Stereoselective Formation of Tetrahydrofuran Rings via [3 + 2] Annulation: Total Synthesis of Plakortone L

Article abstract of DOI:10.1021/ol501446w

The [3 + 2] annulation of 2,3-O-isopropylidene-aldehydo-aldose with methallyl ether leads to the stereoselective formation of a substituted tetrahydrofuran system, which is converted to a bicyclic lactone derivative via consecutive deprotection, oxidative cleavage of the terminal diol, oxidation of the resulting lactol, and Barton-McCombie deoxygenation. The efficiency of this process was demonstrated by the first total synthesis of Plakortone L.

Full text of DOI:10.1021/ol501446w

Letter
pubs.acs.org/OrgLett
Stereoselective Formation of Tetrahydrofuran Rings via [3 + 2]
Annulation: Total Synthesis of Plakortone L
Hideyuki Sugimura,* Shougo Sato, Kensei Tokudome, and Takeshi Yamada
Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1, Fuchinobe, Chuo-ku, Sagamihara-shi 252-5258,
Japan
S
* Supporting Information
ABSTRACT: The [3 + 2] annulation of 2,3-O-isopropylidene-aldehydo-aldose with methallyl ether leads to the stereoselective
formation of a substituted tetrahydrofuran system, which is converted to a bicyclic lactone derivative via consecutive
deprotection, oxidative cleavage of the terminal diol, oxidation of the resulting lactol, and Barton−McCombie deoxygenation.
The efficiency of this process was demonstrated by the first total synthesis of Plakortone L.
lakortones L, N, and P represent a novel class of
furanolactone compounds isolated from the Australian
reactions of electron-rich olefins, such as allylsilanes,5 vinyl
ethers,6 or vinyl sulfides,7 with the 2,3-O-isopropylidene
derivatives of aldehydo-aldoses. Recently, we found that
methallyl ether was also applicable in this annulation reaction
as a nucleophile.8 This synthetic protocol enabled the
stereocontrolled installation of two stereogenic centers on the
tetrahydrofuran ring in a single step (Scheme 1). The reaction
proceeds via the attack of the nucleophile on the carbonyl
group from the less-hindered face (Si-face in this case), thus
generating a carbocation intermediate. The carbocation is
P
sponge, Plakinastrella clathrata, in 2011 by Garson et al.1 and
are classified as the Plakortone family due to their structural
similarity. The structures are characterized by an aromatic unit
connected to a bicyclic lactone ring system by a methylene
chain. Their biological activities have not been assessed because
of the small amounts of isolated products available for
screening. To date, several studies concerning the total
syntheses of Plakortones B−F, a series of biologically active
ethyl-branched furanolactones isolated from Caribbean
sponges, have been reported;2−4 however, no synthetic studies
on Plakortones L, N, and P have been reported. Herein, we
describe the first total synthesis of Plakortone L (1, Figure 1),
with the stereoselective formation of the substituted tetrahy-
drofuran moiety.
Scheme 1. Stereoselective Formation of Tetrahydrofuran
Ring
Previously, we reported a novel method for the construction
of tetrahydrofuran derivatives based on the [3 + 2] annulation
Received: May 19, 2014
Figure 1. Structures of Plakortone L, N, and P.
© XXXX American Chemical Society
A
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Letter
trapped with the spatially neighboring oxygen atom on the
sterically favored face to afford the corresponding tetrahy-
drofuran ring in a stereoselective manner. As a part of the study
to apply the annulation reaction to the total synthesis of
tetrahydrofuran-containing natural products, we now demon-
strate the total synthesis of Plakortone L (1).
Our approach for the synthesis of the core structure of
Plakortones is shown in Scheme 2. We planned the
Scheme 2. Synthetic Strategy for the Common Core
Structure of Plakortones
Figure 2. NOESY correlation of compound 7.
detail). These NOE data were consistent with the relative
configurations of C-4 and C-6 in Plakortones.
According to our previous report on the synthesis of trans-
kumausyne,5 tetraol 7 was converted to furanolactone 5
(Scheme 3). The oxidative cleavage of terminal diol using
construction of the tetrahydrofuran part by the [3 + 2]
annulation of aldehyde 2 with protected methallyl alcohol 3.
Based on our previous synthetic route to trans-kumausyne,5
furanolactone 5 was envisaged from furan 4 in a five-step
reaction sequence including the deisopropylidenation, oxidative
cleavage of the terminal diol, oxidation of the resulting lactol,
and Barton−McCombie deoxygenation of the remaining
hydroxyl group. The stereoselective incorporation of the β-
Me group at the C-4 position was expected by following a
strategy such as iodolactonization to afford furanolactone 6,
which is the common core structure for the synthesis of
Plakortones L, N, and P. After removal of the protecting group
from furanolactone 6, oxidation of the primary alcohol would
provide the corresponding aldehyde. The total synthesis of
Plakortone L (1) would be accomplished by the extension of
the side chain via Wittig olefination of the aldehyde derivative,
followed by hydrogenation of the olefin moiety.
Scheme 3. Synthesis of Furanolactone 5
Our approach began with the [3 + 2] annulation of readily
accessible starting materials, isopropylidene-protected D-arabi-
nose 29 and methallyl tert-butyldiphenylsilyl ether (3),10 in the
presence of BF3·OEt2 at −78 °C in CH2Cl2 to afford
tetrahydrofuran 4 in 75% isolated yield as a single stereoisomer
(eq 1).
Because of the overlap of the diagnostic Me protons in the
1H NMR spectrum of compound 4, the stereochemistry of the
newly formed chiral centers on the tetrahydrofuran ring was
established after removal of the isopropylidene groups. The
treatment of 4 with Zn(NO3)2·6H2O11 in MeCN at 50 °C for 5
h afforded tetraol 7 in 78% yield (eq 2). In the NOESY
experiments of compound 7 (Figure 2), both H-3 and H-5b
protons showed a strong NOE correlation to H-4, while H-5a
showed an NOE to Me-24 (see Supporting Information for
NaIO4 in CH2Cl2/H2O at 0 °C for 4 h afforded lactol 8 in 92%
yield; oxidation of 8 with NIS/Bu4NI12 afforded lactone 9 in a
quantitative yield. Subsequent Barton−McCombie deoxygena-
tion13 of lactone 9 afforded furanolactone 5 in a satisfactory
overall yield.
Next, we envisaged that the β-Me group at the C-4 position
could be incorporated via stereospecific formation of cis-fused
B
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Letter
bicyclic lactone by iodolactonization of an exo-methylene
intermediate (Scheme 4). The treatment of 5 with Me2NH/
Scheme 5. Extension of the Side Chain: Synthesis of
Plakortone L (1)
Scheme 4. Synthesis of Furanolactone 6 via Stereospecific
Iodolactonization from 5
0.27, CHCl3)} (ref {[α]D = −20.1 (c 0.0019, CHCl3)} were all
in excellent agreement with those previously reported.1
In conclusion, we have demonstrated the convenience of
applying the [3 + 2] annulation of 2,3-O-isopropylidene-
aldehydo-aldose with methallyl ether to directly access a
substituted tetrahydrofuran system in a highly stereoselective
manner. The utility of this approach was described through its
application to the synthesis of the common structural motif of
Plakortones. We accomplished the first total synthesis of
Plakortone L, and the synthesis of the other members of
Plakortones, N and P, is currently underway in our laboratory.
Me3Al14 afforded hydroxy amide 11, which was oxidized with
Dess-Martin periodinane to afford ketone 12. Wittig methyle-
nation of 12 afforded the desired exo-methylene amide, 13, in a
good overall yield. The key iodolactonization step14,15 was
carried out with iodine in THF/H2O (v/v = 3:1) at 0 °C for 11
h, affording cis-fused bicyclic lactone 14 in a stereospecific
manner. The deiodination of compound 14 with Bu3SnH
afforded furanolactone 6, the common core structure of
Plakortones L, N, and P. The syn-relationship between H-3
and the newly introduced iodomethyl group in compound 14
or the Me group in compound 6 was confirmed by the
observation of NOESY correlations between the corresponding
protons.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and product characterization data
1
with H and 13C NMR spectra for all new compounds and
Plakortone L (1), and NOESY spectrum for compound 7. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
With the core furanolactone 6 in hand, our efforts were
directed toward the extension of the side chain (Scheme 5).
After removal of the protecting group, Swern oxidation of the
resulting primary alcohol afforded aldehyde 16, which was
subjected to Wittig olefination using the ylide prepared in situ
by phosphonium salt 1716 and BuLi to afford the desired
product 18. However, the yield of the Wittig reaction was low
(31%). Attempts to improve the yield of this reaction by longer
reaction times or using several equivalents of the Wittig reagent
were unsuccessful, presumably due to the steric crowding
imposed by the substituents around the formyl group. The
hydrogenation of 18 using H2/Pd−C completed the total
synthesis of Plakortone L (1). The spectroscopic data of
*E-mail: sugimura@chem.aoyama.ac.jp.
Notes
The authors declare no competing financial interest.
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