Synthesis of novel amino squaric acids via addition of dianion enolates derived from N-Boc amino acid esters

Article abstract of DOI:10.1016/j.tetlet.2004.11.044

Novel α-amino squaric acid analogs were synthesized by initial addition reaction of a dianion enolate generated from N-Boc amino acid tert-butyl ester to squaric acid diisopropyl ester, and subsequent decarboxylation of the resulting carboxylic acid moiety.

Full text of DOI:10.1016/j.tetlet.2004.11.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 311–314
Synthesis of novel amino squaric acids via addition of dianion
enolates derived from N-Boc amino acid esters
Toshikazu Ishida, Tetsuro Shinada* and Yasufumi Ohfune*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Received 30 September 2004; revised 1 November 2004; accepted 5 November 2004
Abstract—Novel a-amino squaric acid analogs were synthesized by initial addition reaction of a dianion enolate generated from
N-Boc amino acid tert-butyl ester to squaric acid diisopropyl ester, and subsequent decarboxylation of the resulting carboxylic
acid moiety.
Ó 2004 Elsevier Ltd. All rights reserved.
The carboxyl group in a-amino acids is an important
functional group as a proton-donating or an amide
bond-forming group.1 It has been recognized that sul-
fonic acid,2 phosphonic acid,3 boronic acid,4 and tetr-
azole5 can serve as an important surrogate for the
carboxyl group of a-amino acids (Fig. 1). Many syn-
thetic studies and applications of these analogs focusing
on their metabolic stability, inhibitory effects to pro-
teases,6 and potency for catalytic antibodies7 have been
reported.
groups. In this context, development of an amino acid
analog that possesses a planar conjugate system and
acidic functionality serving for peptide coupling reac-
tions is a challenging task in this area. In this paper,
we report the synthesis of novel amino acid analog
2 bearing a 2-hydroxy-3,4-dioxocyclobut-1-enyl (sq)
group known as a planar square acid surrogate via a
carbon–carbon bonds.8 Squaric acid belongs to a class
of oxocarbons and exhibits unique physicochemical
properties, for example, strong acidity, aromaticity,
strained ring, electron deficiency, and metal chelating
ability.9 The sq group has received considerable atten-
tion as a carboxylic acid mimic in medicinal chemistry,10
a novel chromophore in material science,11 a new chela-
tor in inorganic chemistry,12 and a starting material for
a synthon of quinones, triquinanes, cyclopentenones,
and furanones in organic synthesis.13 Recently, squaric
Sulfonic acid 3 and phosphonic acid 4 are tetrahedral
surrogates. Boric acids 5 and tetrazoles 6 are planar ana-
logs while they are weak acids and are unable to be em-
ployed for peptide coupling reactions. Phosphonate
analogs can be used for peptide coupling reaction via
selective protection and activation of the two hydroxy
R
O
O
Aromaticity
Strained ring
Chelation
R
OH
H2N
H2N
R
CO2H
HO
OH
Acidity
O
O
( pKa = 0.54, 3.48 )
Squaric Acid
1
2
R
R
R
H
N
H2N
N
H2N
PO(OH)2
H2N
B(OH)2
H2N
SO2(OH)
N N
3
5
4
6
Figure 1.
Keywords: Amino acid; Squaric acid; Dianion enolate.
*
Corresponding authors. Tel.: +81 6 6605 3193; fax: +81 6 6605 3153; e-mail addresses: shinada@sci.osaka-cu.ac.jp; ohfune@sci.osaka-cu.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.044

312
T. Ishida et al. / Tetrahedron Letters 46 (2005) 311–314
O
O
Oi-Pr
Oi-Pr
CO2t-Bu
R
R
R
Oi-Pr
Ot-Bu
M
Ot-Bu
BocHN
9
BocN
M
BocHN
HO
O
O
O
Oi-Pr
7
8
10
dianion enolate
R
R
decarboxylation
CO2t-Bu
R
OH
O
O
O
O
H2N
BocHN
BocHN
i-PrO
O
i-PrO
O
2
12
11
Scheme 1.
acid diesters are employed for a linker to develop bio-
conjugate molecules by means of a facile substitution
of a squaric acid diester with amines.14 These multifunc-
tional characteristics prompted us to develop novel
sq-amino acid analog 2.
Base
–78 ˚C, 1h
rac-Phe 7a
+ rac-Phe-d1 13a
L-Phe 7a
CH3CO2D,
then work up
Ph
Bn
Ot-Bu
i-Pr2NLi
+
+
i-Pr2NH
BocN
O
BocN
CO2t-Bu
H
We planned a simple access to 2 from readily available
N-Boc a-amino acid esters such as Phe, Ala, etc.
(Scheme 1). To this end, an addition of dianion enolate
8a
14
Scheme 3.
8
15 derived from N-Boc a-amino acid esters 7 to squaric
acid diester 9 followed by decarboxylation reaction (11
to 12) was devised according to our previous synthesis
of sq-Gly (2: R = H) from a dianion enolate 8.16
Initially, we examined an addition reaction of 9 to a
dianion enolate 8a (R = Bn). Treatment of Boc-L-Phe
tert-butyl ester 7a with 2.2equiv of LDA in THF
at À78°C followed by addition of 9 gave the desired
adduct 10a in low yield (Scheme 2).
Table 1. Deprotonation experiments of 7a
Basea (pKa)b
d-Incorporationd
(%)
[a]D and
e
Entry
Racemization
ratiof (%)
1
2
3
4
LDA (35.7)
LDAc
33
51
<1
43
+7.36:76
+1.58:95
+30.2:<1
+5.96:81
LHMDS (29.5)
LTMP (37.3)
The above insufficient results led us to examine the mag-
nitude of the enolization by means of deuterium incor-
poration experiments (Scheme 3, Table 1). Treatment
of L-7a with 2.2equiv of LDA at À78°C followed by
quenching with CH3CO2D afforded a mixture of d-atom
incorporated 13a and undeuterated 7a in 89% yield
(13a:7a = 33:67, entry 1). Even the use of 6equiv of
LDA gave 51% incorporation ratio (entry 2), suggesting
that the enolizations by LDA were insufficient.17 How-
ever, we found that the optical rotation of a mixture
of 13a and 7a was extremely reduced indicating that
the starting L-7a was racemized via the enolate 8a by
using LDA. A proposed reaction pathway to explain
these results is depicted in Scheme 3. Dianion enolate
8a would be basic enough to deprotonate the resulting
i-Pr2NH. Therefore, a proton exchanging equilibrium
would exist in situ prior to quenching with CH3CO2D.
Protonation of 14 and 8a afforded rac-Phe 7a and 13a,
respectively. The deprotonation efficiency was assessed
a Conditions: 2.2equiv base, THF, À78°C, 1h.
b Ref. 18.
c 6equiv of LDA was used.
d Determined by 1H NMR.
e Values of a mixture of 7a and 13a.
f Based on the [a]D value.
with lithium 1,1,1,3,3,3-hexamethyldisilazide (LHMDS)
or lithium 2,2,6,6-tetramethylpiperidide (LTMP).
LHMDS was not effective at all due probably to its low-
er basicity in comparison with that of LDA (entry 3).18
The use of more basic and bulky LTMP gave slightly
better d-incorporation ratio (43%) accompanied by a
large loss of the optical rotation (entry 4).19
On the basis of the above results, we anticipated that the
use of sec-BuLi instead of amine bases would be advan-
tageous for the exclusive formation of the dienolate 8a
Ph
Ot-Bu
Ph
Bn CO2t-Bu
Oi-Pr
2.2 equiv
9
LDA
BocHN
Ot-Bu
BocN
HO
O
BocHN
THF,
–78 ˚C
–78 ˚C,
4 h
O
Oi-Pr
O
10a
7a
[α]D20 = + 30.5 (C 1.01, CHCl3)
27%
8a
Scheme 2.

T. Ishida et al. / Tetrahedron Letters 46 (2005) 311–314
313
from 7a in three steps. The overall yield was 39%. Other
adducts 10b–h were converted in a similar manner as
those of 2a to the corresponding sq-amino acids 2b–h20
in good to moderate yields (Table 2).
2.2 equiv sec-BuLi
then
Ph
O
Ph
D
20 equiv CH3CO2D
Ot-Bu
Ot-Bu
BocHN
7a
Scheme 4.
BocHN
THF, –78 ˚C
[α]D17.5 = + 2.16
(c 1.02, CHCl3)
O
d-incorporation 90%
racemization ratio 93%
13a
In summary, we have developed a concise synthetic
route to access sq-amino acids by addition of dianion
enolates derived from easily available N-Boc a-amino
acid esters to squaric acid diester followed by the decar-
boxylation reaction. The key to the synthesis was effec-
tive generation of the dianion enolate based on the
elucidation of their equilibrium behavior. Further stud-
ies with respect to incorporation of the novel sq-amino
acids into bioactive peptides are in progress.
(Scheme 4). As expected, the magnitude of d-incorpora-
tion ratio (90%) and loss of the optical rotation (93%)
were found to be nearly equal when 2.2equiv of sec-
BuLi was used. Thus, an effective method for generation
of a dianion enolate from easily available Boc-protected
amino acid esters using sec-BuLi was established.
With efficient method for the dianion enolate formation
in hand, we next examined its condensation with 9.
Treatment of 7a with sec-BuLi in THF at À78°C fol-
lowed by addition of 9 gave the desired adduct 10a in
69% yield. Thus, it was found that the improved ratio
of the enolate formation directly reflected to an increase
in the product yield. The dianion enolate derived from
various amino acid tert-butyl esters 7b–h reacted
smoothly with 9 to give the corresponding adducts
10b–h in satisfactory yields (Table 2).
Acknowledgements
This study was supported by a grant from the Research
for the Future Program (99L01204) and Grant-in-Aid
(No. 15510178) from the Japan Society for the Promo-
tion of Science (JSPS).
References and notes
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groups to give sq-Phe 2a. Thus sq-Phe 2a was prepared
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R
CO2t-Bu
Oi-Pr
R
2 equiv sec-BuLi,
THF, –78 ˚C, 1h,
Ot-Bu
BocHN
BocHN
HO
then 1 equiv 9, 1h
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10
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few drops of concd HCl,
CH2Cl2, rt, 12 h.
concd HCl,
acetone,
rt, 12h
R
R
CO2t-Bu
Oi-Pr
OH
O
H2N
BocHN
O
11
O
O
2
Series
Yieldsa (%)
10a–h
Yieldsb (%)
11a–h
Yieldsc (%)
2a–h
a: Phe
b: Tyr
c: Ala
d: Leu
e: Ile
69
50d
75
52
43
70
36
53
78
77
75
79
85
75
70
81
72
74
65
46
50
80
70
36
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f: Allylgly
g: Val
h: Pro
a Yields from 7a,b.
b Yields from 10a,b.
c Yields from 11a,b.
d 3.3equiv of sec-BuLi was used.

314
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Gharbia, M. A.; Moyer, J. A.; Zaleska, M. M. Drugs
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Horikawa, M.; Shimamoto, K.; Shigeri, Y.; Yumoto, N.;
Ohfune, Y. Org. Lett. 1999, 1, 1663–1666. An alternative
approach for sq-Gly, see: Campbell, E. F.; Park, A. K.;
Kinney, W. A.; Fengl, R. W.; Liebeskind, L. S. J. Org.
Chem. 1995, 60, 1470–1472.
17. Similar examples in monoanion enolates, see: (a) Seebach,
D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624–1654; (b)
Shimamoto, K.; Ohfune, Y. Synlett 1993, 919–920.
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3443–3444.
19. Similar results were observed in the deprotonation experi-
ments of sterically less hindered Boc-L-Phe methyl ester.
(LDA: d-incorporation 33%, racemization ratio 86%;
LTMP: d-incorporation 44%, racemization ratio 89%).
These facts indicated that the equilibrium was not
influenced by the steric demand.
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20. Melting points (dec, recrystallized from H2O–MeOH) and
1
1H NMR data of 2a–h in DMSO-d6 2a: 220–221°C; H
NMR (300MHz) d 8.39 (br s, 3H), 7.27 (m, 5H), 4.25 (br
s, 1H), 3.26 (dd, J = 13.0, 4.8Hz, 1H), 3.13 (dd, J = 13.0,
1
4.8Hz, 1H); 2b: 230–231°C; H NMR (400MHz) d 9.27
13. For recent examples, see: (a) Trost, B. M.; Thiel, O. R.;
Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155–13164; (b)
Buchynskyy, A.; Kempin, U.; Vogel, S.; Hennig, L.;
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Eur. J. Org. Chem. 2002, 7, 1149–1162; (c) Pena-Cabrera,
E.; Liebeskind, L. S. J. Org. Chem. 2002, 67, 1689–1691;
For reviews, see: (d) Clausen, C.; Wartchow, R.; Butens-
chon, H. Eur. J. Org. Chem. 2001, 93–113; (e) Liu, H.;
Tomooka, C. S.; Xu, S. L.; Yerxa, B. R.; Sullivan, R. W.;
Xiong, Y.; Moore, H. W. Org. Synth. 1999, 76, 189–198;
(f) Ohno, M.; Yamamoto, Y.; Eguchi, S. Synlett 1998,
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Org. Chem. 1992, 5, 273–313.
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159; (b) Porter, J. R.; Archibald, S. C.; Childs, K.;
Critchley, D.; Head, J. C.; Linsley, J. M.; Parton, T. A. H.;
Robinson, M. K.; Shock, A.; Taylor, R. J.; Warrellow, G.
J.; Alexander, R. P.; Langham, B. Bioorg. Med. Chem.
Lett. 2002, 12, 1051–1054; (c) Bergh, A.; Magnusson,
B.-G; Ohlsson, J.; Wellmar, U.; Nilsson, U. J. Glycocon-
jugate J. 2001, 18, 615–621.
(br s, 1H), 8.14 (br s, 3H), 6.99 (d, J = 8.5Hz, 2H), 6.63 (d,
J = 8.5Hz, 2H), 4.18 (br s, 1H), 3.13 (dd, J = 13.4, 8.8Hz,
1H), 2.94 (dd, J = 13.4, 5.6Hz, 1H); 2c: 231–232°C; 1H
NMR (300MHz) d 8.21 (br s, 3H), 4.21 (br s, 1H), 1.40 (d,
J = 6.6Hz, 3H); 2d: 213–214°C; 1H NMR (300MHz) d
8.07 (br s, 3H), 4.06 (dd, J = 9.5, 5.7Hz, 1H), 1.89–1.49
(m, 3H), 0.86 (d, J = 6.0Hz, 6H); 2e:21 200–201°C; 1H
NMR (400MHz) d 8.79 (br s, 3H), 4.57 (m, 5/8H), 4.49
(m, 3/8H), 2.08 (m, 3/8H), 1.95 (m, 5/8H), 1.83–1.54 (m,
2H), 1.48 (d, J = 6.8Hz, 9/8H), 1.47–1.41 (m, 30/8H), 1.38
1
(t, J = 7.3Hz, 9/8H); 2f: 198–199°C; H NMR (300MHz)
d 8.05 (br s, 3H), 5.67 (ddt, J = 17.2, 10.1, 7.0Hz, 1H),
5.06 (d, J = 17.0Hz, 1H), 5.00 (d, J = 10.1Hz, 1H), 4.07
(br t, J = 6.0Hz, 1H), 2.66–2.38 (m, 2H); 2g: 199–200°C;
1H NMR (400MHz) d 8.12 (br s, 3H), 3.89 (m, 1H), 2,14
(octet, J = 6.8Hz, 1H), 0.93 (d, J = 6.84Hz, 3H), 0.89 (d,
1
J = 6.84Hz, 3H); 2h: 219–220°C; H NMR (400MHz) d
9.27 (br s, 1H), 8.67 (br s, 1H), 4.44 (br s, 1H), 3.3–3.1 (m,
2H), 1.85–2.20 (m, 4 H).
21. The compound 2e (4-((1R,2S)- and (1S,2S)-1-amino-2-
methylbutyl)-3-hydroxycyclobut-3-ene-1,2-dione, [sq-iso-
leucine])was obtained as an inseparable 5:3 mixture of
diastereomers at the carbon attached to the amino group.
The absolute stereochemistry at C-1 and C-2 are R/S (5:3
or 3:5) and S, respectively. The integral values of the
protons were indicated as a number of observed H/8.
15. (a) Generation of dianion enolates from N-Boc amino acid
esters and their synthetic utilities have not been well
examined. Chemistry of dianion enolates from N-acyl
amino acid esters, see: Kazmaier, U.; Pahler, S.; Ender-