Enantioselective Organocatalytic Friedel-Crafts ... - Ingenta Connect

4022

Current Organic Chemistry, 2011, 15, 4022-4045

Enantioselective Organocatalytic Friedel-Crafts Alkylations Hai-Hua Lu, Fen Tan and Wen-Jing Xiao* The Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China Abstract: Over the last few decades, the catalytic asymmetric Friedel-Crafts alkylation has become a powerful strategy that provides enantioenriched structural motifs of established value in medicinal chemistry or complex target synthesis. While the traditionally chiral Lewis-acid catalyzed Friedel-Crafts alkylation has been extensively reviewed in the literature, we focused this review on the recent advances on organocatalytic Friedel-Crafts alkylations. According to activation modes, this review is divided into three main sections, including 1) alkylations via iminium catalysis, 2) alkylations via SOMO catalysis, and 3) alkylations by chiral hydrogen-bond donors.

Keywords: Organocatalysis, friedel-crafts alkylation, iminium catalysis, SOMO catalysis, hydrogen-bonding catalysis. 1. INTRODUCTION

a benzylic carbon stereocenter, received particular attention and will be the focal point of this review [7-15]. As revealed in the subsequent sections, successful enantioselective organocatalytic Friedel-Crafts alkylation reactions

The last few decades have witnessed a spectacular progress in enantioselective organocatalysis, a process using metal-free low molecular-weight organic molecules as chiral catalysts [1-5]. This O N

Ph

N

N H

Ar

N

N

N N H

N H

Ph

O R

2

Ph

3

4

OMe Ar

Ph

NH2

H

Ar

OH N H

O

N H

1

R

O

Bn

O

N H

N

N

OTMS N

NH2

H N

6 5 7 Fig. (1). Representative chiral amine catalysts for asymmetric Friedel-Crafts Alkylations.

approach, not only complementing the organometallic/bioorganic methods but also emulating and providing unprecedented exciting outcomes, is attractive due to practical concerns such as economical, preparative and environmental issues. Indeed, a number of useful asymmetric carbon-carbon and carbon-heteroatom bond-forming reactions have been discovered and successfully applied in the chemical synthesis of biologically active natural products and important drug candidates [6], and this field continues to expand steadily with novel catalytic modes and reactions developed. In this regard, the venerable Friedel-Crafts alkylation, widely acknowledged as a fundamental carbon-carbon bondforming reaction in organic synthesis and one of the most straightforward approaches to functionalized aromatic systems with

could mainly be categorized into two strategiescovalent and noncovalent activations by means of readily available and benchstable chiral small organic molecules. The former strategy involves the reversible formation of iminiums/enamines with the use of -unsaturated aldehydes or ketones in the presence of chiral primary or secondary amine catalysts (Fig. (1)) [16-17]. In the latter case, organocatalysts bearing hydrogen-bond donors have emerged as a preeminent tool through effective noncovalent interactions between the catalysts and the substrates (Fig. (2)) [18-22]. These two types of activation modes are rather different from those invoked by traditional chiral metal catalysts, such as copper, titanium, etc. And thanks to their uniqueness, a variety of unprecedented reactions and novel organocatalysts have been developed and widely applied in organic synthesis.

*Address correspondence to this author at the The Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China; Tel: +(86)-27-67862041; Fax: (+86)-27-67862041; E-mail: [email protected] 1385-2728/11 $58.00+.00

8

© 2011 Bentham Science Publishers

Enantioselective Organocatalytic Friedel-Crafts Alkylations

Current Organic Chemistry, 2011, Vol. 15, No. 24 4023

R

CF3 S Ph

S F3C

N H

N H

RHN

OH

NH OH

O

Ph NHR

O

BArF24

9

O P

N H

OH

R

10

12

11 CF3

R

S N

O

O P

O

N H

O2 S

CF3

N H

N H

CF3

H N

H N

CF3

R

H N

H R

CF3

S

S

13

H N

CF3

N CF3

14

15

OH

OH

OH

R'

OR

OR

N N HO3S

H

O

N

16

N

N

17

H

N

H 19

18 CF3

S R1

Me N H

N H R2

N

Bn R3

N

S N H

N H

CF3

O 20 21 Fig. (2). Representative organocatalysts bearing hydrogen-bond donors for asymmetric Friedel-Crafts Alkylations.

2. FRIEDEL-CRAFTS CATALYSIS

ALKYLATIONS

VIA

IMINIUM

The covalent LUMO-lowering activation strategy through reversible formation of iminium ions between enals or enones and chiral primary or secondary amines (Scheme 1) plays an important role in enantioselective organocatalysis and modern Friedel-Crafts alkylation chemistry.

N H

O

N R

R' R

R'

Scheme 1.

The most attractive feature of this strategy is that the tendency toward 1,2-addition, which usually occurred under traditional Lewis acid conditions especially in the case of enals, could be effectively minimized or avoided, while with high reactivities and stereoselectivities achieved.

2.1. Alkylation with Enals At the beginning of the millennium, MacMillan and coworkers demonstrated the asymmetric Friedel-Crafts alkylation of pyrroles with enals by using chiral amine catalysts for the first time (Table 1) [23]. The reaction has a broad scope of pyrroles and enals and the Friedel-Crafts alkylation products with high optical purities are useful synthons for the construction of a variety of drug candidates such as (-)-ketorolac [24]. Central to the success of this method is the reversible formation of iminium ion intermediate with chiral imidazolidinone 1, which both provided good enatio-outcome and suppressed 1,2-addition due to steric constraints imposed by the catalyst framework. The indole framework is recognized as a privileged structure widely present in medicinal agents and biologically active natural products. Accordingly, indole is a very important class of compound for enantioselective Friedel-Crafts alkylation chemistry. In 2002, MacMillan and co-workers reported a convenient access to chiral indolic structure by means of iminium catalysis [25]. With the newly developed and more efficient chiral imidazolidinone

4024 Current Organic Chemistry, 2011, Vol. 15, No. 24

Table 1.

Lu et al.

Organocatalytic Friedel-Crafts Alkylation between Enals and Representative Pyrroles

O 20 mol % 1.HX

Y N R

+

Z

O

22

N

Y O N R

THF-H2O

23

N X

Ph

Z

H

24 Z

H

Re-face attack

R

Y

Z

Time (h)

Temp (°C)

Yield (%)

ee (%)

Me Me Me Me Me allyl H Me Me

H H H H H H H 2-Bu 3-Pr

Me i-Pr Ph CH2OBn CO2Me Ph CO2Me Ph Ph

72 72 42 72 104 72 42 120 120

-60 -50 -30 -60 -50 -30 -60 -60 -60

83 80 87 90 72 83 74 87 68

91 91 93 87 90 91 90 90 97

catalyst 2 (Scheme 2), the asymmetric Friedel-Crafts alkylation of indoles displayed a good tolerance of substrate scope and excellent results (Table 2). O

O N N

Ph

N Me Me

H N

X

Ph

H ArH Z

X H ArH

H

Z

Re-face attack Effective Si-face coverage Re-face CH3-ArH interaction Diminished reactivity

H

Re-face attack

Increased Si-face coverage Re-face addition unhindered Increased reaction rate

Scheme 2.

In 2006, Bonini and co-workers employed chiral aziridin-2-yl methanols 5 as organocatalysts in the Friedel-Crafts alkylations of N-methyl pyrroles and indoles, and up to 75% ee was obtained [26]. Recently, Lee et al. used camphor sulfonyl hydrazine (CaSH) as the catalyst in the same reaction, and the reaction gave good to excellent enantioselectivities (81-88%) [27]. It should be noted that a typical process for the organocatlytic Friedel-Crafts alkylations usually utilizes a protic acid as the cocatalyst to facilitate the formation of an iminium ion. However, a recent report by Wang and co-workers revealed that a Lewis base-Lewis base bifunctional catalysis combination could also be successfully applied in the iminium catalysis for the Friedel-Crafts alkylations of indoles without using additional acid catalyst, and excellent results were attained (Scheme 3) [28]. The significance of the asymmetric alkylations of indoles with enals were well presented in the synthesis of a COX-2 inhibitor by

Table 2. Organocatalytic Friedel-Crafts Alkylation between Enals and Representative Indoles X 20 mol % 2a.TFA + Z O Y CH2Cl2-i-PrOH N R 25

X

Z O

Y N R

26

R

X

Y

Z

Temp (°C)

Yield (%)

ee (%)

Me Me Me Me Me Me Me H allyl Bn H Me H

H H H H H H H H H H Me OMe H

H H H H H H H H H H H H Cl

Me Pr i-Pr CH2OBz Ph CO2Me Me Me Me Me Me Me Me

-83 -60 -50 -83 -55 -83 -87 -60 -72 -60 -60 -87 -60

82 80 74 84 84 89 82 72 70 80 94 90 73

92 93 93 96 90 91 92 91 92 89 94 96 97



Ph OTMS N H

Ph

Z

20 mol % 6a 50 mol % Et3N

R' +

Z

O

N H

R'

O

MTBE, -20 oC 66-95% yield 92-98% ee

N H 28

27 Scheme 3.

MeO

Me

MeO (1)

OH

O 20 mol %

Me

N

O

2a.TFA

N

Me

(2) AgNO3, NaOH COX-2 inhibitor

Br

Br

Scheme 4.

O N N H

I Ph + N H 29

NaCN, CuI MeNHCH2CH2NHMe toluene, 100 oC 80-83% yield

Me2NH NaBH(OAc)3

I

O

4a.TFA O

O

CH2Cl2-i-PrOH -25 oC

30

I

83% yield 84% ee

N H

N MeOH quant.

31

N H

32

NC N N H

33 BMS-594726

Scheme 5.

MacMillan and the synthesis of a selective serotonin reuptake inhibitor, BMS-594726, by King, respectively (Schemes 4 and 5) [25, 29]. The iminium activation strategy was elegantly extended to asymmetric alkylations of benzenes by the MacMillan group, and high reaction efficiency as well as excellent stereocontrol was obtained [30]. Comparing with pyrroles and indoles, benzenes exhibits lower reactivities, and therefore, an electron-donating dialkyl amino group is essential in this organocatalytic alkylation (Scheme 6). After the alkylation was carried out, the electrondonating group at the benzene ring could be readily removed in the presence of MeI/Na/NH3 at low temperature. Importantly, the alkylation of electron-riched benzenes has been successfully applied in the expedient synthesis of (R)-Tolterodine, a potent muscarinic receptor antagonist [31]. Perhaps more importantly, the dialkyl amino group could also be replaced by other functional groups as demonstrated by Kim and co-workers in the synthesis of (S)-(+)-Curcuphenol (Scheme 7) [32]. Optically active -aryl phosphonates usually display remarkable biological activities and are widely applied in medicinal

chemistry. The enantioselective synthesis of -substituted phosphonates is highly desirable and has attracted broad interest in the chemical community. Very recently, Xiao and co-workers successfully developed a convenient protocol to access chiral indolyl and phenyl phosphonates in excellent optical purities by means of iminium catalysis (Scheme 8) [33]. Fused aromatic rings are important structural motifs which are widely occurring in natural products and pharmaceuticals. The development of efficient and practical synthesis of the ring system has therefore remained a focal point for extensive research efforts in both industrial and academic settings. Among them, the intramolecular Friedel-Crafts alkylation offers one of the most straightforward approaches. In 2007, Xiao and co-workers established a powerful enantioselective organocatalytic alkylation of indolyl enals using iminium catalysis (Table 3) [34]. Starting from commercially available 1H-indole-2-carboxylates or 1Hindole-2-carbaldehydes, tetrahydropyrano[3,4-b]indoles (THPIs) and tetrahydro--carbolines (THBCs) could be easily obtained in high optical purity under optimal conditions using chiral imidazolidinone catalyst 2a and 3,5-dinitrobenzoic acid (DNBA) as


Lu et al.

Y

Y

10-20 mol % 2a.HCl

X +

Z

Z

X O

O

CHCl3, 1.0 M

R 2N

R2N

68-97% yield 84-99% ee

34

35

OMe

OMe 20 mol % ent-2a.HCl +

Ph

O

THF, 4

N 36

i-Pr2NH, STAB

oC

N

THF

N 38 85% yield 83% ee

37

OMe

Ph

Ph

OH

MeOTf, DCM then, Na/NH3

Ph

1. BBr3, DCM 2. tartaric acid

N

82% yield

N

91% yield >99% ee, recryt. 40

39

(R)-Tolterodine

Scheme 6.

OMe

OMe

10 mol % ent-2a.HCl

+

CHO

OMe

1. NaBH4, EtOH 2. 10% Pd/C, H2

OH

O

Bn2N

Bn2N 41

42

43

44

H2N

90% yield 90% ee

OMe

90% yield OH

NaNO2, CuBr

OH 46 (+)-Curcuphenol

45 55% yield

Br Scheme 7.

O

OMe OMe P

R' R' N R 47 + Y

MeO MeO P O

O

O N R 50

20 mol % 2a.TFA CH2Cl2, -78 oC

49

up to 82% yield 96% ee

Y

O

OMe OMe P O

N 48

N

51

Scheme 8.

the cocatalyst. Continuing this study, they have developed the first enantioselective organocatalytic intramolecular hydroarylations of phenol- and aniline-derived enals. This methodology provides an atom economic approach to optically active chromans and tetrahydroquinolines in good yields and high enantioselectivities (up to 96 % ee) (Scheme 9) [35]. Asymmetric cascade catalysis, a bio-inspired strategy combining multiple transformations in a single operation, is a rapid

and effective synthetic approach to construct optically active complex molecules with multiple stereocenters from readily accessible materials [36-38]. In 2004, MacMillan and co-workers reported the first organocatalytic cascade reaction initiated by imidazolidinone 2a (Table 4) [39]. This cascade addition– cyclization strategy provides an efficient way to construct the synthetically important chiral pyrroloindoline motif in one chemical step. Moreover, this strategy was utilized in the concise synthesis of a marine alkaloid (-)-flustramine B (Scheme 10).


Table 3.


Enantioselective Intramolecular Ring-Closing Friedel-Crafts-Type Alkylation of Representative Indolyl Enals

R' O CO2Me

N

O

52 R or

R' X

R'

Grubbs Metathesis

R' X

N 54 CHO

N

N

R

55

53 R

R

O

R'

20 mol % 2a.DNBA

X

O

N

R'

Et2O, 0.1 M

X

R

N 56

R

R

R’

X

Temp (oC)

Yield (%)

ee (%)

Me Bn Bn Me Me Me Bn Bn Bn

H H 5-F 5-Cl 7-Cl 5-Br 5-MeO 5-Me H

O O O O O O O O NTs

-40 -20 -20 -40 -40 -40 -20 -20 0

85 75 89 73 77 95 58 75 78

90 92 85 90 90 93 92 92 90

O

O

Ar

10-20 mol % 6b/HY up to 96 % ee

R

OTMS N Ar H 6b: Ar = 3, 5-(CF3)2C6H3

R

57 X

58

X

X = O: chroman X = N: tetrahydroquinoline

O

O N Y H

H

N H

(R)

N N

X

O O

N

57a

O

N

O

re-face attack 58a 96 % ee

Scheme 9.

Further advancement in the direction of organocascade catalysis was achieved in 2005 by the MacMillan group. They deliberately combined two orthogonal activation modes of carbonyl compounds using one imidazolidinone catalyst 3 in one single operation initiated again by iminium catalysis (Scheme 11) [40]. Under optimal conditions, a variety of aromatic -systems were tolerated in this protocol and the products thus obtained exhibited excellent

enantioselectivities. On the other hand, the two orthogonal activation modes of carbonyl compounds (iminium and enamine catalysis) could be independently provoked with two different amine catalysts in one single operation as demonstrated in Scheme 12 [41]. The significance of this approach is in that diastereoisomers could be selectively obtained with excellent outcomes.


Lu et al.

OH

BocHN 20 mol % 2a.p-TSA +

Br

O

NaBH4 Br

CH2Cl2

NBoc

N

N 78% yield 90% ee 62

61 1. MsCl 2. NO2PHSeCN, H2O2

H

Br

1. TMSI 2. NaBH4, (CH2O)n

NBoc N

H

Br

NMe N

Grubbs metathesis

H

84% yield

89% yield 64 (-)-Flustramine B

63 Scheme 10. Table 4.

Enantioselective Pyrroloindoline and Furanoindoline Formation with Representative Enals and Indoles

O

HX Z

20 mol % 2a.p-TSA

R' +

Z

O

N 59

R'

CH2Cl2

NBoc N

R = allyl or Bn

R

60 R

H

XH

R’

Z

Time (h)

Yield (%)

dr

ee (%)

BocNH BocNH BocNH BocNH BocNH BocNH BocNH BocNH BocNH OH

H 6-Br H H H 5-Me 5-MeO 6-Br 7-Me H

H H COPh CH2OBz CO2Me CO2Me CO2Me CO2Me CO2Me CO2t-Bu O

25 64 44 28 18 20 36 30 40

85 78 92 66 93 94 99 86 97 80

13:1 22:1 44:1 50:1 10:1 31:1 17:1 12:1

89 90 94 91 91 92 90 97 99 93

Nucleophile (ArH) 65

Cl

Cl +

+ Z

Cl

O

66

Z Im

EtOAc

Cl

En

Ar 67

Cl

Cl

Cl

O

O

O 86% yield 14:1 dr 99% ee Cl

O

O

O

O O 86% yield 14:1 dr 99% ee

O E

Cl

Cl

MeO

10-20 mol % 3.TFA

Cl

Pr

N O

86% yield 14:1 dr 99% ee N Cl

86% yield 14:1 dr 99% ee

OAc

N

Cl

Cl

O

O

S

CO2Et

O Ph

86% yield 14:1 dr 99% ee

Scheme 11.

86% yield 14:1 dr 99% ee

86% yield 14:1 dr 99% ee

86% yield 14:1 dr 99% ee



Z

O +

N

CbzN

O

10 mol % 2a 20 mol % L-proline

10 mol % 2a 20 mol % D-proline

Cbz

CH2Cl2-CH3CN

CH2Cl2-CH3CN

N H

N Me

O N

CbzN

Cbz N H

+ 69a 94% yield 14:1 dr 99% ee

Cbz

N N

69b 86% yield 7:1 dr 99% ee

Cbz

68

Scheme 12.

Traditionally, Friedel-Crafts alkylations require the aromatic nucleophiles to be -rich precursors, such as pyrroles, indoles, etc. -Neutral or -deficient substrates are usually out of the consideration in this field. Another constraint of aromatic ring

2.2. Alkylation with Enones It is noteworthy that 4,7-dihydroindoles, due to their prone to oxidative aromatization, could be considered as good intermediates

C3 C2

Restricted to 1) electron-rich -systems 2) Friedel-Crafts regiochemistry

N H

BF3K

N H

indole

N Boc

BF3K

20 mol % 3.HCl

+

O

70

O

HF (1.0 equiv) DME, -20 oC 79% yield 91% ee

N Boc 71

Scheme 13.

functionalization is the well-known Friedel-Crafts regioselectivity (e.g., pyrrole at 2-position, indole at 3-position, etc.). Developing new strategies to overcome these constraints should be very attractive and a significant step in the Friedel-Crafts alkylation chemistry. In 2007, MacMillan and co-workers documented that heteroaryl trifluoroborate salts are viable substrates as nucleophiles in the amine-catalyzed conjugated addition with enals (Scheme 13) [42]. Significantly, -deficient substrates were successful in this protocol and non-traditional regioselectivities were achieved. Table 5.

Synthesis of 2-Functionalized Indoles from 4,7-Dihydroindoles R 20 mol % 6b 20 mol % Et3N + Z O MTBE N H

to 2-substituted indoles [43, 44]. In 2009, Wang and coworkers developed a highly enantioselective Friedel-Crafts alkylation of 4,7-dihydroindoles and enals under Lewis base-promoted iminium catalysis [45]. After a subsequent one-pot oxidation of the adducts, the optically active 2-substituted indoles could be conveniently obtained in high yields without loss in enantioselectivity (Table 5). While iminium catalysis was established as a reliable strategy in the Friedel-Crafts alkylation of enals, enones have attracted much less attention. This might be partially ascribed to the general low reactivity of enones to form iminium intermediate with chiral

R p-benzoquinone O

CH3CN

N H

72

Z 73

R

Z

Yield (%)

ee (%)

H H H OMe OMe OMe

Pr Ph 4-ClPh Pr Ph 4-ClPh

76 79 83 68 74 81

97 96 99 96 93 95


Lu et al.

O N O

N H O 4b.HOAc

O Ph + N H

CH2Cl2, RT 75

74

N H

52% yield 28% ee

76

Scheme 14.

secondary amine catalysts. The first successful example was reported in 2006 by Xiao and co-workers (Scheme 14). However, modest reactivity and low enantioselectivity were observed when using MacMillan’s imidazolidinone catalyst 4b [46]. Chiral primary amines, due to minimized steric constraints compared with secondary ones in the formation of iminium cations with enones, should be expected to exhibit higher reactivity in the Friedel-Crafts alkylation of enones. In 2007, Chen and co-workers demonstrated that primary amine 7, readily accessible from cinchonine, is very effective for the addition of indoles to enones Table 6.

(Table 6) [47]. Meanwhile, Melchiorre and coworkers independently developed a similar catalytic system by combining two chiral entities, primary amine 8 and D-N-Boc-phenylglycine, for the Friedel-Crafts alkylation of indoles with enones [48]. 3. FRIEDEL-CRAFTS CATALYSIS

ALKYLATIONS

VIA

SOMO

A new branch of covalent activation mode in the area of Friedel-Crafts alkylation is the SOMO catalysis, introduced in 2007

Asymmetric Friedel-Crafts Alkylation Between Enones and Representative Indoles Catalyzed by Chiral Primary Amine Catalysts 30 mol % 7.CF3SO3H R2 R2 or R4 O 20 mol % 8.Boc-D-Phg-OH O + R3 R4 R3 1 R N N H 77 R1 79 78 H R1

R2

H H H H H H H CH3 H CH3 H

R3

H H H H H H H H OMe H OMe

Me Me Et Me Me Me Me Me Me Me n-Pr

LUMO activation iminium catalysis

7·CF3SO 3H

8·Boc-D-Phg-OH

Yield, ee (%)

Yield, ee (%)

72, 65 61, 64 47, 81 70, 75 35, 82 -,-,-,-,78, 82 78, 87

90, 88 92, 89 56, 95 -,-,91, 93 67, 93 87, 94 76, 93 -,-,-

Ph p-CPh Ph n-Pr i-Pr CH3(CH 2)4 Ph(CH2) 2 CH3(CH 2)4 CH3(CH 2)4 i-Pr Ph

HOMO activation enamine catalysis

O

SOMO activation somo catalysis

O N

O N

+ 2e -H

N

N

- 1e [O]

N

Ph

N

Ph R

( )4 O 80

Ph R

20 mol % 2a.TFA CAN (2.0 equiv)

H

Scheme 15.

R4

+

N Boc 81

NaHCO3, DME -20 oC

R BocN 85% yield 84% ee

H ( )4 O 82


CHO


CHO

20 mol % 2a.TFA CAN (2.0 equiv) DME, H2O -30 oC

MeO

MeO

MeO 84 56% yield 90% ee

83

85 Demethyl calamenene

CHO

CHO O

R

R

N H2O Ph

R2 R1

N

N H R2 ent-2a

R1

R

N

R

H

R2

oxidant R1

R2 N R1 H

H

N

oxidant R2

R

R1

Nicolaou

R

R2

N

R

R1

N

R

R2 N R1 H

MacMillan

R Scheme 16.

reaction pathway. However, MacMillan and co-workers favored the radical mechanism over the cationic one based on previous studies and experimental observations in their recent independent work [51]. The power of this strategy was elegantly demonstrated in the concise total synthesis of the antitumor natural product demethyl calamenene 85 and (-)-tashiromine 88 (Scheme 17).

by MacMillan and co-workers as a three--electron radical cation with a singly occupied molecular orbital (SOMO) that is activated toward a range of enantioselective catalytic transformations (Scheme 15) [49]. The reaction of octanal and N-Boc-pyrrole under SOMO conditions afforded formyl -arylated product in good yield and enantioselectivity. In 2009, Nicolaou and co-workers developed an intramolecular Friedel-Crafts type -arylation of aldehydes and a plausible catalytic cycle was proposed based on MacMillan’s SOMO activation (Scheme 16) [50]. They believed that the cationic intermediate rather than the radical one should dominate in the

4. FRIEDEL-CRAFTS ALKYLATIONS HYDROGEN-BOND DONORS

BY

Organocatalysts bearing hydrogen-bond donors have been widely applied in asymmetric catalysis for the construction of

O N N H O

20 mol % 2b.TFA CAN

N

H

O 86 Scheme 17.

O

1. AlCl3, LAH 2. Rh/Al2O3, H2 N

H

NaHCO3, CF3CO2Na acetone, -30 oC 72% yield 93% ee

CHIRAL

HO O

87

H

2 steps 51% yield 89% ee

88 (-)-tashiromine

N


Table 7.

Lu et al.

Friedel-Crafts Alkylation of Nitroalkenes and Representative Indoles

R2

R2

R3 +

Method A or B

NO2

R3

NO2

R1

N H 89

N H

90

R1 91

Method A: 20 mol % 9, CH2Cl2, -24 - -45 oC Method B: 5 mol % 10, CHCl3, 0 - -60 oC R1

R2

R3

Method A Time (h); Yield, ee (%)

Method B Time (h); Yield, ee (%)

H Me H H H H H H

H H OMe Cl H H H H

Ph Ph Ph Ph 2-furyl 2-thienyl n-pentyl i-Pr

72; 78, 85 72; 82, 84 72; 86, 89 142; 35, 71 72; 88, 73 72; 70, 73 72; 76, 83 96; 37, 81

10; 92, -94 --; --, -36; 84, -98 --; --, -2; 88, -91 7; 82, -90 --; --, -90; 92, -94

numerous C-C and C-heteroatom bonds. With these small-molecule chiral hydrogen-bond donors (thioureas, phosphoric acids, etc.), people have made significant progress in the enantioselective organocatalytic Friedel-Crafts alkylation over the last few years. 4.1. Alkylation with Activated Alkenes In 2005, Ricci and co-workers reported the asymmetric FriedelCrafts alkylation of indoles with nitroalkenes catalyzed by a simple thiourea catalyst 9 derived from (1R,2S)-cis-1-amino-2-indanol in CF3

one step. Generally, the reactions gave good yields and exhibited moderate to good enantioselectivities (Table 7) [52]. Moreover, the authors proposed a plausible bifunctional transition state, simultaneous activation of the nitroalkene and the indole, based on some experimental observations (Scheme 18). Based on this study, Seidel and co-workers recently developed a more acidic and effective catalyst 10 for this Friedel-Crafts alkylation reaction [53]. With this newly designed catalyst, significant rate acceleration and improvement in enantioselectivity were observed (Table 7).

CF3 S

F3C

N H

S

S N H

F3C R

R

yield

ee

OH

78%

85%

OTMS

18%

39%

H

15%

0%

N

N

H

H

O

O N

N O

N H

H

H O

H

N

O O

N

N

Ph

Ph

Scheme 18.

Ph

Ph R2

R2

TfHN +

R1

R3

NO2

NHTf

2 mol % 11a CH2Cl2 or toluene -24 oC

N R 92

R3 R1

NO2 93 N R 20-97% yield 11-63% ee R3

+ N Me

Scheme 19.

R3

NO2

10-20 mol % 14 CDCl3, -30 oC

H

NO2 94 N Me 54-98% yield 12-50% ee

H


Table 8.


Chiral Phosphoric Acid Catalyzed Friedel-Crafts Alkylation of Indoles with Nitroalkenes

SiPh3 R2

R2

R3

10 mol % 12a +

R3

NO2

O NO2

benzene-DCE -35 oC

N H

R1

3 A MS

O P OH

O R1

N H

95

SiPh3 96

12a

R1

R2

R3

Time (h)

Yield (%)

ee (%)

H

H

Ph

48

76

91

H

H

4-MeOPh

119

64

90

H

H

4-CF3Ph

72

84

91

H

H

2-thienyl

92

71

90

H

H

Ph(CH2) 2

95

57

88

H

H

n-pentyl

234

77

90

H

Cl

Ph

119

63

90

H

Br

Ph

119

72

90

Me

H

Ph

83

70

94

Meanwhile, C2-symmetric chiral hydrogen-donors were also found to be effective for the reaction of N-alkyl indoles with nitroalkenes, affording the corresponding products in good yields with moderate enantioselectivities (Scheme 19) [54,55]. In 2008, Akiyama and co-workers found that chiral phosphoric acids were also good promoters for the alkylation of indoles with nitroalkenes (Table 8) [56]. Under optimal conditions, various indoles and nitroalkenes reacted to produce alkylated indoles in good yields and enantioselectivities. It is worth to note that molecular sieves (3Å) were found to have dramatic impact on the stereochemical outcome and the reaction efficiency. The optically active products from indoles and nitroalkenes are useful building blocks for the synthesis of mono-amine alkaloid and tetrahydro-carbolines as exemplified in Scheme 20.

Recently, You and co-workers reported that the Friedel-Crafts alkylation of 4,7-dihydroindoles with nitroalkenes could be mediated efficiently by chiral phosphoric acids under low catalyst loadings [57]. With slow addition of the nitroalkene component, the reaction proceeds to completion in 2 h in the presence of 0.5 mol % catalyst ent-12b. This protocol offers a practical method to prepare highly enantiopure 2-substituted indole and tetrahydro--carboline derivatives (Scheme 21). Chiral Brønsted acids are also good promoters for the indole alkylation of less active enones (Scheme 22). In this context, Xia and co-workers found that D-CSA and its drived BmimBr-CSA complex are effective catalysts for the alkylation of various indoles and enones [58]. Chiral phosphoric acids are suitable catalysts for this type alkylation and good yields and reactivities were observed Ph NHTs N H

Ph NO2 N H 97 85% ee

Ph

10% Pd/C HCO2NH4 MeOH

t 3N l, E TsC l CH 2C 2

99 87% yield 85% ee

NH2 N H 98 85% yield

TFA , Ph CHO CH 3 CN , ref lux

Ph

N H

NH

Ph 100 89% yield 91:9 dr tetrahydro--carboline Scheme 20.


Lu et al.

0.5 mol % ent-12b +

R

N H

p-benzoquinone

4 A MS

NO2

101

NO2

N H

CH2Cl2-benzene syringe pump (2h)

R

102

103

R O

R Ph p-MeOPh p-ClPh p-BrPh p-FPh 2-naphthyl

O P OH

O R R = 9-anthryl ent-12b

Yield (%) 85 90 91 89 88 87

ee (%) 93 95 92 93 89 88

R NH

N H

R'

104

Scheme 21.

R O + 105

N H

O

chiral Brnsted acid

R

R'

R'

N H

R

106

O

107

O P

O HO3S

O

OH

R R = 4-ClPh ent-12c 63-92% yield 18-56% ee

16 55-96% yield 19-58% ee Scheme 22.

(Table 9) [60]. Instead of chiral phosphoric acids, Ntriflylphosphoramides were discovered to be better promoters for this transformation. In the presence of 5 mol % 13a, the reaction took place smoothly at low temperature and the products were obtained in good yields and high enantioselectivities.

[59]. Despite the low/moderate enantioselectivities obtained, these reports laid the foundation for development of new catalytic systems. In 2008, Rueping et al. investigated the Friedel-Crafts alkylation of N-methyl indoles with , -unsaturated keto esters

Table 9. Chiral Brønsted acid Catalyzed Friedel-Crafts Alkylation of Indoles with ,-Unsaturated -Ketoesters SiPh3 R2

R2

R3

O + N Me

R1 108

R3

O

O

5 mol % 13a CO2Me

CO2Me

CH2Cl2, -75 oC R1

109

O P

O

N Me 110

13a

N H

O2 S

SiPh3

R1

R2

R3

Time (h)

Yield (%)

ee (%)

H

H

Ph

15

62

88

H

H

4-BrPh

24

60

90

H

H

4-ClPh

22

65

88

H

H

4-MePh

20

69

92

H

H

4-MeOPh

18

88

86

H

H

2-naphthyl

18

70

90

Br

H

Ph

24

43

86

Br

H

4-MePh

22

55

80

H

Me

Ph

22

78

84

CF3



R2

O

5 mol % ent-13b

+ R2

N 111 Me

Me N

CO2Et

*

Et2O, -60 oC

CO2Et

O

112

113 O

R O

Yield (%)

ee (%)

Ph

96

98

p-MeOPh

75

97

m-MePh

82

97

p-BrPh

85

96

2-furyl

89

96

2-thienyl

75

98

O P

O

R2

NHTf

R R = 2,4,6-(i-Pr)3Ph ent-13b

O R2 Me N

O CO2Et

* 114

Scheme 23.

obtained in good yields and excellent enantioselectivities. More interestingly, dimeric products, as shown in Scheme 24, were obtained with excellent enantioselectivities as a result of kinetic resolution. More recently, Zhao and co-workers disclosed the organocatalytic Friedel-Crafts alkylation of 2-naphthols by organocatalyst 20a (Scheme 25) [63, 64]. Generally, the reaction could generate naphthopyran derivatives in good yields and high enantioselectivity.

Intrigued by Rueping’s study, You and co-workers recently reported the Friedel-Crafts alkylation of 4,7-dihydroindoles with , -unsaturated keto esters efficiently catalyzed by chiral N-triflylphosphoramide ent-13b (Scheme 23) [61]. With 5 mol % of ent13b, the corresponding products were gained with up to 98% ee. Moreover, this one-pot alkylation-oxidation procedure offers a convenient approach to 2-alkyl indoles. In 2007, Chen et al. described the enantioselective FriedelCrafts alkylation of naphthols with nitroalkenes (Table 10) [62]. In the presence of cinchona thiourea catalyst 15a, the adducts were

Table 10. Enantioselective Friedel-Crafts Alkylation of 2-Naphthols with Nitroalkenes

R1 R1

OH +

NO2

R3

R3

10 mol % 15a

H N

H NO2

toluene, -50 oC 96 h

R2 115

116

H N

CF3

S

OH

CF3

N

15a

R1

R2

R3

Yield (%)

ee (%)

H

H

Ph

80

93

H

H

p-ClPh

82

94

H

H

p-MeOPh

74

85

H

H

p-MePh

69

85

H

H

m-MePh

72

91

H

H

2-furyl

77

90

H

H

2-thienyl

79

94

MeO

H

Ph

81

91

H

Br

Ph

71

90

NO2

Ph

OH

toluene, -50 oC 144 h

OH

Ph

Ph NO2

10 mol % 15a

+

Scheme 24.

N

R2

+ O

OH 116a 26% yield 90% ee

Ph

N O

116b 64% yield >99.5% ee


Lu et al.

O Ar

Ar

51-91% yield 57-90% ee

CO2Me

CO2Me O

117

R

+ OH

118

20 mol % 20a

R

CH2Cl2

CN 38-99% yield 56-90% ee

+ CN

Ar

Ar

NH2 O

CN

R

CF3

119

120

S N H

N H

CF3

N 20a Scheme 25.

(Scheme 26) [65]. Natural occurring pseudoenantiomeric cinchona alkaloids cinchonine (CN) and cinchonidine (CD) were found to be the most efficient catalysts. Independently, Jørgensen and co-workers realized the reaction of indoles with ethyl glyoxylate or ethyl trifluoropyruvate by a C2-

4.2. Alkylation with Carbonyl Compounds Carbonyl compounds are useful electrophiles for asymmetric Friedel-Crafts alkylations to generate chiral secondary and tertiary alcohols in organic synthesis. However, it seems a challenge task to

HO

R

R

O

CD or CN

+ F3C

N H

124 R = H, 5-MeO, 5-F, 5-Cl, 5-Br, 5-I, 5-CO2Me, 6-Me

CF3 CO2Et

Et2O, -8 oC

CO2Et

N H ent-126 5 mol % CN 96-99% yield 83-92% ee

126 5 mol % CD 96-99% yield 83-95% ee OH

OH N

N N

CF3 CO2Et

or

N H

125

HO

R

H

H Cinchonine (CN)

N

Cinchonidine (CD)

Scheme 26.

carry out the alkylation with simple aldehydes and ketones due to the acid sensitive of the adducts, which might be further alkylated. In 2005, Török and co-workers introduced an organocatalytic Friedel-Crafts reaction of indoles with ethyl trifluoropyruvate

symmetric bis-sulfonamide catalyst (Scheme 27) [66]. With 10 mol % of the most active catalyst 11b, all reactions proceeded smoothly to afford the adducts in good yields and moderate enantioselectivities. Ph

R2 +

R1

R= H, Me R1 = H, Cl R2 = H, MeO Scheme 27.

R2 HO

NfHN R3

CO2Et

N R 121

Ph

O NHNf

R3 = H, CF3

CO2Et

10 mol % 11b CH2Cl2

122

Nf = CF3CF2SO2

R3

R1

N R 123 73-99% yield 23-63% ee



R'

R

R

O

10 mol % 18a

+ R'

N H 127

CO2Et

CO2Et

N H

128

F3C

R

O

OH

10 mol % 18a

+ F3C 130

129

60-97% yield 81-99% ee

R = H, 4-MeO, 5-Cl, 6-Cl, 6-Br, 6-MeO, 7-Me R' = H, alkynyl, aryl OH

R

OH

CO2Et

CO2Et

HO 132

131

58-96% yield 71-94% ee

2- or 2,6-disubstituted OH OPHN

PHN = N

N

H 18a

Scheme 28.

With catalyst ent-12d, Ma and co-workers were able to obtain secondary and tertiary alcohols with good results from the alkylation of indoles or pyrroles with activated carbonyl

Cinchona alkaloid 18a, bearing a C6’-hydroxy group, were found to be an effective bifunctional catalyst for the Friedel-Crafts alkylation of indoles and carbonyl compounds by Deng and co-

R R'

R R

1-10 mol % ent-12d

O + N H 133

OH

O

O P

CXF2 O

F2XC

R' CH2Cl2, RT 134 X = F, H, CF3 R' = CO2Et, aryl, alkyl, CH2CO2Et

N H

135 36-99% yield 26-99% ee

OH

R R = 2,4,6-(i-Pr)3Ph ent-12d

Scheme 29.

compounds (Scheme 29) [69,70]. It is worth to note that this represents the first example of using relatively strong chiral Brønsted acid in Friedel-Crafts alkylation without observation of bisindole products.

workers in 2006 (Scheme 28) [67]. This catalyst exhibited well tolerance in substrates with various indoles and carbonyl compounds. In addition to indoles, phenols could also be used as good nucleophiles for the alkylation with ethyl trifluoropyruvate employing 18a as the catalyst [68]. The reaction occurred regiospecifically and the adducts were obtained in good yields and enantioselectivities. Very recently, chiral phosphoric acids were applied in the asymmetric Friedel-Crafts alkylation with carbonyl compounds.

4.3. Alkylation with Imines Imine constitutes a valuable electrophile in asymmetric synthesis. The Friedel-Crafts alkylation of imines provides a unique NHBoc

NBoc

2 mol % 12e

+

MeO

O

H

136

O

DCE, -35 oC

R

MeO

137

138

R O

O P

O

OH

R R = 3,5-dimesitylphenyl 12e

Scheme 30.

R

Yield (%)

ee (%)

Ph

87

97

p-MeOPh

95

96

o-MePh

84

94

m-BrPh

89

96

p-FPh

82

97

2-furyl

94

86

R


R + H

EtOAc, 50

R'

NHP

R

10 mol % 15b

NP N H

Lu et al.

N

R'

oC

N H

139 140 R = H, 4-MeO, 5-Me, 6-MeO, 6-Br, 6-Cl R' = alkyl, aryl

H N

H

H N

CF3

S

MeO

141 up to 98% yield 97% ee

CF3

N 15b

Scheme 31.

approach to chiral secondary or tertiary amines with a benzylic stereocenter. In 2004, Terada and co-workers developed the first organocatalytic aza-Friedel-Crafts alkylation of imines with 2methoxy furan by means of newly designed chiral phosphoric acids (Scheme 30) [71]. Under optimal conditions, the authors could obtain the 2-furanylamines with excellent reaction efficiency and stereocontrol (80-96% yield and 86-97% ee). Importantly, this reaction can be carried out on a gram scale by using only 0.5 mol % of 12e. The construction of 3-indolyl methanamine structural unit, due to its presence in a variety of indole alkaloids and drug candidates, has attracted a great deal of attention in the chemical community. R

10 mol % 12f or 12g

NP + N H

R'

H

The aza-Friedel-Crafts alkylation of indoles offers one of the most straightforward approaches to such molecules. In 2006, Deng and co-workers developed the first Friedel-Crafts alkylation of indoles with N-sulfonyl imines using bifunctional cinchona alkaloidderived thiourea catalyst 15b (Scheme 31) [72]. The valuable 3indolyl methanamine derivatives were obtained in excellent yields and enantioselectivities under optimal conditions with 10 mol % of 15b. Perhaps most importantly, the catalyst could be anchored on mesoporous silica and therefore recyclable, as demonstrated by He and co-workers [73]. The You group has found that 3-indolyl methanamine derivatives can be obtained in excellent yields and up to 99% ee

R'

toluene

N H 144 56-98% yield 58->99% ee

142 143 R = H, 5-MeO, 5-Me, 5-Br, 6-Cl R' = alkyl, aryl, CO2Et R

R

NHBoc 2-10 mol % 12h

NBoc + N TBS

H

145

Ar

Ar

Cl2CHCHCl2

N TBS

146


R = H, Br, Me

R

5 mol % ent-12a

NBz + N Bn

H

148 R = H, 5-MeO, 5-Me, 5-Br, 5-CO2Me, 2-Me, 7-Me R O

O

Ar

4 A MS, CH2Cl2

149

O R R = 1-naphthyl ent-12f

NHBz

R

Ar N H 150 89-99% yield 64-96% ee

R

R

O

P

Scheme 32.

NHP

R

O

O

P OH

O R R = 9-phenanthryl ent-12g

O P

OH

O

OH

R R = 3,5-diphenylphenyl 12h



R3 NBz

NHBz

R3

5 mol % ent-12a

Ar

+

R2

H

N 151

R2

N

CHCl3 -55 - -60 oC

Ar

R1 152

R1


NTs

154

R2

NHTs

toluene, -40 oC

Ar

H

R1

10 mol % ent-12a

+ N H

R1

R2

N H

155

Ar

156 O

R1

R2

Ar

Yield (%)

ee (%)

H

H

Ph

88

99

H

H

p-MePh

81

98

H

H

p-BrPh

79

99

H

MeO

Ph

74

>99

Me

H

Ph

83

98

O R1 R2

NHTs N H

Ar

157 Scheme 33.

from the reaction of various indoles with a broad scope of Nsulfonyl imines by using catalyst ent-12f or ent-12g (Scheme 32) [74,75]. Independently, the Terada and the Antilla groups developed two chiral phosphoric acids, 12h and ent-12a, respectively, for the aza-Friedel-Crafts alkylation of indoles. Notably, the adducts in these reports were obtained with excellent stereoselectivities [76, 77]. Antilla and co-workers also applied their catalytic system for the alkylation of pyrroles with imines. Thus, a highly enantioselective FriedelCrafts reaction of pyrrole derivatives with N-acyl imines catalyzed by chiral phosphoric acids was developed. The reactions produced the pyrrole derivatives in high yields and

enantioselectivity (Scheme 33) [78]. With the use of the same catalyst ent-12a, You et al. have developed the enantioselective Friedel–Crafts reaction of 4,7-dihydroindoles with imines. The reaction features a high efficiency of the catalyst, high yields, and excellent enantioselectivities, and provides a practical method to synthesize highly enantiopure 2-(4,7-dihydroindolyl) and 2-indolyl methanamine derivatives. (Scheme 33) [79]. Continuing this theme, Enders and co-workers recently developed an elegant method for the synthesis of isoindolines, which are common substructures in a variety of natural products and pharmaceuticals (Scheme 34) [80]. In the presence of 10 mol % of chiral phosphoric acid 12i, the Friedel-Crafts alkylation occurred R R

NTs R

NH

O

R' 10 mol % 12i

+

O

R'

then DBU N H CO2Me 158

NTs

31-71% yield 96->99% ee

R

159 12i

CO2Me

160 ArH

DBU

NHTs R'

ArH

NHTs R'

Ar Ar R'

Scheme 34.

O P

Ar

Ar

R = 4-NO2Ph 12i

OH


Lu et al.

OMe

NH2 R

OH + F3C

N H

10 mol % 12d

+ OMe

MeO

OMe

161 Scheme 35.

162

80-99% yield 79-98% ee

163

smoothly; and subsequent one-pot intramolecular aza-Michael addition mediated by DBU provided the desired isoindoline derivatives in high yields with good diastereo- and enantioselectivities. Interestingly, enhancement of enantiomeric ratio by stereoablative kinetic resolution was observed in the tandem reaction sequence. While a great deal of attention has been paid to the alkylation of imines, the three-component reaction has been less studied. In 2008, Ma and co-workers reported the first three component alkylation of indoles and imines generated in situ from trifluoroacetaldehyde methyl hemiacetal and aniline Scheme 35 [81]. In the presence of 10 mol % chiral phosphoric acid 12d, chiral NHBoc

R + N H

R'

H

N H 164

NHBoc R' (a)

CH3CN

N H 167 90-96% ee

R''

165

OMe

chiral phosphoric acids (Scheme 36a) [82]. Under optimal conditions with 2-5 mol % of catalyst 12d, optically active 3indolyl methanamines were obtained in good yields with up to 96% ee. Independently, Zhou and co-workers reported the asymmetric Friedel-Crafts alkylation of indoles with enamides with the same chiral phosphoric acid 12d (Scheme 36b) [83]. Notably, the construction of chiral quaternary centers was achieved in the later case. Recently, N-acyl iminium ions were also demonstrated to be electrophiles for the enantioselective Friedel-Crafts alkylation by Jacobsen et al. (Scheme 37) [84]. In the presence of 5 mol % of the thiourea catalyst 20a, a highly enantioselective addition of indoles R

2-5 mol % 12d

N H

CH2Cl2, 4A MS

OMe

OMe

CF3

R

166

R

R'' O

O P OH

O R

NHAc

NHAc

R

10 mol % ent-12d

Ar

+ N H

toluene

Ar

168

R R = 2,4,6-(i-Pr)3Ph 12d

(b)

N H 170 up to 99% yield 97% ee

169

Scheme 36.

to cyclic N-acyl iminium ions has been developed. Both electronrich and electron-poor indole nucleophiles can be used as substrates. The products are synthetically useful intermediates that can be elaborated readily: for example, cleavage of the benzyl protecting group with Na/NH3 proceeds without erosion of enantiomeric excess. Moreover, a plausible reaction pathway was

secondary amines containing a trifluoromethyl group were obtained in good yields with up to 98% ee. Imine precursors, instead of the direct imines, are also good electrophilic partners for the asymmetric Friedel-Crafts alkylations. In 2007, Terada and co-workers reported the Friedel-Crafts alkylation of various indoles with enecarbamates catalyzed by

R' N H 171

5-10 mol % 20a 2.0 equiv. TMSCl or 10 mol % BCl3

R'

N

TBME, -30

R'

N

( )n

172

S N H

N H

O

N

oC

12-93% yield 80-99% ee

HO

R'

20a N H 173

AcO

N

( )n Ph

+ O

Ph

O

Et3Si

t-Bu



(Scheme 37) contd…..

O

O BnN

+ HCl

BnN AcO

S

+ HCl R*

R N H

N

N

H

H

R'* O BnN

+ HOAc

Cl

TMSCl

SH R*

N

N

H

H Cl

R'* O

TMSOAc + HCl

S R*

BnN H

N

N

H

H Cl

R

R'* O BnN

N H

R N H Scheme 37.

proposed and the anion-binding seems crucial for the enantiooutcome. In addition to the intermolecular alkylation with imine, the organocatalytic asymmetric Pictet-Spengler reaction, namely the intramolecular Friedel-Crafts alkylation of imines, has become an important method for the preparation of chiral tetrahydroisoquinolines and tetrahydro--carbolines. In 2004, the Jacobsen group developed a acyl-Pictet-Spengler reaction promoted by chiral thiourea catalysts (Scheme 38) [85-87]. All the reaction proceeded R

AcCl, 2,6-lutidine 5-10 mol % 20b

N N H 174

N H

N H

R

177

CF3 Me

N H N

Ph

Bn

N N H

S

N

N H

N H O

20b

NH

39-94% yield 85-99% ee

S

O

R'

R

toluene, RT

176

Scheme 38.

N H 175

20 mol % 21 20 mol% BzOH RCHO (1.0 equiv.)

N H

i-Bu

NAc

86-95% ee

NH2

N

R

Et2O R'

R

i-Bu

smoothly in good yields and up to 95% ee with 20b (10 mol%) as the catalyst. Importantly, they have successfully applied this protocol in the total synthesis of (+)-yohimbine, a member of the monoterpenoid indole alkaloids. In 2007, Jacobsen and co-workers reported a novel asymmetric Pictet-Spengler-type indole cyclization of hydroxylatams with imines generated in situ catalyzed by chiral thiourea 20c (Scheme 39) [88]. Mechanistic studies revealed that hydrogen bonding with the chloride anion played a critical role for the enantio-outcome.

21

CF3

H H H MeO2C

(+)-yohimbine

OH


Lu et al.

( )n

O

R'

N

OH

O

10 mol % 20c TMSCl

N R

TBME -55 or -78 oC

R N H

N H

( )n

12-93% yield 80-99% ee 179

178

Me

S

N

n-C5H11

R'

N H

N N H

O

N 20c

H

N H

Ph

(+)-harmicine

Scheme 39.

Furthermore, the power of this strategy was well demonstrated in the concise total synthesis of (+)-harmicine. Recently, Jacobsen and co-workers further developed the asymmetric Pictet-Spengler-type pyrrole-cyclization of

-carbolines were obtained in good yields and excellent enantioselectivities from a broad spectrum of both tryptamines and aldehydes. The only limitation of this reaction seems to be the requirement of a geminal diester.

( )n

O

O N

O

O

1. R-Li, THF 2. 20 mol % 20c AcCl or TMSCl TBME

( )n

N

N

or R

N P

R

( )n

N P

N P

181b

181a 180

P=H 51-86% yield 52-91% ee

P = TIPS 51-86% yield 52-91% ee

Scheme 40.

hydroxylatams catalyzed by chiral thiourea 20c (Scheme 40) [89]. Interestingly, this protocol displayed unprecedented regioselectivities. The cyclization occurred at the C2-position without substituents on the nitrogen of pyrroles, while sterically demanding triisopropylsilyl group on the nitrogen coursed completely different regioselectivities at the C4-position. The corresponding adducts were generated in good yields with up to 91% ee. In addition to Jacobsen’s thiourea catalysts, chiral phosphoric acids have been employed for the Pictect-Spengler reaction. In 2005, List and co-workers developed the first chiral phosphoric acid-catalyzed Pictect-Spengler reaction (Scheme 41) [90]. Under optimized conditions with 20 mol % of ent-12d, various tetrahydroCO2Et CO2Et

R

NH2 N H 182

Scheme 41.

In 2007, Hiemstra and co-workers developed a novel strategy for the asymmetric Pictet-Spengler reaction catalyzed by chiral phosphoric acids (Scheme 42) [91]. They introduced Nsulfenyliminium ions as intermediates in the reaction and good results were obtained. Significantly, the N-protecting group of the cyclized products could be readily removed. Later, they also succeeded in using simple N-benzyltryptamine for the asymmetric Pictet-Spengler reaction with both aromatic and aliphatic aldehydes [92]. The corresponding tetrahydro--carbolines were generated in good yields and up to 87% ee. Very recently, Dixon and co-workers reported a cascade PictetSpengler-type reaction of tryptamines and enol lactones catalyzed by chiral phosphoric acids (Scheme 43) [93]. The reaction was

20 mol % ent-12d R'CHO

CO2Et CO2Et

R

NH CH2Cl2, Na2SO4 -10 oC

N H

R' 183 40-96 yield 72-96% ee



R

HN

5 mol % 12i PhCH2CHO MS, BHT

SCPh3

O HCl, PhSH

toluene, 0 oC

N H

O

N H

184

R Ar = 3, 5-(CF3)2Ph 12i

2 mol % 12a RCHO, 4A MS

NBn

toluene, RT-70 oC

N H

OH

Bn

185 90% yield 87% ee NHBn

O P

NH

N H

186

R

187 R = alkyl, aryl up to 97% yield up to 87% ee

Scheme 42.

carried out at high temperature with 10-20 mol % of catalysts, and the Pictet-Spengler-type products were obtained in good yields with excellent diastereo- and enantiocontrol.

2006 [94,95]. A novel family of non-biaryl atropisomers was obtained in good yields with up to 98% ee in the presence of 20 mol % cinchona alkaloid-derived catalysts.

5. MISCELLANEOUS

6. CONCLUSION AND OUTLOOK

Azodicarboxylates are useful electrophiles for introduction of an amine group in organic synthesis. At a first glance,

In summary, great advances have been achieved in the enantioselective organocatalytic Friedel-Crafts alkylation over the

O

R1 NH2

O

+

N H

( )n

R2

188

O

10-20 mol % 12a, H8-12a or 12d

N R1

toluene, 110 oC 63-99% yield 72-99% ee

R3 189

( )n

R2

N H

R3

190

Scheme 43.

last few years. Continuing efforts have been devoted to the development of novel activation strategies and synthetically useful reactions, which allow chemists to access a variety of important chiral building blocks and to produce biologically interesting natural products and drug candidates.

azodicarboxylates are not suitable electrophilic component for the asymmetric Friedel-Crafts alkylation due to non-chiral product to be obtained. However, an interesting example of the enantioselective Friedel-Crafts alkylation of 2-naphthols with azodicarboxylates was reported by Jørgensen and coworkers in

O NHR'

tBuO C 2

OH

N

N

tBuO

CO2tBu

H O N OtBu NHR' N

20 mol % 18b, 19a-b

R

OH

up to 98% ee

R

191

192

O

O

N HO

H H

HO

tBuO

N

18b

H

HO

NBoc

H

HO

tBuO

N

N HO

NBoc

H

HO

N Scheme 44.

N

N 19a

N 19b


Lu et al. [28]

However, despite significant progress, a brief survey of the current available protocols revealed that the engage of less reactive aromatic compounds in organocatalytic Friedel-Crafts alkylation remains an unsolved challenge. There is no doubt that continuing effort would be made to develop novel activation strategies and new reactions to extend the scope of the enantioselective organocatalytic Friedel-Crafts alkylation.

[30]

7. ACKNOWLEDGEMENT

[31]

We are grateful to the National Science Foundation of China (20872043) and the Program for Academic Leader in Wuhan Municipality (200851430486) for support of this research.

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Received: September 04, 2009

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Revised: September 27, 2009

Accepted: September 27, 2009