Cyclobutanol synthesis

Cp2TiCl . Hydrogen atom abstraction from THF seems possible, also. Most remarkably, the reaction can be employed in the efficient synthesis of cyclopropanols and cyclobutanols as shown in Scheme 28. 

This efficient cyclobutanol forming reaction has been utilized in the synthesis of terpenes404) (4.4), medium ring compounds40s) (4.5) and strained molecules as in (4,6)406) and (4.7) 407). In the last example the tricycloP. O.O jhexane skeleton is formed. 

The alkoxide generated by KH in THF was believed to be effective in accelerating the vinylcyclobutane ring expansion in the synthesis of 6-membered ring compounds 142). As an example, the cyclobutanol (416) reacted with KH and rearranged to (417), which upon subsequent oxidation, provided (418) 142) in 64.5% yield. The a,P-unsaturated ketone (418) was converted to (—)- 3-selinene (419)142). Similarly, furancyclohexanol (421) could be obtained from the cyclobutanol (420) 142). 

In a more constrained system 2, cyclobutanol formation can also be more efficient15. Note that in Ihis case, it is also highly diastereosclcctive. This photocyclization is a key step in the total synthesis of the sesquiterpene antibiotic (—)-punctatin. 

Treatment of 5-bromo-3,4-dihydro-2ff-pyran with complex bases generates 3,4-dehydrodihydropyran (3), which reacts with ketone enolates to yield fused cyclobutanols (4) and the derived ketones (5) (95T1973). Both (4) and (5) are of value in the synthesis of polycyclic O-heterocycles (95SL742). 

Griesbeck, A.G. and Heckroth, H. (2002) Stereoselective synthesis of 2-amino-cyclobutanols via photocyclization of... 

Murakami, M., Kamaya, H., Kaneko, C and Sato, M. (2003) Synthesis of optically active 1,3-dioxin-4-one derivatives having a hydroxymethyl group at the 2-position and their use for regio-, diastereo-, and enantioselective synthesis of substituted cyclobutanols. Tetrahedron Asymmetry, 14, 201-215. 

Solid supported isoxazolines 40 were prepared starting from a sulfmate-functionalised resin 38. Oxidation of the resin linked cyclobutanols 40, with concomitant cleavage of the sulfone linker, produced isoxazolinocyclobutenones 41 in 34-38% overall yield (4 steps) <02OL741>. A five-step solid phase synthesis of isoxazolino-pyrrole-2-carboxylates that employing the same traceless sulfone linker strategy has also been reported <02JOC6564>. 

In 1993, Corey reported the first synthesis of paeoniflorin.56 The core of paeoniflorin was constructed using a Sml2-mediated Reformatsky-type reaction (Scheme 7.16). Treatment of a-chloronitrile 31 with Sml2 gave cyclobutanol 32 in excellent yield. The sensitivity of cyclobutanol 32 to base precluded the use of more conventional aldol-type cyclisations.56... 

Three successive [2+4] cycloadditions were used in the synthesis of the pentacyclic methyl ether of G-2N by Kraus and Zhao [92] and later, by a slightly modified procedure, also of the natural product G-2N (118) [93] (Scheme 31). Thermal reaction of the cyclobutanol 112 with acrylic ester gave the dihydronaphthalene 113 which was demethylated by treatment with boron tribromide and converted into the exocyclic ketene acetal 114. This unstable diene was reacted in a second cycloaddition with 2,6-dichlorobenzoquinone (115) to afford the tetracyclic chloroquinone 116. In a last Diels-Alder reaction, ring E was anella-ted by treatment of 116 with l-methoxy-l,3-bis[(trimethylsilyl)oxy]-l,3-buta-diene (117) to yield the pentacyclic natural product G-2N (118) [93]. 

Ring expansion of cyclopropylcarbinol to cyclobutanol is the basis of an efficient cyclobutene synthesis (equation 25). An elegant approach to polycyclic hydrocarbons is realized by a cascade of cyclopropylcarbiny 1-cyclobutyl rearrangements (equation 26) . 

The Barbier reaction has been used for the synthesis of alcohols that were difficult to prepare by normal Grignard reagent techniques. This is particularly true for the preparation of cyclic alcohols from halogenated ketones. Several researchers [49-51] have shown that cyclobutanols and cyclopentanols can be prepared in good yields from <5- and y-iodo- and bromoketones in either solvents with Mg or Mg/HgCl2 [Eq. (17)]. 

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