First asymmetric synthesis of new diarylheptanoids, renealtin A and B, with a tetrahydrofuran ring

Article abstract of DOI:10.1055/s-2006-948168

An efficient and convenient process is described for the first preparation of a new diarylheptanoid, renealtin A, isolated from the seeds of the Brazilian medicinal plant Renealmia exaltata. The key trisubstituted tetrahydrofuran ring was constructed thro

Full text of DOI:10.1055/s-2006-948168

LETTER
2031
First Asymmetric Synthesis of New Diarylheptanoids, Renealtin A and B,
with a Tetrahydrofuran Ring
First
A
symmetr
o
ic Synthesis
m
of
N
ew Diarylhepta
o
noids ki Katoh, Daisuke Matsuura, Nobuyuki Mase, Kunihiko Takabe, Hidemi Yoda*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Fax +81(53)4781150; E-mail: tchyoda@ipc.shizuoka.ac.jp
Received 26 April 2006
and 13C NMR spectra assisted with 2D NMR experi-
ments.10 Since Brazilian medicinal plants have proven to
be a rich source of compounds that might be useful for the
development of new pharmaceutical agents,11 these two
Abstract: An efficient and convenient process is described for the
first preparation of a new diarylheptanoid, renealtin A, isolated
from the seeds of the Brazilian medicinal plant Renealmia exaltata.
The key trisubstituted tetrahydrofuran ring was constructed through
Lewis acid mediated stereoselective allylation of the lactol deriva- compounds would capture hereafter the interest as attrac-
tive by featuring the elaboration of the functionalized homochiral
tive and useful targets for synthesis. With these consider-
lactone derived from L-tartaric acid. The synthesis of the other
minor stereoisomer, renealtin B, was also established.
ations in mind, we wish to communicate the details of the
first and short asymmetric synthesis of renealtin A (5)
accompanied with the preparation of the minor stereo-
isomer, renealtin B (6), by means of requisite stereoselec-
Key words: natural product, diarylheptanoid, trisubstituted tetra-
hydrofuran, C2-imide, tartaric acid
tive allylation of the lactol intermediate elaborated from
L-tartaric acid derived C2-imide.
Substituted tetrahydrofurans feature in many biologically
potent natural products such as annonaceous acetoge-
O
pheromones,5 and epoxy lipids.6 To fully exploit the op-
HO
nins,1 macrolides,2 cytotoxic polyethers,3 marine toxins,4
H
portunities offered by these compounds, they require ac-
O
O
O
cess to synthetic methodology capable of targeting chiral
substituted tetrahydrofurans. In this connection many
strategies have been explored in developing synthetic
routes to these compounds and the related natural prod-
ucts. However, most methods were concerned with the
construction of 2,5-disubstituted furans, while few fo-
cused on tri- and tetrasubstituted derivatives,7 although
the synthesis of this type of compounds includes interest-
ing and often unsolved problems of stereocontrol. In spite
of these facts, they serve as good templates for the con-
struction of pharmacologically important furanoid groups
and exhibit various degrees of potency and specificity.7
We have also recently succeeded in the development of
novel and stereoselective asymmetric syntheses of biolog-
ically active furanoid natural products such as sesaminone
(1),8a epoxy lipid (2)8b (trisubstituted tetrahydrofurans,
respectively), virgatusin (3)8c and goniothalesdiol (4)8d
(tetrasubstituted tetrahydrofuran, respectively) employing
Lewis acid induced deoxygenation of the lactol
precursors9 exploited in this laboratory (Figure 1).
O
O
O
sesaminone (1)
H
OH
HO
CH2=CH(CH2)7
(CH2)4Me
H
H
epoxy lipid (2)
Me
OMe
OMe
O
O
O
O
H
H
OMe
virgatusin (3)
HO
MeOOC
O
H
H
OH
On the other hand, new diarylheptanoids, renealtin A (5)
and B (6), possessing a characteristic substitution pattern
such as a trisubstituted tetrahydrofuran ring have been iso-
lated in 2002 from the seeds of the Brazilian medicinal
plant Renealmia exaltata (‘Pacová-catinga’),10 a member
of the Zingiberaceae family. The relative and absolute ste-
goniothalesdiol (4)
OH
7
HO
3
O
1
MeO
HO
OMe
5
O
H
H
renealtin A (5): H-3α
renealtin B (6): H-3β
1
reochemistry of 5 and 6 were determined from H NMR
Figure 1
SYNLETT 2006, No. 13, pp 2031–2034
1
7
.0
8
.2
0
0
6
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-948168; Art ID: U04906ST
© Georg Thieme Verlag Stuttgart · New York

2032
T. Katoh et al.
LETTER
OH
As shown in Scheme 1, N-benzyl C2-imide 8 obtained
from L-tartaric acid (7) was treated with benzyl Grignard
derivative prepared in situ followed by reduction of the a-
hydroxylactam intermediate with NaBH4 according to our
procedure,12 to lead to the corresponding hydroxyamide 9
in good yield with exclusive stereoselectivity.12a Accom-
panying formation of the other stereoisomer 10 was not
observed at all (determined by 13C NMR and HPLC anal-
ysis). Then, 9 was cyclized under acidic conditions to give
the dihydroxylactone 11 almost quantitatively.13 It is
particularly important to note that raising the reaction
temperature for cyclization over 60 °C brought about un-
desirable racemization at C-5 of 11. Next, the a-hydroxy
function of 11 thus obtained was submitted regioselec-
tively to elimination reaction through phenylthiono-
carbonate formation followed by deoxygenation under
radical conditions14 to afford the monohydroxylactone,
which was successively protected with two different
groups (Bn and TBDPS), providing the desired com-
pounds 12a and 12b, respectively.
Bn
N
ref. 12
a
TBSO
HOOC
COOH
O
O
OH
8
7
OTBS
O
OTBS
OMe
OBn
BnHN
+
TBSO
OH
O
OTBS
9
OMe
OBn
BnHN
TBSO
OH
b
10
HO
RO
O
O
MeO
BnO
MeO
BnO
c
O
O
5
H
H
OH
11
12a: R = Bn
12b: R = TBDPS
With the compounds 12 in hand, we further prompted our
research on the synthesis of 5 as shown in Scheme 2.
Thus, benzyl-protected 12a was initially effected with
DIBAL-H reduction at low temperature to afford the lac-
tol intermediate 13a, which was readily treated with allyl-
trimethylsilane in the presence of BF3·OEt2 at the same
temperature, giving the corresponding allylated tetra-
hydrofuran derivative 14a with high stereoselectivity
(14a:15a = 92:8, determined by 1H NMR),15 but in unsat-
isfactory overall yield. After investigation of the reaction
conditions, the use of TBDPS-protected 12b changed the
results and gave the desired isomer 14b16 in good yield as
well as fortunately with the same high stereoselectivity as
mentioned above.17 Then, the double bond of 14b (con-
taining 15b) was cleaved via dihydroxylation with OsO4
to the aldehyde 16, which was successively submitted to
coupling reaction with aryllithium reagent18 to afford the
crude alcohols containing the desired functional groups.
These two stereoisomers derived from 14b and 15b were
easily separated and purified after the next two steps of
tetrapropylammonium perruthenate (TPAP) oxidation
followed by desilylation, leading to the renealtin A di-
benzylether derivative 17, [a]D24 +16.0 (c 1.01, CH2Cl2),
together with the minor isomer, renealtin B derivative 18,
Scheme 1 Reagents and conditions: (a) i, p-BnO(m-MeO)
C6H3CH2Cl, Mg, THF; ii, NaBH4, EtOH; 64% (two steps); (b) 3%
HCl, 1,4-dioxane, 40–50 °C; quant.; (c) i, PhOC(S)Cl, DMAP, pyri-
dine, MeCN; ii, Bu3SnH, AIBN, toluene, reflux; 73% (two steps); iii,
BnBr, Ag2O, EtOAc; 37% (12a); TBDPSCl, imidazole, CH2Cl2; 81%
(12b).
verifies the structure proposed in the literature for these
compounds. This will be widely applicable to the syn-
thesis of other important polysubstituted tetrahydrofuran
natural products.
Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science.
References and Notes
(1) (a) Zeng, L.; Ye, Q.; Oberlies, N. H.; Shi, G.; Gu, Z.-M.; He,
K.; McLaughlin, J. L. Nat. Prod. Rep. 1996, 13, 275.
(b) Cavé, A.; Figadère, B.; Laurens, A.; Cortes, D. In
Progress in the Chemistry of Organic Natural Products,
Vol. 70; Herz, W., Ed.; Springer-Verlag: Wien/New York,
1997, 81.
(2) (a) Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y.;
Huang, S. Tetrahedron Lett. 1995, 36, 709. (b) Sakai, R.;
Rinehart, K. L. J. Nat. Prod. 1995, 58, 773. (c) Wipf, P.;
Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(3) (a) Matsuo, Y.; Suzuki, M.; Masuda, M. Chem. Lett. 1995,
1043. (b) Morte, M. Tetrahedron Lett. 1997, 38, 3137.
(c) Koert, U. Angew. Chem., Int. Ed. Engl. 1995, 34, 298.
(4) Faulkner, D. J. Nat. Prod. Rep. 1997, 14, 259.
(5) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H. F.;
Yasumoto, T. Tetrahedron Lett. 1995, 36, 7093.
(6) (a) Boukouvalas, J.; Fortier, G.; Radu, I.-I. J. Org. Chem.
1998, 63, 916. (b) Fernández de la Pradilla, R.; Montero, C.;
Priego, J.; Martínez-Cruz, L. A. J. Org. Chem. 1998, 63,
9612. (c) Capon, R. J.; Barrow, R. A.; Skene, C.; Rochfort,
S. Tetrahedron Lett. 1997, 38, 7609. (d) Capon, R. J.;
Barrow, R. A. J. Org. Chem. 1998, 63, 75. (e) Capon, R. J.;
Barrow, R. A.; Rochfort, S.; Jobling, M.; Skene, C.; Lacey,
23
[a]D +23.2 (c 1.00, CH2Cl2), respectively. Finally, re-
moval of the two benzyl groups in 17 and 18 was carefully
performed with 5% Pd/C in EtOAc to accomplish the first
23
syntheses of the natural type of renealtin A (5), [a]D
23
+22.0 (c 0.12, MeOH) {natural 5, [a]D +22.4 (c 0.40,
MeOH)10} and B (6), [a]D23 +76.2 (c 0.065, MeOH) {nat-
ural 6, [a]D +73.5 (c 0.15, MeOH)10} in 85% and 91%
23
yields, respectively. The spectral data of synthetic (+)-5
and (+)-6 were completely identical to those of the re-
ported natural products.10
In summary, this work constitutes the first and efficient
asymmetric synthesis of the diarylheptanoid natural prod-
uct containing a tetrahydrofuran ring, renealtin A as well
as the minor isomer, renealtin B, from L-tartaric acid and
Synlett 2006, No. 13, 2031–2034 © Thieme Stuttgart · New York

LETTER
First Asymmetric Synthesis of New Diarylheptanoids
2033
RO
RO
O
MeO
BnO
O
MeO
BnO
OH
O
a
H
H
13a: R = Bn
12a: R = Bn
13b: R = TBDPS
12b: R = TBDPS
RO
O
MeO
RO
H
O
MeO
BnO
b
+
H
BnO
H
H
14a: R = Bn
14b: R = TBDPS
15a: R = Bn
15b: R = TBDPS
(14a : 15a = 92:8)
(14b : 15b = 92:8)
TBDPSO
H
O
MeO
BnO
d
c
CHO
14b
H
+
16
H-3β (15b)
OBn
OMe
7
HO
3
1
O
MeO
BnO
e
5
O
17: H-3α
18: H-3β
H
H
OH
HO
O
MeO
HO
OMe
O
H
H
renealtin A (5): H-3α
renealtin B (6): H-3β
Scheme 2 Reagents and conditions: (a) DIBAL-H, THF, –78 °C to –50 °C; 46% (13a); 95% (13b); (b) allylSi(CH3)3, BF3·OEt2, CH2Cl2,
–80 °C; 40% (14a + 15a); 87% (14b + 15b); (c) i, OsO4, NMO, acetone–H2O (1:1); 95%; ii, NaIO4, THF–H2O (1:1); 93% (two steps); (d) BuLi,
p-BnO(m-CH3O)C6H3Br, THF–Et2O (5:1); ii, TPAP, NMO, MS 4Å, CH2Cl2; iii, Bu4NF, THF; 52% (17; three steps); 4.5% (18; three steps);
(e) H2, Pd/C EtOAc; 85% (5); 91% (6).
E.; Gill, J. H.; Friedel, T.; Wadsworth, D. Tetrahedron 1998,
54, 2227. (f) Wang, Z.-M.; Shen, M. J. Org. Chem. 1998, 63,
1414. (g) Mori, Y.; Sawada, T.; Furukawa, H. Tetrahedron
Lett. 1999, 40, 731; and references cited therein.
(7) (a) Stevens, D. R.; Whiting, D. A. J. Chem. Soc., Perkin
Trans. 1 1992, 633. (b) Mitra, J.; Mitra, A. K. J. Chem. Soc.,
Perkin Trans. 1 1992, 1285. (c) Maiti, G.; Adhikari, S.;
Roy, S. C. J. Chem. Soc., Perkin Trans. 1 1995, 927.
(d) Yoshida, S.-I.; Ogiku, T.; Ohmizu, H.; Iwasaki, T. J.
Org. Chem. 1997, 62, 1310. (e) Chen, I.-S.; Chen, J.-J.;
Duh, C.-Y.; Tsai, I.-L. Phytochemistry 1997, 45, 991.
(f) Garia, C.; Martín, T.; Martín, V. S. J. Org. Chem. 2001,
66, 1420. (g) Chakraborty, T. K.; Das, S.; Raju, T. V. J. Org.
Chem. 2001, 66, 4091. (h) Gadikota, R. R.; Callam, C. S.;
Lowary, T. L. J. Org. Chem. 2001, 66, 9046.
(8) (a) Yoda, H.; Kimura, K.; Takabe, K. Synlett 2001, 400.
(b) Yoda, H.; Maruyama, K.; Takabe, K. Tetrahedron:
Asymmetry 2001, 12, 1403. (c) Yoda, H.; Mizutani, M.;
Takabe, K. Tetrahedron Lett. 1999, 40, 4701. (d) Yoda, H.;
Nakaseko, Y.; Takabe, K. Synlett 2002, 1532.
(9) Yoda, H.; Mizutani, M.; Takabe, K. Heterocycles 1998, 48,
679.
(10) Sekiguchi, M.; Shigemori, H.; Ohsaka, A.; Kobayashi, J. J.
Nat. Prod. 2002, 65, 375.
(12) (a) Yoda, H.; Shirakawa, K.; Takabe, K. Tetrahedron Lett.
1991, 32, 6771. (b) Yoda, H.; Shimojo, T.; Takabe, K.
Synlett 1999, 1969.
(13) Absolute stereochemistry of obtained 11 was easily
determined by comparing its chemical shifts of 1H NMR and
13C NMR spectral data with those of our preceding
compounds.12
Spectral Data for 11.
[a]D25 +73.0 (c 1.00, MeOH). 1H NMR (CDCl3): d = 7.31–
7.15 (m, 5 H), 6.69–6.59 (m, 2 H), 4.94 (s, 2 H), 4.66 (br, 1
H), 4.62 (dd, 1 H, J = 11.7, 7.3 Hz), 4.26 (br t, 1 H), 4.03 (br
s, 2 H), 3.69 (s, 3 H), 2.97 (dd, 1 H, J = 14.7, 4.4 Hz), 2.72
(dd, 1 H, J = 14.7, 7.9 Hz). 13C NMR (CDCl3): d = 175.8,
149.4, 147.1, 137.0, 129.3, 128.5, 127.9, 127.3, 122.0,
114.1, 113.7, 81.5, 73.7, 73.0, 71.1, 56.1, 34.4. Anal. Calcd
for C19H20O6: C, 66.27; H, 5.85. Found: C, 66.15; H, 5.91.
(14) Robins, M. J.; Wilson, J. S. J. Am. Chem. Soc. 1981, 103,
932.
(15) It is well known that these types of allylation reactions via
substituted oxocarbenium ions do not necessarily afford the
corresponding products with good stereoselectivity, but
instead lead to lower non-stereoselective results in some
cases. It mainly depends on the three factors such as the
position and the number of substituents in those
oxocarbenium ions employed as well as their configurations,
see ref. 17. Our satisfactory stereoselective findings at this
(11) Ohsaki, A.; Takashima, J.; Chiba, N.; Kawamura, M.
Bioorg. Med. Chem. Lett. 1999, 9, 1109.
Synlett 2006, No. 13, 2031–2034 © Thieme Stuttgart · New York

2034
T. Katoh et al.
LETTER
stage prompted a further search for practical synthesis of the
targeting natural products.
five-membered-ring oxocarbenium ions can be combined to
predict selectivities in highly substituted oxocarbenium ions
and also iminium ions.
(16) Stereochemistry of the generated stereogenic centers of 14b
and 15b was determined unambiguously based on its
chemical shifts of the protons at the C-1 position, even
though showing multiplet signals; 14b: d = 4.26–4.40 (m, 1
H) ppm, 15b: d = 4.49–4.59 (m, 1 H) ppm.10,17 Compound
14a was also estimated to have the same configuration based
on the similarity of its spectral data to those of 14b.
(17) These stereochemical results are in good accord with those
of the recently reported following references in which the
allylation products were formed by stereoelectronically
preferred inside attack on the lowest energy conformer; see:
(a) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K.
A. J. J. Am. Chem. Soc. 1999, 121, 12208. (b)Smith, D. M.;
Woerpel, K. A. Org. Lett. 2004, 2063. (c) Larsen, C. H.;
Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel, K. A.
J. Am. Chem. Soc. 2005, 127, 10879; and references cited
therein. (d) The studies mentioned in these preceding reports
indicate in detail that a knowledge of the unusual con-
formational preferences of alkoxy groups in oxocarbenium
ions and a stereoelectronic model to explain reactions of
(18) Experimental Procedure for the Crude Synthesis of the
Coupling Product Employing 16 with Aryllithium
Reagent.
To a solution of 4-benzyloxy-3-methoxybromobenzene
(0.30 g, 1.02 mmol) prepared through benzylation of
commercially available 4-bromo-2-methoxyphenol
(Aldrich) in 3 mL of Et2O–THF (5:1) was added 1.60 M
BuLi hexane solution (0.65 mL, 1.04 mmol) at –78 °C under
argon. After the mixture was stirred for 10 min, a solution of
the aldehyde intermediate 16 (0.297 g, 0.50 mmol) cleaved
with NaIO4 via dihydroxylation of 14b in 0.5 mL of THF
was added, and the reaction mixture was further stirred for
1 h at the same temperature. Then, the mixture was quenched
by the addition of sat. NH4Cl solution (3 mL) and extracted
with EtOAc (3 × 50 mL). The combined organic layers were
dried (Na2SO4) and concentrated in vacuo, which were used
in the following oxidation reaction without further
purification.
Synlett 2006, No. 13, 2031–2034 © Thieme Stuttgart · New York