Total syntheses of (+)- and (-)-cacospongionolide B: new insight into structural requirements for phospholipase A(2) inhibition

The first total synthesis of the antiinflammatory marine sponge metabolite (+)-cacospongionolide B has been accomplished in 12 linear steps. The pivotal transformations include a three-step sequence coupling the two main regions of the natural product as well as generating the side chain dihydropyran ring. The activity of the synthetic analogues against bee venom phospholipase A(2) suggests that cacospongionolide B has an enantiospecific interaction with the enzyme that is independent of the gamma-hydroxybutenolide moiety.     

Conformationally restricted (+)-cacospongionolide B analogues. Influence on secretory phospholipase A2 inhibition

A new approach to (+)-cacospongionolide was developed to access conformationally restricted variants of the natural product. The flexible aliphatic region between the decalin and side chain portion of the natural product was replaced with alkenyl and alkynyl linkers to probe the influence of structural rigidity in the inhibition of secretary phospholipase A2 (sPLA2). It was found that when the aliphatic section is replaced with a Z-olefin or an alkyne, sPLA2 inhibitory activity suffered relative to the natural product; however, an E-olefin-containing analogue led to an enhanced activity. These results suggest that preferred sPLA2 binding conformation of the natural product is similar to the geometry of the E-olefin-containing analogue.     

Total syntheses of (+)-temisin, (+)-melitensin and related elemanolides from (-)-artemisin

(+)-Temisin, (+)-melitensin, and related sesquiterpene lactones have been synthesized from (-)-artemisin.     

Total syntheses of (-)- and (+)-goniomitine

The Stille coupling reaction of 3-(benzyloxymethyl)-1-(tert-butyldiphenylsiloxy)ethyl-1-(tributylstannyl)allene with N-(tert-butoxycarbonyl)-2-iodoaniline directly produced the corresponding 2-vinylindole derivative, which was independently transformed into natural (-)-goniomitine and unnatural (+)-goniomitine via the cross-metathesis with chiral oxazolopiperidone lactams. The antiproliferative activity of the synthesized natural (-)-goniomitine in Mock and MDCK/MDR1 cells showed them to be more potent to retard cell growth than unnatural (+)-goniomitine.     

Total syntheses of (-)-haemanthidine, (+)-pretazettine, and (+)-tazettine

[structures: see text] The total syntheses of the amaryllidaceae alkaloids haemanthidine, pretazettine, and tazettine as optically pure enantiomers are reported. Using D-mannose as the starting material, the critical relative stereochemical relationships are established with an intramolecular nitrone-alkene cycloaddition reaction. The synthetic route leads successively to (-)-haemanthidine and then to (+)-pretazettine and (+)-tazettine, taking advantage of the well-established complex relationships among these three alkaloids.     

Total syntheses of (+)- and (-)-peribysin E

A convergent, stereocontrolled route to either antipode of the cell adhesion inhibitor, peribysin E, has been achieved from carvone. Highlights of the synthesis include a Diels-Alder reaction to generate a cis-decalin framework, followed by semipinacol-type ring contraction to secure the stereochemistry of the C7 quaternary center. Potential mechanistic pathways for the critical ring contraction were studied through deuterium incorporation studies. In addition, an optimized olefin isomerization/Saegusa oxidation protocol is described for the conversion of [4+2] cycloadducts of 2-(trialkylsilyloxy)-1,3-dienes to 1,6(2H,7H)-naphthalenediones, having stereochemical arrangements not accessible via conventional Robinson annulation protocols. Finally, the ability to independently prepare either enantiomer of peribysin E from the corresponding antipode of carvone led to a reassignment of the absolute configuration of peribysin E.     

Total syntheses of (+)-australine and (-)-7-epialexine

Three approaches were examined for the synthesis of 3-(hydroxymethyl)pyrrolizidines, a class of compounds that includes the polyhydroxylated pyrrolizidine alkaloids alexine (1), australine (2), and various stereoisomers of thereof. In the first approach, the intramolecular cycloaddition of an azide onto an electron-rich 1, 3-diene bearing a terminal alkoxymethyl substituent (i.e., 21) afforded the dehydropyrrolizidines 22a and 22b, with 22a predominating. A rationale for this stereoselectivity was proposed. Transformation of the major diastereomer 22a into a natural 3-(hydroxymethyl)pyrrolizidine was not possible due to difficulties encountered in transforming the phenyl vinyl sulfide functionality into other useful functional groups. A second approach was examined, wherein the intramolecular cycloaddition of an azide with an optically pure S-t-Bu-substituted diene (i.e., 30) was found to produce the pyrrolizidine 31. In this case, the alkoxymethyl substituent was incorporated into the tether between the azide and the diene, rather than on the diene itself. A key transformation in the synthesis of the diene 30 was the use of the allylic borane R(2)BCH(2)CH=C(TMS)(StBu) for the stereoselective conversion of the D-arabinose-derived azido aldehyde 28 to the E-isomer of 30. The cyclization of 30 to 31 also produced the bicyclic triazene 32, the result of 1,3-dipolar cycloaddition of the azide onto the distal double bond of the diene. Again, difficulties in transformation of the vinyl sulfide functionality of 31 into useful oxygen functionality limited this approach to naturally occurring 3-(hydroxymethyl)pyrrolizidines. A third approach to these compounds was successful. The transformation of L-xylose into the azido epoxy tosylate 46 was accomplished using two Wittig reactions and an epoxidation, in addition to other standard functional group manipulations. Reductive double-cyclization of 46 afforded the pyrrolizidines 47a and 47b, which were debenzylated to afford (+)-australine 2 and (-)-7-epialexine 4, respectively. In the preliminary report of this work, erroneous spectroscopic data in the original literature on the structural assignment of australine led to the conclusion that the synthetic material obtained herein was actually (+)-7-epiaustraline. Recently corrected spectroscopic data have appeared which verify that (+)-australine 2 was indeed synthesized for the first time.     

Total syntheses of Lycopodium alkaloids (+)-fawcettimine, (+)-fawcettidine, and (-)-8-deoxyserratinine

A shared story: Three fawcettimine- and serratinine-type Lycopodium alkaloids are prepared from a common tetracyclic spirodiketone intermediate in concise total syntheses. The intermediate was constructed by a remarkable biosynthesis-inspired transannular N-C bond formation to the spiro-configured carbon center and a hydroxy-directed pinacol coupling promoted by SmI(2).     

Total syntheses of (+)-vigulariol and (-)-sclerophytin A

The total syntheses of (+)-vigulariol and (-)-sclerophytin A are reported in 15 steps and 16 steps, respectively, from a known compound. The flexible, readily scalable synthetic strategy allows for rapid construction of a critical tricyclic intermediate and is demonstrated via the synthesis of these two marine natural products. A key reaction in this synthetic protocol is a combination Wittig/intramolecular Diels-Alder cycloaddition.     

Total synthesis and stereochemistry of (-)-cacospongionolide F

[reaction: see text] The most recently described member of the cacospongionolide class of marine natural products has been assembled using a diastereochemically divergent total synthesis strategy that independently establishes the complete stereochemistry of cacospongionolide F and provides a new entry toward expansion of this phospholipase A(2) inhibitor chemotype.     

Total syntheses of racemic, natural (-) and unnatural (+) glyceollin I

The first total syntheses of racemic glyceollin I and its enantiomers are described. A Wittig approach was utilized as an entry to the appropriately substituted isoflav-3-ene so that an osmium tetroxide mediated asymmetric dihydroxylation could be deployed for stereospecific introduction of the 6a-hydroxy group. While using triphenylphosphine hydrobromide, a novel method was found for gently removing MOM from protected phenolic hydroxyl groups present within sensitive systems.     

Total syntheses of enantiomerically enriched R-(+)- and S-(-)-deplancheine

Total syntheses of indoloquinolizidine alkaloid (+/-)-, R-(+)-, and S-(-)-deplancheine are described here. The synthesis features an enantioselective intramolecular formal aza-[3 + 3] cycloaddition for the construction of the quinolizidine CD-ring. This application serves to introduce a new synthetic strategy for the synthesis of indoloquinolizidine alkaloids.     

Total syntheses of (-)-fumiquinazolines A, B, and I

[structure] The first total syntheses of (-)-fumiquinazolines A, B, and I have been accomplished efficiently using the Pd-catalyzed cyclization of an iodoindole carbamate to construct the imidazoindolone moiety and the dehydrative cyclization of a diamide followed by rearrangement through an amidine to construct the quinazolone moiety.     

Total syntheses of (+)- and (−)-syringolides 3 and of (+)- and (−)-syributins 1, 2 and 3

The first total syntheses of (−)-syringolide 3, (+)-syributin 3 and their unnatural enantiomers (+)-syringolide 3 and (−)-syributin 3 using a common intermediate as starting material are described. In addition, total syntheses of (−)- and (+)-syributins 1 and 2 were accomplished by means of the same methodology.     

Total syntheses of (+)-7-epi-goniofufurone, (+)-goniopypyrone and (+)-goniofufurone from a common precursor

Total syntheses of (+)-7-epi-goniofufurone, (+)-goniopypyrone and (+)-goniofufurone have been achieved from an advanced common precursor formed from D-(+)-mannitol by changing the carbinol protection profile.     

Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (-)-norsecurinine, and phyllanthine

A new strategy for enantiospecific construction of the Securinega alkaloids has been developed and applied in total syntheses of (+)-14,15-dihydronorsecurinine (8), (-)-norsecurinine (6), and phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids originated from trans-4-hydroxy-L-proline (10), which was converted to ketonitrile 13 via a high-yielding eight-step sequence. Treatment of this ketonitrile with SmI2 afforded the 6-azabicyclo[3.2.1]octane B/C-ring system 14, which is a key advanced intermediate for all three synthetic targets. Annulation of the A-ring of (-)-norsecurinine (6) with the required C2 configuration via an N-acyliminium ion alkylation was accomplished using radical-based amide oxidation methodology developed in these laboratories as a key step, providing tricycle 33. Annulation of the D-ring onto alpha-hydroxyketone 33 with the Bestmann ylide 45 at 12 kbar gave (+)-14,15-dihydronorsecurinine (8). In the securinine series, the D-ring was incorporated using an intramolecular Wadsworth-Horner-Emmons olefination of phenylselenylated alpha-hydroxyketone 47. The C14,15 unsaturation was installed late in the synthesis by an oxidative elimination of the selenoxide derived from tetracyclic butenolide 50 to give (-)-norsecurinine (6). The A-ring of phyllanthine (2) was formed from hydroxyketone 14 using a stereoselective Yb(OTf)3-promoted hetero Diels-Alder reaction of the derived imine 34 with Danishefsky's diene, affording adduct 35. Conjugate reduction and stereoselective equatorial ketone reduction of vinylogous amide 35 provided tricyclic intermediate 36, which could then be elaborated in a few steps to stable hydroxyenone 53 via alpha-selenophenylenone intermediate 52. The D-ring was then constructed, again using an intramolecular Wadsworth-Horner-Emmons olefination reaction to give phyllanthine (2).     

Efficient syntheses of pterulone, pterulone B and related analogues

An efficient synthesis of the three halogenated naturally occurring products, pterulone (2), pterulone B (3) and alcohol 5, and of a wide range of related unnatural analogues has been achieved starting from the two readily available 1-benzoxepine sulfonyl-containing intermediates 6a and 6b. The biological activities of pterulone and some of the synthesized analogues were tested against a wide spectrum of phytopathogenic fungi.     

Enantioselective total syntheses of (+)-arborescidine A, (-)-arborescidine B, and (-)-arborescidine C

Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)-arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and 50% overall yield, eight steps and 61% overall yield, and nine steps and 51% overall yield, respectively, from 6-bromotryptamine (7). The syntheses feature the use of the Noyori catalytic asymmetric hydrogen-transfer reaction to introduce chirality in dihydro-beta-carbolines 6 and 8. On the basis of an ample precedent from Noyori's work, the reduction produces dihydro-beta-carbolines, and ultimately the natural products, possessing the R absolute configuration. The synthetic arborescidines displayed optical rotations that were opposite in sign those of the natural products, thereby supporting the S configuration for natural arborescidines A (1) and B (2) and the (3S,17S) configuration for natural arborescidine C (3). Our results are in agreement with the initial stereochemical assignment by Pa?s and co-workers, and are counter to their recently revised assignment.     

Synthesis of Aristotelia-Type Alkaloids. Part XIII. Total syntheses of (+)-makonine, (+)-aristotelinone,and (+)-11,12-didehydroaristoteline

The oxidative transformation of synthetic (+)-aristoteline ((+)- 6 ) into other metabolites which had been isolated from Aristotelia species was investigated. Thus, treatment of (+)- 6 with I₂ as the single oxidant furnished the naturally occurring indole alkaloids (+)-makonine ((+)- 9 ),(+)-aristotelinone ((+)- 11 ), or (+)-11, 12-didehydroaristoteline ((+)- 7 ) in good yields, the selectivity of the oxidation process depending on the chosen reaction conditions.