An 1,2-Elimination Approach to the Enantioselective Synthesis of 1,3-Disubstituted Linear Allenes

Abstract

The construction of 1,3-disubstituted allene skeleton, which is present in many natural allenes, via an i-PrMgBr-mediated elimination of optically active 3-acetoxy-2-iodo-prop-1-ene derviatives is exemplified through the enantioselective total synthesis of two bioactive natural allenes.

Key words

alkynes - carbanions - elimination - halides - natural products

References and Notes

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• 12b

  The substrate utilized in this work was conveniently derived by a Novezyme 435 resolution of the racemic propargylic alcohol. For details, see the Supporting Information.

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5

For clarity, synthesis of 6a-c is given in the Supporting Information.

9

Although i-PrMgBr-mediated elimination of sulfoxides are known (cf. ref. 4b,c), it has never been utilized (to our knowledge) for elimination of α-acetoxyalkenyl halides.

11

Lower level of functional-group tolerance is also a major concern here, although the simultaneous cleavage of the terminal Ac protecting group is beneficial in this synthesis.

15

All attempts to separate the enantiomers of 14 by chiral HPLC failed.

16

Unlike sulfoxides, there is no stereogenic center in iodide. No loss of stereogenic centers occurred with the elimination of the halides.

17

Representative Procedures
Conversion of 6a into 7
A solution of 6a (150 mg, 0.30 mmol) in dry THF (2 mL) was added dropwise via a syringe to a solution of i-PrMgBr (2 M, in Et₂O, 0.9 mL, 1.8 mmol) in dry THF (5 mL) stirred at -78 ˚C under argon. After completion of the addition, the stirring was continued at -60 ˚C for 2.5 h. Aqueous sat. NH₄Cl was added. The mixture was extracted with Et₂O (50 mL), washed with H₂O and brine before being dried over anhyd Na₂SO₄. Removal of the solvent by rotary evaporation and column chromatography (PE-EtOAc, 100:1) on silica gel gave allene 7 as a colorless oil (84 mg, 0.28 mmol, 93%) along with recovered 6a (6 mg, 0.012 mmol, 4%).
Data for 7
[α]_D ^²7 -33.7 (c 0.9, CHCl₃). ^¹H NMR (300 MHz, CDCl₃):
δ = 5.28-5.20 (m, 2 H), 4.54 (dd, J = 5.8, 2.8 Hz, 2 H), 3.62 (t, J = 6.4 Hz, 2 H), 2.07 (s, 3 H), 2.10-2.02 (m, 2 H), 1.54 (quint, J = 7.3 Hz, 2 H), 1.48 (quint, J = 7.1 Hz, 2 H), 0.90 (s, 9 H), 0.05 (s, 6 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 205.4, 170.8, 92.8, 86.9, 62.90, 62.87, 32.1, 28.1, 25.9, 25.3, 21.0, 18.3, -5.3. FT-IR (film): 2955, 2930, 2858, 1963, 1744, 1227, 1103 cm^-¹. ESI-MS: m/z = 321.1 [M + Na]⁺. HRMS (MALDI): m/z calcd for C₁₆H₃₀SiO₃Na [M + Na]⁺: 321.1856; found: 321.1863.