郭嬌美,靳少靜,董華繪,王琪琳,卜站偉

(阻燃與功能材料河南省工程實驗室，河南大學 化學化工學院，河南 開封 475004)

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螺氮雜環(huán)丙烷氧化吲哚的不對稱合成研究

郭嬌美,靳少靜,董華繪,王琪琳*,卜站偉*

(阻燃與功能材料河南省工程實驗室，河南大學 化學化工學院，河南 開封 475004)

螺環(huán)氧化吲哚和氮雜環(huán)丙烷都是非常重要的活性骨架，以3-烯氧化吲哚和雙保護的羥胺為起始原料，基于Michael加成-取代串聯(lián)反應(yīng)，實現(xiàn)了螺氮雜環(huán)丙烷氧化吲哚的不對稱合成.通過對一系列手性催化劑、反應(yīng)溫度等的篩選，最終確定了奎寧和辛克寧為最優(yōu)催化劑，分別以28%和34%的對映選擇性得到目標產(chǎn)物，其結(jié)構(gòu)經(jīng)過1H NMR、13C NMR和HRMS確定.

氮雜環(huán)丙烷；螺環(huán)氧化吲哚；不對稱合成；對映選擇性

螺環(huán)氧化吲哚作為生物堿，是一類非常重要的活性骨架，廣泛存在于具有生理活性的天然產(chǎn)物以及藥物中[1].因此，發(fā)展高效合成該類化合物的方法具有重要的研究價值.然而通過文獻調(diào)研發(fā)現(xiàn)，已報道的方法多集中在螺六元環(huán)[2]、五元環(huán)[3]氧化吲哚的構(gòu)建，對于螺三元環(huán)氧化吲哚的報道相對較少，且已報道合成的螺三元環(huán)主要集中在螺環(huán)丙烷[4]，而對于螺氮雜環(huán)丙烷氧化吲哚的構(gòu)建鮮有報道[5].氮雜環(huán)丙烷也是一類非常重要的結(jié)構(gòu)單元，它是很多藥物的核心成分[6].由于其具有高度的環(huán)張力，很容易發(fā)生開環(huán)或擴環(huán)反應(yīng)[7]，此外，在光照、加熱或Lewis酸的誘導下，它還可以與親偶極體發(fā)生[3+2]環(huán)加成反應(yīng)[8].通過文獻調(diào)研發(fā)現(xiàn)，合成氮雜環(huán)丙烷的方法很多[9]，而雙保護的羥胺作為一類新型的氮雜環(huán)丙烷化試劑，廣泛的用在不飽和羰基化合物的氮雜環(huán)丙烷化反應(yīng)中[10].

以3-烯氧化吲哚1和雙保護的羥胺2為反應(yīng)底物，考察了催化劑、溶劑、溫度等反應(yīng)條件對合成手性螺氮雜環(huán)丙烷氧化吲哚3的收率及立體選擇性的影響.該產(chǎn)物的結(jié)構(gòu)經(jīng)過1H NMR、13C NMR和HRMS表征.

1 實驗部分

1.1 儀器與試劑

1H NMR、13C NMR 用 Bruker Avance-300 型核磁共振儀測定， CDCl3化學位移以Me4Si 作內(nèi)標；高分辨質(zhì)譜用 Bruker Q TOF 質(zhì)譜儀測定；HPLC 分析是在 Shimadzu LC-12ATVP 和 Waters-Breeze 液相色譜儀上完成，手性柱為 Chiralpak AD-H；紅外光譜由 Thermo Fisher Nicolet 6700 紅外光譜儀測定.

3-烯氧化吲哚1[3b]和雙保護的羥胺2[10]均按照文獻方法合成；所有常用的溶劑均為國產(chǎn)分析純試劑.

1.2 手性螺氮雜環(huán)丙烷的合成方法

在干燥的反應(yīng)試管中分別加入 0.15 mmol 1、0.45 mmol 2、0.15 mmol Na2CO3以及0.003 mmol手性催化劑，于 50 ℃下攪拌，TLC 檢測反應(yīng)完全后，反應(yīng)液減壓除去溶劑，柱色譜分離(石油醚/乙酸乙酯作洗脫劑)，即可獲得雙螺環(huán)氧化吲哚 3.白色固體，收率29%.1H NMR (300 MHz, CDCl3),δ7.94 (d,J= 8.3 Hz, 1H), 7.43～7.34 (m, 7H), 7.17 (t,J= 7.5 Hz, 1H), 5.19 (q,J= 12.0 Hz, 2H), 3.91 (s, 1H), 3.75 (s, 3H), 1.64 (s, 9H);13C NMR (75 MHz, CDCl3)δ167.5, 164.7, 157.9, 148.4, 141.4, 134.7, 130.7, 128.7, 128.5, 128.4, 124.9, 123.8, 119.6, 115.4, 85.2, 69.3, 52.8, 49.4, 49.1, 28.0.IR (KBr)ν3 436, 2 924, 2 851, 1 775, 1 741, 1 325, 1 294, 1 252, 1 217, 1 170, 1 100, 762, 731 cm-1.HRMS (ESI) Calcd.for C24H24N2NaO7[M+Na]+: 475.147 6, Found: 475.146 8.

圖1 手性催化劑結(jié)構(gòu)

Table 1 Condition optimization for the synthesis of aziridinesa

EntryCat.t/℃time/hyield/%bee/%c14a305.520524b305.532034c305.518444d305.519054e305.517564f305.523274g305.51858d4a-5129289d4c-512143410d4a-2012152111d4c-20122921

aUnless otherwise specified, the reaction was conducted on a 0.15 mmol scale with 1.5 equiv of 2 and Na2CO3.All reactions afforded 3 as a single diastereomer.bIsolated yields.cDetermined by chiral HPLC.dThe reaction was conducted with 3.0 equiv of 2 and 1.0 equiv of Na2CO3at the specified temperature.

2 結(jié)果與討論

為了探索合成手性螺氮雜環(huán)丙烷氧化吲哚的方法，我們對一系列叔胺雙功能類催化劑進行了篩選 (圖1).首先，以四氫呋喃為溶劑，0.15 mmol 1與1.5當量的雙保護羥胺 2以及碳酸鈉，在奎寧 4a 催化下于30 ℃反應(yīng) 5.5 h 后以 20% 的收率以及 5% 的ee值獲得目標產(chǎn)物3 (表1, Entry 1).為了獲得更好的收率以及對映選擇性，我們繼續(xù)對具有金雞納堿骨架的其他叔胺雙功能催化劑進行了篩選 (表1, Entries 2-7).綜合收率和對映選擇性考慮，奎寧4a和辛克寧4c的結(jié)果相對較好 (表1, Entries 1， 3).接著我們又考察了溫度對反應(yīng)的影響，在 1 與2 的物質(zhì)的量配比為 1∶3 的情況下，我們分別對奎寧4a和奎寧定4c作為催化劑在 -5 ℃與 -20 ℃進行了考察，從篩選的結(jié)果來看，降低溫度，收率有所提高，但是對映選擇性降低 (表1, Entries 8 vs 10, 9 vs 11).

3 結(jié)論

以3-烯氧化吲哚和雙保護的羥胺為底物，碳酸鈉為縛酸劑，通過Michael加成/取代串聯(lián)反應(yīng)，實現(xiàn)了手性螺氮雜環(huán)丙烷氧化吲哚的不對稱合成.通過對反應(yīng)條件的篩選，采用廉價易得的奎寧和辛克寧為催化劑，分別以28%和34%的對映選擇性得到目標產(chǎn)物.

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[責任編輯：張普玉]

Studies on the asymmetric synthesis of spiroaziridine oxindoles

GUO Jiaomei, JIN Shaojing, DONG Huahui, WANG Qilin*, BU Zhanwei*

(HenanProvinceEngineeringLaboratoryofFlameRetardantandFunctionalMaterials,CollegeofChemistryandChemicalEngineering,HenanUniversity，KaifengHenan475004,China)

Spirooxindoles and aziridines are important biologically active scaffolds.In this paper, asymmetric Michael addition/substitution sequence of methyleneindolinones with N-tosyloxycarbamates for the construction of chiral spiroaziridine oxindole was realized.After a systematic screening of chiral catalysts and reaction temperatures, finally, quinine and cinchonine were proved to be the best catalysts, and the corresponding product was obtained in 28% and 34% enantioselectivies, respectively.The structure of the product was determined by1H NMR,13C NMR and HRMS.

aziridine； spirooxindole； asymmetric synthesis； enantioselectivity

2016-10-08.

國家自然科學基金(U1504206).

王琪琳(1987-),男,講師,研究方向為有機合成，不對稱催化.*

O621.3

A

1008-1011(2016)06-0729-04