HCID 10785305, compound → HCID 22878256, compound

HRID 1489212Notes

Reaction equation

[OH:1][C@@:2]1(C)[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C@H:4]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Br:19])=[CH:13][C:12]=2[OH:20])[C:3]1=[CH2:21].O[C@]1(C)CCC(C)(C)[C@H](CC2C=C(OC)C(Br)=CC=2O)C1=C>>[CH2:21]=[C:3]1[C@@H:4]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Br:19])=[CH:13][C:12]=2[OH:20])[C:5]([CH3:8])([CH3:9])[CH2:6][CH2:7][C:2]1=[O:1]

Participants

Reactant 2

HCID 10785305HCID 10785305, compound

HCID 22878253HCID 22878253, compound2×

Product 1

HCID 22878256HCID 22878256, compound

Procedure

To a flame-dried 50 mL round-bottomed flask containing a solution of (3S)-2-methylidene-3-(2-hydroxy-4'-bromo-5'-methoxyphenyl)methyl-4,4-dimethylcyclohexan-1-one (61) (150.0 mg, 0.322 mmol) in 15 mL THF at -70° C. under nitrogen atmosphere was added methyllithium (0.60 mL of a 1.40M solution in ether, 0.840 mmol, 2.61 equiv), and the mixture was allowed to stir for 5 min before quenching with saturated aqueous NH4C1. Upon warming to room temperature, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over Na2SO4, and concentrated under diminished pressure gave a 3:1 (1R,3S: 1S,3S) mixture of the diastereomeric tertiary hydroxyls. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, gradient elution) afforded 28 mg (18%) of the less polar, minor 1S,3S isomer (63), along with 88 mg (57%) of the more polar, major 1R,3S isomer (62), as well as 30.2 mg (20%) recovered starting material. The diastereomeric alcohols were then independently converted to the corresponding free phenols in the usual manner, providing the trans, 1R,3S isomer (62) 1H NMR (400MHz, CDCl3) δ0.84 and 1.04 (2s, 2×3 H, geminal-CH3 's), 1.39 (s, 3H, 5-CH3), 2.43 (br dd, 1H, J-- 11.3, 2.9 Hz, 3-H), 2.72 and 2.85 (d of ABq, 2H, JAB =16.1 Hz, JA =3.1 Hz, JB =11.5 Hz, benzylic-CH2) 3.77 (s, 3H, OCH3), 4.57 and 5.16 (2s, 2×1H, methylidene-CH2), 6.63 (s, 1H, 6'-H), 6.93 ppm (s, 1H, 3'-H); and the cis, 1S,3S isomer (63) 1H NMR (400MHz, CDCl3) δ0.77 and 1.08 (2s, 2×3H, geminal-CH3 's), 1.36 (s, 3H, 5-CH3), 2.65 and 2.82 (d of ABq, 2H, JAB =16.0 Hz, JA =3.0 Hz, JB =11.8 Hz, benzylic-CH2), 2.97 (br dd, 1H, J=11.7, 2.5 Hz, 3-H), 3.79 (s, 3H, OCH3), 4.64 and 4.96 (2s, 2×1H, methylidene-CH2), 6.73 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H). [Compound 63 is hereinafter also referred to as COMPOUND "J" or 120286, and Compound 62 is hereinafter also referred to as COMPOUND "P" or 120273] ##STR12##

Workup

customalong with 88 mg (57%) of the more polar, major 1R,3S isomer (62), as well as 30.2 mg (20%) recovered
customproviding the trans, 1R,3S isomer (62) 1H NMR (400MHz, CDCl3) δ0.84 and 1.04 (2s, 2×3 H, geminal-CH3 's), 1.39 (s, 3H, 5-CH3), 2.43 (br dd, 1H, J-- 11.3, 2.9 Hz, 3-H), 2.72 and 2.85 (d of ABq, 2H, JAB =16.1 Hz, JA =3.1 Hz, JB =11.5 Hz, benzylic-CH2) 3.77 (s, 3H, OCH3), 4.57 and 5.16 (2s, 2×1H, methylidene-CH2), 6.63 (s, 1H, 6'-H), 6.93 ppm (s, 1H, 3'-H)

Sources & evidence

ORD record: ord-cd9b71fbd11343ce8726c2b0fd351450
Source dataset: uspto-grants-1997_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US05677336

Reaction notes

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