Enantioselective total synthesis of (-)-equisetin using a Me3Al-mediated intramolecular Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(01)00217-9

An efficient and enantioselective total synthesis of (-)-equisetin 1 has been accomplished using a diastereoselective Me₃Al-mediated intramolecular Diels-Alder (IMDA) reaction as a key reaction step.

Full text of DOI:10.1016/S0040-4039(01)00217-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2517–2519
Enantioselective total synthesis of (−)-equisetin using a
Me3Al-mediated intramolecular Diels–Alder reaction†
Kumiko Yuki, Mitsuru Shindo and Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Received 15 January 2001; revised 1 February 2001; accepted 2 February 2001
Abstract—An efficient and enantioselective total synthesis of (−)-equisetin 1 has been accomplished using a diastereoselective
Me3Al-mediated intramolecular Diels–Alder (IMDA) reaction as a key reaction step. © 2001 Elsevier Science Ltd. All rights
reserved.
Equisetin 1 and phomasetin 2 have been isolated from
the extracts of two active fungal broths, identified as
Fusarium heterosporum and Phoma sp., respectively.1
These compounds not only inhibit the in vitro recombi-
nant integrase enzyme with IC50 values of 7–20 mM but
also prevent the integration reactions catalyzed by
preintegration complexes isolated from HIV-1 infected
cells. It turns out that phomasetin is a novel enan-
tiomeric homologue of equisetin, which is already
known in the literature.2 The promising biological
profiles of these compounds coupled with their intrigu-
ing structural features inspired us to develop an
efficient and general strategy for the synthesis of natu-
ral products (Fig. 1). To date, two total syntheses of
optically active equisetin have been completed, those of
Danishefsky3 and Dixon.4 We report herein an efficient
tive Takai-olefination as the key reaction steps. Recent
communications by Dixon4 on the total synthesis of 1
have prompted us to report our own efforts in this area.
The enantiomerically pure aldehyde 3, prepared from
R-citronellal via a four-step sequence, was subjected to
OH
NMe
OH
NMe
5'
O
O
H
O
H
O
O
O
H
H
1
2
H
H
total synthesis of (−)-equisetin
1
employing
a
diastereoselective IMDA reaction and a highly E-selec-
Figure 1.
R
OTBDPS
OTBDPS
a - d
e
h - l
OMOM
R-citronellal
R
CHO
f, g
4: R=CH=CHCO2Et
5: R=-B(-OCMe2-)2
6: R=CO2Et
7: R=CHO
3
Scheme 1. (a) HO(CH2)2OH, p-TsOH, benzene, reflux, 88%; (b) O3, CH2Cl2, −78°C then NaBH4, 92%; (c) 5% HCl (aq.), THF;
,
(d) TBDPSCl, imidazole, 4-DMAP, 64% (two steps); (e) (EtO)2POCH2CHꢀCHCO2Et, LiOH·H2O, 4 A MS, THF, reflux, 84%;
(f) dichloromethylboronic ester, CrCl2, LiI, THF, 86%; (g) (E)-ethyl 3-iodoacrylate, Pd2(dba)2·CHCl3, Ph3P, 2N NaOH (aq.),
THF, reflux, 87%; (h) DIBAL-H, THF, −78°C, 99%; (i) MOMCl, i-Pr2NEt, 4-DMAP, CH2Cl2, 94%; (j) n-Bu4NF, THF, 98%;
(k) Swern ox., CH2Cl2, −78°C, 91%; (l) Ph3PꢀC(Me)CO2Et, benzene, reflux, 99%; (m) DIBAL-H, THF, −78°C, 94%; (n) Swern
ox., CH2Cl2, −78°C, 93%.
Keywords: Diels–Alder reactions; stereocontrol; biologically active compounds; polyketides.
* Corresponding author. Tel./fax: +81 88 633 7287; e-mail: shishido@ph2.tokushima-u.ac.jp
†
This work was presented at the 120th annual meeting of the Pharmaceutical Society of Japan, Gifu, March 2000 (Abstract paper: 29[PA]15–56).
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00217-9

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K. Yuki et al. / Tetrahedron Letters 42 (2001) 2517–2519
the Horner–Emmons reaction5 to give the diene 4. The
optimum conditions for obtaining higher selectivity.
After several attempts, the use of Me3Al proved the
most successful. Thus, treatment of a solution of 7 in
CH2Cl2 with 1 equiv. of Me3Al at 0°C for 4 h gave the
cycloadducts in reasonable chemical yield (75%) and
diastereoselectivity (8/1). In addition, the Z-triene 13
was recovered in 3% yield. Separation and structure
determination of both isomers were carried out as
shown in Scheme 2. Thus reduction of the mixture 11
and 12 with NaBH4 produced a chromatographically
separable mixture of the alcohols 14 and 15, and their
stereochemistries were rigorously confirmed by NOE
experiments (Scheme 2).
stereochemistry of the newly generated double bond
1
was an 8:1 mixture (from H NMR) of the E and Z
isomers, which were inseparable. To improve the
stereoselectivity, we examined a stepwise sequence for
the preparation of the diene. Treatment of 3 with
dichloromethylboronic ester, chromous chloride and
LiI6 produced the vinyl borate 5 with E-geometry in a
ratio of 95:5 in 86% yield. The Suzuki coupling7 of 5
with (E)-ethyl 3-iodoacrylate8 provided the diene 4 in
99% yield.
Reduction of the ester moiety with DIBAL-H followed
by protection of the resulting alcohol as the MOM
ether gave the protected diene. It was treated with
TBAF and oxidized by the method of Swern to give the
corresponding aldehyde, which was condensed with the
stabilized Wittig ylide to afford the triene ester 6 in
good overall yield. This was converted by sequential
DIBAL-H reduction and Swern oxidation into the alde-
hyde 7, which has a different kind of dienophilic moiety
(Scheme 1).
A possible mechanism for the diastereoselective IMDA
reaction is shown in Scheme 3. As we predicted, the
reaction proceeded preferentially via the sterically more
favorable endo-transition state Tendo, in which the
methyl group on the tertially stereogenic center occu-
pies an equatrial orientation, to give the trans octahy-
dronaphthalene aldehyde 11 with the desired
stereochemistry. On the other hand, the minor cis-iso-
mer 12 would be generated from the exo-transition
state (Texo), which seems to be sterically congested
(Scheme 3).
Initially we examined the key IMDA reaction of the
triene 6 having the unsaturated ester as the dienophile.
A solution of the triene in toluene was heated at 150°C
for 40 h in the presence of catalytic methylene blue.9
The cycloadduct was obtained as an inseparable 1:1
To introduce a propene moiety with the E-geometry,
the primary alcohol function in 14 was initially pro-
tected as the TBDPS ether and the MOM ether was
cleaved with bromotrimethyl silane10 to produce the
alcohol, which was oxidized with Dess–Martin periodi-
nane. The resulting aldehyde 16 was treated with
diiodoethane and chromous chloride in THF at room
temperature11 and afforded the E-olefin 17 cleanly in a
ratio >99:1 in 90% yield. The TBDPS ether was cleaved
with TBAF to give the alcohol 1812 in 97% yield, the
spectral properties and optical rotation of which were
completely identical with those reported in the litera-
ture.3 Swern oxidation followed by Reformatsky reac-
1
mixture (from H NMR) of trans and cis isomers 8 and
9 along with unreacted starting Z-triene 10 in 64 and
4% yields, respectively. Discouraged by the non-selec-
tivity, we next examined Lewis acid-mediated condi-
tions. However, the results were uniformly
disappointing. Therefore, we turned our attention to
yet another triene. The aldehyde 7 was heated under the
same conditions as for 6 to give a 3:1 inseparable
mixture of the trans/cis cycloadducts 11 and 12 and the
Z-triene 13 in 81 and 4% yields, respectively. Encour-
aged by this result, we continued to search for the
Scheme 2.
Scheme 3.

K. Yuki et al. / Tetrahedron Letters 42 (2001) 2517–2519
2519
OTBDPS
CHO
R
H
H
H
H
i, j
a - c
d - h
14
H
16
MeO2C
17: R=CH2OTBDPS 20: R=CH(OH)CH2CO2Et
OR
18: R=CH2OH
19: R=CHO
21: R=COCH2CO2Et
O
NMe
O
H
k
1
+
5'-epiequisetin
22: R=TBS
23: R=H
H
Scheme 4. (a) TBDPSCl, imidazole, 4-DMAP, CH2Cl2, 92%; (b) TMSBr, CH2Cl2, 62%; (c) Dess–Martin ox., CH2Cl2, 95%; (d)
CH3CHI2, CrCl2, THF, 93%; (e) n-Bu4NF, DMF, 99%; (f) Swern ox., CH2Cl2, 99%; (g) ethyl bromoacetate, Zn, benzene, reflux,
92%; (h) Dess–Martin ox., CH2Cl2, 83%; (i) N-methyl-O-tert-butyldimethylsilylserine methyl ester, toluene, reflux, 96%; (j) HF,
MeCN, 99%; (k) NaH, CH2Cl2, 92%.
tific Research (No.11557172) from the Ministry of Edu-
cation, Science, Sports and Culture, Japan.
tion of the resulting aldehyde 19 provided 20, which
was oxidized with the Dess–Martin periodinane to give
the keto ester 21 in 76% overall yield from 18. Conden-
sation of 21 with the N-methylserine derivative, which
References
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produced an easily separable 4:1 mixture of equisetin 1
and 5%-epiequisetin2c,3 in 92% yield. The synthetic equi-
setin obtained by this procedure was identical to a
natural sample by several criteria: Rf (TLC), mass
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In summary, we have completed a total synthesis of
optically pure (−)-equisetin using a diastereoselective
Me3Al-mediated IMDA reaction and a highly E-selec-
tive Takai olefination reaction as the key reaction steps.
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We thank Dr. S. B. Singh (Merck Research Lab.) for
kindly providing us with a sample of natural (−)-equi-
setin and its NMR spectra. We also thank Dr. N.
Suzuki and M. Nozaki (Takasago International Co.)
for kindly providing R-citronellal and Professor K.
Takai (Okayama University) for helpful discussions.
This work was supported by Grants-in-Aid for Scien-
1
12. The optical purity of 20 was proved to be >99% ee by H
NMR analysis of the corresponding MTPA ester.
13. [h]2D3=−352 (c=1.00, CHCl3) {Ref. 1 [h]2D2=−278 (c=
0.77, CHCl3); Ref. 3 [h]2D3=−253 (c=0.038, CHCl3)};
Ref. 4 [h]2D8=−262 (c=0.038, CHCl3)}.
.