Cu(OTf)2-Promoted 1,4-addition of alkyl bromides to dehydroalanine

Article abstract of DOI:10.1021/acs.joc.9b00369

Zn/Cu(OTf)₂-mediated addition of alkyl bromides to dehydroalanine (Dha) derivatives including dipeptides and tripeptides in good to high yields under an aqueous medium was developed. This protocol allows selective and biocompatible access to various amino acid units from Dha derivatives.

Full text of DOI:10.1021/acs.joc.9b00369

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Note
Cu(OTf)2 promoted 1,4-addition of alkylbromides to dehydroalanine
Jung-Ah Shin, Jiheon Kim, Hongsoo Lee, Sura Ha, and Hee-Yoon Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00369 • Publication Date (Web): 20 Mar 2019
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Page 1 of 8
The Journal of Organic Chemistry
Cu(OTf)2 promoted 1,4-addition of alkylbromides to dehydroalanine
1
2
3
Jung-Ah Shin†‡, Jiheon Kim†, Hongsoo Lee†, Sura Ha†, Hee-Yoon Lee*†
4
5
6
7
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea.
‡The 4th R&D Institute-6, Agency for Defense Development, Daejeon, 34186, Korea.
Supporting Information Placeholder
8
9
RBr
R
O
10
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60
O
O
H
Zn, Cu(OTf)2
H
N
N
N
R1
N
R1
R2
R2
H
H
sat.NH4Cl-EtOH, rt, 6 h
O
amino acids
ABSTRACT : Zn/Cu(OTf)2 mediated addition of alkyl bromides to dehydroalanine (Dha) derivatives including dipeptides and
tripeptides in good to high yields under aqueous medium was developed. This protocol allows selective and biocompatible access to
various amino acid units from Dha derivatives.
Various chemical modifications of proteins have been
developed for chemical biology research, and have helped
understanding and exploration of how the biological functions in
proteins are regulated.1 However, chemical modifications of
proteins that mimic natural posttranslational modification of
proteins have been rare mainly due to selectivity issues of the
corresponding modifications. To mimic various translational
modifications as well as to introduce non-natural modifications of
proteins, a selective method of introducing various functional
groups to proteins with general applicability would be desirable.
For that purpose, we and others have been interested in utilizing
dehydroalanine (Dha) unit in proteins that can be introduced
through chemical or biological means.2 With Dha unit incorporated
in proteins it would be possible to mimic posttranslational
modification of proteins by introducing variously functionalized
amino acid unit through C-C bond forming conjugate addition
reactions. Conjugate addition to electron deficient olefins catalyzed
by transition metals is one of the most powerful tools for the
construction of C-C bonds in organic synthesis, and shows
potential application to biological system.3 To warrant a new C-C
bond formation with proteins, it is necessary to set up
biocompatible reaction environment such as aqueous medium for
the reaction and mild reaction conditions.
by adding Cu(OAc)2 additive to the reaction.10 When, however, we
re-examined the reaction with Dha small amount of dialkylated
product was observed.
Figure 1. Zn mediated alkylation of Dha
O
I
O
O
Zn
,
CbzHN
CbzHN
CbzHN
N
CO2Me
CO2Me
N
CO2Me
N
H
H
H
sat.NH4Cl-dioxane, rt
1.7
:
1.0
nBuI, Zn, Cu(OAc)2
sat.NH4Cl-EtOH, rt
BocHN
CO2Me
BocHN
CO2Me
BocHN
CO2Me
5.3
:
1.0
Though it is clear that radical addition to Dha unit in proteins
became a way of modifying proteins in controlled manner, less than
complete selectivity of the reaction prompted us to further study the
Zn mediated alkylation reaction of Dha.
Firstly, we examined the efficiency of Zn-mediated C-C bond
formation reaction using Dha 1a as the reference substrate with or
without a Cu catalyst in aqueous systems (Table 1). In the absence
of any additives, no reaction occurred in aqueous media (entry 1).
Even though NH4Cl was used as an activator for Zn, the reaction
was sluggish (entry 2-3) and dialkylated product 2a' was observed
as a minor product (entry 3). When Zn and nBuI were added in two
portions with higher overall equivalency, the ratio of dialkylated
adduct was increased without much improvement of the conversion
(entry 4). Then the effect of Cu catalysts such as CuI, CuCl2,
Cu(acac)2, Cu(OAc)2 and Cu(OTf)2 was investigated (entry 5-9).
As a result, the conversion rate was increased up to 41% when
Cu(OTf)2 was used, and 2a and 2a' were observed in a ratio of 98 :
2 (entry 7). In order to maximize the conversion rate, addition of
NH4Cl to the reaction, as anticipated, the reaction efficiency was
greatly improved (entry 10-14). Unfortunately, amount of the
dialkylated product was also increased. When 1 equivalent of each
reagent was used, the formation of 2a' was reduced while the
conversion rate was only 79% (entry 15). When the reagents were
used in large excess (15 equivalent), the conversion rate reached
100% with 1:1 ratio of 2a and 2a' (entry 16). Through these and
the subsequent experiments, it was found out that the addition of
optimized amounts of Zn and nBuI in several portions became the
best reaction condition for the reaction efficiency though the
reaction still produced 2a' in 13% (entry 17). To our delight,
amount of 2a' became less than 10% of the product when only 1
A pioneering work by Luche demonstrated that when Zn-Cu
couple was used, alkyl halides reacted with conjugate carbonyl
compounds in H2O/EtOH to afford 1,4-addition products in good
yields under sonication conditions.4 Diastereoselective alkylations
by introducing chiral acceptors under Zn-CuI in H2O/EtOH system
were also described.5 Extension of this reaction to the captodative
conjugate system of enamides was reported to produce α-amino
acid derivatives using Zn in aqueous NH4Cl.6 More recently,
Lipshutz disclosed the use of Zn-Cu(OAc)2-AuCl3 leading to
conjugate additions of alkyl halides to enones in micellar
environment by non-traditional organocopper chemistry.7
Thus, Zn mediated 1,4-addtion of alkylhalides to Dha moiety
became a good candidate for the C-C bond formation of proteins as
Dha was well known for an effective Michael acceptor.8 In this
context, we and others explored protein modifications using Dha
unit in proteins using Zn based 1,4-addition reactions and
encountered an unexpected dialkylated product formation along
with the desired product (Figure 1).9,10 Davis reported a C-C bond
formation reaction of Dha using alkyliodides and Zn in presence of
NH4Cl in H2O-dioxane, where unexpected dialkylated products
were obtained in appreciable amount.9 We also observed similar
results from the same reaction in EtOH-H2O solvent with a protein
containing a Dha residue. We resolved the problem of dialkylation
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Page 2 of 8
mol% of Cu(OTf)2 was used without sacrificing the conversion of
Scheme 1. Results of Zn/Cu-mediated alkylation of Dha 1a
using alkyl halides in aqueous mediaa
1
2
3
4
5
6
7
8
the reaction (entry 18). These results showed clearly that the
combination of Zn/Cu(OTf)2/NH4Cl system was the most efficient
system to generate a new C-C bond of Dha derivatives in aqueous
media. However, dialkylated by-products 2a' was obtained in all
cases with about 5 to 10% yields. To further improve the selectivity
2a, we envisioned that replacing alkyliodides with alkylbromides
under the optimized reaction condition could suppress the
formation of 2a' though alkylbromides have been known to be
ineffective for the reaction.4a,4b,11 To our delight, when
butylbromide was used under the optimized reactions with 10 mole
% of Cu(OTf)2, 2a was produced with good conversion without the
formation of 2a' (entry 19). To further improve the reaction
conversion, reagents were added in three portions to obtain 2a with
maximum conversion (entry 20).
R
R
X
Zn, Cu(OTf)2
BocHN
CO2Me
2b- 2p
BocHN
1a
CO2Me
sat.NH4Cl/EtOH (1/1)
rt, 6 h
Entry
R-X
Product
Yield(%)b
Br
1
2
2b
2c
92
92
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
Br
3
4
5
2d
2e
2f
50
82
72
Br
Br
Table 1. Optimization of the reaction conditionsa
nBuI, Zn
Br
Cu catalyst
6
2g
92
BocHN
CO2Me
BocHN
CO2Me
1a
O
Solvent, rt, 6 h
BocHN
CO2Me
2a
7
8
2h
2i
52
48
2a'
Br
Entr
y
Solvent (1/1)
Cu
Conv.
2a:2a'b
(2a yield)c
Br
Catalyst
-
9
2j
2k
2l
56
91
59
HO
NC
Br
Br
1
2
H2O/solventd
0
11
13
14
19
4
0
10
11
sat.NH4Cl/EtOH
-
100:0(4)
94:6
O
MeO
Br
3
sat.NH4Cl/Dioxane
sat.NH4Cl/Dioxane
H2O/EtOH
-
O
12
2m
51
4e
-
80:20
N
S
O
Br
5
CuI
100:0(12)
100:0
N
6
H2O/EtOH
CuCl2
13
14
2n
30
71
Ph
Cl
7
H2O/EtOH
Cu(OTf)2
Cu(acac)2
Cu(OAc)2
CuI
41
15
37
55
83
78
98
100
79
100
100
93
53
95
98:2
MeO OMe
O
Br
8
H2O/EtOH
100:0
BocHN
BocHN
CO2Me
2o
9
H2O/EtOH
100:0
15
51
I
10
11
12
13
14
15f
16g
17h
18i
19j
20k
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
sat.NH4Cl/EtOH
100:0(40)
90:10(66)
91:9(56)
84:16(83)
88:12(90)
95:5
CO2Me
2p
CuCl2
aSee Experimental Section. bIsolated yield.
Cu(acac)2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
The radical nature of the reaction was supported in the addition
reaction using cyclopropylmethyl iodide, which produced the
butenylated product 2p (entry 15). Various functional groups such
as hydroxyl, nitrile, ester and dansyl group were well tolerated
under the reaction conditions (entry 9-12). However, alkyl halides
that possess anion stabilizing functionality, W-C-X, did not yield
any products presumably due to the fast second electron transfer
from the initially formed radical intermediates to form anionic
intermediates that would be quenched by water right away. Only in
the case of benzyl chloride, the reaction afforded the desired
homophenylalanine derivative 2n in moderate yield (entry 13).
When a protected carbonyl group was used, the reaction proceeded
smoothly to form the addition product accompanied by
deprotection of the acetal group (entry 14). This result also
demonstrated that acid labile groups would not be tolerated under
the reaction conditions.
51:49
87:13(90)
93:7(82)
100:0
100:0
a-kSee Experimental Section.
With the optimized conditions in hand, various alkyl bromides
were reacted with 1a to provide the corresponding unnatural α-
amino acids and the results are summarized in Scheme 1.
Alkylbromides afforded the addition products in good to excellent
yields regardless of the substitution patterns and steric environment
(entry 1-8). These results strongly indicated that the addition
reaction underwent through alkyl radical intermediate rather than
cuprate species.7
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The Journal of Organic Chemistry
Table 2. Comparison of an alkylation with dipeptide 3a
Scheme 2. Substrate scopes of tripeptide 5aa
1
2
3
4
5
6
7
8
R
O
O
O
X
O
O
O
H
Zn, Cu(OTf)2
O
O
H
BocHN
N
CbzHN
RBr, Zn, Cu(OTf)2
BocHN
N
CbzHN
CbzHN
N
CO2Me
N
OMe
CO2Me
N
OMe
N
CO2Me
N
H
H
sat.NH4Cl/solvent, rt, 6h
H
H
H
O
aq.NH4Cl/EtOH
rt, 6 h
3a
4a
4a'
5a
6a - 6c
Entry
R-X
Cu(OTf)2
(equiv)
sat.NH4Cl
/solvent
Yield
(%, 4a:4a')b
Entry
R-Br
Product
Yield (%)b
70
112
212
3a
-
Dioxane
Dioxane
EtOH
48 : 28
O
O
I
H
N
Br
BocHN
1
2
3
N
H
OMe
9
0.1
0.1
0.1
58 : 15
61 : 9
69 : 0
O
I
I
6a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4a
EtOH
O
O
H
N
Br
BocHN
BocHN
79
65
N
H
OMe
Br
O
6b
aSee Experimental Section. bIsolated yield of 4a and 4a'.
O
O
H
N
At this point, we compared the different reaction conditions for
the addition reaction of isopropyl group to a dipeptide substrate 3a
(Table 2). When the reaction was carried out using sat.
NH4Cl/dioxane system without Cu(OTf)2 additive, 4a and 4a' were
obtained in 48% and 28%, respectively (entry 1) similar to the
reports by Davis.9 Addition of Cu(OTf)2 into this system reduced
the amount of 4a' in the product (entry 2). When solvent system
was switched to sat.NH4Cl/EtOH from sat. NH4Cl/dioxane, the
desired product 4a was obtained 61%, and formation of 4a' was
dramatically reduced to 9% (entry 3). This result again confirmed
that the second alkylation is influenced by changing the solvent.
Different solvent could alter the rate of the second electron transfer
to the acyl radical intermediate formed from the addition reaction,
and thus changes the ratio of the second alkylation. This result also
strongly suggested that the second alkylation occurred via a radical
process as well, though the mechanism of the second alkylation
requires a further study. Lowering the reactivity of alkyl group by
replacing isopropyl iodide with isopropyl bromide did not suppress
the 1,4-addition reaction as 4a was obtained in 69% yields without
the formation of dialkylated product (entry 4). These results
showed clearly that the combination of alkyl bromides, Zn and
Cu(OTf)2 promotes conjugate additions to Dha but effectively
suppress the second alkylation products.
Br
N
H
OMe
O
6c
aSee Experimental Section.bIsolated yield.
Phenyl bromide was added to Dha 1a in aqueous media, however,
the arylation adduct 7a was not formed (entry 1). Unlike the
alkylation of Dha with alkyl bromide, it was observed through
GC/MS monitoring that the reaction rate of transmetallation from
Zn to Cu for generating aryl radical species is slow in the arylation
reaction. Fortuitously, using phenyl iodide instead of phenyl
bromide, the corresponding product 7a was obtained in good yields
without formation of the dialkylated product, showing the viability
of this protocol for the site-specific arylation of non-natural α-
amino acids (entry 2). The lack of the diarylated product also
supports the second alkylation would not be a nucleophilic addition
reaction of the anionic species.10 For aryl iodides containing
electron-donating groups such as –OMe, –OH, and –NH2, desired
products 7b-7e were just obtained 13-32% yields (entry 3-6).
Unfortunately, aryl iodides with electron-withdrawing groups such
as –CF3, –CO2Me, and –CH2OH failed to afford any conversion to
the corresponding products, probably due to the instability and low
reactivity by an electronic effect of aryl iodides.
After successful exploration of the C-C bond formation reaction
with Zn/Cu(OTf)2 to a Dha 1a and a dipeptide 3a, a precursor 5a
possessing a Dha moiety in tripeptide was investigated for a
possible stereoselectivity. Tripeptide 5a was readily prepared from
commercially available Leu-Ser-Phe through two steps, by
employing protecting groups both an amino- and carboxyl group
followed by β-elimination (See. Scheme S1). With the tripeptide 5a
in hand, C-C bond formation reaction was conducted under
optimized reaction conditions, which would confirm the feasibility
of this reaction system for protein incorporations, as shown in
Scheme 2. As expected, tripeptide 5a also proved to be compatible
with primary, secondary, and tertiary alkyl bromides, providing the
product 6a-6c in good to 65-79% yields (entry 1-3). Unfortunately,
under the optimal condition, there was no sign of good
diastereoselectivity regardless of alkylbromides with ~7:3 ratio of
diastereomers though reaction yields were good in all cases.
In summary, we developed a mild and efficient conjugate
addition of alkyl bromides to Dha derivatives in aqueous media. In
the presence of Zn and Cu(OTf)2, various α-amino acid derivatives
were generated in good to high yields, including tolerance to polar,
non-polar, bulky, and modified alkyl residues. Besides, a direct
incorporation of C-C bond of a dipeptide and tripeptide with Dha
moiety was also successfully accomplished. Further improvement
of the diastereoselectivity of alkylation on tripeptides and arylation
of Dha are in progress.
Encouraged by these results, we extended this system to the
arylation of the Dha 1a-1b, using various aryl halides containing
electron-donating or electron-withdrawing groups, the results were
described in Scheme 3.
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tButyl- 2-((tert-butoxycarbonyl)amino)acrylate (1b)
Scheme 3. Zn mediated arylation of Dha derivativesa
N-(tert-butoxycarbonyl)-L-cysteine tert-butyl ester13 (1.84 g, 6.65
mmol) was dissolved in THF. K2CO3 (4.59 g, 33.2 mmol) was added
to the stirred solution followed immediately by 1,4-diiodobutane (1.33
ml, 9.97 mmol) at room temperature. The reaction was stirred for 4 h
at room temperature. The resulting mixture was diluted with Et2O and
washed with water and brine. Combined organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (EtOAc : Hexane = 1 : 50) to
give 1b (61%, 978 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.01 (s, 1H), 6.04 (s, 1H), 5.60 (d, J = 1.9 Hz, 1H), 1.48 (s, 9H), 1.45
(s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 152.6, 132.4, 104.0,
82.6, 80.4, 28.2, 27.9 ; HRMS (ESI-TOF) m/z:[M+Na]+ Calcd for
C12H21NO4Na 266.1368 ; Found 266.1359
1
2
3
4
5
6
7
8
Ar
I
Ar
Zn, Cu(OTf)2
BocHN
CO2R
BocHN
CO2R
sat.NH4Cl/EtOH (1/1)
rt, overnight
1a - 1b
7a - 7e
t
1a
1b
(R=Me),
(R= Bu)
Entry
1
Dha
Ar-X
Product
Yield(%)b
nrc
Br
1a
9
BocHN
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7a
I
2
1a
7a
70
(R)-methyl 2-(2-(((benzyloxy)carbonyl)amino)propanamido)acr
ylate (3a)14
NH2
To a solution of N-carbobenzyloxy Ala-Ser methyl ester (350mg,
1.08 mmol) in CH2Cl2 was added CuCl (32 mg, 0.324 mmol) and N-
(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (228
mg, 1.188 mmol) at room temperature. The reaction was stirred for 18
h at room temperature. The resulting mixture was poured into water.
The resulting mixture was extracted with CH2Cl2 at three times.
Combined organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc : Hexane = 1 : 1) to give 3a (94%,
310 mg) as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H),
7.45 – 7.17 (m, 6H), 6.55 (d, J = 1.3 Hz, 1H), 5.88 (d, J = 1.6 Hz, 1H),
5.52 (d, J = 7.4 Hz, 1H), 5.20 – 4.97 (m, 2H), 4.32 (s, 1H), 3.79 (d, J =
1.3 Hz, 3H), 1.38 (dd, J = 7.1, 1.4 Hz, 3H) ; 13C{1H} NMR (100 MHz,
CDCl3) δ 171.1, 171.1, 164.2, 136.1, 130.7, 128.4, 128.1, 128.0, 109.4,
67.1, 60.3, 54.0, 52.9, 20.9, 18.1, 14.1.
I
3
4
1a
1a
14
13
BocHN
CO2Me
7b
H2N
O
O
I
I
BocHN
CO2Me
7c
O
5
6
1b
1b
32
30
O
BocHN
BocHN
CO2tBu
7d
I
OH
HO
CO2tBu
7e
(6R,12R)-methyl 12-benzyl-9-(hydroxymethyl)-6-isobutyl-2,2-
dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triaza-tridecan-13-oate (5a-1,
Scheme S1)15
aSee Experimental Section. Isolated yield. nr : no reaction.
b
c
To a solution of H-Leu-Ser-Phe-OH (300 mg, 0.82 mmol) in THF :
H2O (1 : 2.4, 6 mL) was added sodium bicarbonate (276 mg, 3.3 mmol)
and boc anhydride (0.285 mL, 1.23 mmol) at room temperature. The
reation mixture was stirred for 20 h at room temperature. The reaction
was quenched with aq. 4N HCl (~pH 5) and the solution was extracted
with EtOAc. The combined extracts were dried, concentrated in vacuo,
and the residue in DMF (1 mL) was added iodomethane (0.128 mL,
2.05 mmol) and K2CO3 (116 mg, 0.836 mmol) at room temperature.
The reaction mixture was stirred for 20 h at room temperature. The
reaction was quenched with water and sat. NH4Cl (~pH 5). The
resulting mixture was extracted with Et2O at three times. Combined
organic layer was treated with MgSO4 and evaporated in vacuo. The
residue was purified with column chromatography (EtOAc : Hexane =
2 : 1) to give 5a-1 (58%, 229 mg) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.38 – 7.00 (m, 7H), 5.06 (d, J = 7.1 Hz, 1H), 4.78 (ddd, J =
7.9, 6.9, 5.8 Hz, 1H), 4.45 (ddd, J = 7.5, 5.4, 4.0 Hz, 1H), 4.17 – 3.99
(m, 1H), 3.99 – 3.82 (m, 1H), 3.68 (s, 3H), 3.63 – 3.54 (m, 1H), 3.51
(s, 1H), 3.20 – 2.95 (m, 2H), 2.02 (d, J = 7.2 Hz, 2H), 1.63 (d, J = 6.6
Hz, 1H), 1.59 – 1.49 (m, 1H), 1.49 – 1.42 (m, 1H), 1.40 (s, 9H), 0.90
(dd, J = 6.4, 1.2 Hz, 6H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 173.3,
171.8, 170.3, 155.8, 135.8, 129.1, 128.6, 127.2, 80.3, 62.6, 54.2, 53.6,
52.4, 41.1, 37.6, 28.3, 24.7, 23.0, 21.7 ; HRMS (ESI-TOF)
m/z:[M+Na]+Calcd for C24H37N3O7Na 502.2529; Found502.2556.
EXPERIMENTAL SECTION
General Experimental Information. Proton nuclear magnetic
resonance spectroscopy (1H NMR) was recorded on Bruker Avance
400 (400 MHz) or Agilent Technologies DD2 (600 MHz). Chemical
shifts were quoted in parts per million (ppm) referenced to the singlet
at 7.24 ppm for chloroform-d. Data are given as: s (singlet), d (doublet),
t (triplet), q (quartet), dd (double of doublet), br (broad) or m
(multiplets), coupling constants (Hz) and integration. Carbon 13
nuclear magnetic resonance spectroscopy (13C NMR) was recorded on
Bruker Avance 400 (100 MHz) or Agilent Technologies DD2 (150
MHz) and was fully decoupled by broad-band decoupling. Chemical
shifts were reported in ppm with the centerline of the triplet for
chloroform-d set at 77.00 ppm. GC/MS analysis was performed on a
model 7890 Agilent GC with a 30 m 0.25 mm HP-5MS capillary
column and a model 5975 mass spectrometer. High-resolution mass
spectra (HRMS) were obtained using
a microTOF-II focus
spectrometer using electrospray ionization (ESI) method.
Experimental Procedure for the synthesis of Dha deriv.
Methyl -2-((tert-butoxycarbonyl)amino)acrylate (1a)
To a solution of N-(tert-butoxycarbonyl)-L-cysteine methyl ester
(407 mg, 1.73 mmol) in DMF was added K2CO3 (692 mg, 8.65 mmol)
and 1,4-diiodobutane (0.346 ml, 2.59 mmol) at room temperature. The
reaction was stirred for 4 h at room temperature. The resulting mixture
was diluted with Et2O and washed with water and brine. Combined
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The residue was purified by column chromatography on silica
gel (EtOAc : Hexane = 1 : 10) to give 1a (80%, 279 mg) as a colorless
oil. 1H NMR (400 MHz, CDCl3) δ 6.97 (s, 1H), 6.10 (s, 1H), 5.66 (d, J
= 1.5 Hz, 1H), 3.77 (s, 3H), 1.43 (s, 9H) ; 13C{1H} NMR (100 MHz,
CDCl3) δ 164.4, 152.5, 131.3, 105.1, 80.6, 52.8, 28.2 ; HRMS (ESI-
TOF) m/z:[M+Na]+ Calcd for C9H15NO4Na 224.0899;Found 224.0898
(6R,12R)-methyl12-benzyl-6-isobutyl-2,2-dimethyl-9-methylene
-4,7,10-trioxo-3-oxa-5,8,11-triazatride-can-13-oate (5a)
To a solution of 5a-1 (228 mg, 0.47 mmol) in CH2Cl2 (4.4 mL) was
added CuCl (14 mg, 0.14 mmol) and N-(3-dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride (101 mg, 0.52 mmol) at room
temperature. The reaction was stirred for 20 h at room temperature. The
resulting mixture was poured into water and extracted with CH2Cl2 at
three times. Combined organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc : Hexane = 1 : 3) to give 5a (72%,
1
157 mg) as a white foam. H NMR (400 MHz, CDCl3) δ 8.70 – 8.33
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(m, 1H), 7.39 – 7.15 (m, 3H), 7.12 – 6.93 (m, 2H), 6.72 – 6.52 (m, 1H),
was purified by column chromatography on silica gel to give 2b-2p or
6.42 (s, 1H), 5.17 (d, J = 1.9 Hz, 1H), 4.96 – 4.75 (m, 2H), 4.20 (s, 1H),
3.73 (d, J = 1.4 Hz, 3H), 3.13 (q, J = 8.1, 7.1 Hz, 2H), 1.82 – 1.62 (m,
2H), 1.59 –1.48 (m, 1H), 1.42 (d, J = 1.5 Hz, 9H), 0.93 (dt, J = 6.1, 2.0
Hz, 6H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 171.7, 171.5, 163.3,
155.5, 135.5, 133.7, 129.2, 128.7, 127.3, 102.4, 80.3, 60.4, 54.1, 53.6,
52.5, 41.5, 37.7, 28.3, 24.8, 23.0, 21.8, 21.0 ; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C24H35N3O6Na 484.2424; Found 484.2416.
4a, and 6a-6c.
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2
3
4
5
6
7
8
Methyl
2-((tert-butoxycarbonyl)amino)octanoate
(2b)16
Following the general experimental procedure, 2b was obtained (92%,
82 mg) as a colorless oil. H NMR (400 MHz, CDCl3) δ 4.99 (d, J =
8.5 Hz, 1H), 4.24 (td, J = 8.1, 5.2 Hz, 1H), 3.69 (s, 3H), 1.80 – 1.67 (m,
1H), 1.62 – 1.51 (m, 1H), 1.40 (s, 9H), 1.33 – 1.18 (m, 8H), 0.83 (t, J
= 6.0 Hz, 3H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 173.5, 155.3, 79.7,
53.4, 52.1, 32.7, 31.5, 28.8, 28.2, 25.2, 22.5, 14.0
1
Procedure of n-butylation of Dha 1a (Table 1).
Methyl
2-((tert-butoxycarbonyl)amino)-4-methylpentanoate
aTo a solution of 1a (0.15 mmol) in solvent (1/1, 0.1 M) was added
Zn (3.0 equiv.), nBuI (3.0 equiv.), and Cu catalyst (1.0 equiv.) at rt.
After stirring for 6 h at rt, reaction mixture was poured into H2O and
extracted with EtOAc. Combined organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The crude mixture was analyzed by
GC-MS and purified by column chromatography on silica gel
(EtOAc/Hx, 1/10) to give 2a (Rf = 0.4) and 2a' (Rf = 0.6) as a colorless
(2c) Following the general experimental procedure, 2c was obtained
(92%, 68 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.87 –
4.85 (d, J = 7.7 Hz, 1H), 4.32 – 4.29 (m, 1H), 3.71 (d, J = 0.7 Hz, 3H),
1.71 (dt, J = 13.0, 6.5 Hz, 1H), 1.67 – 1.57 (m, 1H), 1.57 – 1.50 (m,
1H), 1.45 (s, 9H), 0.92 (dd, J = 6.5, 3.6 Hz, 6H) ; 13C{1H} NMR (100
MHz, CDCl3) δ 174.0, 155.4, 79.8, 52.1 (d, J = 15.6 Hz), 41.9, 28.3,
24.8, 22.8, 21.9 ; HRMS (ESI-TOF) m/z: [M+Na]+:Calcd for
C12H23NO4Na 268.1525; Found 268.1526
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16
17
18
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20
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60
b
oil. Conversion rate and ratio of 2a:2a' in crude mixture by GC-MS
(See. SI). cIsolated yield of 2a. dSolvent screened; THF, EtOH, DMF,
e
Methyl 2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanoate
(2d) Following the general experimental procedure, 2d was obtained
(50%, 62 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.80 (d,
J = 8.5 Hz, 1H), 4.31 (td, J = 8.7, 3.5 Hz, 1H), 3.69 (s, 3H), 1.69 (dd, J
= 14.4, 3.6 Hz, 1H), 1.41 (s, 9H), 0.96 – 0.91 (m, 9H) ; 13C{1H} NMR
(100 MHz, CDCl3) δ 174.4, 155.1, 79.8, 52.2, 51.2, 46.3, 30.6, 29.5,
28.3 ; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C13H25NO4Na
282.1681 ; Found 282.1676.
dioxane. 1a (0.15 mmol), nBuI (10 equiv), Zn (10 equiv) in sat.
NH4Cl/dioxane (1/1, 0.04 M) at rt. After 1 h, nBuI (20 equiv), Zn (20
f
equiv) were added, the reaction mixture was stirred for overnight.
nBuI (1 equiv) and Zn (1 equiv). gnBuI (15 equiv) and Zn (15 equiv).
hCu(OTf)2 (0.1 equiv). Cu(OTf)2 (0.01 equiv). jnBuBr (3 equiv). k1a
i
(0.15 mmol), Zn (3 equiv), Cu(OTf)2 (0.1 equiv) and nBuBr (3 equiv)
in sat.NH4Cl/EtOH for 3h at rt. Additional Zn (1 equiv) and nBuBr (1
equiv) were added, and another hour later, additional Zn (1 equiv) and
nBuBr (1 equiv) were added, the reaction mixture was stirred for 2 h at
rt.
Methyl 2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoate
(2e) Following the general experimental procedure, 2e was obtained
(82%, 106 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.91
(d, J = 7.3 Hz, 1H), 4.27 (d, J = 5.1 Hz, 1H), 3.71 (s, 3H), 1.87 – 1.70
(m, 4H), 1.66 – 1.47 (m, 5H), 1.42 (d, J = 0.8 Hz, 9H), 1.16 – 1.02 (m,
2H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 173.74, 155.27, 79.65, 53.10,
52.02, 38.92, 36.49, 32.64, 32.42, 28.22, 25.06, 24.86 ; HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C14H25NO4Na 294.1681 ; Found
294.1664.
Methyl
2-((tert-butoxycarbonyl)amino)heptanoate
(2a)
Following the general experimental procedure, 2a was obtained (68 mg)
as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.96 (d, J = 7.5 Hz,
1H), 4.33 – 4.20 (m, 1H), 3.71 (s, 3H), 1.75 (t, J = 6.5 Hz, 1H), 1.58
(q, J = 7.7 Hz, 1H), 1.42 (d, J = 0.6 Hz, 9H), 1.37 – 1.20 (m, 6H), 0.91
– 0.80 (m, 3H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 173.6, 155.4, 79.8,
53.4, 52.2, 32.7, 31.3, 28.3, 24.9, 22.4, 13.9 ; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C13H25NO4Na 282.1681; Found 282.1701.
Methyl 2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoate
(2f) Following the general experimental procedure, 2f was obtained
(72%, 98 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.84 (d,
J = 7.4 Hz, 1H), 4.32 (d, J = 5.0 Hz, 1H), 3.70 (s, 3H), 1.79 (d, J = 12.7
Hz, 1H), 1.75 – 1.53 (m, 6H), 1.42 (s, 9H), 1.30 – 1.03 (m, 4H), 0.98 –
0.81 (m, 2H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 174.0, 155.4, 79.7,
52.0, 51.3, 40.3, 34.0, 33.5, 32.4, 28.2, 26.3, 26.1, 25.9 ; HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C15H27NO4Na 308.1838 ; Found
308.1828.
Methyl 2-((tert-butoxycarbonyl)amino)-2-butylheptanoate (2a')
Following the general experimental procedure, 2a' was obtained (23
mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.47 (s, 1H), 3.72
(s, 3H), 2.23 (s, 2H), 1.80 – 1.61 (m, 2H), 1.41 (s, 9H), 1.32 – 1.08 (m,
9H), 0.95 (s, 2H), 0.84 (td, J = 6.9, 3.8 Hz, 6H) ; 13C{1H} NMR (100
MHz, CDCl3) δ 174.9, 153.7, 78.9, 63.9, 52.5, 35.4, 35.2, 31.9, 31.5,
29.7, 28.4, 28.3, 26.3, 23.6, 22.5, 22.4, 13.9, 13.9 ; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C17H33NO4Na 338.2307; Found 338.2319.
Methyl 2-((tert-butoxycarbonyl)amino)-3-(2-methyltetrahydro-
2H-pyran-3-yl)propanoate (2g) Following the general experimental
procedure, 2g was obtained (92%, 131 mg) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ 4.94 (d, J = 73.4 Hz, 1H), 4.40 – 4.17 (m, 1H),
3.96 – 3.78 (m, 1H), 3.69 (s, 4H), 3.65 – 3.39 (m, 1H), 3.33 (tdd, J =
11.5, 5.4, 2.3 Hz, 1H), 3.05 (pd, J = 6.1, 2.9 Hz, 1H), 1.98 – 1.84 (m,
1H), 1.84 – 1.73 (m, 1H), 1.67 – 1.48 (m, 4H), 1.39 (s, 9H), 1.30 (s,
2H), 1.12 (dd, J = 6.1, 2.3 Hz, 3H), 1.06 (dd, J = 15.9, 6.6 Hz, 1H) ;
13C{1H} NMR (100 MHz, CDCl3) δ 173.8, 173.2, 155.4, 154.9, 130.6,
125.2, 79.8, 77.7, 75.1, 67.9, 67.8, 67.1, 62.2, 52.2, 52.1, 52.0, 51.6,
50.6, 39.2, 38.7, 35.6, 34.9, 34.4, 32.3, 29.5, 28.8, 28.5, 28.2, 28.2, 27.6,
26.1, 21.6, 19.6, 17.8 ; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C15H27NO5Na 324.1787; Found 324.1792.
Procedure for a large-scale synthesis of 2b
In a round bottom flask, to a solution of Dha 1a (0.302g, 1.5 mmol)
in sat.NH4Cl/EtOH (7.5 mL/7.5 mL) was added Cu(OTf)2 (55 mg, 0.15
mmol), Zn (294 mg, 4.5 mmol) and 1-bromopentane (564 μL, 4.5 mmol)
at room temperature. After stirring for 3 hours at room temperature, Zn
(98 mg, 1.5 mmol) and 1-bromopentane (188 μL, 1.5 mmol) were
added and 1 hour later, additional Zn (98 mg, 1.5 mmol) and 1-
bromopentane (188 μL, 1.5 mmol) were added, the reaction mixture
was stirred for 2 hours at room temperature. The resulting mixture was
poured into H2O and extracted with EtOAc. Combined organic layer
was dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (EtOAc : Hexane
= 1 : 5) to give 2b (91%, 0.373 g) as a colorless oil.
Methyl 2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoate
(2h) Following the general experimental procedure, 2h was obtained
(52%, 60 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.14 (d,
J = 8.4 Hz, 1H), 4.34 (dt, J = 8.3, 6.0 Hz, 1H), 3.70 (s, 3H), 1.62 (t, J =
6.5 Hz, 2H), 1.40 (s, 9H), 0.72 - 0.6 (m, 1H), 0.49 – 0.38 (m, 2H), 0.14
– 0.04 (m, 2H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 173.3, 155.2, 79.7,
53.8, 52.1, 37.4, 28.3, 6.9, 4.2, 4.0 ; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C12H21NO4Na 266.1368 ; Found 266.1359.
General Experimental Procedure of Alkylation of Dha
(Table 2 and Scheme 1-2).
Dha 1a or 3a or 5a (0.15 mmol-0.45 mmol) in sat.NH4Cl/EtOH (1/1,
1.5 mL) was added Cu(OTf)2 (0.1 equiv.), Zn (3.0 equiv.), and alkyl
bromide (3 equiv.) at room temperature. After 2–3 hours, additional Zn
(1.0 equiv.) and alkyl bromide (1.0 equiv.) were added, and 1 hour later,
additional Zn (1.0 equiv.) and alkyl bromide (1.0 equiv.) were added,
the reaction mixture was stirred for 2 h at room temperature. The
resulting mixture was extracted with EtOAc. Combined organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The residue
Methyl 3-((adamantan-1-yl)-2-((tert-butoxycarbonyl)amino)pro
panoate (2i) Following the general experimental procedure, 2i was
obtained (48%, 77 mg) as a white powder. 1H NMR (400 MHz, CDCl3)
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δ 4.78 (d, J = 8.9 Hz, 1H), 4.32 (td, J = 9.1, 3.4 Hz, 1H), 3.67 (s, 3H),
(m, 5H), 6.51 (d, J = 44.0 Hz, 1H), 5.38 (s, 1H), 5.09 (d, J = 3.8 Hz,
2H), 4.66 – 4.48 (m, 1H), 4.38 – 4.17 (m, 1H), 3.69 (d, J = 6.2 Hz, 3H),
1.62 (s, 2H), 1.56 – 1.43 (m, 1H), 1.36 (dd, J = 7.1, 1.7 Hz, 3H), 0.89
(dd, J = 5.6, 2.5 Hz, 6H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 173.2,
173.1, 172.0, 172.0, 155.9, 136.1, 128.5, 128.2, 128.0, 67.0, 52.3, 52.3,
50.8, 50.7, 41.4, 41.4, 24.9, 24.8, 22.8, 21.8.
1.95 – 1.88 (m, 3H), 1.70 – 1.53 (m, 7H), 1.52 – 1.47 (m, 6H), 1.40 (s,
9H), 1.26 (dd, J = 14.6, 9.1 Hz, 1H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 174.5, 155.0, 79.8, 52.1, 49.8, 47.1, 42.3, 36.8, 32.5, 28.5, 28.3 ;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C19H31NO4Na 360.2151 ;
Found 360.2171.
1
2
3
4
5
6
7
8
Methyl 2-((tert-butoxycarbonyl)amino)-6-hydroxyhexanoate (2j)
Following the general experimental procedure, 2j was obtained (56%,
35 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.01 (s, 1H),
4.29 (s, 1H), 3.72 (s, 3H), 3.62 (td, J = 6.3, 1.1 Hz, 2H), 1.79 (dd, J =
14.8, 5.8 Hz, 1H), 1.68 – 1.50 (m, 5H), 1.42 (s, 12H) ; 13C{1H} NMR
(100 MHz, CDCl3) δ 173.3, 155.4, 79.9, 62.4, 53.3, 52.2, 32.6, 32.1,
28.3, 21.6 ; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C12H23NO5Na
284.1474 ; Found 284.1457.
(S)-methyl 2-((R)-2-(((benzyloxy)carbonyl)amino)propanamido)
-2-isopropyl-4-methylpentanoate (4a') Following the general
experimental procedure, 4a' was obtained (9%, 15 mg, Rf = 0.6 in
EtOAc : Hexane = 1 : 3) as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.44 – 7.24 (m, 5H), 7.03 (s, 1H), 5.31 (d, J = 32.0 Hz, 1H), 5.08 (s,
2H), 4.22 (s, 1H), 3.74 (s, 3H), 2.78 – 2.43 (m, 2H), 1.76 (dd, J = 9.9,
8.2 Hz, 1H), 1.56 – 1.40 (m, 1H), 1.37 (dd, J = 7.0, 4.2 Hz, 3H), 0.94
(dd, J = 6.9, 1.4 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H), 0.77 (dd, J = 7.0, 3.7
Hz, 3H), 0.68 (d, J = 6.6 Hz, 3H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 174.4, 170.7, 170.6, 155.7, 136.3, 128.5, 128.5, 128.1, 128.1, 128.0,
128.0, 67.4, 67.3, 66.9, 52.2, 51.2, 40.9, 40.8, 34.3, 34.1, 24.8, 24.8,
24.2, 24.1, 21.7, 21.5, 19.0, 17.8, 17.5 ; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C21H32N2O5Na 415.2209 ; Found 415.2243.
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53
54
55
56
57
58
59
60
Methyl 2-((tert-butoxycarbonyl)amino)-5-cyanopentanoate (2k)
Following the general experimental procedure, 2k was obtained
(91%, 110 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.11
(d, J = 7.9 Hz, 1H), 4.27 (q, J = 6.8, 6.3 Hz, 1H), 3.70 (s, 3H), 2.41 –
2.30 (m, 2H), 1.99 – 1.87 (m, 1H), 1.76 – 1.63 (m, 3H), 1.38 (s, 9H) ;
13C{1H} NMR (100 MHz, CDCl3) δ 172.44, 155.27, 118.97, 80.04,
52.40, 31.73, 28.15, 21.49, 16.62 ; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C12H20N2O4Na 279.1321 ; Found 279.1316.
Methyl (2-((R)-2-((tert-butoxycarbonyl)amino)-4-methylpentan
amido)octanoyl)-D-phenylalaninate (6a) Following the general
experimental procedure, 6a was obtained (70%, 62 mg) as a white
foam.; Isomer A (Rf = 0.5 in EtOAc : Hexane = 1 : 3) ; 1H NMR (400
MHz, CDCl3) δ 7.30 – 7.21 (m, 3H), 7.13 – 7.00 (m, 2H), 6.53 (d, J =
7.9 Hz, 1H), 6.38 (d, J = 7.1 Hz, 1H), 4.81 (dt, J = 7.8, 5.9 Hz, 2H),
4.31 (td, J = 7.8, 5.7 Hz, 1H), 4.04 (s, 1H), 3.69 (s, 3H), 3.18 – 3.00 (m,
2H), 1.78 (s, 1H), 1.72 – 1.61 (m, 2H), 1.43 (d, J = 4.3 Hz, 9H), 1.23
(s, 6H), 1.02 – 0.87 (m, 6H), 0.83 (t, J = 6.7 Hz, 3H) ; 13C{1H} NMR
(100 MHz, CDCl3) δ 172.4, 171.5, 171.0, 153.8, 135.7, 129.2, 128.6,
127.2, 78.2, 53.2, 52.3, 37.8, 32.3, 31.6, 28.9, 28.3, 25.2, 24.7, 23.0,
22.5, 14.0. ; Isomer B (Rf = 0.45 in EtOAc : Hexane = 1 : 3) ; 1H NMR
(400 MHz, CDCl3) δ 7.31 – 7.21 (m, 3H), 7.16 – 7.05 (m, 2H), 6.74 (s,
1H), 6.65 (d, J = 8.2 Hz, 1H), 4.88 (d, J = 7.5 Hz, 1H), 4.80 (td, J = 7.4,
5.6 Hz, 1H), 4.37 (td, J = 7.9, 5.4 Hz, 1H), 4.06 (s, 1H), 3.68 (s, 3H),
3.21 – 2.93 (m, 2H), 1.74 (s, 1H), 1.61 (s, 2H), 1.48 (s, 1H), 1.41 (s,
9H), 1.20 (s, 6H), 0.90 (dd, J = 6.3, 3.7 Hz, 6H), 0.84 (t, J = 6.9 Hz,
3H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 172.6, 171.8, 171.2, 155.6,
135.9, 129.2, 128.6, 127.1, 80.2, 53.3, 52.8, 52.3, 37.9, 32.1, 31.5, 28.9,
28.3, 25.1, 24.8, 22.9, 22.5, 14.0. ; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C29H47N3O6Na 556.3363 ; Found 556.3389.
Dimethyl 2-((tert-butoxycarbonyl)amino)hexanedioate (2l)
Following the general experimental procedure, 2l was obtained (59%,
1
45 mg) as a colorless oil. H NMR (600 MHz, CDCl3) δ 5.04 (d, J =
7.9 Hz, 1H), 4.27 (d, J = 7.6 Hz, 1H), 3.71 (s, 3H), 3.63 (s, 3H), 2.31
(td, J = 7.3, 4.7 Hz, 2H), 1.84 – 1.77 (m, 1H), 1.70 – 1.58 (m, 3H), 1.41
(s, 9H) ; 13C{1H} NMR (150 MHz, CDCl3) δ 173.4, 173.0, 155.3, 79.9,
53.1, 52.3, 51.6, 33.3, 32.0, 28.3, 20.7 ; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C13H23NO6Na 312.1423 ; Found 312.1393.
Methyl 2-((tert-butoxycarbonyl)amino)-6-(5-(dimethylamino)-
N-methylnaphthalene-1-sulfonamido)-hexanoate (2m)17 Following
the general experimental procedure, 2m was obtained (51%, 24 mg) as
a white solid. 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.5 Hz, 1H),
8.34 (d, J = 8.7 Hz, 1H), 8.12 (dd, J = 7.3, 1.3 Hz, 1H), 7.56 – 7.47 (m,
2H), 7.20 – 7.14 (m, 1H), 4.97 (d, J = 8.5 Hz, 1H), 4.22 (d, J = 7.2 Hz,
1H), 3.70 (s, 3H), 3.23 – 3.10 (m, 2H), 2.88 (s, 6H), 2.78 (s, 3H), 1.80
– 1.67 (mf, 1H), 1.63 – 1.47 (m, 3H), 1.42 (s, 9H), 1.37 – 1.18 (m, 3H)
;
13C{1H} NMR (100 MHz, CDCl3) δ 193.2, 177.6, 173.1, 155.3, 134.2,
130.2, 130.2, 129.7, 127.9, 123.2, 119.9, 115.3, 79.9, 53.1, 52.3, 49.2,
45.4, 34.0, 32.2, 28.3, 27.1, 22.2 ; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C25H37N3O6SNa 530.2301 ; Found 530.2319.
Methyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate (2n)18
Methyl (tert-butoxycarbonyl)-D-leucylleucyl-D-phenylalaninate
(6b) Following the general experimental procedure, 6b was obtained
(79%, 73 mg) as a white foam ; Isomer A (Rf = 0.5 in EtOAc : Hexane
= 1 : 3) 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.15 (m, 3H), 7.17 – 7.02
(m, 2H), 6.74 (s, 1H), 6.55 (d, J = 8.3 Hz, 1H), 4.96 – 4.82 (m, 1H),
4.79 (td, J = 7.5, 5.8 Hz, 1H), 4.49 – 4.29 (m, 1H), 4.05 (s, 1H), 3.67
(s, 3H), 3.24 – 2.89 (m, 2H), 1.60 (d, J = 10.3 Hz, 4H), 1.41 (s, 9H),
Following the general experimental procedure, 2n was obtained (30%,
1
22 mg) as a colorless oil. H NMR (600 MHz, CDCl3) δ 7.29 – 7.23
(m, 2H), 7.20 – 7.13 (m, 3H), 5. 09 – 4.99 (m, 1H), 4.34 (d, J = 7.2 Hz,
1H), 3.70 (s, 3H), 2.70 – 2.60 (m, 2H), 2.17 – 2.08 (m, 1H), 1.97 – 1.87
(m, 1H), 1.44 (s, 9H) ; 13C{1H} NMR (150 MHz, CDCl3) δ 173.1, 155.3,
140.8, 128.5, 128.4, 126.1, 79.9, 53.2, 52.3, 34.4, 31.6, 28.3
1.28 (d, J = 22.5 Hz, 2H), 0.87 (ddd, J = 23.4, 6.3, 3.1 Hz, 12H) ; 13C{1H}
NMR (100 MHz, CDCl3) δ 172.5, 171.6, 171.3, 155.8, 135.8, 135.7,
129.2, 128.6, 127.1, 125.5, 80.3, 53.2, 52.3, 51.6, 40.9, 40.6, 37.8, 34.2,
30.3, 30.3, 29.7, 28.3, 28.2, 24.7, 24.6, 22.9 ; Isomer B (Rf = 0.45 in
EtOAc : Hexane = 1 : 3) 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.16 (m,
4H), 7.17 – 6.99 (m, 2H), 6.47 (dd, J = 13.6, 7.8 Hz, 2H), 4.79 (dt, J =
7.8, 6.0 Hz, 2H), 4.37 (ddd, J = 9.2, 8.0, 5.2 Hz, 1H), 4.03 (d, J = 7.2
Hz, 1H), 3.68 (s, 3H), 3.23 – 2.94 (m, 2H), 1.75 – 1.52 (m, 4H), 1.42
(s, 9H), 1.23 (s, 2H), 1.01 – 0.72 (m, 12H) ; 13C{1H} NMR (100 MHz,
CDCl3) δ 172.7, 171.7, 171.5, 155.6, 135.9, 135.8, 129.2, 128.5, 127.1,
125.5, 80.2, 53.3, 52.2, 51.3, 41.0, 40.7, 37.9, 34.2, 30.3, 29.7, 28.2,
24.8, 24.6, 22.9, 22.7, 21.8.; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C27H43N3O6Na 528.3050 ; Found 528.3064.
Methyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (2o)19
Following the general experimental procedure, 2o was obtained (71%,
1
26 mg) as a colorless oil. H NMR (400 MHz, CDCl3) δ 5.18 – 5.07
(m, 1H), 4.20 (td, J = 8.7, 5.2 Hz, 1H), 3.67 (s, 3H), 2.60 – 2.37 (m,
2H), 2.09 (s, 3H), 2.06 – 1.96 (m, 1H), 1.81 (dtd, J = 14.2, 8.2, 6.4 Hz,
1H), 1.37 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 207.3, 172.7,
155.4, 79.8, 52.8, 52.3, 39.2, 29.9, 28.2, 26.4
Methyl 2-((tert-butoxycarbonyl)amino)hept-6-enoate (2p)20
Following the general experimental procedure, 2p was obtained (51%,
36 mg) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.72 (ddt, J =
16.9, 10.2, 6.6 Hz, 1H), 5.04 – 4.87 (m, 3H), 4.25 (td, J = 8.2, 5.2 Hz,
1H), 3.69 (s, 3H), 2.06 – 1.99 (m, 2H), 1.87 – 1.69 (m, 2H), 1.64 – 1.53
(m, 1H), 1.48 – 1.42 (m, 1H), 1.40 (s, 9H) ; 13C{1H} NMR (100 MHz,
CDCl3) δ 173.4, 155.3, 137.9, 115.0, 79.8, 53.3, 52.2, 33.1, 32.2, 28.3,
24.5
Methyl (2-((R)-2-((tert-butoxycarbonyl)amino)-4-methylpentan
amido)-4,4-dimethylpentanoyl)-D-phenyl-alaninate
(6c)
Following the general experimental procedure, 6c was obtained (65%,
68 mg) as a white foam. Isomer A + isomer B (Rf = 0.45-0.48 in EtOAc
: Hexane = 1 : 3) 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.16 (m, 4H),
7.13 – 7.03 (m, 3H), 6.90 – 6.67 (m, 1H), 6.59 (dd, J = 11.6, 8.0 Hz,
1H), 4.96 – 4.81 (m, 1H), 4.79 – 4.66 (m, 1H), 4.45 – 4.30 (m, 1H),
4.05 (q, J = 10.0, 8.7 Hz, 1H), 3.64 (s, 3H), 3.06 (dqt, J = 35.6, 14.0,
7.6 Hz, 3H), 1.81 (ddd, J = 27.9, 14.5, 3.9 Hz, 1H), 1.61 (s, 3H), 1.39
Methyl 2-((R)-2-(((benzyloxy)carbonyl)amino)propanamido)-4-
methylpentanoate (4a)21 Following the general experimental
procedure, 4a was obtained (69%, 114 mg, Rf = 0.4 in EtOAc : Hexane
1
= 1 : 3) as a colorless oil. H NMR (400 MHz, CDCl3) δ 7.39 – 7.25
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
(d, J = 2.8 Hz, 9H), 1.33 (s, 2H), 0.90 – 0.81 (m, 15H). ; 13C{1H} NMR
AUTHOR INFORMATION
(100 MHz, CDCl3) δ 172.5, 172.2, 172.0, 171.8, 171.5, 163.2, 155.6,
135.9, 135.8, 135.7, 135.4, 129.2, 129.2, 128.7, 128.5, 127.0, 125.5,
80.2, 53.4, 53.3, 52.2, 50.6, 50.4, 45.4, 44.8, 40.7, 37.8, 37.6, 34.2, 30.3,
29.6, 28.2, 24.7, 23.0, 21.7. ; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C28H45N3O6Na 542.3206 ; Found 542.3224.
1
2
3
4
Corresponding Author
E-mail: leehy@kaist.ac.kr
Notes
5
6
7
8
The authors declare no competing financial interest.
General Experimental Procedure of Arylation of Dha
(Scheme 3).
Acknowledgment
The support of the Agency for Defense Development is
gratefully acknowledged.
To a solution of Dha 1a or 1b (0.15 mmol) in sat.NH4Cl/H2O (1/1,
1.5 mL) was added Cu(OTf)2 (0.1 equiv.), Zn (3.0 equiv.), and aryl
iodide (3 equiv.) at room temperature. After 2–3 hours, additional Zn
(1.0 equiv.) and aryl iodide (1.0 equiv.) were added, and 1 hour later,
additional Zn (1.0 equiv.) and aryl iodide (1.0 equiv.) were added, the
reaction mixture was stirred for overnight. The resulting mixture was
extracted with EtOAc. Combined organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel to provide 7a-7e as a powder.
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Reference
1. (a) Walsh, C. T.; Garneau-Tsodikova, S.; Gatto, G. J. Protein
Posttranslational Modifications: The Chemistry of Proteome
Diversifications. Angew. Chem. Int. Ed. 2005, 44, 7342-7372. (b)
Spicer, C. D.; Davis, B. G. Selective Chemical Protein Modification.
Nat. Commun. 2014, 5, 4740.
Methyl (tert-butoxycarbonyl)phenylalaninate (7a)22 Following
the general experimental procedure, 7a was obtained (70%, 95 mg) as
2. (a) Guo, J.; Wang, J.; Lee, J. S.; Schultz, P. G. Site‐Specific
Incorporation of Methyl‐ and Acetyl‐Lysine Analogues into
Recombinant Proteins. Angew. Chem. Int. Ed. 2008, 47, 6399-6401. (b)
Chalker, J. M.; Lercher, L.; Rose, N. R.; Schofield, C. J.; Davis, B. G.
Conversion of Cysteine into Dehydroalanine Enables Access to
Synthetic Histones Bearing Diverse Post‐Translational Modifications.
Angew. Chem. Int. Ed. 2012, 51, 1835-1839. (c) Timms, N.; Windle,
C. L.; Polyakova, A.; Ault, J. R.; Trinh, C. H.; Pearson, A. R.; Nelson,
A.; Berry, A. Structural Insights into the Recovery of Aldolase Activity
in N‐Acetylneuraminic Acid Lyase by Replacement of the
Catalytically Active Lysine with γ‐Thialysine by Using a Chemical
Mutagenesis Strategy. Chembiochem, 2013, 14, 474-481. (d) Lin, Y.
A.; Boutureira, O.; Lercher, L.; Bhushan, B.; Paton, R. S.; Davis, B. G.
Rapid Cross-Metathesis for Reversible Protein Modifications via
Chemical Access to Se-Allyl-selenocysteine in Proteins. J. Am. Chem.
Soc. 2013, 135, 12156-12159. (e) Key, H. M.; Miller, S. J. Site- and
Stereoselective Chemical Editing of Thiostrepton by Rh-Catalyzed
Conjugate Arylation: New Analogues and Collateral Enantioselective
Synthesis of Amino Acids. J. Am. Chem. Soc. 2017, 139, 15460-15466.
(f) Bogart, J. W.; Bowers, A. A. Dehydroamino acids: Chemical Multi-
tools for Late-stage Diversification. Org. Biomol. Chem. 2019/
DOI:10.1039/C8OB03155J.
3. (a) Sibi, M. P.; Manyem, S. Enantioselective Conjugate Additions.
Tetrahedron, 2000, 56, 8033-8061. (b) Hayashi, T.; Yamasaki, K.
Rhodium-Catalyzed Asymmetric 1,4-Addition and Its Related
Asymmetric Reactions. Chem. Rev. 2003, 103, 2829-2844. (c) Tamio,
H. Rhodium-Catalyzed Asymmetric Addition of Organo-Boron and -
Titanium Reagents to Electron-Deficient Olefins. Bull. Chem. Soc. Jpn.
2004, 77, 13-21. (d) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle,
M. Recent Advances in Metal-Catalyzed Asymmetric Conjugate
Additions. Synthesis, 2007, 2007, 1279-1300. (e) Alexakis, A.;
Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Enantioselective
Copper-Catalyzed Conjugate Addition and Allylic Substitution
Reactions. Chem. Rev. 2008, 108, 2796-2823. (f) Harutyunyan, S. R.;
den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Catalytic
Asymmetric Conjugate Addition and Allylic Alkylation with Grignard
Reagents. Chem. Rev. 2008, 108, 2824-2852. (g) Jerphagnon, T.;
Pizzuti, M. G.; Minnaard, A. J.; Feringa, B. L. Recent advances in
enantioselective copper-catalyzed 1,4-addition. Chem. Soc. Rev. 2009,
38, 1039-1075. (h) Hawner, C.; Alexakis, A. Metal-catalyzed
Asymmetric Conjugate Addition Reaction: Formation of Quaternary
Stereocenters. Chem. Commun. 2010, 46, 7295-7306. (i) Tian, P.;
Dong, H.-Q.; Lin, G.-Q. Rhodium-Catalyzed Asymmetric Arylation.
ACS Catalysis, 2012, 2, 95-119. (j) Hayashi, M.; Matsubara, R. Recent
Topics on Catalytic Asymmetric 1,4-addition. Tetrahedron Lett. 2017,
58, 1793-1805.
1
a white powder. H NMR (400 MHz, CDCl3) δ 7.39 – 7.19 (m, 3H),
7.14 (d, J = 7.3 Hz, 2H), 4.99 (s, 1H), 4.61 (s, 1H), 3.73 (s, 3H), 3.10
(dd, J = 15.4, 5.9 Hz, 2H), 1.43 (s, 9H) ; 13C{1H} NMR (100 MHz,
CDCl3) δ 172.3, 155.0, 136.0, 129.3, 128.5, 127.0, 79.9, 54.4, 52.2,
38.4, 28.3.
Methyl 3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)prop
anoate (7b)22 Following the general experimental procedure, 7b was
1
obtained (14%, 19 mg) as a yellow powder. H NMR (400 MHz,
CDCl3) δ 6.87 (d, J = 8.3 Hz, 2H), 6.59 (d, J = 8.3 Hz, 2H), 4.93 (d, J
= 7.7 Hz, 1H), 4.48 (dt, J = 8.5, 6.0 Hz, 1H), 3.68 (s, 3H), 3.00 – 2.87
(m, 2H), 1.39 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3) δ 172.5, 155.1,
145.2, 130.1, 125.6, 115.3, 79.8, 54.5, 52.1, 37.4, 28.3.
Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)
propanoate (7c)22 Following the general experimental procedure, 7c
1
was obtained (13%, 19 mg) as a white powder. H NMR (400 MHz,
CDCl3) δ 7.06 – 6.98 (m, 2H), 6.84 – 6.78 (m, 2H), 4.94 (d, J = 8.2 Hz,
1H), 4.52 (q, J = 6.6 Hz, 1H ), 3.76 (s, 3H), 3.69 (s, 3H), 3.02 (td, J =
11.8, 9.7, 5.8 Hz, 2H), 1.40 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3)
δ 172.4, 158.7, 153.5, 130.3, 127.9, 114.0, 79.9, 55.2, 54.5, 52.2, 37.5,
28.3.
Tert-butyl
2-(tert-butoxycarbonylamino)-3-(4-
methoxyphenyl)
propanoate (7d)23 Following the general experimental procedure,
7d was obtained (32%, 47 mg) as a white powder. 1H NMR (400 MHz,
CDCl3) δ 7.09 – 7.03 (m, 2H), 6.83 – 6.77 (m, 2H), 4.94 (d, J = 8.3 Hz,
1H), 4.38 (q, J = 6.3 Hz, 1H), 3.76 (s, 3H), 2.97 (dd, J = 6.1, 2.7 Hz,
2H), 1.40 (s, 9H), 1.39 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3) δ
171.0, 158.5, 155.1, 130.5, 128.4, 113.8, 81.9, 79.6, 55.2, 55.0, 37.6,
28.3, 28.0
Tert-butyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)
propanoate (7e) Following the general experimental procedure, 7e
1
was obtained (30%, 40 mg) as a white powder. H NMR (400 MHz,
CDCl3) δ 7.01 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 5.05 (s,
1H), 4.97 (d, J = 8.3 Hz, 1H), 4.38 (q, J = 6.5 Hz, 1H), 3.01 – 2.87 (m,
2H), 1.40 (s, 9H), 1.39 (s, 9H) ; 13C{1H} NMR (100 MHz, CDCl3) δ
171.1, 155.2, 154.6, 130.7, 128.4, 115.2, 82.0, 79.7, 55.0, 37.7, 28.3,
28.0, 27.7 ; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C18H27NO5Na
360.1787; Found 360.1789.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Copies of GC, MS spectra in Table 1 and 1H-
NMR, 13C-NMR spectra for all compounds
4. (a) Petrier, C.; Dupuy, C.; Luche, J. L. Conjugate Additions to α,β-
Unsaturated Carbonyl Compounds in Aqueous Media, Tetrahedron
Lett. 1986, 27, 3149-3152. (b) Luche, J. L.; Allavena, C. Ultrasound in
Organic Synthesis 16. Optimisation of the Conjugate Additions to α,β-
Unsaturated Carbonyl Compounds in Aqueous Media. Tetrahedron
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Page 8 of 8
Lett. 1988, 29, 5369-5372. (c) Luche, J. L.; Allavena, C.; Petrier, C.;
(11 equiv.) and Zn (20 equiv.) were added, the reaction mixture was
Dupuy, C. Ultrasound in Organic Synthesis 17. Mechanistic Aspects of
the Conjugate Additions to α-enones in Aqueous Media. Tetrahedron
Lett. 1988, 29, 5373-5374.
stirred for 17 h at rt.
1
2
3
4
5
6
7
8
13. Shen, F.; Zhang, Z. -P.; Li, J.-B.; Lin, Y.; Liu, L. Hydrazine-
Sensitive Thiol Protecting Group for Peptide and Protein Chemistry.
Org. Lett. 2011, 13, 568-571.
14. Wang, H.; Zhang, J.; Xian, M. Facile Formation of
Dehydroalanine From S-Nitrosocysteines. J. Am. Chem. Soc. 2009, 131,
13238-13239.
5. (a) Cornella, I.; Pérez Sestelo, J.; Mouriño, A.; Sarandeses, L. A.
Synthesis of New 18-Substituted Analogues of Calcitriol Using a
Photochemical Remote Functionalization. J. Org. Chem. 2002, 67,
4707-4714. (b) Pérez Sestelo, J.; Cornella, I.; de Uña, O.; Mouriño, A.;
Sarandeses, L. A. Stereoselective Convergent Synthesis of
24,25‐Dihydroxyvitamin D3 Metabolites: A Practical Approach.
Chem. Eur. J. 2002, 8, 2747-2752. (c) Sestelo, J. P.; de Uña, O.;
Mouriño, A.; Sarandeses, L. A. Synthesis of the First 24-Aminovitamin
D3 Derivatives by Diastereoselective Conjugate Addition to a Chiral
Methyleneoxazolidinone in Aqueous Media. Synlett, 2002, 2002, 719-
722. (d) Suárez, R. M.; Pérez Sestelo, J.; Sarandeses, L. A. Practical
and Efficient Enantioselective Synthesis of α-amino acids in Aqueous
Media. Org. Biomol. Chem. 2004, 2, 3584-3587.
6. Huang, T.; Keh, C. C. K.; Li, C.-J. Synthesis of α-amino acid
Derivatives and Amines via Activation of Simple Alkyl halides by Zinc
in Water. Chem. Commun. 2002, 2440-2441.
7. Lipshutz, B. H.; Huang, S.; Leong, W. W. Y.; Zhong, G.; Isley, N.
A. C–C Bond Formation via Copper-Catalyzed Conjugate Addition
Reactions to Enones in Water at Room Temperature. J. Am. Chem. Soc.
2012, 134, 19985-19988.
15. Falck, J. R.; Sangras, B.; Capdevila, J. H. Preparation of N-tBoc
L-glutathione dimethyl and di-tert-butyl esters : Versatile Synthetic
Building Blocks. Bioorg. Med. Chem. 2007, 15, 1062-1066.
16. Shimokawa, K.; Iwase, Y.; Miwa, R.; Yamada, K.; Uemura, D.
Whole Structure−Activity Relationships of the Fat-Accumulation
Inhibitor (−)-Ternatin: Recognition of the Importance of Each Amino
Acid Residue. J. Med. Chem. 2008, 51, 5912-5914.
17. Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F.
Palladium-Catalyzed Arylation of Ethyl Cyanoacetate. Fluorescence
Resonance Energy Transfer as a Tool for Reaction Discovery. J. Am.
Chem. Soc. 2001, 123, 4641-4642.
18. López-Serrano, P.; Wegman, M. A.; Van Rantwijk, F.; Sheldon,
R. A. Enantioselective Enzyme Catalysed Ammoniolysis of Amino
Acid Derivatives. Effect of Temperature. Tetrahedron: Asymmetry,
2001, 12, 235-240.
19. Prause, F.; Kaldun, J.; Arensmeyer, B.; Wennemann, B.;
Fröhlich, B.; Scharnagel, D.; Breuning, M. Flexible and Modular
Syntheses of Enantiopure 5-cis-Substituted Prolinamines from l-
Pyroglutamic Acid. Synthesis, 2015, 47, 575-586.
20. Atmuri, N. D. P.; Lubell, W. D. Insight into Transannular
Cyclization Reactions To Synthesize Azabicyclo[X.Y.Z]alkanone
Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic
Dipeptide Lactam. J. Org. Chem. 2015, 80, 4904-4918.
21. Nuijens, T.; Cusan, C.; Van Dooren, T. J. G. M.; Moody, H. M.;
Merkx, R.; Kruijtzer, J. A. W.; Rijkers, D. T. S.; Liskamp, R. M. J.;
Quaedflieg, P. J. L. M. Fully Enzymatic Peptide Synthesis using
C‐Terminal tert‐Butyl Ester Interconversion. Adv. Synth. Catal. 2010,
352, 2399-2404.
22. Ross, A. J.; Lang, H. L.; Jackson, R. F. W. Much Improved
Conditions for the Negishi Cross-Coupling of Iodoalanine Derived
Zinc Reagents with Aryl Halides. J. Org. Chem. 2010, 75, 245-248.
23. Lu, X.; Yi, J.; Zhang, Z.-Q.; Dai, J.-J.; Liu, J.-H.; Xiao, B.; Fu,
Y.; Liu, L. Expedient Synthesis of Chiral α‐Amino Acids through
Nickel‐Catalyzed Reductive Cross‐Coupling. Chem. Eur. J. 2014, 20,
15339-15343.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8. Bonauer, C.; Walenzyk, T.; König, B. α,β-Dehydroamino Acids.
Synthesis, 2006, 2006, 1-20.
9. Wright, T. H.; Bower, B. J.; Chalker, J. M.; Bernardes, G. J. L.;
Wiewiora, R.; Ng, W.-L.; Raj, R.; Faulkner, S.; Vallée, M. R. J.;
Phanumartwiwath, A.; Coleman, O. D.; Thézénas, M.-L.; Khan, M.;
Galan, S. R. G.; Lercher, L.; Schombs, M. W.; Gerstberger, S.; Palm-
Espling, M. E.; Baldwin, A. J.; Kessler, B. M.; Claridge, T. D. W.;
Mohammed, S.; Davis, B. G. Posttranslational Mutagenesis: A
Chemical Strategy for Exploring Protein Side-chain Diversity. Science,
2016, 354, 597-608.
10. Yang, A.; Ha, S.; Ahn, J.; Kim, R.; Kim, S.; Lee, Y.; Kim, J.;
Söll, D.; Lee, H.-Y.; Park, H.-S. A Chemical Biology Route to Site-
specific Authentic Protein Modifications. Science, 2016, 354, 623-626.
11. Mineyama, K.; Maekawa, H.; Kohsaka, A.; Yamamoto, Y.;
Nishiguchi, I. Zn-promoted Regio- and Sequence-selective One-pot
Joining Reactions of Three Components: Vinylpyridines, Alkyl
iodides, and Carbonyl compounds (or nitriles). Tetrahedron, 2009, 65,
7706-7711.
12. Davis protocol: The reaction was carried out with 3a
(0.48mmol), isopropyl iodide (10 equiv.) and Zn (11 equiv.) in sat.
NH4Cl/dioxane (1/1, v/v) at rt. After 1 hour, additional isopropyl iodide
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