Asymmetric Synthesis of (+)-CP-99,994 and (+)-L-733,060 from Enantio­merically Pure (3S,4S)-4-(tert-Butylcarbamoyl)-4-phenyl-1-buten-3-ol

Abstract

Asymmetric syntheses of neurokinin substance P receptor antagonists (+)-CP-99,994 and (+)-L-733,060 have been accomplished starting from enantiomerically pure (3S,4S)-4-(tert-butylcarbamoyl)-4-phenyl-1-buten-3-ol.

1,2-amino alcohols - 1,2-diamines - hydroformylations - neurokinin-1 antagonists - piperidines

References and Notes

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5a Oshitari T. Mandai T. Synlett  2003,  2374 

5b

The enantiomeric purity of 5 was determined to be >99% ee by HPLC [CHIRALCEL OD-H; hexane-i-PrOH = 9:1; λ = 220 nm; flow rate: 0.8 mL/min; t _R(5) = 6.36 min; t _R(ent-5) = 8.71 min].

5c

Compound 5 was also prepared from (S)-(+)-phenylglycine. See: Denis J.-N., Correa A., Greene A. E.; J. Org. Chem.; 1991, 56: 6939; Greene and co-workers reported therein that 5 was obtained in moderate yield with complete retention of enantiomeric purity by the addition of the crude Swern-oxidation product of N-Boc phenylglycinol to a large excess of vinylmagnesium bromide. Bhaskar et al. adopted this method for the preparation of compound 5 in their synthesis of 2, [2d] whose enantiomeric purity can be estimated below 50% ee in comparison with our own data. Ham and co-workers also synthesized 2 via an oxazoline derivative starting from N-benzoyl phenylglycinol. [2e] The optical rotation of 2 was in agreement with that reported in ref. 2d. These observations clearly imply that special care is required for employing easily racemizable phenylglycinal derivatives as a source of chiron approach.

6 Oshitari T. Akagi R. Mandai T. Synthesis  2004,  1325 

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9

In our preliminary investigation, DMSO was proven to be more effective solvent than toluene, THF and DMF. In addition, we found that DBU, soluble in above solvents, was much superior to other bases such as NaH, t-BuOK and Cs₂CO₃.

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11

The reaction under heating at refluxing temperature in a flask overnight provided 4-phenyl-4-(3-aminopropion-amido)-3-tosylamino-1-butene as the sole product.

12

After removal of ethylenediamine in vacuo, a mixture of the mono-N-Ts-protected 1,2-diamine and 2-imidazolidone was afforded, which was subjected to the next step without further purification.

For recent reviews, see:

13a Breit B. Seiche W. Synthesis  2001,  1 

13b Breit B. Acc. Chem. Res.  2003,  36:  264 

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13c Ojima I. Tzamarioudaki M. Eguchi M. J. Org. Chem.  1995,  60:  7078 

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{[3,3′-di-tert-Butyl-2′-(diphenoxymethoxy)-5,5′-dimethoxybiphenyl-2-yl]oxy}dibenzo[d,f][1,3]dioxepine.

14a Billig E, Abatjoglou AG, and Bryant DR. inventors; U. S. Patent,  4668651. 

14b Billig E, Abatjoglou AG, and Bryant DR. inventors; U. S. Patent,  4769498. 

14c Cuny GD. Buchwald SL. J. Am. Chem. Soc.  1993,  115:  2066 

15

Five-membered N-Boc-enamide (2%) and five-membered N-Boc-aminals (5%) were also isolated after the treatment with CSA. N-Ts-enamide and N-Ts-aminals were not obtained at all.

16

Compound 10: colorless foam; [α]_D ²² -206.0 (c = 1.00, CHCl₃). ¹H NMR (CDCl₃): δ = 1.21 (br s, 6.3 H), 1.41 (br s, 2.7 H), 1.77-1.85 (m, 1 H), 1.89-2.10 (br m, 1 H), 2.45 (s, 3 H), 3.87 (m, 1 H), 3.97 (d, J = 10.1 Hz, 1 H), 4.71 (br, 0.3 H), 4.78 (br, 0.7 H), 4.98 (br, 0.7 H), 5.15 (br, 0.3 H), 6.89-7.22 (m, 2 H), 7.28-7.38 (m, 5 H), 7.78 (m, 2 H). ¹³C NMR (CDCl₃): δ = 21.6, 25.5, 26.1, 27.9, 28.2, 49.8, 57.5, 58.9, 77.2, 81.3, 81.5, 101.0, 126.2, 126.6, 127.0, 128.0, 128.5, 129.9, 137.3, 137.7, 138.1, 143.7, 152.1. Anal. Calcd for C₂₃H₂₈N₂O₄S: C, 64.46; H, 6.59; N, 6.54. Found: C, 64.37; H, 6.71; N, 6.54.

17

In the absence of TBAI, the N-alkylation was very slow at 0 °C. Compound 12, however, was afforded in 81% yield at r.t. in 5 h with the significant loss of enantiomeric purity (77% ee), which was probably caused by the elimination-addition sequence of the N-2-methoxybenzyl-tert-butyl carbamoyl group.

18

Compound 12: colorless foam; [α]_D ²¹ -105.2 (c = 1.32, CHCl₃). ¹H NMR (CDCl₃): δ = 1.19-1.70 (m, 21 H), 1.85 (br m, 1 H), 3.14 (br m, 1 H), 3.33 (br m, 1 H), 3.65 (s, 3 H), 3.75 (br m, 0.45 H), 3.99-4.10 (m, 1.65 H), 4.25 (br m, 0.45 H), 4.50 (br m, 0.45 H), 5.45 (br s, 0.9 H), 5.64 (br s, 0.1 H), 6.71 (m, 1 H), 6.86 (m, 1 H), 7.03 (m, 1 H), 7.12 (m, 1 H), 7.37-7.25 (m, 5 H). ¹³C NMR (CDCl₃): δ = 22.4, 24.6, 28.2, 41.0, 41.6, 42.1, 55.1, 56.2, 57.0, 57.5, 77.2, 79.6, 109.8, 120.2, 126.4, 127.0, 128.0, 128.4, 140.2, 141.2, 155.9. Anal. Calcd for C₂₉H₄₀N₂O₅: C, 70.13; H, 8.12; N, 5.64. Found: C, 69.90; H, 8.28; N, 5.54. The enantiomeric purity of 12 was determined to be >99% ee by HPLC [CHIRALCEL OD; hexane-i-PrOH = 30:1; λ = 220 nm; flow rate: 1.0 mL/min; t _R(12) = 6.8 min; t _R(ent-12) = 11.0 min].

19

(+)-CP-99,994 (1): ¹H NMR (free base, CDCl₃): δ = 1.40 (br d, J = 13.2 Hz, 1 H), 1.60 (m, 1 H), 1.76 (br s, 2 H), 1.93 (m, 1 H), 2.14 (br d, J = 13.1 Hz, 1 H), 2.76-2.83 (m, 2 H), 3.27 (m, 1 H), 3.41 (d, J = 13.8 Hz, 1 H), 3.44 (s, 3 H), 3.67 (d, J = 13.8 Hz, 1 H), 3.88 (d, J = 2.1 Hz, 1 H), 6.68 (br d, J = 8.2 Hz, 1 H), 6.80 (br t, J = 7.3 Hz, 1 H), 6.97 (dd, J = 1.5, 7.3 Hz, 1 H), 7.15 (dt, J = 1.5, 8.2 Hz, 1 H), 7.20-7.31 (m, 5 H). ¹³C NMR (free base, CDCl₃): δ = 20.4, 28.2, 46.7, 47.8, 54.7, 54.8, 64.0, 109.8, 120.0, 126.3, 126.5, 127.8, 128.2, 129.6, 142.4, 157.6.

20

Protection of C3-hydroxyl group as a benzoate was of choice for the subsequent hydroformylation.

21

Compound 13: colorless viscous oil; [α]_D ²⁴ -152.3 (c = 1.02, CHCl₃). ¹H NMR (CDCl₃): δ = 1.25 (br s, 6 H), 1.40-1.55 (br m, 3 H), 2.05-2.25 (m, 1 H), 2.40 (m, 1 H), 4.83 (br m, 0.33 H), 4.93 (br m, 0.67 H), 5.40 (br m, 0.33 H), 5.46-5.63 (m, 1.67 H), 7.00-7.35 (m, 6 H), 7.40 (m, 2 H), 7.55 (m, 1 H), 7.90 (m, 2 H). ¹³C NMR (CDCl₃): δ = 23.7, 24.0, 27.9, 28.2, 56.0, 57.3, 69.2, 81.3, 100.4, 126.1, 126.4, 127.5, 127.6, 128.0, 128.35, 128.38, 129.69, 129.71, 129.8, 133.1, 138.6, 152.3, 165.6. Anal. Calcd for C₂₃H₂₅NO₄: C, 72.80; H, 6.64; N, 3.69. Found: C, 72.76; H, 6.84; N, 3.66.

22

Five-membered aminals (4%) were also isolated.

23

Compound 14: colorless viscous oil; [α]_D ²² +56.7 (c = 1.3, CHCl₃) {Lit. [1g] [α]_D ¹⁵ +53.77 (c = 1.0, CHCl₃); Lit. [2d] [α]_D ²⁵ +38.30 (c = 1.92, CHCl₃)}. ¹H NMR (CDCl₃): δ = 1.37 (s, 9 H), 1.54-1.62 (m, 1 H), 1.69 (m, 1 H), 1.76-1.87 (m, 3 H), 3.04 (m, 1 H), 4.01 (dd, J = 5.8, 12.8 Hz, 1 H), 4.09 (m, 1 H), 5.32 (d, J = 5.8 Hz, 1 H), 7.27 (m, 1 H), 7.37-7.32 (m, 2 H), 7.45 (m, 2 H). ¹³C NMR (CDCl₃): δ = 23.1, 27.7, 28.3, 39.5, 59.3, 70.1, 79.9, 127.2, 128.4, 138.5, 155.4. Anal. Calcd for C₁₆H₂₃NO₃: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.21; H, 8.59; N, 4.77. The enantiomeric purity of 14 was determined to be >99% ee by HPLC [CHIRALCEL OJ-H; hexane-i-PrOH = 9:1; λ = 220 nm; flow rate: 1.0 mL/min; t _R(14) = 4.80 min; t _R(ent-14) = 5.75 min].

24

Compound 15: colorless oil; [α]_D ²³ +43.3 (c = 1.60, CHCl₃) {Lit. [1g] [α]_D ²⁸ +36.90 (c = 1.0, CHCl₃)}. ¹H NMR (CDCl₃): δ = 1.46 (s, 9 H), 1.58-1.76 (m, 2 H), 1.94-2.05 (m, 2 H), 2.77 (ddd, J = 3.3, 13.4, 13.4 Hz, 1 H), 3.88 (m, 1 H), 3.95 (dd, J = 3.3, 13.4 Hz, 1 H), 4.71 (d, J = 12.5 Hz, 1 H), 4.75 (d, J = 12.5 Hz, 1 H), 5.70 (br s, 1 H), 7.25-7.36 (m, 3 H), 7.54 (br s, 1 H), 7.56 (br s, 1 H), 7.71 (br s, 2 H), 7.78 (br s, 1 H). ¹³C NMR (CDCl₃): δ = 24.2, 25.8, 28.4, 39.2, 55.4, 69.1, 78.7, 80.1, 121.4 (m), 123.3 (q, J = 272 Hz), 127.0, 127.2, 128.28, 128.32, 131.6 (q, J = 32.9 Hz), 138.0, 141.0, 155.3. The enantiomeric purity of 15 was determined to be >99% ee by HPLC [CHIRALPAK IA; hexane-i-PrOH = 30:1; λ = 220 nm; flow rate: 0.3 mL/min; t _R(15)= 14.1 min; t _R(ent- 15) = 16.6 min)].

25

L-733,060 (2): ¹H NMR (free base, CDCl₃): δ = 1.53 (m, 1 H), 1.66-1.75 (m, 1 H), 1.88 (m, 1 H), 2.22 (br d, J = 14.0 Hz, 1 H), 2.85 (ddd, J = 3.1, 12.5, 12.5 Hz, 1 H), 3.29 (m, 1 H), 3.68 (br m, 1 H), 3.85 (d, J = 1.2 Hz, 1 H), 4.13 (d, J = 12.5 Hz, 1 H), 4.52 (d, J = 12.5 Hz, 1 H), 7.25-7.29 (m, 1 H), 7.30-7.35 (m, 2 H), 7.35-7.39 (m, 2 H), 7.44 (br s, 2 H), 7.69 (br s, 1 H). ¹³C NMR (free base, CDCl₃): δ = 20.5, 28.4, 47.1, 64.2, 70.0, 77.3, 121.1 (hept, J = 4.1 Hz), 123.2 (q, J = 271 Hz), 126.7, 127.0, 127.4 (m), 128.1, 131.2 (q, J = 32.9 Hz), 141.2, 141.9.