homologation was thus completed (Table 1).2
Palladium-catalyzed coupling of 28 was then investigated.
Carbonylation (26) of compound 28 catalyzed by Pd(OAc)2
led to the α,β-unsaturated ester 29 in 81% yield. This unsat-
urated ester was reduced with a catalytic amount of palla-
dium to give ester 30 in a quantitative yield as a single
isomer. Unfortunately, the isomer obtained at the C-17 cen-
1
ter was α rather than the desired β isomer (confirmed by H
NMR shift of the β proton). To obtain the C-17 β isomer 31,
epimerization conditions were explored but without success.
A survey of the literature (27) indicated that with an ester at
C-17, both the kinetic and thermodynamic isomers corre-
spond to the α isomer when the C–D ring junction is cis.
The only method to obtain the β C-17 center with the C–D
Functionalization of ring A
Starting from alcohol 26, Birch reduction (30) with lith-
ium metal was performed at –78 °C, and the corresponding
enol ether was hydrolyzed with 1 N HCl to afford the α,β-
2 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Building M-55, 1200 Montreal Road, Ottawa, ON
K1A 0R6, Canada. DUD 4073. For more information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml.
CCDC 264404 and 264405 contain the crystallographic data for this manuscript. These data can be obtained, free of charge, via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2006 NRC Canada

34
Can. J. Chem. Vol. 84, 2006
Scheme 7.
O
OH
Me
F
Me
F
TPAP, NMO
1) KHMDS, THF, 0oC to r.t.
Cl
4 Å MS, CH2Cl2
H
H
87%
2)
, r.t.
NTf2
84%
MeO
MeO
N
5
26
CO2Me
OTf
Me
F
Me
F
Pd(OAc)2, PPh3, Et3N
MeOH, DMF, CO, 70oC
H
150 psi, 81%
H
MeO
MeO
29
28
CO2Me
Me
CO2Me
Me
F
H2, 5%Pd/C
EtOH, 100%
X
H
F
H
MeO
MeO
30
31
Scheme 8.
OTf
CN
Me
F
Me
LiCN, Pd(PPh3)4
12-C-4, benzene
79%
H
H
F
MeO
MeO
32
28
CN
CN
Me
F
Me
F
H2, 5% Pd/C
EtOH
+
H
H
MeO
MeO
33a (37%)
33b (58%)
unsaturated ketone 34 in 77% yield (Scheme 9). The proton
at the C-10 position was β, as expected. We were pleased to
see that the fluorine atom was not hydrogenolyzed at –78 °C,
since this had occured at –30 °C.
To obtain the desired cis A–B ring junction, hydrogena-
tion of the α,β-unsaturated ketone 34 was accomplished with
a catalytic amount of palladium (Scheme 9) to yield the cis
and trans isomers 36 and 35 in 60% and 37% yields, respec-
tively. The two isomers were easily separated and the syn-
thesis was continued with tetracycle 36, which had the A–B
cis ring junction. Oxidation of tetracycle 36 with TPAP–
NMO (23) furnished the diketone 37 in 99% yield.
Selective reduction of the ketone at the C-3 position
should be possible with a hydride source sensitive to the
steric hindrance (31). In addition, with such a hydride
source, the reduction of the C-3 center to afford the β alco-
© 2006 NRC Canada

Beaubien and Deslongchamps
35
Table 1. X-ray crystallographic information for nitrile 33b and nitro 47.
Crystal
Nitrile 33b
Nitro 47
Empirical formula
C20H24FNO
C26H31FN2O4
Formula mass
Colour, habit
Crystal dimension (mm3)
Crystal system
Space group
Z
313.40
Colourless, plate
0.4 × 0.3 × 0.3
Prism
P1
4
454.53
Colourless, plate
0.05 × 0.40 × 0.50
Triclinic
P1
2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Collection ranges
Temperature (K)
Volume (Å3)
Dcalcd (Mg m–3)
9.601(2)
16.891(4)
10.3300(19)
90.00
98.40(4)
90.00
–11 < h < 11, 0 < k < 20, 0 < l < 12
293(2)
1657.3(6)
1.256
6.6631(10)
9.5374(15)
18.128(3)
92.969(3)
94.269(3)
102.600(3)
–8 < h < 8, –12 < k < 11, –23 < l < 21
173(1)
1118.4(3)
1.350
Abs. coeff. (µ) (mm–1)
F(000)
0.673
672
0.096
484
θ Range for data collection (°)
No. of obsrvd. reflns.
No. of ind. reflns.
5.05–71.76
3220
2873
2.19–27.50
7872
4952
No. of data/restr./params.
Max. shift/error
Goodness-of-fit on F2
Final R indices [l > 2σ(l)]
3220/0/209
0.002/0.000
1.031
4952/0/422
0.000/0.000
1.083
R1 = 0.0420, wR2 = 0.1123
R1 = 0.0491, wR2 = 0.1362
R indices (all data)
Max. diff. peak and hole (e Å–3)
R1 = 0.0383, wR2 = 0.1092
R1 = 0.0617, wR2 = 0.1429
0.283 and –0.148
0.396 and –0.226
Fig. 2. Single crystal X-ray structure of nitrile β-33b.
92% yield for the two steps. This compound was treated un-
der the same conditions used for the model compound 5
(Scheme 7) to prepare the triflic enol ether 41 without suc-
cess. The starting material was recovered with some decom-
position. We tried other bases (LiHMDS, NaHMDS, and
LDA) to make this triflic enol ether, but the same negative
results were obtained. We therefore looked for an alternative
method via a vinyl iodide intermediate (33).
Starting with ketone 38, the corresponding hydrazone was
formed with hydrazine at reflux over 5 days, and this
hydrazone was treated with iodine to provide the desired
vinylic iodide 42 in 91% yield for the two steps
(Scheme 11). The coupling reaction (LiCN, Pd(PPh3)4, 12-
C-4) on this compound having a free alcohol was attempted,
but gave a very poor yield. Thus, the alcohol was protected
with TBDMSOTf to give compound 43 in a quantitative
yield. The same coupling reaction (LiCN, Pd(PPh3)4, 12-C-
4) was performed with vinylic iodide 43, and the desired
α,β-unsaturated nitrile 44 was obtained in 45% yield. This
unsaturated nitrile was then hydrogenated to give the β-
nitrile 45b (53%) and the α-nitrile 45a (47%), which were
separated by chromatography.
hol should be favored (32). Indeed, the use of L-Selectride as
the reducing agent on diketone 37 gave a quantitative yield
of the β C-3 alcohol 38 (Scheme 9).
Fluoro analog synthesis and biological activities
To complete the synthesis of the fluoro analogs, we had to
carry out the nitrile homologation at the C-17 position devel-
oped in the model study and to introduce the α,β-unsaturated
ester at the C-17 position.
Alcohol 38 was protected with TBDMSOTf (Scheme 10),
and a mixture of the desired silyl ether 40 and silyl enol
ether 39 was obtained. This mixture was treated with TBAF,
and the silyl ether 40 was the only compound obtained in
Deprotection of the silyl ethers 45a and 45b was accom-
plished under acidic conditions to furnish the corresponding
compounds 46a and 46b in a quantitative yield. To confirm
the stereochemistry of the β-nitrile 46b, the p-nitrobenzoate
47 was prepared and an X-ray diffraction analysis was ob-
© 2006 NRC Canada

36
Can. J. Chem. Vol. 84, 2006
Scheme 9.
OH
OH
Me
F
Me
F
1) Li, NH3, EtOH,
THF, -78oC
H
H2, 5%Pd/C
AcOEt
H
H
2) HCl 1 N, THF
77%
O
MeO
34
26
OH
OH
Me
F
Me
TPAP, NMO
H
4 Å MS, CH2Cl2
H
H
+
H
H
F
99%
O
O
36 (60%)
35 (27%)
O
O
Me
Me
F
L-Selectride
THF, 100%
H
H
H
F
H
HO
O
37
38
Scheme 10.
O
O
OTBDMS
Me
F
Me
Me
TBDMSOTf
Et3N, CH2Cl2
H
H
H
+
H
H
F
H
F
TBDMSO
HO
TBDMSO
40
38
39
TBAF, THF
92%, 2 steps
OTf
Me
H
X
H
F
TBDMSO
41
tained, which confirmed the stereochemistry of all the asym-
metric centers (Fig. 3).
To complete the synthesis, only two steps were required:
the reduction of the nitrile to an aldehyde, and a Horner–
Emmons reaction to introduce the α,β-unsaturated ester at
the C-17 center. DIBALH was used to reduce the nitriles
46a and 46b. Reduction of the α-nitrile 46a at 0 °C gave
two compounds (Scheme 12), which were identified as alde-
hydes 48 and 49, each containing an olefin. Clearly, the flu-
oride is sensitive to the presence of Lewis acid. In an
attempt to resolve this problem, many other reducing agents
were tried (LiAlH(OEt)3, LiAlH4, Raney Ni), but in each
© 2006 NRC Canada

Beaubien and Deslongchamps
37
Scheme 11.
O
I
Me
1) NH2NH2·H2O, Et3N
EtOH, reflux
Me
F
Pd(PPh3)4, LiCN
H
H
12-C-4, benzene, 45%
2) I2, Et3N, THF
91%, 2 steps
H
F
H
HO
RO
38
42 R = H
TBDMSOTf, Et3N
CH2Cl2, 100%
43 R = TBDMS
CN
Me
CN
Me
F
H
H
PTSA, MeOH
100%
H2, 5% Pd/C
AcOEt
H
F
H
TBDMSO
TBDMSO
45b 53% C-17 = β
45a 47% C-17 = α
44
CN
Me
CN
Me
F
H
O2NC6H4COCl, pyr
DMAP, CH2Cl2
H
O
H
F
H
O
HO
47
46b C-17 = β
46a C-17 = α
O2N
Fig. 3. Single crystal X-ray structure of p-nitrobenzoate 47.
nitrile 46b. Reduction of β-nitrile 46b with DIBALH worked
well to give the corresponding imine, but when this imine
was passed through the silica gel pad, partial isomerization
of the β- to α-aldehyde took place (Scheme 12).
To resolve this problem of epimerization, we tried to use
aqueous conditions to hydrolyze the β-imine but with no
success. Better results were obtained when the β-imine was
passed rapidly through a short silica gel pad, and the corre-
sponding aldehyde was obtained as a mixture of β-aldehyde
50b and α-aldehyde 50a (9:1). The Horner–Emmons reac-
tion was performed on this mixture of aldehydes to give an
unseparable 9:1 mixture of the β-fluoro analog 3 and α-
fluoro analog 4. This mixture was used to study the biologi-
cal activity for the β-fluoro analog.
The biological activities of these two racemic fluoro
analogs 3 and 4 were studied and compared with digitoxi-
genin 1. Radioligand binding studies were performed to
measure ligand–receptor affinities for 1, 3, and 4 at the
ouabain receptor (i.e., ATPase (Na+/K+) expressed in the
MDCK (dog kidney) cell line). [3H]ouabain was used as the
radioligand for competitive displacement. Compound bind-
ing affinities are reported as IC50 values, indicative of the
drug concentration needed to inhibit 50% of [3H]ouabain
binding to the Na+,K+-ATPase. The results are very surpris-
case, the starting material was recovered with some decom-
position products. After considering these results, we de-
cided to attempt the reduction of the α-nitrile 46a with
DIBALH at a lower temperature. When the reduction was
performed at –78 °C, the starting material was recovered.
The corresponding imine was obtained when the reaction
was performed at –60 °C with 10 equiv. of DIBALH. To hy-
drolyze this imine, the residue was passed through a silica
gel pad and α-aldehyde 50a was obtained. The Horner–
Emmons reaction was carried out on this aldehyde to furnish
the desired α-fluoro analog 4 in 60% yield for the two last
steps.
To complete the synthesis of the β-fluoro analog 3, we had
to repeat the last two steps previously discussed on the ␤-
© 2006 NRC Canada

38
Can. J. Chem. Vol. 84, 2006
Scheme 12.
CHO
Me
CHO
+
CN
Me
Me
F
1) DIBALH, toluene, 0oC
2) silica, 100%
HO
H
H
H
H
H
H
HO
HO
48
49
46b C-17 = β
46a C-17 = α
1) DIBALH, toluene, -60oC
2) silica
CO2Me
CHO
Me
F
Me
NaH, (MeO)2P(O)CH2CO2Me
THF, 60%, 2 steps
H
H
H
H
F
HO
HO
3 C-17 = 9:1 (β:α) unseparable
4 C-17 = α
50b C-17 = β
50a C-17 = α
ing. We expected that the inhibitory activity of the β-fluoro
analog 3 would be superior to that α-fluoro analog 4, but it
was not the case. The β-fluoro analog 3 exhibited no activ-
ity, while the α-fluoro analog 4 had an IC50 of 12 µmol/L, in
comparison to the natural product digitoxigenin 1 (IC50 of
0.35 µmol/L). No explanation can be provided to rationalize
this result. However, the primary result obtained with the α-
fluoro analog 4 has encouraged us to continue with the syn-
thesis of other analogs to optimize the biological activity of
this class of fluoro-steroids, and the results will be presented
in another publication.
tion of the β-nitrile 46b to the corresponding aldehyde at the
end of the sequence that gives 10% epimerization. The bio-
logical activity was measured for the two fluoro analogs.
Surprisingly, the α-fluoro analog 4 provided 5% of the in-
hibitory potency of natural digitoxigenin 1.
Experimental section
General
All reactions were performed under a nitrogen atmosphere
with oven (150 °C) or flame-dried glassware. All solvents
were distilled prior to use: ether and tetrahydrofuran from
sodium–benzophenone; toluene, dichloromethane, and
dimethyl sulfoxyde were distilled over calcium hydride, and
methanol from magnesium–iodine. Most amines were dried
over calcium hydride and distilled. All other starting materi-
als and reagents were obtained commercially and used as
such. For reaction workups, all organic phases were dried
over magnesium sulphate. Analytical TLC was carried out
on precoated glass plates (0.25 mm) with silica gel 60 (230–
400 mesh). The following abbreviations were used for NMR
data: singlet (s), doublet (d), triplet (t), quadruplet (q),
Summary
In summary, the synthesis of the fluoro analogs 3 and 4
was carried out via the formation of β-keto ester 7 with ex-
cellent yields. The macrocyclization reaction with this β-keto
ester afforded the 13-membered macrocycle 6 with the trans-
cis-cis olefin geometry, the precursor needed for the TADA
reaction. The key step of the synthesis, the TADA reaction,
was performed on this macrocycle to give the steroidal
tetracycle 21 with the desired TSC configuration at the ring
junction. With this TADA reaction, four new centers were
created in one step to give the expected tetracycle 21. This
key tetracycle was obtained in 19 steps with very high yields
and complete control of the diastereoselectivity. The
functionalization of the A ring was accomplished and the
homologation of the C-17 position was performed to give
the desired α- and β-fluoro analogs.
multiplet (m), broad (br). Chemical shifts are reported in
1
ppm units relative to chloroform (7.26 ppm for H NMR
δ
and 77.0 ppm for decoupled 13C NMR) as internal standard.
1H and 13C NMR spectra are referenced with respect to the
residual signals of the solvent; they are described using stan-
dard abbreviations. 13C NMR spectra of fluoro compounds
give more carbon signals (one to five) owing to fluorine cou-
pling with carbon. Melting points (mp) are uncorrected.
Mass spectra (MS) were obtained with electronic ionization
(70 eV).
The fluoro analog syntheses have been achieved in 35
steps in a linear sequence with 0.7% overall yield. The
chemoselectivity, regioselectivity, and stereochemistry were
controlled at each step of the synthesis except for the reduc-
© 2006 NRC Canada

Beaubien and Deslongchamps
39
mixture was filtered on a silica gel pad and was further
washed with ethyl acetate. The solvent was evaporated to
give hydroxyaldehyde 12 as a yellow oil (8.0 g, 85%). IR
(CHCl3, cm–1) ν: 3414, 2942, 2872, 1682, 1599, 1566, 1496,
Olefin 11
To a stirred solution of ketone 10 (20 g, 113 mmol) in
tetrahydrofuran (500 mL) at –78 °C was added lithium alu-
minium hydride (2.2 g, 57 mmol). The mixture was stirred
at –78 °C for 1 h and sodium sulfate decahydrate was added.
The mixture was stirred at room temperature for 1 h and the
precipitate was filtrated and washed with dichloromethane.
The solvent was evaporated and crude alcohol was diluted in
benzene. p-Toluenesulfonic acid (215 mg, 1.13 mmol) was
added and the mixture was stirred at reflux with a Dean–
Stark for 1.5 h. Satd. aq. NaHCO3 was added and the aque-
ous phase was extracted with ethyl acetate. The combined
organic phases were dried, filtered, and evaporated. The
crude compound was filtered on a silica gel pad and washed
with ethyl acetate – hexanes (3:7) to give olefin 11 as a col-
orless oil (19 g, 100%). IR (CHCl3, cm–1) ν: 3030, 2933,
2830, 1606, 1569, 1500, 1464, 1428, 1253. 1H NMR
(300 MHz, CDCl3, ppm) δ: 6.96 (1H, d, J = 9.1 Hz, Ph),
6.71–6.68 (2H, m, Ph), 6.42 (1H, dt, J = 9.3, 1.9 Hz,
1
1463, 1431, 1290, 1251, 1121, 1057, 1025, 813. H NMR
(300 MHz, CDCl3, ppm) δ: 10.06 (1H, s, CHO), 7.78 (1H,
d, J = 8.6 Hz, Ph), 6.89 (1H, dd, J = 8.6, 2.5 Hz, Ph), 6.82
(1H, d, J = 2.5 Hz, Ph), 3.90 (3H, s, ArOCH3), 3.68 (2H, t,
J = 6.1 Hz, CH2CH2OH), 3.15 (2H, t, J = 7.8 Hz,
ArCH2CH2), 2.06–1.85 (3H, m, CH2CH2CH2OH). 13C NMR
(75 MHz, CDCl3, ppm) δ: 191.54, 163.85, 147.53, 135.56,
127.29, 116.40, 111.68, 61.52, 55.44, 34.50, 28.93. MS
(m/e): 194 ([M]+). HR-MS calcd. for C11H14O3: 194.0943
([M]+); found: 194.0948 0.0006.
Ester 13
To a stirred solution of hydroxyaldehyde 12 (8.7 g,
44.8 mmol) in tetrahydrofuran (200 mL) were added imidazole
(7.6 g, 112 mmol) and tert-butyldimethylsilyl chloride
(10.1 g, 67.2 mmol). The mixture was stirred at room tem-
perature for 45 min and satd. aq. NH4Cl was added. The
aqueous phase was extracted with ethyl acetate. The com-
bined organic phases were dried, filtered, and evaporated.
The residue was purified by flash chromatography (10%
ethyl acetate, 90% hexanes) to give the corresponding silyl
ether as a yellow oil (13.8 g, 100%). IR (CHCl3, cm–1) ν:
2959, 2929, 2856, 2734, 1689, 1600, 1463, 1225, 1102, 1029,
PhCH=CHCH2), 5.90 (1H, dt,
PhCH=CHCH2), 3.80 (3H, s, ArOCH3), 2.78 (2H, t, J =
8.2 Hz, PhCH2CH2), 2.33–2.26 (2H, m, PhCH=CHCH2). 13
NMR (75 MHz, CDCl3, ppm) δ: 158.53, 137.08, 127.32,
127.14, 126.78, 125.81, 113.79, 111.02, 55.13, 27.97, 22.96.
MS (m/e): 160 ([M]+). HR-MS calcd. for C11H16O3:
160.0888 ([M]+); found: 160.0887 0.0005.
J
=
9.3, 4.4 Hz,
C
1
Diol 9
836. H NMR (300 MHz, CDCl3, ppm) δ: 10.14 (1H, s,
To a stirred solution of olefin 11 (26.0 g, 160.3 mmol) in
methanol (2 L) at –78 °C, O3 was bubbled at –78 °C for
1.5 h. Nitrogen was bubbled for 15 min and sodium boro-
hydride (12.1 g, 319.9 mmol) was added. The mixture was
stirred at room temperature for 2 h and sodium borohydride
(6.1 g, 160.0 mmol) was added. The mixture was stirred for
1 h and solvent was evaporated. The crude compound was
diluted in tetrahydrofuran (1 L) and an aqueous solution of
2.5 mol/L NaOH (330 mL) and 30% hydrogen peroxide
(230 mL) were added. The mixture was stirred at room tem-
perature for 18 h. Aqueous sodium thiosulfate solution
(10%) was added and the aqueous phase was extracted with
chloroform. The combined organic phases were dried, fil-
tered, and evaporated to give diol 9 as an amorphous white
solid (27.1 g, 86%). IR (CHCl3, cm–1) ν: 3327, 2939, 2875,
1610, 1580, 1500, 1460, 1256, 1160, 1111, 1055, 1031, 942,
CHO), 7.80 (1H, d, J = 8.6 Hz, Ph), 6.85 (1H, dd, J = 8.6,
2.6 Hz, Ph), 6.77 (1H, d, J = 2.6 Hz, Ph), 3.87 (3H, s,
ArOCH3), 3.68 (2H, t, J = 6.1 Hz, CH2CH2OTBDMS), 3.07
(2H, dd, J = 7.9, 6.1 Hz, ArCH2CH2), 1.84 (2H, dt, J = 9.5,
6.1 Hz, CH2CH2CH2OTBDMS), 0.91 (9H, s, Si-C(CH3)3),
0.06 (6H, s, Si(CH3)2). 13C NMR (75 MHz, CDCl3, ppm) δ:
190.75, 163.7, 147.8, 134.31, 127.5, 116.18, 111.71, 62.19,
55.43, 34.84, 29.95, 25.95, 18.3, –5.3. MS (m/e): 251 ([M –
C4H9]+). HR-MS calcd. for C13H19O3Si: 251.1103 ([M –
C4H9]+); found: 251.1108 0.0007.
To a suspension of sodium hydride 60% in oil (2.5 g,
61.8 mmol) in tetrahydrofuran (350 mL) was added triethyl
phosphonoacetate (12.3 mL, 61.8 mmol). The mixture was
stirred at room temperature for 15 min and a solution of al-
dehyde (12.7 g, 41.2 mmol) in tetrahydrofuran (50 mL) was
added. The mixture was stirred at room temperature for
20 min and satd. aq. NH4Cl was added. The aqueous phase
was extracted with ethyl acetate. The combined organic
phases were dried, filtered, and evaporated. The residue was
filtered on a silica gel pad and washed with 10% ethyl ace-
tate in hexanes to give ester 13 as a yellow oil (15.2 g, 97%).
IR (CHCl3, cm–1) ν: 2954, 2857, 1712, 1603, 1495, 1464,
1
819. H NMR (300 MHz, CDCl3, ppm) δ: 7.22 (1H, d, J =
8.3 Hz, Ph), 6.78 (1H, d, J = 2.7 Hz, Ph), 6.72 (1H, dd, J =
8.3, 2.7 Hz, Ph), 4.63 (2H, s, ArCH2OH), 3.80 (3H, s,
ArOCH3), 3.57 (2H, t, J = 5.9 Hz, CH2CH2OH), 2.82 (2H, t,
J = 7.3 Hz, ArCH2CH2), 2.49 (2H, broad, ArCH2OH,
CH2CH2OH), 1.93 (2H, quint, J = 6.1 Hz, CH2CH2CH2).
13C NMR (75 MHz, CDCl3, ppm) δ: 159.34, 142.05, 131.06,
130.80, 115.02, 110.88, 62.41, 60.74, 55.17, 33.63, 27.26.
MS (m/e): 196 ([M]+). HR-MS calcd. for C11H16O3:
196.1099 ([M]+); found: 196.1108 0.0006.
1
1366, 1295, 1257, 1159, 1105, 1032, 979, 837. H NMR
(300 MHz, CDCl3, ppm) δ: 7.95 (1H, d, J = 15.8 Hz,
PhCH=CH), 7.56 (1H, d, J = 9.2 Hz, Ph), 6.76–6.73 (2H, m,
Ph), 6.28 (1H, d, J = 15.8 Hz, PhCH=CH), 4.27 (2H, q, J =
7.1 Hz, CO2CH2CH3), 3.84 (3H, s, ArOCH3), 3.77 (2H, t,
J = 6.3 Hz, CH2CH2OTBDMS), 2.81 (2H, dd, J = 9.7,
6.1 Hz, ArCH2CH2), 1.81 (2H, dt, J = 9.7, 6.1 Hz,
Hydroxyaldehyde 12
To a stirred solution of diol 9 (9.5 g, 48.5 mmol) in a mix-
ture of pentane–dichloromethane (4:1) (100 mL) was added
MnO2 (21.0 g, 242.5 mmol) and the mixture was stirred at
room temperature for 30 min. MnO2 was added in portions
of 21.0 g every 30 min until the reaction was finished. The
CH2CH2CH2OTBDMS), 1.35 (3H, t,
J
=
7.1 Hz,
CO2CH2CH3), 0.93 (9H, s, SiC(CH3)3), 0.08 (6H, s,
Si(CH3)2). 13C NMR (75 MHz, CDCl3, ppm) δ: 167.26,
161.01, 143.91, 141.48, 128.14, 125.57, 116.95, 115.15,
© 2006 NRC Canada

40
Can. J. Chem. Vol. 84, 2006
112.17, 62.17, 60.22, 55.16, 34.34, 29.67, 25.95, 18.30,
14.36, –5.31. MS (m/e): 363 [M – CH3]+, 321 ([M –
C4H9]+). HR-MS calcd. for C20H31O4Si: 363.1991 ([M –
CH3]+); found: 363.1995 0.0011.
filtered, and evaporated. The residue was purified by flash
chromatography (50% ethyl acetate, 50% hexanes) to give
alcohol 15 as a yellow oil (31.5 g, 98%). IR (CHCl3, cm–1)
ν: 3390, 3048, 2937, 2859, 1607, 1496, 1465, 1380, 1256,
1202, 1110, 1057, 967. 1H NMR (300 MHz, CDCl3, ppm) δ:
7.75 (4H, dd, J = 7.5, 1.7 Hz, Ph), 7.48–7.38 (7H, m, Ph),
6.89 (1H, dt, J = 15.6, 1.7 Hz, PhCH=CH), 6.78–6.73
(2H, m, Ph), 6.11 (1H, dt, J = 15.6, 4.7 Hz, PhCH=CH),
4.41 (2H, dd, J = 4.7, 1.9 Hz, CH2OTBDPS), 3.82 (3H, s,
ArOCH3), 3.65 (2H, t, J = 6.3 Hz, CH2CH2OH), 2.75 (2H,
dd, J = 7.9, 6.2 Hz, ArCH2CH2), 1.89–1.80 (2H, m,
CH2CH2CH2), 1.61 (1H, massif, CH2OH), 1.11 (9H, s,
SiC(CH3)3). 13C NMR (75 MHz, CDCl3, ppm) δ: 158.94,
140.71, 135.56, 133.72, 129.71, 128.63, 128.35, 127.73,
127.25, 126.29, 114.84, 111.85, 64.68, 62.19, 55.25, 33.78,
29.74, 26.86, 19.32. MS (m/e): 403 ([M – C4H9]+). HR-MS
calcd. for C25H27O3Si: 403.1729 ([M – C4H9]+); found:
403.1734 0.0012.
Disilyl ether 14
To a stirred solution of ester 13 (18.4 g, 48.7 mmol) in
dichloromethane (450 mL) at 0 °C was added 1 mol/L
diisobutylaluminium hydride in dichloromethane (121.8 mL,
121.8 mmol). The mixture was stirred at 0 °C for 1 h and so-
dium sulfate decahydrate was added. The mixture was
stirred for 1 h. The precipitate was filtered and washed with
dichloromethane. The solvent was evaporated to give the
corresponding alcohol as a yellow oil (15.9 g, 97%). IR
(CHCl3, cm–1) ν: 3356, 2952, 2857, 1607, 1494, 1464, 1256,
1
1098, 1033, 967, 836. H NMR (300 MHz, CDCl3, ppm) δ:
7.43 (1H, d, J = 8.4 Hz, Ph), 6.83 (1H, d, J = 15.7 Hz,
PhCH=CH), 6.77–6.72 (2H, m, Ph), 6.18 (1H, dt, J = 15.7,
6.0 Hz, PhCH=CH), 4.32 (2H, dd, J = 6.0, 1.3 Hz, CH2OH),
3.82 (3H, s, ArOCH3), 3.67 (2H, t, J = 6.2 Hz,
CH2CH2OTBDMS), 2.76–2.71 (2H, m, ArCH2CH2), 1.79
(2H, dt, J = 9.9, 6.1 Hz, CH2CH2CH2OTBDMS), 1.60 (1H,
massif, CH2OH), 0.94 (9H, s, SiC(CH3)3), 0.09 (6H, s,
Si(CH3)2). 13C NMR (75 MHz, CDCl3, ppm) δ: 159.13,
141.29, 128.50, 128.11, 128.06, 127.27, 114.85, 111.74,
64.06, 62.44, 55.18, 34.02, 29.76, 25.98, 18.35, –5.25. MS
(m/e): 336 ([M]+). HR-MS calcd. for C19H32O3Si: 336.2121
([M]+); found: 336.2123 0.0010.
Aldehyde 16
To a stirred solution of DMSO (14.6 mL, 205.5 mmol) in
dichloromethane (700 mL) at –78 °C were slowly added
oxalyl chloride (12.0 mL, 137.0 mmol) and the alcohol 15
(31.5 g, 68.5 mmol) in dichloromethane. The mixture was
stirred at –78 °C for 45 min and triethylamine (38.5 mL,
274.0 mmol) was added. The mixture was stirred at room
temperature for 1 h and satd. aq. NH4Cl was added. The
aqueous phase was extracted with dichloromethane. The
combined organic phases were dried, filtered, and evapo-
rated. The residue was filtered on a silica gel pad and
washed with 50% ethyl acetate in hexanes to give aldehyde
16 as a yellow oil (31.5 g, 100%). IR (CHCl3, cm–1) ν:
3078, 2935, 2857, 2721, 1925, 1607, 1496, 1428, 1256,
1110, 967. 1H NMR (300 MHz, CDCl3, ppm) δ: 9.78 (1H, s,
CHO), 7.73 (4H, dd, J = 7.5, 1.6 Hz, Ph), 7.49–7.38 (7H, m,
Ph), 6.83 (1H, dt, J = 15.6, 1.8 Hz, PhCH=CH), 6.77 (1H,
dd, J = 5.8, 2.8 Hz, Ph), 6.71 (1H, d, J = 2.8 Hz, Ph), 6.11
(1H, dt, J = 15.5, 4.7 Hz, PhCH=CH), 4.41 (2H, dd, J = 4.7,
1.9 Hz, CH2OTBDPS), 3.82 (3H, s, ArOCH3), 2.98 (2H, dt,
J = 7.4 Hz, ArCH2CH2), 2.71 (2H, t, J = 7.24 Hz,
CH2CH2CHO), 1.11 (9H, s, SiC(CH3)3). 13C NMR
(75 MHz, CDCl3, ppm) δ: 201.26, 139.06, 135.56, 133.68,
129.76, 129.03, 128.54, 127.83, 127.76, 127.67, 127.51,
125.70, 114.77, 112.26, 64.57, 55.27, 44.74, 26.87, 25.97,
19.33. MS (m/e): 458 ([M]+), 401 ([M – C4H9]+). HR-MS
calcd. for C29H34O3Si: 458.2277 ([M]+); found: 458.2282
0.0014.
To a stirred solution of alcohol (15.9 g, 47.3 mmol) in
tetrahydrofuran (400 mL) were added imidazole (8.1 g,
118.3 mmol) and tert-butyldiphenylsilane chloride (18.5 mL,
71.0 mmol). The mixture was stirred at room temperature
for 1.5 h and satd. aq. NH4Cl was added. The aqueous phase
was extracted with ethyl acetate. The combined organic
phases were dried, filtered, and evaporated. The residue was
purified by flash chromatography (5% ethyl acetate, 95%
hexanes) to give disilyl ether 14 as a yellow oil (25.0 g,
93%). IR (CHCl3, cm–1) ν: 3048, 2934, 2858, 1607, 1495,
1466, 1254, 1106, 1062, 967, 837. 1H NMR (300 MHz,
CDCl3, ppm) δ: 7.74 (4H, dd, J = 7.5, 1.7 Hz, Ph), 7.48–
7.36 (7H, m, Ph), 6.87 (1H, d, J = 15.7 Hz, PhCH=CH),
6.76–6.72 (2H, m, Ph), 6.10 (1H, dt, J = 15.7, 4.9 Hz,
PhCH=CH), 4.39 (2H, dd, J = 6.7, 1.8 Hz, CH2OTBDPS),
3.82 (3H, s, ArOCH3), 3.63 (2H, t, J = 6.3 Hz,
CH2CH2OTBDMS), 2.71 (2H, dd, J = 9.7, 7.7 Hz,
ArCH2CH2), 1.84–1.74 (2H, m, CH2CH2CH2OTBDMS),
1.58 (9H, s, SiC(CH3)3), 1.11 (9H, s, SiC(CH3)3), 0.06
(6H, s, Si(CH3)2). 13C NMR (75 MHz, CDCl3, ppm) δ:
158.92, 141.09, 135.59, 133.79, 129.69, 128.22, 127.73,
127.65, 127.16, 126.46, 114.86, 111.77, 64.84, 62.45, 55.23,
33.97, 29.87, 26.91, 26.02, 19.32, 19.35, –5.20. MS (m/e):
574 ([M]+). HR-MS calcd. for C35H50O3Si2: 574.3298
([M]+); found: 574.3303 0.0017.
Ester 8
To a stirred solution of fluorophosphonate 17 (10.2 g,
42.3 mmol) in tetrahydrofuran (700 mL) at –78 °C was
added a 1.4 mol/L solution of n-butyl lithium in hexanes
(32.0 mL, 42.3 mmol). The mixture was stirred at –78 °C for
10 min and aldehyde 16 (12.9 g, 28.2 mmol) in tetrahydro-
furan was added. The mixture was stirred at –78 °C for
45 min and satd. aq. NH4Cl was added. The aqueous phase
was extracted with ethyl acetate. The combined organic
phases were dried, filtered, and evaporated. The residue was
purified by flash chromatography (10% ethyl acetate, 90%
hexanes) to give ester 8 as a colorless oil (14.3 g, 93%). IR
(CHCl3, cm–1) ν: 3048, 2935, 2858, 1728, 1607, 1496, 1465,
Alcohol 15
To a stirred solution of disilyl ether 14 (40.3 g,
70.2 mmol) in ethanol 95% (500 mL) was added p-
toluenesulfonate pyridinium salt (1.8 g, 7.02 mmol) and the
mixture was stirred at room temperature overnight. Satd. aq.
NaHCO3 was added and the aqueous phase was extracted
with ethyl acetate. The combined organic phases were dried,
© 2006 NRC Canada

Beaubien and Deslongchamps
41
1376, 1254, 1112, 1047, 967, 822. 1H NMR (300 MHz,
CDCl3, ppm) δ: 7.75 (4H, dd, J = 7.5, 1.6 Hz, Ph), 7.46–
7.37 (7H, m, Ph), 6.89 (1H, dt, J = 15.6, 1.7 Hz,
PhCH=CH), 6.78 (1H, dd, J = 8.5, 2.7 Hz, Ph), 6.72 (1H, d,
J = 2.7 Hz, Ph), 6.12 (1H, dt, J = 15.5, 4.8 Hz, PhCH=CH),
5.97–5.84 (1H, m, CH2CH=CFCO2Et), 4.42 (2H, dd, J =
4.8, 1.8 Hz, CH2OTBDPS), 4.26 (2H, q, J = 7.1 Hz,
CO2CH2CH3), 3.83 (3H, s, ArOCH3), 2.80–2.79 (4H, m,
ArCH2CH2), 1.33 (3H, t, J = 7.1 Hz, CO2CH2CH3), 1.12
(9H, s, SiC(CH3)3). 13C NMR (75 MHz, CDCl3, ppm) δ:
158.96, 148.99, 145.65, 139.41, 135.56, 134.84, 133.74,
129.72, 128.71, 127.73 127.36, 126.02, 122.35, 122.10,
114.87, 112.16, 64.68, 61.36, 55.25, 32.83, 26.87, 26.59,
19.33, 14.15. MS (m/e): 546 ([M]+). HR-MS calcd.
C33H39O4SiF: 546.2601 ([M]+); found: 546.2596 0.0016.
110.16, 109.89, 64.60, 55.29, 37.64, 37.20, 33.39, 26.86,
19.33. MS (m/e): 520 ([M]+). HR-MS calcd. for
C31H36O2SiFCl: 522.2157 ([M]+); found: 522.2153 0.0016.
␤-Keto ester 19
Solution 1
To a suspension of 60% sodium hydride in oil (592 mg,
14.8 mmol) in tetrahydrofuran (20 mL) at 0 °C was added
methyl acetoacetate (2.8 mL, 26.3 mmol) and the mixture
was stirred at 0 °C for 30 min. A solution of 1.6 mol/L n-
butyl lithium in hexanes (8.6 mL, 13.8 mmol) was added
and the mixture was stirred at 0 °C for 30 min.
Solution 2
To a stirred solution of chloride 18 (1.03 g, 1.97 mmol) in
tetrahydrofuran (20 mL) was added sodium iodide (885 mg,
5.9 mmol) and the mixture was stirred at room temperature
for 30 min.
Chloride 18
To a solution of ester 8 (33.4 g, 61.2 mmol) in tetrahy-
drofuran (600 mL) at 0 °C was added lithium aluminium hy-
dride (2.32 g, 61.2 mmol). The mixture was stirred at 0 °C
for 20 min and sodium sulfate decahydrate was added. The
mixture was stirred for 1 h and the precipitate was filtered
and washed with dichloromethane. The solvent was evapo-
rated to give the alcohol as a colorless oil (30.8 g, 100%). IR
(CHCl3, cm–1) ν: 3433, 3047, 2936, 2858, 1735, 1607, 1496,
Solution 1 was added to solution 2 and the mixture was
stirred at room temperature overnight. Satd. aq. NH4Cl was
added and the aqueous phase was extracted with ethyl ace-
tate. The combined organic phases were dried, filtered, and
evaporated. The residue was purified by flash chromatogra-
phy (30% ethyl acetate, 70% hexanes) to give β-keto ester 19
as a yellow oil (770 mg, 65%). IR (CHCl3, cm–1) ν: 3020,
2955, 2860, 1745, 1720, 1608, 1496, 1433, 1315, 1217,
1
1429, 1253, 1111, 967, 854. H NMR (300 MHz, CDCl3,
ppm) δ: 7.77 (4H, dd, J = 7.5, 1.7 Hz, Ph), 7.50–7.40
(7H, m, Ph), 6.90 (1H, dt, J = 15.6, 1.6 Hz, PhCH=CH),
6.79 (1H, dd, J = 8.6, 2.7 Hz, Ph), 6.69 (1H, d, J = 2.7 Hz,
Ph), 6.14 (1H, dt, J = 15.5, 4.6 Hz, PhCH=CH), 5.23 (1H,
dt, J = 20.6, 8.4 Hz, CH2CH=CFCH2OH), 4.44 (2H, dd, J =
4.6, 1.9 Hz, CH2OTBDPS), 3.98 (2H, d, J = 21.4 Hz,
CH2OH), 3.83 (3H, s, ArOCH3), 2.76 (2H, t, J = 7.3 Hz,
ArCH2CH2), 2.30 (2H, q, J = 7.6 Hz, ArCH2CH2), 1.49 (1H,
massif, CH2OH), 1.15 (9H, s, SiC(CH3)3). 13C NMR
(75 MHz, CDCl3, ppm) δ: 160.58, 158.82, 157.32, 139.64,
135.55, 133.65, 129.76, 128.77, 127.76, 127.40, 125.97,
115.45, 112.15, 107.54, 107.58, 65.00, 57.27, 56.87, 55.30,
33.68, 26.88, 19.34. MS (m/e): 504 ([M]+). HR-MS calcd.
for C31H37O3SiF: 504.2496 ([M]+); found: 504.2488
0.0015.
1
1110, 967, 756. H NMR (300 MHz, CDCl3, ppm) δ: 12.05
(RC(O)CH=C(OH)R′), 7.75 (4H, dd, J = 7.4, 1.7 Hz, Ph),
7.49–7.37 (7H, m, Ph), 6.92–6.87 (1H, m, CH=CHPh), 7.77
(1H, dd, J = 8.5, 2.7 Hz, Ph), 6.70 (1H, d, J = 2.7 Hz, Ph),
6.11 (1H, dt, J = 15.5, 4.6 Hz, CH=CHPh), 5.06 (1H, dt, J =
21.7, 8.1 Hz, CH=CFR), 4.43 (2H, dd, J = 4.6, 1.8 Hz,
CH2OTBDPS), 3.82 (3H, s, ArOCH3), 3.73 (3H, s,
CO2CH3), 3.39 (2H, s, C(O)CH2C(O)), 2.72 (2H, t, J =
7.3 Hz, ArCH2CH2), 2.55–2.20 (6H, m, CH2CH2C(O),
CH2CH2C(O), CH2CH=CFR), 1.13 (9H, s, Si-C(CH3)3). 13C
NMR (75 MHz, CDCl3, ppm) δ: 167.36, 160.38, 158.83,
157.12, 139.99, 135.54, 133.72, 129.71, 128.70, 128.61,
127.73, 127.25, 126.01, 115.17, 112.07, 105.57, 105.28,
64.58, 55.25, 52.35, 48.89, 39.14, 33.58, 26.86, 22.02,
21.65, 19.31. MS (m/e): 602 ([M]+). HR-MS calcd. for
C36H43O5FSi: 602.2864 ([M]+); found: 602.2870 0.0018.
To a stirred solution of the alcohol (8.6 g, 17.1 mmol) in
tetrahydrofuran (200 mL) at –40 °C were added triphenyl-
phosphine (4.9 g, 18.8 mmol) and hexachloroacetone
(2.6 mL, 17.1 mmol). The mixture was stirred at –40 °C for
20 min and the solvent was evaporated. The residue was pu-
rified by flash chromatography (100% hexanes to 20% ethyl
acetate, 80% hexanes) to give chloride 18 as a yellow oil
(8.8 g, 99%). IR (CHCl3, cm–1) ν: 3017, 2936, 2859, 1732,
Pivaloate ester 7
To a stirred solution of β-keto ester 19 (1.72 g,
2.85 mmol) in tetrahydrofuran (30 mL) was added 1 mol/L
tetrabutylammonium fluoride in tetrahydrofuran (5.7 mL,
5.70 mmol). The mixture was stirred at room temperature
for 1.5 h and solvent was evaporated. The residue was puri-
fied by flash chromatography (70% ethyl acetate, 30% hex-
anes) to give the corresponding alcohol as a colorless oil
(798 mg, 77%). IR (CHCl3, cm–1) ν: 3425, 2949, 2867,
1744, 1716, 1608, 1496, 1441, 1372, 1254, 1084, 1008, 912,
1
1607, 1496, 1465, 1429, 1254, 1217, 1111, 1047, 967. H
NMR (300 MHz, CDCl3, ppm) δ: 7.75 (4H, dd, J = 7.6,
1.6 Hz, Ph), 7.50–7.39 (7H, m, Ph), 6.87 (1H, dt, J = 15.6,
1.8 Hz, PhCH=CH), 6.79 (1H, dd, J = 8.6, 2.7 Hz, Ph), 6.68
(1H, d, J = 2.7 Hz, Ph), 6.13 (1H, dt, J = 15.6, 4.7 Hz,
PhCH=CH), 5.31 (1H, dt, J = 18.8, 8.3 Hz, CH2CH=CFCH2Cl),
4.44 (2H, dd, J = 4.7, 1.9 Hz, CH2OTBDPS), 3.94 (2H, d,
J = 21.4 Hz, CH2Cl), 3.83 (3H, s, ArOCH3), 2.76 (2H, t, J =
7.3 Hz, ArCH2CH2), 2.30 (2H, q, J = 7.8 Hz, ArCH2CH2),
1.13 (9H, s, SiC(CH3)3). 13C NMR (75 MHz, CDCl3, ppm)
δ: 158.92, 156.83, 153.55, 139.27, 135.54, 133.67, 129.74,
128.86, 128.55, 127.74, 127.47, 125.88, 115.14, 112.17,
1
733. H NMR (300 MHz, CDCl3, ppm) δ: 7.41 (1H, d, J =
8.6 Hz, Ph), 6.83 (1H, d, J = 15.7 Hz, CH=CHPh), 6.76 (1H,
dd, J = 8.6, 2.7 Hz, Ph), 6.68 (1H, d, J = 2.7 Hz, Ph), 6.18
(1H, dt, J = 15.6, 5.6 Hz, CH=CHPh), 5.10 (1H, dt, J =
21.6, 8.2 Hz, CH=CFR), 4.34 (2H, dd, J = 5.6, 1.5 Hz,
CH2OH), 3.82 (3H, s, ArOCH3), 3.76 (3H, s, CO2CH3), 3.46
(2H, s, C(O)CH2C(O)), 2.72 (2H, t, J = 8.0 Hz, ArCH2CH2),
© 2006 NRC Canada

42
Can. J. Chem. Vol. 84, 2006
2.63–2.58 (2H, m, CH2CH2C(O)), 2.48–2.36 (2H, m,
CH2CH2C(O)), 2.23 (2H, q, J = 7.8 Hz, CH2CH=CFR), 1.67
(1H, br, OH). 13C NMR (75 MHz, CDCl3, ppm) δ: 201.71,
167.53, 160.32, 158.96, 157.05, 140.21, 128.88, 128.38,
127.35, 115.10, 112.03, 105.68, 105.40, 63.56, 55.18, 52.39,
48.84, 39.12, 33.73, 26.81, 21.96. MS (m/e): 364 ([M]+).
HR-MS calcd. for C20H25O5F: 364.1686 ([M]+); found:
364.1683 0.0011.
CH=CHPh), 5.00 (1H, dt, J = 20.7, 7.7 Hz, CH=CFR), 3.80
(3H, s, ArOCH3), 3.77 (3H, s, CO2CH3), 3.80–3.75 (1H, m,
C(O)CHC(O)), 3.04–1.86 (10H, m, PhCH2CH2CH=CFR,
CH=C(F)CH2CH2C(O), CH2C(H)CO2Me). 13C NMR (75 MHz,
CDCl3, ppm) δ: 204.00, 169.54, 160.98, 159.09, 157.11,
140.77, 131.98, 129.24, 128.38, 126.07, 114.54, 111.63,
105.80, 105.52, 57.71, 55.19, 52.58, 39.06, 33.90, 32.01,
27.89, 22.42. MS (m/e): 346 ([M]+). HR-MS calcd. for
C20H23O4F: 346.1580 ([M]+); found: 346.1576 0.0010.
To a stirred solution of the alcohol (798 mg, 2.19 mmol)
in dichloromethane (20 mL) were added 2,6-lutidine
(765 µL, 6.57 mmol) and trimethylacetyl chloride (809 µL,
6.57 mmol) and the mixture was stirred at room temperature
overnight. Satd. aq. NH4Cl was added and the aqueous phase
was extracted with dichloromethane. The combined organic
phases were dried, filtered, and evaporated. The residue was
purified by flash chromatography (30% ethyl acetate, 70%
hexanes) to give pivaloate ester 7 as a colorless oil (952 mg,
97%). IR (CHCl3, cm–1) ν: 3020, 2957, 2873, 1744, 1719,
1606, 1495, 1438, 1282, 1216, 1158, 1090, 1040, 695, 853,
756. 1H NMR (300 MHz, CDCl3, ppm) δ: 12.05
(RC(O)CH=C(OH)R′), 7.40 (1H, d, J = 8.6 Hz, Ph), 6.83
(1H, d, J = 15.7 Hz, CH=CHPh), 6.75 (1H, dd, J = 8.6,
3.0 Hz, Ph), 6.67 (1H, d, J = 2.7 Hz, Ph), 6.06 (1H, dt, J =
15.6, 6.2 Hz, CH=CHPh), 5.11 (1H, dt, J = 21.6, 8.1 Hz,
CH=CFR), 4.73 (2H, dd, J = 6.2, 1.3 Hz, CH2OPiv), 3.80
(3H, s, ArOCH3), 3.73 (3H, s, CO2CH3), 3.41 (2H, s,
C(O)CH2C(O)), 2.71 (2H, t, J = 7.5 Hz, ArCH2CH2), 2.54–
2.49 (2H, m, CH2CH2C(O)), 2.43–2.31 (2H, m,
CH2CH2C(O)), 2.24 (2H, m, CH2CH=CFR), 1.23 (9H, s,
C(CH3)3). 13C NMR (75 MHz, CDCl3, ppm) δ: 200.94,
167.35, 160.39, 159.29, 157.13, 140.38, 130.54, 127.90,
127.43, 123.48, 115.16, 112.11, 105.48, 105.19, 65.09,
55.22, 52.33, 48.89, 39.05, 38.79, 33.53, 27.21, 26.84,
21.96. MS (m/e): 448 ([M]+). HR-MS calcd. for C25H33O6F:
448.2261 ([M]+); found 448.2270 0.001.
Triene 6
To a stirred solution of 70% benzeneseleninic anhydride
(10.2 g, 19.8 mmol) in dichloromethane (200 mL) was
added triethylamine (4.6 mL, 32.9 mmol) and the mixture
was stirred for 15 min. A solution of macrocycle 20 (2.30 g,
6.65 mmol) in dichloromethane was added and the mixture
was stirred for 15 min. Satd. aq. NaHCO3 was added and the
aqueous phase was extracted with dichloromethane. The
combined organic phases were dried, filtered, and evapo-
rated. The residue was purified by flash chromatography
(5% ethyl acetate, 95% dichloromethane) to give triene 6 as
a yellow solid (2.05 g, 91%); mp 147–149 °C. IR
(CHCl3, cm–1) ν: 3020, 2954, 1696, 1603, 1583, 1436, 1275,
1
1241, 1158, 1077, 1045. H NMR (300 MHz, CDCl3, ppm)
δ: 7.43 (1H, d, J = 11.5 Hz, PhCH=CH=CH), 7.21 (1H, d,
J = 8.5 Hz, Ph), 6.96 (1H, d, J = 16.2 Hz, CH=CHPh), 6.76
(1H, dd, J = 8.4, 2.7 Hz, Ph), 6.71 (1H, d, J = 2.7 Hz, Ph),
6.64 (1H, dd, J = 16.2, 11.5 Hz, PhCH=CH), 5.26 (1H, dt,
J = 22.1, 8.7 Hz, CH=CFR), 3.82 (3H, s, ArOCH3), 3.81
(3H, s, CO2CH3), 2.97–2.93 (2H, m, CH2CH2C(O)), 2.87–
2.81 (2H, m, PhCH2CH2), 2.58 (2H, dt, J = 22.1, 6.9 Hz,
CH2CH2C(O)), 2.22–2.14 (2H, m, PhCH2CH2). 13C NMR
(75 MHz, CDCl3, ppm) δ: 203.17, 164.94, 160.41, 159.01,
155.73, 144.16, 142.15, 136.13, 131.88, 126.46, 123.62,
117.45, 111.76, 107.23, 106.93, 55.29, 52.14, 39.48, 37.15,
26.02, 23.61. MS (m/e): 344 ([M]+). HR-MS calcd. for
C20H21O4F: 344.1424 ([M]+); found: 344.1426 0.0010.
Macrocycle 20
Solution 1
Tetracycle 21
To a stirred solution of pivaloic ester 7 (1.67 g,
3.73 mmol) in tetrahydrofuran (15 mL) degassed with Ar
was added N,O-bis(trimethylsilyl)acetamide (1.8 mL,
7.46 mmol). The mixture was stirred at reflux for 5 h.
To a solution of triene 6 (500 mg, 1.45 mmol) in toluene
(70 mL) degassed with Ar was added triethylamine (1.0 mL,
7.25 mmol) and the mixture was heated in a sealed tube at
165 °C for 4 h. The solvent was evaporated and the residue
was purified by flash chromatography (20% ethyl acetate,
80% hexanes) to give tetracycle 21 as a white solid (389 mg,
78%); mp 162–164 °C. IR (CHCl3, cm–1) ν: 3019, 2954,
Solution 2
To a stirred solution of tetrakis(triphenylphosphine) palla-
dium(0) (1.07 g, 0.93 mmol) in tetrahydrofuran (1.9 L) de-
gassed with Ar was added 1,3-bis(diphenylphospino)propane
(384 mg, 0.93 mmol) and the mixture was stirred at reflux
for 1 h.
1
1761, 1734, 1609, 1502, 1436, 1258, 1216, 1045. H NMR
(300 MHz, CDCl3, ppm) δ: 7.28 (1H, d, J = 8.9 Hz, Ph),
6.76 (1H, dd, J = 8.9, 2.7 Hz, Ph), 6.70 (1H, d, J = 2.7 Hz,
Ph), 6.53 (1H, d, J = 9.9 Hz, CH=CHC(CO2Me)R), 5.64
(1H, ddd, J = 9.9, 5.6, 3.0 Hz, CH=CHC(CO2Me)R), 3.79
(3H, s, ArOCH3), 3.72 (3H, s, CO2CH3), 3.23 (1H, d, J =
11.5 Hz, PhCHCH=CH), 3.00–2.94 (2H, m, PhCH2CH2),
2.91–2.77 (1H, m, CHC(F)R), 2.51–2.23 (4H, m,
C(O)CH2CH2C(F)R), 2.14–1.92 (1H, m, PhCH2CHH), 1.73–
1.57 (1H, m, PhCH2CHH). 13C NMR (75 MHz, CDCl3,
ppm) δ: 209.92, 167.91, 157.95, 137.43, 132.10, 128.26,
125.88, 122.52, 114.30, 111.89, 105.07, 102.64, 65.61,
55.25, 52.88, 40.66, 40.37, 40.01, 35.60, 29.51, 26.43,
21.36. MS (m/e): 344 ([M]+). HR-MS calcd. for C20H21O4F:
344.1424 ([M]+); found: 344.1413 0.0010.
Solution 1 was slowly added to solution 2 at reflux for
14 h and the resulting mixture was heated for 4 h. The sol-
vent was evaporated and the residue was purified by flash
chromatography (5% ethyl acetate, 35% dichloromethane,
60% hexanes) to give macrocycle 20 as a white solid
(1.14 g, 88%); mp 129–131 °C. IR (CHCl3, cm–1) ν: 3020,
2956, 1743, 1714, 1607, 1493, 1436, 1250, 1216, 1165,
1
1115, 1078, 1041, 970, 762. H NMR (300 MHz, CDCl3,
ppm) δ: 7.21 (1H, d, J = 8.4 Hz, Ph), 6.73 (1H, dd, J = 8.4,
2.8 Hz, Ph), 6.67 (1H, d, J = 2.8 Hz, Ph), 6.57 (1H, d, J =
15.7 Hz, PhCH=CH), 5.77 (1H, ddd, J = 15.6, 8.6, 5.3 Hz,
© 2006 NRC Canada

Beaubien and Deslongchamps
43
combined organic phases were dried, filtered, and evapo-
rated. The residue was purified by flash chromatography
(50% ethyl acetate, 50% hexanes) to give a mixture (α:β =
9:1) of tosylates 25 unseparable as a white solid (539 mg,
94%). Tosylate α-25: IR (CHCl3, cm–1) ν: 3602, 3551,
2951, 2872, 1610, 1501, 1464, 1361, 1176, 1097, 1045, 944,
Diol 24
To a stirred solution of tetracycle 21 (594 mg, 1.73 mmol)
in ethanol 95% (75 mL) was added 5% palladium(0) on bar-
ium sulfate (745 mg, 0.35 mmol) and hydrogen was bubbled
through this solution for 15 min. The resulting mixture was
stirred at room temperature overnight under a hydrogen
atmosphere. N2 was bubbled through this mixture and the
solution was filtered on a silica gel pad to give the corre-
sponding tetracycle as a beige solid (594 mg, 100%); mp
154–157 °C. IR (CHCl3, cm–1) ν: 3055, 2954, 1754, 1731,
1
816. H NMR (300 MHz, CDCl3, ppm) δ: 7.78 (2H, d, J =
8.2 Hz, Ph), 7.34 (2H, d, J = 8.2 Hz, Ph), 7.16 (1H, d, J =
8.6 Hz, Ph), 6.72 (1H, dd, J = 8.6, 2.5 Hz, Ph), 6.62 (1H, d,
J = 2.5 Hz, Ph), 4.81 (1H, massif, RR′CHOH), 4.57 (1H, t,
J = 8.0 Hz, RR′CHOH), 4.30 (1H, d, J = 9.9 Hz, CHHOTs),
4.23 (1H, d, J = 9.9 Hz, CHHOTs), 3.78 (3H, s, ArOCH3),
2.86–2.79 (2H, m, PhCH2CH2), 2.44 (3H, s, PhCH3), 2.37–
2.15 (2H, m), 2.08–2.01 (3H, m), 1.88–1.52 (4H, m), 1.46–
1.33 (2H, m), 1.29–1.09 (1H, m). MS (m/e): 474 ([M]+).
HR-MS calcd. for C26H31O5FS: 474.1876 ([M]+); found:
474.1880 0.0014.
1
1611, 1502, 1435, 1266, 1043, 896. H NMR (300 MHz,
CDCl3, ppm) δ: 7.19 (1H, d, J = 8.6 Hz, Ph), 6.74 (1H, dd,
J = 8.6, 2.7 Hz, Ph), 6.65 (1H, d, J = 2.7 Hz, Ph), 3.78
(3H, s, ArOCH3), 3.73 (3H, s, CO2CH3), 2.94–2.89 (2H, m,
PhCH2CH2), 2.83–2.70 (1H, m, PhCH), 2.58–2.49 (2H, m,
RC(O)CH2), 2.38–1.90 (7H, m), 1.65–1.77 (2H, m). 13C
NMR (75 MHz, CDCl3, ppm) δ: 211.61, 169.27, 157.77,
137.43, 130.21, 127.05, 113.72, 112.08, 106.08, 103.66,
62.19, 61.94, 55.16, 52.30, 42.70, 42.40, 39.37, 34.97,
30.05, 29.79, 26.73, 26.19, 22.04. MS (m/e): 346 ([M]+).
HR-MS calcd. for C20H23O4F: 346.1580 ([M]+); found:
346.1576 0.0010.
Alcohol 26 and oxetane 27
To a stirred solution of tosylate 25 (650 mg, 1.37 mmol)
in dimethylsulfoxide (80 mL) was added sodium borohy-
dride (260 mg, 6.85 mmol) and the mixture was stirred at
80 °C overnight. Satd. aq. NH4Cl was added and the aque-
ous phase was extracted with ethyl acetate. The combined
organic phases were dried, filtered, and evaporated. The resi-
due was purified by flash chromatography (50% ethyl ace-
tate, 50% hexanes) to give alcohol 26 as colorless oil
(353 mg, 85%) and about 10% of oxetane 27. Alcohol 26:
IR (CHCl3, cm–1) ν: 3386, 2942, 2870, 1610, 1501, 1466,
1261, 1235, 1042. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.22
(1H, d, J = 8.6 Hz, Ph), 6.73 (1H, dd, J = 8.6, 2.8 Hz, Ph),
6.65 (1H, d, J = 2.8 Hz, Ph), 4.28 (1H, t, J = 8.0 Hz,
RR′CHOH), 3.78 (3H, s, ArOCH3), 2.90–2.85 (2H, m,
PhCH2CH2), 2.46–2.39 (1H, m, PhCH), 2.32–2.00 (4H, m),
1.90–1.74 (2H, m), 1.72–1.57 (3H, m), 1.53–1.36 (3H, m),
1.08 (3H, d, J = 1.3 Hz, CH3). 13C NMR (75 MHz, CDCl3,
ppm) δ: 157.58, 137.76, 131.39, 126.83, 113.71, 111.88,
109.08, 106.71, 80.43, 55.21, 47.48, 47.25, 42.40, 42.11,
40.23, 29.97, 28.42, 28.22, 27.58, 27.24, 25.68, 22.13,
16.33. MS (m/e): 304 ([M]+). HR-MS calcd. for C19H25O2F:
304.1838 ([M]+); found: 304.1843 0.0009. Oxetane 27: IR
(CHCl3, cm–1) ν: 3018, 2945, 2882, 1610, 1502, 1465, 1215,
1038, 974. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.12 (1H, d,
J = 8.6 Hz, Ph), 6.72 (1H, dd, J = 8.6, 2.8 Hz, Ph), 6.62
(1H, d, J = 2.8 Hz, Ph), 4.95 (1H, d, J = 5.9 Hz,
CHHOCHRR′), 4.72 (1H, d, J = 5.9 Hz, CHHOCHRR′),
4.35 (1H, dd, J = 5.6, 4.7 Hz, RR′CHOCH2), 3.78 (3H, s,
ArOCH3), 2.90–2.84 (2H, m, PhCH2CH2), 2.48–1.25
(12H, m). 13C NMR (75 MHz, CDCl3, ppm) δ: 157.51,
137.58, 131.72, 127.84, 113.38, 112.33, 106.60, 104.18,
91.12, 74.36, 74.16, 55.20, 51.18, 50.95, 44.32, 43.97,
36.51, 32.33, 32.16, 32.12, 30.31, 29.05, 27.83, 23.94. MS
(m/e): 302 ([M])+. HR-MS calcd. for C19H23O2F: 302.1682
([M]+); found: 302.1399 0.0009.
To a stirred solution of this tetracycle (575 mg,
1.66 mmol) in tetrahydrofuran (40 mL) were added lithium
borohydride (180 mg, 8.30 mmol) and methanol (336 µL,
8.30 mmol) and the mixture was stirred at room temperature
for 2 h. Lithium borohydride (72 mg, 3.32 mmol) and meth-
anol (134 µL, 3.32 mmol) were added and the mixture was
stirred for 1 h. Satd. aq. NH4Cl was added and the aqueous
phase was extracted with ethyl acetate. The combined or-
ganic phases were dried, filtered, and evaporated. The resi-
due was purified by flash chromatography (100% ethyl
acetate) to give a mixture (α:β = 9:1) of diol 24 as a white
solid (539 mg, 94%). Diol α-24: 1H NMR (300 MHz,
CDCl3, ppm) δ: 7.22 (1H, d, J = 8.6 Hz, Ph), 6.72 (1H, dd,
J = 8.6, 2.7 Hz, Ph), 6.64 (1H, d, J = 2.7 Hz, Ph), 4.74 (1H,
t, J = 8.2 Hz, RR′CHOH), 4.00 (1H, d, J = 10.3 Hz,
CHHOH), 3.90 (1H, d, J = 10.3 Hz, CHHOH), 3.78 (3H, s,
ArOCH3), 2.85 (2H, dd, J = 8.9, 3.8 Hz, PhCH2CH2), 2.47
(1H, t, J = 11.6 Hz, PhCH), 2.38–2.05 (5H, m), 1.92–1.62
(3H, m), 1.87 (2H, br, CHOH, CH2OH), 1.50–1.28 (3H, m).
MS (m/e): 320 ([M]+). HR-MS calcd. for C19H25O3F:
320.1788 ([M]+); found: 320.1779 0.0010. Diol β-24: H
1
NMR (300 MHz, CDCl3, ppm) δ: 7.18 (1H, d, J = 8.6 Hz,
Ph), 6.73 (1H, dd, J = 8.6, 2.7 Hz, Ph), 6.64 (1H, d, J =
2.7 Hz, Ph), 4.18 (1H, d, J = 11.7 Hz, RCHHOH), 4.01 (1H,
dd, J = 7.3, 2.2 Hz, RR′CHOH), 3.78 (3H, s, ArOCH3), 3.71
(1H, d, J = 11.7 Hz, CHHOH), 2.86 (2H, dd, J = 8.6,
3.5 Hz, PhCH2CH2), 2.49–2.35 (2H, m), 2.31–1.83
(10H, m), 1.74 (1H, qd, J = 11.7, 2.0 Hz), 1.53–1.34
(1H, m), 1.05–0.96 (1H, m).
Tosylate 25
To a stirred solution of diol 24 (460 mg, 1.4 mmol) in a
mixture of benzene–DMF (3:1, 12 mL) was added dibutyl-
stannane oxide (430 mg, 1.73 mmol) and the mixture was
stirred at reflux with a Dean–Stark for 1.5 h. The mixture
was cooled down and p-toluenesulfonyle chloride (320 mg,
1.68 mmol) was added. The mixture was stirred at room
temperature for 1 h. Satd. aq. NH4Cl was added and the
aqueous phase was extracted with ether–hexanes (1:1). The
Ketone 5
To a stirred solution of alcohol 26 (312 mg, 1.03 mmol) in
dichloromethane (50 mL) were added molecular sieve 4 Å
(515 mg), 4-methylmorpholine-N-oxide (241 mg, 2.06 mmol),
and tetrapropylammonium perruthenate (35 mg, 0.10 mmol).
The resulting mixture was stirred at room temperature for
© 2006 NRC Canada

44
Can. J. Chem. Vol. 84, 2006
2 h and filtered on a silica gel pad. The solvent was evapo-
rated and the residue was purified by flash chromatography
(30% ethyl acetate, 70% hexanes) to give ketone 5 as an
amorphous white solid (269 mg, 87%). IR (CHCl3, cm–1) ν:
2944, 2869, 1741, 1611, 1502, 1464, 1274, 1232, 1093,
1043, 936. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.19 (1H, d,
J = 8.6 Hz, Ph), 6.74 (1H, dd, J = 8.6, 2.8 Hz, Ph), 6.67
(1H, d, J = 2.8 Hz, Ph), 3.79 (3H, s, ArOCH3), 2.93 (2H, dd,
J = 9.0, 3.9 Hz, PhCH2CH2), 2.59–2.48 (3H, m, PhCH,
RC(O)CH2), 2.42–2.13 (4H, m), 1.92 (1H, qd, J = 11.9,
2.1 Hz), 1.65–1.41 (4H, m), 1.13 (3H, d, J = 1.5 Hz, CH3).
13C NMR (75 MHz, CDCl3, ppm) δ: 219.62, 157.80, 137.56,
130.58, 126.78, 113.82, 112.03, 107.01, 104.64, 55.21,
52.94, 52.67, 42.19, 41.90, 40.27, 33.30, 32.42, 29.90,
25.57, 25.21, 21.97, 12.72. MS (m/e): 302 ([M]+). HR-MS
calcd. for C19H23O2F: 302.1682 ([M]+); found: 302.1689
0.0009.
1044, 885. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.24 (1H, d,
J = 8.7 Hz, Ph), 6.75–6.70 (2H, m, Ph, CH=CRCO2Me),
6.65 (1H, d, J = 2.7 Hz, Ph), 3.78 (3H, s, ArOCH3), 3.76
(3H, s, CO2CH3), 2.93–2.88 (2H, m, PhCH2CH2), 2.84–2.59
(2H, m), 2.46–2.32 (2H, m), 2.26–2.05 (2H, m), 2.00–1.86
(1H, m), 1.55–1.22 (3H, m), 1.35 (3H, d, J = 3.2 Hz, CH3).
13C NMR (75 MHz, CDCl3, ppm) δ: 164.98, 157.64, 143.61,
137.89, 137.69, 130.70, 127.27, 113.71, 112.01, 108.74,
106.32, 55.21, 51.25, 42.52, 42.22, 40.58, 38.13, 37.70,
37.34, 30.03, 25.77, 23.07, 14.85. MS (m/e): 344 ([M]+).
HR-MS calcd. for C21H25O3F: 344.1788 ([M]+); found:
344.1779 0.0010.
Ester 30
To a stirred solution of α,β-unsaturated ester 29 (15 mg,
0.044 mmol) in ethanol (2 mL) was added 5% palladium(0)
on activated carbon (9 mg, 0.0044 mmol) and hydrogen was
bubbled through the solution for 10 min. The mixture was
stirred for 1 h under a hydrogen atmosphere and filtered on a
silica gel pad. The solvent was evaporated to give ester 30 as
a colorless oil (15 mg, 100%). IR (CHCl3, cm–1) ν: 2945,
2862, 1732, 1610, 1502, 1466, 1260, 1199, 1166, 1044, 961.
1H NMR (300 MHz, CDCl3, ppm) δ: 7.18 (1H, d, J =
8.6 Hz, Ph), 6.72 (1H, dd, J = 8.6, 2.8 Hz, Ph), 6.64 (1H, d,
J = 2.8 Hz, Ph), 3.78 (3H, s, ArOCH3), 3.71 (3H, s,
CO2CH3), 3.05 (1H, t, J = 9.2 Hz, CHCO2Me), 2.91–2.86
(2H, m, PhCH2CH2), 2.50–2.42 (1H, m, PhCH), 2.29–1.78
(7H, m), 1.58–1.30 (4H, m), 1.21 (3H, d, J = 1.1 Hz, CH3).
13C NMR (75 MHz, CDCl3, ppm) δ: 174.38, 157.62, 137.69,
131.23, 126.80, 113.69, 111.90, 110.58, 55.20, 53.16, 51.47,
42.10, 41.81, 40.05, 31.15, 30.06, 29.69, 29.29, 28.96,
26.05, 23.01, 22.22, 17.58. MS (m/e): 346 ([M])+. HR-MS
calcd. for C21H27O3F: 346.1944 ([M]+); found: 346.1940
0.0010.
Triflic enol ether 28
To a stirred solution of ketone 5 (22 mg, 0.073 mmol) in
tetrahydrofuran (2 mL) at 0 °C was added 0.5 mol/L potas-
sium bis(trimethylsilyl)amide in toluene (740 µL, 0.37 mmol)
and the mixture was stirred at 0 °C for 15 min then at room
temperature for 45 min. N-(5-Chloro-2-pyridyl)triflimide
(93 mg, 0.22 mmol) in tetrahydrofuran (1 mL) was added
and the resulting mixture was stirred at room temperature for
30 min. Satd. aq. NH4Cl was added and the aqueous phase
was extracted with ethyl acetate. The combined organic
phases were dried, filtered, and evaporated. The residue was
purified by flash chromatography (5% ethyl acetate, 95%
hexanes) to give triflic enol ether 28 as a yellow oil (27 mg,
84%). IR (CHCl3, cm–1) ν: 2944, 2868, 1650, 1611, 1502,
1
1423, 1218, 1141, 1085, 1044, 884. H NMR (300 MHz,
CDCl3, ppm) δ: 7.22 (1H, d, J = 8.6 Hz, Ph), 6.74 (1H, dd,
J = 8.6, 2.7 Hz, Ph), 6.65 (1H, d, J = 2.7 Hz, Ph), 5.59 (1H,
t, J = 2.7 Hz, CH=C(OTf)R), 3.79 (3H, s, ArOCH3), 2.93–
2.86 (2H, m, PhCH2CH2), 2.71 (1H, td, J = 17.1, 1.8 Hz,
PhCH), 2.61–2.40 (2H, m), 2.30–2.05 (3H, m), 1.87 (1H, qd,
J = 12.0, 2.1 Hz), 1.57–1.26 (3H, m), 1.18 (3H, d, J =
2.7 Hz, CH3). 13C NMR (75 MHz, CDCl3, ppm) δ: 157.77,
155.04, 137.57, 130.16, 127.23, 120.65, 116.40, 113.76,
112.12, 108.48, 105.33, 102.86, 55.21, 49.48, 49.22, 43.00,
42.70, 40.25, 37.15, 34.05, 33.68, 29.57, 25.54, 22.27,
13.31. MS (m/e): 434 ([M]+). HR-MS calcd. for
C20H22O4F4S: 434.1175 ([M]+); found: 434.1181 0.0013.
␣,␤-Unsaturated nitrile 32
To a stirred solution of triflic enol ether 28 (41 mg,
0.094 mmol) in benzene (10 mL) were added lithium cya-
nide (18 mg, 0.56 mmol), tetrakis(triphenylphosphine) palla-
dium(0) (11 mg, 0.0094 mmol), and 12-C-4 ether (2 µL,
0.0094 mmol). The resulting mixture was stirred at room
temperature overnight and a catalytic amount of palladium
(11 mg, 0.0094 mmol) was added. The mixture was stirred
for an additional 24 h and water was added. The aqueous
phase was extracted with ethyl acetate. The combined or-
ganic phases were dried, filtered, and evaporated. The resi-
due was purified by flash chromatography (10% ethyl
acetate, 90% hexanes) to give α,β-unsaturated nitrile 32 as
an amorphous solid (23 mg, 79%). IR (CHCl3, cm–1) ν:
3054, 2932, 2568, 2219, 1610, 1502, 1422, 1265, 1041, 883.
1H NMR (300 MHz, CDCl3, ppm) δ: 7.22 (1H, d, J =
8.6 Hz, Ph), 6.74 (1H, dd, J = 8.6, 2.7 Hz, Ph), 6.65 (1H, d,
J = 2.7 Hz, Ph), 6.59 (1H, t, J = 2.6 Hz, CH=C(CN)R), 3.79
(3H, s, ArOCH3), 2.93–2.88 (2H, m, PhCH2CH2), 2.84–2.68
(1H, m), 2.47–2.38 (1H, m), 2.31–2.10 (3H, m), 1.90 (1H,
qd, J = 11.9, 2.1 Hz), 1.57–1.22 (4H, m), 1.31 (3H, d, J =
2.6 Hz, CH3). 13C NMR (75 MHz, CDCl3, ppm) δ: 157.79,
142.09, 137.52, 130.03, 127.22, 125.12, 115.38, 113.78,
112.12, 107.07, 104.62, 55.22, 52.57, 52.31, 42.78, 42.48,
40.35, 38.99, 38.63, 37.93, 29.94, 25.69, 23.10, 14.96. MS
␣,␤-Unsaturated ester 29
To a stirred solution of triflic enol ether 28 (20 mg,
0.046 mmol) in dimethylformamide (3 mL) were added
triethylamine (32 µL, 0.23 mmol), methanol (233 µL,
4.60 mmol), triphenylphophine (0.7 mg, 0.0028 mmol), and
palladium(II) acetate (0.3 mg, 0.0014 mmol). CO2 was bub-
bled through the solution and the resulting mixture was
stirred at 70 °C under a pressure of 150 psi (1 psi =
6.894 757 kPa) overnight. Satd. aq. NH4Cl was added and
the aqueous phase was extracted with ether. The combined
organic phases were dried, filtered, and evaporated. The resi-
due was purified by flash chromatography (10% ethyl ace-
tate, 90% hexanes) to give the α,β-unsaturated ester 29 as an
amorphous white solid (13 mg, 81%). IR (CHCl3, cm–1) ν:
2944, 2565, 1717, 1612, 1501, 1436, 1336, 1243, 1191,
© 2006 NRC Canada

Beaubien and Deslongchamps
45
(m/e): 311 ([M]+). HR-MS calcd. for C20H22OFN: 311.1585
(1H, t, J = 7.6 Hz, RR′CHOH), 2.52–1.46 (17H, m), 1.26–
1.10 (3H, m), 1.05 (3H, s, CH3). 13C NMR (75 MHz,
CDCl3, ppm) δ: 199.85, 165.58, 124.76, 108.73, 106.36,
80.00, 47.23, 47.00, 45.78, 43.74, 43.45, 42.73, 36.36,
35.04, 27.91, 27.84, 26.34, 25.26, 25.02, 15.93. MS (m/e):
292 ([M]+). HR-MS calcd. for C18H25O2F: 292.1838 ([M]+);
found: 292.1832 0.0008.
([M]+); found: 311.1678 0.0009.
Nitriles 33a and 33b
To a stirred solution of α,β-unsaturated nitrile 32 (20 mg,
0.064 mmol) in ethanol (2 mL) was added 5% palladium(0)
on activated carbon (28 mg, 0.013 mmol) and hydrogen was
bubbled through the solution for 10 min. The mixture was
stirred for 2 h under a hydrogen atmosphere and filtered on a
silica gel pad. The solvent was evaporated and the residue
was purified by flash chromatography (20% ethyl acetate,
80% hexanes) to give nitrile α-33a as a white solid (7 mg,
35%) and nitrile β-33b as a white solid (12 mg, 60%).
Nitrile β-33b: IR (CHCl3, cm–1) ν: 2932, 2868, 2238, 1610,
Ketones 35 and 36
To a stirred solution of α,β-unsaturated ketone 34
(126 mg, 0.43 mmol) in ethyl acetate (10 mL) was added
5% palladium(0) on activated carbon (91 mg, 0.043 mmol)
and hydrogen was bubbled for 10 min. The mixture was
stirred for 1 h under a hydrogen atmosphere and filtered on a
silica gel pad. The solvent was evaporated and the residue
was purified by flash chromatography (50% ethyl acetate,
50% hexanes) to give ketone 36 (cis) as a colorless oil
(76 mg, 60%) and ketone 35 (trans) as a colorless oil
(33 mg, 27%). Ketone 36 (cis): IR (CHCl3, cm–1) ν: 3444,
1
1501, 1466, 1236, 1161, 1038. H NMR (300 MHz, CDCl3,
ppm) δ: 7.16 (1H, d, J = 8.6 Hz, Ph), 6.74 (1H, dd, J = 8.6,
2.8 Hz, Ph), 6.65 (1H, d, J = 2.8 Hz, Ph), 3.78 (3H, s,
ArOCH3), 2.92–2.87 (2H, m, PhCH2CH2), 2.74 (1H, t, J =
7.7 Hz, R(CN)CHCH2), 2.50–2.42 (1H, m, PhCH), 2.35–
2.15 (5H, m), 2.10–2.03 (1H, m), 1.86 (1H, qd, J = 11.8,
2.2 Hz), 1.71–1.64 (1H, m), 1.57–1.36 (3H, m), 1.33 (3H, d,
J = 1.1 Hz, CH3). 13C NMR (75 MHz, CDCl3, ppm) δ:
157.76, 137.61, 130.64, 126.70, 121.71, 113.73, 112.05,
109.19, 106.78, 55.21, 48.52, 48.26, 42.03, 41.75, 39.93,
36.85, 30.32, 30.02, 26.64, 25.72, 23.17, 16.38. MS (m/e):
313 ([M]+). HR-MS calcd. for C20H24OFN: 313.1842
1
3019, 2932, 2882, 1706, 1466, 1216, 1077, 958. H NMR
(300 MHz, CDCl3, ppm) δ: 4.22 (1H, t, J = 7.8 Hz,
RR′CHOH), 2.52 (1H, t, J = 13.9 Hz, RC(O)CH2CH), 2.31–
1.44 (19H, m), 1.39–1.10 (3H, m), 1.07 (3H, s, CH3). 13C
NMR (75 MHz, CDCl3, ppm) δ: 212.42, 108.91, 106.54,
80.33, 44.79, 44.51, 42.75, 40.31, 37.70, 36.43, 34.95,
30.10, 28.25, 28.00, 27.89, 27.80, 27.30, 24.42, 19.32,
16.12. MS (m/e): 294 ([M]+). HR-MS calcd. for C18H27O2F:
([M]+); found: 313.1849
0.0009. Nitrile α-33a: IR
294.1995 ([M]+); found: 294.1989
0.0009. Ketone 35
(CHCl3, cm–1) ν: 2938, 2239, 1610, 1502, 1467, 1320, 1236,
1043, 957. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.20 (1H, d,
J = 8.6 Hz, Ph), 6.74 (1H, dd, J = 8.6, 2.8 Hz, Ph), 6.65
(1H, d, J = 2.8 Hz, Ph), 3.78 (3H, s, ArOCH3), 3.04 (1H, t,
J = 9.2 Hz, R(CN)CHCH2), 2.91–2.86 (2H, m, PhCH2CH2),
2.47 (1H, td, J= 11.2, 3.5 Hz, PhCH), 2.36–1.77 (8H, m),
1.53–1.33 (3H, m), 1.18 (3H, d, J = 1.0 Hz, CH3). 13C NMR
(75 MHz, CDCl3, ppm) δ: 157.77, 137.47, 130.64, 126.78,
120.51, 113.78, 111.99, 55.21, 42.02, 41.73, 40.10, 39.13,
31.64, 29.90, 29.68, 29.35, 25.85, 24.31, 22.88, 16.81. MS
(m/e): 313 ([M]+). HR-MS calcd. for C20H24OFN: 313.1842
([M]+); found: 313.1849 0.0009.
(trans): 1H NMR (300 MHz, CDCl3, ppm) δ: 4.23 (1H, t, J =
8.2 Hz, RR′CHOH), 2.44–0.89 (23H, m), 1.07 (3H, d, J =
0.8 Hz, CH3). MS (m/e): 294 ([M]+). HR-MS calcd. for
C18H27O2F: 294.1995 ([M]+); found: 294.1989 0.0009.
Diketone 37
To a stirred solution of alcohol 36 (76 mg, 0.26 mmol) in
dichloromethane (5 mL) were added molecular sieve 4 Å
(130 mg), 4-methylmorpholine-N-oxide (61 mg, 0.52 mmol),
and tetrapropylammonium perruthenate (9 mg, 0.026 mmol).
The resulting mixture was stirred at room temperature for
1 h and filtered on a silica gel pad. The solvent was evapo-
rated to give diketone 37 as a colorless oil (76 mg, 99%). IR
(CHCl3, cm–1) ν: 3020, 2930, 2879, 1740, 1708, 1461, 1215,
␣,␤-Unsaturated ketone 34
To a stirred solution of tetracycle 26 (227 mg, 0.75 mmol)
in tetrahydrofuran (10 mL) at –78 °C was added 95% etha-
nol (1 mL), and gaseous ammonia was condensed (20 mL).
Metallic lithium was added by portion until the solution was
blue and the resulting mixture was stirred at –78 °C for 2 h.
Solid NH4Cl was added slowly until the blue color disap-
peared and ammoniac was evaporated at room temperature.
Water was added and the aqueous phase was extracted with
ether. The combined organic phases were dried, filtered, and
evaporated. The residue was dissolved in tetrahydrofuran
(10 mL) and 1 mol/L HCl (1 mL) was added. The mixture
was stirred at room temperature overnight. Satd. aq.
NaHCO3 was added and the aqueous phase was extracted
with ether. The combined organic phases were dried, fil-
tered, and evaporated. The residue was purified by flash
chromatography (60% ethyl acetate, 40% hexanes) to give
α,β-unsaturated ketone 34 as a colorless oil (168 mg, 77%).
IR (CHCl3, cm–1) ν: 3611, 3432, 3016, 2949, 2874, 1662,
1619, 1454, 1364, 1220, 1067, 1007, 952. 1H NMR
(300 MHz, CDCl3, ppm) ␦: 5.81 (1H, s, CH=CRRЈ), 4.18
1
929, 746. H NMR (300 MHz, CDCl3, ppm) δ: 2.59–2.37
(2H, m), 2.32–2.08 (6H, m), 1.88–1.05 (14H, m), 1.12 (3H,
d, J = 1.5 Hz, CH3). 13C NMR (75 MHz, CDCl3, ppm) δ:
219.46, 211.74, 106.80, 104.42, 44.52, 44.24, 42.63, 40.28,
37.45, 36.32, 35.06, 33.07, 31.91, 30.11, 27.20, 26.09,
25.75, 24.22, 19.10, 12.62. MS (m/e): 292 ([M]+). HR-MS
calcd. for C18H25O2F: 292.1838 ([M]+); found: 292.1844
0.0008.
Alcohol 38
To a stirred solution of diketone 37 (71 mg, 0.24 mmol) in
tetrahydrofuran (10 mL) at –78 °C was added a solution of
1
mol/L L-Selectride in tetrahydrofuran (360 µL,
0.36 mmol). The mixture was stirred at –78 °C for 1.5 h. A
2 mol/L NaOH solution and a 30% hydrogen peroxide solu-
tion were added and the aqueous phase was extracted with
ethyl acetate. The combined organic phases were dried, fil-
tered, and evaporated. The residue was purified by flash
chromatography (70% ethyl acetate, 30% hexanes) to give
© 2006 NRC Canada

46
Can. J. Chem. Vol. 84, 2006
alcohol 38 as an amorphous white solid (72 mg, 100%). IR
(CHCl3, cm–1) ν: 3611, 3451, 2933, 2878, 1739, 1447, 1266,
(1H, m), 1.86–1.10 (16H, m), 1.08 (3H, d, J = 2.8 Hz, CH3),
1.05–0.83 (2H, m). 13C NMR (75 MHz, CDCl3, ppm) δ:
132.48, 109.80, 105.63, 103.18, 66.85, 45.97, 45.68, 40.96,
40.63, 40.27, 37.36, 34.93, 33.17, 30.90, 29.28, 27.03,
24.26, 21.13, 20.75, 17.11. MS (m/e): 404 ([M]+). HR-MS
calcd. for C18H26OFI: 404.1012 ([M]+); found: 404.1008
0.0012.
1
1061, 1001, 922. H NMR (300 MHz, CDCl3, ppm) δ: 4.14
(1H, t, J = 2.7 Hz, RR′CHOH), 2.51–2.40 (2H, m), 2.29–
2.05 (3H, m), 1.86–1.15 (18H, m), 1.08 (3H, d, J = 1.3 Hz,
CH3). 13C NMR (75 MHz, CDCl3, ppm) δ: 220.09, 107.25,
104.88, 66.75, 44.74, 44.47, 41.27, 34.51, 33.18, 32.13,
30.81, 29.26, 26.95, 26.07, 25.74, 24.30, 20.97, 19.60,
12.62. MS (m/e): 294 ([M]+). HR-MS calcd. for C18H27O2F:
294.1995 ([M]+); found: 294.2000 0.0009.
Silyl ether 43
To a stirred solution of alcohol 42 (148 mg, 0.37 mmol) in
dichloromethane (10 mL) were added triethylamine (1.3 mL,
1.85 mmol) and tert-butyldimethylsilane trifluoromethane-
sulfonate (94 µL, 0.41 mmol). The mixture was stirred at
room temperature for 1 h. Satd. aq. NH4Cl was added and
the aqueous phase was extracted with dichloromethane. The
combined organic phases were dried, filtered, and evapo-
rated. The residue was purified by flash chromatography
(10% ethyl acetate, 90% hexanes) to give silyl ether 43 as an
amorphous white solid (190 mg, 100%). IR (CHCl3, cm–1) ν:
Silyl ether 40
To a stirred solution of alcohol 38 (36 mg, 0.12 mmol) in
dichloromethane (3 mL) were added triethylamine (84 µL,
0.60 mmol) and tert-butyldimethylsilane trifluoromethane-
sulfonate (41 µL, 0.18 mmol). The mixture was stirred at
room temperature for 1 h. Satd. aq. NH4Cl was added and
the aqueous phase was extracted with dichloromethane. The
combined organic phases were dried, filtered, and evapo-
rated. The residue was dissolved in tetrahydrofuran (2 mL)
and tetrapropylammonium fluoride (1 mol/L) in tetra-
hydrofuran (60 µL, 0.060 mmol) was added. The mixture
was stirred at room temperature for 15 min. Satd. aq. NH4Cl
was added and the aqueous phase was extracted with ethyl
acetate. The combined organic phases were dried, filtered,
and evaporated. The residue was purified by flash chroma-
tography (10% ethyl acetate, 90% hexanes) to give silyl
ether 40 as a colorless oil (46 mg, 92%). IR (CHCl3, cm–1)
ν: 3020, 2931, 2882, 1739, 1471, 1446, 1252, 1212, 1050,
1
3019, 2930, 2856, 1509, 1424, 1364, 1217, 1048. H NMR
(300 MHz, CDCl3, ppm) δ: 6.07 (1H, t, J = 2.4 Hz,
CH=CIR), 4.05 (1H, t, J = 2.4 Hz, RR′CHOTBDMS), 2.62–
2.43 (2H, m, CH2CH=CIR), 2.22–2.13 (1H, m), 1.89–0.91
(17H, m), 1.08 (3H, d, J = 2.8 Hz, CH3), 0.89 (9H, s,
SiC(CH3)3), 0.02 (6H, s, Si(CH3)2). 13C NMR (75 MHz,
CDCl3, ppm) δ: 132.48, 109.92, 105.70, 103.24, 67.17,
54.23, 53.98, 46.08, 45.80, 41.13, 40.65, 40.29, 37.44,
35.11, 34.11, 31.20, 29.28, 27.80, 25.83, 24.35, 21.17,
20.90, 17.14, –4.87. MS (m/e): 461 ([M – C4H9]+). HR-MS
calcd. for C20H31OFISi: 461.1173 ([M – C4H9]+); found:
461.1178 0.0014.
1
930. H NMR (300 MHz, CDCl3, ppm) δ: 4.06 (1H, t, J =
2.6 Hz, RR′CHOTBDMS), 2.47–2.34 (2H, m), 2.29–2.05
(3H, m), 1.89–1.13 (17H, m), 1.09 (3H, d, J = 1.4 Hz, CH3),
0.89 (9H, s, SiC(CH3)3), 0.02 (6H, s, Si(CH3)2). 13C NMR
(75 MHz, CDCl3, ppm) δ: 220.18, 107.37, 105.00, 67.10,
44.83, 44.57, 41.43, 34.70, 34.58, 34.14, 33.15, 32.21,
32.13, 31.10, 29.28, 27.70, 26.07, 25.84, 25.81, 25.73, 24.38,
21.01, 19.73, 18.06, 12.65, 12.55, –4.89. MS (m/e): 208
([M]+), 351 ([M – C4H9]+). HR-MS calcd. for C24H41O2FSi:
408.2860 ([M]+); found: 408.2863 0.0012.
␣,␤-Unsaturated nitrile 44
To a stirred solution of vinylic iodide 43 (47 mg,
0.091 mmol) in benzene (3 mL) were added lithium cyanide
(18 mg, 0.55 mmol), tetrakis(triphenylphosphine) palla-
dium(0) (11 mg, 0.0091 mmol), and 12-C-4 ether (2 µL,
0.0091 mmol). The resulting mixture was stirred at reflux
for 30 min and water was added. The aqueous phase was ex-
tracted with dichloromethane. The combined organic phases
were dried, filtered, and evaporated. The residue was puri-
fied by flash chromatography (7% ethyl acetate, 93% hex-
anes) to give α,β-unsaturated nitrile 44 as an amorphous
white solid (17 mg, 45%). IR (CHCl3, cm–1) ν: 3019, 2930,
Vinylic iodide 42
To a stirred solution of ketone 38 (101 mg, 0.34 mmol) in
ethanol (7 mL) were added triethylamine (952 µL,
6.80 mmol) and hydrated hydrazine (165 µL, 3.40 mmol).
The mixture was stirred at reflux for 5 days and water was
added. The aqueous phases were extracted with dichloro-
methane and the combined organic phases were dried,
filtered, and evaporated. The residue was dissolved in tetra-
hydrofuran (5 mL) and triethylamine (1 mL) was added. Io-
dide was added until a brown color appeared and the
mixture was stirred for 5 min. Water was added and the
aqueous phase was extracted with dichloromethane. The
combined organic phases were washed with saturated aque-
ous sodium thiosulfate and the organic phase was dried, fil-
tered, and evaporated. The residue was purified by flash
chromatography (40% ethyl acetate, 60% hexanes) to give
vinylic iodide 42 as an amorphous white solid (125 mg,
91%). IR (CHCl3, cm–1) ν: 3386, 2931, 2873, 1459, 1447,
1380, 1263, 1000. 1H NMR (300 MHz, CDCl3, ppm) δ: 6.06
(1H, t, J = 2.5 Hz, CH=CIR), 4.14 (1H, t, J = 2.8 Hz,
RRЈCHOH), 2.62–2.40 (2H, m, CH2CH=CIR), 2.19–2.13
1
2546, 2127, 1610, 1504, 1368, 1215, 1168, 1086, 1049. H
NMR (300 MHz, CDCl3, ppm) δ: 6.54 (1H, t, J = 2.6 Hz,
CH=C(CN)R), 4.05 (1H, massif, RR′CHOTBDMS), 2.83–
2.54 (2H, m, CH2CH=C(CN)R), 2.24–2.20 (1H, m), 2.03–
1.96 (1H, m), 1.90–0.90 (16H, m), 1.26 (3H, d, J = 2.5 Hz,
CH3), 0.88 (9H, s, SiC(CH3)3), 0.02 (6H, s, Si(CH3)2). 13C
NMR (75 MHz, CDCl3, ppm) δ: 141.97, 125.37, 115.51,
107.41, 104.95, 67.06, 52.47, 52.21, 45.28, 45.00, 41.02,
39.55, 39.18, 37.4, 34.81, 34.07, 31.10, 29.18, 27.76, 25.80,
24.33, 21.16, 18.06, 14.81, –4.89. MS (m/e): 402 ([M –
CH3]+), 360 ([M – C4H9]+). HR-MS calcd. for C21H31OFNSi:
360.2159 ([M – C4H9]+); found: 360.2166 0.0014.
Nitriles 45a and 45b
To a stirred solution of α,β-unsaturated nitrile 44 (15 mg,
0.036 mmol) in ethyl acetate (2 mL) was added a catalytic
amount of 10% palladium(0) on activated carbon and hydro-
© 2006 NRC Canada

Beaubien and Deslongchamps
47
gen was bubbled through the solution for 15 min. The mix-
ture was stirred for 2 h under a hydrogen atmosphere and
filtered on a silica gel pad. The solvent was evaporated and
the residue was purified by flash chromatography (10%
ethyl acetate, 90% hexanes) to give nitrile β-45a as an amor-
phous white solid (8 mg, 53%) and nitrile α-45b as an amor-
phous white solid (7 mg, 47%). Nitrile α-45a: IR
(CHCl3, cm–1) ν: 2930, 2856, 2363, 1460, 1444, 1252, 1216,
(m/e): 287 ([M – H2O]+). HR-MS calcd. for C19H26FN:
287.2049 ([M – H2O]+); found: 287.2045 0.0008.
p-Nitrobenzoate 47
To a stirred solution of alcohol 46b (1 mg, 0.0033 mmol)
in dichloromethane (250 µL) were added pyridine (250 µL),
p-nitrobenzoyle chloride (6 mg, 0.033 mmol), and 4-
dimethylaminopyridine (catalytic amount). The resulting
mixture was stirred at room temperature for 3 h. HCl
(1 mol/L) was added and the aqueous phase was extracted
with dichloromethane. The combined organic phases were
dried, filtered, and evaporated. The residue was purified by
flash chromatography (30% ethyl acetate, 70% hexanes) to
give p-nitrobenzoate 47 as a white solid (1 mg); mp 210 to
211 °C. IR (CHCl3, cm–1) ν: 2934, 2856, 2244, 1719, 1280,
1
1047. H NMR (300 MHz, CDCl3, ppm) δ: 4.05 (1H, t, J =
2.6 Hz, RR′CHOTBDMS), 2.98 (1H, t, J = 9.0 Hz, RR′CHCN),
2.27–0.95 (22H, m), 1.15 (3H, s, CH3), 0.88 (9H, s,
SiC(CH3)3), 0.02 (6H, s, Si(CH3)2). 13C NMR (75 MHz,
CDCl3, ppm) δ: 120.70, 109.17, 106.76, 67.1, 48.42, 48.18,
44.74, 44.48, 41.38, 39.18, 34.52, 34.14, 31.27, 31.18, 30.25,
29.92, 29.26, 27.67, 25.81, 24.82, 24.14, 20.96, 18.07, 16.66,
–4.90. MS (m/e): 404 ([M – CH3]+), 362 ([M – C4H9]+). HR-
MS calcd. for C24H39OFNSi: 404.2785 ([M – CH3]+); found:
1
1118. H NMR (300 MHz, CDCl3, ppm) δ: 8.30 (2H, d, J =
9.0 Hz, Ph), 8.21 (2H, d, J = 9.0 Hz, Ph), 5.40 (1H, t, J =
2.4 Hz, RR′CHOC(O)Ar), 2.68 (1H, t, J = 6.6 Hz,
RR′CHCN), 2.31–1.07 (22H, m), 1.32 (3H, s, CH3). MS
404.2773
0.0012. Nitrile β-45b: IR (CHCl3, cm–1) ν:
1
3019, 2930, 2856, 2240, 1527, 1477, 1426, 1215, 1048. H
NMR (300 MHz, CDCl3, ppm) δ: 4.05 (1H, t, J = 2.5 Hz,
RR′CHOTBDMS), 2.65 (1H, t, J = 6.0 Hz, RR′CHCN),
2.28–1.96 (5H, m), 1.87–1.03 (17H, m), 1.30 (3H, s, CH3),
0.88 (9H, s, SiC(CH3)3), 0.02 (6H, s, Si(CH3)2). 13C NMR
(75 MHz, CDCl3, ppm) δ: 121.92, 109.58, 107.18, 67.10,
48.46, 48.21, 44.71, 44.44, 41.46, 40.04, 36.65, 34.25, 34.12,
31.23, 30.85, 30.51, 29.24, 27.69, 25.80, 25.59, 21.17,
20.97, 18.06, 16.20, –4.88. MS (m/e): 404 ([M – CH3]+),
362 ([M – C4H9]+). HR-MS calcd. for C24H39OFNSi:
404.2785 ([M – CH3]+); found: 404.2773 0.0012.
(m/e): 472 ([MNH4]+). HR-MS calcd. for C26H35O4FN3
:
472.2611 ([MNH4]+); found: 472.2623 0.0014.
␣,␤-Unsaturated ester 4
To a stirred solution of nitrile 46a (4 mg, 0.013 mmol) in
toluene (1 mL) at –60 °C was added a 1.5 mol/L solution of
DIBALH in toluene (26 µL, 0.039 mmol) and the mixture
was stirred at –60 °C for 1 h. Sodium sulfate decahydrate
was added and the mixture was stirred at room temperature
for 1 h. The residue was filtered and the solvent was evapo-
rated to give the corresponding imine. This imine was
passed rapidly through a short silica gel pad to give alde-
hyde 50a (4 mg) as a crude material. To a stirred suspension
of 60% NaH in oil (5 mg, 0.13 mmol) in tetrahydrofuran
(1 mL) was added trimethyl phosphonoacetate (21 µL,
0.13 mmol). The mixture was stirred at room temperature
for 15 min and crude aldehyde 50a (4 mg, 0.013 mmol) in
tetrahydrofuran (1 mL) was added. The resulting mixture
was stirred at room temperature for 30 min. Satd. aq. NH4Cl
was added and the aqueous phase was extracted with di-
chloromethane. The combined organic phases were dried,
filtered, and evaporated. The residue was purified by flash
chromatography (40% ethyl acetate, 60% hexanes) to
give α,β-unsaturated ester 4 as a colorless oil (3 mg, 60%
for two steps). IR (CHCl3, cm–1) ν: 3501, 2932, 2875, 1718,
1654, 1540, 1558, 1437, 1281, 1216, 1002. 1H NMR
(300 MHz, CDCl3, ppm) δ: 6.91 (1H, dd, J = 15.6, 8.7 Hz,
CH=CHCO2Me), 5.83 (1H, J = 15.6 Hz, CH=CHCO2Me),
4.14 (1H, t, J = 2.6 Hz, RR′CHOH), 3.73 (3H, s, CO2CH3),
2.81 (1H, q, J = 8.7 Hz, RR′CHCH=CHCO2Me), 2.22–1.03
(23H, m), 1.00 (3H, d, J = 1.1 Hz, CH3). 13C NMR
(75 MHz, CDCl3, ppm) δ: 149.70, 149.57, 121.97, 66.93,
51.45, 51.33, 49.00, 45.09, 44.81, 41.27, 34.39, 34.27,
33.26, 31.00, 30.41, 30.06, 29.96, 29.37, 26.97, 25.04,
24.69, 20.98, 20.74, 16.81. MS (m/e) (source temperature:
100 °C): 364 ([M]+), 344 ([M – HF]+). HR-MS (source tem-
perature: 100 °C) calcd. for C22H33O3F: 364.2414 ([M]+);
found: 364.2403 0.0011.
Alcohols 46a
To a stirred solution of nitrile 45a (7 mg, 0.017 mmol) in
methanol was added a catalytic amount of PTSA and the
mixture was stirred at room temperature for 3 h. Satd. aq.
NaHCO3 was added and the aqueous phase was extracted
with dichloromethane. The combined organic phases were
dried, filtered, and evaporated. The residue was purified by
flash chromatography (50% ethyl acetate, 50% hexanes) to
give alcohol 46a as an amorphous white solid (5 mg, 100%).
1H NMR (300 MHz, CDCl3, ppm) δ: 4.15 (1H, t, J = 2.8 Hz,
RR′CHOH), 2.98 (1H, t, J = 9.5 Hz, RR′CHCN), 2.23–2.16
(2H, m), 2.04–1.06 (21H, m), 1.15 (3H, s, CH3). 13C NMR
(75 MHz, CDCl3, ppm) δ: 120.68, 109.07, 106.67, 66.83,
48.46, 48.22, 44.70, 44.43, 41.27, 39.21, 34.38, 33.24,
31.33, 30.93, 30.29, 29.96, 29.29, 27.00, 24.80, 24.16,
20.97, 16.68. MS (m/e): 287 ([M – H2O]+). HR-MS calcd.
for C19H26FN: 287.2049 ([M – H2O]+); found: 287.2045
0.0008.
Alcohol 46b
The procedure used for the synthesis of alcohol 46a was
used with alcohol 46b to give alcohol 46b as an amorphous
white solid (5 mg, 100%). IR (CHCl3, cm–1) ν: 3423, 3019,
1
2933, 2360, 1523, 1423, 1216, 928. H NMR (300 MHz,
CDCl3, ppm) δ: 4.14 (1H, t, J = 2.8 Hz, RR′CHOH), 2.66
(1H, t, J = 7.7 Hz, RR′CHCN), 2.28–1.96 (6H, m), 1.82–
1.00 (17H, m), 1.30 (3H, s, CH3). 13C NMR (75 MHz,
CDCl3, ppm) δ: 121.86, 109.46, 107.42, 66.79, 48.45, 48.21,
44.62, 44.35, 41.30, 40.02, 36.56, 34.19, 33.22, 30.94,
30.51, 29.69, 29.23, 26.93, 25.51, 21.04, 20.94, 16.18. MS
␣,␤-Unsaturated ester 3
The procedure used for the synthesis of α,β-unsaturated
ester 4 was used for ␣,␤-unsaturated ester 3 to give an
© 2006 NRC Canada

48
Can. J. Chem. Vol. 84, 2006
12. A. Thenappan and D.J. Burton. J. Org. Chem. 55, 4639 (1990).
13. R.M. Magid, O. Frucfey, W.L. Johnson, and T.G. Allen. J.
Org. Chem. 44, 359 (1979).
14. N. Stuart, H. Weiler, and L. Weiler. J. Am. Chem. Soc. 96,
1082 (1974).
unseparable mixture of α,β-unsaturated ester 3 and α,β-un-
saturated ester 4 (9:1) as an amorphous white solid (3 mg,
60%). IR (CHCl3, cm–1) ν: 3501, 2931, 2865, 1718, 1654,
1
1541, 1458, 1437, 1269, 1221, 1000. H NMR (300 MHz,
CDCl3, ppm) δ: 7.01 (1H, ddd, J = 15.5, 10.7, 1.8 Hz,
CH=CHCO2Me), 5.65 (1H, J = 15.5 Hz, CH=CHCO2Me),
4.14 (1H, t, J = 2.7 Hz, RR′CHOH), 3.71 (3H, s, CO2CH3),
2.38 (1H, td, J = 8.5, 3.2 Hz, R′RCHCH=CHCO2Me), 2.17–
1.03 (23H, m), 0.90 (3H, s, CH3). 13C NMR (75 MHz,
CDCl3, ppm) δ: 153.55, 153.49, 119.75, 66.93, 53.93, 51.35,
45.09, 44.81, 41.43, 38.08, 37.98, 34.18, 33.27, 31.09,
30.75, 29.37, 26.97, 26.66, 25.42, 21.09, 21.01, 15.63. MS
(m/e) (source temperature: 100 °C): 364 ([M]+), 344 ([M –
HF]+). HR-MS (source temperature: 100 °C) calcd. for
C22H33O3F: 364.2414 ([M]+); found: 364.2403 0.0011.
15. J.A. Marshall, R.C. Andrews, and L. Lebioda. J. Org. Chem.
52, 2378 (1987).
16. D.H.R. Barton, D.J. Lester, and V.J. Leys. J. Chem. Soc.
Chem. Commun. 130 (1978).
17. L.A Paquette and H. Kang. J. Am. Chem. Soc. 133, 2610
(1991).
18. (a) S. Lamothe, A. Ndibwani, and P. Deslongchamps. Tetrahe-
dron Lett. 29, 1639 (1988); (b) S. Lamothe, A. Ndibwani, and
P. Deslongchamps. Tetrahedron Lett. 29, 1641 (1988).
19. X. Kong and T.B. Grindley. Can. J. Chem. 72, 2396 (1994).
20. (a) J.R. Kutney, K. Piotrowska, J. Somerville, S.-P. Hyang, and
S.J. Rettig. Can. J. Chem. 67, 580 (1989); (b) M. Adamczyk,
E.K. Dolence, and D.S. Watt. J. Org. Chem. 49, 1378 (1984);
(c) P. Drasar, V. Pouzar, I. Cerny, M. Havel, V.V. Egorova,
S.N. Ananchemko, I.V. Torgov, and F. Turesek. Steroids, 53,
107 (1989).
Acknowledgments
The authors thank Mr. Andreas Decken and Marc Drouin
for X-ray diffraction analysis and Tranzyme Pharma Inc. for
biological activity. Financial support from Shire BioChem
Inc. and the Natural Sciences and Engineering Research
Council of Canada (NSERC) are highly appreciated.
21. B. Maryanoff and A.B. Reitz. Chem. Rev. 89, 863 (1989).
22. P. Mosset and R. Grée. Synth. Commun. 749 (1985).
23. G. Tsuchihashi and K. Ogura. Bull. Chem. Soc. Jpn. 45, 2023
(1972).
24. W.P. Griffith and S.V. Ley. Aldrichimica Acta, 23, 13 (1990).
25. D.L. Comins and A. Dehghani. Tetrahedron Lett. 33, 6299
(1992).
26. (a) S. Cacchi, E. Morera, and G. Ortar. Tetrahedron Lett. 26,
1109 (1985); (b) M.A. Tuis and S.K. Kannangara. J. Org.
Chem. 55, 5711 (1990).
27. (a) J.F. Templeton, V.P.S. Kumar, D. Dose, and F.S. Labella. J.
Med. Chem. 32, 1977 (1989); (b) N. Daniele, Y. Mazur, and F.
Sondheimer. J. Am. Chem. Chem. 84, 875 (1962); (c) A.
Hastier, A. Pancrazi, and Q. Khuong-Huu. Bull. Soc. Chim. Fr.
1581 (1976).
References
1. L.F. Fieser and M. Fieser. Steroids. Reinhold Publishing Cor-
poration, Baltimore, Md. 1959.
2. T.R. Watson, H.T.A. Cheung, and R.E. Thomas. Natural prod-
ucts and drug development, Alfred Benzon symposium 20.
Munksgaard, Copenhagen. 1984.
3. R.B. Silverman. The organic chemistry of drug design and
drug action. Academic Press Inc., San Diego. 1992.
4. S.D. Munari, P. Barassi, A. Cerri, G. Fedrezzi, M. Gobbini, M.
Mabilia, and P. Melloni. J. Med. Chem. 41, 3033 (1998).
5. O. Diels and K. Alder. Justus Liebigs Ann. Chem. 98, 460
(1928).
28. G. Stork, F. West, H.Y. Lee, R.C.A. Isaacs, and S. Manabe. J.
Am. Chem. Soc. 118, 10660 (1996).
6. (a) P. Deslongchamps. Aldrichimica Acta, 24, 43 (1991); (b) P.
Deslongchamps. Pure Appl. Chem. 64, 1831 (1992).
7. E. Marsault, A. Toro, P. Nowak, and P. Deslongchamps. Tetra-
hedron, 57, 4243 (2001).
29. E. Piers and F.F. Fleming. Can. J. Chem. 71, 1867 (1993).
30. H.L. Dryden, G.M. Webber, R.R. Burtner, and J.A. Cella. J.
Org. Chem. 26, 3237 (1961).
31. G. Goendoes and J.C. Orr. J. Chem. Soc. Chem. Commun.
8. L. Ouellet, P. Langlois, and P. Deslongchamps. Synlett, 689
1239 (1982).
(1997).
32. R. Contreras and L. Mendoza. Steroids, 34, 121 (1979).
33. D.H.R. Barton, G. Bashiardes, and J.-L. Fourrey. Tetrahedron
Lett. 24, 1605 (1983).
9. F.L Greenwood. J. Org. Chem. 20, 803 (1955).
10. J. Boutagy and R. Thomas. Chem. Rev. 74, 87 (1974).
11. A.J. Mancuso and D. Swern. Synthesis, 165 (1981).
© 2006 NRC Canada