Electrophilic cyclization of unsaturated carboxylic acids, alcohols and amines is important biomimetic process in the synthesis of heterocyclic intermediate and the functionalization of double bonds. Also, it has been intended for asymmetric modification. Some of successful reagent-controlled electrophilic cyclization reactions have been developed involving chiral synthetic iodoreagents, mercuric salts, and selenium reagents as electrophiles.
Among various kinds of electrophilic cyclization reactions, iodoetherification was examined for its asymmetric variants because it gave tetrahydrofurans or tetrahydropyrans which were useful synthetic moieties in organic synthesis. The standard substrate 81c was designed to undergo 5-exo iodoetherification giving a chiral tetrahydrofuran-containing compound and used for comparing the level of enantioselectivity in all asymmetric electrophile-promoted cyclization reaction performed. First, chiral iodoreagents 73a-d modeled on N-iodosuccinimide (NCS) were synthesized but failed to promote iodoetherification. Second, a variety of chiral Lewis bases were synthesized and employed to activate iodoreagents at low temperature where no spontaneous iodoetherification reaction occurred without Lewis bases. One-to-one complexes of chiral Lewis bases 85-95 and NIS or $I_2$ were generated in situ and then substrate 81c was added, which gave low enantioselectivity. Among several Lewis base, bisoxazolines 79a and 80 showed the best result (20 - 30% ee).
Asymmetric mercurioetherification was tried with the complexes of bisoxazolines and $Hg(CF_3CO_2)_2$. Bisoxazolines with $C_4-phenyl$ group promoted the desired mercurioetherification and gave higher enantioselectivity than that of iodoetherification. In the case of bisoxazoline 80, the reaction rate was very fast and gave 63% ee in dichloromethane. When diethyl ether or potassium carbonate was added, the enantioselectivity increased to 70% ee.
Many $C_4-phenyl$ bearing bisoxazolines were examined in various reaction conditions and bisoxazoline 113a was found to give the best enantioselectivity, 85% ee.
Bisoxazoline 113a has the unique non $C_2-symmetric$ tartrate moiety having extra chiral centers. Substrates with more than two carbons between terminal bulky substituents and the double bond gave high enantioselectivity. While substrates bearing terminal alkyl groups gave low enantioselectivity directly proportional to the length of alkyl chain. Bisoxazoline 130b with $C_4-naphthyl$ group instead of $C_4-phenyl$ group gave more improved enantioselectivity up to 91% ee. When methanol was added, the enantioselectivity went more up to 95% ee in the case of substrates having bulky terminal groups.
Substrates with terminal alkyl groups also showed drastically increased enantioselectivity up to 91% ee compared with that of bisoxazoline 113a. 50% recovery of used bisoxazoline 130b for recycling was achieved with the aid of potassium carbonate. The rest of bisoxazoline was recovered as the mixture of hydrolyzed form 133 and 134 quantitatively.
Catalytic asymmetric mercurioetherification was carried out by using the difference in the reactivities of $Hg(OAc)_2$ and $Hg(CF_3CO_2)_2$. Catalytic amount of a complex of bisoxazoline and $Hg(CF_3CO_2)_2$, and an equivalent $Hg(OAc)_2$ were employed in mercurioetherification where only chiral bisoxazoline-$Hg^{2+}(CF_3CO_2^-)_2$ complex would promote the reaction.
In addition, the differences in the reactivities of oxazoline 163 and bisoxazoline 80 or 98b could be utilized in the development of catalytic asymmetric mercurioetherification. The complex of 2 equivalents of 163 and $Hg(CF_3CO_2)_2$ transferred $Hg^{++}$ to chiral bisoxazoline 80 and 98b where the asymmetric mercurioetherification actually took place.
유기합성에 있어서 중요한 합성체인 테트라하이드로푸란과 테트라하이드로파이란을 만들 수 있는 에테르고리화반응의 비대칭 개발에 대해 연구하였다. 키랄루이스염기 85-95와 N-아이오드석신이미드나 아이오딘의 일대일 복합체를 형성시킨 후, 기본기질 81c를 첨가시켰으나, 거울상선택성이 낮았다. 여러 루이스 염기중에서는 비스옥사졸린 79a와 80을 사용하였을 때 20-30% ee의 거울상선택성을 얻었다.
비대칭 수은에테르고리화반응은 비스옥사졸린과 트라이플루오르아세트산수은의 복합체를 이용하여 염화메틸렌 용매에서 수행하였는데, 이때 비스옥사졸린의 4번탄소위치에 페닐기가 있는 화합물 80의 경우에는 반응속도가 매우 빨랐으며 63% ee의 거울상선택성을 얻었다. 다이에틸에테르나 탄산칼륨을 첨가하면 거울상선택성이 70% ee까지 상승하였다. 다양한 비스옥사졸린을 다양한 반응조건에서 조사해본 결과 화합물 113a가 85% ee의 가장 좋은 거울상선택성을 주었다.
화합물 113a는 여분의 키랄중심이 있는 비대칭적인 타르탄산 부분을 가지는 독특한 구조를 가지고 있다. 기질은 이중결합과 말단의 치환기 사이에 2개 이상의 탄소를 가진 경우 높은 거울상선택성을 얻을 수 있었다. 4번 탄소위치의 페닐기 대신 나프틸기를 가진 비스옥사졸린 130b를 사용했을 때, 선택성은 91% ee까지 상승하였다. 여기에 메탄올을 첨가하고 비대한 말단기를 가진 기질을 사용한 경우에는 95% ee의 거울상선택성을 얻었다. 또한 말단 알킬기를 가진 기질의 경우에도 91% ee의 높은 거울상선택성을 얻었다. 비스옥사졸린 130b는 반응 후 50%정도 수거하였고 다음 반응에서 재활용되었다. 나머지 50%는 화합물 133과 134의 혼합물의 형태로 수거하였다.
촉매비대칭 수은고리화반응은 아세트산수은과 트라이플루오르아세트산수은의 반응성차이를 이용하여 수행하였다. 비스옥사졸린과 트라이플루오르아세트산수은의 복합체 촉매량과 당량의 아세트산수은을 사용하면, 비스옥사졸린과 트라이플루오르아세트산수은의 복합체만이 반응을 촉진하였다. 또한, 옥사졸린 163과 비스옥사졸린 80 또는 98b의 반응성차이도 이용할 수 있었다. 2당량의 옥사졸린 163과 트라이플루오르아세트산수은의 복합체는 반응을 진행시키지 않고 키랄 비스옥사졸린 80과 98b에게로 수은이온을 전달시키고, 그후 비대칭수은고리화반응이 진행되었다.
