Total Synthesis of Chiral Falcarindiol Analogues Using BINOL-Promoted Alkyne Addition to Aldehydes

Abstract

An enantioselective total synthesis of chiral falcarindiol analogues from buta-1,3-diyn-1-yltriisopropylsilane is reported. The key step in this synthesis is BINOL-promoted asymmetric diacetylene addition to aldehydes. The two chiral centers of the falcarindiol analogues can be produced by using the same kind of catalyst with high selectivity, and the final product can be obtained in only six steps.

Highly Enantioselective Synthesis and Anticancer Activities of Chiral Conjugated Diynols

“…We first prepared buta‐1,3‐diynyltriisopropylsilane according to our previous report (Scheme S1 in the Supporting Information) . To investigate the use of chiral amino alcohols to promote the enantioselective addition of 1,3‐diynes to aldehydes, we chose an inexpensive chiral amino alcohol, (1 S ,2 S )‐2‐amino‐3‐( p ‐nitrophenyl)propane‐1,3‐diol ( AA1 ), to synthesize a serials of chiral ligands AA2 – 6 (Scheme ).…”

“…( S )‐BINOL in combination with ZnEt 2 and Ti(O i Pr) 4 was found to catalyze the highly enantioselective addition of various 1,3‐diynes to aldehydes. In this catalytic system, biscyclohexylamine (Cy 2 NH) was added to facilitate the deprotonation of a terminal 1,3‐diyne to form a nucleophilic diynylzinc, and this method was very efficient for synthesizing chiral falcardiol analogues from buta‐1,3‐diynyltriisopropylsilane in short steps . However, the use of ZnEt 2 in this method limits its application in industrial production owing to its sensitivity to moisture and air and pyrophoric properties.…”

Synthesis, Anticancer Activity, Structure‐Activity Relationship and Mechanistic Investigations of Falcarindiol Analogues

“…found that 1,1’‐binaphth‐2‐ol (BINOL) in combination with ZnEt 2 and Ti(O i Pr) 4 can catalyze the highly enantioselective addition of various 1,3‐diynes to an aldehyde [18] . In this catalytic system, biscyclohexylamine (Cy 2 NH) was added to facilitate the deprotonation of a terminal 1,3‐diyne to form a nucleophilic diynylzinc, and chiral falcarindiol analogues can be efficiently synthesized from buta‐1,3‐diynyl‐triisopropylsilane (TIPS) in short steps [19] . Although the two chiral centers of the falcarindiol analogues can be constructed by using the BINOL‐Ti(O i Pr) 4 ‐ZnEt 2 ‐Cy 2 NH catalytic system, [19] the direct use of ZnEt 2 present an important safety issue for application in large scale industrial production due to its moist and air‐sensitivity [20] .…”

“…In this catalytic system, biscyclohexylamine (Cy 2 NH) was added to facilitate the deprotonation of a terminal 1,3‐diyne to form a nucleophilic diynylzinc, and chiral falcarindiol analogues can be efficiently synthesized from buta‐1,3‐diynyl‐triisopropylsilane (TIPS) in short steps [19] . Although the two chiral centers of the falcarindiol analogues can be constructed by using the BINOL‐Ti(O i Pr) 4 ‐ZnEt 2 ‐Cy 2 NH catalytic system, [19] the direct use of ZnEt 2 present an important safety issue for application in large scale industrial production due to its moist and air‐sensitivity [20] . Recently, we have developed highly enantioselective syntheses of chiral conjugated diynols by using the chiral amino alcohol as well as the BINOL systems to promote the asymmetric 1,3‐diyne addition to an aldehyde [16] .…”

Synthesis and Biological Evaluation of Falcarinol-Type Analogues as Potential Calcium Channel Blockers

“…Our group recently conducted the asymmetric synthesis of several chiral falcarinol analogues, ( R )- 2 , with a conjugated diynol moiety and a triisopropylsilyl (TIPS) group, using a chiral amino alcohol [(1 S ,2 S )-2- N , N -dimethylamino-1-( p -nitrophenyl)-3-( tert -butyldimethylsilyloxy)­propan-1-ol)]-based catalytic process, which exhibited potential antiproliferative activity against certain cancer cell lines . Several optically active falcarinol analogues were also prepared using this chiral 1,1′-binaphth-2-ol (BINOL)-based catalytic system. − Since the TIPS (C 9 + Si) group of these compounds is lipophilic, similar to that of the linear chain (C 10 ) of falcarinol ( 1a ), these falcarinol analogues also may possess neuroprotective effects. In the present study are reported the asymmetric synthesis of ( R )- and ( S )-falcarinol analogues 2 with ( S )- or ( R )-BINOL-based catalysts, the neuroprotective effects of 1a and its analogues 2 against NaN 3 -induced toxicity on PC12 cells, structure–function relationships, and mechanistic investigations including lactate dehydrogenase (LDH) release, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, and reactive oxygen species (ROS) stress, as well as the potential calcium channel-blocking activity.…”