Hydrazide‐Catalyzed Polyene Cyclization: Asymmetric Organocatalytic Synthesis of cis‐Decalins

Polyene cyclizations offer rapid entry into terpenoid ring systems. Although enantioselective cyclizations of (E)‐polyenes to form trans‐decalin ring systems are well precedented, highly enantioselective cyclizations of (Z)‐polyenes to form the corresponding cis‐decalins have not been reported. Here, we describe the first application of iminium catalysis to the initiation of polyene cyclizations. Ethyl 1,2‐diazepane‐1‐carboxylate catalyzes the cyclization of polyenes bearing enal initiators. Moreover, chiral bicyclic hydrazides catalyze the cyclizations of (Z)‐polyene substrates to form cis‐decalins with enantioselectivities of up to 97:3 er. DFT calculations suggest the catalysts promote the reaction by stabilizing positive charge as it develops during the bicyclization.     

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids

Reported is the enantioselective total syntheses of mavacuran alkaloids, (+)‐taberdivarine H, (+)‐16‐hydroxymethyl‐pleiocarpamine, and (+)‐16‐epi‐pleiocarpamine, and their postulated biosynthetic precursor 16‐formyl‐pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1?C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I₂ as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation.     

Hydrazide-Catalyzed Polyene Cyclization: Asymmetric Organocatalytic Synthesis of cis-Decalins

Polyene cyclizations offer rapid entry into terpenoid ring systems. Although enantioselective cyclizations of (E)-polyenes to form trans-decalin ring systems are well precedented, highly enantioselective cyclizations of (Z)-polyenes to form the corresponding cis-decalins have not been reported. Here, we describe the first application of iminium catalysis to the initiation of polyene cyclizations. Ethyl 1,2-diazepane-1-carboxylate catalyzes the cyclization of polyenes bearing enal initiators. Moreover, chiral bicyclic hydrazides catalyze the cyclizations of (Z)-polyene substrates to form cis-decalins with enantioselectivities of up to 97:3 er. DFT calculations suggest the catalysts promote the reaction by stabilizing positive charge as it develops during the bicyclization.     

SmI2‐induced cyclizations and their applications in natural product synthesis

Since the isolation of brevetoxin‐B, a red tide toxin, many bioactive marine natural products featuring synthetically challenging trans‐fused polycyclic ether ring systems have been reported. We have developed SmI₂‐induced cyclization of β‐alkoxyacrylate with aldehyde, affording 2,6‐syn‐2,3‐trans‐tetrahydropyran (THP) or 2,7‐syn‐2,3‐trans‐oxepane with complete stereoselection, as a key reaction of efficient iterative and bi‐directional strategies for the construction of these polycyclic ethers. This reaction is also applicable to the synthesis of 3‐, 5‐, and 6‐methyl‐THPs and 3,5‐dimethyl‐THP. The synthesis of 2‐methyl‐ and 2,6‐dimethyl‐THPs was accomplished by means of a unique methyl insertion. Recently, the SmI₂‐induced cyclization was extended to similar reactions using β‐alkoxyvinyl sulfone and sulfoxide. Reaction of (E)‐ and (Z)‐β‐alkoxyvinyl sulfone‐aldehyde afforded 2,6‐syn‐2,3‐trans‐ and 2,6‐syn‐2,3‐cis‐ THPs, respectively. Reaction of (E)‐β‐alkoxyvinyl (R)‐ and (S)‐sulfoxides gave 2,6‐anti‐2,3‐cis‐ and 2,6‐syn‐2,3‐trans‐THPs, respectively. Reaction of (Z)‐β‐alkoxyvinyl (R)‐sulfoxides gave 2,6‐syn‐2,3‐cis‐THP and an olefinic product, while that of (Z)‐β‐alkoxyvinyl (S)‐sulfoxide afforded a mixture of many products. These SmI₂‐induced cyclizations have been applied to the total syntheses of various natural products, including brevetoxin‐B, mucocin, pyranicin, and pyragonicin. Synthetic studies on gambierol and maitotoxin are also introduced. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 159–172; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900027     

Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane‐type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an α‐iminol rearrangement transforming the 3‐hydroxyindolenine into spiroindolin‐3‐one, b) a highly diastereoselective conformation‐directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza‐pinacol or an unprecedented α‐aminoketone rearrangement converting spiroindolinone back into the indole skeleton.     

Chemical and nuclear magnetic resonance studies of 3,3-diphenyltetrahydrofuran derivatives

Pyrolytic cyclization of a- and β-methadol methiodides afforded cis and trans isomers of 2-ethyl-3,3-diphenyl-5-methyltetrahydrofuran, respectively. Catalytic hydrogenation of 2-ethyli-dene-3,3-diphenyl-5-methyltetrahydrofuran yielded the cis and trans isomers in a 2:1 ratio. The nmr spectra of these and structurally related compounds have been analyzed in terms of a half-chair conformation for 2-ethyl-5-methyl, 2-ethyl, and 5-methyl derivatives. An envelope conformation has been suggested for the compounds containing a double bond at C-2.     

Hydrogallierungsreaktionen mit den Monoalkinen H5C6‐C≡C‐SiMe3 und H5C6‐C≡C‐CMe3 – cis/trans‐Isomerie und Substituentenaustausch

Hydrogallation Reactions Involving the Monoalkynes H₅C₆‐C≡C‐SiMe₃ and H₅C₆‐C≡C‐CMe₃ – cis/trans Isomerisation and Substituent Exchange Phenyl‐trimethylsilylethyne, H₅C₆‐C≡C‐SiMe₃, reacted with different dialkylgallium hydrides, R₂Ga‐H (R = Me, Et, nPr, iPr, tBu), by the addition of one Ga‐H bond to its C≡C triple bond (hydrogallation). The gallium atoms attacked selectively those carbon atoms, which were also attached to trimethylsilyl groups. The cis arrangement of Ga and H across the resulting C=C double bonds resulted only for the sterically most shielded di(tert‐butyl)gallium derivative, while in all other cases spontaneous cis/trans rearrangement occurred with the quantitative formation of the trans addition products. The diethyl compound Et₂Ga‐C(SiMe₃)=C(H)‐C₆H₅ ( 2 ) gave by substituent exchange the secondary products EtGa[C(SiMe₃)=C(H)‐C₆H₅]₂ ( 7 , Z,Z) and Ga[C(SiMe₃)=C(H)‐C₆H₅]₃ ( 8 ). Interestingly, compound 8 has two alkenyl groups with a Z configuration, while the third C=C double bond has the cis arrangement of Ga and H (E configuration). The reversibility of the cis/trans isomerisation of hydrogallation products was observed for the first time. tert‐Butyl‐phenylethyne gave the simple addition product, R₂Ga(C₆H₅)=C(H)‐CMe₃ ( 9 ), only with di(n‐propyl)gallium hydride.     

Through‐Bond/Through‐Space Anion Relay Chemistry Exploiting Vinylepoxides as Bifunctional Linchpins

The development of new bifunctional linchpins that permit the union of diverse building blocks is essential for the synthetic utility of anion relay chemistry (ARC). The design, synthesis, and validation of three vinylepoxide linchpins for through‐bond/through‐space ARC are now reported. For negative charge migration, this class of bifunctional linchpins employs initial through‐bond ARC by an S_N2′ reaction, followed by through‐space ARC exploiting a 1,4‐Brook rearrangement. The trans‐disubstituted vinylepoxide linchpin yields a mixture of E/Z isomers, whereas the cis‐disubstituted and the trans‐trisubstituted vinylepoxide linchpins proceed to deliver three‐component adducts with excellent E selectivity.     

β-Siloxy unsaturated nitriles: stereodivergent cyclizations to cis- and trans-decalins

Nitrile and enolate anions exhibit divergent intramolecular cyclization stereoselectivities. Enolates cyclize to cis-decalones, whereas nitrile anions are predisposed to pyramidalize, cyclizing instead through a less-congested conformation to trans-decalins. Conjugation of nitrile anions with adjacent sp² centers prevents pyramidalization, and redirects cyclization through a planar-delocalized anion to cis-decalins. Collectively these cyclizations allow conversion of a single β-siloxynitrile to either cis- or trans-decalins that are ideally suited for elaboration into terpenoid natural products.     

2-[4-Alkenyloxy)phenyl]-5-alkylpyrimidines The relationship between position and nature (E/Z) of the double bond and transition temperatures

Abstract

The 5-n-alkyl-2-[4-(n-alkoxy)phenyl]pyrimidmes are essential components of most commercial chiral smectic C mixtures for electrooptic display devices based on ferroelectric effects. This is due to their generally relatively low melting points, enantiotropic, relatively wide range smectic C mesophases, low viscosity and ease of preparation. An unsaturated carbon–carbon double bond has now been introduced into the terminal alkoxy chain of the 5-n-alkyl-2-[4-(alkoxy)phenyl]pyrimidines to produce the corresponding alkenyloxy substituted derivatives. The position and nature (E/Z) of the double bond has been varied systematically and the effect on the liquid crystal transition temperatures studied. A number of homologous series of the most interesting alkenyloxy substituted materials has been prepared and evaluated. The position and nature (E/Z) of the double bond changes the conformation of the alkenyloxy chain substantially. This can result in significantly higher smectic C transition temperatures for compounds with a trans double bond (E) at an even number of carbon atoms from the molecular core. Significantly lower transition temperatures (including the melting point) are observed for materials with a cis double bond (Z) at an odd number of carbon atoms from the molecular core. Comparisons with the corresponding alkoxy substituted materials (i.e. without a double bond) are made.     

Stereocontrolled Annulations of Indolo[2,3‐a]quinolizidine‐Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine‐Type Derivatives

The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3‐a]quinolizidine lactams 3 has been studied. Pentacyclic 3‐H/15‐H trans adducts 5 are generated from N_ind‐unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen has a tert‐butyloxycarbonyl (Boc) substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarov‐derived adducts is demonstrated by their conversion into allo and epiallo yohimbine‐type targets.     

2-(4-Alkylphenyl)-5-(alkenyloxy)pyrimidines: Synthesis,liquid crystal transition temperatures and some physical properties

Abstract

We have recently reported the introduction of a carbon-carbon double bond into a wide variety of 5-n-alkyl-2-(4-n-alkoxyphenyl)pyrimidines to produce the corresponding alkenyloxy derivatives. The position and nature (E/Z) of the double bond were varied systematically and the effect on the liquid crystal transition temperatures studied. The position and nature (E/Z) of the double bond changed the conformation of the alkenyloxy chain substantially. This resulted in higher smectic C and nematic transition temperatures for compounds with a trans-double bond (E) at an even number of carbon atoms from the molecular core. Significantly lower transition temperatures (including the melting point) were observed for materials with a cis-double bond (Z) at an odd number of carbon atoms from the molecular core. We have now performed the same operation on the related 2-(4-n-alkylphenyl)-5-n-alkoxypyrimidines to produce the corresponding alkenyloxy derivatives. An interesting feature of the new results is the high melting points of the trans-substituted materials and the low melting points of the terminally substituted compounds. The smectic C transition temperatures of both series are high. No nematic phases could be observed. However, in admixture with other smectic C components, the new compounds lead to surprisingly fast switching times, high smectic C transition temperatures and low melting points/crystallization temperatures in experimental mixtures designed for electro-optic display devices based on ferroelectric effects.     

Smectic C phenylpyridines with an alkenyloxy chain

Abstract

The known 5-n-alkoxy-2-[4-(n-alkoxy)phenyl]pyridines exhibit high smectic C transition temperatures as well as various highly ordered smectic mesophases. An unsaturated carbon-carbon double bond has now been introduced into the terminal alkoxy chain of these heterocyclic materials to produce the corresponding alkenyloxy substituted derivatives. The postion and nature (E/Z) of the double bond has been varied systematically and the effect on the liquid crystal transition temperatures determined. A number of homologous series of the most promising alkenyloxy substituted materials has been prepared and evaluated. The position and nature (E/Z) of the double bond changes the conformation of the alkenyloxy chain to a significant degree. This can lead to slightly higher smectic C transition temperatures for compounds with a trans-double bond (E) at an even number of carbon atoms from the molecular core. However, the highly ordered mesophase transition temperatures are increased to a greater degree leading to a reduction in the smectic C temperature range. Significantly lower transition temperatures (including the melting point) are observed for materials with a cis-double bond (Z) at an odd number of carbon atoms from the molecular core. Comparisons with the corresponding alkoxy substituted materials (i.e. without a double bond) are made. These new alkenyloxy materials can be used to increase the smectic C and nematic transition temperatures of chiral mixtures for electrooptical display devices based on ferroelectric effects.     

Helical Oligoenes: Conformations,Bond Alternation,and Competing Through‐Bond and Through‐Space Transmission

There is a consensus that long‐range electron transfer/transport occurs by a through‐bond rather than through‐space mechanism. In helical all‐Z, all‐s‐cis oligoenes, one can set up an interesting competition in the medium‐separation regime between a closer (in distance) through‐space path and a more distant through‐bond one. Although such oligoene conformations/isomers are unstable (by around 4 kcal mol^?1 per double bond relative to all‐E, all‐s‐trans isomers), recent synthetic efforts on truncated helicenes and oligothiophenes have provided related molecules. On the way to transmission calculations with electrodes attached to the termini of helical oligoenes, we uncover an interesting conformational ambiguity in all‐Z, all‐s‐cis oligoenes, the existence of a broad conformational minimum for helical compression, with hints of end‐to‐end frontier‐orbital‐caused stabilization. There is relationship between helical oligoene structures and the corresponding substructure of a helicene, but there are also significant differences in the number of olefin subunits per helix turn. In Hückel transport calculations, the role of TB or TS mechanisms is obscured to an extent by variations in bond alternation and dihedral angle along the oligomer chain. However, the operation of a dominant through bond mechanism emerges clearly in local transmission plots. In moving the electrodes to carbon position related by quantum interference, it is possible to uncover a through space mechanism.     

Lanthanide‐Catalyst‐Mediated Tandem Double Intramolecular Hydroalkoxylation/Cyclization of Dialkynyl Dialcohols: Scope and Mechanism

Lanthanide‐organic complexes of the general type [Ln{N(SiMe₃)₂}₃] (Ln=La, Sm, Y, Lu) serve as effective precatalysts for the rapid, exo‐selective, and highly regioselective tandem double intramolecular hydroalkoxylation/cyclization of primary and secondary dialkynyl dialcohols to yield the corresponding bi‐exocyclic enol ethers. Conversions are highly selective with products distinctly different from those generally produced by conventional transition metal or other catalysts, and the turnover frequencies with some substrates are too large to determine accurately. The rates of terminal alkynl alcohol hydroalkoxylation/cyclization are significantly more rapid than those of internal alkynyl alcohols, arguing that steric demands dominate the cyclization transition state. The hydroalkoxylation/cyclizations of internal dialkynyl dialcohols afford excellent E selectivity. The rate law for dialkynyl dialcohol hydroalkoxylation/cyclization is first‐order in [catalyst] and zero‐order in [alkynyl alcohol], as is observed for the organolanthanide‐catalyzed hydroamination/cyclization of aminoalkenes, aminoalkynes, and aminoallenes, and the intramolecular single‐step hydroalkoxylation/cyclization of alkynyl alcohols. An ROH/ROD kinetic isotope effect of 0.82(0.02) is observed for the tandem double hydroalkoxylation/cyclization. These mechanistic data implicate turnover‐limiting insertion of C? C unsaturation into the Ln? O bond, involving a highly organized transition state, with subsequent, rapid Ln–C protonolysis.     

Stereochemistry of the Robinson Anellation: Studies on the Mode of Formation of the Intermediate Hydroxy Ketones

The stereochemical outcome of the base-catalyzed cyclization of diketones 5 – 8 has been investigated under protic conditions (Scheme 3). The more stable trans-fused ketols are preferentially formed in kinetically controlled aldol reactions, when the incipient angular substituent R = H (6 → 10a ) or CN ( 7 → 11a , 8a → 12a ). For R = Me (as in 5 ), axial attack of the side-chain enolate double bond on the ring C?O group results in the rather selective formation of cis- 9b. It is assumed that these cyclizations are controlled by relative product stabilities (product-like transition state) and steric effects. The competition between fused (e.g. 9 ) and bridged ketol (e.g. 13 ) formation in these cyclizations is discussed. The cis-fused (‘steroid’) ketols were readily equilibrated with their trans-counterparts (9b ? 9a, 10b ? 10a, 11b ? 11a) under aprotic conditions (5 mol-% of LDA, THF, 0°), thus, allowing assessments of relative stabilities.     

Total Syntheses of the Monoterpenoid Indole Alkaloids (±)‐Alstoscholarisine B and C

Total syntheses of the monoterpenoid indole alkaloids (±)‐alstoscholarisine B and C were accomplished starting from a readily available indole‐2‐acetic ester and an α,β‐unsaturated N ‐sulfonyllactam.     

Synthesis,Structure, and Reactivity of Secosteroids Containing a Medium-Size Ring. Part 35. Photooxidations of some (Z)- and (E)-1(10)-unsaturated 5,10-secosteroids in acetone solution

UV Irradiation of (Z)- and (E)-1(10)-unsaturated 5,10-secosteroids 1–4 in acetone solution effected, besides (Z/E)-isomerization, (i) a stereospecific epoxidation (only in the presence of O₂), which, depending on the configuration ((Z) or (E)) in the starting steroid, gave cis-epoxides 5 and 8 (from the (Z)-compounds 1 and 3 ) or trans-epoxides 6,9 , and 10 (from the (E)-compounds 2 and 4 ), and (ii) oxidative acetone addition to the olefinic double bond producing 1-acetonyl derivatives 7 and 11a, b .     

Enantioselective Synthesis of Chiral Cyclopent‐2‐enones by Nickel‐Catalyzed Desymmetrization of Malonate Esters

The enantioselective synthesis of highly functionalized chiral cyclopent‐2‐enones by the reaction of alkynyl malonate esters with arylboronic acids is described. These desymmetrizing arylative cyclizations are catalyzed by a chiral phosphinooxazoline/nickel complex, and cyclization is enabled by the reversible E/Z isomerization of alkenylnickel species. The general methodology is also applicable to the synthesis of 1,6‐dihydropyridin‐3(2H)‐ones.     

Synthesis of (Z)-alkene-containing cis-proline dipeptide mimetics using samarium(II) diiodide (SmI2)-mediated reductive alkylation reaction

The amide bond between an amino acid and proline can take the trans- or cis-conformation. The conformation influences both the structure and function of peptides and proteins. Therefore, constrained mimetic, which corresponds to Pro-dipeptides whose amide bond is replaced with an (E)- or (Z)-alkene, is a useful bioprobe for elucidating the structure-function relationship of peptides and proteins. Herein, we report the synthesis of cis-(Z)-alkene-containing Pro-dipeptide mimetics via a samarium(II) diiodide (SmI₂)-mediated reductive alkylation reaction.