Efficient synthesis of a tricyclic BCD analogue of ouabain: Lewis acid catalyzed Diels-Alder reactions of sterically hindered systems

Article abstract of DOI:10.1002/1521-3773(20021104)41:21<4125::AID-ANIE4125>3.0.CO;2-E

The right mix! A 10:1 mixture of AlBr₃ and AlMe₃ promotes the Diels-Alder reaction of hindered dienophiles. For example, the Diels-Alder reaction of an acetyldiene with a tert-butyldimethylsilyl (TBS) enol ether gave mainly the exo c

Full text of DOI:10.1002/1521-3773(20021104)41:21<4125::AID-ANIE4125>3.0.CO;2-E

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[5] a) S. E. Denmark, A. Thorarensen, Chem. Rev. 1996, 96, 137; b) S. E.
Denmark, J. J. Cottell in The Chemistry of Heterocyclic Compounds:
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry To-
ward Heterocycles and Natural Products (Eds.: A. Padwa, W. H.
Pearson), Wiley-Interscience, New York, 2002, pp. 83 167.
[6] S. E. Denmark, D. S. Middleton, J. Org. Chem. 1998, 63, 1604.
[7] a) D. Seebach, G. Calderari, P. Knochel, Tetrahedron 1985, 41, 4861;
b) P. Knochel, D. Seebach, Tetrahedron Lett. 1982, 23, 3897.
Efficient Synthesis of a Tricyclic BCDAnalogue
of Ouabain: Lewis Acid Catalyzed Diels Alder
Reactions of Sterically Hindered Systems**
Michael E. Jung* and Pablo Davidov
The naturally occurring cardenolide ouabain (1a) and its
aglycone ouabagenin (1b) are members of a class of highly
oxygenated cardiotonic steroids
[8] D. L. J. Clive, C. C. Paul, Z. Wang, J. Org. Chem. 1997, 62, 7028.
[9] a) E. Vedejs, D. Gapinski, J. P. Hagen, J. Org. Chem. 1981, 46, 5451;
b) E. Vedejs, D. W. Powell, J. Am. Chem. Soc. 1982, 104, 2046.
[10] a) F. Bohlmann, M. Ganzer, M. Kr¸ger, E. Nordhoff, Tetrahedron
1983, 39, 123; b) W. F. Bailey, Y. Tao, Tetrahedron Lett. 1997, 38, 6157.
[11] T. K. Chakraborty, S. Chandrasekaran, Synth. Commun. 1980, 10, 951.
[12] a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans. 1
1975, 1574; b) D. H. R. Baron, J. Dorchak, J. C. Jaszberenyi, Tetrahe-
dron 1992, 48, 7435; c) M. J. Robins, J. S. Wilson, F. Hansske, J. Am.
Chem. Soc. 1983, 105, 4059.
O
(digitalis glycosides) used in the
O
treatment of congestive heart fail-
Me
ure.[1] Ouabain has been synthe-
HO
HO
HO
sized starting from other natural
steroids,[2] however, no total syn-
thesis[3] has been reported to date
although an excellent synthetic
route has been described.[4] We
have reported some preliminary
results on an approach to the
H
H
OH
RO
1
OH
[13] Data for 1: b.p.: 408C (0.1 Torr); H NMR (500 MHz, CHCl3, TMS):
d ¼ 1.33 (m, 4H, HC(5), HC(4)), 1.46 (m, 2H; HC(2)), 1.78 (m, 4H;
HC(5), HC(4)), 1.89 (m, 2H; HC(2)), 2.02 (m, 1H; HC(6)), 2.18 (m,
2H; HC(3)), 2.70 (dt, J ¼ 10.5, 6.2 Hz, 2H; HC(1)), 2.92 ppm (dt, J ¼
10.5, 6.4 Hz, 2H; HC(1)); 13C NMR (126 MHz, CHCl3): d ¼ 29.6, 30.3,
30.5 (C(2), C(4), C(5)), 50.9 (C(3)), 51.9 (C(6)), 52.4 (C(1)), 93.1 ppm
(C(7)); IR (CH2Cl2): n˜ ¼ 2945 (s), 2864 (m), 1454 (w), 1269 (vw), 1209
(vw), 1173 (vw), 1119 (vw); MS (FAB): m/z (%): 178 (Mþþ1, 100);
TLC (CHCl3/MeOH 20:1, Al2O3): Rf ¼ 0.64; C,H,N analysis (%):
calcd for C12H19N: C 81.30, H 10.80, N 7.90; found: C 81.02, H 10.95, N
7.97.
1a R = L-rhamnose
1b R = H
bicyclic CD ring system of ouabain in which we attempted
to use an anionic [1,3] sigmatropic shift of a 7-alkenylbicy-
clo[3.2.1]heptane-1,7-diol, which afforded products from an
unusual anion-accelerated retroene reaction.[5] We report
here a completely different route that allowed us to prepare a
tricyclic BCD ring system analogue of ouabain in a very
efficient manner. In this route we have developed a novel
Diels Alder reaction of sterically hindered enones and dienes
to afford heavily substituted cyclohexene systems extremely
easily.
Initially, we decided to investigate a possible Diels Alder
approach for the synthesis of the CD ring system of ouabain.
Cycloaddition of a 1-(alkoxyvinyl)cyclohexene 2 with the
enone 3 followed by conversion of the ketone to an acetate by
a Baeyer Villiger oxidation and final hydrolysis and reduc-
tion of the cyclic ketone would give the diol 4, which has the
required five contiguous asymmetric centers of the BCD ring
system of ouabain (Scheme 1). The anticipated difficulty of
carrying out a Diels Alder reaction with a hindered dien-
ophile such as 3 made us first investigate a simpler model
system. All attempts at effecting the cycloaddition of 2-
trimethylsilyloxybutadiene (5) with the known dienophile 6
[14] X-ray crystal structure analysis of 1¥BH3. A single crystal deposited
from Et2O solution at À258C: formula C12H22BN. Mr ¼ 191.12, crystal
size 0.2 î 0.2 î 0.02 mm3, a ¼ 6.2685(13) ä, b ¼ 12.773(3) ä, c ¼
7.5043(15) ä, b ¼ 111.517(4)8, V¼ 558.93(19) ä3, 1calcd ¼ 1.136 gcmÀ3
,
m ¼ 0.064 mmÀ1, absorption correction by integration, Z ¼ 2, mono-
clinic space group P21, Siemens 3-circle platform diffractomer with a
molybdenum (Ka ¼ 0.71073 ä) X-ray source and CCD area detector,
T¼ 193(2) K, 5835 measured reflections (Æ h, Æ k, Æ l), 1074 inde-
pendent and 722 observed reflections with I > 2s(I), R ¼ 0.0423, wR ¼
0.0494 (against j F2 j ), residual electron density 0.12 eä3; programs
used: SHELXTL V6. CCDC-189803 contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (þ 44)1223-336-033; or deposit@ccdc.ca-
m.ac.uk).
[15] A similar twist has been established by electron diffraction (12.48) in
the parent hydrocarbon that gives rise to an overall D2 symmetry: J.
Brunvoll, R. Guidetti-Grept, I. Hargittai, R. Keese, Helv. Chim. Acta
1993, 76, 2838.
MeR
R
H
R'O
HO
1) Diels-
Alder
2) Baeyer-
Villiger
3) Hydrolysis
4) Reduction
H
Me
Me
H
+
H
OH
O
3
2
4
Scheme 1. Diels Alder approach to the diol 4, which contains the BCD
ring system of ouabain (1a).
[*] Prof. M. E. Jung, Dr. P. Davidov
Department of Chemistry and Biochemistry
University of California, Los Angeles
405 Hilgard Ave, Los Angeles, CA 90095-1569 (USA)
Fax : (þ 1)310-206-3722
E-mail: jung@chem.ucla.edu
[**] We thank the National Institutes of Health for their support and the
National Science foundation under equipment grant CHE-9974928.
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(see Scheme 2; prepared in one step from cyclohexane)[6]
were unsuccessful; thermal conditions (toluene, 1108C)
returned the starting materials, and Lewis acid catalysis
(AlCl3 or TiCl4) resulted in decomposition of the diene.[7]
Even the highly reactive Danishefsky©s diene (trans-1-me-
thoxy-3-trimethylsilyloxy-1,3-butadiene) did not give the
expected product with the enone 6, either at 238C for seven
days or at 1108C for several hours, thus implicating the
unreactivity of the dienophile 6.
Since the trimethylsilyl enol ether did not withstand the
Lewis acidic conditions, we decided to study the more stable
diene 7 (see Scheme 2). We have shown that this diene is quite
useful in various cycloadditions.[8] Again thermal conditions
(1108C/48 h) did not effect cycloaddition and starting materi-
als were returned. However, use of mixed Lewis acid systems
afforded a mixture containing the desired product in good
yield. Thus treatment of 7 and 6 in toluene with 50 mol% of a
10:1 AlCl3 and AlMe3 mixture at 08C for 2 h furnished a
1.2:1:0.3 mixture of the desired exo isomer 8x, the endo
experiments; the undesired minor isomer 10n was highly
crystalline and was characterized by X-ray crystal structure
analysis.[15] The last stereocenter was introduced by Li/NH3
reduction of the cyclic ketone 10x, which yielded the expected
equatorial alcohol and a 1:1 diastereomeric mixture of
secondary alcohols from the acetyl group (Scheme 3). The
H
Me
Me
Me
O
1) Li/NH3
80%
2) TBSOTf
96%
3) Dess-Martin
86%
Me
O
H
H
O
TBSO
H
H
10x
11
Me
OAc
H
H
TBSO
Ox
X
H
12
Scheme 3. Conversion of 10x to the silyl ether ketone 11 as a proposed
route to 12.
isomer 8n, and an unknown impurity tentatively assigned
12]
structure 9[9] in 73% yield (Scheme 2).[10
However, we
two alcohols were easily differentiated by selective protection
of the equatorial alcohol with a tert-butyldimethylsilyl (TBS)
group. The acetyl moiety was regenerated in quantitative
yield by exposure to the Dess Martin periodinane to give the
silyl ether ketone 11. At this point we were ready to attempt
the second key step of the route, the Baeyer Villiger
oxidation. Unfortunately, the acetyl moiety is so sterically
hindered that all attempts to effect this oxidation failed to
yield any of the desired product 12.[16] This result seemed to
doom this attempt at the preparation of a tricyclic BCD ring
system analogue of ouabain by this route.
TBSO
Me
Me
AlCl3/Me3Al/0 °C/2h 73%
+
8x:8n:9 1.2 : 1 : 0.3
AlBr3/Me3Al/0 °C/1h 86%
8x:8n:9 3 : 1 : 0.5
O
6
7
Me
Me
TBSO
TBSO
Me
Me
H
H
+
+
O
Me
O
O
Me
OTBS
Thus, we decided to try to effect an inverse electron
demand in the key cycloaddition, namely the coupling of an
electron-poor diene with an electron-rich dienophile
(Scheme 4). The desired 2-acetyl-1,3-diene 14 was prepared
9
8n
8x
Me
O
Me
O
MeOH
PPTs
H
H
+
O
25 °C
90%;
SiO2
H
H
AlBr3
Me3Al
-78 °C
5 min
1) 48% HBr
2) tBuLi;
Me
O
Me
Me
Me
+
OMe
10n
10x
TBSO
Me
N
Me
59%
Scheme 2. Reaction between the dienophile 6 and hindered diene 7 in the
presence of the mixed Lewis acid system 10:1 AlCl3/AlMe3. TBS ¼ tert-
butyldimethylsilyl, PPTs ¼ pridinium p-toluenesulfonate.
15
77%
O
13
14
Me
Me
O
AcO
found that AlBr3 is much easier to work with[13] than AlCl3
and was thus preferable as a catalyst. Use of 50 mol% of a
10:1 mixture of AlBr3/AlMe3 in a toluene/dichloromethane
mixture at 08C for 1 h afforded the same three products 8x,
8n, and 9 in 86% yield in a 3:1:0.5 ratio. We propose that the
small amount of AlMe3 eliminates any trace of HX in the
medium thereby extending the stability of the silyloxy diene.
The two diastereomeric products were inseparable by column
chromatography but conversion of the silyl enol ethers
proceeded in excellent yield under mildly acidic conditions[14]
to give the two diastereomeric ketones, 10x and 10n, which
were separable by simple column chromatography. The
structures of these ketones were assigned by NOE NMR
K2CO3
MeOH
quant.
Me
(TMSO)2
BF3 OEt2
H
H
.
OTBS
OTBS
50%
16 βH + 17 αH 10 : 1
18
NOE
H H
Me
OH
Me
H
1) Li/NH3
85%
O
HO
OTBS
2) KF/18-C-6
DMSO
∆/36 h
83%
H
20
19
Scheme 4. Synthesis of the desired ketone 19 and its conversion to the diol
20, a BCD ring system analogue of ouabain (1a). 18-C-6 ¼ [18]crown-6.
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from ethynylcyclohexene (13) in two steps (addition of HBr[17]
and coupling of the derived organometallic compound with
the Weinreb amide).[18] This enone was then treated with the
TBS-protected enol ether 15 under the same conditions as
before–50 mol% of a 10:1 mixture of AlBr3 and AlMe3 in
toluene/dichloromethane at À788C for 5 min–to afford a
10:1 diastereomeric mixture of the desired exo adduct 16 and
the endo adduct 17 in 77% yield, which were easily separable
by chromatography, affording 16 in 72% yield. Baeyer
Villiger oxidation of this mixture of enones was effected by
using bis(trimethylsilyl) peroxide and BF3¥OEt2 to furnish the
desired acetate 18 in 50% yield. This enol acetate was
hydrolyzed in quantitative yield under mildly basic conditions
to yield the desired ketone 19. The structure of this ketone
was assigned based on a strong NOE between the quaternary
methyl group and the equatorial proton a to the ketone group
(Scheme 4). Reduction of the ketone 19 with Li/NH3 yielded
the desired equatorial alcohol in 85% yield. Finally depro-
tection of the TBS group required forcing conditions,[19]
namely heating with KF in DMSO for 36 h, to cleanly remove
the protecting group and yield the desired diol 20 in 83%
yield along with 15% of the recovered hydroxy silyl ether.
The structure of 20 was confirmed by a single-crystal X-ray
structure analysis (Figure 1).[16]
TMS
O
O
AlBr3
Me3Al
Me
+
Me
-78 °C
5 min
TBSO
28%
TMS
Me
21
14
TMS
Me
O
O
O
O
Me
Me
H
H
+
OTBS
OTBS
22
10 : 1
23
Scheme 5. Synthesis of 22 and 23 by using the highly functionalized silyl
enol ether 21 as ring D precursor.
In summary, we have been able to prepare the diol 20, a
tricyclic BCD ring system analogue of the steroid ouabain 1a,
by an efficient route that highlights a new procedure for the
formation of hindered cyclohexyl systems through the use of a
mixed Lewis acid medium for effecting cycloadditions of
hindered systems bearing acid-sensitive functionalities. Fur-
ther studies on this reaction and the synthesis of ouabain 1a
are currently in progress.
Experimental Section
Diels Alder adducts 8x and 8n: The enone 6 (1.5 g, 12 mmol) was
dissolved in a solution of toluene (20 mL) and dichloromethane (7 mL),
and the mixture was cooled to À88C. Trimethylaluminum (0.3 mL of a 2.0m
solution in toluene, 0.6 mmol) was slowly added to the solution, followed
after 15 min by aluminum bromide (6 mL of a 1.0m solution in dibromo-
methane, 6 mmol). The mixture was stirred 15 min and the silyl enol ether 7
(3.8 g, 16 mmol) in dichloromethane (5 mL) was slowly added to the
mixture. The reaction was warmed to 08C over 1 h and quenched with
pyridine (20 mL) and the mixture warmed to 238C. The suspension was
filtered over a small pad of silica gel, and the solvent removed in vacuo. The
product was purified by column chromatography over silica gel (94:6
hexanes/ethyl acetate) to yield the desired compound (3.724 g, 10.3 mmol,
86%) as a 3:1 mixture of the diastereomers 8x and 8n. The diastereomers
were inseparable by column chromatography. 8x: 1H NMR (500 MHz,
CDCl3): d ¼ 2.92 (bd, 1H), 2.73 (bd, 1H), 2.19 (s, 3H), 1.99 (m, 1H), 1.55
1.81 (m, 8H), 1.03 1.48 (m, 6H), 1.00 (s, 3H), 0.93 (s, 9H), 0.10 (s, 3H),
0.09 ppm (s, 3H); 13C NMR (125.75 MHz, CDCl3): d ¼ 214.8, 138.2, 113.3,
64.1, 44.2, 42.1, 40.0, 38.6, 31.5, 30.7, 30.1, 29.5, 25.9, 25.6, 22.6, 20.1, 18.2,
Figure 1. X-ray structure analysis of diol 20.
Finally, we have some preliminary results that indicate that
more functionalized silyl enol ethers can be used as ring D
precursors in this process (Scheme 5). A racemic mixture of
the silylfuran 21 was synthesized by using a modified version
of the procedure developed by Kim and Park.[20] Treatment of
the diene 14 and the dienophile 21 with 0.5 equivalents of
AlBr3 and 0.05 equivalents of AlMe3 at À788C for 5 min
furnished a 10:1 mixture of the exo adduct 22 and the endo
adduct 23 in 28% yield. The structures were assigned based
on our previous results (for the exo/endo stereocenter) and
NOE experiments which displayed a through-space interac-
tion between the protons of the quaternary methyl group and
a proton from the furyl group, thus implying that the two
groups were syn to each other. Although this unoptimized
reaction provided low yields of the desired exo adduct 22, it
demonstrated the feasibility of this approach to obtain
advanced tricyclic adducts containing four correct contiguous
stereocenters plus a butenolide-equivalent moiety.
1
14.1, À3.8, À3.9 ppm. 8n: H NMR (500 MHz, CDCl3): d ¼ 2.98 (bd, 1H),
2.12 (s, 3H), 1.55 1.81 (m, 8H), 1.03 1.48 (m, 8H), 0.95 (s, 9H), 0.90 (s, 3H),
0.13 (s, 3H), 0.11 ppm (s, 3H); 13C NMR (125.75 MHz, CDCl3): d ¼ 214.1,
140.0, 113.9, 63.8, 43.2, 41.2, 39.3, 38.8, 31.7, 30.9, 30.2, 29.3, 25.8, 25.7, 22.7,
20.0, 18.4, 14.3, À3.7, À4.0 ppm; IR of mixture (thin film on NaCl): n˜ : 2955
(s), 2930 (s), 2857 (m), 1696 (s), 1471 (m), 1361 (m), 1251 (m), 1179 (m), 851
(s), 777 cmÀ1 (m); MS of mixture (m/z): 362.29 [Mþ], 319.26, 239.20, 182.12.
Diels Alder adducts 16: The dienone 14 (0.793 g, 5.27 mmol) was dissolved
in a solution of toluene (7 mL) and dichloromethane (3.5 mL) and the
mixture was cooled to À788C. Trimethylaluminum (0.125 mL of a 2.0m
solution in toluene, 0.25 mmol) was added as a chemical dessicant. Shortly
afterwards (5 min), aluminum bromide (2.5 mL of a 1.0m solution in
dibromomethane, 2.5 mmol) was added dropwise followed immediately by
the silyl enol ether 15 (1.27 g, 6 mmol) neat. After 5 min the reaction was
quenched by adding pyridine (10 mL) at À788C and warming the mixture
to 238C. The suspension was filtered through a small pad of silica and the
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filtrate was concentrated in vacuo. 1H NMR spectroscopy of the crude
product reveals a 10:1 mixture of diastereomers 16 and 17 in favor of the
desired exo adduct. The residue was purifed by column chromatography on
silica gel (95:5 hexanes/ethyl acetate) to yield the desired isomer 16 (1.46 g,
4.03 mmol, 76.5%). 1H NMR (500 MHz, CDCl3): d ¼ 2.77 (bd, 1H), 2.19 (s,
3H), 2.12 (m, 1H), 2.05 (m, 2H), 1.89 (bd, 1H), 1.72 1.85 (m, 4H), 1.65 (m,
3H), 1.40 (m, 2H), 1.23 (m, 2H), 1.15 (m, 1H), 0.92 (s, 3H), 0.86 (s, 9H),
0.11 (s, 3H), 0.10 ppm (s, 3H); 13C NMR (125.75 MHz, CDCl3): d ¼ 205.8,
140.8, 129.8, 87.3, 46.1, 44.7, 38.6, 37.0, 33.4, 30.8, 29.9, 29.4, 27.0, 26.1, 25.9,
18.9, 18.3, 18.1, À2.3, À2.8; IR (thin film on NaCl): u˜ ¼ 2953 (s), 2928 (s),
2855 (s), 1690 (s), 1471 (m), 1350 (m), 1251 (s), 1226 (m), 1124 (s), 1062 (s),
1005 (m), 833 (s), 770 cmÀ1 (s); high-resolution MS (m/z) [MþH]þ
362.2616, calcd for C22H38O2Si 362.2641.
[11] Although this Diels Alder reaction could be a concerted [4þ2]
cycloaddition, we propose that the cycloaddition occurs by a stepwise
mechanism, namely a double Mukaiyama-type Michael addition
rather than a concerted [4þ2] cycloaddition and thus produces the exo
product as the major isomer. For an example of a Diels Alder
reaction of the diene 6 with 2-methylcyclohexenone under Lewis acid
catalysis to give mainly the endo adduct, see: a) M. Ge, B. M. Stoltz,
E. J. Corey, Org. Lett. 2000, 2, 1927; since the endo isomer is the minor
isomer in our case, we favor the double Michael process. For examples
of Mukaiyama Michael additions, see: b) K. Narasaki, K. Soai, T.
Mukaiyama, Chem. Lett. 1974, 1223; c) D. A. Evans, K. A. Scheidt,
J. N. Johnston, M. C. Willis, J. Am. Chem. Soc. 2001, 123, 4480; d) G.
Desimoni, G. Faita, S. Filippone, M. Mella, M. G. Zampori, M. Zema,
Tetrahedron 2001, 57, 10203; for examples of double Michael additions
to produce [4þ2] cycloadducts, see: e) M. E. Jung in Comprehensive
Organic Synthesis, Vol. 4 (Ed.: B. M. Trost), Pergamon, Oxford, 1991,
chap. 1.1, pp. 1 67 (especially pp. 30 32).
[12] It should be pointed out that Diels and Alder just described the
reaction of a diene and dienophile to give cyclohexene systems
without implying any mechanistic detail and thus this reaction is a
Diels Alder reaction by their definition even if the mechanism is
more likely stepwise than concerted.
[13] Aluminum tribromide (AlBr3) is commercially available as a 1m
solution in dibromomethane, while aluminum trichloride (AlCl3) is
supplied as a 1m solution in nitrobenzene. The lower boiling point and
lack of a chromophore makes the use of the former preferable. All of
the solutions of AlBr3 and AlMe3 were prepared by mixing the
commercially available solutions (a 2m solution of AlMe3 in toluene
was used).
[14] Hydrolysis of the silyl enol ether with tetrabutylammonium fluoride
(TBAF) gave poor yields, presumably due to retro-Michael reactions.
[15] We thank Dr. Saeed Khan for obtaining the X-ray crystal structures.
CCDC-194419 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
n.ac.uk/conts/retrieving.html (or from the Cambridge Crystallograph-
ic Centre, 12 Union Road, Cambridge CB21EZ, UK; Fax: (þ
44)1223-336033; or deposit@ccdc.cam.ac.uk).
[16] For example, oxidation with meta-chloroperoxybenzoic acid
(MCPBA) (alone or in the presence of a radical inhibitor at elevated
temperatures), trifluoroperacetic acid, 3,5-dintiroperbenzoic acid,
hydrogen peroxide, and bis(trimethylsilyl)peroxide in the presence
of trimethylsilyl triflate gave only starting material or desilylated
starting material under all conditions tried. The addition of several
other nucleophiles to this very hindered ketone was also unsuccessful.
[17] J. C. Traynard, Bull. Soc. Chim. Fr. 1962, 19.
Received: June 17, 2002 [Z19541]
[1] a) R. Thomas, P. Gray, J. Andrew, Adv. Drug Res. 1990, 19, 312;
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[2] J. R. Hanson, Nat. Prod. Rep. 1993, 10, 313.
[3] a) For the total synthesis of digitoxigenin, see: G. Stork, F. West, Y. H.
Lee, R. C. Isaacs, S. Manabe, J. Am. Chem. Soc. 1996, 118, 10660;
b) for the total synthesis of a derivative of 9,11-dehydrodigitoxigenin,
see: A. R. Daniewski, M. M. Kabat, M. Masnyk, J. Wicha, W.
Wojciechowska, H. Duddeck, J. Org. Chem. 1988, 53, 4855.
[4] Overman and co-workers have reported significant progress toward
the total synthesis of ouabain. a) L. E. Overman, P. V. Rucker,
Heterocycles 2000, 52, 1297; b) S. Laschat, F. Narjes, L. E. Overman,
Tetrahedron 1999, 55, 347; c) L. E. Overman, P. V. Rucker, Tetrahe-
dron Lett. 1998, 39, 4643; d) J. Hynes, Jr., L. E. Overman, T. Nasser,
P. V. Rucker, Tetrahedron Lett. 1998, 39, 4647; e) W. Deng, M. S.
Jensen, L. E. Overman, P. V. Rucker, J. P. Vionnet, J. Org. Chem. 1996,
61, 6760.
[5] M. E. Jung, P. Davidov, Org. Lett. 2001, 3, 3025; for earlier work in this
area, see: M. E. Jung, P. Davidov, Org. Lett. 2001, 3, 627.
[6] K. E. Harding, K. S. Clement, J. Org. Chem. 1984, 49, 2049.
[7] An attempt to effect a tandem Michael Michael process by treating
the silyl enol ether with methyllithium consumed the starting material
but no desired bicyclic product was isolated.
[8] For examples, see: M. E. Jung, N. Nishimura, J. Am. Chem. Soc. 1999,
121, 3529; M. E. Jung, Nishimura, N. Org. Lett. 2001, 3, 2113.
[9] This impurity decomposes on attempted chromatographic purifica-
1
tion. It exhibits a TBS group and an olefinic proton in the H NMR
spectrum of the crude product mixture and thus is most likely
compound 9.
[18] a) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815; b) M. P.
Sibi, Org. Prep. Proced. Int. 1993, 25, 15.
[19] Hydrolysis of the TBS ether could not be effected with TBAF in THF
at 238C or at reflux. Acidic conditions caused extensive elimination of
the silyl ether to give the trisubstituted alkene.
[10] For examples of somewhat hindered cycloadditions of this type, see:
a) T. Fujiwara, T. Ohsaka, T. Inoue, T. Takeda, Tetrahedron Lett. 1988,
29, 6283; b) I. S. Levina, L. E. Kulikova, A. V. Kamernitskii, B. S.
El©yanov, E. M. Gonikberg, Izv. Akad. Nauk, Ser. Khim. 1992, 1622;
c) R. D. Hubbard, B. L. Miller, J. Org. Chem. 1998, 63, 4143.
[20] S. Kim, J. H. Park, Synlett 1995, 163.
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