CA2004125A1 - Phosphonate reagent compositions and methods of making same - Google Patents

Abstract

ABSTRACT

Novel phosphonate compounds of the formula

Description

20n~s BACRGROUND OF T~E INVENTION

The present invention relates to novel phosphonates which can be employed as precursors to a variety of biologically-active materials; including 13-cis-retinoic acid (accutane), retin-A and beta carotene. The phosphonates of the present invention can be synthesized by the reaction of a cyclohexenyl-group-containing C-14 through C-16 aldehyde, such as 2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butenal, with a phosphonic acid ester, such as methylenebisphosphonic acid, tetraethyl ester.
A procedure for producing vitamin A acetate from beta-ionone has been described by Rei~ and Grassner [Chemie-Inq.Techn., 45, 646-652 (1973)]:

OH
1 H ~ C ~ ~ HX

2 H2/cataly~t ~
r~ 1 , ~ ~ x ~
~ ~tr ph nyl -o ~ 2 3 ~ 2 3 t--~ormyl-~ crotyl ~c-tate vitamin A ~c-t~t-2n~4l2s Similarly, Pommer and Kuhn [Angew.Chem., 72, 911 (1960)~ have described a procedure for preparing beta-carotene from the same beta-ionone-derived triphenylphosphonium salt:

~ ~ X ~

formed in the course of the ~eif, et al. synthesis. The disadvantages of these procedures include the fact that the triphenylphosphine reactant required for the syntheses is relatively expensive and that the byproduct of the reactions, Ph3PO, is not water soluble, thus making it difficult to isolate the desired product.
Surmatis and Thommen have described a process for preparing beta-carotene utilizing a phosphonate in a Wittig-type reaction lJ.Org.Chem., 34, 559 (1969)]. An essential step of this procedure invoi~es the reaction of a C-20 dibromo compound with a trialkyl phosphite:

~ CH29r o ~ c~c ~ cH2~lo~2 ^~t-iyrt >

~ o ~ N-OCJ3, pyr~d~n-- >
~ ~, Ç~2Pl01l~2 2- ~X~Ho r-eLnyL pbo~phon-t- ~
~-t~n~l ~t--e-rot-n-Although the C-20 dibromo compound of Surmatis, et al. can be reacted with trialkyl phosphites, the literature does not report similar reactions for structurally related C-15 halides.
Indeed, the literature shows that the compound l-bromo-3-methyl-5-(2~6~6-trimethyl-l-cyclohexen-l-yl)-2~4 pentadiene ~ CH2Br is not stable at room temperature. (aull.Soc.Chim.Fr., 15 Part II, 746-50 (1973)].
Other procedures for preparing retinoid intermediates and beta-carotene are shown in the prior art, e.g., Babler U.S. Patent 4,175,204; F. Frickel, "The Retinoids", edited by M.B. Sporn, A.B. ~oberts and D.S. Goodman, Academic Press (Orlando, Florida, 1984), pp. 77-145; and R.S.H. Liu and A.E. Asato, Tetrahedron, 40, 1931-196g (1984).

SUMMARY OF THE INVENTION
The novel phosphonate compounds of the present invention have the structural formula:

C~3 CH3 ~ R1- P~OR)2 c~3 20n4l2~

in which R is an alkyl group having up to four carbon atoms, and Rl is a 3-alkyl pentadienyl group wherein the alkyl group at the 3 position is methyl, ethyl or propyl. The two double bonds in the 3-alkyl pentadienyl group, Rl, can be in the 1,3 or 2,4 positions (conjugated) or in the 1,4 positions (non-conjugated).
The compounds of the present invention are systematically named as esters of an alkenylphosphonic acid~ Thus, for example, when Rl is:

I

-CH=CH-C=CH-CH2-and R is ethyl, the compound is named 3-methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4-pentadienylphosphonic acid, diethyl ester. When Rl is:

-CH=CH-CH-CH=CH-and R is isopropyl, the compound is named 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,4-pentadienylphosphonic acid, diisopropyl ester.
Other compounds within the scope o~ the present invention include:
3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienylphosphonic acid, diethyl ester;
3-ethyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, diethyl ester;

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3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, dimethyl ester;
3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, dipropyl ester;
3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, dibutyl ester;
3-propyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienylphosphonic acid, diethyl ester; and 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, diisopropyl ester.

Because of their ability to form known biologically-active compounds, dialkyl esters of 3-methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4-pentadienylphosphonic acid, are especially preferred.
The compounds of thè present invention can be formed by the base-promoted reaction of a C-14 through C-16 aldehyde having the structure ~ R2CHO

wherein R2 is -CH=CH-CH- or -CH2-CH=C- and R3 is methyl, ethyl or propyl, with a methylenebisphosphonic acid ester having the structure:

O O
Il 11 (R0)2PcH2p(oR)2 2~)04125 wherein each R, which can be the same or different, is selected from the class consisting of alkyl groups having up to four carbon atoms. The preferred aldehydes are C-14 materials which are derived from beta-ionone.
At room temperature, reaction of the aldehyde and bisphosphonate ester proceeds rapidly (< 30 minutes) in an organic solvent containir.g one equivalent of a base (e.g., a Group I metal alkoxide or sodium hydr ~e):

o o X~ Q2C~ = O + (RO) 2PCH2P(OR~ 2 + base or~anic solvent r 1 ~ room temp .
15 ~

~<,~ Rl -- P(OR~ 2 `~' ~

wherein Rl is a 3~alkyl pentadienyl group, as defined above, and R is a C-l to C-4 alkyl group. The phosphonate ester product is soluble in a variety of organic solvents and can be isolated from the reaction mixture by convention~l techniques. Yields are typically in excess of 90%.
A variety of organic solvents, both polar and nonpolar, can be employed in the foregoing reaction, 3Q including hydrocarbons such as benzene, hexane, cyclohexane, and toluene; ethers such as tetrahydrofuran and diethyl ether; ethyl alcohol; polar solvents such as dimethylformamide and dimethyl sulfoxide; or mixtures of such organic solvents. Suitable bases include sodium hydride, Group I metal alkoxides, and alkali metal carbonates.

Z0041Z~

As noted previously, the double bonds in the pentadienyl moiety can be in the 1,3-; 1,4- or 2,4-positions. The 1,3- and 1,4- compounds can be isomerized to the preferred 2,4- pentadienyl phosphonates by employing a base catalyst such as an alkoxide of a Group I metal, i.e., KOC(CH3)3, NaOCH3, or NaOCH2CH3 with an organic solvent such as dimethyl sulfoxide (DMSO).

10 ~CH = CHPIOR) 2 O

OR alk~xid~ ~ fX~. CH2P ~OR) 2 / C~3 DMSo X' CH2CH = C
~J~ ~ CH = CHP(OR) 2 In general, any orqanic solvent in which the reactants are soluble may be employed in the practice of the above two steps ~i.e., preparation of the phosphonate ester and its subsequent isomerization).
Any base whose conjuqate acid has a PKa of approximately 8 or above can be utilized to promote these reactions.
The aldehyde reactant ~e.q., 2-methyl-4-(2',6',6'-tri-methyl-1'-cyclohexen-1'-yl)-3-~utenal]
used to synthesize the phosphonate esters can be prepared in accordance with known procedures. Processes for synthesi2ing such aldehydes from ~eta-ionone are shown, for example, in O. Isler, et al., Helv.Chim.Acta., 30, 1911 (1947); V. Ramamurthy, et al., Tetrahedron, 31, 193 (1975), or M~ ~osenberqer, et al., Helv.Chim.Acta, 63, 1665 (1980).

20~ 2~

The methylenebisphosphonic acid ester reactant can be prepared by reacting methylene bromide with a trialkyl phosphite [P(OR)3] in accordance with the procedure shown in B. Costisella, J. fur prakt. Chemie, 324, 537 (1982), e.g., 2Br2 + 2 P[OCH(C~ ) ] heat O O
Il 11 [(CH3)2CHO]2 PCH2P[OCH(CH3)2]2 methylenebisphosphonic acid, tetraisopropyl ester, 73 yield.
The compounds of the present invention can be used in the synthesis of retinoids or beta-carotene.
Illustrative examples of three such syntheses employing the novel phosphonate compounds are as follows:

~0~)4125 SYnthesis of all-trans-retinoic acid (retin-A~

CH3 O O organic solvent, ~ CHCH = O ~(cH3cH2o)2pcH2p~ocH2cH3)2 2base >

2-methyl-4-l2',6',6'-methyieneb~ho~phonic trim-thyl-l'-cyclo-acld/tetraet yl eJter hexen-l '-yl)-3-butenal CH3 o ~ CHCH = CHp(ocH2cH3)2 ba-e ~c g , KoclcH3)~ ~r ~ 90~ yield Il ~ CH2P~OCH2CH3)2 CH3 C / COOCH3 ~OC(CH3)3 ~ CH3 CH ~ \ H

~solc product) methyl e~t-r of reeinoic acit 200~1~5 Synthesis of 13-cis-retinoic acid ~accutane) o CH2P~OCH2CH3)2 CH3 + 2 equiv. KOC(CH3)3 + OH ~ ~O

5-hydroxy-4-methyl 2-(5H) furanone THF/DMSO ~ ~
COOH

13~cls-retinoic acid SYnthesis of beta-carotene o 2 equiv ~ ~ CH2P~OCH2CH3)2 + 2 equlv KOC(CH3)3 +
o H\ / CH = ~/

/ ~ THF/DMSO ~
~C = CH H 20-C ~' o 2,7-di~ethyl-2,4,6-octatrie~edial ~ ~ ~ _ 3-c~roten- 1>60- yield) 20n4~25 DETAILED DESCRIPTION OF THE INVENTION
The following examples illustrate in greater detail the practice of the present invention, S specifically: (i) the preparation of intermediates which can be utilized to form the phosphonate compounds of the present invention (Examples I-V); (ii) the preparation of representative novel phosphonate compounds (Examples VI-XI); (iii) the preparation of intermediates which can be reacted with the compounds of the present invention to form biologically-active materials (Examples XII-XIV); and, (iv) the preparation of biologically-active compounds utilizing the novel phosphonate compounds of the invention (Examples XV-XVII).
EXAMPLE I
Preparation of Methylenebisphosphonic Acid, TetraethY1 Ester In accordance with a procedure suggested by H. Gross, et al., Journal fur prakt. Chemie, 324, 537 (1982~, a mixture of 4.00 ml (57.0 mmoles) of dibromomethane and 30 mL (175 mmoles) of triethyl phosphite was gradually warmed to 90C over a period of 15 minutes. After maintaining the temperature at 90C
for an additional 10 minutes, the solution ~as warmed to 140C and kept at that temperature for 2 hours. At that point, the mixture was warmed to 160C ~external bath temperature) and heated at that temperature for an addi-tional 15 hours, during which time ethyl bromide was slowly distilled out of the reaction mixture. Next, excess triethyl phosphite was distilled from the reaction flask, followed by distillative removal of minor amounts of ethylphosphonic acid, diethyl ester.
The desired product was then obtained by distillation under reduced pressure, affording 9.03g (55% yield) of 2(~4125 bisphosphonate: bp 145-160C (bath temperature, 0.25 mm). H. Gross, et. al., reported a 70% yield of the same compound, prepared on a larger scale (150 mmoles of dibromomethane).

EXAMPLE II
Preparation of Methylenebisphosphonic Acid, Tetraisopropyl Ester A mixture of 1.00 ml (14.25 mmoles) of dibromomethane and 11.0 mL (44.5 mmoles) of triisopropyl phosphite was heated in the same manner as described in the procedure of Example I. Removal of excess triisopropyl phosphite, followed by a minor amount of isopropylphosphonic acid, diisopropyl ester, by distillation at reduced pressure, and subsequent evaporative distillation [bath temperature: 138-152C
(0.25 mm)] afforded 3.57 g (73% yieid) of the desired bisphosphonate.

EXAMPLE III
Preparation of 2-Methyl-2-[2-l2,6,6-trimethYl-l-cvclohexen-l-yl)ethenYlloxirane A mixture of 762 mg (19.1 mmoles) of sodium hydride (60% dispersion in mineral oil, which was removed ~y washing with hexane prior to the addition of DMSO) and 6.0 m~ of anhydrous dimethyl sulfoxide (DMSO) was heated, protected from atmospheric moisture, at a bath temperature of 65C for approximately 45 minutes --until evolution of hydrogen had ceased. After cooling this mixture to room temperature, it was added dropwise over a period of 10 minutes to a stirred slurry of 3.9549 (19.38 mmoles) of trimethylsulfonium iodide in 12.0 mL of 1:1 ~v/v) anhydrous DMSO: tetrahydrofuran, protected from atmospheric moisture and kept cold in an ice-brine bath at approximately -5C. The resulting 2()~)412~

gray suspension was stirred for an additional 5 minutes, after which a solution of 1.42g (7.38 mmoles) of beta-ionone in 3.00 mL of anhydrous tetrahydrofuran was added dropwise rapidly. This mixture was subsequently stirred at approximately O~C for 2 hours, after which it was allowed to warm to room temperature. The product was isolated, after addition of 1 mL of water to quench the reaction, by dilution of the mixture with 50 mL of pentane and 100 mL of 10% aqueous sodium chloride.
Separation of the layers was followed by washing the organic layer with 10% aqueous sodium chloride (2 x 100 mL), water (1 x 100 mL), and saturated brine (1 x 100 mL) in successive order. The organic extracts were then dried over anhydrous sodium sulfate and subsequently filtered. Removal of the pentane and tetrahydrofuran by evaporation at reduced pressure afforded 1.52 g (100~ yield) of the desired epoxide.

EXAMPLE IV
Preparation of 2-Methyl-4-~2,6,6-trimethyl-l-cyclohexen-l-yl)-3-butenal ~ solution of 1.502 9 (7.28 mmoles) of the epoxide, prepared as described in Example III, in 6.00 mL of anhydrous ether was added dropwise over 5 minutes to a stirred suspension of magnesium bromide [prepared _ situ from 355 mg (1.88 mmoles) of 1,2-dibromoethane and 48 mg (1.98 milli-g-atoms) of magnesium turnings] in 3.00 mL of anhydrous ether, protected from atmospheric moisture, at -10C. The resulting mixture was stirred at -10C for an additional 5 minutes, after which it was diluted with 20 mL of solvent ether~ The organic layer was washed in successive order with 15 mL portions of water and saturated brine, after which it was dried over anhydrous sodium sulfate and subsequently filtered.
Removal of the ether by evaporation at reduced pressure 20(~1XS

afforded 1.40 g (93% yield) of the desired aldehyde, whose structure was verified by NMR analysis [~ 9.69, doublet, J = 1.8 Hz, CHO; ~ 1.25, doublet, J = 7 Hz, CHCH3]. The procedure used in Examples III a~d IV was developed by M. Rosenberger, et al. [Helv. Chim. Acta., _ , 1665 (1980)]. An alternate route to this same aldehyde can be found in O. Isler, et al., Helv. Chim.
Acta., 30, 1911 (1947), subsequently modified by R.S.H.
Liu, et al., Tetrahedron, 31, 193 (1975).
EXAMPLE V
Preparation of 2-Methyl-4-(2,6,6-trimethyl-l-cYclohexen-l-yl)-2-butenal A mixture of 920 mg (4.46 mmoles) of the aldehyde prepared as described in Example IV and 45 mg of potassium hydroxide pellets in 3.0 mL of methyl alcohol containing 0.05 mL of water ;~as stirred, protected from atmospheric moisture, at 20C for 35 minutes. The product was isolated after dilution of the mixture with 30mL of 1:1 (v/v) pentane: ether and subsequent washing of the organic layer with 25 mL
portions of 10% aqueous sodium chloride and saturated brine. Drying of the organic extracts over anhydrous magnesium sulfate, followed by filtration and removal of the pentane and ether at reduced pressure, afforded 916 mg (99.6% yield) of the isomerized aldehyde, whose structural identity was confirmed by NMR analysis (~ 9.45, singlet, CHO~.

EXAMPLE VI
Preparation of 3-Methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-1,3-~ntadienylphosphonic acid, Diethyl E~ter A solution of 508 mg (1.76 mmoles) of methylenebisphosphonic acid, tetraethyl ester, prepared Z0~12~

as described in Example I, in 2.5 mL of benzene and 1.5 mL of anhydrous tetrahydrofuran (THF) was added dropwise slowly over 5 minutes to a stirred mixture of 69 mg (1.7 mmoles) of sodium hydride (60~ dispersion in mineral oil, which was removed prior to the reaction by washing with hexane) and 1.0 mL of benzene, protected from atmospheric moisture and maintained at a temperature o~
15-20C by use of an external cold water bath. This mixture was stirred for an additional 15 minutes, after which a solution of 20~ mg (1.01 mmole) of aldehyde (prepared as described in Example V) in 2.5 mL of benzene was added dropwise rapidly. After stirring this mixture at room temperature for 25 minutes, it was diluted with 20 mL of 1:1 ~v/v) pentane: ether and washed in successive order with 7:3 (v/v) lM aqueous sodium hydroxide: methyl alcohol (2 x 40 mL) to remove excess bisphosphonate and then with saturated brine (20 mL). The organic layer was then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the pentane, ether, and benzene by evaporation at reduced pressure afforded 320 mg (93~ yield) of the desired vinyl phosphonate.

EXAMPLE VII
Preparation of 3-Methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-1,3-pentadienylphosphonic Acid, Diisopropyl Ester The ylide was prepared in the manner described in the procedure of Example VI by reaction of 605 mg (1.76 mmoles) of methylenebisphosphonic acid, tetraisopropyl ester (produced in accordance with Example II), with 69 mg (1.7 mmoles) of 60~ sodium hydride. Subsequent addition of 195 mg (0.95 mmole) of the unsaturated aldehyde produced in accordance with Example V and stirring of the mixture at 20C for 25 ZO(~4125 minutes completed the reaction. The product was isolated after dilution of the mixture with 20 mL of 1:1 (v/v) pentane: ether and washing in successive order with 1:1 (v/v) lM aqueous sodium hydroxide: methyl S alcohol (2 x 40 mL) to remove excess bisphosphonate and then with saturated brine (20 mL). The organic layer was then dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the pentane, ether, and benzene by evaporation at reduced pressure afforded 313 mg (90% yield) of the desired vinyl phosphonate.

EXAMPLE VIII
Preparation of 3-Methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl~-1,4-pentadienylphosphonic Acid, DiethYl Ester The reaction was conducted in the mannerdescribed in the procedure of Example VI using the following reagents: 2.96 g (10.25 mmoles) of methylenebisphosphonic acid, tetraethyl ester (produced in accordance with Example I), in 20 mL of 3:2 (v/v) benzene: anhydrous tetrahydrofuran; 413 mg (10.3 mmoles) of 60% sodium hydride in 8.0 mL of benzene; and 1.204 g (5.85 mmoles) of unsaturated aldehyde (produced in accordance with Example IV) in 12.0 mL of benzene.
Isolation of the product as described in the procedure of Example VI afforded 1.901 g (95.5% yield) of the desired vinyl phosphonate.

EXAMPLE IX
Preparation of 3-Methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-1,4-pentadienYlphosphonic Acid, DiisoPropyl Ester The reaction was conducted in the manner described in the procedure of Example VII using the following reagents: 303 mg (0.88 mmole) of X0~4~2~j methylenebisphosphonic acid, tetraisopropyl ester (produced in accordance with Example II), in 2.5 mL of 3:2 (v/v~ benzene: anhydrous tetrahydrofuran; 36 mg (0.90 mmole) of 60% sodium hydride in 1.0 mL of benzene;
and 98 mg (0.47 mmole) of unsaturated aldehyde (produced in accordance with Example IV) in 1.5 mL of benzene.
Isolation of the product as described in the procedure of Example VII afforded 104 mg (60% yield) of the desired vinyl phosphonate.
EXAMPLE X
Preparation of 3-Methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4-pentadienylPhosphonic Acid, Diethyl E ter A mixture of the vinyl phosphonate produced in accordance with Example VIII (943 mg, 2.77 mmoles) and 99 mg (0.88 mmoles) of potassium tert-butoxide in 12 mL
of anhydrous dimethyl sulfoxide (DMSO) was stirred, protected from atmospheric moisture, at 20C for 80 minutes. The prGduct was isolated by dilution of the reaction mixture with 100 mL of ether and subsequent washing with 120 mL portions of 10% aqueous sodium chloride (4 x 120 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the e~her by evaporation at reduced pressure afforded 718 mg (76% yield) of the desired allylic phosphonate, whose structural integrity was confirmed by NMR analysis [~ 2.75, doublet of doublets, J = 8 Hz and 22 Hz, CH2P]. In a similar manner, this allylic phosphonate could be prepared by isomerization of 3-methyl-5-~2,6,6-trimethyl-l-cyclohexen-l-yl)-1,3-pentadienylphosphonic a~id, diethyl ester, produced in accordance with Example VI.

;~O~lZ5 EXAMPLE XI
Preparation of 3-Methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4-p~n~adienylphosphonic Acid, Diisopropyl Ester A mixture of vinyl phosphonate produced in accordance with Example VII (308 mg, 0.84 mmole) and 88 mg. (0.78 mmole) of potassium tert-butoxide in 4 mL of anhydrous dimethyl sulfoxide was stirred, protected from atmospheric moisture, at 20C for 30 minutes. Isolation of the product in the manner described in the procedure of Example X afforded 238 mg (77% yield) of the desired allylic phosphonate. This latter compound could also be prepared by isomerization of 3-methyl-5-(2,6,6-trimethyl-l-cyclohexen-l-yl)-1,4-pentadienylphosphonic acid, diisopropyl ester, produced in accordance with Example IX.

EXAMPLE XII
Preparation of 2-Butenyl-1,4-bi~phosphonic Acid, Tetraethvl Ester A solution of 2.00 mL (18.9 mmoles) of trans-1,4-dichloro-2-butene in 3.00 mL (17.5 mmoles) of triethyl phosphite was added dropwise slowly over 25 minutes to a flask containing 5.00 mL (29.2 r~moles) of triethyl phosphite, maintained at a temperature of approximately 140C (external oil bath temperature).
This mixture was subsequently heated at 140C for an additional 12 hours, during which time ethyl chloride was continuously distilled out of the reaction flask.
At that point, the external oil bath temperature was raised to 180C to distill over as much of the remaining triethyl phosphite as possible. The desired product was then obtained by fractional distillation under reduced pressure, affording 5.40 9 (87.5% yield) of bis-phosphonate: bp 161-184C ~bath temperature, 0.25 mm).

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EXAMPLE XIII
Preparation of 1,1,8,8-Tetramethoxy-2,7-dimethyl-2,4,6-octatriene To a solution of 312 mg (0.95 mmole) of 2-butenyl-1,4-bisphosphonic acid, tetraethyl ester (produced in accordance with Example XII), and 0.25 mL
(2.07 mmoles) of pyruvic aldehyde dimethyl acetal (available from Aldrich Chemical Co.) in 3.25 mL of 12:1 (v/v) anhydrous tetrahydrofuran: dimethyl sulfoxide, protected from atmospheric moisture and maintained at a temperature of approximately 5C by use of an external ice water bath, was added 211 mg (1.88 mmoles) of potassium tert-butoxide. This mixture was subsequently stirred in the cold for 15 minutes and then at room temperature for 7 hours. The product was isolated by dilution of the mixture with 30 mL of 1:1 (v/v) ether:
pentane and subsequent washing of the organic layer with 10% aqueous sodium chloride (3 x 30 ml). The organic layer was then dried over anhydrous sodium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 151 mq (62 yield) of bisacetal.

EXAMPLE XIV
Preparation of 2,7-Dimethvl-2,4,6-octatrienedial A solution of 150 mg (0.585 mmole) of 1,1,8,8-tetramethoxy-2,7-dimethyl-2,4,6-octatriene, produced in accordance with Example XIII, in 3.5 mL of 4:2:1 (v/v/v) glacial acetic acid: tetrahydrofuran: water was heated at 45~C ~external oil bath temperature) for 3 hours.
After cooling the solution to room temperature, the product was isolated by dilution of the mixture with 25 mL of 4:1 (v/v) ether: dichloromethane and washing the organic layer in successive order with saturated brine 2()~)412~ri (2 x 25 mL), 4:1 (v/v) saturated brine: lM aqueous sodium hydroxide (2 x 25 mL), and saturated brine (~5 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure afforded 86 mg (90% yield) of the desired bisaldehyde, previously prepared in a similar manner by H. Pommer, et al., Anqew. Chem., 72, 911 (1960).

EXAMPLE XV
Preparation of Beta-Carotene To a solution of 192 mg (0.564 mmole) of 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, diethyl ester (produced in accordance with Example X) and 41 mg (0.25 mmole) of 2,7-dimethyl-2,4,6-octatrienedial (produced in accordance with Example XIV) in 2.25 mL of 8:1 (v/v) anhydrous tetrahydrofuran: dimethyl sulfoxide, protected from atmospheric moisture and maintained at a temperature of approximately 5C by use of an external ice water bath, was added 59 mg ~0.526 mmole) of potassium tert-butoxide. This mixture was subsequently stirred in the cold for 15 minutes and then at room temperature for 3~5 hours. The product was isolated by dilution of the mixture with 25 mL of 4:1 (v/v) ether:
dichloromethane and subsequent washinq of the organic layer with 25 mL portions of 10% aqueous sodium chloride (3 x 25 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure, followed by filtration through a small column of silica gel (10 mL, 60-200 mesh, elution with 40 mL of 3:1 (v/vj hexane: benzene~ to remove any unreacted starting materlals afforded 82 mg (61% yield) of deep-purple crystals, identifi~d by NMR analysis as beta-carotene: mp 183-185C.

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EXAMPLE XVI
Preparation of all-trans Retinoic Acid, Ethyl Ester .

To a solution of 57 mg (0.40 mmole) of ethyl 3-methyl-4-oxobutenoate (prepared according to a procedure described by R.W. Curley, Jr.v et al., J.Org.Chem., 51, 256 (1986); an alternate synthesis has been described by A. Guingant, et al., J.Org.Chem., 52, 4788 (1987); the compound is commercially available from Fluka Chemical Corp., Ron Kon Koma, New York 11779.] and 132 mg (0.388 mmole) of 3-methyl-5-(2,6,6-trimethyl~l-cyclohexen-l-yl)-2,4-pentadienylphosphonic acid diethyl ester (produced in accordance with Example X) in 3.5 mL
of 6:1 (v/v) anhydrous tetrahydrofuran: dimethyl sulfoxide, protected from atmospheric moisture and maintained at a temperature of approximately 5C by use of an ice water bath, was added 43 mg (O.38 mmole) of potassium tert-butoxide. This mixture was subsequently stirred in the cold for 10 minutes and then at room temperature for 6 hours. The product was isolated by dilution of the mixture with 30 mL of 1:1 (v/v) pentane:
ether and subseqùent washing of the organic layer with 30 mL portions of 10% aqueous sodium chloride (3 x 30 mL). The organic layer was then dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure, followed by filtration through a small column of silica gel (15 mL, 60-200 mesh, elution with 75 mL of hexane -4~ ether) to remove any unreacted starting materials, afforded 76 mg (61% yield) of ethyl retinoate shown by high-field (300 MHz) NMR analysis to be predominantly the all trans stereoisomer. The product was characteri~ed by three broad singlets of equal intensity at 6 2.37, 2.02, and 1.73 (3 vinyl methyls). For tables listing spectroscopic properties of retinoids, see:

R.S.H. Liu, et al. Tetrahedron, 40, 1931-1969 (1984).
Ethyl retinoate was also prepared in a similar manner from ethyl 3-methyl-4-oxobutenoate and 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid diisopropyl ester (producedin accordance with Example XI).

EXAMPLE XVII
Preparation of 13-cis-Retinoic Acid To a solution of 88 mg (0.258 mmole) of 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid diethyl ester (produced in accordance with Example X) and 37 mg (0.324 mmole) of 5-hydroxy-4-methyl-2-(SH) furanone [prepared according to a procedure described by G. Pattenden, et al., J.Chem.Soc.(C), 1984 (1968). An alternate synthesis has been described by C.G. Wermuth, et al., J.Org.Chem., 46, 4889 (1981).] in 2.25 mL of 8:1 (v/v) anhydrous tetrahydrofuran: dimethyl sulfoxide, protected from atmospheric moisture and maintained at a temperature of approximately 5C by use of an ice water bath, was added 64 mg (0.57 mmole) of potassium tert-butoxide. This mixture was subsequently stirred in the cold for 15 minutes and then at room temperature for 3.5 hours.
After aci'difying the mixture by addition of 0.50 mL of 2M aqueous hydrochloric acid, it was diluted wi~h 25 mL
of 4:1 (v/v) ether: dichloromethane. The organic layer was washed in successive order with 10% aqueous sodium chloride (2 x 25 mL), water (1 x 25 mL), and saturated brine (1 x 25 mL), dried over anhydrous magnesium sulfate, and filtered. Removal of the volatile organic solvents by evaporation at reduced pressure, followed by filtration throu~h a small column of silica gel (6 mL, 40-140 mesh, elution with 25 mL of pentane - 20% ether~
to remove any unreacted phosphonate afforded 44 mg (57 ~o~

yield) of orange crystals, shown by NMR analysis (in CDC13 solution) to be a mixture of stereoisomers. The predominate stereoisomer (comprising approximately 75-80% of the mixture) was characterized by a doublet (J =
15 Hz) at ~ 7.81 (vinyl hydrogen bonded to C-12), a broad singlet at ~ 5.~8 (vinyl hydrogen bonded to C-14), and a broad singlet at ~ 2.11 (CH3 bonded to C-13). By comparison with the NMR data reported (in "tau values", where "tau" = 10 -~) for various stereoisomers of retinoic acid by Pattenden, et al., [J.Chem.Soc.,C., 1984-1997 (1968)], this major component was shown to be 13-cis-retinoic acid. The other (minor) component in the product exhibited broad singlets at ~ 5.82 (vinyl hydrogen bonded to C-14) and ~ 2.37 (CH3 bonded to C-13), absorptions characteristic of all-trans retinoic acid.
Although the foregoing invention has been described in some detail by way of example, various changes and modifications to the specific procedures which have been illustrated may be practiced within the scope of the appended claims.

Claims (30)

1. Phosphonates of the formula:

in which R is an alkyl group having up to four carbon atoms, and R1 is a 3-methyl pentadienyl group.

2. The phosphonate of Claim 1 wherein R1 is selected from the group consisting of , and

3. The phosphonate of Claim 1 which is 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4 pentadienylphosphonic acid, diethyl ester.

4. The phosphonate of Claim 1 which is 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, diisopropyl ester.

5. The phosphonate of Claim 1 which is 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienylphosphonic acid, diethyl ester.

6. The phosphonate of Claim 1 which is 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienylphosphonic acid, diisopropyl ester.

7. The phosphonate of Claim 1 which is 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,4-pentadienylphosphonic acid, diethyl ester.

8. The phosphonate of Claim 1 which is 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,4-pentadienylphosphonic acid, diisopropyl ester.

9. A process for forming a phosphonate ester comprising:
A) forming a reaction mixture in an organic solvent of (i) an aldehyde having the structure:

wherein R2 is , or and R3 is methyl, ethyl or propyl;
(ii) a methylene-bis-phosphonic acid ester of the formula:

wherein each R, which can be the same or different, is selected from the group consisting of alkyl groups having up to four carbon atoms; and, (iii) at least one equivalent of a base;
and B) isolating said phosphonate ester from said reaction mixture.

10. The process of Claim 9 wherein said aldehyde is selected from the group consisting of:

and

11. The process of Claim 10 wherein said methylene-bis-phosphonic acid ester is methylenebisphosphonic acid, tetraisopropyl ester.

12. The process of Claim 10 wherein said methylene-bis-phosphonic acid ester is methylenebisphosphonic acid, tetraethyl ester.

13. The process of Claim 9 wherein said aldehyde is 2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-butenal.

14. The process of Claim 9 wherein said base is selected from the group consisting of: sodium hydride; alkoxides of Group I metals; and, alkali metal carbonates.

15. A process for forming a 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, dialkyl ester, comprising the following steps:
A) forming a first reaction mixture in an organic solvent of (i) a C-14 aldehyde selected from the group consisting of and (ii) a methylene-bis-phosphonic acid ester of the formula:

; and (iii) at least one equivalent of a base;
B) separating a pentadienylphosphonic acid, dialkyl ester intermediate from said first reaction mixture;
C) forming a second reaction mixture comprising:
(i) the dialkyl ester intermediate of step B, (ii) an organic solvent, and (iii) a basic catalyst; and D) isolating 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)2,4-pentadienylphosphonic acid, dialkyl ester from said second reaction mixture.

16. The process of Claim 15 wherein said methylenebisphosphonic acid ester is selected from the group consisting of methylenebisphosphonic acid, tetraethyl ester and methylenebisphosphonic acid, tetra-isopropyl ester.

17. The process of Claim 15 wherein said base employed in step A is selected from the group consisting of: sodium hydride; alkoxides of Group I metals; and, alkali metal carbonates.

18. The process of Claim 15 wherein said basic catalyst employed in isomerization step C
comprises an alkoxide of a Group I metal.

19. The process of Claim 18 wherein said Group I metal alkoxide is selected from the group consisting of KOC(CH3)3, NaOCH3 or NaOCH2CH3.

20. The process of Claim 15 wherein said organic solvent utilized in isomerization step C
comprises dimethyl sulfoxide.

21. A process for forming beta-carotene comprising:
A) forming a reaction mixture in an organic solvent of (i) a 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-l-yl)-2,4-pentadienylphosphonic acid, dialkyl ester, (ii) a base: and (iii) 2,7-dimethyl-2,4-6-octatrienedial;
and B) isolating beta-carotene from said reaction mixture.

22. The process of Claim 21 wherein said organic solvent comprises a mixture of tetrahydrofuran and dimethyl sulfoxide.

23. The process of Claim 21 wherein said base comprises an alkoxide of a Group I metal.

24. A process for forming an alkyl ester of all-trans-retinoic acid comprising:
A) forming a reaction mixture in an organic solvent of (i) a 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, dialkyl ester, (ii) a base, and (iii) an aldehyde of the formula where R is an alkyl group having up to four carbons; and B) isolating an alkyl ester of retinoic acid from said reaction mixture.

25. The process of Claim 24 wherein said aldehyde is selected from the group consisting of methyl 3-methyl-4-oxobutenoate and ethyl 3-methyl-4-oxobutenoate.

26. The process of Claim 24 wherein said base comprises an alkoxide of a Group I metal.

27. The process of Claim 24 wherein said organic solvent comprises a mixture of tetrahydrofuran and dimethyl sulfoxide.

28. A process for forming 13-cis-retinoic acid comprising:
A) forming a reaction mixture in an organic solvent of (i) a 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonic acid, dialkyl ester, (ii) a base; and (iii) 5-hydroxy-4-methyl-2-(SH) furanone;
and B) isolating 13-cis-retinoic acid from said reaction mixture.

29. The process of Claim 28 wherein said base comprises an alkoxide of a Group I metal.

30. The process of Claim 28 wherein said organic solvent comprises a mixture of tetrahydrofuran and dimethyl sulfoxide.