Synthesis of pseudopterosin compounds

Details Synthesis of pseudopterosin compounds Synthesis of pseudopterosin compounds

2000-11-15

2002-07-23

Richter, Johann (Department: 1621)

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

Organic compounds

Oxygen containing

C568S733000, C435S135000

Reexamination Certificate

active

06423877

ABSTRACT:

BACKGROUND OF THE INVENTION
The pseudopterosins are compounds produced by the Caribbean sea whip
Pseudopteragoria elisabethae.
These compounds are exemplified by the structures shown below, pseudopterosin A (Compound 1) and E (Compound 2),
1
which are remarkably active antiinflammatory agents
2
that were discovered by W. Fenical and collaborators.
The analgesic activity of Compound 1 (administered subcutaneously) is several fold greater than that of indomethacin,
2
and that of Compound 2 is some 50 times greater.
3
This potency and the fact that the biological mode of action of Compounds 1 and 2 appears to be novel
2
have made these substances (and their analogues) attractive targets for synthetic and for biological/biochemical research.
Further interest in the pseudopterosins derives from their commercial use as topical antiinflammatory agents in the cosmetic field and the limited supply available from natural sources.
4
A number of laboratories have described studies on the total synthesis of pseudopterosins. The earliest syntheses were developed by C. A. Broka and co-workers
5
and in these laboratories,
6
including the first sterocontrolled enantioselective syntheses of Compounds 1 and 2 from either (+)-menthol
6a
or (S)-citronellal.
6b
Subsequently, a variety of additional synthetic approaches have been developed b other groups.
7-10
Although the more recent syntheses involve fascinating and elegant design, they appear to fall short of practicality.
SUMMARY OF THE INVENTION
One preferred embodiment of the present invention is a new synthetic route to pseudopterosin aglycone (3):
an intermediate for the synthesis of a group of antiinflammatory natural products including pseudopterosin A (Compound 1) and E (Compound 2).
The synthetic pathway of the present invention is outlined below in Scheme I, and starts with the abundant and inexpensive (S)-(−)-limonene and its long-known cyclic hydroboration product (Compound 4) and leads to the chiral hydroxy ketone (Compound 6). Conversion of Compound 6 to Compound 10, followed by a novel aromatic annulation produced Compound 15 which underwent highly diasterioselective cyclization to afford the protected pseudopterosin aglycone (Compound 16). The naturally occurring pseudopterosins such as (Compound 1) and (Compound 2) are readily available from this intermediate. This intermediate will also serve as a source of novel synthetic pseudopterosin compounds.
Thus, one preferred embodiment of the present invention is a new process for the synthesis of pseudopterosin compounds which has a number of advantages over previously known methods; including (1) an inexpensive chiral starting material (limonene), (2) the use of common or readily available reagents, (3) stereocontrol, (4) simplicity of execution, (5) good yields, and (6) directness. In addition, this synthesis illustrates a number of new and potentially widely useful synthetic methods of noteworthy aspects of stereocontrol and site selectivity.
The present invention is thus directed to the synthetic process outlined in Scheme 1, to the novel intermediates obtained therein, and to the uses of these compounds as synthetic precursors to the pseudopterosins. Other embodiments and aspects of the present invention include the novel synthetic procedures described herein, as detailed below.
DETAILED DESCRIPTION OF THE INVENTION
As described above, the starting material for the present synthesis of pseudopterosin compounds was diol mixture (4) which can be obtained in nearly quantitative yield from (S)-(−)-limonene by cyclic hydroboration and alkaline peroxide oxidation.
11
Although this mixture of diols (nearly 1:1) is readily available in quantity, it is believed that this mixture has neither been separated nor been used as starting material in a stereocontrolled synthesis. Neither distillation nor chromatographic methods allow separation of the mixture. Nonetheless, it has been found that the diastereomeric mixture can be utilized for synthesis using the novel separation process, as outlined above in Scheme 1.
Referring to Scheme 1, the process of the present invention was started by subjecting a nearly 1 to 1 diastereomeric mixture of diols (4) (54:46 C(8)) to selective oxidation at C(2) upon exposure to 1.5 equiv of sodium hypochlorite
12
in aqueous acetic acid. This formed the diastereomeric mixture of hydroxy ketones 5 in excellent yield. Exposure of this hydroxy ketone mixture to isopropenyl acetate in isopropyl ether at 23° C. using Amano PS lipase as the catalyst resulted in selective acetylation of the (8S)-hydroxy ketone after 17 h. Flash chromatography of the resulting mixture on silica gel afforded the desired (8R)-alcohol 6 (36% based on 5) as an oil (ratio 8R/8S=99:1 as determined by HPLC analysis of the corresponding p-nitrobenzoate ester) and the acetate of the (8S)-diastereomer of 6. Oxidation of 6 in a CH
2
Cl
2
—H
2
O system with sodium hypochlorite and 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) as catalyst
13
at pH 8 gave keto aldehyde 7 in 92% yield. Wittig -Vedejs E-selective olefination
14a
of 7 using the ylide 8
14b
as reagent in dimethozyethane produced the E-diene 9 in excellent yield, as shown in Scheme 1, without the loss of stereochemical integrity at the labile C(8) position.
With the successful establishment of three of the four stereocenters of pseudopterosin aglycone (3), the next task called for in the synthetic plan was the attachment of the aromatic ring, i.e., the conversion 9-14 in Scheme 1. This was accomplished using a new aromatic annulation protocol starting with Mukaiyama-type Michael coupling of the enol silyl ether 10 and the functionalized &agr;,&bgr;-enone 11.
15,16
This coupling product was obtained in 74% yield (correcting for a small amount of recovered 9) using 1.1 equiv of SnCl
4
as the catalyst in CH
2
Cl
2
at −78° C. of 40 min. Treatment of Compound 12 with ethanolic KOH at 0° C. effected aldol cyclizaton to a &bgr;-hydroxy ketone which was dhydrated by treatment with SOCl
2
-pyridine at 23° C. for 1 h to form the &agr;,&bgr;-enone 13. The enol tert-butyldimethylsiyl (TBS) either of Compound 13 was prepared by deprotonation (alpha to methyl) and silylation with TBS-triflate, and then the resulting ether was aromatized by stirring with activated MnO
2
(Aldrich Co., Milwaukee) in methylcyclohexane at 70° C. for 36 h to provide the aromatic hydronaphthalene 14 in 90% overall yield from 13.
It was found that the MnO
2
-induced aromatization process proceeds more readily and in higher yield with methylcyclohexane as solvent than in benzene or toluene as solvent
17
and that by using the dry MnO
2
-methylcyclohexane system aromatization of a wide range of Compound 1,4- and 1,3-cyclohexadienes can be effected efficiently. A summary of these studies is presented below. In contrast to the success achieved using the MnO
2
-methylcyclohexane aromatization system, a number of other oxidants that have previously been recommended for aromatization failed, including (q) Pd-X, (2)dichlorodicyano-quinone, (3) o-chloranil, (4) 2,6-dichloro-1,4-benzo-quinone, and (5) Cr(CO)
3
.3CH
3
CN, norbornene.
18
Desilylation of Compound 14 (Bu
4
NF in THF) and reaction with CH
3
—SO
2
Cl—Et
3
N in CH
2
Cl
2
provided the mesylate 15 which upon treatment with 5 equiv of CH3SO3H in CH
2
Cl
2
at −50° C. underwent highly diasteroselective cationic cyclization (25:1) to form 16 in very high yield. Reaction of Compound 16 with MeMgBr produced cleanly the monophenol 17 which was debenzylated to give pseudopterosin aglycone (3). The various pseudopterosins may be accessed from 17 or 3 by procedures previously developed in these laboratories.
6
Comparison of synthetic 3 [&agr;]
23
D
−95 (c=1, CHCl
3
) with authentic 3
6
revealed identical IR,
1
H NMR,
13
C NMR, and high-resolution mass spectra.
It is interesting that the methanesulfonic acid cyclization of TBS ether 14 afforded primarily (8:1) the product 18, corresponding to 16 with the (S)-configuration at C(1). This remarkab

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