Sequential Intermolecular Radical Addition and Reductive Radical Cyclization of Tyrosine and Phenylalanine Derivatives with Alkenes via Photoinduced Decarboxylation: Access to Ring-Constrained γ-Amino Acids

Article abstract of DOI:10.1021/acs.joc.9b00970

Sequential radical addition to alkenes and reductive radical cyclization of phenylalanine and tyrosine derivatives via photoinduced decarboxylation furnished ring-constrained γ-amino acids under mild conditions. A variety of alkenes such as acrylamides and acrylic esters could be employed in the photoinduced radical cascade cyclization. The yields of the ring-constrained γ-amino acids are dependent on the electron-accepting ability and steric hindrance of the alkene used. The proposed sequential reaction can also be applied for direct tethering of dipeptides to yield unique ring-constrained tetrapeptides.

Full text of DOI:10.1021/acs.joc.9b00970

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Article
Sequential Intermolecular Radical Addition and Reductive Radical
Cyclization of Tyrosine and Phenylalanine Derivatives with Alkenes via
Photoinduced Decarboxylation: Access to Ring-constrained #-Amino Acids
Kazuyuki Osaka, Ayuka Usami, Tomoya Iwasaki, Mugen Yamawaki, Toshio Morita, and Yasuharu Yoshimi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00970 • Publication Date (Web): 17 Jun 2019
Downloaded from http://pubs.acs.org on June 17, 2019
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Sequential Intermolecular Radical Addition and Reductive Radical Cyclization of
Tyrosine and Phenylalanine Derivatives with Alkenes via Photoinduced
Decarboxylation: Access to Ring-constrained γ-Amino Acids
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Kazuyuki Osaka, Ayuka Usami, Tomoya Iwasaki, Mugen Yamawaki, Toshio Morita, Yasuharu
Yoshimi*
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering,
University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
Corresponding author; Y. Yoshimi Tel: +81-776-27-8633, Fax: +81-776-27-8747
E-mail of corresponding author: yyoshimi@u-fukui.ac.jp
TOC

h
R
R
Phen
1,3-DCB
NaOH
Phen:
R'
+
O
R'
1,3-DCB: NC
BocHN
CO2H
BocHN
Alkene
Phenylalanine
Tyrosine
CN
O
R' = NH2, NHt-Bu,
-
Ring-constrained Amino Acids
OCH2CH3,
R = H, OBoc
Ot-Bu, et. al.

h
O
Phen
1,3-DCB
NaOH
H
H
O
H
H
N
N
CO2Me
N
CO2H
N
N
CO2Me
BocHN
N
H
BocHN
H
O
O
O
O
OBoc
OBoc
▪Abstract
Sequential radical addition to alkenes and reductive radical cyclization of phenylalanine and
tyrosine derivatives via photoinduced decarboxylation furnished ring-constrained γ-amino acids
under mild conditions. A variety of alkenes such as acrylamides and acrylic esters could be
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employed in the photoinduced radical cascade cyclization. The yields of the ring-constrained
γ-amino acids are dependent on the electron-accepting ability and steric hindrance of the alkene
used. The proposed sequential reaction can also be applied for direct tethering of dipeptides to
yield unique ring-constrained tetrapeptides.
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▪Introduction
Radical cascade (tandem) reactions have been considered as powerful and facile tools for the
preparation of complex organic molecules.1 This sequential radical reaction has been applied to
synthesize numerous valuable heterocycles and fused structures,2 especially, some natural
products such as (S)-mappicine and (+)-strychnine.3 In this protocol, alkyl radicals are generated
by the reaction of an organic halide (RX where X = Br or I) with AIBN as the radical initiator
and Bu3SnH as the halogen and/or hydrogen transfer agent. However, the utility of this method
is limited by the toxicity of the substrates and reagents, as well as the difficulties associated with
the removal of tin containing byproducts (Bu3SnX).
Recently, photoindued decarboxylative radical reactions of aliphatic carboxylic acids in the
presence of
a
photoredox catalyst have been established as an effective and
environmentally-friendly method for the generation of alkyl radicals.4-7 This is because
carboxylic acids occur widely in nature and are easy to handle; moreover, decarboxylation
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releases the nonflammable and nontoxic product CO2 under mild conditions (e.g., at room
temperature), and light is a traceless reagent. According to our previous report,5
decarboxylation of aliphatic carboxylic acids by the radical cation of phenanthrene (Phen) via
photoinduced electron transfer (PET) between the excited state of Phen and 1,4-dicyanobenzene
(1,4-DCB) furnished alkyl radicals (Scheme 1a). These radicals reacted with a variety of radical
acceptors to provide the corresponding products in high yields. In particular, the addition of
alkyl radicals to electron-deficient alkenes proceeds efficiently to generate the addition-radical,
even with the use of only 1 eq. of alkene.6 Subsequently, back electron transfer (BET) from the
radical anion of 1,4-DCB to the resulting radical generates an anion, which is protonated to
generate the adduct in high yields. This finding encouraged us to explore the intermolecular
radical addition of carboxylic acids to N-acryloyl amino acid esters and peptides as radical
acceptors via PET-promoted decarboxylation, because N-alkylcarbonyl amino acids and
peptides are potential pharmaceutical agonists and inhibitors.7 During this investigation, it was
unexpectedly revealed that sequential radical addition and reductive cyclization of
phenylalanine and tyrosine derivatives with acrylamides onto the benzene ring occurred to
afford ring-constrained γ-amino acids (Scheme 1b). To the best of our knowledge, this is the
first example of sequential intermolecular radical addition to alkenes and reductive radical
cyclization onto the benzene ring. Furthermore, the ring-constrained γ-amino acids are
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structurally similar to 3-aminocyclohexane carboxylic acid (Scheme 1c (a)), which is used as
the building block for peptide nanotubes8 (Scheme 1c (b)) and “foldamers”9 (Scheme 1c (b), (c),
and (d)). Herein, we report a facile and metal-free route to ring-constrained γ-amino acids via a
new radical cascade reaction of tyrosine and phenylalanine with acrylamides and acrylic esters,
initiated by PET-promoted decarboxylation under mild photoredox catalyst conditions.
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Scheme 1. a. PET-promoted Decarboxylative Radical Addition of Carboxylic Acids to Alkenes,
b. Sequential Intermolecular Radical Addition and Reductive Radical Cyclization of
Phenylalanine and Tyrosine Derivatives with Alkenes via PET-promoted Decarboxylation, and
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c. Examples of Ring-constrained -Amino Acids.
a. Previous work
Phen*
1,4-DCB

h
Phen:
Phen
1,4-DCB:
NC
+H
CN
Phen
– CO2
1,4-DCB
O
O
O
– H
X
X
X
X
R
R
R
R
R
O
R
O
O
R
OH
Alkyl radicals
(X = CN, CO2CH3, CO2H, SO2Ph)
b. This work

h
R
R
1,3-DCB:
R'
Phen
1,3-DCB
NaOH
NC
R'
+
CN
BocHN
CO2H
BocHN
Alkene
Phenylalanine
Tyrosine
O
R' = NH2, NHt-Bu,
OCH2CH3,

Ring-constrained -amino acids
R = H, OBoc
Ot-Bu, et. al.

c. Examples of ring-constrained -amino acids
(d)
(a)
(c)
(b)
O
H
H
H
N
OH
N
N
N
H
H2N
N
H
N
O
H
O
R"
R"
O
3-Aminocyclohexane
carboxylic acid

Ring-constrained -amino acids containing peptide
nanotubes and foldamers
▪Results and Discussion
Initially, we attempted to optimize the photochemical reaction conditions by using
N-Boc-L-tyrosine(OBoc) 1a (Boc = t-butoxycarbonyl) and acrylamide 2A (Scheme S1 and
Table S1 in SI). The use of 1,3-dicyanobenzene (1,3-DCB) instead of 1,4-DCB as an electron
acceptor resulted in improved product yields because substitution between the radical generated
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via photoinduced decarboxylation and the radical anion of 1,3-DCB suppressed the formation of
alkylcyanobenzene, as reported by us.10 Irradiation (100 W high-pressure mercury lamp with a
Pyrex glass filter; λ > 280 nm) of 1a (5 mM) in an aqueous acetonitrile solution (CH3CN/H2O =
9:1, v/v) containing Phen (5 mM), 1,3-DCB (5 mM), and 2A (5 mM) under the optimized
conditions in an argon atmosphere for 6 h at room temperature afforded major ring-constrained
γ-amino acid 3aA (47%), minor ring-constrained γ-amino acid 4aA (15%), and adduct 5aA
(24%) as all-racemic mixtures (Scheme 2). The structure and stereochemistry of cyclized
product 3aA was confirmed by measurement of NOESY (as shown in SI) and X-ray
crystallographic analysis (Figure 1), and Boc-protected amino group, carbamoyl group, and ring
junction part in 3aA are in equatorial positions. Measurement of NOESY of the minor product
4aA (as shown in SI) suggested that 4aA which the carbamoyl group occupies an axial position
is diastereomer of 3aA, even though stereochemistry of 4aA was not confirmed at present, and
further investigation about stereochemistry of 4aA is underway. When the corresponding
D-tyrosine derivative 1b was subjected to the photochemical conditions, almost identical
product yields were observed, indicating that the chirality at the -position in 1a,b did not affect
the photoreaction. The radical at the -position generated from chiral N-Boc-L--amino acids
via photoinduced decarboxylation lost its chirality to yield a racemic mixture of the products
due to the generation of the planar radical by hyperconjugation (-radical).6 Moreover,
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all-racemic mixtures of 3aA, 4aA, and 5aA in the photoreaction with 1a or 1b were observed
even though chiral 1a and 1b were used as the substrates. As reported by us earlier,11 the
unprotected phenolic OH group of tyrosine prevented PET-induced decarboxylation, and
protection of the phenolic OH by the Boc group in 1 is essential for the promoting photoinduced
decarboxylative reactions.
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Scheme 2. Photoreactions of N-Boc-L-tyrosine(OBoc) 1a or N-Boc-D-tyrosine(OBoc)1b with
Acrylamide 2A.

h , 6 h
OBoc
OBoc
Phen (5 mM)
1,3-DCB (5 mM)
NaOH (5 mM)
NH2
or
+
CH3CN/H2O = 9:1
O
BocHN
1b (5 mM)
BocHN
1a (5 mM)
CO2H
CO2H
2A (5 mM)
NOESY correlations
OBoc
H
2
H
+
NH2
4
BocHN
BocHN
5
H
4a
OBoc
O
H2NOC
H
3aA
1a
: 47% from
48% from 1b
OBoc
OBoc
H
CONH2
+
NH2
NH2
BocHN
BocHN
BocHN
5aA
OBoc
H
H
O
H
O
4aA
1a
: 15% from
1a
: 24% from
15% from 1b
25% from 1b
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H
H
BocHN
≡
OBoc
H2NOC
H
3aA
Figure 1. X-ray Crystallographic Analysis of 3aA.
Next, the effect of alkenes 2B–I in the photoinduced decarboxylative radical reactions of 1a
was evaluated (Table 1). Photoreactions of 1a with slightly bulky N-alkyl substituted
acrylamides such as N-isopropyl acrylamide 2B and N-tert-butyl acrylamide 2C marginally
decreased the yields of cyclized products 3aB–aC and 4aB–aC. The use of the bulkier
acrylamide such as N,N-dimethyl acrylamide 2D decreased the yields of cyclized products 3aD
and 4aD, but increased the yield of adduct 5aD. These results indicated that reductive
cyclization onto benzene rings with acrylamides was weakly dependent on the steric hindrance
of the acrylamide. Interestingly, the use of acrylic esters such as ethyl acrylate 2E and t-butyl
acrylate 2F instead of acrylamide exclusively afforded major ring-constrained γ-amino acids
3aE (34%) and 3aF (40%) without minor product 4, along with adducts 5aE (42%) and 5aF
(43%). The strong electron-accepting ability of alkenes such as acrylonitrile 2G and styrene 2H,
and the high steric hindrance of alkene such as methacrylamide 2I at the position of radical
generation prevented the formation of cyclized products 3 and 4, and exclusively yielded
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adducts (5aG: 58%, 5aH: 61%, 5aI: 88%). Thus, the ratio of the photoreaction products was
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strongly dependent on the electron-accepting ability and steric hindrance of the alkene used.
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Table 1. Effect of Alkenes 2A–I in Photoreaction of 1a.

h , 6 h
Phen (5 mM)
1,3-DCB (5 mM)
NaOH (5 mM)
OBoc
OBoc
OBoc
OBoc
+
+
+
R'
CH3CN/H2O = 9:1
2B-I
(5 mM)
BocHN
R'
4aB-aI
BocHN
1a
BocHN
R'
BocHN
R'
5aB-aI
CO2H
(5 mM)
3aB-aI
O
O
O
O
N
OEt
N
N
H
H
2E
2D
2B
2C
3aE: 34% 4aE: 0%
3aD
4aD
: 9%
: 41%
: 29%
5aD
3aB
: 38%
4aB
3aC
4aC
: 16%
: 31%
: 10%
: 23%
: 31%
5aC
5aE
: 42%
5aB
O
O
CN
2G
O
NH2
2F
3aF: 40% 4aF: 0%
5aF
2H
2I
3aG
: 0%
4aG
: 0% 3aH: 0% 4aH: 0% 3aI: 0% 4aI: 0%
5aG: 58% 5aH 5aI
: 43%
: 61%
: 88%
Next, the substrate scope of the radical cascade reaction was investigated using
N-Boc-L-phenylalanine 1c and 3-phenylpropionic acid derivatives 6 and 9. The weaker
electron-donating ability of the benzene ring of 1c compared to that of 1a decreased the yields
of major cyclized products 3cA,3cF and minor product 4cA, while slightly increased the yields
of adducts 5cA,5cF,5cG (Scheme 3). Similar trends in the product ratio were observed for 1c.
The use of 3-phenylpropionic acid 6 and phenoxyacetic acid 9, which lack the amine unit
bearing the N-Boc group in 1a–c, did not lead to the formation of the desired cyclized products
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7 and 10, and only adducts 8 and 11 were obtained (Scheme 4). Thus, we conclude that radical
cyclization via photoinduced decarboxylation requires tyrosine and phenylalanine derivatives as
the substrates.
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Scheme 3. Photoreactions of N-Boc-L-Phenylalanine 1c with 2A,F,G.

h , 6 h
Phen (5 mM)
1,3-DCB (5 mM)
NaOH (5 mM)
+
+
R'
+
CH3CN/H2O = 9:1
2A F G
, ,
BocHN
1c
CO2H
(5 mM)
(5 mM)
BocHN
R'
R'
: 18%
BocHN
3cA
BocHN
R'
: 33%
5cF: 54%
5cG: 72%
4cA
4cF: 0%
5cA
: 24%
3cF: 24%
3cG: 0%
4cG: 0%
Scheme 4. Photoreactions of 6 and 9 with 2A.

h , 6 h
Phen (5 mM)
1,3-DCB (5 mM)
NaOH (5 mM)
2A
(5 mM)
+
+
+
NH2
CH3CN/H2O = 9:1
NH2
CO2H
O
: 0%
O
: 26%
6
(5 mM)
7
8

h , 6 h
Phen (5 mM)
1,3-DCB (5 mM)
NaOH (5 mM)
O
O
O
2A
(5 mM)
+
NH2
CH3CN/H2O = 9:1
NH2
CO2H
O
O
: 30%
9
(5 mM)
10
: 0%
11
Finally, the sequential photoinduced decarboxylative radical cascade reaction of dipeptide 1d
(N-Boc-ValTyr(OBoc)OH) having a tyrosine residue was demonstrated (Scheme 5). A similar
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photoreaction of dipeptide 1d with 2A led to the formation of dipeptides 3dA (36%) and 4dA
(6%) containing the ring-constrained γ-amino acid along with adduct 5dA (3%). The connection
between 1d and N-acryloyl dipeptide 2J with the ring-constrained γ-amino acid in the
photoinduced decarboxylative radical reaction was successfully achieved to yield
ring-constrained tetrapeptides 3aJ (29%) and 4aJ (6%). Although the low solubility of the
resulting peptides decreased the yields of the ring-constrained peptides, the photochemical
method can allow for the direct tethering of peptides containing a ring-constrained γ-amino acid.
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Scheme 5. Photoreactions of 1d with 2A,J.
8
9

h , 6 h
Phen (5 mM)
1,3-DCB (5 mM)
NaOH (5 mM)
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O
H
N
H
N
CO2H
2A
(5 mM)
+
BocHN
NH2
BocHN
CH3CN/H2O = 9:1
O
O
OBoc
OBoc
1d
(5 mM)
3dA: 36%
O
O
H
H
N
N
BocHN
NH2
BocHN
NH2
+
+
O
O
OBoc
OBoc
5dA: 3%
4dA: 6%

h , 6 h
O
Phen (5 mM)
1,3-DCB (5 mM)
NaOH (5 mM)
O
H
H
H
N
N
N
CO2Me
CO2Me
BocHN
N
H
N
+
H
O
O
CH3CN/H2O = 9:1
O
2
J (5 mM)
OBoc
3dJ: 29%
O
O
H
H
H
N
H
N
N
CO2Me
N
CO2Me
BocHN
N
H
BocHN
N
H
+
+
O
O
O
O
OBoc
OBoc
4dJ: 6%
5dJ: 12%
A plausible mechanism for the sequential radical addition and reductive radical cyclization of
1a by PET-promoted decarboxylation is shown in Scheme 6. The alkyl radical generated by
photoinduced decarboxylation adds to electron-deficient alkene 2 to form radical intermediate
12. As shown in Scheme 4, the presence of the amine unit bearing a Boc group in radical 12
promotes radical cyclization onto the benzene ring at the closed-space position. The resulting
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radical is reduced through BET from the radical anion of 1,3-DCB to yield ring-constrained
γ-amino acids 3 and 4, similar to Birch reduction, after protonation. We have previously
reported a similar reductive cyclization of alicyclic -amino acids onto the benzene ring at the
ipso-position via photoinduced decarboxylation under photoredox catalyst conditions.12 The rate
of radical cyclization onto the benzene ring is dependent on both the electron-donating ability of
the benzene ring of 1 and the steric hindrance of alkene 2. The photoreaction of 1a having a
strongly electron-donating benzene ring (C6H4OBoc) with 2A having low steric hindrance gave
the best yields of ring-constrained γ-amino acids 3aA and 4aA. A very bulky alkene such as 2I
restricted the radical cyclization to exclusively yield adduct 5aI. In addition to the radical
cyclization of 12, BET from the radical anion of 1,3-DCB to radical 12 proceeded to yield
adduct 5. In the cases of acrylonitrile 2G and styrene 2H, the strong electron-accepting ability
of radical 12 accelerated BET from the radical anion of 1,3-DCB to yield mainly adducts 5aG
and 5aH. Thus, the ratio of two competitive processes between the radical cyclization and BET
is determined by the electron-donating ability of the benzene ring in 1, steric hindrance of
alkene 2, and electron-accepting ability of radical 12. Although the difference in the product
ratio and stereochemistry between the acrylamide and the acrylic ester is not clear at present,
two six-membered transition states of radicals 12a and 12b in which the Boc-protected amino
group is in the equatorial position as shown in Scheme 6 led to the respective formation of 3 and
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4.
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Scheme 6. A Plausible Mechanism for Radical Cascade Reaction of 1 with 2.
1a

h
Photoinduced
Decarboxylation
- CO2
Phen
1,3-DCB
O
OBoc
OBoc
1,3-DCB
OBoc
R'
OBoc
R
OBoc
R'
1,3-DCB
2
+ H
R
BocHN
R
BET
BocHN
BocHN
BocHN
BocHN
O
O
O
O
12
3, 4
OBoc
+ H
OBoc
1,3-DCB
1,3-DCB
R'
R'
BET
BocHN
BocHN
O
O
5
H
H
R'OC
H
OBoc
OBoc
3, 4
BocHN
BocHN
R'OC
H
12a
12b
Conclusion
Sequential inter- and intramolecular radical cascade reactions of tyrosine and phenylalanine
derivatives 1 onto aromatic rings with acrylamides and acrylic esters 2 via PET-promoted
decarboxylation under mild conditions proceed efficiently to yield ring-constrained γ-amino
acids 3 and 4 in moderate yields. The product ratio is dependent on the electron-donating ability
of the benzene ring in 1, steric hindrance of alkene 2, and electron-accepting ability of radical
12. This organic photoredox catalyst method provides a facile and environmentally-friendly
route to unique ring-constrained γ-amino acids from simple starting materials such as
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phenylalanine, tyrosine, acrylamide, and acrylic ester. Further, our protocol allows for direct
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tethering of peptides with ring-constrained γ-amino acids.
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Experimental Section
General Information. All reagents and solvents were used as received from commercial
1
suppliers. IR spectra were recorded on an FT-IR spectrometer. H NMR spectra were recorded
in CDCl3 containing tetramethylsilane as an internal standard, and were acquired on either a 300
or 500 MHz spectrometers. 13C{1H} NMR spectra were acquired on a 125 MHz spectrometer.
High-resolution mass spectra were obtained using double-focusing magnetic sector mass
spectrometer coupled with FAB. The light source was a Riko UV-100HA high-pressure (100
W) mercury arc, and Pyrex vessels (18 mm x 180 mm) were directly attached to the light source
(λ > 280 nm, Phen mainly absorbed at 313 nm light). Column chromatography was performed
on Wakogel C-300, particle size 45-75 m. Further purification by GPC was conducted for 3aB,
4aB, 3aC, 4aC, 3aD, 4aD, 3cG, 4dA, 5dA, 3dJ, and 4dJ.
General procedure for synthesis of N-Boc tyrosine(OBoc) 1a,b
Benzyl alcohol (90 mmol, 14 mL) was added to a solution of L-tyrosine (30 mmol, 5.40 g) and
p-TsOH (5.70 g, 1.0 eq) in toluene (90 mL). The mixture was refluxed for 27 h using
Dean-Stark trap, and white solids was formed. The mixture was filtered to yield the desired
benzyl protected L-tyrosine p-toluenesulfonate as a white solid (8.44 g, 64%).
K2CO3 (0.871 g, 2.5 eq) and DMAP (0.0301 g, 0.10 eq) were added to the solution of benzyl
protected L-tyrosine p-toluenesulfonate (2.5 mmol, 1.10 g) and (Boc)2O (7.5 mmol, 1.7 mL) in
DMF (8.4 mL). The mixture was stirred at room temperature for 4 h, and quenched by water.
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The aqueous layer was acidified (1M HCl) to a pH 2–3 and then extracted with EtOAc, and
washed with brine. The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified by silica-gel column
chromatography using hexane/EtOAc = 20:1 as the eluent to yield N,O-bisBoc benzyl protected
L-tyrosine as a colorless liquid (1.10 g, quant.).
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Debenzylation of N,O-bisBoc benzyl protected L-tyrosine (1.5 mmol, 0.700 g) was carried out
by 10 % Pd/C (0.0427 g) and H2 in MeOH (3.0 mL) with TLC monitoring. After complete
consumption of starting material (about 1.5 h), the mixture was filtered through a celite, and
then concentrated under reduced pressure. The crude product was purified by silica-gel column
chromatography using hexane/EtOAc = 5:1 to 1:1 as the eluent to yield 1a as a white solid
(0.460 g, 83%).
Similar procedure from D-tyrosine (30 mmol, 5.40 g) provided 1b in the similar yield (0.460 g,
53%). Compounds 1a–c have been previously reported.
1
N-Boc-L-tyrosine(OBoc) 1a4b: H NMR (300 MHz, CDCl3) δH 9.09 (br, 1H), 7.19 (d, J = 8.4
Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.64 (br, 0.3H), 5.01 (br, 0.7H), 4.64–4.58 (m, 0.7H), 4.39 (br,
0.3H), 3.27–2.85 (m, 2H), 1.55 (s, 9H), 1.42 (s, 6H), 1.28 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δC 175.9, 175.5, 155.4, 151.9, 150.0, 133.4, 130.3, 121.3, 83.6, 81.6, 80.4, 54.1, 37.0,
28.2, 27.9, 27.6.
1
N-Boc-D-tyrosine(OBoc) 1b4b: H NMR (300 MHz, CDCl3) δH 9.35 (br, 1H), 7.19 (d, J = 8.6
Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 6.66 (br, 0.3H), 5.01 (br, 0.7H), 4.58–4.65 (m, 0.7H), 4.38 (br,
0.3H), 3.27–2.86 (m, 2H), 1.55 (s, 9H), 1.42 (s, 6H), 1.28 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δC 175.9, 175.1, 155.4, 151.9, 150.1, 133.4, 130.3, 121.3, 83.6, 81.7, 80.4, 54.1, 37.0,
28.2, 27.9, 27.6.
N-Boc-L-phenylalanine 1c6a: 1H NMR (300 MHz, CDCl3) δH 9.88 (br, 1H), 7.33–7.17 (m, 5H),
6.64 (br, 0.3H), 4.98 (br, 0.7H), 4.65–4.59 (m, 0.7H), 4.41 (br, 0.3H), 3.27–2.88 (m, 2H), 1.42
(s, 6H), 1.27 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δC 176.6, 175.9, 155.3, 135.8, 129.5,
129.3, 128.6, 127.1, 126.9, 80.3, 56.0, 54.2, 37.7, 28.2, 27.9.
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General procedure for synthesis of dipeptides N-BocValTyr(OBoc)OH 1d and N-Acryloyl
ValValOMe 7
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EDC hydrochloride (1.2 eq, 0.732 g) and HOBt·H2O (1.4 eq, 0.681 g) were added to solution
of N-BocValOH (3.2 mmol, 0.690 g), benzyl protected tyrosine p-toluenesulfonate (3.2 mmol,
1.41 g), and i-Pr2NEt (1.2 eq, 0.66 mL) in DMF (22 mL) at 0 °C. This mixture was stirred for 2
h at 0 °C, and overnight at room temperature, quenched by water, and then extracted with
EtOAc. The combined organic layer was washed with 0.1 M H2SO4, water, and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of a crude product was conducted by silica gel column chromatography using
hexane/ EtOAc = 2:1 as an eluent to yield N-BocValTyr(OH)CO2Bn as a white solid (1.18 g,
79%).
K2CO3 (1.5 eq, 0.260 g) and (Boc)2O (2.0 eq, 0.58 mL) were added to the solution of
N-BocValTyr(OH)CO2Bn (1.2 mmol, 0.601 g) in acetone (8.1 mL). The mixture was stirred at
room temperature for 2.5 h, quenched by water, and extracted with EtOAc. The combined
organic layer was washed with water and brine, and dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by silica-gel column chromatography using
hexane/EtOAc = 2:1 as the eluent to yield N-BocValTyr(OBoc)CO2Bn as a white solid (0.688 g,
94%).
Similar debenzylation of N-BocValTyr(OBoc)CO2Bn (0.52 mmol, 0.300 g) with 10% Pd/C
(0.0456 g) in MeOH (1.0 mL) and purification by silica-gel column chromatography using
hexane/EtOAc = 2:1 to 0:1 as the eluent yielded N-BocValTyr(OBoc)CO2H 1d as a white solid
(0.218 g, 84%). Synthesis of N-acryloyl dipeptide 2J has been previously reported by us.7
N-BocValTyr(OBoc)OH 1d: white solid, mp 86–87 °C; IR (KBr, cm-1) 3401, 2980, 1740, 1535,
1397; 1H NMR (300 MHz, CDCl3) δH 9.25 (br, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.6 Hz,
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2H), 6.90 (br, 1H), 5.37 (br, 1H), 4.84 (br, 1H), 4.04–3.86 (m, 1H), 3.21–2.98 (m, 2H), 2.08–
1.96 (m, 1H), 1.53 (s, 9H), 1.44 (s, 9H), 0.89–0.85 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3)
δC 173.6, 171.8, 156.1, 151.8, 150.0, 133.4, 130.4, 121.2, 83.5, 80.4, 60.0, 53.0, 36.7, 30.6, 28.3,
27.6, 19.1, 17.8; HRMS (FAB) calcd for (M+H)+ C24H37N2O8: 481.2550, found 481.2544.
N-Acryloyl ValValOMe 2J7: 1H NMR (300 MHz, CDCl3) δH 7.82 (br, 1H), 7.57 (br, 1H), 6.35–
6.19 (m, 2H), 5.59 (dd, J = 9.4, 2.5 Hz, 1H), 4.81–4.65 (m, 1H), 4.55–4.42 (m, 1H), 3.74 (s, 3H),
2.20–2.03 (m, 2H), 1.01–0.83 (m, 12H); 13C{1H} NMR (125 MHz, CDCl3) δC 172.3, 172.2,
165.6, 130.7, 126.6, 58.3, 57.5, 51.9, 31.5, 30.6, 19.1, 19.0, 18.6, 17.9.
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General procedure for the photoreaction of 1 with 2. An aqueous CH3CN solution (CH3CN
45 mL, H2O 5 mL) of 1 (5 mM), 2 (5 mM), NaOH (5 mM, 0.0100g), Phen (5 mM, 0.0455g),
and 1,3-DCB (5 mM, 0.0320g) in Pyrex vessels (18 mm x 180 mm) was purged with Ar for 10
min. The mixture was irradiated with a 100 W high-pressure mercury lamp for 6 h, and then the
solvent was removed under reduced pressure. The crude product was purified by silica-gel
column chromatography using hexane/EtOAc = 4:1 to 1:2 as the eluent to yield cyclized
products 3 and 4 along with adduct 5. Photoreactions of 6 and 9 with 2A were carried out under
the same conditions to yield 8 and 11. Compounds 5cG and 11 have been previously reported.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
4aR)-2-N-Boc-amino-4-carbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthalene (3aA):
1
0.0480 g, 47%, white solid, mp 218–219 °C; IR (KBr, cm-1) 3352, 2977, 1754, 1672, 1522; H
NMR (300 MHz, CDCl3) δH 5.81 (br, 1H), 5.62 (br, 1H), 5.50–5.44 (br, 2H), 4.62 (br, 1H), 3.53
(br, 1H), 3.04 (br, 1H), 2.85 (br, 1H), 2.60–2.56 (m, 1H), 2.20–2.09 (m, 2H), 1.91–1.82 (m, 2H),
1.49 (s, 9H), 1.43 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δC 175.3, 155.1, 151.3, 146.7,
133.1, 118.5, 112.8, 83.0, 79.4, 50.3, 49.3, 41.1, 39.8, 36.7, 29.7, 28.4, 27.9, 27.6; HRMS
(FAB) calcd for (M+H)+ C21H33N2O6: 409.2338, found 409.2320.
rac-(2S,
4S,
4aS)
and
(2R,
4R,
4aR)-2-N-Boc-amino-4-carbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthalene (4aA):
1
0.0153 g, 15%, white solid, mp 195–196 °C; IR (KBr, cm-1) 3447, 2978, 1710, 1672, 1502; H
NMR (300 MHz, CDCl3) δH 5.52 (br, 3H), 5.45 (br, 1H), 4.56 (br, 1H), 4.03 (br, 1H), 3.12 (br,
1H), 2.98–2.81 (m, 2H), 2.40–2.06 (m, 4H), 1.94–1.84 (m, 1H), 1.50 (s, 9H), 1.40 (s, 9H);
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13C{1H} NMR (125 MHz, CDCl3) δC 175.6, 154.8, 151.4, 146.5, 132.0, 119.7, 113.1, 83.1, 79.5,
47.5, 46.1, 40.1, 39.0, 34.3, 28.4, 28.0, 27.6; HRMS (FAB) calcd for (M+H)+ C21H33N2O6:
409.2338, found 409.2320.
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4-N-Boc-amino-5-(4’-O-Boc-phenoxy)pentylamide (5aA): (using hexane/EtOAc = 4:1 to 1:2,
and then chloroform/acetone = 3:1 as the eluent), 0.0245 g, 24%, white solid, mp 162–163 °C;
IR (KBr, cm-1) 3418, 3369, 2981, 1756, 1680, 1448; 1H NMR (300 MHz, CDCl3) δH ; 7.17 (d, J
= 8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 6.23 (br, 1H), 5.66 (br, 1H), 4.64 (br, 1H), 3.84 (br, 1H),
13
2.83–2.71 (m, 2H), 2.30–2.20 (m, 2H), 1.96–1.60 (m, 2H), 1.55 (s, 9H), 1.39 (s, 9H); C{1H}
NMR (125 MHz, CDCl3) δC 175.2, 156.0, 151.9, 149.5, 135.1, 130.1, 121.1, 83.5, 79.5, 51.0,
41.1, 32.5, 30.4, 28.2, 27.6; HRMS (FAB) calcd for (M+H)+ C21H33N2O6:409.2338, found
409.2326.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
4aR)-2-N-Boc-amino-4-N-isopropylcarbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthal
ene (3aB): (using hexane/EtOAc = 5:1 to chloroform/acetone = 10:1 as the eluent), 0.0428 g,
38%, white solid, mp 205–206 °C; IR (KBr, cm-1) 3284, 2974, 1758, 1686, 1550; 1H NMR (300
MHz, CDCl3) δH 5.63 (br, 1H), 5.46 (br, 1H), 5.35 (br, 1H), 4.75 (br, 1H), 4.01–4.12 (m, 1H),
3.50–3.48 (br, 1H), 3.03–2.99 (m, 1H), 2.81 (br, 2H), 2.57–2.53 (br, 1H), 2.11–1.83 (m, 3H),
1.70–1.56 (m, 1H), 1.49 (s, 9H), 1.43 (s, 9H), 1.16–1.11 (m, 6H); 13C{1H} NMR (125 MHz,
CDCl3) δC 171.6, 155.0, 151.3, 146.4, 133.5, 118.2, 112.8, 82.9, 79.4, 51.6, 49.4, 41.2, 40.2,
36.5, 28.4, 28.0, 27.6, 22.6; HRMS (FAB) calcd for (M+H)+ C24H39N2O6: 451.2807, found
451.2798.
rac-(2S,
4S,
4aS)
and
(2R,
4R,
4aR)-2-N-Boc-amino-4-N-isopropylcarbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthal
ene (4aB): (using hexane/EtOAc = 5:1 to chloroform/acetone = 10:1 as the eluent), 0.0113 g,
10%, white solid, mp 222–223 °C; IR (KBr, cm-1) 3363, 2978, 1747, 1631, 1528; 1H NMR (300
MHz, CDCl3) δH 5.49 (br, 1H), 5.40–5.33 (m, 2H), 4.55 (br, 1H), 4.13–4.01 (m, 2H), 3.13–3.11
(br, 1H), 2.87 (br, 2H), 2.39–2.35 (br, 1H), 2.21–1.87 (m, 4H), 1.50 (s, 9H), 1.45 (s, 9H), 1.14–
1.07 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δC 171.9, 155.0, 151.3, 146.3, 130.6, 119.0,
112.8, 83.0, 79.1, 52.2, 51.4, 49.4, 40.3, 36.6, 28.6, 28.3, 28.0, 27.6; HRMS (FAB) calcd for
(M+H)+ C24H39N2O6: 451.2807, found 451.2798.
4-N-Boc-amino-5-(4’-O-Boc-phenoxy)-N-isopropyl-pentylamide (5aB): (using hexane/EtOAc
= 5:1 to chloroform/acetone = 10:1 as the eluent), 0.0259 g, 23%, white solid, mp 106–107 °C;
1
IR (KBr, cm-1) 3349, 2930, 1758, 1684, 1456; H NMR (300 MHz, CDCl3) δH 7.17 (d, J = 8.7
Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 5.83 (br, 1H), 4.59–4.56 (br, 1H), 4.13–3.98 (m, 1H), 3.78 (br,
1H), 2.85–2.63 (m, 2H), 2.18–2.11 (m, 2H), 1.85–1.64 (m, 2H), 1.55 (s, 9H), 1.39 (s, 9H), 1.15–
1.12 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δC 171.9, 156.1, 152.1, 149.7, 135.5, 130.4,
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121.3, 83.7, 79.5, 51.5, 41.5, 33.7, 30.2, 28.5, 27.8, 22.9; HRMS (FAB) calcd for (M+H)+
C24H39N2O6: 451.2807, found 451.2810.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
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4aR)-2-N-Boc-amino-4-N-t-butylcarbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthalene
(3aC): (using hexane/EtOAc = 10:1 to chloroform/acetone = 10:1 as the eluent), 0.0360 g, 31%,
white solid, mp 237–238 °C; IR (KBr, cm-1) 3383, 2927, 1753, 1685, 1547; 1H NMR (300 MHz,
CDCl3) δH 5.47 (br, 1H), 5.40–5.37 (m, 2H), 4.58–4.55 (br, 1H), 3.54–3.46 (m, 1H), 3.04–2.94
(m, 1H), 2.83–2.81 (m, 2H), 2.58–2.53 (m, 1H), 2.17–2.05 (m, 1H), 1.92–1.77 (m, 2H), 1.66–
1.55 (m, 1H), 1.50 (s, 9H), 1.43 (s, 9H), 1.34 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δC
171.9, 155.0, 151.3, 146.3, 119.0, 112.8, 83.0, 52.2, 51.4, 49.4, 40.3, 36.6, 28.6, 28.0, 27.6;
HRMS (FAB) calcd for (M+H)+ C25H41N2O6: 465.2965, found 465.2988.
rac-(2S,
4S,
4aS)
and
(2R,
4R,
4aR)-2-N-Boc-amino-4-N-t-butylcarbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthalene
(4aC): (using hexane/EtOAc = 10:1 to chloroform/acetone = 10:1 as the eluent), 0.0186 g, 16%,
white solid, mp 219–220 °C; IR (KBr, cm-1) 3356, 2930, 1751, 1635, 1537; 1H NMR (300 MHz,
CDCl3) δH 5.49 (br, 1H), 5.38–5.33 (m, 2H), 4.57–4.55 (br, 1H), 4.03 (br, 1H), 3.12–3.07 (m,
1H), 2.87 (br, 2H), 2.39–2.31 (m, 1H), 2.02–2.16 (m, 1H), 2.00–1.88 (m, 3H), 1.51 (s, 9H), 1.46
(s, 9H), 1.34 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δC 172.3, 151.6, 146.2, 132.6, 119.3,
113.4, 83.2, 79.5, 51.5, 49.5, 46.3, 40.6, 39.2, 34.2, 28.5, 28.1, 27.7; HRMS (FAB) calcd for
(M+H)+ C25H41N2O6: 465.2965, found 465.2975 .
4-N-Boc-amino-5-(4’-O-Boc-phenoxy)-N-t-butyl-pentylamide (5aC): (using hexane/EtOAc =
10:1 to chloroform/acetone = 10:1 as the eluent), 0.0360 g, 31 %, white solid, mp 60 °C; IR
(KBr, cm-1) 3373, 2925, 1751, 1685, 1456; 1H NMR (300 MHz, CDCl3) δH 7.17 (d, J = 8.7 Hz,
2H), 7.08 (d, J = 8.7 Hz, 2H), 5.63 (br, 1H), 4.59–4.56 (br, 1H), 3.75 (br, 1H), 2.81–2.66 (m,
2H), 2.12–2.08 (m, 2H), 1.84–1.63 (m, 2H), 1.55 (s, 9H), 1.39 (s, 9H), 1.33 (s, 9H); 13C{1H}
NMR (125 MHz, CDCl3) δC 172.0, 155.8, 151.9, 149.5, 130.3, 121.1, 83.5, 79.2, 51.5, 51.1,
41.4, 34.3, 29.7, 28.7, 28.3, 27.6; HRMS (FAB) calcd for (M+H)+ C25H41N2O6: 465.2965, found
465.2990.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
4aR)-2-N-Boc-amino-4-N,N-dimethylcarbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphth
alene (3aD): (using hexane/EtOAc = 4:1 to chloroform/acetone = 3:1 as the eluent), 0.0316 g,
1
29%, white solid, mp 88–89 °C; IR (KBr, cm-1) 3365, 2978, 1752, 1634, 1523; H NMR (300
MHz, CDCl3) δH 5.50 (br, 1H), 5.29–5.28 (br, 1H), 4.53–4.51 (br, 1H), 3.53 (br, 1H), 3.17–3.05
(m, 1H), 3.02 (s, 3H), 2.97 (s, 3H), 2.86–2.84 (m, 2H), 2.66–2.57 (m, 2H), 2.08–2.03 (m, 1H),
1.92–1.83 (m, 1H), 1.69–1.57 (m, 1H), 1.48 (s, 9H), 1.43 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3) δC 173.0, 155.0, 151.2, 146.8, 133.5, 118.3, 113.1, 82.9, 79.4, 49.4, 45.5, 41.3, 40.4,
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37.5, 36.1, 35.7, 28.4, 28.0, 27.6; HRMS (FAB) calcd for (M+H)+ C23H37N2O6: 437.2652, found
437.2671.
rac-(2S,
4S,
4aS)
and
(2R,
4R,
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4aR)-2-N-Boc-amino-4-N,N-dimethylcarbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphth
alene (4aD): (using hexane/EtOAc = 4:1 to chloroform/acetone = 3:1 as the eluent), 0.00982 g,
9%, white solid, mp 161–162 °C; IR (KBr, cm-1) 3351, 2979, 1751, 1628, 1534; 1H NMR (300
MHz, CDCl3) δH 5.51 (br, 1H), 5.34 (br, 1H), 4.58–4.56 (br, 1H), 3.96 (br, 1H), 3.28–3.18 (m,
1H), 2.97 (s, 3H), 2.95 (s, 3H), 2.90–2.83 (m, 1H), 2.74–2.67 (m, 1H), 2.43–2.38 (m, 1H), 2.20–
2.10 (m, 2H), 1.79–1.65 (m, 2H), 1.49 (s, 9H), 1.45 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3)
δC 173.3, 154.9, 151.4, 146.3, 132.5, 119.9, 113.9, 83.0, 79.4, 46.4, 42.5, 40.3, 39.0, 37.0, 35.7,
33.3, 28.3, 28.0, 27.6; HRMS (FAB) calcd for (M+H)+ C23H37N2O6: 437.2652, found 437.2648.
4-N-Boc-amino-5-(4’-O-Boc-phenoxy)-N,N-dimethyl-pentylamide
(5aD):
(using
hexane/EtOAc = 4:1 to chloroform/acetone = 3:1 as the eluent), 0.0447 g, 41%, white solid, mp
84–85 °C; IR (KBr, cm-1) 3432, 2930, 1757, 1684, 1507; 1H NMR (300 MHz, CDCl3) δH 7.19 (d,
J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.69–4.66 (br, 1H), 3.77 (br, 1H), 2.95 (s, 3H), 2.92 (s,
3H), 2.77–2.61 (m, 2H), 2.38–2.28 (m, 2H), 1.89–1.66 (m, 2H), 1.55 (s, 9H), 1.40 (s, 9H);
13C{1H} NMR (125 MHz, CDCl3) δC 172.6, 155.6, 151.9, 149.4, 135.5, 130.3, 121.0, 83.4, 79.0,
51.8, 41.3, 37.1, 35.4, 29.9, 28.8, 28.2, 27.5; HRMS (FAB) calcd for (M+H)+ C23H37N2O6:
437.2652, found 437.2628.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
4aR)-2-N-Boc-amino-4-ethoxycarbonyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthalene
(3aE): (using hexane/EtOAc = 10:1 to 5:1 as the eluent), 0.0372 g, 34%, white solid, mp 99–
1
100 °C; IR (KBr, cm-1) 3373, 2946, 1751, 1725, 1688, 1522; H NMR (300 MHz, CDCl3) δH
5.50 (br, 1H), 5.37 (br, 1H), 4.61–4.52 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.51 (br, 1H), 3.13–
2.99 (m, 1H), 2.90–2.84 (m, 2H), 2.61–2.56 (m, 1H), 2.37–2.17 (m, 2H), 1.89–1.70 (m, 2H),
1.49 (s, 9H), 1.43 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δC 173.7,
154.9, 151.1, 146.9, 132.5, 118.9, 112.5, 83.1, 79.4, 60.6, 49.0, 41.3, 40.4, 36.5, 28.3, 27.9,
14.2; HRMS (FAB) calcd for (M+H)+ C23H36NO7: 438.2493, found 438.2480.
ethyl 4-N-Boc-amino-5-(4’-O-Boc-phenoxy)pentanoate (5aE): (using hexane/EtOAc = 10:1 to
5:1 as the eluent), 0.0459 g, 42%, white solid, mp 85–86 °C; IR (KBr, cm-1) 3332, 2930, 1760,
1681, 1457; 1H NMR (300 MHz, CDCl3) δH 7.18 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H),
4.11 (q, J = 7.1 Hz,, 2H), 3.80 (br, 1H), 2.84–2.69 (m, 2H), 2.35 (t, J = 7.3 Hz, 2H), 1.90–1.62
(m, 2H), 1.55 (s, 9H), 1.39 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3)
δC 173.5, 155.4, 151.9, 149.5, 135.3, 130.3, 121.1, 83.5, 79.2, 60.5, 51.3, 41.0, 31.2, 28.3, 27.6,
14.1; HRMS (FAB) calcd for (M+H)+ C23H36NO7: 438.2493, found 438.2495.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
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4aR)-2-N-Boc-amino-4-t-butoxycarbonyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthalene
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(3aF): (using hexane/EtOAc = 10:1 to 6:1 as the eluent), 0.0466 g, 40%, white solid, mp 80–
1
81 °C; IR (KBr, cm-1) 2984, 1756, 1718, 1692, 1523; H NMR (300 MHz, CDCl3) δH 5.49 (br,
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1H), 5.39 (br, 1H), 4.44 (br, 1H), 3.55 (br, 1H), 3.09–2.83 (m, 3H), 2.61–2.55 (m, 1H), 2.36–
2.14 (m, 2H), 1.87–1.58 (m, 2H), 1.49 (s, 9H), 1.45 (s, 9H), 1.44 (s, 9H); 13C{1H} NMR (125
MHz, CDCl3) δC 173.0, 154.9, 151.2, 146.7, 132.7, 118.7, 112.5, 82.6, 80.9, 79.4, 49.9, 49.2,
41.3, 39.8, 36.6, 28.3, 28.0, 27.6; HRMS (FAB) calcd for (M+H)+ C25H40NO7: 466.2805, found
466.2805.
t-butyl 4-N-Boc-amino-5-(4’-O-Boc-phenoxy)pentanoate (5aF): (using hexane/EtOAc = 10:1
to 6:1 as the eluent), 0.0500 g, 43%, colorless oil; IR (neat, cm-1) 3356, 2806, 1762, 1723, 1510,
1392; 1H NMR (300 MHz, CDCl3) δH 7.16 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.41–
4.30 (m, 1H), 3.78 (br, 1H), 2.26–2.14 (m, 2H), 1.83–1.64 (m, 2H), 1.55 (s, 9H), 1.43 (s, 9H),
1.39 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δC 172.1, 155.0, 151.9, 149.6, 135.3, 130.3,
121.0, 83.4, 80.3, 51.1, 49.7, 43.1, 42.1, 32.8, 28.3, 28.1, 27.6, 14.1; HRMS (FAB) calcd for
(M+H)+ C25H40NO7: 466.2805, found 466.2811.
4-N-Boc-amino-5-(4’-O-Boc-phenoxy)pentanitrile (5aG): (using hexane/EtOAc = 5:1 to 2:1 as
the eluent), 0.0566 g, 58%, white solid, mp 68 °C; IR (KBr, cm-1) 3385, 2933, 2243, 1759,
1456; 1H NMR (300 MHz, CDCl3) δH 7.20–7.09 (m, 4H), 4.44 (d, J = 9.2 Hz, 1H), 3.91–3.76 (m,
1H), 2.89–2.71 (m, 2H), 2.48–2.29 (m, 2H), 1.95–1.76 (m, 2H), 1.55 (s, 9H), 1.40 (s, 9H);
13C{1H} NMR (125 MHz, CDCl3) δC 155.5, 152.0, 149.9, 134.6, 130.3, 121.5, 119.6, 83.7, 79.9,
51.2, 40.6, 30.3, 28.3, 27.7, 14.4; HRMS (FAB) calcd for (M+H)+ C21H31N2O5: 391.2234, found
391.2220.
2-N-Boc-amino-4-phenyl-1-(4’-O-Boc-phenoxy)butane (5aH): (using hexane/EtOAc = 20:1 as
the eluent), 0.0673 g, 61%, white solid, mp 112–113 °C; IR (KBr, cm-1) 3393, 2930, 1760,
1
1456; H NMR (300 MHz, CDCl3) δH 7.24–7.06 (m, 9H), 4.36–4.33 (br, 1H), 3.87 (br, 1H),
2.80–2.65 (m, 4H), 1.86–1.74 (m, 2H), 1.55 (s, 9H), 1.42 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3) δC 155.4, 152.0, 149.6, 141.7, 135.5, 130.4, 128.4, 125.9, 121.1, 83.5, 79.2, 51.3, 40.7,
36.0, 32.5, 28.4, 27.7; HRMS (FAB) calcd for (M+H)+ C26H36NO5: 442.2594, found 442.2599.
4-N-Boc-amino-5-(4’-O-Boc-phenoxy)-2-methylpentylamide (5aI): (diastereomer mixture,
using hexane/EtOAc = 10:1 to 3:1 as the eluent), 0.0930 g, 88%, white solid, mp 90 °C; IR
(KBr, cm-1) 3420, 2933, 1757, 1684, 1457; 1H NMR (300 MHz, CDCl3) δH 7.16–7.08 (m, 4H),
6.98 (br, 1H), 5.56 (br, 1H), 4.50–4.45 (m, 1H), 3.99 (br, 1H), 2.84–2.61 (m, 2H), 2.39–2.34 (m,
1H), 1.97–1.76 (m, 2H), 1.55 (s, 9H), 1.38 (s, 9H), 1.12 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (125
MHz, CDCl3) δC 179.2, 155.7, 151.9, 149.5, 135.4, 130.3, 121.1, 83.5, 79.3, 50.7, 41.6, 38.3,
37.9, 28.3, 28.2, 27.6, 18.4; HRMS (FAB) calcd for (M+H)+ C22H35N2O6: 423.2496, found
423.2498.
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rac-(2S,
4R,
4aS)
and
(2R,
(3cA):
4S,
4aR)-2-N-Boc-amino-4-carbamoyl-1,2,3,4,4a,7-hexahydronaphthalene
(using
hexane/EtOAc = 10:1 to 1:3 as the eluent), 0.0175 g, 24%, white solid, mp 232–233 °C; IR
(KBr, cm-1) 3336, 2974, 1661, 1615, 1525; 1H NMR (300 MHz, CDCl3) δH 5.76–5.70 (m, 1H),
5.66–5.60 (m, 1H), 5.54–5.40 (m, 3H), 4.49 (br, 1H), 3.57–3.46 (m, 1H), 2.88–2.80 (m, 1H),
2.67–2.65 (m, 2H), 2.56–2.50 (m, 1H), 2.22–2.17 (m, 1H), 2.09–2.00 (m, 1H), 1.92–1.81 (m,
1H), 1.64–1.59 (m, 1H), 1.44 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δC 175.6, 155.1, 133.2,
125.3, 120.2, 79.5, 50.6, 49.4, 41.9, 38.4, 37.1, 28.3, 26.7; HRMS (FAB) calcd for (M+H)+
C16H25N2O3: 293.1866, found 293.1846.
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rac-(2S,
4S,
4aS)
and
(2R,
(4cA):
4R,
4aR)-2-N-Boc-amino-4-carbamoyl-1,2,3,4,4a,7-hexahydronaphthalene
(using
hexane/EtOAc = 10:1 to 1:3 as the eluent), 0.0132 g, 18%, white solid, mp 197–198 °C; IR
(KBr, cm-1) 3410, 2926, 1712, 1662, 1500; 1H NMR (300 MHz, CDCl3) δH 5.77–5.73 (m, 1H),
5.64–5.57 (m, 2H), 5.34–5.36 (m, 2H), 4.59 (br, 1H), 4.01 (br, 1H), 2.96–2.90 (m, 1H), 2.72 (br,
2H), 2.42–2.32 (m, 1H), 2.17–2.04 (m, 1H), 1.93–1.83 (m, 1H), 1.45 (s, 9H); 13C{1H} NMR
(125 MHz, CDCl3) δC 176.0, 154.8, 132.9, 124.8, 121.4, 81.2, 47.5, 46.1, 39.9, 38.7, 34.6, 29.7,
28.4, 26.7; HRMS (FAB) calcd for (M+H)+ C16H25N2O3: 293.1866, found 293.1851.
4-N-Boc-amino-5-phenylpentylamide (5cA): (using hexane/EtOAc = 10:1 to 3:1 as the eluent),
0.0241 g, 33%, white solid, mp 162 °C; IR (KBr, cm-1) 3414, 3353, 2923, 1684, 1653, 1456; 1H
NMR (300 MHz, CDCl3) δH 7.32–7.16 (m, 5H), 6.25 (br, 1H), 5.47 (br, 1H), 4.52 (d, J = 9.0 Hz,
1H), 3.91–3.85 (m, 1H), 2.80–2.74 (m, 2H), 2.30–2.23 (m, 2H), 1.94–1.59 (m, 2H), 1.39 (s,
13
9H); C{1H} NMR (125 MHz, CDCl3) δC 175.5, 156.3, 137.7, 129.4, 128.5, 126.6, 79.6, 51.2,
42.0, 32.8, 30.8, 28.4; HRMS (FAB) calcd for (M+H)+ C16H25N2O3: 293.1866, found 293.1871.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
4aR)-2-N-Boc-amino-4-t-butoxycarbonyl-1,2,3,4,4a,7-hexahydronaphthalene (3cF): (using
hexane/EtOAc = 9:1 as the eluent), 0.0210 g, 24%, white solid, mp 87–88 °C; IR (KBr, cm-1)
1
3383, 2972, 1719, 1689, 1522; H NMR (300 MHz, CDCl3) δH 5.74–5.70 (m, 1H), 5.58–5.53
(m, 2H), 4.46–4.43 (br, 1H), 3.51 (br, 1H), 2.81–2.64 (m, 4H), 2.55–2.50 (m, 1H), 2.24–2.11
(m, 2H), 1.87–1.79 (m, 1H), 1.45 (s, 9H), 1.44 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δC
173.5, 154.9, 133.0, 125.3, 125.0, 120.1, 80.6, 79.3, 50.3, 49.2, 42.1, 38.6, 36.9, 28.4, 28.0,
26.6; HRMS (FAB) calcd for (M+H)+ C20H32NO4: 350.2331, found 350.2312.
t-butyl 4-N-Boc-amino-5-phenylpentanoate (5cF): (using hexane/EtOAc = 9:1 to 6:1 as the
1
eluent), 0.0472 g, 54%, colorless oil; IR (neat, cm-1) 3471, 2958, 1706, 1505, 1445; H NMR
(300 MHz, CDCl3) δH 7.30–7.16 (m, 5H), 4.46–4.44 (br, 1H), 3.85–3.78 (m, 1H), 2.85–2.68 (m,
2H), 2.27 (t, J = 7.2 Hz, 2H), 1.84–1.73 (m, 1H), 1.64–1.54 (m, 1H), 1.42 (s, 9H), 1.39 (s, 9H);
13C{1H} NMR (125 MHz, CDCl3) δC 173.3, 155.4, 137.9, 129.4, 128.3, 126.3, 80.3, 79.0, 51.6,
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41.8, 32.4, 29.7, 28.8, 28.3, 27.9; HRMS (FAB) calcd for (M+H)+ C20H32NO4: 350.2331, found
350.2316.
4-N-Boc-amino-5-phenylpentanitrile (5cG)6a: (using hexane/EtOAc = 10:1 to 2:1 as the
eluent), 0.0494 g, 72%, white solid, mp 107 °C; 1H NMR (300 MHz, CDCl3) δH 7.34–7.15 (m,
5H), 4.38–4.32 (m, 1H), 3.91–3.79 (m, 1H), 2.89–2.72 (m, 2H), 2.48–2.29 (m, 2H), 1.97–1.86
(m, 1H), 1.75–1.61 (m, 1H), 1.40 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δC 155.4, 137.0,
129.3, 128.6, 126.8, 119.5, 79.7, 51.2, 41.3, 30.4, 28.3, 14.3; HRMS (FAB) calcd for (M+H)+
C16H22N2O2: 275.1759, found 275.1776.
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5-phenylpentanitrile (8): (using hexane/EtOAc = 10:1 to 2:1 as the eluent), 0.0115 g, 26%,
white solid, mp 98 °C; IR (KBr, cm-1) 3403, 2944, 1684, 1456; 1H NMR (300 MHz, CDCl3) δH
7.31–7.23 (m, 2H), 7.20–7.16 (m, 3H), 5.45 (br, 2H), 2.66–2.61 (m, 2H), 2.29–2.22 (m, 2H),
1.73–1.64 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δC 175.3, 142.0, 128.5, 128.3, 125.7, 35.7,
35.6, 31.0, 25.0; HRMS (FAB) calcd for (M+H)+ C11H16NO: 178.1233, found 178.1215.
4-phenoxybutylnitrile (11)4b: (using hexane/EtOAc = 10:1 to 2:1 as the eluent), 0.0134 g, 30%,
1
white solid, H NMR (300 MHz, CDCl3) δH 7.32–7.24 (m, 2H), 7.00–6.83 (m, 3H), 5.52 (br,
2H), 4.13–3.96 (m, 2H), 2.53–2.39 (m, 2H), 2.18–2.09 (m, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δC 174.7, 158.7, 129.4, 120.7, 114.4, 66.60, 32.13, 24.95.
rac-(2S,
4R,
4aS)
and
(2R,
4S,
4aR)-2-N-(N’-Boc-Val)-amino-4-carbamoyl-6-O-Boc-oxyo-1,2,3,4,4a,7-hexahydronaphthale
ne (3dA): (using hexane/EtOAc = 4:1 to 1:3 as the eluent), 0.0457 g, 36%, white solid, mp 256–
257 °C; IR (KBr, cm-1) 3332, 2952, 1763, 1662, 1516; 1H NMR (300 MHz, CDCl3) δH 7.05 (br,
1H), 6.38 (br, 1H), 5.69 (br, 1H), 5.51–5.43 (m, 2H), 5.24–5.17 (m, 1H), 3.98–3.93 (m, 1H),
3.84 (br, 1H), 3.03 (br, 1H), 2.86 (br, 2H), 2.64–2.53 (m, 1H), 2.17–1.70 (m, 5H), 1.50 (s, 9H),
1.43 (s, 9H), 0.97–0.88 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δC 175.5, 171.2, 155.9,
151.3, 146.9, 132.9, 118.7, 112.8, 83.0, 79.8, 59.8, 50.5, 47.8, 40.8, 39.8, 35.5, 31.4, 30.8, 28.3,
27.6, 19.3, 18.2; HRMS (FAB) calcd for (M+H)+ C26H42N3O7: 508.3023, found 508.3017.
rac-(2S,
4S,
4aS)
and
(2R,
4R,
4aR)-2-N-(N’-Boc-Val)-amino-4-carbamoyl-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydronaphthalen
e (4dA): (using hexane/EtOAc = 4:1 to 1:3 as the eluent), 0.00761 g, 6%, white solid, mp 114–
115 °C; IR (KBr, cm-1) 3373, 2916, 1745, 1667, 1539; 1H NMR (300 MHz, CDCl3) δH 6.02 (br,
1H), 5.79 (br, 1H), 5.46–5.41 (m, 2H), 5.19 (br, 1H), 5.00–4.97 (br, 1H), 4.24 (br, 1H), 3.63–
3.57 (m, 1H), 3.11–3.06 (m, 1H), 2.85–2.82 (m, 2H), 2.39–2.21 (m, 2H), 2.13–1.77 (m, 4H),
1.43 (s, 9H), 1.35 (s, 9H), 0.91–0.87 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δC 180.0, 170.9,
151.3, 146.3, 139.0, 132.2, 120.1, 113.2, 83.1, 80.3, 54.8, 47.0, 45.1, 39.9, 38.8, 34.0, 30.4, 28.3,
27.6, 19.3, 18.4; HRMS (FAB) calcd for (M+H)+ C26H42N3O7: 508.3023, found 508.3011.
4-N-(N’-Boc-Val)-amino-5-(4’-O-Boc-phenoxy)pentylamide (5dA): (using hexane/EtOAc =
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4:1 to 0:1 as the eluent), 0.00381 g, 3%, white solid, mp 199–200 °C; IR (KBr, cm-1) 3409,
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8
1
2950, 1744, 1556, 1409; H NMR (300 MHz, CDCl3) δH 7.17 (d, J = 8.7 Hz, 2H), 7.07 (d, J =
8.7 Hz, 2H), 6.36 (br, 1H), 6.00 (br, 1H), 5.37 (br, 1H), 5.00–4.97 (br, 1H), 4.23 (br, 1H), 3.86–
3.64 (m, 1H), 2.83–2.74 (m, 2H), 2.26–2.13 (m, 3H), 2.00– 1.76 (m, 2H), 1.55 (s, 9H), 1.42 (s,
9H), 0.89–0.73 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δC 176.7, 175.4, 156.0, 151.8, 149.9,
134.9, 130.0, 121.3, 83.5, 80.0, 60.5, 56.1, 50.2, 40.9, 32.3, 30.9, 30.3, 28.2, 27.6, 19.1, 17.7;
HRMS (FAB) calcd for (M+H)+ C26H42N3O7: 508.3023, found 508.3017.
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rac-(2S,
4R,
4aS)
and
(2R,
4S,
4aR)-2-N-(N’-Boc-Val)-amino-4-carbonyl[ValVal(OMe)]-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydr
onaphthalene (3dJ)): (using chloroform/acetone = 1:0 to 3:1 as the eluent), 0.0523 g, 29%,
white solid, mp 244–245 °C; IR (KBr, cm-1) 3381, 2940, 1753, 1643, 1547; 1H NMR (300 MHz,
CDCl3) δH 6.63 (br, 2H), 5.51 (br, 1H), 5.35 (br, 1H), 5.17 (br, 1H), 4.50–4.46 (m, 1H), 4.30–
4.25 (m, 1H), 4.00 (br, 1H), 3.84 (br, 1H), 3.71 (s, 3H), 3.06–3.02 (m, 1H), 2.83 (br, 2H), 2.63–
2.57 (m, 1H), 2.24–1.87 (m, 7H), 1.47 (s, 9H), 1.43 (s, 9H), 0.86–0.99 (m, 18H); 13C{1H} NMR
(125 MHz, CDCl3) δC 173.2, 172.0, 171.6, 171.0, 156.0, 151.1, 146.8, 133.0, 118.6, 112.4, 82.8,
79.5, 59.2, 59.0, 57.4, 51.8, 50.7, 47.5, 41.4, 40.1, 35.6, 32.0, 30.6, 30.5, 28.4, 27.6, 19.1, 18.9,
18.1, 18.0; HRMS (FAB) calcd for (M+H)+ C37H61N4O10: 721.4387, found 721.4374.
rac-(2S,
4S,
4aS)
and
(2R,
4R,
4aR)-N-2-(N’-Boc-Val)-amino-4-carbonyl[ValVal(OMe)]-6-O-Boc-oxy-1,2,3,4,4a,7-hexahydr
onaphthalene (4dJ): (using chloroform/acetone = 1:0 to 3:1 as the eluent), 0.0108 g, 6%, white
1
solid, mp 222–223 °C; IR (KBr, cm-1) 3385, 2950, 1748, 1647, 1528; H NMR (300 MHz,
CDCl3) δH 6.96 (br, 1H), 6.35–6.30 (m, 1H), 5.50–5.44 (m, 2H), 5.18–5.12 (m, 1H), 4.60–4.52
(m, 1H), 4.25–4.18 (m, 1H), 4.01–3.90 (m, 2H), 3.71 (s, 3H), 2.95 (br, 1H), 2.82 (br, 2H), 2.52–
2.47 (m, 1H), 2.25–1.92 (m, 7H), 1.49 (s, 9H), 1.43 (s, 9H), 0.98–0.86 (m, 18H); 13C{1H} NMR
(125 MHz, CDCl3) δC 172.1, 171.1, 170.8, 155.8, 151.5, 146.8, 132.7, 119.0, 112.7, 82.9, 79.8,
59.4, 57.0, 51.9, 50.7, 47.3, 40.7, 36.4, 31.7, 30.6, 30.3, 28.3, 27.6, 19.3, 17.8, 19.1, 19.0, 18.1;
HRMS (FAB) calcd for (M+H)+ C37H61N4O10: 721.4387, found 721.4380.
4-N-(N’-Boc-Val)-amino-5-(4’-O-Boc-phenoxy)-N-[ValVal(OMe)]pentylamide (5dJ): (using
chloroform/acetone = 1:0 to 3:1 as the eluent), 0.0216 g, 12%, white solid, mp 201–202 °C; IR
(KBr, cm-1) 3376, 2936, 1757, 1523, 1423; 1H NMR (300 MHz, CDCl3) δH 7.40–7.37 (br, 1H),
7.20–7.16 (m, 2H), 7.07–7.02 (m, 2H), 6.70–6.55 (m, 2H), 5.13–5.10 (br, 1H), 4.58–4.54 (m,
1H), 4.29–4.16 (m, 2H), 3.83–3.69 (m, 4H), 2.79–2.70 (m, 2H), 2.22–1.83 (m, 7H), 1.54 (s, 9H),
1.43 (s, 9H), 1.00–0.74 (m, 18H); 13C{1H} NMR (125 MHz, CDCl3) δC 173.6, 172.6, 172.3,
171.9, 151.7, 149.6, 135.6, 130.1, 121.1, 83.4, 79.9, 60.4, 59.5, 57.1, 52.2, 50.1, 41.0, 32.2, 31.1,
30.3, 29.5, 28.3, 27.6, 19.3, 19.1, 18.9, 18.5, 18.2, 17.8; HRMS (FAB) calcd for (M+H)+
C37H61N4O10: 721.4387, found 721.4377.
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Supporting Information
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1H and C NMR spectra for all compounds and CIF file for X-ray crystallographic analysis of
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3aA. This material is available free of charge via Internet at http://pubs.acs.org/.
Acknowledgments
This work was partially supported by the Japan Society for the Promotion of Science (JSPS),
Grant-in-Aid no. 17K05779, for scientific research.
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