Tetrahydropyran Systems

Developing electron-deficient orbital Is stabilized by conjugation with jc-orbita in a planar arrangement 

It is important to emphasize that the hydroxy dithioketal cyclization can be conducted under mild reaction conditions and can be successfully applied to a variety of substrates.15 However, the utility of this method for the synthesis of didehydrooxocane-contain-ing natural products requires the diastereoselective, reductive removal of the ethylthio group. Gratifyingly, treatment of 13 with triphenyltin hydride and a catalytic amount of the radical initiator, azobisisobutyronitrile (AIBN), accomplishes a homolytic cleavage of the C-S bond and furnishes didehydrooxocane 14 in diastereo-merically pure form (95 % yield), after hydrogen atom transfer. 

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In order to overcome the special problems posed by brevetoxin B s tetrahydropyran systems, the decision was made to develop and test regio- and stereoselective ring closures employing two types of substrates hydroxy epoxides and hydroxy a,/ -unsaturated esters. The basic concepts of these reactions are shown in Schemes 1 and 2, respectively. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

Steric effects similar to those shown in equations (39) and (40) are found when the substitution pattern leads to tetrahydropyran systems through 6-endo cyclization. Cyclizations of systems with an allylic oxygen and a syn alkene substituent give products rationalized by cyclization through H-in-plane conformations as shown earlier in equations (31) and (32).105 128 Examples with allylic methyl substitution have been reported also.1040... 

Nicolaou, KC, Prasad, C VC, Somers, PK, Hwang, CK, Activation of 7-emio over 6-exo epoxide openings. Synthesis of oxepane and tetrahydropyran systems, J. Am. Chem. Soc., Ill, 5335-5340, 1989. 

Acid-catalyzed opening of saturated hydroxy epoxides via intramolecular participation of the hydroxyl group leads to regio- and stereoselective formation of tetrahy-drofuran and tetrahydropyran systems. 

Nicolaou, K.C., Duggan. M.E.. Hwang. C.K., and Somers, P.K., Activation of 6-endo over 5-exo epoxide openings. Ring-selective formation of tetrahydropyran systems and stereocontrolled synthesis of the ABC ring framework of brevetoxin B, J. Chem. Soc.. Chem. Commun.. 1359. 1985. 

Electronegative substituents (alkoxy groups, halogens) in the 2(6) position of the tetrahydropyran system prefer to adopt the axial position in the conformational equilibrium. 

The increase of the A-value on protonation is the measure of the increase in size of the protonated substituent relative to the unprotonated one. This extra bulk is due to the additional proton itself and also to the additional solvent molecules attached to the positive charge needed to stabilize it The increase in protic solvent is due to hydrogen bonding, which clusters solvent molecules around the polar group [63, 64]. Since the C-O bond is shorter than the C-C bond, steric repulsimis in the tetrahydropyran system with the axially oriented 2-amino group are greater than in the cyclohexane system with the axially oriented amino group, and should be corrected to 2-2.5 kcal/mol for aprotic solvents and 2.4—2.9 kcal/mol for protic solvents. 

Nicolaou KC, Prasad CVC, Somcas PK, Hwang C-K (1989) Activation of 6-endo over 5-exo hydroxy epoxide openings. Stereoselective and ring selective synthesis of tetrahydrofiiran and tetrahydropyran systems. J Am Chtan Soc 111 5330-5334... 

Thromboxane A2 (Figure 14) and thromboxane B2 both have a tetrahydropyran system in their chains. 

A new entry into the tetrahydropyran system is suggested by some work on adamantanes. Treatment of adamantan-2-ol in CCI4 or benzene with HgO and I2, followed by irradiation with a tungsten lamp at 70 °C, gives a 50% yield of oxa-adamantane (235). Similar treatment of cyclohexanol gives a 2%... 

The incorporation of heteroatoms can result in stereoelectronic effects that have a pronounced effect on conformation and, ultimately, on reactivity. It is known from numerous examples in carbohydrate chemistry that pyranose sugars substituted with an electron-withdrawing group such as halogen or alkoxy at C-1 are often more stable when the substituent has an axial, rather than an equatorial, orientation. This tendency is not limited to carbohydrates but carries over to simpler ring systems such as 2-substituted tetrahydropyrans. The phenomenon is known as the anomeric ect, because it involves a substituent at the anomeric position in carbohydrate pyranose rings. Scheme 3.1 lists... 

In the cyclization of the corresponding cis-epoxides, with the aim of obtaining the corresponding cis-2,3-disubstituted tetrahydropyrans, a similar trend was observed. For these systems, however, the 6-endo pathway was less favored, which was ascribed to difficulties in attaining a TS conformation that would allow for maximum stabilization of the developing p-orbital with the adjacent 7t-system. Alternatively, palladium-catalyzed cyclization of the tetrabutylammonium alkoxide derived from 33b results in the corresponding ris-2,3-disubstituted tetrahydro-pyran in excellent yield and selectivity (90%, dr >99 1), while the ris-epoxide gives stereoisomer 37b (86%, dr 98 2) [112]. 

The cyclization of the homologous epoxide 36 under acidic conditions was also investigated (Table 9.5) [110]. As would be expected, compound 36a reacted by a 6-exo cyclization to give tetrahydropyran 38a (Entry 1). The a, 3-unsaturated hydroxy epoxide 36b gave a 1 3.5 mixture of oxepane 37b and tetrahydropyran 38b (Entry 2). Subjection of 36c and 36d, which both contain more electron-rich 71-systems, to the reaction conditions resulted in preferential 7-endo cyclization to give 37c and 37d, thus confirming the powerful regiodirecting effect of the vinyl moiety (Entries 3 and 4). 

The outcomes of intramolecular cyclizations of hydroxy vinylepoxides in more complicated systems can be difficult to predict. In a study of the synthesis of the JKLM ring fragment of dguatoxin, epoxide 44 was prepared and subjected to acid-mediated cydization conditions (Scheme 9.24) [114]. Somewhat surprisingly, the expected oxepane 45 was not formed, but instead a mixture of tetrahydropyran 46 and tetrahydrofuran 47 was obtained, both compounds products of attack of the C6 and C5 benzyl ether oxygens, respectively, on the allylic oxirane position (C3). Repetition of the reaction with dimsylpotassium gave a low yield of the desired 45 along with considerable amounts of tetrahydropyran 48. 

Zur Reduktion von Alkin-al-dialkylacetalen mit Lithiumalanat zu Allylalkoholen s. Lit.7, 2-[Propin-(2)-yloxy]-tetrahydropyran wird durch das System Natriumbora-nat/Trialkyl-zinnhydrid in Athanol leicht hydrostanniert, z. B.8 ... 

Phenylthio)nitroalkenes are also excellent intermediates for the synthesis of other heterocyclic ring systems. For example, tetrahydropyran carboxylic acid derivatives are formed by the intramolecular addition of oxygen nucleophile to l-(phenylthio)nitroalkene predominantly as the m-isomer (9.1 1) (see Eq. 4.40). The reaction may proceed via the chair-like transition state with two pseudo-equatorial substituents.50... 

The bottle is connected to the hydrogenation apparatus and alternately evacuated and filled with hydrogen twice. Hydrogen is then admitted to the system until the pressure gauge reads 40 lb. The shaker is started, and the pressure drops to the theoretical value for absorption of 0.6 mole in 15-20 minutes beyond this point shaking causes no further absorption of hydrogen (Note 2). The bottle is removed and the nickel catalyst is allowed to settle. The tetrahydropyrane is decanted, but enough... 

To illustrate signal assignments in 13C NMR spectra of the benzotriazol-l-yl system, chemical shifts for five a-(benzotriazol-l-yl)tetrahydrofurans (structures 39-43) <2003JP0158> and three corresponding tetrahydropyrans (structures 27-29) <2001CJC1655> are listed in Table 5. Selected 13C NMR spectral data for triazolyl nucleoside analogs 44-50 <2003SPL461> are collected in Table 6. 

Prolonged reaction of the triols 25 with trimethyl orthoacetate and a weakly acidic catalyst affords a mixture of the 5- and 6-membered oxacycles from which the tetrahydropyran is obtained on equilibration (Scheme 13). By selection of the reaction conditions, it is possible to obtain either ring system exclusively <00CC1781>. 

There are relatively few entries in the non-fused dioxepin area, and most of these focus on reactions of these systems. For example the triflic acid-initiated polymerisation of 1,3-dioxepane in the presence of acetic acid and hexanedicarboxylic acid has been studied and mechanistic aspects discussed <00JPS(A)1232>. Biodegradable microspheres for the controlled delivery of drugs have been made from copolymers and homopolymer blends of L-lactide and l,5-dioxepan-2-one <00PP1628>. Ring contraction of 5-methylene-l,3-dioxepanes (eg. Ill) on reaction with trimethylsilyl trifluoromethanesulfonate in the presence of base afforded the exo tetrahydropyrans, in good yields <00TL2171>. 

Japanese researchers varied aryl substituent at C-4 in nitronate (147), LA, and the reaction conditions, they used successfully diastereomerically pure nitronates (147) (Scheme 3.121) for the synthesis of various fused-ring systems, such as benzofuro-[3,2-d]-l,2-oxazines (322), furo-[3,4-d]-isoxazoles (323—326), indolo-[2,3-b]-l-pyrroline 1-oxides (327), 4//-1,2-benzoxazines (328), benzofuro-[2,3-c]-tetrahydropyrans (329), and monocyclic 1,2-oxazines (330). 

This article deals with the conformational analysis of substituted oxanes (tetrahydropyranes) and derivatives in which ring methylenes are replaced by further oxygen atoms (di-, tri-, tetroxanes, pentoxanes, and O ) or by carbonyl group(s) (oxanones, Meidrum s acid derivatives) and, if conforma-tionally of interest, systems incorporating these rings in polycyclic structures... 

Precedent had been established for mercury (II) mediated cycloetherification reactions (24,25) but not in such a highly functionalized molecule and to give a strained system. Since it was also known that oxidative removal of the mercury transformed the alkylmercurial into an alcohol (26), this method would not only allow access to the tetrahydropyran portion of the molecule, but the criterion of a functionalized terminus (C-8 ) would also be met. 

Common substructural motifs in polyketide natural products are six-membered ring lactones, lactols, and tetrahydropyrans. It was recognized by Wuts and co-workers that hydroformylation of readily available homoaUyhc alcohols would provide a direct and efficient entry into these ring systems. Such an approach was employed in a synthesis of Prelog-Djerassi lactone (Scheme 5.11) [13]. 

Tetrahydropyrans hydroxylated at the 4-position have good synthetic value [113]. Although many synthetic methods have been reported [17-23,114,115], the search for potential alternate approaches and the development of eco-friendly and high-yielding reactions resulted in the development of a method that poses less problems for the environment. Synthesis of tetrahydropyranol derivatives can be achieved through the Prins-type cyclization reaction of homoallylic alcohols with aldehydes using bismuth triflate as catalyst in [bmim]PF6 solvent system [108] (Fig. 22). 

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