A Flexible Stereoselective Synthesis of the Spirosesquiterpenes (±)-β-Acorenol, (±)-β-Acoradiene, (±)-Acorenone-B and (±)-Acorenone via an Intramolecular Ene-Reaction

The racemic spirosesquiterpenes β-acorenol ( 1 ), β-acoradiene ( 2 ), acorenone-B ( 3 ) and acorenone ( 4 ) (Scheme 2) have been synthesized in a simple, flexible and highly stereoselective manner from the ester 5 . The key step (Schemes 3 and 4), an intramolecular thermal ene reaction of the 1,6-diene 6 , proceeded with 100% endo-selectivity to give the separable and interconvertible epimers 7a and 7b . Transformation of the ‘trans’-ester 7a to (±)- 1 and (±)- 2 via the enone 9 (Scheme 5) involved either a thermal retro-ene reaction 10 → 12 or, alternatively, an acid-catalysed elimination 11 → 13 + 14 followed by conversion to the 2-propanols 16 and 17 and their reduction with sodium in ammonia into 1 which was then dehydrated to 2 . The conversion of the ‘cis’-ester 7b to either 3 (Scheme 6) or 4 (Scheme 7) was accomplished by transforming firstly the carbethoxy group to an isopropyl group via 7b → 18 → 19 → 20 , oxidation of 20 to 21 , then alkylative 1,2-enone transposition 21 → 22 → 23 → 3 . By regioselective hydroboration and oxidation, the same precursor 20 gave a single ketone 25 which was subjected to the regioselective sulfenylation-alkylation-desulfenylation sequence 25 → 26 → 27 → 4 .     

Einfache Synthese von 6-[4-Methyl-3-cyclohexen-1-yl]-hept-5-en-2-on,einer Vorstufe für α-Bisabolen und dessen Isopropenyl-Isomers. Terpene und Terpen-Derivate, 10. Mitteilung

Simple Synthesis of 6-[4-Methyl-3-cyclohexen-1-yl]-5-hepten-2-on, a Precursor of α-Bisabolene and Its Isopropenyl Isomer The alcohol 14 reacts with vinyl resp isopropenyl ether by Claisen rearrangement to give the aldehyde 16/17 resp. the ketone 3/4. Contrary to other reports this separable (E/Z)-mixture also occurs as a result of the synthesis following the pathway 7 → 8/9 → 10/11 → 12/13 (see also [2]). The bisabolene isomers 5 resp. 6 are obtained by reaction of 3 resp. 4 with methylidene triphenyl phosphorane. A mixture of 1 and 5. however, is formed from 3 via the alcohol 18 and its acetate 19. Likewise 4 reacts via 20 and 21 to give a (2/6) -mixture.     

Nucleophilic Addition to C,C-Double Bonds. IV. Ether formation by intramolecular addition to unsymmetrically alkyl-substituted C,C-double bonds

Tricyclic olefinic alcohols containing an unsymmetrically alkyl-substituted C, C-double bond were cyclized intramolecularly to their corresponding ethers under basic conditions: 9 → 12 , 10 → 17 + 18 , and 11 → 12 (Scheme 3, Table 1). The reactivity is mainly due to relieve of ground state strain. Alcohol 9 (endocyclic double bond) isomerized under intramolecular assistance by the hydroxyl group to 11 (exocyclic double bond) before cyclization to 12 occurred (Scheme 5). The latter step being the faster one, no isomerization 11 → 9 was observed.     

Electrofugal Fragmentation of Alkylcobalamin Derivatives Using Cob(I)Alamin and Heptamethyl Cob (I)yrinate as Catalysts

The cob (I)alamin- ( 1(I) ) and the heptamethyl cob(I)ynnate- ( 2(I) ) catalyzed transformation of an epoxide to the corresponding saturated hydrocarbon 3→4→5 is examined (see Schemes 1 and 3–5). Under the reaction conditions, the epoxyalkyl acetate 3 is opened by the catalysts with formation of appropriate (b?-hydroxyalkyl)-corrinoid derivatives ( 13 , 14 , 17 , 18 , see Schemes 12 and 14). Triggered by a transfer of electrons to the Co-corrin-π system, the Co, C-bond of the intermediates is broken, generating the alkenyl acetate 4 (cf. Schemes 12 and 14) following an electrofugal fragmentation (cf. Schemes 2 and 12). The double bond of 4 is also attacked by the catalysts, leading to the corresponding alkylcorrinoids ( 15 , 19 , see Schemes 12 and 14) which in turn are reduced by electrons from metallic zinc, the electron source in the system, inducing a reductive cleavage of the Co, C-bond with production of the saturated monoacetate 5 (see Schemes 2, 5 and 12). In the cascade of steps involved, the transfer of electrons to the intermediate alkylcorrinoids ( 13–15 , 17–19 , see Schemes 12 and 14) is shown to be rate-limiting. Comparing the two catalytic species 1(I) and 2(I) , it is shown that the ribonucleotide loop protects intermediate alkylcobalamins to some extent from an attack by electrons. The protective function of the ribonucleotide side-chain is shown to be present in alkylcobalamins existing in the base-on form (cf. Chap. 4 and see Scheme 14).     

Route Scouting towards a Methyl Jasmonate Precursor

For the synthesis of methyl jasmonate ( 1 ), via the strategic intermediates 3, 4 , and 6a , we constructed a synthetic network via the diverse intermediates 7 – 10, 13, 14, 17 , and 18 . This allowed us to compare the efficiency of more than 20 novel routes. The most productive pathway with a total yield of 38% is represented by the sequence→ 5a → 5m → 13b → 13a → 6a → 4 and proceeds via sequential bromination, basic elimination, decarbomethoxylation, isomerization, and finally Lindlar hydrogenation. The shortest selective way, 2a →[(E,E)‐ 12b ]→ 3 → 4 , is a two‐pot sequence using a modification of Naef's method, based on an aldol condensation between inexpensive cyclopentanone ( 2a ) and crotonaldehyde, with in situ Corey? Chaykovsky cyclopropanation under phase transfer conditions. The key intermediate 3 was then simply pyrolyzed to afford 4 in 27% total yield. The alternative isomerization method via the six‐step deviation→ 5a → 5c → 8c → 13a → 6a → 4 was longer, although more efficient, with a total yield of 32%. Alternatively, a yield of 34% was obtained via the five‐step sequence→ 5a → 5c → 2h → 2i → 4 . Another favored six‐step pathway,→ 5a → 5c → 2h → 17a → 14a → 4 afforded the target compound in 35% total yield.     

Cyclic and Acyclic N═N Bonds in Reactions with Some Alkenes and Dienes

The kinetics of the Diels–Alder (DA) reactions of 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione 1 , trans‐diethyl azodicarboxylate 2 , and tetracyanoethene 3 with 1,3‐cyclohexadiene 4 , cycloheptatriene 5 , 1,3‐cycloheptadiene 6 , cyclooctatetraene 7 , and 1,3‐cyclooctadiene 8 in a range of temperatures and pressures has been studied. Values of the enthalpy, entropy, and volume of activation, as well as the enthalpy and volume of reaction have been obtained. Observed reaction rates of 5+1 and 7+1 have been compared with the known rate of norcaradiene 17 formation in the equilibrium , and that of bicyclo[4,2,0]‐octa‐2,4,7‐triene 20 in the equilibrium . The kinetic data show that the rate of formation of 17 from 5 is much greater than the loss rate of dienophile 1 in reaction of 5+1 . In contrast, the formation rate of tautomer 20 is less than the loss rate of dienophile 1 in reaction of 7+1 . This reflects that the consecutive reaction of 5 → 17 (+ 1 ) → 15 is possible whereas the consecutive reaction of 7 → 20 (+ 1 ) → 22 does not occur as the only way.     

Nucleophilic Addition to CC Bonds,Part X

A mechanistic model is presented for the base‐catalyzed intramolecular cyclization of polycyclic unsaturated alcohols of type A to ethers D (Scheme 1). The alkoxide anion B is formed first in a fast acid‐base equilibrium. For the subsequent reaction to D , a carbanion‐like transition state C is proposed. This mechanism is in full agreement with our results regarding the influence of substituents on the regioselectivity and the rate of cyclization. We studied the effect of alkyl substituents in allylic position (alkylated endocylic olefinic alcohols 1 – 3 ) and, especially, at the exocyclic double bond ( 12 – 15 ). The fastest cyclization (k_rel=1) is 12 → 16 , which proceeds via a primary carbanion‐like transition state ( E : R¹=R²=H). The corresponding processes 13 → 17 and 14 → 17 are characterized by a less‐stable secondary carbanion‐like transtition state ( E : R¹=Me, R²=H, or vice versa) and are slower by a factor of 10⁴. The slowest reaction (k_rel ca. 10⁻⁶) is the cyclization 15 → 18 via a tertiary carbanion‐like transition state ( E : R¹=R²=Me).     

Investigation of the Cyclopentenone Formation via the α-Alkynone Cyclisation: Synthesis of the Acorone Intermediate 8-Methylspiro[4.5]deca-3,7-dien-2-one

As a further application of the cyclopentenone formation A→C via the thermal α-alkynone cyclisation B→C and in order to test the fate of an isolated C,C-double bond within a molecule under these conditions, we investigated the synthesis of the acorone intermediate 3 starting from the known carboxylic acid 1 . The α-alkynone 2 was obtained from 1 via the acyl chloride 6 and a Pd(II)-catalysed route (22%). The thermolysis of 2 at 550° provided the target molecule 3 (48%) together with the product 9 (20%) of a competing intramolecular ene reaction and its dimer 10 (4%). At a higher thermolysis temperature (650°), the spiro ketone 3 was found to be unstable, affording the retro-Diels-Alder fragments 4-methylidene-2-cyclopentenone ( 12 ) (33%) and isoprene (32%). A further example of the influence of an isolated double bond on the yield of the cyclopentenone-formation sequence A→C was provided by the comparison of the annelation 14→20 (5% overall with Pd(II)-catalysed acylation) with that of its non-olefinic analogue 17→21 (53% overall with Friedel-Crafts acylation).     

Synthese einer Calicen-Vorstufe für Retro-Diels-Alder-Reaktionen

Synthesis of a Calicene Precursor for Retro-Diels-Alder Reactions In view of retro-Diels-Alder reactions (RDA reactions), the calicene precursor 9 has been synthesized in a comparably simple four-step synthesis by dibromocarbene addition at dibenzobarrelene ( 10 → 11 , 44%), halogenlithium exchange followed by reaction with cyclopentenone ( 11→12 , 91%) and H₂O as well as HBr elimination ( 12→14→9 , 43%) (Scheme 5). First experiments with respect to the thermal behavior of 9 show that, although RDA reaction seems to be relatively easily occurring according to the results of ‘Curie-Point’ pyrolysis, only anthracene and no calicene 2 has been detected so far.     

Synthesis of Pyrrolidine Analogues of N-Acetylneuraminic Acid as Potential Sialidase Inhibitors

The pyrrolidine derivatives 3 , 4 , and 5 were prepared from the methyl ester 7 of Neu2en5Ac via lie pyrrolidine-borane adduct 33 . They inhibit Vibrio cholerae sialidase competitively with K_i = 4. 4 10^?3 M, 5. 3 10^?3 M, and 4. 0 10^?2 M, respectively. Benzylation of 7 gave the fully O-benzylated 8 besides 9, 10 , and 11. Ozonolysis and reduction with NaBH₄ of 8 and 9 gave the 1, 4-diols 12 and 15 , the hydroxy acetates 13 and 16 , and the furanoses 14 and 17 (Scheme 1), respectively. The diol 12 was selectively protected (→ 19 → 20 → 23 ) and transformed into the azide 27 by a Mitsunobu reaction. Selective base-catalysed deprotection of the diacetate 22 , obtained from 12 , was hampered by an easy acetyl-group migration. The mesylate 28 proved unstable. The azide 27 was transformed via 29 into the ketone 30 (Scheme 2). Hydrogenation of 30 gave the dihydropyrrole 31 and, hence, the pyrrole 32. The adduct 33 was obtained from 30 by a Staudinger reaction (→31) and reduction with LiBH₄/HBF⁴. It was transformed into the pyrroudine 34 . The structure of 34 was established by X-ray analysis. Reductamination of the pyrrolidine-borane adduct with glyoxylic acid gave 40 and, hence, 3. N-Alkylation afforded 44 and, hence, the phosphonate 4. The acid 5 was obtained from 33 by acylation (→ 47 ) and deprotection (Scheme 4).     

Neue Bi(cyclopropylidene) durch CuCl2-katalysierte ‘Carben-Dimerisieiung’ von 1-Bromo-1-lithiocyclopropanen

New Bi(cyclopropylidenes) by CuCl₂-Induced ‘Carbene Dimerization’ of 1-Bromo-1-lithiocycIopropanes A series of so far unknown bi(cyclopropylidenes) 5 are prepared in a simple one-pot reaction by halogenolithio exchange between 1,1-dibromocyclopropanes 1a – c as well as 1e – i and BuLi at ?95°, to give 1-bromo-1-lithiocyclopropanes 2a – c as well as 2e – i , followed by treatment with CuCl₂ at low temperature and a simple workup at room temperature (Table 1). The influence of reaction parameters on yields of 5 (Tables 2, 4, and 5) and diastereoselectivity of the reaction 2 → 5 (Table 3) are discussed. In view of an elucidation of the reaction mechanism, first kinetic experiments of the quantitative reaction 1c → 2c → 5c are reported.     

Generation and Trapping of Triafulvene

Substituted methylidenecyclopropanes 12a – d , being easily available from 1,1-dibromo-2-(phenylthio)-cyclopropane ( 9a ), are attractive precursors of triafulvene (2-methylidene-1-cyclopropene; 1 ). Both the sulfoxide 12b and the sulfone 12c react with an excess of alkoxides (t-BuOK and NaOMe) to give 12e and 12f , respectively, while the sulfinyl group of 12b may be replaced by the PhCH₂S substituent in the presence of PhCH₂SH/t-BuOK. These reactions (Scheme 4) may be explained by assuming 1 as a reactive intermediate, although an alternative sequence including carbene 20 (Scheme 6) is not completely ruled out. D -labelling experiments (Scheme 5) do not give conclusive evidence due to D scrambling, but deprotonation/methylation sequences show that H? C(2) of 12a – c is the most acidic proton. Final evidence for 1 results from the reaction of 12d with cyclopentadienide (Scheme 7): the reaction of 1 with cyclopentadiene produces the expected [4 + 2]-cycloaddition product 23 , while some mechanistic insight results from the sequence 12d → 24 → 25 .     

3-Azawurtzitan und 3(4 → 5)abeo-3-Azawurtzitan

3-Azawurtzitane and 3(4 → 5)abeo-3-Azawurtzitane 3-Azawurtzitane (14) and 3(4 → 5)abeo-3-azawurtzitane (15) as well as derivatives thereof are described. The known tricyclic unsaturated ketone 1 was transformed to the properly functionalized endo-amines 3, 5 and 12. Entry to the azawurtzitane system and its corresponding abeo-compounds was achieved by three different cyclization procedures: aminomercuration with mercuric acetate in water (3 → 14, 5 → 16) , olefin amination with mercuric acetate in dimethyl sulfoxide (3 → 18, 5 → 20 + 21) and intramolecular attack at an epoxide (12 → 24 + 25). Molecular rearrangements of 3-azawurtzitanes to 3(4 → 5)abeo-3-azawurtzitanes and vice versa are described involving neighbouring group participation of the N (3) atom.     

Enantioselective Synthesis of β-Necrodol and of 1-Epi-β-necrodol via Asymmetric 1,4-Addition and Magnesium-Ene Cyclization. Preliminary Communication

Enantiomerically pure β-necrodol ( 1 ) and its 1-epimer 16 have been synthesized starting from aldehyde 5 . The two key steps are an asymmetric conjugate addtion/Mannich reaction tandem ( 10 → 12 ) and a type-II-magnesiumene cyclization/oxidation sequence ( 14 → 1 + 16 ).     

Total Synthesis of β-Bulnesene and 1-Epi-β-bulnesene by Intramolecular Photoaddition

dl-β-Bulnesene (1) and dl-1-epi-α-bulnesene (15) have been synthesized starting from the bromide 4 (Schemes 2 and 3). In the key step 9→10 the bonds of the final product were formed by an intramolecular photoaddition. The synthesis was completed by the fragmentation 12→14 and the Wittig reaction 14→15+1 .     

The Enantioselective Synthesis of 3-Methoxy-1, 3, 5 (10)-estratrien-11, 17-dione by a Thermal Intramolecular Cycloaddition Reaction. Preliminary communication

The enantiomerically pure (+)-3-methoxy-1, 3, 5 (10)-estratrien-11, 17-dione 11 (with trans-anti-trans configuration) was synthesized in a highly stereocontrolled fashion from (±)-t-butyl 4-methoxy-1-benzocyclobutene carboxylate (8) and the (+)-carboxylic acid 6 , obtained from 4 in two steps, followed by one crystallization of the (+)-ephedrine salt. The key step 10→11 (Scheme 2) involves a thermal intramolecular cycloaddition reaction.     

Säurekatalysierte Umlagerungen von 1,5-Dimethyl-6-methyliden-tricyclo[3.2.1.02,7]oct-3-en-8endo-olen

Acid Catalysed Rearrangement of 1,5-Dimethyl-6-methyliden-tricyclo[3.2.1.0^2,7]oct-3-en-8endo-ols The tricyclic alcohols 2,3,4 and 6 (Scheme 1) are synthesized by the reaction of the tricyclic ketone 1 with sodiumborohydrid or metalloorganic reagents. Their configuration at C(8) is determined by NMR. in the presence of Eu(fod)₃. The exo-attack of 1 by the nucleophil forming the endo-alcohol is favored, the π-electrons of C(3) = C(4) hindering the endo-attack. On treatment with sulfuric acid in dioxane/water at 25° the tertiary alcohols yield aryl-substituted ketones. 3 gives in 78.5% yield a mixture of the 3-(dimethylphenyl)-2-butanones 12 and 13 , in addition to 16.5% of (2,3,4-trimethylphenyl)-2-propanon ( 14 ) (Scheme 2). The alcohols 4 and 6 yield mixtures of the 2-(dimethylphenyl)-3-pentanones 19 and 20 (72%), and 2-(dimethylphenyl)-propiophenones 21 and 22 (68%), respectively (Scheme 2). In the case of the secondary alcohol 2 mainly products derived from hydration at the C(6), C(9) double bond are formed, namely the mixture of diols 23 and 24 (21%), and the mixture of the isomeric 2-(dimethylphenyl)propanals 25, 26 and 27 (3%) (Scheme 3). - The structures of 12–14, 19/20, 21/22, 23/24 and 25/26/27 were established by spectroscopic data. In the case of 12 and 13 the degradation of their mixture to the known 1-(dimethylphenyl)ethanols 17/18 confirmed the assignment. - The most probable mechanism for the rearrangement of 3 is shown in Schemes 4 and 5. The reaction proceeds from 3 through a, b and g to 12 and 13; 14 is formed via e, f and i . In the case of 4 and 6 only the reaction analogue to 3 → a → b → g ?12/13 takes place. The isomeric aldehyds 25–27 formed from 2 could have the structures s, t , and v . The former two could be generated in a similar way as 12/13 from 3 , the latter one as shown in Scheme 8.     

Acid-Catalysed Backbone Rearrangement of cholesta-6,8(14)-dienes

Rearrangement of 5α- and 5β-cholesta-6,8(14)-dienes ( 13a and 13b , resp.) in the presence of anhydrous toluene-4-sulfonic acid in acetic acid leads to 5α- and 5β-12(13 → 14)-abeo-cholesta-8,13(17)-dienes ( 15a and 15b , resp.) via 5α- and 5β-cholesta-8,14-dienes ( 14a and 14b , resp.), respectively. Epimerization at C(20) of the spirosteradienes 15a and 15b occurs with increasing reaction time. Molecular-mechanics calculation of the relative stabilities of these compounds and of congeners thereof is in agreement with the observed reaction pathway.     

Asymmetric α-Acetoxylation of Carboxylic Esters. Preliminary Communication

Using the readily accessible chiral auxiliaries 1 – 3 the sulfonamide-shielded O-silylated esters 5 underwent π-face-selective α-acetoxylation on successive treatment with Pb(OAc)₄ and NEt₃ HF to give after recrystallization α-acetoxy ester 6 in 55–67% yields and in 95–100% d.e. Starting from conjugated enoates addition of RCu and subsequent acetoxylation 10 → 11 → 12 yielded α,β-bifunctionalized esters 12 with >95% configurational control at both C_α and C_β. Nondestructive removal of the auxiliary ( 6 → 7 , 6 → 8 and 12 → 13 ) gave either α-hydroxycarboxylic acids or terminal α-glycols in high enantiomeric purity. The prepared glycols 8c and 13a are key intermediates for previously reported syntheses of the natural products 16 and 17 , respectively.     

Totalsynthese von natürlichem α-Tocopherol. 2. Mitteilung. Aufbau der Seitenkette aus (−)-(S)-3-Methyl-γ-butyrolacton

Total Synthesis of Natural α-Tocopherol A short and efficient route to optically pure (+)-(3 R, 7 R)-trimethyldodecanol ( 14 ) is demonstrated, 14 serving as side chain unit in the preparation of natural vitamin E. The synthesis of 14 is based on the concept of using a single optically active C₅-synthon of suitable configuration and functionalization to introduce both asymmetric centres in 14 . (?)-(S)-3-Methyl-γ-butyrolacton ( 1 ) and ethyl (?)-(S)-4-bromo-3-methylbutyrate ( 2 ), respectively, is used in a sequence of either two Grignard C,C-coupling reactions 5 → 8 and 12 → 13 or two Wittig reactions 17a → 18 and 20 → 21 to achieve this goal. 14 is converted to (2 R, 4′R, 8′R)-α-tocopherol (= vitamin E) by coupling with a chroman unit in known manner. Optical purity of products and intermediates is established.