Helical-Peptide-Catalyzed Enantioselective Michael Addition Reactions and Their Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.6b00982

Helical peptide foldamer catalyzed Michael addition reactions of nitroalkane or dialkyl malonate to α,β-unsaturated ketones are reported along with the mechanistic considerations of the enantio-induction. A wide variety of α,β-unsaturated ketones, including β-aryl, β-alkyl enones, and cyclic enones, were found to be catalyzed by the helical peptide to give Michael adducts with high enantioselectivities (up to 99%). On the basis of X-ray crystallographic analysis and depsipeptide study, the amide protons, N(2)-H and N(3)-H, at the N terminus in the α-helical peptide catalyst were crucial for activating Michael donors, while the N-terminal primary amine activated Michael acceptors through the formation of iminium ion intermediates.

Full text of DOI:10.1021/acs.joc.6b00982

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Article
Helical Peptide-Catalyzed Enantioselective Michael
Addition Reactions and Their Mechanistic Insights
Atsushi Ueda, Tomohiro Umeno, Mitsunobu Doi, Kengo Akagawa, Kazuaki Kudo, and Masakazu Tanaka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00982 • Publication Date (Web): 06 Jul 2016
Downloaded from http://pubs.acs.org on July 7, 2016
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Helical Peptide-Catalyzed Enantioselective Michael Addition Reactions and Their Mechanistic Insights
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Atsushi Ueda,†,* Tomohiro Umeno,† Mitsunobu Doi,‡ Kengo Akagawa,§ Kazuaki Kudo,§ Masakazu Tanaka†,*
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†Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
‡Osaka University of Pharmaceutical Sciences, Osaka 569-1094, Japan
§Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan
*aueda@nagasaki-u.ac.jp
*matanaka@nagasaki-u.ac.jp
ABSTRACT: Helical peptide foldamer-catalyzed Michael addition reactions of nitroalkane or dialkyl malonate to
α,β-unsaturated ketones are reported along with their mechanistic considerations of enantio-induction. A wide
variety of α,β-unsaturated ketones, including β-aryl, β-alkyl enones, and cyclic enones were found to be catalyzed by
the helical peptide to give Michael adducts with high enantioselectivities (up to 99%). On the basis of an X-ray
crystallographic analysis and depsipeptide study, the amide protons, N(2)-H and N(3)-H, at the N terminus in the
α-helical peptide catalyst were crucial for activating Michael donors, while the N-terminal primary amine activated
Michael acceptors through the formation of iminium ion intermediates.
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INTRODUCTION
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Due to their broad variety, chiral aminocatalysts have attracted increased attention in recent years.1 Peptides are also
potential aminocatalysts because of the amino group on the N terminus. One of the advantages of a peptide catalyst
is its tunability and diversity, which are achieved by changing amino acid components with readily available coded
amino acids as well as non-proteinogenic amino acids. Most of these peptide catalysts possess a specific secondary
structure such as an α-helix or a β-turn.2 We and other groups recently reported the highly enantioselective Juliá–
Colonna epoxidation of α,β-unsaturated ketones using an L-Leu-based peptide-foldamers3 stabilized by
α,α-disubstituted α-amino acid (dAA) components.4–9 We previously showed a positive correlation between the
enantioselectivities and α-helicities of peptides. Moreover, asymmetric Michael additions catalyzed by a
resin-supported peptide were recently described.10 We herein describe helical peptide-catalyzed enantioselective
Michael addition reactions and performed a mechanistic considerations into the origin of enantioselection based on an
X-ray crystallographic analysis and the use of depsipeptides.11
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RESULTS AND DISCUSSION
We initially examined the dAA moieties of peptide catalysts because we previously demonstrated that the structures
of dAAs strongly influenced enantioselectivities in our study on peptide-catalyzed Juliá-Colonna epoxidation.4 We
selected three different dAAs: α-aminoisobutyric acid (Aib, a), 1-aminocyclopentane-1-carboxylic acid (Ac5c, b), and
chiral dAA [(1S,3S)-Ac5cOM, c], as described in Figure 1. Nine dAA-containing L-Leu-based heteropeptides,
H-(L-Leu-L-Leu-dAA)n-OMe [dAA = Aib, Ac5c, (1S,3S)-Ac5cOMe; n = 1, 2, 3], were prepared as a tripeptide (1),
hexapeptide (2), and nonapeptide (3). The results of the Michael addition reaction of nitromethane with the
α,β-unsaturated ketone 4a are summarized in Table 1. It is important to note that the helical secondary structure was
necessary for this peptide catalysis because all of the tripeptides examined, namely, 1a, 1b, and 1c, showed poor
selectivities as well as low conversions (entries 1, 4, and 7). The lengths of tripeptides were insufficient to form
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helical structures. The best result was obtained when the nonapeptide 3c was used as a catalyst (73% ee, entry 9).
This preference in % ee value over Aib-containing peptide such as nonapeptide 3a (62% ee, entry 3) may be explained
hypothetically based on our previous findings that the chiral cyclic dAA, (1S,3S)-Ac5cOM induced the α-helical
structure of its peptides, while Aib-containing peptides preferred the 310-helix.4,12,13
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OMe
(S)
O
O
O
H
N
H
N
H
(S)
N
H
N
N
H
OMe
H
N
H
N
H
OMe
H
N
N
H
OMe
H
H
O
O
O
O
O
O
n
n
n
1a: (n = 1)
2a: (n = 2)
3a: (n = 3)
1b: (n = 1)
2b: (n = 2)
3b: (n = 3)
1c: (n = 1)
2c: (n = 2)
3c: (n = 3)
Figure 1. Chemical structures of peptides having α,α-disubstituted α-amino acids.
Table 1. Screening of peptides.
MeNO2 (20 equiv)
peptide (20 mol %)
O2N
O
O
BzOH (5 mol %)
O2N
O2N
THF/H2O (1:2, 0.05 M), 40 °C, 48 h
4a
5a
entry peptide
conva
eeb
(%)
–17
50
(%)
25
48
70
16
63
69
27
50
57
1
2
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9
1a: Aib, trimer
2a: Aib, hexamer
3a: Aib, nonamer
62
1b: Ac5c, trimer
–9
2b: Ac5c, hexamer
65
3b: Ac5c, nonamer
65
1c: (1S,3S)-Ac5cOM, trimer
2c: (1S,3S)-Ac5cOM, hexamer
3c: (1S,3S)-Ac5cOM, nonamer
–12
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aConversion was determined by 1H NMR analysis. bEe was determined by chiral HPLC analysis.
We then optimized reaction conditions using the readily accessible, excellent catalyst, hexapeptide 2b. No reaction
proceeded without the use of a peptide catalyst (Table 2, entry 1). When the reaction was performed in the absence
of benzoic acid, it was very sluggish, while enantiomeric excess was of a moderate level (61% ee, entry 2).14 We
conducted the reaction in a more concentrated solution (0.2 M) in THF with excess benzoic acid (100 mol %), and
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achieved increases in the conversion to >99% along with 79% ee (entry 7). When the α-helical peptide 3c was
employed, enantioselectivity increased to 84% ee (entry 9). The best reaction was achieved by using the
tryptophan-containing octapeptide 7 possessing sterically demanding indole side-chain (Figure 2) as a catalyst (97%
ee, 96% conversion, entry 11). Furthermore lowering catalyst loading to 5 and 10 mol % were also successful with
excellent enantioselectivities (94–95% ee), albeit with the prolongation of the reaction time (entries 12 and 13).
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Table 2. Optimization of reaction conditions.
MeNO2 (20 equiv)
peptide, BzOH
4a
5a
solvent, 40 °C, 48 h
entry peptide
BzOH
solvent
conva eeb
(%) (%)
(mol %) (mol %) (M)
1
none
5
0
5
5
5
5
THF/H2Oc(0.05)
THF/H2Oc (0.05) 7
0
–
2
2b (20)
2b (20)
2b (20)
2b (20)
2b (20)
61
46
11
57
68
3
TFE (0.05)
DMSO (0.05)
toluene (0.05)
THF (0.05)
THF (0.2)
THF (0.2)
THF (0.2)
THF (0.2)
THF (0.2)
THF (0.4)
4
4
11
46
31
5
6
7
8d
2b (20) 100
2b (20) 100
>99 79
54
89
85
84
9
3c (20)
6 (20)
7 (20)
7 (10)
100
100
100
50
10
11
12
>99 91
96
97
88
95
(95)e (95)e
40 95
(58)e (94)e
13
7 (5)
25
THF (0.4)
aConversion was determined by 1H NMR analysis. bEe was determined by chiral HPLC analysis. cTHF/H2O = 1:2.
dThe reaction was performed at 0 °C. eThe values in parentheses are results obtained after 120 h.
O
O
O
O
H
N
H
N
H
N
H2N
N
H
N
H
OMe
N
H
N
H
OMe
H
O
O
O
O
2
2
2
N
H
N
H
6
7
Figure 2. Structures of peptides 6 and 7.
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We then explored the scope of Michael acceptors under the optimized condition (Scheme 1). Substituent groups at
the p-position of the phenyl group (i.e., electron withdrawing, electron donating, bulky, etc.) did not affect
enantioselectivities (94–96% ee, 5b–5e). Different o-, m-, and p-substitution patterns on the phenyl ring also
afforded the products 5f–5h with good yields and high enantiomeric excess. Substrates possessing an aromatic
group (R1) other than a phenyl group, for example, 2-furyl, 2-naphtyl, and 9-anthracenyl, were also suitable for the
reaction (5i–5k). When conjugated α,β,γ,δ-unsaturated dienone and enynone were used as substrates, complete
1,4-addition was observed rather than 1,6-addition along with slightly decreased enantioselectivities (5l and 5m).
Substrates having an aliphatic group (R1) at the β-position were also applicable (5n and 5o). We also explored other
substrates by replacing methyl group with alkyl substituents (R2). As a result, the linear alkyl groups (e.g., ethyl and
n-propyl, 5p and 5q) showed good yields and bulky substituent groups (e.g., isopropyl and phenyl, 5r and 5s) caused
sluggish reaction rates; however, all these compounds afforded excellent enantioselectivities (94–99% ee).
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Scheme 1. Scope of Michael acceptors.
MeNO2 (20 equiv)
O2N
R1
O
O
7 (20 mol %)
R2
R2
R1
BzOH (100 mol %)
THF (0.2 M), 40 °C
4
5
O2N
O2N
O2N
O2N
O
O
O
O
O2N
Cl
MeO
5a (97% ee)
5b (96% ee)
5c (94% ee)
5d (96% ee)
(66% yield, 72 h)
(85% yield, 48 h)
(79% yield, 48 h)
(84% yield, 72 h)
O2N
O
O2N
O2N
O2N
O
O
O
t-Bu
5g (88% ee)
5h (97% ee)
5e (95% ee)
5f (96% ee)
(87% yield, 72 h)
(81% yield, 72 h)
(69% yield, 72 h)
(83% yield, 72 h)
O2N
O2N
O2N
O
O
O
O
5i (94% ee)
5j (96% ee)
5k (88% ee)
(46% yield, 72 h)
(81% yield, 72 h)
(37% yield, 96 h)
O2N
O
O2N
O2N
O
O
O2N
O
(p-Br)BzO
5o (94% ee)
5n (95% ee)
5l (80% ee)
5m (90% ee)
(55% yield, 72 h)
(41% yield, 96 h)
(62% yield, 96 h)
(80% yield, 96 h)
O2N
O
O2N
O2N
O
O2N
O
O
5s (94% ee)
5p (97% ee)
5q (98% ee)
5r (>99% ee)
(20% yield, 264 h)
(61% yield, 96 h)
(69% yield, 96 h)
(27% yield, 264 h)
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Scheme 2 summarizes the scope of the substrates on Michael donors and acceptors. Other nitroalkanes such as
nitroethane and 2-nitropropane worked well (9a and 9b). The poor diastereoselectivity in compound 9a is possibly
due to the epimerization under the reaction condition via deprotonation of the acidic proton at γ-position catalyzed by
the peptide. Because when we treated pure major diastereomer of 9a under the same reaction condition, the
compound anti-9a epimerized to 1.4:1 dr after 48 h. On the other hand, no epimerization was observed in the
absence of peptide catalyst under the reaction condition. Dimethyl malonate was also a good substrate for this
peptide-catalyzed reaction (9c and 9d). However, a bulkier nucleophile (e.g., diisopropyl malonate, dimedone, and
4-hydroxycoumarin) resulted in decreases in enantioselectivities, albeit with acceptable reactivities (9e–9g). Cyclic
enones were also used for this reaction and they provided the desired adducts 9h–9j with excellent enantioselectivities
(89–98% ee) regardless of the ring sizes of the enones. It is important to note that the cyclic ketone products 9h–9j
were also obtained by other amino acid catalysis, as described in the literature.15–18 However, the substrate scope of
those reported catalysts is limited, since enantioselectivities were significantly affected by the ring sizes of the cyclic
enones. Thus, the wide substrate scope is advantageous to peptide foldamer catalysts compared to simple amino acid
catalysts.
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Scheme 2. Scope of substrates.
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nucleophile (NuH)a
O
Nu
O
7 (20 mol %)
R2
R2
R1
R1
BzOH (100 mol %)
THF (0.2 M), 40 °C
4 or 8
9
5
6
NO2
O2N
MeO2C
CO2Me MeO2C
CO2Me
7
8
9
O2N
9a (95% ee)b
O
O2N
O
O2N
O
O
9d (94% ee)
9b (88% ee)
9c (94% ee)
(97% yield, 72 h)
(85% yield, 48 h)
(78% yield, 72 h)
(95% yield, 96 h)
10
11
12
13
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23
O
iPrO2C
CO2iPr
O
O
O
OH
O
O2N
O
O2N
O
O2N
9f (47% ee)
9g (73% ee)
9e (63% ee)
(45% yield, 96 h)
(quant, 48 h)
(77% yield, 72 h)
O
O
O
CO2Bn
CO2Bn
CO2Bn
CO2Bn
CO2Bn
9i (93% ee)
(92% yield, 96 h)
BnO2C
9h (89% ee)
9j (98% ee)
(69% yield, 96 h)
(58% yield, 96 h)
a20 equivalents of Michael donors (nucleophiles) were used for 9a and 9b, and 3 equivalents of nucleophiles were
used for 9c–9j against enones. bEe for the major anti-isomer (dr = 1.1:1).
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The secondary structure of peptide foldamer 7 in the crystal state was confirmed using an X-ray crystallographic
analysis. Figure 3 shows that peptide 7 formed a right-handed α-helical secondary structure, in which i←i+4 type
hydrogen bonds were observed.19 Regarding a helix structuration, it should be noted that N-terminal tetrapeptide
stretch of 7 devoid of any strongly helicogenic α,α-disubstituted α-amino acid is indeed a remarkable event. We
also studied the secondary structure of peptide 7 in solution. The NOESY spectrum of peptide 7 revealed that a
helical structure was formed due to the observed correlation between each NH amide proton.19–22 However, it was
unclear whether the helical structure was an α- or 310-helix from the NOESY spectrum due to the complexity of the
spectrum.23
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Figure 3. X-ray crystallographic structure of octapeptide 7. (a) A view perpendicular to the α-helical axis and (b)
an ORTEP drawing as viewed along the helical axis from the N terminus (ellipsoids at 50% probability).
Figure 4 illustrates plausible mechanisms for the helical peptide-catalyzed Michael addition of nitromethane or
dibenzyl malonate to an α,β-unsaturated ketone based on an X-ray crystallographic analysis. The primary amino
group of the α-helical peptide reacts with an α,β-unsaturated ketone to form the iminium intermediate with the
minimized allylic 1,3- and 1,2-strain,24–26 and this process is promoted by benzoic acid. Meanwhile, the Michael
donor is activated by the exposed amide protons, N(2)-H and N(3)-H, on the N terminus. Two tryptophan units
possibly regulate the rotation of the iminium intermediate. Consequently, the Michael donor attacks from the si-face
of the α,β-unsaturated iminium to provide the product.
(a)
(b)
HN
N
HN
3
3
N
N
H
H
H
H
N 6
N 6
O
H
O
O
O
O
O
H
BnO
si-face
attack
si-face
attack
O
O
N 2
N
O
N 4
N 4
H
2 O
H
H
H
N
1
N
5
N
O
O
Ar
H
H
O
O
N
5
1
OBn
HN
HN
Figure 4. Plausible mechanisms for the reaction catalyzed by peptide 7. (a) The reaction of acyclic enone 4 with
nitromethane and (b) the reaction of cyclic enone 8 with dibenzyl malonate.
The plausible mechanism described above was supported by a comparative study of peptides and depsipeptides as
shown in Table 3. We prepared the octapeptide 10 and its depsipeptide analogs 11a, 11b, and 11c. This peptide
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and the depsipeptides were subjected to the Michael addition of nitromethane to enone 4a in order to reveal which NH
of amides is crucial for the reaction through hydrogen-bonding activation. When the octapeptide 10 was employed
as a catalyst, we obtained the 1,4-adduct with 100% conversion and 81% ee (entry 1). On the other hand, the
depsipeptides 11a and 11b showed low conversions and poor enantioselectivities (entries 2 and 3). These results
indicated that amide N(2)-H and N(3)-H both play a key role in the activation of Michael donors as well as
asymmetric induction through hydrogen bonding. Since the depsipeptide 11c showed good conversion (89%) with
moderate enantiomeric excess (54% ee), it is reasonable to assume that the amide N(4)-H may not affect the activation
of the Michael donor. For the reaction of 2-cyclohexen-1-one (8i) with dibenzyl malonate, depsipeptides 11a–11c
provided low conversion in all cases (28–38% conversion, entries 6–8), although complete conversion and excellent
enantioselectivity (98% ee, entry 5) was achieved by the regular peptide 10. Therefore, the amide protons, N(2)-H,
N(3)-H, and N(4)-H, contributed greatly to activation of Michael donors for the reaction of cyclic enones and
malonates.
10
11
12
13
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17
18
19
20
21
22
23
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25
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Table 3. Reactions catalyzed by depsipeptides.
O
O
O
H
N
X
Z
N
H
CO2Me
H2N
N
H
Y
O
O
O
+
MeNO2 (20 equiv)
4a
8i
5a
2
10 or 11 (20 mol %)
BzOH (100 mol %), THF (0.2 M), 40 °C
or
+
or
CH2(CO2Bn)2 (3 equiv)
9i
entry
SM
4a
4a
4a
4a
8i
catalyst
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X
Y
Z
time (h)
48
product conva (%) eeb (%)
1
2
3
4
5
6
7
8
NH NH NH
5a
5a
5a
5a
9i
100
15
82
–6
20
54
98
75
33
63
11a
11b
11c
10
O
NH NH
48
NH
O
NH
O
48
11
NH NH
48
89
NH NH NH
96
100
28
8i
11a
11b
11c
O
NH NH
96
9i
8i
NH
O
NH
O
96
9i
26
8i
NH NH
96
9i
38
aConversion was determined by 1H NMR analysis. bEe was determined by chiral HPLC analysis.
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As shown in Scheme 3, we synthesized a 2,4,5-trisubstituted tetrahydropyran ring system from the ketone 9d, which
was obtained by the peptide-catalyzed Michael addition reaction. The ketone 9d was protected as an acetal,
followed by the reduction of the ester moieties providing the diol 12. Compound 12 was diastereoselectively
cyclized by the Kishi reduction27–29 to give the 2,4,5-trisubstituted tetrahydropyran 13 as a single diastereomer with
two newly formed chiral centers and without any loss of ee value (94% ee). The prochiral diol in compound 12 was
successfully differentiated during the course of cyclization. This stereoselectivity may be derived from the phenyl
substituent oriented in the equatorial direction in the reaction intermediate. Since substituted tetrahydropyran rings
are common motifs that are frequently observed in biologically active compounds,30–32 this de novo synthetic pathway
may provide a facile access to these compounds.
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Scheme 3. Synthesis of the 2,4,5-trisubstituted THP ring.
1) Me2C(CH2OH)2
Me Me
H
H
O
HO
Et3SiH
p-TsOH, benzene
reflux, 75%
H
HO
Me
Ph
TMSOTf
HO
Ph
9d
(94% ee)
O
O
H
H
H
2) LiAlH4, THF
0 °C to rt, 86%
CH2Cl2, –78 °C
84%
Me
12
13
(94% ee)
: NOE
CONCLUSION
In summary, we herein demonstrated the α-helical peptide foldamer-catalyzed Michael addition of nitroalkanes and
dialkyl malonates to α,β-unsaturated ketones. The α-helical chirality and N-terminal amide protons of peptide
catalysts seemed to be crucial for the enantio-induction of this catalysis based on the experimental results. These
results will be helpful for design of new peptide catalysts and their application to other organocatalytic reaction.
Based on these results, further studies on the modification of peptide catalysts and expansion of the substrate scope,
including applications to bulkier nucleophiles, are currently ongoing in our laboratories.
EXPERIMENTAL SECTION
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General Experimental Methods: Optical rotations were measured using CHCl3 or MeOH as a solvent. 1H NMR
and 13C NMR spectra were recorded on a 500 MHz (500 MHz for 1H and 125 MHz for 13C), 400 MHz (400 MHz for
1H and 100 MHz for 13C), or 300 MHz (300 MHz for 1H) spectrometer. Chemical shifts (δ) are reported in parts per
million (ppm). For 1H NMR spectra (CDCl3), tetramethylsilane was used as the internal reference (0.00 ppm), while
the central solvent peak as the reference (77.0 ppm in CDCl3) for 13C NMR spectra. IR spectra were measured with
KBr or as a thin film. High-resolution mass spectra (HRMS) were obtained using electrospray ionization (ESI) or
direct analysis in real time (DART) ionization in TOF mode or using fast atom bombardment (FAB) ionization in the
dual focusing sector field mode. Circular dichroism (CD) spectra were measured using 1.0 mm path length cell.
Analytical and semi-preparative thin layer chromatography (TLC) was performed with pre-coated TLC plates, silica
gel 60 F254, layer thickness 0.25 and 0.50 mm, respectively. Compounds were observed in UV-light at 254 nm and
then visualized by staining with iodine, p-anisaldehyde, or phosphomolybdic acid stain. Flash and gravity column
chromatography separations were performed on silica gel, spherical neutral, particle size 40-50 µm and 63-210 µm,
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respectively.
Analytical high performance liquid chromatography (HPLC) was carried out with a UV
spectrophotometric detector (254 nm) to which a 4.6 × 250 mm size chiral column (Daicel Chiralpak AD-H or AS-H)
was attached. All moisture sensitive reactions were conducted under an inert atmosphere. Reagents and solvents
were commercial grade and were used as supplied, unless otherwise noted.
General procedure A (peptide coupling): To a solution of carboxylic acid (1.00 equiv) in CH2Cl2 (0.15 M) were
added N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDCI·HCl, 1.00 equiv) and
1-hydroxybenzotriazole hydrate (HOBt·H2O, 1.20 equiv) at 0 °C, the reaction mixture was stirred at 0 °C for 30 min.
A solution of amine (1.00 equiv) in CH2Cl2 (0.3 M) was dropped to the reaction mixture at 0 °C. The resultant
solution was gradually warmed to room temperature and stirred at room temperature overnight. After removal of
CH2Cl2, the residue was diluted with EtOAc and washed successively with 1 M HCl, water, sat. NaHCO3 aq, and
brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give crude product, which
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was purified by flash column chromatography on silica gel eluted with EtOAc in n-hexane to give desired peptide.
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General procedure B (Boc deprotection): To a solution of Boc-protected amine in CH2Cl2 (0.1 M) was dropped
trifluoroacetic acid (1 M) at room temperature and the reaction mixture was stirred overnight at the same temperature.
The reaction mixture was neutralized by adding sat. NaHCO3 aq and the aqueous phase was extracted with CHCl3
four times. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum to
give crude product, which was used for the next step without further purification.
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General procedure C (Cbz deprotection): To a solution of Cbz-protected amine in MeOH (0.1 M) was added
10% palladium on carbon (25–50 wt %) at room temperature, and the reaction mixture was vigorously stirred under a
hydrogen atmosphere overnight at the same temperature. The reaction mixture was passed through a short plug of
Celite and the filtrate was concentrated under vacuum to give crude product, which was used for the next step without
further purification.
General procedure D (preparation of α,β-unsaturated ketone):33 To a solution of aldehyde (1.00 equiv) in
ketone (0.4 M) was added morpholinium trifluoroacetate (0.400 equiv) at room temperature and the resultant mixture
was heated at 75 °C for 2–6 days. The reaction solution was cooled to room temperature and poured into sat.
NaHCO3 aq. The aqueous phase was extracted with EtOAc three times, and the combined organics were dried over
anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash column chromatography on
silica gel (EtOAc in n-hexane) to afford desired α,β-unsaturated ketone.
General procedure E (peptide-catalyzed Michael addition): To a solution of α,β-unsaturated ketone (0.100
mmol), peptide catalyst (0.0200 mmol, 20 mol %), and benzoic acid (12.2 mg, 0.100 mmol, 1 equiv) in THF (0.5 mL)
in a screw vial equipped with a magnetic stirring bar was added Michael donor (2.00 mmol, 20 equiv for nitroalkanes
and 0.300 mmol, 3 equiv for malonates, dimedone, and 4-hydroxycoumarin) at room temperature, and the reaction
mixture was stirred at 40 °C for the given time. The reaction mixture was diluted with EtOAc and washed with sat.
NaHCO3 aq. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to afford crude
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product, which was purified by flash column chromatography on silica gel to give desired product.
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Synthesis of peptides 1b, 2b, 3b, 6, and 7. Peptides 1a, 2a, 3a, 1c, 2c, and 3c were prepared by the literature
procedure.4 Synthesis of peptides 1b, 2b, 3b, 6, and 7 are described in Scheme 4–8.
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Boc-(L-Leu)2-Ac5c-OMe (S-1). According to general procedure A, the coupling of 1-aminocyclopentanecarboxylic
acid methyl ester (1.55 g, 10.8 mmol) with Boc-(L-Leu)2-OH (3.73 g, 10.8 mmol) gave the title compound S-1 (4.36 g,
86%) as a white solid after purification by flash column chromatography on silica gel (40% EtOAc in n-hexane).
Mp 158–160 °C. [α]20D –67.0 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.04 (br s, 1H), 6.71 (d, J = 7.3 Hz,
1H), 5.11 (d, J = 6.3 Hz, 1H), 4.51–4.36 (m, 1H), 4.18–4.05 (m, 1H), 3.68 (s, 3H), 2.28–2.13 (m, 2H), 2.04–1.86 (m,
2H), 1.83–1.59 (m, 8H), 1.59–1.46 (m, 2H), 1.44 (s, 9H), 1.03–0.84 (m, 12H). 13C NMR (100 MHz, CDCl3) δ:
174.5, 172.8, 171.4, 155.8, 80.2, 65.7, 53.3, 52.2, 51.4, 40.8, 40.1, 37.0, 36.9, 28.1 (3C), 24.6, 24.5, 24.4 (2C), 22.8
(2C), 21.9, 21.8. IR (KBr): 3329, 2959, 1744, 1700, 1528, 1172 cm–1. HRMS (DART) m/z: [M + H]+ calcd for
C24H44N3O6, 470.3230; found, 470.3221.
H-(L-Leu)2-Ac5c-OMe (1b). According to general procedure B, Boc deprotection of peptide S-1 (2.50 g, 5.33
mmol) afforded the desired product 1b (1.95 g, 99%) as a white solid after purification by flash column
chromatography on silica gel (5% MeOH in CHCl3). Mp 137–139 °C. [α]21 –64.0 (c 1.00, CHCl3). 1H NMR
D
(400 MHz, CDCl3) δ: 7.72 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 4.44 (dt, J = 8.8, 5.9 Hz, 1H), 3.69 (s, 3H), 3.41 (dd, J =
9.8, 3.9 Hz, 1H), 2.31–2.10 (m, 2H), 2.05–1.86 (m, 2H), 1.82–1.62 (m, 8H), 1.61–1.44 (m, 3H), 1.40–1.30 (m, 1H),
1.04–0.83 (m, 12H). 13C NMR (100 MHz, CDCl3) δ: 176.2, 174.5, 171.7, 65.7, 53.3, 52.3, 50.9, 43.8, 40.0, 37.2,
37.1, 24.7, 24.6, 24.52, 24.50, 23.3, 22.8, 22.0, 21.2. IR (KBr): 3283, 2955, 1747, 1632, 1539 cm–1. HRMS
(DART) m/z: [M + H]+ calcd for C19H36N3O4, 370.2706; found, 370.2693.
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Boc-[(L-Leu)2-Ac5c]2-OMe (S-3). To a solution of tripeptide S-1 (4.00 g, 8.53 mmol) in MeOH (85 mL) was
dropped 0.5 M NaOH aq (68 mL, 34 mmol) at 0 °C and the resultant white suspension was stirred at room
temperature for 2 d. The reaction mixture was acidified with 1 M HCl at 0 °C, and was evaporated to remove MeOH.
The aqueous solution was extracted with EtOAc four times and the combined organic extracts were washed with brine,
dried over anhydrous MgSO4, and concentrated under vacuum. The residue was passed through a short plug of silica
gel (5% MeOH in CHCl3) to give acid S-2 (3.76 g, 97%), which was used for the next step without further purification.
According to general procedure A, the coupling of acid S-2 (2.42 g, 5.30 mmol) with amine 1b (1.96 g, 5.30 mmol)
gave the title compound S-3 (3.95 g, 92%) as a white solid after purification by flash column chromatography on
silica gel (60% EtOAc in n-hexane). Mp 218–220 °C. [α]22D –4.1 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3)
δ: 7.56 (br s, 1H), 7.49–7.41 (m, 2H), 7.29 (s, 1H), 6.90 (d, J = 4.0 Hz, 1H), 5.79 (d, J = 2.4 Hz, 1H), 4.37–4.29 (m,
1H), 4.25–4.17 (m, 1H), 3.99–3.93 (m, 1H), 3.92–3.85 (m, 1H), 3.66 (s, 3H), 2.69–2.57 (m, 1H), 2.37–2.24 (m, 1H),
2.21–2.05 (m, 4H), 1.96–1.66 (m, 17H), 1.65–1.55 (m, 5H), 1.49 (s, 9H), 1.01–0.84 (m, 24H). 13C NMR (100 MHz,
CDCl3) δ: 175.6, 175.3, 174.8, 173.22, 173.20, 173.18, 157.1, 81.3, 66.9, 65.7, 55.3, 54.6, 54.0, 52.2, 52.0, 40.3, 39.9,
39.6, 39.3, 37.7, 37.2, 36.5, 35.7, 28.1 (3C), 25.1, 24.83, 24.75, 24.73, 24.68, 24.44, 24.38, 24.3, 23.32, 23.26, 22.8,
22.6, 21.9, 21.4, 21.0, 20.7. IR (KBr): 3325, 2953, 1734 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for
C42H74N6O9Na, 829.5415; found, 829.5403.
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H-[(L-Leu)2-Ac5c]2-OMe (2b). According to general procedure B, Boc deprotection of peptide S-3 (800 mg, 0.991
mmol) afforded the desired product 2b (668 mg, 95%) as a white solid after purification by flash column
chromatography on silica gel (5% MeOH in CHCl3). Mp 207–209 °C. [α]20 –27.7 (c 1.00, CHCl3). 1H NMR
D
(400 MHz, CDCl3) δ: 8.08 (d, J = 2.9 Hz, 1H), 7.50–7.38 (m, 2H), 7.20 (s, 1H), 6.81 (s, 1H), 4.41–4.30 (m, 1H),
4.28–4.18 (m, 1H), 3.98–3.88 (m, 1H), 3.67 (s, 3H), 3.41 (dd, J = 9.8, 3.4 Hz, 1H), 2.67–2.57 (m, 1H), 2.34–2.22 (m,
1H), 2.19–1.95 (m, 4H), 1.90–1.56 (m, 23H), 1.36 (t, J = 9.5 Hz, 1H), 1.04–0.83 (m, 24H). 13C NMR (100 MHz,
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CDCl3) δ: 178.5, 175.2, 175.0, 173.8, 173.3, 173.2, 66.6, 65.8, 54.8, 53.9, 53.1, 52.3, 52.0, 43.6, 39.9, 39.8, 39.2, 38.8,
37.3, 36.4, 35.9, 25.2, 24.9, 24.7, 24.6, 24.5, 24.4 (3C), 23.30 (2C), 23.25, 22.5, 21.7, 21.2, 21.0, 20.7. IR (KBr):
3314, 2959, 1651, 1532 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C37H67N6O7, 707.5071; found, 707.5057.
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H-[(L-Leu)2-Ac5c]3-OMe (3b): According to general procedure B, Boc deprotection of peptide S-413 (108 mg,
0.0944 mmol) afforded the desired product 3b (91.7 mg, 93%) as a white solid after purification by flash column
chromatography on silica gel (5% MeOH in CHCl3). Mp 255–257 °C. [α]21 –0.1 (c 1.00, CHCl3). 1H NMR
D
(400 MHz, CDCl3) δ: 8.37 (br s, 1H), 7.91 (br s, 1H), 7.75–7.57 (m, 3H), 7.54 (br s, 2H), 7.38 (d, J = 5.9 Hz, 1H),
4.31 (t, J = 11.0 Hz, 1H), 4.25–4.16 (m, 1H), 4.06 (dt, J = 10.0, 5.2 Hz, 1H), 3.97–3.85 (m, 2H), 3.66 (s, 3H), 3.44 (d,
J = 6.3 Hz, 1H), 2.63 (td, J = 13.8, 8.5 Hz, 2H), 2.45–2.22 (m, 2H), 2.20–2.06 (m, 3H), 1.99–1.53 (m, 36H), 1.38 (t, J
= 9.3 Hz, 1H), 1.05–0.80 (m, 36H). 13C NMR (100 MHz, CDCl3) δ: 176.3, 175.9 (2C), 175.8, 175.1 (2C), 174.2,
173.8, 173.7, 66.9, 66.4, 65.8, 55.3, 55.1, 54.8, 54.0, 53.2, 52.6, 52.0 (2C), 43.5, 40.1, 39.9, 39.4, 39.2 (2C), 38.5, 37.7,
37.2, 36.5, 36.0, 35.2, 25.0, 24.93, 24.85, 24.8, 24.7, 24.6, 24.4 (4C), 24.3, 23.32 (2C), 23.28, 23.1, 23.0, 22.4, 21.8,
21.2, 21.14, 21.12, 20.9, 20.8. IR (KBr): 3310, 2959, 1651, 1539 cm–1. HRMS (FAB) m/z: [M]+ calcd for
C55H97N9O10, 1043.7358; found, 1043.7367.
Cbz-L-Trp-[(L-Leu)2-Ac5c]2-OMe (S-5). According to general procedure A, the coupling of Cbz-L-Trp-OH (629
mg, 1.86 mmol) with amine 2b (1.31 g, 1.86 mmol) gave the title compound S-5 (1.74 g, 91%) as a white solid after
purification by flash column chromatography on silica gel (2% MeOH in chloroform). Mp 188–190 °C. [α]22
–
D
0.7 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 9.38 (br s, 1H), 7.61–7.50 (m, 3H), 7.48–7.42 (m, 2H), 7.42–
7.24 (m, 7H), 7.20 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 6.53 (d, J = 3.4 Hz, 1H), 6.12 (br s, 1H), 5.07 (s, 2H),
4.50–4.33 (m, 1H), 4.33–4.20 (m, 2H), 4.01–3.88 (m, 2H), 3.59 (s, 3H), 3.39 (dd, J = 14.6, 3.4 Hz, 1H), 3.28–3.14 (m,
1H), 2.68 (dt, J = 13.4, 8.2 Hz, 1H), 2.47–2.36 (m, 1H), 2.34–2.22 (m, 1H), 2.21–2.06 (m, 3H), 2.03–1.57 (m, 20H),
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1.53–1.44 (m, 1H), 1.40 (dt, J = 13.2, 6.6 Hz, 1H), 1.32–1.22 (m, 1H), 1.04–0.75 (m, 24H). 13C NMR (100 MHz,
CDCl3) δ: 175.8, 175.3, 174.3, 174.2, 174.1, 173.7, 173.6, 157.9, 136.8, 135.6, 128.7 (2C), 128.5, 127.7 (2C), 126.9,
124.5, 122.3, 119.6, 118.1, 111.9, 108.3, 67.3, 66.9, 65.8, 57.4, 54.7, 54.4, 54.0, 52.6, 52.0, 39.9, 39.8, 39.5, 39.3,
38.0, 37.2, 36.7, 35.2, 27.1, 25.2, 24.8, 24.7, 24.53, 24.45, 24.4, 24.30, 24.27, 23.3 (2C), 22.9, 22.6, 21.7, 21.00, 20.98,
20.94. IR (KBr): 3337, 2959, 1655, 1531, 1269 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for C56H82N8O10Na,
1049.6052; found, 1049.6069.
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H-L-Trp-[(L-Leu)2-Ac5c]2-OMe (6). According to general procedure C (using THF as solvent instead of MeOH),
Cbz deprotection of peptide S-5 (680 mg, 0.662 mmol) afforded the desired product 6 (593 mg, quant) as a white
amorphous. This material was used for the next step without further purification. An aliquot of the crude product
was purified by column chromatography on silica gel (10% MeOH in chloroform) for analytical data collection.
[α]21 –21.9 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.63 (br s, 1H), 7.93 (br s, 1H), 7.68–7.54 (m, 2H),
D
7.52–7.38 (m, 2H), 7.31 (d, J = 5.9 Hz, 1H), 7.25–7.19 (m, 2H), 7.16–7.08 (m, 2H), 6.50 (br s, 1H), 4.45–4.31 (m,
1H), 4.30–4.19 (m, 1H), 4.02–3.89 (m, 2H), 3.85–3.75 (m, 1H), 3.65 (s, 3H), 3.35 (dd, J = 14.6, 4.1 Hz, 1H), 3.08 (dd,
J = 14.6, 7.8 Hz, 1H), 2.66 (dt, J = 13.4, 8.4 Hz, 1H), 2.32–2.03 (m, 5H), 2.03–1.58 (m, 21H), 1.58–1.44 (m, 3H),
1.03–0.74 (m, 24H). 13C NMR (100 MHz, CDCl3) δ: 177.9, 175.8, 175.2, 174.2, 173.7, 173.6, 173.5, 136.7, 127.2,
123.8, 121.9, 119.0, 118.4, 111.7, 110.0, 66.9, 65.7, 54.6 (2C), 54.5, 53.9, 52.5, 52.0, 39.9, 39.8, 39.5, 39.4, 38.0, 37.1,
36.5, 35.2, 30.4, 25.1, 24.8, 24.7, 24.5, 24.3 (2C), 24.2 (2C), 23.22, 23.20, 22.5 (2C), 21.6, 21.3, 21.0, 20.8. IR
(KBr): 3321, 2959, 1670, 1528 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for C48H76N8O8Na, 915.5684; found,
915.5662.
Boc-(L-Trp)2-[(L-Leu)2-Ac5c]2-OMe (S-6). According to general procedure A, the coupling of Boc-L-Trp-OH (250
mg, 0.821 mmol) with amine 6 (734 mg, 0.822 mmol) gave the title compound S-6 (930 mg, 96%) as a white solid
after purification by flash column chromatography on silica gel (50% EtOAc in chloroform). Mp 243–245 °C dec.
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[α]22 –14.1 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 9.79 (br s, 1H), 9.63 (br s, 1H), 7.70 (d, J = 6.8 Hz,
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1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.36–7.29 (m, 2H),
7.25–7.20 (m, 1H), 7.17–7.07 (m, 4H), 7.00–6.93 (m, 1H), 6.91 (d, J = 6.3 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 6.35 (d,
J = 3.9 Hz, 1H), 5.22 (br s, 1H), 4.50–4.39 (m, 1H), 4.38–4.28 (m, 1H), 4.23–4.14 (m, 1H), 4.12–4.01 (m, 2H), 4.00–
3.93 (m, 1H), 3.64 (s, 3H), 3.36–3.24 (m, 1H), 3.19–3.09 (m, 1H), 3.08–2.99 (m, 1H), 2.81–2.67 (m, 1H), 2.50–2.26
(m, 3H), 2.25–2.12 (m, 3H), 2.07–1.61 (m, 19H), 1.57–1.47 (m, 1H), 1.46–1.37 (m, 1H), 1.32–1.21 (m, 1H), 1.14 (s,
9H), 1.08–0.79 (m, 24H). 13C NMR (100 MHz, CDCl3) δ: 175.9, 175.5, 175.1, 174.7, 174.1, 174.0 (2C), 173.8,
156.8, 136.8, 136.7, 127.4, 127.0, 124.0, 123.7, 122.4, 122.1, 119.5, 119.4, 118.0, 117.9, 112.2, 112.0, 108.0, 107.9,
81.2, 66.8, 65.9, 56.5, 55.1, 55.0, 54.3, 54.1, 53.1, 52.2, 40.1, 39.84, 39.81, 39.2, 38.2, 37.1, 36.8, 35.1, 27.7 (3C),
26.7, 25.6, 24.99, 24.96, 24.6 (2C), 24.5, 24.4, 24.33, 24.28, 23.33, 23.26, 22.9, 22.4, 21.6, 21.3, 21.2, 21.1. IR
(KBr): 3329, 2959, 1659, 1528 cm–1. HRMS (ESI) m/z: [M + Na]+ calcd for C64H94N10O11Na, 1201.7001; found,
1201.6981.
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H-(L-Trp)2-[(L-Leu)2-Ac5c]2-OMe (7). Peptide S-6 (188 mg, 0.159 mmol) was dissolved in 2 M HCl in MeOH (3.2
mL) at room temperature, and the solution was stirred overnight at 30 °C. The reaction mixture was neutralized by
adding sat. NaHCO3 aq and the aqueous phase was extracted with CHCl3 four times. The combined organic extracts
were dried over anhydrous Na2SO4 and concentrated under vacuum to give crude product, which was purified by
column chromatography on silica gel eluted with 10% MeOH in chloroform to afford desired amine 7 (165 mg, 96%)
as a white solid. Single crystals for the X-ray crystallographic analysis was obtained by recrystallization from
EtOAc/MeOH/n-hexane (ca. 8:1:1) by slow evaporation of the solvents at room temperature. Mp 232–234 °C.
[α]17D –15.4 (c 1.00, MeOH). 1H NMR (400 MHz, CDCl3) δ: 9.57 (br s, 1H), 9.19 (br s, 1H), 7.97 (br s, 1H), 7.74 (s,
1H), 7.66 (d, J = 5.9 Hz, 1H), 7.59 (d, J = 11.2 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.47–7.35 (m, 4H), 7.23–7.13 (m,
2H), 7.11–7.02 (m, 2H), 6.92 (s, 1H), 6.73 (s, 1H), 6.32 (br s, 1H), 4.48–4.36 (m, 1H), 4.35–4.24 (m, 1H), 4.19–4.09
(m, 1H), 4.06–3.94 (m, 2H), 3.75–3.65 (m, 1H), 3.58 (s, 3H), 3.25–2.98 (m, 4H), 2.79–2.64 (m, 1H), 2.48–2.35 (m,
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1H), 2.33–2.23 (m, 1H), 2.22–2.07 (m, 3H), 2.03–1.57 (m, 21H), 1.51–1.35 (m, 2H), 1.33–1.19 (m, 1H), 1.09–0.75
(m, 24H). 13C NMR (100 MHz, CDCl3) δ: 178.2, 176.0, 175.5, 174.7, 174.5, 174.0, 173.9, 173.8, 136.7, 136.6,
127.3, 127.0, 123.64, 123.62, 122.2, 122.1, 119.5, 119.2, 118.4, 118.1, 111.9, 111.8, 109.5, 108.5, 66.9, 65.9, 56.1,
55.0, 54.6, 54.3, 54.2, 53.0, 52.1, 40.0, 39.8, 39.6, 39.2, 38.1, 37.1, 36.7, 35.1, 30.4, 26.7, 25.1, 25.0, 24.7, 24.6, 24.5
(2C), 24.31, 24.28, 23.3, 23.2, 23.0, 22.6, 21.7, 21.2, 21.04, 21.00. IR (KBr): 3325, 2959, 1655, 1531 cm–1. HRMS
(ESI) m/z: [M + Na]+ calcd for C59H86N10O9Na, 1101.6477; found, 1101.6468.
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Preparation of α,β-unsaturated ketones 4. Compounds 4a, 4b, 4h, 4j, 4k, 4l, and 4n were prepared according to
the literature procedure reported by List and co-workers.33 Preparation of compounds 4c and 4d by the above
procedure are also known in the literature.34 Compounds 4e, 4f, 4g, 4i, 4p, 4q, and 4r were synthesized by List’s
procedure1 this time and all these compounds are known compounds. Compound 4m was prepared by known
procedure reported by Kuroda et al.35 Compound 4o was synthesized from 1,3-propanediol as described in Scheme
9. Compound 4s is commercially available.
(E)-4-(4’-tert-Butylphenyl)-3-buten-2-one (4e).36
According to general procedure D, the reaction of
4-tert-butylbenzaldehyde (1.62 g, 10.0 mmol) in acetone (25 mL) gave the title compound 4e (1.96 g, 97%) as a
colorless oil after purification by flash column chromatography on silica gel (5% EtOAc in n-hexane). 1H NMR
(500 MHz, CDCl3) δ: 7.50 (d, J = 16.3 Hz, 1H), 7.50–7.47 (m, 2H), 7.46–7.40 (m, 2H), 6.69 (d, J = 16.3 Hz, 1H),
2.38 (s, 3H), 1.33 (s, 9H).
(E)-4-(4’-Tolyl)-3-buten-2-one (4f).37 According to general procedure D, the reaction of p-tolualdehyde (1.20 g,
10.0 mmol) in acetone (25 mL) gave the title compound 4f (1.56 g, 98%) as an off-white solid after purification by
flash column chromatography on silica gel (7% EtOAc in n-hexane). 1H NMR (300 MHz, CDCl3) δ: 7.49 (d, J =
16.3 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 7.9 Hz, 2H), 6.68 (d, J = 16.3 Hz, 1H), 2.38 (s, 3H), 2.37 (s, 3H).
(E)-4-(3’-Tolyl)-3-buten-2-one (4g).37 According to general procedure D, the reaction of m-tolualdehyde (1.20 g,
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10.0 mmol) in acetone (25 mL) gave the title compound 4g (1.54 g, 97%) as a colorless oil after purification by flash
column chromatography on silica gel (5% EtOAc in n-hexane). 1H NMR (300 MHz, CDCl3) δ: 7.49 (d, J = 16.3 Hz,
1H), 7.40–7.16 (m, 4H), 6.71 (d, J = 16.3 Hz, 1H), 2.38 (s, 3H), 2.38 (s, 3H).
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(E)-4-(Furyl)-3-buten-2-one (4i).37 According to general procedure D, the reaction of furfural (961 mg, 10.0 mmol)
in acetone (25 mL) gave the title compound 4i (1.20 g, 88%) as a light brown solid after purification by flash column
chromatography on silica gel (7% EtOAc in n-hexane). 1H NMR (300 MHz, CDCl3) δ: 7.51 (d, J = 1.7 Hz, 1H),
7.28 (d, J = 16.0 Hz, 1H), 6.67 (d, J = 3.4 Hz, 1H), 6.62 (d, J = 16.0 Hz, 1H), 6.49 (dd, J = 3.4, 1.7 Hz, 1H), 2.33 (s,
3H).
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(E)-1-Phenyl-1-penten-3-one (4p).37 According to general procedure D, the reaction of benzaldehyde (530 mg,
5.00 mmol) in 2-butanone (12.5 mL) gave the title compound 4p (703 mg, 88%) as an off-white solid after
purification by flash column chromatography on silica gel (4% EtOAc in n-hexane). 1H NMR (500 MHz, CDCl3) δ:
7.61–7.51 (m, 3H), 7.45–7.36 (m, 3H), 6.75 (d, J = 16.3 Hz, 1H), 2.70 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3 Hz, 3H).
(E)-1-Phenyl-1-hexen-3-one (4q).38 According to general procedure D, the reaction of benzaldehyde (530 mg, 5.00
mmol) in 2-pentanone (12.5 mL) gave the title compound 4q (796 mg, 91%) as a pale yellow oil after purification by
flash column chromatography on silica gel (5% EtOAc in n-hexane). 1H NMR (500 MHz, CDCl3) δ: 7.62–7.51 (m,
3H), 7.45–7.34 (m, 3H), 6.75 (d, J = 16.2 Hz, 1H), 2.65 (t, J = 7.3 Hz, 2H), 1.72 (qt, J = 7.4, 7.3 Hz, 2H), 0.99 (t, J =
7.4 Hz, 3H).
(E)-4-Methyl-1-phenyl-1-penten-3-one (4r).37 According to general procedure D, the reaction of benzaldehyde
(530 mg, 5.00 mmol) in methyl isopropyl ketone (12.5 mL) gave the title compound 4r (392 mg, 45%) as a yellow oil
after purification by flash column chromatography on silica gel (5% EtOAc in n-hexane). 1H NMR (500 MHz,
CDCl3) δ: 7.61 (d, J = 16.0 Hz, 1H), 7.59–7.53 (m, 2H), 7.43–7.37 (m, 3H), 6.82 (d, J = 16.0 Hz, 1H), 2.94 (hept, J =
6.9 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H).
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3-Hydroxypropyl 4-bromobenzoate (S-7). To a mixture of 1,3-propanediol (500 mg, 6.58 mmol), pyridine (1.06
mL, 13.2 mmol), and 4-(dimethylamino)pyridine (DMAP; 80.3 mg, 0.658 mmol) in CH2Cl2 (20 mL) was added
4-bromobenzoyl chloride (1.44 g, 6.58 mmol) at –40 °C. The reaction mixture was stirred at –40 °C for 40 min, then
gradually warmed to 0 °C over 2 h before addition of MeOH (0.5 mL). The reaction mixture was diluted with
EtOAc and washed twice with 1 M HCl, and once each with water, sat. NaHCO3 aq, and brine. After drying
(anhydrous Na2SO4) and removal of the solvent, the residue was purified by flash column chromatography on silica
gel (20% then 30% EtOAc in n-hexane) to give alcohol S-7 (1.15 g, 68%) as a colorless oil. 1H NMR (500 MHz,
CDCl3) δ: 7.94–7.86 (m, 2H), 7.64–7.55 (m, 2H), 4.48 (t, J = 6.2 Hz, 2H), 3.77 (t, J = 6.1 Hz, 2H), 2.11 (br s, 1H),
2.01 (tt, J = 6.2, 6.1 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ: 166.2, 131.7 (2C), 131.1 (2C), 128.9, 128.1, 62.0,
59.1, 31.8. IR (film): 3418, 1721 cm–1. HRMS (DART) m/z: [M + H]+ calcd for C10H12BrO3, 258.9964; found,
258.9952.
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3-Oxopropyl 4-bromobenzoate (S-8). A solution of potassium bromide (23.0 mg, 0.193 mmol) in sat. NaHCO3 aq
(1.9 mL) was added to a solution of the alcohol S-7 (500 mg, 1.93 mmol) and 2-hydroxy-2-azaadamantane39,40
(AZADOL; 3.0 mg, 0.0193 mmol) in CH2Cl2 (5.2 mL) at 0 °C. To the above solution was dropped a solution of
sodium hypochlorite pentahydrate (382 mg, 2.32 mmol) in sat. NaHCO3 aq (4.7 mL) over 5 min at 0 °C with vigorous
stirring. After additional stirring for 15 min at 0 °C, the reaction was quenched by adding 10 wt % Na2S2O3 aq.
The aqueous phase was extracted with CH2Cl2 twice, and the combined organic phases were dried over anhydrous
Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel
(20% EtOAc in n-hexane) to give aldehyde S-8 (433 mg, 87%) as a white semisolid. 1H NMR (500 MHz, CDCl3) δ:
9.86 (t, J = 1.4 Hz, 1H), 7.92–7.82 (m, 2H), 7.63–7.51 (m, 2H), 4.66 (t, J = 6.1 Hz, 2H), 2.92 (td, J = 6.1, 1.4 Hz, 2H).
13C NMR (125 MHz, CDCl3) δ: 199.1, 165.6, 131.7 (2C), 131.1 (2C), 128.6, 128.3, 58.7, 42.7. IR (KBr): 1721,
1686 cm–1. HRMS (DART) m/z: [M + H]+ calcd for C10H10BrO3, 256.9808; found, 256.9818.
(E)-5-Oxo-3-hexen-1-yl 4-bromobenzoate (4o). To a solution of aldehyde S-8 (350 mg, 1.36 mmol) in CH2Cl2 (14
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mL) was added (acetylmethylene)triphenylphosphorane (476 mg, 1.50 mmol) at room temperature. After 17 h,
another portion of (acetylmethylene)triphenylphosphorane (216 mg, 0.680 mmol) was added to the reaction mixture.
After 17 h, the resultant mixture was concentrated under vacuum and the residue was purified by flash column
chromatography on silica gel (10% EtOAc in n-hexane) to give enone 4o (238 mg, 59%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) δ: 7.90–7.84 (m, 2H), 7.62–7.55 (m, 2H), 6.82 (dt, J = 16.0, 6.9 Hz, 1H), 6.20 (dt, J = 16.0, 1.5 Hz,
1H), 4.46 (t, J = 6.4 Hz, 2H), 2.70 (dtd, J = 6.9, 6.4, 1.5 Hz, 2H), 2.26 (s, 3H). 13C NMR (125 MHz, CDCl3) δ:
198.0, 165.6, 142.6, 133.2, 131.8 (2C), 131.0 (2C), 128.7, 128.2, 62.9, 31.7, 27.1. IR (film): 1721, 1679 cm–1.
HRMS (DART) m/z: [M + H]+ calcd for C13H14BrO3, 297.0121; found, 297.0123.
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Synthesis of nitromethane adducts 5. According to general procedure E, the reaction of α,β-unsaturated ketone
and nitromethane gave the desired product.
(S)-5-Nitro-4-(4-nitrophenyl)pentan-2-one (5a).41 Reaction of 4a and nitromethane gave 5a as a pale yellow solid.
85% yield. [α]23 +3.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.20 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.3
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2.7 Hz, 2H), 2.16 (s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate = 1.0 mL/min): tR = 14.9
min (major), tR = 20.5 min (minor), ee = 97%.
(S)-5-Nitro-4-phenylpentan-2-one (5b).41 Reaction of 4b and nitromethane gave 5b as a white solid. 79% yield.
[α]24 +2.7 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.45–7.15 (m, 5H), 4.70 (dd, J = 12.8, 6.8 Hz, 1H),
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AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR =10.3 min (major), tR = 11.0 min (minor), ee = 96%.
(S)-5-Nitro-4-(4-chlorophenyl)pentan-2-one (5c).41 Reaction of 4c and nitromethane gave 5c as a white solid.
84% yield. [α]23 +2.4 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.31 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3
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Hz, 2H), 4.68 (dd, J = 12.8, 6.8 Hz, 1H), 4.57 (dd, J = 12.8, 7.6 Hz, 1H), 3.99 (quin, J = 7.2 Hz, 1H), 2.90 (d, J = 7.3
Hz, 2H), 2.13 (s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR = 12.2
min (major), tR = 14.0 min (minor), ee = 94%.
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(S)-5-Nitro-4-(4-methoxyphenyl)pentan-2-one (5d).41 Reaction of 4d and nitromethane gave 5d as a white solid.
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66% yield. [α]24 –0.1 (c 0.87, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.14 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8
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Hz, 2H), 4.66 (dd, J = 12.4, 6.8 Hz, 1H), 4.56 (dd, J = 12.4, 8.0 Hz, 1H), 3.96 (quin, J = 7.2 Hz, 1H), 3.78 (s, 3H),
2.89 (d, J = 6.8 Hz, 2H), 2.12 (s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0
mL/min): tR = 15.3 min (major), tR = 17.1 min (minor), ee = 96%.
(S)-5-Nitro-4-(4-tert-butylphenyl)pentan-2-one (5e). Reaction of 4e and nitromethane gave 5e as a colorless oil.
69% yield. [α]19 +2.7 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.33 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3
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Hz, 2H), 4.68 (dd, J = 12.4, 8.0 Hz, 1H), 4.59 (dd, J = 12.4, 8.0 Hz, 1H), 3.99 (quin, J = 7.3 Hz, 1H), 2.91 (d, J = 7.3
Hz, 2H), 2.12 (s, 3H), 1.29 (s, 9H). 13C NMR (100 MHz, CDCl3) δ: 205.7, 150.8, 135.7, 127.0 (2C), 126.0 (2C),
79.5, 46.2, 38.5, 34.4, 31.2 (3C), 30.3. IR (KBr): 2963, 1717, 1549 cm–1. HRMS (DART) m/z: [M + H]+ calcd for
C15H22NO3, 264.1600; found, 264.1601. HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate = 0.8
mL/min): tR = 7.4 min (major), tR = 8.0 min (minor), ee = 95%.
(S)-5-Nitro-4-(4-methylphenyl)pentan-2-one (5f).42 Reaction of 4f and nitromethane gave 5f as clear crystals.
83% yield. [α]22D +1.3 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.23–7.01 (m, 4H), 4.67 (dd, J = 12.4, 8.0
Hz, 1H), 4.58 (dd, J = 12.4, 8.0 Hz, 1H), 3.97 (quin, J = 7.1 Hz, 1H), 2.89 (d, J = 6.8 Hz, 2H), 2.31 (s, 3H), 2.11 (s,
3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR = 9.7 min (major), tR = 10.7
min (minor), ee = 96%.
(S)-5-Nitro-4-(3-methylphenyl)pentan-2-one (5g).43 Reaction of 4g and nitromethane gave 5g as a pale yellow oil.
87% yield. [α]22 +1.9 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.25–7.18 (m, 1H), 7.08 (d, J = 7.8 Hz,
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1H), 7.02 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.68 (dd, J = 12.4, 8.0 Hz, 1H), 4.59 (dd, J = 12.4, 8.0 Hz, 1H), 3.97 (quin,
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J = 7.2 Hz, 1H), 2.90 (d, J = 6.8 Hz, 2H), 2.33 (s, 3H), 2.12 (s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane =
10/90, flow rate = 1.0 mL/min): tR = 8.5 min (major), tR = 9.1 min (minor), ee = 88%.
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(S)-5-Nitro-4-(2-methylphenyl)pentan-2-one (5h).44 Reaction of 4h and nitromethane gave 5h as a pale yellow oil.
81% yield. [α]21D +1.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.22–7.07 (m, 4H), 4.64 (dd, J = 12.4, 7.2
Hz, 1H), 4.56 (dd, J = 12.4, 7.2 Hz, 1H), 4.31 (quin, J = 7.2 Hz, 1H), 2.90 (dd, J = 7.2, 2.7 Hz, 2H), 2.44 (s, 3H), 2.11
(s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 4/96, flow rate = 0.8 mL/min): tR = 16.5 min (major), tR =
17.7 min (minor), ee = 97%.
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(R)-5-Nitro-4-(furan-2-yl)-pentan-2-one (5i).41 Reaction of 4i and nitromethane gave 5i as a brown solid. 46%
yield. [α]24D +4.1 (c 0.51, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.34 (d, J = 2.0 Hz, 1H), 6.30 (dd, J = 2.9, 2.0
Hz, 1H), 6.15 (d, J = 2.9 Hz, 1H), 4.79–4.60 (m, 2H), 4.11 (quin, J = 6.7 Hz, 1H), 3.05–2.84 (m, 2H), 2.18 (s, 3H).
HPLC (Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR = 10.3 min (major), tR = 11.6 min
(minor), ee = 94%.
(S)-4-(Naphthalen-2-yl)-5-nitropentan-2-one (5j).43 Reaction of 4j and nitromethane gave 5j as clear crystals.
81% yield. [α]19 +4.8 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.87–7.77 (m, 3H), 7.67 (s, 1H), 7.54–
D
7.43 (m, 2H), 7.38–7.31 (m, 1H), 4.77 (dd, J = 12.4, 6.8 Hz, 1H), 4.70 (dd, J = 12.4, 7.6 Hz, 1H), 4.18 (quin, J = 7.1
Hz, 1H), 3.00 (d, J = 6.8 Hz, 2H), 2.12 (s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate =
1.0 mL/min): tR = 10.5 min (major), tR = 11.6 min (minor), ee = 96%.
(S)-4-(Anthracen-9-yl)-5-nitropentan-2-one (5k).45 Reaction of 4k and nitromethane gave 5k as an orange solid.
37% yield. [α]23 +25.5 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.66 (d, J = 8.8 Hz, 1H), 8.44 (s, 1H),
D
8.07 (d, J = 8.3 Hz, 1H), 8.04–7.96 (m, 2H), 7.73–7.60 (m, 1H), 7.59–7.53 (m, 1H), 7.52–7.45 (m, 2H), 6.05–5.84 (m,
1H), 5.21 (dd, J = 12.4, 8.5 Hz, 1H), 4.94 (dd, J = 12.4, 6.3 Hz, 1H), 3.56 (dd, J = 18.5, 6.8 Hz, 1H), 3.35 (dd, J =
18.5, 5.1 Hz, 1H), 2.12 (s, 3H). HPLC (Chiralpak AS-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR =
42.4 min (major), tR = 67.7 min (minor), ee = 88%.
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(S)-(E)-4-(Nitromethyl)-6-phenyl-5-hexen-2-one (5l).41 Reaction of 4l and nitromethane gave 5l as clear crystals.
62% yield. [α]24D +6.1 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.50–7.12 (m, 5 H), 6.53 (d, J = 15.6 Hz,
1H), 6.08 (dd, J = 15.6, 8.5 Hz, 1H), 4.60 (dd, J = 12.4, 6.3 Hz, 1H), 4.52 (dd, J = 12.4, 8.5 Hz, 1H), 3.71–3.42 (m,
1H), 2.75 (d, J = 6.3 Hz, 2H), 2.19 (s, 3H). HPLC (Chiralpak AS-H, i-propanol/n-hexane = 20/80, flow rate = 1.0
mL/min): tR = 16.7 min (major), tR = 19.6 min (minor), ee = 80%.
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(S)-4-(Nitromethyl)-6-phenylhex-5-yn-2-one (5m).46 Reaction of 4m and nitromethane gave 5m as a white solid.
80% yield. [α]22 +28.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.44–7.34 (m, 2H), 7.34–7.24 (m, 3H),
D
4.65 (dd, J = 12.8, 6.4 Hz, 1H), 4.59 (dd, J = 12.8, 6.4 Hz, 1H), 3.87 (quin, J = 6.6 Hz, 1H), 2.93 (d, J = 6.6 Hz, 2H),
2.24 (s, 3H). HPLC (Chiralpak AS-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR = 26.1 min (major),
tR = 38.5 min (minor), ee = 89%.
(R)-4-(Nitromethyl)-6-phenylhexan-2-one (5n).41 Reaction of 4n and nitromethane gave 5n as a pale yellow oil.
55% yield. [α]24 +5.2 (c 0.66, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.35–7.27 (m, 2H), 7.26–7.14 (m, 3H),
D
4.57–4.43 (m, 2H), 2.89–2.46 (m, 5H), 2.16 (s, 3H), 1.81–1.68 (m, 2H).
HPLC (Chiralpak AS-H,
i-propanol/n-hexane = 20/80, flow rate = 1.0 mL/min): tR = 15.6 min (major), tR = 19.3 min (minor), ee = 95%.
(R)-4-(Nitromethyl)-6-(4-bromophenyloxy)hexan-2-one (5o). Reaction of 4o and nitromethane gave 5o as a white
solid. 41% yield. Mp 63–65 °C. [α]18 –2.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.89 (d, J = 8.8
D
Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 4.56 (d, J = 5.9 Hz, 2H), 4.50–4.32 (m, 2H), 2.93–2.78 (m, 1H), 2.77–2.59 (m, 2H),
2.19 (s, 3H), 2.04–1.84 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 206.2, 165.8, 131.9 (2C), 131.2 (2C), 128.7, 128.5,
77.8, 62.1, 44.1, 30.4, 30.2, 30.1. IR (KBr): 1717, 1549 cm–1. HRMS (DART) m/z: [M + H]+ calcd for
C14H17BrNO5, 358.0290; found, 358.0288. HPLC (Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0
mL/min): tR = 24.2 min (major), tR = 25.8 min (minor), ee = 94%.
(S)-6-Nitro-5-phenylhexan-3-one (5p).47 Reaction of 4p and nitromethane gave 5p as a white solid. 61% yield.
[α]19 +12.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.45–7.15 (m, 5H), 4.71 (dd, J = 12.4, 6.8 Hz, 1H),
D
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4.61 (dd, J = 12.4, 8.0 Hz, 1H), 4.03 (quin, J = 7.2 Hz, 1H), 2.89 (d, J = 7.2 Hz, 2H), 2.49–2.26 (m, 2H), 1.00 (t, J =
7.3 Hz, 3H). HPLC (Chiralpak AS-H, i-propanol/n-hexane = 20/80, flow rate = 1.0 mL/min): tR = 15.9 min (major),
tR = 20.6 min (minor), ee = 97%.
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(S)-1-Nitro-2-phenylheptan-4-one (5q).47 Reaction of 4q and nitromethane gave 5q as a pale yellow oil. 69%
yield. [α]23D +8.4 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.45–7.11 (m, 5H), 4.70 (dd, J = 12.4, 6.8 Hz,
1H), 4.60 (dd, J = 12.4, 8.0 Hz, 1H), 4.02 (quin, J = 7.2 Hz, 1H), 2.87 (d, J = 7.2 Hz, 2H), 2.42–2.23 (m, 2H), 1.64–
1.54 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0
mL/min): tR = 8.5 min (major), tR = 9.8 min (minor), ee = 98%.
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(S)-2-Methyl-6-nitro-5-phenylhexan-3-one (5r).48 Reaction of 4r and nitromethane gave 5r as a pale yellow oil.
27% yield. [α]27 +12.0 (c 0.64, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.45–7.13 (m, 5H), 4.71 (dd, J = 12.4,
D
6.8 Hz, 1H), 4.62 (dd, J = 12.4, 8.0 Hz, 1H), 4.03 (quin, J = 7.2 Hz, 1H), 2.99–2.93 (m, 2H), 2.63–2.43 (m, 1H), 1.06
(d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H). HPLC (Chiralpak AS-H, i-propanol/n-hexane = 20/80, flow rate = 1.0
mL/min): tR = 8.7 min (major), tR = 12.5 min (minor), ee = >99%.
(S)-4-Nitro-1,3-diphenylbutan-1-one (5s).43 Reaction of 4s and nitromethane gave 5s as a white solid. 20% yield.
[α]24D –17.4 (c 0.52, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.05–7.88 (m, 2H), 7.68–7.55 (m, 1H), 7.55–7.42 (m,
2H), 7.42–7.22 (m, 5H), 4.84 (dd, J = 12.4, 8.0 Hz, 1H), 4.70 (dd, J = 12.4, 8.0 Hz, 1H), 4.24 (quin, J = 7.1 Hz, 1H),
3.57–3.38 (m, 2H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR = 15.9 min
(major), tR = 22.3 min (minor), ee = 94%.
Synthesis of Michael adducts 9. According to general procedure E, the reaction of α,β-unsaturated ketone and
Michael donor gave the desired product.
5-Nitro-4-(S)-(4-nitrophenyl)hexan-2-one (9a). Reaction of 4a and nitroethane gave 9a. 85% yield, dr = 1.1:1.
The major isomer was partially separated by column chromatography. The absolute stereochemistry of the major
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isomer was assigned as (4S,5S) by analogy to the literature compound, (4S,5S)-5-nitro-4-phenylhexan-2-one,41 based
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on the chemical shifts and the coupling constant values. For the major isomer anti-9a; yellow oil. [α]20 +1.7 (c
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1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.18 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 4.92 (quin, J = 6.8
Hz, 1H), 3.85 (q, J = 7.2 Hz, 1H), 3.09 (dd, J = 18.0, 6.0 Hz, 1H), 2.93 (dd, J = 18.0, 8.0 Hz, 1H), 2.16 (s, 3H), 1.53
(d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 204.7, 147.6, 145.5, 129.3 (2C), 124.0 (2C), 85.4, 44.6, 44.2,
30.4, 17.0. IR (KBr): 1717, 1558, 1541, 1522, 1348 cm–1. HRMS (DART) m/z: [M + H]+ calcd for C12H15N2O5,
267.0981; found, 267.0984. HPLC (Chiralpak AD-H, i-propanol/n-hexane = 2/98, flow rate = 1.0 mL/min): tR =
76.3 min (major), tR = 105.3 min (minor), ee = 95%.
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(S)-5-Methyl-5-nitro-4-(4-nitrophenyl)hexan-2-one (9b).49 Reaction of 4a and 2-nitropropane gave 9b as a
colorless oil. 78% yield. [α]23 –39.4 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.18 (d, J = 8.3 Hz, 2H),
D
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1H), 2.09 (s, 3H), 1.58 (s, 3H), 1.53 (s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate = 1.0
mL/min): tR = 23.1 min (major), tR = 15.3 min (minor), ee = 88%.
(R)-2-[1-(4-Nitrophenyl)-3-oxobutyl]-1,3-dimethylester (9c).50 Reaction of 4a and dimethyl malonate gave 9c as a
yellow oil. 97% yield. [α]24 –14.8 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 8.8 Hz, 2H),
D
7.45 (d, J = 8.8 Hz, 2H), 4.10 (td, J = 9.0, 4.9 Hz, 1H), 3.77 (d, J = 9.0 Hz, 1H), 3.75 (s, 3H), 3.55 (s, 3H), 3.15–2.88
(m, 2H), 2.08 (s, 3H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate = 1.0 mL/min): tR = 15.8
min (major), tR = 24.5 min (minor), ee = 94%.
(R)-2-(1-Phenyl-3-oxobutyl)-1,3-dimethylester (9d). Reaction of 4b and dimethyl malonate gave 9d as a white
solid. 95% yield. [α]27 –13.6 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.39–7.11 (m, 5H), 3.98 (td, J =
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9.0, 5.4 Hz, 1H), 3.74 (d, J = 9.0 Hz, 1H), 3.73 (s, 3H), 3.50 (s, 3H), 3.05–2.86 (m, 2H), 2.03 (s, 3H). HPLC
(Chiralpak AD-H, i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR = 12.5 min (major), tR = 14.7 min (minor),
ee = 94%.
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(R)-2-[1-(4-Nitrophenyl)-3-oxobutyl]-1,3-diisopropylester (9e).51 Reaction of 4a and diisopropyl malonate gave
9e as a pale yellow oil. 77% yield. [α]24D –13.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 8.14 (d, J = 8.8
Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 5.06 (dt, J = 12.7, 6.3 Hz, 1H), 4.81 (dt, J = 12.3, 6.3 Hz, 1H), 4.07 (td, J = 9.8, 4.4
Hz, 1H), 3.67 (d, J = 9.8 Hz, 1H), 3.14–2.87 (m, 2H), 2.06 (s, 3H), 1.24 (dd, J = 6.3, 4.4 Hz, 6H), 1.05 (dd, J = 18.0,
6.3 Hz, 6H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate = 1.0 mL/min): tR = 14.3 min (major),
tR = 41.1 min (minor), ee = 63%.
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(R)-2-[1-(Nitrophenyl)-3-oxobutyl]-5,5-dimethyl-1,3-cyclohexanedione (9f).52
Reaction of 4a and
5,5-dimethyl-1,3-cyclohexanedione gave 9f as a pale yellow oil. 45% yield. [α]27 +19.0 (c 1.00, CHCl3). 1H
D
NMR (400 MHz, CDCl3) δ: 8.17–8.08 (m, 2H), 7.35–7.28 (m, 2H), 4.01 (t, J = 5.6 Hz, 0.4H), 3.94 (dd, J = 11.7, 6.8
Hz, 0.6H), 3.10 (br s, 0.6H), 2.83 (br s, 0.4H), 2.54–2.06 (m, 6H), 1.58 (s, 2H), 1.54 (s, 1H), 1.19 (s, 1H), 1.16 (s, 2H),
1.11 (s, 1H), 1.09 (s, 2H). HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate = 1.0 mL/min): tR = 31.3
min (major), tR = 12.4 min (minor), ee = 47%.
(S)-4-Hydroxy-3-[1-(4-nitrophenyl)-3-oxobutyl]-2H-1-benzopyran-2-one (9g).53
Reaction of 4a and
4-hydroxycoumarin gave 9g as a white solid. Quantitative yield. [α]27 +21.4 (c 1.00, CHCl3). 1H NMR (400
D
MHz, CDCl3) δ: 8.16 (d, J = 8.3 Hz, 2H), 7.97–7.77 (m, 1H), 7.67–7.49 (m, 1H), 7.46–7.28 (m, 4H), 4.27 (br s, 1H),
3.44 (br s, 0.7H), 3.08 (br s, 0.3H), 2.44 (d, J = 11.7 Hz, 1.3H), 2.04–1.88 (m, 0.7H), 1.78 (br s, 2H), 1.73 (br s, 1H).
HPLC (Chiralpak AD-H, i-propanol/n-hexane = 20/80, flow rate = 1.0 mL/min): tR = 40.7 min (major), tR = 11.8 min
(minor), ee = 73%.
(S)-2-(3-Oxocyclopentyl)-1,3-dibenzylester (9h).17 Reaction of 2-cyclopenten-1-one (8h) and dibenzyl malonate
gave 9h as a colorless oil. 58% yield. [α]19D –42.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.44–7.21 (m,
10H), 5.26–5.08 (m, 4H), 3.45 (d, J = 9.3 Hz, 1H), 2.99–2.79 (m, 1H), 2.46 (dd, J = 7.3, 18.5 Hz, 1H), 2.37–2.25 (m,
1H), 2.25–2.10 (m, 2H), 1.99 (dd, J = 10.7, 18.5 Hz, 1H), 1.70–1.55 (m, 1H). HPLC (Chiralpak AD-H,
i-propanol/n-hexane = 5/95, flow rate = 0.5 mL/min): tR = 98.3 min (major), tR = 102.5 min (minor), ee = 89%.
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(S)-2-(3-Oxocyclohexyl)-1,3-dibenzylester (9i).17 Reaction of 2-cyclohexen-1-one (8i) and dibenzyl malonate gave
9i as a colorless oil. 92% yield. [α]20D +0.2 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.47–7.16 (m, 10H),
5.15 (d, J = 2.9 Hz, 4H), 3.41 (d, J = 7.8 Hz, 1H), 2.66–2.50 (m, 1H), 2.49–2.32 (m, 2H), 2.30–2.13 (m, 2H), 2.02
(ddd, J = 13.4, 6.3, 3.2 Hz, 1H), 1.96–1.83 (m, 1H), 1.72–1.55 (m, 1H), 1.54–1.38 (m, 1H). HPLC (Chiralpak AS-H,
i-propanol/n-hexane = 10/90, flow rate = 1.0 mL/min): tR = 49.8 min (major), tR = 40.5 min (minor), ee = 93%.
(S)-2-(3-Oxocycloheptyl)-1,3-dibenzylester (9j).17 Reaction of 2-cyclohepten-1-one (8j) and dibenzyl malonate gave
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9j as a colorless oil. 69% yield. [α]20 –22.3 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 7.49–7.21 (m,
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10H), 5.27–5.04 (m, 4H), 3.42 (d, J = 6.3 Hz, 1H), 2.67–2.39 (m, 5H), 2.00–1.76 (m, 3H), 1.60–1.28 (m, 3H).
HPLC (Chiralpak AD-H, i-propanol/n-hexane = 5/95, flow rate = 0.5 mL/min): tR = 88.1 min (major), tR = 94.9 min
(minor), ee = 98%.
Synthesis of peptide 10, and depsipeptides 11a, 11b, and 11c. Synthesis of peptides 10, and depsipeptides 11a,
11b, and 11c are described in Scheme 10–13.
Cbz-(L-Leu)4-Ac5c-(L-Leu)2-Ac5c-OMe (S-9).
According to general procedure A, the coupling of
Cbz-(L-Leu)2-OH (39.7 mg, 0.105 mmol) with amine 2b (70.7 mg, 0.100 mmol) gave the title compound S-9 (99.2
mg, 93%) as a white solid after purification by flash column chromatography on silica gel (80% EtOAc in n-hexane).
Mp 237–240 °C. [α]22 –8.6 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 7.57–7.46 (m, 2H), 7.45–7.31 (m,
D
7H), 7.31–7.23 (m, 3H), 6.21 (s, 1H), 5.19 (d, J = 12.4 Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H), 4.27–4.14 (m, 2H), 4.14–
4.00 (m, 2H), 4.00–3.90 (m, 2H), 3.63 (s, 3H), 2.62 (dt, J = 13.5, 8.3 Hz, 1H), 2.39–2.23 (m, 2H), 2.16–2.04 (m, 3H),
1.99–1.51 (m, 28H), 1.02–0.81 (m, 36H). 13C NMR (125 MHz, CDCl3) δ: 175.7, 175.3, 175.2, 175.0, 174.6, 174.4,
173.9, 173.8, 158.0, 136.0, 128.6 (2C), 128.1, 127.4 (2C), 67.0, 66.9, 65.7, 56.3, 55.1, 54.9, 54.4, 54.0, 53.1, 52.0,
40.2, 40.0, 39.7, 39.5, 39.4, 39.2, 37.7, 37.5, 36.6, 34.8, 25.0, 24.90, 24.86, 24.81 (2C), 24.77, 24.49, 24.45, 24.2, 24.1,
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The Journal of Organic Chemistry
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23.4, 23.1, 23.0, 22.9, 22.5, 22.3, 22.1, 21.8, 21.5, 21.4, 21.2, 20.9. IR (KBr): 3383, 1744, 1655 cm–1. HRMS
(ESI) m/z: [M + Na]+ calcd for C57H94N8O11Na, 1089.6934; found, 1089.6920.
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H-(L-Leu)4-Ac5c-(L-Leu)2-Ac5c-OMe (10). According to general procedure C (by using THF as solvent instead of
MeOH), Cbz deprotection of peptide S-9 (52.7 mg, 0.0494 mmol) afforded the desired product 10 (44.0 mg, 95%) as
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a white amorphous after purification by flash column chromatography on silica gel (5% MeOH in CHCl3). [α]22
–
D
15.5 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 8.32 (br s, 1H), 7.57 (s, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.41 (s,
1H), 7.31 (d, J = 6.1 Hz, 1H), 7.07 (d, J = 4.6 Hz, 1H), 4.31 (ddd, J = 11.6, 7.9, 3.7 Hz, 1H), 4.19 (ddd, J = 11.6, 6.0,
3.2 Hz, 1H), 4.07 (dt, J = 9.8, 5.2 Hz, 1H), 4.02–3.92 (m, 2H), 3.66 (s, 3H), 3.44 (dd, J = 9.8, 4.0 Hz, 1H), 2.63 (dt, J
= 13.2, 8.0 Hz, 1H), 2.32–2.21 (m, 2H), 2.18–2.06 (m, 3H), 2.03–1.54 (m, 29H), 1.38 (ddd, J = 14.0, 9.8, 4.6 Hz, 1H),
1.08–0.76 (m, 36H). 13C NMR (125 MHz, CDCl3) δ: 178.8, 175.6, 175.1, 174.4, 174.29, 174.27, 173.39, 173.37,
66.8, 65.8, 54.9 (2C), 54.3, 54.0, 53.2, 52.6, 52.1, 43.8, 40.0, 39.9, 39.6, 39.5, 39.1, 38.0, 37.2, 36.7, 35.2, 25.1 (2C),
25.03, 24.99, 24.7, 24.6, 24.54, 24.53, 24.4, 24.3, 23.43, 23.38, 23.36, 23.1, 22.8, 22.5, 21.9, 21.5, 21.3, 21.14, 21.11,
20.9. IR (KBr): 3341, 1655 cm–1. HRMS (ESI) m/z: [M + H]+ calcd for C49H89N8O9, 933.6747; found, 933.6736.
Depsi-dipeptide S-10. To a mixture of carboxylic acid Cbz-L-Leu-OH (935 mg, 3.53 mmol) and L-leucic acid
tert-butyl ester54 (664 mg, 3.53 mmol) in CH2Cl2 (35 mL) were added N,N’-diisopropylcarbodiimide (DIC, 0.546 mL,
3.53 mmol) and DMAP (431 mg, 3.53 mmol) at 0 °C, and the resultant mixture was gradually warmed to room
temperature. After stirring for 18 h, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 aq
and brine. Then, the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give crude
product, which was purified by flash column chromatography on silica gel. The fraction eluted with 8% EtOAc in
n-hexane afforded the title compound S-10 (1.44 g, 94%) as a colorless oil. [α]19D –27.3 (c 1.01, CHCl3). 1H NMR
(500 MHz, CDCl3) δ: 7.40–7.28 (m, 5H), 5.18 (d, J = 8.9 Hz, 1H), 5.10 (s, 2H), 4.92 (dd, J = 9.0, 4.3 Hz, 1H), 4.44
(ddd, J = 9.8, 8.9, 4.0 Hz, 1H), 1.85–1.68 (m, 4H), 1.67–1.59 (m, 1H), 1.59–1.50 (m, 1H), 1.45 (s, 9H), 1.04–0.82 (m,
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