This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 8355–8357 8355

Cite this: Chem. Commun., 2011, 47, 8355–8357

Highly diastereo- and enantioselective synthesis of syn-b-substitutedtryptophans via asymmetric Michael addition of a chiral equivalent of

nucleophilic glycine and sulfonylindolesw

Jiang Wang, Shengbin Zhou, Daizong Lin, Xiao Ding, Hualiang Jiang and Hong Liu*

Received 4th May 2011, Accepted 8th June 2011

DOI: 10.1039/c1cc12619a

The asymmetric synthesis of syn-b-substituted tryptophan

derivatives was carried out by the Michael addition of chiral

equivalent of nucleophilic glycine with sulfonylindoles, and high

diastereo- and enantioselectivities were achieved. The resulting

adducts were readily converted to syn-b-substituted tryptophans

in 96% yield, indicating that the proposed method is a highly

efficient route to chiral syn-b-substituted tryptophans.

Optically active heterocyclic amino acids are very attractive

motifs in organic synthesis because of their wide-ranging

biological significance and high versatility as synthetic building

blocks.1 Tryptophan, in addition to being an essential amino

acid for many organisms, is one of the 20 standard amino

acids used in protein biosynthesis.2 Likewise, b-substitutedtryptophan analogs are important building blocks of many

bioactive compounds and natural products, such as celogentin

C,3 stephanotic acid,4 hemiasterlin,5 milnamide A,6 and other

alkaloids. b-Substituted tryptophans have also been used

to investigate peptide–receptor relationships through the

replacement of natural amino acids.7

The development of efficient and practical catalysts for

the asymmetric synthesis of b-substituted tryptophans is of

considerable interest to both academia and industry.8 Laronze

et al. have demonstrated that condensation reactions of

indole, aldehydes, and Meldrum’s acid afford b-substitutedtryptophans as racemic mixtures.8a Chen et al. have reported

that asymmetric Friedel–Crafts alkylation of indoles with

nitroacrylates affords tryptophan nitro-precursors in moderate

diastereoselectivities (deo 44%) and good enantioselectivities

of syn-products (41%–89%).9 With the aim of enhancing the

diastereo- and enantioselectivity of b-substituted tryptophans,

Hou et al. carried out the reaction of glycine derivatives with

sulfonylindoles in the presence of catalytic AgCl and a chiral

monodentate phosphoramidite, this was an efficient route to

anti-b-substituted tryptophans.10

Chiral nickel(II) complexes of the glycine Schiff bases have

been widely used to synthesize enantiopure amino acids via

aldol,11 Michael addition,12 Mannich,13 and C-alkylation14

reactions. Soloshonok et al. reported the first alkylation of

nickel(II) complexes with racemic alkyl halides.15 The asymmetric

synthesis of chiral amino acids mediated by nickel(II) complexes

is notable for its use of readily available and cost-effective

procedures. In addition, the reaction conditions are mild, the

procedures are fairly simple, and high enantioselectivity is

obtained. These unique features of the nickel(II) complexes

mediated asymmetric synthesis of tailor-made amino acids16

make it a superior method for the practical synthesis of

enantiopure b-substituted tryptophans in industrial settings.

On the other hand, sulfonylindoles are known to undergo

elimination of the arenesulfinic group under acidic or basic

conditions leading to reactive (N-acyl)imino species that can

be employed in the reaction with different nucleophilic

systems.17 However, to the best of our knowledge, nickel(II)

complexes have not yet been used for asymmetric synthesis of

chiral syn-b-substituted tryptophans. As part of continuing

effort to assemble b-substituted tryptophans, we aimed to

develop a new protocol for syn-b-substituted tryptophans via

chiral nickel(II) complexes of the glycine Schiff bases in a short

time (Scheme 1). In comparison with the existing methods,

the present approach offers the following advantages: (i) it

proceeds faster and affords good to excellent yields with high

diastereo- and enantioselectivities, (ii) it is very cost-effective,

Scheme 1 Asymmetric synthesis of b-substituted tryptophans via

Michael addition of a chiral nickel(II) complex with sulfonylindoles.

State Key Laboratory of Drug Research, Shanghai Institute ofMateria Medica, Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai,P. R. China. E-mail: hliu@mail.shcnc.ac.cnw Electronic supplementary information (ESI) available: Experimentaldetails and additional spectra. CCDC 796799. For ESI and crystallo-graphic data in CIF or other electronic format see DOI: 10.1039/c1cc12619a

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8356 Chem. Commun., 2011, 47, 8355–8357 This journal is c The Royal Society of Chemistry 2011

the chiral ligand of (S)-BPB can be reused to synthesis of (S)-

1, (iii) it is applicable to a broader range of substrates,

including aryl-, heteroaryl-, and alkyl-derived sulfonylindoles.

Herein, we present the asymmetric reaction of glycine nickel(II)

complex of 1 with sulfonylindoles 2, as a general route leading

to chiral syn-b-substituted tryptophans.

On the basis of the synthesis of a,b-diamino acids,13a we

selected the chiral (S)-nickel(II) complex of glycine 1 with

(S)-o-[N-(N-benzylprolyl)amino]benzophenone as a chiral

equivalent nucleophilic partner. We chose to study (S)-1 and

sulfonylindole 2a derived from benzaldehyde as a model

substrate for optimizing reaction conditions. The results are

summarized in Table 1. In the initial study, 1,8-diazabicyclo-

[5.4.0]undec-7-ene (DBU) was selected as the base, and the

reaction was conducted in dichloromethane. Gratifyingly,

the condensation afforded the adduct (S)(2S,3R)-3a in high

diastereoselectivity (99% de, entry 1). A variety of alternative

bases were also investigated. Moderate diastereoselectivity was

observed with the use of sodium hydride (NaH), potassium

tert-butoxide (tBuOK), sodium hydroxide (NaOH), and

potassium hydroxide (KOH) (entries 2–5). The effect of the

solvent was then investigated (entries 6–9). Acetonitrile and

acetone gave slightly lower yields (entries 6 and 7). The adduct

3a was formed in higher yield and with higher diastereo-

selectivity in dichloromethane than in tetrahydrofuran (entry 8)

or N,N-dimethylformamide (entry 9). The representative

results (entries 1–9) showed that the diastereoselectivity

greatly depends on the reaction conditions: a thermodynamically

controlled stereochemical outcome would be only slightly

influenced by the nature of the base and solvent used. Further

optimization studies on the reaction performed with the base

DBU and dichloromethane at various temperatures, from

60 to �60 1C (entries 10–14), indicated that good yields and

excellent enantioselectivities were achieved in all cases. The

diastereoselectivity increased significantly with the temperature

decrease. From the viewpoint of practical applications, we

chose DBU as the base, and dichloromethane as the solvent,

and ambient temperature conditions to probe the generality of

this asymmetric reaction (entry 1). The relative and absolute

configuration of 3a was determined to be (S)(2S,3R) by X-ray

crystallography18 (Fig. S1 in the ESIw).The substrate scope was investigated under the optimized

reaction conditions, and the results showed that the reaction

has broad applicability (Table 2). Three regioisomeric

sulfonylindoles 2 effectively participated in the asymmetric

reactions to afford equally high levels of yield and selectivity

(entries 1–4). A wide variety of sulfonylindoles were suitable

substrates and afforded the products 3 with syn-selectivity in

53–91% yield and high diastereoselectivity. In general,

functionalized aryl sulfonylindoles were found to be excellent

substrates for the reaction, regardless of electronic effects

(entries 1–4). Both electron-withdrawing and electron-donating

groups at the para position of the phenyl ring were tolerated in

sulfonylindoles 2. Moreover, the reaction could be extended to

heterocyclic compounds (entries 5–9). The aliphatic product

was obtained in lower yield than the aryl ones, which may be

consistent with the view that an aryl substituent reduces the

electron density on the a-carbon atom of the sulfonylindole,

thus enhancing its reactivity, while aliphatic substituent

increases the electron density on the a-carbon atom of the

sulfonylindole (entry 10). Sulfonylindoles 2 bearing a methyl

substituent at the 2- or 4-position of the indole ring were also

suitable substrates and afforded the corresponding products,

albeit in lower yields (entries 11 and 12). Sulfonylindoles 2

Table 1 Optimization of the reaction conditionsa

Entry Base Solvent Temp/1C Yield (%) syn/antib dec (%)

1 DBU CH2Cl2 23 82 81 : 19 4992 NaH CH2Cl2 23 72 67 : 33 913 tBuOK CH2Cl2 23 17 62 : 38 904 NaOH CH2Cl2 23 65 72 : 28 875 KOH CH2Cl2 23 78 69 : 31 876 DBU CHeCN 23 49 71 : 29 4997 DBU Acetone 23 63 74 : 26 4998 DBU THF 23 77 78 : 22 989 DBU DMF 23 78 75 : 25 49910 DBU CH2Cl2 60 86 78 : 22 49911 DBU CH2Cl2 0 80 83 : 17 49912 DBU CH2Cl2 �20 77 83 : 17 49913 DBU CH2Cl2 �40 72 86 : 14 49914 DBU CH2Cl2 �60 67 88 : 12 499

a Reactions were run with 0.20 mmol of (S)-1, 0.21 mmol of 2a in

10 mL of solvent with 0.24 mmol of base for 1 h. b Determined by

HPLC analysis. c Determined by chiral HPLC analysis (see the ESIwfor details).

Table 2 Asymmetric reactions of (S)-nickel(II) complex 1 withsulfonylindoles 2a

Entry 2, R1, R2, R3 Yield (%) syn/antib dec (%)

1 2a, Ph, H, H 82 81 : 19 4992 2b, 2-Me-C6H4, H, H 88 91 : 9 4993 2c, 3-Me-C6H4, H, H 89 92 : 8 4994 2d, 4-Me-C6H4, H, H 87 93 : 7 4995 2e, 4-OMe-C6H4, H, H 90 92 : 8 4996 2f, 4-NO2-C6H4, H, H 67 93 : 7 807 2g, 4-Cl-C6H4, H, H 91 94 : 6 4998 2h, 4-Br-C6H4, H, H 90 93 : 7 709 2i, 2-Furyl, H, H 61 94 : 6 9710 2j, Cy, H, H 53 90 : 10 49911 2k, Ph, Me, H 64 92 : 8 49912 2l, Ph, H, 4-Me 76 90 : 10 9613 2m, Ph, H, 5-Me 88 90 : 10 9714 2n, Ph, H, 5-Cl 84 91 : 9 49915 2o, Ph, H, 7-Me 86 90 : 10 499

a Reactions were run with 0.20 mmol of (S)-1, 0.21 mmol of 2 in 10 mL

of dichloromethane with 0.24 mmol of DBU for 1 h at ambient

conditions. b Determined by HPLC analysis. c Determined by chiral

HPLC analysis (see the ESIw for details).

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This journal is c The Royal Society of Chemistry 2011 Chem. Commun., 2011, 47, 8355–8357 8357

with methyl or chlorine substitution at the 5-position or the

7-position gave excellent diastereoselectivity (entries 13–15).

Disassembly of the diastereomerically pure complex

(S)(2S,3R)-3a under the previously described standard

conditions13a afforded the target amino acid (2S,3R)-2-amino-

3-(1H-indol-3-yl)-3-phenyl-propanoic acid 4a in 96% yield

(Scheme 2). The chiral ligand (S)-BPB was easily recovered

in quantitative yield and could be reused via a simple procedure.

In conclusion, we have developed a practical and highly

efficient enantio- and diastereoselective route to syn-configured

b-substituted tryptophans via the asymmetric Michael

addition of the chiral nickel(II) complex of the Schiff base

of glycine with sulfonylindoles. A broad range of aryl-,

heteroaryl-, and alkyl-derived sulfonylindoles could be

employed under operationally simple and mild conditions.

The absolute configuration of one of the products was

determined. Further studies will focus on mechanistic aspects,

expansion of substrate scope, and further applications of other

chiral nickel(II) complexes in important carbon–carbon

bond-forming reactions.

The authors acknowledge financial support from the

National Natural Science Foundation of China (Grants

20872153, 21021063, and 81025017).

Notes and references

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18 CCDC 796799 contains the supplementary crystallographic datafor this paper.

Scheme 2 Disassembling of a nickel(II) complex to release b-substi-tuted tryptophan and recovery of the ligand (S)-BPB.

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