Synthesis of C-17-functionalized spongiane diterpenes: diastereoselective synthesis of (-)-spongian-16-oxo-17-al, (-)-acetyldendrillol-1, and (-)-aplyroseol-14

The diastereoselective synthesis of spongiane diterpenes (-)-spongian-16-oxo-17-al 2, (-)-acetyldendrillol-1 15, and (-)-aplyroseol-14 16 has been completed efficiently via the common intermediate 14. Compound 14 was prepared in five synthetic steps from (+)-podocarp-8(14)-en-13-one 13, easily available from commercial (-)-abietic acid. The key steps in the syntheses were a regioselective reduction of a 1,4-dialdehyde unit, a one-pot acetalization-acetylation, and a translactonization. The synthesis of 15 and 16 has led us to a revision of the configuration at C-17 for natural (-)-acetyldendrillol-1 and a structural reassignment for aplyroseol-14. Thus, aplyroseol-14 16 presents an unprecedented delta-lactone-based structure for spongiane-type diterpenoids. A theoretical study including a series of ab initio calculations for the mechanism involved in the conversion of ester 22 into natural product 2 has also been carried out.     

Palladium-catalyzed DYKAT of butadiene monoepoxide: enantioselective total synthesis of (+)-DMDP, (-)-bulgecinine, and (+)-broussonetine G

Palladium catalyzed asymmetric allylic alkylation reaction of an amine with two equivalents of butadiene monoxide allows for the expedient synthesis of trans- and cis-2,5-dihydropyrroles. The versatility of these chiral synthons towards the synthesis of a wide variety of iminosugar natural products was demonstrated with the short and high yielding asymmetric syntheses of (+)-DMDP, and (-)-bulgecinine. In addition, the first total synthesis of (+)-broussonetine G, a potent glycosidase inhibitor, is described along with the assignment of its relative and absolute stereochemical configuration.     

Amphidinolides H2-H5, G2, and G3, new cytotoxic 26- and 27-membered macrolides from dinoflagellate Amphidinium sp

Six new macrolides, amphidinolides H2 (5), H3 (6), H4 (7), H5 (8), G2 (9), and G3 (10), have been isolated from a marine dinoflagellate Amphidinium sp. (strain Y-42). Cytotoxicity of five derivatives (11-15) of amphidinolide H (1) in addition to 10 amphidinolides (1-10) containing amphidinolides H (1), G (2), B (3), and D (4) was examined, and it was found that the presence of an allyl epoxide, an S-cis-diene moiety, and the ketone at C-20 was important for the cytotoxicity of amphidinolide H (1)-type macrolides.     

Facile Synthesis of (2R,3S)-2-Benzyloxy-3-hydroxybutyrolactone

The heterocyclic diols derived from L-dimethyl tartrate are important chiral synthons in organic synthesis. In particular, L-threosolactone and L-threosolactam structures are versatile precursors for the synthesis of biologically active molecules. Structurally, these functionalized five-membered rings contain two hydroxyl groups with R and S stereochemistry on C-2 and C-3 respectively. The preparation of (2R,3S)-2-benzyloxy-3-hydroxybutyrolactone (3) and of its derivatives, drawing upon L-dimethyl tartrate as an inexpensive chiral starting material, is described. The presented synthetic procedures are easy and effective for preparing L-threoso analogs. This protocol is also a better alternative in a large scale setup. All structures 3–6 and 8 are characterized using ¹H and ¹³C NMR spectroscopy.     

The synthesis and biological activity of new 7-[2-(cyanomethyl)piperazinyl]- and 7-[3-(cyanomethyl)piperazinyl]quinolone antibacterials

Some novel 7-[2- or 3-(cyanomethyl)piperazinyl]quinolones have been prepared. Most notable, 2-cyanomethyl-piperazine 5 and 1-methyl-2-cyanomethylpiperazine 8 at the quinolone C-7 position produce products with good in vitro antibacterial activity. The key step in the synthesis of these products involves the regioselective deprotection of the benzyl group in function of the time reaction.     

Enantiospecific total synthesis of (-)-(E)16-epiaffinisine, (+)-(E)16-epinormacusine B,and (+)-dehydro-16-epiaffinisine as well as the stereocontrolled total synthesis of alkaloid G

An efficient strategy is described for the total synthesis of the sarpagine-related indole alkaloids (-)-(E)16-epiaffinisine (1), (+)-(E)16-epinormacusine B (2), and (+)-dehydro-16-epiaffinisine (4). A key step employed the chemospecific and regiospecific hydroboration/oxidation at C(16)-C(17); this method has also resulted in the synthesis of (+)-dehydro-16-epinormacusine B (5). The oxy-anion Cope rearrangement followed by protonation of the enolate that resulted under conditions of kinetic control has been employed to generate the key asymmetric centers at C(15), C(16), and C(20) in alkaloid G (7) in a highly stereocontrolled fashion (>43:1). Conditions that favor control of the sarpagine stereochemistry at C(16) vs the epimeric ajmaline configuration at the same stereocenter have been determined. The formation of the required cyclic ether in 4, 5, and 7 was realized with complete control from the top face on treatment of the corresponding alcohols with DDQ/THF or DDQ/aq THF in excellent yields.     

Synthesis and absolute configuration of two diastereoisomeric (1R,2S,3R)-and (1S,2S,3R)-2-amino-1-(2-furyl)-1,3-butandiols

The synthesis of (1R, 2S, 3R) and (1S, 2S, 3R)-2-(N-benzoylamino)-1-(2-furyl)-1, 3-butandiols (15) and (16) from D-threonine is described. The assignment of absolute configuration of the newly formed asymmetric center at C-1 was based on the ¹H-NMR spectra of O-isopropylidene derivatives 17 and 18.     

Cal-B-catalyzed alkoxycarbonylation of a-ring stereoisomeric synthons of 1alpha,25-dihydroxyvitamin D3 and 1alpha,25-dihydroxy-19-nor-previtamin D3: a comparative study. first regioselective chemoenzymatic synthesis of 19-nor-A-ring carbonates

A comparative study of alkoxycarbonylation processes of both 19-nor-A-ring and A-ring stereoisomers of 1alpha,25-dihydroxyvitamin D3 analogues catalyzed by Candida antarctica lipase B (CAL-B) has been described. The presence of the methyl group in the A-ring at C-2, as in 3-6, has a determining role in the regioselectivity of the biocatalysis, mainly allowing the hydroxyl group at C-5 position to react. For the 19-nor-A-ring stereoisomers 7-10, which lack the C-2 methyl group, the configurations at C-3 and C-5 have a high influence in the selectivity exhibited by CAL-B. Thus, each couple of enantiomers showed opposing regioselectivities depending on the C-3 configuration. When C-3 possesses an (S)-configuration, enzymatic alkoxycarbonylations took place at the C-5-(R) or C-5-(S) hydroxyl groups. However, if the chiral centers at C-3 are (R), CAL-B alkoxycarbonylated the C-3-(R) hydroxyl group independently of the configuration at C-5. The corresponding carbonates are useful A-ring precursors of 1alpha,25-dihydroxyvitamin D3 analogues, selectively modified at the C-1 or C-3 positions. In addition, an improved synthesis of cis A-ring synthons 5 and 6 is described using a Mitsunobu methodology.     

A convergent synthesis of (+)-4-demethoxydaunomycinone and ( + )-daunomycinone

A convergent synthesis of (+)-4-demethoxydaunomycinone and (+)-daunomycinone via annelation of a functionalized quinone monoketal with the anion of the corresponding 3-cyano-l(3H)isobenzofuranone is reported. The quinone monoketal, sequence, was prepared without chromatography from 2,5-dimethoxybenzaldehyde in sixteen steps. The monoketal of proper absolute configuration was obtained by resolution of the imine from (?)-α-methylbenzylamine and 1,2,3,4,-tetrahydro - 5,8 - dim cyclic 4-(ethylene mercaptole).Two noteworthy aspects of the synthesis were the highly selective reduction of a bicyclic β-hydroxyketone to afford a diol with the required cis-stereochemistry at the eventual C-7 and C-9 positions of the anthracyclinone and the regioselective hydrolysis of the quinone bisketal to afford the monoketal of proper regiochemistry for the synthesis of( + )-daunomycinone. Thus, ( + )-daunomycinone and (+)-4-demethoxydaunomycinone were prepared in nineteen steps from 2,5-dimethoxybenzaldehyde in respective overall yields of 3 and 5% (the overall yield for the racemic material was 13%). This synthetic strategy allows a convergent approach to a variety of D-ring analogs.     

Synthesis of the sialic acid (-)-KDN and certain epimers from (-)-3-dehydroshikimic acid or (-)-quinic acid

(-)-3-Dehydroshikimic acid (3-DHS, 4), a C(7)-building block now available in large quantity from corn syrup, has been converted into the sialic acid (-)-KDN (3) as well as its C-7- and C-8-epimers. (-)-Quinic acid can be used for the same purpose. [structure: see text]     

G3(QCI)模型化学方法

建立了非微扰外推模式下的几种G3(QCI)方法：G3(QCI/fu1)、G3(QCI/fu2)、G3(QCI/ful)//B3PW91和G3(QCI/fu2)//B3PW91.其中,电子能量用QCISD(T,FC)/G3large直接计算,芯电子相关能分别在MP2/6-31G(d)和MP2/6-31G(d,p)级别上计算,对125个G2-1 test set 的计算结果表明,总体精度与G3和G3 //B3LYP相当;平均绝对偏差分别为4.370、4.389、4.061和4.022kJ mol-1,相应G3和G3//B3LYP分别为4.27和4.05kJ mol-1.文章提出的方法排除了G3中外推办法的不确定因素,且更适用于非平衡几何构型体系能量的定量计算。     

Stereoselective synthesis of (-)-4-epiaxinyssamine

The synthetic studies towards axinyssamine, a cytotoxic and coral-lethal compound isolated from the Caribbean sponge Axinyssa ambrosia were performed. The Ritter reaction on the key intermediate with chloroacetonitrile, resulted in the introduction of the amino group at C-4 generating the configuration of this stereocentre opposite to that of the natural product. As a result, the first total synthesis of the unnatural (-)-4-epiaxinyssamine was achieved.     

Enantioselective total synthesis of (-)-neovibsanin G and (-)-14-epi-neovibsanin G

The first total synthesis of vibsane-type diterpenoids neovibsanin G and 14-epi-neovibsanin G has been achieved. Key to this endeavour was a late stage EtAlCl(2) mediated skeletal rich cascade leading to the bicyclo[3.3.1]nonane core in one step.     

Thiosugars VI: A Simple Stereoselective Approach to (1→3)-3-S-Thiodisaccharides from Levoglucosenone

Summary.  A new stereoselective synthesis of (1→3)-3-S-thiodisaccharides is described. Levoglucosenone-derived chiral building blocks produced by the selenium-mediated iodination at C-3 afforded 3-iodoketones in moderate yield. Iodine displacement with sulfur nucleophiles (1-thiols) resulted in 3-thiodisaccharides. Following reduction of the C-2 keto function constituted a new two-step general approach to these biologically important thiosugars. Received November 11, 2001. Accepted November 22, 2001     

Syntheses of (S)-(+)-trihexyphenidyl hydrochloride and (S)-(+)-procyclidine hydrochloride, two anticholinergics, using (S)-(-)-3-cyclohexyl-3-hydroxy-3-phenylpropanoic acid as chiral synthon

The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.     

Solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones via palladium-catalyzed amination

A new procedure for the solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones is described. The method involves coupling of 2,4,6- and 2,4,7-trichloroquinazoline to a solid support via benzyl alcohol type linkers, subsequent displacement of chlorine at C-2 then at the C-6 or C-7 positions by amines (Fig. 1) and the cleavage of the products from the resin. The palladium-catalyzed amination of C-6 and C-7 positions with a representative set of amines in the presence of 2-(di-t-butylphosphino)biphenyl (DTBPBP), P(t-Bu)₃ and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) ligands has been investigated. This method should prove to be a useful tool for constructing combinatorial libraries containing the 4(3H)-quinazolinone moiety.     

Total synthesis of (-)-scabronine G, an inducer of neurotrophic factor production

The total synthesis of (-)-scabronine G has been achieved in a concise manner from the (-)-Wieland-Miescher ketone. Scabronine G and its more potent methyl ester (also prepared) display activity as nonpeptidyl inducers of nerve growth factor production.     

Chemoenzymatic synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one: a precursor of thiolactomycin and determination of its absolute configuration

A convenient enantioselective synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one, a key intermediate in the synthesis of thiolactomycin has been carried out by a Carica papaya lipase-mediated resolution protocol to provide (R)-2 in a 94% ee and its enantiomer (S)-9 in a 98% ee. The absolute configuration at the C-5 position has been determined by Mosher’s method.     

Enantioselective Diels-Alder approach to C-3-oxygenated angucyclinones from (SS)-2-(p-tolysulfinyl)-1,4-naphthoquinone

Chiral racemic vinylcyclohexenes 2, bearing oxygenated substituents and/or a methyl group at the C-5 position of the cyclohexene ring, were submitted to Diels-Alder reactions with enantiomerically pure (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone [(+)-1]. The domino cycloaddition/pyrolytic sulfoxide elimination process led to the formation of enantiomerically enriched angularly tetracyclic quinones anti-6 and syn-7, which were obtained from the kinetic resolution of the racemic diene. In all cases, (SS)-(2-p-tolylsulfinyl)-1,4-naphthoquinone reacted from the less hindered face of the more reactive s-cis conformation, to form products in good enantiomeric excesses. Steric effects and torsional interactions in the corresponding approaches account for the observed pi-facial diastereoselectivities at both partners. The usefulness of this methodology is illustrated with the four-step totally asymmetric synthesis of the C-3-oxygenated angucyclinone derivative (-)-8-deoxytetrangomycin 10 in 26% overall yield and with 50% enantiomeric purity.     

Total Syntheses of (-)-Papuamine and (-)-Haliclonadiamine

The pentacyclic marine alkaloids (-)-papuamine (1) and (-)-haliclonadiamine (2) have been prepared by total synthesis. The synthesis began with (-)-8, which was converted into diester 20 by way of bis-mesylate 17, dinitrile 18, and diacid 19. Dieckmann cyclization of 20 provided keto ester 21, which was transformed into acetal 22. After hydrolysis of the acetal, ketone 25 was subjected to reductive amination with 1,3-propanediamine and sodium triacetoxyborohydride to obtain diamines 26 and 27 as a 71:29 mixture of diastereomers, favoring the symmetrical isomer having the papuamine relative configuration. After transformation of the diamines to their t-Boc derivatives, the benzyl ethers were cleaved and the resulting diol was oxidized to dialdehyde 30. Application of the Seyferth procedure for conversion of aldehydes to alkynes gave a mixture of diynes 31 and 32. After removal of the t-Boc protecting groups from 31, diamino diyne 15 was treated with tributylstannane and azoisobutyronitrile to obtain the bis-vinylstannane 34. Treatment of this compound with Pd(II) and Cu(I) in the presence of air produced (-)-papuamine (1). (-)-Haliclonadiamine (2) was obtained from the unsymmetrical isomer, 32. The NMR spectra of the synthetic alkaloids were identical to those of authentic samples of the natural alkaloids.