Versatile Use of Hindered Oxalates for the Stereoselective Preparation of Novel 11-Modified Androst-5-ene Derivatives

Article abstract of DOI:10.1021/jo0401016

The 11α- and 11β-modified androst-5-ene derivatives 3a,b as well as the exo- and endocyclic dehydrated compounds 4a-c and 5b-c were produced using the oxalate derivatives of the highly hindered 11β-hydroxyandrost-5-enes 1a-c. The 11-tetrahydrofuran deriva

Full text of DOI:10.1021/jo0401016

SCHEME 1. 11-Mod ified An d r osta n es of Typ e 1
Ver sa tile Use of Hin d er ed Oxa la tes for th e
Ster eoselective P r ep a r a tion of Novel
11-Mod ified An d r ost-5-en e Der iva tives
Vincent Lecomte,† Elie Ste´phan,*,†
Marie-Noelle Rager,‡ and Ge´rard J aouen†
Laboratoire de Chimie et Biochimie des Complexes
Mole´culaires, Ecole Nationale Supe´rieure de Chimie et
CNRS, 11 rue Pierre et Marie Curie, 75005 Paris, France,
and Service de RMN, Ecole Nationale Supe´rieure de
Chimie, 11 rue Pierre et Marie Curie, 75005 Paris, France
TABLE 1. Rea ctivity of Oxa la tes 2a -c u n d er
F r ee-Ra d ica l Con d ition s
elimin-
ationb
(%)
reductionb (%)
entrya strate (°C) (h) R-3a -c S-3a -c
sub-
T
t
6b
(%)
1a -cb
(%)
stephan@ext.jussieu.fr
1
2
2a
2a
2a
2a
2b
2b
2b
2c
110
110 22 28
80
rt
110
80
2
28
0
0
0
0
46 (4a )
46 (4a )
33 (4a )
0
0
0
0
45 (4c)/
55 (5c)
0
26
26
34
100
0
0
100
0
Received J anuary 5, 2004
3
2
3
1
1
2
2
33 (17)
0
24 (21) 38 (31)
22
0
0
Abstr a ct: The 11R- and 11â-modified androst-5-ene deriva-
tives 3a ,b as well as the exo- and endocyclic dehydrated
compounds 4a -c and 5b-c were produced using the oxalate
derivatives of the highly hindered 11â-hydroxyandrost-5-
enes 1a -c. The 11-tetrahydrofuran derivative 6 was pro-
duced for the first time with good diastereoselectivity by an
intramolecular 5-exo cyclization under radical conditions
from the corresponding oxalate as precursor.
4c
5
38 (27)
38
0
6
40
0
0
7c
8
rt
110
9c
2c
rt
2
0
0
100
a
n-Bu3SnH 2 equiv, radical initiator (AIBN 20 mol % unless
b
otherwise specified), toluene. Conversion determined by means
of 1H NMR using the integration for H-6 of the crude mixtures.
When determined, the isolated yield is given in parentheses. c Air-
Et3B as radical initiator.
Our group is involved in the preparation of modified
androstanes at the C-11 position. To date, it has been
possible to prepare several 11R-substituted 11â-hydroxy-
androst-5-enes 1 with various kinds of substituents (aryl,1
alkyl,1 and allyl;2 see Scheme 1). The importance of that
position, especially at C-11â, in the biological implications
of these hormones has been shown,3 but new series of
C-11 modified androstanes are still needed to extensively
explore their structure-activity relationships. Further-
more, the study of such a hindered position is challenging
from the modern chemistry point of view.
To reduce 1, some classical methods were first tried
(among others, ionic hydrogenation, derivatization to
sulfonates followed by addition of hydride, and Barton-
McCombie deoxygenation), but were unsuccessful.4
However, an oxalate moiety can be introduced into
hindered systems, and under free-radical conditions,
oxalates are also known to produce deoxygenated com-
pounds.5 Thus, we present here a study of the reactivity
of hindered oxalates, derived from 11-modified androst-
5-enes 1a -c under free-radical and thermolytic condi-
tions. The oxalate derivatives 2a -c were quantitatively
prepared, by a one-pot procedure, by deprotonation of
1a -c with n-BuLi and treatment with methyl chlo-
rooxoacetate (Scheme 2)
The results concerning the reduction of 2a -c with
n-Bu3SnH in the presence of a radical precursor under
different conditions are presented in Table 1.
The deoxygenation of 2a and 2b was observed at 110
°C with AIBN as initiator (Table 1, entries 1 and 5). In
the case of 2a , only R-3a was observed with a relative
retention of configuration (17% isolated yield, see the
Experimental Section), but in the case of 2b, the two
possible diastereoisomers R- and S-3b were produced
(21% and 31% isolated yield for R-3b and S-3b, respec-
tively, see the Experimental Section). The deoxygenation
of 2c was not observed (Table 1, entry 8).
At temperatures above 80 °C, the elimination of the
oxalate moiety of 2a and 2c was observed, leading to the
unsaturated compounds 4a , 4c, and 5c. The elimination
occurred exclusively from cis-hydrogens. At room tem-
perature, no elimination occurred, but the starting alco-
hols 1a -c were recovered quantitatively (Table 1, entries
4, 7, and 9).
In the case of 2b, a cyclization compound identified as
the 11-tetrahydrofuran derivative 6 was formed during
the course of the reaction at temperatures above 80 °C
(Table 1, entries 5 and 6). Compound 6 was produced as
a 1/0.4/0.2 mixture of three of the four possible diaster-
eomers in 27% isolated yield.
The configuration of the deoxygenated compounds R-3a
and R- and S-3b was determined by NMR methods.
Compounds R-3b and S-3b showed 1H NMR chemical
shifts for H-9 at δ 1.06 (t, J ) 10.2 Hz, 1H) and δ 1.47-
1.55 (m, 1H), respectively. The multiplicity of the NMR
signal of H-9 for R-3b was attributed to an equivalent
axial-axial coupling between H-9 and H-11 and H-8,
* To whom correspondence should be sent. Tel: +33-1-44-27-66-
98. Fax: +33-1-43-26-00-61.
† Laboratoire de Chimie et Biochimie des Complexes Mole´culaires.
‡ Service de RMN.
(1) Lecomte, V.; Ste´phan, E.; LeBideau, F.; J aouen, G. Tetrahedron
2003, 59, 2169-2176.
(2) Lecomte, V.; Ste´phan, E.; Vaissermann, J .; J aouen, G. Steroids
2004, 69, 17-21.
(3) Cleve, A.; Fritzemeier, K.-H.; Heinrich, N.; Klar, U.; Mu¨ller-
Fahrnow, A.; Neef, G.; Ottow, E.; Schwede, W. Tetrahedron 1996, 52,
1529-1542. See also for modification of the symmetrical position 7:
Zheng, Y.; Li, Y. J . Org. Chem. 2003, 68, 1603-1606.
(4) The failure of the Barton-McCombie reaction was due to the
fact that the formation of the starting xanthate did not work by
literature methods on this substrate (see: Barton, D. H. R.; McCombie,
S. W. J . Chem. Soc., Perkin Trans. 1 1975, 1574-1585).
(5) Dolan, S. C.; McMillan, J . J . Chem. Soc., Chem. Commun. 1985,
1588-1589.
10.1021/jo0401016 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/27/2004
3216
J . Org. Chem. 2004, 69, 3216-3219

SCHEME 2. P r od u cts F or m ed u n d er F r ee-Ra d ica l a n d Th er m olytic Con d ition sa
a
Key: (a) n-BuLi, -78 °C, then Cl(CO)2OMe, -70 to -50 °C; (b) n-Bu3SnH, radical initiator, PhCH3; (c) refluxing toluene or mesitylene.
SCHEME 3. P r op osed Mech a n ism for th e Deoxygen a tion of 2a -c
indicating the R configuration. This configuration was
confirmed by cross-peaks in the NOESY spectrum of R-3b
between H-18 and H-11. The stereochemistry of R-3a was
determined by the same method using benzylic H-11
showing a chemical shift at δ 2.91 (ddd, J ) 12.5, 10.4,
4.7 Hz, 1H) due to two axial-axial couplings with H-9
and H-12ax and an equatorial-axial coupling with H-12eq.
The major epimer of 6 was isolated and its configura-
tion was determined by NMR methods as well. This
Scheme 3, a mechanism for the formation of R- and
S-3a ,b as well as for the formation of 6, inspired by the
Barton-McCombie deoxygenation6 is proposed. The first
step would be a reversible addition of the stannyl radical
to the oxalate moiety,7 followed by 3 possible competitive
pathways. In path A, a homolytic cleavage can lead to
3a -c. In the case of 2c, the stability of the radical
centered on C-11 would be too low to yield 3c. Path B
shows the competitive abstraction leading to alcohols 1a -
c. In the case of 2c, path C shows the intramolecular
5-exo cyclization leading to 6. According to literature
reports,8 the chairlike transition state A bearing the
larger groups C-9 and -OSnBu3 in pseudoequatorial
1
epimer showed H NMR chemical shifts for H-3′ and CH3-
ester at δ 2.95 (m, sep, 1H) and δ 3.83 (s, 3H), respec-
tively. Cross-peaks in the NOESY spectrum between H-3′
and H-12 were observed indicating the (R) configuration
at C-3′ of the THF residue. Moreover, cross-peaks be-
tween H of CH3-ester and H-12 were also observed
indicating a cis relation between substituents at C-3′ and
C-2′ and thus the (R) configuration at C-2′ of the THF
residue (see Scheme 2).
(6) Barton, D. H. R.; J ang, D. O.; J aszberenyi, J . C. Tetrahedron
Lett. 1990, 31, 3991-3994.
(7) The addition may reversibly occur on both of the carbonyls of
the oxalate, but no cyclization product from the furthest carbone of
the oxalate has been detected.
(8) Beckwith, A. L. J .; Zimmermann, J . J . Org. Chem. 1991, 56,
5791-5796. Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 41,
3925-3941. Beckwith, A. L. J . Tetrahedron 1981, 37, 3073-3100.
To date, no detailed study of the mechanism of the
radical deoxygenation of oxalates has been available. In
J . Org. Chem, Vol. 69, No. 9, 2004 3217

TABLE 2. Th er m olysis of Oxa la tes 2a -c
modified steroids will provide opportunities to study their
structure-activity relationships. Moreover, this paper
extends the use of oxalate derivatives to radical cycliza-
tion in order to produce valuable tetrahydrofuran deriva-
tives, such as 6. The scope and limitations of this reaction
is under study in our group.
entrya
substrate
conversionc (%)
isolated yield (%)
1
2a
2b
2c
2c
100 (4a )
76 (4a )
42 (5b)
2
100 (5b)
3
45 (4c)/55 (5c)
65 (4c)/35 (5c)
4b
36 (4c)/14 (5c)
a
Refluxing toluene until disappearance of the starting material.
Mesitylene as solvent (bp 162-164 °C). c Conversion determined
b
Exp er im en ta l Section
by means of 1H NMR.
Gen er a l Con d ition s for th e P r ep a r a tion of 2a -c. To a
solution of alcohol 1a -c (2.1 mmol) in THF at -60 °C (20 mL)
was slowly added a commercial solution of n-BuLi 2.1 M (1.6
mL, 3.36 mmol). The solution was stirred for 5 min at -60 °C
followed by addition of methyl chlorooxoacetate (4 mL, 4.2 mmol)
at -60 °C. The mixture was stirred at -60 °C for 30 min, the
temperature was slowly raised to rt, and the mixture was stirred
at rt for 2 h. The mixture was then diluted with ethyl acetate
(50 mL), and water was added (50 mL). The organic phase was
separated, washed with water and brine, and dried over
magnesium sulfate. The solvent was removed under vacuum to
afford a yellowish powder (99% conversion) which was further
used without purification.
positions is proposed to explain the stereochemistry of
the major epimer observed.
To date, the thermolysis of an oxalate moiety has never
been reported. As shown in Table 2, when the oxalate
derivatives 2a -c were stirred in refluxing toluene, 2a
yielded exclusively the endo cyclic compounds 4a (Table
2, entry 1) and 2b the exo cyclic compound 5b9 (Table 2,
entry 2). 2c led to a nonstatistical 45/55 mixture of endo-
and exocyclic compounds 4c and 5c, respectively (Table
2, entry 3). In that case, as the temperature was
increased, the ratio 4c/5c was also increased (Table 2,
entry 4). We assumed this increase, and the fact that the
ratio was far from the statistical 25/75 proportion, could
be explained by the lower stability of an exocyclic
compound versus an endocyclic one, as is the case for the
Chugaev pyrolysis of xanthates,10 but at lower temper-
ature (100-200 °C is usually required for the thermolysis
of xanthates). No other unsaturated product was detected
(namely no double bond in the 9(11) position).
The elimination of 11R-methyl-11â-hydroxy androst-
5-enes derivatives, such as 1c, under acidic (formic or
perchloric acid)11 or basic conditions (thionyl chloride-
pyridine)12 was described in the literature. Mixtures of
endo- (position 9(11)) or exocyclic unsaturated compounds
were obtained, but no mention was found of any elimina-
tion in position 11(12). In our case, such a regioselectivity
could be explained by an Ei mechanism involving a six-
membered cyclic transition state requiring cis hydrogen.
Such a transition state was proposed for the similar
Chugaev thermolysis of xanthates.10
Free-radical cyclization is a widely used method to
prepare substituted tetrahydrofuran derivatives occur-
ring in many natural products,13 but no report was found
on the use of homoallylic oxalates as precursors for such
compounds. However, as shown in Table 1, they may be
considered as new tools for stereoselective access to
2,2,5,5-tetrasubstituted 3-methyltetrahydrofuran.
In summary, we have developped a novel approach to
highly hindered 11R- and 11â-modified androst-5-ene, as
well as to 11-modified androstadiene, starting with the
oxalate derivatives 2a -c obtained in quantitative yields.
This method will especially make 11â derivatives more
easily obtainable than before. The availability of 11-
If desired, an analytical sample of 2b and 2c14 can be obtained
by purification on silica gel chromatographic column using a
100/1 dichloromethane/ethyl acetate mixture.
11R-Allyl-11â-(O-m eth yloxoa ceta te)-3,3,17,17-(eth ylen e-
d ioxy)a n d r ost-5-en e (2b): mp 72 °C; 1H NMR (CDCl3) δ 0.85
(4H, m), 0.92 (3H, s), 1.25 (5H, m), 1.42 (3H, s), 1.61-2.17 (16H,
m), 2.63 (1H, m), 2.65 (1H, d, J ) 15.0 Hz), 2.91 (1H, dd, J )
15.0, 6.0 Hz), 3.48 (1H, dd, J ) 15.0, 6.0 Hz), 3.86 (3H, s, CH3-
O), 3.81-3.96 (8H, m), 5.14 (1H, d, J trans ) 17.4 Hz), 5.16 (1H,
d, J cis ) 10.5 Hz), 5.31 (1H, bs), 5.82 (1H, m); 13C NMR (CDCl3)
δ 14.3, 21.5, 23.5, 31.0, 31.9, 32.9, 34.1, 36.8, 38.0, 41.1, 41.7,
44.2, 44.7, 50.3, 52.4, 53.2, 64.2, 64.5, 64.6, 65.1, 94.1, 108.5,
119.5, 119.7, 121.4, 134.1, 141.8, 156.6, 158.8; MS (m/z) 516 [M]+
(3), 457 [M - CO2Me]+ (5), 413 (9), 99 (100); IR (KBr) cm-1 1737,
1763. Anal. Calcd for C29H40O8: C, 67.42; H, 7.80. Found: C,
67.28; H, 7.99.
11R-Met h yl-11â-(O-m et h yloxoa cet a t e)-3,3,17,17-(et h yl-
1
en ed ioxy)a n d r ost-5-en e (2c):. mp 82 °C; H NMR (CDCl3) δ
0.91 (3H, s), 1.28-1.47 (4H, m), 1.38 (3H, s), 1.60-2.21 (21H,
m), 1.90 (3H, s), 2.61 (1H, bd, J ) 14.8 Hz), 2.69 (1H, d, J )
14.9 Hz), 3.86 (3H, s), 3.82-3.96 (8H, m), 5.35 (1H, m); 13C NMR
(CDCl3) δ 14.5, 21.0, 23.3, 31.1, 31.3, 32.1, 32.4, 34.2, 38.4, 40.4,
41.6, 41.8, 44.6, 51.2, 53.2, 59.4, 64.2, 64.4, 64.6, 65.1, 90.8, 108.6,
119.3, 121.5, 141.0, 156.4, 158.8; MS (m/z) 490 [M]+ (1), 431 [M
- CO2Me]+ (1), 387 (4), 99 (100); IR (KBr) cm-1 1740, 1764. Anal.
Calcd for C27H38O8: C, 66.10; H, 7.81. Found: C, 65.58; H, 8.08.
11R-P h e n y l-3,3,17,17-(e t h y le n e d io x y )a n d r o s t -5-e n e
(R-3a ). A solution of 2a (0.18 mmol, 100 mg), Bu3SnH (0.36
mmol, 0.09 mL), and AIBN (20 mol %, 5 mg) in dry and degassed
toluene (2.2 mL) was heated at 80 °C for 2 h. The solvent was
evaporated, and the crude mixture was chromatographed with
petroleum ether/ethyl acetate 9/1 to afford R-3a (13.8 mg, 17%
yield): mp 91 °C; 1H NMR (CDCl3) δ 0.70-0.91 (3H, m), 0.98
(3H, s), 1.16 (3H, s), 1.21-1.85 (20H, m), 2.01-2.08 (3H, m),
2.48 (1H, dq, J ) 13.7, 3.6 Hz), 2.99 (1H, ddd, J ) 12.5, 10.4,
4.7 Hz), 3.71-3.94 (8H, m), 5.41 (1H, bs), 7.03-7.21 (5H, m);
13C NMR (CDCl3) δ 14.5, 18.4, 23.4, 31.1, 31.7, 33.6, 34.3, 38.0,
39.8, 40.7, 42.3, 43.7, 45.6, 49.4, 53.0, 64.0, 64.3, 64.5, 65.1, 68.2,
77.2, 108.9, 119.1, 119.5, 122.4, 125.6, 128.4, 140.6, 149.2; MS
m/z 451 [M+ + H] (100), 389 (32); HRMS calcd for C29H39O4 (M+
+ H) 451.2848, found 451.2849.
11R-Allyl-3,3,17,17-(eth ylen ed ioxy)a n d r ost-5-en e (R-3b),
11â-Allyl-3,3,17,17-(eth ylen ed ioxy) a n d r ost-5-en e (S-3b),
a n d Sp ir o[3,3,17,17-(eth ylen ed ioxy)a n d r ost-5-en e-11,5′-tet-
r a h yd r ofu r a n -3′-m eth yl-2′-h yd r oxy-2′-m eth yl a ceta te] (6).
A solution of 2b (200 mg, 0.39 mmol), Bu3SnH (0.21 mL, 0.77
(9) Only one elimination product with an exocyclic double bond was
formed, as shown by 13C NMR of the crude mixture, but its stereo-
chemistry could not have been determined. However, on the basis of
the supposed Ei mechanism favoring the most stable alkene, we
assumed that its configuration was s-trans.
(10) Nace, H. R. Org. React. 1962, 12, 57-100.
(11) Elks, J . J . Chem. Soc. 1960, 3333-3339.
(12) Kirk, D. N.; Petrow, V. J . Chem. Soc. 1961, 2091-2098.
(13) For recent reviews on the preparation of oxygen heterocycles,
see, for example: Elliott, M. C. J . Chem. Soc., Perkin Trans. 1 2002,
2301-2323; Elliott, M. C.; Williams, E. J . Chem. Soc., Perkin Trans.
1 2001, 2303-2340.
(14) The intermediate 2a can be stored in air without noticeable
degradation but cannot be purified by silica gel column chromatogra-
phy. However, its formation was confirmed by 1H NMR of the crude
mixture showing chemical shifts for CH3-18 and -19 and CO2CH3 at δ
1.01 (3H, s), 1.37 (3H, s), and 3.94 (3H, s), respectively.
3218 J . Org. Chem., Vol. 69, No. 9, 2004

mmol), and AIBN (10 mg, 20 mol %) in dry and degassed toluene
(4.8 mL) was refluxed for 1 h. The solution was cooled, and water
was added. The organic phase was separated, washed, and dried
on magnesium sulfate. The solvent was evaporated under
vacuum, and the crude was chromatographed on silica gel, first
neutralized with a 5% v/v NEt3 solution in petroleum ether, to
136.9, 140.9, 141.9, 146.7; MS m/z 448 [M+] (9), 386 (1), 99 (100);
IR (KBr) cm-1 759, 694. Anal. Calcd for C29H36O4: C, 77.64; H,
8.09. Found: C, 77.48; H, 8.16.
11-(Vin ylm eth yliden e)-3,3,17,17-(eth ylen edioxy)an dr ost-
5-en e (5b). A solution of 2b (100 mg, 0.19 mmol) in dry toluene
(2 mL) was refluxed overnight. The organic phase was washed
with water and dried on magnesium sulfate. The solvent was
evaporated under vacuum, and the crude was chromatographed
with a mixture petroleum ether/ethyl acetate 9/1 to afford 5b
(33 mg, 42% yield): mp 110 °C; 1H NMR (CDCl3) δ 0.91 (3H, s),
1.08 (3H, s), 1.18-1.37 (3H, m), 1.51 (1H, dt, J ) 13.8, 3.9 Hz),
1.66-2.03 (13H, m), 2.13 (1H, dd, J ) 13.8, 3.3 Hz), 2.25 (1H,
dt, J ) 13.2, 3.6 Hz), 2.48 (1H, bd, J ) 13.8 Hz), 2.84 (2H, m),
3.90-4.01 (8H, m), 5.01 (1H, bd, J trans ) 17.4 Hz), 5.02 (1H, bd,
J cis ) 10.2 Hz), 5.51 (1H, bd, J ) 5.7 Hz), 5.76 (2H, m); 13C NMR
(CDCl3) δ 17.5, 17.7, 21.9, 30.9, 31.3, 33.9, 35.0, 37.5, 41.0, 42.6,
42.7, 46.5, 47.3, 55.9, 64.3, 64.3, 64.4, 65.3, 108.9, 115.9, 118.7,
123.6, 133.5, 137.4, 137.5, 141.7; MS (ICP/NH3) m/z 430 [M +
NH4] (100). Anal. Calcd for C26H36O4: C, 75.69; H, 8.80. Found:
C, 75.53; H, 8.97.
11-Meth yl-3,3,17,17-(eth ylen ed ioxy)a n d r ost-5,11(12)-d i-
en e (4c) a n d 11-Meth ylid en e-3,3,17,17-(eth ylen ed ioxy)-
a n d r ost-5-en e (5c). A solution of 2c (613 mg, 1.25 mmol) in
dry mesitylene was refluxed for 2 h. The organic phase was
washed and dried on magnesium sulfate. The solvent was
evaporated under vacuum, and the crude was chromatographed
with a mixture petroleum ether/ethyl acetate 9/1 to afford 4c
(173 mg, 36% yield) [mp 80 °C; 1H NMR (CDCl3) δ 0.92 (3H, s),
1.07 (3H, s), 1.30 (2H, m), 1.48 (1H, dt, J ) 13.8, 3.9 Hz), 1.66
(2H, m), 1.81 (3H, s), 1.75-1.97 (10H, m), 2.14 (1H, dd, J ) 13.7,
3.0 Hz), 2.31 (1H, dt, J ) 13.1, 3.6 Hz), 2.52 (1H, dq, J ) 13.7,
2.1 Hz), 3.87-4.01 (8H, m), 5.51 (1H, bd, J ) 6.0 Hz), 5.70 (1H,
s); 13C NMR (CDCl3) δ 17.6, 18.0, 22.1, 27.6, 30.9, 31.3, 33.7,
34.9, 37.4, 40.5, 42.6, 46.7, 47.1, 56.7, 64.2, 64.3, 64.4, 65.2, 109.0,
118.7, 123.4, 133.3, 135.0, 141.7; MS (m/z) 386 [M]+ (5), 99 (100).
Anal. Calcd for C24H34O4: C, 74.58; H, 8.87. Found: C, 74.55;
H, 8.96] and 5c (69 mg, 14% yield) [mp 234 °C; 1H NMR (CDCl3)
δ 0.77 ( 3H, s), 1.23 (1H, m), 1.29 (3H, s), 1.38 (1H, dt, J ) 14.1,
3.9 Hz), 1.55-1.98 (11H, m), 2.14 (1H, dt, J ) 14.1, 3.0 Hz),
2.38 (1H, bd, J ) 12.0 Hz), 2.47 (1H, dt, J ) 13.8, 3.7 Hz), 2.61
(1H, dq, J ) 14.4, 2.9 Hz), 3.83-3.99 (8H, m), 4.98 (2H, bd, J )
8.4), 5.30 (1H, bs); 13C NMR (CDCl3) δ 14.4, 18.7, 23.1, 31.1,
32.0, 33.5, 34.5, 34.9, 37.4, 41.9, 45.6, 46.6, 51.1, 54.1, 64.2, 64.4,
64.5, 65.2, 109.1, 113.5, 119.0, 120.7, 141.6, 145.0; MS (m/z) 387
[M + H]+ (100). Anal. Calcd for C24H34O4: C, 74.58; H, 8.87.
Found: C, 74.54; H, 8.95.]
1
afford R-3b (34 mg, 21% yield) [mp 132 °C; H NMR (CDCl3) δ
0.84 (3H, s), 1.06 (1H, t, J ) 10.2 Hz), 1.15 (3H, s), 1.19-1.29
(1H, m), 1.35-1.47 (5H, m), 1.61-1.71 (3H, m), 1.74-1.97 (5H,
m), 2.03-2.22 (3H, m), 2.42 (1H, dm, J ) 14.7 Hz), 2.58 (1H,
dq, J ) 14.0, 2.6 Hz), 3.81-3.98 (8H, m), 4.97 (1H, bd, J trans
)
15.9 Hz), 4.98 (1H, bd, J cis ) 11.5 Hz), 5.43 (1H, bd, J ) 5.6
Hz), 5.73-5.82 (1H, m); 13C NMR (CDCl3) δ 14.8, 17.7, 23.4, 31.3,
31.6, 32.7, 34.2, 37.9, 38.3, 39.9, 41.5, 42.7, 45.3, 49.4, 52.2, 64.3,
64.4, 64.6, 65.2, 109.0, 116.1, 119.7, 122.8, 137.0, 140.7; m/z 414
[M+] (1), 99 (100). Anal. Calcd for C26H38O4 C, 75.32; H, 9.24.
Found: C, 74.97; H, 9.44], S-3b (50 mg, 31% yield) [mp 132 °C;
1H NMR (CDCl3) δ 0.95 (3H, s), 1.15 (3H, s), 1.19-1.30 (1H, m),
1.35-1.42 (1H, m), 1.46-1.55 (3H, m), 1.63-1.78 (7H, m), 1.85
(1H, dt, J ) 13.1, 3.6 Hz), 1.97-2.03 (1H, m), 2.09-2.25 (4H,
m), 2.48-2.52 (1H, m), 2.56 (1H, dq, J ) 14.0, 2.6 Hz), 3.81-
3.98 (8H, m), 4.96-5.02 (2H, m), 5.16-5.17 (1H, m), 5.68-5.78
(1H, m); 13C NMR (CDCl3) δ 16.0, 21.6, 22.9, 29.4, 30.9, 31.8,
32.2, 34.2, 34.7, 36.9, 37.2, 40.8, 45.6, 52.4, 53.4, 64.2, 64.5, 64.6,
65.1, 109.0, 115.6, 119.8, 120.9, 139.7, 141.7; MS m/z 414 [M+]
(1), 99 (100); HRMS calcd for C26H37O4 (M+ - H) 413.2692, found
413.2690], and 6 (49 mg, 27% yield) [mp 132 °C; 1H NMR (CDCl3)
δ 0.86 (3H, s), 0.96 (3H, d, J ) 6.7 Hz), 1.19-1.31 (1H, m), 1.37
(3H, s), 1.36-1.45 (1H, m), 1.50-1.60 (3H, m), 1.65-1.86 (7H,
m), 1.96-2.03 (2H, m), 2.09 (1H, dd, J ) 14.5, 3.2 Hz), 2.16 (1H,
d, J ) 13.6 Hz), 2.57 (1H, dd, J ) 14.5, 2.9 Hz), 2.58 (1H, t, J )
12.5 Hz), 2.74 (1H, dt, J ) 12.2, 3.5 Hz), 2.95 (1H, sep), 3.83
(3H, s), 3.86-3.98 (8H, m), 5.29-5.31 (1H, m); 13C NMR (CDCl3)
δ 13.0, 13.7, 20.7, 23.9, 31.1, 34.0, 36.6, 37.9, 41.7, 41.9, 44.3,
45.2, 48.0, 49.7, 53.0, 53.3, 64.2, 64.3, 64.4, 65.0, 89.0, 102.9,
108.9, 119.8, 121.4, 142.9, 172.7; MS (ICP/NH3) m/z 536 [M +
NH4]+ (7.5), 519 [M + H]+ (100), 501 [M - H2O + NH4]+ (70);
IR (KBr) cm-1 1744 (CdO). Anal. Calcd for C29H42O8: C, 67.16;
H, 8.16. Found: C, 66.78; H, 8.30].
11-P h en yl-3,3,17,17-(eth ylen ed ioxy)a n d r osta -5,11(12)-d i-
en e (4a ). A solution of 2a (604 mg, 1.09 mmol) in dry toluene
(30 mL) was refluxed overnight. The organic phase was washed
with water and dried on magnesium sulfate. The solvent was
evaporated under vacuum, and the crude was chromatographed
with a mixture petroleum ether/ethyl acetate 85/15 to afford 4a
1
(374 mg, 76% yield): mp 211 °C; H NMR (CDCl3) δ 0.77 (1H,
dt, J ) 13.3), 1.00 (1H, dt, J ) 13.7), 1.06 (6H, s), 1.23-1.52
(4H, m), 1.74 (1H, m), 1.82-2.12 (8H, m), 2.41 (1H, dq, J ) 13.7),
2.60 (1H, m), 3.75-3.95 (8H, m), 5.52 (1H, bs), 5.80 (1H, d, J )
1.5 Hz), 7.13-7.29 (5H, m); 13C NMR (CDCl3) δ 17.6, 18.5, 21.9,
31.9, 33.6, 35.0, 38.2, 41.4, 42.3, 46.4, 47.5, 55.6, 64.0, 64.1, 64.3,
65.2, 77.2, 109.0, 118.5, 123.4, 125.9, 126.9, 127.6, 128.1, 128.4,
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0401016
J . Org. Chem, Vol. 69, No. 9, 2004 3219