Synthesis of cis,cis,cis,cis-[5.5.5.5]-1-Azafenestrane

Article abstract of DOI:10.1002/1521-3773(20021104)41:21<4122::AID-ANIE4122>3.0.CO;2-W

To provide an opportunity for X-ray analysis of an unsubstituted fenestrane, one of the ring-fusion carbon atoms was replaced with a nitrogen atom to facilitate salt formation; the key strategic step to the first 1-azafenestrane (see scheme) involves the

Full text of DOI:10.1002/1521-3773(20021104)41:21<4122::AID-ANIE4122>3.0.CO;2-W

COMMUNICATIONS
[1] For recent reviews see: a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95,
2457 2483; b) S. P. Stanforth, Tetrahedron 1998, 54, 263 303; c) A.
Suzuki, J. Organomet. Chem. 1999, 576, 147 168.
prises molecules with planarizing distortion of the central
carbon atom. The magnitude of the distortion is dependent on
the size and configuration of the fused rings. Because the
parent, unsubstituted fenestranes are low molecular weight
hydrocarbons, they are not amenable to X-ray crystallo-
graphic analysis. The few X-ray structures on record are of
substituted and functionalized derivatives.[2]
We were intrigued by the possibility of replacing one of the
ring-fusion carbon atoms with a nitrogen atom to facilitate salt
formation and provide an opportunity for X-ray analysis of an
unsubstituted fenestrane. In addition to establishing the full
molecular structure and the extent of the central carbon
planarization, the pyramidal distortion of the nitrogen atom
would also be of interest; to our knowledge, no monoazafe-
nestranes have been prepared. An unusualtetraamino
[5.5.5.5]fenestrane is known and it exists as an equilibrium
mixture of (degenerate) open and closed forms when proto-
nated.[3] We describe herein the first synthesis of an unsub-
stituted 1-azafenestrane 1 along with the synthesis and X-ray
crystallographic analysis of the borane adduct 1¥BH3.
[2] Recent examples of Suzuki coupling reactions with aryl chlorides: a) L.
Botella, C. Nµjera, Angew. Chem. 2002, 114, 187 189; Angew. Chem.
Int. Ed. 2002, 41, 179 181; b) S.-Y. Liu, M. J. Choi, G. C. Fu, Chem.
Commun. 2001, 2408 2409; c) R. B. Bedford, C. S. J. Cazin, Chem.
Commun. 2001, 1540 1541; d) M. R. Netherton, G. C. Fu, Org. Lett.
2001, 3, 4295 4298; e) A. Zapf, A. Ehrentraut, M. Beller, Angew.
Chem. 2000, 112, 4315 4317; Angew. Chem. Int. Ed. 2000, 39, 4153
4155; f) M. G. Andreu, A. Zapf, M. Beller, Chem. Commun. 2000,
2475 2476; g) D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem.
Soc. 1998, 120, 9722 9723; h) J. P. Wolfe, R. A. Singer, B. H. Yang, S. L.
Buchwald, J. Am. Chem. Soc. 1999, 121, 9550 9561; i) X. Bei, H. W.
Turner, W. H. Weinberg, A. S. Guram, J. Org. Chem. 1999, 64, 6797
6803; j) C. Zhang, J. Huang, M. L. Trudell, S. P. Nolan, J. Org. Chem.
1999, 64, 3804 3805; k) A. F. Littke, G. C. Fu, Angew. Chem. 1998, 110,
3586 3587; Angew. Chem. Int. Ed. 1998, 37, 3387 3388.
[3] Ligand 3 is cheaper than triphenylphosphane (source: Aldrich Chem-
icals catalogue).
[4] D. A. Albisson, R. B. Bedford, S. E. Lawrence, P. N. Scully, Chem.
Commun. 1998, 2095 2096.
[5] R. B. Bedford, S. L. Welch, Chem. Commun. 2001, 129 130.
[6] Complex 4 could not be isolated pure, but rather contained small
amounts of dimer 2a, even when a large excess of PCy3 was used in the
synthesis. 31P NMR spectroscopy the confirmed cis disposition of P
donors (2JP, P ¼ 40 Hz).
H
B
H
H
[7] Fu and co-workers have recently reported that highly sterically
hindered triarylphosphanes can catalyze couplings of electronically
deactivated aryl chlorides (see ref. [2b]), indicating that more subtle
effects than brute donor-strength can play an important role.
[8] Beller and Zapf have shown that non-orthometalated complexes of
triarylphosphites can couple activated aryl chlorides: A. Zapf, M.
Beller, Chem. Eur. J. 2000, 6, 1830 1833.
N
N
a
d
b
c
a
b
c
H
H
H
H
d
H
1
H
1•BH3
[9] We are assuming that the catalytic cycle proceeds by a Pd0/PdII pathway.
This assumption is made on the basis of studies into the activation of
palladacyclic precatalysts in Suzuki coupling reactions. See reference
[2c] for leading references.
Analysis of the tetracyclic ring structure of 1 reveals that it
contains an embedded pyrrolizidine unit fused to a bicy-
clo[3.3.0]octane system. In recent years, a large number of
pyrrolizidine-based alkaloid natural products in the necine,
alexine and australine families have been synthesized in these
laboratories.[4] The key strategic operation in all of these
syntheses is the tandem [4þ2]/[3þ2] cycloaddition of nitro-
alkenes.[5] This process allows for the facile and stereocon-
trolled construction of highly functionalized nitroso acetals
that serve as precursors for pyrrolizidines upon catalytic
hydrogenolysis.
Synthesis of cis,cis,cis,cis-[5.5.5.5]-1-
Azafenestrane**
Scott E. Denmark,* Laurenz A. Kramps, and
Justin I. Montgomery
The application of the tandem cycloaddition strategy to the
synthesis of 1 is outlined in Scheme 1. Constructing the core of
1 requires the creation of one of the four rings in the tandem
[4þ2]/[3þ2] process by cycloaddition of a C2 dienophile (butyl
vinylether ( 3)) with a cyclopentenyl nitro diene 2 (ring C)
bearing the suitable dipolarophilic tether. The tetracyclic
nitroso acetal 4 is then poised for hydrogenolytic unmasking
to a tricyclic pyrrolizidine (third ring, c) which should undergo
spontaneous lactam formation (!5; fourth ring, d) from the
appended carboxylic ester. Thus, three of the four rings of
[5.5.5.5]-1-azafenestrane can be assembled in two chemical
manipulations. Two-stage reduction of the a-hydroxy lactam 5
leads to the target azafenestrane 1. This approach allows for a
modular synthesis of fenestranes containing rings of different
size at various positions. With regard to the configuration at
the ring fusions, only one relationship was expected to be
variable. In the [4þ2] process, the approach of the dienophile
can take place on the two diastereotopic faces of the
nitroalkene to create cis and trans isomers. The [3þ2] process
is formally in the spiro mode family[6] and thus is expected to
The structuraltheory of organic chemistry is one of the
most highly evolved constructs in natural science. The ability
to explain and correctly predict the detailed molecular
structure of millions of compounds naturally inspires research
to test the limits of the theory. One important subset of this
field of investigation probes the extent to which a tetracoor-
dinate carbon atom (bearing all carbon substituents) can
deviate from the van©t Hoff/Le Beltetrahedralgeometry. The
interesting family of compounds called fenestranes[1] com-
[*] Prof. Dr. S. E. Denmark, Dr. L. A. Kramps, J. I. Montgomery
Department of Chemistry
University of Illinois, Urbana, IL 61801 (USA)
Fax : (þ 1)217-333-3984
E-mail: denmark@scs.uiuc.edu.
[**] We are gratefulto the NationalInstitutes of Heatlh for generous
financialsupport (R01 GM30938). J.I.M. thanks the Procter and
Gamble Company for a graduate fellowship.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
4122
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COMMUNICATIONS
O
NO2
H
OnBu
OCH3
O
a
b
O
N
N
N
HO
H
H3CO2C
a
d
b
c
a
b
c
O
H3CO
I
H
H
H
H
H
d
7
9
H
1
H
5
H
4
NO2
OCH3
O
O
2
NO2
H
H3CO
H3CO
H3CO2C
I
NO2
7
NO2
NO2
9
HO
I
OPiv
c
d, e
+
OBu
HO
THPO
3
6
NO2
8
10
2
THPO
I
Scheme 3. a) 1. tBuLi, THF/hexane/Et2O, À1008C, 2. 6, À508C, TsOH, aq.
acetone, 61%; b) trimethylphosphonoacetate, nBuLi, THF, À708C, 22%;
c) 1. tBuLi, THF/hexane/Et2O, À1008C, 2. 6, À508C, TsOH, MeOH, 67%;
d) Dess Martin reagent, CH2Cl2, 89%; e) 1. [(H2bipy)Cl5CrO], CH2Cl2, 2.
MeOH, 3. CH2N2, 36% (three steps).
8
10
Scheme 1. Retrosynthetic strategy for the construction of azafenestrane 1
by tandem [4þ2]/[3þ2] cycloaddition. Piv ¼ pivaloyl, THP ¼ tetrahydro-
pyranyl.
proceed via an exo-mode pathway to create a cis ring fusion
independent of the tether length.
Both the aldehyde 9 and the primary alcohol 10 were obtained
in comparable, synthetically viable yields after hydrolysis of
the protective groups. Homologation of 9 by using either
methyl (triphenylphosphoranylidene)acetate or trimethyl-
phosphonoacetate (with nBuLi) afforded low (15 22%)
yields of 2. The oxidation of alcohol 10 could be effected
with the Jones reagent, but low yields were obtained and the
purification of the product proved to be difficult. Better
results were obtained when [(H2bipy)Cl5CrO][11] in CH2Cl2
was used. This chromium(v) complex afforded a mixture of
acid and acid chloride, which could be converted to the
desired ester 2 simply by treatment with MeOH. The
remaining carboxylic acid could be converted to 2 with
diazomethane.
The [4þ2] cycloaddition of nitroalkene 2 and butylvinyl
ether (3) afforded two diastereomers of nitronate 13. Onl y one
of these diastereomers underwent spontaneous [3þ2] cyclo-
addition to give nitroso acetal 4a (Scheme 4). Nuclear Over-
hauser NMR spectroscopic investigations of 4a confirmed the
relative configuration of this compound (Scheme 5).
The side chain of nitroalkene 2 (that creates ring d) could
be introduced by nucleophilic addition to the nitro allylation
reagent 6.[7] The required nucleophiles (alkyllithium reagents)
could be obtained by halogen metal exchange from the
corresponding iodides 7 and 8. Each side chain precursor
requires a different sequence to complete the construction of
the desired a,b-unsaturated ester: 1) Horner-Wadsworth-
Emmons (HWE) or Wittig reaction with aldehyde 9 and
2) oxidation of an allyl alcohol 10 to the acid followed by
esterification. Both approaches were pursued in view of the
unknown sensitivity of the nitroalkene to these agents.
The synthesis began by preparation of the key subunits
(Scheme 2). Pivalate 6 was prepared by modification of
procedures for the synthesis of the analogous cyclohexene
NO2
NO2
O
a
b
OCH3
H3CO
OH
OPiv
6
The reaction has not been optimized to controlthe
diastereoselectivity by the use of different Lewis-acids.
Increasing the selectivity of the reaction would improve the
yield of nitroso acetal 13a. Nitronate 13b is also a useful
compound and the separation from the nitroso acetal 4a was
easy because of the high polarity of 13b compared to that of
4a. Preliminary investigations indicated that the nitronate
13b can undergo [4þ2] cycloaddition at elevated temperature
(NaHCO3, toluene, 978C) to give the diastereomeric nitroso
acetal 4b, which can potentially be transformed to diastereo-
meric fenestrane 1b (Scheme 4).
Hydrogenation of nitroso acetal 4a afforded hydroxy 1-
azafenestranone 5 in 72% yield. The yield of 5 from
nitroalkene 2 is 48%–remarkable for the formation of a
fenestrane skeleton. Completion of the synthesis required two
deoxygenation steps (Scheme 6). First, the hydroxy group was
removed by conversion to the phenylthionocarbonate 12,
which was reduced with nBu3SnH/AIBN by a method
originally described by Barton and McCombie.[12] The result-
ing lactam 13 was reduced with LiAlH4 to give the target
cis,cis,cis,cis-[5.5.5.5]-1-azafenestrane (1).
c
THPO
THPO
THPO
THPO
OH
OH
I
12
11
d
e
OTs
8
13
Scheme 2. a) 1. HCl, 808C, 2. NaOH, MeNO2, H2O, MeOH, RT, 3. Al2O3,
408C; b) pivalic anhydride, H2SO4, 9% (four steps); c) LiAlH4, Et2O,
reflux, 70%; d) TsCl, Et3N, CH2Cl2 08C, 90%; e) NaI, acetone, reflux,
99%. Ts ¼ tosyl.
derivative.[7] Unfortunately, the cyclopentenyl case could not
be optimized above 9%, but the reactions could be scaled up
by using inexpensive starting materials. The iodo acetal 7[8]
and THP-protected iodide 8[9] were prepared directly and by
adaptation of literature procedures, respectively.
The nitro allylating agent 6 behaved similarly toward the
two organolithium nucleophiles derived from 7 and 8 by
iodine lithium exchange with tert-butyllithium [10] (Scheme 3).
Angew. Chem. Int. Ed. 2002, 41, No. 21
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4123

COMMUNICATIONS
diethylether to afford 1¥BH3 as colorless needles. X-ray
crystallographic analysis[14] of 1¥BH3 (Figure 1) confirms the
gross molecular structure but also reveals that the compound
NO2
OCH3
O
2
a
H
O
OnBu
H
OnBu
O
O
O
N
H
N
H
H
H
+
16a
16b
MeO2C
MeO2C
c
H
O
OnBu
OnBu
H
H
H
O
O
O
H3CO2C
N
H3CO2C
N
H
H
H
H
4b
H
4a
Figure 1. SHELXTL plot of 1¥BH3 from X-ray analysis (35% thermal
ellipsoids).
b
O
HO
H
N
N
H
H
H
H
crystallizes in a chiral space group (P21) because of the twist of
the five-membered rings (dihedralangel B-N(1)-C(13)-
C(7) ¼ 11.68).[15] The planarization of the central carbon atom
(C(13)) is only modest as defined by the two orthogonal bond
angles: N-C(13)-C(7) ¼ 116.18 and C(4)-C(13)-C(10) ¼ 116.68.
This was not unexpected as these angles in the all-cis
stereoisomer of the parent [5.5.5.5]fenestrane hydrocarbon
are calculated to be 1138.[1]
In summary, we have demonstrated the feasibility of a
tandem cycloaddition approach to 1-azafenestranes and the
ability to obtain crystalline adducts suitable for X-ray analysis.
The preparation of more strained and flattened congeners is
underway and will be reported in due course.
H
5
Scheme 4. a) 3, Me3Al, toluene, À708C, 4a (67%) and 16b (27%);
b) Raney nickel, H2 (1100 kPa, 160 psi), MeOH 72%; c) benzene, K2CO3,
808C, 70%.
2.5 %
H
OBu
0.6 %
H
O
O
H3CO2C
N
H
H
H
7.8 %
4a
Scheme 5. nOe analysis of nitroso acetal 4a.
Received: July 18, 2002 [Z19766]
OPh
O
O
S
[1] M. Thommen, R. Keese, Synlett 1997, 231.
HO
N
O
H
N
a
[2] a) W. C. Han, K. Takahashi, J. M. Cook, U. Weiss, J. V. Silverton, J.
Am. Chem. Soc. 1982, 104, 318; b) R. Guidetti-Grept, B. Herzog, B.
Debrunner, V. Siljegovic, R. Keese, H.-M. Frey, A. Hauser, O. Kˆnig,
S. L¸thi, J. Birrer, D. Nyffeler, M. Fˆrtsch, H.-B. B¸rgi, Acta
Crystallogr. Sect. C 1995, 51, 495; c) M. Thommen, R. Keese, M.
Fˆrtsch, Acta Crystallogr. Sect. C 1996, 52, 2051; d) D. Hirschi, W.
Luef, P. Gerber, R. Keese, Helv. Chim. Acta 1992, 75, 1897; e) V. B.
Rao, C. F. George, S. Wolff, W. C. Agosta, J. Am. Chem. Soc. 1985, 107,
5732; f) S. Wolff, B. R. Venepalli, C. F. George, W. C. Agosta, J. Am.
Chem. Soc. 1988, 110, 6785; g) W. A. Smit, S. M. Buhanjuk, S. O.
Simonyan, A. S. Shashkov, Y. T. Struchkov, A. I. Yanovsky, R. Caple,
A. S. Gybin, L. G. Anderson, J. A. Whiteford, Tetrahedron Lett. 1991,
32, 2105; h) P. A. Wender, M. A. de Long, F. C. Wireko, Acta
Crystallogr. Sect. C 1997, 53, 954; i) D. Kuck, H. Bˆgge, J. Am. Chem.
Soc. 1986, 108, 8107; j) B. Bredenkˆtter, U. Flˆrke, D. Kuck, Chem.
Eur. J. 2001, 7, 3387; k) C. A. Dullaghan, G. B. Carpenter, D. A.
Sweigart, D. Kuck, C. Fusco, R. Curci, Organometallics 2000, 19, 2233.
[3] J. E. Richman, H. E. Simmons, Tetrahedron 1974, 30, 1769.
[4] a) S. E. Denmark, A. Thorarensen, D. S. Middleton, J. Am. Chem.
Soc. 1996, 118, 8266; b) S. E. Denmark, E. A. Martinborough, J. Am.
Chem. Soc. 1999, 121, 3046; c) S. E. Denmark, A. R. Hurd, J. Org.
Chem. 2000, 65, 2875; d) S. E. Denmark, B. Herbert, J. Org. Chem.
2000, 65, 2887; e) S. E. Denmark, J. J. Cottell, J. Org. Chem. 2001, 66,
4276.
H
H
H
H
H
5
17
b
O
N
H
N
c
H
H
H
H
1
H
18
Scheme 6. a) Phenylthionocohrloformate, pyridine, DMAP, 77%,
b) nBu3SnH, AIBN, benzene, reflux, 98%; c) LiAlH4, THF, reflux, 83%.
The spectroscopic data for 1 clearly support the structure
and Ch symmetry of the molecule (seven 13C NMR signals).[13]
To secure the detailed molecular structure, we surveyed the
formation of crystalline salts and found that treatment of 1
with a solution of borane in THF formed an adduct (as judged
by 1H NMR analysis) which could be recrystallized from
4124
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Angew. Chem. Int. Ed. 2002, 41, No. 21

COMMUNICATIONS
[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**
MichaelE. 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 totalsyn-
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
[5]
unusualanion-acceelrated retroene reaction.
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 crystalstructure anaylsis 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 ), residualeelctron density 0.12 eä 3; 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 NationalInstitutes of Heatlh for their support and the
NationalScience foundation under equipment grant CHE-9974928.
Angew. Chem. Int. Ed. 2002, 41, No. 21
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4121-4125 $ 20.00+.50/0
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