Synthesis of an Advanced Intermediate toward the hNK-1 Antagonist with the Cyclopentane Core

Abstract

Allylic substitution of monomethoxyacetate of 4-cyclopentene-1,3-diol (91% ee) with 4-FC₆H₄ZnBr (4 equiv) and CuCl (30 mol%) gave anti-S_N2′ product, which upon epoxidation with MCPBA afforded α-epoxide stereoselectively. The epoxide was reduced with LiEt₃BH, and the resulting alcohol was converted into the targeted amine by using Mitsunobu reactions twice with 3,5-(O₂N)₂C₆H₃CO₂H and then with phthalimide.

Key words

substitution - copper - cyclopentane - Grignard reaction - hNK-1 antagonist

References and Notes

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• 3a

  Finke, P. E.; Meurer, L. C.; MacCoss, M.; Mills, S. G.; Sadowski, S.; Cascieri, M. A.; Metzger, J.; Eiermann, G.; MacIntyre, D. E. Abstract 98, 2000, 219^th National Meeting of the ACS, San Francisco, CA, March 2000.

• 3b

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• Related compounds with a cyclopentane ring:
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8

Asymmetric hydrolysis of dimethyoxyacetate i (Figure 3)
at r.t. was summarized in Table 1 (see Supporting Information). Novozyme 435 afforded (1R)-4 with a sufficiently high ee, but in a low yield (supporting Information, Table 1, entry 1), whereas lipases (entries 3-5), olipase 2S (entry 6), and PLE (entry 7) were less effective than Novozyme 435.

Figure 3

10

Checked by chiral HPLC; [α]_D ^²4 +62 (c 0.286, CHCl₃).

12

Epoxidation of ii afforded α-epoxide iii as a major product, whereas TBS ether 16 gave a 1:1 mixture of α- and β-epoxides (Scheme  [5] ).

Scheme 5

13

Mitsunobu inversion of 11 with PhCO₂H afforded the benzoate. However, attempted hydrolysis gave the olefin viii as the sole product (Figure  [4] ).

Figure 4

14

Experimental procedures are presented in Supporting Information.