D- and L-erythrose as sources of chiral quaternary carbon centers. Total synthesis of (-)-malyngolide and (+)-tanikolide

Article abstract of DOI:10.1016/S0040-4039(03)00290-9

A highly efficient and versatile approach was applied for the total synthesis of the marine natural products (-)-malyngolide and (+)-tanikolide from isopropylidene L- and D-erythrose, using a common strategy.

Full text of DOI:10.1016/S0040-4039(03)00290-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2513–2516
D
- and -Erythrose as sources of chiral quaternary carbon
L
centers. Total synthesis of (−)-malyngolide and (+)-tanikolide
Alexandros E. Koumbis,* Kyriaki M. Dieti, Myrofora G. Vikentiou and John K. Gallos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 541 24, Greece
Received 20 December 2002; revised 24 January 2003; accepted 31 January 2003
Dedicated with appreciation to Professor D. N. Nicolaides on the occasion of his 65th birthday
Abstract—A highly efficient and versatile approach was applied for the total synthesis of the marine natural products
(−)-malyngolide and (+)-tanikolide from isopropylidene
Ltd. All rights reserved.
L
- and
D
-erythrose, using a common strategy. © 2003 Elsevier Science
(−)-Malyngolide 1 and (+)-tanikolide 2 (Fig. 1) are
marine metabolites isolated from the lipid extract of a
blue–green algae, cyanobacterium Lyngbya majuscula
from species collected from the coasts of Hawaii1 and
Tanikeli island, Madagascar,2 respectively. Biological
evaluation showed that 1 exhibits significant antibacte-
rial activity against Mycobacterium smegmatis and
Streptococcus pyogenes, whereas 2 is a toxic and anti-
fungal agent. Both compounds share similar skeletal
features, a d-lactonic moiety incorporating a chiral
quaternary center, and a multicarbon side-chain, along
with a hydroxymethyl group. However, they differ in
the absolute stereochemistry of the quaternary carbon
and the length of the aliphatic chain. Additionally, 1
incorporates in its structure a methyl group a to the
carbonyl, thus generating a second chiral center, with
R-configuration.
The interesting activity of 1 combined with the chal-
lenge to selectively construct a stereogenic quaternary
carbon has prompted several groups to address the
total synthesis of this molecule.3,4 Besides the earliest
approaches which led to racemic products, an array of
methodology was successfully employed, including chi-
ral pool, chiral auxiliary and catalytic asymmetric syn-
theses as well as enzymes to obtain optically active
material. Considerable work4,5 has also been reported
for the preparation of 2 despite the fact that the latter
was relatively recently isolated. Although previous
accomplishments confronted the synthesis of 1 and 2 in
diverse and elegant ways, most of them lack the ability
to prepare both natural products following a short,
efficient and relatively simple pathway.
In accordance with our continuing synthetic efforts6
towards molecules with intriguing characteristics and
usefulness we also embarked on the preparation of 1
and 2. The structural similarities between these com-
pounds led us to design a common retrosynthetic strat-
egy (Scheme 1). Thus, we envisioned that desired
products could be obtained upon lactonization of pre-
cursors 4 which in turn could derive from unsaturated
systems 5 through elimination of one oxygen sub-
stituent and hydrogenation. Finally, intermediates 5
could be considered as double olefination products of
protected erythroses 6.
Figure 1. Structures of (−)-malyngolide and (+)-tanikolide.
Keywords: (−)-malyngolide; (+)-tanikolide; erythrose; total synthesis;
d-lactone; quaternary center.
* Corresponding author. Tel.: +30-2310-997839; fax: +30-2310-
997679; e-mail: akoumbis@chem.auth.gr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00290-9

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A. E. Koumbis et al. / Tetrahedron Letters 44 (2003) 2513–2516
The second double bond was constructed using a Wittig
olefination as well, on aldehydes 11 and 19. These were
easily obtained upon Swern oxidation of 10 and 18 and
used without purification. In this case the required
stable ylides were employed. Whereas the geometrical
outcome was poor for disubstituted alkene 20, the
corresponding trisubstituted 12 was isolated as a single
E-isomer. In any case, stereochemistry of the double
bonds was of no importance since both were hydro-
genated later on.
A magnesium reductive elimination9 was then utilized
for the concomitant C-2 double bond migration and the
removal of the unnecessary oxygen substituent of 12
and 20. During this process a complicated mixture of
partially hydrogenated products was formed which was
simply hydrogenated on Pd/C, giving methyl esters 13,
as a mixture of epimers,10 and 21, respectively.
Scheme 1. Retrosynthetic analysis.
Intermediates 13 and 21 were practically one step away
from the desired targets. The successful final steps
included initially acid treatment for removal of the
trityl group. This deprotection was optimized, after
some experimentation, with formic acid in anhydrous
ether. Saponification of the ester group and finally
lactonization upon refluxing in chloroform followed,
without isolation of any of the intermediates.
Readily available isopropylidene
L
- and
D
-erythrose (7
and 15, Schemes 2 and 3) served as the appropriate
chirons for this approach.7 Installation of the hydroxy-
methyl group and construction of the chiral quaternary
center was first achieved via an aldol reaction with
formaldehyde.6k,8 Alcohols 8 and 16 were then selec-
tively protected under forcing conditions to prepare
trityl ethers 9 and 17, respectively.
In contrast, a reverse sequence involving saponification
as the first step and subsequent detritylation with for-
mic acid led also to the partial formation of the pri-
mary alcohol formates.
Subsequently, a Wittig reaction with the unstable phos-
phonium ylides derived from octyl and decyl bromides
was used on the masked aldehydes to introduce the side
chain. It is worth noting that these reactions required a
rather high temperature, probably due to stereochemi-
cal hindrance from the adjacent quaternary carbon
substituent. Olefins 10 and 18 were isolated in excellent
yields as mixtures of Z- and E-isomers (ratios of ca. 2:1
and 7:3, respectively).
By applying this procedure to hydroxy ester 13 a mix-
ture of (−)-malyngolide 1 and (+)-2-epi-malyngolide 14
in a ratio of ca. 1:1 was formed. Pure products were
obtained after separation by column chromatography
and exhibited physical and spectroscopic data identical
Scheme 2. Synthesis of (−)-malyngolide 1. Reagents and conditions: (i) HCHO, K2CO3, MeOH, 65°C, 82%; (ii) TrCl, Py, 60°C,
87%; (iii) Ph3P+(CH2)7CH3Br−, nBuLi, THF, 0°C to room temperature, 97%; (iv) (COCl)2, DMSO, CH2Cl2 then Et3N, −55°C to
room temperature; (v) Ph3PꢀC(CH3)CO2Et, CH2Cl2, room temperature, 87% overall from 10; (vi) Mg, MeOH, room temperature;
(vii) H2, Pd/C, MeOH, room temperature, 65% overall from 12; (viii) HCO2H, Et2O, room temperature; (ix) NaOH, MeOH,
room temperature; (x) CHCl3, 60°C, 40% of 1, 45% of 14 overall from 13.

A. E. Koumbis et al. / Tetrahedron Letters 44 (2003) 2513–2516
2515
Scheme 3. Synthesis of (+)-tanikolide 2. Reagents and conditions: (i) HCHO, K2CO3, MeOH, 65°C, 87%; (ii) TrCl, Py, 60°C, 86%;
(iii) Ph3P+(CH2)9CH3Br−, nBuLi, THF, 0°C to room temperature, 92%; (iv) (COCl)2, DMSO, CH2Cl2 then Et3N, −55°C to room
temperature; (v) Ph3PꢀCHCO2Me, CH2Cl2, room temperature, 90% overall from 18; (vi) Mg, MeOH, room temperature; (vii) H2,
Pd/C, MeOH, room temperature, 60% overall from 20; (viii) HCO2H, Et2O, room temperature; (ix) NaOH, MeOH, room
temperature; (x) CHCl3, 60°C, 80% overall from 21.
with those reported in the literature.1,4b {for 1: [h]D=
−13.4 (c 0.8, CHCl3), lit.1 [h]D=−13.0 (c 2, CHCl3); for
14: [h]D=+12.1 (c 1, CHCl3), lit.3e [h]D=+12.3 (c 1,
CHCl3)}. It is however known that the unnatural
epimer could be isomerized to the natural one upon
treatment with tBuOK in DMSO, leading to ca. 1:1
mixtures.3a,11
3631–3635; (e) Carda, M.; Castillo, E.; Rodr´ıguez, S.;
Marco, J. A. Tetrahedron Lett. 2000, 41, 5511–5513; (f)
Ghosh, A. K.; Shirai, M. Tetrahedron Lett. 2001, 42,
6231–6233; (g) Suzuki, T.; Ohmori, K.; Suzuki, K. Org.
Lett. 2001, 3, 1741–1744; (h) Date, M.; Tamai, Y.; Hat-
tori, T.; Takayama, H.; Kamikubo, Y.; Miyano, S. J.
Chem. Soc., Perkin Trans. 1 2001, 645–653.
4. (a) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122,
10470–10471; (b) Mizutani, H.; Watanabe, M.; Honda,
T. Tetrahedron 2002, 58, 8929–8936.
Accordingly, hydroxy ester 21 provided in a very good
overall yield, (+)-tanikolide 2 which was also found to
have identical physical and spectroscopic properties
with those reported in the literature.2 {[h]D=+2.2 (c
0.75, CHCl3), lit. [h]D=+2.3 (c 0.7, CHCl3)}.
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6. (a) Gallos, J. K.; Koftis, T. V.; Koumbis, A. E. J. Chem.
Soc., Perkin Trans. 1 1994, 611–612; (b) Gallos, J. K.;
Goga, E. G.; Koumbis, A. E. J. Chem. Soc., Perkin
Trans. 1 1994, 613–614; (c) Gallos, J. K.; Koumbis, A. E.;
Apostolakis, N. E. J. Chem. Soc., Perkin Trans. 1 1997,
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V. I.; Koumbis, A. E. J. Chem. Soc., Perkin Trans. 1
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15180; (f) Gallos, J. K.; Koftis, T. V.; Koumbis, A. E.;
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Lett. 2000, 41, 4819–4822; (j) Gallos, J. K.; Dellios, C. C.;
Spata, E. E. Eur. J. Org. Chem. 2001, 79–82; (k) Gallos,
J. K.; Damianou, K. C.; Dellios, C. C. Tetrahedron Lett.
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Dellios, C. C.; Mourtzinos, I. T.; Coutouli-Argyropou-
The work described in this article presents a short and
efficient synthetic approach towards the preparation of
(−)-malyngolide 1 and (+)-tanikolide 2 making use of
readily available, multigram quantities of L- and D-ery-
throse derived chirons and employing a common ret-
rosynthetic plan. The overall yields for both targets are
over 30% [taking into account that (+)-2-epi-malyn-
golide is epimerized to the natural product] in a ten-
step sequence involving
a minimum number of
purifications and relatively simple and inexpensive
procedures.
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