Guanidine catalyzed enantioselective desymmetrization of meso aziridines 2

2.1 Bicyclic guanidine catalyzed enantioselective desymmetrization of meso N-tosyl aziridines with thiols 2.1.1 Bicyclic guanidine catalyzed enantioselective reactions Guanidine deriv

Chapter 2

Guanidine Catalyzed Enantioselective Desymmetrization of meso-Aziridines with Thiols

2.1 Bicyclic guanidine catalyzed enantioselective desymmetrization

of meso N-tosyl aziridines with thiols

2.1.1 Bicyclic guanidine catalyzed enantioselective reactions

Guanidine derivatives (Figure 2.1) are widely utilized as strong bases in synthetic organic chemistry due to their high pKa values.1 Chiral guanidine derivatives function

as asymmetric catalysts by exploiting the great basicity of guanidine group and the special hydrogen bonding pattern of the guanidinium ion This research topic has increasingly attracted great interest and the asymmetric catalytic ability of chiral guanidine and guanidinium has been demonstrated in a large variety of reactions, such

as Henry reaction2, Michael reaction3, Mannich reaction4, electrophilic amination5, Strecker reaction6, alkylation7, trimethylsilylcyanation8, nucleophilic epoxidation9, asymmetric silylation of secondary alcohols10, reduction of phenacyl bromide11, alkylative esterification12, azidation13, transamination14, Claisen rearrangement15

Figure 2.1 General structure of guanidine

Our group has reported an efficient synthetic route to afford a series of chiral bicyclic Brønsted-basic guanidines, from chiral aziridines, with overall yields of 43-71%.16 This synthetic route was modified from Corey’s work.6bBicyclic chiral

guanidine catalyst 39 was prepared according to the reported procedure as shown

below (Scheme 2.1) N-Tosyl aziridine 35 was readily prepared from its corresponding

commercially available α-amino alcohol 34 Triamine unit 37 was easily obtained by

preferentially at the sterically least hindered carbon atom The subsequent triamine 38

was prepared by using sodium in liquid ammonia to remove tosyl groups without

further purification The crude triamine 38 was then subjected to the final cyclization step, leading to the guanidinium salt 39·HI in 71% total yield from its amino alcohol

Scheme 2.1 Synthesis of symmetrical chiral bicyclic guanidine 39.16

Chiral guanidine 39 was found to be an effective catalyst for asymmetric Michael

reactions (Scheme 2.2).17 The initial investigation revealed that the additions of

1,3-diketone 41a and β-ketoester 41b to maleimide 40 provided the Michael adducts

in high enantioselectivities and high yields However, these reactions were slow and

required 20 mol% of catalyst The more reactive β-keto thioesters 41c-d and

dithiomalonates 41e-f were tested and the reaction rate was considerably enhanced With guanidine 39 as the catalyst, adducts 42c-f were obtained in high yields and excellent ees with diastereomeric ratios of approximately 1:1 (42c-d) The catalyst loading of 39 can be decreased to 1 mol% for substrate 41d

Scheme 2.2 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide

with 1,3-diketones, β-ketoesters, dithiomalonates. 17

Thiomalonates were then employed as the donors for further investigation in an attempt to extend the acceptor scope of this reaction (Scheme 2.3) Cyclic enones

43a-b and furanone 43c afforded the Michael adducts 44a-c in high yields and

excellent enantioselectivities The reactions were typically faster as thioesters are

more acidic than their O-esters counterpart due to the poor overlap of their C(2p) and S(3p) orbitals.

Scheme 2.3 Chiral bicyclic guanidine catalyzed Michael reactions of cyclic enones and furanone with dithiomalonate 41f. 17

It was found that trans-4-oxo-4-arylbut-2-enoates 45 were useful acyclic Michael

acceptors (Scheme 2.4).17 In the presence of 5 mol% of guanidine 39, dialkyl thiomalonate 41f reacted with 45 smoothly to give adducts 46 in high yields and high

enantioselectivities This was a highly regioselective reaction in which the addition only occurred at the β position of the enone moiety

Scheme 2.4 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl trans-4-

oxo-4-arylbut-2-enoates. 17

Our group also investigated the Michael reactions between cyclic enone 43a and other 1,3-dicarbonyl compounds catalyzed by guanidine 39.16,18 Sulfonamides and amines were added as additives to enhance the reaction rate Amongst them,

triethylamine (Et3N) was found to be the best additive and it could be used as the solvent, resulting in a significant increase of reaction rate and enantioselectivity Generally, the Michael adducts were obtained in excellent enantioselectivities and high yields (Scheme 2.5) This strategy was expanded to include maleimides as the Michael acceptors Remarkably, the reaction of ethyl maleimide with benzoylacetate

41b was complete within five minutes in triethylamine (Scheme 2.6) It was about

1000 times faster than in toluene We speculated that triethylamine might be involved

in the stabilization of the enolate-guanidinium complex, thereby enhancing the reaction rate

Scheme 2.5 Chiral bicyclic guanidine catalyzed Michael reactions of 2-cyclopenten-

Scheme 2.6 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide

with benzoylacetate using triethylamine as solvent.16,18

Chiral bicyclic guanidine 39 was also found to be effective in catalyzing

phospha-Michael reactions between nitroalkenes and phosphine oxides (Scheme 2.7).19 A series of diaryl phosphine oxides 48 were screened and the best one bore the

1-naphthyl group Excellent enantioselectivities were generally obtained for various

nitroalkenes with di-(1-naphthyl) phosphine oxide at -40 °C The ee values of the

crystalline products could be enhanced by recrystallization It was postulated that the phosphine oxide was tautomerized to the unstable but reactive nucleophile in the presence of guanidine catalyst

Scheme 2.7 Chiral bicyclic guanidine catalyzed phospha-Michael additions of various

diaryl phosphine oxides to conjugated aryl nitroalkenes.19

Our group also reported the protonation of 1-phthalimidoacrylate 50 with thiophenols using chiral guanidine 39 as the catalyst (Scheme 2.8).20 Excellent yields and ee values were obtained for a series of arenethiols The substitution pattern at the phthalimido group did not affect the enantioselectivity This reaction was not

restricted to aromatic thiols; excellent ee value could also be obtained with

diphenylmethanethiol Adducts obtained could be converted into useful analogues of

amino acid cysteine

Scheme 2.8 Chiral bicyclic guanidine catalyzed protonation of 1-phthalimidoacrylate

with thiophenols.20

The scope of the reaction was extended to cyclic imides 52 (Scheme 2.9) Some

optimizations were carried out and it was concluded that the 2,6-positions of N-

substituted-aryl itaconimides were crucial for high enantioselectivities Excellent

yields and ees were obtained when diaryl phosphine oxides 48 were used as donors

Scheme 2.9 Chiral bicyclic guanidine catalyzed protonation of itaconimides with

diaryl phosphine oxides. 20

It was also found that bicyclic guanidine 39 could catalyze both the additions of

phosphine oxide 54 and tert-butylthiol to N-(2-tert-butylphenyl)itaconimide 55,

leading to the formation of axially chiral cyclic imides in high yields with

diastereomeric ratios of approximately 1:1 High ee values were observed for the anti

diastereoisomers

Scheme 2.10 Chiral bicyclic guanidine catalyzed protonation of axially chiral N-(2-

tert-butylphenyl)itaconimide.20

Scheme 2.11 Chiral bicyclic guanidine catalyzed Michael reactions of dithranol 57.21

39.16 It was also found to be a good basic catalyst for enantioselective Michael

reactions of 1,8-hydroxy-9-anthrone 57 (Scheme 2.11).21 In the presence of 10 mol%

of guanidine 58, the reactions were performed well with maleimides and other

activated olefins as the Michael acceptors Excellent enantioselectivities and regioselectivities were obtained in all examples

Our group also successfully exploited chiral guanidine 58 as the catalyst for Diels-Alder reactions between anthrones 61 and activated olefins (Scheme 2.12).21

High yields and enantioselectivities were obtained with various anthrones in combination with maleimides In many examples, the ee values were more than 98%

Excellent regioselectivities were also observed when 1,5-dichloro-9-anthrone 61d and

4-(N-methylamino)-9-anthrone 61e were used as the dienes However, prolonged

reaction time or the treatment with base led to ring-opening products with significant racemization

Scheme 2.12 Chiral bicyclic guanidine catalyzed Diels-Alder reactions of

anthrones.21

2.1.2 Bicyclic guanidine catalyzed enantioselective desymmetrization of

meso N-tosyl aziridines with thiols

As shown above, our group has successfully developed several chiral bicyclic guanidine catalyzed reactions Promoted by these results, we hypothesized that chiral bicyclic guanidine, which can easily extract a proton from thiol, might also be a

powerful catalyst for the enantioselective desymmetrization of meso-aziridines with

thiol as a nucleophile To verify the hypothesis, a series of chiral guanidines were

tested using N-tosyl aziridine 4c and benzenethiol 63a as model substrates (Table 2.1)

In the presence of 10 mol% of bicyclic guanidine 39, the ring opening of N-tosyl

aziridine 4c was complete in 48 hours at room temperature in diethyl ether (Table 2.1,

entry 1), affording trans-product 64c in 24% ee Under the same conditions, the ees of

6% and 5% (entries 2-3) were obtained for the reactions catalyzed by the bicyclic

guanidines 58 and 65, respectively When the linear guanidine 66 was used, only 3%

ee was observed (entry 4) Chiral guanidines 67 and 68 bearing hydroxyl group could

be used as bifunctional catalysts They were also tested and no enantioselectivity was obtained (entries 5-6)

With chiral guanidine 39 as the optimum catalyst, the reaction was optimized by

changing other variables of the reaction conditions Solvent effect was first studied at

room temperature using N-tosyl aziridine 4a as the substrate (Table 2.2) Product 64a

was obtained in 29% ee in diethyl ether (entry 1) The result could not be further improved when other common solvents such as THF and toluene were used (entries 2-3) No enantioselectivity was obtained when the reaction took place in protic solvent (MeOH) or highly polar solvent (MeCN) although the reaction rate was faster (entries 4-5) There was no reaction when chlorinated solvent such as CH2Cl2 was used

Table 2.1 Various chiral guanidines catalyzed desymmetrization of meso N-tosyl

aziridine 4c with benzenethiol 63a. a

All reactions were performed with 0.02 mmol of aziridine, 0.1 mmol of thiol and 0.2

Temperature effect was then studied using diethyl ether as solvent (Table 2.3, entry 1) Lowering the reaction temperature to -20 °C slowed the reaction rate considerably Since the enantioselectivity also decreased to 15% at lower temperature,

Table 2.2 Solvent effect on the chiral guanidine 39 catalyzed desymmetrization of

meso N-tosyl aziridine 4a with benzenethiol 63a. a

All reactions were performed with 0.02 mmol of aziridine, 0.1 mmol of thiol and 0.2

we were interested to know whether higher temperature could make an improvement With toluene as the solvent, when the reaction was carried out at a higher temperature (60 °C), the enantiomeric excess was increased to 32% with a very fast reaction rate

(entry 2) The reaction conditions were applied to aziridine 4d and 46% ee of the

product was obtained (entry 3) Further increasing the reaction temperature to 80 °C caused a relatively lower enantioselectivity (42% ee, entry 4) Concentration effect

was also studied for the reaction of aziridine 4a (entries 5-6) It was found that the enantiomeric excess of 64a could be further improved from 32% to 40% when the

reaction concentration was diluted to 0.05 M, although the reaction rate was a bit slower Conversely, when the concentration was increased to 0.2 M, the ee value dropped to 26% These results suggested that both temperature and concentration

could be the most important factors for the enantioselective desymmetrization of meso

N-tosyl aziridines This is probably because of the fact that the SN2 reaction is under both thermal and dynamic control, and the two enantiomers show different reaction rates under these conditions

Table 2.3 Temperature and concentration effects on the chiral guanidine 39 catalyzed

desymmetrization of meso N-tosyl aziridines 4a, 4d with benzenethiol 63a. a

2.2 Synthesis of novel chiral guanidines

Inspired by the preliminary results obtained from the model reaction between

meso N-tosyl aziridine 4a/4c and benzenethiol 63a, we were keen to develop an

efficient and readily accessible guanidine catalyst for the enantioselective

desymmetrization of meso-aziridines

It was reported that guanidines could be easily generated from 2-chloro-1,3-

This type of reaction provided a simple method to prepare guanidines and

guanidinium salts Our group has successfully employ this method to prepare a novel

obtained after basifying guanidinium salt 73·2HBF4 with 6 M aqueous NaOH With

the guanidinium salt catalyst 73·HBArF4, highly enantioselective phospha-Mannich

reactions were developed with the secondary phosphine oxides and H-phosphinates as

the P nucleophiles

Scheme 2.13 Synthesis of guanidine from DMC 69 and amine

Scheme 2.14 Synthesis of bis-guanidinium salt 73·2HBF4

Figure 2.2 Structural diversity of the aminoindanol isomers

With this easier method in hand, we aimed to develop chiral guanidines from commercially available aminoindanols (Figure 2.2) due to the prevalence of indane scaffold in organic molecules and the application of some chiral aminoindanols as organocatalysts or ligands in asymmetric catalysis.23 The aminoindanol scaffold offers

a wide range of possibilities for chiral induction based on the simple variation of the

Figure 2.2, the aminoindanol family encompasses four different members 74a-d, each

one of them with its corresponding enantiomer

As a starting point, (1R,2S)-1-amino-2-indanol was subjected to the guanidination

with pyrrolidinium salt 75 (Scheme 2.15) The formation of guanidinium salt 76 did

not proceed as expected using this protocol Preliminary 1H NMR studies of the

obtained product indicated the formation of 77 This assumption was supported by

that the secondary alcohol may act as a nucleophile to replace one of the pyrrolidine groups

Scheme 2.15 Synthesis of guanidinium salt from aminoindanol

It was found that protection of hydroxyl group was essential to the synthesis of

aminoindanol derived guanidines O-protected 1-amino-2-indanols 78a, 78b and 78c

(Figure 2.3) were prepared in moderate to high yields by the silylations of the corresponding chiral aminoindanols with TBDMSCl or TBDPSCl Aminoindanol 78d

was synthesized by three steps (Scheme 2.16): (1) Boc protection of amine; (2)

Benzyl protection of alcohol; (3) N-Boc deprotection

Figure 2.3 O-protected aminoindanols

Scheme 2.16 Synthesis of O-Bn aminoindanol

by the guanidinations of chiral O-protected aminoindanols 78a-d with pyrrolidinium

salt 75 in one step with good yields (70-80%) Subsequent basification with 2 M aqueous NaOH afforded the free base guanidines 79a-d in quantitative yields