Total synthesis of the tricyclic marine alkaloids (-)-lepadiformine, (+)-cylindricine c, and (-)-fasicularin via a common intermediate formed by formic acid-induced intramolecular conjugate azaspirocyclization

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).     

An enantioselective total synthesis of (+)-geissoschizine

[formula: see text] A concise asymmetric synthesis of the indole alkaloid (+)-geissoschizine (1) has been completed. The synthesis features the highly diastereoselective vinylogous Mannich reaction of 3 with 4 to give 5, which is elaborated into the key tetracyclic intermediate 7 in two steps. Following the stereoselective introduction of the ethylidene moiety to give 9, reduction of the lactam and radical decarboxylation via an acyl selenide gave 12, which was converted into (+)-geissoschizine by formylation. The synthesis requires only 11 chemical operations and proceeds in an overall yield of 17%.     

Total synthesis of (-)-indolactam V

The total synthesis of protein kinase C activator (-)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from L-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized from l-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using HATU in THF in good yield.     

Total synthesis of (+)-boronolide, (+)-deacetylboronolide,and (+)-dideacetylboronolide

Total synthesis of (+)-boronolide, (+)-deacetylboronolide, and (+)-dideacetylboronolide has been achieved from a single intermediate 26, which was synthesized in 11 steps from a d-mannitol-derived intermediate 8 in an overall yield of 10%. The key steps in the synthesis are inversion of a chiral center by taking an advantage of the inherent mechanism involved in the ring closing to an epoxide via intramolecular S(N)2 reaction and lactonization of a diol using Fetizons reagent. The strategy is amenable to preparation of analogues of (+)-boronolide in sufficient amount for further screening of biological activity.     

Enantioselective total synthesis of quadrigemine C and psycholeine

The first total syntheses of higher-order members of the polypyrrolidinoindoline alkaloid family are reported. The synthesis of quadrigemine C (1) and psycholeine (3) begins with synthetic meso-chimonanthine (4), which is synthesized from commercially available oxindole and isatin in 13 steps and 35% overall yield. Double Stille cross coupling of diiodide 7, available in three steps from 4, with vinylstannane 8 produces dibutenanilide 9. Double catalytic asymmetric Heck cyclization of 9 simultaneously installs the two peripheral quaternary stereocenters and desymmetrizes this advanced meso precursor to deliver the chiral, decacyclic intermediate 11 in 62% yield and 90% ee. In two additional steps, 11 is converted to 1, which upon treatment with acid generates 3. The synthesis of quadrigemine C (1), which rigorously confirms its relative and absolute configuration, was executed in 19 linear steps (2% overall yield) from commercially available starting materials.     

Practical asymmetric synthesis of (S)-MA20565, a wide-spectrum agricultural fungicide

A practical asymmetric synthesis of a wide-spectrum agricultural fungicide, (S)-MA20565 (1), is described. The convergent synthesis was achieved starting from commercially available 3-(trifluoromethyl)aniline (7) in 44% overall yield through five steps and 2-bromobenzaldehyde (9) in 48% overall yield through four steps, respectively. (S)-O-[1-(3-Trifluoromethylphenyl)ethyl]hydroxylamine (2), a key intermediate of 1, was prepared via ruthenium(II)-catalyzed asymmetric transfer hydrogenation of 1-(3-trifluoromethylphenyl)ethanone (6) followed by chlorination using methanesulfonyl chloride and oxyamination using potassium acetohydroxamate with high level of stereocontrol.     

An efficient parallel synthesis of capsazepine and capsazepine analogs

Capsazepine (CPZ, 1) is a well-known vanilloid receptor (VR1) antagonist that has been cited widely used in the literature. However the current synthetic methods used for the total synthesis of CPZ are lengthy, involve multiple purification steps, and produce low yields. Here we describe a new and highly efficient synthesis of benzazepine 3, a synthetic precursor of CPZ, in only two steps and 59% overall yield from a commercially available tetralone 2 via a Schmidt reaction as a key step. Moreover, we apply parallel synthesis techniques to prepare CPZ and CPZ analogs. Our approach enables the possibility of preparing larger, and more diverse libraries of CPZ analogs.     

Enantiospecific total synthesis of the sarpagine related indole alkaloids talpinine and talcarpine as well as the improved total synthesis of alstonerine and anhydromacrosalhine-methine via the asymmetric Pictet-Spengler reaction

The enantiospecific total synthesis of talpinine 1 and talcarpine 2 has been accomplished from D-(+)-tryptophan in 13 steps (11 reaction vessels) in 10% and 9.5% overall yields, respectively. Moreover, this synthetic approach has been employed for the improved synthesis of alstonerine 3and anhydromacrosalhine-methine 4 in 12% and 14% overall yield, respectively. A convenient synthetic route for the enantiospecific, stereospecific preparation of the key intermediate (-)-N(a)-H, N(b)-benzyl tetracyclic ketone 15a via the asymmetric Pictet-Spengler reaction on a multihundred-gram scale has been developed. A diastereocontrolled (>30:1) anionic oxy-Cope rearrangement and the intramolecular rearrangement to form ring-E and an N(b)-benzyl/N(b)-methyl transfer reaction also served as key steps. This general approach can now be utilized for the synthesis of macroline/sarpagine related indole alkaloids and their antipodes for biological screening.     

Diastereoselective amidoalkylation of (3S,7aR)-6-benzyl-7-hydroxy-3-phenyltetra- hydro-5H-imidazo[1,5-c][1,3]thiazol-5-one: a short and highly efficient synthesis of (+)-biotin

A short and highly efficient synthesis of (+)-biotin in 10 steps with 20% overall yield has been achieved from L-cysteine involving amidoalkylation of hydroxy imidazothiazolone 4 via an acyliminium ion intermediate to furnish C-7-substituted imidazothiazolones 5b as the key step.     

A Concise Synthesis of the HCV Protease Inhibitor BILN 2061 and Its P3 Modified Analogs

A concise synthesis of BILN 2061 was achieved through more efficient installation of P2 4‐quinoline moiety via S_N2 displacement of the β‐OBs group located on the 4‐hydroxyl proline intermediate, which was prepared from 4‐α‐hydroxyl proline analog via Mitsunobu reaction with inversion of stereochemistry. In addition, a short and practical synthesis for P3 unit is also described herein. Final assembly of four fragments for BILN 2061 was achieved with an overall yield of 58% in 4 steps from P1 to 15a . Furthermore several analogs of BILN 2061 ( WX‐1 – WX ‐ 5 ) containing modifications on P3 unit were synthesized successfully using the same synthetic route as described for the parent inhibitor BILN 2061 .     

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 naturally occurring iminosugars from D-fructose by the use of a zinc-mediated fragmentation reaction

A short synthesis of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and a formal synthesis of australine are described. In both cases, D-fructose is employed as the starting material and converted into a protected methyl 6-deoxy-6-iodo-furanoside. Zinc-mediated fragmentation produces an unsaturated ketone which serves as a key building block for both syntheses. Ozonolysis, reductive amination with benzylamine and deprotection affords 1,4-dideoxy-1,4-imino-D-arabinitol in only 7 steps and 11% overall yield from D-fructose. Alternatively, reductive amination with homoallylamine, ring-closing metathesis and protecting group manipulations give rise to an intermediate which can be converted into australine in 3 steps. The intermediate is prepared by two different strategies both of which use a total of 9 steps. The first strategy utilizes benzyl ethers for protection of fructose while the second and more effective strategy employs an isopropylidene acetal.     

First total synthesis of ent-gelsedine via a novel iodide-promoted allene N-acyliminium ion cyclization

The first total synthesis of the oxindole alkaloid gelsedine (1) starting from (S)-malic acid is described. The key step is a novel iodide-promoted intramolecular reaction of an allene with an N-acyliminium ion intermediate which provided in a single step the bicyclic vinyl iodide 11. Other important steps are the highly stereoselective Pd-catalyzed Heck cyclization of N-methylanilide 23a which led to the desired spiro-oxindole 24a, the fully regioselective intramolecular oxymercuration of 25a to the desired cyclic ether, and the remarkable oxindole N-demethylation of 29 via a radical mechanism by using dibenzoyl peroxide. The total synthesis was concluded by the stereoselective introduction of the ethyl group from the bis-Boc compound 41 followed by methoxylation of the oxindole nitrogen. This total synthesis leads to the unnatural (+)-enantiomer of gelsedine in 21 steps and 0.10% overall yield.     

Formal synthesis of squalamine from desmosterol

The key intermediate to squalamine, (5alpha,7alpha,24R)-7,24-dihydroxy-cholestan-3-one, was synthesized from the 3-O-acetyl-24R,25-dihydroxy derivative of desmosterol via 10 steps in 16% overall yield and squalamine was also prepared via two further steps in 7.4% total yield from the desmosterol derivative.     

An improved asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (2S,4R,5R)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-142)

Triple monoamine reuptake inhibitors have been implicated in the development of a new generation of antidepressants with higher efficacy than the currently existing therapies. In this paper, we have developed an alternative efficient synthetic route for triple monoamine reuptake inhibitor D-142 in 18.5% overall yield in 11 steps starting from diphenylmethane. D-142 was developed by us recently. The key step of the present synthetic strategy is the preferential formation of a bromohydrin from olefin via a cis-bromoinum intermediate, which introduced significant efficiency in the overall synthesis. Furthermore, we have developed an efficient way to recycle the optically active intermediate diol back to the desired chiral epoxide.     

Formal enantioselective synthesis of (+)-estrone

A formal total synthesis of (+)-estrone (4% overall yield; ca. 12 steps) could be achieved via the Torgov diene. An asymmetric allylic substitution is the key step for the construction of the chiral quaternary carbon center of a synthetic intermediate which was converted in four steps to the Torgov diene. [reaction: see text]     

Asymmetric total synthesis of (+)-cannabisativine

The asymmetric total synthesis of natural (+)-cannabisativine 1 was completed in 19 steps and 7% overall yield. The key synthetic intermediate 29 was prepared with a high degree of stereocontrol in 12 steps starting from chiral 1-acylpyridinium salt 10. Addition of zinc enolate 11 to pyridinium salt 10 furnished dihydropyridone 12 containing two contiguous stereocenters of the correct absolute configuration. Luche reduction of ketone 16 afforded diol 17 in high yield (96%) and excellent diastereoselectivity. The Mukaiyama-Michael reaction of pyridones 27a/b with O-silyl ketene acetal 32 gave phenyl selenyl ketones 33a/b with complete stereoselectivity. Elimination of cis-beta-hydroxyselenides 34 and 35 effected the regiocontrolled preparation of tetrahydropyridine derivative 29. Several approaches to the macrocyclic ring closure of the 13-membered ring were investigated, ultimately leading to the completion of an asymmetric synthesis of the target compound with a high degree of stereocontrol.     

A highly efficient chemical synthesis of Rp and Sp adenyl(3′-5′)adenyl-o,o-phosphorothioate

A method is described for the chemical synthesis of the title compounds (Ap(S)A) via addition of elemental sulfur to a phosphite triester intermediate. Separation of the diastereomers of phosphorus could be accomplished on silica gel after removal of the terminal 5′-hydroxyl protecting group or on DEAE cellulose after complete deblocking. The triester to terminal 5′-hydroxyl. The overall yield of the synthesis (one coupling and four deblocking steps) is 30%.     

Stereoselective approach to the DEF ring system of terpendole E

Diastereoselective construction of a DEF ring model of terpendole E, a M phase-specific antimitotic natural product, has been achieved from a known bicyclic keto ester by a 10-step (or 12-step) sequence that features an efficient one-pot intramolecular etherification of an olefinic alcohol with mCPBA. The synthesis proceeded in an excellent overall yield of 36% through 10 steps or in 56% via 12 steps which involved a highly diastereoselective reduction of a ketone derived from an undesired diastereomeric alcohol intermediate.     

First total synthesis of (−)-(3S,6R)-3,6-dihydroxy-10-methylundecanoic acid

The first total synthesis of (3S,6R)-3,6-dihydroxy-10-methylundecanoic acid was accomplished from commercially available 1-bromo-3-methylbutane in 11 steps and 25.8% overall yield. The key steps were asymmetric allylic alkylations via allyldiisopinocampheylborane and hydroboration-oxidation.