Enantio- and Diastereoselective
Nitro-Mannich Reactions with in situ Generated N-Boc-imines Catalyzed by a Bifunctional
Thiourea-Guanidine Catalyst

Wei Huang; Cheng Peng; Li Guo; Rong Hu; Bo Han

doi:10.1055/s-0031-1289885

LETTER

Enantio- and Diastereoselective Nitro-Mannich Reactions with in situ Generated N-Boc-imines Catalyzed by a Bifunctional Thiourea-Guanidine Catalyst

Wei Huang^a, Cheng Peng*^a,b, Li Guo^a, Rong Hu^b, Bo Han*^a
^a State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. of China
Fax: +86(28)61800231; e-Mail: hanbo@cdutcm.edu.cn;
^b Ministry of Education Key Laboratory of Standardization of Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. of China
Fax: +86(28)61800232; e-Mail: pengchengchengdu@126.com;

Abstract

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Abstract

The asymmetric nitro-Mannich reactions of nitroalkanes and in situ generated N-Boc-imines were achieved with a new type of thiourea-guanidine bifunctional organocatalyst. The novel transformations exhibited good diastereoselectivities, and the adducts bearing adjacent chiral centers were generally obtained in moderate to high enantioselectivities (up to 94% ee). This reaction provides a concise and alternative route converting readily accessible and stable N-carbamate amido sulfones into optically active 1,2-diamino compounds.

Key words

organocatalysis - nitro-Mannich reaction - thiourea-guanidine catalyst - in situ generated imines

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References and Notes

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Typical Procedure for the Asymmetric Nitro-Mannich Reaction for the Synthesis of Compound 4a
To a mixture of α-amido sulfone 3a (0.1 mmol), chiral catalyst (S,S)-1d (0.005 mmol, 5 mol%), and K₂CO₃ (0.4 mmol) in toluene (1.0 mL) at 0 ˚C was added nitroalkane 2a (0.2 mmol) in one portion. The resulting mixture was stirred at 0 ˚C for 2 h. Then, a sat. aq NH₄Cl solution was added, and the organic layer was extracted with EtOAc. The extracts were dried over MgSO₄, filtered, and concentrated in vacuo. Compound 4a was obtained as a white solid in 76% yield after flash column chromatography (PE-EtOAc = 50:1), and the ee was determined to be 86% by HPLC on Chiralpak AD-H column (15% 2-PrOH-n-hexane, 1 mL/min), λ = 220 nm, t _R (major) = 15.9 min, t _R minor) = 17.8 min; mp 189-190 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 7.33-7.41 (m, 3 H), 7.26-7.31 (m, 4 H), 7.12-7.25 (m, 3 H), 5.19-5.30 (m, 2 H), 4.99-5.10 (br s, 1 H), 3.25-3.35 (m, 1 H), 3.13-3.20 (dd, J = 3.5, 14.8 Hz, 1 H), 1.46 (s, 9 H) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 155.0, 136.4, 135.5, 129.2, 129.0, 128.9, 128.8, 127.5, 127.0, 92.7, 80.8, 57.3, 36.2, 28.2 ppm. ESI-HRMS: m/z calcd for C₂₀H₂₄N₂O₄ + Na: 379.1634; found: 379.1636.

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