Tetrahydropyranyl ether → HCID 131732512, compound

HRID 1855022Notes

Reaction equation

O1CCCCC1OC1CCCCO1.[Li]CCCC.[S:19]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([OH:22])(=[O:21])=[O:20].[S:30]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)([OH:33])(=[O:32])=[O:31].[C:41]1(=[O:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[S:19]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([OH:22])(=[O:21])=[O:20].[S:30]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)([OH:33])(=[O:32])=[O:31].[CH:41]1([OH:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1

Participants

Reactant 3

HCID 263182Tetrahydropyranyl ether

HCID 131732513HCID 131732513, compound

HCID 178418339Butyllithium

Product 1

HCID 131732512HCID 131732512, compound

Procedure

Scheme 5 shows the synthesis of more highly substituted aryl analogs 19. A suitably protected hydroxy aryl bromide (e.g., as an acid-labile tetrahydropyranyl ether that can be deprotected selectively in the presence of an ester) is lithiated (e.g., n-BuLi) and reacted with cyclohexanone bis-tosylate 1 to give the corresponding cyclohexanol bis-tosylate 14. Base-mediated intramolecular reaction of the alcohol with a tosylate of 26 provides the oxabicyclo[2.2.2]tosylate 15 (same 2 steps as in Scheme 1). The tosylate 15 is then converted in the same 3 step sequence as described in Scheme 4 to give the 2-oxy-substituted ester 16. Selective deprotection of the phenol is then achieved under mild acid conditions to give phenol ester 17. The phenol intermediate 17 is then subjected to an O-arylation reaction (e.g., Chan-Lam coupling reaction with aryl boronic acids; examples in Qiao, J. et al., Synthesis, 829 (2011)) to give the aryl ethers 18, followed by ester deprotection to give the corresponding 2-oxy-substituted carboxylic acid analogs 19.

Sources & evidence

ORD record: ord-75b095d3ad31468995f559de5f75cab2
Source dataset: uspto-grants-2015_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08962660B2

Reaction notes

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