First enantioselective synthesis of (-)-talaumidin, a neurotrophic diaryltetrahydrofuran-type lignan

Article abstract of DOI:10.1016/j.tetlet.2006.04.006

The first enantioselective total synthesis of a neurotrophic (-)-talaumidin (1) is described in 16 steps from 4-benzyloxy-3-methoxybenzaldehyde in ca. 10.7% overall yield, and thus has established the absolute configurations of the four stereogenic center

Full text of DOI:10.1016/j.tetlet.2006.04.006

Tetrahedron Letters 47 (2006) 3979–3983
First enantioselective synthesis of (ꢀ)-talaumidin, a neurotrophic
diaryltetrahydrofuran-type lignan
Tomoyuki Esumi, Daisuke Hojyo, Haifeng Zhai and Yoshiyasu Fukuyama*
Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho,
Tokushima 770-8514, Japan
Received 13 March 2006; revised 27 March 2006; accepted 7 April 2006
Available online 2 May 2006
Abstract—The first enantioselective total synthesis of a neurotrophic (ꢀ)-talaumidin (1) is described in 16 steps from 4-benzyloxy-3-
methoxybenzaldehyde in ca. 10.7% overall yield, and thus has established the absolute configurations of the four stereogenic centers
C-2 ꢁ C-5 of 1. The synthesis features the construction of the two successive chiral centers C-2 and C-3 by Evans asymmetric anti-
aldol protocol as well as of the two chiral centers C-4 and C-5 in a highly stereocontrolled fashion by hydroboration/oxidation and
epimerization, followed by Friedel–Crafts arylation.
Ó 2006 Elsevier Ltd. All rights reserved.
With the increase in the advanced age population, neuro-
degenerative disorders, such as Alzheimer’s and Par-
kinson’s disease, have been emerging as a major social
issue, thus resulting in a great demand of new therapeu-
tic drugs to prevent these diseases.1 In this context, neuro-
trophins (e.g., NGF and BDNF), which play key roles
in the prevention of neuronal death as well as in the
maintenance and growth of neurons, make hopeful
agents for the treatment of neurodegenerative disorders.
However, neurotrophins are not effective in clinical
trails, mostly because they are not able to pass through
the blood–brain barrier due to the peptidyl properties.
Our continuing efforts on exploring for small-mole-
cule-based natural products with neurotrophic proper-
ties led to the discovery of (ꢀ)-talaumidin (1) from
Brazilian Aristolochia arcuata Masters.2 Talaumidin
and its analogues exhibit significant neurite outgrowth-
promoting and neuroprotective activities in the primary
cultured rat cortical2 and additionally in the hippo-
campal neurons, as shown in Figure 1. Compound 1,
belonging to a diaryltetrahydrofuran-type lignan, pos-
sesses the four continuous stereogenic centers existing
on a tetrahydrofuran ring. The relative configurations
of 1 have been defined as (2S*,3S*,4S*,5S*) on the basis
of NOESY spectrum,3 but its absolute configuration has
not been determined. These promising biological activi-
ties and selective preparation of the possible stereoiso-
mers with regard to the four stereogenic centers of 1
make it an attractive synthetic target. Although a few
elegant enantioselective syntheses of 2,3-diaryl-3,4-di-
alkyltetrahydrofuran lignans, such as (+)- and/or (ꢀ)-
virgatusin, were already reported,4–6 general methodology
for synthesizing their possible stereoisomers has
remained unexplored. Herein, we report the first enan-
tioselective total synthesis of (2S,3S,4S,5S)-1, in which
we apply a flexible and reliable synthetic way involving
Evans asymmetric aldol reaction as well as stereocon-
trolled hydroboration and Friedel–Crafts arylation to
construct the four continuous chiral centers on the tetra-
hydrofuran ring.
Our synthetic plan is outlined in Scheme 1. Considering
all the possible stereoisomers of 1, we envisioned that
the synthesis would start with the Evans asymmetric
aldol reaction7,8 between 3,4-dialkyloxybenzaldehyde 2
and (S)-4-benzyl-3-propionyl-2-oxazolidinone 3 to give
(2S,3S)-aldol adduct 4, which would be converted to
olefin 5. Although the next hydroboration/oxidation of
5 would be anticipated to give rise to the undesirable
(4R)-isomer 6, more stable (4S)-lactone 7b would be
obtained by the epimerization of C-4 in 7a, which is
readily derived from 6. In the final stage, the diastereo-
selective Friedel–Crafts-type arylation toward the
five-membered oxocarbenium cation intermediate 9
generated from acetal 8 would be employed for the
installation of (S)-configuration on the C-5 position.9,10
*
Corresponding author. Tel.: +81 88 622 9611x5911; fax: +81 88 655
3051; e-mail: fukuyama@ph.bunri-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.006

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T. Esumi et al. / Tetrahedron Letters 47 (2006) 3979–3983
Figure 1. Neurite outgrowth-promoting activity of talaumidin (1) in the primary cultured rat hippocampal neurons and structure of 1. After 24 h pre-
culture in NB/B27 medium, rat hippocampal neurons (18 days) were treated with talaumidin and basic fibroblast growth factor (bFGF) for 72 h, and
then fixed for anti-tau immunochemical staining. A, B are representative morphological changes, respectively, in control (0.5% EtOH) and 10 lM
talaumidin. C is the quantitative analysis of the primary neurite outgrowth, and the primary neurite was defined as the longest process. Data were
expressed as means SEM, * P <0.05; *** P <0.001, and compared with control.
According to the plan illustrated in Scheme 1, the synthe-
sis of (ꢀ)-(2S,3S,4S,5S)-talaumidin (1) began with the
recently improved Evans asymmetric anti-aldol reaction
65% yield with low diastereoselectivity (entry 1),
whereas a relatively bulky disiamylborane improved
the diastereoselectivity up to 97%, but the conversion
yield was still unsatisfactory (entry 2). The best result
was accomplished by using 9-BBN-H (entry 3), thereby
giving rise to the primary alcohol 15 with high diastereo-
selectivity (de >99%) in 74% yield. This high stereo-
selectivity can be rationalized by transition state Ts
matched to a Cram rule.16 Oxidation of the primary
alcohol 15 with PDC and then NaClO4/NaH2PO4
yielded carboxylic acid, which was converted to the
c-lactone 16a by deprotection of the TBS group in
72% yield over three steps.
8
catalyzed by MgCl2 (Scheme 2). 4-Benzyloxy-3-meth-
oxybenzaldehyde 2a was reacted with (S)-4-benzyl-3-
propionyl-2-oxazolidinone 3 in the presence of TMSCl,
Et3N, and 10 mol % of MgCl2 to provide (2S,3S)-aldol
adduct 11 in modest yield with high diastereoselectivity
(de = 98%). Then, protection of the hydroxy group as
TBS ether with TBSOTf, followed by reductive removal
of the oxazolidinone using LiBH4,11 gave the primary
alcohol 12 in high yield. The 2,3-anti relative stereochem-
istry for 12 was confirmed by applying the Rychnovsky–
Evans rule12,13 to the acetonide of 12. Methyl ketone 13
was derived from 12 in three steps: by Swern oxidation,
reaction of the formed aldehyde with MeMgBr, and then
by repeating Swern oxidation. To avoid the epimeriza-
tion at the C-3 position, 13 was subjected to the Tebbe
olefination14 without purification, giving rise to the meth-
ylene compound 14 in good yield. The absolute configu-
ration of the C-2 position was defined as 2S by applying
modified Mosher method15 to (+) and (ꢀ)-MTPA esters
prepared from the secondary alcohol obtained by the
removal of the TBS group of 14.
Although the newly generated chiral center C-4 was
opposite to the desired natural 4S, the C-4 chirality
could be readily inversed upon treatment of 16a with
MeONa in MeOH to (4S)-c-lactone 16b.17 The subse-
quent DIBAL reduction of 16b, followed by treatment
of methylorthoformate and p-toluenesulfonic acid in
MeOH, yielded five-membered acetal 17 as an anomeric
mixture in 84%. With acetal 17 set up for the crucial Fri-
edel–Crafts type arylation to construct the remaining
chiral center C-5, we examined a few acidic conditions.
In consequence, we found that upon treatment of 17
with 1,2-methylenedioxybenzene 10 (7 equiv) and SnCl4
(1 equiv) in CH2Cl2 at ꢀ78 °C for 13 h, the reaction
Next, stereoselective hydroboration of 14 was
attempted. As shown in Table 1, BH3ÆSMe2 gave 15 in

T. Esumi et al. / Tetrahedron Letters 47 (2006) 3979–3983
3981
O
O
N
O
OH
O
OR4
O
R3
R1O
R2O
CHO
R1O
R2O
R1O
R2O
3
N
O
R7
2
5
4
OR4
4R
4S
R1O
R2O
OH
R2BH/H2O2
base
R1O
R2O
R1O
R2O
4R
O
O
O
7a
O
6
7b
O
O
Lewis acid
10
R1O
R2O
R1O
R2O
OR5
(−)-(2S,3S,4S,5S)-1
O
O
(R1 = Me, R2 = H)
8
9
Scheme 1. Synthetic plan of (ꢀ)-1.
O
OH
O
O
O
MeO
BnO
CHO
MeO
BnO
3S
a
b,c
2S
N
O
N
O
+
91% (2 steps)
68%
Bn
Bn
2a
11
3b
TBSO
TBSO
TBSO
MeO
BnO
MeO
BnO
MeO
BnO
d,e,d
f
O
OH
60% (4 steps)
12
13
14
Scheme 2. Synthesis of 14. Reagents and conditions: (a) 3, 10 mol % MgCl2, TMSCl, Et3N, EtOAc, rt, 16 h; ii. HF/py/MeCN (1:3:5), 0 °C,
overnight; (b) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 5 min; (c) LiBH4, MeOH, Et2O, rt, 1 h; (d) (COCl)2, DMSO, CH2Cl2, ꢀ78 °C, then Et3N, 0 °C; (e)
CH3MgBr, THF, 0 °C, 11 h; (f) Cp2TiCH2AlClMe2, THF, ꢀ40 °C ! rt, 4.5 h.
Table 1. Diastereoselectivity for hydroboration/oxidation of 14
TBSO
RL
condition
MeO
BnO
OH
4R
Me
Me
14
H
R2B
H
15
Ts
Entry
Condition
Yield (%)
de (%)
1
2
3
BH3ÆSMe2, THF, 0 °C, 5 h, then 30% H2O2, 3 M NaOH, rt
Sia2BH, THF, 0 °C, rt, 3 h, then 30% H2O2, 3 M NaOH, rt
9BBN-H, THF, 0 °C, rt, 16 h, then 30% H2O2, 3 M NaOH, rt
64
60
74
53
97
>99
smoothly proceeded to give only the desired (5S)-18 in
89% yield along with 2% of talaumidin (1). The relative
stereochemistry with regard to C-2 ꢁ C-5 was estab-
lished by NOESY correlation. This perfect b-facial
selectivity is due to a steric interaction between the
C-4 methyl group and the approaching nucleophile 10.

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T. Esumi et al. / Tetrahedron Letters 47 (2006) 3979–3983
1M MeONa
MeOH, rt.
Me
H
Me
H
Me
4R
H
a-c
d
4S
MeO
BnO
OMe
15
O
O
O
72% (3 steps)
O
O
H
Me
Ar
Ar
H
H
17
16b
(96%, 4R : 4S = 6 : 94)
16a
Ar = 4-benzyloxy-3-methoxyphenyl
NOESY
O
10
Me
O
MeO
BnO
10
O
O
O
+
(–)-(2S,3S,4S,5S)-1
H
O
SnCl4, CH2Cl2
-78 °C, 13 hr
Ar
Me
(2%)
9
18 (89%)
77%
e
Scheme 3. Completion of the total synthesis of (ꢀ)-(2S,3S,4S,5S)-1: (a) PDC, DMF, rt, 2 h; (b) NaClO2, NaH2PO4, (CH3)2C@C(H)CH3, t-BuOH/
H2O, rt, 1 h; (c) HF/py/MeCN (1:3:5), 0 °C, overnight; (d) DIBAL, CH2Cl2, ꢀ78 °C, 1 h, then (CH3O)3CH, TsOHÆH2O, MeOH, rt, 10 h; (e) H2/
Pd(OH)2, EtOH, rt, 10 min.
4. Yoda, H.; Mizutani, M.; Takabe, K. Tetrahedron Lett.
1999, 40, 4701–4702.
5. Yamaguchi, S.; Okazaki, M.; Akiyama, K.; Sugahara, T.;
Kishida, T.; Kashiwagi, T. Org. Biomol. Chem. 2005, 3,
1670–1675.
Finally, debenzylation of 18 with Pd(OH)2 in EtOH fur-
nished (ꢀ)-(2S,3S,4S,5S)-1 in 77% yield. All the spectro-
scopic data (1H NMR, 13C NHR, IR, HRMS, [a]D, CD)
of the synthetic 1 were identical with those of natural
talaumidin.18 Herein, we have achieved the first enantio-
selective total synthesis of (ꢀ)-1 and have determined
the absolute configuration of (ꢀ)-talaumidin (1) as
(2S,3S,4S,5S) (Scheme 3).
6. Akindele, T.; Marsden, S. P.; Cumming, J. G. Org. Lett.
2005, 7, 3685–3688.
7. (a) Evans, D. A.; Rieger, D. L.; Biodeau, M. T.; Urpi, F.
J. Am. Chem. Soc. 1991, 113, 1047–1049; (b) Evans, D. A.;
Nelson, J. V.; Taber, T. Top. Stereochem. 1982, 13, 111–
115; (c) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68,
83–91.
8. Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W.
J. Am. Chem. Soc. 2002, 124, 392–393.
9. Smith, D. M.; Tran, M. B.; Woerpel, K. A. J. Am. Chem.
Soc. 2003, 125, 14149–14152.
10. (a) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40–42; (b)
Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893–
3901.
11. Penning, T. D.; Duric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth.
Commun. 1990, 20, 307.
In conclusion, we have achieved the first enantioselective
total synthesis of (ꢀ)-(2S,3S,4S,5S)-talaumidin (1), a
neurotrophic 2,5-diaryl-3,4-dimethyltetrahydrofuran, in
a highly efficient and stereocontrolled fashion requiring
linear 16 steps in 10.7% overall yield. This synthetic
methodology opens the way to prepare other stereoiso-
mers of talaumidin, which will allow us to study the
structure–activity relationship of 1 in detail. Further
synthetic studies on stereoisomers of 1 are now in
progress.
12. Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945–948.
Acknowledgements
13. Evans, D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett.
1990, 31, 7099–7100.
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan (16510172),
the Open Research Center Fund from the Promotion
and Mutual Aid Corporation for Private Schools of
Japan and the Sasakawa Scientific Research Grant from
The Japan Science Society (T.E.; 16-217).
14. (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am.
Chem. Soc. 1978, 100, 3611–3613; (b) Clawson, L.;
Buchwald, S. L.; Grubbs, R. H. Tetrahedron Lett. 1984,
25, 5733–5736. The normal Wittig reaction using triphen-
ylphosphonium methylide gave 14 in 13%.
15. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092–4096.
16. Houk, K. N.; Nelson, G. Rondan; Wu, Y.-D.; Metz, J. T.;
Paddon-Row, M. N. Tetrahedron 1984, 40, 2257–2274.
17. Although 16a and 16b were inseparable, all minor
components could be removed by silica gel column
chromatography after the arylation.
References and notes
1. Mattson, M. P. Nat. Rev. Mol. Cell Biol. 2000, 1, 120–129.
2. (a) Zhai, H.; Nakatsukasa, M.; Mitsumoto, Y.; Fuku-
yama, Y. Planta Med. 2004, 70, 598–602; (b) Zhai, H.;
Inoue, T.; Moriyama, M.; Esumi, T.; Mitsumoto, Y.;
Fukuyama, Y. Biol. Pharm. Bull. 2005, 28, 289–293.
3. Vieira, L. M.; Kijjoa, A.; Silva, A. H. S.; Mondranondra,
I.-O.; Herz, W. Phytochemistry 1998, 48, 1079–1081.
16
18. (ꢀ)-(2S,3S,4S,5S)-1: ½aꢂD ꢀ85.2 (c 0.43, CHCl3); CD
(CHCl3) De ꢀ128.0 (238 nm), ꢀ25.4 (287 nm); HR EIMS
1
calcd 342.1467 for C20H22O5; found 342.1471; H NMR
(300 MHz, CDCl3) d 1.02 (d, J = 5.8 Hz, 3H), 1.04 (d,
J = 5.8 Hz, 3H), 1.73–1.78 (m, 2H), 3.92 (s, 3H), 4.61 (d,
J = 9.1 Hz, 2H), 5.57 (s, 1H), 5.95 (s, 2H), 6.76–6.94 (m,

T. Esumi et al. / Tetrahedron Letters 47 (2006) 3979–3983
3983
6H); 13C NMR (75 MHz, CDCl3) d 147.8, 147.0, 136.6,
J = 5.8 Hz, 3H), 1.06 (d, J = 5.8 Hz, 3H), 1.73–1.78 (m,
2H), 3.93 (s, 3H), 4.63 (d, J = 9.1 Hz, 2H), 5.57 (s, 1H),
5.96 (s, 2H), 6.76–6.94 (m, 6H); 13C NMR (75 MHz,
CDCl3) d 147.8, 147.0, 136.6, 134.1, 119.7, 119.4, 114.0,
108.5, 107.9, 106.6, 101.0, 88.4, 88.2, 56.0, 51.2, 50.9,
13.8.2a
134.1, 119.7, 119.4, 114.0, 108.5, 107.9, 106.6, 101.0, 88.4,
16
88.2, 56.0, 51.2, 50.9, 13.8. Natural (ꢀ)-1: ½aꢂD ꢀ81.8 (c
0.43, CHCl3); CD (CHCl3) De ꢀ36.2 (238 nm), ꢀ7.2
(287 nm); HR EIMS calcd 342.1467 for C20H22O5; found
342.1472; 1H NMR (300 MHz, CDCl3)
d 1.04 (d,