The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment

Article abstract of DOI:10.1021/jo0509760

Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is conver

Full text of DOI:10.1021/jo0509760

The Diazo Route to Diazonamide A.
Studies on the Indole Bis-oxazole Fragment
James R. Davies,† Peter D. Kane,‡ and Christopher J. Moody*,†,§
Department of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, U.K., School of
Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K., and Tripos Receptor
Research Ltd, Bude-Stratton Business Park, Bude, Cornwall EX23 8LY, U.K.
c.j.moody@nottingham.ac.uk
Received May 17, 2005
Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite
diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl
compounds in key steps. Thus, 3-bromophenylacetaldehyde is converted into an R-diazo-â-ketoester,
dirhodium(II)-catalyzed reaction of which with N-Boc-valinamide resulted in N-H insertion of the
intermediate rhodium carbene to give a ketoamide that readily underwent cyclodehydration to
give (S)-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]-5-(3-bromobenzyl)oxazole-4-carboxamide,
after ammonolysis of the initially formed ester. This aryl bromide was then coupled to a 3-formyl-
indole-4-boronate under Pd catalysis to give the expected biaryl. Subsequent conversion of the
aldehyde group into a second R-diazo-â-ketoester gave a substrate for an intramolecular carbene
N-H insertion, although attempts to effect this cyclization were unsuccessful. A second approach
to an indole bis-oxazole involved an intermolecular rhodium carbene N-H insertion, followed by
oxazole formation to give (S)-2-[1-tert-(butoxycarbonylamino)-2-methylpropyl]-5-methyloxazole-4-
carboxamide. A further N-H insertion of this carboxmide with the rhodium carbene derived from
ethyl 2-diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-3-oxopropanoate gave a ketoamide, cyclode-
hydration of which gave the desired indole bis-oxazole. Finally, the boronate formed from
4-bromotryptamine was coupled to another diazocarbonyl-derived oxazole to give the corresponding
biaryl, deprotection and cyclization of which produced a macrocyclic indole-oxazole derivative.
Subsequent oxidation and cyclodehydration incorporated the second oxazole and gave the macrocyclic
indole bis-oxazole.
Introduction
the unique and complex structure, assigned as 1 on the
basis of an X-ray crystallographic study of a derivative,1
ensured that diazonamide A immediately captured the
imagination of synthetic organic chemists. Therefore, in
the 15 years since the structure of diazonamide A was
reported in 1991, more than 10 research groups have
published approaches to this fascinating natural pro-
duct.3-30 The story acquired a new twist in 2001 when
The marine secondary metabolite diazonamide A,
isolated from the colonial ascidian Diazona chinensis, was
reported to have potent in vitro cytoxicity against human
tumor cell lines.1 This biological activity,2 together with
* To whom correspondence should be addressed at the University
of Nottingham. Fax: +44 0115 951 3564.
† University of Exeter.
‡ Tripos Receptor Research.
§ University of Nottingham.
(3) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.; Ve´liz, E. A.;
Yang, Z.-C. Synlett 1996, 609-611.
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10.1021/jo0509760 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/11/2005
J. Org. Chem. 2005, 70, 7305-7316
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Davies et al.
Harran and co-workers completed a total synthesis of
structure 1 only to discover that not only was it rather
unstable, but it was also different from the natural
product.31,32 On the basis of his own studies and a
reexamination of the original X-ray data, Harran pro-
posed the alternative structure 2 for diazonamide A
(Figure 1). Not only did this subsequently prove to be
correct, it also better fits a biosynthetic route in which
the bicyclic core derives from modification of a Tyr-Val-
Trp-Trp tetrapeptide. Unequivocal proof that the revised
structure 2 was indeed that of diazonamide A came in
2002, when Nicolaou and co-workers published the first
total synthesis of the natural product.33,34 Subsequently,
the Nicolaou group reported a second route to diazona-
mide A,35,36 while Harran and co-workers completed their
own total synthesis of the correct structure.37 Despite the
fact that Nicolaou’s and Harran’s endeavors in total
synthesis have now solved the structural problem of
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FIGURE 1. Original and revised structures for the marine
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Our own interest in diazonamide A started over a
decade ago when we reported an approach to a benzo-
furanone related to the original structure and an ap-
proach to 5-(3-indolyl)oxazoles using dirhodium(II)-
catalyzed reactions of diazocarbonyl compounds.38,39 We
have also reported preliminary results on a second
approach to the benzofuran unit of the original structure
using the Claisen rearrangement40 and further studies
on the indole fragments.41,42 We have continued to exploit
diazocarbonyl compounds in the synthesis of oxazoles,43-45
including the oxazole building blocks of the natural
products nostocyclamide46 and promothiocin A,47 and
recently completed the synthesis of a precursor to the
5-(3-indolyl)oxazole martefragin A.48 The method is based
on the chemoselective N-H insertion reactions of rhodium
carbene intermediates, derived by dirhodium(II) cata-
lyzed reactions of diazocarbonyl compounds, with car-
boxamides, followed by Robinson-Gabriel cyclodehydra-
tion (Scheme 1). This is an efficient and versatile route
to a wide range of oxazoles, subsequently adapted to solid
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Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004, 126, 10162-10173.
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Bella, M.; Reddy, M. V.; Rao, P. B.; Koumbis, A. E.; Giannakakou, P.;
O’Brate, A. J. Am. Chem. Soc. 2004, 126, 10174-10182.
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Appl. Chem. 1994, 66, 2107-2110.
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Soc., Perkin Trans. 1 1997, 2413-2419.
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41, 6897-6900.
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Diazo Route to Diazonamide A
SCHEME 1. Diazo Route to Oxazoles
model for the key stepsthe rhodium carbene intramo-
lecular N-H insertion reaction as exemplified by the
simplified substrate 11 (Scheme 2).
Synthesis of the Intramolecular N-H Insertion
Precursor 11. Our route to the model precursor 11 for
the key intramolecular N-H insertion reaction started
with 3-bromophenylacetaldehyde 12 prepared from com-
mercially available 3-bromophenylacetic acid by DIBAL
reduction of the corresponding methyl ester or by LiAlH4
reduction of the Weinreb amide. Although the desired
R-diazo-â-ketoester 14 could in principle be prepared from
aldehyde 12 by diethylzinc-mediated addition of ethyl
diazoacetate52 followed by oxidation of the resulting
R-diazo-â-hydroxyester with IBX (see below), the pre-
ferred route used the Roskamp protocol,53 whereby tin-
(II) chloride mediated addition of ethyl diazoacetate gave
the â-ketoester 13. Diazo transfer using 4-acetamidoben-
zenesulfonyl azide54 and triethylamine gave the diazo-
carbonyl compound 14 (Scheme 3). Dirhodium tetraoc-
tanoate catalyzed reaction of diazo compound 14 with (S)-
N-Boc-valinamide44 resulted in chemoselective insertion
into the carboxamide N-H bond to give ketoamide 15 in
73% yield. No products resulting from alternative rhod-
ium carbene pathways, such as Wolff rearrangement,
intermolecular insertion into the carbamate N-H, or
intramolecular aromatic C-H insertion, were isolated. As
expected, the ketoamide 15, a 1,4-dicarbonyl compound,
underwent Robinson-Gabriel cyclodehydration using the
Wipf Ph3P/I2/Et3N protocol55 to give the oxazole 16. Fin-
ally, in preparation for a further rhodium carbene N-H
insertion reaction, the oxazole ester 16 was converted into
the corresponding carboxamide 17 (Scheme 3).
As outlined in the retrosynthetic analysis (Scheme 2),
the synthesis of the required indole fragment started with
indole 10, readily prepared from the known 4-bromoin-
dole-3-carboxaldehyde 18.56 Model studies of biaryl cou-
pling reactions of the bromobenzyl oxazole 17 quickly
established that Pd-catalyzed reactions with boronic acid
derivatives proceeded more smoothly than with stan-
nanes, and therefore, Suzuki conditions were used to
form the biaryl bond. Thus, the 4-bromoindole 10 was
first reacted with bis(pinacolato)diboron in dioxane in the
presence of potassium acetate and PdCl2(dppf)‚CH2Cl2
complex57 to give the 4-indolylboronic acid derivative 19.
A second Pd-catalyzed reaction under Suzuki conditions
then combined the indole 19 and oxazole 17 fragments
to give the biaryl compound 20 (Scheme 4). The required
diazo functionality was installed using our diethylzinc
protocol,52 the two-step proceduresdiethylzinc-mediated
addition of ethyl diazoacetate to the aldehyde followed
by oxidation of the resulting R-diazo alcohol using IBX
in DMSOsproceeding with reasonable efficiency even in
a relatively complex substrate such as aldehyde 20. Thus,
a sequence involving diazo compounds at three separate
stages (Schemes 3 and 4) gave the key model diazo
compound 11. Attempts to bring about the intramolecular
phase by others,49,50 and therefore seemed an ideal
method for the synthesis of both oxazoles in the indole
bis-oxazole heterocyclic core of diazonamide A, using both
intra- and intermolecular rhodium carbene insertion
approaches.51 It is also highly appealing and appropriate
that diazo chemistry should be used at key stages in
synthetic approaches to a molecule named diazonamide.
Results and Discussion
Retrosynthetic Analysis. Although originally de-
vised some years ago for the “old” structure, our ret-
rosynthetic analysis of diazonamide A 2 remains largely
unaltered in its overall strategy in which the construction
of both oxazole rings by the aforementioned diazocarbonyl
methodology plays a key role. In common with most other
reported strategies, our initial simplification was to
disconnect the R-hydroxy isovaleric acid side chain and
the two chlorine atoms. It was established early on in
the diazonamide saga that both these chlorines could be
introduced by a late-stage electrophilic chlorination reac-
tion.5,12 However, as did Magnus and co-workers,12 we
recognized an additional possibility that the 4-chloroox-
azole might derive by a decarboxylative chlorination of
the corresponding oxazole-4-carboxylic acid. This relates
to the putatitive biosynthetic precursor to diazonamide
A in that C-4 of the oxazole derives from the R-carbon of
tryptophan and therefore would originally bear a car-
boxylic acid. This initial analysis of diazonamide A 2
leads back to the bicycle 3, which is further simplified to
the macrocycle 4 by lactamization and aminal formation
onto a reduced oxindole (Scheme 2). The stage is now set
for the novel intramolecular rhodium carbene N-H inser-
tion reaction to form the indole bis-oxazole macrocycle
by dirhodium(II)-catalyzed reaction of the diazocarbonyl
compound 5. A second oxazole formation by intermolecu-
lar N-H insertion and a standard Pd-catalyzed formation
of the biaryl bond reveals the valine-derived carboxamide
6 and the two R-diazo-â-ketoesters 7 and 8 as precursors.
The choice of an ester substituent in diazo compound 8
correlates with a tryptophan (rather than tryptamine)
in the putative biosynthetic pathway. Finally, it was
envisaged that both diazocarbonyl compounds 7 and 8
would derive from the corresponding aldehydes by our
previously developed diethylzinc-mediated reactions of
ethyl diazoacetate.52 This reveals the 3-formyloxindole
9 (which is not discussed here) and the simple indole-3-
carboxaldehyde 10.
This paper describes our studies on the diazo route to
the indole bis-oxazole fragment and, in particular, a
(53) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258-
3260.
(49) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3, 2173-
2176.
(54) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709-1716.
(50) Clapham, B.; Lee, S. H.; Koch, G.; Zimmermann, J.; Janda, K.
D. Tetrahedron Lett. 2002, 43, 5407-5410.
(55) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604-3606.
(56) Somei, M.; Kizu, K.; Kunimoto, M.; Yamada, F. Chem. Pharm.
Bull. 1985, 33, 3696-3708.
(57) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
(51) Konopelski et al. (ref 3) have used the Lewis acid catalyzed
reaction of a diazoketone with acetonitrile in a synthesis of a simple
indole oxazole model for diazonamide A.
(52) Moody, C. J.; Morfitt, C. N. Synthesis 1998, 1039-1042.
J. Org. Chem, Vol. 70, No. 18, 2005 7307

Davies et al.
SCHEME 2. Retrosynthetic Analysis of Diazonamide A 2a
a Pg ) Protecting Group; R ) H or CO2R′.
carbene N-H insertion reaction involved the addition of
a dilute dichloromethane solution of diazo compound 11
to a heated solution of the dirhodium(II) catalyst. Both
dirhodium tetraoctanoate and dirhodium tetra(perfluo-
7308 J. Org. Chem., Vol. 70, No. 18, 2005

Diazo Route to Diazonamide A
SCHEME 3. Preparation of the Oxazole
Carboxamide 17a
SCHEME 4
a Ar ) 4-AcNH-C6H4; Oct ) OCOC7H15
.
robutyramide) were studied as catalysts, but in both
cases a complex mixture of products was observed, none
of which appeared to show signals expected from the
1
desired N-H insertion product 21 in the H NMR spec-
trum of the mixture. It was at this juncture, in a parallel
study aimed at a simpler 5-(3-indolyl)oxazole martefragin
A, that it was discovered that N-Boc-indol-3-yl diazoke-
toesters are prone to undergo Wolff rearrangement in
competition with insertion reactions.48 However, the
presence of Wolff rearrangement products from the diazo
1
Subsequent Yonemitsu oxidation with DDQ in aqueous
THF58,59 gave the ketoamide 24 in modest yield, cyclo-
dehydration of which gave the indole bis-oxazole 25
(Scheme 5).41
In line with our desire to use diazocarbonyl chemistry
to prepared both oxazoles of diazonamide A, the challenge
now lay in adapting the above route to incorporate a
second dirhodium(II)-catalyzed step. As a prelude to this,
we repeated the earlier work using the diazoindole 27,
readily prepared from N-Boc-indole-3-carboxaldehyde by
compound 11 was also not apparent from the H NMR
spectrum of the mixture, although the possibility of
products derived by competing aromatic C-H insertion,
as observed previously,39 could not be excluded. Hence,
it appears that the proposed intramolecular rhodium
carbene N-H insertion reaction as evidenced by the model
diazo compound 11 is apparently not a viable route to
the indole bis-oxazole fragment of diazonamide A, and
therefore a less ambitious intermolecular N-H insertion
route was investigated.
Synthesis of Indole Bis-oxazoles. We have already
shown in preliminary work that the oxazole carboxylic
acid 22, prepared in three steps from methyl 2-diazo-3-
oxobutanoate,44 could be readily coupled to tryptophan
methyl ester to give the tryptophan derivative 23.
(58) Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu, O. Heterocycles
1979, 12, 1457-1462.
(59) Yoshioka, T.; Mohri, K.; Oikawa, Y.; Yonemitsu, O. J. Chem.
Res., Synop. 1981, 194-195; J. Chem. Res., Miniprint 1981, 2252-
2281.
J. Org. Chem, Vol. 70, No. 18, 2005 7309

Davies et al.
SCHEME 5. Our Previously Reported Route to
Indole Bis-oxazole 2541
SCHEME 6a
a Oct ) OCOC7H15
.
7). However, the use of the N-nosyldiazoindole 33 proved
more satisfactory, resulting in the formation of the N-H
insertion product 37 in 30% yield (plus 32% of Wolff
rearrangement product 38), cyclodehydration of which
gave the indole bis-oxazole 39 in good yield (Scheme 7).
Synthesis of the Macrocyclic Indole Bis-oxazole
45. Although the diazocarbonyl methodology could be
successfully applied to the synthesis of the simple indole
bis-oxazole 39 albeit in modest yield because of competing
Wolff rearrangement, the current failure to effect an
intramolecular variant prompted a reevaluation of our
synthetic route to the complete indole bis-oxazole mac-
rocycle. Thus, we decided to combine the successful
aspects of the current work with the more conventional
peptide coupling approach used in our preliminary study
(Scheme 5). The coupling partners were the 4-bromo-
tryptamine 40 and the bromobenzyl oxazole 41, the
terminal amino and carboxyl protecting groups both
being removable by hydrogenolysis. The 4-bromotryp-
tophan 40 was prepared in a conventional manner from
4-bromoindole-3-carboxaldehyde 18 by condensation with
nitromethane, lithium aluminum hydride reduction of the
nitroalkene, and protection of the amino group as its
benzyl carbamate. The oxazole benzyl ester 41 was
prepared in a manner similar to that of its ethyl ester
analogue starting by transesterification of the ethyl ester
13, followed by diazo transfer, dirhodium(II)-catalyzed
N-H insertion, and cyclodehydration (Scheme 8). After
some experimentation, it was decided to delay the Yone-
mitsu DDQ-oxidation of the tryptamine side chain until
after the biaryl coupling. Likewise, it was also found to
be better to attach the boronic acid unit to the indole
rather than the oxazole for the Suzuki coupling. There-
fore, 4-bromo-N-Z-tryptamine 40 was subject to boration
the diethylzinc-ethyl diazoacetate protocol.41,48,52 Dirhod-
ium(II) tetraoctanoate catalyzed reaction of diazoindole
27 with oxazole-4-carboxamide 26 resulted in exclusive
Wolff rearrangement and the formation of the imide 28
as a single diastereomer (of unknown relative stereo-
chemistry) (Scheme 6). Although the imide 28 was only
formed in 55% yield, there was no evidence for the
formation of the N-H insertion product 29 as suggested
in our preliminary communication.41
Fortunately, in our parallel studies on martefragin A
we had developed a solution to the Wolff rearrangement
problem,48 and this was now adopted in the diazonamide
case. The starting oxazole-4-carboxamide 31 was pre-
pared by our standard diazocarbonyl route via the
ketoamide 30 (Scheme 7); the change in N-protecting
group (i.e., Z in 26 to Boc in 31) was carried out to
increase solubility. Two diazo indoles were investigated,
the N-benzenesulfonyl derivative 32 and the nosyl (2-
nitrobenzenesulfonyl) compound 33, both prepared by
diethylzinc-mediated addition of ethyl diazoacetate to the
corresponding indole-3-carboxaldehydes followed by IBX
oxidation as previously described.48 Dirhodium(II) tet-
raoctanoate catalyzed reaction of the N-benzenesulfonyl-
diazoindole 32 with the oxazole-4-carboxamide 31 gave
the desired N-H insertion product, the ketoamide 34 in
only 12% yield, the major product being imide 35, a result
of Wolff rearrangement followed by trapping of the ketene
with amide 31. Nevertheless, despite the small quantity
of ketoamide 34 obtained, it was readily cyclodehydrated
to the indole bis-oxazole 36 in reasonable yield (Scheme
7310 J. Org. Chem., Vol. 70, No. 18, 2005

Diazo Route to Diazonamide A
SCHEME 7. Diazo Route to Indole Bis-oxazoles 36
and 39a
it was always contaminated with significant and insepa-
rable amounts of N-Z-tryptamine and, therefore, was
coupled directly with the bromobenzyl oxazole 41. The
Suzuki coupling could be conducted under standard
conditions (Ph3P, aq Na2CO3, DME), although the
PdCl2(dppf)‚CH2Cl2 catalyst gave slightly better results.
This gave the desired biaryl 42 in a modest 38% yield.
The terminal protecting groups were removed by hydro-
genolysis over Pearlman’s catalyst and the resulting
amino acid diluted in DMF and treated with diphe-
nylphosphoryl azide (DPPA) and Hu¨nig’s base to effect
macrocyclization to 43 in good yield. The macrocycle 43
1
exhibits a complex H NMR spectrum at room temper-
ature that simplifies considerably at 60 °C. We believe
that this is due to the presence of two interconverting
atropisomers. The issue of biaryl atropisomerism in
diazonamide A precursors has been discussed by Vedejs
and co-workers21 and results when the biaryl bond is
formed before the macrocycle is established. The macro-
cycle 44 was subjected to Yonemitsu oxidation with DDQ
in aqueous THF, although this only proceeded as far as
the alcohol stage and a subsequent IBX oxidation was
required to give the ketone 44. A similarly incomplete
DDQ oxidation was also noted by Nicolaou and co-
workers in their synthetic efforts on diazonamide A when
a bulky substituent was present at the indole 4-position.26
The final cyclodehydration of ketoamide 44 was effected
using a variation of the Wipf protocol with hexachloro-
ethane in place of iodine.6 This resulted in the formation
of the desired indole bis-oxazole macrocycle 45 (Scheme
8).
Conclusions. The present study has highlighted the
use of diazocarbonyl chemistry in the synthesis of ox-
azoles many of which are relatively complex. However,
to date, an intramolecular variant of the key N-H
insertion reaction to form a macrocyclic ring of diazona-
mide A has eluded us, and in some circumstances, the
competing Wolff rearrangement cannot be completely
suppressed. Nevertheless, despite these setbacks, suc-
cessful syntheses of a range of oxazoles and indole bis-
oxazoles related to diazonamide A have been achieved
using diazocarbonyl methodology.
Experimental Section
Commercially available reagents were used throughout
without further purification unless otherwise stated; solvents
were dried by standard procedures. Light petroleum refers to
the fraction with bp 40-60 °C, and ether refers to diethyl
ether. Reactions were routinely carried out under a nitrogen
atmosphere. Chromatography was carried out on Merck Kie-
selgel 60H or Matrex silica 60. Fully characterized compounds
were chromatographically homogeneous. IR spectra were
recorded in the range 4000-600 cm-1. 1H and 13C NMR spectra
were recorded at 300 or 400 MHz (1H frequencies, correspond-
ing 13C frequencies are 75 and 100 MHz); J values are recorded
in Hz. In the 13C NMR spectra, signals corresponding to CH,
CH2, or CH3 groups, as assigned from DEPT, are noted; all
others are C.
General Experimental Procedures. A. Synthesis of
â-Ketoesters from Aldehydes Using Ethyl Diazoacetate
and Tin(II) Chloride.53 Anhydrous tin(II) chloride (1.3 mmol)
a Oct ) OCOC7H15
.
using Baudoin’s modification of Masuda’s method,60,61
involving Pd(OAc)2 and 2-(dicyclohexylphosphino)biphe-
nyl as ligand. This gave the required boronate, although
(60) Baudoin, O.; Guenard, D.; Gueritte, F. J. Org. Chem. 2000, 65,
9268-9271.
(61) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
6458-6459.
J. Org. Chem, Vol. 70, No. 18, 2005 7311

Davies et al.
SCHEME 8. Construction of the Model Indole Bis-oxazole Macrocycle 45a
a DPPA ) diphenylphosphoryl azide; Ar ) 4-AcNH-C6H4; Oct ) OCOC7H15
.
was suspended in dichloromethane (40 mL) to which was
added ethyl diazoacetate (14 mmol). Then the aldehyde (13
mmol) in dichloromethane (10 mL) was added dropwise, and
the mixture was stirred for 4 h. Dilute HCl (2 M; 25 mL) was
added and the mixture stirred for 30 min and then extracted
with dichloromethane (3 × 30 mL). The combined organic
layers were washed with brine, dried (MgSO4), and concen-
trated in vacuo, and the resulting oil was purified by column
chromatography (dichloromethane-light petroleum) to yield
the product.
B. Diazo Transfer. To a stirred mixture of the â-ketoester
(10 mmol) and 4-acetamidobenzenesulfonyl azide54 (11 mmol)
in acetonitrile (60 mL) at 0 °C was added triethylamine (30
mmol) dropwise. After being stirred at room temperature for
16 h, the reaction mixture was concentrated in vacuo and the
resulting solid was triturated with ether-light petroleum. The
filtrate was concentrated in vacuo and purified by flash
chromatography on silica gel eluting with ethyl acetate-light
petroleum (1:4) to yield the product.
C. Rhodium Carbene N-H Insertion Reactions: Prepa-
ration of Ketoamides. To a solution of the carboxamide (5.00
mmol) and dirhodium tetraoctanoate (unless otherwise stated)
(2.5 mol %) in a suitable solvent (10 mL), heated to reflux,
was added a solution of the diazo compound (6.50 mmol) in
the same solvent dropwise over 16 h. The reaction mixture
was heated for a further 2-4 h and evaporated in vacuo and
the residue purified on silica gel eluting with ethyl acetate-
light petroleum (1:4) to yield the product.
D. Cyclodehydration of Ketoamides to Oxazoles. To a
solution of triphenylphosphine (0.20 mmol) and iodine (0.20
mmol) in dry dichloromethane (10 mL) was added triethyl-
amine (0.41 mmol); a solution of the ketoamide (0.10 mmol)
in dry dichloromethane (3 mL) was added. The reaction
mixture was stirred for 16 h and evaporated in vacuo and the
7312 J. Org. Chem., Vol. 70, No. 18, 2005

Diazo Route to Diazonamide A
residue purified on silica gel eluting with ethyl acetate-light
the combined organic layers were washed with saturated
sodium hydrogen carbonate (30 mL) and brine (30 mL), dried
(MgSO4), filtered, and reduced in vacuo. The residue was
purified by column chromatography (ethyl acetate-light pe-
troleum) to yield the title compound as a colorless solid (320
mg, 0.7 mmol, 68%): mp 103-105 °C; [R]30 -33.7 (c 1.05,
CHCl3); IR (KBr/cm-1) 3483 (N-H), 3457 (N-H), 3360 (N-H),
1690 (CdO); 1H NMR (300 MHz; CDCl3) δ 7.43-7.34 (2H, m),
7.24-7.13 (2H, m), 6.85 (1H, s), 5.71 (1H, s), 5.09 (1H, d, J )
8.7), 4.69 (1H, dd, J ) 8.7, 5.8), 4.38 (2H, s), 2.18-2.09 (1H,
m), 1.44 (9H, s), 0.89 (3H, d, J ) 6.6), 0.88 (3H, d, J ) 6.6);
13C NMR (75 MHz; CDCl3) δ 163.3, 161.5, 155.1, 154.1, 138.5,
131.5 (CH), 130.0 (CH), 129.8 (CH), 128.6, 127.3 (CH), 122.4,
80.0, 53.9 (CH), 32.3 (CH), 31.1 (CH2), 28.1 (Me), 18.4 (Me),
17.7 (Me); MS (CI) 454/452 (MH+, 21), 398/396 (100) (found
MH+, 452.1179, C20H2779BrN3O4 requires 452.1185).
petroleum to yield the product.
E. Synthesis of R-Diazo-â-ketoesters by Reaction of
Aldehydes with Ethyl Diazoacetate and Diethylzinc
Followed by IBX Oxidation.52 To a solution of ethyl diazo-
acetate (1.9 mmol) in dichloromethane (5 mL) cooled to -60
°C was added diethylzinc (1.0 M in hexanes; 1.9 mmol)
maintaining the temperature below -50 °C, and the mixture
was stirred for 30 min. A solution of the aldehyde (1.9 mmol)
in dichloromethane (5 mL) was added, and the solution was
stirred for 2 h maintaining the temperature below -50 °C
before being allowed to warm to room temperature overnight.
The mixture was quenched with concentrated aqueous am-
monia (10 mL) and extracted with dichloromethane (3 × 30
mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated under reduced pressure. The resulting oil
was purified by flash chromatography (ethyl acetate-light
petroleum) (1:4) to give impure R-diazo-â-hydroxy ester that
was carried through to the next stage without further purifica-
tion.
Iodoxybenzoic acid (2.1 mmol) was dissolved in DMSO (5
mL) over 20 min, the crude R-diazo-â-hydroxyester (1.4 mmol)
in DMSO (5 mL) was added, and the mixture was stirred for
3 h. The reaction mixture was poured onto water (20 mL) and
extracted with dichloromethane (2 × 20 mL). The combined
organic layers were dried (MgSO4) and concentrated under
reduced pressure. The resulting oil was purified by flash
chromatography (ethyl acetate-light petroleum) (1:9) to yield
the product.
(S)-5-[3-(1-tert-Butoxycarbonyl-3-formylindol-4-yl)]ben-
zyl-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]ox-
azole-4-carboxamide 20. To a solution of boronic indole 19
(219 mg, 0.6 mmol) (see the Supporting Information), oxazole
amide 17 (320 mg, 0.7 mmol), and potassium carbonate (407
mg, 2.9 mmol) in DME (15 mL) was added PdCl2(dppf)‚CH2-
Cl2 (86 mg, 0.1 mmol), and the resulting solution was heated
to 85 °C for 20 h. The mixture was then diluted with ether
(20 mL), and the mixture was washed with brine (20 mL),
dried (MgSO4), filtered and concentrated under reduced pres-
sure. The crude residue was purified by column chromatog-
raphy to yield the title compound as a pale yellow foam (205
mg, 0.3 mmol, 56%): [R]31 -30.6 (c 0.12, CHCl3); IR (KBr/cm-1
)
1
(S)-N2-tert-Butoxycarbonyl-N1-[1-ethoxycarbonyl-3-(3-
bromophenyl)-2-oxopropyl]valinamide 15. According to
general procedure C, the title compound was prepared from
(S)-N-Boc-valinamide44 (1.0 g, 4.6 mmol), diazo compound 14
(2.16 g, 6.9 mmol) (see the Supporting Information), and
dirhodium tetraoctanoate (90 mg, 0.12 mmol) in dichlo-
romethane (50 mL), as a mixture of diastereomers, as a
colorless solid (1.7 g, 3.4 mmol, 73%): mp 99-102 °C; IR (KBr/
cm-1) 3308 (N-H), 1748 (CdO), 1720 (CdO), 1691 (CdO), 1653
(CdO); 1H NMR (300 MHz; CDCl3) δ 7.42 (1H, d, J ) 7.9),
7.37 (1H, s), 7.24-7.14 (3H, m), 5.30 (1H, d, J ) 5.0), 5.06
(1H, m), 4.29-4.18 (2H, m), 4.10-3.93 (3H, m), 2.25-2.18 (1H,
m), 1.45 (9H, s), 1.33-1.25 (3H, m), 1.06-0.92 (6H, m); 13C
NMR (100 MHz; CDCl3) δ 198.0 + 179.9 (diast), 171.7, 165.6
+ 165.5 (diast), 155.8, 134.7, 132.7 + 132.6 (CH, diast), 130.5
(CH), 130.2 + 130.1 (CH, diast), 128.4 + 128.3 (CH, diast),
122.6, 80.1 + 80.0 (diast), 62.9 (CH2), 62.0 (CH), 59.5 (CH),
46.9 + 46.8 (CH2, diast), 30.8 + 30.7 (CH, diast), 28.3 (Me),
19.2 + 19.1 (Me, diast), 17.5 + 17.4 (Me, diast), 14.0 (Me); MS
(CI) 501/499 (MH+, 4), 473 (5), 401/399 (77), 337/335 (23), 72
(100) (found MH+, 499.1446, C22H3279BrN2O6 requires 499.1444).
(S)-Ethyl 5-(3-Bromobenzyl)-[1-(tert-butoxycarbonyl-
amino)-2-methylpropyl]oxazole-4-carboxylate 16. Accord-
ing to general procedure D, the title compound was prepared
from 15 (1.5 g, 3.0 mmol) as a colorless oil (941 mg, 2.0 mmol,
65%): [R]30 -14.0 (c 1.0, CHCl3); IR (KBr/cm-1) 3350 (N-H),
1706 (CdO); 1H NMR (300 MHz; CDCl3) δ 7.41-7.36 (2H, m),
7.20-7.18 (2H, m), 5.27 (1H, d, J ) 5.9), 4.75 (1H, dd, J )
9.1, 5.9), 4.43 (2H, q, J ) 7.1), 4.34 (2H, s), 2.18-2.11 (1H,
m), 1.46-1.39 (12H, m), 0.90 (3H, d, J ) 6.5), 0.88 (3H, d, J )
6.5); 13C NMR (75 MHz; CDCl3) δ 161.6, 160.6, 155.1, 154.0,
136.9, 130.3 (CH), 128.9 (CH), 128.85 (CH), 126.5, 125.9 (CH),
121.3, 78.6, 59.9 (CH2), 52.8 (CH), 31.6 (CH), 30.3 (CH2), 26.9
(Me), 17.3 (Me), 16.6 (Me), 13.0 (Me); MS (CI) 483/481 (MH+,
26), 427/425 (100), 383/381 (34), 366/364 (20); (found MH+,
481.1335, C22H3079BrN2O5 requires 481.1338).
3437 (N-H), 1752 (CdO), 1716 (CdO), 1675 (CdO); H NMR
(400 MHz; CDCl3) δ 9.37 (1H, s), 8.33 (1H, s), 8.27 (1H, d, J )
8.4), 7.44-7.32 (5H, m), 7.27-7.22 (1H, m), 6.95 (1H, s), 5.91
(1H, s), 4.68-4.64 (1H, m), 4.50-4.35 (2H, br m), 2.11 - 2.08
(1H, m), 1.69 (9H, s), 1.37 (9H, s), 0.90 (3H, d, J ) 6.2), 0.84
(3H, d, J ) 6.7), valine NH not observed; 13C NMR (100 MHz;
CDCl3) δ 187.4 (CH), 163.9, 161.7, 155.6, 154.9, 148.8, 141.6,
137.1, 136.3, 135.3, 131.6 (CH), 129.5 (CH), 128.6 (CH), 128.5
(CH), 127.5 (CH), 125.5, 125.4 (CH), 125.2 (CH), 121.2, 114.7
(CH), 85.6, 79.7, 75.0, 65.9 (CH2), 54.4 (CH), 32.4 (CH), 28.3
(Me), 28.1 (Me), 18.8 (Me), 18.1 (Me); MS (CI) 617 (M+, 100)
(found MH+, 617.2968, C34H41N4O7 requires 617.2970).
(S)-Ethyl {1-tert-Butoxycarbonyl-4-{3-[2-(1-tert-butoxy-
carbonylamino-2-methylpropyl)-4-carbamoyloxazol-5-
ylmethyl]phenyl}indol-3-yl}-2-diazo-3-oxopropanoate 11.
According to general procedure E, biaryl aldehyde 20 (140 mg,
0.22 mmol) was treated with ethyl diazoacetate (0.04 mL, 0.22
mmol) and diethylzinc (1 M in hexanes; 0.22 mL, 0.22 mmol)
in dichloromethane (5 mL) followed in a second step by IBX
(95 mg, 0.34 mmol) in DMSO (3 mL) to yield the title compound
as a yellow oil (83 mg, 0.11 mmol, 50%): [R]31 -13.9 (c 0.12,
CHCl3); IR (film/cm-1) 3350 (N-H), 2136 (CdN2), 1711 (CdO),
1
1680 (CdO); H NMR (400 MHz; CDCl3) δ 8.15 (1H, d, J )
8.3), 7.88 (1H, s), 7.24-7.38 (1H, m), 7.34-7.33 (2H, m), 7.29
- 7.26 (1H, m), 7.24-7.22 (1H, m), 7.19-7.17 (1H, m), 6.88
(1H, d, J ) 2.7), 5.67 (1H, d, J ) 3.0), 5.51 (1H, m), 4.72 (1H,
dd, J ) 6.2, 9.2), 4.43 (2H, s), 3.91 (2H, q, J ) 7.1), 2.19-2.16
(1H, m), 1.67 (9H, s), 1.40 (9H, s), 0.95-0.85 (9H, m); 13C NMR
(100 MHz; CDCl3) δ 182.8, 163.8, 161.5, 160.1, 155.5, 154.8,
149.0, 141.2, 137.0, 135.22, 135.16, 129.2 (CH), 128.7, 128.6
(CH), 128.2 (CH), 127.9 (CH), 127.5 (CH), 125.8, 125.2 (CH),
124.4 (CH), 121.2, 114.5 (CH), 84.8, 79.8, 78.1, 61.2 (CH2), 54.2
(CH), 32.2 (CH), 31.6 (CH2), 28.3 (Me), 28.1 (Me), 18.8 (Me),
17.9 (Me), 13.8 (Me); MS (ES+) 729 (MH+, 100) (found MH+,
729.3250, C38H45N6O9 requires 729.3243).
Ethyl 2-(1-tert-Butoxycarbonylindol-3-yl)-N-{[1-ben-
zyloxycarbonylamino-2-(S)-methylpropyl)-4-methylox-
azole-5-carbonyl]amino}malonamate 28. According to gen-
eral procedure C, using oxazole amide 2644 (200 mg, 0.60
mmol) and diazo compound 2748 (647 mg, 1.8 mmol) with
dirhodium tetraoctanoate (12 mg, 0.02 mmol) in dichlo-
romethane (22 mL), the title compound was isolated as a yellow
(S)-2-[(1-tert-Butoxycarbonylamino)-2-methylpropyl]-
5-(3-bromobenzyl)oxazole-4-carboxamide 17. The oxazole
ester 16 (500 mg, 1.0 mmol) was dissolved in a solution of
ethanol (5 mL) and ammonia (5 mL) and the mixture stirred
overnight before being reduced in vacuo and partitioned
between ethyl acetate (25 mL) and water (25 mL). The aqueous
layer was extracted with ethyl acetate (2 × 25 mL), and the
solid (220 mg, 0.33 mmol, 55%): mp 59-62 °C; IR (KBr/cm-1
)
J. Org. Chem, Vol. 70, No. 18, 2005 7313

Davies et al.
3361 (N-H), 1734 (CdO), 1701 (CdO); 1H NMR (300 MHz;
CDCl3) δ 9.44 (0.5H) 9.41 (0.5H, s), 7.97 (1H, d, J ) 7.6), 7.56
(1H, s), 7.45 (1H, d, J ) 7.7), 7.18 - 7.07 (7H, m), 5.66 (1H, s),
5.11-5.05 (1H, m), 4.96-4.93 (2H, m), 4.58 (1H, dd, J ) 5.7,
8.7), 4.11-4.01 (2H, m), 2.45 (3H, s), 2.01-1.95 (1H, m), 1.48
(9H, s), 1.08 (3H, t, J ) 6.4), 0.75 (6H, d, J ) 6.6); 13C NMR
(75 MHz; CDCl3) δ 167.1, 166.7, 160.1, 158.7, 155.7, 154.9,
148.4, 135.0, 134.3, 128.3, 127.6 (CH), 127.3 (CH), 127.2 (CH),
126.8, 124.8 (CH), 123.7 (CH), 121.8 (CH), 118.7 (CH), 114.3
(CH), 111.2, 82.9, 66.3 (CH2), 61.0 (CH2), 53.5 (CH), 50.1 (CH),
31.2 (CH), 27.2 (Me), 17.7 (Me), 16.8 (Me), 13.0 (Me), 11.0 (Me);
MS (ES+) 661 (MH+, 100) (found MH+, 661.2870, C35H41N4O9
requires 661.2868).
bonylamino)-2-methylpropyl]-5-methyloxazole-4-carbox-
amide 31. To a solution of oxazole amide 31 (300 mg, 1.0
mmol) and dirhodium tetraoctanoate (20 mg, 0.03 mmol) in
dichloromethane (10 mL) heated under reflux was added diazo
indole 3248 (521 mg, 1.3 mmol) in dichloromethane (12 mL)
over 16 h. The reaction mixture was heated for a further 30
min, allowed to cool, evaporated in vacuo, and purified by flash
chromatography (ethyl acetate-light petroleum). From the
reaction two products were isolated:
(i) Ethyl 2-(1-benzenesulfonylindol-3-yl)-N-{[(1-tert-
butoxycarbonylamino-2(S)-methylpropyl)-4-methylox-
azole-5-carbonyl]amino}malonamate 35: colorless oil (260
mg, 0.39 mmol, 39%); IR (film/cm-1) 3360 (N-H), 1711 (CdO);
1H NMR (300 MHz; CDCl3) δ 9.57 (1H, s), 7.97 (1H, d, J )
8.2), 7.88 (2H, d, J ) 7.9), 7.81 (1H, s), 7.64 (1H, d, J ) 7.8),
7.49-7.46 (1H, m), 7.41-7.35 (2H, m), 7.32-7.20 (2H, m), 5.87
(1H, s), 5.11-5.09 (1H, m), 4.69 (1H, dd, J ) 5.9, 8.8), 4.26-
4.16 (2H, m), 2.62 (3H, s), 2.16-2.09 (1H, m), 1.43 (9H, s), 1.23
N2-(tert-Butoxycarbonyl)-N1-(1-methoxycarbonyl-2-
oxopropyl)valinamide 30. According to general procedure
C, the title compound was prepared from (S)-N-(tert-butoxy-
carbonyl)valinamide44 (1.2 g, 5.6 mmol) and methyl 2-diazo-
3-oxobutanoate (1.0 g, 7.2 mmol) in dichloromethane, as a
mixture of diastereomers, as a colorless solid (1.4 g, 4.1 mmol,
(3H, t, J ) 7.1), 0.91 (3H, d, J ) 6.6), 0.90 (3H, d, J ) 6.6); 13
C
78%): mp 110-112 °C (lit.44 mp 111-113 °C); IR (KBr/cm-1
)
NMR (75 MHz; CDCl3) δ 168.6, 167.9, 162.0, 160.1, 157.0,
155.8, 138.4, 135.3, 134.3 (CH), 130.2, 129.7 (CH), 128.1, 127.2
(CH), 126.8 (CH), 125.4 (CH), 123.9 (CH), 120.8 (CH), 114.6,
113.9 (CH), 80.7, 62.4 (CH2), 54.5 (CH), 51.4 (CH), 32.8 (CH),
28.7 (Me), 19.2 (Me), 18.3 (Me), 14.4 (Me), 12.4 (Me); MS (ES+)
667 (MH+, 30), 611 (100), 568 (22), 567 (63) (found MH+,
667.2438, C33H39N4O9S requires 667.2432). (ii) Ethyl 3-(1-
benzenesulfonylindol-3-yl)-2-{[(1-tert-butoxycarbonyl-
amino-2(S)-methylpropyl)-4-methyloxazole-5-carbonyl]-
amino}-3-oxopropanoate 34: colorless oil (82 mg, 0.12 mmol,
12%), used directly in the next step, without any characteriza-
tion.
3319 (N-H), 1752 (CdO), 1721 (CdO), 1690 (CdO), 1655 (Cd
1
O); H NMR (300 MHz; CDCl3) δ 7.15 (1H, d, J ) 5.8), 5.25
(1H, d, J ) 6.2), 5.05 (1H, d, J ) 6.2) 4.08 (1H, m), 4.85, 4.83
(3H, 2 × s), 2.42, 2.40 (3H, 2 × s), 2.25-2.19 (1H, m), 1.47
(9H, s), 1.00 (3H, d, J ) 6.8), 0.93 (3H, d, J ) 6.8); 13C NMR
(75 MHz; CDCl3) δ 197.3 + 197.2 (diast), 170.7, 165.6 + 165.5
(diast), 155.0, 79.4, 62.2 + 62.1 (CH, diast), 58.8 (CH), 52.6 +
52.5 (Me, diast), 30.1 + 29.9 (Me, diast), 27.5 (Me), 27.3 + 27.2
(CH, diast), 18.5 + 18.4 (Me, diast), 16.7 + 16.5 (Me, diast);
MS (CI) 331 (MH+, 12), 231 (100) (found MH+, 331.1862,
C15H27N2O6 requires 331.1869).
(S)-2-[1-tert-(Butoxycarbonylamino)-2-methylpropyl]-
5-methyloxazole-4-carboxamide 31. (a) According to gen-
eral procedure D, (S)-methyl 2-[1-(tert-butoxycarbonylamino)-
2-methylpropyl]-5-methyloxazole-4-carboxylate was prepared
from 30 (1.2 g, 3.6 mmol) as a colorless crystalline solid (1.0
g, 3.2 mmol, 89%): mp 88-90 °C (lit.62 oil; lit.63 mp 57 °C);
[R]26 -39.0 (c 1.0, CHCl3) (lit.62 [R]23 20.9 (c 11.7, CHCl3)); IR
(KBr/cm-1) 3394 (N-H), 1715 (CdO), 1700 (CdO); 1H NMR
(300 MHz; CDCl3) δ 5.26-5.23 (1H, d, J ) 9.4), 4.73-4.70 (1H,
dd, J ) 9.4, 6.1), 3.88 (3H, s), 2.59 (3H, s), 2.19-2.13 (1H, m),
1.41 (9H, s), 0.90 (3H, d, J ) 6.7), 0.89 (3H, d, J ) 6.7); 13C
NMR (75 MHz; CDCl3) δ 163.1, 162.5, 156.7, 155.8, 127.6, 80.3,
54.5 (CH), 52.4 (Me), 33.3 (CH), 28.7 (Me), 19.2 (Me), 18.3 (Me),
12.4 (Me); MS (CI) 313 (MH+, 32), 257 (100) (found MH+,
313.1761, C15H25N2O5 requires 313.1763). Anal. Calcd for
C15H24N2O5: C, 57.7; H, 7.7; N, 9.0. Found: C, 57.7; H, 7.9; N,
8.9.
(S)-Ethyl 5-(1-Benzenesulfonylindol-3-yl)-2′-[1-(tert-bu-
toxycarbonylamino)-2-methylpropyl]-5′-methyl-
[2,4′]ioxazolyl-4-carboxylate 36. According to general pro-
cedure D, the title compound was prepared from 34 (80 mg,
0.12 mmol) as a colorless solid (50 mg, 0.08 mmol, 64%): mp
160-162 °C; [R]30 -38.5 (c 0.96, CHCl3); IR (KBr/cm-1) 3350
1
(N-H), 1711 (CdO), 1685 (CdO); H NMR (300 MHz; CDCl3)
δ 8.99 (1H, s), 8.11 (1H, d, J ) 7.8), 8.06 (1H, d, J ) 8.0), 7.99
(2H, d, J ) 7.5), 7.57-7.55 (1H, m), 7.49-7.46 (2H, m), 7.39-
7.36 (2H, m), 5.33 (1H, d, J ) 8.8), 4.79 (1H, dd, J ) 5.7, 8.8),
4.49 (2H, q, J ) 7.1), 2.74 (3H, s), 2.25-2.20 (1H, m), 1.47-
1.44 (12H, m), 0.95 (6H, d, J ) 6.7); 13C NMR (75 MHz; CDCl3)
δ 163.0, 162.1, 155.5, 154.0, 150.6, 150.4, 137.8 134.6, 134.3
(CH), 129.8 (CH), 129.5 (CH), 127.90, 127.88, 127.1 (CH), 125.5
(CH), 124.5, 124.3 (CH), 121.8 (CH), 113.7 (CH), 109.2, 79.9,
61.5 (CH2), 54.1 (CH), 32.9 (CH), 28.3 (Me), 18.8 (Me), 17.9
(Me), 14.4 (Me), 12.0 (Me); MS (CI) 649 (MH+, 8), 593 (25),
549 (61), 409 (100) (found MH+, 649.2316, C33H37N4O8S
requires 649.2332).
Reaction of Ethyl 2-Diazo-3-[1-(2-nitrobenzenesulfo-
nyl)indol-3-yl]-3-oxopropanoate 33 with (S)-2-[1-tert-Bu-
toxycarbonylamino)-2-methylpropyl]-5-methyloxazole-
4-carboxamide 31. To a solution of oxazole amide 31 (347
mg, 1.2 mmol) and dirhodium tetraoctanoate (23 mg, 36 µmol)
in dichloromethane (10 mL) heated under reflux was added
diazo indole 3348 (670 mg, 1.5 mmol) in dichloromethane (12
mL) over 16 h. The reaction mixture was heated for a further
30 min, allowed to cool, evaporated in vacuo, and purified by
flash chromatography (ethyl acetate-light petroleum). From
the reaction two products were isolated:
(i) Ethyl 3-{[2-(1-tert-butoxycarbonylamino-2-methyl-
propyl)-5-methyloxazole-4-carbonyl]amino}-2-[1-(2-ni-
trobenzenesulfonyl)-1H-indol-3-yl]-3-oxopropionate 38:
mixture of diastereomers, as a yellow oil (272 mg, 0.4 mmol,
32%); IR (film/cm-1) 3352 (N-H), 1724 (CdO), 1703 (CdO); 1H
NMR (400 MHz; CDCl3) δ 9.63, 9.61 (1H, 2 × s), 7.80-7.77
(2H, m), 7.71-7.65 (4H, m), 7.59-7.54 (1H, m), 7.29-7.26 (2H,
m), 5.93 (1H, s), 5.27-5.26 (1H, m), 4.68 (1H, dd, J ) 6.0, 8.5)
4.28-4.22 (2H, m), 2.62 (3H, s), 2.15-2.12 (1H, m), 1.44, 1.42
(9H, 2 × s), 1.24 (3H, t, J ) 7.1), 0.91 (3H, d, J ) 6.4), 0.90
(3H, d, J ) 6.7); 13C NMR (100 MHz; CDCl3) δ 167.60 + 167.58
(b) The above oxazole ester (1.0 g, 3.2 mmol) was dissolved
in a solution of methanol (10 mL) and ammonia (0.88; 10 mL),
and the mixture was stirred overnight. The mixture was
reduced in vacuo and partitioned with ethyl acetate (40 mL)
and water (20 mL) and the aqueous layer was extracted with
ethyl acetate (2 × 40 mL). The combined organic layers were
washed with saturated sodium hydrogen carbonate (60 mL)
and brine (60 mL), dried (MgSO4), filtered, and reduced in
vacuo to yield the title compound as a colorless oily solid (940
mg, 3.2 mmol, 99%): [R]30 -58.3 (c 1.04, CHCl3); IR (KBr/cm-1
)
3473 (N-H), 3355 (N-H), 1680 (CdO); 1H NMR (300 MHz;
CDCl3) δ 6.81 (1H, s), 5.78 (1H, s), 5.15-5.12 (1H, d, J ) 8.9),
4.70-4.65 (1H, dd, J ) 6.1, 8.9), 2.60 (3H, s), 2.17-2.10 (1H,
m), 1.44 (9H, s), 0.92 (3H, d, J ) 6.8), 0.91 (3H, d, J ) 6.8);
13C NMR (75 MHz; CDCl3) δ 164.9, 161.7, 156.2, 154.6, 129.4,
81.0, 55.0 (CH), 33.4 (CH), 29.2 (Me), 19.6 (Me), 18.8 (Me),
12.6 (Me); MS (CI) 298 (MH+, 11), 242 (100) (found MH+,
298.1763, C14H24N3O4 requires 298.1767).
Reaction of Ethyl 3-(1-Benzenesulfonylindol-3-yl)-2-
diazo-3-oxopropanoate 32 with (S)-2-[1-tert-Butoxycar-
(62) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207-
8215.
(63) Haberhauer, G.; Rominger, F. Eur. J. Org. Chem. 2003, 3209-
3218.
7314 J. Org. Chem., Vol. 70, No. 18, 2005

Diazo Route to Diazonamide A
(diast), 167.5, 161.58 + 161.55 (diast), 159.8, 156.8, 155.4,
147.8, 135.0 (CH), 134.8, 132.6 (CH), 131.7, 129.8 (CH), 128.7,
127.7, 127.30 + 127.26 (CH) (diast), 125.3 (CH), 125.0 (CH),
124.0 (CH), 120.9 (CH), 114.1 + 114.0 (diast), 113.3 (CH), 80.3,
62.2 (CH2), 54.1 (CH), 51.0 (CH), 32,4 (CH), 28.3 (Me), 18.8
(Me), 17.9 (Me), 14.0 (Me), 12.0 (Me); MS (ES+) 734 (M + Na,
100), 712 (MH+, 76), 656 (66), 612 (55), 320 (38), 264 (58), 242
(40), 196 (50), 181 (76) (found MH+, 712.2277, C33H38N5O11S
requires 712.2283). (ii) Ethyl 2-{[2-(1-tert-butoxycarbonyl-
amino-2-methylpropyl)-5-methyloxazole-4-carbonyl]ami-
no}-3-[1-(2-nitrobenzenesulfonyl)-1H-indol-3-yl]-3-oxo-
propionate 37: mixture of diastereomers, as a yellow oil (252
mg, 0.4 mmol, 30%); IR (film/cm-1) 3402 (N-H), 1747 (CdO),
128.9 (CH), 128.8 (CH), 122.9, 67.6 (CH2), 45.7 (CH2), diazo C
not observed; MS (CI) 375/373 (MH+, 9), 107 (30), 91 (100)
(found MH+, 373.0172, C17H1479BrN2O3 requires 373.0188).
(c) According to general procedure C, (S)-N1-[1-benzyloxy-
carbonyl-3-(2-bromophenyl)-2-oxopropyl]-N2-tert-butoxycarbo-
nylvalinamide was prepared from (S)-N-Boc-valinamide (591
mg, 2.7 mmol), the above diazo compound (1.7 g, 5.5 mmol),
and dirhodium tetraoctanoate (106 mg, 0.14 mmol) in dichlo-
romethane, as a mixture of diastereomers, as a colorless solid
(880 mg, 1.6 mmol, 58%): mp 122-124 °C (ethyl acetate/light
petroleum); IR (KBr/cm-1) 3426 (N-H), 3314 (N-H), 1759 (Cd
O), 1724 (CdO), 1688 (CdO); 1H NMR (300 MHz; CDCl3) δ
7.40-7.32 (6H, m), 7.20-7.11 (3H, m), 6.99-6.96 (1H, m), 5.34
(1H, d, J ) 6.0), 5.30-5.14 (2H, m), 5.00-4.98 (1H, m), 4.10-
4.04 (1H, m), 3.99-3.83 (2H, m), 2.21-2.17 (1H, m), 1.44 (9H,
s), 0.98-0.94 (3H, m), 0.90-0.87 (3H, m); 13C NMR (75 MHz;
CDCl3) δ 197.9, 172.0, 165.9, 156.2, 134.9, 134.7, 133.0 (CH),
131.0 (CH), 130.5 (CH), 129.4 (CH), 129.3 (CH), 129.1 (CH),
128.7 (CH), 123.0, 80.6, 69.0 (CH2), 62.4 (CH), 59.9 (CH), 47.3
(CH2), 31.1 (CH), 28.7 (Me), 19.6 (Me), 17.7 (Me); MS (CI) 563/
561 (MH+, 35), 507/505 (100), 463/461 (83), 311/309 (59) (found
MH+, 561.1589, C27H3479BrN2O6 requires 561.1600). Anal.
Calcd for C27H33BrN2O6: C, 57.8; H, 5.9; N, 5.0. Found: C,
57.6; H, 6.0; N, 4.8.
1
1709 (CdO), 1666 (CdO); H NMR (400 MHz; CDCl3) δ 8.75
(1H, s), 8.39-8.36 (1H, m), 8.19-8.15 (2H, m), 7.83-7.77 (4H,
m), 7.40-7.37 (2H, m), 6.09 (1H, d, J ) 7.1), 5.18 (1H, d, J )
9.0), 4.71 (1H, dd, J ) 5.7, 9.0), 4.32-4.25 (2H, m), 2.59 (3H,
s), 2.18-2.16 (1H, m), 1.44 (9H, s), 1.26 (3H, t, J ) 7.1), 0.93
(3H, d, J ) 6.6), 0.92 (3H, d, J ) 6.5); 13C NMR (100 MHz;
CDCl3) δ 186.2, 166.6, 161.5, 161.1, 155.5, 153.9, 148.0, 138.0
(CH), 134.5, 132.9 (CH), 131.22 (CH), 131.20 (CH), 130.6,
128.3, 127.5, 126.3 (CH), 125.6 (CH), 125.5 (CH), 123.3 (CH),
118.1, 112.9 (CH), 80.0, 62.9 (CH2), 59.4 + 59.3 (diast) (CH),
54.1 (CH), 32.7 (CH), 28.34 + 28.33 (diast) (Me), 18.8 (Me),
17.9 (Me), 14.0 (Me), 11.7 (Me); MS (ES+) 712 (MH+, 30), 657
(32), 656 (100) (found MH+, 712.2286, C33H38N5O11S requires
712.2283).
(S)-Ethyl 2′-(1-tert-Butoxycarbonylamino-2-methyl-
propyl)-5′-methyl-5-[1-(2-nitrobenzenesulfonyl)-1H-indol-
3-yl][2,4′]bioxazolyl-4-carboxylate 39. According to general
procedure D, the title compound was prepared from 37 (220
mg, 0.31 mmol) as a colorless solid (163 mg, 0.24 mmol, 76%):
mp 125 °C dec; [R]31 -57.6 (c 0.11, CHCl3); IR (KBr/cm-1) 3420
(N-H), 1716 (CdO); 1H NMR (400 MHz; CDCl3) δ 8.95 (1H, s),
8.19-8.14 (1H, m), 7.91-7.88 (2H, m), 7.80-7.74 (2H, m),
7.70-7.66 (1H, m), 7.42-7.40 (2H, m), 5.33 (1H. d, J ) 9.2),
4.79 (1H, dd, J ) 6.1, 9.2), 4.48 (2H, q, J ) 7.2), 2.75 (3H, s),
2.25-2.20 (1H, m), 1.47-1.43 (12H, m), 0.95 (6H, d, J ) 6.0);
13C NMR (100 MHz; CDCl3) δ 163.0, 161.9, 155.5, 154.3, 150.8,
149.8, 147.9, 135.3 (CH), 134.5, 132.7 (CH), 131.5, 130.3 (CH),
130.1 (CH), 128.4, 127.8, 125.8 (CH), 125.3 (CH), 124.8 (CH),
124.5, 122.2 (CH), 113.6 (CH), 109.3, 80.0, 61.6 (CH2), 54.2
(CH), 32.9 (CH), 28.3 (Me), 18.8 (Me), 18.0 (Me), 14.3 (Me),
12.0 (Me); MS (ES+) 694 (MH+, 30), 656 (25), 639 (36), 638
(100) (found MH+, 694.2183, C33H36N5O10S requires 694.2177).
(d) According to general procedure D, the above ketoamide
(280 mg, 0.53 mmol) was cyclodehydrated to give the title
compound as an orange oily solid (230 mg, 0.45 mmol, 85%):
[R]31 -33.3 (c 0.10, CHCl3); IR (film/cm-1) 3348 (N-H), 1713
(CdO); 1H NMR (400 MHz; CDCl3) δ 7.41-7.30 (7H, m), 7.11-
7.07 (2H, m), 5.39 (1H, d, J ) 12.2), 5.35 (1H, d, J ) 12.2),
5.30 (1H, d, J ) 9.2), 4.72 (1H, dd, J ) 5.8, 9.2), 4.21 (2H, s),
2.17-2.09 (1H, m), 1.44 (9H, s), 0.88 (3H, d, J ) 6.7), 0.87
(3H, d, J ) 6.7); 13C NMR (100 MHz; CDCl3) δ 163.1, 161.7,
156.6, 155.4, 138.1, 135.4, 131.6 (CH), 130.3 (CH), 130.2 (CH),
128.7 (CH), 128.6 (CH), 128.5 (CH), 127.7, 127.2 (CH), 122.7,
80.0, 67.0 (CH2), 54.1 (CH), 32.9 (CH), 31.7 (CH2), 28.3 (Me),
18.7 (Me), 17.9 (Me); MS (CI) 545/543 (MH+, 72), 489/487 (100),
445/443 (22), 91 (39) (found MH+, 543.1479, C27H3279BrN2O5
requires 543.1495).
(S)-Benzyl 5-{3-[3-(2-Benzyloxycarbonylaminoethyl)-
1H-indol-4-yl]-benzyl}-2-(1-tert-butoxycarbonylamino-2-
methylpropyl)oxazole-4-carboxylate 42. To a solution of
bromotryptamine 40 (1.0 g, 2.7 mmol) (see the Supporting
Information) in dioxane (10 mL) were added triethylamine (1.1
mL, 8.0 mmol), palladium acetate (36 mg, 0.16 mmol), and
2-(dicyclohexylphosphino)biphenyl (94 mg, 0.27 mmol). The
mixture was degassed for 10 min, and then 4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (1.6 mL, 11 mmol) was added
cautiously to the mixture, which was then heated to 70 °C for
45 min. The mixture was allowed to cool, carefully quenched
with ammonium chloride solution (10 mL), and extracted with
ethyl acetate (3 × 10 mL). The combined organic extractions
were dried (MgSO4), filtered, concentrated in vacuo, and
purified by column chromatography to yield impure pinaco-
latoboronic tryptamine (ca. 55%; contaminated with the de-
bromo compound). The impure boronate (310 mg, 0.7 mmol),
oxazole 41 (200 mg, 0.4 mmol), and potassium carbonate (510
mg, 3.6 mmol) were dissolved in DME (20 mL) and degassed
for 10 min. PdCl2(dppf)‚CH2Cl2 (54 mg, 75 µmol) was added
to the mixture, which was then heated to 85 °C for 3 h. The
mixture was allowed to cool, diluted with ether (30 mL), and
washed with brine. The aqueous wash was extracted with
ether (30 mL), the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo, and the residue
was purified by column chromatography to yield the title
compound as a colorless oil (105 mg, 0.14 mmol, 38%): [R]33
-5.6 (c 0.18, CHCl3); IR (CHCl3/cm-1) 3479 (N-H), 3442 (N-
H), 1714 (CdO); 1H NMR (400 MHz; CDCl3) δ 8.49 (1H, s),
7.38-7.34 (4H m), 7.32-7.24 (9H, m), 7.21-7.16 (3H, m), 7.00
(1H, s), 6.90 (1H, d, J ) 6.6), 5.46 (1H, d, J ) 8.8), 5.33 (2H,
s), 5.02 (2H, s), 4.72 (1H, dd, J ) 6.1, 8.8), 4.51 (1H, m), 4.35
(2H, s), 2.85 (2H, m), 2.45 (2H, t, J ) 6.4), 2.12-2.09 (1H, m),
(S)-Benzyl 5-(3-Bromobenzyl)-[1-(tert-butoxycarbonyl-
amino)-2-methylpropyl]oxazole-4-carboxylate 41. (a) A
solution of ketoester 13 (500 mg, 1.8 mmol), benzyl alcohol
(379 mg, 3.6 mmol), and DMAP (100 mg, 0.8 mmol) in toluene
was heated under reflux for 48 h. The reaction was quenched
with aqueous ammonium chloride (15 mL) and extracted with
ethyl acetate (3 × 15 mL). The combined organic layers were
dried (MgSO4), filtered, and reduced in vacuo, and the residue
was purified by flash chromatography to yield benzyl 4-(3-
bromophenyl)-3-oxobutanoate as an oily yellow solid (410 mg,
1
1.2 mmol, 67%): IR (KBr/cm-1) 1742 (CdO), 1716 (CdO); H
NMR (300 MHz; CDCl3) δ 7.41-7.32 (7H, m), 7.18 (1H, t, J )
7.7), 7.09-7.07 (1H, m), 5.16 (2H, s), 3.78 (2H, s), 3.51 (2H, s);
13C NMR (75 MHz; CDCl3) δ 199.8, 167.2, 135.7, 135.5, 133.0
(CH), 130.9 (CH), 130.7 (CH), 129.1 (CH), 129.0 (CH), 128.9
(CH), 128.7 (CH), 123.2, 67.7 (CH2), 49.6 (CH2), 48.9 (CH2);
MS (EI) 348/346 (M+, 3), 91 (100) (found M+, 346.0216,
C17H1579BrO3 requires 346.0205). Anal. Calcd for C17H15BrO3:
C, 58.8; H, 4.4. Found: C, 58.5; H, 4.1.
(b) According to general procedure B, the above benzyl
ketoester (770 mg, 2.2 mmol) was subjected to diazo transfer
to yield benzyl 4-(3-bromophenyl)-2-diazo-3-oxobutanoate as
a red oily solid (650 mg, 1.7 mmol, 78%): IR (KBr/cm-1) 2154
(CdN2), 1717 (CdO), 1698 (CdO); 1H NMR (300 MHz; CDCl3)
δ 7.43-7.33 (7H, m), 7.22-7.14 (2H, m), 5.28 (2H, s), 4.15 (2H,
s); 13C NMR (75 MHz; CDCl3) δ 189.8, 161.4, 136.5, 135.4,
131.1 (CH), 130.7 (CH), 130.4 (CH), 129.2 (CH), 129.0 (CH),
J. Org. Chem, Vol. 70, No. 18, 2005 7315

Davies et al.
1.40 (9H, s), 0.85 (3H, d, J ) 6.6), 0.83 (3H, d, J ) 6.6); 13C
NMR (100 MHz; CDCl3) δ 163.0, 161.9, 157.6, 156.2, 155.5,
142.3, 137.1, 136.7, 135.4, 135.3, 135.0, 129.8 (CH), 128.64
(CH), 128.57 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.13
(CH), 128.10 (CH) 128.0 (CH), 127.4, 127.2 (CH), 124.3, 123.6
(CH), 121.7 (CH), 121.3 (CH), 112.9, 110.6 (CH), 79.9, 66.9,
66.5, 54.2 (CH), 41.1 (CH2), 32.8 (CH), 32.1 (CH2), 28.3 (Me),
27.4 (Me), 18.7 (Me), 17.9 (Me); MS (ES+) 757 (M+, 27), 658
(48), 657 (100) (found MH+, 757.3590, C45H49N4O7 requires
757.3596).
atropisomers, as a yellow crystalline solid (75 mg, 0.14 mmol,
95%, 84% over two steps): mp 150 °C dec; IR (CHCl3/cm-1
)
1
3459 (N-H), 3281 (N-H), 1713 (CdO), 1661 (CdO); H NMR
(400 MHz; 60 °C; CDCl3) δ 9.71 (1H, s), 7.45-7.43 (1H, m),
7.36-7.26 (3H, m), 7.21-7.19 (2H, m), 7.12-7.10 (1H, m), 6.80
(1H, br m), 5.21 (1H, br m), 4.76 (1H, br m), 4.14 (4H, br m),
2.20-2.16 (1H, m), 1.48 (9H, s), 0.99 (3H, d, J ) 7.1), 0.97
(3H, d, J ) 7.1); 13C NMR (100 MHz; 25 °C; CDCl3) δ 191.9,
167.3, 161.8, 155.7, 143.0, 137.5, 136.5, 135.9, 130.75 (CH),
130.68, 130.4 (CH), 130.0, 128.6 (CH), 126.6, 125.8 (CH), 124.6
(CH), 123.8 (CH), 122.0 (CH), 119.4, 110.9 (CH), 80.1, 54.3
(CH), 47.8 (CH2), 32.7 (CH), 31.4 (CH2), 28.4 (Me), 18.8 (Me),
18.2 (Me); MS (ES+) 551 (M + Na, 100), 529 (MH+, 15), 495
(40), 473 (60), 445 (10), 412 (found MH+, 529.2445, C30H33N4O5
requires 529.2457).
Macrocycle 43. A solution of the biaryl 42 (130 mg, 0.17
mmol) in methanol was evacuated and purged with nitrogen
five times. Palladium hydroxide on carbon (20 w/w; 12 mg, 17
µmol) was added to the solution, and the reaction vessel was
then evacuated and purged with nitrogen five times and then
evacuated and purged with hydrogen five times and left under
an atmosphere of hydrogen for 1 h. The mixture was filtered
through Celite and concentrated in vacuo. The residue was
dissolved in DMF (170 mL) and cooled to 0 °C, diisopropyl-
ethylamine (300 µl, 1.7 mmol) followed by DPPA (76 µl, 0.35
mmol) were added, and the solution was stirred at 0 °C for 3
days. The reaction was quenched with citric acid (1 M; 50 mL)
at 0 °C and concentrated in vacuo, partitioned between ethyl
acetate (150 mL) and citric acid (1 M; 75 mL), and separated
and the aqueous layer extracted further with ethyl acetate (3
× 100 mL). The combined organic extractions were washed
with water (50 mL), sodium hydrogen carbonate (2 × 50 mL),
and brine (50 mL), dried (MgSO4), filtered, and concentrated
in vacuo. The residue was purified by column chromatography
to yield the title compound as a colorless oil (69 mg, 0.13 mmol,
77%) as a mixture of atropisomers: IR (CHCl3/cm-1) 3477 (N-
H), 3443 (N-H), 3332 (N-H), 1713 (CdO), 1660 (CdO); 1H
NMR (300 MHz; 25 °C; CDCl3) δ 8.69 (1H, s), 7.43-7.30 (3H,
m), 7.26-7.25 (1H, m), 7.12 (1H, t, J ) 7.2), 7.07 (1H, s), 6.81-
6.79 (2H, m), 6.18 (1H, m), 5.23 (0.5H, d, J ) 9.2), 5.08 (0.5H,
d, J ) 9.2), 4.72 (0.5H, m), 4.65 (0.5H, m), 4.25 (2H, s), 3.98
(1H, m), 2.88 (1H, m), 2.46-2.32 (2H, m), 2.13-2.02 (1H, m),
1.40 (9H, s), 0.93-0.84 (6H, m); 13C NMR (100 MHz; 60 °C;
CDCl3) δ 162.6, 155.1, 153.4, 142.2, 136.3, 136.1, 135.5, 132.7,
128.4 (CH), 128.2 (CH), 128.1 (CH), 127.0 (CH), 126.0, 123.2
(CH), 121.12 (CH), 121.07 (CH), 115.7, 115.6, 110.4 (CH), 80.0,
54.6 (CH), 43.7 (CH2), 32.7 (CH), 31.9 (CH2), 28.2 (Me), 23.9
(CH2), 18.6 (Me), 17.9 (Me); MS (CI) 515 (MH+, 8), 416 (30),
415 (100), 398 (39) (found MH+, 515.2671, C30H35N4O4 requires
515.2658).
Ketoamide Macrocycle 44. To a solution of DDQ (85 mg,
0.38 mmol) in THF/H2O (9/1, 3.5 mL) was added a solution of
macrocycle 43 (88 mg, 0.17 mmol) in THF/H2O (9/1, 3.5 mL)
dropwise, and the resulting mixture was stirred at ambient
temperature for 1 h. The mixture was diluted with ethyl
acetate (20 mL) and extracted with sodium hydrogen carbonate
(4 × 20 mL), dried (MgSO4), filtered, reduced in vacuo, and
purified by column chromatography to yield the hydroxy
intermediate as a pale red solid (80 mg, 0.15 mmol, 88%). The
resulting solid was dissolved in DMSO (1.0 mL), added to a
solution of IBX (80 mg, 0.15 mmol) in DMSO (1.0 mL), and
stirred at ambient temperature overnight. The mixture was
quenched with water (15 mL) and extracted with dichlo-
romethane (3 × 10 mL), and the combined extracts were dried
(MgSO4), filtered, reduced in vacuo, and purified by column
chromatography to yield the title compound, as a mixture of
Indole Bis-oxazole Macrocycle 45. To a solution of
triphenylphosphine (30 mg, 113 µmol) and hexachloroethane
(27 mg, 113 µmol) in dichloromethane (1 mL) was added
triethylamine (32 µl) followed by a solution of ketoamide
macrocycle 44 (30 mg, 57 µmol) in dichloromethane (1 mL).
The resulting mixture was stirred overnight and then reduced
in vacuo and the residue purified by column chromatography
to yield the title compound, as a mixture of atropisomers, as
a pale brown solid (14 mg, 27 µmol, 48%): mp 140 °C dec; IR
1
(CHCl3/cm-1) 3470 (N-H), 3442 (N-H), 1711 (CdO); H NMR
(400 MHz; CDCl3) δ 9.16 (1H, s), 9.01 (1H, s), 7.86 (2H, d, J )
6.6), 7.47 (2H, t, J ) 7.4), 7.37-7.26 (6H, m), 7.17-7.00 (6H,
m), 6.80 (1H, s), 6.77 (1H, s), 5.44 (1H, d, J ) 9.3), 5.40 (1H,
d, J ) 9.2), 4.85 (1H, dd, J ) 8.9, 5.7), 4.78 (1H, dd, J ) 8.6,
6.1), 4.35 (1H, d, J ) 16.4), 4.20 (1H, d, J ) 16.4), 4.09 (1H, d,
J ) 16.2), 3.81 (1H, d, J ) 16.2), 2.25-2.20 (2H, m), 1.46 (18H,
s), 1.00-0.95 (12H, m); 13C NMR (100 MHz; CDCl3) δ 162.4 +
162.2 (atrop), 155.9, 154.5, 152.3, 146.6 + 146.5 (atrop), 139.7
+ 139.6 (atrop), 135.9 + 135.8 (atrop), 135.4, 135.3, 132.3,
132.1, 128.0 (CH), 127.7 (CH), 127.5 (CH), 127.4 (CH), 126.63
+ 126.58 (CH, atrop), 125.7 + 125.5 (CH, atrop), 122.7 + 122.6
(CH, atrop), 121.3 (CH), 111.3 + 111.1 (CH, atrop), 104.0, 80.1
+ 79.9 (atrop), 54.4 + 54.0 (CH, atrop), 33.4 + 32.9 (CH, atrop),
33.1 (CH2), 28.3 (Me), 18.9 + 18.7 (Me, atrop), 18.2 + 17.9 (Me,
atrop); MS (ES+) 511 (MH+, 48), 478 (15), 477 (42), 455 (100),
433 (13) (found MH+, 511.2347, C30H31N4O4 requires 511.2340).
Acknowledgment. We thank the EPSRC and Tri-
pos Receptor Research for funding, the EPSRC Mass
Spectrometry Center at Swansea for mass spectra, and
the EPSRC Chemical Database Service at Daresbury.64
Supporting Information Available: Copies of 1H and 13
C
NMR spectra of compounds N-methoxy-N-methyl-3-bromophen-
ylacetamide, 10-17, 19, 20, 28, 31, 35-45, trans-4-bromo-3-
(2-nitroethenyl)-1H-indole, benzyl 4-(3-bromophenyl)-3-oxobu-
tanoate, benzyl 4-(3-bromophenyl)-2-diazo-3-oxobutanoate, and
(S)-N1-[1-benzyloxycarbonyl-3-(2-bromophenyl)-2-oxopropyl]-
N2-tert-butoxycarbonylvalinamide; experimental details for
compounds 10, 12-14, 19, and 40. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0509760
(64) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. J. Chem. Inf.
Comput. Sci. 1996, 36, 746-749.
7316 J. Org. Chem., Vol. 70, No. 18, 2005