Application of the palladium(0)-catalyzed ullmann cross-coupling reaction in a total synthesis of (±)-aspidospermidine and thus representing an approach to the lower hemisphere of the binary indole-indoline alkaloid vinblastine

Article abstract of DOI:10.1071/CH05181

As part of ongoing studies directed towards the construction of the anti-cancer agent vinblastine (1), the related but structurally less complex natural product aspidospermidine (3) has been synthesized. Two approaches to target 3 were pursued. In the fir

Full text of DOI:10.1071/CH05181

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2005, 58, 722–737
www.publish.csiro.au/journals/ajc
Application of the Palladium(0)-Catalyzed Ullmann Cross-Coupling
Reaction in a Total Synthesis of ( )-Aspidospermidine and thus
Representing an Approach to the Lower Hemisphere of the
Binary Indole–Indoline Alkaloid Vinblastine∗
Martin G. Banwell,A,B David W. Lupton,A and Anthony C. WillisA
A Research School of Chemistry, Institute of Advanced Studies, Australian National University,
Canberra ACT 0200, Australia.
B Corresponding author. Email: mgb@rsc.anu.edu.au
As part of ongoing studies directed towards the construction of the anti-cancer agent vinblastine (1), the related
but structurally less complex natural product aspidospermidine (3) has been synthesized. Two approaches to target
3 were pursued. In the first, which was unsuccessful, the amine-tethered enone 6 was prepared but this failed to
engage in the pivotal intramolecular conjugate addition reaction to give the bicyclic system 5. In contrast, the
related compound 46, incorporating tethered enone and azide moieties, engaged in an intramolecular 1,3-dipolar
cycloaddition reaction to give, presumably via an intermediate triazoline, the isolable and ring-fused aziridine
47. This was then converted, over two steps, into the previously reported tetrahydrocarbazole 4. Application of
established protocols to this last compound allowed for the installation of the E-ring of the title alkaloid 3 and
completion of the total synthesis.
Manuscript received: 1 August 2005.
Final version: 22 September 2005.
OH
Introduction
N
The binary indole–indoline alkaloid vinblastine (1, Fig. 1)
and related compounds are used clinically in the treatment
of various human cancers including Hodgkin’s and non-
Hodgkin’s lymphoma, testicular cancer, bladder cancer, and
lung cancer, as well as acute childhood leukemia.[1] As such,
compounds of this class have been the subject of many
synthetic studies over more than three decades.[1] Notwith-
standing important contributions from the laboratories of
Kuehne, Kutney, Langlois/Potier, and Magnus,[2] the daunt-
ing structural complexity of vinblastine (1) meant that it
eluded de novo total synthesis until 2002 when Fukuyama and
co-workers reported their landmark work.[3] The complexity
of this alkaloid has also meant that the minimum structure
responsible for the therapeutic properties of compound 1
remains ill-defined.[1,4]
H
N
H
CO2Me
MeO
N
D
E
A
C
B
N
OAc
N
H
Me
MeO2C
OH
1
D
E
A
OH
B
C
OH
N
HO2C
H
H
As part of endeavours within our laboratories aimed at
developing an efficient and flexible synthesis of vinblastine
(1) we have recently shown that the microorganism Pseu-
domonas putida BGXM1 can convert m-ethyltoluene into the
metabolite 2,[5] a compound that incorporates key elements
associated with the C-ring of compound 1. Furthermore,
we have disclosed a two-step process for the preparation
of indoles[6] that should provide access to the key indole
2
3
Fig. 1.
and indoline substructures embedded within compound 1.
Finally, we have also recently developed a method for the
stereoselective linkage of the upper and lower hemispheres of
vinblastine.[7] Ultimately we hope to deploy these protocols
∗Aspects of this work have been presented in preliminary form: M. G. Banwell, D. W. Lupton, Org. Biomol. Chem. 2005, 3, 213. doi:10.1039/B415977B
© CSIRO 2005 10.1071/CH05181 0004-9425/05/100722

Application of the Ullmann Cross-Coupling Reaction in a Total Synthesis of ( )-Aspidospermidine
723
O
EtO
AcO
N
HN
E-ring
annulation
(a), (b), (c)
D
E
A
C
B
9
8
N
N
H
H
(d)
H
3
4
X
OAc
CO2H
X
Reductive
cyclization
(g)
(e)
O
11 X ꢀ OH
12 X ꢀ OAc
13 X ꢀ H
7 X ꢀ I
HN
10
H2N
(f)
(h)
Conjugate
addition
D
(i)
O2N
O2N
O
O
5
6
OAc
NO2
OAc
Pd(0)-cat.
Ullmann
(j)
O
cross-coupling
O2N
O
O
AcO
See ref. [9] and
herein
14
15
EtO
O
I
(k), (l)
C
NO2
O
NO2
NO2
O
7
8
Fig. 2. Retrosynthetic analysis of aspidospermidine (3).
(m)
O
O
O
O
in developing a reasonably concise synthesis of vinblas-
tine (1). However, before undertaking such a task it seemed
prudent to define methods that would allow the assembly of
the southern hemisphere of vinblastine from an intact C-ring,
as would be required if metabolite 2 were to be the starting
point in the final total synthesis. To such ends we now detail
a relevant total synthesis of the somewhat simpler alkaloid
aspidospermidine (3)[8] which embodies the ABCDE-ring
system associated with the ultimate target 1.
17
16
Scheme 1. Reagents and conditions: (a) EtMgBr (1.66 mol equiv.),
THF, 0◦C, 3 h then 10% aq. HCl, 18◦C, 16 h; (b) NaBH4 (1.2 mol
equiv.), MeOH, 0 → 18◦C, 16 h; (c) Ac2O (excess), DMAP (cat.), pyri-
dine, 0 → 18◦C, 10 h; (d) LDA (1.2 mol equiv.), TBDMS-Cl (1.3 mol
equiv.), THF, −78 → 66◦C, 6 h then MeOH, 18◦C, 16 h; (e) LiAlH4
(7 mol equiv.), THF, 0 → 18◦C, 2 h; (f ) Ac2O (excess), DMAP (cat.),
pyridine, 0 → 18◦C, 1.5 h; (g) CrO3·3,5-DMP (15 mol equiv.), −10 to
−20◦C, 8 h; (h) I2 (4 mol equiv.), 1:1 v/v CCl4/pyridine, 18◦C, 60 h;
(i) o-iodonitrobenzene (2 mol equiv.), Cu (5 g atom equiv.), Pd2(dba)3
(cat.), DMSO, 70◦C, 5 h; (j) ethylene glycol (2.5 mol equiv.), p-TsOH
(cat.), C6H6, 80◦C, 22 h; (k) 1 mol aq. KOH, MeOH, 18◦C, 1 h;
(l) Dess–Martin periodinane (2 mol equiv.), pyridine, CH2Cl2, 18◦C,
3 h; (m) CH3NO2, NH4OAc, 80◦C, 1.5 h.
The studies presented here serve to highlight the synthetic
utility of the title cross-coupling process in the assembly of
complex indole alkaloids.
Results and Discussion
feature of the analysis shown is the use of an intact C-ring
precursor as the starting point and as would be required
for the effective use of metabolite 2 in a total synthesis of
vinblastine 1.
The retrosynthetic analysis of target 3 used in the present
work is shown in Fig. 2. Thus, in the closing stages of the
synthesis it was anticipated that the E-ring could be annulated
onto the tetrahydrocarbazole 4 using a two-fold alkyla-
tion sequence analogous to that developed by Wenkert,[8g]
Magnus,[8f ] Heathcock,[8r] and Rubiralta/Rawal.[8n,8t] The
tetrahydrocarbazole 4 would, in turn, be prepared by the
reductive cyclization of an α-(o-nitrophenyl)enone such as
compound 5. Furthermore, it was expected that installation
of the D-ring associated with arylketone 5 could be achieved
through the stereoselective intramolecular conjugate addi-
tion reaction of an α-arylated cyclohexenone incorporating
a tethered primary-amine moiety, as seen in compound 6.
The α-arylated enone 6 itself would be prepared by the
Pd(0)-catalyzed Ullmann cross-coupling of iodide 7 and
o-iodonitrobenzene. Compound 7 should be accessible
through straightforward protocols.[9] Of course, a central
Examination of an Intramolecular Conjugate Addition
Reaction as a Means for Assembling the CD-Ring
System of Aspidospermidine
The approach to aspidospermidine (3) initially investigated
is outlined in Scheme 1 and involved targeting nitrostyrene
17 which, it was believed, could be reduced in either a step-
wise or one-pot manner to provide, following closure of the
B and D-rings, the pivotal tetrahydrocarbazole 4. So the
synthesis began with the reaction of commercially avail-
able 3-ethoxycyclohex-2-enone (8) with ethylmagnesium
bromide. Following an acidic work-up, the previously
reported[10] 3-ethylcyclohex-2-enone was obtained in 89%

724
M. G. Banwell, D. W. Lupton, and A. C. Willis
OMe
yield. Subjection of this last compound to 1,2-reduction using
NaBH4 afforded the corresponding allylic alcohol which was
immediately acetylated to provide the allylic acetate 9[11] in
quantitative yield over the two steps. Treatment of compound
9 with LDA followed by tert-butyldimethylsilyl chloride
(TBDMS-Cl) then provided the corresponding ketene acetal
which engaged in an Ireland–Claisen rearrangement[12] reac-
tion upon heating in refluxing THF. In this manner, and
after aqueous work-up, cyclohexene acetic acid 10[13] was
obtained in 62% yield. Acid 10 was reduced to the corre-
sponding alcohol 11[14] (96%) using LiAlH4 and this was,
in turn, converted into acetate 12 (87%) under conventional
conditions. Allylic oxidation of this last compound using
the CrO3·3,5-DMP complex[15] then provided enone 13 in
67% yield. Subjection of compound 13 to Johnson’s iodi-
nation protocol[16] then gave the iodide 7 (83% yield) which
readilyengagedinthepivotalPd(0)-catalyzedUllmanncross-
coupling reaction with o-iodonitrobenzene upon exposure to
5 g atom equiv. of copper powder and using Pd2(dba)2 as cat-
alyst. In this manner the α-arylated cyclohexenone 14 was
obtained in 81% yield.
HO
O
(a)
(b)
11
18
19
(c), (d)
NHBoc
NHBoc
X
X
(i)
(h)
O
25 Xꢀ H
26 Xꢀ I
20 Xꢀ OH
21 Xꢀ OMs
22 Xꢀ N3
24
(e)
(g)
(j)
(f)
23 Xꢀ NH2
NHX
(k)
The final steps employed in attempts to obtain a sub-
strate that might be used to examine the effectiveness of the
proposed conjugate addition reaction required construction
of a propylamine side-chain. The Henry reaction was seen
as offering the best prospects for introducing, in one step,
both the necessary carbon and nitrogen functionality. How-
ever, before doing this the cyclohexenone carbonyl needed
to be protected in some way. So, using conventional reaction
conditions, enone 14 was converted into the corresponding
ketal 15 (63%). The acetate group within the latter com-
pound was then cleaved and the resulting alcohol oxidized
using Dess–Martin periodinane. In this fashion aldehyde
16 was obtained in 87% overall yield from compound 15.
The aldehyde was then subjected to the standard conditions
employed for the Henry reaction.As a result the E-configured
nitrostyrene 17 was obtained in 72% yield. At this point
it was anticipated that removal of the ketal unit followed
by reduction of both the β-nitrostyrene and nitroarene moi-
eties would, after a Michael addition reaction and a separate
indolization step, provide the carbazole 4 as foreshadowed
in Fig. 2. Unfortunately when a variety of conditions[17]
were explored in an effort to implement this sequence in
a one-pot (nitrosyrene 17 → carbazole 4) or stepwise man-
ner (nitrosyrene 17 → primary amine 6 → piperidine 5 →
carbazole 4) decomposition of the starting materials was the
only outcome observed. As a consequence alternate routes to
the key conjugate addition precursor 6 were pursued.
O2N
O
27 Xꢀ Boc
6 Xꢀ H
(l)
Scheme 2. Reagents and conditions: (a) 4-AcN(H)TEMPO
(10 mol%), PhI(OAc)2 (1.05 mol equiv.), CH2Cl2, 18◦C, 3 h;
(b) NaHMDS (1.3 mol equiv.), CH3OCH2PPh3Cl (1.3 mol equiv.),
THF, 0 → 18◦C, 16 h; (c) 3 M aq. HCl, THF, 0 → 18◦C, 16 h; (d)
NaBH4 (1 mol equiv.), MeOH, 0◦C, 3 h; (e) MsCl (1.2 mol equiv.),
triethylamine (1.2 mol equiv.), Et2O, 0◦C, 2 h; (f ) NaN3 (3 mol equiv.),
DMF, 67◦C, 5 h; (g) SnCl2·2H2O (2 mol equiv.), MeOH, 18◦C, 5 h; (h)
Boc2O (1.2 mol equiv.), triethylamine (3.6 mol equiv.), CH2Cl2, 16 h;
(i) CrO3·3,5-DMP (15.3 mol equiv.), −10 to −20◦C → 0◦C, 4 h; (j) I2
(4 molequiv.), 1:1v/vCCl4/pyridine, 18◦C, 16 h;(k)o-iodonitrobenzene
(2 mol equiv.), Cu (5 g atom equiv.), Pd2(dba)3 (cat.), DMSO, 70◦C,
5 h; (l) TFA, CH2Cl2, 18◦C, 2 h.
way a 1:1 mixture of the E- and Z-isomers of compound 19
was obtained in 80% yield. Acid-catalyzed hydrolysis of
this enol ether and reduction of the resulting aldehyde with
NaBH4 then afforded the higher homologue, 20 (92% from
19), of alcohol 11. Introduction of nitrogen onto this homolo-
gated side-chain was achieved by first converting alcohol
20 into the corresponding mesylate 21 (93%) then treat-
ing the latter material with NaN3. The resulting azide 22
was then reduced, using SnCl2,[19] to afford amine 23 (70%
from alcohol 20). With the aminated side chain required
for the proposed conjugate addition reaction now in place,
attention turned to the installation of the required enone func-
tionality. To such ends, the amine 23 was converted, upon
treatment with Boc2O, into carbamate 24 (quant.) which was
then allylically oxidized, using the conditions outlined previ-
ously, to afford the enone 25 in 63% yield. Iodination of this
last compound was, once again, achieved using Johnson’s
α-iodination protocol to afford iodide 26 (quant.). Com-
pound 26 was then subjected to Pd(0)-catalyzed Ullmann
cross-coupling with o-iodonitrobenzene and so providing
the arylated enone 27 (82%). With this last compound in
hand it was now possible to explore the pivotal conjugate
In an attempt to circumvent the difficulties encountered as
detailed above, access to the conjugate addition precursor 6
was pursued by installing (onto alcohol 11) the extra carbon
andnitrogenatomsoftheD-ringbeforeperformingthePd(0)-
catalyzed Ullmann cross-coupling reaction (Scheme 2).Thus
alcohol 11 was oxidized, under conditions related to those
described by De Mico et al.,[18] to aldehyde 18 (89%) which
was reacted with (methoxymethylene)triphenylphosphorane
generated in situ by treating the corresponding phosphonium
salt with sodium hexamethyldisilazide (NaHMDS). In this

Application of the Ullmann Cross-Coupling Reaction in a Total Synthesis of ( )-Aspidospermidine
addition reaction. Relevant studies were undertaken using
725
X
both carbamate 27 and its deprotected counterpart, namely
O
O
amine 6, which was prepared in quantitative yield by treat-
(a)
ing the former compound with TFA. Unfortunately, and
despite examining a variety of conditions,[20] neither sub-
EtO
EtO
strate participated in the desired intramolecular conjugate
addition reaction. In order to develop an understanding of
28 XꢀCl
29 XꢀOTBS
8
this disappointing result molecular modelling studies were
carried out on compound 6 and its desaryl derivative. Energy-
(b)
minimized structures were obtained using density functional
X
X
theory[21] with the B3LYP[22] functional 6-31G*[23] basis set.
From these studies it appears that while effective HOMO–
LUMO interactions necessary for the desired reaction are
Y
(d)
possible within the framework of the desaryl analogue of
O2N
compound 6,[8a] they are not within compound 6 itself due
O
O
30 XꢀCl, YꢀH
31 XꢀOTBS, YꢀH
34 XꢀCl
to an unfavourable distribution of the LUMO. In addition,
35 XꢀOTBS
(e)
(c)
the aryl group imparts a significant steric impediment to the
desired process as it is orthogonally orientated with respect
to the enone.
36 XꢀOH
(f)
32 XꢀCl, YꢀI
33 XꢀOTBS, YꢀI
37 XꢀOMs
(g)
N3
Using an Intramolecular 1,3-Dipolar Cycloaddition
Reaction for Assembling the CD-Ring System of
Aspidospermidine
N
N
N
(h)
Having been unable to utilize an intramolecular conjugate
addition reaction to assemble the D-ring of target 3, atten-
tion turned to the identification of alternative methods for
the formation of this motif. Early in 2004 Schulz and
Guo[24] reported the use of an intramolecular 1,3-dipolar
cycloaddition reaction of an azide to an α-arylated enone to
provide, following nitrogen extrusion and reductive cleav-
age of the resultant aziridine, a piperidine cis-fused to a
cyclohexenone.[25] In order to ascertain the feasibility of
applying such an approach in the present context, a model
system was investigated which lacked an ethyl group attached
to the γ-position of the cyclohexenone residue.The substrate,
38, required for this study was prepared by the route outlined
in Scheme 3 which began with the α-alkylation[26] of 3-
ethoxycyclohex-2-enone (8) using 1-chloro-3-iodopropane.
The resulting β-ethoxyenone 28 (72%) was then reduced,
with LiAlH4, and the ensuing enol ether hydrolyzed on work-
up to afford the γ-substituted enone 30 in 65% yield. The
α-arylation of enone 30 began with the application of John-
son’s iodination conditions and thereby providing iodide 32 in
68% yield. This last compound was then cross-coupled with
o-iodonitrobenzene using the previously mentioned Pd(0)-
catalyzed Ullmann reaction to provide the α-arylated enone
34 in 77% yield. The chlorine within compound 34 was
then displaced upon heating this material at 80◦C in the
presence of NaN3, thus affording an inseparable mixture
of azide 38 and the isomeric triazoline 39 (see below).
In a parallel and slightly more useful reaction sequence,
3-ethoxycyclohex-2-enone (8) was α-alkylated with theTBS-
ether of 3-iodopropanol so as to provide compound 29 (83%)
that, following reduction and hydrolytic work-up, gave the
γ-substituted enone 31 in 66% yield. Iodination then pro-
vided compound 33 in 82% yield which, upon subjection to
Pd(0)-catalyzed Ullmann cross-coupling, gave the α-arylated
enone 35 in 69% yield. Removal of the TBS group followed
O2N
O
O
O2N
38
39
Scheme 3. Reagents and conditions: (a) LiHMDS (1.1 mol equiv.),
HMPA (1.1 mol equiv.), ICH2CH2CH2OTBS (1 mol equiv.) or
ICH2CH2CH2Cl (1 mol equiv.), THF, −30 → 18◦C, 16 h; (b) LiAlH4
(1.07 mol equiv.), THF, 0 → 18◦C, 0.5 h; (c) I2 (4 mol equiv.), 1/1 v/v
CCl4/pyridine, 18◦C, 16 h; (d) o-iodonitrobenzene (2 mol equiv.), Cu
(5 g atom equiv.), Pd2(dba)3 (cat.), DMSO, 70◦C, 16 h; (e) Conc. aq.
HCl (cat.), EtOH, 0 → 18◦C, 3 h; (f ) MsCl (1.2 mol equiv.), triethy-
lamine (1.2 mol equiv.), Et2O/CH2Cl2 (3/1), 0◦C, 2 h; (g) NaN3 (3 mol
equiv.), DMF, 67–80◦C (X = Cl) or 67◦C (X = OMs), 3 h; (h) C6H6,
80◦C, 16 h.
by conversion of the resulting alcohol into the mesylate and
displacement with NaN3 then gave the azide 38 in 61% over-
all yield and without any accompanying triazoline 39. The
clean formation of azide 38 via this second route is attributed
to the lower temperature (67◦C versus 80◦C) required for
displacement of the mesylate (as compared to the chloride).
Thermolysis of a sample of azide 38 in refluxing ben-
zene resulted in the smooth formation of the crystalline
triazoline 39 (72%), the structure of which follows from
a single-crystal X-ray analysis (see Fig. 3 and Experimen-
tal section). Although the corresponding aziridine, which
might be expected to form via expulsion of nitrogen from
the triazoline 39, was not isolated the acquisition of the latter
compound indicated that the D-ring of target 3 could be annu-
lated, in a cis-selective manner, to an existing C-ring using
a 1,3-dipolar cycloaddition reaction. After some preliminary,
and unsuccessful, attempts to reductively cleave triazoline
39 and thus form the desethyl version of compound 5, it was
decided to seek the ethyl analogue of compound 38 since the
quaternary centre within such a compound may impart suffi-
cient strain on the intermediate triazoline to facilitate in situ
nitrogen expulsion.

726
M. G. Banwell, D. W. Lupton, and A. C. Willis
OAc
OH
OAc
C4
N2
C18
C5
X
(a)
(b)
C19
C14
N3
N1
O
20
40
41 X ꢀ H
42 X ꢀ I
C17
C12
(c)
C6
C11
(d)
C7
C8
C16
C10
X
O13
C15
N20
N
C9
(h)
O21
O2N
O2N
O
O
O22
47
43 X ꢀ OAc
44 X ꢀ OH
45 X ꢀ OMs
46 X ꢀ N3
(e)
(g)
(f)
Fig. 3. ORTEP derived from a single-crystal X-ray analysis of triazo-
line 39.
(i)
ClH2N
Cl
HN
Preparationoftheethyl-containingaziridine47(Scheme4)
began with alcohol 20 that had been obtained by the route
outlined in Schemes 1 and 2. This alcohol was protected as
the corresponding acetate 40 which was oxidized with 15
equivalents of CrO3·3,5-DMP to afford enone 41 in 65%
yield (from 20). Unfortunately, when this allylic oxidation
was performed on large scales the work-up became diffi-
cult due to the presence of a vast excess of reagent. In order
to improve matters the operationally more simple protocol
described by Pearson[27] was investigated. Thus, by heat-
ing an acetonitrile solution of alkene 40 at reflux in the
presence of half a mole equivalent of Cr(CO)6 and 3 mol
equivalents of t-butyl hydroperoxide enone 41 was obtained
in 62% yield. While this second protocol was slightly less
efficient, the work-up was much more straightforward. Hav-
ing installed the enone functionality it was now a matter of
performing the α-arylation reaction. This was achieved using
the by now standard sequence of α-iodination, to convert
enone 41 into the α-iodoenone 42, then cross-coupling with
o-iodonitrobenzene in the presence of 5 g atom equiv. of cop-
per powder and using Pd2(dba)2 as catalyst. In this manner the
α-arylated enone 43 was obtained in 75% yield over the two
steps. Exposure of the last compound to K2CO3 in methanol
then afforded the corresponding alcohol 44 which was con-
verted into the mesylate 45.The latter compound was, in turn,
reacted with NaN3 in DMF at 67◦C to afford azide 46 (87%
yield from acetate 43). The key 1,3-dipolar cycloaddition
reaction was performed by heating a dilute benzene solu-
tion of azide 46 at ca. 75◦C for three days and in this way the
ring-fused aziridine 47 was obtained in 72% yield. The inter-
mediate triazoline arising from the 1,3-dipolar cycloaddition
of the azide moiety within substrate 46 to the tethered α-(o-
nitroaryl)enone could be detected by 1H NMR spectroscopy
but was never isolated. From this point it was hoped that
reductive cleavage of the superfluous C–N bond within aziri-
dine 47 and reduction of the associated nitro-group could
be achieved in the one pot to afford tetrahydrocarbazole 4
directly. Reagents that might be expected to achieve such
transformations, e.g. Pearlmann’s catalyst–H2–MeOH,[28] Pd
on charcoal–H2–MeOH, Pd on charcoal–H2–MeOH–AcOH,
(j)
O2N
N
O
H
48
4
Scheme 4. Reagents and conditions: (a)Ac2O (excess), DMAP (cat.),
pyridine, 0 → 18◦C, 1.5 h; (b) Cr(CO)6 (0.5 mol equiv.), 70% ButOOH
(3.0 mol equiv.), CH3CN, 82◦C, 16 h; (c) I2 (4 mol equiv.), 1/1 v/v
CCl4/pyridine, 18◦C, 16 h; (d) o-iodonitrobenzene (2 mol equiv.), Cu
(5 g atom equiv.), Pd2(dba)3 (cat.), DMSO, 70◦C, 5 h; (e) 1 M aq.
K2CO3, MeOH, 18◦C, 16 h; (f ) MsCl (1.2 mol equiv.), triethylamine
(1.2 mol equiv.), Et2O, 0 → 18◦C, 2 h; (g) NaN3 (3 mol equiv.), DMF,
67◦C, 3 h; (h) C6H6, 75◦C, 72 h; (i) 1 M HCl in Et2O (2.0 mol equiv.),
CH2Cl2, −15◦C, 1.5 h; (j) TiCl3·3THF (10 mol equiv.) in 1/2/2 v/v/v
H2O/2.5 M aq. NH4OAc/acetone, 18◦C, 0.33 h.
TiCl3–NH4Ac in acetone,[29] SmI2 in MeOH,[30] zinc in
acetic acid,[31] and AIBN–Bun3SnH,[32] were all explored but
each proved ineffective.
Having been unable to convert aziridine 47 directly into
tetrahydrocarbazole 4 a two-step strategy involving the acid-
promoted ring-opening of aziridine 47[24,33] followed by
reductive cyclization of the nitroarene functionality was
explored. After much experimentation it was established that
regioselective cleavage of the aziridine could be achieved by
treating a chilled (−20◦C) CH2Cl2 solution of compound
47 with an ethereal solution of HCl. The resulting, and
highly unstable, hydrochloride salt 48, which was obtained
in quantitative yield and as a single diastereoisomer, was
then subjected to reduction with titanium trichloride[28] in
the presence of ammonium acetate. In this manner the by
now long sought after carbazole 4 was obtained in 46% yield
from aziridine 47.The physical and spectral data derived from
this material proved a good match, in all respects, with those
reported previously.[8g]
A Familiar End-Game: Completion of a Total Synthesis
of Aspidospermidine via Annulation of the E-ring
to the ABCD-Core
WhileWenkertandHudlicky[8g] havetransformedcompound
4, via a two step sequence, into aspidospermidine (3), for

Application of the Ullmann Cross-Coupling Reaction in a Total Synthesis of ( )-Aspidospermidine
727
X
as δ values in parts per million (ppm). Infrared spectra (νmax) were
recorded on a Perkin–Elmer 1800 Series FTIR Spectrometer and sam-
ples were analyzed as KBr disks (for solids) or plates (for oils). Low
resolution mass spectra were recorded on a Micromass–Waters LC-
ZMD single quadrupole liquid chromatograph-MS or a VG Quattro II
triple quadrupole MS instrument using electron impact techniques. High
resolution mass spectra were recorded on an AUTOSPEC spectrometer.
CH2Cl2 was distilled from calcium hydride andTHF was distilled, under
nitrogen, from sodium benzophenone ketyl. Where necessary, reactions
were performed under a nitrogen atmosphere.
HN
O
N
N
(a)
N
H
H
49 X ꢀ Cl
50 X ꢀ I
4
3
(b)
(c)
Synthetic Studies
O
(
)-1-Ethyl-2-cyclohexene-1-acetic Acid 10
N
(d)
A magnetically stirred solution of diisopropylamine (17.8 mL,
127 mmol) in THF (200 mL) was cooled to 0◦C then treated, drop-
wise, with BunLi (55.2 mL of a 2.3 M solution in hexane, 110 mmol).
The resulting mixture was then cooled to −78◦C and acetate 9[9]
(16.8 g, 100 mmol) added dropwise. The resulting orange reaction mix-
ture was stirred at −78◦C for 10 min then treated with TBDMS-Cl
(20.6 g, 138 mmol) and after the reaction had become homogeneous
(∼0.25 h) it was allowed to warm to 18◦C then heated at reflux. After
6 h the dark-orange solution was cooled to 18◦C, treated with methanol
(150 mL) and stirred at 18◦C for 16 h during which time the formation
of precipitates was often observed.The resulting suspension was poured
into NaOH (400 mL of a 5% w/v aqueous solution) and washed with
diethyl ether (1 × 200 mL). The aqueous phase was acidified with HCl
(300 mL of a 10% w/v aqueous solution) and extracted with diethyl
ether (3 × 500 mL). The combined organic fractions were then dried
(MgSO4), filtered, and concentrated under reduced pressure to yield
the carboxylic acid 10[13] (11.2 g, 62%) as a clear, colourless oil, Rf
0.6 (silica, 1/4 v/v ethyl acetate/hexane elution) (Found: M+• 168.1152.
C10H16O2 requires M+• 168.1150). νmax (neat)/cm−1 3018, 2934, 1703,
1448, 1407, 1298, 941, 728, 697. δH (300 MHz) 11.95 (1H, broad s),
5.70 (1H, dt, J 10.2 and 3.6), 5.51 (1H, dt, J 10.2 and 2.1), 2.33 (2H,
d, J 1.2), 1.95 (2H, m), 1.66–1.44 (6H, complex m), 0.86 (3H, t, J 7.5).
δC (75 MHz) 178.8 (C), 133.4 (CH), 127.2 (CH), 43.6 (CH2), 37.0 (C),
32.1 (CH2), 32.0 (CH2), 25.0 (CH2), 18.8 (CH2), 8.3 (CH3). m/z (EI,
70 eV) 168 (M+•, 15%), 150 (10), 139 (57), 121 (20), 109 (57), 108
(93), 93 (62), 79 (100), 67 (52).
N
51
Scheme 5. Reagents and conditions: (a) α-chloroacetyl chloride
(1.0 mol equiv.), triethylamine (1.1 mol equiv.), CH2Cl2, 0 → 18◦C, 2 h;
(b) NaI (10 mol equiv.), acetone, 56◦C, 2 h; (c) AgOTf (2 mol equiv.),
THF, 18◦C, 0.5 h; (d) LiAlH4 (4 mol equiv.), THF, 66◦C, 4 h.
the purposes of completing the present study the conversion
of compound 4 into target 3 was achieved by following the
slightly longer, but higher yielding, procedures (Scheme 5)
described by Toczko and Heathcock.[8r] Thus, reaction of
carbazole 4 with α-chloroacetyl chloride[34] afforded the α-
chloroamide 49[8r] (69%) that was, in turn, converted into the
corresponding α-iodoamide 50[8r] under Finkelstein condi-
tions. Treatment of this last compound with silver(i) triflate
then gave the lactam 51[8r] (50% from 49) which was reduced
with LiAlH4 to give ( )-aspidospermidine (3, 77%).
While the spectral data obtained on ( )-aspidospermidine
(3) derived by the sequence just described matched those
reported in the literature[8r] (see Table 1), the 300 MHz
1H NMR spectrum was difficult to interpret because of the
presence of overlapping signals and non-first order splitting
patterns. Accordingly, aspidospermidine (3), was analyzed at
800 MHz and the resulting 1H NMR spectrum, with partial
assignments, is shown in Fig. 4.
(
)-1-Ethyl-2-cyclohexene-1-ethanol 11
A magnetically stirred suspension of LiAlH4 (17.2 g, 452 mmol) inTHF
(500 mL) was cooled to 0◦C then treated, dropwise, with carboxylic acid
10 (10.8 g, 65 mmol). The resulting suspension was stirred at 18◦C for
2 h then cooled to 0◦C and the excess LiAlH4 destroyed by the slow
addition of ice (CAUTION: exothermic process). Once the vigorous
reaction had subsided, KHSO4 (1 L of a saturated aqueous solution) was
added and the resulting mixture extracted with diethyl ether (4 × 1 L).
The combined organic fractions were washed with brine (2 × 200 mL)
then dried (MgSO4), filtered, and concentrated under reduced pressure
to yield the alcohol 11[14] (9.5 g, 96%) as a clear, colourless oil, Rf
0.2 (silica, 1/4 v/v ethyl acetate/hexane elution) (Found: M+• 154.1360.
C10H18O M+• requires 154.1358). νmax (neat)/cm−1 3333, 2942, 1458,
1374, 1046, 1020. δH (300 MHz) 5.67 (1H, dt, J 10.5 and 3.6), 5.42
(1H, dt, J 10.5 and 1.8), 3.67 (2H, t, J 7.5), 1.91 (2H, m), 1.62–1.25
(8H, complex m), 0.82 (3H, t, J 7.5) (H of OH group not detected).
δC (75 MHz) 134.9 (CH), 126.8 (CH), 59.7 (CH2), 42.1 (CH2), 36.2
(C), 33.0 (CH2), 32.1 (CH2), 25.1 (CH2), 19.1 (CH2), 8.3 (CH3). m/z
(EI, 70 eV) 154 (M+•, 10%), 136 (12), 125 (62), 109 (100), 107 (88),
84 (72), 79 (85), 67 (82).
Conclusions
The studies detailed above demonstrate that the synthesis of
aspidospermidine (3) can be achieved in a relatively efficient
manner when starting from an intact C-ring precursor. This
outcome suggests that construction of the ABCDE-ring sys-
tem of vinblastine (1), and vinblastine (1) itself, might be
accessible from metabolite 2. Studies aimed at realizing such
goals are ongoing endeavours within our laboratories and will
be reported upon in due course.
Experimental
(
)-1-Ethyl-2-cyclohexene-1-ethanol Acetate 12
Melting points were measured on a Reichert hot-stage microscope appa-
ratus and are uncorrected. Proton (1H) and carbon (13C) NMR spectra
wererecordedoneitheraBruker800, aVarianInova500oraGemini300
NMR spectrometer. Unless otherwise specified, spectra were acquired
at 20◦C in deuterochloroform (CDCl3) that had been filtered through
basic alumina immediately before use. Chemical shifts are recorded
A magnetically stirred solution of alcohol 11 (9.5 g, 61 mmol) in acetic
anhydride (25 mL) was cooled to 0◦C then treated with pyridine (10 mL)
followed by DMAP (100 mg, 1 mol%). After 0.3 h at this temperature
the cooling bath was removed and the resulting mixture stirred at 18◦C
for 1.5 h then recooled to 0◦C and treated with methanol (50 mL) to

728
M. G. Banwell, D. W. Lupton, and A. C. Willis
Table 1. Comparison of 13C NMR chemical shift data recorded for
aspidospermidine (3)
quench the unreacted acetic anhydride. The ensuing mixture was stirred
for 2 h at 18◦C before being diluted with diethyl ether (1 L) then washed
with water (1 × 500 mL) and HCl (2 × 100 mL of a 1 M aqueous solu-
tion). The combined aqueous phases were extracted with diethyl ether
(2 × 300 mL) and the combined organic fractions then washed with
Na2CO3 (2 × 100 mL of a saturated solution) and brine (1 × 100 mL)
before being dried (MgSO4), filtered, and concentrated under reduced
pressuretoyieldtheacetate 12(11.3 g, 87%)asapale-yellowoil(Found:
Reported by
Heathcock et al.[8r]
Data obtained at 125 MHz
in CDCl3
Recorded on synthetically
derived 3 (present work).
Data obtained at 75 MHz
in CDCl3
C18
C13
C16
C14
C15
C17
C19
C2
149.6
135.9
127.2
123.0
119.1
110.5
71.4
65.8
54.0
53.6
53.2
39.0
35.8
34.7
30.1
28.3
23.2
22.0
7.0
149.3
135.6
127.1
122.7
118.9
110.3
71.2
65.5
53.8
53.2
52.9
38.7
35.6
34.3
29.9
28.0
22.9
21.6
6.8
•
•
M+ 196.1461. C12H20O2 requires M+ 196.1463). νmax (neat)/cm−1
2934, 1742, 1460, 1365, 1237, 1032, 730. δH (300 MHz) 5.68 (1H, dt,
J 10.2 and 3.9), 5.40 (1H, d, J 10.2), 4.09 (2H, t, J 7.8), 2.03 (3H, s),
1.94–1.91 (2H, complex m), 1.66–1.34 (8H, complex m), 0.84 (3H, t, J
8.1). δC (75 MHz) 170.7 (C), 134.1 (CH), 126.7 (CH), 61.6 (CH2), 37.2
(CH2), 36.0 (C), 32.5 (CH2), 32.0 (CH2), 25.0 (CH2), 21.0 (CH3), 18.9
(CH2), 8.0 (CH3). m/z (EI, 70 eV) 196 (M+•, 5%), 167 (20), 136 (40),
107 (100).
C8
C12
C10
C11
C5
C6
C20
C4
C3
C7
C21
(
)-4-[2-(Acetyloxy)ethyl]-4-ethyl-2-cyclohexen-1-one 13
A magnetically stirred suspension of chromium trioxide (54.2 g,
540 mmol) in CH2Cl2 (500 mL) was cooled to −20◦C then treated
with 3,5-dimethylpyrazole (52.1 g, 540 mmol). After 0.25 h the dark-
red solution was treated, dropwise, with alkene 12 (7.06 g, 36 mmol)
and the resulting mixture stirred for 8 h at −10 to −20◦C then warmed
to 0◦C and NaOH (200 mL of a 5 M aqueous solution) added.After 1.5 h
the organic phase was separated and the aqueous phase extracted with
CH2Cl2 (2 × 200 mL). The combined organic fractions were washed
with HCl (2 × 100 mL of a 1 M aqueous solution) then dried (MgSO4),
8
10
15
14
13
N
H-19
6
16
19
20
21
17
18
2
N
1
H
H
H-2
H-1
H-10ꢁ
H-8ꢂ
H-10ꢂ
H-8ꢁ
H-21
3.6
2.4
2.2
3.4
3.2
3.0
2.8
2.6
H-20
H2O
1.0
0.8
2.0
1.8
1.6
1.4
1.2
H-15
H-16
H-14
H-17
4
2
1
ppm
7
6
5
3
Fig. 4. 800 MHz 1H NMR spectrum of synthetically derived ( )-aspidopsermidine (3) (recorded in CDCl3) with expansions of the upfield regions.

Application of the Ullmann Cross-Coupling Reaction in a Total Synthesis of ( )-Aspidospermidine
729
filtered, and concentrated under reduced pressure to yield a brown
solid. This residue was subjected to column chromatography (silica, 1/4
v/v ethyl acetate/hexane elution) to provide, after concentration of the
appropriate fractions•(Rf 0.3), enone 13 (5.07 g, 67%) as a clear, colour-
νmax (neat)/cm−1 2956, 1736, 1678, 1461, 1389, 1364, 1234, 1024. δH
(300 MHz) 6.69 (1H, d, J 10.5), 5.90 (1H, d, J 10.5), 4.11 (2H, td, J 6.3
and 1.2), 2.42 (2H, t, J 7.2), 2.01 (3H, s), 1.90–1.76 (4H, complex m),
1.54 (2H, m), 0.90 (3H, t, J 7.8). δC (75 MHz) 198.8 (C), 170.6 (C),
157.1 (CH), 128.2 (CH), 60.7 (CH2), 37.6 (C), 35.5 (CH2), 33.7 (CH2),
30.8 (CH2), 30.6 (CH2), 21.0 (CH3), 8.3 (CH3). m/z (EI, 70 eV) 210
(M+•, 10%), 182 (5), 168 (15), 167 (14), 151 (25), 150 (90), 135 (45),
121 (100), 93 (88).
connected to a Dean–Stark trap. After 22 h the cooled reaction
mixture was diluted with diethyl ether (800 mL) and washed with
NaHCO3 (1 × 75 mL of a saturated aqueous solution). The separated
organic phase was then dried (MgSO4), filtered, and concentrated under
reduced pressure. The ensuing residue was subjected to column chro-
matography (silica, 1/4 → 3/7 v/v ethyl acetate/hexane gradient elution)
and concentration of the appropriate fractions [Rf 0.5 (3/7 v/v ethyl
acetate/hexane elution)] then afforded ketal 15 (945 mg, 63%) as a pale-
yellow oil. νmax (neat)/cm−1 2964, 1738, 1607, 1572, 1530, 1462, 1359,
1237, 1168, 1102, 1030, 948, 855, 753, 684. δH (300 MHz) 7.80 (1H,
d, J 7.8), 7.47 (1H, t, J 7.8), 7.37 (1H, t, J 7.8), 7.28 (1H, d, J 7.8),
5.58 (1H, s), 4.14 (2H, m), 3.69 (2H, m), 3.29 (2H, broad s), 1.98 (3H,
s), 1.89–1.69 (6H, complex m), 1.46 (2H, m), 0.87 (3H, t, J 7.5). δC
(75 MHz) 170.9 (C), 149.8 (C), 139.6 (CH), 136.0 (C), 133.4 (C), 132.8
(CH), 131.8 (CH), 127.9 (CH), 123.3 (CH), 106.5 (C), 64.8 (CH2), 61.3
(CH2), 37.0 (CH2), 36.5 (C), 31.5 (CH2), 30.8 (CH2), 29.0 (CH3), 8.3
(CH3) (two signals obscured or overlapping).
•
less oil (Found: M+ 210.1257. C12H18O3 requires M+ 210.1256).
(
)-4-[2-(Acetyloxy)ethyl]-4-ethyl-2-iodo-2-cyclohexen-1-one 7
A magnetically stirred solution of enone 13 (6.80 g, 34.6 mmol) in
CCl4/pyridine (140 mL of a 1/1 v/v mixture) was cooled to 0◦C then
treated, dropwise, withasolutionofmoleculariodine(35.2 g, 139 mmol)
in CCl4/pyridine (140 mL of a 1/1 v/v mixture). The cooling bath was
then removed and the by now black solution was stirred at 18◦C for 60 h.
The reaction mixture was then poured into diethyl ether (600 mL) and
washed sequentially with water (1 × 200 mL), HCl (5 × 100 mL of a
1 M aqueous solution), water (1 × 200 mL), and Na2S2O3 (1 × 150 mL
of a 20% w/v aqueous solution). The aqueous phases were combined
and extracted with diethyl ether (1 × 300 mL). The combined organic
fractions were then washed with brine (1 × 200 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure to provide
iodide 7 (9.10 g, 83%) as a clear, colourless•oil, Rf 0.3 (silica, 1/4
v/v ethyl acetate/hexane elution) (Found: M+ 336.0223. C12H17IO3
(
)-8-Ethyl-6-(2-nitrophenyl)-1,4-dioxaspiro[4.5]dec-6-
ene-8-ethanal 16
Step (i): A magnetically stirred solution of acetate 15 (210 mg,
0.56 mmol) in methanol (10 mL) was cooled to 0◦C then treated,
dropwise, with KOH (1 mL of a 1 M aqueous solution). The result-
ing mixture was stirred at 18◦C for 1 h then diluted with diethyl
ether (1 × 100 mL) and washed with water (1 × 50 mL). The separated
aqueous phase was extracted with diethyl ether (1 × 100 mL) and the
combined organic phases then dried (MgSO4), filtered, and concentrated
under reduced pressure to afford the expected alcohol (185 mg, 100%)
as a clear, colourless oil, Rf 0.3 (silica, 3/7 v/v ethyl acetate/hexane elu-
tion)[Found:(M − HO•)+ 316.1542. C18H23NO5 requires(M − HO•)+
316.1549]. νmax (neat)/cm−1 3401, 2961, 2937, 1607, 1571, 1529, 1357,
1224, 1165, 1100, 1026, 947, 855, 786, 753, 710, 684. δH (300 MHz)
7.76 (1H, dd, J 8.1 and 1.2), 7.47 (1H, td, J 7.5 and 1.2), 7.36 (1H, td, J 8.1
and 1.5), 7.27 (1H, dd, J 7.5 and 1.5), 5.61 (1H, s), 3.74–3.65 (4H, com-
plex m), 3.35–3.22 (2H, complex m), 2.59 (1H, broad s), 1.86–1.62 (6H,
complex m), 1.45 (2H, q, J 7.5), 0.87 (3H, t, J 7.5). δC (75 MHz) 149.7,
140.7, 135.4, 133.4, 132.9, 131.9, 127.9, 123.3, 106.7, 64.7, 59.2, 41.1,
37.1, 32.2, 30.9, 28.8, 8.3 (one signal obscured or overlapping). m/z (EI,
70 eV) 316 [(M − HO•)+, 1%], 199 (15), 155 (17), 111 (15), 99 (100).
Step (ii): A magnetically stirred suspension of Dess–Martin period-
inane (1.14 g, 2.7 mmol) in CH2Cl2 (15 mL) was treated with pyridine
(1 mL) and, after 5 min, a solution of the abovementioned alcohol
(450 mg, 1.35 mmol) in CH2Cl2 (6 mL). After 3 h at 18◦C the reaction
mixture was quenched by the sequential addition of NaHCO3 (2 mL of
a saturated aqueous solution) and Na2S2O3 (2 mL of a 5% w/v aqueous
solution). After 0.3 h the organic phase was separated and the aqueous
phase extracted with diethyl ether (2 × 75 mL). The combined organic
phases were washed with brine (1 × 100 mL) then dried (MgSO4), fil-
tered, and concentrated under reduced pressure to give a pale-yellow
oil. Subjection of this material to column chromatography (silica, 3/7
v/v ethyl acetate/hexane elution) yielded, upon concentration of the
appropriate fractions (Rf 0.35), the aldehyde 16 (390 mg, 87%) as a
clear, colourless oil [Found: (M + H)+ 332.1498. C18H21NO5 requires
(M + H)+ 332.1498]. νmax (neat)/cm−1 2964, 2881, 1718, 1607, 1571,
1529, 1357, 1168, 1099, 1026, 948, 855, 786, 753, 683. δH (300 MHz)
9.82 (1H, t, J 3.0), 7.80 (1H, dd, J 8.1 and 1.5), 7.49 (1H, dt, J 7.5 and
1.5), 7.39 (1H, dt, J 8.1 and 1.5), 7.27 (1H, dd, J 7.5 and 1.5), 5.71 (1H,
s), 3.69 (2H, m), 3.28 (2H, m), 2.48–2.42 (2H, complex m), 1.92–1.76
(4H, complex m), 1.57 (2H, m), 0.91 (3H, t, J 7.2). δC (75 MHz) 202.6,
149.6, 138.1, 136.9, 132.9, 132.7, 131.9, 128.1, 123.3, 106.1, 64.8, 51.4,
37.7, 31.9, 30.6, 29.4, 8.3 (one signal obscured or overlapping). m/z (EI,
70 eV) 332 [(M + H)+, 1%], 302 (3), 165 (27), 153 (23), 115 (19), 99
(100), 86 (51).
•
requires M+ 336.0222). νmax (neat)/cm−1 2920, 1739, 1689, 1458,
1371, 1234. δH (300 MHz) 7.52 (1H, s), 4.15 (2H, td, J 6.9 and 2.1),
2.68 (2H, t, J 7.2), 2.06 (3H, s), 1.97 (2H, t, J 6.9), 1.86 (2H, m), 1.59
(2H, m), 0.94 (3H, t, J 7.5). δC (75 MHz) 191.4 (C), 170.6 (C), 166.0
(CH), 102.7 (C), 60.4 (CH2), 42.8 (CH2), 35.4 (C), 32.8 (CH2), 30.7
•
(CH2), 30.5 (CH2), 21.1 (CH3), 8.5 (CH3). m/z (EI, 70 eV) 336 (M+
,
40%) 294 (17), 276 (40), 247 (55), 207 (27), 149 (100).
(
)-4-[2-(Acetyloxy)ethyl]-4-ethyl-2-(2-nitrophenyl)-
2-cyclohexen-1-one 14
A magnetically stirred solution of iodide 7 (4.70 g, 14.5 mmol) and
o-iodonitrobenzene (7.25 g, 29.0 mmol) in DMSO (40 mL) was treated
with Pd2(dba)3 (753 mg, 0.728 mmol) and copper powder (4.65 g,
72.8 mmol). The resulting mixture was heated at 70◦C for 2 h, cooled to
18◦C, diluted with diethyl ether (500 mL) then filtered through a pad of
Celite which was washedwith diethyl ether (1 × 100 mL).The combined
filtrates were washed with water (2 × 200 mL) and brine (1 × 200 mL)
before being dried (MgSO4), filtered, and concentrated under reduced
pressure to provide a dark-yellow residue. Subjection of this residue to
column chromatography (silica, 1/4 → 3/7 v/v ethyl acetate/hexane gra-
dient elution) afforded, after concentration of the appropriate fractions
[Rf 0.6 (1/1 v/v ethyl acetate/hexane elution)], the title compound 14
(3.8 g, 81%)asaviscous, yellowoil(Found:M+• 331.1421. C18H21NO5
•
requires M+ 331.1420). νmax (neat)/cm−1 2963, 2934, 1736, 1685,
1523, 1353, 1234, 1154, 1028. δH (300 MHz) 8.02 (1H, dd, J 8.1 and
1.0), 7.60 (1H, td, J 7.5 and 1.0), 7.47 (1H, td, J 8.1 and 1.5), 7.23 (1H,
dd, J 7.5 and 1.5), 6.70 (1H, s), 4.21 (2H, t, J 7.2), 2.61 (2H, t, J 4.5),
2.03 (3H, s), 1.96 (4H, m), 1.69 (2H, q, J 7.5), 1.00 (3H, t, J 7.5). δC
(75 MHz) 195.8 (C), 170.7 (C), 152.9 (CH), 148.3 (C), 138.1 (C), 133.2
(CH), 131.9 (C), 131.5 (CH), 128.8 (CH), 124.2 (CH), 60.8 (CH2), 38.3
(CH2), 35.8 (C), 34.1 (CH2), 30.9 (CH2), 30.5 (CH2), 21.0 (CH3), 8.6
(CH3). m/z (EI, 70 eV) 331 (M+•, 1%), 315 (3), 299 (10), 242 (60), 225
(60), 196 (55), 162 (55), 134 (100), 120 (80), 104 (75).
(
)-8-Ethyl-6-(2-nitrophenyl)-1,4-dioxaspiro[4.5]dec-6-
(
)-8-Ethyl-6-(2-nitrophenyl)-8-(2E-3-nitroprop-2-enyl)-
ene-8-ethanol Acetate 15
1,4-dioxaspiro[4.5]dec-6-ene 17
A magnetically stirred solution of enone 14 (1.32 g, 4 mmol) in ben-
zene (80 mL) was treated with ethylene glycol (1.24 g, 10 mmol) and
p-TsOH (69 mg, 0.4 mmol) then brought to reflux in an apparatus
A magnetically stirred solution of aldehyde 16 (330 mg, 1 mmol) in
nitromethane (5 mL) was treated with ammonium acetate (81.4 mg,

730
M. G. Banwell, D. W. Lupton, and A. C. Willis
1.1 mmol) and the resulting mixture heated at 80◦C for 1.5 h then cooled
and concentrated under reduced pressure. A solution of the ensuing
residue in CH2Cl2 (50 mL) was washed with water (1 × 20 mL) and
the aqueous phase extracted with CH2Cl2 (1 × 50 mL). The combined
organic extracts were then washed with brine (1 × 20 mL) before being
dried (MgSO4), filtered, and concentrated under reduced pressure to
afford a dark-red oil. Subjection of this material to column chromatogra-
phy (silica, 3/7 v/v ethyl acetate/hexane elution) provided, upon concen-
tration of the appropriate fractions (Rf 0.4), the nitrostyrene 17 (270 mg,
72%) as a red oil [Found: (M − HO•)+ 357.1455. C19H22N2O6 requires
(M − HO•)+ 357.1450]. νmax (neat)/cm−1 2963, 2831, 1647, 1607,
1572, 1527, 1354, 1168, 1099, 1022, 949, 855, 785, 752, 710, 680. δH
(300 MHz) 7.83 (1H, dd, J 8.1 and 1.5), 7.51 (1H, td, J 7.5 and 1.5), 7.41
(1H, td, J 8.1 and 1.5), 7.34–7.22 (2H, complex m), 7.03 (1H, dt, J 13.2
and 1.2), 5.54 (1H, s), 3.71 (2H, m), 3.32 (2H, m), 2.44–2.30 (2H, com-
plex m), 1.89–1.47 (6H, complex m), 0.93 (3H, t, J 7.2). δC (75 MHz)
149.7 (C) 141.0 (CH), 139.0 (CH), 138.1 (CH), 137.5 (C), 133.0 (C),
132.6 (CH), 132.0 (CH), 128.2 (CH), 123.5 (CH), 106.2 (C), 64.8 (CH2),
38.7 (CH2), 36.9 (C), 31.5 (CH2), 30.7 (CH2), 29.2 (CH2), 8.3 (CH3)
(one signal obscured or overlapping). m/z (EI, 70 eV) 374 (M+•, 1%),
357 (2), 328 (5), 310 (2), 288 (20), 200 (17), 99 (100), 86 (37).
7.8), 4.34 (0.5H, dt, J 7.5 and 6.6), 3.56 (1.5H, s), 3.51 (1.5H, s), 2.08
(1H, m), 1.93–1.89 (2H, complex m), 1.60 (2H, m), 1.45–1.28 (5H,
complex m), 0.82 (1.5H, t, J 7.5), 0.81 (1.5H, t, J 7.5). δC (75 MHz)
148.1, 147.1, 135.4, 135.3, 126.3, 126.1, 103.1, 98.8, 59.3, 55.8, 37.3,
37.2, 37.1, 33.2, 31.8, 31.6(3), 31.5(5), 31.5(1), 25.2(1), 25.1(7), 19.0,
18.9, 8.1, 8.0. m/z (EI, 70 eV) 180 (M+•, 17%), 110 (30), 109 (100),
108 (48), 71 (63), 67 (82).
(
)-1-Ethyl-2-cyclohexene-1-propanol 20
Step (i): A magnetically stirred solution of enol ether 19 (8.50 g,
47.2 mmol) in THF (220 mL) was cooled to 0◦C then treated with
HCl (20 mL of a 3 M aqueous solution). The cooling bath was
removed and the reaction mixture allowed to warm to 18◦C over 16 h
before being diluted with brine (300 mL) then extracted with diethyl
ether (4 × 250 mL). The combined organic fractions were then dried
(MgSO4), filtered, and concentrated under reduced pressure to yield
(
)-1-ethyl-2-cyclohexene-1-propanal (7.84 g, 100%)asaclear, colour-
less oil, Rf 0.3 (silica, 5/95 v/v ethyl acetate/hexane elution). νmax
(neat)/cm−1 2927, 1721, 1454, 1382, 1179, 937, 728, 695. δH (300 MHz)
9.74 (1H, t, J 1.8), 5.68 (1H, dt, J 10.2 and 3.6), 5.31 (1H, dt, J 10.2 and
2.1), 2.39–2.31 (2H, complex m), 1.95–1.86 (2H, complex m), 1.62–
1.54 (4H, complex m), 1.46–1.24 (4H, complex m), 0.80 (3H, t, J 7.5).
δC (75 MHz) 203.0 (CH), 134.1 (CH), 127.4 (CH), 39.1 (CH2), 36.2 (C),
32.1 (CH2), 31.5 (CH2), 30.7 (CH2), 25.0 (CH2), 18.9 (CH2), 8.0 (CH3).
Step (ii):A magnetically stirred solution of the abovementioned alde-
hyde (9.50 g, 57.2 mmol) in methanol (175 mL) was cooled to 0◦C then
treated, in two portions, with NaBH4 (2.12 g, 57.2 mmol). After 3 h the
reaction mixture was diluted with brine (250 mL) then extracted with
diethyl ether (3 × 250 mL). The combined organic phases were washed
with brine (2 × 150 mL) then dried (MgSO4), filtered, and concentrated
under reduced pressure to provide the alcohol 20 (8.8 g, 92%) as a
clear, pale-yellow•oil, Rf 0.2 (silica, 1/9 v/v ethyl acetate/hexane elu-
(
)-1-Ethyl-2-cyclohexene-1-acetaldehyde 18
A magnetically stirred solution of alcohol 11 (6.10 g, 39.6 mmol)
in CH2Cl2 (50 mL) was treated, at 18◦C, with PhI(OAc)2 (14.02 g,
43.5 mmol) and 4-AcN(H)TEMPO (840 mg, 3.96 mmol). After 3 h the
reaction mixture was diluted with CH2Cl2 (400 mL) and washed with
NaHCO3 (1 × 300 mL of a saturated solution). The separated aqueous
phase was extracted with diethyl ether (1 × 100 mL) and the combined
organic phases were then washed with Na2S2O3 (1 × 200 mL of a 5%
w/v aqueous solution). Once again, the separated aqueous phase was
extracted with diethyl ether (1 × 100 mL) and all the organic phases
were combined then washed with brine (1 × 100 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure to afford a
light-yellow oil.This material was subjected to column chromatography
(silica, 5/95 v/v ethyl acetate/hexane elution) to give, upon concentra-
tion of the appropriate fractions (Rf 0.2), the aldehyde 18† (5.34 g, 89%•)
•
tion) (Found: M+ 168.1518. C11H20O requires M+ 168.1514). νmax
(neat)/cm−1 3340, 2934, 2862, 1454, 1378, 1056, 937, 728, 695. δH
(300 MHz) 5.65 (1H, dt, J 10.2 and 3.9), 5.40 (1H, dt, J 10.2 and 2.1),
3.61 (2H, t, J 6.6), 1.96–1.88 (2H, complex m), 1.64–1.22 (10H, com-
plex m), 0.81 (3H, t, J 7.5) (H of OH group not detected). δC (75 MHz)
135.3 (CH), 126.3 (CH), 63.7 (CH2), 36.4 (C), 35.0 (CH2), 32.0 (CH2),
31.9 (CH2), 27.1 (CH2), 25.1 (CH2), 19.0 (CH2), 8.0 (CH3). m/z (EI,
70 eV) 168 (M+•, 45%) 149 (32), 139 (50), 121 (75), 109 (100), 105
(48), 93 (55), 79 (65), 67 (75).
as a clear, colourless oil (Found: M+• 152.1204. C10 16O requires M+
H
152.1201). νmax (neat)/cm−1 2966, 2936, 1721, 1462, 1380, 1182, 1057,
1027, 730. δH (300 MHz) 9.75 (1H, t, J 3.0), 5.74 (1H, dt, J 10.2 and 3.6),
5.52 (1H, dt, J 10.2 and 2.1), 2.31 (2H, d, J 3.0), 1.98–1.90 (2H, complex
m), 1.63–1.36 (6H, complex m), 0.84 (3H, t, J 7.5). δC (75 MHz) 204.0
(CH), 133.1 (CH), 128.0 (CH), 52.6 (CH2), 37.1 (C), 33.2 (CH2), 32.4
(
)-1-Ethyl-2-cyclohexene-1-propanol Methanesulfonate 21
•
(CH2), 24.8 (CH2), 18.7 (CH2), 8.1 (CH3). m/z (EI, 70 eV) 152 (M+
,
A magnetically stirred solution of alcohol 20 (1.66 g, 9.88 mmol) and
triethylamine (1.36 g, 11.86 mmol) in diethyl ether (25 mL) was cooled
to 0◦C then treated, dropwise, with methanesulfonyl chloride (1.36 g,
11.86 mmol). After 2 h the reaction mixture was diluted with diethyl
ether (200 mL) and washed with water (1 × 100 mL). The aqueous
phase was then extracted with diethyl ether (2 × 250 mL) and the com-
bined organic phases washed with brine (1 × 50 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure to afford a
yellow oil. This material was subjected to column chromatography (sil-
ica, 1/4 v/v ethyl acetate/hexane elution) to afford, after concentration
of the appropriate fractions (Rf 0.5), the mesylate 21 (2.26 g, 93%) as a
15%) 124 (10), 123 (90), 109 (75), 108 (81), 95 (45), 79 (100), 67 (58).
(
(
)-3-Ethyl-3-(E-3-methoxy-2-propenyl)-1-cyclohexene and
)-3-Ethyl-3-(Z-3-methoxy-2-propenyl)-1-cyclohexene 19
A
magnetically
stirred
suspension
of
(methoxymethyl)
triphenylphosphonium chloride (20.1 g, 55.9 mmol) in THF (150 mL)
was cooled to 0◦C then treated, dropwise, with NaHMDS (55.9 mL of
a 1 mol solution in hexane, 55.9 mmol). The resulting orange-red reac-
tion mixture was stirred at 0◦C for 10 min then treated with a solution
of aldehyde 18 (6.54 g, 43 mmol) in THF (30 mL). The ensuing sus-
pension was allowed to warm to 18◦C over 16 h then filtered through a
sintered funnel.This step served to remove the bulk of the triphenylphos-
phine oxide. Concentration of the filtrate under reduced pressure gave
a residue that was triturated (hexane) repeatedly to remove additional
triphenylphosphine oxide. The ensuing residue was subjected to col-
umn chromatography (silica, hexane → 5/95 v/v ethyl acetate/hexane
gradient elution) to afford, following concentration of the appropriate
fractions (Rf 0.3 in hexane), a 1:1 mixture of the E- and Z-isomers of enol
ether 19 (6.19 g, 80%) as a clear, colourless oil (Found: M+• 180.1522.
C12H20O requires M+• 180.1514). νmax (neat)/cm−1 2927, 1663, 1649,
1458, 1447, 1385, 1262, 1208, 1107, 934, 728, 695. δH (300 MHz) 6.25
(0.5H, dt, J 12.6 and 1.2), 5.94 (0.5H, dt, J 6.6 and 1.5), 5.69–5.63 (1H,
complex m), 5.45–5.39 (1H, complex m), 4.68 (0.5H, dt, J 12.6 and
•
•
clear, colourless oil (Found: M+ 246.1286. C12H22O3S requires M+
246.1290). νmax (neat)/cm−1 2934, 1461, 1353, 1176, 973, 934, 825,
742. δH (300 MHz) 5.68 (1H, dt, J 10.2 and 3.6), 5.37 (1H, dt, J 10.2 and
1.8), 4.20 (2H, t, J 6.6), 3.00 (3H, s), 1.94 (2H, m), 1.75–1.50 (4H, com-
plex m), 1.45–1.20 (6H, complex m), 0.80 (3H, t, J 7.5). δC (75 MHz)
134.4, 126.5, 70.8, 36.7, 36.0, 34.4, 31.7, 31.4, 24.8, 23.5, 18.6, 7.7. m/z
(EI, 70 eV) 246 (M+•, 17%), 217 (25), 150 (27), 122 (41), 121 (100),
109 (97), 93 (53), 79 (65), 67 (90).
(
)-3-(3-Azidopropyl)-3-ethyl-1-cyclohexene 22
A magnetically stirred solution of mesylate 21 (2.52 g, 10.2 mmol)
in DMF (15 mL) was treated with sodium azide (2.00 g, 30.7 mmol)
† The S-enantiomer of compound 18 has been reported: see ref. [14].

Application of the Ullmann Cross-Coupling Reaction in a Total Synthesis of ( )-Aspidospermidine
731
and the resulting mixture heated to 67◦C for 5 h. The cooled reaction
mixture was then diluted with diethyl ether (300 mL) before being
washed sequentially with water (2 × 60 mL) and brine (1 × 60 mL). The
separated organic phase was then dried (MgSO4), filtered, and concen-
trated under reduced pressure to afforded the azide 22 (1.88 g, 95%)
as a clear, pale-yellow oil, Rf 0.7 (silica, 1/9 v/v ethyl acetate/hexane
elution) [Found: (M − N•)+ 179.1546. C11H19N3 requires (M − N•)+
179.1548]. νmax (neat)/cm−1 2862, 2096, 1455, 1379, 1350, 1259, 957,
931, 920, 863, 729. δH (300 MHz) 5.66 (1H, dt, J 10.2 and 3.6), 5.38 (1H,
dt, J 10.2 and 2.1), 3.22 (2H, t, J 6.6), 1.92 (2H, m), 1.63–1.22 (10H,
complex m), 0.81 (3H, t, J 7.5). δC (75 MHz) 134.9 (CH), 126.6 (CH),
52.2 (CH2), 36.5 (C), 36.1 (CH2), 32.0 (CH2), 31.8 (CH2), 25.1 (CH2),
23.4 (CH2), 19.0 (CH2), 8.0 (CH3). m/z (EI, 70 eV) 179 [(M − N•)+,
100%], 149 (31), 136 (20), 109 (51), 105 (46), 67 (52), 41 (63).
separated. The aqueous phase was extracted with CH2Cl2 (2 × 80 mL)
and the combined organic phases then washed with brine (1 × 100 mL)
before being dried (MgSO4), filtered, and concentrated under reduced
pressure to yield a brown solid. Subjection of this material to column
chromatography (silica, 1/4 → 3/7 v/v ethyl acetate/hexane gradient elu-
tion) yielded, after concentration of the appropriate fractions [Rf 0.3
(3/7 v/v ethyl acetate/hexane elution)], enone 25 (673 mg, 63%) as a
clear, colourless oil [Found: (M − H•)+ 280.1901. C16H27NO3 requires
(M − H•)+ 280.1913]. νmax (neat)/cm−1 3347, 2934, 1696, 1519, 1454,
1389, 1364, 1252, 1168, 1042, 800. δH (300 MHz) 6.66 (1H, d, J 7.5),
5.89 (1H, d, J 7.5), 4.63 (1H, broad s), 3.08 (2H, m), 2.41 (2H, t, J 7.2),
1.83 (2H, m), 1.51–1.43 (6H, complex m), 1.41 (9H, s), 0.86 (3H, t,
J 7.5). δC (75 MHz) 199.6, 158.3, 155.9, 128.2, 79.1, 40.9, 38.0, 34.2,
33.8, 30.5, 30.1, 28.3, 24.7, 8.3. m/z (EI, 70 eV) 280 [(M − H•)+, 5%],
225 (51), 208 (57), 196 (22), 181 (50), 180 (57), 164 (55), 124 (72), 96
(100), 95 (90), 57 (67).
(
)-1-Ethyl-2-cyclohexene-1-propanamine 23
A magnetically stirred solution of azide 22 (1.5 g, 7.7 mmol) in methanol
(50 mL) was treated with SnCl2·2H2O (3.50 g, 15.4 mmol) and the ensu-
ing mixture stirred at 18◦C for 5 h. The reaction mixture was then
diluted with water (50 mL), basified to pH 10 with NaHCO3 (satu-
rated aqueous solution) and extracted with ethyl acetate (3 × 200 mL).
The combined organic fractions were washed with brine (1 × 100 mL)
then dried (MgSO4), filtered, and concentrated under reduced pressure
to p•rovide the amine 23 (1.03 g, 79%) a•s a clear, colourless oil (Found:
M+ 167.1674. C11H21N requires M+ 167.1674). νmax (neat)/cm−1
3398, 2927, 1635, 1566, 1458, 1378, 1317, 1183, 1118. δH (300 MHz)
5.60 (1H, dt, J 10.2 and 3.6), 5.36 (1H, dt, J 10.2 and 1.8), 2.63 (2H,
t, J 7.2), 2.40 (2H, broad s), 1.92–1.83 (2H, complex m), 1.58–1.48
(2H, complex m), 1.40–1.16 (8H, complex m), 0.76 (3H, t, J 7.5). δC
(75 MHz) 135.3 (CH), 126.2 (CH), 42.7 (CH2), 36.4 (C), 36.2 (CH2),
31.8(9) (CH2), 31.8(8) (CH2), 27.4 (CH2), 25.1 (CH2), 19.0 (CH2), 8.0
(CH3). m/z (EI, 70 eV) 167 (M+•, 2%), 150 (20), 138 (11), 121 (41), 109
(80), 79 (57), 67 (100), 56 (71). This material was used immediately,
and without purification, in the next step of the reaction sequence.
(
)-1-Ethyl-3-iodo-4-oxo-2-cyclohexene-1-propanamine Carbamic
Acid 1,1-Dimethylethyl Ester 26
A magnetically stirred solution of enone 25 (1.20 g, 5.35 mmol) in
CCl4/pyridine (20 mL of a 1/1 v/v mixture) maintained at 18◦C
was treated, dropwise, with a solution of molecular iodine (5.44 g,
21.4 mmol) in CCl4/pyridine (20 mL of a 1/1 v/v mixture). The reac-
tion mixture was allowed to stir for 16 h at 18◦C then diluted with
diethyl ether (400 mL), washed sequentially with water (1 × 150 mL),
HCl (2 × 150 mL of a 1 mol aqueous solution), Na2S2O3 (1 × 150 mL
then 1 × 50 mL of a 20% w/v aqueous solution), and brine (1 × 150 mL)
before being dried (MgSO4), filtered, and concentrated under reduced
pressure to afford the iodide 26 (2.00 g, 100%), as •a clear, yellow oil
•
(Found: M+ 407.0951. C16H26INO3 requires M+ 407.0957). νmax
(neat)/cm−1 3369, 2927, 1707, 1685, 1515, 1454, 1364, 1262, 1165,
739, 702. δH (300 MHz) 7.48 (1H, s), 4.61 (1H, broad s), 3.10 (2H,
broad s), 2.65 (2H, m), 1.90 (2H, t, J 6.6), 1.55–1.44 (6H, complex m),
1.42 (9H, s), 0.90 (3H, t, J 7.5). δC (75 MHz) 192.0 (C), 166.8 (CH),
155.9 (C), 102.8 (C), 79.3 (C), 43.4 (CH2), 40.8 (CH2), 33.9 (CH2),
32.8 (CH2), 30.5 (CH2), 29.9 (C), 28.3 (CH3), 24.8 (CH2), 8.4 (CH3).
m/z (EI, 70 eV) 407 (M+•, 1%), 351 (2), 334 (2), 307 (7), 281 (8), 225
(12), 208 (13), 181 (14), 180 (22), 57 (100).
(
)-1-Ethyl-2-cyclohexene-1-propanamine Carbamic Acid
1,1-Dimethylethyl Ester 24
A magnetically stirred solution of amine 23 (1.03 g, 6.2 mmol) in
CH2Cl2 (20 mL) maintained at 18◦C was treated with Boc2O (1.61 g,
7.4 mmol) then triethylamine (2.24 g, 22.2 mmol). After 16 h the reac-
tion mixture was diluted with CH2Cl2 (100 mL) then washed with
water (1 × 40 mL). The separated aqueous phase was extracted with
CH2Cl2 (1 × 75 mL) and the combined organic fractions washed
with brine (1 × 100 mL) then dried (MgSO4), filtered, and concentrated
under reduced pressure to provide the carbamate 24 (1.26 g, 100%)
as a clear, colourless oil, Rf 0.7 (silica, 1/4 v/v ethyl acetate/hexane
(
)-1-Ethyl-3-(2-nitrophenyl)-4-oxo-2-cyclohexene-1-
propanamine Carbamic Acid 1,1-Dimethylethyl Ester 27
Iodide 26 (216 mg, 0.54 mmol) was cross-coupled with
o-iodonitrobenzene (270 mg, 1.08 mmol) in the same manner as
employed in the conversion 7 → 14. Subjection of the light-yellow oil
obtained on work-up to column chromatography (silica, 3/7 v/v ethyl
acetate/hexane elution) afforded, after concentration of the appropriate
fractions (Rf 0.2), the title compound 27 (178 mg, 82%) as a yellow
oil (Found: M+• 402.2152. C22H30N2O5 requires M+• 402.2155). νmax
(neat)/cm−1 3355, 2963, 2927, 1707, 1682, 1523, 1454, 1356, 1270,
1248, 1165. δH (300 MHz) 8.01 (1H, dd, J 8.4 and 1.2), 7.59 (1H, dt, J
8.4 and 1.2), 7.46 (1H, dt, J 8.4 and 1.5), 7.22 (1H, dd, J 8.4 and 1.5),
6.66 (1H, s), 4.64 (1H, broad s), 3.13 (2H, broad d, J 4.8), 2.58 (2H, t, J
6.9), 1.97 (2H, t, J 7.5), 1.68–1.52 (6H, complex m), 1.43 (9H, s), 0.96
(3H, t, J 7.2). δC (75 MHz) 196.5 (C), 155.9 (C), 154.2 (CH), 148.5 (C),
138.0 (C), 133.3 (CH), 132.2 (C), 131.7 (CH), 128.8 (CH), 124.2 (CH),
•
•
elution) [Found: M+ 267.2188. C16H29NO2 requires M+ 267.2198.
•
•
Found: M − (C4H8)+ 211.1572. C16H29NO2 requires M − (C4H8)+
211.1572]. νmax (neat)/cm−1 3311, 2927, 1660, 1458, 1360, 1215, 1150,
1067. δH (300 MHz) 5.62 (1H, dt, J 10.2 and 3.9), 5.36 (1H, dt, J 10.2
and 2.1), 4.55 (1H, broad s), 3.05 (2H, m), 1.89 (2H, m), 1.59–1.51
(2H, complex m), 1.42 (9H, s), 1.38–1.17 (8H, complex m), 0.77 (3H,
t, J 6.9). δC (75 MHz) 155.9 (C), 135.3 (CH), 126.3 (CH), 78.9 (C),
41.4 (CH2), 36.4 (C), 36.2 (CH2), 32.0 (CH2), 31.9 (CH2), 28.4 (CH3),
25.1•(CH2), 24.5 (CH2), 19.0 (CH2), 8.1 (CH3). m/z (EI, 70 eV) 267
(M+ , 0.1%), 211 [M − (C4H8)+•, 21], 182 (37), 150 (27), 121 (72),
109 (92), 67 (70), 57 (100). This material was used immediately, and
without purification, in the next step of the reaction sequence.
79.2 (C), 41.0 (CH2), 38.7 (CH2), 34.5 (CH2), 34.2 (CH2), 30.4 (CH2),
•
30.2 (CH2), 28.3 (CH3), 24.9 (C), 8.5 (CH3). m/z (EI, 70 eV) 402 (M+
,
2%), 329 (4), 139 (27), 111 (100), 96 (41), 69 (54).
(
)-1-Ethyl-4-oxo-2-cyclohexene-1-propanamine Carbamic
(
)-4-(3-Aminopropyl)-4-ethyl-2-(2-nitrophenyl)-2-
Acid 1,1-Dimethylethyl Ester 25
cyclohexen-1-one 6
A magnetically stirred suspension of CrO3 (5.66 g, 56.6 mmol) in
CH2Cl2 (50 mL) was cooled to −20◦C then treated with 3,5-
dimethylpyrazole (5.43 g, 56.6 mmol). After 0.25 h the by now dark-red
solution was treated, dropwise, with alkene 24 (1.0 g, 3.7 mmol). The
resulting mixture was then stirred for 4 h at −10 to −20◦C then warmed
to 0◦C and treated with NaOH (20 mL of a 5 M aqueous solution). The
resultingbiphasicmixturewasstirredfor1.5 hat0◦Candthephasesthen
A magnetically stirred solution of carbamate 27 (30 mg, 0.07 mmol)
in CH2Cl2 (3 mL) maintained at 18◦C was treated with trifluoroacetic
acid (500 µL). After 2 h the reaction mixture was concentrated under
reduced pressure to afford the title compound 6 (23 mg, 100%) as a
•
clear, dark-yellow oil (Found: M+ 302.1636. C17H22N2O3 requires
M+• 302.1630). νmax (neat)/cm−1 3436, 1678, 1525, 1353, 1204, 1140.
δH (300 MHz) 7.98 (1H, d, J 7.5), 7.64–7.40 (2H, complex m), 7.20

732
M. G. Banwell, D. W. Lupton, and A. C. Willis
(1H, d, J 6.6), 6.68 (1H, s), 3.01 (2H, broad s), 2.56 (2H, m), 1.96 (2H,
m), 1.82–1.53 (8H, complex m), 0.95 (3H, t, J 7.2). δC (75 MHz) 197.8,
154.6, 148.2, 138.4, 133.8, 131.8, 131.7, 129.1, 124.3, 40.7, 38.8, 34.1,
34.0, 30.9, 29.5, 22.4, 8.3. m/z (EI, 70 eV) 302 (M+•, <1%), 212 (10),
167 (17), 149 (18), 139 (17), 111 (100), 96 (40), 69 (37).
νmax (neat)/cm−1 2938, 2863, 1679, 1452, 1417, 1390, 1251, 1211, 868,
650. δH (300 MHz) 6.78 (1H, ddd, J 10.2, 2.7 and 1.2), 5.92 (1H, dd, J
10.2 and 2.4), 3.51 (2H, t, J 6.6), 2.49–2.23 (3H, complex m), 2.13–2.00
(1H, complex m), 1.87–1.76 (1H, complex m), 1.70–1.45 (4H, complex
m). δC (75 MHz) 199.4 (C), 154.1 (CH), 129.1 (CH), 44.6 (CH2), 36.7
(CH2), 35.3 (CH), 31.6 (CH2), 29.7 (CH2), 28.3 (CH2). m/z (EI, 70 eV)
) )
174 [M(Cl37 +•, 24%], 172 [M(Cl35 +•, 70], 146 (22), 144 (61), 94
(35), 82 (55), 81 (100), 68 (70), 67 (60), 53 (45), 41 (60).
(
)-6-(3-Chloropropyl)-3-ethoxy-2-cyclohexen-1-one 28
A magnetically stirred solution of LiHMDS (22 mL of a 1 M solution
in THF, 22 mmol) in THF (80 mL) was cooled to −30◦C then treated,
dropwise, with 3-ethoxycyclohex-2-enone 8 (2.80 g, 20 mmol). After
0.5 h at this temperature HMPA (3.94 g, 22 mmol) was added followed
by 1-chloro-3-iodopropane (4.08 g, 20 mmol). The cooling bath was
removed and the resulting mixture allowed to warm to 18◦C over 16 h
then diluted with diethyl ether (400 mL) and NH4Cl (20 mL of a satu-
rated solution). The separated organic phase was washed, sequentially,
with water (1 × 200 mL), NaHCO3 (1 × 100 mL of a saturated aque-
ous solution), and brine (1 × 100 mL) before being dried (MgSO4),
filtered, and concentrated under reduced pressure to provide a yellow
oil. Subjection of this material to column chromatography (silica, 3/7
v/v ethyl acetate/hexane elution) gave, upon concentration of the appro-
priate fractions (Rf 0.3), compound 28 (2.91 g, 72%) a•s a pale-yellow oil
(
)-4-[3-{[(1,1-Dimethylethyl)dimethylsilyl]oxy}propyl]-2-
cyclohexen-1-one 31
A sample of compound 29 (912 mg, 2.9 mmol) was reduced with LiAlH4
in the same manner as employed for the conversion 28 → 30. Subjection
of the light-yellow oil obtained on work-up to column chromatography
(silica, 1/9 v/v ethyl acetate/hexane elution) afforded, upon concentra-
tion of the appropriate fractions (Rf 0.3), the enone 31 (535 mg, 66%)
as a clear, pale-yellow oil (Found: M+• 268.1864. C15H28O2Si requires
M+• 268.1859). νmax (neat)/cm−1 2953, 2930, 1685, 1472, 1418, 1254,
1106, 836, 776. δH (300 MHz) 6.80 (1H, ddd, J 10.2, 2.7 and 1.5), 5.91
(1H, dd, J 10.2 and 2.4), 3.60 (2H, t, J 5.4), 2.50–2.20 (2H, complex
m), 2.07 (1H, m), 1.70–1.38 (6H, complex m), 0.83 (9H, s), −0.01 (6H,
s). δC (75 MHz) 199.7 (C), 155.0 (CH), 128.8 (CH), 62.7 (CH2), 36.8
(CH2), 35.8 (CH), 30.8 (CH2), 29.9 (CH2), 28.5 (CH2), 25.8 (CH3),
18.2 (C), −5.5 (CH3). m/z (EI, 70 eV) 268 (M+•, <1%), 253 (5), 211
(100), 151 (64), 75 (95).
•
(Found: M+ 216.0919. C11H1735ClO2 requires M+ 216.0917). νmax
(neat)/cm−1 2941, 1651, 1605, 1476, 1453, 1379, 1359, 1192, 1044,
909, 844, 817, 649. δH (300 MHz) 5.17 (1H, s), 3.77 (2H, q, J 6.9), 3.43
(2H, dt, J 6.6 and 2.7), 2.32 (2H, m), 2.12–1.35 (7H, complex m), 1.23
(3H, t, J 6.9). δC (75 MHz) 200.5 (C), 176.5 (C), 101.8 (CH), 63.9 (CH2),
44.8 (CH2), 44.1 (CH2), 29.9 (CH2), 27.8 (CH2), 26.8 (CH), 26.2 (CH2),
(
)-4-(3-Chloropropyl)-2-iodo-2-cyclohexen-1-one 32
•
13.8 (CH3). m/z (EI, 70 eV) 218 [M(37Cl)+ , 5%], 216 [M(35Cl)+•, 10],
α-Iodination of enone 30 (600 mg, 2.23 mmol) in the same manner
as employed for the conversion 25 → 26 afforded iodide 32 (429 mg,
68%) as a yellow oil, Rf 0.6 (silica, 3/7 v/v ethyl acetate/•hexane elu-
tion) (Found: M+•, 299.9593. C9H1237ClIO requires M+ 299.9592.
181 (100), 153 (35), 140 (77), 112 (50), 84 (67), 69 (55), 68 (53).
(
)-6-{3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]propyl}-3-
ethoxy-2-cyclohexen-1-one 29
•
•
Found: M+ 297.9615. C9H1235ClIO requires M+ 297.9621). νmax
(neat)/cm−1 2942, 2860, 1686, 1583, 1450, 1415, 1323, 1155, 894, 802,
717, 646. δH (300 MHz) 7.60 (1H, dd, J 3.0 and 0.9), 3.54 (2H, t, J 6.6),
2.73 (1H, td, J 16.5 and 4.8), 2.60–2.42 (2H, complex m), 2.14 (1H, m),
1.90–1.50 (5H, complex m). δC (75 MHz) 191.9 (C), 162.7 (CH), 103.8
(C), 44.4 (CH2), 39.9 (CH), 35.6 (CH2), 31.3 (CH2), 29.5 (CH2), 28.4
A magnetically stirred solution of LiHMDS (22 mL of a 1 M solu-
tion in THF, 22 mmol) in THF (80 mL) was cooled to −30◦C then
treated, dropwise, with 3-ethoxycyclohex-2-enone 8 (2.80 g, 20 mmol).
After 0.5 h at this temperature HMPA (3.94 g, 22 mmol) then (tert-
butyl)(3-iodopropoxy)dimethylsilane[22] (6.0 g, 20 mmol) were added
to the reaction mixture. The cooling bath was removed and the resulting
mixture allowed to warm to 18◦C over the following 16 h then diluted
with diethyl ether (400 mL) and NH4Cl (20 mL of a saturated solu-
tion). The separated organic phase was washed sequentially with water
(1 × 200 mL), NaHCO3 (1 × 100 mL of a saturated aqueous solution),
and brine (1 × 100 mL) then dried (MgSO4), filtered, and concentrated
under reduced pressure to provide a yellow oil. Subjection of this mate-
rial to column chromatography (silica, 1/4 v/v ethyl acetate/hexane
elution) gave, upon concentration of the appropriate fractions (Rf 0.4),
compound 29 (3.20 g, 83%) as a pale-yellow oil (Found: M+• 312.2120.
•
(CH2). m/z (EI, 70 eV) 300 [M(37Cl)+ , 33%] 298 [M(35Cl)+•, 100],
206 (30), 171 (35), 107 (37), 79 (52), 66 (95).
(
)-4-{3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-
propyl}-2-iodo-2-cyclohexen-1-one 33
α-Iodination of enone 31 (600 mg, 2.23 mmol) in the same manner as
employed for the conversion 25 → 26 afforded iodide 33 (697 mg, 82%)
as a yellow oil, Rf 0.3 (silica, 1/9 v/v ethyl acetate/hexane eluti•on)
•
[Found: (M − But )+ 337.0120. C15H27IO2Si requires (M − But )+
337.0121]. νmax (neat)/cm−1 2953, 2857, 1691, 1584, 1471, 1462, 1415,
1388, 1360, 1255, 1099, 837, 776. δH (300 MHz) 7.63 (1H, d, J 3.0),
3.61 (2H, t, J 5.4), 2.73 (1H, m), 2.60–2.42 (2H, complex m), 2.14 (1H,
m), 1.80–1.65 (1H, complex m), 1.60–1.40 (4H, complex m), 0.86 (9H,
s), 0.02 (6 H, s). δC (75 MHz) 192.2 (C), 163.7 (CH), 103.4 (C), 62.5
(CH2), 40.4 (CH2), 35.8 (CH), 30.6 (CH2), 29.8 (CH2), 28.6 (CH2),
•
C17H32O3Si requires M+ 312.2l21). δH (300 MHz) 5.24 (1H, s), 3.83
(2H, q, J 7.2), 3.57 (2H, m), 2.37 (2H, t, J 5.7), 2.20–1.32 (7H, complex
m), 1.30 (3H, t, J 6.9), 0.83 (9H, s), −0.02 (6H, s). δC (75 MHz) 201.4,
176.5, 102.0, 64.0, 63.1, 44.8, 30.2, 27.8, 26.1, 25.8 (CH3), 25.7, 18.1,
14.0, −5.4 (CH3). m/z (EI, 70 eV) 312 (M+•, 2%), 256 (22), 255 (100),
227 (10), 180 (12), 140 (6), 84 (7), 75 (18).
•
25.8 (CH3), 18.2 (C), −5.4 (CH3). m/z (EI, 70 eV) 337 [(M − But )+,
100%], 277 (47), 210 (45), 181 (75), 168 (65), 75 (95).
(
)-4-(3-Chloropropyl)-2-cyclohexen-1-one 30
A magnetically stirred solution of LiAlH4 (3 mL of a 1 mol solution in
THF, 3 mmol) inTHF (18 mL) was cooled to 0◦C then treated, dropwise,
with a solution of compound 28 (606 mg, 2.8 mmol) in THF (1.5 mL).
The cooling bath was removed and the reaction mixture stirred at 18◦C
for 0.5 h then treated, sequentially, with water (1.5 mL) [CAUTION:
exothermic] and NaOH (3 mL of a 8% w/v aqueous solution). The
ensuing heterogeneous mixture was filtered through a pad of Celite
and the filtrate concentrated under reduced pressure to afford a light-
yellow oil. Subjection of this material to column chromatography (silica,
3/7 v/v ethyl acetate/hexane elution) afforded, upon concentration of
the appropriate fractions (Rf 0.5), the enone 30 (308 mg, 65%) as a
(
)-4-(3-Chloropropyl)-2-(2-nitrophenyl)-2-cyclohexen-1-one 34
Iodide 32 (170 mg, 0.57 mmol) was cross-coupled with
o-iodonitrobenzene (281 mg, 1.1 mmol) in the same manner as
employed for the conversion 7 → 14. Subjection of the light-yellow oil
obtained on work-up to column chromatography (silica, 1/4 v/v ethyl
acetate/hexane elution) afforded, after concentration of the appropriate
fractions (Rf 0.2), the title compound 34 (130 mg, 77%) as a•light-yellow
•
oil (Found: M+ 293.0819. C15H1635ClNO3 requires M+ 293.0819).
νmax (neat)/cm−1 2943, 2861, 1682, 1573, 1525, 1451, 1353, 1161, 787.
δH (300 MHz) 7.99 (1H, dd, J 8.1 and 1.2), 7.59 (1H, td, J 7.5 and 1.2),
7.46 (1H, td, J 8.1 and 1.5), 7.24 (1H, dd, J 7.5 and 1.5), 6.83 (1H, dd,
J 3.0 and 1.5), 3.58 (2H, t, J 6.6), 2.70–2.44 (3H, complex m), 2.19
•
clear, pale-yellow oil (Found: M+• 174.0627. C9H1337ClO requires M+
174.0625. Found: M+• 172.0655. C9H1335ClO requires M+• 172.0655).

Application of the Ullmann Cross-Coupling Reaction in a Total Synthesis of ( )-Aspidospermidine
733
(1H, m), 1.96–1.60 (5H, complex m). δC (75 MHz) 196.3 (C), 150.1
(CH), 148.4 (C), 138.8 (C), 133.3 (CH), 131.8 (C), 131.6 (CH), 128.8
(CH), 124.1 (CH), 44.7 (CH2), 37.0 (CH2), 35.9 (CH), 31.7 (CH2), 29.7
(CH2), 28.1 (CH2). m/z (EI, 70 eV) 293 [M(35Cl)+•, 5%], 278 (8), 276
(20), 249 (33), 247 (100), 172 (63), 159 (79), 115 (80), 104 (62), 77
(62), 55 (58), 41 (74).
3.00 (3H, s), 2.70–2.40 (3H, complex m), 2.19 (1H, m), 1.95–1.60 (5H,
complex m). m/z (EI, 70 eV) 353 (M+•, 20%), 336 (10), 307 (21), 240
(60), 212 (90), 211 (60), 184 (89), 134 (72), 115 (91), 104 (100), 79 (83).
(
)-4-(3-Azidopropyl)-2-(2-nitrophenyl)-2-cyclohexen-1-one 38
A magnetically stirred solution of mesylate 37 (354 mg, 1.0 mmol) in
DMF (9 mL) was treated with sodium azide (195 mg, 3.0 mmol) and the
resultingmixtureheatedat67◦Cfor3 hthencooledto18◦C, dilutedwith
diethyl ether (100 mL) and washed with water (2 × 40 mL) then brine
(1 × 20 mL). The organic phase was then dried (MgSO4), filtered, and
concentrated under reduced pressure to provide the azide 38 (255 mg,
85%) as a dark-yellow oil, Rf 0.3 (silica, 3/7 v/v ethyl acetate/hexane
elution) (Found: M+• 300.1218. C15H16N4O3 requires M+• 300.1222).
νmax (neat)/cm−1 2942, 2863, 2096, 1682, 1607, 1573, 1525, 1478,
1453, 1418, 1354, 1257, 1162, 908, 860, 835, 788, 753, 726, 702, 566.
δH (300 MHz) 8.02 (1H, dd, J 8.1 and 1.2), 7.60 (1H, td, J 7.5 and 1.5),
7.47 (1H, td, J 8.1 and 1.5), 7.24 (1H, dd, J 7.5 and 1.5), 6.83 (1H, m),
3.36 (2H, t, J 6.3), 2.70–2.44 (3H, complex m), 2.21 (1H, m), 1.92–1.56
(5H, complex m). δC (75 MHz) 196.4 (C), 149.9 (C), 148.5 (CH), 139.0
(C), 133.3 (CH), 131.8 (C), 131.6 (CH), 128.9 (CH), 124.2 (CH), 51.2
(CH2), 37.0 (CH2), 36.2 (CH), 31.7 (CH2), 28.2 (CH2), 26.2 (CH2). m/z
(EI, 70 eV) 300 (M+•, 4%), 255 (15), 227 (25), 226 (31), 199 (34), 171
(25), 138 (100), 104 (65), 55 (62), 41 (94).
(
)-4-[3-{[(1,1-Dimethylethyl)dimethylsilyl]oxy}propyl]-
2-(2-nitrophenyl)-2-cyclohexen-1-one 35
Iodide 33 (170 mg, 0.43 mmol) was cross-coupled with
o-iodonitrobenzene (212 mg, 0.86 mmol) in the same manner as
employed for the conversion 7 → 14. Subjection of the light-yellow oil
obtained on work-up to column chromatography (silica, 1/4 v/v ethyl
acetate/hexane elution) afforded, after concentration of the appropriate
fractions (Rf 0.4), the coupled product 35 (114 mg, 69%) as a yel-
•
•
low oil [Found: M+ 389.2006. C21H31NO4Si requires M+ 389.20•22.
•
Found: (M − But )+ 332.1319. C21H31NO4Si requires (M − But )+
332.1318]. νmax (neat)/cm−1 2952, 2929, 2885, 2857, 1685, 1528, 1472,
1255, 1098, 941, 836, 777, 706. δH (300 MHz) 8.01 (1H, dd, J 8.1 and
1.2), 7.59 (1H, td, J 7.5 and 1.2), 7.46 (1H, td, J 8.1 and 1.5), 7.25 (1H,
dd, J 7.5 and 1.5), 6.87 (1H, m), 3.67 (2H, t, J 5.7), 2.70–2.44 (3H,
complex m), 2.20 (1H, m), 1.86 (1H, m), 1.74–1.56 (4H, complex m),
0.89 (9H, s), 0.06 (6H, s). δC (75 MHz) 196.7 (C), 151.0 (CH), 148.6
(C), 138.6 (C), 133.3 (CH), 132.1 (C), 131.7 (CH), 128.8 (CH), 124.2
(CH), 62.8 (CH2), 37.2 (CH2), 36.5 (CH), 31.0 (CH2), 30.0 (CH2), 28.3
(6aSR,9aSR,9bSR)-9a-(2-Nitrophenyl)-4,5,6,6a,7,8,9a,9b-
octahydro-9H-1,2,3-triazolo[4,5,1-ij]quinolin-9-one 39
•
(CH2), 25.9 (CH3), 18.3 (C), −5.3 (CH3). m/z (EI, 70 eV) 389 (M+
,
•
<<1%), 332 [(M − But )+, 70], 300 (45), 75 (100).
Method A: A magnetically stirred solution of azide 38 (100 mg,
0.333 mmol) in benzene (3 mL) was heated at reflux for 16 h then cooled
to 18◦C and concentrated under reduced pressure to provide a dark-
yellow residue. Subjection of this residue to column chromatography
(silica, 3/7 v/v ethyl acetate/hexane elution) afforded, after concentra-
tion of the appropriate fractions (Rf 0.4), the triazoline 39 (72 mg, 72%)
as a yellow, crystalline but unstable solid. vmax (neat)/cm−1 2938, 1713,
1575, 1525, 1446, 1424, 1351, 1221, 939, 911, 855, 789, 747, 734, 708.
δH (300 MHz) 8.16 (1H, dd, J 8.1 and 1.5), 7.62 (1H, dt, J 7.8 and 1.5),
7.49 (1H, dt, J 8.1 and 1.5), 7.26 (1H, dd, J 7.5 and 1.5), 4.52 (1H, dd,
J 14.6 and 2.7), 3.93 (1H, dd, J 4.8 and 1.5), 3.36 (1H, m), 2.73 (1H,
ddd, J 16.2, 5.4 and 1.8), 2.62–2.36 (2H, complex m), 2.00 (1H, dq, J
13.5 and 8.4), 1.89–1.80 (3H, complex m), 1.68–1.58 (2H, complex m).
δC (75 MHz) 199.3, 134.9, 134.2, 129.1, 129.0, 123.8, 90.6, 67.0, 47.2,
42.8, 38.2, 33.0, 27.9, 22.6, 21.5. m/z (EI, 70 eV) 272 [(M − N2)+•, 3],
255 (5), 244 (11), 227 (27), 226 (25), 199 (35), 170 (24), 138 (100), 121
(45), 110 (42), 104 (57). Crystals of compound 39 suitable for X-ray
analysis were obtained by slow evaporation from chloroform.
Method B: A magnetically stirred solution of chloride 34 (130 mg,
0.44 mmol) in DMF (3 mL) was treated with sodium azide (85 mg,
1.33 mmol) and the resulting mixture heated at 67◦C for 3 h and then
at 80◦C for a further 2 h. The cooled reaction mixture was diluted with
diethyl ether (100 mL), then washed with water (2 × 40 mL) and brine
(1 × 20 mL). The separated organic phase was dried (MgSO4), filtered,
and concentrated under reduced pressure to give a mixture of azide 38
and triazoline 39. This mixture was dissolved in benzene (5 mL) and the
resulting solution heated at reflux for 16 h then cooled to 18◦C and con-
centrated under reduced pressure. Subjection of this material to column
chromatography (silica, 3/7 v/v ethyl acetate/hexane elution) afforded,
upon concentration of the appropriate fractions (Rf 0.4), triazoline 39
(82 mg, 63%).This material was identical, in all respects, to the material
prepared via Method A.
(
)-4-(3-Hydroxypropyl)-2-(2-nitrophenyl)-2-cyclohexen-1-one 36
A magnetically stirred solution of silyl ether 35 (800 mg, 2.06 mmol) in
ethanol (50 mL) was cooled to 0◦C then treated, dropwise, with HCl (10
drops of a 36% v/v aqueous solution).The cooling bath was removed and
the reaction mixture allowed to warm to 18◦C over 3 h then poured onto
a mixture of brine (100 mL) and NaHCO3 (2 mL of a saturated aqueous
solution) before being extracted with diethyl ether (3 × 200 mL). The
combinedorganicphaseswerewashedwithbrine(1 × 50 mL)thendried
(MgSO4), filtered, and concentrated under reduced pressure to give the
alcohol 36 (565 mg, 100%) as a viscous yellow oil, Rf 0.2 (silica, 3/1
•
v/v ethyl acetate/hexane elution) (Found: M+ 275.1153. C15H17NO4
•
requires M+ 275.1158). νmax (neat)/cm−1 3436, 1662, 1524, 1353,
1162, 1053. δH (300 MHz) 7.99 (1H, dm, J 8.1), 7.58 (1H, tm, J 7.5),
7.45 (1H, tm, J 8.1), 7.23 (1H, dm, J 7.5), 6.86 (1H, d, J 3.0), 3.67
(2H, t, J 5.1), 2.70–2.42 (4H, complex m), 2.19 (1H, m), 1.90–1.56
(4H, complex m) (H of OH group not detected). δC (75 MHz) 196.8
(C), 150.9 (CH), 148.5 (C), 138.6 (C), 133.3 (CH), 131.9 (C), 131.7
(CH), 128.8 (CH), 124.1 (CH), 62.4 (CH2), 37.1 (CH2), 36.4 (CH),
30.8 (CH2), 29.8 (CH2), 28.2 (CH2). m/z (EI, 70 eV) 275 (M+•, 20%),
240 (22), 212 (30), 184 (43), 170 (47), 160 (92), 115 (82), 104 (71),
97 (72), 77 (75), 55 (100).
(
)-4-(3-Hydroxypropyl)-2-(2-nitrophenyl)-2-cyclohexen-1-one
Methanesulfonate 37
A magnetically stirred solution of alcohol 36 (480 mg, 1.75 mmol) and
triethylamine (228 mg, 2.09 mmol) in diethyl ether/CH2Cl2 (20 mL of a
3/1v/vmixture)wascooledto0◦Cthentreated, dropwise, withmethane-
sulfonyl chloride (238.5 mg, 2.09 mmol). Following the addition a
precipitate formed and after 2 h the reaction mixture was diluted with
diethyl ether (300 mL) then washed with water (2 × 75 mL). The com-
bined aqueous phases were extracted with diethyl ether (1 × 100 mL)
and the organic phases were then combined and washed with brine
(1 × 50 mL) before being dried (MgSO4), filtered, and concentrated
under reduced pressure to afford the mesylate 37 (443 mg, 72%) as
a clear, yellow oil, Rf 0.2 (silica, 1/1 v/v ethyl aceta•te/hexane elution)
(
)-1-Ethyl-2-cyclohexene-1-propanol Acetate 40
A sample of alcohol 20 (8.00 g, 47.6 mmol) was acetylated in the same
manner as employed for the conversion 11 → 12. Subjection of the light-
yellow oil obtained on work-up to column chromatography (silica, 1/19
v/v ethyl acetate/hexane elution) afforded, after concentration of the
appropriate fractions [Rf 0.6 (1/4 v/v ethyl acetate/hexane)], the acetate
40 (10 g, 100%) as a clear, colourless oil. νmax (neat)/cm−1 3014, 2934,
1743, 1459, 1383, 1365, 1242, 1036, 947, 730. δH (300 MHz) 5.60 (1H,
dt, J 10.2 and 3.9), 5.33 (1H, dt, J 10.2 and 1.2), 3.96 (2H, t, J 6.9),
•
(Found: M+ 353.0927. C16H19NO6S requires M+ 353.0933). νmax
(neat)/cm−1 3028, 2941, 2863, 1681, 1607, 1573, 1525, 1477, 1454,
1415, 1352, 1174, 959, 924, 835, 789, 727, 529. δH (300 MHz) 7.94
(1H, dd, J 8.1 and 1.5), 7.59 (1H, td, J 7.5 and 1.2), 7.45 (1H, td, J 8.1
and 1.5), 7.23 (1H, dd, J 7.5 and 1.2), 6.81 (1H, m), 4.26 (2H, t, J 6.0),

734
M. G. Banwell, D. W. Lupton, and A. C. Willis
1.99 (3H, s), 1.86 (2H, m), 1.58–1.45 (4H, complex m), 1.40–1.18 (6H,
complex m), 0.75 (3H, t, J 7.5). δC (75 MHz) 170.9, 134.9, 126.4, 65.2,
36.3, 35.0, 31.8 (5), 31.7 (6), 25.0, 23.1, 20.8, 18.9, 7.9.
νmax (neat)/cm−1 3411, 2929, 1680, 1607, 1573, 1525, 1458, 1353,
1163, 1144, 1060, 911, 859, 832, 788, 729. δH (300 MHz) 7.97 (1H, d,
J 7.5), 7.57 (1H, t, J 7.5), 7.44 (1H, t, J 7.5), 7.20 (1H, d, J 7.5), 6.69
(1H, s), 3.61 (2H, t, J 3.6), 2.56 (2H, t, J 6.9), 2.24 (1H, broad s), 1.96
(2H, t, J 6.9), 1.66–1.54 (6H, m), 0.94 (3H, t, J 7.5). δC (75 MHz) 196.8,
154.7, 148.4, 137.7, 133.3, 132.1, 131.6, 128.7, 124.1, 62.8,•38.6, 34.1,
33.4, 30.3, 30.0, 27.1, 8.4. m/z (EI, 70 eV) 257 [(M − NO2)+, 37%],
256 (48), 244 (30), 228 (70), 183 (48), 134 (80), 104 (72), 77 (48), 56
(100). This material was used immediately and without purification in
the next step in the reaction sequence.
4-[3-(Acetyloxy)propyl]-4-ethyl-2-cyclohexen-1-one 41
A magnetically stirred solution of compound 40 (4.20 g, 20 mmol) in
acetonitrile (160 mL) was treated with Cr(CO)6 (2.20 g, 10 mmol) and
t-butyl hydroperoxide (8.4 mL of a 70% aqueous solution, 60 mmol)
and the resulting mixture heated at reflux for 16 h. The cooled reaction
mixture was filtered through a pad of Celite that was then washed with
diethyl ether (700 mL). The combined filtrates were washed with water
(2 × 200 mL) and brine (1 × 300 mL) before being dried (MgSO4), fil-
tered, and concentrated under reduced pressure to provide a pale-green
oil. Subjection of this material to column chromatography (silica, 1/4 v/v
ethyl acetate/hexane elution) afforded, after evaporation of the appropri-
ate fractions (Rf 0.2), the enone 41 (2.77 g, 62%) as •a clear, colourless
4-Ethyl-4-(3-hydroxypropyl)-2-(2-nitrophenyl)-2-cyclohexen-1-one
Methanesulfonate 45
A magnetically stirred solution of alcohol 44 (1.00 g, 3.30 mmol) and
triethylamine (400 mg, 3.96 mmol) in diethyl ether (50 mL) was cooled
to 0◦C then treated, dropwise, with methanesulfonyl chloride (451 mg,
3.96 mmol). After 0.25 h the cooling bath was removed and the reac-
tion mixture allowed to warm to 18◦C over 2 h then diluted with diethyl
ether (400 mL) and washed with water (2 × 150 mL). The combined
aqueous phases were extracted with diethyl ether (1 × 100 mL) and
the combined organic phases dried (MgSO4), filtered, and concentrated
under reduced pressure to give a yellow oil. Subjection of this material
to column chromatography (silica, 1/1 v/v ethyl acetate/hexane elution)
afforded, following concentration of the appropriate fractions (Rf 0.2),
•
oil (Found: M+ 224.1415. C13H20O3 requires M+ 224.1412). νmax
(neat)/cm−1 2963, 1739, 1682, 1461, 1386, 1366, 1242, 1122, 1036,
963, 802, 606. δH (300 MHz) 6.69 (1H, d, J 10.2), 5.93 (1H, d, J 10.2),
4.05 (2H, t, J 6.3), 2.44 (2H, m), 2.05 (3H, s), 1.86 (2H, m), 1.66–1.44
(6H, complex m), 0.90 (3H, t, J 7.5). δC (75 MHz) 199.1, 170.7, 157.8,
128.0, 64.3, 37.7, 33.5, 33.0, 30.2, 29.8, 23.0, 20.6, 8.0. m/z (EI, 70 eV)
224 (M+•, 15%), 195 (3), 182 (7), 164 (31), 135 (55), 123 (39), 107
(47), 79 (41), 43 (100).
•
the mesylate 45 (1.19 g, 93%) as an o•paque, yellow oil (Found: M+
381.1252. C18H23NO6S requires M+ 381.1246). νmax (neat)/cm−1
2938, 1683, 1680, 1526, 1352, 1174, 974, 959, 938, 921, 832, 789,
726. δH (300 MHz) 8.00 (1H, dd, J 8.1 and 1.2), 7.60 (1H, td, J 7.5 and
1.2), 7.47 (1H, td, J 7.5 and 1.2), 7.22 (1H, dd, J 8.1 and 1.2), 6.65 (1H,
s), 4.25 (2H, t, J 5.7), 3.00 (3H, s), 2.58 (2H, m), 2.06–1.94 (2H, com-
plex m), 1.88–1.76 (2H, complex m), 1.72–1.58 (4H, complex m), 0.97
(3H, t, J 7.5). δC (75 MHz) 196.2, 153.4, 148.4, 138.3, 133.4, 132.0,
131.6, 128.9, 124.2, 70.0, 38.5, 37.3, 34.0, 33.2, 30.4, 30.0, 24.1, 8.4.
m/z (EI, 70 eV) 381 (M+•, 1%), 336 (7), 335 (55), 256 (48), 228 (42),
134 (100), 104 (72), 79 (76), 55 (61), 41 (48).
4-[3-(Acetyloxy)propyl]-4-ethyl-2-iodo-2-cyclohexen-1-one 42
α-Iodination of enone 41 (1.20 g, 5.35 mmol) in the same manner as
employed for the conversion 25 → 26 afforded the iodide 42 (2.00 g,
quant.) as an opaque, colourless oil, Rf 0.4 (silica, 1/4 v/v ethyl
•
acetate/hexane elution) (Found: M+ 350.0382. C13H19IO3 requires
M+• 350.0379). νmax (neat)/cm−1 2961, 1737, 1688, 1583, 1459, 1384,
1364, 1324, 1240, 1141, 1035, 969, 943, 802. δH (300 MHz) 7.43 (1H,
s), 3.98 (2H, t, J 6.3), 2.59 (2H, t, J 7.2), 1.97 (3H, s), 1.86 (2H, m),
1.61–1.41 (6H, complex m), 0.85 (3H, t, J 7.2). δC (75 MHz) 191.6,
170.7, 166.3, 102.8, 64.1, 43.1, 32.8, 32.6, 30.2, 29.6, 23.1, 20.7, 8.2.
m/z (EI, 70 eV) 350 (M+•, 22%), 261 (35), 249 (21), 223 (40), 207 (35),
181 (25), 163 (65), 43 (100).
4-(3-Azidopropyl)-4-ethyl-2-(2-nitrophenyl)-2-cyclohexen-1-one 46
A magnetically stirred solution of mesylate 45 (465 mg, 1.22 mmol) in
DMF (10 mL) was treated with sodium azide (238 mg, 3.66 mmol) and
the resulting mixture heated at 67◦C for 3 h then cooled to 18◦C and
diluted with diethyl ether (300 mL). The ensuing mixture was washed
with water (2 × 100 mL) and brine (1 × 50 mL) before being dried
(MgSO4), filtered, and concentrated under reduced pressure to afford
the azide 46 (376 mg, 94%) as a viscous yellow oil, Rf 0.7 (silica,
1/1 v/v ethyl acetate/hexane elution) [Found: (M − N•3)+ 286.1456.
C17H20N4O3 requires (M − N•3)+ 286.1443]. νmax (neat)/cm−1 2937,
2096, 1682, 1526, 1456, 1353, 1260, 1198, 956, 787, 726. δH (300 MHz)
7.97 (1H, dd, J 7.8 and 1.2), 7.57 (1H, td, J 7.5 and 1.2), 7.43 (1H, td,
J 7.8 and 1.2), 7.19 (1H, dd, J 7.5 and 1.2), 6.64 (1H, s), 3.29 (2H,
m), 2.55 (2H, m), 1.96 (2H, m), 1.66–1.58 (6H, complex m), 0.94 (3H,
t, J 7.5). δC (75 MHz) 196.2, 153.7, 148.3, 138.0, 133.3, 132.0, 131.5,
128.8, 124.1,•51.6, 38.6, 34.4, 34.0, 30.3, 29.9, 23.6, 8.3. m/z (EI, 70 eV)
286 [(M − N3)+, 5%], 272 (21), 271 (52), 254 (41), 166 (72), 134 (60),
104 (68), 55 (100).
4-[3-(Acetyloxy)propyl]-4-ethyl-2-(2-nitrophenyl)-
2-cyclohexen-1-one 43
Iodide 42 (2.00 g, 5.71 mmol) was cross-coupled with
o-iodonitrobenzene (2.84 g, 11.2 mmol) in the same manner as
employed for the conversion 7 → 14. Subjection of the light-yellow
oil obtained on work-up to column chromatography (silica, 1/4 → 3/7
v/v ethyl acetate/hexane gradient elution) afforded, after concentration
of the appropriate fractions [Rf 0.3 (1/4 v/v ethyl acetate/hexane)],
the title compound 43 (1.58 g, 75%) as a viscous yellow oil (Found:
M+• 345.1577. C19H23NO5 requires M+•, 345.1576). νmax (neat)/cm−1
2962, 1736, 1682, 1573, 1526, 1461, 1354, 1242, 1036, 859, 788, 727.
δH (300 MHz) 7.95 (1H, dm, J 8.1), 7.55 (1H, tm, J 7.5), 7.42 (1H, tm, J
8.1), 7.19 (1H, dm, J 7.5), 6.65 (1H, s), 4.04 (2H, t, J 5.4), 2.53 (2H, t, J
6.6), 2.00 (3H, s), 1.94 (2H, m), 1.72–1.50 (6H, complex m), 0.92 (3H, t,
J 8.1). δC (75 MHz) 196.2 (C), 170.8 (C), 153.8 (CH), 148.3 (C), 137.9
(C), 133.2 (CH), 131.9 (C), 131.5 (CH), 128.7 (CH), 124.0 (CH), 64.4
(CH2), 38.4 (CH3), 33.9 (CH2), 33.4 (CH2), 30.1 (CH2), 29.9 (CH2),
23.2 (CH2), 20.7 (C), 8.2 (CH3). m/z (EI, 70 eV) 345 (M+•, 1%), 299
(12), 256 (37), 134 (65), 104 (47), 43 (100).
(3aSR,3bSR,7aSR)-7a-Ethyloctahydro-3a-(2-nitrophenyl)-
3H-azirino[2,3,1-ij]quinolin-3-one 47
A magnetically stirred solution of azide 46 (1.30 g, 3.96 mmol) in ben-
zene (220 mL) was heated at 75◦C for 72 h then cooled to 18◦C and
concentrated under reduced pressure to afford a dark-yellow oil. Sub-
jection of this material to column chromatography (silica, 3/7 v/v ethyl
acetate/hexane elution) afforded, upon concentration of the appropriate
fractions (Rf 0.3), the title co•mpound 47 (850 mg, 72%) as a dark•-
yellow viscous oil (Found: M+ 300.1472. C17H20N2O3 requires M+
300.1474). νmax (neat)/cm−1 2938, 1696, 1609, 1575, 1524, 1461, 1348,
1173, 1099, 1047, 983, 856, 789, 745, 731, 699. δH (300 MHz) 8.03 (1H,
dd, J 8.1 and 1.5), 7.90 (1H, dd, J 7.8 and 1.5), 7.63 (1H, m), 7.43 (1H,
m), 3.62 (1H, dt, J 12.9 and 3.6), 2.68 (1H, ddd, J 18.3, 4.5 and 1.5), 2.50
4-Ethyl-4-(3-hydroxypropyl)-2-(2-nitrophenyl)-2-cyclohexen-1-one 44
A magnetically stirred solution of acetate 43 (1.2 g, 3.47 mmol) in
methanol (70 mL) was cooled to 0◦C then treated, dropwise, with
K2CO3 (15 mL of a 1 M aqueous solution). The resulting red solution
was stirred at 18◦C for 16 h then acidified with HCl (∼5 mL of a 10%
v/v aqueous solution) and extracted with ethyl acetate (3 × 175 mL).
The combined organic phases were dried (MgSO4), filtered, and con-
centratedunderreducedpressuretoprovidealcohol 44(1.05g, 100%)as
a yellow oil, Rf 0.2 (silica, 3/7 v/v ethyl acetate/hexane elution) [Found:
(M − NO•2)+ 257.1542. C17H21NO4 requires (M − NO•2)+ 257.1542].

Application of the Ullmann Cross-Coupling Reaction in a Total Synthesis of ( )-Aspidospermidine
735
(2H, m), 2.39–2.24 (2H, complex m), 1.80–1.36 (7H, complex m), 0.99
(3H, t, J 7.5). δC (75 MHz) 205.9, 147.3, 136.2, 133.6, 133.1, 128.3,
124.2, 49.5, 47.7, 42.9, 37.7, 37.3, 36.3, 29.4, 28.9, 21.2, 7.9. m/z (EI,
70 eV) 300 (M+•, 1%), 286 (8), 230 (10), 166 (100), 120 (20), 110 (34),
55 (32), 41 (24).
119.6, 118.4, 118.2, 110.7, 110.4, 107.8, 107.0, 59.4, 53.0, 42.3, 41.8,
41.7, 37.9, 36.9, 36.8, 36.3, 31.4, 28.5, 28.2, 25.1, 23.8, 21.7, 20.3, 19.6,
•
•
19.5, 7.8, 7.7. m/z (EI, 70 eV) 332 [M(37Cl)+ , 10%], 330 [M(35Cl)+
,
30], 295 (80), 253 (30), 252 (27), 196 (30), 149 (35), 143 (37), 119 (42),
105 (92), 55 (72), 43 (100).
(
)-(5α,12β,19α)-1,2-Didehydroaspidospermidin-10-one 51[8r]
cis-4a-Ethyl-2,3,4,4a,5,6,7,11c-octahydro-1H-
pyrido[3,2-c]carbazole 4
Following the procedure of Heathcock,[8r] a magnetically stirred solu-
tion of acetamide 49 (140 mg, 0.42 mmol) in acetone (5 mL) was treated
with sodium iodide (636 mg, 4.2 mmol) and heated at reflux for 2 h then
cooled to 18◦C and poured into ethyl acetate (5 mL). The resulting mix-
ture was washed with water (1 × 5 mL) and the separated organic phase
concentrated under reduced pressure. The resulting light-yellow oil was
taken up in THF (5 mL) and the solution so obtained was treated with
AgOTf (180 mg, 0.84 mmol). After 0.5 h at 18◦C the reaction mixture
was poured into ethyl acetate (5 mL), washed with NaHCO3 (1 × 3 mL
of a saturated aqueous solution), dried (MgSO4), filtered, and then con-
centrated under reduced pressure to yield a yellow oil. Subjection of
this material to column chromatography (silica, 0.3/2.7/97 v/v/v aq.
NH3/MeOH/CH2Cl2) provided, after concentration of the appropriate
fractions (Rf 0.3), the indolenine 51 (63 mg, 50%) as an opaque, colour-
Step (i): A magnetically stirred solution of aziridine 47 (75 mg,
0.25 mmol) in CH2Cl2 (2.0 mL) was cooled to −15◦C then treated,
dropwise, with HCl (500 µL of a 1 M ethereal solution, 0.50 mmol).
The resulting mixture was stirred at this temperature for 1.5 h then the
solvent was removed under reduced pressure, at temperatures below
30◦C, to provide the amine HCl salt 48 (93 mg, 100%), a highly unsta-
ble foam. δH (300 MHz) 8.17 (1H, broad d, J 7.8), 7.85 (2H, broad d, J
4.5), 7.65 (1H, m), 4.09 (1H, m), 3.35 (1H, s), 3.05–2.85 (2H, complex
m), 2.75–2.60 (2H, complex m), 2.02–1.65 (7H, complex m), 1.06 (3H,
t, J 7.5) (two protons not observed). δC (75 MHz) 144.3, 134.5, 134.1,
131.3, 129.8, 125.2, 63.7, 48.0, 40.0, 36.7, 36.2, 32.6, 28.4, 27.6, 18.4,
7.8 (one signal obscured or overlapping).
Step (ii): A magnetically stirred solution of TiCl3·3THF (1.04 g,
2.5 mmol) in water (3 mL) was treated with NH4OAc (6 mL of a 2.5 mol
aqueous solution) then acetone (6 mL) and the ensuing mixture strirred
at 18◦C for 10 min. The by now dark-blue solution was then treated
with a solution of compound 48 (93 mg, 0.25 mmol) in acetone (6 mL).
After 0.3 h the reaction mixture, which had turned slate grey in colour,
was poured into NaHCO3 (20 mL of a saturated aqueous solution) then
extracted with ethyl acetate (3 × 200 mL). These extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure to provide
a pale-blue oil. Subjection of this material to column chromatography
(silica, 1/9/20/20 v/v/v/v aq. NH3/MeOH/ethyl acetate/hexane elution)
afforded, following concentration of the appropriate fractions (Rf 0.3),
the title compound 4 (32 mg, 46%) as a cream-coloured solid, mp 172–
177◦C (lit.[8g] 180–182◦C) (Found: M+• 254.1786. C17H22N2 requires
M+• 254.1783). νmax (neat)/cm−1 3400, 2929, 2858, 1464, 1432, 1375,
1330, 1304, 1226, 1166, 1106, 907, 861, 738. δH (300 MHz) 8.26 (1H,
broads), 7.57(1H, m), 7.28–7.22(1H, complexm), 7.12–7.02(2H, com-
plex m), 3.70 (1H, s), 3.03 (1H, broad d, J 12.0), 2.80–2.60 (3H, complex
m), 2.29 (1H, m), 1.81 (1H, broad d, J 12.0), 1.70–1.38 (5H, complex
m), 1.08 (1H, m), 0.84 (3H, t, J 7.5) (H of the NH group not detected). δC
•
•
less oil (Found: M+ 294.1732. C19H22N2O requires M+ 294.1732).
νmax (neat)/cm−1 2936, 2860, 1688, 1579, 1457, 1363, 1289, 1260,
1157, 1106, 1030, 756, 638. δH (300 MHz) 7.54 (1H, d, J 8.4), 7.34–
7.24 (2H, complex m), 7.18 (1H, t, J 8.2), 4.34 (1H, m, J 12.9), 3.60
(1H, s), 2.91 (2H, m), 2.74 (1H, d, J 18.0), 2.70 (1H, m), 2.49 (1H, d,
J 18.0), 2.12 (1H, m), 1.82 (1H, d, J 12.3), 1.66–1.45 (4H, complex
m), 1.32 (1H, dt, J 13.5 and 4.8), 1.00 (1H, complex m), 0.74 (3H, t,
J 6.9). δC (75 MHz) 186.7, 170.1, 154.2, 145.4, 128.3, 126.0, 120.7,
120.2, 70.0, 53.7, 40.7, 38.5, 36.8, 33.7, 29.1, 24.3, 22.6, 20.0, 7.0. m/z
(EI, 70 eV) 294 (M+•, 91%), 265 (27), 223 (19), 156 (58), 149 (70),
105 (70), 69 (70), 57 (84), 55 (82), 43 (100).
(
)-Aspidospermidine 3[8r]
Following the work of Heathcock,[8r] a solution of indolenine 51 (63 mg,
0.21 mol) inTHF (6 mL) was treated with LiAlH4 (856 µL of a 1 M solu-
tion in THF, 0.86 mmol) and the resulting mixture heated at reflux for
4 h. After this time the reaction mixture was cooled to 18◦C, stirred at
this temperature for 16 h then quenched (CAUTION: exothermic pro-
cess) by the sequential addition of water (60 µL), KOH (60 µL of a 15%
aqueous solution) and water (180 µL). The ensuing suspension was fil-
tered through a sintered funnel and the retained solids rinsed with THF
(1 mL). Concentration of the combined filtrates under reduced pressure
gaveapale-yellowresiduethatwassubjectedtocolumnchromatography
(silica, 1/5/94 v/v/v triethylamine/MeOH/CH2Cl2 elution). Concentra-
tion of the appropriate fractions (Rf 0.3) under reduced pressure gave
(75 MHz) 136.1, 134.4, 127.3, 120.9, 119.2, 117.6, 111.7, 110.5, 56.5,
•
46.1, 34.5, 34.0, 29.4, 24.1, 22.5, 20.1, 7.6. m/z (EI, 70 eV) 254 (M+
,
22%), 236 (18), 225 (12), 185 (17), 97 (49), 83 (58), 69 (85), 57 (95),
55 (87), 43 (100).
cis-1-(Chloroacetyl)-4a-ethyl-2,3,4,4a,5,6,7,11c-
octahydro-1H-pyrido[3,2-c]carbazole 49[8r]
•
aspidospermidine (3) (45 mg, 77%) as a pale-yellow film (Found: M+
282.2096. C19H26N2 requires M+• 282.2096). δH (800 MHz) 7.08 (1H,
d, J 7.2), 7.01 (1H, td, J 7.2 and 1.6), 6.73 (1H, td, J 7.2 and 0.8), 6.64
(1H, d, J 7.2), 3.51 (1H, dd, J 10.4 and 5.6), 3.48 (1H, broad s), 3.12
(1H, td, J 8.8 and 3.2), 3.05 (1H, m, J 10.4), 2.29 (1H, dt, 12.8 and 8.0),
2.24 (1H, m), 2.22 (1H, s), 1.98–1.92 (2H, complex m), 1.74 (1H, qt,
J 13.6 and 4.8), 1.65–1.59 (3H, complex m), 1.53–1.44 (2H, complex
m), 1.39 (1H, m), 1.11 (1H, td, J 13.6 and 4.0), 1.05 (1H, dt, J 13.6 and
3.2), 0.87 (1H, m), 0.64 (3H, t, J 7.2). δC (75 MHz) see Table 1. m/z (EI,
70 eV) 282 (M+•, 1), 236 (5), 234 (5), 181 (2), 138 (1), 137 (10), 124
(30), 121 (100), 45 (42).
Following the procedure of Rodriguez,[34] a magnetically stirred solu-
tion of carbazole 4 (170 mg, 0.57 mmol) and triethylamine (60 mg,
0.62 mmol) in CH2Cl2 (20 mL) was cooled to 0◦C then treated, drop-
wise, with α-chloroacetyl chloride (64 mg, 0.57 mmol). The cooling
bath was removed and the by now pale-green solution was warmed to
18◦C over 2 h then poured into water (5 mL) and extracted with CH2Cl2
(1 × 5 mL). The separated organic phase was then dried (MgSO4), fil-
tered, and concentrated under reduced pressure to yield a light-yellow
oil. Subjection of this material to column chromatography (silica, 1/4
v/v ethyl acetate/hexane elution) provided, after concentration of the
appropriate fractions (Rf 0.2), the•α-chloro acetamide 49 (145 mg, 69%)
as a light-yellow oil (Found: M+ 330.1498. C19H2335ClN2O requires
M+• 330.1499). νmax (neat)/cm−1 3398, 3297, 2940, 2879, 1635, 1619,
1584, 1457, 1434, 1348, 1328, 1256, 909, 736. δH (300 MHz) (mixture
of amide rotamers) 8.20 (0.3H, broad s), 8.05 (0.7H, broad s), 7.32–7.20
(2H, complex m), 7.15–7.07 (1H, complex m), 7.05–6.97 (1H, complex
m), 5.76 (0.7H, s), 4.74 (0.3H, s), 4.52 (0.3H, d, J 10.8), 4.39 (0.7 H,
s), 4.27 (1.3H, complex m), 3.59 (0.7H, d, J 13.2) 2.96–2.62 (2.7H,
complex m), 2.50–2.38 (0.3H, complex m), 1.95–1.33 (8H, complex
m), 0.91 (3H, t, J 7.5). δC (75 MHz) (mixture of amide rotamers) 166.0,
165.9, 136.2, 135.0, 134.8, 126.2, 126.0, 124.6, 121.4, 121.2, 120.1,
Crystallographic Studies
Crystal data for compound 39: C15H16N4O3, M 300.32, T 200(1) K,
monoclinic, space group P21/c, Z 4, a 9.9614(2), b 10.5183(2),
c 13.8393(3) Å, β 106.3808(13)◦, V 1391.18(5) Å3, Dx 1.434 g cm−3
,
3177 unique data (2θmax 55◦), 2171 with I > 2.0σ(I); R 0.0330, Rw
0.0363, S 1.0799.
Structure Determination
Images were measured on a Nonius Kappa CCD diffractometer
(MoKα, graphite monochromator, λ 0.71073 Å) and data extracted

736
M. G. Banwell, D. W. Lupton, and A. C. Willis
using the DENZO package.[35] Structure solution was by direct
methods (SIR92).[36] The structure of compound 39 was refined,
on F, using the CRYSTALS program package.[37] Atomic coordi-
nates, bond lengths and angles, and displacement parameters have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC reference number 278077). These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44 1223 336033.
doi:10.1021/JO00280A040
(j) M. Node, H. Nagasawa, K. Fuji, J. Org. Chem. 1990, 55, 517.
doi:10.1021/JO00289A025
(k) P. Le Menez, N. Kunesch, S. Liu, E. Wenkert, J. Org. Chem.
1991, 56, 2915. doi:10.1021/JO00008A060
(l) D. Desmaële, J. d’Angelo, J. Org. Chem. 1994, 59, 2292.
doi:10.1021/JO00088A008
(m) E. Wenkert, S. Liu, J. Org. Chem. 1994, 59, 7677.
doi:10.1021/JO00104A023
(n) P. Forns, A. Diez, M. Rubiralta, J. Org. Chem. 1996, 61, 7882.
doi:10.1021/JO9609900
(o) A. G. Schultz, L. Pettus, J. Org. Chem. 1997, 62, 6855.
doi:10.1021/JO9707592
Acknowledgements
(p) O. Callaghan, C. Lampard, A. R. Kennedy, J. A. Murphy,
We thank the Institute of Advanced Studies as well as the
Australian Research Council Discovery Program for gener-
ous financial support. D.W.L. would like to thank Drs Regan
J. Thomson, Jens Renner, and Oliver E. Hutt, as well as
Dr Darragh O’Neil for helpful discussions.
J. Chem. Soc., Perkin Trans.
1 1999, 995. doi:10.1039/
A900335E
(q) R. Iyengar, K. Schildknegt, J. Aubé, Org. Lett. 2000, 2, 1625.
doi:10.1021/OL005913C
(r) M.A.Toczko, C. H. Heathcock, J. Org. Chem. 2000, 65, 2642.
doi:10.1021/JO991599S
(s) B. Patro, J. A. Murphy, Org. Lett. 2000, 2, 3599.
doi:10.1021/OL006477X
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