Chemical equations presented. The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-d-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an γ,ß-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.
(2010) Asymmetric synthesis via aziridinium ions: Exploring the stereospecificity of the ring opening of aziridinium ions and a formal synthesis of (-)-swainsonine. Tetrahedron Asymmetry, 21 (11-12) pp. 1563-1568. .
In the preferred practice of the invention a highly efficient method of synthesizing swainsonine involves protecting the 1,2-diol moiety of swainsonine as an isopropylidene group followed by removal thereof as by acidic hydrolysis.
Taylor, Synthesis of selective agonists for the alpha7 nicotinic acetylcholine receptor with in situ click-chemistry on acetylcholine-binding protein templates, , 82 (4), 687-699 (2012).
DESCRIPTION OF THE PREFERRED EMBODIMENT
In general, the present invention contemplates construction of a bicyclic imine which may be employed to create the enamide of the invention with subsequent stereospecific hydroboration of the enamide being employed to synthesize swainsonine orits analogues.
There are several key features of our syntheses. The first is stereoselective and efficient synthesis of three fragments (118, 119, and 121). The second is CsF- and Pd(0)-mediated convergent assembly of these three fragments. The third is an atropselective macrocyclization of 122 controlled by strategic protection of both the C9-OH and C23-OH groups. Without this protection, the atropselectivity was decreased or reversed; in addition, the C9-protection was also effective for preventing dimerization of the cyclopentadiene moiety introduced via deprotection of the MOM group followed by phenylselenenylation and H2O2 oxidation. The fourth key feature is a cerium amide promoted nine-membered diyne ring cyclization between C5 and C6 of 123, assisted by the ansa-macrolide linkage with a diBoc-protected amine. The final feature is an extremely facile SmI2-mediated reductive 1,2-elimination of 124 using -trifluoromethylbenzoate as an electron acceptor for chemoselective olefination in the presence of potentially reactive functionalities such as the doubly allylic OTES group at C9 and the propargylic OAr moiety at C8. However, when the benzoxazine ester was attached, its α,β-unsaturated carbonyl group was reduced preferentially and rapidly to afford 128 (). Therefore, this functionality was masked in the hydrate form as 129 for the SmI2–reduction, then dehydrated to complete the total synthesis of the labile aglycon (131), a more stable compound than the core structure (125) (in preparation for publication). A stereocontrolled glycosylation method was developed,, and further studies directed toward the total synthesis of 97 is under way.
The antitumor antibiotic C-1027, which is a complex between the reactive chromophore 97 and an apoprotein, was discovered by Otani and coworkers at Taiho Co. Ltd. in 1988. The chromophore 97 is responsible for DNA recognition and damage, and the apoprotein functions as an effective drug-delivery system (). The free chromophore (97) is the most labile enediyne studied to date. Chromophore 97 was transformed in ethanol at room temperature by Masamune-Bergman cyclization and subsequent hydrogen abstraction to provide an aromatized chromophore (109) with a half-life of 50 min and in 82% yield (). In a biological setting, the -benzyne biradical 108 abstracts hydrogen atoms from DNA in a sequence-selective manner to cause oxidative double-strand cleavage. The structure of 97 as well as kedarcidin chromophore (98b) is highly unusual. The complicated fused-ring system of 97 comprises a cyclopentadiene ring, a highly strained nine-membered enediyne ring, a functionalized benzoxazine ring, and a chlorocatechol-containing 17-membered macrolactone that displays nonbiaryl atropisomerism. These structural and functional complexities make the total synthesis of the chromophore (97) extremely challenging. We first determined the absolute configuration of 97,, and then developed new and effective methodologies for the construction of the nine-membered enediyne structure., This approach enabled the first synthesis of the exceedingly unstable core structure (125) of the chromophore (97) ()– and the labile protected aglycon (131) (; in preparation for publication).
Neocarzinostatin (NCS), the first chromoprotein enediyne antibiotic, was isolated from a culture of in 1965 by Ishida and coworkers at Tohoku University., Its potent antibacterial and antitumor activities derive from the inhibition of DNA synthesis and DNA degradation in cells by the labile chromophore (95). The chromophore-binding structure and the stabilization interactions in the NCS complex was elucidated by 2D-NMR method.– Mechanistic studies using 95 and synthetic chromophore analogs clarified the various chemical mechanisms of triggering the aromatization, the carbon-radical formation, and DNA cleaving abilities.– Then, an efficient route to the highly strained neocarzinostatin chromophore aglycon (117) was developed ().,– The present strategy involved a stereoselective intramolecular cerium acetylide-aldehyde cyclization to form the C4,C5-trans-diol system, which was adequate to form the α-epoxide. This aglycon (117) was extremely unstable, but was nonetheless glycosylated by the Myers group to complete the total synthesis of labile neocarzinostatin chromophore (95).,
A novel and unstable nine-membered epoxyenediyne, N1999-A2 (96), was reported to exhibit extremely potent cytotoxicity toward cultured cancer cells in 1998 by Ando and coworkers at Ajinomoto Co. Ltd. The structure of 96 is very similar to that of the aglycon of neocarzinostatin chromophore (95) but lacks a stabilizing carrier apoprotein. Since the stereochemistry of 96 was unknown, we synthesized its stereoisomers through C7,C8- or C5,C6-cyclization using cerium acetylide ().,, Comparison of the NMR and CD spectra, and the base-selectivities of these stereoisomers during DNA cleavage (), resulted in the determination of the stereochemistry including the absolute configuration of 96.,
Based on the observed kinetics, we anticipated that the ground state of the intermediate -benzyne biradical would be a triplet and thus detectable by ESR. We were delighted to find that the natural chromophore-apoprotein complex (holoprotein) of C-1027 and synthetic bicyclic nine-membered enediyne (105) are paramagnetic in the solid form and in solution, respectively, and exhibit steady ESR signals under deoxygenated conditions ( and ). The spectra of 105 observed in CH2Cl2, CD2Cl2, and CD3CN were identical, demonstrating that the detected radical species did not arise from the solvents. The g values (2.0023) of 105 confirmed that the radical spectra were carbon-centered. Thus, to help determine the position of the observed radical species, C3- and C6-13C labeled isotopomers, 105a and 105b, respectively, were synthesized. However, their spectra showed no significant broadening compared to that of unlabeled 105 (). Based on the reported value of the 13C hyperfine splitting constant of phenyl radical (a13C-α = 12.25 mT), it was unlikely that the spin density is located at the 13C labeled C3 or C6 position. These results, including spin trapping experiments, indicated that the p-benzyne intermediate 106 was generated but the observed paramagnetic species should not be directly attributed to the equilibrated 106, but rather to more stable secondary radical species.