Asymmetric synthesis of kavalactones

Details Asymmetric synthesis of kavalactones Asymmetric synthesis of kavalactones

2001-08-06

2004-01-13

Richter, Johann (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C560S106000, C560S178000, C568S008000, C568S017000, C568S445000

Reexamination Certificate

active

06677462

ABSTRACT:

BACKGROUND
It is believed that the use of kava (Piper methysticum Forst.) predates written history. The origination of the plant is attributed to the New Guinea/Indonesia area and it is believed that Polynesian explorers were responsible for its spread from island to island. Oceania (i.e., the Pacific island communities of Micronesia, Melanesia and Polynesia) is an area where islanders have been known for centuries to consume a drink, also called kava and derived from the root of kava, in ceremonies and celebrations due to its reported calming effect and ability to promote sociability. The root and the drink were apparently first described in the Western world by Captain James Cook as a result of his exploration of the South Seas in 1768. Many myths and anecdotal stories surround the use of kava, and these vary from culture to culture.
In recent years, the Kava plant has been scientifically scrutinized, with certain of its active constituents being identified. The psychoactive ingredients of the Kava root have been identified as a class of structurally related chemical compounds known as kavalactones, including compounds such as compounds 1 and 2 (below). At least sixteen kavalactones have been identified to date, including kawain, dihydrokawain (a.k.a. marindinin), methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin. These compounds are neutral, nitrogen-poor compounds that may be specifically referred to as substituted alpha.-pyrones. The lactone ring is substituted by a methoxy group in the C-4 position, and the compounds vary in their substitution by either a styryl residue (e.g., yangonin, desmethy-oxyyangonin, kawain, and methysticin) or by a phenylethyl residue (e.g., dihydrokawain and dihydromethysticin) at the C-6 position.
The absolute stereochemistry of the lactones was established by chemical degradation to (+)-malic acid. Judging from the positive cotton effect of the lactones in circular dichroism, the chiral center of C-6 of the lactones was assigned to be the R configuration.
Although the synthesis of racemic kawain or dihydrokawain was reported in the 1970's (See, T. Izawa and T. Mukaiyama,
Chemistry Letters
1975, 161-164; Z. H. Israili and E. E. Smissman,
J. Org. Chem.,
1976, 41(26), 4070-4073), the asymmetric synthesis of (S)-(+)-dihydrokawain was not realized until 1996 (See, C. Spino, N. Mayes and H. Desfosses,
Tetrahedron Letters,
1996, 37(36), 6503-6506). A key intermediate for the asymmetric kavalactone synthesis is (S)-(+)-3-hydroxy-5-aryl-pentanoic acid methyl ester, Compound 3. In order to procure this intermediate in non-racemic form, an enantioselective method of some type (e.g., chiral separation, purification, derivatization, or asymmetric reduction) is necessary. In their synthesis, Spino et al. employed the reduction conditions of Noyori (see, R. Noyori,
Science
1990, 248, 1194), however, very harsh conditions are required (e.g., 100° C., 10-100 atm) and it was reported that without the addition of HCl, no product was detected. In order to explore the potential medicinal application of the optically pure kavalactones and to conduct structure-activity relationship (SAR) studies of their analogs, a more practical and facile approach to the asymmetric synthesis of such chiral lactones is desirable.
SUMMARY
This invention relates to preparation of enantio-enriched compounds, and more particularly to enantio-enriched kavalactone compounds and derivatives thereof. The methods provide compounds that are useful as reagents, or building blocks, in the construct of other enantio-enriched compounds. The methods delineated herein demonstrate for the first time the application of chiral organoborane reducing agents to asymmetric reduction of &bgr;-keto ester compounds, which are important intermediates that can be further elaborated to kavalactones of increased optical purity.
In one embodiment, the invention relates to a method of making a compound comprising reacting a compound of formula (II),
wherein
R
1
is independently alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, or heteroarylalkyl;
R
2
is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR
6
R
6
, C(O)NR
6
R
6
, OR
6
, SR
6
, C(O)OR
6
, C(O)R
6
, S(O)
n
R
6
, NO
2
, CN, halo, NR
6
C(O)R
6
, or NR
6
S(O)
n
R
6
;
Each R
6
is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
n is 1 or 2;
with a chiral borane reducing agent to give a compound of formula (I):
wherein R
1
and R
2
are as defined above. The reaction can be performed at room temperature.
In another embodiment, the method is any method delineated herein further comprising converting a compound of formula (I) to a compound of formula (III):
wherein
R
1
is independently alkyl, arylalkyl, or heteroarylalkyl;
R
2
is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR
6
R
6
, C(O)NR
6
R
6
, OR
6
, SR
6
, C(O)OR
6
, C(O)R
6
, S(O)
n
R
6
, NO
2
, CN, halo, NR
6
C(O)R
6
, or NR
6
S(O)
n
R
6
;
Each R
6
is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
n is 1 or 2.
In another embodiment, the method is any method delineated herein wherein the compound of formula (I) is reacted with a nucleophile, or salt thereof, of formula (IV):
wherein
R
1
is independently alkyl, arylalkyl, or heteroarylalkyl;
to give the compound of formula (III). In one aspect the nucleophile of formula (IV) is the lithium salt of the t-butylacetate anion.
In another embodiment, the method is any method delineated herein further comprising converting a compound of formula (I) to a compound of formula (V):
wherein
R
2
is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR
6
R
6
, C(O)NR
6
R
6
, OR
6
, SR
6
, C(O)OR
6
, C(O)R
6
, S(O)
n
R
6
, NO
2
, CN, halo, NR
6
C(O)R
6
, or NR
6
S(O)
n
R
6
;
Each R
6
is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile; and
n is 1 or 2.
The method of converting includes reacting with an acid catalyst, such as an inorganic acid (e.g., HCl, H
2
SO
4
) or an organic acid (e.g., an acetic acid or a sulfonic acid (e.g., trifluoroacetic acid, p-toluenesulfonic acid, or camphorsulfonic acid)).
In another embodiment, the method is any method delineated herein further comprising converting a compound of formula (I) to a compound of formula (VI) (alternatively, including via a compound of formula (V)):
wherein
R
2
is independently alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR
6
R
6
, C(O)NR
6
R
6
, OR
6
, SR
6
, C(O)OR
6
, C(O)R
6
, S(O)nR
6
, NO
2
, CN, halo, NR
6
C(O)R
6
, or NR
6
S(O)
n
R
6
;
n is 1 or 2;
R
3
is independently H, alkyl, arylalkyl, heteroarylalkyl, each optionally substituted with 1 to 4 independent NR
6
R
6
, C(O)NR
6
R
6
, OR
6
, SR
6
, C(O)OR
6
, C(O)R
6
, S(O)
n
R
6
, NO
2
, CN, halo, NR
6
C(O)R
6
, or NR
6
S(O)
n
R
6
; and
Each R
6
is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, arylalkyl, or heteroarylalkyl, each optionally substituted with 1-4 independent substituents selected from the group hydroxy, mercapto, amino, alkoxy, carboxylic acid, ester, amido, N-alkyl-substitited amido, halo, nitro, and nitrile. In oth

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