High-Yielding Enantioselective Synthesis of the Macrolactam Aglycon of Sch 38516 from Two Units of (2R)-2-Ethyl-4-penten-1-ol

The same precursor —namely, (2R)-2-ethyl-4-penten-1-ol—was used to obtain fragments C9–C13 and C1–C8 of 1 , the aglycon of Sch 38516 (which is active against Candida sp.) and fluvirucin B₁ (which is active against influenza A virus). The key steps of the synthesis were the aldol-like reaction between the two fragments and the macrolactamization of a 13-azidotridecanoic acid derivative (see scheme). MOM=methoxymethyl, Py=2-pyridyl.     

Asymmetric total synthesis of (+)-1-deoxy-6-epi-castanospermine

(+)-1-Deoxy-6-epi-castanospermine was asymmetrically synthesized in ten steps from α-furfuryl amine derivative 6 in 2.9% overall yield. The kinetic resolution of α-furfuryl amine derivative 6 and Sharpless AD reaction of 14 were used as key steps.     

Total Synthesis,Stereochemical Assignment,and Biological Activity of Chamuvarinin and Structural Analogues

A highly stereocontrolled synthesis of (+)‐chamuvarinin has been completed in 1.5 % overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin–Anh control), followed by the two step activation/cyclization to close the C20–C23 2,5‐cis‐substituted tetrahydrofuran ring and a Julia–Kocienski olefination at C8–C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2 % overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness.     

Preparation of Optically Enriched Secondary Alkyllithium and Alkylcopper Reagents—Synthesis of (−)‐Lardolure and Siphonarienal

Optically enriched secondary alkyl iodides were converted into secondary alkyllithium and secondary alkylcopper compounds with very high retention of configuration. Quenching with various electrophiles, including chiral epoxides, provided a range of chiral molecules with high enantiomeric purity (>90 % ee). This method has been applied in an iterative fashion in the total synthesis of (?)‐lardolure in 13 steps and 5.4 % overall yield (>99 % ee, dr>99:1) and siphonarienal in 15 steps and 5.6 % overall yield (>99 % ee, dr>99:1) starting from commercially available ethyl (R)‐3‐hydroxybutyrate (>99 % ee).     

Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)‐Myrioneurinol

The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)‐myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl‐protected lactam titanium enolate to an α,β‐unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza‐Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product.     

Asymmetric Synthesis of the C（17）——C（28） Subunit of Didemnaketal B

The stereocontrolled synthesis of the C（17）--C（28） fragment 3 of didemnaketal B was accomplished in 21 steps from the natural （R）-（＋）-pulegone and （S）-（--）-citronellal. The key steps involved diastereoselective construction of two chiral carbon centers through the intramolecular chiral induction and uncommon Julia olefination of ketone forming the E-trisubstituted C（22）--C（23） double bound.     

Enantioselective Total Synthesis of Dysidavarone A,a Novel Sesquiterpenoid Quinone from the Marine Sponge Dysidea avara

Dysidavarone A, a structurally unprecedented sesquiterpenoid quinone, was synthesized in 30 % overall yield in a longest liner sequence of 13 steps from commercially available o‐vanillin. A highly strained and bridged eight‐membered carbocyclic core was established by the C7?C21 carbon bond formation through a copper enolate mediated Michael addition to the internal quinone ring.     

Regio/Stereoselective Glycosylation of Diol and Polyol Acceptors in Efficient Synthesis of Neu5Ac‐α‐2,3‐LacNPhth Trisaccharide

A concise approach to a Neu5Ac‐α‐2,3‐LacNPhth trisaccharide derivative was developed. First, the regio/stereoselective glycosylation between glycoside donors and glucoNPhth diol acceptors was investigated. It was found that the regioselectivity depends not only on the steric hindrance of the C2‐NPhth group and the C6‐OH protecting group of the glucosamine acceptors, but also on the leaving group and protecting group of the glycoside donors. Under optimized conditions, LacNPhth derivatives were synthesized in up to 92 % yield through a regio/stereoselective glycosylation between peracetylated‐α‐galactopyranosyl trichloroacetimidate and p‐methoxyphenyl 6‐O‐tert‐butyldiphenylsilyl‐2‐deoxy‐2‐phthalimido‐β‐d ‐glucopyranoside, avoiding the formation of glycosylated orthoesters and anomeric aglycon transfer. Then, the LacNPhth derivative was deacylated and then protected on the primary position by TBDPS to form a LacNPhth polyol acceptor. Finally, the Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in 48 % yield through the regio/stereoselective glycosylation between the LacNPhth polyol acceptor and a sialyl phosphite donor. Starting from d ‐glucosamine hydrochloride, the target Neu5Ac‐α‐2,3‐LacNPhth derivative was synthesized in a total yield of 18.5 % over only 10 steps.     

A Concise Total Synthesis of (+)‐Tetrabenazine and (+)‐α‐Dihydrotetrabenazine

Highly concise asymmetric total syntheses of (+)‐tetrabenazine ( 1 ), a drug for the treatment of chorea associated with Huntington’s disease, and of (+)‐α‐dihydrotetrabenazine ( 2 ), an active metabolite of 1 , have been accomplished. Our synthetic route features a trans‐selective enol etherification, followed by an unprecedented cation‐dependent aza‐Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34 % overall yield) for (+)‐ 2 and eight steps (22 % overall yield) for (+)‐ 1 .     

Formal Syntheses of (±)‐Methylenomycins A and B

The syntheses of methyl ester of (±)‐desepoxy‐4,5‐didehydromethylenomycin A ( 4 ) and 2,3‐dimethyl‐5‐methoxycarbonyl‐2‐cyclopentenone ( 5 ) were accomplished from a common starting material, 2,3‐dimethyl‐4‐methoxyphenol (8), in only four and two steps in 35% and 53% overall yields, respectively. Photochemical rearrangements of masked p‐benzoquinones in methanol are the key steps.     

Total Synthesis and Biological Evaluation of Seiricuprolide and Pestalotioprolide B

The first total syntheses of seiricuprolide and pestalotioprolide B, rare 14-membered α,β-unsaturated macrolides embedding a chiral epoxide motif, were achieved in 17 steps with 1.9 % and 1.6 % overall yields, respectively. Our synthesis featured the key Shiina macrolactonization to construct the 14-membered macrocyclic skeleton, Wittig olefination to generate the (E)-α,β-unsaturated ester and selective reduction of advanced chiral propargylic alcohol intermediate to enable the exclusive formation of Z- or E-olefin at C8−C9. Synthetic seiricuprolide and pestalotioprolide B were evaluated for their cytotoxic activity against the HCT116 colon cancer cell line as well as their inhibitory effect on CFTR chloride channel activity in human intestinal epithelial (T84) cells. Preliminary structure–activity relationship suggested that the C5−C6 β-epoxide moiety suppressed both biological activities.     

Synthesis and isomerization studies of cyclotrisazobiphenyl

We report an efficient synthesis of cyclotris[(E)‐3′‐(biphenyl‐3‐yldiazenyl)] compounds (CTBs). An unsubstituted CTB molecule is accessible in four steps in 10 % yield overall, whereas a hexa(methoxymethyl ether) CTB analogue was prepared in nine steps (26 % yield). The final macrocyclization step was accomplished in up to 80 % yield by using a metal‐template effect. Furthermore, the photochromic properties were investigated, and all four isomers were detected and characterized by NMR spectroscopy. A strong influence from the solvent and the irradiation wavelength on the switching process was observed. Irradiation in pyridine yielded the highest amount of the all‐Z isomer in the photostationary state. For a full conversion to the all‐E isomer, the reaction has to be heated to 45 °C. The isomerization to the all‐E isomer is slow at room temperature, with a half‐life time of the all‐Z isomer of more than nine days in dimethyl sulfoxide (DMSO). Conditions were established to access each possible isomer as the major component in the photostationary state.     

Concise,Enantioselective, and Versatile Synthesis of (−)‐Englerin A Based on a Platinum‐Catalyzed [4C+3C] Cycloaddition of Allenedienes

A practical synthesis of (?)‐englerin A was accomplished in 17 steps and 11 % global yield from commercially available achiral precursors. The key step consists of a platinum‐catalyzed [4C+3C] allenediene cycloaddition that directly delivers the trans‐fused guaiane skeleton with complete diastereoselectivity. The high enantioselectivity (99 % ee) stems from an asymmetric ruthenium‐catalyzed transfer hydrogenation of a readily assembled diene–ynone. The synthesis also features a highly stereoselective oxygenation, and a late‐stage cuprate alkylation that enables the preparation of previously inaccessible structural analogues.     

(-)-（3S, 6R）-3, 6-羟基-10-甲基十一酸及其三聚体的全合成

以廉价易得的异戊基溴为起始原料,以烯丙基二异松莰烷基硼烷参与的不对称烯丙基化反应和Yamaguchi酯化反应为关键步骤,实现了对(-)-(3S,6R)-3,6-二羟基-10-甲基十一酸(总收率27.5％)及其三聚体(总收率24.5％)的不对称全合成。     

Enantioselective syntheses of 2,5-disubstituted pyrrolidines based on iridium-catalyzed allylic aminations--total syntheses of alkaloids from amphibian skins

A broadly applicable route to trans‐2,5‐disubstituted pyrrolidines has been developed. Key steps are an asymmetric iridium‐catalyzed allylic amination, a Suzuki–Miyaura coupling, and an intramolecular aza‐Michael addition. Enantiomeric excesses in the range of 93–99 % ee have been achieved. Total syntheses of the alkaloids (?)‐ 225 C , (+)‐ and (?)‐ 223 H (xenovenine), (+)‐ 223 AB , (+)‐ 195 B , and (+)‐ 223 R have been carried out as applications.     

Practical Synthesis of (20S)‐10‐(3‐Aminopropyloxy)‐7‐ethylcamptothecin,a Water‐Soluble Analogue of Camptothecin

A robust, practical synthesis of (20S)‐10‐(3‐aminopropyloxy)‐7‐ethylcamptothecin (T‐2513, 5 ), which is a water‐soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N‐arylsulfonyl‐(R)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl‐(S)‐2‐acyloxy‐2‐(6‐cyano‐5‐oxo‐1,2,3,5‐tetrahydroindolizin‐7‐yl)butanoate ( 8 k ) in 93 % yield and 87 % de. Optically pure compound 8 k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5 . This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi‐gram scale in 6.3 % overall yield (16 steps).     

Iodine‐Catalyzed Highly Diastereoselective Synthesis of trans‐2,6‐Disubstituted‐3,4‐Dihydropyrans: Application to Concise Construction of C28–C37 Bicyclic Core of (+)‐Sorangicin A

A novel iodine‐catalyzed highly diastereoselective synthesis of trans‐2,6‐disubstituted‐3,4‐dihydropyrans have been achieved from δ‐hydroxy α,β‐unsaturated aldehydes by treating with allyltrimethyl silane in THF at room temperature with good to excellent yields. This methodology has been successfully implemented for a concise asymmetric synthesis of C28–C37 dioxabicyclo[3.2.1]octane ring system of (+)‐sorangicin A in 8 steps with 21 % overall yield.     

Total Synthesis of Meloscine by a [2+2]‐Photocycloaddition/Ring‐Expansion Route

The stereogenic centers at C3 and C12 of meloscine ( 3 ) can be established in the photochemical key step 1 → 2 . 1,2‐retro‐Benzilic acid rearrangement to a five‐membered ring, reductive amination, Claisen rearrangement, and ring‐closing metathesis are further key steps in the transformation of cyclobutane 2 into the target molecule 3 (14 steps, 9 % overall yield). Enantioselective access to (+)‐meloscine was possible when the [2+2]‐photocycloaddition was conducted in the presence of a chiral template.

     

A flexible asymmetric approach to methyl 5-alkyltetramates and its application in the synthesis of cytotoxic marine natural product belamide A

By using a methyl tetramate derivative (R)‐ or (S)‐ 9 as a novel chiral building block, a direct, flexible, and highly enantioselective approach to methyl (R)‐ or (S)‐5‐alkyltetramates ( 2 ) is disclosed. Among the synthesized methyl 5‐alkyltetramates 2 , methyl 5‐methyltetramate ( 2 a ) is found in cytotoxic mirabimide E ( 4 ) and dysideapyrrolidone ( 5 ), and methyl 5‐benzyltetramate ( 2 g ) is a substructure in the potent antineoplastic dolastatin 15 ( 3 ). On the basis of this method, the first asymmetric synthesis of the antimitotic tetrapeptide belamide A ( 7 ) has been achieved in seven steps from (S)‐ 9 , with an overall yield of 23.8 %. Not only have the structure and absolute configuration of (+)‐belamide A ( 7 ) been confirmed, but also the solvent used for recording the ¹³C NMR spectrum, the ¹³C NMR spectrum data correlation, and optical rotation data of natural belamide A ( 7 ) have been revised.     

Concise Stereoselective Total Synthesis of Leiocarpin C

A simple and highly concise strategy has been developed for the stereoselective total synthesis of leiocarpin C starting from commercially available mandelic ester. The strategy utilizes the OsO₄‐catalyzed cis‐hydroxylation and selective reduction with K‐Selectride as key steps.