Stereoselective Synthesis of Highly-Functionalized Cyclohexene Derivatives Having a Diethoxyphosphoryldifluoromethyl Functionality from Cyclohex-2-enyl-1-phosphates

Abstract

Reaction of diethoxyphsphoryldifluoromethylzinc bromide (BrZnCF₂PO₃Et₂) with highly functionalized cyclohex-2-enyl-1-phosphates in the presence of CuBr in THF was examined. The reaction provides a facile method for introducing a difluoro­methylenephosphonate unit to the allylic position within a cyclic array in a stereo- and regioselective manner.

diastereoselectivity - regioselectivity - phosphonates - fluorine

References

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9

Burton discussed mechanisms for reaction between 2 and allychlorides and proposed that the reaction may proceed through an S_N2/S_N2′ substitution mechanism. [7b]

10

trans-Isomer i of 4c reacted with 2 under the same conditions to give a 62:38 mixture of α-alkylated product ii and γ-alkylated product iii in 71% yield (Scheme [5] ). The
α-alkylated product showed virtually no de. However, the
γ-alkylated product showed modest de preferable to 1,2-trans-stereochemistry showing that the reaction proceeded from the less-hindered syn-face of the phosphate to avoid the bulky pivaloyl group. These results also support that the reactions would involve a process for leaving the phosphate group prior to the carbon-carbon bond formation.

Scheme 5

11

Compounds 5c and 6c were not readily separated on column chromatography on silica gel. However, these products were also separated by using the difference in their chemical reactivity; selective deprotection of the Piv functional group of 5d occurred to give 6b upon treatment with ethylmagnesium bromide in diethyl ether at -15 °C.

12

All new compounds gave satisfactory spectroscopic and analytical data. Compound 5b obtained as a colorless oil, [α]_D ²⁵ +55.2 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃):
δ = 5.94 (1 H, d, J = 10.6 Hz), 5.87 (1 H, dd, J = 10.6, 1.2 Hz), 4.31-4.22 (4 H, m), 3.01-2.85 (1 H, m), 2.21-2.12
(1 H, m), 2.10-2.01 (1 H, m), 1.80-1.69 (3 H, m), 1.52-1.40 (1 H, m), 1.39 (3 H, t, J = 7.0 Hz), 1.38 (3 H, t, J = 7.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 123.13 (t, J _CF = 4.3 Hz), 120.79 (dt, J _CF = 262.2 Hz, J _CP = 211.0 Hz), 115.36, 77.20, 66.04, 64.56 (d, J _CP = 6.9 Hz), 64.38 (d, J _CP = 6.9 Hz), 40.93 (dt, J _CF = 19.9 Hz, J _CP = 15.4 Hz), 31.04, 20.15, 16.27. ³¹P NMR (162 MHz, CDCl₃): δ = 7.09 (t, J _PF = 107.9 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = -51.07 (1 F, ddd, J _FF = 300.8 MHz, J _FP = 107.9 Hz, J _FH = 16.2 Hz), -53.04 (1 F, ddd, J _FF = 300.8 MHz, J _FP = 107.9 Hz, J _FH = 13.9 Hz). IR (film): 3433, 1632, 1263 cm^-1. MS (ESI): m/z = 307 [M + Na]⁺. HRMS (ESI) calcd for C₁₁H₁₉O₄F₂NaP: 307.0887. Found: 307.0876. Compound 6d obtained as a colorless oil, [α]_D ²⁵
-23.4 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.72-7.66 (4 H, m), 7.40-7.36 (6 H, m), 6.06 (1 H, dd, J = 10.3, 1.9 Hz), 5.72 (1 H, d, J = 8.8 Hz), 4.55 (1 H, s), 4.56-4.07 (4 H, m), 2.99-2.85 (1 H, m), 2.38-2.25 (1 H, m), 1.68-1.60 (m), 1.30-1.26 (6 H, m), 1.10 (3 H, s), 1.07 (3 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 135.8, 135.3, 132.0, 129.6, 123.0-116.0 (m), 118.0, 65.1, 64.3, 47.1 (dt, J _CF = 19.1 Hz, J _CP = 19.1 Hz), 27.3, 26.9, 26.5, 20.3, 19.1, 19.0, 16.2 (d, J _CP = 5.4 Hz). ³¹P NMR (162 MHz, CDCl₃): δ = 7.00 (t, J _PF = 110.4 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = -47.13 (1 F, ddd, J _FF = 298.9 Hz, J _FP = 110.4 Hz, J _FH = 11.3 Hz),
-51.87 (1 F, ddd, J _FF = 298.9 Hz, J _FP = 110.4 Hz, J _FH = 24.8 Hz). IR (film): 1657, 1271 cm^-1. MS (EI): m/z = 523 [M⁺ + 1]. Anal. Calcd for C₂₇H₃₇F₂O₄PSi: C, 62.05; H, 7.14. Found: C, 61.58; H, 6.99. Compound 13b obtained as an oil, [α]_D ²⁵ -51.4 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃):
δ = 8.12 (2 H, d. J = 7.3 Hz), 7.57 (1 H, dd, J = 7.3, 7.3 Hz), 7.44 (2 H, dd, J = 7.3, 7.3 Hz), 5.95 (1 H, d with small splits, J = 10.6 Hz), 5.92 (1 H, d, J = 10.6 Hz), 5.70 (1 H, dd, J = 8.8, 2.3 Hz), 4.72-4.71 (1 H, m), 4.64-4.62 (1 H, m), 4.28-4.15 (4 H, m), 3.64-3.55 (1 H, m), 1.37 (3 H, s), 1.33 (3 H, s), 1.29 (6 H, t, J = 7.1 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 165.73, 133.13, 130.06, 129.15, 128.30, 124.00-116.00 (m), 121.59, 110.04, 73.52, 72.58, 67.72 (d, J = 3.7 Hz), 64.81 (t, J = 5.6 Hz), 42.03 (dt, J = 15.3, 20.2 Hz), 27.51, 26.52, 16.24 (d, J = 5.7 Hz), 16.25 (d, J = 4.9 Hz). ³¹P NMR (162 MHz, CDCl₃): δ = 6.12 (t, J _PF = 106.7 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = -47.73 (2 F, dd, J _FP = 106.7 Hz, J _FH = 15.8 Hz). IR (film): 1723, 1602, 1451, 1271 cm^-1. MS (ESI): m/z = 483 [M + Na]⁺. HRMS (ESI) calcd for C₂₁H₂₇O₇F₂NaP: 483.1360. Found: 483.1316. Compound 19a obtained as an oil, [α]_D ²⁵ -72.6 (c 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 6.03 (2 H, broad s), 5.46 (1 H, dd, J = 5.8, 4.3 Hz), 4.63 (1 H, dd, J = 6.0, 2.4 Hz), 4.45 (1 H, t, J = 6.1 Hz), 4.32-4.23 (5 H, m), 3.48-3.39 (1 H, m), 2.07 (3 H, s), 1.40 (3 H, s), 1.37 (3 H, t, J = 6.9 Hz), 1.37 (3 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 170.35, 128.96, 124.00-116.00 (m), 122.17, 109.61, 72.57, 71.53, 69.53, 64.63 (dt, J _CF = 22.1 Hz, J _CP = 6.8 Hz), 39.90 (dt, J = 15.3, 19.8 Hz), 27.60, 25.90, 21.00, 16.30. ³¹P NMR (162 MHz, CDCl₃): δ = 6.25 (t, J _PF = 105.5 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = -48.79 (1 F, ddd, J _FF = 280.5 Hz, J _FP = 105.5 Hz, J _FH = 12.0 Hz), -50.22 (1 F, ddd, J _FF = 280.5 Hz, J _FP = 105.5 Hz, J _FH = 23.7 Hz). IR (film): 1750, 1372, 1271, 1233 cm^-1. MS (ESI): m/z = 421 [M + Na]⁺. Anal. Calcd for C₁₆H₂₅F₂O₇P: C, 48.24; H, 6.33. Found: C, 48.51; H, 6.41. Compound 20c obtained as an oil, [α]_D ²⁵ +3.85 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.05 (1 H, d with small splits, J = 10.0 Hz), 5.81 (1 H, ddd, J = 10.0, 3.1, 2.1 Hz), 4.63 (1 H, dd, J = 6.5, 4.3 Hz), 4.35-4.24 (4 H, m), 4.19-4.16 (1 H, m), 4.15-4.07 (2 H, m), 3.08-2.92 (1 H, m), 1.46 (3 H, m), 1.40-1.31 (9 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 132.1, 121.0, 108.9, 78.7, 70.0, 68.0, 47.3 (t, J _CF = 11.8 Hz), 27.6, 25.4, 16.3, 16.1. ³¹P NMR (162 MHz, CDCl₃): δ = 6.74 (dd, J _PF = 108.8, 102.9 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = -47.25 (1 F, ddd, J _FF = 303.4 Hz, J _FP = 102.9 Hz, J _FH = 16.2 Hz), -49.91 (1 F, ddd, J _FF = 304.4 Hz, J _FP = 108.8 Hz, J _FH = 16.2 Hz). IR (film): 3419, 1645, 1445, 1263 cm^-1. MS (ESI): m/z = 379 [M + Na]⁺. HRMS (ESI) calcd for C₁₄H₂₃O₆F₂NaP: 379.1098. Found: 379.1081.

13

Compound 5b was chemically correlated to 5a and 5c to determine their trans-stereochemistry in the usual manner (Ac₂O, pyridine, PivCl, pyridine).

14 Chin Y. Levy GC. J. Am. Chem. Soc.  1984,  106:  6533 

15 Jørgensen M. Iversen EH. Paulsen AL. Madsen R. J. Org. Chem.  2001,  66:  4630 

16 The absolute stereochemistry of 8 was determined after its transformation to (+)-14 by the Mitsunobu inversion of the hydroxyl group with acetic acid (DEAD, Ph₃P, THF). The sign of the specific rotation was identical to that of the authentic specimen prepared by resolution of (±)-14 according to the method of Chung, see: Kwon Y.-U. Chung S.-K. Org. Lett.  2001,  3:  3013 

17

Although 12b and 13b were not readily separated by column chromatography on silica gel, 13b was isolated in pure state after osmium oxidation (cat. OsO₄, NMO, quinuclidine, CH₂Cl₂). In the osmium oxidation, 12b was rapidly dihydoxylated but 13b remained unreacted to be isolated by column chromatography. The details will be described elsewhere.

18a Liu Z. Classon B. Samuelsson B. J. Org. Chem.  1990,  55:  4273 

18b Pakulski Z. Zamojski A. Carbohydr. Res.  1990,  205:  410 

18c Garegg PJ. Synthesis  1979,  469 

19

See the reference in note 16.

20

Stereo- and regiochemistry of 20c was confirmed by 2D-NMR including HMBC, HMQC, COSY and NOESY.