Enantioselective Synthesis of Renieramide

Abstract

A highly chemo- and enantioselective PTC alkylation has been developed that allows rapid access to orthogonally protected (S,S)-isodityrosine. Utility of this material in the construction of isodityrosine-containing cyclic peptides is demonstrated by synthesis of the natural product renieramide.

Key words

amino acids - asymmetric alkylation - phase-transfer ­catalysis - quaternary ammonium salts

References

• 1 Fry SC. Biochem. J.  1982,  204:  449 
• 2 Zhu Z. Synlett  1997,  133 
• K13:
• 3a Kase H. Kaneko M. Yamada K. J. Antibiot.  1987,  40:  450 
• 3b Yasuzawa T. Shirahata K. Sano H. J. Antibiot.  1987,  40:  455 
• OF-4949-I-IV:
• 4a Sano S. Ikai K. Kuroda H. Nakamura T. Obayashi A. Ezure Y. Enomoto H. J. Antibiot.  1986,  39:  1674 
• 4b Sano S. Ikai K. Katayama K. Takesako K. Nakamura T. Obayashi A. Ezure Y. Enomoto H. J. Antibiot.  1986,  39:  1685 
• 5 Eurypamides A-D: Reddy MVR. Harper MK. Faulkner DJ. Tetrahedron  1998,  54:  10649 
• Renieramide:
• 6a Ciasullo L. Casapullo A. Cutignano A. Bifulco G. Debitus C. Hooper J. Gomez-Paloma L. Riccio R. J. Nat. Prod.  2002,  65:  407 
• 6b Itokawa H, Watanabe K, Kawaoto S, and Inoue T. inventors; Jpn. Kokai Tokkyo Koho JP  63203671. 
• For leading references to the syntheses of K13, OF4949-I-IV and the eurypamides see:
• 7a Ito M. Yamanaka M. Kutsumura N. Nishiyama S. Tetrahedron  2004,  60:  5623 
• 7b Jackson RFW. Perez-Gonzalez M. Chem. Commun.  2000,  2423 
• 7c Bigot A. Bois-Choussy M. Zhu J. Tetrahedron Lett.  2000,  41:  4573 
• 7d Janetka JW. Rich DH. J. Am. Chem. Soc.  1997,  119:  6488 
• 7e Pearson AJ. Zhang PL. Lee K. J. Org. Chem.  1996,  61:  6581 
• 7f Rao AVR. Gurjar MK. Reddy AB. Khare VB. Tetrahedron Lett.  1993,  34:  1657 
• 7g Boger DL. Yohannes D. J. Org. Chem.  1990,  55:  6000 
• 7h Evans DA. Ellman JA. J. Am. Chem. Soc.  1989,  111:  1063 
• 7i Nishiyama S. Suzuki Y. Yamamura S. Tetrahedron Lett.  1989,  30:  379 
• 7j Schmidt U. Weller D. Holder A. Lieberknecht A. Tetrahedron Lett.  1988,  29:  3227 
• 8 Lygo B. Tetrahedron Lett.  1999,  40:  1389 
• 9a Lygo B. Allbutt B. Synlett  2004,  326 
• 9b Lygo B. Allbutt B. James SR. Tetrahedron Lett.  2003,  44:  5629 
• 11 Reinholtz E. Becker A. Hagenbruch B. Schäfer S. Schmitt A. Synthesis  1990,  1069 
• 12a Lygo B. Andrews BI. Slack D. Tetrahedron Lett.  2003,  44:  9039 
• 12b Lygo B. Andrews BI. Tetrahedron Lett.  2003,  44:  4499 
• 12c Lygo B. Humphreys LD. Tetrahedron Lett.  2002,  43:  6677 
• 12d Lygo B. Andrews BI. Crosby J. Peterson JA. Tetrahedron Lett.  2002,  43:  8015 
• 12e Lygo B. Crosby J. Lowdon TR. Wainwright PG. Tetrahedron  2001,  57:  2391 
• 12f Lygo B. Crosby J. Lowdon TR. Peterson JA. Wainwright PG. Tetrahedron  2001,  57:  2403 
• 12g Lygo B. Crosby J. Peterson JA. Tetrahedron  2001,  57:  6447 
• 12h Lygo B. Wainwright PG. Tetrahedron Lett.  1997,  38:  8595 
• 13 For application of a related alkylation to the synthesis of the dityrosine fragment of RP66453 see: Boisnard S. Carbonnelle A.-C. Zhu J. Org. Lett.  2001,  3:  2061 
• 15 For an alternative approach to orthogonally protected (S,S)-isodityrosines see: Jorgensen KB. Gautun OR. Tetrahedron  1999,  55:  10527 
• 16 Kiso Y. Nakamura S. Ito K. Ukawa K. Kitagawa K. J. Chem. Soc., Chem. Commun.  1979,  971 

10

The enantioselectivity of this alkylation was determined by chiral-phase HPLC comparison of the product 10 with racemic material generated using n-Bu₄NBr as the PTC. Use of catalyst 8 led to similar regioselectivity and yield, but gave 10 with only 50% ee.

14

Representative Alkylation-Hydrolysis Procedure (Preparation of 12): A solution of glycine imine 4a (161 mg, 0.54 mmol) in toluene (4 mL) was placed under a nitrogen atmosphere. Iodide 11 (312 mg, 0.45 mmol), catalyst 8 (36 mg 10 mol%) and 9 M aq KOH (400 µL) were added sequentially, and the resulting mixture stirred at r.t. for 18 h. The toluene layer was then separated and the aqueous layer extracted with EtOAc (3 × 2 mL). The combined organics were dried (MgSO₄), and concentrated under reduced pressure. The residue was dissolved in Et₂O (10 mL), filtered (to remove catalyst), and again concentrated under reduced pressure. The residue was then dissolved in THF (5 mL) and 15% aq citric acid (1.5 mL) added. The mixture was stirred at r.t. for 18 h, then extracted with CHCl₃ (4 × 3 mL). The combined organics were washed with 10% aq Na₂CO₃ (2 × 4 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CHCl₃-MeOH, 50:1) to yield the orthogonally protected isodityrosine 12 (269 mg, 85%) as a pale yellow oil. R _f = 0.3 (CHCl₃-MeOH, 25:1). [α]_D +1 (c 0.9, CHCl₃). IR (film): ν_max = 3376, 2977, 2632, 1714, 1505 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.34-7.23 (10 H, m, ArH), 7.13 (2 H, d, J = 8.0 Hz, ArH), 6.84 (1 H, s, CHPh₂), 6.81 (2 H, d, J = 8.0 Hz, ArH), 6.76 (1 H, d, J = 8.0 Hz, ArH), 6.68 (1 H, d, J = 8.0 Hz, ArH), 6.65 (1 H, s, ArH), 4.97 (1 H, br d, J = 8.0 Hz, NH), 4.68-4.60 (1 H, m, CHN), 3.78 (3 H, s, OCH₃), 3.64-3.56 (1 H, m, CHN), 3.04 (1 H, dd, J = 6.0, 14.0 Hz, CHCH _a H_b), 2.99-2.95 (2 H, m, CHCH_a H _b , CHCH _a H_b), 2.82 (1 H, dd, J = 8.0, 14.0 Hz, CHCH_a H _b ), 1.44 [9 H, s, C(CH₃)₃], 1.40 [9 H, s, C(CH₃)₃]. ¹³C NMR (125 MHz, CDCl₃): δ = 174.2 (C), 170.9 (C), 156.9 (C), 155.0 (C), 150.0 (C), 144.6 (C), 139.6 (C), 139.4 (C), 131.3 (C), 130.5 (CH), 128.6 (CH), 128.5 (CH), 128.2 (CH), 128.0 (CH), 127.5 (CH), 127.0 (CH), 125.7 (CH), 122.4 (CH), 116.9 (CH), 112.8 (CH), 81.3 (C), 80.0 (C), 78.0 (CH), 56.3 (CH), 56.0 (CH₃), 54.5 (CH), 40.3 (CH₂), 37.4 (CH₂), 28.3 (CH₃), 28.1 (CH₃). MS (ES⁺): m/z (%) = 719 (28) [M + Na⁺], 697 (100) [M + H⁺], 641 (10) [M - t-Bu + H⁺], 296 (68). HRMS: m/z calcd for C₄₁H₄₉N₂O₈ [M + H]⁺: 697.3489. Found: 697.3528.

17

Selected data for synthetic renieramide (2): Mp 185-195 °C (decomp). [α]_D -32 (c 0.1, MeOH) (lit. [α]_D -30 (c 0.1, MeOH).^{6 1}H NMR (500 MHz, CD₃OD): δ = 7.42 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 7.20 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 7.01 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 6.86 (1 H, dd, J = 2.5, 8.0 Hz, ArH), 6.81 (1 H, d, J = 8.0 Hz, ArH), 6.65 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 5.98 (1 H, d, J = 2.0 Hz, ArH), 4.52 (1 H, dd, J = 3.5, 11.5 Hz, CHN), 4.48 (1 H, dd, J = 3.5, 12.5 Hz, CHN), 3.97 (1 H, dd, J = 2.0, 6.0 Hz, CHN), 3.38 (1 H, dd, J = 3.5, 13.0 Hz, CHCH _a H_b), 3.15 (1 H, dd, J = 2.0, 15.0 Hz, CHCH _a H_b), 2.91 (1 H, dd, J = 6.0, 15.0 Hz, CHCH_a H _b ), 2.60 (1 H, app. t, J = 12.5 Hz, CHCH_a H _b ) 1.70-1.62 [2 H, m, CH ₂ CH(CH₃)₂], 1.61-1.51 [1 H, m, CH₂CH(CH₃)₂], 0.95 (3 H, d, J = 6.0 Hz, CH₃), 0.93 (3 H, d, J = 6.0 Hz, CH₃). ¹³C NMR (125 MHz, CD₃OD): δ = 178.1 (C), 172.7 (C), 169.1 (C), 154.6 (C), 149.8 (C), 147.2 (C), 137.1 (C), 133.0 (CH), 131.7 (CH), 125.0 (2 × CH), 123.1 (CH), 122.7 (CH), 117.2 (CH), 116.9 (CH), 58.1 (CH), 53.7 (CH), 52.1 (CH), 43.6 (CH₂), 40.9 (CH₂), 37.4 (CH₂), 26.0 (CH), 23.8 (CH₃), 21.6 (CH₃).

18

There is a typographical error in the ¹³C NMR (CD₃OD) reported for natural renieramide,⁶ the CH₂ carbon of the l-DOPA fragment occurs at δ = 37.7 ppm (not 43.6). We thank Prof. R. Riccio and Dr. A. Casapullo for kindly providing this information.