Streamlined, asymmetric synthesis of 8,4′-oxyneolignans

Article abstract of DOI:10.1021/jo061521t

Highly direct, modular syntheses of several natural 8,4′- oxyneolignans [(-)-1, (+)-1, (-)-2, and (-)-3] and some related variants [(-)-26, (+)-26, (+)-27, and (-)-28] are reported. Utilizing (S)- or (R)-methyl lactate as the chiral sources, two complementary syn- or anti-oriented routes were designed, encompassing nine and five steps, which were carried out to deliver the targets in an enantiomerically pure form. The embodiment of the two independent aryl and aryloxy moieties onto the lactate frame was performed according to a diversity-oriented protocol from the common precursors, aldehydes 6 and ent-6 for the syn-oriented routes and mesyl esters 19 and ent-19 for the anti-oriented routes. These syntheses set the stage for the generation of a wide and diverse repertoire of 8,4′-oxyneolignan compounds and the broad biological interrogation of its members.

Full text of DOI:10.1021/jo061521t

Streamlined, Asymmetric Synthesis of 8,4′-Oxyneolignans
Claudio Curti,§ Franca Zanardi,*,§ Lucia Battistini,§ Andrea Sartori,§ Gloria Rassu,‡
Luigi Pinna,† and Giovanni Casiraghi*,§
Dipartimento Farmaceutico, UniVersita` degli Studi di Parma, Viale G.P. Usberti 27A, I-43100 Parma,
Italy, Istituto di Chimica Biomolecolare del CNR, TraVersa La Crucca 3, I-07040 Li Punti, Sassari, Italy,
and Dipartimento di Chimica, UniVersita` degli Studi di Sassari, Via Vienna 2, I-07100 Sassari, Italy
franca.zanardi@unipr.it
ReceiVed July 21, 2006
Highly direct, modular syntheses of several natural 8,4′-oxyneolignans [(-)-1, (+)-1, (-)-2, and (-)-3]
and some related variants [(-)-26, (+)-26, (+)-27, and (-)-28] are reported. Utilizing (S)- or (R)-methyl
lactate as the chiral sources, two complementary syn- or anti-oriented routes were designed, encompassing
nine and five steps, which were carried out to deliver the targets in an enantiomerically pure form. The
embodiment of the two independent aryl and aryloxy moieties onto the lactate frame was performed
according to a diversity-oriented protocol from the common precursors, aldehydes 6 and ent-6 for the
syn-oriented routes and mesyl esters 19 and ent-19 for the anti-oriented routes. These syntheses set the
stage for the generation of a wide and diverse repertoire of 8,4′-oxyneolignan compounds and the broad
biological interrogation of its members.
Introduction
fungal,7 anti-leishmanial,5,8 anti-oxidant,9 and anti-schistoso-
mial10 activities.
Lignans and neolignans comprise a large group of secondary
plant metabolites which are biochemically related to the shikimic
acid pathway.1 These products are formed in nature by oxidative
coupling of two phenylpropanoid units (e.g., eugenol, coniferyl
alcohol, isoeugenol), whose site of connection determines their
classification into lignans (8,8′-linkage), neolignans (all other
C,C′-linkages), and oxyneolignans (C-O-C′-linkages).2 Among
the 8,4′-oxyneolignan subgroup, various naturally occurring
members, such as polysphorin (1),3 raphidecursinol B (2),3b
virolin (3),4 and surinamensin (4)4,5 (Figure 1), were isolated
from the Myristicaceae and other primitive plant families in
neotropical regions, which displayed interesting and varied
biological properties spanning from anti-malarial3b,6 to anti-
The chemical characteristics of these oxyneolignans, featuring
a propane diol backbone equipped with aryl and aryloxy
components, offer the possibility of achieving a high level of
(3) (a) Ma, Y.; Han, G. Q.; Li, C. L.; Arison, B. H.; Hwang, S. B. Acta
Pharm. Sin. 1991, 26, 345-350. (b) Zhang, H.-J.; Tamez, P. A.; Hoang,
V. D.; Tan, G. T.; Van Hung, N.; Xuan, L. T.; Huong, L. M.; Cuong, N.
M.; Thao, D. T.; Soejarto, D. D.; Fong, H. H. S.; Pezzuto, J. M. J. Nat.
Prod. 2001, 64, 772-777.
(4) Barata, L. E. S.; Baker, P. M.; Gottlieb, O. R.; Ruveda, E. A.
Phytochemistry 1978, 17, 783-786.
(5) Barata, L. E. S.; Santos, L. S.; Ferri, P. H.; Phillipson, J. D.; Paine,
A.; Croft, S. L. Phytochemistry 2000, 55, 589-595.
(6) (a) Ridley, R. G. Nature 2002, 415, 686-693. (b) Miller, L. H.;
Baruch, D. I.; Marsh, K.; Doumbo, O. K. Nature 2002, 415, 673-679.
(7) (a) Zacchino, S.; Rodr´ıguez, G.; Pezzenati, G.; Orellana, G. J. Nat.
Prod. 1997, 60, 659-662. (b) Zacchino, S.; Rodr´ıguez, G.; Santocchia, C.;
Pezzenati, G.; Giannini, F.; Enriz, R. J. Ethnopharmacology 1998, 62, 35-
41. (c) Pinheiro, A. A. C.; Borges, R. S.; Santos, L. S.; Alves, C. N. J.
Mol. Struct. (THEOCHEM) 2004, 672, 215-219.
(8) (a) Andreazza Costa, M. C.; Takahata, Y. J. Mol. Struct. (THEOCHEM)
2003, 625, 257-263. (b) Aveniente, M.; Barata, L. E. S.; Santos, E. C. T.;
Pinto, E. F.; Rossi-Bergmann, B. 24a Reunin˜ao Anual da SBQ; Abstract
Book, MD 051, 2001. (c) Andreazza Costa, M. C.; Takahata, Y. J. Mol.
Struct. (THEOCHEM) 2003, 638, 21-25.
§ Universita` degli Studi di Parma.
‡ Istituto di Chimica Biomolecolare.
† Universita` degli Studi di Sassari.
(1) (a) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96. (b) Saleem, M.;
Kim, H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005, 22, 696-716. (c)
Ma, C.; Zhang, H. J.; Tan, G. T.; Hung, N. V.; Cuong, N. M.; Soejarto, D.
D.; Fong, H. H. S. J. Nat. Prod. 2006, 69, 346-350. (d) Apers, S.; Vlietinck,
A.; Pieters, L. Phytochem. ReV. 2004, 2, 201-207.
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10.1021/jo061521t CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/06/2006
8552
J. Org. Chem. 2006, 71, 8552-8558

Asymmetric Synthesis of 8,4′-Oxyneolignans
SCHEME 1. Synthesis Plan to the 7,8-syn and
7,8-anti-Configured Targeted 8,4′-Oxyneolignans
FIGURE 1. Representative members of the 8,4′-oxyneolignan family
and conventional atom numbering.2
structural diversity, as both the aromatic rings may possess
varying numbers and types of substituents (e.g., OH, OMe,
O-CH2-O, (E)-propenyl, allyl) and the molecule may sustain
four different stereodispositions.
Nature itself offers an extensive library of representatives of
this compound class, which the organic synthesis practitioner
may faithfully reproduce or, even, expand upon by adding a
huge number of non-natural variants. However, obtaining
supplies from Nature is an arduous task due to the scarce
quantity of isolable compounds and the fact that most of the
isolated neolignans reported present themselves as racemic
mixtures.3,11,12 On the other hand, the alternative of obtaining
useful quantities of enantiopure materials via synthesis has not
been carefully pursued. Most of the pioneering synthetic studies
have given rise to racemic mixtures of syn- and anti-configured
products,4,5,7a,9a,13,14 while existing enantioselective routes appear
limited by scarce overall efficiency, poor diastereo- and enan-
tioselective processes,14 and somewhat confusing stereochemical
assignments.15 More recently, a noteworthy enantioselective
synthesis of both enantiomers of polysphorin and analogues was
reported,16 shedding light on the true absolute configuration of
these compounds.
raphidecursinol B (-)-2, (7R,8R)-virolin (-)-3, and the five-
step synthesis of the corresponding anti-configured counterparts
(-)-26, (+)-26, (+)-27, and (-)-28.
Results and Discussion
Synthesis Planning. Arrival at the targeted oxyneolignan
compounds was planned from two directions that are stere-
ochemically complementary. In the first approach (Scheme 1),
the aryl module Ar1 is embodied first into the lactate frame
(nucleophilic carbonyl addition), followed by aryloxylation with
a second aryloxy module Ar2O (nucleophilic displacement). In
the event, the nature of the two operations, as well as their
sequence, should dictate the stereochemical outcome of the
reaction, possibly resulting in production of 7,8-syn-configured
compounds (R,R absolute configuration from S-lactate, and vice
versa).
In the alternative route, the aryloxylation (Ar2O) precedes
arylation (Ar1) so as to generate the product with a 7,8-anti
configuration (S,R absolute configuration from S-lactate, and
vice versa). Of course, for this issue to be realized, the
stereochemical bias of the two critical reactions has to be equally
operative in both approaches, that is, a Felkin-type mode for
the carbonyl aryl addition and a configuration reversal for the
aryloxy displacement.
Herein, the design and development of a new, truly general
and modular asymmetric route to all four possible stereoisomers
of the 8,4′-oxyneolignan compound class is outlined and
exemplified by the nine-step synthesis of syn-configured
(7R,8R)-polysphorin (-)-1, (7S,8S)-polysphorin (+)-1, (7R,8R)-
(9) (a) Ko´nya, K.; Varga, Zs.; Antus, S. Phytomedicine 2001, 8, 454-
459. (b) Ahn, B.-T.; Lee, S.; Lee, S.-B.; Lee, E.-S.; Kim, J.-G.; Bok, S.-
H.; Jeong, T.-S. J. Nat. Prod. 2001, 64, 1562-1564.
(10) Alves, C. N.; Pereira Barroso, L.; Santos, L. S.; Jardim, I. N. J.
Braz. Chem. Soc. 1998, 9, 577-582 and references therein.
(11) Hada, S.; Hattori, M.; Tezuka, Y.; Kikuchi, T.; Namba, T.
Phytochemistry 1988, 27, 563-568.
(12) In effect, most of the in vitro and in vivo biological evaluations
reported so far were effected on racemic mixtures.
Should this tactical move prove truly feasible, access to all
four stereoisomers of a given oxyneolignan target should be
close at hand by simply employing cheap and commercially
available (S)- and (R)-methyl lactate as starting materials. We
wish to put forward our evidence for this school of thought.
(13) Zacchino, S. A.; Badano, H. J. Nat. Prod. 1985, 48, 830-832.
(14) (a) Sefkow, M. Synthesis 2003, 2595-2625. (b) Zacchino, S.;
Badano, H. J. Nat. Prod. 1988, 51, 1261-1265. (c) Zacchino, S.; Badano,
H. J. Nat. Prod. 1991, 54, 155-160. (d) Li, K.; Helm, R. F. J. Chem. Soc.,
Perkin Trans. 1 1996, 2425-2526. (e) Chen, X.; Ren, X.; Peng, K.; Pan,
X.; Chan, A. S. C.; Yang, T.-K. Tetrahedron: Asymmetry 2003, 14, 701-
704.
(15) (a) Zacchino, S. J. Nat. Prod. 1994, 57, 446-451. (b) Shimomura,
H.; Sashida, Y.; Oohara, M. Phytochemistry 1987, 26, 1513-1515.
(16) (a) Lee, A.-L.; Ley, S. V. Org. Biomol. Chem. 2003, 1, 3957-
3966. (b) Zanardi, F.; Appendino, G.; Casiraghi, G. Chemtracts Org. Chem.
2004, 17, 587-592.
Synthesis of syn- and anti-Configured 8,4′-Oxyneolignans.
The syn-oriented route to (-)-polysphorin (-)-1, (-)-raphide-
cursinol B (-)-2, and (-)-virolin (-)-3 (Scheme 2) commenced
with (S)-methyl lactate (-)-5, which was quickly transformed
into protected lactaldehyde 6 by three highly productive and
J. Org. Chem, Vol. 71, No. 22, 2006 8553

Curti et al.
SCHEME 2. Synthesis of 7,8-syn-Configured
8,4′-Oxyneolignansa
FIGURE 2. Models for stereoselective aryl lithium additions to
p-methoxybenzyl-substituted (S)-lactaldehyde 6.
influence the stereochemical behavior of the nucleophilic
addition process, imparting a good anti-favoring stereocontrol.20
Advancement to the penultimate polysphorin precursor 16
needed an aryloxy substitution reaction. Drawing from previous
discouraging results obtained through applying the Mitsunobu
displacement with these substrates,16a we envisaged to follow
the stepwise C-8 activation/SN2 displacement procedure. Thus,
the free C-7 hydroxyl within 9 was first protected (acetylation),
the p-methoxybenzyl ether was successively dismantled (DDQ
in wet CH2Cl2), and the C-8 hydroxyl mesylated (MsCl, Et3N,
toluene). Compound 11 was obtained in 80% yield in three
steps.21
Subsequent, non-routine nucleophilic substitution was effected
by exposure of 11 to the cesium phenoxylate derived from 1322
in the presence of 18-crown-6 under microwave irradiation (200
W, 2 bar, 120 °C, 10 min). This procedure23 gratifyingly led to
the 7,8-syn-disposed protected polysphorin precursor 16 as the
sole stereoisomer (70% isolated yield), which was quickly and
almost quantitatively converted to natural (-)-polysphorin (-)-1
by sodium methoxide deacetylation (40% overall yield for the
nine-step sequence; g97% ee as determined by chiral HPLC
measurements). The physical and NMR spectral characteristics
of (-)-1 matched the value for the (7R,8R)-enantiomer as
reported by Ley and co-workers in the literature (J7,8 ) 8.4 Hz,
[R]D25 -100.4° (c 1.0, CHCl3); [lit.16a J7,8 ) 8.4 Hz, [R]D25 -87°
(c 0.34, CHCl3)]) (see also Table S1 in the Supporting
Information).
a Reagents and conditions: (a) PMBOC(CCl3)dNH, Sc(OTf)3, toluene;
(b) LiAlH4, THF; (c) (COCl)2, DMSO, CH2Cl2, -80 °C, then Et3N (91%,
three steps); (d) 5-bromo-1,2,3-trimethoxybenzene (7) or 4-bromo-1,2-
dimethoxybenzene (8), tBuLi, THF, -85 °C (9: 80%, dr ) 83:17, 10: 80%,
dr ) 82:18); (e) Ac2O, Et3N, DMAP, MeCN; (f) DDQ, wet CH2Cl2; (g)
MsCl, Et3N, toluene (11: 80%, 12: 83%, three steps); (h) cat. PdCl2 (90%),
MeOH; (i) Cs2CO3, 18-crown-6, DMF, sonication, then MW (200 W, 2
bar, 120 °C, 10 min) (16: 70%, 17: 72%, 18: 75%); (j) NaOMe, MeOH
(1: 98%, 2: 99%, 3: 99%).
enantioconservative maneuvers17 consisting of hydroxyl protec-
tion with the PMB-acetimidate/scandium triflate system,18 ester
reduction (LiAlH4), and Swern oxidation (91% yield for the
three steps). To target (-)-polysphorin (-)-1, arylation of 6
was carried out using the lithium derivative of 5-bromo-1,2,3-
trimethoxybenzene (7) (tBuLi, THF, -85 °C), affording the anti-
configured compound 9 as the predominant isomer (80%
isolated yield), accompanied by minor amounts of the syn
counterpart (dr ) 83:17, as determined by 1H NMR analysis of
the crude product mixture). Compound 9 (as well as 10) emerges
from the nucleophilic attack of aryl lithium onto the carbonyl
re face of the R-alkoxyaldehyde 6, according to a Felkin dipolar
model (Figure 2).19 It would seem plausible that, even in the
presence of a highly coordinating R-alkoxy group, which
typically would favor a “Cram-chelate” addition mode leading
to syn-configured products, in this case, the nature of the aryl
lithium reagent and the overall conditions seem to strongly
The same protocol was successfully applied to (-)-raphide-
cursinol B (-)-2 and (-)-virolin (-)-3 utilizing the competent
couples of aryl/aryloxy components, namely, aryl bromide 7
and phenol 14 for (-)-2 and aryl bromide 8 and phenol 15 for
(19) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9,
2199-2204. (b) Anh, N. T.; Eisenstein, O. New J. Chem. 1977, 1, 61-70.
(c) Gawley, R. E.; Aube´, J. Principles of Asymmetric Synthesis; Tetrahedron
Organic Chemistry Series, Vol. 14; Pergamon Press: Elsevier: Oxford, 1996;
pp 121-160. (d) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556-
569.
(20) (a) Luanphaisarnnont, T.; Ndubaku, C. O.; Jamison, T. F. Org. Lett.
2005, 7, 2937-2940. (b) Banfi, L.; Bernardi, A.; Colombo, L.; Gennari,
C.; Scolastico, C. J. Org. Chem. 1984, 49, 3784-3790.
(21) It is worth noting that the acetyl protection in 11 was critical since
installation of electron-donating groups at C-7 hydroxyl causes 11 to collapse
into stable epoxide derivatives.
(22) Conveniently, propenyl-substituted phenol 13 was obtained from
commercially available allyl phenol 14 by clean and efficient PdCl2-
catalyzed isomerization. Jing, X.; Gu, W.; Bic, P.; Ren, X.; Pan, X. Synth.
Commun. 2001, 31, 861-867.
(23) The experimental conditions capitalized on the findings previously
reported by Helm and Li (excess cesium 2-methoxyphenolate, 18-crown-
6, benzene, reflux, 24 h; ref 14d).
(17) Evidence of the full preservation of the enantiopurity of compound
6 was given by optical activity data which were comparable to those reported
in the literature (see experimental section in the Supporting Information).
(18) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267-2269.
8554 J. Org. Chem., Vol. 71, No. 22, 2006

Asymmetric Synthesis of 8,4′-Oxyneolignans
SCHEME 3. Synthesis of 7,8-anti-Configured
8,4′-Oxyneolignansa
(-)-3. There, the key non-routine arylation and aryloxylation
reactions occurred with the same chemical efficiency and
stereocontrol as that observed during the synthesis of (-)-1, as
shown in Scheme 2. Overall, the nine-step sequence provided
(-)-raphidecursinol B (-)-2 in a 42% yield, which displayed
the same characteristics as those reported in the literature for
the pure (R,R)-enantiomer (J7,8 ) 8.4 Hz, [R]D25 -77.0° (c 1.0,
25
CHCl3); [lit.16a J7,8 ) 8.1 Hz, [R]D -58.2° (c 5.26, CHCl3),
lit.7a J7,8 ) 8.0 Hz]) (Table S1, Supporting Information).
For (-)-virolin (-)-3, obtained here in a 45% overall yield,
a (7R,8R)-absolute configuration was assigned, based on the
configuration of the starting lactate ester as well as the faithful
stereochemical behavior of the chemistry experienced. Disap-
pointingly enough, while the NMR spectral characteristics of
our synthetic (-)-virolin (J7,8 ) 8.4 Hz) wholly matched the
reported data for both the natural and synthetic racemic
substances,13 as well as for an enantioenriched sample previously
obtained via synthesis (Table S1, Supporting Information),15a
25
the optical rotation of our (7R,8R)-configured sample ([R]D
-99.6° (c 1.0, CHCl3)) strongly deviates both in sign and value
from that reported in the literature for a 78% ee synthetic virolin
sample ([R]D -29° (c 1.0, CHCl3)) to which a (7S,8S)-
25
configuration was allegedly attributed.15a,24
The reaction platform of Scheme 2 proved to be also
utilitarian in paving the way to stereoisomeric (+)-1, provided
that (R)-methyl lactate (+)-5 was employed as the starting
chirality source. Thus, the (7S,8S)-configured polysphorin (+)-1
was obtained in a 38% overall yield for the sequence of nine
steps, thus confirming the reliability and predictability of our
a Reagents and conditions: (a) MsCl, Et3N, toluene (98%); (b) 13, 14,
or 15, Cs2CO3, 18-crown-6, DMF, sonication (20: 88%, 21: 87%, 22:
90%); (c) LiAlH4, THF; (d) (COCl)2, DMSO, CH2Cl2, -80 °C, then Et3N
t
(23: 95%, 24: 95%, 25: 96%, two steps); (e) BuLi, Ti(OiPr)3Cl, THF,
25
25
synthesis protocol ([R]D +99.3° (c 1.0, CHCl3); lit.16a [R]D
-85 °C (26: 90%, dr ) 90:10, 27: 81%, dr ) 85:15, 28: 82%, dr )
85:15).
+95° (c 0.8, CHCl3)).
Having a solid, modular protocol to create 7,8-syn-configured
8,4′-oxyneolignan compounds, we next challenged the same
systems in the 7,8-anti stereoisomeric series. Thus, as depicted
in Scheme 3, (S)-lactate (-)-5 was quickly transformed into
mesyl derivative 19 (98% yield),25 which was directly and
parallely subjected to nucleophilic displacement by means of
the suitable phenols 13,22 14, or 15.26 Three aryloxy lactate esters
20, 21, and 22 were produced in yields ranging from 87 to 90%.
Next, a two-step ester-to-aldehyde conversion was carried out,
consisting of an ester-to-alcohol reduction (LiAlH4) followed
by Swern oxidation. The three aldehyde intermediates 23, 24,
and 25 eventually were formed in excellent isolated yields (95-
96%), ready for the subsequent arylation maneuvers.
To access anti-configured oxyneolignans (-)-26 and (+)-
27, intermediates 23 and 24 had to be coupled to 7, while to
arrive at (-)-28, coupling of 25 to 8 was needed. All the planned
nucleophilic additions occurred smoothly and, even in this case,
a Felkin-type addition mode nicely applied, producing the anti-
configured targets (-)-26, (+)-27, and (-)-28 with high
efficiency (81-90% yields) and high level of diastereocontrol
(dr g 85:15).
synthesis, avoiding lengthy protection/deprotection maneuvers,
with the aryloxy moiety itself serving as a protecting element
for the target C-8 hydroxyl. Overall, the C-7 epimers of
polysphorin, raphidecursinol B, and virolin, (-)-26, (+)-27, and
(-)-28, were synthesized on a gram-scale and in an enantio-
merically pure form from (S)-methyl lactate in only five steps
and good 74, 66, and 69% overall yields, respectively. The
spectral data for 7,8-erythro-configured compounds (+)-27, and
(-)-28 matched the published data for the respective previously
reported substances (Table S1, Supporting Information),7a,14b,27
while (-)-26 (J7,8 ) 3.0 Hz) represents a new compound. To
further confirm the (7S,8R)-configurational assignment to (-)-
26, (+)-27, and (-)-28, circular dichroism analysis was
performed, based on the established empirical relationship28
between the characteristic CD transitions and the absolute
configuration of the stereocenters in anti-disposed 8,4′-oxyneo-
lignans (positive Cotton effects in the range of 230-290 nm
correspond to 7R,8S configurations, and vice versa).29
As for the syn-oriented (R,R)-series, the dextrorotatory
(7R,8S)-configured enantiomer of 8-epi-polysphorin (+)-26 was
assembled, by starting with (R)-methyl lactate (+)-5 and
faithfully paralleling the chemistry just disclosed. Thus, in this
special case, the polysphorin family was fully represented by
all four diastereoisomers.
Noteworthily, implementation of the aryloxy moiety onto the
lactate frame prior to arylation allowed us to speed up the
(24) On the basis of our results, the absolute configuration of levorotatory
virolin in ref 15a should be reverted (7R,8R).
(25) Hillis, L. R.; Ronald, R. C. J. Org. Chem. 1981, 46, 3348-3349.
(26) Here, milder conditions were found (Cs2CO3, 18-crown-6 in DMF,
sonication) as compared to the previous microwave-assisted substitution
procedure (see text) since it is known that the presence of a carboxylate or
a carbonyl group adjacent to the alcohol (or bromine) function strongly
activates the substrate for nucleophilic displacement. See, for example, ref
16a.
(27) Herrera Braga, A. C.; Zacchino, S.; Badano, H.; Sierra, M. G.;
Ru´veda, E. A. Phytochemistry 1984, 23, 2025-2028.
(28) Ko´nya, K.; Kiss-Szikszai, A.; Kurta´n, T.; Antus, S. J. Chromatogr.
Sci. 2004, 42, 478-483.
(29) Overall, these findings indirectly confirmed a (7R,8R)-configuration
for the minor syn-configured products, whose structures coincide with those
of compounds (-)-1, (-)-2, and (-)-3.
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Curti et al.
(1R,2S)-1-Acetoxy-1-(3,4,5-trimethoxyphenyl)-2-propyl meth-
anesulfonate (11). Typical Procedure. To a stirring solution of
compound 9 (4.20 g, 11.58 mmol) in dry acetonitrile (150 mL)
under argon were sequentially added acetic anhydride (5.46 mL,
57.90 mmol), Et3N (3.23 mL, 23.17 mmol), and 4-dimethylami-
nopyridine (DMAP, 707 mg, 5.79 mmol) at room temperature. The
reaction mixture was allowed to stir for 1 h, after which time it
was quenched with brine and saturated aqueous NH4Cl, until neutral
pH was achieved. The reaction mixture was extracted with hexanes
(3 × 20 mL), and the combined organic layers were dried over
MgSO4, filtered, and concentrated under vacuum to give a colorless
oily residue (4.66 g, 100% yield) which was used as such in the
subsequent reaction: 1H NMR (300 MHz, CDCl3) δ 7.11 (m, 2H),
6.81 (m, 2H), 6.54 (m, 2H), 5.71 (d, J ) 5.4 Hz, 1H), 4.46 (1/2
ABq, J ) 11.3 Hz, 1H), 4.36 (1/2 ABq, J ) 11.3 Hz, 1H), 3.84 (s,
3H), 3.82 (s, 6H), 3.77 (s, 3H), 3.74 (m, 1H), 2.12 (s, 3H), 1.19 (d,
J ) 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0, 159.2, 153.2
(2C), 135.9, 132.2, 130.2, 128.5 (2C), 113.9 (2C), 104.2 (2C), 77.3,
76.6, 71.0, 60.7, 56.0 (2C), 55.2, 21.2, 15.9.
To a solution of the previous acetyl intermediate (4.66 g, 11.58
mmol) in CH2Cl2 (200 mL) at 0 °C were added water (25 mL) and
DDQ (2.63 mg, 11.58 mmol). The reaction mixture was stirred for
3 h at room temperature, and then brine (100 mL) and saturated
NaHCO3 (50 mL) were added. After separation of the organic layer,
the aqueous phase was washed with dichloromethane (2 × 30 mL),
and the collected organic layers were dried over magnesium sulfate.
After filtration of the mixture and evaporation of the solvent, the
crude product was purified by silica gel flash chromatography (Et2O/
hexanes 90:10) to afford a partially deprotected intermediate (2.63
g, 80% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 6.52
(m, 2H), 5.46 (d, J ) 5.6 Hz, 1H), 3.98 (quint, J ) 6.0 Hz, 1H),
3.78 (s, 6H), 3.75 (s, 3H), 2.33 (br s, 1H), 2.05 (s, 3H), 1.12 (d, J
) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.1, 153.1 (2C),
137.7, 132.8, 104.4 (2C), 79.4, 69.7, 60.7, 56.0 (2C), 21.1, 18.5.
To a stirring solution of the previously obtained intermediate
(2.63 g, 9.26 mmol) in toluene (100 mL) at 0 °C was added
triethylamine (Et3N, 1.68 mL, 12.04 mmol). After 10 min, meth-
anesulfonyl chloride (MsCl, 0.79 mL, 10.19 mmol) was added over
a 15 min period. The light orange suspension was kept an additional
hour in the ice bath and then was allowed to warm to room
temperature. The mixture was filtered through Celite and concen-
trated under vacuum to give a light brown oil. Silica gel flash
chromatographic purification (hexanes/EtOAc 60:40) afforded pure
mesyl derivative 11 (3.36 g) in a 100% yield as a colorless oil:
[R]D25 -41.6° (c 0.8, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.54
(m, 2H), 5.73 (d, J ) 4.3 Hz, 1H), 4.94 (qd, J ) 6.2, 4.8 Hz, 1H),
3.80 (s, 6H), 3.76 (s, 3H), 2.80 (s, 3H), 2.10 (s, 3H), 1.31 (d, J )
6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.5 (C), 153.2 (2C,
C), 138.3 (C), 130.9 (C), 104.7 (2C, CH), 79.3 (CH), 76.1 (CH),
60.7 (CH3), 56.2 (2C, CH3), 38.4 (CH3), 20.9 (CH3), 16.7 (CH3).
Anal. Calcd for C15H22O8S: C, 49.71; H, 6.12. Found: C, 49.66;
H, 6.25.
Conclusions
To recapitulate, two complementary and large-scale adaptable
syntheses of enantiomerically pure (>95% ee) 7,8-syn- and 7,8-
anti-configured oxyneolignans are reported, which employ (S)-
or (R)-lactate esters as convenient sources of chirality. Apart
from a few run-of-the mill transformations, both routes are
centered upon two highly stereoselective and predictable opera-
tions of grafting the aromatic modules onto the lactate frame
which are sequenced in opposite directions. In the longest syn-
oriented route (nine steps), a Felkin-type carbonyl addition
precedes a bimolecular nucleophilic substitution reaction, while
in the shortest anti-oriented path (five steps) these two operations
are reversed.
In principle, as well as in practice, the overall plan ensures
that all four possible stereoisomers of a given target skeleton
are accessible in high yields. Bearing in mind the uncertainty
which has accompanied several structural attributions of com-
pounds in this class, the intent of this work is to provide a sure
means of establishing the relationship between molecular
structure and both spectral and chiro-optical properties.
A definitive biological interrogation of the eight 8,4′-
oxyneolignans in this study and structurally modified congeners
in the anti-malarial compound area will be the subject of future
investigations.
Experimental Section
(1R,2S)-2-(4-Methoxybenzyloxy)-1-(3,4,5-trimethoxyphenyl)-
propan-1-ol (9). Typical Procedure. A 1 L three-neck round-
bottom flask equipped with a dropping funnel and an argon inlet/
outlet was charged with anhydrous THF (200 mL). 5-Bromo-1,2,3-
trimethoxybenzene (7) (7.63 g, 30.88 mmol) was then added in
one portion, and the resulting solution was cooled to -85 °C.
tBuLi (1.7 M in pentane, 18.16 mL, 30.88 mmol) was added during
a 25 min period. After 15 min at -85 °C, a solution of aldehyde
6 (3.00 g, 15.44 mmol) dissolved in anhydrous THF (50 mL) was
added in a 15 min period, and the resulting mixture was allowed
to stir for 1 h at -85 °C. The reaction mixture was quenched by
the addition of citrate-sodium hydroxide buffer (65 mL) at -85
°C, allowed to warm to 25 °C, and extracted with hexanes (3 × 50
mL). The organic layers were dried (MgSO4), filtered, and
concentrated to give a crude residue which was purified by silica
gel flash chromatography (hexanes/EtOAc 1:1). Protected com-
pound 9 (4.48 g, 80%) was obtained, along with minor amounts of
the syn-configured diastereoisomer 7-epi-9 (not shown) (dr ) 83:
17). Compound 9: a colorless oil; 1H NMR (300 MHz, CDCl3) δ
7.23 (m, 2H), 6.88 (m, 2H), 6.58 (m, 2H), 4.79 (m, 1H), 4.58 (1/2
ABq, J ) 11.3 Hz, 1H), 4.44 (1/2 ABq, J ) 11.3 Hz, 1H), 3.87 (s,
3H), 3.85 (s, 6H), 3.82 (s, 3H), 3.70 (qd, J ) 6.2, 4.3 Hz, 1H),
2.60 (br s, 1H), 1.09 (d, J ) 6.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 159.3 (C), 153.1 (2C, C), 137.1 (C), 136.6 (C), 129.5
(C), 129.3 (2C, CH), 113.8 (2C, CH), 103.3 (2C, CH), 78.4 (CH),
75.3 (CH), 70.7 (CH2), 60.8 (CH3), 56.1 (2C, CH3), 55.3 (CH3),
13.8 (CH3). Anal. Calcd for C20H26O6: C, 66.28; H, 7.23. Found:
C, 66.39; H, 7.05.
2,6-Dimethoxy-4-[(E)-prop-1-enyl]phenol (13). Typical Pro-
cedure. To a stirring solution of commercially available 4-allyl-
2,6-dimethoxyphenol (14) (1.0 g, 5.15 mmol) in anhydrous and
previously degassed methanol (40 mL) was added a catalytic
amount of PdCl2 (46 mg, 0.26 mmol) at room temperature. After
24 h, the brown reaction mixture was filtered and concentrated under
vacuum to leave an oily crude residue which was purified by silica
gel flash chromatography under argon flow (petroleum ether/EtOAc
85:15). Pure phenol 13 was obtained (900 mg, 90%) as a pale
yellow oil: 1H NMR (300 MHz, CDCl3) δ 6.59 (s, 2H), 6.33 (dq,
J ) 15.6, 1.5 Hz, 1H), 6.11 (dq, J ) 15.6, 6.5 Hz, 1H), 5.48 (s,
1H), 3.91 (s, 6H), 1.88 (dd, J ) 6.5, 1.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 147.1 (2C, C), 134.0 (C), 131.0 (CH), 129.6 (C),
123.8 (CH), 102.7 (2C, CH), 56.2 (2C, CH3), 18.3 (CH3).
Compound 7-epi-9: a colorless oil; [R]D25 +11.9° (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.26 (m, 2H), 6.90 (m, 2H), 6.58
(m, 2H), 4.63 (1/2 ABq, J ) 11.0 Hz, 1H), 4.41 (1/2 ABq, J )
11.1 Hz, 1H), 4.38 (dd, J ) 7.5, 1.8 Hz, 1H), 3.86 (s, 3H), 3.84 (s,
6H), 3.80 (s, 3H), 3.61 (dq, J ) 7.6, 6.1 Hz, 1H), 3.24 (d, J ) 2.1
Hz, 1H), 1.11 (d, J ) 6.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
158.0 (C), 152.8 (2C, C), 132.1 (C), 129.1 (C), 129.0 (C), 128.3
(2C, CH), 113.6 (2C, CH), 103.8 (2C, CH), 79.2 (CH), 73.6 (CH),
70.6 (CH2), 60.6 (CH3), 55.9 (CH3), 55.8 (CH3), 55.0 (CH3), 14.4
(CH3).
(1R,2R)-2-[2,6-Dimethoxy-4-((E)-prop-1-enyl)phenoxy]-1-(3,4,5-
trimethoxyphenyl)propyl acetate (16). Typical Procedure. To a
flame-dried round-bottom flask were sequentially added anhydrous
8556 J. Org. Chem., Vol. 71, No. 22, 2006

Asymmetric Synthesis of 8,4′-Oxyneolignans
Cs2CO3 (228 mg, 0.70 mmol) and anhydrous DMF (5 mL) under
argon atmosphere at room temperature. The suspension was kept
under ultrasonic irradiation for 5 min, then phenol 13 (0.124 mL,
0.7 mmol) was added. The resulting dark green suspension was
allowed to stir under ultrasonic irradiation for an additional 30 min
period, after which time the supernatant solution was transferred
to a 10 mL glass vessel containing a solution of mesyl derivative
11 (100 mg, 0.28 mmol) in DMF (1 mL). To the resulting green
mixture was added 18-crown-6 ether (209 mg, 0.56 mmol), and
the vessel was sealed with a septum, placed in the microwave cavity,
and locked with the pressure device. The microwave source was
then turned on. Constant microwave irradiation (200 W, 2 bar, 120
°C) as well as simultaneous air-cooling (2 bar) was used during
the entire reaction time (10 min). After cooling to room temperature,
the brown mixture was quenched with citrate-sodium hydroxide
buffer (3 mL) and brine (3 mL) and extracted with hexanes (3 ×
10 mL). The combined organic layers were dried over MgSO4,
filtered, concentrated under reduced pressure, and purified by silica
gel flash chromatography (hexanes/Et2O 50:50) to give compound
16 (90 mg, 70%) as a colorless oil: [R]D25 -10.9° (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3) δ 6.62 (s, 2H), 6.58 (s, 2H), 6.35 (dq,
J ) 15.6, 1.2 Hz, 1H), 6.16 (dq, J ) 15.6, 6.5 Hz, 1H), 5.87 (d, J
) 7.2 Hz, 1H), 4.47 (quint, J ) 6.8 Hz, 1H), 3.87 (s, 6H), 3.84 (s,
9H), 1.94 (s, 3H), 1.89 (dd, J ) 6.4, 1.2 Hz, 3H), 1.15 (d, J ) 6.4
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0 (C), 153.1 (4C, C),
136.5 (2C, C), 133.8 (2C, C), 130.9 (CH), 125.1 (CH), 104.6 (2C,
CH), 103.1 (2C, CH), 80.2 (CH), 79.8 (CH), 60.8 (CH3), 56.2 (2C,
CH3), 56.1 (2C, CH3), 21.1 (CH3), 18.3 (CH3), 17.3 (CH3). Anal.
Calcd for C25H32O8: C, 65.20; H, 7.00. Found: C, 65.11; H, 7.18.
(1R,2R)-2-[2,6-Dimethoxy-4-((E)-prop-1-enyl)phenoxy]-1-(3,4,5-
trimethoxyphenyl)propan-1-ol [(-)-Polysphorin] (-)-1. Typical
Procedure.30 To a stirring solution of protected polysphorin (16)
(90 mg, 0.19 mmol) in methanol (5 mL) was slowly added a 1%
methanolic NaOMe solution (2 mL). After 1 h at room temperature,
methanol was removed under vacuum, affording an oily colorless
residue which was purified by silica gel flash chromatography
(hexanes/EtOAc 55:45) providing pure polysphorin (-)-1 (78 mg,
98% yield, corresponding to a 40% overall yield for nine steps
from (-)-5) as a white resin. The enantiomeric excess was 97% as
determined by chiral HPLC analysis (Chiralcel OD-H; hexane/2-
propanol, 90:10, 1.0 mL/min, λ ) 254 nm; 25 °C; major isomer,
tR,R ) 20.30 min; minor isomer, tS,S ) 15.98 min): [R]D25 -100.4°
(c 1.0, CHCl3); [lit.16a [R]D25 -87° (c 0.34, CHCl3)]; CD (hexane/
2-propanol, 90:10) 266 nm (∆ꢀ ) -2.56), 221 nm (∆ꢀ ) -3.32);
1H NMR (600 MHz, CDCl3) δ 6.56 (s, 2H, Ar), 6.54 (s, 2H, Ar),
6.31 (dq, J ) 15.6, 1.2 Hz, 1H, H7′), 6.15 (dq, J ) 15.6, 6.6 Hz,
1H, H8′), 4.93 (br s, 1H, OH), 4.57 (d, J ) 8.4 Hz, 1H, H7), 3.92
(dq, J ) 7.8, 6.0 Hz, 1H, H8), 3.86 (s, 6H, OMe), 3.82 (s, 6H,
OMe), 3.78 (s, 3H, OMe), 1.85 (dd, J ) 6.6, 1.2 Hz, 3H, H9′),
1.19 (d, J ) 6.6 Hz, 3H, H9); 13C NMR (150 MHz, CDCl3) δ
153.3 (2C, C Ar), 153.0 (2C, C Ar), 136.6 (2C, C Ar), 134.1 (2C,
C Ar), 130.9 (C7′), 125.9 (C8′), 104.4 (2C, CH Ar), 103.0 (2C,
CH Ar), 86.7 (C8), 79.6 (C7), 61.0 (OMe), 56.3 (2C, OMe), 56.2
(2C, OMe), 18.6 (C9′), 17.9 (C9). Anal. Calcd for C23H30O7: C,
66.01; H, 7.23. Found: C, 65.89; H, 7.30. HRMS (ESI) m/z [M +
Na]+ calcd for C23H30O7Na 441.1889. Found 441.1875.
was 97% as determined by chiral HPLC analysis (Chiralcel OD-
H; hexane/2-propanol, 90:10, 1.0 mL/min, λ ) 254 nm; 25 °C;
major isomer, tS,S ) 15.98 min; minor isomer, tR,R ) 20.30 min):
[R]D25 +99.3° (c 1.0, CHCl3); [lit.16a mp 107-108 °C; [R]D25 +95°
1
(c 0.8, CHCl3)]; H and 13C NMR data identical to those reported
for its enantiomer (-)-1. Anal. Calcd for C23H30O7: C, 66.01; H,
7.23. Found: C, 66.20; H, 7.16. HRMS (ESI) m/z [M + Na]+ calcd
for C23H30O7Na 441.1889. Found 441.1902.
(1R,2R)-2-[4-Allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxy-
phenyl]propan-1-ol [(-)-Raphidecursinol B] (-)-2.30 The title
compound was prepared from protected raphidecursinol B 17 (93
mg, 0.20 mmol) following the procedure described for (-)-1. After
silica gel flash chromatographic purification (Et2O/petroleum ether
70:30), (-)-raphidecursinol B (-)-2 was obtained (84 mg, 99%
yield, corresponding to a 42% overall yield for the nine-step
25
sequence from (-)-5) as a white resin: [R]D -77.0° (c 1.0,
CHCl3); [lit.16a white solid; mp 81-82 °C; [R]D -58.2° (c 5.26,
25
CHCl3)]; CD (hexane/2-propanol, 90:10) 278 nm (∆ꢀ ) +0.40),
243 nm (∆ꢀ ) -5.28); 1H NMR (600 MHz, CDCl3) δ 6.55 (s, 2H,
Ar), 6.42 (s, 2H, Ar), 5.93 (ddt, J ) 17.4, 10.2, 6.6 Hz, 1H, H8′),
5.10 (dq, J ) 16.8, 1.8 Hz, 1H, H9′), 5.07 (dq, J ) 10.8, 1.2 Hz,
1H, H9′), 4.96 (d, J ) 1.2 Hz, 1H, OH), 4.56 (br d, J ) 8.4 Hz,
1H, H7), 3.91 (dq, J ) 8.4, 6.0 Hz, 1H, H8), 3.84 (s, 6H, OMe),
3.82 (s, 6H, OMe), 3.79 (s, 3H, OMe), 3.32 (bd, J ) 6.6 Hz, 2H,
H7′), 1.18 (d, J ) 6.6 Hz, 3H, H9); 13C NMR (150 MHz, CDCl3)
δ 153.3 (2C, C Ar), 152.8 (2C, C Ar), 137.2 (C8′), 136.6 (C Ar),
136.2 (2C, C Ar), 135.4 (C Ar), 116.4 (C9′), 105.6 (2C, CH Ar),
104.5 (2C, CH Ar), 86.6 (C8), 79.6 (C7), 61.0 (OMe), 56.3 (2C,
OMe), 56.2 (2C, OMe), 40.7 (C7′), 17.9 (C9). Anal. Calcd for
C23H30O7: C, 66.01; H, 7.23. Found: C, 66.16; H, 7.11. HRMS
(ESI) m/z [M + Na]+ calcd for C23H30O7Na 441.1889. Found
441.1899.
(1R,2R)-2-[2-Methoxy-4-((E)-prop-1-enyl)phenoxy]-1-(3,4-
dimethoxyphenyl)propan-1-ol [(-)-Virolin] (-)-3.30 The title
compound was prepared from protected virolin 18 (90 mg, 0.22
mmol) following the procedure described for (-)-1. After silica
gel flash chromatographic purification (hexanes/EtOAc 55:45), (-)-
virolin (-)-3 was obtained (79 mg, 99% yield, corresponding to a
45% overall yield for the nine-step sequence from (-)-5) as a white
25
resin: [R]D -99.6° (c 1.0, CHCl3); [lit.15a for the (1S,2S)-
enantiomer [R]D25 -29.0° (c 1.0, CHCl3)]; CD (hexane/2-propanol,
90:10) 298 nm (∆ꢀ ) -1.57), 290 nm (∆ꢀ ) -1.41), 249 nm (∆ꢀ
1
) -4.98); H NMR (600 MHz, CDCl3) δ 6.7-7.0 (m, 6H, Ar),
6.32 (dq, J ) 15.6, 1.8 Hz, 1H, H7′), 6.12 (dq, J ) 16.2, 6.6 Hz,
1H, H8′), 4.60 (br d, J ) 7.8 Hz, 1H, H7), 4.14 (br s, 1H, OH),
4.07 (dq, J ) 8.4, 6.0 Hz, 1H, H8), 3.89 (s, 3H, OMe), 3.86 (s,
3H, OMe), 3.84 (s, 3H, OMe), 1.85 (dd, J ) 6.6, 1.8 Hz, 3H, H9′),
1.13 (dd, J ) 6.6, 1.2 Hz, 3H, H9); 13C NMR (150 MHz, CDCl3)
δ 151.0 (C Ar), 149.2 (C Ar), 149.0 (C Ar), 146.9 (C Ar), 133.7
(C Ar), 132.7 (C Ar), 130.6 (C7′), 125.1 (C8′), 120.2 (CH Ar),
119.2 (CH Ar), 119.0 (CH Ar), 111.0 (CH Ar), 110.1 (CH Ar),
109.3 (CH Ar), 84.4 (C8), 78.6 (C7), 56.1 (2C, OMe), 55.9 (OMe),
18.6 (C9′), 17.3 (C9). Anal. Calcd for C21H26O5: C, 70.37; H, 7.31.
Found: C, 70.21; H, 7.39. HRMS (ESI) m/z [M + Na]+ calcd for
C21H26O5Na 381.1678. Found 381.1666.
(R)-Methyl 2-[2,6-dimethoxy-4-((E)-prop-1-enyl)phenoxy)pro-
panoate (20). The title compound was prepared from methyl ester
19 (3.0 g, 16.46 mmol) and phenol 13 (8.0 g, 41.15 mmol) following
the procedure described for 16. The use of microwave apparatus
was here replaced by sonication for 1 h. After silica gel flash
chromatographic purification (hexanes/EtOAc 80:20), methyl ester
20 was obtained (4.06 g, 88% yield) as a white solid: mp 43-45
°C; [R]D +42.9° (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ
6.51 (s, 2H), 6.29 (br d, J ) 16.0 Hz, 1H), 6.12 (dq, J ) 15.6, 6.5
Hz, 1H), 4.62 (q, J ) 6.8 Hz, 1H), 3.80 (s, 6H), 3.74 (s, 3H), 1.84
(br d, J ) 6.4 Hz, 3H), 1.51 (d, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 172.6 (C), 153.1 (2C, C), 135.0 (C), 134.0 (C),
130.9 (CH), 125.3 (CH), 102.9 (2C, CH), 77.3 (CH), 56.0 (2C,
(1S,2S)-2-[2,6-Dimethoxy-4-((E)-prop-1-enyl)phenoxy)-1-(3,4,5-
trimethoxyphenyl]propan-1-ol [(+)-Polysphorin] (+)-1. The title
compound was prepared from (R)-methyl lactate (+)-5 (20 µL, 0.20
mmol) following exactly the nine-step sequence described for its
enantiomer (-)-1.
In the last deprotective step, after silica gel flash chromatographic
purification (hexane/EtOAc 55:45), (+)-polysphorin (+)-1 was
obtained (40 mg, 97% yield, corresponding to a 38% overall yield
for nine steps from (+)-5) as a white resin. The enantiomeric excess
25
1
(30) For direct comparison with NMR data reported in the literature, 1H
and 13C chemical shift assignments follow the conventional 8,4′-oxyneo-
lignan numbering. See ref 2.
J. Org. Chem, Vol. 71, No. 22, 2006 8557

Curti et al.
CH3), 51.9 (CH3), 18.3 (2C, CH3). Anal. Calcd for C15H20O5: C,
64.27; H, 7.19. Found: C, 64.13; H, 7.11.
gel flash chromatographic purification (Et2O/petroleum ether 70:
30), 8,4′-oxyneolignan (+)-27 was obtained (1.51 g, 81% yield,
corresponding to a 66% overall yield for five steps from (-)-5)
along with minor amounts of the syn-configured diastereoisomer
(corresponding to (-)-raphidecursinol B (-)-2) (dr ) 85:15).
(1S,2R)-2-[2,6-Dimethoxy-4-((E)-prop-1-enyl)phenoxy]-1-(3,4,5-
trimethoxyphenyl)propan-1-ol (-)-26. Typical Procedure.30
A
solution of aldehyde 23 (800 mg, 3.20 mmol) was dissolved in
THF (8 mL) at room temperature and treated with Ti(OiPr)3Cl (0.76
mL, 3.20 mmol). The resulting yellow mixture was transferred via
cannula dropwise over 30 min to a solution cooled at -85 °C
previously obtained by treatment of 5-bromo-1,2,3-trimethoxyben-
zene (7) (1.97 g, 8.0 mmol) in anhydrous THF (30 mL) with tBuLi
(1.7 M in pentane, 4.7 mL, 8.0 mmol) at -85 °C for 15 min. The
resulting brownish mixture was allowed to stir for 2 h at this
temperature, turning colorless. The reaction mixture was quenched
by the addition of citrate-sodium hydroxide buffer (20 mL) at -85
°C. The reaction mixture was allowed to warm to 25 °C, diluted
with brine (20 mL), and extracted with hexane (3 × 20 mL). The
organic layer was dried (MgSO4), concentrated, and the yellow oily
residue was purified by silica gel flash chromatography (hexanes/
Et2O 50:50) to afford 8,4′-oxyneolignan (-)-26 as a white resin
(1.27 g, 90%, corresponding to a 74% overall yield for five steps
from (-)-5) along with minor amounts of the syn-configured
diastereoisomer (corresponding to (-)-polysphorin (-)-1) (dr )
90:10). The enantiomeric excess of 96% was determined by chiral
HPLC analysis (Chiralcel OD-H; hexane/2-propanol, 95:5, 1.0 mL/
min, λ ) 254 nm; 25 °C; major isomer, tS,R ) 27.19 min; minor
25
Compound (+)-27: a white resin; [R]D +13.5° (c 0.9, CHCl3);
25
[lit.14b [R]D +7.2° (c 1.0, CHCl3)]; CD (hexane/2-propanol, 90:
10) 275 nm (∆ꢀ ) -1.77), 244 nm (∆ꢀ ) -12.40), 230 nm (∆ꢀ
1
) +1.86); H NMR (600 MHz, CDCl3) δ 6.49 (s, 2H, Ar), 6.42
(s, 2H, Ar), 5.93 (ddt, J ) 16.8, 9.6, 6.6 Hz, 1H, H8′), 5.09 (dq, J
) 17.2, 1.8 Hz, 1H, H9′), 5.06 (dq, J ) 9.6, 1.8 Hz, 1H, H9′),
4.74 (d, J ) 1.8 Hz, 1H, H7), 4.29 (qd, J ) 6.0, 2.4 Hz, 1H, H8),
4.12 (br s, 1H, OH), 3.82 (s, 6H, OMe), 3.79 (s, 6H, OMe), 3.76
(s, 3H, OMe), 3.31 (d, J ) 6.6 Hz, 2H, H7′), 1.07 (d, J ) 6.6 Hz,
3H, H9); 13C NMR (150 MHz, CDCl3) δ 153.7 (2C, C Ar), 153.2
(2C, C Ar), 137.2 (C8′), 136.4 (2C, C Ar), 135.9 (2C, C Ar), 116.4
(C9′), 105.6 (2C, CH Ar), 103.1 (2C, CH Ar), 82.4 (C8), 73.3 (C7),
61.0 (OMe), 56.3 (4C, OMe), 40.8 (C7′), 13.1 (C9). Anal. Calcd
for C23H30O7: C, 66.01; H, 7.23. Found: C, 66.10; H, 7.30. HRMS
(ESI) m/z [M + Na]+ calcd for C23H30O7Na 441.1889. Found
441.1904.
(1S,2R)-2-[2-Methoxy-4-((E)-prop-1-enyl)phenoxy]-1-(3,4-
dimethoxyphenyl)propan-1-ol (-)-28.30 The title compound was
prepared from aldehyde 25 (1.04 g, 4.72 mmol) and bromide 8
(2.56 g, 11.80 mmol) following the procedure described for (-)-
26. After silica gel flash chromatographic purification (Et2O/
petroleum ether 55:45), 8,4′-oxyneolignan (-)-28 was obtained
(1.39 g, 82% yield, corresponding to a 69% overall yield for five
steps from (-)-5) along with minor amounts of the syn-configured
diastereoisomer (corresponding to (-)-virolin (-)-3) (dr ) 85:15).
25
isomer, tR,S ) 30.40 min): [R]D -3.06° (c 0.9, CHCl3); CD
(hexane/2-propanol, 90:10) 267 nm (∆ꢀ ) -5.74), 233 nm (∆ꢀ )
1
+7.45); H NMR (600 MHz, CDCl3) δ 6.56 (s, 2H, Ar), 6.49 (s,
2H, Ar), 6.31 (dq, J ) 15.6, 1.8 Hz, 1H, H7′), 6.16 (dq, J ) 15.6,
6.6 Hz, 1H, H8′), 4.75 (d, J ) 3.0 Hz, 1H, H7), 4.30 (qd, J ) 6.6,
3.0 Hz, 1H, H8), 4.07 (br s, 1H, OH), 3.85 (s, 6H, OMe), 3.80 (s,
6H, OMe), 3.77 (s, 3H, OMe), 1.85 (dd, J ) 6.6, 1.8 Hz, 3H, H9′),
1.09 (d, J ) 6.6 Hz, 3H, H9); 13C NMR (150 MHz, CDCl3) δ
153.8 (2C, C Ar), 153.3 (2C, C Ar), 135.8 (2C, C Ar), 134.3 (2C,
C Ar), 130.9 (C7′), 125.1 (C8′), 103.1 (2C, CH Ar), 103.0 (2C,
CH Ar), 82.6 (C8), 73.3 (C7), 61.0 (OMe), 56.3 (2C, OMe), 56.2
(2C, OMe), 18.6 (C9′), 13.0 (C9). Anal. Calcd for C23H30O7: C,
66.01; H, 7.23. Found: C, 65.88; H, 7.12. HRMS (ESI) m/z [M +
Na]+ calcd for C23H30O7Na 441.1889. Found 441.1894.
25
Compound (-)-28: a white resin; [R]D -44.8° (c 0.9, CHCl3);
CD (hexane/2-propanol, 90:10) 289 nm (∆ꢀ ) -1.96), 255 nm
(∆ꢀ ) -4.95), 234 nm (∆ꢀ ) +4.89); 1H NMR (600 MHz, CDCl3)
δ 6.8-7.0 (m, 4H, Ar), 6.79 (M, 2H, Ar), 6.32 (dq, J ) 15.6, 1.2
Hz, 1H, H7′), 6.12 (dq, J ) 16.0, 6.6 Hz, 1H, H8′), 4.81 (d, J )
2.4 Hz, 1H, H7), 4.31 (qd, J ) 6.0, 3.0 Hz, 1H, H8), 3.85 (s, 6H,
OMe), 3.82 (s, 3H, OMe), 3.51 (br s, 1H, OH), 1.84 (dd, J ) 6.6,
1.2 Hz, 3H, H9′), 1.14 (d, J ) 6.0 Hz, 3H, H9); 13C NMR (150
MHz, CDCl3) δ 151.6 (C Ar), 149.0 (C Ar), 148.3 (C Ar), 145.8
(C Ar), 133.8 (C Ar), 132.7 (C Ar), 130.7 (C7′), 125.2 (C8′), 120.0
(CH Ar), 119.2 (CH Ar), 118.6 (CH Ar), 111.0 (CH Ar), 109.6
(CH Ar), 109.5 (CH Ar), 82.6 (C8), 73.7 (C7), 56.1 (2C, OMe),
56.0 (OMe), 18.6 (C9′), 13.6 (C9). Anal. Calcd for C21H26O5: C,
70.37; H, 7.31. Found: C, 70.42; H, 7.39. HRMS (ESI) m/z [M +
Na]+ calcd for C21H26O5Na 381.1678. Found 381.1687.
(1R,2S)-2-[2,6-Dimethoxy-4-((E)-prop-1-enyl)phenoxy]-1-(3,4,5-
trimethoxyphenyl)propan-1-ol (+)-26. The title compound was
prepared from (R)-methyl lactate (+)-5 (20 µL, 0.21 mmol)
following exactly the five-step sequence described for its enantiomer
(-)-26. In the last aryl addition step, after silica gel flash
chromatographic purification (hexanes/Et2O 50:50), 8,4′-oxyneo-
lignan (+)-26 was obtained (62 mg, 88% yield, corresponding to
a 70% overall yield for five steps from (+)-5) as a white resin.
The enantiomeric excess of 97% was determined by chiral HPLC
analysis (Chiralcel OD-H; hexane/2-propanol, 95:5, 1.0 mL/min,
λ ) 254 nm; 25 °C; major isomer, tR,S ) 30.45 min; minor isomer,
tS,R ) 27.22 min): [R]D25 +3.6° (c 1.0, CHCl3); 1H and 13C NMR
data are identical to those reported for its enantiomer (-)-26. Anal.
Calcd for C23H30O7: C, 66.01; H, 7.23. Found: C, 65.98; H, 7.15.
HRMS (ESI) m/z [M + Na]+ calcd for C23H30O7Na 441.1889.
Found 441.1901.
Acknowledgment. We thank the Ministero dell’Istruzione,
dell’Universita` e della Ricerca (MIUR, COFIN 2004 and FIRB
2001) for financial support. We also thank the Centro Interfa-
colta` Misure “G. Casnati” (Universita` di Parma) for instrumental
facilities.
Supporting Information Available: Experimental procedures
and spectral data for compounds 6, 10, 12, 15, 17-19, 21-25,
NMR data (Table S1), and copies of 1H and 13C NMR spectra for
compounds (-)-1, (-)-2, (-)-3, (-)-26, (+)-27, and (-)-28. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(1S,2R)-2-(4-Allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethox-
yphenyl)propan-1-ol (+)-27.30 The title compound was prepared
from aldehyde 24 (1.12 g, 4.47 mmol) and bromide 7 (2.76 g, 11.17
mmol) following the procedure described for (-)-26. After silica
JO061521T
8558 J. Org. Chem., Vol. 71, No. 22, 2006