Free-radical-mediated conjugate additions. Enantioselective synthesis of butyrolactone natural products: (-)-Enterolactone, (-)-arctigenin, (-)-isoarctigenin, (-)-nephrosteranic acid, and (-)-roccellaric acid

Article abstract of DOI:10.1021/jo015501x

Lewis acid-mediated conjugate addition of alkyl radicals to a differentially protected fumarate 10 produced the monoalkylated succinates with high chemical efficiency and excellent stereoselectivity. A subsequent alkylation or an aldol reaction furnished the disubstituted succinates with syn configuration. The chiral auxiliary, 4-diphenylmethyl-2-oxazolidinone, controlled the stereoselectivity in both steps. Manipulation of the disubstituted succinates obtained by alkylation furnished the natural products (-)-enterolactone, (-)-arctigenin, and (-)-isoarctigenin. The overall yields for the target natural products were 20-26% over six steps. Selective functionalization of the disubstituted succinates obtained by aldol condensation gave the paraconic acid natural products (-)-nephrosteranic acid (8) and (-)-roccellaric acid (9). The overall yield of the natural products 8 and 9 over four steps was 53% and 42%, respectively.

Full text of DOI:10.1021/jo015501x

1738
J . Org. Chem. 2002, 67, 1738-1745
Articles
F r ee-Ra d ica l-Med ia ted Con ju ga te Ad d ition s. En a n tioselective
Syn th esis of Bu tyr ola cton e Na tu r a l P r od u cts: (-)-En ter ola cton e,
(-)-Ar ctigen in , (-)-Isoa r ctigen in , (-)-Nep h r oster a n ic Acid , a n d
(-)-Roccella r ic Acid
Mukund P. Sibi,* Pingrong Liu,† J ianguo J i, Saumen Hajra, and J ian-xie Chen
Department of Chemistry, North Dakota State University, Fargo, North Dakota 58105-5516
Mukund.Sibi@ndsu.nodak.edu
Received J anuary 3, 2001
Lewis acid-mediated conjugate addition of alkyl radicals to a differentially protected fumarate 10
produced the monoalkylated succinates with high chemical efficiency and excellent stereoselectivity.
A subsequent alkylation or an aldol reaction furnished the disubstituted succinates with syn
configuration. The chiral auxiliary, 4-diphenylmethyl-2-oxazolidinone, controlled the stereoselectivity
in both steps. Manipulation of the disubstituted succinates obtained by alkylation furnished the
natural products (-)-enterolactone, (-)-arctigenin, and (-)-isoarctigenin. The overall yields for the
target natural products were 20-26% over six steps. Selective functionalization of the disubstituted
succinates obtained by aldol condensation gave the paraconic acid natural products (-)-nephroster-
anic acid (8) and (-)-roccellaric acid (9). The overall yield of the natural products 8 and 9 over four
steps was 53% and 42%, respectively.
Sch em e 1
In tr od u ction
The readily available simple four-carbon dicarboxylic
acids, succinic, fumaric, and maleic acid, serve as impor-
tant building blocks in organic chemistry. Recently,
succinates with substituents on the carbon backbone
have received attention because of their potential use as
components in the development of metalloproteinase
inhibitors.1 In this regard, a differentially protected
succinate is an extremely useful synthon for ready
functionalization of the carbon backbone. We have re-
cently shown that conjugate radical additions to enoates
proceed with high chemical efficiency and excellent
stereoselectivity.2 In an effort to expand the utility of this
chemistry in total synthesis, we have undertaken the
regio- and stereocontrolled radical additions to differen-
tially protected fumarates.3 This should allow for the
ready preparation of functionalized succinates as shown
in Scheme 1. In step 1, the remote chiral center is
established through a regio- and stereoselective radical
addition to the fumarate 1 (Xc ) chiral auxiliary). In step
2, the chiral auxiliary controls the regio- and stereochem-
istry in the introduction of the second substituent by an
alkylation or an aldol process. Thus, a single chiral center
in the auxiliary allows for the sequential introduction of
multiple stereocenters with control over both regio- and
stereochemistry of each substituent.
Natural products containing the butyrolactone skeleton
continue to attract considerable attention due to their
interesting biological profile.4,5 For example, enterolac-
tone (5), a lignan present in human urine, has been
* To whom correspondence should be addressed. Tel: 1-701-231-
8251. Fax: 1-701-231-8831.
(3) For work on radical addition to fumarates using imides derived
from Kemp’s triacid, see: (a) Stack, J . G.; Curran, D. P.; Rebek, J .,
J r.; Ballester, P. J . Am. Chem. Soc. 1991, 113, 5918. (b) Stack, J . G.;
Curran, D. P.; Geib, S. V.; Rebek, J r., J .; Ballester, P. J . Am. Chem.
Soc. 1992, 114, 7007. For examination of selectivity in radical addition
to fumarates and related systems, see: (c) Porter, N. A.; Bruhnke, J .
D.; Wu, W.-X.; Rosenstein, I. J .; Breyer, R. A.; McPhail, A. T. J . Am.
Chem. Soc. 1992, 114, 7664. (d) Giese, B.; Zehnder, M.; Roth, M.; Zeitz,
H.-G. J . Am. Chem. Soc. 1990, 112, 6741. (e) Porter, N. A.; Scott, D.
M.; Lacher, B.; Giese, B.; Zeitz, H. G.; Lindner, H. J . J . Am. Chem.
Soc. 1989, 111, 8311. (f) Scott, D. M.; McPhail, A. T.; Porter, N. A.
Tetrahedron Lett. 1990, 31, 1679. (g) Bulliard, M.; Zeitz, H.-G.; Giese,
B. Synlett 1991, 423.
† Taken in part from the MS thesis of Pingrong Liu, North Dakota
State University, September 2000.
(1) For a recent review article see: Whittaker, M.; Floyd, C. D.;
Brown, P.; Geraing, A. J . H. Chem. Rev. 1999, 99, 2735 and references
therein.
(2) For Lewis acid-mediated conjugate radical additions, see: (a)
Sibi, M. P.; J i, J .; Sausker J . B.; J asperse, C. P. J . Am. Chem. Soc.
1999, 121, 7517. (b) Sibi, M. P.; J asperse, C. P.; J i, J . J . Am. Chem.
Soc. 1995, 117, 10779. (c) Sibi, M. P.; J i, J .; Wu, J . H.; Gu¨rtler, S.;
Porter, N. A. J . Am. Chem. Soc. 1996, 118, 9200. (d) Sibi, M. P.; J i, J .
J . Org. Chem. 1997, 62, 3800. (e) Sibi, M. P.; J i, J . J . Org. Chem. 1996,
61, 6090.
10.1021/jo015501x CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/08/2002

Free-Radical-Mediated Conjugate Additions
J . Org. Chem., Vol. 67, No. 6, 2002 1739
Ta ble 1. Lew is Acid -Med ia ted Isop r op yl Ra d ica l Ad d ition to Desym m etr ized F u m a r a te 10
Lewis acida
(equiv)
diastereoselectivity
regioselectivity
entry
solvent
CH2Cl2
CH2Cl2
CH2Cl2
yieldb (%)
(11)c
11/12d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
92
86
87
88
95
90
95
95
88
92
91
95
90
91
88
93
90
1.6:1.0
1.2:1.0
1.0:1.0
1.6:1.0
2.1:1.0
21:1
29:1
5.0:1.0
13:1
47:1
10:1
31:1
33:1
11:1
9:1
7:1
33:1
6:1
BF3‚Et2O (1)
Mg(OTf)2 (1)
Zn(OTf)2 (1)
Sc(OTf)3 (1)
Y(OTf)3 (1)
Sm(OTf)3 (1)
Sm(OTf)3 (2)
Ho(OTf)3 (1)
Tm(OTf)3 (1)
Yb(OTf)3 (1)
Lu(OTf)3 (1)
Er(OTf)3 (1)
Er(OTf)3 (3)
Er(OTf)3 (0.2)
Er(OTf)3 (1)
Er(OTf)3 (1)
CH2Cl2
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
CH2Cl2/THF ) 4/1
THF
>100:1
>100:1
24:1
>100:1
>100:1
80:1
87:1
>100:1
>100:1
11:1
>100:1
>100:1
71:1
3.0:1
53:1
Et2O
34:1
a
b
See the Experimental Section for reaction conditions. Isolated yield. c Diastereomeric ratios were determined by 1H 400 MHz NMR
of the crude reaction mixture. Regioselectivity was determined by 1H 400 MHz NMR analysis of the crude reaction mixture.
d
shown to possess protective properties toward certain
types of cancers.6 Arctigenin (6), another example of a
bisbenzylbutyrolactone lignan, exhibits anti-HIV proper-
ties.7 Besides the disubstituted lignans, there are trisub-
stituted butyrolactones that contain a carboxylic acid
group at the C-4 position, which also show promising
biological activities. Nephrosteranic acid (8), roccellaric
acid (9), and methylenolactocin are examples of this class
of butyrolactones known as paraconic acids. In this paper,
we describe the selective functionalization of fumarates
by the strategy outlined in Scheme 1 and apply it in the
highly efficient synthesis of enterolactone8 (5) and arc-
tigenin (6),8h,9 and the first enantioselective synthesis of
isoarctigenin (7).10 Additionally, the enantioselective
synthesis of paraconic acid natural products nephroster-
anic (8)11 and roccellaric acid (9)11a,12 is also described.13
(4) (a) Schottner, M.; Spiteller, G.; Gansser, D. J . Nat. Prod. 1998,
61, 119. (b) Ayres, D. C.; Loike, J . D. In Lignans. Chemical, Biological,
and Clinical Properties; Cambridge University: Cambridge, 1990;
Chapters 3 and 4 and references therein. (c) Ward, R. S. Chem. Soc.
Rev. 1982, 11, 75. (d) Ward, R. S. Tetrahedron 1990, 46, 5029.
(5) (a) Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama, M. J .
Antibiot. 1988, 41, 751. (b) Murta, M. M.; de Azevedo, M. B. M.; Greene,
A. E. J . Org. Chem. 1993, 58, 7537 and references therein.
(6) (a) Stitch, S. R.; Funke, C. W.; Groen, M. B.; Leemhuis, J .;
Toumba, J . K.; Vink, J .; Woods, G. F. Nature 1980, 287, 738. (b)
Walters, A. P.; Knowler, J . T. J . Reprod. Fertil. 1982, 66, 379. (c)
Mousavi, Y.; Adlercreutz, H. J . Steroid Biochem. Mol. Biol. 1992, 41
(3-8), 615.
(7) (a) Eich, E.; Pommier, Y.; Pertz, H.; Kaloga, M.; Schulz, J .; Fesen,
M. R.; Mazumder, A. J . Med. Chem. 1996, 39, 86. (b) Vlietinck, A. J .;
DeBruyne, T.; Apers, S.; Pieters, L. A. Planta Med. 1998, 64, 97. (c)
Cho, J . Y.; Kim, A. R.; Yoo, E. S.; Baik, K. U.; Park, M. H. J . Phar.
Pharmacol. 1999, 51, 1267.
Resu lts a n d Discu ssion
(8) For selected synthesis of enterolactone in racemic form, see: (a)
Srikrishna, A.; Venkateswarlu, S.; Danieldoss, S.; Sattigeri, J . A. Ind.
J . Chem. Sect. B 1995, 34, 679. (b) Asaoka, M.; Fujii, N.; Shima, K.;
Takei, H. Chem. Lett. 1988, 805. (c) Snieckus, V.; Mahalanabis, K. K.;
Mumtaz, M. Tetrahedron Lett. 1982, 23, 3975. (d) Ma¨kela¨, T.; Mati-
kainen, J .; Wa¨ha¨la¨, K.; Hase, T. Tetrahedron 2000, 56, 1873. For
enantioselective synthesis, see: (e) Sibi, M. P.; Liu, P.; J ohnson, M.
D. Can. J . Chem. 2000, 78, 133. (f) Yoda, H.; Katagiri, T.; Kitayama,
H.; Takabe, K. Tetrahedron 1992, 48, 3313. (g) Feringa, B. L.; J ansen,
J . F. G. A.; van Oeveren, A. J . Org. Chem. 1994, 59, 5999. (h) Doyle,
M. P.; Bode, J . W.; Lynch, V. J .; Protopopova, M. N.; Simonsen, S. H.;
Zhou, Q.-L. J . Org. Chem. 1995, 60, 6654. (i) Doyle, M. P.; Bode, J .
W.; Protopopva, M. N.; Zhou, Q.-L. J . Org. Chem. 1996, 61, 9146. (j)
Chenevert, R.; Mohammadi-Ziarani, G.; Caron, D.; Dasser, M. Can.
J . Chem. 1999, 77, 223.
Application of free-radical-based synthetic methods for
the stereoselective construction of carbon-carbon bonds
(9) For the conversion of the corresponding glucoside to arctigenin,
see: Nishibe, S.; Hisada, S.; Inagaki, I. Chem. Pharm. Bull. 1971, 19,
866.
(10) For racemic synthesis, see: (a) Ozawa, S.; Davin, L. B.; Lewis,
N. G. Phytochemistry 1993, 32, 643. (b) Mitra, J .; Mitra, A. K. Ind. J .
Chem. Sect. B. 1994, 33, 953. (c) Burden, J . K.; Cambie, R. C.; Craw,
P. A.; Rutledge, P. S.; Woodgate, P. D. Aust. J . Chem. 1988, 41, 919.
(11) (a) Takahata, H.; Uchida, Y.; Momose, T. J . Org. Chem. 1995,
60, 5628. (b) Takahata, H.; Uchida, Y.; Momose, T. Tetrahedron Lett.
1994, 35, 4123.

1740 J . Org. Chem., Vol. 67, No. 6, 2002
Sibi et al.
has continued to increase.14 A major breakthrough in this
area was the discovery that Lewis acids can be effectively
used for obtaining high levels of diastereo- and enantio-
selectivity in radical reactions.15 Lewis acid mediated
addition of isopropyl radical to desymmetrized fumarate
1016 was initially evaluated to establish optimal reaction
conditions (Table 1). The auxiliary of choice was the
oxazolidinone derived from diphenylalanine17 since it had
shown the best characteristics in our earlier work.
Several trends are evidenced from Table 1.
strate for conjugate addition â to the imide carbonyl
resulting in high regioselectivity. Chelation to the Lewis
acid also locks the substrate in an s-cis rotamer, and
radical addition takes place from a face opposite to the
bulky diphenylmethyl substituent providing high dia-
stereoselectivity. We have previously established that
radical addition to crotonates and cinnamates can be
accomplished with substoichiometric amounts of Lewis
acid with minimal change in yield and selectivity.2a
However, with the more reactive fumarate 10, radical
addition to uncomplexed substrate presumably competes
effectively (Table 1, entry 1) with substoichiometric Lewis
acid-substrate complex (Table 1, entry 15), leading to
lower selectivity. The dependence of regio- and diaste-
reoselectivity with variation in chelating Lewis acids
remains unexplained.
The conjugate addition reaction proceeds in excellent
chemical yields. High regio- and diastereoselectivity was
observed with lanthanide and pre-lanthanide Lewis acids
(Table 1, entries 6, 7, 9, 10, 12, and 13), but the reaction
was essentially nonselective in the absence of a Lewis
acid (Table 1, entry 1). The regioselectivity in the radical
addition experiments was determined by NMR analysis
of the reaction mixture. Authentic samples of the racemic
regio- and diastereomeric (1:1) monoethyl succinic acids
were prepared by independent synthesis18 and the chiral
auxiliary introduced by standard techniques. The four
regio- and diastereomeric products show well-separated
signals for the methylene protons (400 MHz NMR) to
allow for unambiguous determination of product ratios.
The regiochemistry in the conjugate addition was further
confirmed by the preparation of the natural products
(vide infra). Of the lanthanide Lewis acids examined,19
samarium, thulium, lutetium, and erbium triflates gave
the best selectivity (Table 1, entries 7, 10, 12, and 13).
Yttrium triflate also gave high regio- and diastereose-
lectivity (Table 1, entry 6). Stoichiometric amount of
Lewis acid was required for high selectivity (compare
Table 1, entry 13 with 15). Whereas excess erbium triflate
led to a small enhancement in diastereoselectivity, excess
samarium triflate greatly lowered both regio- and dia-
stereoselectivity (compare Table 1, entry 13 with 14 and
7 with 8).
Having established that regio- and stereocontrolled i-Pr
radical addition to 10 was feasible, we turned our
attention to the introduction of benzylic fragments.
Intermolecular conjugate addition of benzylic radicals to
enoates has not been reported in the literature. We began
our investigation with the addition of benzylic radicals20
to 10 under the condition established from i-Pr radical
addition. A stoichiometric amount of Sm(OTf)3 was used
as the Lewis acid. The reaction produced the desired
products along with ethyl addition product 17, which was
produced from the ethyl radical generated by Et3B and
remaining starting material 10. However, the benzyl
radical added to the â-position of the chiral imide, and
only one diastereomer was obtained. After brief optimiza-
tion of the reaction conditions by variation of the amounts
of radical precursors, Bu3SnH, Et3B, and multiple addi-
tion of those reagents, the reactions went to completion
and produced the desired products in 71-84% yields as
single diastereomers after purification by flash column
chromatography (Table 2). Three-time addition and
larger scale of reagents helped to improve the conversions
(compare Table 1, entries 2, 3, and 5). The use of iodide
instead of bromide decreased the conversion (compare
Table 1, entry 4 with 3). Larger scale reaction improved
the yield of 14 from 50% to 71% (compare Table 1, entry
5 with 6) and also increased the yield of 15 from 74% to
80% (compare Table 1, entry 8 with 9). 3,4-Dimethoxy-
benzyl radical was more reactive than 3-methoxybenzyl
radical; thus, less radical precursor and shorter reaction
time were needed for the reaction, and higher yields and
less amount of ethyl product were obtained (compare
Table 1, entries 8 and 9 with entries 5 and 6). The
addition of 3-methoxy-4-benzyloxybenzyl radical worked
quite well. We obtained 84% of isolated yield for the
product 16, with <10% of ethyl product 17 (Table 1, entry
10). However, there was a problem with the simple benzyl
radical addition (Table 1, entry 1) experiment. The
desired product and ethyl product had the same polarity.
Therefore, neither flash column chromatography nor
crystallization could completely separate both products.
These results indicate that a chelating Lewis acid is
required for obtaining high selectivity (compare Table 1,
entry 10 or 13 with 2). The Lewis acid selectively
coordinates to the imide group and activates the sub-
(12) (a) Mulzer, J .; Salimi, N.; Hartl, H. Tetrahedron: Asymmetry
1993, 4, 457. (b) Bella, M.; Margarita, R.; Orlando, C.; Orsini, M.;
Parlanti, L.; Piancatelli, G. Tetrahedron Lett. 2000, 41, 561. (c) Martin,
T.; Rodriguez, C. M.; Martin, V. S. J . Org. Chem. 1996, 61, 6450. (d)
Chen, M.-J .; Liu, R.-S. Tetrahedron Lett. 1998, 39, 9465. For formal
syntheses, see: (e) Mandal, P. K.; Roy, S. C. Tetrahedron 1999, 55,
11395. (f) Masaki, Y.; Arasaki, H.; Itoh, A. Tetrahedron Lett. 1999,
40, 4829. (g) Bohm, C.; Reiser, O. Org. Lett. 2001, 3, 1315.
(13) For a preliminary account of this work, see: Sibi, M. P.; J i, J .
Angew. Chem., Int. Ed. Engl. 1997, 36, 274.
(14) For discussion on acyclic diastereoselection in radical reactions
see: (a) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Weinheim, 1995. (b) Giese, B. Radical in
Organic Synthesis. Formation of Carbon-Carbon Bond; Pergamon:
Oxford, 1986. (c) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem.
Res. 1991, 24, 296. (d) Smadja, W. Synlett 1994, 1.
(15) For recent reviews on Lewis acid-mediated radical reactions,
see: (a) Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. Engl. 1998,
37, 2562. (b) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163.
(16) Substrate 10 was prepared in 87% yield by acylation of the
chiral auxiliary (R)-4-diphenylmethyl-2-oxazolidinone with the acid
chloride derived from commercially available monoethyl fumaric acid.
(17) The choice of the 4-diphenylmethyl-2-oxazolidinone as a chiral
auxiliary was based on its known superiority in radical reactions. For
synthesis of the auxiliary see: Sibi, M. P.; Deshpande, P. K.; La Loggia,
A. J .; Christensen, J . W. Tetrahedron Lett. 1995, 36, 8961. Sibi, M. P.
Aldrichim. Acta 1999, 32, 93. This chiral auxiliary is now available
commercially from Aldrich Chemical Co.
In conjugate addition reactions using relatively unre-
active nucleophilic radicals, competitive ethyl radical
addition was a problem when Et3B was used as an
initiator. Recently, Schiesser has reported the utility of
9-BBN as a radical initiator to avoid the competitive
addition associated with Et3B.21 We found that conjugate
(18) For synthesis of the racemic compound, see ref 3b.
(19) Other lanthanide Lewis acids (La(OTf)3, Gd(OTf)3, Pr(OTf)3, Tb-
(OTf)3, Eu(OTf)3) were also evaluated, but they showed inferior
selectivity.
(20) Reaction of benzylic radicals has been noted in the literature.
See: Bury, A.; Cooksey, C. J .; Funabiki, T.; Gupta, B. D.; J ohnson, M.
D. J . Chem. Soc., Perkin Trans. 2 1979, 1050.

Free-Radical-Mediated Conjugate Additions
J . Org. Chem., Vol. 67, No. 6, 2002 1741
Ta ble 2. Ben zylic Ra d ica l Con ju ga te Ad d ition to 10 In itia ted by Et3B
entrya
RX/(equiv)
Bu3SnH (equiv)
Et3B (equiv)
time (h)
10/product/17b
product/yieldc(%)
yieldc of 17 (%)
1
2
3
R1Br/10.0
R2Br/10.0
R2Br/10.0
R2I/10.0
6.0d
5.0
5.0
3.0d
2.0
3
3
3
3
3
3
2
2
2
2
1:6:2
2:2:1
2:3:1
6:3:1
1:6:3
0:3.5:1
0:4.6:1
0.1:4:1
0:5.3:1
0:8:1
2.0d
2.0d
3.0d
3.0d
3.0d
3.0d
3.0d
3.0d
4
5.0
5
6e
7
8
9f
10
R2Br/10.0d
R2Br/10.0d
R3Br/10.0
R3Br/8.0
6.0d
6.0d
6.0d
6.0d
6.0d
6.0d
14/50
14/71
27
19
15/74
15/80
16/84
17
12
<10
R3Br/8.0
R4Br/10.0
a
b
0.2 mmol scale reaction unless otherwise noted. Product ratios were determined by 1H 500 MHz NMR of the crude reaction mixture.
c Isolated yield. Three-time addition of the reagent. e 2.6 mmol scale reaction. f 4.52 mmol scale reaction.
d
Sch em e 2
addition of benzyl radical to 10 using 9-BBN as an
initiator (1 equiv of Sm(OTf)3, -78 °C, CH2Cl2/THF (4:
1), 10 equiv of benzyl bromide, 2 equiv of 9-BBN (0.5 M
in THF), and 5 equiv of Bu3SnH) provided the desired
product 13 with reaction going to completion. Similar
results were obtained from the substituted benzylic
radicals furnishing products 14-16. The regio- and
diastereoselectivity in the benzylic radical additions were
similar irrespective of the initiator (Et3B or 9-BBN) used
for the reaction. But the reactions with 9-BBN were
difficult to control; sometimes reactions were very messy
and the byproducts were hard to separate.
one only requires the readily available benzylic bromides
as starting materials.
Generally, the benzyl radicals are stable and undergo
reduction (hydrogen atom transfer) rather than inter-
molecular addition to simple esters or amides. The
reasons for the successful formation of benzylic radical
conjugate addition products are 2-fold. Compound 10 is
a highly activated substrate by the presence of the two
electron poor functional groups, an imide and an ester.
The reactivity of the substrate is further enhanced by
chelation of the Lewis acid to the imide. Additionally, the
nucleophilic character of the benzylic radical comple-
ments the electrophilicity of the fumarate 10. The
preferential chelation of the Lewis acid to the imide
functionality in 10 and the reaction proceeding through
an s-cis conformer of the side chain accounts for the
observed high regio- and diastereoselectivity in the
formation of 14-16. The preparation of benzyl copper or
Grignards are often problematic owing to their relative
instability and formation of dimeric compounds, and this
in turn complicates their use in conjugate addition to
activated enoates.22 Thus, the present methodology using
radical intermediates offers practical advantage in that
We have been interested in developing efficient and
general methods for the preparation of lignan natural
products with the caveat that a common precursor
provides access to several targets (Scheme 2). A 2,3-
disubstituted monosuccinate unit (structure 18, Scheme
2) functions as one such intermediate that on selective
functional group manipulations furnishes the target
lignans.
Having achieved the successful introduction of the
remote benzyl substituent, we turned our attention to
the introduction of the second benzylic group by an ionic
process en route to the target natural products (Scheme
3). This was accomplished using the standard Evans
protocol (base, -78 °C, alkylating agent).23 Thus, treat-
ment of 14 with 1.1 equiv of NaHMDS at -78 °C for 1.25
h followed by addition of 3-methoxybenzyl bromide gave
the alkylated product 21 in moderate yield (<40%) and
excellent diastereoselectivity. Improvement in chemical
yield could be achieved by using the corresponding benzyl
iodide as the alkylating agent (50%). The stereochemistry
in the alkylation step is controlled by the chiral auxiliary
resulting in the formation of the syn product (vide infra).
The auxiliary could be cleaved readily using LiOH/H 2O2/
(21) Perchyonok, V. T.; Schiesser, C. H. Tetrahedron Lett. 1998, 39,
5437.
(22) For the preparation and reactions of benzyl organometallics,
see: (a) Bernardon, C. J . Organomet. Chem. 1989, 367, 11. (b) van
Heerden, P. S.; Bezuidenhoudt, B. C. B.; Steenkamp, J . A. Tetrahedron
Lett. 1992, 33, 2383. (c) van Heerden, P. S.; Bezuidenhoudt, B. C. B.;
Ferreira, D. Tetrahedron 1996, 52, 12313. (d) van Hereden, P. S.;
Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron Lett. 1997, 38, 1821.
(e) J ubert, C.; Knochel, P. J . Org. Chem. 1992, 57, 5425. (f) For a recent
discussion on benzyl organometallics, see: Kim, S.-H.; Rieke, R. D. J .
Org. Chem. 2000, 65, 2322.
(23) For selective alkylation of a similar C-4 unit, see: (a) Evans,
D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981, 103, 2127. (b)
Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J . S.; Bilodeau, M. T. J .
Am. Chem. Soc. 1990, 112, 8215. (c) Evans, D. A.; Bilodeau, M. T.;
Somers, T. C.; Clardy, J .; Cherry, D.; Kato, Y. J . Org. Chem. 1991, 56,
5750. (d) Oppolzer, W.; Cintas-Moreno, P.; Tamura, O. Cardinaux, F.
Helv. Chim. Acta 1993, 76, 187.

1742 J . Org. Chem., Vol. 67, No. 6, 2002
Sibi et al.
Sch em e 3
Sch em e 4
THF in excellent yield providing the key intermediate
22. The chiral auxiliary was recovered in >95% yield.
Two complimentary sequences were carried out to
convert 22 to the target enterolactone. Selective reduction
of the carboxyl group in 22 using borane gave the ester
alcohol, which was cyclized using PPTS to furnish the
lactone 23 in 78% yield over two steps. The spectral and
analytical characteristics of lactone 23 were identical to
that reported in the literature [[R]25 -38.8 (c 1.06,
D
CHCl3) for 23; literature value: -39.2 (c 0.78, CHCl3)].8h
Demethylation of 23 using borontribromide provided (-)-
enterolactone 5 in 88% yield. The overall yield for the
natural product was 21% over six steps. We have
exploited the inherent C2 symmetry in the precursor
molecule and carried out an alternate sequence of steps
for the preparation of the lactone precursor 23. Chemose-
lective reduction of the ester group in 22 using LiBH4/
MeOH in ether gave an alcohol that was lactonized using
PPTS to provide 23. The combined yield for the two steps
was 74%. Boron tribromide mediated demethylation8h
furnished the (-)-enterolactone 5 in excellent yield. The
overall yield for 5 was 20%, which was similar to the
sequence using borane reduction.
natural products in a simple way. Compound 16 was
converted to (-)-arctigenin (6) in overall higher chemical
efficiency (24% overall) by alkylation with 3,4-dimethoxy-
benzyl iodide (64%) followed by hydrolysis (74%), borane
reduction and lactonization (76% over two steps), and
debenzylation (78%).
The synthesis of nephrosteranic and roccellaric acids
required the addition of methyl radical to 10 followed by
syn selective aldol reaction at the R-methylene to the
chiral auxiliary carbonyl. Addition of methyl radical to
10 using methyl iodide and tributyl tin hydride gave
mostly the starting material.24 The successful installation
of the methyl group was achieved in two steps (Scheme
5). Addition of chloromethyl radical to 10 (ClCH2I/Bu3-
SnH) in the presence of samarium triflate gave 28 as a
single regio- and diastereomer in 91% chemical yield.
Surprisingly, use of erbium triflate led to product with
lower diastereoselectivity (10:1). Reduction of the chlorine
substituent in 28 using freshly distilled Bu3SnH gave
29.25 We have recently shown that differentially protected
succinates undergo aldol reactions in a highly regio- and
stereoselective manner.26 Treatment of 29 with dibutyl-
boron triflate and triethylamine27 followed by quenching
of the boron enolate with lauraldehyde and myristyl-
aldehyde gave the lactones 30 and 31, respectively. Both
aldol reactions were >98% syn selective as evidenced by
Compound 18 serves as a common intermediate for the
synthesis of two different natural products depending on
which of the two-carboxyl groups is selectively reduced.
The preparation of isoarctigenin followed a similar reac-
tion sequence as described above except for the final
debenzylation reaction (Scheme 4). Thus, 15 was con-
verted to disubstituted monosuccinate 25 in good chemi-
cal yield as a single diastereomer. Conversion of 25 to
26 involved selective carboxyl reduction followed by
lactonization. Debenzylation under reductive conditions
furnished (-)-isoarctigenin (7), whose spectral and ana-
lytical characteristics were identical to those reported in
the literature.10a,b The overall yield for isoarctigenin was
26%. The synthesis of (-)-arctigenin (6) was achieved by
the selective reduction of the ester functionality in 25
using LiBH4/MeOH in THF followed by lactonization and
debenzylation (20% overall) [[R]25D -28.9 (c 0.71, MeOH)
for 6; literature value -27.5 (c 4.5, MeOH)].9a Thus, a
common precursor 25 provides access to two different
(24) A minor amount of ethyl radical addition (from triethylborane)
was also observed.
(25) Aged tributyltin hydride led to some epimerization.
(26) Sibi, M. P.; Deshpande, P. K.; La Loggia, A. J . Synlett 1996,
343.
(27) (a) Gage, J . R.; Evans, D. A. Org. Synthesis 1989, 68, 83. (b)
Boger, D. L.; Colletti, S. L.; Honda, T.; Menezes, R. F. J . Am. Chem.
Soc. 1994, 116, 5607.

Free-Radical-Mediated Conjugate Additions
J . Org. Chem., Vol. 67, No. 6, 2002 1743
Sch em e 5a
reduced pressure. The silica gel together with the compounds
were loaded onto a fritted-filter funnel and washed with
hexanes (700 mL) (to remove nonpolar tin). The receiving flask
was changed, and the silica gel was washed with Et2O (700
mL). The filtrate was then concentrated to provide the crude
product. Flash column chromatography (20:80 ethyl acetate/
hexanes as eluent) followed by crystallization (from ethyl
acetate/hexanes) provided 14 (0.93 g, 71%): colorless solid; Rf
1
0.77 (50:50 ethyl acetate/hexanes); mp 120 °C; H NMR (300
MHz, CDCl3) δ 1.18 (t, J ) 7.0 Hz, 3H), 2.69 (dd, J ) 13.3, 8.1
Hz, 1H), 2.79 (dd, J ) 18.5, 3.6 Hz, 1H), 2.96-3.12 (m, 2H),
3.35 (dd, J ) 18.5, 9.7 Hz, 1H), 3.82 (s, 3H), 4.10 (q, J ) 7.0
Hz, 2H), 4.33-4.45 (m, 2H), 4.62 (d, J ) 6.0 Hz, 1H), 5.26 (m,
1H), 6.73-6.82 (m, 3H), 7.03-7.09 (m, 4H), 7.22-7.29 (m, 7H);
13C NMR (75 MHz, CDCl3) δ 174.7, 171.5, 159.9, 153.5, 140.2,
139.6, 138.1, 129.7, 129.4, 129.1, 128.8, 128.6, 128.1, 127.3,
121.7, 114.7, 112.5, 65.6, 61.0, 56.6, 55.5, 51.2, 42.5, 38.1, 37.1,
a
Key: (a) Sm(OTf)3, ClCH2I, Bu3SnH, Et3B/O2, CH2Cl2/THF,
14.4; [R]25 -79.3 (c 0.42, CHCl3). Anal. Calcd for C30H31NO6:
D
1 h, -78 °C, 91% (>100:1); (b) Bu3SnH, AlBN, toluene, reflux, 12
h, 76%; (c) Bu2BOTf, CH2Cl2, Et3N, -78 to 0 °C, RCHO, 12 h, 84%
for 30 and 65% for 31; (d) LiOH, H2O2, THF/H2O, rt, 92% for 8
and 94% for 9.
C, 71.84; H, 6.23; N, 2.79. Found: C, 71.51; H, 6.24; N, 2.78.
(R)-4-(Dip h en ylm eth yl)-3-[(2R,3R)-2-(3′-m eth oxyp h en -
yl)m eth yl-3-(eth oxyca r bon yl)-4-(3′-m eth oxyp h en yl)]bu -
ta n oyl-2-oxa zolid in on e (21). To a rapidly stirred mixture
of 14 (0.47 g, 0.94 mmol) and THF (25 mL) at -78 °C was
added NaHMDS (1.0 M in THF, 1.03 mL, 1.03 mmol) dropwise.
The mixture was stirred at -78 °C for 1 h and 15 min. A
solution of 3-methoxybenzyl iodide (0.373 g, 1.5 mmol) in THF
(5 mL) was added dropwise. The reaction mixture was then
warmed to -54 °C and stirred at this temperature for 26 h.
The reaction was quenched with saturated aqueous NaHCO3
solution (50 mL) and extracted with Et2O (3 × 60 mL). The
organic layers were combined, washed with brine (50 mL),
dried over MgSO4, and concentrated. Flash column chroma-
tography (15:85 ethyl acetate/hexanes) provided 21 (0.292 g,
50%): colorless amorphous solid; Rf 0.83 (50:50 ethyl acetate/
crude NMR analysis. Selective removal of the chiral
auxiliary from 30 gave nephrosteranic acid (8) in 92%
yield, and a similar sequence starting with 31 gave
roccellaric acid (9) in 94% yield.28 The overall yield for
nephrosteranic and roccellaric acid was 53% and 42%,
respectively, over four synthetic steps from 10.
Con clu sion s
In conclusion, we have described a highly regio- and
stereoselective method for the addition of radicals to a
desymmetrized fumarate. We have developed a novel
methodology for the synthesis of lignan natural products
from a common intermediate. The application of the
addition methodology in the efficient total synthesis of
paraconic acid natural products nephrosteranic and
roccellaric acids has also been demonstrated. The present
methodology alleviates some of the problems encountered
in our alternate approach to these natural products.29
Extension of the methodology to enantioselective radical
additions, the synthesis of more complex natural prod-
ucts, and development of tandem addition protocols are
underway in our laboratory.
1
hexanes); H NMR (500 MHz, CDCl3) δ 1.20 (t, J ) 7.3 Hz,
3H), 2.84-3.05 (m, 5H), 3.76 (s, 3H), 3.79 (s, 3H), 4.07-4.12
(m, 2H), 4.32-4.37 (m, 2H), 4.49-4.54 (m, 2H), 5.15 (m, 1H),
6.62-6.68 (m, 4H), 6.75 (dd, J ) 8.4, 1.7 Hz, 1H), 6.82 (dd,
J ) 8.3, 1.7 Hz, 1H), 6.91 (m, 2H), 7.04 (d, J ) 7.4 Hz, 2H),
7.15-7.32 (m, 8H); 13C NMR (125 MHz, CDCl3) δ 174.0, 173.9,
160.1, 159.8, 153.2, 140.7, 140.5, 140.0, 138.2, 129.8, 129.6,
129.5, 129.0, 128.6, 128.0, 127.3, 122.3, 121.7, 114.9, 114.7,
113.1, 112.4, 64.8, 61.0, 56.8, 55.4, 55.3, 50.8, 48.1, 46.1, 36.2,
35.7, 14.4; [R]25D -127.3 (c 2.63, CHCl3). Anal. Calcd for C38H39
-
NO7: C, 73.41; H, 6.32; N, 2.25. Found: C, 73.69; H, 6.46; N,
2.18.
(2R,3R)-2,3-Bis-(3′-m eth oxyben zyl)su ccin ic Acid 4-Eth -
yl Ester (22). To a rapidly stirred solution of 21 (0.387 g, 0.62
mmol), THF (4.5 mL), and H2O (1.5 mL) at 0 °C was added a
solution of LiOH‚H2O (0.039 g, 0.93 mmol) in H2O (0.85 mL)
dropwise. After 2 min, H2O2 (30%, 0.255 mL, 2.48 mmol) was
added. The mixture was stirred at 0 °C for 3 h, and aqueous
Na2SO3 (10%, 5 mL) was then added. After the mixture was
stirred at 0 °C for 10 min, THF was removed on a rotary
evaporator (<35 °C). HCl (5 M) was used to achieve pH ) 6.
The mixture was made basic again using aqueous NaOH (2
M) to pH ) 8-9. The organic layer was extracted with CH2-
Cl2 (60 mL). The organic layer was washed using aqueous
NaOH (0.5 M, 2 × 20 mL) followed by brine, dried over MgSO4,
and concentrated to provided chiral auxiliary (0.15 g, 97%).
The basic aqueous layers were combined and made acidic by
HCl (5 M) to pH ) 2-3. The organic compound was extracted
with CH2Cl2 (3 × 50 mL) (each time of extraction, keep the
pH ) 2-3). The organic layers were combined, washed with
brine, dried over MgSO4, and concentrated. Flash column
chromatography (40:60 ethyl acetate/hexanes as eluent) pro-
vided the acid 22 (0.21 g, 88%): colorless liquid; Rf 0.25 (50:
Exp er im en ta l Section
(4R)-4-(Dip h en ylm eth yl)-3-[(3R)-3-(eth oxyca r bon yl)-4-
(3′-m eth oxyp h en yl)]bu ta n oyl-2-oxa zolid in on e (14). To a
solution of chiral fumarate ester 10 (0.985 g, 2.6 mmol), Sm-
(OTf)3 (1.55 g, 2.6 mmol), CH2Cl2 (60 mL), and THF (15 mL)
at -78 °C under N2 were added 3-methoxybenzyl bromide (1.82
mL, 13.0 mmol) and Bu3SnH (2.08 mL, 7.8 mmol). Et3B (1.0
M in hexane, 3.9 mL, 3.9 mmol) was then added. O2 (20 mL)
was added by syringe. After the mixture was stirred at -78
°C for 40 min, 3-methoxybenzyl bromide (0.91 mL, 6.5 mmol),
Bu3SnH (1.04 mL, 3.9 mmol), and Et3B (1.0 M in hexane, 1.95
mL, 1.95 mmol) were added sequentially. O2 (10 mL) was
added by syringe. After another 40 min, 3-methoxybenzyl
bromide (0.91 mL, 6.5 mmol), Bu3SnH (1.04 mL, 3.9 mmol),
and Et3B (1.0 M in hexane, 1.95 mL, 1.95 mmol) were added
sequentially. O2 (10 mL) was added by syringe. The reaction
mixture was stirred for 1 h and 40 min at -78 °C before
dilution with Et2O (300 mL). The mixture was washed with 2
M HCl (2 × 50 mL) and brine (2 × 50 mL). Silica gel 60 (230-
400 mesh, 50 mL) was added. The solvent was removed under
1
50 ethyl acetate/hexanes); H NMR (500 MHz, CDCl3) δ 1.18
(t, J ) 7.0 Hz, 3H), 2.92-3.00 (m, 4H), 3.04-3.09 (m, 2H),
3.74 (s, 6H), 4.09 (q, J ) 7.1 Hz, 2H), 6.61 (s, 2H), 6.67 (d,
J ) 7.3 Hz, 2H), 6.73-6.76 (m, 2H), 7.14-7.18 (m, 2H); acidic
proton in baseline; 13C NMR (125 MHz, CDCl3) δ 179.5, 173.5,
159.8, 159.8, 140.3, 140.1, 129.7, 129.6, 121.7, 121.6, 114.6,
114.6, 112.4, 112.4, 61.1, 55.3, 55.3, 47.4, 47.4, 35.8, 35.5, 14.3;
(28) The chiral auxiliary was recovered in 99% yield.
(29) Reference 26. The installation of the C-3 methyl group by
enolate alkylation of the butyrolactone proceeds in low yields and is
possible only with the carboxylic acid as the C-4 substituent.

1744 J . Org. Chem., Vol. 67, No. 6, 2002
Sibi et al.
[R]25D -41.6 (c 3.20, CHCl3); HRMS (FAB+) calcd for C22H26O6
(M + H)+ 387.1808, found 387.1800.
J ) 8.1, 2.0 Hz, 1H), 6.60 (dd, J ) 7.7, 1.7 Hz, 1H), 6.63 (d, J
) 2.0 Hz, 1H), 6.74 (d, J ) 8.1 Hz, 1H), 6.82 (d, J ) 8.1 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 179.0, 149.2, 148.1, 146.9,
144.8, 130.7, 129.7, 122.3, 120.8, 114.3, 112.0, 111.7, 111.5,
71.5, 56.1, 56.1, 56.0, 46.8, 41.1, 38.4, 34.7; [R]25D -28.9 (c 0.71,
MeOH) [lit.30 -27.5 (c 4.5, MeOH)].
(3R,4R)-3,4-Bis[(3-m et h oxyp h en yl)m et h yl]d ih yd r o-2-
(3H)-fu r a n on e (23). BH3 reduction: To a rapidly stirred
solution of acid 22 (173 mg, 0.447 mmol) and THF (15 mL) at
-15 °C was added BH3‚THF (1.0 M, 0.67 mL, 0.67 mmol)
slowly. After the mixture was stirred at this temperature for
18 h, MeOH (1 mL) was added dropwise to quench the
reaction. The solvents were removed under reduced pressure.
HCl (0.5 M, 5 mL) was added. The organic compound was
extracted with CH2Cl2 (3 × 25 mL). The organic layers were
combined, washed with brine, dried over MgSO4, and concen-
trated.
(3R,4R,5S,4′R)-4-[Ca r boxyl-(4-diph en ylm eth yl-2-oxa zo-
lid in -3-on yl)]-3-m eth yl-5-u n d ecyl-4,5-d ih yd r o-2(3H)-fu r a -
n on e (30). To 29 (395.5 mg, 1.0 mmol) in CH2Cl2 (10 mL) was
added Bu2BOTf (freshly prepared, 1 M in CH2Cl2, 1.2 mL, 1.2
mmol) at 0 °C, followed by Et3N (0.2 mL, 1.4 mmol). The yellow
solution was stirred at 0 °C for 1 h. It was then cooled to -78
°C, and lauraldehyde (freshly distilled, 221 mg, 1.2 mmol, in
5 mL of CH2Cl2) was added over 10 min. The reaction was
then gradually warmed to -10 °C and stirred at that temper-
ature for 10 h. The reaction was quenched with MeOH-H2O2
(30%, 3:1, 4 mL). The mixture was then extracted with EtOAc
(3 × 15 mL). The extracts were washed with brine (until
pH ) 7), dried over MgSO4, and concentrated. Flash column
chromatography (1:10 ethyl acetate/hexanes as eluent) puri-
fication provided 30 (450 mg, 84%): oil; Rf 0.55 (10:90 ethyl
acetate/hexanes); 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J )
6.7 Hz, 3H), 1.05 (d, J ) 7.2 Hz, 3H), 1.22-1.70 (m, 20H), 2.44
(dq, J ) 10.2, 7.3 Hz, 1H), 4.20 (dd, J ) 10.2, 8.6 Hz, 1H),
4.38 (m, 2H), 4.53 (dt, J ) 8.6, 3.8 Hz, 1H), 4.64 (d, J ) 7.5
Hz, 1H), 5.39 (dt, J ) 7.2, 3.2 Hz, 1H), 7.15-7.38 (m, 10H);
13C NMR (65 MHz, CDCl3) δ 176.9, 171.5, 153.2, 139.0, 137.9,
129.4, 129.0, 128.8, 128.6, 128.2, 127.6, 80.3, 65.8, 57.0, 52.1,
42.1, 34.9, 32.0, 29.7, 29.6, 29.5, 29.4, 29.3, 25.5, 22.8, 14.6,
14.2; [R]26D -68.3 (c 1.85, CH2Cl2). Anal. Calcd for C33H43NO5:
C, 74.26; H, 8.12; N, 2.62. Found: C, 74.03; H, 8.11; N, 2.24.
To the residue were added benzene (7 mL) and PTSA (2 mg).
The reaction mixture was heated to reflux for 4 h and then
cooled to room temperature. EtOAc was added. The mixture
was sequentially washed with saturated aqueous NaHCO3 (5
mL), water, and brine, dried over MgSO4, and concentrated.
Flash column chromatography (20:80 ethyl acetate/hexanes as
eluent) provided 23 (100 mg, 78%): 1H NMR (400 MHz, CDCl3)
δ 2.43-2.62 (m, 4H), 2.90 (dd, J ) 14.0, 7.2 Hz, 1H), 3.05 (dd,
J ) 14.0, 5.1 Hz, 1H), 3.76 (s, 3H), 3.77 (s, 3H), 3.83 (dd, J )
9.0, 7.3 Hz, 1H), 4.09 (dd, J ) 9.0, 7.5 Hz, 1H), 6.53 (s, 1H),
6.59 (d, J ) 7.6 Hz, 1H), 6.73-6.79 (m, 4H), 7.15-7.25 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 178.6, 159.9, 159.9, 139.6,
139.4, 129.8, 129.7, 121.7, 121.0, 114.9, 114.6, 112.4, 111.9,
71.3, 55.2, 55.2, 46.4, 41.3, 38.6, 35.2; [R]25 -38.8 (c 1.06,
D
CHCl3) [lit.8h [R]23 -39.2 (c 0.78, CHCl3)].
D
LiBH4 reduction: To a rapidly stirred solution of 22 (200
mg, 0.52 mmol) in Et2O (15 mL) were added LiBH4 (2.0 M,
0.52 mL, 1.04 mmol) and dry MeOH (44 µL, 1.04 mmol)
dropwise. After being stirred at room temperature for 24 h,
the reaction mixture was cooled to 0 °C. HCl (2 M, 5 mL) was
added. The mixture was extracted using EtOAc. The organic
layers were combined, washed with brine, dried over MgSO4,
and concentrated. Same lactonization procedure as BH3 reduc-
tion provided 23 (126 mg, 74%).
(3R,4R,5S,4′R)-4-[Ca r boxyl-(4-diph en ylm eth yl-2-oxa zo-
lid in -3-oyl)]-3-m eth yl-5-tr id ecyl-4,5-d ih yd r o-2(3H)-fu r a -
n on e (31). A procedure similar to that for the preparation of
30 was used to prepare 31 from 29 and myristylaldehyde:
yield 65%; oil; Rf 0.55 (10:90 ethyl acetate/hexanes); 1H NMR
(400 MHz, CDCl3) δ 0.87 (t, J ) 6.7 Hz, 3H), 1.05 (d, J ) 7.2
Hz, 3H), 1.22-1.70 (m, 24H), 2.43 (dq, J ) 10.2, 7.2 Hz, 1H),
4.20 (dd, J ) 10.2, 8.3 Hz, 1H), 4.39 (m, 2H), 4.53 (dt, J ) 8.3,
4.6 Hz, 1H), 4.64 (d, J ) 7.5 Hz, 1H), 5.39 (dt, J ) 7.0, 3.8 Hz,
1H), 7.15-7.38 (m, 10H); 13C NMR (65 MHz, CDCl3) δ 176.9,
171.4, 153.2, 139.0, 137.9, 129.4, 129.0, 128.8, 128.6, 128.2,
127.6, 80.4, 65.8, 57.0, 52.1, 51.1, 42.1, 34.9, 32.0, 29.8, 29.7,
(3R,4R)-3,4-Bis[(3-h yd r oxyp h en yl)m et h yl]d ih yd r o-2-
(3H)-fu r a n on e (5). (-)-En ter ola cton e. Literature procedure
as described in ref 8h was used for the synthesis of 5: yield
1
88%; colorless solid; H NMR (300 MHz, acetone-d6) δ 2.46-
3.00 (m, 6H), 3.06 (s, 1H), 3.85-4.06 (m, 2H), 6.59-6.78 (m,
6H), 7.06-7.16 (m, 2H), 8.29 (s, 1H); 13C NMR (100 MHz,
acetone-d6) δ 178.1, 157.6, 157.6, 140.5, 140.0, 129.7, 129.6,
120.7, 119.9, 116.3, 115.7, 113.7, 113.5, 70.8, 46.0, 41.3, 37.8,
34.5; [R]25 -38.3 (c 0.29, CHCl3) [lit.8h [R]23 -38.4 (c 0.25,
29.7, 29.6, 29.5, 29.5, 29.3, 25.5, 22.8, 14.6, 14.2; [R]26 -53.3
D
(c 1.82, CH2Cl2). Anal. Calcd for C35H47NO5: C, 74.83; H, 8.43;
D
D
N, 2.49. Found: C, 74.54; H, 8.52; N, 2.41.
CHCl3)].
(3R,4R,5S)-4-Ca r boxy-3-Meth yl-5-u n d ecyl-4,5-d ih yd r o-
2(3H)-fu r a n on e (8): (-)-Nep h r oster a n ic Acid . To a solu-
tion of 30 (320 mg, 0.6 mmol) in THF (4 mL) and H2O (1 mL)
were added H2O2 (30%) (0.27 mL, 2.4 mmol) and LiOH‚H2O
(37 mg, 0.9 mmol) at 0 °C. The reaction was stirred for 1 h at
0 °C. The reaction was monitored by TLC. After completion,
excess H2O2 was quenched with NaS2O3 solution (10%). Most
of the THF was removed under reduced pressure at room
temperature. The residue (pH ) 12) was then extracted with
EtOAc (3 × 10 mL) (recovery of chiral auxiliary, 150 mg, 99%).
The aqueous solution was then acidified with HCl (10%) (until
pH ) 1) and extracted with EtOAc (5 × 10 mL). The extracts
were washed with brine (2 × 5 mL), dried over MgSO4, and
concentrated. The white solid was recrystallized (from hex-
anes) to provide 8 (155 mg, 92%): mp 105-107 °C [lit.11a mp:
(3R,4R)-3-[(3,4-Dim eth oxyp h en yl)m eth yl]-4-[(3-m eth -
oxy-4-h yd r oxyp h en yl)m et h yl]d ih yd r o-2(3H )-fu r a n on e-
(7): (-)-Isoa r ctigen in . A H2 balloon was placed over a
rapidly stirred solution of 26 (0.069 g, 0.15 mmol), EtOAc (7
mL), AcOH (0.7 mL), and Pd/C (10%, 38 mg, 20 mol %). The
reaction mixture was stirred under H2 for 1.5 h. The reaction
was quenched by the addition of EtOAc (15 mL) and H2O (15
mL). The organic layer was separated, sequentially washed
with saturated aqueous NaHCO3 (15 mL) and brine (15 mL),
dried over MgSO4, and concentrated. Flash column chroma-
tography (40:60 ethyl acetate/hexanes as eluent) provided 7
(0.046 g, 82%): colorless amorphous solid; Rf 0.28 (50:50 ethyl
acetate/hexanes); 1H NMR (500 MHz, CDCl3) δ 2.43-2.52 (m,
2H), 2.55-2.62 (m, 2H), 2.87-2.98 (m, 2H), 3.80 (s, 3H), 3.82
(s, 3H), 3.85-3.89 (m, 4H), 4.10-4.14 (m, 1H), 5.56 (broad,
1H), 6.42 (d, J ) 1.3 Hz, 1H), 6.50-6.52 (m, 1H), 6.64-6.65
(m, 2H), 6.74-6.81 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
179.0, 149.3, 148.1, 146.8, 144.6, 130.5, 130.0, 121.6, 121.5,
114.7, 112.6, 111.3, 111.2, 71.5, 56.1, 56.1, 56.0, 46.7, 41.3, 38.5,
1
96-98 °C ((+)-8)]; H NMR (400 MHz, CDCl3) δ 0.86 (t, J )
6.3 Hz, 3H), 1.24 (m, 17H), 1.36 (d, J ) 7.1 Hz, 3H), 1.40 (m,
1H), 1.65-1.85 (m, 2H), 2.68 (dd, J ) 11.3 Hz, 9.4, 1H), 2.96
(dq, J ) 11.6, 7.0 Hz, 1H), 4.47 (dt, J ) 9.1, 4.0 Hz, 1H); 13C
NMR (65 MHz, CDCl3) δ 177.2, 176.8, 79.4, 53.8, 39.6, 34.7,
34.7; [R]25 -27.6 (c 0.87, CHCl3).
D
31.7, 29.4, 29.5, 29.1, 29.1, 29.0, 25.1, 22.4, 14.2, 13.8; [R]26
D
(3R,4R)-3-[(3-Meth oxy-4-h ydr oxyph en yl)m eth yl]-4-[(3,4-
d im et h oxyp h en yl)m et h yl]d ih yd r o-2(3H )-fu r a n on e (6):
(-)-Ar ctigen in . A procedure described for the preparation of
7 was used to prepare 6 from 27: yield 75%; colorless
amorphous solid; Rf 0.27 (50:50 ethyl acetate/hexanes); 1H
NMR (500 MHz, CDCl3) δ 2.44-2.65 (m, 4H), 2.87-2.96 (m,
2H), 3.81 (s, 6H), 3.84 (s, 3H), 3.86-3.89 (m, 1H), 4.11-4.15
(m, 1H), 5.56 (broad, 1H), 6.46 (d, J ) 1.7 Hz, 1H), 6.54 (dd,
-28.1 (c 1.02, CHCl3) [lit.11a [R]26
((+)-8)].
: +27.2 (c 1.45, CHCl3)
D
(3R,4R,5S)-4-Ca r boxy-3-m eth yl-5-tr id ecyl-4,5-d ih yd r o-
2(3H)-fu r a n on e (9): (-)-Roccella r ic Acid . A procedure
(30) Rahman, M. M. A.; Dewick, P. M.; J ackson, D. E.; Lucas, J . A.
Phytochemistry 1990, 29, 1971.

Free-Radical-Mediated Conjugate Additions
J . Org. Chem., Vol. 67, No. 6, 2002 1745
described for the preparation of 8 from 30 was used to prepare
9 from 31: Yield: 94%; mp 110-111 °C (lit.12a mp 108 °C); 1H
NMR (400 MHz, CDCl3) δ 0.87 (t, J ) 6.4 Hz, 3H), 1.36 (d,
J ) 6.9 Hz, 3H), 1.25 (m, 21H), 1.50 (m, 1H), 1.70 (m, 1H),
1.80 (m, 1H), 2.69 (dd, J ) 11.4, 9.4 Hz, 1H), 2.96 (dq, J )
11.8, 7.0 Hz, 1H), 4.46 (dt, J ) 9.1, 4.3 Hz, 1H); 13C NMR (65
MHz, CDCl3) δ 176.7, 176.2, 79.4, 54.0, 39.9, 35.0, 32.0, 29.8,
Ack n ow led gm en t. Financial support for this pro-
gram was provided by the NIH (GM-54656).
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal details, procedures for the preparation of 10, 11, 13, 15-
17, and 24-29 and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 25.4, 22.8, 14.6, 14.2; [R]26
D
-26.3 (c 1.24, CHCl3) [lit.12a [R]26 -26 (c 1.93, CHCl3)].
J O015501X
D