β-AMINO ALCOHOL ORGANOCATALYSTS FOR ... - HeteroCycles

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Jun 20, 2018 - H3PO4 dienophile. Diels-Alder reaction. N. N. MeO ibogaine oseltamivir phosphate. (tamiflu) chiral isoquinuclidines new drugs vinblastine or.
HETEROCYCLES, Vol. 97, No. , 2018, pp. -. © 2018 The Japan Institute of Heterocyclic Chemistry Received, 10th February, 2018, Accepted, 6th June, 2018, Published online, 20th June, 2018 DOI: 10.3987/REV-18-SR(T)3

β -AMINO ALCOHOL ORGANOCATALYSTS FOR ASYMMETRIC ADDITIONS Hiroto Nakano,* a Isiaka Alade Owolabi, a M a d h u C h e n n a p u r a m , a Yuko Okuyama,b Eunsang Kwon,c Chigusa Seki, 1 Michio Tokiwa,d and Mitsuhiro Takeshitad a

Division of Sustainable and Environmental Engineering, Graduate School of

Engineering, Muroran Institute of Technology, 27-1 Mizumoto-cho, Muroran 050-8585, Japan, E-mail: [email protected] b

Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku,

Sendai 981-8558, Japan, E-mail: [email protected] c

Research and Analytical Center for Giant Molecules, Graduate School of

Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan, E-mail: [email protected] d

Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053, Japan,

E-mail: [email protected] Abstract – A design of a chiral organocatalyst is very important for obtaining of a chiral product with a high optical purity in a catalytic asymmetric reaction. Recently, we developed a series of chiral β-amino alcohol organocatalysts A that showed high level of catalytic activity in some asymmetric reactions. These β-amino alcohols are stable in air, and have two advantageous features, easy preparation and exhibiting high stereoselectivity in an enantioselective reaction. This review summarizes our recent works involving the Diels-Alder (DA) reactions of 1,2-dihydropyridines, anthrones or 3-hydroxy-2-pyridones as dienes with dienophiles, the asymmetric 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated aldehydes and the crossed aldol reaction of isatins with acetaldehyde, by the use of the simple primary β-amino alcohols as efficient chiral organocatalysts for the asymmetric reactions.

Dedicated to Dr. Kiyoshi Tomioka on the occasion of his 70th birthday

CONTENTS 1. Introduction 2. Asymmetric additions using β-amino alcohol-based organocatalysts 2-1. Diels-Alder reaction of 1,2-dihydropyridines 2-2. Diels-Alder reaction of anthrones 2-3. 1,3-Dipolar cycloaddition of nitrones 2-4. Diels-Alder reaction of 3-hydroxy-2-pyridones 2-5. Crossed aldol reaction of isatins with acetaldehyde 3. Conclusion 1. INTRODUCTION Most of the bioactive compounds, including medicines, are optically active substances. It is well known that a pair of enantiomers exhibit different biological activities, hence one of enantiomers is usually required for certain purposes. In medicines particularly, the differences in the absolute configuration are often related not only to the presence or absence of a pharmacological action, but also to the expression of toxicity that causes serious harmful side effects. Therefore, an asymmetric synthesis for bioactive compounds, which affords a desired optically active substance in a highly selective manner, must be developed. A catalytic asymmetric synthesis, in which a trace amount of chiral molecules catalyzes a reaction and produces many chiral products, has been actively studied from energy-saving and environmentally friendly viewpoints.1,2 The asymmetric catalysts used for catalytic asymmetric synthesis are classified into organometallic and organocatalysts that do not contain metals. Although organometallic catalysts have advantages of being highly active and they afford the desired optically active substances in a high optical yield, they also suffer from several disadvantages, for example, they are sensitive to air and moisture; they are made of metals that are expensive, toxic, and difficult to dispose; and they are not environmentally friendly. In contrast, organocatalysts have been receiving much attention as next-generation environment-friendly catalysts and are being actively studied and developed because they are stable in air, easy to handle and inexpensive. The mechanisms of the action of organocatalysts are broadly divided into two types: noncovalent and covalent.3 While a noncovalent asymmetric organocatalyst fixes a substrate by hydrogen bonding and activates a reaction site by the same mechanism with Lewis acids, a covalent asymmetric organocatalyst with an amine moiety forms imine, iminium or enamine to firmly fix the substrate to the catalyst and activate a reaction site of the substrate. We conducted research to fabricate general, versatile, and highly active asymmetric organocatalysts with multiple recognition sites, with the functionality of both noncovalent- and covalent-type catalysts. We have also been focusing particularly on amino alcohol A to

develop novel organocatalysts that can be synthesized in a single-step process from easily available substrates (Scheme 1).4 β-Amino alcohol A can be easily synthesized from various amino acid derivatives,4d and it has high stability. β-Amino alcohols can form imines (iminiums) and enamines, and have a nitrogen atom, which acts as a base, and a hydroxy group, which can form a hydrogen bond with a substrate. Hence, they are expected to work as multiple-recognition catalysts that use their different functionalities for different substrates. However, systematic studies focusing on the functionality of such organocatalysts have not yet been conducted. Our review will discuss the detailed applications of β-amino alcohol-based organocatalysts for asymmetric additions, and development of various strategies to synthesis of bioactive compounds. steric influence

R2 R2 noncovalent site R1 OH * covalent NH2 bonding

amino acids

β-amino alcohols   A

Scheme 1. Functionality of β-amino alcohols 2. ASYMMETRIC CYCLOADDITIONS USING β -AMINO ALCOHOL-BASED ORGANOCATALYSTS 2-1. Asymmetric Diels-Alder reaction of 1,2-dihydropyridines Isoquinuclidine derivatives obtained by the catalytic asymmetric Diels-Alder (DA) reaction using 1,2-dihydropyridines4d-f as diene are useful synthetic intermediates for various bioactive compounds, MeO

N N

N R

R'

R

dienophile

Diels-Alder reaction

1,2-dihydropyridines organocatalyst

ibogaine

N R'

chiral isoquinuclidines

new drugs

vinblastine or vincristine

CO2Et

O AcHN

NH2

• H3PO4

oseltamivir phosphate (tamiflu)

Scheme 2. Utility of isoquinuclidines

including the anti-influenza drug Tamiflu and the anticancer drug vinblastine (Scheme 2).5 Although Tamiflu has been widely used as an anti-influenza drug, a virus resistant to Tamiflu has been detected, which may make Tamiflu ineffective. Therefore, it is necessary to develop new drugs that are effective against the Tamiflu-resistant virus.5d We studied the synthesis of optically active isoquinuclidine derivatives by the catalytic asymmetric DA reaction of 1,2-dihydropyridines using β-amino alcohol salts as organocatalysts. We examined the asymmetric catalytic activity of β-amino alcohol-based organocatalysts (Scheme 3) in

the DA reaction of 1,2-dihydropyridines (diene) 4a-c with various substituents on their rings with acrolein (dienophile) 5 (Scheme 4). Trifluoroacetate catalyst 2a with a bulky tert-butyl group at the β-position afforded the desired endo-DA adducts (7S)-6a,c in good chemical yield and an almost complete enantioselectivity (6a: 98%, 96% ee, respectively; 6c: 75%, 96% ee, respectively).

amino acid esters

a: b: c: d: e: f : g: h: i : j : k: l : m: n: o: p:

R1

R1 = tBu, R1 = iPr, R1 = Me, R1 = Ph, R1 = Bn, R1 = tBu, R1 = tBu, R1 = tBu, R1 = tBu, R1 = tBu, R1 = tBu, R1 = CH2OH, R1 = tBu, R1 = tBu, R1 = tBu, R1 = tBu,

R2 R2 OH

NH2 1a-j,l

R1 CH2Cl2 0 oC, 5 min quant.

R2 = Ph, R3 = OH, R2 = Ph, R3 = OH, R2 = Ph, R3 = OH, R2 = Ph, R3 = OH, 2 R = Ph, R3 = OH, R2 = p-F-Ph, R3 = OH, R2 = p-Me-Ph,R3 = OH, R2 = Et, R3 = OH, R2 = Me, R3 = OH, R2 = H, R3 = OH, R2 = Ph, R3 = H, R2 = Ph, R3 = OH, R2 = Ph, R3 = OH, R2 = Ph, R3 = OH, R2 = Ph, R3 = OH, R2 = Ph, R3 = OH,

R2 R2 3

α β R NH2 • HA 2a-p

HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TFA HA = TCA HA = TBA HA = AcOH HA = HCl

Ph Ph 1l

TTMSSO

NH2

OH

ii

Ph Ph TTMSSO 2q

1q

NH2

OH

• TFA

i) TTMSSCl, Et3N,CH2Cl2, 0 oC to rt, 24 h ii) TFA, CH2Cl2, 0 oC, 5 min

1a

i

tBu

Ph Ph

HN

OH Me

1r

ii

tBu

Ph Ph

HN

OH Me • TFA 3

i) MeI, K2CO3,EtOH, 80 oC, 24 h ii) TFA, CH2Cl2, 0 oC, 5 min

Scheme 3. Synthesis of β-amino alcohol organocatalysts To expand the substrate applicability of the β-amino alcohol organocatalysts with good results, we examined the asymmetric DA reaction between 1,2-dihydropyridine derivatives 4a,c and two dienals

(methyl fumaraldehydate 8a and 4-oxo-2-butenenitrile 8b) used as dienophiles in the presence of 2a (Scheme 4). First, the DA reaction between diene 4a and dienophile 8a was carried out. As a result, the

desired DA adduct 9a was obtained in an excellent chemical yield (96%) and almost complete enantioselectivity (98%). A similar reaction between diene 4c and dienophile 8a also successfully

afforded the DA adduct 9b in an excellent chemical yield (93%) and almost complete enantioselectivity

(98%). Furthermore, the reaction between diene 4a and dienophile 8b provided the desired DA adduct 9c in a fair chemical yield (50%) and an excellent enantioselectivity (95%). These results strongly suggest that the β-amino alcohol-based organocatalysts can be applied to various kinds of dienophiles in the arymmetric DA reaction, and this DA reaction can be used for the synthesis of optically active isoquinuclidine derivatives with several substituents on their rings, which are synthetic intermediates observed during the synthesis of Tamiflu analogs.

N

cat. 2a-q

+

CO2R

O

4a-c a: R = Ph b: R = tert-Bu c: R = Bn

5

RO2C

PhO2C

N

and/or

MeCN H2O (19:1) 0 oC, 24 h

6a-c

6a'

a: R = Ph b: R = tert-Bu c: R = Bn

RO2C cat. 2a

MeCN-H2O (19:1) 8a: X = CO2Me 0 oC, 24 h 8b: X = CN

O

N

CHO

CHO

rt, 1 h quant.

NaBH4 EtOH

2a : 6a, R = Ph, 98%, 96% ee 2b : 6a, R = Ph, 90%, 94% ee 2c : 6a, R = Ph, 31%, 64% ee, endo-6a:exo-6a' = 17:1 2d : 6a, R = Ph, 27%, 13% ee, endo-6a:exo-6a' = 4:1 2e : 6a, R = Ph, 80%, 87% ee 2f : 6a, R = Ph, 73%, 93% ee 2g : 6a, R = Ph, 75%, 95% ee 2h : 6a, R = Ph, trace 2i : 6a, R = Ph, 10%, 21% ee, endo-6a:exo-6a' = 6:1 2j : 6a, R = Ph, trace 2k : 6a, R = Ph, trace 2l : 6a, R = Ph, 50%, 83% ee, endo-6a:exo-6a' = 19:1 2m: 6a, R = Ph, 65%, 95% ee 2n : 6a, trace 2o : 6a, trace 2p : 6a, R = Ph, 10%, 90% ee 2q : 6a, R = Ph, 64%, 86% ee, endo-6a:exo-6a' = 50:1 2e : 6b, R = tert-Bu, trace 2e : 6c, R = Bn, 75%, 96% ee

X 4a or + 4c

N

RO2C

N

OH

7a-c and/or RO2C

N OH

7a'

RO2C X

NaBH4

9a-c CHO

EtOH rt, 1 h quant.

N

10a-c

X

OH

9a: R = Ph, X = CO2Me, 96%, 98% ee, endo only 9b: R = Bn, X = CO2Me, 93%, 98% ee, endo only 9c: R = Ph, X = CN, 50%, 95% ee, endo only

Scheme 4. Asymmetric DA reaction between 1,2-dihydropyridines with acrolein using β-amino alcohols 2-2. Asymmetric Diels-Alder reaction of anthrones Research on organocatalysts acting as Brønsted bases (organic base catalysts) has been actively conducted in recent years. We focused herein on the use of β-amino alcohols as organic base catalysts and examined the asymmetric DA reaction6 between anthrones (diene)4c and maleimides (dienophile) in

the presence of β-amino alcohols (Scheme 5). The hydroanthracenes obtained from the reaction were used as precursors for the synthesis of α,β-unsaturated lactams,7 which are useful synthetic intermediates of various bioactive compounds, including medicines. Hence, it is very important to develop a DA reaction using organic base catalysts, which will afford hydroanthracenes in high optical purity. O +

R1 R2

anthrones

O N

R4 maleimides

biologically active compounds

R4

R4

O

R1

O

asymmetric Diels-Alder reaction

chiral organobase catalyst

R3

O

R3 N

R6

O

N R5 R3 α,β-unsaturated lactams

R2

HO hydroanthracenes

Scheme 5. Utility of hydroxyanthracenes

R1

Ph

Ph OH

NH2 1a-e

a : R1 = t-Bu b : R1 = i-Pr c : R1 = Me d : R1 = Ph e : R1 = Bn

OH

R2OTf or R2'Cl Et3N

Ph

NH2

Ph OH

(R2')R2O

CHCl3 -40 °C to rt 24 h

1l

Ph

NH2 1q, 11a-h

Ph OH

a : R2 = TIPS b : R2' = TBDMS c : R2' = DPMS d : R2' = TPS e : R2 = TES f : R2' = TPrS g : R2' = THS 1q: R2' = TTMSS

11e

CHCl3 TMSOTf -40 °C to rt Et3N 24 h OSET

Ph NH2 12

Ph OTMS

MeI EtOH K2CO3 rt, 24 h Ph

OSET

Ph OH

NMe2

13

PhCH2Br K2CO3

CHCl3 rt, 72 h

OSET

Ph HN 14

Ph OH

Bn

Scheme 6. Synthesis of β-amino alcohol organocatalysts We designed and synthesized amino alcohol-based organic base catalysts by introducing bulky trialkylsilyl groups onto the oxygen atom at γ-position of amino alcohols (Scheme 6). We then examined the DA reaction using these organic bases.

The asymmetric catalytic activity of the synthesized β-amino alcohol-based organic base catalysts 1a-e, 11a-g, 1q, 12-14, was investigated in the DA reaction between anthrones 15, 16a,b (diene) and N-phenylmaleimide 17 (dienophile) (Table 1). The reaction using catalyst 11e with a triethylsilyl (TES) group on the γ-oxygen atom provided the best chemical yield and enantiomeric excess (92%, 42% ee, respectively, entry 1). The asymmetric DA reaction between anthrones 15, 16a,b and maleimides 17, 18a-f using catalyst 11e was also examined (Table 1). The reaction, in which N-(2-nitrophenyl)maleimide 18d was

used as a dienophile, afforded the corresponding DA adduct 20d in the best enantioselectivity (94% ee, entry 6). Interestingly, the configuration of 20d was opposite to that of the products of other substrates, which suggested that the products with the desired configuration can be selectively synthesized by considering the characteristics of the β-amino alcohol-based organocatalysts and substrates and by changing the combination of the reactants to change their interaction. Table 1. Asymmetric Diels-Alder reaction between anthrones and maleimides using β-aminoalcohol organocatalysts R2

R2

O

O +

R1 15 16a 16b

= =H = Cl, R2 = H = H, R2 = Cl

entry 1 2 3 4 5 6 7 8 9 10

R2

17, 18a-f

R2

15 15 15 15 15 15 15 15 16a 16b

17 18a 18b 18c 18d 18d 18e 18f 17 17

time temp. (h) (°C) 48 48 48 48 48 72 48 48 48 48

O

N

N O

R1

HO

NO2

OH

R2 19, 20a-c,e-h

20d

19 : R1 = R2 = H, R3 = Ph 20a : R1 = R2 = H, R3 = Me 20b : R1 = R2 = H, R3 = 4-Me-Ph 20c : R1 = R2 = H, R3 = Bn 20d : R1 = R2 = H, R3 = 2-NO2-Ph 20e : R1 = R2 = H, R3 = 3-NO2-Ph 20f : R1 = R2 = H, R3 = 4-NO2-Ph 20g : R1 = Cl, R2 = H, R3 = Ph 20h : R1 = H, R2 = Cl, R3 = Ph

17 : R3 = Ph 18a : R3 = Me 18b : R3 = 4-Me-Ph 18c : R3 = Bn 18d : R3 = 2-NO2-Ph 18e : R3 = 3-NO2-Ph 18f : R3 = 4-NO2-Ph

diene dienophile

O

O R1

CH2Cl2

O

R1

15, 16a,b

: R1 : R1 : R1

N R3

R3

catalyst 1a-e,q, 11a-g,12-14 (20 mol%)

rt rt rt rt rt 0 rt rt rt rt

DA adduct

yield (%)

19 20a 20b 20c 20d 20d 20e 20f 20g 20h

92 97 91 93 97 83 97 95 98 98

ee (%) 19, 20a-c,e-h 20d 42 39 32 46 32 35 25 38

66 94

2-3. Asymmetric 1,3-dipolar cycloaddition of nitrones 1,3-Dipolar cycloaddition (1,3-DC) is a useful reaction to synthesize optically active isoxazolidine derivatives.4b Isoxazolidines are useful chiral building blocks that lead to γ-amino alcohols, β-amino acids,

and β-lactams. Isoxazolidines are also known as the synthetic intermediates of various bioactive compounds, including medicines.8 Therefore, we used amino alcohol-based organocatalysts for the asymmetric 1,3-DC reaction between nitrones and α,β-unsaturated aldehydes. We used β-amino alcohols as amino alcohol-based organocatalysts with a primary amino group and a bulky substituent at the γ-position (Scheme 7).

R1

N

O

R2

R3

H

O

R2 N O

catalyst A acid additive (RSO3H, etc.)

R3

R1

1,3-DC

HO

CHO

α,β-unsaturated aldehydes

nitrones

biological active compounds

optically active isoxazolidines

R O

OH

R N H

R

alkaloids

H H R

N

CO2H β-lactams

OH N H

O amino acids

Scheme 7. Utility of isoxazolidine intermediates We planned to examine this reaction using the following catalysts: amino alcohol catalysts with aliphatic or aromatic substituents at the β-position (1a,b,d,e); amino alcohol catalysts with bulky silyl groups at the γ-oxygen atom (11a,b,d,e); dihydroxy amino alcohol (1l), which is a precursor of the silylated catalysts;

Ph Ph R

Ph

Ph

α

OH

OR'

NH2

a : R = tBu b : R = iPr d : R = Ph e : R = Bn N O

22 O H

23

OH

OH NH2

NH2

-30 °C to rt 24 h

1l

1q

NH2

Ph

catalysts 1a,b,d,e,l,q 11a,b,d,e,h,21 (10 mol%) co-catalysts (10 mol%) solvent temp, 24 h

CHCl3 -30 °C to rt 24 h

TMSOTf Et3N Ph OTMS

TTMSSO

a : R' = TIPS b : R' = TBDMS d : R' = TPS e : R' = TES Bn

Ph OH

TTMSSO

CH2Cl2

11a,b,d,e

1a,b,d,e

Ph

β

HO

Ph

Ph

TTMSSOTf Et3N

Ph

NH2

21

Bn

Ph

N

O

3

5

4

CHO

endo-(3R,4S,5R)-24

Bn

Bn N

O NaBH4

Ph

EtOH

CHO

exo-(3S,4S,5R)-24'

0 °C, 1 h quant.

N

Bn

O

N

O

Ph

Ph

OH

OH

endo-25

exo-25'

cat 1q: DC adduct 24 ( 73%, 95% ee, endo:exo = 96:4)

Scheme 8. 1,3-Dipolar cycloaddition of nitrones with α,β-unsaturated aldehydes using β-amino alcohol organocatalysts

amino alcohol with the most bulky supersilyl group [tris(trimethylsilyl) group (TTMSS group)] (1q); and the α-hydroxy group of 1q masked with the TMS group (21) (Scheme 8). The 1,3-DC reaction between nitrone 22 and α,β-unsaturated aldehyde 23 using the above mentioned

amino alcohol catalysts was examined under various conditions (Scheme 8). The obtained adducts 24,24’ were converted into alcohols 25,25’ by using NaBH4 to determine their chemical yields and the enantioselectivities. The reaction in the presence of 1q having the bulkiest TTMSS group on the γ-oxygen

atom and a co-catalyst trifluoromethanesulfonic acid (TfOH) provided the corresponding DC adduct endo-(3R,4S,5R)-24 afforded in the best chemical yield and enantioselectivity (73%, 95% ee). Next, to expand the substrate applicability of the amino alcohol catalyst, the 1,3-DC reaction between substituted nitrones 22, 26a-k and α,β-unsaturated aldehydes 23,27 in the presence of catalyst 1q was

examined (Table 2). All reactions afforded the corresponding DC adducts 28a-l in good chemical yields

and enantioselectivity. This finding suggested the broad applicability of the amino alcohol catalysts in this reaction. Table 2. 1,3-Dipolar cycloaddition between nitrones and α,β-unsaturated aldehydes using β-amino alcohol organocatalysts

R1

N

R2

R2

N O R3

R1

CHO

22, 26a-k

catalyst 1q (10 mol%)

endo-28a-l

TfOH Et2O

O H

R3

R1

O

R2

N O

R3

R2

0 °C, 24 h

OH

NaBH4 EtOH

0 °C, 1 h quant.

N O R3

R1

endo-29a-l R2

N O

CHO

23 : R3 = Me 27 : R3 = H

R3

R1 OH

exo-28a'-l'

exo-29a'-l'

entry

nitrone 22,26

R1

R2

aldehyde

DC adduct 28

yield (%)

endo/exo

endo ee (%)

1 2 3 4 5 6 7 8 9 10 11 12

26a 26b 26c 26d 26e 26f 26g 26h 26i 26j 26k 22

4-MePh 4-iPrPh 4-OMePh 4-ClPh 4-BrPh 2-ClPh 4-CF3Ph 1-Naph 2-Naph Ph 4-ClPh Ph

Bn Bn Bn Bn Bn Bn Bn Bn Bn Me Me Bn

23 23 23 23 23 23 23 23 23 23 23 27

28a 28b 28c 28d 28e 28f 28g 28h 28i 28j 28k 28l

67 75 76 59 44 49 58 59 63 65 37 79

95:5 96:4 96:4 89:11 90:10 93:7 92:8 92:8 92:8 96:4 90:10 61:39

94 64 64 89 90 93 62 71 92 97 96 70

2-4. Asymmetric Diels-Alder reaction of 3-hydroxy-2-pyridones The DA reaction using 3-hydroxy-2-pyridones as diene is a useful reaction for providing 4-hydroxyisoquinuclidine derivatives which are synthetic intermediates for bioactive compounds such as the anti-influenza drug Tamiflu and the anti-glucosidase inhibitor Validamine, which show a glucosidase

X

OH N O X 3-hydroxy2-pyridones

HO HO

dienophile Diels-Alder reaction

organocatalyst OH

O N

OH

biological active compounds

chiral 4-hydroxyisoquinuclidines CO2Et

OH

NH2

2-epi-validamine

HO HO

OH

OH

NH2

O

NH2

NHCOMe H3PO4

oseltamivir (Tamiflu)

validamine

Scheme 9. Utility of 4-hydroxy-isoquinuclidines inhibitory activity, in a single step (Scheme 9).9 However, almost no reports have been presented till date on this useful asymmetric DA reaction.6a We examined the asymmetric DA reaction using 3-hydroxy-2-pyridones4a as diene and β-amino alcohol organocatalysts as Brønsted bases to develop organocatalysts useful for this DA reaction (Scheme 10). We examined the asymmetric DA reaction between 3-hydroxy-2-pyridones 34a,b and maleimides 35a-c in the presence of amino alcohol organocatalysts 1a,b,d-k,r, 30-33 (Scheme 10). The DA reaction between pyridone 34b and maleimide 35b in the presence of catalyst 1a with a tert-butyl group at the

β-position afforded the desired isoquinuclidine derivative 36e in an excellent chemical yield and almost complete enantioselectivity (95%, 98% ee, respectively). We are now trying to develop the new hybrid type anti-influenza drug candidates using the obtained DA adducts as the synthetic intermediates.

Ph R

a : R = tBu b : R = iPr d : R = Ph e : R = Bn f : R = p-F-Ph g : R = p-Me-Ph h : R = Et i : R = Me

Ph OH

NH2 1a,b,d,e tBu

HN

tBu Ph Ph + OH Me N

Me 1r

H2N

tBu

Ph Ph OH

N

O

O

+

N R' O

34a,b

a : R = MesSO2 b : R = Ts

1j

CH2Cl2 rt, 1h

35a-c

a : R' = Ph b : R' = Me c : R' = Et

H OH

tBu

H2N

31 catalyst 1a,b,d-k,r 30-33 (10 mol%)

O

HO O R'

tBu

H

Ph Ph OH

Me 30

OH N R

tBu

H2N

Ph Ph OTMS 32

R

N

1k

N

O 36a-f

a: b: c: d: e: f:

Ph Ph H

tBu

H2N

33

Ph Ph NH2

R = MesSO2, R' = Ph R = MesSO2, R' = Me R = MesSO2, R' = Et R = Ts, R' = Ph R = Ts, R' = Me R = Ts, R' = Et

up to 95%, up to 98% ee

Scheme 10. DA reaction between 3-hydroxy-2-pyridones and maleimides using β-amino alcohol organocatalysts 2-5. Asymmetric aldol reaction of isatins with acetaldehyde The asymmetric aldol reaction is one of the important methods for carbon-carbon bond formation,10 therefore, in the last decade, there is a significant progress in the development of enantioselective organocatalyzed aldol reaction of various aldehydes.11 But the direct crossed aldol reaction of acetaldehyde, which is the simplest enolizable carbonyl compound, has been known to be a challenging task.12,13 This reaction between acetaldehyde as a nucleophile and ketone as an electrophile has great significance since it results in a chiral quaternary carbon center, which is immensely valuable in synthetic chemistry.14 Specifically, enantioselective crossed aldol reaction of isatin 37a with acetaldehyde 38 is a straightforward method to acquire chiral 3-substituted 3-hydroxyindolin-2-one 41a, which is a valuable building block for the synthesis of broad range of biologically important compounds (Scheme 11). Owing to its significance as a pharmacophore, in recent years, few research groups have developed the asymmetric

crossed

aldol

reaction

of

acetaldehyde

with

isatins

to

afford

3-substituted

3-hydroxyindolin-2-one derivatives 4115 that are versatile synthetic intermediate for the synthesis of tryptanthrin architecture based indoloquinazoline alkaloids, phaitanthrin B 39 and cephalanthrin A 40, isolated recently from Phaius mishmensis (Orchidaceae)16a and Cephalantheropsis gracilis,16b with potential anticancer and antiviral activities.16,17 Furthermore, the intermediate 41a were expected to work for the synthesis of anti-bacterial indolidine alkaloids such as chimonamidine 42, donaxaridine 43 and

CPC-1 44.

OMe

HO N

N

O

N

O

38

O

O

N

O

40 39 cephalanthrin A phaitanthrin B anti-cancer activity

O N H 37a isatin +

OH

HO

O

O

HO

aldol reaction di-amino alcohol organocatalyst

acetaldehyde

HO

O N H 41a chiral 3-hydroxyindolin-2-ones

N Me NH Me

O

42 chimonamidine

HO

MeO

N Me

N

N H Me 44

O

NH2 43 donaxaridine

Me

CPC-1

anti-bacterial activity

Scheme 11. Utility of 3-hydroxyindolin-2-ones We designed and prepared a series of new type of di-amino alcohols B (Scheme 12) with two kinds of covalents and a non-covalent bonding and steric influence sites for the enantioselective crossed aldol reaction of isatin 37a with acetaldehyde 38. These new type of di-amino alcohols B might coordinate

with acetaldehyde 38 through enamine formation and with isatin 37a through hydrogen bonding between carbonyl oxygen of isatin and cationized nitrogen of pyrrolidine ring of the ethenamine derivative. Moreover, we also tried the total synthesis of biologically active compounds 39-43 and the formal synthesis of 44 via intermediate 41 that is obtained from the reaction of 37a with 38. steric influence

N

amino acids noncovalent site

R2 R2 noncovalent β

*

α

NH2 ホイ

OH

site

covalent site

di-amino alcohol organocatalyst B

Scheme 12. Functionality of di-amino alcohol organocatalysts

New catalyst was prepared by the following methodology. The protection of primary amine of compound 45 with (Boc)2O followed by masking of primary hydroxy group with mesyl chloride afforded compound

46 in good yield. Subsequently, the substitution reaction of mesylate 47 with various cyclic amines (pyrrolidine, piperidine, azepane, morpholine and thiomorpholine) under neat reaction conditions provided 48a-e in moderate to good yields. Finally, deprotection of Boc group of 48a-e by treating with

TFA furnished the targeted new type of multifunctional organocatalysts 49a-e in good overall yields (Scheme 13).

Ph Ph OH

HO H2N 45

(Boc)2O, Et3N oC

to rt CH2Cl2, 0 3 h, 90%

Ph Ph OH

HO BocHN 46

N

X

n N

H2N

Ph Ph BocHN OH n = 0, 1, 2 X= CH2, O, S

TFA, CH2Cl2 0 oC to rt 3h

48a-e

oC

CH2Cl2, 0 to rt 5 h, 85%

N

Ph Ph OH

H2N

49a: 90% O

BocHN

Ph Ph OH

H2N

Ph Ph OH

49d:85%

NH n oC,

6h 70 55% - 65%

47

N H2N

Ph Ph OH

49c: 86%

49b:95%

N

X

Ph Ph OH

MsO

MsCl, Et3N

S

N H2N

Ph Ph OH

49e:85%

Scheme 13. Preparations of new di-amino alcohol organocatalysts We examined the aldol reaction of isatins 37a,b with acetaldehyde 38 in the presence of usual amino alcohols 1a,b,d,e,q, 11a,b,e,g and new desired di-amino alcohol catalysts 49a-e (Scheme 14). The

obtained adducts 41a,b were changed to alcohols 50a,b by NaBH4 reduction to determine the chemical

yield and enantioselectivity. As a result, the usual amino alcohol catalysts 1, 11 did not work effectively in this reaction (up to 67%, up to 24% ee). On the other hand, the new designed di-amino alcohol catalysts 49 showed good catalytic activity (up to 90%, up to 80% ee) in this reaction. Especially, the use

of catalyst 49a bearing pyrrolidine ring showed an excellent asymmetric catalytic activity in this reaction at lower temperature (-10 oC) led to the aldol product 50b in excellent yield (95%) and good enantioselectivity (88% ee). Although the several reaction conditions for improving the chemical and optical yield of the desired aldol product 50b using the superior catalyst 49a were examined,

unfortunately, no improvement was observed regarding either chemical yield or optical yield than the previous obtained results (95%, 88% ee).

R

Ph a : R = t-Bu Ph b : R = i-Pr H2N OH d : R = Ph e : R = Bn 1a,b,d,e

N H2N

N

Ph Ph OH

H2N

49a

H2N

1q, 11a,b,e,g

N

Ph Ph OH

Ph Ph OH

R1O

H2N

Ph Ph OH

11a : R1 = TIPS 11b : R1 = TBDMS 11e : R1 = TES 11g : R1 = THS 1q : R1 = TTMSS

N

O

H2N

49d

49c

49b

N

S

Ph Ph OH

Ph Ph OH

H2N

49e

O N 37a,b R

O

a: H, b: Bn +

catalyst 1a,b,d,e,q, 11a,b,e,g, 49a-e (20 mol%) PhCO2H (30 mol%)

O

HO N R 41a. b

toluene 0 oC, 48 h

O 38

NaBH4

O

OH

HO

catalysts 49a-e: 50a,b, 0 °C: 55-90%, 18-80% ee

O

N

MeOH, 0 oC 1h

catalysts 1a,b,d,e,q, 11a,b,e,g: 50a,b, 28-67%, 7-24% ee

catalyst 49a: 50b, -10 °C: 95%, 88% ee

R 50a,b

Scheme 14. Aldol reaction using di-amino alcohol organocatalysts This superior catalyst applied to the reactions using some isatins and acetaldehyde under the optimized N

N

O

O

R 37a,c-l

N Me 50c

O

50d

OH

HO

OH

HO

O

N H

R

50a,c-l

OH

O

O N PMB 50f

-10 oC, 77%, 89% ee

Br

OH

HO N H

OH

HO

O N MOM 50e

-10 oC, 82%, 88% ee

O

N

MeOH 0 oC, 1 h

HO

O

N

-10 oC, 75%, 84% ee

N H

OH

HO

OH

NaBH4

PhCO2H (30 mol%) toluene, temp., 48 h

38

OH

HO

HO

H2N 49a (20 mol%)

O

R1

Ph Ph OH

O

-10 oC, 95%, 90% ee OH

HO

Cl

N H

O

50a

50a

50g

50h

-10 oC, 40%, 76% ee

0 oC, 59%, 89% ee

0 oC, 67%, 84% ee

0 oC, 74%, 84% ee

I

HO

OH

O N H 50i 0 oC, 85%, 79% ee

F

HO

OH

O N H 50j 0 oC, 49%, 91% ee

Me

HO

OH

O N H 50k 0 oC, 64%, 84% ee

O2N

OH

HO N H

O

50l 0 oC, 57%, 92% ee

Scheme 15. Substrate scope of crossed-aldol reaction

conditions (Scheme 15). All reactions smoothly proceeded and afforded the corresponding aldol products in good chemical yields and enantioselectivities. Thus N-protected isatins such as N-methyl, N-allyl, N-MOM and N-PMB isatins 37c-f afforded the corresponding aldol products 50c-f in good chemical and

optical yields (up to 75-95%, up to 84-90% ee). Isatin 37a was also tested using catalyst 49a, which is essential for utility of this method effectively for natural product synthesis. The respective product 50a

was afforded with good enantioselectivity (76% ee). Furthermore, the temperature from -10 oC to 0 oC afforded the product 50a with notable improvement in chemical yield (59%) and enantioselectivity (89% ee). Halogen-substituted isatins 37g-j, were also compatible with this protocol and satisfactory results

were obtained (up to 49-85%, up to 79-91% ee). Moreover, 5-methylisatin 37k afforded the product 50k in moderate yield and selectivity (64%, 84% ee). The best result was obtained with 5-nitro-isatin 37l to

afford the corresponding product 50l (57%, 92% ee).

From these satisfactory results in hand, we aimed our attention towards total synthesis of biologically active natural products (Scheme 16). We attempted for direct synthesis of cephalanthrin A 40 from the

aldol product 41a. Condensation of diol 41a with isatoic anhydride 51 yielded the coupled product 52 in H N O

OH

HO N H

O

51 O

O

N

Et3N, toluene

100 oC,

6 h, 55%

H2N 49 (20 mol%)

O O

O 38

Ph Ph OH

H N TMSCHN2 THF, 0 oC 3h 80%

OMe

HO N H 54: 99% ee

O

O

NaH2PO4 NaClO4 t-BuOH/H2O

O

O

OMe

HO N O

N

O

39 phaitanthrin B 99% ee

MeOH aq. NaOH (20 mol%) 0 oC, 30 min 80%

O

HO N H 53

0 oC to rt, 3h 55%

41a

51 O Et3N, toluene 100 oC, 6 h 60%

OH

40 cephalanthrin A

O N H

O

N

O

HO

PhCO2H (30 mol%) toluene, 0 oC 48 h

O

HO N

52: 88% ee N

37a

Oxidation

N

O

41a: 89% ee

N H

OH

HO

O

OH

OH

HO N

N

O

O

40 cephalanthrin A 99% ee

Scheme 16. Total synthesis of phaitanthrin B and cephalanthrin A

moderate chemical yield without loss of enantioselectivity (88% ee). Then, we anticipated that oxidation of primary alcohol of 52 could result in cephalanthrin A 40. However, the oxidation conditions using TEMPO/BAIB did not afford the desired product. Also, the use of either Jones reagent,18 KMnO4 in

strong alkali condition19 or Cornforth reagent,20 unfortunately, did not result in the desired product 40 (Scheme 5).

After these failed attempts, synthetic route was changed. Pinnick oxidation21 of aldehyde 41a (aldol product), followed by esterification by treating with TMSCHN2 afforded the β-hydroxy ester 54 in good yield without loss of enatioselectivity. Condensation of 54 with isatoic anhydride 51 offered the targeted phaitanthrin B 39 without affecting the enantioselectivity. Afterwards, cephalanthrin A 40 was conveniently obtained from phaitanthrin B 39 by its treatment with base. After single recrystallization in

diethyl ether the two targeted molecules phaitanthrin B 39 and cephalanthrin A 40 were obtained in 99% ee.

We next synthesized the proposed 3-hydroxy-2-oxindole derived natural products. Tosylated product 54 was obatained by treatment of diol 50c with tosyl chloride. Tosylate 54 was then converted to the desired (S)-chimonamidine 42 by treatment with methylamine under refluxing conditions. Following the same

path, donaxaridine 43 was also obtained from 50a through tosylation followed by treatment with OH

HO N Me

O

TsCl pyridine, rt 10 h 80%

50c: 84% ee

N H

O

50a: 89% ee

N Me

O

MeNH2

TsCl pyridine, rt 10 h 90%

N H

N Me NH Me

O

chimonamidine 42: 94% ee (2 times washed with ether) OTs

HO

HO

65 oC, 10 h 60%

54: 84% ee

OH

HO

OTs

HO

O

MeNH2

HO

65 oC, 10 h 65%

N Me O NH2

donaxaridine 43: 98% ee (2 times washed with ether)

55: 89% ee NaN3, DMF 6 h. 65% 60 oC N3

HO O

N H 56: 90% ee

MeO Ref.

N

N H Me 44: CPC-1

Me

Scheme 17. Total synthesis of chimonamidine, donaxaridine and formal synthesis of CPC-1 methylamine. The resulted final compounds i.e. chimonamidine 42 and donaxaridine 43 were washed

with diethyl ether (two times) to increase to the sufficient ee values (chimonamidine 42: 94% ee,

donaxaridine 43: 98% ee). Azidation of tosylate 55 using NaN3 yielded the azide 56 in good yield without loss of enantioselectivity. CPC-1 44 could be synthesized from 56 via reported procedure (Scheme 17).15c 3. CONCLUSION Up to this point, we have described the synthesis of the β-amino alcohol organocatalysts that we developed and their applications to asymmetric additions. Our catalysts showed excellent asymmetric catalytic activity in each reaction we tried. We will apply our catalysts to other asymmetric catalytic reactions to find further usefulness. We are also trying to develop the novel bioactive compounds, including anti-influenza drug candidates that can be synthesized from the chiral asymmetric adducts obtained from the reactions that we examined. ACKNOWLEDGEMENTS We would like to acknowledge the contributions of many co-workers and their efforts in helping to obtain the results we described here. Also, we appreciate Adaptable & Seamless Technology Transfer Program through Target-driven R&D from Japan Science and Technology Agency (JST), NOASTEC foundation, and Muroran Institute of Technology for partial financial support to this study. REFERENCES 1.

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Professor Hiroto Nakano received his Ph. D. degree in 1989 from Tohoku Pharmaceutical University. He joined the Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University as a research associate in 1989. During the period of 1997 to 1999, he also joined Albert I. Meyers’ group at Colorado State University in USA as a postdoctoral fellow. At Tohoku Pharmaceutical University, he was promoted to assistant professor in 2001 and to associate professor in 2006. From 2010, he is a professor of Muroran Institute of Technology. He was awarded Pharmaceutical Society of Japan Northeast Branch Award for Young Scientist in 1999. His research interest is catalytic asymmetric syntheses in the field of synthetic organic chemistry. Mr. Isiaka Alade Owolabi obtained a Masters of Technology degree in chemistry in 2015 from Tshwane University of Technology, Pretoria, South Africa. He later joined the Graduate School of Engineering, Synthetic Organic Chemistry Laboratory at Muroran Institute of Technology as a Ph.D. student under the supervision of Prof. Hiroto Nakano in 2016. His research interest is in the area of organocatalytic asymmetric synthesis in the field of synthetic organic chemistry. He is a member of the Society of Synthetic Organic Chemistry, Japan.

Dr. Madhu Chennapuram was born and raised in Hyderabad, India. He obtained his M.Sc. degree in 2011 (drugs and pharmaceuticals chemistry) from Jawaharlal Nehru Technological University, Hyderabad. Afterwards, he worked at the Indian Institute of Chemical Technology, Hyderabad, as a project assistant in the Crop Protection Chemicals Division from 2012 to 2015. In 2015, he moved to Prof. Hiroto Nakano laboratory at Muroran Institute of Technology, Japan. He received his Ph.D. (synthetic organic chemistry) in March 2018, at present he is working as a postdoctoral fellow with Prof. Hiroto Nakano at Muroran Institute of Technology. His research interests are in the development of new hybrid type amino alcohol organocatalysts and their applications in catalytic asymmetric synthesis. Associate Professor Yuko Okuyama received her Ph. D. degree in 2001 from Tohoku Pharmaceutical University. She joined the Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University as a research associate in 1991. From 2011, she is an associate professor of the same university. Her research interest is catalytic asymmetric syntheses in the field of synthetic organic chemistry.

Associate Professor Eunsang Kwon was received his Dr. degree in science from Tohoku University in 2001. He was a post-doctoral fellow at RIKEN Frontier Research System from 2001 to 2005, and he served as a research fellow of Institute of Multidisciplinary Research for Advanced Materials (IMRAM), Tohoku University, in 2005-2008. He started his independent career as an Assistant Professor at Research and Analytical Center for Giant Molecules at the Tohoku University in 2008, and he was promoted to Associate Professor in 2015. His research interests include theoretical/computational chemistry, structures and properties of nanoscale functional materials based on endohedral metallofullerenes and their applications.

Assistant Professor Chigusa Seki was received her Dr. degree in engineering from Muroran Institute of Technology in 2012. She was a research assistant at Muroran Institute of Technology in 1996-2007. From 2007, she is an assistant professor at Division of Applied Sciences at Muroran Institute of Technology. Her research interests include properties of a conducting polymer modified electrodes, electrochemical reaction on their electrodes, catalytic asymmetric synthesis of heterocyclic compounds.

Michio Tokiwa M.D. was graduated Iwate Medical University in 1972. He joined the Faculty of Tohoku Rosai Hospital in 1972, Tohoku University Hospital in 1979, and Fukushima Rosai Hospital in 1980. He established himself Iwaki Urological Office in 1982. He was a permanent member of Fukushima medical Association in 2004. He established himself Joban Hospital in 2011. During the period of 2012 to 2014, he was the executive member of an Iwaki city medical Association. He is a medical specialist at Urology.

Dr. Mitsuhiro Takeshita recived his Ph. D. degree in 1976 from Tohoku University. During the period of 1978 to 1980, he also joined F. M. Menger’s Group at Emory University in USA as a postdoctoral fellow. He joined Tohoku Pharmaceutical University as a research associate in 1981. At Tohoku Pharmaceutical University, he was promoted to associate professor in 1987, and was promoted to professor in 1996. He retired from Tohoku Pharmaceytical University in 2012. He was a executive adviser of Tokiwakai group at Iwaki in 2012. During the period of 2013 to 2018, he also joined Iwaki Meisei University as a guest professor