Diastereoselective Synthesis of Chiral [4.4]- and [4.5]-Spiroketals from Furan Derivatives: Study on the Asymmetric Synthesis of Tonghaosu Analogs

Abstract

Diastereoselective syntheses of [4.4]-and [4.5]-spiroketal featured tonghaosu analogs were explored. An excellent diastereoselectivity was achieved for [4.5]-spiroketals due to anomeric, steric, and perhaps p-p interactions; [4.4]-spiroketal could be obtained in good diastereoselectivity by tuning substituted pattern of the tetrahydrofuran ring. Spiroketals as characteristic segments have been found in many natural products isolated from a number of sources such as insects, microbes, plants, fungi, and marine organisms. 1-3 Correspondingly, a series of efforts have been made towards the syntheses of these spiroketal characterized bio-active natural products. [1][2][3][4][5] The stereoselective control of the chirality for the spiro carbon is always a focus of their syntheses. With respect to the formation of [5.5]-spiroketal via acid-catalyzed intramolecular ketalization the stereoselective control of the stereochemistry of the spiro carbon is successful in most of cases due to three factors: 1 (1) steric interaction, (2) anomeric and related effects, 6 and (3) intramolecular hydrogen bonding and other chelation effects. However, the corresponding control in the [4.5] and especially the [4.4] system is less successful because of the absence of anomeric effect and substituent's (axial-equatorial) effect in the five-membered ring. Therefore, the diastereoselectivity of acid catalyzed spiroketalization of substituted [4.4]-spiroketal is usually moderate, 7 yet a few cases with excellent diastereoselectivity were reported. 8,9 Recently, diastereoselective formation of the spiro-carbon in a trisubstituted [4.5]-system under acidic reaction conditions has been reported and the formation of another diastereoisomer was not mentioned. 10 Tonghaosu, a special [4.4]-spiroketal [1, 2-(2¢,4¢-hexadiynylieden)-1,6-dioxaspiro-[4.4]-non-3-ene], is an antifeedant component of vegetable tonghao (Chrysanthemum segetum L. or C. coronarium L.) and some other plants of tribe Athemdeae. 11,12 Its B-ring homolog, a [4.5]-spiroketal 2, is also a natural product with antifeeding activity. 13 Tonghaosu and B-homo tonghaosu were first synthesized in the early 1960's by Bohlman in quite low overall yield. 14 Recently, a concise and general method for the synthesis of tonghaosu and its spiroketal enol-ether characterized analogs (3) was developed in our laboratory, 15-17 which employed dehydration spiroketalization under acid conditions as the key step (Scheme 1) and allowed for facile preparation of dozens of tonghaosu analogs on multi-gram scales. However this established method so far could only give racemic compounds. In order to better understand the structure-activity relationships of this kind of compounds and to search for more effective green agrochemicals, efforts towards the stereoselective control of the spiroketal carbon for tonghaosu analogs were prompted.Scheme 1 Tonghaosu and the synthetic strategy.At first, our effort was directed to prepare a tonghaosu analog precursor with chiral centers next to the furan ring. As shown in S...