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Synlett 2006(4): 0543-0546  
DOI: 10.1055/s-2006-933127
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Bianca Flavia Bonini, Francesca Boschi, Mauro Comes Franchini*, Mariafrancesca Fochi, Francesco Fini, Andrea Mazzanti, Alfredo Ricci
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
e-Mail: mauro.comesfranchini@unibo.it;
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Publikationsverlauf

Received 30 November 2005
Publikationsdatum:
20. Februar 2006 (online)

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Abstract

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

Key words

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

    References and Notes

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    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).
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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+].

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.