Stereoselective synthesis of 24-hydroxylated compounds...

Details Stereoselective synthesis of 24-hydroxylated compounds... Stereoselective synthesis of 24-hydroxylated compounds...

2001-04-12

2003-08-26

Pryor, Alton N. (Department: 1616)

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

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

C552S521000, C552S610000, C552S611000, C552S623000, C552S633000, C552S634000, C552S636000, C552S637000, C568S579000, C568S583000, C568S591000

Reexamination Certificate

active

06610866

ABSTRACT:

BACKGROUND OF THE INVENTION
Several aminosterol compositions have been isolated from the liver of the dogfish shark,
Squalus acanthias
. One important aminosterol is squalamine (3&bgr;-(N-[3-aminopropyl]-1,4-butanediamine)-7&agr;,24&zgr;-dihydroxy-5&agr;-cholestane 24-sulfate), the chemical structure of which is shown in FIG.
1
. This aminosterol, which includes a sulfate group at the C-24 position, is the subject of U.S. Pat. No. 5,192,756 to Zasloff, et al., which patent is entirely incorporated herein by reference. This patent describes antibiotic properties of squalamine.
Since the discovery of squalamine, however, several other interesting properties of this compound have been discovered. For example, as described in U.S. patent application Ser. Nos. 08/416,883 (filed Apr. 20, 1995) and 08/478,763 (filed Jun. 7, 1995), squalamine may function as an antiangiogenic agent. These patent applications are entirely incorporated herein by reference. Additional uses of squalamine (e.g., as an agent for inhibiting NHE3 and as an agent for inhibiting endothelial cell growth) are disclosed in U.S. patent application Ser. No. 08/474,799 (filed Jun. 7, 1995) and U.S. patent application Ser. No. 08/840,706 (filed Apr. 25, 1997). These patent applications also are entirely incorporated herein by reference.
Methods for synthesizing squalamine have been devised, such as the methods described in WO 94/19366 (published Sep. 1, 1994). This PCT publication is entirely incorporated herein by reference. This PCT application relates to U.S. patent application Ser. No. 08/023,347, which application also is entirely incorporated herein by reference. Additionally, U.S. patent application Ser. No. 08/474,799 also discloses squalamine isolation and synthesis techniques.
Stemming from the discovery of squalamine, other aminosterols have been discovered in the dogfish shark liver and have been investigated. One important aminosterol that has been isolated and identified has the structure shown in FIG.
2
. In this application, the compound having the structure shown in
FIG. 2
will be referred to as “compound 1436” or simply “1436.” This compound has the general molecular formula C
37
H
72
N
4
O
5
S and a calculated molecular weight of 684.53017. Like squalamine, this aminosterol also has a sulfate group at the C-24 position.
Compound 1436 previously has been described in U.S. patent application Ser. Nos. 08/483,057 and 08/487,443, each filed Jun. 7, 1995. Each of these U.S. patent applications is entirely incorporated herein by reference. As further described in these patent applications, compound 1436 has a variety of interesting properties. For example, compound 1436 inhibits human T-lymphocyte proliferation, as well as the proliferation of a wide variety of other cells and tissues. Additional uses of compound 1436 are disclosed in U.S. Provisional Patent Appl. No. 60/017,627 (filed May 17, 1996) and the subsequently filed U.S. patent application Ser. Nos. 08/857,288 filed May 16, 1997 and 08/962,290 filed Oct. 31, 1997. These patent applications also are entirely incorporated herein by reference.
U.S. patent application Ser. Nos. 08/483,057 and 08/487,443 describe the structure of compound 1436 as well as processes for synthesizing and isolating the compound. For example, as described in these applications, compound 1436 can be prepared from a squalamine starting material.
When squalamine is isolated from dogfish shark liver, the sulfate group is located at the C-24 position, and there is no difficulty in providing the sulfate group at this location in a stereoselective manner. Likewise, when compound 1436 is derived from a squalamine starting material, the sulfate group already is located at the C-24 position, and therefore, there is no difficulty in obtaining a stereoselective structure at the C-24 position.
Difficulties have been encountered, however, when attempting to provide a process for synthesizing squalamine or compound 1436 from commercially available starting materials (i.e., not from shark liver isolates). These difficulties include low overall yields of the desired steroid product, because many steps are involved in the synthesis process. Additional difficulties are encountered in providing a sulfate group at the C-24 position. Particularly, it is difficult to provide the sulfate group at the C-24 position in a highly stereoselective orientation. See, for example, Pechulis, et al., “Synthesis of 24&xgr;- Squalamine, an Anti-Infective Steroidal Polyamine,”
J. Org. Chem
., 1995, Vol. 60, pp. 5121-5126; and Moriarty, et al., “Synthesis of Squalamine. A Steroidal Antibiotic from the Shark,”
Tetrahedron Letters
, Vol. 35, No. 44, (1994), pp. 8103-8106. These articles each are entirely incorporated herein by reference. This invention seeks to overcome those difficulties in synthesizing squalamine and compound 1436.
Squalamine and compound 1436 are not the only compounds of interest that include a specified substituent, in a stereospecific orientation, at the C-24 position. For example, the above-noted patent applications describe many different aminosterol compounds that have various C-24 substituents. As another steroid example, cerebrosterol, includes a hydroxyl group in an S-orientation at the C-24 position. MC 903, a 1,24-dihydroxyvitamin D analogue, also includes a hydroxyl group in an S-orientation at the 24 position. 1&agr;,24(R)-dihydroxyvitamin D
3
includes a hydroxyl group in an R-orientation at the 24 position. The chemical structures for cerebrosterol, MC 903 and 1&agr;,24(R)-dihydroxyvitamin D
3
are shown in
FIGS. 3A
,
3
B and
3
C, respectively.
Because of the importance of squalamine, compound 1436, other aminosterols, 24R and 24S-hydroxylated steroids and vitamin-D
3
metabolites, there has been considerable interest in preparing compounds with a single stereospecific orientation at the C-24 position. Processes for producing squalamine and compound 1436 are described in the patent documents noted above. These processes, while effective in producing squalamine and compound 1436, do not enable large scale production of the desired aminosterol materials because relatively low yields are realized by these processes.
Other researchers have developed processes for stereoselectively producing cerebrosterol, MC 903, and 1&agr;,24(R)-dihydroxyvitamin D
3
. A process for producing cerebrosterol is described in Koch, et al., “A Stereoselective Synthesis and a Convenient Synthesis of Optically Pure (24R)- and (24S)-24 hydroxycholesterols,”
Bulletin de la Société Chimique de France
, 1983, (No. 7-8), Vol. II, pp. 189-194. A process for producing MC 903 is described in Calverley, “Synthesis of MC 903, a Biologically Active Vitamin D Metabolite Analogue,”
Tetrahedron
, 1987, Vol. 43, No. 20, pp. 4609-4619. A process for producing 1&agr;,24(R)-dihydroxyvitamin D
3
is described in Okamoto, et al. “Asymmetric Isopropylation of Steroidal 24-Aldehydes for the Synthesis of 24(R)-Hydroxycholesterol,
Tetrahedron:Asymmetry
, 1995, Vol. 6, No. 3, pp. 767-778. These articles each are entirely incorporated by reference.
One approach, as described in the above-noted articles, has been to reduce a 22-ene-24-one system in a stereoselective manner. This scheme is illustrated in FIG.
4
A. The 22-ene-24-one system (material B from
FIG. 4A
) can be produced in a single step from the corresponding 22-aldehyde (material A) using an appropriate Wittig reagent (prepared in 2 steps). Therefore, if this reduction procedure was stereoselective, this would be a convenient two step procedure for preparing chiral C-24 alcohols (material C).
Unfortunately, this reaction is not stereospecific. Calverley described attempts to reduce a vitamin-D
3
-22-ene-24-one with sodium borohydride and cerium (III) chloride; however, he achieved only a 38:61 ratio of the desired 24S product to the undesired 24R allylic alcohol. In the process of Calverley, the product had to be purified by chromatography and recrystallization to separate the 24R product from the desired 24S product. The 24S and 24R allylic alc

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