Cascade oxime formation, cyclization to a nitrone, and intermolecular dipolar cycloaddition

Article abstract of DOI:10.1039/C6OB01871H

Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with displacement of halide to give intermediate nitrones; these nitrones undergo in situ intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine alkaloid macronecine and a formal synthesis of petasinecine.

Full text of DOI:10.1039/C6OB01871H

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Saruengkhanphasit, H. Holberry, J. Shewring, H. Guerrand, H. Adams and I. Coldham, Org. Biomol.
Chem., 2016, DOI: 10.1039/C6OB01871H.
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DOI: 10.1039/C6OB01871H
PAPER
Cascade oxime formation, cyclization to a
nitrone, and intermolecular dipolar
cycloaddition
Cite this: DOI:
10.1039/x0xx00000x
Rachel C. Furnival, Rungroj Saruengkhanphasit, Heather E. Holberry,
Jonathan R. Shewring, Hélène D. S. Guerrand, Harry Adams, Iain
Coldham*
Received ,
Accepted
DOI: 10.1039/x0xx00000x
www.rsc.org/obc
Simple haloaldehydes, including enolisable aldehydes, were found to be suitable for the
formation of cyclic products by cascade (domino) condensation, cyclisation, dipolar
cycloaddition chemistry. This multi-component reaction approach to heterocyclic compounds
was explored by using hydroxylamine, a selection of aldehydes, and a selection of activated
dipolarophiles. Initial condensation gives intermediate oximes that undergo cyclisation with
displacement of halide to give intermediate nitrones; these nitrones undergo in situ
intermolecular dipolar cycloaddition reactions to give isoxazolidines. The cycloadducts from
using dimethyl fumarate were treated with zinc/acetic acid to give lactam products and this
provides an easy way to prepare pyrrolizinones, indolizinones, and pyrrolo[2,1-
a]isoquinolinones. The chemistry is illustrated with a very short synthesis of the pyrrolizidine
alkaloid macronecine and a formal synthesis of petasinecine.
underwent successful condensation with hydroxylamine,
followed by cyclization then intramolecular cycloaddition onto
the internal unactivated alkene, and this was used in a synthesis
of myrioxazine A.4c
Introduction
Cycloaddition reactions of nitrones have been known for over
50 years.1 The majority of examples involve the condensation
of an aldehyde with an N-alkyl-hydroxylamine or oxidation of
an amine to form the nitrone, followed by cycloaddition with an
alkene dipolarophile.2 An alternative approach makes use of the
condensation of an aldehyde or ketone with hydroxylamine to
give an oxime that undergoes subsequent N-alkylation to give
the nitrone. Various N-alkylating agents can be used and the
most common are unsaturated systems that allow the nitrogen
atom of the oxime to undergo conjugate addition.3 We have
been exploring the N-alkylation of oximes by intramolecular
substitution of an alkyl halide. This cyclization reaction
provides the desired nitrone that undergoes intramolecular
dipolar cycloaddition with an alkene.4,5
So far, we have reported only two examples of
intermolecular cycloaddition using this strategy and these make
use of a non-enolisable aldehyde as the substrate for reaction
with hydroxylamine.6,7 For example, the aldehyde 1 reacts to
give the intermediate oxime 2 that undergoes cyclization onto
the alkyl chloride to give the nitrone 3 that can be trapped
intermolecularly with dimethyl maleate to give the product 4 as
a mixture of diastereoisomers (Scheme 1).6 The enolisable
aldehyde 5 failed to give the desired tricyclic product and led
instead to 3-(pent-4-enyl)pyrrole.4f However, the aldehyde 6
CO2Me
NH2OH·HCl, PhMe
iPr2NEt, 110 °C
H
CHO
Cl
CO2Me
N
O
CO2Me
MeO2C
1
4
dr 1.6 : 1
77%
N
OH
Cl
N
O
2
3
CHO
Cl
CHO
Cl
5
6
Scheme 1 Previous studies with related aldehydes.4,6
This journal is © The Royal Society of Chemistry 2016
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In this paper, we report successful reactions of aldehydes, then heating to 110 °C in the presence of the dipolarophile.
including enolisable aldehydes, with hydroxylamine, followed Product 14 has been reported to be formed as a mixture of
by in situ cyclization and intermolecular dipolar cycloaddition. isomers starting from oxidation of N-hydroxypyVrireowliAdrtiicnleeOanlninde
DOI: 10.1039/C6OB01871H
The ability to undergo such chemistry is likely due to the use of cycloaddition of the resulting 1-pyrroline-1-oxide.10 The
reactive, electron-poor alkene dipolarophiles. This chemistry dipolarophiles N-phenylmaleimide and N-methylmaleimide
allows the formation of a greater range of substituted products gave the desired cycloaddition products 15 and 16 in good
without the need to block enolisation.
yield. The reaction was cleaner on addition of some MgSO4 and
n-Bu4NI. The diastereoisomers were separable by column
chromatography, although the minor isomer of the N-phenyl
adduct 15 was isolated together with the adduct of
hydroxylamine and N-phenylmaleimide. The stereochemistry of
the major isomer of 16 was determined by single crystal X-ray
analysis. This has the same relative stereochemistry as that for
the major isomer of the homolog 10. We assume that the major
isomer of 15 also has this relative stereochemistry.
Results and discussion
Our initial work in this area focused on the simple aldehyde
substrate 7 (Scheme 2). This was prepared by Swern oxidation
of commercially available 5-chloro-1-pentanol.8 Treatment of
the aldehyde 7 with hydroxylamine hydrochloride salt, the base
iPr2NEt, and the dipolarophile dimethyl fumarate gave the
desired bicyclic product
8 in high yield as a single
diastereoisomer. The stereochemistry could not be determined
at this stage, although NMR spectroscopic analysis and later
single crystal X-ray analysis of a derivative (see below),
revealed the stereochemistry as shown. The 1H NMR
spectroscopic data for the product 8 match those reported from
oxidation of N-hydroxypiperidine and cycloaddition of the
resulting nitrone with dimethyl fumarate.9
CO2Me
NH2OH·HCl, PhMe
iPr2NEt, 110 °C
H
CHO
Cl
CO2Me
N
CO2Me
O
7
8
82%
MeO2C
Scheme 2 Aldehyde substrate 7 with dimethyl fumarate.
Changing the dipolarophile from dimethyl fumarate to N-
phenylmaleimide gave the desired bicyclic product 9 in high
yield as the major diastereoisomer (dr 4:1) (Scheme 3). The
diastereoisomers were separable by column chromatography
and the stereochemistry of the major isomer 9 was determined
by single crystal X-ray analysis. In a similar way, the use of N-
methylmaleimide gave the desired product 10 in high yield as
the major diastereoisomer (dr 4:1). The coupling constants for
the methine protons in the cycloadduct 10 matched those of the
cycloadduct 9, indicating the same relative stereochemistry for
the major isomer.
Treatment of the cycloadduct 8 with zinc in acetic acid
resulted in reductive cleavage of the N–O bond and subsequent
cyclization of the amine onto one of the ester groups to give the
lactam 11 as a single diastereoisomer (Scheme 4). This product
was crystalline but the needles were too fine for X-ray analysis.
However, conversion of the alcohol 11 to the ester 12 using p-
bromobenzoyl chloride gave crystals suitable for X-ray analysis
and allowed the determination of the relative stereochemistry of
12 (and hence of the cycloadduct 8).
O
R
NH2OH·HCl, PhMe
iPr2NEt, 110 °C
H
N
CHO
Cl
O
N
O
O
O
N
7
9
R = Ph dr 4:1
81%
76%
R
10 R = Me dr 4:1
Scheme 3 Aldehyde substrate 7 with N-phenyl- or N-methylmaleimide (major
diastereoisomer of product drawn).
CO2Me
CO2Me
H
H
Zn, AcOH, 70 °C
CO2Me
OH
N
N
O
O
8
70%
11
CO2Me
O
H
p-BrC6H4COCl
O
N
CH2Cl2, pyridine
Br
O
12
Cyclization of the oxime derived from the aldehyde 7 gives
a six-membered ring nitrone. We had previously found that a
six-membered ring nitrone could be prepared and reacted
intramolecularly (by using aldehyde 6, see Scheme 1).4c
However, aldehyde 5 was unsuccessful and resulted in a pyrrole
product. To test the feasibility of conducting the intermolecular
chemistry with the homologous aldehyde containing one less
methylene unit, we prepared the aldehyde 13. We were pleased
to find that treatment of aldehyde 13 with hydroxylamine
Scheme 4 Preparation of lactam 11 and ester 12.
i
hydrochloride salt, the base Pr2NEt, and the dipolarophile
dimethyl fumarate gave the desired bicyclic product 14 (as a
mixture of diastereoisomers) in high yield (Scheme 5). The
reaction was best conducted by pre-forming the oxime at 60 °C,
2 | Org. Biomol. Chem., 2016, 00, 1-3
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Treatment of the 2:1 mixture of cycloadducts 14 with
CO2Me
NH2OH·HCl, PhMe
iPr2NEt, 60 °C
H
Zn/AcOH gave the desired lactams 19 and 20 (ratio 2:1) that
View Article Online
CHO
were separable by careful column chromatography (Scheme 7).
CO2Me
DOI: 10.1039/C6OB01871H
then, 110 °C
N
O
The major product was stereoisomer 19 and the spectroscopic
data matched the reported data.12 The major isomer, lactam 19,
was reduced with LiAlH4 to give the pyrrolizidine alkaloid (±)-
macronecine following a literature procedure (Scheme 7).12 The
1H NMR spectroscopic data matched that reported for the
natural product.13 The chemistry also provides a formal
synthesis of the alkaloid (±)-petasinecine by reduction.12
Therefore the chemistry allows a rapid access to these natural
products in just three steps from 4-chlorobutanal (13).
To complement the examples above, we studied the same
cascade chemistry with the benzaldehyde substrate 21. This
was prepared in two steps from isochroman.6b,14 Condensation
of aldehyde 21 with hydroxylamine at 60 °C followed by
addition of dimethyl fumarate, N-phenylmaleimide or N-
methylmaleimide gave the cycloadducts 22–24 (Scheme 8).
These products were all formed as a single diastereoisomer.
The relative stereochemistry for adducts 22 and 24 was
confirmed by single crystal X-ray analysis. The preference for
the exo adducts matches that reported from reaction of the
isolated nitrone.15
CO2Me
Cl
13
87% 14 dr 2:1
MeO2C
O
NH2OH·HCl, PhMe
iPr2NEt, MgSO4, 60 °C
10 mol% Bu4NI
R
H
N
CHO
O
then, 110 °C
N
O
Cl
13
15 R = Ph major isomer
16 R = Me dr 2.2:1
65%
71%
O
O
N
R
Scheme 5 Aldehyde substrate 13 with dimethyl fumarate, N-phenyl- or N-
methylmaleimide.
With the aldehyde substrate 13 we also tested the
dipolarophile β-nitrostyrene. This resulted in two products, the
minor one of which was amenable to single crystal X-ray
analysis, revealing the unexpected isomer 17 (Scheme 6). We
have not been able to determine the stereochemistry of the other
isomer 18, but on standing in CDCl3, this converts to a mixture
of 17 and 18. The isomer 17 could arise either from the isomer
18 (for example by epimerization or via retro-Mannich
reaction) or from a stepwise rather than concerted cycloaddition
process.11
In a similar way, the aldehyde 2514 was treated with
hydroxylamine at 60 °C followed by addition of dimethyl
fumarate, N-phenylmaleimide or N-methylmaleimide to give
the cycloadducts 26–28 (Scheme 9). The relative
stereochemistries of the adducts 27 and 28 were confirmed by
single crystal X-ray analysis.
NH2OH·HCl, PhMe
iPr2NEt, MgSO4, 60 °C
10 mol% Bu4NI
NO2
NO2
H
CHO
+
Ph
Ph
then, 110 °C
N
N
O
O
Cl
13
NH2OH·HCl, PhMe
Br
NO2
Ph
89% 17
dr 1:2.7
18
iPr2NEt, 60 °C
N
O
then, 110 °C
MeO2C
Scheme 6 Aldehyde substrate 13 with β-nitrostyrene.
CHO
21
H
MeO2C
22
CO2Me
CO2Me
CO2Me
H
CO2Me
H
76%
Zn, AcOH, H2O
+
14
OH
OH
heat, 22 h
79%
N
N
O
O
19
20
N
NH2OH·HCl, PhMe
iPr2NEt, 60 °C
Br
O
H
O
LiAlH4, THF
heat, 17 h
ref.12
then, 110 °C
70%
CHO
21
O
N
OH
OH
H
H
O
O
N
R
23 R = Ph
24 R = Me
61%
76%
R
OH
OH
N
N
Scheme 8 Aldehyde substrate 21 with dimethyl fumarate, N-phenyl- or N-
methylmaleimide.
macronecine
Scheme 7 Preparation of the alkaloid macronecine.
petasinecine
From the results above, it is clear that the aldehyde 13 is
amenable to the desired cascade chemistry involving oxime
formation, cyclization to give
a nitrone, followed by
intermolecular cycloaddition. This requires an activated alkene
to promote cycloaddition, otherwise (as found for compound 5)
the five-membered nitrone is prone to conversion to a pyrrole
ring.
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5-Chloropentanal 7
DMSO (3.4 mL, 48 mmol) in CH2Cl2 (10 mL) was added to
freshly distilled oxalyl chloride (2.1 mL, 24 mmol) in CH2Cl2
MeO
NH2OH·HCl
PhMe, iPr2NEt, 60 °C
MeO
MeO
Cl
View Article Online
DOI: 10.1039/C6OB01871H
N
MeO
CO2Me
then, 110 °C
MeO2C
O
CHO
25
(60 mL) at –78 °C. After 10 min, 5-chloropentan-1-ol (2.4 mL,
20 mmol) in CH2Cl2 (10 mL) was added slowly. After 30 min,
triethylamine (13.9 mL, 100 mmol) was added. The mixture
was allowed to warm to room temperature, then CH2Cl2 (20
mL) and water (20 mL) were added. The aqueous layer was
washed with CH2Cl2 (3 × 50 mL). The combined organic layers
were dried (MgSO4) and evaporated. Purification by column
chromatography, eluting with CH2Cl2, gave aldehyde 7 (2.05 g,
85%) as an oil; Rf 0.8 (CH2Cl2); νmax (film)/cm–1 2935, 2865,
H
MeO2C
CO2Me
78%
26
MeO
NH2OH·HCl, PhMe
iPr2NEt, 60 °C
N
MeO
MeO
Cl
MeO
O
H
O
then, 110 °C
CHO
25
1
O
2730, 1720; H NMR (400 MHz, CDCl3) δ = 9.80 (1H, t, J 1.5
N
O
O
N
Hz, CHO), 3.60–3.54 (2H, m, CH2), 2.55–2.48 (2H, m, CH2),
1.88–1.77 (4H, m, 2 × CH2); 13C NMR (100 MHz, CDCl3) δ =
201.8, 44.5, 43.0, 31.8, 19.4. Data consistent with the
literature.8
R
27 R = Ph
28 R = Me
74%
81%
R
Scheme 9 Aldehyde substrate 25 with dimethyl fumarate, N-phenyl- or N-
methylmaleimide.
(2R*,3R*,3aR*)-Dimethyl
Hexahydro-2H-isoxazolo[2,3-
a]pyridine-2,3-dicarboxylate 8
Zn, AcOH
Hydroxylamine hydrochloride (142 mg, 2.04 mmol) and N,N-
diisopropylethylamine (0.74 mL, 4.3 mmol) were added to
aldehyde 7 (204 mg, 1.70 mmol) in PhMe (17 mL) and the
mixture was heated to 110 °C. After 30 min, dimethyl fumarate
(368 mg, 2.55 mmol) was added and heating was continued at
110 °C. After 3.5 h, the mixture was cooled to room
temperature and the solvent was evaporated. Purification by
column chromatography, eluting with CH2Cl2–MeOH (98:2),
gave the product 8 (340 mg, 82%) as an oil; Rf 0.36 [CH2Cl2–
N
N
O
O
70 °C, 1.5 h
H
MeO2C
22
H
MeO2C
29
CO2Me
OH
75%
MeO
MeO
MeO
Zn, AcOH
N
N
O
MeO
O
70 °C, 1.5 h
H
H
1
MeOH (98:2)]; νmax (film)/cm–1 2950, 2850, 1730; H NMR
MeO2C
MeO2C
CO2Me
OH
(400 MHz, CDCl3) δ = 4.84 (1H, d, J 5.5 Hz, CH), 3.81 (3H, s,
CH3), 3.79 (3H, s, CH3), 3.60–3.52 (1H, m, CH), 3.42 (1H, dd,
J 10, 5.5 Hz, CH), 2.54 (1H, ddd, J 12, 10, 3 Hz, CH), 2.41–
2.32 (1H, m, CH), 2.19–2.10 (1H, m, CH), 1.72–1.65 (3H, m, 2
× CH), 1.50 (1H, qd, J 13, 4 Hz, CH), 1.31–1.17 (1H, m, 2 ×
CH); 13C NMR (100 MHz, CDCl3) δ = 172.0, 171.2, 75.8, 70.5,
56.0, 55.2, 52.7, 52.5, 28.6, 24.3, 23.2; HRMS (ES) Found:
MH+, 244.1186. C11H18NO5 requires MH+, 244.1185.
26
47%
30
Scheme 10 Preparation of lactams 29 and 30.
The products 22 and 26 were treated with zinc in acetic acid
to give the lactams 29 and 30 respectively as single isomers
(Scheme 10).
Conclusions
(3aR*,3bS*,8aS*)-2-Phenyl-hexahydro-8-oxa-2,7a-diaza-
cyclopenta[a]indene-1,3-dione 9
In conclusion, cascade chemistry involving condensation of
hydroxylamine, cyclization and intermolecular dipolar
cycloaddition has been shown to be successful with a range of
aldehydes, including enolisable aldehydes, together with
electron-deficient dipolarophiles to give a variety of bicyclic,
tricyclic and tetracyclic products. The isoxazolidine
cycloadducts from using dimethyl fumarate as the dipolarophile
were subjected to N–O bond cleavage to give, after cyclization,
α-hydroxylactams. The chemistry provides a rapid entry to
nitrogen-containing heterocycles of potential pharmaceutical
interest and application to natural product synthesis, as
demonstrated by a short synthesis of the alkaloid macronecine
and a formal synthesis of petasinecine.
Hydroxylamine hydrochloride (147 mg, 2.11 mmol) and N,N-
diisopropylethylamine (0.77 mL, 4.4 mmol) were added to
aldehyde 7 (211 mg, 1.76 mmol) in PhMe (17 mL) and the
mixture was heated to 110 °C. After 30 min, N-
phenylmaleimide (457 mg, 2.63 mmol) was added and heating
was continued at 110 °C. After 2 h, the mixture was cooled to
room temperature and the solvent was evaporated. Purification
by column chromatography, eluting with CH2Cl2–MeOH
(99:1), gave the product 9 (307 mg, 64%) as a solid and its
diastereomer (83 mg, 17%) as a solid. The product 9 was
recrystallized from CH2Cl2–hexanes (1:1) as needles; m.p. 157–
159 °C; Rf 0.43 [CH2Cl2–MeOH (98:2)]; νmax (film)/cm–1 2960,
2935, 1710; 1H NMR (400 MHz, CDCl3) δ = 7.52–7.47 (2H, m,
2 × CH), 7.45–7.39 (1H, m, CH), 7.36–7.31 (2H, m, 2 × CH),
4.93 (1H, d, J 7.5 Hz, CH), 3.74–3.68 (1H, m, CH), 3.56–3.48
Experimental
4 | Org. Biomol. Chem., 2016, 00, 1-3
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ARTICLE
(1H, m, CH), 3.39 (1H, dd, J 7.5, 1.5 Hz, CH), 3.08–2.98 (1H, needles; m.p. 124–127 °C; Rf 0.10 [CH2Cl2–MeOH (99:1)];
1
m, CH), 1.89–1.60 (4H, m, 4 × CH), 1.55–1.31 (2H, m, 2 × νmax (film)/cm–1 3220, 2950, 2920, 2895, 2865, 1740, 1680; H
View Article Online
CH); 13C NMR (100 MHz, CDCl3) δ = 175.2, 174.5, 131.5, NMR (400 MHz, CDCl3) δ = 4.50 (1H, d, J 7.5 Hz, CH), 4.13
DOI: 10.1039/C6OB01871H
129.2, 128.8, 126.4, 75.1, 63.4, 54.3, 50.3, 25.7, 22.5, 19.3; (1H, dt, J 13, 5 Hz, CH), 3.95–3.87 (1H, m, CH), 3.80 (3H, s,
HRMS (ES) Found: MH+, 273.1250. C15H17N2O3 requires CH3), 2.93 (1H, t, J 7.5 Hz, CH), 2.78 (2H, dt, J 13, 3.5 Hz, 2 ×
MH+, 273.1239.
Crystal data deposited at CCDC 1006040
Unit Cell Parameters:
CH), 2.14–2.06 (1H, m, CH), 1.96–1.87 (1H, m, CH), 1.81–
1.72 (1H, m, CH), 1.50 (1H, qt, J 13, 3.5 Hz, CH), 1.40–1.24
(1H, m, CH), 1.11 (1H, qd, J 13, 3.5 Hz, CH); 13C NMR (100
MHz, CDCl3) δ = 170.4, 169.8, 70.2, 56.8, 52.2, 50.4, 40.5,
a 12.9691(19) b 6.6225(11) c 15.583(3) P21/n
Data for minor stereoisomer: m.p. 135–137 °C; Rf 0.27 32.4, 24.1, 23.4; HRMS (ES) Found: MH+, 214.1070.
[CH2Cl2–MeOH (98:2)]; νmax (film)/cm–1 2960, 2935, 1710; H C10H16NO4 requires MH+, 214.1079.
1
NMR (400 MHz, CDCl3) δ = 7.52–7.45 (2H, m, 2 × CH), 7.45–
7.39 (1H, m, CH), 7.34–7.29 (2H, m, 2 × CH), 4.91 (1H, d, J (1R*,2R*,8aR*)-Methyl
2-(4-Bromobenzoyloxy)-3-oxo-
7.5 Hz, CH), 3.64–3.55 (2H, m, 2 × CH), 2.61–2.50 (2H, m, 2 × octahydroindolizine-1-carboxylate 12
CH), 2.28–2.18 (1H, m, CH), 1.85–1.79 (2H, m, 2 × CH), 1.68– p-Bromobenzoyl chloride (875 mg, 5.0 mmol) and DMAP (60
1.53 (1H, m, CH), 1.50–1.37 (1H, m, CH), 1.34–1.19 (1H, m, mg, 0.5 mmol) were added to the lactam 11 (425 mg, 2.0
CH); 13C NMR (100 MHz, CDCl3) δ = 176.8, 175.6, 131.5, mmol) in pyridine (2 mL) at room temperature. After 16 h, the
129.2, 129.0, 126.4, 75.1, 55.1, 50.6, 26.9, 24.4, 23.5, 19.4; solvent
was
evaporated.
Purification
by
column
HRMS (ES) Found: MH+, 273.1239. C15H17N2O3 requires chromatography, eluting with CH2Cl2–MeOH (99:1), gave ester
MH+, 273.1239.
12 (687 mg, 87%) as fine needles; m.p. 90–92 °C; Rf 0.2
[CH2Cl2–MeOH (99:1)]; νmax (film)/cm–1 2940, 2855, 1735,
1695; 1H NMR (400 MHz, CDCl3) δ = 7.92 (2H, d, J 8.5 Hz, 2
× CH), 7.60 (2H, d, J 8.5 Hz, 2 × CH), 5.76 (1H, d, J 6.5 Hz,
(3aR*,3bS*,8aS*)-2-Methyl-hexahydro-8-oxa-2,7a-diaza-
cyclopenta[a]indene-1,3-dione 10
Hydroxylamine hydrochloride (142 mg, 2.04 mmol) and N,N- CH), 4.23 (1H, d, J 14 Hz, CH), 3.75–3.66 (2H, m, 2 × CH),
diisopropylethylamine (0.74 mL, 4.3 mmol) were added to 2.75 (1H, t, J 14 Hz, CH), 2.04–1.97 (1H, m, CH), 1.92–1.85
aldehyde 7 (204 mg, 1.70 mmol) in PhMe (17 mL) and the (1H, m, CH), 1.83–1.76 (1H, m, CH), 1.55–1.38 (3H, m, 3 ×
mixture was heated to 110 °C. After 30 min, N- CH); 13C NMR (100 MHz, CDCl3) δ = 169.0, 166.1, 164.5,
methylmaleimide (283 mg, 2.55 mmol) was added and heating 131.8, 131.4, 129.7, 128.6, 70.2, 56.9, 52.4, 48.7, 40.8, 32.4,
was continued at 110 °C. After 3.5 h, the mixture was cooled to 24.0, 23.4; HRMS (ES) Found: MH+, 396.0444.
room temperature and the solvent was evaporated. Purification C17H19NO579Br requires MH+ 396.0447.
by column chromatography, eluting with CH2Cl2–MeOH Crystal data deposited at CCDC 1022997
(98:2), gave the product 10 (218 mg, 61%) as a solid and its Unit Cell Parameters:
diastereomer (54 mg, 15%) as a solid. Data for the major a 11.0353(7) b 21.5973(13) c 15.0726(9) P21/c
stereoisomer 10: m.p. 80–83 °C; Rf 0.44 [CH2Cl2–MeOH
(95:5)]; νmax (film)/cm–1 2925, 2860, 1695; 1H NMR (400 MHz, 4-Chlorobutanal 13
CDCl3) δ = 4.78 (1H, d, J 7 Hz, CH), 3.60–3.54 (1H, m, CH), DMSO (2.9 mL, 40.6 mmol) in CH2Cl2 (10 mL) was added
3.51–3.47 (1H, m, CH), 3.22 (1H, dd, J 7, 1.5 Hz, CH), 3.05 dropwise to oxalyl chloride (1.8 mL, 20.3 mmol) in CH2Cl2 (60
(3H, s, CH3), 3.01–2.90 (1H, m, CH), 1.84–1.74 (2H, m, 2 × mL) at –78 °C. After 10 min, 4-chlorobutanol (1.8 mL, 16.9
CH), 1.67–1.54 (2H, m, 2 × CH), 1.51–1.38 (1H, m, CH), 1.37– mmol) in CH2Cl2 (10 mL) was added dropwise. After 30 min,
1.20 (1H, m, CH); 13C NMR (100 MHz, CDCl3) δ = 176.0, Et3N (11.8 mL, 84.5 mmol) was added. After 30 min, the
175.4, 75.1, 62.8, 54.4, 50.2, 25.7, 25.0, 22.5, 19.2; HRMS mixture was allowed to warm to room temperature then water
(ES) Found: MH+, 211.1084. C10H15N2O3 requires MH+, (20 mL) and CH2Cl2 (20 mL) were added. The layers were
211.1083.
separated and the aqueous layer was extracted with CH2Cl2 (3 ×
50 mL). The combined organic layers were dried (MgSO4),
(1R*,2R*,8aR*)-Methyl
2-Hydroxy-3-oxo- filtered
and
evaporated.
Purification
by
column
octahydroindolizine-1-carboxylate 11
chromatography, eluting with CH2Cl2, gave aldehyde 13 (1.09
Zinc powder (186 mg, 2.85 mmol) was added to cycloadduct 8 g, 61%) as an oil; Rf 0.9 (CH2Cl2); 1H NMR (400 MHz, CDCl3)
(165 mg, 0.678 mmol) in AcOH/H2O (14 mL, 5:9). The 9.84 (1H, s, CHO), 3.62 (2H, t, J 6.5 Hz, CH2), 2.70 (2H, t, J
mixture was heated to 70 °C for 2 h before being cooled to 6.5 Hz, CH2), 2.13 (2H, pent., J 6.5 Hz, CH2). Data consistent
room temperature. The zinc salts were filtered, washed with with the literature.16
CH2Cl2 and the solvent was evaporated. The solute was
partitioned between aqueous ammonia (5 mL) and CH2Cl2 (10 (2S*,3S*,3aS*)-2,3-Dimethyl
Hexahydropyrrolo[1,2-
mL), and the aqueous layer was extracted with CH2Cl2 (3 × 15 b][1,2]oxazole-2,3-dicarboxylate 14a and (2S*,3S*,3aR*)-
mL). The organic fractions were dried (MgSO4), filtered and 2,3-Dimethyl
evaporated to give the lactam 11 (102 mg, 70%) as a solid, dicarboxylate 14b
which was recrystallized from CH2Cl2–hexanes (1:1) as
Hexahydropyrrolo[1,2-b][1,2]oxazole-2,3-
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To aldehyde 13 (106 mg, 1 mmol) in PhMe (10 mL) was added (1R*,2S*,6R*)-4-Methyl-7-oxa-4,8-
hydroxylamine hydrochloride (85 mg, 1.2 mmol) and Pr2NEt diazatricyclo[6.3.0.01]undecane-3,5-dione 16b
i
View Article Online
(0.41 mL, 2.4 mmol) and the mixture was warmed to 60 °C. To aldehyde 13 (106 mg, 1 mmol) in PhMe (10 mL) was added
DOI: 10.1039/C6OB01871H
After 30 min, dimethylfumarate (217 mg, 1.5 mmol) was added hydroxylamine hydrochloride (76 mg, 1.1 mmol), iPr2NEt (0.41
and the mixture was heated under reflux. After 3.5 h, the mL, 2.4 mL), dry MgSO4 (~200 mg) and Bu4NI (37 mg, 0.1
mixture was allowed to cool to room temperature and the mmol) and the mixture was warmed to 60 °C. After 30 min, N-
solvent
was
evaporated.
Purification
by
column methylmaleimide (260 mg, 1.5 mmol) was added and the
chromatography, eluting with CH2Cl2–MeOH (99:1) gave mixture was heated under reflux. After 3.5 h, the mixture was
cycloadducts 14a and 14b (200 mg, 0.87 mmol, 87%) as an oil, allowed to cool to room temperature and the solvent was
as an inseparable mixture of diastereoisomers (dr 2:1);
evaporated. Purification by column chromatography, eluting
alternatively, aldehyde 13 (500 mg, 4.7 mmol) in PhMe (50 with CH2Cl2–MeOH (99:1), gave cycloadduct 16a (96 mg,
mL), hydroxylamine hydrochloride (390 mg, 5.6 mmol), 49%) as an oil and the cycloadduct 16b (43 mg, 22%) as an oil,
iPr2NEt (2.0 mL, 11 mmol) and dimethylfumarate (1.0 g, 7.0 both of which recrystallised from EtOAc as cubes.
mmol) gave, after heating for 17 h then purification as above, Data for adduct 16a: m.p. 91–93 ºC; Rf 0.4 [CH2Cl2–MeOH
the cycloadducts 14a and 14b (770 mg, 3.4 mmol, 72%) as an (95:5)]; νmax (film)/cm–1 2955, 1705; 1H NMR (400 MHz,
oil (dr 2:1);
CDCl3) δ = 4.86 (1H, d, J 7.0 Hz, CH), 4.00–3.91 (2H, m, 2 ×
Rf 0.5 [CH2Cl2–MeOH (98:2)]; νmax (film)/cm–1 2955, 1735; 1H CH), 3.38–3.30 (1H, m, CH), 3.18–3.06 (1H, m, CH), 3.04 (3H,
NMR (500 MHz, CDCl3) δ = 4.98 (0.35H, d, J 5.5 Hz, CH), s, CH3), 2.07–1.94 (2H, m, 2 × CH), 1.90–1.80 (1H, m, CH),
4.85 (0.65H, d, J 7.5 Hz, CH), 4.13–4.08 (0.35H, dd, J 7.5, 5.0 1.75–1.64 (1H, m, CH); 13C NMR (101 MHz, CDCl3) δ =
Hz, CH), 3.93–3.85 (1H, m, CH), 3.81 (3H, s, 2 × Me), 3.79 174.8, 172.0, 77.6, 67.9, 55.8, 53.6, 29.7, 25.0, 24.1; HRMS
(3H, s, 2 × Me), 3.57–3.49 (0.35H, ddd, J 14.0, 8.0, 3.5 Hz, (ES) Found: MH+, 197.0922. C9H13N2O3 requires MH+,
CH), 3.39 (0.65H, dd, J 7.5, 5.0 Hz CH), 3.39–3.43 (0.35H, m, 197.0926.
CH), 3.13–3.02 (1.3H, m, 2 × CH), 2.13–1.99 (1.65H, m, 3 × Crystal data deposited at CCDC 1051097
CH), 1.86–1.72 (2H, m, 2 × CH), 1.63–1.53 (0.35H, m, CH); Unit Cell Parameters:
13C (125.7 MHz, CDCl3) δ = 171.7, 170.9, 170.5, 169.9, 78.9, a 7.9208(3) b 16.5681(9) c 6.7713(3) Pna21
76.0, 69.7, 68.3, 57.4, 56.3, 56.2, 55.1, 52.7, 52.65, 52.6, 52.4, Data for adduct 16b: m.p. 88–91 ºC; Rf 0.3 [CH2Cl2–MeOH
29.8, 26.6, 24.3, 23.2; HRMS (ES) Found: MH+, 230.1022. (95:5)]; νmax (film)/cm–1 2955, 1700; 1H NMR (400 MHz,
1
C10H16NO5 requires MH+ 230.1028. H NMR data consistent CDCl3) δ = 4.83 (1H, d, J 7.0 Hz, CH), 3.77 (1H, t, J 8.5 Hz,
with the literature.9
CH), 3.61–3.52 (2H, m, 2 × CH), 3.06 (3H, s, CH3), 3.04–2.96
(1H, m, CH), 2.23–2.12 (2H, m, 2 × CH), 1.88–1.80 (1H, m,
CH), 1.75–1.68 (1H, m, CH); 13C NMR (101 MHz, CDCl3) δ =
174.8, 172.1, 77.6, 67.9, 55.8, 53.6, 25.7, 25.0, 24.1; HRMS
(1S*,2S*,6R*)-4-Phenyl-7-oxa-4,8-
diazatricyclo[6.3.0.01]undecane-3,5-dione 15
To aldehyde 13 (106 mg, 1 mmol) in PhMe (10 mL) was added (ES) Found: MH+, 197.0917. C9H13N2O3 requires MH+,
hydroxylamine hydrochloride (76 mg, 1.1 mmol), iPr2NEt (0.41 197.0926.
mL, 2.4 mL), dry MgSO4 (~200 mg) and Bu4NI (37 mg, 0.1
mmol) and the mixture was warmed to 60 °C. After 30 min, N- (2R*,3R*,3aR*)-3-Nitro-2-phenyl-hexahydropyrrolo[1,2-
phenylmaleimide (260 mg, 1.5 mmol) was added and the b][1,2]oxazole 17 and another isomer of 3-Nitro-2-phenyl-
mixture was heated under reflux. After 3.5 h, the mixture was hexahydropyrrolo[1,2-b][1,2]oxazole 18
allowed to cool to room temperature and the solvent was To aldehyde 1 (106 mg, 1 mmol) in PhMe (10 mL) was added
evaporated. Purification by column chromatography, eluting hydroxylamine hydrochloride (76 mg, 1.1 mmol), iPr2NEt (0.41
with CH2Cl2–MeOH (99:1), gave cycloadduct 15 (168 mg, mL, 2.4 mL), MgSO4 (~200 mg) and Bu4NI (37 mg, 0.1 mmol)
65%) as an oil; Rf 0.4 [CH2Cl2–MeOH (99:1)]; νmax (film)/cm–1 and the mixture was warmed to 60 °C. After 30 min, trans-β-
1
2960, 1710, 1498; H NMR (400 MHz, CDCl3) δ = 7.55–7.33 nitrostyrene (224 mg, 1.5 mmol) was added and the mixture
(5H, m, Ph), 4.97 (1H, d, J 7.5 Hz, CH), 3.90 (1H, t, J 8.0 Hz, was heated under reflux. After 3.5 h, the mixture was allowed
CH), 3.73 (1H, d, J 7.5 Hz, CH), 3.66–3.58 (2H, m, 2 × CH), to cool to room temperature and the solvent was evaporated.
3.07 (1H, dt, J 14.5, 8.5 Hz, CH), 2.07–1.98 (1H, m, CH), Purification by column chromatography, eluting with petrol–
1.93–1.73 (2H, m, 2 × CH); 13C NMR (101 MHz, CDCl3) δ = EtOAc (8:2 to 1:1), gave cycloadducts 17 (56 mg, 24%) as a
174.8, 174.4, 131.4, 129.2, 128.9, 126.4, 75.9, 70.8, 55.9, 54.2, solid and 18 (152 mg, 65%) as an oil.
30.0, 24.3; HRMS (ES) Found: MH+, 259.1074. C14H15N2O3 Data for adduct 17: m.p. 89–92 °C; Rf 0.4 [petrol–EtOAc (1:1)];
requires MH+, 259.1083.
νmax (film)/cm–1 2980, 1550, 1455; 1H NMR (400 MHz, CDCl3)
The minor diastereomer was isolated as a mixture with the δ = 7.41–7.34 (5H, m, Ph), 5.50 (1H, d, J 5.5 Hz, CH), 5.24
adduct formed from conjugate addition of hydroxylamine with (1H, dd, J 5.5, 1.5 Hz, CH), 4.51 (1H, broad t, J 7.5 Hz, CH),
the maleimide.
3.50 (1H, dt, J 11.5, 5.5 Hz, CH), 3.21 (1H, dt, J 11.5, 7.5 Hz,
CH), 2.35–2.25 (1H, m, CH), 2.08–1.99 (1H, m, CH), 1.94–
1.77 (2H, m, 2 × CH); 13C NMR (101 MHz CDCl3) δ = 132.0,
and 129.3, 128.6, 126.5, 98.4, 80.8, 68.7, 56.4, 29.9, 24.0; HRMS
(1S*,2S*,6R*)-4-Methyl-7-oxa-4,8-
diazatricyclo[6.3.0.01]undecane-3,5-dione
16a
6 | Org. Biomol. Chem., 2016, 00, 1-3
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ARTICLE
(ES) Found: MH+, 235.1073. C12H15N2O3 requires MH+, NaOH (0.3 mL, 2 M) was added. After 1 h, the suspension was
235.1083; Anal. Calcd for C12H14N2O3: C, 61.5; H, 6.0; N, filtered and was washed with MeOH (60 mL). The filtrate was
12.0. Found: C, 61.9; H, 6.0; N, 11.7.
Crystal data deposited at CCDC 1006037
Unit Cell Parameters:
concentrated to give a white solid which wasViepwuArritficileedOnlbinye
DOI: 10.1039/C6OB01871H
column chromatography on silica with a plug of Celite, eluting
with CH2Cl2–MeOH–NH3 (10:5:1), to give macronecine (70
a 9.0398(3) b 7.2748(3) c 17.0449(6) P21/c
mg, 70%) as an amorphous solid; m.p. 106–108 °C, lit.13g m.p.
Data for adduct 18: Rf 0.6 [petrol–EtOAc (4:1)]; νmax (film)/cm– 107–108 °C; Rf 0.1 [CH2Cl2–MeOH–NH3 (10:5:1)]; H NMR
1 2980, 1545, 1500; 1H NMR (400 MHz, CDCl3) δ = 7.49–7.35 (400 MHz, CDCl3) δ = 4.50 (1H, t, J 4.0 Hz, CH), 4.34 (2H, br
(5H, m, Ph), 5.75 (1H, d, J 6.0 Hz, CH), 5.43 (1H, dd, J 8.5, 6.0 s, 2 × OH), 3.89–3.82 (2H, m, 2 × CH), 3.56–3.50 (1H, m, CH),
Hz, CH), 4.29 (1H, br q, J 7.5 Hz, CH), 3.50 (1H, dt, J 12.5, 6.5 3.17 (1H, d, J 11.0 Hz, CH), 2.97 (1H, td, J 11.0, 6.5 Hz, CH),
Hz, CH), 3.32 (1H, dt, J 12.5, 7.0 Hz, CH), 2.08–1.97 (4H, m, 4 2.67 (1H, dd, J 11.0, 3.5 Hz, CH), 2.59–2.54 (1H, m, CH),
× CH); 13C NMR (101 MHz CDCl3) δ = 132.3, 128.9, 128.8, 2.00–1.92 (1H, m, CH), 1.87–1.76 (3H, m, 3 × CH), 1.57–1.50
126.3, 96.4, 79.4, 68.1, 56.7, 26.4, 23.9; HRMS (ES) Found: (1H, m, CH). Data corresponds to the literature.12,13
MH+, 235.1088. C12H15N2O3 requires MH+, 235.1083.
1
(1S*,2S*,10bR*)-1,2-Dimethyl
2,5,6,10b-Tetrahydro-1H-
(1S*,2S*,6aR*)-Methyl
2-Hydroxy-3-oxo-hexahydro-1H- isoxazolo[3,2-a]isoquinoline-1,2-dicarboxylate 22
pyrrolizine-1-carboxylate 19 and (1S*,2S*,6aS*)-Methyl 2- Hydroxylamine hydrochloride (56 mg, 0.81 mmol) and N,N-
Hydroxy-3-oxo-hexahydro-1H-pyrrolizine-1-carboxylate 20 diisopropylethylamine (0.28 mL, 1.62 mmol) were added to
To a 2:1 mixture of cycloadducts 14 (215 mg, 0.9 mmol) in aldehyde 2114 (154 mg, 0.67 mmol) in PhMe (7 mL) and the
H2O (3.5 mL) and AcOH (2.5 mL) was added zinc (280 mg, 4.3 mixture was heated to 60 °C. Dimethyl fumarate (117 mg, 0.81
mmol) and the mixture was heated under reflux. After 22 h, the mmol) was added and the mixture was heated under reflux.
mixture was cooled to room temperature. The mixture was After 1 h, the mixture was cooled to room temperature and the
diluted with CH2Cl2 (50 mL) and aqueous NH3 (5 mL, 35%), solvent evaporated. Purification by column chromatography,
the layers separated and the aqueous layer was extracted with eluting with CH2Cl2–MeOH (99.7:0.3), gave the product 22
CH2Cl2 (3 × 50 mL). The combined organic layers were dried (150 mg, 76%), which was recrystallised from CH2Cl2–hexanes
(MgSO4), filtered and concentrated under reduced pressure. as needles; m.p. 83–85 ºC, lit.13 m.p. 89–90 °C; Rf 0.5 [CH2Cl2–
Purification by column chromatography, eluting with CH2Cl2– MeOH (99.5:0.5)]; νmax (film)/cm–1 2955, 1735; 1H NMR
iPrOH (97:3), gave the lactams 19 and 20 (combined yield of (400MHz, CDCl3) δ = 7.26–7.19 (2H, m, 2 × CH), 7.16–7.13
142 mg, 79%). The pure lactams were isolated after careful (1H, m, CH), 7.07 (1H, d, J 7.0 Hz, CH), 4.95 (1H, d, J 7.5 Hz,
chromatography: 19 (72 mg, 40%), 20 (32 mg, 18%) and both CH), 4.89 (1H, d, J 8.5 Hz, CH), 3.88 (3H, s, CH3), 3.80–3.76
were recrystallized from hot EtOAc as needles.
(1H, m, CH), 3.77 (3H, s, CH3), 3.42–3.38 (1H, m, CH), 3.23–
Alternatively, a 2:1 mixture of cycloadducts 14 (500 mg, 2.2 3.15 (1H, m, CH), 3.08–3.00 (1H, m, CH), 2.96–2.92 (1H, m,
mmol), H2O (11 mL), AcOH (5.5 mL) and zinc (600 mg, 9.2 CH); 13C NMR (100 MHz, CDCl3) δ = 171.5, 171.1, 133.2,
mmol) gave, after heating for 22 h then purification as above, 132.5, 128.9, 127.6, 127.1, 126.5, 80.9, 67.4, 57.7, 52.8, 52.7,
the lactams 19 (129 mg, 30%) and 20 (70 mg, 16%).
49.7, 27.9; HRMS (ES) Found MH+, 292.1172, C15H18NO5
Data for lactam 19: m.p. 138–141 °C, lit.12 m.p. for (+)-19: requires MH+, 292.1185.
191–192 °C; Rf 0.6 [CH2Cl2–iPrOH–NH3 (90:9:1)]; H NMR Crystal data deposited at CCDC 1006038
1
(400 MHz, CDCl3) δ = 4.63 (1H, dd, J 6.0, 4.0 Hz, CH), 4.42 Unit Cell Parameters:
(1H, ddd, J 9.0, 8.0, 5.5 Hz, NCH), 3.85 (1H, d, J 4.0 Hz, OH), a 9.1248(8) b 32.242(3) c 9.4579(9) P21/c
3.80 (3H, s, CH3), 3.52 (1H, dt, J 12.0, 8.0 Hz, NCH), 3.22
(1H, ddd, J 12.0, 8.5, 3.5 Hz, NCH), 2.95 (1H, dd, J 8.0, 6.0 (8aR*,
11aS*,
11bR*)-10-Phenyl-5,8a,11a,11b-
Hz, CH), 2.28–2.13 (3H, m, 3 × CH), 1.44–1.32 (1H, m, CH). tetrahydropyrrolo[3’,4’:4,5][1,2]oxazolo[3,2-a]isoquinoline-
Data correspond to the literature.12
9,11(6H,10H)-dione 23
Data for lactam 20: m.p. 182–185 °C, lit.12 m.p. for 20 was not Hydroxylamine hydrochloride (124 mg, 1.78 mmol) and N,N-
reported; Rf 0.5 [CH2Cl2–iPrOH–NH3 (90:9:1)]; H NMR (400 diisopropylethylamine (0.62 mL, 3.55 mmol) were added to
1
MHz, CDCl3) δ = 4.76 (1H, br s, CH), 3.98 (1H, dt, J 8.0, 6.5 aldehyde 2114 (339 mg, 1.48 mmol) in PhMe (15 mL) and the
Hz, NCH), 3.74 (3H, s, CH3), 3.67 (1H, t, J 6.5 Hz, CH), 3.63 mixture was heated to 60 °C. After 2 h, N-phenylmaleimide
(1H, dt, J 11.5, 7.0 Hz, NCH), 3.10–3.22 (2H, m, NCH and (308 mg, 1.78 mmol) was added and the mixture was heated
OH), 2.13–1.97 (3H, m, 3 × CH), 1.59–1.47 (1H, m, CH). Data under reflux. After 1 h, the mixture was allowed to cool to
correspond to the literature.12
room temperature and the solvent was evaporated. Purification
by column chromatography, eluting with CH2Cl2–MeOH
(99.8:0.2), gave cycloadduct 23 (291 mg, 61%) as an
Macronecine
The lactam 19 (126 mg, 0.63 mmol) in THF (9 mL) was added amorphous solid; m.p. 172–174 °C, lit.15 m.p. 178–179 °C; Rf
to a solution of LiAlH4 (148 mg, 3.91 mmol) in THF (4 mL). 0.8 [CH2Cl2–MeOH (99.5:0.5)]; νmax (film)/cm–1 2935, 1715;
The grey suspension was then heated under reflux. After 17 h, 1H NMR (400MHz, CDCl3) δ = 7.55–7.51 (2H, m, 2 × CH),
the mixture was cooled to room temperature and aqueous 7.47–7.44 (2H, m, 2 × CH), 7.41–7.39 (1H, m, CH), 7.35–7.31
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(1H, m, CH), 7.28–7.25 (1H, m, CH), 7.16 (1H, d, J 7.5, CH), (ES) Found: MH+, 352.1381. C17H22NO7 requires MH+,
4.98–4.95 (2H, m, 2 × CH), 3.93 (1H, dd, 7.5, 2.0 Hz, CH), 352.1396.
3.74–3.66 (1H, m, CH), 3.33–3.21 (2H, m, CH), 2.69–2.62 (1H,
m, CH); 13C NMR (101 MHz, CDCl3) δ = 174.7, 173.8, 133.9, (8aR*,
View Article Online
DOI: 10.1039/C6OB01871H
11bR*)-2,3-Dimethoxy-10-phenyl-
11aS*,
132.9, 131.4, 129.2, 128.9, 128.8, 127.3 (2 × CH), 127.2, 126.4, 5,8a,11a,11b-tetrahydropyrrolo[3’,4’:4,5][1,2]oxazolo[3,2-
75.7, 65.8, 56.8, 47.8, 22.9; HRMS (ES) Found MH+, a]isoquinoline-9,11(6H,10H)-dione 27
321.1232. C19H17N2O3 requires MH+, 321.1239.
Hydroxylamine hydrochloride (150 mg, 2.1 mmol) and N,N-
diisopropylethylamine (0.75 mL, 4.3 mmol) were added to
(8aR*,
tetrahydropyrrolo[3’,4’:4,5][1,2]oxazolo[3,2-a]isoquinoline- mixture was heated to 60 °C. After 2.5 h, N-phenylmaleimide
9,11(6H,10H)-dione 24 (370 mg, 2.1 mmol) was added and the mixture was heated
11aS*,
11bR*)-10-Methyl-5,8a,11a,11b- aldehyde 2514 (410 mg, 1.8 mmol) in PhMe (18 mL) and the
Hydroxylamine hydrochloride (120 mg, 1.73 mmol) and N,N- under reflux. After 1 h, the mixture was cooled to room
diisopropylethylamine (0.60 mL, 3.47 mmol) were added to temperature and the solvent was evaporated. Purification by
aldehyde 2114 (327 mg, 1.43 mmol) in PhMe (15 mL) and the column chromatography, eluting with CH2Cl2–MeOH
mixture was heated to 60 °C. N-Methylmaleimide (192 mg, (99.5:0.5), gave the cycloadduct 27 (500 mg, 74%) as an
1.73 mmol) was added and the mixture was heated under amorphous solid; m.p. 185–187 °C (decomposed); Rf 0.7
1
reflux. After 1 h, the mixture was allowed to cool to room [CH2Cl2–MeOH (98:2)]; νmax (film)/cm–1 2985, 1710, 1615; H
temperature and the solvent was evaporated. Purification by NMR (400 MHz, CDCl3) δ = 7.55–7.51 (2H, m, 2 × CH), 7.47–
column chromatography, eluting with CH2Cl2–MeOH 7.44 (1H, m, CH), 7.40–7.38 (2H, m, 2 × CH), 6.90 (1H, s,
(99.7:0.3), gave the product 24 (280 mg, 76%), which was CH), 6.63 (1H, s, CH), 5.03 (1H, d, J 7.5 Hz, CH), 4.90 (1H, br,
recrystallised from CH2Cl2-hexanes as needles; m.p. 162–164 CH), 3.93 (3H, s, CH3), 3.90 (3H, s, CH3), 3.91–3.89 (1H, m,
°C, lit.11 m.p. 164–166 °C; Rf 0.5 [CH2Cl2–MeOH (99.5:0.5)]; CH), 3.63–3.57 (1H, m, CH), 3.31–3.25 (1H, m, CH), 3.15–
νmax (film)/cm–1 2915, 2825, 1700; 1H NMR (400MHz, CDCl3) 3.08 (1H, m, CH), 2.67–2.60 (1H, m, CH); 13C NMR (101
δ = 7.40 (1H, d, J 7.5, CH), 7.31 (1H, t, J 7.5, CH), 7.24 (1H, t, MHz, CDCl3) δ = 174.9, 173.5, 148.4, 148.3, 131.4, 129.3,
J 7.5, CH), 7.14 (1H, d, J 7.5, CH), 4.82–4.80 (2H, m, 2 × CH), 129.0, 126.4, 125.8, 124.3, 111.0, 109.6, 76.0, 65.9, 56.5, 56.2,
3.76 (1H, dd, J 7.5, 2.0 Hz, CH), 3.76–3.66 (1H, m, CH), 3.26– 56.0, 48.0, 23.4; HRMS (ES) Found: MH+, 381.1447.
3.20 (2H, m, 2 × CH), 3.12 (3H, s, CH3), 2.64–2.56 (1H, m, C21H21N2O5 requires MH+, 381.1450; Anal. Calcd for
CH); 13C NMR (100 MHz, CDCl3) δ = 175.6, 174.9, 133.8, C21H20N2O5: C, 66.3; H, 5.3; N, 7.4. Found: C, 66.6; H, 5.1; N,
132.9, 128.8, 127.3, 127.2, 127.1, 75.7, 65.2, 56.7, 47.7, 25.2, 7.4.
22.9; HRMS (ES) Found MH+, 259.1084. C14H15N2O3 requires Crystal data deposited at CCDC 1006041
MH+, 259.1083.
Unit Cell Parameters:
Crystal data deposited at CCDC 1006039
Unit Cell Parameters:
a 10.6709(10) b 7.6760(7) c 22.1886(18) P21/c
a 6.8159(2) b 26.7835(7) c 7.0628(2) P21/c
(8aR*,
11aS*,
11bR*)-2,3-Dimethoxy-10-methyl-
5,8a,11a,11b-tetrahydropyrrolo[3’,4’:4,5][1,2]oxazolo[3,2-
(1S*,2S*,10bR*)-1,2-Dimethyl
tetrahydro-1H-isoxazolo[3,2-a]isoquinoline-1,2-
dicarboxylate 26
8,9-Dimethoxy-2,5,6,10b- a]isoquinoline-9,11(6H,10H)-dione 28
Hydroxylamine hydrochloride (91 mg, 1.3 mmol) and N,N-
diisopropylethylamine (0.45 mL, 2.6 mmol) were added to
Hydroxylamine hydrochloride (56 mg, 0.81 mmol) and N,N- aldehyde 2514 (250 mg, 1.1 mmol) in PhMe (11 mL) and the
diisopropylethylamine (0.28 mL, 1.62 mmol) were added to mixture was heated to 60 °C. After 2.5 h, N-methylmaleimide
aldehyde 2514 (154 mg, 0.67 mmol) in PhMe (7 mL) and the (150 mg, 1.3 mmol) was added and the mixture was heated
mixture was heated to 60 °C. After 2.5 h, dimethyl fumarate under reflux. After 1 h, the mixture was cooled to room
(126 mg, 0.88 mmol) was added and the mixture was heated temperature and the solvent was evaporated. Purification by
under reflux. After 1 h, the mixture was cooled to room column chromatography, eluting with CH2Cl2–MeOH
temperature and the solvent was evaporated. Purification by (99.5:0.5), gave the cycloadduct 28 (280 mg, 81%) as an
column chromatography, eluting with CH2Cl2–MeOH amorphous solid; m.p. 154–156 °C (decomposed); Rf 0.7
1
(99.5:0.5), gave the cycloadduct 26 (182 mg, 78%) as an [CH2Cl2–MeOH (98:2)]; νmax (film)/cm–1 2940, 1700, 1610; H
amorphous solid; m.p. 96–99 °C; Rf 0.5 [CH2Cl2–MeOH NMR (400 MHz, CDCl3) δ = 6.84 (1H, s, CH), 6.60 (1H, s,
(98:2)]; νmax (film)/cm–1 2940, 1730, 1610; 1H NMR (400 MHz, CH), 4.86 (1H, d, J 7.5 Hz, CH), 4.75 (1H, br, CH), 3.93 (3H, s,
CDCl3) δ = 6.61 (1H, s, CH), 6.58 (1H, s, CH), 4.96 (1H, d, J CH3), 3.89 (3H, s, CH3), 3.73 (1H, dd, J 7.5, 2.5 Hz, CH),
7.5 Hz, CH), 4.80 (1H, d, J 8.5 Hz, CH), 3.87 (6H, s, 2 × CH3), 3.60–3.57 (1H, m, CH), 3.24–3.17 (1H, m, CH), 3.12 (3H, s,
3.84 (3H, s, CH3), 3.78 (3H, s, CH3), 3.78–3.74 (1H, m, CH), CH3), 3.13–3.06 (1H, m, CH), 2.58–2.52 (1H, m, CH); 13C
3.40–3.37 (1H, m, CH), 3.17–3.13 (1H, m, CH), 3.01–2.94 (1H, NMR (101 MHz, CDCl3) δ = 175.7, 174.7, 148.3, 148.2, 125.8,
m, CH), 2.85–2.80 (1H, m, CH); 13C NMR (101 MHz, CDCl3) 124.3, 111.0, 109.5, 75.8, 65.2, 56.2, 55.9, 55.5, 47.9, 25.2,
δ = 171.7, 171.2, 148.5, 147.7, 125.5, 124.0, 110.8, 109.7, 80.9, 23.0; HRMS (ES) Found: MH+, 319.1308. C16H19N2O5 requires
67.2, 57.6, 55.9 (2 × CH3), 52.8 (2 × CH3), 49.9, 27.7; HRMS MH+, 319.1294.
8 | Org. Biomol. Chem., 2016, 00, 1-3
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Organic & Biomolecular Chemistry
Organic & Biomolecular Chemistry
ARTICLE
Crystal data deposited at CCDC 1006042
Unit Cell Parameters:
a 9.8243(10) b 8.6128(8) c 17.8328(18) P21/c
Notes and references
Department of Chemistry, University of Sheffield, BrookVHiewillA,rtSichleefOfinelilnde,
DOI: 10.1039/C6OB01871H
S3 7HF, UK. E-mail: i.coldham@sheffield.ac.uk
(1S*,2S*,10bR*)-Methyl
2-Hydroxy-3-oxo-1,2,3,4,5,10b-
Electronic supplementary information (ESI) available.
hexahydropyrrolo[2,1-a]isoquinoline-1-carboxylate 29
Zinc powder (56 mg, 0.85 mmol) was added to cycloadduct 22
(59 mg, 0.20 mmol) in AcOH/H2O (1.5 mL, 1:2). The mixture
was heated to 70 °C for 1.5 h before being cooled to room
temperature. The zinc salts were filtered, washed with CH2Cl2
(8 mL) and the solvent was evaporated. The solute was
partitioned between aqueous ammonia (4 mL, 18 M) and
CH2Cl2 (8 mL), and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The organic fractions were dried
(MgSO4), filtered and evaporated to give the lactam 29 (39 mg,
75%) as needles; m.p. 181–184 °C, lit.15 m.p. 190–192 °C; Rf
0.4 [CH2Cl2–MeOH (95:5)]; νmax (film)/cm–1 3250, 2950, 1730,
1
2
3
(a) R. Grashey, R. Huisgen and H. Leitermann, Tetrahedron Lett.,
1960, 1, 9. (b) N. A. LeBel, M. E. Post, J. J. Whang, J. Am. Chem.
Soc. 1964, 86, 3759.
For some reviews on nitrone cycloadditions, see (a) J. Revuelta, S.
Cicchi, A. Goti and A. Brandi, Synthesis, 2007, 485. (b) A. J. M.
Burrell and I. Coldham, Curr. Org. Synth., 2010, 7, 312.
(a) R.Grigg, J. Markandu, S. Surendrakumar, M. Thornton-Pett, and
W. J. Warnock, Tetrahedron, 1992, 48, 10399. (b) E. C. Davison, M.
E. Fow, A. B. Holmes, S. D. Roughley, C. J. Smith, G. M. Williams,
J. E. Davies, P. R. Raithby, J. P. Adams, I. T. Forbes, N. J. Press and
M. J. Thompson, J. Chem. Soc., Perkins Trans. 1, 2002, 1494. (c) R.
A. Stockman, A. Sinclair, L. G. Arini, P. Szeto and D. L. Hughes, J.
Org. Chem., 2004, 69, 1598. (d) M. S. Wilson and A. Padwa, J. Org.
Chem., 2008, 73, 9601. (e) A. C. Flick, M. J. A. Caballero and A.
Padwa, Tetrahedron, 2010, 66, 3643.
1
1680; H NMR (400 MHz, CDCl3) δ = 7.27–7.15 (4H, m, 4 ×
CH), 5.66 (1H, br, OH), 5.48 (1H, d, J 8.0 Hz, CH), 4.61 (1H,
d, J 7.5, CH), 4.26 (1H, ddd, J 13.0, 6.0, 3.0, CH), 3.90 (3H, s,
CH3), 3.25–3.18 (2H, m, 2 × CH), 3.00–2.92 (1H, m, CH),
2.87–2.81 (1H, m, CH); 13C NMR (100 MHz, CDCl3) δ =
170.8, 170.1, 135.6, 133.4, 129.2, 127.4, 127.2, 125.2, 71.5,
56.5, 52.6, 52.1, 37.4, 28.5; HRMS (ES) Found MH+,
262.1075. C14H16NO4 requires MH+, 262.1079.
4
(a) I. Coldham, A. J. M. Burrell, L. E. White, H. Adams and N.
Oram, Angew. Chem. Int. Ed., 2007, 46, 6159. (b) A. J. M. Burrell, I.
Coldham, L. Watson, N. Oram, C. D. Pilgram and N. G. Martin, J.
Org. Chem., 2009, 74, 2290. (c) A. J. M. Burrell, I. Coldham and N.
Oram, Org. Lett., 2009, 11, 1515. (d) A. J. M. Burrell, L. Watson, N.
G. Martin, N. Oram and I. Coldham, Org. Biomol. Chem., 2010, 8,
4530. (e) I. Coldham, A. J. M. Burrell, H. D. S. Guerrand and N.
Oram, Org. Lett., 2011, 13, 1267. (f) I. Coldham, L. Watson, H.
Adams and N. G. Martin, J. Org. Chem., 2011, 76, 2360. (g) I.
Coldham, A. J. M. Burrell, L. Watson, N. Oram and N. G. Martin,
Heterocycles, 2012, 84, 597.
(1S*,2S*,10bR*)-Methyl 2-Hydroxy-8,9-dimethoxy-3-oxo-
1,2,3,4,5,10b-hexahydropyrrolo[2,1-a]isoquinoline-1-
carboxylate 30
Zinc powder (145 mg, 2.2 mmol) was added to cycloadduct 26
(185 mg, 0.53 mmol) in AcOH/H2O (5 mL, 1:2) and the
mixture was heated to 70 °C. After 1.5 h, the zinc salts were
filtered, washing the filtrate with CH2Cl2 (15 mL) and the
solvent was evaporated. The solute was partitioned between
aqueous ammonia (5 mL) and CH2Cl2 (10 mL), and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The
organic fractions were dried (MgSO4), filtered and evaporated.
The residue was recrystallized with hot MeOH to give the
lactam 30 (81 mg, 47%) as an amorphous solid; m.p. 190–192
°C; Rf 0.29 [CH2Cl2–MeOH (97:3)]; νmax (film)/cm–1 3300,
5
For recent examples of cascade nitrone formation by cyclization then
intramolecular cycloaddition, see (a) X. Peng, B. M. K. Tong, H.
Hirao and S. Chiba, Angew. Chem. Int. Ed., 2014, 53, 1959. (b) C. V.
Suneel Kumar and C. V. Ramana, Org. Lett., 2014, 16, 4766.
(a) I. Coldham, S. Jana, L. Watson and C. D. Pilgram, Tetrahedron
Lett., 2008, 49, 5408. (b) I. Coldham, S. Jana, L. Watson and N. G.
Martin, Org. Biomol. Chem., 2009, 7, 1674.
6
7
For a related cascade nitrone formation by cyclization then
1
2990, 1730, 1665; H NMR (400 MHz, DMSO-d6) δ = 6.76
intermolecular cycloaddition, see A. Siriwardena, D. P. Sonawane, O.
P. Bande, P. R. Markad, S. Yonekawa, M. B. Tropak, S. Ghosh, B.
A. Chopade, D. J. Mahuran and D. D. Dhavale, J. Org. Chem., 2014,
79, 4398.
(1H, s, CH), 6.66 (1H, s, CH), 6.30 (1H, d, J 6.0 Hz, OH), 5.12
(1H, d, J 8.0 Hz, CH), 4.26 (1H, dd, J 7.0, 6.0 Hz, CH), 4.06–
4.00 (1H, m, CH), 3.75 (3H, s, CH3), 3.72 (3H, s, CH3), 3.66
(3H, s, CH3), 3.17 (1H, dd, J 8.0, 7.0 Hz, CH), 3.07–2.98 (1H,
m, CH), 2.70–2.68 (2H, m, 2 × CH); 13C NMR (101 MHz,
DMSO-d6) δ = 171.0, 169.9, 148.2, 148.1, 128.2, 126.4, 112.8,
108.7, 71.5, 55.95, 55.9, 55.5, 53.0, 52.4, 36.9, 28.1; HRMS
(ES) Found: MH+, 322.1301. C16H20NO6 requires MH+,
8
For an alternative method, see N. C. Deno, K. A. Eisenhardt, D. G.
Pohl, H. J. Spinnelli and R. C. White, J. Org. Chem., 1974, 39, 520.
(a) T. Shono, Y. Matsumura and K. Inoue, J. Org. Chem., 1986, 51,
549. (b) S. A. Ali and M. I. M. Wazeer, J. Chem. Soc., Perkins Trans.
1, 1988, 597.
9
322.1291; Anal. Calcd for C16H19NO6: C, 59.8; H, 6.0; N, 4.4. 10 (a) J. J. Tufariello and J. P. Tette, J. Org. Chem., 1975, 40, 3866. (b)
Found: C, 60.1; H, 5.8; N, 4.3.
G. Pandey, G. Kumaraswamy, A. Krishna, Tetrahedron Lett., 1987,
28, 2649. (c) S. A. Ali, J. H. Khan, M. I. M. Wazeer and H. P.
Perzanowski, Tetrahedron, 1989, 45, 5979.
Acknowledgements
We acknowledge support from the University of Sheffield, the
EPSRC, and the Thai Government. We are grateful to
Alexandra Kirchner for related studies.
11 M. Burdisso, A. Gamba, R. Gandolfi and P. Pevarello, Tetrahedron,
1987, 43, 1835.
12 S. E. Denmark and A. R. Hurd, J. Org. Chem., 1998, 63, 3045.
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13 For other syntheses of macronecine and petasinecine, see (a) A. J.
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View Article Online
DOI: 10.1039/C6OB01871H
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16 K. M. Laemmerhold and B. Breit, Angew. Chem. Int. Ed., 2010, 49,
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