Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-01-23
2002-11-26
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S112000
Reexamination Certificate
active
06486324
ABSTRACT:
BACKGROUND OF THE INVENTION
The need for new classes of chemical compounds for use in pharmaceutical and agricultural applications has received much attention. For example, modem synthetic chemical methods for producing regio- and stereochemically defined compounds have made possible drugs with previously unattainable activity and specificity. Nevertheless, many currently-available drugs have been designed to avoid structural complexity, due to the traditionally difficult task of economically developing compounds with dense and diverse functional arrays. Thus, new methods for the production of functionally and stereochemically diverse compounds have the potential to exploit this heretofore underexplored area.
Transition-metal mediated olefin metathesis has been recognized as an effective means for carbon—carbon bond formation (see, e.g., Grubbs, R. H.; Miller, S. J.; Fu, G. C.
Acc. Chem. Res
. (1995) 28:446; Schmalz, H. -G.
Angew. Chem. Int. Ed Engl
. (1995) 34(17):1833). Ring closing-metathesis has been extensively utilized for the synthesis of macrocycles, carbocycles and heterocycles (see (a) Fu, G. C. Grubbs, R. H.
J. Am. Chem. Soc. (
1992) 114:5426. (b) Fu, G. C. Grubbs, R. H. J
Am. Chem. Soc
. (1992) 114:7324. (c) Fu, G. C.; Grubbs, R. H.
J. Am. Chem. Soc
. (1993) 115:3800. (d) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H.
J. Am. Chem. Soc. (
1993) 115:9856. (e) Fujimura, O.; Fu. G. C.; Grubbs, R. H.
J. Org. Chem
. (1994) 59:4029. (f) Kim, S. -H.; Bowden, N.; Grubbs, R. H.
J. Am. Chem. Soc
. (1994) 116:10801. (g) Miller, S. J.; Kim, S. -H.; Chen, Z. -R; Grubbs, R. H.
J. Am. Chem Soc
. (1995) 117:2108. (h) Miller, S. J.; Grubbs, R. H.
J. Am. Chem. Soc
. (1995) 117:5855. (i) Martin, S. F.; Liao, Y.; Rein, T.
Tetrahedron Lett
. (1994) 35:691. (j) Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K.
Tetrahedron Lett
. (1994) 35:3191. (k) Martin, S. F.; Liao, Y.; Chen. H. J.; Patzel, M.; Ramser, M. N.
Tetrahedron Lett
. (1994) 35:6005. (1) Martin, S. F.; Wagman, A. S.
Tetrahedron Lett
. (1995) 36:1169. (m) Houri, A. F.; Xu, Z.; Cogan, D.; Hoveyda, A.
J. Am. Chem. Soc. (
1995) 117:2943. (n) Kim, S. -H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H.
J. Org. Chem. (
1996) 61:1073. (o) Fürstner, A.; Langemann, K.
J. Org. Chem
. (1996) 61:3942. (p) Crimmins, M. T.; King, B. W.
J. Org. Chem
. (1996) 61:4192. (q) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H.
J. Am. Chem. Soc
. (1996) 118:6634). However, the application of intermolecular ring opening cress-metathesis (ROM) for the convergent synthesis of small organic molecules has remained relatively unexplored. Recently, solution-phase ROM of fused and bicyclic olefin systems with aliphatic alkenes yielding cyclopentane and tetrahydrofuran derivatives was reported (see (a) Schneider, M. F.; Blechert, S.
Angew. Chem. Int. Ed. Engl
. (1996) 35: 411. (b) Randall, M. L.; Tallarico, J. A.; Snapper, M. L.
J. Am. Chem. Soc
. (1995) 117:9610. (c) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S.
Angew. Chem. Int. Ed. Engl
. (1997) 36: 257). (d) Snapper et al. J. Am. Chem.
Soc.
119:1478 (1997)). For unsymmetrically substituted substrates only slight regioselectivity was generally observed. In addition, other reaction pathways, such as ring opening metathesis polymerization of the bicyclic or fused olefins competed with the desired cross-metathesis reactions.
Terminal aryl olefins have been shown to participate in selective cross-metathesis reactions utilizing a molybdenum alkylidene catalyst (see Crowe, W. E.; Zhang, Z. J.
J. Am. Chem. Soc
. (1993) 115:10998). The cross-metathesis of norbomene and styrene in the presence of Ru
2
(OAc)
4
and ethyldiazoacetate has also been reported (see Noels, A. F.; Demonceau, A.; Carlier, E.; Hubert A. J.; Márquez-Silva, R. -L.; Sánchez-Delgado, R. A.
J. Chem. Soc., Chem. Commun
. (1988) 783). However, an extensive utilization of aryl olefins in ROM has been absent.
Thus, previously reported ROM methods suffer from drawbacks which can render them undesirable for the synthesis of highly complex chemical compounds.
SUMMARY OF THE INVENTION
The invention relates to ring-opening cross-metathesis reactions, and to substituted cyclic compounds, libraries of compounds, and methods of preparing and using the compounds.
In one aspect, the invention provides a compound represented by the formula (Formula I):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR
5
, and CR′
1
R′
2
Q;
Y is a moiety selected from the group consisting of O, S, NR
5
, and CR
1
R
2
Q;
Q is independently for each occurrence a direct bond or a moiety selected from the group consisting of O, S, NR
5
, and CR
1
R
2
;
R
1
and R
2
are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R
1
and R
2
taken together are O or S;
R′
1
and R′
2
are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R
1
and R
2
taken together are O or S;
R
3
and R
4
are each independently hydrogen, halogen, cyano, nitro, boronato, stannyl, silyl, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, or aminocarbonyloxy;
R
5
is independently for each occurrence hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
or a first occurrence of R
1
or R
2
, taken together with a second occurrence of R
1
or R
2
, and the carbon atoms to which they are attached, form a carbocyclic or heterocyclic ring;
or at least one of R
1
, R
2
, R′
1
, R′
2
, or R
5
is a linker group to a solid support;
or a salt thereof.
In another embodiment, the invention provides compounds represented by the formula (Formula Ia):
in which
W is CH
2
or O;
Z is CHC(O)R
8
or NR
5
;
R
5
is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl or heterocyclyl;
R
6
and R
7
taken together are O, or R
6
is CHC(O)R′
8
and R
7
is hydrogen;
R
8
and R′
8
are each independently hydroxy, alkoxy, aryloxy, or amino; and
one of R
9
and R
10
is hydrogen and the other of R
9
and R
10
is alkyl or aryl;
or a salt thereof.
In another aspect, the invention provides compounds represented by the formula (Formula II):
in which
X is a direct bond or a moiety selected from the group consisting of O, S, NR
5
, and CR′
1
R′
2
Q;
Q is a direct bond or a moiety selected from the group consisting of O, S, NR
5
, and CR
1
R
2
;
R
1
and R
2
are each independently for each occurrence hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R
1
and R
2
taken together are O or S;
R′
1
and R′
2
are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, amino, acylamino, hydroxy, alkoxy, aryloxy, carboxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio; or R
1
and R
2
taken together are O or S;
R
3
and R
4
are each independently hydrogen, halogen, cyano, nitro, boronato,
Cao Jingrong
Cuny Gregory D.
Hauske James R.
Gerstl Robert
Gordon Dana M.
Hoag LLP Foley
Sepracor Inc.
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