Radical Hydrostannation Research Articles

EPR evidence for α-triphenylstannylvinyl radicals in the O-directed hydrostannation of dialkylacetylenes with Ph3SnH/cat. Et3B/O2.

Here we provide definitive EPR evidence for the existence of α-triphenylstannylvinyl radicals in the low temperature O-directed free radical hydrostannation of dialkyl propargylic alcohols with Ph3SnH/cat. Et3B and O2 in PhMe. Isotropic hyperfine splitting patterns and spectral simulations confirm the assignments made. In the case of the α-triphenylstannylvinyl radical (Z)-2, an isotopic 119/117Sn hyperfine coupling constant of 9.5 mT (95 G) was measured along with a 1Hβ hyperfine coupling constant of 1.1 mT.

The stannylvinyl cation that never was! New concentration- and temperature-dependent probe studies confirm an entirely free radical mechanism and O–Sn coordinative control of the hydrostannation of propargylically-oxygenated dialkyl acetylenes with stannanes and cat. Et3B

O-Directed free radical hydrostannation of the β-cyclopropyl propargyl alcohol 57 with stannanes and cat. Et3B in THF/H2O or PhMe/MeOH failed to deliver any of the expected products of α-stannylvinyl cation capture. Instead only α-stannyl-β-cyclopropylvinyl radical intermediates were detected, which underwent fast H-atom abstraction and/or cyclopropane ring-opening as a result of eliminative β-scission. A second alkynol probe 23 was also studied in this O-directed free radical hydrostannation process. It gave rise to an α:β stannyl radical addition regiochemistry that changed markedly in favor of the α-adduct (26) when the reaction was conducted at high stannane concentrations. This outcome confirmed that O–Sn coordinative control must be responsible for the strong α-regiochemical preference of hydrostannations run at higher stannane concentrations, since a non-coordinative, electronically-controlled, stannyl radical addition would always give rise to a fixed and identical ratio of α:β-regioisomers. The formation of 27 further confirmed the exclusively free radical nature of these reactions.

Fast ring-opening of an intermediary α-stannyl-β-cyclopropylvinyl radical does not support formation of an α-stannylvinyl cation in the O-directed free radical hydrostannation of dialkyl acetylenes.

O-directed hydrostannation of β-cyclopropyl propargyl alcohol 22 with stannanes and cat. Et3B in THF/H2O or PhMe/MeOH fails to deliver any detectable products of α-stannylvinyl cation capture. Instead only α-stannyl-β-cyclopropylvinyl radical intermediates can be detected, which undergo fast H-atom abstraction and/or cyclopropane ring-opening as a result of eliminative β-scission.

The O‐Directed Free Radical Hydrostannation of Propargyloxy Dialkyl Acetylenes with Ph3SnH/cat. Et3B. A Refutal of the Stannylvinyl Cation Mechanism

In this Personal Account, we will give an overview of the room temperature O-directed free radical hydrostannation reaction of propargylically-oxygenated dialkyl acetylenes with Ph3 SnH and catalytic Et3 B/O2 in PhMe. We will show how this excellent reaction evolved, and how it has since been used to stereoselectively construct the complex trisubstituted olefin regions of three synthetically challenging natural product targets: (+)-pumiliotoxin B, (-)-(3R)-inthomycin C, and (+)-acutiphycin. Throughout this Account, we will pay special attention to highlighting important facets of the I-SnPh3 exchange processes that have so far been used in the various different steric settings that we have addressed, and we will document the range of cross coupling protocols that have critically underpinned the first successful applications of this method in complex natural product total synthesis. Last, but not least, we will comment on various aspects of the O-directed free radical hydrostannation mechanism that have been published by ourselves, and others, and we will discuss all of the factors that can contribute to the observed stereo-and regio-chemical outcomes. We will also challenge and refute the recent non-directed stannylvinyl cation mechanism put forward by Organ, Oderinde and Froese for our reaction, and we will show how it cannot be operating in these exclusively free radical hydrostannations.

Synthesis and reactivity of β-stannylated phenylalanines

Abstract The free radical hydrostannation of a series of N-benzoyl and N-acetyl dehydrophenylalanine esters 2a – h yields β-stannylated phenylalanine derivatives 3 and 4. This addition of tin hydride to such unsaturated compounds simultaneously creates two new chiral centers leading to mixtures of two diastereomeric pairs of enantiomers. The reaction of 3-stannylated phenylalanine 3 with methanolic HCl yields chlorostannyl-substituted compounds 5 and 6 and, with one equivalent of bromine, the bromostannylated compounds 7 and 8 are formed. The bromostannylated phenylalanine derivative 7 reacts with one further equivalent of bromine to produce the dibromostannylated compound 9. Even the chlorostannylated phenylalanine derivative 5 reacts with one further equivalent of HCl to give the dichlorostannylated compound 10. The products were characterized by elemental analysis, infrared (IR), and multinuclear (1H, 13C, 119Sn) nuclear magnetic resonance (NMR) spectroscopy. Attempts were made to assign the preferred conformation of the stannylated phenylalanine derivatives using Karplus-type relationship of coupling constants 3 J(H,H), 3 J(Sn,H), and 3 J(Sn,C=O). The results of these analyses have been confirmed by three crystal structure determinations.

Unusual reaction behavior of gem-difluorocyclopropane derivatives: stereoselective synthesis of β-monofluoroallylic alcohols, ethers, esters, and amide.

On treating gem-difluorocyclopropylstannanes, derived from the radical hydrostannation of gem-difluorocyclopropenes, with 1.5 equiv of MeLi in THF at -78 °C for 5 min, followed by quenching the reaction with various agents, such as H2O, alcohols, carboxylic acids, and tosylamide, the corresponding β-fluoroallylic alcohols, ethers, esters, and amide were obtained with exclusive Z-selectivity in acceptable yields.

ChemInform Abstract: Asymmetric Total Synthesis of (+)‐Inthomycin C via O‐Directed Free Radical Alkyne Hydrostannation with Ph3SnH and Catalytic Et3B: Reinstatement of the Zeeck—Taylor (3R)‐Structure for (+)‐Inthomycin C.

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (−)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive interaction could interfere. Our stereochemical studies on the alkynol (−)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyama’s (3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and Taylor’s original (3R)-stereostructure for (+)-inthomycin C is correct.

Synthesis of the C(7)–C(22) Sector of (+)-Acutiphycin via O-Directed Double Free Radical Alkyne Hydrostannation with Ph3SnH/Et3B, Double I–Sn Exchange, and Double Stille Coupling

Herein a new double O-directed free radical hydrostannation reaction is reported on the structurally complex dialkyldiyne 11. Through our use of a conformation-restraining acetal to help prevent stereocenter-compromising 1,5-H-atom abstraction reactions by vinyl radical intermediates, the two vinylstannanes of 10 were concurrently constructed with high stereocontrol using Ph3SnH/Et3B/O2. Distannane 10 was thereafter elaborated into the bis-vinyl iodide 9 via O-silylation and double I-Sn exchange; double Stille coupling of 9, O-desilylation, and oxidation thereafter furnished 8.

Asymmetric Total Synthesis of (+)-Inthomycin C via O-Directed Free Radical Alkyne Hydrostannation with Ph3SnH and Catalytic Et3B: Reinstatement of the Zeeck–Taylor (3R)-Structure for (+)-Inthomycin C

A new pathway to (+)-inthomycin C is reported that exploits an O-directed free radical hydrostannation reaction on (-)-12 and a Stille cross-coupling as key steps. Significantly, the latter process was effected on 19 where a gauche-pentane repulsive interaction could interfere. Our stereochemical studies on the alkynol (-)-12 and the enyne (+)-7 confirm that Ryu and Hatakeyama's (3S)-stereochemical revision of (+)-inthomycin C is invalid and that Zeeck and Taylor's original (3R)-stereostructure for (+)-inthomycin C is correct.

Synthesis of dineophyltin dihydride and stereoselective hydrostannation of alkynes and (E)-trisubstituted alkenes

This paper reports the synthesis of dineophyltin dihydride ( 3) following two procedures. The four steps synthesis starting from benzyl chloride and Sn was shown to be more convenient than the two step direct alkylation of SnCl 4. The study of the free radical hydrostannation of mono- and disubstituted acetylenes with hydride 3 shows that they are stereoselective and that the stereoisomers obtained in higher proportion are stable and easily separated by column chromatography. Some preliminary studies on the chemical reactivity of the new divinylsubstituted dineophyltin compounds in Stille reactions are also informed. Radical hydrostannatation of (E)-trisubstituted ethylenes with 3 did not succeed probably due to steric factors. The preparation of dineophyltin bromohydride ( 27) is also reported. Radical addition of 27 to methyl (E)-2,3-disubstituted propenoates leads to mixtures of the corresponding erythro and threo adducts in diastereomeric excesses (d.e.) in the range of 74–90%.

Enantioselective formal total synthesis of the Dendrobatidae frog toxin, (+)-pumiliotoxin B, via O-directed alkyne free radical hydrostannation

Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkylacetylenes (with Ph 3SnH and Et 3B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate the great utility of this process in a complex natural product total synthesis setting for the very first time. We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Overman’s pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of preparative HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original synthesis of 9.

ChemInform Abstract: Stereoselective Hydrostannation: Synthesis and Absolute Configuration of (-)-Menthyl 2,3-Diphenyl-3-(trimethylstannyl) Propanoates and Derivatives.

Abstract Free radical hydrostannation of (−)-menthyl ( E )-2,3-diphenylpropenoate ( 1 ) leads to a mixture of four adducts: two threo diastereoisomers (approx. 90%) and two erythro diastereoisomers (approx. 10%). Whereas threo diastereoisomers 2 (38%) and 3 (51.2%) could be isolated by column chromatography and fractional recrystallization, erythro diastereoisomers 4 and 4′ (6.5% and 4.3%) could not be separated. Bromodestannylation of 2 and 3 yielded two diastereoisomers in each case, 9–10 and 11–12 , respectively, which were isolated and characterized by spectroscopic methods. The reduction of bromo esters 9–12 with lithium aluminium hydride gave ( R )-(−)- and ( S )-(+)-2,3-diphenyl propanols 13 and 14 of known absolute configuration. Working back from the stereochemistry of 13 and 14 and taking into account the NMR data, the stereochemistry of their precursors was assigned. Full 1 H, 13 C, and 119 Sn NMR data are given.

Stereoselective hydrostannation of substituted alkynes initiated by triethylborane and reactivity of bulky triorganotin hydrides

This paper reports the results obtained in a study on the radical hydrostannation of mono- and disubstituted alkynes with bulky triorganotin hydrides using triethylborane as initiator. The addition of trineophyl- ( 1), tris[(phenyldimethylsilyl)methyl]- ( 2), and 9-tripticyldimethyltin ( 3) hydride to eight alkynes was carried out at room temperature leading to vinylstannanes in good to excellent yields and, mostly, with complete stereoselectivity. The results obtained in a study on the relative reactivity of trineophyl- ( 1), tris[(phenyldimethylsilyl)methyl]- ( 2), 9-triptycyldimethyltin ( 3) hydrides, and tri- n-butyltin hydride ( 29) using the radical reactions between these hydrides and 6-bromo-1-hexene ( 28) are also reported. Full 1H-, 13C-, and 119Sn NMR characteristics are included.

Stereoselective Synthesis of Stannyl Enones via Palladium‐Catalyzed and Free Radical Hydrostannation of Alkynyl Ketones with Trineophyltin Hydride.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Stereospecific Preparation of (Z)‐α‐Stannyl‐1‐alkenylphosphonates as Precursors of Stereodefined α‐Substituted Vinylphosphonates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective synthesis of stannyl enones via palladium-catalyzed and free radical hydrostannation of alkynyl ketones with trineophyltin hydride.

A study on the addition of trineophyltin hydride (1) to alkynones under free radical (AIBN and Et3B) and palladium-catalyzed [(PPh3)2PdCl2] conditions is reported. The results obtained indicate that the addition of 1 to eight ynones catalyzed by bis(triphenylphosphine)palladium(II) chloride led in all cases to addition products in very high yields (80-96%). These additions take place with excellent regio- and stereochemistry, leading to the alpha adducts as major products in seven out of the eight cases studied. Also the E adducts, resulting from a syn attack, were the only (seven cases) or the predominant (one case) products. The radical hydrostannations initiated by AIBN of ynones 2-5 with 1 led to addition products in good yields (60-88%); with the more hindered ketones 6 and 7-9 the yields obtained were lower. The radical additions initiated by triethylboron to ynones 2-6 follow a similar pattern but with lower yields; no addition products in the hydrostannation of ynones 7-9 were detected. The new acyl-substituted vinylstannanes, owing to their greater stability compared with that of their tributyl- and trimethylstannyl analogues, can be purified by column chromatography using neutral alumina (in all cases) or silica gel 60 (in most cases) as adsorbents. Full 1H, 13C, and 119Sn NMR data are given.

The Stereospecific Preparation of (Z)-α-Stannyl-1-Alkenylphosphonates as Precursors of Stereodefined α-Substituted Vinylphosphonates

The radical hydrostannation of 1-alkynylphosphonates gives the ( Z)-α-stannyl-1-alkenylphosphonates 2 stereoselectively; 2 can be transformed into α-iodo-1-alkenylphosphonates and α-substituted vinylphosphonates with retention of configuration.

1,2-Stereoinduction in the asymmetric hydrostannation of ( E)- and ( Z)-trisubstituted ethylenes with (−)-menthyldimethyltin hydride

Free radical hydrostannation of methyl ( 2) and (−)-menthyl ( 3) ( E)-2,3-diphenylpropenoates and ( Z)-2,3-diphenylpropenenitrile with (−)-menthyldimethyltin hydride ( 1) takes place with high diastereoselectivity. The observed 1,2-stereoinduction is explained taking into account that the combination of both allylic strain effects and the hyperconjugation existing between the β-trialkyltin substituent and the half filled carbon p orbital leads to particularly stable conformations in the intermediate radicals. These results, together with those reported earlier, indicate that it is possible to predict the stereochemistry of the hydrostannation products by considering the type of substituents attached to the olefinic bond and the preferred conformation of the intermediate radicals resulting from the addition of the organotin radical. These studies also demonstrate that it is possible to achieve asymmetric hydrostannations using organotin hydrides with chiral organic ligands. Full 1H-, 13C-, and 119Sn-NMR data of the new organotin adducts are given.

1,2-Asymmetric induction in the radical addition of organotin hydrides to (−)-menthyl( E)-2,3-disubstituted propenoates

The results obtained in the free radical hydrostannation of (−)-menthyl( E)-2,3-diphenylpropenoate ( 1) with tri- n-butyl- and triphenyltin hydride, and of (−)-menthyl( E)-2-phenyl-2-butenoate ( 7) with trimethyltin hydride are reported. The absolute configuration of the new organotin adducts was determined by combining 1H- and 13C-NMR data with chemical correlation. The additions took place in all cases following a syn stereochemistry that led to diastereomeric excesses ranging between 73 and 100%. The observed stereochemistry is explained, taking into account both the allylic strain and the hyperconjugation with β-trialkyltin substituent existing in the intermediate radicals. Full 1H-, 13C- and 19Sn-NMR data are given.

Tributylstannyl 4-tributylstannylbut-3-enoate: a useful C-4 homologating agent. Application to the synthesis of aryl iodolactones

Tributylstannyl 4-tributylstannylbut-3-enoate, readily prepared by radical hydrostannation, is used for the transfer of a but-3-enoic acid synthon. Some of the potentialities of this synthon are established by the synthesis of aryl iodolactones or tetralones (one of them is a key intermediate for ABT-200 synthesis).