Chiral Bronsted acid catalyzed stereoselective addition of azlactones to 3-vinylindoles for facile access to enantioenriched tryptophan derivatives

Article abstract of DOI:10.1002/anie.201105562

Syn-gled out: The syn diastereo- and enantioselective addition of azlactones to 3-vinylindoles was accomplished by using a chiral, binapthol-derived, Bronsted acid catalyst (see scheme). This method enables facile access to tryptophan derivatives with adj

Full text of DOI:10.1002/anie.201105562

Communications
DOI: 10.1002/anie.201105562
Organocatalysis
Chiral Brønsted Acid Catalyzed Stereoselective Addition of
Azlactones to 3-Vinylindoles for Facile Access to Enantioenriched
Tryptophan Derivatives**
Masahiro Terada,* Kenichi Moriya, Kyohei Kanomata, and Keiichi Sorimachi
3-Substituted indoles are common structural motifs in a
number of synthetic and naturally occurring compounds. The
broad spectrum of their biological activity has stimulated
intensive interest in their asymmetric synthesis. A number of
excellent approaches for the preparation of optically active
3-substituted indoles have been reported to date
(Scheme 1).[1] The most common strategy is through an
enantioselective Friedel–Crafts reaction with electrophiles
(El) at the 3-position (Scheme 1a).[2] In recent years, nucleo-
philic substitution of a leaving group (Lg) at the “benzylic” 1’-
position[3] has emerged as an alternative approach for
introducing a chiral side chain at the 3-position of indoles
(Scheme 1b).[4–7] Enantioselective catalysis with organocata-
lysts[4–6] or chiral metal complexes[7] accelerates this substitu-
tion reaction through the formation of vinylimine (or
iminium) intermediates A (Scheme 1b), with the concomitant
loss of a leaving group, such as an arylsulfonyl,[4a,6,7]
hydroxy,[4b,c,5a–d] or sulfonamido[5e] group. Binaphthol-derived
phosphoric acids 1 (Scheme 1) are one class of efficient
organocatalysts for these substitution reactions.[5]
Chiral phosphoric acids 1 were developed independently
by Akiyama et al. and by our group.[8] These compounds have
become some of the most versatile chiral Brønsted acid
catalysts,[9] and have been applied to a broad range of
enantioselective transformations.[10,11] As part of our continu-
Scheme 1. Methods for the asymmetric synthesis of 3-substituted
indole derivatives.
ing efforts to broaden the scope of enantioselective catalysis
with 1,[11] we envisioned the enantioselective addition of a
nucleophile (H-Nu) to the double bond of 3-vinylindoles 2
catalyzed by (R)-1 (Scheme 1c). 3-Vinylindoles have been
employed as the diene component in enantioselective
(hetero) Diels–Alder reactions, which give rise to enantioen-
riched polycyclic indoles.[12,13] However, to our knowledge,
they have never been utilized in enantioselective addition
reactions. Our method provides an alternative approach to
enantioenriched indoles with a chiral side-chain at the 3-
position.
[*] Prof. Dr. M. Terada, K. Moriya, K. Kanomata, Dr. K. Sorimachi
Department of Chemistry
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@m.tohoku.ac.jp
Homepage: http://www.orgreact.sakura.ne.jp/index.html
Prof. Dr. M. Terada
To validate the proposed transformation, we aimed to
develop the enantioselective addition reaction of azlactones 3
to 3-vinylindoles 2 catalyzed by (R)-1 to yield the addition
products 4 (Scheme 2). The substituted indoles 4 can be
readily converted into b-substituted tryptophan derivatives 5,
which have quaternary stereogenic centers at the a-posi-
tion,[14,15] through ring opening of the azlactone subunit.
Tryptophan plays a key role in protein stability and recog-
nition, despite its scarcity in known proteins.[16] The substitu-
tion of non-natural a-amino acids for natural amino acids in
nonproteinogenic analogues of conformationally restricted
peptides is increasingly important. Therefore, the asymmetric
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
[**] This work was supported by JSPS through a Grant-in-Aid for
Scientific Research (Grant No. 20245021) and the Uehara Memorial
Foundation. We gratefully acknowledge Prof. T. Iwamoto and Prof.
S. Ishida (both from Tohoku University) for the X-ray crystal
structure determination of 6. We also thank Prof. T. Ooi and Prof. D.
Uraguchi (both from Nagoya University) and Dr. J. Takehara
(Mitsubishi Chemical Group, Science and Technology Research
Center, INC) for the HRMS analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105562.
12586
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12586 –12590

Table 1: Enantioselective addition of 3 to 2a catalyzed by (R)-1.[a]
Scheme 2. Diastereo- and enantioselective synthesis of 5 through the
addition of 3 to 2, catalyzed by (R)-1.
Entry Cat.
3
Product Solvent Yield syn-5/
ee [%]
[%][b] anti-5[c] for syn-5[d]
synthesis of non-natural a-amino acids has received much
attention.[17] In this context, stereoregulated tryptophan
analogues, in particular multi-substituted derivatives, are
attractive targets in peptide design. However, methods for
the stereoselective synthesis of these compounds have
achieved limited success.[7,18] Herein, we report the enantio-
selective addition reaction of azlactones 3 to 3-vinylindoles 2,
catalyzed by chiral phosphoric acids (R)-1. The present
method provides a highly stereoselective and facile route to
tryptophan derivatives 5, which have adjacent quaternary and
tertiary stereogenic centers.
1
2
3
4
5
6
7
8
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
3a 5aa
3a 5aa
3a 5aa
3b 5ab
3c 5ac
3d 5ad
3c 5ac
3c 5ac
3c 5ac
3c 5ac
3c 5ac
3c 5ac
3c 5ac
3c 5ac
toluene 47
toluene 62
toluene 59
toluene 62
toluene 75
toluene 49
CH3CN 88
70:30
56:44
87:13
93:7
39
13
40
21
78
19
10
25
71
85
93
94
93
94[j]
93:7
76:24
58:42
75:25
92:8
97:3
98:2
98:2
98:2
98:2
CH2Cl2
Et2O
57
28
9
10[e]
toluene 70
toluene 85
toluene 75
toluene 82
toluene 85
11[e,f] 1c
12[e,g] 1c
13[e,h] 1c
At the outset of our studies, we tested a range of chiral
phosphoric acid catalysts (R)-1 with different G groups,[19]
and several azlactones 3 with various Ar1 substituents. The
initial screening was performed with N-benzyl-protected 3-
vinylindole 2a,[20] 3(Ar2=Ph), and (R)-1 (5 mol%) at 08C in
toluene. The diastereo- and enantioselectivity of the reaction
was determined after ring opening of the azlactone subunit of
4 with sodium methoxide to prepare 5. As shown in Table 1,
the addition reaction of 3 to 2a and subsequent ring opening
afforded 5 in moderate to good yields. A marked effect of the
substituent G on the diastereoselectivity was noted (Table 1,
entries 1–3). Although catalysts (R)-1a (G = 2,4,6-(iPr)3
C6H2-)[15f] and (R)-1b (G = 9-anthryl) provided low to mod-
erate syn diastereoselectivity (Table 1, entries 1 and 2), (R)-
1c (G = 4-biphenyl) afforded syn-5aa in good diastereoselec-
tivity, but modest enantioselectivity (Table 1, entry 3). Sub-
sequent manipulation of the Ar1 substituent of 3 had a
significant impact on the reactivity, as well as the diastereo-
and enantioselectivity (Table 1, entries 4–6). The introduction
of either 4-bromophenyl (3b) or 3,5-dimethoxyphenyl sub-
stituents (3d)[15f,21] as the Ar1 group resulted in a considerable
decrease in the enantioselectivity (Table 1, entries 4 and 6). In
contrast, when Ar1 was changed to a 4-methoxyphenyl group
(PMP, 3c), the yield and the stereoselectivity both increased
(Table 1, entry 5). The effects of different solvents on the
reaction of 2a with 3c were also investigated. All our attempts
to change the solvent were unsuccessful in improving the
yield, or the stereochemical outcome (Table 1, entries 7–9).
As expected, when the reaction temperature was reduced to
À208C, the diastereo- and enantioselectivity increased to
14[e,i]
1c
[a] Unless otherwise noted, all reactions were carried out with (R)-1
(0.01 mmol, 5 mol%), 2a (0.21 mmol, 1.05 equiv), and 3 (0.20 mmol) in
toluene (1.0 mL) at 08C. [b] Yield of isolated product. [c] Determined by
HPLC analysis. [d] Determined by HPLC analysis on a chiral stationary
phase. [e] At À208C for 24 h. [f] Molecular sieves (3 ꢀ, 100 mg) were
added. [g] Molecular sieves (4 ꢀ, 100 mg) were added. [h] Molecular
sieves (5 ꢀ, 100 mg) were added. [i] 1.2 equiv of 2a (0.24 mmol) and
molecular sieves (4 ꢀ, 100 mg) were used. [j] The ee value was 17% for
anti-5ac.
97% syn and 85% ee, respectively (Table 1, entry 10). Fur-
ther improvement of the stereoselectivity was achieved by
adding molecular sieves (3 ꢀ, 4 ꢀ, and 5 ꢀ; Table 1,
entries 11–14).[13b,22] The reaction gave rise to 5ac with an
excellent syn diastereoselectivity (98%), and the enantiose-
lectivity for syn-5ac reached 94% ee when 4 ꢀ molecular
sieves were used (Table 1, entry 12). The yield was improved
by increasing the amount of 2a to 1.2 equivalents (Table 1,
entry 12 versus entry 14).
The relative and absolute stereochemistry of the major
isomer 5ac was unambiguously determined to be 2S,3S by X-
ray crystallographic analysis of 6.[23] Compound 6 was
obtained by reducing the methyl ester 5ac to an alcohol,
then transforming the alcohol into ester 6, by treatment with
camphorsultam of known configuration (XsOH; Scheme 3).
As an alternative to the addition reaction (Scheme 1c),
product 5 can also be synthesized by a substitution reaction
(Scheme 1b). Hence, we conducted this substitution reaction
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Communications
Scheme 3. Derivatization of the major diastereomer 5ac (Table 1,
entry 14) to 6. DMAP=4-dimethylaminopyridine; EDCl=ethyldimethyl-
aminopropylcarbodiimide hydrochloride.
with 3-substituted indoles 7, of which the leaving group at the
1’ position was a methoxy moiety,[24] under conditions similar
to the optimized addition reaction. The stereochemical
outcomes of the addition and substitution methods were
then compared (addition reaction: Table 1, entry 13).[25]
Despite the striking resemblance of the plausible reactive
intermediate A (Scheme 1) which is generated during the
course of the substitution reaction of 7 and the addition
reaction with 2a, the substitution reaction of 7a afforded 5ac
with almost no stereoselectivity (Scheme 4). Interestingly,
syn-5ac had the opposite absolute configuration, albeit with a
Scheme 5. Addition reaction of 3c to (E)- and (Z)-8 catalyzed by (R)-
1c. MS=molecular sieves; PMP=4-methoxyphenyl.
Notably, the stereochemical outcome of the reaction was
highly dependent on the geometry of 8.[26] These results imply
that the common intermediate A (Scheme 1) is unlikely to be
involved in these reactions.[27] Although the precise mecha-
nism has not yet been determined, it seems likely that the
addition reaction proceeds through an ene reaction, such as
ternary system B (Scheme 5).[28]
Having identified a promising method for the stereose-
lective transformation of 2, we explored the scope of the
addition reaction with different substrates (Table 2).[29] Excel-
lent syn diastereo- and enantioselectivity were maintained
with C5-substituted indoles, irrespective of the electronic
properties of the substituent X (Table 2, entries 1–3). How-
ever, the introduction of an electron-withdrawing group at the
6 position led to a considerable reduction in the yield and the
enantioselectivity, although a high level of syn diastereose-
lectivity was retained (Table 2, entry 4). Further investigation
into the scope of the reaction revealed that the introduction of
substituents to the Ar2 group of 3 significantly affected the
outcome of the reaction (Table 2, entries 5–10). Ortho
substitution of the Ar2 group prevented the formation of
5ae. (Table 2, entry 5). In contrast, azlactones with meta- or
para-substituted Ar2 groups underwent the addition reaction
to afford the corresponding products 5, with high syn
diastereo- and enantioselectivity (Table 2, entries 6–10). In
these cases, the yields were dependent on the electronic
properties of the substituents. Electron-donating substituents
furnished higher yields than those obtained with electron-
withdrawing substituents (Table 2, entries 6–8 versus entries 9
and 10).
Scheme 4. Substitution reaction of 7 with 3c catalyzed by
(R)-1c. MS=molecular sieves; PMP=4-methoxyphenyl.
low enantioselectivity, even when the same (R)-1c was
employed in the substitution reaction. In addition, the
substitution reaction of 5-methoxyindole derivative 7b also
produced quite low stereoselectivity. These results clearly
indicate that the mechanisms of the substitution and addition
reactions are entirely different, and that the addition method
is essential for achieving high stereoselectivity in the present
reaction system.
To gain further insight into the mechanism of the addition
reaction, we attempted the reaction of 3c with (E)- and (Z)-3-
(prop-1-enyl)indoles 8. As shown in Scheme 5, there were
marked differences in the reactivity of (E)-8 and (Z)-8.
In conclusion, we have demonstrated a highly syn
diastereo- and enantioselective addition of azlactones to 3-
vinylindoles catalyzed by a chiral phosphoric acid. The
present method enables facile access to tryptophan deriva-
tives with adjacent quaternary and tertiary stereogenic
12588 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12586 –12590

Table 2: Scope of the addition reaction catalyzed by (R)-1c.[a]
Received: August 5, 2011
Revised: September 23, 2011
Published online: October 28, 2011
Keywords: asymmetric catalysis · azlactones · indoles ·
.
organocatalysis · tryptophan
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Entry
2
3
5
Yield [%][b] syn-5/
anti-5[c] for syn-5[d]
ee [%]
1
2b: 5-MeO
2c: 5-MeO2C 3c 5cc 73
2d: 5-Br
2e: 6-Br
2a
2a
2a
2a
2a
3c 5bc 76
96:4
98:2
98:2
96:4
–
91
94
95
75
–
2[e]
3
3c 5dc 63
3c 5ec 41
3e 5ae trace
4
5
6
7
8
9
10
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3 f
5af
82
93:7
98:2
98:2
91:9
93:7
89
90
89
83
90
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50.
3g 5ag 87
3h 5ah 71
3i
3j
5ai
5aj
58
35
2a
Unless otherwise noted, all reactions were carried out with (R)-1c
(0.01 mmol, 5 mol%), 2 (0.24 mmol, 1.2 equiv), 3 (0.20 mmol), and
molecular sieves (4 ꢀ, 100 mg) in toluene (1.0 mL) at À208C. [b] Yield of
isolated product. [c] Determined by HPLC analysis. [d] Determined by
HPLC analysis on a chiral stationary phase. [e] 2.0 equiv of 2c
(0.4 mmol) was used.
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Experimental Section
Representative procedure: Vinylindole 2a (56.0 mg, 0.24 mmol),
azlactone 3c (53.5 mg, 0.20 mmol), and molecular sieves (4 ꢀ,
100 mg) were added to a dried test tube, under nitrogen. After
cooling to À208C, toluene (1.0 mL) and then (R)-1c (5 mol%, 6.5 mg,
0.01 mmol) were added. The mixture was stirred for 24 h, then
NaOMe (1.0 mL, 0.5m in MeOH) was added. The mixture was
allowed to warm to room temperature and stirred for 10 min. After
cooling to 08C, the reaction was quenched with saturated aqueous
NH4Cl and extracted with CH2Cl2 (10 mL ꢁ 3). The combined organic
layers were dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by column chromatography
(silica gel, gradient elution with hexane/EtOAc from 4:1 to 2:1) and
gel permeation chromatography to give the product 5ac as a white
solid in 85% yield. The diastereomeric ratio and enantiomeric excess
were determined by HPLC analysis on a chiral stationary phase (syn/
anti = 98:2, 94% ee for syn-5ac).
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www.angewandte.org 12589

Communications
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[23] CCDC 815051 (6) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[24] We employed methyl ether 7 instead of the indole derivative
bearing a hydroxy group at the 1’-position to avoid the formation
of the homodimmeric ether of the indole substrate.
[25] Molecular sieves (5 ꢀ) were employed as a scavenger for the
methanol generated during the reaction.
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phosphoric acid (R)-1a (see Ref. 15f). The aldol-type reaction of
both (E)- and (Z)-vinyl ethers resulted in exactly identical
stereochemical outcomes. Hence, we proposed that the common
intermediate, an oxocarbenium ion generated by protonation of
vinyl ethers, was involved in the aldol-type reaction.
[27] On the basis of this mechanistic consideration, the substitution
reaction shown in Scheme 4 might proceed through a vinyl-
iminium intermediate (as previously postulated by several
research groups; see Refs. [4–7]), or, given the minimal stereo-
selectivity, through an SN2-type pathway. In an SN2-type process,
the stereochemical outcome would substantially reflect the
stereochemistry of the 1’-position of 7, thus, racemic mixtures
would be expected.
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[19] Chiral phosphoric acids 1 were washed with 2m aqueous HCl
after purification by silica-gel column chromatography. (R)-1c
was then further purified by recrystallization from methanol/
diethyl ether.
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[29] The reaction of an alkyl-substituted azlactone (Ar2 = Bu) did not
produce any of the desired product under the optimized reaction
conditions. The azlactone was recovered in > 80% yield along
with polymerized 3-vinylindole 2a.
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