Enantioselective synthesis of stimulus-responsive amino acid via asymmetric α-amination of aldehyde

Article abstract of DOI:10.1016/j.tet.2010.07.033

Development of a methodology to control the function of peptides and proteins is an indispensable task in the field of chemical biology and drug delivery. Recently, we reported synthesis of racemic stimulus-responsive amino acids and their application for controlling peptidyl function. In this study, we report enantioselective synthesis of a key intermediate of stimulus-responsive amino acids via asymmetric α-amination reaction of an aldehyde. The obtained chiral intermediate was converted to an Fmoc protected UV-responsive amino acid with (S)-configuration, and it was successfully incorporated into a model peptide by Fmoc solid phase peptide synthesis.

Full text of DOI:10.1016/j.tet.2010.07.033

Tetrahedron 66 (2010) 7367e7372
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Tetrahedron
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Enantioselective synthesis of stimulus-responsive amino acid via asymmetric
a-amination of aldehyde
*
*
Akira Shigenaga , Jun Yamamoto, Naomi Nishioka, Akira Otaka
Institute of Health Biosciences and Graduate School of Pharmaceutical Sciences, The University of Tokushima, Shomachi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2010
Received in revised form 13 July 2010
Accepted 14 July 2010
Available online 21 July 2010
Development of a methodology to control the function of peptides and proteins is an indispensable task
in the field of chemical biology and drug delivery. Recently, we reported synthesis of racemic stimulus-
responsive amino acids and their application for controlling peptidyl function. In this study, we report
enantioselective synthesis of a key intermediate of stimulus-responsive amino acids via asymmetric
a
-amination reaction of an aldehyde. The obtained chiral intermediate was converted to an Fmoc pro-
tected UV-responsive amino acid with (S)-configuration, and it was successfully incorporated into
a model peptide by Fmoc solid phase peptide synthesis.
Keywords:
Asymmetric a-amination
Organocatalyst
Ó 2010 Elsevier Ltd. All rights reserved.
Peptide bond cleavage
Stimulus-responsive
UV-responsive
1. Introduction
Development of a methodology to control the function of pep-
tides/proteins is an indispensable task in the field of chemical
biology and drug delivery. Photo-responsive processing (peptide
bond cleavage)1aei or conformational change1j has been success-
fully applied for controlling peptide/protein function. Previously,
we reported a stimulus-responsive amino acid2 including a photo-
responsive one2a,c,d and its application for controlling peptidyl
function in living cells2d (Scheme 1). Peptide 1, possessing the
stimulus-responsive amino acid, was converted to processing
products 2 and 3 by stimulus-induced removal of PG (protective
group removable by a stimulus) followed by lactonization of the
trimethyl lock moiety.3 In previous reports, the racemic material
was used as a stimulus-responsive amino acid;2 therefore, its in-
corporation into a peptide afforded a diastereomeric mixture of the
peptide. Consequently, it has been desirable to synthesize a chiral
stimulus-responsive amino acid for ease of purifying synthetic
peptides. In this paper, we report enantioselective synthesis of
a key intermediate of the stimulus-responsive amino acid and its
application for preparing the Fmoc protected UV-responsive amino
acid with (S)-configuration identical to that of naturally occurring
amino acids. Incorporation of the UV-responsive amino acid into
a model peptide is also reported.
Scheme 1. Stimulus-responsive processing system (PG: protective group removable by
a stimulus).
2. Results and discussion
2.1. Enantioselective
a-amination of aldehyde 4
An enantioselective
a
-amination of an aldehyde with a dialkyl
azodicarboxylate in the presence of proline4,5 or its derivatives4,6is
one of the most attractive methods for preparing chiral amino acid
derivatives. Therefore, we applied these systems for enantiose-
* Corresponding authors. E-mail addresses: ashige@ph.tokushima-u.ac.jp
(A. Shigenaga), aotaka@ph.tokushima-u.ac.jp (A. Otaka).
lective a
-amination of aldehyde 42d (Table 1). Aldehyde 4 was
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.033

7368
A. Shigenaga et al. / Tetrahedron 66 (2010) 7367e7372
Table 1
Asymmetric a-amination of aldehyde 4
Entry
Catalyst (equiv)
Solvent
Time
Yield of 5 (%)
ee of 5 (%)
1
2
3
4
5
6
7
8
6 (0.5)
6 (0.1)b
6 (0.1)b
7 (0.2)b
7 (0.2)b
8 (0.1)
9 (0.1)
9 (0.1)
9 (0.1)
9 (0.1)
9 (0.5)
9 (0.5)
9 (0.5)
9 (0.5)
9 (0.5)
DMSO
CH2Cl2
7 days
7 days
7 days
7 days
7 days
3 days
3 days
7 days
1.5 days
4 days
3 days
3 days
1.5 days
1 days
3 days
da
da
da
da
da
22
67
42
42
da
85
37
54
56
70
20
2c
Acetonitrile
CH2Cl2
Acetonitrile
Toluene
CH2Cl2
10c
d
d
>99c
>99
98
CH2Cl2
9
Acetonitrile
Acetonitriled
CH2Cl2
CH2Cl2
Acetonitrile
DMF
78
18
>99
84
78
10
11
12
13
14
15
d
63
79
THF
Reagents and conditions. (i) di-tert-butyl azodicarboxylate, catalyst, solvent, rt. (ii) NaBH4, MeOH.
a
Almost all starting material was recovered.
An enantiomer of the catalyst was used.
An enantiomer of alcohol 5 was obtained as a major product.
Water (10% (v/v)) was added.
b
c
d
treated with di-tert-butyl azodicarboxylate in the presence of pro-
line or its derivatives, and the resulting mixture was immediately
reduced to alcohol 5 with sodium borohydride to prevent a racemi-
zation reaction. An enantiomeric excess was determined by chiral
HPLC analysis of alcohol 5. Determination of the absolute configu-
ration of alcohol 5 will be mentioned later. When proline 6 or sul-
fonamide 76n,7 was used as a catalyst, almost all starting material
was recovered after a week of reaction (entries 1e5). In the presence
of 0.1 equiv of silyl ether 8,6j,7 an enantiomer of 5 was obtained
enantioselectively (>99% ee); however, the chemical yield after 72 h
of reaction was not sufficient (entry 6). A moderate chemical yield
and high enantioselectivity were achieved using 0.1 equiv of tetra-
zole 96m,7 in CH2Cl2 (entry 7). Prolonged reaction time decreased the
chemical yield and enantioselectivity presumably due to side re-
actions of the generated aldehyde (entries 7 and 8). After optimi-
zation of reaction conditions (entries 7e15), alcohol 5 with high
enantiomeric purity was obtained in high yield using 0.5 equiv of
tetrazole 9 in CH2Cl2 (entry 11, 85% yield, >99% ee).
Ha, Hb, Hc, and Hd were assigned on the basis of NOE experiment
(Fig. 1a). Then, the Dd values were calculated and the absolute
configuration of amide 12 was ascertained as (S) (Fig. 1b).8b It is
Scheme 2. Reagents and conditions: (i) di-tert-butyl azodicarboxylate, 9 (0.5 equiv),
CH2Cl2. (ii) NaBH4, MeOH. (iii) TBSOTf, Et3N, CH2Cl2, 0 ꢁC, 75% (three steps). (iv) Tri-
fluoroacetic anhydride, Et3N, CH2Cl2. (v) SmI2, t-BuOH, HMPA, THF, 64% (two steps).
(vi) HCl, 1,4-dioxane. (vii) (S) or (R)-1-methoxy-1-phenyl-1-trifluoromethylacetic acid,
EDC$HCl, Et3N, CH2Cl2, 36% (two steps) for (R)-MTPA derivative, 38% (two steps) for (S)-
MTPA derivative.
2.2. Determination of absolute configuration
Next, we attempted to determine the absolute configuration of
alcohol 5 using Kusumi’s method, also known as a modified
Mosher’s method (Scheme 2).8 Aldehyde 4 was converted to alco-
hol 5 under the reaction conditions of entry 11 in Table 1. According
to the previous report,2d crude alcohol 5 was derivatized to pro-
tected amino alcohol 11. Briefly, the hydroxyl group of 5 was pro-
tected with
a
tert-butyldimethylsilyl (TBS) group. Then,
trifluoroacetylation of the terminal nitrogen of 10 and subsequent
reductive cleavage of the activated NeN bond afforded protected
amino alcohol 11. Deprotection of the Boc group and the TBS group
of 11 under acidic conditions followed by acylation with (R) or (S)-
1-methoxy-1-phenyl-1-trifluoromethylacetic acid afforded (R) or
(S)-MTPA amide 12, respectively. For calculation of Dd values, which
was obtained by subtracting the chemical shift of (R)-MTPA de-
Figure 1. Determination of the absolute configuration using Kusumi’s method. (a)
Observed NOEs (arrows) with MTPA amide 12. (b) Dd values
(
d(S)-MTPA d(R)-MTPA)
ꢀ
rivative from that of (S)-MTPA derivative (Dd
¼
d(S)-MTPA d(R)-MTPA),
ꢀ
obtained for (S)- and (R)-MTPA amide 12 in CDCl3 with 5% (v/v) D2O.

A. Shigenaga et al. / Tetrahedron 66 (2010) 7367e7372
7369
widely accepted that tetrazole 9-mediated
a
-amination of an al-
Unfortunately, attempts to determine the enantiomeric excess
of 16 using chiral HPLC (ChiralPak IA, i-PrOH/hexane system) were
unsuccessful. In the previous report, we noted that peptide 17 and
its diastereomer 170 derived from racemic 16 can be easily sepa-
rated by reverse phase HPLC (Scheme 4).2d Therefore, we decided to
estimate an enantiomeric excess of amino acid derivative 16 on the
basis of a diastereomeric excess of the peptide. Peptide 17 was
synthesized by Fmoc solid phase peptide synthesis according to the
previous report. The obtained crude material was analyzed by re-
verse phase HPLC, and peptide 17 was eluted at 21.0 min (Fig. 3a).
When racemic 16 was incorporated in the peptide, 17 and its di-
astereomer 170 were eluted separately (retention time of 170:
22.6 min) (Fig. 3b). Based on these results, a diastereomeric excess
of the peptide derived from 16 was calculated as >99% de. There-
fore, an enantiomeric excess of Fmoc amino acid 16 was estimated
as >99% ee.
dehyde proceeds via hydrogen bonding of a tetrazole moiety of an
enamine intermediate to a dialkyl azodicarboxylate to generate an
aminated product with (S)-configuration (Fig. 2).4a,6m Therefore,
the enantioselectivity observed in our experiments agrees well
with that of the previous report.
Figure 2. Proposed transition state for the a-amination of aldehyde 4.
2.3. Synthesis of chiral stimulus-responsive amino acid
derivative
Having chiral intermediate 11 with (S)-configuration, we then
attempted to synthesize a chiral UV-responsive amino acid pos-
sessing an o-nitrobenzyl group as a phenolic protective group
(Scheme 3).2d The benzyl group of 11 was removed by hydro-
genolysis to afford phenol 13. In this reaction, accidental removal of
the TBS group was sometimes observed;9 however, it was sup-
pressed by the addition of sodium bicarbonate. Phenol 13 is a key
synthetic intermediate of stimulus-responsive amino acids.2a,b,d
Therefore, an enantiomeric excess of 13 was ascertained by chiral
HPLC and was determined as >99% ee. To demonstrate the appli-
cability of chiral synthetic intermediate 13 for synthesis of the
stimulus-responsive amino acids, it was converted to UV-
responsive amino acid derivative 16. Phenol 13 was alkylated with
o-nitrobenzyl bromide to afford ether 14 (o-NB: o-nitrobenzyl).
Then, the silyl group of 14 was removed under acidic conditions to
generate alcohol 15. Oxidation of alcohol 15 using pyridinium di-
chromate (PDC) in DMF was examined; however, a mixture of
corresponding aldehyde and a small amount of the carboxylic acid
was obtained. The use of PDC in DMF for oxidation of primary
alcohols has been well documented to afford corresponding car-
boxylic acids.10 However in our case, the second step for the
carboxylic acid did not proceed well, presumably due to the pres-
ence of a sterically hindered side chain functionality. Therefore, the
obtained crude material was subjected to subsequent oxidation
with NaClO2, followed by deprotection of the Boc group and pro-
tection of the generated amine with an Fmoc group to yield Fmoc
amino acid 16 in 84% yield over four steps.
Scheme 4. Reagents and conditions: (i) Fmoc solid phase peptide synthesis on a
NovaSyn TGR resin. (ii) TFA/triethylsilane/H2O¼95/2.5/2.5 (v/v/v). (o-NB: o-nitro-
benzyl; F: phenylalanine; G: glycine; L: leucine; Y: tyrosine).
3. Conclusions and summary
In conclusion, enantioselective synthesis of a key intermediate
of stimulus-responsive amino acids via asymmetric
a-amination
reaction of the aldehyde was reported. An absolute configuration of
the intermediate was ascertained as (S) using Kusumi’s method.
The obtained chiral intermediate was applied for preparing the
Fmoc protected UV-responsive amino acid with (S)-configuration
and was successfully incorporated into a model peptide by Fmoc
solid phase peptide synthesis. These results enable us to prepare
chiral stimulus-responsive amino acids, not just the UV-responsive
compound. Its application in synthesizing other stimulus-
responsive amino acids is in progress.
4. Experimental section
4.1. General methods
All reactions were carried out under a positive pressure of argon
unless otherwise noted. For column chromatography, silica gel
(KANTO KAGAKU N-60) was employed. NMR spectra were mea-
sured using a JEOL GSX400, a Bruker AV400 N, or a JEOL JNM-AL300
spectrometer. Exact mass spectra were recorded on a Waters
MICROMASSÒ LCT PREMIERÔ or a Bruker Esquire200 T. Enantio-
meric excesses were estimated by HPLC on a ChiralPak IA (Daicel
Chiral Industries, Ltd., 4.6ꢂ250 mm, detection at 220 nm). For re-
verse phase HPLC analysis, a Cosmosil 5C18-AR-II analytical column
(Nacalai Tesque, 4.6ꢂ250 mm) was employed and eluting products
were detected by UV at 220 nm. Optical rotations were measured
using a JASCO P-2200 polarimeter (concentration in g/100 mL).
4.2. Typical procedure of
in Table 1 (entry 11)
a-amination reaction described
To a solution of aldehyde 42d (50.0 mg, 169
(250 L) were added di-tert-butyl azodicarboxylate (54.3 mg,
236 mol), and the reaction
mol) and tetrazole 96m,7 (11.7 mg, 84.0
mixture was stirred at room temperature for 72 h. After addition of
saturated aqueous solution of NH4Cl, the resulting mixture was
mmol) in CH2Cl2
m
m
Scheme 3. Reagents and conditions: (i) H2, Pd/C, NaHCO3, MeOH, 83%, >99% ee (ii)
o-nitrobenzyl bromide, K2CO3, DMF, 84%. (iii) AcOH, H2O, THF, 93%. (iv) PDC, DMF. (v)
NaClO2, 2-methyl-2-butene, NaH2PO4, acetonitrile, acetone, H2O. (vi) HCl, AcOEt. (vii)
FmocOSu, Na2CO3, acetonitrile, H2O, 84% (four steps). (o-NB: o-nitrobenzyl).
m

7370
A. Shigenaga et al. / Tetrahedron 66 (2010) 7367e7372
reaction mixture was stirred for 30 min and then extracted with
AcOEt. The combined organic layer was washed with 5% (w/v)
aqueous solution of KHSO4 followed by brine, dried over Na2SO4,
and concentrated in vacuo. The crude product was purified by pre-
parative TLC (SiO2, hexane/AcOEt¼2/1 (v/v)), and 75.7 mg of alcohol
5 (143 m
mol, 85%, >99% ee) was obtained as awhite powder.1H NMR
spectrum was identical with that of the racemic one.2d HPLC con-
ditions: ChiralPak IA (hexane/i-PrOH¼95/5 (v/v), 0.25 mL/min).
Retention times: 36.3 min (minor) and 57.6 min (major).
4.3. Asymmetric synthesis of Fmoc protected UV-responsive
amino acid derivative
4.3.1. (S)-3-(2-Benzyloxy-4,6-dimethylphenyl)-2-(1,2-di-tert-butoxy-
carbonylhydrazinyl)-3,3-dimethylpropanol (5). Aldehyde 42d (1.33 g,
4.47 mmol) was converted to corresponding alcohol 5 according to
the experiment in the Section 4.2. The crude product was repreci-
pitated from hexane, and 2.34 g of alcohol 5 was obtained as
a white powder. It was used for a subsequent reaction without
19
further purification. [
a]
þ5.47 (c 1.45, CHCl3); 1H NMR spectrum
D
was identical with that of the racemic one.2d
4.3.2. (S)-3-(2-Benzyloxy-4,6-dimethylphenyl)-2-(1,2-di-tert-butoxy-
carbonylhydrazinyl)-3,3-dimethylpropanol
tert-butyldimethylsilyl
ether (10). Alcohol 5 (2.34 g) was converted to corresponding silyl
ether 10 (2.16 g, 3.36 mmol, 75% over three steps) according to the
previous report.2d
identical with that of the racemic one.
[
a]
19 þ17.1 (c 1.03, CHCl3); 1H NMR spectrum was
D
4.3.3. (S)-3-(2-Benzyloxy-4,6-dimethylphenyl)-2-tert-butoxy-
carbonylamino-3,3-dimethylpropanol tert-butyldimethylsilyl ether
(11). Hydrazine derivative 10 (2.16 g, 3.36 mmol) was converted to
corresponding amine 11 (1.14 g, 2.16 mmol, 64% over two steps)
21
according to the previous report.2d
[
a
]
D
ꢀ29.3 (c 1.06, CHCl3); 1H
NMR spectrum was identical with that of the racemic one.
4.3.4. (S)-2-tert-Butoxycarbonylamino-3,3-dimethyl-3-(4,6-di-
methyl-2-hydroxyphenyl)propanol
tert-butyldimethylsilyl
ether
(13). Benzyl ether 11 (1.14 g, 2.16 mmol) was converted to corre-
sponding phenol 13 (0.782 g, 1.79 mmol, 83%) according to the
previous report.2d When desilylation had been observed, sodium
bicarbonate (50 mg/MeOH 1.0 mL) was added to the reaction
mixture. The enantiomeric excess was estimated as >99% ee. HPLC
conditions: ChiralPak IA (hexane/i-PrOH¼99/1 (v/v), 0.25 mL/min).
20
Retention times: 32.4 min (minor) and 37.4 min (major). [a]
D
ꢀ36.7 (c 0.95, CHCl3); 1H NMR spectrum was identical with that of
the racemic one.
4.3.5. (S)-2-tert-Butoxycarbonylamino-3,3-dimethyl-3-[2,4-di-
methyl-6-(2-nitrobenzyloxy)phenyl]propanol tert-butyldimethylsilyl
ether (14). Phenol 13 (0.770 g, 1.76 mmol) was converted to cor-
responding nitrobenzyl ether 14 (0.840 g, 1.47 mmol, 84%) accord-
20
ing to the previous report.2d
[
a]
ꢀ35.5 (c 1.02, CHCl3); 1H NMR
D
spectrum was identical with that of the racemic one.
Figure 3. HPLC profiles of a crude material of the peptide derived from (a) 16, or (b)
racemic 16. Peptide 170 is a diastereomer of peptide 17. Retention times, 17: 21.0 min;
170: 22.6 min. Only a critical retention time region of the HPLC charts was enlarged.
HPLC conditions: Cosmosil 5C18-AR-II column (4.6ꢂ250 mm) with a linear gradient of
0.1% (v/v) TFA in acetonitrile/0.1% (v/v) aqueous TFA solution (20e80% over 30 min) at
a flow rate of 1.0 mL/min, detection at 220 nm.
4.3.6. (S)-2-tert-Butoxycarbonylamino-3,3-dimethyl-3-[2,4-di-
methyl-6-(2-nitrobenzyloxy)phenyl]propanol (15). Silyl ether 14
(0.840 g, 1.47 mmol) was converted to corresponding alcohol 15
19
(0.623 g, 1.36 mmol, 93%) according to the previous report.2d
[
a]
D
ꢀ18.9 (c 0.93, CHCl3); 1H NMR spectrum was identical with that of
stirred for 30 min and then extracted with diethyl ether. The organic
phase was washed with brine, dried over Na2SO4, and concentrated
in vacuo. To the obtained crude material were successively added
the racemic one.
4.3.7. (S)-3,3-Dimethyl-3-[2,4-dimethyl-6-(2-nitrobenzyloxy)phe-
nyl]-2-(9-fluorenylmethoxycarbonylamino)propionic acid (16). Pyr-
idinium dichromate (1.93 g, 5.13 mmol) was added to a solution of
alcohol 15 (470 mg, 1.02 mmol) in DMF (5.20 mL). The reaction
MeOH (2.00 mL) and sodium borohydride (8.0 mg, 210 mmol) at
0 ꢁC. The resulting suspension was stirred at room temperature for
30 min. After addition of saturated aqueous solution of NH4Cl, the

A. Shigenaga et al. / Tetrahedron 66 (2010) 7367e7372
7371
mixture was stirred overnight. After addition of 5% (v/v) aqueous
solution of KHSO4, the obtained mixture was extracted with
diethyl ether. The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated in vacuo. The obtained crude
material was subjected to subsequent reactions without purifi-
cation according to the literature.2d Fmoc protected amino acid
derivative 16 was obtained as a pale yellow amorphousness
IT) calcd for C76H96N13O16 ([MþH]þ): 1446.7, 17: found 1446.5, 170:
found 1446.4.
Acknowledgements
We thank Prof. T. Ooi, The University of Tokushima, for valuable
discussions. This research was supported in part by a Grant-in-Aid
for Scientific Research (KAKENHI), Takeda Science Foundation, and
Nagase Science and Technology Foundation.
(514 mg, 84% over four steps). [
a
]
23 ꢀ6.69 (c 1.12, CHCl3); 1H NMR
D
spectrum was identical with that of the racemic one.
4.4. Determination of absolute configuration using Kusumi’s
method
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.07.033.
4.4.1. General procedure for synthesis of MTPA derivatives. Hydro-
gen chloride in 1,4-dioxane (4 M, 1.0 mL) was added to substrate
11 (51 mg, 95 mmol) and the resulting mixture was stirred for 6 h.
References and notes
After being quenched with 1 M aqueous NaOH, the reaction
mixture was extracted with CH2Cl2. The organic phase was dried
over Na2SO4, and concentrated in vacuo to give a crude product.
To the crude product in CH2Cl2 (1.0 mL) were added 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDC$HCl,
1.2 equiv), (R) or (S)-1-methoxy-1-phenyl-1-trifluoromethyl-
acetic acid (1.2 equiv) and triethylamine (1.0 equiv), and the re-
action mixture was stirred overnight. After being quenched with
saturated aqueous solution of NH4Cl, the reaction mixture was
extracted with AcOEt. The organic phase was washed with brine,
dried over Na2SO4, and concentrated in vacuo. The obtained
product was purified by column chromatography (hexane/
AcOEt¼6/1 (v/v)), and MTPA amide (R)-12 or (S)-12 was obtained,
respectively, as a yellow oil.
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28
4.4.2. (R)-MTPA derivative ((R)-12). [
a
]
ꢀ9.89 (c 2.17, CHCl3); 1H
D
NMR (CDCl3 with 5% (v/v) D2O, 400 MHz)
d
¼1.495 (3H, s),
3. (a) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735e1766, and references
therein; (b) Amsberry, K. L.; Borchardt, R. T. J. Org. Chem. 1990, 55, 5867e5877;
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Cohen, L. A. J. Am. Chem. Soc. 1972, 94, 9166e9174; (f) Milstien, S.; Cohen, L. A.
Proc. Natl. Acad. Sci. U.S.A. 1970, 67, 1143e1147.
1.566 (3H, s), 2.228 (3Hc, s), 2.507 (3Ha, s), 3.17 (3H, s), 3.533
(1H, dd, J¼11.6 and 8.0 Hz), 3.687 (1H, dd, J¼11.6 and 2.8 Hz), 4.912
(1H, td, J¼8.0 and 2.8 Hz), 5.060 (1H, d, J¼11.8 Hz), 5.133 (1H, d,
J¼12.0 Hz), 6.594 (1Hb, s), 6.673 (1Hd, s), 7.25e7.45 (8H, m), 7.54
(2H, m); 13C NMR (CDCl3, 75 MHz)
d
¼20.7 (CH3), 25.9 (CH3), 27.9
4. Recent reviews: (a) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38,
2178e2189; (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
(CH3), 29.0 (CH3), 43.3 (C), 54.8 (CH3), 58.9 (CH), 64.7 (CH2), 71.1
(CH2),112.9 (CH),127.6 (CH),127.7 (CH),127.9 (CH),127.9 (CH),128.5
(CH), 128.6 (CH), 129.4 (CH), 129.5 (C), 132.8 (C), 136.8 (C), 137.0 (C),
138.1 (C), 158.4 (C), 168.0 (C); HRMS (ESI-TOF) calcd for
C30H34F3NNaO4 ([MþNa]þ): 552.2338, found: 552.2357.
€
2007, 107, 5471e5569; (c) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev.
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28
4.4.3. (S)-MTPA derivative ((S)-12). [
a
]
D
þ11.3 (c 1.19, CHCl3); 1H
€
Grossa, P. J.; Niegerb, M.; Brase, S. Org. Biomol. Chem. 2009, 7, 5059e5062; (e)
NMR (CDCl3 with 5% (v/v) D2O, 400 MHz)
d
¼1.492 (3H, s), 1.540
Makino, K.; Kubota, S.; Hara, S.; Sakaguchi, M.; Hamajima, A.; Hamada, Y.
Tetrahedron 2009, 65, 9468e9473; (f) Nuzzi, A.; Massi, A.; Dondoni, A. Org. Lett.
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(3H, s), 2.243 (3Hc, s), 2.484 (3Ha, s), 3.27 (3H, s), 3.589
(1H, dd, J¼11.2 and 8.0 Hz), 3.791 (1H, dd, J¼11.2 and 2.4 Hz), 4.927
(1H, td, J¼8.0 and 2.4 Hz), 4.955 (1H, d, J¼12.4 Hz), 4.985 (1H, d,
J¼12.4 Hz), 6.571 (1Hb, s), 6.579 (1Hd, s), 7.09 (2H, d, J¼7.8 Hz), 7.21
(2H, t, J¼7.8 Hz), 7.28e7.46 (6H, m); 13C NMR (CDCl3, 75 Hz)
€
49, 4882e4885; (i) Baumann, T.; Vogt, H.; Brase, S. Eur. J. Org. Chem. 2007,
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B. J. Am. Chem. Soc. 2002, 124, 5656e5657.
d
¼20.8 (CH3), 25.8 (CH3), 28.4 (CH3), 28.7 (CH3), 43.3 (C), 54.8
(CH3), 58.8 (CH), 64.4 (CH), 71.2 (CH2), 100.5 (C), 112.9 (CH), 127.5
(CH), 127.8 (CH), 128.0 (CH), 128.3 (CH), 128.6 (CH), 129.2 (CH),
129.8 (C), 1323 (C), 136.8 (C), 136.8 (C), 137.8 (C), 158.4 (C), 167.9
(C); HRMS (ESI-TOF) calcd for C30H34F3NNaO4 ([MþNa]þ):
552.2338, found: 552.2321.
4.5. Synthesis of peptide 17
€
€
6. (a) Baumann, T.; Bachle, M.; Hartmann, C.; Brase, S. Eur. J. Org. Chem. 2008,
2207e2212; (b) Ait-Youcef, R.; Sbargoud, K.; Moreau, X.; Greck, C. Synlett
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Peptide 17 was synthesized on NovaSyn TGR resin using Fmoc
solid phase peptide synthesis reported in the previous report.2d The
resulting crude material was analyzed by reverse phase HPLC. HPLC
conditions: Cosmosil 5C18-AR-II analytical column (0.1% (v/v) TFA in
acetonitrile/0.1% (v/v) aqueous TFA solution¼20e80% over 30 min,
1.0 mL/min). Retention times, 17: 21.0 min; 170: 22.6 min. MS (ESI-

7372
A. Shigenaga et al. / Tetrahedron 66 (2010) 7367e7372
T. C.; Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
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Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84e96;
Toluene solution of silyl ether 8 was purchased from SIGMA-ALDRICH.
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€
3477e3481; (o) Vogta, H.; Vanderheidena, S.; Brase, S. Chem. Commun. 2003,
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