Stereochemical Assignment of the 36-Membered Macrolide Ring Portion of Poecillastrin C.

Absolute configuration at 12 stereocenters in the 36-membered macrocyclic ring portion of poecillastrin C (1) was disclosed by chemical degradation and NMR analyses of 1, chemical synthesis, and molecular modeling techniques.

First synthesis of (±)-halichonadins A-D.

Described herein is the first total synthesis of a marine isocyanide terpene, (±)-halichonadin C. Our synthetic strategy features nitrile-to-isocyanide interconversion utilizing hypervalent iodine-promoted Hofmann rearrangement. This approach led to successful construction of an isocyanide group at the stereochemically encumbered C-6 position in (±)-halichonadin C. Furthermore, in accord with a scenario we propose for the biosynthesis of halichonadins A-D, (±)-halichonadin C was transformed to halichonadins A and B via the missing link intermediate, halichonadin isocyanate.

Total Syntheses of Borolithochromes A, D and G.

Total syntheses of borolithochromes A, D and G, red pigments isolated from fossils of Jurassic putative red alga Solenopora jurassica, have been achieved. The benzo[gh]tetraphene skeletons of the borate ligands in these substances were constructed using Diels-Alder reactions of aryl dienes with naphthoquinone, followed by intramolecular Corey-Chaykovsky reactions. Complexation of these ligands with trimethyl borate generated homocomplexes, which upon sequential O-demethylation produced borolithochromes A and G. In the route to borolithochrome D, a heterocomplex was prepared by stepwise complexation of the ligands with 2-(dimethylamino)ethyl dimethyl borate. The strategy devised to accomplish the first total synthesis of borolithochromes A, D and G should be applicable to the preparation of other borolithochromes as well as spiroborates possessing two fused polycyclic aromatic ligands.

Total Synthesis of Alcyonolide.

The total synthesis of alcyonolide, an antitumor xenicn diterpenoid, has been achieved. The inverse electron demand hetero-Diels-Alder reaction using a dienophile possessing an electron-withdrawing group provided the endo adduct which included a condensed lactone and dihydropyran rings with the desired three stereogenic centers. After introduction of the side chain by the Negishi coupling, the lactone ring was opened to form a Weinreb amide. The sequential transformation including conversion of Weinreb amide to aldehyde, PMB to acetate, and allylation of the aldehyde gave a mixture of separable four diastereomers. The desired stereoisomer was submitted to the 2,2,6,6-tetramethylpiperidine 1-oxyl oxidation, which afforded the δ-lactone and the methyl ketone side chain. Finally, the olefin metathesis of the desired isomer gave racemic alcyonolide.

Bioinspired total synthesis of boneratamides A-C.

We disclose the first synthesis of the marine natural product, (+)-boneratamide A, whose structure is composed of a terpene unit linked via an amide bond to a pyroglutamic acid moiety. The key step in this route is a bioinspired Ugi reaction of (+)-axisonitrile-3 with acetone as the carbonyl component and L-glutamic acid. This reaction brings about a remarkably efficient, one-pot assembly of reaction components concomitant with γ-lactam ring formation to produce (+)-boneratamide A in 70% yield. (+)-Boneratamide B and (-)-boneratamide C methyl esters were also synthesized using a similar bioinspired strategy, and the relative stereochemistries at the stereogenic centers in these substances were elucidated using X-ray analysis.

Iodide-Mediated [3 + 2]-Cycloaddition Reaction with N-Tosylaziridines and α,ß-Unsaturated Ketones.

The [3 + 2]-cycloaddition reaction between N-tosylaziridines and α,ß-unsaturated ketones was promoted with lithium iodide. The reaction proceeded under mild conditions to provide N-tosylpyrrolidines. Quaternary carbon-possessing 3,3-disubstituted pyrrolidines including spiro compounds were afforded in high yields. A simple procedure with easy to handle reagents makes this reaction concise. The intramolecular version of this reaction was applied to synthesize tropane skeletons.

Synthesis of Karrikinolide Using the Aldol-Type Acetal Addition Reaction.

A short step total synthesis of karrikinolide has been achieved. Both α and α' positions of O-acylated acetol were alkylated by the boron-mediated aldol-type acetal addition reaction. The one-pot sequence including the Arbuzov reaction, intramolecular Horner-Wadsworth-Emmons reaction, acidic hydrolysis of acetals, and pyran formation provided karrikinolide. This procedure was applicable to the gram-scale synthesis of karrikinolide.

Total synthesis of exigurin: the Ugi reaction in a hypothetical biosynthesis of natural products.

The first total synthesis of a marine natural product, exigurin, has been accomplished in 13 steps starting from (+)-menthone. The key intermediate (-)-10-epi-axisonitrile-3 was prepared by stereoselective intramolecular cyclopropanation followed by a cyclopropane ring opening reaction by the azide anion. The bioinspired Ugi reaction of (-)-10-epi-axisonitrile-3, formaldehyde, sarcosine and methanol successfully constructed the target exigurin in which its terpene and amino acid units were linked through an amide bond.

Synthesis of C3-C21 Segment of Aflastatin A Using Remote Asymmetric Induction Reactions.

The C3-C21 segment of aflastatin A has been synthesized by converging three segments including the C3-C8 segment, the C9-C15 segment, and the C16-C21 segment. Each segment has been synthesized from a vinylketene silyl N,O-acetal possessing a chiral auxiliary by a wide-range stereocontrol strategy. The C3-C8 segment was constructed in seven steps including the stereoselective vinylogous Mukaiyama alkylation, while the C9-C15 segment and the C16-C21 segment were synthesized using the vinylogous Mukaiyama aldol reaction in seven and eight steps, respectively.

Remote Asymmetric Induction Reactions using a E, E-Vinylketene Silyl N, O-Acetal and the Wide Range Stereocontrol Strategy for the Synthesis of Polypropionates.

The construction of libraries of acyclic polyketides remains a challenging topic, mostly due to the difficulties associated with finding the right balance between diversity and brevity for the synthetic routes leading to polyketides. Recently, relatively short methods have been developed and applied to the synthesis of natural products. However, these short routes often suffer from limited diversity with respect to the arrangement of functional groups and stereochemistry, as these usually require reactions that direct multiple functional groups simultaneously in one step. Therefore, methods that combine a small number of reaction steps with structural diversity remain an attractive research target for the construction of acyclic polyketide libraries. In 2004, we reported a remote asymmetric induction reaction using chiral vinylketene silyl N, O-acetal 1, which is commensurate to an anti-selective vinylogous Mukaiyama aldol reaction. Ever since, this reaction has been applied to the synthesis of numerous natural products, as this synthetic route is short and efficient on account of the simultaneous introduction of both asymmetric centers and the multiply functionalized carbon chain. Recently, we have developed a variety of this remote asymmetric induction reaction based on the E, E-vinylketene N, O-acetal 1, which includes syn-selective vinylogous Mukaiyama aldol reactions, as well as alkylation, acylation, and bromination reaction. These reactions provide polypropionates in a highly stereoselective manner. The proposed transition states of these reactions are discussed in this Account. Additionally, we have developed a new short synthesis of polypropionates by combining reactions for the remote asymmetric induction and the functionalization of double bonds (wide-range stereocontrol, WRS). The remote asymmetric induction reaction simultaneously constructs the stereogenic centers at the central part of the products and introduces the α,ß-unsaturated imide, while the new strategy is based on the initial construction of the central part of the molecule and a subsequent functionalization of the surroundings (WRS). This strategy successfully furnished stereoisomers in a few steps, and the stereodivergent synthesis of 2,4,6-trimethyloctanoic acid derivatives was accomplished. This strategy should also be feasible to construct an acyclic polyketide library. Moreover, we applied this method to the concise synthesis of natural products. In this Account, the development of remote asymmetric induction reactions and the new WRS strategy are described. Applications of the WRS strategy as well as reactions for the stereodivergent synthesis of polypropionates and natural products are also described. The aforementioned acyclic polyketide library should be constructed in the future with the help of the WRS strategy and become a powerful tool in drug discovery.

Total Syntheses of Stoloniferol B and Penicitol A, and Structural Revision of Fusaraisochromanone.

The first total synthesis of stoloniferol B and penicitol A has been achieved. Stoloniferol B, which is the common structure of citrinin derivatives, has been constructed by a sequential elaboration that includes a stereoselective vinylogous Mukaiyama aldol reaction, a thermal esterification with methyl acetoacetate, an intramolecular Michael reaction, and a vinylogous Dieckmann cyclization. The enantiomer of the proposed structure of fusaraisochromanone and ( S)-7-hydroxy-3-(( R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3 H)-one (the enantiomer of a natural stoloniferol derivative) also have been synthesized. The synthesis revised the structure of fusaraisochromanone to ( S)-7-hydroxy-3-(( R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3 H)-one.

Total Synthesis and Structural Determination of XR774, a Tyrosine Kinase Inhibitor.

Total synthesis and structural determination of XR774 has been accomplished. The benzo[ j]fluoranthene skeleton has been constructed by regioselective coupling between tetraline 3 and tetralone 4 successively followed by the sequential transformation including the Birch reduction to prepare allylic alcohol, simultaneous bromination of vinylic and aromatic moieties, and the nickel-mediated intramolecular coupling reaction. The optical resolution of racemic 17 led to the first total synthesis of (-)-XR774.

Stereoselective Synthesis of Tabtoxinine-ß-lactam by Using the Vinylogous Mukaiyama Aldol Reaction with Acetate-Type Vinylketene Silyl N,O-Acetal and α-Keto-ß-lactam.

Stereoselective total synthesis of tabtoxinine-ß-lactam has been achieved. The vinylogous Mukaiyama aldol reaction with vinylketene silyl N,O-acetal and α-keto-ß-lactam proceeded to afford the adduct possessing a TßL-skeleton with a tert-alcohol in high yield and stereoselectivity. Stereoselective introduction of the amino group has been accomplished by azidation at the α position of the imide followed by hydrogenolysis. A straightforward method to achieve the potent inhibitor of glutamine synthetase, possessing both α-hydroxy-ß-lactam and α-amino acid moieties, has been established.

Remote Asymmetric Bromination Reaction with Vinylketene Silyl N,O-Acetal and Its Application to Total Synthesis of Pellasoren A.

Stereoselective bromination of the E,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved and applied to introduction of heteroatom at γ-position of α,ß-unsaturated imide. The reactions proceeded in high stereoselectivity. Total synthesis of pellasoren A, an antitumor propionate from the myxobacteriun Sorangium cellulosum, has been accomplished in short steps by this methodology and our method of reduced polypropionate synthesis.

Syn Selective Vinylogous Mukaiyama Aldol Reaction Using Z,E-Vinylketene N,O-Acetal with Acetals.

Stereoselective vinylogous Mukaiyama aldol reactions using the Z,E-vinylketene silyl N,O-acetal possessing a chiral auxiliary, derived from (E)-3-pentenoic acid and l-valine, have been achieved. The reaction proceeded smoothly to give a syn adduct in high stereoselectivity. Since the products possess structures including δ-alkoxy-γ-methyl-α,ß-unsaturated imide, this reaction would be applicable to synthesize polyketides in a short procedure.

Remote Asymmetric Induction Using Acetate-Type Vinylketene Silyl N,O-Acetals.

Remote asymmetric induction by the vinylogous Mukaiyama aldol reaction using the acetate-type vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved. The silyl N,O-acetal derived from crotonate and l-valine afforded the O-silylated 5R- and 5S-adducts selectively by treatment with SnCl4 and BF3·OEt2, respectively. The SnCl4-mediated isomerization of silyl dienol ether was found, and the resulting major isomer showed high reactivity to give γ-adduct in high stereoselectivity.

Synthesis of Diastereomers of 1,3-cis-25-Dihydroxy-19-norvitamin D3.

1ß,3ß,25-Dihydroxy-19-norvitamin D3 (4a) and 1α,3α,25-dihydroxy-19-norvitamin D3 (4b) were synthesized by employing a new A-ring synthon, (1R,3S)-3-((tert-butyldimethylsilyl)oxy)-5-oxocyclohexyl benzoate (19), which was derived from D-(-)-quinic acid in 12 steps. The A-ring was coupled with the circular dichroism (CD) ring by means of Julia-Kocienski olefination to construct the diene unit. The structures of the products were confirmed by (1)H-NMR and nuclear Overhauser effect (NOE) experiments.

Synthesis and antileishmanial activity of the core structure of cristaxenicin A.

The core structure of cristaxenicin A having trans-fused dihydropyran and nine membered ring has been synthesized and evaluated the antileishmanial activity. The dihydropyran ring was synthesized by [4+2] cycloaddition reaction between an unsaturated aldehyde and a ß-alkoxy-α,ß-unsaturated ketone. The nine membered ring possessing α,ß-unsaturated aldehyde was constructed by the intramolecular NHK reaction followed by the Mitsunobu rearrangement. The racemic core structure of cristaxenicin A was evaluated the anti-leishmanial activity with an IC50 value of 2.4µM.

Synthesis of 24,24-Difluoro-1,3-cis-25-dihydroxy-19-norvitamin D3 Derivatives and Evaluation of Their Vitamin D Receptor-Binding Affinity.

Two vitamin D3 derivatives, namely 24,24-difluoro-1ß,3ß,25-dihydroxy-19-norvitamin D3 (6a) and 24,24-difluoro-1α,3α,25-dihydroxy-19-norvitamin D3 (6b), were synthesized via a convergent route employing Julia-Kocienski olefination as a key step. Compounds 6a and b bound to vitamin D receptor (VDR) with IC50 values of 64.8 and 57.6 nM, respectively, exhibiting about 400- and 30-fold greater binding affinity than the corresponding non-fluorinated derivatives 5a and b.

Stereoselective Alkylation of the Vinylketene Silyl N,O-Acetal and Its Application to the Synthesis of Mycocerosic Acid.

Stereoselective alkylation of the vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved by using activated alkyl halides including allyl iodides, benzyl iodides, and propargyl iodide with Ag(I) ion in the presence of BF3·OEt2. The reaction proceeded to give reduced polyketides in high stereoselectivity. The synthesis of mycocerosic acid, a component of the cell envelope of Mycobacterium tuberculosis, has been accomplished by this methodology. During the synthetic studies, 2-methylbenzimidazole was found to be a bulky proton source which worked in the presence of liquid ammonia.