Enantioselective lithiation-trapping is a facile route to α-substituted carbamates in high yields and enantioselectivity. However, this methodology is hindered by the lack of an ideal chiral ligand. (–)-Sparteine 3 can be obtained by extraction from papilionaceous plants such as C. scoparius.120 It is thus suitable for use on a small scale but is rather expensive for industrial use (£181.50/100 g, Aldrich, 2009). Unreliable supply is also a problem, as (–)-sparteine has been commercially unavailable throughout 2010/early 2011. (+)-Sparteine surrogate 6 is accessed through a three-step synthesis, starting from the natural product (–)-cytisine 40 (US$ 920.00/50 g, Chemdel, 2011). (–)-Cytisine 40 may also be extracted in the laboratory from the seeds of L. anagyroides cytisus.121 (+)-Sparteine surrogate 6 has recently become commercially available but is expensive even for use on a small scale in the research laboratory (£140.50/100 mg, Aldrich 2011). In 2008, our group reported the use of trans-cyclohexane diamine (R,R)-8 in lithiations of
-Boc pyrrolidine 38.59 Originally introduced by Alexakis, (R,R)- and (S,S)-8 have since become commercially available, but remain expensive (€164.30/1 g for either enantiomer, TCI, 2011).6
Figure 3.3
N N
3
N N
Me
N
N Me
Me
t -Bu t -Bu
6 (R,R)-8
Due to the lack of a readily accessible or cheap chiral diamine, our group decided to investigate lithiation using a substoichiometric amount of chiral diamine. Simply reducing the amount of chiral diamine in the lithiation reaction did not facilitate catalytic turnover. For example, lithiation of O-alkyl carbamate 100 with 1.4 equivalents of s-BuLi and 0.2 equivalents of (–)-sparteine 3 followed by trapping with n-Bu3SnCl gave stannane (S)-161 in only 17% yield and 85:15 er, compared to the 73% yield and 99:1 er obtained with stoichiometric (–)-sparteine 3 (scheme 3.1).5
Scheme 3.1 equivalents of (–)-sparteine 3 followed by trapping with trimethylsilyl chloride gave silyl pyrrolidine (S)-39 in 34% yield and 75:25 er compared with 87% yield and 95:5 er for lithiation using a stoichiometric amount of chiral diamine (scheme 3.2).5
Scheme 3.2 enantioselectivities are obtained due to competing racemic lithiation from a s-BuLi/Et2O complex. Low yields are obtained as the most active lithiating species, the s-BuLi/(–)-sparteine complex, is only present in low amounts. After lithiation, the chiral diamine remains coordinated to the lithiated carbamate intermediate until electrophile is added.
In 2005, Chong reported an asymmetric alkynyl boration of enones such as 162.122 In this study, boration was achieved using a substoichiometric amount of chiral binaphthol (S)-163. Following the boration of one molecule of substrate, cheap achiral boronate 164 was used to displace the chiral ligand back into solution, where further enantioselective
Scheme 3.3 enantioselective reaction by releasing the chiral ligand from the reaction intermediate using a second achiral ligand. It was hypothesised in our group that this approach could allow use of a substoichiometric amount of chiral diamine in asymmetric lithiations. Such a protocol is termed “two-ligand catalysis” or “ligand exchange catalysis.”
Chong’s work suggested a plausible experimental set-up under which catalytic turnover of a chiral ligand in asymmetric lithiations might be achieved. However, a suitable achiral secondary ligand needed to be identified. Our group decided that such a ligand must either be cheap or accessible from cheap starting materials in one or two synthetic steps, must promote catalytic turnover of the chiral ligand, and must not cause competing racemic lithiation via its own s-BuLi complex.
During research into the development of a (+)-sparteine surrogate 6, i-Pr analogue 160 was synthesised. It was found that s-BuLi/160 did not give rise to lithiation of -Boc pyrrolidine 38, despite DFT calculations suggesting that if a prelithiation complex
diamine di-i-Pr bispidine 7 would be a suitable achiral ligand to investigate in ligand exchange catalytic lithiation (figure 3.2).
Figure 3.4
Fortunately, di-i-Pr bispidine 7 did indeed effect catalytic turnover of both (–)-sparteine 3 and (+)-sparteine surrogate 6. Thus, lithiation of -Boc pyrrolidine 38 in the presence of 1.3 equivalents of s-BuLi, 0.2 equivalents of chiral diamine and 1.2 equivalents of bispidine 7 in Et2O at –78 °C for 5 h followed by trapping with trimethylsilyl chloride gave silyl pyrrolidine (S)-39 in 76% yield and 90:10 er with (–)-sparteine 3 and (R)-39 in 66% yield and 94:6 er with (+)-sparteine surrogate 6 (scheme 3.4).5
Scheme 3.4
Better enantioselectivity was observed when using (+)-sparteine surrogate 6 compared with (–)-sparteine 3. This is explained by the observation that the s-BuLi complex of 6 is a faster lithiater than s-BuLi/(–)-sparteine 3 as shown by a competition experiment. Thus, lithiation of -Boc pyrrolidine 38 with 2.6 equivalents of s-BuLi in the presence of 1.3 equivalents each of (–)-sparteine 3 and (+)-sparteine surrogate 6 followed by trapping with trimethylsilyl chloride gave silyl pyrrolidine (R)-39 in 62% yield and 90:10 er (scheme 3.5).
Scheme 3.5
It was shown that two-ligand catalytic lithiations could also be carried out on O-alkyl carbamate 100. Here, lithiation by 1.3 equivalents of s-BuLi in the presence of 0.2 equivalents of (–)-sparteine 3 and 1.2 equivalents of di-i-Pr bispidine 7 in Et2O at –78 °C followed by trapping with n-Bu3SnCl gave stannane (S)-161 in 77% yield and 92:8 er.
Similarly, lithiation by 1.3 equivalents of s-BuLi in the presence of 0.2 equivalents of (+)-sparteine surrogate 6 and 1.2 equivalents of di-i-Pr bispidine 7 and trapping gave stannane (R)-161 in 72% yield and 94:6 er (scheme 3.6).5
Scheme 3.6
Finally, it was also shown that two-ligand catalytic lithiation could be carried out with phosphine borane 166. Thus, lithiation of 166 with 1.3 equivalents of s-BuLi, 0.2 equivalents of (–)-sparteine 3 and 1.2 equivalents of di-i-Pr bispidine 7 followed by trapping with Ph2CO gave alcohol (S)-167 in 67% yield and 83:17 er.5 It should be noted, however, that it was later found that unlike the carbamates 38 and 100, catalytic turnover of chiral diamine was successful with phosphine borane 166 without the need for a secondary ligand. In this case, lithiation of 166 with 1.1 equivalents of s-BuLi and 0.2 equivalents of (–)-sparteine 3 followed by trapping with O2 gave alcohol (R)-168 in 57%
yield and 77:23 er (scheme 3.7).124
Scheme 3.7
Enantioselective lithiations using a substoichiometric amount of chiral diamine ligand without a secondary achiral ligand have also been reported on a number of other substrates. Examples include cyclooctene-derived epoxides,125 phosphine sulfides,126 ferrocene amides127 and paracyclophanes.128
Having demonstrated two-ligand catalytic lithiation using di-i-Pr bispidine 7, our group subsequently investigated other secondary achiral ligands for use with this methodology.
A range of different diamines were investigated, roughly divided into three “families”:
TMEDA analogues, TMPDA analogues, and a hybrid of the two, 1,4-homopiperazine
The results of the best ligands are shown in scheme 3.8.129 Using di-i-Pr bispidine 7, two-ligand catalytic lithiation of -Boc pyrrolidine 38 (using 0.3 equivalents of (–)-sparteine 3) followed by trapping with trimethylsilyl chloride gave silyl pyrrolidine (S)-39 in 70%
yield and 95:5 er. The TMEDA analogue 169 gave (S)-39 in 64% yield and 89:11 er. An alternative TMEDA analogue, rac-170, gave (S)-39 in 61% yield and 90:10 er. Finally, homopiperazine analogue 171 gave (S)-39 in 64% yield and 86:14 er.129 Ultimately, it was found that in two-ligand catalytic lithiations the best yields and enantioselectivities were obtained through the use of original bispidine 7.
Scheme 3.8 enantioselectivity could be obtained using lithium dimethylamino ethoxide (LiDMAE) 172: silyl pyrrolidine (S)-39 was obtained in 66% yield and 88:12 er after trapping with trimethylsilyl chloride. Interestingly, it was found that both the dimethylamino motif and the lithium alkoxide motif were necessary for high yield and enantioselectivity. Use of lithium ethoxide gave (S)-39 in low yield (33%) and high er (90:10), while ,-dimethyl-2-methoxyethylamine 174 gave rac-39 in 74% yield (scheme 3.9).130
Scheme 3.9
Two-ligand catalytic lithiation-trapping of -Boc pyrrolidine 38 using LiDMAE 172 was then used to complete a formal total synthesis of the neurokinin-1 substance P receptor agonist (+)-L-733,060.130 The use of LiDMAE 172 differs from diamine secondary ligands as extra equivalent of alkyllithium must be added to the lithiation reaction mixture in order to deprotonate dimethylamino-ethanol. Crucially, however, it was shown that the chiral diamine could be recovered from the reaction mixture after work-up by extraction of ,-dimethylamino ethanol into NaOH(aq).130 Such a separation of chiral diamine from achiral ligands had not previously been demonstrated.
Investigation of the use of a range of secondary achiral ligands in two-ligand catalytic lithiation of -Boc pyrrolidine 38 had failed to discover a ligand superior to di-i-Pr bispidine 7. We therefore wished to investigate the use of a small range of analogous bispidine achiral diamines. As part of this study, we would also attempt to optimise the two-ligand catalytic lithiation conditions. Furthermore, we hoped to use an optimised procedure to effect two-ligand catalytic lithiation-arylations which were previously unreported.