Asymmetric trienamine catalysis for the construction of structurally rigid cyclic α,α-disubstituted amino acid derivatives

Article abstract of DOI:10.1002/chem.201101539

2,4-Dienals are shown to undergo highly stereoselective Diels-Alder reactions with olefinic azlactones by asymmetric trienamine catalysis. The obtained cycloadducts are easily transformed into the corresponding cyclic α,α-disubstituted N-protected amino acid methyl esters under mild reaction conditions. Furthermore, it is demonstrated that in situ ligation of the crude cycloaddition products with amino acid hydrochloride salts leads to the formation of non-natural dipeptide motifs in a one-pot fashion.

Full text of DOI:10.1002/chem.201101539

DOI: 10.1002/chem.201101539
Asymmetric Trienamine Catalysis for the Construction of Structurally Rigid
Cyclic a,a-Disubstituted Amino Acid Derivatives
Hao Jiang, Bjçrn Gschwend, Łukasz Albrecht, Signe Grann Hansen, and
Karl Anker Jørgensen*[a]
The activity of proteins, peptides, and potent pharmaceut-
ical compounds is usually coupled to a given three-dimen-
sional conformation.[1] Therefore, it is commonly accepted
that incorporation of structurally restrained non-proteogenic
amino acids serves as an effective template to lock mole-
cules in biologically active conformations. Such structural re-
striction may lead to improvements in both selectivity and
efficiency during interaction with the corresponding recep-
tor.[2] Site-specific introduction
Recently, it was discovered that small-molecule amines[7]
may catalyze enantioselective Diels–Alder reactions[8] of
2,4-dienals with dienophiles through the intermediacy of an
activated catalytic trienamine species.[6] The successful appli-
cation of olefinic oxindoles and cyanoacetates as dienophiles
and a detailed mechanistic investigation have recently been
outlined.[6] Interestingly, the cyclic skeleton of the cycloaddi-
tion adducts obtained in these Diels–Alder reactions resem-
of constrained amino acids is
also a powerful tool to probe
the conformational behavior
and to optimize the pharmaco-
logical properties of polypep-
tides or peptidomimetics.[3] Ac-
cordingly, cyclic analogues of
natural amino acids and deriva-
tives have attracted increased
attention by virtue of their abil-
ity to provide molecular rigidi-
ty.[4] Especially the a,a-disubsti-
tuted cyclic amino acids are in-
teresting in this respect due to
the improved biostability rising
from the quaternary a-center.[5]
However,
asymmetric
ap-
proaches for the generation of
such compounds are highly lim-
ited and mostly rely on stoi-
choimetric enantiopure starting
materials. Herein, we describe a
facile route to highly enantioen-
riched protected carbacyclic
a,a-disubstituted amino acids
by asymmetric trienamine catal-
ysis.[6]
Scheme 1. Synthetic strategy and mechanistic outline.
bled the perfect rigid scaffold for carbacyclic amino acids.
By application of an appropriate dienophile, we envisioned
that cyclic a,a-disubstituted amino acids could be rapidly as-
sembled in a modular and highly stereoselective manner
(Scheme 1). Initial evaluations revealed (Z)-olefinic azlac-
tones,[9] easily available by condensation of hippuric acid
and aldehydes, to be the prime candidates for the requisite
organocatalyzed cycloaddition reaction using trienamines.
The strategic design of the reaction involves the effective
[a] H. Jiang, Dr. B. Gschwend, Dr. Ł. Albrecht, Dr. S. G. Hansen,
Prof. K. A. Jørgensen
Center for Catalysis, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
Fax : (+45)8942-3596
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101539.
9032
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Chem. Eur. J. 2011, 17, 9032 – 9036

COMMUNICATION
rising of the highest occupied molecular orbital (HOMO) of
the e-center of the original dienal (C6), powered by an
amino-catalyst. Consequently, regiospecifity is successfully
governed by optimal orbital overlap of the HOMO of the
catalyst-bound trienamine with the lowest unoccupied mo-
lecular orbital (LUMO) of the dienophile (C3’).[10] More-
over, it is suggested that secondary orbital interactions and
catalyst-induced face-shielding should provide the desired
diastereo- and enantiocontrol of the reaction. Noteworthy,
the obtained a-quaternary azlactones can be easily depro-
tected in both acidic and basic media to afford the parent
amino acids.[11]
A preliminary screening indicated that the presence of an
aromatic ring-substituent on the azlactone was vital for the
course of the reaction. Results from previous work also indi-
cated that the rate of the trienamine formation was signifi-
cantly enhanced by performing the reaction in polar aprotic
media co-catalyzing with o-fluorobenzoic acid (OFBA).[6]
Summarizing these factors, the initial reaction was set up by
reacting 2,4-hexadienal (1a) with 2-naphthyl-substituted ole-
finic azlactone 2a in the presence of 20 mol% catalyst 3a[o,p]
and OFBA. Gratifyingly, the desired cycloadduct 4a was
formed in good stereoselectivity, albeit with moderate con-
version (Table 1, entry 1). To determine the enantiomeric
ing a weak acid, base, or no additive at all, the conversion
of reactants improved (Table 1, entries 3–5). Full conversion
could be achieved by using no additive and a twofold in-
crease of substrate concentration (Table 1, entry 6). Lower-
ing the catalyst loading to 10 mol% was also possible; how-
ever, to achieve complete consumption of 2a within a simi-
lar time frame, heating the reaction media at 408C was re-
quired (Table 1, entry 8). Under the optimal reaction condi-
tions, product 4a was obtained in 70% yield (isolated as a
diastereomeric mixture), 5:1 d.r., and 98% ee.
The scope of the reaction is summarized in Table 2. The
use of different homologation reagents had a significant
effect on the yield and the resulting diastereomeric ratio of
the isolated products (compare entry 1, A/B). The shorter
reaction time of the Ramirez olefination (method B)[12] com-
pared with that of the Wittig reaction (method A) is be-
lieved to significantly reduce the degree of partial decom-
postition of the intermediary aldehyde taking place during
prolonged stirring, apparently affecting the major diastereo-
isomer more. A variety of aromatic azlactones 2 was evalu-
ated as dienophiles in the developed Diels–Alder reaction.
Both electron-donating (-OMe, -Me) and electron-with-
drawing aryl substituents (-F, -Cl, -Br, -CO2Me, -NO2) were
tolerated, providing the desired cycloaddition products with
Table 2. Scope of the reaction.
Table 1. Initial screening results.
Entry[a]
Additive
Conv. [%][b]
d.r.[c]
ee [%][d]
Entry[a] R (2)
Yield [%][b]
A (4) B (5)
d.r.[c]
A
ee [%][d]
1
2
3
4
OFBA
ONBA
BzOH
none
NaOAc
none
65
<15
75
75
75
>95
85
>95 (70)
5:1
–
98
–
B
A
B
5:1
5:1
5:1
5:1
5:1
5:1
98
98
98
98
98
98
1
2
2-naphthyl (2a)
Ph (2b)
70
82
90
66
60
83
51
68
67
84
71
51
84
56
63
63
5:1 7:1 98 98[e]
8:1
98[e]
5
3
4
4-Me-Ph (2c)
4-OMe-Ph (2d)
2-Br-Ph (2e)
3-pyridyl (2 f)
2-thiophenyl (2g)
51
47
55
7:1 7:1 98 99[e]
6:1 7:1 98 99[e]
4:1 7:1 98 99[e]
6[e]
7[e,f]
8[e,f,g]
none
none
5[f]
6[g]
7
5:1
8:1
99[e]
99[e]
[a] Reactions performed with 2a (0.1 mmol), 1a (0.15 mmol),
3
(0.02 mmol), and the given additive (0.02 mmol, 20 mol%) in CHCl3
(0.5 mL) at room temperature for 20 h. In situ homologation carried out
with PPh3=CHCO2Et (0.15 mmol), room temperature, 18 h. [b] Deter-
8
3,4-OCH2O-Ph (2h) 53
4-CO2Me-Ph (2i)
4-F-Ph (2j)
4-Cl-Ph (2k)
3-Cl-Ph (2l)
4-NO2-Ph (2m)
2-NO2-Ph (2n)
1-heptyne (2o)
5:1 7:1 98 99
9[f]
10[f]
11
12[f]
13
14[f]
15[h]
8:1
7:1
6:1
8:1
6:1
6:1
5:1
96
98
99
98
96
99
97
1
mined by H NMR spectroscopy. Yield of isolated product as a diastereo-
meric mixture is given in parenthesis. [c] Determined by 1H NMR spec-
troscopy. [d] Determined by CSP-HPLC analysis. [e] Using 0.25 mL
CHCl3 as solvent. [f] 10 mol% of 3 was used. [g] Reaction performed at
408C for 18 h.
[a] Reaction conditions: i) 2 (0.1 mmol), 1 (0.15 mmol), 3 (0.01 mmol) in
CHCl3 (0.25 mL), 408C, 18 h. ii) Method A: PPh3=CHCO2Et
(0.15 mmol), room temperature, 18 h. Method B: PPh3 (0.6 mmol), CBr4
(0.3 mmol), À108C, 15 min. [b] Yield of isolated product (as a diastereo-
isomeric mixture). [c] Determined by 1H NMR spectroscopy. [d] Deter-
mined by CSP-HPLC analysis. [e] Determined after opening of the azlac-
tone (see Table 3). [f] Reaction at room temperature. [g] Using ent-3 as
the catalyst. [h] Addition of OFBA (0.01 mmol) as co-catalyst was neces-
sary for full conversion.
excess and improve the product stability, the aldehyde cyclo-
adduct was in situ homologated by using a stabilized phos-
phonium ylide. Increasing the acid strength of the additive
by using o-nitrobenzoic acid (ONBA) diminished the reac-
tivity completely (Table 1, entry 2). Contrary to the inhibito-
ry effect of stronger acids, it was discovered that by employ-
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9033

K. A. Jørgensen et al.
excellent stereocontrol (Table 2, entries 3–5, 9–14). The re-
action also proved to be unbiased towards the substitution
pattern on the aryl ring coping with para, meta, and ortho
substituents (compare Table 2, entries 5, 11, 12). Moreover,
heteroaromatic groups, such as pyridyl and thiophenyl
(Table 2, entries 6 and 7) as well as doubly substituted aryl
groups (Table 2, entry 8) were also compatible with the de-
veloped reaction conditions, leading to the formation of the
protected amino acid derivatives in good yields, good diaste-
reoisomeric ratios, and excellent enantiomeric excesses. An
additional acid co-catalyst such as OFBA (10 mol%) proved
to be necessary for the full consumption of dienophile 2o,
which carried an alkynic side chain (Table 2, entry 15).
Under these modified reaction conditions, the corresponding
cycloadduct 5o was formed (after homologation) in 63%
yield, 5:1 d.r., and 97% ee. It should be noted that for the
isolation of the Diels–Alder products carrying a more sensi-
tive side chain, such as an alkynic group, only the Ramirez
protocol was applicable. The use of Ph3P=CHCO2Et as the
homologation reagent proved to be unsuccessful, resulting
in highly complex reaction mixtures making product isola-
tion an impossible task. Azlactones 2 carrying an aliphatic
side chain were unstable under the present reaction condi-
tions, and decomposed readily in the reaction solution.
To demonstrate the generality of this selective ring-open-
ing reaction, a broad range of azlactones 5 were subjected
to the reaction conditions. The nature of the side chain did
not alter the course of reaction. In all cases, the amino
esters 6 were formed as single diastereoisomers in 50–85%
yield and 98–99% ee. In addition, the previously suggested
higher reactivity of the major diastereisomer of the cycload-
duct towards decomposition during prolonged stirring may
be indirectly confirmed by the observed selective ring-open-
ing reaction.
The absolute configuration of 6e was unambiguously es-
tablished to be (1S,2R,6S) by single-crystal X-ray analysis
(Figure 1).[13] The configurations of the other derivatives
were assigned by analogy.
One apparent transformation of product 5 is the opening
of the azlactone moiety thereby revealing the parent amino
acid motif.[11] Treatment of the azlactone with trimethylsilyl
chloride in MeOH gave the corresponding benzamide
methyl esters 6 in good yields without epimerization of the
stereogenic centers (Table 3). The acid-catalyzed ring-open-
Figure 1. X-ray analysis of compound 6e.
Encouraged by the successful transformation of the azlac-
tone motif to the parent N-protected amino acid methyl
esters, we questioned whether amines may substitute MeOH
as the nucleophilic reaction partner in the ring-opening re-
action, hence resulting in a direct amino acid ligation reac-
tion (Scheme 2).[14] To our delight, we discovered that by
Table 3. Opening of the azlactone under acidic conditions.
Entry[a]
R (5)
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
2-naphthyl (5a)
Ph (5b)
50 (7)
56 (7)
67 (9)
65 (6)
79 (15)
75 (12)
85 (11)
98
98
99
99
99
99
99
4-Me-Ph (5c)
4-OMe-Ph (5d)
2-Br-Ph (5e)
3-pyridyl (5 f)
2-thiophenyl (5g)
[a] Reactions performed on 0.07–0.1 mmol scale with two equivalents of
TMSCl in MeOH (0.5m). [b] Isolated yield of 6 as single diastereoiso-
mers. The yield of recovered 5 (minor diastereoisomer) is given in paren-
thesis. [c] Determined by CSP-HPLC.
ing reaction proceeded in a highly selective manner, in
which only the major diastereoisomer of 5 was converted,
while the minor diastereoisomer was recovered unchanged
after flash chromatography.
Scheme 2. Direct amino acid ligation reactions.
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Chem. Eur. J. 2011, 17, 9032 – 9036

Asymmetric Trienamine Catalysis
COMMUNICATION
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Acknowledgements
[6] Z.-J. Jia, H. Jiang, J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grou-
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We acknowledge financial support from the Carlsberg Foundation, FNU,
and OChem Graduate School. B.G. thanks The Swiss National Science
Foundation and Ł.A. thanks the Foundation for Polish Science (Kolumb
Programme) for financial support. Thanks are expressed to Dr. Jacob
Overgaard and Nina Lock for performing the X-ray analysis.
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Keywords: amino acids
· asymmetric organocatalysis ·
azlactones · ligation · trienamines
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benzoyl-protected amino acid methyl esters may be transformed to
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[12] F. Ramirez, N. B. Desai, N. McKelvie, J. Am. Chem. Soc. 1962, 84,
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[13] CCDC-817920 contains the supplementary crystallographic data.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[8] For general reviews on asymmetric Diels–Alder reactions, see for
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Dawson, T. W. Muir, L. Clark-Lewis, S. B. H. Kent, Science 1994,
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[15] R. B. Woodward, R. Hoffmann, The Conservation of Orbital Sym-
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Received: April 6, 2011
Published online: July 8, 2011
9036
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