Novel Asymmetric Formylation of Aromatic Compounds: Enantioselective Synthesis of Formyl 7,8‐Dipropyltetrathia[7]helicenes

Abstract

Asymmetric formylation of aromatic compounds is virtually unexplored. We report the synthesis and evaluation of a library including 20 new chiral formamides in the kinetic resolution of 7,8-dipropyltetrathia[7]helicene, affording the corresponding formyl- or diformylhelicenes in up to 73 % ee, making enantiopure compounds available by recrystallisation. With the N,N-disubstituted formamides used in this study, the best enantioselectivity has been achieved with R(1) =iPr, R(2) =Me, R(3) =H, R(4) =1-naphthyl or its 1-pyrenyl equivalent.

The Use of (−)‐Sparteine/Organolithium Reagents for the Enantioselective Lithiation of 7,8‐Dipropyltetrathia[7]helicene: Single and Double Kinetic Resolution Procedures

“…Lengthening this initial lithiation time from 45 min to 4h Figure 1. New strategies for kinetic resolution of C 2 symmetric racemates by double-KR using:a)enantioselectivef ormylation, [27] and b) enantioselective lithiation(this work).…”

“…Despite reports [57] of isolated examples of reaction sequences that contain more than one KR step, and the careful analysiso ft he prospective advantages of double-KRb yV änttinen and Kanerva in 1997, [58] the method has until now been almost entirely overlooked [59,60] in practical applications. In our recent development of asymmetric formylation [27] for the kinetic resolutiono ft etrathia [7]helicenes, however,o ur best results (73 % ee)w ere obtained by applying the principle of double kinetic resolution( double-KR). The formylation studyd rew attention to the fact that with C 2 symmetric substrates such as helicenes, the double-KR methodi su niquely convenient and allowed us to developa na ttractive one-pot version of the double-KR process.…”

“…First, substantially enantioenriched samples of TMS-helicene 2 or helicene 1 were generated and separated by column chromatography. ( P)-2 was desilylated and then both (M)-1 and (P)-1 were examined separately in asymmetricf ormylation reactions with the chiral formamide 7 [27] in the matched configuration. Importantly,t his two-step protocol (Scheme 4) allows us to switch solvents between diethyl ether for the (À)-sparteine-mediated step to THF which is required for our fomylation chemistry.C ompared to the mono-KR examples, this incorporation of the second enantiorecognition step provedt ob eo fc onsiderable practical advantage, as (M)-8 and (P)-8 were obtained, respectively,i n8 8% (Table 4, entry 3) and 92 % ee (Table 4, entry 7) demonstrating once again the value of the double-KR principle.A nother advantage of this approach is that using as ingle enantiomer of sparteine, both enantiomersoft he formylhelicene 8 were obtained.…”

“…We have, for example, described as eries of novel chiral formyl donors (for example, see Figure 1a)a nd the first asymmetricf ormylation procedure for aromatic substrates was recently developed by our group in the field of helicene synthesis. [27] In this approach, conventional lithiation is followed by reaction of the resulting racemic 2-lithiotetrathia [7]helicene with achiralelectrophile.…”

“…Over the past decade, our established interest in the applications of tetrathia[7]helicenes,22 which are important scaffolds in chiral ligands,22b, 23 to bind to DNA,24 and as organocatalysts,25 and which provide novel (D)–(chiral‐π)–(A) analogues22a of widely used (D)–(π)–(A) NLOphores,26 has drawn attention to the need to develop new practical methods for the large scale preparation of enantiomerically pure tetrathia[7]helicene derivatives. We have, for example, described a series of novel chiral formyl donors (for example, see Figure 1 a) and the first asymmetric formylation procedure for aromatic substrates was recently developed by our group in the field of helicene synthesis 27. In this approach, conventional lithiation is followed by reaction of the resulting racemic 2‐lithiotetrathia[7]helicene with a chiral electrophile…”