Full text of DOI:10.1002/1521-3773(20010601)40:11<2145::AID-ANIE2145>3.0.CO;2-M

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3
3222.32(8) Š3, 1calcd ˆ 1.29 gcm
,
2Vmax ˆ 52.38, MoKa radiation (l ˆ
Rapid Access to Complex Molecular
0.71069 Š), w scans, Tˆ 1158C, of 15644 measured reflections, 10891
were unique, and 8247 were observed (with I > 3.00s(I)), data corrected for
Lorentz and polarization effects, analyzed for agreement and absorption
using XPREP with an empirical absorption correction using SADABS
(Tmax ˆ 0.78, Tmin ˆ 0.71). The structure was solved by direct methods
(SIR92) and developed by least-squares refinement against jF j . No. of
parameters, 739; H atoms were calculated but not refined; R ˆ 0.032, Rw ˆ
0.039, GOF ˆ 1.61.
Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC-153030 (3),
CCDC-153031 (4), and CCDC-153749 ([Cp2Zr(bpy)]). Copies of the data
can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.
cam.ac.uk).
Architectures via o-Azaquinones**
K. C. Nicolaou,* Yong-Li Zhong, Phil S. Baran, and
Kazyuki Sugita
We have recently reported a number of new synthetic
technologies[1] based on the use of the hypervalent iodine
reagent DMP and its precursor IBX (for abbreviations of
reagents, see legends to schemes). Despite their similar
structures and ability to oxidize alcohols to carbonyl com-
pounds, IBX and DMP exhibit distinctly different reactivity
profiles towards a multitude of organic substrates. The facile
generation of o-azaquinone-type structures from anilides and
DMP, and their demonstrated ability to undergo inter- and
intramolecular Diels ± Alder reactions as heterodienes
(Scheme 1, path a)[1a,f] or to undergo further oxidation to p-
quinones[1f] (Scheme 1, path b) prompted us to investigate
Received: January 12, 2001 [Z16411]
[1] D. Parker, Macrocycle Synthesis:
University Press, Oxford, 1996.
A Practical Approach, Oxford
[2] a) Templated Organic Synthesis (Eds.: F. Diederich, P. J. Stang), Wiley-
VCH, Weinheim, 2000; b) M. Nakash, Z. Clyde-Watson, N. Feeder,
J. E. Davies, S. J. Teat, J. K. M. Sanders, J. Am. Chem. Soc. 2000, 122,
5286 ± 5293, and refs therein; c) S. Anderson, H. L. Anderson, J. K. M.
Sanders, Acc. Chem. Res. 1993, 26, 469 ± 475.
[3] a) S. Höger, J. Polym. Sci. Part A 1999, 37, 2685 ± 2698, and refs therein;
b) C. R. Woods, J. P. Bourgeois, P. Seiler, F. Diederich, Angew. Chem.
2000, 112, 3971 ± 3974; Angew. Chem. Int. Ed. 2000, 39, 3813 ± 3816, and
refs therein.
[4] a) J. R. Nitschke, S. Zürcher, T. D. Tilley, J. Am. Chem. Soc. 2000, 122,
10345 ± 10352; b) J. R. Nitschke, T. D. Tilley, J. Org. Chem. 1998, 63,
3673 ± 3676; c) F. Q. Liu, G. Harder, T. D. Tilley, J. Am. Chem. Soc.
1998, 120, 3271 ± 3272; d) S. S. H. Mao, T. D. Tilley, J. Am. Chem. Soc.
1995, 117, 7031 ± 7032; e) S. S. H. Mao, T. D. Tilley, J. Am. Chem. Soc.
1995, 117, 5365 ± 5367.
[5] a) E. Uhlig, Pure Appl. Chem. 1988, 60, 1235 ± 1240; b) L. A. Bishop,
M. A. Turner, L. B. Kool, J. Organomet. Chem. 1998, 553, 53 ± 57; c) R.
Beckhaus, K. H. Thiele, J. Organomet. Chem. 1986, 317, 23 ± 31; d) P. C.
Wailes, H. Weigold, J. Organomet. Chem. 1971, 28, 91 ± 95; e) U.
Thewalt, W. Lasser, J. Organomet. Chem. 1989, 363, C12 ± C14; f) R.
Scheme 1. Reactivity of o-azaquinones as versatile chemical entities.
a) Participation in inter- and intramolecular Diels ± Alder reactions
(ref. [1a,f]), b) oxidation to p-quinones (ref. [1f]), and c) proposed intra-
molecular Diels ± Alder reactions.
them further. Close inspection revealed the potential of
utilizing these quinones to construct rapidly complex mimics
of known natural products and potential protein ligands.
Herein we report a new mode of reactivity of these under-
explored molecular entities in which the double bond
adjacent to the imide moiety (Scheme 1, path c) is richly
exploited by means of cascade reactions. Initiated by DMP,
this pathway proceeds through an intramolecular Diels ±
Alder reaction of the generated o-azaquinone ± diene con-
structs and leads, via ketohydroxyamides, to a multitude of
molecules (e.g. 1, 2a, and 3a, Scheme 2), which resemble the
pseudopterosin natural products.[2] Alternatively, further
Â
Â
Gypes, P. T. Witte, M. Horacek, I. Císarova, K. Mach, J. Organomet.
Chem. 1998, 551, 207 ± 213; g) A. M. McPherson, B. F. Fieselmen, D. L.
Lichtenberger, G. L. McPherson, G. D. Stucky, J. Am. Chem. Soc. 1979,
101, 3425 ± 3430.
[6] U. Rosenthal, A. Ohff, W. Baumann, A. Tillack, H. Görls, V. V.
Burlakov, V. B. Shur, Z. Anorg. Allg. Chem. 1995, 621, 77 ± 83.
[7] A. Almenningen, O. Bastiansen, S. Gundersen, S. Samdal, Acta Chem.
Scand. 1989, 43, 932 ± 937.
[8] J. Sandström, Dynamic NMR Spectroscopy, Academic Press, New
York, 1982, p. 182.
[*] Prof. Dr. K. C. Nicolaou, Dr. Y.-L. Zhong, P. S. Baran, Dr. K. Sugita
Department of Chemistry
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (‡1)858-784-2469
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
E-mail: kcn@scripps.edu
[**] We thank Dr. D. H. Huang, G. Siuzdak, and Dr. R. Chadha for NMR
spectroscopic, mass spectrometric, and X-ray crystallographic assis-
tance, respectively. This work was supported financially by The Skaggs
Institute for Chemical Biology, the National Institutes of Health
(USA), a predoctoral fellowship from the National Science Founda-
tion (P.S.B), and grants from ArrayBiopharma, Pfizer, Glaxo, Merck,
Schering Plough, Hoffmann ± La Roche, Boehringer Ingelheim, Du-
Pont, and Abbott Laboratories.
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To investigate the reactivity of the olefin adjacent to the
imide group in o-azaquinones (Scheme 1, path c), the diene 5
(Scheme 3) was designed and targeted for synthesis. Anilide 5
was prepared efficiently from the commercially available
amino acid 4 in 72% overall yield by means of the sequence
summarized in Scheme 3. Exposure of 5 to DMP (4.0 equiv)/
H2O (2.0 equiv) led to ketohydroxyamide 1 (Scheme 2, Ta-
ble 5) and quinone 8 (Scheme 3, Table 5). The former
presumably arises from the hydration of the initially formed
intramolecular Diels ± Alder product 9. To the best of our
knowledge, the intramolecular Diels ± Alder reaction of o-
azaquinones (acting as a dienophile) has not been explored.
More importantly, ketohydroxyamide 1 closely resembles the
pseudopserin natural products. The quinone 8, which em-
bodies the full carbon skeleton of the naturally occurring
elisabethin A,[3] was undoubtedly formed by means of an
intramolecular Diels ± Alder fusion of the intermediate p-
quinone 7, which was generated from 6 by the oxidative action
of DMP.[1f]
The easy access to ketohydroxyamides such as 1 coupled
with their scarcely investigated chemistry[4] offered us the
opportunity to explore their reactivity and synthetic potential
(Scheme 3). We were able to access compounds 11 (99%
yield) and 12 (99% yield) under reductive conditions
(NaBH4) simply by altering the temperature of the reaction.
On the other hand, compound 1 was cleanly converted into
diphenol 10 by the catalytic action of PPTS (75% yield).
We reasoned that a dicarbonyl compound was a fleeting
intermediate in the conversion of ketohydroxyamide 1 into
diphenol 10 (Scheme 3) and sought to trap this reactive
Scheme 2. ORTEP diagrams of complex, natural product like compounds
obtained from chemical synthesis.[7]
oxidation to p-quinones and intramolecular Diels ± Alder
fusion leads to the full carbon skeleton of the elisabethin type
of natural products.[3]
Scheme 3. Rapid entry into complex pseudopterosin and elisabethin analogues from anilides and DMP. Reagents and conditions: a) LiAlH4 (5.0 equiv),
THF, 0 !258C, 2 h, 96 %; b) 1. Me2CHC(O)Cl (3.0 equiv), Et3N (4.0 equiv), CH2Cl2, 0 !258C, 1 h, 2. NaOH (1n, 3.0 equiv), MeOH, 508C, 2 h, 95% for two
ˆ
steps; c) IBX (2.0 equiv), DMSO, 258C, 6 h, 95%; d) Ph2P(O)CH2CH CH2 (3.0 equiv), nBuLi (2.5 equiv), HMPA (6.0 equiv), THF, 788C, 20 min; then
add aldehyde, 78 !258C, 14 h, 83%; e) DMP (4.0 equiv), H2O (2.0 equiv), CH2Cl2, 258C, 3 h, 28% (1), 25% (8); f) PPTS (0.2 equiv), H2O, 50 8C, 30 min,
75%; g) NaBH4 (5.0 equiv), CeCl3 (10.0 equiv), THF, 258C, 99%; h) NaBH4 (5.0 equiv), CeCl3 (1.1 equiv), THF, 08C, 99%. IBX ˆ o-iodoxybenzoic acid,
DMP ˆ Dess ± Martin periodinane, HMPA ˆ hexamethyl phosphoramide, PPTS ˆ pyridinium 4-toluenesulfonate.
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Table 2. Synthesis of complex polycyclic systems from ketohydroxyamide
species with an array of nucleophiles as a means of expanding
the accessible molecular complexity. Thus, in the presence of
catalytic amounts of PPTS, anilines were treated with com-
pound 1 at 908C to afford polycyclic amines (2a ± d, [Eq. (1)],
1 and C-protected amino acid derivatives.[a]
Protected amino acid
Product
Bis-phenol 10
(yield [%])
(yield [%])
14a (51)
23
14b (49)
14c (80)
20
5
Table 1. Synthesis of polycyclic anilines from ketohydroxyamide 1.[a]
RNH2
Product
Yield [%]
14d (53)
14e (72)
14 f (66)
15
10
10
84
14g (39)
31
71
[a] Reagents and conditions: C-protected amino acid (3.0 equiv), PPTS
(0.2 equiv), NaHCO3 (3.0 equiv), DMF, 908C, 6 ± 24 h.
45[b]
of 16 followed by aromatization may then furnish, via 17,
intermediate 18, which rapidly cyclizes and undergoes oxida-
tion by air to give the observed product 14 (Scheme 4).
89
[a] Reagents and conditions: ArNH2 (5.0 equiv), PPTS (0.2 equiv), toluene,
908C, 3 ± 24 h. [b] Accompanied with 20% of 10.
Table 1, Table 5). As this reaction was highly efficient, we
treated 1 with C-protected amino acids and discovered an
interesting cascade heterocyclic annulation. Under similar
conditions as those used for the amines, ketohydroxyamide 1
was easily converted into the complex polycyclic scaffolds
14a ± g ([Eq. (2)], Table 2). A postulated mechanism for this
cascade reaction begins with the conversion of 1 into the
corresponding diketone 15 after the expulsion of isobutyr-
amide. This is followed either by the formation of diphenol 10
(after aromatization), or by addition of the amino group of the
amino acid derivative to form intermediate 16. Dehydration
Scheme 4. Postulated mechanism for the cascade reactions that lead to
polycyclic systems 14 from ketohydroxyamide 1 and amino acid deriva-
tives.
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Given the importance of N-heterocycles in medicinal
chemistry,[5] we then turned our attention to the synthesis of
pyrazines. The combination of ketohydroxyamide 1 with a
number of 1,2-diamines led smoothly to complex polycyclic
pyrazines ([Eq. (3)], Table 3, 19a ± e) in a highly efficient
Table 4. Synthesis of complex spiroheterocycles from ketohydroxyamide 1
and 1,2-hydroxyamines.[a]
Amino alcohol
Products (Yield)
Table 3. Synthesis of polycyclic pyrazines from ketohydroxyamide 1.[a]
Diamine
Product
Yield [%]
85
73
94
90
[a] Reagents and conditions: Amino alcohol (3.0 equiv), PPTS (0.2 equiv),
toluene, 908C, 6 ± 24 h.
88
Finally, amino acid- and diamine-derived polycycles
([Eq. (2)], Table 2 and [Eq. (3), Table 3, respectively) could
easily be dehydrogenated by heating in air at 1008C in N,N-
dimethylformamide or toluene (48 h), to furnish unusual
polyaromatic systems such as 14d' (95% yield) and 19c'.
In conclusion, we have demonstrated a new and highly
productive mode of reaction of o-azaquinones, which can be
derived from anilides and DMP, and explored its scope and
generality. Through a series of cascade reactions that involve
two previously unexplored chemical species (o-azaquinones
and ketohydroxyamides), a number of complex natural
[a] Reagents and conditions: diamine (5 ± 10 equiv), PPTS (0.2 equiv),
toluene, 908C, 3 ± 8 h.
manner (73 ± 94% yield). Additionally, by enlisting 1,2-amino
alcohols in this reaction we were able to effect a unique
heterocyclic spiroannulation reaction and obtain yet another
series of novel heterocycles ([Eq. (4)]; Table 4, 3a ± d, 20a ±
d; Table 5).
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Table 5. Data for selected compounds: 1, 2a, 3a, and 8.
[1] a) K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, Angew. Chem. 2000, 112,
636 ± 639; Angew. Chem. Int. Ed. 2000, 39, 622 ± 625; b) K. C. Nicolaou,
Y.-L. Zhong, P. S. Baran, Angew. Chem. 2000, 112, 639 ± 642; Angew.
Chem. Int. Ed. 2000, 39, 625 ± 628; c) K. C. Nicolaou, P. S. Baran, Y.-L.
Zhong, J. A. Vega, Angew. Chem. 2000, 112, 2625 ± 2629; Angew. Chem.
Int. Ed. 2000, 39, 2525 ± 2529; d) K. C. Nicolaou, Y.-L. Zhong, P. S.
Baran, J. Am. Chem. Soc. 2000, 122, 7596 ± 7597; e) K. C. Nicolaou, P. S.
Baran, R. Kranich, Y.-L. Zhong, K. Sugita, N. Zou, Angew. Chem. 2001,
113, 208 ± 212; Angew. Chem. Int. Ed. 2001, 40, 202 ± 206; f) K. C.
Nicolaou, K. Sugita, P. S. Baran, Y.-L. Zhong, Angew. Chem. 2001, 113,
213 ± 216; Angew. Chem. Int. Ed. 2001, 40, 207 ± 210; g) K. C. Nicolaou,
P. S. Baran, Z.-L. Zhong, J. Am. Chem. Soc. 2001, 123, 3183 ± 3185.
[2] The pseudopterosins are potent anti-inflammatory agents: S. A. Look,
W. Fenical, G. Matsumoto, J. Clardy, J. Org. Chem. 1986, 51, 5140 ±
5145; W. Fenical, J. Nat. Prod. 1987, 50, 1001 ± 1008; S. A. Look, W.
Fenical, Tetrahedron 1987, 43, 3363 ± 3370. For synthetic studies, see
E. J. Corey, S. E. Lazerwith, J. Am. Chem. Soc. 1998, 120, 12777 ±
12782, and references therein.
1: Colorless needles; m.p. 112 ± 1138C (hexane/Et2O 2/1); Rf ˆ 0.35 (silica
gel, hexane/EtOAc 1:1); IR (film): nÄmax ˆ 3378, 2967, 2931, 2867, 1664,
1
1506, 1463, 1427, 1399, 1239, 1180, 1081, 1055, 754 cm
;
1H NMR
(500 MHz, CDCl3) d ˆ 7.20 (br s, D2O exchangeable, 1H), 5.85 (t, J ˆ
2.2 Hz, 1H), 5.66 ± 5.61 (m, 1H), 5.46 (ddd, J1 ˆ 9.9 Hz, J2 ˆ 4.1 Hz, J3 ˆ
1.2 Hz, 1H), 4.82 (br s, D2O exchangeable, 1H), 3.26 (ddd, J1 ˆ 11.0 Hz,
J2 ˆ 7.0 Hz, J3 ˆ 4.0 Hz, 1H), 3.23 ± 3.18 (m, 1H), 2.73 ± 2.66 (m, 1H), 2.50 ±
2.30 (m, 1H), 2.45 (sep, J ˆ 7.0 Hz, 1H), 2.35 ± 2.36 (m, 1H), 1.95 ± 1.82 (m,
2H), 1.75 ± 1.61 (m, 2H), 1.57 ± 1.48 (m, 1H), 1.44 ± 1.31 (m, 1H), 1.18 (d,
J ˆ 7.0 Hz, 3H), 1.17 (d, J ˆ 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d ˆ
191.8, 179.5, 167.9, 131.2, 126.3, 121.1, 84.0, 40.4, 36.7, 35.9, 34.7 (2 C), 30.5,
23.2, 20.4, 19.7, 19.0; HR-MS (MALDI-FTMS) calcd for C17H23NO3Na
‡
[M‡Na ]: 312.1570, found: 312.1573
2a: Colorless plates; m.p. 206 ± 2088C (hexane/CH2Cl2); Rf ˆ 0.29 (silica
gel, hexane/EtOAc 1/1); IR (film): nÄmax ˆ 3347, 2919, 2847, 1655, 1592,
1
1519, 1477, 1452, 1384, 1332, 1241, 1159, 1123, 1093, 1027, 787 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 6.77 (s, 1H), 6.67 (bd, J ˆ 7.9 Hz, 1H),
6.47 (bd, J ˆ 7.9 Hz, 1H), 6.15 (br s, 1H), 6.09 (br s, D2O exchangeable,
1H), 5.82 ± 5.75 (m, 2H), 5.24 (br s, D2O exchangeable, 1H), 4.70 (br s, D2O
exchangeable, 1H), 3.21 (dt, J1 ˆ 20.2 Hz, J2 ˆ 4.4 Hz, 1H), 3.10 ± 3.00 (m,
1H), 2.96 (dd, J1 ˆ 20.2 Hz, J2 ˆ 8.3 Hz, 1H), 2.87 ± 2.75 (m, 2H), 2.19 ± 2.11
(m, 1H), 2.10 (s, 3H), 2.00 ± 1.82 (m, 2H), 1.51 ± 1.40 (m, 1H); 13C NMR
(100 MHz, CDCl3): d ˆ 152.7, 141.7, 137.1, 135.5, 133.9, 132.4, 132.2, 129.0,
124.6, 123.2, 120.2, 115.3, 114.9, 112.8, 35.2, 30.4, 29.5, 26.6, 22.9, 21.0; HR-
[3] A. D. Rodriguez, E. Gonzalez, S. D. Huang, J. Org. Chem. 1998, 63,
7083 ± 7091.
[4] To the best of our knowledge, there have been no reported synthetic
studies of a,b-unsaturated ketohydroxyamides such as 1, except for a
brief study of the related 3-bromo-2-hydroxy-2-acetamidocyclohexa-
none, see: K. M. Ermolaev, V. I. Maimind, Biol. Aktiv. Soedin. 1968,
142 ± 146.
[5] G. W. Bemis, M. A. Murcko, J. Med. Chem. 1996, 39, 2887.
[6] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, J. Am. Chem. Soc. 2000, 122,
10246 ± 10248.
‡
MS (MALDI-FTMS) calcd for C20H21NO2 308.1645 [M‡H ], found:
308.1646
3a: colorless cubes; m.p. 142 ± 1438C (hexanes/Et2O); Rf ˆ 0.49 (silica gel,
[7] Crystallographic data (excluding structure factors) for the structures 1,
2a, and 3a reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
nos. CCDC-159145 ± 159147. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB21EZ,
UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
hexane/EtOAc 1/1); [a]D ˆ ‡139.78 (0.35, CHCl3); IR (film) nÄmax ˆ 3283,
1
3017, 2929, 2862, 1740, 1678, 1437, 1374, 1239, 1202, 1147, 1086, 786 cm
;
1H NMR (400 MHz, CDCl3): d ˆ 5.88 (t, J ˆ 2.3 Hz, 1H), 5.71 ± 5.63 (m,
1H), 5.46 (dq, J1 ˆ 10.0 Hz, J2 ˆ 2.0 Hz, 1H), 4.11 (br s, D2O exchangeable,
1H), 3.77 (s, 3H), 3.58 (d, J ˆ 8.6 Hz, 1H), 3.23 (br s, D2O exchangeable,
1H), 3.80 (s, 3H), 3.74 ± 3.63 (m, 1H), 3.46 (d, J ˆ 9.0 Hz, 1H), 3.15 ± 3.08
(m, 1H), 2.73 ± 2.64 (m, 1H), 2.47 (bd, J ˆ 15.5 Hz, 1H), 2.38 ± 2.11 (m,
2H), 2.20 ± 2.10 (m, 1H), 1.84 (dt, J ˆ 13.2, 2.2 Hz, 1H), 1.75 ± 1.53 (m, 5H),
1.46 ± 1.36 (m, 1H), 1.35 (d, J ˆ 5.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d ˆ 194.2, 171.3, 167.8, 131.7, 127.6, 123.1, 96.8, 76.9, 66.5, 52.8, 42.6, 36.8,
34.9 (2C), 30.7, 23.4, 20.5, 18.5; HR-MS (MALDI-FTMS) calcd for
‡
C18H23NO4 [M‡H ]: 318.1700, found: 318.1698
8: Yellow oil; Rf ˆ 0.51 (silica gel, hexane/EtOAc 2/1); IR (film): nÄmax
ˆ
Separation of Spliceosome Assembly from
Catalysis with Caged pre-mRNA Substrates**
3330, 3028, 2969, 2932, 2873, 1688, 1668, 1613, 1504, 1467, 1385, 1318, 1157,
1099, 1026, 944, 884 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 7.89 (br s, D2O
exchangeable, 1H), 7.39 (s, 1H), 6.02 (dq, J1 ˆ 9.9 Hz, J2 ˆ 2.0 Hz, 1H), 5.47
(dq, J1 ˆ 9.9 Hz, J2 ˆ 3.2 Hz, 1H), 3.08 (dd, J1 ˆ 9.8 Hz, J2 ˆ 8.3 Hz, 1H),
2.60 ± 2.49 (m, 2H), 2.25 ± 2.13 (m, 3H), 2.00 (dd, J1 ˆ 12.9 Hz, J2 ˆ 8.5 Hz,
1H), 1.88 ± 1.59 (m, 4H), 1.22 (d, J ˆ 6.9 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d ˆ 202.2, 198.3, 177.5, 138.3, 131.0, 124.0, 118.5, 59.7, 53.4, 45.7,
37.1, 35.8, 30.0, 26.0, 21.5, 19.4, 19.3; HR-MS (MALDI-FTMS) calcd. for
Steven G. Chaulk and Andrew M. MacMillan*
Pre-messenger RNAs (pre-mRNAs) in eukaryotes are
characterized by a split-gene structure in which coding exon
sequences are separated by noncoding intron sequences.[1]
The process by which the introns are excised from the pre-
mRNA and the exons are joined together is known as pre-
mRNA splicing and is catalyzed by the spliceosomeÐa
biochemical machine that contains both protein and RNA
components.[2] The spliceosome includes the U1, U2, and U4/
‡
C17H21NO3 [M‡H ]: 288.1594, found: 288.1589
O
N
O
N
N
CO2Et
[*] A. M. MacMillan
Department of Biochemistry
University of Alberta
19c'
14d'
Edmonton, AB T6G 2H7 (Canada)
Fax : (‡1)780-492-3813
product like compounds are now readily accessible. A solid-
phase version that uses ketohydroxyamides in a ªheterocycle
releaseº strategy[6] may expand the scope of the reported
chemistry. Biological screening of the synthesized and pro-
jected compound libraries is expected to facilitate chemical
biology studies and pharmaceutical research.
E-mail: andrew.macmillan@ualberta.ca
S. G. Chaulk
Department of Chemistry
University of Toronto
Toronto, ON M5S 3H6 (Canada)
[**] A.M.M. acknowledges support from the Natural Sciences and
Engineering Research Council of Canada and the Alberta Heritage
Foundation for Medical Research.
Received: February 28, 2001 [Z16702]
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