Total synthesis of GEX1A

An efficient and readily modifiable synthesis of GEX1A/herboxidiene/TAN-1609 ( 1) was developed. This modular synthesis featured a Suzuki coupling to install the conjugated diene and a Ru-catalyzed lactonization and Roush crotylation to construct the functionalized tetrahydropyran moiety. Myers' alkylation, cross-metathesis, and Keck crotylation were employed for assembly of the biologically essential side-chain domain.     

A stereoselective synthesis of (+)-herboxidiene/GEX1A

A stereoselective synthesis of (+)-herboxidiene is described. The convergent synthesis utilized a Suzuki cross-coupling reaction to assemble the key segments. The synthesis of the functionalized tetrahydropyran ring utilized an Achmatowicz reaction as the key step. The synthesis of the C10-C19 segment was accomplished using Brown's crotylboration, asymmetric alkylation, and a stereoselective allylic chlorination reactions.     

Total synthesis of bafilomycin A1

A convergent synthesis of bafilomycin A(1), a potent inhibitor of V-type ATPases, is presented. The synthesis relies on the zinc triflate mediated diastereoselective addition of a complex enyne to a sensitive aldehyde as the key fragment coupling. A ruthenium-catalyzed trans-reduction of the resulting propargylic enyne efficiently installs the required C10-C13 trans,trans-diene subunit, implementing an alternative strategy to traditional palladium-catalyzed cross-coupling strategies. A highly selective oxidation of a secondary hydroxyl group in a triol sets the stage for the completion of the synthesis.     

Total synthesis of Cinncassin A1

In this communication, we report the first total synthesis of the phenolic natural product Cinncassin A₁, which was recently isolated from the twigs of the cinnamon plant (Cinnamomum cassia). The novel and concise synthesis strategy involves a highly diastereoselective titanium enolate homocoupling and a permanganate-mediated oxidative lactonization reaction as key steps. The structure of the compound was verified by single-crystal X-ray crystallography.     

Total synthesis of myxovirescin A1

A convergent total synthesis of the antibiotic macrolide myxovirescin A1 (1) is described that is largely based on reagent- and catalyst-controlled transformations. This includes a highly regioselective Negishi reaction of dibromo-alkene 48 with an alkynylzinc reagent, and a palladium catalyzed alkyl-Suzuki coupling of the resulting enyne derivative 12 with the 9-BBN-adduct derived from alkene 61. The latter was obtained via an asymmetric hydrogenation of the chlorinated beta-ketoester 49 and an anti-selective oxyallylation of the functionalized aldehyde 53 as the key steps. The preparation of the bis-borylated allyl-donor 57 used in the oxyallylation step, however, required careful optimization and led to important insights into the nature of the classical hydroborating agent "di(isopinocampheyl)borane (Ipc2BH)". It was unambiguously shown by X-ray crystallography that in the solid state this compound is dimeric, but it is prone to undergo an essentially quantitative mono-deborylation when dissolved in CH2Cl2 or benzene; its composition in ethereal solvents is even more complex as evident from 11B NMR data. Product 71 derived from 12 and 61 was elaborated into the enyne-yne derivative 75, which served as the substrate for an exquisitely selective ring closing alkyne metathesis reaction (RCAM) catalyzed by the molybdenum tris-amido complex 20 activated in situ with CH2Cl2. The resulting cyclic enyne 76 was subjected to a ruthenium catalyzed trans-hydrosilylation/proto-desilylation tandem. Although [Cp*Ru(MeCN)3]PF6 had previously been recommended as catalyst of choice for trans-hydrosilylation reactions of internal alkynes, this complex failed to afford the desired product, whereas its sterically less hindered congener [CpRu(MeCN)3]PF6 permitted the reaction to be performed in appreciable yield, but at the expense of a lower stereoselectivity. AgF-mediated proto-desilylation of the isomeric silanes 79 and 80 followed by cleavage of the remaining acetal protecting groups afforded myxovirescin A1 and its hitherto unknown 14Z-isomer 81, respectively.     

Total synthesis of bleomycin A21)

Bleomycin A2 has been synthesized for the first time.     

Total synthesis of piericidin A1 and B1

The first total syntheses of piericidin A1 and B1 are disclosed and unambiguously establish the relative and absolute stereochemistry of the natural products by an approach that will facilitate the synthesis of a series of analogues. Central to the approach is an inverse electron demand Diels-Alder reaction of a N-sulfonyl-1-aza-1,3-butadiene with tetramethoxyethene followed by Lewis acid-promoted aromatization used to assemble the functionalized pyridine core. Additional key elements in the convergent approach include the use of an anti-aldol reaction to install the C9 and C10 relative and absolute stereochemistry, a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chain, and a penultimate heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain.     

Total synthesis of hyacinthacine A1 and 3-epi-hyacinthacine A1

[reaction: see text] Total synthesis of hyacinthacine A(1) and its epimer at C3 is described. The synthesis includes a stereocontrolled carboazidation of a chiral allylsilane as a key step. C-Si bond oxidation and reduction of the azide, with ring-closure, complete the total synthesis, which establishes the absolute configuration of 3.     

Total synthesis of fluvirucinine A1

An efficient and highly stereocontrolled convergent synthesis of fluvirucinine A₁ is reported herein. In fluvirucinine A₁ both C₅-C₁₃ and C₁-C₄ fragments were accessed from a common intermediate 6 derived from (S)-Roche ester in 15 and 7 steps, respectively. The key steps involve Evans asymmetric alkylation, Sharpless asymmetric epoxidation, amidation and a ring-closing metathesis reaction (RCM) for macrocyclization.     

Total synthesis of bryostatin 1

Bryostatin 1 is a marine natural product that is a very promising lead compound because of the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic route adopted is a highly convergent one in which the preformed, heavily functionalized pyran rings A and C are united by "pyran annulation", the TMSOTf-promoted reaction between a hydroxyallylsilane appended to the A-ring fragment and an aldehyde contained in the C-ring fragment, with concomitant formation of the B ring. Further elaborations of the resulting very highly functionalized intermediate include macrolactonization and selective cleavage of just one of five ester linkages present.     

Total synthesis of 1-(Z)-atractylodinol

The total synthesis of 1-(Z)-atractylodinol, a natural polyacetylenic alcohol with several biological activities, has been achieved using a newly developed telluride synthon and a novel use for the Negishi type coupling reaction employing vinyl tellurides.     

Total synthesis of Eudistomins Y1-Y6

The first total synthesis of Eudistomins Y₁-Y₆, brominated phenolic β-carboline marine metabolites with a unique benzoyl moiety at C1, have been prepared in three steps, utilizing MAOS, in overall yields ranging from 6% to 25%.     

Total synthesis of (+)-piericidin A1 and (−)-piericidin B1

The convergent syntheses of (+)-piericidin A₁ 1 and (?)-piericidin B₁ 2 have been achieved based on classical Julia-Lythgoe olefination between 4-hydroxy-5,6-dimethoxy-3-methyl-2-[5-oxo-3-methyl-pent-(2E)-enyl]-pyridine 3 corresponding to the left half of the final molecule, and chiral phenyl sulfones, (4R,5R)-2,4,6-trimethyl-5-methoxy-1-phenylsulfonyl-octa-(2E,6E)-diene 20 and (4R,5R)-5-tert-butyldimethylsiloxy-2,4,6-trimethyl-1-phenylsulfonyl-octa-(2E,6E)-diene 33, corresponding to the right halves. The construction of the two stereogenic centers in the right half of piericidins was achieved based on lipase-catalyzed hydrolysis of methyl (2,3)-anti-3-acetoxy-2,4-dimethyl-hex-(4E)-enoate (±)-22.     

Total synthesis of resolvin E1

Resolvin E1 (RvE1), which is an endogenous mediator to resolve inflammation, was synthesized by Wittig reaction between the C15-C20 aldehyde and the C10-C14 phosphonium salt possessing the vinyl iodo moiety followed by Suzuki-Miyaura coupling of the resulting vinyl iodide with the vinyl borane of the C1-C9 part, which was derived from the corresponding acetylene by hydroboration. The C5 and C18 chiral centers in these parts were created by the kinetic resolution of the racemic γ-TMS allylic alcohols using the asymmetric epoxidation, while that of the C10-C14 part was constructed by the asymmetric hydrogen transfer reaction of the corresponding γ-TMS acetylene ketone.