Total synthesis of an exceptional brominated 4-pyrone derivative of algal origin: An exercise in gold catalysis and alkyne

Article abstract of DOI:10.1002/chem.201500437

A concise approach to the algal metabolite 1 is described, which also determines the previously unknown stereostructure of this natural product. Compound 1 is distinguished by a rare brominated 4-pyrone nucleus linked as a ketene-acetal to a polyunsaturated macrocyclic scaffold comprising an extra homoallylic bromide entity. The synthesis of 1 is based on the elaboration and selective functionalization of the linear precursor 23 endowed with no less than six different sites of unsaturation including the highly enolized oxo-alkanoate function. Key to success was the formation of the 2-alkoxy-4-pyrone ring by a novel gold-catalyzed transformation which engages only the acetylenic β-ketoester substructure of 23 but leaves all otherπ-bonds untouched. The synthesis was completed by a ring-closing alkyne metathesis to forge the signature cycloalkyne motif of 1 followed by selective bromination of the ketene-acetal site in the resulting product 27 without touching the skipped diene-yne substructure resident within the macrocyclic tether.

Full text of DOI:10.1002/chem.201500437

DOI: 10.1002/chem.201500437
Communication
&
Natural Products
Total Synthesis of an Exceptional Brominated 4-Pyrone Derivative
of Algal Origin: An Exercise in Gold Catalysis and Alkyne
Metathesis
Laura Hoffmeister, Tsutomu Fukuda, Gerit Pototschnig, and Alois Fꢀrstner*[a]
bone including a rare cycloalkyne motif needs careful consider-
Abstract: A concise approach to the algal metabolite 1 is
described, which also determines the previously unknown
stereostructure of this natural product. Compound 1 is
distinguished by a rare brominated 4-pyrone nucleus
linked as a ketene–acetal to a polyunsaturated macrocy-
clic scaffold comprising an extra homoallylic bromide
entity. The synthesis of 1 is based on the elaboration and
selective functionalization of the linear precursor 23 en-
dowed with no less than six different sites of unsaturation
including the highly enolized oxo-alkanoate function. Key
to success was the formation of the 2-alkoxy-4-pyrone
ring by a novel gold-catalyzed transformation which en-
gages only the acetylenic b-ketoester substructure of 23
but leaves all other p-bonds untouched. The synthesis
was completed by a ring-closing alkyne metathesis to
forge the signature cycloalkyne motif of 1 followed by se-
lective bromination of the ketene–acetal site in the result-
ing product 27 without touching the skipped diene–yne
substructure resident within the macrocyclic tether.
ation.
For these very reasons, compound 1 was deemed syntheti-
cally most challenging. While the formation of the cycloalkyne
substructure of 1 by ring-closing alkyne metathesis (RCAM)
seemed fairly obvious (B ! A, Scheme 1),[6,7] it was hoped that
the peculiar ketene–acetal motif linking the heterocyclic ring
in 1 to the lipophilic tether renders this site sufficiently elec-
tron rich to broker a selective late-stage bromination of a pre-
cursor of type A even in the presence of other potentially reac-
tive p-systems. Although this projected maneuver bore consid-
erable risk,[8] the formation of the 2-alkoxy-4-pyrone ring itself
under conditions that allow the resident functionality to
endure was even less intuitive. 4-Pyrones are privileged motifs
for chemical biology and medicinal chemistry,[9] but only few
methods are known for their synthesis, especially for the
subset containing a 2-alkoxide substituent.[10] Because these
procedures usually require fairly harsh conditions and/or are
inherently limited to the formation of 4-methoxy-2-pyrones,[11]
none of them seemed adequate for an application to the total
synthesis of 1.
Although the secondary metabolites 1–6 isolated from south-
ern Australian red algae of the genus Phacelocarpus labillardieri
are unique in structural terms,[1–3] they escaped total synthesis
for more than three decades.[4] This paradox may perhaps be
attributed to the missing stereochemical assignment of the
chiral centers in 1–3 and 5, as well as to the only limited infor-
mation about their biological properties and ecological func-
tions.[5] From a synthetic viewpoint, these truly exceptional
pyrone derivatives constitute attractive targets for the ensem-
ble of unorthodox structural elements comprised within their
macrocyclic frames. While skipped polyenes (enynes) are per
se often fragile and difficult to work with, the presence of the
unusual enol ether linkages in 4–6 or the homoallylic bromide
functions in 1–3 with latent non-classical carbocation reactivity
certainly augment the task. Likewise, the proper buildup of
two different brominated sites within a polyunsaturated back-
For this very reason it was planned to forge this characteris-
tic heterocyclic ring system by re-programming a gold cata-
lyzed procedure previously developed by our group for the
preparation of 2-pyrones G (Scheme 1, bottom).[12–14] This trans-
formation hinges on a 6-endo-dig cyclization of alkynoic b-ke-
toesters (R2 =tBu). Complexation of the triple bond with a p-
acidic catalyst,[15,16] as shown in D, leads to a first cyclic inter-
[a] L. Hoffmeister, Dr. T. Fukuda, G. Pototschnig, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500437.
Chem. Eur. J. 2015, 21, 1 – 6
1
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
Our apprehension was further raised by the fact that a litera-
ture search gave only very few hits of homoallyl bromides
made in such a way.[19]
Scheme 2. Biosynthetic hypothesis, suggesting that the bromohydrin junc-
tion in 1 is syn-configured (only the relative stereochemistry is implied).
The actual synthesis commenced with the desymmetrization
of cheap
7
by the Sharpless epoxidation protocol
(Scheme 3).[20] TBS-protection of the resulting product 8 fol-
lowed by hydrogenation of the remaining double bond over
palladium on charcoal furnished multigram quantities of com-
pound 9. A Lewis-acid assisted opening of the epoxide ring[21]
by the lithiated skipped diyne 11[22] followed by cleavage of
the acetal protecting group in the resulting product 12 gave
a labile diol, which was immediately processed by catalytic
semi-reduction of both triple bonds over nickel boride (P2-
Ni),[23] followed by conversion of the primary hydroxyl group
into the corresponding bromide. Although the resulting prod-
uct 13 is sensitive and can only be kept in frozen benzene
glass for limited periods of time, it was amenable to a highly
selective nucleophilic substitution on treatment with propynyl-
magnesium bromide in the presence of sub-stoichiometric
amounts of CuI; provided that the temperature was carefully
controlled, the competing SN2’ attack of the nucleophile was
suppressed and the stereochemical integrity of the Z-config-
ured allylic bond fully preserved to give the skipped diene–yne
14 in respectable yield.[12,24]
Substantial optimization was necessary to find a reliable
method for the conversion of 14 into the homoallylic bromide
15. In the end, surprisingly harsh conditions gave the best re-
sults and allowed 15 to be obtained in well reproducible 60%
yield. Complications arose from partial elimination of the alco-
hol as well as from competing Z/E isomerization, which—
somewhat unexpectedly—affected the distal D13,14-bond more
than the homoallylic alkene. For analytical purposes, the result-
ing by-products 17 and 18 were removed and the integrity of
15 was unambiguously confirmed; in the preparative context,
however, this tedious homework was unnecessary as the iso-
meric compounds could be separated in the final steps of the
synthesis. It is also emphasized that all attempts to install the
bromide function in the tether at a later stage met with de-
composition of the precious material.[25]
Scheme 1. Retrosynthetic analysis of 1 (top) and rationale of the envisaged
synthesis of 2-alkoxy-4-pyrones by a gold catalyzed cycloisomerization of an
acetylenic b-ketoester (bottom).
mediate of type E, which is prone to rapid loss of isobutene
and a proton as necessary for product release and catalyst re-
cycling. Because an analogous intermediate E with R2 ¼ tBu
cannot collapse in this way, it should be longer lived and
might therefore give tautomerization to the corresponding 2-
alkoxy-4-pyrone H a chance. Even if successful, however, the
challenge of imposing this novel transformation onto an inher-
ently labile precursor of type C remains, which might have
many other options to react (or decompose) upon activation
of the different p-bonds by a carbophilic Lewis acid catalyst.
Under the premise that the gold-catalyzed cyclization can
eventually be steered towards the required 4-pyrone tauto-
mer,[17] we embarked on the total synthesis of 1. Although the
relative and absolute configuration of the two resident chiral
centers had remained unassigned by the different isolation
teams,[1–3] syn-1 was deliberately chosen as our prime target.
Because of the likely biosynthetic origin of 1 from a polyunsa-
turated fatty acid precursor of type I, its bromohydrin entity is
thought to derive from the attack of the pyrone (or its immedi-
ate progenitor) onto a Z-alkene activated by a bromonium
cation equivalent (see intermediate J, Scheme 2). This hypo-
thetic scenario is in accord with the oxidative halogenation
paradigm accounting for the biosynthesis of most halogen-
containing natural products[18] and necessarily leads to a syn-
configured linkage. For preparative purposes however, it was
planned to introduce the bromide substituent at C19 by an
SN2 -type inversion of an anti-configured secondary alcohol
precursor. However, this transformation might be far from trivi-
al, given the homoallylic environment of the C19 position in 1.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
2
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
Equally gratifying was the outcome of the subsequent ring-
closing alkyne metathesis (RCAM)[6] of the sensitive diyne 25
which eventually degrades even upon storage in a freezer. Yet,
treatment of this compound with the molybdenum alkylidyne
26 (5 mol%) at ambient temperature in the presence of MS
5 ꢂ to sequester the released 2-butyne furnished cycloalkyne
27 in excellent yield.[28] As expected, the chosen catalyst rigor-
ously distinguished between the alkene and the alkyne groups
of 25. Moreover, the chemical character of this formally high-
valent metal species is obviously sufficiently tempered by the
ancillary silanolate ligands not to cause any configurational or
migratory isomerization of the highly susceptible skipped
diene-yne motif.[29,30]
At this point, only the selective bromination of the 4-pyrone
ring in 27 was missing. A screening of different [Br+] sources
under a variety of experimental conditions showed that the re-
action indeed favored the ketene-acetal site, as originally
hoped;[8] however, rapid Z ! E isomerization turned out to be
a serious complication, again mostly at the D13,14-double bond.
Upon lowering the temperature, the desired bromination
would stall while the isomerization continued to compromise
the sterochemical integrity of the material. Therefore the total
synthesis was completed on treatment of 27 with freshly re-
crystallized NBS at ambient temperature; the conversion was
closely monitored and the reaction stopped as soon as the
starting material was consumed, because extended stirring ag-
gravated the isomerization problem. Under these conditions,
syn-1 was isolated in well reproducible 40% yield, which we
deemed acceptable in view of the unusual sensitivity of sub-
Scheme 3. a) Ti(OiPr)4 (10 mol%), (+)-diisopropyl tartrate (13 mol%), cumene
hydroperoxide, CH2Cl2, MS 4 ꢂ, ꢀ258C, 82%; b) TBSCl, imidazole, DMF, 08C
! RT, 90%; c) H2 (1 atm), Pd/C (10 mol% Pd), EtOAc, 95%; d) ethyl vinyl
ether, pTsOH·H2O (10 mol%), 08C, 84%; e) (i) EtMgBr, THF, 458C; (ii) CuCl
(5 mol%), propargyl bromide, 608C, 68%; f) (i) 11, nBuLi, THF, ꢀ788C; (ii)
BF3·Et2O, then 9, ꢀ788C, 72%; g) PPTS, MeOH, 308C, 98%; h) H2 (1 atm), P2-
Ni (25 mol%), EtOH, 79%; i) CBr4, PPh3, CH2Cl2, 08C, 91%; j) propynylmagnesi-
um bromide, CuI (50 mol%), THF, ꢀ158C ! ꢀ108C, 81%; k) CBr4, PPh3, tolu-
ene, 658C, 15 (60%), 17 (ca. 12%), 18 (ca. 11%); l) HF·pyridine, THF, 08C,
83%; EE=1-ethoxyethyl; MS=molecular sieves; PPTS=pyridinium p-tolu-
enesulfonate; TBS=tert-butyldimethylsilyl.
With a good amount of this delicate building block
in hand, the stage was set for the key strategic ma-
neuvers to close the pyrone ring and the macrocyclic
scaffold (Scheme 4). To this end, alcohol 16 was es-
terified with the alkynoic b-ketoacid 22, which in
turn was obtained from commercial 1,7-octadiyne
(19) in a few robust operations. Although the result-
ing ester 23 contains five different sites of unsatura-
tion in addition to the highly enolized b-ketoester
unit, treatment with catalytic amounts of the cationic
gold complex 24[12,26] resulted in exclusive and
almost quantitative formation of the desired 2-
alkoxy-4-pyrone derivative 25. The reaction was best
performed in MeCN/HOAc (4:1); the Brønsted acid is
believed to assist in the protodeauration of an inter-
mediate of type E (see Scheme 1) as the likely rate-
determining step of the catalytic cycle.[27] In any case,
the excellent preparative outcome is the result of a fa-
vorable kinetic selectivity profile: although the triple
bond flanked by the carbonyl group is the least elec-
tron-rich of the unsaturations in substrate 23 and
Scheme 4. a) LiHMDS, THF, ꢀ788C, then TMSCl, ꢀ788C ! RT, 52%; b nBuLi, THF, ꢀ788C,
therefore a priori the least affine to the p-acidic cata- then MeI, ꢀ788C ! RT, 91%; c) MeLi, THF, ꢀ788C, then ClC(O)OMe, ꢀ78 ! 08C, 86%;
lyst,[15] it is the only one poised for being attacked by
the internal nucleophile; this opens an irreversible
pathway that siphons the substrate off to the desired
pyrone nucleus.
d) tBuOAc, LDA, ꢀ788C, then 21, 87%; e) TFA, CH2Cl2, 99%; f) 16, DCC, DMAP cat.,
CH2Cl2, 08C, 70%; g) 24 (3 mol%), MeCN/HOAc (4:1), 97%; h) 26 (5 mol%), MS 5 ꢂ, tolu-
ene, 82%; i) NBS, THF, 40%; DCC=dicyclohexylcarbodiimide; DMAP=4-dimethylamino-
pyridine; LDA=lithium diisopropylamide; LiHMDS=lithium hexamethyldisilazide;
NBS=N-bromosuccinimide; TFA=trifluoroacetic acid; TMS=trimethylsilyl.
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
3
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
strate and product and of the associated chemical challenges
referred to above.
assure. The fact that this novel transformation was deliberately
implemented at a very late stage shows our growing trust in
p-acid catalysis in general, a field that has seen exponential
growth in the recent past but remained surprisingly short of
convincing applications to elaborate and precious sub-
strates.[34] From a somewhat larger perspective, this study
therefore also helps illustrate the tremendous opportunities
that p-acid catalysis provides for heterocyclic chemistry and
natural product synthesis.[35] Together with the selective triple-
bond metathesis event as the other key step en route to 1, it
adds a new entry into a now rapidly growing list of examples
featuring the strategic advantages of contemporary (catalytic)
alkyne chemistry, to which our group is strongly committed.[36]
The recorded 13C NMR data of syn-1 matched those of the
natural product very well,[2,31] thus establishing the stereostruc-
ture of this algal metabolite and confirming our biosynthetic
hypothesis.[32] To exclude any doubt, we also prepared anti-
1 by an analogous route,[33] the spectral data of which deviated
from those of the authentic compound. Finally, crystals of syn-
1 suitable for X-ray diffraction could be grown, which con-
firmed the assignments. Figure 1 shows the puckered confor-
mation imposed on the macrocycle by the two Z-alkenes and
the essentially linear alkyne unit. Interestingly, the large dihe-
dral angle between the protons H19 and H20 at the bromohy-
drin junction (V=179.098) observed in the crystal structure
has no correspondence in the recorded coupling constant of
3
Acknowledgements
these protons in CDCl3 solution (Figure 2); rather, a J19,20
=
2.5 Hz indicates a synclinal orientation and therefore suggests
that the conformations adopted by syn-1 in the solid state and
in solution are substantially different.
Generous financial support by Max-Planck-Society, the JSPS
(fellowship to T.F.) and FWF Austria (MolTag stipend to G.P.) is
gratefully acknowledged. We thank J. Lenartowicz for assis-
tance, Dr. R. Le Vezouet and Mrs. S. Holle for exploratory stud-
ies, Mrs. H. Schucht and Prof. C. W. Lehmann for solving the X-
ray structure, and Mrs. B. Gabor for excellent NMR support.
Keywords: alkyne metathesis
·
biosynthesis
·
gold
·
heterocycles · molybdenum · natural products
[1] a) R. Kazlauskas, P. T. Murphy, R. J. Wells, A. J. Blackman, Aust. J. Chem.
1982, 35, 113–120; b) A. J. Blackman, J. B. Bremner, A. M. C. Paano, J. H.
Skerratt, M. L. Swann, Aust. J. Chem. 1990, 43, 1133–1136.
[2] J. Shin, V. J. Paul, W. Fenical, Tetrahedron Lett. 1986, 27, 5189–5192.
[3] L. Murray, G. Currie, R. Capon, Aust. J. Chem. 1995, 48, 1485–1489.
[4] For a model study, see: D. Song, G. Blond, A. Fꢀrstner, Tetrahedron
2003, 59, 6899–6904.
[5] Compound 1 inhibits phospholipase A2 (93% inhibition at 4.4 mm con-
centration) whereas 4 is a feeding deterrent for herbivorous gastropods
and sea urchins and therefore likely plays a role for the chemical de-
fense of the producing algae, see: a) A. M. S. Mayer, V. J. Paul, W. Feni-
cal, J. N. Norris, M. S. de Carvalho, R. S. Jacobs, Hydrobiologia 1993,
260–261, 521–529; b) K. Sakata, Y. Iwase, K. Kato, K. Ina, Y. Machiguchi,
Nippon Suisan Gakkaishi 1991, 57, 261–265.
Figure 1. Structure of compound 1 in the solid state; co-crystallized MeCN
has been removed for clarity (the entire structure is contained in the Sup-
porting Information).
[6] A. Fꢀrstner, Angew. Chem. Int. Ed. 2013, 52, 2794–2819; Angew. Chem.
2013, 125, 2860–2887.
[7] a) A. Fꢀrstner, G. Seidel, Angew. Chem. Int. Ed. 1998, 37, 1734–1736;
Angew. Chem. 1998, 110, 1758–1760; b) A. Fꢀrstner, O. Guth, A. Rumbo,
G. Seidel, J. Am. Chem. Soc. 1999, 121, 11108–11113.
[8] Only the bromination of 4-pyrones devoid of additional unsaturations
is known, see: a) T. Oguchi, K. Watanabe, K. Ohkubo, H. Abe, T. Katoh,
Chem. Eur. J. 2009, 15, 2826–2845; b) G. A. Poulton, T. D. Cyr, E. E.
McMullan, Can. J. Chem. 1979, 57, 1451–1455.
[9] W. Wilk, H. Waldmann, M. Kaiser, Bioorg. Med. Chem. 2009, 17, 2304–
2309.
[10] Reviews: a) P. Sharma, K. J. Powell, J. Burnley, A. S. Awaad, J. E. Moses,
Synthesis 2011, 2865–2892; b) S. Yamamura, S. Nishiyama, Bull. Chem.
Soc. Jpn. 1997, 70, 2025–2037.
Figure 2. A Newman-like projection along the C19ꢀC20 bond of compound
syn-1 shows the antiperiplanar orientation of H19 and H20 in the solid state;
in contrast, these protons are most likely synclinal to each other in solution
as suggested by the recorded coupling constant.
[11] Only 2-methoxy-4-pyrones are reasonably common in nature; for illus-
trative total syntheses of such compounds, see the following and litera-
ture cited therein: a) A. K. Miller, D. Trauner, Angew. Chem. Int. Ed. 2005,
44, 4602–4606; Angew. Chem. 2005, 117, 4678–4682; b) A. K. Miller,
D. H. Byun, C. M. Beaudry, D. Trauner, Proc. Natl. Acad. Sci. USA 2004,
101, 12019–12023; c) M. Mꢀller, B. Kusebauch, G. Liang, C. M. Beaudry,
D. Trauner, C. Hertweck, Angew. Chem. Int. Ed. 2006, 45, 7835–7838;
Angew. Chem. 2006, 118, 7999–8002; d) G. Liang, A. K. Miller, D. Trauner,
Org. Lett. 2005, 7, 819–821; e) H. Shimamura, T. Sunazuka, T. Izuhara, T.
To summarize, the present investigation established, by way
of total synthesis, the stereostructure of a marine metabolite
that is fairly unique in structural terms and highly challenging
for its chemical character. This goal was reached by a gold-cat-
alyzed cyclization that allows readily available alkynoic b-ke-
toesters to be converted into pyrones under mild conditions
that no other known entry into these privileged scaffolds can
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
4
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
¯
Hirose, K. Shiomi, S. Omura, Org. Lett. 2007, 9, 65–67; f) M. F. Jacobsen,
[26] A. Leyva, A. Corma, J. Org. Chem. 2009, 74, 2067–2074.
J. E. Moses, R. M. Adlington, J. E. Baldwin, Org. Lett. 2005, 7, 641–644;
g) B. H. Lipshutz, B. Amorelli, Tetrahedron Lett. 2009, 50, 2144–2146;
h) S. Hosokawa, K. Yokota, K. Imamura, Y. Suzuki, M. Kawarasaki, K. Tatsu-
ta, Chem. Asian J. 2008, 3, 1415–1421; i) S. J. Eade, M. W. Walter, C.
Byrne, B. Odell, R. Rodriguez, J. E. Baldwin, R. M. Adlington, J. E. Moses,
J. Org. Chem. 2008, 73, 4830–4839; j) D. W. Jefferey, M. V. Perkins, J. M.
White, Org. Lett. 2005, 7, 1581–1584; k) K. A. Parker, Y.-H. Lim, J. Am.
Chem. Soc. 2004, 126, 15968–15969.
[27] Protodeauration likely has to outperform diauration of the reactive in-
termediates, see: a) G. Seidel, C. W. Lehmann, A. Fꢀrstner, Angew. Chem.
Int. Ed. 2010, 49, 8466–8470; Angew. Chem. 2010, 122, 8644–8648;
b) A. Zhdanko, M. E. Maier, Chem. Eur. J. 2014, 20, 1918–1930.
[28] a) J. Heppekausen, R. Stade, A. Kondoh, G. Seidel, R. Goddard, A. Fꢀrst-
ner, Chem. Eur. J. 2012, 18, 10281–10299; b) J. Heppekausen, R. Stade,
R. Goddard, A. Fꢀrstner, J. Am. Chem. Soc. 2010, 132, 11045–11057.
[29] V. Hickmann, A. Kondoh, B. Gabor, M. Alcarazo, A. Fꢀrstner, J. Am. Chem.
Soc. 2011, 133, 13471–13480.
[30] For applications of RCAM to other natural products of polyacetate
origin, see: a) A. Guy, C. Oger, J. Heppekausen, C. Signorini, C. De Felice,
A. Fꢀrstner, T. Durand, J.-M. Galano, Chem. Eur. J. 2014, 20, 6374–6380;
b) A. Fꢀrstner, K. Grela, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc.
2000, 122, 11799–11805.
[31] The 1H NMR data are also matching, but the comparison is less informa-
tive because the recorded data of the natural product are not suffi-
ciently precise (for all multiplets, only the median was given); our data
resolve the uncertainty about the shift of H19 at the foot of the bro-
mine substituent, which was reported to resonate at dH =4.74 ppm in
ref.[1a], but at dH =4.14 ppm in ref. [2]; for details see the Supporting
Information.
[12] W. Chaładaj, M. Corbet, A. Fꢀrstner, Angew. Chem. Int. Ed. 2012, 51,
6929–6933; Angew. Chem. 2012, 124, 7035–7039.
[13] This reaction enabled the total synthesis of neurymenolide A; although
this compound is a 2-pyrone with a cyclophane scaffold, it is arguably
the closest relative of 1–6 currently known.
[14] Our 2-pyrone synthesis has already been used by others, see: a) Y.
Chen, L. Wang, N. Sun, X. Xie, X. Zhou, H. Chen, Y. Li, Y. Liu, Chem. Eur. J.
2014, 20, 12015–12019; b) J. S. Lee, J. Shin, H. J. Shin, H.-S. Lee, Y.-J.
Lee, H.-S. Lee, H. Won, Eur. J. Org. Chem. 2014, 4472–4476.
[15] a) A. Fꢀrstner, P. W. Davies, Angew. Chem. Int. Ed. 2007, 46, 3410–3449;
Angew. Chem. 2007, 119, 3478–3519; b) A. Fꢀrstner, Chem. Soc. Rev.
2009, 38, 3208–3221.
[16] a) D. J. Gorin, F. D. Toste, Nature 2007, 446, 395–403; b) A. S. K. Hashmi,
Chem. Rev. 2007, 107, 3180–3211; c) E. Jimꢃnez-NfflÇez, A. M. Echavar-
ren, Chem. Rev. 2008, 108, 3326–3350.
[32] Because the [a]D of 1 has not been reported, the absolute configuration
cannot be defined.
[17] Our previous publication shows a single example to support this
notion.[12]
[18] F. H. Vaillancourt, E. Yeh, D. A. Vosburg, S. Garneau-Tsodikova, C. T.
Walsh, Chem. Rev. 2006, 106, 3364–3378.
[33] For the sake of brevity, the -OH group in 16 was inverted and the re-
sulting alcohol 20-epi-16 advanced to anti-1; for details, see the Sup-
porting Information.
[34] A. Fꢀrstner, Acc. Chem. Res. 2014, 47, 925–938.
[19] a) M. T. Crimmins, M. T. Powell, J. Am. Chem. Soc. 2003, 125, 7592–7595;
b) B. S. Dyson, J. W. Burton, T. Sohn, B. Kim, H. Bae, D. Kim, J. Am. Chem.
Soc. 2012, 134, 11781–11790.
[20] a) D. B. Smith, Z. Wang, S. L. Schreiber, Tetrahedron 1990, 46, 4793–
4808; b) A. Fꢀrstner, O. R. Thiel, J. Org. Chem. 2000, 65, 1738–1742.
[21] K. Kai, J. Takeuchi, T. Kataoka, M. Yokoyama, N. Watanabe, Tetrahedron
2008, 64, 6760–6769.
[22] H. Tecle, S. D. Barrett, D. J. Lauffer, C. Augelli-Szafran, M. R. Brann, M. J.
Callahan, B. W. Caprathe, R. E. Davis, P. D. Doyle, D. Eubanks, W. Lipinski,
T. Mirzadegan, W. H. Moss, D. W. Moreland, C. B. Nelson, M. R. Pavia, C.
Raby, R. D. Schwarz, C. J. Spencer, A. J. Thomas, J. C. Jaen, J. Med. Chem.
1998, 41, 2524–2536.
[23] C. A. Brown, V. K. Ahuja, J. Chem. Soc. Chem. Commun. 1973, 553–554.
[24] The corresponding allylic iodide underwent quantitative isomerization
to the E-configured substitution product under otherwise identical con-
ditions.
[35] For other instructive cases from our group, see: a) G. Valot, C. S.
Regens, D. P. O’Malley, E. Godineau, H. Takikawa, A. Fꢀrstner, Angew.
Chem. Int. Ed. 2013, 52, 9534–9538; Angew. Chem. 2013, 125, 9713–
9717; b) S. Benson, M.-P. Collin, A. Arlt, B. Gabor, R. Goddard, A. Fꢀrstner,
Angew. Chem. Int. Ed. 2011, 50, 8739–8744; Angew. Chem. 2011, 123,
8898–8903; c) K. Gebauer, A. Fꢀrstner, Angew. Chem. Int. Ed. 2014, 53,
6393–6396; Angew. Chem. 2014, 126, 6511–6514; d) L. Hoffmeister, P.
Persich, A. Fꢀrstner, Chem. Eur. J. 2014, 20, 4396–4402; e) L. Brewitz, J.
Llaveria, A. Yada, A. Fꢀrstner, Chem. Eur. J. 2013, 19, 4532–4537; f) G.
Valot, D. Mailhol, C. S. Regens, D. P. O’Malley, E. Godineau, H. Takikawa,
P. Philipps, A. Fꢀrstner, Chem. Eur. J. 2015, 21, 2398–2408.
[36] A. Fꢀrstner, Angew. Chem. 2014, 126, 8728–8740; Angew. Chem. Int. Ed.
2014, 53, 8587–8598.
Received: February 3, 2015
[25] Details will be reported in a future full paper.
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Natural Products
L. Hoffmeister, T. Fukuda, G. Pototschnig,
A. Fꢀrstner*
&& – &&
Total Synthesis of an Exceptional
Brominated 4-Pyrone Derivative of
Algal Origin: An Exercise in Gold
Catalysis and Alkyne Metathesis
The gentle way: Certain red algae pro-
duce highly unusual 4-pyrone deriva-
tives which cluster several remarkable
functionalities into a macrocyclic frame.
The first member of this series (see
figure) has now been conquered and
a biosynthetic hypothesis predicting its
relative stereochemistry has been con-
firmed. The successful route is based on
the selective transformation of an acy-
clic precursor containing six different
sites of unsaturation, without scram-
bling the labile skipped p-systems.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!