First 1,3-Dipolar Cycloaddition of Azomethine Ylides with (E)-Ethyl 3-Fluoroacrylate: Regio- and Stereoselective Synthesis of Enantiopure ­Fluorinated Prolines

Abstract

Enantiopure fluorinated prolines with four chiral centers were obtained from 1,3-dipolar cycloaddition of azomethine ylides and (E)-ethyl 3-fluoroacrylate.

1,3-dipolar cycloaddition - fluoroolefins - azomethine ylides - fluorinated prolines

References and Notes

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3b Gothelf KV. In Cycloaddition Reaction in Organic Synthesis   Kobayashi S. Jorgensen KV. Wiley-VCH; Weinheim: 2001.  Chap. 6.

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4a Synthetic Application of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products   Padwa A. Pearson W. Wiley-VCH; Weinheim: 2002.  p.169 

4b Kanemasa S. Synlett  2002,  1371 

4c Longmire JM. Wang B. Zhang X. J. Am. Chem. Soc.  2002,  124:  13400 

4d Chen C. Xiaodong L. Schreiber S. J. Am. Chem. Soc.  2003,  125:  10174 

4e Nyerges M. Bendell D. Arony A. Hibbs DE. Coles SJ. Hursthouse MB. Synlett  2003,  947 

5a Enantiocontrolled Synthesis of Fluoro-Organic Compounds. Stereochemical Challenges and Biomedicinal Targets   Soloshonok VA. John Wiley and Sons, Inc.; New York: 1999. 

5b Asymmetric Fluoroorganic Chemistry   Ramachandran PV. ACS Symposium Series; Washington, DC: 2000. 

5c Smart BE. Chemistry of Organic Fluorine Compound: A Critical Review   Hudlicky M. Pavlath AE. ACS Monograph 187, American Chemical Society; Washington, DC: 1995.  p.979 

5d Smart BE. Organofluorine Chemistry: Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum Publishing Corporation; New York: 1994.  p.57 

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6 Hodges JA. Reines RT. J. Am. Chem. Soc.  2003,  125:  9262 

7a Paolella DN, Gruskin EA, and Buechter DD. inventors; PCT Int. Appl. WO  2000015789. 

7b Fukui H, Shibata T, Nakano J, Naita T, Senda N, Maejima T, Watanuki Y, and Aryoshi T. inventors; JP  07300471. 

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9 McElroy KT. Purrington S. Bumgardner CL. Burgess JP. J. Fluorine Chem.  1999,  95:  117 

10

A solution of BocNHglycine (3.5 g, 20.2 mmol) in 50 mL of CH₂Cl₂ was cooled to 0 °C. N,N-dicyclohexylcarbodiimide (4.18 g, 20.2 mmol) was added in several portions and a white precipitate formed quickly. After 10 min, l-menthol was added (3.78 g, 24.2 mmol) in 60 mL of CH₂Cl₂ and DMAP (110 g, 0.9 mmol). The mixture was stirred at r.t. for 24 h. After addition of H₂O (15 mL), the organic phase was extracted with Et₂O and dried over MgSO₄. The residue was purified on column chromatography on silica gel (PE-Et₂O, 2:1) to afford the l-menthol ester (5.4 g, 86%) as a yellow oil. [α]_D ²⁰ -46.5 (c 0.99, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 5.06 (s, 1 H), 4.70 (dt, 1 H, J = 12.3, 6.1 Hz), 3.83 (d, 2 H, J = 4.2 Hz), 1.98-1.90 (m, 1 H), 1.85-1.73 (m, 1 H), 1.67-1.59 (m, 2 H), 1.40 (s, 9 H), 1.37-1.29 (m, 1 H), 1.07-0.76 (m, 4 H), 0.85 (d, 3 H, J = 7.3 Hz), 0.84 (d, 3 H, J = 7.3 Hz), 0.70 (d, 3 H, J = 6.6 Hz). ¹³C NMR (75.3 MHz, CDCl₃): δ = 169.7, 155.4, 79.2, 75.4, 46.8, 42.5, 40.7, 34.0, 31.3, 28.2, 26.1, 23.3, 21.9, 20.6, 16.2. MS (EI): m/e = 313 [M⁺]. Standard procedures for the removal of the Boc were followed giving (1R,2S,5S)-2 as a yellow oil. [α]_D ²⁰ -77.3 (c 0.50, MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 4.60 (dt, 1 H, J = 12.2, 6.1 Hz), 3.32 (s, 2 H), 2.28 (s, 2 H), 1.92-0.60 (18H). ¹³C NMR (75.3 MHz, CDCl₃): δ = 173.1, 74.3, 46.6, 43.3, 40.4, 33.8, 30.9, 25.8, 23.0, 21.5, 20.3, 15.9. MS (EI): m/e = 213 [M⁺].

11

For the condensation see ref. 4c and 4d. Starting from (1R,2S,5S)-2 (860 mg, 4.0 mmol), Na₂SO₄ (3.2 g, 22.8 mmol) and PhCHO (0.4 mL, 4.0 mmol), 1.03 g (86%) of (1R,2S,5S)-3a as a yellow oil were obtained. [α]_D ²⁰ -54.0 (c 0.16, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 8.17 (s, 1 H), 7.67-7.63 (m, 2 H), 7.32-7.26 (m, 3 H), 4.66 (dt, 1 H, J = 4.0, 11.3 Hz), 4.26 (s, 2 H), 1.93 (d, 1 H, J = 11.8 Hz), 1.84-1.73 (m, 1 H), 1.61-1.50 (m, 2 H), 1.44-1.24 (m, 2 H), 1.00-0.81 (m, 3 H), 0.77 (d, 6 H, J = 5.5 Hz), 0.64 (d, 3 H, J = 7.3 Hz). ¹³C NMR (100.6 MHz, CDCl₃): δ = 169.4, 164.9, 136.4, 128.7, 128.6, 128.5, 74.6, 62.4, 47.3, 41.2, 34.4, 31.4, 26.6, 23.8, 22.1, 20.8, 16.6. MS (ESI): m/z = 324 [M⁺ + Na]. Starting from (1R,2S,5S)-2 (1.67 g, 7.8 mmol), Na₂SO₄ (6.34 g, 44.6 mmol) and 4-CNC₆H₄CHO (1.03g, 7.8 mmol), 2.28 g (90%) of (1R,2S,5S)-3b as a yellow oil were obtained. [α]_D ²⁰ -42.4 (c 0.50, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 8.33 (s, 1 H), 7.89 (d, 2 H, J = 8.6 Hz), 7.72 (d, 2 H, J = 8.6 Hz), 4.87 (dt, 1 H, J = 11.0, 4.3 Hz), 4.43 (s, 2 H), 2.09-0.70 (m, 18 H). ¹³C NMR (100.6 MHz, C₆D₆): δ = 168.9, 163.1, 139.5, 132.5, 132.2, 129.4, 128.7, 118.4, 114.5, 75.0, 62.2, 47.3, 41.2, 34.3, 31.4, 26.7, 23.8, 22.1, 20.8, 16.6. MS (ESI): m/z = 349 [M⁺ + Na].

12

According to ref. 4c and 4d. Starting from 1 (212 mg, 1.8 mmol) and 3a (541 mg, 1.8 mmol), 565 mg (75%) of 4a,a′ were obtained as mixture after column chromatography on silica with CH₂Cl₂-EtOAc 200:1. After column chromatography the two cycloadducts were subjected to semi-preparative HPLC separation. HPLC (hexane-i-PrOH gradient starting from 0.5% i-PrOH, to 11 min, then 1.05% i-PrOH to 25 min, then 2.25% i-PrOH). Selected data for 4a,a′.
l-Menthol-(2S,3R,4R,5S)-4a: elution time 9.00 min; yellow oil; [α]_D ²⁰ -60.5 (c 0.55, MeOH). ¹H NMR (600 MHz, C₆D₆): δ = 7.22-7.19 (m, 1 H), 7.02-6.95 (m, 4 H), 5.77 (ddd, 1 H, J _HF = 53.1 Hz, J = 3.1, 1.6 Hz), 4.99 (dt, 1 H, J = 11.1, 4.6 Hz), 4.62 (d, 1 H, J = 7.4 Hz), 4.21 (dd, 1 H, J _HF = 28.6 Hz, J = 3.1 Hz), 3.46 (dd, 1 H, J = 10.5, 7.3 Hz), 3.44 (dd, 1 H, J = 10.5, 7.3 Hz), 3.27 (ddd, 1 H, J _HF = 20.1 Hz, J = 7.2, 1.6 Hz), 3.11 (s, 1 H), 2.16-2.06 (m, 1 H), 1.47-1.34 (m, 3 H), 1.21-1.08 (m, 1 H), 0.99-0.60 (m, 3 H), 0.90 (d, 3 H, J = 7.6 Hz), 0.87 (d, 3 H, J = 7.6 Hz), 0.75 (d, 3 H, J = 7.1 Hz), 0.48 (t, 3 H, J = 7.6 Hz). ¹³C NMR (150 MHz, C₆D₆): δ = 169.7 (d, J _CF = 9.6 Hz), 169.4 (d, J _CF = 14.0 Hz), 137.9, 128.0-127.4, 126.9, 98.3 (d, J _CF = 187.6 Hz), 75.5, 68.1 (d, J _CF = 24.6 Hz), 64.5, 60.0, 56.1 (d, J _CF = 22.2 Hz), 46.9, 40.6, 34.0, 31.1, 26.2, 23.1, 21.8, 20.7, 16.0, 13.2. ¹⁹F NMR (376 MHz, C₆D₆): δ = -173.77 (ddd, J _FH = 51.9, 28.9, 21.0 Hz). MS (ESI): m/z = 419 [M⁺].
l-Menthol-(2R,3S,4S,5R)-4a′: elution time 9.30 min; yellow oil; [α]_D ²⁰ -27.1 (c 0.75, MeOH). ¹H NMR (600 MHz, C₆D₆): δ = 7.23-7.21 (m, 1 H), 7.04-6.95 (m, 4 H), 5.71 (ddd, 1 H, J _HF = 52.8 Hz, J = 2.7, 1.6 Hz), 5.02 (dt, 1 H, J = 10.9, 4.8 Hz), 4.63 (d, 1 H, J = 6.8 Hz), 4.20 (dd, 1 H, J _HF = 28.7 Hz, J = 2.7 Hz), 3.45 (q, 2 H, J = 7.3 Hz), 3.27 (ddd, 1 H, J _HF = 20.1 Hz, J = 7.1, 1.5 Hz), 3.08 (s, 1 H), 2.18-2.13 (m, 1 H), 2.06-2.00 (m, 1 H), 1.48-0.58 (m, 7 H), 0.85 (d, 6 H, J = 7.0 Hz), 0.74 (d, 3 H, J = 6.5 Hz), 0.47 (t, 3 H, J = 7.6 Hz). ¹³C NMR (150 MHz, C₆D₆): δ = 169.9 (d, J _CF = 9.3 Hz), 169.4 (d, J _CF = 12.3 Hz), 137.9, 128.0-127.4, 126.8, 98.4 (d, J _CF = 186.5 Hz), 75.3, 67.8 (d, J _CF = 25.9 Hz), 64.5, 60.0, 56.5 (d, J _CF = 24.2 Hz), 47.0, 40.7, 34.1, 31.2, 26.4, 23.4, 21.8, 20.6, 16.4, 13.2. ¹⁹F NMR (376 MHz, C₆D₆): δ = -173.95 (ddd, J _FH = 48.9, 28.9, 19.9 Hz). MS (ESI): m/z = 419 [M⁺].

13a Stonehouse J. Adell P. Keeler J. Shaka AJ. J. Am. Chem. Soc.  1994,  116:  6037 

13b Stott K. Stonehouse J. Keeler J. Hwang TL. Shaka AJ. J. Am. Chem. Soc.  1995,  117:  4199 

13c Stott K. Keeler J. Van Q N. Shaka AJ. J. Magn. Reson.  1997,  125:  302 

13d Van Q N. Smith EM. Shaka AJ. J. Magn. Reson.  1999,  141:  191 

14

In the case of 5a, on selective saturation of the H₃ signal NOE effects were observed only on H₂ and H₄ (relative distance from H₃: 1.07:1.00), while saturation of H₄ showed NOE effects on H₅ and H₃ (relative distance from H₄: 1.00:1.14). Saturation of H₅ revealed strong NOE effects on H₂ and H₄ and a very small effect on H₃ (relative distance from H₅: 1.00:1.13:ca. 1.8); finally, saturation of H₂ revealed strong NOE effects on H₃ and H₅ and a not negligible effect on H₄ (relative distance from H₂: 1.09:1.00:1.33). These data imply a trans relationship between H₂ and H₃, a trans relationship between H₃ and H₄, and a cis relationship between H₄ and H₅. This concatenation (trans-trans-cis) corresponds to the 2R*,3S*,4S*,5R* configuration. Analogous data were obtained for 5a′, 4a and 4a′.

15

MMFF force field as implemented in Titan 1.0.5, Wavefunction, Inc. The standard conformational search was applied to 5a and 5a′, and the structures within 3 kcal/mol above the global minima were analyzed for the determination of the distances between the pyrrolidine hydrogens and the menthol hydrogens. In Figure [1] are reported the two global energy minima.

16a According to: Nyerges M. Bendell D. Arany A. Hibbs DE. Coles SJ. Hursthouse MB. Groundwater PW. Meth-Cohn O. Synlett  2003,  947 

16b

Selected data for 7a,a′. Starting from 5a (130 mg, 0.29 mmol) 44.3 mg (50%) of (2S,3R,4R,5S)-7a were obtained as a colorless oil; [α]_D ²⁰ 17.3 (c 0.2, MeOH). ¹H NMR (600 MHz, C₆D₆): δ = 7.32-7.28 (m, 2 H), 7.12-7.06 (m, 2 H), 5.71 (dd, 1 H, J = 52.0, 3.5 Hz), 4.50 (d, 1 H, J = 7.1 Hz), 4.15 (dd, 1 H, J = 27.9, 3.6 Hz), 3.45 and 3.40 (2 s, 6 H), 3.30 (dd, 1 H, J = 20.5, 7.0 Hz), 2.90 (s, 1 H, NH). ¹³C NMR (150 MHz, C₆D₆): δ = 171.4 (d, J = 9.6 Hz), 170.6 (d, J = 11.5 Hz), 138.8, 128.7, 128.6, 127.1, 127.0, 117.2, 98.8 (d, J = 187.4 Hz), 67.5 (d, J = 26.2 Hz), 65.0, 64.6, 56.3 (d, J = 22.4 Hz), 52.6. ¹⁹F NMR (376 MHz, C₆D₆): δ = -174.00 (ddd, J _FH = 51.0, 28.0, 20.7 Hz). MS (ESI): m/z = 306 [M⁺]. Starting from 5a′ the same procedure gave (2R,3S,4S,5R)-7a′ in 52% yield; [α]_D -17.8 (c 0.2, MeOH).

17a Singh RP. Schreeve JM. J. Fluorine Chem.  2002,  116:  23 

17b Singh RP. Schreeve JM. Synthesis  2002,  2561