Stereoselective Access to Functionalized Dihydrophenanthrenes via Reductive Cyclization of Biaryl Ene-Aldehydes

Abstract

Stereoselective access to 9-alkyl-10-hydroxy-9,10-dihydrophenanthrenes has been developed via the samarium(II) iodide mediated reductive cyclization of an ene-aldehyde appended to a biphenyl scaffold.

ene-aldehyde - samarium(II) iodide - reductive cyclization

References and Notes

For benanomicin-pradimicin, see:

1a Oki T. Konishi M. Tomatsu K. Saitoh K. Tsunakawa M. Nishio M. Miyaki T. Kawaguchi H. J. Antibiot.  1988,  41:  1701 

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1e For compound 4, see: Zheng G. Ho DK. J. Nat. Prod.  1994,  57:  32 

2a Ohmori K. Kitamura M. Suzuki K. Angew. Chem. Int. Ed.  1999,  38:  1226 

2b Kitamura M. Ohmori K. Kawase T. Suzuki K. Angew. Chem. Int. Ed.  1999,  38:  1229 

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6

Although a mixture of dl- and meso-isomers of 2,4-pentanediol was employed, the latter preferentially took part in the reaction, giving the diastereomer 12 in 81% yield with a small amount of other diastereomers (<6% yields). The structure of 12 was assigned by ¹H NMR and diagnostic NOE interactions (Figure [2] ).

7

This reaction also proceeded in the absence of a proton source, giving the product in 10% yield with a sizable amount of unidentified byproducts.

8

Typical procedure for the reductive cyclization: SmI₂ (0.10 M in THF, [17] 4.4 mL, 0.44 mmol) was added to a solution of the ene-aldehyde 8a (49.9 mg, 0.178 mmol) and MeOH (0.160 mL 3.92 mmol) in degassed THF (1.6 mL) at 0 °C. After stirring for 5 min at 0 °C, the reaction was stopped by adding aqueous K₂CO₃ and the products were extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by preparative TLC (silica gel 60 PF₂₅₄) to give 7a (trans/cis = 10:1) in quantitative yield as a colorless oil.

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11

The coupling constant between H_a and H_b in 17 was 4.6 Hz, indicating a cis relationship. The diagnostic NOE interactions between H_aŽH_b and H_bŽH_c in 17 suggested the conformation shown below (Figure [3] ).

12

Compound 16 was conformationally stable at room temperature. However, it underwent isomerization in toluene in 5 h at 90 °C. The equilibrium ratio was 36:64, diequatorial/diaxial (Figure [4] ).

13

The stereostructure of trans-7b was determined by X-ray crystal structure analysis (Figure [5] ).

14

The PTLC purification gave four separable diastereomers associated with relation between the 9,10-stereogenic centers in the phenanthrene skeleton and the sulfur chiral center. Oxidation of trans-7c and trans-7c′ by MCPBA led to the same compound 18. The stereostructure of 18 was determined by X-ray analysis (Scheme [9] ). In a similar manner, cis isomers of 7c and 7c′ were both converted into cis-19.

15a Pummerer R. Ber. Dtsch. Chem. Ges.  1910,  43:  1401 

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16

Isolation of the Pummerer product was attempted; however, it was prone to undergo hydrolysis to form the corresponding aldehyde. This aldehyde was easily dehydrated to afford 9-phenanthrene carboxaldehyde.

17 For preparation of SmI₂ in THF, see: Girard P. Namy JL. Kagan HB. J. Am. Chem. Soc.  1980,  102:  2693