An efficient sequential reaction process to polysubstituted indolizidines and quinolizidines and its application to the total synthesis of indolizidine 223A

The reaction of iodides 1 with delta-chloropropylamines 5 in MeCN assisted with K2CO3 undergoes a sequential S(N)2/Michael addition/SN2/SN2 reaction process to give polysubstituted indolizidines and quinolizidines. Using this method, indolizidine 223A is synthesized from 2-ethyl-2-hexenoic acid in 12 linear steps and 14.5% overall yield. [Reaction: see text]     

Synthesis of chiral 1-substituted tetrahydroisoquinolines by the intramolecular 1,3-chirality transfer reaction catalyzed by Bi(OTf)3

The intramolecular 1,3-chirality transfer reaction of chiral amino alcohols 1 with 99% ee was developed to construct chiral 1-substituted tetrahydroisoquinoline 2. Bi(OTf)(3) (10 mol %)-catalyzed cyclization of 1 (R = H) afforded (S)-1-(E)-propenyl tetrahydroisoquinoline 2 (R = H) in 83% yield with a ratio of 98:2. The stereochemistry at the newly formed chiral center was produced by a syn S(N)2'-type process. In this reaction, the substituent on the benzene ring of 1 significantly affected the reactivities and selectivities. A plausible reaction mechanism was proposed.     

Novel products from oxidation of the norditerpenoid alkaloid pseudaconine with HIO4.

Oxidation of pseudaconine 8, a norditerpenoid alkaloid, with HIO4 led to a series of novel interesting products, depending greatly on reaction medium and work-up conditions. Treatment of 8 in MeOH-H2O (1:1) with NaIO4 gave compounds 10 and 11, but compound 12 was obtained quantitatively when the final reaction solution was alkalized with conc. NH4OH. The imine 12 was also obtained in 100% yield by treating 8 in 5% HCl solution with NaIO4 followed by alkalizing the reaction products to pH>9 with conc. NH4OH. When the work up pH was 7-8, only N,O-mixed acetal-ketal 13 was formed in 96% yield, which was converted quantitatively to 12 by further alkalizing. When the reaction mixture was alkalized to pH 7-8 with Na2CO3, a hemiacetalketal 14 was afforded quantitatively, which was converted to 15 in 87% yield by further treatment with Na2CO3 or 5% NaOH methanol. Compound 15 could be converted back to 14 by treatment with 10% HCl solution. Acetylation of the imine 12 gave the compounds 16 and 17 in 15% and 19% yields, respectively. All of the new compounds were isolated and fully characterized.     

An efficient chemoenzymatic approach to (S)-gamma-fluoroleucine ethyl ester

[reaction: see text] An asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester 1 is described. The key transformation involves a lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone 7b with EtOH to give amide ester (S)-6b in 84% enantiomeric excess. Removal of the N-pentenoyl group with N,N'-dibromodimethylhydantoin in the presence of trifluoroacetic acid afforded the titled compound, which was isolated as its hydrogen sulfate salt in 75% yield and >97% ee.     

Short,enantioselective total synthesis of okaramine N

The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6).     

New convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling between A-ring and C,D-ring parts

A new convergent method for the synthesis of 1alpha,25-dihydroxyvitamin D(3) and its analogues has been developed that involves efficient preparation of the A-ring part 1a, (Z)-(3S,5R)-1-bromomethylene-3,5-bis(tert-butyldimethylsilyloxy)-2-methylenecyclohexane, starting from epichlorohydrin (4) and its Suzuki-Miyaura coupling reaction with the C,D-ring part 12. Thus, (R)-4 was converted to (3S,5R)-5-(tert-butyldimethylsilyloxy)-8-(trimethylsilyl)-oct-1-en-7-yn-3-ol (3a) through a ten-step reaction sequence in 49% overall yield. Compound 3a thus obtained was treated with a Ti(O-i-Pr)(4)/2 i-PrMgCl reagent and then with NBS to afford (Z)-(1S,2S,5R)-2-bromomethyl-3-[bromo(trimethylsilyl)methylene]-5-(tert-butyldimethylsilyloxy)cyclohexanol (10a) in 51% yield, from which 1a was obtained in 87% yield by sequential treatment with TBSCl/imidazole, DBU, and Cs(2)CO(3). The resulting A-ring intermediate 1a was reacted with alkenylboronate 12 in the presence of a PdCl(2)(dppf) catalyst to furnish 1alpha,25-dihydroxyvitamin D(3) in 82% yield after protodesilylation. Similarly, all of the other three possible stereoisomers of A-ring parts 1b, 1c, and 1d were prepared, from which 1-epi-, 3-epi-, and 1,3-di-epi-1alpha,25-dihydroxyvitamin D(3) were synthesized by coupling with 12 in excellent yield, respectively. Starting from 1a and 1c, des-C,D-1alpha,25-dihydroxyvitamin D(3) analogues, retiferol 13 and its 3-epi derivative, were also prepared, respectively.     

Highly enantioselective and efficient synthesis of flavanones including pinostrobin through the rhodium-catalyzed asymmetric 1,4-addition

An efficient synthesis of bioactive chiral flavanones (1) was achieved through the Rh-catalyzed asymmetric 1,4-addition of arylboronic acid to chromone. The reaction in toluene proceeded smoothly at room temperature in the presence of 0.5% Rh catalyst with electron-poor chiral diphosphine MeO-F(12)-BIPHEP. In this reaction, the 1,2-addition to (S)-1 frequently occurred to yield (2S,4R)-2,4-diaryl-4-chromanol as a byproduct, which could be reduced by changing the reaction solvent to CH(2)Cl(2) to deactivate the Rh catalyst (3% required).     

Cadmium(II) and mercury(II) complexes of an NO2S2-donor macrocycle and its ditopic xylyl-bridged analogue

The NO2S2-donor macrocycle (L1) was synthesised from the ring closure reaction between Boc-N-protected 2,2'-iminobis(ethanethiol) (3) and 2,2'-(ethylenedioxy)bis(benzyl chloride) (4) followed by deprotection of the Boc-group. alpha,alpha'-Dibromo-p-xylene was employed as a dialkylating agent to bridge two L1 to yield the corresponding N-linked product (L2). The X-ray structure of L2 (as its HBr salt) is described. A range of Cd(II) and Hg(II) complexes of L1 (6-9) and L2 (10-12) were prepared and characterised. Reaction of HgX2 (X = Br or I) with L1 afforded [Hg(L1)Br]2[Hg2Br6].2CH2Cl2 6 and [Hg(L1)I(2)] 7, respectively. For 6, the Hg(II) ion in the complex cation has a distorted tetrahedral coordination environment composed of S2N donor atoms from L1 and a bromo ligand. In 7 the coordination geometry is highly distorted tetrahedral, with the macrocycle coordinating in an exodentate manner via one S and one N atom. The remaining two coordination sites are occupied by iodide ions. [Hg(L1)(ClO4)]ClO4 8 was isolated from the reaction of Hg(ClO4)2 and L1. The X-ray structure reveals that all macrocyclic ring donors bind to the central mercury ion in this case, with the latter exhibiting a highly distorted octahedral coordination geometry. The O2S2-donors from the macrocyclic ring define the equatorial plane while the axial positions are occupied by the ring nitrogen as well as by an oxygen from a monodentate perchlorato ion. Reaction of Cd(NO3)(2).4H2O with L1 afforded [Cd(L1)(NO3)2](.)0.5CH2Cl2 9 in which L1 acts as a tridentate ligand, binding exo-fashion via its S2N donors. The remaining coordination positions are filled by two bidentate nitrate ions such that, overall, the cadmium is seven-coordinate. Reactions of HgX2(X = Br or I) with L2 yielded the isostructural 2 : 1 (metal : ligand) complexes, [Hg2(L2)Br4] 10 and [Hg2(L2)I(4)] 11. Each mercury ion has a distorted tetrahedral environment made up of S and N donors from an exodentate L2 and two coordinated halides. Contrasting with this, the reaction of L2 with Cd(NO3)(2).4H2O yielded a 1-D coordination network, {[Cd2(L2)(NO3)4].2CH2Cl2}n 12 in which each ring of L2 is exo-coordinated via two S atoms and one N atom to a cadmium ion which is also bound to one monodentate and one bidentate nitrate anion. The latter also has one of its oxygen atom attached to a neighboring cadmium via a nitroso (mu2-O) bridge such that the overall coordination geometry about each cadmium is seven-coordinate. The [Cd(L2)0.5(NO3)2] units are linked by an inversion to yield the polymeric arrangement.     

Total synthesis of (+)-hatomarubigin B.

The first total synthesis of (+)-hatomarubigin 3 is described. The tetra-O-acetyl diborate promoted Diels-Alder reaction of 5-hydroxy-8-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-1,4-naphthoquinone 8 and (E, 1R*,5R*)-3-(2'-methoxyvinyl)cyclohex-2-enol (+/-)-7 gave a mixture of four cycloadducts from which (1S,3S,6S,6aR,12aR,12bS)-1,8-dihydroxy-6-dimethoxy-1-hydroxy-3-methyl-11-(2',3',4',6'-tetra-O-acetyl-beta-D-glucopyranosyloxy)-1,2,3,4,6,6a,12a,12b-octahydrobenz[a]anthracene-7,12-dione 12 was isolated in 51% yield. Selective methylation and acetylation of 12 gave (1S,3S,6S,6aR,12aR,12bS)-1-acetoxy-6,8-dimethoxy-3-methyl-11-(2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyloxy)-1,2,3,4,6,6a,12a,12b-octahydrobenz[a]anthracene-7,12-dione 10a. Sequential aromatization, photooxidation and hydrolysis of the glucosyl unit gave (+)-3 (98% ee) in an 8% overall yield from 8.     

Direct catalytic asymmetric aldol reaction of hydroxyketones: asymmetric Zn catalysis with a Et(2)Zn/linked-BINOL complex

Full details of our newly developed catalyses with asymmetric zinc complexes as mimics of class II zinc-containing aldolase are described. A Et(2)Zn/(S,S)-linked-BINOL complex was developed and successfully applied to direct catalytic asymmetric aldol reactions of hydroxyketones. A Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was initially developed, which efficiently promoted the direct aldol reaction of 2-hydroxy-2'-methoxyacetophenone (7d). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et(2)Zn, we obtained 1,2-dihydroxyketones syn-selectively in high yield (up to 95%), good diastereomeric ratio (up to 97/3), and excellent enantiomeric excess (up to 99%). Mechanistic investigation of Et(2)Zn/(S,S)-linked-BINOL 1, including X-ray analysis, NMR analysis, cold spray ionization mass spectrometry (CSI-MS) analysis, and kinetic studies, provided new insight into the active oligomeric Zn/(S,S)-linked-BINOL 1/ketone 7d active species. On the basis of mechanistic investigations, a modified second generation Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 with molecular sieves 3A (MS 3A) system was developed as a much more effective catalyst system for the direct aldol reaction. As little as 0.1 mol % of (S,S)-linked-BINOL 1 and 0.4 mol % of Et(2)Zn promoted the direct aldol reaction smoothly, using only 1.1 equiv of 7d as a donor (substrate/ligand = 1000). This is the most efficient, in terms of catalyst loading, asymmetric catalyst for the direct catalytic asymmetric aldol reaction. Moreover, the Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 system was effective in the direct catalytic asymmetric aldol reaction of 2-hydroxy-2'-methoxypropiophenone (12), which afforded a chiral tetrasubstituted carbon center (tert-alcohol) in good yield (up to 97%) and ee (up to 97%), albeit in modest syn-selectivity. Newly developed (S,S)-sulfur-linked-BINOL 2 was also effective in the direct aldol reaction of 12. The Et(2)Zn/(S,S)-sulfur-linked-BINOL 2 = 4/1 system gave aldol adducts anti-selectively in good ee (up to 93%). Transformations of the aldol adducts into synthetically versatile intermediates were also described.     

RRKM理论研究N(4S)+CH2X(X=F,Cl)的反应通道

采用RRKM理论和疏松过渡态模型计算了N(4S)+CH2X(X=F,Cl)反应的微正则速率常数和通道分支比.计算结果表明,在较低的内能下(E=280.29 kJ/mol), N(4S)+CH2F的主要产物为NCHF+H,占总产物的59.2%,次要产物为H2CN+F,占37.4%.而N(4S)+CH2Cl反应在E＝267.78 kJ/mol时,主要产物是H2CN+Cl,占90.3%, NCHCl+H只占9.0%.在内能较高的时候(取E=500.00 kJ/mol), N(4S)+CH2F的主要通道并未变化,而N(4S)+CH2Cl的主要通道变为NCHCl+H,比例为51.5%, H2CN+Cl的比例降到40.4%.     

Total synthesis of an immunosuppressive glycolipid, (2S,3S,4R)-1-O- (alpha-d-galactosyl)-2- tetracosanoylamino-1,3,4-nonanetriol

[reaction: see text] A practical and efficient total synthesis of (2S,3S,4R)-1-O-(alpha-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonanetriol, OCH 1b, a potential therapeutic candidate for Th1-mediated autoimmune diseases, is described. The synthesis incorporates direct alkylation onto epoxide 5 and stereospecific halide ion catalyzed alpha-glycosidation reaction. A key intermediate 10 was obtained in only eight steps and 37% overall yield from commercially available d-arabitol 2, and the total synthesis of 1b was accomplished in 12 steps and 19% overall yield. This method will enable the synthesis of a variety of phytosphingolipids, especially that with the shorter sphingosine side chain than 1a, in a highly stereoselective manner.     

Facile O-deallylation of allyl ethers via S(N)2' reaction with tert-butyllithium

[reaction: see text] Allylic ethers are converted to the corresponding alcohol or phenol in virtually quantitative yield at temperatures below ambient simply by stirring a hydrocarbon solution of the ether with 1 molar equiv of tert-butyllithium. The reaction, which produces 4,4-dimethyl-1-pentene as a coproduct, most likely involves an S(N)2' attack of the organolithium on the allyl ether.     

On the reaction of Ph2PNHPPh2 with RNCS (R=Et, Ph, p-NO2C6H4): preparation of the zwitterionic ligand EtNHC(S)Ph2P==NPPh2C(S)NEt (HSNS) and the zwitterionic metalate [(SNS)Rh(CO)

The reaction of Ph(2)PNHPPh(2) (PNP) with RNCS (Et, Ph, p-NO(2)(C(6)H(4))) gives addition products resulting from the attack of the P atoms of PNP on the electrophilic carbon atom of the isothiocyanate. When PNP is reacted with EtNCS in a 1:2 molar ratio, the zwitterionic molecule EtNHC(S)PPh(2)==NP(+)Ph(2)C(S)N(-)Et (HSNS) is obtained in high yield. HSNS can be protonated (H(2)SNS(+)) or deprotonated (SNS(-)), behaving in the latter form as an S,N,S-donor pincer ligand. The reaction of HSNS with [(acac)Rh(CO)(2)] (acac=acetylacetonate) affords the zwitterionic metalate [(SNS)Rh(CO)]. Other products can be obtained depending on the R group, the PNP/RNCS ratio (1:1 or 1:2), and the reaction temperature. The proposed product of the primary attack of PNP on RNCS, Ph(2)PN==PPh(2)C(S)NHR (A), cannot be isolated. Reaction of A with another RNCS molecule leads to 1:2 addition compounds of the general formula RNHC(S)PPh(2)==NP(+)Ph(2)C(S)N(-)R (1), which can rearrange into the non-zwitterionic product RNHC(S)PPh(2)==NP(S)Ph(2) (2) by eliminating a molecule of RNC. Two molecules of A can react together, yielding 1:1 PNP/RNCS zwitterionic products of the formula RNHCH[PPh(2)==NP(S)Ph(2)]PPh(2)==NP(+)Ph(2)C(S)N(-)R (3). Compound 3 can then rearrange into RNHCH[PPh(2)==NP(S)Ph(2)](2) (4) by losing a RNC molecule. When R=Et (a), compounds 1 a, 2 a (HSNS), and 4 a have been isolated and characterized. When R=Ph (b), compounds 2 b and 4 b can be prepared in high yield. When R=p-NO(2)C(6)H(4) (c), only compound 3 c is observed and isolated in high yield. The crystal structures of HSNS, [(SNS)Rh(CO)], and of the most representative products have been determined by X-ray diffraction methods.     

A probable hydrogen-bonded Meisenheimer complex: an unusually high S(N)Ar reactivity of nitroaniline derivatives with hydroxide ion in aqueous media

Observations show that nitroanilines exhibit an unusually high S(N)Ar reactivity with OH(-) in aqueous media in reactions that produce nitrophenols. S(N)Ar reaction of 4-nitroaniline (2a) in aqueous NaOH for 16 h yields 4-nitrophenol (4a) quantitatively, whereas a similar reaction of 4-nitrochlorobenzene (1a) gave 4a in 2% yield together with recovered 1a in 97%, suggesting that the leaving ability of the NH(2) group far surpasses that of Cl under these conditions. An essential feature of S(N)Ar reactions of nitroanilines is probably that the NH(2) leaving group participates in a hydrogen-bonding interaction with H(2)O. Density functional theory (DFT) calculations for a set of 4-nitroaniline, OH(-), and H(2)O suggest a possible formation of a Meisenheimer complex stabilized by hydrogen-bonding interactions and a six-membered ring structure. The results obtained here contrast with conventional S(N)Ar reactivity profiles in which nitroanilines are nearly unreactive with nucleophiles in organic solvents.     

The Asymmetric Syntheses of Methyl <small>D</small>-Digitoxoside, <small>L</small>-Oleandrose and <small>L</small>-Cymarose from Methyl Sorbate, an Achiral Precursor

The addition of 4?eq of chloral to osmundalactone (4S,5R)-4 gave quantitative formation of the hemiacetal derivative (4S,5R)-8, which was treated with methane sulfonic acid to afford the intramolecular Micheal addition product (+)-(3S,4S,5R)-9 possessing a 3,4-cis-dihydroxy-δ-lactone in 78% overall yield from (4S,5R)-4. The obtained (+)-(3S,4S,5R)-9 was subsequently converted to methyl D-digitoxoside (pyranoside) (12) in 13% overall yield and methyl D-digitoxoside (furanoside) (12) in 20% overall yield. The reaction of benzyl-osmundalactone (4R,5S)-3 and MeOH in the presence of Amberlyst A-26 as a basic catalyst gave 3,4-trans-δ-lactone (－)-(3S,4R,5S)-20 in 28% yield and 3,4-cis-δ-lactone (－)-(3R,4R,5S)-21 in 45% yield. Dibal-H reduction of (－)-(3S,4R,5S)-20 followed by catalytic hydrogenation gave L-oleandrose (6) in 86% overall yield, while Dibal-H reduction of (－)-(3R,4R,5S)-21 followed by catalytic hydrogenation provided L-cymarose (7) in 85% overall yield.     

Efficient and beta-Stereoselective Synthesis of 4(5)-(beta-D-Ribofuranosyl)- and 4(5)-(2-Deoxyribofuranosyl)imidazoles(1)

A synthetic route to 4(5)-(beta-D-ribofuranosyl)imidazole (1), starting from 2,3,5-tri-O-benzyl-D-ribose (5), was developed via a Mitsunobu cyclization. Reaction of 5 with the lithium salt of bis-protected imidazole afforded the corresponding 5-ribosylimidazole 7RS. Hydrolysis of 7RS gave a 1:1 mixture of diol isomers 8R and 8S having an unsubstituted imidazole. Mitsunobu cyclization of the mixture 8RS using N,N,N',N'-tetramethylazodicarboxamide and Bu(3)P exclusively afforded benzylated beta-ribofuranosyl imidazole 9beta in 92% yield, accompanied by alpha-anomer 9alpha, in a ratio of 26.3:1. The configuration of 9beta was established by X-ray crystallography of ethoxycarbonyl derivative 10beta. Reductive debenzylation of 9beta over Pd/C was carried out, and the synthesis of 1 was attained from starting 5 in four steps and 87% overall yield. This synthetic methodology was extended to the synthesis of 4(5)-(2-deoxy-beta-D-ribofuranosyl)imidazole (2). Mitsunobu cyclization of a 1:1 mixture of the corresponding diol isomers 14RS produced 15beta and 15alpha in a ratio of 5.4:1. The synthesis of 2 was attained in a 59% overall yield from the starting 3,5-di-O-benzyl-2-deoxy-D-ribose (12). beta-Stereoselective glycosylation in the key step is discussed and explained by intramolecular hydrogen bonding between an NH in the imidazole and the oxygen functional group in the sugar moiety.     

Reactions of hydro(pero)xy derivatives of polyunsaturated fatty acids/esters with nitrite ions under acidic conditions. Unusual nitrosative breakdown of methyl 13-hydro(pero)xyoctadeca-9,11-dienoate to a novel 4-nitro-2-oximinoalk-3-enal product

13(S)-hydroperoxy- and 13(S)-hydroxyoctadeca-9,11-dienoic acids (1a/b), 15(S)-hydroperoxy- and 15(S)-hydroxyeicosa-5,8,11,13-tetraenoic acids (2a/b), and their methyl esters reacted smoothly with NO2- in phosphate buffer at pH 3-5.5 and at 37 degrees C to afford mixtures of products. 1b methyl ester gave mainly the 9-nitro derivative 3b methyl ester (11% yield) and a peculiar breakdown product identified as the novel 4-nitro-2-oximinoalk-3-enal derivative 4 methyl ester (15% yield). By GC-MS hexanal was also detected among the products. Structures 3b and 4 methyl esters were secured by 15N NMR analysis of the products prepared from 1b methyl ester upon reaction with Na15NO2. 4 methyl ester (14% yield) was also obtained from 1a methyl ester along with the nitrated hydroperoxy derivative 3a methyl ester (10% yield). Under the same conditions, 2a/b methyl esters gave mainly the corresponding nitrated derivatives 5a/b, with no detectable breakdown products, whereas the model compound (E,E)-2,4-hexadienol (6) afforded two main nitrated derivatives identified as 7 and 8. A reaction pathway for 1a/b methyl esters was proposed involving conversion of nitronitrosooxyhydro(pero)xy intermediates which would partition between two competing routes, viz., loss of HNO2, to give 3a/b methyl esters, and a remarkably facile fission leading to 4 methyl ester and hexanal.     

Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem

An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.     

Stereocontrolled synthesis of kelsoene by the homo-favorskii rearrangement

[reaction: see text] (+/-)-Kelsoene (4) has been synthesized from 2,5-dihydroanisole in 16 steps in 12.5% overall yield. The key step involves a base-catalyzed reaction of gamma-keto tosylate (5), which effects a homo-Favorskii rearrangement to 16 as well as the corresponding intramolecular S(N)2 product 15 from the enolate of 5. Ketone 15 can efficiently be isomerized to cyclobutanone 17 having the kelsoene carbon skeleton upon acid treatment.