A total synthesis of (±)-α-cyclopiazonic acid using a cationic cascade as a key step

Article abstract of DOI:10.1016/j.tet.2011.08.094

The indole alkaloid α-cyclopiazonic acid 1 has been synthesised by a route, which features at its core an acid-catalysed cationic cascade cyclisation terminated by a sulfonamide group.

Full text of DOI:10.1016/j.tet.2011.08.094

Tetrahedron 67 (2011) 8515e8528
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A total synthesis of (ꢀ)-
Charlotte M. Griffiths-Jones (nee Haskins), David W. Knight
a
-cyclopiazonic acid using a cationic cascade as a key step
*
ꢀ
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2011
Received in revised form 12 August 2011
Accepted 31 August 2011
Available online 10 September 2011
The indole alkaloid
acid-catalysed cationic cascade cyclisation terminated by a sulfonamide group.
Ó 2011 Elsevier Ltd. All rights reserved.
a-cyclopiazonic acid 1 has been synthesised by a route, which features at its core an
Keywords:
a
-Cyclopiazonic acid
Synthesis
Carbenium ion
Cascade
Indole alkaloid
1. Introduction
a
-Cyclopiazonic acid 1 (a-CPA) was first identified as a metabo-
O
OH
lite of the fungal species Penicillium cyclopium in the late 1960s,
along with a derived imine, and suggested as the main cause of its
toxicity, especially significant in stored grain and derived products.1
Subsequent biosynthetic studies resulted in the identification of
O
O
N
OH
HN
H
O
H
H
b
-cyclopiazonic acid 2 as a likely precursor in the fungus (Fig. 1).2
Subsequently, the cyclopiazonic acids 1 and 2 have been found in
a very large range of Penicillium species; for example, an exami-
nation3 of some 1400 Penicillium extracts identified the presence in
many of these.4 Perhaps somewhat concerning is the fact that such
fungal species grow especially well on cheese agar; it is therefore
N
N
H
H
1
2
not surprising that a-cyclopiazonic acid 1 has been identified in the
Fig. 1.
a- and b-Cyclopiazonic acids 1 and 2.
organisms responsible for producing two of the best known and
arguably most delicious ‘blue’ cheeses, Penicillium camemberti and
Penicillium roqueforti.5 Fortunately, extracts from the latter source
turn out to be amongst the least toxic of many examined.
during the past five years, either concerning its occurrence as
a mould metabolite or applications as a standard in calcium-ATPase
work.8
The cyclopiazonic acids 1 and 2 belong to the prenylated alka-
loid class of natural products.6 The former has also gained consid-
erable prominence in recent years as a standard in research into
calcium-ATPase in the sarcoendoplasmic reticulum: its ability to
Only two total syntheses of a-cyclopiazonic acid 1 have so far
been reported, from the Kozikowski group9 and the Japanese duo of
Muratake and Natsume;10 both completed their total syntheses
during the mid-1980s. These approaches share a common final
strategy which, fortunately, significantly simplifies the initially ar-
guably fearsome-looking pentacyclic structure 1 and consists of
a classical method for formation of the substituted tetramic acid
structural feature by a Dieckmann ring closure (Scheme 1). Thus,
the less complex intermediate 3 is homologated at nitrogen by
condensation with diketene 4 to give the keto-amide 5, which is not
inhibit this enzyme is the origin of its toxicity.7
a-Cyclopiazonic acid
1 has found particular use as a standard in this area of research as
this inhibition impacts upon calcium reuptake in muscle contrac-
tion and relaxation cycles. A literature search elicits around 500 hits
* Corresponding author. Tel.: þ44 2920 874210; fax: þ44 2920 874030; e-mail
addresses: knightdw@cardiff.ac.uk, knightdw@cf.ac.uk (D.W. Knight).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.094

ꢀ
C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8516
isolated as it undergoes a base-catalysed closure, which offers the
additional benefit of delivering the correct stereochemistry at the
tetramic acid stereogenic centre adjacent to nitrogen by epimer-
isation, should this prove necessary.
2. Results and discussion
Our ideas for a new cyclopiazonic acid synthesis were stimu-
lated by our discovery that homoallylic sulfonamides such as the
cinnamyl derivative 12 underwent smooth and rapid cyclisation to
give the corresponding pyrrolidines 13, as a mixture of isomers,
when exposed to strong acid (Scheme 4).12 All accumulated evi-
dence suggests a benzylic carbenium ion trapping mechanism.
O
O
O
NH
H
N
CO2R2
H
CO2R2
H
H
O
4
H
H
TfOH
1
Ph
CO2Et
Ph
CO2Et
> 90%
N
CHCl3
20 °C, 1 h
NR1
NR1
TsHN
Ts
3
5
12
13
Scheme 1. The final synthetic steps to a-cyclopiazonic acid 1.
Scheme 4. Trapping a benzylic carbenium ion with a sulfonamide group.
Some recent biosynthesis studies suggest that this way of
forming the tetramic acid residue may be, effectively, biomimetic.11
In the Kozikowski synthesis,9 relatively well-established meth-
In addition to this, we have also found that cascade cyclisations,
which have some resemblance to those found in terpene bio-
synthesis, are possible in this type of chemistry. Thus, brief expo-
sure of the geranyl glycine derivative 14 to strong acid gives an
excellent yield of the bicyclic products 15.12
odology was used to obtain the a-phenylthio-ketone 6 from indole-
4-carboxaldehyde, which then underwent smooth intramolecular
Michael ring closure and subsequent desulfurization to provide the
necessary cis stereochemistry about the newly formed six-
membered ring 7 (Scheme 2). In the absence of the phenylthio
function, cyclisation led to the corresponding trans isomer, which
could not then be further manipulated.
That b-cyclopiazonic acid 2 is a likely biosynthetic precursor to
the target 12 led us to speculate that this could form the basis of
a new synthesis featuring interception of a benzylic carbenium ion
rather than the biologically more likely interaction between the
indolylic methylene and the ‘lower’ alkene carbon (Fig. 2). This idea
of achieving a biomimetic synthesis from the precursor 2 has been
highlighted before by the Aggarwal group.13
PhS
O
O
H
CO2Et
NAc
H
CO2Et
NHAc
PhS
H
CO2Et
NHAc
H
O
H
N
NCO2Et
NCO2Et
?benzylic
NCO2Et
OH
carbenium ion
6
7
8
Scheme 2. Key cyclisation steps in the Kozikowski synthesis of 1.
O
A second ring closure leading to the pyrrolidine 8 was achieved
by treatment of intermediate 7 with thiophenol and magnesium
triflate. Replacement of the sulfur group by methyl was then carried
out using, specifically, dimethylzinc; N-deprotection then led into
the final sequence shown in Scheme 1.
N
H
2
Fig. 2. A (bio)synthetic speculation.
The MuratakeeNatsume synthesis10 first exploits this group’s
approach to indoles, which features construction of the benzene
ring onto an existing pyrrole (Scheme 3). Cyclisation of the pre-
cursor 9 is achieved by exposure to tin(IV) chloride; subsequent
homologation of the resulting indole 10 then gave the 3-substituted
indole 11.
Our plans, however, followed a different idea: we speculated
that a suitable precursor 16 for the final sequence of tetramic acid
assembly (Scheme 1) could be obtained by a cascade cyclisation in
which the benzylic carbenium ion 17 was trapped. Hence, the
synthesis led us back to the 3,4-disubstituted indole 18 (Scheme 6).
While this looked to be an obtainable target, we were concerned
about the sense of stereocontrol which would result from the key
acid-catalysed cyclisation which would have to lead to the cis-
isomer 16 as, by this stage, there would be no easy way to epi-
merise either of the stereogenic centres at the new ring junction.
Happily, both our own molecular models and the preferred con-
formations similarly deduced for the natural product itself 1 in the
original report of its isolation1a suggested that formation of the
desired cis-isomer would be a favoured outcome of such a cascade
cyclisation. Of course, such models are just that and it was clearly
still a somewhat risky plan. As will become plain subsequently,
these predictions were fine but we missed a crucial feature shown
by the models, that of the steric crowding present in the various
intermediates.
O
O
O
O
O
NHCHO
CO2Et
O
NCO2Me
NCO2Me
NTs
11
9
10
Scheme 3. Key stages of the Natsume synthesis of 1.
As in the Kozikowski synthesis, direct Michael ring closure of
the ketone derived from indole 11 by dioxolane hydrolysis led to
the undesired trans-ring fusion but, in this case, epimerisation was
used to obtain the cis-stereochemistry by prior cyclic imine
formation.
We felt it prudent to carry out a simpler mimic of the projected
key step to determine that a pyrrolidine could indeed be obtained

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C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8517
NO2
CO2Et
H
TfOH
CO2Me
NHTs
O
O
CO2Me
CHCl3
0 °C, 0.25 h
i
ii
N
Ts
N
N
N
90%
H
Ts
Ts
14
15
22
23
24
Scheme 5. An acid-catalysed cascade cyclisation.
iii
NHR2
NHNs
NR2
R3O
NO2
CO2Et
H
CO2Et
NHTs
CO2Et
CO2Et
H
CO2Et
iv, v
NR1
NR1
NTs
N
N
Ts
Ts
16
17
18
26
25
Scheme 8. Reagents and conditions: (i) TsCl, DMAP (cat.), Et3N, 20 ꢁC,
4 h; (ii)
Scheme 6. Key cascade strategy for a synthesis of a-cyclopiazonic acid 1.
EtO2CCH2NO2, TiCl4, N-methylmorpholine, THF, mix at 0 ꢁC then 20 ꢁC, 16 h; (iii)
Me2C]CHMgBr, ZnCl2, THF, mix at 0 ꢁC then 20 ꢁC, 2 h, 88%; (iv) Zn, AcOH, EtOH,
20 ꢁC, 2 h; (v) TsCl, DMAP (cat.), Et3N, CH2Cl2, 20 ꢁC, 16 h, 32% for two steps.
by such an acid-catalysed cyclisation in the presence of an N-pro-
tected indole. A suitable precursor 19 was therefore required,
which we felt could be prepared from indole and the acetate 21,
which was easily obtained from senecialdehyde 20 by condensa-
tion with the dianion of methyl N-tosylglycinate in the presence of
tin(II) chloride14 followed by acetylation (Scheme 7). Unfortunately,
all attempts to couple this electrophile with indole in the presence
of various palladium catalysts15 or lithium perchlorate16 were
unsuccessful.
NTs
CO2Et
NHTs
CO2Et
i
N
N
t:c ~ 2:1
Ts
Ts
NHTs
26
27
ref. 14
Scheme 9. Reagents and conditions: (i) TfOH (0.6 equiv), CHCl3, reflux, 1 h, 79%.
OAc
CO2Et
O
1H NMR coupling constant values suggested that the major
product was the trans-isomer 28 [J2,3¼8.5 Hz]; a possible confor-
mation is shown in Fig. 3. In contrast, the minor cis-isomer 29
showed J2,3¼4.3 Hz and in addition, an extraordinary chemical shift
of the ester methyl group to dH¼0.09. A likely explanation for this is
that the ester group and the terminal methyl in particular, are
positioned directly over the indole ring, as shown in conformation
29; presumably, this conformation is favoured as it avoids any in-
teraction with the pyrrolidine tosyl group. Natsume and Muratake
noted similar effects in some advanced intermediates during their
N
TsHN
CO2Me
Ts
19
20
21
Scheme 7. Initial attempt to form model 19.
We therefore resorted to a more conventional, linear approach,
set out in Scheme 8, starting with indole-3-carboxaldehyde 22, N-
tosylation of which was followed by a Henry condensation of the
resulting protected indole 23 with ethyl nitroacetate, triggered by
titanium(IV) chloride.17
synthesis of
a
-cyclopiazonic acid 1.10
The resulting doubly activated alkene 24, which was formed in
a 1.5:1 ratio of geometric isomers, then underwent a smooth Mi-
chael addition of an organozinc reagent18 to establish the required
isoprene unit. The product 25 was obtained as an unassigned 3:1
mixture of two diastereoisomers, which were reduced with zinc in
acetic acid, followed by N-tosylation of the resulting amines. The
desired model precursor 26, again isolated as a 3:1 mixture of di-
astereoisomers, which were not separated, was then exposed to
0.4 equiv of triflic acid in ice-cold chloroform for 0.25 h, conditions
which had previously been used (Scheme 5) for generation and
trapping of a tertiary carbenium ion.12 However, this resulted in
essentially no reaction. Happily, by increasing both the acid con-
centration and the temperature, complete conversion into the de-
sired pyrrolidines 27 was observed (Scheme 9), which were
isolated in 79% yield from a small-scale trial in a ratio of di-
astereoisomers of 2:1, which were not separated. We were there-
fore at least confident that an N-tosyl indole residue would survive
the acidic conditions which would be necessary to induce the
planned cascade cyclisation (Scheme 6).
O
H
O
H
TsN
TsN
NTs
NTs
H
CO2Et
H
28
29
Fig. 3. Possible conformations of the trans- and cis-pyrrolidines 28 and 29.
Thus encouraged, we next embarked upon the synthesis of
necessary precursor(s) for the synthesis of the target 1. Starting
with the commercially available nitrobenzoate 30,
grubereBatchko protocol was used, which proceeded via the en-
amine 31, the nitro group of which was reduced using iron in
ethanolic acetic acid (Scheme 10).19 Despite a strong exotherm,
during which cyclisation took place as well, this method could be
used reliably on a reasonably large scale, in contrast to the
a Leim-

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C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8518
hydrogenolysis method reported by Kozikowski20 which, in our
hands, was only effective on a small scale. A second reduction of the
resulting ester 32a using Dibal-H gave a complex mixture of
products, despite a report to the contrary;20 by contrast, reduction
using Red-Al21 delivered a decent overall yield of indole-4-
methanol 32b.
of a 2-methylpropenyl residue to complete the assembly of the
required cascade precursor. Unhappily, many attempts using both
methylpropenyl Grignard or the corresponding lithio reagent
modified by copper(I) salts or various Lewis acids (e.g., ZnCl2, InCl3,
SnCl2) delivered none or no more than mediocre yields of the de-
sired adduct (cf. Schemes 6 and 8), but rather desilylated material
and a number of unidentified products (Fig. 4). We regarded this as
a somewhat ominous indication of the excessive steric crowding at
this site which, of course could have a potentially deleterious effect
on the viability of any subsequent alternative schemes.
R
CO2Et
CO2Et
NMe2
i
ii, iii
N
H
NO2
NO2
32
a) R = CO2Et;
b) R = CH2OH
31
30
NO2
TBDPSO
Scheme 10. Reagents and conditions: (i) DMF dimethyl acetal, DMF, reflux, 16 h, 93%;
(ii) Fe, AcOH, EtOH, 50ꢁe80 ꢁC, then reflux, 0.5 h, 57%; (iii) Red-Al (2 M in toluene),
Et2O, 0e20 ꢁC, 16 h, 64%.
CO2Et
37
Attempted direct Vilsmeier formylation22 of the unprotected
alcohol 32b using POCl3/DMF gave a complex mixture of products,
probably because of undesired reaction(s) at the acid-sensitive
benzylic alcohol site, and so we protected this function with a ro-
bust silicon-based group. While an initial attempt to achieve this
(Scheme 11) led to a mixture of O- and N-silylated products 33 and
34, using tetrahydrofuran as solvent in place of DMF delivered an
excellent yield of the desired product 33 (Scheme 12).
N
Ts
38
Fig. 4. Unsuccessful Michael addition.
We therefore chose to use 4-bromoindole derivatives instead,
with a view to introducing the 4-hydroxymethyl group at a much
later stage. Using the same methodology as before, but starting
with the aryl bromide 39, the Michael acceptor 41 was prepared via
4-bromoindole 4023 (Scheme 13). Our views on the high level of
steric hindrance around the top face of this type of molecule, such
as analogue 37, were vindicated when the latter 4-bromo derivative
41 underwent very smooth Michael addition of a propenylzinc
species to deliver an excellent yield of the desired adduct 42. A final
nitro group reduction and N-tosylation then gave the target 43 in
moderate yield, the result apparently of extreme sensitivity at the
intermediate amino-ester stage, as a separable 2:1 mixture of di-
astereoisomers, whose exact structures were not determined.
TBDPSO
HO
HO
i
+
N
H
N
N
H
TBDPS
~ 2:1
32b
33
34
Scheme 11. Reagents and conditions: (i) TBDPSCl, 0.1 equiv imidazole, DMF, 20 ꢁC,
16 h. [TBDPS¼tert-butyldiphenylsilyl].
TBDPSO
TBDPSO
NO2
O
Br
Br
Br
CO2Et
i
ii
i
ii
32b
N
H
N
H
N
H
N
NO2
Ts
33
35
iii
39
40
41
iii
NO2
TBDPSO
TBDPSO
iv
O
CO2Et
NHTs
NO2
CO2Et
Br
Br
CO2Et
iv
N
N
Ts
Ts
N
N
37
36
Ts
Ts
Scheme 12. Reagents and conditions: (i) TBDPSCl, 0.1 equiv imidazole, THF, 20 ꢁC, 16 h,
95% [TBDPS¼tert-butyldiphenylsilyl]; (ii) POCl3, pyridine, DMF 35 ꢁC, 0.75 h then aq
NaOH, 100 ꢁC, 2 min, 82%; (iii) TsCl, Et3N, DMAP (cat.), CH2Cl2, 20 ꢁC, 16 h, 85%; (iv)
EtO2CCH2NO2, TiCl4, THF, 0 ꢁC, 0.5 h then N-methylmorpholine, 20 ꢁC, 16 h, 43%.
43
42
Scheme 13. Reagents and conditions: (i) as Scheme 10, 30 to 32a, except pyrrolidine
used in place of Me2NH (Ref. 23); (ii) as Scheme 12, 33 to 37; (iii) Me2C]CHMgBr,
ZnCl2, THF, 0 ꢁC, 2 h, 90%; (iv) as Scheme 8, 25 to 26, 36%.
A Vilsmeier formylation was now successful when carried out in
the presence of pyridine, without which extensive desilylation
occurred. Subsequent N-tosylation of the resulting aldehyde 35
then gave the protected indole 36, which was converted into the
nitro-ester 37, in anticipation of this undergoing Michael addition
Unfortunately, a wide range of palladium-catalysed homologa-
tion methods (Suzuki, Stille, carbonylations, low temperature hal-
ogen/metal exchange etc.) failed at this stage when applied to
a mixture of isomers of the bromo derivative 43; instead, extensive

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C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8519
polymerisation seemed to be the primary outcome. Other metals
were equally unsuccessful; the only partly successful method was
a carbonylation reaction [Co2(CO)8, CO, MeLi, NaOH] reported by
Miura,24 which delivered a moderate 27% yield of the methyl ke-
tone 44, of possible use except that the amino group had also been
methylated. This signalled another return to the planning stage
(Fig. 5).
It was only when the reaction was similarly quenched but at
ꢂ78 ꢁC that the expected secondary alcohol 46 was successfully
isolated. The sensitivity of this compound was evident when it
underwent smooth rearrangement to the isomeric tertiary allylic
alcohol 47, together with a lesser amount of the diene 48 after 72 h
at ambient temperature; the latter was the only product when at-
tempts were made to acylate the alcohol 47. Halogenations, not
surprisingly, were also unproductive.
We therefore altered our strategy again, this time to one in
which the amino group was introduced at a much later stage. In
order to assess the various methods available in the presence of
a protected indole nucleus, the indole-3-propanoate 50 was syn-
thesised from the N-tosyl aldehyde 23 by sequential Hor-
nereWadswortheEmmons homologation26 to give the (E)-
alkenoate 49 and a Michael addition,27 which delivered a good
yield of this desired target, understandably after a lengthier re-
action period than those required for similar additions to the more
activated nitro-ester 24 and 41 (Scheme 15).
N(Me)Ts
O
CO2Et
N
Ts
44
CO2Et
ii
Fig. 5. A possibly useful carbonylation product.
CO2Et
i
23
As similar failures were encountered when the ‘free’ NH in the
brominated substrate 43 was masked by a methoxycarbonyl group,
this strategy overall seemed likely to be unproductive, perhaps
again a victim of excessive steric crowding. We thought to reverse
the order of introduction of the various functionalities in the
amino-ester side chain by first forming an allylic acetate and then
N
N
Ts
Ts
49
50
Scheme 15. Reagents and conditions: (i) (EtO)2P(O)CH2CO2Et, LiCl, DBU, MeCN, 20 ꢁC,
2 h, 77%; (ii) Me2C]CHMgBr, PhSCu, THF, ꢂ40 to 0 ꢁC then ꢂ40 ꢁC, add enoate, 20 ꢁC,
2 h, 81%.
adding the amino-ester function by nucleophilic attack onto a
p-
allyl complex formed from the former.25 Thus, the N-protected
indole-3-carboxaldehyde 23 was homologated using a propenyl
Grignard reagent with the aim of forming the allylic alcohol 46. This
proved to be unexpectedly sensitive. A standard Grignard reaction
quench using aqueous ammonium chloride at ambient tempera-
ture gave instead the tertiary alcohol 47, accompanied by small
amounts of the dehydration product, the diene 48, but in excellent
overall yield (Scheme 14).
Our first attempt to functionalise the methylene group adjacent
to the ester involved formation of its potassium enolate and re-
action with the oxaziridine 51.28
In the event, the reaction worked well, delivering a 76% iso-
lated yield of the desired a-hydroxy-ester 52 along with a much
smaller amount, 12%, of the readily separable amino derivative
53, a potential final intermediate from this sequence (Scheme
16). Unfortunately, two types of Mitsunobu nucleophile
54 (Fig. 6), whose use was aimed at introducing the 4-
nitrophenylsulfonylamino (nosylamino) group, which we antic-
ipated would be more readily deprotected at the appropriate
later stage,29 failed to deliver under a range of reagent combi-
O
O
nations and conditions.30 The triflate 55 derived from
a-hy-
i
droxy-ester 52, while readily formed using triflic anhydride
(pyridine, CH2Cl2, 0 ꢁC), proved far too sensitive to elimination to
give the corresponding conjugated diene to allow either purifi-
cation or subsequent azide displacement.
N
N
Ts
Ts
23
45
OH
CO2Et
NHSO2Ph
CO2Et
ii
iii
50
+
i
OH
+
OH
N
N
O
Ts
Ts
~6:1
NSO2Ph
iv
Ph
+
52
53
51
N
N
N
Ts
Ts
Ts
Scheme 16. Reagents and conditions: (i) KHMDS, THF, ꢂ78 ꢁC, 0.75 h, 76% (52).
~6:1
v
46
47
48
An alternative oxaziridine 56, which has been reported as being
useful for the direct amination of ester enolates31 unfortunately
reacted with the potassium enolate of the ester 50 to give an ap-
proximately equal mixture of the desired amino-ester derivative 57
Scheme 14. Reagents and conditions: (i) Me2C]CHMgBr, THF, ꢂ78 ꢁC, 2 h; (ii) aq
NH4Cl, ꢂ78 ꢁC; (iii) warm to 20 ꢁC, quench with aq NH4Cl; (iv) 20 ꢁC, 72 h; v) Ac2O,
pyridine, CH2Cl2, 0 ꢁC or ClCO2Et, pyridine, CHCl3, 0 ꢁC, 1e2 h, 81e84%.

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8520
We therefore applied this new strategy to an original a-CPA
precursor 36 and were delighted to find that the chemistry con-
tinued to be viable (Scheme 19). HWE homologation smoothly
provided the unsaturated ester 60 necessary for the following Mi-
chael addition, which then delivered an unoptimised yield of 53% of
the propenyl homologue 61, the potassium enolate of which reac-
OTf
CO2Et
O
NHR
S
O
O2N
54
N
ted smoothly with trisyl azide to give the
sentially as single diastereoisomer whose stereochemistry was not
assigned. A Staudinger reaction then provided the corresponding
a-azide ester 62 as es-
Ts
a) R = H
b) R = t-butyloxycarbonyl (Boc)
55
a
-
amino ester, which was immediately protected as its 4-nosyl de-
rivative 63, in anticipation of a relatively simple deprotection step
at the final stages of the synthesis, by exposure to a thiolate.29 We
have previously found that such sulfonamides participate in acid-
catalysed ring closures as effectively as the related toluenesulfo-
namides, despite their obviously rather dissimilar electronic
properties.12 The 4-nosyl derivative 63 was isolated as a ca. 4:1
mixture of diastereoisomers which were neither separated nor
structurally assigned.
Fig. 6. More unsuccessful reagents and intermediates.
together with the adduct 58 formed from the enolate and the al-
dehyde released after the oxaziridine had donated its nitrogen
group as desired (Scheme 17).
NHBoc
CO2Et
CO2Et
TBDPSO
TBDPSO
50
CO2Et
i
ii
N
36
Ts
+
N
N
Ts
Ts
O
NBoc
57
i
+
~1:1
60
61
iii
NC
CO2Et
56
OH
NHNs
N3
CO2Et
TBDPSO
TBDPSO
N
CO2Et
Ts
iv
58
N
N
CN
Ts
Ts
Scheme 17. Reagents and conditions: (i) KHMDS, THF, ꢂ78 ꢁC, 0.75 h, 79% (1:1 mix).
63
62
Scheme 19. Reagents and conditions: (i) (EtO)2P(O)CH2CO2Et as Scheme 15, 62%; (ii)
Me2C]CHMgBr, PhSCu as Scheme 15, 53%; (iii) KHMDS, trisyl azide as Scheme 18, 56%;
(iv) PPh3, aq THF as Scheme 18 then 4-NsCl, pyridine, DMAP (cat.), CHCl3, 0e20 ꢁC,
16 h, 52%.
Despite continued concerns regarding the level of steric hin-
drance around this reactive site, the successful introduction of
a suitable nitrogen function into the unsaturated ester 50 was finally
achieved using the bulky reagent 2,4,6-triisopropylbenzenesulfonyl
(trisyl) azide,32 which reacted smoothly with the same potassium
Having finally obtained a sample of a suitable intermediate 63
for the projected cascade cyclisation, we chose to first try the key
step using this material directly, rather than to remove the silyl
group in a separate reaction, reasoning that this could occur
rapidly upon exposure to the acid or that the entire silyloxy
group could leave the molecule after O-protonation to generate
the desired benzylic carbenium ion (See Scheme 6). In the event,
we were extremely pleased to observe that exposing the pre-
cursor 63 to a solution of triflic acid in chloroform at ambient
temperature for 1 h resulted in smooth cascade cyclisation to give
an excellent 74% isolated yield of the tetracyclic product 64
(Scheme 20). Happily, this was isolated as essentially as single
diastereoisomer, which evidently possessed the required cis-
stereochemistry at the newly created ring junction, as anticipated
from molecular models (see above). A value of 4.1 Hz for J6a,9a led
to this conclusion; a very similar derivative but one having the
trans-stereochemistry across this ring junction obtained by Nat-
sume and Muratake10 during their synthesis of a-CPA showed
J6a,9a¼12.5 Hz. The stereochemistry of the ester was assigned as
syn to the adjacent ring junction proton on the basis of
J9,9a¼9.5 Hz, also in line with a value of 10.0 Hz observed by the
Japanese workers.
enolate33 to give a good but unoptimised yield of the
a-azido-ester
59 (Scheme 18). A subsequent Staudinger reaction34 then led to the
corresponding amino-ester, which was N-tosylated to provide
a mixture of diastereoisomers (w2:1 ratio) of the ester 26, prepared
previously for the model cyclisation methodology (Scheme 8). The
identity of the two samples, except for the isomer ratio, served to
confirm the validity of this method of amine group introduction.
N3
CO2Et
CO2Et
i
ii
26
N
N
Ts
Ts
50
59
Scheme 18. Reagents and conditions: (i) KHMDS, THF/toluene, ꢂ78 ꢁC, 0.5 h then add
trisyl azide, 5 min then add AcOH and warm to 20 ꢁC, 63%; (ii) PPh3, H2O, THF, 65 ꢁC,
6 h then TsCl as Scheme 8, 35%.

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C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8521
Some of the scope and limitations of this new method for the N-
detosylation of indoles and a few related heteroaromatic systems
are presented in Table 1.36 Simple tosylated indoles were very ef-
ficiently deprotected (entries aec), but not surprisingly, the return
from the conjugated ester (entry d) was much lower, presumably
NNs
NH
H
9
CO2Et
CO2Et
H
H
H
6a
9a
H
H
i
ii
63
due to competing Michael addition of the thiolate. The 3-a-keto-
NTs
NH
ester (entry e) proved too sensitive for any product to be isolated. 2-
Phenylindole was, not surprisingly, obtained in excellent yield
(entry f) as were the two carbazole-based models (entries g and h),
along with the 4-indole ester used in the present study (entry i) The
success with two simple imidazole derivatives (entries j and k)
suggest a generality which should be applicable to many more
complex N-tosylated heteroaromatic systems.
Completion of the a-CPA synthesis, while mechanistically
somewhat complex, in practise simply involves heating the pen-
ultimate intermediate 65 with diketene and base in dichloro-
methane (Scheme 21).9,10 In our hands, this gave a decent return of
a-CPA 1, which proved to be identical in all respects, except of
course for optical rotation, with a commercial sample of natural
material (Tocris).
64
65
Scheme 20. Reagents and conditions: (i) 2$TfOH, CHCl3, 20 ꢁC,
2$HSCH2CO2H, 4$LiOH, DMF, 20 ꢁC, 4 h, 85%.
1 h, 74%; (ii)
A second piece of good fortune followed immediately: during
the next step, removal of the nosyl group from the pyrrolidine ring
using thioglycolate,29 the indole tosyl group was also completely
removed. While cleavage of this group was not expected to be too
difficult in view of the relatively low pKa value of the indole nucleus,
we had anticipated that this would require an additional step, such
as warming with ethanolic hydroxide, for example.35 Clearly this
was of great benefit to the present synthesis although, as ever, the
loss of so much mass in a single step was somewhat disconcerting.
With the isolation of compound 65, a new total synthesis of a-CPA
had effectively been completed as this has previously served as
a penultimate intermediate.9,10 Although the stereochemistry of
the ester group was that required in the natural product, this was of
no concern as this centre undergoes epimerisation if necessary
during the final tetramic acid ring formation (see above).
O
OH
NH
H
N
CO2Et
H
H
H
O
H
Table 1
H
i
Model indole and imidazole detosylations
R
R
LiS
CO2Li
NH
N
H
DMF, 20 °C
N
N
H
Ts
65
1
66
67
Scheme 21. Reagents and conditions: (i) Diketene, t-BuOK, CH2Cl2, 40 ꢁC, 24 h, 79%.
Entry
R
Mp N-tosyl derivative ꢁC
% Yield NeH indole
a
H
CHO
CH2CO2Et
CH]CHCO2Et
86e8828
148e15014
99e101
99e101
105e110
86
95
79
41
0
In particular, the 1H NMR spectra were super-imposable, even to
the extent of showing around 8% of a second enol tautomer,
probably involving the 1,3-dione function, in both samples. Rele-
vant, clear and identical resonances exhibited by this tautomer
were dH (CDCl3, 400 MHz) 4.19 (d, J w10.8 Hz) and 2.45 (s); the
corresponding resonances for the main tautomer were dH 4.00 (d, J
w11.1 Hz) and 2.38 (s). Approximately 5% of a stereoisomer may
also have been present in the synthetic sample, appearing as dH 4.47
(d, J w4 Hz), suggesting the isomer with all three relevant protons
cis to each other. This was not however confirmed by other obvious
and assignable resonances. This may account for the slightly lower
melting point (230e236 ꢁC) to that recorded for the natural ma-
terial (245e246 ꢁC).1a
b (¼23)
c
d (¼49)
e
C(O)CO2Et
Ph
f
108e110
93e9629
87
80
N
Ts
g
N
Ts
h
i
128e13130
145e14731
87
81
N
3. Conclusions
Ts
CO2Me
Overall therefore, this represents a relatively brief synthesis of
a
-cyclopiazonic acid 1, which could be made better by further
optimisation of some of the approach work and which also has
the potential for leading to optically active material. It was good
to read that this has very recently been achieved: a German
group has succeeded in obtaining the advanced intermediate 63
on multigram scale using an Evans’ chiral auxiliary to guide the
[1.4]-propenyl group addition and then to desymmetrize the
subsequent introduction of azide using an optimized version of
the method we employed (Scheme 19).37 The only place where
N
Ts
N
j
78e8032
127e130
92
88
N
Ts
N
Ph
k
N
this could now go wrong would be if the stereogenic centre
a-to
Ts
the ester group underwent epimerization upon exposure to acid

ꢀ
C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8522
but prior to cyclisation, as this would be expected to give the
opposite enantiomer of the natural product and hence less op-
tically pure product, or even racemic material. This feature has
yet to be tested.
[C20H18N2O6S: calcd C 58.0, H 4.4; N 6.8; found: C 57.8, H 4.5, N
6.6%]; 1H NMR (400 MHz, CDCl3):
d
¼(major) 8.17 (d, J¼8.3 Hz, 1H;
70-H), 7.94 (s, 1H; 20-H), 7.93 (s, 1H; 3-H), 7.75 (d, J¼8.2 Hz, 2H, 2ꢃ
ArH), 7.58 (d, J¼7.8 Hz, 1H, 40-H), 7.35-7.31 (m, 2H, 50- and 60-H),
7.28 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 4.33 (q, J¼7.1 Hz, 2H, OCH2), 2.33 (s,
3H; ArMe), 1.31 (t, J¼7.1 Hz, 3H, CH2CH3); (minor) 8.17 (d, J¼8.3 Hz,
1H; 70-H), 7.95 (s, 1H; 20-H), 7.89 (s, 1H; 3-H), 7.75 (d, J¼8.2 Hz, 2H,
2ꢃ ArH), 7.59 (d, J¼7.8 Hz,1H, 40-H), 7.35e7.31 (m, 2H, 50- and 60-H),
7.27 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 4.43 (q, J¼7.1 Hz, 2H, OCH2), 2.34 (s,
3H; ArMe), 1.35 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR (100 MHz,
4. Experimental section
4.1. General remarks
NMR spectra were recorded using a Bruker DPX spectrometer
operating at 400 MHz for 1H spectra and at 100.6 MHz for 13C
spectra, respectively. Unless stated otherwise, NMR spectra were
measured using dilute solutions in deuteriochloroform. All NMR
measurements were carried out at 30 ꢁC and chemical shifts are
reported as parts per million on the delta scale downfield from
CDCl3):
d
¼(major) 178.2 (CO), 159.7 (2-C), 146.5 (s), 134.7 (s), 132.4
(s), 130.7 (s), 129.0 (d), 128.9 (s), 127.8 (d), 126.5 (d), 124.8 (d), 124.3
(d), 119.2 (d), 114.2 (d), 111.6 (d), 53.9 (OCH2), 22.1 (Me), 14.5 (Me);
(minor) 176.4 (CO), 159.8 (2-C), 146.5 (s), 134.8 (s), 132.5 (s), 130.7
(s), 129.1 (d), 128.7 (s), 127.0 (d), 126.5 (d), 124.9 (d), 124.3 (d), 119.1
(d), 114.2 (d), 111.8 (d), 53.7 (OCH2), 22.3 (Me), 16.2 (Me); IR (KBr):
nmax¼1728, 1640, 1534, 1448, 1175 cmꢂ1; HRMS: m/z: calcd for
C20H22N3O6S: 432.1224; found: 432.1221 [MþNH4]þ.
tetramethylsilane (TMS:
d
¼0.00) or relative to the resonances of
CHCl3
(dH¼7.27 ppm in proton spectra and dC¼77.0 ppm for the
central line of the triplet in carbon spectra, respectively). Coupling
constants (J) are reported in hertz. Infrared spectra were recorded
as thin films on sodium chloride plates for liquids and as KBr disks
for solids, using a PerkineElmer 1600 series FTIR spectrophotom-
eter and sodium chloride plates. Low resolution mass spectra were
obtained using a VG Platform II Quadrupole spectrometer operating
in the electron impact (EI; 70 eV) or atmospheric pressure chemical
ionization (ApcI) modes, as stated. High resolution mass spectro-
metric data was obtained from the EPSRC Mass Spectrometry Ser-
vice, University College, Swansea, using the electrospray ionisation
(ES) mode unless otherwise stated. Melting points were de-
termined using a Kofler hot stage apparatus and are uncorrected.
Elemental analyses were obtained using a PerkineElmer 240C El-
emental Microanalyser.
4.1.2. Ethyl (2RS,3RS)- and (2RS,3SR)-5-methyl-2-nitro-3-[1-(4-
toluenesulfonyl)-indole-3-yl]-hex-4-enoate 25. 2-Methyl-1-propen-
ylmagnesium bromide (33.6 mL of a 0.5 M solution in toluene,
17.0 mmol) was added dropwise to a suspension of zinc chloride
(1.50 g, 11.0 mmol) in tetrahydrofuran (10 mL) maintained at 0 ꢁC.39
The resulting solution was stirred at this temperature for 0.25 h
then transferred by cannula to a second flask containing the fore-
going nitroacrylate 24 (1.50 g, 4.00 mmol) in dry tetrahydrofuran
(20 mL) also stirred at 0 ꢁC. The resulting mixture was stirred for 2 h
without additional cooling then quenched by the addition of pH 8
buffer (40 mL) and extracted with ether (2ꢃ30 mL). The combined
extracts were dried, filtered and evaporated and the crude product
separated by column chromatography (70% dichloromethane/pet-
rol) to give the nitro-ester 25 (1.10 g, 63%) as a 1.2:1 mixture of
diastereoisomers and a pale yellow, oily solid [C24H26N2O6S: calcd C
61.3, H 5.6; N 6.0; found: C 61.6, H 5.5, N 5.9%], which showed: 1H
All reactions were conducted in oven-dried apparatus under an
atmosphere of dry nitrogen unless otherwise stated. All organic
solutions from aqueous work-ups were dried by brief exposure to
dried magnesium sulfate, followed by gravity filtration. The
resulting dried solutions were evaporated using a Buchi rotary
NMR (400 MHz, CDCl3):
d
¼(major) 7.88 (d, J¼8.3 Hz, 1H, 70-H), 7.70
€
evaporator under water aspirator pressure and at ambient tem-
perature unless otherwise stated. Column chromatography was
carried out using Merck Silica Gel 60 (230e400 mesh). TLC analyses
were carried out using Merck silica gel 60 F254 pre-coated, alu-
minium-backed plates, which were visualized using ultraviolet
light or potassium permanganate or ammonium molybdenate
sprays.
(d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.48 (d, J¼7.7 Hz, 1H, 40-H), 7.39 (s, 1H, 20-
H), 7.38-7.34 (m, 2H, 50- and 60-H), 7.27 (d, J¼8.2 Hz, 2H, 2ꢃ ArH),
5.48e5.33 (m, 2H, 2- and 4-H), 4.76e4.73 (m, 1H, 3-H), 3.82e3.78
(m, 2H, OCH2), 2.27 (s, 3H, ArMe), 1.72 (s, 3H, Me), 1.66 (s, 3H, Me),
1.23e1.21 (m, 3H, CH2CH3); (minor) 7.85 (d, J¼8.3 Hz,1H, 70-H), 7.66
(d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.45 (d, J¼7.7 Hz, 1H, 40-H), 7.43 (s, 1H, 20-
H), 7.35e7.31 (m, 2H, 50- and 60-H), 7.28 (d, J¼8.2 Hz, 2H, 2ꢃ ArH),
5.48e5.33 (m, 2H, 2- and 4-H), 4.76e4.73 (m, 1H, 3-H), 4.18 (q,
J¼7.2 Hz, 2H, OCH2), 2.26 (s, 3H, ArMe), 1.74 (s, 3H, Me), 1.65 (s, 3H,
Me), 0.78 (t, 3H, J¼7.2 Hz, CH2CH3); 13C NMR (100 MHz, CDCl3):
Ether refers to diethyl ether and petrol to the fraction boiling
60e80 ꢁC unless stated otherwise.
4.1.1. Ethyl (E)- and (Z)-3-[1-(4-toluenesulfonyl)-indole-3-yl]-2-
nitroacrylate 24. Anhydrous tetrahydrofuran (20 mL), placed in
a three-necked round bottomed flask equipped with a dropping
funnel, was stirred and cooled to 0 ꢁC. Titanium(IV) chloride
(2.95 mL, 26.0 mmol) was added dropwise via syringe and a bright
d¼(major) 172.2 (CO), 152.1 (s), 149.8 (s), 143.0 (s), 138.0 (s), 134.9
(s), 129.9 (d), 126.9 (d), 126.7 (d), 125.2 (d), 123.4 (d), 119.5 (d), 118.7
(d), 113.8 (d), 90.9 (d), 63.0 (OCH2), 37.4 (d), 25.9 (q), 21.6 (q), 18.1
(q),13.4 (q); (minor) 172.2 (CO),154.3 (CO), 150.2 (s), 143.5 (s), 138.3
(s), 134.9 (s), 130.0 (d), 126.7 (d), 123.9 (d), 123.6 (d), 120.3 (d), 119.6
(d), 118.6 (d), 113.9 (d), 89.2 (d), 62.9 (OCH2), 37.7 (d), 26.0 (q), 21.6
(q), 18.3 (q), 13.9 (q); IR (CHCl3): nmax¼1748, 1563, 1447, 1372,
1175 cmꢂ1; HRMS [APCI]: m/z: calcd for C24H27N2O6S: 471.1590;
found: 471.1588 [MþH]þ.
yellow precipitate formed immediately.
A mixture of 1-(4-
toluenesulfonyl)-indole-3-carboxaldehyde 23 (4.00 g, 13.0 mmol;
mp 148e150 ꢁC [lit.17,38 mp 148e150 ꢁC]) and ethyl nitroacetate
(1.48 mL, 13.0 mmol) in tetrahydrofuran (10 mL) was then added
slowly from the dropping funnel. The now brown solution was
stirred for 0.25
h
at the same temperature before 4-
4.1.3. Ethyl (2RS,3RS)- and (2RS,3SR)-5-methyl-2-(4-toluenesu-
lfonylamino)-3-[1-(4-toluenesulfonyl)-indol-3-yl]-hex-4-enoate
26. The foregoing nitro-ester 25 (0.195 g, 0.41 mmol) was dis-
solved in glacial acetic acid (10 mL) and zinc dust (0.80 g,
12.2 mmol) added in three portions during 10 min. The resulting
mixture was stirred at ambient temperature for 2 h then filtered
and basified using 2 M aqueous sodium hydroxide. Dichloro-
methane (20 mL) was added and the resulting layers separated.
The organic solution was washed with saturated aqueous sodium
carbonate (10 mL) then dried, filtered and evaporated to leave
methylmorpholine (5.89 mL, 52.0 mmol) was added during 0.5 h.
The resulting mixture was then stirred overnight without the ad-
dition of any more coolant and finally quenched by the addition of
water (50 mL). Ether (20 mL) was added and the resulting two
layers separated. The aqueous layer was extracted with ether
(2ꢃ50 mL) and the combined organic solutions dried, filtered and
evaporated. The resulting solid was crystallised from ethyl acetate/
hexanes to give the nitroacrylate 24 (3.70 g, 67%) as an orange solid
in a ratio of (E)- and (Z)-isomers of 1.5:1. Mp 162e165 ꢁC;

ꢀ
C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8523
a crude amine (0.15 g, 0.34 mmol) as a yellow oil. This was im-
mediately dissolved in dry dichloromethane (10 mL) to which was
added tosyl chloride (0.40 mmol), triethylamine (0.40 mmol) and
a few crystals of DMAP. The resulting mixture was stirred over-
night at ambient temperature then quenched by the addition of
2 M hydrochloric acid (2 mL). The organic phase was separated and
the aqueous phase extracted with dichloromethane (2ꢃ5 mL). The
combined organic solutions were washed with brine then dried,
filtered and evaporated. Column chromatography (dichloro-
methane) separated the sulfonamide 26 (0.08 g, 32%) as an off-
white solid in a 3:1 ratio of diastereoisomers, which showed mp
126e131 ꢁC [C31H34N2O6S2: calcd C 62.6, H 5.7; N 4.7; found: C
(q); IR (CHCl3): nmax¼1745 cmꢂ1; HRMS [APCI]: m/z: calcd for
C31H35N2O6S2: 595.1940; found: 595.1936 [MþH]þ.
4.1.5. 4-[(tert-Butyldiphenylsilyloxy)methyl]indole 33. Indole-4-
methanol 32b (7.00 g, 48.0 mmol)19,21 was dissolved in dry tet-
rahydrofuran (100 mL) and tert-butyldiphenylchlorosilane
(11.4 mL, 52.0 mmol) added dropwise via syringe, followed by
imidazole (0.66 g, 5.20 mmol). The resulting suspension was
stirred overnight at ambient temperature then quenched by the
addition of 2 M hydrochloric acid (100 mL). The resulting two
layers were separated and the aqueous layer extracted with ether
(2ꢃ50 mL). The combined organic solutions were dried, filtered
and evaporated to leave the silyl ether 33 (17.41 g, 95%) as a brown
62.6, H 5.8, N 4.7%]; 1H NMR (400 MHz, CDCl3):
d
¼(major) 7.80 (d,
J¼8.3 Hz, 1H, 70-H), 7.67 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.49 (s, 1H, 20-H),
7.38e7.34 (m, 4H), 7.20e7.05 (m, 3H), 6.98 (d, J¼8.2 Hz, 2H, 2ꢃ
ArH), 5.26 (d, J¼9.6 Hz, 1H, NH), 5.11 (d, J¼9.4 Hz, 1H, 4-H),
4.15e4.10 (m, 2H, 2- and 3-H), 3.85e3.81 (m, 2H, OCH2), 2.27 (s,
3H, ArMe), 2.25 (s, 3H, ArMe), 1.67 (s, 3H, Me), 1.48 (s, 3H, Me), 0.95
(t, J¼7.2 Hz, 3H, CH2CH3); (minor) 7.85 (d, J¼8.3 Hz, 1H, 70-H),
7.69e7.65 (m, 4H), 7.51 (s, 1H, 20-H), 7.38e7.34 (m, 4H), 7.20e7.05
(m, 3H), 5.24 (d, J¼9.8 Hz, 1H, NH), 4.95 (d, J¼9.3 Hz, 1H, 4-H),
4.15e4.10 (m, 2H, 2- and 3-H), 3.82 (q, J¼7.1 Hz, 2H, OCH2), 2.30 (s,
3H, ArMe), 2.26 (s, 3H, ArMe), 1.63 (s, 3H, Me), 1.53 (s, 3H, Me), 0.79
oil, 1H NMR (400 MHz, CDCl3):
(m, 4H), 7.40e7.05 (m, 10H), 6.42 (d, J¼3.2 Hz, 1H, 3-H), 5.02 (s,
d
¼8.14 (br s, 1H, NH), 7.72e7.67
t
2H, CH2O), 1.03 (s, 9H, Bu); 13C NMR (100 MHz, CDCl3):
d
¼159.2
(s), 146.0 (s), 134.4 (s), 130.3 (d), 129.0 (d), 127.2 (d), 126.1 (d),
124.4 (d), 123.8 (d), 118.9 (d), 113.8 (d), 111.2 (s), 65.6 (t), 15.3 (q),
12.9 (s); IR (CHCl3): nmax¼3426, 2931, 2857, 1589, 1471 cmꢂ1; m/z:
[APCI] 386 (MþHþ, 32%), 130 (100).
4.1.6. 4-[(tert-Butyldiphenylsilyloxy)methyl]indole-3-carboxaldehyde
35. Phosphorus oxychloride (2.3 mL, 24.0 mmol) was added to ice-
cold, stirred, dry dimethylformamide (7.8 mL, 99.0 mmol) followed
by dry pyridine (2.0 mL, 26.0 mmol). A solution of the foregoing
protected indole-4-methanol 33 (8.50 g, 22.0 mmol) in dime-
thylformamide (3 mL) was then added dropwise and the resulting
solution warmed to 35 ꢁC for 0.75 h before being poured onto ice.
Sodium hydroxide (4.00 g) in water (200 mL) was added in portions
and the resulting mixture boiled for 2 min then cooled and
extracted with dichloromethane (3ꢃ50 mL). The combined extracts
were dried, filtered and evaporated to give the indole-3-carbox-
aldehyde 35 (7.52 g, 82%) as a brown oil, which showed 1H NMR
(t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
¼(major)
d
172.0 (CO), 152.7 (s), 149.9 (s), 146.0 (s),136.3 (s), 135.5 (s), 133.9 (s),
132.2 (s), 130.2 (d), 129.5 (d), 126.4 (d), 125.7 (d), 123.2 (d), 122.5
(d), 121.5 (d), 120.7 (d), 119.7 (d), 111.8 (d), 59.5 (OCH2), 58.8 (d),
42.6 (d), 25.6 (q), 21.0 (q), 20.9 (q), 19.6 (q), 18.7 (q); (minor) 171.4
(CO), 152.7 (s), 150.1 (s), 146.3 (s), 136.0 (s), 135.7 (s), 133.9 (s), 132.4
(s), 129.8 (d), 128.7 (d), 126.6 (d), 125.7 (d), 122.6 (d), 121.9 (d), 121.0
(d), 120.3 (d), 119.8 (d), 111.4 (d), 59.6 (OCH2), 57.2 (d), 45.6 (d), 25.2
(q), 21.0 (q), 20.8 (q), 19.1 (q), 18.9 (q); IR (CHCl3): nmax¼2966, 1750,
1640, 1441 cmꢂ1; HRMS [APCI]: m/z: calcd for C31H35N2O6S2:
595.1940; found: 595.1940 [MþH]þ.
(400 MHz, CDCl3):
1H, 2-H), 7.65e7.63 (m, 4H), 7.39e7.20 (m, 9H), 5.28 (s, 2H, CH2O),
1.03 (s, 9H, tBu); 13C NMR (100 MHz, CDCl3):
d¼9.95 (s, 1H, CHO), 9.31 (br s, 1H, NH), 7.78 (s,
4.1.4. Ethyl (2RS,3RS)- and (2RS,3SR)-5,5-dimethyl-1-(4-
toluenesulfonyl)-3-[1-(4-toluenesulfonyl)indol-3-yl]-pyrrolidine-2-
carboxylate 28 and 29. The foregoing sulfonamide 26 (30 mg,
d¼186.1 (CHO), 162.6
(s), 149.8 (s), 136.1 (s), 135.6 (d), 134.8 (d), 133.7 (s), 129.6 (d), 127.7
(d), 123.8 (d), 120.2 (d), 111.9 (d), 65.7 (CH2O), 26.9 (q), 25.2 (s); IR
(CHCl3): nmax¼2931, 1667, 1427, 1112 cmꢂ1; m/z [APCI] 414 (MþHþ,
60%), 74 (100).
50.0 mmol) was dissolved in dry chloroform (3 mL) containing triflic
acid (45 mg, 0.60 equiv) and the resulting solution refluxed for 1 h
then cooled and neutralised with saturated aqueous sodium car-
bonate. The two layers were separated and the aqueous layer
extracted with dichloromethane (2ꢃ10 mL). The combined organic
solutions were dried and filtered through a pad of silica gel and the
combined filtrates and washings evaporated to leave the pyrroli-
dines 28 and 29 (25 mg, 83%) in a ca. 2:1 ratio, as a yellowish solid,
4.1.7. 4-[(tert-Butyldiphenylsilyloxy)methyl]-1-(4-toluenesulfonyl)
indole-3-carboxaldehyde 36. The indole-3-carboxaldehyde 35
(7.30 g, 18.0 mmol) was N-tosylated as described above for the
preparation of the sulfonamide 26 and was purified by column
chromatography to give the N-tosyl indole-3-carboxaldehyde 36
(8.50 g, 85%) as an off-white solid, mp 123e126 ꢁC; 1H NMR
mp 107e110 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼(major) 7.90 (d,
J¼8.4 Hz, 1H, 70-H), 7.78 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.65e7.60 (m,
3H), 7.32e7.08 (m, 7H), 4.43 (d, J¼8.5 Hz, 1H, 2-H), 4.15e4.00 (m,
2H, OCH2), 3.59 (td, J¼8.5, 8.1 Hz, 1H, 3-H), 2.38 (s, 3H, ArMe), 2.27
(s, 3H, ArMe), 2.02e1.93 (m, 2H, 4-CH2), 1.54 (s, 3H, 5-Me), 1.29 (s,
3H, 5-Me), 1.11 (t, J¼7.1 Hz, 3H, CH2CH3); (minor) 7.88 (d, J¼8.3 Hz,
1H, 70-H), 7.67 (app. d, J¼8.2 Hz, 4H, 4ꢃ ArH), 7.44 (d, J¼8.0 Hz, 1H,
40-H), 7.32e7.08 (m, 6H), 4.70 (d, J¼4.3 Hz, 1H, 2-H), 3.63 (td, J¼7.9,
4.3 Hz, 1H, 3-H), 3.09 (dq, J¼10.7, 7.2 Hz, 1H, OCHa), 2.75 (dq, J¼10.7,
7.2 Hz, 1H, OCHb), 2.32 (s, 3H, ArMe), 2.25 (s, 3H, ArMe), 2.02e1.93
(m, 2H, 4-CH2), 1.73 (s, 3H, 5-Me), 1.59 (s, 3H, 5-Me), 0.09 (t,
J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3; some resonances
(400 MHz, CDCl3):
d
¼9.98 (s, 1H, CHO), 8.22 (s, 1H, 2-H), 7.82 (d,
J¼8.3 Hz, 2H, 2ꢃ ArH), 7.78 (d, J¼8.3 Hz, 2H, 2ꢃ ArH), 7.58e7.54 (m,
4H), 7.40e7.10 (m, 10H), 5.14 (s, 2H, CH2O), 2.31 (s, 3H, ArMe), 0.99
t
(s, 9H, Bu); 13C NMR (100 MHz, CDCl3):
d¼185.7 (CHO), 162.7 (s),
135.6 (s), 135.4 (d), 134.8 (d), 134.3 (s), 133.4 (s), 130.3 (s), 130.2 (d),
129.7 (d), 127.7 (d), 127.3 (d), 127.1 (s), 125.9 (d), 123.0 (d), 112.4 (d),
65.3 (CH2O), 26.9 (q), 21.9 (q), 19.4 (s); IR (CHCl3): nmax¼2931, 2856,
1748, 1562, 1427, 1373 cmꢂ1
; HRMS [APCI]: m/z: calcd for
C33H34NO4SSi: 568.1972; found: 568.1968 [MþH]þ.
4.1.8. Ethyl (E)- and (Z)-3-{4-[(tert-butyldiphenylsilyloxy)methyl]-1-
(4-toluenesulfonyl)indole-3-yl}-2-nitroacrylate 37. Following the
same method used to prepare the nitroacrylate 24, reaction be-
tween the foregoing N-tosyl indole-3-carboxaldehyde 36 (3.70 g,
6.50 mmol) and ethyl nitroacetate (0.74 mL, 6.50 mmol) gave the
nitroacrylate 37 (1.91 g, 43%) as an orange-brown solid, mp
obscured):
d
¼(major) 171.3 (CO), 151.1 (s), 150.2 (s), 146.3 (s), 136.7
(s), 135.2 (s), 130.2 (d), 129.6 (d), 126.7 (d), 125.8 (d), 124.2 (d), 121.8
(d), 119.6 (d), 113.8 (d), 59.3 (OCH2), 56.5 (2-CH), 42.5 (5-C), 42.1 (4-
CH2), 25.9 (3-CH), 25.2 (q), 24.7 (q), 21.3 (q), 21.1 (q), 17.8 (q);
(minor) 169.2 (CO), 151.3 (s), 149.9 (s), 146.3 (s), 136.9 (s), 135.0 (s),
132.6 (s), 130.4 (d), 129.1 (d), 126.3 (d), 125.9 (d), 124.2 (d), 121.3 (d),
119.8 (d), 118.3 (d), 112.5 (d), 54.2 (OCH2), 56.2 (2-CH), 43.7 (5-C),
42.6 (4-CH2), 25.0 (3-CH), 24.9 (q), 24.3 (q), 21.2 (q), 21.1 (q), 13.6
131e135 ꢁC (MeOH); 1H NMR (400 MHz, CDCl3):
d
¼(major isomer)
8.42 (s, 1H, 3-H), 7.89 (s, 1H, 20-H), 7.87e7.68 (m, 3H), 7.53e7.49 (m,
4H), 7.34e7.10 (m, 10H), 4.84 (s, 2H, CH2O), 4.26 (q, J¼7.1 Hz, 2H,

ꢀ
C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8524
OCH2), 2.30 (s, 3H, ArMe), 1.12 (t, J¼7.1 Hz, 3H, CH2CH3), 0.99 (s, 9H,
tBu); (minor isomer) 8.90 (s, 1H, 3-H), 8.07 (s, 1H, 20-H), 7.87e7.68
(m, 3H), 7.53e7.49 (m, 4H), 7.34e7.10 (m, 10H), 4.84 (s, 2H, CH2O),
4.40 (q, J¼7.1 Hz, 2H, OCH2), 2.31 (s, 3H, ArMe), 1.35 (t, J¼7.1 Hz, 3H,
138.2 (s), 133.9 (s), 130.3 (d), 127.5 (d), 125.8 (d), 124.9 (d), 121.6 (d),
120.5 (d),119.8 (d),115.8 (s),113.6 (d), 78.3 (d), 58.6 (OCH2), 34.5 (d),
25.7 (q), 20.9 (q), 18.2 (q), 15.4 (q); IR (CHCl3): nmax¼1740 cmꢂ1; m/z
[APCI] 551 (81BrꢂMþHþ,100%), 549 (79BrꢂMþHþ,100%); HRMS: m/
t
79
CH2CH3), 0.99 (s, 9H, Bu); m/z [APCI] 683 (MþHþ, 30%), 427 (Mþ-
z: calcd for C24
H
BrN2O6S: 549.0695; found: 549.0699 [MþH]þ.
26
TBDPSO, 100).
4.1.11. Ethyl (2RS,3RS)- and (2RS,3SR)-3-[4-bromo-1-(toluene-
sulfonyl)indole-3-yl]-5-methyl-2-(4-toluenesulfonylamino)-hex-4-
enoate 43. The foregoing nitro-ester 42 (1.00 g, 1.80 mmol) was
dissolved in glacial acetic acid (20 mL) and zinc dust (3.61 g,
55.0 mmol) was added in portions during 10 min. The resulting
mixture was stirred at ambient temperature for 1 h then filtered
and basified using 2 M aqueous sodium hydroxide. Dichloro-
methane (50 mL) was added, the mixture shaken and the resulting
two layers separated. The organic solution was washed with satu-
rated aqueous sodium carbonate (10 mL) then dried, filtered and
evaporated to leave the free amine as a pale yellow oil which was
immediately tosylated as described above for the preparation of the
sulfonamide 26. The final product 43 was formed as a 2:1 mixture
of diastereoisomers, which were separated by column chroma-
tography (2:1 EtOAc/petrol) to give:
4.1.9. Ethyl (E)- and (Z)-3-[4-bromo-1-(4-toluenesulfonyl)indole-3-
yl]-2-nitroacrylate
41. 4-Bromo-1-(4-toluenesulfonyl)indole-3-
carboxaldehyde23,40 (2.50 g, 6.50 mmol), prepared from 4-
bromoindole 40,19,21 as described above, was condensed with
ethyl nitroacetate (0.74 mL, 6.50 mmol) using titanium(IV) chloride
(1.48 mL, 13.0 mmol), as described for nitroacrylate 24, to give the
nitroacrylate 41 (2.00 g, 63%) as an orange solid and a 1.3:1 mixture
of stereoisomers, mp 112e115 ꢁC; C20H17BrN2O6S: calcd C 48.7, H
3.4; N 5.7; found: C 48.5, H 3.6, N 5.6%; 1H NMR (400 MHz, CDCl3):
d
¼(major) 8.54 (s, 1H; 3-H), 7.92 (d, J¼8.7 Hz, 1H; 70-H), 7.90 (s, 1H;
20-H), 7.72 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.41 (d, J¼8.0 Hz, 1H, 50-H),
7.28 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.22 (dd, J¼8.7, 8.0 Hz, 1H, 60-H),
4.35e4.30 (m, 2H, OCH2), 2.31 (s, 3H; ArMe), 1.35e1.30 (m, 3H,
CH2CH3); (minor) 9.05 (s, 1H; 3-H), 8.11 (s, 1H; 20-H), 7.93 (d,
J¼8.6 Hz, 1H; 70-H), 7.73 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.42 (d, J¼8.1 Hz,
1H, 50-H), 7.28 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.24e7.21 (m, 1H, 60-H),
4.35e4.30 (m, 2H, OCH2), 2.31 (s, 3H; ArMe), 1.35e1.30 (m, 3H,
(i) The major isomer as a colourless crystalline solid, mp
145e149 ꢁC; [C31H33BrN2O6S2: calcd C 55.3, H 4.9; N 4.2; found: C
55.5, H 5.2, N 4.0%]; 1H NMR (400 MHz, CDCl3):
d
¼7.74 (d, J¼8.2 Hz,
CH2CH3); 13C NMR (100 MHz, CDCl3):
d¼(major) 171.6 (CO), 162.3
1H, 70-H), 7.69 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.46 (s, 1H, 20-H), 7.33 (d,
J¼8.2 Hz, 2H, 2ꢃ ArH), 7.28 (d, J¼8.0 Hz, 1H, 50-H), 7.23 (app. d,
J¼8.2 Hz, 4H, 4ꢃ ArH), 7.01 (dd, J¼8.2, 8.0 Hz, 1H, 60-H), 6.97 (d,
J¼8.2 Hz, 2H, 2ꢃ ArH), 5.29 (d, J¼10.3 Hz,1H, 4-H), 5.18 (d, J¼10.0 Hz,
1H, NH), 5.02 (dd, J¼10.3, 7.2 Hz,1H, 3-H), 4.33 (dd, J¼10.0, 7.2 Hz,1H,
2-H), 3.98e3.90 (m, 2H, OCH2), 2.26 (s, 3H, ArMe), 2.23 (s, 3H, ArMe),
(s), 159.8 (s), 147.3 (s), 146.7 (s), 136.0 (s), 134.8 (s), 133.2 (s), 130.8
(d), 129.3 (d), 127.6 (d), 127.4 (d), 127.0 (d), 125.5 (d), 113.4 (d), 63.5
(t), 22.1 (q), 14.4 (q); (minor; some resonances obscured or co-
incident with major) 172.4 (CO), 162.4 (s), 159.6 (s), 147.5 (s), 136.4
(s), 133.7 (s), 130.5 (d), 129.9 (d), 127.4 (d), 127.3 (d), 125.8 (d), 112.3
(d), 64.1 (t), 22.1 (q), 14.5 (q); IR (KBr): nmax¼2922, 1722, 1632, 1530,
1.68 (s, 3H, Me), 1.49 (s, 3H, Me), 1.06 (t, J¼7.1 Hz, 3H, CH2CH3); 13
C
1463, 1377 cmꢂ1
;
m/z [APCI] 494
(
81BrꢂMþHþ, 100%), 492
NMR (100 MHz, CDCl3):
d
¼170.3 (CO), 145.4 (s), 143.7 (s), 137.1 (s),
79
(
79BrꢂMþHþ, 100%); HRMS: m/z: calcd for C20
H
BrN3O6S:
136.5 (s), 135.9 (s), 134.6 (s), 130.1 (d), 129.4 (d), 128.3 (d), 128.0 (d),
127.3 (d), 127.0 (d), 125.8 (d), 125.4 (d), 121.9 (d), 120.7 (s), 114.0 (s),
112.8 (d), 61.1 (OCH2), 60.0 (d), 29.7 (d), 26.0 (q), 21.6 (q), 21.5 (q),18.8
21
510.0329; found: 510.0329 [MþNH4]þ.
4.1.10. Ethyl (2RS,3RS)- and (2RS,3SR)-3-[4-bromo-1-(4-
toluenesulfonyl)indole-3-yl]-5-methyl-2-nitrohex-4-enoate 42. Zinc
chloride (1.70 g, 12.1 mmol) was stirred in ice-cold tetrahydrofuran
(10 mL) and 2-methyl-1-propenylmagnesium bromide (36.0 mL of
a 0.5 M solution in toluene, 18.0 mmol) was added dropwise. The
resulting pale yellow solution was stirred at this temperature for
0.25 h then transferred via cannula to a second flask, which con-
tained an ice-cold, stirred solution of the foregoing nitroacrylate 41
(2.00 g, 4.10 mmol) in tetrahydrofuran (20 mL). The resulting mix-
ture was stirred for 2 h without further cooling then quenched using
aqueouspH 8 bufferand theseparated aqueous layerextractedusing
ether (2ꢃ30 mL). The combined organic solutions were dried, fil-
tered and evaporated and the residue separated using column
chromatography (70% dichloromethane/petrol) to give the nitro-
ester 42 (2.00 g, 90%) as a bright yellow oily solid and as a mixture of
two diastereoisomers which showed: 1H NMR (400 MHz, CDCl3):
(q),13.7(q); IR (CHCl3):nmax¼2924,1741,1596,1411,1370,1164cmꢂ1
;
m/z [APCI] 676 (81BrꢂMþHþ, 100%), 674 (79BrꢂMþHþ, 100%);
79
HRMS: m/z: calcd for C31
[MþNH4]þ and
H BrN3O6S2: 690.1307; found: 690.1305
37
(ii) The minor isomer, also as a colourless crystalline solid, mp
138e141 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼7.82 (d, J¼8.1 Hz, 1H, 70-
H), 7.66 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.51 (d, J¼8.2 Hz, 2H, 2ꢃ ArH),
7.36 (s, 1H, 20-H), 7.29 (d, J¼8.1 Hz, 1H, 50-H), 7.16 (d, J¼8.3 Hz, 2H,
2ꢃ ArH), 7.11 (d, J¼8.3 Hz, 2H, 2ꢃ ArH), 7.03 (dd, J¼8.1, 8.1 Hz, 1H,
60-H), 5.27 (d, J¼10.4 Hz, 1H, 4-H), 5.15 (d, J¼10.0 Hz, 1H, NH), 4.90
(dd, J¼10.4, 7.3 Hz, 1H, 3-H), 4.20 (dd, J¼10.0, 7.3 Hz, 1H, 2-H), 4.05
(q, J¼7.2 Hz, 2H, OCH2), 2.31 (s, 3H, ArMe), 2.26 (s, 3H, ArMe), 1.68
(s, 3H, Me), 1.56 (s, 3H, Me), 0.81 (t, J¼7.2 Hz, 3H, CH2CH3); IR
(CHCl3): nmax¼2928, 1743, 1416, 1382, 1156 cmꢂ1; m/z [APCI] 676
(
81BrꢂMþHþ, 100%), 674 (79BrꢂMþHþ, 100%); HRMS: found:
690.1304 [MþNH4]þ.
d
¼(major isomer) 7.86 (d, J¼8.2 Hz, 1H, 70-H), 7.61 (d, J¼8.2 Hz, 2H,
2ꢃ ArH), 7.50 (s, 1H, 20-H), 7.35 (d, J¼8.4 Hz, 1H, 50-H), 7.19 (d,
J¼8.2 Hz, 2H, 2x ArH), 7.07 (dd, J¼8.4, 8.1 Hz,1H, 60-H), 5.82e5.76 (m,
1H, 4-H), 5.59e5.48 (m, 2H, 2- and 3-H), 4.26 (q, J¼7.1 Hz, 2H, OCH2),
2.28 (s, 3H, ArMe), 1.86 (s, 3H, Me), 1.67 (s, 3H, Me), 1.29 (t, J¼7.1 Hz,
3H, CH2CH3); (minor isomer) 7.86 (d, J¼8.2 Hz, 1H, 70-H), 7.62 (d,
J¼8.3Hz, 2H, 2ꢃ ArH), 7.50 (s, 1H, 20-H), 7.35 (d, J¼8.4 Hz, 1H, 50-H),
7.17 (d, J¼8.3Hz, 2H, 2x ArH), 7.07 (dd, J¼8.4, 8.1 Hz, 1H, 60-H),
5.82e5.76 (m,1H, 4-H), 5.59e5.48 (m, 2H, 2-and 3-H), 4.13e4.06 (m,
2H, OCH2), 2.28 (s, 3H, ArMe),1.73 (s, 3H, Me),1.70 (s, 3H, Me),1.14 (t,
4.1.12. 3-(3-Hydroxy-3-methyl-1-buten-1-yl)-1-(4-toluenesulfonyl)
indole 47. N-Tosylindole-3-carboxaldehyde 23 (3.00 g, 10.0 mmol)
was dissolved in dry tetrahydrofuran (50 mL), the solution cooled
to ꢂ78 ꢁC and 2-methyl-1-propenylmagnesium bromide (40 mL of
a 0.5 M solution in toluene, 20.0 mmol) added dropwise. The
resulting solution was stirred overnight without further cooling
then quenched by the addition of saturated aqueous ammonium
chloride (100 mL) and diluted with ether (50 mL). The two layers
were separated and the aqueous layer extracted with ether
(2ꢃ50 mL). The combined organic solutions were dried, filtered and
evaporated and the crude product separated by column chroma-
tography (dichloromethane) to give the alcohol 47 (3.20 g, 90%), as
J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
¼(major isomer)
d
171.3 (CO), 152.2 (s), 150.1 (s), 144.2 (s), 138.9 (s), 133.6 (s), 129.9 (d),
127.1 (d), 126.2 (d), 125.8 (d), 121.6 (d), 120.1 (d), 119.3 (d), 115.2 (s),
114.3 (d), 87.4 (d), 58.8 (OCH2), 33.7 (d), 25.6 (q), 20.8 (q), 19.2 (q),
18.1 (q); (minor isomer) 168.8 (CO), 152.2 (s), 150.3 (s), 144.8 (s),
a pale yellow oil which showed 1H NMR (400 MHz, CDCl3):
(d, J¼7.1 Hz, 1H, 7-H), 7.67 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.64 (d,
d
¼7.91

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C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8525
J¼8.2 Hz, 1H, 4-H), 7.50 (s, 1H, 2-H), 7.24 (t, J¼7.2 Hz, 1H, 6-H), 7.19
(t, J¼8.2 Hz, 1H, 5-H), 7.18 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 6.86 (d,
J¼16.2 Hz,1H, 10-H), 6.34 (d, J¼16.2 Hz,1H, 20-H), 2.22 (s, 3H, ArMe),
7.32 (d, J¼8.2 Hz, 1H, 50-H), 7.25 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 6.52 (d,
J¼16.2 Hz, 1H, 3-H), 4.26 (q, J¼7.2 Hz, 2H, OCH2), 2.35 (s, 3H, ArMe),
1.27 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR (100 MHz, CDCl3):
¼173.2
d
1.33 (s, 6H, 2ꢃ Me); 13C NMR (100 MHz, CDCl3):
d
¼144.0 (s), 137.9
(CO),167.1 (s),145.6 (s),135.6 (d),134.7 (s),130.3 (d),128.5 (d),127.3
(d), 125.5 (d), 124.1 (d), 120.7 (d), 118.3 (d), 117.9 (d), 113.8 (d), 60.6
(OCH2), 21.6 (q), 14.4 (q); IR (CHCl3): nmax¼1712, 1640, 1446, 1364,
1316 cmꢂ1; m/z [APCI] 369 (Mþ,100%), 86 (44); HRMS: m/z: calcd for
C20H20NO4S: 370.1105; found: 370.1108 [MþH]þ.
(s), 134.4 (s), 131.8 (s), 128.8 (d), 128.1 (s), 125.8 (d), 123.9 (d), 122.5
(d), 119.8 (d), 119.3 (d), 116.2 (d), 115.9 (d), 112.7 (d), 70.0 (s), 20.5
(q), 17.3 (q); IR (CHCl3): nmax¼3584, 2970, 1597, 1446 cmꢂ1; m/z
[APCI] 356 (MþHþ, 28%), 338 (MþꢂOH, 100); HRMS: m/z: calcd for
C20H22NO3S: 356.1320; found: 356.1325 [MþH]þ.
4.1.16. Ethyl (E)-5-methyl-3-[1-(4-toluenesulfonyl)indol-3-yl]hex-4-
enoate 50. Copper(I) thiophenolate (0.24 g, 1.70 mmol) was sus-
pended in dry tetrahydrofuran (10 mL) and the mixture stirred at
ꢂ40 ꢁC during the dropwise addition of 2-methyl-1-
propenylmagnesium bromide (10 mL of a 0.5 M solution in tetra-
hydrofuran, 5.00 mmol) and the resulting mixture warmed to 0 ꢁC
during 1 h. The resulting green solution was re-cooled to ꢂ40 ꢁC
and a solution of the foregoing enoate 49 (0.63 g, 1.70 mmol) in dry
tetrahydrofuran (20 mL) was added dropwise after which the
mixture was warmed to ambient temperature and stirred for 2 h
before the addition of saturated aqueous ammonium chloride
(20 mL). The resulting mixture was filtered and the solid washed
with ether (10 mL). The combined filtrate was separated and the
aqueous portion extracted with ether (2ꢃ10 mL). The combined
organic solutions were washed with saturated aqueous sodium
carbonate (3ꢃ20 mL) then dried, filtered and evaporated. The crude
product was filtered through silica gel eluted with dichloro-
methane to give the hexenoate 50 (0.585 g, 81%) as a pale yellow
4.1.13. 3-(1-Hydroxy-3-methyl-2-buten-1-yl)-1-(4-toluenesulfonyl)
indole 46. The foregoing reaction was repeated on exactly the same
scale but was maintained at ꢂ78 ꢁC for only 2 h after the addition of
the Grignard reagent then quenched at this temperature and
worked up in exactly the same manner to give, without chroma-
tography, the alcohol 46 (2.90 g, 81%) as a yellow oily solid; 1H NMR
(400 MHz, CDCl3):
d
¼7.87 (d, J¼8.2 Hz, 1H, 7-H), 7.64 (d, J¼8.2 Hz,
2H, 2ꢃ ArH), 7.52 (d, J¼7.9 Hz, 1H, 4-H), 7.42 (s, 1H, 2-H), 7.19 (t,
J¼8.2 Hz,1H, 6-H), 7.10 (dd, J¼8.2, 7.9 Hz,1H, 5-H), 7.04 (d, J¼8.2 Hz,
2H, 2ꢃ ArH), 5.83 (d, J¼8.8 Hz, 1H, 20-H), 5.40 (dd, J¼8.8, 1.3 Hz, 1H,
10-H), 2.45 (d, J¼1.3 Hz, 1H, OH), 2.17 (s, 3H, ArMe), 1.65 (s, 3H, Me),
1.55 (s, 3H, Me); IR (CHCl3): nmax¼3590, 1597, 1446, 1388 cmꢂ1; m/z
[APCI] 338 (MþꢂOH, 100%).
The sample was contaminated with ca. 15% of the derived diene
48 (see below).
4.1.14. 3-(3-Methyl-1,3-butadien-1-yl)-1-(4-toluenesulfonyl)indole
48. The foregoing crude alcohol 46 (0.52 g, 1.50 mmol) was dis-
solved in dry pyridine (5 mL) and treated with either acetic anhy-
dride (0.18 mL, 1.80 mmol) or ethyl chloroformate (0.17 mL,
1.80 mmol). A few crystals of DMAP were then added and the
resulting solutions stirred at ambient temperature for 6 h then
poured into a stirred mixture of water (10 mL) and ether (10 mL).
The separated aqueous layers were extracted with ether (10 mL)
and the combined organic solutions washed with saturated aque-
ous copper(II) sulfate (4ꢃ10 mL) then water (10 mL) before being
dried and filtered through a pad of silica gel. Evaporation of the
combined filtrates and washings left the diene 48 (0.39 g, 81% from
Ac2O and 0.41 g, 84%, from ClCO2Et) as a yellow oily solid; 1H NMR
solid, mp 108e112 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼8.18 (d,
J¼8.2 Hz, 1H, 70-H), 7.66 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.43 (d, J¼7.9 Hz,
1H, 40-H), 7.21e7.05 (m, 5H), 5.13 (d, J¼9.7 Hz, 1H, 4-H), 4.19e4.15
(m, 1H, 3-H), 3.99 (q, J¼7.2 Hz, 2H, OCH2), 2.73 (dd, J¼14.7, 6.2 Hz,
1H, 2-Ha), 2.51 (dd, J¼14.7, 8.8 Hz, 1H, 2-Hb), 2.27 (s, 3H, ArMe), 1.67
(s, 3H, Me), 1.63 (s, 3H, Me), 1.10 (t, J¼7.2 Hz, CH2CH3); 13C NMR
(100 MHz, CDCl3):
d
¼171.8 (CO), 144.8 (s), 135.4 (s), 135.2 (s), 133.8
(s), 130.1 (s), 129.6 (d), 127.0 (d), 125.6 (s), 125.3 (d), 124.8 (d), 123.8
(d), 121.4 (d), 119.9 (d), 113.8 (d), 60.0 (OCH2), 40.4 (2-CH2), 32.5 (3-
CH), 25.8 (q), 22.6 (q), 18.2 (q), 14.2 (q); IR (CHCl3): nmax¼2980,
2924, 1762, 1447 cmꢂ1; m/z [APCI] 425 (Mþ, 54%), 91 (100); HRMS:
m/z: calcd for C24H31N2O4S: 443.1999; found: 443.1998 [MþNH4]þ.
(400 MHz, CDCl3):
d
¼7.91 (d, J¼8.2 Hz, 1H, 7-H), 7.66 (d, J¼7.7 Hz,
1H, 4-H), 7.65 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.20e7.17 (m, 2H, 5- and 6-
H), 7.06 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 6.87 (d, J¼16.3 Hz, 1H, 10-H), 6.49
(d, J¼16.3 Hz, 1H, 20-H), 5.04 (app. s, 1H, 40-Ha), 5.07 (app. s, 1H, 40-
Hb), 2.17 (s, 3H, ArMe), 1.88 (s, 3H, 3-Me); 13C NMR (100 MHz,
4.1.17. Ethyl (2RS,3RS)- and (2RS,3SR)-2-hydroxy-5-methyl-3-[1-(4-
toluenesulfonyl)indol-3-yl]hex-4-enoate 52. Potassium hexame-
thyldisilazide (KHMDS; 0.20 mL of a 1.6 M solution in toluene,
0.30 mmol) in tetrahydrofuran (5 mL) was stirred and cooled to
ꢂ78 ꢁC before a solution of the foregoing hexenoate 50 (85 mg,
0.20 mmol) in tetrahydrofuran (1 mL) was added dropwise. The
resulting orange solution was stirred for 20 min then a solution of 2-
(4-toluenesulfonyl)-3-phenyloxaziridine 51 (78 mg, 0.30 mmol)28
was added. After a further 20 min at this temperature, saturated
aqueous ammonium chloride (10 mL) was added, the resulting
mixture warmed to ambient temperature, the layers separated and
the aqueous layer extracted with ether (2ꢃ10 mL). The combined
organic solutions were dried, filtered and evaporated. Column
chromatography of the residue separated the hydroxy-ester 52
(68 mg, 76%) as a pale yellow oily solid and a 3:1 mixture of di-
astereoisomers which showed: 1H NMR (400 MHz, CDCl3):
CDCl3):
d
¼155.2 (s), 145.0 (s), 138.9 (s), 135.5 (s), 135.3 (s), 130.3 (d),
129.9 (d), 126.8 (d),126.7 (s),126.3 (d),125.0 (d), 123.7 (d),123.4 (d),
120.3 (d), 117.2 (:CH2), 113.8 (d), 29.9 (q), 21.4 (q); IR (CHCl3):
nmax¼2855, 1597, 1447 cmꢂ1; m/z 338 (MþHþ, 100%); HRMS: m/z:
calcd for C20H20NO2S: 338.1205; found: 338.1209 [MþH]þ.
4.1.15. Ethyl (E)-3-[1-(4-toluenesulfonyl)indole-3-yl]propenoate 49.
Lithium chloride (0.17 g, 4.00 mmol) was suspended in dry ace-
tonitrile (10 mL), triethyl orthophosphonoacetate (0.80 mL,
4.00 mmol) was added followed by DBN (0.40 mL, 3.30 mmol) and
the resulting mixture stirred at ambient temperature for 0.25 h. A
solution of the indole-3-carboxaldehyde 23 (1.00 g, 3.30 mmol) in
dry acetonitrile (20 mL) was then added dropwise and stirring
continued at the same temperature with TLC monitoring. Upon
completion of the reaction (ca. 2 h), saturated aqueous ammonium
chloride (50 mL) and ether (40 mL) were added and the resulting
two layers separated. The organic fraction was washed with water
(2ꢃ50 mL) then dried, filtered and evaporated. Further filtration
through a pad of silica gel eluted with EtOAc/petrol (1:3) separated
the enoate 49 (0.94 g, 77%) as an off-white solid, mp 136e138 ꢁC; 1H
d
¼(major isomer) 7.78 (d, J¼8.0 Hz, 1H, 70-H), 7.55 (d, J¼8.2 Hz, 2H,
2ꢃ ArH), 7.40e7.36 (m, 2H, 20- and 40-H), 7.19 (d, J¼8.2 Hz, 2H, 2ꢃ
ArH), 7.15e7.10 (m, 2H, 50- and 60-H), 5.43 (d, J¼9.5 Hz,1H, 4-H), 4.29
(d, J¼3.8 Hz,1H, 2-H), 4.08 (dd, J¼9.5, 3.8 Hz,1H, 3-H), 3.83e3.78 (m,
2H, OCH2), 2.14 (s, 3H, ArMe),1.59 (s, 3H, Me),1.53 (s, 3H, Me),1.11 (t,
J¼7.1 Hz, 3H, CH2CH3); (minor isomer) 7.79 (d, J¼8.1 Hz, 1H, 70-H),
7.60 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.40e7.36 (m, 2H, 20- and 40-H), 7.19 (d,
J¼8.2 Hz, 2H, 2ꢃ ArH), 7.15e7.10 (m, 2H, 50- and 60-H), 5.33 (d,
J¼9.3 Hz,1H, 4-H), 4.36 (d, J¼3.0 Hz,1H, 2-H), 3.99 (dd, J¼9.3, 3.0 Hz,
1H, 3-H), 3.83e3.78 (m, 2H, OCH2), 2.14 (s, 3H, ArMe), 1.58 (s, 3H,
NMR (400 MHz, CDCl3):
d
¼8.01 (d, J¼8.2 Hz,1H, 70-H), 7.85 (s,1H, 20-
H), 7.82e7.77 (m, 4H, 2-, 40- and 2ꢃ ArH), 7.39 (t, J¼8.2 Hz,1H, 60-H),

ꢀ
C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8526
Me), 1.51 (s, 3H, Me), 0.85 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR
(d), 129.5 (d), 128.9 (d), 127.7 (d), 127.1 (d), 124.9 (d), 124.0 (d), 119.6
(d), 113.2 (d), 64.6 (t), 60.4 (t), 28.3 (q), 21.7 (q), 19.8 (s), 14.5 (q); IR
(CHCl3): nmax¼2935, 2922, 1746, 1522, 1438 cmꢂ1; m/z [APCI] 638
(MþþH, 100%), 608 (31); HRMS: m/z: calcd for C37H40NO5SSi:
638.2396; found: 638.2392 [MþH]þ.
(100 MHz, CDCl3):
d
¼(major isomer) 178.3 (CO), 150.4 (s), 143.8 (s),
134.8 (s), 129.9 (s), 129.8 (d), 128.8 (d), 127.0 (s), 126.7 (d), 124.7 (d),
122.3 (d), 119.6 (d), 113.7 (d), 73.7 (2-CH), 61.7 (OCH2), 39.5 (3-CH),
25.9 (q), 21.6 (q), 18.2 (q), 13.9 (q); (minor isomer) 177.2 (CO), 149.1
(s),143.7 (s),134.1 (s),129.7 (s),129.2(d),128.5 (d),127.1 (s),126.9 (d),
124.7 (d),122.3 (d),119.8 (d),115.1 (d), 73.1 (2-CH), 61.9 (OCH2), 39.4
(3-CH), 26.0 (q), 21.6 (q),18.3 (q),14.1 (q) (tworesonances obscured);
IR (CHCl3): nmax¼3316, 2919, 1730, 1447, 1369 cmꢂ1; m/z [APCI] 442
(MþþH, 100%); HRMS: m/z: calcd for C24H28NO5S: 442.1683; found:
442.1685 [MþH]þ.
4.1.21. Ethyl 5-methyl-3-{[4-(tert-butyldiphenylsilyloxy)methyl]-1-
(4-toluenesulfonyl)indol-3-yl}hex-4-enoate 61. Using exactly the
same method as described above for the preparation of the hex-
enoate 50, reaction between the foregoing enoate 60 (1.60 g,
2.50 mmol), copper(I) thiophenolate (0.36 g, 2.50 mmol) and 2-
methyl-1-propenylmagnesium bromide (15.0 mL of a 0.5 M solu-
tion in tetrahydrofuran, 7.50 mmol) gave the hexenoate 61 (0.92 g,
4.1.18. Ethyl (2RS,3RS)- and (2RS,3SR)-2-azido-5-methyl-3-[1-(4-
toluenesulfonyl)indol-3-yl]hex-4-enoate 59. A solution of the indol-
3-yl hexenoate 50 (0.15 g, 0.35 mmol) in dry tetrahydrofuran (3 mL)
was added to a solution of KHMDS (0.78 mL of a 0.5 M solution in
toluene, 0.39 mmol) maintained at ꢂ78 ꢁC. The resulting orange
solutionwas stirred for 0.5 h at this temperature before a pre-cooled
solution of trisyl azide (0.136 g, 0.44 mmol) in tetrahydrofuran
(3 mL) was added. After a further 5 min, glacial acetic acid (0.09 mL,
1.60 mmol) was added and the mixture warmed to ambient tem-
perature and stirred for 0.5 h then dichloromethane (20 mL) and
diluted brine (40 mL) were added. The resulting two layers were
separated and the aqueous fraction extracted with dichloromethane
(20 mL). The combined organic solutions were washed with satu-
rated aqueous sodium hydrogen carbonate then dried, filtered and
evaporated. Column chromatography of the residue (1:3 EtOAc/
petrol) separated the azide 59 (0.105 g, 63%) as a thickpaleyellowoil;
53%) as a pale yellow semi-solid; 1H NMR (400 MHz, CDCl3):
d¼7.81
(d, J¼8.3 Hz, 1H, 70-H), 7.62e7.58 (m, 4H), 7.54 (d, J¼8.2 Hz, 2H, 2ꢃ
ArH), 7.30e7.10 (m, 11H), 5.14 (d, J¼13.8 Hz, 1H, 100-Ha), 4.99 (d,
J¼13.8 Hz,1H,100-Hb), 4.94 (d, J¼9.0 Hz,1H, 4-H), 4.14e4.10 (m,1H, 3-
H), 3.85 (q, J¼7.2 Hz, 2H, OCH2), 2.56 (dd, J¼14.9, 6.9 Hz, 1H, 2-Ha),
2.33 (dd, J¼14.9, 8.2 Hz,1H, 2-Hb), 2.27 (s, 3H, ArMe),1.40 (s, 3H, Me),
1.21 (s, 3H, Me), 0.99 (s, 9H, tBu), 0.98 (t, J¼7.1 Hz, CH2CH3); 13C NMR
(100 MHz, CDCl3):
d
¼171.3 (CO), 144.8 (s), 135.7 (s), 135.6 (d), 135.1
(s), 134.6 (s), 133.7 (s), 133.3 (s), 129.9 (s), 129.8 (d), 129.7 (d), 127.9
(d), 126.8 (d), 126.7 (d), 124.8 (d), 124.6 (d), 122.7 (d), 121.2 (d), 112.5
(d), 63.3 (t), 60.3 (t), 41.7 (2-CH2), 33.2 (3-CH), 25.5 (q), 21.6 (q), 19.4
(q), 19.1 (s), 18.0 (q), 14.1 (q); IR (CHCl3): nmax¼2946, 1748, 1535,
1477 cmꢂ1; m/z [APCI] 694 (MþþH, 32%), 437 (MꢂTBDPSO, 100).
4.1.22. Ethyl (2RS,3RS)- and (2RS,3SR)-2-azido-5-methyl-3-{4-[(tert-
butyldiphenylsilyloxy)methyl]-1-(4-toluenesulfonyl)-indol-3-yl}-hex-
4-enoate 62. Using exactly the same procedure as described above
for the synthesis of the azide 59, reaction between the homologous
hex-4-enoate derivative 61 (0.693 g, 1.00 mmol) in tetrahydrofuran
(5 mL) with KHMDS (2.6 mL of a 0.5 M solution in toluene, 1.30 mol)
and trisyl azide (0.34 g, 1.10 mmol) and finally chromatography in
dichloromethanegave the azide 62 (0.48 g, 66%) asessentiallya single
1H NMR (400 MHz, CDCl3):
d
¼7.79 (d, J¼8.1 Hz, 1H, 70-H), 7.67 (d,
J¼8.2 Hz, 2H, 2ꢃ ArH), 7.43e7.38 (m, 2H, 20- and 40-H), 7.24 (d,
J¼8.2 Hz, 2H, 2ꢃ ArH), 7.15e7.10 (m, 2H, 50- and 60-H), 5.18 (d,
J¼8.9 Hz,1H, 4-H), 4.31 (dd, J¼7.6, 4.1 Hz,1H, 2-H), 3.70 (q, J¼7.1 Hz,
2H, OCH2), 3.56e3.60 (m, 1H, 3-H), 2.26 (s, 3H, ArMe), 1.65 (s, 3H,
Me), 1.61 (s, 3H, Me), 0.92 (t, J¼7.1 Hz, CH2CH3); 13C NMR (100 MHz,
CDCl3):
d
¼173.1 (CO),150.1 (s),143.6 (s),144.2 (s),135.8 (s),134.8 (d),
131.5 (d), 129.2 (s), 128.9 (d), 128.0 (d), 125.2 (d), 124.3 (d), 113.4 (d),
66.5 (d), 59.8 (OCH2), 35.3 (3-CH), 28.3 (q), 22.3 (q), 21.0 (q),19.9 (q),
18.5 (q) (one sp2-C obscured); IR (CHCl3): nmax¼2962, 2109, 1739,
1598, 1447, 1370 cmꢂ1; m/z [APCI] 467 (Mþ, 80%), 438 (MꢂN2, 100).
diastereoisomer showing 1H NMR (400 MHz, CDCl3):
d¼7.78 (d,
J¼8.0 Hz,1H, 70-H), 7.63 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.52e7.42 (m, 5H),
7.37 (s, 1H, 20-H), 7.20e7.00 (m, 8H), 5.22 (d, J¼9.4 Hz,1H, 4-H), 4.97 (s,
2H, CH2OSi), 4.26e4.22 (m, 1H, 2-H), 3.81 (q, J¼7.2 Hz, 2H, OCH2),
3.72e3.67 (m,1H, 3-H), 2.22 (s, 3H, ArMe),1.53(s, 3H, Me),1.24 (s, 3H,
Me), 0.99 (s, 9H, But), 0.80 (t, J¼7.2 Hz, 3H, CH2CH3); 13C NMR
4.1.19. Ethyl (2RS,3RS)- and (2RS,3SR)-5-methyl-2-(4-
toluenesulfonylamino)-3-[1-(4-toluenesulfonyl)-indol-3-yl]-hex-4-
enoate 26. The foregoing azide 59 (25 mg) was dissolved in tetra-
hydrofuran (3 mL) containing triphenylphosphine (26 mg) and
water (0.03 mL) and the resulting solution refluxed for 6 h then
cooled and evaporated. The crude residue was N-tosylated as de-
scribed above for the preparation of the same sulfonamide 26 to
give a sample of this sulfonamide (20 mg, 59%), which showed
identical spectroscopic and analytical data, but which was isolated
as a 2:1 ratio of diastereoisomers.
(100 MHz, CDCl3):
d
¼169.9 (CO),148.1 (s),135.5 (s),134.7 (s),133.2 (s),
133.1 (d), 132.9 (d), 132.5 (s), 132.2 (s), 132.0 (s), 128.1 (d), 127.4 (d),
127.3 (d), 126.9 (d), 123.3 (d), 122.6 (d), 121.2 (d), 112.6 (d), 68.0 (d),
61.2 (t), 60.2 (t), 34.1 (d), 26.8 (q), 24.9 (q), 23.9 (q), 21.5 (q), 19.3 (q),
13.6 (s) (one sp2-Cobscured);IR(CHCl3):nmax¼2965, 2108,1743,1432,
1287 cmꢂ1; m/z 735 (MþþH, 21%), 706 MꢂN2, 100), 451 (87).
Starting material 61 (0.174 g, 25%) was also recovered.
4.1.23. Ethyl (2RS,3RS)- and (2RS,3SR)-2-(4-nitrobenzenesulf-
onylamino)-5-methyl-3-{4-[(tert-butyldiphenylsilyloxy)methyl]-1-
(4-toluenesulfonyl)-indol-3-yl}-hex-4-enoate 63. The foregoing
azide 62 (0.18 g, 0.24 mmol) was dissolved in tetrahydrofuran
(5 mL) containing triphenylphosphine (0.13 g, 0.48 mmol) and
water (0.5 mL, 0.5 mmol). The resulting solution was refluxed for
6 h the cooled and the volatiles evaporated to leave a crude amine,
IR (CHCl3): nmax¼3438, 2959, 1732, 1435, 1372 cmꢂ1 (the azide
stretch at 2108 cmꢂ1 was absent).
This crude material was dissolved in dry, ice-cold, stirred
dichloromethane (5 mL) and treated with 4-nitrobenzenesulfonyl
chloride (66 mg, 0.30 mmol), triethylamine (0.3 mL) and a crystal
of DMAP. The resulting solution was stirred overnight without
further cooling then evaporated and the residual paste separated
directly by column chromatography (dichloromethane) to give the
N-nosyl derivative 63 (0.12 g, 52%) as an off-white solid and a 4:1
mixture of diastereoisomers, mp 87e89 ꢁC. The major isomer
4.1.20. Ethyl (E)-3-{4-[(tert-butyldiphenylsilyloxy)methyl]-1-(4-
toluenesulfonyl)indol-3-yl]}propenoate 60. Following exactly the
same procedure as described above for the preparation of the
enoate 49, condensation of the indole-3-carboxaldehyde 36 (3.10 g,
5.50 mmol) with triethyl orthophosphonoacetate (1.5 mL,
7.00 mmol) using DBN (0.80 mL, 6.60 mmol) and finally column
chromatography in dichloromethane gave the enoate 60 (2.20 g,
62%) as an off-white solid, mp 93e97 ꢁC; 1H NMR (400 MHz,
CDCl3):
d
¼8.13 (d, J¼15.3 Hz, 1H, 3-H), 7.82 (s, 1H, 20-H), 7.81 (d,
J¼8.2 Hz, 1H, 70-H), 7.67 (d, J¼8.2 Hz, 2H, 2ꢃ ArH), 7.51 (d, J¼7.8 Hz,
4H, 2ꢃ2ꢃ ArH), 7.25e7.05 (m, 9H), 6.81 (d, J¼7.3 Hz, 1H, 50-H), 6.23
(d, J¼15.3 Hz, 1H, 2-H), 4.87 (s, 2H, CH2OSi), 4.12 (q, J¼7.1 Hz, 2H,
OCH2), 2.17 (s, 3H, ArMe), 1.14 (t, J¼7.1 Hz, 3H, CH2CH3); 13C NMR
(100 MHz, CDCl3):
d
¼176.8 (CO), 149.7 (s), 149.2 (s), 144.1 (s), 137.2
(d), 136.6 (s), 135.6 (d), 134.8 (d), 133.8 (s), 133.2 (s), 132.7 (s), 129.9

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C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8527
showed 1H NMR (400 MHz, CDCl3):
d
¼7.95 (d, J¼8.4 Hz, 1H, ArH),
yields after crystallisation from (aq) methanol or EtOAc/petrol.
Melting point data and literature references are given in Table 1.
7.87 (d, J¼8.3 Hz, 2H, 2ꢃ ArH), 7.70 (d, J¼8.2 Hz, 2H, 2ꢃ ArH),
7.68e7.50 (m, 7H), 7.38e7.00 (m, 10H), 5.45 (d, J¼9.8 Hz, 1H, NH),
5.21 (d, J¼12.4 Hz, 1H, 100-Ha), 5.18 (d, J¼10.1 Hz, 1H, 4-H), 4.97 (d,
J¼12.4 Hz, 1H, 100-Hb), 4.35 (dd, J¼9.7, 3.2 Hz, 1H, 2-H), 3.86 (dd,
J¼10.1, 3.2 Hz, 1H, 3-H), 3.80e3.70 (m, 2H, OCH2), 2.24 (s, 3H,
4.1.27. Detosylation of N-tosyl-indoles and -imidazolesdgeneral
procedure. The N-tosyl indole or imidazole 66 (0.50 mmol) was
dissolved in DMF (2 mL). Lithium hydroxide (48 mg, 2.00 mmol)
was added followed by thioglycolic acid (30 mL, 0.60 mmol). The
resulting solution was stirred at ambient temperature and the re-
action progress monitored by TLC. Once reaction was complete
(1.5e5 h), the solution was diluted with ethyl acetate (4 mL) and
water (2 mL) and the layers separated. The aqueous layer was
extracted with ethyl acetate (2ꢃ4 mL) and the combined organic
solutions washed with saturated aqueous sodium carbonate
(3ꢃ5 mL) then dried, filtered and evaporated to leave an essentially
pure NeH indole or imidazole 67. Each product was identified by
comparisons of mp and 1H NMR data with authentic material.
t
ArMe), 1.62 (s, 3H, Me), 1.24 (s, 3H, Me), 0.96 (s, 9H, Bu), 0.81 (t,
J¼7.1 Hz, CH2CH3); the bulk showed IR (CHCl3): nmax¼3290, 1740,
1610, 1435 cmꢂ1; m/z: [ES] 893 (Mþ, 100%).
4.1.24. Ethyl (6aRS,9SR,9aSR)-hexahydro-7,7-dimethyl-2-(4-
toluenesulfonyl)-8-(4-nitrobenzenesulfonyl)iso-indolo[4,5,6-cd]in-
dole-9-carboxylate 64. Triflic acid (20 mg) was added dropwise to
a stirred, ice-cold solutionof the foregoing sulfonamide 63 (60 mg) in
dry chloroform (2 mL). The cooling bath was removed and stirring
continued at ambient temperature for 1 h when saturated aqueous
sodium carbonate (2 mL) was added and the resulting layers sepa-
rated. The aqueous layer was extracted with chloroform (2ꢃ2 mL)
and the combined organic solutions washed with water (2 mL) then
dried, filtered and evaporated. The residue was separated using
preparative TLC (1:2 EtOAc/petrol) to give the pyrrolidine 64 (32 mg,
74%)as a yellowish solid, mp 90e93 ꢁC, which was essentiallya single
4.1.28. Indole 67a. 1-4-(Toluenesulfonyl)indole 66a (135 mg,
0.50 mmol) was detosylated by the general procedure during 3 h to
give indole 67a (50 mg, 86%) as a beige solid, mp 52e54 ꢁC [lit.41 mp
52e54 ꢁC], 1H NMR spectrum identical to the starting indole.
4.1.29. Indole-3-carboxaldehyde 22 (67b). 1-(4-Toluenesulfonyl)in-
dole-3-carboxaldehyde 66b (23) (150 mg, 0.50 mmol) was deto-
sylated using the general procedure during 1.5 h to give the
aldehyde 22 (67b) (69 mg, 95%) as an off-white solid, mp
197e199 ꢁC [lit.41 mp 195e198 ꢁC], 1H NMR (400 MHz, CDCl3):
stereoisomer, 1H NMR (400 MHz, CDCl3):
d¼8.22 (d, J¼8.3 Hz, 2H, 2ꢃ
ArH), 7.95 (d, J¼8.3 Hz, 2H, 2ꢃ ArH), 7.88 (d, J¼8.2 Hz, 2H, 2ꢃ ArH),
7.79 (d, J¼8.1 Hz,1H,ArH), 7.65e7.55 (m, 7H), 7.45 (d, J¼8.2 Hz, 2H, 2ꢃ
ArH), 7.37e7.00 (m, 5H), 6.90 (dd, J¼7.5, 3.3 Hz, 1H, ArH), 4.73 (d,
J¼9.5Hz,1H, 9-H), 3.86 (q, J¼7.1, 2H, OCH2), 3.57 (dd, J¼9.5, 4.1 Hz,1H,
9a-H), 2.80e2.65 (m, 2H), 2.28 (s, 3H, ArMe), 2.03 (td, J¼12.2, 4.1 Hz,
1H, 6a-H), 1.60 (s, 3H, Me), 1.54 (s, 3H, Me), 0.99 (t, J¼7.1 Hz, 3H,
d
¼9.62 (s, 1H, CHO), 8.86 (br s, 1H, NH), 8.03 (d, J¼7.3 Hz, 1H), 7.97
(s, 1H), 7.34 (d, J¼7.7 Hz, 1H), 7.20e6.95 (m, 2H).
Alternatively, the N-tosyl aldehyde 66b (23) (0.50 mmol) in DMF
was treated only with lithium hydroxide (48 mg, 2.00 mmol) and the
resulting mixture stirred at ambient temperature for 24 h (TLC
monitoring) before a similar work-up delivered an 82% yield (60 mg)
of thedetosylatedaldehyde 22(67b), which showed mp 196e198 ꢁC.
CH2CH3); 13C NMR (100 MHz, CDCl3):
d¼174.2 (CO), 169.9 (s), 150.0
(s),146.5 (s),145.1 (s),135.1 (s),134.9 (d),132.4 (s),130.0 (d),129.7 (s),
129.2 (d), 128.4 (d), 127.1 (s), 125.5 (d), 124.1 (d), 120.1 (d), 111.5 (d),
60.2 (OCH2), 58.7 (d), 46.5 (d), 35.6 (d), 28.9 (t), 28.8 (q), 26.6 (q), 23.6
(q), 21.6 (q) (the 7-C signal was not detected with certainty); IR
(CHCl3): nmax¼1740 cmꢂ1; m/z: [ES] 637 (Mþ, 12%), 618 (100).
4.1.30. Ethyl indole-3-ethanoate 67c. TheN-tosyl indole 66c(178 mg,
0.50 mmol) was detosylated using the general procedure for 3 h to give
the indole 67c (80 mg, 79%) as an off-while solid, mp 42e45 ꢁC [lit.41
4.1.25. Ethyl (6aRS,9SR,9aSR)-hexahydro-7,7-dimethylisoindolo
[4,5,6-cd]indole-9-carboxylate 65. The foregoing pyrrolidine
(25 mg, 0.04 mmol) was dissolved in ice-cold dimethylformamide
(2 mL) to which was then added lithium hydroxide (7.5 mg,
0.16 mmol) followed by thioglycolic acid (0.08 mL, 0.08 mmol). The
resulting solution was stirred without further cooling for 4 h then
diluted with ether (2 mL) and water (2 mL). The two layers were
separated and the aqueous layer extracted with ether (2ꢃ2 mL).
The combined organic solutions were washed with saturated
aqueous sodium carbonate (3ꢃ2 mL) then dried, filtered and
evaporated. Purification using preparative TLC (dichloromethane)
gave the deprotected indole 65 (9 mg, 80%) as an off-white solid, mp
mp 44e45 ꢁC], 1H NMR (400 MHz, CDCl3):
(d, J¼7.9 Hz, 1H), 7.30 (d, J¼8.1 Hz,1H), 7.20 (s, 2-H), 7.15e7.02 (m, 2H),
4.05 (q, J¼7.1 Hz, OCH2), 3.87 (s, 2H, 3-CH2), 1.19 (t, J¼7.1 Hz, CH3).
d
¼8.12 (br s, 1H, NH), 7.56
4.1.31. Ethyl (E)-3-(indol-3-yl)propenoate 67d. The N-tosyl indole
66d (49) (185 mg, 0.50 mmol) was detosylated according to the
general procedure during 3 h to give the indole-4-carboxylate 67d
(43 mg, 41%) as an off-white solid, mp 118e121 ꢁC [lit.42 mp
119.5e120 ꢁC], 1H NMR (400 MHz, CDCl3):
d
¼8.91 (br s, 1H, NH),
7.98 (d, J¼16.2 Hz, 1H, 2-H), 7.92e7.78 (m, 3H), 7.45e7.42 (m, 1H),
7.25e7.21 (m, 1H), 6.47 (d, J¼16.2 Hz, 1H, 3-H), 4.27 (q, J¼7.2 Hz, 2H,
OCH2), 1.35 (t, J¼7.2 Hz, 3H, CH3).
100e103 ꢁC; 1H NMR (400 MHz, CDCl3):
d¼8.12 (br s, 1H, NH), 7.23
(s, 1H, 1-H), 7.20e7.05 (m, 2H), 6.90e6.85 (m, 1H), 4.59 (d,
J¼10.3 Hz, 1H, 9-H), 3.72e3.68 (m, 2H, OCH2), 3.50e3.47 (m, 1H, 9a-
H), 3.02e2.95 (m, 2H, CH2), 2.50e2.40 (m, 1H, 6a-H), 1.62 (s, 3H,
Me), 1.51 (s, 3H, Me), 0.96 (t, J¼7.2 Hz, 3H, CH2CH3); m/z [APCI] 299
(MþHþ, 100%), 279 (65); HRMS [APCI]: m/z: calcd for C18H23N2O2:
299.1764; found: 299.1768 [MþH]þ.
4.1.32. 2-Phenylindole 67f. 2-Phenyl-1-4-(toluenesulfonyl)indole
66f (174 mg, 0.50 mmol) was detosylated by the general procedure
during 3 h to give 2-phenylindole 67f (85 mg, 87%) as an off-white
solid, mp 187e190 ꢁC [lit.41 mp 188e190 ꢁC], 1H NMR (400 MHz,
CDCl3):
d
¼8.62 (br s, 1H, NH), 7.61 (dd, J¼8.2, 1.3 Hz, 2H), 7.56 (d,
J¼7.8 Hz,1H), 7.40e7.33(m, 3H), 7.25e7.05 (m, 3H), 6.73 (s,1H, 3-H).
4.1.33. Tetrahydrocarbazole 67g. 1-(4-Toluenesulfonyl)tetrahy-
4.1.26. Preparation of N-tosylates 66. An NeH indole or imidazole
67 (2.00 mmol) was dissolved in triethylamine (30 mL) and tosyl
chloride (2.20 mmol) and DMAP (w20 mg) were added. The
resulting solution was stirred at ambient temperature overnight
then poured into a mixture of water (50 mL) and dichloromethane
(100 mL). The separated organic solution was washed with 2 M
hydrochloric acid (2ꢃ50 mL) and water (50 mL) then dried filtered
and evaporated. The residue was usually of sufficient purity to use
directly after high vacuum drying. If this were not the case, crys-
tallisation from methanol provided pure material, generally in >85%
drocarbazole 66g (163 mg, 0.50 mmol) was detosylated according
to the general procedure during 3 h to give tetrahydrocarbazole 67g
(69 mg, 80%) as a cream solid, mp 118e120 ꢁC [lit.41 mp
118e120 ꢁC], 1H NMR (400 MHz, CDCl3):
(d, J¼8.1 Hz,1H), 7.30 (d, J¼8.3 Hz,1H), 7.15e6.85 (m, 2H), 2.75 (app.
t, J¼5.8 Hz, 4H), 2.20e1.70 (m, 4H).
d
¼7.72 (br s, 1H, NH), 7.50
4.1.34. 1H-Carbazole 67h. The carbazole 66h (160 mg, 0.50 mmol)
was detosylated according to the general procedure during 5 h to

ꢀ
C.M. Griffiths-Jones (nee Haskins), D.W. Knight / Tetrahedron 67 (2011) 8515e8528
8528
Biochim. Biophys. Acta 1973, 309, 440e456; Neethling, D. C.; McGrath, R. M.
Can. J. Microbiol. 1977, 23, 856e872.
3. Fora standardised HPLC analysis method, see: Frisvad, J.; Thrane, U. J. Chromatogr.
give carbazole 67h (74 mg, 87%) as
a colourless solid, mp
246e248 ꢁC [lit.41 mp 243e246 ꢁC] 1H NMR (400 MHz, CDCl3):
d
¼9.03 (br s, 1H, NH), 8.08 (d, J¼7.7 Hz, 2H), 7.44e7.38 (m, 4H), 7.22
1987, 404, 195e214.
4. El-Banna, A. A.; Pitt, J. I.; Leistner, L. Syst. Appl. Microbiol. 1987, 10, 42e46.
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6. For a review of the biosynthesis of prenylated alkaloids, see: Williams, R. M.;
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8. Web of Science search for a-cyclopiazonic acid; 09/06/2011.
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6873e6874.
10. Muratake, H.; Natsume, M. Heterocycles 1985, 23, 1111e1117.
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J. A.; Parker, J. L. Aust. J. Chem. 1987, 40, 187e192; Takahashi, T.; Ootake, A.; Tsuji,
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(dt, J¼7.7, 1.4 Hz, 2H).
4.1.35. Methyl indole-4-carboxylate 67i. The N-tosyl indole 66i
(165 mg, 0.50 mmol) was detosylated according to the general
procedure to give the indole-4-carboxylate 67i (70 mg, 81%) as an
off-white solid, mp 64e67 ꢁC [lit.41 69e71 ꢁC], 1H NMR (400 MHz,
CDCl3):
d
¼8.36 (br s, 1H, NH), 7.86 (d, J¼7.7 Hz, 1H), 7.52 (d,
J¼7.7 Hz, 1H), 7.25e7.19 (m, 1H), 7.17 (t, J¼7.7 Hz, 1H), 7.11e7.06 (m,
1H), 3.92 (s, 3H, OMe).
4.1.36. 1H-Imidazole 67j. N-Tosylimidazole 66j (111 mg, 0.50 mmol)
was detosylated during 2 h according to the general procedure to
give imidazole 67j (31 mg, 92%) as a colourless solid, mp 89e92 ꢁC
[lit.41 mp 89e91 ꢁC].
4.1.37. 2-Phenylimidazole 67k. 2-Phenyl-1-tosylimidazole 66k (150
mg, 0.50 mmol) was detosylated according to the general procedure
during 2.5 h to give 2-phenylimidazole 67k (65 mg, 88%) as a col-
ourless solid, mp 147e150 ꢁC [lit.41 mp 144e147 ꢁC], 1H NMR
19. Ponticello, G. S.; Baldwin, J. J. J. Org. Chem. 1979, 44, 4003e4005.
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a recent alternative, see Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 131,
10806e10807.
(400 MHz, CDCl3):
7.25e7.20 (m, 3H), 7.11 (s, 2H).
d
¼11.24 (br s, 1H, NH), 7.82e7.77 (m, 2H),
22. Bagley, M. J.; Moody, C. J.; Pepper, A. G. Tetrahedron Lett. 2000, 41, 6901e6904.
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W. F.; Venslavaky, J. W.; Yuan, C. C.-K. Tetrahedron Lett. 1997, 38, 3131e3134.
25. See, for example Genet, J. P.; Juge, S.; Besnier, I.; Uziel, J.; Ferroud, D.;
Kardos, N.; Achi, S.; Ruiz-Montes, J.; Thorimbert, S. Bull. Soc. Chim. Fr. 1990,
127, 781e786.
26. Hibino, S.; Sugino, E.; Yamochi, T.; Kuwaki, M.; Hashimoto, H. Chem. Pharm. Bull.
1987, 35, 2261e2265.
27. Behforouz, M.; Curran, T. T.; Bolan, J. L. Tetrahedron Lett. 1986, 27,
3107e3110.
28. Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy, T. J. Org. Chem. 1988,
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1992, 42, 335e656.
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Chem. 2001, 66, 3220e3223.
4.1.38. (ꢀ)-
a-Cyclopiazonic acid 1. The deprotected indole 65
(35 mg) was dissolved in dry dichloromethane (2 mL) containing
diketene (two drops) and potassium tert-butoxide (a few crystals)
and the resulting mixture gently refluxed for 48 h then cooled and
concentrated. The crude product was purified by preparative TLC
(3:2 EtOAc/petrol) to give (ꢀ)-
a-Cyclopiazonic acid 1 (15 mg, 36%) as
almost one diastereoisomer which displayed spectroscopic and
analytical data [mp 230e236 ꢁC; lit.1a mp 245e246 ꢁC], which was
identical to an authentic natural sample (Tocris) except for its op-
tical rotation, including showing exactly the same relative amount
of a second enol form (see discussion): 1H NMR (400 MHz, CDCl3):
d
¼8.05 (br s, 1H, NH), 7.19 (s, 1H, 1-H), 7.18e7.05 (m, 2H), 6.85 (d,
J¼7.0 Hz, 1H, ArH), 4.00 (d, J¼11.1 Hz, 1H, 9-H), 3.60 (dd, J¼11.1,
5.8 Hz, 1H, CH), 3.02e2.95 (m, 2H, CH2), 2.60e2.50 (m, 1H, 6a-H),
2.38 (s, 3H, Me), 1.57(s, 3H, Me), 1.45 (s, 3H, Me); m/z [APCI] 337
(MþHþ, 100%); HRMS [APCI]: m/z: calcd for C20H21N2O3: 337.1547;
found: 337.1548 [MþH]þ.
Acknowledgements
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7119e7123.
38. Vangveravong, S.; Nichols, D. E. J. Org. Chem. 1995, 60, 3409e3413.
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40. Krogsgaard-Larsen, N.; Begtrup, M.; Frydenvang, K.; Kehler, J. Tetrahedron 2010,
66, 9297e9303.
We thank the EPSRC Mass Spectrometry Service, University
College, Swansea for the provision of high resolution mass spec-
trometric data and the EPSRC for financial support.
References and notes
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42. Lingens, F.; Lange, J. Annalen 1970, 738, 46e53.