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Africane-type sesquiterpenoids consist of a bicyclo[5.3.0]decane structure and have been isolated from various natural environments. Their characteristic C C bond motifs, including a seven-membered ring core, fascinate many synthetic organic chemists. Thirteen total syntheses have been reported over the past four decades. The purpose of this digest is to provide an overview of these total syntheses of africane-type sesquiterpenoids, with an emphasis on methods for constructing the seven-membered ring structure.

The combination of pivalic or acetic acid as a promoter and EtOAc as a solvent and acetyl donor proved to be efficient for the chemoselective N-acetylation of primary aliphatic amines to afford the corresponding acetamides. We developed a simple and convenient approach, which requires mild reaction conditions. Competitive inter- and intramolecular reactions between aliphatic amines, alcohols, and aromatic amines were examined, and chemoselectivity was achieved by adjusting the conditions of the reaction.

(R)-(+)-N-methylbenzoguanidine ((R)-NMBG) functioned as an efficient acyl transfer catalyst for the acylative kinetic resolution of racemic β-hydroxy esters using cyclohexane carboxylic anhydride under mild reaction conditions. A tert-butyl ester moiety is necessary to achieve a high selectivity. The effects of the substituents on the aromatic rings of the substrates were systematically investigated, and diverse substrates participated in the reaction with good s-values (>20) irrespective of the type of substituents and their patterns, except for o-methoxy group.

Tin(IV) bromide was found to act as an efficient Lewis acid catalyst for the Friedel–Crafts type dehydrative alkylation reaction of diarylmethanols with 2-naphthol derivatives under mild conditions. The effects of the substituents on the substrates were systematically evaluated, and the reaction could be applied to a variety of substrates by tuning the conditions depending on the electronic properties of the starting materials.

Intramolecular decarboxylative etherification of readily available benzylic carbonates derived from benzylic alcohols and chloroformates was achieved using InCl3 in an SN1-type reaction. A fairly broad range of substrates could be used for the reaction by tuning the conditions depending on the electron density of the substituents on the substrates. A variety of secondary benzyl–alkyl, –allyl, –benzyl, and –aryl ethers were readily produced using the novel protocol under mild reaction conditions.

We developed an efficient synthetic route for functionalized aryl-β- C -glycosides, which are difficult to prepare by conventional methods. An aryl halide having an ester, cyano, or carbonyl group was treated with 2,4,6-triisopropylphenyllithium in the presence of a δ-lactone (Barbier-type reaction conditions) to afford a coupling product. The following deoxygenation gave the desired aryl-β- C -glycoside in good yield.

This Letter describes a series of [2]rotaxanes featuring a 3,5-diphenylaniline terminus in their dumbbell-shaped component and crown ethers as the macrocyclic component, prepared through imine formation and hydrogen bond—guided self-assembly. Electrochemical studies of these [2]rotaxanes revealed that the oxidation potential of the aniline moiety when positioned within the cavity of a crown ether was shifted negatively relative to that of the corresponding dumbbell-shaped compound, and that a crown ether possessing a small cavity and a large number of aromatic rings had a more negative effect on the oxidation potential of the aniline moiety than did a large-cavity crown ether featuring no aromatic rings. UV experiments showed that absorption band of the rotaxanes bearing small crowns shifted to longer wavelengths as compared to those of the rotaxanes having large crowns.

Two novel elemanolide dimers, vernodalidimers A (1) and B (2), possessing a rare tricyclic ortho ester moiety, were isolated from the seeds of Vernonia anthelmintica. Their structures were elucidated by 1D and 2D NMR data and CD spectra. Vernodalidimers A (1) and B(2) exhibited potent cell growth inhibitory activity against HL-60 cells (IC(50) 0.72 and 0.47 mu M, respectively).

A general method for the kinetic resolution of racemic α-arylalkanoic acids with achiral alcohols is described. It was determined that bis(9-phenanthryl)methanol is a suitable nucleophile which reacts with the intermediary mixed anhydrides generated from aromatic anhydrides with α-arylpropanoic acids or β-substituted-α-arylpropanoic acids in the presence of (+)-benzotetramisole to produce the corresponding optically active esters with high ee’s under very mild conditions.

Total synthesis of theopederin B, isolated from marine sponge, was accomplished by coupling pederic acid, as the left half, with trioxodecaline amine as the right half. Key reactions for synthesizing the amine were SmI 2 -promoted Reformatsky reaction, stereoselective allylation followed by Sharpless asymmetric epoxidation for construction of the functionalized side chain, and 1,3-dioxane ring construction followed by azide insertion.

Stereoselective synthesis of (−)-centrolobine, an anti-Leishmania agent, was accomplished via an intramolecular Barbier-type reaction of iodo-ester with n- or t-butyllithium followed by Lewis acid-promoted Et3SiH reduction of the resulting hemiacetal.

This Letter describes an efficient method for constructing a C3-symmetric [4]rotaxane through hydrogen bond-guided self-assembly and boroxine formation. The reactions proceed under mild conditions in solution, with entropically driven forces promoting the formation of the [4]rotaxane.

SmI2-induced reductive cyclization of optically active (E)- and (Z)-β-alkoxyvinyl sulfoxides with aldehyde was developed for the construction of several stereoisomers of tetrahydropyran derivatives.

A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic secondary benzylic alcohols using free carboxylic acids with benzoic anhydride and tetramisole derivatives. 4-Methoxybenzoic anhydride (PMBA) is the best reagent to use in producing the corresponding esters in high ee when the reaction is catalyzed by (+)-benzotetramisole (BTM); by contrast, when non-substituted benzoic anhydride is used as a coupling reagent, the resulting optically active alcohols are obtained with high selectivities. This protocol directly produces chiral carboxylic esters from free carboxylic acids and racemic secondary alcohols by utilizing the trans-acylation process to generate mixed anhydrides from acid components and benzoic anhydride derivatives under the influence of chiral catalysts.

We have succeeded in the total synthesis of siomycin A, a representative compound of the thiostrepton family of peptide antibiotics, featuring the one-pot cyclization–elongation of our strategic intermediates and the late-stage formations of the thiazoline and dehydroamino acid moieties.

SmI 2 -induced reductive cyclization of ( E )- and ( Z )-β-alkoxyvinyl sulfones with aldehyde stereoselectively afforded 2,6- syn -2,3- trans - and 2,6- syn -2,3- cis -tetrahydropyrans, respectively. The product having a sulfonylmethyl group was converted to a cyclic ether having a methyl group by reduction with Raney-Ni.

Both (E)- and (Z)-3-hydroxy-2-methyl-1-alkenyl iodides were stereoselectively synthesized from iodomethylated epoxides by treatment with sodium hexamethyldisilazane in DMF and with LDA in THF (or lithium 2,2,6,6-tetramethylpiperidide in THF), respectively.

Highly unstable pigments, hipposudoric acid and norhipposudoric acid, isolated from the red sweat of hippopotamus were synthesized using the Pschorr reaction for the construction of the fluorene nucleus as the key step and the careful oxidation in the last step.

Synthesis of the dihydroquinoline portion of thiostrepton, the siomycins, and the thiopeptins, members of the thiostrepton family of peptide antibiotics, has been achieved featuring the one-pot olefination via the Matsumura–Boekelheide rearrangement “using trifluoromethanesulfonic anhydride and triethylamine” and the stereoselective addition reaction controlled by the stereocenter of the peri-position.

The cyclic core portion containing the dehydropiperidine, dihydroquinoline, l -valine, and masked dehydroalanine (i.e., β-phenylselenoalanine) segments of the thiostrepton family of peptide antibiotics was synthesized via the consecutive coupling of these four segments followed by cyclization at the amide bond between the dehydropiperidine and masked dehydroalanine segments.

The asymmetric total synthesis of a marine natural product, methyl sarcoate, has been achieved featuring the asymmetric Michael addition, the dithiane coupling, the Kosugi–Migita–Stille coupling, and the ring-closing metathesis.

The Mukaiyama aldol coupling of the second-generation C1C14 (AB) fragment of altohyrtins (spongistatins) with the model α-methyl-β-alkoxyaldehydes revealed that the stereochemistry at the newly formed carbon centers was controlled by the β-alkoxy chiral center of the model aldehydes. The union of the AB fragment with the C15C28 (CD) fragment under the same conditions gave the fully elaborated C1C28 (ABCD) subunit in good yield.

Coupling of the C1C14 (AB) crotylstannane with the C15C28 (CD) aldehyde followed by stereochemical arrangements gave the C1C28 (ABCD) fragment of altohyrtin C. The C29C44 (EF) fragment was also prepared. The syntheses of these two fragments, both of which were identical with those prepared by the Smith group, constitute a formal total synthesis of altohyrtin C.

The 6,6-spiroacetal segment of spirofungin A, an antifungal antibiotic isolated from Streptomyces violaceusniger Tu 4113, was efficiently prepared via the coupling reaction of the Weinreb amide and the alkyne which are readily available from the common intermediate. The synthesis includes the unsymmetrization through a stereoinversion at the C11 position and the transacetalization as the key steps.

An antitumor acetogenin, muconin, was synthesized through a coupling reaction of a THF–THP segment and a terminal butenolide. The key reactions include 6- exo cyclization of an epoxy tetraol, regioselective cyclization of hydroxy tosylate, and stereoselective reduction of an acyclic ketone adjacent to the 2,6- cis THP ring with Zn(BH 4 ) 2 .

An approach joining highly diastereoselective Mukaiyama aldol reaction (process A) to the following radical debromination reaction (process B) provides a reliable way to the stereoselective divergent synthesis of polypropionate frameworks. A practical and reliable synthesis of the complete set of propionate stereotetrads from enantiopure syn- and anti-2-methyl-3-methoxy-3-phenylpropanals was achieved by using the straightforward strategy.

The tetrasubstituted dehydropiperidine and piperidine cores of the thiostrepton family of peptide antibiotics were synthesized which featured the coupling between the azomethine ylide and the enantiopure sulfinimine, and the subsequent stereoselective reduction of the six-membered imine.

An efficient method for cross-coupling using phthalate-tethered ring-closing metathesis was developed. Based on this method, the stereocontrolled syntheses of both (R,R)- and (S,R)-1-methoxypentadecane-2,9-diol ( 17 , 20 ) were achieved from (R)-1-undecen-5-ol ( 4e ) and (R)-1-methoxy-5-hexen-2-ol ( 13 ).

The C29–C44 portion of altohyrtins (spongistatins) has been prepared from 1,5-pentanediol and d -glucose in a stereoselective manner. The convergent synthesis relied on a coupling reaction of the C29–C37 vinyl bromide and the C38–C44 Weinreb amide, diastereoselective reduction of the C38 ketone, and stereoselective formation of the C33–C37 (E ring) acetal.

The stereoselective synthetic methods for anti - and syn -fused tricyclic guanidine compounds 4a and 4b were developed based on a successive 1,3-dipolar cycloaddition. Through these synthetic studies, the stereochemistry of the left-hand tricyclic guanidine unit of batzelladine F ( 3 ) was confirmed as a syn -fused one, which is identical with the structure reported by the Murphy and Snider groups.

The C15–C27 portion of venturicidin X was prepared using substitution reactions of alkyl trifluoromethanesulfonates with a vinylmetal compound followed by homogeneous hydrogenation. Together with our previous synthesis of the C1–C14 portion of venturicidin X, a formal total synthesis of venturicidin X was completed.

Simple reduction of O,S-acetals with SmI2 yielding ethers with selective liberation of the sulfenyl group can be accomplished using benzene–HMPA with t-BuOH. When O,S-acetals possess an O-allyl group, the [2,3]-Wittig rearrangement yielding homoallyl alcohols follows the elimination of a sulfenyl group. For chemoselective elimination of an alkoxy group to give sulfides, MeOTf serves as a moderately effective additive.

The EFG-ring system of brevetoxin-B, having an α-methyl group on the D-ring, was stereoselectively synthesized based on the stereoselective Michael addition of the α-methyl group, novel ring-expansion reaction, and 6-endo-cyclizations of the vinylepoxide and methylepoxide.