Novel Synthesis of Highly Functionalized 14-β-Hydroxysteroids Related to Batrachotoxin and Ouabain

Article abstract of DOI:10.1021/jo0355606

The use of anionic polycyclization was investigated in an effort to develop a versatile and convergent synthesis of advanced tetracyclic intermediates of batrachotoxin and ouabain analogues. Two new 5-(trialkylsilyl)-2-cyclohexenones as A ring precursors

Full text of DOI:10.1021/jo0355606

Novel Syn th esis of High ly F u n ction a lized 14-â-Hyd r oxyster oid s
Rela ted to Ba tr a ch otoxin a n d Ou a ba in
Ste´phane Trudeau and Pierre Deslongchamps*
Laboratoire de synthe`se organique, Institut de Pharmacologie de Sherbrooke,
Universite´ de Sherbrooke, Sherbrooke, Que´bec J 1H 5N4, Canada
pierre.deslongchamps@usherbrooke.ca
Received October 21, 2003
The use of anionic polycyclization was investigated in an effort to develop a versatile and convergent
synthesis of advanced tetracyclic intermediates of batrachotoxin and ouabain analogues. Two new
5-(trialkylsilyl)-2-cyclohexenones as A ring precursors and a new Nazarov intermediate (D ring
precursor) were prepared for this purpose. The reaction of the unsaturated â-keto aldehyde A ring
precursor with the enolate of the Nazarov intermediate afforded, after subsequent transformations,
a 14-â-hydroxysteroid with complete control of stereochemistry.
SCHEME 1a
In tr od u ction
We recently reported the use of anionic polycyclization
for constructing the steroidal backbone of the cardeno-
lides. It was shown that the reaction of 2-carbomethoxy-
2-cyclohexenone (-)-5 with the enolate of Nazarov inter-
mediate (-)-6 gave, after decarboxylation and aldol
condensation, steroid (-)-7 with control of stereochem-
istry (Scheme 1).1 With the stereoselective generation of
five contiguous chiral centers, the crucial groundwork
was established for the asymmetric total synthesis of
interesting natural products such as ouabain. To pursue
this line of research, we then focused our attention on
investigating other A ring cyclohexenones and another
D ring precursor. This strategy was intended to synthe-
size an advanced intermediate of batrachotoxin (4) and
analogues of ouabain (2) (Figure 1).2 Batrachotoxin is one
of the most potent known cardiotoxins (LD50 in mice ) 2
µg/kg). This molecule acts by binding to sites in nerve
and muscle cells associated with sodium ion transport
channels. The binding prevents closure of the channel
allowing a massive influx of sodium ions to flow into the
cell leading to membrane depolarization.3 In this paper,
we wish to report the synthesis of two new A ring
cyclohexenones ((+)-10 and (+)-12) having a dimethyl-
phenylsilyl group at C(3) (steroid numbering) for stereo-
control and a new Nazarov intermediate (D ring precur-
sor (-)-29) and the results of anionic polycyclization with
both cyclohexenones.
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2, 61%; (b)
Pd(PPh3)4, morpholine, THF, 71%; (c) KHMDS, THF reflux, 71%.
E ) CO2Me; R ) TBDPS.
Resu lts a n d Discu ssion
F IGURE 1. Target structures.
Previous studies in our group used unsaturated â-keto
ester as A ring precursors which were allowed to react
in a cycloaddition reaction4 with a Nazarov intermediate
to afford after subsequent steps a tetracyclic compound
with an ester at the C(10) position (Scheme 1).1,5 In many
of our planned synthetic routes, these esters would need
(1) Yang, Z.; Shannon, D.; Truong, V.-L.; Deslongchamps, P. Org.
Lett. 2002, 4, 4693.
(2) For a total synthesis of batrachotoxinin A, see: Kurosu, M.;
Marcin, L. R.; Grinsteiner, T. J .; Kishi, Y. J . Am. Chem. Soc. 1998,
120, 6627.
(3) Albuquerque, E. X.; Daly, J . W.; Witkop, B. Science 1971, 72,
995.
(4) This cycloaddition process can be looked as a double Michael
addition or a highly desymmetrized Diels-Alder reaction.
10.1021/jo0355606 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/10/2004
832
J . Org. Chem. 2004, 69, 832-838

Synthesis of Highly Functionalized 14-â-Hydroxysteroids
carbene via the iodonium ylide moiety.10,11 With racemic
17 in hand, opening of the cyclopropane was carried out
with Mg(OMe)2 in refluxing methanol to afford â-keto
ester 18.12 Next, we used chiral auxiliary (R)-(-)-panto-
lactone ((-)-40) to execute a transesterification using
Taber’s methodology.13 In a recent publication, Covey
and co-workers reported the use of (R)-(-)-pantolactone
((-)-40) as a good chiral auxiliary to separate diastereo-
isomers of compounds similar to â-keto ester 18.14 In our
case, it also gave good results; the lactone diastereo-
isomers (+)-19 and (-)-20 were easily separated by
flash chromatography. Identification of diastereoisomer
(-)-20 was performed by single-crystal X-ray diffrac-
tion crystallography.15 After methanolysis, we obtained
enantiopure â-keto ester (-)-18.
The construction of the backbone of the Nazarov
intermediate began with the addition of methyl vinyl
ketone to â-keto ester (-)-18 under basic conditions
(K2CO3 in benzene at room temperature) to afford methyl
ketone (-)-22 in 92% yield. Cyclization of the latter with
pyrrolidine in refluxing benzene gave the enamine, which
was hydrolyzed with a heterogeneous mixture of buffered
aqueous solution and benzene to afford enone (+)-23 in
70% yield.16 Following the method previously developed
in our laboratory, the enone (+)-23 was transformed into
compound (-)-29.1 Introduction of the acetate was made
with lead tetraacetate in toluene in a high-pressure tube.
Heating of the mixture at 150 °C for a prolonged time
permitted thermodynamic equilibration and gave the
R-acetoxy ketone (+)-24 in 72% yield in a >20:1 ratio of
diastereoisomers. The enone of acetate (+)-24 was cleaved
to afford carboxylic acid (-)-25 in 74% yield. Thioesteri-
fication of the acid with DCC, DMAP, and ethanethiol
in dichloromethane furnished thioester (-)-26. Homolo-
gation of the latter was accomplished by reduction of the
thioester with Et3SiH and Pd(OAc)2 to give aldehyde
(-)-27, which was immediately treated with phosphorane
39 to afford enol ether (-)-28 in 80% yield for both
steps.17 Final deprotection of the enol ether in 80%
aqueous acetic acid at 80 °C provided Nazarov intermedi-
ate (-)-29 in 74% yield.
SCHEME 2a
a
Reagents and conditions: (a) (i) KH, THF, (ii) HCO2Et, 84%;
(b) PhSeCl, pyridine, CH2Cl2, 88%; (c) H2O2, CH2Cl2, quant.; (d)
(i) (TMS)2NH, n-BuLi, THF, -78 °C, (ii) ClCOSEt, 72%; (e)
PhSeCl, pyridine, CH2Cl2, 83%; (f) H2O2, CH2Cl2, 97%.
to be reduced to the corresponding alcohols or alkanes.
This step could be problematic since there are other
carbonyl functionalities in these compounds. We then
decided to investigate the use of unsaturated â-keto
aldehydes and â-keto thioesters (a masked â-keto alde-
hyde) as A ring precursors. Furthermore, a couple of
years ago, Corey and co-workers reported the facile
synthesis of enantiomerically pure 5-(trialkylsilyl)-2-
cyclohexenones where the silyl group was used as a
stereocontrolling group in Diels-Alder reaction.6,7 With
this in mind, the synthesis of unsaturated â-keto alde-
hyde (+)-10 was then undertaken starting from ketone
(+)-86 (Scheme 2). Kinetic deprotonation of ketone (+)-8
with potassium hydride gave, after addition of ethyl
formate, â-keto aldehyde (+)-9 in 84% yield. The intro-
duction of the unsaturation was accomplished by forma-
tion of the selenide derivative with PhSeCl and pyridine
in CH2Cl2. Treatment of the selenide derivative with
H2O2 gave the unsaturated â-keto aldehyde (+)-10 in 88%
yield for the last two steps. In the same fashion, unsatu-
rated â-keto thioester (+)-12 was prepared by depro-
tonation of ketone (+)-8 with LiHMDS and trapping of
the kinetic enolate with ethyl chlorothiolformate, forma-
tion of the selenide with PhSeCl and pyridine, and
oxidation with H2O2 in a three-step sequence with an
overall yield of 58%.
We then investigated the synthesis of the Nazarov
intermediate bearing an ester at C(13) (steroid number-
ing). An ester functionality at this position was as yet
unexplored in the anionic polycyclization strategy. This
ester would also provide a handle for facile access to the
E ring of batrachotoxin. The synthesis of Nazarov inter-
mediate (-)-29 started from the previously reported
cyclopropane 17 (Scheme 3).8 The latter was made by
coupling of the dianion of methyl acetoacetate (14) and
1-bromo-2-butyne (13), partial hydrogenation with
Lindlar’s catalyst,9 and cyclization after formation of the
The cycloaddition reaction could now be performed on
both A ring cyclohexenones. The Nazarov intermediate
(-)-29 was allowed to react with unsaturated â-keto
thioester (+)-12 (Scheme 4). Under standard conditions
(Cs2CO3 in CH2Cl2), cycloaddition gave poor results. We
only managed to obtain a 16% yield of tricycle 30 as
indicated by its NMR spectrum. Decomposition of the
â-keto thioester starting material seemed to be the major
problem. Nonetheless, decarboxylation of the allyl ester
with Pd(PPh3)4 and morpholine in THF yielded tricycle
(10) Morizawa, Y.; Hiyama, T.; Oshima, K.; Nozaki, H. Bull. Chem.
Soc. J pn. 1984, 57, 1123.
(11) (a) Moriarty, R. M.; Prakash, O.; Vaid, R. K.; Zhao, L. J . Am.
Chem. Soc. 1989, 111, 6443. (b) Moriarty, R. M.; Kim, J .; Guo, L.
Tetrahedron Lett. 1993, 34, 4129. (c) Mu¨ller, P.; Fernandez, D. Helv.
Chim. Acta 1995, 78, 947.
(5) (a) Guay, B.; Deslongchamps, P. J . Org. Chem. 2003, 68, 6140.
(b) Chapdelaine, D.; Belzile, J .; Deslongchamps, P. J . Org. Chem. 2002,
(12) Lim, Y.-H.; McGee, K. F., J r.; Sieburth, S. McN. J . Org. Chem.
2002, 67, 6535.
67, 5669.
(13) Taber, D. F.; Amedio, J . C., J r.; Patel, Y. K. J . Org. Chem. 1985,
50, 3618.
(6) Sarakinos, G.; Corey, E. J . Org. Lett. 1999, 1, 811.
(7) Stoltz, B. M.; Kano, T.; Corey, E. J . J . Am. Chem. Soc. 2000,
122, 9044.
(8) Taber, D. F.; Amedio, J . C., J r.; Raman, K. J . Org. Chem. 1988,
(14) J iang, X.; Covey, D. F. J . Org. Chem. 2002, 67, 4893.
(15) We thank Mr. Andreas Decken for the X-ray diffraction
analysis.
53, 2984.
(16) Scanio, C. J . V.; Hill, L. P. Synthesis 1970, 651.
(17) Dube´, P.; Chapdelaine, D.; Deslongchamps, P. Synlett 2000,
1819.
(9) Tunemoto, D.; Araki, N.; Kondo, K. Tetrahedron Lett. 1977, 18,
109.
J . Org. Chem, Vol. 69, No. 3, 2004 833

Trudeau and Deslongchamps
SCHEME 3a
a
Reagents and conditions: (a) (i) NaH, THF 0 °C, (ii) n-BuLi, 77%; (b) Lindlar’s cat., H2, Et2O, 95%; (c) (i) KOH, PhI(OAc)2, MeOH, 0
°C, (ii) hν, 60%; (d) Mg, MeOH reflux, 74%; (e) (R)-(-)-pantolactone ((-)-40), DMAP, toluene reflux, 75% (ratio of (+)-19/(-)-20 ) 1/1); (f)
sealed tube, MeOH, 105 °C, 95%; (g) methyl vinyl ketone, K2CO3, benzene, 92%; (h) (i) pyrrolidine, benzene reflux, (ii) NaOAc, AcOH,
H2O, benzene reflux, 70%; (i) Pb(OAc)4, sealed tube, toluene 150 °C, 72%; (j) NaIO4, RuCl3, H2O, MeCN, CHCl3, 74%; (k) EtSH, DCC,
DMAP, CH2Cl2, 73%; (l) Et3SiH, Pd(OAc)2, acetone; (m) phosphorane 39, benzene reflux, 80% (two steps); (n) AcOH, H2O, 80 °C, 74%. E
) CO2Me; E* ) CO2-â,â′-dimethyl-γ-butyrolactone.
31. Unfortunately, the subsequent aldol reaction was not
successfully accomplished with this tricycle. We then
turned our attention to unsaturated â-keto aldehyde (+)-
10 as an A ring precursor. Cycloaddition with Nazarov
intermediate (-)-29 went very smoothly to afford allyl
ester (+)-33 in excellent yield (97%). Interestingly, we
observed only one product from the cyclization. We
concluded that the silyl group at the C(3) position very
efficiently controlled the stereoselectivity of the cyclo-
addition reaction. Due to these results, the thioester
approach was not further investigated as it was only
intended to be used as a masked aldehyde.
Decarboxylation of the allyl ester was then performed
with Pd(PPh3)4 and morpholine in THF to give rise to
tricycle (+)-34 in 62% yield. We had to be very careful
with the amount of morpholine used in this reaction
because the aldehyde at the C(10) position was prone
to deformylation. Next, we decided to selectively reduce
the aldehyde with lithium tris[(3-ethyl-3-pentyl)oxy]-
aluminohydride at -45 °C to afford alcohol (-)-35, which
was protected as an acetate with acetic anhydride and
DMAP in pyridine. The next step was the aldol con-
densation. Initially, the reaction was carried out with
KHMDS in refluxing THF to obtain tetracycle (-)-37 in
an unoptimized yield of 35% with complete control of
stereochemistry. Compound (-)-37 is assumed to have
the H(8) â-configuration as in previous related cases.1
This tetracycle could be looked at as an advanced
intermediate of batrachotoxin or as precursors of ouabain
analogues. Finally, we also tried Cs2CO3 in refluxing
acetonitrile for 16 h and it afforded cyclopropane (+)-38
in an unoptimized yield of 38%. The structure and
stereochemistry of cyclopropane (+)-38 was confirmed by
single-crystal X-ray diffraction crystallography.15 Pre-
834 J . Org. Chem., Vol. 69, No. 3, 2004

Synthesis of Highly Functionalized 14-â-Hydroxysteroids
SCHEME 4 a
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2, 16%; (b) Pd(PPh3)4, morpholine, THF, 81%; (c) Cs2CO3, CH2Cl2, 97%; (d) Pd(PPh3)4,
morpholine, THF, 62%; (e) LiAl(OCEt3)3H, THF, -45 °C, 72%; (f) Ac2O, DMAP, pyridine, 94%; (g) KHMDS, THF reflux, 35%; (h) Cs2CO3,
MeCN reflux, 38%. E ) CO2Me; ES ) COSEt.
sumably, the long reaction time in refluxing acetonitrile
allowed the formation of the cyclopropane via an ad-
ditional deprotonation at C(8) on compound (-)-37 fol-
lowed by displacement of the acetate at C(11) by the
resulting enolate.
out perturbing other functionalities. Current efforts in
our laboratories are now directed at the optimization of
the last steps in the sequence to produce more advanced
intermediates. Developments regarding these efforts will
be reported in due time.
Con clu sion
Exp er im en ta l Section
All reactions were performed under nitrogen atmosphere
with flame-dried glassware. Solvents were distilled and dried
according to standard procedures. 1H and 13C NMR spectra
are referenced with respect to the residual signals of the
solvent; they are described with standard abbreviations.
Melting points are uncorrected.
â-Keto Ald eh yd e (+)-9. Potassium hydride (35 wt %
dispersion in mineral oil) was rinsed three times with pentane
to afford pure material (0.072 g, 1.8 mmol), which was
We have elaborated an efficient stereocontrolled route
for the synthesis of a tetracyclic precursor to batracho-
toxin and analogues of ouabain. The use of 5-(trialkyl-
silyl)-2-cyclohexenones controlled in a very efficient man-
ner the stereoselectivity of the cycloaddition reaction.
Furthermore, the aldehyde group on the A ring cyclo-
hexenone afforded a very good yield for the cycloaddition
step and permitted facile, selective transformation with-
J . Org. Chem, Vol. 69, No. 3, 2004 835

Trudeau and Deslongchamps
suspended in THF (5.0 mL). This solution was then cooled to
0 °C. A solution of ketone (+)-8 (0.38 g, 1.6 mmol) in THF (6.0
mL) was added to the first solution dropwise. The reaction
mixture was stirred for 0.5 h at room temperature and cooled
to 0 °C. Ethyl formate (0.27 mL, 3.3 mmol) was added and
the mixture was stirred for 0.5 h at room temperature.
Saturated aqueous NaHCO3 was added and the mixture was
extracted with ether. The combined organic phase was washed
with brine, dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography (8/2 hexane/ether) to afford â-keto aldehyde
La cton es (+)-19 a n d (-)-20. To a stirring solution of â-keto
ester 18 (8.1 g, 0.040 mol) in toluene (360 mL) was added (R)-
(-)-pantolactone ((-)-40) (6.3 g, 0.049 mol) and DMAP (2.5 g,
0.020 mol). The solution was heated at reflux, with a Dean-
Stark apparatus, for 16 h. The reaction mixture was cooled to
room temperature and filtered through a silica gel pad. The
pad was rinsed with ether and the combined filtrates were
concentrated under reduced pressure. The crude product was
purified by flash chromatography (7/3 to 3/7 hexane/ether) to
afford lactone (+)-19 (5.13 g, 43%) and lactone (-)-20 (3.91 g,
32%). Both products were recrystallized in hexane/ether to give
white needles. (+)-19: mp 51-54 °C. [R]25 +30.3 (c 1.30,
(+)-9 (0.36 g, 84%) as a clear oil. [R]25 +78.8 (c 0.95, CHCl3).
D
D
CHCl3). IR (thin film, ν cm-1): 3479, 2972, 1798, 1781, 1770,
1738, 1470, 1372, 1280, 1110, 1011, 914, 733. 1H NMR (300
MHz, CDCl3): δ 5.41 (1H, s), 4.02 (2H, d, J ) 4.5 Hz), 3.32
(3H, s), 3.26 (1H, m), 3.22 (1H, d, J ) 11.1 Hz), 2.74 (1H, m),
2.40 (2H, m), 2.11 (1H, m), 1.64 (1H, m), 1.18-1.05 (9H, m).
13C NMR (75 MHz, CDCl3): δ 211.0, 172.1, 169.1, 79.9, 76.2,
75.5, 58.9, 56.5, 47.7, 40.5, 38.5, 23.8, 22.8, 19.7, 16.7. MS (EI):
298 (M+). HRMS (M+) calcd for C15H22O6 298.1416, found
IR (thin film, ν cm-1): 2925, 2949, 1637, 1587, 1409, 1365, 1308,
1250, 1177, 1114, 1076, 1036, 889, 831, 815, 734, 700. 1H NMR
(300 MHz, CDCl3): δ 8.58 (1H, d, J ) 3.3 Hz), 7.50 (2H, m),
7.38 (3H, m), 2.46-2.14 (5H, m), 1.91 (1H, m), 1.28 (1H, m),
1.10 (1H, m), 0.32 (6H, d, J ) 1.3 Hz). 13C NMR (75 MHz,
CDCl3): δ 187.1, 185.6, 136.7, 133.9, 129.3, 127.9, 108.8, 32.4,
24.4, 23.7, 20.2, -5.4, -5.4. MS (CI): 261 (MH+). HRMS (MH+)
calcd for C15H21O2Si 261.1311, found 261.1318.
298.1422. (-)-20: mp 91-93 °C. [R]25 -35.1 (c 2.63, CHCl3).
D
Un sa tu r a ted â-Keto Ald eh yd e (+)-10. To a stirring
solution of phenylselenenyl chloride (0.55 g, 2.9 mmol) in
CH2Cl2 (12.0 mL) at 0 °C was added pyridine (0.28 mL, 3.5
mmol). The solution was stirred for 0.75 h, then a solution of
â-keto aldehyde (+)-9 (0.60 g, 2.3 mmol) in CH2Cl2 (11.0 mL)
was added. The mixture was stirred for 0.25 h at 0 °C and
0.75 h at room temperature. It was then extracted twice with
1 M HCl. The organic phase was dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by flash chromatography (95/5 hexane/ether) to
afford the selenide (0.84 g, 88%) as a yellow oil (mixture of
diastereoisomers). [R]25D +169 (c 0.74, CHCl3). IR (thin film, ν
cm-1): 3069, 2953, 2851, 1706, 1690, 1438, 1260, 1194, 1114,
1022, 813, 739, 701. 1H NMR (300 MHz, CDCl3): δ 9.89 and
9.20 (1H, 2 d, J ) 0.5 and 1.1 Hz), 7.54-7.26 (10H, m), 2.91
(<1H, t, J ) 14.7 Hz), 2.65 (<1H, dt, J ) 15.0 and 1.2 Hz),
2.23 (1H, m), 2.15-1.88 (3H, m), 1.79 (1H, m), 1.35 (1H, m),
0.38 and 0.29 (6H, 2 s). 13C NMR (75 MHz, CDCl3): δ 206.6,
205.4, 194.1, 187.1, 138.3, 137.8, 133.9, 133.8, 130.4, 129.8,
129.5, 129.1, 128.0, 70.0, 61.7, 43.3, 39.4, 34.8, 31.6, 26.5, 26.4,
24.5, 22.0, -5.4, -5.4. MS (EI): 416 (M+), 388 (M+ - CO).
HRMS (M+ - CO) calcd for C20H24OSeSi 388.0762, found
388.0771. To a stirring solution of the above selenide (0.24 g,
0.58 mmol) in CH2Cl2 (5.8 mL) was added 35% aqueous H2O2
(0.10 mL, 1.2 mmol). The mixture was stirred vigorously for 5
min, then another portion of 35% aqueous H2O2 (0.10 mL, 1.2
mmol) was added and the mixture was stirred vigorously for
another 5 min. The reaction mixture was extracted twice with
water. The solvent was dried over MgSO4, filtered, and
concentrated under reduced pressure. The unsaturated â-keto
aldehyde (+)-10 (0.16 g, quant.) obtained was used directly in
the next step without purification because of its high instabil-
ity.
IR (thin film, ν cm-1): 2974, 1791, 1761, 1733, 1466, 1378, 1116,
1
1013. H NMR (300 MHz, CDCl3): δ 5.33 (1H, s), 3.98 (2H, s),
3.26 (3H, s), 3.25 (1H, m), 3.19 (1H, d, J ) 10.5 Hz), 2.73 (1H,
m), 2.33 (2H, m), 2.08 (1H, m), 1.69 (1H, m), 1.17 and 1.02
(6H, 2 s), 1.16 (3H, d, J ) 6.4 Hz). 13C NMR (75 MHz, CDCl3):
δ 210.9, 171.8, 168.9, 79.1, 76.0, 75.3, 58.2, 56.2, 47.7, 40.5,
38.3, 24.0, 22.9, 19.6, 16.6. MS (EI): 298 (M+). HRMS (M+)
calcd for C15H22O6 298.1416, found 298.1422.
â-Keto Ester (-)-18. A solution of lactone (-)-20 (3.9 g,
0.013 mol) in methanol (100 mL) was placed in a sealed tube
under an argon atmosphere and heated in an oil bath at 105
°C for 3 days. The reaction mixture was cooled to room
temperature, concentrated under reduced pressure, and puri-
fied by flash chromatography (8/2 to 6/4 hexane/ether) to afford
â-keto ester (-)-18 (2.5 g, 95%), which was recrystallized in
hexane to give a white solid as an analytically pure material.
Mp 50-51 °C. [R]25 -85.2 (c 0.89, CHCl3). IR (thin film, ν
D
cm-1): 2974, 2825, 1759, 1728, 1436, 1376, 1340, 1283, 1200,
1
1118. H NMR (300 MHz, CDCl3): δ 3.72 (3H, s), 3.28 (3H, s),
3.24 (1H, quint, J ) 6.4 Hz), 3.08 (1H, d, J ) 10.7 Hz), 2.70
(1H, m), 2.32 (2H, m), 2.08 (1H, m), 1.63 (1H, m), 1.14 (3H, d,
J ) 6.2 Hz). 13C NMR (75 MHz, CDCl3): δ 211.8, 170.3, 79.6,
58.8, 56.4, 52.3, 47.5, 38.4, 23.9, 16.6. MS (EI): 200 (M+), 185
(M+ - CH3), 168 (M+ - CH3OH). HRMS (M+) calcd for
C
10H16O4 200.1048, found 200.1051.
Meth yl Keton e (-)-22. To a stirring solution of â-keto ester
(-)-21 (2.5 g, 0.012 mol) in benzene (70.0 mL) was added
K2CO3 (2.4 g, 0.017 mol) and methyl vinyl ketone (1.5 mL,
0.017 mol). The solution was stirred for 3 h at room temper-
ature then a second portion of methyl vinyl ketone (1.5 mL,
0.017 mol) was added. The solution was stirred another 16 h
at room temperature. A third portion of methyl vinyl ketone
(1.5 mL, 0.017 mol) was added and the solution was stirred
for 24 h at room temperature. Water was added to quench the
reaction mixture and it was extracted with ether. The organic
layer was washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure to afford the crude
â-Keto Ester 18. Magnesium (13.3 g, 0.55 mol) was added
to methanol (375 mL) and the suspension was stirred at reflux
for 1 h then cooled to room temperature. A solution of the
cyclopropane 17 (9.2 g, 0.055 mol) in methanol (41.0 mL) was
then added and the mixture was stirred for 0.5 h at room
temperature and 0.5 h at reflux. After the solution was cooled
to 0 °C, 10% HCl was added and the mixture was extracted
with ether. The combined organic phase was dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified twice by flash chromatography (9/1 to
1/1 hexane/ether) to give the â-keto ester 18 (8.1 g, 74%) as
an oil. IR (thin film, ν cm-1): 2973, 2824, 1758, 1728, 1436,
1376, 1340, 1283, 1200, 1118, 1025. 1H NMR (300 MHz,
CDCl3): δ 3.68 (3H, s), 3.24 (3H, s), 3.20 (1H, m), 3.04 (1H, d,
J ) 10.7 Hz), 2.66 (1H, m), 2.32 (2H, m), 2.05 (1H, m), 1.59
(1H, m), 1.11 (3H, d, J ) 6.2 Hz). 13C NMR (75 MHz, CDCl3):
δ 211.8, 170.3, 79.6, 58.7, 56.4, 52.3, 47.5, 38.4, 23.9, 16.6. MS
(EI): 200 (M+), 185 (M+ - CH3), 168 (M+ - CH3OH). HRMS
(M+) calcd for C10H16O4 200.1048, found 200.1043.
methyl ketone (-)-22 (3.1 g, 92%) as a light yellow oil. [R]25
D
-91.4 (c 1.74, CHCl3). IR (thin film, ν cm-1): 2972, 1751, 1731,
1715, 1435, 1374, 1230, 1196, 1167, 1110. 1H NMR (300 MHz,
CDCl3): δ 3.69 (3H, s), 3.20 (3H, s), 3.17 (1H, m), 2.70 (1H, m),
2.57-2.12 (6H, m), 2.12 (3H, s), 1.99 (1H, m), 1.69 (1H, m),
1.16 (3H, d, J ) 6.0 Hz). 13C NMR (75 MHz, CDCl3): δ 215.6,
208.3, 170.7, 78.6, 61.6, 56.0, 52.3, 51.8, 38.9, 38.5, 29.7, 28.2,
23.8, 16.9. MS (EI): 270 (M+). HRMS (M+) calcd for C14H22O5
270.1467, found 270.1460.
En on e (+)-23. To a stirring solution of methyl ketone (-)-
22 (3.1 g, 0.011 mol) in benzene (113 mL) was added pyrroli-
dine (2.4 mL, 0.028 mol). The solution was heated at reflux,
under a Dean-Stark apparatus, for 16 h. Pyrrolidine (2.4 mL,
0.028 mol) was added and the mixture was again heated at
836 J . Org. Chem., Vol. 69, No. 3, 2004

Synthesis of Highly Functionalized 14-â-Hydroxysteroids
reflux for 8 h. The reaction mixture was cooled to room
temperature and concentrated under reduced pressure. The
crude product was dissolved in benzene (46.0 mL) and a
solution of NaOAc (0.46 g, 5.6 mmol) and acetic acid (0.91 mL)
in water (22.6 mL) was added. The reaction mixture was
stirred at reflux for 4 h and cooled to room temperature, then
it was washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (6/4 to 1/1
hexane/ether) to afford enone (+)-23 (2.0 g, 70%), which was
recrystallized in hexane to give a yellow solid as an analytically
was then stirred at -45 °C for 16 h. Lithium tris[(3-ethyl-3-
pentyl)oxy]aluminohydride (0.5 M in THF) (0.036 mL, 0.018
mmol) was added and the mixture was stirred another 6 h at
-45 °C. The mixture was quenched with a saturated aqueous
solution of NH4Cl and extracted with EtOAc. The combined
organic phase was washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (4/6 to 0/1
hexane/ether) to afford alcohol (-)-35 (0.014 g, 72%) as a white
solid. [R]25D -0.69 (c 1.45, CHCl3). IR (thin film, ν cm-1): 3458,
3015, 2954, 1754, 1732, 1714, 1428, 1375, 1236, 1198, 1112,
1
pure material. Mp 50-52 °C. [R]25 +111 (c 0.99, CHCl3). IR
1050, 953, 816, 754, 703, 668. H NMR (300 MHz, CDCl3): δ
D
(thin film, ν cm-1): 2950, 1730, 1670, 1447, 1330, 1232, 1198,
1168, 1097. 1H NMR (300 MHz, CDCl3): δ 5.84 (1H, s), 3.73
(3H, s), 3.28 (3H, s), 3.11 (1H, m), 3.05 (1H, m), 2.90 (1H, qt,
J ) 11.1 and 2.1 Hz), 2.63-2.32 (3H, m), 1.98-1.61 (4H, m),
1.13 (3H, d, J ) 6.0 Hz). 13C NMR (75 MHz, CDCl3): δ 199.3,
171.7, 171.1, 123.7, 78.8, 57.2, 56.7, 56.0, 52.0, 34.9, 34.1, 30.7,
25.8, 17.6. MS (EI): 252 (M+). HRMS (M+) calcd for C14H20O4
252.1361, found 252.1365.
7.44 (2H, m), 7.35 (3H, m), 5.14 (1H, d, J ) 9.7 Hz), 4.24 (1H,
d, J ) 12.5 Hz), 4.05 (1H, t, J ) 9.8 Hz), 3.66 (3H, s), 3.31
(1H, m), 3.14 (3H, s), 3.12 (1H, m), 3.01 (1H, q, J ) 4.2 Hz),
2.73 (1H, m), 2.57 (3H, m), 2.50-1.93 (9H, m), 1.91 (3H, s),
1.70 (3H, m), 1.49 (1H, dt, J ) 14.3 and 5.4 Hz), 1.14 (3H, d,
J ) 5.9 Hz), 0.32 (6H, s). 13C NMR (75 MHz, CDCl3): δ 213.8,
213.3, 209.8, 171.7, 170.4, 136.2, 133.8, 129.5, 128.0, 78.9, 71.2,
62.9, 61.4, 55.9, 55.8, 52.2, 49.1, 43.0, 40.6, 39.6, 38.9, 37.8,
37.6, 35.8, 27.1, 23.8, 22.6, 21.2, 16.9, -4.7, -4.8. MS (EI):
614 (M+). HRMS (M+) calcd for C33H46O9Si 614.2911, found
614.2917.
Allyl Ester (+)-33. To a stirring solution of Nazarov
intermediate (-)-29 (0.23 g, 0.53 mmol) in CH2Cl2 (10.0 mL)
was added Cs2CO3 (0.34 g, 1.0 mmol) and the mixture was
stirred at room temperature for 10 min then cooled to 0 °C. A
solution of unsaturated â-keto aldehyde (+)-10 (0.27 g, 1.0
mmol) in CH2Cl2 (9.4 mL) was added to the reaction mixture
and stirring continued at 0 °C for 0.75 h. The solution was
then diluted with EtOAc and filtered through a pad of Celite.
The pad was rinsed with EtOAc and the solvent was concen-
trated under reduced pressure. The crude product was purified
by flash chromatography (8/2 to 1/1 hexane/ether) to afford
allyl ester (+)-33 (0.35 g, 97%) as a yellow oil (mixture of keto-
Aceta te (-)-36. To a solution of alcohol (-)-35 (0.012 g,
0.020 mmol) in pyridine (1.0 mL) was added acetic anhydride
(9.2 µL, 0.098 mmol) and DMAP (0.5 mg, 4.1 µmol). The
solution was stirred for 16 h at room temperature, quenched
with a saturated aqueous solution of NH4Cl, and extracted
with EtOAc. The organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
(95/5 hexane/ether) to give acetate (-)-36 (0.012 g, 94%) as a
enol). [R]25 +8.2 (c 2.03, CHCl3). IR (thin film, ν cm-1): 2953,
light yellow solid. [R]25 -2.8 (c 1.20, CHCl3). IR (thin film, ν
D
D
1752, 1735, 1693, 1660, 1428, 1399, 1374, 1237, 1217, 1113,
cm-1): 2952, 1752, 1736, 1710, 1428, 1375, 1236, 1111, 1031,
912, 817, 732. 1H NMR (300 MHz, CDCl3): δ 7.44 (2H, m), 7.37
(3H, m), 5.10 (1H, quint, J ) 4.3 Hz), 4.61 (1H, s), 3.65 (3H,
s), 3.17 (3H, s), 3.06 (1H, m), 3.05 (1H, m), 2.76 (1H, m), 2.54
(4H, m), 2.44 (2H, m), 2.29 (2H, m), 2.23 (2H, m), 2.05 (3H, s),
1.97 (3H, m), 1.87 (3H, s), 1.70 (3H, m), 1.53 (1H, dt, J ) 14.1
and 5.8 Hz), 1.18 (3H, d, J ) 5.9 Hz), 0.33 (6H, s). 13C NMR
(75 MHz, CDCl3): δ 214.1, 210.9, 209.3, 170.8, 170.4, 170.1,
136.2, 133.7, 129.6, 128.1, 79.2, 69.8, 63.5, 61.5, 55.8, 53.4, 52.2,
48.2, 43.0, 40.8, 40.3, 38.8, 37.9, 37.8, 34.7, 27.5, 23.4, 22.1,
21.1, 20.7, 16.8, -4.7, -4.8. MS (EI): 656 (M+). HRMS (M+)
calcd for C35H48O10Si 656.3017, found 656.3021.
1
1047, 912, 816, 734, 703. H NMR (300 MHz, CDCl3): δ 12.16
(<1H, s), 9.18 (1H, d, J ) 1.0 Hz), 7.45 (2H, m), 7.35 (3H, m),
5.86 (1H, m), 5.34-5.24 (3H, m), 4.61 (2H, qd, J ) 13.0 and
5.8 Hz), 3.66 (3H, s), 3.32 (1H, dd, J ) 9.0 and 4.1 Hz), 3.20
(3H, s), 3.06 (2H, m), 2.79 (1H, m), 2.64 (2H, d, J ) 15.2 Hz),
2.47 (2H, dd, J ) 12.6 and 6.5 Hz), 2.38 (1H, d, J ) 8.9 Hz),
2.22 (5H, m), 2.00 (2H, m), 1.75 (3H, s), 1.71 (1H, m), 1.50
(1H, m), 1.15 (3H, d, J ) 5.9 Hz), 0.31 (6H, s). 13C NMR (75
MHz, CDCl3): δ 215.8, 199.0, 171.8, 170.8, 170.7, 170.4, 162.0,
136.8, 133.9, 131.7, 129.4, 128.0, 127.9, 127.8, 119.2, 98.9, 79.1,
69.1, 65.4, 62.0, 55.6, 52.2, 48.3, 40.2, 38.9, 37.6, 36.7, 36.2,
29.9, 29.0, 23.1, 20.7, 16.8, -3.8, -4.2. MS (EI): 696 (M+).
HRMS (M+) calcd for C37H48O11Si 696.2966, found 696.2955.
Tetr a cycle (-)-37. To a stirring solution of acetate (-)-36
(0.052 g, 0.079 mmol) in THF (8.0 mL) was added KHMDS
(0.5 M in toluene) (0.079 mL, 0.040 mmol). The reaction
mixture was stirred at reflux for 10 min, allowed to cool to
room temperature, and filtered through a pad of silica gel. The
pad was rinsed with EtOAc and the solvent was removed in
vacuo. The crude product was purified by flash chromatogra-
phy (6/4 to 0/1 hexane/ether) to give tetracycle (-)-37 (0.018
Tr icycle (+)-34. To a stirring solution of allyl ester (+)-33
(0.35 g, 0.51 mmol) in THF (10.0 mL) was added Pd(PPh3)4
(0.019 g, 0.017 mmol) and morpholine (0.22 mL, 2.5 mmol).
The reaction mixture was stirred at room temperature for 0.5
h and the solvent was then removed in vacuo. The crude
product was purified by flash chromatography (1/1 to 0/1
hexane/ether) to afford tricycle (+)-34 (0.19 g, 62%) as a white
solid. [R]25D +80.1 (c 1.07, CHCl3). IR (thin film, ν cm-1): 2953,
1753, 1732, 1428, 1375, 1231, 1111, 1042, 912, 836, 734. 1H
NMR (300 MHz, CDCl3): δ 9.48 (1H, s), 7.41 (2H, m), 7.34 (3H,
m), 5.00 (1H, t, J ) 8.4 Hz), 3.66 (3H, s), 3.23 (1H, m), 3.18
(3H, s), 3.08 (1H, m), 2.97 (1H, m), 2.79 (1H, m), 2.62-2.12
(11H, m), 1.99 (1H, m), 1.83 (3H, s), 1.75 (1H, m), 1.52 (2H,
m), 1.19 (3H, d, J ) 6.0 Hz), 0.29 (6H, d, J ) 2.0 Hz). 13C NMR
(75 MHz, CDCl3): δ 215.2, 208.6, 207.4, 198.6, 170.6, 170.4,
135.9, 133.7, 129.6, 128.0, 79.3, 68.8, 67.4, 61.8, 55.9, 52.2, 48.6,
42.8, 40.5, 39.5, 37.9, 37.8, 36.7, 28.1, 23.4, 21.5, 21.0, 16.8,
g, 35%). [R]25 -0.17 (c 1.80, CDCl3). IR (thin film, ν cm-1):
D
3422, 2953, 1749, 1708, 1428, 1376, 1230, 1156, 1113, 1044,
817, 754. 1H NMR (300 MHz, CDCl3): δ 7.44 (2H, m), 7.37 (3H,
m), 5.32 (1H, s), 4.72 (1H, six, J ) 4.3 Hz), 4.60 (1H, d, J )
11.6 Hz), 4.46 (1H, d, J ) 11.6 Hz), 3.80 (3H, s), 3.44 (1H, m),
3.09 (3H, s), 2.96 (2H, d, J ) 5.2 Hz), 2.60 (3H, m), 2.40 (2H,
m), 2.08 (3H, s), 2.06-1.85 (2H, m), 1.84 (3H, s), 1.72 (3H, m),
1.57 (1H, m), 1.26 (4H, m), 1.04 (3H, d, J ) 5.9 Hz), 0.30 (6H,
d, J ) 2.1 Hz). 13C NMR (75 MHz, CDCl3): δ 209.4, 205.4,
176.6, 170.4, 168.9, 136.9, 133.6, 129.4, 128.0, 81.9, 78.9, 67.8,
60.9, 56.2, 55.9, 55.7, 54.0, 53.1, 52.1, 44.9, 44.8, 39.9, 39.4,
37.9, 31.5, 28.2, 25.0, 24.3, 20.9, 20.4, 17.1, -3.1, -3.5. MS
-5.2. MS (EI): 584 (M+ - CO), 581 (M+ - OMe), 552 (M+
-
CH3CO2H). HRMS (M+ - CO) calcd for C32H44O8Si 584.2805,
found 584.2800. HRMS (M - OMe)+ calcd for C32H41O8Si
581.2570, found 581.2578.
(EI): 656 (M+), 641 (M+ - CH3), 648 (M+ - H2O), 624 (M+
-
CH3OH). HRMS (M+) calcd for C35H48O10Si 656.3017, found
656.3007.
Alcoh ol (-)-35. To a stirring solution of tricycle (+)-34
(0.020 g, 0.033 mmol) in THF (0.70 mL) at -78 °C was added
lithium tris[(3-ethyl-3-pentyl)oxy]aluminohydride (0.5 M in
THF) (0.072 mL, 0.036 mmol) dropwise. The reaction mixture
Cyclop r op a n e (+)-38. To a stirring solution of acetate (-)-
36 (5.3 mg, 8.1 µmol) in acetonitrile (1.0 mL) was added
Cs2CO3 (1.5 mg, 4.5 µmol). The solution was heated at reflux
for 16 h then cooled to room temperature. The solvent was
J . Org. Chem, Vol. 69, No. 3, 2004 837

Trudeau and Deslongchamps
removed in vacuo. The crude product was purified by flash
chromatography (4/6 to 2/8 hexane/ether) to give cyclopropane
NSERC Canada to S.T. is greatly appreciated. The
authors thank Dr. Hongxing Zhang for the preparation
of compounds (+)-9 and (+)-10 and Dr. Andrew Corbett
for the preparation of the manuscript.
(+)-38 (1.8 mg, 38%). [R]25 +72.7 (c 0.11, CHCl3). IR (thin
D
film, ν cm-1): 3384, 2950, 1743, 1711, 1657, 1428, 1379, 1231,
1
1114, 1041, 816, 754. H NMR (300 MHz, CDCl3): δ 7.41 (5H,
m), 6.25 (1H, s), 4.68 (1H, d, J ) 11.2 Hz), 4.15 (1H, d, J )
11.3 Hz), 3.73 (3H, s), 3.36 (1H, m), 3.21 (1H, m), 3.12 (3H, s),
2.67 (1H, m), 2.48 (1H, t, J ) 14.2 Hz), 2.31-1.89 (7H, m),
2.04 (3H, s), 1.77 (1H, quint, J ) 9.5 Hz), 1.58 (2H, m), 1.25
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds (+)-11, (+)-
12, 15, 16, (+)-24, (-)-25, (-)-26, (-)-27, (-)-28, (-)-29, 30,
and 31, 1H NMR spectra for all compounds, and X-ray crystal
structure for compounds (-)-20 and (+)-38. This material is
available free of charge via the Internet at http://pubs.acs.org.
The following crystal structures have been deposited at the
Cambridge Crystallographic Data Centre: (-)-20 (CCDC
212046) and (+)-38 (CCDC 212047).
(4H, m), 1.05 (3H, d, J ) 5.9 Hz), 0.32 (6H, d, J ) 3.3 Hz). 13
C
NMR (75 MHz, CDCl3): δ 211.3, 209.3, 172.4, 170.3, 135.5,
133.7, 129.7, 128.1, 96.7, 79.7, 69.2, 67.6, 59.5, 56.0, 51.4, 51.3,
39.3, 38.3, 37.2, 34.9, 34.9, 31.9, 31.8, 29.6, 26.0, 21.5, 20.6,
18.3, -5.3, -5.6. MS (EI): 596 (M+), 578 (M - H2O)+. HRMS
(M+) calcd for C33H44O8Si 596.2805, found 596.2797.
Ack n ow led gm en t. Funding from Merck Frosst
Canada Inc. is deeply appreciated. A fellowship from
J O0355606
838 J . Org. Chem., Vol. 69, No. 3, 2004