Cu(OTf)2 promoted 1,4-addition of alkylbromides to dehydroalanine

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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 Downloaded from http://pubs.acs.org on March 21, 2019

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The Journal of Organic Chemistry

Cu(OTf)2 promoted 1,4-addition of alkylbromides to dehydroalanine Jung-Ah Shin†‡, Jiheon Kim†, Hongsoo Lee†, Sura Ha†, Hee-Yoon Lee*† †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

O

R1

N H

H N O

RBr Zn, Cu(OTf)2 R2

R

O

R1

sat.NH4Cl-EtOH, rt, 6 h

H N

N H

R2 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. 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

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 CbzHN

I N H

CO2Me

, Zn

O CbzHN

sat.NH4Cl-dioxane, rt

O N H

CO2Me

CbzHN

N H

CO2Me

1.7 : 1.0

n

BocHN

CO2Me

BuI, Zn, Cu(OAc)2

sat.NH4Cl-EtOH, rt

BocHN BocHN

CO2Me

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

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mol% of Cu(OTf)2 was used without sacrificing the conversion of 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).

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Scheme 1. Results of Zn/Cu-mediated alkylation of Dha 1a using alkyl halides in aqueous mediaa

BocHN

CO2Me

1a

Entry

R

R X Zn, Cu(OTf)2

BocHN

sat.NH4Cl/EtOH (1/1) rt, 6 h

R-X

1

Product Br

CO2Me 2b- 2p

Yield(%)b

2b

92

2c

92

2d

50

2e

82

2 Br

3 Br

4

Table 1. Optimization of the reaction conditionsa

Br

5

Br

2f

72

6

Br

2g

92

2h

52

2i

48

2j

56

2k

91

2l

59

2m

51

n

BocHN

1a

CO2Me

BuI, Zn Cu catalyst Solvent, rt, 6 h

BocHN

O

BocHN

CO2Me

2a

Entr y 1

Solvent (1/1)

Cu

H2

7

2a'

Conv.

Catalyst O/solventd

CO2Me

8

2a:2a'b

Br

(2a yield)c

9

-

0

0

10 11

2

sat.NH4Cl/EtOH

-

11

100:0(4)

3

sat.NH4Cl/Dioxane

-

13

94:6

4e

sat.NH4Cl/Dioxane

-

14

80:20

5

H2O/EtOH

CuI

19

100:0(12)

6

H2O/EtOH

CuCl2

4

100:0

13

7

H2O/EtOH

Cu(OTf)2

41

98:2

14

8

H2O/EtOH

Cu(acac)2

15

100:0

9

H2O/EtOH

Cu(OAc)2

37

100:0

10

sat.NH4Cl/EtOH

CuI

55

100:0(40)

11

sat.NH4Cl/EtOH

CuCl2

83

90:10(66)

12

sat.NH4Cl/EtOH

Cu(acac)2

78

91:9(56)

13

sat.NH4Cl/EtOH

Cu(OAc)2

98

84:16(83)

14

sat.NH4Cl/EtOH

Cu(OTf)2

100

88:12(90)

15f

sat.NH4Cl/EtOH

Cu(OTf)2

79

95:5

16g

sat.NH4Cl/EtOH

Cu(OTf)2

100

51:49

17h

sat.NH4Cl/EtOH

Cu(OTf)2

100

87:13(90)

18i

sat.NH4Cl/EtOH

Cu(OTf)2

93

93:7(82)

19j

sat.NH4Cl/EtOH

Cu(OTf)2

53

100:0

sat.NH4Cl/EtOH

Cu(OTf)2

95

100:0

20k a-kSee

Experimental Section.

With the optimized conditions in hand, various alkyl bromides were reacted with 1a to provide the corresponding unnatural αamino 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

Br

Br

HO

Br

NC O

Br

MeO

12

O S N O

Br

N

Ph

2n

Cl

O BocHN

15


71

CO2Me

2o

51

I BocHN

aSee

30

MeO OMe Br

bIsolated

2p

CO2Me

yield.

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.


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The Journal of Organic Chemistry Table 2. Comparison of an alkylation with dipeptide 3a X

O CbzHN

N H

CO2Me

Zn, Cu(OTf)2

O CbzHN

sat.NH4Cl/solvent, rt, 6h

3a

O

O N H

CO2Me

CbzHN

4a

Scheme 2. Substrate scopes of tripeptide 5aa

N H

CO2Me

BocHN

H N

N H

O

O

RBr, Zn, Cu(OTf)2

BocHN

aq.NH4Cl/EtOH

5a

4a'

112 212 3a 4a aSee

R-X

I

I

I

Br

Cu(OTf)2

sat.NH4Cl

Yield

(equiv)

/solvent

(%, 4a:4a')b

-

Dioxane

48 : 28

0.1

Dioxane

58 : 15

0.1

EtOH

61 : 9

0.1

EtOH

69 : 0

Entry

R-Br

Product O

1

Br

BocHN

H N

N H

H N

O OMe

O

Yield (%)b O OMe

70

O

6a

2

O Br

BocHN

H N

N H

Experimental Section. bIsolated yield of 4a and 4a'.

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. 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. 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.

N H

6a - 6c

rt, 6 h

Entry

R

O OMe

O OMe

79

O

6b

3

O Br

BocHN

H N

N H

O OMe

65

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 αamino 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. 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.



Scheme 3. Zn mediated arylation of Dha derivativesa Ar

1a

Ar-X

Product

Yield(%)b

Br

nrc BocHN

2

CO2R

7a - 7e

rt, overnight

1a (R=Me), 1b (R= Bu)

1

BocHN

sat.NH4Cl/EtOH (1/1)

t

Dha

Ar

Zn, Cu(OTf)2

BocHN CO2R 1a - 1b

Entry

I

I

1a

7a

CO2Me

7a

70

1a H2N

4

14

I BocHN

CO2Me 7b

I

1a

13

O

O BocHN

7c

5

CO2Me

I

1b

O

32

OH

30

O BocHN

7d

6

CO2tBu

I

1b HO

BocHN

CO2tBu

7e

aSee


bIsolated

yield.

cnr

2-((tert-butoxycarbonyl)amino)acrylate (1b)

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 (R)-methyl 2-(2-(((benzyloxy)carbonyl)amino)propanamido)acr ylate (3a)14

NH2

3

tButyl-

Page 4 of 8

: no reaction.

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 (ESITOF) m/z:[M+Na]+ Calcd for C9H15NO4Na 224.0899;Found 224.0898

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. (6R,12R)-methyl 12-benzyl-9-(hydroxymethyl)-6-isobutyl-2,2dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triaza-tridecan-13-oate (5a-1, Scheme S1)15 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. (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%, 157 mg) as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.70 – 8.33


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The Journal of Organic Chemistry (m, 1H), 7.39 – 7.15 (m, 3H), 7.12 – 6.93 (m, 2H), 6.72 – 6.52 (m, 1H), 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.

Procedure of n-butylation of Dha 1a (Table 1). 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 oil. bConversion rate and ratio of 2a:2a' in crude mixture by GC-MS (See. SI). cIsolated yield of 2a. dSolvent screened; THF, EtOH, DMF, dioxane. e1a (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 equiv) were added, the reaction mixture was stirred for overnight. f nBuI (1 equiv) and Zn (1 equiv). gnBuI (15 equiv) and Zn (15 equiv). hCu(OTf) (0.1 equiv). iCu(OTf) (0.01 equiv). jnBuBr (3 equiv). k1a 2 2 (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)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)-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.

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 1bromopentane (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.

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

was purified by column chromatography on silica gel to give 2b-2p or 4a, and 6a-6c. Methyl 2-((tert-butoxycarbonyl)amino)octanoate (2b)16 Following the general experimental procedure, 2b was obtained (92%, 82 mg) as a colorless oil. 1H 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 Methyl 2-((tert-butoxycarbonyl)amino)-4-methylpentanoate (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 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. 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 (ESITOF) m/z: [M+Na]+ Calcd for C14H25NO4Na 294.1681 ; Found 294.1664. 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 (ESITOF) m/z: [M+Na]+ Calcd for C15H27NO4Na 308.1838 ; Found 308.1828. Methyl 2-((tert-butoxycarbonyl)amino)-3-(2-methyltetrahydro2H-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, CDCl ) δ 173.8, 173.2, 155.4, 154.9, 130.6, 3 125.2, 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. 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. 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)



δ 4.78 (d, J = 8.9 Hz, 1H), 4.32 (td, J = 9.1, 3.4 Hz, 1H), 3.67 (s, 3H), 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. 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. 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, CDCl ) δ 172.44, 155.27, 118.97, 80.04, 3 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. Dimethyl 2-((tert-butoxycarbonyl)amino)hexanedioate (2l) Following the general experimental procedure, 2l was obtained (59%, 45 mg) as a colorless oil. 1H 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 Following the general experimental procedure, 2n was obtained (30%, 22 mg) as a colorless oil. 1H 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 Methyl 2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (2o)19 Following the general experimental procedure, 2o was obtained (71%, 26 mg) as a colorless oil. 1H 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-(((benzyloxy)carbonyl)amino)propanamido)-4methylpentanoate (4a)21 Following the general experimental procedure, 4a was obtained (69%, 114 mg, Rf = 0.4 in EtOAc : Hexane = 1 : 3) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.25

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(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. (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. 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. 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), 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-((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


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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 (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.

AUTHOR INFORMATION Corresponding Author E-mail: [email protected]

Notes The authors declare no competing financial interest.

General Experimental Procedure of Arylation of Dha (Scheme 3). 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. Methyl (tert-butoxycarbonyl)phenylalaninate (7a)22 Following the general experimental procedure, 7a was obtained (70%, 95 mg) as a white powder. 1H 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 obtained (14%, 19 mg) as a yellow powder. 1H 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 was obtained (13%, 19 mg) as a white powder. 1H 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-(4methoxyphenyl) 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 was obtained (30%, 40 mg) as a white powder. 1H 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 1HNMR, 13C-NMR spectra for all compounds

Acknowledgment The support of the Agency for Defense Development is gratefully acknowledged.

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