Total synthesis of FR901483

[structure: see text]. The total synthesis of FR901483, a structurally novel immunosuppressant, has been accomplished by the use of technology recently developed in this laboratory for the oxidative cyclization of phenolic oxazolines to spirolactams. Our approach may reflect the biosynthetic pathway leading to the natural product.     

Stereocontrolled total synthesis of potent immunosuppressant FR901483

A total synthesis of the potent immunosuppressant FR901483 (1) has been accomplished. The key feature of our convergent synthesis is the stereoselective incorporation of the p-methoxybenzyl and methylamino groups within the core moiety 10. Tricycle 10 was itself constructed by an intramolecular aldol reaction of the symmetrical keto-aldehyde 7. [Structure: see text]     

Synthetic studies toward the immunosuppressant FR901483. Facile construction of the azatricyclic skeleton

A concise synthesis of the azatricyclic core structure of FR901483, a potent immunosuppressant, has been accomplished. The key elements of the approach involve a nucleophilic addition to an acyl iminium ion, a ring closing metathesis and a lactone-lactam rearrangement to provide the tricyclic structure.     

Total synthesis of tricyclic azaspirane derivatives of tyrosine: FR901483 and TAN1251C

A solution to the long-standing problem presented by the oxidative cyclization of a phenolic 3-arylpropionamide to a spirolactam has been developed in this laboratory via oxazoline chemistry. This research was motivated by our interest in some novel tricyclic azaspirane natural products formally derived from tyrosine, such as FR901483 and TAN1251C. In this paper, we disclose full details of the total synthesis of these substances.     

Total synthesis of (+)-epilupinine via an intramolecular nitrile oxide-alkene cycloaddition

Total synthesis of (+)-epilupinine was accomplished in nine steps and in 48% overall yield, in which INOC was used as the key step for the construction of the quinolizidine skeleton. We found that it was an extremely difficult task to prepare the key intermediates (R)-N-(3-nitropropyl)-2-vinylpiperidine or (R)-(2-vinylpiperid-1-yl)propanal by routine methods. Thus, by using Fukuyama's oxime synthesis, a general method was developed for highly efficient conversion of 3-(N,N-dialkylamino)propanols into 3-(N,N-dialkylamino)propanal oximes without using the corresponding aldehydes.     

Toward the total synthesis of FR901483: concise synthesis of the azatricyclic skeleton

A concise synthesis of the azatricyclic core of FR901483 has been accomplished using a novel strategy that involves a nucleophilic addition to an N-acyl iminium ion, a ring-closing metathesis, a diastereoselective hydroboration, and a lactone-lactam rearrangement that worked well in a preliminary model study. Extension of this approach to the synthesis of a more highly functionalized intermediate that could be transformed into (-)-FR901483 first required the development of a new protecting group, the 1-ethylallyloxycarbamate group, for amines that may be removed under mild conditions. However, because the stereoselectivity in a key step in which a functionalized allyl zinc reagent was added to an intermediate hydroxy-substituted imine was low, this route to (-)-FR901483 is no longer being pursued.     

Studies on a total synthesis of the microbial immunosuppresive agent FR901483

A strategy is outlined for construction of the fungal immunosuppressant FR901483 (1). It was possible to convert 1,4-cyclohexanedione monoethylene ketal in five simple steps to iodoacetamide ketone 10, which was cyclized in good yield to the key bridged keto lactam 11 containing the A/B 2-azabicyclo[3.3.1]nonane ring system of the natural product. This intermediate could be transformed to N-Boc lactam 16, whose derived enolate underwent stereoselective hydroxylation with the Davis oxaziridine to produce alcohol 17 having the desired C-2 configuration. Compound 17 was then converted in three steps to alkoxy carbamate 20. The N-acyliminium ion derived from intermediate 20 could be alkylated in good overall yield with p-methoxybenzylmagnesium chloride to afford a 5:4 mixture of the desired PMB product 21 and the epimer 23. In an attempt to improve the stereoselectivity in this alkylation, the inverted C-4 protected alcohol N-Boc lactam 33 was prepared and its enolate was hydroxylated. Inexplicably, the product of this reaction was the undesired equatorial alcohol 34. Some model systems were investigated toward annulation of the C-ring of the natural product. It was found that homoallylic amine 40 could be cyclized with PhSCl in the presence of silica gel to generate the desired 5-endo tetracyclic product 42 in moderate yield. This cyclization protocol was also successfully applied to the actual FR901483 system 22, leading to the requisite tricycle 43.     

Total synthesis of cyclic tetrapeptide FR235222, a potent immunosuppressant that inhibits mammalian histone deacetylases

[structure: see text] The total synthesis of FR235222, a potent immunosuppressant with in vivo activities, has been achieved. The key steps include assembling its (2S,9R)-2-amino-9-hydroxy-8-oxodecanoic acid residue via an olefin cross-metathesis of a methyl (R)-lactate-derived homoallyl ketone with protected allyl amino acid and constructing its trans-(2R,4S)-4-methylproline unit from protected (R)-pyroglutamic acid in seven steps.     

Efficient approach to the Azaspirane core of FR 901483

[reaction: see text] An efficient approach to the azaspirane core of FR 901483 is described employing lithiated methoxyallene as a crucial C3 building block and a suitably protected enantiopure ketimine as the second component. The resulting dihydropyrrole derivative was smoothly converted into a spiro keto aldehyde which under acidic conditions provided a novel azanorbornane derivative 15. Under basic reaction conditions, the desired 5-azatricyclo[6.3.1.0(1,5)]dodecane skeleton 16 was generated. The ratio of diastereomers strongly depends on the reaction conditions employed with l-proline in DMSO providing the highest selectivity in favor of one azaspirane product.     

Total synthesis of the sesquiterpene (+/-)-illudin C via an intramolecular nitrile oxide cycloaddition

[reaction: see text] A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide-olefin cycloaddition.     

Synthesis of the optically active key intermediate of FR901483

Efficient synthesis of the tricyclic key intermediate 2 for (−)-FR901483 1 was accomplished. The precursor of the intramolecular aldol reaction 4b is constructed by the Ugi 4CC reaction and subsequent intramolecular Dieckmann condensation. This approach allows a fully stereocontrolled total synthesis of (−)-FR901483, which would provide various derivatives.     

Total synthesis of (+/-)fasicularin via a 2-amidoacrolein cycloaddition

The total synthesis of the cytotoxin fasicularin is described. The key steps include the following: (1) an intermolecular Diels-Alder cycloaddition of a 2-(triflamido)acrolein with the dioxolane ketal of trideca-1,3-dien-7-one to establish the trans-perhydroisoquinoline stereochemistry, (2) a stereoelectronically controlled hydride addition to a N(1)-C(2) iminium ion to introduce the equatorial hexyl substituent, and (3) elaboration of the pyrido ring by an internal aldol reaction.     

Total synthesis of (-)-colchicine via a Rh-triggered cycloaddition cascade

[reaction: see text] A synthesis of the antimitotic alkaloids (-)-colchicine and (-)-isocolchicine is reported. Important steps are (a) enantioselective transfer-hydrogenation of an alkynone, (b) iodine/magnesium exchange with subsequent aromatic acylation, (c) Rh-catalyzed transformation of an alpha-diazoketone into an oxatetracyclic key intermediate through intramolecular [3 + 2]-cycloaddition of an in situ generated carbonyl ylide, and (d) regioselective conversion of the cycloadduct into a tropolone derivative. The new synthetic strategy opens an efficient enantioselective access to colchicine and structural analogues.     

Tandem cationic aza-cope rearrangement-Mannich cyclization approach to the core structure of FR901483 via a Bridgehead iminium ion

[reaction in text] An approach to the potent immunosuppressant FR901483 is described. This route utilizes a tandem cationic aza-Cope rearrangement-Mannich cyclization to generate the core structure of this compound. In addition, this is the first demonstration of this tandem reaction passing through a bridgehead iminium ion.     

Total synthesis of FR901464: second generation

FR901464, a potent cell cycle inhibitor, was synthesized in a convergent manner using natural chiral pool, l-threonine, ethyl (S)-lactate and 2-deoxy-d-glucose as starting materials.     

Synthesis of a promising immunosuppressant: FR252921

A concise and highly convergent synthesis of the promising immunosuppressant FR252921 was achieved by using optically active titanium complexes to control the configuration of the three stereogenic centers.     

Total synthesis of jimenezin via an intramolecular allylboration

[structure: see text] An efficient total synthesis of the annonaceous acetogenin jimenezin was achieved. The key steps used were a highly stereoselective intramolecular allylboration to establish the tetrahydropyran ring and an intramolecular Williamson reaction to close the tetrahydrofuran ring.     

Enantiospecific synthesis of β-lactams via cycloaddition

Enantiospecific synthesis of variously substituted cis-β-lactams can be achieved by the annelation of Schiff bases from optically active ketal aldehydes derived from D-threonine. Similar annelation of Schiff bases from the triphenylsilyl ether of D-threonine ester and cinnamaldehyde leads to cis-β-lactams with high diastereofacial selectivity.