Control of competing N-H insertion and Wolff rearrangement in dirhodium(II)-catalyzed reactions of 3-indolyl diazoketoesters. Synthesis of a potential precursor to the marine 5-(3-indolyl)oxazole martefragin A

Article abstract of DOI:10.1021/jo050303h

Dirhodium(II)-catalyzed reaction of 3-indolyl α-diazo-β- ketoester 25 in the presence of hexanamide results in competing metal carbene N-H insertion and Wolff rearrangement. The corresponding phenyl diazoketoester 32, on the other hand, gives only the product of N-H insertion, suggesting that the indole moiety is more prone to 1,2-rearrangement. The competing processes were investigated in a range of 3-indolyl α-diazo-β-ketoesters (36, 38, 40, 44); these studies established that the Wolff rearrangement could be effectively suppressed by the presence of a strong electron-withdrawing group on the indole nitrogen. Dirhodium(II) catalysts were also more effective than copper or Lewis acid catalysts in favoring the insertion process. The products of N-H insertion, the ketoamides (26, 47, 49, 51, 53), were readily cyclodehydrated to the corresponding 5-(3-indolyl)-oxazoles. The N-H insertion/cyclodehydration methodology was used in a formal synthesis of the marine natural product martefragin A. Thus the N-Boc homoisoleucine amide 23, prepared by asymmetric hydrogenation of a dehydro amino acid, underwent N-H insertion with the rhodium carbene derived from the N-nosyl indolyl diazoester 40, followed by cyclodehydration and deprotection to give the 5-(3-indolyl)oxazole martefragin A precursor 75.

Full text of DOI:10.1021/jo050303h

Control of Competing N-H Insertion and Wolff Rearrangement in
Dirhodium(II)-Catalyzed Reactions of 3-Indolyl Diazoketoesters.
Synthesis of a Potential Precursor to the Marine
5-(3-Indolyl)oxazole Martefragin A
James R. Davies,† Peter D. Kane,‡ Christopher J. Moody,*,† and Alexandra M. Z. Slawin§
Department of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, United Kingdom, Tripos
Receptor Research Ltd, Bude-Stratton Business Park, Bude, Cornwall, EX23 8LY, United Kingdom, and
School of Chemistry, University of St. Andrews, Fife, Scotland, KY16 9ST, United Kingdom
c.j.moody@ex.ac.uk
Received February 17, 2005
Dirhodium(II)-catalyzed reaction of 3-indolyl R-diazo-â-ketoester 25 in the presence of hexanamide
results in competing metal carbene N-H insertion and Wolff rearrangement. The corresponding
phenyl diazoketoester 32, on the other hand, gives only the product of N-H insertion, suggesting
that the indole moiety is more prone to 1,2-rearrangement. The competing processes were
investigated in a range of 3-indolyl R-diazo-â-ketoesters (36, 38, 40, 44); these studies established
that the Wolff rearrangement could be effectively suppressed by the presence of a strong electron-
withdrawing group on the indole nitrogen. Dirhodium(II) catalysts were also more effective than
copper or Lewis acid catalysts in favoring the insertion process. The products of N-H insertion,
the ketoamides (26, 47, 49, 51, 53), were readily cyclodehydrated to the corresponding 5-(3-indolyl)-
oxazoles. The N-H insertion/cyclodehydration methodology was used in a formal synthesis of the
marine natural product martefragin A. Thus the N-Boc homoisoleucine amide 23, prepared by
asymmetric hydrogenation of a dehydro amino acid, underwent N-H insertion with the rhodium
carbene derived from the N-nosyl indolyl diazoester 40, followed by cyclodehydration and
deprotection to give the 5-(3-indolyl)oxazole martefragin A precursor 75.
Introduction
5,3,6 through martefragin A 6,7,8 to the complex marine
natural product diazonamide A 7 (Figure 1).9
The synthetic challenges posed by diazonamide A have
stimulated much interest in indolyloxazoles, although
there remain relatively few methods to access this ring
The 5-(3-indolyl)oxazole ring system occurs in a small
number of natural products. These range from the simple
pimprinine alkaloids, pimprinine 1 itself,1,2 pimprineth-
ine 2,3,4 WS-30581A and B 3 and 4,5 and pimprinaphine
(4) Noltenmeyer, M.; Sheldrick, G. M.; Hoppe, H.-U.; Zeeck, A. J.
Antibiot. 1982, 35, 549-555.
(5) Umehara, K.; Yoshida, K.; Okamoto, M.; Iwami, M.; Tanaka, H.;
Kohsaka, M.; Imanaka, H. J. Antiobiot. 1984, 37, 1153-1160.
(6) The APHE natural products appear to be identical with the
pimprinine alkaloids: Kelly, T. R.; Fu, Y.; Xie, R. L. Tetrahedron Lett.
1999, 40, 1857-1860.
(7) Takahashi, S.; Matsunaga, T.; Hasegawa, C.; Saito, H.; Fujita,
D.; Kiuchi, F.; Tsuda, Y. Chem. Pharm. Bull. 1998, 46, 1527-1529.
(8) Nishida, A.; Fuwa, M.; Fujikawa, Y.; Nakahata, E.; Furuno, A.;
Nakagawa, M. Tetrahedron Lett. 1998, 39, 5983-5986.
(9) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am.
Chem. Soc. 1991, 113, 2303-2304.
* To whom correspondence should be addressed. Fax: +44 1392
263434.
† University of Exeter.
‡ Tripos Receptor Research.
§ University of St Andrews.
(1) Bhate, D. S.; Hulyalker, R. K.; Menon, S. K. Experientia 1960,
16, 504.
(2) Joshi, B. S.; Taylor, W. I.; Bhate, D. S.; Karmarkar, S. S.
Tetrahedron 1963, 19, 1437.
(3) Koyama, Y.; Yokose, K.; Dolby, L. J. Agric. Biol. Chem. 1981,
45, 1285-1287.
10.1021/jo050303h CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/23/2005
5840
J. Org. Chem. 2005, 70, 5840-5851

Wolff Rearrangement in Dirhodium(II)-Catalyzed Reactions
SCHEME 1
FIGURE 1. Structures of naturally occurring 5-(3-indolyl)-
oxazoles.
system. Most routes rely on some variation of the
classical Robinson-Gabriel method whereby a 3-ami-
noacetylindole 8 is acylated and the resulting ketoamide
1,4-dicarbonyl compound 9 cyclodehydrated to the in-
dolyloxazole 10 with reagents such as POCl3/pyridine, the
Burgess reagent, or the Wipf hexachloroethane/triph-
enylphosphine protocol (Scheme 1).10-12
Alternatively, the 1,4-dicarbonyl ketoamide 9 can be
accessed by Yonemitsu DDQ-oxidation of the N-acyl-
tryptamine 11,13-16 subsequent cyclodehydration leading
to the indolyloxazole 10. Under anhydrous conditions, the
Yonemitsu oxidation of N-acyltryptamines 11 can lead
directly to the indolyloxazole 10 (Scheme 1).13,14,17,18 Other
methods employed include the Scho¨llkopf lithioisonitrile
method as exemplified by the conversion of indole-3-
carboxylate 12 to indolyloxazole 13,19 methods based on
TOSMIC,20 the HCI/BF3‚Et2O mediated reaction of al-
dehydes with indolylacyl cyanides 14 that gives dichloro
indolyloxazoles 15 directly related to diazonamide A,21
reactions proceeding via iminophosphoranes derived by
reaction of tri-n-butylphosphine with 3-azidoacetylindole
16,22 and palladium-catalyzed coupling of 3-tri-n-butyl-
stannylindoles with 5-bromooxazoles.23
Our own interest in indolyloxazoles started over a
decade ago when we developed a simple route based on
rhodium carbene chemistry. Thus dirhodium(II)-cata-
lyzed decomposition of N-Boc-diazoindole 17 in the pres-
ence of simple alkyl nitriles gave the Boc-protected
derivatives 18, subsequently deprotected to the indoly-
loxazole alkaloids pimprinine 1, pimprinethine 2, and
WS-30581A 3 (Scheme 1).24
However, attempted extension of this reaction to more
highly functionalized nitriles (derived by dehydration of
the corresponding amides), and hence to structurally
more complex oxazoles, was unsatisfactory. Therefore an
alternative was developed in which the starting amide
was reacted directly with the diazocarbonyl compound
19 under dirhodium(II) catalysis in an N-H insertion
(10) Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998, 39, 2223-2226.
(11) Wipf, P.; Methot, J.-L. Org. Lett. 2001, 3, 1261-1264.
(12) Kreisberg, J. D.; Magnus, P.; McIver, E. G. Tetrahedron Lett.
2001, 42, 627-629.
(13) Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu, O. Heterocycles
1979, 12, 1457-1462.
(14) Yoshioka, T.; Mohri, K.; Oikawa, Y.; Yonemitsu, O. J. Chem.
Res. (S) 1981, 194-195; J. Chem. Res. (M) 1981, 2252-2281.
(15) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem., Int.
Ed. 2001, 40, 4765-4770.
(16) Nicolaou, K. C.; Snyder, S. A.; Huang, X.; Simonsen, K. B.;
Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004, 126, 10162-10173.
(17) Magnus, P.; McIver, E. G. Tetrahedron Lett. 2000, 41, 831-
834.
(18) Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew. Chem.,
Int. Ed. 2003, 42, 4961-4966.
(19) Vedejs, E.; Barda, D. A. Org. Lett. 2000, 2, 1033-1035.
(20) Dhar, T. G. M.; Shen, Z.; Fleener, C. A.; Rouleau, K. A.; Barrish,
J. C.; Hollenbaugh, D. L.; Iwanowicz, E. J. Bioorg. Med. Chem. Lett.
2002, 12, 3305-3308.
(21) Radspieler, A.; Liebscher, J. Synthesis 2001, 745-750.
(22) Molina, P.; Fresneda, P. M.; Almendros, P. Synthesis 1993, 54-
56.
(23) Boto, A.; Ling, M.; Meek, G.; Pattenden, G. Tetrahedron Lett.
1998, 39, 8167-8170.
(24) Doyle, K. J.; Moody, C. J. Synthesis 1994, 1021-1022.
J. Org. Chem, Vol. 70, No. 15, 2005 5841

Davies et al.
SCHEME 2
SCHEME 3
SCHEME 4
reaction to give a ketoamide 1,4-dicarbonyl compound 20
that subsequently underwent a Robinson-Gabriel cyclo-
dehydration to the oxazole 21.25 Although this is a very
general route to 2,5-di- or 2,4,5-trisubstituted oxazoles
21 (Scheme 2),26 our preliminary studies on its applica-
tion to more complex oxazoles, such as the indolyl-
bisoxazole fragment of diazonamide A,27 did not, for
reasons that will become apparent later, prove entirely
satisfactory. Therefore, before continuing with this ap-
proach to diazonamide A, we undertook the less daunting
challenge posed by martefragin A 6.
SCHEME 5
Results and Discussion
Martefragin A 6 was isolated from the Japanese alga
Martensia fragilis Harvey and shown to be a potent
inhibitor of lipid peroxidation.7 The structure and ster-
eochemistry were subsequently confirmed by synthesis
by Nishida et al., the indolyloxazole being formed by
Yonemitsu DDQ oxidation (cf. 11 to 10).8 Subsequently,
Nishida et al. have reported the synthesis of a range of
analogues of martefragin, again using DDQ oxidation to
establish the indolyloxazole system.28 To apply our dia-
zocarbonyl methodology, we required a 3-indolyl-R-diazo-
â-ketoester 22 and the amide 23 (Scheme 3). However,
before using the precious 2-amino-4-methylhexanoic
amide derivative 23, the N-protected amide derivative
of homoisoleucine, we undertook a model study using the
readily available hexanoic amide.
Model Study and Advent of Competing Wolff
Rearrangement. The required 3-indolyl-R-diazo-â-ke-
toester 25 was prepared from N-Boc-indole-3-carboxal-
dehyde 24 with use of our diethylzinc mediated addition
of ethyl diazoacetate protocol,29 followed by IBX oxidation
of the intermediate R-diazo-â-hydroxyester. The diazo-
carbonyl compound 25 was then added over 16 h to a
mixture of hexanamide and dirhodium tetraoctanoate in
boiling dichloromethane. Much to our surprise, the
reaction gave two major products, of which the desired
carbene N-H insertion product 26 was formed in only
39% yield. This is in direct contrast to earlier work with
related diazoketoesters (19, R4 ) CO2Et; R5 ) alkyl or
aryl) where the N-H insertion product was essentially
the only observed product of reaction.26 The structure of
the ketoamide N-H insertion product 26 was confirmed
by its subsequent cyclodehydration to the oxazole (see
below) and also by X-ray crystallography (see the Sup-
porting Information).
The second product formed from the diazocarbonyl
compound 25 was spectroscopically very similar to the
ketoamide 26 with one main exception, the absence of
coupling between the NH and CH. When the reaction was
repeated with 4-bromobenzamide in place of hexanamide,
only the analogous “unknown” product was formed, X-ray
crystallography (see the Supporting Information) estab-
lishing its structure as imide 28 (Scheme 5), the product
of Wolff rearrangement followed by interception of the
ketene by the amide. These experiments, therefore,
established the structure of the second hexanamide
derived product as the imide 27 (Scheme 4).
Although the origin of imide 27 by Wolff rearrange-
ment is clear, it remained a puzzle since similar products
had not been observed in related reactions.26 Indeed, the
use of dirhodium(II) catalysts for the decomposition of
diazoketones rarely results in Wolff rearrangement.
However, this is clearly not the case, and there are
examples of competing or predominating Wolff rear-
rangement in dirhodium(II)-catalyzed reactions of diaz-
oketones.30,31 Of particular relevance is the observation
by Marsden and co-workers that the triethylsilyl ana-
logue 29 of our indolyl diazoketoester gave only Wolff
(25) Bagley, M. C.; Buck, R. T.; Hind, S. L.; Moody, C. J. J. Chem.
Soc., Perkin Trans. 1 1998, 591-600.
(26) Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60,
3967-3977.
(27) Bagley, M. C.; Hind, S. L.; Moody, C. J. Tetrahedron Lett. 2000,
41, 6897-6900.
(30) Dayoub, W.; Diab, Y.; Doutheau, A. Tetrahedron Lett. 2001, 42,
(28) Nishida, A.; Fuwa, M.; Naruto, S.; Sugano, Y.; Saito, H.;
Nakagawa, M. Tetrahedron Lett. 2000, 41, 4791-4794.
(29) Moody, C. J.; Morfitt, C. N. Synthesis 1998, 1039-1042.
8455-8457.
(31) Ronan, B.; Bacque´, E.; Barrie`re, J.-C. Tetrahedron 2004, 60,
3819-3824.
5842 J. Org. Chem., Vol. 70, No. 15, 2005

Wolff Rearrangement in Dirhodium(II)-Catalyzed Reactions
SCHEME 6
SCHEME 8
SCHEME 7
TABLE 1. Competing N-H Insertion and Wolff
Rearrangement in the Dirhodium
Tetraoctanoate-Catalyzed Reactions of 3-Indolyl and
3-Benzothienyl Diazoketoesters
rearrangement product 30 upon dirhodium(II) tetraoc-
tanoate- catalyzed decomposition.32 In contrast, Konopel-
ski observed only oxazole 31 formation on Lewis acid-
catalyzed reaction of an indolyl diazoketoester with
acetonitrile (Scheme 6).33
N-H
Wolff Rearrangement vs Insertion: Effect of
Indole Structure. Our rationale was that the preva-
lence for Wolff rearrangement of the indolyl diazoketone
25 was due to the electronic properties of the indole
heterocycle. This view was reinforced when the analogous
phenyldiazoketone 3226 when treated with dirhodium-
(II) tetraoctanoate in the presence of hexanamide under-
went clean N-H insertion (88%) to give ketoamide 33,
cyclodehydration of which gave the expected oxazole 34
in good yield (Scheme 7).
Therefore we investigated a range of other indolyl
diazoketones in which the electronic properties of the
indole ring were modified by the presence of a chlorine
at the 2-position, or attenuated by different substituents
on nitrogen [methyl, Boc, benzenesulfonyl (Bs), 2-ni-
trobenzenesulfonyl (Ns)]. Indolyl diazoketoesters (36, 38,
40) were readily prepared from the corresponding indole-
3-carboxaldehydes (35, 37, 39) by using the same two step
procedure as for diazo compound 25. The benzothiophene
derivative 42 was also prepared from benzothiophene-
3-carboxaldehyde 41 for comparison. The N-methylindole
diazoketone 44 was prepared from 3-acetyl-1-methylin-
dole 43 by acylation of the enolate with ethyl cyanofor-
mate followed by diazo transfer reaction, using 4-aceta-
diazo
X
Y
insertion
yield/%
Wolff
yield/%
25
36
38
40
44
42
NBoc
NBoc
NBs
NNs
NMe
S
H
Cl
H
H
H
H
26
47
49
51
39
47
52
52
0
27
48
50
55
38
23
0
81
30
52
54
53
38
midobenzenesulfonyl azide.34 Finally, the 2-indolyl diazo-
ketoester 46 was prepared from the aldehyde 45 in the
same way as the analogous 3-indolyl isomer 25 (Scheme
8).
The six new diazoketones were all reacted with hex-
anamide under similar conditions in the presence of
dirhodium(II) tetraoctanoate and the results are shown
in Table 1. The most significant result to emerge is that
the Wolff rearrangement is suppressed by more electron-
withdrawing substituents on the indole nitrogen. Thus
the N-methyl derivative 44 leads to only Wolff rear-
rangement whereas the N-(2-nitrobenzenesulfonyl) de-
rivative 40 gives only N-H insertion, with the N-Boc and
N-Bs compounds being intermediate in reactivity. The
effect of the chlorine substituent is less marked, although
less Wolff rearrangement is observed than with its
unchlorinated analogue. The benzothiophene diazoke-
toester 42 behaves similarly to the N-Boc-2-chloroindole
(32) Marsden, S. P.; Pang, W.-K. J. Chem. Soc., Chem. Commun.
1999, 1199-1200.
(33) Konopelski, J. P.; Hottenroth, J. M.; Oltra, H. M.; Ve´liz, E. A.;
Yang, Z.-C. Synlett 1996, 609-611.
(34) Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709-1716.
J. Org. Chem, Vol. 70, No. 15, 2005 5843

Davies et al.
TABLE 3. Cyclodehydration of Ketoamides to
5-(3-Indolyl)oxazoles and a 5-(3-Benzothienyl)oxazole
SCHEME 9
TABLE 2. Competing O-H Insertion and Wolff
Rearrangement in Catalyzed Reactions of 3-Indolyl
Diazoketoester 25: Ratio of Insertion Product 56 to Wolff
Rearrangement 57
ketoamide
X
Y
oxazole
yield/%
26
47
49
51
53
NBoc
NBoc
NBs
NNs
S
H
Cl
H
H
H
58
59
60
61
62
78
80
65
85
75
SCHEME 10
O-H
insertiona
56
Wolff
rearrangementa
57
entry
catalyst
1
2
3
4
5
6
7
8
9
Rh2(OAc)4
1
2
1
4
2
Rh2Oct4
1
Rh2(OCOCF3)4
Rh2(NHCOC3F7)4
Cu(acac)2
RuCl2(Ph3P)3
FeCl3
Sc(OTf)3
BF3‚Et2O
3
1
are effective catalysts for diazo decomposition and sub-
sequent N-H insertion reactions, they proved ineffective
in the present case. Likewise iron(III) chloride and boron
trifluoride etherate also proved ineffective.
traceb
1b
6
traceb
traceb
traceb
Cyclodehydration of Ketoamides: Synthesis of
5-(3-Indolyl)oxazoles. Although the dirhodium(II)-
catalyzed reactions of diazoketoesters led to mixtures of
ketoamides (from N-H insertion) and imides (from Wolff
rearrangement), the ketoamides were isolated in suf-
ficient quantity to allow subsequent Robinson-Gabriel
cyclodehydration. Thus the ketoamides 26, 47, 49, 51,
and 53 were readily cyclodehydrated to the corresponding
oxazoles 58-62, using the Wipf Ph3P/I2/Et3N method
(Table 3).39 The structure of the 5-(3-indolyl)oxazole 58
was confirmed by X-ray crystallography (see the Sup-
porting Information), and the nosyl protecting group was
readily removed from indolyloxazole 61 to give 63 in high
yield (Scheme 10) with use of the standard Fukuyama
protocol.40
Formal Synthesis of Normartefragin A and Mar-
tefragin A. To adapt our indolyl diazocarbonyl method-
ology to the synthesis of martefragin A, the amide
derivative 23 of (S,S)-homoisoleucine was required
(Scheme 3). In their synthesis, Nishida et al. prepared
(S,S)-N-Boc-homoisoleucine in a linear nine-step se-
quence starting from (R)-citronellol and introducing the
second stereogenic center by azidation of an Evans’
oxazolidinone.8 We elected to use a shorter sequence
starting from commercially available (S)-2-methylbu-
tanol, oxidation of which with TEMPO/NaClO2 gave the
corresponding aldehyde 64,41 a compound reported to
participateinWittigolefinationreactionswithoutracemiza-
tion.41-43 The Horner-Wadsworth-Emmons reaction of
aldehyde 64 with trimethyl 2-(tert-butoxycarbonylamino)-
phosphonoacetate, itself prepared in an N-H insertion
a Ratio as determined by 1H NMR. b Diazoketoester is recovered
largely unchanged.
36. The results are consistent with more electron-rich
groups migrating more easily to the electron-deficient
carbene (or rhodium carbene) center.
In the case of 2-indolyl diazoketoester 46, an entirely
different result was observed upon dirhodium(II)-cata-
lyzed reaction in the presence of hexanamide. Neither
N-H insertion nor Wolff rearrangement occurred; in-
stead intramolecular capture of the rhodium carbene by
the Boc-group carbonyl oxygen supervened to give, after
loss of isobutene, the oxazinoindole 55 in 56% yield
(Scheme 9).
Wolff Rearrangement vs Insertion: Effect of
Catalyst. To study the effect of catalyst, the indolyl
diazoketoester 25 was decomposed in dichloromethane
in the presence of methanol (ca. 10 equiv). Methanol was
chosen as the reactant to facilitate analysis of the
reaction mixture by 1H NMR spectroscopy since the O-H
insertion product 56 is readily distinguishable from the
product 57 of Wolff rearrangement/ketene trapping. The
results are shown in Table 2. Although the catalysts were
studied under identical conditions, only the dirhodium-
(II) catalysts were effective in causing rapid reaction of
the diazoketoester 25. As expected on the basis of our
previous work,35 the fluorinated amide ligand proved the
most effective for carbene insertion. Although others have
reported that Cu(acac)2,36 Sc(OTf)3,37 and RuCl2(Ph3P)3
38
(35) Cox, G. G.; Kulagowski, J. J.; Moody, C. J.; Sie, E.-R. H. B.
Synlett 1992, 975-976.
(38) Sengupta, S.; Das, D.; Sen Sarma, D. Tetrahedron Lett. 1996,
37, 8815-8818.
(39) Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604-3606.
(40) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353-359.
(41) Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.;
Masuma, R.; Kuwajima, I.; Omura, S. Org. Lett. 2001, 3, 2289-2291.
(36) Wang, J.; Hou, Y.; Wu, P. J. Chem. Soc., Perkin Trans. 1 1999,
2277-2280.
(37) Pansare, S. V.; Jain, R. P.; Bhattacharyya, A. Tetrahedron Lett.
1999, 40, 5255-5258.
5844 J. Org. Chem., Vol. 70, No. 15, 2005

Wolff Rearrangement in Dirhodium(II)-Catalyzed Reactions
SCHEME 11
SCHEME 12
reaction by dirhodium(II)-catalyzed reaction of trimethyl
diazophosphonoacetate with tert-butyl carbamate,44 using
DBU as base at room temperature, gave the desired
dehydro amino acid 65. NOE studies established the
geometry of the dehydro amino acid as (Z), as expected
from the use of the Schmidt method,45 but unfortunately,
HPLC analysis on a chiral stationary phase suggested
that some epimerization had occurred during the olefi-
nation step (65, ca. 75% ee). The amount of epimerization
could be reduced significantly by running the reaction
at 0 °C, although the yield was reduced from 78% to 42%.
However, use of tetramethylguanidine (TMG) as base
resulted in both high yield (88%) and improved ee (ca.
95%), although the material could never be obtained as
a pure single enantioner. Asymmetric hydrogenation of
the dehydro amino acid 65 in methanol with Burk’s (S,S)-
EtDuPHOS system, [(+)-1,2-bis((2S,5S)-2,5-diethylphos-
pholano)benzene(1,5-cyclooctadiene)rhodium(I) trifluo-
romethanesulfonate],46,47 gave the protected (S,S)-
homoisoleucine 66 in high yield. The Et-DuPHOS catalyst
system is extremely effective for the asymmetric hydro-
genation of dehydro amino acids and generally proceeds
with excellent stereocontrol. Hence the fact that small
amounts of another diastereomer of 66 were observed in
the 13C NMR spectrum were attributed to the fact that
the starting alkene 65 was not enantiomerically pure;
unfortunately, the presence of small amounts of a dias-
tereomer persisted to the end of the synthesis. Finally,
the homoisoleucine ester 66 was converted into the
required amide 23 by standard methodology (Scheme 11).
ran through the sequence of reactions using the readily
available isoleucine derived amide 67. The dirhodium-
(II)-catalyzed reaction of 40 with 67 did indeed give the
required N-H insertion product 68, although the yield
was poor (ca. 33%) and it could not be separated from
the Wolff rearrangement product 69 (ca. 11%). Neverthe-
less, when the mixture was subjected to standard cyclo-
dehydration conditions, the indolyloxazole 70 was readily
obtained in pure form (33% over two steps) and depro-
tected to give the normartefragin A precursor 71 (Scheme
12). Fortunately, when the homoisoleucine amide 23 was
used in the dirhodium(II)-catalyzed reaction of diazoke-
toester 40, not only was the overall yield better (ca. 60%),
but the ratio of N-H insertion 72 to Wolff rearrangement
73 was also much improved (ca. 16:1), with the Wolff
rearrangement effectively completely suppressed. Again,
the two products 72/73 could not be separated, so the
mixture was cyclodehydrated. This resulted in the forma-
tion of the desired indolyl oxazole 74 (51% over the two
steps), deprotection of which gave indolyl oxazole 75, a
potential precursor to martefragin A 6 (Scheme 12), since
Nishida et al. have shown that the NHBoc substituent
can be converted into the dimethylamino substituent of
the natural product.8
On the basis of the earlier studies on the competing
N-H insertion and Wolff rearrangement processes, we
elected to use the N-(2-nitrobenzenesulfonyl) (nosyl)
indole derivative 40 as the diazoketoester component
together with a dirhodium(II) catalyst. However, before
committing our precious homoisoleucine amide 23, we
(42) Ley, S. V.; Armstrong, A.; Diez-Martin, D.; Ford, M. J.; Grice,
P.; Knight, J. G.; Kolb, H. C.; Madin, A.; Marby, C. A.; Mukherjee, S.;
Shaw, A. N.; Slawin, A. M. Z.; Vile, S.; White, A. D.; Williams, D. J.;
Woods, M. J. Chem. Soc., Perkin Trans. 1 1991, 667-692.
(43) El Hadrami, M.; Lavergne, J.-P.; Viallefont, P.; Itto, M. Y. A.;
Hasnaoui, A. Tetrahedron Lett. 1991, 32, 3985-3988.
(44) Ferris, L.; Haigh, D.; Moody, C. J. J. Chem. Soc., Perkin Trans.
1 1996, 2885-2888.
(45) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487-490.
(46) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J.
Am. Chem. Soc. 1993, 115, 10125-10138.
(47) Burk, M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee,
J. R.; Martinez, J. P. Pure Appl. Chem. 1996, 68, 37-44.
Conclusions
The above work has shown that our previously re-
ported efficient synthesis of 5-R-oxazoles from amides,
RCONH2, by rhodium carbene N-H insertion does not
necessarily extend to 3-indolyl diazoketoesters owing to
J. Org. Chem, Vol. 70, No. 15, 2005 5845

Davies et al.
carbonyl-2-chloroindole-3-carboxaldehyde 3549 (1.2 g, 4.3 mmol)
as a yellow crystalline solid (1.4 g, 3.6 mmol, 84%), mp 120 °C
dec; IR (KBr/cm-1) 2141 (CdN2), 1752 (CdO; 1H NMR (300
MHz; CDCl3) δ 7.98 (1H, d, J ) 7.7), 7.53 (1H, dd, J ) 1.3,
7.0), 7.27-7.19 (2H, m), 4.16 (2H, q, J ) 7.1), 1.63 (9H, s),
1.13 (3H, t, J ) 7.1); 13C NMR (75 MHz; CDCl3) δ 179.1, 159.8,
147.5, 134.0, 125.2, 125.1, 124.3 (CH), 123.1 (CH), 118.5 (CH),
117.2, 114.2 (CH), 85.2, 77.2, 60.9 (CH2), 27.2 (Me), 13.2 (Me);
m/z (FI) 391 (M+, 100%). Found: M+, 391.0939. C18H1835ClN3O5
requires: 391.0935.
the propensity of the indole moiety to migrate in Wolff
rearrangements. However, the competing Wolff rear-
rangement and the desired N-H insertion processes can
be effectively controlled by the appropriate choice of
indole N-protecting group, strong electron-withdrawing
groups favoring the carbene (rhodium carbene) insertion.
Armed with this knowledge, the diazocarbonyl methodol-
ogy has been applied in a synthesis of a potential
precursor to the marine natural product martefragin A.
Ethyl 3-(1-Benzenesulfonylindol-3-yl)-2-diazo-3-oxo-
propanoate, 38. According to the above general procedure,
the title product was isolated from 1-benzenesulfonylindole-
3-carboxaldehyde 3750 (1.2 g, 4.2 mmol) as a yellow crystalline
solid (1.2 g, 3.0 mmol, 71%), mp 131-133 °C dec; IR (KBr/
Experimental Section
General Experimental Details. 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. Fully
characterized compounds were chromatographically homoge-
1
cm-1) 2136 (CdN2), 1716 (CdO); H NMR (300 MHz; CDCl3)
δ 8.66 (1H, s), 8.19-8.16 (1H, m), 8.00-7.93 (3H, m), 7.61-
7.55 (1H, m), 7.51-7.46 (2H, m), 7.36-7.32 (2H, m), 4.35 (2H,
q, J ) 7.0), 1.35 (3H, t, J ) 7.0); 13C NMR (75 MHz; CDCl3) δ
179.3, 161.5, 138.0, 134.8 (CH), 134.6, 134.2 (CH), 129.9 (CH),
129.1, 127.6 (CH), 126.0 (CH), 125.2 (CH), 123.0 (CH), 118.7,
113.5 (CH), 78.5, 62.1 (CH2), 14.7 (Me); m/z (CI) 398 (MH+,
100%). Found: C, 57.2; H, 3.6; N, 10.5. C19H15N3O5S re-
quires: C, 57.4; H, 3.8; N, 10.6.
Ethyl 2-Diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-
3-oxopropanoate, 40. According to the above general proce-
dure, 1-(2-nitrobenzenesulfonyl)indole-3-carboxaldehyde 39
(300 mg, 0.9 mmol) was converted to the title compound, which
was obtained as a pale yellow crystalline solid (223 mg, 0.5
mmol, 56%), mp 150-151 °C; IR (KBr/cm-1) 2146 (CdN2), 1706
(CdO); 1H NMR (300 MHz; CDCl3) δ 8.64 (1H, s), 8.24 (1H, d,
J ) 7.4), 7.97-7.94 (1H, dd, J ) 0.5, 7.4), 7.81-7.65 (4H, m),
7.38-7.35 (2H, m), 4.34 (2H, q, J ) 7.1), 1.34 (3H, t, J ) 7.1);
13C NMR (75 MHz; CDCl3) δ 179.3, 161.4, 148.4, 135.8 (CH),
134.7 (CH), 134.5, 133.2 (CH), 131.5, 130.8 (CH), 129.0, 126.2
(CH), 125.7 (CH), 125.5 (CH), 123.3 (CH), 118.7, 113.4 (CH),
78.6, 62.2 (CH2), 14.7 (Me); m/z (CI) 443 (M+, 6%), 415 (13),
146 (100). Found: MH+, 443.0663. C19H15N4O7S requires:
443.0661.
Ethyl 3-(Benzothien-3-yl)-2-diazo-3-oxopropanoate, 42.
According to the above general procedure, the title product was
isolated from benzothiophene-3-carboxaldehyde 41 (1.2 g, 7.4
mmol) as a yellow crystalline solid (1.4 g, 5.2 mmol, 70%), mp
35-37 °C; IR (KBr/cm-1) 2136 (CdN2), 1711 (CdO); 1H NMR
(300 MHz; CDCl3) δ 8.25 (1H, dd, J ) 0.9, 7.2), 8.20 (1H, s),
7.86 (1H, dd, J ) 1.5, 7.3), 7.48-7.37 (2H, m), 4.26 (2H, q, J
) 7.2), 1.25 (3H, t, J ) 7.2); 13C NMR (75 MHz; CDCl3) δ 178.3,
159.5, 137.7 (CH), 135.4, 134.1, 131.0, 123.9 (CH), 123.6 (CH),
122.6 (CH), 120.8 (CH), 60.1 (CH2), 12.6 (Me), diazo C not
observed; m/z (FI) 274 (M+, 100%).Found: C, 56.7; H, 3.4; N,
10.3. C13H10N2O3S requires: C, 56.9; H, 3.7; N, 10.2.
neous. 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, corresponding 13C frequencies are 75 and 100
MHz); J values were 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. Specific rotations are
quoted in 10-1 deg cm2 g-1
.
Reaction of Aldehydes with Ethyl Diazoacetate and
Diethylzinc for the Formation of â-Ketodiazoesters. (a)
To a solution of ethyl diazoacetate (1.9 mmol) in dichlo-
romethane (5 mL) cooled to -60 °C was added diethylzinc (1.0
M in hexanes; 1.9 mmol) maintaining the temperature below
-50 °C then the mixture was stirred for 30 min. A solution of
the aldehyde (1.9 mmol) in dichloromethane (5 mL) was then
added and the resulting solution was stirred for 2 h maintain-
ing the temperature below -50 °C and then allowed to warm
to room temperature overnight. The reaction was then quenched
with concentrated aqueous ammonia (10 mL) and extracted
with dichloromethane (3 × 30 mL). The combined organic
layers were then dried (MgSO4) and concentrated under
reduced pressure. The resulting oil was purified by flash
chromatography (ethyl acetate-light petroleum) (1:4) to give
the still impure hydroxydiazoindole that was carried through
to the next stage without further purification.
(b) Iodoxybenzoic acid (2.1 mmol) was dissolved in DMSO
(5 mL) over 20 min. To this was added the crude hydroxydia-
zoindole (1.4 mmol) in DMSO (5 mL) and the solution was
stirred for 3 h. The reaction mixture was then poured onto
water (20 mL) and extracted with dichloromethane (2 × 20
mL). The combined organic layers were than dried (MgSO4)
and concentrated under reduced pressure. The resulting oil
was then purified by flash chromatography (ethyl acetate-
light petroleum) (1:9) to yield the desired product.
Ethyl 3-(1-tert-Butoxycarbonylindol-2-yl)-2-diazo-3-
oxopropanoate, 46. According to the above general proce-
dure, the title product was isolated from 1-tert-butoxycarbo-
nylindole-2-carboxaldehyde 4551 (1.2 g 4.9 mmol) as a yellow
crystalline solid (1.3 g, 3.5 mmol, 71%), mp 70-72 °C; IR (KBr/
Ethyl (1-tert-Butoxycarbonylindol-3-yl)-2-diazo-3-oxo-
propanoate, 25. According to the above general procedure,
the title product was isolated from 1-tert-butoxycarbonylindole-
3-carboxaldehyde 2448 (4.5 g, 18.3 mmol) as a yellow crystalline
1
cm-1) 2134 (CdN2), 1739 (CdO), 1696 (CdO); H NMR (300
solid (4.3 g, 12.1 mmol, 66%); mp 89-91 °C; IR (KBr/cm-1
)
MHz; CDCl3) δ 8.13 (1H, d, J ) 8.4), 7.58 (1H, d, J ) 7.8),
7.41-7.35 (2H, m), 6.80 (1H, s), 4.15 (2H, q, J ) 7.1), 1.61
(9H, s), 1.11 (3H, t, J ) 7.1); 13C NMR (75 MHz; CDCl3) δ 180.5,
161.3, 149.6, 136.3, 135.9, 128.7, 126.6 (CH), 123.6 (CH), 122.3
(CH), 115.8 (CH), 111.4 (CH), 85.2, 62.0 (CH2), 28.3 (Me), 14.5
(Me), diazo C not observed; m/z (CI) 358 (MH+, 40%), 357 (13),
302 (100). Found: C, 60.4; H, 5.4; N, 11.7. C18H19N3O5
requires: C, 60.5; H, 5.4; N, 11.8.
2139 (CdN2), 1740 (CdO); 1H NMR (300 MHz; CDCl3) δ 8.61
(1H, s), 8.20 (1H, m), 8.13 (1H, m), 7.35 (2H, m), 4.32 (2H, q,
J ) 7.2), 1.70 (9H, s), 1.32 (3H, t, J ) 7.2); 13C NMR (75 MHz;
CDCl3) δ 178.4, 160.6, 148.3, 134.1, 132.8 (CH), 127.6, 124.5
(CH), 123.4 (CH), 121.3 (CH), 116.7, 114.2 (CH), 84.4, 60.8
(CH2), 27.3 (Me), 13.5 (Me), diazo carbon not observed; m/z
(CI) 357 (MH+, 6%), 302 (100). Found: C, 60.8; H, 5.2; N, 11.6.
C18H19N3O5 requires: C, 60.5; H, 5.4; N, 11.8.
Ethyl 3-(1-tert-Butoxycarbonyl-2-chloroindol-3-yl)-2-
diazo-3-oxopropanoate, 36. According to the above general
procedure, the title product was isolated from 1-tert-butoxy-
(49) Kutschy, P.; Suchy, M.; Andreani, A.; Dzurilla, M.; Kova´cik,
V.; Alfo¨ldi, J.; Rossi, M.; Gramatova´, M. Tetrahedron 2002, 58, 9029-
9039.
(50) Gribble, G. W.; Jiang, J.; Liu, Y. J. Org. Chem. 2002, 67, 1001-
1003.
(48) Bringmann, G.; Tasler, S.; Endress, H.; Peters, K.; Peters, E.-
M. Synthesis 1998, 1501-1505.
(51) Carlier, P. R.; Lam, P. C.-H.; Wong, D. M. J. Org. Chem. 2002,
67, 6256-6259.
5846 J. Org. Chem., Vol. 70, No. 15, 2005

Wolff Rearrangement in Dirhodium(II)-Catalyzed Reactions
1
Ethyl 2-Diazo-3-(1-methylindol-3-yl)-3-oxopropanoate
,44. (a) To a solution of 1,1,1,3,3,3-hexamethyldisilazane (1.9
mL, 9.0 mmol) in THF (25 mL) cooled to 0 °C was added
n-butyllithium (1.6 M in hexanes; 5.6 mL, 9.0 mmol) and the
resulting mixture was stirred for 30 min before being cooled
to -78 °C. A solution of 3-acetyl-1-methyl indole 4352 (780 mg,
4.5 mmol) in THF (20 mL) was added to the reaction over 20
min. After stirring for a further 1 h, DMPU (0.54 mL, 4.5
mmol) and then ethyl cyanoformate (0.89 mL, 9.0 mmol) were
added to the reaction mixture. The mixture was then stirred
for a further 30 min before being quenched with water (60 mL)
and extracted with ether (3 × 75 mL). The combined organic
extractions were washed with brine, dried (MgSO4), concen-
trated in vacuo, and then purified by column chromatography
(ethyl acetate/light petroleum) to yield ethyl 3-(1-methylindol-
3-yl)-3-oxopropanoate as a yellow crystalline solid (897 mg, 3.7
mmol, 82%), mp 72-74 °C (ethyl acetate/light petroleum); IR
(KBr/cm-1) 1736 (CdO), 1635 (CdO); 1H NMR (300 MHz;
CDCl3) δ 8.37-8.34 (1H, m), 7.73 (1H, s), 7.31-7.28 (3H, m),
4.20 (2H, q, J ) 7.2), 3.83 (2H, s), 3.80 (3H, s), 1.26 (3H, t, J
) 7.2); 13C NMR (75 MHz; CDCl3) δ 186.6, 168.6, 137.9, 137.0
(CH), 126.7, 124.1 (CH), 123.3 (CH), 122.9 (CH), 116.2, 110.2
(CH), 61.8 (CH2), 47.8 (CH2), 34.0 (Me), 14.6 (Me); m/z (FI)
245 (M+, 100%). Found: C, 68.4; H, 6.1; N, 5.6. C14H15NO3
requires: C, 68.6; H, 6.2; N, 5.7.
(b) To a solution of the above â-ketoester (1.0 g, 4.1 mmol)
and 4-acetamidobenzenesulfonyl azide34 (4.5 mmol) in aceto-
nitrile (30 mL) at 0 °C was added triethylamine (12 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 title compound as a yellow solid
(1.05 g, 3.9 mmol, 94%), mp 125 °C dec; IR (KBr/cm-1) 2136
(CdN2), 1711 (CdO); 1H NMR (300 MHz; CDCl3) δ 8.39-8.35
(1H, m), 8.29 (1H, s), 7.36-7.25 (3H, m), 4.30 (2H, q, J ) 7.2),
3.81 (3H, s), 1.34 (3H, t, J ) 7.2); 13C NMR (75 MHz; CDCl3)
δ 178.0, 162.5, 138.2 (CH), 137.2, 128.1, 123.7 (CH), 123.1
(CH), 122.9 (CH), 113.8, 110.0 (CH), 61.7 (CH2), 34.1 (Me), 14.8
(Me), diazo C not observed; m/z (FI) 271 (M+, 100%). Found:
C, 61.6; H, 4.6; N, 15.4. C14H13N3O3 requires: C, 62.0; H, 4.8;
N, 15.5.
(CdO); H NMR (400 MHz; CDCl3) δ 8.69 (1H, s), 8.33-8.30
(1H, m), 8.18 (1H, d, J ) 7.6), 7.42-7.34 (2H, m), 6.96 (1H, d,
J ) 7.2), 5.94 (1H, d, J ) 7.3), 4.24-4.17 (2H, m), 2.38-2.27
(2H, m), 1.71-1.66 (11H, m), 1.34-1.30 (4H, m), 1.23 (3H, t,
J ) 7.1), 0.88 (3H, t, J ) 7.0); 13C NMR (100 MHz; CDCl3) δ
185.9, 173.0, 167.0, 148.6, 135.6, 135.3 (CH), 127.2, 126.0 (CH),
124.8 (CH), 122.4 (CH), 117.2, 115.1 (CH), 85.9, 62.5 (CH2),
59.6 (CH), 36.2 (CH2), 31.3 (CH2), 28.1 (Me), 25.2 (CH2), 22.4
(CH2), 13.9 (2 × Me); m/z (CI) 445 (MH+, 11%), 345 (100).
Found: C, 64.7; H, 7.3; N, 6.0. C24H32N2O6 requires: C, 64.9;
H, 7.3; N, 6.3.
Ethyl 2-(1-tert-Butoxycarbonylindol-3-yl)-N-(4-bro-
mobenzoyl)-malonamate, 28. To a solution of 4-bromoben-
zamide (500 mg, 2.5 mmol) and dirhodium tetraacetate (30
mg, 0.06 mmol) in 1,2-dichloroethane (22 mL), heated to reflux,
was added a solution of the diazo indole 25 (1.2 g, 3.2 mmol)
in the same solvent dropwise over 16 h. The reaction mixture
was then heated for a further 2-4 h until complete by TLC
and then evaporated in vacuo and purified on silica gel eluting
with ethyl acetate-light petroleum (1:4) to yield the title
compound as a colorless crystalline solid (75%), mp 156-158
°C (hexanes); IR (film/cm-1) 3296 (N-H), 1730 (CdO), 1687
(CdO); 1H NMR (300 MHz; CDCl3) δ 9.45 (1H, br s), 8.09 (1H,
d, J ) 8.4), 7.63 (2H, d, J ) 8.5), 7.57 (1H, d, J ) 7.9), 7.45
(2H, d, J ) 8.6), 7.29 (1H, app. t, J ) 7.2), 7.21-7.16 (2H, m),
5.56 (1H, s), 4.23-4.14 (2H, m), 5.56 (9H, s), 1.19 (3H, t, J )
7.1); 13C NMR (75 MHz; CDCl3) δ 169.6, 168.9, 165.3, 149.8,
135.8, 132.5 (CH), 131.3, 129.9 (CH), 129.6, 129.0, 126.0 (CH),
125.3 (CH), 123.4 (CH), 120.2 (CH), 115.8 (CH), 112.8, 84.6,
62.7 (CH2), 52.1 (CH), 28.6 (Me), 14.4 (Me); m/z (CI) 531/529
(MH+, 2%), 200 (100). Found: MH+, 529.0990. C25H2679BrN2O6
requires: 529.0974.
Ethyl 2-Hexanoylamino-3-oxo-3-phenylpropanoate, 33.
According to the above procedure, hexanamide (240 mg, 2.1
mmol) and diazoindole 3226 (545 mg, 2.5 mmol) in dichlo-
romethane yielded the title compound as a colorless oil (561
mg, 1.8 mmol, 88%); IR (film/cm-1) 3373 (N-H), 1751 (CdO),
1661 (CdO); 1H NMR (300 MHz; CDCl3) δ 8.15-8.11 (2H, m),
7.67-7.61 (1H, m), 7.53-7.48 (2H, m), 6.90 (1H, d, J ) 7.5),
6.22 (1H, d, J ) 7.5), 4.17 (2H, q, J ) 7.2), 2.31 (2H, t, J )
6.6), 1.71-1.61 (2H, m), 1.37-1.27 (4H, m), 1.15 (3H, t, J )
7.2), 0.88 (3H, t, J ) 6.8); 13C NMR (75 MHz; CDCl3) δ 192.3,
173.4, 167.2, 134.8 (CH), 134.6, 130.0 (CH), 129.2 (CH), 62.9
(CH2), 58.5 (CH), 36.6 (CH2), 31.7 (CH2), 25.5 (CH2), 22.8 (CH2),
14.3 (Me), 14.2 (Me); m/z (FI+) 305 (M+, 83%), 105 (100).
Found: M+, 305.1620. C17H23NO4 requires: 305.1627.
Reaction of Ethyl 3-(1-tert-Butoxycarbonyl-2-chlor-
oindol-3-yl)-2-diazo-3-oxopropanoate, 36, with Hexana-
mide. To a solution of hexanamide (200 mg, 1.7 mmol) and
dirhodium tetraoctanoate (90 mg, 0.1 mmol) in dichlo-
romethane (45 mL) heated under reflux was added diazo indole
36 (816 mg, 2.1 mmol) in dichloromethane (15 mL) over 16 h.
The reaction mixture was then 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:
Reaction of Ethyl (1-tert-Butoxycarbonylindol-3-yl)-
2-diazo-3-oxopropanoate, 25, with Hexanamide. To a
solution of hexanamide (500 mg, 4.3 mmol) and dirhodium
tetraoctanoate (85 mg, 0.1 mmol) in dichloromethane (10 mL)
heated under reflux was added diazo indole 25 (1.9 g, 5.3
mmol) in dichloromethane (10 mL) over 16 h. The reaction
mixture was then 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 prod-
ucts were isolated:
(i) Ethyl 2-(1-tert-butoxycarbonylindol-3-yl)-N-hexanoylma-
lonamate 27 as a pale yellow oily solid (1.1 g, 2.4 mmol, 55%);
1
IR (KBr/cm-1) 3269 (N-H), 1738 (CdO); H NMR (400 MHz;
CDCl3) δ 9.06, (1H, s), 8.14 (1H, d, J ) 7.9), 7.71 (1H, s), 7.56
(1H, d, J ) 7.9), 7.33 (1H, app. t, J ) 7.2), 7.23 (1H, app. t, J
) 7.2), 5.21 (1H, s), 4.25 (2H, m), 2.61 (2H, t, J ) 5.6), 1.66
(9H, s), 1.59 (2H, app. t, J ) 5.6), 1.27 (7H, m), 0.86 (3H, t, J
) 5.1); 13C NMR (100 MHz; CDCl3) δ 174.6, 168.2, 167.3, 149.3,
135.4, 128.9, 125.4 (CH), 125.0 (CH), 123.0 (CH), 119.4 (CH),
115.4 (CH), 112.0, 84.2, 62.3 (CH2), 51.5 (CH), 37.4 (CH2), 31.1
(CH2), 28.1 (Me), 23.8 (CH2), 22.3 (CH2), 14.0 (Me), 13.9 (Me);
m/z (CI) 445 (MH+, 10%), 444 (5), 116 (100). Found: MH+,
445.2333. C24H33N2O6 requires: 445.2338). (ii) Ethyl 3-(1-tert-
butoxycarbonylindol-3-yl)-2-hexanoylamino-3-oxopropanoate 26
as a colorless crystalline solid (749 mg, 1.7 mmol, 39%), mp
108-110 °C; IR (KBr/cm-1) 3431 (N-H), 1745 (CdO), 1664
(i) Ethyl 2-(1-tert-butoxycarbonyl-2-chloroindol-3-yl)-N-hex-
anoylmalonamate 48 as a colorless crystalline solid (315 mg,
0.7 mmol, 38%), mp 98-101 °C; IR (KBr/cm-1) 3252 (N-H),
1
1737 (CdO), 1701 (CdO); H NMR (300 MHz; CDCl3) δ 8.83
(1H, s), 8.10 (1H, d, J ) 8.3), 7.52 (1H, dd, J ) 0.8, 7.9), 7.34-
7.23 (2H, m), 5.40 (1H, s), 4.26-4.18 (2H, m), 2.61 (2H, t, J )
7.4), 1.69 (9H, s), 1.68-1.59 (2H, m), 1.33-1.26 (4H, m), 1.22
(3H, t, J ) 7.1), 0.87 (3H, t, J ) 6.8); 13C NMR (75 MHz; CDCl3)
δ 175.0, 168.3, 167.9, 149.4, 136.1, 127.3, 125.7 (CH), 125.6,
124.2 (CH), 120.1 (CH), 116.0 (CH), 112.1, 86.2, 63.1 (CH2),
51.6 (CH), 38.2 (CH2), 31.9 (CH2), 28.9 (Me), 24.6 (CH2), 23.1
(CH2), 14.8 (Me), 14.6 (Me); m/z (CI) 481/479 (MH+, 29/58%),
379 (100). Found: MH+, 479.1945. C24H3235ClN2O6 requires:
479.1949. (ii) Ethyl 3-(1-tert-butoxycarbonyl-2-chloroindol-3-
yl)-2-hexanoylamino-3-oxopropanoate 47 as an orange oil (394
mg, 0.8 mmol, 47%); IR (film/cm-1) 3256 (N-H), 1753 (CdO),
(52) Biswas, K. M.; Jackson, A. H. Tetrahedron 1968, 24, 1145-
1162.
J. Org. Chem, Vol. 70, No. 15, 2005 5847

Davies et al.
1653 (CdO); 1H NMR (300 MHz; CDCl3) δ 8.19-8.15 (1H, m),
7.99-7.96 (1H, m), 7.35-7.30 (2H, m), 6.86 (1H, d, J ) 7.7),
6.57 (1H, d, J ) 7.7), 4.15 (2H, q, J ) 7.1), 2.33-2.28 (2H, t,
J ) 7.3), 1.69-1.63 (11H, m), 1.32-1.27 (4H, m), 1.12 (3H, t,
J ) 7.1), 0.86 (3H, t, J ) 7.1); 13C NMR (75 MHz; CDCl3) δ
188.5, 173.4, 167.2, 148.4, 135.3, 130.9, 126.4, 126.1 (CH),
125.1 (CH), 121.7 (CH), 116.9, 114.7 (CH), 87.3, 62.7 (CH2),
60.1 (CH), 36.5 (CH2), 31.7 (CH2), 28.4 (Me), 25.5 (CH2), 22.7
(CH2), 14.3 (Me), 14.2 (Me); m/z (CI) 481/479 (MH+, 24/66%),
289 (100). Found: MH+, 479.1946. C24H3235ClN2O6 requires:
479.1949.
Reaction of Ethyl 3-(1-Benzenesulfonylindol-3-yl)-2-
diazo-3-oxopropanoate, 38, with Hexanamide. To a solu-
tion of hexanamide (250 mg, 2.2 mmol) and dirhodium
tetraoctanoate (43 mg, 0.06 mmol) in dichloromethane (45 mL)
heated under reflux was added diazo indole 38 (1.5 g, 53.8
mmol) in dichloromethane (20 mL) over 16 h. The reaction
mixture was then 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 prod-
ucts were isolated:
anamide (520 mg, 4.5 mmol) and dirhodium tetraoctanoate (90
mg, 0.1 mmol) in dichloromethane (45 mL) heated under reflux
was added diazo indole 42 (1.5 g, 5.5 mmol) in dichloromethane
(15 mL) over 16 h. The reaction mixture was then heated for
a further 30 min, allowed to cool, evaporated in vacuo and
purified by flash chromatography (ethyl acetate-light petro-
leum). From the reaction two products were isolated:
(i) Ethyl 2-(benzothien-3-yl)-N-hexanoylmalonamate 54 as
a pale green oily solid (497 mg, 1.4 mmol, 30%); IR (KBr/cm-1
)
3257 (N-H), 1737 (CdO), 1685 (CdO); 1H NMR (300 MHz;
CDCl3) δ 9.13 (1H, s), 7.88-7.81 (2H, m), 7.53 (1H, s), 7.40-
7.36 (2H, m), 5.41 (1H, s), 4.29-4.20 (2H, m), 2.61 (2H, t, J )
7.4), 1.61-1.56 (2H, m), 1.32-1.15 (7H, m), 0.87 (3H, t, J )
6.7); 13C NMR (75 MHz; CDCl3) δ 174.9, 168.4, 167.0, 140.6,
138.0, 126.9, 126.7 (CH), 125.3 (CH), 125.0 (CH), 123.4 (CH),
122.3 (CH), 62.8 (CH2), 54.2 (CH), 37.9 (CH2), 31.5 (CH2), 24.2
(CH2), 22.7 (CH2), 14.4 (Me), 14.3 (Me); m/z (CI) 362 (MH+,
100%). Found: MH+, 362.1418. C19H24NO4S requires: 362.1426.
(ii) Ethyl 3-(benzothien-3-yl)-2-hexanoylamino-3-oxopropanoate
53 as an oily yellow solid (630 mg, 1.7 mmol, 38%); IR (KBr/
cm-1) 3242 (N-H), 1753 (CdO), 1672 (CdO); 1H NMR (300
MHz; CDCl3) δ 8.89 (1H, s), 8.71-8.68 (1H, m), 7.88 (1H, dd,
J ) 1.2, 7.6), 7.54-7.42 (2H, m), 6.93 (1H, d, J ) 7.6), 6.14
(1H, d, J ) 7.6), 4.21 (2H, q, J ) 7.1), 2.32 (2H, t, J ) 7.6),
1.72-1.64 (2H, m), 1.35-1.25 (4H, m), 1.20 (3H, t, J ) 7.1),
0.87 (3H, t, J ) 6.8); 13C NMR (75 MHz; CDCl3) δ 186.0, 173.4,
167.5, 142.1 (CH), 140.0, 136.9, 132.3, 126.6 (CH), 126.3 (CH),
125.7 (CH), 122.8 (CH), 63.0 (CH2), 59.8 (CH), 36.6 (CH2), 31.7
(CH2), 25.5 (CH2), 22.8 (CH2), 14.4 (Me), 14.3 (Me); m/z (CI)
362 (MH+, 100%). Found: MH+, 362.1431. C19H24NO4S re-
quires: 362.1426.
(i) Ethyl 2-(1-benzenesulfonylindol-3-yl)-N-hexanoylma-
lonamate 50 as a colorless solid (240 mg, 0.5 mmol, 23%), mp
153-155 °C; IR (KBr/cm-1) 3257 (N-H), 1737 (CdO), 1726
(CdO), 1685 (CdO); 1H NMR (300 MHz; CDCl3) δ 8.62 (1H, s,
NH), 7.98 (1H, d, J ) 8.2), 7.91-7.88 (2H, m), 7.75 (1H, s),
7.56-7.53 (2H, m), 7.47-7.43 (2H, m), 7.36-7.32 (1H, m),
7.27-7.23 (1H, m), 5.20 (1H, s), 4.28-4.19 (2H, m), 2.58 (2H,
t, J ) 7.4), 1.65-1.55 (2H, m), 1.33-1.22 (7H, m, 2 × CH2 +
OCH2Me), 0.87 (3H, t, J ) 6.8); 13C NMR (75 MHz; CDCl3) δ
174.5, 168.3, 167.1, 138.3, 134.4 (CH), 129.8 (CH), 129.7, 127.2
(CH), 126.2 (CH), 125.7 (CH), 124.1 (CH), 120.5 (CH), 112.4,
114.0 (CH), 62.8 (CH2), 51.7 (CH), 37.9 (CH2), 31.5 (CH2), 24.2
(CH2), 22.7 (CH2), 14.4 (Me), 14.3 (Me), one C not observed;
m/z (CI) 485 (MH+, 10%), 116 (100). Found: MH+, 485.1739.
C25H29N2O6S requires: 485.1746. (ii) Ethyl 3-(1-benzenesulfo-
nylindol-3-yl)-2-hexanoylamino-3-oxopropanoate 49 as a color-
less oil (550 mg, 1.1 mmol, 52%); IR (film/cm-1) 3384 (N-H),
Reaction of Ethyl 2-Diazo-3-(1-methylindol-3-yl)-3-
oxopropanoate, 44, with Hexanamide. According to gen-
eral procedure used for compound 33, using hexanamide (300
mg, 2.6 mmol), diazoindole 44 (848 mg, 3.1 mmol), dirhodium
tetraoctanoate (51 mg, 0.07 mmol), and dichloromethane (50
mL), ethyl 2-(1-methylindol-3-yl)-N-hexanoylmalonamate 52
was isolated as a colorless oil (758 mg, 2.1 mmol, 81%); IR
1
1
1744 (CdO), 1663 (CdO); H NMR (300 MHz; CDCl3) δ 8.76
(KBr/cm-1) 3292 (N-H), 1730 (CdO), 1695 (CdO); H NMR
(1H, s), 8.27-8.25 (1H, dd, J ) 1.2, 7.0), 8.02-7.95 (3H, m),
7.61-7.56 (1H, m), 7.51-7.46 (2H, m), 7.41-7.29 (2H, m), 7.02
(1H, d, J ) 7.4), 6.00 (1H, d, J ) 7.4), 4.23-4.15 (2H, m), 2.34-
2.28 (2H, m), 1.70-1.60 (2H, m), 1.30-1.26 (4H, m), 1.21 (3H,
t, J ) 7.2), 0.85 (3H, t, J ) 6.8); 13C NMR (75 MHz; CDCl3) δ
186.4, 173.4, 167.3, 137.7, 135.7 (CH), 135.2 (CH), 135.1, 130.1
(CH), 127.8, 127.7 (CH), 126.6 (CH), 125.6 (CH), 123.3 (CH),
118.6, 113.6 (CH), 63.0 (CH2), 60.0 (CH), 36.6 (CH2), 31.7 (CH2),
25.6 (CH2), 22.8 (CH2), 14.32 (Me), 14.30 (Me); m/z (CI) 485
(MH+, 27%), 255 (100). Found: MH+, 485.1750. C25H29N2O6S
requires: 485.1746.
Reaction of Ethyl 2-Diazo-3-[1-(2-nitrobenzenesulfo-
nyl)indol-3-yl]-3-oxopropanoate, 40, with Hexanamide.
According to general procedure used for compound 33, hex-
anamide (100 mg, 0.9 mmol) and diazoindole 40 (480 mg, 1.1
mmol) were reacted in the presence of catalytic dirhodium
tetraoctanoate to yield ethyl 2-hexanoylamino-3-[1-(2-nitroben-
zenesulfonyl)indol-3-yl]-3-oxopropanoate 51 as an oily solid
(240 mg, 0.45 mmol, 52%); IR (KBr/cm-1) 3293 (N-H), 1721
(CdO), 1685 (CdO), 1655 (CdO); 1H NMR (300 MHz; CDCl3)
δ 8.73 (1H, s), 8.35 (1H, dd, J ) 3.1, 6.2), 8.19 (1H, dd, J )
1.6, 6.7), 7.84-7.78 (4H, m), 7.42-7.39 (2H, m), 6.91 (1H, d, J
) 7.1), 5.97 (1H, d, J ) 7.1), 4.32-4.20 (2H, m), 2.34 (2H, t, J
) 7.3), 1.71-1.64 (2H, m), 1.36-1.29 (4H, m), 1.26 (3H, t, J )
7.1), 0.89 (3H, t, J ) 7.1); 13C NMR (75 MHz; CDCl3) δ 186.7,
173.4, 167.1, 148.4, 136.5 (CH), 136.3 (CH), 134.9, 133.3 (CH),
131.6 (CH), 131.1, 127.9, 126.7 (CH), 126.0 (CH), 125.9 (CH),
123.7 (CH), 118.5, 113.3 (CH), 63.3 (CH2), 60.3 (CH), 36.6
(CH2), 31.7 (CH2), 25.5 (CH2), 22.8 (CH2), 14.3 (Me), 14.2 (Me);
m/z (CI) 530 (M+, 36%), 345 (100). Found: MH+, 530.1600.
C25H28N3O5S requires: 530.1597.
(300 MHz; CDCl3) δ 8.85 (1H, s), 7.63 (1H, d, J ) 7.9), 7.33-
7.23 (2H, m), 7.19 (1H, s), 7.17-7.12 (1H, m), 5.11 (1H, s),
4.29-4.18 (2H, m), 3.75 (3H, s), 2.68 (2H, t, J ) 7.5), 1.63 (2H,
m), 1.30-1.24 (7H, m), 0.86 (3H, t, J ) 6.6); 13C NMR (75 MHz;
CDCl3) δ 175.4, 169.6, 168.2, 137.4, 128.9 (CH), 127.1, 122.9
(CH), 120.5 (CH), 119.5 (CH), 110.1 (CH), 105.8, 62.5 (CH2),
52.4 (CH), 37.8 (CH2), 33.4 (Me), 31.6 (CH2), 24.2 (CH2), 22.8
(CH2), 14.5 (Me), 14.3 (Me); m/z (FI) 358 (M+, 85%). Found:
M+, 358.1892. C20H26N2O4 requires: 358.1893.
Ethyl 1-Hydroxy-4-oxo-(1,3)-oxazino[3,4-a]indole-2-
carboxylate, 55. To a solution of hexanamide (100 mg, 0.87
mmol) and dirhodium tetraoctanoate (17 mg, 0.02 mmol) in
dichloromethane (5 mL) heated under reflux was added diazo
indole 46 (372 mg, 1.0 mmol) in dichloromethane (5 mL) over
16 h. The reaction mixture was then heated for a further 30
min, allowed to cool, evaporated in vacuo, and purified by flash
chromatography (ethyl acetate-light petroleum) to yield the
title compound as a colorless crystalline solid (160 mg, 0.58
1
mmol, 56%), mp 172-174 °C; IR (KBr/cm-1) 1767 (CdO); H
NMR (300 MHz; CDCl3) δ 10.60 (1H, s), 8.70 (1H, dd, J ) 0.8,
7.5), 7.95 (1H, dd, J ) 1.0, 7.6), 7.75-7.46 (2H, m), 7.40 (1H,
s), 4.67 (2H, q, J ) 7.1), 1.65 (3H, t, J ) 7.1); 13C NMR (75
MHz; CDCl3) δ 165.5, 145.4, 143.0, 135.2, 130.1, 128.2, 127.0
(CH), 125.7 (CH), 122.2 (CH), 122.0, 116.3 (CH), 106.6 (CH),
62.9 (CH2), 14.6 (Me); m/z (CI) 274 (MH+, 100%). Found: MH+,
274.0708. C14H12NO5 requires: 274.0715.
Reaction of Ethyl (1-tert-Butoxycarbonylindol-3-yl)-
2-diazo-3-oxopropanoate, 25, with Methanol. To a solution
of methanol (0.11 mL, 5.6 mmol) and dirhodium tetraoctanoate
(12 mg, 0.02 mmol) in dichloromethane (5 mL) heated under
reflux was added diazo indole 25 (200 mg, 0.6 mmol) in
dichloromethane (7 mL) over 16 h. The reaction mixture was
then heated for a further 30 min, allowed to cool, evaporated
Reaction of Ethyl 3-(Benzothien-3-yl)-2-diazo-3-oxo-
propanoate, 42, with Hexanamide. To a solution of hex-
5848 J. Org. Chem., Vol. 70, No. 15, 2005

Wolff Rearrangement in Dirhodium(II)-Catalyzed Reactions
in vacuo, and purified by flash chromatography (ethyl acetate-
Ethyl 5-(1-Benzenesulfonylindol-3-yl)-2-pentyloxazole-
4-carboxylate, 60. According to the above general procedure,
the title compound was isolated from 49 (550 mg, 1.1 mmol)
as a colorless crystalline solid (345 mg, 0.72 mmol, 65%), mp
light petroleum). From the reaction two products were isolated:
(i) Ethyl methyl 2-(1-tert-butoxycarbonylindol-3-yl)malonate
57 as a colorless oil (51 mg, 0.14 mmol, 25%); IR (film/cm-1
)
1
123-125 °C; IR (KBr/cm-1) 1706 (CdO); H NMR (300 MHz;
1
1737 (CdO); H NMR (300 MHz; CDCl3) δ 8.09 (1H, d, J )
8.1), 7.69 (1H, s), 7.50 (1H, d, J ) 7.5), 7.28-7.14 (2H, m),
4.81 (1H, s), 4.20-4.13 (2H, m), 3.69 (3H, s), 1.58 (9H, s), 1.19
(3H, t, J ) 7.1); 13C NMR (75 MHz; CDCl3) δ 167.3, 166.6,
148.4, 134.3, 128.1, 124.4 (CH), 123.6 (CH), 121.7 (CH), 118.3
(CH), 114.3 (CH), 111.1, 82.9, 61.0 (CH2), 51.9 (CH), 48.4 (Me),
27.1 (Me), 13.0 (Me); m/z (CI) 362 (MH+, 35%), 306 (100).
Found: MH+, 362.1591. C19H24NO6 requires: 362.1604. (ii)
Ethyl 3-(1-tert-butoxycarbonylindol-3-yl)-2-methoxy-3-oxopro-
panoate 56 as a colorless oil (120 mg, 0.33 mmol, 60%); IR
(film/cm-1) 1747 (CdO); 1H NMR (300 MHz; CDCl3) δ 8.66 (1H,
s), 8.39-8.36 (1H, m), 8.13-8.10 (1H, m), 7.38-7.34 (2H, m),
4.75 (1H, s), 4.28-4.20 (2H, m), 3.54 (3H, s), 1.70 (9H, s), 1.25
(3H, t, J ) 7.2); 13C NMR (75 MHz; CDCl3) δ 188.8, 167.7,
149.1, 135.2, 135.1 (CH), 127.9, 125.9 (CH), 124.8 (CH), 122.8
(CH), 116.5, 115.1 (CH), 87.0 (CH), 85.8, 62.2 (CH2), 58.6 (Me),
28.2 (Me), 14.3 (Me); m/z (CI) 362 (MH+, 18%), 306 (100).
Found: MH+, 362.1591. C19H24NO6 requires: 362.1604).
Synthesis of 5-(Indol-3-yl)oxazoles and Related Com-
pounds. To a solution of triphenylphosphine (0.20 mmol) and
iodine (0.20 mmol) in dry dichloromethane (10 mL) was added
triethylamine (0.41 mmol) and then a solution of the keto
amide substrate (0.10 mmol) in dry dichloromethane (3 mL).
The reaction mixture was then stirred for 16 h and then
evaporated in vacuo and purified on silica gel eluting with
ethyl acetate-light petroleum to yield the desired product.
CDCl3) δ 9.02 (1H, s), 8.07-8.03 (2H, m), 8.00-7.97 (2H, m),
7.59-7.54 (1H, m), 7.49-7.45 (2H, m), 7.42-7.33 (2H, m), 4.48
(2H, q, J ) 7.2), 2.90 (2H, t, J ) 7.6), 1.88-1.84 (2H, m), 1.46
(3H, t, J ) 7.2), 1.42-1.36 (4H, m), 0.90 (3H, t, J ) 7.0); 13C
NMR (75 MHz; CDCl3) δ 163.0, 162.2, 150.9, 137.8, 134.6,
134.2 (CH), 129.5 (CH), 129.4 (CH), 127.9, 127.0 (CH), 126.6,
125.5 (CH), 124.2 (CH), 121.8 (CH), 113.6 (CH), 109.5, 61.4
(CH2), 31.3 (CH2), 28.1 (CH2), 26.8 (CH2), 22.3 (CH2), 14.5 (Me),
13.9 (Me); m/z (CI) 467 (MH+, 8%). Found: C, 64.3; H, 5.6; N,
5.8. C25H26N2O5S requires: C, 64.4; H, 5.6; N, 6.0.
Ethyl 5-[1-(2-Nitrobenzenesulfonyl)indol-3-yl]-2-pen-
tyloxazole-4-carboxylate, 61. According to the above general
procedure, ketoamide 51 (280 mg, 0.53 mmol) was cyclodehy-
drated to give the title compound as a yellow crystalline solid
(230 mg, 0.45 mmol, 85%), mp 165-167 °C (ethyl acetate/light
1
petroleum); IR (KBr/cm-1) 1708 (CdO); H NMR (300 MHz;
CDCl3) δ 9.00 (1H, s), 8.10 (1H, app. t, J ) 4.9), 7.92-7.89
(2H, m), 7.78-7.68 (3H, m), 7.43-7.40 (2H, m), 4.49 (2H, q, J
) 7.1), 2.93 (2H, t, J ) 7.7), 1.94-1.84 (2H, m), 1.47-1.40 (7H),
0.92 (3H, t, J ) 7.2); 13C NMR (100 MHz; CDCl3) δ 175.5, 163.3,
162.1, 150.3, 148.0, 135.2 (CH), 134.5, 132.6 (CH), 131.5, 130.1
(CH), 130.0 (CH), 127.8, 125.7 (CH), 125.2 (CH), 124.6 (CH),
122.1 (CH), 113.6 (CH), 109.5, 61.5 (CH2), 31.3 (CH2), 28.1
(CH2), 26.8 (CH2), 22.3 (CH2), 14.4 (Me), 13.9 (Me); m/z (CI)
512 (MH+, 7%), 327 (100). Found: MH+, 512.1491. C25H26N3O7S
requires: 512.1491.
Ethyl 2-Pentyl-5-phenyloxazole-4-carboxylate, 34. Ac-
cording to the above general procedure, ketoamide 33 (300 mg,
0.98 mmol) was cyclodehydrated to give the title compound
as a colorless oil (193 mg, 0.68 mmol, 69%); IR (film/cm-1) 1720
(CdO); 1H NMR (300 MHz; CDCl3) δ 8.06-8.02 (2H, m), 7.50-
7.40 (3H, m), 4.42 (2H, q, J ) 7.0), 2.85 (2H, t, J ) 7.5), 1.88-
1.78 (2H, m), 1.46-1.31 (7H, m), 0.91 (3H, t, J ) 6.8); 13C NMR
(100 MHz; CDCl3) δ 163.9, 162.7, 155.4, 130.4 (CH), 128.7 (2
× CH), 127.6, 127.3, 61.7 (CH2), 31.7 (CH2), 28.5 (CH2), 27.2
(CH2), 22.6 (CH2), 14.7 (Me), 14.3 (Me); m/z (FI+) 287 (M+,
87%), 192 (100). Found: M+, 287.1505. C17H21NO3 requires:
287.1521.
Ethyl 5-(1-tert-Butoxycarbonylindol-3-yl)-2-pentylox-
azole-4-carboxylate, 58. According to the above general
procedure, the title compound was isolated from 24 (350 mg,
0.79 mmol) as a colorless crystalline solid (263 mg, 0.61 mmol,
78%), mp 35-37 °C; IR (KBr/cm-1) 1741 (CdO), 1709 (CdO);
1H NMR (400 MHz; CDCl3) δ 8.95 (1H, s), 8.24 (1H, d, J )
7.7), 8.07-8.85 (1H, m), 7.40-7.34 (2H, m), 4.45 (2H, q, J )
7.1), 2.92 (2H, t, J ) 7.6), 1.88 (2H, m), 1.71 (9H, s), 1.46-
1.37 (7H, m), 0.92 (3H, t, J ) 6.9); 13C NMR (100 MHz; CDCl3)
δ 162.7, 162.3, 151.7, 149.3, 135.2, 129.4 (CH), 127.7, 126.0,
125.1 (CH), 123.6 (CH), 121.3 (CH), 115.4 (CH), 107.9, 84.7,
61.1 (CH2), 31.4 (CH2), 28.1 (Me + CH2), 26.8 (CH2), 22.3 (CH2),
14.5 (Me), 13.9 (Me); m/z (CI) 427 (MH+, 74%), 371 (100).
Found: C, 67.6; H, 7.2; N, 6.3. C24H30N2O5 requires: C, 67.6;
H, 7.1; N, 6.6.
Ethyl 5-(1-tert-Butoxycarbonyl-2-chloroindol-3-yl)-2-
pentyloxazole-4-carboxylate, 59. According to the above
general procedure, the title compound was isolated from 47
(390 mg, 0.81 mmol) as a pale orange solid (300 mg, 0.65 mmol,
80%), mp 77-79 °C; IR (KBr/cm-1) 1747 (CdO), 1639 (CdO);
1H NMR (300 MHz; CDCl3) δ 8.13 (1H, d, J ) 8.1), 7.39-7.27
(3H, m), 4.31 (2H, q, J ) 7.1), 2.89 (2H, t, J ) 7.6), 1.88-1.83
(2H, m), 1.71 (9H, s), 1.43-1.37 (4H, m), 1.22 (3H, t, J ) 7.1),
0.94-0.89 (3H, m); 13C NMR (75 MHz; CDCl3) δ 165.8, 161.8,
148.9, 147.7, 135.4, 130.9, 126.9, 126.5, 125.5 (CH), 124.0 (CH),
119.7 (CH), 115.7 (CH), 108.9, 86.2, 61.5 (CH2), 31.7 (CH2),
28.6 (CH2), 28.5 (Me), 27.1 (CH2), 22.6 (CH2), 14.5 (Me), 14.3
(Me); m/z (CI) 463/461 (MH+, 7/17%), 361 (100). Found: MH+,
461.1826. C24H3035ClN2O5 requires: 461.1843.
Ethyl 5-(Benzothien-3-yl)-2-pentyloxazole-4-carboxy-
late, 62. According to the above general procedure, the title
compound was isolated from 53 (630 mg, 1.7 mmol) as an oily
orange solid (450 mg, 1.3 mmol, 75%); IR (KBr/cm-1) 1716 (Cd
O); 1H NMR (300 MHz; CDCl3) δ 8.66 (1H, s), 8.15-8.12 (1H,
m), 7.91-7.88 (1H, m), 7.48-7.40 (2H, m), 4.40 (2H, q, J )
7.1), 2.92 (2H, t, J ) 7.5), 2.03-1.83 (2H, m), 1.46-1.33 (7H,
m), 0.92 (3H, t, J ) 7.3); 13C NMR (75 MHz; CDCl3) δ 163.5,
162.7, 151.9, 140.0, 137.3, 132.2 (CH), 128.0, 125.4 (CH), 125.3
(CH), 124.0 (CH), 123.2 (CH), 122.7, 61.7 (CH2), 31.7 (CH2),
28.5 (CH2), 27.2 (CH2), 22.7 (CH2), 14.7 (Me), 14.3 (Me); m/z
(CI) 344 (MH+, 100%). Found: MH+, 344.1318. C19H22NO3S
requires: 344.1320.
Ethyl 5-(Indol-3-yl)-2-pentyloxazole-4-carboxylate, 63.
To a solution of nosylindole 61 (100 mg, 0.20 mmol) in DMF
(4 mL) was added lithium hydroxide (33 mg, 0.80 mmol) and
then mercaptoacetic acid (27 µL, 0.40 mmol) and the resulting
mixture was stirred overnight. The solution was then partition
with ether (30 mL) and saturated sodium hydrogen carbonate
(30 mL) and the aqueous layer was extracted with ether (10
mL). The combined organic layers were then washed with
brine, dried (MgSO4), concentrated in vacuo, and purified by
flash chromatography to yield the title compound as a yellow
solid (55 mg, 0.17 mmol, 86%), mp 83-85 °C (ethyl acetate/
light petroleum); IR (KBr/cm-1) 3146 (N-H), 1702 (CdO); 1H
NMR (300 MHz; CDCl3) δ 9.07 (1H, s), 8.81 (1H, d, J ) 2.9),
8.19-8.15 (1H, m), 7.47-7.43 (1H, m), 7.33-7.25 (2H, m), 4.45
(2H, q, J ) 7.1), 2.92 (2H, t, J ) 7.7), 1.95-1.85 (2H, m), 1.49-
1.32 (7H, m), 0.92 (3H, t, J ) 7.0); 13C NMR (75 MHz; CDCl3)
δ 163.5, 161.9, 154.9, 136.2, 129.7 (CH), 125.6, 123.6, 123.5
(CH), 121.8 (CH), 121.7 (CH), 112.1 (CH), 104.7, 61.4 (CH2),
31.8 (CH2), 28.5 (CH2), 27.3 (CH2), 22.7 (CH2), 14.9 (Me), 14.4
(Me); m/z (CI) 327 (MH+, 100%). Found: MH+, 327.1703.
C19H23N2O3 requires: 327.1709.
Methyl (S)-2-tert-Butoxycarbonylamino-4-methylhex-
2-enoate, 65. To a solution of trimethyl 2-(tert-butoxycarbo-
nylamino)phosphonoacetate53 (1.0 g, 3.5 mmol) in dichlo-
romethane (1 mL) was added TMG (0.40 mL, 3.2 mmol) and
(53) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53-
60.
J. Org. Chem, Vol. 70, No. 15, 2005 5849

Davies et al.
the mixture was then stirred for 10 min. The reaction was then
cooled to 0 °C, (S)-2-methylbutanal 64 (250 mg, 2.9 mmol) was
added dropwise, and the mixture was then allowed to warm
to ambient temperature overnight. The reaction was then
diluted with ethyl acetate and washed with potassium hydro-
gen sulfate (1 M; 20 mL) and brine (2 × 20 mL). The combined
aqueous layers were then back extracted with ethyl acetate
(3 × 20 mL) and the combined organic layers were dried
(MgSO4) and concentrated in vacuo. The resulting oil was then
purified by flash chromatography to yield the title compound
as a colorless solid (656 mg, 2.6 mmol, 88%), mp 45-47 °C,
[R]33 26.0 (c 0.96, CHCl3); IR (KBr/cm-1) 3437 (N-H), 1731
130.6 (CH), 128.2, 127.7, 126.2 (CH), 125.7 (CH), 125.2 (CH),
122.5 (CH), 113.9 (CH), 109.6, 80.5, 62.1 (CH2), 53.9 (CH), 39.8
(CH), 29.7 (Me), 25.5 (CH2), 15.8 (Me), 14.8 (Me), 11.9 (Me);
m/z (FI+) 626 (M+, 15%), 123 (100). Found: M+, 626.2049.
C30H34N4O9S requires: 626.2047.
(S,S)-Ethyl 2-(1-tert-Butoxycarbonylamino-2-methyl-
butyl)-5-(indol-3-yl)oxazole-4-carboxylate, 71. To a solu-
tion of nosylindoleoxazole 70 (180 mg, 0.29 mmol) in DMF (6
mL) was added lithium hydroxide (48 mg, 1.1 mmol) and then
mercaptoacetic acid (40 µL, 0.57 mmol) and the resulting
solution was stirred at ambient temperature overnight. The
reaction was then partitioned with ether (40 mL) and sodium
hydrogen carbonate solution (40 mL). The aqueous layer was
then extracted with ether (20 mL) and the combined organic
extractions were washed with brine, dried (MgSO4), concen-
trated in vacuo, and purified by column chromatography to
yield the title compound as a colorless foam (112 mg, 0.26
mmol, 88%), [R]31 -53.7 (c 1.03, CHCl3); IR (CDCl3)/cm-1) 3468
1
(CdO), 1706 (CdO); H NMR (300 MHz; CDCl3) δ 6.35 (1H,
br), 5.87 (1H, s), 3.77 (3H, s), 2.55-2.43 (1H, m), 1.46 (9H, s),
1.42-1.36 (2H, m), 1.04 (3H, d, J ) 6.7), 0.87 (3H, t, J ) 7.4);
13C NMR (75 MHz; CDCl3) δ 165.7, 153.8, 143.2 (CH), 125.1,
80.4, 52.2 (CH2), 34.2 (CH), 29.2 (CH2), 28.2 (Me), 19.2 (Me),
11.8 (Me); m/z (CI) 258 (M+, 12%), 202 (100). Found: C, 60.9;
H, 9.0; N, 5.4. C13H23NO4 requires: C, 60.7; H, 9.0; N, 5.4.
(S,S)-N-(tert-Butoxycarbonyl)homoisoleucine Methyl
Ester, 66. The alkene 65 (400 mg, 1.6 mmol) and (+)-1,2-bis-
((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)-
rhodium(I) trifluoromethanesulfonate (4 mg) were placed in
the reaction vessel and then the system was evacuated and
purged with nitrogen (× 5); the vessel was then charged with
methanol (2 mL) and evacuated and purged with nitrogen (×
5) and then with hydrogen (× 5), pressurized with hydrogen
to 90 psi, and stirred for 3 days under pressure. The reaction
mixture was then concentrated in vacuo and purified by
column chromatography to yield the title compound as a
colorless oil (360 mg, 1.4 mmol, 89%) (lit.54 data not given),
[R]32 5.5 (c 1.02, CHCl3); IR (KBr/cm-1) 3366 N-H), 1747 (Cd
1
(N-H), 1711 (CdO); H NMR (300 MHz; CDCl3) δ 9.11 (1H,
s), 8.71 (1H, s), 8.10-8.07 (1H, m), 7.45-7.43 (1H, m), 7.30 -
7.22 (2H, m), 5.42 (1H, d, J ) 9.0), 4.99 (1H, dd, J ) 6.0, 9.0),
4.44 (2H, q, J ) 6.8), 2.08 (1H, m), 1.58-1.45 (10H, m), 1.41
(3H, t, J ) 6.8), 1.31-1.26 (1H, m), 0.98 (3H, d, J ) 6.4), 0.93
(3H, t, J ) 7.3); 13C NMR (75 MHz; CDCl3) δ 163.3, 160.5,
155.9, 154.9, 136.2, 130.0 (CH), 125.5, 123.7, 123.6 (CH), 121.9
(CH), 121.6 (CH), 112.1 (CH), 104.4, 80.5, 61.4 (CH2), 54.0
(CH), 39.9 (CH), 28.8 (Me), 25.5 (CH2), 15.9 (Me), 14.9 (Me),
11.9 (Me); m/z (FI+) 441 (M+, 100%). Found: M+, 441.2260.
C24H31N3O5 requires: 441.2264.
(S,S)-N-(tert-Butoxycarbonyl)homoisoleucinamide, 23.
To a solution of (S,S)-N-(tert-butoxycarbonyl)homoisoleucine
methyl ester 66 (480 mg, 1.9 mmol) in methanol (20 mL) cooled
to 0 °C was added a solution of lithium hydroxide (1 M; 10
mL). The mixture was allowed to warm to ambient tempera-
ture over 3 h and then concentrated in vacuo. The residue was
then partitioned between ethyl acetate and water (25 mL each)
and the aqueous layer was then acidified with 2 M HCl and
extracted with ethyl acetate (3 × 25 mL). The combined
organic extractions were then dried (MgSO4) and concentrated
to yield the free acid. The free acid was then dissolved in THF
(10 mL) to which was added triethylamine (0.28 mL, 1.9 mmol)
and the resulting mixture was cooled to 0 °C. Ethyl chloro-
formate (0.19 mL, 1.9 mmol) was added and the mixture was
stirred for 30 min at 0 °C. The reaction was then quenched
with concentrated ammonia (3 mL) and THF (2 mL) and
stirred for 30 min. The mixture was then partitioned with ethyl
acetate/water (15 mL each) and the aqueous layer was
extracted with ethyl acetate (2 × 15 mL). The combined
organic layers were then washed with saturated sodium
hydrogen carbonate solution and brine, dried (MgSO4), and
concentrated in vacuo to yield the title compound as a colorless
solid (366 mg, 1.5 mmol, 81%), mp 138-140 °C, [R]32 -24.9 (c
1.07, CHCl3); IR (KBr/cm-1) 3429 (N-H), 3362 (N-H), 3305
1
O), 1718 (CdO); H NMR (300 MHz; CDCl3) δ 4.95 (1H, d, J
) 7.7), 4.37-4.32 (1H, m), 3.73 (3H, s), 1.75-1.65 (1H, m),
1.55-1.37 (11H, m), 1.26-1.11 (2H, m), 0.92 (3H, d, J ) 6.0),
0.87 (3H, t, J ) 7.0); 13C NMR (100 MHz; CDCl3) δ 174.0, 155.3,
79.8, 52.2 (Me), 52.1 + 51.9 (CH, diast.), 39.8 + 39.6 (CH2,
diast.), 30.94 + 30.87 (CH, diast.), 28.6 + 28.7 (CH2, diast.),
28.3 (Me), 19.2 + 18.5 (Me, diast.), 10.9 + 11.2 (Me, diast.);
m/z (CI) 260 (M+, 100%). Found: MH+, 260.1861. C13H26NO4
requires: 260.1862.
(S,S)-Ethyl 2-(1-tert-Butoxycarbonylamino-2-methyl-
butyl)-5-[1-(2-nitrobenzenesulfonyl)indol-3-yl]oxazole-4-
carboxylate, 70. To a stirred solution of (S)-N-tert-butylox-
ycarbonylisoleucinamide 6755 (300 mg, 1.3 mmol) and dirhodium
tetraoctanoate (25 mg, 0.03 mmol) in dichloromethane (15 mL)
heated under reflux conditions was added a solution of nosyl
diazoindole 40 (692 mg, 1.6 mmol) in dichloromethane (15 mL)
over 16 h. The resulting mixture was then concentrated in
vacuo and purified by column chromatography (ethyl acetate/
light petroleum 4:6) to yield an inseparable mixture of products
68 (ca. 33%) and 69 (ca. 11%) (yields were based on analysis
of the 1H NMR spectrum of the mixture). To a solution of
triphenylphosphine (244 mg, 0.93 mmol) and iodine (118 mg,
0.93 mmol) in dichloromethane (5 mL) was added triethy-
lamine (0.27 mL, 1.9 mmol) and then a mixture of 68/69 in
dichloromethane (5 mL). The resulting mixture was stirred
overnight and concentrated in vacuo, and the resulant oil was
purified by column chromatography to yield the title compound
as a yellow oil (271 mg, 0.43 mmol, 33%, over two steps), [R]31
-9.0 (c 0.52, CHCl3); IR (CDCl3)/cm-1) 3440 (N-H), 1713 (Cd
O); 1H NMR (300 MHz; CDCl3) δ 8.96 (1H, s), 8.10-8.07 (1H,
m), 7.94-7.88 (2H, m), 7.81-7.77 (2H, m), 7.74-7.67 (1H, m),
7.45-7.38 (2H, m), 5.39 (1H, d, J ) 9.1), 4.99 (1H, dd, J )
6.2, 9.1), 4.51 (2H, q, J ) 7.2), 2.09-2.05 (1H, m), 1.66-1.42
(13H, m), 1.33-1.21 (1H, m), 0.97 (3H, d, J ) 7.7), 0.96 (3H,
t, J ) 7.5); 13C NMR (75 MHz; CDCl3) δ 162.6, 162.3, 155.8,
150.7, 148.4, 135.7 (CH), 134.9, 133.1 (CH), 131.8, 130.7 (CH),
1
(N-H), 1666 (CdO); H NMR (300 MHz; CDCl3) δ 6.23 (1H,
s), 5.56 (1H, s), 4.94 (1H, d, J ) 7.7), 4.22-4.15 (1H, m), 1.86-
1.77 (1H, m), 1.45-1.31 (11H, m), 1.29-1.10 (2H, m), 094-
9.85 (6H, m); 13C NMR (75 MHz; CDCl3) δ 175.7 + 176.1
(diast.), 156.2, 80.5, 52.8 (CH), 39.8 (CH2), 31.4 (CH), 29.1 +
30.3 (CH2, diast.), 28.7 (Me), 19.7 + 19.0 (Me, diast.), 11.4 +
11.7 (Me, diast.); m/z (FI+) 244 (M+, 100%). Found: M+,
244.1776. C12H24N2O3 requires: 244.1787.
(S,S)-Ethyl 2-(1-tert-Butoxycarbonylamino-3-methyl-
pentyl)-5-[1-(2-nitrobenzenesulfonyl)indol-3-yl]oxazole-
4-carboxylate, 74. To a stirred solution of (S,S)-N-tert-
butyloxycarbonylhomoisoleucinamide 23 (250 mg, 1.0 mmol)
and dirhodium tetraoctanoate (20 mg, 0.03 mmol) in dichlo-
romethane (10 mL) heated under reflux conditions was added
a solution of nosyl diazoindole 40 (543 mg, 1.2 mmol) in
dichloromethane (15 mL) over 16 h. The resulting mixture was
then concentrated in vacuo and purified by column chroma-
tography to yield an inseparable mixture of products 72 (ca.
56%) and 73 (ca. 4%) (yields were based on analysis of the 1H
(54) Papageorgiou, C.; Florineth, A.; Mikol, V. J. Med. Chem. 1994,
37, 3674-3676.
(55) Nozaki, S.; Muramatsu, I. Bull. Chem. Soc. Jpn. 1988, 61,
2647-2648.
5850 J. Org. Chem., Vol. 70, No. 15, 2005

Wolff Rearrangement in Dirhodium(II)-Catalyzed Reactions
NMR spectrum of the mixture). To a solution of triphenylphos-
phine (300 mg, 1.1 mmol) and iodine (145 mg, 1.1 mmol) in
dichloromethane (5 mL) was added triethylamine (0.33 mL,
2.3 mmol) and then a mixture of 72/73 in dichloromethane (5
mL). The resulting mixture was stirred overnight and con-
centrated in vacuo and the resulting oil was purified by column
chromatography to yield the title compound as a yellow oil (334
mg, 0.52 mmol, 51%, over two steps), [R]33 -11.0 (c 1.09,
CHCl3); IR (CHCl3)/cm-1) 3440 (N-H), 1713 (CdO); 1H NMR
(300 MHz; CDCl3) δ 8.98 (1H, s), 8.14-8.11 (1H, m), 7.92-
7.89 (2H, m), 7.83-7.66 (3H, m), 7.44-7.37 (2H, m), 5.16-
5.11 (2H, m), 4.53 (2H, q, J ) 7.0), 2.05-2.00 (1H, m), 1.79-
1.70 (1H, m), 1.52-1.42 (13H, m), 1.33-1.16 (2H, m), 0.99 (3H,
d, J ) 6.4), 0.88 (3H, t, J ) 7.2); 13C NMR (75 MHz; CDCl3) δ
161.0, 159.9, 148.4, 145.9, 133.2 (CH), 132.5, 130.6 (CH), 129.4,
128.3 (CH), 128.1 (CH), 125.7, 125.2, 123.8 (CH), 123.6, 123.2
(CH), 122.7 (CH), 120.2 (CH), 111.5 (CH), 107.2, 78.1, 59.7
(CH2), 45.2 (CH), 39.2 (CH2), 28.9 (CH), 26.7 (CH2), 26.3 (Me),
17.2 (Me), 12.4 (Me), 9.0 + 9.3 (Me, diast.); m/z (FI+) 640 (M+,
10%), 355 (100). Found: M+, 640.2209. C31H36N4O9S re-
quires: 640.2203.
(S,S)-Ethyl 2-(1-tert-Butoxycarbonylamino-3-methyl-
pentyl)-5-(indol-3-yl)oxazole-4-carboxylate, 75. To a solu-
tion of nosylindoleoxazole 74 (250 mg, 0.39 mmol) in DMF (8
mL) was added lithium hydroxide (65 mg, 1.6 mmol) and then
mercaptoacetic acid (54 µL, 0.78 mmol) and the resulting
solution was stirred at ambient temperature overnight. The
reaction was then partitioned with ether (40 mL) and sodium
hydrogen carbonate solution (40 mL). The aqueous layer was
then extracted with ether (20 mL) and the combined organic
extractions were washed with brine, dried (MgSO4), concen-
trated in vacuo, and purified by column chromatography to
yield the title compound as a colorless crystalline solid (157
mg, 0.34 mmol, 88%), mp 197-199 °C (ethyl acetate-light
petroleum), [R]33 -34.0 (c 1.02, CHCl3); IR (CHCl3/cm-1) 3468
1
(N-H), 1710 (CdO); H NMR (400 MHz; CDCl3) δ 9.06 (1H,
s), 9.71 (1H, s), 8.11 (1H, d, J ) 7.5), 7.43 (1H, d, J ) 7.5),
7.29-7.22 (2H, m), 5.28 (1H, d, J ) 6.8), 5.14-5.12 (1H, br),
4.43 (2H, q, J ) 7.0), 2.04-2.01 (1H, m), 1.77-1.73 (1H, m),
1.51-1.46 (10H, m), 1.41 (3H, t, J ) 7.1), 1.26-1.19 (2H, m),
0.99 (3H, d, J ) 6.5), 0.87 (3H, t, J ) 7.1); 13C NMR (100 MHz;
CDCl3) δ 162.5, 160.9, 155.1, 154.4, 135.6, 129.5 (CH), 125.0,
123.0 (CH), 121.4 (CH), 121.1 (CH), 111.4 (CH), 103.8, 80.0,
60.9 (CH2), 47.2 (CH), 41.2 + 41.0 (CH2, diast.), 30.8 (CH), 28.7
+ 29.5 (CH2, diast.), 28.2 (Me), 19.0 (Me), 14.3 (Me), 10.9 +
11.1 (Me, diast.), 1 ArC unobserved; m/z (FI+) 455 (M+, 100%).
Found: C, 65.9; H, 7.5; N, 9.0. C25H33N3O5 requires: C, 65.9;
H, 7.3; N, 9.2.
Acknowledgment. We thank the EPSRC and Tri-
pos Receptor Research for funding, David Bentley for
helpful discussions on asymmetric hydrogenation, and
the EPSRC Mass Spectrometry Center at Swansea for
mass spectra.
Supporting Information Available: Experimental de-
tails for preparation of compounds 24, 35, 37, 39, 43, 45, 64,
and 67; X-ray crystal structures of compounds 26, 28, and 58;
1
copies of H and 13C NMR spectra of compounds 23, 25-28,
33, 34, 36, 38, 40, 42, 44, 46-63, 65, 66, 70, 71, 74, and 75.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050303H
J. Org. Chem, Vol. 70, No. 15, 2005 5851