Unified Total Synthesis of 3‐epi‐Ryanodol,Cinnzeylanol, Cinncassiols A and B,and Structural Revision of Natural Ryanodol and Cinnacasol

Ryanodane diterpenoids structurally share an extremely complex fused ring system, but differ in the substitution patterns of the hydroxy groups. Since these congeners exhibit various biologically important functions, their efficient chemical constructions have been greatly anticipated. We previously accomplished the total synthesis of ryanodine ( 1 ) using pentacycle 8 as the advanced intermediate. Here, we report the unified total syntheses of four distinct diterpenoids, 3‐epi‐ryanodol ( 3 ), cinnzeylanol ( 4 ), cinncassiols B ( 5 ), and A ( 6 ), from 8 , all within 10 steps. A series of highly optimized chemo‐ and stereoselective reactions and protecting‐group manipulations enabled assembly of the densely oxygenated structures of 3 – 6 . Furthermore, the present synthetic studies established the C13S stereochemisty of 5 – 7 and revised the proposed structures of natural ryanodol ( 2 ) and cinnacasol ( 7 ) to be those of 3 and 6 , respectively.     

Unified Total Synthesis of 3‐epi‐Ryanodol,Cinnzeylanol, Cinncassiols A and B,and Structural Revision of Natural Ryanodol and Cinnacasol

Ryanodane diterpenoids structurally share an extremely complex fused ring system, but differ in the substitution patterns of the hydroxy groups. Since these congeners exhibit various biologically important functions, their efficient chemical constructions have been greatly anticipated. We previously accomplished the total synthesis of ryanodine ( 1 ) using pentacycle 8 as the advanced intermediate. Here, we report the unified total syntheses of four distinct diterpenoids, 3‐epi‐ryanodol ( 3 ), cinnzeylanol ( 4 ), cinncassiols B ( 5 ), and A ( 6 ), from 8 , all within 10 steps. A series of highly optimized chemo‐ and stereoselective reactions and protecting‐group manipulations enabled assembly of the densely oxygenated structures of 3 – 6 . Furthermore, the present synthetic studies established the C13S stereochemisty of 5 – 7 and revised the proposed structures of natural ryanodol ( 2 ) and cinnacasol ( 7 ) to be those of 3 and 6 , respectively.     

A concise route to a key intermediate in the total syntheses of (+)-tirandamycic acid and (-)-tirandamycin a 2

An efficacious, asymmetric synthesis of the 2,9-dioxabicyclo[3,3,1]nonane 4 has been completed in nine chemical steps from 4,5-dimethylfuraldehyde (8). Since enantiomerically pure 4 has been previously converted in five steps by Ireland into (+)-tirandamycic acid (3) and more recently by Schlessinger into (-)-tirandamycin A (1), this achievement constitutes in a strictly formal sense the total syntheses of these substances. The key step in the synthesis of 4 features the transformation of the enantiomerically pure furfuryl diol 25 into 29 by initial selective oxidation of (the furan ring and subsequent acid-catalyzed bicycloketalization.     

First total synthesis of natural products cajanolactone A and cajanonic acid A

First total synthesis of cajanolactone A and cajanonic acid A has been achieved through steps of anion–anion condensations,cyclization,Williams etherification,selective demethylation,1 3-sigmatropic rearrangement and hydrolysis.This work provides an efficient method for future cajanonic acid A derivatives synthesis.     

A concise route to (−)-shikimic acid and (−)-5-epi-shikimic acid, and their enantiomers via Barbier reaction and ring-closing metathesis

A simple route for the synthesis of naturally occurring (−)-shikimic acid, (−)-5-epi-shikimic acid, and their enantiomers from d-ribose-derived enantiomeric aldehydes 8a and 8b by employing Barbier reaction and ring-closing metathesis as key steps has been developed.     

Concise syntheses of coronarin A, coronarin E, austrochaparol and pacovatinin A

Total syntheses of (+)-coronarin A (1), (+)-coronarin E (2), (+)-austrochaparol (3) and (+)-pacovatinin A (4) were achieved from the synthetic (+)-albicanyl acetate (6). Dess-Martin oxidation of (+)-albicanol (5) derived from the chemoenzymatic product (6) gave an aldehyde (7), which was subjected to Julia one-pot olefination using beta-furylmethyl-heteroaromatic sulfones (8 or 9 ) gave (+)-trans coronarin E (2) and (+)-cis coronarin E (12) with high cis-selectivity. The synthesis of (+)-coronarin A (1) from (+)-trans coronarin E (2) was achiev-ed, while (+)-cis coronarin E (12) was converted to the natural products (+)-(5S,9S,10S)-15,16-epoxy-8(17),13(16),14-labdatriene (13) and (+)-austrochaparol (3). By the asymmetric synthesis of (+)-3, the absolute structure of (+)-3 was determined to be 5S, 7R, 9R, 10S configurations. Homologation of (+)-albicanol (5) followed by allylic oxidation gave (7 alpha)-hydroxy nitrile (17), which was finally converted to the natural (+)-pacovatinin A (4) in 8 steps from (+)-albicanol (5).     

Total synthesis and biological evaluation of (-)-apicularen A and its analogues

The total synthesis of (-)-apicularen A (1), a highly cytostatic 12-membered macrolide, and its analogues is described. The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesize C10-C11 functional analogues of 1. The key steps of the total synthesis include assembling of iodoalkene 12 and aldehyde 13by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in the side chain is installed by an efficient Cu(I)-mediated coupling to complete the synthesis. Analogues of C11-epi-, C11-deoxy-C10-α-hydroxy-, and C10-C11 dehydrated apicularen A 3-5 were also prepared. Cytostatic activities of (-)-apicularen A and the three analogues for three different cancer cell lines are described.     

A concise approach for the total synthesis of pseudolaric acid A

A new strategy for the stereoselective total synthesis of natural product pseudolaric acid A (1) was accomplished in 16 steps from commercially available starting material, featuring a samarium diiodide (SmI(2))-mediated intramolecular alkene-ketyl radical cyclization and a ring-closing metathesis (RCM) reaction to stereoselectively cast the unusual trans-fused [5-7]-bicyclic core of pseudolaric acid A (1).     

Total synthesis of lathyranoic acid A

The first total synthesis of lathyranoic acid A (1) was accomplished stereoselectively in a linear sequence of 20 steps and an overall yield of 1.4%. This modular synthesis featured a cyclic, stereocontrolled Cu-catalyzed intramolecular cyclopropanation to construct the cis-cyclopropane unit, a Grubbs metathesis to construct the γ-substituted cyclopentenone moiety, and an anion-mediated conjugate addition.     

Furan‐Derived Chiral Bicycloaziridino Lactone Synthon: Collective Syntheses of Oseltamivir Phosphate (Tamiflu), (S)‐Pipecolic acid and its 3‐Hydroxy Derivatives

A unified synthetic strategy for oseltamivir phosphate (tamiflu), (S)‐pipecolic acid, and its 3‐hydroxy derivatives from furan derived common chiral bicycloaziridino lactone synthon is described here. Key features are the short (4‐steps), enantiopure, and decagram‐scale synthesis of common chiral synthon from furan and its first‐ever application in the total synthesis of biologically active compounds by taking the advantages of high functionalization ability of chiral synthon.     

Highly Stereoselective Synthesis of (E, E)-3,7-Dimethyl-2,6-decadiene-1, 10-diol

Thediol1,aqueenbutterflypheromonewasisolatedfromqueenbutterfly(Danausgillippusbelenice).SynthesesofthiscompoundwerereportedfromtheorthoesterClaisenrearrangement2,therearrangementofallylsiloxylinylether3andtheanionic[2,3]-sigmatropicrearrangementofallylicsulfide4.Inlightoftheirbiologicalinterest,itseemeddesirabletodesignamoreefficientroutetothissubstance.Thus,wewishtoreportashort,stereoselectivesynthesisof1utilizingthe1,3-transformationof2,3-epoxyalcoholandtheClaisenrearrangementofallylvinylet…     

A facile synthesis of cajaninstilbene acid and its derivatives

A facile synthesis of cajaninstilbene and its derivatives by using a building block has been developed.     

A total synthesis of (-)-hemiasterlin using N-Bts methodology.

A total synthesis of (-)-hemiasterlin has been accomplished in nine steps from 25(8) (>35% yield overall). An improved enantiocontrolled route to the tetramethyltryptophan subunit 32 was developed using an asymmetric Strecker synthesis (five steps, 50% yield from 25), and the dipeptide 22 was prepared in seven steps, 37% yield from valinol. The synthesis exploits the high reactivity of a Bts-protected amino acid chloride in the difficult peptide coupling of sterically hindered amino acid residues 18 and 20 to form 21 (70%, recrystallized) and also uses N-Bts intermediates for the high-yielding N-methylations of 14 and 31. In addition, the Bts-protected di-tert-butyl N-acylimidodicarbonate 33 is shown to undergo efficient coupling with 22 to form 34 (97% in the coupling step; 79% over the activation; coupling sequence from 32).     

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).     

Diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid

A diastereoselective synthesis of (+)-nephrosterinic acid and (+)-protolichesterinic acid, common members of the paraconic acids is described. The synthesis is based on a diastereoselective orthoester Johnson–Claisen rearrangement of a (Z)-allyl alcohol with a vicinal dioxolane moiety as key steps. The synthesis is completed in 10 steps and with overall yields of 15.9% for (+)-nephrosterinic acid and 16.4% for (+)-protolichesterinic acid.     

The synthesis of 3-bromo-2,4,5-trifluorobenzoic acid and its conversion to 8-bromoquinolonecarboxylic acids

A series of 8-bromo-4-oxo-3-quinolinecarboxylic acids was prepared via the borate ester, 8 . The key intermediate in the synthesis of the final products 10a-10d was 3-bromo-2,4,5-trifluorobenzoic acid ( 3 ), conveniently prepared in two steps from the known oxazoline, 1 . The preparation of 10a-10d is a significant improvement of the literature procedure currently available for the synthesis of these compounds.     

Biomimetic Total Synthesis of Hyperjapones A–E and Hyperjaponols A and C

Hyperjapones A–E and hyperjaponols A–C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A–E using a biomimetic, oxidative hetero‐Diels–Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid‐catalyzed epoxide ring‐opening; and 3) a concerted, asynchronous alkene cyclization and 1,2‐alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponol C to be completed in which six carbon–carbon bonds, six stereocenters, and three rings were constructed in just four steps.     

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.     

Enantioselective Total Synthesis of Secalonic Acid E

The first enantioselective synthesis of a secalonic acid containing a dimeric tetrahydroxanthenone skeleton is described, using a Wacker‐type cyclization of a methoxyphenolic compound to form a chiral chroman with a quaternary carbon stereogenic center with >99 % ee. Further steps are a Sharpless dihydroxylation and a Dieckmann condensation to give a tetrahydroxanthenone. A late‐stage one‐pot palladium‐catalyzed Suzuki‐dimerization reaction leads to the 2,2′‐biphenol linkage to complete the enantioselective total synthesis of secalonic acid E in 18 steps with 8 % overall yield.     

Asymmetric Total Synthesis of Onoseriolide,Bolivianine, and Isobolivianine

In this article, we describe our efforts on the total synthesis of bolivianine ( 1 ) and isobolivianine ( 2 ), involving the synthesis of onoseriolide ( 3 ). The first generation synthesis of bolivianine was completed in 21 steps by following a chiral resolution strategy. Based on the potential biogenetic relationship between bolivianine ( 1 ), onoseriolide ( 3 ), and β‐(E)‐ocimene ( 8 ), the second generation synthesis of bolivianine was biomimetically achieved from commercially available (+)‐verbenone in 14 steps. The improved total synthesis features an unprecedented palladium‐catalyzed intramolecular cyclopropanation through an allylic metal carbene, for the construction of the ABC tricyclic system, and a Diels–Alder/intramolecular hetero‐Diels–Alder (DA/IMHDA) cascade for installation of the EFG tricyclic skeleton with the correct stereochemistry. Transformation from bolivianine to isobolivianine was facilitated in the presence of acid. The biosynthetic mechanism and the excellent regio‐ and endo selectivities in the cascade are well supported by theoretical chemistry based on the DFT calculations.