C-15 phosphonate reagent compositions for the manufacture of compounds such as lycopene and methods of synthesizing the same

The present invention describes novel phosphonate reagent compositions of the formula: ##STR1## wherein R and R'=C.sub.1 -C.sub.4 alkyl groups, or R, R'=(CH.sub.2).sub.n (n=2 or 3) or [CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 ]. The invention also describes allylic C-15 phosphonate compounds of the formula: ##STR2## wherein R and R'=C.sub.1 -C.sub.4 alkyl groups. The invention also describes methods of preparing phosphonate reagent compositions (4), allylic phosphonate compounds (5), and lycopene.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention describes novel phosphonate reagent compositions of 
the formula: 
##STR3## 
wherein R and R'=C.sub.1 -C.sub.4 alkyl groups, or R, R'=(CH.sub.2).sub.n 
(n=2 or 3) or [CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 ]. 
Also described are novel methods for forming allenic C-15 phosphonate 
reagent compositions (4) from ethynyl-pseudoionone (3) (systematically 
named as 3,7,11-trimethyl-4,6,10-dodecatrien-1-yn-3-ol). 
Allenic reagent compositions (4) can be partially hydrogenated to form 
allylic C-15 phosphonate compounds of the formula: 
##STR4## 
wherein R and R'=C.sub.1 -C.sub.4 alkyl groups. 
Phosphonate compounds (5) can be employed as precursors to a variety of 
biologically-active materials, including lycopene (7). Accordingly, the 
invention also describes a four-step route for the conversion of 
pseudoionone (2) to lycopene (7). 
2. Description of Related Art 
(a) Prior Art Processes for Preparation of Lycopene and Utility of Lycopene 
There are approximately 600 naturally occurring carotenoids, but only six 
of these have so far been produced industrially. Insofar as applicants are 
aware, the only companies that manufacture synthetic "nature-identical" 
carotenoids at the present time are Roche (since 1954) and BASF (since 
1960). Sales of such compounds are growing rapidly and in 1995 surpassed 
500 million U.S. dollars. [Reference: "Carotenoids; Volume 2: Synthesis," 
edited by G. Britton, et al. (Birkhauser Verlag, Basel, 1996), page 259]. 
This reference indicates that the symmetrical acyclic C.sub.40 -carotenoid 
lycopene (7), which is the red coloring matter of tomatoes, has potential 
commercial value. Indeed, chemists at Roche have recently developed an 
industrially feasible synthesis of lycopene, although it requires the use 
of a very costly raw material (triphenylphosphine). See: K. Meyer, et al., 
Helv. Chim. Acta 1992, 75, 1848. 
Compared to .beta.-carotene, lycopene exhibits higher radical scavenging 
properties, which makes it an interesting candidate for antioxidant 
activity studies in humans [H. Gerster, J. Am. Coll. Nutr. 1997, 16, 109]. 
Levy and coworkers [Nutr. Cancer 1995, 24, 257] showed the inhibitory 
effect of lycopene on the growth of human endometrial, mammary, and lung 
cancer cells; and it has been verified that a lycopene-rich diet decreases 
the risk of prostate cancer [E. Giovannucci, et al., J. Natl. Cancer Inst. 
1995, 87, 1767]. Indeed, it is now thought that lycopene is important in 
giving protection against a variety of serious disorders including cancer, 
heart disease, and degenerative eye diseases. For example, lycopene is 
known to be an antitumor agent against brain tumors [Chem. Abstracts 1990, 
112 91375w]. Also interesting is the report in a recent Japanese patent 
[Chem. Abstracts 1991, 115, 214528v] that a topical solution of lycopene 
controls acne and also markedly promotes hair growth in mice. 
The first synthesis of lycopene (7) was reported in 1950 [P. Karrer, et 
al., Helv. Chim. Acta 1950, 33, 1349], but suffered from a low overall 
yield (0.1%) starting with pseudoionone (2). Subsequent syntheses of 
lycopene starting with pseudoionone proceeded in overall yields as high as 
20% [e.g., B. C. L. Weedon, et al., J. Chem. Soc. 1965, 2019]. However, 
all such syntheses required too many steps and/or the use of costly raw 
materials (e.g., triphenylphosphine). Other syntheses of lycopene can be 
found in: O. Isler, et al., Helv. Chim. Acta 1956, 39, 463; K. Bernhard 
and H. Mayer, Pure & Appl. Chem. 1991, 63, 35; and Chem. Abstracts 1991, 
114, 82198e. 
(b) Prior Art Processes for Forming Pseudoionone 
A preliminary step in a preferred method for preparing the compounds of the 
present invention involves the preparation of pseudoionone (2) [IU 
name: 6,10-dimethyl-undeca-3,5,9-trien-2-one]. This specialty chemical can 
be prepared by a crossed-aldol condensation of citral (1) [IU name: 
3,7-dimethylocta-2,6-dienal] with acetone: 
##STR5## 
Alternatively, pseudoionone (2) can be prepared by the following four-step 
route starting with isoprene (as disclosed in Babler et al., U.S. patent 
application Ser. No. 09/161,983, filed on Sep. 19, 1998, the disclosure of 
which is hereby incorporated by reference): 
##STR6## 
(c) Prior Art Processes for Forming 3.degree. Propargylic Alcohols. 
The first step in a preferred method for preparing the compounds of the 
present invention involves the addition of acetylide to pseudoionone (2) 
to form a 3.degree. propargylic alcohol (3) in high yield: 
##STR7## 
See O. Isler, et al., Helv. Chim. Acta 1961, 44, 985. (d) Prior Art 
Processes for Converting 3.degree. Propargylic and Allylic Alcohols to 
Allenic and Allylic Phosphonates 
The second step in the preparation of phosphonate reagent compositions (4) 
is a novel process wherein ethynyl-pseudoionone (3) (systematically named 
as 3,7,11-trimethyl-4,6,10-dodecatrien-1-yn-3-ol) is reacted with a 
dialkyl chlorophosphite. Processes wherein structurally-simple 3.degree. 
propargylic alcohols have been converted to allenic phosphonates have been 
described: 
##STR8## 
For examples of the above reaction, see: H. J. Altenbach and R. Korff, 
Tetrahedron Lett., 1981, 22, 5175 and U.S. Pat. No. 3,197,497. 
In a similar process, 3.degree. allylic alcohols have been converted into 
allylic phosphonates: 
##STR9## 
However, ethynyl-pseudoionone (3) could have undergone dehydration 
(yielding 3,7,11-trimethyl-3,5,7,10-dodecatetraen-1-yne) when treated with 
ClP(OCH.sub.2 CH.sub.3).sub.2 in the presence of a tertiary amine, instead 
of being converted into the novel C-15 allenic phosphonate (4). Indeed, 
the closely-related ethynyl-.beta.-ionol has been reported to undergo 
dehydration when treated (0.degree. C. to room temperature) with 
phosphorous oxychloride and a non-nucleophilic base (e.g., a tertiary 
amine such as pyridine or triethylamine): 
##STR10## 
See M. J. Szwedo, Jr., STUDIES DIRECTED TOWARDS THE TOTAL SYNTHESIS OF 
RETINOIDS, Ph.D. Dissertation, Loyola University of Chicago, 1983, pages 
24 & 57-59. 
SUMMARY OF THE INVENTION. 
The present invention describes novel allenic phosphonate reagent 
compositions (4) which can be synthesized in one reaction from 
ethynyl-pseudoionone (3): 
##STR11## 
wherein R and R'=C.sub.1 -C.sub.4 alkyl groups, or R, R'=(CH.sub.2).sub.n 
(n=2 or 3) or [CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 ]. 
When R and R' are alkyl groups having up to four carbon atoms, the 
compounds of the invention are systematically named as esters of an 
alkapentaenylphosphonic acid. For example, when R=R'=ethyl, the compound 
is named: 
3,7,11-trimethyl-1,2,4,6,10-dodecapentaenylphosphonic acid, diethyl ester. 
Other compounds within the scope of the present invention include: 
3,7,11-trimethyl-1,2,4,6,10-dodecapentaenylphosphonic acid, dimethyl ester; 
3,7,11-trimethyl-1,2,4,6,10-dodecapentaenylphosphonic acid, diisopropyl 
ester; 
3,7,11-trimethyl-1,2,4,6,10-dodecapentaenylphosphonic acid, dipropyl ester; 
and 
3,7,11-trimethyl-1,2,4,6,10-dodecapentaenylphosphonic acid, dibutyl ester. 
Phosphonate reagents (4) also include C-15 allenic phosphonate compounds in 
which R and R' form part of a 5- or 6-membered heterocyclic ring. Thus, 
for example, when R, R'=CH.sub.2 CH.sub.2, the compound is named 
2-(3,7,11-trimethyldodeca-1,2,4,6,10-pentaenyl)-1,3,2-dioxaphospholan-2-on 
e: 
##STR12## 
The present invention also describes novel C-15 allylic phosphonates (5), 
which can be represented by the following formula: 
##STR13## 
wherein R and R'=C.sub.1 -C.sub.4 alkyl groups. 
As described in more detail below, allylic phosphonates (5) can be prepared 
by partial reduction of the phosphonate reagents (4). The allylic 
phosphonates (5) are named as ester derivatives of an 
alkatetraenylphosphonic acid. Thus, for example when R=R'=ethyl, the 
compound is named: 
3,7,11-trimethyl-2,4,6,10-dodecatetraenylphosphonic acid, diethyl ester. 
Other compounds within the scope of the present invention include: 
3,7,11-trimethyl-2,4,6,10-dodecatetraenylphosphonic acid, dimethyl ester; 
3,7,11-trimethyl-2,4,6,10-dodecatetraenylphosphonic acid, diisopropyl 
ester; 
3,7,11-trimethyl-2,4,6,10-dodecatetraenylphosphonic acid, dipropyl ester; 
3,7,11-trimethyl-2,4,6,10-dodecatetraenylphosphonic acid, dibutyl ester; 
and 
3,7,11-trimethyl-2,4,6,10-dodecatetraenylphosphonic acid, ethyl 
beta-hydroxyethyl diester. 
The invention also describes methods for preparing allenic phosphonate 
reagent compositions (4) and allylic phosphonates (5). The invention also 
relates to a four-step route for the conversion of pseudoionone (2) to 
lycopene (7). Attractive features of this route to lycopene include: the 
route does not require any oxidative transformations; it avoids the use of 
organic halides and metals (other than sodium); all steps proceed in high 
yield; and all raw materials necessary for this route are low-cost 
compounds which are manufactured on an industrial scale. 
A method of preparing allenic phosphonate reagent compositions (4) includes 
the following steps: 
(I) forming a reaction mixture in an aprotic solvent comprising: 
(a) ethynyl-pseudoionone; 
(b) at least one molar equivalent of a non-nucleophilic base; and 
(c) at least one molar equivalent of a dialkyl chlorophosphite reagent; and 
(II) maintaining the reaction mixture until the allenic phosphonate is 
formed. 
A method of preparing allylic phosphonates (5) includes the following 
steps: 
(I) forming a first reaction mixture in an aprotic solvent comprising: 
(a) ethynyl-pseudoionone; 
(b) at least one molar equivalent of a non-nucleophilic base; and 
(c) at least one molar equivalent of a dialkyl chlorophosphite reagent; 
(II) maintaining the first reaction mixture until the allenic phosphonate 
is formed; and 
(III) partially reducing the allenic phosphonate of step II. 
The partial reduction step (III) may include the steps of forming a second 
reaction mixture in an alcohol solvent including the allenic phosphonate 
of step II, ammonium formate, and 10% Pd--C; and vigorously agitating the 
second reaction mixture while heating it to a temperature in excess of 
room temperature. The partial reduction step (III) may include the step of 
forming a second reaction mixture including the allenic phosphonate of 
step II and sodium borohydride. 
The methods for preparing compounds (4) and (5) are analogous to reactions 
disclosed in Babler, U.S. patent application Ser. No. 08/975,819 filed 
Nov. 21, 1997, the disclosure of which is hereby incorporated by 
reference. 
The methods for preparing an allenic phosphonate reagent composition (4), 
an allylic phosphonate (5), and lycopene (7) are summarized by the 
following reaction sequence: 
##STR14## 
Step (b) of the reaction sequence--the conversion of ethynyl-pseudoionone 
(3) to phosphonate reagent compositions (4)--utilizes a reagent with a 
phosphorus-chlorine bond in the presence of a 3.degree. amine. This 
conversion requires: 
(A) ethynyl-pseudoionone (3) in an aprotic organic solvent; 
(B) the presence of at least one molar equivalent of a non-nucleophilic 
base: tertiary amines such as pyridine or triethylamine, Na.sub.2 CO.sub.3 
and K.sub.2 CO.sub.3 are especially preferred; and 
(C) addition of one molar equivalent of a dialkyl chloro-phosphite reagent, 
(RO).sub.2 PCl, to a mixture of (A) and (B): preferred phosphite reagents 
include diethyl chlorophosphite and 2-chloro-1,3,2-dioxaphospholane. Step 
(b) proceeds at reaction temperatures from approximately 0.degree. C. to 
room temperature, although higher temperatures can be employed. In a 
preferred method, a dialkyl chlorophosphite reagent is added, dropwise, 
with external cooling, to a stirred reaction mixture which is maintained 
at approximately 0.degree. C. under an atmosphere of a non-reactive gas 
(e.g., nitrogen gas). Once addition of the dialkyl chlorophosphite reagent 
is complete, the reaction mixture is allowed to warm up to room 
temperature to enable the reaction to go to completion, and the reaction 
proceeds rapidly (less than one hour). Upon completion, the addition of a 
small amount of water to the reaction mixture will destroy any unreacted 
dialkyl chlorophosphite reagent. 
The dialkyl chlorophosphite reagent utilized in step (b) can be prepared by 
treating PCl.sub.3 with 2 equivalents of alcohol (e.g., ethyl alcohol) in 
a nonpolar solvent as described by J. Michalski, et. al. in J. Chem. Soc., 
1961, 4904. Alternatively, the desired transformation can be effected by 
adding PCl.sub.3 to the mixture of (A) and (B), followed by the addition 
of two equivalents of alcohol. 
Allenic phosphonate compounds (4) can be partially reduced to form allylic 
phosphonate compounds (5), as depicted in step (c), above. This 
transformation was achieved using one equivalent of ammonium formate in 
methyl alcohol (chemistry analogous to that described in U.S. patent 
application Ser. No. 08/975,819). More conveniently, as a small-scale 
laboratory transformation, partial reduction of (4) to obtain (5) was 
achieved in quantitative yield by use of NaBH.sub.4 in ethyl alcohol at 
room temperature--a reaction for which there is no literature precedent 
(i.e., NaBH.sub.4 has never been utilized to reduce allenic phosphonates). 
The novel route to lycopene is concluded by a modified Wittig reaction 
involving the alkoxide-base promoted coupling of C-15 phosphonate reagent 
(5) to C-10 dialdehyde (6) [IU name: 
2,7-dimethylocta-2,4,6-triene-1,8-dial]. Many syntheses of the latter 
compound (6) are known, including two routes in recent U.S. Pat. No. 
[5,107,030 (Apr. 21, 1992) and U.S. Pat. No. 5,471,005 (Nov. 28, 1995)] 
granted to J. Babler. For previous syntheses of dialdehyde (6), see: O. 
Isler, Carotenoids, Birkhauser-Verlag, pp. 431-36 (1971). 
The selective hydrogenation of only one of the five double bonds in C-15 
allenic phosphonate (4) to obtain C-15 allylic phosphonate (5), the direct 
precursor to lycopene, could not be predicted in advance. Initial attempts 
to convert (4) to (5) using 6 equivalents of ammonium formate and a 
palladium catalyst in methyl alcohol [as reported by B. C. Ranu, et al, J. 
Org. Chem., 63, 5250 (1998)] resulted in reduction of the double bonds 
between C-4 and C-5, as well as C-1 and C-2. Indeed, the relatively 
unhindered disubstituted double bond between C-4 and C-5 might be easier 
to hydrogenate than the olefinic linkage between C-1 and C-2 (due to the 
presence of the bulky phosphonate group). Consistent with this concern is 
a report by C. J. Palmer, et al., Tetrahedron Lett. 1990, 31, 2857, that 
unhindered olefin moieties can be selectively hydrogenated in the presence 
of the easily reduced terminal alkyne functionality if a bulky substituent 
is bonded to the latter. 
The other methodology used to selectively reduce one of the five double 
bonds in C-15 allenic phosphonate (4) to obtain C-15 allylic phosphonate 
(5) utilizes a metal hydride reducing agent (NaBH.sub.4). No prior art 
directly related to that transformation ((4).fwdarw.(5)) could be found. 
Indeed, allylic phosphonates themselves are known to be subject to 
reduction by use of a suitable metal hydride at room temperature. For 
example, see the conversion of allylic phosphonate 1 g to alkene 2 g 
reported by T. Hirabe, et al., J. Org. Chem., 49, 4084 (1984).

DETAILED DESCRIPTION OF THE INVENTION 
The following examples are presented for purposes of illustration and 
should not be construed as limiting the invention which is delineated in 
the claims. 
EXAMPLE I 
Preparation of 6,10-Dimethyl-3,5,9-undecatrien-2-one (pseudoionone) 
1.00 mL (5.84 mmoles) of citral (purchased from Aldrich Chemical Co., 
Milwaukee, Wis.), 20 mL of acetone (HPLC-grade, purchased from Aldrich 
Chemical Co.), and 1.66 g of alumina (weakly acidic, activated, Brockmann 
I, 150 mesh, Aldrich catalog #26,774-0) were added to a 200 mL glass 
pressure bottle containing a Teflon-coated spin bar. After sweeping the 
bottle briefly with a stream of nitrogen gas, the bottle was closed; and 
the mixture was subsequently heated at 65-70.degree. C. (external oil bath 
temperature) for 20 hours. After cooling the mixture to room temperature, 
the product was isolated by dilution of the reaction mixture with 160 mL 
of 3:1 (v/v) ether: dichloromethane and removal of the alumina by 
filtration through a small pad of Hyflo Super-Cel.RTM. filtering aid. For 
large-scale reactions, fractional distillation of this filtrate would be 
the only requirement to complete the process of isolating the product. For 
convenience in a small-scale reaction, the filtrate was washed three times 
with 140 mL portions of 5% (w/v) aqueous sodium chloride to remove 
4-hydroxy-4-methyl-2-pentanone (formed in minor amounts by the self-aldol 
condensation of acetone), then dried over anhydrous magnesium sulfate, and 
filtered. Removal of the ether and dichloromethane by evaporation at 
reduced pressure and subsequent evaporative ("Kugelrohr oven") 
distillation afforded 1.03 g (91% yield) of the named unsaturated ketone: 
boiling point 102-110.degree. C. (bath temperature, 0.40 mm). The identity 
and purity of this compound was ascertained by IR and proton NMR analysis 
(recorded at 400 MHz). The latter spectrum exhibited a multiplet at 
.delta. 7.42 (C-4 vinyl H), a doublet (J=14.8 Hz) at .delta. 6.08 (C-3 
vinyl H), a doublet (J=12 Hz) at .delta. 6.004 (C-5 vinyl H), a multiplet 
at .delta. 5.09 (C-9 vinyl H), a singlet at .delta. 2.27 (CH.sub.3 
C.dbd.O), and signals for three vinyl methyl groups at .delta. 1.90 
(CH.sub.3 bonded to C-6), 1.676, and 1.606. 
For an alternative procedure to convert citral to pseudoionone, see: 
ORGANIC SYNTHESES, Collective Volume 3, page 747. 
EXAMPLE II 
Preparation of 3,7,11-Trimethyl-4,6,10-dodecatrien-1-yn-3-ol by Treatment 
of Pseudoionone with Ethynylmagnesium Chloride 
20 mL of 0.5 M solution of ethynylmagnesium chloride (10 mmoles) in 
tetrahydrofuran (purchased from Aldrich Chemical Co., Milwaukee, Wis.) was 
added to a 100 mL 3-neck reaction flask fitted with an addition funnel and 
an adapter connected to an apparatus similar to that described by Johnson 
and Schneider [Org. Synth., 30, 18 (1950)] so that the mixture in the 
flask could be protected from atmospheric moisture, et al. throughout the 
course of the reaction. After sweeping the system briefly with a stream of 
nitrogen gas and placing the flask in an ice-water bath (0.degree. C.), a 
solution of 926 mg (4.815 mmoles) of pseudoionone (prepared as described 
in Example I) in 2.50 mL of anhydrous tetrahydrofuran was added dropwise 
over 5 minutes to the stirred Grignard reagent. The resulting mixture was 
stirred at 0.degree. C. for an additional 90 minutes; after which it was 
diluted with 5 mL of hexane and the excess organometallic reagent was 
destroyed by slow, dropwise addition of 8 mL of saturated aqueous ammonium 
chloride. After allowing the mixture to warm to room temperature, it was 
diluted with 50 mL of 1:1 (v/v) hexane: ether and 200 mL of saturated 
brine mixed with 5 mL of 2 M aqueous HCl. After separation from the 
aqueous layer, the organic layer was washed with saturated brine 
(2.times.150 mL), dried over anhydrous magnesium sulfate, and subsequently 
filtered. Removal of the volatile organic solvents by evaporation at 
reduced pressure and subsequent evaporative ("Kugelrohr oven") 
distillation in the presence of 10 mg of powdered CaCO.sub.3 afforded 970 
mg (92% yield) of the named unsaturated alcohol: boiling point 
105-120.degree. C. (bath temperature, 0.25 mm). The identity and purity of 
this compound was ascertained by IR and proton NMR analysis (recorded in 
CDCl.sub.3 solution at 300 MHz). The latter spectrum exhibited a multiplet 
at .delta. 6.748 (C-4 vinyl H), a doublet (J=10.8 Hz) at .delta. 5.840 
(C-6 vinyl H), a doublet of doublets (J=15, 10.8 Hz) at .delta. 5.662 (C-5 
vinyl H), a multiplet at .delta. 5.096 (C-10 vinyl H), a singlet at 
.delta. 2.582 (C.tbd.CH), and a singlet at .delta. 1.579 (CH.sub.3 bonded 
to C-3). An alternate route to this same alkynol can be found in R. Ruegg, 
et al., Helv-. Chim. Acta, 44, 985 (1961). 
EXAMPLE III 
Preparation of 3,7,11-Trimethyl-1,2,4,6,10-dodecapentaenylphosphonic acid, 
Diethyl Ester 
To a 15 mL 2-neck reaction flask fitted with an adapter connected to an 
apparatus similar to that described by Johnson and Schneider [Org. Synth., 
30, 18 (1950)] so that the mixture in the flask could be protected from 
atmospheric moisture, et al. throughout the course of the reaction were 
added 328 mg (1.502 mmoles) of distilled alkynol prepared as described in 
Example II, 0.50 mL (3.59 mmoles) of triethylamine (purchased from Aldrich 
Chemical Co., Milwaukee, Wis.), 2 mg of hydroquinone (or other suitable 
antioxidant), and 3.5 mL of dichloromethane (A.C.S. reagent-grade, 
purchased from Aldrich Chemical Co.). After placing the flask in an 
ice-water bath (0.degree. C.), 0.35 mL (2.42 mmoles) of diethyl 
chlorophosphite (95%, purchased from Aldrich Chemical Co.) was added 
dropwise via syringe while simultaneously maintaining the stirred reaction 
mixture under a gentle stream of nitrogen gas. The resulting mixture was 
stirred at 0.degree. C. for an additional 10 minutes and subsequently at 
room temperature for 75 minutes. The mixture was then cooled to 
approximately 0.degree. C. by means of an external ice-water bath, and 
0.10 mL of water was added to destroy any unreacted diethyl 
chlorophosphite. After dilution of the mixture with 45 mL of 2:1 (v/v) 
hexane:dichloromethane, the organic layer was washed in successive order 
with 25 mL portions of 10% aqueous sodium chloride and saturated brine. 
The organic extracts were then dried over anhydrous magnesium sulfate and 
subsequently filtered. Removal of the volatile organic solvents by 
evaporation at reduced pressure, subsequent addition of 5 mL of benzene to 
the residual material, and removal of the benzene accompanied by trace 
amounts of triethylamine under reduced pressure afforded 511 mg of crude 
product. The latter material was purified via chromatography on Florisil 
(20 mL, 60-100 mesh). After removal of any non-polar impurities by washing 
the column with 60 mL of 19:1 (v/v) hexane:ether, the named phosphonate 
(428 mg, 84% yield) was eluted using 100 mL of 1:1(v/v) 
ether:dichloromethane. The identity and purity of this compound were 
ascertained by IR (1935 cm.sup.-1, C.dbd.C.dbd.C) and proton NMR analysis 
(recorded in CDCl.sub.3 solution at 300 MHz). The latter spectrum 
exhibited a singlet (broad) at .delta. 5.48 (C-1 vinyl H), a multiplet at 
.delta. 5.092 (C-10 vinyl H), a multiplet at .delta. 4.098 (two OCH.sub.2 
moieties), a broad singlet at .delta. 1.92 (CH.sub.3 bonded to C-3), 
singlets at .delta. 1.797, 1.681 and 1.607 (the other three vinyl CH.sub.3 
's), and a triplet (J=7.2 Hz) at .delta. 1.321 (2.times.CH.sub.3 in the 
phosphonate moiety). In order to prevent aerobic oxidation of this 
unsaturated phosphonate, it should be stored in the presence of a small 
amount of a suitable antioxidant (e.g., hydroquinone). 
NOTE: In lieu of purchasing diethyl chlorophosphite from Aldrich Chemical 
Co., it can be prepared from phosphorus trichloride and ethyl alcohol in 
accordance with a procedure suggested by J. Michalski, et al., J. Chem. 
Soc., 4904 (1961). 
EXAMPLE IV 
Partial Reduction of 3,7,11-Trimethyl-1,2,4,6,10-dodecapentaenylphosphonic 
Acid, Diethyl Ester 
In accordance with a procedure suggested by B. C. Ranu, et al., J. Org. 
Chem., 63, 5250 (1998), the following experiment was conducted: To a 25-mL 
1-neck reaction flask fitted with a reflux condenser connected to an 
apparatus similar to that described by Johnson and Schneider [Org. Synth., 
30, 18 (1950)] so that the mixture in the flask could be protected from 
atmospheric moisture, et al. throughout the course of the reaction were 
added 135 mg (0.40 mmole) of allenic phosphonate produced in accordance 
with Example III, 1 mg of hydroquinone (or other suitable antioxidant), 
4.0 mL of methyl alcohol (HPLC-grade, purchased from Aldrich Chemical 
Co.), 148 mg (2.35 mmoles) of ammonium formate (purchased from Aldrich 
Chemical Co.), and 21 mg of 10% Pd--C (available from Aldrich Chemical 
Co.). After sweeping the system briefly with nitrogen gas, the mixture was 
heated, with vigorous stirring, at 60-65.degree. C. (external oil bath 
temperature) for 20 hours. After cooling the mixture to room temperature, 
the product was isolated by dilution of the reaction mixture with 25 mL of 
4:1 (v/v) ether:dichloromethane and removal of the palladium catalyst by 
filtration through a small pad of Hyflo Super-Cel.RTM. filtering aid. The 
filtrate was subsequently washed with saturated brine (2.times.50 mL), 
then dried over anhydrous magnesium sulfate and filtered. Removal of the 
ether and dichloromethane by evaporation at reduced pressure afforded 120 
mg (88% yield, not corrected for over-reduction) of a mixture of 
unsaturated phosphonates. IR analysis of the latter indicated that the 
double bond between C-1 and C-2 had been reduced [i.e., lack of absorption 
at 1935 cm.sup.-1 arising from the allenic moiety (C.dbd.C.dbd.C)]; 
however, proton NMR analysis indicated that some over-reduction (i.e., 
hydrogenation of the double bond between C-4 and C-5) had occurred. 
Although over-reduction could be prevented by use of a stoichiometric 
amount (i.e., 1-1.2 equivalents) of ammonium formate under similar 
reaction conditions, the process was quite slow. For small-scale 
experiments, it was more convenient to effect the partial reduction of the 
named allenic phosphonate by use of sodium borohydride in ethyl alcohol as 
described in Example V. 
EXAMPLE V 
Preparation of 3,7,11-Trimethyl-2,4,6,10-dodecatetraenylphosphonic Acid, 
Diethyl Ester 
To a 25 mL reaction flask fitted with an adapter connected to an apparatus 
similar to that described by Johnson and Schneider [Org. Synth., 30, 18 
(1950)] so that the mixture in the flask could be protected from 
atmospheric moisture, et al. throughout the course of the reaction were 
added 272 mg (0.80 mmole) of allenic phosphonate produced in accordance 
with Example III, 4.0 mL of absolute ethanol, and 60 mg (1.59 mmoles) of 
sodium borohydride (purchased from Aldrich Chemical Co., Milwaukee, Wis.). 
This mixture was subsequently stirred at room temperature for 3 hours. The 
product was isolated after dilution of the reaction mixture with 30 mL of 
2:1 (v/v) hexane:dichloromethane and subsequent washing of the organic 
layer in successive order with 5% (w/v) aqueous sodium chloride (50 mL) 
and 10% (w/v) aqueous sodium chloride (2.times.40 mL). The organic layer 
was then dried over anhydrous magnesium sulfate and subsequently filtered. 
Removal of the volatile organic solvents by evaporation at reduced 
pressure afforded 265 mg (97% yield) of the named allylic phosphonate. The 
identity of this compound was confirmed by proton NMR analysis (recorded 
in CDCl.sub.3 solution at 400 MHz). The latter spectrum exhibited a 
doublet of doublets (J=22.5, 8.4 Hz) at .delta. 2.72 (CH.sub.2 P). IR 
analysis of the product confirmed the absence of any unreacted starting 
compound (i.e., no absorption at 1935 cm.sup.-1). 
EXAMPLE VI 
Preparation of 
2-(3,7,11-Trimethyldodeca-1,2,46,10-pentaenyl)-1,3,2-dioxaphospholan-2-one 
The reaction was conducted in the manner described in the procedure of 
Example III using the following reagents: 292 mg (1.34 mmoles) of 
distilled 3,7,11-trimethyl-4,6,10-dodecatrien-1-yn-3-ol (produced in 
accordance with Example II), 1.5 mg of hydroquinone, 0.35 mL (2.51 mmoles) 
of triethylamine, 2.50 mL of dichloromethane (A.C.S. reagent-grade), and 
150 microliters (1.69 mmoles) of 2-chloro-1,3,2-dioxaphospholane 
(purchased from Aldrich Chemical Co., Milwaukee, Wis.). Isolation of the 
product as described in the procedure of Example III afforded (with no 
need for purification by chromatography) 372 mg (90% yield) of the named 
allenic phosphonate. The identity and purity of this compound were 
ascertained by IR (1935 cm.sup.-1, C.dbd.C.dbd.C) and proton NMR analysis 
(recorded in CDCl.sub.3 solution at 300 MHz). The latter spectrum 
exhibited a broad singlet at .delta. 5.587 (C-1 vinyl H), a multiplet at 
.delta. 5.083 (C-10 vinyl H), two multiplets at .delta. 4.43 and 4.20 
(OCH.sub.2 CH.sub.2 O), a multiplet at .delta. 1.930 (CH.sub.3 bonded to 
C-3), a singlet at .delta. 1.797 (CH.sub.3 bonded to C-7), and two broad 
singlets at .delta. 1.678 and 1.602 (the other two vinyl CH.sub.3 's). 
Storage of this compound in the presence of a small amount of a suitable 
antioxidant (e.g., hydroquinone) is recommended. 
EXAMPLE VII 
Partial Reduction of 
2-(3,7,11-Trimethyldodeca-1,2,4,6,10-pentaenyl)-1,3,2-dioxaphospholan-2-on 
e 
The reaction was conducted in the manner described in the procedure of 
Example V using the following reagents: 196 mg (0.636 mmole) of the 
above-named allenic phosphonate (produced in accordance with Example VI), 
4.0 mL of absolute ethyl alcohol, and 47 mg (1.24 mmoles) of sodium 
borohydride. Isolation of the product as described in the procedure of 
Example V afforded 207 mg of a phosphonate that was shown by IR and proton 
NMR analysis (300 MHz) to have a structure different from the anticipated 
2-[3,7,11-trimethyldodeca-2,4,6,10-tetraenyl]-1,3,2-dioxaphospholan-2-one. 
The product was identified as 
3,7,11-trimethyl-2,4,6,10-dodecatetraenyl-phosphonic acid, ethyl 
beta-hydroxyethyl diester--an allylic phosphonate that can still be used 
in the synthesis of lycopene. The formation of this product can be 
explained by the facile ethanolysis of the strained heterocyclic ring 
(i.e., a 1,3,2-dioxaphospholan-2-one) present in the starting material. 
The proton NMR spectrum of this product exhibited a multiplet at .delta. 
4.124 (4H's, 2.times.POCH.sub.2), a multiplet at .delta. 3.777 (CH.sub.2 
bonded to an OH), a doublet of doublets (J=23.1, 8.4 Hz) at .delta. 2.78 
(CH.sub.2 P), and a triplet (J=6.9 Hz) at .delta. 1.31 (CH.sub.3 in the 
phosphonate moiety). 
EXAMPLE VIII 
Preparation of Lycopene 
To a solution of 211 mg (0.62 mmole) of 
3,7,11-trimethyl-2,4,6,10-dodecatetraenylphosphonic acid, diethyl ester 
(produced in accordance with Example V) and 40 mg (0.24 mmole) of 
2,7-dimethyl-2,4,6-octatrienedial (prepared as described in Example XIV of 
U.S. Pat. No. 5,061,819) in 2.25 mL of 8:1 (v/v) anhydrous 
tetrahydrofuran:dimethyl sulfoxide, protected from atmospheric moisture 
and maintained at a temperature of approximately 50.degree. C. by use of 
an external ice water bath was added 70 mg (0.62 mmole) of potassium 
tert-butoxide. This mixture was subsequently stirred in the cold for 15 
minutes and then at room temperature for 3 hours. The product was isolated 
by dilution of the mixture with 25 mL of chloroform and subsequent washing 
of the organic layer with 5% (w/v) aqueous sodium chloride (3.times.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 
Florisil (10 mL, 60-100 mesh, elution with 90 mL of benzene) to remove any 
unreacted starting materials afforded 70 mg (54% yield) of lycopene, the 
identity of which was confirmed by proton NMR analysis (recorded in 
CDCl.sub.3 solution at 300 MHz). The latter spectrum exhibited absorptions 
at .delta. 5.106, 5.949, 6.198, 6.266, 6.341, 6.493, 6.627, and 6.674 (due 
to the vinyl H's) and broad singlets at .delta. 1.960, 1.817, 1.686, and 
1.615 (ascribed to the vinyl methyl groups in lycopene). The latter data 
is fully consistent with that reported for lycopene in an article by U. 
Hengartner, et al., Helv. Chim. Acta, 75, 1848-1865 (1992) [see Column 1 
in Table 2 on page 1854 of that article]. 
NOTE: For a large-scale synthesis of lycopene, use of potassium 
tert-butoxide as the base is undesirable. More conveniently, one can use 
sodium methoxide as the base in a solvent mixture of methyl alcohol and 
dichloromethane--as reported in an alternate route to lycopene. See: 
European patent application EP 382,067 (Aug. 16, 1990), cited in Chem. 
Abstracts, 114, 82198e (1991).