Amidyls in radical cascades. The total synthesis of (±)-aspidospermidine and (±)-13-deoxyserratine

Article abstract of DOI:10.1016/j.tet.2008.02.107

Concise routes to aspidospermidine and 13-deoxyserratine are described, hinging on a cascade starting from an amidyl radical and allowing the construction of the key indolizidine cores in one step.

Full text of DOI:10.1016/j.tet.2008.02.107

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4803e4816
www.elsevier.com/locate/tet
Amidyls in radical cascades. The total synthesis of (ꢀ)-aspidospermidine
and (ꢀ)-13-deoxyserratine
´ ˆ
´
Anne-Claude Callier-Dublanchet, Jerome Cassayre, Fabien Gagosz, Beatrice Quiclet-Sire,
*
Lisa A. Sharp, Samir Z. Zard
Laboratoire de Synthe`se Organique associe´ au C. N. R. S., De´partement de Chimie, Ecole Polytechnique, F-91128 Palaiseau, France
Received 7 October 2007; received in revised form 27 November 2007; accepted 29 February 2008
Available online 18 March 2008
This paper is dedicated with much affection to Professor William B. Motherwell
Abstract
Concise routes to aspidospermidine and 13-deoxyserratine are described, hinging on a cascade starting from an amidyl radical and allowing
the construction of the key indolizidine cores in one step.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
alkaloids, whereas the last, relatively rare, combination is
found in the stemona alkaloids (Fig. 1).
The use of radical reactions in organic synthesis became
widespread about three decades ago yet, despite this popular-
ity, most of the synthetic applications have involved carbon
centred radicals, while heteroatom based radicals remained es-
sentially just curiosities.1 This limited attention stems in part
from a lack of convenient and general methods for generating
these species, and perhaps a certain absence of a feel regarding
their reactivity.
O
O
5-exo / 5-exo
N
N
pyrrolizidine
O
N
O
N
5-exo / 6-endo
indolizidine
R
R
We and others recently developed a number of processes
for creating nitrogen-centred radicals, which, when captured
by internal olefins, give rise to various types of nitrogen con-
taining heterocycles.2e4 Thus, pyrrolizidine, indolizidine and
related structures commonly found in many alkaloid families
can be constructed by employing radical cascades involving,
for example, an amidyl radical, as shown in Scheme 1.5 De-
pending on the nature of R and the length of the tether,
[3,3,0], [4,3,0], and even [5,3,0] azabicyclic motifs can be
readily assembled by this approach. The first two correspond
to the core motif of the ubiquitous pyrrolizidine and indoline
O
O
N
N
5-exo / 7-endo
stemona
R
R
Scheme 1.
We have implemented strategies based on such cascades for
the synthesis of aspidospermidine 1 and 13-deoxyserratine 2,
both of which contain a key indolizidine subunit.5 As will
be apparent in the present, more detailed account of this
work, the method we ultimately adopted for generating the
key nitrogen centred radical relies on the cleavage of hydroxa-
mic acid benzoates with stannyl radicals. This method can be
* Corresponding author. Tel.: þ33 169335971; fax: þ33 169335972.
E-mail address: zard@poly.polytechnique.fr (S.Z. Zard).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.107

4804
A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
16
1. AlCl3, AcCl, CH2Cl2, 98%
2. H2, Pd(C), MeOH, 91%
3. MeI, K2CO3, acetone, 85%
Me
CO2Me
CO2Me
R2
R3
MeO
R1
HO
8
8
12
7
N
H
13
H
4
9
5
N
Li, NH3, t-BuOH, THF
then BrCH2CO2t-Bu, 85%
N
H
H
1
O
13-Deoxyserratine 2, R1= R3= H, R2=OH
Serratine 3, R1= OH, R2=OH, R3= H
Serratinine 4, R1= OH, R2= H, R3= OH
O
O
Aspidospermidine 1
MeO2C
MeO2C
MeO
OH
MeO
OtBu
TMSOTf,
2,6-lutidine
Figure 1.
CH2Cl2, 98%
9
10
adapted to produce a number of other synthetically useful
nitrogen radicals, in particular iminyls and amidinyls.3j,q
1.
OH
Cl
HN
O
N
EDC, THF, H2O
69%
MeO2C
MeO
OBz
2. Results and discussion
11
12
2. BzCl, Et3N, CH2Cl2,
The aspidosperma family of indole alkaloids have inspired
many synthetic strategies for the construction of the pentacyclic
framework, in particular aspidospermidine 1, the parent com-
pound.6 Our proposed synthesis of this alkaloid is outlined in
Scheme 2; it hinges on a 5-exo/6-endo cascade starting with
amidyl radical 7 to provide the key tricyclic system 5, via inter-
mediate 6. Compound 5 had already been converted into aspi-
dopermidine by the known Fischer indole reaction, initially
by Stork6a and later by other groups. We envisaged, based on
a literature precedent,7 that placing the chlorine atom on the
side chain in intermediate 7 would inhibit the 5-exo closure
and favour a 6-endo in the second cyclisation. This chlorine
atom would then be removed by adding an extra equivalent of
tributyl stannane. Finally, the required cyclohexadiene radical
precursor would be prepared starting from a simple aromatic
precursor 8 by an alkylative Birch reduction.
Cl
81%
O
N
MeO2C
MeO
CO2Me
OBz
Bu3SnH, ACCN,
PhCF3, reflux
MeO
Cl
13
8
Scheme 3.
(a useful replacement for benzene), no amidyl radical cyclisa-
tion to give compound 6 took place: aromatisation occurred in-
stead to give benzoate ester 8. Thus, ironically, the key radical
cyclisation just removed, in one fell swoop, the side chain we
had painstakingly attached. Presumably, this is the result of ab-
straction of a doubly allylic hydrogen by a tributyltin radical or
by radicals derived from the initiator to give cyclohexadienyl
radical 13, which aromatises through CeC bond scission.
Such fragmentations are well precedented in the literature
and have been exploited in ingenious radical sequences.8
Our wish to keep the enol ether group as a masked ketone
in the cyclisation product 6 stemmed from the subsequent
need to reduce the lactam carbonyl selectively in order to at-
tain Stork’s intermediate 5. However, the unexpected and un-
toward fragmentation mentioned above thwarted our initial
plans. We were therefore forced to hydrolyse the methyl
enol ether first, in order to prevent the undesired abstraction
of a doubly allylic hydrogen and subsequent fragmentation
from occurring. As for the hurdle of the later reduction step,
we hoped to overcome it by exploiting the presence of the
methyl ester to sterically shield the ketone and allow perhaps
the selective reduction of the lactam.
By treating the crude Birch reduction product with aqueous
hydrochloric acid in THF, deprotection of both the tert-butyl
ester and methyl enol ether groups readily took place to give
the carboxylic acid, which existed mostly in the lactol form
14 (Scheme 4). This compound was converted into the new
benzoate ester radical precursor 15 by the same procedure as
above. Pleasingly, the amidyl radical formed upon treatment
of 15 with tributyltin hydride and ACCN underwent 5-exo cyc-
lisation in useful yield. The major product of the reaction was
N
N
H
H
N
O
O
H
H
1
5
N
H
6
MeO2C
MeO
O
N
CO2Me
MeO2C
MeO
MeO
Cl
8
7
Scheme 2.
The desired precursor for the amidyl radical cyclisation was
synthesised as shown in Scheme 3. Birch reduction and alkyl-
ation of ester 8 with tert-butylbromoacetate formed cyclohexa-
diene 9. Numerous conditions for the cleavage of the tert-butyl
ester also resulted in destruction of the enol ether. Finally,
TMSOTf and 2,6-lutidine cleanly provided the required acid
10, which was coupled to chloroallyl hydroxylamine 11 using
EDC, followed by benzoylation to give hydroxamic benzoate
12. However, we were disappointed to find that when 12 was
treated with tributyltin hydride and 1,10-azobis(cyclohexane-
carbonitrile) (ACCN) in refluxing a,a,a-trifluorotoluene

A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
4805
tricycle 16, where the desired 6-endo cyclisation had followed.
The minor product (29%) was the monocyclised derivative 17.
It is interesting to note that, under the same conditions, ana-
logue 18, lacking a chlorine atom, suffered two consecutive
5-exo ring closures to furnish derivative 19 with a pyrrolizidine
structure in 46% yield. The chlorine substituent is therefore
necessary for regiocontrol.
selective reduction of the lactam. In case of success, this
will result in a shorter and better synthesis of the target
alkaloid.
Treatment with boraneedimethylsulfide complex gave only
the undesired alcohol 21, the product of reduction of both the
lactam and the ketone (Scheme 5). In contrast, the much bulk-
ier 9-BBN cleanly and selectively effected the reduction of the
lactam to give tricyclic ketoester 22 in 93% yield.9 Finally,
decarboxylation of the b-keto ester supplied Stork’s intermedi-
ate 5, which was converted into aspidosperidine 1 through
a Fischer indole reaction with phenyl hydrazine followed by
sodium borohydride reduction.
O
i. Li, NH3, t-BuOH, THF,
CO2Me
CO2Me
BrCO2t-Bu
O
HO
MeO
ii. HCl(aq), THF, 90%
The cascade starting with amidyl radicals thus provides ac-
cess to both indolizidine and pyrrolizidine skeletons by a 5-exo
cyclisation followed by either a 5-exo or 6-endo cyclisation.
This second cyclisation is directed 6-endo versus 5-exo by
the presence or absence of the chlorine on the alkene. An
extension of this work would be to investigate the analogous
system involving 5-exo followed by 7-endo cyclisation, which
would generate the 5,7 system found in the Stemona alkaloids.
The precursor for the desired radical cascade, benzoate 26a,
was prepared in a similar way to cyclohexadiene 9, used above
in the synthesis of aspidospermidine. Thus, Birch reduction
and alkylation of methyl p-ethyl benzoate 23 followed by
hydrolysis of the tert-butylester gave an equal mixture of
two diastereomeric acids 24a/b, which could be separated by
crystallisation of their benzylamine salts, even though the rel-
ative stereochemistry of each could not be determined by NOE
experiments (Scheme 6). Coupling of one of these diastereo-
mers with homoallyl hydroxylamine 25 and treatment with
benzoyl chloride provided radical precursor 26a. Upon treat-
ment of this compound with tributyltin hydride and ACCN,
a relatively clean reaction ensued to give 27a as the major
product along with lesser amounts of bicyclic derivative 28a.
8
14
1. i. isobutylchloroformate, Et3N,
ii.hydroxylamine 11
2. BzCl, Et3N, CH2Cl2, 67%
O
MeO2C
O
N
O
N
H
MeO2C
OBz
Bu3SnH, ACCN,
O
PhCF3, reflux
16, 53%
X
O
MeO2C
O
15, X = Cl
18, X = H
N
H
Cl
Bu3SnH, ACCN,
PhCF3, reflux
O
17, 29%
MeO2C
O
N
19, 46%
H
Scheme 4.
Tricycle 16 could be decarboxylated with lithium chloride
in DMSO to give tricyclic ketone 20 (Scheme 5), which has
previously been converted into aspidospermidine1a,q,w in a se-
quence requiring protection of the ketone for reduction of the
amide, and then subsequent Fischer indole reaction. However,
as mentioned above, we hoped that the ester in 16 would pro-
vide sufficient steric shielding of the ketone group to allow
O
CO2Me
1. Li, NH3, t-BuOH, THF,
BrCH2CO2t-Bu
MeO2C
OH
24a/b
2. CF3COOH, CH2Cl2, 60%
O
O
N
N
23
LiCl, DMF, 140 °C
1.i. isobutylchloroformate, Et3N,
THF
MeO2C
Cl
H
O
H
H
ii.
NH
25
HO
O
16,93%
20, 75%
BH3.SMe2,
THF, reflux
2. BzCl, Et3N, CH2Cl2, 66%
9-BBN, THF
reflux
O
O
O
N
MeO2C
MeO2C
OBz
MeO2C
Bu3SnH
ACCN
N
N
N
MeO2C
H
H
+
H
N
HO
PhCF3, reflux
LiCl, DMF
140 °C
21, 85%
Cl
H
Cl
MeO2C
O
H
26a
28a, 8%
27a, 39%
N
22
O
O
H
O
H
H
N
N
H
N
1. PhNHNH2,
5, 88%
O
H
H
AcOH, 62%
2. NaBH4, MeOH,
88%
O
N
H
Stenine 29
H
O
Stemoamide 30
H
1
O
Scheme 5.
Scheme 6.

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A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
It is thus possible to accomplish a 5-exo followed by 7-endo
cyclisation and to assemble three of the four rings of stenine,
29, in only four steps from methyl p-ethyl benzoate 23. Only
one isomer was obtained in the cyclisation and is very likely
that indicated for 27a in Scheme 6, according to molecular
models, but this has not been totally ascertained yet. Another
example of a stemona alkaloid, stemonamide 30, is displayed
in the same scheme.
The second target that we explored belongs to the Lycopo-
dium alkaloids,10 a family with a fascinating structural com-
plexity that has yielded challenging synthetic targets in recent
years. In the serratinane subgroup, with the exception of (ꢀ)-
serratinine 4,11 and the corresponding 8-deoxy derivative,12
each of which has previously been synthesised by a long and
low yielding route, not much attention has been paid to other
alkaloids of this structural family. So far, only one approach
to serratine 310,13 has been reported by Livinghouse and
co-workers.14
36 gave keto-alkyne 37 in modest yield. Palladium catalysed
regioselective hydration of the triple bond16 delivered smoothly
diketone 38, which was subjected to a Robinson type annelation
using methanolic potassium hydroxide to provide cyclopente-
none 39 in quantitative yield. Acid hydrolysis of the acetal
group furnished intermediate aldehyde 34. This was not iso-
lated but condensed in situ with hydrazide 35 to give iminyl
radical precursor 33 in 65% yield. Unfortunately, all our at-
tempts to induce ring closure and capture with methyl acrylate
using the usual stannane techniques met with complete failure.
No evidence even for occurrence of the first cyclisation step
could be adduced by spectroscopic analysis of the crude
reaction mixtures.
O
Br
O
O
O
O
O
O
O
O
O
36
37
40%
In principle, the indolizidine framework of serratine 3 could
also be constructed by a cascade of radical cyclisations starting
with a nitrogen centred radical. In the first instance, however,
we aimed for the slightly less complex (ꢀ)-13-deoxyserratine
2. Our initial synthetic plan towards 13-deoxyserratine is out-
lined in Scheme 7 and relies on the obtention of lactam 30 by
cyclisation of tricyclic ester 31 upon selective reduction of the
imine group. The formation of intermediate 31 would result
from ring closure of iminyl radical 32 and capture of the ensuing
carbon radical at C-12 with methyl acrylate. We had shown that
such sequences were indeed possible on simpler structures.2a
The iminyl radical would be generated from the thiosemi-
carbazone precursor 33, itself made by simple condensation
of hydrazide 35 with aldehyde 34.3k,l
PdCl2(CH3CN)2
ultrasound
O
O
O
O
O
O
KOH, MeOH
O
O
O
O
O
39, 100%
38, 75%
1. HCl aq. 2%
S
2.
H2N
N
OMe
Me
O
O
O
O
Bu3SnH, AIBN
COOMe
N
Me
OMe
N
N
MeO2C
33, 65%
S
31
H
Me
O
OH
Scheme 8.
O
O
13
D
MeOOC
H
H
In parallel, we examined a far more efficient three-step route
to an advanced precursor exploiting the formidable Pausone
Khand reaction.17 This second synthetic plan is summarised
in Scheme 9. Thus, enyne 40, made in two trivial steps from
1-hexyn-5-one, underwent smooth conversion into cyclopente-
none 41, after treatment of the intermediate alkyneecobalt
complex with N-methyl morpholine N-oxide.18 The formation
of 5/6 ring combination, as compared with bicyclic 5/5 systems,
is relatively uncommon using the PausoneKhand reaction.17
The high efficiency in our case is presumably the result of a
favourable ThorpeeIngold effect exerted by the substituents
on the carbon bearing the protected tertiary alcohol.
The high diastereoselectivity (93/7) observed in the Pau-
soneKhand reaction, as determined by analysis of the 1H
NMR spectra, may be explained by considering the relative
stability of the intermediates leading to 41 (7a) and 41 (7b),
in the light of earlier studies in the literature.19 The preferred
conformers for the alkyneeCo(CO)6 complex can be regarded
as A and B, in which the TBSO group points in a pseudo-equa-
torial position. A weaker repulsion between H(7) and the
axial-like methyl group would be expected in conformer A,
H
A
C
N
N
O
N
B
O
O
31
O
30
13-Deoxyserratine 2
O
O
O
H
MeOOC
12
H
O
O
H
Me
N
H
N
MeO
33
N
34
O
H
O
S
S
H
32
H2N
N
OMe
35
Me
Scheme 7.
For the synthesis of hydrazone 33, we followed the classical
approach depicted in Scheme 8. Thus, alkylation of mono-pro-
tected 1,4-cyclohexanedione with known15 propargyl bromide

A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
4807
1.
the desired tetracyclic compound 46 or even tricyclic deriva-
tive 47.
MgBr
ether, rt
O
TBSO
2. TBSOTf,
2,6-lutidine,
CH2Cl2, 0 °C
1. n-BuLi, THF
H
1. NaBH3CN,
TBSO
-78 °C
MeOH, pH 4
2. Et3N, ether,
Cl
O
96%
2. DMPU
O
S
45, 85%
42
Br
O
O
N
N
H
Me
OMe
1. Co2(CO)8,
CH2Cl2
TBSO
TBSO
O
O
O
O
Bu3SnH
ACCN
2. NMO.H2O
THF, 0 °C
H
H
41 95% (93/7)
toluene
O
TBSO
TBSO
O
O
40, 53%
O
N
N
1. HCl 5%, THF
H
2. MeOH,
46
O
O
47
S
TBSO
O
NH2
N
Me
Bu3SnH,
ACCN
toluene
Scheme 11.
MeO
N
H
H
In the final attempt to access our elusive target, we consid-
ered accelerating the ring closure of the amidyl radical by
placing the carbonyl group inside the ring being formed (cf.
49 in Scheme 12) instead of outside as in the last approach.
The former variant was shown by Newcomb and colleagues
to cyclise at least one order of magnitude faster.20 To access
the corresponding amidyl radical, however, it proved easier
to prepare the hydroxamic acid benzoate precursor, as for as-
pidospermidine, rather than the thiosemicarbazide methodol-
ogy we had been using so far. Our synthetic plan, outlined
in Scheme 12, hinges on two key steps allowing the stereocon-
trolled introduction of the four stereogenic centres at C(4),
C(7), C(12) and C(15). The same diastereoselective Pausone
Khand reaction17 would allow an easy access to the key bicy-
clo [4.3.0] nonenone intermediate 50 starting from the very
simple enyne 51. The concave shape of this molecule would
then control the stereochemistry in the cascade sequence in-
volving amidyl radical 49 to give keto-lactam 48 and thence
(ꢀ)-13-deoxyserratine 2.
TBSO
43
O
COOMe
N
H
S
N
42, 100%
TBSO
O
Me
OMe
N
MeOOC
44
Scheme 9.
in comparison with the one between H(6) and the axial-like
methyl group in conformer B, thus favouring cyclisation
through conformer A (Scheme 10).
Me
OTBS
H
Me
7
6
7
OTBS
A
H
41 (7 )
R
Co2(CO)6
O
O
O
Me
OTBS
6
H
H
Me
Me
R
Me
Me
OTBS
7
OH
H
15
7
OTBS
H
H
O
OTBS
41 (7 )
(CO)6Co2
13
12
7
B
R
H
O
4
O
N
N
N
O
O
O
Scheme 10.
O
O
48
49
13-deoxyserratine 2
The major isomer 41 (7a) was easily converted into thiose-
micarbazone 42 in quantitative yield. However, we were again
disappointed to find that slow addition of tributyl stannane to
a mixture of 42 and methyl acrylate did not accomplish the
desired transformation and no cyclic imine 43 or 44 could
be detected. Faced with this second setback, we decided to
try starting with an amidyl radical and to render intramolecular
the second ring closure. To this end, thiosemicarbazone 42 was
reduced with sodium cyanoborohydride under mildly acidic
conditions and the intermediate hydrazide acylated with
acryloyl chloride to furnish 45 in good overall yield (Scheme
11). In this case, too, treatment with stannane did not provide
Me OTBS
H
Me OTBS
HOOC
R
51
50
O
Scheme 12.
Practically, this was achieved by the reaction sequence pic-
tured in Scheme 13: 4-hexyne-2-one 52 was alkylated with
allylmagnesium bromide and the resulting tertiary alcohol

4808
A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
protected as the silyl ether alkyne 53 in 96% yield using
tert-butyldimethylsilyl trifluoromethanesulfonate. Subsequent
deprotonation with n-BuLi followed by alkylation with 2-(3-
bromopropoxy)tetrahydro-2H-pyran furnished precursor 51
for the PausoneKhand reaction. Exposure of the alkynee
Co(CO)6 complex derived from 51 with N-methyl morpholine
oxide hydrate18 resulted in a rapid conversion into the desired
bicyclo [4.3.0] nonenone 55 in 89% isolated yield, as a 93:7
mixture of epimers at the level of C-7. Submitting the major
isomer to Jones oxidation finally led to the formation of the
key intermediate acid 50 (64% overall from 52).
the lactam moiety then reduced with LiAlH4.21 Finally, depro-
tection of both the alcohol and ketone using TBAF provided
(ꢀ)-13-deoxyserratine 2 in 48% yield for the last three steps.
Me
Me
OTBS
H
OTBS
H
Bu3SnH
(1eq.)
ACCN
56
12
toluene
N
N
O
O
58
O
59, 48%
O
Me
Me
O
1.
OTBS
Me OTBS
Bu3SnH
(2eq.)
MgBr
OTBS
1. n-BuLi
2. HMPA,
ACCN
2. TBSOTf,
2,6-lutidine
Br
57
12
Cl
H
H
trifluoro-
toluene
53, 96%
52
THPO
N
N
O
O
O
49
Me
OTBS
O
48, 52%
Me OTBS
H
Me OTBS
Jones
oxidation
(on 37 7a)
Me
Me
OTBS
7
H
1. Co2(CO)8
OR
TBSOTf
Et3N
2. NMO.H2O
CH2Cl2/THF
HOOC
1. LiAlH4
2. TBAF
12
4
O
H
H
THPO
O
OTHP
50, 97%
51, 83%
N
55, 89%
(7 /7 : 93/7)
N
O
OTBS
60, 83%
1. isobutyl-
chloroformate, Et3N
O
61, R = -TBS, 58%
2, R = H, 96%
Me
OTBS
R
2.
NHOH
H
O
Scheme 14.
R
O
Et3N
3. BzCl, Et3N
56, R=H, 78%
57, R=Cl, 81%
We thus have in hand a concise (10 steps) and efficient
N
(12% overall yield) synthesis of (ꢀ)-13-deoxyserratine 2. It
is worth stressing that the use of an amidyl radical intermedi-
ate has allowed us to create in one step the two adjacent qua-
ternary centres at C(4) and C(12) with the correct relative
stereochemistry. The presence of these centres in serratine
and related alkaloids such as serratinine has considerably ham-
pered previous approaches. The concise access to both (ꢀ)-
aspidospermidine 1 and (ꢀ)-13-deoxyserratine 2 showcases
the considerable potential for nitrogen centred radicals for
the total synthesis of various families of alkaloids.
BzO
Scheme 13.
The synthesis of the corresponding O-benzoyl N-allyl- and
N-2-chloroallyl-hydroxamic acids, 56 and 57, was accom-
plished in the same manner as for the aspidospermidine pre-
cursors without isolation of the intermediates. Slow addition
of Bu3SnH and ACCN to a refluxing solution of 56 in toluene
furnished the undesired pyrrolizidine structure 59 in 48% yield
via a 5-exo/5-exo cyclisation cascade starting with radical 58
(Scheme 14). This result was not unexpected, but we were
nevertheless hoping that steric hindrance around the tertiary
radical, derived from the first 5-exo cyclisation and localised
at C-12, would favour a subsequent 6-endo mode without
the need to place a directing chlorine atom on the allylic
side chain of the hydroxylamine moiety. In contrast, treatment
of the chlorinated analogue 57 with 2 equiv of Bu3SnH in
a,a,a-trifluorotoluene under dilute conditions indeed resulted
in the formation of the desired indolizidinone 48 as the major
product (52%) possessing the correct serratine skeleton
(Scheme 14). To complete the synthesis, it was necessary to
reduce the lactam without affecting the more reactive ketone.
Various reagents that could possibly accomplish this task di-
rectly were tried but with little success. The ketone was there-
fore protected as a tert-butyldimethylsilyl-enol-ether 60 and
3. Experimental
3.1. General conditions
All reactions were carried out under an inert atmosphere.
Commercial reagents were used as-received without further pu-
rification. All products were purified by using silica gel (SDS,
Silice 60 A. C. C. 40e63 mm) or by crystallisation. Analytical
TLC was carried out on Merck silica gel plates using short
wave (254 nm) UV light, 1% aq KMnO4 solution to visualise
components. NMR spectra were recorded in CDCl3 using
a Bruker AMX400 operating at 400 MHz for 1H and 100 MHz
for 13C. The chemical shifts are expressed in parts per million
(ppm) referenced to residual chloroform. 1H NMR data are re-
ported as follows: d, chemical shift; multiplicity (recorded as: s,

A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
4809
singlet; br s, broad singlet; d, doublet; t, triplet; q, quadruplet;
qt, quintuplet; ht, heptuplet; dd, double doublet; ddd, double
double doublet; dddd, double double double doublet; dt, double
triplet; ddt, double double triplet; dq, double quadruplet; tt,
triple triplet; td; triple doublet; tdd, triple double doublet; m,
multiplet), coupling constants (J are given in hertz, Hz) and in-
tegration. Infrared absorption spectra were recorded as thin
films or as solutions in CCl4 with a PerkineElmer 1600 Fourier
Transform Spectrophotometer. Mass spectra were recorded
with an HP 5989B mass spectrometer via direct introduction
for chemical positive ionisation (CI) using ammonia as the re-
agent gas. Melting points were determined by Reichert micro-
scope apparatus and were uncorrected. HRMS were performed
on JEOL JMS-GcMate II, GC/MS system spectrometer. Micro-
analyses were performed by the Service de Microanalyse, Insti-
tut de Chimie des Substances Naturelles, CNRS, F-91198,
Gif-sur-Yvette.
d 173.1, 169.9, 152.3, 139.4, 119.2, 93.5, 79.8, 54.4, 52.5,
50.9, 41.9, 29.5, 28.9, 27.9, 12.0; IR (thin film) nmax 3040,
2951, 1752, 1739, 1638, 1392, 1208, 1093 cmꢁ1; MS (CI):
m/z (%) 311 [MþH]þ, 328 [MþNH3]þ; HRMS (EI) calcd for
C17H26O5 [M]þ 310.1780, found 310.1793.
3.1.3. (ꢀ)-2-(1-(Methoxycarbonyl)-5-ethyl-2-methoxy-
cyclohexa-2,5-dienyl)acetic acid (10)
To a solution of the tert-butyl ester 9 (438 mg, 1.5 mmol) in
dichloromethane (15 mL) at 0 ꢂC was added 2,6-lutidine
(700 mL, 3.2 mmol) and trimethylsilyltrifluoromethanesulfo-
nate (700 mL, 3.4 mmol). After 1 h, water was added, the aque-
ous phase was acidified and extracted with dichloromethane.
The combined organic phases were dried over anhydrous mag-
nesium sulfate and the solvent was removed in vacuo to leave
acid 10 as a colourless oil (372 mg, 98%): 1H NMR
(400 MHz, CDCl3) d 10.2 (1H, br s), 5.40e5.36 (1H, m),
4.85 (1H, t, J¼3.5 Hz), 3.69 (3H, s), 3.55 (3H, s), 3.01 (1H,
d, J¼14.9 Hz), 2.82 (1H, d, J¼14.9 Hz), 2.77 (2H, s), 2.07
(2H, qd, J¼7.3, 3.5 Hz), 1.03 (3H, t, J¼7.3 Hz); 13C NMR
(100 MHz, CDCl3) d 166.8, 157.1, 139.5, 131.1, 119.4, 93.5,
65.7, 54.6, 51.6, 41.7, 29.0, 27.6, 11.3; IR (thin film) nmax
3051, 2936, 1746, 1692, 1408, 1361, 1207, 1104 cmꢁ1; MS
(CI): m/z (%) 255 [MþH]þ, 272 [MþNH3]þ; HRMS (EI) calcd
for C13H18O5 [M]þ 254.1154, found 254.1142.
3.1.1. Methyl 5-ethyl-2-methoxybenzoate (8)
To a solution of methyl 5-ethyl-2-hydroxybenzoate (1.8 g,
10 mmol) in acetone (50 mL) at room temperature were added
potassium carbonate (2 g, 15 mmol) and methyl iodide
(1.3 mL, 20 mmol). After 6 h, the reaction mixture was concen-
trated then diluted with diethyl ether and water. The organic
phase was separated and the aqueous phase was extracted
with diethyl ether. The combined organic phases were dried
over anhydrous magnesium sulfate and the solvent was re-
moved in vacuo. The residue was purified by flash chromatog-
raphy (1:9 ethyl acetate/hexanes) to yield the title compound as
3.1.4. (ꢀ)-Methyl 1-[(N-2-chloroallyl-N-benzyloxy-
carbomoyl)methyl]-5-ethyl-2-methoxy-cyclohexa-
2,5-diene carboxylate (12)
1
a colourless oil (1.65 g, 85%): H NMR (400 MHz, CDCl3)
A solution of the acid 10 (960 mg, 4.02 mmol) and N-(2-
chloroallyl) hydroxylammonium trifluoroacetate22 (1.83 g) in
THF (18 mL) and water (18 mL) was adjusted to pH 5. EDC
(1.30 g, 6.78 mmol, 1.7 equiv) was added, and the resulting
mixture was stirred at room temperature for 2 h. The mixture
was diluted with diethyl ether, the aqueous phase was separated
and extracted with diethyl ether, and the combined organic ex-
tracts were washed with water. The organic phase was dried
over anhydrous magnesium sulfate and the solvent was re-
moved in vacuo. The residue was purified by flash chromatog-
raphy (1:5 diethyl ether/hexanes) to yield the hydroxylamine
(960 mg, 2.79 mmol, 69%). This hydroxylamine (800 mg,
2.33 mmol) was dissolved in dichloromethane (44 mL), and
triethylamine (3.3 mL, 20 mmol, 10 equiv) and benzoyl chlo-
ride (1.16 mL, 10 mmol, 4.3 equiv) were added at room temper-
ature. The mixture was stirred at room temperature for 15 min
then was washed with water. The organic phase was dried
over anhydrous magnesium sulfate and the solvent was re-
moved in vacuo. The residue was purified by flash chromatog-
raphy (3:7 diethyl ether/hexanes) to yield the title compound
d 7.70 (1H, d, J¼2.8 Hz), 7.23 (1H, dd, J¼6.2, 2.8 Hz), 6.80
(1H, d, J¼6.2 Hz), 3.84 (6H, s), 2.63 (2H, q, J¼7.4 Hz), 1.32
(3H, t, J¼7.4 Hz); 13C NMR (100 MHz, CDCl3) d 167.1,
158.6, 133.2, 131.8, 130.1, 113.8, 113.5, 56.4, 52.4, 33.6,
15.2; IR (thin film) nmax 3027, 2940, 1680, 1437, 1260,
1102 cmꢁ1; MS (CI): m/z (%) 195 [MþH]þ, 212 [MþNH3]þ;
HRMS (EI) calcd for C11H14O3 [M]þ 194.0943, found
194.0937.
3.1.2. (ꢀ)-Methyl 5-ethyl-2-methoxy-1-(tert-butoxy-
carbonylmethyl)cyclohexa-2,5-diene carboxylate (9)
To a solution of the ester 8 (5.0 g, 25.6 mmol) in THF
(8.8 mL), tert-butanol (2.1 mL) and ammonia (250 mL) at
ꢁ40 ꢂC was added lithium (448 mg, 74 mmol, 3 equiv). A per-
manent blue colour resulted and after 5 min, tert-butylbromoa-
cetate (7.3 mL, 49.4 mmol, 1.9 equiv) was added slowly. After
a further 5 min the ammonia was allowed to evaporate at room
temperature. The residue was neutralised with 2 M HCl and the
aqueous layer was extracted with diethyl ether. The combined
organic phases were dried over anhydrous magnesium sulfate
and the solvent was removed in vacuo. The residue was purified
by flash chromatography (1:5 diethyl ether/hexanes) to yield the
title compound 9 as a colourless oil (5.36 g, 21.8 mmol, 85%):
1H NMR (400 MHz, CDCl3) d 5.33e5.31 (1H, m), 4.81 (1H, t,
J¼3.5 Hz), 3.64 (3H, s), 3.52 (3H, s), 2.80e2.72 (3H, m), 2.67
(1H, dd, J¼22.0, 3.7 Hz), 2.01 (2H, qd, J¼7.9, 3.5 Hz), 1.34
(9H, s), 1.00 (3H, t, J¼7.9 Hz); 13C NMR (100 MHz, CDCl3)
1
12 as a colourless oil (810 mg, 1.88 mmol, 81%): H NMR
(400 MHz, CDCl3) d 8.07 (2H, d, J¼7.2 Hz), 7.66 (1H, t,
J¼7.2 Hz), 7.51 (2H, t, J¼7.6 Hz), 5.53 (1H, s), 5.43 (1H, s),
5.37 (1H, s), 4.84 (1H, s), 4.64 (1H, d, J¼16.4 Hz), 4.50 (1H,
d, J¼16.4 Hz), 3.67 (3H, s), 3.50 (3H, s), 3.20 (1H, d,
J¼15.6 Hz), 2.85e2.74 (3H, m), 2.07 (2H, q, J¼7.6 Hz), 1.04
(3H, t, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3) d 173.1,
170.8, 164.1, 152.1, 139.5, 135.5, 134.4, 130.1 (2 aromatic

4810
A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
Cþ1C), 128.8, 119.3, 115.4, 94.0, 54.6, 53.3, 52.6, 50.3, 37.8,
29.2 (2C), 12.1; IR (thin film) nmax 2963, 1766, 1735, 1640,
1452, 1219 cmꢁ1; MS (CI): m/z (%) 448 [MþH]þ.
(1H, m), 2.09 (2H, q, J¼7.6 Hz), 1.01 (3H, t, J¼7.6 Hz); 13C
NMR (100 MHz, CDCl3) d 206.8, 170.7, 170.5, 163.9, 144.3,
135.0, 134.6, 130.0, 128.8, 126.2, 119.8, 115.6, 56.5, 53.2,
52.7, 38.0, 37.2, 30.0, 28.5, 11.9; IR (thin film) nmax 2965,
1767, 1739, 1717, 1688, 1452, 1434, 1228 cmꢁ1; MS (CI):
m/z (%) 434 [MþH]þ, 451 [MþNH3]þ.
3.1.5. Methyl 5-ethyl-2,3,3a,6,7,7a-hexahydro-7a-hydroxy-
2-oxobenzofuran-3a-carboxylate (14)
To a solution of the ester 8 (3.00 g, 15.4 mmol) in ammonia
(150 mL), THF (5.3 mL) and tert-butanol (1.3 mL) at ꢁ40 ꢂC
was added lithium (270 mg, 44.8 mmol, 3 equiv). A perma-
nent blue colour resulted and after 5 min, tert-butylbromoace-
tate (7.3 mL, 49.4 mmol, 3.2 equiv) was added slowly. After
a further 5 min, ammonia was allowed to evaporate at room
temperature, then THF (100 mL) and hydrochloric acid
(2 M, 100 mL) were added. The reaction mixture was stirred
for an additional 2 h, then hydrochloric acid (6 M, 50 mL)
was added. After a further 4 h, the reaction mixture was
diluted with water and diethyl ether. The organic phase was
separated, the aqueous phase was extracted with diethyl ether
and the combined organic extracts were dried over anhydrous
magnesium sulfate. The solvent was removed in vacuo and the
residue was purified by flash chromatography (1:1 diethyl
ether/hexanes) to provide the title compound 14 as a colourless
3.1.7. Methyl 6a-ethyl-nonahydro-2,9-dioxo-1H-
pyrrolo[3,2,1-ij]quinoline-9a-carboxylate (16)
To a degassed solution of 15 (120 mg, 0.20 mmol) in trifluo-
rotoluene (5 mL) was added a solution of tributyltin hydride
(126 mL, 0.46 mmol, 2.3 equiv) and ACCN (10 mg,
0.041 mmol, 0.02 equiv) in trifluorotoluene (5 mL) over a pe-
riod of 12 h. The solvent was removed in vacuo and the residue
was purified by flash chromatography (diethyl ether) to provide
the tricycle 16 as a colourless oil (35 mg, 0.106 mmol, 53%)
and the bicycle 17 as a colourless oil (18 mg, 0.057 mmol,
29%). Data for tricycle 16: 1H NMR (400 MHz, CDCl3)
d 4.05 (1H, d, J¼12.8 Hz), 3.82 (1H, d, J¼2.4 Hz), 3.74 (3H,
s), 3.14 (1H, d, J¼17.2 Hz), 2.71 (1H, d, J¼17.2 Hz), 2.63
(1H, ddd, J¼16.4, 14.8, 6.4 Hz), 2.58e2.50 (1H, m), 2.42
(1H, ddd, J¼16.4, 4.8, 2.4 Hz), 2.02 (1H, t, J¼14.4, 4.8 Hz),
1.75 (1H, d, J¼13.6 Hz), 1.65 (2H, qd, J¼7.6, 7.6 Hz), 1.69e
1
oil (3.31 g, 13.9 mmol, 90%): H NMR (400 MHz, CDCl3)
d 5.09 (1H, s), 3.72 (3H, s), 3.47 (1H, d, J¼17.2 Hz), 2.48
(1H, d, J¼17.2 Hz), 2.38e2.08 (4H, m), 2.02 (2H, q,
J¼7.2 Hz), 0.98 (3H, t, J¼7.2 Hz); 13C NMR (100 MHz,
CDCl3) d 174.9, 170.9, 143.4, 118.4, 54.8, 52.9, 38.2, 29.7,
26.0, 11.8 (two quaternary C could not be observed); IR
(thin film) nmax 3409, 2965, 1769, 1738, 1434, 1281,
1238 cmꢁ1; HRMS (EI) calcd for C12H16O5 [M]þ 240.0978,
found 240.1002.
1.50 (3H, m), 1.38e1.30 (1H, m), 0.90 (3H, t, J¼7.2 Hz); 13
C
NMR (100 MHz, CDCl3) d 204.4, 171.5, 171.5, 69.1, 57.4,
53.3, 40.7, 38.0, 34.9, 34.8, 32.9, 28.6, 24.8, 18.7, 6.8; IR
(thin film) nmax 2952, 1704, 1434 cmꢁ1; MS (CI): m/z (%)
280 [MþH]þ, 297 [MþNH3]þ; HRMS (EI) calcd for
C15H21O4N [M]þ 279.1471, found 279.1464. Data for bicycle
1
17: H NMR (400 MHz, CDCl3) d 5.18 (1H, t, J¼2.0 Hz),
5.00 (1H, t, J¼2.0 Hz), 4.41 (1H, s), 4.32 (1H, d, J¼16.0 Hz),
3.78 (3H, s), 3.68 (1H, d, J¼16.0 Hz), 3.21 (1H, d,
J¼16.8 Hz), 3.10 (1H, d, J¼16.8 Hz), 2.65 (1H, ddd, J¼16.8,
8.4, 5.6 Hz), 2.33 (1H, ddd, J¼16.8, 7.2, 4.8 Hz), 2.00e1.88
(3H, m), 1.71 (2H, dq, J¼14.4, 7.6 Hz), 0.98 (3H, t,
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3) d 204.9, 170.2,
169.4, 150.7, 108.2, 69.7, 59.7, 53.4, 46.5, 45.8, 41.0, 35.8,
31.6, 28.7, 8.4; IR (thin film) nmax 2929, 1714, 1434,
1242 cmꢁ1; HRMS (EI) calcd for C15H20O4NCl [M]þ
313.1081, found 313.1074.
3.1.6. Synthesis of radical precursor (15)
To a solution of the acid 14 (200 mg, 0.84 mmol) in THF
(11 mL) at 0 ꢂC were added triethylamine (146 mL,
1.04 mmol, 1.2 equiv) and isobutylchloroformate (125 mL,
0.96 mmol, 1.1 equiv). The reaction mixture was stirred for
15 min, then additional triethylamine (282 mL, 2.00 mmol,
2.4 equiv) was added followed by a solution of N-(2-chloroallyl)
hydroxylammonium trifluoroacetate22 (400 mg) in THF
(2 mL). After 2 h the reaction mixture was diluted with diethyl
ether and was washed with 2 M hydrochloric acid. The organic
phase was dried over anhydrous magnesium sulfate and the
solvent was removed in vacuo. The residue was dissolved in di-
chloromethane (7 mL), and triethylamine (490 mL, 3.48 mmol,
4.4 equiv) and benzoyl chloride (300 mL, 2.59 mmol, 3 equiv)
were added. After 15 min, the reaction mixture was washed
with water and the organic phase was separated and dried over
anhydrous magnesium sulfate. The solvent was removed in va-
cuo and the residue was purified by flash chromatography (3:10
diethyl ether/hexanes) to provide the title compound 15 as a col-
3.1.8. (ꢀ)-(4S,6aR)-6a-Ethyl-hexahydro-1H-pyrrolo-
[3,2,1-ij]quinoline-2,9(9aH)-dione (20)
A solution of the ester 16 (10 mg, 0.036 mmol) and lithium
chloride (3 mg, 0.072 mmol, 2 equiv) in DMF (145 mL) was
heated to 140 ꢂC overnight. The mixture was cooled, diluted
with dichloromethane and was washed with water. The organic
phase was dried over anhydrous magnesium sulfate and the sol-
vent was removed in vacuo. The residue was purified by flash
chromatography (6:4 diethyl ether/hexanes) and the title com-
pound 20 was isolated as
a colourless solid (6 mg,
1
1
ourless oil (255 mg, 0.56 mmol, 67%): H NMR (400 MHz,
0.027 mmol, 75%): H NMR (400 MHz, CDCl3) d 4.06 (1H,
d, J¼12.8 Hz), 3.42 (1H, dd, J¼6.4, 2.0 Hz), 2.96 (1H, d,
J¼17.2 Hz), 2.88 (1H, dd, J¼9.2, 6.4 Hz), 2.57e2.48 (1H,
m), 2.47e2.31 (2H, m), 2.28 (1H, d, J¼17.2 Hz), 2.01 (1H,
td, J¼13.6, 5.6 Hz), 1.90e1.80 (2H, m), 1.62e1.25 (5H, m),
0.97 (3H, t, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3) d 209.1,
CDCl3) d 8.06 (2H, d, J¼7.6 Hz), 7.56 (1H, t, J¼7.2 Hz), 7.49
(2H, t, J¼7.6 Hz), 5.42 (1H, s), 5.36 (1H, s), 5.32 (1H, s), 4.56
(1H, d, J¼16.4 Hz), 4.47 (1H, d, J¼16.4 Hz), 3.63 (3H, s),
3.18 (1H, d, J¼17.2 Hz), 3.03 (1H, d, J¼17.2 Hz), 2.85e2.76
(1H, m), 2.64e2.56 (1H, m), 2.55e2.48 (1H, m), 2.46e2.38

A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
4811
174.5, 65.8, 42.5, 40.5, 35.4, 34.1, 33.0, 32.6, 29.2, 24.0, 18.8,
6.9; IR (thin film) nmax 2952, 1704, 1434 cmꢁ1; MS (CI): m/z
(%) 222 [MþH]þ, 239 [MþNH3]þ; HRMS (EI) calcd for
C13H19O2N [M]þ 221.1416, found 221.1418.
0.053 mmol, 88%): 1H NMR (400 MHz, CDCl3) d 3.04e
2.97 (2H, m), 2.66 (1H, ddd, J¼9.2, 5.2, 2.0 Hz), 2.45e2.20
(3H, m), 1.98e1.85 (3H, m), 1.79 (1H, dd, J¼10.8, 2.0 Hz),
1.76e1.57 (3H, m), 1.52e1.45 (2H, m), 1.37e1.26 (2H, m),
1.10 (1H, td, J¼13.2, 4.4 Hz), 0.93 (3H, t, J¼7.6 Hz); 13C
NMR (100 MHz, CDCl3) d 211.6, 73.6, 53.3, 53.0, 48.2,
36.9, 34.8, 32.9, 30.3, 30.1, 26.1, 21.3, 7.2; IR (thin film)
3.1.9. (ꢀ)-(4R,6aR,9aS)-Methyl 6a-ethyl-nonahydro-9-
hydroxy-1H-pyrrolo[3,2,1-ij]quinoline-9a-carboxylate (21)
To a solution of the lactam 16 (10 mg, 36 mmol) in THF
(216 mL) was added boraneedimethylsulfide complex (36 mL,
2 M in THF, 72 mmol, 2 equiv). The reaction mixture was
brought to reflux for 1 h, cooled and methanol was added.
The solvent was removed in vacuo and the residue was purified
by flash chromatography (1:1 diethyl ether/hexanes) to yield the
title compound 21 as a colourless oil (8.2 mg, 30.7 mmol, 85%):
1H NMR (400 MHz, CDCl3) d 3.70 (3H, s), 3.70e3.60 (1H, m),
3.17e3.10 (1H, m), 2.99 (1H, d, J¼10.8 Hz), 2.30e2.20 (3H,
m), 1.98e1.86 (2H, m), 1.86e1.77 (2H, m), 1.77e1.62 (2H,
m), 1.50e1.37 (3H, m), 1.25 (1H, d, J¼11.2 Hz), 1.10e0.98
(2H, m), 0.76 (3H, t, J¼7.6 Hz); 13C NMR (100 MHz,
CDCl3) d 178.2, 76.1, 74.3, 53.9, 53.3, 53.3, 51.7, 35.6, 33.1,
32.7, 29.6, 28.8, 26.6, 21.5, 7.0; IR (thin film) nmax 3400,
2934, 1708, 1443 cmꢁ1; MS (CI): m/z (%) 268 [MþH]þ;
HRMS (EI) calcd for C15H25O3N [M]þ 267.1835, found
267.1828.
nmax 2931, 1712, 1448 cmꢁ1
; HRMS (EI) calcd for
C13H21ON [M]þ 207.1623, found 207.1614.
3.1.12. (ꢀ)-Dehydroaspidospermidine
The title compound was prepared according to the proce-
dure of Gnecco et al.6w (ꢀ)-(4S,6aR)-6a-Ethyl-octahydro-
9aH-pyrrolo[3,2,1-ij]quinolin-9-one 5 (8.0 mg, 39 mmol) was
converted into the title compound (6.7 mg, 0.024 mmol,
62%). All spectral data corresponded to that quoted in Ref. 6w.
3.1.13. (ꢀ)-Aspidospermidine (1)
The title compound was prepared according to the procedure
of Gnecco et al.6w Dehydroaspidospermidine (4.0 mg, 14 mmol)
was converted into the title compound (3.4 mg, 12.3 mmol,
88%). All spectral data corresponded to that quoted in Ref. 6w.
The synthesis of hydroxylamine 25 follows the sequence in
Scheme 15.
3.1.10. (ꢀ)-(4R,6aR,9aS)-Methyl 6a-ethyl-nonahydro-9-
oxo-1H-pyrrolo[3,2,1-ij]quinoline-9a-carboxylate (22)
OH
OTs
TsCl, Et3N
CH3CN
(CH2O)n
To a solution of the lactam 16 (35 mg, 0.106 mmol) in THF
(500 mL) was added 9-BBN (464 mL, 0.5 M in THF,
0.23 mmol, 2.2 equiv) and the mixture was brought to reflux.
After 1 h, the mixture was cooled, ethanolamine was added
and the solvent was removed in vacuo. The residue was treated
with hexane and the solid was filtered and washed with hex-
ane. The filtrate was evaporated and the residue was purified
by flash chromatography (3:7 diethyl ether/hexanes) to yield
the title compound 22, which was isolated as a colourless oil
(26 mg, 0.098 mmol, 93%): 1H NMR (400 MHz, CDCl3)
d 3.71 (3H, s), 3.01 (2H, td, J¼8.8, 2.8 Hz), 2.86e2.79 (1H,
m), 2.72 (1H, td, J¼14.4, 6.0 Hz), 2.49 (1H, s), 2.40e2.25
(2H, m), 2.23e2.16 (1H, m), 1.94e1.80 (2H, m), 1.72e1.60
(2H, m), 1.52e1.44 (2H, m), 1.40e1.10 (3H, m), 0.89 (3H,
t, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3) d 206.4, 173.8,
77.2, 62.5, 53.2, 52.7, 52.6, 36.4, 35.8, 32.5, 29.8, 29.2,
27.3, 21.0, 7.1; IR (thin film) nmax 2936, 1734, 1716,
Et2AlCl
CH2Cl2
Cl
Cl
62, 25%
Cl
63, 63%
BocNHOBoc
K2CO3, DMF
Boc
Cl
N
OBoc
NH3
TFA
OCOCF3
Cl
25, 100%
64, 70%
Scheme 15.
3.1.14. 3-Chlorobut-3-enol (62)
To a solution of paraformaldehyde (1.17 g) and 2-chloro-
propene (3 g, 2.70 mL, 39 mmol) in dichloromethane
(94 mL) at 0 ꢂC was added diethylaluminium chloride
(39 mL, 1.0 M in hexanes, 39 mmol, 1 equiv). The reaction
mixture was stirred overnight then was quenched by addition
of saturated aqueous ammonium chloride. The organic layer
was separated and the aqueous layer was extracted with
dichloromethane. The solvent was removed in vacuo and the
residue was purified by flash chromatography (2:3 diethyl
ether/hexanes) to yield 3-chlorobut-3-enol as a colourless oil
(1.05 g, 9.9 mmol, 25%): 1H NMR (400 MHz, CDCl3)
d 5.24 (1H, d, J¼0.8 Hz), 5.22 (1H, d, J¼0.8 Hz), 3.79 (2H,
t, J¼6.0 Hz), 2.55 (2H, t, J¼6.0 Hz), 2.36 (1H, br s); 13C
NMR (100 MHz, CDCl3) d 139.1, 114.5, 59.4, 42.2; IR (thin
film) nmax 3358, 2957, 1636 cmꢁ1; HRMS (EI) calcd for
C4H7OCl [M]þ 106.0186, found 106.0185.
1447 cmꢁ1
;
HRMS (EI) calcd for C15H23O3N [M]þ
265.1678, found 265.1673.
3.1.11. (ꢀ)-(4S,6aR)-6a-Ethyl-octahydro-9aH-
pyrrolo[3,2,1-ij]quinolin-9-one (5)
A solution of the ester 22 (16 mg, 0.060 mmol) and lithium
chloride (5 mg, 0.120 mmol, 2 equiv) in DMF (242 mL) was
heated to 140 ꢂC for 3 h. The mixture was cooled, diluted
with dichloromethane and was washed with water. The or-
ganic phase was dried over anhydrous magnesium sulfate
and the solvent was removed in vacuo. The residue was puri-
fied by flash chromatography (6:4 diethyl ether/hexanes) and
the title compound 5 was isolated as a colourless oil (11 mg,

4812
A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
3.1.15. 3-Chlorobut-3-enyl-4-methylbenzenesulfonate (63)
To a solution of 3-chlorobut-3-enol (1.05 g, 9.9 mmol) and
DMAP (catalytic) in acetonitrile (9.9 mL) and triethylamine
(2.0 mL) was added p-toluenesulfonyl chloride (2.79 g,
14.6 mmol, 1.5 equiv). The mixture was stirred at room tem-
perature for 2 h, then was diluted with diethyl ether and
washed with saturated aqueous sodium hydrogen carbonate
then 2 M HCl. The organic phase was dried over anhydrous
magnesium sulfate and the solvent was removed in vacuo.
The residue was purified by flash chromatography (1:4 diethyl
ether/hexanes) and the tosylate was isolated as a colourless oil
3.1 equiv) was added. After a further 15 min, ammonia was
allowed to evaporate, the residue was neutralised with 2 M
HCl and the aqueous layer was extracted with diethyl ether.
The combined organic phases were dried over anhydrous mag-
nesium sulfate and the solvent was removed in vacuo. The res-
idue was dissolved in dichloromethane (50 mL) and was treated
with trifluoroacetic acid (10 mL) at room temperature. After 2 h
the solvent was removed and the title compound was purified by
flash chromatography (3:10 diethyl ether/hexanes with 0.05%
acetic acid) yielding the mixture of diastereomers 24a/b
(3.0 g, 0.0134 mol, 38%). The mixture of diastereomeric
acids was dissolved in isopropanol and benzylamine (1.44 g,
1.46 mL, 1 equiv) was added. Crystallisation gave separation
of the diastereomeric salts, which were dissolved in ethyl
acetate and washed with 2 M HCl to recover the free acid.
24a: 1H NMR (400 MHz, C6D6) d 5.94 (2H, dd, J¼10.2,
2.0 Hz), 5.55 (2H, dd, J¼10.2, 3.2 Hz), 3.35 (3H, s), 2.74
(2H, s), 2.49e2.44 (1H, m), 1.18 (2H, qd, J¼7.6, 6.0 Hz),
0.68 (3H, t, J¼7.6 Hz); 13C NMR (100 MHz, C6D6) d 177.2,
173.9, 131.2, 127.1, 52.5, 46.6, 45.3, 37.1, 28.2, 10.8; IR
(thin film) nmax 2962, 1732, 1434 cmꢁ1; MS (CI): m/z (%)
225 [MþH]þ, 242 [MþNH3]þ, MS HRMS (EI) calcd for
C12H15O4 [MꢁH]þ 223.0970, found 223.0970; 24b: 1H
NMR (400 MHz, C6D6) d 5.74e5.66 (4H, m), 3.58 (3H, s),
2.66 (2H, s), 2.57e2.52 (1H, m), 0.98 (2H, qd, J¼7.6,
6.0 Hz), 0.48 (3H, t, J¼7.6 Hz); 13C NMR (100 MHz, C6D6)
d 175.9, 173.7, 131.1, 127.0, 53.5, 52.3, 46.5, 37.0, 28.4,
10.7; IR (thin film) nmax 2962, 1731, 1434 cmꢁ1; MS (CI):
m/z (%) 225 [MþH]þ, 242 [MþNH3]þ; MS HRMS (EI) calcd
for C12H16O4 [M]þ 224.1049, found 224.1060.
1
(1.61 g, 6.2 mmol, 63%): H NMR (400 MHz, CDCl3) d 7.75
(2H, d, J¼8.0 Hz), 7.32 (2H, d, J¼8.0 Hz), 5.19 (1H, s), 5.18
(1H, s), 4.17 (2H, t, J¼6.4 Hz), 2.62 (2H, t, J¼6.4 Hz), 2.41
(3H, s); 13C NMR (100 MHz, CDCl3) d 144.9, 136.6, 132.6,
129.9, 127.7, 115.4, 66.5, 38.4, 21.5; IR (thin film) nmax
1637, 1598, 1360, 1177 cmꢁ1; HRMS (EI) calcd for
C11H13O3SCl [M]þ 260.0274, found 260.0280.
3.1.16. N-(3-Chloro-3-propenyl)[N,O-bis(tert-butyl-
oxycarbonyl)] hydroxylamine (64)
To a solution of the tosylate (1.61 g, 6.2 mmol) and N,O-bis-
(tert-butyl-oxycarbonyl) hydroxylamine (1.45 g, 6.25 mmol) in
DMF (6.4 mL) was added potassium carbonate (920 mg). The
reaction mixture was stirred for 24 h, then was diluted with di-
ethyl ether and was washed with water. The organic phase was
separated and dried over anhydrous magnesium sulfate. The
solvent was removed in vacuo and the residue was purified by
flash chromatography (1:9 diethyl ether/hexanes) to yield the
title compound as a colourless oil (1.45 g, 4.36 mmol, 70%):
1H NMR (400 MHz, CDCl3) d 5.22 (1H, d, J¼1.2 Hz), 5.20
(1H, d, J¼1.2 Hz), 3.80 (2H, br s), 2.62 (2H, t, J¼6.8 Hz),
1.50 (9H, s), 1.45 (9H, s); 13C NMR (100 MHz, CDCl3)
d 154.4, 152.1, 138.9, 114.4, 84.9, 47.9, 36.9, 28.0, 27.5; IR
(thin film) nmax 2981, 1785, 1719, 1395, 1370 cmꢁ1; MS (CI):
m/z (%) 322 [MþH]þ, 339 [MþNH3]þ; HRMS (EI) calcd for
C14H25O5NCl [MþH]þ 322.1421, found 322.1431.
3.1.19. Synthesis of radical precursor (26a)
To a solution of the acid 24a (35 mg, 0.16 mmol) in THF
(2.2 mL) at 0 ꢂC were added triethylamine (27.1 mL,
0.17 mmol, 1.1 equiv) and isobutylchloroformate (23.0 mL,
0.17 mmol, 1.1 equiv). The reaction mixture was stirred for
15 min, then additional triethylamine (52.4 mL, 0.33 mmol,
2.1 equiv) was added followed by a solution of the N-(3-
chloro-3-butenyl) hydroxylammonium trifluoroacetate 25
(36 mg) in THF (2 mL). After 2 h, the reaction mixture was di-
luted with diethyl ether and was washed with 2 M hydrochloric
acid. The organic phase was dried over anhydrous magnesium
sulfate and the solvent was removed in vacuo. The residue
was dissolved in dichloromethane (1.2 mL), and triethylamine
(91.1 mL, 0.54 mmol, 3.4 equiv) and benzoyl chloride
(56.1 mL, 0.40 mmol, 2.5 equiv) were added. After 15 min,
the reaction mixture was washed with water and the organic
phase was separated and dried over anhydrous magnesium sul-
fate. The solvent was removed in vacuo and the residue
was purified by flash chromatography (3:10 diethyl ether/hex-
anes) to provide the title compound 26a as a colourless oil
(36 mg, 0.083 mmol, 52%): 1H NMR (400 MHz, CDCl3)
d 8.06 (2H, d, J¼7.6 Hz), 7.67 (1H, t, J¼7.2 Hz), 7.52 (2H, t,
J¼7.6 Hz), 5.89e5.73 (4H, m), 5.26 (1H, s), 5.24 (1H, s),
4.02 (2H, t, J¼6.4 Hz), 3.73 (3H, s), 2.67e2.60 (5H, m),
1.50e1.40 (2H, m), 0.83e0.75 (3H, m); 13C NMR (100 MHz,
CDCl3) d 174.2, 170.6, 164.1, 139.1, 134.6, 130.8, 130.0,
3.1.17. N-(3-Chloro-3-propenyl)-hydroxylammonium
trifluoroacetate (25)
A solution of N-(3-chloro-3-propenyl)[N,O-bis(tert-butyl-
oxycarbonyl)] hydroxylamine (740 mg, 2.3 mmol) in dichloro-
methane (4.4 mL) was treated with trifluoroacetic acid
(1.89 mL). The reaction mixture was stirred at room tempera-
ture for 6 h, then the solvent was removed in vacuo to yield
the title compound 25 as a colourless oil (550 mg, 2.3 mmol,
100%): 1H NMR (400 MHz, CDCl3) d 5.34 (2H, s), 3.53 (2H,
t, J¼7.2 Hz), 2.84 (2H, t, J¼7.2 Hz); 13C NMR (100 MHz,
CDCl3) d 135.6, 116.9, 49.0, 33.1.
3.1.18. 2-(1-(Methoxycarbonyl)-4-ethylcyclohexa-2,5-
dienyl)acetic acid (24a/b)
To a solution of methyl p-ethyl benzoate 23 (5.8 g,
0.035 mol) in ammonia (341 mL), THF (12 mL) and t-BuOH
(2.86 mL) at ꢁ40 ꢂC was added lithium (614 mg, 0.102 mol,
3 equiv). The mixture was stirred at the same temperature for
15 min, then tert-butylbromoacetate (16 mL, 0.108 mol,

A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
4813
129.8, 126.6, 126.5, 114.4, 52.6, 46.3, 45.7, 43.1, 38.6, 36.5,
27.7, 10.4; IR (thin film) nmax 2962, 1766, 1727, 1684,
1451 cmꢁ1; MS (CI): m/z (%) 432 [MþH]þ, 468 [MþNH3]þ.
pressure. The residue was purified by flash column chromatog-
raphy (silica gel, heptane) to give 53 (2.81 g, 100%) as a col-
1
ourless oil: H NMR (400 MHz, CDCl3) d 5.80 (1H, m), 5.05
(2H, m), 2.26 (2H, td, J¼8.2, 2.3 Hz), 2.22 (2H, d, J¼7.6 Hz),
1.92 (1H, t, J¼2.3 Hz), 1.71 (2H, m), 1.20 (3H, s), 0.87 (9H,
s), 0.09 (6H, s); 13C NMR (100 MHz, CDCl3) d 134.7, 117.7,
85.3, 74.8, 67.8, 47.2, 41.2, 27.3, 26.0, 18.4, 13.3, ꢁ1.9; IR
(CCl4) nmax 3313, 2955, 2929, 2856, 2120, 1640, 1472,
1375, 1254, 1125, 1081, 1042 cmꢁ1; MS (CIþ NH3) m/z
253 (MHþ), 211, 138, 121. Anal. Calcd for C15H28OSi: C,
71.36; H, 11.18, found: C, 71.32; H, 11.22.
3.1.20. (4R,7aR)-Methyl 10-ethyl-1,2,3,4,4,6,7,7a,10,10a-
decahydro-6-oxoazepino[3,2,1-hi]indole-7a-carb-
oxylate (27a)
To a degassed solution of 26a (36 mg, 0.083 mmol) in
trifluorotoluene (2 mL) was added a solution of tributyltin
hydride (52.3 mL, 0.19 mmol, 2.3 equiv) and ACCN (4.1 mg,
0.017 mmol, 0.02 equiv) in trifluorotoluene (2 mL) over a pe-
riod of 12 h. The solvent was removed in vacuo and the residue
was purified by flash chromatography (diethyl ether) to provide
the tricycle 27a as a colourless oil (9 mg, 0.032 mmol, 39%)
and the bicycle 28a as a colourless oil (2 mg, 6.4 mmol, 8%).
3.1.23. [1-Allyl-1-methyl-8-(tetrahydro-pyran-2-yloxy)-oct-
4-ynyloxy]-tert-butyl-dimethyl-silane (51)
To a solution of 53 (1.0 g, 3.96 mmol) in dry THF under ar-
gon at ꢁ78 ꢂC was added n-BuLi (1.53 M in hexanes,
2.84 mL, 4.35 mmol) and the reaction mixture was stirred
for 30 min. HMPT (3.5 mL) was added and the mixture was
slowly cooled to 0 ꢂC. 2-(3-Bromo-propoxy)-tetrahydropyran
was then added and the mixture was stirred for 1 h at 0 ꢂC
and 3 h at room temperature. Saturated aqueous ammonium
chloride was added and the mixture was extracted with ether.
The combined organic layer was dried over magnesium sul-
fate, filtered, and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatog-
raphy (silica gel, heptaneeEtOAc, 95:5) to give 51 (1.29 g,
83%) as a colourless oil: 1H NMR (400 MHz, CDCl3)
d 5.80 (1H, m), 5.03 (2H, m), 4.60 (1H, dd, J¼2.9, 2.9 Hz),
3.90e3.74 (2H, m), 3.53e3.44 (2H, m), 2.20 (2H, d,
J¼7.6 Hz), 2.28e2.18 (4H, m), 1.77 (2H, t, J¼6.4 Hz),
1.85e1.50 (8H, m), 1.18 (3H, s), 0.86 (9H, s), 0.08 (6H, s);
13C NMR (250 MHz, CDCl3) d 134.8, 117.4, 98.8, 80.9,
79.0, 74.9, 66.1, 62.1, 47.1, 41.8, 30.8, 29.3, 27.3, 25.9,
25.6, 19.6, 18.3, 15.8, 13.5, ꢁ1.9; IR (neat) nmax 3076,
2930, 2856, 1640, 1472, 1441, 1374, 1359, 1254, 1159,
1137, 1121, 1077, 1036 cmꢁ1; MS (CIþ NH3) m/z 412
(MNHþ4 ). Anal. Calcd for C23H42O3Si: C, 70.00; H, 10.73,
found: C, 70.29; H, 10.87.
1
Data for tricycle 27a: H NMR (400 MHz, CDCl3) d 5.74e
5.68 (2H, m), 3.93 (1H, d, J¼10.8 Hz), 3.88 (1H, ddd,
J¼11.2, 7.6, 5.2 Hz), 3.72 (3H, s), 3.09e3.02 (1H, m), 2.98
(1H, d, J¼16.8 Hz), 2.48 (1H, d, J¼16.8 Hz), 2.19 (1H, d,
J¼14.8 Hz), 2.05e1.87 (3H, m), 1.70e1.52 (3H, m), 1.30e
1.23 (2H, m), 1.15e1.02 (1H, m), 0.85 (3H, t, J¼7.2 Hz); 13
C
NMR (100 MHz, CDCl3) d 174.5, 172.3, 133.2, 125.7, 64.1,
53.0, 50.7, 42.5, 42.3, 41.4, 40.4, 33.3, 26.6, 25.3, 24.5, 9.3;
IR (thin film) nmax 2929, 1734, 1692, 1437 cmꢁ1; MS (CI):
m/z (%) 278 [MþH]þ; HRMS (EI) calcd for C16H23O3N
[M]þ 277.1678, found 277.1667.
3.1.21. 4-Methyloct-1-en-7-yn-4-ol
To a solution of 5-hexyn-2-one 52 (2.28 g, 23.7 mmol) in
dry ether under argon was added allylmagnesium bromide
(1.0 M in ether, 26 mL, 26 mmol) and the reaction mixture
was stirred at room temperature for 15 min. Saturated aqueous
ammonium chloride was added and the mixture was extracted
with ether. The combined organic layer was dried over magne-
sium sulfate, filtered and the solvents were removed under re-
duced pressure. The residue was purified by flash column
chromatography (silica gel, heptaneeEtOAc, 90:10) to give
the title compound (5.73 g, 96%) as a colourless oil: 1H
NMR (200 MHz, CDCl3) d 5.85 (1H, m), 5.14 (2H, m), 2.32
(2H, td, J¼7.3, 2.5 Hz), 2.24 (2H, d, J¼8.1 Hz), 1.98 (1H, t,
J¼2.5 Hz), 1.86 (1H, s), 1.74 (2H, t, J¼7.3 Hz), 1.19 (3H,
s); 13C NMR (50 MHz, CDCl3) d 133.6, 119.1, 84.9, 71.9,
68.6, 46.5, 40.0, 26.4, 13.2; IR (thin film) nmax 3405, 3304,
3076, 2976, 2929, 2117, 1639, 1438, 1376, 1115 cmꢁ1; MS
(CIþ NH3) m/z 156 (MNHþ4 ), 138 (MꢁOHþNH3þ), 121
(MꢁOHþ).
3.1.24. 6-(tert-Butyl-dimethyl-silanyloxy)-6-methyl-3-[3-
(tetrahydro-pyran-2-yloxy)-propyl]-1,4,5,6,7,7a-hexahydro-
inden-2-one (55)
To a solution of 51 (560 mg, 1.42 mmol) in dichloro-
methane (7 mL) was added dicobalt octacarbonyl (533 mg,
1.56 mmol) and the black reaction mixture was stirred at
room temperature for 1 h. The mixture was diluted with di-
chloromethane (7 mL) and THF (14 mL), and 4-methylmor-
pholine N-oxide monohydrate (1.9 g, 14.2 mmol) was added.
The solution was stirred at room temperature for 1 h, at which
time the mixture has turned purple and no cobalt complex was
visible by TLC. The mixture was filtered through Celite
(washing solvent diethyl ether) and the solvents were removed
under reduced pressure. The residue was purified by flash col-
umn chromatography (silica gel, heptaneeEtOAc, 90:10) to
give major isomer 55 (497 mg, 83%) as a colourless oil.
55 (mixture of THP isomers): 1H NMR (200 MHz, CDCl3)
d 4.44 (1H, m), 3.80e3.70 (1H, m), 3.64e3.54 (1H, m),
3.1.22. (1-Allyl-1-methyl-pent-4-ynyloxy)-tert-butyl-
dimethyl-silane (53)
To a solution of 4-methyloct-1-en-7-yn-4-ol (1.55 g,
11.2 mmol) in dry dichloromethane under argon at 0 ꢂC
were added 2,6-lutidine (3.26 mL, 28.0 mmol) and tert-butyl-
dimethylsilyl trifluoromethanesulfonate (2.82 mL, 12.3 mmol)
and the reaction mixture was stirred for 30 min. Aqueous
1.0 M HCl was added and the mixture was extracted with
ether. The combined organic layer was dried over magnesium
sulfate, filtered, and the solvents were removed under reduced

4814
A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
3.42e3.34 (1H, m), 3.28e3.17 (1H, m), 2.91 (1H, dddd,
J¼12.6, 6.5, 5.2, 2.5 Hz), 2.68e2.42 (2H, m), 2.44 (1H,
dd, J¼18.5, 6.5 Hz), 2.16 (2H, br t, J¼7.5 Hz), 2.01 (1H, ddd,
J¼12.6, 5.2, 2.5 Hz), 1.19 (3H, s), 1.88e1.21 (11H, m), 0.98
(1H, dd, J¼12.6, 12.6 Hz), 0.85 (9H, s), 0.05 (6H, s); 13C
NMR (50 MHz, CDCl3) d 208.3, 176.2, 136.5, 98.7, 72.3,
66.7, (62.2, 62.3), 48.0, 40.9, 39.8, 35.6, 30.7, 30.2, 28.5,
25.9, 25.4, 24.1, (19.6, 19.7), 19.2, 18.3, ꢁ2.0; IR (neat)
nmax 2930, 2856, 1699, 1651, 1440, 1373, 1255, 1137,
1035 cmꢁ1; MS (CIþ NH3) m/z 339 (MꢁTHPþ2Hþ).
separated organic layer was dried over magnesium sulfate, fil-
tered and the solvents were removed under reduced pressure.
The residue was purified by flash column chromatography (sil-
ica gel, heptaneeEtOAc, 85:15) to give 57 (250 mg, 81%) as
1
a colourless oil: H NMR (300 MHz, CDCl3) d 8.05 (2H, d,
J¼7.9 Hz), 7.65 (1H, t, J¼7.9 Hz), 7.50 (2H, t, J¼7.9 Hz),
5.38 (2H, d, J¼9.2 Hz), 4.57 (2H, br s), 2.99 (1H, ddd,
J¼12.9, 6.5, 5.5 Hz), 2.79 (1H, ddd, J¼13.8, 4.6, 2.1 Hz),
2.65e2.45 (5H, m), 2.50 (1H, dd, J¼18.0, 6.5 Hz), 2.07
(1H, ddd, J¼12.9, 5.5, 2.3 Hz), 1.90 (1H, m), 1.85 (1H, d,
J¼18.0 Hz), 1.36 (1H, ddd, J¼13.4, 13.4, 4.6 Hz), 1.25 (3H,
s), 1.09 (1H, dd, J¼12.9, 12.9 Hz), 0.88 (9H, s), 0.12 (3H,
s), 0.11 (3H, s); 13C NMR (75 MHz, CDCl3) d 208.0, 178.0,
172.9, 164.2, 135.6, 134.9, 134.5, 130.1, 128.9, 126.5,
115.9, 72.4, 53.5, 47.9, 41.0, 39.8, 35.9, 30.2, 30.1, 26.0,
24.4, 18.4, 18.1, ꢁ1.9, ꢁ2.0; IR (neat) nmax 2929, 2855,
1766, 1694, 1650, 1452, 1254, 1099, 1038, 1006 cmꢁ1; MS
(CIþ NH3) m/z 546 (MHþ), 426 (MꢁBzOþ2Hþ), 390, 322.
Anal. Calcd for C29H40ClNO5Si: C, 63.77; H, 7.38, found:
C, 63.78; H, 7.45.
3.1.25. 3-[5-(tert-Butyl-dimethyl-silanyloxy)-5-methyl-2-
oxo-3,3a,4,5,6,7-hexahydro-2H-inden-1-yl]-propionic
acid (50)
To a solution of 55 in acetone (25 mL) at 0 ꢂC was added
Jones’ solution (2.6 [Cr] M, 1.31 mL, 3.42 mmol) and the
solution was stirred for 2 h. Water was added and the mixture
extracted with dichloromethane. The organic layer was basi-
fied with 1.0 M NaOH until pH 9 and the aqueous layer was
separated, acidified with 1.0 M HCl until pH 1 and extracted
with ether. The organic layer was dried over magnesium sul-
fate, filtered and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica
gel, heptaneeEtOAc, 50:50) to give 50 (390 mg, 97%) as
a colourless oil, which crystallised with time as a white solid;
mp 88e90 ꢂC (heptane): 1H NMR (400 MHz, CDCl3) d 10.50
(1H, br s), 3.01 (1H, dddd, J¼12.9, 6.5, 5.3, 2.3 Hz), 2.71 (1H,
ddd, J¼14.0, 4.7, 2.3 Hz), 2.54 (1H, dd, J¼18.8, 6.5 Hz),
2.55e2.45 (5H, m), 2.08 (1H, ddd, J¼12.9, 5.3, 2.3 Hz),
1.87 (1H, dd, J¼18.8, 2.3 Hz), 1.91 (1H, m), 1.33 (1H, ddd,
J¼13.5, 13.5, 4.7 Hz), 1.26 (3H, s), 1.06 (1H, dd, J¼12.9,
12.9 Hz), 0.88 (9H, s), 0.12 (3H, s), 0.11 (3H, s); 13C NMR
(100 MHz, CDCl3) d 209.1, 178.7, 178.3, 135.0, 72.4, 48.1,
41.0, 39.9, 36.1, 32.4, 30.2, 26.1, 24.4, 18.4, 18.1, ꢁ1.9,
ꢁ2.0; IR (CCl4) nmax 2955, 2929, 2856, 1708, 1652, 1255,
1098, 1050, 1036 cmꢁ1; MS (CIþ NH3) m/z 353 (MHþ).
Anal. Calcd for C19H32O4Si: C, 64.73; H, 9.15, found: C,
64.57; H, 9.13.
3.1.27. 2-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-
decahydro-indeno[7a,1-h]indolizine-9,12-dione (48)
To a degassed solution of 57 (100 mg, 0.183 mmol) and
ACCN (2 mg, 0.009 mmol) in refluxing a,a,a-trifluorotoluene
(1.5 mL) was added a degassed solution of Bu3SnH (103 mL,
0.384 mmol) and ACCN (9 mg, 0.037 mmol) in a,a,a-trifluo-
rotoluene (3 mL) over 8 h. The reaction mixture was then
cooled to room temperature and concentrated. The residue
was purified by flash column chromatography (silicagel, hep-
tane to heptaneeEtOAc 70:30) to give 48 (37 mg, 52%) as
1
a white solid; mp 136e139 ꢂC: H NMR (400 MHz, CDCl3)
d 3.98 (1H, m), 2.66 (1H, dd, J¼20.5, 10.0 Hz), 2.26 (1H,
m), 2.44e2.33 (3H, m), 2.13 (1H, m), 2.09 (1H, dd, J¼20.5,
3.9 Hz), 1.94e1.82 (3H, m), 1.75e1.67 (2H, m), 1.62 (1H,
m), 1.54e1.43 (2H, m), 1.39 (1H, m), 1.29 (3H, s), 1.32e
1.28 (1H, m), 1.26 (1H, dd, J¼13.5, 13.5 Hz), 0.90 (9H, s),
0.11 (3H, s), 0.10 (3H, s); 13C NMR (100 MHz, CDCl3)
d 216.7, 175.5, 74.1, 71.8, 45.9, 38.9, 38.8, 38.6, 38.0, 37.8,
34.4, 31.0, 28.7, 27.2, 26.2, 25.8, 19.3, 18.5, ꢁ1.8, ꢁ1.9; IR
(CCl4) nmax 2933, 2856, 1748, 1703, 1393, 1253, 1153,
1122, 1106, 1020; MS (CIþ NH3) m/z 392 (MHþ), 260
(MꢁOTBSþ). HRMS (CIþ CH4) Calcd for C22H38NO3Si
392.2621, found 392.2626.
3.1.26. N-Benzoyloxy-3-[5-(tert-butyl-dimethyl-silanyloxy)-
5-methyl-2-oxo-3,3a,4,5,6,7-hexahydro-2H-inden-1-yl]-N-
(2-chloro-allyl)-propionamide (57)
To a solution of 50 (200 mg, 0.567 mmol) in THF under ar-
gon at 0 ꢂC were added triethylamine (87 mL, 0.624 mmol)
and isobutylchloroformate (81 mL, 0.624 mmol) and the reac-
tion mixture was stirred for 10 min. Excess of triethylamine
was added (2 mL) and a solution of N-(2-chloroallyl)-hydrox-
ylamine (610 mg, 5.68 mmol) in THF was added. The reaction
mixture was stirred for 10 min at 0 ꢂC and 30 min at room
temperature. Aqueous 1.0 M HCl was added and the mixture
was extracted with ether. The separated organic layer was
dried over magnesium sulfate, filtered and the solvents were
removed under reduced pressure. The residue was taken up
in dichloromethane and triethylamine (210 mL, 1.50 mmol)
and benzoyl chloride (131 mL, 1.13 mmol) were added. The
mixture was stirred for 1 h at room temperature. Water was
then added and the mixture was extracted with ether. The
3.1.28. 2,12-Bis-(tert-butyl-dimethyl-silanyloxy)-2-methyl-
1,3,4,6,7,10,11,13a-octahydro-2H,5H-indeno[7a,1-h]-
indolizin-9-one (60)
To a solution of 48 (28 mg, 0.071 mmol) in dry dichlorome-
thane (0.8 mL) were added triethylamine (50 mL, 0.357 mmol)
and tert-butyldimethylsilyl trifluoromethanesulfonate (65 mL,
0.286 mmol) and the reaction mixture was stirred at room tem-
perature for 3 h. The mixture was diluted with dichloromethane
and saturated aqueous sodium hydrogenocarbonate was added.
The organic layer was separated dried over sodium sulfate,
filtered and concentrated. The residue was purified by flash
column chromatography (silica gel, heptaneeEtOAc, 80:20)

A.-C. Callier-Dublanchet et al. / Tetrahedron 64 (2008) 4803e4816
4815
to give 60 (29 mg, 83%) as a colourless oil: 1H NMR
References and notes
(400 MHz, CDCl3) d 4.63 (1H, d, J¼3.5 Hz), 4.05 (1H, m),
2.53e2.31 (3H, m), 2.25e2.15 (2H, m), 1.85e1.57 (6H, m),
1.48e1.23 (4H, m), 1.25 (3H, s), 1.01 (1H, dd, J¼12.3,
12.3 Hz), 0.89 (18H, s), 0.18 (3H, s), 0.17 (3H, s), 0.09 (6H,
s); 13C NMR (100 MHz, CDCl3) d 175.6, 155.7, 104.4, 73.6,
72.1, 44.9, 43.2, 40.9, 39.2, 39.1, 38.2, 31.4, 31.1, 30.5, 26.6,
26.2, 25.6, 20.5, 17.8, ꢁ1.8, ꢁ4.6, ꢁ5.1; IR (CCl4) nmax
2930, 2857, 1695, 1644, 1402, 1252, 1100; MS (CIþ NH3)
m/z 507 (MHþ).
1. For recent books on radicals in synthesis, see: (a) Radicals in Organic Syn-
thesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vols. 1
& 2; (b) Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford
University Press: Oxford, 2003; (c) Parsons, A. F. An Introduction to
Free-Radical Chemistry; Blackwell Science: Oxford, 2000.
2. For reviews of cyclizations of nitrogen-centered radicals, see: (a) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543; (b) Zard, S. Z. Synlett
1996, 1148.
3. (a) Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1990, 31, 85; (b)
Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1990, 31, 3545; (c)
Boivin, J.; Fouquet, E.; Zard, S. Z. J. Am. Chem. Soc. 1991, 113, 1054; (d)
Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1991, 32, 4299; (e)
Boivin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron 1994, 50, 1745; (f) Boi-
vin, J.; Fouquet, E.; Zard, S. Z. Tetrahedron 1994, 50, 1757; (g) Boivin, J.;
Fouquet, E.; Zard, S. Z. Tetrahedron 1994, 50, 1769; (h) Boivin, J.;
Schiano, A.-M.; Zard, S. Z. Tetrahedron Lett. 1994, 35, 249; (i) Callier,
A.-C.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1994, 35, 6109; (j)
Boivin, J.; Callier-Dublanchet, A.-C.; Quiclet-Sire, B.; Zard, S. Z. Tetra-
hedron 1995, 51, 6517; (k) Callier-Dublanchet, A.-C.; Quiclet-Sire, B.;
Zard, S. Z. Tetrahedron Lett. 1995, 36, 8791; (l) Callier-Dublanchet,
A.-C.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1997, 38, 2463;
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1999, 39, 2125; (n) Boivin, J.; Schiano, A.-M.; Zard, S. Z.; Zhang, H. Tet-
rahedron Lett. 1999, 40, 4531; (o) Gagosz, F.; Zard, S. Z. Synlett 1999,
1978; (p) Gagosz, F.; Moutrille, C.; Zard, S. Z. Org. Lett. 2002, 4,
2707; (q) Gennet, D.; Zard, S. Z.; Zhang, H. Chem. Commun. 2003,
1870; (r) Moutrille, C.; Zard, S. Z. Chem. Commun. 2004, 1848; (s)
Barclay, G.; Quiclet-Sire, B.; Sanchez-Jimenez, G.; Zard, S. Z. Org.
Biomol. Chem. 2005, 3, 823.
4. (a) Alonso, R.; Campos, P. J.; Garcia, B.; Rodriguez, M. A. Org. Lett.
2006, 8, 3521; (b) Van Speybroeck, V.; De Kimpe, N.; Waroquier, M. J.
Org. Chem. 2005, 70, 3674; (c) Kitamura, M.; Mori, Y.; Narasaka, K. Tet-
rahedron Lett. 2005, 46, 2373; (d) Lu, H.; Li, C. Tetrahedron Lett. 2005,
46, 5983; (e) Lin, X.; Artman, G. D.; Stien, D.; Weinreb, S. M. Tetrahe-
dron 2001, 57, 8779; (f) Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron
Lett. 2000, 41, 2333; (g) Lin, X.; Stien, D.; Weinreb, S. M. Org. Lett.
1999, 1, 637; (h) Bowman, W. R.; Cloonan, M. O.; Fletcher, A. J.; Stein,
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Stephenson, P. T.; Young, A. R. Tetrahedron 1996, 52, 11445; (m) Blake,
J. A.; Pratt, D. A.; Lin, S.; Walton, J. C.; Mulder, P.; Ingold, K. U. J. Org.
3.1.29. 2-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-
decahydro-indeno[7a,1-h]indolizin-12-one (61)
To a solution of 60 (26 mg, 0.051 mmol) in dry THF
(4 mL) was added LiAlH4 (19 mg, 0.514 mmol) and the reac-
tion mixture was heated to reflux for 45 min. The mixture was
cooled to 0 ꢂC, diluted with diethyl ether and carefully
quenched with water. The organic layer was separated, dried
over magnesium sulfate, filtered and concentrated. The residue
was purified by flash column chromatography (silica gel, hep-
taneeEtOAc, 70:30) to give the title compound (11 mg, 58%)
1
as a white solid; mp 65e67 ꢂC: H NMR (300 MHz, CDCl3)
d 3.18 (1H, m), 2.97 (1H, m), 2.72 (1H, td, J¼11.0, 4.3 Hz),
2.52 (1H, dd, J¼11.0, 11.0 Hz), 2.51 (1H, dd, J¼19.8,
9.7 Hz), 2.33 (1H, dddd, J¼10.9, 9.7, 5.5, 3.0 Hz), 1.92 (1H,
dd, J¼19.8, 3.0 Hz), 1.89e1.30 (14H, m), 1.25 (3H, s), 0.89
(9H, s), 0.09 (6H, s); 13C NMR (75 MHz, CDCl3) d 216.2,
75.2, 72.2, 50.4, 47.2, 44.8, 40.0, 38.9, 37.9, 37.2, 34.2,
31.0, 30.2, 26.5, 26.2, 21.9, 19.9, 18.5, ꢁ1.7, ꢁ1.8; IR
(neat) nmax 2930, 2854, 1734, 1471, 1252, 1106, 1058,
1022 cmꢁ1
;
MS (CIþ NH3) m/z 378 (MHþ), 246
(MꢁOTBSþ). HRMS (CIþ CH4) Calcd for C22H40NO2Si
378.2828, found 392.2825.
3.1.30. 13-Deoxyserratine (2)
To a solution of 61 (11 mg, 0.029 mmol) in dry THF
(0.8 mL) was added tetrabutylammonium fluoride (1.0 M in
THF, 87 mL, 0.087 mmol) and the reaction mixture was heated
to reflux for 6 h. Aqueous 1.0 M NaOH was added and the
mixture extracted with ether. The separated organic layer
was dried over sodium sulfate, filtered and concentrated to
give pure 2 (7.2 mg, 96%) as a colourless oil: 1H NMR
(400 MHz, CDCl3) d 3.10 (1H, m), 2.90 (1H, m), 2.64e2.58
(2H, m), 2.58 (1H, dd, J¼19.4, 9.9 Hz), 2.48 (1H, m), 2.01
(1H, dd, J¼19.4, 4.1 Hz), 1.89e1.25 (14H, m), 1.27 (3H, s);
13C NMR (100 MHz, CDCl3) d 76.1, 69.7, 50.9, 47.8, 42.1,
39.4, 36.3, 34.4, 33.7, 30.8, 29.8, 28.3, 27.1, 21.5, 20.0 (the
C]O resonance could not be observed); IR (CCl4) nmax
3612 (OH), 2975, 2930, 2855, 1734 (C]O), 1117; MS
(CIþ NH3) m/z 264 (MHþ), 246 (MꢁOHþ); MS (EI) m/z
263 (Mþ, 9), 235 (Mþꢁ28, 38), 136 (100). These fragmenta-
tions are in good agreement with those reported by Inubushi
and co-workers for serratinine and its derivatives.23 HRMS
(CIþ CH4) Calcd for C16H26NO2 [MþH]þ 264.1964, found
264.1965.
´
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´
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