Organocatalytic Enantioselective
Mannich-Type Reactions of Fluorinated Keto Esters with N-Boc-Aldimines

Sung Je Yoon; Young Ku Kang; Dae Young Kim

doi:10.1055/s-0030-1259319

LETTER

Organocatalytic Enantioselective Mannich-Type Reactions of Fluorinated Keto Esters with N-Boc-Aldimines

Sung Je Yoon, Young Ku Kang, Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax: +82(41)5301247; e-Mail: dyoung@sch.ac.kr;

Abstract

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Abstract

The catalytic enantioselective Mannich reaction promoted by chiral bifunctional organocatalysts is described. The treatment of α-fluoro-β-keto esters with N-Boc aldimines under mild reaction conditions afforded the corresponding β-aminated α-fluoro-β-keto esters with excellent enantioselectivities (up to 98% ee).

Key words

Mannich reaction - asymmetric catalysis - bifunctional organocatalyst - α-fluoro-β-keto esters - aldimines

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References

References and Notes

<A NAME="RU09810ST-1A">1a</A> Hudlicky M. Pavlath AE. Chemistry of Organic Fluorine Compounds II American Chemical Society; Washington DC: 1995.

<A NAME="RU09810ST-1B">1b</A> Kirk KLJ. J. Fluorine Chem. 2006, 127: 1013

<A NAME="RU09810ST-1C">1c</A> Isanobor C. O’Hagan D. J. Fluorine Chem. 2006, 127: 303

<A NAME="RU09810ST-1D">1d</A> Muller K. Faeh C. Diederich F. Science 2007, 317: 1881

<A NAME="RU09810ST-1E">1e</A> Kirk KL. Org. Process Res. Dev. 2008, 12: 305

<A NAME="RU09810ST-2A">2a</A> Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev. 2008, 37: 320

<A NAME="RU09810ST-2B">2b</A> Hiyama T. Kanie K. Kusumoto T. Morizawa Y. Shimizu M. Organofluorine Compounds: Chemistry and Applications Springer-Verlag; Berlin: 2000.

<A NAME="RU09810ST-3A">3a</A> Enantiocontrolled Synthesis of Fluoroorganic Compounds Soloshonok VA. John Wiley & Sons; Chichester: 1999.

<A NAME="RU09810ST-3B">3b</A> Bravo P. Resnati G. Tetrahedron: Asymmetry 1990, 1: 661

<A NAME="RU09810ST-3C">3c</A> Ramachandran PV. Asymmetric Fluoroorganic Chemistry: Synthesis, Application, and Future Directions ACS Symposium Series 746: American Chemical Society; Washington / DC: 2000.

For reviews, see:

<A NAME="RU09810ST-4A">4a</A> Mikami K. Itoh Y. Yamanaka M. Chem. Rev. 2004, 104: 1

<A NAME="RU09810ST-4B">4b</A> Ibrahim H. Togni A. Chem. Commun. 2004, 1147

<A NAME="RU09810ST-4C">4c</A> Ma J.-A. Cahard D. Chem. Rev. 2008, 108: PR1

<A NAME="RU09810ST-4D">4d</A> France S. Weatherwax A. Lectka T. Eur. J. Org. Chem. 2005, 475

<A NAME="RU09810ST-4E">4e</A> Oestreich M. Angew. Chem. Int. Ed. 2005, 44: 2324

<A NAME="RU09810ST-4F">4f</A> Pihko PM. Angew. Chem. Int. Ed. 2006, 45: 544

<A NAME="RU09810ST-4G">4g</A> Prakash GKS. Beier P. Angew. Chem. Int. Ed. 2006, 45: 2172

<A NAME="RU09810ST-4H">4h</A> Bobbio C. Gouverneur V. Org. Biomol. Chem. 2006, 4: 2065

<A NAME="RU09810ST-4I">4i</A> Shibata N. Ishimaru T. Nakamura S. Toru T.
J. Fluorine Chem. 2007, 128: 469

<A NAME="RU09810ST-4J">4j</A> Brunet VA. O’Hagan D. Angew. Chem. Int. Ed. 2008, 47: 1179

<A NAME="RU09810ST-4K">4k</A> Smits R. Cadicamo CD. Burger K. Koksch B. Chem. Soc. Rev. 2008, 37: 1727

<A NAME="RU09810ST-4L">4l</A> Kang YK. Kim DY. Curr. Org. Chem. 2010, 14: 917

For recent selected examples of catalytic asymmetric fluorinations of active methines, see:

<A NAME="RU09810ST-5A">5a</A> Hintermann L. Togni A. Angew. Chem. Int. Ed. 2000, 39: 4359

<A NAME="RU09810ST-5B">5b</A> Kim DY. Park EJ. Org. Lett. 2002, 4: 545

<A NAME="RU09810ST-5C">5c</A> Hamashima Y. Yagi K. Takano H. Tamás L. Sodeoka M. J. Am. Chem. Soc. 2002, 124: 14530

<A NAME="RU09810ST-5D">5d</A> Ma J.-A. Cahard D. Tetrahedron: Asymmetry 2004, 15: 1007

<A NAME="RU09810ST-5E">5e</A> Shibata N. Ishimaru T. Nagai T. Kohno J. Toru T. Synlett 2004, 1703

<A NAME="RU09810ST-5F">5f</A> Bernardi L. Jørgensen KA. Chem. Commun. 2005, 1324

<A NAME="RU09810ST-5G">5g</A> Kim SM. Kim HR. Kim DY. Org. Lett. 2005, 7: 2309

<A NAME="RU09810ST-5H">5h</A> Kim HR. Kim DY. Tetrahedron Lett. 2005, 46: 3115

<A NAME="RU09810ST-5I">5i</A> Ishimaru T. Shibata N. Horikawa T. Yasuda N. Nakamura S. Toru T. Shiro M. Angew. Chem. Int. Ed. 2008, 47: 4157

<A NAME="RU09810ST-5J">5j</A> Lee NR. Kim SM. Kim DY. Bull. Korean Chem. Soc. 2009, 30: 829

<A NAME="RU09810ST-5K">5k</A> Kang SH. Kim DY. Adv. Synth. Catal. 2010, 352: 2783

For asymmetric Michael-type reactions of α-fluoromalonates, see:

<A NAME="RU09810ST-6A">6a</A> Kim DY. Kim SM. Koh KO. Mang JY. Bull. Korean Chem. Soc. 2003, 24: 1425

<A NAME="RU09810ST-6B">6b</A> Nichols PJ. DeMattei JA. Barnett BR. LeFur NA. Chuang T.-H. Piscopio AD. Koch K. Org. Lett. 2006, 8: 1495

<A NAME="RU09810ST-6C">6c</A> Kwon BK. Kim SM. Kim DY.
J. Fluorine Chem. 2009, 130: 759

<A NAME="RU09810ST-6D">6d</A> Companyo X. Hejnova M. Kamlar M. Vesely J. Moyano A. Rios R. Tetrahedron Lett. 2009, 50: 5051

For asymmetric Michael-type reactions of α-fluoro-β-keto esters, see:

<A NAME="RU09810ST-7A">7a</A> Nakamura M. Hajra A. Endo K. Nakamura E. Angew. Chem. Int. Ed. 2005, 44: 7248

<A NAME="RU09810ST-7B">7b</A> He R. Wang X. Hashimoto T. Maruoka K. Angew. Chem. Int. Ed. 2008, 47: 9466

<A NAME="RU09810ST-7C">7c</A> Mang JY. Kwon DG. Kim DY. J. Fluorine Chem. 2009, 130: 259

<A NAME="RU09810ST-7D">7d</A> Han X. Luo J. Liu C. Lu Y. Chem. Commun. 2009, 2044

<A NAME="RU09810ST-7E">7e</A> Li H. Zhang S. Yu C. Song X. Wang W. Chem. Commun. 2009, 2136

<A NAME="RU09810ST-7F">7f</A> Oh Y. Kim SM. Kim DY. Tetrahedron Lett. 2009, 50: 4674

<A NAME="RU09810ST-7G">7g</A> Ishimaru T. Ogawa S. Tokunaga E. Nakamura S. Shibata N. J. Fluorine Chem. 2009, 130: 1049

<A NAME="RU09810ST-7H">7h</A> Cui H.-F. Yang Y.-Q. Chai Z. Li P. Zheng C.-W. Zhu S.-Z. J. Org. Chem. 2010, 75: 117

<A NAME="RU09810ST-8A">8a</A> Fukuzumi T. Shibata N. Sugiura M. Yasui H. Nakamura S. Toru T. Angew. Chem. Int. Ed. 2006, 45: 4973

<A NAME="RU09810ST-8B">8b</A> Mizuta S. Shibata N. Goto Y. Furukawa T. Nakamura S. Toru T. J. Am. Chem. Soc. 2007, 129: 6394

<A NAME="RU09810ST-8C">8c</A> Furukawa T. Shibata N. Mizuta S. Nakamura S. Toru T. Shiro M. Angew. Chem. Int. Ed. 2008, 47: 8051

<A NAME="RU09810ST-8D">8d</A> Moon HW. Cho MJ. Kim DY. Tetrahedron Lett. 2009, 50: 4896

<A NAME="RU09810ST-8E">8e</A> Furukawa T. Goto Y. Kawazoe J. Tokunaga E. Nakamura S. Yang Y. Du H. Kakehi A. Shiro M. Shibata N. Angew. Chem. Int. Ed. 2010, 49: 1642

For selected recent reviews, see:

<A NAME="RU09810ST-9A">9a</A> Verkade JMM. van Hemert LJC. Quaedflieg PJLM. Rutjes FPJT. Chem. Soc. Rev. 2008, 37: 29

<A NAME="RU09810ST-9B">9b</A> Ting A. Schaus SE. Eur. J. Org. Chem. 2007, 5797

<A NAME="RU09810ST-9C">9c</A> Marques MMB. Angew. Chem. Int. Ed. 2006, 45: 348

<A NAME="RU09810ST-9D">9d</A> Cordova A. Acc. Chem. Res. 2004, 37: 102

For selected examples of Mannich-type reactions of enolates, see:

<A NAME="RU09810ST-10A">10a</A> Sikert M. Schneider C. Angew. Chem. Int. Ed. 2008, 47: 3631

<A NAME="RU09810ST-10B">10b</A> Itoh J. Fuchibe K. Akiyama T. Synthesis 2008, 1319

<A NAME="RU09810ST-10C">10c</A> Kobayashi S. Yazaki R. Seki K. Ueno M. Tetrahedron 2007, 63: 8425

<A NAME="RU09810ST-10D">10d</A> Saruhashi K. Kobayashi S. J. Am. Chem. Soc. 2006, 128: 11232

<A NAME="RU09810ST-10E">10e</A> Kobayashi S. Ueno M. Saito S. Mizuki Y. Ishitani H. Yamashita Y. Proc. Natl. Acad. Sci. U.S.A. 2004, 101: 5476

<A NAME="RU09810ST-10F">10f</A> Akiyama T. Itoh J. Yokota K. Fuchibe K. Angew. Chem. Int. Ed. 2004, 43: 1566

<A NAME="RU09810ST-10G">10g</A> Wenzel AG. Jacobsen EN. J. Am. Chem. Soc. 2002, 124: 12964

<A NAME="RU09810ST-11A">11a</A> Hamashima Y. Sasamoto N. Umebayashi N. Sodeoka M. Chem. Asian J. 2008, 3: 1443

<A NAME="RU09810ST-11B">11b</A> Chen Z. Morimoto H. Matsunaga S. Shibasaki M. J. Am. Chem. Soc. 2008, 130: 2170

<A NAME="RU09810ST-11C">11c</A> Kobayashi S. Gustafsson T. Shimizu Y. Kiyohara H. Matsubara R. Org. Lett. 2006, 8: 4923

<A NAME="RU09810ST-11D">11d</A> Hamashima Y. Sasamoto N. Hotta D. Somei H. Umebayashi N. Sodeoka M. Angew. Chem. Int. Ed. 2005, 44: 1525

<A NAME="RU09810ST-11E">11e</A> Kim EJ. Kang YK. Kim DY. Bull. Korean Chem. Soc. 2009, 30: 1437

<A NAME="RU09810ST-11F">11f</A> Kang YK. Kim DY. J. Org. Chem. 2009, 74: 5734

<A NAME="RU09810ST-11G">11g</A> Lee JH. Kim DY. Adv. Synth. Catal. 2009, 351: 1779

<A NAME="RU09810ST-11H">11h</A> Lee JH. Kim DY. Synthesis 2010, 1860

<A NAME="RU09810ST-12A">12a</A> Han X. Kwiatkowski J. Xue F. Huang K.-W. Lu Y. Angew. Chem. Int. Ed. 2009, 48: 7604

<A NAME="RU09810ST-12B">12b</A> Jiang Z. Pan Y. Zhao Y. Ma T. Lee R. Yang Y. Huang K.-W. Wong MW. Tan C.-H. Angew. Chem. Int. Ed. 2009, 48: 3627

<A NAME="RU09810ST-12C">12c</A> Pan Y. Zhao Y. Ma T. Yang Y. Liu H. Jiang Z. Tan C.-H. Chem. Eur. J. 2010, 16: 779

<A NAME="RU09810ST-13A">13a</A> Kim DY. Huh SC. Kim SM. Tetrahedron Lett. 2001, 42: 6299

<A NAME="RU09810ST-13B">13b</A> Kim DY. Huh SC. Tetrahedron 2001, 57: 8933

<A NAME="RU09810ST-13C">13c</A> Park EJ. Kim MH. Kim DY.
J. Org. Chem. 2004, 69: 6897

<A NAME="RU09810ST-13D">13d</A> Kang YK. Kim DY. Tetrahedron Lett. 2006, 47: 4565

<A NAME="RU09810ST-13E">13e</A> Kang YK. Cho MJ. Kim SM. Kim DY. Synlett 2007, 1135

<A NAME="RU09810ST-13F">13f</A> Cho MJ. Kang YK. Lee NR. Kim DY. Bull. Korean Chem. Soc. 2007, 28: 2191

<A NAME="RU09810ST-13G">13g</A> Kim SM. Kang YK. Cho MJ. Mang JY. Kim DY. Bull. Korean Chem. Soc. 2007, 28: 2435

<A NAME="RU09810ST-13H">13h</A> Lee JH. Bang HT. Kim DY. Synlett 2008, 1821

<A NAME="RU09810ST-13I">13i</A> Mang JY. Kim DY. Bull. Korean Chem. Soc. 2008, 29: 2091

<A NAME="RU09810ST-13J">13j</A> Kang YK. Kim DY. Bull. Korean Chem. Soc. 2008, 29: 2093

<A NAME="RU09810ST-13K">13k</A> Kim DY. Bull. Korean Chem. Soc. 2008, 29: 2036

<A NAME="RU09810ST-13L">13l</A> Mang JY. Kwon DG. Kim DY. Bull. Korean Chem. Soc. 2009, 30: 249

<A NAME="RU09810ST-13M">13m</A> Kang YK. Kim SM. Kim DY. J. Am. Chem. Soc. 2010, 132: 11847

<A NAME="RU09810ST-14A">14a</A> Kim SM. Lee JH. Kim DY. Synlett 2008, 2659

<A NAME="RU09810ST-14B">14b</A> Jung SH. Kim DY. Tetrahedron Lett. 2008, 49: 5527

Typical General Procedure for the Mannich-Type Reaction of α-Fluoro-β-keto Ester 1 with N -Boc Aldimine 2: To a solution of α-fluoro-β-keto ester 1 (0.3 mmol) and catalyst I (0.03 mmol, 20 mg) in Et₂O (6 mL) was added N-Boc aldimine 2 (0.45 mmol). The reaction mixture was stirred for 24-36 h. The catalyst I was removed by short column chromatography (EtOAc-hexane, 1:5). The crude oil was purified by flash column chromatography (EtOAc-hexane, 1:7) to afford the Mannich adduct 3.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(4-chlorophenyl)propanoate (3c): major diastereomer: [α]^²6 _D 7.0 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.28 (t, J = 13.9 Hz, 3 H), 1.39 (s, 9 H), 4.18-4.41 (m, 2 H), 5.45 (d, J = 10.4 Hz, 1 H), 5.87 (dd, J = 28.8, 10.4 Hz, 1 H), 7.35-7.44 (m, 5 H), 7.54-7.58 (m, 2 H), 7.80-7.84 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.82, 28.15, 56.78 (d, J = 17.7 Hz), 63.32, 80.35, 102.01 (d, J = 204.4 Hz), 128.54, 129.56, 129.81, 130.24 (2), 134.01, 135.12, 154.30, 165.32 (d, J = 26.5 Hz), 190.33 (d, J = 25.7 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 23.8 min (minor), t _R = 28.1 min (major); 81% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-propanoate (3d): major diastereomer: [α]^²9 _D 39.3 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.26 (t, J = 13.6 Hz, 3 H), 1.38 (s, 9 H), 4.16-4.39 (m, 2 H), 5.57 (d, J = 10.5 Hz, 1 H), 6.02 (dd, J = 28.8, 10.5 Hz, 1 H), 7.19-7.33 (m, 4 H), 7.36-7.51 (m, 4 H), 7.80-7.83 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.75, 28.08, 57.38 (d, J = 18.5 Hz), 63.11, 79.97, 102.19 (d, J = 204.0 Hz), 128.01, 128.26, 128.34, 128.74, 129.28, 129.39, 133.69, 136.50, 154.31, 165.38 (d, J = 27.1 Hz), 190.80 (d, J = 25.6 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 23.5 min (minor), t _R = 31.0 min (major); 88% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(2-chlorophenyl)propanoate (3e): major diastereomer: [α]^²8 _D 55.5 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.28 (t, J = 12.1 Hz, 3 H), 1.39 (s, 9 H), 4.23-4.35 (m, 2 H), 5.55 (d, J = 10.1 Hz, 1 H), 6.47 (dd, J = 26.1, 10.1 Hz, 1 H), 7.10-7.18 (m, 2 H), 7.33-7.55 (m, 5 H), 7.87-7.91 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.53, 27.88, 53.62 (d, J = 18.7 Hz), 63.02, 79.84, 101.30 (d, J = 205.4 Hz), 126.76, 128.30, 128.85, 129.09, 129.22, 129.85 (2), 133.71, 134.57, 134.97, 153.89, 165.15 (d, J = 26.7 Hz), 190.22 (d, J = 24.9 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 30.4 min (minor), t _R = 51.2 min (major); 86% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(furan)propanoate (3f): major diastereomer: [α]^²8 _D 35.3 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃):
δ = 1.28 (t, J = 14.0 Hz, 3 H), 1.43 (s, 9 H), 4.18-4.38 (m, 2 H), 5.35 (d, J = 10.7 Hz, 1 H), 6.17 (dd, J = 28.2, 10.7 Hz, 1 H), 6.24-6.26 (m, 2 H), 7.27-7.29 (m, 1 H), 7.38-7.46 (m, 2 H), 7.53-7.60 (m, 1 H), 7.90-7.94 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.79, 28.15, 52.07 (d, J = 19.7 Hz), 63.24, 80.33, 101.45 (d, J = 204.5 Hz), 108.84, 110.30, 128.51, 129.49, 129.61, 133.90, 142.37, 149.35, 154.32, 164.90 (d, J = 26.6 Hz), 190.39 (d, J = 25.2 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 20.9 min (minor), t _R = 34.5 min (major); 98% ee.
(2 S ,3 S )-Ethyl 2-Benzoyl-3-( tert -butoxycarbonylamino)-2-fluoro-3-(thiophene)propanoate (3g): major diastereomer: [α]^²6 _D 54.7 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.27 (t, J = 13.9 Hz, 3 H), 1.41 (s, 9 H), 4.17-4.40 (m, 2 H), 5.36 (d, J = 10.4 Hz, 1 H), 6.31 (dd, J = 28.3, 10.4 Hz, 1 H), 6.86-6.90 (m, 1 H), 7.06-7.08 (m, 1 H), 7.16-7.18 (m, 1 H), 7.36-7.44 (m, 2 H), 7.51-7.59 (m, 1 H), 7.89-7.93 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.74, 28.10, 53.53 (d, J = 19.35 Hz), 63.12, 80.27, 101.92 (d, J = 204.2 Hz), 125.53, 126.56, 127.18, 128.46, 129.45, 129.56, 133.91, 138.75, 154.11, 164.96 (d, J = 26.9 Hz), 190.34 (d, J = 25.3 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 90:10; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 30.9 min (minor), t _R = 44.4 min (major); 95% ee.
(2 S ,3 S )-Ethyl 2-(4-Nitrobenzoyl)-3-( tert -butoxy-carbonylamino)-2-fluoro-3-(furan)propanoate (3h): major diastereomer: [α]^³¹ _D 19.7 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.31 (t, J = 14.4 Hz, 3 H), 1.44 (s, 9 H), 4.20-4.41 (m, 2 H), 5.36 (d, J = 10.2 Hz, 1 H), 6.15 (dd, J = 28.2, 10.2 Hz, 1 H), 6.27-6.31 (m, 2 H), 7.30 (m, 1 H), 8.01-8.06 (m, 2 H), 8.24-8.28 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.83, 28.16, 52.21 (d, J = 19.3 Hz), 63.69, 80.67, 101.58 (d, J = 204.4 Hz), 109.13, 110.48, 123.62, 130.64, 138.59, 142.66, 148.90, 150.51, 154.30, 164.15 (d, J = 26.7 Hz), 189.96 (d, J = 25.7 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 26.8 min (minor), t _R = 45.6 min (major); 98% ee.
(2 S ,3 S )-Ethyl 2-[4-(Trifluoromethyl)phenyl]-3-( tert -butoxycarbonylamino)-2-fluoro-3-(furan)propanoate (3i): major diastereomer: [α]^³0 _D 26.0 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.30 (t, J = 14.5 Hz, 3 H), 1.44 (s, 9 H), 4.20-4.40 (m, 2 H), 5.35 (d, J = 10.5 Hz, 1 H), 6.17 (dd, J = 28.4, 10.5 Hz, 1 H), 6.25-6.27 (m, 2 H), 7.27-7.29 (m, 1 H), 7.67-7.71 (m, 2 H), 7.99-8.03 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.79, 28.14, 52.14 (d, J = 19.2 Hz), 63.51, 80.53, 101.54 (d, J = 204.5 Hz), 109.01, 110.39, 123.35 (q, J = 271.5 Hz), 125.55, 129.80, 134.94 (q, J = 32.5 Hz), 136.66, 142.55, 149.07, 154.31, 164.42 (d, J = 26.6 Hz), 189.56 (d, J = 29.0 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 15.7 min (minor), t _R = 28.5 min (major); 96% ee.
(2 S ,3 S )-Ethyl 2-(4-Methoxybenzoyl)-3-( tert -butoxy-carbonylamino)-2-fluoro-3-(furan)propanoate (3j): major diastereomer: [α]^³0 _D 19.1 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.26 (t, J = 13.9 Hz, 3 H), 1.43 (s, 9 H), 3.84 (s, 3 H), 4.16-4.36 (m, 2 H), 5.36 (d, J = 10.5 Hz, 1 H), 6.16 (dd, J = 28.3, 10.5 Hz, 1 H), 6.23-6.25 (m, 2 H), 6.86-6.93 (m, 2 H), 7.79 (m, 1 H), 7.95-8.00 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.74, 28.10, 51.96 (d, J = 19.5 Hz), 55.42, 63.06, 80.19, 101.50 (d, J = 204.4 Hz), 108.70, 110.24, 113.79, 126.60, 132.25, 142.22, 149.57, 154.31, 164.18, 165.20 (d, J = 26.9 Hz), 188.24 (d, J = 24.3 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 85:15; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 26.6 min (minor), t _R = 49.6 min (major); 96% ee.
(2 S ,3 S )-Ethyl 2-(4-Bromobenzoyl)-3-( tert -butoxy-carbonylamino)-2-fluoro-3-(furan)propanoate (3k): major diastereomer: [α]^³¹ _D 21.1 (c = 1.0, CHCl₃). ^¹H NMR (200 MHz, CDCl₃): δ = 1.28 (t, J = 14.0 Hz, 3 H), 1.43 (s, 9 H), 4.19-4.37 (m, 2 H), 5.32 (d, J = 10.1 Hz, 1 H), 6.14 (dd, J = 28.4, 10.1 Hz, 1 H), 6.23-6.31 (m, 2 H), 7.27-7.29 (m, 1 H), 7.54-7.59 (m, 2 H), 7.78-7.81 (m, 2 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.81, 28.16, 52.08 (d, J = 19.3 Hz), 63.40, 80.45, 101.51 (d, J = 204.1 Hz), 108.93, 110.36, 129.47, 131.00, 131.92, 132.48, 142.46, 149.22, 154.31, 164.68 (d, J = 27.9 Hz), 189.64 (d, J = 25.5 Hz). HPLC (Chiralpak IA column; n-hexane-i-PrOH, 90:10; λ = 254 nm, flow rate: 0.5 mL/min); t _R = 24.7 min (minor), t _R = 55.2 min (major); 98% ee.