Stereoselective synthesis of the C9-C19 fragment of lyngbyaloside B and C via ether transfer

Article abstract of DOI:10.1021/ol301455p

A stereoselective synthesis of the C9-C19 fragment of lyngbyaloside B and C highlighted, by an extension of our ether transfer methodology, enables the formation of tertiary ethers. 2-Naphthylmethyl ethers have been shown to proceed efficiently through ether transfer with high stereoselectivity and are easily deprotected by DDQ oxidation. Variation of the workup conditions results in the stereoselective formation of syn-1,3-diol mono- or diethers.

Full text of DOI:10.1021/ol301455p

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3490–3493
Stereoselective Synthesis of the C9ꢀC19
Fragment of Lyngbyaloside B and C via
Ether Transfer
Eric Stefan and Richard E. Taylor*
Department of Chemistry and Biochemistry and the Mike and Josie Harper Cancer
Research Institute, University of Notre Dame, 251 Niewland Science Hall, Notre Dame,
Indiana 46556, United States
taylor61@nd.edu
Received May 27, 2012
ABSTRACT
A stereoselective synthesis of the C9ꢀC19 fragment of lyngbyaloside B and C highlighted, by an extension of our ether transfer methodology, enables
the formation of tertiary ethers. 2-Naphthylmethyl ethers have been shown to proceed efficiently through ether transfer with high stereoselectivity and
are easily deprotected by DDQ oxidation. Variation of the workup conditions results in the stereoselective formation of syn-1,3-diol mono- or diethers.
Polyketide metabolites of marine cyanobacteria are
increasingly attracting the attention of synthetic groups
due to their unique structural features and diverse bio-
logical activity. These compounds have demonstrated a
broad spectrum of biological activities, including antiviral,
antibiotic, antifungal, anticancer, and protein synthesis
inhibition. For example, investigations of L. bouillonii
collections from the Ulong Channel in Palau led to the
discovery of lyngbyaloside B by Moore (Figure 1).1 More
recently, Luesch and co-workers isolated congeners,
18E- and 18Z-lyngbyaloside C, from Papua New Guinea.2
Many polyketides from marine cyanobacteria have been
shown to possess β-branching, methyl substituents at odd
numberedcarbons, resulting from anHMG-CoA synthase
(HCS) cassette within the polyketide synthase.3 The lyng-
byalosides are structurally interesting due to a lactone
Figure 1. Structure of Lyngbyalosides B and C from L.
bouillonii.
generated by acylation of a tertiary alcohol. Despite initial
efforts, lyngbyaloside B and C have yet to be synthesized.4
We have recently developed a novel approach to the
formation of syn-1,3-diol mono- and diethers through
electrophilic activation of homoallylic alkoxymethyl
ethers.5 As shown in Scheme 1, activation of alkene 1a
with iodine monochloride, in toluene at low temperature,
initiates a stereoselective cyclization to form oxonium ion
2a through a chairlike transition state. NMR evidence
supported the ultimate generation of chloromethyl ether
(1) Luesch, H.; Yoshida, W. Y.; Harrigan, G. G.; Doom, J. P.;
Moore, R. E.; Paul, V. J. J. Nat. Prod. 2002, 65, 1945–1948.
(2) Matthew, S; Salvador, L. A.; Schupp, P. J.; Paul, V. J.; Luesch, H.
J. Nat. Prod. 2010, 73, 1544–1552.
(3) Kerr, J.-C.; Gatte Picchi, D.; Dittmann, E. Beilstein J. Org. Chem.
2011, 7, 1622–1635.
(4) (a) Hoye, T. R.; Danielson, M. E.; May, A. E.; Zhao, H. Angew.
Chem., Int. Ed. 2008, 47, 9743–9746. (b) For a recent synthesis of the
aglycone of the structurally related polyketide, lyngbouilloside, see: El
Marrouni, A.; Lebeuf, R.; Gebauer, J.; Heras, M.; Arseniyadis, S.;
Cossy, J. Org. Lett. 2012, 14, 314–317.
r
10.1021/ol301455p
Published on Web 06/20/2012
2012 American Chemical Society

3a, which can be selectively functionalized with a variety of
nucleophiles. Hydrolytic workup directly generates a 1,3-
syn-diol monoether 4a with excellent stereocontrol.
Interestingly, the use of IBr in toluene (entry 9) also
resulted in benzyl cleavage although rationale for the
sensitivity of the reaction to the halide counterion and
solvent is currently unclear.
Scheme 1. Syn-1,3-Diol Mono- and Diethers via Ether Transfer
Table 1. Electrophile-Induced Methoxy Transfer
More recently, we envisaged extension of this methodol-
ogy to the preparation of tertiary ether 4b from 1,1-
disubstituted alkene 1b. The effect of an axial methyl
substituent (R0) in 2b on the stereoselectivity of the cycliza-
tion was an important question. However, good dia-
stereoselectivities were observed in related iodine-induced
carbonate cyclization previously demonstrated by
Cardillo.6
sm
conditions
yield (dr)a
yield 7a (dr)
1
2
3
4
5
6
7
8
9
5a ICl, PhCH3, ꢀ78 °C
5a IBr, PhCH3, ꢀ78 °C
5a I2, PhCH3, ꢀ78 °C
6a 78% (5:1)
6a 62% (1.1:1)
trace
not obs.
not obs.
not obs.
not obs.
not obs.
not obs.
not obs.
15%
5a IPy2BF4, PhCH3, ꢀ78 °C NR
5a ICl, CH2Cl2, ꢀ78 °C
5a ICl, PhCH3, ꢀ95 °C
5a ICl, pentane, ꢀ115 °C
5b ICl, PhCH3, ꢀ78 °C
5b IBr, PhCH3, ꢀ78 °C
6a 63% (2.4:1)
6a 75% (8.5:1)
6a 53% (7.5:1)
6b 63% (8.5:1)
6b 5%
The homoallylic methoxymethyl ether 5a was readily
obtained as a racemate from ring opening of the corre-
sponding terminal epoxide with isopropenyl magnesium
bromide followed by protection with commercially avail-
able methoxymethyl chloride. Initial studies focused on
subjecting 5a to a variety of electrophilic activation con-
ditions followed by a hydrolytic workup, and the results
are listed in Table 1. The choice of activating agent and
solvent proved critical for high yield and diastereoselec-
tivity of the desired methyl ether transfer product and
suppression of side reactions. As in our previous study,5a
iodine monochloride and toluene at low temperature were
found to be the best activation conditions (entry 1) and
increased diastereoselectivity was observed by lowering the
temperature to ꢀ95 °C (entry 6). With favorable reaction
conditions in hand, the analogous benzyloxymethyl ether
5b was investigated. Benzyl ether transfer provides access
to orthogonally protected syn-1,3-diol units since benzyl
groups can typically be removed by hydrogenolysis. The
choice of the activating agents and solvents were again
critical in the formation of the ether transfer product 6b
over acetal 7a which results from benzyl cleavage of
intermediate 8.5a The use of ICl in toluene provided
predominantly the ether transfer product 6b (entry 8),
while activation in DCM led to preferential formation of
the 1,3-dioxane 7a as the major product (entry 10).
71% (5:1)
60% (3:1)
trace
10 5b ICl, CH2Cl2, ꢀ78 °C
11 5b ICl, CH3CN, ꢀ78 °C
12 5b ICl, PhCH3, ꢀ95 °C
13 5c ICl, PhCH3, ꢀ95 °C
14 5c IBr, PhCH3, ꢀ78 °C
trace
6b 50% (2.5:1)
6b 60% (10:1)
6c 65% (11:1)
6c 51% (20:1)
not obs.
not obs.
20%
a Diastereomeric ratio was determined by 1H and 13C NMR.
The use of an alternative arylmethyl ether in the
transfer, a 2-naphthylmethyl group, improved the
selectivity for ether transfer product 6c over dioxane
7a even under the IBr activation conditions (entries 13
and 14). The stereochemistry of ether transfer products
6aꢀc were all inferred from 7a, unambiguously as-
signed by ROESY (Rotating-frame Overhauser Effect
Spectroscopy) experiments, since each of these com-
pounds arise from intermediate 8.
Our original publication on ether transfer provided in
situ NMR evidence to support the intermediacy of chloro-
methyl ether intermediate 3 prior to aqueous workup and
loss of the acetal methylene as formaldehyde.5a This
enabled the development of a number of nucleophilic
workup conditions to provide syn-1,3-diethers.5 Of partic-
ular interest was the regeneration of the methoxymethyl
ether through a basic methanol quench. As shown in Table
2, ICl-induced ether transfer followed by a basic methanol
quench provided orthogonally protected diethers 9aꢀc
from 5aꢀc in high yields and stereoselectivities. The
2-naphthylmethyl ether was found to be a particularly
useful transferable group as the resulting product could
be easily deprotected with aqueous DDQ providing 10 in
84% yield.
(5) (a) Liu, K.; Taylor, R. E.; Kartika, R. Org. Lett. 2006, 8, 5393–
5395. For applications of the ether transfer, see: (b) Kartika, R.; Gruffi,
T. R.; Taylor, R. E. Org. Lett. 2008, 10, 5047–5050. (c) Kartika, R.;
Taylor, R. E. Angew. Chem., Int. Ed. 2007, 46, 6874–6877. (d) Kartika,
R.; Taylor, R. E. Heterocycles 2007, 74, 447–459. (e) Liu, K.; Arico,
J. W.; Taylor, R. E. J. Org. Chem. 2010, 75, 3953–3975. (f) Kartika, R.;
Frein, J. D.; Taylor, R. E. J. Org. Chem. 2008, 73, 5592–5594.
(6) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Org.
Chem. 1982, 47, 4626–4633.
Org. Lett., Vol. 14, No. 13, 2012
3491

biosynthetic pathways. Having accomplished the devel-
opment of a reliable ether transfer protocol to stereo-
chemically defined tertiary ethers, we next focused our
efforts on an application to the synthesis of the C9ꢀC19
fragment of lyngbyaloside B and C, Scheme 2. The epoxy
alcohol 13, obtained in three steps from propargyl alco-
hol and 2-methyl-2-propen-1-ol,8 was regioselectively
opened with methylmagnesium bromide in the presence
of a copper bromide dimethyl sulfide complex.9 BPS
protection of the primary alcohol followed by incorpora-
tion of the transferable naphthylmethyloxymethyl group
provided 15.
Table 2. Ether TransferꢀMethanol Quench
sm
R
product
yield (dr)
1
2
3
5a
5b
5c
ꢀCH3
9a
9b
9c
88% (7:1)
65% (12:1)
74% (12:1)
ꢀCH2Ph
ꢀCH2(2-Naphth)
Despite its critical role in the ether transfer, the use of
Scheme 2. Application to the C9ꢀC19 Fragment Synthesis
iodine monochloride has also shown some limitations.
With some substrates, an appreciable amount of ICl
addition products have been observed leading to low yields
of the desired ether transfer. Recently, Snyder reported
polyene cyclizations affected by new electrophilic halogen
sources such as bromodiethylsulfoniumbromopentachlo-
roantimonate (BDSB) as well as the iodine version (IDSI).7
These new conditions were successfully applied to the ether
transfer, Table 3, to provide methoxy and benzyloxy
transfer products in higher yield (entries 11 and 12) but,
unfortunately, at the expense of the diastereomeric ratio.
Table 3. New Activating Conditions
Upon treatment with our optimized conditions followed
by the methanolic quench, the MOM protected 16 was
obtained in 88% yield as a 10:1 mixture of diastereomers.
Mild oxidative deprotection, which selectively liberated
the tertiary alcohol, was followed by coupling to allylmag-
nesium bromidein the presenceof copper iodide. Carbonꢀ
carbon bond formation and generation of 17 likely occurs
through nucleophilic addition to an in situ generated
epoxide. Confirmation of the 1,3-syn-stereochemical as-
signment was obtained by conversion of MOM ether 17 to
the corresponding methylene acetal under acidic condi-
tions (see Supporting Information). Toward our natural
product target, the tertiary alcohol was protected as a
triethylsilyl ether and subjected to an E-selective cross-
metathesis homologation. Finally, Wittig olefination with
(bromomethyl)triphenylphosphonium bromide gave the
C9ꢀC19 fragment of lyngbyaloside 18 as a 1:2 mixture of
E/Z isomers.
sm
conditions
yield (dr)
1
5a
5a
5a
5a
5b
5b
5b
5b
5a
5a
5a
5b
5b
BDSB, CH3NO2, ꢀ29 °C
BDSB, CH3CH2NO2, ꢀ78 °C
BDSB, CH3CN, ꢀ45 °C
11 75% (4:1)
11 72% (6.1:1)
11 62% (7.4:1)
11 46% (17:1)
12 71% (4.3:1)
7b only
2
3
4
BDSB, CH3CH2CN, ꢀ78 °C
BDSB, CH3NO2, ꢀ29 °C
BDSB, CH3CH2NO2, ꢀ78 °C
BDSB, CH3CN, ꢀ45 °C
5
6
7
12 52% (6.3:1)
7b only
8
BDSB, CH3CH2CN, ꢀ78 °C
IDSI, CH3NO2, ꢀ29 °C
9
6a 78% (3.2:1)
6a 76% (3.3:1)
6a 95% (2.8:1)
6b 75% (4:1)
6b 67% (5:1)
10
11
12
13
IDSI, CH3CH2NO2, ꢀ78 °C
IDSI, CH3CH2CN, ꢀ78 °C
IDSI, CH3NO2, ꢀ29 °C
In summary we have successfully applied our ether
transfer conditions to the stereoselective formation of
tertiary ethers. Electrophilic activation of homoallylic
alkoxymethyl ethers enabled the formation of syn-1,3-diol
mono- and orthogonally protected diethers through ether
transfer. As an additional advancement of our previously
described method, 2-naphthylmethyl ethers have been
IDSI, CH3CH2CN, ꢀ78 °C
The oxygenation pattern found in ether transfer pro-
ducts such as 6aꢀc and 9aꢀc is of significant utility in the
synthesis of polyketides with unique patterns of methy-
lation such as those derived from cyanobacterial PKS
(8) Alegret, C.; Santacana, F.; Riera, A. J. Org. Chem. 2007, 72,
7688–7692.
(9) Hodgson, D. M.; Arif, T. Org. Lett. 2010, 12, 4204–4207.
(7) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc.
2010, 132, 14303–14314.
3492
Org. Lett., Vol. 14, No. 13, 2012

shown to proceed efficiently through ether transfer with
high stereoselectivity and are easily deprotected by DDQ
oxidation. This new, stereoselective route to structural
units containing tertiary ethers has found application in
the synthesis of the C9ꢀC19 fragment of lyngbyaloside B
and C. Additional efforts toward the total synthesis of
these cyanobacteria-derived polyketides are currently un-
derway in our laboratories and will be reported in due
course.
Acknowledgment. Support of this work by the National
Institutes of Health and the National Institute of General
Medical Sciences is gratefully acknowledged (GM084922).
Supporting Information Available. Full experimental and
data characterization for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3493