Practical formal total synthesis of (rac)- and (S)-camptothecin

A practical, efficient and scalable formal total synthesis of (rac)- and (S)-camptothecin is described, which proceeds via the known DE ring building blocks 19 and (S)-19, respectively. The racemic synthesis starts from diethyl oxalate and uses straightforward carbonyl chemistry in order to generate the pyridone ring system. 19 was formed in 8.4% overall yield over 9 linear steps avoiding any chromatographic purification. The asymmetric version of this approach encompassed a diastereoselective Grignard addition to the enantiomerically pure alpha-ketoester 30 in order to generate the (S)-configured quaternary stereocenter. The auxiliary could be recycled in high yield and was successfully reused multiple times. The final steps paralleled the racemic approach. (S)-19 was thus prepared in 9.4% overall yield (er = 95 : 5) over 10 steps.     

Asymmetric synthesis of the highly potent anti-metastatic prostacyclin analogue cicaprost and its isomer isocicaprost

An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling of a chiral bicyclic C6-C14 ethynyl building block with a chiral C15-C21 omega-side chain amide building block with formation of the C14-C15 bond of the target molecules. A highly stereoselective reduction of the thereby obtained C6-C21 intermediate carrying a carbonyl group at C15 of the side chain was accomplished by the chiral oxazaborolidine method. The chiral phosphono acetate method was used for the highly stereoselective attachment of the alpha-side chain to the bicyclic C6-C21 intermediate carrying a carbonyl group at C6. Asymmetric syntheses of the bicyclic C6-C14 ethynyl building blocks were carried out starting from achiral bicyclic C6-C12 ketones by using the chiral lithium amide method. In the course of these syntheses, a new method for the introduction of an ethynyl group at the alpha-position of the carbonyl group of a ketone with formation of the corresponding homopropargylic alcohol was devised. Its key steps are an aldol reaction of the corresponding silyl enol ether with chloral and the elimination of a trichlorocarbinol derivative with formation of the ethynyl group. In addition, a new aldehyde to terminal alkyne transformation has been realized. Its key steps are the conversion of an aldehyde to the corresponding 1-alkenyl dimethylaminosulfoxonium salt and the elimination of the latter with a strong base. Two basically different routes have been followed for the synthesis of the enantiomerically pure C15-C21 omega-side chain amide building block. The first is based on the chiral oxazolidinone method and features a highly stereoselective alkylation of (4R)-N-acetyl-4-benzyloxazolidin-2-one, and the second encompasses a malonate synthesis of the racemic amide and its efficient preparative scale resolution by HPLC on a chiral stationary phase containing column.     

(-)-Lytophilippine A: synthesis of a C1-C18 building block

The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved. A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing d-galactose as inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence consisting of esterification and ring-closing metathesis (five steps, 56%).     

Total synthesis of (+)-cystothiazole A

[structure: see text]. The total synthesis of cystothiazole A is described. Key steps of the synthesis include an Evans asymmetric catalytic aldol reaction, which established the required C4-C5 stereochemistry. The [2,4']-bis(thiazole) was obtained applying our methodology of electrophilic activation of amide. Semistabilized Wittig reaction between the phosphonium salt 3 and the aldehyde 2 afforded 1 in nine linear steps and 38% overall yield.     

A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.     

A "chiral aldehyde" equivalent as a building block towards biologically active targets

Chiral gamma-aryloxybutenolides, readily accessible through dynamic kinetic asymmetric transformation (DYKAT) of racemic acyloxybutenolides, were utilized as "chiral aldehyde" building blocks for intermolecular cycloadditions and Michael reactions. Unprecedented selectivity in trimethylenemethane cycloadditions with this building block allowed an efficient synthesis of a novel metabotropic glutamate receptor 1 antagonist in development by the Bayer corporation. These studies further inspired work that culminated in the total synthesis of (+)-brefeldin A, a natural product with a range of significant biological properties. All of the stereochemistry in this target molecule was derived from two palladium-catalyzed asymmetric allylic alkylation reactions. The trans-alkenes were synthesized by a Julia olefination and a ruthenium-catalyzed trans-hydrosilylation-protodesilylation protocol. The route to (+)-brefeldin A lends itself to analogue syntheses and was completed in 18 steps in 6 % overall yield.     

Stereocontrolled synthesis of the ABCDE ring moiety of ciguatoxin CTX3C

The ABCDE ring moiety of ciguatoxin CTX3C, a major causative agent of ciguatera poisoning, was stereoselectively synthesized. The key transformations are a chiral auxiliary-based asymmetric alkylation and an asymmetric aldol condensation, which controlled the formation of the C11 and C21-stereocenters, respectively. A highly practical and efficient route to the ABCD ring fragment, a common precursor for the divergent synthesis of the left wings of ciguatoxins, was also established.     

Synthetic studies on the bryostatins: synthetic routes to analogues containing the tricyclic macrolactone core

[reaction: see text]. Synthesis of the first of a projected series of bryostatin analogues has been accomplished in 26 steps and 2.2% overall yield. In this letter, we detail two approaches to the structural core of these tricyclic macrolactone bryostatin analogues. The key features of the route include BITIP-catalyzed asymmetric allylation reactions and Mukaiyama aldol reactions, a chelation-controlled allylation, pyran annulation reactions, and macrolactonization.     

Synthetic studies on cyathins: enantioselective total synthesis of (+)-allocyathin B2

[reaction: see text] The enantioselective total synthesis of (+)-allocyathin B(2) has been achieved. Our approach features a convergent enantioselective construction of the 5-6-7 tricyclic core system using the originally developed chiral building blocks via asymmetric catalysis, the intramolecular aldol reaction in high yield, successful samarium diiodide-mediated ring expansion, and a newly developed double-bond installation method.     

The first stereoselective synthesis of orostanal isolated from a marine sponge Stelletta hiwasaensis

The synthesis of orostanal, containing novel 6-5-6-5 fused rings and exhibiting meaningful bioactivity against HL-60 cells, has been achieved via 12 steps in 18% total yield from a readily accessible intermediate 7. The key steps for the synthesis entailed an alumina-mediated intramolecular aldol cyclization and asymmetric crotylation to construct the chirality of carbon-25.     

Concise and highly stereoselective synthesis of the C20-C26 building block of halichondrins and Eribulin

A concise, stereoselective, and scalable synthesis of the C20-C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective S(N)2' substitution, and selective conversion of a C-Si to C-I bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration through a silica-gel plug, to give the C20-C26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1.     

Asymmetric total synthesis of (-)-azaspirene,a novel angiogenesis inhibitor

The asymmetric total synthesis of (-)-azaspirene, an angiogenesis inhibitor, has been accomplished, establishing its absolute stereochemistry. The key steps are a MgBr2.OEt2-mediated, diastereoselective Mukaiyama aldol reaction, a NaH-promoted, intramolecular cyclization of an alkynylamide, and the aldol reaction of a ketone containing functionalized gamma-lactam moiety without protection of tert-alcohol and amide functionalities.     

Concise and stereoselective synthesis of the N7-C25 fragment of psymberin

[reaction: see text] The N7-C25 fragment of the potent and selective cytotoxic agent psymberin has been prepared through a short (12 linear steps, 15 total steps) and stereoselective sequence. Highlights of this route include a very rapid construction of the pentasubstituted arene, a substrate-controlled diastereoselective fragment coupling using a Mukaiyama aldol reaction, and an efficient entry into a key tetrahydropyranyl cyanide.     

(－)-7(R)-羟罗汉脂素的全合成研究

以4-戊烯酸及(R)-4-苯基-2-噁唑烷酮为起始原料, 以氯化镁在三乙胺和三甲基氯化硅存在下催化的(R)-4-苯基-3-戊烯酰基-2-噁唑烷酮的埃文斯（Evans)反式羟醛缩合反应为关键步骤, 经9步反应合成了(－)-7(R)-羟罗汉脂素, 其光谱数据与文献报道的天然产物一致.     

All-catalytic, efficient, and asymmetric synthesis of alpha,omega-diheterofunctional reduced polypropionates via "one-pot" Zr-catalyzed asymmetric carboalumination-Pd-catalyzed cross-coupling tandem process

A highly efficient method for the synthesis of stereochemically pure (>/=99% ee and >50/1 dr) alpha,omega-diheterofunctional reduced polypropionates has been developed. The essential features of the method are represented by the conversion of inexpensive styrene into 2-methyl-4-phenyl-1-pentanol (1) in 50% yield over two steps from styrene via Zr-catalyzed asymmetric carboalumination (ZACA) reaction in the presence of (NMI)2ZrCl2 and Pd-catalyzed vinylation of the in situ generated isoalkylalanes in the presence of Zn(OTf)2 and a catalytic amount of Pd(DPEphos)Cl2. This ZACA-Pd-catalyzed vinylation may be repeated as needed without purification. After the final ZACA reaction, oxidation with O2 provides alpha-hydroxy-omega-phenyl reduced polypropionates, which can be fully or partially purified by chromatography. After acetylation, Ru-catalyzed oxidative cleavage of the Ph ring, and reduction with BH3.THF, the second chromatographic purification provides stereoisomerically pure alpha,omega-diheterofunctional reduced polypropionates (e.g., 9 and 11) that can be further converted to key intermediates 6 and 7 for the synthesis of ionomycin (4) and borrelidin (5), respectively, by known reactions.     

Synthetic studies on ecteinascidin 743: asymmetric synthesis of the versatile amino acid component

The asymmetric synthesis of the modified tyrosine derivative as a basic building block for the ecteinascidin and safracin family of antitumor alkaloids has been achieved in nine steps and 39% overall yield.     

Total Synthesis of (−)‐Morphine

We have developed an efficient total synthesis of (?)‐morphine in 5 % overall yield with the longest linear sequence consisting of 17 steps from 2‐cyclohexen‐1‐one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki–Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6‐addition. Furthermore, mild deprotection conditions to remove the 2,4‐dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N‐methyl‐DNs‐amide moiety.     

不对称合成(+)-(11R, 12S)-盐酸甲氟喹

疟疾药物、(+)-(11R, 12S)-盐酸甲氟喹的不对称合成,由购买得到的2－三氟甲基苯胺、三氟乙酰乙酸乙酯,环戊酮为起始原料经过7步反应以14％的收率得到。关键步骤为脯氨酸催化的不对称aldol反应和贝克曼重排,绝对构型由Mosher的方法确定。     

Asymmetric total synthesis of (-)-saframycin A from L-tyrosine

The asymmetric total synthesis of (-)-saframycin A, a natural antitumor product of the tetrahydroisoquinoline antitumor antibiotics family, has been accomplished by employing L-tyrosine as the starting chiral building block in 24 steps for the longest linear sequence in an overall yield of 9.7%. The key steps in the synthesis involve stereoselective intermolecular and intramolecular Pictet-Spengler reactions, which induced the correct stereochemistry at C-1 and C-11, respectively. The selective protection-deprotection protocol of an amino group in the two-step transformation from intermediate 10 to 12 and a hydroxyl group in the first two steps resulted in both high selectivity and efficiency of the synthetic route.     

Total synthesis of a novel macrotetrolide

The total synthesis of a novel macrotetrolide, an isobutyl nonactin analog, has been achieved in 15% yield by coupling both enantiomers of the corresponding nonactic acid analogs followed by macrolactonization. These building blocks were prepared starting from β-ketoester in nine steps and 34% overall yield, in an efficient and highly stereoselective sequence. The key steps of the strategy are asymmetric hydrogenation, chelation-controlled allylation, intramolecular haloetherification of bishomoallylic ether presenting a trisubstituted double bond deactivated by an ester, and finally a stereoselective reduction of α-bromoester.