Synthesis of nonracemic allylic hydroxy phosphonates via alkene cross metathesis

Article abstract of DOI:10.1021/jo0490090

Allylic hydroxy phosphonates and their derivatives can be interconverted by using cross metathesis with second generation Grubbs catalyst. The absolute stereochemistry of the starting phosphonate is conserved in the product. Cross metathesis reaction of t

Full text of DOI:10.1021/jo0490090

Synthesis of Nonracemic Allylic Hydroxy Phosphonates via Alkene
Cross Metathesis
Anyu He, Bingli Yan, Anchalee Thanavaro, Christopher D. Spilling,* and Nigam P. Rath
Department of Chemistry and Biochemistry, University of Missouri-St. Louis,
8001 Natural Bridge Road, St. Louis, Missouri 63121
cspill@umsl.edu
Received June 11, 2004
Allylic hydroxy phosphonates and their derivatives can be interconverted by using cross metathesis
with second generation Grubbs catalyst. The absolute stereochemistry of the starting phosphonate
is conserved in the product. Cross metathesis reaction of the acrolein-derived phosphonate 2a yields
a series of functionalized allylic hydroxy phosphonates. However, the cross metathesis reaction is
often accompanied by competing dimerization and alkene migration reactions leading to a reduction
in yield. The cinnamaldehyde- and crotonaldehyde-derived phosphonates 2b and 2c were also
examined. In general, the metathesis reactions of phosphonates 2b and 2c are considerably slower
than those for phosphonate 2a leading to mixtures. Several hydroxyl-protected derivatives of the
phosphonate 2a (methyl carbonate 3a, acetate 4a, N-tosyl carbamate 5a, TBDMS 6a, and
acetoacetate 7a) undergo metathesis without competing side reactions to give substituted allylic
phosphonates in good to excellent yield.
Introduction
hydroxy phosphonates are particularly attractive be-
cause, like allylic alcohols, they participate in a number
of stereoselective or stereospecific reactions leading to
highly functionalized phosphonates.7
Although there are many attractive routes for the
synthesis of hydroxy phosphonates,2,3 nonracemic allylic
hydroxy phosphonates are most conveniently generated
by enzymatic kinetic resolution,8 or asymmetric cataly-
sis.9 Both methods have attained varying levels of suc-
cess, but a general, reproducible, high-yielding, and
highly selective method is still unavailable. We reasoned
that it would be easier to optimize reaction conditions to
A major emphasis in the development of new organic
reactions is the control of absolute stereochemistry via
chiral catalysts.1 For over 10 years there has been an
interest in the asymmetric synthesis of hydroxy phos-
phonates,2,3 precipitated not only by their biological
activity,4 but also because they are attractive precursors
to other R- and γ-substituted phosphonates.5-7 Allylic
(1) For examples see: Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH: New York, 1993. Noyori, R. Asymmetric Catalysis in
Organic Synthesis; John Wiley and Sons: New York, 1994. Cervinka,
O. Enantioselective Reactions in Organic Chemistry; Ellis Horwood:
New York, 1995. Asymmetric Synthesis; Morrison, J. D., Ed.; Chiral
Catalysis, Vol. 5; Academic Press: New York, 1985.
(2) For reviews of the asymmetric synthesis of hydroxy phosphonates
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. (c) Gro¨ger, H.; Hammer, B. Chem.
Eur. J. 2000, 6, 943.
(3) For recent reports of the asymmetric synthesis of hydroxy
phosphonates see: (a) Skropeta, D.; Schmidt R. R. Tetrahedron:
Asymmetry 2003, 14, 265. (b) Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem.
2003, 68, 4815. (c) Zhang, Y.; Yuan, C.; Li, Z. Tetrahedron 2002, 58,
2973. (d) Burk, M. J.; Stammers, T. A.; Straub, J. A. Org. Lett. 1999,
1, 387. (e) Kolodiazhnyi, O. I.; Griskkun, E. V.; Sheiko, S.; Demchuk,
O.; Thoennessen, H.; Jones, P. G.; Schmutzler, R. Tetrahedron:
Asymmetry 1998, 9, 1645.
(4) For examples see: (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D.
E. Tetrahedron Lett. 1990, 31, 5587. (b) Stowasser, B.; Budt, K.-H.;
Jian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33, 6625.
(5) For examples see: (a) Gajda, T.; Matisiak, M. Synthesis 1992,
367. (b) Yokomatsu, T.; Shibuya, S. Tetrahedron: Asymmetry 1992, 3,
377.
(7) (a) Yan, B.; Spilling, C. D. J. Org. Chem. 2004, 69, 2859. (b) Rowe,
B. J.; Spilling, C. D. J. Org. Chem. 2003, 68, 9502. (c) Rowe, B. J.;
Scholten, J.; Spilling, C. D. Phosphorus, Sulfur Silicon 2002, 177, 1881.
(d) De la Cruz, M. A.; Shabany, H.; Spilling, C. D. Phosphorus, Sulfur
Silicon 1999, 146, 181. (e) Shabany, H.; Spilling, C. D. Tetrahedron
Lett. 1998, 39, 1465.
(8) (a) Heisler, A.; Rabiller, C.; Douillard, R.; Goalou, N.; Ha¨gele,
G.; Levayer, F. Tetrahedron: Asymmetry 1993, 4, 959. (b) Li Y.-F.;
Hammerschmidt, F. Tetrahedron: Asymmetry 1993, 4, 109. (c) Drescher,
M.; Li F.-Y.; Hammerschmidt, F. Tetrahedron 1995, 51, 4933 (d)
Drescher, M.; Hammerschmidt, F.; Kahlig, H. Synthesis 1995, 1267.
(e) Eidenhammer, G.; Hammerschmidt, F. Synthesis 1996, 748. (f)
Drescher, M.; Hammerschmidt, F. Tetrahedron 1997, 53, 4627. (g)
Wuggenig, F.; Hammerschmidt, F. Monatsh. Chem. 1998, 129, 423.
(h) Hammerschmidt, F.; Wuggenig, F. Tetrahedron: Asymmetry 1999,
10, 1709.
(9) (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.; Jiang,
M.; Kee, T. P. Tetrahedron Lett. 2000, 41, 6181.
(6) For example see: (a) Zhu, J.; Lu, X. Tetrahedron Lett. 1987, 28,
1897. (b) Zhu, J.; Lu, X. Chem. Commun. 1987, 1318. (c) Cooper, D.;
Trippett, S. J. Chem. Soc., Perkin Trans. 1 1981, 2127. (d) O¨ hler, E.;
Kotzinger, S. Synthesis 1993, 497. (e) O¨ hler, E.; Kanzler, S. Liebigs
Ann. 1997, 1437. (f) Blackburn, G. M.; Kent, D. E. Chem. Commun.
1981, 511. (g) Hammond, G. B.; de Mendonca J. Fluorine Chem. 1999,
1. (h) Attolini, M.; Maffei, M.; Principato, B.; Peiffer, G. Synlett 1997,
384.
10.1021/jo0490090 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/09/2004
J. Org. Chem. 2004, 69, 8643-8651
8643

He et al.
SCHEME 1. Proposed Cross Metathesis
The acrolein-derived phosphonate 2a (Table 1, entry
1) rapidly underwent self-metathesis with the Grubbs
second generation ruthenium benzylidene catalyst in
CH2Cl2 even in the presence of other alkenes to give
dimer 8 in good yield. The dimer is insoluble in CH2Cl2
and precipitated from the reaction solution. Fortunately,
when the cross metathesis reaction was performed in
chloroform with excess alkene, dimer formation was
suppressed in favor of heterometathesis.
SCHEME 2. A Generic Cross Metathesis Reaction
The acrolein-derived phosphonate 2a was converted to
substituted allylic hydroxy phosphonates 2b,d-g by
treatment with Grubbs second-generation catalyst and
a terminal alkene in chloroform at 40-45 °C in modest
yield (Table 1). The formation of the substituted products
was always accompanied by the formation of varying
amounts of dimer 8. The trans geometry (cis <10%) of
the products was confirmed by comparison of the spec-
troscopic data of allylic hydroxy phosphonates with
known alkene geometry. In the 13C NMR spectra, the
signals for C-1 in the trans isomers (∼69 ppm) are
downfield of the cis isomers (∼64 ppm). In the 31P NMR,
the signals for the trans isomers are upfield of the cis
isomers by approximately 0.5 ppm.
In addition to terminal olefins, metathesis of disubsti-
tuted olefins provided the corresponding products oc-
casionally in higher yield. Phosphonate 2f prepared
utilizing cis-1,4-diacetoxy-2-butene (entry 7) provided the
product in 61% yield, whereas a reaction utilizing allyl
acetate (entry 6) gave less than a 30% yield. However,
trans-stilbene (entry 3), a disubstituted olefin, was not
as efficient as styrene (entry 2), a terminal alkene, in the
formation of phosphonate 2b. It was also observed that
prolonged heating resulted in the formation of acyl
phosphonate 9 as a new byproduct. The acyl phosphonate
9, which exhibits a characteristic peak at 0.5 ppm in the
31P NMR spectrum, probably arises via migration of the
alkene from C(2)dC(3) to C(1)dC(2), followed by enol to
ketone tautomerism.
produce a single, structurally simple phosphonate in high
enantiomeric excess, high yield, and large quantities,
which would serve as a convenient precursor to more
complex substituted allylic hydroxy phosphonates. This
could conceivably be achieved by a cross metathesis
reaction of an acrolein-derived phosphonate and an
alkene (Scheme 1).
The cross metathesis reaction has become a powerful
tool for alkene synthesis.10 Potentially, three possible
products can be obtained including the desired hetero-
dimeric product and two undesired homodimeric products
(Scheme 2). Examples of cross metathesis (CM) and ring
closing metathesis (RCM) involving vinyl and allyl phos-
phonates and related compounds have been reported.11,12
However, metathesis reactions involving interconversion
of allylic hydroxy phosphonates remain to be explored.
The hydroxy phosphonates 2a-c were prepared by the
addition of dimethyl phosphite to the corresponding
aldehyde. The nonracemic phosphonates were prepared
by catalytic asymmetric phosphonylation, using dimethyl
tartrate and titanium isopropoxide as the catalyst,9a
whereas the racemic compounds were prepared with use
of Et3N.13 The enantiomeric excess of the nonracemic
phosphonates was determined by HPLC on a chiral
stationary phase or 31P NMR spectroscopy with quinine
as the shift reagent.9a,14 The hydroxy phosphonate 2a was
converted into the corresponding carbonate 3a, acetate
4a, N-tosylcarbamate 5a, tert-butyldimethylsilyl 6a, and
acetoacetate 7a derivatives with standard reaction condi-
tions (Scheme 3).
Dimerization of the racemic acrolein phosphonate 2a
should, assuming the reaction rates are unaffected by
stereochemistry, give a 50:50 mixture of the meso and
RR/SS diastereoisomers, whereas the cross metathesis
reaction of nonracemic acrolein phosphonate 2a (70% ee,
85:15 R:S) is expected to give a mixture consisting of the
meso diastereoisomer (26% y) and the RR/SS diastereo-
isomer (74% y, 97% ee). In practice, the racemic phos-
phonate 2a typically gave a 75:25 mixture (by HPLC) of
the meso and RR/SS diastereoisomers in the precipitated
product isolated by filtration of the reaction mixture. The
isolated dimer mixture (from racemic 2a) was recrystal-
lized from methanol to give pure meso diastereoisomer.
Both the crude dimer mixture and the recrystallized meso
(10) For examples see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C.
Acc. Chem. Res. 1995, 28, 446. (b) Blackwell, H. E.; O’Leary, D. J.;
Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 58. (c) O’Leary, D. J.; Blackwell, H.
E.; Washenfelder, R. A.; Miura, K.; Grubbs, R. H. Tetrahedron Lett.
1999, 40, 1091. (d) Crowe, W. E.; Zhang, Z. J. J. Am. Chem. Soc. 1993,
115, 10998. (e) Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995,
117, 5162. (f) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet.
Chem. 2001, 624, 327. (g) Chatterjee, A. K.; Grubbs, R. H. Org. Lett.
1999, 1, 1751.
(11) For examples see: (a) Chatterjee, A. K.; Choi, T.-L.; Grubbs,
R. H. Synlett 2001, 1034. (b) Lera, M.; Hayes, C. J. Org. Lett. 2001, 3,
2765. (c) Demchuk, O. M.; Pietrusiewicz, K. M.; Michrowska, A.; Grela,
K. Org. Lett. 2003, 5, 3217.
(12) For examples see: (a) McReynolds, M. D.; Dougherty, J. M.;
Hanson, P. R. Chem. Rev. 2004, 104, 2239. (b) Stoianova, D. S.; Hanson,
P. R. Tetrahedron Lett. 1998, 39, 3939. (c) Stoianova, D. S.; Hanson,
P. R. Tetrahedron Lett. 1999, 40, 3297. (d) Stoianova, D. S.; Hanson,
P. R. Org. Lett. 2000, 2, 1769. (e) Bujard, M.; Gouverneur, V.;
Mioskowski, C. J. Org. Chem. 1999, 64, 2119. (f) Timmer, M. S. M.;
Ovaa, H.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H.
Tetrahedron Lett. 2000, 41, 8635.
1
isomer exhibited identical 31P (24.5 ppm) and H NMR
spectra in DMSO solution. X-ray crystal data, obtained
for several single crystals from a sample crystallized from
MeOH, showed the presence of only the meso diastereo-
isomer (Figure 1). HPLC of samples of the crystallized
(MeOH) or insoluble solid (CH2Cl2) and the corresponding
solutions revealed that the RR/SS isomer is more soluble
than the meso isomer in both methanol and CH2Cl2 since
it remains in the mother liquor.
(13) (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.
(14) Zymanczyk-Duda, E.; Skwarczynski, M.; Lejczak, B.; Karfarski,
P. Tetrahedron: Asymmetry 1996, 7, 1277.
Alternatively, the nonracemic phosphonate (70% ee)
gave a 25:75 mixture of meso to RR/SS diastereoisomers.
Recrystallization of this mixture gave a solid predomi-
8644 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Nonracemic Allylic Hydroxy Phosphonates
SCHEME 3. Preparation of Allylic Hydroxy Phosphonate Derivativesa
a Reagents and conditions: (a) dimethyl tartrate, Ti(OiPr)4, Et2O, (MeO)2P(O)H; (b) (MeO)2P(O)H, Et3N; (c) ClCO2Me, Py, DMAP,
CH3CN; (d) AcCl, PVP, CH2Cl2; (e) TsNCO, CH2Cl2; (f) t-BuMe2SiCl, imidazole, CH2Cl2; (g) diketene, DMAP, CH2Cl2:THF (1:1).
TABLE 1. Metathesis with Acrolein-Derived Phosphoate
a 5% catalyst 10, CH2Cl2. b 5% catalyst 10, CHCl3, 5 equiv of alkene.
nating in the meso isomer (70:30) and a mother liquor
containing an excess (12:88) of the RR/SS diastereo-
isomer. Attempted cross metathesis reaction with the
meso dimer and 4-methyl-1-pentene or styrene in MeOH
solution resulted in low conversion (<30%) over extended
reaction times. In other solvents, little or no reaction was
observed.
The cinnamyl 2b and crotonyl 2c phosphonates were
examined to study the effect of allylic phosphonate
substitution on the metathesis reaction. The cinnamyl
phosphonate, in particular, was interesting because it can
be recrystallized to >95% ee and, therefore, appeared to
be a promising precursor for the synthesis of other
hydroxy phosphonates of high enantiomeric excess.7a,9a
J. Org. Chem, Vol. 69, No. 25, 2004 8645

He et al.
TABLE 2. Metathesis with Substituted Allylic Phosphonates
a Determined by 31P NMR spectroscopy.
TABLE 3. Metathesis with Protected Acrolein
Phosphonate Derivatives
entry
protecting group (R2)
% yield
1
2
3
4
5
CO2Me 3
92
90
88
89
82
Ac 4
CONHTs 5
SiMe2t-Bu 6
COCH2COCH3 7
FIGURE 1. Projection view of the meso dimer with 50%
thermal ellipsoids.
In general, the metathesis reactions of phosphonates 2b
and 2c (Table 2) are considerably slower than those for
the acrolein phosphonate 2a. Cross metathesis reaction
of phosphonate 2b with 1.7 equiv of 3-(3-methoxyphenyl)-
propene (entry 1) stopped at approximately 50% conver-
sion, presumably reaching equilibrium. However, reac-
tion with 5 equiv of 4-methyl-1-pentene (entry 2) proceeded
further and the product 2d was isolated in 74% yield. In
both reactions, there was no erosion of enantiomeric
excess in the products. Allyl acetate (entry 3) was
unreactive toward the phosphonate 2b and the carbonate
derivative 3b (entry 4) was unreactive toward 3-(3-
methoxyphenyl)propene and several other alkenes. The
crotonyl phosphonate 2c reacted with 4-methyl-1-pentene
(entry 5) to give the phosphonate 2d in 48% isolated yield.
Unlike phosphonate 2b, the crotonyl phosphonate 2c
showed some reactivity toward allyl acetate (entry 6)
leading to mixtures of the starting material 2c, the
8646 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Nonracemic Allylic Hydroxy Phosphonates
TABLE 4. Metathesis with Carbonate Protected Acrolein Phosphonate Derivatives
a 5% catalyst 10, CH2Cl2. b 5% catalyst 10, PhMe. c 7.5% total catalyst 10 added in 3 portions, CH2Cl2. d 5% total catalyst 10 added in
2 portions, CH2Cl2. e 5% catalyst 10, CH2Cl2, 3 equiv of phosphonate 3a.
expected product 2f, and surprisingly the acrolein phos-
phonate 2a. Similarly, reaction of the carbonate 3c with
3-(3-methoxyphenyl)propene led to product mixtures
(entry 7).
In an effort to optimize the cross metathesis reaction
and suppress the unwanted side reaction, the cross
metathesis reaction of several protected phosphonates
3a-7a (Table 3) and 4-methylpent-1-ene was examined.
Reaction of the protected phosphonates 3a-7a and
4-methyl-1-pentene in CH2Cl2 with 5 mol % of Grubbs
second generation catalyst gave the hetero-cross-metath-
esis products in high isolated yields (82-92%). The
J. Org. Chem, Vol. 69, No. 25, 2004 8647

He et al.
found 364.0622. Anal. Calcd for C13H18NO7PS: C, 42.98; H,
4.99. Found: C, 43.07; H, 5.06.
homodimer of alkene was also formed; however, no
homodimerization of the phosphonates or alkene bond
migration was observed. Fortunately, the dimer of the
alkene also entered into the metathesis reaction with the
phosphonates 3a-7a, so its formation had little conse-
quence on the reaction outcome.
Dimethyl {1-[Dimethyl(tert-butyl)silyloxy]-2-propenyl}-
phosphonate (6a). Imidazole (0.71 g, 10.4 mmol) was added
to a stirred solution of phosphonate 2a (1.08 g, 6.51 mmol) in
anhydrous CH2Cl2 (10 mL). The solution was cooled to 0 °C
and dimethyl(tert-butyl)silyl chloride (1.47 g, 9.76 mmol) was
added. After 30 min at 0 °C, the reaction mixture was warmed
to room temperature and stirred overnight. The solvent was
evaporated in vacuo and the crude product was purified by
chromatography (SiO2, hexane:EtOAc, 1:1) to give the silyl
ether 6a as a colorless oil (1.55 g, 85%): 1H NMR (CDCl3) δ
5.93 (1H, m), 5.38 (1H, m), 5.22 (1H, m), 4.45 (1H, m), 3.71
(6H, d, JHP ) 10.4 Hz), 0.85 (9H, s), 0.05 (3H, s), 0.01 (3H, s);
Since the carbonates are useful substrates for pal-
ladium-catalyzed additions,6,7a,b the carbonate derivative
3a was examined more extensively. In general, the yields
with terminal alkenes were good to excellent (Table 4).
Only hetero-substituted allyl systems (e.g., entries 3, 4,
and 7) failed to give satisfactory yields. Several functional
groups including esters, alcohols, imide, carbamate, and
halide could be incorporated into the phosphonates by
using the metathesis reaction (entries 8-12). In all cases,
the E isomer was predominant (>10:1). The signals for
C-1 in the trans isomers in the 13C NMR spectra are
downfield of the cis isomers by approximately 5 ppm.
Where examined, the enantiomeric excess of the starting
material was preserved in the product, for example (Table
4, entry 5), the reaction of phosphonate 3a (69% ee by
HPLC) with 3-(3-methoxyphenyl)propene gave the sub-
stituted phosphonate 3h (69% ee by HPLC) in 68% yield.
In summary, the alkene cross metathesis reaction
between acrolein-derived phosphonates and alkenes was
successfully applied to the preparation of E allylic hy-
droxy phosphonates. The enantiomeric excess of the
starting phosphonates was preserved in the products. The
cinnamaldehyde- and crotonaldehyde-derived phos-
phonates 2b and 2c were also examined. In general, the
metathesis reactions of phosphonates 2b and 2c are
considerably slower than those for phosphonate 2a lead-
ing to product mixtures. We are currently applying this
chemistry to the synthesis of allylic hydroxy phos-
phonates as chiral building blocks for use in the asym-
metric synthesis of natural products.
13C NMR (CDCl3) δ 133.7 (d, JCP ) 3.8 Hz), 117.1 (d, JCP
)
12.0 Hz), 70.9 (d, JCP ) 169 Hz), 53.8 (d, JCP ) 7.3 Hz), 53.4
(d, JCP ) 7.1 Hz), 25.7, 18.3, -4.9, -5.2; 31P NMR (CDCl3) δ
22.8; HRMS(FAB, MH+) calcd for C11H26O4PSi 281.1338, found
281.1339.
Dimethyl [1-(2-Keto-butanoyloxy)-2-propenyl]phos-
phonate (7a). Diketene (0.3 mL, 4.15 mmol) was added to a
solution of hydroxy phosphonate 2a (0.53 g, 3.19 mmol) in THF
(5 mL) and CH2Cl2 (5 mL) at -20 °C, followed by addition of
DMAP (0.009 g, 0.0013 mmol). The reaction mixture was
stirred at -20 °C for 30 min. The mixture was allowed to warm
to room temperature, and then it was stirred overnight. The
reaction mixture was washed with 0.1% NaOH (twice) and the
aqueous layer was re-extracted with CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4 and the
solvent was evaporated in vacuo. The crude product was
purified by chromatography (SiO2, hexane:EtOAc, 1:1) to give
the acetoacetate 7a as a pale yellow oil (0.66 g, 82%) (14%
enol): IR (neat, NaCl) 1754, 1720 cm-1
;
1H NMR (CDCl3) δ
5.94 (1H, m), 5.75 (1H, m), 5.42 (2H, m), 3.81 (3H, d, JHP
)
10.7 Hz), 3.80 (3H, d, JHP ) 10.7 Hz), 3.57 (2H, s), 2.28 (3H,
s); 13C NMR (CDCl3) δ 199.6, 165.4 (d, JCP ) 7.7 Hz), 128.6 (d,
JCP ) 4.4 Hz), 120.0 (d, JCP ) 11.6 Hz), 69.7 (d, JCP ) 168 Hz),
54.0 (d, JCP ) 7.0 Hz), 53.7 (d, JCP ) 6.4 Hz), 49.8, 30.2; 31P
NMR (CDCl3) δ 19.9 (86%), 20.5 (14%); HRMS (FAB, MH+)
calcd for C9H16O6P 251.0684, found 251.0687.
General Procedure for the Alkene Cross Metathesis
Reaction. An oven-dried flask was charged with Grubbs
second generation catalyst 10 (68 mg, 0.08 mmol) under an
argon atmosphere. A solution of the phosphonate (0.550 g, 3.31
mmol) in freshly distilled solvent (usually CH2Cl2) was added,
followed by addition of terminal or disubstituted olefin (0.5 to
10 equiv). The septum was then quickly replaced with a
condenser connected to an argon bubbler. The flask was
immersed in an oil bath preheated to 45 °C until the reaction
was complete (monitored by 31P NMR spectroscopy). The
mixture was concentrated in vacuo and purified directly by
silica gel chromatography or pretreated with DMSO15 and then
concentrated in vacuo and purified directly by silica gel
chromatography. Quantities, experimental variations, yields,
and characterization data are given below.
Experimental Section
Dimethyl [1-(Acetoxy)-2-propenyl]phosphonate (4a).
Acetyl chloride (0.9 mL, 12.3 mmol) was added to a stirred
suspension of poly(4-vinyl)pyridine (PVP) (0.97 g, 9.3 mmol)
in CH2Cl2 (10 mL) at 0 °C, followed by addition of hydroxy
phosphonate 2a (1.02 g, 6.17 mmol). The reaction mixture was
stirred at room temperature until the reaction was complete
as indicated by TLC. The reaction mixture was filtered to
remove the polymer and the solvent was evaporated in vacuo.
The crude product was purified by chromatography (SiO2,
hexane:EtOAc, 1:1) to give the pure acetate 4a as a colorless
oil (0.78 g, 61%): IR (neat, NaCl) 1751 cm-1; 1H NMR (CDCl3)
δ 5.88 (1H, m), 5.66 (1H, m), 5.35 (2H, m), 3.76 (3H, d, JHP
)
Tetramethyl (1,4-Dihydroxybut-2-enyl)-1,4-diphospho-
nate (8). Hydroxy phosphonate 2a (0.550 g, 3.31 mmol) and
Grubbs catalyst (0.068 g, 0.08 mmol) in CH2Cl2 (3 mL) for 15
h at 40 °C gave, after filtration, the diphosphonate 8 as a white
solid (0.381 g, 76% yield): mp 200-203 °C (MeOH); 1H NMR
(d6-DMSO) δ 5.90 (1H, br s), 5.83 (1H, m), 4.53 (1H, m), 3.67
(3H, d, JHP ) 10.1 Hz); 13C NMR (d6-DMSO) δ 127.5 (app t,
10.7 Hz), 3.74 (3H, d, JHP ) 10.7 Hz), 2.11 (3H, s); 13C NMR
(CDCl3) δ 169.3 (d, JCP ) 7.6 Hz), 129.3 (d, JCP ) 4.4 Hz), 119.6
(d, JCP ) 11.6 Hz), 69.1 (d, JCP ) 168 Hz), 54.0 (d, JCP ) 7.0
Hz), 53.8 (d, JCP ) 6.4 Hz), 20.9; 31P NMR (CDCl3) δ 20.7;
HRMS (FAB, MH+) calcd for C7H14O5P 209.0579, found
209.0582.
Dimethyl[1-(p-Tolylsulfamylcarbonyloxy)-2-propenyl]-
phosphonate (5a). To a solution of phosphonate 2a (0.135 g,
1 mmol) in CH2Cl2 was added tosyl isocyanate (0.168 mL, 1.1
mmol) at room temperature. After being stirred for 2 h, the
mixture was concentrated in vacuo to yield the crude product.
Recrystallization from EtOAc/hexanes gave a white solid
JCP ) 5.3 Hz), 68.2 (dd, JCP ) 164, 3.7 Hz), 53.0 (app t, JCP
)
3.0 Hz), 52.6 (app t, JCP ) 3.1 Hz); 31P NMR (DMSO) δ 24.5.
Anal. Calcd for C8H18O8P2: C, 31.60; H, 5.96. Found: C, 30.69;
H, 5.95.
Dimethyl [1-Hydroxy-5-methyl-2-hexenyl]phospho-
nate (2d). Hydroxy phosphonate 2a (0.255 g, 1.53 mmol),
4-methyl-1-pentene (1.0 mL, 7.67 mmol), and Grubbs catalyst
(0.0651 g, 0.0766 mmol) in CHCl3 (3 mL) for 24 h at 40 °C
1
(0.262 g, 72%): IR (neat, NaCl) 1748 cm-1; H NMR (CDCl3)
δ 7.93 (2H, d, JHH ) 8.4 Hz), 7.34 (2H, d, JHH ) 8.0 Hz), 5.80
(1H, m), 5.46 (1H, m), 5.35 (2H, m), 3.77 (3H, d, JHP ) 10.8
Hz), 3.75 (3H, d, JHP ) 10.8 Hz), 2.44 (3H, s); 31P NMR (CDCl3)
δ 20.0; HRMS (FAB, MH+) calcd for C13H19NO7PS 364.0620,
(15) Ahn, Y. M.; Yang, K. L.; Georg, G. I. Org. Lett. 2001, 3, 1411.
8648 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Nonracemic Allylic Hydroxy Phosphonates
gave, after chromatography (SiO2, hexane:EtOAc, 1:1), the
hydroxy phosphonate 2d as a colorless oil (0.19 g, 57%) (E:Z,
12:1): IR (neat, NaCl) 3298 cm-1; 1H NMR (CDCl3) δ 5.88 (1H,
m), 5.59 (1H, m), 4.47 (1H, dd, JHH ) 7.0 Hz, JHP ) 10.4 Hz),
3.82 (3H, d, JHP ) 10.4 Hz), 3.81 (3H, d, JHP ) 10.4 Hz), 1.98
(2H, m), 1.67 (1H, m), 0.90 (3H, d, JHH ) 6.7 Hz), 0.89 (3H, d,
JHH ) 6.6 Hz); 13C NMR (CDCl3) δ 134.7 (d, JCP ) 13.1 Hz),
d, JHP ) 10.7 Hz), 3.80 (3H, s), 3.79 (3H, d, JHP ) 10.7 Hz),
1.97 (2H, m), 1.65 (1H, m), 0.87 (6H, d, JHH ) 6.6 Hz); 13C
NMR (CDCl3) δ 154.9 (d, JCP ) 9.9 Hz), 137.9 (d, JCP ) 12.5
Hz), 121.5 (d, JCP ) 4.0 Hz), 73.2 (d, JCP ) 170 Hz), 55.5, 53.9
(d, JCP ) 7.2 Hz), 53.8 (d, JCP ) 6.6 Hz), 41.8 (d, JCP ) 1.2
Hz), 28.2 (d, JCP ) 2.6 Hz), 22.4; 31P NMR (CDCl3) δ 20.5;
HRMS(EI, M+) calcd for C11H21O6P 280.1076, found 280.1074.
125.2 (d, JCP ) 3.9 Hz), 69.5 (d, JCP ) 161 Hz), 53.8 (d, JCP
)
Dimethyl [1-Acetoxy-5-methyl-2-hexenyl]phosphonate
(4d). The acetoxy phosphonate 4a (0.255 g, 1.23 mmol),
4-methyl-1-pentene (0.8 mL, 6.13 mmol), and Grubbs catalyst
(0.052 g, 0.0613 mmol) in CH2Cl2 (4.5 mL) at 40 °C for 24 h
gave, after chromatography (SiO2, hexane:EtOAc, 1:1), the
phosphonate 4d as a colorless oil (0.291 g, 90%) (E:Z, 9.5:1):
7.1 Hz), 41.9 (d, JCP ) 1.5 Hz), 28.4 (d, JCP ) 2.9 Hz), 22.5,
22.4; 31P NMR (CDCl3) δ 24.9; HRMS (EI, M+) calcd for
C9H19O4P 222.1021, found 222.1017.
Dimethyl [1-Hydroxy-4-(trimethylsilyl)-2-butenyl]-
phosponate (2e). Hydroxy phosphonate 2a (0.251 g, 1.51
mmol), allyl trimethylsilane (1.2 mL, 7.57 mmol), and Grubbs
catalyst (0.0643 g, 0.0757 mmol) in CHCl3 (5 mL) at 40 °C for
23 h gave after chromatography (SiO2, hexane:EtOAc, 1:1) the
hydroxy phosphonate 2e as a colorless oil (0.313 g, 82%) (E:Z,
1
IR (neat, NaCl) 1751 cm-1; H NMR (CDCl3) δ 5.87 (1H, m),
5.65 (1H, dd, JHH ) 7.8 Hz, JHP ) 12.6 Hz), 5.51 (1H, m), 3.79
(3H, d, JHP ) 10.6 Hz), 3.78 (3H, d, JHP ) 10.6 Hz), 2.12 (3H,
s), 1.96 (2H, m), 1.65 (1H, m), 0.87 (6H, d, JHH ) 6.6 Hz); 13C
NMR (CDCl3) δ 169.4 (d, JCP ) 7.8 Hz), 137.4 (d, JCP ) 12.6
Hz), 121.9 (d, JCP ) 4.1 Hz), 69.2 (d, JCP ) 170 Hz), 53.8 (d,
JCP ) 7.0 Hz), 53.7 (d, JCP ) 6.4 Hz), 41.8 (d, JCP ) 1.4 Hz),
28.2 (d, JCP ) 2.7 Hz), 22.4, 21.0; 31P NMR (CDCl3) δ 21.6;
HRMS(EI, MH+) calcd for C11H22O5P 265.1205, found 265.1205.
1
10.7:1): IR (neat, NaCl) 3300 cm-1; H NMR (CDCl3) δ 5.86
(1H, m), 5.42 (1H, m), 4.42 (1H, dd, JHH ) 7.5 Hz, JHP ) 8.5
Hz), 3.81 (6H, d, JHP ) 10.4 Hz), 1.55 (2H, dd, JHH ) 8.3 Hz,
JHP ) 3.3 Hz), 0.02 (9H, s); 13C NMR (CDCl3) δ 133.3 (d, JCP
) 13.7 Hz), 122.3 (d, JCP ) 4.1 Hz), 69.8 (d, JCP ) 162 Hz),
53.7 (d, JCP ) 7.1 Hz), 53.6 (d, JCP ) 7.2 Hz), 23.6, -1.8; 31P
NMR (CDCl3) δ 25.4; HRMS(FAB, M+) calcd for C9H21O4PSi
252.0947, found 252.0938.
Dimethyl [1-(p-Tolylsulfamylcarbonyloxy)-5-methyl-
2-hexenyl]phosphonate (5d). Phosphonate 5a (0.251 g,
0.692 mmol), 4-methyl-1-pentene (0.9 mL, 6.92 mmol), and
Grubbs catalyst (0.0294 g, 0.0345 mmol) in CH2Cl2 (5 mL) at
40 °C for 22 h gave, after chromatography (SiO2, hexane:
EtOAc, 1:1), the phosphonate 5d as a colorless oil (0.256 g,
88%) (E:Z, 10:1): IR (neat, NaCl) 1754 cm-1; 1H NMR (CDCl3)
δ 7.94 (2H, d, JHH ) 8.3 Hz), 7.33 (2H, d, JHH ) 8.3 Hz), 5.83
(1H, m), 5.42 (2H, m), 3.76 (3H, d, JHP ) 10.7 Hz), 3.74 (3H,
d, JHP ) 10.7 Hz), 2.45 (3H, s), 1.92 (2H, m), 1.59 (1H, m),
0.83 (3H, d, JHH ) 6.6 Hz), 0.82 (3H, d, JHH ) 6.6 Hz); 13C
NMR (CDCl3) δ 149.8 (d, JCP ) 10.7 Hz), 145.2, 139.2 (d, JCP
) 12.8 Hz), 135.9, 129.8, 128.6, 120.9 (d, JCP ) 3.7 Hz), 71.5
(d, JCP ) 174 Hz), 54.2 (d, JCP ) 6.8 Hz), 54.0 (d, JCP ) 6.8
Hz), 41.8 (d, JCP ) 1.2 Hz), 28.2 (d, JCP ) 2.4 Hz), 22.4, 22.3,
22.0; 31P NMR (CDCl3) δ 20.3; HRMS (FAB, MH+) calcd for
C17H2N7O7PS 420.1246, found 420.1249.
Dimethyl (1-Hydroxy-4-acetoxy-2-butenyl)phospho-
nate (2f). Hydroxy phosphonate 2a (1.01 g, 6.08 mmol), cis-
1,4-diacetoxy-2-butene (2.09 g, 12.17 mmol), and Grubbs
catalyst (0.125 g, 0.15 mmol) in CHCl3 (3 mL) for 24 h at 40
°C gave, after chromatography (SiO2, hexane:EtOAc, 1:1), the
hydroxy phosphonate 2f as a light brown oil (0.88 g, 61%): IR
(neat, NaCl) 3299, 1739 cm-1 1H NMR (CDCl3) δ 6.01 (2H,
;
m), 4.57 (3H, m), 3.82 (6H, d, JHP ) 10.4 Hz), 2.08 (3H, s); 13
C
NMR (CDCl3) δ 171.1, 128.6, 127.5 (d, JCP ) 12.7 Hz), 68.8 (d,
JCP ) 161 Hz), 64.4, 54.3 (d, JCP ) 6.9 Hz), 54.1 (d, JCP ) 7.4
Hz), 21.3; 31P NMR (CDCl3) δ 24.6.
Dimethyl [1-Hydroxy-3-(1,3-dioxan-1-yl)prop-2-enyl]-
phosphonate (2g). Hydroxy phosphonate 2a (0.30 g, 1.81
mmol), 2-vinyl-1,3-dioxalane (0.362 mL, 3.62 mmol), and
Grubbs catalyst (0.042 g, 0.05 mmol) in CHCl3 (3 mL) for 9 h
at 40 °C gave, after chromatography (SiO2, hexane:EtOAc, 1:1),
the hydroxy phosphonate 2g as a light brown oil (0.12 g, 30%)
(E:Z, 7.8:1): 1H NMR (CDCl3) δ 6.00 (2H, m), 5.33 (1H, m),
4.59 (1H, m), 3.90 (4H, m), 3.81 (3H, d, JHP ) 10.4 Hz), 3.80
(3H, d, JHP )10.3 Hz); 13C NMR (CDCl3) δ 130.4 (d, JCP ) 3.5
Hz), 129.0 (d, JCP ) 11.9 Hz), 103.0 (d, JCP ) 1.9 Hz), 68.3 (d,
JCP ) 161 Hz), 65.11, 65.08, 54.2 (d, JCP ) 7.1 Hz), 53.9 (d,
JCP ) 7.4 Hz); 31P NMR (CDCl3) δ 24.3.
Dimethyl [1-Hydroxy-5-methyl-2-hexenyl]phospho-
nate (2d) from (1R),(2E)-Dimethyl (1-Hydroxy-3-phenyl-
2-propenyl)pPhosphonate (2b). Phosphonate 2b (>95% ee,
0.3 g, 1.24 mmol), 4-methyl-1-pentene (0.521 g, 6.19 mmol),
and Grubbs catalyst (0.051 g, 0.062 mmol) in CH2Cl2 (5 mL)
at 40 °C for 36 h gave, after chromatography (SiO2, hexane:
EtOAc 4:1, then hexane:EtOAc 1:1), the phosphonate 2d as a
colorless oil (0.202 g, 74%, >95% ee) (E:Z, 12.5:1).
Dimethyl [1-Hydroxy-5-methyl-2-hexenyl]phospho-
nate (2d) from Dimethyl (1-Hydroxy-2E-butenyl)Phos-
phonate (2c). Phosphonate 2c (0.3 g, 2.22 mmol), 4-methyl-
1-pentene (0.701 g, 8.33 mmol), and Grubbs catalyst (0.069 g,
0.084 mmol) in CH2Cl2 (5 mL) at 40 °C for 12 h gave, after
chromatography (SiO2, hexane:EtOAc, 4:1, then hexane:
EtOAc, 1:1), the phosphonate 2d as a colorless oil (0.176 g,
48%) (E:Z, 14.3:1).
Dimethyl[1-(Methoxycarbonyloxy)-5-methyl-2-hexenyl]-
phosphonate (3d). Phosphonate 3a (3.0 g, 13.4 mmol),
4-methyl-1-pentene (8.5 mL, 67 mmol), and Grubbs catalyst
(0.568 g, 0.67 mmol) in CH2Cl2 (30 mL) at 40 °C for 20 h gave,
after chromatography (SiO2, hexane:EtOAc, 1:1), the phos-
phonate 3d as a pale yellow oil (3.43 g, 92%) (E:Z 11.8:1): IR
(neat, NaCl) 1754 cm-1; 1H NMR (CDCl3) δ 5.92 (1H, m), 5.53
(1H, m), 5.43 (1H, dd, JHH ) 7.8 Hz, JHP ) 12.4 Hz), 3.81 (3H,
Dimethyl {1-[Dimethyl(tert-butyl)silyloxy]-5-methyl-
2-hexenyl}phosphonate (6d). Phosphonate 6a (0.255 g,
0.909 mmol), 4-methyl-1-pentene (0.6 mL, 4.55 mmol), and
Grubbs catalyst (0.0386 g, 0.0454 mmol) in anhydrous CH2Cl2
(4.5 mL) at 40 °C for 24 h gave, after chromatography (SiO2,
hexane:EtOAc, 1:1), the phosphonate 6d as a colorless oil
(0.272 g, 89%) (E:Z, 10:1): 1H NMR (CDCl3) δ 5.81 (1H, m),
5.57 (1H, m), 4.47 (1H, dd, JHH ) 6.4 Hz, JHP ) 14.0 Hz), 3.79
(3H, d, JHP ) 10.3 Hz), 3.78 (3H, d, JHP ) 10.3 Hz), 1.98 (2H,
m), 1.66 (1H, m), 0.92 (9H, s), 0.90 (3H, d, JHH ) 6.7 Hz), 0.89
(3H, d, JHH ) 6.7 Hz), 0.12 (3H, s), 0.08 (3H, s); 13C NMR
(CDCl3) δ 133.5 (d, JCP ) 13.0 Hz), 126.5 (d, JCP ) 3.9 Hz),
70.9 (d, JCP ) 171 Hz), 53.9 (d, JCP ) 7.2 Hz), 53.5 (d, JCP
)
7.1 Hz), 41.8 (d, JCP ) 2.0 Hz), 28.5 (d, JCP ) 3.2 Hz), 25.9,
22.5, 22.4, 18.5, -4.5, -4.9; 31P NMR (CDCl3) δ 23.7; HRMS
(FAB, MH+) calcd for C15H34O4SiP 337.1964, found 337.1960.
Dimethyl[1-(2-Keto-butanoyloxy)-5-methyl-2-hexenyl]-
phosphonate (7d). Phosphonate 7a (3 g, 12 mmol), 4-methyl-
1-pentene (4.6 mL, 36 mmol), and Grubbs catalyst (0.509 g,
0.6 mmol) in CH2Cl2 (30 mL) at 40 °C for 20 h gave, after
chromatography (SiO2, hexane:EtOAc, 1:1), the phosphonate
7d as a pale yellow oil (2.99 g, 82%) (E:Z, 10:1): IR (neat, NaCl)
1
1754, 1721 cm-1; H NMR (CDCl3) δ 5.84 (1H, m), 5.44 (1H,
m), 3.72 (3H, d, JHP ) 10.7 Hz), 3.71 (3H, d, JHP ) 10.7 Hz),
3.45 (2H, s), 2.2 (3H, s), 1.90 (2H, m), 1.56 (1H, m), 0.80 (6H,
d, JHH ) 6.6 Hz); 13C NMR (CDCl3) δ 199.8, 165.7 (d, JCP
)
8.0 Hz), 138.2 (d, JCP ) 12.6 Hz), 121.4 (d, JCP ) 4.1 Hz), 70.0
(d, JCP ) 171 Hz), 53.9 (d, JCP ) 6.5 Hz), 53.8 (d, JCP ) 6.0
Hz), 50.1, 41.8, 30.3, 28.2 (d, JCP ) 2.5 Hz), 22.4; 31P NMR
(CDCl3) δ 20.9; HRMS (EI, MH+) calcd for C13H24O6P 307.1310,
found 307.1311.
Dimethyl [1-(Methoxycarbonyloxy)-4-(3-methoxyphen-
yl)-2-butenyl]phosphonate (3h).7a Phosphonate 3a (1.5 g,
J. Org. Chem, Vol. 69, No. 25, 2004 8649

He et al.
6.7 mmol), 3-(3-methoxyphenyl)propene (1.49 g, 10.0 mmol),
and Grubbs catalyst (0.284 g, 0.335 mmol) in CH2Cl2 (10 mL)
at 40 °C for 12 h gave, after chromatography (SiO2, CH2Cl2:
EtOAc, 1:4), the phosphonate 3h as a pale yellow oil (1.56 g,
68%): IR (neat, NaCl) 1755 cm-1; 1H NMR (CDCl3) δ 7.20 (1H,
t, JHH ) 7.8 Hz), 6.74 (3H, m), 6.07 (1H, m), 5.65 (1H, m), 5.49
(1H, dd, JHH ) 7.9 Hz, JHP ) 13 Hz), 3.81 (3H, s), 3.79 (6H, d,
JHP ) 11 Hz), 3.78 (3H, s), 3.42 (2H, m); 13C NMR (CDCl3) δ
160.0, 154.9 (d, JCP ) 9.5 Hz), 140.7 (d, JCP ) 2.3 Hz), 136.4
(d, JCP ) 12.3 Hz), 129.7, 122.1 (d, JCP ) 3.9 Hz), 121.1, 114.4,
112.0, 72.9 (d, JCP ) 169 Hz), 55.6, 55.3, 55.1 (d, JCP ) 7.1
Hz), 53.9 (d, JCP ) 6.5 Hz), 38.8 (d, JCP ) 1.3 Hz); 31P NMR
(CDCl3) δ 20.7; HRMS (EI, M+) calcd for C15H21O7P 344.1025,
found 344.1027.
2.6 Hz), 30.8 (d, JCP ) 1.0 Hz); 31P NMR (CDCl3) δ 20.1; HRMS
(FAB, MH+) calcd for C10H19O6BrP 345.0103, found 345.0101.
Dimethyl [(N-(tert-Butoxycarbonyl)-N-(methyl 2-
acetate)-6-amino-1-(methoxycarbonyloxy)-2-hexenyl]-
phosphonate (3l). Phosphonate 3a (0.5 g, 2.2 mmol), alkene
(1.15 g, 4.46 mmol), and Grubbs catalyst (0.078, 0.036, and
0.056 mmol at 0, 16, and 40 h, respectively) in toluene (5 mL)
at 75 °C for 52 h gave, after DMSO addition15 (24 h) and
chromatography (SiO2, hexane then hexane:EtOAc, 4:1), the
phosphonate 3l as a pale yellow oil (0.692 g, 68%): IR (neat,
NaCl) 1755, 1698 cm-1; 1H NMR (CDCl3) δ 5.95 (1H, m), 5.56
(1H, m), 5.43 (1H, m), 3.93 (1H, s), 3.84 (1H, s), 3.81 (6H, br
s), 3.78 (3H, s), 3.72 (3H, s), 3.25 (2H, m), 2.11 (2H, m), 1.62
(2H, m), 1.46 and 1.41 (9H, s); 13C NMR (CDCl3) (reported as
rotomer pairs) δ 170.8 and 170.7, 155.9 and 155.3, 154.9 (d,
JCP ) 9.8 Hz), 137.9 and 137.7 (d, JCP ) 12.6 Hz), 121.2 (app
m), 80.5 and 80.4, 73.1 and 73.0 (d, JCP ) 170 Hz), 55.5, 54.0
(d, JCP ) 7.2 Hz), 53.9 (d, JCP ) 6.7 Hz), 52.15 and 54.12, 49.6
and 48.95, 48.2 and 48.1, 29.8, 28.5 and 28.4, 27.6 and 27.3;
31P NMR (CDCl3) δ 20.3; HRMS (FAB, MH+) calcd for
C18H33O10NP 454.1842, found 454.1834.
Dimethyl [4-(1,3-Dioxan-1-yl)-1-(methoxycarbonyloxy)-
2-butenyl]phosphonate (3g). Phosphonate 3a (0.26 g, 1.16
mmol), 2-vinyl-1,3-dioxolane (0.6 mL, 5.81 mmol), and Grubbs
catalyst (0.0493 g, 0.058 mmol) in CH2Cl2 (5 mL) at 40 °C for
20 h gave, after chromatography (SiO2, hexane:EtOAc, 1:1),
the phosphonate 3g as a pale yellow oil (0.11 g, 32% yield):
1
IR (neat, NaCl) 1758 cm-1; H NMR (CDCl3) δ 6.03 (1H, m),
Dimethyl [N-(tert-Butoxycarbonyl)-N-(methyl 2-
acetate)-7-amino-1-(methoxycarbonyloxy)-2-heptenyl]-
phosphonate (3m). Phosphonate 3a (0.5 g, 2.2 mmol), alkene
(1.21 g, 4.46 mmol, 2 equiv), and Grubbs catalyst (0.075 and
0.036 mmol at 0 and 17 h, respectively) in toluene (5 mL) at
75 °C for 31 h gave, after DMSO addition15 (24 h) and
chromatography (SiO2, hexane:EtOAc 5:1 then hexane:EtOAc
1:1), the phosphonate 3m as a pale yellow oil (0.94 g, 90%):
IR (neat, NaCl) 1755, 1698 cm-1; 1H NMR (CDCl3) δ 5.92 (1H,
m), 5.52 (1H, m), 5.42 (1H, m), 3.91 (1H s), 3.82 (1H, s), 3.79
(6H, br s), 3.77 (3H, s), 3.71 (3H, s), 3.24 (2H, m), 2.10 (2H,
m), 1.43 (4H, m), 1.39 and 1.33 (9H, s); 13C NMR (CDCl3)
(reported as rotomer pairs) δ 170.8 and 170.7, 155.9 and 155.3,
154.9 (d, JCP ) 9.9 Hz), 138.4 (m), 120.8 (m), 80.3 and 80.2,
73.1 (d, JCP ) 170 Hz), 55.5, 54.0 (d, JCP ) 8.7 Hz), 53.9 (d,
JCP ) 6.6 Hz), 52.1, 49.3 and 48.6, 48.2 and 48.1, 32.2, 28.5
and 28.4, 27.9 and 27.7, 25.8; 31P NMR (CDCl3) δ 20.3; HRMS
(FAB, MH+) calcd for C19H35O10NP 468.1999, found 468.2011.
5.87 (1H, m), 5.56 (1H, ddd, JHH )1.4, 5.6 Hz, JHP ) 15.3 Hz),
5.30 (1H, dd, JHH ) 5.2 Hz, JHP ) 1.9 Hz), 3.95 (2H, m), 3.88
(2H, m), 3.80 (3H, s), 3.79 (6H, d, JHP ) 10.6 Hz); 13C (CDCl3)
δ 154.7 (d, JCP ) 8.7 Hz), 131.1 (d, JCP ) 11.0 Hz), 126.1 (d,
JCP ) 3.8 Hz), 102.3 (d, JCP ) 1.8 Hz), 71.7 (d, JCP ) 167 Hz),
65.1, 65.0, 55.7, 54.3 (d, JCP ) 7.1 Hz), 54.0 (d, JCP ) 6.5 Hz);
31P NMR (CDCl3) δ 18.8; HRMS (FAB, MH+) calcd for
C10H18O8P 297.0739, found 297.0735.
Dimethyl [1-(Methoxycarbonyloxy)-2-hexenyl]phos-
phonate (3i). Phosphonate 3a (0.3 g, 1.34 mmol), 1-hexene
(1.13 g, 13.4 mmol), and Grubbs catalyst (0.055 g, 0.067 mmol)
in CH2Cl2 (5 mL) at 40 °C for 22 h gave, after chromatography
(SiO2, hexane then hexane:EtOAc, 4:1), the phosphonate 3i
as a pale yellow oil (0.362 g, 97%) (E:Z, 10:1): IR (neat, NaCl)
1755 cm-1; 1H NMR (CDCl3) δ 5.95 (1H, m), 5.54 (1H, m), 5.43
(1H, dd, JHH ) 7.8 Hz, JHP ) 12.5 Hz), 3.82 (3H, d, JHP ) 10.6
Hz), 3.81 (3H, s), 3.81 (3H, d, JHP ) 10.6 Hz), 2.09 (2H, m),
1.35 (4H, m), 0.88 (3H, t, JHH ) 7.0 Hz); 13C NMR (CDCl3) δ
154.9 (d, JCP ) 9.9 Hz), 139.2 (d, JCP ) 12.5 Hz), 120.3 (d, JCP
) 3.8 Hz), 73.2 (d, JCP ) 171 Hz), 55.4, 54.0 (d, JCP ) 7.0 Hz),
Dimethyl [7-Hydroxy-1-(methoxycarbonyloxy)-2-hep-
tenyl]phosphonate (3n). Phosphonate 3a (1.0 g, 4.5 mmol),
5-hexenol (0.89 g, 8.9 mmol), and Grubbs catalyst (0.18 g, 0.22
mmol, 5%) in CH2Cl2 (10 mL) at 40 °C for 30 h gave, after
chromatography (SiO2, hexane then hexane:EtOAc, 4:1), the
phosphonate 3n as a pale yellow oil (0.28 g, 62%) (E:Z, 27:1):
IR (neat, NaCl) 3439, 1755 cm-1; 1H NMR (CDCl3) δ 5.95 (1H,
m), 5.55 (1H, m), 5.42 (1H, ddd, JHH ) 7.7, 0.7 Hz, JHP ) 12.5
Hz), 3.80 (3H, d, JHP ) 10.6 Hz), 3.80 (3H, s), 3.79 (3H, d, JHP
) 10.6 Hz), 3.60 (2H, t, JHH ) 6.1 Hz), 2.13 (2H, m), 1.97 (1H,
s), 1.53 (4H, m); 13C NMR (CDCl3) δ 154.9 (d, JCP ) 9.9 Hz),
53.8 (d, JCP ) 6.5 Hz), 32.2 (d, JCP ) 1.0 Hz), 30.8 (d, JCP
)
2.4 Hz), 22.3, 14.0; 31P NMR (CDCl3) δ 20.4; HRMS (FAB,
MH+) calcd for C11H22O6P 281.1154, found 281.1157.
Dimethyl [1-(Methoxycarbonyloxy)-4-(trimethylsilyl)-
2-butenyl]phosphonate (3e). Phosphonate 3a (0.3 g, 1.34
mmol), allyltrimethylsilane (0.76 g, 6.69 mmol), and Grubbs
catalyst (0.055 g, 0.067 mmol) in toluene (5 mL) at 75 °C for
37 h gave, after chromatography (SiO2, hexane:EtOAc 3:1), the
phosphonate 3e as a pale yellow oil (0.224 g, 60%) (E only):
138.7 (d, JCP ) 12.5 Hz), 120.7(d, JCP ) 3.9 Hz), 73.1 (d, JCP
)
1
IR (neat, NaCl) 1755 cm-1; H NMR (CDCl3) δ 5.97 (1H, m),
171 Hz), 62.5, 55.5, 54.0 (d, JCP ) 7.1 Hz), 53.9 (d, JCP ) 6.5
Hz), 32.2 (d, JCP ) 0.9 Hz), 32.1, 24.8 (d, JCP ) 2.5 Hz); 31P
NMR (CDCl3) δ 20.4; HRMS (FAB, MH+) calcd for C11H22O7P
297.1103, found 297.1106.
5.37 (2H, m), 3.80 (6H, d, JHP ) 10.7 Hz), 3.79 (3H, s), 3.79
(6H, d, JHP ) 10.7 Hz), 1.56 (2H, dd, JHH ) 8.3 Hz, JHP ) 2.7
Hz), 0.00 (9H, s); 13C NMR (CDCl3) δ 155.0 (d, JCP ) 11.0 Hz),
137.4 (d, JCP ) 13.2 Hz), 118.3 (d, JCP ) 3.8 Hz), 73.8 (d, JCP
) 174 Hz), 55.4, 53.8 (d, JCP ) 7.0 Hz), 53.7 (d, JCP ) 6.4 Hz),
23.8, -1.8; 31P NMR (CDCl3) δ 20.9; HRMS (FAB, M2H+) calcd
for C22H47O12P2Si2 621.2081, found 621.2070.
Carbohydrate Phosphonate (3o). Phosphonate 3a (0.081
g, 0.36 mmol, 3 equiv), O-pentenyl glycoside (0.06 g, 0.12 mmol)
in CH2Cl2 (2 mL), and Grubbs catalyst (5.1 mg, 0.006 mmol)
at 40 °C for 24 h gave, after chromatography (SiO2, hexane:
EtOAc, 1:1), a diastereoisomeric mixture of phosphonates 3o
as a colorless oil (0.073 g, 87%): IR (neat, NaCl) 1750, 1716
cm-1; 1H NMR (CDCl3) δ 7.86 (2H, dd, JHH ) 3.1, 5.5 Hz), 7.74
(2H, dd, JHH ) 3.1, 5.4 Hz), 5.76 (2H, m), 5.33 (3H, m), 5.16
(1H, t, JHH ) 9.8 Hz), 4.31 (2H, m), 4.16 (1H, dd, JHH ) 1.9,
12.3 Hz), 3.75-3.88 (11H, m), 3.43 (1H, m), 2.10 (3H, s), 2.02
(3H, s), 1.90 (2H, m), 1.85 (3H, s), 1.55 (2H, m); 13C NMR
(CDCl3) δ 170.9, 170.3, 169.7, 167.8, 154.8 (2), 137.4(m), 134.6,
131.5, 123.8, 121.0 (m), 98.3, 72.9 (m), 72.0, 70.9, 69.2, 62.2,
55.5, 54.8, 53.9 (2), 53.8 (d, JCP ) 5.9 Hz), 53.7 (d, JCP ) 6.0
Hz), 28.6, 28.5 (2), 20.9, 20.8, 20.6; 31P NMR (CDCl3) δ 20.22,
20.20; HRMS (FAB, MH+) calcd for C30H39NO16P 700.2007,
found 700.2016.
Dimethyl [6-Bromo-1-(methoxycarbonyloxy)-2-hexenyl]-
phosphonate (3k). Phosphonate 3a (0.3 g, 1.34 mmol),
5-bromo-1-pentene (0.998 g, 6.69 mmol), and Grubbs catalyst
(0.055 g, 0.067 mmol) in CH2Cl2 (5 mL) at 40 °C for 26 h gave,
after chromatography (SiO2, hexane then hexane:EtOAc, 4:1),
the phosphonate 3k as a pale yellow oil (0.285 g, 62%): IR
(neat, NaCl) 1755 cm-1; 1H NMR (CDCl3) δ 5.90 (1H, m), 5.62
(1H, m), 5.44 (1H, ddd, JHH ) 7.4, 0.7 Hz, JHP ) 13.0 Hz), 3.81
(3H, d, JHP ) 10.6 Hz), 3.81 (3H, s), 3.80 (3H, d, JHP ) 10.6
Hz), 3.39 (2H, t, JHH ) 6.6 Hz), 2.27 (2H, m), 1.95 (2H, m); 13
C
NMR (CDCl3) δ 154.9 (d, JCP ) 9.9 Hz), 136.3 (d, JCP ) 12.3
Hz), 120.1 (d, JCP ) 4.0 Hz), 73.0 (d, JCP ) 171 Hz), 55.6, 54.0
(d, JCP ) 7.1 Hz), 53.9 (d, JCP ) 6.4 Hz), 32.9, 31.5 (d, JCP
)
8650 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Nonracemic Allylic Hydroxy Phosphonates
Acknowledgment. We are grateful to the National
Science Foundation for funding this work (CHE-
0313736), we also thank the National Science Founda-
tion, the U.S. Department of Energy, and the University
of Missouri Research Board for grants to purchase the
NMR spectrometers (CHE-9318696, CHE-9974801, DE-
FG02-92-CH10499), the mass spectrometer (CHE-
9708640), and X-ray diffractometer (CHE-9309690) used
in this work. The authors also thank Mallinckrodt for
a fellowship for A.T. and the UMSL Graduate School
for a Fellowship for B.Y. and Mr. Joe Kramer and Prof.
R. E. K. Winter for mass spectra.
Supporting Information Available: General experimen-
tal, 1H and 13C NMR spectra for compounds 4a, 5a, 6a, 7a, 8,
2d, 2e, 2f, 3d, 4d, 5d, 6d, 7d, 3e, 3g, 3h, 3i, 3k, 3l, 3m, 3n,
and 3o, HPLC data for compounds (+)2b, (R)2b, (+)2d,
(R)2d, and 8, and X-ray data for 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0490090
J. Org. Chem, Vol. 69, No. 25, 2004 8651