The Carreira Synthesis of (+)-Daphmanidin E

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Primary Alcohol ◽  
Selective Reduction ◽  
Catalytic Amount ◽  
Rat Aorta ◽  
Compact Structure ◽  
Enantiomerically Pure ◽  
Claisen Rearrangements ◽  
Cu Catalyst ◽  
Aldol Addition

(+)-Daphmanidin E 3, isolated from the leaves of Daphniphyllum teijsmanni, shows moderate vasorelaxant activity on the rat aorta. Considering the curiously compact structure of 3, Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2011, 50, 11501) to start the synthesis from the enantiomerically pure bicyclic diketone 2. The mono enolate of 2 was readily prepared, but the steric bulk of the ketal of 4 was needed to direct the subsequent hydroboration. Indeed, the alkene of 5 was so congested that excess BH3 at elevated temperature was required. Under those conditions, the esters were also partially reduced, so the reduction was completed with Dibal to deliver the crystalline triol 6. After protection of the alcohols, the remaining carbon atoms of 3 were added by sequential Claisen rearrangements. O-Alkylation with 7 delivered 8, which rearranged with 10:1 diastereoselectivity. After O-allylation, the second Claisen rearrangement led to 9 as the only isolable product. Selective hydroboration of 9 led to 10, which was deprotected, then dehydrated following the Grieco protocol. Functional group manipulation of 11 led to the aldehyde 12, which was condensed with nitromethane to give 13. Direct conjugate addition to 13 gave at best a 1:3 preference for the wrong diastereomer. With a chiral Cu catalyst, this was improved to 5:1 in favor of the desired diastereomer. Ozonolysis of 14 followed by selective reduction of the aldehyde gave the primary alcohol, which was carried onto the iodide. Elimination with DBU then delivered 15, setting the stage for the key intramolecular bond connection. After extensive exploration, it was found that irradiation of 15 in the presence of a catalytic amount of a cobaloxime catalyst and a stoichiometric amount of Hünig’s base gave clean cyclization to 16. The last carbocyclic ring of (+)-daphmanidin E 3 was closed by intramolecular aldol addition of the aldehyde of 17 to the ketone, followed by dehydration. The seemingly simple intramolecular imine formation to prepare the natural product, initially elusive, was effected by heating the ammonium salt in ethanol. The Co-catalyzed cyclization of 15 to 16 is particularly striking.

The Zakarian Synthesis of ( + )-Pinnatoxin A

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Claisen Rearrangement ◽  
Aldol Condensation ◽  
Primary Alcohol ◽  
Allylic Alcohol ◽  
University Of California ◽  
Santa Barbara ◽  
Enantiomerically Pure ◽  
Calcium Channel Activator ◽  
The University ◽  
Nabh4 Reduction

( + )-Pinnatoxin A 3, isolated from the shellfish Pinna muricata, is thought to be a calcium channel activator. A key transformation in the synthesis of 3 reported (J. Am. Chem. Soc . 2008, 130, 3774) by Armen Zakarian, now at the University of California, Santa Barbara, was the diastereoselective Claisen rearrangement of 1 to 2. The alcohol portion of ester 1 was derived from the aldehyde 4, prepared from D-ribose. The absolute configuration of the secondary allylic alcohol was established by chiral amino alcohol catalyzed addition of diethyl zinc to the unsaturated aldehyde 5. The acid portion of the ester 1 was prepared from (S)-citronellic acid, by way of the Evans imide 7. Methylation proceeded with high diasterocontrol, to give 8. Functional group manipulation provided the imide 9. Alkylation then led to 10, again with high diastereocontrol. In each case, care had to be taken in the further processing of the α-chiral acyl oxazolidinones. Direct NaBH4 reduction of 8 delivered the primary alcohol. To prepare the acid 10, the alkylated acyl oxazolidinone was hydrolyzed with alkaline hydrogen peroxide. On exposure of the ester 1 to the enantiomerically-pure base 11, rearrangement proceeded with high diastereocontrol, to give the acid 2. This outcome suggests that deprotonation proceeded to give the single geometric form of the enolate, that was then trapped to give specifically the ketene silyl acetal 12. This elegant approach is dependent on both the ester 1 and the base 11 being enantiomerically pure. The carbocyclic ring of pinnatoxin A 3 was assembled by intramolecular aldol condensation of the dialdehyde 11. This outcome was remarkable, in that 11 is readily epimerizable, and might also be susceptible to β-elimination. Note that the while the diol corresponding to 11 could be readily oxidized to 11 under Swern conditions, attempts to oxidize the corresponding hydroxy aldehyde were not fruitful.

The Smith Synthesis of ( + )-Lyconadin A

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Total Synthesis ◽  
Aldol Condensation ◽  
Primary Alcohol ◽  
Selective Reduction ◽  
Axial Direction ◽  
In Vitro Cytotoxicity ◽  
University Of Pennsylvania ◽  
Enantiomerically Pure ◽  
The University

The pentacyclic alkaloid ( + )-lyconadin A 3, isolated from the club moss Lycopodium complanatum, showed modest in vitro cytotoxicity. A key step in the first reported (J. Am. Chem. Soc. 2007, 129, 4148) total synthesis of 3, by Amos B. Smith III of the University of Pennsylvania, was the cyclization of 1 to 2. The pentacyclic alkaloid (+)-lyconadin A 3, isolated from the club moss Lycopodium complanatum, showed modest in vitro cytotoxicity. A key step in the first reported (J. Am. Chem. Soc. 2007, 129, 4148) total synthesis of 3, by Amos B. Smith III of the University of Pennsylvania, was the cyclization of 1 to 2. The pentacyclic skeleton of 3 was constructed around a central organizing piperidine ring 9. This was prepared from the known (and commercial) enantiomerically-pure lactone 4. The akylated stereogenic center of 9 was assembled by diastereoselective hydroxy methylation of the acyl oxazolidinone 5 with s-trioxane, followed by protection. Reduction of the imide to the alcohol led to the mesylate 7, which on reduction of the azide spontaneously cyclized to give, after protection, the piperidine 8. Selective desilylation of the primary alcohol then enabled the preparation of 9. The plan was to assemble the first carbocyclic ring of 3 by intramolecular aldol condensation of the keto aldehyde 15. The enantiomerically-pure secondary methyl substituent of 15 derived from the commercial monoester 10. Activation as the acid fluoride followed by selective reduction led to the volatile lactone 11. Opening of the lactone with H3CONHCH3HCl gave, after protection, the Weinreb amide 12. Alkylation of the derived hydrazone 13, selectively on the methyl group, led, after deprotection, to 15. The intramolecular aldol condensation of 15 did deliver the unstable cyclohexenone 1. Under the acidic conditions of the aldol condensation, the enol derived from the piperidone added in a Michael sense, from the axial direction on the newly-formed ring, to give the trans-fused bicyclic diketone 2.

The Dixon Synthesis of (-)-Nakadomarin A

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Low Temperature ◽  
Direct Reduction ◽  
Primary Alcohol ◽  
Selective Reduction ◽  
Minor Component ◽  
Enantiomerically Pure ◽  
University Of Oxford ◽  
Nakadomarin A ◽  
The Face ◽  
Diastereoselective Addition

(-)-Nakadomarin A 4, isolated from the sponge Amphimedon sp. off the coast of Okinawa, shows interesting antifungal and antibacterial activity. The key step in the total synthesis of 4 reported (J. Am. Chem. Soc. 2009, 131, 16632) by Darren J. Dixon of the University of Oxford was the diastereoselective addition of the enantiomerically pure ester 1 to the prochiral nitroalkene 2. The assembly of 2 began with the linchpin ketophosphonate 5. Alkylation of the dianion of 5 with allyl bromide followed by direct condensation of the resulting monoanion with the diacetate 6 gave 7. On exposure to aqueous acid, 7 cyclized to the furan. Oxidation of the liberated primary alcohol followed by condensation with nitromethane then completed the preparation of 2. The starting material for the synthesis of 1 was the enantiomerically pure pyroglutamate derivative 8. Sulfide displacement followed by N-alkylation with the bromide 10 delivered 11 . Oxidation followed by deprotection then set the stage for the intramolecular Julia-Kocienski cyclization, which gave 12 with the expected (eight-membered ring) high geometric control. Addition of the ester 1 to Michael acceptors proceeded across the open face of the lactam, but it was still necessary to control the face of the nitro alkene 2 to which the lactam anion added. Catalysis of the addition with the urea 13 delivered 3 with 10:1 diasterocontrol. Mannich condensation of the nitroalkane 3 with formaldehyde and the amine 14 gave the bis-lactam 15, conveniently as a single diastereomer. After free radical removal of the nitro group, it was necessary to achieve selective reduction of the δ-lactam in the presence of the γ-lactam. Low-temperature LiAlH4 was found to be effective. Direct reduction of the resulting hemiaminal with formic acid led to the monolactam 16. The hemiaminal from monoreduction of 16 was found to be unstable and sensitive to overreduction. Nevertheless, exposure of 16 to Dibal at low temperature followed by acid-mediated cyclization delivered the diamine 17. Cyclization of the free base of 17 with the first generation Grubbs catalyst gave (-)-nakadomarin A 4 as the minor component of a 40:60 Z/E mixture. Carrying out the cyclization on the camphorsulfonate salt improved the ratio to 63:37 Z/E.

C-O Ring Containing Natural Products: Paeonilactone B (Taylor), Deoxymonate B (de la Pradilla), Sanguiin H-5 (Spring), Solandelactone A (White), Spirastrellolide A (Paterson)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Oxidative Coupling ◽  
Claisen Rearrangement ◽  
Cyclic Carbonate ◽  
Membered Ring ◽  
State University ◽  
Enantiomerically Pure ◽  
University Of Cambridge ◽  
Spirastrellolide A ◽  
The University ◽  
Oregon State University

Richard J. K. Taylor of the University of York has developed (Angew. Chem. Int. Ed. 2008, 47, 1935) the diasteroselective intramolecular Michael cyclization of phosphonates such as 2. Quenching of the cyclized product with paraformaldehyde delivered ( + )-Paeonilactone B 3. Roberto Fernández de la Pradilla of the CSIC, Madrid established (Tetrahedron Lett. 2008, 49, 4167) the diastereoselective intramolecular hetero Michael addition of alcohols to enantiomerically-pure acyclic sulfoxides such as 4 to give the allylic sulfoxide 5. Mislow-Evans rearrangement converted 5 into 6, the enantiomerically-pure core of Ethyl Deoxymonate B 7. The ellagitannins, represented by 10, are single atropisomers around the biphenyl linkage. David R. Spring of the University of Cambridge found (Organic Lett. 2008, 10, 2593) that the chiral constraint of the carbohydrate backbone of 9 directed the absolute sense of the oxidative coupling of the mixed cuprate derived from 9, leading to Sanguiin H-5 10 with high diastereomeric control. A key challenge in the synthesis of the solandelactones, exemplified by 14, is the stereocontrolled construction of the unsaturated eight-membered ring lactone. James D. White of Oregon State University found (J. Org. Chem. 2008, 73, 4139) an elegant solution to this problem, by exposure of the cyclic carbonate 11 to the Petasis reagent, to give 12. Subsequent Claisen rearrangement delivered the eight-membered ring lactone, at the same time installing the ring alkene of Solandelactone E 14. AD-mix usually proceeds with only modest enantiocontrol with terminal alkenes. None the less, Ian Paterson, also of the University of Cambridge, observed (Angew. Chem. Int. Ed. 2008, 47, 3016, Angew. Chem. Int. Ed. 2008, 47, 3021) that bis-dihydroxylation of the diene 17 proceeded to give, after acid-mediated cyclization, the bis-spiro ketal core 18 of Spirastrellolide A Methyl Ester 19 with high diastereocontrol.

scholarly journals Zinc Chloride Catalyzed Amino Claisen Rearrangement of 1-N-Allylindolines: An Expedient Protocol for the Synthesis of Functionalized 7-Allylindolines

2019 ◽  
Vol 25 (1) ◽  
pp. 22-26 ◽  
Author(s):  
Seema Jain
Keyword(s):  
Zinc Chloride ◽  
Claisen Rearrangement ◽  
Reaction System ◽  
Biologically Active ◽  
Catalyst Loading ◽  
One Pot ◽  
Substitution Pattern ◽  
Claisen Rearrangements ◽  
Lower Temperature ◽  
Molecular Libraries

Abstract7-Allylindolines are valuable synthons for designing biologically active molecular libraries. Lewis acid catalyzed amino-Claisen rearrangement provides a one pot synthetic entry to these heteroarenes. In this context, Zinc chloride (ZnCl2)–N,N-dimethylformamide system efficiently catalyzed amino-Claisen rearrangements of 1-N-allylindolines to 7-allylindolines. The rearrangement is influenced by stereoelectronic effects of substituents present in 1-N-allylindolines. The substrates containing electron donating functionalities underwent rearrangement at lower temperature than substrates with electron withdrawing functional groups. The regioselectivity of the process is governed by the substitution pattern on allyl moiety in 1-N-allylindoline as well as ZnCl2 catalyst loading in the reaction system.

A Metal-free Catalytic Reduction of α,β-unsaturated Carbonyl Compounds with Phenyldimethylsilane

2005 ◽  
Vol 2005 (7) ◽  
pp. 469-470 ◽  
Author(s):  
Ruizhu Mu ◽  
Zhengang Liu ◽  
Zhongquan Liu ◽  
Li Yang ◽  
Longmin Wu ◽  
...  
Keyword(s):  
Ambient Temperature ◽  
Carbonyl Compounds ◽  
Catalytic Reduction ◽  
Selective Reduction ◽  
Catalytic Amount ◽  
Metal Free

Selective reduction of α,β-unsaturated carbonyl compounds to the corresponding saturated ones by phenyldimethyl silane was promoted by a catalytic amount of I2O5 at ambient temperature in CH2Cl2.

Efficient and selective iron-mediated reductive Claisen rearrangement of propargyloxyanthraquinones to anthrafurandiones in ionic liquids

2017 ◽  
Vol 95 (10) ◽  
pp. 1045-1051
Author(s):  
Samaneh Nadali ◽  
Ghasem Aghapour ◽  
Zahra Rafieepour
Keyword(s):  
Ionic Liquids ◽  
Iron Powder ◽  
Rapid Method ◽  
Present Method ◽  
Claisen Rearrangement ◽  
Major Product ◽  
Claisen Rearrangements ◽  
First Time

An efficient and rapid method is described for the reductive Claisen rearrangement of different propargyloxyanthraquinones to anthra[1,2-b]furan-6,11-diones for first time using iron powder in a mixture of two ionic liquids, namely 1-methylimidazolium tetrafluoroborate [Hmim]BF4 and 1-benzyl-3-methylimidazolium chloride [Bzmim]Cl. The present method is able to execute single or double Claisen rearrangements of 1,4- or 1,5-bispropargyloxyanthraquinones selectively, so that the desired anthra(mono)furandiones or anthra(bis)furandiones are produced, respectively, as the major product.

Sequential O-Arylation/Lanthanide(III)-Catalyzed [3,3]-Sigmatropic Rearrangement of Bromo-Substituted Allylic Alcohols

Synlett ◽  
2017 ◽  
Vol 28 (20) ◽  
pp. 2865-2870 ◽  
Author(s):  
Timothy Ramadhar ◽  
Jun-ichi Kawakami ◽  
Robert Batey
Keyword(s):  
Claisen Rearrangement ◽  
Cross Coupling ◽  
Sigmatropic Rearrangement ◽  
Mitsunobu Reaction ◽  
Allylic Alcohols ◽  
Aryl Ether ◽  
Claisen Rearrangements ◽  
Snar Reaction ◽  
Aryl Ethers

Lanthanide(III)-catalyzed aryl-Claisen rearrangement of substrates bearing halo-substituted allyl groups, specifically 2-bromoallyl aryl ethers, afford ortho-2-bromoallylphenols. Aryl ether substrates were synthesized from brominated allylic alcohols via Mitsunobu reaction, Cu(II)-catalyzed arylation using potassium aryltrifluoroborate salts, or SNAr reaction. Aryl-Claisen rearrangements proceeded in moderate to excellent yields using Eu(III) catalysis. The alkenylbromide functionality remains intact, illustrating the compatibility of synthetically important alkenylhalides during C–O/C–C σ-bond migration processes. Subsequent derivatization of the ortho-2-bromoallylphenol products through O-alkylation or C-arylation/alkenylation via Suzuki–Miyaura cross-coupling demonstrate the potential to access densely-functionalized molecules.

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