Concise total synthesis of (-)-spongotine A

The first asymmetric total synthesis of spongotine A is described. The oxidative synthesis of the imidazoline/ketone unit from keto aldehyde and diamine is a key step in this synthesis. The absolute stereochemistry of the asymmetric center of natural spongotine A is revealed as the (S)-configuration.     

Stereoselective synthesis of (-)-acanthoic acid

[reaction: see text] The first stereoselective synthesis of (-)-acanthoic acid (1) has been designed and accomplished. Our synthetic plan departs from (-) Wieland-Miesher ketone (7) and calls upon a Diels-Alder cycloaddition reaction for the construction of the C ring of 1. The described synthesis confirms the proposed stereochemistry of 1 and represents an efficient entry into an unexplored class of biologically active diterpenes.     

The total synthesis of (--)-lemonomycin

The first total synthesis of the novel glycosylated tetrahydroisoquinoline antitumor antibiotic (-)-lemonomycin has been accomplished (15 steps from 9). The highly convergent synthesis relies on a key asymmetric dipolar cycloaddition to set the stereochemistry of the aglycone core, a Suzuki fragment coupling to connect the diazabicycle to the aryl subunit, and a stereoselective Pictet-Spengler reaction that incorporates the aminoglycoside subunit directly into the core structure without the need for late-stage glycosylation or protecting group manipulations. The novel aminoglycoside was prepared using a highly diastereoselective Felkin-controlled acetate aldol addition reaction to a threonine-derived ketone.     

De novo asymmetric synthesis of 8a-epi-swainsonine

An enantioselective and diastereocontrolled approach to 8a-epi-d-swainsonine has been developed from achiral furfural. The key step to this synthesis was a one-pot procedure for the hydrogenolytic removal of two protecting groups and two intramolecular reductive amination reactions. The absolute stereochemistry was introduced by asymmetric Noyori reduction of furfuryl ketone. This route relies on diastereoselective palladium-catalyzed glycosylation to install the anomeric bond, and Luche reduction, diastereoselective dihydroxylation to set up the manno-stereochemistry of the indolizidine precursor.     

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.     

Stereoselective synthesis of malyngic acid and fulgidic acid

A new stereoselective total synthesis of malyngic acid has been achieved from a known oxazolidinone derivative via eight steps involving the Evans asymmetric alkylation as the chirality-inducing step and chelation-controlled Zn(BH₄)₂ reduction of an α-hydroxy ketone intermediate for the installation of the 12,13-anti stereochemistry. Fulgidic acid, the C12-epimer of malyngic acid, has also been synthesized in eight steps from the same starting material by using syn-selective K-Selectride reduction of an α-alkoxy ketone intermediate.     

Improved total synthesis of the potent HDAC inhibitor FK228 (FR-901228)

A scaleable synthesis of the potent histone deacetylase (HDAC) inhibitor FK228 is described. A reliable strategy for preparing the key beta-hydroxy mercapto heptenoic acid partner was accomplished in nine steps and 13% overall yield. A Noyori asymmetric hydrogen-transfer reaction established the hydroxyl stereochemistry in >99:1 er via the reduction of a propargylic ketone.     

Total synthesis of the CP-molecules (CP-263,114 and CP-225,917, phomoidrides B and A). 1. Racemic and asymmetric synthesis of bicyclo[4.3.1] key building blocks

A brief introduction into the chemistry of the CP-molecules is followed by first-generation synthetic sequences toward key building blocks for their total synthesis. Processes for both racemic and enantiomerically enriched bicyclo[4.3.1] ketone 6 or its equivalent are described, and the absolute stereochemistries of the optically enriched intermediates are determined. The efficient route developed to racemic 6 and the ready access to both enantiomers of key building blocks provided the opportunity for the total synthesis of the CP-molecules and determination of their absolute stereochemistry.     

A general approach to cyathin diterpenes. Total synthesis of allocyathin B(3)

[reaction: see text] The synthesis of allocyathin B(3) from an advanced intermediate possessing the ring system and relative stereochemistry but lacking the isopropyl and hydroxymethyl groups is reported. The isopropyl group was introduced by radical cyclization of a methyl propargyl acetal of an alpha-bromo ketone, and the hydroxymethyl group was generated by Pd-catalyzed carbonylation of a vinyl triflate. The route provides functionalized intermediates that could allow access to more complex members of the cyathin family of diterpenes.     

Stereoselective synthesis of polyhydroxylated quinolizidines from C-glycosides by one-pot double-conjugate addition

An effective one-pot synthesis of polyhydroxylated quinolizidines from 1-C-(2'-oxo-4'-pentenyl)-5-azido-C-glycofuranosides was developed. Reduction of the 5-azido group using triphenylphosphine followed by base treatment produced quinolizidines in good yield. The base-mediated ring-opening beta-elimination produced an acyclic alpha,beta-conjugated ketone as a Michael acceptor, which was followed by an intramolecular nitrogen conjugate addition to form an aza-C-glycopyranoside intermediate. Meanwhile, the beta,gamma-double bond of the aglycon migrated under the basic conditions to form another alpha,beta-conjugated ketone. The subsequent intramolecular conjugate addition by the azasugar nitrogen led to the formation of the quinolizidines in a highly stereoselective manner. The stereoselectivity of the first conjugate addition giving azasugar is affected by the stereochemistry of the monosaccharide substrate, whereas the stereoselectivity in the second conjugate addition was likely directed entirely by steric repulsion from the azasugar.     

Enantioselective synthesis of the antiinflammatory agent (-)-acanthoic acid.

An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.     

A formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid

[reaction: see text] A stereocontrolled approach for the preparation of the Danishefsky intermediates has been developed starting with the azaspirobicyclic ketone as a common precursor, representing a formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid. This approach involves the construction of the 1,7-disubstituted 6-azaspiro[4.5]decane with the proper stereochemistry established by olefin hydrogenation followed by C-methylation of the spirotricyclic lactam and the subsequent processes involving lactam ring-opening using methyl triflate and RCM to form the azaspirotricyclic quinolizidine skeleton.     

Total synthesis of guanacastepene a: a route to enantiomeric control

[reaction: see text] The goal of the total synthesis of guanacastepene A served as a focus to bring together several chemical inquiries. One involved the synthesis of fused 5,7-hydrazulenones (see structure 20). Another issue had to do with the mechanistic intermediates in reductive cyclizations (see 17 to 18 and 19). The total synthesis required a mastery of an intramolecular Knoevenagel condensation of a beta,gamma-unsaturated ketone (see compound 41). Actually, cyclization was best accomplished when the terminal double bond of 41 was first converted to an epoxide. Further issues related to the stereochemistry at C5 and, rather surprisingly, the propensity for beta-face acetoxylation at C13. Crystallographic verification of the assigned beta-stereochemistry at C13 is provided. Finally, a route to optically active material is provided (see compound 20). A key element in this construction was an enantioselective addition of isopropenyl cuprate to 2-methylcyclopentenone (see compound 99).     

Enantiospecific synthesis of the phospholipase A2 inhibitors (-)-cinatrin C1 and (+)-cinatrin C3

The enantiospecific synthesis of (-)cinatrin C1 (3) and (+)-cinatrin C3 (5) from the D-arabinose derivative 9 is described. The stereochemistry at C2 was introduced via a chelation-controlled addition of a carbanion to alpha-hydroxy ketone 8. The best selectivity was achieved by use of the Grignard reagent derived from trimethylsilylacetylene. Transformation of the terminal alkyne into methyl ester 17 followed by acetal hydrolysis and selective lactol oxidation gave cinatrin C1 dimethyl ester (7). Base hydrolysis and acid induced relactonization then gave a 1:1 mixture of cinatrins C1 (3) and C3 (5).     

3 + 2] Annulation of allylic silanes in acyclic stereocontrol: total synthesis of (9S)-dihydroerythronolide A

The [3 + 2] annulation reactions of allylic silanes can be utilized to achieve acyclic stereocontrol. This method was employed as a key step in an enantioselective total synthesis of (9S)-dihydroerythronolide A. The key annulation reaction served to establish most of the stereochemistry of the target, including the two tetrasubstituted carbon stereocenters. The symmetry of the target molecule allowed it to be disconnected into two equally sized fragments, both of which were generated from the same annulation reaction. The two fragments were coupled using a tin(II)-mediated chelation-controlled aldol reaction of an alpha-benzyloxy ethyl ketone. This convergent total synthesis of (9S)-dihydroerythronolide A was accomplished with the longest linear sequence of 29 steps and in 5.4% overall yield.     

Formal enantiospecific synthesis of (+)-FR900482

The enantiospecific synthesis of FK973, and thus a formal enantiospecific synthesis of the antitumor antibiotic (+)-FR900482, is reported. Addition of aniline 8 to chiral epoxide 9, prepared from l-vinylglycine, afforded amino alcohol 12. After protection of the aliphatic nitrogen with the 9-phenylfluoren-9-yl group, to preserve the acidic stereocenter from racemization, formation of the aziridine 14 and intramolecular condensation under basic conditions gave azocinone 15. Hydroxymethylation at the benzylic position was achieved by a process involving methylenation, epoxidation, and hydrogenolysis; the absolute stereochemistry of the resulting alcohol 23 was determined by X-ray crystallographic analysis. The hydroxyl group of 23 was carbamoylated, and the aromatic amine was deprotected electrochemically and then oxidized to give an unstable hydroxylamine that was immediately protected as acetate 26. Oxidation of 26 with DMP, followed by hydrazinolysis of the acetyl group led to spontaneous closure of the resulting N-hydroxyamino ketone to hemiketal 28, which can be considered as a fully protected precursor of FR900482 and derivatives. Acid treatment to remove the protecting groups and acetylation afforded the triacetate FK973.     

Novel approach to the zaragozic acids. Enantioselective total synthesis of 6,7-dideoxysqualestatin H5

The total synthesis of 6,7-dideoxysqualestatin H5 (3) has been completed by a concise approach that features the stereoselective intramolecular vinylogous aldol reaction of the furoic ester 25a to give 30 or its trimethylsilyl ether derivative 34, which possess the requisite absolute stereochemistry at C(3)-C(5) of 3. Compound 34 was reduced to the saturated bislactone 39, and the C(1) side chain subunit 47 was introduced leading to a mixture of the hemiacetals 48 and the corresponding ketone 49. When this mixture was stirred with methanolic acid, transketalization occurred to give a mixture of 50 and the spirocyclic methyl acetals 51a,b. Oxidation of the primary alcohol group in 50 followed by saponification of the two remaining ester groups gave 3. The longest linear sequence in the synthesis commences with commercially available erythronolactone (26) and requires 17 chemical steps with only 10 isolated intermediates.     

A stereocontrolled synthesis of a novel prostacyclin analog “allene-carbacyclin”. Application of molecular mechanics calculations to organic synthesis.

The synthesis of a novel Prostacyclin/Carbacyclin analog 1a has been achieved in a stereocontrolled manner starting from the readily available bicyclic ketone 3. A key strategic feature of the synthesis is a nucleophilic acetylide anion addition to 3, the stereochemistry of which is predicted by MM2 calculations.     

A sort synthesis of polyhydroxylated pyrrolizidines via sequential 1,3-dipolar cycloaddition and reductive amination

Polyhydroxylated pyrrolizidines bearing a methyl group at C-5 have been synthesized by 1,3-dipolar cycloaddition of five membered cyclic nitrones with methyl vinyl ketone followed by a N–O reductive cleavage and in situ intramolecular reductive amination. The stereochemistry of the obtained compounds is examined in relation to the reactions mechanism.     

A practical synthesis of (+)-discodermolide and analogues: fragment union by complex aldol reactions

A practical stereocontrolled synthesis of (+)-discodermolide (1) has been completed in 10.3% overall yield (23 steps longest linear sequence). The absolute stereochemistry of the C(1)-C(6) (7), C(9)-C(16) (8), and C(17)-C(24) (9) subunits was established via substrate-controlled, boron-mediated, aldol reactions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling reactions were a lithium-mediated, anti-selective, aldol reaction of aryl ester 8 (under Felkin-Anh induction from the aldehyde component 9), followed by in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheylboron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discodermolide, which should serve as valuable probes for structure-activity studies.