Journal of Synthetic Organic SYNTHESIS Chemistry REPRINT

With compliments of the Author

Thieme REVIEW 1929

Chiral Phosphoric Acids as Versatile Catalysts for Enantioselective l Transformations ChiralMasahiro Phosphoric Acids as Enantioselective Catalysts Terada* Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan Fax +81(22)7956602; E-mail: [email protected] Received 25 March 2010; revised 13 April 2010

Brønsted acid catalysis’, the innovative methods of which Abstract: Chiral phosphoric acids derived from axially chiral biar- yls and related chiral Brønsted acids have emerged as an attractive have afforded enantioenriched products using a catalytic and widely applicable class of enantioselective organocatalysts for amount of a chiral organic molecule bearing an acidic 2 a variety of organic transformations. This review focuses on recent functionality. The first example of chiral Brønsted acid achievements in the development of enantioselective transforma- catalysis was reported by Jacobsen and co-workers in the tions using these axially chiral phosphoric acids and their analogues enantioselective Strecker reaction catalyzed by peptide- as chiral Brønsted acid catalysts. The contents are arranged accord- based thiourea derivatives acting as hydrogen-bond donor ing to the specific types of carbon–carbon bond-forming reactions, catalysts.3 Their landmark report in 1998 has fueled great followed by carbon–heteroatom bond-forming reactions and func- tional group transformations, including reduction and oxidation. interest in the enantioselective catalysis by chiral Brønsted Further applications to combined phosphoric acid and metal com- acids. Their achievement has clearly indicated that a plex catalytic systems and new aspects in the development of chiral chiral Brønsted acid enables discrimination between the Brønsted acid catalysts are also highlighted. enantiotopic faces of an imine substrate via hydrogen bonds, and has opened up a new avenue in enantioselec- 1 Introduction tive catalysis without the use of chiral metal (Lewis acid) 2 Chiral Phosphoric Acids as Enantioselective Brønsted Acid catalysts. Thereafter, excellent work on the enantioselec- Catalysts 3 Mannich and Related Reactions tive hetero-Diels–Alder reaction was reported by Rawal 4 One-Carbon Homologation Reactions via Activation of and co-workers in 2003 using TADDOL (tetraaryl-1,3-di- Imines oxolane-4,5-dimethanol) as the chiral Brønsted acid cata- 5 Friedel–Crafts and Related Reactions lyst.4 These milestones have strongly influenced current 6 Ene (Type) Reactions studies on the development of chiral Brønsted acid cata- 7 Cycloaddition Reactions lysts. However, the acidity of the thiourea and aliphatic al- 8 Cyclization Reactions cohol functionalities is rather weak, with pKa values 9 Transformations via Protonation of Electron-Rich Double 5,6 Bonds ranging from 20 to 28 in DMSO. In contrast to these ad- 10 Miscellaneous Carbon–Carbon Bond-Forming Reactions vanced studies, an innovative approach to the develop- 11 Carbon–Heteroatom Bond-Forming Reactions ment of chiral Brønsted acid catalysts that possess 12 Transfer Hydrogenation Reactions

strongly acidic functionalities was independently accom- This is a copy of the author's personal reprint 13 Oxidations 7 l plished by Akiyama and co-workers and Terada and co- l 14 Combined Use of Metal Complex and Phosphoric Acid workers8 in 2004. Highly enantioselective transforma- Catalysts tions using 1,1¢-bi-2-naphthol (BINOL)-derived mono- 15 New Aspects in the Development of Chiral Brønsted Acid Catalysts phosphoric acids 1 as chiral Brønsted acid catalysts were 2a,c,9 16 Conclusions demonstrated by these two research groups (Figure 1). 2 Key words: asymmetric catalysis, diastereoselectivity, electro- Among the chiral Brønsted acids reported hitherto, chiral philic addition, enantioselectivity, multicomponent reaction phosphoric acids derived from axially chiral biaryls repre- sent an attractive and widely applicable class of enantiose- lective organocatalysts for a variety of organic transformations. The present review focuses on recent 1 Introduction achievements in the development of enantioselective transformations using axially chiral phosphoric acid cata- Over the past decade, enantioselective catalysis by a small lysts 1 and related chiral Brønsted acids. organic molecule, so-called organocatalysis, has become a rapidly growing area of research as it offers operational G G simplicity, uses mild reaction conditions, and is environ- O O 1 O O mentally benign. Among the procedures for organocatal- P P OH ysis reported to date, researchers have focused on ‘chiral O OH O

G G 1

SYNTHESIS 2010, No. 12, pp 1929–1982xx.xx.2010 (R)-1 (S)- Advanced online publication: 27.05.2010 Figure 1 BINOL-derived monophosphoric acids 1 as chiral DOI: 10.1055/s-0029-1218801; Art ID: E26710SS Brønsted acid catalysts © Georg Thieme Verlag Stuttgart · New York

Synthesis 2000, No. X, x–xx ISSN 0039-7881 © Thieme Stuttgart · New York 1930 M. Terada REVIEW

2 Chiral Phosphoric Acids as Enantioselective As shown in Figure 1, axially chiral biaryls, especially Brønsted Acid Catalysts BINOL derivatives, were mainly employed as chiral sources for the construction of the ring structure. BINOL The desirable features of phosphoric acids as chiral Brønsted is well known as an axially chiral molecule having C2- acid catalysts are summarized as follows (Figure 2): symmetry. Its derivatives have been utilized extensively 12 1) Phosphoric acids are expected to capture electrophilic as chiral ligands for metal catalysts. This C2-symmetry components through hydrogen-bonding interactions with- is crucial because it means that the same catalyst molecule out forming loose ion pairs, owing to their relatively is generated when the acidic proton migrates to the phos- strong yet appropriate acidity.10 phoryl oxygen. In addition, both enantiomers of BINOLs are commercially available and numerous protocols for 2) The phosphoryl oxygen would function as a Brønsted the modification of BINOLs have been reported to date, in basic site and hence it is anticipated that it would convey which a variety of substituents (G) can be introduced to acid/base dual function even to monofunctional phospho- the 3,3¢-positions of the binaphthyl backbone. These ster- ric acid catalysts. This catalyst design is conceptually sim- ically but also electronically adjustable substituents (G) ilar to the mainstream of bifunctional organocatalyst can be utilized to create an appropriate chiral environment 1,11 design reported to date. However, in a strict sense, the for enantioselective transformations.13 phosphoric acid catalysts should be distinguished from most bifunctional organocatalysts, in which rather weakly acidic and basic functionalities are introduced individual- 3 Mannich and Related Reactions ly to the catalyst molecule. 3) An acidic functionality is available even with the intro- Akiyama et al. reported enantioselective catalysis in the duction of a ring system. It is likely that this ring system Mukaiyama type Mannich reaction that used BINOL- effectively restricts the conformational flexibility of the derived phosphoric acids 1 as chiral Brønsted acid cata- chiral backbone. lysts.7 In the same year, Terada and Uraguchi indepen- dently demonstrated a highly enantioselective direct 4) Substituents (G in Figure 2) can be introduced to the 8 ring system to provide a chiral environment for enantiose- Mannich reaction using similar phosphoric acids. As lective transformations. these enantioselective Mannich reactions were success- fully developed, chiral phosphoric acids have been widely It is anticipated that an efficient substrate recognition site utilized as efficient enantioselective organocatalysts for would be constructed around the activation site, namely, numerous organic transformations. Among the asymmet- the acidic proton, of the phosphoric acid catalyst, as a re- ric reactions investigated, the electrophilic activation of sult of the acid/base dual function and the steric and elec- imines by chiral phosphoric acid has been proven to be an tronic influence of the substituents (G). attractive and efficient method for the construction of nitrogen-substituted stereogenic centers in optically ac-

substrate recognition site tive forms.14

dual function by G

monofunctional catalyst 3.1 Mannich Reaction

Brønsted basic site O

O

P

O

Brønsted acidic site H Enantioselective Mannich reactions are widely utilized

O stereo & electronic effect for the construction of optically active b-amino carbonyl

G compounds15 that serve as versatile intermediates for the synthesis of biologically active compounds and drug can- Figure 2 Phosphoric acids to be developed as chiral Brønsted acid didates. Highly enantioselective Mannich reactions have catalysts

Biographical Sketch

Masahiro Terada was born at Harvard University in Chemical Society of Japan in 1964 in Tokyo, Japan. He 1999–2000 and moved to Award for Creative Work graduated in 1986 and re- Tohoku University as an (2008), and the Mukaiyama ceived his PhD in 1993 from Associate Professor in Award (2010). His current Tokyo Institute of Technol- 2001. He has been a Profes- research interests are fo- ogy. He was appointed as an sor of Chemistry at the cused on the development of Assistant Professor in Pro- Graduate School of Science, new and useful synthetic fessor Mikami’s Laboratory Tohoku University (Japan) methodologies based on the at Tokyo Institute of Tech- since 2006. He is the recipi- design of novel chiral nology in 1989. He worked ent of the Incentive Award Brønsted acid and base cata- as a postdoctoral fellow in Synthetic Organic Chem- lysts as well as the utilization with Professor M. D. Shair istry, Japan (2003), The of transition-metal catalysts.

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1931 been established using other types of organocatalysts, In the present direct Mannich reaction, it is considered such as proline and its derivatives, chiral secondary that the dual function of the phosphoric acid moiety amines.16 smoothly accelerates the reaction (Figure 3). The enol In 2004, Terada and Uraguchi developed the chiral phos- proton of the acetylacetone tautomer and the O-H proton phoric acid 1 catalyzed enantioselective direct Mannich of 1 function as acidic sites, while the nitrogen atom of 2a reaction of imine 2 with acetylacetone (3).8 Chiral phos- and the phosphoryl oxygen function as basic sites. In the phoric acid 1a exhibited extremely high catalytic activity direct Mannich reaction of 2a with 3, 1 would enable the for the direct Mannich reaction of N-Boc-protected imine formation of a transient structure through a hydrogen- 2aa with acetylacetone (3) (Scheme 1). The resulting b- bonding network that connects the acidic and basic sites amino ketone 4a was obtained in an optically active form with each other (Figure 3a). Thus, phosphoric acid cata- (12% ee). The beneficial effects of the diaryl substituents lyst 1 electrophilically activates 2a through the acidic pro- at the 3,3¢-positions of the binaphthyl backbone are note- ton, and the Brønsted basic phosphoryl oxygen interacts worthy in regards to the enantioselectivity. For instance, with the O-H proton of the enol form of 3. Subsequent performing the direct Mannich reaction using 3,3¢-phenyl- bond recombination results in the formation of Mannich substituted phosphoric acid 1b furnished the correspond- product 4 and the regeneration of catalyst 1 (Figure 3b). ing product in 56% ee. Interestingly, the simple extension More importantly, the reaction proceeds under a chiral en- of the aromatic substitution to the para-position improved vironment created by the chiral conjugate base of 1 the enantioselectivity dramatically. Use of 1d as the cata- through hydrogen-bonding interactions to furnish optical- lyst further increased the enantioselectivity to 95% ee, ly active products 4.

giving the product 4a in nearly quantitative yield.

a) b)

Boc

NH 3

Boc

R)-1 (2 mol%) (

N

G G

O

O +

Ph O

CH Cl , r.t., 1 h

2 2

H

Ph H O

O

O

O H Ar

2aa O O

O 3

( R)-4a

P

P

O

O

H

O

O

O H N

O H

11

2a

Boc

N *

G

1a: G = H 1b: G =

Boc Ar

G

G

4

O

O 92%, 12% ee 95%, 56% ee

P

β-naphthyl

OH

Ph

O hydrogen-bonding network formation of product 4

1c: G = 1d: G = under chiral environment via bond recombination

G

(R)-1

: acidic sites : hydrogen bonds : basic sites 88%, 90% ee 99%, 95% ee

Scheme 1 Direct Mannich reaction catalyzed by 1 Figure 3 Assumed mechanism of enantioselective direct Mannich reaction catalyzed by chiral phosphoric acid 1 The present catalytic reaction was applicable to ortho-, meta-, and para-substituted N-Boc-protected aromatic Akiyama and co-workers independently reported the imines 2a and the corresponding products were obtained Mukaiyama-type Mannich reaction of ketene silyl acetals in excellent chemical yields with high enantioselectivities 5 with imines 2b derived from 2-hydroxyaniline 7,17 (Scheme 2). The reaction proceeded smoothly without (Scheme 3). The introduction of 4-nitrophenyl groups any detrimental effects even on a gram scale and the cata- at the 3,3¢-positions of the catalyst binaphthyl backbone, lyst load could be decreased to 1 mol% while maintaining giving 1e, yielded the best results in terms of catalytic ac- high yield and enantioselectivity. In addition, more than tivity and enantioselectivity. Mannich products 6 were ob- 80% of catalyst 1d could be recovered. tained with high syn-selectivity and the enantioselectivity of the major syn-isomers reached as high as 96% ee. In the

present Mannich reaction, an ortho-hydroxy functionality

Boc introduced onto the N-aryl moiety of the imine is essential

NH

Boc to achieve the high stereoselectivities. Yamanaka, Akiyama,

R)-1d (2 mol%) (

N

Ar O O

+ and co-workers rationalized the re-facial selectivity of the

CH Cl , r.t., 1 h 2 2

Ar H

O

O present reaction on the basis of experimental results and

2a 3 4 density functional theory (DFT) calculations,18 in which

93–99%, 90–98% ee the phosphoric acid catalyst and the imine form a nine- membered cyclic structure (A) through a double hydro-

Ar = gen-bonding interaction.

X X = MeO, Me, Br, F The creation of a new structural motif of chiral phosphoric acids is a challenging task to broaden the scope of chiral Scheme 2 Direct Mannich reaction of imines 2a Brønsted acid catalysis. Akiyama et al. demonstrated that

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1932 M. Terada REVIEW

a)

NO G =

2 Ar

Ar HO

OTMS

O

O

O HO (R)-1e (10 mol%)

P +

2

N OR

toluene OH

O O

1

N R

–78 °C, 24 h

Ar R H

Ar 5

HO

Ar H

2b (R = Ph)

(Ar = 4-F CC H ) HO HO

3 6 4

2c (Ar = Ph)

7 (5 mol%)

+

HN

HN HN toluene

+

CO Me

2

OTMS 2 2

–78 °C, 30 h

CO R CO R Ar

2 2

R R

OMe 1 1

R R 8

syn-6 anti-6 100%, 89% ee

5d

syn-6 anti-6

b)

O S Ar

2

1 2 (87% R = Me = Et E) 5a: R 87 (96% ee) 100% yield : 13

N

O

1 2 = Bn = Et E) R R (87% 5b: 93 (91% ee) 100% yield : 7

Ph P

1 2

= Ph SiO = Me E) R R (91% 5c: 100 (91% ee) 79% yield : 0

3 OH

N

N O

O S Ar

2

Ph

Ar H

(Ar = 4-MeC H ) H O 6 4 O O

2d (Ar = Ph)

NH O

(R)-9 (2 mol%)

P *

+

H

O O

N toluene, r.t., 4 h Ar O

Ph H

O O

10

A 42%, 56% ee O

Scheme 3 Mukaiyama-type Mannich reaction of imines 2b with ke- 3 tene silyl acetals 5 Scheme 4 Other structural motifs of chiral phosphoric acid catalysts chiral phosphoric acid 7, derived from TADDOL, func- catalysis in the direct Mannich reaction of acyclic ke- tioned as an efficient enantioselective catalyst for the 23 Mukaiyama-type Mannich reaction of imines 2c with tones. The reaction of N-aryl imines with acetophenone ketene silyl acetals 5d (Scheme 4a).19 Akiyama et al. also was conducted using a chiral phosphoric acid catalyst in developed a phosphoric acid catalyst derived from an ax- combination with acetic acid as the co-catalyst. The cor- ially chiral biphenol,20 which was also applied to the responding products were obtained in acceptable yields Mukaiyama-type Mannich reaction of ketene silyl acetals even when the amount of acetophenone employed was de- 5 with imines 2b, affording Mannich products in good creased (2 equiv). yields albeit with a slight decrease in enantioselectivities.

Terada et al. also developed phosphorodiamidic acid 9 for Ph

O

use as an efficient Brønsted acid catalyst in the direct O

1f: G = Cl

Mannich reaction of N-acyl imines 2d with acetylacetone P OH

(3) (Scheme 4b).21 Although the asymmetric induction of O

Mannich product 10 is still moderate, phosphorodiamidic Ph

( )-14a

acid 9 is a viable structural motif of chiral Brønsted acid R O

+ catalysts. Further modification of the chiral diamine back- Ph

Ar H

NH O

H N

2

R)-1f (0.5 mol%)

bone or the substituents on the nitrogen atoms of the cata- ( 11 12a

or ( R)-14a (2 mol%)

Ar lyst could lead to its becoming an efficient O

enantioselective catalyst. toluene, 0 °C, 48 h X +

-15

Gong and co-workers applied chiral phosphoric acid cat- anti

X

alysts to the three-component direct Mannich reaction to 13

X = CH , O, NBoc 80–95% ee 83 to >99%, R)-1f 77–92% anti, realize a one-pot reaction among aromatic aldehyde 11, ( 2

X = S 83–98% ee 74–97%, ( 89–98% R)-14a , aniline (12a), and ketones (Scheme 5).22 The reaction of anti cyclic ketones 13 as the nucleophilic component proceed- Scheme 5 Three-component direct Mannich reaction ed smoothly in the presence of 0.5 mol% 1f or 2 mol% 14a, giving desired products 15 in good yields with high enantio- and anti-selectivities. They also extended the 3.2 Nucleophilic Addition of Diazoacetates to coupling method to the reaction of acyclic ketones, such Aldimines as acetone and acetophenone, which gave products in a-Diazocarbonyl compounds have an electronically good yields when the catalyst load was increased to 5 unique sp2-carbon to which the diazo group is attached. mol% and excess amounts of these ketones (10 equiv) Thus, these compounds have a partially negative charge were used, although slight decreases in enantioselectivi- and function as nucleophiles. In the reactions of imines, a- ties were observed. Shortly thereafter, Rueping et al. re- diazocarbonyl compounds are commonly used in aziri- ported achiral Brønsted acid assisted chiral Brønsted acid dine formation reactions (aza-Darzens reaction) under

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1933

Lewis24 and Brønsted25 acid catalyzed conditions. Mean-

while, Terada and co-workers reported an enantioselec- O P O O

PG tive direct substitution at the a-position of diazoacetate H O

using a chiral phosphoric acid catalyst.26 Phosphoric acid N

1

H R

catalyst 1g efficiently promoted the substitution reaction 2 R O C H of a-diazoacetates 16 with N-acyl imines 2e to give 2

Mannich-type products 17, which are b-amino esters hav- N

ing a diazo substituent at the a-position, in optically active N

forms (Scheme 6). Interestingly, the electronic properties addition

of the acyl protective group of the imine nitrogen pro- O

a) PG = b) PG =

foundly affected the enantioselectivity. The para-substit- OMe

NMe uents of the N-acyl aromatic moiety had a marked effect 2 on the enantioselectivity, and the introduction of an

electron-donating dimethylamino moiety gave the best re-

sults. A series of aromatic imines 2e were applicable to 1 R

O

2

O C R these substitution reactions. Para-substituted aromatics PG

2

P O O N

H PG showed excellent enantioselectivities irrespective of their H

O N

H

N

electronic properties. Ortho- and meta-substitutions as N

2

O

R O C O

2 1

R

well as fused-ring systems were also applicable. The thus- P

O

O N

obtained b-amino-a-diazoester products 17 could be H N transformed into common synthetic intermediates, such as B

b-amino acid derivatives, via simple reduction or oxida- C

deprotonation

tion of the diazo moiety. elimination

1

R PG

PG

2

N R O C

2

2

N R O C

2

1 H R

N G = O

O H

N

aziridine

4-Me NC H NH

2 6 4

(R)-1g (2 mol%)

+ t-BuO C H

4-Me NC H N Mannich-type product 2 2 6 4

t-BuO C

2

toluene, r.t., 24 h

Ar

N H Ar

2 Figure 4 Mechanistic proposal for reactions of diazoacetate with

N 2 16a 2e

17 imines

O

Ar =

X in high yields. The electron-withdrawing property of the

O

X N-benzoyl protective group significantly decreased the X = F, Ph, Me, MeO

X = 2-F, 2-MeO, 3-F electron density of the nitrogen atom, effectively sup-

62–74% 75%

84–89% pressing nucleophilic substitution by the nitrogen atom.

97% ee 91–93% ee 95% ee Meanwhile, Zhong and co-workers reported the trans- Scheme 6 a-Substitution reaction of diazoacetate with imines selective aza-Darzens reaction of diazoacetamide 21 with N-Boc aromatic imines 2a (Scheme 8).28 In the presence The phosphoric acid is expected to promote the substitu- of chiral phosphoric acid catalyst 1g, the corresponding tion reaction as a result of its dual function (Figure 4a). In- aziridine products 22 were obtained with excellent trans- tracomplex deprotonation from B by the basic phosphoryl selectivities, in this case, with high enantioselectivities. oxygen would allow the direct substitution of diazoace- Although the dramatic changes in the stereochemical out- tate, giving Mannich-type products without the formation comes have not been clarified yet, the amide moiety may of aziridine products. function as a hydrogen-bond donor site to the phosphoric

Akiyama et al. reported the aziridine formation reaction

t-BuC H ) Si G = (4- OH 4 3

(aza-Darzens reaction) using a-diazoacetate 16b and p- 6

(R)-1h (2.5 mol%) Ar

+

OH H N OMe

methoxyphenyl (PMP)-protected imines 18 prepared in 2

MgSO

4

O

situ from glyoxal monohydrate 19 and 4-methoxyaniline toluene, r.t., 1 h 19

(12b) in the presence of magnesium sulfate (Scheme 7).27 12b

Chiral phosphoric acid catalyst 1h gave the corresponding N

aziridine products 20 with high enantioselectivities and 2

PMP

H CO Et

2 PMP

N

the cis-isomer was formed exclusively. The PMP protec- N

Ar H

16b

tive group would preserve the nucleophilicity of the nitro- Ar

H toluene CO Et O

gen atom and hence the intramolecular substitution by the 2 –30 °C, 23 h

O

-20

nitrogen atom would proceed predominantly via interme- cis 91–100%

18 diate C (Figure 4b). This contrasts the reaction of N-ben- 92–97% ee zoyl imines where Mannich-type products were obtained Scheme 7 Enantio- and cis-selective aza-Darzens reaction

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1934 M. Terada REVIEW

X O O O

+ +

1 2

H N NH

R H OR 2 2

G =

Boc

1123 24

N

N 2 Boc

H

H

1 N

(X = S or O)

(R)-1g (5 mol%) = aromatic or (R

N

Ar +

H PMP cyclohexyl)

CH Cl , r.t., 10 min

PMP Ar H 2 2

O Ph O N

2a H

21

O trans-22

O

90–97%, 88–96% ee P OH

Scheme 8 Enantio- and trans-selective aza-Darzens reaction O

Ph

(R)-14a (10 mol%)

or acid catalyst and affect the configuration of the transient X

G = Ph Si

assembly composed of ternary constituents. 3 HN NH ( R)-1i (10 mol%)

1

* R

2

CO R

3.3 Biginelli Reaction 2

25

1

R) 51–86%, 85–97% ee (

R

= aromatic

CH Cl

2 Gong and co-workers reported the enantioselective 2 ( R)-14a

1

40%, 92% ee ( R) R = cyclohexyl

Biginelli reaction via the three-component coupling of al- 25 °C, 6 d

1

toluene = aromatic R

dehydes 11, (thio)urea 23, and b-keto esters 24 54–98%, 91–98% ee (S)

(R)-1i

1

50 °C, 60 h R = cyclohexyl

54%, 90% ee ( ) (Scheme 9).29 Utilizing the Mannich reaction as the initial S step, the method enabled efficient access to 3,4-dihydro- Scheme 9 Biginelli reaction pyrimidine-2(1H)-one derivatives 2530 that possess a wide

array of pharmaceutical properties and hence are consid- O

S O O

ered to be medicinally relevant compounds. Catalyst 14a F

+ + H

H N NH

having the H -binaphthyl backbone most effectively fur- OMe 2 8 2

F

23a nished the corresponding pyrimidinone derivatives in 24a

moderate to high yields with high enantioselectivities. A 11a S

wide variety of aldehydes 11 are employable in this reac- O

(R)-1i (10 mol%) HN NH

tion. Gong and co-workers further optimized the substitu- HN NH

Cl , 50 °C, 6 d

31 CH OMe

2 2

ent of catalyst 1 in the present Biginelli reaction. Ar

Ar

F

CO Me

2

Me Triphenylsilyl-substituted catalyst 1i was found to pro- CO 2

25a

26

F

vide higher enantioselectivity than that obtained by 14a in Ar = 86%, 91% ee ( S) most cases. In addition, the reaction catalyzed by (R)-1i ref. 32

gave product 25 whose enantiofacial selection is opposite O

that of catalyst (R)-14a even when using the same axial O

N N

chirality of the catalysts. They performed transition-state NNH H

OMe

analysis by DFT calculations to elucidate the reverse of F

N CO Me the enantiofacial selection in these catalyses. They also 2

demonstrated the synthetic utility of the enantioselective F

S)-L-771688

Biginelli reaction in the preparation of optically active in- ( 32 termediate 26 of (S)-L-771688, a selective a1a receptor Scheme 10 Application to asymmetric synthesis of (S)-L-771688 antagonist (Scheme 10). precursor

Gong and co-workers further applied this reaction using

catalyst 1i to the Biginelli-like condensation, employing O

S

O

enolizable ketones, including not only cyclic ketones 13 O + +

or

1

R

H N NHBn 2 Ar H

2 but also acyclic ketones 27, in place of b-keto esters 24 R

n

31 X

11

(Scheme 11). A broad range of cyclic ketones 13 and 28 13 27

1

X = CH , O, NBoc, S

= aliphatic) 27 (R acyclic ketones were applicable to the Biginelli-like 2

2

(R = aliphatic condensation with aromatic aldehyde 11 and N-benzyl- n = 1–3

thiourea (28), giving the corresponding products 29 and or aromatic)

S

30 with excellent enantioselectivities. S

Bn Bn

HN N HN N

or (R)-1i (10 mol%)

2

Ar R

3.4 Vinylogous Mannich Reaction Ar

toluene

1

R

n 50 °C, 6 d

X

The asymmetric Mannich reaction is one of the most ubiq- 30 29

+ regio isomer <20%

uitous carbon–carbon bond-forming reactions in organic 39–86%

2

33–83%, 92–96% ee R = aliphatic

90 to >99% ee

chemistry. The vinylogous extension of this fundamental 2 49%, 61% ee R carbon–carbon bond-forming reaction to nucleophilic = aromatic components, namely, the vinylogous Mannich reaction, Scheme 11 Biginelli-like reaction via three-component coupling

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1935 has been little exploited33 despite its potential to provide ing chiral phosphoric acid catalyst 1k (Scheme 13).36 The efficient access to highly functionalized d-amino carbonyl reaction provided highly valuable d-amino-a,b-unsaturat- compounds bearing a double bond. 2-Siloxyfuran 31 is an ed carboxylic esters 34 in optically active forms with attractive vinylogous nucleophile that has been utilized complete regioselectivities. Schneider and co-workers extensively in vinylogous variants of fundamental trans- also reported the enantioselective vinylogous Mannich formations, such as the aldol reaction,34 because the reac- reaction of vinylketene silyl N,O-acetals with aromatic tions provide g-substituted butenolides, an important imines.37 The piperidine-derived vinylketene silyl N,O- structural motif existing in naturally occurring products acetals proved to be more suitable substrates than their di- and biologically active compounds. Akiyama et al. suc- alkylamine- and pyrrolidine-derived counterparts, fur- cessfully developed the enantioselective vinylogous nishing the corresponding vinylogous products, d-amino- Mannich reaction of 2-trimethylsiloxyfuran (31) with al- a,b-unsaturated amides, in good yields with high enantio- dimines 2b using chiral phosphoric acid catalyst 1j bear- selectivities. ing iodine groups at the 6,6¢-positions of the binaphthyl backbone (Scheme 12).35 A series of aldimines, including 3.5 Aza-Petasis–Ferrier Rearrangement aliphatic ones, were utilized in the present reaction and g- butenolide products 32 were obtained in good yields with Organocatalysis in the direct Mannich reactions of alde- moderate to high diastereo- and enantioselectivities. hydes with aldimines using chiral secondary amine cata- lysts has emerged as a powerful tool to provide b-amino

38

HO aldehydes with high diastereo- and enantioselectivities. HO However, one critical drawback inherent to the methodol-

N ogies reported to date is that aromatic or glyoxylate-

R H HN

R)-1j (5 mol%)

( derived aldimines are employed as adaptive substrates in

syn-32 + 2b

toluene, 0 °C, 18–22 h

R most cases. The enantioselective direct Mannich reaction

+ 38c

O of aliphatic aldimines has largely been unexploited.

O OTMS Terada and Toda developed an alternative strategy to fur-

O

anti-32 31 nish optically active b-amino aldehydes 35 having an ali- phatic substituent (R) at the b-position by combining two

39

I

G catalytic reactions (Scheme 14). The sequence involves -Pr

i initial nickel complex catalyzed Z-selective isomerization O

O

i-Pr G = P of a double bond, followed by chiral phosphoric acid cat-

OH 40

O alyzed aza-Petasis–Ferrier rearrangement, using readily -Pr

i available hemiaminal allyl ethers 36 as the substrate. The G I

R)-1j

( aza-Petasis–Ferrier rearrangement of hemiaminal vinyl

anti-32 -32

syn ethers 37 proceeded via carbon–oxygen bond cleavage of

9 R = Ph 100% yield 91 (82% ee)

: the ether moiety by acid catalyst 1l, generating a reactive

31 R = 4-F CC H 95% yield 69 (99% ee) : 3 6 4

3 R = 4-O NC H 85% yield 97 (96% ee) : iminium intermediate and an enol form of the aldehyde. 2 6 4

12 84% yield 88 (92% ee) i-Pr R = Subsequent recombination with carbon–carbon bond for-

Scheme 12 Vinylogous Mannich reaction of 2-trimethylsiloxyfuran

Boc Boc

(31) HN

HN

[Ni-H] (cat.)

O R O R

(±)-37 (±)-36

Z >95%

G =

i-Pr

PMP

t-Bu G =

OTBS

N (R)-1k (5 mol%)

+

OEt i-Pr t-BuOH–2-Me-2-BuOH = 1:1:1 THF– Boc R H

O HN

33 (R)-1l (2 mol%)

–30 °C, 3–48 h 2f

(±)-37

H R

AcOEt or acetone

>95% Z

PMP 40 °C, 2–7 h

NH O 35

R OEt Boc Boc

HN HN 34

NaBH +

4

R = Ph 87%, 88% ee

HO HO R R

MeOH, 0 °C, 1 h

R = 4-EtC H 88%, 92% ee 6 4

83%, 82% ee R = t-Bu

anti syn

: 5 95 70% yield (94% ee)

Scheme 13 Vinylogous Mannich reaction of silyl dienol ether 33 R = Bn

: 5 95 55% yield (97% ee) R = isobutyl

: 5 95 75% yield (>99% ee) R = cyclohexyl

: 7 93 87% yield (98% ee)

Schneider and Sickert were the first to demonstrate the R = Ph catalytic and enantioselective vinylogous Mannich reac- Scheme 14 Double-bond isomerization/aza-Petasis–Ferrier rear- tion of acyclic silyl dienol ether 33 with aldimines 2f us- rangement sequence for the preparation of b-amino aldehydes 35

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1936 M. Terada REVIEW mation resulted in rearranged products 35, thus providing Tsogoeva and Zamfir developed a highly enantioselective b-amino aldehydes having not only aliphatic but also aro- Strecker-type reaction of hydrazones 42 using chiral matic substituents at the b-position with high anti- and phosphoric acid 1e (Scheme 16).46 Readily prepared and enantioselectivities. air-stable aliphatic hydrazones 42 are employable for this reaction, giving synthetically valuable a-hydrazinonitriles 44 in moderate to good yields with high enantioselectivi- 4 One-Carbon Homologation Reactions via ties. The thus-obtained a-hydrazinonitriles 44 can be Activation of Imines readily transformed into the corresponding a-hydrazino acids 45 in a quantitative manner under acid hydrolysis. 4.1 Strecker Reaction and Related Reactions The authors also proposed that the active catalyst is an in situ generated O-silylated BINOL-phosphate, thus shift- The hydrocyanation of imines, namely, the Strecker reac- ing the mode of catalysis from a Brønsted acid catalysis to tion, offers a practical route to a-amino acids or 1,2-di- a Lewis acid catalysis. amines, which can be transformed from the corresponding

a-amino nitrile products through simple hydrolysis or re-

NO G = duction of the nitrile moiety. The development of the cat- 2

alytic enantioselective Strecker reaction is hence a vital NO

2 (R)-1e (5 mol%)

H -BuOH (20 mol%) step toward the efficient synthesis of these amines in op- t

N

+ TMSCN

tically active forms. A number of methods for the enan- N

CH Cl , –10 °C, 3 d 2 2

43

tioselective Strecker reaction have been intensively O R H

(R = aliphatic) investigated using either chiral metal catalysts or organo- 42

41

NO catalysts. Chiral phosphoric acid catalysts were also suc- 2

H

HCl

NH ⋅ cessfully applied to the enantioselective Strecker reaction 2 N HCl HN

(Scheme 15). Rueping et al. were able to attain excellent HN

O R COOH

R performance using chiral catalyst 1m, which has sterically CN

45 demanding 9-phenanthryl substituents at the 3,3¢-posi- 44

tions of the binaphthyl backbone.42 The method offers ef- 26–95%, 71–93% ee ficient access to a broad range of aromatic amino nitriles Scheme 16 Hydrocyanation of hydrazones 42 derived from alipha- 39 with high enantioselectivities (Scheme 15a). They also tic aldehydes developed the enantioselective Strecker reaction of ketimines 40 catalyzed by the same chiral phosphoric acid 4.2 Aza-Henry Reaction 1m to give products 41, having a chiral quaternary stereo- genic center, with moderate to high enantioselectivities The synthesis of b-nitro amines via the addition of nitroal- (Scheme 15b).43,44 kanes to imines, or the so-called aza-Henry reaction, is an attractive tool for the creation of carbon–carbon bonds.

The products obtained can be readily converted into vici-

a) nal diamines and a-amino acids by simple reduction and

G = N the Nef reaction, respectively, highlighting the several im-

portant synthetic applications of these compounds. In this

Ar H X

( R)-1m (10 mol%)

HN context, enantioselective versions of the aza-Henry reac- 2g

toluene, –40 °C, 2–3 d

+ Ar X CN tion have been actively investigated using chiral metal

47

HCN complexes and organocatalysts. Rueping and Antonchick

39

38 demonstrated the enantioselective direct aza-Henry reac- X = H 55–97%, 85–99% ee

53–87%, 86–96% ee X = OMe tion of a-imino esters 2h with nitroalkanes 46 using chiral

b) phosphoric acid catalysts (Scheme 17).48 Catalyst 14b,

N with its sterically demanding triphenylsilyl substituents,

Ar X

R)-1m (5 mol%)

( significantly accelerated the reaction to provide b-nitro-a-

HN

40

* * amino acid esters 47 in good yields. A variety of nitroal-

+ toluene, –40 °C, 3 d Ar X

CN kanes were applicable to this reaction, giving desired HCN

41

38 products 47 with high diastereo- and enantioselectivities.

X = OMe 81–95%, 56–72% ee

X = Br 69–90%, 76–80% ee

Scheme 15 Strecker reaction 4.3 Imino-Azaenamine Reaction Formaldehyde dialkylhydrazones, such as azaenamines In contrast to the Strecker reaction that involves the hy- (nitrogen analogues of enamines), possess a carbon atom drocyanation of imines, the cyanation of hydrazone to that shows nucleophilic character, and are thus utilized as give synthetically valuable a-hydrazinonitriles is poorly formyl anion equivalents.49 The reaction enables efficient exploited45 despite its ability to provide efficient access to one-carbon homologation of electrophilic substrates. a-hydrazino acids of therapeutically intriguing molecules. Rueping et al. utilized this nucleophilic species in a reac-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1937

SiPh

3 oxazoles 51 in good yields with moderate to high

O enantioselectivities. O

P

OH

O

O

CF

3

O

CN

+ +

N

SiPh

3

1

R H

2 PMP H N

2

X R

2 (R)-14b (10 mol%)

N R

1

= aliphatic) 11 (R

12c

+

50 (X = O or CH ) 2

1

benzene, 30 °C, 12–166 h

R O C H

NO 2 2

1 = Me) 46

2h (R

CF

3

PMP (10 equiv)

G = HN

2

R + syn-47

HN

MeO C 2

R)-1k (20 mol%) (

O

1

NO R 2

N X anti-47

toluene, –20 °C, 16 h N

2

R = Me 61% yield 91 (92% ee) : 9

2

R

2

R = Me(CH ) 65% yield 90 (92% ee) : 10

2 4

51

2

R = Bn 93% yield 93 (88% ee) : 7 51–93%, 56–90% ee Scheme 17 Aza-Henry reaction of a-imino esters 2h Scheme 19 Three-component reaction of isocyanides, aldehydes, and anilines tion of imines 2a under the influence of chiral phosphoric acid 14c (Scheme 18).50 The reaction of pyrrolidine- derived methylenehydrazine 48 with a series of N-Boc ar- omatic imines 2a provided a-amino hydrazones 49 with 5 Friedel–Crafts and Related Reactions moderate to high enantioselectivities. Products 49 have been proven to be useful synthetic intermediates that can Enantioselective Friedel–Crafts reactions using metal- be readily transformed into a diverse array of chiral nitro- based chiral catalysts or chiral organocatalysts have been gen-containing compounds, such as a-amino aldehydes, investigated intensively, and provide atom-economical a-amino nitriles, and 1,2-diamines, without racemization. methods for the production of alkylated arenes in optically

active forms.55 The chiral phosphoric acid catalyzed Boc Friedel–Crafts reaction was first accomplished via the ac-

N tivation of imines, but currently, the scope of electrophilic

Boc Ar H

HN components has been broadened to include (a,b-unsatur-

2a

(R)-14c (10 mol%)

N ated) carbonyl compounds, nitroalkenes, and others.

+

Ar N

CHCl , 0 °C, 16 h 3

H N

N 49

H

48–82%, 74–90% ee 5.1 Friedel–Crafts Reaction via Activation of 48 Aldimines or Hemiaminals

G The Friedel–Crafts reaction via the activation of electro-

O

O philes functionalized by a nitrogen atom, such as imines,

P (R)-14c: G = OH is undoubtedly the most practical approach to introduce a

O nitrogen-substituted side chain onto aromatic compounds.

G The enantioselective version of the Friedel–Crafts reac- Scheme 18 Imino-azaenamine reaction of hydrazone 48 tion of imines with electron-rich aromatic compounds en- ables efficient access to enantioenriched aryl methanamine derivatives. Several excellent approaches to 4.4 Addition of Isocyanide to Aldimines highly enantioselective Friedel–Crafts reactions have Isocyanides are useful one-carbon sources in organic syn- been established using chiral phosphoric acid catalysts. thesis. The Passerini three-component reaction51 and the 52 Terada and co-workers successfully demonstrated for the Ugi four-component reaction are representative trans- first time an enantioselective 1,2-aza-Friedel–Crafts reac- formations that use isocyanides as one-carbon homologa- tion of 2-methoxyfuran (52) with N-Boc aldimines 2a us- tion reagents having a formally divalent carbon center, ing a catalytic amount of chiral phosphoric acid and the isocyanides can react with electrophiles and nu- (Scheme 20).56 In the presence of 2 mol% 1n having ster- cleophiles. Wang, Zhu, and co-workers developed enan- ically hindered 3,5-dimesitylphenyl substituents, the cor- tioselective Ugi-type multicomponent reactions53 that 54 responding Friedel–Crafts products 53 were obtained involved the a-addition of isocyanides to imines cata- with excellent enantioselectivities, irrespective of the lyzed by chiral phosphoric acids (Scheme 19). Catalyst 1k electronic properties of the aromatic imines 2a employed. efficiently accelerated the three-component reaction of Most notable was that the reaction could be performed in aliphatic aldehydes 11, aniline derivative 12c, and a-iso- the presence of as little as 0.5 mol% 1n without any detri- cyanoacetamides 50, giving 2-(1-aminoalkyl)-5-amino- mental effects even on a gram scale (Ar = Ph: 95%, 97% ee).

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1938 M. Terada REVIEW

Boc N syl imine 2i with unprotected indole 56a (Scheme 22a),

coordination between the phosphoric acid and both com-

Boc Ar H

NH

2a ponents, the imine and the indole, was observed by DFT

( R)-1n (2 mol%)

O 61 +

Ar calculations of the transition states. These components

OMe

(CH Cl) , –35 °C, 24 h

2 2

O were brought together under the chiral environment creat-

OMe

53 ed by the chiral phosphoric acid catalyst through hydro-

82–96%, 86–97% ee 52 gen bonds formed between the OH proton of the phosphoric acid and the nitrogen atom of imine 2i, as well

as the NH proton of indole 56a and the phosphoryl oxy- : G =

1n gen. It is noteworthy that the enantioselectivities were as high as that observed in the reaction using unprotected in- Scheme 20 1,2-Aza-Friedel–Crafts reaction of N-Boc imines 2a doles 56a, even when N-protected indoles 56b and 56c

with 2-methoxyfuran (52) were employed (Schemes 22b and 22c).

1

PG

The synthetic utility of this transformation is highlighted NH

1 PG

1 (cat.)

by the derivatization of the furyl ring to form a g-buteno- N

Ar * R

R

lide (Scheme 21). As the g-butenolide architecture is a +

N Ar H N

2

2 common building block in the synthesis of various natural 2 PG PG

57 products, Friedel–Crafts reaction product 53 represents a 56

new addition to the synthetic precursors of nitrogen- toluene

1

68–90%

2i: PG = Ts

–60 °C a)

G =

2

89 to >99% ee 56a: PG containing molecules. The aza-Achmatowicz reaction, = H

followed by reductive cyclization of 1,4-dicarbonyl inter- 15 min to 2 h

S)-1o (10 mol%)

mediate 54 under Luche conditions, produced g-buteno- ( 4 Å MS

1

Cl CH

G = Ph 89–99% Si 2d: PG = PhCO-

2 2 lide 55 in good yield. 3

b)

2 –30 °C 90–97% ee ( S)-1i (5 mol%) 56b: PG = Bn

15 h

NHBoc

NHBoc Ph

NBS, NaHCO

(CHCl )

3 2 2 Ph O

1

65–91%

2a: PG = Boc

Ph

–40 °C

c) OMe

G =

Et O–H O, 0 °C, 30 min

2 O 2 2

82–98% ee

56c: PG = TBS

24 h O OMe

53a Ph 54

97% ee 90% (R)-1p (2–10 mol%)

NHBoc Scheme 22 1,2-Aza-Friedel–Crafts reaction of indoles 56 with aro-

O

7H O, NaBH

CeCl ⋅ 3 2 4

Ph

O matic imines

MeOH, –78 °C to r.t., 5 h

55

95%, 85% , 96% ee syn The reaction of a-imino esters as an electrophilic compo- nent was also reported independently by Hiemstra and co- Scheme 21 Synthetic utility of furan-2-yl amine products workers (Scheme 23a)62 and You and co-workers (Scheme 23b).63 In Hiemstra’s approach, indolyl glycine Further applications of the chiral phosphoric acid cata- products 58a were obtained with opposite absolute con- lyzed 1,2-aza-Friedel–Crafts reaction were investigated figurations, depending on the sulfur substituent as well as by several research groups and the developed methods the structures of catalysts 1i and 14d, even when chiral yielded a diverse array of optically active aryl methan- phosphoric acids having axial chirality in the same R- amine derivatives with high enantioselectivities. In partic- configuration were employed. ular, the 1,2-aza-Friedel–Crafts reaction of indoles was Ma and co-workers reported an enantioselective synthesis intensively investigated because the enantioenriched of trifluoromethylated indole derivatives via the three- products, namely, 3-indolyl methanamine derivatives, are component coupling reaction among trifluoroacetalde- widely known as valuable structures of pharmacophores hyde hemiaminal 59, aniline derivative 12, and indoles and are present in thousands of natural products and many 56a (Scheme 24).64 Catalyst 1q having bulky 2,4,6-triiso- medicinal agents possessing versatile therapeutic ef- 9b 57 58 propylphenyl substituents worked well, giving the cor- fects. You and co-workers (Scheme 22a), Antilla and responding products 60 in excellent yields. In the present co-workers (Scheme 22b),59 and Terada et al. 60 Friedel–Crafts reaction, the aniline derivative exhibited a (Scheme 22c) almost simultaneously developed the marked effect on the enantioselectivity: 3,4,5-trimethoxy- highly enantioselective Friedel–Crafts reaction of indoles aniline (12d) gave products 60 with much higher enantio- with aromatic imines. Their approaches differed in the selectivities than 4-methoxyaniline (12b). Although the substituents (G) of catalysts 1 introduced at the 3,3¢-posi- introduction of a substituent at the 2-position of the indole tions of the binaphthyl backbone and the protective group ring resulted in slight decreases in both reactivity and of imines 2, and more interestingly, with or without the enantioselectivity, a wide range of functional groups, in- protective group at the nitrogen atom of indoles 56. cluding electron-donating and electron-withdrawing sub- Goodman and Simón reported that, in the reaction of N-to-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1939

a) a)

SR

Ph

N PhOC

G = Ph Si Me

3 Me NH

( S)-1i (5 mol%)

N N O RS

N MeO C H

2

NH

Ar

+

* 2j

R)-1i or (R)-14d (5 mol%) (

CHCl

3 R

R

Ar H

+

–60 °C, 23–41 h

MeO C *

MS, 0 °C, 24 h 2 2d 62a

61a

66–97%, 42 to >99% ee

N

b)

CHPh H 2

58a

N

PyO S

G = Ph Si 2

O H 3

N

NH

O

H

H

( R)-1i (10 mol%)

56aa N

P

N R

R

+ SO OH Ar

2 *

O toluene, r.t., 12 h N

61b (R = H)

62b CHPh

2 H Ar

52–80%, 64–95% ee 2k (R)-14d

c)

benezene–toluene (4:1)

(R)-1i: G = Ph Si R = 2-nitrophenyl S) 86% ee (

3

H

5 Å MS G = Ph Si

3

N

Ts

( S)-1i (10 mol%)

N

Cl CH

2 2

C R)-14d ( R = Ph R) 88% ee ( +

3

3 Å MS

toluene, –40 °C, 5–80 min

Ar H

R

2i b) 63a

PMP

N

Ts Ts

G = NH

NH

1

H H

R O C H

2

PMP

N

N

p-benzoquinone

NH

1

Ar

= Et) 2h (R Ar

( S)-1m (10 mol%)

+ 2

* EtO C R 2

5 Å MS

R

64 R

65

N

toluene, –50 °C, 1.5 h

H 80–97%, 86 to >99% ee

2 R

58b

N 85–93%, 51–87% ee

H Scheme 25 1,2-Aza-Friedel–Crafts reaction of pyrroles 61 and 4,7- 56a dihydroindoles 63a Scheme 23 1,2-Aza-Friedel–Crafts reaction of indoles 56 with a- imino esters derivatives 57 were obtained exclusively (see Scheme 22). stituents, were tolerated by the indole ring. The authors extended this methodology to difluoroacetaldehyde hemi- Enders et al. demonstrated the one-pot synthesis of enan- aminal to demonstrate the scope of this three-component tioenriched isoindolines based on a consecutive transfor- reaction. mation that involved a chiral Brønsted acid catalyzed

Friedel–Crafts reaction followed by a base-catalyzed aza-

OMe Michael addition reaction using indole (56aa) and bifunc- 2

R 68 OH

OMe tional e-iminoenoates 2l as substrates (Scheme 26). In

++

C OMe F this one-pot transformation, the initial Friedel–Crafts re-

3

N

1

R

H N OMe H

2

59 action catalyzed by chiral BINOL-derived N-triflyl phos- 12d

56a phoramide 66, which was originally developed by

i-Pr

OMe

MeO

NTs

i-Pr G =

NH

+ H

MeO NH

i-Pr

2 R

( S)-1q (10 mol%)

CO Me

2

NH

F C

56aa 3

2l

4 Å MS

N DBU

1

R

CH Cl , r.t., 1–4 d

H 2 2

( R)-66a (10 mol%) (50 mol%)

60

NTs

1 15 min

CH Cl , r.t., 10 min

2 2 R = H 83–99%, 90–98% ee

1 2

R = Me, R = H 80%, 79% ee

CO Me 2

67

Scheme 24 Friedel–Crafts reaction via three-component coupling G 94%, 90% cis, 90% ee of trifluoroacetaldehyde hemiaminal 59, aniline derivative 12d, and O

indoles 56a O P

NHTf

O

The enantioselective Friedel–Crafts reactions catalyzed G

(R)-66 by chiral phosphoric acids were further applied to such G

electron-rich aromatic compounds as pyrroles 61

O

(Schemes 25a and 25b)65,66 and 4,7-dihydroindoles 63a O (R)-66a: G = NO P

67 2 NHTf (Scheme 25c). The reaction of 4,7-dihydroindoles 63a O yielded 2-substituted indole derivatives 65 after oxidation of Friedel–Crafts products 64. This approach comple- G ments current studies of enantioselective Friedel–Crafts Scheme 26 One-pot synthesis of enantioenriched isoindolines 67 reactions of parent indoles 56, where 3-substituted indole based on chiral Brønsted acid catalyzed Friedel–Crafts reaction/base- catalyzed aza-Michael addition sequence

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1940 M. Terada REVIEW

Yamamoto and Nakashima,69 followed by the DBU- nyliminium ions as intermediates, generated from the promoted intramolecular aza-Michael addition, furnished reaction of N-sulfenyl tryptamines 73 with aldehydes 11, isoindoline derivatives 67 in good yields with high in the Pictet–Spengler reaction and established an effi- diastereo- and enantioselectivities. cient method for the preparation of tetrahydro-b-carboline derivatives 74 in optically active forms using chiral phos- Rueping and Nachtsheim reported the nucleophilic substi- 73 tution reaction of g-alkyl-g-hydroxylactams 68 with in- phoric acid 1r (Scheme 28b). With this approach, not dole (56aa) catalyzed by chiral phosphoramide 66 only aromatic but also aliphatic substituents can be intro- (Scheme 27).70 The reaction proceeds via in situ generat- duced to the stereogenic center. ed N-acyliminium ions 69 from 68 under the influence of

66b. The reaction provides optically active g-lactams 70 a)

X

CO Et

2 S)-1q (20 mol%) having a quaternary stereogenic center at the g-position. (

+ Et CO RCHO 2

SO

The method furnishes an efficient approach to the g-ami- Na 2 4

11

NH

2

N

toluene or CH Cl

2 2

(R = aliphatic no acid derivatives of biologically relevant molecules and H

–30 to –10 °C, 3–6 d or aromatic)

can be extended to other nucleophilic components. 71

X

CO Et 2

SiPh i-Pr

3

CO Et 2

NH

O

N

1q: G = i-Pr O

H

P

R

NHTf

72 i-Pr O

40–98%, 62–94% ee

b)

SiPh 3

O R O R)-66b (5 mol%) (

+

R)-1r (5–10 mol%) (

N

N

R

HO

CH Cl , –65 to 20°C, 2–3 d

+ RCHO 2 2

N

HN

Ph

Ph 3 Å MS, BHT

N H

S

11

H

69 56aa 68 (R = aliphatic) toluene, 0 °C, 0.5–24 h

(R = aliphatic

Ph Ph

or aromatic)

Ph

73

R O

HCl

∗ N

CF

3 Ph

NH

N

N

PhSH

H H

70

1r: G = R

39~93%, 53~84% ee

74

CF 77–90%, 30–88% ee

Scheme 27 Nucleophilic substitution reaction of g-alkyl-g-hydro- 3

tert-butyl)-4-hydroxytoluene

xylactams 68 with indole BHT: 3,5-di( Scheme 28 Pictet–Spengler reaction of tryptamine derivatives with aldehydes 5.2 Pictet–Spengler Reaction The Pictet–Spengler reaction of tryptamines and phenyl Hiemstra and co-workers applied their iminium ion strat- ethylamines with an aldehyde is a powerful and efficient egy to natural product synthesis and accomplished the method for the preparation of tetrahydro-b-carbolines and asymmetric total synthesis of the tetracyclic indole alka- tetrahydroisoquinolines, respectively,71 which are struc- loid (–)-arboricine (78) using the enantioselective Pictet– 74 tural motifs of many alkaloids and related naturally occur- Spengler reaction as a key step (Scheme 29). The Pictet– ring compounds. The enantioselective variants of the Spengler reaction of N-allyl-substituted tryptamine 75 Pictet–Spengler reaction are in high demand because of with aldehyde 76 catalyzed by phosphoric acid 14b gave the versatile synthetic applicability of the corresponding the corresponding product 77 in good yield with high products to biologically active molecules. The reaction enantioselectivity. consists of a two-step transformation: an initial dehydra- tive imine formation, followed by an intramolecular 5.3 Friedel–Crafts Reaction via Activation of Friedel–Crafts reaction. An excess amount of Brønsted Nitroalkenes acid is usually required to promote the reaction. List and co-workers accomplished the enantioselective Pictet– The enantioselective Friedel–Crafts reaction of indoles Spengler reaction by directly reacting substituted with nitroalkenes has been known for a long time. This re- tryptamines 71 with aldehydes 11 in the presence of chiral action offers considerable synthetic utility by enabling ac- phosphoric acid catalyst 1q (Scheme 28a).72 The method cess to versatile precursors for the preparation of indole provided efficient access to tetrahydro-b-carboline deriv- alkaloids. The enantioselective catalysis of this reaction atives 72 with high enantioselectivities, although the in- has been investigated by using chiral catalysts, including 75 troduction of a gem-disubstituent adjacent to the reactive metal complexes and organic molecules. However, the imine was required to suppress competing aldol pathways. enantioselectivities were not always good. Akiyama and Hiemstra and co-workers circumvented this intrinsic co-workers developed a highly enantioselective Friedel– drawback, the requirement of a gem-disubstituent, by im- Crafts reaction of nitroalkenes 79 with indoles 56a using 76 plementing an iminium ion strategy. They used N-sulfe- chiral phosphoric acid 1i (Scheme 30). They pointed out

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1941

SiPh

3 cellent performance; however, the syringe pump tech-

O nique was required to achieve high enantioselectivities

O

P because of considerable background reaction. Aromatic

OH

O nitroalkenes 79 were useful substrates for this transforma-

H O

SiPh tion. Meanwhile, the use of aliphatic nitroalkenes signifi- 3

HN R)-14b (2 mol%)

( cantly decreased the enantioselectivity. Oxidation of + N

H O

4 Å MS Friedel–Crafts products 84 by p-benzoquinone provided

I

toluene, r.t., 24 h

O 2-substituted indole derivatives 85 in excellent yield with- 75 76 out racemization. As shown in Scheme 30, this approach complements the reaction of parent indoles 56 in which 3-

substituted indole derivatives 80 are obtained exclusively.

N

N N

N

H

H H

I

O G = H

O

O

S)-1g (0.5 mol%) (

77 78

R

+ X

NO

2 4 Å MS 86%, 89% ee (–)-arboricine N

H

79

CH Cl –benzene (1:1), r.t. 2 2

63a Scheme 29 Synthetic application of the enantioselective Pictet– syringe pump addition over 2 h

Spengler reaction

R R

p-benzoquinone

X X

N N NO NO

2 the beneficial effects of molecular sieves on both chemi- 2 H H

85 cal yield and enantioselectivity in the present Friedel– 84

Crafts reaction. Among the molecular sieves tested, the R = aromatic 93–98%, 88–97% ee

R = cyclohexyl 94%, MS 3A exhibited the best results, giving Friedel–Crafts 24% ee products 80 in good yields with high enantioselectivities. Scheme 31 Friedel–Crafts reaction of 4,7-dihydroindoles 63a with The method is applicable not only to aromatic but also to nitroalkenes 79 aliphatic nitroalkenes. Friedel–Crafts product 80 can be readily transformed into tryptamine derivative 81 via a simple reduction of the nitro group, giving melatonin ana- Shortly thereafter, You and co-workers further extended logue 82 and tetrahydro-b-carboline derivative 83 without the substrate scope to include pyrroles 61b in the enantio- racemization. The reaction of N-methylindole 56d provid- selective Friedel–Crafts reaction of nitroalkenes 79, giv- ing products 86 in high yields and enantioselectivities ed a racemic Friedel–Crafts product in low yield and 78 hence, the N-H moiety of indoles was deemed essential (Scheme 32). for accelerating the reaction as well as controlling the ste-

reochemical outcome.

X

G =

N

G = Ph Si

3 X H

R R)-1i (10 mol%) (

61b

NO

2 S)-1g (5 mol%) ( +

R X

3 Å MS

+

N

NO 79

4 Å MS N

2

H benzene–DCE (1:1)

R H

86

CH Cl –benzene (1:1)

NO 2 2 –35 °C, 2–5 d 2 56a

r.t., 3~24 h

79

syringe pump addition over 2 h

R Ph

X

NO NH

[H] 2 2 R = aromatic 81–94% ee 87–94%,

ortho-substituted (2-BrC H )

11% ee 81%, 6 4

(X = H, R = Ph)

N N R = cyclohexyl <5%

H H 81

80 Scheme 32 Friedel–Crafts reaction of pyrroles 61b with nitro- R = aromatic 63–84%, 90–94% ee

R = aliphatic 57–77%, 88–91% ee alkenes 79

Ph

Ph 5.4 Friedel–Crafts Reaction via Activation of H

N

Ac Carbonyl Compounds

NTs

N

H

N A number of enantioselective transformations have been

H Ph

82 83 established using chiral phosphoric acids via the activa- Scheme 30 Friedel–Crafts reaction of indoles 56 with nitroalkenes tion of imines and related nitrogen-substituted functional- 79 ities. However, the activation of carbonyl compounds, including a,b-unsaturated carbonyl compounds, by chiral phosphoric acids has been limited and hence it is a chal- You and co-workers employed 4,7-dihydroindoles 63a, lenging task to expand the synthetic utility of chiral phos- instead of indoles 56, in the Friedel–Crafts reaction with phoric acid catalysts. Although the Friedel–Crafts nitroalkenes 79 (Scheme 31).77 Catalyst 1g displayed ex-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1942 M. Terada REVIEW

reaction with a,b-unsaturated carbonyl compounds in- a)

O

volves fundamental transformations, simple a,b-unsatur- R

(R)-66b (5 mol%)

+

CO Me ated ketones are still challenging substrates in the chiral Ar

2

CH Cl , –75 °C, 15–24 h 2 2

89a phosphoric acid catalyzed Friedel–Crafts reactions. Only N

Me

moderate enantioselectivities were reported by Zhou, He, 56d

Ar O

and co-workers in the Friedel–Crafts reaction of chalcone R

SiPh

3

CO Me

derivatives 87 with indole (56aa) using H8-BINOL- 2

O

N

derived chiral phosphoric acid 14e as catalyst O

Me

P

79 90

(Scheme 33). NHTf

O 43–88%, 80–92% ee

SiPh 3 O

(R)-14e (2 mol%) (R)-66b

+

1 2

Ar Ar

b)

CH Cl , 25 °C, 24 h

2 2

87 N

H

R

O

56aa

1 (S)-66c (5 mol%) Ar O

+ G

CO Et Ar

2

O, –60 °C, 1–30 h Et N

2

2

Ar 89b Me

O

O 63b R

N

P H

88 OH

G O

CO Et 67–89%, 34–56% ee

2 N *

Me

O G

O

Ar O

P

91

(R)-14e: G = Cl NHTf

O

59–96%, 87–98% ee

G

p-benzoquinone

Scheme 33 Friedel–Crafts reaction of chalcone derivatives 87 with (Ar = Ph, R = H)

-Pr

indole i

( S)-66c: G = i-Pr

CO Et

2

N *

On the other hand, activated b,g-unsaturated a-keto esters * Me

i-Pr

O

89 functioned as efficient electrophiles in the enantio- Ph selective Friedel–Crafts reaction catalyzed by chiral phos- 92 80 phoramides 66 (Scheme 34). Rueping et al. and You and Scheme 34 Friedel–Crafts reaction of b,g-unsaturated a-keto esters 81 co-workers independently reported the enantioselective 89 with indole derivatives Friedel–Crafts reactions of b,g-unsaturated a-keto esters 89 with N-methylindole 56d (Scheme 34a) and N-methyl- separable as a stable isomer. After optimization of the cat- 4,7-dihydroindole 63b (Scheme 34b), respectively. The alyst substituents and the reaction conditions, the authors use of chiral N-triflyl phosphoramide 66, which was de- succeeded in obtaining bisindolyl product 93 in an atrop- 69 veloped by Yamamoto and Nakashima and is a stronger isomeric ratio of 81:19 using catalyst 66d.

acid than chiral phosphoric acid, is crucial for the acceler- ation of the reaction. The C3 and C2 functionalization of G

the indole derivatives was accomplished to give 90 and O

92 O R)-66d: G = , respectively, in a highly enantioselective manner. ( P

NHTf

Rueping et al. also reported interesting regioselectivity O

(1,2- vs. 1,4-addition) in the Friedel–Crafts reaction of G b,g-unsaturated a-keto esters 89 with N-methylindole 56d Me

by tuning the steric and electronic effects of the substitu- N

N

CO Me

2 ents introduced at the 3,3¢-positions of phosphoramide Me

56da

(R)-66d (5 mol%)

catalysts 66. When a sterically demanding triphenylsilyl Ph +

toluene, –78 °C

group was introduced at the 3,3¢-positions of the binaph- O

N

thyl backbone to give catalyst 66b, 1,4-addition products Me

CO Me Ph 2

93 90 were obtained exclusively (Scheme 34a). In contrast, 89aa

when aryl groups were introduced at the 3,3¢-positions, 62% ee the catalytic reaction yielded predominantly bisindolyl 56da

product 93, which was derived from intermediary 1,2-ad-

HO CO Me MeO C 2

dition product 94 under the acid-catalyzed conditions 2

Ph

80 Ph R)-66d

(Scheme 35). The formation of bisindolyl products is (

– H O

well known in the reactions of aldehydes, ketones, and 2

N

N R)-66d (

Me 1,2-diketones with indole derivatives catalyzed by Lewis Me

and Brønsted acids.82 However, most interestingly, this 94 95 bisindolyl product 93 exhibited atropisomerism and was Scheme 35 Formation of atropisomeric bisindolyl product 93 via 1,2-addition reaction

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1943

CF You and co-workers focused their attention on the forma- 3

tion of intermediary vinylogous iminium ion 95 during the

G =

transformation into bisindolyl products (Scheme 35). TsHN

Ar

CF

They successfully demonstrated the tandem intermolecu- 3 (S)-1s (5 mol%)

lar/intramolecular Friedel–Crafts reaction of indole 56a +

5 Å MS

R

N

N benzene or m-xylene, r.t., 4–52 h

with 2-formylbiphenyl derivatives 96 catalyzed by chiral Me H

83 56da phosphoric acid 1o (Scheme 36). In general, the use of 99 molecular sieves enhanced the chemical yield and the

enantioselectivity, because water is generated during the Ar

*

course of the second Friedel–Crafts reaction. Among NMe

those screened, MS 5A was the best, giving fluorene de- R

N

rivatives 97 in good yields with high enantioselectivities. H 100 In the reaction of N-methylindole derivative 56d, both the 64–96%, 45–68% ee reaction rate and the enantioselectivity (35% ee) deterio- Scheme 37 Enantioselective synthesis of unsymmetrically substitu- rated considerably and hence the N-H moiety of indoles ted triarylmethanes 100 56a functions not only to accelerate the reaction but also to efficiently control the stereoselectivity in the interme- diary benzylidene indolium ion 98. trifluoromethyl alkyl ketone to afford the desired product in high yield albeit with a slight decrease in enantioselec- tivity. The method is applicable to the reaction of difluo-

romethyl- and perfluoroethyl-substituted phenyl ketones,

G =

OMe MeO giving the corresponding products with high enantioselec- 2

R tivities, and hence provides an efficient route to the asym-

S)-1o (5 mol%)

( metric synthesis of tertiary alcohols bearing a fluorinated +

OHC

5 Å MS alkyl group in a highly enantioselective manner. Ma and

HN

CCl , –15 °C to r.t., 0.33–24 h 4

1

R co-workers also reported the enantioselective Friedel–

3

R 56a Crafts alkylation of indoles 56a with trifluoroacetoacetate

96 86

OMe 103 (Scheme 38b). Optically active trifluoromethylated

2 MeO

R tertiary alcohols 104 were also obtained with moderate to

H high enantioselectivities.

MeO OMe

HN

2 R

O

1 R

CF

3

3

HO

R

2

R CF

2 97 3 R

101

37–96%, 73–96% ee

N

(S)-1q (5 mol%)

1

3 H

1

R R R a)

N

Cl , r.t., 1.5–3 d CH

2 2

98 H

102

2

R = aromatic 85–98% ee Scheme 36 Tandem intermolecular/intramolecular Friedel–Crafts 52–99%,

2

R = Bn 76% ee reaction of indole 56a with 2-formylbiphenyl derivatives 96 86%,

i-Pr

1 R

N : G = You and co-workers further applied the methodology to 1q i-Pr

H

the in situ generation of the benzylidene indolium ion 56a

i-Pr

O from N-tosyl(3-indolyl)methanamine 99 under the influ- O

84

CF

EtO CF

CO Et 3 ence of chiral phosphoric acid 1s (Scheme 37). The 3 2

HO

103

* method provides efficient access to the enantioselective *

(S)-1q (10 mol%)

synthesis of indole-containing unsymmetrically substitut- b)

1

CH Cl , r.t., 3–5 d R

2 2

ed triarylmethane derivatives 100, albeit with moderate N

H

enantioselectivities. In this catalytic system, the authors 104 observed an interesting feature: the kinetic resolution of 36–99%, 55–78% ee racemic (3-indolyl)methanamine 99 by chiral phosphoric Scheme 38 Friedel–Crafts reaction of trifluoromethyl-substituted acid catalyst 1s. ketones with indoles 56a Ma and co-workers successfully developed the enantiose- lective Friedel–Crafts alkylation of indoles 56a with tri- fluoromethyl ketones 101, giving chiral tertiary alcohols 6 Ene (Type) Reactions 102 in good yields without the formation of bisindolyl byproducts (Scheme 38a).85 Further substitution at the 6.1 Aza-Ene-type Reaction of Aldimines with quaternary stereogenic center by indole 56a would be ef- Enecarbamates ficiently suppressed by the trifluoromethyl group. Cata- Kobayashi and co-workers pioneered the use of enamides lyst 1q is also effective for the relatively less reactive or enecarbamates as nucleophiles in enantioselective reac-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1944 M. Terada REVIEW tions with either glyoxylate-derived imines or glyoxylates 6.2 Cascade Transformation Based on Tandem catalyzed by chiral copper complexes.87 The reaction us- Aza-Ene-type Reaction ing enamides or enecarbamates as nucleophilic compo- The development of efficient methods to access complex nents, namely, the aza-ene-type reaction, with imines molecules with multiple stereogenic centers continues to provides b-amino imines that can be readily transformed be a formidable challenge in both academia and industry. into 1,3-diamine derivatives via nucleophilic addition to One approach is the use of catalytic enantioselective cas- the imine moiety of the corresponding products. cade reactions90 that have emerged as powerful tools to Organocatalysis has been proven to be beneficial in many rapidly increase molecular complexity from simple and respects. However, one critical drawback inherent to the readily available starting materials, thus producing enan- methodologies reported to date is the inadequate catalytic tioenriched compounds in a single operation. efficiency. Most organocatalytic reactions are performed Terada et al. successfully applied the aza-ene-type reac- at catalyst loads of 10 mol% or more to achieve sufficient tion to the cascade transformation by taking advantage of chemical yields and avoid loss of enantioselectivity. To the formation of imine products (Scheme 40).91 They em- ensure high efficiency, one of the greatest challenges in ployed monosubstituted enecarbamates 10987f instead of practical organocatalysis is to decrease the catalyst the disubstituted versions and, as a result, piperidine de- load.3c,88 Terada et al. demonstrated a highly efficient or- rivatives 110 with multiple stereogenic centers were ob- ganocatalytic reaction that uses phosphoric acid with a tained with high stereoselectivities. The acid-catalyzed significantly low catalyst load in the aza-ene-type reaction aza-ene-type reaction of initial aldimines 2a with mono- (Scheme 39).89 The reaction of aromatic imines 2d with substituted enecarbamates 109a afforded aza-ene-type enecarbamates 105 could be accomplished in the presence products of N-acyl aldimines 111 as reactive intermedi- of 0.1 mol% phosphoric acid catalyst 1g. Both para- and ates and 111 underwent further aza-ene-type reaction to meta-substitution to aromatic imines, or substitution to generate aldimines 112. The intramolecular cyclization of fused aromatic and a,b-unsaturated imines, resulted in ex- intermediate 112 was conducted to terminate the tandem cellent chemical yields and enantioselectivities, irrespec- aza-ene-type reaction sequence. It is noteworthy that one tive of the electronic properties of the substituents. stereoisomer was formed exclusively from among the Although ortho-substitution reduced the catalytic effi- eight possible stereoisomers, consisting of four pairs of ciency, giving products 106 in moderate chemical yields, enantiomers, under the influence of phosphoric acid cata- the yields were improved by increasing the catalyst load lyst 1c. Not only aromatic but also aliphatic aldimines 2a to 0.5 mol%. It is noteworthy that the reaction can be per- could be used in this cascade reaction. Moreover, the gly- formed without considerable loss of enantioselectivity oxylate-derived aldimine could be transformed into the even when the catalyst load is decreased to as little as 0.05 highly functionalized piperidine derivative with excellent mol%. The synthetic applicability of the present highly ef- enantioselectivity. This cascade methodology allows rap- ficient organocatalysis was demonstrated by the reduction id access to piperidine derivatives 110 with multiple ste- of the imine moiety by Red-Al, giving predominantly the

anti-1,3-diamine derivatives 108.

Cbz

HN

Bz CO Me

2

Boc

NH HN

2 N

Boc

Cbz Ar Ph

N

6 4

R N

108 (Ar = Ph)

H G =

anti 87% trans-110

R H Bz

N (2,4- trans-4,6-trans) 2a

(R)-1c (2–5 mol%)

G =

Red-Al

+ +

Ar H

CH Cl , 0 °C, 1–5 h

2 2 Cbz

Cbz

Bz

2d HN

HN

NH NCO Me R)-1g (0.05–0.5 mol%) ( 2

Boc +

N toluene, r.t., 5 h

H

Ar Ph

CO Me

2

109a

106 HN Cbz

R N (2.1 equiv)

H

+

H O Ph

3 cis-110

105 (2,4- cis-4,6-cis)

Bz

NH O 1st aza-ene

cyclization

Ar Ph

0.1 mol% of ( R)-1g: 82–97%, 92–98% ee

107

Cbz

Boc Cbz Boc Cbz X = 4-MeO, 4-Me, 4-F, 4-Cl, 4-Br, 4-NC,

Ar =

NH NH N

NH N 2nd aza-ene X

3-Me, 3-Br

* * R H

* R H -naphthyl, (E)-PhCH=CH- α-naphthyl, β

112 111

0.5 mol% of ( R)-1g: 82–84%, 93–96% ee

aromatic E)-PhCH=CH- MeCO - cyclohexyl ( R = 2

70% 68% 84% 76 to >99%

Ar = X = Me, Br

trans 95% trans trans trans 94% 88% 88–95%

X

97% ee 98 to >99% ee 98% ee 97% ee Scheme 39 Enantioselective aza-ene-type reaction under low cata- Scheme 40 One-pot access to piperidine derivatives 110 via tandem lyst load aza-ene-type reaction/cyclization cascade

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1945

3

CO R Boc

reogenic centers, as key structural elements of natural 2

1 3 HN NH a) K-Selectride ( : R = aromatic, R = Bn

products. 115a

1 3

= aliphatic, R = Me 115b: R ( a) 1) KOH, MeOH

1 R

2) K-Selectride 115

6.3 Two-Carbon Homologation Reaction a

R)-1p or 1q (

2

2

CO R

Boc CO R Boc

2

2

HN

The homologation of a carbon unit is an important and HN

HN NH (2 mol%)

fundamental methodology in the construction of carbon +

i-Pr O or 1

1

2 H R OMe OMe R

1 1

toluene 109

113a: R = aromatic = aromatic : R frameworks in synthetic organic chemistry. Much atten- 114a

1 1 r.t. to 50 °C

113b: R 114b: R = aliphatic tion has been devoted to the development of the two- = aliphatic carbon homologation reaction using acetaldehyde anion equivalents, as these can be directly utilized in further transformations.92 From a synthetic viewpoint, monosub- stituted enecarbamates are attractive as acetaldehyde an- MeOH

ion equivalents for the two-carbon homologation reaction

2

Boc CO R Boc

2 109

N N because they are readily available and can provide ald- NH

87f,93

1

imine products. These aldimines can be directly trans- 1 R H H R

111 formed into 1,3-diamine derivatives when the two-carbon 2a

homologation reactions are conducted with imines as the Ph

1

R = aromatic substrate. 115a

1p: G =

2 44–99%, 84–95% ee R = Cbz 109a: CO

Although the high reactivity of aldimine products 111 hin- 2

Ph

-Pr dered the completion of the two-carbon homologation re- i

1

= aliphatic R action because of overreaction, Terada et al. neatly 115b

i-Pr

1q: G =

2

56–84%, 86–98% ee R = Troc 109b: CO demonstrated two-carbon homologation using enecar- 2

-Pr bamates 109 and hemiaminal ethers 113, instead of imines i 2a, as the substrate (Scheme 41).94 In the acid-catalyzed Scheme 41 Two-carbon homologation of hemiaminal ethers by reaction of hemiaminal methyl ethers 113, intermediary enecarbamate

and reactive aldimine 111 was trapped by methanol that

was generated during the formation of imine 2a. A series a)

CO Me

2

Boc

HN CO Me Boc

113a 2 of aromatic hemiaminal ethers were employable for HN

(R)-1p (2 mol%)

HN NH

this homologation reaction in the presence of phosphoric + H

CH Cl , r.t., 24 h Ph OMe 2 2 OMe

acid catalyst 1p, giving hemiaminal products 114a with Ph

113aa 116a high enantioselectivities. The enantioselectivities were 117

determined only after the reduction of the hemiaminal

CO Me CO Me Boc Boc

2 2

HN HN NH

moiety to 1,3-diamine derivatives 115, although the reac- NH K-Selectride

+

Ph tivity of hemiaminal ethers 113a was considerably depen- Ph

dent on the electronic properties of the substituents on the

syn-118 -118

aromatic ring. Aliphatic hemiaminal ethers 113b were anti

: 99% yield 98 (94% ee) 2 (3% ee) ( E)-116a

: 67% yield 5 (51% ee) 95 (88% ee) ( )-116a also applicable to the present homologation, but in this Z

case, protection of the nitrogen atom of 119 by the more

electron-withdrawing trichloroethoxycarbonyl (Troc) b)

Boc Troc Troc Boc

(R)-1q (2 mol%)

HN HN HN group was required to suppress the formation of byprod- NH

+

ucts. toluene, r.t., 12 h

Et OMe H OMe Et

114ba This homologation reaction can be applied to substituted 113ba 109b

enecarbamate 116a (Scheme 42a). Either anti- or syn-

Troc Boc

indole

HN

products 118 were obtained in a highly diastereoselective NH 56aa

manner from the respective geometric isomers of enecar- Et 40 °C, 24 h bamates 116a, and each of the major diastereomers 118, N

furnished by the reduction of the hemiaminal moiety of H 1,3- syn-119

70%, 76% , >99% ee 117, exhibited good to high enantioselectivities. The syn- syn thetic utility of this homologation is highlighted by the sequential transformation of the homologation/Friedel– Scheme 42 Application of the two-carbon homologation reaction Crafts reaction in one pot (Scheme 42b). Catalyst 1q also accelerated the Friedel–Crafts reaction of hemiaminal Shortly thereafter, Masson, Zhu, and co-workers devel- ether 114ba with indole (56aa) to afford the desired 1,3- oped a multicomponent approach to the two-carbon ho- diamine derivatives 119 in good yields and nearly optical- mologation reaction among aldehydes 11, anilines 12, and ly pure forms, albeit with only moderate syn-diastereose- enecarbamates 109 in the presence of excess ethanol as the trapping reagent to intercept initial product 120 lectivities. The method enables facile access to highly 95 enantioenriched 1,3-diamine derivatives as pharmaceuti- (Scheme 43). The use of aniline derivative 12e, with its cally and biologically intriguing molecules. electron-withdrawing nitro group, resulted exclusively in

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1946 M. Terada REVIEW four-component adducts 121 at the expense of the (G = Ph), was used. The fact that the simple phenyl- Povarov products, tetrahydroquinolines 122, which were substituted catalyst provides excellent enantioselectivity formed from the inverse-electron-demand aza-Diels– is noteworthy, since in experiments on the activation of Alder reaction of N-aryl imines with enecarbamate 109 imines, it was found that catalysts 1 required modified (see Section 7.3).96 In this regard, tetrahydroquinolines phenyl substituents, bulky ones in general, to achieve high 122 were the only products obtained in the absence of eth- enantioselectivities. To rationalize the stereochemical anol under otherwise identical conditions. Aromatic as outcome, Terada and co-workers97 proposed double hy- well as aliphatic aldehydes 11 can be used in the present drogen-bonding interaction D as the complexation mode99 four-component reaction, affording hemiaminal ethyl of glyoxylate 124 and phosphoric acids 1 on the basis of a ethers 121 in good yields with high enantioselectivities. screening of catalysts 1 having a series of substituted phe- The potential of this multicomponent reaction is further nyl rings instead of simple phenyl groups, and DFT com- demonstrated using substituted enecarbamate 116b. The putational analysis of the hydrogen-bonding interaction reaction of 4-nitroaniline (12e) and (E)-116b with a range between glyoxylate 124 and phosphoric acids 1 of aromatic and aliphatic aldehydes 11 gave anti-products (Scheme 44). The additional hydrogen bond that exists 123 with high diastereoselectivities (>95% anti) after the between the formyl hydrogen atom and the phosphoryl reduction of the hemiaminal moiety of 121. oxygen atom creates a coplanar orientation between the

formyl group and the phosphoric acid subunit,100 and

G hence the formyl carbon of glyoxylate 124 would be ex-

O posed to an efficient chiral environment created by the

O

(R)-14e: G = Cl

P phosphoric acid catalyst.

OH

O

G

G =

Cbz

CO Me NO HN

2 2

O

O (R)-1b (5 mol%) (R)-14e (10 mol%) HN

+ + +

H

1

EtO C H

4 Å MS EtOH (17 equiv)

R H

2

Ph H N 2

2

Cl , r.t., 1 h CH R

Cl , 0 °C, 24 h CH

2 2 2 2 124 105

11 12e

2

= H 109a: R

2

116b: R = Me

+

OH NCO Me OH O

O H 2

3

Cbz Ar

Cbz Ar

NH N

HN

NH

EtOH

EtO C Ph EtO C Ph 2 2

126 125

1

R H

1

OEt R

93%, 95% ee

2

NO R Ar =

2 2 R

120

121

G

Cbz

NaBH CN

3

HN O

H O

p-TsOH

O

2

X R P

MeO O

Cbz Ar

O

H

HN NH

1

N R

O

H

G

1 R

122 (X = NO )

2

2

R D

123

1 2

R = aromatic 74–86%, 79–96% ee = H

R Scheme 44 Aza-ene-type reaction of glyoxylate 124 with ene-

1

2

R = aliphatic R = H

76–97%, 88–90% ee carbamate 105 catalyzed by (R)-1b

1

2

R = aromatic 82 to >99% ee 55–80%, >95% anti, = Me R

1

2

R = aliphatic R = Me 90–97% ee 62–95%, >95% anti, The applicability of the aza-ene-type reaction of glyoxy- Scheme 43 Two-carbon homologation via multicomponent ap- late 124 with a series of substituted enecarbamates 127 proach demonstrates the stereochemical issue of enantio- and diastereoselection (Scheme 45). Catalysts 1t exhibited ex- 6.4 Aza-Ene-type Reaction of Aldehyde with cellent performance in the reaction of (E)-127 to give Enecarbamates anti-products 128 in nearly optically pure forms. How- Terada et al. accomplished the enantioselective activation ever, (Z)-127 retarded the reaction markedly and low of aldehydes using a chiral phosphoric acid catalyst.97 enantioselectivity was observed for major anti-128. The Their aza-ene-type reaction of glyoxylate 124 as a reac- exclusive formation of anti-products from the E-isomers could be attributed to the well-defined exo-transition tive aldehyde with enecarbamate 105 afforded the corre- 87d sponding products 125 with excellent enantioselectivities state. (Scheme 44).87d–g Catalyst 1b efficiently accelerated the aza-ene-type reaction of glyoxylate 124 in the presence of 6.5 Carbonyl-Ene Reaction MS 4A, which was employed as a scavenger of acidic im- purities.98 After hydrolysis of products 125 to b-hydroxy The carbonyl-ene reaction is an important carbon–carbon bond-forming reaction that affords synthetically valuable ketones 126, excellent enantioselectivities were observed 101 even when catalyst 1b, bearing unmodified phenyl groups homoallylic alcohols. The enantioselective catalysis of the carbonyl-ene reaction has been extensively investigat-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1947

2m (Scheme 47b).106 One of the intrinsic problems asso-

t-Bu

G = ciated with Brassard’s diene lies in its instability under

CO Me

2

O

+

H O HN (R)-1t (5 mol%)

3 acidic conditions. In order to suppress the decomposition

+

EtO C H

2 4 Å MS of the diene by the phosphoric acid catalysts, they em- R

CH Cl , r.t., 2–24 h

2 2

127 (R = Ph, Et) 124 ployed pyridinium salts of the catalysts. The pyridinium

OH O O OH salt of 1g displayed excellent performance for the hetero-

+ Diels–Alder reaction of Brassard’s diene with a broad

EtO C R EtO C R 2

2 range of imines, including aromatic and aliphatic deriva-

anti-128 -128

syn tives. Uniformly high enantioselectivities and chemical

73%, ( 99 to >99% ee for E)-127 anti, anti-128

96 to >99% yields of dihydropyridin-2(1H)-one products 135 were

26–28% ee for anti-128

11–74%, (Z)-127 anti,

50–72% noted after treatment with an acid.

69–88% ee for syn-128

Scheme 45 Diastereo- and enantioselective aza-ene-type reaction a)

of glyoxylate 124 with enecarbamate 127 HO i-Pr

N Me

G =

i-Pr

ed using chiral metal complexes.102 However, no highly OH

Ar H

-Pr enantioselective organocatalysis of the carbonyl-ene reac- i

Me N

103 104 2m

R)-1q (5 mol%)

tion was reported until the work of Rueping et al., (

+

Ar 69 O

AcOH (1.2 equiv) who used chiral phosphoramide 66 as the strongly acidic OMe 133

catalyst (Scheme 46). The reaction of trifluoropyruvate toluene, –78 °C, 10–35 h

129 with a-methyl styrene derivatives 130 in the presence 72–100%, 76–91% ee of chiral phosphoramide 66e gave the corresponding ho- OTMS

moallylic alcohols 131, having the quaternary stereogenic 132

O

b)

R)-1g/pyridine center substituted by a trifluoromethyl group, with high (

2m

Ar

(3 mol%) PhCOOH

enantioselectivities. N +

mesitylene

OTMS R OMe

–40 °C, 24 h

135 G

R = aromatic MeO 63–91%, 94–99% ee

O

R = aliphatic 65–69%, 93–99% ee O

OMe

(R)-66e: G = OMe P

HO 134

NHTf

O

Ar =

G Me

(R)-66e G

O

(1 mol%) HO CF 3

+

O

O

HN

o-xylene Ar

EtO C CF

EtO C Ar 2 3 2

P

G =

10 °C, 34 h 129 130 131

O

O 55–96%, 92–97% ee

Scheme 46 Carbonyl-ene reaction of trifluoropyruvate 129 with a- G

R)-1g/pyridine methyl styrene derivatives 130 ( Scheme 47 Enantioenriched nitrogen heterocycles by hetero-Diels– Alder reaction of siloxydienes 7 Cycloaddition Reactions

7.1 Hetero-Diels–Alder Reaction of Aldimines 7.2 Direct Cycloaddition Reaction of Aldimines with Cyclohexenone The enantioselective hetero-Diels–Alder reaction of sil- 107 108 oxydienes, such as Danishefsky’s and Brassard’s dienes, Gong and co-workers and Rueping and Azap inde- with imines provides an efficient route for the preparation pendently reported the enantioselective direct cycloaddi- of functionalized nitrogen heterocycles in optically active tion reaction of cyclohexenone 136 with aromatic imines forms, which can be utilized as synthetic precursors of bi- 2n. Rueping and Azap employed acetic acid as the co-cat- ologically interesting alkaloid families and aza sugars. alyst to accelerate the tautomerization of cyclohexenone Akiyama et al. developed the enantioselective hetero- 136, by which a reactive dienol for the enantioselective Diels–Alder reaction of Danishefsky’s diene (132) with cycloaddition was generated in situ (Scheme 48). They aromatic imines 2m using chiral phosphoric acid catalyst proposed a stepwise mechanism for the reaction. The ini- 1q (Scheme 47a).105 The reaction catalyzed by 1q provid- tial step is the chiral phosphoric acid 1u catalyzed Mannich ed dihydropyridin-4(1H)-one derivatives 133 in good reaction of imines 2n with the dienol generated in the yields with high enantioselectivities in the presence of presence of acetic acid, giving intermediate 137. The sub- acetic acid as the stoichiometric additive. Akiyama and sequent intramolecular aza-Michael reaction provides the co-workers also reported an enantioselective hetero- corresponding cycloaddition products 138, the so-called Diels–Alder reaction of Brassard’s diene (134) with imines isoquinuclidine derivatives, in moderate to good yields.

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1948 M. Terada REVIEW

a)

OR

G =

G =

OR

Br

O

139 R)-1u (10 mol%) (

(R)-1g (10 mol%)

136

AcOH (20 mol%)

+ N

+

toluene, –10 to 0 °C, 10–55 h

H N Ar

toluene, r.t., 4 h

H H

Br

O OH

Ar

cis-140

138 N Ar

59–89%

N

54–84%

OH

96–99% cis

75–89% endo

2b

87–96% ee Ar H

82–88% ee

2n b)

G H

O

H NH

O

O

NHCbz

Ar

(R)-14e: G = Cl P

OH

O

109a

NHCbz

Br

G +

X 137

MeO

(R)-14e (10 mol%)

CH Cl , –30 to 0 °C

2

Scheme 48 Direct cycloaddition reaction of imines with cyclo- 2 N R

NH

2

hexenone H 12b

cis-122 (X = OMe)

+

R = aromatic 64–89%, cis, 97 to >99% ee >99%

R = aliphatic 77–90%, >99% cis, 92–95% ee

7.3 Inverse-Electron-Demand Aza-Diels–Alder H

O

Reaction (Povarov Reaction) R

11

MeO C CF

2 3

The Povarov reaction, an inverse-electron-demand aza- N

F C

Diels–Alder reaction of 2-azadienes with electron-rich 3

CF alkenes, enables facile access to tetrahydroquinoline de- 3

rivatives of pharmaceutical and biological importance. N

EtO C

2 Akiyama et al. developed the highly enantioselective torcetrapib Povarov reaction of N-aryl imines 2b with vinyl ethers 109 Scheme 49 Inverse-electron-demand aza-Diels–Alder reaction 139 using chiral phosphoric acid 1g (Scheme 49a). The (Povarov reaction) method provides an efficient approach to enantioenriched tetrahydroquinolines 140 having an oxygen functionality ities (Scheme 50a). However, the conditions that were op- at the 4-position. Masson, Zhu, and co-workers applied a timized for the reaction of 2-vinylindole (141) could not three-component coupling process to the enantioselective be applied to that of 3-vinylindole (142), because 142 is Povarov reaction using enecarbamates 109, instead of vi- much more sensitive to the acidic catalyst than 141. After nyl ethers 139, as electron-rich alkenes (Scheme 49b).96 thorough optimization of the reaction conditions, namely,

The three-component approach employing 4-methoxy-

H

aniline (12b), enecarbamate 109a, and aldehydes 11 in the N presence of chiral phosphoric acid 14e is applicable to a OMe

broad range of aromatic aldehydes, giving the correspond-

141

HN

ing products 122 with excellent enantioselectivities, irre- H

(S)-1q (10 mol%)

N

a)

spective of their electronic properties. Aliphatic R 3 Å MS

aldehydes were also applicable to the present reaction. In- toluene, 45 °C, 3–20 h

terestingly, tetrahydroquinolines 140 and 122 have differ- 143

91–98%, R = aromatic 92 to >99% ee cis,

ent absolute stereochemistries (Scheme 49a vs. 49b), 90 to >98% 95–98%, R = aliphatic 96 to >99% ee >98% cis,

although the chiral phosphoric acid catalysts have the OMe -Pr

same axial chirality. Masson, Zhu, and co-workers further i

N

1q: G = -Pr demonstrated the power of the present reaction in the i

R enantioselective synthesis of torcetrapib, an inhibitor of H

-Pr

96 i

cholesteryl ester transfer protein. 2f

Vinylindole derivatives are also good candidates for the OMe

N

Povarov reaction because of their peculiar reactivity as H

142

electron-rich alkenes. Ricci and co-workers successfully HN

( S)-1q (10 mol%)

b) demonstrated the enantioselective Povarov reaction of N- R

aryl imines with 2-vinylindoles and 3-vinylindoles THF, 45 °C, 13 h syringe pump addition over 12 h

N

110 H

(Scheme 50). Phosphoric acid catalyst 1q functioned as 144

53–96%, 84–97% ee 90 to >98% cis, an efficient catalyst for the reaction of 2-vinylindole (141) R = aromatic

90%, 73–89% ee 98 to >98% R = aliphatic ,

with a variety of imines 2f, affording the corresponding cis cycloadducts 143 in good yields with high stereoselectiv- Scheme 50 Inverse-electron-demand aza-Diels–Alder reaction (Po- varov reaction) of vinylindoles

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1949 use of a coordinating solvent such as tetrahydrofuran and gration was not observed when sterically demanding sub- the slow addition of 142 over 12 hours, cycloadducts 144 stituents, such as benzyl moieties, were employed as the were obtained (Scheme 50b) with results that were com- R group. parable to those of 143 using the same catalyst 1q. A va- riety of aryl substituents introduced at the nitrogen atom 7.5 Hetero-Diels–Alder Reaction of Aldehydes can be utilized in this reaction, giving the cycloadducts in high yields with excellent stereoselectivities. The hetero-Diels–Alder reactions of dienes with alde- hydes are an efficient way to provide dihydropyran deriv- atives.114 The development of catalytic enantio- and 7.4 Diels–Alder Reaction of Enone diastereoselective variants is an area of considerable im- The enantioselective Diels–Alder reaction of a,b-unsatur- portance.115 Extensive studies of the use of chiral Lewis ated carbonyl compounds with dienes is one of the most acid catalysts to control high levels of stereoselectivity well-studied transformations using chiral metal have been conducted.116 It is noteworthy that vicinal sub- catalysts111 and organocatalysts.112 However, chiral phos- stituents of the dihydropyran are controlled exclusively in phoric acids do not effectively accelerate the Diels–Alder a syn-selective manner, where the diene approaches the reaction of a,b-unsaturated carbonyl compounds because aldehyde with an endo-orientation, presumably because they lack sufficient acidity to activate these dienophiles. of secondary p-orbital interactions and more importantly Yamamoto and Nakashima overcame this intrinsic draw- to avoid steric repulsion between the incoming diene and back by designing a novel chiral Brønsted acid catalyst the sterically demanding Lewis acid catalyst.117 In con- with improved acidity (Scheme 51).69 They successfully trast, alternative exo-oriented enantioselective processes developed stronger chiral Brønsted acids, N-triflyl phos- that afford anti-isomers have yet to be fully established.118 phoramides 66, by introducing a strong electron acceptor, Terada and co-workers developed an unprecedented anti- the TfN-H group,113 into the phosphoric acid subunit in and enantioselective hetero-Diels–Alder reaction of sil- place of the phosphoric acid O-H group. N-Triflyl phos- oxy- or methoxydienes with glyoxylate 124 using chiral phoramide catalyst 66c exhibited significant activity in phosphoric acid catalyst 1 (Schemes 52 and 53).119 Cata- the reaction of a,b-unsaturated ketone 145 with siloxy- lyst 1b, bearing unmodified phenyl groups (G = Ph), ex- dienes 146a, affording enantioenriched cycloadducts 147 hibited excellent performance in the hetero-Diels–Alder in excellent yields in most cases, although the yields were quite sensitive to the stability of the siloxydiene 146a, be-

cause the protonation of the diene resulted in silylation G =

O

(R)-1b (5 mol%)

and thus deactivation of the catalyst. In contrast, parent + EtO

H 4 Å MS

phosphoric acid 1b (G = Ph) showed no catalytic activity OTBS toluene, r.t., 24 h

and thus, the introduction of the electron-withdrawing O 124

NTf group into the phosphoric acid is quite effective in in- 146b (1.5 equiv)

( ,E)/(E,E) = 90:10 creasing the catalytic activity. The reaction of non-substi- Z

tuted and methyl-substituted siloxydienes at the R group

O

furnished olefin regioisomers 148. However, olefin mi- O

+

EtO C OTBS EtO C OTBS 2 2

G

i-Pr

O anti-149a syn-149a

O

anti, 99% ee for anti 95%, >99% (S)-66c: G = P i-Pr

NHTf

O

i-Pr

G

O

( S)-66c (5 mol%)

Et +

anti-149a O

toluene, –78 °C, 3–12 h H

O

O O P OTIPS

O

145

R O

H

146a (1.5 equiv)

OSi O

O Me O Me

E

Ph R Et Et

+

O

O O OTIPS OTIPS

R R

EtO C OTBS

2

EtO C OTBS EtO C OTBS 2 2

147 148 (R = H or Me)

R = Me, Bn, BzOCH CH , 4-TBSOC H CH : 149b 149d (R = CH=CHMe) 149e 149c (R = Ph) 2 2 6 4 2

95 to >99%, >98% endo, 85–92% ee 92% 75% 90% 92%

R = H: >99% >95% >99% anti anti anti anti >99%

43%, >98% endo, 88% ee 98% ee 97% ee 99% ee 98% ee

Scheme 51 Diels–Alder reaction of enone 145 with siloxydienes Scheme 52 Hetero-Diels–Alder reaction of siloxydienes 146 with 146 catalyzed by N-triflyl phosphoramide 66c glyoxylate 124 catalyzed by (R)-1b

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1950 M. Terada REVIEW reaction of glyoxylate 124 with tert-butyldimethylsilyl- electron-withdrawing group to the aromatic ring, Ar2, is protected siloxydienes 146b, giving the corresponding necessary to ensure the high enantioselectivity. In addi- product 149a in high yield with extremely high stereose- tion, endo-153 was furnished as the major diastereomer in lectivity (Scheme 52). It is noteworthy that chiral phos- the present reaction. The predominance of endo-products phoric acid 1b is uniquely efficient in affording anti- contrasted the formation of exo-isomers as major products cycloadduct 149a as the single diastereomer in nearly op- under Lewis acid catalysis.123

tically pure form. In order to rationalize this unprecedent-

ed anti-selectivity observed in the 1b-catalyzed reaction, G

-Pr

120 i

they proposed exo-transition state E, where the small O O

P (S)-66f: G = phenyl groups at the 3,3¢-positions of 1b allow the diene Ad

NHTf

to occupy an exo-position, giving the anti-isomer exclu- O

i-Pr

sively. G

(S)-66f

(Ad = 1-adamantyl)

1

1 The anti- and enantioselective hetero-Diels–Alder reac- Ar

Ar O

OEt O

(5 mol%) N N

OEt tion catalyzed by 1b is applicable to a series of 2-siloxy- +

CHCl

3

2

2 H Ar

dienes, giving the corresponding products 149 in good Ar

–55 to –40 °C, 1–6 h

139a

endo-153

yields with excellent stereoselectivities (Scheme 52). Al- 152 66 to >99%

87–97% though the alkenyl-substituted siloxydiene resulted in a endo

decrease in reactivity, the stereoselectivity was main- 70–93% ee tained at a high level. Furthermore, methoxydienes 150 Scheme 54 1,3-Dipolar cycloaddition reaction of nitrones 152 with were also well tolerated, providing the corresponding ethyl vinyl ether (139a) anti-dihydropyrans 151 predominantly with excellent enantioselectivities (Scheme 53). The asymmetric 1,3-dipolar cycloaddition reaction of

azomethine ylides with electron-deficient olefins provides OMe

OMe

(R)-1b

1

R

1 chiral pyrrolidine derivatives, an important class of nitro- R

O

(5 mol%) 121c,124

+ 124 gen heterocycles, as the precursors of biologically

2 4 Å MS

EtO C R

2

2

R active compounds. Gong and co-workers reported the

toluene, r.t., 48 h

3

R 3

R enantioselective catalysis by chiral Brønsted acids in the

anti-151

150 three-component 1,3-dipolar cycloaddition reaction

OMe

OMe

OMe among aldehydes 11, a-amino-1,3-dicarbonyl compounds

R O

O O 154, and maleate 155 as an electron-deficient dipolaro-

125

EtO C

2 phile (Scheme 55). As none of the chiral monophos-

EtO C EtO C 2

2 phoric acids 1 provided sufficient enantioselectivities,

151a (R = H) 151c (R = Me) 151d

151b they developed the new bisphosphoric acid 156, derived

84% 51% 75%

93% from linked BINOL, that displayed excellent performance 93% 91% 94% 95% anti anti anti anti

99% ee 95% ee 97% ee 98% ee in this cycloaddition reaction in terms of diastereo- and enantioselectivities as well as catalytic efficiency. A Scheme 53 Hetero-Diels–Alder reaction of methoxydienes 150 broad range of aldehydes 11, including aromatic and a,b- with glyoxylate 124 catalyzed by (R)-1b

unsaturated aldehydes, were used in the reaction, giving

CO Et O

7.6 1,3-Dipolar Cycloaddition Reactions 2

MeO C CO Me

2 2 ++

H N CO Et R H 2

The 1,3-dipolar cycloaddition reaction of nitrones with vi- 2

nyl ethers provides an efficient route to 1,3-amino alco- 11 154 155

CO Me

121 2

C hols, which can be transformed from the corresponding MeO

2

(R,R)-156 (10 mol%) CO Et

isoxazolidine products through reductive cleavage of the 2

CO Et

3 Å MS 2

N

R

nitogen–oxygen bond. The development of the catalytic H

CH Cl , r.t., 24–96 h 2 2

enantioselective 1,3-dipolar cycloaddition reaction is 157

67–97%, >99% 84–99% ee hence a vital step toward the efficient synthesis of these endo, amino alcohols in optically active forms. Yamamoto and co-workers successfully developed the enantioselective 1,3-dipolar cycloaddition reaction of diaryl nitrones 152

with ethyl vinyl ether (139a) (Scheme 54).122 They ap- O O

plied acidic NHTf-substituted chiral phosphoramide cata- O

O O P P

HO

lysts 66, originally developed by the same research O O

group,69 to the present dipolar cycloaddition reaction. HO R,R)-156

Chiral phosphoramide 66f effectively catalyzed the cy- ( cloaddition reaction to give the corresponding isoxazoli- Scheme 55 1,3-Dipolar cycloaddition reaction via three-component dine derivatives 153 in high yields. The introduction of an coupling

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1951 the corresponding pyrrolidine derivatives 157 with excel- methylene moiety (Scheme 56b).127 Although aliphatic lent endo- and enantioselectivities. aldehydes resulted in decreased chemical yields and enan- Gong and co-workers further developed an enantioselec- tioselectivities, excellent enantioselectivities were tive three-component 1,3-dipolar cycloaddition reaction achieved using aromatic aldehydes as the 1,3-dipolaro- among aldehydes 11, a-amino-1,3-dicarbonyl compound phile precursors in most cases. The activation of azometh- 154, and a series of electron-deficient dipolarophiles, ine ylides by chiral phosphoric acid catalysts is also N 158 159 applicable to the cycloaddition reaction of methylenein- namely, -aryl imines , 2,3-allenoates , and meth- 128 yleneindolinones 160 (Scheme 56). The reaction of N- dolinones 160 (Scheme 56c). A broad range of alde- aryl imines 158 as the dipolarophiles, generated in situ hydes 11 and 160 were well tolerated for the cyclization from aldehydes 11 and 4-tert-butoxyaniline (12f), afford- reaction in the presence of chiral phosphoric acid 1u, giv- ed diastereomeric mixtures of cycloadducts 161 with ex- ing spirocyclic adducts 163 in good yields with high enan- cellent enantioselectivities under the influence of tioselectivities. Thus, both aromatic and aliphatic 1q 126 aldehydes 11, as well as 160 with either aromatic or ali- phosphoric acid (Scheme 56a). The diastereoselec- 2 tivities were markedly dependent on the substitution pat- phatic R substituents, were adaptive substrates, despite 11 yn 161 the formation of regioisomeric byproducts when aliphatic tern of the aldehyde . The s -isomers were 2 obtained predominantly in the reaction of para- and meta- R substituents were introduced into 160. substituted benzaldehydes, regardless of the electronic properties of these substituents. In contrast, ortho-substi- tution resulted in a significant decrease in diastereoselec- 8 Cyclization Reactions tivities. Meanwhile, in the reaction of 2,3-allenoates 159 as the dipolarophile, bisphosphoric acid catalyst 156 was 8.1 Electrocyclic Reactions the most effective in terms of enantioselectivity to give The Nazarov reaction is classified as an electrocyclic re- cycloadducts 162 as a single diastereomer having an exo- action and is one of the most versatile methods for the construction of five-membered cyclic enones, which are

11 the key structural motif of numerous natural products.129 in situ H

+ Ot-Bu

Ar In general, the Nazarov cyclization is accelerated by

1

N R

Ot-Bu Ar = Lewis acid or Brønsted acid catalysts. However, the enan-

158 tioselective Nazarov cyclization has rarely been exploit-

H N

2 130

1

12f ed, even by using chiral metal complexes. Rueping et R

Ar al. developed for the first time an organocatalytic ap-

(R)-1q (10 mol%) N CO Et

2

a)

Et

CO proach to the enantioselective Nazarov cyclization of 2

3 Å MS N

1

R

H

toluene, –10 °C, 60 h dienones 164 using chiral phosphoramide 66 as the

-161

syn 131

-Pr i Brønsted acid catalyst (Scheme 57). The reactivities

1 R = para- or meta-substituents

73–91%, 76–91% syn, 93–98% ee and the enantioselectivities were strongly dependent on

1q: G = i-Pr

1

R ortho-substituents

= the solvent employed. While no reaction was observed in

76–99%, 45–88% 85–90% ee syn,

-Pr i polar solvents, such as tetrahydrofuran and acetonitrile,

the reaction proceeded smoothly in halogenated and aro-

2

CO R

2

2 matic solvents to afford diastereomeric mixtures of cy- R = 9-anthracenylmethyl

O

3

R

• clized products 165. The best enantioselectivities were

1

2 R H

159

R O C

2 achieved using chiral phosphoramide 66d in chloroform,

11

b)

3

(R,R)-156 (10 mol%)

R CO Et 2

+ and a variety of dienones 164 were transformed into cy-

CO Et

2

3 Å MS

N

1

R

CO Et

H clopentenones 165 with moderate to high diastereoselec- 2

toluene, 25 °C, 36–144 h

162 tivities. Major product syn-165 can be isomerized

H N CO Et

2 2

1

R = aromatic 67–99%, 75–96% ee

154 exclusively to anti-165 under basic conditions without

1 R 29–69%, 17–69% ee

= aliphatic any loss of enantiomeric purity.

3

R

G

Ac

N

O

O

O (R)-66d: G = P

NHTf

O

2

3 R R

Ac

160

G N

(R)-1u (10 mol%)

O

O

2 O

R c)

O O

O

O R

(R)-66d (2 mol%)

3 Å MS

Et CO

2

R +

R

Cl , 25 °C, 24–96 h CH

2 2

, 0 °C, 1–2 h CHCl

N CO Et

1

3 2 R

H

Ar

163 Ar 164 Ar

1u: G =

1

R = aromatic 74–97%, 81–98% ee syn-165 anti-165

1

R = aliphatic 59–95%, 82–93% ee 87–93% ee 91–98% ee 61–92%, 60–90%

Scheme 56 1,3-Dipolar cycloaddition reaction of 1,3-dipolarophi- syn les via multicomponent coupling Scheme 57 Nazarov cyclization of dienones 164

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1952 M. Terada REVIEW

2

Rueping and Ieawsuwan further applied the enantioselec- R

2 tive Nazarov cyclization to the preparation of a-substitut- R ed cyclopentenones 167, lacking a b-substituent, using

dienones 166 (Scheme 58).132 In this transformation, the (S)-1g (10 mol%)

NH

N

stereo-determining step is the Brønsted acid catalyzed NN

C H Cl

6 5

1

R

enantioselective protonation of intermediately generated 30 °C, 75–96 h

130c 1

enol 168. H8-BINOL-derived phosphoramide 66g ex- R 170

hibited the best performance in this case, giving cyclopen- 169 85–99%, 76–96% ee : G =

tenones 167 with fairly good enantioselectivities. 1g

2 R

G

O

2

Ar

P O O

O

O

N H

O

H N P

(R)-66g: G = NNH

NHTf

O

1

1 R Ar

(Z)-s-cis conformation G

O F O 171

O

O R (R)-66g (5 mol%)

R Scheme 59 6p-Electrocyclic reaction of phenylhydrazones 169 lea- CHCl , –10 °C, 20 h

3 ding to pyrazolines 170

166 167

OH

44–93%, 67–78% ee

O

R 8.2 Multicomponent Cyclization Reactions 168 Multicomponent reactions, in which three or more reac- tants are combined in a single process to deliver new mol- Scheme 58 Nazarov cyclization of dienones 166 ecules containing substantial elements of all reactants, have received much attention with respect to synthetic ef- In contrast to the Nazarov reaction, which is a 4p-electro- ficiency and an increase in molecular diversity from the cyclization, List and Müller reported the enantioselective reactants.135 Gong and co-workers developed an efficient catalysis of 6p-electrocyclization using benzylidene- three-component cyclization that involved a,b-unsaturat- acetone-derived phenylhydrazone 169 as a 6p-electron ed aldehydes 172, aniline derivatives 12, and b-keto esters system for the first time (Scheme 59).133,134 Chiral phos- 24 in the presence of chiral phosphoric acid catalyst 14c, phoric acid 1g exhibited promising catalytic activity and and 1,4-dihydropyridine derivatives 173 were obtained in enantioselectivity in the 6p-electrocyclization of 169, giv- the optically active forms (Scheme 60).136 Both the reac- ing the cyclized products, pyrazolines 170, which are in- tion efficiency and the enantioselectivity displayed signif- teresting synthetic targets in terms of broad potent icant dependence upon the substituents of these reactants. biological activities, in excellent yields with high enantio- Among the aniline derivatives 12 tested, 3-methoxy- selectivities. The electrocyclic reaction is well suited for aniline (12g) gave the highest enantioselectivities albeit hydrazones bearing either an electron-withdrawing or with accompanying decrease in chemical yields. In most electron-donating substituent at the aromatic ring of the cases, the reaction of ethyl or isopropyl b-keto esters 24 enone moiety. To undergo the cyclization, carbon–nitro- provided cyclized products 173 with higher enantioselec- gen double-bond isomerization of hydrazone (E)-169 is tivities than the reaction of their methyl or allyl counter- required and this E/Z isomerization is also catalyzed by parts. a,b-Unsaturated aldehydes 172 with electron- phosphoric acid 1g. After adopting the cyclization-reac- withdrawing substituents, such as a nitro group or halogen tive Z-s-cis-conformation, protonated intermediate F un- atom, at the aromatic ring exhibited high enantioselectiv- dergoes 6p-electrocyclization in the chiral environment ities compared with the parent cinnamaldehyde and enals created by a chiral counteranion of the phosphoric acid, bearing an electron-donating group on the aromatic ring. affording optically active 3-pyrazolines 171. Subsequent The application of enantioenriched 1,4-dihydropyridines isomerization of the double bond yields thermodynami- has been reported in the synthesis of alkaloids and a vari- cally more stable 2-pyrazolines 170. They also developed ety of biologically active molecules,137 in particular, mol- a direct method for the enantioselective 6p-electrocycliza- ecules that show activity against calcium channels,138 and tion from enones and hydrazines without the isolation of optically pure 4-substituted 1,4-dihydropyridine deriva- hydrazones 169. In this direct method, the prior formation tives have been utilized as chiral models of NAD(P)H.139 of hydrazones 169 using MS 4A was necessary in the ab- The present method enables efficient access to these dihy- sence of catalyst 1g, because the overall reaction proceed- dropyridine derivatives in a highly enantioselective man- ed sluggishly when enones and phenylhydrazine reacted ner. in the presence of the catalyst. The Hantzsch synthesis is one of the most efficient meth- ods for the preparation of 1,4-dihydropyridine deriva- tives. Gestwicki and Evans reported the highly

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1953

G products. The use of MS 4A was crucial to obtain desired

O products 178 in good yields. When the reaction was con-

O

1

Ar

(S)-14c: G =

P ducted in the absence of molecular sieves, considerable

OH

O amounts of byproducts 179 were formed via direct nu-

G cleophilic ring opening of azlactones 177a by 12.

O H

1 172 Ar

+

R O CO R

2 (S)-14c (20 mol%) N

2

2

+ +

Ar NH

Ar NH Ph

2 2

1

Ar H

C H CN, 50 °C, 24 h

6 5

O N 12

O

2 177a 12 172 + Ar

O O

173

1

Ar

40–93%, 81–98% ee

R H

Si G = Ph

OR 3

H

Ph N

( R)-1i (15–20 mol%) N R Ph 24

O

4 Å MS

O N O

2

Ar HN O CHCl Scheme 60 1,4-Dihydropyridine synthesis via three-component , 0–20 °C, 72 h 3

2

coupling Ar 179 178 62–90%, 62–96% ee enantioselective Hantzsch four-component coupling reac- Scheme 62 Cyclization reaction via three-component coupling tion of dimedone (174), ethyl acetoacetate (24b), aromatic among azlactones 177a, aniline derivatives 12, and a,b-unsaturated aldehydes 11, and ammonium acetate (175) using chiral aldehydes 172 phosphoric acid 1v (Scheme 61).140 The use of excess dimedone (174) was required to avoid the formation of Gong and co-workers also accomplished the enantioselec- byproducts, namely, symmetrical 1,4-dihydropyridines, tive synthesis of benzo[a]quinolizidine derivatives 180 and the desired four-component coupling products 176 using aryl ethylamine derivative 181, instead of aniline were afforded in good yields with high enantioselectivi- derivatives 12 (Scheme 63).142 Aryl ethylamine derivative ties. 181 participated in the smooth cyclization reaction of azlactone 177aa with various cinnamaldehydes 172 in the

O presence of 1i, affording cyclized products 182. Subse- O O O

+ + + NH OAc

4 quent treatment of 182 with boron trifluoride–diethyl

OEt Ar H 175

O 24b

11 ether complex resulted in the clean formation of ben- 174 zo[a]quinolizidine derivatives 180 via the Pictet–

(1.5 equiv) Spengler-type cyclization in good overall yield with ex-

G = cellent diastereo- and enantioselectivities.

O Ar

CO Et

2

( S)-1v (10 mol%)

* N

Ph

MeCN, r.t., 5 h

N

O

H O

176 177aa

1 Ar

69–94%, 87 to >99% ee

+

G = Ph Si

3 NHCOPh

NH ( R)-1i (20 mol%) 2

Scheme 61 1,4-Dihydropyridine synthesis via Hantzsch four- R

CO Et

2

4 Å MS O N

Et component coupling reaction CO

2

CHCl , 0 °C, 72 h

181

3

Ar CO Et 2

+

CO Et 2

141 182

Azlactones 177 possess multiple reactive sites. For ex- 172 1

ample, the acidic nature at the C4 position allows for the Ar

formation of an enol tautomer that functions as a nucleo- NHCOPh

BF OEt O ⋅ N 2 philic site and reacts with a variety of electrophiles, while 3

R

CH Cl , –15 °C

CO Et

2 2 the electrophilic nature of the carbonyl allows for nucleo- 2

CO Et

philic attack to furnish a ring-opening product. Hence, the 2

180 rich reactivity of the azlactone scaffold enables a large va- 65–75%, 90–97% ee riety of transformations, making azlactones very useful as versatile reactants in the synthesis of biologically interest- Scheme 63 Cyclization reaction via three-component coupling among azlactones 177aa, aryl ethylamine derivative 181, and a,b-un- ing molecules. Gong and co-workers developed an enan- saturated aldehydes 172 tioselective cyclization reaction via three-component coupling by taking advantage of the multiple reactive sites of azlactones 177a (Scheme 62).142 Chiral phosphoric 8.3 Intramolecular Aldol Reaction (Robinson- acid 1i efficiently catalyzed the three-component cou- type Annulation) pling among azlactones 177a, aniline derivatives 12, and The Robinson annulation reaction is one of the most fun- a,b-unsaturated aldehydes 172, affording cyclized prod- damental methods for providing cyclohexenone structural ucts 178 as a single diastereomer with high enantioselec- motifs and has been applied to a number of natural product tivity, although aliphatic enals failed to give the desired syntheses. The enantioselective catalysis of the Robinson

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1954 M. Terada REVIEW

-Pr annulation reaction is recognized as a prominent transfor- i

mation in organocatalysis research.143 The key step in the G = -Pr

enantioselective Robinson annulation reaction is the ini- i

O i-Pr

tial enantioselective Michael addition to enones using the O

O (R)-1q

chiral catalysts. Akiyama et al. have developed a novel (10 mol%)

-hexane or toluene strategy for the enantioselective Robinson annulation re- n R

R 70–90 °C, 48–96 h action, which has two enantioselective processes. They O

combined a chiral phosphoric acid catalyzed enantiose- O

187 188 lective Michael addition of a-alkyl-b-keto esters 183 to 72–94%, 87–94% ee methyl vinyl ketone (184) with a chiral phosphoric acid catalyzed kinetic resolution in the intramolecular aldol re- Scheme 65 Desymmetrization of s-symmetric triketones 187 lea- ding to enantioenriched cyclohexenones 188 action followed by dehydration (Scheme 64).144 Enan- tiomers 185 that were delivered predominantly by the as protonating agents of electron-rich double bonds to enantioselective Michael addition were transformed pref- generate cationic species for further elaboration. The ap- erentially by the kinetic resolution to give the correspond- proach opens a new avenue for utilization of chiral phos- ing Robinson-type annulation products 186 with excellent phoric acids towards advanced enantioselective catalysis.

enantioselectivities.

G 9.1 Carbon–Carbon Bond Formation via Proto-

C F 3

O nation of Enamides or Enecarbamates

O

(R)-14f: G = CF P 3 OH Enantioselective Friedel–Crafts reactions have been in-

O vestigated intensively, using metal-based chiral catalysts

G or chiral organocatalysts.55 These enantioselective cataly-

(R)-14f O

(2–10 mol%) O ses have been accomplished via the activation of electron-

+

Me

CO deficient multiple bonds, such as C=O, C=NR, and C=C– m-xylene 2 R

Z 20–50 °C, 24–48 h

184 X (X: electron-withdrawing group). The acid-catalyzed

183 Friedel–Crafts reactions of arenes with electron-rich alk-

(Z = CH or O) 2

-Pr i enes are practical and atom-economical methods for the

production of alkylated arenes and have been applied to

G = -Pr

i numerous industrial processes. However, there had been

-Pr

i no reports of the enantioselective catalysis of the Friedel–

O

(R)-1q

O O Crafts reaction initiated by the activation of electron-rich

(10 mol%) multiple bonds, even using chiral metal catalysts, until

toluene R

R

CO Me Z

2

reflux, 48 h 2007. Terada and Sorimachi successfully developed a

Z

CO Me 2

186 185 highly enantioselective Friedel–Crafts reaction initiated

54–74%, 96–99% ee 79–99%, 70–83% ee by the activation of electron-rich multiple bonds using a Scheme 64 Robinson-type annulation reaction via two enantiosel- chiral Brønsted acid catalyst for the first time. Chiral ective processes phosphoric acid 1q exhibited excellent performance for the activation, enabling the catalytic reaction of indoles 56a with enecarbamates 189 as electron-rich alkenes Akiyama and co-workers further developed the chiral (Scheme 66).146 Uniformly high enantioselectivities and phosphoric acid catalyzed desymmetrization of meso-1,3- chemical yields were achieved in the reaction of indole diones 187 to yield optically active cyclohexenone deriv- (56aa) with enecarbamates 189 bearing either a linear or atives 188 based on consecutive processes that included a branched alkyl group as well as an aromatic substituent. the enantioselective intramolecular aldol reaction as the In addition, the enantioselectivities were maintained at an key step (Scheme 65).145 The method provides an efficient equally high level for a wide variety of indole derivatives approach to cyclohexenone derivatives 188 in a highly 56a, irrespective of their electronic properties. The enantioselective manner via the desymmetrization of s- present approach provides efficient access to enantioen- symmetric triketones 187 followed by dehydration in a riched 3-indolyl methanamines 190 with a variety of ali- one-pot operation. phatic substituents and effectively complements previous methods that afforded aromatic-group-substituted 3-in- dolyl methanamines 57 via the activation of aromatic 9 Transformations via Protonation of imines (see Scheme 22). Electron-Rich Double Bonds The present Friedel–Crafts reaction proceeds through the Brønsted acid activation of an electron-rich double bond in situ generation of aliphatic imines 191 that are deliv- is a fundamental method to generate reactive carbocation ered via the protonation of enecarbamates 189 by the species. Brønsted acid catalyst molecules 1 undoubtedly phosphoric acid catalyst (Figure 5). Phosphoric acid func- possess relatively strong acidity and hence can be utilized tions as an efficient catalyst for the dual transformation

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1955

-Pr

i yield of Friedel–Crafts products 194 was remarkably im-

Boc

HN proved by the addition of MS 4A that prevented the hy-

G = i-Pr

1

R

H drolysis of enamides 193. It is noteworthy that in this Boc

NH 2

i-Pr

R catalytic Friedel–Crafts reaction, a quaternary stereogenic

1 189 R)-1q (2 mol%) (

R center bearing a nitrogen atom can be constructed in a +

MeCN, –20 to 50 °C, 12–48 h 2

R

N highly enantioselective manner.

H

190a

1 2

i-Pr R = H, R = H, Me, n-Bu, i-Pr, Ph

N

H 63–98%, 90–94% ee

Ac

1 2

56aa R = Me, R = Me G = i-Pr HN

69%, 94% ee Ac

X

Ar

i-Pr

HN Me

Boc Boc

193

(S)-1q (10 mol%) NH NH

Br

Ar R +

4 Å MS

N

toluene, 0–25 °C, 6–48 h

H

NH NH

R

194

190b 190c

95–99%, 86–97% ee

N

X = MeO, Me, Br, CO Me 78%, 96% ee

2

H

Ar: except ortho-substituents

84–91%, 90–93% ee 56a

Scheme 66 Friedel–Crafts reaction via activation of enecarbamates Scheme 68 Formation of quaternary stereogenic center bearing a 189 by phosphoric acid catalyst nitrogen atom in the Friedel–Crafts reaction that involves the in situ generation of imine 191 and the Tsogoeva and co-workers reported the enantioselective enantioselective carbon–carbon bond formation with in- formation of a quaternary stereogenic center bearing a ni- doles 56a. This protocol offers the distinct advantage of trogen atom through the homo-coupling reaction of en- generating, in situ, unstable aliphatic imines 191 from amides 193 (Scheme 69).149 Enamides 193 were isomerized storable and thus easily handled enecarbamates 189, and in situ to ketimines 195 under the influence of phosphoric hence is applicable to other organic transformations. In acid catalyst 1e, as depicted in Scheme 69. Electrophilic fact, Terada et al. applied this method to an enantioselec- ketimines 195 were generated under equilibrium condi- 147 tive direct Mannich reaction (Scheme 67). The method tions and their homo-coupling reaction with nucleophilic provides an efficient pathway to produce b-alkyl-b-ami- enamides 193 proceeded via the aza-ene-type mechanism nocarbonyl derivatives 192 in optically active forms. to give the corresponding imine products 196.87,89 Result-

ant imines 196 were readily isomerized to the enamine

O form under acidic conditions, giving enamide products

O

O

O

P 197 with high enantioselectivities. Hydrolysis of the en- O P

O

O

56a 1q

O

H amide moiety yielded optically active b-amino ketones

Boc H 189

190

Boc

N

H

N having a quaternary carbon atom, which are potentially

1

R 1

R

H useful as synthetic building blocks. H

2

R

2 R

aliphatic imines 191 generated via

G = NO 2 protonation of enecarbamates 189

Ac

Ar

AcHN HN

(R)-1e (10 mol%)

Figure 5 Mechanistic considerations of the Friedel–Crafts reaction 2

*

Ar NHAc

toluene, r.t., 72 h

of enecarbamates 189 with indole 56a Ar

193 197

79–83%, 88 to >99% ee

i-Pr

isomerization isomerization

Boc

G = i-Pr HN

Boc

R

NH

Ac

H

i-Pr Ar

AcHN

193 N

189

R

(R)-1q (5 mol%)

O

aza-ene * Ar NAc +

Ar

THF, 50 °C, 24 h

195 196 O 192

O Scheme 69 193 n-Bu, i-Bu, cyclohexyl, Bn R = Me, Homo-coupling reaction of enamides

O

49–73%, 49–89% ee 3 9.2 Enantioselective Protonation of Silyl Enol Scheme 67 Direct Mannich reaction via activation of enecarba- mates 189 Ethers The enantioselective protonation of prochiral enol deriva- Shortly thereafter, Zhou and co-workers independently tives is an attractive route for the preparation of optically reported the enantioselective Friedel–Crafts reaction of active a-substituted carbonyl compounds and has been indoles 56a with aryl-substituted enamides 193 catalyzed studied extensively for the enantioselective catalysis us- by chiral phosphoric acid catalyst 1q (Scheme 68).148 The ing chiral metal complexes or a metal complex (Lewis

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1956 M. Terada REVIEW acid) assisted chiral Brønsted acid system in the presence use of chiral phosphoric acids gives rise to ion pairs of a of achiral proton sources.150 Yamamoto and Cheon report- chiral conjugate base and an oxocarbenium ion via the ed a highly enantioselective protonation of cyclic silyl protonation of vinyl ether 139. Terada et al. developed enol ethers 198 using a metal-free chiral Brønsted acid for chiral conjugate base controlled enantioselective the first time (Scheme 70).88i They developed a new fam- transformations152 involving the oxocarbenium ion as the ily of chiral phosphoramide catalysts 199 and 200 in order reactive intermediate.153 They applied the intermediary to achieve higher acidity to promote the enantioselective oxocarbenium154 to a direct aldol-type reaction of azlac- protonation. tones 177b141 via their oxazole tautomers 177b¢

(Scheme 71). The method enables efficient access to bio-

i-Pr

: X = O Y = NHTf

66c logically and pharmaceutically intriguing b-hydroxy-a-

199a: X = S Y = NHTf

G amino acid derivatives having a quaternary stereogenic

G = i-Pr 200: X = Se Y = NHTf

: X = O Y = OH 1q center at the a-carbon atom.

O

X

201: X = O Y = SH i-Pr

P

O Y i-Pr

O

2

Ar

O

G = t-Bu 199b: X = S Y = NHTf G

N

1 i-Pr

Ar

i-Pr 177b

OTMS O

G = i-Pr

R R S)-199b (1–5 mol%) (

1 OH

R i-Pr

PhOH (203) (1.1 equiv)

O

R)-1q (5 mol%) (

toluene, r.t., 6–40 h 2

n

n Ar

2

+ O R

202 198

CH Cl , 0 °C to r.t., 12–48 h

2 2

N

(n = 1 or 2)

>99%, R = aromatic 72–90% ee

139

1

Ar

>99%, R = aliphatic 58–68% ee

177b'

1

Ar = 3,5-(MeO) C H 6 3

Scheme 70 Protonation of cyclic silyl enol ethers 198 2

1

R

1

O O O R O

2

2

R R MeONa

*

OMe * O + -205

It is noteworthy that almost no reaction was observed anti

2

2 MeOH

Ar

Ar NH

when the parent chiral phosphoric acid 1q and its thiol N

1

151 Ar

1

Ar O analogue 201 were employed. Meanwhile, the intro- 204

-205

duction of an NHTf group into the phosphoryl moiety, syn

1 t-Bu R

O i.e., phosphoramide catalyst 66c, is crucial to enhance the O

2 2

2

Ar = Ph Ar = Ph

catalytic activity, leading to the quantitative formation of R

1 2

-Bu n-Bu Bn Me n-Pr 202 t =R = enantioenriched product . Further substitution of the R

99% oxygen with sulfur 199a or selenium 200 in the phos- 66% 99% 94% 62%

syn syn 96% 88% 98% syn syn syn 80% phoramide catalyst improved enantioselectivity as well as 82%

97% ee 94% ee 96% ee 93% ee

reactivity. The enantioselectivities and the reactivities 98% ee

t-Bu

were also strongly dependent on the achiral proton sourc- O

2

Ar =

es and higher enantioselectivities could be achieved with X

X = 4-MeO, 4-Me, 4-CF , 4-Br, 3-Me X = 2-F sterically less hindered phenol or carboxylic acid deriva- 3

45% tives. Among the catalytic systems tested, 199b coupled 67–99%

70% syn syn

with phenol (203) as the achiral proton source displayed 94–98% 91–97% ee the best result in terms of catalytic activity and enantiose- 37% ee lectivity. Although moderate enantioselectivities were ob- Scheme 71 Aldol-type reaction of azlactones 177b via protonation served in the protonation of cyclic ketones having an of vinyl ethers 139 aliphatic substituent at the a-position, the method is well suited for cyclic ketones bearing either an electron- The electronic manipulation of Ar1 substituents intro- withdrawing or an electron-donating aromatic substituent. duced at the C2 position of azlactone 177 had a significant More importantly, the catalyst load can be reduced to as impact not only on the reactivity but also on the stereo- little as 0.05 mol% without any significant loss of enantio- chemical outcome in terms of both enantio- and diastereo- selectivity.88 selectivities. When electron-donating methoxy sub- stituents were introduced to the 3,5-positions of the phe- 9.3 Aldol-type Reaction via Protonation of Vinyl nyl ring, giving 177b, b-alkoxy-a-amino acid derivatives Ethers 205 were obtained with excellent enantio- and diastereo- selectivities after opening the azlactone ring of initial al- The activation of vinyl ethers by a Brønsted acid catalyst dol products 204. An investigation of the substituent is an extensively utilized and fundamental method in syn- effect of vinyl ethers 139 showed that the sterically de- thetic organic chemistry, and is employed in the protec- manding tert-butyl ether is important to achieve high dia- tion of alcohols and the formation of carbon–carbon stereoselectivity. Vinyl ethers 139 with an alkyl group bonds, among other processes. In this activation mode, the substitution at the terminal position were also applicable,

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1957 affording b-alkoxy-a-amino acid derivatives 205 with mild and weakly acidic conditions, effectively realizing high enantioselectivities. Azlactones 177b having a series the semi-pinacol rearrangement of 206. of aromatic groups (Ar2) revealed uniformly high enantio- and diastereoselectivities for para- and meta-substituted 9.5 Hydroamination via Protonation of Non- aromatic rings (Ar2), irrespective of their electronic prop- activated Alkenes erties. However, the ortho substitution led to a marked re- duction of selectivity and chemical yield. Terada et al. The intramolecular addition of amines to unsaturated car- proposed that the interaction, namely, C–H···O hydrogen- bon–carbon multiple bonds is one of the most direct meth- bond formation, between the chiral conjugate base and the ods for the preparation of nitrogen heterocycles. A variety oxocarbenium ion would allow the reaction to proceed un- of methodologies for the intramolecular hydroaminations der a chiral environment regulated by the chiral conjugate of alkynes and allenes have been reported so far.157 In con- base,153 and hence high stereoselectivities were achieved trast, the hydroamination of electronically nonactivated in this transformation. alkenes remains a challenging topic. The enantioselective hydroamination of nonactivated alkenes has relied thus far entirely on the use of chiral metal complexes. 9.4 Semi-Pinacol Rearrangement via Protona- Ackermann and Althammer reported the enantioselective tion of Vinyl Ethers intramolecular hydroamination of nonactivated alkenes The semi-pinacol rearrangement is one of the most funda- having a basic amine terminus under metal-free condi- mental skeletal rearrangements of carbon frameworks and tions (Scheme 73).158 Chiral phosphoric acid 1r enabled is considered to be a variant of the pinacol rearrangement, the hydroamination of aminoalkene 209, giving the corre- where a carbon–oxygen double bond is formed at C1 with sponding pyrrolidine derivatives 210 in optically active concomitant migration of a group from C1 to adjacent C2, forms, although the enantioselectivity was not sufficiently with or without loss of a leaving group, other than the hy- high.

droxy group, from C2.155 Tu and co-workers accom-

CF plished the enantioselective synthesis of spiroethers that 3 feature two fused rings joined by a single chiral oxo qua-

ternary carbon center, on the basis of the semi-pinacol re- G =

156 Bn

CF

3

arrangement (Scheme 72). Although a highly strained Bn

NH

Ph N (R)-1r (20 mol%)

cyclobutanol unit was necessary to promote the rearrange- Ph

Ph Ph

ment, allylic alcohol derivatives 206 were rearranged to 1,4-dioxane, 130 °C, 20 h

210 spiroethers 207 via protonation of the vinyl ether by chiral 209 phosphoric acid catalyst 1q and subsequent ring expan- 72%, 17% ee sion of the cyclobutane skeleton. The addition of MS 5A Scheme 73 Intramolecular hydroamination of nonactivated alkene was necessary for the reproducibility of the enantioselec- 209 tivity, affording the corresponding products 207 in good yields with high enantioselectivities. The authors also at- tempted the in situ generation of phosphoric acid 1q, us- 10 Miscellaneous Carbon–Carbon Bond- ing the corresponding silver phosphate 208 of 1q, because Forming Reactions of the lability of 206 under acidic conditions. This proce- dure, which involves a silver–proton exchange between 10.1 Aza-Cope Rearrangement alcohol 206 and silver phosphate 208, provides relatively Sigmatropic rearrangements are one of the most funda- mental methods for the construction of carbon frame-

works and have widespread application in the synthesis of -Pr

i biologically relevant molecules. A variety of enantiose-

G = -Pr i lective sigmatropic rearrangements have been established

using chiral metal catalysts or organocatalysts.159 Enantio- -Pr

i selective versions of the aza-Cope rearrangement provide (R)-1q (10 mol%)

R

or ( R)-208 (10 mol%) R O

O efficient routes to optically active homoallylic amines,

OH

R

R

5 Å MS which are useful precursors for the synthesis of natural

O

CCl , 0 °C to r.t., 2 h 4

n n products. However, this valuable transformation was not

206

207 successfully developed until 2008. Rueping and Anton- (n = 1, 2)

51–98%, 74–98% ee chick reported for the first time a highly enantioselective G

-Pr

i aza-Cope rearrangement that uses chiral phosphoric acid

O 160

O catalysts (Scheme 74). The reaction of aromatic alde-

P (R)-208: G = i-Pr

OAg hydes 11 with achiral homoallylic amine 211 proceeds O

-Pr i smoothly via the in situ generation of imines 212 in the

G presence of catalyst 14g to afford rearranged products Scheme 72 Semi-pinacol rearrangement of allylic alcohols 206 via 213, homoallylic amine derivatives, in good yields with protonation of vinyl ether high enantioselectivities. The method furnishes a practical

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1958 M. Terada REVIEW

route to the catalytic enantioselective aminoallylation of G

i-Pr

aromatic aldehydes on the basis of a condensation–rear- O

O

(R)-66c: G = i-Pr rangement sequence. Free primary homoallylic amines P

NHTf

214 were obtained by treating rearranged products 213 O

i-Pr

with hydroxylamine hydrochloride (215). G

Ph

G

(R)-66c (30 mol%)

N

) HSi(SiMe + + O RI

3 3

O

BEt , O 3 2

216 217 P

(R)-14g: G = Ar H THF, –40 °C, 24 h

OH

a: R = Et 2o O

i-Pr b: R =

O

c: R = t-Bu G

Ph

Ar H

Ph Ph

11 (R)-14g (10 mol%) N Ph

+

3 Å MS HN HN

+ Ar

Ph Ph

t-BuOMe, 50 °C, 48 h

213

* Ar Ar R Et

*

52–87%, 80–94% ee H N 2

218a R = Et (218a):

211

20–35%, 4–85% ee 56–77%, 73–84% ee

H HCl NOH⋅ 2

215 byproducts obtained in the R = i-Pr (218b), t-Bu (218c):

reaction of 216b and 216c

31–56%, 74–80% ee

Ph

Ph Ph

NH

2

Ph R)-14g

( Scheme 75 Reductive alkylation of imines 2o catalyzed by chiral

N N

Ar phosphoramide 66c

214

Ar Ar

212 213 forming strategy in organic synthesis. However, this im-

aza-Cope rearrangement portant methodology has remained a longstanding issue in Scheme 74 Aza-Cope rearrangement of in situ generated imine 212 asymmetric catalysis and hence various approaches have been investigated. Among those approaches, Petrini, 10.2 Radical Reaction Melchiorre, and co-workers and Cozzi et al. accomplished efficient methods for the enantioselective a-alkylation of Stereoselective radical reactions have received much at- simple aldehydes with stable and unsymmetrically substi- tention due to the uniqueness of the radical processes and tuted diarylcarbocations using chiral secondary amine hence, the enantioselective catalysis of radical reactions catalysts.163 Shortly thereafter, Gong and co-workers re- has been approached in various ways.161 In particular, be- ported that H8-BINOL-derived phosphoric acid 14a en- cause it is favorable for catalytic processes, reductive abled the highly enantioselective a-alkylation of alkylation has been investigated extensively in enantiose- enamides 219 with indolyl alcohols 220 to give b-aryl-b- lective radical reactions, where the addition of alkyl radi- indolylpropanones 221 in good yields (Scheme 76).164 cals to multiple bonds, followed by trapping of the The reaction proceeds via stabilized cation 222, a vinylo- resulting radicals with a hydrogen atom source, leads to gous iminium intermediate, generated in situ from indolyl reduced products. Kim and Lee developed an enantiose- alcohols 219 under the influence of acid catalyst 14a. lective radical reaction of imines 2o catalyzed by chiral

phosphoramide 66c on the basis of the reductive alkyla-

tion process using tris(trimethylsilyl)silane (217) as the Ph

hydrogen source and triethylborane as the initiator O

162 O

(Scheme 75). The enantioselective reductive alkylation P

OH

of imines 2o by ethyl iodide (216a) gave the correspond- O

R

2

Ar ing products 218a in good yields with relatively high Ph

Bz

(R)-14a (10 mol%)

enantioselectivities. Meanwhile, in the reaction of isopro- HN HO +

CH Cl , –30 °C, 34–68 h

2 2

pyl iodide (216b) and tert-butyl iodide (216c), desired 1 Ar

N

H products 218b and 218c were obtained in modest yields 219

220

R because of the considerable amount of byproduct 218a 2 O

furnished by the direct addition of an ethyl radical, gener- Ar

1 *

ated from triethylborane, to imines 2o. Ar R

N

H

221

2

Ar

10.3 Alkylation of Enamides via Activation of 69–96%, 88–96% ee

N Alcohols H

The catalytic enantioselective a-alkylation of carbonyl 222 derivatives is a highly valuable carbon–carbon bond- Scheme 76 a-Alkylation of enamides 219 with indolyl alcohols 220

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1959

11 Carbon–Heteroatom Bond-Forming Reac- between imines 227 and enamines 228 with concomitant tions racemization at the a-position. Dynamic kinetic resolu- tion occurs under the influence of catalyst (S)-1w, where- 11.1 Hydrophosphonylation (Kabachnik–Fields by the hydrophosphonylation of (R)-227 proceeds faster Reaction) than that of (S)-227 to give b-branched a-amino phospho- nates 225 with high diastereo- and enantioselectivities, es- The Kabachnik–Fields reaction, which involves the hy- pecially for aldehydes 226 bearing a secondary alkyl drophosphonylation of phosphites with imines generated group at the a-position. in situ from carbonyl compounds and amines, is an attrac-

tive method for the preparation of a-amino phosphonates.

OMe Et Et

Optically active a-amino phosphonic acids and their O

O (S)-1w (10 mol%)

R

+ +

phosphonate esters are an interesting class of compounds HP H

O

5 Å MS

O

due to their potent biological activities as non-proteino- Ar

cyclohexane

NH

Et Et

2

(±)-226 genic analogues of a-amino acids. Therefore, consider- 50 °C, 168 h 12b

able attention has been paid to their enantioselective 223b

synthesis by the hydrophosphonylation of preformed PMP

HN i-Pr Et

O imines, using either metal-based catalysts or organocata- R

165 P

1w: G = Et

lysts. O

Ar O

i-Pr Et

Akiyama et al. reported that chiral phosphoric acid 1r Et

functioned as an efficient catalyst in the addition reaction 225

R = secondary alkyl (cyclopentyl, -Pr, cyclohexyl)

of diisopropyl phosphite (223a) with N-PMP-protected i 76–94% ee 61–86%, 87–97% ,

166 anti

aldimines 2f (Scheme 77). Aromatic and a,b-unsaturat- R = primary alkyl (Me, Et)

2–84% ee 63–84%, 60–67% ,

ed imines could be used in the reaction, giving a-amino anti

PMP PMP phosphonate esters 224 in high yields. The use of sterical- PMP

HN N

ly demanding dialkyl phosphites 223 and aldimines de- N R R R

H H

rived from cinnamaldehyde derivatives is essential to H

Ar Ar

achieve high enantioselectivities. The same research Ar

(S)-227 228 (R)-227 group and Yamanaka and Hirata conducted DFT compu- (racemization)

tational analysis of the hydrophosphonylation reaction.167

fast

Chiral phosphoric acid 1r plays a significant role in the slow hydrophosphonylation

activation of both imine 2f and phosphite 223 based on its hydrophosphonylation dual functional catalysis. Scheme 78 Stereoselective synthesis of b-branched a-amino phos-

phonates 225 by Kabachnik–Fields reaction

CF

3

G = 11.2 Formation of (Hemi)Aminals

CF

3

PMP Aminals, compounds having two amino groups bound to

PMP

HN

Oi-Pr (R)-1r (10 mol%)

N the same carbon atom, are represented in many medicinal HP

+

Oi-Pr

R P(Oi-Pr)

m-xylene, r.t., 24–171 h

2

O R H agents that have versatile therapeutic actions, such as pro-

O 2f 223a teinase inhibitors and neurotensins. Antilla and co-work-

224 ers developed an enantioselective synthesis of protected R = aromatic e 72–84%, 52–77% e

R = alkenyl e 76–97%, 81–90% e aminals 229, which involved the addition reaction of ni- trogen nucleophiles 230 with N-Boc aromatic imines 2a Scheme 77 Hydrophosphonylation of imines catalyzed by chiral phosphoric acids (Scheme 79).170 In this novel enantioselective transformation, they employed List and co-workers reported an excellent approach to the a new type of axially chiral phosphoric acid 231, derived enantioselective synthesis of b-branched a-amino phos- from VAPOL (vaulted 3,3¢-biphenanthrol), originally de- phonates 225, which involved the dynamic kinetic resolu- veloped by Antilla’s research group. Indeed, 231 exhibit- tion strategy (Scheme 78)168 that they had previously ed excellent catalytic activity and enantioselectivity in the applied to the enantioselective reductive amination of ra- addition to N-Boc aromatic imines 2a. Enantioenriched cemic a-branched aldehydes 226 (see Scheme 91).169 aminal products 229a were obtained in the reaction of sul- They successfully accomplished the highly stereoselec- fonamides 230a (Scheme 79a) and were stable on storage; tive direct three-component Kabachnik–Fields reaction of neither decomposition nor racemization was observed in one equivalent each of racemic aldehyde 226, 4-methoxy- solution over several days. The same research group re- aniline (12b), and di(3-pentyl)phosphite (223b) in the ported the enantioselective addition reaction of phthal- presence of the newly developed chiral phosphoric acid imide or its derivatives 230b with N-Boc aromatic imines 1w by combining dynamic kinetic resolution with the par- 2a, affording the corresponding aminals 229b with excel- allel creation of an additional stereogenic center. The hy- lent enantioselectivities (Scheme 79b).171 drophosphonylation proceeds through a tautomerization

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1960 M. Terada REVIEW

a)

i-Pr

O

G =

O

O

NH 2 Ph

P

X

i-Pr O

Ph

OH

NH 2 O

233

S)-1w (10 mol%) ( NH

+ X

5 Å MS

N R O

Boc H

toluene, –45 °C, 24 h

HN

Boc

PG 232

(S)-231 (5–20 mol%)

H R N

PG

+

HN 11

89–98% ee R = primary alkyl 79–96%,

Ar N

*

O Et

1

2

R

i-Pr 26–50% ee R = Ph or 67–72%, Ar H

1 R

2a 230 229

O

O O

O O

H NO S H NO S S

2 2 2 2

NH NH

2

R

2

or b) (230a) a)

H NSOR HN HN 2 2

Cl N Cl N

2

R = aromatic or Me

H H

O O 230b

aquamox thiabutazide

( R)-231: 78%, 61% ee (S)-1x: 81%, 91% ee ( S)-231 (5–20 mol%), r.t., 1–20 h S)-231 (5 mol%), r.t., 24 h (

Boc

O O

i-Pr

Boc

HN

O

S H NO S

2 2

HN

NH

2

SO R Ar N

2 1x: G = Ad

Ar N

*

F C N

3 4

H

H

2 O

R i-Pr

penflutizide

229a 229b

Ad = 1-adamantyl ( S)-1x: 74%, 90% ee

80–99%, 73–99% ee 82–94%, 89–99% ee b)

Scheme 79 Preparation of aminals via addition of nitrogen nucleo- O

philes to imines NH 2

G =

O

NH 2

233a

R)-1g (10 mol%)

Cyclic aminals are relatively common structural elements ( NH

of diverse pharmaceutical compounds. However, no effi- + 3 Å MS

N R

O

CHCl , r.t., 24–48 h H

cient method was available to prepare these compounds 3

172 173 232

R

until 2008. The research groups of List and Rueping H

73–93%, 80–92% ee R = aromatic 11 independently reported a highly enantioselective direct (R = aromatic) synthesis of cyclic aminals 232 from aldehydes 11 and o- aminobenzamide derivatives 233 using chiral phosphoric Scheme 80 Direct transformation of o-aminobenzamides 233 with aldehydes into cyclic aminals 232 acids (Scheme 80). The catalytic reaction involves the imine formation/intramolecular amine addition sequence

using 11 and 233. In List’s approach, aliphatic aldehydes

G =

O were mainly employed as the substrate and the corre- O

sponding dihydroquinazolinones 232 were furnished with

(R)-1g (5 mol%) Ph HN Ph N

2

+ OH excellent enantioselectivities when primary alkyl-substi- R

EtOAc, r.t., 24 h

1 1 2

R H R OR tuted aldehydes and phosphoric acid catalyst 1w were 234

used (Scheme 80a). They also applied the enantioselec- 2d 235

1 2

76–99%, 83–95% ee R R = aromatic = primary alkyl

2

81–84%, 81–88% ee R tive method to sulfonamide analogues instead of benz- = secondary alkyl

1 2

62%, 65% ee R R = Et amides 233. The method provides a practical and efficient = Me route to pharmaceutically relevant compounds, namely, Scheme 81 Preparation of hemiaminal ethers 235 via addition of al- the benzo(thia)diazine class of cyclic aminals. In fact, cohols 234 to imines 2d they synthesized several benzo(thia)diazines, including aquamox, thiabutazide, and penflutizide, with high enan- tioselectivities using their modified methodology. Mean- phosphoric acid 1g. The method provides straightforward while, Rueping et al. focused on the preparation of access to chiral hemiaminal ethers 235 with high enantio- aromatic-substituted cyclic aminals 232 using aromatic selectivities. aldehydes and 233a as the substrates (Scheme 80b). Phos- phoric acid 1g was the best catalyst in their case. 11.3 Nucleophilic Ring Opening of Aziridines and Antilla and co-workers further extended their methodolo- Related Reactions gy to the addition of an oxygen nucleophile, instead of a The ring opening of aziridines with nitrogen nucleophiles nitrogen nucleophile (see Scheme 79), to imines provides an efficient route to a vicinal diamine structural 174 (Scheme 81). They successfully developed the catalytic moiety175 that exists in numerous biologically active com- enantioselective addition reaction of alcohols 234 as oxy- pounds and medicinal agents, as well as chiral ligands of gen nucleophiles with N-benzoyl imines 2d using chiral metal complexes. In this context, considerable effort has been devoted to their enantioselective synthesis. One of

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1961 the most direct methods for the preparation of enantio- corresponding products 240 with low to moderate enantio- enriched vicinal diamines is the enantioselective desym- selectivities. Della Sala and Lattanzi independently re- metrization of meso-aziridines 236 with nitrogen ported the highly enantioselective ring opening of meso- nucleophiles.176 Antilla and co-workers developed a high- aziridine 236 by (phenylthio)trimethylsilane (241; not ly enantioselective synthesis of vicinal diamines based on shown), instead of thiols 239, using the same catalyst the desymmetrization strategy using chiral phosphoric 231.179 A range of meso-aziridines 236b having a 3,5- acid 231 and azidotrimethylsilylane (237) as the nitrogen dinitrobenzoyl group at the nitrogen atom could be used nucleophile (Scheme 82).177 The 3,5-bis(trifluorometh- for this catalytic system, affording phenyl thioethers in yl)benzoyl substituent introduced on the nitrogen atom of good yields with high enantioselectivities. They also pro- aziridines, giving 236a, optimized both yield and enantio- posed that silylated phosphate generated in situ from cat- selectivity. A series of meso-aziridines 236a derived from alyst 231 with silylated nucleophile 241 would be a (hetero)cyclic and acyclic alkanes having aliphatic or aro- catalytically active species, following Antilla’s mechanis- matic substituents were applicable to the enantioselective tic proposal in the ring opening by azidotrimethylsilylane aziridine ring opening reaction, giving the corresponding (237).177

products 238 in optically active forms. They proposed that

NO

the silylated phosphate generated in situ by the reaction of 2

H

N

S)-231 (10 mol%) chiral phosphoric acid with azidotrimethylsilylane (237) (

COAr

1

+ R SH

is a catalytically active species. N

Et O, r.t., 20 h

2 NO

1 2 239 SR

O 240

CF

3

236b

N) C H Ar = 3,5-(O

2 2 6 3 H

N

1

R = aromatic 70–99%, 74 to >99% ee (S)-231 (10 mol%) COAr

1

+ R = heteroaromatic 71–78%, 55–82% ee TMSN N

3

DCE, r.t., 21–91 h

CF

1

3 N

R = aliphatic 15–86%, 18–62% ee 3 237

O 238

236a

) C H Ar = 3,5-(CF

3 2 6 3 H H H

2 R N N N

COAr COAr COAr

H H H

2 N R N N R SPh SPh SPh

COAr

COAr COAr

2 2

= Me R 99%, 95% ee 95%, 96% ee R = n-Pr

n

97%, 95% ee 94%, 87% ee

R N

N N 3 3 3

n = 1–3 R = Me R = Ph 84%, 92% ee

64–97%, 91–95% ee 88%, 86% ee 95%, 83% ee Scheme 83 Desymmetrization of meso-aziridines 236b with thiols

239 H H

N N

COAr COAr

X

N N

3 3 Toste and co-workers successfully demonstrated an enan-

90%, 70% ee X = NCbz

X = O tioselective synthesis of b-alkoxy amines from racemic b- 94%, 71% ee

49%, 87% ee chloro tertiary amines 242 and alcohols 243 as an oxygen Scheme 82 Desymmetrization of meso-aziridines 236a with azide nucleophile under the influence of an equimolar amount of silver(I) salt and a catalytic amount of chiral phospho- 180 Antilla and co-workers further applied their method to the ric acid 1q (Scheme 84). The methodology is based on the chiral counteranion mediated enantioselective trans- enantioselective ring opening of meso-aziridines 236 by a 152 series of thiols 239, instead of azide, as the nucleophile formation. The reaction proceeds via the asymmetric (Scheme 83).178 This expansion of the substrate scope en- ring opening of intermediary meso-aziridinium ions 244 abled the asymmetric synthesis of optically active b-ami- that were generated from the ring closure of b-chloro ter- no thioether derivatives 240. Phosphoric acid 231 also tiary amines 242 by silver(I) salts. Subsequent nucleo- functioned as an efficient catalyst for the ring opening by philic ring opening of meso-aziridinium ions 244 by thiols 239 in terms of catalytic activity and enantioselec- alcohols 243 provided the corresponding b-alkoxy amines tivity. Interestingly, a silyl group is not required in this 245. Secondary, tertiary, and relatively hindered primary ring opening of aziridines 236, which is in contrast to the alcohols could be used in the reaction, giving b-alkoxy reaction with azide as the nucleophile (Scheme 82). The amines 245 with high enantioselectivities. The efficient introduction of 3,5-dinitrobenzoyl to the nitrogen atom of desymmetrization of meso-aziridinium ion 244 was aziridine, giving 236b, is highly desirable in achieving the achieved under the influence of the chiral counteranion high enantioselectivities. 3,5-Bis(trifluoromethyl)ben- derived from phosphoric acid 1q, as the ion pair G was zoyl, which was employed for the ring opening by azide formed between cationic 244 and the counteranion of 1q. (Scheme 82),177 and 4-nitrobenzoyl protective groups dis- They pointed out that the resulting catalytic process can be regarded as chiral anion phase-transfer catalysis in played much lower enantioselectivities. Arylthiols are 181 suitable for the reaction. Thus, a wide variety of electron- analogy to the established chiral cation alternative. withdrawing and electron-donating substituents can be in- Toste and co-workers further extended their chemistry to troduced to the ortho-, meta-, and para-positions of the the sulfur analogue of the ring opening reaction, namely, aromatic ring. Meanwhile, heteroaryl- and alkylthiols the desymmetrization of meso-episulfonium ions 246 proved to be relatively poor reaction partners, giving the (Scheme 85).180a However, in this application, the silver–

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1962 M. Terada REVIEW

Ph Cl

OMe 12 Transfer Hydrogenation Reactions

+

HO Ph

N 12.1 Transfer Hydrogenation of Acyclic and

243a 242 (±)- Cyclic Imines -Pr

i The enantioselective reduction of ketimines is a straight-

G = -Pr i forward approach to synthesizing optically active amines.

OMe Although the catalytic enantioselective hydrogenations

i-Pr

O

Ph and the transfer hydrogenations of ketones and olefins ( )-1q (15 mol%)

S have been intensively investigated using chiral metal

Ag CO (0.6 equiv)

2 3 Ph N

4 Å MS complexes, the corresponding enantioselective reductions

toluene, 50 °C, 24–36 h of imines are less advanced and hence the development of 245a

81%, 92% ee efficient methods for these transformations is still one of

O

Ph the greatest challenges in the practical synthesis of chiral R

O P O

N amines. Most catalytic enantioselective hydrogenations of

R

O

Ph ketimines have been conducted using common hydrogen

244 1q G sources, such as high-pressure hydrogen gases, di- or tri- alkylsilanes, and ammonium formate, under the influence

182

Ph O

O Ph of chiral transition-metal complexes. Recently, List and

R co-workers and MacMillan and co-workers independently

NO 2 Ph N

Ph

N reported the organocatalytic transfer hydrogenations of

N a,b-unsaturated aldehydes using Hantzsch esters 249

R =

R = t-Bu

O (Figure 6), which are dihydropyridine derivatives, as a

245b 245d

245c biomimetic hydrogen source.183 Following these excellent

87%, 96% ee 70%, 99% ee

56%, 92% ee reports, Hantzsch esters gained popularity as an efficient Scheme 84 Desymmetrization of meso-aziridinium ions 244 with hydrogen source for the enantioselective reduction of or-

alcohols 243 ganic compounds, including imines.184

1 2 3

, R = Et, R = Me a: R H halogen abstraction method for the generation of the cat- H

1 2 3

1 2

= Me, R = t-Bu, R = Me b: R R O C CO R

2

ionic intermediate could not be utilized, because the sul- 2

1 2 3

, R = allyl, R = Me c: R

1 2 3

, R = t-Bu, R = Me

: R

fide would likely bind silver(I). Therefore, they employed d

3

N R

1 2 3

, R = Me, R = i-Pr e: R

trichloroacetimidate as the leaving group. The trichloro- H acetimidate moiety is directly activated by chiral phos- 249 phoric acid 1q, and this is followed by ring closure with Figure 6 Hantzsch esters 249 concomitant loss of trichloroacetamide from substrates 247 generating ion pair H of meso-episulfonium ions 246 and the chiral counteranion. The interception of interme- In 2005, Rueping et al. reported that chiral phosphoric acid 1r functions as an efficient catalyst for the enantiose- diate 246 with an oxygen nucleophile, such as alcohols 185 243, affords chiral sulfide products 248 in excellent yields lective reduction of ketimines 250 (Scheme 86a-1). A with good enantioselectivities. variety of aryl methyl ketimines 250 were reduced to the corresponding amines 251 in optically active forms using

Hantzsch ester 249a as the hydrogenation transfer re- -Pr

i agent.186 In the same year, List and co-workers indepen-

G =

-Pr

i dently reported the highly enantioselective transfer

HN CCl

3 250 -Pr i hydrogenation reaction of ketimines using Hantzsch

2

Ph OR

Ph O

S)-1q (15 mol%)

( ester 249a by thorough optimization of the substituents

2 + R OH

toluene, r.t., 12 h

1 (G) that were introduced onto the phosphoric acid catalyst

1 Ph SR

243 Ph

SR 187

2

248 = primary or (R (Scheme 86a-2). Almost simultaneously, MacMillan

(±)-247

90–98%, 87–92% ee secondary alkyl)

1 and co-workers successfully developed the enantioselec- (R

= Me or Bn) tive reductive amination reaction using Hantzsch ester

Ph

O 249a via simple fragment coupling between ketones 252

1

SR

O

OP and aniline derivatives 12b (Scheme 86b).188 Acid cata- Ph

O lyst 1i, with its sterically demanding triphenylsilyl groups,

246 1q H was optimal for the enantioselectivity. Although the reac- tion required a methyl ketone subunit, this operationally Scheme 85 Desymmetrization of meso-episulfonium ions 246 with simple method is applicable to not only aryl but also alkyl alcohols 243 methyl ketones and provides a highly efficient route to structurally diverse chiral amines. In their conscientious studies on the reductive aminations, MacMillan and co-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1963

a)

1 (cat.)

PMP PMP

HN N 249a

R * R G =

250 251 a)

(R)-1m

a-1) a-2)

i-Pr

CF 3

X X

249a

( (R)-1r: G = S)-1q: G = i-Pr

CHCl , r.t., 12 h

3

N Ar N Ar

H (10 mol%) (1 mol%)

253a: X = O

255 i-Pr CF

3

b: X = S

R = aromatic or isopropyl R = aromatic 255a: X = O 0.1 mol% of 1m

toluene, 35 °C, 42–71 h benzene, 60 °C, 16 h 92–95%, 98 to >99% ee

80–98%, 80–93% ee ( 46–91%, 70–84% ee ( R) S)

255b: X = S 1 mol% of 1m

50–87%, 93 to >99% ee

b)

b)

G = Ph Si 3 (R)-1m (1 mol%)

( R)-1i (10 mol%)

O O O O

249a

OMe

PMP

O

249a HN

CHCl , r.t. to 60 °C, 15–24 h + 3

N Ar

N Ar 5 Å MS

R

H N

R

2 H

254a benzene, 40–50 °C

252 12b 251

256a

24–96 h

49–92%

(R = aromatic or aliphatic) 55–92%, 90 to >99% ee

83–96% ee

Ts

PMP

N

G = HN

c)

PMP

HN

HN

H

H ( R)-1g (10 mol%)

Z N

N Z

F

249a

Ph

Ph

X X

90%, 93% ee 75%, 85% ee 70%, 88% ee

N Ar

N Ar

H

H

253c: Z = H, H

PMP

c: Z = H, H 255 N

HN

254b: Z = O

b: Z = O 256

BzO

255c: Z = H, H CHCl , 35 °C, 24 h O O 3

73–98%, 92–98% ee 72%, 81% ee 82%, 97% ee

256b: Z = O THF, 50 °C, 24 h Scheme 86 Transfer hydrogenation of acyclic ketimines 250 using 42–75%, 92–98% ee Hantzsch ester 249 as the biomimetic hydrogen source Scheme 87 Transfer hydrogenation of cyclic imines, 253 and 254 workers also reported a couple of examples using cyclic imines as the substrate. You’s studies. In both cases, excellent enantioselectivities Shortly thereafter, a detailed investigation of the transfer were achieved. You and co-workers further applied the hydrogenation of cyclic imines was conducted by method to the enantioselective reduction of a-imino esters Rueping et al. (Scheme 87a).88g Benzoxazines 253a un- 259 having an alkynyl substituent at the a-position 192 derwent the transfer hydrogenation in good yields with (Scheme 89). Both alkyne and imine moieties were re- extremely high enantioselectivities even with a remark- duced under transfer hydrogenation conditions with an ably low catalyst load of 1m (0.1 mol%). Benzothiazines excess amount of Hantzsch ester 249a (2.2 equiv) to give 253b (Scheme 87a) and benzoxazinones 254a b,g-unsaturated a-amino esters 260. Although the chemi- (Scheme 87b) were also hydrogenated by Hantzsch ester cal yields were moderate, high enantio- and trans-selec- 249a in the presence of the same catalyst 1m (1 mol%) to tivities were achieved using the same chiral phosphoric give the corresponding products, 255b and 256a, with ex- acid catalyst 1g.

cellent enantioselectivities. They further extended the

(S)-231 (5 mol%)

PMP

transfer hydrogenation to quinoxalines 253c and quinox- PMP N HN

alinones 254b using 1g (10 mol%) as the catalyst, giving 249a

toluene, 50 °C, 18–22 h R CO Et R CO Et 2

rise to 2-tetrahydroquinoxalines 255c and 3-dihydroqui- 2 258

noxalinones 256b, respectively, with high enantioselec- 257 85–98%, 94–99% e e

189 (R = aromatic or tivities (Scheme 87c). aliphatic)

190

O

Soon after these initial reports, the groups of Antilla O

Ph

and You191 independently applied the chiral phosphoric P Ph OH

acid catalysis approach to the enantioselective hydrogena- O tion of a-imino esters 257. The method provides an alter-

native route to the enantioselective synthesis of a-amino

S)-231 esters 258. Antilla and co-workers employed VAPOL- ( derived phosphoric acid 231,177 originally developed by Scheme 88 Transfer hydrogenation of a-imino esters 257 his research group (Scheme 88), whereas 1g was used in

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1964 M. Terada REVIEW

O

1

R

+ H NAr

2

H G =

–c 12a

2 R

C H )

(Ar = Ph, PMP, 4-CF 3 6 4

PMP PMP (±)-226 (S)-1g (1 mol%)

N HN

1

249a (2.2 equiv)

(R = aromatic, aliphatic, CF ) 3

2

(R = Me, Et)

i-Pr

CO Et Ar CO Et

2 2 Et O, r.t., 24 h 2

Ar

259 260

G = i-Pr

27–64%, 83–96% ee

i-Pr

Scheme 89 Transfer hydrogenation of a-imino esters 259 having an Ar

(R)-1q (5 mol%) HN

alkynyl substituent at the a-position 249b

1 R

5 Å MS, benzene, 6 °C, 72 h 2

As shown in Schemes 86, 88, and 89, the reductive ami- R

262

1

R = aromatic 88–98% ee nation of ketones and the hydrogenation of ketimines cat- 46–96%,

1

R = aliphatic, CF 40–80% ee 39–81%,

alyzed by chiral phosphoric acids were accomplished with 3

Ar Ar high enantioselectivities. However, in these reductions, Ar

HN N

aryl derivatives, such as PMP, were primarily employed N

1 1 1 R R R

H H

as the nitrogen protective group. The removal of these H

2 2 2

R R

protective groups usually required somewhat harsh reac- R

228 R)-227 (S)-227

tion conditions. Antilla and Li circumvented this draw- ( back by using enamides 193 as the substrates (racemization)

(Scheme 90).193 The reduction of enamides 193 proceed- slow reduction ed via tautomerization to intermediary imines to give fast reduction amine products 261 having an N-acetyl protective group Scheme 91 Enantioselective synthesis of b-branched amines 262 that can be readily removed under standard conditions. through dynamic kinetic resolution Acetic acid was employed as the co-catalyst, which al- lowed for the reduction of the catalyst load of 1g to 1 genic center via the transfer hydrogenation of 2,4-diaryl- mol% while maintaining the high enantioselectivity. Ace- 2,3-dihydrobenzodiazepine derivatives 264 on the basis tic acid accelerated the tautomerization of the enamide to of dynamic kinetic resolution (Scheme 92).194 The trans- the imine, while it was inactive in the subsequent reduc- fer hydrogenation of the S-enantiomer among racemic tion and only chiral phosphoric acid 1g functioned as the 264 proceeds rapidly in the presence of (R)-14a to afford active catalyst for the successive transfer hydrogenation (2S,4R)-syn-263 predominantly along with (2S,4S)-anti- of the imine. 263. Meanwhile, the opposite enantiomer, (R)-264, un- dergoes slow transfer hydrogenation and the remaining (R)-264 racemizes via intermediate 265 through the retro-

Mannich and Mannich sequences. G =

Ac Ac (S)-1g (1 mol%), AcOH (10 mol%)

(R)-14a (10 mol%)

HN HN

249a

249c

Ar Ar toluene, 50 °C, 14–44 h

NNH

Na SO

2 4 193 261

CHCl , –10 °C, 5.5 d

3

43–99%, 71–95% ee Ar

Ar

o-substituted aryl except

(±)-264

Scheme 90 Transfer hydrogenation of enamides 193

+

Ph HN NH HN NH

Ar Ar

O

Ar List and co-workers developed an excellent approach to Ar O

P

-263 anti-263

synthesize b-branched amines in optically active forms by syn

OH

O

combining the enamine and reductive amination process- 63–97%

/anti = 2:1 to 8:1

169 syn

es (Scheme 91). The reductive amination of unsymmet- Ph

63–86% ee for syn (2S,4R)

(R)-14a

75–94% ee for (2S,4S) rically a,a-disubstituted aldehydes 226 and aniline anti derivatives 12a–c proceeded through a tautomerization

227 228 retro- between imine and enamine . Dynamic kinetic Mannich Mannich

(S)-264 R)-264

resolution occurred under the influence of catalyst (R)-1q, ( HN N

retro-

Mannich

whereby the hydrogenation of (R)-227 proceeded more Mannich Ar

rapidly than that of (S)-227 to give b-branched amines 262 Ar

fast reduction 265 slow reduction with moderate to high enantioselectivities (see (racemization) Scheme 78). Scheme 92 Enantioselective synthesis of 1,3-diamine derivatives Gong and co-workers reported a facial synthesis of chiral 263 through dynamic kinetic resolution 1,3-diamine derivatives 263 bearing a quaternary stereo-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1965

In organocatalytic hydrogenations, the hydrogen sources reaction proceeds via a tandem hydrogenation cascade. were, until recently, limited to Hantzsch esters 249, which The first step of the cascade generates enamines 269 via are the most well used cofactors in biochemical hydroge- the 1,4-hydride addition to quinolines 267. Under acidic nation reactions.184 Akiyama and Zhu utilized benzothia- conditions, the subsequent isomerization of 269 provides zoline derivative 266,195 which functioned as an efficient imines 270, which are delivered to the second step of the antioxidant with potent reducing ability,196 as a novel hy- cascade. The 1,2-hydride addition to imines 270 with gen- drogen source, instead of Hantzsch esters 249 eration of the stereogenic center provides enantioenriched (Scheme 93). Aromatic methyl ketimines 250 having tetrahydroquinoline products 268. electron-donating and electron-withdrawing substituents were well tolerated in this hydrogenation system and even

aliphatic ketimine underwent the reduction while main- taining excellent enantioselectivity. It is noteworthy that G =

the present method, using 266 as a novel hydrogen source,

R)-1m (1–5 mol%) provides the corresponding products 251 with higher ( (2.4 equiv)

enantioselectivities than those obtained in previous re- 249a

185,187,188 benzene, 60 °C, 12–60 h

R N R

ports (see Scheme 86) in which Hantzsch ester N

H

267

249a was employed. The distinct advantage of this proto- 268 (R = aromatic or aliphatic)

91 to >99% ee R = aromatic:

col is that benzothiazoline 266 can be generated in situ 54–93%,

87–91% ee R = aliphatic:

from 2-naphthalenecarbaldehyde and 2-aminothiophenol. 88–95%,

1,4-hydride

1,2-hydride

Thus, the three-component reaction between 250 and the addition in situ generated 266 becomes operative without consid- addition

erable loss of enantioselectivity and chemical yield. acid-catalyzed

isomerization

H

N

N R N R

H

269 270 S

266 Scheme 94 Transfer hydrogenation of 2-substituted quinolines 267 -Pr

i to tetrahydroquinolines 268

G = i-Pr

-Pr i Du and co-workers reported the enantioselective hydroge-

(R)-1q (2 mol%) PMP PMP

N nation of quinolines using a new type of axially chiral HN

266 phosphoric acid catalyst 271 having a bis-BINOL scaffold

mesitylene, 50 °C, 25–30 h R

R (Scheme 95).88h Newly developed catalyst 271 showed 250 251

84–97%, 95–98% ee R = aromatic higher efficiency than the parent mono-BINOL-derived

80%, 98% ee R = cyclohexyl phosphoric acid catalysts. The enantioselectivities of Scheme 93 Transfer hydrogenation using benzothiazoline derivati- alkyl and aryl 2-substituted quinolines 267 were uniform- ve 266 as a novel hydrogen source ly high and the corresponding tetrahydroquinolines 268 were obtained quantitatively even when the catalyst load was reduced to as little as 0.2 mol%. 2,3-Disubstituted 12.2 Tandem Transfer Hydrogenation of Quino- quinolines were also hydrogenated with high diastereo- lines and Pyridine Derivatives and enantioselectivities.

The asymmetric hydrogenation of nitrogen-substituted

R,R)-271 (0.2 mol%)

heteroaromatic compounds provides a straightforward ( (2.4 equiv)

and attractive route to enantioenriched nitrogen heterocy- 249d

O, 35 °C, 20 h Et

2

1 1

N R R

cles. In contrast, the enantioselective hydrogenation of N H

267

268

these heteroaromatics using chiral transition-metal cata- 1 (R = aromatic or aliphatic)

1

R = aromatic >99%,

lysts has not been fully established and successful exam- 94–98% ee

except -substituent

197 ortho

ples of these transformations are limited. The use of 1 R = aliphatic >99%,

Hantzsch esters 249 as the hydrogen source was proven to 88–95% ee

OH

be beneficial for the asymmetric hydrogenation of these O

2 2

R R P

O

heteroaromatics by Rueping et al. The enantioselective re- O

O O

duction of quinolines 267 to tetrahydroquinolines 268 us- 2 = ing Hantzsch ester 249a proceeded smoothly in the R presence of chiral phosphoric acid catalyst 1m

198

( ,R)-271 (Scheme 94). The method is applicable to a variety of R 2-aryl- and 2-alkyl-substituted quinolines 267 and pro- vides direct access to tetrahydroquinoline alkaloids 268 in Scheme 95 Transfer hydrogenation of quinolines 267 using newly developed chiral phosphoric acid catalyst 271 a highly enantioselective manner. They proposed that the

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1966 M. Terada REVIEW

Rueping and Antonchick successively applied the cascade Rueping et al. further extended the method to the hydro- transfer hydrogenation strategy to the enantioselective re- genation of 3-substituted quinolines 276 (Scheme 97).201 duction of pyridine derivatives (Scheme 96a).199 Catalyst Here, the key step is the enantioselective protonation of 1g functioned efficiently in the hydrogenation of pyridine intermediary enamine 277. The mechanisms of the stereo- derivatives 272 to furnish the corresponding products 273, determining step are entirely different from those of the hexahydroquinolinones, with high enantioselectivities. asymmetric hydrogenation of 2-substituted quinolines The method allows access to enantioenriched nitrogen 267, where the 1,2-hydride addition step is the key to de- heterocycles as useful precursors of various natural prod- termining the stereochemical outcome (see Scheme 94). ucts. Metallinos et al. reported the enantioselective reduc- After thorough optimization of the phosphoric acid cata- tion of 2-substituted and 2,9-disubstituted 1,10- lyst, 14b was found to be the best, giving 3-substituted tet- phenanthrolines 274 (Scheme 96b).200 Although consider- rahydroquinolines 279 with good enantioselectivities. able amounts of meso-isomers were formed in the hydro- genation of 2,9-disubstituted 1,10-phenanthrolines 274b, 12.3 Transfer Hydrogenation of a,b-Unsaturated dl-octahydrophenanthrolines 275b were obtained with ex- Carbonyl Compounds cellent enantioselectivities. Most organic transformations proceed via ionic interme- diates or transition states and hence are influenced by the

counterion, particularly in organic solvents, because ion G =

a) pairs are ineffectively solvated in these media. Although

O

O

R)-1g (5 mol%)

( efficient asymmetric catalytic transformations involving (4 equiv)

249a anionic intermediates have been realized using chiral cat-

R

benzene R 181

N

N ionic catalysts, such as phase-transfer catalysts, an anal-

50 °C, 30–36 h H

272 ogous version of inverse polarity was not accomplished 273 66–84%, 87–92% ee until recently. In this context, List and Mayer introduced the concept of ‘asymmetric counteranion directed cataly- sis (ACDC)’ as a useful strategy in enantioselective orga-

152 G = b) nocatalytic transformations and applied their ACDC

concept to a metal-free biomimetic transfer hydrogena-

R)-1m (2 mol%)

( tion of a,b-unsaturated aldehydes 280,183 in which a bina-

249a (6 equiv)

1

N R

1

N R

H ry catalytic system of an achiral amine and a chiral

N benzene

NH 152

60 °C, 24 h phosphoric acid was employed (Scheme 98). They

2

R

2

R

274 275 found that the morpholine salt of 1q, prepared readily by

1 2

= Me, n-Bu; R = H : R 275a simple mixing, was a widely applicable and highly enan-

54%, 78–83% ee tioselective catalyst for the transfer hydrogenation of a,b-

1 2 275b: R = Me, n-Bu

= R unsaturated aldehydes 280. The catalytic salt of morpho- 72–88%, /meso = 3:2, 99% ee for dl-isomer

dl line and 1q generates the ion pair, I, of achiral iminium Scheme 96 Transfer hydrogenation of pyridine and 1,10-phenan- cation and chiral phosphate anion, where the chiral phos- throline derivatives phate anion could induce the asymmetry in the process. a,b-Unsaturated aldehydes having aromatic substituents

at the b-position were reduced to their corresponding sat- SiPh

3 urated aldehydes 281 in good yields with excellent enan-

O

O tioselectivities. The method is also applicable to a,b-

P OH unsaturated aldehydes with less sterically hindered ali-

O phatic substituents, the transfer hydrogenations of which SiPh

3 could not be achieved by previous methods using chiral

(R)-14b (5 mol%)

Ar Ar

(2.4 equiv) 249c amine base catalysts in a highly enantioselective man-

ner.183,184

benzene

N N

60 °C, 22–48 h H

276 List and Martin further applied their salt catalyst to the

279 30–84%, 77–86% ee enantioselective hydrogenation of a,b-unsaturated ke-

202

1,4-hydride tones 282 (Scheme 99). Although, in the reduction of

1,2-hydride addition 282, the morpholine/chiral phosphoric acid salt system

addition failed to provide the corresponding saturated ketones 283

enantioselective in satisfactory yields and enantioselectivities, ammonium Ar Ar

protonation phosphate, derived from (R)-1q and primary amine (S)-

N

N valine tert-butyl ester, proved to be effective for the

H

278 277 present transfer hydrogenation. It is noteworthy that the salt derived from the opposite enantiomer of 1q, namely, Scheme 97 Transfer hydrogenation of 3-substituted quinolines to (S)-1q, and (S)-valine tert-butyl ester displayed a consid- tetrahydroquinolines

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1967

G for the cascade transformation, giving the corresponding

i-Pr

O O 3-substituted (hetero)cyclohexylamines 284 with high

O

P G = -Pr i enantio- and cis-selectivities. The reductive amination of

O

O

N 3-substituted cyclohexanones, intermediate 288 of the

H 2

i-Pr

G present cascade, generally provides the corresponding

R)-1q/morpholine (20 mol%)

( trans-isomer under standard reductive amination condi- CHO CHO

249e tions. In contrast, in the present cascade transformation,

R

R cis-284 was obtained predominantly.

280 281

1,4-dioxane, 50 °C, 24 h R = aromatic 63–90%, 96 to >98% ee

O

THF, r.t., 24–96 h R = aliphatic 71–77%, 90–92% ee

i-Pr

O

X O

G = i-Pr O

N R

OPO

Ar 285

i-Pr

HN

O

H (R = 2-naphthyl or aliphatic)

R)-1q (10 mol%) (

, O, S) (X = CH 1q

2

249a (2.2 equiv)

R

+

X

I 5 Å MS

R

H NAr

cyclohexane, 50 °C, 72 h 2

284

Scheme 98 Asymmetric counteranion directed organocatalytic 12 35–89%

Ar = 4-MeOC H

12b:

6 4

67–99% , 82–96% ee

transfer hydrogenation of a,b-unsaturated aldehydes 280 cis

Ar = 4-EtOC H 12h: 6 4

N CO t-Bu H 1,2-hydride 3 2

enamine (R)-1q

addition formation

i-Pr O O

(5 mol%)

intramolecular

249a

NHAr

NAr NAr

1,4-hydride aldol

1 1

R

R

2 3

2 3

R R n-Bu O, 60 °C, 48 h R R addition condensation 2

282 283

X O

X X

1 2

R R R , R = cyclic 68 to >99%, 94–98% ee

1 2

287 288 R R , R = acyclic 81 to >99%, 70–84% ee 286

Scheme 99 Transfer hydrogenation of a,b-unsaturated ketones 282 Scheme 100 Intramolecular aldol condensation/tandem transfer hy- drogenation cascade erable decrease in yields and enantioselectivities. Not only cyclic but also acyclic ketones 282 were reduced ef- Rueping and Antonchick developed an organocatalytic ficiently in the presence of (R)-1q and (S)-valine tert-bu- multiple-cascade sequence using enamines 289 and a,b- tyl ester, giving saturated products 283 in good yields and unsaturated ketones 290 as substrates to obtain enantioen- enantioselectivities. riched nitrogen heterocycles 291 (Scheme 101).206 The multiple-cascade sequence comprises Michael addition, geometrical isomerization, cyclization, dehydration, 12.4 Application of Transfer Hydrogenation to isomerization, and 1,2-hydride addition, in which each Cascade Reaction single step is efficiently catalyzed by chiral phosphoric Cascade transformations involving different organocata- acid catalyst 1g. The method enables direct, rapid, and ef- lytic processes have emerged as a powerful and efficient ficient access to a diverse set of tetrahydropyridine and method for the rapid construction of complex molecules azadecalinone derivatives 291 with excellent enantio- starting from simple materials in one pot.90 In particular, selectivities. organocatalyses by amines or their salts were intensively applied to cascade transformations, including enamine or iminium ion, as the reactive intermediate.203 List and 13 Oxidations Zhou successfully combined chiral phosphoric acid catal- ysis with these amine catalyses based on enamine and imi- 13.1 Epoxidation 204 nium ion mechanisms (Scheme 100). They developed a Catalytic asymmetric epoxidation occupies a privileged highly enantioselective synthesis of 3-substituted (hete- position in organic synthesis owing to the fundamental ro)cyclohexylamines 284 from 2,6-diketones 285 via a 205 importance of enantioenriched epoxides as key synthetic three-step organocatalysis, namely, (i) intramolecular intermediates. A number of efficient protocols for the 286 aldol condensation via enamine formation to give cy- enantioselective epoxidation using chiral metal 287 clized product ; (ii) 1,4-hydride addition under the catalysts207 and organocatalysts208 have been reported to 288 iminium ion mechanism to give saturated imine ; and date. The Julia–Colonna epoxidation is one of the most ef- (iii) 1,2-hydride addition cascade catalyzed by chiral ficient synthetic methods for the enantioselective func- 12b phosphoric acid and accelerated by aniline substrate tionalization of a,b-unsaturated ketones using hydrogen or 12h. Acid catalyst 1q exhibited excellent performance peroxide under basic conditions.209 Since its discovery in

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1968 M. Terada REVIEW

List et al. applied their ACDC concept152 to the develop- ment of the enantioselective epoxidation of a,b-unsaturat-

G = ed aldehydes 292 using an ammonium phosphate salt

211

(R)-1g (5 mol%)

EWG

EWG catalytic system (Scheme 102). They identified a new

249a (1.1 equiv)

+ catalytic salt that was derived from dibenzylamine deriv-

3 Å MS

1 2

1

2

N R R R NH O R

2 ative 293 and phosphoric acid 1q, and functioned as an ef-

H CHCl or benzene

3

289 290

50 °C, 12–18 h 291 ficient enantioselective catalyst for 1,2-disubstituted enals

292a having aromatic substituents at the b-position. The 1,2-hydride

Michael corresponding epoxides 294a, with excellent trans- and addition

addition enantioselectivities, were obtained in the presence of tert-

EWG

EWG

O butyl hydroperoxide (TBHP) as the oxidant, although an

2 enal having an aliphatic substituent at the b-position ex-

R

1 2

H N R N R

1 2

R hibited a slight decrease in stereoselectivity. Notably, this

geometrical salt-catalyzed reaction is well suited for trisubstituted isomerization

isomerization

cyclization enals 292b to afford trisubstituted epoxides 294b with

&

EWG high enantioselectivities, because these enals 292b have EWG O

dehydration previously been elusive substrates for all types of enantio-

2

1 2

R R N R

1

R

H

NH selective epoxidation. 2

NC MeO C

2 13.2 Baeyer–Villiger Oxidation

N Ar N Ar

H

H The Baeyer–Villiger reaction represents one of the most 77–89%, 96–97% ee

55–56%, 97–99% ee fundamental and widely applied reactions in organic syn- O

O thesis.212 However, the enantioselective Baeyer–Villiger

reaction is largely unexplored in comparison with other

2 catalytic enantioselective transformations. In addition, N Ar N R H

H there are only a few cases where aqueous hydrogen perox-

2

42–54%, 97–99% ee R = aryl or n-pentyl 47–78%, 89–99% ee ide is utilized as the terminal oxidant in the enantioselec- tive Baeyer–Villiger reactions, despite the distinct Scheme 101 Multiple-cascade sequence leading to tetrahydropyri- advantage that its reduction product is water. Ding and co- dine and azadecalinone derivatives 291 workers successfully developed a highly enantioselective

Baeyer–Villiger reaction of cyclobutanone derivatives

CF CF 3

3 295 using chiral phosphoric acid catalyst 14h in combina-

tion with aqueous hydrogen peroxide as the oxidant H

N 213

F C CF (Scheme 103). A variety of 3-aryl- and alkyl-substitut- 3 3

293 ed cyclobutanones 295 can be oxidized by 10 mol% 14h

G

-Pr i with hydrogen peroxide. High enantioselectivities were

O

O achieved in the reaction of cyclobutanones having aro-

(R)-1q: G =

i-Pr

P matic substituents. It is noteworthy that the value (R = Ph: OH

O

-Pr

i 88% ee) represents the highest enantioselectivity obtained

G in the asymmetric Baeyer–Villiger oxidation of 295a

R)-1q/293 (10 mol%)

( (R = Ph) with chemical catalysts, although the oxidation TBHP

O

OHC

OHC of 295 having aliphatic substituents gave the correspond-

R R 1,4-dioxane, 35 °C, 72 h

trans-294a

292a ing g-butyrolactones 296 with modest enantioselectivi-

R = aromatic 63–90%, 84–96% ee trans,

98 to >99% ties. Ding, Li, and co-workers also elucidated the

R = n-hexyl 67%, 70% ee 94% ,

trans mechanism of the Baeyer–Villiger oxidation on the basis

of experimental and theoretical studies.213b The phospho- (R)-1q/293 (10 mol%)

R R

TBHP ric acid catalyst participates in both the carbonyl addition O

OHC OHC

t-BuOMe, 0 °C, 24 h

R

R and the subsequent rearrangement steps in a synergistic

292b 294b manner through hydrogen-bonding interactions. The cata- (R = aliphatic)

75–85%, 90–94% ee lyst simultaneously enhances the electrophilicity of the Scheme 102 Stereoselective epoxidation using ammonium phos- carbonyl carbon via protonation and the nucleophilicity of phate salt catalyst the hydrogen peroxide through Brønsted basic site in the addition step followed by the rearrangement step, in which the dissociation of the hydroxy group from the 1980, the enantioselective epoxidation of a,b-unsaturated Criegee intermediate is also accelerated by the catalyst. carbonyl compounds has emerged as an efficient route for preparing highly functionalized synthetic intermedi- ates.210

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1969

G 14 Combined Use of Metal Complex and Phos-

O phoric Acid Catalysts O

(R)-14h: G = P

OH

O In the past decade, tremendous progress has been made in G the field of catalysis using small organic molecules,

1 R)-14h

( namely, organocatalysis. Meanwhile, catalysis by transi-

O

(1–10 mol%)

O

aq H O + R O 2 2 tion-metal complexes has continued to be applied to a

CHCl

3

R broad range of organic transformations and it occupies a –40 °C, 18–80 h 295

296 privileged position in synthetic organic chemistry. Much

R = aromatic 91–99%, 82–93% ee

99%, 55–58% ee R = aliphatic of the research on catalysis has centered on the use of met- al complexes to activate a variety of chemical bonds. In Scheme 103 Baeyer–Villiger reaction of cyclobutanone derivatives recent years, armed with the idea of taking advantage of 295 both of these catalytic processes, researchers have com- bined metal complexes and organic molecules to con- 13.3 a-Hydroxylation of 1,3-Dicarbonyl Com- struct binary catalytic systems,217 and this has attracted pounds much attention as it has the potential to realize unprece- dented transformations. Recently, several excellent ap- The a-hydroxylation of 1,3-dicarbonyl compounds has proaches were established with the chiral phosphoric acid/ been well utilized, affording a-hydroxy carbonyl com- metal complex binary catalytic system in catalytic enanti- pounds that serve as key structural elements in a number oselective transformations. There are two types of combi- of natural products and pharmaceuticals. In this regard, nation in the binary catalytic system. One is that each considerable effort has been devoted to the establishment reactant is activated simultaneously by one type of cata- of efficient methods for the preparation of a-hydroxy 1,3- lyst; thus, the metal complex activates nucleophiles, while dicarbonyl compounds in optically active forms. Howev- the phosphoric acid activates electrophiles in a coopera- er, the development of catalytic enantioselective a-hy- tive manner. The other is the consecutive transformation droxylations of 1,3-dicarbonyl compounds has faced using a binary catalytic system, that is, relay catalysis for limited success.214 Zhong and co-workers developed a a multi-step sequence in which each catalyst promotes one highly enantioselective a-hydroxylation of 1,3-dicarbonyl type of reaction in a one-pot sequential manner. compounds 297 using chiral phosphoric acid catalyst 1i (Scheme 104).215 In general, a-hydroxylation reactions are accomplished by using oxaziridines and peroxides as 14.1 Cooperative Catalysis by Metal Complex and oxygen sources. Zhong and co-workers, however, em- Phosphoric Acid ployed 4-chloronitrosobenzene (298) as the oxygen Krische and Komanduri developed a highly enantioselec- source.216 Chiral phosphoric acid catalyst 1i activates the tive reductive coupling reaction of 1,3-enynes with het- nitroso compound via protonation of the basic nitrogen eroaromatic aldehydes and ketones catalyzed by a chiral atom of the nitroso moiety and promotes bond formation rhodium complex under hydrogenation conditions.218 In between the oxygen atom and the a-carbon atom of 1,3- the course of their studies, they found that a Brønsted acid dicarbonyl compounds 297. Subsequent nitrogen–oxygen co-catalyst accelerated the rate of the reaction significant- bond cleavage affords a-hydroxylation products 299 in ly. In order to elucidate the role of the Brønsted acid co- optically active forms. b-Keto esters 297a bearing a five- catalyst, they attempted to use a combination of achiral membered ring were well tolerated in the a-hydroxyla- rhodium complex 300 with chiral phosphoric acid 1q in tion, giving the corresponding products 299a with excel- the reductive coupling between 2-pyridinecarboxalde- lent enantioselectivities, irrespective of the steric demand hyde (301) and 1,3-enyne 302 (Scheme 105). The product of the ester moiety. Although in the reaction of 1,3-dike- 303 was obtained in an optically active form, although the tones 297b, a slight decrease in enantioselectivities was enantioselectivity obtained in this combination was lower observed, the a-hydroxylation of 1,3-diketones was than that observed in the parent combination of the chiral achieved in high yields with good enantioselectivities for rhodium complex and the achiral Brønsted acid co-cata- the first time.

lyst. This result indicates that the rhodium complex and

O the Brønsted acid functioned as the cooperative catalyst.

O Thus, 1q protonates 2-pyridinecarboxaldehyde (301) to

X

1 give intermediate J in advance of the carbon–carbon

R

Si G = Ph

3

1 2

297a: R = OR

O bond-forming step, hence accelerating the coupling reac-

(R)-1i

1

b: R = Me

O

(1 mol%) tion because of the lowered LUMO of aldehyde 301. Fur-

+

X

benzene, 4 °C, 22 h

1 thermore, the enantioenrichment of product 303 suggests

R OH

299 that the chiral counteranion of 1q is incorporated into the Cl NO

1 2

299a: R = OR 92 to >98% ee

73–85%, transient assembly of the coupling reaction through hy-

1

299b:

R = Me 65–75%, 80–86% ee 298 drogen-bonding interactions. The authors disclosed that Scheme 104 a-Hydroxylation of 1,3-dicarbonyl compounds 297 by the protonation of 301 by 1q is responsible for the asym- 4-chloronitrosobenzene (298) metric induction and not the ion pairing to the rhodium

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1970 M. Terada REVIEW

i-Pr

G = i-Pr

PMP

N G =

O

i-Pr

1

R O C H

N

2 PMP

(R)-1q (4 mol%)

H

(R)-1m (10 mol%) HN

1

2h (R = Me)

Rh(cod) OTf/BIPHEP

AgOAc (5 mol%) 2

OH

300

+ MeO C

2

301

toluene, 30 °C, 10–12 h

N

(4 mol% each)

2

R

305 +

2

H (1 atm), DCE R 2 Ph 60–93%, 86–92% ee

40 °C, 3 h

2

304 (R = aromatic) 303

Ph

56%, 82% ee

302

O

P O O O

O [Ag] O P O

H PMP

H O

N

+

O

N

2

R

1q

H

MeO C H 2 K

J Scheme 106 Silver complex/chiral phosphoric acid cooperative ca- Scheme 105 Rhodium complex/chiral phosphoric acid cooperative talysis for enantioselective alkynylation of a-imino ester 2h catalysis for reductive coupling between heteroaromatic aldehyde

301 and 1,3-enyne 302

3

Ar 1

Ar N 2 complex, on the basis of these results coupled with their N

+

219 +

R previous studies. CO

2 OH 2 H Ar

307

2 3

= aromatic, Ar = PMP Ar

:

Rueping et al. developed an excellent cooperative process 2f

1

(Ar = aromatic)

2 3

Ar = aromatic, Ar = Ph 2p:

308 that comprised an enantioselective Brønsted acid and sil- (R = Me, Et) ver complex catalyzed alkynylation (Scheme 106).220 The enantioselective alkynylation under binary catalytic con- ditions was accomplished in the reaction of a-imino ester

2h with a series of aryl-substituted terminal alkynes 304, G =

(R)-1m (2 mol%)

a 3 in which the -imino ester and the alkyne were activated Ar

HN

(OAc) (2 mol%) Rh

4

by phosphoric acid 1m and the silver complex, respective- 2

1

Ar 306

2

ly. a-Amino acid products 305 having an alkynyl substit- Ar

4 Å MS O CO R

uent were obtained in good yields with high 2 4

CH Cl , –20 °C, 4 h

Ar 2 2

309

enantioselectivities. Although, from a mechanistic view- 4 (Ar point, an exchange of the metal counteranion from acetate = 9-anthryl) to chiral phosphate, leading to the formation of a chiral 82–98%, >99% dr, 84 to >99% ee silver complex, cannot be ruled out, both catalysts are re- Scheme 107 Rhodium complex/chiral phosphoric acid cooperative quired for the reaction to proceed, and, more importantly, catalysis for three-component coupling reaction the reaction that proceeded under the influence of a chiral silver complex and an achiral phosphoric acid catalyst re- nent coupling reaction among a-diazoesters, primary 222 sulted in racemic products 305. As shown in reactive in- alcohols, aromatic aldehydes, and aniline derivatives. termediate K, the simultaneous activation of both a-imino The enantioselective reduction of imines provides direct ester 2h and alkyne 304 by cooperative organic and me- access to chiral amines, one of the most important func- tallic catalyses is crucial in furnishing a-amino ester prod- tionalities in fine chemical and pharmaceutical com- ucts 305 in optically active forms. pounds. As shown in Schemes 86–97, the organocatalytic Hu, Gong, and co-workers developed a system that in- approach has been established to provide an efficient volved cooperative catalysis by chiral phosphoric acid 1m route to the enantioselective transfer hydrogenation of and achiral rhodium complex 306 (Scheme 107).221 They ketimines using Hantzsch ester 249 as the hydrogen applied the binary catalytic system to a three-component source. However, in the hydrogenation of ketimines using coupling reaction among a-diazoesters 307, primary alco- chiral metal catalysts, this transformation remains chal- hols, and aldimines 2. The steric bulk of the primary alco- lenging, particularly in the case of acyclic ketimines 250. hol had a significant effect on both diastereo- and Xiao and co-workers successfully developed a binary cat- enantioselectivities. The sterically demanding 9-an- alytic system for the enantioselective hydrogenation of thracenemethanol (308) was the best component to give acyclic ketimines 250, where diamine-ligated iridium b-amino-a-alkoxy esters 309 with excellent stereoselec- complex 310, in combination with chiral phosphoric acid tivities under cooperative catalysis by phosphoric acid 1m 1q, enabled the highly enantioselective hydrogenation of and rhodium complex 306. Hu and co-workers further ap- 250, affording the corresponding amines 251 in good 223 plied this cooperative catalysis approach to a four-compo- yields with excellent enantioselectivities (Scheme 108). Notably, the preformed iridium complex 311, prepared from 310 and 1q, functioned as an efficient catalyst with-

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1971 out any detrimental effect on the enantioselectivity. More List and Mukherjee developed the enantioselective a-ally- interestingly, the addition of 1q to preformed 311 marked- lation of a-branched aldehydes 314 using cooperative ca- ly enhanced the catalytic activity with higher conversion talysis (Scheme 110).226 The transformation of 314 with being observed at 1 mol% each of 311 and 1q. Xiao and allylamine derivatives 315 was mediated in a highly enan- co-workers further applied the present cooperative cataly- tioselective manner under the influence of chiral phospho- sis to the enantioselective reductive amination reaction of ric acid 1q with achiral palladium complex 316, ketones with aniline derivatives under hydrogenation con- Pd(PPh3)4. The reaction likely proceeded through reactive ditions.224 intermediate L, including a p-allyl palladium complex, an

enamine, and chiral phosphate counteranion 1q–, to afford

-Pr i the corresponding chiral aldehydes 317 bearing a quater-

nary stereogenic center with high enantioselectivities. In G = -Pr

i this transformation, the chiral phosphate counteranion ac-

-Pr

i tivates the nucleophilic enamine and this activation mode

(1 mol%) / (R)-1q (6 mol%)

310 is in contrast to the previous cooperative catalyses where or

PMP

PMP

311 (1 mol%) / ( R)-1q (1 mol%)

HN N the phosphoric acid activates electrophilic imines (see

(20 atm)

H Schemes 106–108). The method enables efficient access 2

* R Me R Me

toluene, 20 °C, 15–20 h

250 251 to the enantioselective construction of all-carbon quater-

R = aromatic 92–96%,

84–98% ee nary stereogenic centers, which represents an important R)-1q (1 mol%): 311 (1 mol%) / (

R = aliphatic 88–91%

92–95% ee yet considerable challenge in organic synthesis.227 The

R = Ph 60%, 97% ee R)-1q (6 mol%): (1 mol%) / (

310 same authors also demonstrated a concise synthesis of

(+)-cuparene by taking advantage of this method for pre- Ar

Ar paring 317a as the key building block (Scheme 111).228 O S O O S O

Ph Ph

N N

Ir Ir i-Pr

X N N

Ph Ph

H H

2

G = i-Pr

310 311 (X = 1q )

1 R

i-Pr) C H Ar = 2,4,6-(

3 6 2 i-Pr

CHO (R)-1q (1.5 mol%)

2

Scheme 108 Iridium complex/chiral phosphoric acid cooperative R

314

Pd(PPh ) (3 mol%) 3 4

2 M HCl

catalysis for enantioselective hydrogenation of ketimines 250 316

+

2

R

5 Å MS Et O

1 2 R

t-BuOMe, 40–60 °C, 8–72 h r.t., 30 min

Ph

Xiao and co-workers established the present cooperative CHO

317

Ph

catalysis by taking into consideration Norton’s mechanis- N

H

1 2

R = aromatic R = H 71–89%,

tic studies on ruthenium-catalyzed ionic hydrogenation of 94–97% ee

315

1 2

R R = Ph = Me, Ph 40–82%, 82–92% ee

2 iminium cations where imines can be reduced through an 1 R R = cyclohexyl = H 65%, ionic pathway,225 while it is generally believed that the 70% ee

metal-catalyzed hydrogenation proceeds via the coordina-

O O

tion between the nitrogen atom of imine and the metal P

O O

center. Hydrolytically hydrogen-activating catalyst 312 is 2 R

3

H R – Pd

associated with chiral counteranion 1q , which influences N

1 the enantio-discrimination by ion pairing with resulting R

iminium cation 313 (Scheme 109). In fact, the enantiose- H lectivity observed was significantly affected by the chiral L phosphoric acids employed. Scheme 110 Palladium complex/chiral phosphoric acid cooperative As shown in Schemes 106– 108, one type of catalyst acti- catalysis for a-allylation of a-branched aldehydes 314 vates each reactant simultaneously: the phosphoric acid activates imines as the electrophilic component while the

metal complex activates nucleophiles in a cooperative

Rh(dppe) Cl

2

manner. (1 mol%)

CHO

p-tol p-xylene, 160 °C, 12 h

O 30%

1q O

317a

1 step (ref. 228)

O O P

1

L

Cp*

O

250

1

Ir

* 1q

L + H

Cp*

2

H PMP

2

L

Ir N p-tol *

311

2 H L

R Me (+)-cuparene 312 313 Scheme 111 Synthetic application of palladium complex/chiral Scheme 109 Cooperative catalysis by iridium complex/chiral phos- phosphoric acid cooperative catalysis phoric acid binary system

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1972 M. Terada REVIEW

14.2 Relay Catalysis by Metal Complex and Phos- dicarbonyl compound, instead of 2-methoxyfuran (52), as phoric Acid the nucleophilic component (see Section 9.1). The corre- sponding Mannich product was obtained in an acceptable As shown in Schemes 105– 108 and 110, each reactant yield. was activated by one type of catalyst simultaneously. Terada and Sorimachi reported an unprecedented consec- The enantioselective version of the relay transformation utive transformation using a binary catalytic system, that by organic and metallic catalyses was successfully dem- is, relay catalysis for the tandem isomerization/carbon– onstrated by Gong and co-workers (Scheme 113).230 They carbon bond-formation sequence promoted by a binary accomplished the direct transformation of o-propargyl- catalyst consisting of ruthenium hydride complex 318 and aniline derivatives 322 into tetrahydroquinolines 268 in a Brønsted acid 319 (Scheme 112).229 The reaction of N- highly enantioselective manner through the hydroamina- Boc-protected allylamine 320 with 2-methoxyfuran (52) tion of alkynes/isomerization/enantioselective transfer proceeded smoothly to give product 321, with a nitrogen hydrogenation (see Section 12.2) sequence under the relay functionality at the stereogenic center, in good yield. Con- catalysis of an achiral gold complex 323/chiral phospho- trol experiments revealed that both catalysts, ruthenium ric acid 1m binary system. A control experiment using complex 318 and Brønsted acid 319, are indispensable to chiral gold phosphate, prepared from the silver salt of 1m the sequential processes. Although a racemic acid catalyst and Ph3PAuCl, showed that the reaction was incomplete was employed in this case, an enantioselective version and the enantioselectivity was lower than that obtained in would also be applicable, considering recent progress in the binary catalytic system. Therefore, it can be excluded enantioselective Friedel–Crafts reactions using chiral that the chiral gold phosphate, even if it were generated in phosphoric acid catalysts (see Sections 5.1 and 9.1). situ, functions as the dominant catalytic species at the last

step, namely, the enantioselective transfer hydrogenation Ph of 270. Instead, chiral phosphoric acid 1m plays the dom-

inant role in the actual enantioselective catalyst.

O

O

P

OH

O

O

Ph

G =

EtO C CO Et

2 2

(±)-319 (5 mol%)

H OMe

N

RuClH(CO)(PPh ) (1 mol%)

3 3

52

Boc

N

318 R)-1m (15 mol%) (

H

+

(Ph P)AuMe (5 mol%)

3

toluene, 40 °C, 12 h O 249a

323 H

+

2 N

R

Boc

toluene, r.t., 16–27 h

1 OMe

N R

321

320 H

2

69% R 268

1 R

NH 82 to >99%, 88 to >99% ee 2

1st isomerization

322

C–C bond formation

[RuH] 318

52 Brønsted acid 319

acid-catalyzed

gold-catalyzed

enantioselective 249a

hydroamination

2nd isomerization

transfer hydrogenation

H Brønsted acid 319

N N

Boc Boc

acid-catalyzed

189a 191a

isomerization

2

R

2

R

1

N R

1

N R

Scheme 112 Relay catalysis by ruthenium complex/Brønsted acid H

binary system 269 270

Scheme 113 Enantioselective relay catalysis by gold complex/chir- The present sequential transformation involves a three- al phosphoric acid binary system for tetrahydroquinoline synthesis step relay catalysis where: (i) the isomerization of N-allyl- carbamate 320 to enecarbamate 189a is catalyzed by the ruthenium hydride complex 318; (ii) the subsequent Meanwhile, Che and Liu reported an intermolecular ver- isomerization of 189a to intermediary imine 191a is re- sion of Gong’s relay catalysis, that is, the hydroamination of alkynes/isomerization/enantioselective transfer hydro- layed by acid catalyst 319; and (iii) the catalytic sequence 231 is terminated by a carbon–carbon bond-forming reaction genation sequence (Scheme 114). The intermolecular of 191a with electron-rich aromatic compounds 52 as a relay catalysis was accomplished via a three-component nucleophilic component under the influence of acid cata- reaction among terminal alkynes 304, aniline derivatives lyst 319. The advantage of this relay catalysis is that the 12, and Hantzsch ester 249a in the binary catalytic system method enables the generation of reactive imines 191 composed of gold complex 324 and chiral phosphoric acid from readily available allylcarbamates in a one-pot reac- 1q. This relay catalysis exhibited a very broad substrate tion via tandem isomerization. Terada and Sorimachi also scope toward diversely substituted chiral amines 325 in applied the present relay catalysis to the reaction of a 1,3- good yields with high enantioselectivities.

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1973

-Pr i sure, polycyclic tetrahydro-b-carboline derivatives 333

were formed in good yields with high enantioselectivities.

G = i-Pr

X You and co-workers combined olefin cross-metathesis

i-Pr H N

2 with intramolecular Friedel–Crafts reaction in a one-pot 12

( )-1q (5–10 mol%)

S sequence using ruthenium complex 334 and chiral phos- + (t-Bu) (o-biphenyl)PAuOTf (1–2 mol%) X

2 234

324

HN phoric acid 1m (Scheme 116). This sequential transfor-

R

5 Å MS mation involves two distinct catalytic cycles: the first

R 304

benzene, 40–60 °C, 40–120 h

325 cycle is the olefin cross-metathesis between aryl vinyl ke- +

83–96% ee R = aromatic

70–98%, tones 335 and allyl indolylmethyl ethers 336a by rutheni- 249a

83–95% ee R = aliphatic

54–98%, um complex 334, giving rise to enones 338, and the Scheme 114 Relay catalysis by gold complex/chiral phosphoric subsequent catalytic cycle involves the intramolecular acid binary system for amine synthesis Friedel–Crafts reaction of 338 under the influence of chiral phosphoric acid 1m. This binary catalytic process Shortly thereafter, Dixon and co-workers reported a bina- indeed worked well in the reaction of 335 with 336a to af- ry catalytic system composed of gold complex 326 and ford the corresponding cyclized products 337a in good chiral phosphoric acid 1i for a one-pot sequential transfor- yields with high enantioselectivities. However, this meth- mation of alkynoic acids 327 and tryptamines 328 od affords products 337a with slightly lower enantioselec- (Scheme 115).232 The initial step of this sequential trans- tivities than that observed in the chiral phosphoric acid formation is the gold-catalyzed cycloisomerization of catalyzed intramolecular Friedel–Crafts reaction of 338a 1 2 327, affording substituted furanones 329. In a previous (e.g., 337aa: R =Me, R = H, Ar = Ph, 94% ee vs. 96% publication, it was pointed out that this initial cyclo- ee), presumably owing to the generation of Lewis acidic isomerization is not promoted by Brønsted acid cata- ruthenium complex 339 during the course of the first cat- 235 lysts.233 Subsequent steps were conducted by adding alytic cycle. Thus, the activation of enones 338 by tryptamines 328 and phosphoric acid catalyst 1i in a one- achiral ruthenium complex 339 leads to undesired racem- pot procedure; nucleophilic ring opening of furanone de- ic product 337a, although this achiral catalytic process is rivatives 329 by tryptamines 328 led to acyclic ketoamide not a dominant cycle because of little loss of enantioselec- intermediate 330, and this was followed by dehydrative tivity during the sequential catalysis. The method is also recyclization to afford enamides 331. Resulting enamides applicable to the construction of the tetrahydro-b-carbo- 331 generated N-acyl iminium ions 332 as the reactive in- line skeleton: the reaction of nitrogen analogue 336b with termediate under the influence of chiral phosphoric acid phenyl vinyl ketone (335a) provided cyclized product

catalyst 1i and, following Pictet–Spengler-type ring clo-

(PhP )AuCl (0.5 mol%) 3

O

O 326

C HO

Ar 2

Ar AgOTf (0.5 mol%) O G =

N toluene, r.t., 1 h

(S)-1m (5 mol%)

X

then 328 and

335

X

N R

334 (5 mol%)

( R)-1i (G = Ph Si) (10 mol%)

H 3 R

2 +

R

80 °C, 24 h

333

toluene 327 N

then 110 °C, 24 h 77–96%, 83–95% ee

40–60 °C, 40–120 h (R = aliphatic)

1 R

337 a: X = O X

acid-catalyzed

b: X = NBoc

2 R

enantioselective

gold-catalyzed

N

43–97%, 80–94% ee 337a:

Pictet–Spengler- cycloisomerization

1

R

90%, 83% ee 337b:

type reaction

a: X = O 336

b: X = NBoc

1i O O

O O N

Mes NNMes

X

R

R

Cl Ar

N

Ru 329

H X Cl

332

2

R

NH

O SO NMe

2 2 2

N

1

R X

N

338 a: X = O

334 H

328 b: X = NBoc

O O

NN Mes Mes

N

Mes = N

Cl H

Ru

O

X

R

Cl X

N

N

339

H

R H 330

331 Scheme 116 Relay catalysis by ruthenium complex/chiral phospho- Scheme 115 Relay catalysis by gold complex/chiral phosphoric ric acid binary system in olefin cross-metathesis/intramolecular acid binary system for polycyclic tetrahydro-b-carboline synthesis Friedel–Crafts reaction sequence

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York 1974 M. Terada REVIEW

337b (R1 =Me, R2 = H, Ar = Ph) in good yield, albeit Combined acid and base salts, such as pyridinium p-tolu- with a slight decrease in enantioselectivity. enesulfonate (PPTS), are one of the most utilized acid cat- alysts in organic synthesis. These acid–base salts have several advantages over single-molecule catalysts in 15 New Aspects in the Development of Chiral terms of flexibility in the design of their dynamic com- Brønsted Acid Catalysts plexes. Ishihara and co-workers focused their attention on the superior properties of these acid–base combined or- Since the development of chiral phosphoric acids and ganic salts and developed novel chiral Brønsted acids de- their analogues as enantioselective catalysts, continuous rived from binaphthyldisulfonic acid 342 and pyridine effort has been made to cultivate novel structural motifs of derivatives 343 (Scheme 118).240 The salt catalyst gener- chiral Brønsted acid catalysts having acidic functional- ated in situ from 342a (G = H)241 and 2,6-diphenylpyri- ities other than phosphoric acid, and several efficient dine (343a) exhibited excellent performance in the direct chiral acid catalysts have been reported to date. This sec- Mannich reaction of N-Cbz imines 2q with acetylacetone tion reviews recent progress in the development of chiral (3), affording the corresponding products 344 with high Brønsted acid catalysts, especially those bearing strongly enantioselectivities. The distinct advantage of the salt cat- acidic functionalities. alyst is that both the Brønsted acidity and the bulk can be readily controlled by achiral pyridine derivatives 343 without substituents at the 3,3¢-positions of the binaphthyl 15.1 Chiral Brønsted Acid Catalysts Other Than backbone (G = H). In fact, catalytic activities and enantio- Phosphoric Acid Catalysts selectivities were markedly dependent on the achiral pyri- One of the key principles in the design of chiral Brønsted dine 343 employed. The use of pyridine derivative 343b, acid catalysts is the choice of a catalyst having an appro- with its sterically bulky tert-butyl substituents at the 2,6- priate acidity. Although an important class of moderate positions, resulted in a considerable decrease in chemical Brønsted acids, carboxylic acids, is often utilized as one yield with slightly lower enantioselectivity (76% ee). The of the most fundamental acid catalysts in a variety of or- importance of the salt formation with the pyridine deriva- ganic transformations, these carboxylic acids have rarely tive is obvious, because a significant decrease in enantio- been employed in enantioselective catalyses,236 presum- selectivity (to only 17% ee) was observed in the absence ably because of the poor catalytic activity of the carboxy- of pyridine derivatives, despite furnishing 344a in good lic acid and the difficulty of constructing an efficient yield.

chiral environment around it. Maruoka and Hashimoto overcame these intrinsic problems by introducing two car- G

boxylic acid moieties in the catalyst molecule. They de- R R N

SO H

veloped novel chiral Brønsted acid catalysts 340, which 3

SO H

consist of two carboxylic acids and an axially chiral bi- 3

: R = Ph

237 343a

naphthyl moiety (Scheme 117). Dicarboxylic acid 340a G b: R = t-Bu

R)-342a: G = H

functioned as an efficient enantioselective catalyst in the (

Mannich-type reaction of N-Boc imines 2a with diazo- G = H

Cbz

( R)-342a (1 mol%)

NH

acetate 16a, affording the corresponding products 341 Cbz

343a (2 mol%) N

O

+

Ar

with high enantioselectivities. They also applied dicar- O

MgSO 4

Ar H

O

Cl , 0 °C, 30 min boxylic acid catalysts 340 to the enantioselective aziridi- CH 2 2

O

238 2q 3

nation of diazoacetamides with N-Boc imines and the 344 enantioselective imino azaenamine reaction of arylalde- 91–99%, 89–98% ee

239

hyde N,N-dialkylhydrazones with N-Boc imines. yield of

344a (Ar = Ph) acid–base combined salt catalysts

( R)-342a (5 mol%)/343a (10 mol%) 74% 92% ee G

( R)-342a (5 mol%)/343b (10 mol%) 32% 76% ee

( R)-342a (5 mol%)/ – 81% 17% ee

COOH

340a: G =

t-Bu COOH Scheme 118 Mannich reaction of N-Cbz imines 2q with acetylace-

tone (3) catalyzed by chiral disulfonic acid/pyridine derivative com-

G bined organic salts

(R)-340

Boc (R)-340a

HN

Boc

CO t-Bu H Strong chiral Brønsted acids have great potential for high-

(5 mol%) 2 N

t-Bu CO +

2

Ar performance enantioselective catalysis in general and are

4 Å MS

N

2 Ar H

CH Cl

N

2 2 2 particularly promising for the activation of important but

2a 16a

0 °C, 5–72 h 341 less basic substrate classes, such as aldehydes. List and

38–89%, 85–96% ee co-workers reported that a disulfonimide is a promising Scheme 117 Mannich-type reaction of N-Boc imines 2a with diazo- acid catalyst for the activation of simple aldehydes acetate 16a, catalyzed by a novel chiral Brønsted acid having two car- (Scheme 119).242 They identified that the newly devel- boxylic acids oped chiral cyclic disulfonimide 345, with a binaphthyl

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1975

G

backbone, functioned as a powerful enantioselective cata- G

O lyst for the Mukaiyama aldol reaction of aldehydes 11 O

O O

P with ketene silyl acetals 346. P

NHTf OH

O O

G

G

G G

CF

3

(R)-1r (R)-66h

SO

2

SO H

3

CF

3 (R)-345: G = NH

SO H 3

SO

2

G =

CF 3

G G

( R)-342b CF 3

(R)-345

4

4

OSiR

OSiR 3

3

O

(0.01–2 mol%)

catalyst

2

3

OSiMe

R

OSiMe

3

CO R

+ 3

2

3

O

1

(2 mol%) OR

R

1 O, –78 °C, 12–24 h Et

2 R H

CO Me

2

2 2 + 2

OMe

R R R

β-Nap

O, r.t., 12 h Et

11

2

H β-Nap

347

346

11b

1

2

347a 346a R = aromatic 70–98%, 72–94% ee (R = Me or H)

1 catalyst R 46–95%, = aliphatic 50–94% ee

( R)-1r - <2%,

( R)-66h

-

Scheme 119 Mukaiyama aldol reaction catalyzed by chiral disul- <2%,

( R)-342b

-

fonimide 345 <2%,

( R)-345 80% ee >99%,

G

CF 3

SO

Their basic idea in the design of chiral disulfonimide cat- 2

NSiMe (R)-348: G =

alysts originates from the resemblance in relative reactiv- 3 SO

ity between triflic acid (TfOH) and triflylimide (Tf2NH), 2 CF

3 which are both powerful Brønsted acid catalysts: TfOH G (pKa –5.9 in water) is much more Brønsted acidic than Scheme 120 Mukaiyama aldol reaction catalyzed by various chiral Tf2NH (pKa 1.7 in water); however, the relationship is re- acid catalysts versed if one regards the Lewis acidity of the correspond- ing silylated species, with that of TMSNTf2 being much Brønsted acid is generated as the conjugate acid of a chiral 243 stronger than that of TMSOTf. Furthermore, the C2- organic Brønsted base. However, the development of cat- symmetric binaphthyl disulfonimide topology is of partic- ionic Brønsted acid catalysts for enantioselective transfor- ular interest as it differs from that of the corresponding mations has been largely unexploited in comparison with 244 pseudo-C2-symmetric phosphoric acids, and hence the that of nonionic chiral Brønsted acid catalysts. Jacobsen corresponding silylated species may serve as promising and Uyeda successfully developed a cationic chiral chiral Lewis acid catalysts. Indeed, a comparison of phos- Brønsted acid catalyst that was furnished from a chiral phoric acid 1r and phosphoramide 66h with disulfonic guanidine base (Scheme 121).245 Thus, chiral guanidini- acid 342b and disulfonimide 345 revealed that disulfon- um ion 349 having a fluorinated tetraarylborate as the imide catalyst 345 was not only far more active than the counteranion functioned as an efficient enantioselective alternative catalysts, 1r, 66h, and 342b, but also provided catalyst for the Claisen rearrangement of ester-substituted product 347a with high enantioselectivity in the Mukaiyama allyl vinyl ethers 350. Notably, the enantioselectivity is aldol reaction of 11b with 346a (Scheme 120). List and strongly dependent on the substrate employed; introduc- co-workers concluded that the Lewis acid mechanism tion of the ester substituent on the allyl vinyl ethers is in- seems to be more plausible than the Brønsted acid cataly- dispensable for achieving high enantioselectivity, sis in this Mukaiyama aldol reaction.242 Thus, sulfonimide although the guanidinium catalyst induces rate enhance- catalyst 345 is first silylated by ketene acetal 346, afford- ments in the rearrangement of a variety of substituted allyl ing N-silyl disulfonimide 348 that is responsible for the vinyl ethers. Substrates having an alkyl group (Me or Et) active enantioselective catalyst through the O-silylation at the vinyl terminus afforded rearranged products 351 of aldehyde 11. They also pointed out that N-silyl disul- with high enantioselectivities. Although the introduction fonimide 348 represents a powerful catalyst for enantiose- of substituents at the allyl terminus resulted in a slight de- lective silicon catalysis and a number of reactions crease in enantioselectivities, not only anti-isomers but catalyzed by TMSNTf2, and similar catalysts should be also products having a quaternary stereogenic center were accessible in an enantioselective fashion. obtained with high diastereoselectivities. Meanwhile, Ooi and co-workers designed and synthe- 15.2 Chiral Conjugate Acid Catalysts Derived sized novel cationic chiral Brønsted acid catalyst 352 from Chiral Bases (Scheme 122).246 Their strategy for the molecular design was to employ a chiral P-spiro tetraaminophosphonium Most of the chiral Brønsted acid catalysts developed can cation framework as the primary structure, which is a be classified as nonionic compounds.2 In contrast, the hy- unique structural motif introduced by their research drogen-bonding donor capability of a cationic organic group,247 where the core structure of HN-P+-NH interacts molecule with a less coordinatable anion, such as tetra- with electrophiles through two hydrogen bonds that seem arylborate, has been well investigated. This type of chiral to regulate the relative location between the electrophile

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York

1976 M. Terada REVIEW

BArF

BArF

CF G 3

NH

2 HH

N N

352a: G = Ph F = BArF B

N N

(R)(S)

P H H

N N

352b: G = F Ph Ph

CF N N

3 4

HH

G

F 349

(R,S)-352

MeO C

2

1 349

1 4 BArF R R R

(20 mol%)

Ph

O MeO C 2

HH

hexanes

2 3

3 N N

R R

R O

22–40 °C, 5–14 d 4

R

(R)(R)

P

351

2

R

2 3

N N (R R ) 350 /syn = >19:<1 anti ≠

HH

1 2 3 4 Ph R R R R

Me or Et H H H (R,R)-354a 92% ee 80–86%,

Et H H n-Pr or Ph 81–85% ee 91–92%,

Me H Me H 96% ee MeO 73%,

Et Me H Me 81% ee 89%,

Et Me H Ph or alkyl chain 82–84% ee 73–89%,

NH 2 MeO OMe

OMe

Scheme 121 Claisen rearrangement catalyzed by chiral guanidini- catalyst

12i

(2 mol%)

um ion 349 NH +

NO i-Pr O toluene or

2 2

R

NO

2 –15 °C to r.t., 0.5–24 h

R

and the chiral catalyst. In addition, they introduced a bi- 353 79

87%, 83% ee ( R,S)-352a: naphthyl-derived axially chiral diamine as a readily acces- R = Ph (at 0 °C)

86%, 61% ee ( R,R)-354a:

sible and modifiable chiral source, instead of chiral R = Ph (at 0 °C) 98%, 94% ee

( R = Ph (at 0 °C) ,S)-352b:

247 R

89–99%, 91–97% ee aliphatic diamines, to the phosphorus center by taking R = aromatic

93–98%, 86–87% ee into consideration the enhancement of the acidity of NH R = aliphatic protons. A newly developed arylaminophosphonium cat- Scheme 122 Conjugate addition of aniline derivatives 12i to nitro- ion (R,S)-352, with the [7.7]-spirocyclic core, exhibited alkenes 79 catalyzed by arylaminophosphonium cation excellent catalytic activity in the conjugate addition of 12i 79 aniline derivative to nitroalkenes , affording prod- logues. Numerous bond-forming reactions, including 353 ucts in good yields. The enantioselectivity is marked- carbon–carbon, carbon–heteroatom, and carbon–hydro- ly dependent on the axial chiralities of the diamines gen bond-forming reactions, have been successfully es- introduced; switching the unsubstituted binaphthyl unit to tablished in a highly enantioselective manner by using the opposite enantiomer, which gives rise to homochiral these acid catalysts. However, the enantioselective ver- arylaminophosphonium cation (R,R)-354a, results in a sions of many reactions remain to be developed using considerable decrease in the enantioselectivity [(R,S)- chiral phosphoric acids or other types of chiral Brønsted 352a R R 354a : 83% ee vs. ( , )- : 61% ee]. Heterochiral cata- acids. Further elaboration of novel chiral Brønsted acids 352b lyst , with its 3,4,5-trifluorophenyl groups, facilitat- derived not only from other types of chiral backbones, 353a ed the reaction, affording (R = Ph) in nearly such as diols, diamines, and amino alcohols, but also from quantitative yield with the highest enantioselectivity. A stronger acid functionalities could lead to the discovery of 79 broad range of nitroalkenes , including aromatic, het- even more selective and efficient methods for a wide va- eroaromatic, and aliphatic ones, can be transformed into riety of enantioselective organic transformations. the corresponding products 353 in high yields with high enantioselectivities in the presence of catalyst 352b. Note Added in Proof After acceptance of this review article, Ishihara and co-workers re- 16 Conclusions ported the direct Mannich reaction of N-Boc imine 2aa with ace- tylacetone (3) using chiral phosphoric acids and their metal salt This review focused on recent advances in the chemistry derivatives, where calcium salt of chiral phosphoric acid (R)-1d of chiral Brønsted acid catalysis using BINOL-derived (G = 4-b-naphthylphenyl) functioned as an efficient catalyst to 1 yield the corresponding product (R)-4a with high enantioselectivi- phosphoric acids of general type for enantioselective 248 transformations. In initial studies, chiral phosphoric acids ty. The result obtained with the calcium salt of (R)-1d is compa- rable to that using (R)-1d which was purified by silica gel (the result were utilized for the activation of imines in most cases. As shown in Scheme 1). However, an HCl wash of the silica gel puri- introduced in this review, it has been convincingly dem- fied (R)-1d resulted in the formation of 4a with low and opposite onstrated that tremendous progress has been made in the enantioselectivity. They also reported that chiral phosphoric acid development of chiral phosphoric acid catalysis and the (R)-1g (G = 9-anthryl) washed with HCl exhibited good perfor- broadening of the scope of functionalities that can be ac- mance in the direct Mannich reaction, giving rise to (S)-4a with high tivated by chiral phosphoric acid catalysts and their ana- enantioselectivity under optimal reaction conditions.

Synthesis 2010, No. 12, 1929–1982 © Thieme Stuttgart · New York REVIEW Chiral Phosphoric Acids as Enantioselective Catalysts 1977

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