Tefmhedron L.&m, Vol. 36. No. 26. pp. 4583-4584, 1995 Bkevia Science Ud

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Novel Syntheses of j3-Halo-cx$-Unsaturated Ketones

Michael H. Kress and Yoshito Kishi* Department of Chemistry, Harvard University

12 Oxford Street. Cambridge, Massachusetts 02138, U.S.A.

Abstruct: Novel methods have been developed for the transformation of unsymmetrical 1,3- diketones to phalo-a&unsaturated ketones. These new methods complement known syntheses of this functional group, allowing efficient access to a previously unattainable regioisomer.

During synthetic studies of O-cinnamoyltaxicin-I and -II triacetates, we required a mild synthesis of cyclic fi-iodo-a&unsaturated ketones. 1 The method of Piers and coworkers has found wide utility for the preparation of cyclic 3-haloenones from the corresponding 1,3-diketones.2 In the case of an unsymmetrically substituted 1,3-diketone, it has been shown that the reaction selectively takes place at the. sterically most accessible oxygen atom.:! As a relevant example, treatment of 2,4,4-trimethyl-1,3- cyclohexanedione (3) with either Ph3PBr2 or Ph3PI2 Icd to the exclusive formation of the corresponding 3- halo-2,6,6-trimethyl-2cyclohexen-l-ones (4a,b). In this letter, we report three methods for the selective transformation of 3 into regioisomerically pure halokctones 5.

s pTss

&!&I,#O~O~.,O ‘OCinn

x : OR .

&

X: 5 OR \O

5

OCinnamoyltaxicin-I Triacetate (X=OH) OCinnamyltaxkin-II Triacetate (X=H)

0 X

unknown

48 : X=l 4b : X=Br

3 5

The basis of our strategy was to first protect the most accessible oxygen atom, and subsequently activate the ste.rically less accessible oxygen atom for halide replacement. To this end, treatment of diketone 3 with i-BuOH in the presence of p-TsOH was known to yield exclusively vinylogous ester 6.3 As expected, 6 reacted with PBr3 or PI3 in melhylene chloride to yield the bromide 5b (67% yield; not optimized) or iodide Sa (36% yield; not optimijrcd) free from 4b or 4a, respectively. These experiments demonstrated that our general strategy allowed for the regiosclective preparation of ~-halo-@-unsaturated ketones. However, the vigorous reaction conditions required may preclude its application to substrates bearing fragile functional groups. Therefore, we sought milder, alternative methods for such cases.

Treatment of diketone 3 with TBSCI and Et3N produced exclusively vinylogous silylester 7.4 Deprotonation at the gamma position of enone, followed by dicthylchlorophosphate addition, providql diene 8 in 65-70% yield. Conversion of dicnc 8 to the desired b-iodoenonc Sa was accomplished cleanly by treatment with TMSI in CH2Cl2.5

4583

4584

Reagents and Conditions: a. i-BuOH, p-TsOH, C6Ho; b. PI3 or PBq, CH2Cl2 (36% or 67%; not optimized); c. TBSCI, Et3N. CH2Cl2 (82%); d. LHMDS, (EtO)2P(O)Cl, THF (67%); e, TMSI, CH2Cl2 (77%); f. l.ON HCI, THF (90%); g. (n-Bu$n)n-BuCuCNLi2, THF; h. 12, CH2Cl2 (85% overall yield from 9).

Alternatively, mild acid hydrolysis of 8 provided the cnone 9. Conjugate addition of a tributylstannyl anion to 9 was accompanied by elimination of the phosphate group, to afford the & tributylstannylenone 10 in 85% yield. 6.7 Addition of iodine to a solution of g-tributylstannylenone 10 in CH2Cl2 gave exclusively 3-iodo-2,4,4-trimetbyl-2_cyclohexen- l-one (Sa).

In conclusion, we have devclopcd three methods for the regioselective transformation of unsymmetrical 1,3-diketones to g-halo-a&unsaturated ketones. In comparison to previously established approaches, these methods afford complementary regioselcctivity for g-haloenone formation. In summary, the first route requires the fewest steps, but vigorous reaction conditions required may preclude its application to substrates bearing fragile functional groups. The last route requires the most steps, but the mildness of each step may allow its application to a wider range of substrates.

Acknowledgments: Financial support from the National Institutes of Health (CA-22215 and CA 55 148) is gratefully acknowledged.

References

1.

2.

3.

4.

5.

6.

7.

Kress, M. H.; Ruel, R.; Miller, W. H.; Kishi, Y. Tetruhe&un Letr. 1993,34, 5999 and 6003.

Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I. Can. J. Chem 1982.60, 210.

Rosenberger, M.; McDougal, P.; Bahr, J. 1. Org. Chem. 1982,47, 2130.

Treatment of 7 with PBq (CH$$/RT or reflux), TMSI (CH$l2/RT), or (COCl)2 (CHCl~teflux) did not yield the desired product.

For the reaction of vinyl phosphates with TMSI to afford vinyl iodides, see: Lee, K.; Wiemer, D. F. Tetrahedron L&t. 1993,34,2433.

For the formation of mixed higher order stannyl cuprates, see: Lipshutz, B. H.; Ellsworth. E. L.; Dimock, S. H.; Reuter, D. C. Tetrahedron Letr. 1989.30, 2065.

For the reaction of dialkyl cuprates with the cnol phosphate derivatives of g-keto esters, see: Sum, F.- W.; Weiler, L. Can. J. Chem 1979.57, 143 1.

(Received in USA 24 April 1995; revised 10 May 1995; accepted 12 May 1995)