On the origin of siphonariid polypropionates: Total synthesis of baconipyrone A, Baconipyrone C, and siphonarin B via their putative common precursor

Article abstract of DOI:10.1021/ja102356j

The hypothesis that siphonariid polypropionates originate from nonenzymatic processes on acyclic biosynthetic precursors was tested by examining the properties of the putative common precursor for the S. zelandica decapropionates siphonarin B, caloundrin B, baconipyrone A, and baconipyrone C, i.e., (4S,5S,6S,8RS,10S,11S,12R,14R)-14-(6-ethyl-3,5-dimethyl-4-oxo-4H-pyran-2-yl)-5, 11-dihydroxy-4,6,8,10,12-pentamethylpentadecane-3,7,9,13-tetraone. The first synthesis of such a precursor was achieved in an efficient and fully enantioselective manner using a thiopyran-based strategy for polypropionate synthesis. This putative precursor, a complex mixture of ring-chain and keto-enol tautomers, was kinetically stable and isomerized exceedingly slowly to the thermodynamically more stable siphonarin B. In the presence of imidazole, the mixture reached apparent equilibrium within several hours giving siphonarin B as the predominant component (ca. 70%), thereby constituting its enantioselective total synthesis. In the presence of alumina, both siphonarin B and the dihydroxytetraone precursor underwent retro-Claisen rearrangements (via a hemiacetal tautomer) to give baconipyrones A and C among other products. This is the first total synthesis of baconipyrone A and biomimetic synthesis of baconipyrone C. Control experiments suggested that baconipyrone A was produced in an unprecedented cascade process where the intermediate enol(ate) of the retro-Claisen rearrangement was directly engaged in aldol cyclization while baconipyrone C resulted from simple ketonization of the enol(ate). These experiments provide the first unambiguous demonstration that the baconipyrones are plausible isolation artifacts and suggest they are most likely derived from siphonarins rather than an acyclic precursor. Caloundrin B was not detected among the products from any of the isomerization experiments, suggesting the possibility that it is an unstable biosynthetic product.

Full text of DOI:10.1021/ja102356j

Published on Web 05/04/2010
On the Origin of Siphonariid Polypropionates: Total Synthesis
of Baconipyrone A, Baconipyrone C, and Siphonarin B via
their Putative Common Precursor
Garrison E. Beye and Dale E. Ward*
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place, Saskatoon,
SK S7N 5C9, Canada
Received March 20, 2010; E-mail: dale.ward@usask.ca
Abstract: The hypothesis that siphonariid polypropionates originate from nonenzymatic processes on acyclic
biosynthetic precursors was tested by examining the properties of the putative common precursor for the
S. zelandica decapropionates siphonarin B, caloundrin B, baconipyrone A, and baconipyrone C, i.e.,
(4S,5S,6S,8RS,10S,11S,12R,14R)-14-(6-ethyl-3,5-dimethyl-4-oxo-4H-pyran-2-yl)-5,11-dihydroxy-
4,6,8,10,12-pentamethylpentadecane-3,7,9,13-tetraone. The first synthesis of such a precursor was achieved
in an efficient and fully enantioselective manner using a thiopyran-based strategy for polypropionate
synthesis. This putative precursor, a complex mixture of ring-chain and keto-enol tautomers, was kinetically
stable and isomerized exceedingly slowly to the thermodynamically more stable siphonarin B. In the presence
of imidazole, the mixture reached apparent equilibrium within several hours giving siphonarin B as the
predominant component (ca. 70%), thereby constituting its enantioselective total synthesis. In the presence
of alumina, both siphonarin B and the dihydroxytetraone precursor underwent retro-Claisen rearrangements
(via a hemiacetal tautomer) to give baconipyrones A and C among other products. This is the first total
synthesis of baconipyrone A and “biomimetic” synthesis of baconipyrone C. Control experiments suggested
that baconipyrone A was produced in an unprecedented cascade process where the intermediate enol(ate)
of the retro-Claisen rearrangement was directly engaged in aldol cyclization while baconipyrone C resulted
from simple ketonization of the enol(ate). These experiments provide the first unambiguous demonstration
that the baconipyrones are plausible isolation artifacts and suggest they are most likely derived from
siphonarins rather than an “acyclic” precursor. Caloundrin B was not detected among the products from
any of the isomerization experiments, suggesting the possibility that it is an unstable biosynthetic product.
(3, 4)5,6 have been isolated from extracts of S. zelandica (Chart
Introduction
1).7 It is noteworthy that the siphonarins and baconipyrones have
Mollusks of the marine pulmonate genus Siphonaria, often
referred to as false limpets, are air-breathing intertidal herbi-
vores. Although a plethora of structurally diverse polypropi-
onates have been isolated from extracts of siphonariids,1 their
role in the chemical ecology of these organisms is poorly
understood. Indeed, the natural product status and relevance of
the observed biological activities for many of the isolated
compounds have been subjects of speculation for many years.
In these cases, the reported structures are suggested to be
isolation artifacts formed via nonenzymatic processes (e.g.,
cyclizations, dehydrations, retro-Claisen reactions, etc.) on
unstable acyclic biosynthetic products.1 For example, the
siphonarins (1),2,3 caloundrin B (2b),4 and the baconipyrones
identical absolute configurations at related centers, and the same
configurations are presumed for caloundrin B. This relationship
is consistent with the hypothesis that the structural isomers with
R ) Me (1a, 3a, 4a) and with R ) Et (1b-4b) arise, possibly
during isolation, via decarboxylaton and alternative cyclization/
rearrangement cascades of the putative acyclic biosynthetic
products 5a and 5b, respectively.1,2b,4,5,8
(4) Isolation and structure: Blanchfield, J. T.; Brecknell, D. J.; Brereton,
I. M.; Garson, M. J.; Jones, D. D. Aust. J. Chem. 1994, 47, 2255–
2269.
(5) Isolation and structure: (a) Manker, D. C.; Faulkner, D. J.; Stout, T. J.;
Clardy, J. J. Org. Chem. 1989, 54, 5371–5374. Also see ref 10c.
(6) Total syntheses of 4b: (a) Paterson, I.; Chen, D. Y.-K.; Acena, J. L.;
Franklin, A. S. Org. Lett. 2000, 2, 1513–1516. (b) Gillingham, D. G.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 3860–3864. (c)
Yadav, J. S.; Sathaiah, K.; Srinivas, R. Tetrahedron 2009, 65, 3545–
3552.
(1) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998, 15, 477–
493.
(7) The baconipyrones were isolated from S. baconi (ref 5), a designation
that is synonymous with S. zelandica: (a) Jenkins, B. W. J. Malac.
Soc. Aust. 1983, 6, 1–35. For reports of isolation of these polypropi-
onates from other siphonariid species, see ref 2 and: (b) Fu, X.; Zeng,
L.; Su, J. Zhongshan Daxue Xuebao, Ziran Kexueban 1995, 34, 129-
132; Chem. Abstr. 1996, 124, 51067.
(2) Isolation and structure: (a) Hochlowski, J.; Coll, J.; Faulkner, D. J.;
Clardy, J. J. Am. Chem. Soc. 1984, 106, 6748–6750. (b) Garson, M. J.;
Jones, D. D.; Small, C. J.; Liang, J.; Clardy, J. Tetrahedron Lett. 1994,
35, 6921–6924. (c) For other reports of isolation, see refs 4, 5, and
10c.
(3) Total synthesis of 1b: Paterson, I.; Chen, D. Y.-K.; Franklin, A. S.
Org. Lett. 2002, 4, 391–394.
(8) Garson, M. J.; Goodman, J. M.; Paterson, I. Tetrahedron Lett. 1994,
35, 6929–6932.
9
7210 J. AM. CHEM. SOC. 2010, 132, 7210–7215
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Origin of Siphonariid Polypropionates
A R T I C L E S
Chart 1. Polypropionates from S. zelandica
8R diastereomers, 7d, can cyclize to give caloundrin B (2b).
Alternatively, retro-Claisen rearrangement of any of the hemi-
acetal diastereomers 7 leads to baconipyrone C (4b) that can
be converted to baconipyrone A (3b) via aldol cyclization. While
plausible, these hypotheses have never been demonstrated
experimentally and present several anomalies. If the cyclizations
leading to 1b and 2b are thermodynamically driven nonenzy-
matic processes, as proposed,1,8 then one would expect to find
1b and 2b together and in a ratio that reflects their relative
stability. Thus, it is surprising that 1b has been isolated several
times from several sources,2,7 but 2b has been found only once.4
Several “noncontiguous” polypropionate esters (e.g., 3 and 4)
have been isolated from marine sources, and these are generally
suspected to be artifacts arising from retro-Claisen rearrange-
ment of 2-hydroxydihydro-2H-pyran-4(3H)-ones (e.g., 7).1
Although similar transformations have been observed experi-
mentally,2a,3,10 the direct synthesis of a “natural product” via
this process has been demonstrated only in a rather simple
case.10a Moreover, 3b was isolated as a single diastereomer
whose formation from 4b would require a diastereotopic group
and face selective aldol reaction. It seems improbable that such
a reaction would occur during isolation. Faulkner et al.5 noted
that the proposed retro-Claisen rearrangement of 7 might provide
the required differentiation of the carbonyl groups via intermedi-
ate A, at least in a biosynthetic context. However, to the best
of our knowledge, laboratory examples of such retro-Claisen/
aldol cascades have not been reported. To address the above
issues, we sought to prepare the putative common precursor 6
and examine its properties. Herein, we describe the first total
synthesis of 6, demonstrate its isomerization to 1b, 3b, and 4b,
and discuss the implication of our results on the possible origins
of these sipnonariid polypropionates.
Scheme 1. Proposed Pathways for Formation of 1b-4b from 6
Results and Discussion
The total synthesis of 6 was expected to be challenging
because, in addition to the stereochemical complexity, the
embedded 5-hydroxy 3,7,9-trione moiety is known to be highly
sensitive to acid and base, and the isomerization products 1b-4b
are also reported to be unstable. Thus, extrapolating from our
earlier model study,11 we planned to obtain 6 under mild
conditions by unraveling the thermodynamically unstable 8S-
epimer of 2b (i.e., 8) available via desulfurization of 9 (Scheme
2). The latter would result from acid-catalyzed deprotection and
cyclization of 10 that, in turn, could be assembled from suitably
protected derivatives of the known ketone 1312 and aldehyde
15. A plausible path to 15 would involve annulation of the
pyrone onto the known ketone 1712b using the method13 we
recently developed for this purpose. In this thiopyran-based
approach to polypropionate synthesis, it is noteworthy that 28
of the 29 carbons in 6 would originate from simple 3-carbon
carboxylic acid derivatives (i.e., 21 and 22) and that six of the
seven stereocenters arise from highly enantioselective organo-
Given that spontaneous formation of 4-pyrones by dehydrative
cyclization of 1,3,5-triones is unlikely to occur during isolation,9
the above hypothesis is illustrated starting from the putative
common precursor 6 (Scheme 1). The C-8 stereocenter in 6 is
expected to be labile via keto-enol tautomerism of the 7,9-
diketone. Of the numerous possible cyclization modes available
to 6, addition of the C-5 hydroxy group to the C-9 carbonyl
produces up to four diastereomers of the hemiacetal 7. The more
stable anomer of the 8S diastereomers, 7a, can cyclize directly
to give siphonarin B (1b), while the less stable anomer of the
(10) (a) Hochlowski, J. E.; Faulkner, D. J. J. Org. Chem. 1984, 49, 3838–
3840. (b) Sundram, U. N.; Albizati, K. F. Tetrahedron Lett. 1992, 33,
437–440. (c) Brecknell, D. J.; Collett, L. A.; Davies-Coleman, M. T.;
Garson, M. J.; Jones, D. D. Tetrahedron 2000, 56, 2497–2502. (d)
Lister, T.; Perkins, M. V. Aust. J. Chem. 2004, 57, 787–797. (e) Lister,
T.; Perkins, M. V. Org. Lett. 2006, 8, 1827–1830.
(11) Beye, G. E.; Goodman, J. M.; Ward, D. E. Org. Lett. 2009, 11, 1373–
1376.
(12) (a) Ward, D. E.; Jheengut, V.; Beye, G. E. J. Org. Chem. 2006, 71,
8989–8992. (b) Ward, D. E.; Jheengut, V.; Akinnusi, O. T. Org. Lett.
2005, 7, 1181–1184.
(9) (a) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1990,
31, 5619–5620. (b) Pratt, N. E.; Zhao, Y.; Hitchcock, S.; Albizati,
K. F. Synlett 1991, 361–363. (c) Arimoto, H.; Ohba, S.; Nishiyama,
S.; Yamamura, S. Tetrahedron Lett. 1994, 35, 4581–4584.
(13) The details of the development, scope, and limitations of this protocol
will be reported separately.
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A R T I C L E S
Beye and Ward
the known6 26b (Scheme 3). To verify that conclusion, 25c was
subjected to Hg(OAc)2/NaBH4 to obtain 26b (51%) along with
its C-6′ epimer (16%). The endgames for the three previous
syntheses of baconipyrone C (4b) are identical and involve a
two-step oxidation of 26b to the corresponding ketoacid
followed by esterification with 27 and deprotection of the PMB
group.6 To complete a formal synthesis of 4b according to that
route, we prepared 27 from 1312a in a single step by Raney
nickel desulfurization with an acidic workup. Our syntheses of
26b and 27 (24 total steps; longest linear sequence: 14 steps,
7.8%) compare favorably with the others6 in terms of the total
number of steps, longest linear sequence, and overall ef-
ficiency.16
Scheme 2. Retrosynthetic Analysis of 6
Aldol reaction of the Cl3Ti enolate of 14a (>98% ee)12 with
15a gave adduct 28 essentially as a single diastereomer
presumably with the indicated configurations at C-3′′ and C-7′
(Scheme 4). The stereoselectivities of similar aldol reactions
under these conditions are largely governed by the diastereoface
selectivities of the reactants with little preference for the relative
topicity (i.e., no mismatched reaction).19a Additions to the
enolate of 14a are known19 to occur selectively from the
face trans to the C-3 substituent, and additions to aldehyde 15a
are expected20 to be highly Felkin-selective due to the anti
relative configuration of the R-methyl and ꢀ-O-benzyl substit-
uents. Accordingly, aldol coupling of 14a with 15a is expected
to give the 3′′,5′′-trans-7′,6′-syn adduct 28 selectively and
requires syn relative topicity. IBX oxidation of 28 produced the
corresponding dione (enol and ꢀ-diketone tautomers); however,
despite considerable experimentation we were unable to induce
its transformation to the desired trioxadithiapentacycle analogous
to 9.11 Alternatively, desulfurization of 28 followed by
FeCl3-mediated11,21 hydrolysis of the acetals provided 29a in
excellent yield. Selective protection of the C-5 alcohol in 29a
was required to advance to 6, and this was achieved by treatment
with Et3SiOTf in the presence of 2,6-lutidine to give a 5:1
mixture of triethylsilyl (TES) ethers, 29c, and presumably its
9-O-TES regioisomer, respectively (50%), along with the bis-
TES derivative 29b (10%) and recovered 29a (35%). Because
separation of the two mono-TES ethers was inefficient, the
reaction was run to high conversion to deplete the minor
isomer22 and obtain 29c conveniently and in serviceable yield
(46%; 85% based on recovered 29a obtained by deprotection
of 29b) along with 29b (44%). Treatment of 29c with IBX
produced the tetraone 30a that was a mixture of enol (ca. 25%)
and ꢀ-diketone tautomers (ca. 75%; ca. a 6:1 mixture of
diastereomers) by NMR in CDCl3 solution. Sequential removal
of the benzyl and silyl ethers in 30a efficiently provided the
desired 6 as a complex mixture of ring-chain and keto-enol
catalyzed direct aldol reactions12 of 1214 with racemic 1115 and
meso/dl 16,12b respectively.
Our synthesis commenced with the pivaloylation of 17 (92%
ee)12b followed by Raney nickel desulfurization (Scheme 3).
The latter occurred with partial reduction (<10%) of the ketone
necessitating oxidation of the crude with 2-iodoxybenzoic acid
(IBX) to obtain 23 as a 1:1 mixture of epimers in good yield.
In a three-step sequence, the LDA-generated enolate of 23
reacted with (()-1816 and the resulting complicated mixture of
aldols was oxidized with IBX in DMSO to give a mixture of
diketones that was subjected to IBX and trifluoromethansulfonic
acid (TfOH) in acetonitrile to the give the pyrone-dihydropyrone
24 in 62% yield from 23. Although formation of the pyrone
was expected from this sequence,13 the facile elimination of
the pivaloate and hydrolysis of the ketal were not anticipated.
To take advantage of the transformation of 23 into 24 requires
regeneration of the stereocenter at C-5′′ that was lost as a
consequence of the pivaloate elimination; however, stereose-
lective hydration of C-5 substituted 2H-pyran-4(3H)-ones (e.g.,
24) or analogous 3,4-dihydro-2H-pyran-4-ols (e.g., 25) appears
to be unprecedented.17 Toward that end, stereoselective reduc-
tion (dr >20:1) of 24 followed by benzylation of the resulting
alcohol gave 25b. After considerable experimentation, 25b was
converted the desired 26a (62%) along with the corresponding
C-6′ epimer (16%) by adaptation of Piancatelli’s oxymercuration
protocol.18 The C-3′ hydroxy group in 26a was surprisingly3
resistant to Et3SiOTf in the presence of 2,6-lutidine, facilitating
a simple “one pot” procedure for its selective protection as a
methoxymethyl (MOM) ether. Oxidation of the resulting alcohol
26c with IBX gave aldehyde 15a in quantitative yield.
1
tautomers. Careful analysis of the H and 13C NMR spectra of
6 in CDCl3 suggested the presence of a 2:1:4 mixture of three
major hemiacetal forms (OH signals at δΗ 6.46, 6.39, 6.19,
respectively, and acetal carbons at δC 104.4, 104.6, 104.7,
respectively; ca. 80% of the mixture) along with minor amounts
The C-6′ configuration in 26a was assigned on the basis of
the close correspondence of the 13C NMR spectra of 26a and
(19) (a) Ward, D. E.; Beye, G. E.; Sales, M.; Alarcon, I. Q.; Gillis, H. M.;
Jheengut, V. J. Org. Chem. 2007, 72, 1667–1674. (b) Ward, D. E.;
Becerril-Jimenez, F.; Zahedi, M. M. J. Org. Chem. 2009, 74, 4447–
4454.
(14) Ward, D. E.; Rasheed, M. A.; Gillis, H. M.; Beye, G. E.; Jheengut,
V.; Achonduh, G. T. Synthesis 2007, 1584–1586.
(15) Ward, D. E.; Sales, M.; Man, C. C.; Shen, J.; Sasmal, P. K.; Guo, C.
J. Org. Chem. 2002, 67, 1618–1629.
(20) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322–4343.
(16) See the Supporting Information for details.
(17) For a multistep solution to this problem, see: Danishefsky, S. J.; Myles,
D. C.; Harvey, D. F. J. Am. Chem. Soc. 1987, 109, 862–867.
(18) (a) Bettelli, E.; Cherubini, P.; D’Andrea, P.; Passacantilli, P.; Pianca-
telli, G. Tetrahedron 1998, 54, 6011–6018. (b) Passacantilli, P.;
Centore, C.; Ciliberti, E.; Leonelli, F.; Piancatelli, G. Eur. J. Org.
Chem. 2006, 3097–3104.
(21) Sen, S. E.; Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath, J. J.
Org. Chem. 1997, 62, 6684–6686.
(22) The regioisomeric purity of products from a chemoselective reaction
increases with conversion if the groups can react sequentially. For a
discussion and analysis of this phenomenon, see: Ward, D. E.; Liu,
Y.; Rhee, C. K. Can. J. Chem. 1994, 72, 1429–1446.
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Origin of Siphonariid Polypropionates
A R T I C L E S
Scheme 3. Synthesis of Aldehyde 15a and Formal Synthesis of Baconipyrone C (4b)
Scheme 4. Synthesis of 6, Siphonarin B (1b), Baconipyrone A (3b), and Baconipyrone C (4b)
of other hemiacetals, enol (OH signal at δΗ 17.05), ꢀ-diketone
tautomers (2 diastereomers; C-8 signals at δC 61.9, 61.1), and
a trace of siphonarin B (1b) (OH signal at δΗ 5.12; ca. 2% of
the mixture). We believe the major hemiacetals present include
7a and 32 (vide infra). The ratio of tautomers remained
essentially unchanged on standing in CDCl3 solution at rt; after
28 days, the ratio of major hemiacetals was 2:1:3 and ca. 9%
of 1b was present.
The isomerization of 6 was examined under the conditions
that proved efficacious in our model study (Scheme 4).11
Treatment of 6 with HF ·pyridine and pyridine in THF slowly
produced siphonarin B (1b). After 16 h, a 2.5:1 ratio of 6
(mainly an ca. 2:1:3 mixture of 3 hemiacetals; 60% isolated)
and 1b (20% isolated), respectively, along with several unidenti-
fied byproducts were observed by 1H NMR; however, the
reaction was not clean, and prolonged reaction did not improve
the isolated yield of 1b. In the presence of imidazole, a solution
of 6 in CDCl3 (initially a 2:1:4 mixture of hemiacetal forms
along with ca. 2% of 1b) isomerized to siphonarin B (1b, ca.
70%), an unidentified product (OH signal at δΗ 5.01; ca. 10%),
and 6 (as a 0.1:1.5:1 mixture of hemiacetals; ca. 20%) after
24 h (by H NMR after work up), and siphonarin B (1b) was
1
isolated in 70% yield from the mixture. This ratio of products
appeared to represent equilibrium as a similar ratio was also
observed after exposure of either 6 or 1b to imidazole in CDCl3
1
solution for 48 h. Interestingly, the H NMR spectrum of a
natural sample of 1b suggests the presence of the same minor
products as evidenced by observable signals at ca. 6.46, 6.39,
6.19, and 5.01 ppm.23 Unfortunately, we were unable to isolate
1
the product responsible for the H NMR signal at δΗ 5.01 but
suggest that it may be the alternative spiroacetal 33 (Scheme
5) or perhaps a diastereomer of 1b (e.g., 14-epi-1b). We did
not detect the presence of 2b in any of the above experiments
or similar ones conducted at 40 °C.11
Addition of DBU to a solution of 6 in C6D6 resulted in retro-
Claisen rearrangement and produced a 2:1 mixture (by 1H NMR)
of baconipyrone C (4b; 50% isolated) and 14-epi-4b (30%
isolated), respectively, within 1 h (Scheme 4). Other products
(23) This spectrum is included in the Supporting Information of ref 3.
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A R T I C L E S
Beye and Ward
mixture of hemiacetals), respectively (by 1H NMR), with little
or no 31 present. Importantly, both baconipyrone A (3b) and
baconipyrone C (4b) were stable to these conditions. These
experiments suggest that both 3b and 4b are formed by an
irreversible retro-Claisen rearrangement of 7. Ketonization of
the intermediate enol(ate) product (e.g., A in Scheme 1)
produces 4b, whereas as 3b is formed in a retro-Claisen/aldol
cascade where the enol(ate) product of the retro-Claisen
rearrangement (e.g., A in Scheme 1) is directly engaged in the
aldol cyclization. To the best of our knowledge, this is the first
example of such a process. Reaction via intermediate enol A
and transition-state model B accounts for the diastereotopic
group and face selectivity of the aldol cyclization leading to
3b (Scheme 1). The transition-state model B is analogous to
the model proposed by Vogel et al.25 for a closely related aldol
cyclization via a Bu3Sn enolate. The required (Z)-enol(ate) in
A and B would result from retro-Claisen rearrangement of 7a.
These experiments provide the first unambiguous demonstrations
of the hypotheses that the baconipyrone A (3b) and baconipy-
rone C (4b) can be isolation artifacts originating from retro-
Claisen rearrangement of hemiacetal 7a formed either by
cyclization of the “acyclic” precursor 6 or by ring-opening of
siphonarin B (1b). Interestingly, we could not find evidence
for the presence of 2b among the products from any of the above
experiments.
It is reasonable to assume that 7a and 32 are among the three
major ring-chain tautomers of our synthetic 6 (Scheme 5).
These hemiacetals should be similar in energy because they have
identical relative and absolute configurations about their tet-
rahydropyrone rings and only relatively subtle differences in
the nature of the substituents at C-5 and C-9 in 7a vs those at
C-11 and C-7 in 32. In analogy with previous molecular
modeling studies,11 7a should be the most stable hemiacetal
from (8S)-6 and 31 the most stable hemiacetal from (8R)-6 with
the epimers 7c and 8-epi-32 expected to be 1-2 kcal/mol higher
in energy. Although synthetic 6 initially existed in three major
hemiacetal forms, only two of these are present to a significant
degree after equilibration in the presence of imidazole. We
believe the latter are the more stable hemiacetals 7a and 32
with the kinetically stable but thermodynamically unstable third
isomer initially present being either 7c or 8-epi-32.26 Under these
conditions, 1b emerges as the most stable tautomer along with
minor amounts of 7a, 32, and a new isomer, possibly 33
resulting from cyclization of 32. The concurrent formation of
1b, 3b, 4b, and 31 on heating a solution of 6 (mainly as a
mixture of hemiacetals 7a and 32) in the presence of alumina
can be rationalized by assuming that retro-Claisen rearrangement
of 32 is faster than its equilibration to 7a and 1b. The same
assumption explains the formation of 3b and 4b, but not 31, on
reaction of 1b under these conditions. Alternatively, reaction
of 6 with DBU at ambient temperature produces 4b and 14-
epi-4b but not 31, implying, in this case, that equilibration of
32 is faster than its retro-Claisen rearrangement.
Scheme 5. Revised Scheme for Isomerizations of 6 and 1b
were not detected in the reaction mixture. Previous syntheses
of 4b have reported the formation of a minor diastereomer,
suspected to be 14-epi-4b, originating during esterification6a of
27 or spontaneously6b from 4b. Spectral data for our 14-epi-4b
were distinct from those reported24 previously. Two lines of
evidence support our assignment. First, the most acidic proton
in 4b is expected to be HC-14 (vinylogous ꢀ-ketoester), and
treatment of 4b with DBU in C6D6 rapidly produces a mixture
of 4b and 14-epi-4b. Second, the 13C NMR spectra of 4b and
14-epi-4b are very similar, giving ∆δ’s of e0.2 ppm for 21
carbons; 0.5 ppm for 3 carbons; 0.8-1.2 ppm for C-10, C-11,
C-12, and C-15; 2.5 ppm for C-14.16 In contrast, comparison
of the 13C NMR spectra of 4b and the diastereomer previously
suspected as 14-epi-4b (assignments not available)24 reveals at
least seven carbons with ∆δ >1.5 and significant differences in
the chemical shifts for the methyl carbons. We suspect the latter
diastereomer is 10-epi-4b considering that it originates during
esterification (i.e., formed by enolization of the active ester or
via the ketene); however, the available data are insufficient for
an unambiguous assignment. Contrary to a previous report,6b
we found 4b to be stable (in solution or neat) for at least 2
months at room temperature.
In an effort to induce retro-Claisen rearrangement without
concomitant epimerization, we treated 6 with neutral alumina10b
in refluxing ethanol for 1 h to give a 10:3:7:5 mixture of 31
(40% isolated), 3b (10% isolated), 4b, and 1b, respectively, by
1H NMR (Scheme 4). The structure of 31 was determined by
1
extensive 1D and 2D NMR experiments; all H spin systems
were identified and their connectivities established by the
indicated HMBC correlations (Scheme 5). The relative and
absolute configurations in 31 are assumed on the basis of the
structure of 6. The hypothesis outlined in Scheme 1 readily
explains the formation of 1b, 3b, and 4b from 6 (via 7a or
diastereomer). The concurrent formation of 31 must result from
retro-Claisen rearrangement of the alternative hemiacetal 32 (or
diastereomer). Subjecting siphonarin B (1b) to the identical
conditions gave a 2.3:3:1:1 mixture of 1b, 4b, 3b, and 6 (as a
We reasoned that using a derivative of 6 where the hydroxy
group at C-11 was protected would facilitate selective formation
of 2b or 3b and 4b. Such derivatives cannot form a hemiacetal
analogous to 32 and are not expected3 to cyclize to a C-11-
(25) Turks, M.; Murcia, M. C.; Scopelliti, R.; Vogel, P. Org. Lett. 2004,
6, 3031–3034.
(26) For a related hemiacetal that is kinetically stable (i.e., isolable) but
thermodynamically unstable relative to other diastereomers, see
compound 11 in: Paterson, I.; Perkins, M. V. J. Am. Chem. Soc. 1993,
115, 1608–1610.
(24) Chen, D. Y.-K. Ph.D. Thesis, University of Cambridge, Cambridge,
U.K., 2002.
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7214 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Origin of Siphonariid Polypropionates
A R T I C L E S
protected derivative of 1b; with these forms removed from the
equilibrium, it was hoped that the cyclization cascades could
be directed toward C-11-protected derivatives of 2b or 3b and
4b. The desired 30b was readily obtained on treatment of 30a
with HF·pyridine (Scheme 4). Unfortunately, we were unable
to detect the presence of the 11-OBn derivative of 2b among
the products obtained after exposure of 30b to imidazole in
CDCl3. Surprisingly, 30b was stable to neutral alumina in
refluxing ethanol for 1 h; however, using basic alumina under
the same conditions for 7 h cleanly produced a 4:1 mixture of
retro-Claisen products that gave 3b (18%) and 4b (70%) after
hydrogenolysis of the benzyl ether. Reaction of 4b under the
latter conditions produced 14-epi-4b (ca. 40%) but not 3b.
synthetic efficiency for production of 3b and 4b was substan-
tially enhanced by executing the same chemistry on the 11-O-
benzyl derivative 30b followed by removal of the protecting
group. This retro-Claisen synthetic route approach (“biomi-
metic”) to baconipyrone C (4b) is necessarily less convergent
than the previous approaches based on esterification.6 Although
the route is less efficient than Paterson’s6a very concise synthesis
of 4b (and our own formal synthesis, vide supra), it compares
favorably with the Hoveda6b and Yadav6c approaches.16 The
same route constitutes the first total synthesis of baconipyrone
A (3b) (Scheme 4).
The ring-chain tautomerization of 6 is reversible, but retro-
Claisen rearrangements are irreversible, at least under the
conditions we examined.27 Thus, the set of polypropionates
1b-4b isolated from S. zelandica could, in principle, originate
from an “acyclic” precursor like 6 or any of its ring-chain
tautomers (e.g., 1b, 2b, 7, etc.). The putative common precursor
6 readily forms hemiacetals 7a and 32 that are stable to
chromatography and undergo retro-Claisen rearrangement with
similar propensity, but neither 7a, 31, 32, nor 14-epi-4b have
ever been found in siphonariid extracts. Therefore, if the
baconipyrones are isolation artifacts, it is more likely that they
are derived from the siphonarins rather than from an “acyclic”
precursor like 6. Similarly, if an incompletely folded precursor
like 6 or 7 is the actual biosynthetic product, then we presume
that it must have equilibrated (with or without catalysis) to the
thermodynamically more stable 1b prior to isolation. Alterna-
tively, 1b could be the biosynthetic product; it is commonly
found in sipohanriid extracts and the above experiments establish
that the 3b and 4b could be obtained as isolation artifacts from
1b. However, the origin of caloundrin B (2b) remains a missing
piece of the puzzle. We were unable to detect 2b among the
products of isomerization of 1b or 6 under a variety of
conditions. These results suggest that either 2b is much less
stable that 1b or the energy barrier to reach 2b is very high.
Either scenario seriously challenges the hypothesis that 2b is
an artifact of isolation. It is plausible that 2b is an unstable
biosynthetic product from which the formation of 1b, 3b, and
4b could be readily explained (Scheme 5). To explore that issue,
we are currently pursuing the synthesis of 2b by a different
route, and our results will be reported in due course.
Summary and Conclusions
In summary, we have achieved the first total synthesis of 6,
the putative common precursor of the siphonariid polypropi-
onates siphonarin B (1b), caloundrin B (2b), baconipyrone A
(3b), and baconipyrone C (4b). The fully enantioselective
synthetic route highlights the power and versatility of our
thiopyran-based strategy. The synthesis proceeds in only 20 total
steps (longest linear sequence: 18 steps, 3.1%) by convergent
aldol coupling of the readily available simple precursors (()-
11, 12 (×2), (meso/dl)-16, and (()-18. Enantioselective orga-
nocatalyzed direct aldol reactions of 12 with (()-11 and with
(meso/dl)-16, processes that proceed with dynamic kinetic
resolution, generate five of the seven stereocenters in 6 (C-4,
5, 6, 12, 14; dr >20:1).12 The remaining two stereocenters result
from substrate-controlled carbonyl reduction (C-11; dr >20:1)
and an unusual enol ether oxymercuration/reductive demercu-
ration (C-10; dr 3.5:1). It is noteworthy that 28 of the 29 carbons
in 6 originate from methyl acrylate or ethyl propanoate.
Synthetic 6 initially exists as complex mixture of ring-chain
and keto-enol tautomers; however, the three hemiacetal forms
7a, 32, and either 7c or 8-epi-32 predominate. These hemiacetals
show remarkable kinetic stability (i.e., unchanged on SiO2
chromatography, on storage, and in CDCl3 solution for weeks)
with exceedingly slow accumulation of the thermodynamically
more stable 1b. However, in the presence of imidazole,
equilibration occurs within several hours giving 1b (70%
isolated) and three significant minor tautomers (7a, 32, and
perhaps 33) along with lesser amounts of other forms. A similar
mixture was obtained from 1b in the presence of imidazole and
the same set of minor tautomers appear to be present as
impurities in the 1H NMR spectrum of a natural sample of 1b.23
This constitutes the first enantioselective total synthesis of
siphonarin B (1b) (cf. Paterson’s3 seminal diastereoselective
synthesis).16 Exposure of 1b to neutral alumina in refluxing
ethanol produced a mixture of 1b, 3b, 4b, and 6. Reaction of 6
under identical conditions gave a similar mixture in addition to
31 as the major product. These experiments clearly demonstrate
that the baconipyrones are easily derived from 1b or 6 under
conditions that make them plausible isolation artifacts. Impor-
tantly, 3b and 4b do not interconvert under these conditions.
These results suggests that 3b is formed from 7a in an
unprecedented retro-Claisen/aldol cascade with the intermediates
A and B accounting for the observed stereoselectivity, whereas
4b results from ketonization of intermediate A (Scheme 1). The
Acknowledgment. We thank Prof. Ian Paterson (Cambridge)
for providing experimental procedures and copies of NMR spectra
for some intermediates from his total syntheses of 1b and 4b.
Financial support from the Natural Sciences and Engineering
Research Council (Canada) and the University of Saskatchewan is
gratefully acknowledged.
Note Added after ASAP Publication. The structure of com-
pound 28 in Scheme 4 was corrected on May 19, 2010.
Supporting Information Available: Experimental procedures,
1
characterization data, and copies of H and 13C NMR spectra
for all reported compounds; comparison of NMR data for natural
and synthetic material; comparison of synthetic routes to 1b,
3b, and 4b. This material is available free of charge via the
Internet at http://pubs.acs.org.
(27) For an exception, see ref 10e.
JA102356J
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