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(huán)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(huán)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(xiàn)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(yǎng)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(yè)體系,被稱為氨基酸工業(yè),生產(chǎn)技術日新月異,品種和產(chǎn)量逐年增加,1969年世界氨基酸的總產(chǎn)量約為25萬噸,1979年為40萬噸,10年內(nèi)增加約1.7倍,至1989年調查統(tǒng)計總產(chǎn)出55萬噸[1].

在生物體內(nèi),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(xiàn)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(xiàn)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(yōu)點.但是大多數(shù)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(fā)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(fā)現(xiàn)吡哆醛1與一系列的氨基酸2之間可以發(fā)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(jīng)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(fā)展成熟,具有較大的發(fā)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?shù)膲A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(jīng)鈉絲干燥處理后使用;二氯甲烷、N,N-二甲基甲酰胺等經(jīng)CaH2干燥處理后使用;CH3CN經(jīng)五氧化二磷干燥處理后使用;三乙胺 (TEA) 經(jīng)氫氧化鉀干燥處理后使用.固體商業(yè)試劑除非特別說明外,均未經(jīng)純化直接使用;液體試劑均經(jīng)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(yè)化的吡哆素鹽酸鹽1為起始原料,經(jīng)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(fā)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(fā)生縮合,以很好的產(chǎn)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(jīng)過二氧化錳氧化以較好的產(chǎn)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(chǎn)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(yōu)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(chǎn)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(xiàn)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(yōu)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(xiàn)出較高的反應活性,轉氨化產(chǎn)物收率較高;脂肪族類的α-酮酸轉氨化產(chǎn)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(xiàn)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(jīng)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(huán)[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(nèi)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(qū)桂林路100號,上海師范大學生命與環(huán)境科學學院,郵編:200234,E-mail:zhaobg2006@hotmail.com

O 62

A

1000-5137(2016)06-0719-10