Hydroxy-ketone cyclization

Scheme 10. Synthesis of compound 49 by the reductive hydroxy ketone cyclization method.

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

Scheme 11. Bis(oxepane) synthesis using a photochemical dithioester cyclization and a reductive hydroxy ketone cyclization.

The mechanism is analogous to the hydroxy-ketone cyclization except that the mixed ketal is isolable. It can be reductively cleaved using PhsSnH/AIBN ... 

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

A key step in the approach to 3(2//)-furanone ring systems via the acid-catalyzed cyclization-dehydration of appropriately substituted a -hydroxy-l,3-diketones involves the acylation of a-hydroxy-ketone dianions 11141... 

The cyclization of y -hydroxy ketones is useful for the formation of pyrans,306,403 both directly and via rearrangement, as illustrated in Eq. 231.153 As with their acyclic counterparts, these cyclizations also occur with the silyl ethers of the hydroxy ketones where Et3SiH/BiBr3 is used with the TBS and TES ethers.342,404 A methyl thiomethyl ether is also capable of undergoing the reductive cyclization 405 In like manner, 1,4-diols and e-hydroxy ketones provide oxepanes, with I ds Si H or PhMe2SiH/TMSOTf being especially effective (Eqs. 232 and 233).336,406 The trimethylsilyl ether of the alcohol also provides the oxepane.306... 

Three tactical approaches were surveyed in the evolution of our program. As outlined in Scheme 2.7, initially the aldol reaction (Path A) was performed direcdy between aldehyde 63 and the dianion derived from tricarbonyl 58. In this way, it was indeed possible to generate the Z-lithium enolate of 58 as shown in Scheme 2.7 which underwent successful aldol condensation. However, the resultant C7 P-hydroxyl functionality tended to cyclize to the C3 carbonyl group, thereby affording a rather unmanageable mixture of hydroxy ketone 59a and lactol 59b products. Lac-tol formation could be reversed following treatment of the crude aldol product under the conditions shown (Scheme 2.7) however, under these conditions an inseparable 4 1 mixture of diastereomeric products, 60 (a or b) 61 (a or b) [30], was obtained. This avenue was further impeded when it became apparent that neither the acetate nor TES groups were compatible with the remainder of the synthesis. 

Several syntheses of tetrahydropyrans revolve around the cyclization of 1,5-hydroxy-ketones, the differences between them lying in the routes to the acyclic precursors. 

TL4391). The benzologs of naphtho[bc]furan-6-ones 60 (so-called furan-anthrones) are obtained by cyclization of anthracene peri-hydroxy ketones 58 or carbomethoxychloromethylanthraquinones 59 (80MI3 84ZOR818). 

Treatment of tertiary a-hydroxy ketones with chlorosulfonyl isocyanate yields intermediates which are hydrolyzed to carbamates. The latter cyclize to 2(5//)-oxazolones on heating (equation 143). Acetone cyanohydrin is converted into the chloro derivative (292) by the... 

Hydrolysis of alkylated products and carbonyl compound adducts derived from a-lithiated DHF and DHP with 2 M HC1 in THF at room temperature gave y- and 5-hydroxy ketones, respectively824,865 (Scheme 162). Jones oxidation generated keto acids866,887 and when the R substituent bears an hydroxy group, cyclization occurred in the presence of pyridinium tosylate (PPTS) in CH2C12 or HC1 in ether to provide spiroketals875,883,894,901. 

Aldol condensation. The final step in a synthesis of the tricyclic taxane ring system involves an intramolecular aldol condensation of 2. Treatment with the usual bases results in a retro Michael reaction, but the desired cyclization to 3 can be effected in 90% yield by use of bromomagnesium diisopropylamide (1) or isopropylcyclohexylamide. The hydroxy ketone undergoes retroaldolization in the presence of mild acids or bases, but can be reduced and stored as the corresponding stable diol. 

Spiroketalization. The synthesis of talaron ycin B (3) with four chiral centers by cyclization of an acyclic precursor presents stcrcot hcmical problems. A solution involves cyclization of a protected (3-hydroxy ketone witii only one chiral center. Because of thermodynamic considerations (i.e.. all substituents being equatorial and the anomcric effect), cyclization of 1 with HgCl, in CH,CN lollowcd by acetonation results in the desired product (2, 65% yield) with a stereoselectivity of —10 1. Final steps involve conversion of the hydroxymethyl group to ethyl by tosylation and displacement with lithium dimethylcupratc (80% yield) and hydrolysis of the acetonidc group. 

In addition to the foregoing 1,4-difunctional compounds used for cyclizations, the following have been used to give pyridazines or theirreduced analogs , 4-hydroxy ketones, l,4-haloketones, l,4-dibromobutane, 2,5-dibromohexane, 1,4-halo-esters, or butadiene dioxide. Hexahydropyridazine results as one of the oxidation products of 1,4-diaminobutane and its 1-butyl analog is formed in the reduction of iV-nitroso-4-chloro-dibutylamine. ... 

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