A cationic cyclisation route to prenylated indole alkaloids: Synthesis of malbrancheamide B and brevianamide B, and progress towards stephacidin A

Article abstract of DOI:10.1016/j.tet.2010.04.093

The synthesis of the prenylated indole alkaloids, malbrancheamide B and brevianamide B have been accomplished, starting with a prenylated proline derivative created using the Seebach 'self-reproduction of chirality' method, and using a cationic cascade se

Full text of DOI:10.1016/j.tet.2010.04.093

Tetrahedron 66 (2010) 6585e6596
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A cationic cyclisation route to prenylated indole alkaloids: synthesis of
malbrancheamide B and brevianamide B, and progress towards stephacidin A
*
Frédéric C. Frebault, Nigel S. Simpkins
School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the prenylated indole alkaloids, malbrancheamide B and brevianamide B have been
accomplished, starting with a prenylated proline derivative created using the Seebach ‘self-reproduction
of chirality’ method, and using a cationic cascade sequence as the key step to form late-stage bridged
diketopiperazine intermediates.
Received 26 February 2010
Received in revised form 12 April 2010
Accepted 22 April 2010
Available online 29 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Steve Ley, with
best wishes, affection and thanks to an
inspirational chemist
Keywords:
Malbrancheamide
Brevianamide
Stephacidin
Diketopiperazine
Cationic cyclisation
1. Introduction
traced to binding with the nuclear chaperone nucleophosmin,
which regulates the tumour suppressor protein p53.7
The numbers of fascinating structures belonging to the preny-
lated indole alkaloid family have been growing steadily over the
years.1 These compounds possess a bicyclo[2.2.2]diazaoctane core
structure in the form of a bridged diketopiperazine (DKP) (or in
some cases a partly reduced variant) fused to an indole, oxindole,
indoxyl or similar grouping. The first members of this intriguing
class of mycotoxins, brevianamides AeF, e.g., brevianamide B (1),
were isolated in low yield from Penicillium brevicompactum by
Birch and Wright in 1969.2 Much more recent additions, such as
the stephacidin family, include stephacidin A (2), aspergamide B
(3), avrainvillamide (4) and its immensely complex dimer ste-
phacidin B (5).3e5
These compounds, isolated by fermentation of Aspergillus
ochraceus WC76466, display potent in vitro cytotoxic activity
against a number of human tumour cell lines. Stephacidin B shows
particularly potent and selective activity, for example, against
testosterone-dependent prostate LNCaP cell line with an IC50
The malbrancheamides, 6 and 7, are a pair of compounds very
recently isolated from Malbranchea aurantiaca, a fungus found on
bat detritus in a Mexican cave.8 They are unique amongst this class
of alkaloid in having a chlorinated indole nucleus, and have been
shown to exhibit significant, and structure-dependent, calmodulin
(CaM) inhibitory activity.9
The combination of challenging structures, intriguing bio-
synthetic origins and, in many cases, potent biological activities,
displayed by these compounds makes them attractive targets for
synthesis. The most notable contributions, by far, in this arena have
been made by the Williams group, who have achieved numerous
total syntheses of key natural products (including all but 3, shown
above), and have also provided much detailed evidence for the
biosynthesis.1,10
The most concise existing routes to these compounds have
been described by Williams, and employ a bio-mimetic Diels-
Alder cycloaddition as the key step to construct the bridged DKP
core. This approach, whilst concise at around 11e14 steps (in-
cluding brevianamide B, malbrancheamides and stephacidin A),
suffers the drawback of providing racemic product.11 Alternative
enantioselective approaches, including those by Williams, Baran,
Myers and Trost have involved significantly longer overall
sequences.12e14
value of 0.06 mM. Myers has demonstrated that this activity is in
fact due to dissociation of stephacidin B into avrainvillamide in
solution.6 The antiproliferative effects of this compound were
* Corresponding author. E-mail address: n.simpkins@bham.ac.uk (N.S. Simpkins).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.093

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F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
Our interest in the selective substitution of DKP structures via
carbon centre augured well for syntheses of the stephacidins or
malbrancheamides. At this point it is worth clarifying, that all of
our synthetic work has been done in the (cheaper) L-proline
either metal enolate or N-acyliminium type reactive intermediates
led us to explore a new entry to this type of alkaloid, involving
a cationic cascade process to set up the core structure.15 We re-
cently demonstrated the utility of this new approach with a concise
synthesis of ent-malbrancheamide B,16 and here we describe this
work in full, including the genesis of the new route, a previously
unreported synthesis of brevianamide B, and progress towards the
stephacidins.
series, and so product 10 is enantiomeric to the natural product
drawings of 1e7. It is also worth noting that some of these nat-
ural products have been obtained in either enantiomeric form,
depending upon the source (e.g., stephacidin A),20 some others
are of the same series as 10,21 and that Williams’ studies have
demonstrated that either enantiomeric series of compounds may
possess potent biological activity.9 Needless to say, the chemistry
described herein should apply equally well to the proline
2. Results and discussion
D
-series.
Having achieved the cyclisation of 9 to give 10, it became clear to
2.1. Synthesis and cationic cyclisation
of a proline-derived DKP
us that a cascade process might be productively engaged if a mixed
proline/tryptophan systemwere employed, i.e., Scheme 2 (shown in
same series as 1e7).
Formation of an appropriately substituted system 12, e.g.,
X¼SPh, ready for cation formation appeared plausible using the
chemistry outlined above. We presumed that suitable protecting
groups would be required on the ring amide (P in 12) and possibly
on the indole nitrogen. The second cyclisation in the sequence,
involving indole participation was well precedented by the work of
Williams.22
Unfortunately, our first efforts to realise this concept by fol-
lowing the DKP substitution route proved highly problematic, due
to the extreme reluctance of prenylated DKP 16 to undergo useful
enolate substitution chemistry. Although we are now re-examining
this tactic using alternative free radical methods, at the time we
chose to adopt a modified approach.
Our interest in the chemistry of DKPs originated in a study of
the regio- and stereoselective substitution of mixed proline-con-
taining systems, e.g., DKP 8, via enolates.15 Such systems were
found to undergo initial alkylation with retention of configuration
at the proline residue, and with one so-formed product we carried
out a subsequent sulfenylation to give fully substituted DKP 9.
Bearing in mind the known ability to effect substitutions on DKP
scaffolds via cationic-type intermediates, demonstrated by several
groups, including those of Liebscher,17 Davies18 and Williams,19
we reacted DKP 9 with AgOTf, and were delighted to observe se-
lective and reasonably efficient formation of bridged DKP product
10, Scheme 1.
This product was formed stereoselectively at the position of
the new alkenyl substituent, and the relative configuration at this
H
O
H
O
O
Ph
(i) LHMDS, THF
O
N
P
N
AgOTf, THF
65%
PMBN
Bn
prenyl bromide
PMBN
PhS
N
N
O
(ii)
Bn
N
N Bn
H
O
Bn
Li
THF, PhSSPh
Li
8
9
10
Scheme 1. An initial cationic DKP cyclisation.

F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
6587
H
N
H
N
H
N
O
O
H
N
N-protection(s)
cation formation
X
NH
H
O
N
O
N
+
P
P
two substitutions
via enolisation
N
N
O
O
ent-brevianamide F 11
12
13
H
H
N
N
O
O
+
H
H
prenyl
trapping
indole
trapping
NPMB
BocN
6
O
P
O
N
N
P
N
N
N
O
O
16
14
15
Scheme 2. Planned double cyclisation to give natural product frameworks.
It occurred to us that if the group X in 12 was simply a hydroxyl
function, then cation initiation should be possible by treatment
with acids, or perhaps, after derivatisation (e.g., acetylation or
methylation), with Lewis acids. Further inspection reveals that this
DKP would be expected to form spontaneously from a corre-
sponding open chain keto-amide 17, which itself should be avail-
able via a standard peptide coupling, Scheme 3.
2.2. Initial explorations of a cationic cascade
Our preliminary synthesis exploration began with the well-
known Seebach proline ‘acetal’ 20, which was prenylated under
standard conditions to give 21.23 Opening of the oxazolone system
with lithiated para-methoxybenzylamine (PMBNH2) then gave
proline amide 22 in practically quantitative yield, Scheme 4.24
H
O
N
NHP
O
O
OH
N
ring
closure
amide
HO
O
N
P
NHP
formation
O
N
O
O
+
NH
N
O
Boc
BocN
17
19
12 (X = OH)
18
Scheme 3. Revised disconnection for cation precursor.
This approach immediately appeared very attractive in terms of
convergency, and it was clear that the required prenylated proline
derivative 18, in the L-series, would be easily available using See-
bach’s ‘self-reproduction of chirality’ method. To facilitate peptide
coupling between the two partners, as shown, we envisaged using
indole pyruvic acid derivatives (with or without indole nitrogen
protection), such as 19.
Coupling of the pyrrolidine of amide 22 with the carboxyl
function of commercially available phenylpyruvic acid, using PyBOP
reagent according to Czarnocki and co-workers,25 gave hydroxy-
DKP 23 directly, as a 3:1 mixture of diastereoisomers, Scheme 5.
Treatment of this compound with acids (e.g., HCl, PTSA, or TFA)
in THF proved insufficient to initiate cationic chemistry.26 However,
addition of TMSOTf to DKP 23, initially at 0 ꢀC and then at room
O
H
NH
O
O
MeO
(i) LDA, THF, -78°C
O
NHPMB
O
N
n-BuLi, THF, -78°C
N
Br
NH
(ii)
76%
99%
22
20
21
Scheme 4. Synthesis of quaternary proline amide.

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F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
H
O
PyBOP, Et3N
TMSOTf, CH2Cl2
PMBN
O
N
Me
Bn
THF, reflux 48h
P
Me
10
N
22
+
Ph
N
0 oC to RT
OH
O
O
HO
O
46 %
23
30 %
24
Scheme 5. TMSOTf initiated cyclisation of a hydroxy-DKP.
temperature overnight, led to the formation of bridged DKP 10,
identical to that observed from the silver triflate reaction. Again, we
observed only one diastereomeric product, and the outcome is
consistent with a conformation of the reactive intermediate that
places the bulk of the prenyl group over the ‘front’ C]O function, as
shown in 24, and away from the relatively bulky N-PMB group.
Although at this stage the chemical yields for the peptide cou-
pling and the key cyclisation were somewhat modest, we decided
to test our double cyclisation strategy by incorporating indole
pyruvic acid into the sequence. In this case, coupling with 22
proved problematic using the PyBOP reagent, and only by
employing standard, base-free, DCC/HOBt conditions did we ach-
ieve workable, albeit modest, yields of product, Scheme 6.
block for our new synthetic approach we required a replacement for
the troublesome PMB protection. After considering the virtues of
a range of groups we decided to explore the use of an OBn group on
the DKP nitrogen, since this would enable eventual lactam depro-
tection (i.e., NeO cleavage) under reductive conditions (SmI2) that
had previously been shown to be compatible with rather highly
functionalised and sensitive intermediates.29
2.3. Synthesis of brevianamide B using a modified cascade
The synthetic route using the modified nitrogen substituent
proceeded largely as we required, although with a few significant
differences to the N-PMB series, Scheme 7.
O
H
N
O
CO2H
H
PMBN
H
N
H
TMSOTf, CH2Cl2
0 oC to RT, 16h
6
H
N
N
O
22
O
N
P
DCC, HOBt
THF, RT
N
O
O
41 %
25
68%
26 (P= PMB)
Scheme 6. TMSOTf cascade to give a known intermediate for brevianamide B.
The coupling product was isolated as the linear keto-amide 25,
rather than the corresponding cyclised hydroxy-DKP, presumably
due to the milder, base-free conditions, and lower temperatures
employed. To our delight, treatment of this compound with
TMSOTf, as before, resulted in clean formation of the doubly
cyclised product 26, as a single diastereomer. The yield and high
stereoselectivity of this process were especially pleasing, as was the
realisation that the seemingly complex polycyclic framework of 26
had been prepared in only five steps from proline!
Since both C-6 epimers of DKP 26 had been prepared previously
by Williams, in his pioneering synthesis of brevianamide B,24 we
were able to confirm our stereochemical assignment, and to match
our spectroscopic data to those measured previously. Unfortunately,
Williams had also established that removal of the PMB protecting
group from the DKP lactam function could be problematic, and we
were destined to re-discover this problem.27 Despite attempts in
which material was tested to destruction, wewere unable to identify
either reductive (hydrogenolysis with Pd/C, PdCl2 or Pd(OH)2 as
catalyst in various solvents) or oxidative (DDQ, CAN, TFA/anisole,
PTSA in toluene) conditions that provided even modest yields for
this deprotection.28 As this problem presented a major stumbling
The required O-benzyl proline hydroxamic acid 27 was prepared
straightforwardly along the same lines as 22, and coupling to indole
pyruvic acidproceeded insimilar moderateyield, but inthiscasegave
the product in the closed, hydroxy-DKP, form 28. We ascribe this
difference to the combination of diminished steric encumbrance, and
increased nucleophilic properties, of the hydroxamic acid nitrogen,
compared to the corresponding amide in 25. Cyclisation of 28 using
TMSOTf proceeded smoothly, but resulted in the formation of the
desired product 29, along with the corresponding C-6 epimer in a 4:1
ratio. This slightly disappointing erosion of selectivity in the cyclisa-
tion may be due to reduced effective steric screening by NeOBn
compared to NePMB, according to the model represented by 24, al-
though we have not probed this effect further to date.
As shown, with the separated diastereomer 29, we were pleased
to establish that NeO bond cleavage could be effected using sa-
marium iodide.30 This reaction was ineffective with SmI2 alone, and
reasonable yields of the desired DKP 30 could only be obtained
using the activation method involving addition of LiCl, as described
by Flowers and co-workers.31 This compound had been prepared by
both the Williams and Liebscher research groups, and our data
corresponded well with those published earlier.32

F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
6589
O
H
N
CO2H
O
H
O
H
N
BnO
N
N
H
TMSOTf, CH2Cl2
0 oC to RT, 3h
6
NHOBn
O
N
N
P
DCC, HOBt
THF, RT
N
NH
HO
O
O
29 (P= OBn) 4 : 1 C-6 epimer
30 (P = H) 62%
46 %
82 %
27
28
SmI2
LiCl
THF
Scheme 7. Modified cascade using NeOBn DKP protection.
Bridged DKP 30 is clearly a very close relative to stephacidin A
and to the malbrancheamides, and incorporation of additional in-
dole substitution into our synthetic scheme, so as to provide access
to these natural products, appeared viable. However, as an addi-
tional test of our tactic of employing the NeOBn DKP protection, we
first decided to progress the minor diastereomeric cyclisation
product from Scheme 7 (i.e., the C-6 epimer of 29) towards bre-
vianamide B, Scheme 8.
2.4. Synthesis of malbrancheamide B
Our new diastereoselective access to polycyclic bridged indoles
related to structure 29 prompted us to focus on the synthesis of
stephacidin A (2) and the malbrancheamides (6 and 7). A complete
natural product synthesis in the major C-6 epimeric series available
from our chemistry would both underline the utility of our cascade
strategy and would also enable us to test its compatibility with
H
N
N
H
H
mCPBA, THF
MeONa, MeOH
O
O
RT
reflux
HO
N
N
BnO
BnO
N
N
O
O
69% over 2 steps
29 (minor C-6 epimer)
31
H
N
H
H
N
Dess-Martin
SmI2, LiCl
THF, RT
H
ent-1
CH2Cl2, RT
O
O
N
O
H
HO
N
N
BnO
N
O
O
33
48% over 2 steps
32
Scheme 8. Synthesis of ent-brevianamide B.
The overall transformation of linearly fused indoles, like 29, into
the corresponding spiro-indoxyls found in brevianamides, followed
closely the ample precedent set by the Williams group.1,28 Peracid
oxidation of the minor C-6 epimer of 29, followed by base treat-
ment effected the key oxidationerearrangement to give yellow
spiro-indoxyl 32. Although, to our chagrin, reductive cleavage of
the NeOBn bond, using SmI2/LiCl as before, resulted in concomitant
indoxyl reduction, giving 33, we were able to complete a synthesis
of ent-brevianamide B (1) by Dess-Martin oxidation.
Despite the unwanted intervention of indoxyl reduction, and
notwithstanding the fact that we employed only a minor di-
astereomeric intermediate in our synthesis, the brevity of this route
to brevianamide B, at only nine steps from proline, highlights the
power of this approach.
additional indole substitution required in these natural products
(and others such as paraherquamides).
As described in our previous communication, a synthesis of ent-
malbrancheamide B (7) emerged, based on the preliminary studies
described above, and as summarised in Scheme 9.
The synthesis required coupling of 6-chloroindole pyruvic acid
(or a derivative) to the proline hydroxamic acid component 27.
Throughout this project, we had experienced consistently low
yields in the couplings of indole pyruvic acids, and preliminary
experiments with synthesized samples of pyruvic acids (i.e., non-
commercial samples) gave extremely poor results. Such com-
pounds were found to exist exclusively in the enol form, rather than
the keto-acid form depicted in Schemes 5e7. As a means of cir-
cumventing this problem it was decided to prepare O-alkylated

6590
F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
CO2H
OSEM
BnO
O
O
O
Boc
N
O
N
H
BnO
iPrOH, CBr4
50 oC
Boc
N
N
34
N
Cl
SEMO
Boc
NHOBn
N
N
HATU, iPrNEt2
MeCN, RT
Cl
NH
Cl
HO
O
74 %
52%
27
35
36
H
N
H
N
Cl
Cl
H
H
TMSOTf, CH2Cl2
0 oC to RT, 3h
DIBAL-H, toluene
RT
O
O
H
P
N
N
N
N
O
63%
64 %
ent-7
37 (P= OBn) 4 : 1 C-6 epimer
SmI2
LiCl
THF
38 (P = H) 70%
Scheme 9. Synthesis of ent-malbrancheamide B (7).
enol derivatives that might better participate in peptide couplings
but could subsequently be unmasked to give the -ketoamide (and
indole, or a chlorinated indole, respectively, we considered that
stephacidin A (2) should also be available by this method, by the
simple expedient of starting with an indole pyruvate incorporating
a fused pyrano ring. Synthesis of the appropriate hydroxy-DKP
precursor, following the same strategy as before, proved quite
straightforward, starting from known indole 39,35 Scheme 10.
Theschemeillustrates ourpreferred method foraccessingtheSEM
enol ethers of indole pyruvic acids, which involves an aldoledehy-
dration sequencewiththeintermediate indole carboxaldehydes, such
as 40, to give, in this case, ester 41. Since ester hydrolysis of 41 was
accompanied by slow removal of the indole Boc protecting group, we
chose not to carry hydrolysis to completion, and the 50% yield of
product 42wasaccompaniedbyca.5%ofthecorrespondingindoleNH
carboxylic acid and 36% of starting ester 41. Peptide coupling to give
43, and subsequent enol ether hydrolysis proceeded very much as
before, to give DKP 44 ready for cyclisation. Interestingly, these mild
acidic conditions, although effective for SEM group removal, did not
provoke any sign of useful cyclisation chemistry.
Much to our disappointment, all of our efforts to effect cycli-
sation reactions of DKP 44 were destined to meet with failure.
Reaction with TMSOTf, under the conditions used previously,
resulted in rapid decomposition of the starting material. Attempts
using this same reagent at lower temperatures effected only the
removal of the Boc protection, and no clean cyclisation products
were observed. Alternative procedures, involving acetylation of
the DKP tertiary hydroxyl function, followed by treatment with
BF3eOEt2 did not provide useful products. Likewise, removal of the
indole N-Boc protection, in an attempt to enhance indole nucleo-
philicity, followed by treatment with protic acids (TFA or HCl) or
Lewis acids (TiCl4) resulted only in complete destruction of the
starting DKP 44.
a
thus the hydroxy-DKP) required for the cationic cascade. Several
alkylated enol pyruvates (OMe, O-allyl, OPMB) proved surprisingly
robust, and the most suitable was found to be O-SEM derivative 34,
which was prepared by a short and straightforward route, starting
with commercial 6-chloroindole (the approach is exemplified for
an analogous system below).
Coupling of 27 and 34 gave amide 35 in an acceptable yield of
74%. Unfortunately, even this compound, which we anticipated
would be prone to hydrolysis to the desired ketoamide by reaction
with fluoride, proved remarkably stable to reagents such as TBAF,
TBAT and HF/pyridine. Exposure of 35 to the conditions described
by Chen and Lee for SEM deprotections,33 involving treatment with
CBr4 in warm isopropanol, gave a moderate yield of DKP 36, which
we have not optimised further to date.
Pleasingly, DKP 36 underwent the key double cyclisation
sequence on treatment with TMSOTf, as before, giving 37 as
a 4:1 mixture with the corresponding C-6 epimer, which was
easily separated by chromatography. Subsequent NeO bond
cleavage using SmI2 was followed by regioselective lactam re-
duction, following the method of Williams, to provide the un-
natural antipode of malbrancheamide B (ent-7) as shown. The
structure of our final product was secured by comparison of our
1H NMR and 13C NMR data with those of Williams, which pro-
vided an exact match.34
Our synthesis of malbrancheamide B requires 10 synthetic steps
from 6-chloroindole, and proceeds in around 4.4% overall yield.
Although this already ranks as one of the most concise entries to
such natural products there is clearly room for further streamlining
and improvement, particularly in the low-yielding enol ether
deprotection.
In retrospect, this problem was predictable, based on analysis of
the mechanism of the TMSOTf initiated reaction, our observations
of the ‘cascade’ process, and previous observations of the Williams
and Baran groups concerning the sensitivity of stephacidin A to
acids.12,13 We envisage that the double cyclisation of our DKP sys-
tems proceeds as outlined in Scheme 11.
2.5. Advances towards stephacidins
Having already effected the successful cationic cascade syn-
theses of intermediates 29 and 37, incorporating either a simple

F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
6591
CO2Me
OSEM
CHO
(i) POCl3, DMF
then NaOH(aq)
(i) SEMOCH2CO2Me
LHMDS, THF (94 %)
N
LiOH
N
H
N
O
THF(aq)
O
O
(ii) Boc2O, DMAP
THF
(ii) MsCl, CH2Cl2, Et3N
then DBU (88 %)
Boc
Boc
87 %
50 %
39
40
41
CO2H
OSEM
BnO
O
O
N
H
iPrOH, CBr4
50 o
Boc
Boc
27
BnO
N
N
N
HATU, iPrNEt2
SEMO
C
N
N
O
N
Boc
MeCN
78 %
O
O
HO
O
O
45-60 %
42
43
44
Scheme 10. Synthesis of an advanced intermediate towards stephacidin A.
+
TMS
TfO
+
OH
HO
-
-
-
TfO
TMSOTf
O
N
O
N
O
N
O
N
+
TfO
P
P
P
O
N
P
N
P
N
N
N
In
N
In
In
In
In
O
O
O
O
O
45
46
47 + TMSOH
49 + TfOH
48
Scheme 11. Proposed sequence in TMSOTf initiated DKP cyclisations.
Initial silylation of DKP 45 (In¼indole) on oxygen forms a good
leaving group, leading to the unusual N-acyliminium type in-
termediate 46, which can then cyclise to give the tertiary cation 48.
In principle, this intermediate could directly alkylate the pendant
indole, leading to the observed products. However, in a number of
our earlier reactions, we observed intermediates by TLC, which
correspond to the mono-cyclised DKP structure 49, and which are
then consumed in the (usually) slow conversion to doubly cyclised
product. This seems to point to the initial formation of alkenyl in-
termediates like 49, which then undergo cyclisation due to (prob-
ably reversible) alkene protonation by the by-product, triflic acid.
In the case of our successful syntheses the presence of strong
acid is of no consequence, but in the case of stephacidin A the
pyrano ring is known to be rather acid labile, and Baran demon-
strated that acid-mediated cyclisation of intermediates corre-
sponding to alkene 49 was very problematic and low-yielding at
best.13c In our case it seems the intermediates are destroyed by the
extremely strong acid liberated in the early steps of the reaction.
Addition of base from the outset stops productive cyclisation
chemistry, presumably due to rapid deprotonation of silylated in-
termediate 46.
3. Conclusion
A new strategy has been demonstrated for the synthesis of
members of the prenylated indole family of alkaloids that employs
a double cationic cyclisation to build the key bridged DKP structure
present in these natural products. Non-racemic brevianamide B
and malbrancheamide B were prepared by very concise sequences
using this approach. A present deficiency in the method is the
presence of strong acid in the key cyclisation step. Present work is
aimed at by-passing this issue, as well as extending the scope of the
cation-termination step and application to other targets.
4. Experimental part
4.1. General methods
All glassware were flame dried under a steady flow of nitrogen
before use; all reactions were performed under an atmosphere of
nitrogen or argon unless otherwise stated. THF was distilled im-
mediately prior to use from sodium and benzophenone. CH2Cl2 was
distilled from calcium hydride. Prenylbromide and pyridine were
distilled before use. All other solvents and reagents were used as
received from commercial suppliers unless otherwise stated. So-
lution infra-red spectra were recorded using a PerkineElmer 1600
series FTIR spectrometer using chloroform as solvent. Neat infra-
red spectra were recorded using a Nicolet AVATAR 370 DTGS
At present, we have not been able to find a direct way around this
synthetic impasse, which casts some doubt over the applicability of
this approach for systems with sensitive oxygenated rings fused to
the indole system. However, this situation can be rescued if the
desired sensitive rings can be incorporated post-cyclisation, using
intermediatescarryingmorerobustoxygen functions (maybe OAcor
similar), or perhaps reactive halogens (Br, I) capable of conversion
into ethers. Efforts to establish these possibilities are underway.
spectrometer. Wavelengths (n
) are reported in cmꢁ1. Optical rota-
tions were recorded as dilute solutions of the indicated solvent in
a 50 mm glass cell using a JASCO DIP370 digital polarimeter at

6592
F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
294 nm. Mass spectra were obtained using a VG Micromass 70E or
VG Micron Autospec spectrometer, using electrospray ionization
extracts were dried (MgSO4) and concentrated in vacuo. The resi-
due was purified by flash column chromatography on silica gel (pet.
ether/EtOAc, 2:1) to give hydroxy-DKP 23 (308 mg, 46%) as a yellow
oil. The less polar diastereoisomer, which is the major one, was
isolated in the first fractions of the column chromatography and
(ESI) with meta-nitrobenzyl alcohol as matrix. All 1H NMR and 13
C
NMR experiments were recorded using Bruker 300, AV400,
AMX400 and DRX500 spectrometers. Chemical shifts ( ) are quoted
d
in parts per million and coupling constants (J) are quoted in hertz.
The 7.27 ppm resonance of residual CHCl3 for proton spectra and
77.16 ppm resonance of CDCl3 for carbon spectra were used as in-
ternal references. Reaction progress was monitored by thin layer
chromatography (TLC) performed on aluminium plates coated with
keiselgel F254 with 0.2 mm thickness. Visualisation was achieved by
a combination of ultraviolet light (254 nm) and acidic potassium
permanganate or anisaldehyde. Flash column chromatography was
performed using silica gel 60 (230e400 mesh, Merck and co.).
Experimental conditions and full spectral data were published
previously for compounds 10, and for ent-7 (malbrancheamide B),
21, 27 and 34e38.16
was fully characterised. [
a
]
D
20 þ59.2 (c 1.2, CHCl3); FTIR (CHCl3) nmax
3546, 2934, 1659, 1454, 1352, 1108, 1080, 1037; 1H NMR (400 MHz,
CDCl3)
d 7.59 (d, J 8.6, 2H, Ar, CH), 7.32e7.22 (m, 3H, Ar, CH),
7.09e7.06 (m, 2H, Ar, CH), 6.85 (d, J 8.6, 2H, Ar, CH), 4.94 (d, J 13.6,
1H, NCHHAr), 4.51 (d, J 13.6, 1H, NCHHAr), 4.42 (m, 1H, CH]C), 4.06
(br s, 1H, OH), 3.79 (s, 3H, OCH3), 3.53 (ddd, J 12.4, 9.6, 5.6, 1H,
NCHHCH2), 3.39 (d, J 13.4, 1H, CCHHPh), 3.32 (d, J 13.4, 1H,
CCHHPh), 3.22 (ddd, J 12.4, 9.2, 4.4, 1H, NCHHCH2), 2.14e2.08 (m,
2H, CH2CH]C), 1.69e1.60 (m, 2H), 1.49 (s, 3H, CH3), 1.33 (m, 1H),
1.30 (s, 3H, CH3), 0.54 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 167.9
(C]O), 164.6 (C]O), 158.7 (Ar, C), 137.3 (CH]C), 134.2 (Ar, C), 131.7
(2ꢂAr, CH), 130.0 (2ꢂAr, CH), 129.3 (Ar, C), 128.5 (2ꢂAr, CH), 127.5
(Ar, CH), 116.9 (CH]C), 113.3 (2ꢂAr, CH), 88.5 (C-3), 67.7 (C-8a),
55.2 (OCH3), 46.3 (CCH2Ph), 45.7 (NCH2Ar), 43.7 (NCH2CH2), 36.7
(CH2CH]C), 33.5 (CCH2CH2), 25.6 (CH3), 19.1 (CH2CH2CH2), 17.6
(CH3); HRMS (ESI) calculated for C27H32N2O4Na [MþNa]þ 471.2260,
found 471.2250.
4.1.1. Preparation of (R)-N-(4-methoxybenzyl)-2-(3-methylbut-2-
enyl)pyrrolidine-2-carboxamide (22). To a stirred solution of 4-
methoxybenzylamine (4.3 mL, 33.4 mmol, 2.0 equiv) in THF
(70 mL), n-BuLi (22.3 mL, 1.6 M in hexane, 33.4 mmol, 2.0 equiv)
was added at ꢁ78 ꢀC and the resulting mixture was stirred for
30 min. In another flask, a solution of prenylated oxazolidinone 21
(4.21 g, 16.7 mmol) in THF (15 mL) was prepared and cooled to
ꢁ78 ꢀC. The substrate was added to the base via cannula at ꢁ78 ꢀC.
After stirring for 1.5 h at the same temperature, the solution was
quenched by a saturated aqueous ammonium chloride solution
(5 mL) and allowed to warm to room temperature. The solution was
concentrated under reduced pressure and the residue was parti-
tioned between CH2Cl2 (50 mL) and water (50 mL). The layers were
separated and the aqueous phase was extracted with CH2Cl2
(2ꢂ50 mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. Excess 4-methoxybenzylamine was re-
moved by Kugelrhor distillation and the residue afforded amine 22
(5.02 g, 99%). This material was directly used in the next step
without further purification. An analytical sample was obtained by
flash column chromatography on silica gel (pet. ether/EtOAc, 1:1 to
4.1.3. Preparation of (1R,7R,10R)-1-benzyl-2,8-diketo-9-(4-methoxy-
benzyl)-10-(1-methyl-ethenyl)-3,9-diazatricyclo[4.4.3.0]-undecane
10. 4.1.3.1. General procedure for TMSOTf-mediated cationic cy-
clisation. To
a stirred solution of hydroxy-DKP 23 (72 mg,
0.16 mmol) in CH2Cl2 (0.5 mL) was added TMSOTf (32 mL,
0.17 mmol, 1.1 equiv) at 0 ꢀC. The resulting mixture was allowed to
warm to room temperature and stirred for 16 h before addition of
triethylamine (24 mL, 0.17 mmol, 1.1 equiv). The resulting mixture
was diluted with CH2Cl2 (5 mL), washed with water (5 mL) and the
aqueous layer was extracted with CH2Cl2 (2ꢂ5 mL). The combined
organic extracts were dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by flash column chro-
matography on silica gel (pet. ether/EtOAc, 2:1) to afford tricyclic
compound 10 (20 mg, 30%) as a white solid. Mp 161e163 ꢀC, with
spectroscopic data as described previously.15
1:4) to give amine 22 as a colourless oil. [
a]
20 ꢁ14.7 (c 1.0, CHCl3);
D
FTIR (CHCl3) nmax 3330, 2930, 2875, 1651, 1613, 1461, 1036; 1H NMR
4.1.4. Preparation of (R)-1-(3-(1H-indol-3-yl)-2-oxopropanoyl)-N-
(4-methoxybenzyl)-2-(3-methyl-but-2-enyl)pyrrolidine-2-carbox-
amide (25). To a stirred solution of commercially available indole
pyruvic acid (382 mg, 1.88 mmol, 1.1 equiv) and amine 22 (517 mg,
1.71 mmol) in THF (40 mL) was added HOBt (254 mg, 1.88 mmol,
1.1 equiv) and then DCC (1.88 mL, 1.0 M in DCM, 1.88 mmol,
1.1 equiv) at room temperature. The resulting mixture was stirred
for 16 h and the resulting urea was removed by filtration through
a pad of CeliteÒ. The filtrate was concentrated under reduced
pressure and the residue was purified by flash column chroma-
tography on silica gel (pet. ether/EtOAc, 7:3) to afford pyruvic amide
(400 MHz, CDCl3) d 8.20 (br s, 1H, NH), 7.17 (d, J 8.8, 2H, Ar, CH), 6.84
(d, J 8.8, 2H, Ar, CH), 5.05 (m, 1H, CH]C), 4.38 (dd, J 14.6, 6.2, 1H,
NHCHHAr), 4.29 (dd, J 14.6, 5.6, 1H, NHCHHAr), 3.78 (s, 3H, OCH3),
3.00 (ddd, J 10.4, 6.8, 6.8, 1H, NHCHHCH2), 2.82 (ddd, J 10.4, 6.4, 6.4,
1H, NHCHHCH2), 2.68 (dd, J 14.6, 6.6, 1H, CHHCH]C), 2.33 (dd, J
14.6, 8.4, 1H, CHHCH]C), 2.18 (ddd, J 12.8, 6.8, 6.8, 1H, CCHHCH2),
1.79e1.67 (m, 4H, CCHHCH2, NH), 1.68 (s, 3H, CH3), 1.62 (s, 3H, CH3);
13C NMR (67.5 MHz, CDCl3)
d 176.6 (C]O), 158.8 (Ar, C), 135.8 (CH]
C), 131.1 (Ar, C), 128.9 (2ꢂAr, CH), 119.1 (CH]C), 114.0 (2ꢂAr, CH),
69.6 (C-2), 55.3 (OCH3), 47.1 (CH2), 42.6 (NHCH2Ar), 36.8 (CH2), 36.1
(CH2), 26.3 (CH2), 26.1 (CH3), 18.0 (CH3); HRMS (ESI) calculated for
C18H27N2O2 [MþH]þ 303.2073, found 303.2061.
25 (338 mg, 41%) as an orange oil. [
a
]
18 ꢁ27.7 (c 0.65, CHCl3); FTIR
D
(neat) nmax 3297, 2931, 1639, 1511, 1242, 743; 1H NMR (400 MHz,
CDCl3)
d 8.01 (br s, 1H, NH), 7.56 (d, J 8.0, 1H, Ar, CH), 7.31 (d, J 8.0,
4.1.2. Preparation
ybenzyl)-8a-(3-methylbut-2-enyl)-hexahydro
of
(8aR)-3-benzyl-3-hydroxy-2-(4-methox-
pyrrolo[1,2-a]pyr-
1H, Ar, CH), 7.22e7.10 (m, 5H, NH, Ar, CH), 6.95 (d, J 2.4, 1H, Ar, CH),
6.90 (d, J 8.8, 2H, Ar, CH), 4.81 (m, 1H, CH]C), 4.29 (dd, J 15.0, 6.4,
1H, NHCHHAr), 4.28 (d, J 15.2, 1H, CCHHAr), 4.25 (dd, J 15.0, 6.0, 1H,
NHCHHAr), 4.02 (d, J 15.2, 1H, CCHHAr), 3.82 (s, 3H, OCH3), 3.24
(ddd, J 10.4, 10.4, 6.6, 1H, NCHHCH2), 3.13 (ddd, J 10.4, 7.6, 2.8, 1H,
NCHHCH2), 2.89 (dd, J 14.8, 8.4, 1H, CHHCH]C), 2.78 (dd, J 14.8, 6.4,
1H, CHHCH]C), 2.40 (ddd, J 10.0, 6.6, 3.0, 1H, CCHHCH2), 1.69 (m,
1H, CCHHCH2), 1.58 (m, 1H, CH2CHHCH2), 1.66 (s, 3H, CH3), 1.56 (s,
3H, CH3), 1.45 (m, 1H, CH2CHHCH2); 13C NMR (125 MHz, CDCl3)
azine-1,4-dione (23). To a stirred solution of phenylpyruvic acid
(740 mg, 4.5 mmol, 3.0 equiv) in THF (20 mL) was added triethyl-
amine (1.05 mL, 7.5 mmol, 5.0 equiv) and PyBOP (2.35 g, 4.5 mmol,
3.0 equiv) at room temperature under N2. The resulting mixture
was stirred at room temperature for 1 h before addition of a solu-
tion of proline derivative 22 (461 mg, 1.5 mmol) in THF (6 mL). The
resulting mixture was heated to reflux for 48 h and after cooling to
room temperature, the solvent was evaporated under reduced
pressure. The residue was partitioned between CH2Cl2 (30 mL) and
water (30 mL) and the layers were separated. The aqueous phase
was extracted with CH2Cl2 (2ꢂ20 mL) and the combined organic
d
196.0 (C]O), 172.5 (C]O), 165.6 (C]O), 158.9 (Ar, C), 136.0 (CH]
C, Ar, C), 130.7 (Ar, C), 128.8 (2ꢂAr, CH), 127.1 (Ar, C), 124.3 (Ar, CH),
122.6 (Ar, CH), 120.1 (Ar, CH), 118.5 (Ar, CH), 117.6 (CH]C), 114.0
(2ꢂAr, CH), 111.4 (Ar, CH), 104.9 (Ar, C), 72.8 (C-2), 55.3 (OCH3), 49.8

F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
6593
(NCH2), 43.1 (NHCH2Ar), 36.1 (CCH2Ar), 34.4 (CCH2CH2), 32.1
(CH2CH]C), 26.0 (CH3), 23.4 (CH2CH2CH2), 18.2 (CH3); HRMS (ESI)
calculated for C29H33N3O4Na [MþNa]þ 510.2369, found 510.2374.
by flash column chromatography on silica gel (pet. ether/EtOAc,
1:1) to afford the major diastereoisomeric product 29 (see Scheme
7, 384 mg, 66%) as a white solid followed by the minor C-6 epimer
(95 mg, 16%) as a white solid.
4.1.5. Double cyclisation of amide 25 to give bridged DKP 26. The
general procedure for TMSOTf-mediated cationic cyclisation was
followed starting from pyruvic amide 25 (54 mg, 0.11 mmol),
Data for major epimer of 29: mp 246e248 ꢀC; [
a
]
D
21 ꢁ45 (c 0.94,
CHCl3); FTIR (KBr) nmax 3332, 2927, 1708, 1684, 1437, 1362; 1H NMR
(400 MHz, CDCl3)
d 7.89 (br s, 1H, NH), 7.55 (m, 1H, Ar, CH), 7.
TMSOTf (24
m
L, 0.13 mmol, 1.1 equiv), Et3N (76
m
L, 0.55 mmol,
51e7.49 (m, 2H, Ar, CH), 7.43e7.37 (m, 3H, Ar, CH), 7.27 (m, 1H, Ar,
CH), 7.18e7.10 (m, 2H, Ar, CH), 5.10 (d, J 9.6, 1H, OCHHAr), 5.01 (d, J
9.6, 1H, OCHHAr), 3.66 (d, J 15.6, 1H, CCHHAr), 3.56 (ddd, J 11.2, 6.6,
6.6, 1H, NCHH), 3.42 (ddd, J 11.2, 7.2, 7.2, 1H, NCHH), 3.37 (d, J 15.6,
1H, CCHHAr), 2.88 (ddd, J 13.2, 6.6, 6.6, 1H, CCHHCH2), 2.60 (dd, J
10.4, 4.4, 1H, CH2CH), 2.19 (dd, J 13.6, 10.4, 1H, CHHCH), 2.07e2.01
(m, 2H, CH2CH2CH2), 1.98e1.89 (m, 2H, CCHHCH2, CHHCH), 1.24 (s,
5.0 equiv) and CH2Cl2 (1.5 mL). The residue was purified by flash
column chromatography on silica gel (EtOAc/pet. ether, 3:2) to give
DKP 26 (35 mg, 68%) as a white solid. Mp 292e294 ꢀC; [
a
]
22 ꢁ40 (c
D
0.81, CHCl3), lit.24
[a
]
25 ꢁ49.6 (c 0.80, CHCl3); FTIR (KBr) nmax 3323,
D
2959, 1675, 1512, 1395, 1246, 746; 1H NMR (500 MHz, CDCl3)
d 7.74
(br s, 1H, NH), 7.50 (d, J 7.5, 1H, Ar, CH), 7.24 (d, J 8.0, 1H, Ar, CH), 7.15
(d, J 8.0, 2H, Ar, CH), 7.13e7.08 (m, 2H, Ar, CH), 6.82 (d, J 8.5, 2H, Ar,
CH), 5.03 (d, J 16.0, 1H, NCHHAr), 4.41 (d, J 16.0, 1H, NCHHAr), 3.76
(s, 3H, OCH3), 3.72 (d, J 14.8, 1H, CCHHAr), 3.57 (ddd, J 13.4, 6.8, 6.8,
1H, NCHHCH2), 3.41 (ddd, J 13.4, 6.8, 6.8, 1H, NCHHCH2), 3.17 (d, J
14.8, 1H, CCHHAr), 2.96 (ddd, J 12.8, 6.8, 6.8, 1H, CCHHCH2), 2.46
(dd, J 10.2, 4.0, 1H, CHHCH), 2.25 (dd, J 13.5, 10.2, 1H, CH2CH),
2.09e1.94 (m, 4H, CHHCH, CCHHCH2, CH2CH2CH2), 1.24 (s, 3H, CH3),
3H, CH3), 1.06 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d 169.9 (C]
O),167.1 (C]O),138.7 (Ar, C),136.5 (Ar, C),134.3 (Ar, C),129.8 (2ꢂAr,
CH), 129.2 (Ar, CH), 128.6 (2ꢂAr, CH), 127.2 (Ar, C), 121.8 (Ar, CH),
119.3 (Ar, CH), 118.4 (Ar, CH), 110.6 (Ar, CH), 104.8 (Ar, C), 79.7
(OCH2Ar), 68.9 (C-18), 66.1 (C-4), 47.8 (CH2CH), 44.2 (NCH2), 34.8 (C
(CH3)2), 31.3 (CH2CH), 29.7 (CCH2CH2), 28.2 (CH3), 24.3
(CH2CH2CH2), 22.4 (CH3), 20.2 (CCH2Ar); HRMS (ESI) calculated for
1.10 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
d
173.3 (C]O), 168.1
C28H29N3O3Na [MþNa]þ 478.2107, found 478.2101.
21
(C]O), 158.8 (Ar, C), 138.5 (Ar, C), 136.4 (Ar, C), 130.4 (Ar, C), 127.9
(2ꢂAr, CH), 126.9 (Ar, C), 121.9 (Ar, CH), 119.4 (Ar, CH), 118.4 (Ar, CH),
114.3 (2ꢂAr, CH), 110.5 (Ar, CH), 105.0 (Ar, C), 65.9 (C-4), 65.0 (C-18),
55.2 (OCH3), 48.5 (CH2CH), 44.6 (NCH2Ar), 44.2 (NCH2CH2), 35.2 (C
(CH3)2), 30.9 (CCH2CH2), 30.2 (CH2CH), 28.6 (CH3), 24.4
(CH2CH2CH2), 22.8 (CH3), 22.3 (CCH2Ar); HRMS (ESI) calculated for
C29H32N3O3 [MþH]þ 470.2444, found 470.2452.
Data for minor C-6 epimer: mp 210e212 ꢀC; [
a]
þ61 (c 1.02,
D
CHCl3); FTIR (KBr) nmax 3266, 2955, 1679, 1460, 1310; 1H NMR
(400 MHz, CDCl3) 7.77 (br s, 1H, NH), 7.54 (d, J 6.8, 1H, Ar, CH), 7.
d
33e7.29 (m, 2H, Ar, CH), 7.25e7.21 (m, 2H, Ar, CH), 7.19e7.13 (m, 4H,
Ar, CH), 4.93 (d, J 10.0, 1H, OCHHAr), 4.83 (d, J 10.0, 1H, OCHHAr),
3.69 (d, J 18.0, 1H, CCHHAr), 3.57e3.53 (m, 2H, NCH2), 3.21 (d, J 18.0,
1H, CCHHAr), 2.90 (ddd, J 13.2, 6.6, 6.6, 1H, CCHHCH2), 2.40 (dd, J
9.6, 4.8, 1H, CH2CH), 2.19e2.05 (m, 4H, CH2CH2CH2, CH2CH), 1.93
(m, 1H, CCHHCH2), 1.33 (s, 3H, CH3), 1.26 (s, 3H, CH3); 13C NMR
4.1.6. (8aR)-3-((1H-Indol-3-yl)methyl)-2-(benzyloxy)-3-hydroxy-8a-
(3-methylbut-2-enyl)hexa-hydropyrrolo[1,2-a]pyrazine-1,4-dione
(28). To a stirred solution of indole pyruvic acid (337 mg,1.66 mmol,
1.2 equiv) and proline derivative 27 (400 mg, 1.38 mmol) in THF
(32 mL) was added successively HOBt (224 mg, 1.66 mmol,
1.2 equiv) and DCC (1.66 mL, 1.0 M in DCM, 1.66 mmol, 1.2 equiv) at
room temperature. The mixture was stirred at room temperature for
24 h and the resulting urea was filtered though a pad of CeliteÒ. The
volatile organics were removed under reduced pressure and the
residue was purified by flash column chromatography on silica gel
(pet. ether/EtOAc, 7:3) to afford hydroxy-DKP 28 (284 mg, 46%) as
(75 MHz, CDCl3) d 168.6 (C]O),167.9 (C]O),139.2 (Ar, C),136.3 (Ar,
C), 134.0 (Ar, C), 129.5 (2ꢂAr, CH), 128.9 (Ar, CH), 128.4 (2ꢂAr, CH),
126.9 (Ar, C), 121.6 (Ar, CH), 119.3 (Ar, CH), 118.3 (Ar, CH), 110.6 (Ar,
CH), 104.7 (Ar, C), 79.0 (OCH2Ar), 68.8 (C-18), 67.1 (C-4), 46.3
(CH2CH), 44.1 (NCH2), 34.3 (C(CH3)2), 32.4 (CH2CH), 29.4
(CCH2CH2), 28.6 (CH3), 24.3 (CH2CH2CH2), 23.2 (CH3), 20.2
(CCH2Ar); HRMS (ESI) calculated for C28H29N3O3Na [MþNa]þ
478.2107, found 478.2111.
4.1.8. Synthesis of 30 via NeO cleavage. 4.1.8.1. General procedure
for SmI2 mediated cleavage of OBn protecting group. A solution of
LiCl (2.9 mL, 0.90 M in THF, 2.64 mmol, 12.0 equiv) was added to
a stirred solution of freshly prepared SmI2 (3.6 mL, 0.24 M in THF,
0.88 mmol, 4.0 equiv) at room temperature. After 30 min, a solution
of DKP 29 (major epimer) (100 mg, 0.22 mmol) in THF (2.0 mL) was
added and the resulting mixturewas stirred at roomtemperature for
24 h. Low boiling organics were removed under reduced pressure
and the residue was dissolved in EtOAc (20 mL). The organic layer
was washed with a 10% aqueous sodium thiosulfate solution (10 mL)
and the aqueous phase was extracted with EtOAc (2ꢂ10 mL). The
combined organic extracts were washed with brine (20 mL), dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (CH2Cl2/acetone, 7:1) to
afford NeH DKP 30 as a white solid (47 mg, 62%). Mp 318e320 ꢀC;
a pale yellow solid. Mp 184e186 ꢀC; [
a
]
D
20 þ84 (c 0.98, CHCl3); FTIR
(KBr) nmax 3317, 2928, 1645, 1406, 1109, 1067; 1H NMR (400 MHz,
CDCl3) d 8.62 (br s, 1H, NH), 7.65e7.61 (m, 3H, Ar, CH), 7.40e7.37 (m,
3H, Ar, CH), 7.26 (t, J 7.8,1H, Ar, CH), 7.10 (t, J 7.8,1H, Ar, CH), 7.07e7.02
(m, 2H, Ar, CH), 5.15 (d, J 9.4,1H, OCHHAr), 5.11 (d, J 9.4,1H, OCHHAr),
5.00 (m, 1H, CH]C), 4.29 (br s, 1H, OH), 3.73 (d, J 14.2, 1H, CCHHAr),
3.56 (d, J 14.2,1H, CCHHAr), 3.27 (ddd, J 12.4, 9.6, 5.2,1H, NCHH), 3.04
(ddd, J 12.4,10.4, 5.2,1H, NCHH), 2.39 (dd, J 14.2, 8.2,1H, CHHCH]C),
2.13 (dd, J 14.2, 7.4,1H, CHHCH]C),1.74 (s, 3H, CH3),1.56 (s, 3H, CH3),
1.55 (m, 1H, CCHHCH2), 1.40 (m, 1H, CH2CHHCH2), 0.60 (m, 1H,
CH2CHHCH2), 0.25 (m, 1H, CCHHCH2); 13C NMR (75 MHz, CDCl3)
d
166.1 (C]O),164.7 (C]O),137.2 (Ar, C),135.5 (CH]C),135.3 (Ar, C),
129.5 (2ꢂAr, CH),128.7 (Ar, CH),128.4 (2ꢂAr, CH),127.1 (Ar, C),126.2
(Ar, CH), 121.9 (Ar, CH), 119.3 (Ar, CH), 119.2 (Ar, CH), 117.1 (CH]C),
110.9 (Ar, CH), 107.4 (Ar, C), 91.1 (C-3), 78.8 (OCH2Ar), 67.7 (C-8a),
44.2 (NCH2), 36.2 (CH2CH]C), 34.5 (CCH2Ar), 33.0 (CCH2CH2), 25.9
(CH3), 18.5 (CH2CH2CH2), 18.0 (CH3); HRMS (ESI) calculated for
C28H31N3O4Na [MþNa]þ 496.2212, found 496.2215.
[a
]
19 ꢁ14.2 (c 0.90, MeOH); FTIR (KBr) nmax 3296, 2965, 1678, 1459,
D
1395,1238, 746; 1H NMR (400 MHz, CDCl3)
d
7.79 (br s,1H, NH), 7.53
(d, J 7.4,1H, Ar, CH), 7. 30 (d, J 7.4,1H, Ar, CH), 7.19e7.10 (m, 2H, Ar, CH),
6.09 (br s, 1H, NH), 3.91 (d, J 15.2, 1H, CCHHAr), 3.58 (ddd, J 11.8, 6.4,
6.4,1H, NCHH), 3.42 (ddd, J 11.8, 7.6, 7.6,1H, NCHH), 2.83 (ddd, J 13.2,
6.8, 6.8, 1H, CCHHCH2), 2.67 (d, J 15.2, 1H, CCHHAr), 2.62 (dd, J 10.4,
5.0,1H, CH2CH), 2.26 (dd, J 13.2,10.4,1H, CHHCH), 2.08e2.01 (m, 2H,
CH2CH2CH2), 1.98 (dd, J 13.2, 5.0, 1H, CHHCH), 1.96 (ddd, J 13.2, 7.6,
7.6, 1H, CCHHCH2), 1.33 (s, 3H, CH3), 1.14 (s, 3H, CH3); 13C NMR
4.1.7. Cyclisation of 28 to give bridged DKP 29, along with a minor C-
6 epimer. The general procedure for TMSOTf-mediated cationic
cyclisation was followed starting from hydroxy-DKP 28 (600 mg,
1.27 mmol), TMSOTf (0.25 mL, 1.40 mmol, 1.1 equiv), Et3N (0.88 mL,
6.35 mmol, 5.0 equiv) and CH2Cl2 (20 mL). The residue was purified
(100 MHz, DMSO)
d 173.0 (C]O), 168.5 (C]O), 140.7 (Ar, C), 136.4
(Ar, C),126.4 (Ar, C),120.6 (Ar, CH),118.1 (Ar, CH),117.5 (Ar, CH),110.7

6594
F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
(Ar, CH), 103.3 (Ar, C), 65.9 (C-18), 59.6 (C-4), 49.1 (CH2CH), 43.5
(NCH2), 34.5 (C(CH3)2), 30.1 (CH2CH), 28.6 (CCH2CH2), 27.9 (CH3),
24.0 (CH2CH2CH2), 23.8 (CH3), 21.6 (CCH2Ar); HRMS (ESI) calculated
for C21H23N3O2Na [MþNa]þ 372.1688, found 372.1696.
(CH2CH), 46.5 (C(CH3)2), 43.9 (NCH2), 36.1 (CCH2C), 29.1 (CCH2CH2),
28.6 (CH2CH), 24.9 (CH2CH2CH2), 22.6 (CH3), 20.3 (CH3); HRMS (ESI)
calculated for C21H23N3O3Na [MþNa]þ 388.1637, found 388.1626.
4.1.11. Indole formylation to give 40. To a stirred solution of POCl3
(0.28 mL, 3.06 mmol, 1.1 equiv) in dry DMF (4 mL) at 0 ꢀC was
added a solution of pyranoindole 39 (553 mg, 2.78 mmol) in dry
DMF (3 mL). The resulting mixture was allowed to warm to room
temperature and stirred for 1 h. The mixture was then cooled to
0 ꢀC and a solution of sodium hydroxide (1.11 g, 27.8 mmol,
10 equiv) in water (4 mL) was added. The reaction mixture was
allowed to warm to room temperature and stirred for another 1.5 h.
The solution was diluted with water (20 mL) and extracted with
EtOAc (3ꢂ25 mL). The combined organic extracts were washed
with brine (3ꢂ25 mL), dried (MgSO4) and concentrated under re-
duced pressure. This material was directly used in the next step
without additional purification. An analytical sample was obtained
by flash column chromatography (pet. ether/Et2O, 9:1) affording
the formylated indole intermediate as a pale brown oil. FTIR (film)
nmax 3238, 2977, 1636, 1446, 1135, 758; 1H NMR (300 MHz, CDCl3)
4.1.9. Synthesis of spiro-indoxyl 32 via 31. To a stirred solution of
indole 29 (minor epimer) (95 mg, 0.208 mmol) in THF (10 mL) was
added m-CPBA (67 mg, 70% in water, 0.271 mmol, 1.3 equiv) at
room temperature and the resulting mixture was stirred for 1.5 h.
Excess m-CPBA was quenched with two drops of dimethyl sulfide
and the solvent was evaporated under reduced pressure. The resi-
due was dissolved in a 1 M solution of sodium methoxide in
methanol (16 mL) and the resulting mixture was heated to 85 ꢀC for
1.5 h. The resulting yellow solution was cooled to room tempera-
ture and 3 M aqueous HCl (14 mL) was slowly added. Low boiling
organics were removed in vacuo and the cloudy solution was di-
luted in water (10 mL). The solution was extracted with CH2Cl2
(3ꢂ10 mL) and the combined organic extracts were dried (MgSO4).
After concentration in vacuo, the residue was purified by flash
column chromatography on silica gel (CH2Cl2/acetone, 95:5) to af-
ford spiro-indoxyl 32 (68 mg, 69% over two steps) as a fluorescent
d 10.02 (br s, 1H, NH), 9.96 (s, 1H, CHO), 8.03 (d, J 8.4, 1H, Ar, CH),
21
yellow oil. [
a
]
D
ꢁ114 (c 0.90, CHCl3); FTIR (film) nmax 3351, 2952,
7.76 (d, J 3.3, 1H, Ar, CH), 6.85 (d, J 8.4, 1H, Ar, CH), 6.71 (d, J 9.7, 1H,
2877, 1693, 1618, 1469, 1325, 752; 1H NMR (500 MHz, CDCl3)
d 7.54
CH]CH), 5.68 (d, J 9.7, 1H, CH]CH), 1.46 (s, 6H, C(CH3)2); 13C NMR
(d, J 7.0, 1H, Ar, CH), 7.42e7.35 (m, 6H, Ar, CH), 6.78e6.75 (m, 2H, Ar,
CH), 4.91 (d, J 9.5, 1H, OCHHAr), 4.82 (br s, 1H, NH), 4.70 (d, J 9.5, 1H,
OCHHAr), 3.49e3.45 (m, 2H, NCH2), 3.31 (dd, J 10.5, 7.0, 1H, CHCH2),
3.05 (d, J 15.4, 1H, CCHHC), 2.77 (ddd, J 13.2, 6.8, 6.8, 1H, CCHHCH2),
2.46 (d, J 15.4, 1H, CCHHC), 2.05e1.83 (m, 4H, CH2CH2CH2, CHHCH,
CCHHCH2), 1.78 (dd, J 12.8, 7.0, 1H, CHHCH), 0.99 (s, 3H, CH3), 0.81
(75 MHz, CDCl3) d 185.6 (HC]O), 150.2 (Ar, C), 136.0 (Ar, C), 133.6
(Ar, C), 130.7 (CH]CH), 121.8 (Ar, CH), 119.8 (Ar, C), 118.7 (Ar, C),
116.4 (CH]CH), 113.6 (Ar, CH), 105.8 (Ar, C), 76.1 (C(CH3)2), 27.4 (C
(CH3)2); HRMS (ESI) calculated for C14H13NO2Na [MþNa]þ
250.0844, found 250.0847.
To a stirred solution of the crude indole-3-carboxaldehyde
obtained above (27.8 mmol) in THF (13 mL) was added successively
Boc2O (668 mg, 3.06 mmol, 1.1 equiv) and DMAP (34 mg,
0.28 mmol, 0.1 equiv) at room temperature. The resulting mixture
was stirred at room temperature for 1.5 h and then the solvent was
evaporated under reduced pressure. The residue was purified by
flash column chromatography (pet. ether/EtOAc, 9:1) to give N-Boc
formyl indole 40 (793 mg, 87% over two steps) as a white solid. Mp
158e160 ꢀC; FTIR (KBr) nmax 2978, 2931, 1753, 1672, 1259, 1137, 982;
(s, 3H, CH3); 13C NMR (125 MHz, CDCl3)
d 204.0 (C]O), 168.1 (C]
O), 167.2 (C]O), 160.2 (Ar, C), 137.2 (Ar, CH), 133.4 (Ar, C), 130.0
(2ꢂAr, CH),129.3 (Ar, CH),128.6 (2ꢂAr, CH),124.9 (Ar, CH),119.5 (Ar,
C), 118.6 (Ar, CH), 111.1 (Ar, CH), 78.3 (OCH2Ph), 77.6 (C-2), 73.2 (C-
9), 68.6 (C-12), 50.7 (CH2CH), 46.2 (C(CH3)2), 43.8 (NCH2), 31.5
(CCH2C), 29.4 (CCH2CH2), 28.4 (CH2CH), 24.8 (CH2CH2CH2), 22.4
(CH3), 19.0 (CH3); HRMS (ESI) calculated for C28H29N3O4Na
[MþNa]þ 494.2056, found 494.2062.
1H NMR (300 MHz, CDCl3)
d 10.02 (s, 1H, CHO), 8.06 (s, 1H, Ar, CH),
4.1.10. Synthesis of (ꢁ)-brevianamide B (ent-1) via 33. The general
procedure for cleavage of OBn protecting group was followed
starting from 32 (16 mg, 0.034 mmol), LiCl (0.45 mL, 0.90 M in THF,
0.408 mmol, 12.0 equiv), SmI2 (0.84 mL, 0.24 M in THF, 0.204 mmol,
6.0 equiv) and THF (1.0 mL). The crude residue from the NeO
cleavage process was dissolved in CH2Cl2 (1.5 mL) and commer-
cially available Dess/Martin periodinane (0.14 mL, 15% in CH2Cl2,
0.068 mmol, 2.0 equiv) was added at 0 ꢀC. The resulting mixture
was stirred at the same temperature for 2 h before a saturated
aqueous sodium thiosulfate solution (2 mL) was added. CH2Cl2
(3 mL) was added and the layers were separated. The aqueous
phase was extracted with CH2Cl2 (2ꢂ5 mL) and the combined or-
ganic extracts were washed with brine (10 mL), dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (CH2Cl2/MeOH, 30:1) to
8.05 (d, J 8.8, 1H, Ar, CH), 6.95e6.92 (m, 2H, Ar, CH, CH]CH), 5.64
(d, J 10.4, 1H, CH]CH), 1.67 (s, 9H, C(CH3)3), 1.46 (s, 6H, C(CH3)2);
13C NMR (75 MHz, CDCl3)
d 185.6 (HC]O), 152.7 (Ar, C), 148.9 (C]
O), 137.7 (Ar, CH), 132.6 (Ar, C), 127.5 (CH]CH), 122.3 (Ar, CH), 121.6
(Ar, C), 121.0 (Ar, C), 120.9 (CH]CH), 115.5 (Ar, CH), 109.5 (Ar, C),
87.5 (C(CH3)3), 75.0 (C(CH3)2), 27.9 (C(CH3)3), 27.1 (C(CH3)2); HRMS
(ESI) calculated for C19H21NO4Na [MþNa]þ 350.1368, found
350.1376.
4.1.12. Aldol addition and elimination to give ester 41. To a stirred
solution of O-SEM ester (1.52 g, 6.90 mmol, 3.0 equiv), in THF
(40 mL) was added LHMDS (7.13 mL, 1.0 M in THF, 7.13 mmol,
3.1 equiv) at ꢁ78 ꢀC. The resulting mixture was stirred at the same
temperature for 30 min before a solution of formyl indole 40
(755 mg, 2.30 mmol), in THF (5 mL) was added. The solution was
stirred at ꢁ78 ꢀC for an additional 2 h and then quenched with
a saturated aqueous ammonium chloride solution (10 mL). The
solution was allowed to warm to room temperature and then
concentrated in vacuo. The residue was partitioned between EtOAc
(50 mL) and water (50 mL) and the layers were separated. The
aqueous phase was extracted with EtOAc (2ꢂ50 mL) and the
combined organic extracts were washed with brine (50 mL), dried
(MgSO4) and concentrated under reduced pressure to afford an
give ent-1 (6.0 mg, 48% over two steps) as a fluorescent yellow oil.
22
[
a]
ꢁ147 (c 0.23, 2.5% HCO2H in CH2Cl2), lit.24
[
a
]
25 ꢁ124 (c 0.81,
D
D
2.5% HCO2H in CH2Cl2); FTIR (film) nmax 3261, 2924, 2853, 1693,
1619, 1466, 1390, 1326, 1260, 753; 1H NMR (400 MHz, CDCl3)
d 7.56
(d, J 7.2, 1H, Ar, CH), 7.41 (m, 1H, Ar, CH), 6.84 (br s, 1H, NH), 6.83 (d, J
8.4, 1H, Ar, CH), 6.78 (t, J 7.2, 1H, Ar, CH), 5.08 (br s, 1H, NH),
3.50e3.44 (m, 2H, NCH2), 3.27 (dd, J 9.6, 8.0, 1H, CHCH2), 3.21 (d, J
15.4, 1H, CCHHAr), 2.73 (ddd, J 12.8, 6.8, 6.8, 1H, CCHHCH2),
2.04e1.94 (m, 3H, CH2CH2CH2, CHHCH), 1.85 (d, J 15.4, 1H, CCHHAr),
1.87e1.76 (m, 2H, CHHCH, CCHHCH2), 1.14 (s, 3H, CH3), 0.84 (s, 3H,
intermediate b-hydroxy ester as a light brown oil. This material was
CH3); 13C NMR (75 MHz, CDCl3)
d 204.3 (C]O), 173.7 (C]O), 169.3
directly used in the next step without additional purification.
Toasolutionofthealdoladductobtainedabove(1.19 g,2.17 mmol)
in CH2Cl2 (30 mL) was added MsCl (0.34 mL, 4.34 mmol, 2.0 equiv)
(C]O), 160.4 (Ar, C), 137.3 (Ar, CH), 125.0 (Ar, CH), 119.7 (Ar, C), 118.8
(Ar, CH), 111.4 (Ar, CH), 77.2 (C-2), 68.8 (C-12), 66.5 (C-9), 49.7

F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
6595
and Et3N (0.90 mL, 6.51 mmol, 3.0 equiv). After 1 h, DBU (1.62 mL,
(CH2CH2Si), 28.0 (C(CH3)3), 27.9 (C(CH3)3
*
), 27.1 (C-7(CH3)2
*
), 27.0 (C-
10.8 mmol, 5.0 equiv) was added and the mixture was stirred at room
temperature for 16 h. The mixture was quenched with a saturated
aqueousammoniumchloridesolution(10 mL)andwater(40 mL)was
then added. The layers were separated and the aqueous phase was
extracted with CH2Cl2 (2ꢂ50 mL). The combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by flash column chromatography (pet.
7(CH3)2), 18.0 (CH2Si
*
),17.9 (CH2Si), ꢁ1.4 (Si(CH3)3), ꢁ1.7 (Si(CH3)3);
*
HRMS (ESI) calculated for C27H37NO7SiNa [MþNa]þ 538.2237,
found 538.2214.
4.1.14. Peptide coupling to give 43. To a stirred solution of proline
derivative 27 (407 mg, 1.41 mmol) and acid 42 (727 mg,1.41 mmol),
in dry MeCN (30 mL) was sequentially added DIPEA (0.37 mL,
2.11 mmol, 1.5 equiv) and HATU (590 mg, 1.55 mmol, 1.1 equiv), at
room temperature. The resulting mixture was stirred at room
temperature for 16 h. After concentration under reduced pressure,
the resulting crude oil was dissolved in EtOAc (25 mL) and washed
successively with a 1 N aqueous potassium hydrogen sulfate solu-
tion (10 mL), water (10 mL) and brine (10 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo.
ether/Et2O, 9:1) to yield (Z)-41 and (E)-41 as an inseparable 1.3:1
*
mixture of stereoisomers (1.01 g, 88%), as a yellow oil. FTIR (film)
nmax 2977, 2953, 1721, 1370, 1250, 1153, 1075, 758; 1H NMR
(400 MHz, CDCl3)
(d, J 8.4, 1H, Ar, CH), 7.26 (d, J 8.8, 1H, Ar, CH
7.03 (d, J 10.0,1H, CH]CHC-7 ), 6.99 (d, J 10.0, 1H, CH]CHC-7), 6.88
(d, J 8.4, 1H, Ar, CH), 6.85 (d, J 8.4, 1H, Ar, CH ), 6.69 (d, J 1.0, 1H, CH]
), 5.63 (d, J 10.0,1H, CHC-7), 5.62 (d, J 10.0, 1H, CHC-7 ), 5.26 (s, 2H,
OCH2O), 5.18 (s, 2H OCH2O ), 3.86 (s, 3H, OCH3), 3.85e3.81 (m, 2H,
CH2CH2Si ), 3.78 (s, 3H, OCH3), 3.71e3.67 (m, 2H, CH2CH2Si), 1.65 (s,
18H, C(CH3)3, C(CH3)3), 1.49 (s, 6H, C-7(CH3)2), 1.48 (s, 6H, C-7
(CH3)2
(Si(CH3)3
d
8.19 (s,1H, Ar, CH), 7.93 (d, J 1.0,1H, Ar, CH
*
), 7.47
*
), 7.21 (s, 1H, CH]C),
*
*
C
*
*
The residue was purified by flash column chromatography (pet.
ether/EtOAc, 4:1) to afford (E)-43 (377 mg, 34%) as a light yellow oil
followed by (Z)-43 (483 mg, 44%) as a light yellow oil.
*
*
*
22
*
Data for (E)-43; [
a
]
ꢁ33.0 (c 0.96, CHCl3); FTIR (film) nmax
D
*
), 1.04e0.99 (m, 2H, CH2Si
*
*
), 0.87e0.83 (m, 2H, CH2Si), 0.05
3284, 3013, 2978, 1742, 1687, 1633, 1370, 1217, 1154, 755; 1H NMR
(500 MHz, CDCl3) 10.50 (s, 1H, NH), 7.48 (d, J 1.0, 1H, Ar, CH),
), ꢁ0.12 (Si(CH3)3); 13C NMR (100 MHz, CDCl3)
d
164.3 (C]
), 149.6
, Ar, C), 128.8 (Ar,
), 125.6 (Ar, C ), 124.7
), 121.5 (CHC-7), 119.0 (Ar, CH), 118.7 (Ar, CH ),
115.1 (CH]C), 114.0 (Ar, CH), 113.7 (Ar, CH ), 113.5 (Ar, C), 113.3 (Ar,
), 109.7 (Ar, C, Ar, C ), 109.6 (CH]C ), 95.1 (OCH2O), 94.7
(OCH2O ), 84.2 (C(CH3)3), 83.8 (C(CH3)3), 74.9 (C-7), 74.8 (C-7 ), 67.5
(CH2CH2Si), 66.6 (CH2CH2Si ), 52.0 (OCH3, OCH3), 28.0 (C(CH3)3, C
(CH3)3), 27.1 (C-7(CH3)2, C-7(CH3)2), 18.1 (CH2Si
), 18.0 (CH2Si), ꢁ1.4
(Si(CH3)3
d
O), 164.1 (C]O
(C]O), 143.8 (CH]C
CH), 126.9 (CH]CHC-7, CH]CHC-7
(Ar, C), 121.6 (CHC-7
*
), 151.9 (Ar, C), 151.7 (Ar, C
*
), 149.8 (C]O
*
7.42e7.40 (m, 2H, Ar, CH), 7.35e7.30 (m, 3H, Ar, CH), 7.26 (d, J 8.0,
1H, Ar, CH), 7.05 (d, J 10.0, 1H, CH]CHC-7), 6.84 (d, J 8.5, 1H, Ar, CH),
6.09 (d, J 1.0, 1H, CH]C(OSEM), 5.62 (d, J 10.0, 1H, CHC-7), 5.16 (d, J
6.8, 1H, OCHHO), 5.07 (d, J 6.8, 1H, OCHHO), 4.93 (d, J 11.2, 1H,
OCHHPh), 4.83 (d, J 11.2, 1H, OCHHPh), 4.67 (m, 1H, CH]C(CH3)2),
3.85e3.73 (m, 2H, OCH2CH2Si), 3.60 (m, 1H, NCHHCH2), 3.11e3.06
(m, 2H, NCHHCH2, CHHCH]C), 2.57 (dd, J 14.5, 6.0, 1H, CHHCH]C),
2.49 (m, 1H, CCHHCH2),), 1.68e1.57 (m, 3H, CCHHCH2, CH2CH2CH2),
1.55 (s, 12H, C(CH3)3, CH3), 1.53 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.47 (s,
3H, CH3), 1.02e0.98 (m, 2H, CH2Si), ꢁ0.06 (s, 9H, Si(CH3)3); 13C NMR
*
), 141.5 (CH]C), 131.6 (Ar, C
*
*
, Ar, CH
*
*
*
*
*
*
C
*
*
*
*
*
*
*
*
*
*
*
), ꢁ1.7 (Si(CH3)3); HRMS (ESI) calculated for C28H39NO7
-
SiNa [MþNa]þ 552.2393, found 552.2389.
(125 MHz, CDCl3) d 170.5 (C]O), 165.6 (C]O), 152.0 (Ar, C), 149.5
(CH]C(OSEM)), 149.3 (C]O), 135.6 (CH]C(CH3)2), 135.4 (Ar, C),
131.9 (Ar, C),129.2 (2ꢂAr, CH),128.4 (Ar, CH),128.3 (2ꢂAr, CH),127.0
(CHC-7), 125.3 (Ar, CH), 124.6 (Ar, C), 121.5 (CH]CHC-7), 118.8 (Ar,
CH), 117.8 (CH]C(CH3)2), 113.8 (Ar, CH), 113.4 (Ar, C), 109.9 (Ar, C),
97.2 (CH]C(OSEM)), 93.2 (OCH2O), 83.8 (C(CH3)3), 77.8 (OCH2Ph),
74.8 (C-7), 70.5 (C-2), 67.2 (CH2CH2Si), 50.4 (NCH2CH2), 34.8
(CCH2CH2), 32.3 (CH2CH]C), 27.8 (C(CH3)3), 27.4 (CH3), 26.9 (CH3),
25.9 (CH3), 22.9 (CH2CH2CH2), 18.1 (CH3), 18.0 (CH2Si), ꢁ1.4 (Si
(CH3)3); HRMS (ESI) calculated for C44H59N3O8SiNa [MþNa]þ
808.3969, found 808.3979.
4.1.13. Hydrolysis of ester 41 to give acid 42. To a stirred solution of
enol ester 41 (1.17 g, 2.21 mmol) in a mixture THF/H2O (42 mL, 2:1)
was added LiOH/H2O (464 mg, 11.0 mmol, 5.0 equiv) at room tem-
perature under N2 and the resulting mixture was stirred for 8 h. The
volatile organics were then removed under reduced pressure and
the residue was diluted with water (40 mL). The solution was
acidified by slow addition of a 1 M aqueous potassium hydrogen
sulfate solution to reach pHz2. The resulting cloudy and oily so-
lution was extracted with EtOAc (3ꢂ20 mL). The combined organic
extracts were washed with brine (20 mL), dried (Na2SO4) and
concentrated in vacuo.
Data for (Z)-43; [
a
]
D
22 ꢁ45.0 (c 1.1, CHCl3); FTIR (film) nmax 3310,
3016, 2979, 1736, 1682, 1630, 1370, 1216, 1154, 754; 1H NMR
The residue was purified by flash column chromatography (pet.
(500 MHz, CDCl3) d 10.15 (s,1H, NH), 7.94 (s,1H, Ar, CH), 7.45 (d, J 7.0,
ether/Et2O, 95:5 to 1:1) to give (Z)-42 and (E)-42
*
as an inseparable
2H, Ar, CH), 7.37e7.32 (m, 3H, Ar, CH), 7.29 (d, J 8.0, 1H, Ar, CH), 6.98
(d, J 10.0,1H, CH]CHC-7), 6.86 (d, J 8.5,1H, Ar, CH), 5.87 (s,1H, CH]C
(OSEM)), 5.63 (d, J 10.0, 1H, CHC-7), 5.12 (d, J 6.8, 1H, OCHHO), 5.09
(m,1H, CH]C(CH3)2), 4.99 (d, J 11.2,1H, OCHHPh), 4.88 (d, J 11.2,1H,
OCHHPh), 4.87 (d, J 6.8, 1H, OCHHO), 3.78e3.68 (m, 2H, CHHCH2Si,
NCHHCH2), 3.60e3.51 (m, 2H, CHHCH2Si, NCHHCH2), 3.14 (dd, J 15.0,
7.5, 1H, CHHCH]C), 2.79 (dd, J 15.0, 7.5, 1H, CHHCH]C), 2.50 (dd, J
13.0, 6.0,1H, CCHHCH2), 2.03 (td, J 13.0, 7.0,1H, CCHHCH2),1.81e1.72
(m, 2H, CH2CH2CH2), 1.79 (s, 3H, CH3), 1.65 (s, 3H, CH3), 1.64 (s, 9H, C
(CH3)3), 1.49 (s, 3H, CH3), 1.48 (s, 3H, CH3), 0.95 (m, 1H, CHHSi), 0.82
(m, 1H, CHHSi), ꢁ0.05 (s, 9H, Si(CH3)3); 13C NMR (125 MHz, CDCl3)
1.3:1 mixture of stereoisomers (552 mg, 50%), as a yellow oil, along
with recovered starting ester 41 (419 mg, 36%). FTIR (film) nmax
2977, 2253, 1738, 1694, 1633, 1371, 1277, 985, 732; 1H NMR
(400 MHz, CDCl3)
J 8.8, Ar, CH), 7.40 (s, 1H, CH]C), 7.32 (d, J 8.8, 1H, Ar, CH
10.4, CH]CHC-7 ), 6.99 (d, J 9.6, CH]CHC-7), 6.92 (s, 1H, CH]C
6.90 (d, J 8.8, 1H, Ar, CH), 6.88 (d, J 8.8, 1H, Ar, CH ), 5.64 (d, J 10.4,
CHC-7), 5.64 (d, J 9.6, CHC-7 ), 5.30 (s, 2H, OCH2O), 5.22 (s, 2H
OCH2O ), 3.88e3.84 (m, 2H, CH2CH2Si ), 3.75e3.71 (m, 2H,
CH2CH2Si),1.66 (s, 9H, C(CH3)3),1.65 (s, 9H, C(CH3)3),1.50 (s, 6H, C-7
d
8.28 (s,1H, Ar, CH
*
), 8.26 (s,1H, Ar, CH
), 7.05 (d, J
),
*
), 7.48 (d,
*
*
*
*
*
*
*
*
(CH3)2), 1.49 (s, 6H, C-7(CH3)2
0.91e0.87 (m, 2H, CH2Si), 0.06 (Si(CH3)3
NMR (75 MHz, CDCl3)
151.7 (Ar, C ), 149.7 (C]O
(CH]C), 131.5 (Ar, C , Ar, C), 129.4 (Ar, CH), 128.9 (Ar, CH
(CH]CHC-7, CH]CHC-7 ), 125.6 (Ar, C ), 124.5 (Ar, C), 121.4 (CHC-
), 121.3 (CHC-7), 118.9 (Ar, CH), 118.4 (Ar, CH ), 117.4 (CH]C),
114.1 (Ar, CH), 113.9 (CH]C ), 113.8 (Ar, CH ), 113.4 (Ar, C), 112.4 (Ar,
), 109.7 (Ar, CH, Ar, CH ), 95.3 (OCH2O), 95.1 (OCH2O ), 84.3 (C
(CH3)3), 84.0 (C(CH3)3), 74.8 (C-7, C-7 ), 67.7 (CH2CH2Si), 66.8
*
), 1.06e1.02 (m, 2H, CH2Si
*
),
d 171.5 (C]O),164.7 (C]O),151.8 (Ar, C),149.9 (C]O),145.3 (CH]C
*
), ꢁ0.10 (Si(CH3)3); 13C
(OSEM)),136.6 (CH]C(CH3)2),135.8 (Ar, C),131.5 (Ar, C),129.2 (2ꢂAr,
CH), 128.4 (Ar, CH), 128.3 (2ꢂAr, CH), 126.9 (CHC-7), 126.7 (Ar, CH),
124.8 (Ar, C),121.7 (CH]CHC-7),118.4 (Ar, CH),117.4 (CH]C(CH3)2),
113.7 (Ar, CH), 113.3 (Ar, C), 109.9 (Ar, C), 103.2 (CH]C(OSEM)), 92.2
(OCH2O), 84.0 (C(CH3)3), 77.7 (OCH2Ph), 74.8 (C-7), 70.5 (C-2), 67.4
(CH2CH2Si), 52.2 (NCH2CH2), 35.0 (CCH2CH2), 31.5 (CH2CH]C), 28.1
(C(CH3)3), 27.2 (CH3), 26.9 (CH3), 26.3 (CH3), 23.1 (CH2CH2CH2), 18.2
(CH3), 17.8 (CH2Si), ꢁ1.6 (Si(CH3)3); HRMS (ESI) calculated for
C44H59N3O8SiNa [MþNa]þ 808.3969, found 808.3951.
d
168.9 (C]O), 167.1 (C]O ), 152.0 (Ar, C),
*
*
*
), 149.5 (C]O), 141.8 (CH]C
*
), 140.7
*
*
), 127.0
*
*
7
*
*
*
*
C
*
*
*
*
*

6596
F.C. Frebault, N.S. Simpkins / Tetrahedron 66 (2010) 6585e6596
6. Wulff, J. E.; Herzon, S. B.; Siegrist, R.; Myers, A. G. J. Am. Chem. Soc. 2007,129, 4898.
7. Wulff, J. E.; Siegrist, R.; Myers, A. G. J. Am. Chem. Soc. 2007, 129, 14444.
8. (a) Martínez-Luis, S.; Rodríguez, R.; Acevedo, L.; González, M. C.; Lira-Rocha, A.;
Mata, R. Tetrahedron 2006, 62, 1817; (b) Figueroa, M.; Del Carmen González, M.;
Mata, R. Nat. Prod. Res. 2008, 22, 709.
4.1.15. SEM removal to give DKP 44. To a stirred solution of SEM enol
ether 43 (200 mg, 0.255 mmol), in dry isopropanol (5.0 mL) was
added CBr4 (17.0 mg, 0.051 mmol, 0.2 equiv) at room temperature,
and the resulting mixture was then heated to 50 ꢀC for 24 h. The
mixturewascooledandthesolventremoved underreduced pressure.
The residue was purified by flash column chromatography (pet.
ether/EtOAc, 4:1) to afford hydroxy-DKP 44 (100 mg, 60%) as a pale
9. Miller, K. A.; Figueroa, M.; Valente, M. W. N.; Greshock, T. J.; Mata, R.; Williams,
R. M. Bioorg. Med. Chem. Lett. 2008, 18, 6479.
10. (a) For a recent example, see Tsukamoto, S.; Kato, H.; Greshock, T. J.; Hirota, H.;
Ohta, T.; Williams, R. M. J. Am. Chem. Soc. 2009, 131, 3834; (b) For studies re-
lating to malbrancheamide, see Ding, Y.; Greshock, T. J.; Miller, K. A.; Sherman,
D. H.; Williams, R. M. Org. Lett. 2008, 10, 4863.
11. (a) Miller, K. A.; Welch, T. R.; Greshock, T. J.; Ding, Y.; Sherman, D. H.; Williams,
R. M. J. Org. Chem. 2008, 73, 3116; (b) Greshock, T. J.; Williams, R. M. Org. Lett.
2007, 9, 4255.
brown solid. Mp 80e81 ꢀC; [
a
]
21 þ39 (c 1.6, CHCl3); FTIR (film) nmax
D
3330, 2978, 2930, 1740, 1647, 1371, 1155, 754; 1H NMR (400 MHz,
CDCl3) d 7.67e7.64 (m, 2H, Ar, CH), 7.45e7.39 (m, 3H, Ar, CH), 7.30 (t, J
4.0, 2H, Ar, CH), 6.98 (d, J 10.0, 1H, CHC-7), 6.77 (d, J 8.4, 1H, Ar, CH),
5.60 (d, J 10.0, 1H, CH]CHC-7), 5.19 (d, J 9.2, 1H, OCHHPh), 5.07 (d, J
9.2,1H, OCHHPh), 5.03 (m,1H, CH]C(CH3)2), 3.87 (br s,1H, OH), 3.61
(d, J 14.0, 1H, CCHHAr), 3.35 (d, J 14.0, 1H, CCHHAr), 3.28 (m, 1H,
NCHHCH2), 3.12 (m,1H, NCHHCH2), 2.41 (dd, J 14.0, 8.4,1H, CHHCH]
C), 2.19 (dd, J 14.0, 7.2,1H, CHHCH]C),1.76 (m,1H, CCHHCH2),1.74 (s,
3H, CH3), 1.63 (s, 9H, C(CH3)3), 1.57 (m, 1H, CH2CHHCH2), 1.55 (s, 3H,
CH3), 1.46 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.00 (m, 1H, CH2CHHCH2),
12. Artman, G. D., III; Grubbs, A. W.; Williams, R. M. J. Am. Chem. Soc. 2007, 129,
6336.
13. (a) Baran, P. S.; Guerrero, C. A.; Ambhaikar, N. B.; Hafensteiner, B. D. Angew.
Chem., Int. Ed. 2005, 44, 606; (b) Baran, P. S.; Guerrero, C. A.; Hafensteiner, B. D.;
Ambhaikar, N. B. Angew. Chem., Int. Ed. 2005, 44, 3892; (c) Baran, P. S.; Hafen-
steiner, B. D.; Ambhaiker, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am. Chem. Soc.
2006, 128, 8678.
14. (a) Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342 See also; (b)
Myers, A. G.; Herzon, S. B. J. Am. Chem. Soc. 2003, 125, 12080; (c) Trost, B. M.;
Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129, 3086.
15. Pichowicz, M.; Simpkins, N. S.; Blake, A. J.; Wilson, C. Tetrahedron 2008, 64, 3713.
16. Frebault, F.; Simpkins, N. S.; Fenwick, A. J. Am. Chem. Soc. 2009, 131, 4214.
17. Liebscher, J.; Jin, S. Chem. Soc. Rev. 1999, 28, 251 See also Ref. 32.
18. Bull, S. D.; Davies, S. G.; Garner, A. C.; Savory, E. D.; Snow, E. J.; Smith, A. D.
Tetrahedron: Asymmetry 2004, 15, 3989.
19. (a) Williams, R. M.; Armstrong, R. W.; Maruyama, L. K.; Dung, J.-S.; Anderson, O. P.
J. Am. Chem. Soc. 1985, 107, 3246; (b) Williams, R. M.; Anderson, O. P.; Armstrong,
R. W.; Josey, J. A.; Meyers, H.; Eriksson, C. J. Am. Chem. Soc. 1982, 104, 6092.
20. See for example Tsukamoto, S.; Kawabata, T.; Kato, H.; Greshock, T. J.; Hirota, H.;
Ohta, T.; Williams, R. M. Org. Lett. 2009, 11, 1297.
21. For example, VM55599, which is very unusual in this respect, see Ding, Y.;
Gruschow, S.; Greshock, T. J.; Finefield, J. M.; Sherman, D. H.; Williams, R. M. J.
Nat. Prod. 2008, 71, 1574.
0.73 (m, 1H, CCHHCH2); 13C NMR (125 MHz, CDCl3)
d 165.5 (C]O),
164.3 (C]O), 151.6 (Ar, C), 149.7 (C]O), 137.5 (CH]C(CH3)2), 135.5
(Ar, C),131.6 (Ar, C),129.4(2ꢂAr, CH),128.7(Ar, CH),128.4 (2ꢂAr, CH),
128.1 (Ar, CH), 127.0 (CH]CHC-7), 125.3 (Ar, C), 121.4 (CHC-7), 119.8
(Ar, CH),117.1 (CH]C(CH3)2),113.4 (Ar, CH),112.7 (Ar, C),109.4(Ar, C),
90.6 (C-3), 83.7 (C(CH3)3), 78.6 (OCH2Ph), 74.8 (C-7), 67.8 (C-8a), 44.2
(NCH2CH2), 36.3 (CH2CH]C), 33.6 (CCH2CH2), 33.5 (CCH2C-4), 27.9
(C(CH3)3), 27.3 (CH3), 26.8 (CH3), 25.9 (CH3), 18.9 (CH2CH2CH2), 18.0
(CH3); HRMS (ESI) calculated for C38H45N3O7Na [MþNa]þ 678.3155,
found 678.3146.
22. Williams, R. M.; Glinka, T. Tetrahedron Lett. 1986, 27, 3581.
23. Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 105,
5390.
Acknowledgements
24. Williams, R. M.; Glinka, T.; Kwast, E.; Coffman, H.; Stille, J. K. J. Am. Chem. Soc.
1990, 112, 808.
25. Siwicka, A.; Wojtasiewicz, K.; Rosiek, B.; Leniewski, A.; Maurin, J. K.; Czarnocki,
Z. Tetrahedron: Asymmetry 2005, 16, 975.
26. We tried conditions used for typical N-acyliminium reactions, see for a review
Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431.
27. Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451.
28. Yamaura, M.; Suzuki, T.; Hashimoto, J.; Okamoto, T.; Shin, C. Bull. Chem. Soc. Jpn.
1985, 58, 1413.
We thank Pfizer, Sandwich, UK, and the Universities of Not-
tingham and Birmingham for financial support. We thank staff at
Pfizer, including Dr. Ashley Fenwick, Dr. David Gethin, and Dr.
Richard Webster, for their support and input into this project.
The NMR instruments used in this research were obtained
through Birmingham Science City: Innovative Uses for Advanced
Materials in the Modern World (West Midlands Centre for Ad-
vanced Materials Project 2), with support from Advantage West
Midlands (AWM) and part funded by the European Regional De-
velopment Fund (ERDF).
29. Williams, D. R.; Kammler, D. C.; Donnell, A. F.; Goundry, W. R. F. Angew. Chem.,
Int. Ed. 2005, 44, 6715.
30. Organic Synthesis using Samarium Diiodide Proctor, D. J.; Flowers, R. A.;
Skrydstrup, T.; RSC publishing: Cambridge, 2009; ISBN: 978-1-84755-110-8.
31. Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., II. Tetrahedron Lett. 1997,
38, 8157.
32. Jin, S.; Wessig, P.; Liebscher, J. J. Org. Chem. 2001, 66, 3984.
33. Chen, M.-Y.; Lee, A. S.-Y. J. Org. Chem. 2002, 67, 1384.
34. Although all of our NMR data matched those of the synthetic sample de-
scribed by Williams, we found an apparent discrepancy between our 13C
NMR data and those originally reported by the Mata group in Ref. 8. Al-
though the original paper indicates NMR spectra were recorded in DMSO-d6,
it later transpired that MeOH-d4 was actually used. This accounts for minor
differences in chemical shift throughout the spectrum. Also there is an ap-
References and notes
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2003, 36, 127; (d) Williams, R. M. Chem. Pharm. Bull. 2002, 50, 711.
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5. Sugie, Y.; Hirai, H.; Inagaki, T.; Ishiguro, M.; Kim, Y.; Kojima, Y.; Sakakibara, T.;
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parent misprint for a signal at
spectrum, and at
fessor Williams and Professor Mata for clarfying these issues. Full compar-
ison tables can be found as ESI to our initial communication.
35. Grubbs, A. W.; Artman, G. D., III; Williams, R. M. Tetrahedron Lett. 2005, 46,
9013.
d
¼125.6, which appears at
d
¼118.6 in our
d
¼118.7 in that of Williams. We are grateful to both Pro-