5-Adamantylated 1,2,4-Trioxanes: Adamantane Position is Crucial for Antiparasitic Activity

Abstract

Allylic alcohols with 1′- and 2′-adamantanyl functionalization, available by reaction of 3-methylcrotonaldehyde with 1- and 2-bromoadamantane, respectively, were reacted with singlet oxygen under solution conditions with high diastereoselectivities to give the β-hydroperoxy alcohols. Lewis acid catalyzed peroxyacetalization of the β-hydroperoxy alcohols resulted in two sets of 1,2,4-trioxanes. The allylic alcohol 11 delivered the rearrangement product - the less strained primary hydroperoxide - upon singlet oxygenation and Lewis acid treatment.

Key words

singlet oxygen - ene reaction - peroxides - peracetalization - trioxanes

References and Notes

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13

Typical Procedure for the Synthesis of Compound 7 (Following Method B)
Under a slight stream of argon, lithium foil (80 mg, 9.2 mmol) was added in small pieces to dry THF (10 mL) and stirred vigorously for 2 h. To this suspension, a mixture of 2-bromo-adamantane (500 mg, 2.3 mmol) and 3-methyl-crotonic aldehyde (280 µL, 2.9 mmol) in dry THF (10 mL) were added during 15 min at 0 ˚C. After 30 min stirring by 0 ˚C and warming to r.t., the solution was quenched with sat. aq NaHCO₃, extracted with Et₂O (3 × 20 mL), washed with brine, and dried with Na₂SO₄. After solvent evaporation the product was purified by column chromatography (cyclohexane-EtOAc = 9:1). Compound 7 was obtained as viscous colorless oil in 59% yield (296 mg).
^¹H NMR (300 MHz, CDCl₃): δ = 1.40-1.90 (m, 15 H, adamantyl), 1.74 (d, 6 H, J = 0.78 Hz), 2.17 (s, 1 H), 4.58 (m, 1 H, J = 3.15, 9.42 Hz), 5.10 (dd, J = 1.29, 9.24 Hz) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 18.4, 25.8, 22.7-50.4 (10 C adamantyl), 68.2, 127.8, 135.7 ppm.

15

Compound 9a
Colorless oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.35 (s, 3 H), 1.51 (s, 3 H), 1.75 (s, 3 H), 1.45-2.20 (m, 15 H, adamantyl), 3.57 (d, 1 H, J = 9.7 Hz), 4.51 (d, 1 H, J = 9.7 Hz), 5.11 (m, 1 H), 5.19 (s, 1 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 19.9, 20.5, 25.7, 28.0-39.6 (10 C, adamantyl), 75.9, 84.7, 102.0, 118.8, 141.4.
Compound 10a
Colorless oil. IR (NaCl): ν_max = 2906, 2852, 1722, 1714, 1702, 1699, 1487, 1470, 1453, 1371, 1259, 1234, 1208, 1168, 1098, 1046, 1025 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.38 (s, 3 H), 1.66 (s, 3 H), 1.78 (s, 3 H), 1.45-2.20 (m, 15 H, adamantyl), 3.16 (dd, 1 H, J = 8.2, 9.1 Hz), 4.28 (d, 1 H, J = 9.1 Hz), 5.04 (m, 1 H), 5.14 (m, 1 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 19.9, 20.3, 26.0, 25.9-45.4 (10 C, adamantyl), 70.1, 89.1, 102.8, 117.8, 140.3 ppm. Both compounds were isolated prior to purification as 5:1 trans/cis diastereoisomers.

16

Compound 9d
Colorless solid. ^¹H NMR (300 MHz, CDCl₃): δ = 1.83 (s, 3 H), 1.38-2.18 (m, 30 H, adamantyl), 3.57 (d, 1 H, J = 9.8 Hz), 4.52 (d, 1 H, J = 9.8 Hz), 5.09 (m, 1 H), 5.17 (s, 1 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 20.0, 26.9-38.3 (15 separated signals, adamantyl), 74.6, 84.6, 104.2, 118.9, 141.2 ppm.

19

Griesbeck, A. G.; Schlundt, V.; Specht, S.; Hörauf, A. unpublished results.