The synthesis of compounds related to the indole-indoline core of the vinca alkaloids (+)-vinblastine and (+)-vincristine

Article abstract of DOI:10.1016/j.tetlet.2008.05.082

A series of α′-aryl-α′-carbomethoxycycloalk-2-en-1-ones, 16, has been prepared using the Pinhey arylation methodology for introducing the aromatic residue. Subjection of these compounds to Johnson iodination and Pd[0]-catalyzed Ullmann cross-coupling of the resulting α-iodocycloalkenones 11 with 2-iodonitrobenzene (5, X = I) then affords α,α′-diaryl-α′-carbomethoxycycloalk-2-en-1-ones of the general form 10. Reductive cyclization of this last type of compound gives the corresponding indoles 9a-f (n = 1-3), some of which resemble the indole-indoline cores of the clinically important alkaloids (+)-vinblastine (1) and (+)-vincristine (2).

Full text of DOI:10.1016/j.tetlet.2008.05.082

Tetrahedron Letters 49 (2008) 4780–4783
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Tetrahedron Letters
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The synthesis of compounds related to the indole–indoline core of the
vinca alkaloids (+)-vinblastine and (+)-vincristine
*
Michael J. Harvey, Martin G. Banwell , David W. Lupton
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
A series of a0-aryl-a0-carbomethoxycycloalk-2-en-1-ones, 16, has been prepared using the Pinhey
arylation methodology for introducing the aromatic residue. Subjection of these compounds to Johnson
Article history:
Received 23 April 2008
Accepted 19 May 2008
Available online 23 May 2008
iodination and Pd[0]-catalyzed Ullmann cross-coupling of the resulting
a-iodocycloalkenones 11 with
2-iodonitrobenzene (5, X = I) then affords
a
,
a0-diaryl-a0-carbomethoxycycloalk-2-en-1-ones of the
general form 10. Reductive cyclization of this last type of compound gives the corresponding indoles
9a–f (n = 1–3), some of which resemble the indole–indoline cores of the clinically important alkaloids
(+)-vinblastine (1) and (+)-vincristine (2).
Keywords:
Alkaloid
Analogs
Arylation
Indole
Ó 2008 Elsevier Ltd. All rights reserved.
Indoline
Vinblastine
Vincristine
The binary indole–indoline alkaloids (+)-vinblastine (1) and (+)-
vincristine (2) were originally isolated from the Madagascan peri-
winkle Cartharanthus roseus (L.) G. Don. Subsequently, it was
shown that these natural products are generated biosynthetically
by oxidative coupling of the co-occurring and structurally simpler
metabolites catharanthine (3) and (ꢀ)-vindoline (4).1 This coupling
leads, inter alia, to the establishment of the C10–C160-bond within
compounds 1 and 2.
key substructures of compounds 1 and 2.5 Without exception, the
established routes4 to the indole–indoline core within these alka-
loids have mimicked the proposed biosynthetic pathway for link-
ing the progenitors 3 and 4 to one another.6 In particular, these
processes exploit the nucleophilic character at C10 within the
latter compound and the electrophilic properties of C16 that is
revealed upon conversion of compound 3 into an azafulvinium
ion derivative. On this basis, we now outline a distinctly different
The potent tubulin binding properties of (+)-vinblastine (1) and
(+)-vincristine (2) have resulted in their being used clinically for
the treatment of a range of cancers including various lymphomas
and sarcomas, advanced testicular cancer, breast cancer and acute
leukemia.1 However, their application can be severely limited by
damage to the patient’s bone marrow or because of neurotoxico-
logical effects.1 Accordingly, considerable effort has been and con-
tinues to be devoted to the identification of analogs, especially
structurally simpler ones, that might display improved therapeutic
properties.1,2 Such studies are being facilitated by the recent dis-
closure of the X-ray crystal structure of a vinblastine–tubulin com-
plex.3 While the structural complexity of the title compounds has
created significant challenges for the synthetic chemist, various
spectacular achievements have been recorded in the area,4 includ-
ing Fukuyama’s first de novo syntheses of these alkaloids which
were reported in 20024b and 2004.4a Nevertheless, the search con-
tinues for new and efficient methods that allow for the assembly of
OH
N
H
N
16'
OAc
OH
10
N
CO2Me
MeO
CO2Me
N
H
H
R
1 R = Me
2 R = CHO
N
N
OAc
OH
CO2Me
16
10
N
H
21
CO2Me
N
H
MeO
* Corresponding author. Tel.: +61 2 6125 8202; fax: +61 2 6125 8114.
E-mail address: mgb@rsc.anu.edu.au (M. G. Banwell).
3
4
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.082

M. J. Harvey et al. / Tetrahedron Letters 49 (2008) 4780–4783
4781
approach to the carbomethoxymethyl-bridged indole–indoline
Pd[0] cat.
Ullmann
reductive
core structures of the title compounds. A major motivation for pur-
suing the present lines of enquiry was the prospect that biologi-
cally active analogs of compounds 1 and 2 could emerge since
certain diarylmethanes and benzophenones are known to strongly
inhibit tubulin polymerization and thus halt mitosis.7
I
cyclization
rxn with 5
n
n
n
O2N
N
O
O
Ar
Ar
Ar
H
MeO2C
MeO2C
MeO2C
A key element associated with the work described herein was
our development, in 2003, of an effective two-step protocol for
the synthesis of indoles that starts, as shown in Scheme 1, with
the Pd[0]-catalyzed Ullmann cross-coupling of o-halonitroarenes
9
10
11
Figure 1.
(e.g., 5) and
a-iodo- or a
-bromo-enones (e.g., 6) or -enals.8 This
reaction proceeds smoothly using copper in DMSO at temperatures
as low as 35 °C and with Pd[0]-catalyst loadings of as little as a few
mol %. The ensuing cross-coupling product (e.g., 7) is then sub-
jected to reductive cyclization, most often using dihydrogen in
the presence of palladium on carbon, and thereby affording the tar-
O
CO2Me
pyridine, CHCl3
12
O
get indole (e.g., 8). The starting
a-halo-enone or -enal (e.g., 6) is
+
18—40 °C, ca. 16 h
Ar
generally readily prepared by reaction of the corresponding non-
halogented enone or enal with molecular iodine or bromine in
the presence of a nucleophilic species such as pyridine according
to procedures developed by Johnson and others.9
MeO2C
(AcO)3PbAr
Path A
14a,b,f
13b,e
(n = 1)
Bearing such results in mind, we sought methods for the con-
struction of a-iodoenones of the general type 11 (Fig. 1) incorpo-
a Ar = C6H5
LDA,
DMF,
b Ar = o-MeC6H4
rating, at the a0-position, both a carbomethoxy group and various
aryl (Ar) units including indoles. If such systems could be con-
structed it was anticipated that they would participate in Pd[0]-
catalyzed Ullmann cross-coupling reactions8 with o-iodonitroben-
zene (5, X = I) to give products of the general type 10 and these
would, in turn, engage in reductive cyclization reactions to deliver
the target carbomethoxylated diarylmethanes, including bis-
indoles if Ar = indole in structure 9.
TMS-Cl 110 °C, 5 h
c Ar = 3,4,5-(MeO)3C6H2
d Ar = 2,3,4-(MeO)3C6H2
e Ar =
N
Boc
TMSO
Ar
MeO2C
f Ar =
15a,b,f
Clearly, the successful implementation of such an approach
requires, at the outset, establishing serviceable routes to the non-
iodinated equivalents of the enones of the general type 11. In the
event this proved to be a straightforward matter. So, for example,
commercially available methyl 2-oxo-1-phenylcyclopentanecarb-
oxylate (14a) (Scheme 2) was converted, under conventional con-
ditions, into the corresponding silyl enol ether 15a (n = 1) which
was then subjected to a Saegusa-type oxidation10 with Pd(OAc)2
and p-benzoquinone thus affording compound 16a (n = 1) in 70%
yield over these two steps. The synthesis of congener 16b (n = 1)
required initial preparation of methyl 2-oxo-1-(20-methoxy-
phenyl)cyclopentanecarboxylate [14b (n = 1)] which was achieved
by ‘cross-coupling’ methyl 2-oxocyclopentanecarboxylate (12)
with o-methoxyphenyl lead triacetate (13b)11 (Path A, Scheme 2)
in the presence of pyridine using protocols developed by Pinhey
and co-workers.12 Subjection of this ‘cross-coupling’ product to
the same two-step dehydrogenation protocol (Saegusa oxidation)
as detailed immediately above then afforded compound 16b
N
Boc
(n = 1)
MeO
Pd(OAc)2,
p-benzoquinone 18 °C, 2 h
MeCN,
n
O
CO2Me
17
pyridine, CHCl3
n
(n = 2 or 3)
O
Ar
18—40 °C, ca. 16 h
+
MeO2C
(AcO)3PbAr
16
n = 1, 2 or 3
Path B
13a—f
Scheme 2.
Table 1
Details of the synthetic routes, as depicted in Scheme 2, used to obtain compounds
16a–f (n = 1, 2 or 3)
Cpd
Path
Aryl lead
triacetate involved
Intermediate(s) Number Yield/
Pd cat.
X
of steps
step (%)
Cu-bronze
+
Part of A NRa
A
15a (n = 1)
14b (n = 1)
and 15b (n = 1)
14e (n = 1)
and 15e (n = 1)
None
None
None
None
None
2
3
72 and 97
72, 96 and 61
X
16a (n = 1)
16b (n = 1)
DMSO, Δ
O
13b
O2N
O2N
O
16e (n = 1)
A
13e
3
81, 72 and 60
5
6
7
16a (n = 2)
16b (n = 2)
16c (n = 2)
16d (n = 2)
16e (n = 2)
16f (n = 2)
16a (n = 3)
16b (n = 3)
16e (n = 3)
B
B
B
B
B
B
B
B
B
13a
13b
13c
13d
13e
13f
13a
13b
13e
1
1
1
1
1
1
1
1
1
79
76
84
75
71
82
63
70
71
H2,
Pd on C
X = Br or I
None
None
None
None
N
H
8
a
NR = not required.
Scheme 1.

4782
M. J. Harvey et al. / Tetrahedron Letters 49 (2008) 4780–4783
Table 2
I2, pyridine,
CCl4
Details of the conversions depicted in Scheme 3
n
11
Starting
material
Iodination
product
Yield
(%)
Ullmann
product
Yield
(%)
Indolic
product
Yield
(%)
O
0—18 °C,
ca. 16 h
Ar
MeO2C
16a (n = 1)
16b (n = 1)
16e (n = 1)
16a (n = 2)
16b (n = 2)
16c (n = 2)
16d (n = 2)
16e (n = 2)
16f (n = 2)
16a (n = 3)
16b (n = 3)
16e (n = 3)
11a (n = 1)
11b (n = 1)
11e (n = 1)
11a (n = 2)
11b (n = 2)
11c (n = 2)
11d (n = 2)
11e (n = 2)
11f (n = 2)
11a (n = 3)
11b (n = 3)
11e (n = 3)
60
96
93
60
60
98
75
73
70
58
68
61
10a (n = 1)
10b (n = 1)
10e (n = 1)
10a (n = 2)
10b (n = 2)
10c (n = 2)
10d (n = 2)
10e (n = 2)
10f (n = 2)
10a (n = 3)
10b (n = 3)
10e (n = 3)
60
58
86
58
56
56
56
62
91
68
56
56
9a (n = 1)
9b (n = 1)
9e (n = 1)
9a (n = 2)
9b (n = 2)
9c (n = 2)
9d (n = 2)
9e (n = 2)
9f (n = 2)
9a (n = 3)
9b (n = 3)
9e (n = 3)
97
98
87
95
95
95
67
87
75
71
95
88
5 (X = I),
16
Cu, Pd[0] cat.,
DMSO,
ca. 70 °C, 2 h
H2,
10% Pd on C
10
n
MeOH,
N
18 °C, 7 h
Ar
H
MeO2C
9
Scheme 3.
enolate anion trapped with Mander’s reagent (methyl cyanofor-
mate)13 to give the previously unreported compound 17 (n = 3)
in 74% yield. Ester 17 (n = 3) was then ‘cross-coupled’ with the rel-
evant aryl lead triacetate 13a, 13b and 13c to give products 16a
(n = 3) (63%), 16b (n = 3) (70%) and 16e (n = 3) (71%), respectively.
Details of the outcomes of the above-mentioned reaction se-
quences are presented in Table 1.
(n = 1) in 42% yield over the three steps involved. In a related man-
ner, methyl 2-oxocyclopentanecarboxylate (12) was cross-coupled
with the readily prepared N-tert-butoxycarbonyl-5-indole lead tri-
acetate (13e)11 in the presence of pyridine to give, after silyl enol
ether formation and Saegusa-type oxidation, compound 16e
(n = 1). In the six-membered ring series, each of the required reac-
tion sequences started with commercially available enone 17
(n = 2) that was reacted, via Path B, with the relevant aryl lead tri-
acetate 13a–e to give products 16a (n = 2) (79%), 16b (n = 2) (76%),
16c (n = 2) (84%), 16d (n = 2) (75%), 16e (n = 2) (71%) and 16f (n = 2)
(82%), respectively. In the seven-membered ring series, the reac-
tion sequences began with commercially available 2-cyclohep-
ten-1-one which was deprotonated with LDA and the resulting
When each of the 12 compounds represented by the generic
structure 16 was subjected to the Johnson-type
a-iodination condi-
tions9 the corresponding
a-iodoenones 11 were obtained (Scheme
3) in yields (Table 2) ranging from a low of 58% [for product 11a
(n = 3)] to a high of 98% [for product 11c (n = 2)]. Most significantly,
the iodination protocol works surprisingly effectively for systems
incorporating the N-Boc-protected indoles [i.e., compounds 16e
(n = 2), 16f (n = 2) and 16e (n = 3)] given that such electron-rich
OMe
N
N
N
N
H
H
H
H
MeO2C
MeO2C
MeO2C
MeO2C
N
Boc
9a (n = 1)
9b (
n
= 1)
9e (n
= 1)
9a (n = 2)
N
N
N
N
OMe
OMe
OMe
OMe
H
H
H
MeO2C
H
MeO2C
MeO2C
MeO
= 2)
MeO2C
OMe
OMe
N
Boc
9b (n = 2)
9c (
n
9d (n = 2)
9e (n = 2)
N
N
N
N
OMe
H
H
H
H
MeO2C
MeO2C
MeO2C
MeO2C
MeO
N
Boc
N
Boc
9f (n = 2)
9a (
n
= 3)
9b (n = 3)
9e (n = 3)
Figure 2.

M. J. Harvey et al. / Tetrahedron Letters 49 (2008) 4780–4783
4783
4. For useful points-of-entry into the literature on studies directed towards the
total synthesis of the title alkaloids see: (a) Kuboyama, T.; Yokoshima, S.;
Tokuyama, H.; Fukuyama, T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11966; (b)
Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.;
Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137; (c) Magnus, P.; Mendoza, J. S.;
Stamford, A.; Ladlow, M.; Willis, P. J. Am. Chem. Soc. 1992, 114, 10232; (d)
Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J. Org. Chem. 1991, 56, 513; (e)
Kutney, J. P.; Choi, L. S. L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C. A.
Heterocycles 1988, 27, 1845; (f) Mangeney, P.; Andriamialisoa, R. Z.; Langlois,
N.; Langlois, Y.; Potier, P. J. Am. Chem. Soc. 1979, 101, 2243.
5. See, for example: (a) Johnson, P. D.; Sohn, J.-H.; Rawal, V. H. J. Org. Chem. 2006,
71, 7899; (b) Ishikawa, H.; Elliot, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am.
Chem. Soc. 2006, 128, 10596; (c) Fekete, M.; Kolonits, P.; Novak, L. Heterocycles
2005, 65, 165; (d) Fahy, J.; Thillaye du Boullay, V.; Bigg, D. C. H. Bioorg. Med.
Chem. Lett. 2002, 12, 505.
and acid-sensitive moieties might be considered especially prone to
electrophilic and protic attack. Equally gratifying was the observa-
tion that each of the 12
a-iodoenones 11a–f (n = 1–3) readily
engaged in a Pd[0]-catalyzed Ullmann cross-coupling reaction with
o-iodonitrobenzene (5, X = I) to give the anticipated products 10a–f
(n = 1–3) in yields ranging from a low of 56% [for products such as
10c (n = 2)] to a high of 91% [for product 10f (n = 2)].
The reductive cyclizations of compounds of the general form 10
proceeded relatively smoothly when the relevant substrates were
exposed to dihydrogen in the presence of 10% Pd on C. In this man-
ner, the target compounds 9 were produced in yields ranging from
67% to 98%. The full range of analogs of the indole–indoline core of
the natural products 1 and 2 generated using the present protocols
is shown in Figure 2. The spectral data derived from these com-
pounds were in complete accord with the assigned structures.14
The results described serve to highlight the utility of the Pinhey
arylation and Pd[0]-catalyzed Ullmann cross-coupling reactions in
the synthesis of rather densely functionalized indoles, a situation
that augers well for the application of such protocols in the rapid
construction of a wide range of analogs of the title natural prod-
ucts. In this connection, it was also interesting to observe that
reductive cyclization of the Ullmann cross-coupling product 10b
6. Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008, 130, 420; and
references cited therein.
7. See, for example: (a) Hu, L.; Jiang, J.-d.; Qu, J.; Li, Y.; Jin, J.; Li, Z.-r.; Boykin, D. W.
Bioorg. Med. Chem. Lett. 2007, 17, 3613; (b) Álvarez, C.; Álvarez, R.; Corchete, P.;
Pérez-Melero, C.; Peláez, R.; Medarde, M. Bioorg. Med. Chem. Lett. 2007, 17,
3417; (c) Romagnoli, R.; Baraldi, P. G.; Jung, M. K.; Iaconinoto, M. A.; Carrion, M.
D.; Remusat, V.; Preti, D.; Tabrizi, M. A.; Francesca, F.; De Clercq, E.; Balzarini, J.;
Hamel, E. Bioorg. Med. Chem. Lett. 2005, 15, 4048; (d) Pettit, G. R.; Toki, B.;
Herald, D. L.; Verdier-Pinard, P.; Boyd, M. R.; Hamel, E.; Pettit, R. K. J. Med. Chem.
1998, 41, 1688; (e) Getahun, Z.; Jurd, L.; Chu, P. S.; Lin, C. M.; Hamel, E. J. Med.
Chem. 1992, 35, 1058.
8. Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org. Lett. 2003, 5, 2497;
This type of protocol has also been extended to the synthesis of quinolines and
related systems: Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O.
Org. Lett. 2004, 6, 2741; Some, S.; Ray, J. K.; Banwell, M. G.; Jones, M. T.
Tetrahedron Lett. 2007, 48, 3609.
15
(n = 3) proceeded smoothly using TiCl3 (rather than dihydrogen
in the presence of 10% palladium on carbon) to give the novel
indole 17 in 68% yield. While the mechanism of this conversion
remains uncertain, it should provide a means for the construction
of a series of new bis-indoles related to the core of (+)-vinblastine
(1) and (+)-vincristine (2). Work directed toward such ends is now
underway in our laboratories and results will be reported in due
course.
9. (a) Krafft, M. E.; Cran, J. W. Synlett 2005, 1263; (b) Ramanarayanan, G. V.;
Shukla, V. G.; Akamanchi, K. G. Synlett 2002, 2059; (c) Posner, G. H.; Afarinkia,
K.; Dai, H. Org. Synth. 1996, 73, 231; (d) Smith, A. B., III; Braca, S. J.; Pilla, N. N.;
Guaciaro, M. A. J. Org. Chem. 1982, 47, 1855; (e) Johnson, C. R.; Adams, J. P.;
´
Braun, M. P.; Senanayake, C. B. W.; Wovkulich, P. M.; Uskokovic, M. R.
Tetrahedron Lett. 1992, 33, 917.
10. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
11. This and the other aryl lead compounds reported here, viz. compounds 13a–e,
were prepared using protocols defined by Pinhey and co-workers: Kozyrod, R.
P.; Morgan, J.; Pinhey, J. T. Aust. J. Chem. 1985, 38, 1147. Details will be provided
in a forthcoming full paper.
12. Pinhey, J. T. Pure Appl. Chem. 1996, 68, 819.
13. Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
14. Spectral data for 9e (n = 1), 9e (n = 2) and 9f (n = 2):
CO2Me
O
O2N
O
Compound 9e (n = 1): 1H NMR (300 MHz, CDCl3) d 8.28 (s, 1H), 8.02 (d,
J = 8.0 Hz, 1H), 7.58–7.54 (complex m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.24–7.09
(complex m, 4H), 6.46 (d, J = 3.7 Hz, 1H), 3.77 (s, 3H), 3.55 (m, 1H), 2.91–2.82
(complex m, 2H), 2.70–2.64 (complex m, 1H), 1.65 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 173.8, 149.6, 141.2, 137.4, 134.1, 130.8, 127.5, 126.5, 124.2, 122.1,
121.8, 119.8, 119.3, 118.6, 118.1, 115.4, 111.9, 107.3, 83.8, 59.5, 52.7, 44.0,
28.1, 22.8; mmax (neat)/cmꢀ1 (NaCl) 3385, 2950, 1733, 1467, 1371, 1257, 731;
MeO2C
OMe
MeO
N
H
10b (n = 3)
Acknowledgments
17
MS m/z (EI) 430 (M+, 16%), 371 (17), 315 (65), 84 (100); HRMS found: M+Å
,
430.1892. C26H26N2O4 requires M+Å, 430.1893.
Compound 9e (n = 2): 1H NMR (300 MHz, CDCl3) d 8.51 (s, 1H), 8.03 (d,
J = 8.9 Hz, 1H), 7.60–7.58 (complex m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.25–7.12
(complex m, 3H), 7.01 (dd, J = 8.9 and 1.8 Hz, 1H), 6.45 (d, J = 3.6 Hz, 1H), 3.83
(s, 3H), 2.81–2.69 (complex m, 4H), 2.21–2.05 (complex m, 1H), 1.86–1.68
(complex m, 1H), 1.65 (s, 9H); 13C NMR (75 MHz, CDCl3) d 174.4, 149.7, 138.5,
135.9, 131.3, 130.5, 129.0, 127.0, 126.5, 122.8, 122.1, 119.4, 119.2, 118.6, 115.0,
114.1, 111.0, 107.4, 83.8, 53.3, 52.7, 37.0, 28.1, 21.0, 19.7; mmax (neat)/cmꢀ1
(NaCl) 3403, 2935, 1733, 1464, 1371, 1255, 1143, 731; MS m/z (EI) 444 (M+,
88%), 385 (42), 329 (100); HRMS found: M+Å, 444.2048. C27H28N2O4 requires
M+Å, 444.2049.
We thank the Institute of Advanced Studies and the Australian
Research Council for financial support.
References and notes
Compound 9f (n = 2): 1H NMR (300 MHz, CDCl3) d 8.27 (s, 1H), 7.80 (s, 1H),
7.60 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.24–
7.13 (complex m, 2H), 6.67 (s, 1H), 6.31 (d, J = 3.7 Hz, 1H), 3.93 (s, 3H), 3.79
(s, 3H), 2.80–2.76 (complex m, 3H), 2.25 (complex m, 2H), 1.87 (complex m,
1H), 1.67 (s, 9H); 13C NMR (75 MHz, CDCl3) d 175.0, 154.4, 149.8, 135.8,
130.7, 128.9, 127.3, 124.5, 123.3, 122.0, 121.8, 119.2, 118.5, 118.2, 114.3,
111.0, 107.4, 98.3, 83.5, 55.7, 52.4, 51.0, 32.1, 28.1, 21.0, 19.3; mmax (neat)/
cmꢀ1 3400, 2945, 1733, 1623, 1535, 1373; MS m/z (EI) 474 (M+, 91%), 415
(53), 374 (100), 359 (100); HRMS found: M+Å, 474.2145. C28H30N2O5 requires
M+Å, 474.2155.
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