Tandem Michael-Michael-ring closure reactions
Research kindly provided
3925
a
sample of 9,11-dehydro-estrone
was cooled to -30° (CaCh + CO2 + H20) and a soln of 2-methyl-
2-cyclopentenone (100rag, 1.14 mmol) in 2ml anhyd THF was
added dropwise via syringe. After 30 rain at -30* the cold bath
was removed. After warming to 0*, the reaction was treated with
10ml sat NaH2PO4 aq and 5ml distilled water. The 2 phase
system was rotary evaporated (25 mm Hg) to remove the THF
then poured into a separatory funnel and extracted with 100 ml
ether. The organic phase was dried over NazSO,; filtration and
rotary evaporation gave the crude product (ca 360mg). Pre-
parative tic (8% EtOAc/benzene, Rt =0.30) gave the pure
Michael adduct 6a, 154 mg (56%): NMR (CDCh, 100 MHz): ~58.15
(d, IH); 7.1-6.8 (m, 2H), 3.93 (s, 3H), 3.2-1.6 (m, IIH), 1.05 (d,
J = 6 Hz, 3H); IR (CHCh): 1735 (s), 1675 (s), 1600 (s) cm-~; Exact
Mass: CITHzoO3 Calc: 272.1412, Found: 272.1406.
methyl ether (le). We also thank Prof. C. H. Robinson (Johns
Hopkins) for a helpful discussion.
REFERENCES
~°The term MIRC reaction was first coined by R. D. Little and J.
R. Dawson, Tetrahedron Letters, 2609 (19801; bfor a review of
the Michael reaction, see E. D. Berg,mann, D. Ginsburg and R.
Pappo, Org. Reactions 10, 179 0975) which includes as Michael
acceptors alkenes activated by groups other than carbonyl (e.g.
phosphonium groups).
:'~G. H. Posner, J. J. Sterling, C. E. Whitten, C. M. Lentz and D.
J. Brunelle, J. Am. Chem. Soc. 97, 107 (1975); UA. Alexakis, M.
J. Chapdelaine, G. H. Posner and A. W. Runquist, Tetrahedron
Letters 4205 (1978).
(-)-9,11-Dehydro-8-epiestrone Ib
A
dry 3-necked 250ml flask fitted with N: inlet, magnetic
J°G. H. Posner, M. J. Chapdelaine and C. M. Lentz, J. Org.
Chem. 44, 3661 (1979); bG. H. Posner, J. P. Mallamo and K.
Miura, J. Am. Chem. Soc. 103, 2886 (1981).
stirring bar, 50 ml pressure equalizing dropping funnel and serum
cap was charged with 4a (137mg, 0.55mmol) and 10ml anhyd
THF. The flask was cooled to 0° and treated, via syringe, with
MeLi (483 ~.l, 1.2 M, 0.58 mmol) in Et20 and stirred at room temp
for 60min. The flask was then cooled to -30° and treated
dropwise (via syringe) with 2-methyl-2-cyclopentenone (65 mg,
0.67 mmol) in I ml THF. After 30 min the reaction was diluted
with 150 ml anhyd THF and 10 ml anhyd DMF, then warmed to
room temp. The resulting orange-yellow soln was treated drop-
wise with a solution of VTB (426 mg, 1.15 mmol) in 50ml anhyd
DMF over a period of 4--6 hr. Stirring was continued at room
temp overnight. Transfer to a I-necked round-bottomed flask and
rotary evaporation to remove the THF was followed by removal
of DMF under vacuum (0.1 mm Hg) at 30° to give a crude viscous
oil which was diluted with CHCh for preparative tic (8%
EtOAc/benzene, RI = 0.40). Desorption of this band with EtOAc
(100ml) gave, after concentration, 13.2rag of lb (8.4%), m.p.
141-146°, which was recrystallized from EtOAc/EtOH (12.6mg,
8.0%, m.p. 149.5-150.: NMR (CI)Ch, 80 MHz): 87.54-6.60 (m,
3H), 6.01 (m, 1H), 3.79 (s, 3H), 2.99-1.56 (m, 12H), 0.96 (s, 3H);
IR (CHCI3: 1735, 1603 cm-J; MS (70 eV): 282 m/e (M', base); UV
(EtOH): A,~ 264nm (e = 17,900). Found: C, 80.69; H, 7.83. Calc
for CI9H2202: C, 80.82; H, 7.85.
Exact Mass: CI9Hz202, calc: MW=282.1620 Found:
282.1615.
This reaction was also performed on 2.9 mmol scale to give
62 mg of Ib (7.8%) and 482 mg of recovered 6-methoxy-l-tetra-
lone. Therefore the yield of lb based on reacted tetralone is
'intramolecular Wittig reactions have been used extensively in
preparation of natural products (e.g. of penicillin and analogs)
and of many structurally interesting compounds: "for a review.
see K. B. Becker, Tetrahedron 36, 1717 (1980): Ufor Michael
initiated intramolecular Wittig reactions see W. Flitsch and E.
R. Gesing, Chem. Ber. 113, 614 (1980) and J. M. Muchowski and
P. H. Nelson, Tetrahedron Letters 4585 (1980) and I.
Kawamoti, S. Muramatsu and Y. Yura, Ibid. 4223 (1974).
'aG. A. Kraus and J. U. Pezzanite, J. Org. Chem. 44, 2480
(1979); bj. Boyer, R. J. P. Corniu, R. Perz and C. R6y6, J.
Chem. Soc. Chem. Commun. 122 (1981).
~I'his biological screening was kindly performed by Dr. L. J.
Chinn and his associates at the G, D. Searle research and
development laboratories in Chicago, Illinois.
7~M. Demuth and P. R. Raghavan, Heir. Chim. Acta 62, 239
(1979); Up. Bennet, J. A. Donnelly and M. J. Fox, J. Chem. Soc.
Perkin I, 2990 (1979); ~C. N. Rentzea, Angew. Chem. Int. Ed.
Engl 19, 199 (1980); aW. S. Murphy and S. Wattanasin, Tetra-
hedron Letters 1887 (1980).
alsoilludins: A. Ichihara and T. Matsumoto, Bull. Chem. Soc.
Japan 47, 1030 0974).
9,j. Gosselck, H. Ahlbrecht, F. Dost. H. Shenk and G. Schmidt,
Tetrahedron Letters 995 (1968); UC. R. Johnson and J. P.
Lockard, Ibid. 4589 (1971); "C. R. Johnson and P. E. Rogers, J.
Org. Chem. 38, 1793 (1973); dK. Takaki and T. Agawa, Ibid. 42,
3303 (1977); eK. Takaki and K. Negoro, J. Chem. Soc. Perkin 1,
1490 (1979) and refs therein.
21.3%. Similar results were obtained using
a motor-driven
syringe to deliver the VTB to enolate 3b slowly and continuously
over a 10hr period.
~°Cyclopropane formation via intramolecular 1.3-displacement of
halide and oxyanion leaving groups has also been reported: "U.
Schmidt, Angew. Chem. Int. Ed. Engl. 4, 238 (1965); hM. S.
Newman, V. DeVries and R. Darlak, J. Org. Chem. 31, 2171
0966); 'H. Takei, Y. Fukuda, K. Sugaya, T. Taguchi and T.
Kawara, Chem. Letters 1307 (1380). Vinyl selenides have also
recently been used successfully: M. Shimizu and I. Kuwajima,
J. Org. Chem. 45, 2921 (1980).
"aJ. Causse-Zoller and R. Fraisse-Ju]lien, Bull. Soc. Chim. Fr
430 (1966); UR. Becker, G. Berz, M. R6sner, U. Rosentreter and
E. Winterfeldt, Chem. Ber. !12, 1879 (1979).
~2°p. Bravo, G. Gaudiano, C. Ticozzi and A. Umani-Ronchi,
Tetrahedron Letters 4481 (1968); Up. Bennett and J. A. Don-
nelly, Chem. Ind. 783 0969): cp. Bravo, G. Fromza, G. Gaudi-
ano, C. Ticozzi and M. G. Zubiani, Tetrahedron 27, 3563 (1971).
~3See E. E. Schweizer, A. T. Wehman and D. M. Nycz. J. Org.
Chem. 38, 1583 (1973).
14The acidities of the a-H in intermediate 13 and of the protons
adjacent to a phosphonium P atom appear to be approximately
of the same magnitude: ~H. O. House, Modern Synthetic
Reactions (2nd Edn) p. 684; Benjamin Menlo Park, Calif.
(1972); bH. O. House, W. F. Fischer Jr., M. Gall, T. E.
McLaughlin and N. P. Peet, J. Org. Chem. 36, 3429 (1971).
t~°Very little of neutral product 14 was formed before exposing
Isomerization of 8-epiestrone lb into (~-)-9,11-dehydroestrone
methyl ether (lc)
8-Epiestrone Ib (5.2 mg, 18.4 ~.mol, 'H NMR, C~r--CH3, ~50.96)
was refluxed in 3 ml of 5:1 MeOH/10 N HCI for 6 hr. The MeOH
was removed with gentle heating under a stream of N2. The
remaining aqueous suspension was cooled, diluted with 5 ml
NaH2PO4 buffer (pH = 4) and extracted 3 times with 5 ml Et20.
The combined Et20 extracts were dried over MgSO4. Filtration
and rotary evaporation gave 5.1 mg (98%) of a white solid m.p.
139-146°. NMR analysis of this sample (CDCh, 80MHz) in-
dicated the presence of a 3:1 mixture of le (CIs-CH3, ~50.93)~
and 20 (C~a-CH3, ~50.89). n These characteristically different
positions of the angular Gs-Me groups in the ~H NMR spectra of
lb, It and 20 allow very easy and clear distinction among the
three.
Acknowledgements--We thank the National Science Foundation
(CHE 79-15161), the Donors of the Petroleum Research Fund,
administered by the American Chemical Society, and the G.D.
Searle Co. for generous financial support. We also thank Martin
Hulce and Leah Frye for experimental assistance with parts of
this project, and Drs. D. J. Duchamp, G. Bundy, and J. A.
Campbell of the Upjohn Company for performing the x-ray
analysis of estrone lb and for providing us with a sample of
9,11-dehydroestrone. Drs. J. Ackrell and J. A. Edwards of Syntex
the reaction mixture to hydroxide ions;
cyclopropyl-
phosphonium salts are known to give neutral cyclopropanes in
good yield upon treatment with aqueous hydroxide; F. Ham-
merschmidt and E. Zbiral, Liebigs Ann. 1026 0977).
Posner, Gary H.
