Synthetic Study of Versipelostatin A: Synthesis of the Spirotetronate Unit Starting from Pulegone

Abstract

The synthesis of the spirotetronate unit of versipelostatin A, a down-regulator of molecular chaperone GRP78, was achieved in ten steps starting from pulegone, via the Johnson-Claisen rearrangement. A model study of the coupling reaction with the octalin unit was also performed.

Key words

versipelostatin A - natural products - spiro compounds - Claisen rearrangement

References and Notes

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15

The ^¹H NMR spectrum of crude 3 indicated that this material is present as a single diastereomer. Complete consumption of (R)-pulegone was also confirmed

17

NOESY correlations were observed between 6-Me, 9-Me and 10-Hb of compound 7

23

Analytical data for (5R,6S,9S)-6-[2-(tert-butyldimethyl-silyloxy)ethyl]-4-methoxy-6,8,9-trimethyl-1-oxaspiro-[4.5]deca-3,7-dien-2-one (14): [α]_D ^²6 -16 (c 0.46, CHCl₃); IR (Nujol): 2956, 1760, 1628, 1089, 962 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 0.04 (s, 6 H), 0.88 (s, 9 H), 0.89 (s, 3 H), 1.04 (d, J = 7.3 Hz, 3 H), 1.66 (s, 3 H), 1.72-1.83 (m, 2 H), 1.85 (dd, J = 13.7, 6.4 Hz, 1 H), 2.03 (dd, J = 13.7, 10.0 Hz, 1 H), 2.37 (m, 1 H), 3.67-3.75 (m, 2 H), 3.78 (s, 3 H), 4.99 (s, 1 H), 5.10 (s, 1 H); ^¹³C NMR (100 MHz, CDCl₃): δ =
-5.3, -5.3, 18.2, 19.5, 20.9, 21.2, 25.9, 32.6, 37.6, 39.8, 42.2, 59.2, 60.0, 88.5, 88.9, 127.4, 136.2, 171.9, 186.0; MS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₁H₃₆NaO₄Si: 403.2275; found: 403.2247

25

Preparation of (5R,6S,9S)-6-[2-(tert-butyldimethylsilyl-oxy)ethyl]-3-[(RS)-1-hydroxybenzyl]-4-methoxy-6,8,9-trimethyl-1-oxaspiro[4.5]deca-3,7-dien-2-one (15): To a solution of tetronate 14 (21 mg, 0.066 mmol) in THF (2 mL), was added a solution of tert-butyllithium (1.0 M in pentane, 49 µL, 0.085 mmol) at -78 ˚C under argon and the mixture was stirred for 10 min. To the mixture was then added benzaldehyde (8.6 µL, 0.085 mmol). After stirring for 20 min, the reaction mixture was poured into saturated aqueous NH₄Cl and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous MgSO₄ and concentrated in vacuo. The residue was subjected to flash chromatography over silica gel (hexanes-acetone, 12:1) to give a 6:4 mixture of diastereomers of 15 (17 mg, 63%) as an amorphous solid. [α]_D ^²6 -11 (c 0.46, CHCl₃); IR (Nujol): 3423, 1725, 1635, 1067, 836 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 0.04, 0.04, 0.05 (3 × s, total 6 H, TBS), 0.88 (s, 3.6 H, TBS), 0.89 (s, 5.4 H, TBS), 0.95 (s, 1.2 H, 6-Me), 0.97 (s, 1.8 H, 6-Me), 1.05 (d, J = 7.3 Hz, 1.8 H, 9-Me), 1.05 (d, J = 6.9 Hz, 1.2 H, 9-Me), 1.63-1.68 (m, 3 H, 8-Me), 1.74-1.83 (m, 2 H, 6-CH₂-), 1.88 (dd, J = 13.7, 6.8 Hz, 0.6 H, 10-Ha), 1.94 (dd, J = 13.8, 6.9 Hz, 0.4 H, 10-Ha), 2.05 (m, 1 H, 10-Hb), 2.38 (m, 1 H, 9-H), 3.69-3.77 (m, 2 H, 6-CH₂-CH ₂-), 3.88 (s, 1.8 H, 4-OMe), 3.94 (s, 1.2 H, 4-OMe), 4.14 (d, J = 10.0 Hz, 0.6 H), 4.33 (d, J = 10.0 Hz, 0.4 H), 5.10 (m, 1 H, 7-H), 5.96 (s, 0.6 H, OH), 5.98 (s, 0.4, OH), 7.25-7.43 (m, 5 H, ArH); ^¹³C NMR (100 MHz, CDCl₃): δ = -5.3 (1.2 C), -5.3 (0.8 C), 18.2 (0.4 C), 18.2 (0.6 C), 19.5 (0.4 C), 19.6 (0.6 C), 20.9 (1 C), 21.6 (0.6 C), 21.6 (0.4 C), 25.9 (3 C), 32.6 (1 C), 37.7 (0.6 C), 37.9 (0.4 C), 49.2 (1 C), 42.3 (0.4 C), 42.4 (0.6 C), 59.9 (0.4 C), 59.9 (0.6 C), 60.3 (0.6 C), 60.4 (0.4 C), 67.2 (0.6 C), 67.7 (0.4 C), 87.7 (0.6 C), 87.9 (0.4 C), 103.1 (0.4 C), 103.2 (0.6 C), 125.8 (1.2 C), 125.9 (0.8 C), 127.2 (0.4 C), 127.3 (0.6 C), 127.5 (0.6 C), 127.6 (0.4 C), 128.6 (2 C), 136.0 (0.6 C), 136.2 (0.4 C), 142.9 (0.4 C), 143.1 (0.6 C), 173.5 (0.4 C), 173.7 (0.6 C), 177.9 (0.4 C), 178.4 (0.6 C); MS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₈H₄₂N₂NaO₅Si: 509.2694; found: 509.2661