Stannane synthesis of prostanoids

Details Stannane synthesis of prostanoids Stannane synthesis of prostanoids

2001-03-23

2002-05-14

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Carboxylic acids and salts thereof

C549S469000, C549S475000, C562S465000, C562S500000, C562S503000, C548S468000, C548S491000

Reexamination Certificate

active

06388128

ABSTRACT:

The present invention is directed to novel methods of prostanoid synthesis. More specifically, the invention is directed to the addition of alpha chains to prostanoids using cis-alkenylstannane intermediates.
BACKGROUND OF THE INVENTION
Naturally occurring prostaglandins are biologically active in a myriad of ways including hormone action, muscular contraction/relaxation, platelet aggregation/inhibition, intraocular pressure reduction and other cellular transduction mechanisms. Prostaglandins are enzymatically produced in nature from arachidonic acid. The arachidonic acid cascade is initiated by the prostaglandin synthase catalyzed cyclization of arachidonic acid to prostaglandin G
2
and subsequent conversion to prostaglandin H
2
. Other naturally occurring prostaglandins are derivatives of prostaglandin H
2
. A number of different types of prostaglandins have been discovered including A, B, C, D, E, F and I-Series prostaglandins. These descriptions delineate substitution patterns of the various cyclopentane group central to all prostaglandins. Still other naturally occurring derivatives include thromboxane A2 and B2.
Due to their potent biological activity, prostaglandins have been studied for possible pharmaceutical benefit. However, due to potency of these molecules, as well as the ubiquitous presence of these agents and receptors and other biologically responsive tissue sites to their presence, numerous side effects have prevented the exploitation of the naturally occurring prostaglandins. It has also been difficult to pharmaceutically exploit the naturally occurring prostaglandins due to the relatively unstable nature of these molecules. As a result, researchers have been preparing and testing synthetic prostaglandin analogs, also known as “prostanoids,” for several decades.
In general, prostanoids can be described generically as consisting of (1) an alpha chain; (2) an omega chain; and (3) a cyclopentane group (or a heterocycle or other ring structure), as shown in formula I.
In general, the E groups of the ring structure are independently O, CH—OH, C═O, CH-halogen and CH
2
groups. The omega chain has generally consisted of linear carbon backbones of varying lengths. The omega chains have also been of varying degrees of saturation, containing optional hetero-atoms and have terminated with a variety of alkyl and cycloalkyl groups. Alpha chains have consisted of numerous linear moieties and have involved various degrees of saturation. The alpha chains generally consist of a seven carbon chain and generally terminate with a carboxylic acid group or a variety of corresponding esters.
Of particular interest are a set of prostanoids having a double bond at carbons 5 and 6 and an oxygen or carbon at the three position, according to formula II:
wherein, the E groups are as defined above; A is oxygen or carbon; Q is H or C
1-4
alkyl: and the omega chain (&ohgr;) is generally five to twelve carbons in length with various substitutions including substitutions of hetero-atoms within the chain.
As summarized in Scheme A, prostanoids of formula II can be prepared by reacting a methylene ketone 1 with a cis-alkenylcuprate 2 to install the alpha chain and thereby form the cis-alkenyl intermediate 3, wherein X is O, CH
2
, CH—OH (or CH—O-protected), &ohgr; is as defined above, R is generally a nontransferring group, R′ is generally a hydroxyl protecting group and Z′ is generally a masked carboxyl group.
The cis-alkenylcuprate 2a or 2b can be one of several different types known to those skilled in the art. Homocuprates bear two identical carbon groups bonded to copper, only one of which can efficiently form a carbon-carbon bond by transfer from copper, the remaining group being by definition the nontransferring group R. Heterocuprates bear two different carbon groups bonded to copper, one of which (R) has a low tendency to form a carbon-carbon bond compared with the transferring group, in this case the cis-alkenyl group. Higher-order cuprates contain a metal cyanide salt, typically LiCN. Lower-order cuprates do not contain metal cyanide salts but can contain other components capable of modifying reactivity, for example, a trialkylphosphine. The cis-alkenylcuprates of formulas 2a and 2b are optionally associated with a metal cyanide salt or other component. See, generally, Lipshutz,
Organic Reactions,
volume 41, page 135 (1992).
Stork and Isobe,
J. Am. Chem. Soc
., volume 97, page 4745 (1975), disclose a method of preparing racemic 3-carba prostanoids as shown in Scheme A, wherein X is CHOCH
2
Ph (in the rel-R configuration), &ohgr; is trans-CH═CHCH(OCH
2
OCH
2
Ph)-n-C
5
H
11
, Z′ is CH
2
OCH(Me)OEt, and the cis-alkenyl cuprate 2a is the lower-order homocuprate cis-(EtOCH(Me)O(CH
2
)
4
CH═CH)
2
CuLi.PBu3. The cis-alkenylcuprate 2a was prepared from the cis-iodoalkene cis-EtOCH(Me)O(CH
2
)
4
CH═CHI by lithium-iodine exchange with tert-butyllithium, forming the intermediate cis-alkenyllithium compound cis-EtOCH(Me)O(CH
2
)
4
CH═CHLi, which was then reacted with CuI—PBu
3
complex to yield 2a.
Sato,
Tetrahedron: Asymmetry,
volume 3, page 1525 (1992), discloses a method of preparing nonracemic 3-oxa prostanoids as shown in Scheme A, wherein X is CHOSiMe
2
t-Bu (in the R configuration), &ohgr; is trans-CH═CHCH(OSiMe
2
t-Bu)-cyclo-C
6
H
11
(in the S configuration), R′ is CH(Me)OEt, and the cis-alkenylcuprate 2b is the higher-order heterocuprate cis-EtOCH(Me)OCH
2
CH═CHCu(2-thienyl)Li.LiCN. The cis-alkenylcuprate 2b was prepared from the cis-iodoalkene cis-EtOCH(Me)OCH
2
CH═CHI by lithium-iodine exchange with tert-butyllithium, forming the intermediate cis-alkenyllithium compound cis-EtOCH(Me)OCH
2
CH═CHLi, which was then reacted with (2-thienyl)Cu(CN)Li to yield 2b.
The cis-iodoalkene to cis-alkenyllithium to cis-alkenylcuprate sequence employed in the foregoing examples has several disadvantages. The preparation of cis-iodoalkenes typically involves reaction of a 1-iodoalkyne with diimide, which is not suitable for large scale work and always produces some 1-iodoalkane; see Luthy,
J. Am. Chem. Soc.,
volume 100, page 6211 (1978). Other methods of preparing cis-iodoalkenes give variable amounts of the trans isomer, see Dieck,
J. Org. Chem.,
volume 40, page 1083 (1975), and Stork and Zhao,
Tetrahedron Letters,
volume 30, page 2173 (1989). The reagent of choice for converting the cis-iodoalkene to the cis-alkenyllithium has been tert-butyllithium, which is pyrophoric and not suitable for large scale work. This conversion must be performed at low temperature, typically −60° C. or below, in order to realize good yields.
Transmetalation methods have been described in the art. For example, U.S. Pat. No. 4,777,275 (Campbell et al.) discloses a direct tin-to-copper transmetalation. In that disclosure, a trans-alkenylstannane is directly converted to a trans-alkenylcuprate, which is used for the addition of a trans omega chain to a prostanoid.
A need has arisen, therefore, to develop superior synthetic methods for the preparation of the various prostanoids of interest, in greater yields.
SUMMARY OF THE INVENTION
The present invention is directed to methods of prostanoid synthesis. More specifically, the invention is directed to methods involving cis-alkenylstannanes for prostanoid alpha chain addition.
The use of cis-alkenylstannanes obviates problems existing with traditional synthetic methods involving treatment of cis-iodoalkenes with alkyllithiums to form cis-alkenyllithiums, which are then converted to cis-alkenylcuprates. The avoidance of the cis-iodoalkene and cis-alkenyllithium intermediates minimizes unwanted side products and also allows for greater yield of key intermediates useful in prostanoid synthesis.
Preferred methods of the present invention employ the novel intermediate synthesis of the present invention in the synthesis of 3-oxa prostanoids.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel methods of prostanoid synthesis. More specifically, the present inventio

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