Chapter 1 Introduction 1-1 Chiral thioether
Chiral thioether catalysts attract much attention from chemists in the fields of asymmetric synthesis because of its extensive applications of optically active reagents such as sulfide ylide, bromoetherification, P-S ligand and so on. Thioethers are characterized by a divalent sulfur atom that possesses a strong nucleophilicity and a high affinity to soft metals but a weak affinity to hard acids. In addition, the sulfur atom can stabilize both positive and negative charges at the neighboring carbon.
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There are mainly two type of application with chiral thioethers in sulfur-ylide chemistry: one is to prepare chiral sulfonium salt, which is then used stoichiometrically to prepare a wide range of optically active compounds; the other with more challenges is directly using chiral sulfide in an one-pot reaction such as epoxidation, aziridination, cyclopropanation and so forth. We believed in its potential to extend the development of sulfur-catalysted asymmetric reaction.
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1-1-1 Epoxidation
It is important for transformation from sulfide to sulfur ylide in an one-pot reaction for epoxidation
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and two methods have to be discussed.The first method: Sulfur ylides were afforded by the reaction of sulfides with alkyl bromide and the treatments of base to proceed deprotonation. Then, the sulfide ylides react with aldehydes to form epoxides as shown in Figure 1.1. So far, several sulfide ylides were explored by numerous researchers for epoxidation, which as summarized in Figure 1.2. In most of case, the better results were obtained by using stoichiometric amount of chiral sulfide. Furukawa and Dai et al. reported the successful example of using champhor-derived sulfide 20, 23 for asymmetric epoxidation. The used of catalytic amount of sulfide gave moderate to high yield and up to 47% e.e.. In 2013, our lab achieved high yield and good enantioselectivity by using catalytic amount of sulfides 2a and accelerated the reaction rate efficiently, although the d.r. ratio was not extraordinary.
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Figure 1.1 The mechanism of epoxidation via sulfonium salt.
catalyst
reporting groups
# of synthetic steps
time for epoxidation catalyst loading
yield trans/cis
e.e.
20, Furukawa
32 steps
21, Metzner
4,4b2 steps
22, Goodman
53 steps
reporting groups
# of synthetic steps
time for epoxidation catalyst loading
yield
Figure 1.2 Results of asymmetric epoxidation by using different sulfides.
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The second method is using metal carbenes as an intermediate, which is more reactive than alkyl halides and therefore promots ylide formation even with less reactive sulfides. Metallocarbene is obtained by decomposition of the diazo compound in the presence of a transition metal complex and reacts with sulfide to form the sulfur ylide. The sulfide ylide then reacts with the aldehyde to sulfide returns to catalytic cycle (Figure 1.3). Around 80% yield, over 90% e.e. and good diastereoselectivity (trans/cis = 98/2) were reported by Prof. Aggarwal in 1996 and 2001 under this condition (Figure 1.4).
Figure 1.3 The mechanism of asymmetric epoxidation by using metallic catalyst.
catalyst
reporting groups
# of synthetic steps
catalyst loading metal loading
yield trans/cis
e.e.
25, Aggarwal
92 steps
26, Aggarwal
104 steps
Figure 1.4 The results of epoxidation via metal carbene by using different sulfides.
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1-1-2 Aziridination
Aggarwal et al. reported a catalytic aziridination using an organometallic compound as a catalyst in moderate to good results (Figure 1.5). The mechanism followed Figure 1.3 and imine was used as the start material. In 2014, a transition metal-free aziridination derived from Corey-Chaykovsky reaction was reported by our lab using asymmetric organocatalyst (S)-2a with high optical purity (95-98% e.e.) and good to high yield.
catalyst
reporting groups
# of synthetic steps
catalyst loading metal loading
yield trans/cis
e.e.
25, Aggarwal
112 steps
26, Aggarwal
124 steps
2a, Chein
134 steps
Figure 1.5 The results of asymmetric aziridination by using different sulfide.
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1-1-3 Cyclopropanation
Since the [2,2,1] bicyclic sulfide 26 designed by Aggarwal et al. failed to give good yields on cyclopropanation of electron-poor alkenes. They further designed new sulfide [2,2,2] bicyclic sulfide 27, with provided better result than sulfide 26 (Figure 1.6).
catalyst
reporting groups
# of synthetic steps
catalyst loading metal loading
additive yield trans/cis
e.e.
27, Aggarwal
124 steps
20 mol%
1 mol% Rh
2(OAc)
420 mol% BnEt
3N
+Cl
-50-73%
4/1-1/7 91-92% (R,R) or (S,S)
Figure 1.6 The results of cyclopropanation by using [2,2,2] bicyclic sulfide 27
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1-2 Aziridine
Aziridine, a three-membered heterocycle with nitrogen atom, is a reactive substrate in ring-opening reactions with several nucleophiles due to their ring strain.
This stable but strain-loaded three-membered ring allows regio- and stereoselective installation of a wide range of functional groups. On the other hand, they are important building blocks in organic synthesis, because amines, amino alcohols, diamines, and other useful nitrogen-containing molecules can be conveniently accessed. The aziridine functionality is also present in a small number of naturally occurring molecules.
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The biological properties of aziridine contained compounds such as mitomycins, azicemicins, ficellomycinare are of significant interest (Figure 1.7). The antibiotic and antitumor properties of these compounds are well known.Figure 1.7 Aziridine-containing compounds.
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1-2-1 Aziridination
According to the literature, there are at least two ways to synthesize aziridines, one by using olefins and another by using imines as start materials (Figure 1.8).
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Figure 1.8 The strategies of aziridination.
Several groups reported asymmetric aziridinations according to Route A by using (N-(p-toluenesulfonyl)imino)phenyliodinane as the nitrene precursor and chiral copper as the catalyst. For example, aziridination from cinnamate esters was reported by Prof. Evans in 1993
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using copper(I) triflate (CuOTf) as the catalyst and oxazoline as a ligand in moderate yields (60-70%) and high enantioselectivity (94-97%). In Prof.Jacobsen
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and Prof. Scott18
’s reports, they used copper(I) triflate (CuOTf) and copper(I) tetra(acetonitrile) tetrafluoroborate (Cu(MeCN)4
BF4
) as catalysts with chiral diimine ligands 29, 30, respectively, higher yields and high enantioselectivities (80-90%) were achieved on chromene derivatives (Scheme 1.1).9
Scheme 1.1 The result of asymmetric aziridination by using copper catalyst.
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Three types of different nucleophiles such as carbenes, carbenoids, and ylides are better nucleophiles, which react well with imine as shown in Route B (Figure 1.9).
Figure 1.9 Aziridination via three kinds of nucleophiles.
The following section, we will give more detail about processing aziridination with sulfur ylides.
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1-2-2 Aziridination by using sulfonium ylides
In 1996, Dai et al. reported a racemic aziridination, which used racemic sulfides
via the ylide route (Scheme 1.4). 6
At first, they tried to treat sulfonium ylides with imines containing different protection group on the nitrogen atom. Only aziridine with tosyl group containing imines were obtained in good yield. Moreover, they optimized this condition by screening different solvents, base, and sulfonium ylides. The best condition was applied to others aryl imine and the reaction completed within several minutes.Scheme 1.2 Aziridination with racemic sulfide.
Afterword, in 1997, they developed a method to asymmetric aziridination by using a camphor derived chiral sulfide ylide (Scheme 1.5).
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At first, 3-bromo-1-(trimethylsilyl)propyne was treated with the chiral sulfide to give a chiral sulfonium ylides followed by the addition of imines. Aziridines with R or S form were occurred by using sulfonium ylides with exo or endo form. The trans/cis ratio was over 1/99, e.e. were 78% and 56%, respectively.12
Scheme 1.3 Asymmetric aziridination used chiral sulfonium ylides.
In 2010, Aggarwal et al. synthesized a sulfide with 98% e.e. from (R)-Limonene in only one step (Scheme 1.6).
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The chiral sulfide was treated with benzyl bromide and LiOTf to form chiral sulfonium ylides followed by the reaction with imines to form aziridines. The reaction under this condition was very fast (only one hour).They also explored a broad scope of imines, and high yields and excellent enantioselectivities were obtained.
Scheme 1.4 Asymmetric aziridination with benzyl sulfonium salt.
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1-2-3 Aziridination in an one-pot reaction
Saito et al. used a camphor-derived chiral sulfide simply in the one-pot with a mixture of N-sulfonyl imine, bromide under basic condition.
7,21
Steric hindrance of the chiral catalyst resulting in long reaction time when catalytic amount was used.Thus, sulfide was raised to stoichiometry and then got good results (Scheme 1.7).
Scheme 1.5 Aziridination catalyzed by a camphor-derived chiral sulfide in one-pot.
In 2007, Huang et al. also reported an one-pot method in enantioselective syntheses of aziridines using two equivalents of C
2
-symmetric sulfide (Scheme 1.8).22
They also optimized the condition by adding TBAI as a phase-transfer catalyst to improve the yield. Following this optimal conditions, they got results in moderate to good yields d.r. ratio and e.e..Scheme 1.6 Aziridination of using a C
2
-symmetric sulfide in one-pot reaction.14
Aggarwal et al. obtained good result by employing mentallocarbene as the catalyst for epoxidation in 1994.
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And later, they extended this method for the preparation of asymmetric aziridines from imines and diazo compounds in the presence of catalytic amounts of metal salts and sulfides (Scheme 1.2). Using sulfonium ylide, high enantioselectivity (89-95%) was achieved in this aziridination process.11
Scheme 1.7 Aziridination of using organometallic catalyst.
In 2001, Aggarwal et al. generated the diazocompound in situ from tosyl hydrazones and used it for asymmetric aziridination catalyzed by a new class of chiral sulfides ([2,2,1] bicyclic sulfide), that is more stable and easier to scale up than previous catalyst 26. After optimization this reaction gave good yield, high enantioselectivity, and moderate to high diastereoselectivity (Scheme 1.3).
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Scheme 1.8 Aziridination of using the [2,2,1] bicyclic sulfide.
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In 2013, our lab first synthesized a novel chiral sulfide catalyst (S)-2a from 5-bromopentanoic acid in 6 steps and applied it successfully for the epoxidation of benzyl bromide and aryl aldehyde with up to 92% e.e. excellent yield and good diastereoselectivity.
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Further, in 2014, the synthesis of (S)-2a was shortened from 5-bromovalerate (to 5 steps) and extended its application to aziridination with high enantioselectivity and good to excellent yield (Figure 1.10).13
Although, compared to other published, the diastereoselectivity was not the best one. As forementioned, it was worth to further explore the applications of catalyst (S)-2a and improve the diastereoselectivity, and we are going to discuss this issue in the next chapter.Figure 1.10 Aziridination with tetrahydrothiophene chiral sulfide.