Total synthesis of debromoflustramines B and e based on the intramolecular carbamoylketene-alkene [2 + 2] cycloaddition

Article abstract of DOI:10.1021/jo301817w

Total synthesis of debromoflustramines B and E has been accomplished by using a platinum-catalyzed addition reaction of o-aminophenylboronic acid with the allene and an intramolecular carbamoylketene-alkene [2 + 2] cycloaddition for the construction of the basic carbon framework of the target alkaloids as the key steps.

Full text of DOI:10.1021/jo301817w

Article
pubs.acs.org/joc
Total Synthesis of Debromoflustramines B and E Based on the
Intramolecular Carbamoylketene−Alkene [2 + 2] Cycloaddition
Tsukasa Ozawa, Makoto Kanematsu, Hiromasa Yokoe, Masahiro Yoshida, and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
S
* Supporting Information
ABSTRACT: Total synthesis of debromoflustramines B and
E has been accomplished by using a platinum-catalyzed
addition reaction of o-aminophenylboronic acid with the allene
and an intramolecular carbamoylketene−alkene [2 + 2]
cycloaddition for the construction of the basic carbon
framework of the target alkaloids as the key steps.
Scheme 1. Synthesis of Physovenine via the Intramolecular
Carbamoylketene−Alkene [2 + 2] Cycloaddition
INTRODUCTION
■
Debromoflustramines B (1) and E (2), members of the
pyrrolidinoindoline alkaloid family, have been isolated from the
marine bryozoan Flustra foliacea1 and from Australian
myobatrachid frogs Pseudophryne,2 respectively. These alkaloids
possess a characteristic prenylated hexahydropyrrolo[2,3-b]-
indole backbone and are known to exhibit selective
butyrylcholinesterase inhibitory3 and antibacterial activity
against vancomycin-resistant Enterococci and methicillin-resist-
ant Staphylococcus aureus.4 Due to their intriguing structures
and promising biological profiles, these compounds have
attracted much attention in the synthetic community as targets
for total synthesis. To date, a number of syntheses of the
racemic5 and optically active forms6 have been reported.
Whereas the endo-olefinic products 12 are formed when the
hydroxopalladium complex 10 is used in the reaction, the exo-
olefinic products 11 predominated when the hydroxoplatinum
complex 9 was employed8 (Scheme 2).
RESULTS AND DISCUSSION
■
As an application of the combined methodologies of the
originally developed [2 + 2] cycloaddition and the platinum-
catalyzed exo-selective alkenylation to the synthesis of
Scheme 2. Regiocontrolled Addition of Arylboronic Acids to
Allenes Using Pt and Pd Catalyst
Figure 1. Debromoflustramines.
During the course of our synthetic studies directed toward
the Calabar bean alkaloids, we reported the synthesis of
( )-physovenine (3), employing an efficient intramolecular
carbamoylketene−alkene [2 + 2] cycloaddition reaction (4→5)
followed by Baeyer−Villiger (B−V) oxidation (5→6) as the
key steps.7 (Scheme 1)
Furthermore, we have recently developed a regiocontrolled
addition of the arylboronic acids 8 to the allenes 7 using a
palladium or platinum catalyst. The selectivity of the reaction
can be controlled by the choice of the metal species and base.
Received: August 24, 2012
Published: September 26, 2012
© 2012 American Chemical Society
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pyrrolidinoindoline alkaloids, we report here the total synthesis
of ( )-debromoflustramines B (1) and E (2). Our retro-
synthetic analysis of the debromoflustramines is shown in
Scheme 3. We envisaged reducing the lactam and N-
Table 1. Platinum-Catalyzed Coupling of 17 with 7a−f
Scheme 3. Retrosynthetic Analysis
prenylation in the last stage of the synthesis. By means of a
Beckmann-type ring expansion, the γ-lactam 13 could be
derived from the cyclobutanone 14, the [2 + 2] cycloadduct of
the alkenyl carbamoylketene 15, which would be generated
from a ketene precursor 16. Compound 16 can be derived from
the aniline derivative 18, which would be prepared through a
platinum-catalyzed coupling reaction of o-aminophenylboronic
acid 179 and the corresponding allene 7 (R = CH2C-
(Me)2OR′).10 (Scheme 3)
cycloadducts 23 and 24 as shown in Table 2. The stereo-
chemistry of the endo-olefin derived cycloadduct 24c was
established by observation of a diagnostic NOE between the
methyl and the methylene protons shown in entry 3. The
cycloaddition of the substrate 21d/22d with an unprotected
hydroxyl group resulted in 23d and an inseparable mixture of
the olefinic isomers 25 and 26 (entry 4). To improve the yield
of 23d, treatment of a mixture of the carboxylic acids with ethyl
chloroformate and triethylamine in THF at room temperature
produced cleanly a separable mixture of 23d and the cyclized
product 24d in 60% and 2% yield, respectively (entry 5). Thus,
we were able to develop an alternative and mild procedure
(condition B) for the generation of the carbamoylketene13
(Table 2).
With the requisite tricycle 23c in hand, we advanced to the
key ring expansion. The cyclobutanone was converted to the
oxime 27, the configuration of which, determined by 1H NMR
using a shift reagent Eu(dpm)3,14 proved to be Z.15 On
exposure of 27 to the conditions of the Beckmann rearrange-
ment (SOCl2, benzene, RT, 11 h),16 the desired tricyclic lactam
28 was not obtained at all but the ring-opened hemiaminal 29,
which was characterized as the methyl aminal 30, was produced
in 73% yield for the three steps (Scheme 4).
Unsuccessful attempts at the Beckmann rearrangement led
us to seek an efficient, regioselective ring expansion from 23c to
the lactam. After numerous attempts, we found that rearrange-
ment through a nitrone14,17 could be applied to the conversion;
thus, treatment of 23c with N-methylhydroxylamine hydro-
chloride, NaHCO3, and 3 Å molecular sieves in ethanol at 50
°C provided the nitrone 31, which, without purification, was
immediately reacted with p-TsCl and 4-pyrrolidinopyridine in
refluxing chloroform to give the requisite γ-lactam 32 in 75%
yield for the two steps. As a result, we were able to overcome a
key hurdle and in so doing demonstrated that the procedure
Because the addition of o-aminoarylboronic acid 17 with
allenes had never been attempted before, we initially examined
the reaction of 17 with a variety of allenes 7a−f, which were
prepared as has been described in ref 8. The results are shown
in Table 1. Treatment of 17 with the allenes 7a−f in the
presence of platinum catalyst 911 and K2CO3 as the base12
resulted in the predominant formation of the exo-olefinic
adducts 19 rather than the endo-adducts 20 in a ratio of 3:1 to
>20:1 in good yield. It was revealed that allenes with bulky
substituents near the reaction center (i.e., the central carbon of
the allenes) showed higher selectivity for the expected exo-
olefin formation (entries 3−6). Particularly, in the case of the
allene 7e, the exclusive formation of 19e could be realized
(entry 5). The amino alkene 19c, the required adduct for the
synthesis of the debromoflustramines, was obtained as a
mixture of isomers in a ratio of 9:1, which can be separated
by HPLC, in 90% yield (entry 3). The E-geometry of the
undesired endo-adduct 20c was confirmed by an NOE between
the olefinic methyl and the allylic methylene proton. It should
be noted that the coupling reaction proceeds cleanly without
protection of the amino group (Table 1).
To verify the generality and substrate scope of the
intramolecular [2 + 2] cycloaddition, we examined the reaction
using these amino alkenes. Treatment of a mixture of adducts
19a−f/20a−d,f with methyl chloroformate and potassium
carbonate followed by methyl bromoacetate and sodium
hydride provided 21a−f/22a−d,f. After alkaline hydrolysis,
the resulting carboxylic acids were treated with oxalyl chloride
in refluxing benzene. Triethylamine was then added to the
mixture in one pot7 to give a readily separable mixture of the
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could be successfully applied to install the hexahydropyrrolo-
[2,3-b]indole backbone. Debenzylation followed by selective
dehydration by treatment of the resulting 33 with p-TsOH in
the presence of magnesium sulfate18 provided the angular-
prenylated tricycle 34 in good yield (85% for the two steps).
After removal of the carbomethoxy group via alkaline
hydrolysis, reduction of the lactam carbonyl of 13 with lithium
aluminum hydride (LAH) in refluxing THF produced
debromoflustramine E (2). On the other hand, prenylation of
13 gave 35, which was reduced with LAH to give
debromoflustramine B (1) uneventfully. The spectroscopic
properties of the synthetic 1 and 2 were completely identical
with those for the debromoflustramines B and E5b (Scheme 5).
Table 2. [2 + 2] Cycloaddition
Scheme 5. Total Synthesis of Debromoflustramines B and E
CONCLUSION
■
In summary, the total synthesis of debromoflustramines B (1)
and E (2) has been accomplished in 18% (12 steps) and 20%
(11 steps) overall yield, respectively, from o-aminophenylbor-
onic acid. The unique features of this work include the
combined use of the two originally developed reactions, that is,
the platinum-catalyzed addition reaction of o-aminophenylbor-
onic acid with allenes and the intramolecular [2 + 2]
cycloaddition, for the construction of the basic carbon
framework of the target alkaloids. We were also able to
demonstrate the wide generality of the intramolecular
carbamoylketene−alkene [2 + 2] cycloaddition, which could
be applied not only to the synthesis of a variety of alkaloids but
also to the assembly of nitrogen-containing heterocyclic
compounds. In addition, it was revealed that the nitrone
rearrangement could be successfully applied to the regiose-
lective ring expansion of the indoline-fused cyclobutanone to
give the γ-lactam for the installation of the hexahydropyrrolo-
[2,3-b]indole backbone. Although there have been many
synthetic reports on the flustramine families, the synthetic
route developed here is quite unique and efficient and could
also be applied to the synthesis of other alkaloids with more
complex molecular structures.
a
b
c
Isolated yield. Single product. Not detected.
Scheme 4. Attempted Beckmann Rearrangement
EXPERIMENTAL SECTION
General Procedure. All nonaqueous reactions were carried out
under a positive atmosphere of argon in dried glassware unless
■
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otherwise indicated. Materials were obtained from commercial
suppliers and used without further purification expect when otherwise
noted. Solvents were dried and distilled according to standard
protocols. NMR spectra were recorded on a 400 MHz instrument.
1H NMR were measured in CDCl3 solution and referenced to TMS
(0.00 ppm) or in C6D6 solution and referenced to C6D5H (7.16 ppm).
13C NMR were measured in CDCl3 solution and referenced to CDCl3
(CH2), 29.4 (CH2), 24.6 (CH2); HRMS (ESI) calcd for C19H24NO
[M + H]+: 282.1858, found 282.1855.
20b: Rf (hexane:AcOEt = 4:1) 0.66; IR (neat) 3460, 3366, 2926,
1613 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35−7.29 (5 H, m), 7.03
(1 H, t, J = 8.0 Hz), 6.95 (1 H, d, J = 8.0 Hz), 6.71 (1 H, t, J = 8.0 Hz),
6.66 (1 H, d, J = 8.0 Hz), 5.48 (1 H, t, J = 6.8 Hz), 4.52 (2 H, s), 3.69
(2 H, br), 3.53 (2 H, t, J = 6.8 Hz), 2.29 (2 H, q, J = 6.8 Hz), 1.94 (3
H, s), 1.77 (2 H, quint, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
143.0 (C), 138.6 (C), 134.1 (C), 131.5 (C), 129.9 (CH), 128.7 (CH),
128.4 (CH), 128.0 (2CH), 127.5 (2CH), 127.5 (CH), 118.2 (CH),
115.4 (CH), 73.0 (CH2), 69.9 (CH2), 29.7 (CH2), 25.1 (CH2), 17.3
(CH3); HRMS (ESI) calcd for C19H24NO [M + H]+: 282.1858, found
282.1860.
2-[5-(Benzyloxy)-5-methylhex-1-en-2-yl]aniline and (E)-2-[5-
(Benzyloxy)-5-methylhex-2-en-2-yl]aniline (19c and 20c). These
compounds were prepared from allene 7c (1.00 g, 4.9 mmol).
Purification by silica gel column chromatography (hexane:AcOEt =
9:1) gave 19c and 20c as a colorless oil (1.30 g, 90%, 9:1 mixture of
19c and 20c). For analysis, the mixture of 19c and 20c were partially
separated by HPLC (Mightysil, 3% i-PrOH-hexane, 3.8 mL/min).
19c: Rf (hexane:AcOEt = 9:1) 0.53; IR (neat) 3468, 3374, 3028,
2972, 1614 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.33−7.22 (5 H, m),
7.06 (1 H, t, J = 8.0 Hz), 6.98 (1 H, d, J = 8.0 Hz), 6.72 (1 H, t, J = 8.0
Hz), 6.69 (1 H, d, J = 8.0 Hz), 5.29 (1 H, s), 5.05 (1 H, s), 4.34 (2 H,
s), 3.79 (2 H, br), 2.49 (2 H, dt, J = 3.8 and 16.8 Hz), 1.69 (2 H, dt, J
= 3.8 and 16.8 Hz), 1.24 (6 H, s); 13C NMR (100 MHz, CDCl3) δ
148.1 (C), 143.2 (C), 139.7 (C), 128.5 (C), 128.5 (CH), 128.2
(2CH), 127.8 (CH), 127.3 (2CH), 127.1 (CH), 118.0 (CH), 115.4
(CH), 114.1 (CH2), 74.8 (C), 63.5 (CH2), 38.5 (CH2), 31.7 (CH2),
25.7 (2CH3); HRMS (ESI) calcd for C20H26NO [M + H]+: 296.2014,
found 296.2014.
20c: Rf (hexane:AcOEt = 9:1) 0.53; IR (neat) 3466, 3371, 3028,
2972, 1613 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.35−7.24 (5 H, m),
7.04 (1 H, t, J = 7.6 Hz), 6.98 (1 H, d, J = 7.6 Hz), 6.72 (1 H, t, J = 7.6
Hz), 6.66 (1 H, d, J = 7.6 Hz), 5.63 (1 H, t, J = 7.6 Hz), 4.40 (2 H, s),
3.70 (2 H, br), 2.48 (2 H, d, J = 7.6 Hz), 1.97 (3 H, s), 1.33 (6 H, s);
13C NMR (100 MHz, CDCl3) δ 143.1 (C), 139.7 (C), 135.4 (C),
131.5 (C), 128.6 (CH), 128.3 (CH), 127.5 (2CH), 127.3 (CH), 127.1
(2CH), 126.2 (CH), 118.1 (CH), 115.4 (CH), 75.8 (C), 63.9 (CH2),
39.6 (CH2), 25.6 (2CH3), 17.6 (CH3); HRMS (ESI) calcd for
C20H26NO [M + H]+: 296.2014, found 296.2010.
5-(2-Aminophenyl)-2-methylhex-5-en-2-ol and (E)-5-(2-Amino-
phenyl)-2-methylhex-4-en-2-ol (19d and 20d). These compounds
were prepared from allene 7d (19.0 mg, 0.16 mmol). Purification by
silica gel column chromatography (hexane:AcOEt = 7:3) gave 19d and
20d as a colorless oil (20.4 mg, 62%, 9:1 mixture of 19d and 20d). For
analysis, the mixture of 19d and 20d was partially separated by HPLC
(Mightysil, 3% i-PrOH-hexane, 3.8 mL/min).
19d: Rf (hexane:AcOEt = 7:3) 0.20; IR (neat) 3367, 2970, 1614
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.06 (1 H, t, J = 7.6 Hz), 7.00 (1
H, d, J = 7.6 Hz), 6.73 (1 H, t, J = 7.6 Hz), 6.70 (1 H, d, J = 7.6 Hz),
5.31 (1 H, s), 5.07 (1 H, s), 3.79 (2 H, br), 2.47 (2 H, t, J = 8.4 Hz),
1.60 (2 H, t, J = 8.4 Hz), 1.54 (1 H, br), 1.21 (6 H, s); 13C NMR (100
MHz, CDCl3) δ 147.9 (C), 143.0 (C), 128.5 (C), 128.4 (CH), 127.8
(CH), 118.0 (CH), 115.4 (CH), 114.2 (CH2), 70.5 (C), 41.8 (CH2),
32.0 (CH2), 29.1 (2CH3); HRMS (ESI) calcd for C13H20NO [M +
H]+: 206.1545, found 206.1549.
(77.0 ppm), in C6D6 solution and referenced to C6D5H (128.06 ppm),
or in DMSO-d6 and referenced to DMSO (39.3 ppm). Chemical shifts
are reported in ppm (from TMS). When peak multiplicities are
reported, the following abbreviations are used: s, singlet; d, doublet; t,
triplet; q, quartet; quint, quintet; m, multiplet; br, broadened. IR
spectra were measured on FT/IR spectrometer. Type of mass analyzer
was time of flight mass spectrometry (TOF-mass). Column
chromatography was performed on silica gel using the indicated
solvent. Thin layer chromatography was performed on precoated
plates, and compounds were visualized with UV light and p-
anisaldehyde stains. All melting points were reported as uncorrected.
General Procedure for Platinum-Catalyzed Coupling Re-
action of o-Aminophenylboronic Acid (17) and the Corre-
sponding Allenes. To a stirred solution of corresponding allenes
(1.0 equiv) in dioxane−H2O (20:1, 0.25 M) were added K2CO3 (5.0
equiv), boronic acid 17 (1.5 equiv), and [Pt2(OH)2(PPh3)4][BF4]2 (5
mol %). After being stirred at 100 °C for 13−16 h, the mixture was
filtered through a pad of silica gel and evaporated in vacuo. The
residue was purified by silica gel column chromatography.
2-[5-(Benzyloxy)pent-1-en-2-yl]aniline and (E)-2-[5-(Benzyloxy)-
pent-2-en-2-yl]aniline (19a and 20a). These compounds were
prepared from allene 7a (120 mg, 0.68 mmol). Purification by silica
gel column chromatography (hexane:AcOEt = 9:1) gave 19a and 20a
as a colorless oil (175 mg, 92%, 3:1 mixture of 19a and 20a; the ratio
1
was determined by H NMR). For analysis, the mixture of 19a and
20a was partially separated by HPLC (Mightysil, 3% i-PrOH-hexane,
3.8 mL/min).
19a: Rf (hexane:AcOEt = 4:1) 0.59; IR (neat) 3467, 3366, 2856,
1613 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.34−7.26 (5 H, m), 7.05
(1 H, t, J = 7.6 Hz), 6.97 (1 H, d, J = 7.6 Hz), 6.71 (1 H, t, J = 7.6 Hz),
6.67 (1 H, d, J = 7.6 Hz), 5.28 (1 H, s), 5.06 (1 H, s), 4.47 (2 H, s),
3.75 (2 H, br), 3.48 (2 H, t, J = 7.6 Hz), 2.48 (2 H, t, J = 7.6 Hz), 1.74
(2 H, quint, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 147.3 (C),
143.2 (C), 138.5 (C), 128.6 (C), 128.4 (CH), 128.3 (2CH), 127.9
(CH), 127.7 (2CH), 127.5 (CH), 118.0 (CH), 115.4 (CH), 114.7
(CH2), 72.9 (CH2), 69.7 (CH2), 33.8 (CH2), 28.0 (CH2); HRMS
(ESI) calcd for C18H22NO [M + H]+: 268.1701, found 268.1699.
20a: Rf (hexane:AcOEt = 4:1) 0.59; IR (neat) 3464, 3367, 2856,
1613 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.52−7.27 (5 H, m), 7.02
(1 H, t, J = 7.6 Hz), 6.97 (1 H, d, J = 7.6 Hz), 6.71 (1 H, t, J = 7.6 Hz),
6.67 (1 H, d, J = 7.6 Hz), 5.50 (1 H, t, J = 6.8 Hz), 4.58 (2 H, s), 3.73
(2 H, br), 3.59 (2 H, t, J = 6.8 Hz), 2.52 (2 H, q, J = 6.8 Hz), 1.96 (3,
s); 13C NMR (100 MHz, CDCl3) δ 143.1 (C), 138.5 (C), 135.5 (C),
131.3 (C), 128.6 (CH), 128.4 (CH), 127.6 (CH), 127.6 (2CH), 127.5
(2CH), 126.7 (CH), 118.2 (CH), 115.4 (CH), 73.0 (CH2), 69.9
(CH2), 29.1 (CH2), 17.5 (CH3); HRMS (ESI) calcd for C18H22NO
[M + H]+: 268.1699, found 268.1699.
2-[6-(Benzyloxy)hex-1-en-2-yl]aniline and (E)-2-[6-(Benzyloxy)-
hex-2-en-2-yl]aniline (19b and 20b). These compounds were
prepared from allene 7b (50.0 mg, 0.26 mmol). Purification by silica
gel column chromatography (hexane:AcOEt = 9:1) gave 19b and 20b
as a colorless oil (68.0 mg, 93%, 4:1 mixture of 19b and 20b). For
analysis, the mixture of 19b and 20b was partially separated by HPLC
(Mightysil, 3% i-PrOH-hexane, 3.8 mL/min).
19b: Rf (hexane:AcOEt = 4:1) 0.66; IR (neat) 3467, 3369, 2936,
1613 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.48−7.23 (5 H, m), 7.05
(1 H, t, J = 7.6 Hz), 6.96 (1 H, d, J = 7.6 Hz), 6.70 (1 H, t, J = 7.6 Hz),
6.67 (1 H, d, J = 7.6 Hz), 5.26 (1 H, s), 5.05 (1 H, s), 4.47 (2 H, s),
3.75 (2 H, br), 3.45 (2 H, t, J = 8.0 Hz), 2.38 (2 H, t, J = 8.0 Hz), 1.65
(2 H, quint, J = 8.0 Hz), 1.50 (2 H, quint, J = 8.0 Hz); 13C NMR (100
MHz, CDCl3) δ 147.8 (C), 143.2 (C), 138.7 (C), 128.6 (C), 128.5
(2CH), 128.3 (2CH), 127.8 (CH), 127.6 (CH), 127.4 (CH), 118.0
(CH), 115.4 (CH), 114.5 (CH2), 72.8 (CH2), 70.2 (CH2), 37.1
20d: Rf (hexane:AcOEt = 7:3) 0.20; IR (neat) 3372, 2970, 1615
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.05 (1 H, t, J = 7.2 Hz), 6.98 (1
H, d, J = 7.2 Hz), 6.72 (1 H, t, J = 7.2 Hz), 6.69 (1 H, d, J = 7.2 Hz),
5.59 (1 H, t, J = 7.6 Hz), 3.75 (2 H, br), 2.39 (2 H, t, J = 7.6 Hz), 1.97
(3 H, s), 1.43 (1 H, br), 1.29 (6 H, s); 13C NMR (100 MHz, CDCl3) δ
143.0 (C), 136.8 (C), 131.5 (C), 128.7 (CH), 127.7 (CH), 125.9
(CH), 118.3 (CH), 115.5 (CH), 71.5 (C), 42.4 (CH2), 29.4 (2CH3),
17.6 (CH3); HRMS (ESI) calcd for C13H20NO [M + H]+: 206.1545,
found 206.1555.
2-[5-(Benzyloxy)-4,4-dimethylpent-1-en-2-yl]aniline (19e). This
compound was prepared from allene 7e (30.0 mg, 0.14 mmol).
Purification by silica gel column chromatography (hexane:AcOEt =
9:1) gave 19e as a colorless oil (26.5 mg, 64%); Rf (hexane:AcOEt =
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1
4:1) 0.57; IR (neat) 3477, 3383, 2956, 1611 cm−1; H NMR (400
MHz, CDCl3) δ 7.34−7.28 (5 H, m), 7.03 (1 H, t, J = 8.2 Hz), 7.01 (1
H, d, J = 8.2 Hz), 6.68 (1 H, t, J = 8.2 Hz), 6.65 (1 H, d, J = 8.2 Hz),
5.27 (1 H, s), 5.17 (1 H, s), 4.27 (2H, s), 3.82 (2 H, br), 3.02 (2 H, s),
2.52 (2 H, s), 0.85 (6 H, s); 13C NMR (100 MHz, CDCl3) δ 145.2
(C), 142.7 (C), 139.0 (C), 129.4 (C), 128.8 (CH), 128.2 (2CH),
127.6 (CH), 127.4 (2CH), 127.2 (CH), 118.3 (CH2), 118.0 (CH),
115.6 (CH), 78.5 (CH2), 72.8 (CH2), 46.2 (CH2), 35.8 (C), 25.2
(2CH3); HRMS (ESI) calcd for C20H26NO [M + H]+: 296.2014
found 296.2014.
δ 7.51−7.43 (1 H, m), 7.35−7.27 (7 H, m), 7.18−7.16 (1 H, m), 5.42
(0.33 H, t, J = 6.4 Hz), 5.19 (1 H, s), 4.95 (1 H, s), 4.65 (1 H, d, J =
17.6 Hz), 4.54 (0.66 H, s), 4.46 (2 H, s), 3,73 (3 H, s), 3.72 (1 H, d, J
= 17.6 Hz), 3.65 (1 H, s), 3.62 (3 H, s), 3.54 (0.66 H, t, J = 6.4 Hz),
3.44 (2 H, t, J = 6.4 Hz), 2.41 (2 H, m), 1.91 (0.66 H, s), 1.69 (2 H,
m); 13C NMR (100 MHz, CDCl3) δ 169.9 (C), 156.3 (C), 155.9 (C
isomer), 147.9 (C), 140.6 (C), 138.6 (C), 138.5 (C), 135.5 (C
isomer), 129.9 (CH), 129.7 (CH), 128.3 (CH), 127.9 (2CH), 127.8
(2CH), 127.6 (CH), 127.5 (CH), 115.3 (CH2), 115.2 (CH isomer),
73.0 (CH2 isomer), 72.9 (CH2), 69.5 (CH2), 53.0 (CH3), 52.5 (CH3
isomer), 52.0 (CH3), 52.0 (CH3 isomer), 51.7 (CH2), 33.0 (CH2),
29.1 (CH2 isomer), 28.2 (CH2), 17.0 (CH3 isomer); HRMS (ESI)
calcd for C23H28NO5 [M + H]+: 398.1967, found 398.1967.
2-[6-(Benzyloxy)-5,5-dimethylhex-1-en-2-yl]aniline and (E)-2-[6-
(Benzyloxy)-5,5-dimethylhex-2-en-2-yl]aniline (19f and 20f). These
compounds were prepared from allene 7f (34.0 mg, 0.15 mmol).
Purification by silica gel column chromatography (hexane:AcOEt =
9:1) gave 19f and 20f as a colorless oil (31.2 mg, 67%, 12:1 mixture of
19f and 20f); Rf (hexane:AcOEt = 4:1) 0.61; IR (neat) 3471, 3374,
2953, 1612 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.33−7.26 (5 H, m),
7.05 (1 H, t, J = 7.6 Hz), 6.97 (1 H, d, J = 7.6 Hz), 6.71 (1 H, t, J = 7.6
Hz), 6.69 (1 H, d, J = 7.6 Hz), 5.28 (0.08 H, t, J = 8.0 Hz), 5.26 (1 H,
s), 5.04 (1 H, s), 4.51 (0.16 H, s), 4.48 (2 H, s), 3,76 (2 H, br), 3.19
(0.17 H, s), 3.13 (2 H, s), 2.30 (2 H, dt, J = 8.0 and 8.4 Hz), 2.19 (0.17
H, d, J = 8.0 Hz), 1.93 (0.25 H, s), 1.45 (2 H, dt, J = 8.0 and 8.4 Hz),
0.97 (0.5 H, s), 0.89 (6 H, s); 13C NMR (100 MHz, CDCl3, major
isomer only) δ 148.5 (C), 143.1 (C), 139.0 (C), 129.0 (C), 128.4
(2CH), 128.2 (CH), 127.7 (2CH), 127.3 (CH), 127.2 (CH), 118.0
(CH), 115.4 (CH), 113.9 (CH2), 79.0 (CH2), 73.2 (CH2), 37.5
(CH2), 34.4 (C), 31.8 (CH2), 24.6 (2CH3); HRMS (ESI) calcd for
C21H27NONa [M + Na]+: 332.1990 found 332.1986.
Methyl 2-[(2-{6-(Benzyloxy)hex-1-en-2-yl}phenyl)-
(methoxycarbonyl)amino)acetate and (E)-Methyl 2-[{2-(6-
(Benzyloxy)hex-2-en-2-yl)phenyl}(methoxycarbonyl)amino]acetate
(21b and 22b). The mixture of carbamates was prepared from
aminoalkene (19b/20b) (20.0 mg, 0.71 mmol). Purification by silica
gel column chromatography (hexane:AcOEt = 9:1) gave the
corresponding carbamates as a colorless oil (35.0 mg, 90%, an
inseparable 4:1 mixture of methyl 2-[6-(benzyloxy)hex-1-en-2-yl]-
phenylcarbamate and (E)-methyl 2-[6-(benzyloxy)hex-2-en-2-yl]-
phenylcarbamate); Rf (hexane:AcOEt = 4:1) 0.68; IR (neat) 3412,
2939, 2857, 1740 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.07 (1 H, d, J
= 7.6 Hz), 7.35−7.27 (6 H, m), 7.05 (1 H, t, J = 7.6 Hz), 7.01 (1 H, d,
J = 7.6 Hz), 6.96 (1 H, br, J = 8.0 Hz), 5.44 (0.25 H, t, J = 8.0 Hz),
5.34 (1 H, s), 5.02 (1 H, s), 4.53 (0.43 H, s), 4.48 (2 H, s), 3,75 (3 H,
s), 3.54 (0.52 H, t, J = 6.4 Hz), 3.45 (2 H, t, J = 8.0 Hz), 2.35 (2 H, t, J
= 8.0 Hz), 1.94 (0.5 H, s), 1.64 (2 H, quint, J = 8.0 Hz), 1.49 (2 H,
m); 13C NMR (100 MHz, CDCl3) δ 153.9 (C), 150.7 (C isomer),
146.9 (C), 138.6 (C), 134.4 (C), 132.2 (C isomer), 128.4 (C), 128.3
(CH), 128.1 (2CH), 127.9 (2CH), 127.6 (CH), 127.5 (CH), 122.8
(CH), 119.2 (CH), 116.1 (CH2), 73.0 (CH2 isomer), 72.9 (CH2),
70.0 (CH2 isomer), 69.9 (CH2), 69.7 (CH2 isomer), 52.2 (CH3), 37.7
(CH2), 29.4 (CH2), 25.2 (CH2 isomer), 24.4 (CH2), 17.9 (CH3
isomer); HRMS (ESI) calcd for C21H26NO3 [M + H]+: 340.1913,
found 340.1902. The mixture of the carbamates (95.0 mg, 0.27 mmol)
was converted to an inseparable 4:1 mixture of 21b and 22b (103 mg,
91%) as a colorless oil, after purification by silica gel column
chromatography (hexane:AcOEt = 4:1); Rf (hexane:AcOEt = 4:1)
General Procedure for Preparation of Esters 21 and 22. To a
stirred solution of the aminoalkenes (1.0 equiv) in THF−H2O (3:1,
0.3 M) were added K2CO3 (10 equiv) and methyl chloloformate (1.5
equiv). After being stirred at RT for 3 h, H2O was added and extracted
with Et2O. The organic layers were dried over MgSO4, filtered, and
evaporated in vacuo. The residue was purified by silica gel column
chromatography to give an inseparable mixture of the carbamates. The
1
ratio of the mixture was determined by H NMR. To a suspention of
NaH (1.5 equiv) in DMF (0.2 M) was added the carbamate (1.0
equiv) in DMF at 0 °C. After being stirred at 0 °C for 30 min, methyl
bromoacetate (1.5 equiv) was added at 0 °C and the mixture was
stirred at RT. After completion of the reaction, H2O was added at 0 °C
and extracted with Et2O. The organic layers were washed with brine,
dried over MgSO4, filtered, and evaporated in vacuo. The residue was
purified by silica gel column chromatography.
1
0.41; IR (neat) 2951, 2858, 1756, 1712 cm−1; H NMR (400 MHz,
CDCl3) δ 7.51−7.43 (1 H, m), 7.35−7.26 (7 H, m), 7.19−7.17 (1 H,
m), 5.37 (0.25 H, t, J = 6.4 Hz), 5.17 (1 H, s), 4.94 (1 H, s), 4.64 (1 H,
d, J = 17.6 Hz), 4.52 (0.45 H, s), 4.47 (2 H, s), 3,73 (1 H, d, J = 17.6
Hz), 3.72 (3 H, s), 3.64 (3 H, s), 3.52 (0.25 H, t, J = 6.4 Hz), 3.43 (2
H, t, J = 7.6 Hz), 2.30 (2 H, t, J = 7.6 Hz), 1.87 (0.67 H, s), 1.59 (2 H,
quint, J = 7.6 Hz), 1.45 (2 H, quint, J = 7.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 169.9 (C), 156.4 (C), 148.2 (C), 140.8 (C), 138.6 (C),
130.0 (C), 129.7 (2CH), 128.4 (CH isomer), 128.3 (CH), 127.9
(2CH), 127.8 (2CH), 127.7 (CH isomer), 127.6 (CH), 127.5 (CH),
115.2 (CH2), 114.9 (CH isomer), 73.0 (CH2 isomer), 72.9 (CH2),
70.2 (CH2 isomer), 70.1 (CH2), 53.1 (CH3), 52.1 (CH3), 51.7 (CH2),
36.2 (CH2), 29.4 (CH2), 24.7 (CH2), 22.6 (CH2 isomer), 21.0 (CH2
isomer), 16.7 (CH3 isomer); HRMS (ESI) calcd for C24H30NO5 [M +
H]+: 412.2124, found 412.2113.
Methyl 2-[{2-(5-Benzyloxy-5-methylhex-1-en-2-yl)phenyl}-
(methoxycarbonyl)amino]acetate and (E)-Methyl 2-[{2-(5-Benzyl-
oxy-5-methylhex-2-en-2-yl)phenyl}(methoxycarbonyl)amino]-
acetate (21c and 22c). The mixture of carbamates was prepared from
aminoalkene (19c/20c) (300 mg, 1.0 mmol). Purification by silica gel
column chromatography (hexane:AcOEt = 9:1) gave the correspond-
ing carbamates as a colorless oil (347 mg, 98%, an inseparable 9:1
mixture of methyl 2-[5-(benzyloxy)-5-methylhex-1-en-2-yl]-
phenylcarbamate and (E)-methyl 2-[5-(benzyloxy)-5-methylhex-2-en-
2-yl]phenylcarbamate); Rf (hexane:AcOEt = 9:1) 0.54; IR (neat)
3412, 3064, 2972, 1740 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09 (1
H, br), 7.52−7.22 (6 H, m), 7.08 (1 H, d, J = 7.8 Hz), 7.02 (1 H, t, J =
7.8 Hz), 7.00 (1 H, br), 5.62 (0.11 H, t, J = 8.0 Hz), 5.37 (1 H, s), 5.01
(1 H, s), 4.59 (0.22 H, s), 4.32 (2 H, s), 3,73 (3 H, s), 3.67 (0.34 H, s),
2.46 (2 H, dt, J = 4.4 and 8.4 Hz), 1.95 (0.33 H, s), 1.65 (2H, dt, J =
Methyl 2-[{2-((5-Benzyloxy)pent-1-en-2-yl)phenyl}-
(methoxycarbonyl)amino]acetate and (E)-Methyl 2-[{2-(5-
(Benzyloxy)pent-2-en-2-yl)phenyl}(methoxycarbonyl)amino]-
acetate (21a and 22a). The mixture of carbamates was prepared from
aminoalkene (19a/20a) (45.0 mg, 0.16 mmol). Purification by silica
gel column chromatography (hexane:AcOEt = 9:1) gave the
corresponding carbamates as a colorless oil (49.6 mg, 95%, an
inseparable 3:1 mixture of methyl 2-[5-(benzyloxy)pent-1-en-2-
yl]phenylcarbamate and (E)-methyl 2-[5-(benzyloxy)pent-2-en-2-yl]-
phenylcarbamate); Rf (hexane:AcOEt = 4:1) 0.61; IR (neat) 3412,
1740, 1521 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.05 (1 H, d, J = 8.0
Hz), 7.52−7.22 (6 H, m), 7.11 (1 H, br), 7.05 (1 H, t, J = 8.0 Hz),
6.99 (1 H, d, J = 8.0 Hz), 5.46 (0.33 H, t, J = 6.4 Hz), 5.35 (1 H, s),
5.02 (1 H, s), 4.57 (0.62 H, s), 4.48 (2 H, s), 3,74 (3 H, s), 3.68 (1 H,
s), 3.58 (0.65 H, t, J = 6.8 Hz), 3.47 (2 H, t, J = 8.0 Hz), 2.52 (0.65 H,
q, J = 6.8 Hz), 2.00 (2 H, t, J = 8.0 Hz), 1.95 (0.6 H, s), 1.72 (2 H,
quint, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 154.0 (C), 146.6
(C), 138.4 (C), 134.6 (C), 132.1 (C), 128.4 (2CH), 128.1 (CH),
127.9 (CH), 127.6 (2CH), 127.5 (CH), 122.8 (CH), 119.3 (CH),
116.2 (CH2), 72.9 (CH2), 69.8 (CH2), 69.4 (CH2 isomer), 52.1
(CH3), 34.8 (CH2), 29.1 (CH2 isomer), 27.8 (CH2), 18.2 (CH3
isomer); HRMS (ESI) calcd for C20H23NO3Na [M + Na]+: 348.1576,
found 348.1572. The mixture of the carbamates (50.0 mg, 0.15 mmol)
was converted to an inseparable 3:1 mixture of 21a and 22a (58.0 mg,
98%) as a colorless oil, after purification by silica gel column
chromatography (hexane:AcOEt = 4:1); Rf (hexane:AcOEt = 4:1)
0.48; IR (neat) 2952, 1756, 1712 cm−1; 1H NMR (400 MHz, CDCl3)
9244
dx.doi.org/10.1021/jo301817w | J. Org. Chem. 2012, 77, 9240−9249

The Journal of Organic Chemistry
Article
4.4 and 8.4 Hz), 1.34 (0.67 H, s), 1.24 (6 H, s); 13C NMR (100 MHz,
CDCl3, major isomer only) δ 153.9 (C), 147.2 (C), 139.6 (C), 134.5
(C), 132.1 (C), 128.2 (2CH), 128.0 (CH), 127.9 (CH), 127.2 (2CH),
127.1 (CH), 122.8 (CH), 119.2 (CH), 115.8 (CH2), 74.7 (C), 63.6
(CH2), 52.2 (CH3), 38.3 (CH2), 32.3 (CH2), 25.6 (2CH3); HRMS
(ESI) calcd for C22H27NO3Na [M + Na]+: 376.1889, found 376.1889.
The mixture of the carbamates (390 mg, 1.1 mmol) was converted to
an inseparable 9:1 mixture of 21c and 22c (494 mg, 95%) as a
colorless oil, after purification by silica gel column chromatography
(hexane:AcOEt = 7:3); Rf (hexane:AcOEt = 7:3) 0.54; IR (neat) 2970,
1757, 1712 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47−7.44 (1 H, m),
7.32−7.26 (7 H, m), 7.20−7.18 (1 H, m), 5.43 (0.11 H, t, J = 7.6 Hz),
5.56 (0.1 H, t, J = 6.4 Hz), 5.20 (1 H, s), 4.92 (1 H, s), 4.62 (1 H, d, J
= 7.6 Hz), 4.47 (0.2 H, s), 4.36 (2 H, d, J = 6.4 Hz), 3.79 (1 H, d, J =
6.4 Hz), 3,72 (3 H, s), 3.54 (3 H, s), 2.41 (2 H, m), 1.89 (0.33 H, s),
1.64 (2H, m), 1.30 (0.67 H, s), 1.21 (6 H, s); 13C NMR (100 MHz,
CDCl3, major isomer only) δ 169.9 (C), 156.4 (C), 148.6 (C), 140.9
(C), 139.7 (C), 138.7 (C), 129.8 (CH), 129.7 (CH), 128.2 (2CH),
127.9 (2CH), 127.8 (CH), 127.2 (CH), 127.0 (CH), 114.7 (CH2),
74.8 (C), 63.6 (CH2), 53.0 (CH3), 52.0 (CH2), 51.8 (CH3), 39.3
(CH2), 30.9 (CH2), 25.5 (CH3), 25.4 (CH3); HRMS (ESI) calcd for
C25H31NO5Na [M + Na]+: 448.2100, found 448.2095.
Methyl 2-[{2-(5-Hydroxy-5-methylhex-1-en-2-yl)phenyl}-
(methoxycarbonyl)amino]acetate and (E)-Methyl 2-[{2-(5-Hy-
droxy-5-methylhex-2-en-2-yl)phenyl}(methoxycarbonyl)amino]-
acetate (21d and 22d). The mixture of carbamates was prepared
from aminoalkene (19d/20d) (30.0 mg, 0.14 mmol). Purification by
silica gel column chromatography (hexane:AcOEt = 7:3) gave the
corresponding carbamates as a colorless oil (37.3 mg, quant., an
inseparable 9:1 mixture of methyl 2-(5-hydroxy-5-methylhex-1-en-2-
yl)phenylcarbamate and (E)-methyl 2-(5-hydroxy-5-methylhex-2-en-2-
yl)phenylcarbamate); Rf (hexane:AcOEt = 7:3) 0.20; IR (neat) 3412,
2968, 1726 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (1 H, d, J = 7.6
Hz), 7.26 (1 H, t, J = 7.6 Hz), 7.11 (1 H, br), 7.08 (1 H, d, J = 7.6 Hz),
7.03 (1 H, t, J = 7.6 Hz), 5.56 (0.11, t, J = 7.2 Hz), 5.38 (1 H, s), 5.02
(1 H, s), 3.80 (3 H, s), 2.45 (2 H, t, J = 8.0 Hz), 2.39 (0.09, d, J = 7.6
Hz), 1.95 (0.30, s), 1.56 (2 H, t, J = 8.0 Hz), 1.35 (1 H, br), 1.30 (0.65,
s), 1.20 (6 H, s); 13C NMR (100 MHz, CDCl3, major isomer only) δ
154.1 (C), 147.1 (C), 134.5 (C), 132.3 (C), 128.1 (CH), 128.0 (CH),
122.9 (CH), 119.5 (CH), 115.9 (CH2), 70.7 (C), 52.2 (CH3), 41.4
(CH2), 32.7 (CH2), 29.3 (2CH3); HRMS (ESI) calcd for C15H22NO3
[M + H]+: 264.1600, found 264.1595. The mixture of the carbamates
(45.0 mg, 0.17 mmol) was converted to an inseparable 9:1 mixture of
21d and 22d (34.0 mg, 57%) as a colorless oil, after purification by
silica gel column chromatography (hexane:AcOEt = 1:1); Rf
(hexane:AcOEt = 1:1) 0.57; IR (neat) 3487, 2964, 1755, 1710
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.52−7.44 (1 H, m), 7.33−7.23
(2 H, m), 7.20−7.18 (1 H, m), 5.51 (0.11 H, t, J = 8.0 Hz), 5.21 (1 H,
s), 4.95 (1 H, s), 4.66 (1 H, d, J = 17.6 Hz), 3.74 (1 H, d, J = 17.6 Hz),
3,73 (3 H, s), 3.67 (3 H, s), 2.45 (1 H, br), 2.38 (2 H, t, J = 8.4 Hz),
1.96 (0.21 H, s), 1.54 (2 H, t, J = 8.4 Hz), 1.46 (0.21 H, t, J = 8.0 Hz),
1.27 (0.6 H, s), 1.12 (6 H, s); 13C NMR (100 MHz, CDCl3, major
isomer only) δ 169.9 (C), 156.4 (C), 148.6 (C), 140.1 (C), 138.6 (C),
130.0 (CH), 129.7 (CH), 128.0 (CH), 127.8 (CH), 114.9 (CH2), 70.5
(C), 53.1 (CH3), 52.0 (CH2), 51.8 (CH3), 42.2 (CH2), 31.2 (CH2),
29.3 (CH3), 29.1 (CH3); HRMS (ESI) calcd for C18H26NO5 [M +
H]+: 336.1811, found 336.1804.
122.8 (CH), 119.8 (CH2), 78.6 (CH2), 72.9 (CH2), 52.2 (CH3), 47.3
(CH2), 35.9 (C), 25.4 (2CH3); HRMS (ESI) calcd for C22H28NO3 [M
+ H]+: 354.2069, found 354.2065. The carbamate (95.0 mg, 0.26
mmol) was converted to 21e (120 mg, 89%) as a colorless oil, after
purification by silica gel column chromatography (hexane:AcOEt =
4:1); Rf (hexane:AcOEt = 4:1) 0.47; IR (neat) 2953, 1757, 1713 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.40 (1 H, d, J = 7.6 Hz), 7.31−7.29
(4 H, m), 7.27−7.20 (4 H, m), 5,17 (1 H, s), 5.07 (1 H, s), 4.60 (1 H,
d, J = 16.8 Hz), 4.30 (1 H, d, J = 12.0 Hz), 4.21 (1 H, d, J = 12.0 Hz),
3.72 (1 H, d, J = 16.8 Hz), 3.70 (3 H, s), 3.60 (3 H, s), 3.04 (1 H, d, J
= 12.0 Hz), 2.97 (1 H, d, J = 12.0 Hz), 2.40 (1 H, d, J = 13.6 Hz), 2.28
(1 H, d, J = 13.6 Hz), 0.80 (3 H, s), 0.79 (3 H, s); 13C NMR (100
MHz, CDCl3) δ 170.0 (C), 156.3 (C), 146.8 (C), 142.0 (C), 138.8
(C), 138.6 (C), 130.5 (CH), 129.5 (CH), 128.1 (2CH), 127.7 (CH),
127.6 (CH), 127.4 (2CH), 127.2 (CH), 119.9 (CH2), 78.8 (CH2),
72.9 (CH2), 52.9 (CH3), 51.9 (CH3), 51.3 (CH2), 44.3 (CH2), 35.8
(C), 25.6 (CH3), 24.6 (CH3); HRMS (ESI) calcd for C25H32NO5 [M
+H]+: 426.2280, found 426.2280.
Methyl 2-[{2-(6-(Benzyloxy)-5,5-dimethylhex-1-en-2-yl)phenyl}-
(methoxycarbonyl)amino]acetate and (E)-Methyl 2-[{2-(6-(Benzyl-
oxy)-5,5-dimethylhex-2-en-2-yl)phenyl}(methoxycarbonyl)amino]-
acetate (21f and 22f). The mixture of carbamates was prepared from
aminoalkenes (19f/20f) (33.0 mg, 0.10 mmol). Purification by silica
gel column chromatography (hexane:AcOEt = 9:1) gave the
corresponding carbamates as a colorless oil (35.0 mg, 90%, an
inseparable 12:1 mixture of methyl 2-[6-(benzyloxy)-5,5-dimethylhex-
1-en-2-yl]phenylcarbamate and (E)-methyl 2-[6-(benzyloxy)-5,5-di-
methylhex-2-en-2-yl]phenylcarbamate); Rf (hexane:AcOEt = 4:1)
0.61; IR (neat) 3413, 2953, 1741 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.06 (1 H, d, J = 8.0 Hz), 7.34−7.24 (6 H, m), 7.05 (1 H, t, J
= 8.0 Hz), 7.02 (1 H, d, J = 8.0 Hz), 6.97 (1 H, br), 5.48 (0.07 H, t, J =
6.4 Hz), 5.34 (1 H, s), 5.00 (1 H, s), 4.52 (0.16 H, s), 4.47 (2 H, s),
3.74 (3 H, s), 3.19 (0.16 H, s), 3.10 (2 H, s), 2.25 (2 H, dt, J = 4.0 and
8.0 Hz), 2.21 (0.2 H, d, J = 8.0 Hz), 1.91 (0.25 H, s), 1.41 (2 H, dt, J =
4.0 and 8.0 Hz), 0.98 (0.5 H, s), 0.83 (6 H, s); 13C NMR (100 MHz,
CDCl3, major isomer only) δ 154.0 (C), 147.7 (C), 138.9 (C), 134.4
(C), 128.3 (C), 127.9 (2CH), 127.8 (3CH), 127.3 (2CH), 122.8
(CH), 119.1 (CH), 115.5 (CH2), 78.9 (CH2), 73.2 (CH2), 52.2
(CH3), 37.3 (C), 34.4 (CH2), 32.5 (CH2), 24.6 (2CH3); HRMS (ESI)
calcd for C23H30NO3 [M + H]+: 368.2226, found 368.2220. The
mixture of the carbamates (85.0 mg, 0.23 mmol) was converted to an
inseparable 12:1 mixture of 21f and 22f (88.0 mg, 87%) as a colorless
oil, after purification by silica gel column chromatography
(hexane:AcOEt = 4:1); Rf (hexane:AcOEt = 4:1) 0.30; IR (neat)
2953, 1757, 1713 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.50−7.43 (1
H, m), 7.33−7.27 (7 H, m), 7.18−7.16 (1 H, m), 5.42 (0.08 H, t, J =
6.8 Hz), 5.17 (1 H, s), 4.90 (1 H, s), 4.65 (1 H, d, J = 18 Hz), 4.51
(0.16 H, s), 4.48 (2 H, s), 3.75 (1 H, d, J = 18 Hz), 3.72 (3 H, s), 3.62
(3 H, s), 3.18 (0.16 H, s), 3.10 (2 H, s), 2.24 (2 H, m), 1.86 (0.2 H, s),
1.37 (2 H, m), 0.96 (0.5 H, s), 0.87 (6 H, s); 13C NMR (100 MHz,
CDCl3, major isomer only) δ 169.9 (C), 156.4 (C), 148.9 (C), 140.9
(C), 138.9 (C), 138.8 (C), 129.9 (CH), 129.7 (CH), 128.2 (2CH),
127.8 (CH), 127.7 (CH), 127.3 (3CH), 114.6 (CH2), 79.1 (CH2),
73.2 (CH2), 53.1 (CH3), 52.0 (CH3), 51.7 (CH2), 37.8 (CH2), 34.4
(C), 30.9 (CH2), 24.8 (CH3), 24.4 (CH3); HRMS (ESI) calcd for
C26H34NO5 [M + H]+: 440.2437, found 440.2426.
General Procedure for [2 + 2] Cycloaddition: Condition A.
To a stirred solution of corresponding esters (1.0 equiv) in THF−
H2O (3:1, 0.2 M) was added LiOH·H2O (2.0 equiv). After being
stirred at RT for 3 h, the mixture was evaporated in vacuo and the
residue was washed with Et2O. The water layers were treated with 1 N
HCl (pH 1−2) and then extracted with Et2O. The organic layers were
dried over MgSO4, filtered, and evaporated in vacuo. The product was
used in the next steps without further purification. To a stirred
solution of carboxylic acid (1.0 equiv) in dry benzene (0.2 M) was
dropwised oxalyl chrolide (5.0 equiv) at 0 °C. After being stirred at RT
for 1 h and then refluxed for 30 min, the mixture was evaporated in
vacuo. The residue was diluted with dry benzene (0.2 M), and Et3N
(3.0 equiv) was added and then refluxed for 1.5 h. H2O was added and
extracted with benzene. The organic layers were dried over MgSO4,
Methyl 2-[{2-(5-(Benzyloxy)-4,4-dimethylpent-1-en-2-yl)phenyl}-
(methoxycarbonyl)amino]acetate (21e). The carbamate was pre-
pared from aminoalkene (19e) (110 mg, 0.37 mmol). Purification by
silica gel column chromatography (hexane:AcOEt = 9:1) gave the
corresponding carbamate as a colorless oil (127 mg, 95% of methyl 2-
[5-(benzyloxy)-4,4-dimethylpent-1-en-2-yl]phenylcarbamate); Rf (hex-
1
ane:AcOEt = 4:1) 0.57; IR (neat) 3414, 2955, 1740 cm−1; H NMR
(400 MHz, CDCl3) δ 8.05 (1 H, d, J = 7.6 Hz), 7.35−7.25 (4 H, m),
7.24−7.21 (2 H, m), 7.14 (1 H, d, J = 7.6 Hz), 7.00 (1 H, t, J = 7.6
Hz), 5.35 (1 H, s), 5.12 (1 H, s), 4.29 (2 H, s), 3.79 (3 H, s), 3.00 (2
H, s), 2.51 (2 H, s), 0.82 (6 H, s); 13C NMR (100 MHz, CDCl3) δ
154.0 (C), 144.6 (C), 138.7 (C), 134.2 (C), 128.3 (C), 128.1 (2CH),
127.7 (CH), 127.4 (CH), 127.3 (CH), 127.2 (2CH), 124.1 (CH),
9245
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filtered, and evaporated in vacuo. The residue was purified by silica gel
column chromatography.
(1.20 g, 2.8 mmol). 23c and 24c could be separated by silica gel
column chromatography (hexane:AcOEt = 9:1).
Methyl 7b-[3-(Benzyloxy)propyl]-2-oxo-2,2a-dihydro-1H-
cyclobuta[b]indole-3(7bH)-carboxylate and Methyl 1-[2-
(Benzyloxy)ethyl]-7b-methyl-2-oxo-2,2a-dihydro-1H-cyclobuta[b]-
indole-3(7bH)-carboxylate (23a and 24a). These compounds were
prepared from the mixture of ester (21a/22a) (48.0 mg, 0.12 mmol).
23a and 24a could be separated by silica gel column chromatography
(hexane:AcOEt = 9:1).
23c: Yield (985 mg, 85%); colorless oil. Rf (hexane:AcOEt = 7:3)
0.60; IR (neat) 2972, 1792, 1716 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.89 (1 H, br), 7.51−7.28 (6 H, m), 7.20 (1 H, d, J = 7.2 Hz), 7.06
(1 H, t, J = 7.2 Hz), 5.17 (1 H, s), 4.35 (2 H, dd, J = 1.2 and 15.4 Hz),
3.86 (3 H, s), 3.38 (1 H, d, J = 18.0 Hz), 3.16 (1 H, dd, J = 2.8 and
18.0 Hz), 2.28 (1 H, dt, J = 3.4 and 12.8 Hz), 2.10 (1 H, dt, J = 3.4 and
12.8 Hz), 1.51 (1 H, dt, J = 4.0 and 12.8 Hz), 1.32 (1 H, dt, J = 4.0 and
12.8 Hz), 1.24 (3 H, s), 1.22 (3 H, s); 13C NMR (100 MHz, CDCl3,
50 °C) δ 203.1 (C), 152.8 (C), 143.3 (C), 139.7 (C), 134.3 (C), 128.8
(2CH), 128.2 (2CH), 127.1 (2CH), 127.0 (CH), 123.9 (CH), 115.6
(CH), 79.0 (CH), 74.5 (C), 63.7 (CH2), 60.8 (CH2), 52.9 (CH3),
43.8 (C), 36.6 (CH2), 31.3 (CH2), 25.6 (CH3), 25.4 (CH3); HRMS
(ESI) calcd for C24H27NO4Na [M + Na]+: 416.1838, found 416.1839.
24c: Yield (106 mg, 9%); colorless oil. Rf (hexane:AcOEt = 7:3)
0.64; IR (neat) 2956, 1785, 1714 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.91 (1 H, br), 7.36−7.21 (2 H, m), 7.24−7.20 (4 H, m), 6.97−6.92
(2 H, m), 4.88 (1 H, br), 4.35 (2 H, dd, J = 10.8 and 13.2 Hz), 3.85 (3
H, s), 3.59 (1 H, m), 1.97 (2 H, d, J = 6.4 Hz), 1.52 (3 H, s), 1.29 (3
H, s), 1.22 (3 H, s); 13C NMR (100 MHz, DMSO-d6, 60 °C) δ 205.4
(C), 152.2 (C), 141.2 (C), 139.2 (C), 138.1 (C), 127.7 (2CH), 127.0
(3CH), 126.7 (CH), 123.2 (CH), 123.1 (CH), 114.4 (CH), 80.5
(CH), 73.6 (C), 66.9 (CH3), 62.9 (CH2), 52.5 (CH), 42.1 (C), 35.9
(CH2), 25.4 (CH3), 24.9 (CH3), 16.9 (CH3); HRMS (ESI) calcd for
C24H27NO4Na [M + Na]+: 416.1838, found 416.1836.
23a: Yield (26.5 mg, 61%); colorless oil. Rf (hexane:AcOEt = 4:1)
1
0.45; IR (neat) 2952, 2856, 1790, 1715 cm−1; H NMR (400 MHz,
CDCl3) δ 7.89 (1 H, br), 7.37−7.22 (6 H, m), 7.23 (1 H, d, J = 7.2
Hz), 7.07 (1 H, t, J = 7.2 Hz), 5.24 (1 H, br), 4.48 (2 H, s), 3.84 (3 H,
s), 3.44 (2 H, t, J = 6.2 Hz), 3.40 (1 H, d, J = 18.4 Hz), 3.16 (1 H, dd, J
= 2.4 and 18.4 Hz), 2.23 (1 H, dt, J = 4.8 and 12.8 Hz), 2.12 (1 H, dt, J
= 4.8 and 12.8 Hz), 1.62−1.45 (2 H, m); 13C NMR (100 MHz,
CDCl3, 50 °C) δ 203.2 (C), 152.8 (C), 143.3 (C), 138.4 (C), 134.1
(C), 128.9 (2CH), 128.4 (2CH), 127.6 (2CH), 124.1 (CH), 123.9
(CH), 115.7 (CH), 79.2 (CH), 73.1 (CH2), 69.7 (CH2), 60.6 (CH2),
52.9 (CH3), 43.9 (C), 33.9 (CH2), 26.2 (CH2); HRMS (ESI) calcd for
C22H23NO4Na [M + Na]+: 388.1525, found 388.1521.
24a: Yield (2.80 mg, 7%; dr = 1:0.6); colorless oil. Rf
1
(hexane:AcOEt = 4:1) 0.50; IR (neat) 2863, 1784, 1715 cm−1; H
NMR (400 MHz, CDCl3) δ 7.89 (1.6 H, br), 7.36−7.28 (10 H, m),
7.16 (0.6 H, d, J = 7.2 Hz), 7.11 (1.0 H, d, J = 7.2 Hz), 7.04−6.99 (1.6
H, m), 5.18 (0.6 H, br), 4.99 (1.0 H, br), 4.51 (1.2 H, s), 4.48 (2.0 H,
s), 3.85 (4.8 H, s), 3.64−3.49 (3.8 H, m), 3.38 (1.0 H, t, J = 7.6 Hz),
2.02 (2.0 H, q, J = 7.6 Hz), 1.71 (1.9 H, s), 1.56 (3.0 H, s); 13C NMR
(100 MHz, CDCl3, 50 °C) δ 206.3 (C), 205.0 (C isomer), 152.9 (C),
138.3 (2C), 138.2 (C), 137.9 (CH isomer), 128.9 (CH isomer), 128.4
(2CH), 127.8 (2CH), 127.7 (CH), 123.7 (CH), 123.4 (CH), 123.1
(CH), 116.2 (CH isomer), 115.5 (CH), 81.2 (CH), 79.2 (CH), 73.2
(CH2), 68.4 (CH2 isomer), 68.0 (CH2), 52.8 (CH3), 45.2 (C isomer),
42.8 (C), 26.4 (CH2), 25.9 (CH2 isomer), 25.2 (CH3 isomer), 17.2
(CH3); HRMS (ESI) calcd for C22H23NO4Na [M + Na]+: 388.1525,
found 388.1534.
Methyl 7b-(3-Hydroxy-3-methylbutyl)-2-oxo-2,2a-dihydro-1H-
cyclobuta[b]indole-3(7bH)-carboxylate, (2a,7b)-Methyl 7b-(3-meth-
ylbut-2-enyl)-2-oxo-2,2a-dihydro-1H-cyclobuta[b]indole-3(7bH)-
carboxylate and (2a,7b)-Methyl 7b-(3-Methylbut-3-enyl)-2-oxo-
2,2a-dihydro-1H-cyclobuta[b]indole-3(7bH)-carboxylate (23d, 25,
and 26). These compounds were prepared from the mixture of ester
(21d/22d) (20 mg, 0.09 mmol). 23d and 25/26 could be separated by
silica gel column chromatography (hexane:AcOEt = 7:3).
23d: Yield (3.00 mg, 10%); colorless oil. Rf (hexane:AcOEt = 7:3)
1
0.50; IR (neat) 3502, 2968, 1791, 1714 cm−1; H NMR (400 MHz,
Methyl 7b-[4-(Benzyloxy)butyl]-2-oxo-2,2a-dihydro-1H-
cyclobuta[b]indole-3(7bH)-carboxylate and Methyl 1-[3-
(Benzyloxy)propyl]-7b-methyl-2-oxo-2,2a-dihydro-1H-cyclobuta[b]-
indole-3(7bH)-carboxylate (23b and 24b). These compounds were
prepared from the mixture of ester (21b/22b) (40.0 mg, 0.097 mmol).
23b and 24b could be separated by silica gel column chromatography
(hexane:AcOEt = 9:1).
CDCl3) δ 7.88 (1 H, br), 7.29−7.23 (2 H, m), 7.08 (1 H, t, J = 7.2
Hz), 5.21 (1 H, br), 3.86 (3 H, s), 3.40 (1 H, d, J = 19.6 Hz), 3.18 (1
H, dd, J = 2.8 and 19.6 Hz), 2.26 (1 H, dt, J = 4.0 and 13.0 Hz), 2.10
(1 H, dt, J = 4.0 and 13.0 Hz), 1.46 (1 H, dt, J = 4.0 and 13.0 Hz), 1.25
(1 H, dt, J = 4.0 and 13.0 Hz), 1.05 (6 H, s); 13C NMR (100 MHz,
CDCl3, 50 °C) δ 203.1 (C), 152.8 (C), 143.3 (C), 134.2 (C), 128.9
(CH), 124.0 (CH), 123.9 (CH), 115.7 (CH), 79.1 (CH), 70.3 (C),
60.7 (CH2), 53.0 (CH3), 43.9 (C), 39.3 (CH2), 31.7 (CH2), 29.6
(CH3), 29.3 (CH3); HRMS (ESI) calcd for C17H22NO4 [M + H]+:
304.1549, found 304.1548.
23b: Yield (26.0 mg, 68%); colorless oil. Rf (hexane:AcOEt = 7:3)
1
0.57; IR (neat) 2937, 2858, 1791, 1715 cm−1; H NMR (400 MHz,
CDCl3) δ 7.88 (1 H, br), 7.33−7.21 (6 H, m), 7.21 (1 H, d, J = 7.2
Hz), 7.07 (1 H, t, J = 7.2 Hz), 5.22 (1 H, br), 4.46 (2 H, s), 3.85 (3 H,
s), 3.42 (2 H, t, J = 6.2 Hz), 3.37 (1 H, d, J = 18.4 Hz), 3.13 (1 H, d, J
= 18.4 Hz), 2.12 (1 H, dt, J = 4.8 and 12.4 Hz), 1.98 (1 H, dt, J = 4.8
and 12.4 Hz), 1.62 (2 H, quint, J = 6.2 Hz), 1.42 (1 H, m), 1.25 (1 H,
m); 13C NMR (100 MHz, CDCl3, 50 °C) δ 203.1 (C), 152.7 (C),
143.2 (C), 138.4 (C), 134.2 (C), 128.7 (CH), 128.2 (CH), 127.5
(2CH), 127.4 (2CH), 123.9 (CH), 123.7 (CH), 115.5 (CH), 79.0
(CH), 72.8 (CH2), 69.6 (CH2), 60.3 (CH2), 52.8 (CH3), 44.0 (C),
36.8 (CH2), 29.6 (CH2), 22.4 (CH2); HRMS (ESI) calcd for
C23H25NO4Na [M + Na]+: 402.1681, found 402.1684.
24b: Yield (2.50 mg, 7%); colorless oil. Rf (hexane:AcOEt = 7:3)
0.64; IR (neat) 2926, 1784, 1717 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.90 (1 H, br), 7.34−7.26 (6 H, m), 7.17 (1 H, d, J = 7.6 Hz), 7.05
(1 H, t, J = 7.6 Hz), 5.01 (1 H, br), 4.49 (2 H, s), 3.86 (3 H, s), 3.49 (2
H, m), 3.20 (1 H, s), 1.81−1.72 (4 H, m), 1.58 (3 H, s); 13C NMR
(100 MHz, CDCl3, 50 °C) δ 205.6 (C), 138.6 (2C), 138.0 (C), 128.5
(C), 128.4 (2CH), 127.6 (2CH), 127.5 (2CH), 123.8 (CH), 122.9
(CH), 115.6 (CH), 81.1 (CH2), 73.0 (CH2), 70.9 (CH), 69.6 (CH),
52.9 (CH3), 43.0 (C), 28.0 (CH2), 23.4 (CH2), 17.2 (CH3); HRMS
(ESI) calcd for C23H26NO4 [M + H]+: 380.1862, found 380.1862.
Methyl 7b-[3-(Benzyloxy)-3-methylbutyl]-2-oxo-2,2a-dihydro-1H-
cyclobuta[b]indole-3(7bH)carboxylate and Methyl 1-[2-
(Benzyloxy)2-methylpropyl]-7b-methyl-2-oxo-2,2a-dihydro-1H-
cyclobuta[b]indole-3(7bH)-carboxylate (23c and 24c). These
compounds were prepared from the mixture of ester (21c/22c)
25/26: Yield (6.10 mg, 22%, 1:0.8 mixture; 1H NMR); colorless oil;
1
Rf (hexane:AcOEt = 7:3) 0.75; IR (neat) 2956, 1792, 1716 cm−1; H
NMR (400 MHz, CDCl3) δ 7.88 (1.8 H, br), 7.37−7.10 (1.8 H, m),
7.09−7.04 (2.8 H, m), 5.38 (0.8 H, br), 5.24 (1 H, br), 5.16 (2 H, t, J
= 6.8 Hz), 4.71 (0.8 H, s), 4.63 (0.8 H, s), 3.86 (5.4 H, s), 3.43 (2.0 H,
t, J = 16.0 Hz), 3.13 (1.6 H, dd, J = 18.0 and 36.4 Hz), 2.70 (2.0 H,
ddd, J = 6.4, 16.0, and 32.0 Hz), 2.28 (0.8 H, m), 2.13 (0.8 H, m), 1.96
(0.8 H, m), 1.84 (0.8 H, m), 1.72 (2.4 H, s), 1.70 (3 H, s), 1.67 (3 H,
s); 13C NMR (100 MHz, CDCl3, 50 °C) δ 203.3 (C), 203.2 (C),
144.4 (C), 136.3 (C), 128.9 (C), 128.8 (C), 128.3 (CH), 124.1 (CH),
123.9 (CH), 123.8 (CH), 118.5 (CH), 115.7 (CH2), 115.6 (CH),
110.6 (CH), 79.1 (CH), 78.9 (CH), 60.7 (CH2), 59.1 (CH2), 52.9
(CH3), 44.1 (C), 35.2 (CH2), 35.0 (CH2), 33.8 (CH2), 25.8 (CH3),
22.4 (CH3), 18.0 (CH3); HRMS (ESI) calcd for C17H19NO3Na [M +
Na]+: 308.1263, found 308.1256.
Methyl 7b-[3-(Benzyloxy)-2,2-dimethylpropyl]-2-oxo-2,2a-dihy-
dro-1H-cyclobuta[b]indole-3(7bH)-carboxylate (23e). This com-
pound was prepared from the ester (21e) (56.0 mg, 0.15 mmol).
Purification by silica gel column chromatography (hexane:AcOEt =
4:1) gave 23e as a colorless oil (43.0 mg, 72%); Rf (hexane:AcOEt =
1
4:1) 0.62; IR (neat) 2956, 1792, 1715 cm−1; H NMR (400 MHz,
CDCl3) δ 7.88 (1 H, d, J = 7.4 Hz), 7.38−7.23 (7 H, m), 7.03 (1 H, t, J
= 7.4 Hz), 5.46 (1 H, br), 4.38 (1 H, d, J = 12.0 Hz), 4.32 (1 H, d, J =
12.0 Hz), 3.85 (3 H, s), 3.37 (1 H, d, J = 17.8 Hz), 3.16 (1 H, dd, J =
9246
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2.4 and 17.8 Hz), 2.92 (1 H, d, J = 9.4 Hz), 2.78 (1 H, d, J = 9.4 Hz),
2.42 (1 H, d, J = 14.8 Hz), 2.14 (1 H, d, J = 14.8 Hz), 0.79 (3 H, s),
0.69 (3 H, s); 13C NMR (100 MHz, CDCl3, 50 °C) δ 204.7 (C), 152.8
(C), 143.0 (C), 138.6 (C), 134.7 (C), 128.7 (CH), 128.3 (2CH),
127.5 (CH), 127.4 (2CH), 125.1 (CH), 123.6 (CH), 115.9 (CH),
78.6 (CH), 73.0 (CH2), 64.7 (CH2), 52.9 (CH3), 45.2 (CH2), 43.4
(C), 36.2 (C), 26.4 (CH2), 26.1 (2CH3); HRMS (ESI) calcd for
C24H27NO4Na [M + Na]+: 416.1838, found 416.1843.
(1 H, dt, J = 4.0 and 13.2 Hz), 1.26 (3 H, s), 1.21 (3 H, s); 13C NMR
(100 MHz, C6D6, 60 °C) δ 154.8 (C), 153.3 (C), 144.2 (C), 140.5
(C), 135.6 (C), 128.9 (2CH), 128.5 (2CH), 128.4 (CH), 127.3 (CH),
127.2 (CH), 123.6 (CH), 116.1 (CH), 74.4 (C), 68.3 (CH), 63.9
(CH2), 52.5 (CH3), 47.8 (C), 43.7 (CH2), 36.0 (CH2), 30.9 (CH2),
25.6 (CH3), 25.4 (CH3); HRMS (ESI) calcd for C24H29N2O4 [M +
H]+: 409.2127, found 409.2130.
Methyl 3-[3-(Benzyloxy)-3-methylbutyl]-3-(cyanomethyl)-2-me-
thoxyindoline-1-carboxylate (30). To a stirred solution of oxime
(27) (crude, 0.024 mmol) in benzene (0.5 mL) was added SOCl2
(0.025 mL, 0.073 mmol). After being stirred at RT for 12 h, H2O was
added and extracted with benzene. The organic layers were dried over
MgSO4, filtered and evaporated in vacuo. The residue was diluted with
MeOH (0.5 mL), and 3 N HCl (one drop) was added. After being
stirred at RT for 24h, the mixture was evaporated in vacuo. Water layer
was extracted with AcOEt, dried over MgSO4, filtered, and evaporated
in vacuo. The residue was purified by silica gel column
chromatography (hexane:AcOEt = 7:3) to afford 30 (7.30 mg, 72%)
as a colorless oil; Rf (hexane:AcOEt = 7:3) 0.75; IR (neat) 2970, 2250,
Methyl 7b-[4-(Benzyloxy)-3,3-dimethylbutyl]-2-oxo-2,2a-dihy-
dro-1H-cyclobuta[b]indole-3(7bH)-carboxylate (23f). This com-
pound was prepared from the mixture of ester (21f/22f) (51.0 mg,
0.11 mmol). Purification by silica gel column chromatography
(hexane:AcOEt = 4:1) gave 23f as a colorless oil (31.6 mg, 70%);
1
Rf (hexane:AcOEt = 4:1) 0.50; IR (neat) 2971, 1792, 1715 cm−1; H
NMR (400 MHz, CDCl3) δ 7.88 (1 H, br), 7.35−7.27 (6 H, m), 7.18
(1 H, d, J = 7.2 Hz), 7.05 (1 H, t, J = 7.2 Hz), 5.16 (1 H, br), 4.50 (1
H, d, J = 12.0 Hz), 4.45 (1 H, d, J = 12.0 Hz), 3.83 (3 H, s), 3.33 (1 H,
d, J = 16.8 Hz), 3.12 (1 H, dd, J = 2.4 and 16.8 Hz), 3.09 (2 H, s), 2.04
(1 H, dt, J = 4.0 and 13.2 Hz), 1.86 (1 H, dt, J = 4.0 and 13.2 Hz), 1.33
(1 H, dt, J = 4.0 and 13.2 Hz), 1.09 (1 H, dt, J = 4.0 and 13.2 Hz), 0.88
(3 H, s), 0.87 (3 H, s); 13C NMR (100 MHz, CDCl3, 50 °C) δ 203.3
(C), 152.8 (C), 143.2 (C), 138.8 (C), 134.5 (C), 128.7 (2CH), 128.3
(2CH), 127.5 (2CH), 127.4 (CH), 123.9 (CH), 115.5 (CH), 79.0
(CH), 78.6 (CH2), 73.3 (CH2), 60.4 (CH2), 52.9 (CH3), 44.0 (C),
34.6 (C), 34.2 (CH2), 31.3 (CH2), 24.8 (CH3), 24.6 (CH3); HRMS
(ESI) calcd for C25H29NO4Na [M + Na]+: 430.1994, found 430.1995.
General Procedure for [2 + 2] Cycloaddition: Condition B.
Methyl 7b-(3-Hydroxy-3-methylbutyl)-2-oxo-2,2a-dihydro-1H-
cyclobuta[b]indole-3(7bH)-carboxylate and Methyl 8b-Hydroxy-
2,2,3b-trimethyl-3,3a,8a,8b-tetrahydro-2H-furo[3′,2′:3,4]cyclobuta-
[1,2-b]indole-8(3bH)-carboxylate (23d and 24d). To a stirred
solution of ester (21d/22d) (22.0 mg, 0.065 mmol) in THF−H2O
(0.9−0.3 mL) was added LiOH·H2O (5.40 mg, 0.13 mmol). After
being stirred at RT for 3 h, the mixture was evaporated in vacuo and
the residue was washed with Et2O. The water layers were treated with
1 N HCl (pH 1−2) and then extracted with Et2O. The organic layers
were dried over MgSO4, filtered, and evaporated in vacuo. The
product was used in the next steps without further purification. To a
stirred solution of carboxylic acid (crude, 0.065 mmol) in THF (0.5
mL) were added Et3N (0.02 mL, 0.14 mmol) and ethyl chloloformate
(0.01 mL, 0.078 mmol). After being stirred at RT for 3 h, the reaction
mixture was filtrated through a pad of Celite and evaporated in vacuo.
The residue was purified by silica gel column chromatography
(hexane:AcOEt = 4:1) to afford 23d and 24d (23d: 11.8 mg, 60%,
24d: 0.50 mg, 2%) as a colarless oil.
1
1717 cm−1; H NMR (400 MHz, CDCl3, 50 °C) δ 7.67 (1 H, br),
7.30−7.26 (3 H, m), 7.23−7.18 (3 H, m), 7.09 (1 H, dd, J = 1.2 and
7.4 Hz), 7.03 (1 H, dt, J = 1.2 and 7.4 Hz), 5.32 (1 H, s), 4.20 (1 H, d,
J = 11.2 Hz), 4.12 (1 H, d, J = 11.2 Hz), 3.90 (3 H, s), 3.61 (3 H, s),
2.83 (1 H, d, J = 16.8 Hz), 2.74 (1 H, d, J = 16.8 Hz), 1.88 (1 H, dt, J =
4.8 and 13.6 Hz), 1.81 (1 H, dt, J = 4.8 and 13.6 Hz), 1.46 (1 H, dt, J =
4.8 and 13.6 Hz), 1.35 (1 H, dt, J = 4.8 and 13.6 Hz), 1.17 (3 H, s),
1.16 (3 H, s); 13C NMR (100 MHz, CDCl3, 50 °C) δ 154.0 (C), 140.2
(C), 139.5 (C), 133.7 (C), 128.9 (CH), 128.2 (2CH), 127.2 (2CH),
127.1 (CH), 123.6 (CH), 122.7 (CH), 118.1 (C), 116.5 (CH), 96.7
(CH), 74.4 (C), 63.6 (CH2), 58.4 (CH3), 52.9 (CH3), 49.8 (C), 33.9
(CH2), 32.1 (CH2), 25.6 (CH3), 25.5 (CH3), 20.9 (CH2); HRMS
(ESI) calcd for C25H31N2O4 [M + H]+: 423.2284, found 423.2286.
Methyl 3a-[3-(Benzyloxy)-3-methylbuthyl]-1-methyl-2-oxo-
1,2,3,3,a-tetrahydropyrrolo[2,3-b]indoline-8(8aH)-carboxylate (32).
To a stirred solution of cyclobutanone (23c) (450 mg, 1.1 mmol) and
3 Å molecular sieves in EtOH (23 mL) were added NaHCO3 (554 mg,
6.6 mmol) and N-methylhydroxylamine hydrochloride (184 mg, 2.2
mmol). After the mixture was stirred at 50 °C for 15 h, AcOEt was
added and the solution was washed with brine, dried over Na2SO4,
filtered, and evaporated in vacuo. The residue was diluted with CHCl3
(23 mL), and 4-pyrrolidinopyrridine (244 mg, 1.7 mmol) and p-
toluenesulufonyl chloride (419 mg, 2.2 mmol) were added at 0 °C.
After the mixture was refluxed for 3.5 h, H2O was added and stirred at
RT for 1.5 h. To the mixture was added CH2Cl2, and it was washed
with brine, dried over MgSO4, filtered, and evaporated in vacuo. The
residue was purified by silica gel column chromatography
(hexane:AcOEt = 2:1) to afford 32 (348 mg, 75%) as a colorless
24d: Rf (hexane:AcOEt = 7:3) 0.54; IR (neat) 3424, 2966, 1716
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.81 (1H, br), 7.20 (1 H, t, J =
6.4 Hz), 7.05 (1 H, d, J = 6.4 Hz), 6.99 (1 H, t, J = 6.4 Hz), 4.23 (1 H,
s), 3.86 (3 H, s), 2.80 (2 H, dd, J = 4.8 and 9.2 Hz), 2.05 (2 H, ddd, J =
4.8, 13.6, and 23.0 Hz), 1.46 (3 H, s), 1.39 (3 H, s), 1.36 (3 H, s); 13C
NMR (100 MHz, CDCl3, 50 °C) δ 142.5 (C), 139.1 (2C), 128.0
(CH), 123.4 (CH), 122.4 (CH), 115.1 (CH), 105.4 (C), 86.1 (C),
71.3 (CH), 56.0 (CH), 52.9 (CH3), 41.4 (C), 40.9 (CH2), 30.0
(CH3), 28.6 (CH3), 19.7 (CH3); HRMS (ESI) calcd for:
C17H21NO4Na [M + Na]+: 326.1368, found 326.1362.
1
oil; Rf (hexane:AcOEt = 3: 2) 0.25; IR (neat) 2970, 1703 cm−1; H
NMR (400 MHz, DMSO-d6) δ 7.60 (1 H, br), 7.36 (1 H, d, J = 7.6
Hz), 7.32−7.20 (6 H, m), 7.10 (1 H, t, J = 7.6 Hz), 5.70 (1 H, s), 4.21
(2 H, s), 3.83 (3 H, s), 2.72 (3 H, s), 2.66 (2 H, s), 1.86−1.75 (2 H,
m), 1.47 (1 H, dt, J = 5.2 and 12.2 Hz), 1.24 (1 H, dt, J = 5.2 and 12.2
Hz), 1.11 (6 H, s); 13C NMR (100 MHz, C6D6, 60 °C) δ 170.9 (C),
153.9 (C), 140.7 (C), 140.3 (C), 137.0 (C), 129.0 (CH), 128.5
(2CH), 127.3 (2CH), 127.3 (CH), 124.3 (CH), 123.9 (CH), 117.1
(CH), 83.1 (CH), 74.3 (C), 63.8 (CH2), 52.4 (CH3), 48.9 (C), 42.1
(CH2), 35.4 (CH2), 33.4 (CH2), 27.4 (CH3), 25.4 (CH3), 25.3
(CH3); HRMS (ESI) calcd for C25H31N2O4 [M + H]+: 423.2284,
found 423.2283.
Methyl 1-Methyl-3a-(3-methylbut-2-enyl)-2-oxo-1,2,3,3a-
tetrahydropyrrolo[2,3-b]indole-8-(8aH)-carboxylate (34). A mixture
of lactam 32 (100 mg, 0.23 mmol) and Pd−C (10.0 mg, 10% w/w) in
EtOH (2 mL) was stirred at RT under H2 for 5 h. The solution was
filtered, and the filtrate was evaporated in vacuo. The residue was
diluted with toluene, and MgSO4 (17.0 mg, 0.14 mmol) and p-
TsOH·H2O (27.0 mg, 0.14 mmol) were added and then stirred at 60
°C for 24 h. After completion of the reaction, AcOEt was added and
washed with sat. NaHCO3 and brine. The organic layers were dried
over MgSO4, filtered, and evaporated in vacuo. The residue was
purified by silica gel column chromatography (hexane:AcOEt = 1:9) to
Methyl 7b-[3-(Benzyloxy)-3-methylbutyl]-2-(hydroxyimino)-2,2a-
dihydro-1H-cyclobuta[b]indole-3(7bH)-carboxylate (27). To a
stirred solution of cyclobutanone (23c) (10.0 mg, 0.024 mmol) in
pyridine (0.5 mL) was added hydroxylamine hydrochloride (8.00 mg,
0.12 mmol). After being stirred at RT for 3 h, H2O was added and
extracted with Et2O. The organic layers were washed with brine, dried
over MgSO4, filtered, and evaporated in vacuo. The product was used
in the next step without further purification. [For analysis, 27 was
purified by silica gel column chromatography (hexane:AcOEt = 7:3).];
1
Rf (hexane:AcOEt = 1:1) 0.60; IR (neat) 3281, 1711, 1600 cm−1; H
NMR (400 MHz, CDCl3) δ 7.91 (1 H, d, J = 7.6 Hz), 7.52−7.26 (6 H,
m), 7.14 (1 H, d, J = 7.6 Hz), 7.04 (1 H, t, J = 7.6 Hz), 5.13 (1 H, br),
4.36 (1 H, d, J = 11.6 Hz), 4.32 (1 H, d, J = 11.6 Hz), 3.85 (3 H, s),
3.06 (2 H, s), 2.12 (1 H, dt, J = 4.0 and 13.2 Hz), 2.01 (1 H, dt, J = 4.0
and 13.2 Hz),1.61 (1 H, br), 1.49 (1 H, dt, J = 4.0 and 13.2 Hz), 1.29
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afford 34 (60.0 mg, 85%) as a colorless oil; Rf (AcOEt) 0.67; IR (neat)
as a colorless oil (23.0 mg, 90%); Rf (AcOEt) 0.30; IR (neat) 2927
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.04 (1 H, t, J = 8.0 Hz), 6.97 (1
H, d, J = 8.0 Hz), 6.65 (1 H, t, J = 8.0 Hz), 6.41 (1 H, d, J = 8.0 Hz),
5.17 (1 H, t, J = 6.0 Hz), 4.97 (1 H, t, J = 6.0 Hz) 4.26 (1 H, s), 3.92
(1 H, dd, J = 6.0 and 15.8 Hz), 3.80 (1 H, dd, J = 6.0 and 15.8 Hz),
2.69−2.64 (1 H, m), 2.59−2.58 (1 H, m), 2.48 (3 H, s), 2.42 (2 H, d, J
= 7.2 Hz), 2.07−2.02 (1 H, m), 1.93−1.90 (1 H, m), 1.71 (3 H, s),
1.70 (3 H, s), 1.65 (3 H, s), 1.58 (3 H, s); 13C NMR (100 MHz,
CDCl3) δ 151.9 (C), 135.7 (C), 134.0 (C), 133.4 (C), 127.5 (CH),
122.8 (CH), 121.5 (CH), 120.8 (CH), 117.4 (CH), 107.3 (CH), 91.5
(CH), 57.1 (C), 52.8 (CH2), 46.8 (CH2), 39.0 (CH2), 38.5 (CH2),
38.0 (CH3), 25.9 (CH3), 25.7 (CH3), 18.1 (CH3), 18.0 (CH3); HRMS
(ESI) calcd for C21H30N2Na [M + Na]+: 333.2307, found. 333.2309.
1
2958, 1703 cm−1; H NMR (400 MHz, CDCl3) δ 7.76−7.44 (1 H,
br), 7.26 (1 H, t, J = 8.0 Hz), 7.17 (1 H, d, J = 8.0 Hz), 7.08 (1 H, t, J =
8.0 Hz), 5.65 (1 H, br), 5.00 (1 H, t, J = 8.0 Hz), 3.92 (3 H, s), 2.88 (3
H, s), 2.72 (2 H, d, J = 17.2 and 20.6 Hz), 2.35 (1 H, dd, J = 8.0 and
14.6 Hz), 2.43 (1 H, dd, J = 8.0 and 14.6 Hz), 1.68 (3 H, s), 1.53 (3 H,
s); 13C NMR (100 MHz, CDCl3, 50 °C) δ 172.3 (C), 139.8 (C),
136.9 (2C), 136.6 (C), 128.8 (CH), 124.3 (CH), 123.6 (CH), 117.8
(CH), 116.8 (CH), 82.5 (CH), 53.0 (CH3), 49.5 (C), 40.9 (CH2),
36.8 (CH2), 27.5 (CH3), 25.8 (CH3), 18.0 (CH3); HRMS (ESI) calcd
for C18H22N2O3Na [M + Na]+: 337.1528, found 337.1525.
1-Methyl-3a-(3-methylbut-2-enyl)-3,3a,8,8a-tetrahydropyrrolo-
[2,3-b]indol-2(1H)-one (13). A stirred solution of lactam 34 (50.0 mg,
0.15 mmol) in 5 N NaOH (2 mL) and MeOH (4 mL) was refluxed
for 6 h. After the mixture was cooled to RT, sat. NaHCO3 was added,
extracted with AcOEt, and then washed with brine. The organic layers
were dried over Na2SO4, filtered, and evaporated in vacuo. The residue
was purified by silica gel column chromatography (AcOEt) to afford
13 (33.0 mg, 68%) as a colorless oil; Rf (AcOEt) 0.57; IR (neat) 3317,
2917, 1677 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.10 (1 H, t, J = 8.0
Hz), 7.09 (1 H, d, J = 8.0 Hz), 6.83 (1 H, t, J = 8.0 Hz), 6.67 (1 H, d, J
= 8.0 Hz), 5.01 (1 H, t, J = 8.0 Hz), 4.92 (1 H, s), 2.84 (3 H, s), 2.71
(2 H, s), 2.44 (1 H, dd, J = 8.0 and 15.0 Hz), 2.38 (1 H, dd, J = 8.0,
15.0 Hz), 1.70 (3 H, s), 1.57 (3 H, s); 13C NMR (100 MHz, CDCl3) δ
172.8 (C), 147.4 (C), 135.8 (C), 134.9 (C), 128.5 (CH), 123.6 (CH),
120.2 (CH), 118.4 (CH), 110.7 (CH), 81.9 (CH), 51.1 (C), 41.6
(CH2), 36.8 (CH2), 26.7 (CH3), 26.9 (CH3), 18.1 (CH3): HRMS
(ESI) calcd for C16H20N2ONa [M + Na]+: 279.1473, found 279.1478.
1-Methyl-3a- (3-methylbut-2-e nyl)-1, 2, 3, 3a, 8, 8a-
hexahydropyrrolo[2,3-b]indole: Debromoflustramine E [( )-2]. This
material was prepared according to the literature method5e from
lactam 13 (27.0 mg, 0.10 mmol). ( )-2 was obtained as a colorless oil
(21.0 mg, 85%); Rf (AcOEt:MeOH = 4:1) 0.15; IR (neat) 3288, 2961
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental procedures for preparation of 17 and 7a−f. H
and 13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: shishido@ph.tokushima-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A Grant-in-Aid for JSPS Fellows (22-9957) to T.O. from the
JSPS is gratefully acknowledged. This work was supported
financially by a Grant-in-Aid for the Program for Promotion of
Basic and Applied Research for Innovations in the Bio-oriented
Industry (BRAIN).
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.03 (1 H, d, J = 7.6 Hz), 7.01
(1 H, t, J = 7.6 Hz), 6.71 (1 H, t, J = 7.6 Hz), 6.58 (1 H, d, J = 8.0 Hz),
5.06 (1 H, t, J = 7.6 Hz), 4.35 (1 H, s), 4.11 (1 H, br), 2.66−2.57 (2 H,
m), 2.42 (2 H, s), 2.42 (3 H, s), 2.09 (1 H, dt, J = 5.2 and 12.0 Hz),
1.95 (1 H, dt, J = 5.2 and 12.0 Hz), 1.66 (3 H, s), 1.58 (3 H, s); 13C
NMR (100 MHz, CDCl3) δ 150.0 (C), 135.5 (C), 133.9 (C), 127.5
(CH), 123.3 (CH), 120.3 (CH), 118.8 (CH), 109.1 (CH), 86.4 (CH),
57.8 (C), 52.4 (CH2), 38.8 (CH2), 38.0 (CH2), 37.0 (CH3), 25.9
(CH3), 18.2 (CH3); HRMS (ESI) calcd for C16H23N2 [M + H]+:
243.1861, found. 243.1859.
REFERENCES
■
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