Enantioselective tandem conjugate addition elimination reactions 1

1.1 Tandem conjugate addition-elimination CA-E reactions Tandem conjugate addition-elimination CA-E reaction is the in situ addition of a nucleophile to an α,β-unsaturated compound foll

Chapter 1

Introduction

1.1 Tandem conjugate addition-elimination (CA-E) reactions

Tandem conjugate addition-elimination (CA-E) reaction is the in situ addition of a

nucleophile to an α,β-unsaturated compound followed by the elimination of a good

mechanisms The substrates of tandem CA-E reactions typically consist of

To the best of our knowledge, the tandem CA-E reaction is not widely studied There are few reported examples of tandem CA-E reactions, especially asymmetric versions In

Nu Nu

(1)

R' O

Nu

R' O

Nu

R Nu

O R'

(2)

Scheme 1.1SN2′ reaction and tandem conjugate addition-elimination (CA-E) reaction Morita-Baylis-Hillman reaction has been regarded as a useful carbon carbon bond forming reaction because it produces multi-functionalized molecules like α-methylene β-carbonyl compounds The products of the Morita-Baylis-Hillman reaction, also known as MBH adducts, contain a minimum of three functional groups: hydroxyl, olefin, and

1 D Basavaiah, A J Rao and T Satyanarayana, Chem Rev., 2003, 103, 811-891

are synthetically very useful in various transformations including the synthesis of

MBH allylic bromides, which derived from MBH adducts through a single

useful for its broad substrate scope and environmental friendly conditions Similar strategy was utilized in the preparation of functionalized 1,4-pentadienes from MBH

reactions

R

Br

CO2Me DABCO

THF/H2O (1:1)

R

N

CO2Me

N Br

rt, 15 min

NaBH4

rt, 15 min

R CO2Me

72-90%

R = aryl, alkyl

Ar

Br

CO2Me

+

CN DABCO

rt, 7days

MeO2C

Ar CN

37-67%

Scheme 1.2 Reaction of MBH allylic bromides promoted by DABCO

Recently, Lee and co-workers reported that amine nucleophiles can attack MBH

the solvents, the basicity and amount of base strongly affect the addition of the amine to

2 G Masson, C Housseman and J Zhu, Angew Chem Int Ed., 2007, 46, 4614-4628

3 (a) H M R Hoffmann and J Rabe, J Org Chem., 1985, 50, 3849-3859 (b) C Börner, J Gimeno, S Gladiali, J

Goldsmith, D Ramazzotti and S Woodward, Chem Comm., 2000, 2433-2434 (c) L Fernandes, A J Bortoluzzi and

M M Sá, Tetrahedron, 2004, 60, 9983-9989

4 D Basavaiah and N Kumaragurubaran, Tetrahedron Lett., 2001, 42, 477-479

5 D Basavaiah, N Kumaragurubaran and D S Sharada, Tetrahedron Lett., 2001, 42, 85-87

the allylic bromides.6 The SN2′ type product can be obtained through a substitution reaction of triethylamine followed by the tandem CA-E process of the amine nucleophile

O

Br

0.5 eq Et3N, 2eq PhNH2

hexane

7 eq Et3N, 2eq PhNH2

CH2Cl2

O

NHPh

SN2 type product, major

Ar

NH

OMe

O Ph

SN2' type product, only

O

Br

Et3N

excess

O

NEt3

Br ammonium salt

Ar

NH

OMe O Ph

SN2' type product PhNH2

Scheme 1.3 Lee’s regioselective amination of allylic bromides

achieved by using DABCO as the promoter (Scheme 1.4) The product could be

intramolecular Friedel-Crafts type cyclization followed by aromatization process

Ar

Br

CO2Me

NO2

CO2Et

1 DABCO

aq THF, 20 min

Ar CO2Me

O2N CO2Et

2.

Scheme 1.4 Reaction between MBH allylic bromides and ethyl nitroacetate

6 H.-Y Chen, L N Patkar, S.-H Ueng, C.-C Lin, A S.-Y Lee, Synlett, 2005, 13, 2035-2038

7 K Y Lee, J Seo and J N Kim, Tetrahedron Lett., 2006, 47, 3913-3917

8 K Y Lee, S Gowrisankar, Y J Lee and J N Kim, Tetrahedron, 2006, 62, 8798-8804

In order to develop a practical and efficient method to prepare allylic azide, Sá reported a straightforward nucleophilic substitution of azide anion to MBH allylic

terms of reaction rate, workup method and product yield The mechanistic aspects involved in this transformation remains ambiguous as it could be a direct displacement of azide anion or a conjugate addition-elimination (CA-E) process followed by a [3,3]-sigmatropic rearrangement

R

Br

O

OMe NaN3 acetone:H2O (3:1)

25oC, 10min

R

N3

O

OMe

93-97%

Scheme 1.5 Synthesis of allylic azide

In addition to MBH allylic bromide, Orena and co-workers reported a regioselective

employed as the catalyst, product A was obtained exclusively However, the reaction was

interesting results could be due to the higher nucleophilicity of DABCO with respect to DBU

H O

R

CO2Et

Ts

CH2Cl2, rt DABCO N N

DBU

CH2Cl2, rt

R CO2Et

NHTs

A

NHTs

R

CO2Et

B

N

N

Scheme 1.6 Reactions of MBH carbamate

1.2 Asymmetric tandem CA-E reactions

9 M M Sá, M D Ramos and L Fernandes, Tetrahedron, 2006, 62, 11652-11656

10 M Ciclosi, C Fava, R Galeazzi, M Orena and J Sepulveda-Arques, Tetrahedron Lett., 2002, 43, 2199-2202

1.2.1 Chiral auxiliary strategy

An approach to an asymmetric tandem CA-E reaction is the installation of a chiral auxiliary as the leaving group It was first shown by Fuji et al that chiral nitro enamines could be used for the asymmetric synthesis of quaternary carbon centers through an

prepare the chiral substrate and strong bases such as Lithium diisopropylamide (LDA) were essential to generate the lactone enolates Low temperature was also required for good enantioselectivity

N NO2

R1

OMe

+ O

O

R2 M

R1= H, CH3or C2H5 R2 = CH3, C2H5or

CH2CH=CH2

ether, -78oC O

O

NO2

R1

R2

30-96% ee

M+= Li+, Cu+or Zn2+

Scheme 1.7 Asymmetric nitroolefination of lactone enolates

Using chiral pyrrolidines as the auxiliary, Tamura showed that it is possible to achieve moderate to high diastereoselectivity with lithium diorganocuprates, leading to optically

synthesis of Clavularin A with high enantio-and diastereoselectivity was also achieved by

O

N

MeO

1) LiBr, THF, -90oC to 0oC 2) NH4Cl or SiO2

n

n = 1,2,3

+ R 2 CuLi-LiBr

R = Me, Et, Ph,nBu, CH=CH2

90-97% ee

O

11 K Fuji, M Node, H Nagasawa, Y Naniwa, T Taga, K Machida and G Snatzke, J Am Chem Soc., 1989, 111,

7921-7925

12 R Tamura, K.-i Watabe, N Ono, Y Yamamoto, J Org Chem., 1992, 57, 4895-4903

13 R Tamura, K.-i Watabe, N Ono, Y Yamamoto, J Org Chem., 1993, 58, 4471-4472

Scheme 1.8 Asymmetric synthesis of 3-substituted 2-exo-methylene-cycloalkanones

Although Tamura’s methodology works well with a variety of substrates, the selectivity of the reaction was highly dependent on the types of organometallic nucleophiles and Lewis acids In addition, the main drawback of this reaction is the preparation of substrates with chiral directing group, which is similar to Fuji’s method

On the contrary, we were interested in developing a fully organocatalytic process for the tandem CA-E reaction

1.2.2 Organocatalytic asymmetric tandem CA-E reactions or S N 2 ′ type reactions

Kim and co-workers firstly disclosed an enantioselective synthesis of MBH alcohols

OAc

CO2Me

(DHQD)2PHAL

NR3

*

H2O/THF

CO2Me

NR3 AcO

*

NaHCO3

OH

CO2Me

+

OAc

CO2Me (S)

13 days, 25%, 92% ee 21%, 80% ee

NR3 =

N

MeO

N

OMe

N N

H3C

CH3

Scheme 1.9 Enantioselective synthesis of MBH alcohols

14 J N Kim, H J Lee and J H Gong, Tetrahedron Lett., 2002, 43, 9141-9146

Although up to 92% ee was obtained, the reaction was very slow and low-yielding (25-42% yield) Reactions between MBH acetate and phenols or sulfonamides under similar reaction conditions have also been investigated The enantioselectivities were moderate along with very poor yields

It was reported by Lu and co-workers that Cinchona alkaloids can catalyze the reaction between tert-butyl carbonate of MBH adduct and various pronucleophiles

after elimination of carbon dioxide The anion can deprotonate the pronucleophile and

generate nucleophilic anion in situ, which makes the reaction catalytical

OBoc

CO2Me + NuH

N

OH

N O

toluene, rt TQO

Nu

CO2Me

N

CO 2 Me

96%, 68% ee

O

CO2Me

93%, 72% ee

CO2Me

CO2Me MeO2C

90%, 51% ee

Scheme 1.10 Enantioselective reactions of tert-butyl carbonate of MBH adduct

Allylic amination of MBH acetates with similar strategy using catalytic chiral

of this transformation is the generation of an electrophile-nucleophile ion pair, which

15 Y Du, X Han and X Lu, Tetrahedron Lett., 2004, 45, 4967-4971

16 C.-W Cho, J.-R Kong and M J Krische, Org Lett., 2004, 6, 1337-1339

might suppress direct addition of nucleophile to the less substituted enone moiety of the starting MBH acetate Nevertheless, this reaction is highly dependent on the basicity

AcO

EWG

R1 R2

NuH (200 mol%)

PR3(20 mol%)

Nu EWG

R1 R2

EWG

R1 R2

PR3

OAc

Electrophile-Leaving Group

Ion-Pair

EWG

R1 R2

PR3

Nu

Electrophile-Nucleophile Ion-Pair

OAc + NuH HOAc + Nu

OAc

CO2Me

O

O THF, 50oC, 62 hrs

(R)-Cl-MeO-BIPHEP (20 mol%)

N

CO2Me

O2N

O2N

80%, 56% ee

PPh2

Cl MeO PPh2

Cl

MeO

Scheme 1.11 Phosphine catalyzed reaction of MBH acetate

A successful tandem CA-E reaction has been developed by Ramachandran for the

reaction of various MBH acetates using quaternary Cinchona alkaloids under phase

acid derivatives However, this methodology is only applicable to benzophenone imine of

glycine tert-butyl ester

17 P V Ramachandran, S Madhi, L Bland-Berry, M V R Reddy and M J O’Donnell, J Am Chem Soc., 2005, 127,

13450-13451

Bu

O Ph

Ph +

(10 mol%)

CsOH H2O (10 eq)

CH2Cl2, -78oC

Ph

N=CPh2

CO2tBu OMe O

30h, 92%, 92% ee N

N

OR Ar

Br

R = allyl

Ar = 9-anthracenyl

Scheme 1.12 Enantioselective tandem CA-E reaction under PTC conditions

Although a few enantioselective reactions of MBH allylic acetates have been reported, examples of MBH allylic bromides are still limited It was shown by Basavaish that with

2 equivalents of quinidine, propargyl alcohol can add in a tandem CA-E fashion (Scheme

enantioselectivities obtained were moderate (25-40%)

Ar

Br

CO2Me

+

OH

Quinidine (NR3)

2 eq

*

CH2Cl2, rt, 24 hr Ar

CO2Me O

25-40% ee

Scheme 1.13 Reaction between MBH allylic bromides and propargyl alcohol

Inspired by these results, we envisage that the MBH allylic bromides could be a useful substrate for an easy introduction of a range of nucleophiles onto the allylic framework As we know, atom economy, efficiency and selective transformations have become the prime criteria for the development of synthetic reactions Thus, we are interested in exploring the tandem CA-E reaction of MBH allylic bromides, regio- and

stereoselectively using the chiral leaving group strategy

18 D Basavaiah, N Kumaragurubaran, D S Sharada and R M Reddy, Tetrahedron, 2001, 57, 8167-8172