새로운 베스타틴 유사체의 입체선택적 합성

서영란; 이수범; 김영규; Youngran Seo; SooBeom Lee; Young Gyu Kim

Applied Chemistry for Engineering, Vol.26, No.1, 111-115, February, 2015

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새로운 베스타틴 유사체의 입체선택적 합성

Stereoselective Synthesis of Novel Bestatin Analogs

서영란, 이수범, 김영규 ^†

서울대학교 공과대학 화학생물공학부

Youngran Seo, SooBeom Lee, and Young Gyu Kim^†

Department of Chemical and Biological Engineering, Seoul National University, Seoul 151-742, Korea

E-mail:

초록

두 종류의 새로운 베스타틴(bestatin) 유사체를 D-leucine과 D-valine으로부터 효율적이면서 입체선택적으로 합성하였다. 아미노펩티데이즈 억제제인 베스타틴은 면역조절 효과를 보이며 급성백혈병 치료제로 상품화되어 있다. 주요 중간체인 trans-옥사졸리딘 메틸에스터 2a와 2b는 페닐설포닐나이트로메테인(PhSO2CH2NO2)과 N-하이드록시 메틸기가 보호기로 도입된 α-아미노 알데하이드(4a와 4b) 간의 일련의 세 단계 연속반응과 연이은 가오존분해 반응으로부터 20 : 1 이상의 입체선택성으로 합성되었다. 2a와 2b의 가수분해 반응 후에 L-Leu-OMe와의 펩타이드 결합을 통하여 베스타틴의 새로운 유사체인 3a와 3b를 보호기가 도입된 형태로 얻었다. 이소부틸기와 이소프로필기를 갖는 두 종류의 새로운 베스타틴 유사체(1a와 1b)는 해당 α-아미노알데하이드 4로부터 높은 입체선택성으로 6단계에 걸쳐 각각 51%와 38%의 수율로 합성되었다.

Two new analogs of bestatin were prepared from D-leucine and D-valine in a stereoselective and efficient way. An aminopeptidase inhibitor bestatin shows significant biological effects on immunomodulation and is marketed for the treatment of acute myelocytic leukemia. The key intermediates, trans-oxazolidine methyl esters 2a and 2b, were obtained with more than 20 to 1 stereoselectivity in a one-pot procedure by the three cascade reactions between N-hydroxymethyl protected α-amino aldehydes (4a and 4b) and phenylsulfonylnitromethane (PhSO2CH2NO2) and the following in-situ ozonolysis. Basic hydrolysis of 2a and 2b, and then the peptide coupling with L-Leu-OMe produced the protected derivatives of two new bestatin analogs, 3a and 3b, respectively. The new isobutyl and isopropyl analogs of bestatin (1a and 1b) were produced in overall 51% and 38% yields, respectively, with high stereoselectivity from the corresponding protected α-amino aldehydes 4 in a six-step process.

Keywords:bestatin analogs;aminopeptidase inhibitor;β-amino-α-hydroxy acid;intramolecular conjugate addition.

[References]

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Scornik OA, Botbol V, Curr Drug Metab., 2, 67 (2001)
Bauvois B, Dauzonne D, Med. Res. Rev., 1, 88 (2006)
Wickstrom M, Larsson R, Nygren P, Gullbo J, Cancer Sci., 102, 501 (2011)
Umezawa H, Aoyagi T, Suda H, Hamada M, Takeuchi T, J. Antibiot., 29, 97 (1976)
Hirayama Y, Sakamaki S, Takayanaqi N, Tsuji Y, Sagawa T, Chiba H, Matsunaga T, Niitsu Y, Gan To Kagaku Ryoho, 30, 1113 (2003)
Gordon EM, Godfrey JD, Delaney NG, Asaad MM, Langen DV, Cushman DW, J. Med. Chem., 31, 2199 (1988)
Ocain TD, Rich DH, J. Med. Chem., 31, 2193 (1988)
Yuan W, Munoz B, Wong CH, J. Med. Chem., 36, 211 (1993)
Harbeson SL, Rich DH, Biochemistry, 27, 7301 (1988)
Harbut MB, Velmourougane G, Reiss G, Chandramohanadas R, Greenbaum DC, Bioorg. Med. Chem. Lett., 18, 5932 (2008)
Aoyagi T, Tobe H, Kojima F, Hamada M, Takeuchi T, Umezawa H, J. Antibiot., 31, 636 (1978)
Lampret BR, Kidric J, Kralj B, Vitale L, Pokorny M, Renko M, Arch. Microbiol., 171, 397 (1999)
Bergmeier SC, Stanchina DM, J. Org. Chem., 64, 2852 (1999)
Wassermen HH, Xia M, Petersen AK, Jorgensen MR, Curtis EA, Tetrahedron Lett., 40, 6163 (1999)
Lee BW, Lee JH, Jang KC, Kang JE, Kim JH, Park KM, Park KH, Tetrahedron Lett., 44, 5905 (2003)
Gogoi N, Boruwa J, Barua NC, Tetrahedorn Lett., 46, 7581 (2005)
Seo Y, Kim H, Chae DW, Kim YG, Tetrahedron: Asymmetry, 25, 625 (2014)
Hyun SI, Kim YG, Tetrahedron Lett., 39, 4299 (1998)
Yoo D, Oh JS, Lee DW, Kim YG, J. Org. Chem., 68, 2979 (2003)
Yoo D, Oh JS, Kim YG, Org. Lett., 4, 1213 (2002)
Yoo D, Kwon S, Kim YG, Tetrahedron: Asymmetry, 16, 3762 (2005)
Kim H, Yoo D, Kwon S, Kim YG, Tetrahedron: Asymmetry, 20, 2715 (2009)
Yoo D, Song J, Kang MS, Kang ES, Kim YG, Tetrahedron: Aymmetry, 22, 1700 (2011)
Trost BM, Madsen R, Guile SD, Brown B, J. Am. Chem. Soc., 122(25), 5947 (2000)
Wade PA, Murray JK, Shah-Patel S, Palfey BA, Carroll PJ, J. Org. Chem., 65, 7723 (2000)
Jeon J, Kim SH, Lee JH, Oh JS, Park DY, Kim YG, Bull. Korean Chem. Soc., 30, 1003 (2009)
Jeon J, Shin N, Kim YG, Appl. Chem. Eng., 25(5), 437 (2014)

[Related Articles]

[1] Ota K, Biomed. Pharmacother., 45, 55 (1991)

[2] Scornik OA, Botbol V, Curr Drug Metab., 2, 67 (2001)

[3] Bauvois B, Dauzonne D, Med. Res. Rev., 1, 88 (2006)

[4] Wickstrom M, Larsson R, Nygren P, Gullbo J, Cancer Sci., 102, 501 (2011)

[5] Umezawa H, Aoyagi T, Suda H, Hamada M, Takeuchi T, J. Antibiot., 29, 97 (1976)

[6] Hirayama Y, Sakamaki S, Takayanaqi N, Tsuji Y, Sagawa T, Chiba H, Matsunaga T, Niitsu Y, Gan To Kagaku Ryoho, 30, 1113 (2003)

[7] Gordon EM, Godfrey JD, Delaney NG, Asaad MM, Langen DV, Cushman DW, J. Med. Chem., 31, 2199 (1988)

[8] Ocain TD, Rich DH, J. Med. Chem., 31, 2193 (1988)

[9] Yuan W, Munoz B, Wong CH, J. Med. Chem., 36, 211 (1993)

[10] Harbeson SL, Rich DH, Biochemistry, 27, 7301 (1988)

[11] Harbut MB, Velmourougane G, Reiss G, Chandramohanadas R, Greenbaum DC, Bioorg. Med. Chem. Lett., 18, 5932 (2008)

[12] Aoyagi T, Tobe H, Kojima F, Hamada M, Takeuchi T, Umezawa H, J. Antibiot., 31, 636 (1978)

[13] Lampret BR, Kidric J, Kralj B, Vitale L, Pokorny M, Renko M, Arch. Microbiol., 171, 397 (1999)

[14] Bergmeier SC, Stanchina DM, J. Org. Chem., 64, 2852 (1999)

[15] Wassermen HH, Xia M, Petersen AK, Jorgensen MR, Curtis EA, Tetrahedron Lett., 40, 6163 (1999)

[16] Lee BW, Lee JH, Jang KC, Kang JE, Kim JH, Park KM, Park KH, Tetrahedron Lett., 44, 5905 (2003)

[17] Gogoi N, Boruwa J, Barua NC, Tetrahedorn Lett., 46, 7581 (2005)

[18] Seo Y, Kim H, Chae DW, Kim YG, Tetrahedron: Asymmetry, 25, 625 (2014)

[19] Hyun SI, Kim YG, Tetrahedron Lett., 39, 4299 (1998)

[20] Yoo D, Oh JS, Lee DW, Kim YG, J. Org. Chem., 68, 2979 (2003)

[21] Yoo D, Oh JS, Kim YG, Org. Lett., 4, 1213 (2002)

[22] Yoo D, Kwon S, Kim YG, Tetrahedron: Asymmetry, 16, 3762 (2005)

[23] Kim H, Yoo D, Kwon S, Kim YG, Tetrahedron: Asymmetry, 20, 2715 (2009)

[24] Yoo D, Song J, Kang MS, Kang ES, Kim YG, Tetrahedron: Aymmetry, 22, 1700 (2011)

[25] Trost BM, Madsen R, Guile SD, Brown B, J. Am. Chem. Soc., 122(25), 5947 (2000)

[26] Wade PA, Murray JK, Shah-Patel S, Palfey BA, Carroll PJ, J. Org. Chem., 65, 7723 (2000)

[27] Jeon J, Kim SH, Lee JH, Oh JS, Park DY, Kim YG, Bull. Korean Chem. Soc., 30, 1003 (2009)

[28] Jeon J, Shin N, Kim YG, Appl. Chem. Eng., 25(5), 437 (2014)