Microwave-aided one-pot dehydration of the alcohol derived from (-)-shikimic acid for efficient synthesis of pericosines

Article abstract of DOI:10.3987/COM-14-13053

Dehydrating conditions of shikimate-derived alcohol 7, an early intermediate in the synthesis of the pericosine family of marine natural products, were examined. The triflate 8 was effectively converted to cyclohexadiene 9 with excess 4-N,N-dimethylaminopyridine (DMAP) at room temperature for 24 h. The reaction time was dramatically shortened by heating under microwave (MW) irradiation, preventing formation of the Diels-Alder type byproduct 14. Furthermore, the MW-aided one-pot dehydration of alcohol 7 with Tf₂O and DMAP (2.4 eq.) to form diene 9 was realized.

Full text of DOI:10.3987/COM-14-13053

HETEROCYCLES, Vol. 89, No. 9, 2014
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HETEROCYCLES, Vol. 89, No. 9, 2014, pp. 2161 - 2167. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 3rd July, 2014, Accepted, 29th July, 2014, Published online, 8th August, 2014
DOI: 10.3987/COM-14-13053
MICROWAVE-AIDED ONE-POT DEHYDRATION OF THE ALCOHOL
DERIVED FROM ()-SHIKIMIC ACID FOR EFFICIENT SYNTHESIS OF
PERICOSINES
Koji Mizuki, Yusuke Yoneshige, Rikiya Kawahata, Hiroki Yoneyama, Shinya
Harusawa, and Yoshihide Usami*
Laboratory of Pharmaceutical Organic Chemistry, Osaka University of
Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan; Tel:
+81-726-90-1087, Fax: +81-726-90-1005, E-mail: usami@gly.oups.ac.jp
Abstract – Dehydrating conditions of shikimate-derived alcohol 7, an early
intermediate in the synthesis of the pericosine family of marine natural products,
were examined. The triflate 8 was effectively converted to cyclohexadiene 9 with
excess 4-N,N-dimethylaminopyridine (DMAP) at room temperature for 24 h. The
reaction time was dramatically shortened by heating under microwave (MW)
irradiation, preventing formation of the Diels–Alder type byproduct 14.
Furthermore, the MW-aided one-pot dehydration of alcohol 7 with Tf2O and
DMAP (2.4 eq.) to form diene 9 was realized.
Isolation of pericosines A–E (1–4, 6) and Do (5), metabolites of the fungus Periconia byssoides
OUPS-N133, originally isolated from the sea hare Aplysia kurodai, was reported by Numata and
co-workers.1,2 These compounds have unique C7 cyclohexenoid structures3 with condensed functional
groups on the six-membered ring (Figure 1). We have been studying syntheses of pericosines with the
primary aim of confirming their relative or absolute configurations.4-8
Figure 1. Structure of naturally occurring pericosines

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Since pericosine A (1) has shown remarkable growth inhibition against several human cancer cell lines,1,2
several other research groups have also taken on the challenge of the total syntheses of pericosines.9-14
Recently, our interest has been in developing more efficient synthetic processes towards pericosines, which
will enable more effective searching for biologically active compounds.6,15 Our efforts afforded a
microwave (MW)-aided one-pot synthesis of alcohol 7 from ()-shikimic acid, a regioselective
bromohydrination of cyclohexadiene 9 (Scheme 1), and a regioselective epoxidation of 9. They also led to
the first total synthesis of ()-pericosine E (6).15 Chlorohydrin 12 participated as a key intermediate in this
total synthesis and is, of course, a precursor of ()-1 (Scheme 1).
Following this, our interest was focused on a one-pot synthesis of diene 9 from 7, since it had been observed
that a small amount of 9 was formed during O-trifluoromethansulfonylation of the 5-hydroxyl group in 7.
The two-step dehydration included use of cesium acetate (CsOAc) as a base and N,N-dimethylformamide
(DMF) as a solvent.6,15,16 These, however, are not ideal conditions as CsOAc is harmful and extremely
hygroscopic, and DMF has a high boiling point because of which it must be removed during extraction
through several washes with water or brine. Therefore, a CsOAc- and DMF-free dehydration process is
desirable. This paper describes optimization of the conditions for the elimination step to convert 8 to 9 and
a one-pot operation for the transformation of alcohol 7 into diene 9.
Scheme 1. Synthetic route to pericosine intermediates 11 and 12
Initially, two commercially available dehydrating reagents, Martin sulfurane dehydrating agent17 and
Burgess reagent,18 were tested for the direct dehydration of alcohol 7. The Martin sulfurane dehydrating
agent did not react with 7 in CH2Cl2 at room temperature. Reaction of 7 with the Burgess reagent under the
same conditions led to a complex mixture, which did not contain 9. Due to these unfruitful attempts, our

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study was redirected to modify the reaction conditions of our previous method for the preparation of 9. It
had been shown that alcohol 7 could be successfully converted to triflate 8 at room temperature in a few
hours (Scheme 1). In this reaction, pyridine was essential, since the reaction in the absence of pyridine did
not afford 8, and 4-N,N-dimethylaminopyridine (DMAP) participates as an effective catalyst.
Subsequently, attention was directed to the CsOAc- and DMF-free elimination step to convert 8 to 9.
Various bases were tested for this process, the results of which are summarized in Table 1. All reactions
were carried out at room temperature for 24 h. Neither pyridine nor N,N-diisopropyl-N-ethylamine (DIPEA,
known as Hünig’s base) promoted the reaction (entries 1 and 3, respectively). The stronger base,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) effected the aromatization of 8 to form methyl
3-hydroxybenzoate (13) (entry 4). Triethylamine and DMAP (1.2 eq.) gave desired diene 9 (entries 2 and 5,
respectively), with the reaction with DMAP giving a slightly improved yield. Examination of the pKa
values of the protonated bases20 suggests that basicity does not affect the reaction. An improved yield was
obtained with excess DMAP (2.4 eq.) (entry 6). Entry 7 is a trial reaction at the same concentration as that
of entry 6 with respect to DMAP (1.2 eq.) in CH2Cl2. This gives a similar yield to entry 5. From the results
of entries 5–7, excess DMAP was proven to be necessary for smooth elimination. However, the reason for
this is not clear. The optimum conditions given in entry 6 will be used in the following study. A closely
related study had been reported on dehydration of steroidal alcohols with Tf2O and DMAP (3 eq.).19 The
reaction with 3 equivalents of DMAP did not increase the chemical yield (entry 8).
Table 1. Elimination with Various Bases
entry
1
2
base
pyridine
Et3N
(pKa of H+base)20
9, yield (%)
recovery of 8 (%)
5.2
10.6
11
12
9.2
0a
14
0a
73
3
DIPEA
DBU
DMAP
DMAP
DMAP
DMAP
4b
5c
6d
7e
8f
16
63
71
65
63
7
11
9
20
a. Since the reaction did not proceed, recovery of starting material 8 was not purified.
b. The aromatized product 13 was obtained in 67%. c. Byproduct 14 was obtained in only 4% yield.
d. DMAP (2.4 eq.) was used. e. DMAP (1.2 eq.) was used in 1/2 volume of CH2Cl2. f. DMAP (3.0 eq.) was used.

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The major problem with the optimal conditions (entry 6) is the long reaction time required for the reaction
(24 h). MW irradiation was suggested as a solution to overcome this issue. MW-aided reactions have often
been used in our recent synthetic studies to reduce reaction time dramatically.21-25 However, another
problem may arise when using MW irradiation at higher temperatures for the preparation of 9 because 9 is
known to be unstable.16,26 Indeed, some byproduct 14, which is formed by Diels–Alder reaction between
two molecules of 9, was observed in the preparation of bromohydrin 10 from 9 in our recent synthetic study
on the total synthesis of pericosine E (6).15 Results of the MW-aided reactions are summarized in Table 2.
MW irradiation over long times (30 min) (entries 2–4) afforded trace amounts of the predicted byproduct 14,
but a shortened irradiation time prevented the formation of 14. Irradiation at 120 °C for 5 min afforded
desired 9 in 85% yield with no formation of 14 (entry 8). As references, experiments with conventional
heating in 1,2-dichloroethane were listed in entries 1 and 5. The reaction in 30 min yielded 9 in 86% yield
(entry 1) but the reaction did not complete in 5 min (entry 5).
Table 2. Microwave-Aided Elimination with DMAP
entry
1a
2b
3b
4b
5a
6
temp. (oC) time (min.)
9, yield (%) recovery of 8 (%)
80
80
100
120
80
30
30
30
30
5
86
76
72
67
46
57
75
85
-
-
-
-
34
35
13
-
80
5
7
8
100
120
5
5
a. Conventional heating in 1,2-dichloroethane as a solvent.
b. Trace amount of 14 was observed in the 1H-NMR spectra of crude reaction mixture.
Finally, we performed the one-pot dehydration of 7 to 9 using the MW method. It was found that conversion
of 7 to 8 did not proceed in the presence of catalytic DMAP without pyridine. Following this, the one-pot
synthesis of 9 was examined with Tf2O (1.2 eq), pyridine (1.2 eq), and DMAP (2.4 eq) in CH2Cl2 under
MW irradiation (Scheme 2). The best result was obtained under MW irradiation at 120 °C for 30 min, which
afforded 9 in 65% yield. When the same reaction mixture was reacted under MW irradiation at 120 °C for 5
min or at 100 °C for 30 min, significant amounts of unreacted 7 were observed in the 1H-NMR spectrum of
the crude residue. Prolonged reaction time to 30 min might be required for the conversion of 7 to triflate 8.

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Scheme 2. One-pot dehydration from alcohol 7 to diene 9
In conclusion, DMAP was proven to be an effective base for the elimination of the
trifluoromethanesulfonyloxy group in 8 to afford 9. MW irradiation shortened the reaction time, and
irradiating for just 5 min prevented the formation of Diels–Alder byproduct 14. One-pot dehydration of 7 to
9 was realized with Tf2O (1.2 eq.), pyridine (1.2 eq.), and DMAP (2.4 eq.) by a MW-aided reaction at
120 °C for 30 min. This one-pot procedure reduced the reaction time to one-twelfth that of the previous
two-step processes. The procedure described in this paper will be useful for the synthesis of pericosines and
other related biologically active analogues.
EXPERIMENTAL
NMR spectra were recorded at 27 °C on Agilent 300- and 400-MR-DD2 spectrometers in CDCl3 with
tetramethylsilane (TMS) as an internal standard. Liquid column chromatography was conducted over silica
gel (Nacalai, silica gel 60, mesh 70230 or 230400). Analytical TLC was performed on precoated Merck
glass plates (silica gel 60 F254) and compounds were detected by dipping the plates in an ethanol solution of
phosphomolybdic acid, followed by heating. All microwave-aided reactions were carried out with Biotage
Initiator® (Switzerland). Dry CH2Cl2, pyridine, and DMAP were purchased from Wako Pure Chemical
Industries (Osaka, Japan). Tf2O was purchased from Nakalai Tesque, Inc. (Kyoto, Japan). Martin sulfurane
dehydrating agent and Burgess reagent were purchased from Sigma Aldrich Co. LLC. (St. Louis, MO,
USA). (−)-Shikimic acid was purchased from Carbosynth, Ltd. (UK).
Elimination with Various Bases: Table 1
General Procedure (Table 1, entry 5): To a solution of triflate 8 (130 mg, 0.33 mmol) in dry CH2Cl2 (20
mL), under an argon atmosphere, was added DMAP (72 mg, 0.39 mmol) at 0 °C with stirring. The reaction
mixture was then allowed to warm to room temperature followed by stirring for 24 h. After quenching with
aq. NH4Cl, the reaction mixture was extracted with CH2Cl2. The organic layer was dried over anhydrous
MgSO4, filtered, and evaporated under reduced pressure to afford a crude residue that was purified by silica
gel column chromatography (hexane:EtOAc = 6:1) to give 9 (51 mg, 63%) and 14 (6.5 mg, 8%*) with

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recovery of 7 (14 mg, 11%).
*Mol ratio to 8 or 9 is 4% since 2 mol of 7 should be consumed to give 1 mol of 14.
Microwave-Aided Elimination with DMAP: Table 2
General Procedure (Table 2, entry 1): To a solution of triflate 8 (24 mg, 0.059 mmol) in dry CH2Cl2 (4 mL)
contained in a MW reactor vial, was added DMAP (17 mg, 0.14 mmol). The sealed vessel was heated under
MW irradiation at 80 °C for 30 min. After cooling, the reaction mixture was neutralized by slow addition of
aqueous HCl and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered, and
evaporated under reduced pressure to afford a crude residue that was purified by silica gel column
chromatography (hexane:EtOAc = 6:1) to give 9 (11 mg, 76%).
Microwave-Aided One-pot Dehydration from 7 to 9
To a solution of alcohol 7 (48 mg, 0.18 mmol), pyridine (20 L, 0.25 mmol), and DMAP (53 mg, 0.43
mmol) in dry CH2Cl2 (4 mL), contained in a MW reactor vial, was added a solution of Tf2O (36 L, 0.22
mmol) in CH2Cl2 (1 mL) at 0 °C with stirring. The sealed vessel was heated under MW irradiation at 120 °C
for 30 min. After cooling in an ice bath, the reaction mixture was neutralized by slow addition of aqueous
HCl and extracted with CH2Cl2 (3 ×10 mL). The organic layer was dried over anhydrous MgSO4, filtered,
and evaporated under reduced pressure to afford a crude residue that was purified by silica gel column
chromatography (hexane:EtOAc = 6:1) to give 9 (29 mg, 65%).
* The one-pot dehydration experiment in 2.2 mmol scale showed 59% yield.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid from the Alumni Association of the Osaka University of
Pharmaceutical Sciences.
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