Dual macrolactonization/pyran-hemiketal formation via acylketenes: Applications to the synthesis of (-)-callipeltoside A and a lyngbyaloside B model system

Article abstract of DOI:10.1002/anie.200804049

Two for one: Thermal generation of acylketenes in diol-containing substrates results in the title transformation. This transformation expands the scope of acylketene macrolactonizations and their application to the synthesis of complex macrolides. Triol and tetraol substrates have also been cyclized in highly regioselective fashion. Additionally, the challenging macrolactonization of a tertiary alcohol was achieved. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200804049

Angewandte
Chemie
DOI: 10.1002/anie.200804049
Synthetic Methods
Dual Macrolactonization/Pyran–Hemiketal Formation via
Acylketenes: Applications to the Synthesis of (À)-Callipeltoside A and
a Lyngbyaloside B Model System**
Thomas R. Hoye,* Michael E. Danielson, Aaron E. May, and Hongyu Zhao
Acylketenes (Scheme 1, 2) are often employed as electro-
philes to trap alcohols to construct b-ketoesters (4) via the
transient enols (3) produced by concerted addition[1] of the
Scheme 1. b-Ketoester formation via acylketenes derived from
dioxinones.
Figure 1. Pyran–hemiketal-containing macrolides.
hydroxylic nucleophile (Scheme 1).[2] Thermolysis of 1,3-
dioxin-4-one derivatives (1) is the most common method
used for the generation of 2.[3] Boeckman and co-workers
pioneered the application of these reactive species in the
synthesis of complex molecules[4] such as macrocyclic lactones
and lactams, which can be constructed by intramolecular
reactions of hydroxy- or amino-containing acylketenes.[5]
As part of our research toward the synthesis of the
complex pyran-containing macrolides callipeltoside A
(Figure 1, 5) and lyngbyaloside B (Figure 1, 6), we have
expanded the scope of this powerful transformation[6] by
exploring the use of substrates containing multiple hydroxy
groups.[7] The mechanism of addition of hydroxylic nucleo-
philes to acylketene renders this process highly regioselective,
as reported herein for substrates containing up to four free
hydroxy groups. This reagent- and catalyst-free transforma-
tion allows for rapid, direct, and selective construction of the
macrolactone/pyran–hemiketal substructure units present in
callipeltoside A (5)[8] and lyngbyaloside B (6).[9]
We chose the prototypical substrate 7[10] for use in testing
the concept of dual macrolactonization/pyran–hemiketal
formation (Scheme 2). When this diol was heated in benzene
at 808C the macrolactone/pyran 8 was cleanly formed (in a
9:1 ratio of 8 to its C3 anomer) and isolated in 80% yield.
Scheme 2. Dual macrolactonization/pyran formation via the acylketene
diol 9.
[*] Prof. T. R. Hoye, Dr. M. E. Danielson, A. E. May, Dr. H. Zhao
Department of Chemistry
University of Minnesota
Minneapolis, Minnesota 55455 (USA)
E-mail: hoye@umn.edu
Although we do not know the exact sequence of events
that give rise to 8, if the distal C13-hydroxy group in
acylketene 9 were to add in a concerted 1,4-addition,[1] the
enol-lactone 10 would be formed. Rapid tautomerization
followed by hemiketal formation within ketone 11 accounts
for formation of 8. Several alternative intermediates or
processes can be envisioned for the transformation of 7 to
[**] This research was supported by the National Cancer Institute of the
U.S. National Institutes of Health (CA76497).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804049.
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8: a) Hemiketal formation in 9 prior to lactonization would
afford 12, which could further cyclize to the macrolactone/
pyran 8. We presume that the acylketene 9 would lactonize
considerably faster than the simple ketene 12 (for example,
= =
water reacts with acetylketene (AcCH C O) approximately
[11]
= =
42000 times faster than with ketene (H2C C O) itself).
Moreover, whereas no intermediates are involved in the
transformation of 9 to 10, hemiketal formation (9 to 12) likely
requires catalysis by an external agent. Thus, we are inclined
to believe that 12 is not involved in the process. b) Conjugate
addition of the secondary carbinol to the enoate moiety in 10
could give rise directly to 8. c) Trapping of the ketene by the
secondary C7-hydroxy group in 9 would give rise to the eight-
membered lactone 13.[12] Although 13 was not detected, its
further conversion into 8 by translactonization cannot be
ruled out. d) Adventitious water could trap either of the
ketenes 9 or 12 to afford the b-ketoacid 14, which would be
expected to decarboxylate to the methyl ketone 15. When the
benzene solvent was not predried, no methyl ketone 15 was
detected. Even when excess water (0.5m; biphasic system)
was added at the outset to a solution of 7 in benzene
(0.0003m) that was then heated to reflux, lactone 8 was still
the predominant product, but methyl ketone 15 was also
1
detected (approximately 2:1 molar ratio by H NMR spec-
troscopic analysis). When purified 8 was heated for 12 h in a
benzene solution to which excess water had been added, no
reaction occurred. When this experiment was repeated using
D2O, partial (mono- and di-) deuteration of C2 in 8 occurred.
The results listed under (d) are consistent with the
reversion of lactone 8 to the ketone/enol pair 11 and 10, but
not reversion of 10 to the acylketene 9. Conversely, both the
t1/2 values for the disappearance of 7 as well as the formation
of methyl ketone 15 are consistent with an initial, rate-limiting
thermolysis of dioxinone 7 to form the acylketene 9.[13]
Notably, 8 was formed in preference to 15, even when the
benzene reaction medium was saturated with water. Since the
addition of a hydroxylic nucleophile to an acylketene is a
Scheme 3. Dual macrolactonization/pyran formation of substrates
used in the synthesis of callipeltoside A (5). TMS=trimethylsilyl,
TBS=tert-butyldimethylsilyl, PMB=para-methoxybenzyl[15]
hydroxy group was exposed. This substrate also cyclized in
good yield, to the lactone 23. The six-membered pyranone
ring that would have arisen by acylation of the C5-hydroxy
group by the ketene was not detected.[18] To test whether
pyranone formation was feasible, the thermolysis of the
monoalcohol 24 was examined (Scheme 3). The pyranone 25
was isolated in 54% yield, establishing that the C5-hydroxy
group is capable of trapping the acylketene in the absence of
remote hydroxy groups that are geometrically suited for
concerted addition.
Finally, the fully deprotected 5,7,13,14-tetrol substrate 18
was studied (Scheme 3). Remarkably, this substrate, with four
free hydroxy groups, each, in principle, capable of participat-
ing in lactonization, cyclized to give the macrolactone 19 as
the major product, in 53% yield. No other constitutional
isomers were identified. Most interesting of all, perhaps, is the
selective reaction of the secondary C13-hydroxy group in
preference to the vicinal, primary C14-hydroxy group. To
benchmark the inherent reactivity difference within a termi-
nal vicinal diol, we treated an excess of 1,2-butanediol with
2,2,6-trimethyl-4H-1,3-dioxin-4-one in refluxing benzene or
toluene and detected a 3:1 preference for formation of the
primary b-ketoester. This result suggests that the regioselec-
tivity of lactonization to the secondary C13-hydroxy group in
18 is conformational in origin, rather than a function of a
À
concerted event, the relative O H bond strengths in water
(119 kcalmolÀ1) versus those in alcohols (104–107 kcalmolÀ1)
are important.[14] We suggest that partial cleavage of the O H
À
bond, uniquely strong in water, renders hydrolysis consider-
ably slower than alcoholysis. That is, lactonization within 9 is
favored over the competitive hydrolysis reaction. We can
further suggest that this preference is likely why acylketene
macrolactonization reactions have proven to be so successful
in late-stage (and often small-scale) constructions of complex
molecules.[6]
We have used the dual cyclization process to synthesize
callipeltoside A (5),[15] a natural product that was first
synthesized using an acylketene cyclization to produce a
late-stage b-ketomacrolactone intermediate.[16] Key experi-
ments towards this end involved a series of polyhydroxylated
substrates (Scheme 3). The 7,13-diol 16[17] incorporates two
free hydroxy groups and two that are capped as silyl ethers.
Likewise, the C13-epimeric diol bis-silylether 20 was studied.
Each of these dioxinone derivatives smoothly cyclized to its
corresponding hemiketal 17 or 21 (in 76% and 86% yield,
respectively) when refluxed in benzene solution for 12 h. We
next examined the 5,7,13-triol substrate 22, in which the C5-
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more inherent property, such as preferential hydrogen bond-
ing or nucleophilicity, of a 1,2-diol moiety.
which is encouraging in the context of ongoing studies into the
synthesis of lyngbyaloside B. Broadly speaking, the dual
cyclization transformation described here adds dimensional-
ity to the Boeckman cyclization, particularly in the context of
complex molecule synthesis.
Lyngbyaloside B (6) incorporates both a pyran hemiketal
and a tertiary macrolactone subunit, the latter an uncommon
structural element in natural products. Macrolactonization
reactions involving the OH group of a tertiary alcohol are also
quite rare.[19] To test the feasibility of synthesizing a tertiary
macrolactone, such as 6, using the dual macrolactonization/ Experimental Section
Synthesis of representative macrolactone/pyran 21: Diol 20 (18 mg,
pyran formation, we prepared the model C7/C13-diol sub-
strates 26a and 26b (each as a 1:1 mixture of C11 epimers,
Scheme 4).[10] In both substrates, competing eight-membered-
lactone formation[12] was seen as a potential complication, if
0.030 mmol) in benzene (2 mL) was added with a pipette to predried
benzene (180 mL, dried azeotropically using Dean–Stark apparatus).
The mixture was heated at reflux for 12 h and then allowed to cool to
room temperature. Solvent was removed under reduced pressure, and
the residue was purified by flash column chromatography on silica gel
(10% ethyl acetate in hexanes) to afford macrolactone 21 (14 mg,
86%).
See the Supporting Information for characterization data for
compounds 7, 8, 17, 19, 21, 23, 25, 26b, 26a, 27b, and 27a.
Received: August 15, 2008
Published online: October 31, 2008
Keywords: acylketenes · alcohols · concerted addition · lactones ·
.
regioselectivity
Scheme 4. Dual macrolactonization/pyran–hemiketal formation of sub-
strates relevant to the synthesis of lyngbyaloside B (6). Each of 26b,
26a, 27b, and 27a was an approximate 1:1 mixture of C11 epimers.
TES=triethylsilyl, BOM=benzyloxymethyl.
[1] a) B. Freiermuth, C. Wentrup, J. Org. Chem. 1991, 56, 2286 –
2289; b) D. M. Birney, P. E. Wagenseller, J. Am. Chem. Soc.
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[2] For a review on the preparation and use of acylketenes, see: C.
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[7] The only example we have located of an acyclketene lactoniza-
tion of a substrate containing more than one hydroxy group is
that of a 28/38 diol substrate used in the synthesis of (À)-
kromycin and reported in reference [4b]. Such a process might
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the tertiary C13-hydroxy group trapped the acylketene too
slowly. It was also unclear whether the macrolactone product
would be stable over the course of the reaction, since tert-
butylacetoacetate thermally extrudes tert-butanol at essen-
tially the same rate as acetone extrusion from dioxinones.[20]
In the event, heating 26b or 26a (benzene, 808C, 12 h)
cleanly produced the desired lactone/pyran 27b or 27a,
respectively, as the only isolable product. To our knowledge,
these results constitute the most efficient macrolactonization
involving a tertiary carbinol center, a fact that further
demonstrates the power of acylketene methodology. When
a solution of 27b in toluene that had been doped with excess
water was heated at reflux for 40 minutes (approximately two
half-lives for acylketene formation from either dioxinones or
tert-alkyl acetoacetates),[20] no decomposition was detected. It
is likely that the internal trapping of the b-ketolactone as its
hemiketal, thereby minimizing reversion to the reactive
acylketene intermediate, contributes to the success of these
transformations.
In summary, we have developed a process for dual
macrolactonization/pyran–hemiketal formation through the
trapping of thermally generated acylketenes by various diol
substrates, thus expanding the scope of acylketene macro-
cyclizations. We have further exploited the concerted nature
of the mechanism of the key cyclization event to regioselec-
tively lactonize triol and tetraol substrates (Scheme 3, 22 and
18, respectively). Additionally, the challenging macrolactoni-
zation of the tertiary alcohols 26b and 26a was achieved,
[9] a) H. Luesch, W. Y. Yoshida, G. G. Harrigan, J. P. Doom, R. E.
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[10] For the preparation of this substrate, see the Supporting
Information.
[11] Y. Chiang, H. X. Guo, A. J. Kresge, O. S. Tee, J. Am. Chem. Soc.
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[12] N. A. Petasis, M. A. Patane, J. Chem. Soc. Chem. Commun. 1990,
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[13] R. J. Clemens, J. S. Witzeman, J. Am. Chem. Soc. 1989, 111,
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[17] For preparation of compounds 16, 18, 20, 22, and 24 see
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[18] M. Sato, J. Sakaki, Y. Sugita, S. Yasuda, N. Sakoda, C. Kaneko,
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[14] For a critical analysis of bond dissociation energies, see: S. J.
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