Total synthesis of aeruginosin 298-A analogs containing ring oxygenated variants of 2-carboxy-6-hydroxyoctahydroindole

Aeruginosins are a family of naturally occurring oligopeptides sharing a common perhydroindole-2-carboxylic acid (l-Choi) core structure. Many aeruginosins exhibit inhibitory activity against serine proteases including thrombin. Aeruginosin 298-A is a tetrapeptide containing the l-Choi core structure and three other unusual amino acids or their derivatives; it is a thrombin and trypsin inhibitor. As part of our effort in finding effective thrombin inhibitors from natural product analogs and to understand the influence of the rigid bicyclic amino acid to the thrombin inhibition activities, we synthesized two aeruginosin 298-A analogs in which the l-Choi is replaced with ring oxygenated perhydroindole-2-carboxylic acids. The Choi variants are enantiomers synthesized from d- and l-glucose, respectively. The preparation of the aeruginosin 298-A analogs containing the ring oxygenated Choi variants and their inhibition activities toward thrombin and trypsin are reported.     

Enantioselective syntheses of aeruginosin 298-A and its analogues using a catalytic asymmetric phase-transfer reaction and epoxidation

We developed a versatile synthetic process for aeruginosin 298-A as well as several attractive analogues, in which all stereocenters were controlled by a catalytic asymmetric phase-transfer reaction and epoxidation. Furthermore, drastic counteranion effects in phase-transfer catalysis were observed for the first time, making it possible to three-dimensionally fine-tune the catalyst (ketal part, aromatic part, and counteranion).     

Solid-phase combinatorial synthesis of aeruginosin derivatives and their biological evaluation

A 24-member combinatorial library based on the structure of aeruginosin 298-A (1a) was synthesized utilizing solid-phase, and their inhibitory activity against trypsin was evaluated. Among the library, we found that D-Hpla-D-Leu-L-Choi-Agma (1h) is 300 times more potent than the parent natural product 1a.     

Enantioselective total syntheses of several bioactive natural products based on the development of practical asymmetric catalysis

I present herewith enantioselective total syntheses of several bioactive natural products, such as (-)-strychnine, (+)-decursin, (-)-cryptocaryolone diacetate, (-)-fluoxetine, and aeruginosin 298-A, based on practical asymmetric catalyses (Michael reaction, epoxidation, and phase-transfer reaction) that I developed with co-workers in Prof. Shibasaki's group over the past 5 years. In the first part of this review, I discuss the great improvement of catalyst efficiency in an ALB-catalyzed asymmetric Michael reaction of malonate and application to the pre-manufacturing scale (greater than kilogram scale) and enantioselective total synthesis of (-)-strychnine with the development of novel domino cyclization. To broaden the substrate generality of the Michael reaction, we developed a highly stable, storable, and reusable La-O-linked-BINOL complex. Further extension of the reaction using beta-keto ester as a Michael donor was achieved with the development of a La-NR-linked-BINOL complex, thereby improving indole alkaloid syntheses. In the second section, I discuss enantioselective total synthesis of (+)-decursin using catalytic asymmetric epoxidation. To achieve the synthesis, we developed a new La-BINOL-Ph(3)As = O (1:1:1) complex catalyst system, which has much higher reactivity and broader substrate generality than the previously developed catalyst systems. This allowed us to achieve catalytic asymmetric epoxidation of alpha,beta-unsaturated carboxylic acid derivatives with high enantioselectivity and broad substrate generality for the first time by changing the lanthanide metal and reaction conditions. Among them, catalytic asymmetric epoxidation of alpha,beta-unsaturated morpholinyl amides is quite useful in terms of synthetic utility of the corresponding alpha,beta-epoxy morpholinyl amides. Highly catalyst-controlled enantio- or diastereoselective epoxidation of the alpha,beta-unsaturated morpholinyl amides, coupled with diastereoselective reduction of beta-hydroxy ketones, enabled the synthesis of all possible stereoisomers of 1,3-polyol arrays with successful enantioselective total synthesis of several 1,3-polyol natural products, such as (-)-cryptocaryolone diacetate. In addition, the development of a new regioselective epoxide-opening reaction of alpha,beta-epoxy amides to the corresponding alpha- and beta-hydroxy amides enhanced the usefulness of the present epoxidation and was applied to the enantioselective total synthesis of (-)-fluoxetine. In the final section, I report the development of a new asymmetric two-center organocatalyst (TaDiAS) and its application to the enantioselective synthesis of aeruginosin 298-A and its analogues. Because of the remarkable structural diversity of TaDiAS, a practical asymmetric phase-transfer reaction with broad substrate generality was achieved. As a result, we succeeded in developing a highly versatile synthetic method for aeruginosin 298-A and its analogues. Inhibitory activity studies of the compounds against the serine protease trypsin provided preliminary information about their structure-activity relations.     

Syntheses of both the putative and revised structures of aeruginosin EI461 bearing a new bicyclic alpha-amino acid

[structure: see text] The putative structure of the naturally occurring aquatic peptide aeruginosin EI461 has been prepared from d-tyrosine. A corrected structure for aeruginosin EI461 is proposed, and the structure is proven by synthesis, which was accomplished using the new alpha-amino acid (2S,3aR,6R,7aR)-6-hydroxy-2-carboxyoctahydroindole, prepared from l-tyrosine. Succesive couplings of the dipeptide d-Leu-3a,7a-diepi-l-Choi with l-Hpla and NH(4)OH and a deprotection step gave aeruginosin EI461.     

甘露聚糖肽的结构鉴定

采用离子交换柱层析和凝胶柱层析从甘露聚糖肽原料中分离纯化得到4种均一糖肽MT1-A,MT1-B,MT2-A和MT2-B;通过单糖组成分析、甲基化分析、氢核磁共振谱(~1H NMR)、红外光谱(IR)和氨基酸组成分析等手段对均一糖肽MT1-A,MT1-B和MT2-B的结构进行了鉴定.结果表明,3种均一糖肽的单糖组成、糖残基的连接方式与MT2-A相同,但是分子量以及氨基酸总量有所不同.测定了不同批次甘露聚糖肽原料的~1H NMR谱,以MT2-A的~1H NMR谱图为标准谱,以异头氢区域为鉴定区域,通过计算不同批次甘露聚糖肽原料以及其它3种均一糖肽与MT2-A的~1H NMR谱的相关系数,定量评价了不同批次甘露聚糖肽原料与4种均一糖肽的相似程度.结果表明,甘露聚糖肽是由糖链结构一致、分子量和氨基酸含量不同的几种均一糖肽构成的混合物.     

Catalytic asymmetric phase-transfer reactions using tartrate-derived asymmetric two-center organocatalysts

A new highly versatile asymmetric two-center catalyst, tartrate-derived diammonium salt (TaDiAS), was designed and a catalyst library containing more than 70 new two-center catalysts was constructed. A variety of (S,S)- and (R,R)-TaDiAS were easily synthesized from diethyl l- and d-tartrate, respectively, using common and inexpensive reagents under operationally simple reaction conditions. TaDiAS was used in phase-transfer alkylations and Michael additions to afford various optically active α-amino acid equivalents in up to 93% yield. Moreover, dramatic counter anion effects were observed in phase-transfer catalysis (PTC) for the first time, making it possible to further improve reactivity and selectivity. These findings validate the usefulness of three-dimensional fine-tuning of the catalyst (acetal, Ar, and counter anion) for optimization. Recovery and reuse of the catalyst was also possible using simple procedures. The present asymmetric PTC was successfully applied to enantioselective syntheses of serine protease inhibitor aeruginosin 298-A and its analogues.     

A convenient new route to piperidines, pyrrolizidines, indolizidines, and quinolizidines by cyclization of acetylenic sulfones with beta and gamma-chloroamines. Enantioselective total synthesis of indolizidines (-)-167B, (-)-209D, (-)-209B, and (-)-207A

The methyl esters of (L)-phenylalanine and (L)-methionine underwent conjugate additions via their free amino groups to 1-(p-toluenesulfonyl)hexyne, followed by intramolecular acylation of the corresponding enamide anions and tautomerization to afford 2-benzyl-5-n-butyl-3-hydroxy-4-(p-toluenesulfonyl)pyrrole and 5-n-butyl-3-hydroxy-2-(2-methylthioethyl)-4-(p-toluenesulfonyl)pyr role, respectively. The conjugate additions of a series of acyclic and cyclic secondary beta- and gamma-chloroamines to acetylenic sulfones proceeded similarly under mild conditions. The resulting adducts were deprotonated with LDA in THF at -78 degrees C, and the resulting sulfone-stabilized carbanions underwent intramolecular alkylation to afford cyclic enamine sulfones. Thus, acyclic gamma-chloroalkyl-benzylamines afforded the corresponding 2- or 2,6-disubstituted piperidines, while 2-(chloromethyl)pyrrolidines, 2-(2-chloroethyl)pyrrolidines, 2-(chloromethyl)piperidines, and 2-(2-chloroethyl)piperidines produced the corresponding 3-substituted pyrrolizidines, 5- or 3-substituted indolizidines, and 4-substituted quinolizidines, respectively. 8-Methyl-5-substituted indolizidines were also prepared from the appropriate methyl-substituted chloroamine precursor. Enantioselective syntheses were achieved by employing chiral chloroamines derived from amino acids or other enantiopure precursors. Further transformations of several of the products provided concise syntheses of four dendrobatid alkaloids. Thus, reduction of (8aS)-5-n-propyl-6-(p-toluenesulfonyl)-delta5,6-indolizidine with sodium cyanoborohydride in trifluoroacetic acid, followed by reductive desulfonylation, afforded (-)-indolizidine 167B. The corresponding 5-n-hexyl derivative similarly produced (-)-indolizidine 209D, while (-)-(8R, 8aS)-8-methyl-5-n-pentyl-6-(p-toluenesulfonyl)-delta5,6-indo lizidine furnished (-)-indolizidine 209B. Finally, the similar reduction and debenzylation of (-)-(8R,8aS)-5-(2-benzyloxyethyl)-8-methyl-6-(p-toluenesulfo nyl)-delta5,6-indolizidine produced the corresponding 5-hydroxyethyl indolizidine. This was subjected to chlorination of the alcohol group with thionyl chloride and substitution with a higher order allyl cuprate reagent to afford (-)-indolizidine 207A.     

Practical synthesis of 2-keto-3-deoxy-D-glycero-D-galactononulosonic acid (KDN)

Reaction of propargylmagnesium bromide with 2,3;5,6-di-O-isopropylidene-D-mannonolactone followed by highly stereoselective reduction of the so-formed lactol with sodium borohydride gives a syn-diol from which practical syntheses of 2-keto-3-deoxy-D-glycero-D-galactononulosonic acid (KDN) and various partially protected derivatives have been achieved all of which feature the oxidative unmasking of the α-keto acid moiety from the alkyne.     

Cyclopropane-annelated azaoligoheterocycles by Ti-mediated intramolecular reductive cyclopropanation of cyclic amino Acid amides

Starting from pyrrole- and indole-2-carboxylic acids 5 a and 5 b, the tri- and tetracyclic N,N-dibenzylcyclopropylamines 7 a and 7 b have been synthesized in 52 and 33 % overall yield, respectively. The synthesis of the enantiopure tetracyclic diamine 10 has been achieved applying the established set of reactions to N-tert-butoxycarbonylindoline-2-carboxylic acid (8) in 46 % overall yield. The amide 15 could not be prepared in the same way starting from the N-tert-butoxycarbonylproline 11. In fact, in the allylation step the stereogenic center was deprotonated and the doubly alkylated amide 13 was formed. However, the desired intermediate 15 could be obtained from L-proline in 49 % yield performing first the N-allylation step, then the introduction of the amide function. From 15, the cyclopropane-annelated pyrrolizidine 16 was obtained in 70 % yield as a mixture of (1aS,6aS,6bR)-16 and (1aR,6aS,6bS)-16 diastereoisomers in a ratio of 1:2.9.     

Some crystal chemical aspects of A3B(β-W) type compounds

All the known A₃B compounds with the A15(β-W) type structure have been compiled. The compilation shows that the formation of the A₃B compounds to be strongly dependent on atomic orbitals of both the A and B elements. Specifically A elements come exclusively from the transition atoms of 4-A 5-A and 6-A groups, whereas B elements come exclusively from 8-A, 9-A, 10-A groups of transition atoms as well as from 1-B, 2-B, 3-B, 4-B and 5-B groups of nontransition atoms.Roughly, there is a one-to-one correspondence between the population (therefore the stability) of the A₃B compounds and their superconducting critical temperature; the more stable is the compound, the higher is the critical temperature.     

Can cytosine, thymine and uracil be formed in interstellar regions? A theoretical study

This theoretical study investigates possible synthetic routes to cytosine, uracil and thymine in the gas phase from precursor molecules that have been detected in interstellar media. Studies at the CCSD(T)/6-311++G(d,p)//B3LYP/6-311++G(d,p) level of theory suggest that: The reactions between :CCCNH and :CCCO with monosolvated urea may constitute viable interstellar syntheses of cytosine and uracil. No low energy equilibration between cytosine and uracil has been demonstrated. The interaction of :CH(2) with the 5 C-H bond of uracil may form thymine in an energetically favourable reaction, but competing reactions where :CH(2) reacts with double bonds and other CH and NH bonds of uracil, reduce the effectiveness of this synthesis. The reaction between the hydrated propional enolate anion and isocyanic acid may produce thymine, in a reaction sequence where ΔG(reaction)(298 K) is -22 kJ mol(-1) and the maximum energy requirement (barrier to the first transition state) is only 47 kJ mol(-1).     

Asymmetric synthesis of trans-2,3-piperidinedicarboxylic acid and trans-3,4-piperidinedicarboxylic acid derivatives

Asymmetric syntheses of (2S,3S)-3-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid (1b), (3R,4S)-4-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (2b), and their corresponding N-Boc and N-Cbz protected analogues 8a,b and 17a,b are described. Enantiomerically pure 1b has been synthesized in five steps starting from L-aspartic acid beta-tert-butyl ester. Tribenzylation of the starting material followed by alkylation with allyl iodide using KHMDS produces the key intermediate 5a in a 6:1 diastereomeric excess. Upon hydroboration, the alcohol 6a is oxidized, and the resulting aldehyde 7 is subjected to a ring closure via reductive amination, providing 1b in an overall yield of 38%. Optically pure 2b has been synthesized beginning with N-Cbz-beta-alanine. The synthesis involves the induction of the first stereogenic center using Evans's chemistry and sequential LDA-promoted alkylations with tert-butyl bromoacetate and allyl iodide. Further elaboration by ozonolysis and reductive amination affords 2b in an overall yield of 28%.     

Total Synthesis of Diverse Tetramic Acid Bearing cis-Decalin Natural Products

We report herein the first total syntheses of four natural antibiotics, vermisporin, PF1052/AB4015-A, AB4015-L, AB4015-B, and one hydrogenated natural product derivative, AB4015-A2, that all feature a tetramic acid bearing cis-decalin ring. The construction of the functionalized cis-decalin ring was achieved by a diastereoselective intramolecular Diels-Alder (IMDA) reaction, which proceeded via a rare endo-boat transition state. Through an intramolecular neighboring-group-oriented strategy, the sterically hindered epoxy group in vermisporin, PF1052/AB4015-A and AB4015-L was installed efficiently. A one-pot aminolysis/Dieckmann condensation cascade using l -amino acid derivatives afforded the desired tetramic acid structure. The total synthesis led to the unambiguous verification of the absolute configuration of these natural products.     

Divergent Synthesis of Aeruginosins Based on a C(sp3)H Activation Strategy

A general and scalable access to the aeruginosin family of marine natural products, exhibiting potent inhibitory activity against serine proteases, is reported. This was enabled by the strategic use of two recently implemented Pd‐catalyzed C(sp³)?H activation reactions. The first method allowed us to obtain the common 2‐carboxy‐6‐hydroxyoctahydroindole (Choi) core of the target molecules on a large scale, whereas the second method provided a rapid and divergent access to various hydroxyphenyllactic (Hpla) subunits, including halogenated ones. This unique strategy, together with an optimization of the fragment coupling sequence allowed the synthesis of four aeruginosins, that is, 98A–C and 298A from the chiral pool. Among them, aeruginosin 298A was synthesized on an unprecedentedly large scale. In addition, halogenated aeruginosins 98A and 98C were synthesized for the first time, thanks to a fine‐tuning of the final hydrogenation step.     

Stereoselective total synthesis of cis- and trans-3-hydroxypipecolic acid

[reaction: see text] 3-Hydroxypipecolic acid, a nonproteinogenic cyclic alpha-amino acid, is a common structural moiety found in a large number of natural and synthetic compounds of medicinal significance. Utilizing D-serine as a chiral template, the present research describes efficient and straightforward routes to cis- and trans-3-hydroxypipecolic acids in enantiopure form. The key steps in the syntheses involve chelation-controlled addition of a homoallyl Grignard reagent to a protected serinal derivative toward stereoselective formation of the corresponding syn-amino alcohol adduct 3. On the other hand, zinc borohydride-mediated chelation-controlled reduction of a serine-derived alpha-aminoketone precursor leads to the formation of the corresponding anti-amino alcohol adduct 4 with high stereoselectivity. Following an efficient sequence of reactions, the above amino alcohol derivatives were subsequently transformed to the corresponding cis- and trans- title compounds, respectively.     

A general enantioselective approach to jasmonoid fragrances: synthesis of (+)-(1R,2S)-methyl dihydrojasmonate and (+)-(1R,2S)-magnolione

Methyl dihydrojasmonate 1 and magnolione 3 are of both academic and industrial interest. In this paper, we describe a flexible, high-yielding route to diastereomerically pure (+)-cis-(1R,2S)-methyl dihydrojasmonate 1 and the first synthesis of (+)-cis-(1R,2S)-magnolione 3, both with enantiomeric excesses up to 93%. The two syntheses diverged from the same advanced intermediate 5, readily available from the enantioenriched hydroxymethyl delta-lactone (-)-(3aS,4S,6aR)-6. The olfactory properties of (1R,2S)-1 and (1R,2S)-3 are reported.     

A solid-phase approach to the phallotoxins: total synthesis of [Ala7]-phalloidin

Herein we report a solid-phase synthetic approach to [Ala7]-phalloidin (1). Prior syntheses of phallotoxins were carried out using solution-phase routes that required large scale and preclude library production. The route presented here consists of solution-phase preparation of key orthogonally protected amino acid building blocks, followed by a solid-phase peptide synthesis sequence, featuring two resin-bound macro-cyclization reactions. The final product mixture was composed of two atropisomeric compounds, one designated "natural" (1) and the other designated "non-natural" (1'). The structures of these species were modeled using restrained energy minimization with NMR-derived restraints.     

Total synthesis and stereochemical revision of (+)-aeruginosin 298-A

[structure:see text] Novel routes toward both enantiomers of the bicyclic proline surrogate 2-carboxy-6-hydroxyoctahydroindole, i.e., Choi, were developed on the basis of the oxidative cyclization of L-tyrosine. Synthesis of the proposed sequence of (+)-aeruginosin 298-A did not provide the natural product. Incorporation of a D-leucine residue, in contrast, led to the total synthesis of this thrombin inhibitor.     

Postsynthetic modification of a metal-organic framework for stabilization of a hemiaminal and ammonia uptake

In our study, we show by solid-state (15)N NMR measurements that an important zirconium metal-organic framework (UiO-66) with amino-functionalized links is composed of a mixture of amino and -NH(3)(+)Cl(-) salt functionalities rather than all amino functionality to give a composition of Zr(6)O(4)(OH)(4)(BDC-NH(2))(4)(BDC-NH(3)(+)Cl(-))(2) (UiO-66-A). UiO-66-A was postsynthetically modified to form a mixture of three functionalities, where the hemiaminal functionality is the majority species in UiO-66-B and aziridine is the majority functionality in UiO-66-C. UiO-66-A-C are all porous with surface areas ranging from 780 to 820 m(2)/g and have chemical stability, as evidenced by reversible ammonia uptake and release showing capacities ranging from 134 to 193 cm(3)/g.