The Chen Synthesis of (-)-Nakiterpiosin

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Medical Center ◽  
Secondary Alcohol ◽  
Enantiomeric Excess ◽  
Selective Reduction ◽  
Sodium Formate ◽  
Allylic Alcohol ◽  
Silyl Ether ◽  
Synthetic Route ◽  
P388 Leukemia ◽  
Terpios Hoshinota

(-)-Nakiterpiosin 3, isolated from the thin encrusting sponge Terpios hoshinota, has an IC50 against murine P388 leukemia cells of 10 ng/mL. Chuo Chen of UT Southwestern Medical Center developed (J. Am. Chem. Soc. 2010, 132, 371) a practical synthetic route to 3 based on the convergent coupling of 1 and 2. The preparation of 1 was based on the intramolecular [4 + 2] cyclization of the furan 9, prepared by Friedel-Crafts acylation of furan 4 with maleic anhydride 5 . The absolute confi guration of the secondary alcohol was set by Noyori reduction, using sodium formate as the hydride source. The cyclization of 9 to 10 proceeded with high diastereocontrol, presumably by way of a chelated transition state. As expected, cyclization of the silyl ether of 9 delivered the complementary diastereomer. Because the cyclization of 9 was readily reversible, it was taken quickly to the bromide 11. Oxidative cleavage of the diol followed by selective reduction and protection then completed the synthesis of 1. The preparation of 2 began with the commercial bromo acid 12. The enantiomerically enriched epoxide 13 was constructed in the usual way by homologation of the aldehyde to the allylic alcohol followed by Sharpless epoxidation. On exposure to the Yamamoto catalyst, 13 smoothly rearranged to the aldehyde 14. Condensation of 14 with 15 then gave 16, with only minimal erosion of enantiomeric excess over the two steps. Unfortunately, 16 was the incorrect diastereomer, so it had to be inverted. With the aldehyde 17 in hand, conversion to the dichloride followed by functional group interchange completed the construction of 2 . Carbonylative coupling of 1 and 2 led to the enone 18. The photochemical Nazarov cyclization of 18 proceeded with the expected high diastereocontrol, to give, after epimerization, the desired trans-anti-trans product. Deprotection then completed the synthesis of (-)-nakiterpiosin 3. It is noteworthy that the full A-ring functionality of 3 was compatible with the conditions of the photochemical cyclization. The work of Chen toward the total synthesis of (-)-nakiterpiosin 3 led to a correction of the relative configurations both of the dichloromethyl substituent and of the secondary bromide.

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.

Improved synthetic route to enantiomerically pure samples of the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic polyketide herboxidiene

2000 ◽  
Vol 53 (8) ◽  
pp. 659 ◽  
Author(s):  
Martin G. Banwell ◽  
Malcolm D. McLeod ◽  
Rajaratnam Premraj ◽  
Gregory W. Simpson
Keyword(s):  
Natural Product ◽  
Phosphine Oxide ◽  
Enantiomeric Excess ◽  
Allylic Alcohol ◽  
Asymmetric Epoxidation ◽  
Ring Cleavage ◽  
Synthetic Route ◽  
Enantiomerically Pure ◽  
Sharpless Asymmetric Epoxidation ◽  
Ylacetic Acid

The phosphine oxide (2), which embodies the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic polyketide herboxidiene (1) and which is a key intermediate in a projected synthesis of this natural product, has been prepared in a highly enantio- and diastereo-selective manner. The pivotal steps in this new and improved synthesis of compound (2) involve Katsuki–Sharpless asymmetric epoxidation of the allylic alcohol (4) to give epoxide (7) and subsequent ring-cleavage of the latter compound with trimethylaluminium to give diol (9). The derived acetate (10) is then readily ozonolysed to give the previously reported aldehyde (11), although now in high enantiomeric excess. Compound (11) can be elaborated, by established chemistry, to the target oxide (2).

Cinchona Alkaloid-Silyl Ether Derivatives as Organocatalysts for Asymmetric “Interrupted” Feist-Bénary Reaction

2013 ◽  
Vol 864-867 ◽  
pp. 456-459
Author(s):  
Ying Jin ◽  
Sheng Chang ◽  
Tian Yi Zhang ◽  
Bo Feng
Keyword(s):  
Enantiomeric Excess ◽  
Cinchona Alkaloid ◽  
Silyl Ether ◽  
Ethyl Bromopyruvate

Four cinchona alkaloid-silyl ether derivatives have been used to catalyze the asymmetric “interrupted” Feist-Bénary reaction of ethyl bromopyruvate/substituted bromo-ketoesters and 1,3-Cyclohexadione. The corresponding hydroxydihydrofurans have been obtained in excellent yields (85-96%) with high enantiomeric excess (ee) values of up to 90%.

The Keck Synthesis of Epothilone B

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Total Synthesis ◽  
Secondary Alcohol ◽  
Allylic Alcohol ◽  
Ring Closing Metathesis ◽  
Relative Configuration ◽  
University Of Utah ◽  
Epothilone B ◽  
Hydride Reduction ◽  
Epothilone A ◽  
The University

The total synthesis of Epothilone B 4, the first natural product (with Epothilone A) to show the same microtubule-stabilizing activity as paclitaxel (Taxol®), has attracted a great deal of attention since that activity was first reported in 1995. The total synthesis of 4 devised (J. Org. Chem. 2008, 73, 9675) by Gary E. Keck of the University of Utah was based in large part on the stereoselective allyl stannane additions (e.g. 1 + 2 → 3 ) that his group originated. The allyl stannane 2 was prepared from the acid chloride 5. Exposure of 5 to Et3N generated the ketene, that was homologated with the phosphorane 6 to give the allene ester 7. Cu-mediated conjugate addition of the stannylmethyl anion 8 then delivered 2. The silyloxy aldehyde 1 was prepared from the ester 9 by reduction with Dibal. Felkincontrolled 1,2-addition of the allyl stannane 2 established the relative configuration of the secondary alcohol of 3, that was then used to control the relative configuration of the new alcohol in 10. Addition of the crotyl borane 12 to the derived aldehyde 11 also proceeded with high diastereocontrol. The other component of 4 was prepared from the aldehyde 14. Enantioselective allylation, by the method the authors developed, delivered the alcohol 16. The Z trisubstituted alkene was then assembled by condensing the aldehyde 17 with the phosphorane 18. Dibal reduction of the product lactone 19 gave a diol, the allylic alcohol of which was selectively converted to the chloride with the Corey-Kim reagent. Hydride reduction then delivered the desired homoallylic alcohol, that was converted to the phosphonium salt 21. Condensation of 21 with 13 gave the diene, that was carried on to Epothilone B 4. The synthesis of Epothilone B 4 as originally conceived by the authors depended on ring-closing metathesis of the triene 22. They prepared 22, but on exposure to the second-generation Grubbs catalyst it was converted only to 23. The authors concluded that the trans acetonide kept 22 in a conformation that did not allow the desired macrocyclization.

Alkene and Alkyne Metathesis: Phaseolinic Acid (Selvakumar), Methyl 7-Dihydro-trioxacarcinoside B (Koert), Arglabin (Reiser) and Amphidinolide V (Fürstner)

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Organic Synthesis ◽  
Second Generation ◽  
Secondary Alcohol ◽  
Allylic Alcohol ◽  
Alkyne Metathesis ◽  
Max Planck ◽  
Ring Closing Metathesis ◽  
Relative Configuration ◽  
Stereogenic Centers ◽  
Ru Complexes

As N. Selvakumar of Dr. Reddy’s Laboratories, Ltd., Hyderabad approached (Tetrahedron Lett. 2007, 48, 2021) the synthesis of phaseolinic acid 6, there was some concern about the projected cyclization of 2 to 3, as this would involve the coupling of two electron-deficient alkenes. In fact, the Ru-mediated ring-closing metathesis proceeded efficiently. The product unsaturated lactone 3 could be reduced selectively to either the trans product 4 or the cis product 5. There has been relatively little work on the synthesis of the higher branched sugars, such as the octalose 13, a component of several natural products. The synthesis of 13 (Organic Lett. 2007, 9, 4777) by Ulrich Koert of the Philipps-University Marburg also began with a Baylis-Hillman product, the easily-resolved secondary alcohol 8. As had been observed in other contexts, cyclization of the protected allylic alcohol 9a failed, but cyclization of the free alcohol 9b proceeded smoothly. V-directed epoxidation then set the relative configuration of the stereogenic centers on the ring. Ring-closing metathesis to construct tetrasubstituted alkenes has been a challenge, and specially-designed Ru complexes have been put forward specifically for this transformation. Oliver Reiser of the Universität Regensburg was pleased to observe (Angew. Chem. Int. Ed. 2007, 46, 6361) that the second-generation Grubbs catalyst itself worked well for the cyclization of 17 to 18. Again in this synthesis, catalytic V was used to direct the relative configuration of the epoxide. Intramolecular alkyne metathesis is now well-established as a robust and useful method for organic synthesis. It was also known that Ru-mediated metathesis of an alkyne with ethylene could lead to the diene. The question facing (Angew. Chem. Int. Ed . 2007, 46, 5545) Alois Fürstner of the Max-Planck-Institut, Mülheim was whether these transformations could be carried out on the very delicate epoxy alkene 21. In fact, the transformations of 21 to 22 and of 22 to 23 proceeded well, setting the stage for the total synthesis of Amphidinolide V 25.

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 Hoveyda Synthesis of Disorazole C1

2017 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Anticancer Activity ◽  
Vinyl Acetate ◽  
Secondary Alcohol ◽  
Butyl Ester ◽  
Geometric Isomer ◽  
Allylic Alcohol ◽  
Starting Material ◽  
Boston College ◽  
Cross Metathesis ◽  
Disorazole C1

Disorazole C1 3, isolated from fermentation of the myxobacterium Sorangium cellu­losum, shows antifungal and anticancer activity. Amir H. Hoveyda of Boston College applied (J. Am. Chem. Soc. 2014, 136, 16136) recent advances in alkene metathesis from his group to enable the efficient assembly of 2 and so of 3. The ester 1 was assembled from the alcohol 11 and the acid 18. The preparation of 11 began with the enantioselective addition of 5 to 4 to give 6 and then 7, as described by Kalesse (Angew. Chem. Int. Ed. 2010, 49, 1619). Leighton allylation led to 8, that was then coupled with 9 to give 10 with high Z selectivity. Iodination of 10 followed by deprotection then completed the assembly of 11. The starting material for the acid 18 was the allylic alcohol 13. As reported by Cramer (Angew. Chem. Int. Ed. 2008, 47, 6483), exposure of the racemic alcohol 12 to vinyl acetate in the presence of Amano lipase PS converted one enantiomer to the acetate, leaving 13. Methylation of the secondary alcohol followed by acid-mediated removal of the t-butyl ester led to the acid 14, that was converted to the correspond­ing acyl fluoride and coupled with serine Me ester 15 to give 16. After cyclization to the oxazole 17, cross metathesis with five equivalents of 4-bromo-1-butene gave the homoallylic bromide, that was readily eliminated with DBU to give, after saponifica­tion, the acid 18. The cross metathesis of the coupled ester 1, a polyene, with 9 proceeded with remarkable selectivity to give 2, again as the Z geometric isomer. On exposure to the Heck catalyst Pd [(o-tolyl)3P]2, 2 dimerized efficiently. The deprotection was not straightforward, but conditions (H2SiF6, CH3OH, 4°C, 72 h) were found that deliv­ered 3 in 68% yield.

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.

Reactions of Alkenes: The RajanBabu Synthesis of Pseudopterosin G-J Aglycone Dimethyl Ether

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Medical Center ◽  
Selective Reduction ◽  
Oxidative Cleavage ◽  
University Of Texas ◽  
Furman University ◽  
National University ◽  
Institute Of Technology ◽  
Seoul National University ◽  
The University ◽  
Medical University

Xiangge Zhou of Sichuan University showed (Tetrahedron Lett. 2011, 52, 318) that even the monosubstituted alkene 1 was smoothly converted to the methyl ether 2 by catalytic FeCl3. Brian C. Goess of Furman University protected (J. Org. Chem. 2011, 76, 4132) the more reactive alkene of 3 as the 9-BBN adduct, allowing selective reduction of the less reactive alkene to give, after reoxidation, the monoreduced 4. Nobukazu Taniguchi of the Fukushima Medical University added (Synlett 2011, 1308) Na p-toluenesulfinate oxidatively to 1 to give the sulfone 5. Krishnacharya G. Akamanchi of the Indian Institute of Chemical Technology, Mumbai oxidized (Synlett 2011, 81) 1 directly to the bromo ketone 6. Osmium is used catalytically both to effect dihydroxylation, to prepare 8, and to mediate oxidative cleavage, as in the conversion of 7 to the dialdehyde 9. Ken-ichi Fujita of AIST Tsukuba devised (Tetrahedron Lett. 2011, 52, 3137) magnetically retrievable osmium nanoparticles that can be reused repeatedly for the dihydroxylation. B. Moon Kim of Seoul National University established (Tetrahedron Lett. 2011, 52, 1363) an extraction scheme that allowed the catalytic Os to be reused repeatedly for the oxidative cleavage. Maurizio Taddei of the Università di Siena showed (Synlett 2011, 199) that aqueous formaldehyde could be used in place of Co/H2 (syngas) for the formylation of 1 to 10. Hirohisa Ohmiya and Masaya Sawamura of Hokkaido University prepared (Org. Lett. 2011, 13, 1086) carboxylic acids (not illustrated) from alkenes using CO2. Joseph M. Ready of the University of Texas Southwestern Medical Center selectively arylated (Angew. Chem. Int. Ed. 2011, 50, 2111) the homoallylic alcohol 11 to give 12. Many reactions of alkenes are initiated by hydroboration, then conversion of the resulting alkyl borane. Hiroyuki Kusama of the Tokyo Institute of Technology photolyzed (J. Am. Chem. Soc. 2011, 133, 3716) 14 with 13 to give the ketone 15. William G. Ogilvie of the University of Ottawa added (Synlett 2011, 1113) the 9-BBN adduct from 1 to 16 to give 17. Professors Ohmiya and Sawamura effected (Org. Lett. 2011, 13, 482) a similar conjugate addition, not illustrated, of 9-BBN adducts to α,β-unsaturated acyl imidazoles.

1,3-Dioxan-5-ones: synthesis, deprotonation, and reactions of their lithium enolates

1995 ◽  
Vol 73 (10) ◽  
pp. 1616-1626 ◽  
Author(s):  
Marek Majewski ◽  
D. Mark Gleave ◽  
Pawel Nowak
Keyword(s):  
Enantiomeric Excess ◽  
Addition Reactions ◽  
Synthetic Route ◽  
Enol Ethers ◽  
Lithium Amide ◽  
Silyl Enol Ethers ◽  
Lithium Amides ◽  
Alkyl Groups ◽  
Lithium Enolates ◽  
Enantioselective Deprotonation

A general synthetic route to 2-alkyl- and 2,2-dialkyl-1,3-dioxan-5-ones, using tris(hydroxymethyl)-nitromethane as the starting material, is described. Deprotonation of these compounds was studied. It was established that these dioxanones could be deprotonated with LDA; however, the reduction of the carbonyl group via a hydride transfer from LDA, giving the corresponding dioxanols, often competed with deprotonation. The reduction could be minimized by using Corey's internal quench procedure to form silyl enol ethers and was less pronounced in 2,2-dialkyldioxanones (ketals) than in 2-alkyldioxanones (acetals). Self-aldol products were observed when dioxanone lithium enolates were quenched with H2O. Addition reactions of lithium enolates of dioxanones to aldehydes were threo-selective as predicted by the Zimmerman–Traxler model. Dioxanones having two different alkyl groups at the 2-position were deprotonated enantioselectively by chiral lithium amide bases with enantiomeric excess (ee) of up to 70%. Keywords: 1,3-dioxan-5-ones, enantioselective deprotonation, chiral lithium amides.

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