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A highly efficient methylenecyclopentane annulation process has been developed based on the Pd(II)-mediated oxidative cyclization of omega-unsaturated alpha-cyano ketones, readily accessed via the Michael addition of 3-butenylmagnesium bromide with 2-cyano-2-cycloalkenones.
Synthesis of novel substituted tetrahydropyrans with adjacent exo-methylene groups at the C3 and C4 positions via Prins-type cyclization has been described.
Bis[1,2,3]triazolo[1,5-f:5',1'-b][1,3,6]thiadiazepine and [1,5-g:5',1'-b][1,3,7]thiadiazocine ring systems have been synthesized from 5-halo-1,2,3-thiadiazoles and aliphatic diamines. We have found that the last step of the process is the cyclization of initially formed bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides. The structures of the intermediates and products were supported by different NMR spectroscopic methods (1H coupled 13C NMR, 2D HETCOR, HMBC and 1D INADEQUATE experiments) and mass spectrometry. Differences in the reaction pathway for aliphatic and less nucleophilic aromatic diamines were determined.
Free-radical mediated cyclizative carbonylations of azaenynes were carried out using TTMSS as a radical mediator to compare the efficiency and the stereochemistry with those using tributyltin hydride. Using a substrate concentration of 0.1 M, the reactions gave good yields of alpha-silylmethylene lactams having four to seven-membered rings. The observed E-diastereoselectivity of the resulting vinylsilane moiety is in sharp contrast to the Z-selectivity observed during the analogous carbonylation using tributyltin hydride. When hexanethiol was used as the radical mediator, alpha-thiomethylene lactams were formed with E-favoring stereoselectivity again. Ab initio and DFT molecular orbital calculations on the stability of E and Z products were carried out for a set of five-membered methylene lactams bearing SnH3, SiH3, and SMe groups. The distinct thermodynamic preference for the Z-isomer was only predicted for the Sn-bearing lactam. A steric effect due to the bulky (TMS)3Si group is proposed for the E-selectivity observed in the TTMSS-mediated reaction.
Zinc(II) and cadmium(II) acetates were reacted in methanol under various experimental conditions with thiosemicarbazones derived from beta-keto amides or beta-keto esters (HTSC). Some of these reactions afforded thiosemicarbazonate complexes [M(TSC)2] with IR and NMR spectra compatible with N,S-coordination, but most gave complexes [ML2], where HL is a substituted 2,5-dihydro-5-oxo-1H-pyrazole-1-carbothioamide resulting from cyclization of the HTSC. Some of these pyrazolonates and two of the HL ligands were studied by X-ray diffractometry, and their structures are discussed. Surprisingly, the reactions of zinc(II) acetate with HTSC in 1:1 mol ratio usually gave a third, previously unreported type of complex with a dideprotonated ligand, [Zn(L-H)], which was also formed when [ZnL2] and Zn(OAc)2 interacted at room temperature in 1:1 mol ratio. These L-H complexes are highly insoluble in all common solvents, which hinders their characterization but suggests that they are polymeric in nature.
Conjugate reduction of alkynones by stoichiometric [(Ph(3)P)CuH](6) or catalytic [(Ph(3)P)CuH](6) and polymethyl-hydrosiloxane proceeds to cyclization by an aldol reaction with tethered ketones to generate [small beta]-hydroxyenones with good diastereoselectivity.
A novel cyclization reaction of ethenetricarboxylate derivative aromatic compounds in the presence of various Lewis acids gave benzo-annulated cyclic compounds such as oxindole and benzofuran derivatives via Friedel-Crafts intramolecular Michael addition in high yields. For example, the reaction of diethyl 2-[(N-methyl-N-phenylcarbamoyl)methylene]malonate (1a) in the presence of ZnCl2 at room temperature gave diethyl 2-(1-methyl-2-oxoindolin-3-yl)malonate (2a) in 98% yield. The reactions also proceeded with a catalytic amount of a Lewis acid such as AlCl3, ZnCl2, ZnBr2, Sc(OTf)3, or InBr3.
Radical cyclization of vinyl iodides in 6-(pi-exo)-exo-dig mode were effected by SmI2 to give exo-cyclic dienes fused to six-membered rings.
o-(1,6-Enynyl)benzaldehydes underwent a novel mode of cycloaddition using Rh(I)-precatalyst, via[3+2] cycloaddition of presumed dipolar carbonyl ylide intermediate generated by Rh-catalyst and the utility of this mechanistically intriguing enyne cyclization can be found in a number of polycyclic natural product skeletons.
Acetylenic sulfones attached to solid supports by means of ester linkers were employed in a variety of cyclization and cycloaddition reactions, followed by cleavage of the products from the resin by ester hydrolysis or reductive desulfonylation.
In the presence of 1-hexynyllithium (0.2-0.6 equiv.), 1,omega-diiodo-1-alkynes undergo a new type of cyclization reaction without the loss of two iodine atoms to afford (diiodomethylene)cycloalkanes.
Upon UV irradiation of the hydrogen-bond confined crystal state of a dithienylhexafluorocyclopentene with (R)-N-phenylethylamide substituents, the photochemical cyclization reaction proceeds diastereoselectively to form the coloured, closed-ring isomer with 97% de.
1. beta-Amyrin synthesized by pea seedlings in the presence of (3RS)-[2-(14)C,(4R)-4-(3)H(1)]mevalonic acid (for nomenclature see Cahn, Ingold & Prelog, 1956) was subjected to a series of degradations to locate the positions within the molecule of the incorporated tritium. 2. The location of five of the six labelled hydrogen atoms at C-3, C-9, C-18 and C-19 (two) confirms that the mechanism of cyclization of squalene expected from the biogenetic isoprene rule is functioning in vivo.
The n.m.r. spectrum of abscisic acid (ABA) formed from [1,2-13C2]acetate by the fungus Cercospora rosicola shows 13C-13C coupling between C-6' (41.7 p.p.m.; 36 Hz) and the downfield 6'-methyl group (6'-Me) (24.3 p.p.m, 36 Hz). This 6'-Me, therefore, is derived from C-3' of mevalonate [Bennett, Norman & Maier (1981) Phytochemistry 20, 2343-2344]. An i.n.e.p.t. (insensitive nuclei enhanced by polarization transfer) pulse sequence demonstrated that the downfield 13C signal is produced by the 6'-Me that gives rise to the upfield 1H 6'-Me signal (23.1 d). The absolute configuration of this, the equatorial 6'-Me group, was determined as 6'-pro-R by decoupling and n.O.e. (nuclear-Overhauser-enhancement) experiments at 300 MHz using ABA, ABA in which the axial 6'-pro-S 5'-hydrogen atom had been exchanged with 2H in NaO2H and the 1',4'-cis- and 1',4'-trans-diols formed from these samples. The configuration at C-1' and at C-6' are now compatible with a chair-folded intermediate during cyclization, as proposed for beta- and epsilon-rings of carotenoids. ABA in solution exists, as in the crystalline form, with the ring in a pseudo-chair conformation. The side chain is axial and the C-3 Me and the C-5 hydrogen atoms are predominantly cis(Z).
Cyclodextrin glycosyltransferase (CGTase) (EC 2.4.1.19) is used for the industrial production of cyclodextrins. Its application, however, is hampered by the limited cyclodextrin product specificity and the strong inhibitory effect of cyclodextrins on CGTase activity. Recent structural studies have identified Arg47 in the Bacillus circulans strain 251 CGTase as an active-site residue interacting with cyclodextrins, but not with linear oligosaccharides. Arg47 thus may specifically affect CGTase reactions with cyclic substrates or products. Here we show that mutations in Arg47 (to Leu or Gln) indeed have a negative effect on the cyclization and coupling activities; Arg47 specifically stabilizes the oligosaccharide chain in the transition state for these reactions. As a result, the mutant proteins display a shift in product specificity towards formation of larger cyclodextrins. As expected, both mutants also showed lower affinities for cyclodextrins in the coupling reaction, and a reduced competitive (product) inhibition of the disproportionation reaction by cyclodextrins. Both mutants also provide valuable information about the processes taking place during cyclodextrin production assays. Mutant Arg47-->Leu displayed an increased hydrolyzing activity, causing accumulation of increasing amounts of short oligosaccharides in the reaction mixture, which resulted in lower final amounts of cyclodextrins produced from starch. Interestingly, mutant Arg47-->Gln displayed an increased ratio of cyclization/coupling and a decreased hydrolyzing activity. Due to the decreased coupling activity, which especially affects the production of larger cyclodextrins, this CGTase variant produced the various cyclodextrins in a stable ratio in time. This feature is very promising for the industrial application of CGTase enzymes with improved product specificity.
Three new cyclized geranyl stilbenes, ugonstilbene A ( 1), ugonstilbene B ( 2), and ugonstilbene C ( 3), and one known compound 3-hydroxyacetophenone, were isolated from the dried rhizomes of H. zeylanica. The structures of these three new compounds were elucidated on the basis of spectral analysis. Compounds 1 - 3 exhibited moderate antioxidant activity by the DPPH assay with IC (20) of 11.31 +/- 1.11, 38.72 +/- 0.47, and 30.80 +/- 1.19 microM, respectively, while the IC (20) of Trolox was 8.70 +/- 0.95 microM.
We have investigated cyclization of a Rouse chain at long and short times by a Langevin dynamics simulation method. We measure St, the fraction of nonreacted chains, for polymerizations ranging from Z=5 to Z=800 and capture distances ranging from a=0.1b to a=8b where b is the bond length. Comparison is made with two theoretical approaches. The first is a decoupling approximation used by Wilemski and Fixman to close the relevant master equation [J. Chem. Phys. 58, 4009 (1973); 60, 866 (1974)]. The second approach is the renormalization group arguments of Friedman and O'Shaughnessy [Phys. Rev. Lett 60, 64 (1988); J. Phys. II 1, 471 (1991)]. We find that at long times St decays as a single exponential with rate k(infinity). The scaled decay rate K=k(infinity)tauR appears to approach a constant value independent of the capture distance for very large chains consistent with the predictions of both the renormalization group (RG) and Wilemski-Fixman closure approximation. We extract K*, the long chain limit of K, from the fixed point a=a* where K is independent of Z. K* is larger than both the RG and closure predictions but much closer to the RG result. More convincing evidence for the RG analysis is obtained by comparing the short-time decay of St to long-time results. The RG analysis predicts that dSdt should decay as a power law at early times and that the exponent in the power law is related to K by a simple expression with no free parameters. Our simulations find remarkable agreement with this parameter-free prediction even for relatively short chains. We discuss possible experimental consequences of our result.
Two conceptually different and novel radical-mediated cascade reactions leading to a total synthesis of the steroid (+/-)-estrone 1 and to a synthesis of 14-epiestrone 40 are described. Treatment of the iododienynone 23 with Bu(3)SnH/2,2'-azobis(isobutyronitrile) (AIBN) triggers a 13-endo-dig radical macrocyclization followed by two sequential radical transannulation reactions leading to the crystalline estrane 24 in 50% yield. The x-ray crystal structure of 24 established its trans, syn, stereochemistry. Transposition of the enone functionality in 24 next led to 38, which was then converted into 39 by reductive methylation. Deprotection of the methyl ether 39 finally gave 14-epiestone 40. When the substituted iodovinylcyclopropane 55 was treated similarly with Bu(3)SnH/AIBN, the resulting radical center underwent a different sequence of cascade macrocyclization-transannulation reactions producing the trans, anti, trans estrane 56 in 12% overall yield. Oxidation of 56, using CrO(3)-H(2)SO(4) next led to the cyclopentanone 57, which, on deprotection using BBr(3) gave (+/-)-estrone 1. A number of alternative substituted iodopolyenynones and iodovinylcyclopropanes, i.e., 8a, 8b, 33, 49a, and 49b, underwent similar radical-mediated cascade cyclizations leading to other estranes, i.e., 21a, 21b, 35, and 50, and, in one case, to the 6,6,5,6-tetracycle 51, in variable overall yields. The structures and stereochemistries of several estranes were established by using x-ray crystal structure measurements in combination with analysis of their NMR spectroscopic data and correlation with literature precedent.