Strategy for O-alkylation of serine and threonine from serinyl and threoninyl acetic acids by photoinduced decarboxylative radical reactions: Connection between serine/threonine and carbohydrates/amino acids at the side chain

Article abstract of DOI:10.1021/acs.joc.8b00061

O-Alkylations of serine and threonine derivatives at the hydroxy group were achieved using photoinduced decarboxylative radical reactions of serinyl and threoninyl acetic acids with an organic photocatalyst without racemization under mild conditions. Photoinduced decarboxylative radical additions of serinyl and threoninyl acetic acids to electron-deficient alkenes provided linked serine and threonine with carbohydrates and amino acids at the side chain. In addition, O-methylations containing deuterium and O-benzylation of serine were performed under similar photochemical conditions.

Full text of DOI:10.1021/acs.joc.8b00061

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A Strategy for O-Alkylation of Serine and Threonine from
Serinyl and Threoninyl Acetic Acids by Photoinduced
Decarboxylative Radical Reactions: Connection between Serine/
Threonine and Carbohydrates/Amino Acids at the Side Chain
Takashi Yamamoto, Tomoya Iwasaki, Toshio Morita, and Yasuharu Yoshimi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00061 • Publication Date (Web): 09 Mar 2018
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A Strategy for O-Alkylation of Serine and Threonine from Serinyl and Threoninyl Acetic
Acids by Photoinduced Decarboxylative Radical Reactions: Connection between
Serine/Threonine and Carbohydrates/Amino Acids at the Side Chain
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Takashi Yamamoto, Tomoya Iwasaki, Toshio Morita, Yasuharu Yoshimi*
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering,
University of Fukui, 3ꢀ9ꢀ1 Bunkyo, Fukui 910ꢀ8507, Japan
Eꢀmail of corresponding author: yyoshimi@uꢀfukui.ac.jp
Table of Contents
O
ν
h
R
O
X
R
O
R
O
Phen, DCB
OH
CONHCH3
CbzHN
CONHCH3
CbzHN
CbzHN
CONHCH3
X = CH2CH2R, H,
D, C6H4CN,
Phen:
R = H, CH3
Alkyl radicals
DCB:NC
CN
O
O
O
ν
h
O
O
O
Phen, DCB
O
OH
+
O
O
CbzHN
CbzHN
N
CONHCH3
O
N
CONHCH3
OAc
OAc
H
AcO
AcO
O
OAc
H
AcO
AcO
OAc
Abstract
OꢀAlkylations of serine and threonine derivatives at the hydroxy group were achieved using
photoinduced decarboxylative radical reactions of serinyl and threoninyl acetic acids with an
organic photocatalyst without racemization under mild conditions. Photoinduced
decarboxylative radical additions of serinyl and threoninyl acetic acids to electronꢀdeficient
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alkenes provided linked serine and threonine with carbohydrates and amino acids at the side
chain. In addition, Oꢀmethylations containing deuterium and Oꢀbenzylation of serine were
performed under similar photochemical conditions.
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Introduction
OꢀAlkylatedꢀserine and ꢀthreonine 1 have high bioactivities1 and are used as precursors for
synthesis of highꢀvalue designer peptides2 (Scheme 1a). Therefore, Oꢀalkylations of serine and
threonine at the hydroxy group are important processes for the preparation of modified serine
and threonine. In particular, connections (Oꢀalkylations) of serine and threonine with
carbohydrates at the hydroxy group provide glycoꢀamino acids and ꢀpeptides, which are of
pharmaceutical interest in many areas, including juvenile human growth hormone and tissue
plasminogen activator studies.3 A large effort in the past several decades has been devoted to the
study of introducing alkyl groups at the hydroxy group in serine and threonine; however, the
reactant is limited to high reactive electrophiles such as methyl iodide, allyl bromide, and
benzyl bromide.4 When the usual electrophile, such as alkyl halide, is used, the formation of
undesired products is observed. In the case of serine, the alkoxide formed by the reaction with a
base does not attack alkyl halide, but rather intramolecularly attacks to an Nꢀprotecting group
such as Boc (R = tꢀBu) and Cbz (R = Bn) groups (Scheme 1b). This primarily yields an
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oxazolidinone derivative 2.5 Furthermore, the hindering alkoxide of threonine leads to the
formation of the corresponding oxazolidinone 3 and dehydrothreonine 4 via proton abstraction
at the αꢀposition by the alkoxide (Scheme 1c).6 Thus, a method for the preparation of
alkylatedꢀserine and –threonine without racemization and hydrolysis under mild conditions is a
desirable goal.
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Recently, we reported a general method for generating alkyl radicals from aliphatic carboxylic
acids via decarboxylation by using organic photoredox catalyst such as phenanthrene (Phen) and
1,4ꢀdicyanobenzene (DCB) (Scheme 2).7 Decarboxylative radical reactions of carboxylic acids
have recently attracted increasing attention as a synthetic method, because they offer several
advantages, for example, carboxylic acids are easy to store and handle, and decarboxylation
releases only CO2, which is nonflammable, nontoxic, and easily removed from the reaction
medium.8 The process is initiated by photoinduced electron transfer from Phen to DCB,
generating the radical cation of Phen, which oxidizes the carboxylate ions to form carboxy
radicals. Carboxy radicals smoothly decarboxylate to generate the corresponding alkyl radicals.
The generated alkyl radicals reacted with a variety of reagents such as electronꢀdeficient alkenes,
oxime ethers, thiols, and radical anions of dicyanobenzenes to provide the respective
addition,7d,f,g reduction,7b,e and substitution7c products in high yields. This finding encouraged us
to apply photoinduced decarboxylation to Oꢀalkylation of serine and threonine employing
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serinyl and threoninyl acetic acids 5 as a substrate (Scheme 1d). The results of this effort, which
led to a facile access to introduce alkyl group in serine and threonine without racemization
through the formation of alkyl radicals, are described below.
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a. O-Alkylated serine and threonine
R1 = H, protective group
R4
OR3
R2 = OH, protective group
R3 = alkyl, carbohydrate
R4 = H, CH3
R1HN
COR2
1
b. O-Alkylation of serine with usual alkyl halide
R-X
O
O
O
OH
base
O
O
HN
N
COR2
N
COR2
H
RO
COR2
2
H
RO
R = t-Bu or Bn
c. O-Alkylation of threonine with usual alkyl halide
O
O
R-X
O
OH
O
base
O
O
+
HN
N
COR2
N
COR2
H
RO
N
COR2
COR2
H
RO
H
RO
4
3
d. This work
O
ν
h
R
O
X
R
O
R
O
Phen, DCB
OH
CbzHN
CONHCH3
CbzHN
CONHCH3
CbzHN
CONHCH3
O-Alkylated serine
and threonine
R = H, CH3
Alkyl radicals
5
Scheme 1. OꢀAlkylation of serine and threonine.
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Phen*
DCB
Phen;
DCB;
ν
h
Phen
NC
X
CN
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Phen
– CO2
DCB
O
O
O
+H
– H
X
X
X
R
R
R
R
R
OH
R
O
R
O
(X = CN, CO2CH3, CO2H, SO2Ph)
Scheme 2. Photoinduced decarboxylative radical addition of carboxylic acids to
electronꢀdeficient alkenes.
Results and Discussion
Preparation of serinyl and threoninyl acetic acids 5a,b
Initially, the preparation of Lꢀserinyl and Lꢀthreoninyl acetic acids 5a,b from NꢀCbz Lꢀserine
and Lꢀthreonine amides 6a,b and the high reactive electrophile 7 for the photoreaction substrate
to avoid the formation of undesired products was examined by the modified method9 (Scheme
3). A THF solution containing 6a and 3 equiv. of αꢀbromo tꢀbutyl acetate 7 was slowly added to
the THF solution with 1.2 equiv. of NaH at 0 °C and stirred for 3 h at room temperature to afford
8a in a low yield (22%). Instead of amide 6a, the use of an ester such as NꢀCbz serine methyl
ester and NꢀBoc serine methyl ester with 7 yielded a complex mixture. An attempt to carry out a
reaction involving 6a with αꢀbromo ethyl acetate in the place of 7 failed. Thus, NꢀCbz Lꢀserine
N’ꢀmethyl amide 6a and 7 are found to be suitable for etherification of serine by NaH. When the
effects of NaH concentration, solvent (THF or DMF), base (NaH or LDA or tꢀBuOK or NaNH2),
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and synthetic procedure were assessed (Table S1 in SI), ethers 8a,b formed optimally in DMF
containing 6a,b, 3 equiv. of 7, and 2 equiv. of NaH for 3 h at room temperature. This was
followed by deprotection of the tꢀbutyl group in 8a,b by TFA to yield the corresponding
carboxylic acids 5a,b. In order to verify αꢀchirality retention in 8 during etherification using
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NaH, the corresponding
Dꢀ8a was synthesized by the same method from Dꢀ6a. Chiral HPLC
analysis of 8a,
Dꢀ8a, and a 1:1 mixture of 8a and
Dꢀ8a showed that the retention of the chirality
was observed (Figure S1 in SI).
O
R
OH
CONHCH3
R
O
OtBu
2 equiv. of NaH
DMF
OtBu
+
Br
O
CbzHN
CbzHN
CONHCH3
7
6a: R = H
6b
8a: R = H (43%)
8b
: R = CH3
: R = CH3 (53%)
O
R
O
TFA
OH
CH2Cl2
CbzHN
CONHCH3
5a: R = H (96%)
5b
: R = CH3 (95%)
Scheme 3. Preparation of 5a,b from 6a,b.
Photoinduced decarboxylative radical additions of 5 or 12 to electron-deficient alkenes 9
for the preparation of O-alkylated serine and threonine derivatives 10 or13
An initial photochemical experiment was carried out by the photoinduced decarboxylative
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radical addition of 5 to electronꢀdeficient alkene 9 such as acrylonitrile 9A and methyl acrylate
9B for the preparation of Oꢀalkylated serine and threonine 10. Table 1 shows the effects of
concentrations of photocatalyst, irradiation time, base, and the nature of electronꢀdeficient
alkene in photoinduced reactions of 5a,b to 9A,B. An aqueous acetonitrile solution
(CH3CN/H2O = 9:1) containing 5a (20 mM) and 9A (20 mM) was mixed with catalytic amounts
of Phen (1 mM, 5 mol%) and DCB (1 mM, 5 mol%) in 15 × 180 mm Pyrex vessels. The
mixture was irradiated for 9 h in an Ar atmosphere at room temperature (100 W, highꢀpressure
mercury lamp (λ > 280 nm)). Irradiation resulted in the formation of Oꢀalkylated serine amide
10aA in high yield (83%) through the decarboxylative radical addition (Entry 1, Table 1).
Addition of NaOH (1 equiv.) to the reaction mixture shortens the irradiation time (6 h) in a
similar yield (79%, Entry 1); however, photoreactions in the absence of a base were preferred,
due to the possibility of baseꢀpromoted racemization and hydrolysis in the sensitive amino acids
and carbohydrates. Instead of Phen and DCB, the use of biphenyl (BP) and
1,4ꢀdicyanonaphthalene (DCN) under the same photochemical conditions provided the similar
yield of 10aA (86%, Entry 2). As reported by us,10 the use of relatively poorly electronꢀdeficient
alkenes such as 9B in the place of 9A led to a significantly lower yield of adduct, along with
formation of polymeric materials11. When higher concentrations of BP and DCN were used as
photocatalyst, the yield of adduct slightly improved. In fact, the photoreaction of 5a with 9B for
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6 h using Phen (4 mM, 20 mol%) and DCB (4 mM, 20 mol%) led to a lower yield of 10aB
(35%, Entry 3), and an improved yield of 10aB (66%) was obtained in the photoreaction of 5a
with 9B using BP (4 mM, 20 mol%) and DCN (4 mM, 20 mol%) (Entry 4). In addition, these
photochemical conditions enabled the efficient photoinduced decarboxylative radical addition of
a threonine derivative 5b with 9A,B to afford high and moderate yields of 10bA and 10bB,
respectively (Entries 5 and 6). Thus, the photoinduced decarboxylative radical addition of 5 to a
poorly electronꢀdeficient alkene in the absence of a base was optimized for the use of BP (4
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mM) and DCN (4 mM) with 6 h irradiation time. Similar yield of Dꢀ10aA was obtained in the
photoreaction of
Dꢀ5a with 9A (Entry 7), and the chirality retention of 10aA in the
photoreaction was confirmed by chiral HPLC analysis of 10aA, Dꢀ10aA, and a 1:1 mixture of
10aA and Dꢀ10aA (Figure S2 in SI).
Table 1 Photoinduced decarboxylative radical addition of 5a,b to 9A,B.
Phen:
ν
h
R
O
X
DCB:
BP:
NC
CN
CN
Photocatalyst
5a,b
(20 mM)
+
X
CH3CN/H2O = 9:1
CbzHN
CONHCH3
9A: X = CN
9B
: X = CO2CH3
10aA: R = H, X = CN
: R = H, X = CO2CH3
10bA: R = CH3, X = CN
10aB
(20 mM)
DCN: NC
10bB
: R = CH3, X = CO2CH3
Entry
Photocatalyst
Irrad. time/h Yield of 10/%a
5
9
1
2
Phen (1 mM), DCB (1 mM)
BP (1 mM), DCN (1 mM)
9 (6)b
83 (79)b
5a
5a
9A
9A
9
86
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Phen (4 mM), DCB (4 mM)
BP (4 mM), DCN (4 mM)
BP (4 mM), DCN (4 mM)
BP (4 mM), DCN (4 mM)
BP (4 mM), DCN (4 mM)
6
6
6
6
6
35
66
87
68
85
5a
5a
5b
5b
9B
9B
9A
9B
9A
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D
ꢀ5a
aIsolated yield. bAddition of 1 equiv. of NaOH.
To demonstrate the utility of the photoinduced radical addition of 5, electronꢀdeficient
alkenes 9C–K were subjected to this photoreaction (Table 2). Similarly, the photoreactions of
5a,b with tꢀbutyl acrylate 9C and acrylamide 9D provided adducts 10aC–bD in moderate yields,
respectively (Entries 1 and 2). It is notable that the protected carbohydrateꢀacrylate and
ꢀacrylamide, such as βꢀDꢀglucosyl acrylate 9E, αꢀDꢀmannosyl acrylate 9F, and
αꢀDꢀglucosaminyl acrylamide 9G, can be employed in the photoreaction to yield the connected
products 10aE–aG between 5 and carbohydrates by alkyl chain (Entries 3–5). In addition, the
linked amino acids 10aH–aK at the side chain were obtained in the photoreactions of 5a,b with
L
ꢀserinyl acrylate 9H, Lꢀthreoninyl acrylate 9I, Lꢀtyrosyl acrylate 9J, and Lꢀlisinyl acrylamide
9K (Entries 6–9). Other diastereomers of 10 were not observed in these photoreactions. Thus,
this photochemical radical addition can provide the connected serine and threonine with
carbohydrates and amino acids at the side chain without racemization.
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Table 2 Photoinduced decarboxylative radical addition of 5a,b to 9C–K.
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8
9
ν
h , 6 h
BP (4 mM), DCN (4 mM)
10aC-10ak
10bC 10bH
5a,b
9C-K
+
10
11
12
13
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-
(20 mM) (20 mM)
CH3CN/H2O = 9:1
Entry
Electronꢀdeficient alkene 9
Product 10a
R
O
CO2tBu
CO2tBu
CbzHN
CONHCH3
1
2
9C
10aC: 67%
10bC
: 65%
R
O
CONH2
CONH2
CbzHN
CONHCH3
9D
10aD: 55%
10bD
: 52%
O
O
R
O
O
O
O
CbzHN
CONHCH3
AcO
O
OAc
3
4
OAc
AcO
AcO
OAc
AcO
OAc
10aE: 47%
10bE
9E
: 45%
O
O
O
O
O
OAc
O
CbzHN
CONHCH3
AcO
OAc
O
AcO
AcO
AcO
OAc
OAc
9F
10aF: 44%
OAc
O
AcO
AcO
OAc
HN
OAc
O
O
AcO
AcO
5
HN
OAc
O
O
9G
CbzHN
CONHCH3
10aG: 44%
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O
O
R
O
O
7
8
9
O
CO2CH3
NHBoc
CbzHN
CONHCH3
6
7
BocHN
CO2CH3
10
11
12
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10aH: 66%
9H
10bH
: 63%
O
O
O
O
O
O
O
CO2CH3
NHBoc
CbzHN
CONHCH3
BocHN
CO2CH3
9I
10aI: 66%
O
O
O
CbzHN
CONHCH3
O
8
BocHN
CO2CH3
9J
10aJ: 49%
CO2CH3
NHBoc
O
O
NH
HN
CbzHN
CONHCH3
9
BocHN
CO2CH3
9K
BocHN
CO2CH3
10aK: 66%
aIsolated yield.
This methodology can also apply to the modification of dipeptide 12 with 9E, which was
prepared from 8a coupling with NꢀCbz Lꢀvaline 11 at three steps, to provide the connected
dipeptide 13 with the carbohydrate at the side chain (Scheme 4).
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1. H2, Pd-C/EtOH
ν
h , 6 h
11
2. , EDC, HOBt
BP (4 mM)
O
CO2H
O
i-Pr2EtN/DMF
3. TFA/CH2Cl2
DCN (4 mM)
9E
(20 mM)
CbzHN
N
CONHCH3
8a
CH3CN/H2O = 9:1
H
9
12: 67% at three steps
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O
O
O
O
CbzHN
N
CONHCH3
AcO
O
OAc
H
OAc
AcO
13: 46%
Scheme 4 Photoinduced decarboxylative radical addition of dipeptide 12 to 9E.
Photoinduced decarboxylative reduction and deuteration of 5a
To further prepare another type of Oꢀalkylated serine, photoinduced reduction7b and
deuteration7e of 5a were investigated (Scheme 5). The photoreaction of 5a with Phen (20 mM),
DCB (20 mM), and tꢀdodecanethiol (RSH, 1 mM, 5 mol%) for 24 h led to the high yield of
reduction product 14 (83%) through hydrogen abstraction in the thiol by the generated radical.
As reported by us,7e the use of D2O instead of water in the solvent causes exchange of SH to SD
in the thiol, and the generated radicals by photoinduced decarboxylation abstract D atom from
SD to yield deuterated products. In fact, a high yield and deuteriumꢀcontent of 15 was obtained
in the photoreaction of 5a in CH3CN/D2O = 9:1. Thus, Oꢀmethylation containing a deuterium of
serine is achieved by photoreaction of 5 using thiol and D2O.
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ν
h , 24 h
Phen (20 mM), DCB (20 mM)
O
H(D)
RSH
5a
(20 mM) (1 mM)
+
CH3CN/H2O = 9:1
CbzHN
14: 83%
CONHCH3
9
or CH3CN/D2O = 9:1
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15
: 80%, d-content 93%
Scheme 5 Photoinduced decarboxylative reduction and deuteration of 5a.
Photoinduced substitution of DCB with 5a via decarboxylation
Finally, substitution of DCB by 5a via photoinduced decarboxylation was demonstrated
(Scheme 6).7c The photoreaction of 5a (30 mM), Phen (10 mM), and DCB (10 mM) in the
absence of alkene and thiol provided Oꢀbenzylated serine amide 16 via the sequent
decarboxylative radical addition to the radical anion of DCB and decyanation.
CN
ν
h , 6 h
O
Phen (10 mM), DCB (10 mM)
5a
(30 mM)
CH3CN/H2O = 9:1
CbzHN
CONHCH3
16: 31%
Scheme 6 Photoinduced substitution of DCB with 5a via decarboxylation
Conclusion
Photoinduced decarboxylative radical reactions of 5 were found to be a useful method for the
preparation of Oꢀalkylated serine and threonine (Scheme 7). In particular, photoinduced
decarboxylative radical additions of 5 to 9 are proven to connect serine and threonine with
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carbohydrates and amino acids at the side chain through the similar reaction mechanism to
Scheme 2. OꢀAlkylation by using this photochemical method proceeded with complete retention
of αꢀchirality of serine and threonine, because base, heating, and metal are not used in the
photoreaction. Further investigation into modification of peptides at the side chain using this
photochemical method is in progress.
9
10
11
12
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R
O
R
+
R
CbzHN
R
CONHCH3
ν
h
O
10
Phen, DCB
or BP, DCN
R
O
R
O
O
H(D)
+ RSH(D)
OH
CbzHN
CONHCH3
CbzHN
CONHCH3
CbzHN
CONHCH3
14,15
Alkyl radicals
R = H, CH3
DCB
+
5
R
O
Ar
CbzHN
CONHCH3
16
Scheme 7 Photoinduced decarboxylative radical reactions for the preparation of Oꢀalkylated
serine and threonine 10, 14, 15, 16
Experimental Section
All reagents and solvents were used as received from commercial suppliers. IR spectra were
1
recorded on an FTꢀIR spectrometer. H NMR spectra were recorded in CDCl3 or CD3OD
containing tetramethylsilane as an internal standard, and were acquired on either a 500 or a 600
MHz spectrometer. 13C NMR spectra were acquired on either a 125 or a 150 MHz spectrometer.
Highꢀresolution mass spectra were obtained using doubleꢀfocusing magnetic sector mass
spectrometer coupled with FAB. The light source was a highꢀpressure (100 W) mercury arcs.
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Column chromatography was performed on Wakogel Cꢀ300, particle size 45ꢀ75 ꢀm.
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Procedure for the synthesis of N-Cbz serine and threonine amides 5a,b
Benzylchloroformate (9.38 g, 55 mmol) was added dropwise to serine or threonine (5.25 or
5.96 g, 50 mmol) in an aq. NaHCO3 (10.5 g, 125 mmol) solution (100 mL) at 0 °C. The mixture
was stirred overnight at room temperature and washed with EtOAc. The aqueous solution was
acidified by the slow addition of 1M HCl until the pH decreased to 1 and was then extracted
with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude
product was recrystallized by hexane/EtOAc = 1:1 to give the corresponding NꢀCbz serine or
threonine as a white solid (10.9g, 91% or 12.0g, 95%).
EDC hydrochloride (2.74 g, 14 mmol) and HOBt (2.18 g, 14 mmol) were added to solutions of
NꢀCbz serine or threonine (3.00 or 3.29 g, 13 mmol), methylammonium hydrochloride (0.93 g,
14 mmol), and iꢀPr2NEt (3.24 g, 25 mmol) in DMF (50 mL) at 0 °C. The mixture was stirred for
2 h at 0 °C and overnight at room temperature, and then concentrated in vacuo. The residue was
dissolved in EtOAc, and sequentially washed with 4% NaHCO3, 1M HCl, and water. The
organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified
by silicaꢀgel column chromatography using chloroform/acetone = 20:1–10:1 as the eluent to
give the corresponding NꢀCbz serine and threonine amides 6a,b as a white solid in 79 or 73%
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yield (2.59 or 2.53g), respectively.
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6a: white solid, mp 120–121°C; IR (KBr, cmꢀ1) 3391, 3367, 2968, 2928, 1685, 1656, 1554,
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1515; H NMR (500 MHz, CD3OD) δ 7.36–7.29 (m, 5H), 5.13–5.06 (m, 2H), 4.17–4.14 (m,
1H), 3.76–3.74 (m, 2H), 2.73 (s, 3H); 13C NMR (125 MHz, CD3OD) δ 172.1, 157.1, 137.0,
128.1, 127.8, 127.7, 66.5, 61.9, 57.3, 25.1; HRMS (FAB, m/z) calcd for (M+H)+ C12H17N2O4:
253.1188, found: 253.1180.
6b: white solid, mp 160–161°C; IR (KBr, cmꢀ1) 3395, 3301, 2974, 2923, 1693, 1636, 1577,
1
1523; H NMR (500 MHz, CD3OD) δ 7.38–7.29 (m, 5H), 5.15–5.06 (m, 2H), 4.16–4.03 (m,
2H), 2.71 (s, 3H), 1.16 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 172.2, 157.3, 136.7,
128.2, 127.8, 127.6, 67.0, 66.6, 60.7, 25.1, 18.9; HRMS (FAB, m/z) calcd for (M+H)+
C13H19N2O4: 267.1345, found: 267.1346.
DMF solution (5 mL) containing 6 (6a,b and Dꢀ6a, 1.19 mmol, 0.300g, 0.317g, and 0.300g)
and 3 equiv. of αꢀbromo tꢀbutyl acetate 7 (0.53 mL, 3.57 mmol) was slowly added to DMF
solution (5 mL) of 2 equiv. of 60% NaH (0.10 g, 2.38 mmol) at 0 °C and stirred for 3 h at room
temperature. Then, water was added to the mixture and extracted with EtOAc. The organic layer
was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silicaꢀgel
column chromatography using hexane/EtOAc = 4:1–1:1 as the eluent to give 8a,b and Dꢀ8a (43,
53%, 0.187g, 0.240g, and 0.187g).
8a: white solid, mp 78–79°C; IR (KBr, cmꢀ1) 3303, 2975, 2923, 1743, 1692, 1650, 1575, 1542;
1H NMR (500 MHz, CDCl3) δ 7.44–7.24 (m, 5H), 6.95 (s (br), 1H), 6.24 (s (br), 1H), 5.13 (s,
2H), 4.30–4.27 (m, 1H), 4.12–3.88 (m, 3H), 3.65–3.61 (m, 1H), 2.84 (d, J = 4.0 Hz, 3H), 1.47 (s,
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9H); 13C NMR (125 MHz, CDCl3) δ 170.4, 170.3, 156.5, 136.3, 128.6, 128.3, 128.1, 82.5, 71.5,
68.9, 67.1, 54.3, 28.1, 26.5; HRMS (FAB, m/z) calcd for (M+H)+ C18H27N2O6: 367.1869, found:
367.1891.
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8b: colorless oil; IR (neat, cmꢀ1) 3340, 2979, 2931, 1726, 1669, 1522, 1508; H NMR (500
MHz, CDCl3) δ 7.41 (s (br), 1H), 7.35–7.29 (m, 5H), 6.14 (s (br), 1H), 5.11–5.05 (m, 2H),
4.27–4.01 (m, 3H), 3.92–3.85 (m, 1H), 2.83 (d, J = 4.6 Hz, 3H), 1.44 (s, 9H), 1.09 (d, J = 6.3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.2, 169.0, 156.2, 136.3, 128.6, 128.2, 128.0, 82.5,
68.2, 67.0, 56.6, 28.1, 26.4, 15.5; HRMS (FAB, m/z) calcd for (M+H)+ C19H29N2O6: 381.2026,
found: 381.2013.
D
ꢀ8a: white solid, mp 78–79°C; IR (KBr, cmꢀ1) 3306, 2923, 1739, 1692, 1650, 1577, 1545; 1H
NMR (600 MHz, CDCl3) δ 7.41–7.29 (m, 5H), 6.93 (s (br), 1H), 6.22 (s (br), 1H), 5.14 (s, 2H),
4.30–4.27 (m, 1H), 4.12–3.89 (m, 3H), 3.65–3.61 (m, 1H), 2.85 (d, J = 4.1 Hz, 3H), 1.48 (s,
9H); 13C NMR (150 MHz, CDCl3) δ 170.4, 170.3, 156.5, 136.3, 128.6, 128.3, 128.1, 82.5, 71.5,
68.9, 67.1, 54.4, 28.1, 26.5; HRMS (FAB, m/z) calcd for (M+H)+ C18H27N2O6: 367.1869, found:
367.1891.
CH2Cl2/TFA= 1:1 (5 mL : 5 mL) solution containing 8 (8a,b and
Dꢀ8a, 2.06 mmol, 0.755g,
0.784g, and 0.755g) was stirred overnight at room temperature, and concentrated in vacuo.
Purification by column chromatography on silica gel using hexane/EtOAc = 2:1–1:2 as eluents
gave NꢀCbz serinyl and threoninyl acetic acids 5a,b and
Dꢀ5a as a white solid (96, 95, 96%,
0.614g, 0.653g, and 0.614g).
5a: white solid, mp 126–128°C; IR (KBr, cmꢀ1) 3377, 3274, 2969, 2939, 1755, 1716, 1642,
1
1524; H NMR (500 MHz, CD3OD) δ 7.40–7.26 (m, 5H), 5.13–5.06 (m, 2H), 4.29–4.20 (m,
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1H), 4.09–4.07 (m, 2H), 3.86–3.81 (m, 1H), 3.74–3.71 (m, 1H), 2.74 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 172.9, 171.7, 157.2, 136.7, 128.1, 127.7, 127.6, 70.7, 67.4, 66.6 55.4, 25.1;
HRMS (FAB, m/z) calcd for (M+H)+ C14H19N2O6: 311.1243, found: 311.1243.
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5b: white solid, mp 146–147°C; IR (KBr, cmꢀ1) 3305, 2969, 2936, 1743, 1686, 1651, 1554; 1H
NMR (500 MHz, CD3OD) δ 7.45–7.19 (m, 5H), 5.15–5.07 (m, 2H), 4.23–3.95 (m, 4H), 2.74 (s,
3H), 1.16 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.5, 171.9, 157.4, 136.7, 128.1,
127.7, 127.6, 75.7, 66.6, 66.0, 59.6, 25.1, 15.1; HRMS (FAB, m/z) calcd for (M+H)+
C15H21N2O6: 325.1400, found: 325.1408.
D
ꢀ5a: white solid, mp 126–128°C; IR (KBr, cmꢀ1) 3373, 3271, 2969, 2939, 1753, 1716, 1644,
1
1527; H NMR (500 MHz, CD3OD) δ 7.41–7.26 (m, 5H), 5.14–5.06 (m, 2H), 4.29–4.20 (m,
1H), 4.09–4.07 (m, 2H), 3.86–3.81 (m, 1H), 3.74–3.70 (m, 1H), 2.73 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 172.9, 171.7, 157.2, 136.7, 128.1, 127.7, 127.6, 70.7, 67.4, 66.6, 55.4, 25.1;
HRMS (FAB, m/z) calcd for (M+H)+ C14H19N2O6: 311.1243, found: 311.1243.
Procedure for the synthesis of dipeptide 12
Debenzylation of 8a (0.961 g, 2.62 mmol) was performed by treatment with 10 % Pd/C (0.1 g)
and H2 in EtOH (50 mL) with TLC monitoring. After complete consumption of the starting
material, the mixture was filtered through celite, and the filtrate was evaporated. The following
coupling with 11 was carried out without further purification.
EDC hydrochloride (0.550 g, 2.88 mmol), HOBt (0.480 g, 3.14 mmol), and iꢀPr2EtN (0.560
mL, 3.14 mmol) were added to a solution containing the corresponding debenzylated serine
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°
amide and NꢀCbz valine 11 (0.660 g, 2.62 mmol) in DMF (20 mL) at 0 C. The mixture was
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9
°
stirred at 0 C for 2 h and overnight at room temperature, and then concentrated in vacuo. The
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residue was dissolved in EtOAc, and sequentially washed with 1 M HCl, 4% NaHCO3, and
water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by silicaꢀgel column chromatography using hexane/EtOAc = 4:1–1:1 as the eluent
to give the corresponding dipeptide as a white solid (79%, 0.9661g).
The tꢀbutyl group in the peptide (0.960 g, 2.06 mmol) was removed by the abovementioned
method using TFA/CH2Cl2 = 1:1 solution to give dipeptide 12 (85%, 0.822g).
12: white solid, mp 187–188°C; IR (KBr, cmꢀ1) 3297, 2962, 2873, 1696, 1643, 1538; 1HꢀNMR
(500 MHz, CD3OD) δ 7.36–7.28 (m, 5H), 5.17–5.07 (m, 2H), 4.43 (s (br), 1H), 4.12–3.88 (m,
4H), 3.68–3.66 (m, 1H), 2.67 (s, 3H), 2.17–2.13 (m, 1H), 1.00–0.95 (m, 6H); 13C NMR (125
MHz, CDCl3) δ 173.0, 170.8, 157.9, 136.9, 128.2, 127.7, 127.4, 70.4, 67.2, 66.5, 61.4, 53.6,
30.2, 25.0, 18.3, 17.0; HRMS (FAB, m/z) calcd for (M+H)+ C19H28N3O7: 410.1927, found:
410.1924.
General Procedure for the synthesis of alkenes 9E–K
Acryloyl chloride (0.17 g, 2.2 mmol) was slowly added to solution of alcohol or amine (1.9
°
mmol) and Et3N (2 mL) in THF (30 mL) at 0 C under Ar atmosphere, and stirred for 2 h at
room temperature. Water (50 ml) was added to the mixture, and extracted with EtOAc, and
dried over Na2SO4, and concentrated under reduced pressure. Purification by column
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chromatography on silica gel using hexane/EtOAc = 10:1 as eluents gave the corresponding
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acrylate or acrylamide 9E–K.
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9E: white solid, mp 144–145°C; IR (KBr, cmꢀ1) 2966, 2950, 1751, 1635; H NMR (500 MHz,
CDCl3) δ 6.45 (d, J = 17.2 Hz, 1H), 6.15 (dd, J = 17.2, 10.4 Hz, 1H), 5.89 (d, J = 10.4 Hz, 1H),
5.73 (d, J = 8.0 Hz, 1H), 5.27 (t, J = 9.5 Hz, 1H), 5.16–5.12 (m, 2H), 4.32–4.26 (m, 2H),
3.91–3.89 (m, 1H), 2.14 (s, 3H), 2.12–1.99 (m, 9H); 13C NMR (125 MHz, CDCl3) δ170,2. 169.4,
169.3, 169.0, 165.7, 131.9, 127.7, 91.7, 72.9, 72.7, 70.3, 68.0, 61.8, 20.9, 20.6; HRMS (FAB,
m/z) calcd for (M+Na)+ C17H22NaO11: 425.1060, found: 425.1069.
9F; white solid, mp 106–107°C; IR (KBr, cmꢀ1) 2989, 2870, 1750, 1637, 1545; H NMR (500
1
MHz, CDCl3) δ 6.46 (d, J = 17.8 Hz, 1H), 6.16 (dd, J = 17.8, 10.3 Hz, 1H), 5.89–5.87 (m, 2H),
5.49 (d, J = 2.9 Hz, 1H), 5.31 (t, J = 9.7 Hz, 1H), 5.15 (dd, J = 9.7, 3.4 Hz, 1H), 4.31 (s, 2H),
3.88–3.85 (m, 1H), 2.23 (s, 3H), 2.09–2.01 (m, 9H); 13C NMR (125 MHz, CDCl3) δ 170.3,
169.9, 169.6, 168.5, 165.7, 131.8, 127.8, 90.4, 73.3, 70.7, 68.2, 65.6, 62.4, 20.9, 20.8, 20.7,
20.6; HRMS (FAB, m/z) calcd for (M+Na)+ C17H22NaO11: 425.1060, found: 425.1079.
9G: white solid, mp 110–111°C; IR (KBr, cmꢀ1) 3383, 2952, 2925, 1751, 1662, 1630, 1544; 1H
NMR (500 MHz, CDCl3) δ 6.28 (d, J = 17.2 Hz, 1H), 6.22 (d, J = 4.0 Hz, 1H), 6.04 (dd, J =
17.2, 10.3 Hz, 1H), 5.89 (d, J = 9.2 Hz, 1H), 5.70 (d, J = 10.3 Hz, 1H), 5.30–5.24 (m, 2H),
4.59–4.55 (m, 1H), 4.27 (dd, J = 12.6, 4.0 Hz, 1H), 4.09–4.02 (m, 2H), 2.22 (s, 3H), 2.10–2.01
(m, 9H); 13C NMR (125 MHz, CDCl3) δ 171.9, 170.8, 169.2, 168.7, 165.4, 129.8, 128.1, 90.7,
70.7, 69.8, 67.5, 61.6, 51.2, 21.0, 20.8, 20.6; HRMS (FAB, m/z) calcd for (M+H)+ C17H24NO10:
402.1400, found: 402.1389.
9H: white solid, mp 57–58°C; IR (KBr, cmꢀ1) 3342, 2969, 2928, 1738, 1707, 1637, 1531; H
1
NMR (600 MHz, CDCl3) δ 6.42 (d, J = 17.2 Hz, 1H), 6.11 (dd, J = 17.2, 10.3 Hz, 1H), 5.87 (d,
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J = 10.3 Hz, 1H), 5.33 (d (br), J = 7.6 Hz, 1H), 4.65–4.59 (m, 1H), 4.55–4.40 (m, 2H), 3.78 (s,
7
8
13
3H), 1.46 (s, 9H); CNMR (150 MHz, CDCl3) δ 170.3, 165.6, 155.2, 131.9, 127.7, 80.4, 64.5,
9
53.0, 52.9, 28.3; HRMS (FAB, m/z) calcd for (M+H)+ C12H20NO6: 274.1291, found: 274.1287.
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9I: colorless oil; IR (neat, cmꢀ1) 3362, 2979, 1748, 1722, 1636, 1509; H NMR (500 MHz,
CDCl3) δ 6.39 (d, J = 17.2 Hz, 1H), 6.07 (dd, J = 17.2, 10.3 Hz, 1H), 5.85 (d, J = 10.3 Hz, 1H),
5.46 (s (br), 1H), 5.30–5.21 (m, 1H), 4.51–4.45 (m, 1H), 3.73 (s, 3H), 1.47 (s, 9H), 1.35 (d, J =
6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.7, 164.9, 155.9, 131.6, 128.0, 80.3, 70.9, 57.2,
52.7, 28.3, 17.0; HRMS (FAB, m/z) calcd for (M+H)+ C13H22NO6: 288.1447, found: 288.1436.
9J: white solid, mp 66–67°C; IR (KBr, cmꢀ1) 3384, 2982, 1743, 1688, 1632, 1504; H NMR
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(500 MHz, CDCl3) δ 7.18 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 17.2 Hz,
1H), 6.34 (dd, J = 17.2, 10.3 Hz, 1H), 6.04 (d, J = 10.3 Hz, 1H), 5.01 (d (br), J = 8.0 Hz, 1H),
4.62–4.55 (m, 1H), 3.74 (s, 3H), 3.24–2.87 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 172.3,
164.6, 155.2, 149.7 133.8, 132.7, 130.5, 130.2, 127.9, 121.9, 121.5, 80.1, 54.5, 52.4, 37.8, 28.4;
HRMS (FAB, m/z) calcd for (M+H)+ C18H24NO6: 350.1604, found: 350.1606.
9K: colorless oil; IR (neat, cmꢀ1) 3307, 3289, 2976, 2941, 2871, 1743, 1710, 1664, 1626, 1536;
1H NMR (500 MHz, CDCl3) δ 6.29 (d, J = 16.9, 1H), 6.16–6.02 (m, 2H, NH and CH=CH2),
5.63 (d, J = 10.0 Hz, 1H), 5.20 (d (br), J = 8.0 Hz, 1H), 4.32–4.23 (m, 1H), 3.74 (s, 3H), 3.33 (q,
J = 6.7 Hz, 2H), 1.88–1.75 (m, 1H), 1.73–1.51 (m, 3H), 1.48–1.36 (m, 11H); 13C NMR (125
MHz, CDCl3) δ 173.4, 165.8, 155.7, 130.9, 126.4, 80.0, 53.2, 52.4, 39.1, 32.5, 28.9, 28.4, 22.6;
HRMS (FAB, m/z) calcd for (M+H)+ C15H27N2O5: 315.1920, found: 315.1910.
Photoreactions of 5a,b or 12
An aqueous CH3CN solution (CH3CN 90 mL, H2O 10 mL) of 5 (20 mM), 9 (20 mM), BP (4
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mM), and DCN (4 mM) in Pyrex vessels (18 mm x 180 mm) was purged with Ar for 10 min.
The mixture was irradiated with a 100 W highꢀpressure mercury lamp for 6 h, and then the
solvent was removed under reduced pressure. The crude product was purified by silicaꢀgel
column chromatography using hexane/EtOAc as the eluents to give adducts 10. The
photoinduced decarboxylative reduction, deuteration, and substitution of 5 or photoinduced
decarboxylative radical addition of dipeptide 12 were also carried out in a similar manner.
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10aA: mp 107–108°C; IR (KBr, cmꢀ1) 3298, 2934, 2875, 2244, 1686, 1653, 1545; H NMR
(500 MHz, CDCl3) δ 7.62–7.30 (m, 5H), 6.41 (s (br), 1H), 5.73 (s (br), 1H), 5.15 (s, 2H),
4.35–4.27 (m, 1H), 3.93–3.84 (m, 1H), 3.58–3.44 (m, 3H), 2.85 (d, J = 4.6 Hz, 3H), 2.43 (t, J =
6.9 Hz, 2H), 1.98–1.79 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 170.3, 156.2, 136.1, 128.7,
128.4, 128.3, 119.9, 70.5, 69.4, 67.4, 54.6, 26.5, 25.4, 14.5; HRMS (FAB, m/z) calcd for
(M+H)+ C16H22N3O4: 320.1610, found: 320.1616.
D
ꢀ10aA: white solid, mp 106–107°C; IR (KBr, cmꢀ1) 3302, 2935, 2878, 2244, 1685, 1654,
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1545; H NMR (500 MHz, CDCl3) δ 7.60–7.28 (m, 5H), 6.38 (s (br), 1H), 5.71 (s (br), 1H),
5.13 (s, 2H), 4.35–4.27 (m, 1H), 3.93–3.84 (m, 1H), 3.58–3.47 (m, 3H), 2.83 (d, J = 4.6 Hz, 3H),
2.40 (t, J = 6.9 Hz, 2H), 2.00–1.77 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 170.3, 156.2, 136.1,
128.7, 128.4, 128.3, 119.9, 70.5, 69.4, 67.4, 54.6, 26.5, 25.4, 14.5; HRMS (FAB, m/z) calcd for
(M+H)+ C16H22N3O4: 320.1610, found: 320.1624.
10bA: white solid, mp 127–128°C; IR (KBr, cmꢀ1) 3294, 2970, 2939, 2896, 2244, 1686, 1652,
1547, 1458; 1H NMR (500 MHz, CDCl3) δ 7.43–7.28 (m, 5H), 6.46 (s (br), 1H), 5.78–5.71 (m,
1H), 5.13 (s, 2H), 4.35–4.23 (m, 1H), 4.17–4.01 (m, 1H), 3.77–3.68 (m, 1H), 3.63–3.45 (m, 1H),
2.83 (d, J = 5.2 Hz, 3H), 2.40 (t, J = 6.9 Hz, 2H), 1.98–1.76 (m, 2H), 1.13 (d, J = 6.3 Hz, 3H);
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13C NMR (125 MHz, CDCl3) δ 170.1, 156.5, 136.1, 128.7, 128.4, 128.2, 120.1, 74.9, 67.5, 67.3,
58.7, 26.4, 25.7, 15.4, 14.6; HRMS (FAB, m/z) calcd for (M+H)+ C17H24N3O4: 334.1767, found:
334.1770.
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10aB: white solid, mp 86–87°C; IR (KBr, cmꢀ1) 3302, 2946, 2871, 1737, 1687, 1656, 1544; 1H
NMR (600 MHz, CDCl3) δ 7.46–7.26 (m, 5H), 6.39 (s (br), 1H), 5.72 (s (br), 1H), 5.11 (s, 2H),
4.29–4.18 (m, 1H), 3.88–3.77 (m, 1H), 3.65 (s, 3H), 3.56–3.38 (m, 3H), 2.82 (d, J = 4.1 Hz, 3H),
2.35 (t, J = 6.9 Hz, 2H), 1.91–1.80 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 174.1, 170.5, 156.2,
136.1, 128.7, 128.4, 128.3, 70.5, 70.3, 67.3, 54.3, 51.8, 31.0, 26.5, 24.9; HRMS (FAB, m/z)
calcd for (M+H)+ C17H25N2O6: 353.1713, found: 353.1721.
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10bB: colorless oil; IR (neat, cmꢀ1) 3302, 2930, 2898, 1736, 1690, 1652, 1551; H NMR (500
MHz, CDCl3) δ 7.37–7.33 (m, 5H), 6.55 (s (br), 1H), 5.81 (s (br), 1H), 5.12 (s, 2H), 4.24–4.15
(m, 1H), 4.03–3.90 (m, 1H), 3.66 (s, 3H), 3.60–3.51 (m, 2H), 2.83 (d, J = 4.6 Hz, 3H), 2.36 (t, J
= 6.9 Hz, 2H), 1.91–1.86 (m, 2H), 1.07 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
174.2, 170.0, 156.3, 136.2, 128.6, 128.3, 128.2, 74.8, 68.6, 67.2, 58.0, 51.7, 31.1, 26.3, 25.3,
15.3; HRMS (FAB, m/z) calcd for (M+H)+ C18H27N2O6: 367.1869, found: 367.1880.
10aC: white solid, mp 58–59°C; IR (KBr, cmꢀ1) 3300, 2969, 2933, 1728, 1686, 1656, 1551; 1H
NMR (500 MHz, CDCl3) δ 7.37–7.31 (m, 5H), 6.55 (s (br), 1H), 5.79 (s (br), 1H), 5.12 (s, 2H),
4.31–4.20 (m, 1H), 3.89–3.72 (m, 1H), 3.50–3.47 (m, 3H), 2.83 (d, J = 5.2 Hz, 3H), 2.26 (t, J =
7.2 Hz, 2H), 1.85–1.82 (m, 2H), 1.44 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.0, 170.6,
156.2, 136.2, 128.6, 128.3, 128.2, 80.5 70.5, 70.3, 67.2, 54.2, 32.6, 28.2, 26.4, 25.1; HRMS
(FAB, m/z) calcd for (M+H)+ C20H31N2O6: 395.2182, found: 395.2202.
10bC: white solid, mp 58–59°C; IR (KBr, cmꢀ1) 3294, 2973, 2929, 1729, 1694, 1650, 1542; 1H
NMR (500 MHz, CDCl3) δ 7.37–7.32 (m, 5H), 6.62 (s (br), 1H), 5.85 (s (br), 1H), 5.12 (s, 2H),
4.27–4.15 (m, 1H), 4.05–3.91 (m, 1H), 3.57–3.51 (m, 2H), 2.84 (d, J = 4.6 Hz, 2H), 2.27 (t, J =
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7.2 Hz, 2H), 1.84–1.82 (m, 2H), 1.44 (s, 9H), 1.08 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 173.1, 170.0, 156.3, 136.2, 128.6, 128.3, 128.2, 80.5 74.8, 68.7, 67.2, 57.9, 32.6, 28.2,
26.3, 25.5, 15.4; HRMS (FAB, m/z) calcd for (M+H)+ C21H33N2O6: 409.2339, found: 409.2315.
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10aD: white solid, mp 149ꢀ150°C; IR (KBr, cmꢀ1) 3303, 2961, 2884, 1687, 1647, 1554; H
NMR (500 MHz, CD3OD) δ 7.38–7.29 (m, 5H), 5.14–5.06 (m, 2H), 4.30–4.18 (m, 1H),
3.69–3.60 (m, 2H), 3.47–3.44 (m, 2H), 2.73 (s, 3H), 2.23 (t, J = 7.4 Hz, 2H), 1.85–1.80 (m, 2H);
13C NMR (125 MHz, CD3OD) δ 177.5, 172.0, 157.1, 136.7, 128.2, 127.8, 127.7, 70.1 70.0, 66.6,
55.4, 31.8, 25.4, 25.1; HRMS (FAB, m/z) calcd for (M+H)+ C16H24N3O5: 338.1716, found:
338.1703.
10bD: white solid, mp 172–173°C; IR (KBr, cmꢀ1) 3312, 3195, 2973, 2875, 1688, 1646, 1541;
1H NMR (500 MHz, CD3OD) δ 7.39–7.30 (m, 5H), 5.16–5.07 (m, 2H), 4.12–4.01 (m, 1H),
3.97–3.88 (m, 1H), 3.59–3.50 (m, 1H), 3.34–3.29 (m, 1H), 2.74 (s, 3H), 2.22 (t, J = 7.6 Hz, 2H),
1.81–1.75 (m, 2H), 1.14 (d, J = 6.3 Hz, 3H); 13CNMR (125 MHz, CD3OD) δ 177.6, 172.3,
157.3, 136.7, 128.2, 127.8, 127.7, 75.0, 68.1, 66.7, 59.8, 31.8, 25.8, 25.1, 15.2; HRMS (FAB,
m/z) calcd for (M+H)+ C17H26N3O5: 352.1872, found: 352.1895.
10aE: white solid, mp 90–91°C; IR (KBr, cmꢀ1) 3383, 3327, 2962, 2884, 1758, 1658, 1531; 1H
NMR (500 MHz, CDCl3) δ 7.37–7.29 (m, 5H), 6.55 (s (br), 1H), 5.78 (s (br), 1H), 5.72 (d, J =
8.0 Hz, 1H), 5.26 (t, J = 9.5 Hz, 1H), 5.15–5.09 (m, 4H), 4.27 (dd, J = 12.6, 4.6 Hz, 2H), 4.12 (d,
J = 10.9 Hz, 1H), 3.83–3.81 (m, 2H), 3.53–3.49 (m, 3H), 2.83 (d, J = 4.6 Hz, 3H), 2.40 (t, J =
7.2 Hz, 2H), 2.10–1.98 (m, 12H), 1.89–1.86 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 173.1,
170.6, 170.1, 169.5 169.3, 169.0, 156.2, 136.2, 128.6, 128.3, 128.2, 91.7, 72.8, 72.7, 70.3, 70.2,
67.8, 67.2, 61.5, 54.4, 30.8, 26.4, 24.7, 20.8, 20.6; HRMS (FAB, m/z) calcd for (M+H)+
C30H41N2O15: 669.2507, found: 669.2491.
10bE: white solid, mp 75–76°C; IR (KBr, cmꢀ1) 3392, 2971, 2935, 1759, 1672, 1543, 1508; 1H
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NMR (600 MHz, CDCl3) δ 7.37–7.28 (m, 5H), 6.55 (s (br), 1H), 5.78–5.72 (m, 2H), 5.26 (t, J =
8.9 Hz, 1H), 5.14–5.09 (m, 4H), 4.25–4.14 (m, 3H), 4.01–3.99 (m, 1H), 3.85–3.82 (m, 1H),
3.59–3.55 (m, 1H), 3.53–3.49 (m, 1H), 2.84 (d, J = 4.1 Hz, 3H), 2.43–2.40 (m, 2H), 2.10 (s, 3H),
2.05–2.01 (m, 9H), 1.89–1.86 (m, 2H), 1.09 (d, J = 5.5 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
173.2, 170.1, 170.0, 169.5, 169.3, 169.0, 156.3, 136.3, 128.6, 128.3, 128.2, 91.7, 74.8, 72.8,
72.7 70.3, 68.5, 67.8, 67.2, 61.5, 58.0, 31.0, 26.3, 25.1, 20.9, 20.6, 15.3; HRMS (FAB, m/z)
calcd for (M+H)+ C31H43N2O15: 683.2663, found: 683.2668.
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10aF: colorless oil; IR (neat, cmꢀ1) 3395, 3322, 2940, 2876, 1752, 1669, 1516; H NMR (500
MHz, CDCl3) δ 7.37–7.30 (m, 5H), 6.58 (s (br), 1H), 5.87 (s, 1H), 5.80 (s (br), 1H), 5.49 (d, J =
2.9 Hz, 1H), 5.27 (t, J = 9.7 Hz, 1H), 5.18–5.12 (m, 3H), 4.30–4.27 (m, 2H), 4.15 (d, J = 10.9
Hz, 1H), 3.83–3.81 (m, 2H), 3.52–3.49 (m, 3H), 2.83 (d, J = 4.6 Hz, 3H), 2.41 (t, J = 6.9 Hz,
2H), 2.20 (s, 3H), 2.10–2.00 (m, 9H), 1.92–1.88 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 173.2,
170.6, 170.2, 169.9, 169.8, 168.5, 156.2, 136.2, 128.6, 128.3, 128.2, 90.4, 73.2, 70.7, 70.3, 70.2,
68.3, 67.2, 65.5 62.1, 54.3, 30.8, 26.4, 24.7, 20.8, 20.8, 20.7, 20.6 ; HRMS (FAB, m/z) calcd for
(M+Na)+ C30H40N2NaO15: 691.2326, found: 691.2325.
10aG: white solid, mp 130–131°C; IR (KBr, cmꢀ1) 3310, 2956, 2870, 1749, 1685, 1659, 1537;
1H NMR (500 MHz, CDCl3) δ 7.29–7.22 (m, 5H), 6.59 (s (br), 1H), 6.38 (d (br), J = 8.6 Hz,
1H), 6.13 (s (br), 1H), 5.78 (d (br), J = 6.9 Hz, 1H), 5.24 (t, J = 10.0 Hz, 1H), 5.14–5.06 (m, 3H),
4.50–4.45 (m, 1H), 4.21–4.17 (m, 2H), 4.00–3.96 (m, 2H), 3.75–3.72 (m, 1H), 3.39–3.32 (m,
3H), 2.73 (d, J = 4.6 Hz, 3H), 2.22–1.95 (m, 14H), 1.75–1.71 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 172.2, 170.4, 169.7, 169.6, 168.2, 168.1, 155.3, 135.0, 127.6, 127.3, 127.1, 89.6, 69.8,
69.0, 68.7, 68.5, 66.8, 66.2, 60.6, 53.6, 49.7, 31.5, 25.3, 24.3, 20.0, 19.8, 19.7, 19.6; HRMS
(FAB, m/z) calcd for (M+Na)+ C30H41N3NaO14: 690.2486, found: 690.2474.
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MHz, CDCl3) δ 7.41–7.30 (m, 5H), 6.49 (s (br), 1H), 5.76 (s (br), 1H), 5.53 (s (br), 1H), 5.13 (s,
2H), 4.58–4.50 (m, 1H), 4.45–4.26 (m, 3H), 3.89–3.81 (m, 1H), 3.76 (s, 3H), 3.60ꢀ3.42 (m, 3H),
2.83 (d, J = 4.0 Hz, 3H), 2.36 (t, J = 6.6 Hz, 2H), 1.92–1.81 (m, 2H), 1.46 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 173.2, 170.6, 170.5, 156.3, 155.3, 136.1, 128.7, 128.6, 128.3, 80.4, 70.4,
70.2, 67.3, 64.3, 54.4, 52.9, 31.0, 28.4, 28.3, 26.3, 24.8; HRMS (FAB, m/z) calcd for (M+H)+
C25H38N3O10: 540.2557, found: 540.2549.
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10bH: colorless oil; IR (neat, cmꢀ1) 3359, 2974, 1740, 1711, 1672, 1512, 1454; H NMR (500
MHz, CDCl3) δ 7.48–7.29 (m, 5H), 6.52 (s (br), 1H), 5.78 (s (br), 1H), 5.52 (s (br), 1H),
5.15–5.10 (m, 2H), 4.59–4.56 (m, 1H), 4.47–4.30 (m, 2H), 4.21–4.18 (m, 1H), 4.01–3.95 (m,
1H), 3.76 (s, 3H), 3.64–3.41 (m, 2H), 2.84 (d, J = 4.6 Hz, 3H), 2.44–2.27 (m, 2H), 1.92–1.79 (m,
2H), 1.45 (s, 9H), 1.09 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.2, 170.4, 170.0,
156.4, 155.3, 136.2, 128.7, 128.4, 128.2, 80.4, 74.8, 68.3, 67.2, 64.3, 58.2, 53.0, 52.8, 30.9, 28.4,
26.4, 25.1, 15.4; HRMS (FAB, m/z) calcd for (M+H)+ C26H40N3O10: 554.2714, found: 554.2717.
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10aI: colorless oil; IR (neat, cmꢀ1) 3352, 2974, 2879, 1739, 1718, 1675, 1512; H NMR (500
MHz, CDCl3) δ 7.41–7.28 (m, 5H), 6.62 (s (br), 1H), 5.84 (s (br), 1H), 5.50–5.39 (m, 2H), 5.12
(s, 2H), 4.51–4.37 (m, 1H), 4.32 (s, 1H), 3.91–3.78 (m, 1H), 3.71 (s, 3H), 3.59–3.38 (m, 3H),
2.82 (d, J = 4.6 Hz, 3H), 2.42–2.23 (m, 2H), 1.91–1.76 (m, 2H), 1.45 (s, 9H), 1.29 (d, J = 6.3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.4, 171.1, 170.6, 156.3, 156.0, 136.2, 128.6, 128.3,
128.2, 80.3, 70.5, 70.4, 70.1, 67.2, 57.1, 54.4, 52.7, 31.1, 28.3, 26.4, 24.8, 17.1; HRMS (FAB,
m/z) calcd for (M+H)+ C26H40N3O10: 554.2714, found: 554.2708.
10aJ: white solid, mp 123–124°C; IR (KBr, cmꢀ1) 3304, 2975, 2876, 1752, 1714, 1690, 1654,
1533, 1511; 1H NMR (500 MHz, CDCl3) δ 7.46–7.30 (m, 5H), 7.12 (d, J = 8.0 Hz, 2H), 7.01 (d,
J = 8.0 Hz, 2H), 6.42 (s (br), 1H), 5.74 (s (br), 1H), 5.12 (s, 2H), 5.02 (s (br), 1H), 4.61–4.52 (m,
1H), 4.33–4.21 (m, 1H), 3.96–3.80 (m, 1H), 3.70 (s, 3H), 3.65–3.45 (m, 3H), 3.20–2.96 (m, 2H),
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2.77 (d, J = 4.6 Hz, 3H), 2.67–2.53 (m, 2H), 2.09–1.93 (m, 2H), 1.42 (s, 9H) 13C NMR (125
MHz, CDCl3) δ 172.3, 172.1, 170.5, 156.2, 155.2, 149.7, 136.1, 133.8, 130.4, 128.7, 128.4,
128.2, 121.6, 80.1, 70.4, 70.3, 67.3, 54.4, 54.3, 52.4, 37.8, 31.4, 28.4, 26.4, 24.9; HRMS (FAB,
m/z) calcd for (M+H)+ C31H42N3O10: 616.2870, found: 616.2875.
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10aK: colorless oil; IR (neat, cmꢀ1) 3304, 2957, 2878, 1709, 1688, 1653, 1540; H NMR (500
MHz, CDCl3) δ 7.35 (s, 5H), 6.81 (s (br), 1H), 6.29 (s (br), 1H), 5.93 (s (br), 1H), 5.31 (s (br),
1H), 5.12 (s, 2H), 4.45–4.15 (m, 2H), 3.90–3.78 (m, 1H), 3.72 (s, 3H), 3.55–3.38 (m, 3H),
3.25–3.20 (m, 2H), 2.82 (d, J = 4.6 Hz, 3H), 2.25–2.14 (m, 2H), 1.94–1.71 (m, 3H), 1.71–1.59
(m, 1H), 1.59–1.33 (m, 13H); 13C NMR (125 MHz, CDCl3) δ 173.5, 173.1, 170.9, 156.4, 155.7,
136.1, 128.6, 128.4, 128.2, 80.0, 70.3, 69.8, 67.3, 54.6, 53.4, 52.4, 39.1, 33.1, 32.2, 29.0, 28.4,
26.5, 25.7, 22.7; HRMS (FAB, m/z) calcd for (M+H)+ C28H45N4O9: 581.3200, found: 581.3193.
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13: white solid, mp 122–123°C; IR (KBr, cmꢀ1) 3300, 2963, 2874, 1760, 1692, 1645, 1540; H
NMR (500 MHz, CDCl3) δ 7.35–7.32 (m, 5H), 6.95 (d (br), J = 7.4 Hz, 1H), 6.71 (s (br), 1H),
5.72 (d, J = 8.6 Hz, 2H), 5.32–5.27 (m, 1H), 5.16–5.10 (m, 4H), 4.51 (s, 1H), 4.26–4.23 (m, 1H),
4.15–4.06 (m, 2H), 3.91–3.83 (m, 2H), 3.56–3.41 (m, 3H), 2.79 (s, 3H), 2.39–2.35 (m, 2H),
2.23–1.86 (m, 15H), 1.01–0.88 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 173.2, 171.3, 170.2,
170.1, 169.7, 169.4, 169.1, 157.0, 136.2, 128.7, 128.4, 128.2, 91.7, 72.8, 72.6, 70.2, 70.0, 69.8,
67.8, 67.2, 61.5, 61.0, 52.4, 30.9, 30.8, 26.4, 24.7, 20.9, 20.6, 19.3, 17.6; HRMS (FAB, m/z)
calcd for (M+H)+ C35H50N3O16: 768.3191, found: 768.3162.
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14: white solid, mp 141–142°C; IR (KBr, cmꢀ1) 3302, 2991, 2926, 1684, 1655, 1577, 1550; H
NMR (500 MHz, CDCl3) δ 7.47–7.23 (m, 5H), 6.39 (s (br), 1H), 5.65 (s (br), 1H), 5.10 (s, 2H),
4.29–4.20 (m, 1H), 3.83–3.77 (m, 1H), 3.46–3.39 (m, 1H), 3.34 (s, 3H), 2.81 (d, J = 5.2 Hz,
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3H); C NMR (125 MHz, CDCl3) δ 170.5, 156.2, 136.1, 128.7, 128.4, 128.3, 72.0, 67.3, 59.2,
54.2, 26.5; HRMS (FAB, m/z) calcd for (M+H)+ C13H19N2O4: 267.1345, found: 267.1324.
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15: white solid, mp 141ꢀ142°C; IR (KBr, cmꢀ1) 3305, 2982, 2902, 1684, 1651, 1576, 1546; H
NMR (600 MHz, CDCl3) δ 7.43–7.26 (m, 5H), 6.39 (s (br), 1H), 5.67 (s (br), 1H), 5.11 (s, 2H),
4.29–4.20 (m, 1H), 3.84–3.76 (m, 1H), 3.49–3.40 (m, 1H), 3.35 (s, 2H), 2.81 (d, J = 5.0 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 170.5, 156.2, 136.1, 128.7, 128.4, 128.3, 72.0, 67.3, 59.2 (t,
J = 21.7 Hz), 54.2, 26.5; HRMS (FAB, m/z) calcd for (M+H)+ C13H18DN2O4: 268.1408, found:
268.1411.
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16: white solid, mp 172–173°C; IR (KBr, cmꢀ1) 3299, 2961, 2227, 1685, 1647, 1536; 1H NMR
(500 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.38–7.27 (m, 7H), 6.37 (s (br), 1H), 5.66 (s (br),
1H), 5.12 (s, 2H), 4.58 (s, 2H), 4.41–4.30 (m, 1H), 3.99–3.91 (m, 1H), 3.67–3.58 (m, 1H), 2.83
(d, J = 4.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.2, 156.1, 143.0, 136.0, 132.4, 128.7,
128.5, 128.3, 127.8, 118.8, 111.7, 72.5, 70.3, 67.5, 54.5, 26.5; HRMS (FAB, m/z) calcd for
(M+H)+ C20H22N3O4: 368.1610, found:368.1613.
Supporting Information
1H and C NMR spectra data for all compounds. This material is available free of charge via
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Internet at http://pubs.acs.org/.
Acknowledgments
This work was partially supported by the Japan Society for the Promotion of Science (JSPS),
GrantꢀinꢀAid no. 17K05779, for scientific research. Y. Y. thanks Prof. S. H. Gellman at UW
Madison. This method was inspired while visiting his lab.
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