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Synlett 2003(10): 1407-1410
DOI: 10.1055/s-2003-40862
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Tsutomu Yokomatsu*, Junya Kato, Chiseko Sakuma, Shiroshi Shibuya
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
e-Mail: yokomatu@ps.toyaku.ac.jp;
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Publication History

Received 30 May 2003
Publication Date:
24 July 2003 (online)

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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.

Key words

diastereoselectivity - regioselectivity - phosphonates - fluorine

9

Burton discussed mechanisms for reaction between 2 and allychlorides and proposed that the reaction may proceed through an SN2/SN2′ 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).

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.

19

See the reference in note 16.

20

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