A Rapid Access to the Spiroaminoketal Framework

Abstract

A convergent and stereoselective synthesis of 1-oxa-7-azaspiro[5.5]undecane is described. This functional new spiroheterocycle is readily available from acetone N,N-dimethylhydrazone via a double alkylation and subsequent spiroannulation process.

spiro compounds - alkylations - hydrazones - synthesis - amino acid

References

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<A NAME="RG16505ST-10">10</A>

Selected data for (S)-4: yellow solid; mp 57 °C; [α]_D ²⁵ -17.3 (c 0.15, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.07 (s, 9 H), 1.44 (s, 9 H), 2.10 (m, 2 H), 3.13 (m, 2 H), 3.60 (dd, J = 10.0, 2.0 Hz, 1 H), 3.69 (dd, J = 10.0, 3.0 Hz, 1 H), 3.75 (m, 1 H), 4.70 (d, J = 8.0 Hz, 1 H), 7.41 (m, 6 H), 7.62 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 1.0, 18.9, 26.6, 28.0, 36.4, 52.5, 64.9, 79.0, 127.5, 129.5, 132.6, 135.1, 155.1. HRMS: m/z calcd for C₂₅H₃₆INO₃Si [M + Na⁺]: 576.1407. Found: 576.1421.

<A NAME="RG16505ST-11">11</A>

Selected data for 2: pale yellow oil; [α]_D ²⁵ -9.3 (c 0.80, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.05 (s, 9 H), 1.33 (s, 3 H), 1.39 (s, 3 H), 1.43 (s, 9 H), 1.40-1.72 (m, 8 H), 2.39 (m, 2 H), 2.42 (t, J = 6.5 Hz, 2 H), 3.49 (t, J = 7.0 Hz, 1 H), 3.57 (dd, J = 9.0, 3.0 Hz, 1 H), 3.65 (m, 2 H), 4.02 (t, J = 7.0 Hz, 1 H), 4.04 (m, 1 H), 4.65 (d, J = 8.5 Hz, 1 H), 7.39 (m, 6 H), 7.62 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.3, 19.9, 20.0, 25.7, 26.8, 26.9, 28.4, 31.2, 32.9, 42.3, 51.4, 65.6, 69.3, 75.7, 79.0, 108.7, 127.7, 129.7, 133.2, 135.5, 155.6, 210.3. HRMS: m/z calcd for C₃₅H₅₃NO₆Si [M + Na⁺]: 634.3540. Found: 634.3549.

<A NAME="RG16505ST-12">12</A>

Selected data for 1a: foam; [α]_D ²⁵ -29.2 (c 0.88, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 0.98 (m, 1 H), 1.12 (s, 9 H), 1.33 (m, 2 H), 1.46 (s, 9 H), 1.46 (m, 1 H), 1.49 (m, 2 H), 1.58 (m, 3 H), 1.74 (m, 3 H), 3.48 (dd, J = 10.0, 4.0 Hz, 1 H), 3.55 (t, J = 6.5 Hz, 1 H), 3.59 (m, 2 H), 3.87 (m, 1 H), 4.08 (m, 1 H), 4.47 (d, J = 9.0 Hz, 1 H, OH), 7.23 (m, 6 H), 7.73 (m, 4 H). ¹³C NMR (100 MHz, C₆D₆): δ = 17.3, 19.5, 20.1, 27.1, 28.6, 28.7, 32.3, 34.4, 38.0, 52.3, 66.3, 69.0, 74.7, 78.4, 108.8, 128.1, 130.0, 133.9, 136.0, 155.6. HRMS: m/z calcd for C₃₂H₄₇NO₅Si [M + Na⁺]: 576.3121. Found: 576. 3134.

<A NAME="RG16505ST-13">13</A>

Selected data for 1b: white solid; mp 86 °C. [α]_D ²⁵ -41.8 (c 1.00, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 0.97 (m, 1 H), 1.21 (m, 1 H), 1.35 (m, 2 H), 1.43 (s, 9 H), 1.49 (m, 2 H), 1.56 (m, 3 H), 1.69 (m, 3 H), 2.55 (br s, 1 H, OH), 3.34 (m, 1 H), 3.44 (m, 1 H), 3.56 (m, 2 H), 3.68 (m, 1 H), 4.08 (m, 1 H), 4.60 (d, J = 7.5 Hz, 1 H, OH). ¹³C NMR (100 MHz, C₆D₆): δ = 17.3, 20.1, 28.5, 28.6, 31.8, 34.3, 37.8, 53.1, 65.7, 69.0, 74.7, 78.8, 108.8, 156.5. HRMS: m/z calcd for C₁₆H₂₉NO₅ [M + Na⁺]: 338.1943. Found: 338.1938.

Conformational analysis was performed using the Monte-Carlo Multiple Minimum Method with MM3:

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<A NAME="RG16505ST-14C">14c</A> Force field Macromodel 7.0 program was used: Macromodel 7.0   Schroedinger Inc.; Portland, OR: 2001. 

<A NAME="RG16505ST-14D">14d</A> Quantum semi-empirical calculations AM1, were carried out: Dewar MJS. Zoebisch EG. Healy EF. Stewart JJP. J. Am. Chem. Soc.  1985,  107:  3902 

<A NAME="RG16505ST-14E">14e</A> Geometries of global minima of both 6-S and 6-R 1a isomers were carried out using AMPAC 7.0: Ampac 7.0   Semichem; USA: 2000.