Stereospecific Pd(O)-Catalyzed Malonate Additions to Allylic Hydroxy Phosphonate Derivatives: A Formal Synthesis of (-)-Enterolactone

Article abstract of DOI:10.1021/jo035795h

A combination of cross-metathesis and malonate addition was applied to a formal synthesis of the mammalian lignan enterolactone 5. The cross-metathesis of alkene 6 and phosphonate 3a gave the substituted allylic phosphonate 3d. The palladium-catalyzed add

Full text of DOI:10.1021/jo035795h

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 (O)-Ca ta lyzed Ma lon a te
Ad d ition s to Allylic Hyd r oxy P h osp h on a te
Der iva tives: A F or m a l Syn th esis of
(-)-En ter ola cton e
Bingli Yan and Christopher D. Spilling*
Department of Chemistry and Biochemistry, University of
Missouri-St. Louis, 8001 Natural Bridge Road,
St. Louis, Missouri 63121
cspill@umsl.edu
Received December 8, 2003
SCHEME 2. Retr osyn th etic An a lysis for
En ter ola cton e
Abstr a ct: A combination of cross-metathesis and malonate
addition was applied to a formal synthesis of the mammalian
lignan enterolactone 5. The cross-metathesis of alkene 6 and
phosphonate 3a gave the substituted allylic phosphonate 3d .
The palladium-catalyzed addition of malonate 10d to the
allylic phosphonate 3d was stereospecific and highly regi-
oselective and yielded the vinyl phosphonate 11d . The vinyl
phosphonate 11d was converted in two steps into the lactone
14, a known intermediate in the synthesis of enterolactone
5.
Recent advances in catalytic asymmetric phosphony-
lation of unsaturated aldehydes1 and other methods2,3
have resulted in the availability of allylic hydroxy phos-
phonates in high enantiomeric excess. These nonracemic
hydroxy phosphonates display some of the rich chemistry
associated with allylic alcohols and consequently should
prove to be useful as building blocks for asymmetric syn-
thesis. It has been shown that allylic hydroxy phospho-
nates can serve as useful intermediates in the synthesis
of γ-substituted phosphonates by 1,3-transposition of
functionality and that the steric and electronic influence
of the phosphorus moiety can enhance the stereochemical
and regiochemical outcome of the reactions.4,5 In a nice
illustration of the effect of the phosphonate on regiose-
lectivity, Zhu and Lu demonstrated that the palladium-
catalyzed addition of nucleophiles (amine and malonate)
to the acetate derivatives 2 of racemic allylic hydroxy
phosphonates 1 (Scheme 1) takes place exclusively at the
3-position to give the γ-substituted vinyl phosphonates
4 in high yield.5 Palladium-catalyzed additions of nitro-
gen and carbon nucleophiles to racemic allylic phospho-
nates were later employed in the successful synthesis of
fosfomycin and ω-phosphono amino acids.5c-f Having
demonstrated that the palladium (0)-catalyzed intermo-
lecular addition of amines to nonracemic allylic hydroxy
phosphonate derivatives proceeds with complete chirality
transfer,6 we turned our attention to the exploration of
reactions with carbon-based nucleophiles.7,8
(1) (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.
(2) For reviews of the asymmetric synthesis of hydroxy phospho-
nates, 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.; J ones, P. G.; Schmutzler, R. Tetrahedron:
Asymmetry 1998, 9, 1645. (f) Drescher, M.; Hammerschmidt, F.
Tetrahedron 1997, 53, 4627. (g) Hammerschmidt, F.; Wuggenig, F.
Tetrahedron: Asymmetry 1999, 10, 1709 and references therein.
Lignans are widely distributed plant natural products
with diverse biological activity.9 However, enterolactone
5 (Scheme 2) was the first lignan isolated from a mam-
malian source.10 Enterolactone 5 and structurally related
(4) (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. Chem.
Commun. 1981, 511. (f) Hammond, G. B.; de Mendonca, D. J . J .
Fluorine Chem. 1999, 1.
(5) (a) Zhu, J .; Lu, X. Tetrahedron Lett. 1987, 28, 1897. (b) Zhu, J .;
Lu, X. Chem. Commun. 1987, 1318. (c) O¨ hler, E.; Kanzler, S. Synthesis
1995, 539. (d) O¨ hler, 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.
(6) De la Cruz, M. A.; Shabany, H.; Spilling, C. D. Phosphorus,
Sulfur Silicon Relat. Elem. 1999, 144-146, 181.
(7) 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 Relat. Elem.
2002, 177, 1881.
(8) Rowe, B. J .; Spilling, C. D. J . Org. Chem. 2003, 68, 9502.
(9) Whiting, D. Nat. Prod. Rep. 1987, 499; Ward, R. S. Nat. Prod.
Rep. 1995, 183.
10.1021/jo035795h CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/23/2004
J . Org. Chem. 2004, 69, 2859-2862
2859

lactones display some interesting biological activities11
and consequently have been the targets of several suc-
cessful racemic and enantioselective syntheses.12,13
SCHEME 3. Syn th esis of Allylic P h osp h on a tes
We proposed a highly convergent route to enterolactone
5, in which the benzyl side chains are derived from an
alkene and a substituted malonate (Scheme 2). It was
planned to couple an alkene to a simple, nonracemic
acrolein-derived phosphonate via an alkene cross-me-
tathesis reaction. Palladium-catalyzed addition of a
substituted malonate would then give a fully function-
alized vinyl phosphonate. Further functional group ma-
nipulation on the vinyl phosphonate would yield entero-
lactone 5.
SCHEME 4. Cr oss-Meta th esis Rea ction s of Allylic
P h osp h on a tes
The cross-metathesis reaction has become a powerful
tool for alkene synthesis,14 and examples of both cross-
metathesis (CM) and ring-closing metathesis (RCM) in-
volving vinyl and allyl phosphonates have been report-
ed.15,16 However, metathesis reactions involving inter-
conversion of allylic hydroxy phosphonates remain to be
explored. Cross-metathesis of a simple acrolein-derived
hydroxy phosphonate with an alkene potentially provides
an efficient way to synthesize structurally more complex
(10) (a) Kamlage, S.; Sefkow, M.; Pool-Zobel, B. L.; Peter, M. G.
Chem Commun. 2001, 331. (b) Ma¨kela¨, T.; Matikainen, J .; Wa¨ha¨la¨,
K.; Hase T. Tetrahedron 2000, 56, 1873. (c) Wa¨ha¨la¨, K.; Ma¨kela¨, T.;
Ba¨ckstro¨m, R.; Brunow, G.; Hase, T. J . Chem. Soc., Perkin. Trans. 1
1986, 95. (d) Belletire, J . L.; Fremont, S. L. Tetrahedron Lett. 1986,
27, 127. (e) Kirk, D. N.; McLaughlin L. M.; Lawson, A. M.; Setchell,
K. D. R.; Patel, S. K. J . Chem. Soc., Perkin Trans. 1 1985, 35. (f)
Mahalanabis, K. K.; Mumtaz, M.; Snieckus, V. Tetrahedron Lett. 1982,
23, 3975. (g) Pelter, A.; Satyanarayana, P.; Ward, R. S. Tetrahedron
Lett. 1981, 22, 1549. (h) Groen, M. B.; Leemhuis, J . Tetrahedron Lett.
1980, 21, 5043.
substituted allylic hydroxy phosphonates with the ad-
vantage of utilizing a single nonracemic precursor.17
The racemic hydroxy phosphonates 1a -c were pre-
pared (Scheme 3) by the Et3N-catalyzed addition of di-
methyl phosphite to the corresponding aldehyde.18 The
nonracemic (R)-phosphonates were prepared by catalytic
asymmetric phosphonylation using L-dimethyl tartrate
and titanium isopropoxide as a catalyst.1a The hydroxy
phosphonates 1a -c were reacted with methyl chlorofor-
mate in pyridine to give the corresponding carbonates
3a -c.
Attempted cross-metathesis of hydroxy phosphonate 1a
and alkene 6 in CHCl3 (5 mol % second-generation
Grubbs catalyst) yielded the phosphonate 1d in a low
26% isolated yield (Scheme 4). The formation of 1d was
complicated by a competing alkene migration reaction
leading to acyl phosphonate 8 and homodimerization to
give the diphosphonate 9. Reactions performed in CH2-
Cl2 led almost exclusively to the diphosphonate 9, which
precipitates from solution.17 Since the carbonates 3 are
ultimately required for the palladium-catalyzed addi-
tions, the cross-metathesis between phosphonate 3a and
alkene 6 was examined. Reaction of phosphonate 3a with
alkene 6 in CH2Cl2 (5 mol % second-generation Grubbs
catalyst) gave the hetero-cross-metathesis product 3d in
a 68% isolated yield. The homodimer of alkene 6 was also
formed; however, no homodimerization of the phospho-
nate was observed. Fortunately, the dimer of alkene 6
(11) (a) Stitch, R. S.; Toumba, J . K.; Groen, M. B.; Funke, C. W.;
Leemhuis, J .; Vink, J .; Woods, G. F. Nature 1980, 287, 738. (b) Setchell,
K. D. R.; Lawson, A. M.; Mitchell, F. L.; Adlercreutz, H.; Kirk, D. N.;
Axelson, M. Nature 1980, 287, 740.
(12) (a) Mousavi, Y.; Adlercreutz, H. J . Steroid Biochem. Mol. Biol.
1992, 41, 615. (b) Evans, B. A. J .; Griffiths, K.; Morton, M. S. J .
Endocrinol. 1995, 147, 295. (c) Novelo, M.; Cruz, J . G.; Herna´ndez, L.;
Pereda-Miranda, R.; Chai, H.; Mar. W.; Pezzuto, J . M. J . Nat. Prod.
1993, 56, 1728. (d) Eich, E.; Pertz, H.; Kaloga, M.; Schulz, J .; Fesen,
M. R.; Mazumder, A.; Pommier, Y. J . Med. Chem. 1996, 39, 86.
(13) (a) Eklund, P.; Lindholm, A.; Mikkola, J .-P.; Smeds, A.; Lehtila¨,
R.; Sjo¨holm, R. Org. Lett. 2003, 5, 491. (b) Sibi, M. P.; Liu, P.; J i, J .;
Hajra, S.; Chen, J . J . Org. Chem. 2002, 67, 1738. (c) Sibi, M. P.; Liu,
P.; J ohnson, M. D. Can. J . Chem. 2000, 78, 133. (d) Chenevert, R.;
Mohammadi-Ziarani, G.; Caron, D.; Dasser, M. Can. J . Chem. 1999,
77, 223. (e) Nymann, K.; Svendsen, J . S. Acta Chem. Scand. 1998, 52,
338. (f) Bode, J . W.; Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L. J .
Org. Chem. 1996, 61, 9146. (g) Doyle, M. P.; Protopopova, M. N.; Zhou,
Q.-L.; Bode, J . W.; Simonsen, S. H.; Lynch, V. J . Org. Chem 1995, 60,
6654. (h) Oeveren, A. V.; J ansen, J . F. G. A.; Feringa, B. L. J . Org.
Chem. 1994, 59, 5999. (i) Yoda, H.; Kitayama, H.; Katagiri, T.; Takabe,
K. Tetrahedron 1992, 48, 3313.
(14) 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.
(15) For examples, see: Chatterjee, A. K.; Choi, T.-L.; Grubbs, R.
H. Synlett 2001, 1034. Lera, M.; Hayes, C. J . Org. Lett. 2001, 3, 2765.
Demchuk, O. M.; Pietrusiewicz, K. M.; Michrowska, A.; Grela, K. Org.
Lett. 2003, 5, 3217.
(16) For examples, see: Stoianova, D. S.; Hanson, P. R. Tetrahedron
Lett. 1998, 39, 3939. Stoianova, D. S.; Hanson, P. R. Tetrahedron Lett.
1999, 40, 3297. Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000, 2, 1769.
Bujard, M.; Gouverneur, V.; Mioskowski, C. J . Org. Chem. 1999, 64,
2119. Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G.
A.; van Boom, J . H. Tetrahedron Lett. 2000, 41, 8635.
(17) A full account of the cross-metathesis reactions of allylic
hydroxy phosphonates and their derivatives will be reported elsewhere.
(18) (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.
2860 J . Org. Chem., Vol. 69, No. 8, 2004

TABLE 1. P a lla d iu m -Ca ta lyzed Ma lon a te Ad d ition to Allylic P h osp h on a tes
phosphonate
R1
malonate
R3
product
yield
compd
ee
compd
R4
compd
ee
3b
3b
3d
3c
3d
Ph
Ph
95%
88%
(()
10a
10b
10c
10c
10d
Me
Me
t-Bu
t-Bu
t-Bu
H
11a
11b
12
11c
11d
75%(E)a 13% (Z) + Ph3P(O)a
95%c
3-MeOC6H4CH2
3-MeOC6H4CH2
3-MeOC6H4CH2
H
45%a
>80%d
3-MeOC6H4CH2
Me
3-MeOC6H4CH2
38%a
(()
24%a(68%)b
85%a
(()
70%
95%
70%e
92%e
85%a
a
b
Isolated yield. Conversion based on 31P NMR spectrum of the crude product. c Determined by HPLC on a ChiralPak AD column.
Determined by HPLC on a Whelk-O column. e Determined by HPLC of lactone 14 on a Chirobiotic-T column.
d
SCHEME 5. F or m a l Syn th esis of
(-)-En ter ola cton e
also entered into the metathesis reaction with phospho-
nate 3a ; therefore, its formation had little consequence
on the reaction outcome. Furthermore, nonracemic 3a
(70% ee) gave nonracemic 3d with no erosion of the
enantiomeric excess.
Hydroxy phosphonate 1b 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. Cross-metathesis reaction of phos-
phonate 1b with alkene 6 stopped at approximately 50%
conversion (Scheme 4). Unfortunately, phosphonates 1b
and 1d were inseparable. However, cycling the isolated
product mixture (1b + 1d ) through the metathesis
reaction four times afforded 1d (95% ee, 36% yield) with
sufficient purity to proceed. The hydroxy phosphonate 1d
was converted to the corresponding carbonate 3d by
reaction with methyl chloroformate in pyridine (95%
yield) with no loss of enantiomeric excess.
substituted malonate 10c to phosphonate 3d , none were
successful. Fortunately, the less bulky tert-butyl methyl
malonate 10d underwent clean addition to phosphonate
3d with almost complete chirality transfer.
Zhu and Lu reported the addition of malonate anion
to the acrolein-derived acetoxy allylic phosphonate 2.5a,b
However, the effect of substitution on the malonate or
phosphonate and the stereochemical course of the reac-
tion were not described. Therefore, several malonate
addition reactions were carried out to examine these
parameters (Table 1). Addition of dimethyl malonate 10a
to the nonracemic cinnamyl phosphonate 3b (95% ee)
proceeded smoothly to give predominantly the (E)-vinyl
phosphonate 11a (E) (75% yield, 95% ee) with complete
chirality transfer. In addition, a small amount of the (Z)-
vinyl phosphonate was observed and isolated as a co-
mixture with triphenyl phosphine oxide. The P-H cou-
Given the results shown in Table 1, the planned
synthesis of enterolactone was revised (Scheme 5). (1R)-
Phosphonate 3d , prepared in 95% ee, was reacted with
tert-butyl methyl malonate 10d to give the adduct 11d
as a mixture of diastereomers in 85% yield (Table 1).
Ozonolysis of the vinyl phosphonate 11d and in situ
reduction of the oxidation products with sodium borohy-
dride in methanol gave the lactone 13 (57%) (Scheme 5).
The tert-butyl ester was cleaved and decarboxylated by
treatment with LiCl in DMSO at 140 °C to give the
lactone 14 in 65% yield. The lactone had an enantiomeric
excess of 92% measured by HPLC. The optical rotation
{[R]D +6.7 (c 1.1, CHCl3)} of the lactone 14 confirmed the
absolute configuration (4R), and the magnitude of the
rotation was consistent with enantiomeric excess deter-
mined by HPLC.13 Sibi et al. reported the conversion of
lactone 14 to enterolactone 5.13c Thus, synthesis of lactone
14 represents a formal synthesis of enterolactone 5.
1
plings of the vinyl protons in the H NMR spectra easily
distinguish the (E)- and (Z)-isomers 11a . In particular,
H-2 of the (Z)-vinyl phosphonate 11a (Z) exhibits a trans
P-H coupling constant of 49 Hz, whereas H-2 of the (E)-
vinyl phosphonate 11a (E) shows a cis P-H coupling
constant of 25 Hz. The benzyl-substituted malonate 10b
also added to phosphonate 3b with high chirality trans-
fer, albeit in a lower yield for a similar reaction time.
Unfortunately, the addition of the benzyl-substituted
malonate 10c to phosphonate 3d , required for the
proposed synthesis of enterolactone, resulted in formation
of the diene 12 as the major isolable product. However,
the addition of 10c to the crotanyl phosphonate 3c was
successful and no elimination product (diene) was ob-
served. Although a variety of conditions and palladium
catalysts were examined for the addition of the benzyl-
The observed lactone stereochemistry is consistent
with the expected reaction mechanism20,21 for malonate
addition to a carbonate involving inversion of configura-
tion during π-allyl formation and inversion during nu-
(19) Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve, Y.; Beaudoin,
S. J . Org. Chem. 1993, 58, 5032. Helmchen, G.; Kudis, S.; Sennhenn,
P.; Steinhagen, H. Pure Appl. Chem. 1997, 69, 513.
J . Org. Chem, Vol. 69, No. 8, 2004 2861

) 11 Hz), 3.53 (3H, d, J HP ) 11 Hz), 3.41 (1H, app t, J HH ) 7.6
Hz), 3.20 (1H, m), 2.92 (1H, m), 2.65 (1H, m), 1.47 (4.5H, s),
1.46 (4.5H, s); 13C NMR (CDCl3) 168.9, 168.5 167.9, 166.7, 159.9,
152.5 (d, J CP ) 4.9 Hz), 139.9, 129.7, 121.8 (d, J CP ) 3.8 Hz),
118.8 (d, J CP ) 183 Hz), 115.1 (d, J CP ) 3.5 Hz), 112.3, 82.9 (x2),
56.1, 55.9, 55.3, 52.7, 52.5 (d, J CP ) 5 Hz), 52.4 (d, J CP ) 5 Hz),
46.1 (d, J CP ) 11 Hz), 45.8 (d, J CP ) 11 Hz),38.3, 28.1(x2); 31P
NMR (CDCl3) δ 20.6; HRMS (FAB, NBA/CsI, [M + Cs]+) calcd
for C21H31O8PCs 575.0810, found 575.0820.
3-(ter t-Bu toxyca r bon yl)-4-[(3-m eth oxyp h en yl)m eth yl]-
d ih yd r o-2(3H)-fu r a n on e 13. The vinyl phosphonate 11d (0.873
g, 1.97 mmol) was dissolved in anhydrous MeOH (16 mL) and
CH2Cl2 (20 mL), and the resulting solution was cooled to -78
°C. O3 was bubbled into the solution until the starting material
had been consumed (TLC). The reaction flask and solution were
flushed with argon to remove residual O3, and then NaBH4
(0.448 g, 11.8 mmol) was added. The mixture was allowed to
warm to room temperature, and stirring was continued over-
night. The reaction mixture was washed twice with H2O, and
the aqueous layer was re-extracted with CH2Cl2. The combined
organic layers were dried over anhydrous Na2SO4, and the
solution was concentrated in vacuo. The crude product was
purified by chromatography (SiO2, EtOAc/hexanes 1:1) to give
the lactone 13 (0.34 g, 57%): IR (neat) 1780, 1729 cm-1; 1H NMR
(CDCl3) δ 7.21 (1H, t, J ) 7.9 Hz), 6.73 (3H, m), 4.38 (1H m),
3.93 (1H, m), 3.77 (3H, s), 3.20 (2H, m), 2.76 (2H, m), 1.38 (9H,
s); 13C NMR (CDCl3) δ 171.3, 166.4, 159.9, 138.9, 129.9, 121.2,
114.7, 112.3, 82.7, 71.2, 55.2, 53.0, 41.5, 37.9, 27.8; HRMS (EI,
M+) calcd for C17H22O5 306.1467, found 306.1469.
cleophilic attack (i.e., overall retention). It is believed that
the diene 12 is formed from the π-allyl intermediate via
a base-induced elimination,21 a process that is known to
compete with addition.22 The substituted malonate 10c
is probably too bulky and acts as a base rather than a
nucleophile. Furthermore, the conjugation of the aromatic
ring to the diene makes elimination favorable.
In summary, the palladium-catalyzed addition of tert-
butyl methyl malonate 10d to (1R)-phosphono allylic
carbonate 3d results in the formation of the vinyl
phosphonate 11d . The vinyl phosphonate 11d , formed
with retention of configuration, was converted to the
known (-)-enterolactone precursor (4R)-4-[(3-methox-
yphenyl)methyl]dihydro-2-(3H)-furnanone.
Exp er im en ta l Section
(()- or (R)-(2E)-Dim eth yl [1-(Meth oxyca r bon yloxy)-4-(3-
m eth oxyp h en yl)-2-bu ten yl]p h osp h on a te 3d . Second-genera-
tion Grubbs catalyst (0.284 g, 0.335 mmol) was dissolved in
CH2Cl2 (10 mL). Phosphonate 3a (1.5 g, 6.7 mmol) and 3-(3-
methoxyphenyl)propene 6 (1.49 g, 10.0 mmol) were added, and
the reaction flask was placed in a preheated oil bath and heated
at 40 °C for 12 h. The reaction mixture was allowed to cool, and
then the solvent was evaporated in vacuo. The crude product
was purified by chromatography (SiO2, CH2Cl2/EtOAc 20:80) to
give dimethyl [1-(methoxycarbonyloxy)-4-(3-methoxyphenyl)-2-
butenyl]phosphonate 3d as a pale yellow oil (1.56 g, 68%): IR
(neat, NaCl) 1755 cm-1; 1H NMR (CDCl3) δ 7.20 (1H, t, J ) 7.8
Hz), 6.74 (3H, m), 6.07 (1H, m), 5.65 (1H, m), 5.49 (1H, dd, J HH
) 7.9 Hz, J HP ) 13 Hz), 3.81 (3H, s), 3.79 (6H, d, J HP ) 11 Hz),
3.78 (3H, s), 3.42 (2H, m); 13C NMR (CDCl3) δ 160.0, 154.9 (d,
J CP ) 9.5 Hz), 140.7 (d, J CP ) 2.3 Hz), 136.4 (d, J CP ) 12.3 Hz),
129.7, 122.1 (d, J CP ) 3.9 Hz), 121.1, 114.4, 112.0, 72.9 (d, J CP
) 169 Hz), 55.6, 55.3, 55.1 (d, J CP ) 7.1 Hz), 53.9 (d, J CP ) 6.5
Hz), 38.8 (d, J CP ) 1.3 Hz); 31P NMR (CDCl3) δ 20.7; HRMS (EI,
M+) calcd for C15H21O7P 344.1025, found 344.1027.
Gen er a l P r oced u r e for th e Ad d ition of Ma lon a tes to
Allylic Ca r bon a tes 3b-d . NaH (3.47 mmol) was suspended
in anhydrous THF (16 mL), and then the malonate (3.47 mmol)
in THF (1 mL) was added. The mixture was stirred at room
temperature for 3-4 min. The phosphonate (2.9 mmol) was
added, followed by Pd(PPh3)4 (0.09 mmol, 3 mol %). The reaction
flask was placed in a preheated oil bath and heated at 70 °C for
1 h. The reaction mixture was allowed to cool, and then it was
partitioned between brine and Et2O. After separation, the
aqueous layer was re-extracted with Et2O and the combined
organic layers were dried over anhydrous Na2SO4. The solvent
was evaporated in vacuo to give the crude product.
4-[(3-Meth oxyph en yl)m eth yl]dih ydr o-2(3H)-fu r an on e 14.
The lactone 13 (0.032 g, 0.11 mmol) was dissolved in DMSO (2
mL) and H2O (1 drop), and then LiCl (0.0089 g, 0.21 mmol) was
added. The reaction mixture was heated at 140 °C for 17 h. The
reaction mixture was cooled, diluted with H2O, and extracted
with EtOAc (3×). The combined EtOAc extracts were washed
with 1 N HCl, saturated NaHCO3, and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by chromatography (SiO2, EtOAc/hexanes
50:50) to give the lactone 14 (0.014 g, 65%): IR (neat) 1778 cm-1
;
1H NMR (CDCl3) δ 7.24 (1H, t, J ) 7.9 Hz), 6.8 (3H, m), 4.34
(1H, dd, J ) 6.9, 9.1 Hz), 4.03 (1H, dd, J ) 6.0, 9.1 Hz), 3.80
(3H, s), 2.84 (1H, m), 2.76 (2H, m), 2.61 (1H, dd, J ) 7.9, 17
Hz), 2.29 (1H, dd, J ) 6.9, 17 Hz), 13C NMR (CDCl3) δ 177.0,
160.1, 140.0, 130.0, 121.1, 114.8, 112.0, 72.8, 55.4, 39.1, 37.2,
34.4; HRMS (EI, M+) calcd for C12H14O3 206.0943, found
206.0944. The lactone had 92% ee determined by HPLC, [R]D
+6.7 (1.1, CHCl3) (lit.3c (4R)-4-[(3-m eth oxyp h en yl)m eth yl]-
d ih yd r o-2(3H)-fu r a n on e [R]D +6.7 (1.66, CHCl3).
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.Y. We are also grateful to the NSF,
the US DOE, and the University of Missouri Research
Board for grants to purchase the NMR spectrometers
(CHE-9318696, CHE-9974801, DE-FG02-92-CH10499)
and mass spectrometer (CHE-9708640) used in this
work. We thank Brad Rowe and J eff Scholten for some
preliminary investigations, Mr. J oe Kramer and Prof.
R. E. K. Winter for mass spectra, and Anyu He for
synthesis of dimethyl (1-hydroxy-2-propenyl)phospho-
nate.
Ad d ition of ter t-Bu tyl Meth yl Ma lon a te 10d to Dim eth yl
[1-(Meth oxyca r bon yloxy)-4-(3-m eth oxyp h en yl)-2-bu ten yl]-
p h osp h on a te 3d . NaH (0.139 g, 3.48 mmol) in THF (16 mL),
malonate 10d (0.61 mL, 3.48 mmol) in THF (1 mL), phosphonate
3d (0.99 g, 2.9 mmol), and Pd(PPh3)4 (0.101 g, 0.09 mmol). The
crude product was purified by chromatography (SiO2, hexane/
acetone 50:50) to give a diastereoisomeric (50:50) mixture of
malonate adducts 11d as a pale yellow oil (1.08 g, 84%): IR
(neat) 1728 cm-1; 1H NMR (CDCl3) δ 7.18 (1H, t, J HH ) 8.0 Hz),
6.72 (3H, m), 6.63 (1H, m), 5.48 (1H, m), 3.78 (3H, s), 3.75 (1.5H,
s), 3.72 (1.5H, s), 3.63 (1.5H, d, J HP ) 11 Hz), 3.62 (1.5H, d, J HP
(20) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules, 2nd ed.; University Science Books: Sausalito, CA,
1999. (b) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley &
Sons: Chichester, 1995. (c) Heck, R. F. Palladium Reagents in Organic
Synthesis; Academic Press: London, 1987. (d) Trost, B. M. Acc. Chem.
Res. 1980, 13, 385.
(21) (a) Tsuji, J .; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron
Lett. 1978, 2075. (b) Matsushita, H.; Negishi, E.-I. J . Org. Chem. 1982,
47, 4161.
Su p p or tin g In for m a tion Ava ila ble: Experimental and
characterization data for compounds 1a , (R)1a , (R)1b, 3a , 3b,
(R)3d , 6, 11a -c, and 12, spectra for compounds 1a , 1b, 3a ,
3b, 3d , 6, 11a -d , and 12-14, and HPLC data for compounds
1b, 3b, 11a , 3d , and 14. This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) (a) Trost, B. M.; Verhoeven, T. R. Fortunak, J . M. Tetrahedron
Lett. 1979, 2301. (b) Shimizu, I.; Yamada, T.; Tsuji, J . Tetrahedron
Lett. 1980, 21, 3199.
J O035795H
2862 J . Org. Chem., Vol. 69, No. 8, 2004