Guanidine catalyzed enantioselective desymmetrization of meso aziridines 5

Chapter 5 Enantioselective Catalytic Intramolecular Michael Additions: Asymmetric Synthesis of Chiral γ-Lactones... Martín et al.6-7 reported a base-induced intramolecular Michael addit

Chapter 5

Enantioselective Catalytic Intramolecular Michael Additions: Asymmetric Synthesis of Chiral γ-Lactones

Figure 5.1 Structure of γ-lactone

Naito et al.4-5 successfully developed a novel tandam radical addition-cyclization method for the asymmetric synthesis of polyfuctionalized γ-lactones based on the formation of the C3-C4 bond As shown in Scheme 5.1, the chiral substrate had two different radical acceptors (acrylate and oxime ether moieties) intermolecularly connected In the presence of a bulky substituent CH2OTBDPS of chiral oxime ether, the tandam reaction provided various chiral γ-lactones with high diastereoselectivity The remarkable feature of this reaction is the construction of two C-C bonds and two

chiral centers via a tandom process

Scheme 5.1 Synthesis of γ-lactones via tandem radical addition-cyclization reaction. 4-5

Martín et al.6-7 reported a base-induced intramolecular Michael addition of enantiomerically enriched α-[(phenylthio)acyloxy]-α,β-unsaturated esters to obtain highly substituted γ-lactones with a high degree of stereocontrol (Scheme 5.2) The key step in the synthesis of α,β-unsaturated esters was the regioselective opening of 2,3-epoxy alcohols using thiophenyl acetic acid

Scheme 5.2 Synthesis of γ-lactones via intramolecular Michael addition. 6-7

Merey et al.8 reported a 1,5-electrocyclic ring closure reaction of carbonyl ylides

from conjugated esters and diazo bis(carbonyl) compounds (Scheme 5.3) This is an

easy and highly efficient method for the preparation of γ-lactones based on C4-C5 bond generation by the intramolecular Michael addition to conjugated esters

Scheme 5.3 Synthesis of γ-lactones via 1,5-electrocyclic ring closure reaction.8

As shown above, α,β-unsaturated carbonyl compounds have been widely used as carbon electrophiles for the preparation of γ-lactones On the other hand the intramolecular Michael addition reaction from readily available acyclic precursors have been shown to be a general and useful shortcut for the preparation of a variety of

hetero- and carbocyclic compounds.9 Due to the important role of γ-lactones in the field of biological and pharmaceutical chemistry, we were interested in developing a novel and efficient stereoselctive synthetic method to chiral γ-lactones through an intramolecular Michael addition

5.2 Synthesis of substrates

The donor-acceptor functionalized substrates 102, with a 1,3-dicarbonyl nucleophile

tethered to an α,β-unsaturated ester or ketone, were synthesized according to the

reaction sequence shown in Scheme 5.4 The trans-γ-hydroxy-α,β-unsaturated

carbonyl compounds 100 were prepared by the Wittig reactions of glycoaldehyde

with the appropriate stabilized ylides in refluxing THF.10 Subsequently, the

esterification reactions between the carboxylic acids 101 and alcohols 100 in the

presence of one equivalent dicyclohexylcarbodiimide (DCC) afforded the desired

α,β-unsaturated carbonyl compounds 102.11

Scheme 5.4 Synthesis of donor–acceptor functionalized substrates 102.

5.3 TBD catalyzed intramolecular Michael additions

Our group reported that 1,5,7-triazabicyclo[4.4.0]dec-5-ene 103 (TBD), a bicyclic

guanidine base, can efficiently catalyze the Michael addition reactions between 1,3-dicarbonyl donors and a range of alkenes.12 Inspired by these result, we decided to

investigate the inherent reactivity of α,β-unsaturated carbonyl compounds 102 towards base-catalyzed intramolecular Michael addition reactions by using TBD as the catalyst

for the racemic reactions

Table 5.1 TBD catalyzed intramolecular Michael addition reactions

entry substrate product time /h yield /%a

Isolated yield dr = 6:1 (determined by 1HNMR)

As shown in Table 5.1, various α,β-unsaturated carbonyl compounds 102a-d were

examined by using 20 mol% of TBD in CH2Cl2. To our delight, all the reactions

proceeded smoothly to afford the corresponding α,β-disubstituted γ-lactones 104a-d

in good yields with diastereomeric ratios of approximately 6:1 The cyclization of

trans-enone 102a was complete after only 0.5 hour (entry 1) The replacement of

ketoester with O,S-dialkyl thiomalonate led to slightly slower reaction rate (entry 2)

tert-Butyl enone 102c provided the cyclized product with even longer reaction time

than that of phenyl enone 102b (entry 3) The intramolecular Michael addition reaction of α,β-unsaturated ester 104d was also tolerable, albeit prolonged reaction

time was required (entry 4)

5.4 Cinchona alkaloids catalyzed intramolecular Michael additions

With the racemic results in hand, we then turned our attention to chiral organic base- catalyzed intramolecular Michael addition reactions A series of chiral guanidines were first examined, resulting in very slow reaction rate As we known, readily accessible

Cinchona alkaloids have been identified as efficient organocatalysts for Michael

addition reactions.13 Herein we envisioned that the employment of Cinchona alkaloids

as catalysts for asymmetric intramolecular Michael addition reactions might lead to the enantioselective formation of γ-lactones

For the optimization screening, compound 102b was used as a model substrate The decarboxylation of thioester at the C3 position of the cyclized product 104b could provide γ-lactone 105a in quantitative yield The enantiomeric excess of 105a was

determined; hence the diastereoselectivity of the intramolecular Michael addition

reaction was not considered Among the commercially available Cinchona alkaloids

that were tested, cinchonine gave the best yield (76%) and enantioselectivity (77% ee, Table 5.3, entry 3) Solvent effect was then studied with cinchonine as the optimum catalyst The use of non-polar solvents such as toluene and xylene afforded γ-lactone

105a with faster reaction rates and similar enantioselectivities (entries 5-6) However,

low yields were obtained due to some side reactions Chlorobenzene provided the product in 76% yield with only 50% ee (entry 7) Inferior results were observed when THF and MeCN were utilized in the reactions (entries 8-9)

Table 5.2 Optimization of the reaction conditions for intramolecular Michael addition

reactions of α,β-unsaturated carbonyl compound 102b.a

entry catalyst solvent time /h yield /%b ee /%c

Table 5.3 Preparation of various chiral γ-lactones by enantioselective intramolecular

Michael addition reactions of α,β-unsaturated carbonyl compounds 102.a

/h

yield /%b

ee /%c

The optimal reaction conditions were then applied to the preparation of chiral

γ-lactones 105a-e with a ketone functionality at the C4 position from various

α,β-unsaturated ketones (Table 5.3) The intramolecular Michael addition reaction of

naphthyl enone 102e provided the cyclized product 105b in 71% yield with 70% ee (entry 2) For the reaction of biphenyl enone 102f, the corresponding product was

generated in low yield and enantioselectivity (entry 3) When 4-methyl-phenyl enone

102g was used as the substrate, γ-lactone 105d was obtained in 74% yield with 60%

ee (entry 4) The introduction of nitrile group to the 4-position of phenyl enone led to

a slightly faster reaction rate (entry 5); and γ-Lactone 105e was afforded in 67% yield

with 66% ee

5.5 Conclusion

In this chapter, an efficient and practical organic base-catalyzed intramolecular Michael addition reaction was developed as a synthetic approach towards γ-lactones The cyclization of α,β-unsaturated ketones tethered a 1,3-dicarbonyl nucleophile could

be effectively catalyzed by cinchonine to afford chiral γ-lactones in moderated to good yields and enantioselectivities However, there are still some unsolved problems of this methodology For instance, the cyclization reaction of α,β-unsaturated ester was quite slow In addition, the enantiometric purities of γ-lactones were still not excellent Therefore expanding the substrate scope and improving the enantioselctivity could be the targets for future efforts

5.6 Experimental

5.6.1 General Procedures

The general procedures of Chapter 4 were followed

5.6.2 Preparation of substrates 102a-h

5.6.2.1 General procedure for the synthesis of trans-γ-hydroxy-α,β-unsaturated

carbonyl compounds 100

To a solution of the stabilized ylide (1.2 mmol, 1.2 eq.) in THF (5 mL) was added

glycoaldehyde dimer (60 mg, 1.0 mmol, 1.0 eq.) The resulting solution was heated under reflux for 3 hours The solution was cooled and the solvent was evaporated in vacuo The product was purified by flash column chromatography (Florisil,

hexane/EA mixture, 1/1) and was used immediately

5.6.2.2 General procedure for the synthesis of trans-α,β-unsaturated carbonyl

compounds 102

To a solution of carboxylic acid 101 (0.75 mmol, 1.5 eq.) and trans-γ-hydroxy-

α,β-unsaturated carbonyl compounds 100 (0.5 mmol, 1.0 eq.) in THF (2.5 mL) was

added a solution of DCC (0.5 mmol, 1.0 eq.) in THF (0.5 mL) The reaction mixture was stirred overnight, filtered, and the filtrate was evaporated The residue was purified by flash column chromatography (silica gel, gradient elution with hexane/EA

mixture, 8/1 to 2/1) to afford the product 102

5.6.2.3 Characterization of substrates 102a-h

(102a) (E)-4-oxo-4-phenylbut-2-enyl 3-oxo-3-phenylpropanoate

Colorless oil, 60% yield 1H NMR (300 MHz, CDCl3, ppm): δ 4.12 (s, 1H), 4.95 (dd, 1H, J = 1.9, 4.3 Hz), 4.99 (dd, 1H, J = 1.3, 3.7 Hz), 6.02 (dt, 1H, J = 3.7, 19.0 Hz), 7.14 (dd, 1H, J = 1.6, 15.6 Hz), 7.43-7.60 (m, 6H), 7.79-7.82 (m, 1H), 7.94-7.99 (m, 3H)

13

C NMR (75 MHz, CDCl3, ppm): δ 62.8, 86.6, 125.8, 126.1, 128.4, 128.5, 128.6,

128.7, 128.9, 131.5, 133.0, 133.1, 133.9, 140.1, 141.0, 172.4, 189.9 The compound existed as enolate form in CDCl3.FTIR (film): 1032, 1182, 1277, 1333, 1369, 1452,

(102c) (E)-5,5-dimethyl-4-oxohex-2-enyl 3-(ethylthio)-3-oxopropanoate

Colorless oil, 70% yield.1H NMR (300 MHz, CDCl3, ppm): δ 1.12 (s, 9H), 1.24 (t, 3H,

J = 7.5 Hz), 2.90 (dd, 2H, J = 7.5, 14.7 Hz), 3.61 (s, 2H), 4.80 (dd, 2H, J = 2.1, 4.5 Hz),

6.68 (dt, 1H, J = 1.7, 15.3 Hz), 6.81 (dt, 1H, J = 4.2, 15.3 Hz) 13C NMR (75 MHz, CDCl3, ppm): δ 14.3, 24.0, 25.9, 43.1, 49.3, 63.9, 124.6, 138.2, 165.3, 190.8, 203.4.

FTIR (film): 1020, 1259, 1460, 1635, 1684, 1744, 2855, 2928, 2961, 3427 cm-1 LRMS (EI) m/z 272.1 (M+)

(102d) (E)-4-ethoxy-4-oxobut-2-enyl ethyl malonate

Colorless oil, 72% yield.1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (t, 6H, J = 7.3 Hz), 3.43 (s, 2H), 4.16-4.25 (m, 4H), 4.80 (dd, 2H, J = 2.0, 4.5 Hz), 6.02 (dt, 1H, J = 1.7, 15.7 Hz), 6.90 (dt, 1H, J = 4.5, 15.7 Hz) 13C NMR (75 MHz, CDCl3, ppm): δ 14.0,

14.1, 41.3, 60.6, 61.7, 63.3, 122.6, 140.2, 165.6, 165.8, 166.1.FTIR (film): 1032, 1182,

1277, 1333, 1369, 1452, 1641, 1653, 1720, 3427 cm-1 LRMS (EI) m/z 267.2 (M+Na+)

(102e) (E)-4-(naphthalen-2-yl)-4-oxobut-2-enyl 3-(ethylthio)-3-oxopropanoate

Colorless oil, 70% yield.1H NMR (300 MHz, CDCl3, ppm): δ 1.28 (m, 3H), 2.99 (m, 2H), 3.74 (s, 2H), 4.98 (t, 2H, J = 2.1 Hz), 7.06 (dt, 1H, J = 4.2, 15.5 Hz), 7.35 (dt, 1H,

J = 1.5, 15.6 Hz), 7.52-7.62 (m, 2H), 7.88 (t, 2H, J = 8.2 Hz), 8.05 (q, 2H, J = 8.2, 19.2

Hz), 8.58 (s, 1H) 13C NMR (75 MHz, CDCl3, ppm): δ 14.4, 24.1, 49.4, 64.0, 124.3,

125.6, 126.7, 127.7, 128.5, 129.5, 130.5, 132.5, 134.5, 135.5, 140.0, 165.4, 189.3, 191.1.FTIR (film): 1020, 1182, 1228, 1271, 1456, 1525, 1645, 1692, 1745, 2856, 2934,

(102g) (E)-4-oxo-4-p-tolylbut-2-enyl 3-(ethylthio)-3-oxopropanoate

Colorless oil, 72% yield.1H NMR (300 MHz, CDCl3, ppm): δ 1.26 (t, 3H, J = 7.3 Hz), 2.39 (s, 3H), 2.95 (dd, 2H, J = 7.5, 15.0 Hz), 3.67 (s, 2H), 4.90 (dd, 2H, J = 1.8, 4.3 Hz), 6.94 (dt, 1H, J = 4.3, 15.5 Hz), 7.17 (dt, 1H, J = 1.8, 15.5 Hz), 7.24 (d, 2H, J = 8.1 Hz), 7.86 (d, 2H, J = 8.2 Hz) 13C NMR (75 MHz, CDCl3, ppm): δ 14.3, 21.6, 24.0, 49.3,

64.0, 125.8, 128.8, 129.3, 134.7, 139.5, 143.9, 165.4, 189.0, 190.9 FTIR (film): 1013,

1149, 1265, 1648, 1692, 1733, 2817, 2856, 2911, 3237, 3419 cm-1 LRMS (EI) m/z 306.1 (M+)

5.6.3 TBD catalyzed intramolecular Michael additions

5.6.3.1 General procedure for TBD catalyzed intramolecular Michael additions

To a solution of the substrate 102 (0.1 mmol, 1.0 eq.) in CH2Cl2 (1 mL) under nitrogen was added TBD (2.8 mg, 0.02 mmol, 0.2 eq.) The reaction was stirred at

room temperature and monitored by TLC After starting material 102 disappeared, the

reaction mixture was concentrated in vacuo The residue was purified by flash column chromatography (silica gel, hexane/EA mixture, 4/1)

5.6.3.2 Characterization of disubstituted γ-lactones 104a-d

(104a) 3-benzoyl-4-(2-oxo-2-phenylethyl)dihydrofuran-2(3H)-one

1

H NMR (300 MHz, CDCl3, ppm): δ 3.26 (dd, 1H, J = 8.0, 17.6Hz), 3.38 (dd, 1H, J = 6.1, 17.8 Hz), 3.78 (td, 1H, J = 6.3, 13.8 Hz), 4.20 (dd, 1H, J = 6.1, 9.1 Hz), 4.48 (d, 1H,

J = 6.6 Hz), 4.90 (dd, 1H, J = 7.4, 9.2 Hz), 7.48-7.70 (m, 6H), 7.60 (d, 2H, J = 7.2 Hz),

7.85 (d, 2H, J = 7.2 Hz ).

(104b) S-ethyl 2-oxo-4-(2-oxo-2-phenylethyl)tetrahydrofuran-3-carbothioate

H NMR (300 MHz, CDCl3, ppm): δ 1.31 (t, 3H, J = 7.5 Hz), 2.99 (dd, 2H, J = 7.3, 15.5

Hz),3.17 (dd, 1H, J = 8.4, 17.8 Hz), 3.40 (dd, 1H, J = 4.8, 18.1 Hz), 3.52-3.59 (m, 2H), 4.02 (dd, 1H, J = 6.7, 9.1 Hz), 4.81 (dd, 1H, J = 7.0, 9.1 Hz), 7.49 (t, 2H, J = 7.8 Hz), 7.61 (d, 1H, J = 7.5 Hz), 7.92(d, 2H, J = 7.2 Hz ).

(104d) ethyl 4-(2-ethoxy-2-oxoethyl)-2-oxotetrahydrofuran-3-carboxylate

1

H NMR (300 MHz, CDCl3, ppm): δ 1.24-1.34 (m, 6H), 2.47-2.66 (m, 2H), 3.33-3.36 (m, 2H), 4.03 (t, 1H, J = 7.7 Hz), 4.14 (dd, 2H, J = 6.9, 14.3 Hz), 4.26 (dd, 2H, J = 6.9, 14.3 Hz), 4.65 (dd, 1H, J = 7.5, 9.0 Hz)

5.6.4 Cinchona alkaloids catalyzed intramolecular Michael additions

5.6.4.1 General procedure for Cinchona alkaloids catalyzed intramolecular

Michael additions

To a solution of the substrate 102 (0.05 mmol, 1.0 eq.) in CH2Cl2 (1 mL) under

nitrogen was added Cinchona alkaloid (0.01 mmol, 0.2 eq.) The reaction was stirred

at room temperature and monitored by TLC After starting material 102 disappeared,

the reaction mixture was concentrated in vacuo The residue was purified by flash column chromatography (silica gel, hexane/EA mixture, 4/1) to give the disubstitued

chromatography on silica gel to give mono substituted γ-lactone 105 in quantitative yield

5.6.4.3 Characterization of mono substituted γ-lactones 105a-e

(105a) 4-(2-oxo-2-phenylethyl)dihydrofuran-2(3H)-one

White solid, 76% yield,77% ee Mp = 105-106 oC.1H NMR (300 MHz, CDCl3, ppm):

2.27 (dd, 1H, J = 6.6, 17.4 Hz), 2.82 (dd, 1H, J = 7.7, 17.4 Hz), 3.16-3.29 (m, 3H), 4.03 (dd, 1H, J = 5.9, 9.4 Hz), 4.64 (dd, 1H, J = 6.6, 9.0 Hz), 7.49 (t, 2H, J = 7.5 Hz), 7.60(t, 2H, J = 7.2 Hz), 7.93 (d, 2H, J = 7.3 Hz) LRMS (ESI) m/z 227.2 (M+Na+), HRMS (ESI) m/z 227.0668 (M+Na+), calc for C12H12O3Na 227.0679

The enantiomeric excess was determined by chiral HPLC; CHIRALCEL OD-H (4.6

mm i.d x 250 mm); hexane/2-propanol 80/20; flow rate 1.0 mL/min; temp 25 °C; detection UV 210 nm; retention time: 23.6 min (minor) and 26.0 min (major)