Cascade and RCM syntheses of chiral tricyclic alkaloids from (S)-1,2,3,4-tetrahydro isoquinoline carboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2009.04.003

Concise syntheses of novel chiral pyrroloazacyclo and chiral tricyclic isoquinoline alkaloids, starting from the readily available (S)-1,2,3,4-tetrahydroisoquinoline carboxylic acid methyl ester, by utilizing cascade spiro-to fused and RCM protocols, are

Full text of DOI:10.1016/j.tetasy.2009.04.003

Tetrahedron: Asymmetry 20 (2009) 1154–1159
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cascade and RCM syntheses of chiral tricyclic alkaloids from (S)-1,2,3,4-tetra-
hydro isoquinoline carboxylic acid
*
Daniele Muroni, Mauro Mucedda, Antonio Saba
Dipartimento di Chimica, Facoltà di Scienze, Università di Sassari, Via Vienna 2, 07100 Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise syntheses of novel chiral pyrroloazacyclo and chiral tricyclic isoquinoline alkaloids, starting from
the readily available (S)-1,2,3,4-tetrahydroisoquinoline carboxylic acid methyl ester, by utilizing cascade
spiro-to fused and RCM protocols, are reported.
Received 24 February 2009
Accepted 17 April 2009
Available online 11 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
benzoazepinone 6. In previous studies, in which both possibilities
were available, the benzylic shift has been observed,9 while exclu-
Chiral pyrroloazacylo and chiral tricyclic isoquinoline alkaloids
have been the subject of intense investigation, due to their impor-
tant biological and therapeutic properties.1 Recently, we have car-
ried out concise and highly stereoselective syntheses of azabicyclic
and tricyclic alkaloids, by using cascade cyclization processes2 or
ring-closing metathesis (RCM),3 starting from simple and conve-
nient starting materials.
In connection with our previous work, we herein report the syn-
theses of new medium-sized chiral azacyclic systems and chiral
tricyclic isoquinolines performed with the aforementioned proto-
cols, starting from the readily available (S)-1,2,3,4-tetrahydro iso-
quinoline carboxylic acid methyl ester 1.
sive [1,2]-shift of CH2CO2R has been also reported.10
2. Results and discussion
The diazocompound 2 was conveniently prepared in two-step
one-pot reaction by conjugate addition of 1 to ethyl 3-keto-pent-
4-enoate,11 followed by diazo-transfer reaction with tosyl azide.
The Cu(acac)2-catalyzed decomposition of 2 has been per-
formed in refluxing xylene, affording a 2:2:1 mixture of benzoaz-
epinones 4, 5, and 6. No traces of the intermediate ylide 3 have
been observed, its isolation or spectroscopic detection being
unsuccessful.
The cascade process is a powerful strategy for building complex
molecules from relatively simple reagents, due to a combination of
two or more distinct reactions into a single transformation.4 Partic-
ularly, the formation of ammonium ylides generated by metallo
carbenoids and their spontaneous Stevens [1,2]-shift5 or [2,3]-sig-
matropic rearrangement6 has been shown to give very rapid access
to nitrogen heterocycles with high stereoselectivity.
By reduction with NaBH4, compound 4 afforded the tetracyclic
lactone 7 (Fig. 1) in mixture with partial and total reduction prod-
ucts. Then, by submitting alkaloid 5 to the same reaction, no lact-
onization product has been obtained: this result allowed the trans
and cis configuration to be assigned to benzazepinones 4 and 5,
respectively.
The diazoketoester 2, bearing a diazo function at the appropri-
ate position on the ester chain tethered to the tetrahydroisoquino-
line nitrogen atom, has been selected as an appropriate carbenoid
cyclization precursor (Scheme 1). Initiation of the cascade process
is based upon diazo catalytic decomposition. As the nitrogen is part
of a pre-existing ring system, an intramolecular carbenoid attack to
this heteroatom is expected to furnish the transient spirocyclic
ammonium ylide 3.7 Due to the presence of two possible migratory
groups on the nitrogen atom, this intermediate could reasonably
undergo two different [1,2]-shifts.8 Migration of the ester-substi-
tuted carbon atom would lead to pyrrolobenzoazepinones 4 and
5, while migration of the benzylic carbon would give the pyrrolo-
N
O
OH
O
7
Figure 1.
Given the stereoselectivity in the nitrogen quaternarization
step,12 the high stereoselectivity of overall process needs high ste-
reoselectivity in the final Stevens [1,2]-shift. The enantioselectivity
of the latter step involves intramolecular transfer of chirality from
the quaternary asymmetric nitrogen to the adjacent C-position,
namely from the ylide spirocycle axis to the newly formed sp3
* Corresponding author. Tel.: +39 79 229538; fax: +39 79 229559.
E-mail address: saba@uniss.it (A. Saba).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.04.003

D. Muroni et al. / Tetrahedron: Asymmetry 20 (2009) 1154–1159
1155
O
N2
H
1)
CH2=CHCOCH2CO2Et
N
N
cat.
CO2Et
2) TsN3, Et3N
CO2Me
CO2Me
1
2
N
N
O
CO2Et
O
CO2Et
EtO2C
O
_
CO2Me
CO2Me
+
N
5
[1,2]-shif t
4
O
N
CO2Me
EtO2C
3
CO2Me
6
Scheme 1.
stereogenic center. A transfer of chirality in the [1,2]-Stevens shift
could occur, despite the fact that the diradical character is usually
accepted for the reaction mechanism.13
olefination of the latter via standard Wittig conditions to acquire
the requisite vinyl appendage. Diazoalkene 9 has been prepared
by deprotection of amine 8, conjugate addition of the latter to
ethyl 3-keto-pent-4-enoate followed by a diazo-transfer to the
activated methylene with tosyl azide in one pot and in 51% over-
all yield. Catalytic decomposition of 9 was then performed under
the same conditions adopted for the diazo compound 2 to afford
the pyrrolo benzoazacyclononenone 11 as the only product. This
is the result of a cascade involving the cyclization of a Cu(a-
cac)2-generated metallo carbenoid species to spiricyclic ammo-
nium ylide 10 followed by [2,3]-sigmatropic rearrangement of
the latter through the pendant vinyl group. The overall process
resulted in a three carbon expansion of the starting amine ring
moiety.
The enantiomeric excesses for compounds 4 and 5 (52% and 40%,
respectively) were measured by using the chiral reagent Eu(hfc)3,
and by comparing the shift separations observed in the 1H NMR
spectra to those of the benzazepinones obtained submitting the
racemic diazocompound 2 to the same treatment. Current efforts
are directed to optimizing the synthetic approach to larger cyclic
aminoacids that could prove useful in peptide mimic design.14
The cascade strategy based on [2,3]-sigmatropic rearrangement
of a spirocyclic ammonium ylide has been then adopted for the
synthesis of an optically active nine-membered azacycle,15 even
starting from the ester 1. For this purpose, the preparation of dia-
zoketoester 9 from tetrahydroisoquinoline 8, with the requisite vi-
nyl appendage, has been planned (Scheme 2).
This rearrangement regiospecificity is noticeable, due to the
migratory aptitude of both the carbon atoms situated at the
a-
Therefore compound 8 has been prepared from 1 following a
literature route16 involving N-BOC protection; reduction of the es-
ter function to an alcohol; Swern oxidation to an aldehyde and
and a0-position relative to the spirocyclic ammonium group, as-
sisted by the presence of stabilizing allylic and benzylic functions,
respectively. A Stevens [1,2]-shift with a one carbon ring expansion
O
1)
2)
CF3CO2H
BOC
N2
N
CH2=CHCOCH2CO2Et
N
catalyst
CO2Et
3) TsN3, Et3N
8
9
O
EtO2C
[1,2]-shift
N
A
x
EtO2C
O
_
N
+
N
O
[2,3]-rearrangement
CO2Et
11
10
x
[1,2]-shift
N
O
CO2Et
B
Scheme 2.

1156
D. Muroni et al. / Tetrahedron: Asymmetry 20 (2009) 1154–1159
to afford the pyrrolobenzazepines A and B as the secondary prod-
ucts, would not be avoided in principle.
As in the case of 3, the intermediate ylide 10 has never been ob-
served or detected. Olefin cis geometry has been assigned to 11 on
the basis of spectroscopic data.17
deoxygenation and catalytic dihydroxylation of azacycloisoquin-
olinones, new enantiopure epimers benzoanalogs of lentiginosine,
a glycosidase inhibitor, could be concisely and conveniently pre-
pared. Biological evaluations and structure-activity relationship
will be reported in due course.
Asymmetric variants of ammonium ylides [2,3]-sigmatropic
rearrangement have relied on intramolecular chirality transfer.18
We have found that azacyclononene 11 displays highly efficient
transfer of chirality.19
4. Experimental
4.1. General
Chiral polycyclic systems, which possess the 1,2,3,4-tetrahydro
isoquinoline moiety, are useful in medicinal chemistry for their
interesting pharmacological activities.20 With the aim of preparing
tricyclic 1,2,3,4-tetrahydro isoquinoline alkaloids starting from 1,
we herein report the syntheses of compounds 13a–c by ring-clos-
ing metathesis of dienes 12a–c easily obtained from (S)-3-ethenyl-
isoquinoline 8.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were re-
corded on a Varian VXR-300 spectrometer with TMS as internal
standard. Infrared (IR) spectra were performed on a FT/IR-480plus
JASKO spectrophotometer. The optical rotations were measured by
a polarimeter P-1010 JASCO in a 1 dm tube. All reagents and sol-
vents employed were reagent grade materials purified by standard
methods and redistilled before use.
Thus, deprotection of 8 followed by acylation with acryloyl,
x-
butenoyl, and -pentenoyl chlorides, in the presence of triethyl-
x
amine or pyridine, allowed the preparation of the requisite chiral
dienes 12a–c in good overall yields.
4.1.1. (S)-Methyl 2-(4-diazo-5-ethoxy-3,5-dioxopentyl)-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate 2
It is well documented that Grubb’s RCM catalytic protocol may
fail in metathesizing compounds containing amino groups, whose
nitrogen lone pair may coordinate the metal center, poisoning and
deactivating the ruthenium catalyst.21 Notwithstanding the
increasing number of examples of successful metathesized amine
compounds are reported,22 N-acyl alkenyl- in the place of N-alke-
nyl-derivatives was selected, in order to prevent this inconve-
nience. After examining several catalysts and solvents, Grubb’s
second generation (Grubb’s II) and ClCH2CH2Cl were chosen, and
these gave better efficiency. The catalytic intramolecular cycliza-
tions, performed in refluxing ClCH2CH2Cl solutions, in the presence
of Grubb’s II catalyst (5 mol %) afforded the chiral target alkaloids
13a, 13b, and 13c as the sole products in good yields. The enantio-
mer of compound 13a has recently been prepared as a precursor of
A solution of (S)-1,2,3,4-tetrahydroisoquinolinecarboxylic acid
methyl ester hydrochloride 1 (1.50 g, 6.60 mmol), 3-oxo-pent-4-
enoic acid ethyl ester (1.22 g, 8.58 mmol), and Et3N (1.02 mL,
7.20 mmol) in CH2Cl2 (30 mL) was stirred at rt for 2 h. Tosyl azide
(1.69 g, 8.58 mmol) and Et3N (1.85 mL, 13.2 mmol) were then
added at 0 °C. After completion of the addition, the solution was
stirred at rt for 6 h. The solvent was evaporated and the residue
gave, after flash chromatography on silica gel (light petroleum
ether/ethyl acetate 8:2), the diazo compound 2, (1.395 g, 59%), yel-
low oil, ½a 2D5
ꢀ
¼ þ5:8 (c 0.65, CHCl3). 1H NMR (CDCl3): d 1.31 (t, 3H,
J = 7.2 Hz), 3.05–3.19 (m, 6H), 3.65 (s, 3H), 3.86 (t, 1H, J = 5.1 Hz),
3.91 (AB system, 1H), 4.07 (AB system, 1H), 2.28 (q, 2H,
J = 7.2 Hz), 7.01–7.13 (m, 4H). 13C NMR (CDCl3): d 14.2, 31.1,
38.4, 49.9, 50.8, 51.3, 59.6, 61.2, 76.1, 125.8, 125.9, 126.3, 128.3,
131.9, 133.8, 161.2, 172.8, 191.5. IR (neat): 2982, 2951, 2134,
1715, 1652, 1455, 1372, 1299, 1197, 1172, 1127, 1100, 1071,
1015, 744 cmꢁ1. Anal. Calcd for C18H21N3O5: C, 60.16; H, 5.89; N,
11.69. Found: C, 60.08; H, 5.91; N, 11.73.
new benzoanalogs of lentiginosine starting from
(Scheme 3).
L
-glutamic acid23
3. Conclusions
Successful RCM and cascade spiro-to fused protocols allow
ready access to a variety of nitrogen heterocyclic systems that
are widespread in Nature. Novel optically active tricyclic azacyclo-
isoquinolinones in a two-step one-pot reaction and chiral pyrrolo
benzoazacyclononenone alkaloids in a three-step two-pot reaction,
starting from the readily available (S)-1,2,3,4-tetrahydro isoquino-
line carboxylic acid, have been prepared by utilizing these
procedures.
Moreover, the cascade ylide formation/[2,3]-sigmatropic rear-
rangement can function as an expedient route to medium-sized
nitrogen containing cyclic natural products. It should be noted that
an efficient transfer of chirality based on a pool route has been
accomplished in this rearrangement.
4.1.2. Diazo-decomposition of 2
A solution of the diazoketoester 2 (0.693 g, 1.93 mmol) in 20 ml
anhydrous xylene was added dropwise to a solution of Cu(acac)2
(0.022 g, 5 mol %) in dry xylene (40 mL) over 30 min. After stirring
for other 40 min at reflux, the solvent was evaporated and the res-
idue gave, after silica gel column chromatography (light petroleum
ether/ethyl acetate 9.5:0.5), the (9R,9aS)-9a-ethyl-9-methyl-1-
oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]benzo[c]azepine-9, 9a-
dicarboxylate 4, (0.182 g, 28%) as white crystals mp 117–119 °C,
½
a 2D5
ꢀ
¼ ꢁ103:5 (c 0.39, CHCl3). 1H NMR (CDCl3): d 1.27 (t, 3H,
J = 7.2 Hz), 2.50–2.60 (m, 1H), 2.75–2.86 (m, 1H), 3.25–3.27 (m,
2H), 3.43 (dd, 2H, J = 7.8, 4.5 Hz), 3.49 (s, 3H), 3.81 (AB system,
1H), 4.03 (dd, 1H, J = 5.7, 1.8 Hz), 4.21 (q, 2H, J = 7.2 Hz), 4.30 (AB
system, 1H), 7.12 (s, 4H). 13C NMR (CDCl3): d 14.1, 33.7, 36.9,
47.6, 48.5, 51.5, 54.1, 61.9, 76.1, 126.6, 127.1, 128.2, 130.4, 137.0,
139.1, 169.6, 171.9, 210.5. IR (CHCl3): 2953, 2929, 1759, 1730,
In addition, amino esters, conformationally constrained analogs
to aspartic acid,24 and other aminoacids,25 can be envisioned in
azepinone and azacyclononenone frames, respectively. Finally, by
O
O
1) CF3CO2H
2)
CH2=CH(CH2)
n
COCl
( )n
RCM
( )n
N
N
H
8
12a-c
13a-c
12a, 13a, n = 0; 12b, 13b, n = 1; 12c, 13c, n = 2
Scheme 3.

D. Muroni et al. / Tetrahedron: Asymmetry 20 (2009) 1154–1159
1157
1448, 1437, 1384, 1354, 1259, 1211, 1177, 1132, 1101, 1021 cmꢁ1
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C,
65.08; H, 6.41; N, 4.21.
Further chromatographic elution (light petroleum ether/
ethyl acetate 9:1) afforded (9R,9aR)-9a-ethyl-9-methyl-1-oxo-
2,3,5, 8,9,9a-hexahydro-1H-pyrrolo[1,2-a]benzo[c]azepine-9,9a-
.
J = 16.5, 4.8 Hz), 3.04–3.18 (m, 3H), 3.40 (q, 1H, J = 5.1 Hz), 3.74
(AB system, 1H), 3.89 (AB system, 1H), 4.29 (q, 2H, J = 7.2), 5.17–
5.27 (m, 2H), 5.80–5.92 (m, 1H), 7.01–7.13 (m, 4H). 13C NMR
(CDCl3): d 14.2, 34.3, 37.5, 48.6, 52.5, 61.1, 61.2, 76.0, 117.0,
125.5, 126.0, 126.1, 128.4, 133.1, 133.9, 137.6, 161.1, 191.5. IR
(neat): 2980, 2925, 2134, 1717, 1654, 1447, 1372, 1299, 1213,
dicarbo- xylate 5 (0.185 g, 29%), colorless oil, ½a D25
ꢀ
¼ ꢁ33:4 (c
1121, 1067, 1015, 743 cmꢁ1
. Anal. Calcd for C18H21N3O3: C,
0.16, CHCl3). 1H NMR (CDCl3): d 1.29 (t, 3H, J = 7.2 Hz), 2.39–2.50
(m, 1H), 2.56–2.67 (m, 1H), 2.99 (AB system, 1H), 3.07–3.19 (m,
2H), 3.27 (q, 1H, J = 6.3 Hz), 3.63 (s, 3H), 3.73 (AB system, 1H),
3.76 (AB system, 1H), 4.27 (q, 2H, J = 7.2 Hz), 4.88 (AB system,
1H), 7.15 (s, 4H). 13C NMR (CDCl3): d 14.1, 34.1, 35.5, 46.9, 47.7,
51.9, 53.1, 61.3, 73.4, 126.7, 127.1, 128.3, 130.2, 137.7, 139.0,
167.4, 172.6, 206.9. IR (neat): 2981, 2951, 2856, 1752, 1738,
66.04; H, 6.47; N, 12.84. Found: C, 66.21; H, 6.51; N, 12.85.
4.1.5. Diazo-decomposition of 9
A solution of the diazoketoester 9 (0.157 g, 0.48 mmol) and
Cu(acac)2 (0.006 g, 5 mol%) in xylene (11 mL) was refluxed for
20 min. The solvent was evaporated and the residue gave, after
silica gel column chromatography (light petroleum ether/ethyl
acetate 8:2), the (R,Z)-ethyl-1-oxo-2.3.4,5,10,13,13a-heptahydro-
1H-pyrrolo-benzo[c]-azonine-13a-carboxylate 11 (0.10 g, 70%),
1438, 1366, 1319, 1272, 1235, 1183, 1129, 1103, 1018, 755 cmꢁ1
.
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C,
65.12; H, 6.45; N, 4.33.
Final chromatographic elution (light petroleum ether/ethyl ace-
tate 8:2) gave (S)-9a-ethyl-5-methyl-1-oxo-2,3,5,6,9,9a-hexahy-
as yellow crystals, mp 57–59 °C, ½a D25
ꢀ
¼ ꢁ6:4 (c 0.44, CHCl3). 1H
NMR (CDCl3): d 1.31 (t, 3H, J = 7.2 Hz), 1.73–1.81 (m, 1H), 2.42–
2.62 (m, 2H), 3.05–3.23 (m, 2H), 3.10 (AB system, 1H), 3.45–
3.55 (m, 2H), 3.71–3.79 (m, 1H), 4.12 (AB system, 1H), 4.14–
4.31 (m, 2H), 5.67 (dd, 2H, J = 8.1, 3.9 Hz), 7.07–7.25 (m, 4H).
13C NMR (CDCl3): d 14.4, 36.3, 41.0, 41.6, 47.8, 56.3, 61.3, 76.3,
125.7, 126.3, 127.8, 131.2, 132.7, 137.7, 137.8, 138.6, 169.4,
211.4. IR (neat): 2977, 2918, 2833, 1757, 1729, 1450, 1269,
1216, 1196, 1172, 1123, 1096, 1046, 1027, 982, 755 cmꢁ1. Anal.
Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 6.48. Found: C, 72.33;
H, 7.09; N, 6.46.
dro-1H-pyrrolo[1,2-a]benzo[c]azepine-5,9a-dicarboxylate
6
(0.091 g, 14%), colorless oil, ½a D25
ꢀ
¼ ꢁ5:7 (c 0.15, CHCl3). 1H NMR
(CDCl3): d 1.06 (t, 3H, J = 7.2 Hz), 2.41–2.63 (m, 2H), 2.95 (dd, 1H,
J = 14.7, 2.1), 3.13 (Ab system, 1H), 3.13–3.32 (m, 3H), 3.53 (Ab sys-
tem, 1H), 3.82 (s, 3H), 3.91 (q, 2H, J = 7.2 Hz), 4.36 (dd, 1H, J = 9.9,
1.8 Hz), 7.10–7.21 (m, 4H). 13C NMR (CDCl3): d 13.9, 34.1, 39.0,
40.0, 44.5, 52.2, 61.2, 61.3, 73.4, 126.9, 127.2, 129.4, 130.4, 135.8,
138.2, 167.1, 172.8, 206.2. IR (neat): 2951, 1762, 1728, 1438,
1273, 1234, 1183, 1129, 1017, 756 cmꢁ1
. Anal. Calcd for
C18H21NO5: C, 65.24; H, 6.39; N, 4.23. Found: C, 65.27; H, 6.29;
N, 4.20.
4.1.6. (S)-2-[1-Oxo-propenyl]-3-vinyl-3,4-dihydroisoquinolin-
2(1H)-yl 12a
A solution of 8 (0.4 g, 1.54 mmol) and CF3COOH (0.6 mL,
7.90 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at rt for
2.5 h, evaporated under reduced pressure and the residue was dis-
solved in anhydrous CH2Cl2 (5 mL). Triethyl amine (1.1 mL,
7.70 mmol) and acroleyl chloride (0.112 g, 2.31 mmol) were then
added under nitrogen at 0 °C. The reaction mixture was allowed
to warm at rt, stirred for 1 h, and washed with water (3 mL), dried
over Na2SO4, filtered, and the solvent was removed under reduced
pressure. Purification of the crude residue by flash chromatography
on silica gel (light petroleum ether/ethyl acetate 7:3), gave the iso-
4.1.3. (2aS,4aR,10bR)-10b-Hydroxymethyl-1,2,2a,4a,5,10,10b-
heptahydro-3-oxa-10a-aza-benzo [e]-cyclopenta-[cd]azulene-4-
one 7
NaBH4 (0.039 g, 1.03 mmol) was added to a solution of 4
(0.114 g, 0.34 mmol), in anhydrous MeOH (8 mL), and the resulting
mixture was stirred at rt under nitrogen for 2 h. The solvent was
evaporated under reduced pressure and the residue was purified
by chromatography on silica gel (light petroleum ether/ethyl ace-
tate 7:3), to afford the tetracyclic lactone 7 (0.057 g, 64%), white
crystals, mp 152–154 °C, ½a D25
ꢀ
¼ ꢁ35:4 (c 0.20, CHCl3). 1H NMR
quinolinone diene 12a (0.25 g, 78%) as a pale yellow oil,
(CDCl3): d 1.93–1.98 (m, 2H), 2.53 (q, 1H, J = 8.1 Hz), 2.67 (t, 1H,
J = 4.5 Hz), 2.89 (m, 2H), 3.15 (dd, 2H, J = 15, 3.9 Hz), 3.29 (dd,
2H, J = 15.0, 4.8 Hz), 3.52 (AB system, 1H), 3.77 (AB system, 1H),
3.82 (AB system, 1H), 4.37 (AB system, 1H), 4.74 (s, 1H), 7.11–
7.26 (m, 3H), 7.35 (d, 1H, J = 6.9 Hz). 13C NMR (CDCl3): d 29.9,
31.0, 42.5, 48.6, 49.7, 63.3, 70.8, 87.7, 126.9, 127.9, 128.9, 131.2,
136.3, 137.3, 175.3. IR (CHBr3): 3382, 2642, 1765, 1453, 1361,
1318, 1251, 1200, 1177, 1141, 1089, 1018, 754, 651 cmꢁ1. Anal.
Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.37;
H, 6.58; N, 5.42.
½
a 2D5
ꢀ
¼ þ56:4 (c 0.37, CHCl3). 1H NMR (CDCl3): d 2.89 (dd, 1H,
J = 15.6, 2.7 Hz), 3.08–3.20 (m, 1H), 4.54 (d, 1H, J = 17.7 Hz), 4.75–
5.17 (m, 3H), 5.07 (d, 1H, J = 9.6 Hz), 5.58–5.80 (m, 2H), 6.36 (dd,
1H, J = 16.8, 1.8 Hz), 6.59 (dd, 1H, J = 16.8, 1.8 Hz), 7.06–7.30 (m,
4H). 13C NMR (CDCl3): d 34.2, 43.0, 53.7, 116.5, 126.1, 126.5,
127.6, 127.9, 128.1, 132.1, 132.8, 135.4, 136.6, 166.4. IR (neat):
3422, 1646, 1610, 1427, 1286, 1240, 976, 925, 793, 747 cmꢁ1. Anal.
Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.75; H,
7.13; N, 6.50.
4.1.7. (S)-2-[1-Oxo-3-butenyl]-3-vinyl-3,4-dihydroisoquinolin-
2(1H)-yl 12b
4.1.4. (S)-Ethyl 2-diazo-3-oxo-5-[3-vinyl-3,4-
dihydroisoquinolin-2(1H)-yl] pentanoate 9
A solution of 8 (0.412 g, 1.59 mmol) and CF3COOH (0.61 mL,
7.90 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at rt for
2.5 h, evaporated under reduced pressure and the residue was dis-
solved in anhydrous CH2Cl2 (5 mL). Triethyl amine (1.1 mL,
7.70 mmol) and freshly prepared 3-butenoyl chloride (0.217 g,
2.34 mmol) were then added under nitrogen at 0 °C. The reaction
mixture was allowed to warm at rt, stirred for 15 h, washed with
water (3 mL), dried over Na2SO4, filtered and the solvent was re-
moved under reduced pressure. Purification of the crude residue
by flash chromatography on silica gel (light petroleum ether/ethyl
acetate 7:3), gave the isoquinolinone diene 12b (0.199 g, 55%) as a
A solution of 8 (0.514 g, 1.98 mmol) and CF3COOH (0.76 mL,
9.9 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at rt for 4 h,
evaporated under reduced pressure and the residue was dissolved
in CH2Cl2 (10 mL). Then Et3N (1.38 mL, 9.8 mmol) and 3-oxo-pent-
4-enoic acid ethyl ester (0.36 g, 2.57 mmol) were added and the
reaction mixture was stirred at rt for 16 h. Tosyl azide (0.51 g,
2.58 mmol) in CH2Cl2 (2 mL) was then added dropwise at 0 °C.
The resulting solution was stirred at rt for 4 h. The solvent was
evaporated and the residue gave, after flash chromatography on
silica gel (petroleum ether/ethyl acetate 8:2), the diazo compound
9, (0.33 g, 51%), yellow oil, ½a D25
ꢀ
¼ ꢁ21:8 (c 0.63, CHCl3). 1H NMR
pale yellow oil, ½a D25
ꢀ
¼ þ52:9 (c 0.46, CHCl3). 1H NMR (CDCl3): d
(CDCl3): d 1.32 (t, 3H, J = 7.2 Hz), 2.76–2.89 (m, 2H), 2.96 (dd, 1H,
2.87 (dd, 1H, J = 13.2, 2.4 Hz), 3.05–3.34 (m, 3H), 4.58 (AB system,

1158
D. Muroni et al. / Tetrahedron: Asymmetry 20 (2009) 1154–1159
1H), 4.61 (AB system, 1H), 4.74 (s,1H), 5.00–5.24 (m, 4H), 5.61–
5.74 (m, 1H), 5.94–6.10 (m, 1H), 7.03–7.24 (m, 4H). 13C NMR
(CDCl3): d 34.1, 38.8, 42.6, 53.6, 116.4, 117.5, 126.1, 126.5, 126.8,
128.1, 131.5, 131.8, 132.7, 136.3, 170.5. IR (neat): 3079, 3024,
2980, 1647, 1409, 1241, 992, 921, 745 cmꢁ1. Anal. Calcd for
C15H17NO: C, 79.26; H, 7.54; N, 6.16. Found: C, 79.15; H, 7.49; N,
6.18.
4.1.11. (S)-3,4,12,12a-Tetrahydro-7H-azepino[1,2-
b]isoquinolin-5-one 13c
A solution of diene 12c (0.106 g, 0.43 mmol) and Grubb’s II cat-
alyst (0.008 g, 2.2 mol %) in anhydrous CH2ClCH2Cl (8 mL) was re-
fluxed under argon for 14 min. After filtration on silica gel, the
solvent was removed under reduced pressure. Purification of the
crude residue by flash chromatography on silica gel (light petro-
leum ether/ethyl acetate 7:3), gave the azepinoisoquinolinone
4.1.8. (S)-2-[1-Oxo-4-pentenyl]-3-vinyl-3,4-
dihydroisoquinolin-2(1H)-yl 12c
13c (0.080 g, 86%) as a brown oil, ½a D25
¼ þ35:1 (c 0.47, CHCl3).
ꢀ
1H NMR (CDCl3): d 2.37–2.50 (m, 3H), 2.81 (dd, 1H, J = 15.0,
7.2 Hz), 3.04–3.16 (m, 2H), 4.58 (AB system, 1H), 4.72 (AB system,
1H), 4.80–4.86 (m, 1H), 5.44 (dd, 1H, J = 11.1, 2.7 Hz), 5.65 (dd, 1H,
J = 11.1, 2.4 Hz), 7.20–7.27 (m, 4H). 13C NMR (CDCl3): d 25.1, 33.8,
35.6, 42.7, 49.9, 126.1, 126.9, 127.0, 127.3 130.7, 131.4, 134.8,
135.7, 173.5. IR (neat): 3020, 2896, 2841, 1640, 1453, 1433,
1415, 1235, 1200, 1158, 763, 747, 729, 607 cmꢁ1. Anal. Calcd for
C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found: C, 78.72; H, 7.10; N,
6.60.
A solution of 8 (0.510 g, 1.97 mmol) and CF3COOH (0.75 mL,
9.80 mmol) in anhydrous CH2Cl2 (5 mL) was stirred at rt for
2.5 h, evaporated under reduced pressure and the residue was dis-
solved in anhydrous CH2Cl2 (15 mL). Pyridine (0.68 mL,
8.40 mmol), DMAP (0.024 g, 0.19 mmol), and 4-pentenoyl chloride
(0.310 g, 2.95 mmol) were then added under nitrogen at 0 °C. The
reaction mixture was allowed to warm at rt, stirred for 2 h, and
washed with water (5 mL), dried over Na2SO4, filtered and the sol-
vent was removed under reduced pressure. Purification of the
crude residue by flash chromatography on silica gel (light petro-
leum ether/ethyl acetate 7:3), gave the isoquinolinone diene 12c
Acknowledgment
(0.350 g, 75%) as a pale yellow oil, ½a D25
¼ þ44:6 (c 0.70, CHCl3).
ꢀ
The authors are thankful to the Fondazione Banco di Sardegna
for financial support.
1H NMR (CDCl3): d 2.35–2.57 (m, 4H), 2.84–2.87 (m, 1H), 3.09
(ddd, 1H, J = 15.6, 9.6, 5.4 Hz), 4.38–5.08 (m, 7H), 5.55–5.69 (m,
1H), 5.81–5.94 (m, 1H), 7.02–7.20 (m, 4H). 13C NMR (CDCl3): d
28.9, 32.5, 34.1, 42.5, 53.3, 114.9, 116.2, 126.0, 126.4, 126.7,
127.9, 131.8, 132.8, 136.3, 137.2, 171.8. IR (neat): 2978, 2922,
2850, 1645, 1420, 1304, 1205, 993, 917, 747 cmꢁ1. Anal. Calcd for
C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.51; H, 7.90; N,
5.81.
References
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4.1.9. (S)-10,10a-Dihydro-5H-pyrrolo[1,2-b]isoquinolin-3-one
13a
A solution of diene 12a (0.166 g, 0.77 mmol) and Grubb’s II cat-
alyst (0.014 g, 2.2 mol %) in anhydrous CH2ClCH2Cl (12 mL) was re-
fluxed under argon for 2 h. After filtration on silica gel, the solvent
was removed under reduced pressure. Purification of the crude res-
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ethyl acetate 1:1), gave the pyrroloisoquinolinone 13a (0.131 g,
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8. For some examples of spiro-to-fused ammonium ylides strategy: (a) Curtis,
E. A.; Padwa, A.; Worsencroft, K. J. Tetrahedron Lett. 1997, 38, 3319; (b)
Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheean, S. M. J. Org. Chem.
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Padwa, A.; Snyder, J. P.; Curtis, E. A.; Sheean, S. M.; Worsencroft, K. J.;
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G. Org. Lett. 2002, 4, 2813.
91%) as a colorless oil, ½a D25
ꢀ
¼ ꢁ116 (c 0.13, CHCl3). 1H NMR
(CDCl3): d 2.56 (dd, 1H, J = 15.0, 2.7 Hz), 3.15 (dd, 1H, J = 15.6,
4.2 Hz), 4.22 (dd, 1H, J = 12.0, 3.9 Hz), 4.42 (AB system, 1H), 5.12
(AB system, 1H), 6.30 (dd, 1H, J = 5.7, 1.5 Hz), 7.16–7.30 (m, 5H).
13C NMR (CDCl3): d 33.5, 41.7, 58.2, 126.8, 126.9, 127.0, 128.3,
129.0, 131.6, 131.7, 147.1, 169.8. IR (neat): 3446, 2853, 1680,
1580, 1495, 1453, 1422, 1266, 809, 752 cmꢁ1. Anal. Calcd for
C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.71; H, 5.95; N,
7.54.
9. West, F. G.; Glaeske, K. W.; Naidu, B. N. Synthesis 1993, 977.
10. Vanecko, J. A.; West, F. G. Org. Lett. 2005, 7, 2949.
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4.1.10. (S)-11,11a,3-Trihydro-6H-pyridino[1,2-b]isoquinolin-4-
one 13b
12. Glaeske, K. W.; West, F. G. Org. Lett. 1999, 1, 31.
A solution of diene 12b (0.169 g, 0.74 mmol) and Grubb’s II
catalyst (0.014 g, 2.2 mol %) in anhydrous CH2ClCH2Cl (12 mL)
was refluxed under argon for 1 h. After filtration on silica gel,
the solvent was removed under reduced pressure. Purification
of the crude residue by flash chromatography on silica gel (light
petroleum ether/ethyl acetate 7:3), gave the pyridinoisoquinoli-
13. Goncalves-Farbos, M-H.; Vial, L.; Lacour, J. Chem. Commun 2008, 829. and
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17. Olefin geometry assigned on the base of selected spectroscopic data for the cis
azacyclononene 11: (1H 300 MHz, CDCl3): d = 5.67, J = 8.1, 3.9 Hz (–HC@CH
from selective decoupling).
18. (a) Blid, J.; Pankin, O.; Somfai, P. J. Am. Chem. Soc. 2005, 127, 9352; (b)
Kaiser, G. W.; Ashbrook, C. W.; Baldwin, J. E. J. Am. Chem. Soc. 1971, 93,
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none 13b (0.140 g, 95%) as a pale yellow oil, ½a D25
¼ ꢁ124:6 (c
ꢀ
0.53, CHCl3). 1H NMR (CDCl3): d 2.74–2.85 (m, 1H), 2.95 (dd,
1H, J = 15.9, 3.6 Hz), 3.04 (d, 2H, J = 4.5 Hz), 4.17–4.23 (m, 1H),
4.20 (AB system, 1H), 5.57 (AB system, 1H), 5.82 (s, 2H), 7.06–
7.25 (m, 4H). 13C NMR (CDCl3): d 31.7, 37.1, 43.9, 54.6, 121.7,
124.6, 126.2, 126.3, 126.6, 128.3, 132.4, 132.9, 166.2. IR (neat):
3460, 2892, 1640, 1466, 1447, 1407, 1329, 1250, 755, 729,
695 cmꢁ1. Anal. Calcd for C13H13NO: C, 78.36; H, 6.58; N, 7.03.
Found: C, 77.99; H, 6.62; N, 7.01.

D. Muroni et al. / Tetrahedron: Asymmetry 20 (2009) 1154–1159
1159
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