Total synthesis of nominal lyngbouilloside aglycon

Article abstract of DOI:10.1021/ol203064r

The first enantioselective total synthesis of the originally assigned structure of lyngbouilloside aglycon has been achieved using a particularly flexible route featuring an acylketene macrolactonization of a tertiary methyl carbinol as the key step. Comp

Full text of DOI:10.1021/ol203064r

ORGANIC
LETTERS
2012
Vol. 14, No. 1
314–317
Total Synthesis of Nominal
Lyngbouilloside Aglycon
Abdelatif ElMarrouni, Raphael Lebeuf, Julian Gebauer, Montserrat Heras,‡
Stellios Arseniyadis,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
stellios.arseniyadis@espci.fr; janine.cossy@espci.fr
Received November 14, 2011
ABSTRACT
The first enantioselective total synthesis of the originally assigned structure of lyngbouilloside aglycon has been achieved using a particularly
flexible route featuring an acylketene macrolactonization of a tertiary methyl carbinol as the key step. Comparison of the C13 chemical shifts of our
synthetic aglycon with the ones pertaining to natural lyngbouilloside and lyngbyaloside C resulted in a possible stereochemical reassignment of
the C11 stereogenic center.
In 2002, two closely related 14-membered lactones, namely
lyngbouilloside 11 and lyngbyaloside B 2,2 were isolated from
two different marine cyanobacteria of the genus Lyngbya
(Oscillatoria). Belonging to the interesting class of antitumor-
al glycosyl macrolides,3 1 and 2 were found to exhibit
moderate activity against neuroblastoma and KB cells with
IC50 values of 17 and 4.3 μM, respectively. In addition, 1 and
2 were also found to possess unique structural elements
including more than 10 stereogenic centers, a six-membered
ring hemiketal, and an (E,E)-octadienyl side chain (Figure 1).
However, the most characteristic and synthetically challen-
ging feature remains to be the unusual tertiary methyl
carbinol at C13, as macrolactonizations of sterically encum-
bered alcohols are particularly rare and, more importantly,
low yielding.4 Hence, due to its challenging molecular archi-
tecture, its natural scarcity, and the fact that the absolute
configuration of both the sugar and the aglycon fragments is
still unknown, lyngbouilloside 1 presents a unique opportu-
nity for chemical synthesis. We herein present a general and
highly flexible synthetic approach toward this intriguing
‡ Present address: Department of Chemistry, Faculty of Sciences,
University of Girona, Campus de Montilivi, E-17071 Girona, Spain.
ꢀ
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Figure 1. Proposed structures of lyngbouilloside1 and lyngbya-
loside B2 and C.
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natural product which resulted in the first total synthesis of
the originally assigned structure of lyngbouilloside aglycon 4.
In2008, weinitiallyreportedthestereoselective synthesis
of the fully functionalized carbon backbone of 1 featuring
r
10.1021/ol203064r
Published on Web 12/07/2011
2011 American Chemical Society

Scheme 1. First and Second Generation Approach to Lyng-
bouilloside Aglycon 4
Scheme 2. Second and Third Generation Approach to Lyng-
bouilloside Aglycon 4
a cross-metathesis (CM) between a C1ꢀC8 and a C9ꢀC13
fragment, the latter being derived from (S)-citramalic
acid 7.5 Albeit we were in the following able to cyclize the
advanced intermediate 6 via the intended intramolecular
acylketene-trapping,4a,6 the synthesis of the desired methyl
vinyl carbinol from the corresponding hydroxy aldehyde
and the attempted side chain introduction via a sequential
hydroboration/Suzuki coupling proved to be rather low
yielding (Scheme 1).
Encouraged by this overall proof-of-concept, we finally
decided to adapt our strategy by already installing half of
the side chain early in the synthesis thus avoiding the
delicate late-stage aldehyde methylenation (Scheme 1). In
practice, the synthesis of the C9ꢀC17 fragment began by
converting commercially available 3-methylbut-3-enol
(11) to the known isoprenol-derived (R)-epoxide 12 fol-
lowing a reported procedure,7 which consists of a Mitsu-
nobu etherification,8 a Sharpless dihydroxylation9 using
AD-mix R (ee = 94%), and an epoxidation of the resulting
(5) Gebauer, J.; Arseniyadis, S.; Cossy, J. Synlett 2008, 712–714.
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38, 3022–3034.
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Hennig, L.; Findeisen, M.; Reinhardt, G.; Oehme, R.; Welzel, P.
Tetrahedron 2003, 59, 5295–5306. (b) Sparks, S. M.; Chen, C.; Martin,
S. F. Tetrahedron 2007, 63, 8619–8635.
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2380–2382. (b) Mitsunobu, O. Synthesis 1981, 1–28.
(9) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968–1970. (b) Kolb,
H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483–2547.
1,2-diol,10 to afford the title compound in 75% overall
yield (Scheme 2). Ring opening of the latter with a pro-
pargyl Grignard11 reagent gave alkynol 13 as an adequate
€
(10) Tietze, L. F.; Gorlitzer, J. Synthesis 1998, 873–878.
Org. Lett., Vol. 14, No. 1, 2012
315

substrate for subsequent side chain elongation. Triisopro-
pylsilyl (TIPS)-protection of the terminal alkyne and PMP-
deprotection with cerium ammonium nitrate (CAN) then
provided 1,3-diol 14 which, after sequential TEMPO
oxidation/asymmetric crotyltitanation (dr >95:5),12 furn-
ished the alternative CM precursor 15 in nine steps and
36% overall yield starting from 3-methylbut-3-enol (11).
While attempted CM between diol 15 and the previously
reported enantiopure β-hydroxy dioxinone fragment 175
was accompanied by pyrane formation via intramolecular
oxa-Michael addition,13 cross-coupling with the corre-
sponding PMP-acetal 16 employing 20 mol % of the
HoveydaꢀGrubbs second generation catalyst proceeded
smoothly to afford enone 18 in both high yield (78% over
two steps) and excellent E-selectivity (E/Z > 95:5). Con-
jugate reduction using an in situ generated hydridocuprate14
and treatment with DDQ then gave hydroxy ketone 19 in
60% overall yield. Tetramethylammonium triacetoxyboro-
hydride (TABH)-mediated reduction (dr >95:5),15 bis-
triethylsilyl (TES)-protection of the resulting 1,3-anti-diol
(84% over two steps), and thermolysis in refluxing toluene
eventually afforded the desired orthogonally protected
macrolactone 20 along with trace amounts of the corre-
sponding methyl ketone derivative resulting from keto-
acid decarboxylation. After removal of the silyl protect-
ing groups (60% over three steps),16 the stereoselective
introduction of the (E,E)-octadienyl side chain was best
achieved via a Sonogashira coupling with (E)-1-iodo-
1-butene [PdCl2(PPh3)2, CuI, Et3N, DMF] followed
by a one-pot hydrosilylation/protodesilylation17 sequence
[HSi(OEt)3, Cp*Ru(MeCN)3]PF6, CH2Cl2, 0 °C to rt, then
Agf, THF/MeOH, rt followed by an aqueous HCl workup]
thus giving rise to the para-methoxybenzoyl (PMBz)-protected
aglycon 21 in an acceptable 20% overall yield. Unfortu-
nately, despite the wide range of reaction conditions tested,
the final cleavage of the PMBz protecting group met with no
success most likely due to an intramolecular hydrogen
bonding between the carbonyl of the PMBz and the hydroxyl
of the hemiketal rendering the former particularly con-
gested and therefore nonaccessible. To overcome this unex-
pected drawback without significantly altering the synthesis
and with the idea that a selective glycosylation of the less hind-
ered C5 hydroxyl would be favored in the final steps of the
synthesis, we decided to simplify our protecting group strategy
by choosing a silyl protecting group instead of an ester
derivative. Diol 15 was thus converted to the corresponding
Table 1. C1 to C13 Chemical Shifts (δ, ppm) for Lyngbouillo-
side 1, Lyngbyaloside C 3, and Our Synthetic Aglycon 4, and the
Differences (Δδ, ppm) with Lyngbouilloside 1a
carbon
δ for (1)a
δ for (4)a (Δδ)
δ for (3)b (Δδ)
1
172.9
47.5
97.2
41.9
69.8
38.4
70.2
31.9
33.0
37.5
66.0
44.7
86.9
172.3 (þ0.6)
47.1 (þ0.4)
96.3 (þ0.9)
43.4 (ꢀ1.5)
64.9 (þ4.9)
40.7 (ꢀ2.3)
68.9 (þ1.3)
33.5 (ꢀ1.6)
31.5c (þ1.5)
37.6 (ꢀ0.1)
67.4 (ꢀ1.4)
45.8c (ꢀ1.1)
86.4 (þ0.5)
172.3 (þ0.6)
46.9 (þ0.6)
96.6 (þ0.6)
41.5 (þ0.4)
69.2 (þ0.6)
37.7 (þ0.7)
69.8 (þ0.4)
31.4 (þ0.5)
32.4 (þ0.6)
37.0 (þ0.5)
65.5 (þ0.5)
44.1 (þ0.6)
86.2 (þ0.7)
2
3
4
5
6
7
8
9
10
11
12
13
a 150 MHz. b 100 MHz. c Chemical shifts determined by HMQC correlation.
(11) (a) Nakayama, Y.; Kumar, G. B.; Kobayashi, Y. J. Org. Chem.
2000, 65, 707–715. (b) Dimitrieva, L. L.; Nikitina, L. P.; Albanov, A. I.;
Nedolya, N. A. Russ. J. Org. Chem. 2005, 41, 1583–1593.
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P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321–2336. (b)
Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807–832.
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Soc. 1988, 11, 3560–3578.
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12727. (b) Bressy, C.; Bargiggia, F.; Guyonnet, M.; Arseniyadis, S.;
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10140.
Figure 2. Graphically depicted 13C chemical shift differences
(Δδ, ppm) for each carbon between C1 and C13 of lyngbouillo-
side 1 and our synthetic aglycon 4 (top), and lyngbouilloside 1
and lyngbyaloside C 3 (bottom).
316
Org. Lett., Vol. 14, No. 1, 2012

bis-triethylsilyl ether 22, and the resulting product was en-
gaged in the same HoveydaꢀGrubbs second generation
catalyst-mediated CM as mentioned previously (16f18).
Next, as reduction of the enone under the hydrostannylation
conditions afforded slightly lower yields compared to those
previously obtained (18f19), compound 23 was treated
with Stryker’s reagent18 instead, and the resulting hydroxy
ketone was subjected to the approved Evans TABH-mediated
1,3-anti reduction to furnish the 1,3-anti diol 24 as a single dia-
stereoisomer (dr >95/5) in 71% overall yield. After removal
of the TES protecting groups under mild conditions
lyngbouilloside (Table 1, Figure 2, top), particularly in the
C9ꢀC13 region, strongly suggests that the structure of the
natural product may have been originally misassigned. This
observation, which was also made by Ley and co-workers
after spectroscopical analysis and DFT chemical shift cal-
culations of a closely related PMB-protected macrolac-
one,20 is also supported by the fact that the 13C NMR data
of both lyngbouilloside and the more recently reported
lyngbyaloside C, 3 (Figure 1),21 are virtually identical within
the region of the macrocycle (Figure 2, bottom) while the
proposed structures of the two natural products differ at
C11.
using a catalytic amount of FeCl3 6H2O in methanol,19
3
the three secondary alcohols were selectively reprotected
(TESCl, imidazole) to complete the synthesis of the key
macrocyclization precursor in 60% yield over two steps.
Thermolysis of the dioxinone under rigorously anhy-
drous conditions then resulted in the generation of the
corresponding acylketene which was efficiently trapped
intramolecularly by the remaining free alcohol thus
allowing us to isolate the 14-membered macrocyclic
lactone 25. The TES groups were eventually removed
In summary, we have completed the first total synthesis
of the originally assigned structure of lyngbouilloside
aglycon 4 in 20 steps and 2.1% overall yield starting from
commercially available 3-methylbut-3-enol (11) and sug-
gested a stereochemical reassignment at C11. This straight-
forward and particularly flexible approach featuring an
acylketene macrolactonization and a late stage side chain
introduction and glycosylation provides an expedient en-
try into the lyngbouilloside framework as well as to the
various lyngbyalosides.
with HF Py, resulting in the concomitant formation of
3
the pyrane ring, while treatment with AgF gave the
terminal alkyne. Finally, Sonogashira coupling followed
by the approved one-pot hydrosilylation/protodesilyla-
tion sequence completed the synthesis, leading to the
desired lyngbouilloside aglycon 4 in 18% yield over four
steps.
Acknowledgment. We would like to thank Generalitat
de Catalunya for financial support to A.E.
Supporting Information Available. Experimental de-
tails and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Interestingly, comparison of the NMR chemical shifts of
our synthetic aglycon with the ones reported for the natural
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Org. Lett., Vol. 14, No. 1, 2012
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