Formal Total Synthesis of Diazonamide A by Indole Oxidative Rearrangement

Article abstract of DOI:10.1002/chem.201601605

A short formal total synthesis of the marine natural product diazonamide A is described. The route is based on indole oxidative rearrangement, and a number of options were investigated involving migration of tyrosine or oxazole fragments upon oxidation of open chain or macrocyclic precursors. The final route proceeds from 7-bromoindole by sequential palladium-catalysed couplings of an oxazole fragment at C-2, followed by a tyrosine fragment at C-3. With the key 2,3-disubstituted indole readily in hand, formation of a macrocyclic lactam set the stage for the crucial oxidative rearrangement to a 3,3-disubstituted oxindole. Notwithstanding the concomitant formation of the unwanted indoxyl isomer, the synthesis successfully delivered, after deprotection, the key oxindole intermediate, thereby completing a formal total synthesis of diazonamide A.

Full text of DOI:10.1002/chem.201601605

DOI: 10.1002/chem.201601605
Full Paper
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Total Synthesis |Hot Paper|
Formal Total Synthesis of Diazonamide A by Indole Oxidative
Rearrangement
Nadꢀge David, Raffaele Pasceri, Russell R. A. Kitson, Alexandre Pradal, and
Christopher J. Moody*[a]
Abstract: A short formal total synthesis of the marine natu-
ral product diazonamide A is described. The route is based
on indole oxidative rearrangement, and a number of options
were investigated involving migration of tyrosine or oxazole
fragments upon oxidation of open chain or macrocyclic pre-
cursors. The final route proceeds from 7-bromoindole by se-
quential palladium-catalysed couplings of an oxazole frag-
ment at C-2, followed by a tyrosine fragment at C-3. With
the key 2,3-disubstituted indole readily in hand, formation of
a macrocyclic lactam set the stage for the crucial oxidative
rearrangement to a 3,3-disubstituted oxindole. Notwith-
standing the concomitant formation of the unwanted indox-
yl isomer, the synthesis successfully delivered, after depro-
tection, the key oxindole intermediate, thereby completing
a formal total synthesis of diazonamide A.
Introduction
Moreover, treatment with diazonamide A showed no evidence
of the side effects observed with taxanes and vinca alkaloids at
doses sufficient to regress human tumor xenografts in mice.[7]
However, it has been shown that the compound does not act
by binding directly to tubulin like other antimitotic agents.[6]
Further studies identified a unique mechanism of action for di-
azonamide A,[8] with its antimitotic effects mediated through
ornithine d-aminotransferase (OAT), previously known as a mi-
tochondrial enzyme that regulates flux through the urea cycle
and indirectly promotes l-proline biosynthesis.[9] Although OAT
may not be essential for normal development, it appears to be
critical for cell division in human tumor cells that are sensitive
to diazonamide A. Recently, a number of diazonamide ana-
logues have been patented as antimitotic agents.[10]
In 1991, Fenical, Clardy and co-workers reported the composi-
tion and stereochemistry of two unusual marine toxins pos-
sessing potent cytotoxic activities. These toxins were extracted
from tissues of the sea squirt Diazona angulata (originally mis-
identified as Diazona chinensis), collected from caves along the
northwest coast of Siquijor Island (Philippines).[1] The structure
of the major isolate, diazonamide B (4) was determined by X-
ray crystallographic studies of a derivative, whilst the minor
metabolite, diazonamide A was subsequently assigned struc-
ture 1 by analogy (Figure 1). The scarcity of diazonamide A, its
biological activity (see below), and its challenging structure
soon attracted the attention of the synthetic chemistry com-
munity. Much to our chagrin, since we, like many others,[2] had
entered the race to synthesize the core dihydrobenzofuran
structure,[3] this structure 1 proved to be incorrect some 10
years later with the completion of its synthesis.[4] Not only did
Harran complete the synthesis of the originally assigned
diazonamide A 1, he also proposed an alternative structure 2,
that was more in accord with a possible biosynthesis from four
amino acids, tyrosine, valine and two tryptophans. This struc-
ture was proven to be correct with Nicolaou’s first synthesis of
the natural product.[5]
Notwithstanding the confusion over the true structure of di-
azonamide A, its unique and complex structure has continued
to serve as a challenge to organic chemists,[2] fuelled by the in-
terest in its biological properties, and by the isolation of three
new diazonamide compounds (C (3), D (5), E (6)) (Figure 1).[11]
Nicolaou’s first synthesis was quickly followed by a second syn-
thesis from the same group,[12] and, in the same year, a synthe-
sis inspired by the possible biogenesis from the Harran
group.[13] The most recent total synthesis was achieved by Mac-
Millan and co-workers in 2011,[14] whilst both the Magnus and
Sammakia groups have completed a formal synthesis,[15] by
converging on the key intermediate 7 (or its protected version)
in Nicolaou’s first synthesis. In addition to the total and formal
syntheses, a wide range of different approaches to this fasci-
nating molecule has been published.[2,16]
It was observed that diazonamide A blocks cell division
during mitosis with an efficacy comparable to current anti-tu-
bulin drugs, such as vinblastine, vincristine and paclitaxel.[6]
[a] Dr. N. David, Dr. R. Pasceri, Dr. R. R. A. Kitson, Dr. A. Pradal,
Prof. C. J. Moody
The key to any synthesis of diazonamide A 2 is the construc-
tion of the all-carbon quaternary centre at C-10, and the suc-
cessful approaches differ in their tactics towards this crucial el-
ement. Essentially, the six syntheses (four total, two formal)
divide into two groups—those that form a bond from C-10 to
School of Chemistry, University of Nottingham
University Park, Nottingham NG7 2RD (UK)
E-mail: c.j.moody@nottingham.ac.uk
Supporting information and ORCID from the author for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201601605.
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Figure 2. A) Summary of key disconnections at the C-10 quaternary centre in
the four total and two formal syntheses of diazonamide A. B) Proposed
route to key intermediate 7 by oxidative rearrangement.
synthesis of diazonamide A 2 by a different strategy based on
the oxidative rearrangement of a 2,3-disubstituted indole
during which the oxazole migrates stereospecifically to gener-
ate the new C-10 centre (Figure 2B).[17]
Results and Discussion
As noted above, a key strategic intermediate towards diazon-
amide A is a suitable 3,3-disubstituted oxindole, and hence we
sought to explore the oxidative rearrangement of indoles as
a potential route. The oxidative rearrangement of 2,3-disubsti-
tuted indoles to 3,3-disubstituted oxindoles upon treatment
with electrophiles such as halogenating agents or oxidants has
been known for about 50 years. The reaction was originally in-
vestigated in simple indoles,[18] but it has also been applied to
indole alkaloids,[19] and has been used in a biosynthesis-in-
spired formation of the Strychnos alkaloid skeleton by rear-
rangement of the Corynanthe system.[20] Our own work started
with an extension of the seminal work of Walser et al.[18d] into
more complex indole systems. Thus the 2,3-disubstituted
indole 8, assembled by a selective palladium-catalysed cou-
pling of a 7-bromo-3-iodoindole with a tyrosine-derived boron-
ate, was treated under Walser’s conditions (tert-butyl hypo-
chlorite, followed by acid), and gave the desired 3,3-disubsti-
tuted oxindole 9 by rearrangement of the chloroindolenine in-
termediate, in good yield, but as a 1:1 mixture of diastereoiso-
mers (Scheme 1).[21] In an attempt to introduce some
stereoselectivity into the rearrangement, we employed the (S)-
methoxymethylpyrrolidine-containing indole 10, and were
pleased to observe significant asymmetric induction in the for-
Figure 1. Structures of the diazonamides.
the tyrosine residue to generate the quaternary centre, or
those that form the oxazole (or oxazole precursor) bond to C-
10 (Figure 2). Thus both Nicolaou and Magnus generate an
electrophile at C-3 (indole numbering) of an oxindole inter-
mediate, employing the nucleophilicity of the tyrosine ben-
zene ring to form the key bond,[5,15a] whereas Harran exploits
the natural nucleophilicity of indoles at C-3 to react with an
electrophile generated by a biomimetic oxidation of the tyro-
sine moiety.[13] On the other hand, in Nicolaou’s second synthe-
sis,[12] and in MacMillan’s route,[14] the quaternary centre is as-
sembled from an oxindole or indole that already bears the ty-
rosine group by addition of an electrophilic residue (formalde-
hyde or propargyl aldehyde, respectively) that can subsequent-
ly be converted into the desired oxazole ring. Sammakia’s
route differs in that the complete oxazole unit is added to an
oxindole anion by an intramolecular SNAr reaction on a bromo-
oxazole (Figure 2A).[15b] We now report the details of a formal
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Preparation of indole, oxazole and tyrosine building blocks
All of our putative diazonamide A precursors 12–15 should be
accessible from relatively simple indole, oxazole and tyrosine
fragments. After a considerable number of preliminary experi-
ments towards indole 12 entailing C-2 iodination, and subse-
quent Pd-catalysed coupling reactions, we reverted to a strat-
egy adopted by Snieckus and co-workers involving ipso-boro-
desilylation with boron trichloride, followed by Suzuki reaction
of the chloroborane intermediate carried out in situ.[23] Thus
our target building block became the N-Boc-protected 7-
bromo-2-trimethylsilylindole (18). This was readily prepared by
a Bartoli synthesis of 7-bromoindole (16),[24] followed by intro-
duction of the Boc-group, and lithiation/silylation of the result-
ing N-protected indole 17 to give the desired building block
18 (Scheme 3).
Scheme 1. Oxidative rearrangements of 2,3-disubstituted indoles to 3,3-di-
substituted oxindoles.[21,22]
The oxazole building blocks were the complementary boron-
ic acid 24 and iodide 25 (Scheme 4). These were obtained
from the known methyl oxazole-4-carboxylate 21, prepared as
mation of the oxindole 11, which could be obtained optically
pure after a single recrystallization (Scheme 1).[22] This pleasure
was, however, short lived when it proved impossible to elabo-
rate the 3-carboxamido substituent into the required oxazole
ring, and therefore we turned our attention to 2,3-disubstitut-
ed indoles that already contained a preformed oxazole.
Hence we focused on indoles that contained both tyrosine-
and valine-derived oxazole fragments, reasoning that these
should be easily available by successive palladium-catalysed
sp2–sp2 coupling reactions. On this basis, we identified four
possible precursors to the pivotal intermediate 7 in the form
of the indoles 12–15. These were classified according to
whether the tyrosine or oxazole group migrates from C-2 to C-
3 in the rearrangement step, and whether the rearrangement
occurs in the non-cyclized form or in a preformed macrocycle
(Routes A–D, Scheme 2), and we embarked on an investigation
of all four possibilities.
Scheme 3. Synthesis of indole building block 18. Reagents and conditions:
a) vinylmagnesium bromide (3.0 equiv), THF, ꢀ408C, 1 h, 55%; b) Et3N
(1.5 equiv), DMAP (0.3 equiv), Boc2O (2.3 equiv), CH2Cl2, 08C, 40 min, 90%;
c) TMSCl (1.5 equiv), THF, 08C, then LDA (1.5 equiv), 08C, 30 min, 100%.
Scheme 2. Possible precursors to a key diazonamide A intermediate 7 by oxidative rearrangement of 2,3-disubstituted indoles. Although specific protecting
groups are shown in compounds 12–15, the optimum choice of such groups was unknown at the outset.
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Scheme 4. Synthesis of oxazole building blocks 24 and 25. Reagents and conditions: a) EDC (1.05 equiv), HOBt (1.05 equiv), THF, 258C, 5 min, then Et3N
(2.0 equiv), 258C, 15 h, 96%; b) Burgess reagent (1.5 equiv), THF, 658C, 4 h, 61%; or c) DAST (1.1 equiv), CH2Cl2, ꢀ788C, 1.5 h, then K2CO3 (1.5 equiv), ꢀ788C!
258C, 1.5 h, 100%; d) BrCCl3 (1.1 equiv), DBU (1.1 equiv), CH2Cl2, 08C!258C, 18 h, 91%; e) LiBH4 (2.0m in THF, 3.0 equiv), EtOH (5.0 equiv), THF, 08C!258C,
3 h, 95%; f) NaHMDS (1.0m in THF, 2.1 equiv), THF, ꢀ788C, 10 min, then nBu4NI (0.1 equiv), BnBr (0.8 equiv), ꢀ788C!258C, 24 h, 61%; g) nBuLi (2.5 equiv),
THF, ꢀ788C, 1 h, then B(OMe)3 (7.0 equiv), ꢀ788C, 1 h, then 258C, 2 h, HCl, 80% crude; h) nBuLi (2.5 equiv), THF, ꢀ788C, 1 h, then I2 (2.0 equiv), ꢀ788C, 1 h,
74%.
previously described.[5] Lithium borohydride reduction of ester
21 was followed by benzylation of the primary alcohol 22 to
give oxazole 23. Subsequent lithiation at the 5-position was
followed by quenching with trimethyl borate to give, after acid
hydrolysis, the boronic acid 24, or with iodine to give iodide
25 (Scheme 4).
were conducted using the aforementioned ipso-borodesilyl-
ation with boron trichloride followed by Suzuki reaction carried
out in situ.[23] The optimized Suzuki conditions employed
Finally a number of tyrosine derivatives containing different
protecting groups were prepared as coupling partners. These
were obtained from iodotyrosine using standard methods as
outlined in Scheme 5. For the formation of compound 29,
some problems were encountered with the palladium-cata-
lysed borylation reaction, since the boronate was difficult to
purify by flash chromatography over silica gel due its tendency
to remain adsorbed on the column. Indeed, only a small
amount of compound 29 could be isolated in this manner, and
elution with more polar solvents resulted in contamination
with polar byproducts. To address this problem, the purifica-
tion process was performed using freshly prepared silica gel
impregnated with boric acid, which is reported to help in the
purification of pinacolboronates and boronic acids by column
chromatography.[25]
Scheme 5. Synthesis of tyrosine building blocks 27–29 [PinB=4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl]: Reagents and conditions: a) SOCl2
(1.1 equiv), MeOH, 258C, 20 h, 100%; b) Boc2O (1.2 equiv), Et3N (2.0 equiv),
CH2Cl2, 258C, 3.5 h, 72%; c) BnBr (1.3 equiv), K2CO3 (1.4 equiv), nBu4NI
(0.15 equiv), acetone, 568C, 16 h, 89%; d) pinacolborane (3.0 equiv),
Pd(OAc)2 (0.1 equiv), iPr2NEt (5.0 equiv), 2-(biphenyl)dicyclohexylphosphine
(0.4 equiv), 1,4-dioxane, 858C, 3 h, 73%; e) CbzCl (1.0 equiv), Na2CO3
(3.0 equiv), Et2O/H2O (1:1), 258C, 16 h, 100%; f) BTEAC (2.4 equiv), tert-BuBr
(46 equiv), K2CO3 (25 equiv), H2O, THF, 608C, 48 h, 57%; or tert-butyl 2,2,2-tri-
chloroacetimidate (3.5 equiv), CH2Cl2/THF (4:1), 258C, 16 h, 100%; g) BnBr
(1.3 equiv), K2CO3 (1.4 equiv), nBu4NI (0.15 equiv), acetone, 568C, 16 h, 88%;
h) SOCl2 (1.1 equiv), MeOH, 08C to reflux, 100%; i) CbzCl (1.1 equiv), Na2CO3
(1.0 equiv), acetone/H2O (1:1), 258C, 2 h, 100%; j) BnBr (1.2 equiv), K2CO3
(2.4 equiv), nBu4NI (0.10 equiv), acetone, reflux, 18 h, 97%; k) pinacolborane
(3 equiv), Et3N (4 equiv), Pd(OAc)2 (0.05 equiv), 2-(biphenyl)dicyclohexylphos-
phine (0.4 equiv), 1,4-dioxane, 508C, 1 h, 84% (Purification by flash column
chromatography over boric acid-impregnated silica gel).
Oxidative rearrangement model studies
A crucial question for our oxidative strategy as set out in
Scheme 2 is the relative propensity of tyrosine-derived frag-
ments versus oxazole moieties to migrate from C-2 to C-3 in
the key rearrangement step. To this end we investigated two
simpler model systems 32 and 35 as substitutes for the real
systems 12 and 14, wherein a phenyl group replaces the tyro-
sine fragment, not only as model substrates, but also as
a chance to develop and optimize the critical sp2–sp2 coupling
methodology. Both compounds 32 and 35 were synthesized
by the initial coupling of either iodobenzene or iodooxazole
moiety 25 with the indole derivative 18. The coupling steps
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sodium carbonate as base in 1,2-dimethoxyethane (DME) with
the reaction carried out under microwave irradiation. The Boc
protecting group on the indole was removed during the cou-
pling, probably due to the formation of hydrochloric acid in
the reaction mixture at the time of the addition of boron tri-
chloride, but this was of little consequence, since it had to be
cleaved at some stage. The coupled products were then iodin-
ated at C-3 in very good yield using N-iodosuccinimide. Further
functionalization at C-3 with either oxazole boronic acid 24 or
phenylboronic acid using similar Suzuki conditions in the mi-
crowave afforded compounds 32 in 37% yield and 35 in 65%
yield (Scheme 6). To form compound 35, it was necessary to
decrease the amount of boronic acid from 1.5 to 0.9 equiva-
lents, lower the temperature from 1058C to 708C and reduce
the reaction time from 45 min to 10 min. This avoided the for-
mation of the undesired double coupling of benzeneboronic
acid with both the 3-iodo and the 7-bromo substituents.
reprotection of the amino group, which underwent cleavage
of the Boc-group under the reaction conditions, with di-tert-
butyl dicarbonate. However, when precursor 38 was rear-
ranged, it only resulted in the formation of the undesired in-
doxyl product 39, again after reprotection of the amino group
(Scheme 7). The structures were readily differentiated from
their 13C NMR spectra: the oxindole C-2 amide signal appears
in the region of 180 ppm, whilst the indoxyl ketonic carbonyl
signal C-3 appears at about 200 ppm. Additionally, the oxin-
dole quaternary carbon C-3 is observed at about 55 ppm,
whilst the indoxyl quaternary carbon C-2 comes around
70 ppm.
The competing formation of indoxyls upon rearrangement
of 3-hydroxyindolenines had been previously noted by Movas-
saghi and co-workers,[26] although in their case, the indoxyls
could be isomerized to oxindoles by further heating with scan-
dium triflate. Unfortunately subjecting indoxyl 39 to these con-
ditions resulted in its degradation. These preliminary model
studies led us to the initial conclusion that Routes A and B
(Scheme 2) in which the tyrosine fragment migrates upon oxi-
dative activation were more likely to result in the formation of
the desired oxindole in the real system and avoid the forma-
tion of the undesired indoxyl.
With both model precursors in hand, we were able to inves-
tigate the pivotal oxidative rearrangement steps. However, it
quickly became clear that whilst acyl groups migrated from C-
2 to C-3 upon formation of a 3-chloroindolenine intermediate
under Walser’s conditions (Scheme 1), aromatic groups did not.
However, application of a Lewis acid mediated rearrangement
of 3-hydroxyindolenines reported by Movassaghi and co-work-
ers,[26] looked more promising. Accordingly, both precursors
were treated with dimethyldioxirane (DMDO) generated in situ
from acetone and Oxoneꢂ (Scheme 7). This gave hydroxyindol-
enines 36 and 38 in good yields, which without separation of
the diastereoisomers, were subjected to the rearrangement
conditions. When treated with scandium triflate in toluene
under reflux, precursor 36 was converted into the desired oxin-
dole 37, in good yield as a mixture of diastereoisomers, after
Route A: rearrangement of the tyrosine fragment in non-cy-
clized precursor
The precursor for our initial approach was the 2,3-disubstituted
indole 12. After a number of preliminary experiments, it was
established that the tyrosine phenol had to be protected in
order to carry out the subsequent macrocyclization step.
Therefore a benzyl group was preferred, since it would be re-
Scheme 6. Synthesis of model systems 32 and 35 for oxidative rearrangement. Reagents and conditions: a) 18 (1.2 equiv), BCl3 (1.35 equiv), CH2Cl2, 358C,
2.5 h, then evaporation of solvent and addition of iodobenzene (1.0 equiv), [Pd(PPh3)4] (0.15 equiv), aq. Na2CO3 (5.0 equiv), DME, MW (300 W), 1008C, 20 min,
51%; b) NIS (1.2 equiv), DMF, 258C, 2 h, 84%; c) 24 (1.5 equiv), [PdCl2(dppf)]·CH2Cl2 (0.2 equiv), Cs2CO3 (5.0 equiv), 1,4-dioxane/H2O (8:2), MW (300 W), 1058C,
45 min, 37%; d) 18 (1.25 equiv), BCl3 (3.75 equiv), CH2Cl2, 358C, 3 h, then evaporation of solvent and addition of 25 (1.0 equiv), [Pd(PPh3)4] (0.10 equiv), aq.
Na2CO3 (2m, 4.00 equiv), DME, MW (300 W), 1008C, 30 min, 75%; e) NIS (1.2 equiv then extra 0.5 equiv), DMF, 08C!rt, 16 h, 95%; f) benzeneboronic acid
(0.9 equiv), [PdCl2(dppf)]·CH2Cl2 (0.2 equiv), Cs2CO3 (5.0 equiv), 1,4-dioxane/H2O (8:2), MW (300 W), 708C, 10 min, 65%.
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Scheme 7. Application of the oxidative rearrangement on model systems. Reagents and conditions: a) Oxoneꢂ (3.0 equiv), sat. aq. NaHCO3, acetone, 08C, 1 h,
68%; b) i) Sc(OTf)3 (1.0 equiv), toluene, 1108C, 6 h, ii) Boc2O (1.2 equiv), NaHCO3 (5.0 equiv) THF, rt, 16 h, 58% (2 steps); c) Oxoneꢂ (5.0 equiv), sat. aq. NaHCO3,
acetone, 258C, 1 h, 70%; d) i) Sc(OTf)3 (1.0 equiv), toluene, 1108C, 6 h, ii) Boc2O (1.2 equiv), NaHCO3 (5.0 equiv) THF, rt, 16 h, 58% (2 steps).
sistant to a range of conditions and could be removed at the
same time as the benzyl group on the primary alcohol on the
oxazole ring at the end of the synthesis. A Boc group was
chosen for protection of the tyrosine amino group to comple-
ment that present on the oxazole moiety, which had already
been employed in the model rearrangement studies
(Scheme 7). The 2,3-disubstituted indole 12 was synthesized
by coupling the indole derivative 18 with iodotyrosine deriva-
tive 26 using the presumed dichloroborane indole generated
in situ, and further palladium-catalysed cross-coupling under
microwave irradiation. After iodination at C-3, the indole 41
was coupled with oxazole boronic acid 24 to give the key pre-
cursor indole 12 in 47% yield. This was treated with DMDO to
give 3-hydroxyindolenine 42 in 80% yield as a mixture of dia-
stereoisomers (Scheme 8). Unfortunately, when treated with
scandium triflate in toluene under reflux, only indoxyl 43 was
formed in poor yield. Thus, in comparison with the results ob-
tained from the model compound 32 (Scheme 7), it appears
that the introduction of the tyrosine side chain, as opposed to
a simple phenyl substituent, surprisingly prevents the rear-
rangement to the desired oxindole.
and Hꢃnig’s base in dichloromethane at high dilution to give
the desired product 13 in 75% yield. In addition, the alcohol-
deprotected product 47 was formed in 18% yield. Monitoring
of these last two steps by mass spectrometry suggests that
the partial loss of the benzyl-protecting group on the primary
alcohol occurs during the macrocyclization step. A similar phe-
nomenon was observed by Nicolaou in his first total synthesis,
with partial loss of the methoxymethyl ether (MOM)-protecting
group on the phenol during the macrocyclization.[5] Oxidation
of macrocycle 13 with DMDO proved to be very slow and only
traces of product were generated. In contrast, the free alcohol
47 was readily oxidized under the same conditions, although
the resulting 3-hydroxyindolenine failed to undergo the de-
sired rearrangement. Nevertheless, upon changing the oxidant
to the Davis oxaziridine, the desired 3-hydroxyindolenine 48
was obtained in 63% yield, although the reaction mixture did
require heating in 1,2-dichloroethane under reflux. Interesting-
ly, 3-hydroxyindolenine 48 was obtained as a single diastereo-
isomer, although we were unable to determine the stereo-
chemistry at the indole C-3 position. On treatment with scandi-
um triflate, 3-hydroxyindolenine 48 underwent rearrangement
to give, after reaction with benzyl chloroformate to reprotect
the tyrosine-derived amino group, only the undesired indoxyl
49 in 56% yield (Scheme 9), as a single diastereoisomer of un-
known configuration at the indoxyl C-2 position. Further treat-
ment of indoxyl 49 with scandium triflate in toluene did not
result in the rearrangement to the desired oxindole, and at-
tempts to effect the rearrangement under alternative condi-
tions, such as copper triflate or formic acid in toluene[27] or in
different solvents, were also ineffective. The failure of the oxi-
dative rearrangement to deliver any of the required oxindole
was a puzzle. It is possible that the stereoselective oxidation
with the Davis oxaziridine gives a 3-hydroxyindolenine that
cannot rearrange by migration of the tyrosine fragment due to
the constraints of the macrocycle.
Route B: rearrangement of the tyrosine fragment in macro-
cyclic precursor
Undeterred by the above set back, we next investigated the
macrocyclic precursor 13. To this end, indole 18 was coupled
with tyrosine fragment 28 as described above, again with con-
comitant removal of the Boc-protecting group to give indole
44. Iodination and coupling to oxazole boronic acid 24 gave
the macrocycle precursor 46. Next, treatment with trifluoroace-
tic acid in dichloromethane afforded the deprotected inter-
mediate, which underwent macrocyclization using N-[(di-
methylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-
methylmethanaminium hexafluorophosphate N-oxide (HATU)
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The key substrate 14 was obtained from 3-iodoindole 34
and tyrosine-derived boronate 27, which were successfully
coupled under our usual Suzuki conditions. Lowering the tem-
perature from 105 to 858C improved the yield from 30 to
47%. Next, the indole 14 was successfully oxidized to 3-hy-
droxyindolenine 50 in 67% yield using DMDO. Fortunately,
under treatment with scandium triflate, hydroxy compound 50
rearranged to the desired oxindole 51 in 10% yield, together
with 20% of the undesired indoxyl 43 (Scheme 10), after repro-
tection of the amino group. This result seems to confirm our
hypothesis that the oxazole ring does indeed migrate more
easily than the tyrosine, although indoxyl 43, the same com-
pound as prepared in Route B, was still formed alongside the
required oxindole 51. Further treatment of indoxyl 43 with
scandium triflate did not cause its conversion into the desired
oxindole 51. At this stage, rather than attempt to optimize this
reaction sequence, we chose to investigate the rearrangement
in the macrocyclic system 15.
Route D: rearrangement of the oxazole fragment in macro-
cyclic precursor—a formal total synthesis of diazonamide A
Encouraged by the successful formation of oxindole 51
(Scheme 10), we embarked upon the synthesis and oxidative
rearrangement of the macrocyclic indole 15 (Scheme 2). With
the indole, oxazole and tyrosine building blocks already to
hand, the macrocycle 15 was readily accessible. However, the
coupling of 3-iodo-2-oxazolylindole 34, prepared during our in-
itial model studies (Scheme 6), with tyrosine-derived boronate
29 under our standard microwave Suzuki conditions, was
highly capricious because the deiodo indole and proto-
deboronated tyrosine were often obtained, especially at high
temperatures. Following considerable investigation into the
choice of catalyst, ligand, base and solvent, we were pleased
to find that the use of potassium carbonate as the base, a 9:1
mixture of acetonitrile and water as the solvent and the intro-
duction of a slight excess of boronate 29 (1.2 equiv) led to the
formation of the desired 2,3-disubstituted indole 52 in 70%
yield at 608C with thermal heating (Scheme 11). Hydrolysis of
the methyl ester, acid cleavage of the N-Boc group and HATU-
mediated macrolactamization gave the desired macrocyclic
indole 15 in good yield. Unlike the isomeric macrocycle 13
(Scheme 9), compound 15 was readily oxidized in good yield
with DMDO to give the diastereomeric 3-hydroxyindolenines
53 and 54 in a ratio of 2.5:1. At this stage, we were unable to
assign the configuration of the new stereocentre in com-
pounds 53 and 54, and therefore in common with other syn-
theses of diazonamide A,[5,12] we were obliged to continue the
synthesis with both compounds in parallel. The stereochemis-
try shown for the 3-hydroxyindolenines 53 and 54 in
Scheme 11 was assigned post facto upon completion of the
formal synthesis, with isomer 54 having the desired stereo-
chemistry. At this point, we devoted considerable effort to ad-
dressing the selectivity of the oxidation procedure to deliver
the desired hydroxyindolenine 54. Armed with the knowledge
that we required the minor diastereomer, we attempted to
override the apparent substrate control through reagent con-
Scheme 8. Synthesis and oxidative rearrangement of 2,3-disubstituted
indole 12. Reagents and conditions: a) 18 (1.2 equiv), BCl3 (3.5 equiv), CH2Cl2,
358C, 2.5 h, then evaporation of solvent and addition of 27 (1.0 equiv),
[Pd(PPh3)4] (0.15 equiv), aq. Na2CO3 (5.0 equiv), DME, MW (300 W), 1008C,
20 min, 45%; b) NIS (1.2 equiv), DMF, 258C, 1.5 h, 100%; c) 24 (1.5 equiv),
[PdCl2(dppf)]·CH2Cl2 (0.2 equiv), Cs2CO3 (5.0 equiv), 1,4-dioxane/H2O (8:2),
MW (300 W), 1058C, 45 min, 47%; d) Oxoneꢂ (3.0 equiv), sat. aq. NaHCO3,
acetone, 08C!258C, 1.5 h, then Oxoneꢂ (3 equiv), 258C, 1 h, 80%;
e) Sc(OTf)3 (.01 equiv), anhydrous toluene, 1108C, 6 h; (f) Boc2O (3.0 equiv),
NaHCO3 (5.0 equiv), THF, 258C, 15 h, 19% (2 steps).
Route C: rearrangement of the oxazole fragment in non-cy-
clized precursor
Therefore despite the inauspicious precedent set by our model
studies (Scheme 7), we were compelled to consider Routes C
and D in which the oxazole moiety rearranges from C-2 to C-3
in the indole precursors 14 and/or 15 (Scheme 2), as opposed
to from C-3 to C-2 as it does to give the indoxyls above.
Indeed, in Routes A and B we never observed migration of the
tyrosine fragment from C-2 to C-3, in contrast to the facile mi-
gration of the phenyl ring in the model studies (Scheme 7). Al-
though we initially concluded that the oxazole ring at C-3, as
in model compound 36, would favour the formation of the ox-
indole, our investigations with the real substrates in Routes A
and B strongly suggested that the tyrosine group was less
likely to migrate from C-2 than the oxazole.
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Scheme 9. Synthesis and oxidative rearrangement of macrocyclic indole 13. Reagents and conditions: a) 18 (1.14 equiv), BCl3 (3.0 equiv), CH2Cl2, 358C, 2.5 h,
then evaporation of solvent and addition of 28 (1.0 equiv), [Pd(PPh3)4] (0.15 equiv), aq. Na2CO3 (5.0 equiv), DME, MW (300 W), 1008C, 20 min, 50%; b) NIS
(1.2 equiv), DMF, 258C, 1 h, 90%; c) 24 (1.5 equiv), [PdCl2(dppf)]·CH2Cl2 (0.2 equiv), Cs2CO3 (5.0 equiv), 1,4-dioxane/H2O (8:2), MW (300 W), 1058C, 45 min, 50%;
d) TFA/CH2Cl2 (1:1), 258C, 2.5 h, 100% crude; e) HATU (1.3 equiv), iPr2NEt (6.0 equiv), CH2Cl2, 4ꢄ10ꢀ4 m, 258C, 15 h, 75% of 13 and 18% of 47; f) Davis oxaziri-
dine (4.0 equiv), 1,2-dichloroethane, 838C, 30 h, 63%; g) Sc(OTf)3 (1.2 equiv), anhydrous toluene, 1108C, 2 h; h) CbzCl (0.9 equiv), Na2CO3 (3.0 equiv), ether/
water (1:1), 258C, 16 h, 56% for 2 steps.
Scheme 10. Synthesis and oxidative rearrangement of 2,3-disubstituted
indole 14. Reagents and conditions: a) 34, 27 (1.2 equiv), [PdCl2(dppf)]·CH2Cl2
(0.2 equiv), Cs2CO3 (5.0 equiv), 1,4-dioxane/H2O (8:2), MW (300 W), 858C,
45 min, 47%; b) Oxoneꢂ (3.0 equiv), sat. aq. NaHCO3, acetone, 08C 258C,
2.5 h, 67%; c) Sc(OTf)3 (1.0 equiv), toluene, 1108C, 6 h; d) Boc2O (5.0 equiv),
NaHCO3 (5.0 equiv), THF, 258C, 15 h, 10% oxindole 51 and 20% indoxyl 43,
both yields over two steps.
Scheme 11. Synthesis and oxidation of macrocyclic indole 15. Reagents and
conditions: a) 34, 29 (1.2. equiv), [PdCl2(dppf)]·CH2Cl2 (0.1 equiv), K2CO3
(10.0 equiv), acetonitrile/H2O (9:1), 608C, 15 h, 70%; b) LiOH (20 equiv), THF/
MeOH/H2O (10:2:1), reflux, 10 min; c) TFA/CH2Cl2 (1:1), 258C, 1 h; d) HATU
(1.2 equiv), iPr2NEt, CH2Cl2, 258C, 15 h, 75% over 3 steps; e) Oxoneꢂ
(3.0 equiv), sat. aq. NaHCO3, acetone, 08C to rt, 6 h, 75% (d.r. 2.5:1), 54% 53
and 21% 54.
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Scheme 12. Rearrangement of macrocyclic 3-hydroxyindolenines 53 and 54: completion of formal synthesis of diazonamide A. Reagents and conditions:
a) Sc(OTf)3 (1.0 equiv), toluene, 1108C, 6 h; b) CbzCl (1.1 equiv), NaHCO3 (5.0 equiv), THF, 258C, 16 h, 20% indoxyl 55, 8.4% oxindole 56; c) BCl3 (20 equiv),
CH2Cl2, ꢀ788C, 2.5 h, 65%; d) Sc(OTf)3 (1.1 equiv), toluene, 1108C, 6 h; e) CbzCl (1.0 equiv), NaHCO3 (4.0 equiv), THF, 258C, 16 h, 22% indoxyl 58, 10% oxindole
59; f) BCl3 (20 equiv), CH2Cl2, ꢀ788C, 2.5 h, 63%.
trol with chiral oxidants (Davis’ oxaziridine and Oppolzer’s
sultam-derived oxaziridines, Shi dioxiranes and vanadium cata-
lysts in combination with tert-butyl hydroperoxide). Unfortu-
nately, in all cases it appeared that the substrate was too hin-
dered, with no oxidation being observed under mild condi-
tions and with significant decomposition upon more forcing
reaction conditions. Finally, we resorted to using trifluoroace-
tone to form a more reactive dioxirane in situ in an attempt to
achieve a less diastereoselective oxidation. Although this pro-
tocol significantly increased the amount of the wanted dia-
steromer 54 on a small scale, attempts to scale up the reaction
were less successful.
and colleagues.[26] Repeating the rearrangement-protection se-
quence with the diastereomeric hydroxyindolenine 54 pro-
duced a separable mixture of indoxyl 58 and oxindole 59,
again in a ratio of about 2:1 in favor of the unwanted indoxyl.
Deprotection of oxindole 59 with boron trichloride produced
an oxindole that showed identical NMR spectroscopic proper-
ties to the Nicolaou intermediate 7, thereby completing
a formal total synthesis of diazonamide A (Scheme 12).
Conclusions
A formal total synthesis of the complex marine metabolite di-
azonamide A has been completed. The route is different to
previous approaches in that it is based on oxidative rearrange-
ment of indoles, a strategy that not only ensures that the key
precursors are readily available from simple indole, oxazole
and tyrosine building blocks using uncomplicated, scaleable
chemistry, but also that the overall route to the key oxindole 7
is relatively short (13 steps in longest linear sequence from
commercially available Boc-l-valine and dl-serine methyl ester
hydrochloride).
With both 3-hydroxyindolenines 53 and 54 now readily
available in significant quantities (>100 mg), we were able to
address the crucial rearrangement step. Treatment of the
major diastereomer 53 with scandium triflate in toluene at
reflux, followed by reprotection of the tyrosine-derived amino
group with benzyl chloroformate, gave a separable mixture of
indoxyl 55 and oxindole 56 in a ratio of about 2:1 in very
modest yield (Scheme 12). Removal of the benzyl groups using
boron trichloride gave oxindole 57 in good yield. At this stage
we were able to compare the spectroscopic data with those
reported by Nicolaou.[5] and Sammakia[15b] for the key inter-
mediate 7. We were immediately suspicious that oxindole 57
possessed the wrong stereochemistry at the quaternary centre,
because it proved rather insoluble in deuteroacetonitrile, the
NMR solvent used by both the Nicolaou and Sammakia
groups. Unfortunately this proved to be the case—the NMR
Experimental Section
For full details of all experiments, see the Supporting Information.
spectroscopic data for oxindole 57 are clearly at odds with the Acknowledgements
previously reported data. The fact that oxindole 57 (and 56)
had the wrong configuration at the quaternary centre allowed
us to assign the stereochemistry of the 3-hydroxyindolenine
53 on the basis that the group (the oxazole in this case) that
migrates from C-2 (indole numbering) does so from the oppo-
site side to the hydroxyl group as established by Movassaghi
We thank the EPSRC and the University of Nottingham for sup-
port and Professor Tarek Sammakia for helpful correspondence
and copies of NMR spectra. We also thank Dr. Martyn Inman
for helpful discussions and Kevin Butler and Shazad Aslam for
NMR spectroscopy.
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Published online on && &&, 0000
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FULL PAPER
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Total Synthesis
N. David, R. Pasceri, R. R. A. Kitson,
A. Pradal, C. J. Moody*
&& – &&
Formal Total Synthesis of
Diazonamide A by Indole Oxidative
Rearrangement
Totally indole darling! A formal total
synthesis of the complex marine metab-
olite diazonamide A has been complet-
ed. The route is different to previous ap-
proaches in that it is based on oxidative
rearrangement of indoles
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