The Ding Synthesis of Steenkrotin A

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Intramolecular Cyclization ◽  
Aldol Condensation ◽  
Secondary Alcohol ◽  
Folk Medicine ◽  
Equilibrium Concentration ◽  
Membered Ring ◽  
Silyl Ether ◽  
Enol Ether ◽  
Bond Forming ◽  
Open Face

Steenkrotin A 3 was isolated from Croton steenkampianus Gerstner, widely used in folk medicine for the treatment of coughs, fever, malaria, and rheumatism. Hanfeng Ding of Zhejiang University envisioned (Angew. Chem. Int. Ed. 2015, 54, 6905) that the intriguingly compact core of 3 could be assembled by reductive cyclization of the alde­hyde 1 to 2, followed by intramolecular aldol condensation. The diastereoselective assembly of 1 from the cycloheptenone core 4 depended on the conformational preferences of the seven-membered ring. Enol ether forma­tion followed by Rubottom oxidation led to the silyl ether 5. Oxidative rearrange­ment of the tertiary alcohol generated by 1,2-addition to 5 of in situ generated allyl lithium established the enone 6. Again taking advantage of the conformational pref­erence of the seven-membered ring, cyclopropanation of the silyl enol ether derived from 6 proceeded across the open face of the electron-rich alkene to give 7. The other oxygenated quaternary center of 1 was constructed by O-alkylation of 7 with diazo malonate followed by methylation and reduction. Acetylation of the diol 8 proceeded with 10:1 diastereoselectivity, to give, after oxidation, the aldehyde 9. In the first of a sequence of three intramolecular bond-forming reactions, HF.py cyclized the aldehyde onto the endocyclic alkene, and also freed the alcohol, that was alkylated with the dibromide 10 to give 11 as a 1.5:1 mixture of diastereomers. On exposure to SmI2, the major diastereomer cyclized to give a intermediate that was carried on to 1. The minor diastereomer was merely reduced, to a product that could be recycled to 11. With 1 in hand, the stage was set for the second intramolecular cyclization. Even though 1 was predominantly in the lactol form, there was enough of an equilibrium concentration of aldehyde present for the SmI2-mediated cyclization to proceed smoothly to 2. With 2 in hand, in addition to the last intramolecular cyclization, the two stereo­genic centers (marked by an asterisk) had to be inverted. The methyl group adjacent to the ketone was readily equilibrated. The secondary alcohol could be inverted by late-stage oxidation and reduction, and the authors did do that. However, they also observed a small amount of the desired epimeric alcohol 14 from the intramolecu­lar aldol condensation of 12.

The Procter Synthesis of (+)-Pleuromutilin

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Aldol Condensation ◽  
Secondary Alcohol ◽  
Primary Alcohol ◽  
Conjugate Addition ◽  
Alkoxy Group ◽  
Membered Ring ◽  
Allylic Alcohol ◽  
Silyl Ether ◽  
Radical Reduction ◽  
The University

The fungal secondary metabolite (+)-pleuromutilin 3 exerts antibiotic activity by binding to the prokaryotic ribosome. Semisynthetic derivatives of 3 are used clinically. The central step of the first synthesis of (+)-pleuromutilin 3, devised (Chem. Eur. J. 2013, 19, 6718) by David J. Procter of the University of Manchester, was the SmI2-mediated reductive closure of 1 to the tricyclic 2. The starting material for the synthesis was the inexpensive dihydrocarvone 4. Ozonolysis and oxidative fragmentation following the White protocol delivered 5 in high ee. Conjugate addition with 6 followed by Pd-mediated oxidation of the resulting silyl enol ether gave the enone 7. Subsequent conjugate addition of 8 proceeded with modest but useful diastereoselectivity to give an enolate that was trapped as the triflate 9. The Sakurai addition of the derived ester 10 with 11 led to 12 and so 1 as an inconsequential 1:1 mixture of diastereomers. The SmI2-mediated cyclization of 1 proceeded with remarkable diastereocontrol to give 2. SmI2 is a one-electron reductant that is also a Lewis acid. It seems likely that one SmI2 bound to the ester and the second to the aldehyde. Electron transfer then led to the formation of the cis-fused five-membered ring, with the newly formed alkoxy constrained to be exo to maintain contact with the complexing Sm. Intramolecular aldol condensation of the resulting Sm enolate with the other aldehyde then formed the six-membered ring, with the alkoxy group again constrained by association with the Sm. Hydrogenation of 13 gave 14, which could be brought to diastereomeric purity by chromatography. Elegantly, protection of the ketone simultaneously selectively deprotected one of the two silyl ethers, thus differentiating the two secondary alcohols. Reduction of the ester to the primary alcohol then delivered the diol 15. Selective esterification of the secondary alcohol followed by thioimidazolide formation and free radical reduction completed the preparation of 16. Ketone deprotection followed by silyl ether formation and Rubottom oxidation led to the diol 17. Protection followed by the addition of 18 and subsequent hydrolysis and reduction gave the allylic alcohol 19.

The Smith Synthesis of (−)-Calyciphylline N

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Secondary Alcohol ◽  
Primary Alcohol ◽  
Diels Alder ◽  
University Of Pennsylvania ◽  
Silyl Ether ◽  
Direct Oxidation ◽  
The Third ◽  
Secondary Center ◽  
Open Face ◽  
The University

The Daphniphyllum alkaloids are a diverse group, some of which exhibit potent bio­logical activity. Amos B. Smith III of the University of Pennsylvania envisioned (J. Am. Chem. Soc. 2014, 136, 870) the preparation of the bicyclo[2.2.2] core of (−)-calyciphylline N 3 by the intramolecular Diels–Alder cyclization of 1 to 2, with the silicon of 2 a surrogate for the secondary alcohol of 3. Following the precedent of Mori (Tetrahedron Asymm. 2005, 16, 685), the requi­site secondary center of 1 was set by methylation of the anion derived from the Evans acyl oxazolidinone 4. Reductive removal of the oxazolidinone led to the alcohol 5, that was reduced under Birch conditions, then isomerized with base to the desired conjugated diene 6. This was silylated with the alkenyl silane 7 to give the triene 1. Direct thermal cyclization of 1 gave a mixture of all four possible diastereomers of the cycloadduct. Fortunately, the Lewis acid-activated cyclization delivered 2 as the dominant diastereomer. To differentiate the two ends of the alkene, the ester of 2 was extended to the alco­hol 8. Epoxidation occurred from the more open face of the alkene, setting the stage for intramolecular opening and oxidation to give 9. Reduction with SmI2 and protec­tion then completed the preparation of the ketone 10. The third quaternary center of 3 was constructed by acetylation of 10 followed by Pd-catalyzed allylation, to give 11. On exposure to LDA, the derived iodide 12 smoothly cyclized to the cycloheptanone 13, the structure of which was confirmed by X-ray analysis. The alkene of 13 was converted to the primary alcohol, which was protected. The aryl lithium 14 then was used to selectively open the cyclic silyl ether, to give 15. Coupling with phthalimide followed by carbonylative vinylation of the derived vinyl triflate delivered the dienone 16. Exposure to HBF4 effected the desired Nazarov cyclization, and at the same time converted the aryl silane to the fluorosilane, set for the Tamao oxidation that revealed the secondary alcohol. The two alcohols were sequentially protected to give 17. Direct oxidation of the primary silyl ether gave the aldehyde.

The Nicolaou/Li Synthesis of Tubingensin A

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Aldol Condensation ◽  
Physiological Activity ◽  
Secondary Alcohol ◽  
Hydroxyl Group ◽  
Hydroxy Ketone ◽  
Magnesium Bromide ◽  
Enol Ether ◽  
Quaternary Centers ◽  
Silyl Enol Ether ◽  
Aspergillus Sp

The complex indole diterpene alkaloids, isolated both from Aspergillus sp. and from Eupenicillium javanicum, display a wide range of physiological activity. K.C. Nicolaou of Scripps/La Jolla and Ang Li, now at the Shanghai Institute of Organic Chemistry, conceived (J. Am. Chem. Soc. 2012, 134, 8078) a divergent strategy for the assembly of these alkaloids that enabled syntheses of both anominine (not illustrated) and tubingensin A 3. A key step in the assembly of the carbocyclic skeleton of both alkaloids was the radical cyclization of 1 to 2, establishing the second of the two alkylated quaternary centers of 3. The starting point for the preparation of 1 was commercial pulegone 4. Methylation followed by acid-mediated retro aldol condensation delivered the enantiomerically pure 2,3-dimethyl cyclohexanone 5. To maximize yield, the subsequent Robinson annulation was carried out over three steps, formation of the silyl enol ether, condensation of the enol ether with methyl vinyl ketone 6, and base-mediated cyclization and dehydration of the 1,5-diketone to give 7. The secondary hydroxyl group was introduced by exposure to Oxone of the methyl dienol ether derived from 7. The mixture of diastereomers from the radical Ueno-Stork cyclization of 1 was equilibrated to the more stable 2 by exposure to acid. The authors took advantage of the regioselective enolization of 2, preparing the silyl enol ether, which could then be condensed with formaldehyde to give 10. This hydroxy ketone was carried onto 11 over four steps, commencing with silylation and proceeding through Wittig condensation, desilylation, and oxidation. The addition of the Grignard reagent 12 to the aldehyde 11 gave a secondary alcohol, which was readily dehydrated to the diene 13. The diene resisted thermal cyclization, but on exposure to CuOTf at room temperature it was smoothly cyclized and oxidized to 14. The elaboration of the sidechain had already been worked out in the anominine synthesis. The free lactol derived from 14 resisted many nucleophiles, but vinyl magnesium bromide did add. Bis acetylation of the resulting diol followed by Pd-mediated ionization and reduction of the allylic acetate, and reductive removal of the residual acetate, delivered the terminal alkene 15. Metathesis with isobutylene gave 16, which was deprotected to give tubingensin A 3.

scholarly journals Syn-selective silicon Mukaiyama-type aldol reactions of (pentafluoro-λ6-sulfanyl)acetic acid esters with aldehydes

2018 ◽  
Vol 14 ◽  
pp. 373-380 ◽  
Author(s):  
Anna-Lena Dreier ◽  
Andrej V Matsnev ◽  
Joseph S Thrasher ◽  
Günter Haufe
Keyword(s):  
Acetic Acid ◽  
Aldol Condensation ◽  
Aldol Reactions ◽  
Complex Structures ◽  
Bond Forming ◽  
Hydroxyalkanoic Acid ◽  
Mukaiyama Aldol ◽  
Substituted Benzaldehydes ◽  
Acetic Acid Esters ◽  
Acid Esters

Aldol reactions belong to the most frequently used C–C bond forming transformations utilized particularly for the construction of complex structures. The selectivity of these reactions depends on the geometry of the intermediate enolates. Here, we have reacted octyl pentafluoro-λ6-sulfanylacetate with substituted benzaldehydes and acetaldehyde under the conditions of the silicon-mediated Mukaiyama aldol reaction. The transformations proceeded with high diastereoselectivity. In case of benzaldehydes with electron-withdrawing substituents in the para-position, syn-α-SF5-β-hydroxyalkanoic acid esters were produced. The reaction was also successful with meta-substituted benzaldehydes and o-fluorobenzaldehyde. In contrast, p-methyl-, p-methoxy-, and p-ethoxybenzaldehydes led selectively to aldol condensation products with (E)-configured double bonds in 30–40% yields. In preliminary experiments with an SF5-substituted acetic acid morpholide and p-nitrobenzaldehyde, a low amount of an aldol product was formed under similar conditions.

scholarly journals Five-membered ring annelation in [2.2]paracyclophanes by aldol condensation

2014 ◽  
Vol 10 ◽  
pp. 2021-2026 ◽  
Author(s):  
Henning Hopf ◽  
Swaminathan Vijay Narayanan ◽  
Peter G Jones
Keyword(s):  
Structural Analysis ◽  
Spectroscopic Data ◽  
Acid Treatment ◽  
Aldol Condensation ◽  
Membered Ring ◽  
X Ray

Under basic conditions 4,5,12,13-tetraacetyl[2.2]paracyclophane (9) cyclizes by a double aldol condensation to provide the two aldols 12 and 15 in a 3:7 ratio. The structures of these compounds were obtained from X-ray structural analysis, spectroscopic data, and mechanistic considerations. On acid treatment 12 is dehydrated to a mixture of the condensed five-membered [2.2]paracyclophane derivatives 18–20, whereas 15 yields a mixture of the isomeric cyclopentadienones 21–23. The structures of these elimination products are also deduced from X-ray and spectroscopic data. The sequence presented here constitutes the simplest route so far to cyclophanes carrying an annelated five-membered ring.

scholarly journals Addition of lithiated enol ethers to nitrones and subsequent Lewis acid induced cyclizations to enantiopure 3,6-dihydro-2H-pyrans – an approach to carbohydrate mimetics

2010 ◽  
Vol 6 ◽  
Author(s):  
Fabian Pfrengle ◽  
Hans-Ulrich Reissig
Keyword(s):  
Lewis Acid ◽  
Functional Group ◽  
Tricarboxylic Acid ◽  
Membered Ring ◽  
Enol Ether ◽  
Enol Ethers ◽  
Acidic Conditions ◽  
Hydroxylamine Derivatives

A stereodivergent synthesis of enantiopure 3,6-dihydro-2H-pyrans is presented. The addition of lithiated enol ethers to carbohydrate-derived nitrones afforded syn- or anti-configured hydroxylamine derivatives 4a–d that were cyclized under Lewis acidic conditions to yield functionalized dihydropyrans cis- or trans-5a–d containing an enol ether moiety. This functional group was employed for a variety of subsequent reactions such as dihydroxylation or bromination. Bicyclic enol ether 19 was oxidatively cleaved to provide the highly functionalized ten-membered ring lactone 20. The synthesized enantiopure aminopyrans 24, 26, 28 and 30 can be regarded as carbohydrate mimetics. Trimeric versions of 24 and 28 were constructed via their attachment to a tricarboxylic acid core.

The Burke Synthesis of ( + )-Didemniserinolipid B

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
First Generation ◽  
Secondary Alcohol ◽  
Unsaturated Ester ◽  
Unsaturated Ketone ◽  
Grubbs Catalyst ◽  
University Of Wisconsin ◽  
Set Up ◽  
Open Face ◽  
Vinyl Group ◽  
The University

The sulfate ( + )-didemniserinolipid B 3, isolated from the tunicate Didemnum sp, has an intriguing spiroether core. A key step in the synthesis of 3 reported (Organic Lett. 2007, 9, 5357) by Steven D. Burke of the University of Wisconsin was the selective ring-closing metathesis of 1 to 2. The diol 6 that was used to prepare the ketal 1 was readily prepared from the inexpensive D-mannitol 4. Many other applications can be envisioned for the enantiomerically-pure diol 6 and for the monoacetate and bis acetate that are precursors to it. To set up the metathesis, the β, γ-unsaturated ketone 10 was needed. To this end, the keto phosphonate derived from the addition of the phosphonate anion 8 to the lactone 7 was condensed with phenyl acetaldehyde 9. The derived enone 10 was a 5:1 mixture of β, γ- and α, β-regioisomers. The diol 6 is C2 -symmetrical, but formation of the ketal 1 dissolved the symmetry, with one terminal vinyl group directed toward the styrene double bond, and the other directed away from it. On exposure to the first generation Grubbs catalyst, ring formation proceeded efficiently, to give 2. Williamson coupling with the serine-derived alcohol 11 then gave 12. To establish the secondary alcohol of 13 and so of 3, the more electron rich alkene of 12 was selectively epoxidized, from the more open face. Diaxial opening with hydride then gave 13. With 13 in hand, another challenge of selectivity emerged. The plan had been to attach the ester-bearing sidechain to 13 using alkene metathesis, then hydrogenate. As the side-chain of 3 contained an additional alkene, this had to be present in masked form. To this end, the α-phenylselenyl ester 14 was prepared. Alkene metathesis with 13 proceeded smoothly, this time using the second generation Grubbs catalyst. The unwanted alkene was then removed by reduction with diimide, and the selenide was oxidized to deliver the α, β-unsaturated ester.

Protecting Groups

2008 ◽  
Author(s):  
Jie Jack Li ◽  
Chris Limberakis ◽  
Derek A. Pflum
Keyword(s):  
Low Temperature ◽  
Organic Synthesis ◽  
Secondary Alcohol ◽  
Primary Alcohol ◽  
Protecting Groups ◽  
Silyl Ether ◽  
Benzyl Ether ◽  
Protecting Group ◽  
Selective Protection ◽  
Death Taxes

In his book, Protecting Groups, Philip J. Kocieński stated that there are three things that cannot be avoided: death, taxes, and protecting groups. Indeed, protecting groups mask functionality that would otherwise be compromised or interfere with a given reaction, making them a necessity in organic synthesis. In this chapter, for each protecting group showcased, only the most widely used methods for protection and cleavage are shown. Also, this section is not comprehensive and only addresses some of the most common blocking groups in organic synthesis. For a thorough review of protecting groups, the reader should consult the following references: (a) Wuts, P. G. M.; Greene, T. W.; Protective Groups in Organic Synthesis, 4th ed.; Wiley: Hoboken, NJ, 2007; (b) Kocienski, P. J. Protecting Groups, 3rd edition.; Thieme: Stuggart, 2004. In this section, the formation and cleavage of eight protecting groups for alcohols and phenols are presented: acetate; acetonides for diols; benzyl ether; para-methoxybenzyl (PMB) ether; methyl ether; methoxymethylene (MOM) ether; tert-butyldiphenylsilyl (TBDPS) silyl ether; and tetrahydropyran (THP). Acetate is a convenient protecting group for alcohols—easy on and easy off. Selective protection of a primary alcohol in the presence of a secondary alcohol can be achieved at low temperature. The drawback of this protecting group is its incompatibility with hydrolysis and reductive conditions.

The Baran Synthesis of Ingenol

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Claisen Rearrangement ◽  
Secondary Alcohol ◽  
Cyclic Carbonate ◽  
The Other ◽  
Magnesium Bromide ◽  
Pseudomonas Cepacia ◽  
Pinacol Rearrangement ◽  
Pseudomonas Cepacia Lipase ◽  
La Jolla ◽  
Open Face

The early promise for the biological activity of the derivatives of ingenol 3 has been borne out by the clinical efficacy of the derived angelate, recently approved by the US Food and Drug Administration for the treatment of actinic keratosis. Phil S. Baran of Scripps La Jolla envisioned (Science 2013, 341, 878) a route to 3 based on a rearrange­ment of 2, available by the Pauson–Khand cyclization of the allenyl alkyne 1. One of the partners for the preparation of 1 was available following the Sugai (Synlett 1997, 1297) procedure, by the Claisen rearrangement of triethyl orthopro­pionate 5 with the propargyl alcohol 4 to give 6. Reduction delivered a racemic mix­ture of alcohols. On exposure of the mixture to vinyl acetate and Pseudomonas cepacia lipase, the undesired enantiomer was selectively acetylated to 7, leaving residual 8 of high ee. IBX was found by the Scripps group to be effective at oxidizing 8 without racemization. The other component of 1 was prepared from the inexpensive (+)-3-carene 10. Chlorination followed by ozonolysis delivered 11, that was reduced to the enolate, then alkylated with methyl iodide. Exposure to LiHMDS gave a new enolate, that was added to the aldehyde 9 to give 12. Addition of ethynyl magnesium bromide to the now more open face of 12 proceeded with high diastereoselectivity. Selective silylation of the secondary alcohol followed by silylation of the tertiary alcohol set the stage for the Pauson–Khand cyclization. Following the Brummond protocol, 1 was cyclized to 2. Methyl magnesium bro­mide was added, again to the more open face of the ketone, to give a new tertiary alco­hol. Exposure to stoichiometric OsO4 converted the more available alkene to the cis diol, that was protected as its cyclic carbonate 13. A central challenge in the total synthesis of the ingenanes is the construction of the “inside–outside” skeleton. This was achieved by the pinacol rearrangement of 13 with BF3•OEt2, to give 14. All that remained to complete the synthesis was selective oxidation. Allylic oxi­dation with stoichiometric SeO2 installed the secondary alcohol, that was acety­lated to give 15. The other secondary alcohol was then freed, and dehydrated with the Martin sulfurane, to give 16. A last allylic oxidation completed the synthesis of ingenol 3.

scholarly journals Sugar-derived oxazolone pseudotetrapeptide as γ-turn inducer and anion-selective transporter

2019 ◽  
Vol 15 ◽  
pp. 2419-2427
Author(s):  
Sachin S Burade ◽  
Sushil V Pawar ◽  
Tanmoy Saha ◽  
Navanath Kumbhar ◽  
Amol S Kotmale ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Amino Acid ◽  
Molecular Modeling ◽  
Intramolecular Cyclization ◽  
Membered Ring ◽  
Conformational Study ◽  
Oxazole Ring ◽  
Solution State ◽  
Modeling Studies ◽  
Molecular Modeling Studies

The intramolecular cyclization of a C-3-tetrasubstituted furanoid sugar amino acid-derived linear tetrapeptide afforded an oxazolone pseudo-peptide with the formation of an oxazole ring at the C-terminus. A conformational study of the oxazolone pseudo-peptide showed intramolecular C=O···HN(II) hydrogen bonding in a seven-membered ring leading to a γ-turn conformation. This fact was supported by a solution-state NMR and molecular modeling studies. The oxazolone pseudotetrapeptide was found to be a better Cl−-selective transporter for which an anion–anion antiport mechanism was established.

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