Enantioselective alkylation of tricyclic compounds

Details Enantioselective alkylation of tricyclic compounds Enantioselective alkylation of tricyclic compounds

2000-09-21

2001-09-11

Huang, Evelyn Mei (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06288233

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention provides a process for preparing intermediates useful in the preparation of tricyclic compounds known as inhibitors of farnesyl protein transferase. In particular, the compounds prepared by the process of this invention arc useful as chiral intermediates in the preparation of chiral compounds that are FPT inhibitors such as those disclosed in PCT Publication No. WO97/23478, published Jul. 3, 1997.
Over the last few decades a number of enantiosclective carbon-carbon bond forming reactions have been developed that fall into two distinct groups - those that involve alkylations of a covalently bonded chiral precursor and those that use a non-covalently bonded chiral auxiliary. Examples of the former include Evan's oxazolidinone system, Meyer's oxazoline system and Enders' RAMP/SAMP systems. (See Evans, D. A., et al.,
Encyclopedia of Reagents for Organic Synthesis
; Wiley: Chichester, 1995, Vol. 1, p. 345; Gant, T. G.; Meyers, A. I.
Tetrahedron
1994, 50, 2297; and Enders, D. et al,
Liebigs Ann.
1995, 1127.) Examples of the latter, include alkylations of stabilized anions of ketones, imines, amino acid derived Schiff bases, N-alkyl carbamates and O-alkyl carbamates that are stabilized using non-covalently bonded chiral alkaloid bases or chiral lithium bases. (See, e.g., Hughes, D. L., et al,
J. Org. Chem.
1987, 52, 4745.; Sato, D. et al,
Tetrahedron
1997, 53, 7191; Koga, K.
Pure & Appl. Chem.
1994, 66, 1487; Tomioka, K. et al,
Chem. Pharm. Bull.
1989, 37, 1120; O'Donnell, M. J., et al,
Tetrahedron
1994, 50, 4507; Weisenburger, G. A. et al,
J. Am. Chem. Soc.
1996, 118, 12218; Gallagher, D. J. et al,
J. Am. Chem. Soc.
1996, 118, 11391; and Hoppe, D. et al,
Pure & Appl. Chem.
1996, 68, 613.) These reactions are similar in that the anion that is generated and alkylated has an adjacent carbonyl-type stabilizing group such as a ketone, imine or hydrazone. There have been few examples of a non-carbonyl type group stabilized anion. Gawley reported that an &agr;-aminoorganolithium anion generated from a chiral stannane precursor is configurationally stable, and although alkylation with primary alkyl halides affords products with excellent enantioselectivity in certain cases, the fact that the chiral stannane precursor must be resolved detracts from this procedure. (See Gawley, R. E., et al,
J. Org. Chem.
1995, 60, 5763.) Noyori et al. reported that silylation and carboxylation of the anion of the ethyl benzene/(−)-sparteine complex proceeds in ≈30% enantiomeric excess (e.e.) with low yields and significant amounts of reaction on the aromatic nucleus was also observed. (See Nozaki, H.; Aratani, T.; Toraya, T.; Noyori, R.
Tetrahedron
1971, 27, 905.) White et al. reported that methylation of a 2-methylpyridine/(−)-sparteine complex proceeds in 20% e.e. and 64% yield. (See Papasergio, R. I.; Skelton, B. W.; Twiss, P.; White, A. H.; Raston, C. L.
J. Chem. Soc. Dalton Trans.
1990, 1161.) Hoppe et al. reported that acylation of an indenine system (allylic anion) proceeded in >95% ee with 52-79% yields. (See Hoppe, I. et al,
Agnew. Chem. Int. Ed. Engl.
1995, 34, 2158.)
We have now discovered a process for the enantioselective alkylation of non-ketone/amide/carbamate/imine benzyl type methylene compounds utilizing a chiral amino alcohol as a chiral ligand that results in high e.e. and high yield of intermediates useful for preparing the chiral FPT inhibitors discussed above.
SUMMARY OF THE INVENTION
This invention provides a process for preparing a compound of the formula:
wherein X
1
, X
2
, X
3
, X
4
, and X
5
are independently selected from the group consisting of H, halo, alkyl, alkoxy, aryl, and aryloxy, and R is a protecting group, said process comprising:
treating a compound having the formula
wherein X
1
, X
2
, X
3
, X
4
, and X
5
are as defined above, with the following, in any sequence:
(a) a non-nucleophilic strong base;
(b) a chiral amino alcohol; and
(c) a compound having the formula
wherein L is a leaving group and R is as defined above.
Also claimed herein is a process for preparing a compound having the formula
wherein X
1
, X
2
, X
3
, X
4
, and X
5
are independently selected from the group consisting of H, halo, alkyl, alkoxy, aryl, and aryloxy, and R is a protecting group, said process comprising:
(a) reacting a compound having the formula
wherein X
1
, X
2
, X
3
, X
4
, and X
5
are as defined above, with a non-nucleophilic strong base in the presence of a chiral amino alcohol to form a complex; and
(b) reacting the complex formed in step (a) with a compound having the formula
wherein L is a leaving group and R is as defined above.
DETAILED DESCRIPTION
As used herein, the term “alkyl” means straight or branched hydrocarbon chain groups having 1 to 6 carbon atoms.
“Halo” means fluorine, chlorine, bromine or iodine radicals.
“Alkoxy” refers to groups having the formula —OR, wherein R is alkyl.
“Aryl” refers to a carbocyclic group having at least one aromatic ring.
“Aryloxy” refers to a group having the formula —OR, wherein R is aryl.
“e.e.” represents the percentage obtained by subtracting the amount of the S-enantiomer from the R-enantiomer, and dividing by the sum of the amount of R-enantiomer and S-enantiomer:
e.e. %=100×(R-enantiomer−S-enantiomer)/(R-enantiomer+S-enantiomer).
The following abbreviations are used herein: “Boc” refers to tert-butoxy carbonyl; “LDA” refers to lithium diisopropylamide; “THF” refers to tetrahydrofuran; and “Ph” refers to a phenyl group.
The compounds prepared by the process disclosed above are useful as intermediates for preparing chiral compounds that are FPT inhibitors, such as those disclosed in PCT Publication No. WO97/23478, published Jul. 3, 1997. Such compounds may be prepared by deprotecting the compound of formula (I), i.e., removing the R group by treatment with acid (e.g., H
2
SO
4
) to form the free amine, or optionally reacting the free amine with a suitable acid (e.g., N-acetyl-L-phenylalanine) to form a stable salt, and acylating the free base or the salt with the desired acyl group to form the desired FPT inhibitor. The compounds prepared by the process of the present invention are particularly useful for preparing the following compound:
Preferably, X
1
, X
2
, X
3
, X
4
, and X
5
are selected from H or halo. More preferably, X
2
and X
4
are H, and X
1
, X
3
and X
5
are halo. Halo is most preferably Cl or Br. Most preferably, X
1
is Br, X
2
is H, X
3
is Cl, X
4
is H, and X
5
is Br.
Non-limiting examples of leaving groups, L, include sulfonates (e.g., mesylate, tosylate, closylate (para-chloro tosylate), and brosylate (para-bromo tosylate)), phosphates (e.g., alkyl phosphates, such as diethyl phosphate), benzoates, and halo. Preferably, the leaving group, L, is a sulfonate, more preferably, mesylate or tosylate.
The protecting group may be any group suitable for protecting the nitrogen atom of the piperidine ring. Non-limiting examples of protecting groups include sulfonatcs, and acyl groups, e.g., tert-butoxycarbonyl (BOC),
Preferably, the protecting group is an acyl group, more preferably, tert-butoxycarbonyl
Examples of suitable non-nucleophilic strong bases include, but are not limited to, lithium duisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidine, 1-lithium 4-methylpiperazide, 1,4-dilithium piperazide, lithium bis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, isopropyl magnesium chloride, phenyl magnesium chloride, lithium diethylamide, and potassium tert-butoxide. Preferably, the non-nucleophilic strong base is LDA.
Non-limiting examples of chiral amino alcohols include quinine and quinine derivatives, 1,2- and 1,3-aminoalcohol derivatives, and quinoline alcohol derivatives.
Preferably, the chiral amino alcohol is a compound
(i) having the formula
wherein the dotted line represents an optional second bond and wherein R
1
is selected from alkoxy, aryloxy, or NR
A
R
B
, wherein R
A
and R
B
are selected from alkyl or

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