吡哆醛催化酮酸轉氨化的研究

陳 靜, 趙濬宇, 趙寶國

(上海師范大學 生命與環境科學學院,上海 200234)

吡哆醛催化酮酸轉氨化的研究

陳 靜, 趙濬宇, 趙寶國

(上海師范大學 生命與環境科學學院,上海 200234)

吡哆醛及其衍生物是酶催化轉氨化的活性中心.在酶催化的轉氨化過程中涉及到堿去質子化和酸質子化的過程,而酸或(和)堿的引入有可能降低轉氨化反應的活化能.因此通過在吡哆醛上引入胺、酸或脲等基團可能得到更加有效的轉氨化催化劑.設計合成了一系列的帶有不同官能團的吡哆醛催化劑.這些吡哆醛在α-酮酸轉氨化反應中展現出了較高的活性且能以較好的收率合成多種氨基酸.該反應條件溫和,易于操作,是一種合成α-氨基酸的好方法.

酮酸; 轉氨化; α-氨基酸; 吡哆醛

0 引 言

氨基酸是生物功能大分子蛋白質的基本組成單元,是構成動物營養所需蛋白質的基本物質.自20世紀50年代開始,氨基酸的應用范圍不斷擴大,形成了一個朝氣蓬勃的新興工業體系,被稱為氨基酸工業,生產技術日新月異,品種和產量逐年增加,1969年世界氨基酸的總產量約為25萬噸,1979年為40萬噸,10年內增加約1.7倍,至1989年調查統計總產出55萬噸[1].

在生物體內,酶催化的轉氨化是合成氨基酸的重要途徑,該反應是通過轉氨酶催化實現的[2-4].轉氨酶的活化中心是維生素B6,包括吡哆醛和吡哆胺及其磷酸酯衍生物.轉氨化反應實現了由α-酮酸到α-氨基酸的轉化.酶催化酮酸的轉氨化具有反應速度快,對映選擇性高,底物專一性強等優點.但是大多數轉氨酶不易得到,價格昂貴,另外由于酶專一性過強的特點又限制了底物適用范圍,這些不足限制了酶催化酮酸轉氨化的應用.所以發展維生素B6及其衍生物催化的生物模擬轉氨化反應具有重要意義.該研究很早就被化學家們重視[5-60],如1952年,Snell等[10-11]發現吡哆醛1與一系列的氨基酸2之間可以發生轉氨化,生成相應的吡哆胺3和α-酮酸4(圖1).

圖1 Snell等[10-11]對轉氨化反應的初步探索

從此拉開了生物模擬酮酸轉氨化反應研究的序幕[10-60].生物模擬酮酸轉氨化已經進行了大量的研究,但是到目前為止,生物模擬轉氨化,尤其是以維生素B6的衍生物為催化劑模擬轉氨化遠沒有發展成熟,具有較大的發展空間和應用潛力,需要進一步的探索.

在酶催化的轉氨化過程中,涉及到堿去質子化和酸質子化的過程,因此,設想在吡哆醛分子上合適的位置引入適當的堿或(和)酸的基團,在轉氨化反應中參與去質子或(和)質子化的過程,有可能降低反應的活化能,提高催化活性和選擇性.正是基于這一思路,本文作者通過在吡哆醛的側鏈上的不同位置引入不同官能團,設計并合成了一系列的吡哆醛催化劑,并考察了它們在α-酮酸轉氨化反應中的催化性能.

1 實驗部分

1.1 實驗通則

特別注明除外,溶劑都以標準方法處理.1H NMR和13C NMR在400 MHz 和600MHz Bruker核磁共振儀上測定.甲苯、四氫呋喃、苯等經鈉絲干燥處理后使用;二氯甲烷、N,N-二甲基甲酰胺等經CaH2干燥處理后使用;CH3CN經五氧化二磷干燥處理后使用;三乙胺 (TEA) 經氫氧化鉀干燥處理后使用.固體商業試劑除非特別說明外,均未經純化直接使用;液體試劑均經蒸餾純化后使用.

1.2 合成方法

1.2.1 催化劑9的合成

催化劑9合成路線如圖2所示,以商業化的吡哆素鹽酸鹽1為起始原料,經過五步反應,分別合成了7種催化劑9a-g.首先化合物1在硫酸的作用下與丙酮反應,得到丙酮叉保護的吡哆素5.化合物5在二異丙基乙基胺作堿的條件下,和甲磺酰氯反應生成具有較好離去性能的甲磺酸酯6.6與不同的硫醇化合物進行反應得到化合物7,該化合物在乙酸和水中110 ℃的條件下反應4 h脫去丙酮叉保護基,再用二氧化錳氧化即可得到吡哆醛催化劑9.催化劑9a中引入長鏈,目的是考察脂溶性官能團對轉氨化反應催化活性的影響;催化劑9b-f中分別引入了帶有酸性質子的官能團,目的是考察不同酸度的質子對催化活性的影響;催化劑9g中引入了NMe2,目的是考察堿性基團對催化活性的影響.

圖2 催化劑9a-g的合成

9a:黃色固體;收率80%;1H NMR (400 MHz,CDCl3) δ 11.48 (s,1H),10.52 (s,1H),7.93 (s,1H),3.90 (s,2H),2.50 (s,3H),2.45 (t,J=5.2 Hz,2H),1.59-1.52 (m,2H),1.36-1.20 (m,18H),0.87 (t,J=4.8 Hz,3H);13C NMR (100 MHz,CDCl3) 195.9,154.4,151.7,139.9,131.1,119.6,31.97,31.96,29.69,29.68,29.63,29.54,29.51,29.4,29.2,28.8,22.7,18.8,14.2.

9b:黃色固體;收率30%;1H NMR (400 MHz,DMSO) δ 12.31 (brs,10.51 (s,1H),8.04 (s,1H),4.11 (s,2H),2.64 (t,J=7.6 Hz,2H),2.53 (t,J=7.6 Hz,2H),2.44 (s,1H);13C NMR (100 MHz,CDCl3) δ 196.4,172.8,153.4,150.3,139.7,131.0,119.8,34.0,28.6,26.3,18.2.

9c:黃色固體;收率43%;1H NMR (300 MHz,CDCl3) δ 11.48 (s,1H),10.51 (s,1H),7.93 (s,1H),3.92 (s,2H),3.71 (t,J=6.0 Hz,2H),2.59 (t,J=6.9 Hz,2H),2.50 (s,3H),1.83 (tt,J=6.9,6.0 Hz,2H);13C NMR (100 MHz,CDCl3) δ 196.6,153.1,149.8,140.1,132.2,121.2,59.5,32.2,28.5,27.8,18.7.

9d:黃色固體;收率43%;1H NMR (400 MHz,CDCl3) δ 11.48 (s,1H),10.50 (s,1H),7.91 (s,1H),5.78 (brs.1H),3.91 (s,2H),3.35-3.26 (m,2H),2.50 (s,3H),2.48 (t,J=7.2 Hz,2H),1.94 (s,3H),1.83-1.73 (m,2H);13C NMR (100 MHz,CDCl3) δ 195.8,170.5,154.2,151.6,139.6,130.7,119.5,38.4,29.3,29.1,28.8,23.1,18.6.

9e:黃色固體,收率37%;1H NMR (400 MHz,CDCl3) δ 11.48 (brs,1H),10.46 (s,1H),7.90 (s,1H),7.48 (s,1H) 7.32-7.19 (m,4H),7.06-6.96 (m,1H),5.50 (t,J=5.2 Hz,1H),3.84 (s,2H),3.29-3.20 (m,2H),2.49 (s,3H),2.44 (t,J=7.2 Hz,2H),1.78-1.66 (m,2H);13C NMR (100 MHz,CDCl3) 195.9,156.7,154.5,151.8,139.6,139.0,131.0,129.2,123.3,120.4,119.7,39.0,29.7,29.3,29.2,18.7.

9f:黃色固體;收率22%;1H NMR (400 MHz,CDCl3) δ 11.33,(brs,1H),10.39 (s,1H),7.85 (s,1H),7.36-7.24 (m,2H),7.18-7.10(m,3H),6.46 (s,1H),3.85 (s,2H),3.65-3.55 (m,2H),2.48-2.36 (m,5H),1.85-1.76 (m,2H);13C NMR (100 MHz,CDCl3) δ 195.9,156.7,154.5,151.8,139.6,139.0,131.0,129.2,123.3,120.4,119.7,39.0,29.7,29.3,29.2,18.7.

9g:黃色固體;收率51%;1H NMR (400 MHz,CDCl3) δ 10.49 (s,1H),7.92 (s,1H),3.91 (s,2H),2.58-2.40 (m,7H),2.28 (s,6H),1.84-1.72 (m,2H).

1.2.2 催化劑12的合成

按照圖3所示的方法,發展了催化劑12.化合物5與苯酚在偶氮二甲酸二乙酯(DEAD)和三苯基磷存在下發生縮合,以很好的產率得到化合物10.化合物10在乙酸和水中110 ℃反應4 h,脫去丙酮叉保護基得到化合物11,再經過二氧化錳氧化以較好的產率得到吡哆醛催化劑12.

圖3 催化劑12的合成

12:黃色固體;收率75%;1H NMR (600 MHz,CDCl3) δ 11.45 (s,1H),10.34 (s,1H),8.12 (s,1H),7.26(dd,J=7.8,7.2 Hz,2H),6.96 (t,J=7.2 Hz,1H),6.92 (d,J=7.8 Hz,2H),5.21 (s,2H),2.50 (m,3H);13C NMR (100 MHz,CDCl3) δ 196.8,157.8,154.3,153.3,139.6,129.9,128.7,122.1,120.6,114.9,65.0,22.1.

1.2.3 α-酮酸的轉氨化(以α-酮酸4a的轉氨化為例)

取5 mL的反應瓶,向瓶中稱取酮酸4a(45.6 mg,0.20 mmol),催化劑12 (2.4 mg,0.010 mmol),2,2-二苯基氨基酸13a(47.7 mg,0.21 mmol),再向瓶中加入MeOH(0.90 mL)和水(0.10 mL),加入磁子,塞好瓶塞,置入25 ℃恒溫油浴中反應2 d.停止反應,將瓶中反應物轉移到25 mL茄型瓶中,加入10 mL甲醇使瓶中固體全部溶解,再加入0.2 g硅膠,置于25 ℃水浴的旋蒸中旋干,干法上柱.柱層析(silica gel,EtOH/ethyl acetate/25%～28% ammonia solution=100∶58∶16)得到產品氨基酸2a(44.1 mg,yield=96%).

圖4 α-酮酸4a的轉氨化

2a:白色固體;1H NMR (400 MHz,D2O with 2 equiv.of KOH) δ 8.08-7.96 (m,1H),7.88-7.78 (m,1H),7.75-7.65 (m,1H),7.55-7.20 (m,4H),3.30-3.21 (m,1H),3.06-2.92 (m,2H),1.98-1.75 (m,2H).

2b:白色固體;1H NMR (600 MHz,D2O with 2 equiv.of KOH) δ 3.07 (dd,J=6.4,6.0 Hz,1H),1.50-1.35 (m,2H),1.22-1.06 (m,12H),0.72 (t,J=6.4 Hz,3H).

2c:白色固體:1H NMR (400 MHz,D2O) δ 7.36 (dd,J=7.6 Hz,2H),7.30 (d,J=7.6 Hz,2H),7.25 (t,J=7.6 Hz,1H),3.25 (dd,J=6.4,6.0 Hz,1H),2.64 (t,J=8.0 Hz,2H),1.98-1.76 (m,2H).

2d:白色固體;1H NMR (600 MHz,D2O with 2 equiv.of KOH) δ 6.80 (s,2H),3.20 (t,J=9.0 Hz,1H),2.60-2.50 (m,2H),2.21 (s,6H),2.15 (s,3H),1.68-1.55 (m,2H).

2e:白色固體;1H NMR (400 MHz,D2Owith 2 equiv.of KOH) 3.19 (dd,J=8.4,6.0 Hz,1H),1.66-1.53 (m,1H),1.45-1.25 (m,2H),0.84 (t,J=6.8 Hz,6H).

2g:白色固體;1H NMR (600 MHz,D2Owith 2 equiv.of KOH) δ 7.80 (d,J=8.4 Hz,1H),7.79 (d,J=9.0 Hz,1H),7.71 (s,1H),7.46 (d,J=8.4 Hz,1H),7.30 (s,1H),7.17 (d,J=9.0 Hz,1H),3.91 (s,3H),3.05-2.95 (m,2H),2.09-2.02 (m,1H),1.82-1.73 (m,1H),1.30 (d,J=7.2 Hz,3H).

2h:白色固體;1H NMR (600 MHz,D2Owith 2 equiv.of KOH) δ 7.40-7.25 (m,8H),7.23-7.14 (m,2H),4.08 (t,J=12.0,1H),2.99 (dd,J=12.0,9.0 Hz,1H),2.48-2.36 (m,1H),2.18-2.06 (m,1H).

2i:白色固體;1HNMR (400 MHz,D2Owith 2 equiv.of KOH) δ 7.29-7.14 (m,5H),3.68 (dd,J=9.2,4.4 Hz,1H),3.23 (dd,J=10.4,4.4 Hz,1H),2.90 (dd,J=10.4,9.2 Hz,1H).

2k:白色固體;1H NMR (400 MHz,D2Owith 2 equiv.of KOH) δ 3.27 (dd,J=6.4,6.0 Hz,1H),1.67 (dd,J=14.0,6.4 Hz,1H),1.33 (dd,J=14.0,6.0 Hz,1H),0.88 (s,9H).

2 結果與討論

2.1 反應條件優化

圖5 轉氨化條件的篩選

合成得到吡哆醛類催化劑9a-g和12后,對α-酮酸轉氨化的反應條件進行了考察(表1).以萘乙基酮酸4a為底物,分別對催化劑、溶劑和氨源等進行了篩選.沒有催化劑的情況下,只有微量產物生成,說明催化劑對轉氨化反應至關重要(表1,Entry 1).催化劑9a-g和12都表現出一定的催化活性(表1,Entries 2～9),都有相應的氨基酸2a生成,其中催化劑12最好,轉氨反應收率高達90%.對反應溶劑對反應有較大的影響(表1,Entries 10～16),二氯甲烷中幾乎沒有反應,可能是由于二苯基甘氨酸在二氯甲烷中的溶解度不好(表1,Entry 13).其他的溶劑中轉氨化都有反應,其中以甲醇為溶劑時分離收率最高,因此選用甲醇-水為反應的溶劑.對氨源的篩選表明芐胺13b-c(表1,Entries 17～18)和氨基酸類化合物13a和13d-g(表1,Entries 9 and 19～22)都可以用作該反應的氨源,其中當以二苯基甘氨酸[61-67](13a)為氨源時,反應具有最高的分離收率(表1,Entry 9).

表1 轉氨反應條件的篩選a

aAll reactions were carried out with keto acid 4a(0.050 mmol for entries 1-9 and 0.10 mmol for entries 10-22),2,2-diphenyl amino acids 19 (0.051 mmol for entries 1-9 and 0.101 mmol for entries 10-22),catalyst (0.010 mmol),solvent (0.50 mL) at 25 ℃ for 2 d for entries 1-9 and 3 d for entries 10-22.bIsolated yield based on keto acid 4a.

2.2 底物的拓展

在優化的反應條件下,對α-酮酸底物進行了拓展.如圖6所示,所考察的α-酮酸都有一定的反應活性,芳香族類的α-酮酸(圖6 2a,2c-d,2h-j)在催化劑的作用下表現出較高的反應活性,轉氨化產物收率較高;脂肪族類的α-酮酸轉氨化產物收率相對較低(圖6 2b,2e,2k,2l).底物的立體位阻對反應有一定的影響,β-取代的酮酸(圖6 2l)和β-芳基酮酸(圖6 2m)在該反應中表現出較低的活性.

圖6 底物拓展a

aAll reactions were carried out with α-keto acid 4 (0.20 mmol),α,α-diphenylglycine (13a)(0.21 mmol,and catalyst 12(0.010 mmol) in methanol (0.90 mL)and water (0.10 mL) at 25 ℃ for 2 days.bIsolated yield based on keto acidα-keto acid 4.

2.3 轉氨反應機理

對上述的轉氨化反應,提出了如圖7所示的反應機理.首先,吡哆醛催化劑12與體系中的2,2-二苯基氨基酸(13a)縮合生成席夫堿15,席夫堿15經脫羧、轉氨化和水解生成吡哆胺18;化合物18與α-酮酸4縮合形成酮亞胺19,酮亞胺19的芐位去質子,得到一個離域的碳負離子中間體20,中間體20的羧基α位質子化形成醛亞胺21,再水解釋放出自由的α-氨基酸2,同時再生吡哆醛催化劑12,完成一個催化循環[63-67].

圖7 吡哆醛催化α-酮酸轉氨化的反應機理

3 結 論

通過在吡哆醛的側鏈引入不同的官能團,合成了一系列的吡哆醛催化劑9a-g和12,該吡哆醛可以用于催化α-酮酸的轉氨化,生成一系列α-氨基酸化合物.該反應條件溫和,操作簡單,是一種新的氨基酸合成方法.該轉化還模擬了生物體系內酶催化轉氨化過程,為該生物過程的理解提供了有用的信息,具有一定的化學生物學意義.

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(責任編輯：郁 慧,包震宇)

Transamination of α-keto acids catalyzed by pyridoxals

CHEN Jing, ZHAO Junyu, ZHAO Baoguo

(College of Life and Environment Sciences,Shanghai Normal University,Shanghai 200234,China)

In this paper,we designed and synthesized a series of pyridoxals tagged with different functional groups.The pyridoxals exhibited high catalytic activity in transamination of α-keto acids to obtain various amino acids in good yields.This transamination has some obvious advantages such as mild reaction conditions and easy operation.This workhas provided a potentially practical method for the synthesis of chemically and biologically significant α-amino acids.

α-keto acid; transamination; α-amino acid; pyridoxal

2016-09-22

國家自然科學基金 (21272158,21672148).

趙寶國,中國上海市徐匯區桂林路100號,上海師范大學生命與環境科學學院,郵編:200234,E-mail:zhaobg2006@hotmail.com

O 62

A

1000-5137(2016)06-0719-10