RCM approach to complex polycyclic α-hydroxy γ-lactams: Synthesis of indolizinones and pyrroloazepinones

Article abstract of DOI:10.1002/ejoc.201300889

The allylmagnesium chloride addition/RCM sequence on N-alkenyl-substituted imides provides a mild access to indolizinone and pyrroloazepinone derivatives with the α-hydroxy-γ-lactam framework. The procedure can be applied to the asymmetric synthesis of this type of derivatives, by employing a 2-exo-hydroxy-10-bornylsulfinyl group as a chiral auxiliary. Further functionality can be introduced at the angular position through an α-amidoalkylation reaction. The sequence of allylmagnesium chloride addition/RCM sequence using N-alkenyl-substituted imides provides mild access to indolizinone and pyrrolozepinone derivatives with an α-hydroxy-γ- lactam framework. Copyright

Full text of DOI:10.1002/ejoc.201300889

Job/Unit: O30889
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Date: 31-08-13 10:40:19
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FULL PAPER
DOI: 10.1002/ejoc.201300889
RCM Approach to Complex Polycyclic α-Hydroxy γ-Lactams: Synthesis of
Indolizinones and Pyrroloazepinones
Asier Gómez-SanJuan,[a] Nuria Sotomayor,[a] and Esther Lete*[a]
Keywords: Nitrogen heterocycles / Lactams / Ring-closing metathesis / Diastereoselectivity / Grignard reaction /
α-Amidoalkylation
The allylmagnesium chloride addition/RCM sequence on N-
alkenyl-substituted imides provides a mild access to indoliz-
inone and pyrroloazepinone derivatives with the α-hydroxy-
γ-lactam framework. The procedure can be applied to the
asymmetric synthesis of this type of derivatives, by em-
ploying a 2-exo-hydroxy-10-bornylsulfinyl group as a chiral
auxiliary. Further functionality can be introduced at the
angular position through an α-amidoalkylation reaction.
Introduction
α-Hydroxy-γ-lactams and their derivatives are versatile
building blocks that have been used to prepare numerous
heterocyclic compounds, including alkaloids,[1] vitamins
[e.g. (+)-biotin],[2] Carbacephem antibiotics,[3] angiotensin
converting enzyme inhibitors,[4] and anthelmintic and anti-
cancer drugs such as praziquantel[5] and (R)-(+)-Crispine
A.[6]
Hydroxylactams are readily converted into the corre-
sponding lactams,[7] and are precursors to N-acyliminium
ions.[8] The α-amidoalkylation of π-nucleophiles using N-
acyliminium ions as electrophiles is one of the most attract-
ive methods for C–C bond formation in heterocyclic chem-
istry and has found widespread application in natural prod-
ucts synthesis.[8] Thus, our group has demonstrated the syn-
thetic application of highly stereoselective intramolecular α-
amidoalkylation reactions[9] of cyclic α-hydroxylactams de-
rived from N-phenethylimides for the synthesis of fused or
substituted tetrahydroisoquinoline systems, such as eme-
tine-like alkaloids.[10] We have also developed an intermo-
lecular α-amidoalkylation approach of bicyclic α-hydrox-
ylactams, generated by Parham cyclization, which offers an
efficient alternative route to the isoquinoline alkaloids and
other nitrogen-containing biologically active compounds.[9]
Recent reports include organocatalytic enantioselective α-
amidoalkylation reactions using chiral phosphoric acids as
catalysts[11] (Figure 1).
Figure 1. Selected bioactive polycyclic hydroxylactam derivatives.
On the other hand, the bicyclic α-hydroxy-γ-lactam
framework is present in several natural products, or their
immediate precursors, and therefore, the development of
new synthetic procedures for the synthesis of these hetero-
cycles continues to be an intensely investigated field. More
precisely, the Aporhoedane alkaloids (e.g. Chilenine)[12] and
Stemona alkaloids,[13] having a pyrrolo[1,2-a]azepine skel-
eton, as well as galiellalactone analogues[14] and the hydrox-
ylated indolizidine alkaloids,[15] have interesting and potent
biological activities including antiviral, antitumor, antitus-
sive, and glucosidase inhibitory activity.
The potential utility of α-hydroxy-γ-lactams for natural
products synthesis and medicinal chemistry led us to ex-
plore the construction of indolizidine and pyrroloazepine
ring systems. In this context, we were attracted several years
ago to the potential of olefin ring-closing metathesis
(RCM)[16] for the assembly of complex target molecules
(e.g. erythrinanes[17]) and medium-size nitrogen hetero-
cycles.[18] RCM is now routinely applied to construct cyclic
[a] Departamento de Química Orgánica II, Facultad de Ciencia y
Tecnología, Universidad del País Vasco/Euskal Herriko
Unibertsitatea UPV/EHU,
Apdo. 644, 48080 Bilbao, Spain
E-mail: esther.lete@ehu.es
http://www.ehu.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300889.
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A. Gómez-SanJuan, N. Sotomayor, E. Lete
FULL PAPER
olefins of virtually all ring sizes with a high degree of func- fully characterized; they were subsequently submitted to
tional compatibility. However, there are few precedents of RCM conditions using 4 mol-% of Grubbs’ first-generation
its application to substrates containing an α-hydroxylactam catalyst to afford 8a-hydroxyindolizinone 3b and 9a-
function. Thus, Kim et al.[19] have reported the synthesis of hydroxypyrrolo[1,2-a]azepinone 4b in good yields
indolizidinones using RCM of N,5-hydroxy-α-hydroxylact- (Scheme 2).
ams, though their preparation required the use of PbBr2 in
a zinc-mediated Barbier-type allylation. In a related ap-
proach, Huang[20] has described the construction of the five
membered ring of indolizidine derivatives, starting from
enantiopure piperidine building blocks, but the reaction
product easily dehydrated.
We describe herein the combination of Grignard reagent
addition to N-substituted imides with olefin ring-closing
metathesis (RCM) as a strategy for the construction of six-
or seven-membered azabicycles with polycyclic α-hydroxy-
γ-lactam framework. The method was applied to the syn-
thesis of enantiomerically pure compounds by using nor-
born-5-ene-2,3-dicarboxyimides with a 2-exo-hydroxyborn-
ylsulfinyl as chiral auxiliary to control diastereoselectiv-
ity.[21]
Results and Discussion
We started by studying the synthesis of 8a-hydroxy-
Scheme 2.
indolizinone 3a and 9a-hydroxypyrrolo[1,2-a]azepinone 4a.
Thus, the N-allyl- or N-butenyl maleimides 1a,b were
Having established that the allylmagnesium chloride ad-
treated with allylmagnesium chloride to afford correspond-
dition/RCM sequence on norbornene dicarboxyimides pro-
ing hydroxylactams 2a,b. These hydroxylactams were highly
ceeded with complete diastereoselectivity, we applied this
unstable, and were submitted to RCM conditions without
procedure to the synthesis of an enantiomerically pure 8a-
further purification. Thus, both the six- and seven-mem-
hydroxyindolizinone 3c. For that purpose, we appended a
bered rings could be obtained by this procedure using
2-exo-hydroxy-10-bornylsulfinyl group to the norbornene
4 mol-% of Grubbs’ first-generation catalyst, though only
moiety. The synthetic utility of this group was developed by
in moderate yield (Scheme 1). The moderate overall yield
Arai,[22] and has been applied by our group to the enantio-
could be attributed to the instability of the intermediate hy-
selective synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines
droxylactams. Although several reaction conditions were
through inter- and intramolecular α-amidoalkylation reac-
evaluated, the use of higher catalyst loading or longer reac-
tions,[9d] and also as an activating group for conjugate ad-
tion times did not improve the results.
dition reactions on the α,β-unsaturated amide moiety of
this type of compounds.[23] Thus, our imide precursor
would be (2-exo-hydroxy-10-bornyl)sulfinylnorbornene di-
carboximide 9, prepared as described in Scheme 3. Ad-
dition of 10-mercaptoisoborneol[24] to imide 1a followed by
treatment with NCS afforded maleimide 7, which was oxid-
ized with MCPBA to yield sulfinylmaleimide 8 as a single
diastereoisomer in quantitative yield. As has been reported,
the stereochemical outcome of this reaction is determined
by the hydroxy group of the auxiliary.[25] The sulfoxide
group controlled the stereochemistry of an asymmetric
Diels–Alder reaction with cyclopentadiene in the presence
of ZnCl2 to obtain sulfinyl norbornene dicarboxyimide 9 in
Scheme 1.
good yield (70%), as a single endo diastereoisomer.[26] The
The same protocol was applied to norbornene dicarb- subsequent addition of allylmagnesium chloride occurred
oxyimides 5a and 5b. As has been observed for related sub- with complete diastereoselectivity. As stated before, the
strates,[9d] the ethylidene bridge of the norbornene moiety ethylidene bridge efficiently blocks the Re face of the carb-
blocks one side of the imide carbonyl group. As a result, onyl, leading to hydroxylactam 10 in quantitative yield. The
the addition of allylmagnesium chloride occurred with com- RCM reaction carried out under the usual conditions gave
plete diastereoselectivity to give 6a and 6b as single dia- enantiomerically pure 10b-hydroxypyridoisoindolone 3c in
stereomers. These hydroxylactams were stable and could be high yield (Scheme 3).
2
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Approach to Complex Polycyclic α-Hydroxy γ-Lactams
olizinone 11a and tetrahydropyrroloazepinone 12a were ob-
tained, though only in moderate yields (Scheme 4). When
the reaction was applied to norbornene dicarboxyimide de-
rived α-hydroxylactam 3b, C-10b-substituted pyridoisoind-
olone 11b was obtained in very good yield as a single dia-
stereomer, with complete inversion of configuration at C-
10b. However, when the procedure was applied to 4b, only
low yields of the azepinoisoindolone was obtained due to
competitive dehydration, which afforded 13a as the major
reaction product. In a similar way, reaction of 3c led to
enantiomerically pure dehydrated pyridoisoindolone 13b
(Scheme 4). All attempts to improve yields by varying the
reaction conditions or the identity of the nucleophile have
thus far failed.
Scheme 3.
Thus, the addition of allylmagnesium chloride to N-allyl
or butenyl imides followed by RCM provides an efficient
entry to fused pyrrolidine systems, with high diastereoselec-
tivity. Although it has been reported that the presence of
polar groups close to the double bonds[27] can inhibit RCM,
in our case the metathesis proceeds smoothly in the pres-
ence of the free hydroxy group of the hydroxylactams.
These types of bicyclic hydroxylactams may also be fur-
ther functionalized, as they are precursors of N-acyl-
iminium intermediates. Indeed, the α-amidoalkylation reac-
tion is a widely used method for C–C bond formation in
heterocyclic chemistry and has found widespread applica-
tion in natural products synthesis.[8] Although intermo-
lecular α-amidoalkylation with N-acyliminium ions formed
in situ from cyclic hydroxylactams to form tertiary or qua-
ternary centers has been widely applied, there are very few
examples of α-amidoalkylation of bicyclic N-acyliminium
intermediates so far. In this context, we have previously
shown that intermolecular α-amidoalkylation reaction with
different π-nucleophiles (allylsilanes or enol ethers) can be
accomplished upon treatment of bicyclic α-hydroxylactams,
obtained by Parham cyclization, with Lewis acids to obtain
nuevamine-type[1b] and dihydropyrroloisoquinoline alka-
Scheme 4.
In the case of hydroxylactams 3b and 4b, the α-amidoalk-
loids.[9d] With these precedents in mind, bicyclic α-hydroxy- ylation reaction occurs with complete stereoselectivity, as
γ-lactams 3a and 4a were submitted to intermolecular α- a result of stereoelectronically favored axial attack of the
amidoalkylation conditions using allyltrimethylsilane as the nucleophile at the least hindered face of the N-acyliminium
π-nucleophile. After some experimentation, we found the ion intermediate.[28] A thermal retro-Diels–Alder reaction
best results were obtained by formation of the tertiary N- was attempted to unmask the α,β-unsaturated amide moi-
acyliminium ion using TiCl4 as Lewis acid, followed by alk- ety on 11b and 12b. Thus, these products were subjected to
ylation. Thus, corresponding allyl-substituted dihydroind- previously tested conditions for related substrates[9d,23]
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A. Gómez-SanJuan, N. Sotomayor, E. Lete
FULL PAPER
(FVP at 500 °C and 1 Torr, or heating at reflux in o-di- for the synthesis of Cephalotaxus alkaloids.[29] In fact, one
chlorobenzene). Unfortunately, only decomposition prod- of the most common strategies for the construction of the
ucts were isolated under these conditions.
ABCD ring system of Cephalotaxus alkaloids, pioneered by
Nuclear Overhauser effect difference spectroscopy con- Semmelhack and co-workers,[30] relies on B-ring formation
firmed the stereochemistry of all hydroxylactams 3b,c, 4b, by starting from a spirocyclic precursor.[31]
6a,b and their derivatives 11b and 12b. As an example, the
most significant results obtained with 3c and 11b are shown
Conclusions
in Figure 2. For hydroxylactam 3c, NOE difference spec-
troscopy showed an enhancement between H-9 and the hy-
droxy group on C-10b. On the other hand, for 11b, the ab-
sence of an NOE enhancement between allylic protons on
C-10b and H-9 and the enhancement observed between
methylene protons on C-10b and H-9 confirmed that the
allyl substituent is on the opposite site to the methylidene
C-9 – C-10 bridge. The rest of the NOE experiments carried
out were fully consistent with the proposed stereochemistry
in each case.
In summary, the allylmagnesium chloride addition/RCM
sequence on N-alkenyl-substituted imides provides mild ac-
cess to indolizinone and pyrroloazepinone derivatives with
an α-hydroxylactam framework. This route compares quite
favorably and effectively with other methods described in
the literature.[32] When norbornene dicarboxyimides are
used as substrates, the addition reactions are completely
diastereoselective. Consequently, the procedure can be ap-
plied to the asymmetric synthesis of related derivatives, by
employing a 2-exo-hydroxy-10-bornylsulfinyl group as a
chiral auxiliary. The auxiliary controls the configuration at
sulfur, which, in turn, determines the formation of the endo
adduct in a chelation-controlled Diels–Alder reaction; the
ethylidene bridge of the norbornene moiety is responsible
for the stereochemical control in the addition reaction. Fur-
ther functionality can be introduced at the angular position
using an α-amidoalkylation reaction, though, in some cases
in low yields, due to a competitive dehydration process. On
the other hand, when the starting point is N-benzyl-substi-
tuted imide and an α-amidoalkylation reaction is performed
prior to the RCM, azaspiro[4,4]nonane derivatives can be
synthesized.
Figure 2. Observed critical NOE relationships for 3c and 11b.
A related protocol could be applied for the synthesis of
spiro compounds using sequential introduction of two allyl
groups in the same carbon atom. As outlined in Scheme 5,
allylmagnesium addition to norbornene dicarboxyimide 14,
followed by intermolecular α-amidoalkylation reaction (all-
yltrimethylsilane, TiCl4) to introduce the second allyl group,
and subsequent RCM led to spiro derivative 17 in good
overall yield. Unfortunately, attempts to carry out a retro-
Diels–Alder reaction led to decomposition. These types of
spirocyclic derivatives have been the targets of many syn-
thetic efforts due to their utility as advanced intermediates
Experimental Section
General Methods: Melting points were determined in unsealed cap-
illary tubes and are uncorrected. IR spectra were obtained in film
over NaCl pellets or KBr pellets. NMR spectra were recorded at
20–25 °C, at 300 MHz for 1H and 75.5 MHz for 13C or at 500 MHz
1
for H and 125.7 MHz for 13C in CDCl3 solutions. Assignments of
individual 13C and H resonances are supported by DEPT experi-
1
ments and 2D correlation experiments (COSY, HSQCed or
HMBC). Selective NOE or NOESY experiments were performed
when necessary. Mass spectra were recorded using electron impact
(EI) at 70 eV, under chemical ionization (CI) at 230 eV. Exact mass
was obtained using a TOF detector. TLC was carried out with
0.2 mm thick silica gel plates. Visualization was accomplished by
UV light. Flash column chromatography was performed on silica
gel (230–400 mesh) or on alumina (70–230 mesh).[33] All solvents
used in reactions were anhydrous and purified according to stan-
dard procedures.[34] All air- or moisture-sensitive reactions were
performed under argon; the glassware was dried (130 °C) and
purged with argon.
Synthesis of Imides 1a-b, 5a–b and 14. General Procedure: A solu-
tion of the corresponding amine (1 mmol) and the anhydride (1–
1.8 mmol) in glacial AcOH was heated under reflux for 5–16 h. The
AcOH was removed under reduced pressure. CH2Cl2 (10 mL) and
H2O (20 mL) were added, the organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3ϫ 10 mL). The or-
ganic phase was washed with H2O (3ϫ 20 m). The combined or-
ganic extracts were dried (Na2SO4), filtered, and concentrated in
Scheme 5.
4
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Approach to Complex Polycyclic α-Hydroxy γ-Lactams
vacuo. Flash column chromatography or crystallization afforded
the imides 1a–b, 5a–b and 14.
( d , J = 8 . 7 H z , 1 H , H 8 ) , 2 . 1 8 ( q , J = 7 . 0 H z , 2 H ,
CH2CH2CH=CH2), 3.19–3.21 (m, 2 H, H3a, H7a), 3.36–3.41 (m, 4
H , C H 2 C H 2 C H = C H 2 , H 4 , H 7 ) , 4 . 9 8 – 5 . 0 5 ( m , 2 H ,
CH2CH2CH=CH2), 5.66 (ddt, J = 17.0, 10.2, 7.0 Hz, 1 H,
CH2CH2CH=CH2), 6.03–6.06 (m, 2 H, H5, H6) ppm. 13C NMR
(75.5 MHz, CDCl3 ): δ = 32.0 (CH2 CH2 CH=CH2 ), 37.7
(CH2CH2CH=CH2), 44.8 (C4, C7), 45.7 (C3a, C7a), 52.2 (C8), 117.2
(CH2CH2CH=CH2), 134.4, 134.5 (CH2CH2CH=CH2, C5, C6),
177.6 (C1, C3) ppm. MS (230 eV, CI): m/z (%) = 218 (29) [M +
H]+, 217 (18) [M]+, 180 (25), 152 (100), 151 (21), 110 (9). HRMS
(CI) Calcd. for C13H16NO2 [M + H]+: 218.1181, found 218.1174.
N-Allylmaleimide (1a): According to the general procedure, a solu-
tion of N-allylamine (1.82 g, 31.29 mmol) and maleic anhydride
(5.58 g, 56.32 mmol) in glacial AcOH (60 mL) was heated under
reflux for 5 h. After work-up, flash column chromatography (silica
gel, 40% hexane/AcOEt) afforded maleimide 1a (3.00 g, 70%): m.p.
(hexane): 44–46 °C (Lit.[35] m.p. 42–43) °C. IR (KBr): ν =
˜
1702 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.08 (dt, J = 5.6,
1.4 Hz, 2 H, CH2CH=CH2), 5.10–5.16 (m, 2 H, CH2CH=CH2),
5.76 (ddt, J = 17.2, 10.1, 5.6 Hz, 1 H, CH2CH=CH2), 6.69 (s, 2 H,
C
13H15NO2 (217.27): calcd. C 71.87, H 6.96, N 6.45; found C
H2, H3) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 39.8
71.80, H 7.05, N 6.73.
(CH2CH=CH2), 117.5 (CH2CH=CH2), 131.5 (CH2CH=CH2),
134.2 (C2, C3), 170.3 (C1, C4) ppm. MS (230 eV, CI): m/z (%) =
(100) [M + H]+, 137 (11) [M]+, 110 (6). HRMS (CI) Calcd. for
C7H8NO2 [M + H]+: 138.0555, found 138.0550. C7H7NO2 (137.14):
calcd. C 61.31, H 5.14, N 10.21; found C 61.31, H 5.15, N 9.96.
(3aRS,4SR,7RS,7aSR)-2-Benzyl-3a,4,7,7a-tetrahydro-1H-4,7-meth-
anoisoindol-1,3(2H)-dione (14): According to general procedure, a
solution of N-benzylamine (1.57 mL, 14.20 mmol) and cis-nor-
born-5-en-endo-2,3-dicarboxylic anhydride (2.40 g, 14.20 mmol) in
glacial AcOH (20 mL) was heated under reflux for 5 h. After work-
up, crystallization from MeOH afforded imide 14 (3.55 g, 99%),
whose data are consistent with those previously reported:[38] m.p.
N-(3-Butenyl)maleimide (1b): According to the general procedure,
a solution of N-(3-butenyl)amine (1.06 g, 13.41 mmol) and maleic
anhydride (2.39 g, 24.14 mmol) in glacial AcOH (30 mL) was
heated under reflux for 16 h. After the work-up, flash column
chromatography (silica gel, 40% hexane/AcOEt) afforded maleim-
ide 1b, whose data coincide with those previously reported[36]
(MeOH): 87–89 °C. IR (KBr): ν = 1696 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 1.48 (d, J = 8.8 Hz, 1 H, H8), 1.66 (d, J = 8.8 Hz, 1
H, H8), 3.21–3.24 (m, 2 H, H3a, H7a), 3.33–3.35 (m, 2 H, H4, H7),
4.46 (s, 2 H, NCH2), 5.85–5.88 (m, 2 H, H5, H6), 7.23–7.28 (m, 5
H, Harom) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 41.9 (NCH2),
44.9 (C4, C7), 45.6 (C3a, C7a), 52.0 (C8), 127.6, 128.3, 128.8 (HCa-
rom), 134.2 (C5, C6), 136.0 (CCarom), 177.2 (C1, C3) ppm. MS (70 eV,
EI): m/z (%) = 253 (3) [M]+, 87 (6), 87 (7), 85 (53), 83 (100), 71 (5).
HRMS (EI) Calcd. for C16H15NO2 (M+): 253.1103, found
253.1112.
(1.24 g, 61%): IR (NaCl): ν = 1707 cm–1. 1H NMR (300 MHz,
˜
CDCl3): δ = 2.25 (q, J = 7.0 Hz, 2 H, CH2CH2CH=CH2), 3.50 (t,
J
=
7.0 Hz,
CH2CH2CH=CH2), 5.63 (ddt, J = 17.1, 10.2, 7.0 Hz, 1 H,
CH2CH2CH=CH2), 6.61 (s,
H, H2, H3) ppm. 13C NMR
(75.5 MHz, CDCl3): 32.5 (CH2CH2CH=CH2), 36.9
2 H, CH2CH2CH=CH2), 4.91–4.98 (m, 2 H,
2
δ
=
(CH2CH2CH=CH2), 117.3 (CH2CH2CH=CH2), 133.8, 134.2
(CH2CH2CH=CH2, C2, C3), 170.5 (C1, C4) ppm. MS (230 eV, CI):
m/z (%) = 152 (2) [M + H]+, 137 (29), 135 (95), 132 (94), 97 (17),
89 (10), 88 (13), 87 (58), 86 (70), 85 (91), 84 (100), 83 (18). HRMS
(CI) Calcd. for C8H10NO2 [M + H]+: 152.0712, found 152.0713.
8a-Hydroxy-8,8a-dihydroindolizin-3(5H)-one (3a): Allylmagnesium
chloride (0.75 mL of a 2.0 m solution in THF, 1.5 mmol) was added
dropwise to a solution of maleimide 1a (170 mg, 1.25 mmol) in dry
THF (10 mL) at –78 °C. The reaction mixture was warmed up to
0 °C and stirred for 1 h. The reaction was quenched by the addition
of a saturated aqueous solution of NH4Cl (5 mL). The organic
layer was separated, and the aqueous phase was extracted with
CH2Cl2 (3ϫ 10 mL). The combined organic extracts were dried
(Na2SO4), filtered, and concentrated in vacuo affording corre-
sponding α-hydroxylactam 2a. This intermediate, without purifica-
tion, was dissolved in dry CH2Cl2 (0.01 m), and was treated with
first-generation Grubb’s catalyst (41 mg, 0.05 mmol, 4 mol-%) for
6 h at room temperature. Removal the solvent under reduced pres-
sure, followed by flash column chromatography (silica gel, 80%
(3aRS,4SR,7RS,7aSR)-2-Allyl-3a,4,7,7a-tetrahydro-1H-4,7-meth-
anoisoindole-1,3(2H)-dione (5a): According to the general pro-
cedure, a solution of N-allylamine (0.66 g, 11.30 mmol) and cis-
norborn-5-en-endo-2,3-dicarboxylic anhydride (1.90 g, 11.30 mmol)
in AcOH glacial (20 mL) was heated under reflux for 16 h. After
the work-up, crystallization from MeOH afforded imide 5a (2.20 g,
99%): m.p. (MeOH): 55–57 °C. IR (KBr): ν = 1696 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 1.53 (d, J = 8.8 Hz, 1 H, H8), 1.72 (d, J =
8.8 Hz, 1 H, H8), 3.24–3.28 (m, 2 H, H3a, H7a), 3.37–3.40 (m, 2 H,
H4, H7), 3.93 (dt, J = 5.9, 1.4 Hz, 2 H, CH2CH=CH2), 5.09–5.20
(m, 2 H, CH2CH=CH2), 5.64 (ddt, J = 17.1, 10.2, 5.9 Hz, 1 H,
CH2CH=CH2), 6.09 (broad s, 2 H, H5, H6) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 40.5 (CH2CH=CH2), 44.9 (C4, C7), 45.8
(C3a, C7a), 52.2 (C8), 118.1 (CH2CH=CH2), 130.9 (CH2CH=CH2),
134.5 (C5, C6), 177.2 (C1, C3) ppm. MS (230 eV, CI): m/z (%) = 204
(63) [M + H]+, 203 (14) [M]+, 166 (28), 138 (100). HRMS (CI)
Calcd. for C12H14NO2 [M + H]+: 204.1025, found 204.1023.
C12H13NO2 (203.24): calcd. C 70.92, H 6.45, N 6.89; found C
71.11, H 6.49, N 7.01.
hexane/AcOEt) afforded dihydroindolizinone 3a[39] (63.2 mg, 35%):
1
m.p. (AcOEt): 107–109 °C. IR (KBr): ν = 3290, 1680 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 2.27 (d, J = 17.3 Hz, 1 H, H8), 2.57
(dd, J = 17.3, 3.4 Hz, 1 H, H8), 3.59–3.64 (m, 1 H, H5), 3.90 (broad
s, 1 H, OH), 4.33 (dd, J = 18.2, 2.3 Hz, 1 H, H5), 5.72–5.77 (m, 1
H, H7), 5.80 (dd, J = 10.0, 2.3 Hz, 1 H, H6), 6.03 (d, J = 5.9 Hz, 1
H, H2), 7.07 (d, J = 5.9 Hz, 1 H, H1) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 33.6 (C8), 37.2 (C5), 86.2 (C8a), 120.7 (C7), 122.6 (C6),
126.2 (C2), 150.1 (C1), 167.7 (C3) ppm. MS (230 eV, CI): m/z (%)
= 152 (100) [M + H]+, 151 (22) [M]+, 136 (47), 135 (23), 134 (78),
133 (27), 132 (19). HRMS (CI) Calcd. for C8H10NO2 [M + H]+
152.0712, found 152.0707. C8H9NO2 (151.16): calcd. C 63.56, H
6.00, N 9.27; found C 63.51, H 6.03, N 8.95.
(3aRS,4SR,7RS,7aSR)-2-(But-3-en-1-yl)-3a,4,7,7a-tetrahydro-1H-
4,7-methanoisoindole-1,3(2H)-dion3 (5b): According to general pro-
cedure, a solution of N-(3-butenyl)amine (0.39 g, 5.01 mmol) and
cis-norborn-5-en-endo-2,3-dicarboxylic anhydride (0.85 g,
5.01 mmol) in glacial AcOH (20 mL) was heated under reflux for
16 h. After the work-up, crystallization in MeOH afforded imide
5b (1.07 g, 99%), whose data coincide with those previously re-
9a-Hydroxy-5,6,9,9a-tetrahydro-3H-pyrrolo[1,2-a]azepin-3-one (4a):
According to the procedure described for the synthesis of 3a, N-
(3-butenyl)maleimide (1b) (390 mg, 2.55 mmol) was treated with
ported:[37] m.p. (MeOH): 58–60 °C. IR (KBr): ν = 1684 cm–1. 1H allylmagnesium chloride (1.61 mL of a 2.0 m solution in THF,
˜
NMR (300 MHz, CDCl3): δ = 1.51 (d, J = 8.7 Hz, 1 H, H8), 1.72 3.07 mmol) and the first-generation Grubb’s catalyst (0.13 g,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O30889
/KAP1
Date: 31-08-13 10:40:19
Pages: 12
A. Gómez-SanJuan, N. Sotomayor, E. Lete
FULL PAPER
0.15 mmol). Purification by flash column chromatography (silica
CHHCH2CH=CH2), 4.96–5.02 (m, 2 H, CH2CH2CH=CH2), 5.10–
5.15 (m, 2 H, C3-CH2CH=CH2 ), 5.56–5.64 (m, 1 H, C3-
CH2CH=CH2), 5.67–5.73 (m, 1 H, CH2CH2CH=CH2), 6.08 (dd, J
= 5.4, 3.0 Hz, 1 H, H5), 6.17 (dd, J = 5.4, 3.0 Hz, 1 H, H6) ppm.
gel, AcOEt) afforded pyrroloazepinone 4a (130 mg, 31 %): IR
(NaCl): ν = 3310, 1678 cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
2.25–2.38 (m, 3 H, 2ϫ H6, H9), 2.73 (dd, J = 15.1, 7.7 Hz, 1 H,
H9), 3.01–3.15 (m, 1 H, H5), 3.89 (dt, J = 13.9, 4.1 Hz, 1 H, H5), 13C NMR (125.7 MHz, CDCl3): δ = 33.2 (CH2CH2CH=CH2), 38.6
4.06 (s, 1 H, OH), 5.59–5.66 (m, 1 H, H8), 5.95–6.03 (m, 1 H, H7), (CH2CH2CH=CH2), 44.8, 44.9 (C7, CH2CH=CH2), 45.7 (C4), 47.2
5.97 (d, J = 5.8 Hz, 1 H, H2), 6.86 (d, J = 5.8 Hz, 1 H, H1) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 27.8 (C6), 36.1 (C5), 36.4 (C9),
(C7a), 49.1 (C4a), 51.2 (C8), 90.2 (C3), 116.4 (CH2CH2CH=CH2),
119.9 (C3-CH2CH=CH2), 131.4 (C3-CH2CH=CH2), 133.9 (C6),
90.0 (C9a), 123.9 (C8), 126.1 (C7), 133.3 (C2), 150.3 (C1), 169.1 135.6 (C5), 136.1 (CH2CH2CH=CH2), 173.9 (C1) ppm. MS (230 eV,
(C3) ppm. MS (230 eV, CI): m/z (%) = 166 (42) [M + H]+, 165 (10)
CI): m/z (%) = 260 (100) [M + H]+, 242 (37), 241 (16), 222 (36),
218 (59), 204 (10), 195 (11), 194 (80), 176 (40), 152 (50). HRMS
[M]+, 150 (27), 149 (23), 148 (100), 147 (35). HRMS (CI) Calcd.
for C9H12NO2 [M + H]+ 166.0868, found 166.0874. C9H11NO2 (CI) Calcd. for C16H22NO2 [M + H]+: 260.1651, found 260.1662.
(165.19): calcd. C 65.44, H 6.71, N 8.48; found C 65.69, H 6.77, N
(6aSR,7RS,10SR,10aRS,10bRS)-10b-Hydroxy-1,6a,7,10,10a,10b-
hexahydro-7,10-methanopyrido[2,1-a]isoindol-6(4H)-one (3b): A
8.08.
(3RS,3aRS,4SR,7RS,7aSR)-2,3-Diallyl-3-hydroxy-2,3,3a,4,7,7a-
hexahydro-1H-4,7-methanoisoindol-1-one (6a): Allylmagnesium
chloride (6.01 mL of a 2.0 m solution in THF, 11.42 mmol) was
added dropwise to a solution of norbornene dicarboxyimide 5a
(930 mg, 4.57 mmol) in dry THF (50 mL) at –78 °C, and the reac-
tion mixture was stirred at this temperature for 5 h. The reaction
was quenched by the addition of a saturated aqueous solution of
NH4Cl (10 mL). The organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3ϫ 10 mL). The combined or-
ganic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by flash column chromatography (silica gel,
50% hexane/AcOEt) afforded α-hydroxylactam 6a as a single dia-
solution of α-hydroxylactam 6a (110 mg, 0.44 mmol) in dry CH2Cl2
(0.01M) was treated with first-generation Grubb’s catalyst
(14.60 mg, 0.02 mmol). The reaction mixture was stirred for 6 h at
room temperature. Removal the solvent under reduced pressure,
followed by flash column chromatography (silica gel, 90% hexane/
AcOEt) afforded 3b (83.00 mg, 86%): m.p. (AcOEt) 153–155 °C.
1
IR (KBr): ν = 3340, 1667 cm–1. H NMR (500 MHz, CDCl ): δ =
˜
3
1.41 (d, J = 8.4 Hz, 1 H, H11), 1.58 (d, J = 8.4 Hz, 1 H, H11), 2.26
(dd, J = 13.9, 3.7 Hz, 1 H, H1), 2.46 (s, 1 H, OH), 2.45–2.51 (m, 1
H, H1), 2.77 (dd, J = 9.1, 4.0 Hz, 1 H, H10a), 3.10–3.12 (m, 1 H,
H10), 3.13 (dd, J = 9.1, 4.8 Hz, 1 H, H6a), 3.26–3.27 (m, 1 H, H7),
3.36–3.40 (m, 1 H, H4), 4.20 (dd, J = 17.6, 1.8 Hz, 1 H, H4), 5.62–
5.68 (m, 2 H, H2, H3), 6.15 (dd, J = 5.5, 3.1 Hz, 1 H, H8), 6.26 (dd,
J = 5.5, 2.8 Hz, 1 H, H9) ppm. 13C NMR (125.7 MHz, CDCl3): δ
= 37.2 (C4), 39.6 (C1), 44.8 (C10), 45.4 (C7), 49.6 (C6a, C10a), 51.9
(C11), 85.0 (C10b), 122.4, 123.2 (C2, C3), 134.3 (C9), 135.4 (C8),
171.6 (C6) ppm. MS (230 eV, CI): m/z (%) = 218 (44) [M + H]+,
200 (48), 199 (67), 198 (13), 180 (19), 162 (20), 152 (54), 134 (100),
133 (35), 132 (21). HRMS (CI) Calcd. for C13H16NO2 [M + H]+:
218.1181, found 218.1183. C13H15NO2 (217.27): calcd. C 71.87, H
6.96, N 6.45; found C 72.27, H 6.89, N 6.24.
stereomer (1.00 g, 89 %): m.p. (Et O): 80–82 °C. IR (KBr): ν =
˜
2
3307, 1649 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.31 (d, J =
8.3 Hz, 1 H, H8), 1.48 (d, J = 8.3 Hz, 1 H, H8), 2.40 (dd, J = 14.0,
6.8 Hz, 1 H, C3-CHHCH=CH2), 2.47 (dd, J = 14.0, 7.6 Hz, 1 H,
C3-CHHCH=CH2), 2.78 (dd, J = 8.9, 4.0 Hz, 1 H, H7a), 2.95–2.98
(m, 2 H, H3a, H7), 3.14–3.19 (m, 1 H, H4), 3.32, (s, 1 H, OH), 3.59
(dd, J = 15.5, 5.5 Hz, 1 H, NCHHCH=CH2), 3.74 (dd, J = 15.5,
6.5 Hz, 1 H, NCHHCH=CH2), 4.98 (d, J = 10.2 Hz, 1 H,
NCH2CH=CHH), 5.08–5.13 (m, 3 H, NCH2CH=CHH, C3-
CH2CH=CH2), 5.54–5.63 (m, 1 H, C3-CH2CH=CH2), 5.67–5.75
(m, 1 H, NCH2CH=CH2), 6.03 (dd, J = 5.3, 3.0 Hz, 1 H, H5), 6.17
(dd, J = 5.3, 2.7 Hz, 1 H, H6) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 41.0 (NCH2CH=CH2), 44.9 (C7 ), 45.1 (C3-
CH2CH=CH2), 45.4 (C4), 47.1 (C7a), 48.9 (C3a), 51.3 (C8), 90.3
(C3), 116.5 (NCH2CH=CH2), 119.7 (C3-CH2CH=CH2), 131.5 (C3-
CH2CH=CH2), 134.3 (C6), 134.4 (NCH2CH=CH2), 134.9 (C5),
173.7 (C1) ppm. MS (230 eV, CI): m/z (%) = 246 (100) [M + H]+,
228 (35), 227 (14), 208 (39), 204 (53), 190 (11), 189 (13), 181 (10),
180 (92), 162 (43), 138 (27). HRMS (CI) Calcd. for C15H20NO2 [M
+ H]+: 246.1494, found 246.1486.
(1SR,4RS,4aSR,11aRS,11bRS)-11a-Hydroxy-4,4a,7,8,11,11a-hexa-
hydro-1H-1,4-methanoazepino[2,1-a]isoindol-5(11bH)-one (4b): A
solution of α-hydroxylactam 6b (370 mg, 1.42 mmol) in dry CH2Cl2
(0.01M) was treated with first-generation Grubb’s catalyst
(49.80 mg, 0.06 mmol). The reaction mixture was stirred for 6 h at
room temperature. Removal the solvent under reduced pressure,
followed by flash column chromatography (silica gel, AcOEt) af-
forded 4b (220 mg, 68%): m.p. (AcOEt) 113–115 °C. IR (KBr): ν
˜
1
= 3343, 1655 cm–1. H NMR (500 MHz, CDCl3): δ = 1.34 (d, J =
8.3 Hz, 1 H, H12), 1.52 (d, J = 8.3 Hz, 1 H, H12), 2.16–2.19 (m, 2
H, H8), 2.45 (d, J = 15.1 Hz, 1 H, H11), 2.58–2.63 (m, 2 H, H11,
OH), 2.68–2.75 (m, 2 H, H11b, H7), 3.06–3.09 (m, 1 H, H1), 3.16
(dd, J = 8.9, 4.7 Hz, 1 H, H4a), 3.22–3.26 (m, 1 H, H4), 3.81 (dt, J
= 13.8, 3.7 Hz, 1 H, H7), 5.62–5.67 (m, 1 H, H10), 5.99–6.02 (m, 1
H, H9), 6.04 (dd, J = 5.3, 3.0 Hz, 1 H, H3), 6.13 (dd, J = 5.3,
2.7 Hz, 1 H, H2) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 29.3
(C8), 35.8 (C7), 44.6 (C11), 45.0 (C1), 45.4 (C4), 49.1, 49.5 (C4a,
C11b), 51.3 (C12), 87.7 (C11a), 122.5 (C10), 134.4, 134.5, 134.6 (C2,
C3, C9), 172.3 (C5) ppm. MS (230 eV, CI): m/z (%) = 232 (45) [M
+ H]+, 231 (7) [M]+, 214 (41), 213 (33), 194 (20), 176 (19), 166
(61), 164 (12), 149 (11), 148 (100), 147 (27). HRMS (CI) Calcd. for
C14H18NO2 [M + H]+: 232.1338, found 232.1343.
(3RS,3aRS,4SR,7RS,7aSR)-3-Allyl-2-(but-3-en-1-yl)-3-hydroxy-
2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindol-1-one (6b): Ac-
cording to the procedure described for the synthesis of 6a, allyl-
magnesium chloride (3.09 mL of a 1.9 m solution in THF,
5.87 mmol) was added dropwise to a solution of norbornene di-
carboxyimide 5b (510 mg, 2.35 mmol) in dry THF (50 mL) at
–78 °C, and the reaction mixture was stirred at this temperature for
5 h. After the work-up, flash column chromatography (silica gel,
50% hexane/AcOEt) afforded α-hydroxylactam 6b as a single dia-
1
stereomer (500 mg, 81 %): IR (NaCl): ν = 3308, 1649 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.34 (d, J = 8.3 Hz, 1 H, H8), 1.51
( d , J = 8 . 3 H z , 1 H , H 8 ) , 2 . 2 4 ( q , J = 7 . 2 H z , 2 H ,
CH2 CH2 CH=CH2), 2.40 (dd, J = 13.9, 6.9 Hz, 1 H, C3-
(–)-1-Allyl-3-({[(1R,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]-
CHHCH= CH 2 ) , 2 . 4 7 ( dd , J = 1 3 . 9 , 7 . 6 H z , 1 H , C 3 - heptan-1-yl]methyl}thio)-1H-pyrrole-2,5-dione (7): To a solution of
CHHCH=CH2), 2.79 (dd, J = 8.9, 4.0 Hz, 1 H, H7a), 2.86–2.92 (m,
maleimide 1a (490 mg, 3.56 mmol) in dry CH2Cl2 (400 mL) was
2 H, CHHCH2CH=CH2, OH), 2.95–2.99 (m, 2 H, H7, H3a), 3.16– added at 0 °C a solution of 10-mercaptoisoborneol (730 g,
3 . 2 1 ( m , 1 H , H 4 ) , 3 . 3 1 ( d t , J = 1 4 . 0 , 7 . 2 H z , 1 H , 3.91 mmol) and Et3N (0.82 mL, 5.87 mmol) in dry CH2Cl2
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30889
/KAP1
Date: 31-08-13 10:40:19
Pages: 12
Approach to Complex Polycyclic α-Hydroxy γ-Lactams
(250 mL). The resulting mixture was stirred at this temperature for
30 min, and then at room temperature for 24 h. The solvent was
removed under reduced pressure. The resulting crude reaction mix-
ture was purified by flash column chromatography (silica gel, 40%
hexane/AcOEt) to afford the addition product as a 1:1 ratio of
diastereomers (1.01 g, 99 % combined yield). The diastereomers
could be separated and identified, but in subsequent reactions were
used without separation. A solution of this mixture of dia-
stirred for 30 min. Cyclopentadiene (10 mmol) was added, and the
reaction was stirred at 0 °C for 2 h. The reaction was quenched by
the addition of 1 m HCl (50 mL). The aqueous phase was extracted
with CH2Cl2 (2ϫ 25 mL). The combined organic extracts were
washed with brine (2ϫ 10 mL), dried (Na2SO4), filtered, and con-
centrated in vacuo. Flash column chromatography (silica gel, 50%
hexane/AcOEt, 2% EtN3) afforded imide 9 (1.77 g, 70%): [α]2D0
–24.10 (c = 0.25, CHCl ); m.p. (pentane): 113–116 °C. IR (KBr): ν
=
˜
3
stereomers (2.30 g, 7.12 mmol) and NCS (1.07 g, 7.83 mmol) in dry = 3449, 1698 cm–1. H NMR (500 MHz, CDCl3): δ = 0.87 (s, 3 H,
1
CCl4 (130 mL) was refluxed for 16 h. The solvent was concentrated
in vacuo. The resulting crude reaction mixture was purified by flash
column chromatography (silica gel, 30% hexane/AcOEt) affording
maleimide 7 (2.10 g, 92%): [α]2D0 = –30.13 (c = 0.25, CHCl3); m.p.
CH3), 1.14 (s, 3 H, CH3), 1.14–1.19 (m, 1 H, H5Ј), 1.45 (ddd, J =
12.2, 9.1, 3.5 Hz, 1 H, H6Ј), 1.50–1.56 (m, 1 H, H6Ј), 1.74–1.88 (m,
5 H, 2ϫH3Ј, H4Ј, H5Ј, H8), 2.28 (d, J = 9.2 Hz, 1 H, H8), 3.02 (d,
J = 12.8 Hz, 1 H, OSCHH), 3.43 (d, J = 12.8 Hz, 1 H, OSCHH),
3.47–3.49 (m, 2 H, H7a, H7), 3.57 (d, J = 3.3 Hz, 1 H, OH), 3.80–
(AcOEt) 115–117 °C. IR (KBr): ν = 3490, 1702 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 0.92 (s, 3 H, CH3), 1.11 (s, 3 H, CH3), 3.84 (m, 1 H, H4), 3.97–4.03 (m, 3 H, H2Ј, CH2CH=CH2), 5.16–
1.07–1.12 (m, 1 H, H5Ј), 1.25 (ddd, J = 13.0, 9.4, 4.0 Hz, 1 H, H6Ј),
5.29 (m, 2 H, CH2CH=CH2), 5.66 (ddt, J = 16.5, 10.5, 6.1 Hz, 1 H,
1.58–1.63 (m, 1 H, H6Ј), 1.72–1.85 (m, 4 H, 2ϫH3Ј, H4Ј, H5Ј), 1.97 CH2CH=CH2), 6.26–6.28 (m, 1 H, H5), 6.33 (dd, J = 5.5, 2.6 Hz, 1
(broad s, 1 H, OH), 2.84 (d, J = 11.2 Hz, 1 H, SCHH), 3.23 (d, J
H, H6) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 19.9 (CH3), 20.5
(CH3), 27.1 (C5Ј), 30.8 (C6Ј), 38.6 (C3Ј), 41.1 (CH2CH=CH2), 45.0
= 11.2 Hz, 1 H, SCHH), 3.90 (dd, J = 7.5, 3.6 Hz, 1 H, H2Ј), 4.11
(d, J = 5.7 Hz, 2 H, CH2 CH=CH2 ), 5.15–5.20 (m, 2 H, (C4Ј), 45.4 (C7), 45.8 (C4), 48.4 (C7a), 49.4 (C7Ј), 50.0, 50.1 (C8,
CH2 CH=CH2 ), 5.79 (ddd, J = 15.9, 10.8, 5.7 Hz, 1 H,
CH2SOЈ), 51.1 (C1Ј), 71.5 (C3a), 76.7 (C2Ј), 119.1 (CH2CH=CH2),
CH2CH=CH2), 6.16 (s, 1 H, H4) ppm. 13C NMR (75.5 MHz, 130.1 (CH2CH=CH2), 136.2 (C5), 138.7 (C6), 172.0, 174.0 (C1,
CDCl3): δ = 20.0 (CH3), 20.7 (CH3), 27.0 (C5Ј), 30.9 (C6Ј), 31.7
C3) ppm. MS (230 eV, CI): m/z (%) = 404 (24) [M + H]+, 403 (2)
(SCH2), 40.1 (CH2CH=CH2), 40.4 (C3Ј), 45.3 (C4Ј), 48.2 (C7Ј), 51.6 [M]+, 388 (9), 387 (23), 386 (93), 320 (9), 252 (16), 251 (33), 230
(C1Ј), 76.5 (C2Ј), 117.7, 117.8 (C4, CH2CH=CH2), 131.5 (9), 185 (23), 136 (11), 135 (100), 107 (6). HRMS (CI) Calcd. for
(CH2CH=CH2), 151.8 (C3), 167.5, 169.1 (C2, C5) ppm. MS (230 eV,
C22H30NO4S [M + H]+: 404.1896, found 404.1893. C22H29NO4S
CI): m/z (%) = 322 (51) [M + H]+, 305 (10), 304 (46), 198 (7), 170 (403.54): calcd. C 65.48, H 7.24, N 3.47; found C 65.79, H 7.19, N
(8), 169 (14), 153 (8), 136 (11), 135 (100), 109 (6). HRMS (CI)
Calcd. for C17H24NO3S [M + H]+: 322.1477, found 322.1480.
C17H23NO3S (321.43): calcd. C 63.52, H 7.21, N 4.36; found C
63.37, H 7.21, N 4.30.
3.65.
(+)-(3R,3aS,4S,7R,7aR)-2,3-Diallyl-3-hydroxy-7a-((R)-
{[(1R,2R,4R)-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl]-
methyl}sulfinyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindol-1-
one (10): Allylmagnesium chloride (5.35 mL of a 1.9 m solution in
THF, 10.15 mmol) was added dropwise to a solution of imide 9
(1.64 g, 4.07 mmol) in dry THF (50 mL) at –78 °C, and the reaction
mixture was stirred at this temperature for 5 h. The reaction was
quenched by the addition of a saturated aqueous solution of
NH4Cl (10 mL). The organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3ϫ 10 mL). The combined or-
ganic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by flash column chromatography (50% hexane/
AcOEt) afforded α-hydroxylactam 10 (1.69 g, 99%): [α]2D0 = +21.60
(–)-1-Allyl-3-((R)-{[(1R,2R,4R)-2-hydroxy-7,7-dimethylbicyclo-
[2.2.1]heptan-1-yl]methyl}sulfinyl)-1H-pyrrole-2,5-dione (8): A solu-
tion of m-CPBA (1.42 g, 8.22 mmol) in dry CH2Cl2 (200 mL) was
added at 0 °C to a solution of maleimide 7 (2.03 g, 6.32 mmol)
in dry CH2Cl2 (200 mL). The mixture was warmed up to room
temperature, and was stirred for 3 h. The reaction mixture was co-
oled to –78 °C, and the precipitate was filtered at this temperature.
The filtrate was washed with a saturated aqueous solution of
NaHCO3 (2ϫ 30 mL) and then brine (2ϫ 30 mL). The combined
organic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo, to afford maleimide 8 (2.12 g, 99%): [α]2D0 = –31.87 (c =
(c = 0.5, CHCl ). IR (NaCl): ν = 3350, 1660 cm–1 1H NMR
.
˜
3
0.25, CHCl ). IR (NaCl): ν = 3470, 1707 cm–1 1H NMR
.
˜
(500 MHz, CDCl3): δ = 0.89 (s, 3 H, CH3), 1.13–1.16 (m, 1 H, H5Ј),
1.16 (s, 3 H, CH3), 1.40–1.45 (m, 1 H, H6Ј), 1.51–1.58 (m, 2 H, H6Ј,
H8), 1.73–1.88 (m, 4 H, 2ϫH3Ј, H4Ј, H5Ј), 2.13 (d, J = 8.7 Hz, 1
H, H8), 2.38 (dd, J = 14.0, 7.1 Hz, 1 H, C3-CHHCH=CH2), 2.52
( s, 1 H , C3 - O H ) , 2 . 6 6 ( dd , J = 14. 0, 7. 3 Hz, 1 H, C 3 -
CHHCH=CH2), 3.06–3.10 (m, 1 H, H7), 3.37 (d, J = 13.1 Hz, 1
H, OSCHH), 3.41 (d, J = 4.0 Hz, 1 H, H3a), 3.46 (d, J = 13.1 Hz,
1 H, OSCHH), 3.72–3.77 (m, 4 H, H4, NCH2CH=CH2, C2Ј-OH),
4.02 (m, 1 H, H2Ј), 5.09–5.15 (m, 2 H, NCH2CH=CH2), 5.30 (m,
2 H, C3-CH2CH=CH2), 5.68–5.76 (m, 1 H, NCH2CH=CH2), 5.80–
5.89 (m, 1 H, C3-CH2CH=CH2), 6.25 (dd, J = 5.3, 3.4 Hz, 1 H,
H5 ), 6.47 (dd, J = 5.3, 2.7 Hz, 1 H, H6) ppm. 13 C NMR
(125.7 MHz, CDCl3): δ = 20.0 (CH3), 20.5 (CH3), 27.1 (C5Ј), 30.8
(C6Ј), 38.5 (C3Ј), 41.8 (NCH2CH=CH2), 44.9 (C4Ј), 45.1 (C7), 46.0
(C3-CH2CH=CH2), 46.2 (C4), 48.3 (C7Ј), 49.8, 49.9 (C8, CH2SO),
50.7 (C3a), 51.1 (C1Ј), 74.6 (C7a), 77.2 (C2Ј), 89.3 (C3), 117.0
3
(500 MHz, CDCl3): δ = 0.89 (s, 3 H, CH3), 1.09 (s, 3 H, CH3),
1.19–1.27 (m, 1 H, H5Ј), 1.56–1.60 (m, 1 H, H6Ј), 1.70–1.89 (m, 5
H, 2ϫH3Ј, H4Ј, H5Ј), 3.09 (d, J = 12.9 Hz, 1 H, OSCHH), 3.38
(broad s, 1 H, OH), 3.50 (d, J = 12.9 Hz, 1 H, OSCHH), 4.08–4.10
(m, 1 H, H2Ј), 4.14–4.18 (m, 2 H, CH2CH=CH2), 5.23–5.30 (m, 2
H, CH2CH=CH2), 5.81 (ddt, J = 16.2, 10.8, 5.4 Hz, 1 H,
CH2CH=CH2), 7.17 (s, 1 H, H4) ppm. 13C NMR (125.7 MHz,
CDCl3): δ = 19.8 (CH3), 20.5 (CH3), 27.1 (C5Ј), 30.5 (C6Ј), 38.7
(C3Ј), 39.6 (CH2CH=CH2), 44.7 (C4Ј), 48.7 (C7Ј), 51.8 (C1Ј), 55.8
(CH2SOЈ), 76.7 (C2Ј), 118.8 (CH2CH=CH2), 130.7 (CH2CH=CH2),
133.4 (C4), 154.6 (C3), 165.9, 166.2 (C2, C5) ppm. MS (70 eV, EI):
m/z (%) = 335 (8), 322 (27), 320 (23), 304 (24), 282 (18), 185 (36),
184 (12), 169 (26), 167 (48), 151 (26), 135 (100), 133 (19), 109 (24),
107 (53), 93 (11). C17H23NO4S (337.43): calcd. C 60.51, H 6.87, N
4.15; found C 60.23, H 6.72, N 3.83.
(–)-(3aR,4R,7S,7aS)-2-Allyl-3a-((R)-{[(1R,2R,4R)-2-hydroxy-7,7-di- (NCH2 CH=CH2 ), 121.6 (C3 -CH2 CH=CH2 ), 131.0 (C3 -
methylbicyclo[2.2.1]heptan-1-yl]methyl}sufinyl)-3a,4,7,7a-tetra- CH2CH=CH2), 133.4 (NCH2CH=CH2), 136.2 (C5), 139.5 (C6),
hydro-1H-4,7-methanoisoindole-1,3(2H)-dione (9): To a solution of
maleimide 8 (2.14 g, 6.36 mmol) in dry CH2Cl2 (400 mL) was
added at 0 °C ZnCl2 (1.94 g, 13.98 mmol), and the mixture was
167.8 (C1) ppm. MS (230 eV, CI): m/z (%) = 446 (38) [M + H]+,
429 (29), 428 (100), 411 (10), 410 (41), 362 (23), 344 (12), 294 (31),
293 (25), 276 (11), 228 (12), 227 (26), 226 (26). HRMS (CI) Calcd.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7

Job/Unit: O30889
/KAP1
Date: 31-08-13 10:40:19
Pages: 12
A. Gómez-SanJuan, N. Sotomayor, E. Lete
FULL PAPER
for C2 5 H3 6 NO4 S [M + H]+ : 446.2365, found 446.2354.
C25H35NO4S (445.62): calcd. C 67.38, H 7.92, N 3.14; found C
67.75, H 7.90, N 3.14.
C11H13NO (175.23): calcd. C 75.40, H 7.48, N 7.99; found C 75.19,
H 7.91, N 7.61.
(6aSR,7RS,10SR,10aRS,10bRS)-10b-Allyl-1,6a,7,10,10a,10b-hexa-
(+)-(6aR,7R,10S,10aS,10bR)-10b-Hydroxy-6a-((R)-{[(1R,2R,4R)-2- hydro-7,10-methanopyrido[2,1-a]isoindol-6(4H)-one (11b): Accord-
hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl]methyl}sulfinyl)-
1,6a,7,10,10a,10b-hexahydro-7,10-methanepyrido[2,1-a]isoindol-
6(4H)-one (3c): A solution of α-hydroxylactam 10 (1.60 g,
3.84 mmol) in dry CH2Cl2 (0.01M) was treated with first-genera-
tion Grubb’s catalyst (130 mg, 0.15 mmol, 4 mol-%). The reaction
mixture was stirred for 6 h at room temperature. Removal the sol-
vent under reduced pressure, followed by flash column chromatog-
raphy (silica gel, 70 % hexane/AcOEt) afforded indolizinone 3c
ing to general procedure, a solution of α-hydroxylactam 3b
(120 mg, 0.56 mmol) in dry CH2Cl2, was treated with allyltrimeth-
ylsilane (0.36 mL, 2.23 mmol) and TiCl4 (0.12 mL, 1.12 mmol) at
–78 °C. After the work-up, flash column chromatography (silica
gel, AcOEt) afforded 11b (130 mg, 97 %): IR (NaCl): ν =
˜
1
1673 cm–1. H NMR (500 MHz, CDCl3): δ = 1.34 (d, J = 8.2 Hz,
1 H, H11), 1.53 (d, J = 8.2 Hz, 1 H, H11), 2.04–2.08 (m, 1 H, H1),
2.12 (dd, J = 13.9, 8.0 Hz, 1 H, CHHCH=CH2), 2.20–2.25 (m, 1
H, H1), 2.38 (dd, J = 13.9, 6.7 Hz, 1 H, CHHCH=CH2), 2.68 (dd,
(1.14 g, 71%): [α]2D0 = +9.33 (c = 0.5, CHCl3); m.p. (from AcOEt):
1
202–204 °C. IR (KBr): ν = 3390, 1678 cm–1. H NMR (500 MHz, J = 8.7, 3.7 Hz, 1 H, H10a), 2.92–2.96 (s, 1 H, H10), 3.13 (dd, J =
˜
CDCl3): δ = 0.88 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.13–1.16 (m, 8.7, 5.1 Hz, 1 H, H6a), 3.16–3.20 (s, 1 H, H7), 3.34 (d, J = 5.1 Hz,
1 H, H5Ј), 1.37–1.42 (m, 1 H, H6Ј), 1.50–1.56 (m, 1 H, H6Ј), 1.58 1 H, H4 ), 4.98–5.03 (m, 1 H, H4 ) , 5 . 0 5– 5. 10 (m , 2 H,
(d, J = 8.6 Hz, 1 H, H11), 1.71–1.76 (m, 3 H, H3Ј, H4Ј, H5Ј), 1.82– CH2CH=CH2), 5.60–5.72 (m, 3 H, CH2CH=CH2, H2, H3), 6.03
1.86 (m, 1 H, H3Ј), 2.11 (d, J = 8.6 Hz, 1 H, H11), 2.46–2.57 (m, 2 (dd, J = 5.6, 2.5 Hz, 1 H, H9) 6.08 (dd, J = 5.6, 3.0 Hz, 1 H,
H, H1), 2.88 (broad s, 1 H, C10b-OH), 3.19–3.22 (s, 1 H, H10), 3.26 H8) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 32.2 (C1), 38.2 (C4),
(d, J = 3.9 Hz, 1 H, H10a), 3.38 (s, 2 H, CH2SO), 3.44–3.48 (m, 1
44.4, 44.7, 44.9 (CH2CH=CH2, C10, C6a), 47.5 (C10a), 49.7 (C7),
H, H4), 3.62–3.66 (m, 1 H, H7), 3.85 (d, J = 2.5 Hz, 1 H, C2Ј-OH), 51.2 (C11), 59.6 (C10b), 119.5 (CH2CH=CH2), 121.4, 123.0, 132.6
3.97–3.99 (m, 1 H, H2Ј), 4.14–4.18 (m, 1 H, H4), 5.69–5.72 (m, 2 (CH2CH=CH2, C2, C3), 133.0 (C9), 135.9 (C8), 174.1 (C6) ppm. MS
H, H2, H3), 6.22 (dd, J = 5.2, 3.4 Hz, 1 H, H8), 6.51 (dd, J = 5.2,
(230 eV, CI): m/z (%) = 242 (100) [M + H]+, 204 (34), 201 (11), 200
2.7 Hz, 1 H, H9) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 19.9 (59), 176 (90), 134 (39). HRMS (CI) Calcd. for C16H20NO [M +
(CH3), 20.5 (CH3), 27.1 (C5Ј), 30.9 (C6Ј), 37.8 (C4), 38.5 (C3Ј), 40.0 H]+: 242.1545, found 242.1546. C16H19NO (241.33): calcd. C 79.63,
(C1), 44.6 (C10), 45.0 (C4Ј), 45.8 (C7), 48.3 (C7Ј), 49.6, 49.7 (C11, H 7.94, N 5.80; found C 79.59, H 7.58, N 5.64.
CH2SO), 51.1 (C1Ј), 52.4 (C10a), 75.7 (C6a), 77.2 (C2Ј), 83.8 (C10b),
9a-Allyl-5,6,9,9a-tetrahydro-3H-pyrrolo[1,2-a]azepin-3-one (12a):
According to general procedure, a solution of α-hydroxylactam 4a
122.4, 123.1 (C2, C3), 135.1 (C8), 140.5 (C9), 165.6 (C6) ppm. MS
(230 eV, CI): m/z (%) = 418 (29) [M + H]+, 401 (26), 400 (100), 382
(49.50 mg, 0.30 mmol) in dry CH2Cl2, was treated with allyltri-
(38), 334 (22), 316 (16), 265 (24), 248 (13), 216 (14), 199 (29), 198
methylsilane (0.19 mL, 1.20 mmol) and TiCl4 (0.07 mL, 0.60 mmol)
(34), 135 (25). HRMS (CI) Calcd. for C23H32NO4S [M + H]+:
at –78 °C. After the work-up, flash column chromatography (silica
418.2052, found 418.2042. C23H31NO4S (417.56): calcd. C 66.16,
gel, AcOEt) afforded pyrroloazepinone 12a (12.40 mg, 22%): IR
H 7.48, N 3.35; found C 66.08, H 7.61, N 3.29.
(NaCl): ν = 1680 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.16–
˜
α-Amidoalkylation Reactions. General Procedure: To a solution of
the corresponding α-hydroxylactam 3a–b, 4a–b (1 mmol) in dry
2.19 (m, 1 H, H9), 2.23–2.26 (m, 2 H, H6), 2.44–2.55 (m, 3 H, H9,
CH2CH=CH2), 2.80–2.86 (m, 1 H, H5), 4.25 (dt, J = 14.0, 3.8 Hz,
CH2Cl2 (10 mL), allyltrimethylsilane (4 mmol) and TiCl4 (2 mmol) 1 H, H5), 5.04–5.09 (m, 2 H, CH2CH=CH2), 5.45 (ddt, J = 17.2,
were added sequentially at –78 °C. The reaction mixture was stirred
8 h at –78 °C, warmed up to room temperature, and stirred 24 h.
The reaction was quenched by the addition of a saturated aqueous
solution of NaHCO3 (10 mL). The organic layer was separated,
and the aqueous phase was extracted with CH2Cl2 (3ϫ 10 mL).
The combined organic extracts were dried (Na2SO4), filtered, and
concentrated in vacuo. Flash column chromatography afforded
11a–b, 12a–b.
10.1, 7.2 Hz, 1 H, CH2CH=CH2), 5.67–5.72 (m, 1 H, H8), 6.03–
6.08 (m, 1 H, H7), 6.13 (d, J = 5.9 Hz, 1 H, H2), 6.91 (d, J =
5.9 Hz, 1 H, H1) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 28.2
(C6), 35.8 (C9), 36.5, 36.8 (C5, CH2CH=CH2), 68.1 (C9a), 118.9
(CH2CH=CH2), 125.9, 126.0 (C8, C2), 131.7 (CH2CH=CH2), 133.5
(C7), 152.1 (C1), 169.8 (C3) ppm. MS (230 eV, CI): m/z (%) = 190
(100) [M + H]+, 148 (20), 135 (2). HRMS (CI) Calcd. for
C12H16NO [M + H]+: 190.1232, found 190.1213.
8a-Allyl-8,8a-dihydroindolizin-3(5H)-one (11a): According to gene- (1SR,4RS,4aSR,11aRS,11bRS)-11a-Allyl-4,4a,7,8,11,11a-hexahy-
ral procedure, a solution of α-hydroxylactam 3a (100 mg,
0.67 mmol) in dry CH2Cl2, was treated with allyltrimethylsilane
(0.43 mL, 2.70 mmol) and TiCl4 (0.15 mL, 1.35 mmol) at –78 °C.
After the work-up, flash column chromatography (silica gel, Ac-
OEt) afforded dihydroindolizinone 11a[35] (38.70 mg, 33 %): IR
dro-1H-1,4-methanoazepino[2,1-a]isoindol-5-(11bH)-one (12b) and
(1SR,4RS,4aSR,11bRS)-4,4a,7,8-Tetrahydro-1H-1,4-methanoazep-
ino[2,1-a]isoindol-5-(11bH)-one (13a): According to general pro-
cedure, a solution of α-hydroxylactam 4b (0.10 g, 0.44 mmol) in dry
CH2Cl2, was treated with allyltrimethylsilane (0.28 mL, 1.76 mmol)
and TiCl4 (0.10 mL, 0.88 mmol) at –78 °C. After the work-up, flash
(NaCl): ν = 1683 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.01–
˜
2.06 (m, 1 H, H8), 2.29–2.34 (m, 1 H, H8), 2.37 (d, J = 7.3 Hz, 2 column chromatography (silica gel, AcOEt) afforded pyrroloazep-
H, CH2CH=CH2), 3.48 (ddd, J = 18.8, 3.7, 2.2 Hz, 1 H, H5), 4.47
inones 12a (13.00 mg, 12%), and 13a (45.50 mg, 49%). Data for
(ddd, J = 18.8, 3.7, 2.8 Hz, 1 H, H5), 5.00–5.03 (m, 2 H, 12a: IR (NaCl): ν = 1665 cm–1. H NMR (500 MHz, CDCl ): δ =
1
˜
3
CH2CH=CH2), 5.41–5.50 (m, 1 H, CH2CH=CH2), 5.69–5.73 (m,
1 H, H7), 5.75–5.79 (m, 1 H, H6), 6.13 (d, J = 5.9 Hz, 1 H, H2),
7.07 (d, J = 5.9 Hz, 1 H, H1) ppm. 13C NMR (125.7 MHz, CDCl3):
1.38 (d, J = 8.2 Hz, 1 H, H12), 1.57 (d, J = 8.2 Hz, 1 H, H12), 2.05–
2.27 (m, 4 H, 2ϫH8, H11, CHHCH=CH2), 2.41 (dd, J = 13.9,
6.9 Hz, 1 H, CHHCH=CH2), 2.52 (d, J = 14.9 Hz, 1 H, H11), 2.62
δ = 32.4 (C8), 37.6 (C5), 38.0 (CH2CH=CH2), 63.6 (C8a), 119.0 (dd, J = 8.9, 3.6 Hz, 1 H, H11b), 2.66–2.71 (m, 1 H, H7), 2.92–2.97
(CH2CH=CH2), 121.6 (C7), 123.5 (C6), 126.6 (C2), 131.9
(CH2CH=CH2), 151.9 (C1), 168.9 (C3) ppm. MS (230 eV, CI): m/z
(m, 1 H, H1), 3.12 (dd, J = 8.9, 5.1 Hz, 1 H, H4a), 3.21–3.25 (m, 1
H, H4), 3.94 (ddd, J = 14.0, 5.8, 2.3 Hz, 1 H, H7), 5.09–5.13 (m, 2
(%) = (100) [M + H]+, 176, 135 (4), 134 (32), 132 (2). HRMS (CI) H, CH2CH=CH2), 5.58–5.67 (m, 1 H, CH2CH=CH2), 5.72–5.77
Calcd. for C11H14NO [M + H]+: 176.1075, found 176.1060. (m, 1 H, H9), 5.94–5.99 (m, 1 H, H10), 6.14 (dd, J = 5.6, 3.0 Hz, 1
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30889
/KAP1
Date: 31-08-13 10:40:19
Pages: 12
Approach to Complex Polycyclic α-Hydroxy γ-Lactams
H, H3), 6.19 (dd, J = 5.6, 2.6 Hz, 1 H, H2) ppm. 13C NMR
(125.7 MHz, CDCl3): δ = 27.8 (C8), 35.1 (C11), 37.2 (C7), 42.1
2.6 Hz, 1 H, H5), 6.23 (dd, J = 5.3, 3.1 Hz, 1 H, H6), 7.18–7.32 (m,
5 H, Harom) ppm. 13C NMR (125.7 MHz, CDCl3): δ = 42.3
(CH2CH=CH2), 45.1 (C4), 45.2 (C1), 46.9 (C11b), 48.8 (C4a), 52.4 (NCH2), 44.8, 45.1 (CH2CH=CH2, C4), 45.9 (C7), 47.5 (C3a), 49.1
(C12), 64.0 (C11a), 119.3 (CH2CH=CH2), 128.0 (C9), 132.5 (C10),
(C7a), 52.0 (C8), 91.0 (C3), 120.1 (CH2CH=CH2), 127.1, 128.2,
132.7 (CH2CH=CH2), 134.0 (C2), 135.6 (C3), 175.0 (C5) ppm. MS 128.3 (HCarom), 131.3 (CH2CH=CH2), 133.3 (C5), 136.9 (C6), 138.9
(230 eV, CI): m/z (%) = 256 (100) [M + H]+, 254 (6), 218 (17), 215
(CCarom), 174.0 (C1) ppm. MS (70 eV, EI): m/z (%) = 277 (6) [M+
–
(10), 214 (75), 190 (25), 148 (26). HRMS (CI) Calcd. for C17H22NO
H2O], 254 (29), 211 (63), 188 (39), 120 (11), 110 (32), 91 (100), 83
(11), 65 (19). HRMS (EI) Calcd. for C19H19NO [M+ – H2O]:
227.1467, found 277.1468.
[M + H]+: 256.1701, found 256.1690. Data for 13a: IR (NaCl): ν
˜
= 1658 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.40 (d, J = 8.5 Hz,
1 H, H12), 1.55 (d, J = 8.5 Hz, 1 H, H12), 2.31–2.32 (m, 2 H, H8),
3.09 (dd, J = 8.4, 4.6 Hz, 1 H, H11b), 3.12–3.15 (m, 1 H, H1), 3.25–
3.28 (m, 2 H, H4a, H4), 3.34–3.38 (m, 1 H, H7), 3.70–3.73 (m, 1 H,
H7), 5.02 (d, J = 7.3 Hz, 1 H, H11), 5.62–5.67 (m, 1 H, H9), 5.74
(dd, J = 10.7, 7.3 Hz, 1 H, H10), 6.01 (dd, J = 5.5, 2.8 Hz, 1 H,
H2 ), 6.05 (dd, J = 5.5, 2.7 Hz, 1 H, H3) ppm. 13 C NMR
(125.7 MHz, CDCl3): δ = 29.8 (C8), 42.0, 42.1 (C4a, C7), 44.8 (C4),
46.9, 47.3 (C1, C11b), 50.5 (C12), 99.1 (C11), 124.7 (C10), 128.3 (C9),
134.5, 134.6 (C2, C3), 145.3 (C11a), 175.6 (C5) ppm.
(3aRS,4SR,7RS,7aSR)-3,3-Diallyl-2-benzyl-2,3,3a,4,7,7a-hexahy-
dro-1H-4,7-methanoisoindol-1-one (16): According to the general
procedure for α-amidoalkylation, α-hydroxylactam 15 (210 mg,
0.73 mmol) in dry CH2Cl2 (10 mL), was treated with allyltrimethyl-
silane (0.47 g, 2.90 mmol) and TiCl4 (0.16 mL, 1.45 mmol) at
–78 °C. After the work-up, flash column chromatography (silica
gel, 50% hexane/AcOEt) afforded 16 (130 mg, 53%). IR (NaCl): ν
˜
= 1672 cm–1. 1H NMR (500 MHz, CDCl3): δ = 1.35 (d, J = 8.3 Hz,
1 H, H8), 1.55 (d, J = 8.3 Hz, 1 H, H8), 2.07–2.16 (m, 2 H,
CH2CH=CH2), 2.27–2.38 (m, 2 H, CH2CH=CH2), 2.55 (dd, J =
8.9, 3.5 Hz, 1 H, H3a), 3.12–3.15 (m, 1 H, H4), 3.17 (dd, J = 8.9,
4.9 Hz, 1 H, H7a), 3.25–3.28 (m, 1 H, H7), 3.81 (d, J = 15.7 Hz, 1
H, NCHH), 4.78 (d, J = 15.7 Hz, 1 H, NCHH), 5.02–5.12 (m, 4
H, 2ϫ CH2CH=CH2), 5.58–5.66 (m, 1 H, CH2CH=CH2), 5.79–
5.87 (m, 1 H, CH2CH=CH2), 6.04 (dd, J = 5.5, 2.7 Hz, 1 H, H5),
6.26 (dd, J = 5.5, 2.9 Hz, 1 H, H6), 7.17–7.26 (m, 5 H, Harom) ppm.
13C NMR (125.7 MHz, CDCl3): δ = 42.1 (CH2CH=CH2), 43.2
(NCH2), 43.6 (CH2CH=CH2), 44.9 (C7), 45.6 (C4), 46.5 (C3a), 49.4
(C7a), 52.0 (C8), 66.1 (C3), 118.8, 119.7 (2ϫ CH2CH=CH2), 126.8,
127.5, 128.1 (HCarom), 132.4, 133.4 (2ϫ CH2CH=CH2), 134.0 (C5),
136.0 (C6), 138.8 (CCarom), 176.3 (C1) ppm. MS (230 eV, CI): m/z
(%) = 320 (100) [M + H]+, 282 (27), 278 (45), 254 (50), 212 (24),
91 (9). HRMS (CI) Calcd. for C22H26NO [M + H]+: 320.2014,
found 320.2011. C22H25NO (319.45): calcd. C 82.72, H 7.89, N
4.38; found C 82.73, H 7.83, N 4.56.
(–)-(6aR,7R,10S,10aS)-10b-Hydroxy-6a-((R)-{[(1R,2R,4R)-7,7-di-
methylbicyclo[2.2.1]heptan-1-yl]methyl}sulfinyl)-1,6a,7,10-tetra-
hydro-7,10-methanepyrido[2,1-a]isoindol-6(4H)-one (13b): Accord-
ing to general procedure, a solution of α-hydroxylactam 3c
(180 mg, 0.43 mmol) in dry CH2Cl2, was treated with allyltrimeth-
ylsilane (0.27 mL, 1.71 mmol) and TiCl4 (0.10 mL, 0.85 mmol) at
–78 °C. After the work-up, flash column chromatography (silica
gel, AcOEt) afforded 13b (83 mg, 48%): [α]2D0 = –14.10 (c = 0.5,
CH OH). IR (NaCl): ν = 3413, 1702 cm–1. 1H NMR (500 MHz,
˜
3
CDCl3): δ = 0.87 (s, 3 H, CH3), 1.14 (s, 3 H, CH3), 1.11–1.16 (m,
1 H, H5Ј), 1.40–1.45 (m, 1 H, H6Ј), 1.50–1.56 (m, 1 H, H6Ј), 1.58
(d, J = 8.6 Hz, 1 H, H11), 1.72–1.77 (m, 3 H, H3Ј, H4Ј, H5Ј), 1.82–
1.86 (m, 1 H, H3Ј), 2.13 (d, J = 8.6 Hz, 1 H, H11), 3.16 (d, J =
12.9 Hz, 1 H, CHHSO), 3.36 (d, J = 12.9 Hz, 1 H, CHHSO), 3.52
(d, J = 4.2 Hz, 1 H, H10a), 3.72 (s, 1 H, H7), 3.76 (s, 1 H, C2Ј-OH),
3.99–4.01 (m, 1 H, H2Ј), 4.12–4.16 (m, 1 H, H4), 4.32–4.36 (m, 1
H, H4), 5.01 (d, J = 5.8 Hz, 1 H, H1), 5.33–5.36 (m, 1 H, H3), 5.78–
5.82 (m, 1 H, H2), 6.24 (dd, J = 5.4, 3.2 Hz, 1 H, H8), 6.34 (dd, J
= 5.4, 2.9 Hz, 1 H, H9) ppm. 13C NMR (125.7 MHz, CDCl3): δ =
19.9 (CH3), 20.5 (CH3), 27.1 (C5Ј), 30.9 (C6Ј), 38.5 (C3Ј), 42.4 (C4),
45.0, 45.2, 45.3 (C4Ј, C7, C10a), 47.1 (C10), 48.3 (C7Ј), 49.6, 49.7
(C11, CH2SO), 51.1 (C1Ј), 72.2 (C6a), 77.1 (C2Ј), 97.3 (C1), 116.2
(C3), 121.7 (C2), 136.1 (C8), 138.6 (C9), 138.8 (C10b), 169.0
(C6) ppm. MS (230 eV, EI): m/z (%) = 399 (29) [M]+, 389 (11), 388
(52), 386 (13), 370 (43), 368 (35), 353 (22), 352 (23), 351 (100), 335
(25), 183 (11), 127 (13).
(3aSR,4RS,7SR,7aRS)-2-Benzyl-3a,4,7,7a-tetrahydrospiro(4,7-
methanoisoindol-1,1Ј-cyclopent-3-en)-3(2H)-one (17): A solution of
16 (85.00 mg, 0.25 mmol) in dry CH2Cl2 (0.01M) was treated with
first-generation Grubb’s catalyst (8.0 mg, 0.01 mmol, 4%-mol). The
reaction mixture was heated under reflux for 48 h. A second por-
tion of the catalyst was added after heating for 24 h. The reaction
was allowed to reach room temperature, and removal the solvent
under reduced pressure, followed by flash column chromatography
(silica gel, 50% hexane/AcOEt) afforded 17 (36.6 mg, 50%): m.p.
(hexane/AcOEt): 94–96 °C. IR (KBr): ν = 1666 cm–1. 1H NMR
˜
(3RS,3aRS,4SR,7RS,7aSR)-3-Allyl-2-benzyl-3-hydroxy-
2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindol-1-one (15): Allyl-
magnesium chloride (8.24 mL of a 1.9 m solution in THF,
15.65 mmol) was added dropwise to a solution of imide 14 (1.58 g,
6.26 mmol) in dry THF (40 mL) at –78 °C, and the reaction mix-
ture was stirred at this temperature for 2 h. The reaction was
quenched by the addition of a saturated aqueous solution of
NH4Cl (10 mL). The organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3ϫ 10 mL). The combined or-
ganic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo. Crystallization in hexane afforded α-hydroxylactam 15
(500 MHz, CDCl3): δ = 1.36 (d, J = 8.3 Hz, 1 H, H8), 1.55 (d, J =
8.3 Hz, 1 H, H8), 2.07 (d, J = 17.5 Hz, 1 H, H2Ј), 2.39 (d, J =
17.5 Hz, 1 H, H2Ј), 2.46–2.50 (m, 2 H, H5Ј), 2.75 (dd, J = 8.9,
3.8 Hz, 1 H, H7a), 3.01–3.03 (m, 1 H, H7), 3.27 (dd, J = 8.9, 4.8 Hz,
1 H, H3a), 3.31–3.34 (m, 1 H, H4), 3.81 (d, J = 15.2 Hz, 1 H,
NCHH), 4.62 (d, J = 15.2 Hz, 1 H, NCHH), 5.56–5.57 (m, 1 H,
H3Ј), 5.66–5.67 (m, 1 H, H4Ј), 5.90 (dd, J = 5.5, 2.5 Hz, 1 H, H5),
6.24 (dd, J = 5.5, 2.8 Hz, 1 H, H6), 7.16–7.23 (m, 5 H, Harom) ppm.
13C NMR (125.7 MHz, CDCl3): δ = 29.6 (C2Ј), 40.0 (NCH2), 43.4
(C4), 45.4 (C7), 46.7 (C3a), 49.3, 49.4 (C5Ј, C7a), 51.0 (C8), 70.4 (C1),
126.7, 127.7, 127.8 (HCarom), 128.6, 128.9 (C3Ј, C4Ј), 133.6 (C5),
135.8 (C6), 139.0 (CCarom), 174.9 (C3) ppm. MS (230 eV, CI): m/z
(%) = (83) [M + H]+, 292, 291 (21) [M]+, 254 (36), 227 (16), 226
(100), 225 (19). HRMS (CI) Calcd. for C20H22NO [M + H]+:
292.1701, found 292.1699. C20H21NO (291.39): calcd. C 82.44, H
7.26, N 4.81; found C 82.52, H 7.49, N 4.78.
(1.77 g, 96 %): m.p. (hexane): 132–134 °C. IR (KBr): ν = 3300,
˜
1
1649 cm–1. H NMR (500 MHz, CDCl3): δ = 1.42 (d, J = 8.5 Hz,
1 H, H8), 1.58 (d, J = 8.5 Hz, 1 H, H8), 1.93 (s, 1 H, OH), 2.42–
2.49 (m, 2 H, CH2CH=CH2), 2.90 (dd, J = 9.0, 3.9 Hz, 1 H, H3a),
3.00–303 (m, 1 H, H4), 3.15 (dd, J = 9.0, 4.7 Hz, 1 H, H7a), 3.30–
3.33 (m, 1 H, H7), 4.16 (d, J = 15.1 Hz, 1 H, NCHH), 4.52 (d, J
= 15.1 Hz, 1 H, NCHH), 5.08–5.15 (m, 2 H, CH2CH=CH2), 5.59
(ddt, J = 17.3, 10.2, 7.2 Hz, 1 H, CH2CH=CH2), 6.09 (dd, J = 5.3,
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of compounds described.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Gómez-SanJuan, N. Sotomayor, E. Lete
FULL PAPER
Le Quement, R. Petersen, M. Meldal, T. E. Nielsen, Biopoly-
mers 2010, 94, 242–256; j) U. Martínez-Estibalez, A. Gómez-
SanJuan, O. García-Calvo, E. Aranzamendi, E. Lete, N. Soto-
mayor, Eur. J. Org. Chem. 2011, 3610–3633.
Acknowledgments
The authors wish to thank the Ministerio de Ciencia e Innovación
(MICINN) (CTQ2009-07733), the Gobierno Vasco (IT-623-13)
and the Universidad del País Vasco/Euskal Herriko Unibertsitatea
UPV/EHU (UFI11/22, GIU 09/46) for their financial support.
Technical and human support provided by Servicios Generales de
Investigación SGIker (UPV/EHU, MICINN, GV/EJ, ERDF and
ESF) is gratefully acknowledged. The UPV/EHU is also thanked
for a postdoctoral grant (to A. G.-S).
[9]
For some representative examples of our work, see: a) M. I.
Collado, I. Manteca, N. Sotomayor, M. Villa, E. Lete, J. Org.
Chem. 1997, 62, 2080–2092; b) I. Osante, M. I. Collado, E.
Lete, N. Sotomayor, Eur. J. Org. Chem. 2001, 1267–1277; c) A.
Ardeo, E. Garcia, S. Arrasate, E. Lete, N. Sotomayor, Tetrahe-
dron Lett. 2003, 44, 8445–8448; d) I. González-Temprano, I.
Osante, E. Lete, N. Sotomayor, J. Org. Chem. 2004, 69, 3875–
3885; e) E. García, S. Arrasate, A. Ardeo, E. Lete, N. Soto-
mayor, Tetrahedron Lett. 2001, 42, 1511–1513; f) E. García, S.
Arrasate, E. Lete, N. Sotomayor, J. Org. Chem. 2005, 70,
10368–10374.
E. Garcia, E. Lete, N. Sotomayor, J. Org. Chem. 2006, 71,
6776–6784.
a) E. Aranzamendi, N. Sotomayor, E. Lete, J. Org. Chem. 2012,
77, 2986–2991; b) A. Gómez-SanJuan, N. Sotomayor, E. Lete,
Tetrahedron Lett. 2012, 53, 2157–2159.
[1] For some selected examples of hydroxylactams as intermediates
in synthesis of different type of alkaloids, see the following ci-
tations; lupine alkaloids: a) A. Consonni, B. Danieli, G.
Lesma, D. Passarella, P. Piacenti, A. Silvani, Eur. J. Org. Chem.
2001, 1377–1383; nuevamine-type alkaloids: b) I. Osante, E.
Lete, N. Sotomayor, Tetrahedron Lett. 2004, 45, 1253–1256; c)
A. Moreau, A. Couture, E. Deniau, P. Grandclaudon, Eur. J.
Org. Chem. 2005, 3437–3442; d) J. Selvakumar, C. R. Ramana-
than, Org. Biomol. Chem. 2011, 22, 7643–7646; erythrinane al-
kaloids: e) S. Gao, Y. Q. Tu, X. Hu, S. Wang, R. Hua, Y. Jiang,
Y. Zhao, X. Fan, S. Zhang, Org. Lett. 2006, 8, 2373–2376; f)
F. Zhang, N. S. Simpkins, A. J. Blake, Org. Biomol. Chem.
2009, 7, 1963–1979; nicotine and analogs: g) S. Peixoto, T. M.
Nguyen, D. Crich, B. Delpech, C. Marazano, Org. Lett. 2010,
12, 4760–4763.
[2] a) E. J. Corey, M. M. Mehrotra, Tetrahedron Lett. 1988, 29,
57–60; b) M. J. Moolenaar, W. N. Speckamp, H. Hiemstra, E.
Poetsch, M. Casutt, Angew. Chem. 1995, 107, 2582; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2391–2393; c) M. Shimizu, Y.
Nishigaki, A. Wakabayashi, Tetrahedron Lett. 1999, 40, 8873–
8876; d) F. E. Chen, H. F. Dai, Y. Y. Kuang, H. Q. Jia, Tetrahe-
dron: Asymmetry 2003, 14, 3667–3672; e) W. Bonrath, R.
Karge, T. Netscher, F. Roessler, F. Spindler, Chimia 2009, 63,
265–269.
[3] E. Metais, L. E. Overman, M. I. Rodriguez, B. A. Stearns, J.
Org. Chem. 1997, 62, 9210–9216.
[4] a) P. Lee, K. D. Moeller, J. Am. Chem. Soc. 1993, 115, 11434–
11445; b) A. Reichelt, S. K. Bur, S. F. Martin, Tetrahedron
2002, 58, 6323–6328.
[5] a) D. Frehel, J.-P. Maffrand, Heterocycles 1983, 20, 1731–1735;
b) J. H. Kim, Y. S. Lee, C. S. Kim, Heterocycles 1998, 48, 2279–
2285; c) M. H. Todd, C. Ndubaku, P. A. Bartlett, J. Org. Chem.
2002, 67, 3985–3988.
[6] S. M. Allin, S. N. Gaskell, J. M. R. Towler, P. C. B. Page, B.
Saha, M. J. McKenzie, W. P. Martin, J. Org. Chem. 2007, 72,
8972–8975.
[7] See, for example: a) H. Yoda, H. Kitayama, W. Yamada, T.
Katagiri, K. Takabe, Tetrahedron: Asymmetry 1993, 4, 1451–
1454; b) K. Matsuki, H. Inoue, A. Ishida, M. Takeda, M. Nak-
agawa, T. Hino, Chem. Pharm. Bull. 1994, 42, 9; c) M. D.
Barker, R. A. Dixon, S. Jones, B. J. Marsh, Tetrahedron 2006,
62, 11663–11669; d) Z.-B. Ye, J. Chen, W.-H. Meng, P.-Q. Hu-
ang, Tetrahedron: Asymmetry 2010, 21, 895–902.
[8] For reviews on N-acyliminium ion chemistry, see: a) W. N.
Speckamp, H. Hiemstra, Tetrahedron 1985, 41, 4367–4416; b)
H. Hiemstra, W. N. Speckamp, in: The Alkaloids (Ed.: A.
Brossi), Academic Press, New York, 1988, vol. 32, p. 271–339;
c) H. Hiemstra, W. N. Speckamp, in: Comprehensive Organic
Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon Press, Ox-
ford, UK, 1991, vol. 2, p. 1047–1082; d) W. N. Speckamp, M. J.
Moolenaar, Tetrahedron 2000, 56, 3817–3856; e) B. E. Maryan-
off, H. Zhang, J. H. Cohen, I. J. Turchi, C. A. Maryanoff,
Chem. Rev. 2004, 104, 1431–1628; f) A. Yazici, S. G. Pyne, Syn-
thesis 2009, 339–368; g) A. Yazici, S. G. Pyne, Synthesis 2009,
513–541; h) H. de Koning, W. N. Speckamp, in: Stereoselective
Synthesis (Houben–Weyl) (Eds.: G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, Ger-
many, 1996, workbench ed. E21, vol. 3, p. 1952–2010; i) S. T.
[10]
[11]
[12]
[13]
[14]
For a recent review, see: M. S. Leonard, ARKIVOC 2013, 1–
65.
For a recent review, see: R. A. Pilli, G. B. Rosso, M. C. Fer-
reira de Oliveira, Nat. Prod. Rep. 2010, 27, 1908–1937.
J. Nilsson, R. Gidöf, M. Johansson, O. Sterner, Tetrahedron
2012, 68, 3336–3341, and references cited therein.
[15]
[16]
J. P. Michael, Nat. Prod. Rep. 2008, 25, 139–165.
For selected reviews on RCM, see: a) R. H. Grubbs, Handbook
of Metathesis, Wiley, New York, 2003; b) R. R. Schrock, An-
gew. Chem. 2006, 118, 3832; Angew. Chem. Int. Ed. 2006, 45,
3748–3759; c) R. H. Grubbs, Angew. Chem. 2006, 118, 3845;
Angew. Chem. Int. Ed. 2006, 45, 3760–3765; d) J. C. Conrad,
D. E. Fogg, Curr. Org. Chem. 2006, 10, 185–202; e) S. P. Nolan,
H. Clavier, Chem. Rev. 2010, 39, 3305–3316. For selected re-
views on RCM in natural products synthesis and medicinal
chemistry, see: f) J. B. Brenneman, S. F. Martin, Curr. Org.
Chem. 2005, 9, 1535–1549; g) M. Arisawa, A. Nishida, M.
Nakagawa, J. Organomet. Chem. 2006, 691, 5109–5121; h) J.
Cossy, S. Arseniyadis, C. Meyer (Eds.), Metathesis in Natural
Product Synthesis Wiley-VCH, Weinheim, Germany, 2010; i)
M. J. Perez de Vega, M. I. García-Aranda, R. González-
Muñiz, Med. Res. Rev. 2011, 31, 677–715.
a) I. Osante, M. N. Abdullah, S. Arrasate, E. Lete, N. Soto-
mayor, ARKIVOC 2007, 4, 206–22; b) M. N. Abdullah, S. Ar-
rasate, E. Lete, N. Sotomayor, Tetrahedron 2008, 64, 1323–
1332.
U. Martínez-Estíbalez, N. Sotomayor, E. Lete, Tetrahedron
Lett. 2007, 48, 2919–2922.
a) S. W. Kang, Y. H. Kim, S. H. Kim, Bull. Korean Chem. Soc.
2008, 29, 755–757; b) S. W. Kang, Y. H. Kim, H. J. Kim, J. H.
Lee, S. H. Kim, Bull. Korean Chem. Soc. 2009, 30, 691–694.
K. H. Zhang, X. Lin, H. Huang, P. Q. Huang, Sci. China
Chem. 2011, 54, 737–744.
This work was presented in part at the 9th International Sym-
posium on Carbanion Chemistry (ISCC-9), Florence, Italy,
July, 2010; See book of abstracts: communication P-18.
a) Y. Arai, M. Matsui, T. Koizumi, M. Shiro, J. Org. Chem.
1991, 56, 1983–1985; b) Y. Arai, M. Matsui, A. Fujii, T. Kon-
tani, T. Ohno, T. Koizumi, M. Shiro, J. Chem. Soc. Perkin
Trans. 1 1994, 15–23.
C. Camarero, I. González-Temprano, A. Gómez-SanJuan, S.
Arrasate, E. Lete, N. Sotomayor, Tetrahedron 2009, 65, 5787–
5798.
Mercaptoisoborneol was prepared by LiAlH4 reduction of
commercial (1S)-(+)-10-camphorsulfonyl chloride according to
literature procedure: E. L. Eliel, W. J. Frazee, J. Org. Chem.
1979, 44, 3598–3599.
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
a) R. S. Glass, W. N. Setzer, U. D. G. Prahbu, G. S. Wilson, Tet-
rahedron Lett. 1982, 23, 2335–2338; b) O. de Lucchi, V. Lucch-
ini, C. Marchioro, G. Valle, G. Modena, J. Org. Chem. 1986,
10
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Approach to Complex Polycyclic α-Hydroxy γ-Lactams
51, 1457–1466; c) O. de Lucchi, V. Lucchini, C. Marchioro, G.
Valle, G. Modena, J. Org. Chem. 1989, 54, 3245–3246. The
stereochemical outcome of this kind of oxidation has also been
explained through the formation of an intramolecular hydro-
gen bond, see: d) R. Annunziata, M. Cinquini, F. Cozzi, S.
Farina, V. Montanari, Tetrahedron 1987, 43, 1013–1018.
[26] In the presence of ZnCl2, formation of a zinc chelate with sulf-
inyl and carbonyl oxygen atoms would direct the attack of cy-
clopentadiene from the less hindered side to afford endo prod-
uct 9.
8128; e) L. Ollero, G. Mentink, F. P. J. T. Rutjies, W. N. Speck-
amp, H. Hiemstra, Org. Lett. 1999, 1, 1331–1334; f) S.-H. Kim,
S.-I. Kim, S. Lai, J. K. Cha, J. Org. Chem. 1999, 64, 6771–6775;
g) S. Santra, N. Masalov, O. L. Epstein, J. K. Cha, Org. Lett.
2005, 7, 5901–5904; hydrazinolysis of N-(1,3-dioxoindanyl)
ethyl-substituted imides: h) C. J. Roxburgh, L. Banting, Aust.
J. Chem. 2006, 59, 59–74; silylative Dieckmann-like cyclizations
of ester-imides: i) R. M. de Figuereido, R. Frölich, M.
Christmann, Angew. Chem. 2007, 119, 2941; Angew. Chem. Int.
Ed. 2007, 46, 2883–2886; see also ref.[14] For radical cyclization
of N-substituted cyclic imides, see: j) T. Bootwicha, D. Pan-
ichakul, C. Kuhakarn, S. Prabpai, P. Kongsaeree, P. Tuchinda,
V. Reutrakul, M. Pohmakotr, J. Org. Chem. 2009, 74, 3798–
3805; k) for electroreductive intramolecular coupling of imides
with α,β-unsaturated esters, see: l) N. Kise, S. Isemoto, T. Saku-
rai, Org. Lett. 2009, 11, 4902–4905; and with ketones and O-
methyloximes: m) N. Kise, K. Fukuzawa, T. Sakurai, Tetrahe-
dron Lett. 2010, 51, 5767–5770; for the benzo-fused systems,
see, Parham cyclization; for a recent review, see ref.[8j] Photocy-
clization of N-iodoalkyl-substituted imides: n) A. G. Gries-
beck, A. Henz, K. Peters, E.-V. Peters, H. G. von Schnering,
Angew. Chem. 1995, 107, 498; Angew. Chem. Int. Ed. Engl.
1995, 34, 474–476; for photocyclization of N-silylalkyl-substi-
tuted imides, see: o) U. C. Yoon, S. W. Oh, S. M. Lee, S. J. Cho,
J. Gamlin, P. S. Mariano, J. Org. Chem. 1999, 64, 4411–4418.
[27] See for example: T. J. Brocksom, U. Brocksom, D. Frederico,
Tetrahedron Lett. 2004, 45, 9289–9891, and references cited
therein.
[28] For reviews, see ref.[8] For some representative examples, see:
a) C. Agami, F. Amiot, F. Couty, L. Dechoux, C. Kaminsky,
O. Venier, Tetrahedron: Asymmetry 1998, 9, 3955–3958; b) H.
Dhimane, C. Vanucci-Bacque’, L. Hamon, G. Lhommet, Eur.
J. Org. Chem. 1998, 1955–1963; c) D. Potts, P. J. Stevenson, N.
Thompson, Tetrahedron Lett. 2000, 41, 275–278; d) M. David,
H. Dhimane, C. Vanucci-Bacque’, L. Hamon, G. Lhommet,
Heterocycles 2001, 55, 941–949.
[29] For selected reviews, see: a) M. A. J. Miah, T. Hudlicky, J. W.
Reed, in: The Alkaloids (Ed.: G. A. Cordell), Academic Press,
San Diego, 1998, vol. 51, p. 199–269; b) T. Hudlicky, J. W.
Reed, The Way of Synthesis: Evolution of Design and Methods
for Natural Products, Wiley-VCH, Weinheim, Germany, 2007,
part 4.5, p. 655–687; c) H. Abdelkafi, B. Nay, Nat. Prod. Rep.
2012, 29, 845–869.
[30] M. F. Semmelhack, B. P. Chong, R. D. Stauffer, T. D. Roger-
son, A. Chong, L. D. Jones, J. Am. Chem. Soc. 1975, 97, 2507–
2516.
[33]
[34]
W. C. Still, H. Kann, A. J. Miltra, J. Org. Chem. 1978, 43,
2923–2925.
a) D. D. Perrin, W. L. F Armarego, Purification of Laboratory
Chemicals, Pergamon Press, Oxford, UK, 4th ed., 1997; b)
B. G. Williams, M. Lawton, J. Org. Chem. 2010, 75, 8351–8354.
P. Y. Reddy, S. Kondo, T. Toru, Y. Ueno, J. Org. Chem. 1997,
62, 2652–2664.
[35]
[36]
[31] For a recent example, see: M. G. Goncalves-Martin, S. Sigm-
antas, P. Renaud, Helv. Chim. Acta 2012, 95, 2502–2514, and
references cited therein.
K. L. Burgess, N. J. Lajkiewicz, A. Sanyal, W. Yan, J. K. Sny-
der, Org. Lett. 2005, 7, 31–34.
[32] α-Hydroxyindolizidines and pyrroloazepines have been synthe-
sized by decarbonylation/oxidation of hexahydroindolizin-3-
ones, see: a) M. J. Martín-López, F. Bermejo-González, Tetra-
hedron Lett. 1994, 35, 8843–8846; for reductive cyclization of
N-iodoallyl imides with samarium diiodide, see: b) D.-C. Cha,
C.-S. Yun, E. Yu, Tetrahedron Lett. 1996, 37, 2577–2580; c) D.-
C. Cha, C.-S. Yun, Y. Lee, J. Org. Chem. 2000, 65, 621–623;
titanium-mediated cyclization of ω-vinyl tethered imides: d) J.
Lee, J. D. Ha, J. K. Cha, J. Am. Chem. Soc. 1997, 119, 8127–
[37] B. P. Wijnberg, W. N. Speckamp, A. R. C. Ooestveen, Tetrahe-
dron 1982, 38, 209–217.
[38] K. D. Camm, N. Martinez Castro, Y. Liu, P. Czechura, J. L.
Snelgrove, D. E. Fogg, J. Am. Chem. Soc. 2007, 129, 4168–
4169.
[39] This compound has been reported in ref.[19a], but no spectro-
scopic or other characterization data were given.
Received: June 17, 2013
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 31-08-13 10:40:19
Pages: 12
A. Gómez-SanJuan, N. Sotomayor, E. Lete
FULL PAPER
RCM Reactions
The sequence of allylmagnesium chloride
addition/RCM sequence using N-alkenyl-
substituted imides provides mild access to
indolizinone and pyrrolozepinone deriva-
tives with an α-hydroxy-γ-lactam frame-
work.
A. Gómez-SanJuan, N. Sotomayor,
E. Lete* .......................................... 1–12
RCM Approach to Complex Polycyclic α-
Hydroxy γ-Lactams: Synthesis of Indoliz-
inones and Pyrroloazepinones
Keywords: Nitrogen heterocycles / Lact-
ams / Ring-closing metathesis / Diastereo-
selectivity / Grignard reaction /
α-Amidoalkylation
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