The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the CD-spiroacetal segment

Stereocontrolled syntheses of the C16-C28 CD-spiroacetal subunit of altohyrtin A/spongistatin 1 , relying on kinetic and thermodynamic control of the spiroacetal formation, are described. The kinetic control approach resulted in a slight preference (60 : 40) for the desired spiroacetal isomer. The thermodynamic approach allowed ready access to the desired spiroacetal by acid-promoted equilibration, chromatographic separation of the C23 epimers and resubjection of the undesired isomer to the equilibration conditions. This scalable synthetic sequence provided multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4 of this series.     

Synthesis of the ABC tricyclic fragment of the pectenotoxins via stereocontrolled cyclization of a gamma-hydroxyepoxide appended to the AB spiroacetal unit

The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9 with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36 followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the synthesis of the ABC spiroacetal ring fragment 6.     

The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: the AB-spiroacetal segment

The convergent synthesis of the C1-C15 AB-spiroacetal subunit of altohyrtin A/spongistatin 1 is described. This highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc(2)BCl mediation, to establish the C5, C9 and C11 stereocentres, and formation of the desired thermodynamic spiroacetal under acidic conditions. The scalable synthetic sequence developed provided access to multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4.     

Multigram synthesis of the C29-C51 subunit and completion of the total synthesis of altohyrtin C (spongistatin 2)

A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 aldehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-d-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-acetyl-d-glucal or (S)-malic acid.     

Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.     

Synthesis of the ABC fragment of the pectenotoxins

[reaction: see text] A highly stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing fragment 5 of PTX7 (4) has been achieved. Appendage of the C ring to the AB fragment involved Wittig reaction of spiroacetal aldehyde 8 with a stabilized ylide 9 followed by displacement of allylic iodide 27 with a lithium acetylide to afford enyne 7. Fructose-derived chiral dioxirane and dihydroxylation were then used to introduce the correct functionality in the tetrahydrofuran C ring.     

The stereocontrolled total synthesis of spirastrellolide A methyl ester. Fragment coupling studies and completion of the synthesis

The spirastrellolides are a novel family of structurally unprecedented marine macrolides which show promising anticancer properties due to their potent inhibition of protein phosphatase 2A. In the preceding paper, a modular strategy for the synthesis of spirastellolide A methyl ester which allowed for the initial stereochemical uncertainties was outlined, together with the synthesis of a series of suitably functionalised fragments. In this paper, the realisation of this synthesis is described. Two alternative coupling strategies were explored for elaborating the C26-C40 DEF bis-spiroacetal fragment: a modified Julia olefination of a C26 aldehyde with a C17-C25 sulfone, and a Suzuki coupling of a C25 trialkylborane with a C17-C24 vinyl iodide, which also required the development of a double hydroboration reaction to install the C23/C24 stereocentres. The latter proved a significantly superior strategy, and was fully optimised to provide a C17 aldehyde which was coupled with a C1-C16 alkyne fragment to afford the C1-C40 carbon framework. The BC spiroacetal was then installed within this advanced intermediate by oxidative cleavage of two PMB ethers with spontaneous spiroacetalisation, which also led to unanticipated deprotection of the C23 TES ether. The ensuing truncated seco-acid was cyclised in high yield to construct the 38-membered macrolactone under Yamaguchi macrolactonisation conditions, suggesting favourable conformational pre-organisation. Exhaustive desilylation provided a crystalline macrocyclic pentaol, revealing much about the likely conformation of the macrolactone in solution. Attachment of the remainder of the side chain proved challenging, potentially due to steric hindrance by this macrocycle; an olefin cross-metathesis to install an electrophilic allylic carbonate and subsequent π-allyl Stille coupling with a C43-C47 stannane achieved this goal. Global deprotection completed the first total synthesis of (+)-spirastrellolide A methyl ester which, following detailed NMR correlation with an authentic sample, validated the full configurational assignment. A series of simplified analogues of spirastrellolide incorporating the C26-C47 region were also prepared by π-allyl Stille coupling reactions.     

Synthetic study of azaspiracid-1: synthesis of the EFGHI-ring fragment

Here, we report a synthesis of the lower half C21-C40 fragment of the shellfish toxin, azaspiracid-1. The C28-C40 fragment was synthesized by a coupling between the C28-C35 epoxide and the C36-C40 dithioacetal anion, followed by the HI-ring spiroaminal formation. An aldehyde corresponding to the C28-C40 fragment was then coupled with the C21-C27 allylic stannane by using InCl3. Finally, the FG-ring was constructed by HF.pyridine to accomplish the synthesis of the suitably protected C21-C40 fragment.     

Asymmetric total synthesis of spongistatins 1 and 2

The total synthesis of spongistatin 1 (1) and spongistatin 2 (2) has been achieved through an advanced-stage intermediate. The synthesis is highlighted by a highly convergent assembly of the four key fragments (the C1-C15 AB fragment 2, the C16-C28 CD fragment 3, the C29-C43 EF fragment 4, and the C44-C51 side chain 5) at a very advanced stage of the synthesis with minimal functional group interconversion. The CD fragment 3 functions as the central building block to which the other fragments are attached. The synthesis of the AB and CD spiroketal fragments is accomplished through the addition of a metalated gamma-pyrone to a beta-alkoxy aldehyde followed by spiroketalization. The EF subunit was assembled with high diastereoselectivity relying on asymmetric aldol reactions of chlorotitanium enolates of N-propionyl oxazolidinethiones and a double diastereoselective boron aldol to join the E and F fragments. Wittig coupling of the CD and EF fragments followed by a diastereoselective aldol reaction between the CDEF ketone and an AB aldehyde set the stage for attachment of the C44-C51 side chains and final macrolactonization and deprotection.     

Total synthesis of siphonarin B and dihydrosiphonarin B

The spirocyclic core of the siphonarins was constructed by a directed cyclization of a linear triketone, prepared using a Sn(II)-mediated aldol coupling and Swern oxidation at C9 and C13. To circumvent a facile retro-Claisen pathway generating a baconipyrone-type ester, a Ni(II)/ Cr(II)-mediated coupling reaction with vinyl iodide was used to complete the first synthesis of siphonarin B and dihydrosiphonarin B. A stable isomeric spiroacetal was also prepared which could not be equilibrated to the siphonarin skeleton.     

Total synthesis of pteridic acids A and B

A convergent synthesis of pteridic acids A and B, epimeric spiroacetal polyketides with potent plant growth promoter properties, is described. The use of boron aldol methodology efficiently achieved the stereocontrolled construction of advanced C1-C11 and C12-C16 subunits, which were coupled to generate a linear (Z)-enone precursor that underwent spiroacetalization with HF·pyridine, providing pteridic acids A and B after saponification.     

Total synthesis of incednam, the aglycon of incednine

The first total synthesis of incednam (1), the aglycon of antibiotic incednine (2), is described. Incednine has been reported to exhibit significant inhibitory activity against the antiapoptotic oncoproteins Bcl-2 and Bcl-xL. The synthesis of 1 commenced with the preparation of the C1-C13 subunit 3 and the C14-C23 subunit 4. The construction of the novel 24-membered macrocycle was achieved by the application of a Stille coupling between 3 and 4, followed by macrolactamization.     

The first total synthesis of concanamycin f (concanolide a)

A highly stereoselective total synthesis of the macrolide antibiotic concanamycin F (1), a specific and potent inhibitor of vacuolar H(+)-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 18-membered tetraenic lactone and beta-hydroxyl hemiacetal side chain subunits. The C1-C19 18-membered lactone aldehyde 4 was synthesized through the intermolecular Stille coupling of the C5-C13 vinyl iodide 24 and the C14-C19 vinyl stannane 25, followed by construction of the C1-C4 diene and macrolactonization. Synthesis of 4 via a second convergent route including the esterification of the C1-C13 vinyl iodide 45 and the C14-C19 vinyl stannane 47 followed by the intramolecular Stille coupling was also realized. The highly stereoselective aldol coupling of 4 and the C20-C28 ethyl ketone 5 followed by desilylation provided 1 which was identical with natural concanamycin F.     

Synthesis of the C15-C35 northern hemisphere subunit of the chivosazoles

An advanced C15-C35 subunit of the chivosazole polyene macrolides was prepared in a convergent manner, exploiting boron-mediated aldol reactions for the stereocontrolled construction of the C15-C26 and C27-C35 segments, followed by their Pd/Cu-promoted Stille coupling to configure the signature (23E,25E,27Z)-triene motif. Correlation with a known C28-C35 degradation fragment of chivosazole A was also achieved.     

Total syntheses of naturally occurring diacetylenic spiroacetal enol ethers

A highly stereoselective method for constructing a (2E)-methoxymethylidene-1,6-dioxaspiro[4.5]decane skeleton has been developed on the basis of the palladium(II)-catalyzed ring-closing reaction of the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one derivatives as a crucial step. The newly developed procedures could be successfully applied to the first total synthesis of five diacetylenic spiroacetal enol ether natural products starting from commercially available (R,R)- or (S,S)-diethyl tartrate.     

Access to isocarbacyclin derivatives via substrate-controlled enolate formation: total synthesis of 15-deoxy-16-(m-tolyl)- 17,18,19,20-tetranorisocarbacyclin

[reaction: see text] We describe a convergent and flexible synthesis of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC), a simple isocarbacyclin derivative. The synthesis takes advantage of two key step reactions: a regioselective deprotonation of the described ketone under substrate control which is then trapped, as the enol triflate, to generate the C6-C9alpha endocyclic double bond, followed by an sp2-sp3 Pd-catalyzed cross-coupling reaction (C5-C6) with a suitable primary alkyl Grignard reagent. Introduction of the C13-C14 (E)-double bond in the omega-side chain is performed by the Julia-Kocie?ski olefination.     

First total synthesis of (-)-AL-2

Treatment of the 3,4-dioxygenated-9-hydroxy-1-nonyn-5-one derivative, derived from diethyl l-tartrate, with a palladium catalyst in methanol under a CO atmosphere effected an intramolecular acetalization and a stereoselective construction of the (E)-methoxycarbonylmethylidene functionality resulting in formation of the core framework of the diacetylenic spiroacetal enol ether natural products. Chemical transformations of the 1,6-dioxaspiro[4.5]decane derivative thus formed led to the first total synthesis of (-)-AL-2. [reaction: see text]     

Studies on a urea-directed Stork-Crabtree hydrogenation. Synthesis of the C1-C9 subunit of (+)-zincophorin

A detailed account on the stereoselective synthesis of the C1-C9 subunit of (+)-zincophorin is described here. This approach features the first application of a stereoselective inverse electron demand hetero-[4 + 2] cycloaddition of chiral allenamides in natural product synthesis. The C1-C9 subunit matches Cossy's intermediate, thereby constituting a formal total synthesis. In addition, details of an unusual urea-directed Stork-Crabtree hydrogenation observed during these efforts are also disclosed here.     

Toward the synthesis of spirastrellolide B: a synthesis of the C1-C23 subunit

A synthesis of the C1-C23 subunit of spirastrellolide B is described. The synthesis features two applications of a Kulinkovich-cyclopropanol ring-opening strategy for the coupling of esters with olefins to produce ketones.     

Synthetic studies toward cytostatin, a natural product inhibitor of protein phosphatase 2A

Synthetic approaches toward the natural product cytostatin, an inhibitor of protein phosphatase 2A possessing cytotoxic and antimetastatic activities, have been investigated. A formal synthesis of cytostatin has been achieved according to a strategy relying on the formation of the C8-C9 bond by a nucleophilic addition of a functionalized organolithium (C1-C8 subunit) to an aldehyde (C9-C13 subunit).