Asymmetric Intramolecular Michael Reaction Catalyzed by Proline-Derived Small Anilides

Makoto Kikuchi; Tomohiko Inagaki; Hisao Nishiyama

doi:10.1055/s-2007-977421

LETTER

Asymmetric Intramolecular Michael Reaction Catalyzed by Proline-Derived Small Anilides

Makoto Kikuchi, Tomohiko Inagaki, Hisao Nishiyama*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan
e-Mail: hnishi@apchem.nagoya-u.ac.jp;

Abstract

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Abstract

Simple proline-derived anilide-catalyzed asymmetric intramolecular Michael reaction was described. Chiral cyclic keto-aldehydes were obtained from acyclic formyl enones in excellent yields with good stereoselectivity. The reaction proceeded in exceptionally fast with a commercially available proline anilide. On the other hand, the longer reaction time conduced toward the higher diastereoselectivity through the favorable isomerization of the cyclic keto-aldehydes.

Key words

Michael reaction - organocatalyst - cyclopentane - prolineanilide

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References

References and Notes

For important recent reviews, see:

<A NAME="RU00907ST-1A">1a</A> Krause N. Hoffmann-Röder A. Synthesis 2001, 171

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For reviews, see:

<A NAME="RU00907ST-2A">2a</A> Dalko PI. Moisan L. Angew. Chem. Int. Ed. 2004, 43: 5138

<A NAME="RU00907ST-2B">2b</A> Berkessel A. Gröger H. Asymmetric Organocatalysis Wiley-VCH; Weinheim: 2004. and references cited therein

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<A NAME="RU00907ST-6B">6b</A> Okino T. Hoashi Y. Furukawa T. Xu XN. Takemoto Y. J. Am. Chem. Soc. 2005, 127: 119

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<A NAME="RU00907ST-8A">8a</A> Kozikowski AP. Mugrage BB. J. Org. Chem. 1989, 54: 2274

<A NAME="RU00907ST-8B">8b</A> The use of chiral amine: Hirai Y. Terada T. Yamazaki T. Momose T. J. Chem. Soc., Perkin Trans. 1 1992, 509

<A NAME="RU00907ST-9">9</A> Fonseca MTH. List B. Angew. Chem. Int. Ed. 2004, 43: 3958

<A NAME="RU00907ST-10">10</A> Hayashi Y. Gotoh H. Tamura T. Yamaguchi H. Masui R. Shoji M. J. Am. Chem. Soc. 2005, 127: 16028

Catalyst Preparation
To a solution of N-Boc-protected proline (50 g, 0.23 mol) in anhyd DMF (250 mL), Et₃N (39 mL, 0.28 mol) was added and the mixture was cooled to 0 °C, then ethyl chloroformate (22 mL, 0.23 mol) was added dropwise over 30 min. The reaction temperature was maintained at 0 °C for 40 min, and then diisopropylaniline (44 mL, 0.23 mol) was added at 0 °C. The reaction mixture was stirred at 65 °C for 14 h. The mixture was poured into H₂O (150 mL) and crashed ice (150 mL). The precipitated solid was filtered and dried in air. A part of the crude N-Boc-protected anilide (50 g) was dissolved in CHCl₃ (100 mL) and TFA (98%, 100 mL) was added at r.t. The reaction mixture was stirred at 50 °C for 2 h. The solvent was removed and the pH of the residue was adjusted to 8-9 by the addition of aq NaOH (2 N), the product was extracted with CHCl₃, and dried over MgSO₄. After removal of the solvent, the residue was purified by recrystallization from hexane-TBME-CHCl₃ (1:1:0.1; ca. 400 mL) to give 1d (30 g, 82%). The catalysts 1a-c were prepared in the same manner. Anilide 1a is also available from Fluorochem, Ltd. (order # 032341).
The spectral data for catalyst 1b: colorless needles; mp 79 °C; [α]_D ²⁶ -77.6 (c 1.00, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.19 (br s, 1 H), 7.06 (m, 3 H), 3.92 (dd, J = 9.3, 5.1 Hz, 1 H), 3.14-2.99 (m, 2 H), 2.22 (s, 6 H), 2.14-2.03 (m, 1 H), 1.91-1.74 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.9, 134.6, 133.7, 127.8, 126.4, 60.8, 47.5, 31.1, 26.4, 18.6. IR (KBr): 3281, 3003, 1669, 1501, 1098 cm^-1. HRMS: m/z calcd for C₁₃H₁₈ON₂ [M⁺]: 218.1419; found 218.1414.
Catalyst 1c: colorless needles; mp 78 °C; [α]_D ²⁵ -67.2 (c 1.00, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.22 (br s, 1 H), 7.21-7.09 (m, 3 H), 3.91 (dd, J = 9.3, 5.1 Hz, 1 H), 3.13-2.97 (m, 2 H), 2.56 (q, J = 7.5 Hz, 4 H), 2.25-2.03 (m, 2 H), 1.90-1.75 (m, 2 H), 1.79 (t, J = 7.5 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.7, 140.8, 132.7, 127.2, 126.1, 65.0, 60.7, 47.5, 30.9, 26.4, 25.0, 14.5. IR (KBr): 3280, 2969, 1668, 1500, 1298, 1240, 1100 cm^-1. HRMS: m/z calcd for C₁₅H₂₂ON₂ [M⁺]: 246.1732; found: 246.1741.
Catalyst 1d: colorless needles; mp 155 °C; [α]_D ²⁵ -58.7 (c 1.00, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.14 (br s, 1 H), 7.29-7.15 (m, 3 H), 3.94 (dd, J = 9.3, 5.1 Hz, 1 H), 3.17-2.94 (m, 4 H), 2.30-2.05 (m, 2 H), 1.90-1.75 (m, 2 H), 1.22 (d, J = 3.9 Hz, 6 H), 1.20 (d, J = 3.9 Hz, 6 H); ¹³C NMR (75 MHz, CDCl₃): δ = 174.2, 145.5, 131.4, 127.7, 123.2, 60.8, 47.6, 31.0, 28.9, 26.5, 23.7, 23.6. IR (KBr): 3289, 2966, 1667, 1498, 1100 cm^-1. Anal. Calcd for C₁₇H₂₆N₂O: C, 74.41; H, 9.55; N, 10.21. Found: C, 74.30; H, 9.68; N, 10.10.

The use of both AcOH and H₂O is critical. The cyclization of 2a without AcOH and H₂O furnished lower reactivity in moderate enantioselectivity (catalyst 1a, 5 h, 92%, cis/trans = 44:56, 81% ee for cis, 62% ee for trans). The advantage of additives in aldol reaction, see:

<A NAME="RU00907ST-12A">12a</A> Mase N. Tanaka F. Barbas CF. Org. Lett. 2003, 5: 4369

<A NAME="RU00907ST-12B">12b</A> Pihko PM. Laurikainen KM. Usano A. Nyberg AI. Kaavi JA. Tetrahedron 2006, 62: 317

For the important correspondences about the water effect, see:

<A NAME="RU00907ST-12C">12c</A> Brogan AP. Dickerson TJ. Janda KD. Angew. Chem. Int. Ed. 2006, 45: 8100

<A NAME="RU00907ST-12D">12d</A> Hayashi Y. Angew. Chem. Int. Ed. 2006, 45: 8103 ; and references cited therein

General Procedure for Intramolecular Michael Reaction
To a mixture of anilide 1 (0.06 mmol, 30 mol%) and the corresponding formyl enone 2 (0.2 mmol) were added CHCl₃ (2.5 mL), H₂O (50 µL) and AcOH (0.06 mmol, 30 mol%) at 30 °C. The mixture was stirred at 30 °C until TLC indicated complete reaction. The reaction was quenched at r.t. with H₂O (1 mL) and extracted with Et₂O (3 × 3 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. After purification by column chromatography (silica gel, hexane-Et₂O) furnished analytically pure 3a-c.
Compound cis- 3a: Chiral GC analysis (SUPELCO/β-DEX 325, 95 °C, 60 kPa H₂ as carrier gas); t _R(minor) = 88.0 min, t _R(major) = 89.1 min. ¹H NMR (300 Mz, CDCl₃): δ = 9.70 (d, J = 2.4 Hz, 1 H), 2.99-2.91 (m, 1 H), 2.74-2.49 (m, 3 H), 2.13 (s, 3 H), 2.03-1.56 (m, 5 H), 1.35-1.25 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.5, 204.6, 53.4, 44.7, 37.9, 32.1, 30.3, 25.5, 23.8.
Compound trans-3a: Chiral GC analysis (SUPELCO/β-DEX 325, 95 °C, 60 kPa H₂ as carrier gas); t _R(major) = 94.2 min, t _R(minor) = 99.3 min. ¹H NMR (300 Mz, CDCl₃): δ = 9.59 (d, J = 3.2 Hz, 1 H) 2.60-2.50 (m, 3 H), 2.34-2.26 (m, 1 H), 2.12 (s, 3 H), 2.01-1.94 (m, 1 H), 1.85 (dd, J = 14.9, 7.6 Hz, 2 H), 1.77-1.57 (m, 2 H), 1.30-1.18 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.4, 203.1, 57.6, 48.5, 36.2, 30.2, 26.8, 24.8.
Compound cis-3b: Chiral HPLC analysis; CHIRALPAK AD-H, hexane-i-PrOH (95:5), flow rate 1.0 mL/min, λ = 254 nm; t _R(minor) = 9.3 min, t _R(major) = 9.9 min. ¹H NMR (300 Mz, CDCl₃): δ = 9.77 (d, J = 2.4 Hz, 1 H), 7.96-7.92 (m, 2 H), 7.59-7.53 (m, 1 H), 7.48-7.43 (m, 2 H), 3.24 (dd, J = 17.1, 7.5 Hz, 1 H), 3.127-3.038 (m, 2 H), 2.88-2.75 (m, 1 H), 2.12 (s, 3 H), 2.08-1.61 (m, 5 H), 1.46-1.33 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 204.4, 198.8, 136.6, 132.9, 128.4, 127.8, 53.6, 39.7, 38.4, 32.3, 25.7, 23.9.
Compound trans-3b: HPLC CHIRALPAK AS-H, hexane-i-PrOH (95:5), flow rate 0.5 mL/min, λ = 254 nm; t _R(minor) = 22.5 min, t _R(major) = 25.7 min. ¹H NMR (300 Mz, CDCl₃): δ = 9.66 (d, J = 3.3 Hz, 1 H), 7.94-7.91 (m, 2 H), 7.57-7.51 (m, 1 H), 7.47-7.41 (m, 2 H), 3.12 (dd, J = 17.1, 6.9 Hz, 1 H), 3.04 (dd, J = 17.1, 6.9 Hz, 1 H), 2.78-2.65 (m, 1 H), 2.40 (dt, J = 8.2, 3.3 Hz, 1 H), 2.11-2.00 (m, 1 H), 1.92-1.85 (m, 2 H), 1.83-1.62 (m, 2 H), 1.34 (ddd, J = 16.7, 12.5, 8.2 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 203.1, 198.7, 136.5, 132.9, 128.4, 127.8, 57.8, 43.6, 36.8, 33.1, 26.9, 24.9.
Compound cis-3c: Chiral GC analysis (SUPELCO/β-DEX 325, 105 °C, 80 kPa H₂ as carrier gas); t _R(minor) = 96.2 min, t _R(major) = 97.8 min. ¹H NMR (300 Mz, CDCl₃): δ = 9.68 (d, J = 2.7 Hz, 1 H), 3.03-2.93 (m, 1 H), 2.71-2.57 (m, 3 H), 2.03-1.59 (m, 5 H), 1.34-1.20 (m, 2 H), 1.12 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 214.6, 204.4, 53.4, 44.2, 38.1, 37.8, 32.3, 26.6, 25.7, 23.9.
Compound trans-3c: Chiral GC analysis (SUPELCO/β-DEX 325, 90 °C, 80 kPa H₂ as carrier gas); t _R(major) = 243 min, t _R(minor) = 250 min. ¹H NMR (300 Mz, CDCl₃) δ = 9.57 (d, J = 3.6 Hz, 1 H), 2.71-2.49 (m, 3 H), 2.35-2.18 (m, 1 H), 2.06-1.92 (m, 2 H), 1.92-1.80 (m, 2 H), 1.78-1.56 (m, 1 H), 1.36-1.17 (m, 1 H), 1.11 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 214.4, 203.1, 57.8, 44.0, 41.5, 36.5, 33.1, 26.9, 26.4, 24.9.

The same dr shift during the extended reaction time has been reported by Hayashi’s group. They have succeeded in the isomerization from cis- to trans-isomer under the basic condition without loss of enantiopurity; see ref. 10.

It is assumed that this isomerization occurred through the diastereoselective protonation or hydrolysis of enamine or iminium generated from further reaction between product aldehyde 3 and catalyst. However, it cannot be seen that the isomerization occurred via the same intermediate enamine or iminium in the cyclization reaction, because the dr in the short reaction time is almost none selective (e.g. entry 1, Table [3] ). Therefore we consider that this isomerization occurred via the enolate intermediate forming from the aldehyde 3.

<A NAME="RU00907ST-16A">16a</A> The absolute stereochemistry of 3b was determined by comparison of its HPLC analysis reported by Hayashi et al., see ref. 10 and: Yang JW. Fonseca MTH. List B.
J. Am. Chem. Soc. 2005, 127: 15036

in the light of the reaction mechanism, we speculate that the other keto-aldehydes 3a and 3c have the same absolute configuration S at C2 (Figure [2] ).