Isolation of Intermediary anti-Aldol Adducts of the Horner-Wadsworth-­Emmons Reaction Utilizing Direct Titanium-Aldol Addition and Successive Brønsted Acid Promoted Stereoselective Elimination Leading to (Z)-α,β-Unsaturated Esters

Abstract

The reagent TiCl₄-Et₃N was used in the Horner-­Wadsworth-Emmons (HWE)-type reaction of triethylphosphonocarboxylates with aldehydes, wherein unstable intermediary aldol adducts were isolated with anti-selectivity. Subsequent Brønsted acid promoted stereoselective elimination was successfully performed using TBS-benzamide-pyridinium triflate to give the less-accessible Z-α,β-unsaturated esters

Horner-Wadsworth-Emmons reaction - Ti-aldol addition - stereoselective - Z-alkenes - silylbenzamide

References and Notes

<A NAME="RY07405ST-1A">1a</A> Horner L. Hoffman H. Wippel HG. Klahre G. Chem. Ber.  1959,  92:  2499 

<A NAME="RY07405ST-1B">1b</A> Wadsworth WS. Emmons WD. J. Am. Chem. Soc.  1961,  83:  1733 

For a book and reviews:

<A NAME="RY07405ST-2A">2a</A> Wadsworth DH. Org. React.  1977,  25:  73 

<A NAME="RY07405ST-2B">2b</A> Boutagy J. Thomas R. Chem. Rev.  1974,  74:  87 

<A NAME="RY07405ST-2C">2c</A> Maryanoff BE. Reitz AB. Chem. Rev.  1989,  89:  863 

<A NAME="RY07405ST-2D">2d</A> Nicolaou KC. Harter MW. Gunzner JL. Nadin A. Liebigs Ann./Recl.  1997,  1283 

<A NAME="RY07405ST-2E">2e</A> Motoyoshiya J. Trends Org. Chem.  1998,  7:  63 

<A NAME="RY07405ST-2F">2f</A> Thirsk C. Whiting A. J. Chem. Soc., Perkin Trans. 1  2002,  999 

<A NAME="RY07405ST-3">3</A> Still WC. Gennari C. Tetrahedron Lett.  1983,  24:  4405 

<A NAME="RY07405ST-4A">4a</A> Ando K. Tetrahedron Lett.  1995,  36:  4105 

<A NAME="RY07405ST-4B">4b</A> Ando K. J. Org. Chem.  1997,  62:  1934 

<A NAME="RY07405ST-4C">4c</A> Ando K. J. Org. Chem.  1998,  63:  8411 

<A NAME="RY07405ST-4D">4d</A> Ando K. J. Org. Chem.  1999,  64:  6815 

<A NAME="RY07405ST-4E">4e</A> Ando K. Oishi T. Hirama M. Ohno H. Ibuta T. J. Org. Chem.  2000,  65:  4745 

<A NAME="RY07405ST-4F">4f</A> Ando K. Synlett  2001,  1272 

<A NAME="RY07405ST-5A">5a</A> Sano S. Yokoyama K. Fukushima M. Yagi T. Nagao Y. Chem. Commun.  1997,  559 

<A NAME="RY07405ST-5B">5b</A> Sano S. Teranishi R. Nagao Y. Tetrahedron Lett.  2002,  43:  9183 

<A NAME="RY07405ST-5C">5c</A> Sano S. Saito K. Nagao Y. Tetrahedron Lett.  2003,  44:  3987 

<A NAME="RY07405ST-6A">6a</A> Mukaiyama T. Banno K. Narasaka K. Chem. Lett.  1973,  1011 

<A NAME="RY07405ST-6B">6b</A> Mukaiyama T. Banno K. Narasaka K. J. Am. Chem. Soc.  1974,  96:  7503 

<A NAME="RY07405ST-6C">6c</A> Mukaiyama T. Organic Reactions   Vol. 28:  Wiley; New York: 1982.  p.203 

<A NAME="RY07405ST-7A">7a</A> Evans DA. Clark JS. Metternich R. Novack VJ. Sheppard GS. J. Am. Chem. Soc.  1990,  112:  866 

<A NAME="RY07405ST-7B">7b</A> Evans DA. Urpi F. Somers TC. Clark JS. Bilodeau MT. J. Am. Chem. Soc.  1990,  113:  8215 

<A NAME="RY07405ST-7C">7c</A> Evans DA. Rieger DL. Bilodeau MT. Urpi F. J. Am. Chem. Soc.  1991,  112:  1047 

<A NAME="RY07405ST-7D">7d</A> Crimmins MT. King BW. Tabet EA. Chaudhary K. J. Org. Chem.  2001,  66:  894 

<A NAME="RY07405ST-8A">8a</A> Tanabe Y. Bull. Chem. Soc. Jpn.  1988,  62:  1917 

<A NAME="RY07405ST-8B">8b</A> Misaki T. Nagase R. Matsumoto K. Tanabe Y. J. Am. Chem. Soc.  2005,  127:  2854 ; and other references cited therein

<A NAME="RY07405ST-9A">9a</A> Tanabe Y. Matsumoto N. Higashi T. Misaki T. Itoh T. Nishii Y. Tetrahedron  2002,  58:  8269 

<A NAME="RY07405ST-9B">9b</A> Tanabe Y. Matsumoto N. Funakoshi S. Manta N. Synlett  2001,  1959 

<A NAME="RY07405ST-9C">9c</A> Tanabe Y. Mitarai K. Higashi T. Misaki T. Nishii Y. Chem. Commun.  2002,  2542 

<A NAME="RY07405ST-10">10</A>

Typical Procedure (Table 2, Entry 1). TiCl₄ (neat, 132 µL, 1.20 mmol) and Et₃N (142 mg, 1.40 mmol) in CH₂Cl₂ (0.5 mL) were successively added to a stirred solution of (EtO)₂P(O)CH₂CO₂Et (1; 224 mg, 1.00 mmol) in CH₂Cl₂ (3.5 mL) at -20 °C under an Ar atmosphere. After 15 min, i-PrCHO (110 µL, 1.20 mmol) was added and the reaction mixture was stirred for 2 h. Then, H₂O was added to the mixture, which was extracted twice with Et₂O. The combined organic phase was washed with H₂O, brine, dried (Na₂SO₄) and concentrated to give the desired product 2a (281 mg, 95%). ¹H NMR (300 MHz, CDCl₃): δ = 0.91 (syn, 3 H, d, J = 6.5 Hz), 0.93 (anti, 3 H, d, J = 6.9 Hz), 1.02 (anti, 3 H, d, J = 6.9 Hz), 1.08 (syn, 3 H, d, J = 6.5 Hz), 1.27-1.38 (9 H, m), 1.72-1.88 (1 H, m), 3.20 (syn, 1 H, dd, J = 9.3, 20.6 Hz), 3.27 (anti, 1 H, dd, J = 3.8, 23.4 Hz), 3.80-3.87 (1 H, m), 4.08-4.30 (6 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 13.99, 16.27, 17.99, 19.39, 32.71, 32.85, 48.45 [d, 1J (¹³C, ³¹P) = 132.9 Hz], 62.50 [d, 2J (¹³C, ³¹P) = 7.2 Hz], 63.18 [d, 2J (¹³C, ³¹P) = 7.2 Hz], 74.75 [d, 2J (¹³C, ³¹P) = 4.3 Hz], 163.68 [d, 2J (¹³C, ³¹P) = 4.3 Hz].

<A NAME="RY07405ST-11">11</A>

Among several attempts of O-acetylation procedures, use of Ac₂O (2.0 equiv)-cat. Ph₂N⁺H₂·OTf^- (0.1 equiv) in toluene at r.t. resulted in nearly quantitative conversion yields.
Ethyl 3-acetoxy-2-(diethylphosphono)-2,4-dimethyl-pentanoate (from 2b): ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (3 H, d, J = 6.9 Hz), 1.04 (3 H, d, J = 6.9 Hz), 1.22-1.39 (9 H, m), 2.02 (anti, 3 H, s), 2.22 (syn, 3 H, s), 4.07-4.27 (6 H, m), 5.51 (anti, 1 H, dd, J = 2.8, 6.5 Hz), 5.69 (syn, 1 H, dd, J = 1.4, 9.63 Hz).

<A NAME="RY07405ST-12">12</A> Misaki T. Kurihara M. Tanabe Y. Chem. Commun.  2001,  2478 

<A NAME="RY07405ST-13">13</A>

General Procedure. BSA (367 µL, 1.50 mmol) was added to a stirred solution of 2 and PyH⁺·OTf ^- (46 mg, 0.2 mmol) in THF (2.0 mL) at 20-25 °C under an Ar atmosphere. After 0.5 h, H₂O was added to the mixture, which was extracted twice with Et₂O. The combined organic phase was washed with H₂O, brine, dried (Na₂SO₄) and concentrated. The obtained crude oil was purified by SiO₂ column chromatography (hexane-EtOAc, 1:1) to give the desired product.
Ethyl 2-(diethylphosphono)-4-methyl-3-(trimethyl-siloxy)pentanoate (3a): ¹H NMR (300 MHz, CDCl₃): δ = 0.09 (anti, 9 H, s), 0.18 (syn, 9 H, s), 0.85 (syn, 3 H, d, J = 6.5 Hz), 0.86 (anti, 3 H, d, J = 6.9 Hz), 0.95 (syn, 3 H, d, J = 6.4 Hz), 0.96 (anti, 3 H, d, J = 6.9 Hz), 1.28-1.36 (9 H, m), 2.03-2.13 (1 H, m), 3.26 (syn, 1 H, dd, J = 9.3, 19.9 Hz) 3.29 (anti, 1 H, dd, J = 10.0, 19.6 Hz), 3.99-4.33 (7 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 0.38, 13.96, 14.15, 16.18, 16.27, 21.01, 30.86, 52.26 [d, 1J (¹³C, ³¹P) = 127.2 Hz], 61.19, 62.51 [d, 2J (¹³C, ³¹P) = 5.8 Hz], 62.58 [d, 2J (¹³C, ³¹P) = 5.8 Hz], 75.95 [d, 2J (¹³C, ³¹P) = 2.9 Hz], 168.62 [d, 2J (¹³C, ³¹P) = 7.2 Hz]. IR (neat): 3405, 2976, 1252, 1024, 968, 843 cm^-1.

Seyden-Penne’s group extensively studied HWE reaction using RMgCl as a base to produce the aldol adduct. However, there are no experimental details and some trials in our hands failed to obtain the desired products.

<A NAME="RY07405ST-14A">14a</A> Lefébvre G. Seyden-Penne J. J. Chem. Soc., Chem. Commun.  1970,  1308 

<A NAME="RY07405ST-14B">14b</A> Bottin-Strzalko T. Seyden-Penne J. Tetrahedron Lett.  1972,  1945 

<A NAME="RY07405ST-14C">14c</A> Kyriakakou G. Roux-Schmitt MC. Seyden-Penne J. Tetrahedron  1975,  31:  1883 

<A NAME="RY07405ST-15">15</A>

Acetonide derivative of 2a was prepared as follows: benzyl ester analogue 1′ was used for the present Ti-addition, and the successive debenzylation (H₂-cat. Pd/C) and acetonide formation (2,2-dimethoxy propane-cat. PPTS, Scheme [3] ). ¹H NMR (300 MHz, CDCl₃): δ = 0.90 (3 H, d, J = 6.9 Hz), 1.04 (3 H, d, J = 6.9 Hz), 1.31-1.39 (6 H, m), 1.55 (3 H, s), 1.71 (3 H, s), 1.95-2.11 (1 H, m), 3.13 (1 H, dd, J = 8.9, 27.9 Hz), 4.12-4.36 (5 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 13.94, 16.19, 19.66, 23.98, 28.97, 31.34, 43.09 [d, 1J (¹³C, ³¹P) = 131.5 Hz], 62.82 [d, 2J (¹³C, ³¹P) = 7.2 Hz], 63.89 [d, 2J (¹³C, ³¹P) = 7.2 Hz], 72.11, 106.03, 163.68 [d, 2J (¹³C, ³¹P) = 5.8 Hz].

<A NAME="RY07405ST-16">16</A>

Typical Procedure (Table 4, Entry 2).
TBS-BEZA (467mg, 1.50 mmol) was added to a stirred solution of the obtained aldol adduct (2c) and ^-PyH⁺·OTf^- (23 mg, 0.1 mmol) in THF (2.0 mL) at 20-25 °C under an Ar atmosphere. After 0.5 h, H₂O was added to the mixture, which was extracted twice with Et₂O. The combined organic phase was washed with H₂O, brine, dried (Na₂SO₄) and concentrated. The obtained crude oil was purified by SiO₂ column chromatography (hexane-EtOAc = 20:1) to give the desired product (146 mg, 86%).

<A NAME="RY07405ST-17">17</A>

The reaction of Table [4] , entry 1 resulted in the formation of TBSOP(O)(OEt)₂ (10) in 93% yield based on ¹H NMR measurement, which matched with the authentic sample prepared from HOP(O)(OEt)₂ and TBSCl in the presence of imidazole in MeCN. ¹H NMR (300 MHz, CDCl₃): δ = 0.27 (6 H, s), 0.95 (9 H, s), 1.30-1.35 (6 H, m), 4.05-4.13 (4 H, m).