Stereodivergent Metal-Catalyzed Allene Cycloisomerizations

Ryan D. Reeves; Caitlin N. Kinkema; Eleanor M. Landwehr; Logan E. Vine; Jennifer M. Schomaker

doi:10.1055/s-0037-1610746

Synlett, Table of Contents

Synlett 2020; 31(06): 627-631
DOI: 10.1055/s-0037-1610746

cluster

Stereodivergent Metal-Catalyzed Allene Cycloisomerizations

Ryan D. Reeves

^aDepartment of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, USA Email: schomakerj@chem.wisc.edu

,

Caitlin N. Kinkema

^bBlueprint Medicines, 45 Sidney Street, Cambridge, MA 02139, USA

,

Eleanor M. Landwehr

^aDepartment of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, USA Email: schomakerj@chem.wisc.edu

,

Logan E. Vine

^aDepartment of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, USA Email: schomakerj@chem.wisc.edu

,

Jennifer M. Schomaker∗

^aDepartment of Chemistry, University of Wisconsin, 1101 University Avenue, Madison, WI 53706, USA Email: schomakerj@chem.wisc.edu

› Author Affiliations

Abstract

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Published as part of the ISySyCat2019 Special Issue

Abstract

Metal-catalyzed allene cycloisomerizations provide rapid entry into five-membered carbocyclic frameworks, a common motif in natural products and pharmaceuticals. While both Au(I) and Pd(0)-catalyzed allene cycloisomerizations give 5-endo-dig cyclization, Pd prefers the syn diastereomer in contrast to the anti isomer observed with Au. The change in stereoselectivity is proposed to arise from buildup of A^1,3 strain during the key carbopalladation step to furnish the cycloisomerized products in moderate to good dr with yields comparable to Au(I) catalysts.

Key words

allene - cycloisomerization - cyclopentene - Conia-ene - carbopalladation - carbocycle

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References

References and Notes

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15 Pd(0)-Catalyzed Cycloisomerization of Allenes – General Procedure A flame-dried screw top vial was charged with Pd₂dba₃ (11.0 mg, 0.012 mmol, 0.05 equiv) and dppm (9.2 mg, 0.024 mmol, 0.10 equiv) in a glove box. The vial was sealed with a septum and removed from the glove box, and anhydrous THF (1.2 mL) was added. The resulting orange solution was stirred at room temperature under an N₂ atmosphere for 15 min before a solution of lactone 1h (66.0 mg, 0.24 mmol, 1.00 equiv) in anhydrous THF (1.2 mL) was added, followed by the addition of NaOMe (15.2 mg, 0.28 mmol, 1.20 equiv). The septum was replaced with a screw top, and the resulting suspension was heated to 70 °C and stirred at this temperature for 12 h. After stirring was complete, the solution was cooled to room temperature and quenched by the addition of aqueous NH₄Cl (15 mL) and extracted with 3 × 15 mL portions of EtOAc. The combined organics were dried over Na₂SO₄ and the volatiles removed in vacuo to afford the crude cyclization products. The crude material was purified via flash column chromatography on silica gel using a gradient of 0–20% EtOAc in hexanes to give 33.6 mg (0.12 mmol, 50% isolated yield) of cyclopentene 2h as a pale-yellow oil. ¹H NMR (500 MHz, CDCl₃): δ (major diastereomer) = 5.61 (dt, J = 3.1, 1.6 Hz, 1 H), 4.24 (d, J = 9.0 Hz, 1 H), 4.05 (d, J = 9.1 Hz, 1 H), 3.76 (s, 3 H), 3.16 (t, J = 6.9 Hz, 1 H), 1.95–1.85 (m, 1 H), 1.69 (t, J = 1.5 Hz, 3 H), 1.49–1.22 (m, overlapping signals, 7 H), 1.28 (s, 3 H), 0.89 (ddd, J = 8.7, 4.4, 2.1 Hz, 3 H); δ (minor diastereomer) = 5.41 (q, J = 1.7 Hz, 1 H), 4.27 (d, J = 9.0 Hz, 1 H), 3.94 (d, J = 9.0 Hz, 1 H), 3.79 (s, 3 H), 3.46 (dddd, J = 9.7, 5.8, 2.8, 1.8 Hz, 1 H), 1.86–1.76 (m, 1 H), 1.66 (dd, J = 2.7, 1.5 Hz, 3 H), 1.50–1.22 (m, overlapping signals, 7 H), 1.07 (s, 3 H), 0.89 (ddd, J = 8.8, 4.4, 2.1 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 177.0, 173.9, 169.0, 167.2, 140.1, 138.3, 130.3, 129.4, 72.5, 71.7, 65.7, 65.3, 59.7, 57.6, 52.7, 52.3, 50.2, 47.8, 32.4, 31.9, 31.9, 29.1, 28.6, 27.6, 22.6, 22.6, 17.7, 16.4, 14.1, 14.0, 11.9, 11.8. HRMS (ESI): m/z calcd for C₁₆H₂₄O₄ [M + H]⁺: 281.1747; found: 281.1744.

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