A novel chiral benzoxazinone auxiliary was developed and applied to the synthesis of carbapenem antibiotics. The auxiliary 2 was easily accessible by the synthesis involving dehydrative condensation of l-menthone with salicylamide followed by stereospecific isomerization with a catalytic amount of 1, 8 -diazabicyclo [5. 4. 0] undec-7-ene (DBU). Excellent diastereoselectivity was observed in the auxiliary-mediated aldol reaction, affording syn-aldols 10 in high yields. A dramatic reversal in diastereofacial selectivities was attained simply by changing the metal, permitting either enantiomeric form of β- hy dr oxy -α-methylcarboxylic acid derivatives 10a or 10b to form from a single readily available benzoxazinone derivative 9. The highly stereoselective aldol reaction was successfully applied to the synthesis of acetoxyazetidinone 3, a key intermediate for penems and carbapenems. The propionate enolate derived from the benzoxazinone derivative 28, 31 reacted smoothly with the acetoxyazetidinone 3 to furnish the intermediate 29 carrying four contiguous asymmetric centers of the 1-β-methylcarba-penems 4 in a high yield with a virtually complete β-selectivity. The high-yield Dieckmann-type cyclization thanks to the high leaving group ability of the auxiliary, and subsequent efficient removal of the protective groups completed a practical synthetic scheme of the 1-β-methylcarbapenems 4 of recent pharmaceutical interest.
Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, we devised a new method for restricting the conformation of cyclopropane derivatives. Using this strategy, conformationally restricted analogs of milnacipran, a useful antidepressant, were designed as potent NMDA receptor antagonists, and were synthesized highly enantioselectively from chiral epichlorohydrins. Throughout the synthetic study, we found that nucleophilic addition reactions on cyclopropylcarbaldehyde and -ketones proceeded highly stereoselectively via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Some of the synthesized analogs were significantly effective compared with milnacipran as an NMDA receptor antagonists.
Synthetic studies of annonaceous acetogenins, that are endemic to certain plants of Annonaceae and exhibit a number of interesting biological activities including cytotoxic, antitumor, pesticidal, antiinfective properties are described. We synthesized the following types of compounds : 1) degradation products of annonaceous acetogenins (muricatacin, squamostanal A), 2) monotetrahydrofuranic acetogenins (solamin, reticulatacin, corossoline), 3) oxirane ring-containing acetogenins (epoxyrollin A, diepomuricanin), 4) nonadjacent bis-tetrahydrofuranic acetogenins (4-deoxygigantecin).
The chemistry of compounds that contain a carbon atom substituted with three or four different reactive functional groups has received relatively little attention, despite the considerable theoretical and practical significance these compounds should have for synthetic organic chemistry. Among such compounds containing this multistructural motif, multifunctional carbons, those containing both the carbonyl group and halogens, along with other heteroatom functionalities, would seem to have particular value in synthetic chemistry. However, because of the inherent chemical instability of these structures as well as a paucity of synthetic approaches, the potential of this class of compound has not been realized. On the basis of these considerations, we have focused attention on the synthesis of a new class of compounds (the structure in Figure 1) incorporating into their structures a carbon atom on which an ester carbonyl, halogen (Br or F), and other non-carbon atom (N, 0, and/or S) are substituted. Advantages of using fluorine as the halogen include the stability of the C-F bond, as well as the fundamental chemical and biological interest in fluorine-containing compounds. The synthesis, reactions, spectral data, optical resolutions, and determinations of absolute configurations of examples of these multifunctional compounds are described.
The first isolable, unoxidized dithiirane, 3-phenyl-3- (1, 1, 3, 3-tetramethyl-4-oxo-4-phenylbutyl) dithiirane (16) was prepared by treatment of 2, 2, 4, 4-tetramethyl-1, 5-diphenyl-6, 7-dithiabicyclo- [3.1.1] heptane (14) with 2 KHSO5·KHSO4·K2SO4 (OXONE®) or NaOCl-NaClO4. Monooxides of 14 gave the corresponding dithiirane 1-oxides 17 and 18 by reaction with OXONE®. Under similar conditions, some other dithiirane derivatives were obtained from 5, 6-dithiabicyclo [2.1.1] hexanes, 6, 7-dithiabicyclo [3. 1. 1] heptanes, and 7, 8-dithiabicyclo [4. 1. 1] octanes. It was disclosed by a study on competitive thermal reactions that a 3, 3-di-tert-alkyldithiirane is thermodynamically less stable but kinetically more stable than 3-alkyl-3-aryldithiirane 16. (1RS, 3SR) - and (1RS, 3RS) -Dithiirane 1-oxides, 17 and 18, respectively, were optically resolved by HPLC equipped with a chiral column and absolute configurations of the four stereoisomers were determined by X-ray single-crystal structure analysis and a chemical property. The mechanism of the racemization (1, 2-oxygen migration) between the respective enantiomers were also discussed.
The specific hydroxyl groups of glycosides are selectively activated on treatment with dibutyltin oxide or bistributyltin oxide. These activated species were easily transformable to the products by the action of a variety of reagents, thus achieving regioselective manipulations of hydroxyl groups without protecting other hydroxyl groups in the carbohydrate molecule. Such methods of regioselective manipulation of carbohydrate-hydroxyl groups using tin reagents, for acylation, alkylation, thioacylation, sulfonylation, and oxidation, particularly focusing for preparation of thio-sugars, oxo-sugars, and amino-sugars, are discussed. The products obtained thereby are good precursors in the syntheses of modified carbohydrates. For example, mono-tosylates prepared by the regioselective sulfonylation gave branched furanosides through ring contraction reaction after treatment with metalate complexes such as lithium aluminum hydride. Thioacyl derivatives are smoothly convertible to deoxy sugars by deoxygenation with tin hydrides. The cyclic O, O-thionocarbontes formed by thioacylation with thiophosgene gave O-S rearrangement products, O, S-thiolcarbonates, when treated with a catalytic amount of tin hydride; the products are convertible to thio-sugars upon hydrolysis. Treatment of glycosides with bis (tributyltin) oxide followed by bromine gave single mono-oxo glycosides usually in good yields. These are otherwise hardly accessible compounds and were converted to amino-sugars by oximation followed by stereoselective reduction.
Voglibose (1, N- [2-hydroxy-1- (hydroxymethyl) ethyl] valiolamine, basen®), having more potent disaccharidase inhibitory activity against maltase and sucrase than do naturally occurring pseudo-oligosaccharide α-glucosidase inhibitors, has been developed for the treatment of diabetes mellitus as the blood glucose ameliorating agent. Valiolamine (2), an important key compound for the preparation of N-substituted valiolamine derivatives such as 1, was synthesized by stereoselective hydration of the carbon-carbon double bond of valienamine (3) obtained by microbiological degradation of validamycins. Efficient and practical total synthesis of 2 starting from D-glucose has also been achieved. In animals and healthy volunteers, voglibose (1) significantly reduced postprandial blood glucose concentration. Clinical trials in patients with diabetes mellitus also demonstrated that 1 improves post-pratial glucose levels. In Japan, 1 was approved in July, 1994.