In the course of synthetic work to develop novel antitumor retinoidal compounds, we synthesized 1) g-hydroxybutenolides 1a-d (Fig. 1) containing conjugated double bond structures of various length. Biological activity measurements of these compounds revealed that only compound 1c had promising properties. The compound 1c is the equivalent of a formyl carboxylic acid 1cЈ, which has a structure similar to that of retinoic acid having a formyl group at the C-13 position. In human promyelocytic leukemia (HL-60) cells, only 1c showed both differentiation-and apoptosis-inducing activities in a manner different from retinoic acid.
1)Indeed its apoptosis-inducing potency at 10 Ϫ6 M was almost compatible to that of staurosporine, a well-known potent inducer of apoptosis in HL-60 cells.2)The earlier procedure 1,3) for the synthesis of g-hydroxybutenolides has been unsatisfactory, because the harsh conditions employed in the final step resulted in a low yield. Furthermore it was difficult to purify the desired products from the reaction mixture due to the generation of by-products.Herein, we describe an improved procedure, suitable for the synthesis of not only g-hydroxybutenolides 1a-d but also their analogues 17a-d having various heteroaromatic rings. The anti-tumor activities of these analogues are also reported.
Results and DiscussionImproved Synthesis of g g-Hydroxybutenolides 1a-d Recently, Yamamoto and his coworkers reported 4) that vinylogous crossed aldol condensation between a,b-unsaturated esters and aldehydes in the presence of the bulky Lewis acid, aluminum tris(2,6-diphenylphenoxide) (ATPH), and lithium 2,2,6,6-tetramethylpiperidide (LTMP) regioselectively gave g-addition products. In order to synthesize g-hydroxybutenolides 1a-d effectively, we applied this method for the condensation of aldehydes 2a-d with the protected g-hydroxyb-methylbutenolides 3 or 4 (Chart 1).The preparation of compounds 3 and 4 was initiated by the Emmons-Horner reaction of pyruvic aldehyde dimethyl acetal with triethyl phosphonoacetate in the presence of NaH to give an isomeric mixture (E : Zϭ15 : 1) of the ester 5 (94%). Treatment of 5 with 6 M hydrochloric acid under reflux afforded the g-hydroxy-b-methylbutenolide 6 5) (quant.), which was then protected with the triethylsilyl (TES) or tert-butyldimethylsilyl (TBS) group by the usual method to give the corresponding ethers 3 (86%) and 4 (64%), respectively.According to Yamamoto's procedure, 4) precomplexation of a solution of benzaldehyde 2a (1.0 eq) and the triethylsilyloxy (TESO)-butenolide 3 (2.0 eq) in toluene with ATPH (3.3 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan. Received June 4, 2007; accepted June 27, 2007 An improved synthesis of g g-hydroxybutenolides 1a-d was achieved via crossed aldol condensation between aldehydes 2a-d and the protected g g-hydroxy-b b-methylbutenolides 3 or 4 using the bulky Lewis acid, aluminum tris(2,6-diphenylphenoxide) (ATPH). Using this same methodology, the g g-hydroxybutenolides 17a-d having various heteroaromatic rings w...
