Enantioselective Diels–Alder Cycloadditions in the Synthesis of Two Enantiomeric Sets of Chiral Polyhydroxylated Pipecolic Acid Derivatives

Abstract

(2E)-Penta-2,4-dien-1-ol was combined with electrophilic tert-butyl 2H-azirine-3-carboxylate by using a Lewis acid-catalyzed self-assembled Diels–Alder methodology with 1,1′-binaphthalene-2,2′-diol (BINOL) as a chiral inductor. By changing the chirality of the BINOL inductor, both enantiomeric forms of the resulting cycloadducts could be obtained with high enantioselectivities and yields. Simple chemical transformations of the cyclo­adducts gave two types of polyhydroxylated pipecolic acids. The synthetic strategy provides the first reported synthesis of chain-branched pipecolic acids.

Key words

enantioselectivity - Diels–Alder reaction - amino acids - asymmetric synthesis - azasugars

• References and Notes

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• 10 tert-Butyl (2S,6R)-2-(Hydroxymethyl)-1-azabicyclo[4.1.0]hept-3-ene-6-carboxylate [(–)-7] Orange oil; yield: 130 mg (49%); [α]_D ²⁰ –54.4 (c 2.0, CHCl₃). IR (Nujol): 3234, 1731, 1659 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 1.47 (s, 9 H, 3 × CH₃), 1.93 (s, 1 H, H-1′), 2.01 (s, 1 H, H-1′), 2.58–2.65 (m, 1 H, H-5), 2.65–2.73 (m, 1 H, H-5), 3.60 (dd, J = 10.8, 8.4 Hz, 1 H, H-2′), 3.67 (dd, J = 11.2, 4.8 Hz, 1 H, H-2′), 3.78–3.80 (m, 1 H, H-2), 5.27–5.31 (dm, J = 10.4 Hz, 1 H, H-4), 5.73–5.79 (m, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 22.6 (C-5), 27.7 (C-1′), 27.9 (3 × CH₃), 38.5 (C-6), 56.7 (C-2), 65.0 (C-2′), 81.4 (Cq, t-Bu), 121.8 (C-4), 124.4 (C-3), 171.4 (C=O). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₂₀NO₃: 226.1438; found: 226.1435. tert-Butyl (2R,6S)-2,6-Bis(hydroxymethyl)-1,2,3,6-tetrahydropyridine-2-carboxylate [(+)-8] Orange oil; yield: 63 mg (22%); [α]_D ²⁰ +51.4 (c 1.8, CHCl₃). IR (neat): 3407, 1725, 1642 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 1.47 (s, 9 H, 3 × CH₃), 2.13 (dm, J = 16.8 Hz, 1 H, H-3), 2.50–2.70 (br s, 2 H, 2 × OH), 2.62 (dddd, J = 16.8, 5.8, 2.5, 1.0 Hz, 1 H, H-3), 3.46 (d, J = 9.8 Hz, 1 H, H-2′), 3.54 (dd, J = 10.8, 4.4 Hz, 1 H, H-6′), 3.65 (dd, J = 11.0, 3.8 Hz, 1 H, H-6′), 3.66 (d, J = 10.0 Hz, 1 H, H-2′), 3.91–3.96 (m, 1 H, H-6), 5.57 (dm, J = 10.0 Hz, 2 H, H-5), 5.79 (ddt, J = 10.2, 5.8, 2.2 Hz, 1 H, H-4). ¹³C NMR (100 MHz, CDCl₃): δ = 27.9 (3 × CH₃), 32.4 (C-3), 40.6 (C-2′), 53.6 (C-6), 61.1 (C-2), 65.3 (C-6′), 82.3 (Cq, t-Bu), 124.1 (C-4), 126.8 (C-5), 171.6 (C=O). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₂₂NO₄: 244.1549; found: 244.1520.
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• 20 (2S,3S,4R,6S)-3,4-Dihydroxy-2-(hydroxymethyl)-1-azabicyclo[4.1.0]heptane-6-carboxylic Acid [(+)-12] Yellow oil; yield: 3 mg (43%); [α]_D ²⁰ +52.8 (c 0.6, MeOH). IR (neat): 3422, 1653 cm⁻¹. ¹H NMR (400 MHz, D₂O): δ = 1.86 (s, 1 H, H-1′), 1.95 (s, 1 H, H-1′), 2.29 (dd, J = 15.2, 3.6 Hz, 1 H, H-3), 2.63 (dd, J = 15.2, 4.4 Hz, 1 H, H-3), 3.33–3.41 (m, 1 H, H-6), 3.50 (dd, J = 9.0, 2.2 Hz, 1 H, H-4 or H-5), 3.81 (dd, J = 12.0, 6.4 Hz, 1 H, H-6′), 3.88–3.93 (m, 2 H, H-6′ + H-4 or H-5). ¹³C NMR (100 MHz, D₂O): δ = 30.7 (C-3), 33.8 (C-1′), 38.8 (C-2), 55.6 (C-6), 62.1 (C-6′), 65.8 (C-4 or C-5), 66.1 (C-4 or C-5), 179.9 (C=O). HRMS (ESI): m/z [M⁺] calcd for C₈H₁₃NO₅: 203.0794; found: 203.0801.
• 21 (2S,4R,5S,6S)-4,5-Dihydroxy-2,6-bis(hydroxymethyl)-piperidine-2-carboxylic Acid [(+)-13] Brown oil; yield: 3 mg (35%); [α]_D ²⁰ +44.4 (c 0.6, MeOH). IR (neat) 3435, 1646, 1212 cm⁻¹. ¹H NMR (400 MHz, D₂O): δ = 2.19 (dd, J = 15.2, 2.4 Hz, 1 H, H-3), 2.74 (dd, J = 15.2, 4.0 Hz, 1 H, H-3), 3.64 (s, 2 H, H-2′), 3.88 (dd, J = 11.0, 2.6 Hz, 1 H, H-5), 3.91 (dd, J = 12.2, 6.2 Hz, 1 H, H-6′), 3.99–4.04 (m, 1 H, H-6), 4.10 (dd, J = 12.4, 3.2 Hz, 1 H, H-6′), 4.18–4.22 (m, 1 H, H-4). ¹³C NMR (100 MHz, D₂O): δ = 33.8 (C-3), 38.1 (C-2′), 51.8 (C-6), 55.4 (C-6′), 60.9 (C-2), 63.1 (C-4), 63.3 (C-5), 169.0 (C=O). HRMS (ESI): m/z [M⁺] calcd for C₈H₁₅NO₆: 221.0899; found: 221.0902.