Bicyclic dihydropyrans

Intramolecular [4 + 2]cycloaddition of an enaminelenal(enone). Generation in situ of an aldehyde enamine of a substrate also containing an enal or enone group can result in a facile intramolecular [4 + 2]cycloaddition resulting in bicyclic dihydropyrans. Although several sec-amines can be used, N-methylaniline is particularly suitable because of the stability of the adducts. 

Bicyclic acylcyclobutanes underwent rearrangement at 210 °C to give bicyclic dihydropyrans 2.120 At 150-180 °C a competing Cope rearrangement of the corresponding enol to give 1 predominated.120... 

The sigmatropic reaction is only possible if the proper arrangement of the C—O and the C-C double bonds can be attained. Thus, within 24 hours at room temperature, the endo-nor-bornenyl derivative rearranged quantitatively to the bicyclic dihydropyran 5, whereas the exo-compound was stable2... 

Radical addition of allyl alcohol to cyclododecanone and dehydrative cycli-sation gives a bicyclic dihydropyran. The ring-opening of the cyclic acetal of cyclododecanone with triisopropylaluminium and reclosure using trifluoro-methanesulfonyl anhydride provides an interesting alternative. The 15-hydroxy-pentadecanoic acid is then accessible by means of nitrosation, followed by Wolff-Kishner reduction. Apart from the reduction with hydrazine, catalytic, electrochemical and Clemmensen reduction are also well-established. 

As an alternative to depolymerisation, ring expansions, starting from a common intermediate, have been developed. Hydrogen peroxide adds regiospecificallyto the bicyclic dihydropyran. The hydroperoxide reacts with a second molecule of the educt. Thermolysis leads eventually to exaltolide, with xylene serving as the hydrogen donor. Small amounts of 15-pentadec-ll-enolide are formed as a by-product (Tab. 3.6). 

A domino reaction involving two consecutive oxidations followed by a hetero Diels-Alder reaction led to the formation of bicyclic dihydropyran 14 in 74% yield (Scheme 9.3). In this process, developed by Koo et al. [5] using Mn(OAc)3 and Cu(OAc)2, the P-ketoester 11 having a geranyl group at the a-position is converted into the a-ketoester 12, which undergoes further oxidation to form the tertiary alcohol 13 and is followed by an intramolecular hetero Diels-Alder reaction to provide the desired bicyclic trans-fused dihydro cyclopenta[c]pyran 14. In 2012,... 

The reaction between cyclohexanone enamines and a variety of benzylidene ketones gives rise to some bicyclic dihydropyran derivatives (129). ... 

The reaction of Mannich bases of cycloalkanones with ethyl vinyl ether gives rise to bicyclic dihydropyran derivatives (265), several of whose reactions were investigated. ... 

Ring expansion of tetrahydrofurans to dihydropyrans results when their 2-W-aziiidinyl imines are heated <96CC909> and when their 2-ca-alkyl bromides are treated with Ag20 in a nucleophilic acidic solvent <96JCS(P1)413>. Alkyl carbenes and bicyclic oxonium ion intermediates are invoked, respectively. 

Two syntheses of hongconin (18), a naturally occurring isochroman-4-one which exhibits antianginal activity, have been described. One utilises the annulation of phthalide unit to optically pure dihydropyran-3-ones <96JOC455>, whilst a similar Michael addition to the bicyclic pyranone levo ucosenone and subsequent enolate methylation are essentials of the second route <96JOC459>. 

Further experiments with diols such as 42 and 46 showed that bicyclic acetals 44 and 48 are formed (Scheme 15.9) [21]. With AgN03 the dihydropyrans 45 and 49 were always observed as side-products. 

A substituted dihydropyran, 3,4-dihydro-2-(hydroxymethyl)-2ff-pyran (176), was employed by R. K. Brown and coworkers76 77 as the substrate in a total synthesis of hexoses (see Section III,2). The first steps in this method consisted in (1) intramolecular addition of the hydroxyl group to the double bond, to afford the bicyclic compound 177, and (2) bromination of 177 to the monobromo derivative 178. 

Carbenes add to the double bond of dihydropyrans, as they do to benzopyrans, to form cyclopropapyrans. For example, dichlorocarbene reacts with 2,3-dihydro-4//-pyran (593) to give the bicyclic pyran (618) which on heating at reduced pressure with quinoline undergoes ring expansion to the 3-chlorooxepine (620) the two chlorine atoms are removed by sodium-ammonia (60JA4085). The reaction of dihalocarbenes with pyrans and benzopyrans has been reviewed (630R(13)55). 

The reaction of a,/3-unsaturated carbonyl compounds with enamines also leads to dihydropyrans, although it is not always possible to isolate these since they react further to give either ring-opened by-products or bicyclic derivatives arising from a Stork annelation. There has been considerable discussion on the mechanism of this reaction, although the initial nucleophilic attack of the enamine on the /3-carbon of the diene is not in doubt (63JA207). It is possible that a zwitterionic species is involved, either as an intermediate or merely in equilibrium with the dihydropyran (67JCS(C)226). 

A double intramolecular carbopalladation reaction of the g< -di bromide 250 provides a route to the bicyclic 3,6-dihydropyran 251 in high yield (Equation 112) <1998JOC9156>. 

The stereoselective formation of cw-fused dihydropyrans and the steric requirements for the reaction of the norbornenyl examples support a concerted mechanism. However, boron trifluoride catalyzed rearrangements of mixtures of endo- and exo-compounds to bicyclic pyrans, i.e., stepwise reactions through cationic intermediates, are also possible38. 

Interesting compounds that have been acquired from the metathesis process include bicyclic P-lactams (also those comprising a diene unit by the enyne metathesis ), a-stannyl cyclic ethers, cyclic siloxanes which can be opened to afford (Z)-alkenediols, spiroannulated dihydrofurans and dihydropyrans, and [2]catenanes from precursors organized by Cu(I). ... 

Similar reactions using dihydropyrans and dihydrofurans furnish cyclobutanes or alkenol products upon hydrolysis (Scheme 18). As with the previous applications, zirconacyclic intermediates are implicated. Differences in stereochemistry in the observed products versus the open chain vinyl substrates are thought to arise from geometric restrictions imposed by the bicyclic intermediates. 

Schweizer and Parham prepared 2-oxa-7,7-dichloronorcarane (6) by generating dichlorocarbene in the presence of dihydropyrane and converted the bicyclic compound (6) into 2,3-dihydro-6-chlorooxepine (7) in good yield by heating it with quinoline at 140-150° (7) distilled as formed. 

The l,4 5,6]-typc dihydropyran rearrangement of 1 leads to bicyclic compounds 2321. 

Protonation in methanol first unravels three of the rings to generate the hydroperoxy acetal (102) (Scheme 14). Condensation to (103) followed by cyclization to the dioxetane (104) and cleavage furnishes the pivotal intermediate (105). The latter has the chance to undergo acid-catalyzed bicyclization either through the aldehyde or acetyl function to give the two sets of dihydropyrans... 

In order to cleave the bicyclic C-glycoside to the desired functionalized dihydropyran, 284 was exposed to sodium amalgam. Syn-dihydroxylation of 285 (OSO4-NMO) gave a mixture of diastereomeric tetrads, which after separation, protection-deprotection procedure and oxidation of the product C-l alcohol, using generated in situ ruthenium tetraoxide, gave the acid 254. 

Bicyclic lactones are produced" when dihydropyran and malonic monomethyl ester are treated with CAN and Cu(OAc)2, preferably with ultrasound irradiation. 

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