Two-step electrochemical annulation for the assembly of polycyclic systems

[reaction: see text] A two-step electrochemical annulation has been developed for the preparation of fused furans. The process involves an initial conjugate addition of a furyethyl cuprate and trapping of the enolate as the corresponding silyl enolether. The second step of the annulation involves the anodic coupling of the furan and the silyl enol ether to form a six-membered ring.     

Anodic coupling reactions: a sequential cyclization route to the arteannuin ring skeleton

A pair of intramolecular anodic olefin coupling reactions has been used to construct the arteannuin ring skeleton. Both coupling reactions took advantage of a furan ring as one of the coupling partners. In the first, it was found that an enol ether derived from an aldehyde was not an effective initiating group for the reaction. Instead, the cyclization benefited strongly from the use of a N,O-ketene acetal initiating group. In the second cyclization, an endocyclic enol ether was coupled to the furan ring. This second electrolysis reaction generated the key tetrasubstituted carbon at the center of the arteannuin ring skeleton.     

Convergent assembly of polycyclic ethers via acyl radical addition to unactivated enol ether

A new convergent strategy for assembling 6/6- and 6/7-fused ether ring systems was developed. The key features in our method include Ag+-promoted facile formation of chemically labile enol ether from O,S-acetal and addition of an acyl radical to unactivated enol ether to cyclize a six- or seven-membered ether ring. [reaction: see text]     

Anodic cyclization reactions: the total synthesis of alliacol a

An anodic cyclization-Friedel Crafts alkylation strategy has been used to rapidly assemble the core ring system of alliacol A and to complete a formal total synthesis of the natural product. The anodic cyclization reaction was used to effect the coupling of a nucleophilic furan ring to the normally nucleophilic carbon of a silyl enol ether. The substrate for this initial cyclization reaction contained all of the carbons needed for completing the total synthesis. The electrolysis proceeded in high yield and could be accomplished with the use of a 6 V lantern battery.     

New approaches toward the synthesis of (D-homo) steroid skeletons using Mukaiyama reactions

New, short, and flexible procedures have been developed for syntheses of steroid and D-homo steroid skeletons. A Mukaiyama reaction between the silyl enol ether of 6-methoxytetralone and 2-methyl-2-cyclopentenone or carvone, with transfer of the silyl group to the receiving enone, gave a second silyl enol ether. Addition of a carbocation, generated under Lewis acid conditions from 3-methoxy-2-butenol, 3-ethoxy-3-phenyl-2-propenol or 3-methoxy-2-propenol to this second silyl enol ether gave adducts, which could not be cyclized by aldol condensation to (D-homo) steroid skeletons. The Mukaiyama-Michael reaction of the silyl enol ether of 6-methoxy tetralone with 2-methyl-2-cylopentenone gave a second silyl enol ether, which reacted in high yield with a carbocation generated from 3-hydroxy-3-(4-methoxyphenyl)propene. Ozonolysis of the double bond in this adduct gave a tricarbonyl compound (Zieglers triketone), which has been used before in the synthesis of 9,11-dehydroestrone methyl ether. A second synthesis of C17 substituted CD-trans coupled (D-homo) steroid skeletons has been developed via addition of a carbocation, generated with ZnBr₂ from a Torgov reagent, to a silyl enol ether containing ring D precursor. The obtained seco steroids have been cyclized under formation of the 8-14 bond by treatment with acid. The double bonds in one of the cyclized products have been reduced to a C17-substituted all trans steroid skeleton.     

Oxonia-cope prins cyclizations: a facile method for the synthesis of tetrahydropyranones bearing quaternary centers

A new cationic cascade reaction has been developed that produces 4-tetrahydropyranones in good yield. The reaction is based on the facile 2-oxonia Cope rearrangement of allyl-substituted oxocarbenium ions. In the presence of a more nucleophilic silyl enol ether, such systems rearrange and cyclize to produce tetrahydropyranones. The substrates were prepared by silyl ketene acetal addition to ketenes. The rearrangement is compatible with tetrasubstituted silyl enol ethers, which result in the diastereoselective introduction of quaternary centers at the C3 position of the tetrahydropyran ring. The oxonia-Cope Prins rearrangement is a versatile new route to tetrahydropyrans.     

A Dipolar Cycloaddition Approach Toward the Kopsifoline Alkaloid Framework

Using a metal-catalyzed domino reaction as the key step, the heterocyclic skeleton of the kopsifoline alkaloid family was constructed by a 1,3-dipolar cycloaddition of a carbonyl ylide dipole derived from a Rh(II)-catalyzed reaction of a diazo ketoester across the indole π-bond. Ring opening of the resulting 1,3-dipolar cycloadduct followed by a reductive dehydroxylation step resulted in the formation of a critical silyl enol ether necessary for the final F-ring closure of the kopsifoline skeleton.     

Synthesis and PET oxidative cyclization of silyl enol ethers: build-up of quasi-steroidal carbocycles

PET oxidative cyclization of silyl enol ethers carrying suitable side chains with olefinic double bonds results in the stereoselective formation of carbocycles. Two model compounds for investigating the influence of silyl enol ether ring size are synthesized. Furthermore the synthesis of a quasi-steroidal carbocycle with an unnatural configuration is presented.     

Acyclic stereoselection in the reaction of nucleophilic reagents with chiral N-acyliminium ions generated from N-

Optically active N-[1-(phenylsulfonyl)alkyl]imidazolidin-2-ones react at low temperature in the presence of tin tetrachloride to give acyclic N-acyliminium ions. These electrophilic substrates give addition products upon reaction with pi-nucleophiles. Allyltrimethylsilane affords the corresponding allylated products in good yields and high diastereoselectivity. The stereochemical outcome of this process can be rationalized by taking into account the preference of the intermediate N-acyliminium ion for an E configuration that favors the attack of the nucleophile from the si-si face. Disappointing results are obtained using silyl ketene acetals; conversely trimethylsilyl enol ether of acetophenone gives the corresponding adducts in high diastereoselectivity. The utilization of trimethylsilyl enol ether of 2-acetylfuran is particularly interesting since the corresponding adducts are obtained with good diastereoselectivity and the furan ring could be amenable of further synthetic transformations.     

Synthesis of the hydroazulene portion of guanacastepene A using a [2.3]sigmatropic sulfoxide rearrangement: observations on silyl enol ether electrophilic chemistry for the introduction of the C-13 hydroxyl group

The intermediate 6 can be converted into enone 13 using a [2.3]sigmatropic sulfoxide rearrangement as the key transformation. The C-13 hydroxylation of 13 was studied, and found to give 14 (epimeric to guanacastepene A). Examination of silyl enol ethers of 13 demonstrated the ready isomerization of the kinetic silyl enol ether into the more stable thermodynamic silyl enol ether under mild electrophilic reaction conditions.     

Rhodium‐Catalyzed Dehydrogenative Silylation of Acetophenone Derivatives: Formation of Silyl Enol Ethers versus Silyl Ethers

A series of rhodium–NSiN complexes (NSiN=bis (pyridine‐2‐yloxy)methylsilyl fac‐coordinated) is reported, including the solid‐state structures of [Rh(H)(Cl)(NSiN)(PCy₃)] (Cy=cyclohexane) and [Rh(H)(CF₃SO₃)(NSiN)(coe)] (coe=cis‐cyclooctene). The [Rh(H)(CF₃SO₃)(NSiN)(coe)]‐catalyzed reaction of acetophenone with silanes performed in an open system was studied. Interestingly, in most of the cases the formation of the corresponding silyl enol ether as major reaction product was observed. However, when the catalytic reactions were performed in closed systems, formation of the corresponding silyl ether was favored. Moreover, theoretical calculations on the reaction of [Rh(H)(CF₃SO₃)(NSiN)(coe)] with HSiMe₃ and acetophenone showed that formation of the silyl enol ether is kinetically favored, while the silyl ether is the thermodynamic product. The dehydrogenative silylation entails heterolytic cleavage of the Si?H bond by a metal–ligand cooperative mechanism as the rate‐determining step. Silyl transfer from a coordinated trimethylsilyltriflate molecule to the acetophenone followed by proton transfer from the activated acetophenone to the hydride ligand results in the formation of H₂ and the corresponding silyl enol ether.     

The aldol reaction of silyl enol ethers within a micro reactor

We have demonstrated the use of silyl enol ethers in the aldol reaction within a micro reactor. Quantitative conversion of the silyl enol ether to a beta-hydroxyketone was observed in a 20 min period compared to traditional batch systems, where quantitative yields were only obtained when extended reaction times of 24 h were employed.     

Synthesis of 1-acetyl-2-silyoxycycloheptane derivatives via highly stereoselective formal [5+2] cycloaddition reaction

A stereoselective [5+2] cycloaddition reaction using a new five-carbon unit, that has a dicobalt acetylene complex moiety and an enol silyl ether moiety, was developed. In the presence of a Lewis acid, the five-carbon unit reacted with an enol triisopropylsilyl ether to give a 1-acetyl-2-silyoxycycloheptane derivative, in which the three contiguous substituents on the seven-membered ring arrange cis to each other.     

Synthetic studies on taxanes: construction of the tricyclic skeleton on the basis of a [6+2] cycloaddition reaction

The stereoselective synthesis of a tricyclic model compound of taxane diterpenes was achieved. The eight-membered B ring was constructed on the basis of a [6+2] cycloaddition reaction of a dicobalt acetylene complex with an enol silyl ether of cyclohexanone. After conversion of the cobalt complex moiety to an epoxide and introduction of a 3-cyanopropyl group, the A ring was formed via an intramolecular cyclization reaction under basic conditions.     

Studies on steroidal plant-growth regulators (XVII)--a new synthesis of homobrassinolide and (22S, 23S)-22, 23-epi-homobrassinolide

Homobrassinolide (2) and (22S, 23S)-22,23-epi-homobrassinolide (4) were synthesized from stigmasterol in seven steps respectively in 4.7% and 24.1% overall yields. The ratio of 2 to 4 is 1:5. The key step is the highly regioselective formation of the B-homo-7-oxa-lactone ring by oxidation of an enol silyl ether with 3-chloro-peroxybenzoic acid.     

Synthetic Studies on and Mechanistic Insight into [W(CO)5(L)]‐Catalyzed Stereoselective Construction of Functionalized Bicyclo[5.3.0]decane Frameworks

Stereoselective preparation of a variety of synthetically useful functionalized bicyclo[5.3.0]decane derivatives was achieved by tandem cyclization of 3‐siloxy‐1,3,9‐triene‐7‐yne derivatives based on the electrophilic activation of alkynes catalyzed by [W(CO)₅(L)]. The reaction proceeded smoothly under photoirradiation, and various substrates were cyclized to give the corresponding bicyclic compounds with up to four chiral centers stereospecifically. Reactions of siloxydienes with a silyl substituent as an equivalent of a hydroxyl group also proceeded with wide generality to afford silyl‐substituted bicyclo[5.3.0]decanes, which were highly useful as synthetic intermediates. Stereochemical studies concerning the silyl enol ether moiety suggested that two types of reaction pathway for the formation of seven‐membered rings were present. The reaction of (Z)‐enol silyl ethers proceeded through Cope rearrangement of cis‐divinylcyclopropane intermediates, and that of (E)‐enol silyl ethers by 1,4‐addition of the dienyl tungsten species at the position δ to the metal atom. In the reactions of siloxydiene derivatives with silyl substituents, all possible diastereomers could be synthesized stereoselectively by changing the geometry of the silyl enol ether and enyne moieties.     

Oxidative C-C bond-forming reaction of electron-rich alkylbenzyl ether with trimethylvinyloxysilane

Treatment of an electron-rich benzyl ether with DDQ at ambient temperature followed by addition of a silyl enol ether undergoes a C-C bond-forming reaction to afford 3-alkoxy-3-phenyl-propionyl compound. This is a general reaction and works well with a variety of silyl enol ethers to give carbonyl products in yields ranging from 10 to 85%.     

Total synthesis of 7-ethyl-10-hydroxycamptothecin (SN38) and its application to the development of C18-functionalized camptothecin derivatives

A new chemical synthesis of SN38, the active metabolite of the camptothecin prodrug irinotecan, has been achieved in 12 steps from simple, commercially available starting materials. A mild and efficient FeCl₃‐catalyzed Friedländer condensation was successfully applied to construct the AB ring system. Functionalization of the C ring was accomplished by a vinylogous Mukaiyama reaction of an in situ generated N‐acyliminium intermediate with a silyl enol ether. An intramolecular oxa Diels–Alder reaction efficiently constructed the D and E rings in one step. Successive asymmetric dihydroxylation and I₂‐based hemiacetal oxidation furnished the stereochemistry of SN38 with high enantiopurity. Utilizing the ABC‐ring intermediate and a functionalized silyl enol ether permitted the synthesis of a number of new C18‐functionalized SN38 derivatives. Several of the novel SN38 derivatives that bore a C10 methoxy group were found to exhibit comparable or more potent inhibitory activity against the proliferation of cancer cells relative to SN38.     

The mannich reaction-II : Derivatization of aldehydes and ketones using dimethyl(methylene)ammonium salts

Aldehydes and ketones have been converted efficiently to their corresponding Mannich products by various dimethyl(methylene)ammonium salts under a range of reaction conditions. The several methods used to form these derivatives are compared. Excellent approaches to aldehyde derivatives involve treating the enol silyl ether of the carbonyl compound with methyllithium and then an iminium salt, or directly adding the iminium salt to the enol silyl ether. Ketones may be derivatized effectively by treatment with potassium hydride, followed by an iminium salt, or from the enol silyl ether by addition of the iminium reagent. Use of iminium reagents in the Mannich reaction is recommended because the yields are often good and the site of attachment on an unsymmetrical ketone is both predictable and controllable.     

Acetyltrimethylsilane, trifluoromethyltrimethylsilane, and prenyl esters: a three-component system for the synthesis of gem-difluoroanalogues of monoterpenes

The preparation of 3,3-difluoro-6-methylhept-5-en-2-one 1, a key intermediate for the synthesis of 4,4-difluoroterpenes, and applications in linalool and geraniol series are described. The process involves 1,1-difluoro-2-trimethylsilyoxypropene, an enol silyl ether prepared from acetyltrimethylsilane and trifluoromethyltrimethylsilane, and its reaction in situ with prenyl benzoate, under catalysis by trimethylsilyl trifluoromethanesulfonate. Optimized conditions leading to either the desired enol silyl ether or the unprecedented methyl(trifluoromethyl)trimethylsilyl carbinol 4 have been achieved. The prenylation of the enol silyl ether gives a 9/1 mixture of regioisomers, in favor of the expected ketone 1. Treatment of 1 with vinylmagnesium bromide leads to (+/-)-4,4-difluorolinalool 7. Reaction with the lithium enolate of ethyl diethylphosphonoacetate, and then LAH reduction, converts 1 to 4,4-difluorogeraniol 11, with complete stereoselectivity.