Stereospecific Pd(0)-Catalyzed Arylation of an Allylic Hydroxy Phosphonate Derivative: Formal Synthesis of (S)-(+)-ar-Turmerone

Article abstract of DOI:10.1021/jo0351318

Reaction of the (1S)-allylic hydroxy phosphonate 1(S) with methyl chloroformate in pyridine yields the corresponding carbonate 3(S). The carbonate 3(S) undergoes a palladium-catalyzed arylation with p-tolyl tributylstannane to give both the 1E and 1Z viny

Full text of DOI:10.1021/jo0351318

SCHEME 1. P a lla d iu m (0)-Ca ta lyzed Rea ction s of
Allylic Hyd r oxy P h osp h on a te Der iva tives
Ster eosp ecific P d (0)-Ca ta lyzed Ar yla tion of
a n Allylic Hyd r oxy P h osp h on a te
Der iva tive: F or m a l Syn th esis of
(S)-(+)-a r -Tu r m er on e
Bradley J . Rowe and Christopher D. Spilling*
Department of Chemistry and Biochemistry, University of
MissourisSt. Louis, 8001 Natural Bridge Road,
St. Louis, Missouri 63121
cspill@umsl.edu
catalytic asymmetric phosphonylation of unsaturated
aldehydes.5 These nonracemic hydroxy phosphonates
should be useful building blocks for asymmetric synthe-
sis, provided that appropriate stereoselective or ste-
reospecific transformations can be discovered. Having
demonstrated that the palladium (0)-catalyzed addition
of amines to nonracemic allylic hydroxy phosphonate
derivatives proceeded with complete chirality transfer,6
our attention turned to the exploration of reactions with
carbon-based nucleophiles.7
The aromatic bisabolenes 5a -m are a series of mono-
cyclic sesquiterpenes isolated from both terrestrial plants
and marine organisms (Scheme 2).8 The interesting
biological properties displayed by some members of the
aromatic bisabolene family has contributed to their
attraction as targets for synthesis.9 The aromatic bis-
abolenes contain a characteristic substituted phenyl ring
with a methyl-bearing chiral benzylic carbon. Several
methods have been reported for the enantioselective
synthesis of the benzylic chiral center of the bisabolenes,
including10 enzyme-mediated reduction,10a,b enzyme-
mediated kinetic resolution and desymmetrization,10c-f
conjugate addition utilizing a chiral auxiliary,10g-j and
the Sharpless epoxidation,10k,l among others.
Received J uly 31, 2003
Abstr a ct: Reaction of the (1S)-allylic hydroxy phosphonate
1(S) with methyl chloroformate in pyridine yields the
corresponding carbonate 3(S). The carbonate 3(S) undergoes
a palladium-catalyzed arylation with p-tolyl tributylstan-
nane to give both the 1E and 1Z vinyl phosphonates 6
(85:15). The E and Z vinyl phosphonates 6 were shown to
have the opposite configuration at C-3. The major vinyl
phosphonate isomer (3S,1E), was converted to (3S)-3-(p-
tolyl)-butanal 8(S), completing a formal total synthesis of
(S)-ar-turmerone 5a .
Allylic hydroxy phosphonates 1 display some of the rich
chemistry associated with allylic alcohols; however, the
steric and electronic influence of the phosphorus moiety
can enhance the stereochemical and regiochemical out-
come of the reactions.1,2 This effect is well demonstrated
in the palladium-catalyzed addition of nucleophiles to the
corresponding acetate 2 and carbonate 3 derivatives
(Scheme 1). The acetate and carbonate derivatives (2 and
3) undergo palladium-catalyzed regioselective addition
of various nucleophiles to give γ-substituted vinyl phos-
phonates 4 in high yield.1 The nucleophile adds exclu-
sively to the 3 position, with migration of the double bond
into “conjugation” with the phosphoryl group.1 More
generally, it has been shown that allylic hydroxy phos-
phonates can serve as useful intermediates in the syn-
thesis of γ-substituted phosphonates by 1,3 transposition
of functionality.2
An enantioselective synthesis of the aromatic bis-
abolene core structure was proposed (Scheme 3) wherein
(5) (a) Rowe, B. J .; Spilling, C. D. Tetrahedron: Asymmetry 2001,
12, 1701. (b) Groaning, M. D.; Rowe, B. J .; Spilling, C. D. Tetrahedron
Lett. 1998, 39, 5485. (c) Rath, N. P.; Spilling, C. D. Tetrahedron Lett.
1994, 35, 227. (d) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahe-
dron: Asymmetry 1993, 4, 1783. (e) Yokomatsu, T.; Yamagishi, T.;
Shibuya S. J . Chem. Soc., Perkin Trans. 1 1997, 1527. (f) Sasai, H.;
Bougauchi, M.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1997, 38,
2717. (g) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron:
Asymmetry 1993, 4, 1779. (h) Arai, T.; Bougauchi, M.; Sasai, H.;
Shibasaki, M. J . Org. Chem. 1996, 61, 2926. (i) Duxbury, J . P.; Cawley,
A.; Thorton-Pett, M.; Wantz, L.; Warne, J . N. D.; Greatrex, R.; Brown,
D.; Kee, T. P. Tetrahedron Lett. 1999, 40, 4403. (j) Ward, C. V.; J iang,
M.; Kee, T. P. Tetrahedron Lett. 2000, 41, 6181.
(6) De la Cruz, M. A.; Shabany, H.; Spilling, C. D. Phosphorus,
Sulfur Silicon 1999, 144-146, 181.
(7) The preliminary results of this work were presented at the 15th
ICPC and published as part of the conference proceedings: Rowe, B.
J .; Scholten, J .; Spilling, C. D. Phosphorus, Sulfur Silicon 2002, 177,
1881.
(8) (a) The Merck Index, 12th ed.; Budavari, S., Ed.: Merck & Co.:
Rahway, NJ , 1996; pp 1674-1675. (b) Rupe, H.; Gassman, A. Helv.
Chim. Acta 1936, 19, 569. (c) McEnroe, F. J .; Fenical, W. Tetrahedron
1978, 34, 1661. (d) Bohlmann, F.; Grenz, M. Tetrahedron Lett. 1969,
1005. Chen, C.-Y.; Shen, Y.-C.; Chen, Y.-J .; Sheu, J .-H.; Duh, C.-Y. J .
Nat. Prod. 1999, 62, 573.
(9) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. In The Total Synthesis of Natural Products; ApSimon, J .,
Ed.; Wiley and Sons: New York, 1983; Vol. 5, pp 35-55. Pirrung, M.
C.; Morehead, A. T., J r. In The Total Synthesis of Natural Products;
Goldsmith, D., Ed.; Wiley and Sons: New York, 1997; Vol. 10, pp 29-
77.
The last 10 years have witnessed a rapid advance in
methods for the enantioselective synthesis of hydroxy
phosphonates giving access to compounds with high
enantiomeric purity.3-5 The allylic hydroxy phosphonates,
in particular, are most efficiently accessed through the
(1) (a) Zhu, J .; Lu, X. Tetrahedron Lett. 1987, 28, 1897. (b) Zhu, J .;
Lu, X. J . Chem. Soc., Chem. Commun. 1987, 1318. (c) O¨ hler, E.;
Kanzler, S. Synthesis 1995, 539. (d) Ohler, E.; Kanzler, S. Phosphorus,
Sulfur Silicon 1996, 112, 71. (e) Attolini, M.; Maffei, M.; Principato,
B.; Peiffer, G. Synlett 1997, 384. (f) O¨ hler, E.; Kanzler, S. Liebigs Ann.
1997, 1437.
(2) (a) Shabany, H.; Spilling, C. D. Tetrahedron Lett. 1998, 39, 1465.
(b) Cooper, D.; Trippett, S. J . Chem. Soc., Perkin Trans. 1 1981, 2127.
(c) O¨ hler, E.; Kotzinger, S. Synthesis 1993, 497. (d) O¨ hler, E.; Kanzler,
S. Liebigs Ann. 1993, 269. (e) Blackburn, G. M.; Kent, D. E. J . Chem.
Soc., Chem. Commun. 1981, 511. (f) Hammond, G. B.; de Mendonca
J . Fluorine Chem. 1999, 1.
(3) For reviews, see: (a) Wiemer, D. F. Tetrahedron 1997, 53, 16609.
(b) Davies, S. R.; Mitchell, M. C.; Cain, C. P.; Devitt, P. G.; Taylor, R.
J .; Kee, T. P. J . Organomet. Chem. 1998, 550, 29.
(4) For recent reports of the asymmetric synthesis of hydroxy
phosphonates, see: (a) Burk, M. J .; Stammers, T. A.; Straub, J . A. Org.
Lett. 1999, 1, 387. (b) Drescher, M.; Hammerschmidt, F. Tetrahedron
1997, 53, 4627 and references therein.
10.1021/jo0351318 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003
9502
J . Org. Chem. 2003, 68, 9502-9505

SCHEME 2. Som e Exa m p les of Ar om a tic
Bisa bolen e Sesqu iter p en es
SCHEME 4. Syn th esis of Tu r m er on e
less” catalyst system was developed [Pd2(dba)3/LiCl in
DMF], which allowed the successful coupling of arylstan-
nanes with various allylic acetates.14 Unfortunately, this
system is incompatible with the dimethyl phosphonate
group since the chloride ion in polar solvents leads to
mono-demethylation. A more attractive solution for our
purpose was reported by Farina,15 who showed that the
use of tri(2-furyl)phosphine as a ligand in palladium-
catalyzed cross-coupling reactions led to significant rate
enhancements. In related reactions, there have been
some limited reports of the coupling of arylboronic acids
and boronates with allylic acetates using palladium and
nickel catalysts, respectively.16
The racemic hydroxy phosphonate 1a (() was converted
to the carbonate 3 by reaction with methyl chloroformate
in pyridine (79-89%). Reaction of the carbonate with
p-tolyltributylstannane in N-methylpyrrolidinone (NMP)
at 60 °C in the presence of palladium(0) trifurylphosphine
(TFP) complex (formed in situ) gave a separable mixture
the E-vinyl phosphonate 6E(() (57% isolated) and the
Z-vinyl phosphonate 6Z(() (9% isolated) in an 85:15 ratio
(Scheme 4).
The H-H and P-H couplings of the vinyl protons in
the 1H NMR spectra easily distinguish the E and Z
isomers 6. In particular, H-2 of the Z-vinyl phosphonate
6Z exhibits a trans P-H coupling constant of 53 Hz,
whereas H-2 of the E-vinyl phosphonate 6E shows a cis
P-H coupling constant of 22 Hz. The use of trifurylphos-
phine and NMP was critical in this reaction. Less polar
solvents (THF) or the use triphenylphosphine and tri-
phenylarsine as ligand resulted in slow reactions and led
to complex mixtures predominated by materials derived
SCHEME 3. P r op osed Syn th esis of th e Ar om a tic
Bisa bolen e Sesqu iter p en es
the benzylic chiral center is established by a palladium-
catalyzed addition of an arylstannane to a chiral, non-
racemic allylic hydroxy phosphonate derivative. (S)-(+)-
ar-Turmerone was selected as a demonstration target for
the method. (S)-(+)-ar-Turmerone was isolated from the
rhizomes of Curcuma longa8a,b and has been the target
of many successful syntheses.9 Surprisingly, only a
limited number of enantioselective routes have been
reported.10a,g,m
In general, the reaction conditions required to promote
oxidative addition of Pd(0) to an allylic acetate or
carbonate (i.e., excess phosphine ligand) combined with
the tight binding of the acetate or methoxide leaving
group to the palladium in the π-allyl intermediate serve
to retard the rate of transmetalation.11 Therefore, to
couple an allylic acetate or carbonate with an arylstan-
nane, finely balanced reaction conditions are required.
Stille and co-workers reported that allylic halides react
with arylstannanes12 under typical palladium-catalyzed
coupling conditions with PPh3 as ligand. Most allylic
acetates, however, fail to react.13,14 As a result, a “ligand-
(10) (a) Fuganti, C.; Serra, S.; Dulio, A. J . Chem. Soc., Perkin Trans.
1 1999, 279. (b) Fuganti, C.; Serra, S. J . Chem. Soc., Perkin Trans. 1
2000, 3758. (c) Fuganti, C.; Serra, S. Synlett 1998, 1252. (d) Ono, M.;
Suzuki, K.; Tanikawa, S.; Akita, H. Tetrahedron: Asymmetry 2001,
12, 2597. (e) Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J .
Chem. Soc., Perkin Trans. 1 2000, 1807. (f) Kosaka, T.; Bando, T.;
Shishido, K. J . Chem. Soc., Chem. Commun. 1997, 1167. (g) Meyers,
A. I.; Smith, K. R. Tetrahedron Lett. 1979, 2749. (h) Meyers, A. I.;
Stoinova, D. J . Org. Chem. 1997, 62, 5219. (i) Asaoka, M.; Shima, K.;
Takei, H. Tetrahedron Lett. 1987, 28, 5669. (j) Asaoka, M.; Shima, K.;
Fujii, N.; Takei, H. Tetrahedron 1988, 44, 4757. (k) Takano, S.; Yanase,
M.; Sugihara, T.; Ogasawara, K. J . Chem. Soc., Chem. Commun. 1988,
1538. (l) Takano, S.; Goto, E.; Ogasawara, K. Tetrahedron Lett. 1982,
23, 5567. (m) Sato, T.; Kawara, T.; Nishizawa, A.; Fujisawa, K.
Tetrahedron Lett. 1980, 21, 3377.
(12) Sheffy, F. K.; Stille, J . K. J . Am. Chem. Soc. 1983, 105, 7173.
Sheffy, F. K.; Godschalx, J . P.; Stille, J . K. J . Am. Chem. Soc. 1984,
106, 4833. Moreno-Manas, M.; Pajuelo, F.; Pleixats, R. J . Org. Chem.
1995, 60, 2396.
(13) Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21, 2595.
(14) Del Valle, L.; Stille, J . K.; Hegedus, L. S. J . Org. Chem. 1990,
55, 3019.
(15) (a) Farina, V.; Baker, S. R.; Benigni, D.; Sapino, C., J r.
Tetrahedron Lett. 1988, 29, 5739. (b) Farina, V.; Krishnan, B. J . Am.
Chem. Soc. 1991, 113, 9585. (c) Amatore, C.; J utand, A.; Meyer, G.;
Atmani, H.; Khalil, F.; Chahdi, F. O. Organometallics 1998, 17, 2958.
(16) (a) Uozumi, Y.; Danjo, H.; Hayashi, T. J . Org. Chem. 1999, 64,
3384. (b) Legros, J .-Y.; Fiaud, J .-C. Tetrahedron Lett. 1990, 31, 7453.
(c) Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.; Usmani,
S. B.; Ainai, T. J . Org. Chem. 2002, 67, 7110. (d) Kobayashi, Y.; Ikeda,
E. J . Chem. Soc., Chem. Commun. 1994, 1789.
(11) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules, 2nd ed.; University Science Books: Sausalito, CA,
1999.
J . Org. Chem, Vol. 68, No. 24, 2003 9503

from reduction of the allylic carbonate (31P NMR δ 29.7).
The mixture of E- and Z-vinyl phosphonates 6(() (85:
15) was subjected to hydroboration17 to give exclusively
the R-hydroxy phosphonate 7(() as a 1.5:1 mixture of
diastereoisomers (70%). Treatment of the hydroxy phos-
phonate 7(() with sodium bicarbonate in refluxing
methanol/water solution gave the racemic aldehyde 8(()
(76%).
SCHEME 5. Mech a n ism for th e Ar yla tion Rea ction
w ith th e (S)-P h osp h on a te
In an initial attempt to determine the stereochemical
course of the arylation reaction, the (1R)-hydroxy phos-
phonate 1a (R) was prepared4b in 65% ee and carried
through the reaction sequence. Again, the mixture of E-
and Z-vinyl phosphonates 6 (85:15) was subjected to
hydroboration to give the R-hydroxy phosphonate 7(R).
Treatment of the hydroxy phosphonate 7(R) with sodium
bicarbonate in refluxing methanol/water solution gave
the (R) aldehyde 8(R), but with a significant erosion of
the enantiomeric excess [[R]D -15.2 (c 1, CHCl3), 37% ee].
The stereochemical assignment was made by comparison
with (S)-(+)-3-(p-tolyl)butanal 8(S) [[R]D +39.6 (c 1,
CHCl3), 95.5% ee].10a To synthesize (+)-ar-turmerone
with the natural S configuration, the (1S)-hydroxy phos-
phonate is required. It was postulated that separation
of the E and Z isomers prior to hydroboration would
reduce the level of stereochemical erosion.
The (1S)-hydroxy phosphonate 1a (S) was prepared by
a previously published method in 86% ee.4a Again,
carbonate formation and palladium-catalyzed arylation
with p-tolyltributylstannane gave a separable mixture
of the vinyl phosphonates 6E(S) and 6Z(R). The isomers
were separated and individually subjected to hydrobo-
ration to give the hydroxy phosphonates 7. HPLC analy-
sis of the hydroxy phosphonates 7 from both reactions
confirmed that the vinyl phosphonates 6E (S) and 6Z-
(R) had the opposite configuration at C-3. However,
HPLC also indicated that the enantiomeric excess for the
hydroxy phosphonates 7(S) and 7(R), derived from the
6E(S) and 6Z(R) respectively, had eroded to 73 ( 2%.
The hydroxy phosphonate 7(S) derived from the major
E vinyl phosphonate 6E(S) was treated sodium bicarbon-
ate in refluxing methanol/water solution to give the (S)
aldehyde 8(S). The optical rotation of the aldehyde 8(S)
confirmed the absolute configuration [[R]D +32.2 (c 0.25,
CHCl3), 78% ee] and the magnitude of the rotation was
consistent with enantiomeric excess determined by HPLC
on the hydroxy phosphonate 7(S). Serra et al. reported
the conversion of the (S)-aldehyde 8(S) into (S)-ar-
turmerone 5a by reaction with 2-methyl-2-propenyl Grig-
nard, followed by MnO2 oxidation of the resulting
alcohol.10a Thus, synthesis of aldehyde 8(S) represents a
formal synthesis of (S)-(+)-ar-turmerone.
phosphonate is formed (Scheme 5) from the initial π-allyl
intermediate via a η3-η1 shift to give a σ-bound pal-
ladium species. Bond rotation and η1-η3 shift give rise
to a new π-allyl complex, which upon transmetalation
and reductive elimination would yield the Z vinyl phos-
phonate with the opposite (R) configuration at C-3. The
9% erosion in enantiomeric excess is probably due to a
racemization mechanism involving back-face attack of a
palladium nucleophile on the π-allyl intermediate. It is
believed that a slow transmetalation step gives rise to a
π-allyl intermediate which has a sufficiently long lifetime
to suffer racemization via Pd(0) attack and rearrange-
ment via η1-η3 shift. This is in contrast to the palladium-
catalyzed intermolecular addition of amine nucleophiles
where there was no stereochemical erosion and only
formation of the E vinyl phosphonate was observed.6
In summary, the palladium-catalyzed addition of p-
tolyltributylstannane to a (1S) phosphono allylic carbon-
ate results in the formation of both E and Z vinyl
phosphonates with the S and R configurations at C-3,
respectively. The major 1E,3S isomer, formed with inver-
sion of configuration, was converted to the known (S)-
ar-turmerone precursor (3S)-3-(p-tolyl)butanal.
The observed aldehyde stereochemistry is consistent
with the expected reaction mechanism11,12,18 that involves
inversion of configuration during π-allyl formation and
retention during transmetalation/reductive elimination
(i.e., overall inversion). It is believed that the Z-vinyl
Exp er im en ta l Section
(17) Agnel, G.; Negishi, E. J . Am. Chem. Soc. 1991, 113, 7424.
(18) (a) Faller, J . W.; Thomsen, M. E.; Mattina, M. J . J . Am. Chem.
Soc. 1971, 93, 2642. (b) Trost, B. M.; Vanhoeven, T. R. J . Am. Chem.
Soc. 1976, 98, 630. (c) Trost, B. M. Acc. Chem. Res. 1980, 13, 385. (d)
Hayashi, T.; Hagihara, T.; Konishi, M.; Kumada, M. J . Am. Chem. Soc.
1983, 105, 7767. (e) Mackenzie, P. B.; Whelan, J .; Bosnich, B. J . Am.
Chem. Soc. 1985, 107, 2046. (f) Granberg, K. L.; Ba¨ckvell, J .-E. J . Am.
Chem. Soc. 1992, 114, 6858.
(()-(2E)-Dim eth yl [1-(Meth oxyca r bon yloxy)-2-bu ten yl]
P h osp h on a te 3((). The hydroxy phosphonate 1a (()19 (2.6 g,
14 mmol) was dissolved in acetonitrile (100 mL) and pyridine
(19) (a) Texier-Boullet, F.; Foucaud, A. Synthesis 1982, 165. (b)
Baraldi, P. G.; Guarneri, M.; Moroder, F.; Pollini, G. P.; Simoni, D.
Synthesis 1982, 653.
9504 J . Org. Chem., Vol. 68, No. 24, 2003

(10 mL, 123 mmol, 8.7 equiv), and then (dimethylamino)pyridine
(DMAP) (15 mg) was added. The resulting solution was cooled
to 0 °C, and methyl chloroformate (8.56 g, 90 mmol, 6 equiv)
was added dropwise. The solution was allowed to warm to room
temperature and then was stirred overnight. The solution was
diluted with CH2Cl2 and washed with water (2×) and saturated
copper sulfate solution (4×). The solvent was dried over MgSO4,
filtered, and evaporated in vacuo to give (()-(2E)-d im eth yl
[1-(m eth oxyca r bon yloxy)-2-bu ten yl] p h osp h on a te 3(() as
heated to 50 °C in a preheated oil bath and stirred for 15 min.
The solution was then poured into cold brine and extracted with
CH2Cl2 (2×). The combined extracts were dried over MgSO4,
filtered, and evaporated in vacuo to give a colorless liquid. The
crude product was isolated by flash chromatography (SiO2, 50:
50 ethyl acetate/hexanes, then 100% ethyl acetate) to give
starting material (0.053 g) and (()-d im et h yl [1-h yd r oxy-3-
(p-tolyl)bu tyl] p h osp h on a te 7(() (0.255 g, 70%) as a colorless
oil: 1H NMR (1.5:1 mixture of diastereoisomers) 1H NMR
(CDCl3) δ 7.09 (m, 4H), 4.0 &3 3.9 (m, 1H), 3.78, 3.75 & 3.70 (d,
6H, J HP ) 10.4 Hz), 3.8 & 3.1 (m 1H), 2.31 (s, 3H), 1.99 (m, 2H),
1.27 & 1.25 (d, 3H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 144.1, 142.3,
135.7, 135.7, 129.3, 129.2 127.3, 126.9, 66.5 (d, J CP ) 160 Hz),
665.5 (d, J CP ) 160 Hz), 53.4 (m), 39.9, 39.5, 35.3 (m), 23.4, 21.4,
21.0; 31P NMR (CDCl3) δ 28.2 and 28.0; HRMS (EI) (M+) calcd
for C13H21O4P 272.1177, found 272.1173.
Hydroboration of the (3S,1E)-vin yl p h osp h on a te as de-
scribed above gave (3S)-d im eth yl [1-h yd r oxy-3-(p-tolyl)-
bu tyl] p h osp h on a te (47%, 1.6:1 diastereoisomer ratio) (see the
HPLC data).
Hydroboration of (3R,1Z)-vin yl p h osp h on a te as described
above gave (3R)-d im eth yl [1-h yd r oxy-3-(p-tolyl)bu tyl] p h os-
p h on a te (33%, 1.85:1 diastereoisomer ratio) (see the HPLC
data).
(()-3-(p-Tolyl)bu ta n a l 8((). To a stirred solution of hydroxy
phosphonate 7(() (0.93 mmol, 255 mg) in a methanol-water
mixture (2:1, 10 mL) was added sodium bicarbonate (340 mg, 5
equiv). This solution was stirred at 50 °C until the starting
material disappeared (31P NMR, 3 h). The reaction mixture was
then extracted with CH2Cl2 (3×). The combined extracts were
dried over MgSO4, filtered, and evaporated in vacuo to give a
colorless oil. The crude product was purified by flash chroma-
tography (SiO2, 20% ethyl acetate/hexanes) to give (()-3-(p-
tolyl)bu ta n a l 8(() (0.117 g, 76%) as a colorless liquid: IR (ATR)
a pale yellow oil (2.7 g, 79%): IR (neat, NaCl) 1754 cm-1
;
1H
NMR (CDCl3) δ 5.99 (m, 1H), 5.59 (m, 1H), 5.45 (ddd, 1H, J HP
)
12 Hz, J HH ) 8, 0.8 Hz), 3.86 (d, 3H, J HP ) 11 Hz), 3.83 (s, 3H),
3.82 (d, 3H, J HP ) 11 Hz), 1.79 (m 3H); 13C NMR (CDCl3) δ 154.7,
134.1 (d, J CP ) 12.6 Hz), 121.6 (d, J CP ) 2.1 Hz), 73.1 (d, J CP
)
170 Hz), 55.51, 53.97 (d, J CP ) 6.4 Hz), 53.94 (d, J CP ) 6.2 Hz),
18.28 (d, J CP ) 1.2 Hz); 31P NMR δ 20.1. Anal. Calcd for
C8H15O6P: C, 40.34; H, 6.35. Found: C, 40.22; H, 6.27.
P a lla d iu m -Ca ta lyzed Ar yla tion of (()-(2E)-Dim eth yl
[1-(Met h oxyca r b on yloxy)-2-b u t en yl] p h osp h on a t e. Pd2-
(dba)3 (0.022 g, 0.01 equiv) and tri(2-furyl)phosphine (0.022 g,
0.04 equiv) were dissolved in distilled, degassed N-methylpyr-
rolidinone (6 mL). The mixture was stirred for 5 min while being
heated to 60 °C in a preheated oil bath. The carbonate 3(() (0.59
g) and the aryltributylstannane (1.13 g, 1.2 equiv) were added,
and heating was continued for 5 h. The reaction mixture was
cooled, and Et2O and aqueous KF were added. After the mixture
was stirred for 15 min, the layers were separated and the
aqueous layer was re-extracted with Et2O. The combined Et2O
extracts were washed with H2O and brine, dried (MgSO4), and
evaporated in vacuo to give a yellow oil. The crude product was
purified by flash chromatography (SiO2, gradient 100% hexanes
to 100% ethyl acetate) to give (()-(1Z)-d im eth yl [3-(p-tolyl)-
1-bu ten yl] p h osp h on a te 6Z(() (0.058 g, 9%) as a colorless
oil: 1H NMR (CDCl3) δ 7.19 (d, 2H, J HH ) 8 Hz), 7.12 (2H, d,
J HH ) 8 Hz), 6.54 (ddd, 1H, J HP ) 52 Hz, J HH ) 13, 11 Hz), 5.48
(ddd, 1H, J HP ) 19 Hz, J HH ) 13, 0.5 Hz), 4.48 (m, 1H), 3.74
(d,3 H, J HP ) 11 Hz), 3.69 (d,3H, J HP ) 11.4 Hz), 2.32 (s, 3H),
1.39 (d, 3H, J ) 7 Hz); 13C NMR (CDCl3) δ 158.7 (d, J CP ) 4.6
Hz), 140.8, 136.1, 129.3, 126.9, 112.7 (d, J CP ) 183 Hz), 52.1 (d,
J CP ) 5.5 Hz), 52.0 (d, J CP ) 5.6 Hz), 39.7 (d, J CP ) 7.7 Hz),
21.0, 20.9; 31P NMR (CDCl3) δ 20.4 and (()-(1E)-d im eth yl
[3-(p-tolyl)-1-bu ten yl] p h osp h on a te 6E(() (0.36 g, 57%) as
a colorless oil: 1H NMR (CDCl3 δ 7.13 (d, 2H, J ) 9 Hz), 7.06
(d, 2H, J ) 9.0 Hz), 6.95 (ddd, 1H, J HP ) 22 Hz, J HH ) 17, 6
Hz,), 5.60 (1H, ddd, J HP ) 21 Hz, J HH ) 17, 1.6 Hz, 1H), 3.70
(3H, d, J HP ) 11 Hz), 3.69 (3H, d, J HP ) 11 Hz), 3.58 (m, 2H),
2.33 (s, 3H), 1.41 (d, 3H, J ) 7 Hz); 13C NMR (CDCl3) δ 158.3
(d, J CP ) 4.5 Hz), 139.8, 136.4, 129.4, 127.3, 114.0 (d, J CP ) 187
Hz), 52.3 (d, J CP ) 5.5 Hz), 44.3 (d, J CP ) 21 Hz), 21.0, 20.1 31P
NMR (CDCl3) δ 23.1; HRMS (EI) (M+) calcd for C13H19O3P
254.1072, found 254.1079.
P a lla d iu m -Ca t a lyzed Ar yla t ion of (1S,2E)-Dim et h yl
[1-(Met h oxyca r b on yloxy)-2-b u t en yl] P h osp h on a t e 3(S).
The (1S) carbonate 3(S) (2.0 g) was treated as described above
to give a mixture of E and Z vinyl phosphonates 6 (1.3 g, 64%).
Further careful chromatography resulted in the isolation of
(3R,1Z)-d im eth yl [3-(p-tolyl)-1-bu ten yl] p h osp h on a te 6Z-
(R) as a colorless oil (0.2 g, 10%) [31P NMR (CDCl3) δ 20.4] and
(3S,1E)-d im eth yl [3-(p-tolyl)-1-bu ten yl] p h osp h on a te 6E-
(S) as a colorless oil (0.7 g 35%): 31P NMR (CDCl3) δ 23.1.
Hyd r obor a tion of (()-(1Z)- a n d (1E)-Dim eth yl [3-(p-
Tolyl)-1-bu ten yl] P h osp h on a te To Give Dim eth yl [1-Hy-
d r oxy-3-(p-tolyl)bu tyl] P h osp h on a te 7((). To a stirred so-
lution of E and Z vinyl phosphonates 6(() (0.35 g, 1.4 mmol) in
THF (1 mL) was added borane THF complex (1.5 M, 4.6 mL, 5
equiv) under argon at room temperature. After 45 min, 30%
H2O2 (2.2 mL, xs) was added followed by slow addition of
saturated sodium acetate solution (3.0 mL). The mixture was
1724 cm-1 1H NMR (CDCl3) δ 9.96 (t, J ) 2 Hz, 1H), 7.09 (s,
;
4H), 3.30 (app sextet,1H, J ) 7 Hz), 2.64 (m, 2H), 2.29 (s, 3H),
1.27 (d, J ) 7 Hz, 3H); 13C NMR (CDCl3) δ 202.2, 142.6, 136.3,
129.6, 126.8, 52.0, 34.2, 22.5, 21.2.
(R)-(-)-3-(p-Tolyl)bu ta n a l 8(R). Reaction of the (3R)-hy-
droxy phosphonate (0.32 g) [from (1R)-hydroxy phosphonate (1)
65% ee] as described above gave (R)-(-)-3-(p-tolyl)bu ta n a l
[0.15 g crude, 0.095 g, 50% after column, [R]D -15.2 (c 1, CHCl3)
(37% ee)].
(S)-(+)-3-(p-Tolyl)bu ta n a l 8(S). Reaction of the (3S)-hy-
droxy phosphonate (0.1 g) [from (1S)-hydroxy phosphonate (1)
86% ee] as described above gave (S)-(+)-3-(p-tolyl)bu ta n a l
[(0.05 g, 85%): [R]D +32.2 (c 0.25, CHCl3) (78% ee)].
Ack n ow led gm en t. We are grateful to the donors
of the Petroleum Research Fund, administered by the
American Chemical Society (34428-AC1), for financial
support of this project and the UMSL Graduate School
for a fellowship for B.J .R. We are also grateful to the
NSF, the US DoE, and the University of Missouri
Research Board for grants to purchase the NMR spec-
trometers (CHE-9318696, CHE-9974801, DE-FG02-92-
CH10499) and mass spectrometer (CHE-9708640) used
in this work. We thank Anyu He for preparation of the
arylstannane.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal and spectra for compounds 3, 6E, 6Z, 7, and 8 and a
comparison of HPLC data for compound 7 prepared from (()-
6, (3S,1E)-6, and (3R,1Z)-6. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0351318
J . Org. Chem, Vol. 68, No. 24, 2003 9505