Total synthesis of makaluvamine A/D, damirone B, batzelline C, makaluvone, and isobatzelline C featuring one-pot benzyne-mediated cyclization-functionalization

Total synthesis of pyrroloquinoline alkaloids, such as makaluvamine A/D, damirone B, batzelline C, makaluvone, and isobatzelline C, was achieved featuring a one-pot benzyne-mediated cyclization-functionalization reaction. The synthetic utility was demonstrated by the construction of the common pyrrolo[4,3,2-de]quinoline skeleton.     

Total synthesis of ovalifoliolatin B, acerogenins A and C

A short and concise route for the synthesis of ovalifoliolatin B, a highly strained macrocyclic diaryl ether heptanoid natural product that also provides quick access to acerogenins A and C natural products has been reported.     

Total synthesis and stereochemical confirmation of manassantin A, B, and B1

Stereocontrolled total syntheses of manassantins A, B, and B1 and saucerneol are described for the first time based on a novel cycloetherification of end-differentiated benzylic alcohols as a common intermediate. [structure: see text].     

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 dl-asparenomycins A,B and C,novel carbapenem antibiotics

Total synthesis of dl-asparenomycins was accomplished with direct conversion of carbonates 13a, 13b and 14a, 14b to asparenomycin esters 15 and 16 and carboxy deprotection by the AlCl₃-anisole method.     

Total synthesis of topopyrones B and D

[reaction: see text] We describe a straightforward synthesis of topopyrones B and D, which are potent and selective inhibitors of topoisomerase I. The chemistry should be suitable for additional structure-activity relationship (SAR) work.     

Total synthesis of polemannones B and C

The first total synthesis of polemannones B and C, higly oxygenated benzoxanthenones derivatives from Polemannia montana, is reported employing our new catalytic Cu(II)/sparteine system for β,β-phenolic couplings and tandem inverse-electron demand Diels-Alder reaction cascade in 75-90% yield.     

Total synthesis of the didemnins - 2. Synthesis of didemnin A,B, C and prolyldidemnin A

Didemnin A, C, prolyldidemnin A and the highly cancerostatic, antiviral and immunosuppressive didemnin B have been prepared by deprotecting the benzyloxycarbonyl compound 5 and constructing the side chain that determines the biological properties.     

Total synthesis of norcembrenolide B and scabrolide D

An efficient stereoselective synthesis of norcembrenolide B (8) and scabrolide D (9) is reported. The strategy is inspired by biogenetic relationships of related cembrenoids. Central to this approach is the construction of norbipinnatin J which upon selective C2 deoxygenation and C8 oxygenation produces norrubifolide and norcoralloidolide A. A sequence of site-selective oxidations and skeletal reorganizations then yields, in a divergent manner, compounds 8 and 9. The studies allow revision of the proposed structure of scabrolide D (9), which is identical to norcembrenolide C.     

Total asymmetric synthesis of sperabillins B and D

A concise route to the core fragment of sperabillins B and D, methyl (3R,5R,6R)-3,6-diamino-5-hydroxyheptanoate, has been developed with a subsequent novel protection strategy allowing the total asymmetric synthesis of sperabillins B and D.     

Total synthesis of cryptomoscatones D1 and D2: stereochemical assignment of cryptomoscatone D1

The first total synthesis and structural elucidation of cryptomoscatone D1, and a novel synthetic approach for cryptomoscatone D2 were achieved in 30% and 29% overall yield, respectively. The synthesis relied on the use of a key Mukaiyama aldol reaction followed by a diastereoselective carbonyl reduction that allowed the preparation of four cryptomoscatone isomers in a stereochemically divergent manner. Comparison of NMR data and CD curves of the synthetic stereoisomers and natural products confirmed the stereochemical nature of cryptomoscatone D2, and led to establishing the absolute configuration of cryptomoscatone D1.     

Total synthesis of rutamycin B and oligomycin C

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.     

One-pot multicomponent synthesis of diversely substituted 2-aminopyrroles. A short general synthesis of rigidins A, B, C, and D

Privileged medicinal scaffolds based on the structures of tetra- and pentasubstituted 2-aminopyrroles were prepared via one-pot multicomponent reactions of structurally diverse aldehydes and N-(aryl-, hetaryl-, alkylsulfonamido)acetophenones with activated methylene compounds. This methodology was used in a four-step synthesis of alkaloids rigidins A, B, C, and D in overall yields of 61%, 58%, 60%, and 53%, respectively. Of these, rigidins B, C, and D were synthesized for the first time.     

Total synthesis of lamellarins D, H, and R and ningalin B

A concise total synthesis of lamellarins D (7 steps), H (7 steps), and R (5 steps) and ningalin B (5 steps) is achieved starting from the corresponding aldehydes and amines. The synthesis features three oxidative reactions as key steps in a biomimetic manner, involving an AgOAc-mediated oxidative coupling reaction to construct the pyrrole core, a Pb(OAc)(4)-induced oxidative cyclization to form the lactone, and Kita's oxidation reaction to form the pyrrole-arene C-C bond.     

Total synthesis of piericidin A1 and B1 and key analogues

Full details of the total synthesis of piericidin A1 and B1 and its extension to the preparation of a series of key analogues are described including ent-piericidin A1 (ent-1), 4'-deshydroxypiericidin A1 (58), 5'-desmethylpiericidin A1 (73), 4'-deshydroxy-5'-desmethylpiericidin A1 (75), and the corresponding analogues 51, 59, 76, and 77 bearing a simplified farnesyl side chain. The evaluation of these key analogues, along with those derived from their further functionalizations, permitted a scan of the key structural features providing new insights into the role of the substituents found in both the pyridyl core as well as the side chain. A strategic late stage heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain permitted ready access to the analogues in which each half of the molecule could be systematically and divergently modified. The pyridyl cores were assembled enlisting inverse electron demand Diels-Alder reactions of N-sulfonyl-1-azabutadienes, while key elements of side chain syntheses include an anti selective asymmetric aldol to install the C9 and C10 relative and absolute stereochemistry (for natural and ent-1) and a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chains.     

Total synthesis of everninomicin 13,384-1--Part 1: retrosynthetic analysis and synthesis of the A1B(A)C fragment

In this first of a series of four articles we introduce everninomicin 13,384-1 (1), a powerful antibiotic effective against drug resistant bacteria, as a target for total synthesis and discuss its retrosynthetic analysis. From the three defined fragments required for the synthesis (2: A1B(A)C fragment; 4: DE fragment; 5: FGHA2 fragment), we describe herein two approaches to the A1B(A)C block. The first strategy relied on an olefin metathesis reaction to construct a common intermediate for rings B and C, but was faced with final protecting group problems. The second, and successful approach, involved a 1,2-phenylsulfeno migration and a sulfur directed glycosidation procedure to link rings B and C, as well as an acyl fluoride intermediate to install the sterically hindered aryl ester moiety (ring A1). The final stages of the synthesis of the required 2-phenylseleno glycosyl fluoride 2 required introduction of a phenylseleno group at C-1 of ring C followed by a novel, DAST-promoted 1,2-migration to produce the desired 2-beta-phenylseleno glycosyl fluoride moiety.     

Total synthesis and stereochemistry of pinnatoxins B and C

[Structure: see text] Pinnatoxins B and C were synthesized from diols (34R)-3b and (34S)-3a, respectively, in a stereochemically controlled manner. Through extensive analysis of the 1H NMR spectra of synthetic PnTXs B and C, the diagnostic NMR signals were first identified to differentiate (34S)- and (34R)-diastereomers and then used to establish the C34 configuration of natural PnTXs B and C as 34S and 34R, respectively.     

Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D

The phosphonium salt 35, representing one of the two principal subunits of the epothilones, was prepared from propargyl alcohol via heptenone 22. A Wittig reaction of the phosphorane from 35 with aldehyde 33, obtained from aldol condensation of ketone 27 with aldehyde 28, afforded 37. Seco acid 42 derived from 37 underwent lactonization to give cis-9,10-dehydroepothilone D (43) which was selectively reduced with diimide to yield epothilone D (4) and, after epoxidation, epothilone B (2). An alternative route to epothilone D employed alkyne 39, obtained from 33, in a Castro-Stephens reaction with allylic bromide 34 to furnish enyne 40. The latter was semi-hydrogenated to provide 37. Alkyne 46, prepared from alcohol 45, was converted to trans-vinylstannane 47 which, in a Stille coupling with allylic chloride 50, gave 51. Seco acid 52 derived from 51 underwent lactonization to give trans-9,10-dehydroepothilone D (54). Bioassay data comparing the antiproliferative activity and tubulin polymerization of 43 and 54 with epothilone B (2), epothilone D (4), and paclitaxel (7) showed that the synthetic analogues were less potent than their natural counterparts, although both retain full antiproliferative activity against a paclitaxel-resistant cell line. No significant difference in potency was noted between cis analogue 43 and its trans isomer 54.     

The total synthesis of coleophomones B, C, and D

Members of the coleophomone family of natural products all possess several intriguing and challenging architectural features, as well as exhibit unusual biological activity. They, therefore, constitute attractive targets for synthesis. In this Article, we describe the total synthesis of coleophomones B (2), C (3), and D (4). The highly strained and congested 11-membered macrocycle of coleophomones B (2) and C (3) was constructed using an impressive olefin metathesis reaction. Furthermore, both of the requisite geometric isomers of the Delta(16,17) within the macrocycle could be accessed from a common precursor, facilitating a divergence that lent the coleophomone B (2)/C (3) synthesis an unusually high degree of efficiency. The synthesis of coleophomone D (4) confirmed that it exists as a dynamic mixture of isomeric forms with a different aromatic substitution pattern from the other family members.