Intramolecular regioselective insertion into unactivated prochiral carbon-hydrogen bonds with diazoacetates of primary alcohols catalyzed by chiral dirhodium(II) carboxamidates. Highly enantioselective total synthesis of natural lignan lactones

Article abstract of DOI:10.1021/jo961607u

Intramolecular insertion into unactivated prochiral C-H bonds of 3-aryl-1-propyl diazoacetates catalyzed by dirhodium(II) tetrakis[methyl 1-(3-phenyl propanoyl)imidazolidin-2-one-4(R or S)-carboxylate], Rh₂(4R-MPPIM)₄ or Rh₂(4S-MPPIM)₄, occurs in 91-96% ee and with virtually complete regiocontrol for the formation of β-benzyl-γ-butyrolactones. This methodology has been applied to the total synthesis of dibenzylbutyrolactone lignans (-)- and (+)-enterolactone, (-)- and (+)-hinokinin, and (+)-arctigenin from substituted cinnamic acids in 19-27% overall yields. Aryltetralin lignan (+)-isodeoxypodophyllotoxin was prepared from the reactant 3,4-(methylenedioxy)cinnamic acid in 36% yield overall, and the lactone precursor to (+)-isolauricerisinol was formed in 96.5% ee and 23% yield overall. Applications of the chiral Rh₂(MPPIM)₄ catalysts to fully aliphatic systems resulting in the formation of β-substituted-γ-butyrolactones with high regiocontrol and with 93-96% ee have demonstrated the generality of this methodology. A model that provides accurate predictions of β-substituted-γ-butyrolactone absolute configurations in these asymmetric metal carbene transformations is described.

Full text of DOI:10.1021/jo961607u

9146
J . Org. Chem. 1996, 61, 9146-9155
In tr a m olecu la r Regioselective In ser tion in to Un a ctiva ted
P r och ir a l Ca r bon -Hyd r ogen Bon d s w ith Dia zoa ceta tes of P r im a r y
Alcoh ols Ca ta lyzed by Ch ir a l Dir h od iu m (II) Ca r boxa m id a tes.
High ly En a n tioselective Tota l Syn th esis of Na tu r a l Lign a n
La cton es
J effrey W. Bode, Michael P. Doyle,* Marina N. Protopopova, and Qi-Lin Zhou
Department of Chemistry, Trinity University, San Antonio, Texas 78212
Received August 19, 1996X
Intramolecular insertion into unactivated prochiral C-H bonds of 3-aryl-1-propyl diazoacetates
catalyzed by dirhodium(II) tetrakis[methyl 1-(3-phenyl propanoyl)imidazolidin-2-one-4(R or S)-
carboxylate], Rh2(4R-MPPIM)4 or Rh2(4S-MPPIM)4, occurs in 91-96% ee and with virtually complete
regiocontrol for the formation of â-benzyl-γ-butyrolactones. This methodology has been applied to
the total synthesis of dibenzylbutyrolactone lignans (-)- and (+)-enterolactone, (-)- and (+)-
hinokinin, and (+)-arctigenin from substituted cinnamic acids in 19-27% overall yields. Aryltetralin
lignan (+)-isodeoxypodophyllotoxin was prepared from the reactant 3,4-(methylenedioxy)cinnamic
acid in 36% yield overall, and the lactone precursor to (+)-isolauricerisinol was formed in 96.5% ee
and 23% yield overall. Applications of the chiral Rh2(MPPIM)4 catalysts to fully aliphatic systems
resulting in the formation of â-substituted-γ-butyrolactones with high regiocontrol and with 93-
96% ee have demonstrated the generality of this methodology. A model that provides accurate
predictions of â-substituted-γ-butyrolactone absolute configurations in these asymmetric metal
carbene transformations is described.
The synthesis of enantiomerically pure â-substituted
γ-butyrolactones of general structure 1 represents a
significant challenge for which there have been few
solutions.1,2 These structures are indigenous to a broad
spectrum of natural products of which lignan lactones 2
are prominent.3 Alkylation or carbonyl addition reactions
of 1 afford a convenient stereocontrolled entry into
virtually all of the structurally diverse class of lignans,1,3,4
many of which, including (-)-enterolactone (3) and (+)-
arctigenin (4), have noteworthy biological and medicinal
properties.3,5-7
nans,1,3,4 including diastereoselective conjugate addition
to chiral 2(5H)-furanones and dihydrofurans,8 select
cycloaddition reactions,9 and the employment of chiral
oxazolines.10 However, diastereoselective alkylation of
1 remains the most general and versatile of known
methodologies. Enantioselective syntheses of 1 have
been achieved through resolution of alkylated succinic
acid esters,11 from dichloroketene addition to optically
active alkenyl sulfoxides,12 from l-malic acid via chiral
N-alkyl R,â-unsaturated lactams,8b from functionalized
ketene thioacetals prepared by chiral oxazolidinone-
Numerous strategies have been developed to achieve
stereocontrolled syntheses of naturally occurring lig-
X Abstract published in Advance ACS Abstracts, December 15, 1996.
(1) (a) Ward, R. S. Chem. Soc. Rev. 1982, 11, 75. (b) Ward, R. S.
Tetrahedron 1990, 46, 5029. (c) Koch, S. S. C.; Chamberlin, A. R.
Studies Nat. Prod. Chem. 1995, 16, 687.
(2) (a) Berens, U.; Scharf, H. D. Synthesis 1991, 832. (b) Ohta, T.;
Miyake, T.; Seido, N.; Kumobayashi, H.; Akutagawa, S.; Takaya, H.
Tetrahedron Lett. 1992, 33, 635.
(7) (a) Eich, E.; Pertz, H.; Kaloga, M.; J utta, S.; Fesen, M. R.;
Mazumder, A.; Pommier, Y. J . Med. Chem. 1996, 39, 86. (b) Yang, L.-
M.; Lin, S.-J .; Yang, T.-H.; Lee, K.-H. Biorg. Med. Chem. Lett. 1996,
6, 941.
(3) (a) Ward, R. S. Nat. Prod. Rep. 1995, 12, 183. (b) Ayreas, D. C.;
Loike, J . D. Chemistry & Pharmacology of Natural Products: Lignans;
Chemical, Biological and Clinical Properties; Cambridge University
Press: New York, 1990. (c) Whiting, D. A. Nat. Prod. Rep. 1987, 4,
499.
(4) Morimoto, T.; Chiba, M.; Achiwa, K. Heterocycles 1992, 33, 435.
(5) (a) Evans, B. A.; Griffiths, K.; Morton, M. S. J . Endocrinol. 1995,
147, 295. (b) Wang, C.; Makela, T.; Hase, T.; Adlercreutz, H.; Kurzer,
M. S. J . Steroid Biochem. and Molec. Biol. 1994, 50, 205. (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.
(6) (a) Thurston, L. S.; Imakyura, Y.; Haruna, M.; Li, D.-H.; Liu,
Z.-C.; Cheng, Y.-C.; Lee, K. H. J . Med. Chem. 1989, 32, 604. (b) Hirano,
T.; Gotoh, M.; Oka, K. Life Sci. 1994, 55, 1061. (c) Middel, O.;
Woerdenbag, H. J .; van Uden, W.; van Oeveren, A.; J ansen, J . F. G.
A.; Fierenga, B. L.; Konnigs, A. W. T.; Pras, N.; Kellogg, R. M. J . Med.
Chem. 1995, 38, 2112.
(8) (a) Posner, G. H.; Kogan, T. P.; Harris, S. R.; Frye, L. L.
Tetrahedron Lett. 1984, 25, 2627. (b) Yoda, H.; Kitayama, H.; Katagiri,
T.; Takabe, K. Tetrahedron 1992, 48, 3313. (c) Pelter, A.; Satya-
narayana, P.; Ward, R. S. Tetrahedron Lett. 1981, 22, 1549.
(9) (a) Charlton, J . L.; Alauddin, M. M. J . Org. Chem. 1986, 51, 3490.
(b) Larson, E. R.; Raphael, R. A. J . Chem. Soc., Perkin Trans. 1 1982,
521. (c) Takano, S.; Ohkawa, T.; Tamori, S.; Satoh, S.; Ogaswara, K.
J . Chem. Soc., Chem. Commun. 1988, 189. (d) Cochran, J . E.; Padwa,
A. J . Org. Chem. 1995, 60, 3938.
(10) (a) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Banner, B. A.; Laucher,
D. J . Am. Chem. Soc. 1988, 110, 4611. (b) Andrews, R. A.; Teague, S.
J .; Meyers, A. I. J . Am. Chem. Soc. 1988, 110, 7854. (c) Meyers, A. I.;
Flisak, J . R.; Aitken, R. A. J . Am. Chem. Soc. 1987, 109, 5446. (d)
Warshawsky, A. M.; Meyers, A. I. J . Am. Chem. Soc. 1990, 112, 8090.
(11) (a) Boissin, P.; Dahol, R.; Brown, E. Tetrahedron Lett. 1989,
30, 4371. (b) Brown, E.; Dawgan, A. Tetrahedron Lett. 1985, 26, 3997.
(12) Achiwa, K. Heterocycles 1979, 12, 515.
S0022-3263(96)01607-6 CCC: $12.00 © 1996 American Chemical Society

Total Synthesis of Natural Lignan Lactones
J . Org. Chem., Vol. 61, No. 26, 1996 9147
Sch em e 1
Sch em e 2a
directed alkylation,13 by conjugate addition to butenolides
that possess directive chiral accessories,14 from l-glutamic
acid,15 and from chiral dihydrofuryl ketones, enantiose-
lective deprotonation, or cycloaddition-lipase-mediated
resolution.16 Of methods that do not require access to
chiral auxiliaries, reactants from the chiral pool, or
resolution, asymmetric catalytic hydrogenation of itaconic
acid esters, followed by selective hydride reduction, has
been successfully employed (g94% ee) in several lignan
total syntheses.17 In addition, we have recently given a
preliminary account of an alternative methodology in
which a chiral dirhodium(II) carboxamidate catalyst
controls highly enantioselective carbene insertion into an
unactivated C-H bond of 3-aryl-1-propyl diazoacetates,18
which themselves are conveniently accessible from cin-
namic acids (Scheme 1). We now report that this
catalytic methodology, which requires regiocontrol as well
as enantiocontrol, is general for the synthesis of 1 in high
enantiomeric purity, and we describe its use for the total
synthesis of representative natural lignans.
ium(II)-catalyzed C-H insertion reactions,20 both the
oxygen-activated and benzylic C-H bonds in 6 are
potential sites for insertion.21 The third obstacle is
chemoselectivity since the aryl group of 6, which is
activated by alkoxy substituents, is capable of aromatic
cycloaddition.22
The synthesis of diazoacetates 12a -e was accom-
plished from the corresponding cinnamic acids by initial
reduction with LiAlH4 followed by a one-pot diketene
condensation-diazo transfer-deacylation procedure in
50-60% overall yield, following purification (Scheme 2).
Diazo decomposition of 3-phenyl-1-propyl diazoacetate
(12a ) was evaluated first to determine the extent of
selectivity for C-H insertion and the stereochemistry for
product formation. Chiral dirhodium(II) catalysts rep-
resenting four carboxamidate ligand classes (14a -d )
were employed, each possessing a dirhodium(II) core
Resu lts a n d Discu ssion
In developing an effective general methodology for the
synthesis of 5 in high enantiomeric excess three obstacles
must be overcome. The first is enantioselectivity, and
here dirhodium(II) tetrakis[methyl 2-oxapyrrolidine-5(R
or S)-carboxylate], Rh2(5R-MEPY)4 or Rh2(5S-MEPY)4,
has proven to be moderately successful with enantiomeric
excesses up to 91% for C-H insertion reactions of
2-alkoxyethyl diazoacetates (eq 1).19 Use of Rh2(5S-
MEPY)4 yielded (S)-9, and Rh2(5R-MEPY)4 provided (R)-
9. The second challenge to selectivity is regiocontrol and,
whereas there is generally a high preference for the
formation of five-membered ring products in dirhod-
encased with four bridging amide ligands in a (2,2-cis)
geometry,23-25 and the results obtained with their use are
listed in Table 1. Only 13a and the â-lactone product
(20) (a) Doyle, M. P. In Comprehensive Organometallic Chemistry
II, Vol. 12; Hegedus, L. S., Ed.; Pergamon Press: New York, 1995;
Chapter 5.2. (b) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(21) (a) Doyle, M. P.; Dyatkin, A. B. J . Org. Chem. 1995, 60, 3035.
(b) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J . Chem. Soc., Perkin
Trans. 1 1995, 619. (c) Doyle, M. P.; Shanklin, M. S.; Oon, S.-M.; Pho,
H. Q.; van der Heide, F. R.; Veal, W. R. J . Org. Chem. 1988, 53, 3384.
(22) (a) Padwa, A.; Austin, D. J . Angew. Chem., Int. Ed. Engl. 1994,
33, 1797. (b) Padwa, A.; Austin, D. J .; Price, A. T.; Semones, M. A.;
Doyle, M. P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J . Am.
Chem. Soc. 1993, 115, 8669. (c) Padwa, A.; Austin, D. J .; Hornbuckle,
S. F.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N. J . Am. Chem.
Soc. 1992, 114, 1874. (d) Kennedy, M.; McKervey, M. A.; Maguire, A.
R.; Tuladhar, S. M.; Twohig, M. F. J . Chem. Soc., Perkin Trans. 1 1990,
1047.
(23) Doyle, M. P.; Winchester, W. R.; Hoorn, J . A. A.; Lynch, V.;
Simonsen, S. H.; Ghosh, R. J . Am. Chem. Soc. 1993, 115, 9968.
(24) Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I.;
Miertschin, C. S.; Winchester, W. R. Recl. Trav. Chim. Pays-Bas 1995,
114, 163.
(25) Doyle, M. P.; Zhou, Q.-L.; Raab, C. E.; Roos, G. H. P.; Simonsen,
S. H.; Lynch, V. Inorg. Chem. 1996, 35, 6064.
(13) Koch, S. S. C.; Chamberlin, A. R. J . Org. Chem. 1993, 58, 2725.
(14) van Oeveren, A.; J ansen, J . F. G. A.; Feringa, B. L. J . Org.
Chem. 1994, 59, 5999.
(15) (a) Tomioka, K.; Mizuguchi, H.; Koga, K. Tetrahedron Lett.
1979, 20, 3315. (b) Tomioka, K.; Koga, K. Heterocycles 1979, 12, 1523.
(c) Tomioka, K.; Ishiguro, T.; Koga, K. J . Chem. Soc., Chem. Commun.
1979, 652. (d) Tomioka, K.; Cho, Y.-S.; Sato, F.; Koga, K. J . Org. Chem.
1993, 53, 4094.
(16) (a) Gaboury, J . A.; Sibi, M. P. J . Org. Chem. 1993, 58, 2173. (b)
Rehnberg, N.; Magnusson, G. J . Org. Chem. 1990, 55, 4340. (c) Honda,
T.; Kimura, N.; Sato, S.; Kato, D.; Tominaga, H. J . Chem. Soc., Perkin
Trans. 1 1994, 1043.
(17) (a) Tanaka, M.; Mukaiyama, C.; Mitsuhashi, H.; Maruno, M.;
Wakamatsu, T. J . Org. Chem. 1995, 60, 4339. (b) Landais, Y.; Robin,
J . P.; Lebrun, A. Tetrahedron 1991, 47, 3787. (c) Kosugi, H.; Tagami,
K.; Takahashi, A.; Kanna, H.; Uda, H. J . Chem. Soc., Perkin Trans. 1
1989, 935.
(18) Doyle, M. P.; Protopopova, M. N.; Zhou, Q.-L.; Bode, J . W.;
Simonsen, S. H.; Lynch, V. J . Org. Chem. 1995, 60, 6654.
(19) Doyle, M. P.; van Oeveren, A.; Westrum, L. J .; Protopopova,
M. N.; Clayton, T. W., J r. J . Am. Chem. Soc. 1991, 113, 8982.

9148 J . Org. Chem., Vol. 61, No. 26, 1996
Bode et al.
Ta ble 1. Dia zo Decom p osition of 3-P h en ylp r op -1-yl
Dia zoa ceta te Ca ta lyzed by Ch ir a l Dir h od iu m (II)
Ca r boxa m id a tesa
< Rh2(MACIM)4 < Rh2(MPPIM)4, and Rh2(MPPIM)4 is
the catalyst of choice for these insertion reactions.
Alkylation of (R)-13b and removal of the O-methyl groups
(eq 2) provided the naturally occurring (-)-enterolactone
yield, %
isolated yield % ee
catalystb
13a + 15c 13a :15d
13a , %e
13a f
Rh2(4S-MEOX)4
Rh2(5R-MEPY)4
Rh2(4S-MPPIM)4
Rh2(4R-MPPIM)4
76
49
59
76
93:7
94:6
93:7
93:7
42
23
50
56
51(S)
72(R)
87(S)
91(R)
a
Reactions were performed in refluxing CH2Cl2 with 2.0 mol
b
% of catalyst. Rh2(4S-MACIM)4 gave 13a :15 ) 90:10 with 13a
in 82% ee. c Weight yield after bulb-to-bulb distillation of reaction
d
1
mixture. Determined by H NMR integration of relevant absorp-
tions; 15 undergoes thermal decomposition in GC analyses. e Yield
following radial chromatography; >99% pure 13a . f GC analysis
on a 30-m Chiraldex A-DA column, (2%. Configurational assign-
ment in parentheses.
Ta ble 2. Dia zo Decom p osition of
3-(m -Meth oxyp h en yl)p r op -1-yl Dia zoa ceta te Ca ta lyzed by
Dir h od iu m (II) Ca r boxa m id a tesa
catalyst
yield %b
purity 13b, %c
% ee 13bd
Rh2(4S-MEOX)4
Rh2(5R-MEPY)4
Rh2(4S-MACIM)4
Rh2(4S-MPPIM)4
Rh2(4R-MPPIM)4
56
66
25e
66
63
93
93
80
98
98
45(S)
68(R)
84(S)
91(S)
93(R)
(3) in 70% overall yield. Similar treatment of (S)-13b
gave (+)-enterolactone in 46% yield from diazoacetate
12b.
a
Reactions were performed in refluxing CH2Cl2 with 2.0 mol
b
% of catalyst. Weight yield after chromatographic purification
Neither dirhodium(II) caprolactamate, Rh2(cap)4, nor
Rh2(OAc)4 were effective in converting 12b to 13b; under
the same conditions as those used with catalysts 14a -
d , only products from carbene dimer formation and water
insertion were produced. Thus the advantages of chiral
dirhodium(II) carboxamidates as catalysts extends be-
yond stereocontrol by decreasing the relative rate for
bimolecular reactions. Indeed, the same restrictions
placed by 14a -d on molecular motion in intramolecular
cyclization inhibit intermolecular processes that provide
unwanted byproducts.
of reaction mixture. c Determined by GC and/or 1H NMR integra-
tion of relevant absorptions. Includes water insertion and C-H
d
insertion byproducts. GC analysis on a 30-m Chiraldex A-DA
column. Configurational assignment in parenthesis. e Major byprod-
ucts were those from carbene dimer formation (14%) and water
insertion (20%).
15 from insertion into the oxygen-activated C-H position
(-)- a n d (+)-Hin ok in in (17) were prepared from 12c
in 43-47% overall yield by a two-step procedure involving
initial C-H insertion catalyzed by Rh2(MPPIM)4 followed
by alkylation (eq 3). Conversion of 12c to 13c occurred
were obtained; insertion into the benzylic position was
not observed nor was aromatic cycloaddition. There is a
strong preference for the formation of 13a , and changing
the catalyst does not measurably influence regioselec-
tivity. However, enantioselectivity is markedly increased
from 51% ee with the use of Rh2(4S-MEOX)4 to 89 ( 2%
ee with Rh2(4S-MPPIM)4. Although 2.0 mol % of catalyst
was employed for the reactions listed in Table 1, use of
only 1.0 mol % Rh2(4S-MPPIM)4 gave nearly identical
results (51% versus 59% yield). In these insertion
reactions the catalysts with the S-configuration formed
the γ-lactone product having the S-configuration, and
Rh2(4R-MPPIM)4 produced (R)-13a .
(-)- a n d (+)-En ter ola cton e. Diazoacetate 12b was
similarly evaluated for enantioselective/regioselective/
chemoselective C-H insertion, and these results are
reported in Table 2. Isolated yields and % ee values were
variable, dependent on the catalyst, but use of Rh2(4S-
MPPIM)4 and Rh2(4R-MPPIM)4 gave 13b cleanly without
noticeable intramolecular insertion or cycloaddition
byproducts (<2%) and with minimal competition from
carbene dimer formation and water insertion. With the
Rh2(4S-MACIM)4 catalyst the product from aromatic
cycloaddition to the 1,2-position was detected, but only
in minor amounts, and overall yields were low. As is
evident from the data in Tables 1 and 2, % ee increases
through the catalyst series Rh2(MEOX)4 < Rh2(MEPY)4
with 95 ( 2% ee, and the C-H insertion reactions
catalyzed by Rh2(MPPIM)4 were remarkably free of
byproducts. With Rh2(5R-MEPY)4 catalysis, however, a
minor product, amounting to 7% of the isolated product
yield, was separated and identified as δ-lactone 18.
(-)-Ar ct igen in . Naturally occurring (+)-arctigenin

Total Synthesis of Natural Lignan Lactones
J . Org. Chem., Vol. 61, No. 26, 1996 9149
Sch em e 3a
the reactant cinnamic acid, and this synthesis could be
performed without chromatographic purification of any
synthetic intermediate except 12c.
(+)-Isola u r icer isin ol. To further illustrate the ver-
satility and tolerance of this methodology for the syn-
thesis of lignan lactones, the benzyloxy-protected lactone
(R)-13e was prepared from the corresponding diazoace-
tate 12e (eq 4) in 59% isolated yield with 96.5% ee. The
Sch em e 4a
diazoacetate 12e was prepared from 4-hydroxy-3-meth-
oxycinnamic acid by protection of the phenol and acid
functional groups and then conversion to 12e according
to Scheme 2. The formation of (R)-13e in good yield and
with exceptional enantiocontrol further demonstrates
that the bulky aryl substituent does not interfere with
the excellent enantiodirecting selectivities that charac-
terize the Rh2(MPPIM)4 catalysts. The utility of (R)-13e
for the preparation of lignans is exemplified in its
previously reported uses for the syntheses of (+)-isolau-
ricerisinol (23)28 and several other naturally occurring
lignans.29
Gen er a l Meth od ology for High ly En a n tioselec-
tive Syn th esis of â-Su bstitu ted γ-La cton es fr om
P r im a r y Alcoh ols. To determine if use of the Rh2-
(MPPIM)4 catalysts could be extended to aliphatic sys-
tems without pendant aryl groups, diazoacetates 24a ,b
were prepared and subjected to diazo decomposition (eq
5). The diazoacetates were prepared from commercial
alcohols according to Scheme 2 in 60 and 54% yields,
(4)26 was synthesized from 3,4-dimethoxycinnamic acid
in a convergent nine-step, seven-pot sequence (Scheme
3). The key lactone intermediate 13d was prepared with
94% ee in 62% isolated yield with the use of Rh2(4S-
MPPIM)4. Alkylation of 13d with 4-(benzyloxy)-3-meth-
oxybenzyl bromide (19), prepared in two steps from
4-hydroxy-3-methoxybenzyl alcohol, afforded the O-ben-
zyl protected disubstituted γ-lactone 20. Hydrogenolysis
to remove the benzyl group provided (+)-arctigenin (4)
in 94% optical purity and in 19% overall yield from
commercial reactants.
(+)-Isod eoxyp od op h yllotoxin . The preparation of
(+)-isodeoxypodophyllotoxin (22)27 from chiral monosub-
stituted γ-lactone (S)-13c illustrates the operational
versatility of this methodology for the synthesis of
aryltetralin lignan lactones (Scheme 4). Condensation
of (S)-13c with 3,4,5-trimethoxybenzaldehyde in the
presence of excess LiHMDS produced a mixture of
epimeric alcohols (21) in quantitative yield. Upon treat-
ment with trifluoroacetic acid, 21 underwent intramo-
lecular Friedel-Crafts ring closure to form 22 as a single
diastereoisomer. A single crystallization afforded (+)-
isodeoxypodophyllotoxin with >99% enantiomeric purity
in 68% yield. Overall, 22 was prepared in 36% yield from
respectively. Treatment of 24a with 1.0 mol % Rh2(4S-
MPPIM)4 afforded (S)-25a in 52% isolated yield (96% ee)
with only 4% of the â-lactone as byproduct. The â-isobu-
tyl-γ-lactone (S)-25b was prepared in 60% yield (95% ee)
using Rh2(4S-MPPIM)4 together with 5% of the corre-
sponding â-lactone byproduct. In neither case were
δ-lactone byproducts observed. In addition, â-methoxy-
γ-butyrolactone (S)-919 was produced from 8 (R ) Me) in
nearly quantitative yield (93% ee) with catalysis by Rh2-
(4S-MPPIM)4.
According to our view of the mechanism for C-H
insertion (see Scheme 5), reaction is initiated by overlap
of the metal carbene’s carbon p-orbital with the σ-orbital
of the reacting C-H bond. The formation of C-C and
C-H bonds is concurrent with dissociation of the dirhod-
(26) Suzuki, H.; Lee, K. H.; Haruna, M.; Iida, T.; Ito, K.; Huang,
H.-C. Phytochemistry 1982, 21, 1824.
(27) (a) Zavala, F.; Guenard, D.; Robin, J .-P.; Brown, E. J . Med.
Chem. 1980, 23, 546. (b) Kuhn, M.; von Wartburg, A. Helv. Chim. Acta
1967, 50, 1546.
(28) Brown, E.; Daugan, A. Heterocycles 1987, 26, 1169.
(29) Brown, E.; Daugan, A. J . Nat. Prod. 1991, 54, 110.

9150 J . Org. Chem., Vol. 61, No. 26, 1996
Bode et al.
Sch em e 5
the syn conformer 26 provides the lower energy transition
state for C-H insertion, even when R is as small as ethyl
(25a ) or methoxy [(S)-9]. Catalytic diazo decomposition
of diazoacetates derived from primary alcohols occurs
with highly enantioselective C-H insertion using
Rh2(MPPIM)4 catalysts, and this is indeed a general and
effective methodology for the synthesis of â-substituted-
γ-butyrolactones in high enantiomeric purity.
Exp er im en ta l Section
Gen er a l. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were obtained as solutions in CDCl3, and chemical
shifts are reported in parts per million (ppm, δ) downfield from
internal Me4Si (TMS). Mass spectra were obtained using
electron ionization on a quadrapole instrument. Infrared
spectra were recorded as a thin film on sodium chloride plates
or as solutions as indicated, and absorptions are reported in
wavenumbers (cm-1). Melting points are uncorrected. Ele-
mental analyses were performed at Texas Analytical Labora-
tories, Inc. Anhydrous THF was distilled from Na/benzophe-
none; CH2Cl2 was dried over calcium hydride for 24 h and then
distilled prior to use in catalytic reactions. Diketene was
distilled under reduced pressure. Methanesulfonyl azide was
prepared from methanesulfonyl chloride and sodium azide, but
was not distilled.32 The preparation of the enantiomeric forms
Sch em e 6
25
of Rh2(MEPY)4,23 Rh2(MEOX)4,24 and Rh2(MPPIM)4 and the
synthesis of Rh2(4S-MACIM)425 have been previously reported.
2-Methoxyethyl diazoacetate and its lactone products (9) have
been described.24
3-P h en ylp r op -1-yl Dia zoa ceta te (12a ). To a continu-
ously stirred solution of 3-phenyl-1-propanol (5.02 g, 36.8
mmol), triethylamine (0.018 g, 0.17 mmol), and a catalytic
amount (<2 mg) of DMAP in 30 mL of anhydrous THF at room
temperature was added diketene (3.11 g, 37.0 mmol) in 25 mL
of THF. The resulting solution was stirred overnight at room
temperature after which the light yellow reaction solution was
combined with 50 mL of ether and 30 mL of brine. The
aqueous layer was washed twice with 50 mL portions of ether,
and the combined ether solution was washed twice with 50
mL portions of brine and then dried over anhydrous MgSO4.
The solvent was removed under reduced pressure to afford 7.61
g of a light yellow oil identified as 3-phenyl-1-propyl acetoace-
tate (34.5 mmol, 94% yield); 1H NMR δ 7.32-7.24 (comp, 2
H), 7.23-7.16 (comp, 3 H), 4.17 (t, J ) 6.5 Hz, 2 H), 3.45 (s, 2
H), 2.69 (t, J ) 7.3 Hz, 2 H), 2.28 (s, 3 H), 2.04-1.93 (comp, 2
H), enol form at 5.02 (s, 1 H), 1.96 (s, 3 H).
To a continuously stirred solution of the acetoacetate (7.61
g, 34.6 mmol) and triethylamine (4.35 g, 43.0 mmol) in 35 mL
of CH3CN was added methanesulfonyl azide (5.20 g, 43.0 mol)
in 20 mL of the same solvent dropwise over 30 min. The
resulting solution was stirred overnight at room temperature
whereupon LiOH‚H2O (4.4 g, 100 mol) dissolved in 30 mL of
H2O was added, and stirring was continued for 7 h. The
resulting solution was diluted with brine and then washed
with two 50 mL portions of 3:1 ether:EtOAc. The combined
organic solution was washed with 40 mL of brine and dried
over anhydrous MgSO4, and the solvent was removed under
reduced pressure. The resulting orange liquid was purified
by column chromatography on silica (10:1 hexanes:EtOAc) to
afford 5.32 g of 12a (26.1 mmol, 79% yield) as a yellow oil; 1H
NMR δ 7.31-7.20 (comp, 2 H), 7.19-7.14 (comp, 3 H), 4.73
(br s, 1 H), 4.18 (t, J ) 6.5 Hz, 2 H), 2.68 (t, J ) 7.6 Hz, 2 H),
ium(II) species (Scheme 5).30 As hydrogen migrates to
the carbene center, the substituents on the carbon where
insertion is taking place rotate toward the resting posi-
tions that conform to their placement in the product. The
absolute configurations of the C-H insertion products
formed in the Rh2(MPPIM)4-catalyzed reactions are
predictable from the model in Scheme 6 which depicts
the S-MPPIM-ligated catalyst with the bound carbene
in a resting position that minimizes interactions with the
ligand’s ester (E) attachments.31 The two rotomers, 26
and 27, are positioned to undergo C-H insertion result-
ing in enantiomeric lactones 28 and 29. The high
preference for 28 with Rh2(4S-MPPIM)4, and this cata-
lyst’s enhancement of enantiocontrol over Rh2(5S-ME-
PY)4 or Rh2(4S-MEOX)4, is consistent with steric repul-
sion between anti R and the N-3-phenylpropanoyl
attachment of the imidazolidinone ligands in 27. Thus
2.02-1.92 (comp, 2 H); IR ν 2114 (CdN2), 1705 (CdO) cm-1
.
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72.
Found: C, 64.75; H, 5.94; N, 13.70.
4-(P h en ylm eth yl)-2(3H)-d ih yd r ofu r a n on e, (R)-13a . A
solution of 3-phenylprop-1-yl diazoacetate (0.099 g, 0.48 mmol)
in 5 mL of rigorously dried CH2Cl2 was added via syringe pump
at a rate of 0.40 mL/h to a refluxing solution of 8.8 mg of
Rh2(4R-MPPIM)4(CH3CN)2 (0.009 mol, 2 mol %) dissolved in
7 mL of dry CH2Cl2. The initial purple color of the reaction
(30) Doyle, M. P.; Westrum, L. J .; Wolthuis, W. N. E.; See, M. M.;
Boone, W. P.; Bagheri, V.; Pearson, M. M. J . Am. Chem. Soc. 1993,
115, 958.
(31) Doyle, M. P.; Kalinin, A. V.; Ene, D. G. J . Am. Chem. Soc. 1996,
118, 8837.
(32) Boyer, J . H.; Mack, G. H.; Goebel, W.; Moran, L. R. J . Org.
Chem. 1959, 24, 1051.

Total Synthesis of Natural Lignan Lactones
J . Org. Chem., Vol. 61, No. 26, 1996 9151
solution turned to olive green by the end of the substrate
addition. Refluxing was continued for an additional 3 h, the
reaction solution was cooled to room temperature, and the
catalyst was removed by filtration on silica gel (CH2Cl2). The
resulting light brown oil was distilled, bp 95-100 °C (0.25
torr), to produce 64.8 mg (0.368 mmol, 76% yield) of a mixture
of (R)-13a and 15. This mixture was further purified by radial
chromatography on silica (hexane:EtOAc ) 8:1) to afford 49.8
mg (0.282 mmol, 56% yield) of (R)-13a ; [R]29D ) +6.7° (c 0.574,
EtOH); lit.13 [R]29D ) +6.6° (c 0.92, EtOH) for enantiomerically
The diazoacetoacetate (10.3 g, 32 mmol) was dissolved in
40 mL of acetonitrile and added in one portion to a solution of
LiOH‚H2O (4.9 g, 117 mmol, 3.7 equiv) in 100 mL of H2O. The
reaction mixture was stirred for 1.5 h at room temperature
whereupon the resulting dark brown solution was extracted
with EtOAc (3 × 75 mL), and the organic extract was then
washed with brine (75 mL), saturated aqueous citric acid (75
mL), and brine (2 × 75 mL). After drying over anhydrous
MgSO4, the solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography on
silica gel (hexanes:EtOAc, 3:1) to afford 5.50 g of a yellow oil
identified as 12b (23.5 mmol, 74% yield): 1H NMR δ 7.19 (dd,
J ) 8.7, 7.6 Hz, 1 H), 6.77-6.70 (m, 3 H), 4.74 (br s, 1 H), 4.16
(t, J ) 6.6 Hz, 2 H), 3.77 (s, 3 H), 2.65 (t, J ) 7.8 Hz, 2 H),
1.95 (tt, J ) 7.8, 6.6 Hz, 2 H); 13C NMR δ 159.5, 142.5, 129.2,
120.6, 114.0, 111.1, 63.9, 54.9, 45.9, 31.9, 30.1; IR ν 2113
(CdN2), 1695 (CdO) cm-1. Anal. Calcd for C12H14N2O3: C,
61.53; H, 6.02; N, 11.96. Found: C, 61.46; H, 5.99; N, 12.02.
4-[(3-Me t h o x y p h e n y l)m e t h y l]d ih y d r o -2(3H )-fu r a -
n on e (13b). A solution of diazoacetate 12b (0.65 g, 2.8 mmol)
in 20 mL of rigorously dried CH2Cl2 was added via syringe
1
pure (R)-13a ; H NMR δ 7.35-7.21 (m, 3 H), 7.15 (d, J ) 8.1
Hz, 2 H), 4.33 (dd, J ) 9.0, 6.8 Hz, 1 H), 4.04 (dd, J ) 9.0, 5.9
Hz, 1 H), 2.91-2.76 (comp, 3 H), 2.60 (dd, J ) 17.4, 7.8 Hz, 1
H), 2.29 (dd, J ) 17.4, 6.8 Hz, 1 H). 13H NMR δ 177.1, 138.2,
128.7, 126.4, 70.4, 42.9, 36.4, 31.3, 29.7. Enantiomeric ex-
cesses were determined by GC analysis on a 30-m Chiraldex
A-DA column operated at 148 °C: 126 min ((S)-13a ) 129 min
((R)-13a ).
A minor product identified as the â-lactone 15 was isolated
in <5% chemical yield from the diazo decomposition reactions
performed with Rh2(4S-MEOX)4; 1H NMR δ 7.35-7.16 (comp,
5 H), 4.53-4.47 (m, 1 H), 3.48 (dd, 1 H, J ) 5.8, 16.4 Hz), 3.03
(dd, 1 H, J ) 4.3, 16.4 Hz), 2.89-2.68 (comp, 2 H), 2.17-2.02
(comp, 2 H); 13C NMR δ 176.8, 138.2, 128.8, 128.6, 126.8, 72.6,
38.9, 37.1, 34.2.
pump at
a rate of 2.0 mL/h to a refluxing solution of
Rh2(MPPIM)4 (78 mg, 56 mmol, 2.0 mol %) in 40 mL of dry
CH2Cl2 under N2. The initial blue/purple color of the reaction
solution turned to olive green by the end of the substrate
addition. After addition was complete, the reaction solution
was cooled to room temperature, and the solvent was evapo-
rated under reduced pressure. The residue was purified by
flash chromatography on silica gel (hexanes:EtOAc, 4:1), and
0.379 g of pure 13b (1.84 mmol, 66% yield) was isolated as a
colorless oil: 1H NMR δ 7.26 (s, 1 H), 7.24 (t, J ) 8.0 Hz, 1 H),
6.82-6.69 (comp, 2 H), 4.36 (dd, J ) 9.2, 6.9 Hz, 1 H), 4.06
(dd, J ) 9.2, 6.1 Hz, 1 H), 3.80 (s, 3 H), 2.94-2.81 (m, 1 H),
2.80-2.72 (comp, 2 H), 2.65 (dd, J ) 17.5, 8.0 Hz, 1 H), 2.33
(dd, J ) 17.5, 6.9 Hz, 1 H); 13C NMR δ 176.8, 159.9, 139.8,
129.8, 120.9, 114.6, 111.8, 72.6, 55.2, 38.9, 37.0, 34.2. Spectral
data were consistent with that previously reported.8b Enan-
tiomeric excesses were determined from GC analysis on a 30-m
Chiraldex A-DA column (Table 1) operated at 150 °C for 10
min then programmed at 0.2 °C/min to 180 °C: 181.8 min ((S)-
13b), 184.5 min ((R)-13b). The major byproducts from these
catalytic reactions were carbene dimers and the water inser-
tion product. Carbene dimer formation was controlled by
adjusting the rate of addition of the diazo compound but varied
with the catalyst employed. Water insertion, especially in
small scale reactions, was minimized by using rigorously dried
solvents, reagents, and equipment. The solvent CH2Cl2 was
dried over CaH2 for 12-20 h prior to use. Diazoacetate 12b
and the septa employed were dried in a desiccator over KOH
and Drierite for at least 15 h prior to use. All glassware,
stirring bars, and needles were oven dried. The weighing of
reagents and preparation of solutions took place in a glove bag
under N2.
3-(3-Meth oxyp h en yl)p r op -1-yl Dia zoa ceta te (12b).
A
mixture of 3-methoxycinnamic acid (10b, 9.65 g, 54.2 mmol)
and 5% Pd/C (0.2 g) in methanol/EtOAc (80 mL, 1:1) was
shaken in a Parr hydrogenation apparatus under 2 atm of H2
for 4 h. After filtering through a Celite plug, the solvent was
evaporated under reduced pressure to provide 9.6 g of 3-(3-
methoxyphenyl)propanoic acid (53 mmol, 98% yield), which
was used without further purification.
To a rapidly stirred suspension of LiAlH4 (2.1 g, 55 mmol,
1.5 equiv) in 80 mL of refluxing THF was added over 50 min
a solution of 3-(3-methoxyphenyl) propanoic acid (6.7 g, 38
mmol) in 20 mL of THF. After addition was complete,
refluxing was continued for an additional 40 min, and then
the mixture was cooled to room temperature, poured into ice-
water which was then poured into a solution of 5% HCl over
ice and extracted once with ethyl ether (100 mL) and twice
with 70-mL portions of EtOAc. The combined organic extract
was washed with a saturated solution of NaHCO3 (50 mL) and
brine (100 mL) and dried over anhydrous MgSO4, and the
solvent was evaporated under reduced pressure to provide 6.3
g of 3-(3-methoxyphenyl)propan-1-ol (11b, 38 mmol, 100%
yield).
To a solution of 11b (6.2 g, 37 mmol) in 50 mL of anhydrous
THF was added 80 mg of NaOAc and then, dropwise at room
temperature, a solution of diketene (4.8 g, 55 mmol, 1.5 equiv)
in 10 mL of THF. The reaction solution was continually stirred
for 10 h at room temperature and then refluxed for 1.5 h. After
evaporation of the solvent, the residue was purified by column
chromatography on silica gel (hexanes:EtOAc, 3:1 f 2:1) to
provide 8.8 g (35 mmol, 95% yield) of a colorless oil identified
as 3-(3-methoxyphenyl)prop-1-yl acetoacetate: 1H NMR δ 7.21
(td, J ) 7.4, 1.2 Hz, 1 H), 6.77 (d, J ) 7.4 Hz, 2 H), 6.74 (s, 1
H), 4.16 (t, J ) 6.5 Hz, 2 H), 3.80 (s, 3 H), 3.46 (s, 2 H), 2.67
(t, J ) 7.0 Hz, 2 H), 2.28 (s, 3 H), 2.03-1.93 (m, 2 H) with
enol form at 5.02 (s, 1 H), 2.17 (s, 3 H); 13C NMR δ 167.1, 159.7,
142.6, 129.5, 120.8, 114.2, 111.3, 64.7, 55.2, 50.1, 32.1, 30.2,
30.0.
(3S ,4S )-3,4-Bis[(3-m e t h oxyp h e n yl)m e t h yl]d ih yd r o-
2(3H)-fu r a n on e (16). To lactone 13b (0.300 g, 1.28 mmol,
95% ee) in 10 mL of anhydrous THF at -78 °C was added 1.5
mL of 1.5 M LDA (in cyclohexane, 2.31 mmol, 1.8 equiv) and
0.7 g of HMPA (3.8 mmol, 3 equiv). After 0.5 h a solution of
3-methoxybenzyl bromide (0.48 g, 2.3 mmol, 1.8 equiv) in 1.0
mL of THF was added in one portion to the reaction solution,
and the resulting mixture was stirred for an additional 14 h
at -78 °C and then warmed to -40 °C (2 h) and to +10 °C (1
h). The excess base was quenched at 0 °C with 20 mL of
A solution of methanesulfonyl azide (6.6 g, 54 mmol, 1.5
equiv) in 70 mL of anhydrous acetonitrile was added dropwise
over 20 min to a solution of 3-(3-methoxyphenyl)prop-1-yl
acetoacetate (8.8 g, 35 mmol) and triethylamine (5.5 g, 54
mmol, 1.5 equiv) in 60 mL of anhydrous acetonitrile. The
resulting yellow solution was stirred for 12 h at room tem-
perature, after which the solvent was evaporated under
reduced pressure. The residue was purified by column chro-
matography on silica gel (hexanes:EtOAc, 2:1 f 1:1) to give
10.3 g of 85% pure diazoacetoacetate (32 mmol, 90% yield):
1H NMR δ 7.18 (t, J ) 7.8 Hz, 1 H), 6.76-6.68 (comp, 3 H),
4.24 (t, J ) 6.5 Hz, 2 H), 3.77 (s, 3 H), 2.68-2.63 (comp, 2 H),
2.44 (s, 3 H), 2.05-1.95 (comp, 2 H).
Cl, and the resulting solution was
saturated aqueous NH4
extracted with ethyl ether (1 × 10 mL) and ethyl acetate (2 ×
10 mL). The combined organic layer was washed three times
with 40-mL portions of water and once with 20 mL of brine
and dried over anhydrous MgSO4, and the solvent was
evaporated under reduced pressure. The residue was purified
by column chromatography on silica gel (hexanes:EtOAc, 4:1)
to afford 0.36 g of (S)-16 (1.02 mmol, 80% yield) as a light
brown viscous oil: 1H NMR δ 7.20 (t, J ) 7.9 Hz, 1 H), 7.16 (t,
J ) 7.9 Hz, 1 H), 6.80-6.71 (comp, 4 H), 6.60-6.50 (comp, 2
H), 4.09 (dd, J ) 9.0, 6.9 Hz, 1 H), 3.84 (dd, J ) 9.0, 7.3 Hz,
1 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.05 (dd, J ) 14.0, 5.0 Hz, 1
H), 2.89 (dd, J ) 14.0, 7.0 Hz, 1 H), 2.76-2.53 (comp, 4 H);

9152 J . Org. Chem., Vol. 61, No. 26, 1996
Bode et al.
13C NMR δ 178.5 (159.83, 159.79), 139.5, 139.3, 129.7, 129.6,
121.6, 120.9, 114.8, 114.5, 112.3, 111.8, 71.2, 55.1, 55.1, 46.3,
41.2, 38.5, 35.1. Spectral data were consistent with those
previously reported.33 Enantiomeric excesses were determined
by optical rotation relative to that for optically pure (R)-16
Chiraldex A-DA column operated at 90 °C for 30 min and then
programmed at 0.5°/min to 195 °C: 122.6 min for (S)-13c,
125.0 min for (R)-13c. For reactions performed with Rh2(4R-
MPPIM)4 (57% isolated yield); [R]23 ) +4.42 (c 1.56, CHCl3),
D
and 95 ( 2% ee by GC analysis. 1H NMR δ 6.73 (d, J ) 7.9
Hz, 1 H), 6.61 (d, J ) 1.3 Hz, 1 H), 6.57 (dd, J ) 7.9, 1.3 Hz,
1 H), 5.92 (s, 2 H), 4.31 (dd, J ) 9.1, 6.7 Hz, 1 H), 4.00 (dd, J
) 9.1, 6.0 Hz, 1 H), 2.85-2.70 (m, 1 H), 2.70-2.60 (comp, 2
H), 2.58 (dd, J ) 17.5, 8.0 Hz, 1 H), 2.25 (dd, J ) 17.5, 6.8 Hz,
1 H); 13C NMR δ 176.8, 148.0, 146.4, 131.9, 121.6, 108.8, 108.4,
101.0, 72.5, 38.7, 37.3, 34.1. Spectral data were consistent
with those values reported previously.17c
prepared from L-malic acid, [R]23 ) -42.3 (c 0.98, CHCl3);33
D
for example, observed [R]23D ) +40.9 (c 1.20, CHCl3) for product
from C-H insertion catalyzed by Rh2(4S-MPPIM)4 (96 + 3%
ee). A similar procedure was employed to obtain (R)-16 (64%
yield): [R]23
-39.2 (c 0.78, CHCl3) which specifies 93% ee.
D
)
(3S,4S)-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, (S)-3. To a rapidly stirred solution of lactone
(S)-16 (0.31 g, 0.95 mmol) in 20 mL of anhydrous CH2Cl2 at 0
°C was added BBr3 (3.81 mL of 1.0 M solution in CH2Cl2, 4
equiv) dropwise during 15 min. Stirring was continued at 0
°C for 1 h and then at -18 °C for 12 h, after which the reaction
solution was quenched with water (10 mL) and then extracted
twice with 10-mL portions of CH2Cl2. The combined organic
solution was washed with brine and dried over anhydrous
MgSO4, and the solvent was evaporated under reduced pres-
sure. The residue was passed through a plug of silica gel to
provide 0.278 g (0.933 mmol, 98% yield) of (+)-enterolactone,
(S)-3, as a slightly brown gum, [R]23D ) +38.8 (c 0.51, CHCl3).
Further purification by flash chromatography yielded 0.25 g
A minor product, amounting to only 7% of the product yield,
was isolated as a second chromatography fraction from the
reaction catalyzed by Rh2(5R-MEPY)4 and was identified as
the δ-lactone 4-(1,3-ben zod ioxol-5-yl)tetr a h yd r op yr a n -2-
1
on e: H NMR δ 6.76 (d, J ) 7.9 Hz, 1H), 6.67 (d, J ) 1.8 Hz,
1H), 6.63 (dd, J ) 7.9, 1.8 Hz, 1H), 5.94 (s, 2 H), 4.48 (ddd, J
) 11.5, 4.9, 3.9 Hz, 1 H), 4.34 (ddd, J ) 11.5, 10.4, 3.8 Hz, 1
H), 3.20-3.08 (m, 1 H), 2.86 (ddd, J ) 17.6, 5.9, 1.6 Hz, 1 H),
2.54 (dd, J ) 17.6, 10.5 Hz, 1 H), 2.18-2.07 (m, 1 H), 2.04-
1.89 (m, 1 H); 13C NMR δ 170.6, 148.1, 146.7, 136.7, 119.4,
108.6, 106.8, 101.2, 68.6, 37.8, 37.3, 30.5.
(3S,4S)-3,4-Bis(1,3-ben zod ioxol-5-ylm eth yl)d ih yd r o-2-
(3H)-fu r a n on e, (S,S)-17. To a rapidly stirred solution of
lactone (S)-13c (0.160 g, 0.727 mmol) in 10 mL of anhydrous
THF at -90 °C was added HMPA (0.44 g, 2.4 mmol, 3.4 equiv)
and 1.1 mL of 1.5 M LDA (in cyclohexane, 1.6 mmol, 2.3 equiv).
After 0.5 h at -90 °C, 1,3-benzodioxol-5-ylmethyl bromide
(0.352 g, 1.64 mmol, 2.3 equiv) in 5 mL of THF was added,
and the reaction mixture was warmed to -78 °C and left
stirring at this temperature for 16 h. The reaction mixture
was then warmed to -20 °C and held there for 2 h, and then
the excess base was quenched. Workup as described for 16
and purification by radial chromatography (silica; hexanes:
EtOAc, 4:1) afforded 0.182 g of (+)-hinokinin as a colorless
(88% yield) of (S)-3: [R]23 ) +38.3 (c 0.24, CHCl3); lit. [R]D
D
for (R)-3 ) -43 (c 0.29, CHCl3),14 -40.5 (c 0.553, CHCl3),33
-38.4 (c 0.5, CHCl3).34 Natural (-)-enterolactone, (R)-3, was
prepared by a similar procedure (68% yield): [R]23 ) -38.4
D
(c 0.25, CHCl3). Rotational values were highly dependent on
concentration and temperatures.14
3-(1,3-Ben zod ioxol-5-yl)p r op -1-yl Dia zoa ceta te (12c).
To a stirred suspension of LiAlH4 (1.34 g, 35.3 mmol) in 50
mL of anhydrous THF heated at 40-45 °C was added 3,4-
(methylenedioxy)cinnamic acid (3.84 g, 20.0 mmol) as a solid
in portions during 40 min. The reaction mixture was refluxed
for 1.5 h, cooled to room temperature, and then poured into a
dilute aqueous solution of HCl saturated with NaCl. The
aqueous solution was extracted with EtOAc (200 mL), and the
organic solution was washed with saturated NaHCO3 (70 mL)
and brine (100 mL). After drying over anhydrous MgSO4, the
solvent was evaporated to produce 3.34 g of 3-(1,3-benzodioxol-
5-yl)propan-1-ol (18.8 mmol, 94% yield); 1H NMR δ 6.72 (d, J
) 7.9 Hz, 1 H), 6.69 (d, J ) 1.2 Hz, 1 H), 6.63 (dd, J ) 7.9, 1.2
Hz, 1 H), 5.91 (s, 2 H), 3.64 (t, J ) 6.6 Hz, 2 H), 2.62 (t, J )
7.3 Hz, 2 H), 1.90-1.78 (comp, 2 H), 1.95 (br s, 1 H).
The title compound was prepared from 3-(1,3-benzodioxol-
5-yl)propan-1-ol in 56% yield by the same set of steps and
under the same conditions as those reported for 12b; 1H NMR
δ 6.72 (d, J ) 7.9 Hz, 1 H), 6.66 (d, J ) 1.1 Hz, 1 H), 6.61 (dd,
J ) 7.9, 1.1 Hz, 1 H), 5.91 (s, 2 H), 4.75 (br s, 1 H), 4.16 (t, J
) 6.6 Hz, 2 H), 2.60 (t, J ) 7.3 Hz, 2 H), 1.96-1.86 (comp, 2
H); 13C NMR δ 160.2, 147.5, 145.7, 134.8, 121.0, 108.7, 108.1,
100.7, 63.9, 46.0, 31.7, 30.5; IR ν 2125 (CdN2), 1701 (CdO)
cm-1. Anal. Calcd for C12H12O4N2: C, 58.06; H, 4.87; N, 11.29.
Found: C, 58.12; H, 4.91; N, 11.33.
viscous oil ((S,S)-17, 0.514 mmol, 70% yield); [R]23 ) +29.4°
D
(c 0.90, CHCl3). (-)-Hinokinin was prepared by an identical
procedure in 76% isolated yield; [R]23D ) -28.8 (c 0.99, CHCl3),
lit.14 [R]23 -36 (c 1.00, CHCl3). Spectral data were identical
D
to those reported in the literature.16a
3-(3,4-Dim eth oxyp h en yl)p r op -1-yl Dia zoa ceta te (12d ).
To a stirred suspension of LiAlH4 (1.09 g, 28.8 mmol) in 60
mL of anhydrous THF was added 3,4-dimethoxycinnamic acid
(3.85 g, 18.5 mmol) as a solid in portions over 30 min. The
reaction mixture was refluxed for 4 h, cooled to room temper-
ature, and quenched with 2 mL of EtOAc. Upon addition of 2
mL of H2O, 2 mL of 10% aqueous NaOH, and 5 mL of H2O,
yellow salts formed which were filtered under vacuum and
washed with EtOAc (60 mL). The resulting solution was
washed with brine (60 mL) and dried over anhydrous MgSO4,
and the solvent was removed under reduced pressure to
provide 3.24 g of a 3-(3,4-dimethoxyphenyl)propan-1-ol (11d )
(16.5 mmol, 90% yield) as a pale yellow oil. 1H NMR δ 6.82-
6.73 (comp, 3 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.69 (t, J ) 6.4
Hz, 2 H), 2.67 (t, J ) 7.4 Hz, 2 H), 1.92-1.84 (comp, 2 H),
1.53 (br s, 1 H).
To a solution of 11d (4.21 g, 21.0 mmol), triethylamine
(0.200 g, 2.0 mmol), and a catalytic amount (g2 mg) of DMAP
in 30 mL of anhydrous THF was added, dropwise at room
temperature, a solution of diketene (2.00 g, 24.0 mmol) in 20
mL of THF. The resulting solution was stirred at room
temperature overnight after which triethylamine (2.32 g, 23.0
mmol) was added, followed by dropwise addition of methane-
sulfonyl azide (2.80 g, 23.0 mmol) in 20 of mL THF over 30
min, and the composite was stirred overnight at room tem-
perature. To the resulting orange solution was added
LiOH‚H2O (2.65 g, 63.0 mmol) in 25 mL of H2O, and stirring
was continued for 5.5 h. The reaction mixture was then
diluted with brine and washed with two portions of 3:1 ether:
ethyl acetate (60 mL). The combined organic layer was
washed with brine (50 mL) and dried over anhydrous MgSO4,
and the solvent was removed under reduced pressure to
provide an orange liquid. Purification by flash chromatogra-
phy on silica gel (hexanes:EtOAc ) 3:1) afforded 2.98 g of 12d
(11.3 mmol, 65% yield) as a yellow oil. 1H NMR δ 6.80 (d, J )
4-(1,3-Be n zod ioxol-5-ylm e t h yl)d ih yd r o-2(3H )-fu r a -
n on e (13c). A solution of diazoacetate 12c (0.305 g, 1.23
mmol) in 10 mL of rigorously dried CH2Cl2 was added via
syringe pump at a rate of 0.8 mL/h to a refluxing solution of
Rh2(4S-MPPIM)4 (34 mg, 25 µmol, 2.0 mol %) in 10 mL of dry
CH2Cl2 under N2. The initial blue/purple color of the reaction
solution turned to olive green by the end of the substrate
addition. After cooling to room temperature, the reaction
solution was filtered through a plug of silica which was
subsequently rinsed with 10 mL of CH2Cl2, and the solvent
was evaporated under reduced pressure. After spectral and
GC analyses, the residue was purified by radial chromatog-
raphy (hexanes:EtOAc, 4:1) to give 0.181 g of pure lactone (S)-
13c (0.823 mmol, 67% yield); [R]23 ) -4.62 (c 0.93, CHCl3)
D
for reaction performed with Rh2(4S-MPPIM)4, lit. [R]20 +4.8
D
(c 1.14, CHCl3),27b +5.22 (c 1.13, CHCl3)15a for (R)-13c. Enan-
tiomeric excesses were determined from GC analysis on a 30-m
(33) Yoda, H.; Kitayama, H.; Katigiri, T.; Takabe, K. Tetrahedron
1992, 48, 3313.
(34) Groen, M. B.; Leemhuis, J . Tetrahedron Lett. 1980, 21, 5043.

Total Synthesis of Natural Lignan Lactones
J . Org. Chem., Vol. 61, No. 26, 1996 9153
8.3 Hz, 2 H), 6.73-6.70 (comp, 2 H), 4.76 (br s, 1 H), 4.19 (t,
J ) 6.6 Hz, 2 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 2.64 (t, J ) 7.6
Hz, 2 H), 1.96 (tt, 2 H, J ) 7.6, 6.6 Hz); 13C NMR δ 165.9,
148.8, 147.2, 133.6, 120.1, 111.6, 111.2, 64.1, 55.8, 55.9, 55.7,
31.6, 30.5; IR ν 2109 (CdN2), 1693 (CdO) cm-1. Anal. Calcd
for C13H16N2O4: C, 59.08; H, 6.10; N, 10.60. Found: C, 58.93;
H, 6.10; N, 10.59.
warmed to -20 °C (2 h) and then to 0 °C (2 h). The excess
base was quenched at 0 °C with 10 mL of saturated aqueous
NH4Cl, and the solution was extracted with ether (10 mL) and
EtOAc (2 × 10 mL). The combined organic layer was washed
with H2O (2 × 30 mL) and brine (30 mL) and dried over
anhydrous MgSO4, and the solvent was removed under
reduced pressure. The residue was purified by column chro-
matography on silica gel (hexanes:EtOAc, 4:1) to afford 0.092
g of (3S,4S)-3-[(3-methoxy-4-(benzyloxy)phenyl)methyl]-4-[(3,4-
dimethoxyphenyl)methyl]dihydro-2(3H)-furanone (20) (0.20
mmol, 79% yield): 1H NMR δ 7.43-7.26 (comp, 5 H), 6.95-
6.47 (comp, 6 H), 5.12 (s, 2 H), 4.14-4.11 (m, 1 H), 3.89-3.86
(m, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.00-2.86
(comp, 2 H), 2.62-2.49 (comp, 4 H).
To a solution of this lactone (0.092 g, 0.20 mmol) in 10 mL
of EtOAc and 1 mL of AcOH was added 5% Pd/C (0.05 g, 10
mol %). The resulting mixture was stirred under H2 (balloon
pressure), and the reaction was monitored by TLC (hexanes:
EtOAc ) 2:1). After 1.5 h, the reaction mixture was combined
with 20 mL of EtOAc and 20 mL of H2O. The organic layer
was washed sequentially with saturated aqueous NaHCO3 (20
mL) and brine (20 mL) and dried over anhydrous MgSO4, and
the solvent was removed under reduced pressure to provide
0.068 g of (+)-arctigenin (0.18 mmol, 92% yield) as a light
brown oil. Further purification by radial chromatography
(CH2Cl2:MeOH ) 99:1) yielded 0.060 g (0.16 mmol, 82% yield)
of 4 as an amorphous white solid: [R]25D ) +27.1 (c 0.56, EtOH,
94% ee); lit.26 [R]D ) +28.05 (c 1.23, EtOH) of naturally
occurring 4; 1H NMR δ 6.82 (d, J ) 7.9 Hz, 1 H), 6.75 (d, J )
8.2 Hz, 1 H), 6.63 (d, J ) 1.9 Hz, 1 H), 6.61 (dd, J ) 7.9, 1.9
Hz, 1 H), 6.55 (dd, J ) 8.2, 1.9 Hz, 1 H), 6.46 (d, J ) 1.9 Hz,
1 H), 5.56 (br s), 4.17-4.12 (m, 1 H), 3.91-3.85 (m, 1 H), 3.85
(s, 3 H), 3.82 (s, 6 H), 2.98-2.48 (comp, 2 H), 2.67-2.43 (comp,
4 H).
(+)-Isod eoxyp od op h yllotoxin (22). To 1.0 mL of 1.0 M
LHMDS (in THF, 1.0 mmol) stirred under N2 at -10 °C was
added in one portion a solution of (S)-13c (0.065 g, 0.26 mmol)
and 3,4,5-trimethoxybenzaldehyde (0.052 g, 0.26 mmol) in 3.5
mL of benzene. A precipitate formed immediately, and the
reaction mixture was warmed to 10 °C, stirred for 2 min and
then quenched with 2.5 mL of 50% aqueous HCl cooled to -20
°C. The resulting solution was diluted with EtOAc (10 mL),
and the organic phase was washed with saturated NaHCO3
solution (10 mL) and brine (10 mL) and then dried over
anhydrous MgSO4. Removal of the solvent under reduced
pressure provided 0.116 g of the epimeric alcohols 21 (0.26
mmol, 100% yield) as an oil: 1H NMR δ 6.64 (s, 2 H), 6.58 (d,
J ) 7.9 Hz, 1 H), 6.47 (s, 1 H), 6.30 (d, J ) 7.9 Hz, 1 H), 5.91
(s, 2 H), 5.25 (br s, 1 H), 4.81 (d, J ) 7.9 Hz, 1 H), 4.39 (dd, J
) 8.5, 7.9 Hz, 1 H), 4.14 (dd, J ) 8.8, 7.9 Hz, 1 H), 4.00-3.92
(m, 1 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 3.82 (s, 3 H), 2.87-2.14
(comp, 3 H).
4-[(3,4-Dim eth oxyp h en yl)m eth yl]d ih yd r o-2(3H)-fu r a -
n on e (13d ). A solution of diazoacetate 12d (0.159 g, 0.60
mmol) in 4 mL of rigorously dried CH2Cl2 was added via
syringe pump at a rate of 0.4 mL/h to a refluxing solution of
Rh2(4S-MPPIM)4 (10.8 mg, 1.3 mol %) in 7 mL of dry CH2Cl2.
The initial blue/purple color of the reaction solution turned to
olive green by the end of the substrate addition. Refluxing
was continued for an additional 3 h, the reaction solution was
cooled to room temperature, and the catalyst was removed by
filtration on a short plug of silica gel (CH2Cl2). Removal of
the solvent under reduced pressure provided 0.112 g of (S)-
13d (0.47 mmol, 79% yield) as a light yellow oil. Purification
by radial chromatography (4:1 hexanes:EtOAc) afforded 89 mg
of the lactone (0.37 mmol, 62% yield) as a clear oil. Enantio-
meric excesses were 94% with baseline separation by GC
analysis on a 30-m Chiraldex A-DA column operated at 175
°C for 1 h and then programmed at 0.5 °C/min to 200 °C: 153.1
min (13d , S-enant), 155.2 min (13d , R-enant); [R]25 ) -7.30
D
(c 1.11, CHCl3) (with 1.3 mol % Rh2(4S-MPPIM)4); [R]24
)
D
+7.50 (c 0.971, CHCl3) (with 2.0 mol % Rh2(4R-MPPIM)4); lit.11
[R]D ) -7.52 (c 1.9, CHCl3) of optically pure (S)-13d ; 1H NMR
δ 6.81 (d, J ) 8.0 Hz, 2 H), 6.69 (dd, J ) 8.0, 2.0 Hz, 1H), 6.66
(d, J ) 2.0 Hz, 1 H), 4.34 (dd, J ) 9.1, 6.8 Hz, 1 H), 4.04 (dd,
J ) 9.1, 6.0 Hz, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 2.91-2.76
(m, 1 H), 2.74-2.70 (comp, 2 H), 2.61 (dd, J ) 17.4, 7.9 Hz, 1
H), 2.29 (dd, J ) 17.4, 6.7 Hz, 1 H). Using 2.0 mol % Rh2(4R-
MPPIM)4, (R)-13d was isolated in 61% yield (94% ee) after
purification by radial chromatography.
4-(Ben zyloxy)-3-m eth oxyben zyl Br om id e (19). To a
rapidly stirred slurry of 4-hydroxy-3-methoxybenzyl alcohol
(3.00 g, 19.5 mmol), potassium carbonate (6.22 g, 45.0 mmol),
and 18-crown-6 (0.040 g, 1 mol %) in 35 mL of toluene was
added a solution of benzyl bromide (2.56 g, 15.0 mmol) in 15
mL of toluene over 20 min. The reaction mixture was refluxed
overnight after which the mixture was diluted with 40 mL of
ether and washed with 5% NaOH (50 mL), saturated aqueous
NaHCO3 (50 mL), and brine (60 mL). The ether layer was
dried over anhydrous MgSO4, and the solvent was removed
under reduced pressure to provide 3.11 g of a pale yellow solid
identified as 4-(benzyloxy)-3-methoxybenzyl alcohol (14.4 mol,
96% yield); mp 63-65 °C; lit.35 mp 64-65 °C; 1H NMR δ 7.44-
7.25 (comp, 5 H), 6.94 (s, 1 H), 6.86-6.82 (comp, 2 H), 5.15 (s,
2 H), 4.60 (s, 2 H), 3.90 (s, 3 H), 1.64 (br s, 1 H).
To a solution of this alcohol (2.00 g, 8.26 mmol) in 30 mL of
anhydrous ether under N2 was added in one portion PBr3
(0.400 mL, 4.21 mmol) at room temperature, and the resulting
solution was stirred for 3 h. After dilution with ether (20 mL),
the reaction solution was washed with H2O (2 × 40 mL),
saturated aqueous NaHCO3 (40 mL), and brine (50 mL) and
dried over anhydrous MgSO4, and the solvent was removed
under reduced pressure to provide 2.12 g of 19 (6.91 mmol,
84% yield) as a white solid: mp 67-70 °C; lit.36 mp 73 °C; 1H
NMR δ 7.44-7.26 (comp, 5 H), 6.94 (d, J ) 2.1 Hz, 1 H), 6.88
(dd, J ) 8.2, 2.1 Hz, 1 H), 6.81 (d, J ) 8.2 Hz, 1 H), 5.16 (s, 2
H), 4.48 (s, 2 H), 3.90 (s, 3 H).
The mixture of epimers (80 mg, 0.18 mmol) was dissolved
in 3 mL of rapidly stirred TFA, and the reaction was monitored
by 1H NMR. After 3 h, the reaction solution was diluted with
EtOAc (15 mL), washed with H2O (10 mL), 5% NaHCO3
solution (10 mL), and brine (15 mL), and dried over anhydrous
MgSO4. Removal of the solvent under reduced pressure
provided 69 mg of reddish brown solid. A single recrystalli-
zation from boiling CH2Cl2 triturated with ether afforded 52
mg of (+)-isodeoxypodophyllotoxin (22) (0.122 mmol, 68% yield)
as white needles: [R]25 ) + 86.7° (c 0.51, CHCl3, 100% ee),
D
mp 252-253 °C; lit.28,37 [R]D ) +84.5 (CHCl3), mp 252-254
(3S,4S)-3-[(3-Meth oxy-4-h yd r oxyp h en yl)m eth yl]-4-[3,4-
d im eth oxyp h en yl)m eth yl]d ih yd r o-2(3H)-fu r a n on e. (+)-
Ar ctigen in (4). To a rapidly stirred solution of (S)-13d in 8
mL of anhydrous THF at -78 °C was added 0.35 mL of 1.5 M
LDA (in cyclohexane, 0.48 mmol, 1.9 equiv) and 0.15 g of
HMPA (0.76 mmol, 1.6 equiv). After 0.5 h a solution of
4-(benzyloxy)-3-methoxybenzyl bromide (19) (0.13 g, 0.41
mmol, 1.6 equiv) in 1.0 mL of THF was added in one portion,
and the resulting mixture was stirred for 12 h at -78 °C and
1
°C; H NMR δ 6.60 (s, 1 H), 6.41 (s, 2 H), 6.35 (s, 1 H), 5.96-
5.84 (comp, 2 H), 4.53 (dd, J ) 8.7, 6.4 Hz, 1 H), 4.08-3.94
(comp, 2 H), 3.85 (s, 3 H), 3.82 (s, 6 H), 3.02-2.88 (comp, 2 H),
2.63-2.48 (comp, 2 H); 13C NMR δ 175.4, 153.1, 146.6, 138.7,
127.8, 110.0, 109.9, 108.5, 108.4, 106.4, 101.1, 70.9, 60.9, 56.2,
48.7, 46.7, 40.1, 32.9.
Meth yl 4-(Ben zyloxy)-3-m eth oxycin n a m a te (10e).
A
rapidly stirred solution of 4-hydroxy-3-methoxycinnamic acid
(10.12 g, 52.0 mmol) in 80 mL of methanol was cooled to 5 °C,
SOCl2 (3.88 mL, 52.5 mmol) was added dropwise over 5 min,
(35) Schofield, K.; Ward, R. S.; Choudhury, A. M. J . Chem. Soc.,
Chem. Commun. 1971, 2834.
(36) Enders, D.; Eichenauer, H.; Pieter, R. Chem. Ber. 1979, 112,
3703.
(37) Schrecker, A. W.; Hartwell, J . L. J . Am. Chem. Soc. 1953, 75,
5916.

9154 J . Org. Chem., Vol. 61, No. 26, 1996
Bode et al.
and the resulting solution was stirred overnight at room
temperature. The solvent was removed under reduced pres-
sure, and the residue was dissolved in 1:1 ether:EtOAc (60
mL) and then washed with saturated NaHCO3 solution (40
mL) and brine (50 mL). The organic layer was dried over
anhydrous MgSO4, and the solvent was removed under
reduced pressure to provide 10.8 g of 4-hydroxy-3-methoxy-
cinnamic acid methyl ester (52.0 mmol, 100% yield) as a light
brown oil: 1H NMR δ 7.63 (d, J ) 15.9 Hz, 1 H), 7.06-7.03
(comp, 2 H), 6.92 (d, J ) 8.2 Hz, 1 H), 6.29 (d, J ) 15.9 Hz, 1
H), 5.86 (br s, 1H), 4.14 (s, 3 H), 4.11 (s, 3 H).
To a rapidly stirred slurry of this ester (5.00 g, 24.0 mmol),
potassium carbonate (7.88 g, 57.0 mmol), and a catalytic
amount of 18-crown-6 (0.015 g) in 90 mL of toluene was added
a solution of benzyl bromide (3.88 g, 22.8 mmol) in 15 mL of
toluene over 30 min. The reaction mixture was refluxed
overnight after which the mixture was diluted with 70 mL of
ether and 20 mL of EtOAc, washed with 5% aqueous NaOH
(50 mL), saturated aqueous NaHCO3 (50 mL), and brine (75
mL). The ether layer was dried over anhydrous MgSO4, and
the solvent was removed under reduced pressure to provide
6.21 g of the title compound (22.1 mmol, 92% yield) as a white
solid: mp 98.5-99.5 °C. 1H NMR δ 7.62 (d, J ) 15.9 Hz, 1
H), 7.44-7.33 (comp, 5 H), 7.07-7.02 (comp, 2 H), 6.87 (d, J
) 8.2 Hz, 1 H), 6.30 (d, J ) 15. 9 Hz, 1 H), 5.19 (s, 2 H), 3.92
(s, 3 H), 3.80 (s, 3 H); 13C NMR δ 167.6, 150.2, 149.7, 144.7,
136.5, 128.6, 128.0, 127.7, 127.2, 122.3, 115.6, 113.4, 110.2,
70.8, 56.0, 51.6. Anal. Calcd for C18H18O4: C, 72.73; H, 6.08.
Found: C, 72.76; H, 6.12.
3-[4-(Ben zyloxy)-3-m eth oxyp h en yl]p r op -1-yl Dia zoa c-
eta te (12e). To a stirred suspension of LiAlH4 (0.069 g, 18.2
mmol) in 90 mL of anhydrous THF was added 10e (2.35 g,
7.83 mmol) as a solid in portions over 10 min. The reaction
mixture was refluxed under N2 for 3 h, cooled to room
temperature, and quenched with 1 mL of EtOAc. Upon
addition of 1 mL of H2O, 1.5 mL of 10% aqueous NaOH, and
3 mL of H2O, grey salts formed which were filtered under
vacuum and washed with EtOAc (100 mL). The resulting
solution was washed with brine (70 mL) and dried over
anhydrous MgSO4, and the solvent was removed under
reduced pressure to provide 2.05 g of 3-[4-(benzyloxy)-3-
methoxyphenyl]propan-1-ol (11e) (17.9 mmol, 95% yield) as a
colorless oil. If necessary, further purification was performed
by flash chromatography on silica gel (1:2 hexanes:EtOAc). 1H
NMR δ 7.25-7.29 (comp, 5 H), 6.80 (d, J ) 8.2 Hz, 1 H), 6.75
(d, J ) 2.0 Hz, 1 H), 6.67 (dd, J ) 8.2, 2.0 Hz, 1 H), 5.13 (s, 2
H), 3.88 (s, 3 H), 3.67 (t, J ) 6.4 Hz, 2 H), 2.65 (t, J ) 7.6 Hz,
2 H), 1.87 (tt, J ) 6.4, 7.6 Hz, 2 H).
To a solution of this alcohol (1.85 g, 6.8 mmol) and triethyl-
amine (0.200 g, 2.0 mmol) in 30 mL of anhydrous THF was
added, dropwise at room temperature, a solution of diketene
(0.631 g, 7.5 mmol) in 20 mL of THF. The resulting solution
was stirred at room temperature overnight whereupon tri-
ethylamine (1.00 g, 8.2 mmol) was added to the reaction
solution, followed by dropwise addition of methanesulfonyl
azide (0.836 g, 8.2 mmol) in 20 mL THF over 30 min, and
stirring was continued overnight at room temperature. To the
resulting orange solution was added LiOH‚H2O (0.867 g, 20.4
mmol) in 30 mL of H2O, and stirring was continued for 5.5 h.
The reaction mixture was diluted with brine and extracted
with three portions of 1:1 ether:EtOAc (60 mL). The combined
organic layer was washed with brine (70 mL) and dried over
anhydrous MgSO4, and the solvent was removed under
reduced pressure to provide an orange liquid. Purification by
flash chromatography on silica gel (hexanes:EtOAc ) 4:1)
provided 1.04 g of 12e (3.05 mmol, 45% yield) as a yellow glass.
1H NMR δ 7.45-7.26 (comp, 5H), 6.80 (d, J ) 8.2 Hz, 1 H),
6.72 (d, J ) 1.9 Hz, 1 H), 6.65 (dd, J ) 8.2, 1.9 Hz, 1 H), 5.12
(s, 2 H), 4.73 (br s, 1 H), 4.17 (t, J ) 6.5 Hz, 2 H), 3.88 (s, 3 H),
2.62 (t, J ) 7.6 Hz, 2 H), 1.94 (tt, J ) 7.6, 6.5 Hz, 2 H); 13C
NMR δ 166.8, 149.6, 146.4, 137.3, 134.3, 128.5, 127.7, 127.2,
120.2, 114.2, 112.2, 71.2, 64.1, 55.9, 46.1, 31.6, 30.4; IR: ν 2108
(CdN2), 1686 (CdO) cm-1. Anal. Calcd for C19H20N2O4: C,
67.04; H, 5.92; N, 8.23. Found: C, 67.08; H, 5.96; N, 8.15.
4-[[4-(Ben zyloxy)-3-m eth oxyp h en yl]m eth yl]d ih yd r o-2-
(3H)-fu r a n on e (13e) was formed by the catalytic decomposi-
tion of diazoacetate 12e in the presence of Rh2(4R-MPPIM)4
(1.0 mol%, 59% yield, 96.5% ee). [R]24D ) +3.7 (c 1.03, CHCl3);
mp 79 °C; lit.28 [R]D ) +4 (CHCl3) of optically pure (R)-13e,
mp 80-81.5 °C. 1H NMR δ 7.44-7.27 (comp, 5 H), 6.82 (d, J
) 8.1 Hz, 1 H), 6.68 (s, 1 H), 6.62 (d, J ) 8.1 Hz, 1 H), 5.13 (s,
2 H), 4.33 (d, J ) 9.1, 6.7 Hz, 1 H), 4.03 (dd, J ) 9.1, 5.8 Hz,
1 H), 3.88 (s, 1 H), 2.88-2.75 (m, 1 H), 2.72-2.68 (comp, 2 H),
2.57 (dd, J ) 17.3, 7.9 Hz, 1 H), 2.28 (dd, J ) 17.3, 6.7 Hz, 1
H); 13C NMR δ 176.8, 149.8, 147.0, 137.1, 131.3, 128.5, 127.9,
127.2, 120.6, 114.3, 112.4, 72.6, 71.1, 56.0, 38.6, 37.2, 34.2; m/ z
mass spectrum, m/ z (relative abundance) 313 (M + 1, 1.1),
312 (M, 5.2), 221 (1.1) 137 (1.5), 107 (2.2), 105 (2.0), 92 (8), 91
(100); IR ν 1774 (CdO) cm-1. Anal. Calcd for C19H20O4: C,
73.05; H, 6.45. Found: C, 73.07; H, 6.42.
For the purpose of chiral GC analysis, (R)-13e was converted
to 4-[(4-hydroxy-3-methoxyphenyl)methyl]dihydro-2(3H)-fura-
none by hydrogenolysis over Pd/C in EtOAc:AcOH (99:1) under
1
balloon pressure of H2; H NMR δ 6.86 (d, J ) 8.2 Hz, 1 H),
6.67-6.64 (comp, 2 H), 5.53 (br s, 1 H), 4.33 (dd, J ) 6.8, 9.1
Hz, 1 H), 4.04 (dd, J ) 5.8, 9.1 Hz, 1 H), 3.89 (s, 3 H), 2.82-
2.79 (m, 1 H), 2.72-2.69 (comp, 2 H), 2.62 (dd, J ) 8.0, 17.4
Hz, 1 H), 2.29 (dd, J ) 6.6, 17.4 Hz, 1 H). Other spectral
characteristics were identical to those previously reported.29
Enantiomeric excesses were determined by GC analysis on a
30-m Chiraldex A-DA column operated at 175 °C for 1 h and
then programmed at 0.5 °C/min to 200 °C: 189.8 min (S), 192.7
min (R).
1-Bu tyl Dia zoa ceta te (24a ). The title compound was
prepared from 1-butanol by the same procedure as that
described for 24b in 60% yield as a clear yellow oil; bp 37 °C
(0.7 torr); 1H NMR δ 4.74 (br s, 1 H), 4.17 (t, J ) 6.7 Hz, 2 H),
1.63 (tt, J ) 7.6, 6.7 Hz, 2 H), 1.37 (tq, J ) 7.6, 7.1 Hz, 2 H),
0.94 (t, J ) 7.1 Hz, 3 H). 13C NMR δ 166.8, 64.6, 45.9, 30.7,
18.9, 13.5; IR ν 2110 (CdN2), 1697 (CdO) cm-1. Anal. Calcd
for C6H10N2O2: C, 50.7; H, 7.09; N, 19.72. Found: C, 50.58;
H, 7.13; N, 19.70.
4-Meth yl-1-p en tyl Dia zoa ceta te (24b). To a continuously
stirred solution of 4-methyl-1-pentanol (2.15 g, 21.1 mmol)
and triethylamine (0.40 g, 3.9 mol) in 25 mL of THF was added
diketene (1.86 g, 221 mmol) in 15 mL of THF. The resulting
yellow solution was stirred overnight at room temperature
whereupon triethylamine (2.58 g, 25.3 mmol) and methane-
sulfonyl azide (3.06, 25.3 mmol) in 15 mL of THF were added
to the reaction flask. The resulting dark orange solution was
stirred overnight at room temperature at which time was
added LiOH‚H2O (2.66 g, 63.6 mmol), and stirring was
continued for an additional 4 h. The reaction mixture was
diluted with 30 mL of brine and extracted with three 35 mL
portions of 2:1 ether:EtOAc. The combined organic solution
was washed with 60 mL of brine and dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure.
The resulting orange liquid was purified by flash chromatog-
raphy on silica gel (hexanes:EtOAc ) 8:1), and collection of
the yellow band provided 1.94 g of 24b (11.4 mmol, 54% yield)
1
as a clear yellow oil; H NMR δ 4.73 (br s, 1 H), 4.14 (t, J )
6.7 Hz, 2 H), 1.69-1.52 (comp, 3 H), 1.26-1.18 (m, 2 H), 0.89
(d, J ) 6.7 Hz, 6 H); 13C NMR δ 166.7, 65.0, 45.8, 34.7, 27.5,
26.5, 22.2; IR ν 2111 (CdN2), 1697 (CdO) cm-1. Anal. Calcd
for C8H14N2O2: C, 56.45; H, 8.28; N, 16.46. Found: C, 56.35;
H, 8.38; N, 16.54.
4-Eth yld ih yd r o-2(3H)-fu r a n on e (25a ). This lactone was
prepared according to the procedure described for 13e by
catalytic decomposition of 24a (0.100 g, 0.72 mmol) with
Rh2(4S-MPPIM)4 (10 mg, 1.0 mol %). Purification by bulb-to-
bulb distillation provided 0.042 g of 25a (0.37 mmol, 52% yield,
1
95% ee) as a clear oil which contained 4% of the â-lactone. H
NMR δ 4.42 (dd, J ) 7.3, 9.4 Hz, 1 H), 3.94 (dd, J ) 7.6, 9.4
Hz, 1 H), 2.63 (d, J ) 8.3, 17.0 Hz, 1 H), 2.49 (hept, J ) 7.3
Hz 1 H), 2.20 (dd, J ) 7.6, 17.0 Hz, 1 H), 1.81-1.38 (comp, 2
H), 0.98 (t, J ) 7.3 Hz, 3 H). Other spectral characteristics
were identical to those previously reported.38 Enantiomeric
(38) (a) Kametani, T.; Katoh, T.; Tsubuki, M.; Honda, T. Chem.
Pharm. Bull. 1985, 33, 61. (b) Ueno, Y.; Chino, K.; Watanabe, M.;
Moriya, O.; Okawara, M. J . Am. Chem. Soc., 1982, 104, 5564.

Total Synthesis of Natural Lignan Lactones
J . Org. Chem., Vol. 61, No. 26, 1996 9155
excesses were determined by GC analysis on a 30-m Chiraldex
A-DA column operated at 80 °C: 57.7 min (S-25a ), 59.5 min
(R-25a ).
min (R-25b), 116.7 min (S-25b). Anal. Calcd for C8H14O2: C,
67.58; H, 9.92. Found: C, 67.48; H, 9.81.
Ack n ow led gm en t. We are grateful to the Robert
A. Welch Foundation, the National Institutes of Health
(GM 46503), and the National Science Foundation for
their support of this research. Fellowship support to
J .W.B. for the summer of 1995 was provided by the
Council on Undergraduate Research’s Academic-In-
dustrial Undergraduate Research Partnership program,
sponsored by Boehringer Ingelheim Pharmaceuticals,
Inc. We wish to thank David C. Forbes for the analyses
that he performed.
4-(2-Met h yl-1-p r op yl)d ih yd r o-2(3H )-fu r a n on e (25b ).
This lactone was prepared by catalytic decomposition of 14b
(0.183 g, 1.08 mmol) according to the procedure described for
13e with Rh2(4S-MPPIM)4 (22 mg, 1.5 mol %). Purification
by bulb-to-bulb distillation provided 0.090 g (60% yield) of a
clear oil which contained approximately 5% of the â-lactone.
This material was further purified by column chromatography
on silica gel (hexanes:EtOAc) to afford 0.042 g of 25b (0.29
mmol, 28% yield) as a clear oil; bp 40-41 °C (0.7 torr); 1H NMR
δ 4.42 (dd, J ) 8.9, 8.0 Hz, 1 H), 3.89 (dd, J ) 8.9, 7.1 Hz, 1
H), 2.69-2.57 (comp, 2 H), 2.22 (m, 1 H), 1.58 (oct, J ) 6.7
Hz, 1 H), 1.37 (t, J ) 7.1 Hz, 2 H), 0.93 (d, J ) 6.7 Hz, 3 H),
0.91 (d, J ) 6.7 Hz, 3 H); 13C NMR δ 177.2, 73.5, 42.2, 34.7,
33.8, 26.3, 22.6, 22.4; IR ν 1773 (CdO) cm-1. Enantiomeric
excesses were determined following LiAlH4 reduction by GC
analysis on a 30-m Chiraldex G-DA column operated at 90 °C
for 60 min then programmed at 1.0 °C/min to 185 °C: 103.0
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra of 15 and 18 (4 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O961607U