Consecutive Proline-Catalyzed Aldol Reactions and Metal-Mediated Allylations: Rapid Entries to Polypropionates

Abstract

A concise method for the rapid construction of polypropionate-type structures by consecutive organocatalytic aldol and metal-mediated allylation reactions is described.

aldol reactions - allylations - asymmetric synthesis - ­indium - organocatalysis

References

<A NAME="RG47404ST-1">1</A>

These authors contributed equally to this work.

<A NAME="RG47404ST-2">2</A>

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β-Hydroxyaldehydes are notorious for the facility by which they undergo oligomerization, elimination and other decomposition reactions. For recent documented examples, see:

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<A NAME="RG47404ST-16">16</A>

For the propionaldehyde dimerization-allylation sequence, the following procedure is illustrative. To l-proline (5.8 mg, 0.05 mmol, 10 mol%) in DMF (0.5 mL), was added propionaldehyde (72 µL, 1.0 mmol, 200 mol%) at 0 °C. The reaction mixture was stirred 10 h at 4 °C. Then, to the reaction mixture were added H₂O (0.5 mL), indium (68.9 mg, 0.6 mmol, 120 mol%), and allyl bromide (52 µL, 0.6 mmol, 120 mol%). The reaction mixture was stirred for additional 3 h at r.t. The reaction mixture was then extracted with EtOAc (2 × 3 mL). The combined organic layers were dried over anhyd Na₂SO₄, concentrated in vacuo, and purified by flash chromatography (50% MTBE in hexanes) to yield 57 mg (72%) of 1 as a mixture of diastereomers.

<A NAME="RG47404ST-17A">17a</A> Paquette LA. Mitzel TM. J. Am. Chem. Soc.  1996,  118:  1931 

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<A NAME="RG47404ST-18">18</A>

In addition to indium, tin and zinc were also screened as metals for the allylation, crotylation and prenylation reactions. Tin provided similar yields but lower selectivities and zinc similar selectivities but poor yields.

The enantioselectivity was determined by GC analysis of the 5,5-dimethyl-1,3-dioxane derivatives of 1 or 3 as described in ref.¹⁴ Conditions: Supelco γ-DEX^TM 120 column (30 m × 0.25 mm, 0.25 µm film). The carrier has a velocity of 28 cm/s, FID detection (300 °C) (110 °C isotherm 45 min, then raised to 180 °C at a rate of 2 °C/min);

<A NAME="RG47404ST-19A">19a</A>

for GC analysis of the dimer 1: (2S,3S)-anti-isomer t _R = 50.0 min, (2R,3R)-anti-isomer t _R = 52.3 min, (2R,3S)-syn-isomer t _R = 47.7 min, (2S,3R)-syn-isomer t _R = 48.1 min;

<A NAME="RG47404ST-19B">19b</A>

GC analysis of the cross aldol product 3: anti-isomer t _R = 55.1 min, anti-isomer t _R = 56.0 min, syn-isomer t _R = 54.2 min, syn-isomer t _R = 55.1 min.

<A NAME="RG47404ST-20">20</A> Araki S. Ito H. Butsugan Y. J. Org. Chem.  1988,  53:  1833 

<A NAME="RG47404ST-21">21</A>

For the trans-4-hydroxyproline-catalyzed aldol-prenylation sequence, the following procedure is illustrative. To 4-hydroxy-l-proline in dry DMSO (0.1 mL), was added propionaldehyde (72 µL, 1.0 mmol, 200 mol%) at 0 °C. The reaction mixture was stirred for 24 h at 4 °C and then allowed to warm to r.t. H₂O (0.5 mL) was added, followed by indium (86.5 mg, 0.75 mmol, 150 mol%), NaI (112.9 mg, 0.75 mmol, 150 mol%) and prenyl bromide (88 µL, 0.75 mmol, 150 mol%). The reaction mixture was stirred for 2 h at r.t. EtOAc (5 mL) was added and the resulting mixture was acidified with 6 M HCl and extracted with EtOAc (2 × 5 mL). The combined organic extracts were washed with brine (5 mL), dried over anhyd Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash chromatography (30% MTBE in hexane) to yield 39.3 mg (42%) of pure 8a.

<A NAME="RG47404ST-22">22</A>

Selected characterization data:
2,4-Dimethyloct-7-ene-3,5-diol (5, Table 2, Entries 4 and 5). Mixture of diastereomers; R _f = 0.26 (50% MTBE in hexane). IR (thin film): 3342, 2966, 2938, 1642, 1460, 1333, 1138, 1035, 968, 913 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 5.73-5.93 (m, 1 H), 5.09-5.17 (m, 2 H), 3.97 (ddd, 1 H, J = 7.2, 5.2, 2.1 Hz), 3.89 (ddd, 1 H, J = 7.6, 5.6, 2.1 Hz), 3.85 (ddd, 1 H, J = 7.8, 5.6, 2.0 Hz), 3.83 (ddd, 1 H, J = 8.5, 5.0, 2.2 Hz), 3.75 (ddd, 1 H, J = 7.8, 5.9, 1.8 Hz), 3.67 (dt, 1 H, J = 8.1, 3.0 Hz), 3.64 (dt, 1 H, J = 8.7, 3.3 Hz), 3.53-3.59 (m, 1 H, J = 9.5, 2.0 Hz), 3.40 (dd, 1 H, J = 8.9, 2.6 Hz), 3.29 (t, 1 H, J = 6.1 Hz), 2.11-2.56 (m, 2 H), 1.46-1.91 (m, 2 H), 0.78-1.01 (m, 9 H). ¹³C NMR (150 MHz, CDCl₃): δ = 135.5, 135.3, 135.2, 135.0, 118.3, 118.2, 117.9, 117.8, 81.0, 80.9, 80.4, 78.8, 76.4, 75.7, 75.4, 71.9, 40.9, 40.3, 40.1, 39.6, 38.8, 37.9, 37.8, 37.5, 34.8, 34.7, 31.8, 31.6, 31.0, 30.1, 27.1, 22.8, 20.4, 19.8, 19.1, 17.3, 14.3, 14.1, 13.1, 11.6. The major isomer could be readily correlated with literature data (see ref.²⁵). HRMS (benzaldehyde acetal derivative): m/z calcd for C₁₇H₂₄O₂: 260.1775; found: 260.1775.
(3 S ,4 S ,5 S )-4,6,6-Trimethyl-oct-7-ene-3,5-diol (8a, Table 4, Entries 1 and 2).
R _f = 0.26 (30% MTBE in hexane). [α]_D -5.4 (c 0.5, CH₂Cl₂). IR (thin film): 3467, 3019, 2966, 2935, 1638, 1464, 1414, 1130, 1030, 692 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 5.86 (dd, 1 H, J = 17.5, 10.7 Hz), 5.08 (dd, 1 H, J = 1.3, 10.7 Hz), 5.05 (dd, 1 H, J = 1.3, 17.5 Hz), 3.58 (dt, 1 H, J = 3.1, 8.2 Hz), 3.27 (d, 1 H, J = 5.5 Hz), 1.74-1.67 (m, 1 H), 1.64 (ddq, 1 H, J = 3.1, 7.3, 14.3 Hz), 1.39 (ddq, 1 H, J = 7.3, 8.2, 14.3 Hz), 1.04 (s, 6 H), 0.96 (t, 3 H, 7.3 Hz), 0.89 (d, 3 H, 7.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 145.7, 113.1, 83.3, 76.0, 42.8, 38.6, 27.5, 23.1, 22.3, 18.7, 9.4. HRMS (ESI): m/z calcd for C₁₁H₂₂O₂Na: 209.1517; found: 209.1507. (3 S ,4 S ,5 S )-2,4,6,6-Tetramethyloct-7-ene-3,5-diol (9, Table 4, Entries 3 and 4). Mp 74-75 °C; R _f = 0.33 (30% MTBE in hexane); [α]_D -3.2 (c 0.8, CHCl₃). IR (thin film): 3316, 2965, 2934, 1642, 1469, 1382, 1262, 1100, 1060, 990 cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 5.87 (dd, 1 H, J = 17.6, 10.9 Hz), 5.06 (dd, 1 H, J = 10.7, 1.0 Hz), 5.03 (dd, 1 H, J = 17.8, 1.2 Hz), 3.45 (dd, 1 H, J = 9.0, 2.8 Hz), 3.26 (d, 1 H, J = 5.6 Hz), 1.85 (dq, 1 H, J = 7.0, 3.0 Hz), 1.76 (ddq, 1 H, J = 9.0, 5.6, 7.0 Hz), 1.03 (s, 3 H), 1.02 (s, 3 H), 0.98 (d, 3 H, J = 6.9 Hz), 0.86 (d, 3 H, J = 7.0 Hz), 0.83 (d, 3 H, J = 6.8 Hz). ¹³C NMR (150 MHz, CDCl₃): δ = 145.9, 113.2, 83.8, 79.1, 43.1, 36.5, 29.7, 23.3, 22.9, 20.6, 19.0, 14.2. Anal. Calcd for C₁₂H₂₄O₂: C, 72.0; H, 12.1. Found: C, 71.9; H, 12.5.

<A NAME="RG47404ST-23">23</A>

For the crossed-aldol-allylation sequence, the following procedure is illustrative. To l-proline (11.7 mg, 0.1 mmol, 10 mol%) and isobutyraldehyde (185 µL, 2.0 mmol, 200 mol%) in DMF (0.5 mL), was added with syringe pump a solution of propionaldehyde (72 µL, 1.0 mmol, 100 mol%) in DMF (0.5 mL) at 4 °C during 30 h. The reaction mixture was stirred for additional 10 h at 4 °C. Then, to the reaction mixture were added H₂O (1.0 mL), In (229.6 mg, 2.0 mmol, 200 mol%), and allyl bromide (175 µL, 2.0 mmol, 200 mol%). The reaction mixture was stirred for additional 2 h at r.t. The reaction mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over anhyd Na₂SO₄, concentrated in vacuo, and purified by flash chromatography (50% MTBE in hexane) to yield 109 mg (63%) of 4 as a mixture of diastereomers.

<A NAME="RG47404ST-24">24</A>

The original anti:syn isomer ratio (ca. 25:1) of the aldol products 6a/6b derived from 3 is eroded slightly in the allylation step, possibly as a result of enrichment due to kinetic differences in the rate of the reaction. It should be noted that in the corresponding aldol-prenylation sequence the original anti:syn ratios were faithfully preserved.

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<A NAME="RG47404ST-28A">28a</A>

Data for 9 has been deposited with the CCDC entry number 258398. X-ray crystallographic data collection and processing: Crystallographic data were collected at 173 K on a Nonius Kappa CCD area-detector diffractometer using graphite monochromatized MoKα radiation (λ = 0.71073 Å). The data collection was performed using φ and ω scans. The data were processed using DENZO-SMN v0.93.0. The structures were solved by direct methods using the SHELXS program and full-matrix least-squares refinements on F² were performed using SHELXL-97 program. All heavy atoms were refined anisotropically. The CH hydrogen atoms were included at the fixed distances with fixed displacement parameters from their host atoms, except the vinyl hydrogens, which were refined with fixed displacement parameters. The figure was drawn with Ortep-3 for Windows.

<A NAME="RG47404ST-28B">28b</A> Otwinowski Z. Minor W. Methods in Enzymology, Volume 276: Macromolecular Crystallography, Part A   Carter CW. Sweet RM. Academic Press; New York: 1997.  p.307-326  

<A NAME="RG47404ST-28C">28c</A> Sheldrick GM. SHELX-97   University of Göttingen; Germany: 1997. 

<A NAME="RG47404ST-29">29</A>

A similar boat-chair transition state geometry has been proposed by Chemler and Roush to account for the anti-selectivity of the reactions between crotyltrifluorosilanes and β-hydroxyaldehydes. See ref. 13a.

<A NAME="RG47404ST-30A">30a</A> Isaac MB. Chan T.-H. Tetrahedron Lett.  1995,  36:  8957 

<A NAME="RG47404ST-30B">30b</A> Paquette LA. Mitzel TM. J. Org.Chem.  1996,  61:  8799 

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<A NAME="RG47404ST-31A">31a</A> Hoffmann RW. Dahlmann G. Andersen MW. Synthesis  1994,  629 

<A NAME="RG47404ST-31B">31b</A>

Ref. 13a.