Total Synthesis of 7-epi-Pukalide and 7-Acetylsinumaximol B

Article abstract of DOI:10.1002/chem.201702591

Convergent total syntheses of the furanocembranoids 7-epi-pukalide and 7-acetylsinumaximol B have been achieved using a one-pot Knoevenagel condensation and thioether-mediated furan-forming reaction. Furan formation proceeds via a sulfur ylide and results

Full text of DOI:10.1002/chem.201702591

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Title: Total Synthesis of 7-epi-Pukalide and 7-Acetylsinumaximol B
Authors: J. Stephen Clark and Kirsten McAulay
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To be cited as: Chem. Eur. J. 10.1002/chem.201702591
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Total Synthesis of 7-epi-Pukalide and 7-Acetylsinumaximol B
Kirsten McAulay and J. Stephen Clark*
Abstract: Convergent total syntheses of the furanocembranoids
7-epi-pukalide and 7-acetylsinumaximol B have been achieved using
a one-pot Knoevenagel condensation and thioether-mediated furan-
forming reaction. Furan formation proceeds via a sulfur ylide and
results in rapid introduction of structural complexity during the
coupling of two highly functionalised fragments. The targets have
been prepared in 16 steps from (R)-perillyl alcohol.
(Figure 1). Structural variation occurs at the C4 position, where
an ester, aldehyde or methyl group can be present, and at the
C7–C8 and C11–C12 positions, which can be unsaturated or bear
an epoxide (Figure 1). Positions C2, C7, C8 and C13 can be
substituted with hydroxyl or acetate groups in some cases.
Several furanocembranoids have been reported to possess
significant biological activities. For example, lophotoxin is an
irreversible antagonist of the nicotinic acetylcholine receptor[8] and
pukalide has emetic activity in fish (Figure 1).[7d] As
a
The furanocembrane family of natural products comprises
structurally diverse diterpenoids that have been isolated from
several octocoral species (Figure 1).[1–5] The first
furanocembranoid to be fully characterised was pukalide, a
compound that was first isolated from the alcynacean octocoral
Sinularia abrupta by Scheuer and co-workers in 1975[6] and has
been isolated from several other species of coral more recently.[7]
consequence of their pharmacological activities and interesting
molecular structures, the furanocembranoids have received
considerable attention as synthetic targets.[9–20] The first synthesis
of a furanocembrane natural product – acerosolide (Figure 1) –
was reported by Paquette and co-workers in 1993.[10] Subsequent
pioneering studies by the groups of Pattenden,[11] Marshall[12] and
Trauner[13] resulted in total syntheses of deoxypukalide, rubifolide
and bipinnatin J (Figure 1). Total syntheses of furanocembranoids
have also been reported by the groups of Donohoe (Z-
deoxypukalide)[14] and Rawal (bipinnatin J).[15] In addition, the
groups of Paterson[16] and Wipf[17] have made important
contributions with regard to the synthesis of lophotoxin and
pukalide, the groups of Bach[18] and Honda[19] have prepared
advanced intermediates to bipinnatin J, and Mulzer and co-
workers assembled the complete skeleton of providencin.[20]
In spite of the considerable amount of work that has been
devoted to the synthesis of furanocembrane natural products,
they continue to be extremely challenging targets by virtue of their
complex structures and reactive functionality. It is noteworthy that
all of the previously reported total syntheses have been of family
members possessing low levels of oxygenation.[10–15] Introduction
of the C7–C8 epoxide that is present in lophotoxin and pukalide,
as well as many of the other furanocembranoids, has proved to
be particularly challenging, but the work of Mulzer and co-workers
concerning the total synthesis of providencin has demonstrated
how this problem might be addressed.[20]
Figure 1. Selected furanocembranoid marine natural products.
Pukalide and the other furanocembranoids possess a 14-
membered carbocyclic skeleton that includes a bridging furan
(C3–C6) and a five-membered lactone (C10–C12), and bears an
isopropenyl substituent at C1 and a methyl substituent at C8
Scheme 1. Tetrahydrothiophene-promoted formation of an epoxyfuran.
[a]
Prof. Dr. J. S. Clark and K. McAulay
WestCHEM, School of Chemistry
In 2012, we reported a new method for the synthesis of
trisubstituted furans,[21] including epoxyfurans, from ynenones
that can be obtained by performing Knoevenagel condensation
reactions on propargylic aldehydes.[22] In the course of this work,
the epoxyfuran 2 was prepared in good yield by treatment of the
ynenone substrate 1 with a sub-stoichiometric amount of
tetrahydrothiophene (THT) (Scheme 1). We became interested in
Joseph Black Building, University of Glasgow
University Avenue, Glasgow G12 8QQ (UK)
E-mail: stephen.clark@glasgow.ac.uk
Homepage: http://www.chem.gla.ac.uk/staff/stephenc/
Supporting information for this article is given via a link at the end of
the document
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exploring whether the transformation could be used as the furan-
forming reaction in a total synthesis of pukalide, given that
construction of the epoxyfuran unit present in many
furanocembranoids has proved to be very challenging. Herein, we
describe our efforts to prepare pukalide and the related natural
product 7-acetylsinumaximol B.[6,7,23]
mixture of the corresponding mesylates that underwent SN2'
rearrangement to afford (R)-perillyl alcohol (5) during aqueous
work-up. As far as we are aware, the only other synthesis of (R)-
perillyl alcohol that does not involve the use of a biocatalyst[25] is
that reported by Evans et al., in which a palladium-mediated
rearrangement reaction is employed.[26]
The syntheses of pukalide and 7-acetylsinumaximol B were
planned so that our THT-mediated reaction could be used to
install the C7–C8 epoxide and the furan simultaneously, late in
the synthesis. In the retrosynthetic analysis of both targets
(Scheme 2), disconnection of the furan and butenolide leads to
the macrolactone i as a late-stage intermediate. In the forward
direction, it was anticipated that the butenolide would be formed
by ring-closing metathesis (RCM) and the furan would be
constructed using our organocatalytic reaction; a decision about
the order in which these reactions would be performed was to be
made late in the synthesis. Disconnection of the lactone and the
ynenone (C4–C5) then reveals the propargylic aldehyde ii and the
β-keto ester iii as the key fragments. In the forward direction, it
was expected that formation of the ynenone would precede
macrolactone construction. Disconnection of the methyl and
alkyne groups of the tertiary alcohol (C8) in fragment ii leads to
the amide iv. In the case of fragment iii, cleavage of the β-keto
ester by retro-Claisen condensation, removal of the methylene
group and reconnection of C3 to C12 reveals (R)-perillyl alcohol
as the starting material.[12,14]
Scheme 3. Synthesis of (R)-(+)-perillyl alcohol from (+)-limonene oxide. a) LDA,
Et2O, –78 °C, 87%; b) MeSO2Cl, Et3N, CH2Cl2, rt then sat. aq. NaHCO3, 61%.
(R)-Perillyl alcohol (5) was protected as its triisopropylsilyl
(TIPS) ether and then subjected to selective ozonolysis, under
conditions reported by Donohoe et al.[14] (Scheme 4). The
intermediate aldehyde was subjected to chemoselective
reduction using sodium triacetoxyborohydride to afford
hydroxyketone 6 in 41% yield over three steps.[27] Wittig
methylenation of the ketone gave an alkene that was then
transformed into the allylic alcohol 7 by sequential acetylation and
silyl ether cleavage. The carboxylic acid functionality was installed
in a stepwise manner by formation of the aldehyde using Dess-
Martin periodinane (DMP) and subsequent Pinnick oxidation.
Protection of the resulting carboxylic acid 8 was necessary prior
to the introduction of the β-keto ester and so it was subjected to
DCC-mediated esterification with 2-(trimethylsilyl)ethanol.
Acetate hydrolysis under basic conditions and oxidation of the
resulting alcohol using DMP then gave aldehyde 9. The synthesis
of the β-keto ester 10 was completed by the tin(II) chloride
mediated reaction of the aldehyde 9 with methyl diazoacetate,
following the procedure described by Holmquist and Roskamp.[28]
Scheme 2. Retrosynthetic analysis of 7-acetylsinumaximol B and pukalide.
The chiral pool compound (R)-perillyl alcohol was required for
the synthesis of the β-keto ester fragment (compound iii, Scheme
1). Unlike its S-enantiomer, (R)-perillyl alcohol is not readily
available from commercial suppliers and so a simple synthetic
route to large quantities of this starting material had to be devised.
Commercially available (+)-limonene oxide 3 was subjected to
base mediated epoxide rearrangement to produce the allylic
alcohol 4 as a mixture of diastereomers (Scheme 3).[24] Treatment
of the alcohols 4 with methanesulfonyl chloride delivered a
Scheme 4. Synthesis of the β-keto ester 10 required for the Knoevenagel
condensation reaction. a) iPr3SiCl, imidazole, DMAP, CH2Cl2, rt, 99%; b) O3,
isoprene, pyridine, CH2Cl2-MeOH, –78 °C; c) NaBH(OAc)3, PhMe, rt, 41% (2
steps); d) [Ph3PCH3]+Br–, nBuLi, THF, 0 °C → rt, 86%; e) Ac2O, Et3N, DMAP,
CH2Cl2, rt, 94%; f) nBu4NF, THF, rt, 99%; g) Dess-Martin periodinane, CH2Cl2,
rt; h) NaClO2, NaH2PO4, tBuOH, H2O, rt, 99% (2 steps); i) DCC, DMAP,
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Me3Si(CH2)2OH, CH2Cl2, rt, 87%; j) K2CO3, MeOH, rt; k) Dess-Martin
periodinane, CH2Cl2, rt, 84% (2 steps); l) N2CHCO2Me, SnCl2, CH2Cl2, rt, 67%.
ynenone would be subjected to macrocyclisation prior to the furan
formation. However, the ynenone was unstable and so it was
necessary to perform furan formation prior to macrocyclisation. It
transpired that Knoevenagel condensation and furan formation
could be effected in a simple one-pot process (Table 1). Reaction
of the β-ketoester 10 with the aldehyde 17 in the presence of
piperidine, acetic acid (0.6 equiv.) and tetrahydrothiophene (THT),
produced the epoxy-furan 19 (1:1 mixture of diastereoisomers) in
30% yield and the acetate 20 (~3:2 mixture of diastereoisomers)
in 32% yield (Entry 1, Table 1). It was found that the selectivity of
the reaction could be tuned by altering the amount and type of
carboxylic acid additive or by protecting the tertiary alcohol. When
one equivalent of acetic acid was used in the one-pot
Knoevenagel condensation and cyclisation reaction, the acetate
20 was obtained in 50% yield and the yield of the epoxide 19 was
reduced to 16% (Entry 2, Table 1). The epoxide 19 was obtained
exclusively in 62% yield from the reaction promoted by pivalic acid
(Entry 3, Table 1), and the acetate 21 was obtained in 85% yield
(3:2 mixture of diastereomers) when the bis-protected aldehyde
18 was used as a substrate and the reaction was performed in the
presence 1.2 equivalents of acetic acid (Entry 4, Table 1).
The second fragment was prepared by the route shown in
Scheme 5. The β-hydroxy amide 11 was prepared by the
stereoselective titanium-mediated aldol condensation reaction
between acrolein and an N-acetylthiazolidinethione and
subsequent formation of a Weinreb amide as described by
Venkatesham and Nagaiah.[29] Protection of the hydroxyl group as
a
triethylsilyl ether followed by addition of lithiated
triisopropylsilylacetylene afforded the propargylic ketone 12.
Cleavage of the silyl ether under acidic conditions afforded the
β-hydroxyketone 13 in good yield. The requisite C8 methyl
substituent was introduced stereoselectively by chelation-
controlled addition of MeTi(OiPr)3 to the ketone 13; subsequent
desilylation afforded the diol 14. The syn diol was obtained as the
major product with an excellent dr.[30] Other reaction conditions
were explored, but these resulted in formation of the diol with
diminished dr and lower yield. Interestingly, addition of MeLi to the
ketone 13 in the presence of ZnBr2 resulted in a reversal of
diastereoselectivity and delivered the anti 1,3-diol as the major
product. Selective TIPS-protection of the secondary hydroxyl
group of the diol 14 afforded the alcohol 15 and double TIPS-
protection afforded the bis-silyl ether 16. The alkynes 15 and 16
were formylated thereafter to give the propargylic aldehydes, 17
and 18, required for the key one-pot fragment coupling and furan-
forming reaction.
Table 1. One-pot Knoevenagel condensation and catalytic furan formation.
Entry
Aldehyde
RCO2H
Equiv.
RCO2H
Yield
19 (%)a
Yield
20 (%)a
Yield
21 (%)a
1
2
3
4
17
17
17
18
MeCO2H
MeCO2H
tBuCO2H
MeCO2H
0.6
1.0
0.6
1.2
30
16
62
–
32
50
–
–
–
Scheme 5. Synthesis of the propargylic aldehydes 17 and 18 required for the
Knoevenagel condensation reaction. a) Et3SiCl, imidazole, CH2Cl2, rt, 95%; b)
iPr3SiCCH, nBuLi, THF, rt, 91%; c) PPTS, MeOH, THF, 99%; d) (iPrO)3TiMe,
Et2O, 0 °C, 97% (9:1 d.r.); e) nBu4NF, THF, rt, 89%; f) NaH, iPr3SiCl (1 equiv.),
THF, rt, 98% (15); g) iPr3SiOSO2CF3 (2.1 equiv.), 2,6-lutidine, CH2Cl2, 0 °C →
rt, 97% (16); h) nBuLi, DMF, THF, –78 °C, 90% (17), 94% (18).
–
–
85
a Isolated yield.
Cleavage of both the silyl ether and the ester was
accomplished by treatment of epoxyfuran 19 with TBAF (Scheme
6). The resulting hydroxyacid was then subjected to Yamaguchi
macrolactonisation conditions to afford the lactone 22 as a single
isomer in 39% yield over two steps;31 the other diastereomer
failed to undergo cyclisation under the reaction conditions
The development of robust routes to the β-keto ester 10 and
to the aldehydes 17 and 18 meant that fragment coupling could
be explored. The original synthetic plan (Scheme 1) had been
devised with the expectation that the fragments would be coupled
by use of a Knoevenagel condensation reaction and the resulting
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(Scheme 6). Cyclisation of the hydroxyacid using the Corey-
Nicolaou method delivered the lactone 22 in 46% yield as a single
isomer and none of the diastereomeric lactone was isolated.31
Scheme 7. Completion of the total synthesis of 7-acetylsinumaximol B.
a) nBu4NF, THF, 10 °C; b) Cl3C6H2COCl, iPr2NEt, DMAP, C6H6, rt, 25% (2
steps); c) 25, CH2Cl2, 40 °C, 25% + 73% recovered 25.
In conclusion, convergent total syntheses of both 7-epi-
pukalide and 7-acetylsinumaximol B have been completed with
longest linear sequences of just 16 steps from (R)-perillyl alcohol.
The route represents the first total synthesis of both compounds
and demonstrates an effective strategy for the selective
introduction of oxygen substituents (epoxide or diol) at C7 and C8.
The key THT promoted reaction allowed the rapid and convergent
assembly of the complete furan-containing skeleton and
Scheme 6. Completion of the total synthesis of 7-epi-pukalide (24). a) nBu4NF,
THF, 10 °C; b) Cl3C6H2COCl, iPr2NEt, DMAP, C6H6, rt, 39% (2 steps); c) 2,2’-
dipyridyl disulphide, PPh3, PhMe, rt then reflux 46% (2 steps); d) 23, CH2Cl2,
40 °C, 90%.
Attempts to construct the butenolide by transannular ring-
closing metathesis (RCM) with either the Grubbs second
generation catalyst or the Hoveyda-Grubbs second generation
catalyst were unsuccessful. However, the very reactive modified
Hoveyda-Grubbs second generation catalyst 23, developed by
Matsugi and co-workers,[32] proved to be highly effective for the
required RCM reaction and the butenolide was obtained in 90%
yield (Scheme 6). The 1H and 13C NMR data obtained for the final
compound were found to be inconsistent with the original data
recorded for natural pukalide.[33] Careful analysis of NOE data
revealed that the final compound was the epoxide 24, the C7-
epimer of natural pukalide.[34,35] This result leads to the conclusion
that the isomer of epoxide 19 required for the synthesis of
pukalide did not undergo macrolactonisation (Scheme 6). The
finding that the hydroxyacid obtained from the cis-epoxide isomer
of 19 undergoes cyclization whereas that obtained from the trans-
epoxide isomer of 19 does not, is unsurprising. Mulzer and co-
workers found that installation of an E-alkene at C7–C8 and its
subsequent conversion into the requisite epoxide were both
challenging transformations during the synthesis of 17-
deoxyprovidencin.[20]
permitted completion of the syntheses by
macrolactonisation and RCM sequence.
a
parallel
Acknowledgements
The authors acknowledge the award of a College of Science and
Engineering Scholarship to KM from the University of Glasgow.
We thank Professor W. Fenical (Scripps Institution of
Oceanography, UC San Diego) for very kindly providing us with
the original1H and 13C NMR spectra recorded for natural pukalide.
Keywords: cembrane • furan • epoxide • lactonisation • ring-
closing metathesis
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1,3-diol 14, an NOE was observed between the protons of the methyl
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[34] The configuration of the C7-C8 epoxide was confirmed by 1H NMR
analysis. NOEs were observed between the C7 proton and the protons
of the C8 methyl substituent and between the C7 proton the furan proton
(C5). For further details, see Supporting Information.
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literature, the integrity of related enantiomerically pure epoxides is
maintained in the presence of carboxylic acids, even in cases where
tethering of the epoxide to the carboxylic acid could promote
intramolecular protonation and subsequent nucleophilic opening of the
epoxide; ii) we have found that there is little stereocontrol at the
stereogenic centre adjacent to the furan in cases where furan
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obtained from the reaction; iii) the ratio of the two diastereomers of the
epoxide 19 does not vary during the course of the reaction; iv)
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= 0.080, CHCl3) compared to a literature value of [α]2D5 −56.0 (c = 0.6,
CHCl3) reported for natural material (ref. 23). The discrepancy can be
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10.1002/chem.201702591
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The furanocembranoids 7-epi-
pukalide and 7-acetyl-
Kirsten McAulay, J. Stephen
Clark*
sinumaximol B have been
Page No. – Page No.
synthesised by a convergent
route in which a one-pot
Total Synthesis of 7-epi-
Pukalide and 7-
Acetylsinumaximol B
Knoevenagel condensation and
tetrahydrothiophene-mediated
furan-forming reaction is used to
couple two fragments to give the
complete carbon framework.
This article is protected by copyright. All rights reserved.