Process for preparing saponin compounds

Details Process for preparing saponin compounds Process for preparing saponin compounds

2002-08-06

2004-06-22

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C552S502000

Reexamination Certificate

active

06753414

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides processes for the preparation of saponin compounds, and more specifically, provides processes for the preparation of compounds of formula (1) and to intermediates leading thereto as described herein. The compounds of formula (1) are related to naturally occurring saponins such as OSW-1 and analogues thereof. The compounds are useful as anti-cancer drugs.
BACKGROUND OF THE INVENTION
Saponins are a large family of naturally occurring glycoconjugate compounds with considerable structural diversity. Saponin OSW-1, 3&bgr;,16&bgr;,trihydroxycholest-5-en-22-one 16-O-{O-(2-O-(4-methoxybenzoyl)-&bgr;-D-xylopryanosyl)-(1-3)-2-O-acetyl-&agr;-arabinopryanoside, is the major component of a small group of cholestane saponins isolated by Sashida et al. (
Phytochemistry,
31, 3936, 1992.) from the bulbs of a species of the lily family. OSW-1 is highly toxic against a broad spectrum of malignant tumor cells (Bioorg., Med. Chem. Lett., 7, 633, 1997.) with little toxicity to normal cells in vitro.
Saponins are glycosidic natural plant products, composed of a ring structure (the aglycone) to which is attached one or more sugar chains. The saponins are grouped together based on several common properties. In particular, saponins are surfactants which display hemolytic activity and form complexes with cholesterol. Although saponins share these properties, they are structurally diverse. In particular, the aglycone can be a steroid, triterpenoid or a steroidal alkaloid and the number of sugars attached to the glycosidic bonds vary greatly.
Saponins have been employed as absorption adjuvants in pharmaceutical compositions. For example, U.S. Pat. No. 4,501,734, describes the use of a triterpenoid saponin extract from
Sapindus mukurossi Gaertn.
to increase absorption of a coadministered beta-lactam antibiotic. Saponins have also been used as immunological adjuvants in vaccine compositions against a variety of diseases including protozoal infections and foot and mouth disease. The saponins typically used as immunological adjuvants are triterpene glycosides extracted from the South American tree, Quillaja saponaria, termed Quil A., see for example, U.S. Pat. No. 5,057,540.
Saponins have also been used in pharmaceutical compositions for a variety of other purposes. For example, U.S. Pat. No. 5,118,671, describes the use of aescin, a saponin obtained from
Aesculus hippocastanum
seeds, in pharmaceutical and cosmetic compositions as an anti-inflammatory. Similarly, U.S. Pat. No. 5,147,859, discusses the use of
Glyccyrrhiza glabra
saponin/phospholipid complexes as anti-inflammatory and anti-ulcer agents and U.S. Pat. No. 5,166,139, describes the use of complexes of saponins and aglycons, obtained from
Centella asiatica
and Terminalia sp., with phospholipids in pharmaceutical compositions. International Publication No. WO 91/04052, published 4 Apr. 1991, discusses the use of solid Quillaja saponaria saponin/GnRH vaccine compositions for immunocastration and immunospaying.
Methods for the synthesis of saponins, and OSW-1 particularly, have received considerable attention recently. Fuchs et al., reported the synthesis of the aglycone portion of OSW-1 (
Tetrahedron Lett.,
39, 1099, 1998.). Hui et al., reported a convergent total synthesis of OSW-1 from commercially available dehydroisoandrosterone, L-arabinose, and D-xylose in 27 steps in a 6 percent overall yield. (
J. Org. Chem.,
64, 202, 1999.)
In view of the potential of saponin compounds to treat cancer and related diseases, and the limitations of currently available synthetic methodology, a need exists for efficient processes for the preparation of naturally occurring saponins such as OSW-1 and analogues thereof.
SUMMARY OF THE INVENTION
In accordance with the present invention, processes are provided to prepare naturally occurring saponins such as OSW-1 and analogues thereof, having useful biological activity, and particularly activity as anti-cancer agents. Thus, the present invention provides, in embodiments, a process for preparing the compound of formula (1):
wherein R
1
is independently H or a hydroxyl protecting group, R
2
is independently-C(═O)—Ar or —C(═O)—CR
c
═CR
d
—Ar, wherein Ar is independently aryl or heteroaryl, and R
c
and R
d
are each independently —H, C
1-6
alkyl, C
1-6
alkanoyl, C
1-6
alkoxycarbonyl, aryl, (aryl)C
1-6
alkyl, arylcarbonyl, or aryloxycarbonyl, and R
10
is, for example, C
1-12
alkyl, preferably C
2-6
alkyl, and most preferably —CH
2
—CH(CH
3
)
2
, such as, a compound of the formula
The present invention also provides a process for preparing a saponin intermediate comprising:
reacting, in the presence of a 1,4-addition activating agent, an enone compound of the formula (9)
 wherein R
1
is independently —H or a hydroxyl protecting group, with an alpha-alkoxy vinyl cuprate compound of the formula (8):
 wherein R
3
is an enolic hydroxyl protecting group and R
10
is, for example, C
1-12
alkyl, preferably C
2-6
alkyl, and most preferably —CH
2
—CH(CH
3
)
2
wherein the compound of the formula (8) is:
 wherein R
3
is an enolic hydroxyl protecting group, to form a compound of the formula (18):
 wherein R
4
is an enolic hydroxyl protecting group, for example, with chemical lability or stability different from the aforementioned R
3
enolic hydroxyl protecting group, and R
10
is as defined above. Preferably R
10
is —CH
2
—CH(CH
3
)
2
, such as, in the compound of the formula:
The preparative processes of the present invention can also further comprise:
a) converting the above vinyl ether of compound (18) at —OR
3
to a corresponding ketal;
b) generating a corresponding enolate at —OR
4
of compound (18) wherein R
4
is, for example, a metal counter ion; and
c) oxidizing the resulting enolate to an alpha-hydroxy ketone compound of the formula (20):
The foregoing preparative process of the present invention can further comprise: stereoselectively reducing the ketone of the formula (20) to a 1,2-diol compound of formula (7):
for example, of the formula:
In other embodiments, the present invention provides a process for preparing the compound of formula (1):
wherein R
1
can be independently —H or a hydroxyl protecting group, and R
2
can be independently —C(═O)—Ar or —C(═O)—CR
c
═CR
d
—Ar, wherein Ar can be independently aryl or heteroaryl, and R
c
and R
d
can independently each be —H, C
1-6
alkyl, C
1-6
alkanoyl, C
1-6
alkoxycarbonyl, aryl, (aryl)C
1-6
alkyl, arylcarbonyl, or aryloxycarbonyl, and R
10
is as defined above, comprising:
a) coupling a compound of the formula (7) prepared in accordance with the above description and as illustrated herein:
 with a compound of the formula (6):
 wherein R
6
, R
8
and R
9
are each independently a hydroxyl protecting group, and —OR
7
is a leaving group, that is, a displaceable group which can be substituted by another group or molecule, such as by the secondary alcohol (—OH) functional group of compound (7), and without inversion of the stereochemistry on the sugar ring carbon to which —OR
7
is attached, to form a compound of the formula (36); and
b) deprotecting the compound of formula (36) to afford the compound of formula (1).
In embodiments, the aforementioned R
1
as a hydroxyl protecting group can be, for example, of the formula —Si(R
12
)
3
wherein each R
12
can be independently C
1-4
alkyl, such as —Me, —Et, and the like. The Ar of —C(═O)—Ar can be independently an aryl or a heteroaryl group, optionally substituted with one or more substituents selected independently from, for example, halo, —OH, —CN, —NO
2
, —CF
3
, —OCF
3
, methylene dioxy, C
1-6
alkyl, C
1-6
alkoxy, phenyl, NR
c
R
d
, or —C(═O)NR
c
R
d
; wherein each R
c
and R
d
is independently —H, C
1-6
alkyl, C
1-6
alkanoyl, C
1-6
alkoxycarbonyl, aryl, (aryl)C
1-6
alkyl, arylcarbonyl, aryloxycarbonyl, or like groups; or R
c
and R
d
together with a nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, or thiomorpholino ring; or

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