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1.
J Org Chem ; 82(16): 8725-8732, 2017 08 18.
Article in English | MEDLINE | ID: mdl-28731342

ABSTRACT

The development of an efficient, high yielding six-step convergent synthesis of the semisynthetic alkaloid (-)-perhydrohistrionicotoxin is described. The key transformations include the cross metathesis of a Brønsted-acid masked primary homoallylic amine with a vinyl cyclohexenone and a regioselective palladium catalyzed hydrogenation. This sequence generated the advanced Winterfeldt spirocyclic precursor in 47% overall yield, with a longest linear sequence of five steps.


Subject(s)
Amphibian Venoms/chemical synthesis , Amphibian Venoms/chemistry , Hydrogenation , Molecular Structure , Stereoisomerism
2.
Angew Chem Int Ed Engl ; 56(4): 1087-1091, 2017 01 19.
Article in English | MEDLINE | ID: mdl-27990730

ABSTRACT

Stereoselective total syntheses of (-)-histrionicotoxin and (-)-histrionicotoxin 235A are described. The 1-azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation-cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (-)-histrionicotoxin 235A through a one-pot partial-reduction-allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3-amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (-)-histrionicotoxin.


Subject(s)
Amphibian Venoms/chemical synthesis , Acetals/chemistry , Amphibian Venoms/chemistry , Cyclization , Free Radicals/chemistry , Molecular Conformation , Stereoisomerism
3.
Chem Pharm Bull (Tokyo) ; 61(3): 251-7, 2013.
Article in English | MEDLINE | ID: mdl-23449194

ABSTRACT

Herein we present our unique strategies to synthesize natural products. To prepare mersicarpine, an atypical indole alkaloid, our procedure features an Eschenmoser-Tanabe fragmentation to synthesize an alkyne unit, a combination of a Sonogashira coupling and a gold(III) catalyzed cyclization to construct the indole skeleton, and a one-pot process to arrange the cyclic imine and the hemiaminal moieties. Additionally, we synthesized a frog poison, histrionicotoxin, via a chirality transfer from an allenylsilane to prepare a pseudosymmetrical dienyne, dienyne metathesis to produce an optically active bicyclo [5.4.0] system, and an asymmetric propargylation. To synthesize lyconadin A, a Lycopodium alkaloid, a combination of an aza-Prins reaction and electrocyclic ring opening constructed the highly fused tetracyclic compound. The synthesis of isoschizogamine features a facile construction of the carbon framework through a Wagner-Meerwein rearrangement, a tandem metathesis, a stereoselective rhodium-mediated 1,4-addition of an arylboronic acid, and a ring-closing metathesis via a hemiaminal ether.


Subject(s)
Alkaloids/chemical synthesis , Amphibian Venoms/chemical synthesis , Biological Products/chemical synthesis , Indole Alkaloids/chemical synthesis , Indoles/chemical synthesis , Polycyclic Compounds/chemical synthesis , Alkaloids/chemistry , Amphibian Venoms/chemistry , Animals , Biological Products/chemistry , Indole Alkaloids/chemistry , Indoles/chemistry , Polycyclic Compounds/chemistry
4.
Org Biomol Chem ; 10(45): 8963-74, 2012 Dec 07.
Article in English | MEDLINE | ID: mdl-23051904

ABSTRACT

The intramolecular nitrone dipolar cycloaddition of in situ-generated nitrones such as compound 26 has been used for the synthesis of cyclic isoxazolidines 27 and 29. The regioselectivity of the intramolecular cycloaddition depends on the nature of the terminal substituent on the dipolarophile. The influence of the substituent on the regioselectivity of the cycloaddition has been examined using several model systems and two methods of nitrone formation. These studies demonstrated that the cyano-substituent plays a special role in favouring the formation of the 6,6,5-ring fused adduct 27 under thermodynamically controlled conditions. The utility of the cyclo-adduct 57 (see Scheme 12) as a precursor for the naturally occurring histrionicotoxins is illustrated by the synthesis of three "unsymmetrical" (i.e. with each side chain bearing different functional groups) members of the histrionicotoxin family HTX-259A, HTX-285C and HTX-285E (2, 3 and 4 respectively).


Subject(s)
Alkaloids/chemistry , Alkaloids/chemical synthesis , Amphibian Venoms/chemistry , Amphibian Venoms/chemical synthesis , Biological Products/chemical synthesis , Nitrogen Oxides/chemistry , Spiro Compounds/chemistry , Biological Products/chemistry , Cycloaddition Reaction , Stereoisomerism , Substrate Specificity
5.
Org Lett ; 13(16): 4446-9, 2011 Aug 19.
Article in English | MEDLINE | ID: mdl-21793562

ABSTRACT

A total synthesis of (-)-histrionicotoxin was achieved. Our synthesis features preparation of a pseudosymmetrical dienyne through chirality transfer from an allenylsilane, a dienyne metathesis to produce the bicyclo [5.4.0] system in optically active form, selective functionalization of a diene via a 5-exo-trig iodoetherification, and an asymmetric propargylation.


Subject(s)
Amphibian Venoms/chemical synthesis , Molecular Structure , Stereoisomerism
6.
Org Lett ; 13(3): 526-9, 2011 Feb 04.
Article in English | MEDLINE | ID: mdl-21175153

ABSTRACT

Reaction of 6-chloro-2-fluoro-3-pyridineacetamide with 1,2-bis(trimethylsilyloxy)cyclobutene in ether saturated with hydrogen chloride afforded the keto amide in 85% yield. In the key step, treatment of the keto amide with aqueous KOH in t-BuOH resulted in a tandem intramolecular aldol reaction-intramolecular nucleophilic aromatic substitution sequence to give the tetracylic lactam in 46% yield. Reduction of the lactam with BH(3) in THF gave phantasmidine in 67% yield.


Subject(s)
Amphibian Venoms/chemical synthesis , Cyclobutanes/chemistry , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Hydrocarbons, Halogenated/chemistry , Pyridines/chemistry , Trimethylsilyl Compounds/chemistry , Amphibian Venoms/chemistry , Animals , Anura , Heterocyclic Compounds, Bridged-Ring/chemistry , Hydrochloric Acid , Molecular Structure , Stereoisomerism
7.
Chemistry ; 16(37): 11471-80, 2010 Oct 04.
Article in English | MEDLINE | ID: mdl-20827703

ABSTRACT

The total synthesis of the spiropiperidine alkaloid (-)-perhydrohistrionicotoxin (perhydro-HTX) 2 has been accomplished on a gram scale by employing both conventional batch chemistry as well as microreactor techniques. (S)-(-)-6-Pentyltetrahydro-pyran-2-one 8 underwent nucleophilic ring opening to afford the alcohol 10, which was elaborated to the nitrone 13. Protection of the nitrone as the 1,3-adduct of styrene and side-chain extension to the unsaturated nitrile afforded a precursor 17, which underwent dipolar cycloreversion and 1,3-dipolar cycloaddition to give the core spirocyclic precursor 18 that was converted into perhydro-HTX 2. The principal steps to the spirocycle 18 have successfully been transferred into flow mode by using different types of microreactors and in a telescoped fashion, allowing for a more rapid access to the histrionicotoxins and their analogues by continuous processing.


Subject(s)
Alkaloids/chemical synthesis , Amphibian Venoms/chemical synthesis , Alkaloids/chemistry , Amphibian Venoms/chemistry , Animals , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Molecular Structure , Stereoisomerism
8.
J Nat Prod ; 72(2): 243-7, 2009 Feb 27.
Article in English | MEDLINE | ID: mdl-19245264

ABSTRACT

In 2003, we reported the isolation, structure elucidation, and pharmacology of epiquinamide (1), a novel alkaloid isolated from an Ecuadoran poison frog, Epipedobates tricolor. Since then, several groups, including ours, have undertaken synthetic efforts to produce this compound, which appeared initially to be a novel, beta2-selective nicotinic acetylcholine receptor agonist. Based on prior chiral GC analysis of synthetic and natural samples, the absolute structure of this alkaloid was established as (1S,9aS)-1-acetamidoquinolizidine. We have synthesized the (1R*,9aS*)-isomer (epi-epiquinamide) using an iminium ion nitroaldol reaction as the key step. We have also synthesized ent-1 semisynthetically from (-)-lupinine. Synthetic epiquinamide is inactive at nicotinic receptors, in accord with recently published reports. We have determined that the activity initially reported is due to cross-contamination from co-occurring epibatidine in the isolated material.


Subject(s)
Alkaloids , Quinolizines , Ranidae/metabolism , Receptors, Nicotinic/drug effects , Alkaloids/chemical synthesis , Alkaloids/chemistry , Alkaloids/isolation & purification , Alkaloids/toxicity , Amphibian Venoms/chemical synthesis , Amphibian Venoms/chemistry , Amphibian Venoms/isolation & purification , Amphibian Venoms/toxicity , Animals , Gas Chromatography-Mass Spectrometry , Molecular Structure , Quinolizines/chemical synthesis , Quinolizines/chemistry , Quinolizines/isolation & purification , Quinolizines/toxicity , Sparteine/analogs & derivatives , Sparteine/chemical synthesis , Sparteine/chemistry , Sparteine/economics , Stereoisomerism
9.
Org Lett ; 10(19): 4227-9, 2008 Oct 02.
Article in English | MEDLINE | ID: mdl-18763799

ABSTRACT

Starting from commercially available ( S)-glycidol, and via a common intermediate, the total synthesis of (-)-histrionicotoxin 285A and (-)-perhydrohistrionicotoxin has been achieved. Key to this synthesis was the efficient construction of a six-membered, chiral, cyclic nitrone.


Subject(s)
Amphibian Venoms/chemical synthesis , Alkadienes/chemistry , Alkaloids/chemical synthesis , Alkaloids/chemistry , Amphibian Venoms/chemistry , Stereoisomerism
10.
J Org Chem ; 73(19): 7852-5, 2008 Oct 03.
Article in English | MEDLINE | ID: mdl-18778103

ABSTRACT

In 18 out of 20 examples of the organolithium-mediated conversion of beta-alkoxy aziridines into substituted allylic sulfonamides, use of a Bus (Bus = t-BuSO2) substituent on the nitrogen gave higher yields compared to the analogous N-Ts compounds. The success with the N-Bus aziridines facilitated the development of a new route to the spirocyclic core of the histrionicotoxins and completion of a formal synthesis of (+/-)-perhydrohistrionicotoxin.


Subject(s)
Amphibian Venoms/chemical synthesis , Aziridines/chemistry , Lithium , Sulfonamides/chemical synthesis , Organometallic Compounds
11.
J Org Chem ; 73(24): 9601-9, 2008 Dec 19.
Article in English | MEDLINE | ID: mdl-18715039

ABSTRACT

An efficient stereocontrolled route to the spirocyclic perhydrohistrionicotoxin derivative (+/-)-2,7,8-epi-PHTx (4) is described. The reaction of 2-butyl-3-(methoxymethoxy)cyclohexanone oxime with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to give a transient nitrone which then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish an azaspiro[5.5]undecane. Elaboration to the dihydropyridin-4(1H)-one 24 was followed by stereoselective conjugate addition using n-pentyl cuprate to give azaspirocycle 25. The stereochemistry of the product was deduced from an X-ray crystal structure of the corresponding N-tosylhydrazone derivative. The dominant factor controlling the stereochemistry of the conjugate addition is the A(1,3)-strain present in the planar vinylogous amide. A stereoelectronically preferred axial attack by the organocuprate at the beta-position leads to the observed diastereoselectivity. Azaspirocycle 25 was transformed into 2,7,8-epi-PHTx (4) in five additional steps. Utilizing this tandem conjugate addition/dipolar cycloaddition cascade, we have also successfully synthesized azaspiro[5.5]undecane 36, which had previously been converted into (+/-)-perhydrohistrionicotoxin (2), thereby completing a formal total synthesis of this alkaloid.


Subject(s)
Amphibian Venoms/chemical synthesis , Crystallography, X-Ray , Cyclization , Indicators and Reagents , Magnetic Resonance Spectroscopy , Molecular Conformation , Stereoisomerism
12.
J Org Chem ; 73(16): 6466-9, 2008 Aug 15.
Article in English | MEDLINE | ID: mdl-18637692

ABSTRACT

An efficient formal total synthesis of (+)-gephyrotoxin is described. The key step of our strategy relies on the diastereoselective reduction of a chiral pyrrolidine beta-enamino ester obtained by condensation of ( S)-phenylglycinol on a protected 8-hydroxy-3,6-dioxooctanoate.


Subject(s)
Alkaloids/chemical synthesis , Amphibian Venoms/chemical synthesis , Ethanolamines , Glycine/analogs & derivatives , Glycine/chemistry , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Stereoisomerism
13.
Nat Prod Rep ; 24(2): 298-326, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17389999

ABSTRACT

This article brings together for the first time reviews of all the synthetic attempts towards the spirocyclic histrionicotoxin alkaloids published since the discovery of the group in 1971. This covers 5 total syntheses of the fully unsaturated parent alkaloid HTX-283A, 7 total syntheses of perhydrohistrionicotoxin, 15 total syntheses of other members of this alkaloid family, 25 formal syntheses, and 19 partial syntheses involving the successful formation of the core azaspirocyclic structure but lacking advancement towards the target structure.


Subject(s)
Alkaloids/chemical synthesis , Amphibian Venoms/chemical synthesis , Biological Products/chemical synthesis , Spiro Compounds/chemical synthesis , Molecular Structure
14.
J Am Chem Soc ; 128(39): 12656-7, 2006 Oct 04.
Article in English | MEDLINE | ID: mdl-17002353

ABSTRACT

The synthesis of (+/-)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction.


Subject(s)
Amphibian Venoms/chemical synthesis , Alkynes/chemistry , Amphibian Venoms/chemistry , Animals , Anura , Stereoisomerism
15.
J Org Chem ; 70(14): 5756-9, 2005 Jul 08.
Article in English | MEDLINE | ID: mdl-15989368

ABSTRACT

[reaction: see text] We have successfully synthesized an advanced synthetic intermediate, hydroxy lactam 3, which has previously been converted to perhydrohistrionicotoxin. An important feature of this synthesis is the creation of stereogenic centers by using the cyclic amino acid ester-enolate Claisen rearrangement together with a ring-closing metathesis for azaspirocyclic skeleton construction.


Subject(s)
Alcohols/chemistry , Alkaloids/chemistry , Amino Acids, Cyclic/chemistry , Amphibian Venoms/chemical synthesis , Aza Compounds/chemistry , Cyclization , Esters/chemistry , Lactams/chemistry , Molecular Structure , Stereoisomerism
16.
Regul Pept ; 121(1-3): 65-72, 2004 Sep 15.
Article in English | MEDLINE | ID: mdl-15256275

ABSTRACT

Structural homologues of vertebrate regulatory peptides found in defensive skin secretions of anuran amphibians often display enhanced bioactivity and receptor binding when compared with endogenous mammalian peptide ligands. Maximakinin, a novel N-terminally extended bradykinin (DLPKINRKGPRPPGFSPFR) from the skin venom of a Chinese toad (Bombina maxima), displays such activity enhancement when compared with bradykinin but is additionally highly selective for mammalian arterial smooth muscle bradykinin receptors displaying a 50-fold increase in molar potency in this smooth muscle type. In contrast, a 100-fold decrease in molar potency was observed at bradykinin receptors in intestinal and uterine smooth muscle preparations. Maximakinin has thus evolved as a "smart" defensive weapon in the toad with receptor/tissue selective targeting. Natural selection of amphibian skin venom peptides for antipredator defence, through inter-species delivery by an exogenous secretory mode, produces subtle structural stabilisation modifications that can potentially provide new insights for the design of selectively targeted peptide therapeutics.


Subject(s)
Amphibian Venoms/pharmacology , Anura , Arteries/drug effects , Bradykinin/chemistry , Muscle, Smooth, Vascular/drug effects , Venoms/chemistry , Amino Acid Sequence , Amphibian Venoms/chemical synthesis , Amphibian Venoms/chemistry , Animals , Biological Assay , Bradykinin Receptor Antagonists , Molecular Sequence Data , Muscle, Smooth, Vascular/physiology , Rats , Receptors, Bradykinin/metabolism , Substrate Specificity , Time Factors
17.
J Org Chem ; 69(5): 1598-602, 2004 Mar 05.
Article in English | MEDLINE | ID: mdl-14987016

ABSTRACT

An entirely two-directional synthesis of (+/-)-perhydrohistrionicotoxin is presented, utilizing a tandem oxime formation/Michael addition/[3 + 2] cycloaddition as the key step. This approach also constitutes formal syntheses of (+/-)-histrionicotoxin and (+/-)-histrionicotoxin 235A.


Subject(s)
Amphibian Venoms/chemical synthesis , Amphibian Venoms/chemistry , Amphibian Venoms/isolation & purification , Animals , Anura , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Skin/chemistry , Stereoisomerism
18.
Org Biomol Chem ; 1(3): 547-51, 2003 Feb 07.
Article in English | MEDLINE | ID: mdl-12926258

ABSTRACT

The anodic cyanation of methanolic solutions of the 2-alkyl-N-phenylpiperidines 6b-d was performed in a flow cell equipped with a graphite felt anode. The reaction led to the formation of the 2-cyano-6-alkyl-N-phenylpiperidines 2b-d and proceeded with a high degree of regioselectivity. The 1H NMR spectra of the aminonitriles 2b-d showed an epimeric mixture at C-6. The major isomer has a trans configuration in which the cyano group is axial and the alkyl substituent is equatorial. Conversely, electrochemical oxidation of the 4-methyl-6-pentyl-N-phenylpiperidine 6e afforded the trisubstituted aminonitrile 2e as a single diastereomer (> 98% de). The 4-cyanobutyl side chain was incorporated in a two-step procedure to yield dinitrile 4e. This latter compound was directly converted into spiropiperidine 5e by using the Thorpe-Ziegler annulation procedure. The overall sequence (4 steps, 43%) allows the construction of the basic carbon framework of perhydrohistrionicotoxin.


Subject(s)
Amphibian Venoms/chemistry , Cyanides/chemistry , Piperidines/chemical synthesis , Amphibian Venoms/chemical synthesis , Models, Molecular , Neurotoxins , Piperidines/chemistry , Spiro Compounds/chemistry , Stereoisomerism
19.
J Am Chem Soc ; 124(35): 10435-42, 2002 Sep 04.
Article in English | MEDLINE | ID: mdl-12197745

ABSTRACT

Evidence is described here to support that a highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes is a key step in formal [3 + 3] cycloaddition or annulation reactions of chiral vinylogous amides with alpha,beta-unsaturated iminium salts. This would represent the first highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes. We have also unambiguously demonstrated that these specific ring closures are reversible, leading to the major diastereomer that is also thermodynamically more stable, and that a rotation preference likely also plays a role. A synthetic application is illustrated here to stereoselectively transform the resulting dihydropyridines to cis-1-azadecalins with unique anti relative stereochemistry at C2 and C2a, leading to synthesis of epi isomers of (-)-pumiliotoxin C.


Subject(s)
Alkaloids/chemical synthesis , Amphibian Venoms/chemical synthesis , Naphthalenes/chemical synthesis , Quinolines , Alkaloids/chemistry , Alkenes/chemistry , Amphibian Venoms/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cyclization , Naphthalenes/chemistry , Stereoisomerism
20.
J Org Chem ; 67(16): 5517-26, 2002 Aug 09.
Article in English | MEDLINE | ID: mdl-12153249

ABSTRACT

A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation[bond]cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh(3))(4) catalyst to give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.


Subject(s)
Alkaloids/chemical synthesis , Amphibian Venoms/chemical synthesis , Indolizines , Piperidines , Alkaloids/chemistry , Amphibian Venoms/chemistry , Animals , Anura , Indicators and Reagents , Molecular Conformation , Molecular Structure , Structure-Activity Relationship
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