Oxyanionic sigmatropic rearrangements relevant to cyclooctadienone formation in penostatins i and F

Article abstract of DOI:10.1021/ol3019488

The results of several experiments designed to probe the energetic viability of a reaction path for generation of penostatins I (3) and F (4) via spontaneous [3,3]-sigmatropic rearrangement are reported. In particular, the enolate derived from the 2-vinyl

Full text of DOI:10.1021/ol3019488

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4738–4741
Oxyanionic Sigmatropic Rearrangements
Relevant to Cyclooctadienone Formation
in Penostatins I and F
Matthew J. Jansma and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE
Minneapolis, Minnesota 55455, United States
hoye@umn.edu
Received July 13, 2012
ABSTRACT
The results of several experiments designed to probe the energetic viability of a reaction path for generation of penostatins I (3) and F (4) via
spontaneous [3,3]-sigmatropic rearrangement are reported. In particular, the enolate derived from the 2-vinyl-6-acyldihydropyran 8-cis gave
cyclooctadienone 12 via facile anionic oxy-Claisen rearrangement, demonstrating the feasibility of such an event.
The penostatins A (1), B (2), I (3), and F (4) are four
(of nine total) members of a polyketide-derived family of
secondary metabolites that have been isolated from the
microorganism Penicillium sp. OUPS-79, a fungus that
was originally separated from the marine alga Enteromorpha
intestinalis1,2 (Scheme 1). Each of 1/2 and 3/4 are tetraepi-
meric. That is, each member of a given pair possesses the same
absolute configuration at the C5 carbinol stereogenic center
but the opposite absolute configurations at the remaining four
stereogenic centers. This configurational relationship among
members of the same natural product family is certainly rare,
if not unprecedented.
could, via ketoꢀenol tautomerization [KET], generate 5
or 6 (Scheme 1). Embedded within each of these enol
tautomers is an allyl vinyl ether (AVE) subunit that bears
a donor atom at C1. Spontaneous [3,3]-sigmatropic re-
arrangement of 5 or 6 would then directly generate
the bicyclo[5.3.1]undecenone core of 3 or 4, respectively.
Paquette and co-workers have extensively studied the ring
expansion of architecturally similar 2-alkylidene-6-alke-
nyl pyrans to generate cyclooct-4-enones via thermal
Claisen rearrangement.3
In 1981 a theoretical treatment of the aliphatic Claisen
rearrangement by Carpenter and Burrows qualitatively
demonstrated that π-donor substituents positioned at C1
(as well as C2 and C3) of simple AVEs should result in rate
enhancement.4 The prescience of this analysis was soon
realized when, in 1985, Koreeda and Luengo reported the
discovery of the “anionic oxy-Claisen” rearrangement.5
These authors demonstrated, among other things, that
the [3,3]-sigmatropic rearrangement of the potassium and
We have hypothesized that 3 and 4 are biosynthetically
derived from 1and 2(or their C9 epimers). This mechanistic
thinking is also evident from synthetic studies carried out in
the Snider2a and Barriault2c laboratories. Specifically, 1 or 2
(1) Isolation and structure determination of all members of the
penostatin family: (a) Takahashi, C.; Numata, A.; Yamada, T.;
Minoura, K.; Enomoto, S.; Konishi, K.; Nakai, M.; Matsuda, C.;
Nomoto, K. Tetrahedron Lett. 1996, 37, 655–658. (b) Iwamoto, C.;
Minoura, K.; Hagishita, S.; Nomoto, K.; Numata, A. J. Chem. Soc.,
Perkin Trans. 1 1998, 449–456. (c) Iwamoto, C.; Minoura, K.; Oka, T.;
Ohta, T.; Hagishita, S.; Numata, A. Tetrahedron 1999, 55, 14353–14368.
(2) Synthetic studies toward penostatins A, B, and F: (a) Snider,
B. B.; Liu, T. J. Org. Chem. 1999, 64, 1088–1089. (b) Snider, B. B.; Liu, T.
J. Org. Chem. 2000, 65, 8490–8498. (c) Barriault, L.; Ang, P. J. A.;
Lavigne, R. M. A. Org. Lett. 2004, 6, 1317–1319. Total synthesis of
penostatin B: (d) Fujioka, K.; Yokoe, H.; Yoshida, M.; Shishido, K.
Org. Lett. 2012, 14, 244–247.
(3) For example, see: (a) Kinney, W. A.; Coghlan, M. J.; Paquette,
L. A. J. Am. Chem. Soc. 1984, 106, 6868–6870. (b) Paquette, L. A.;
Philippo, C. M. G.; Yo, N. H. Can. J. Chem. 1992, 70, 1356–1365 and
references cited therein. (c) Paquette, L. A.; Wang, T.-Z.; Vo, N. H.
J. Am. Chem. Soc. 1993, 115, 1676–1683.
(4) Burrows, C. J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103,
6984–6986.
(5) Koreeda, M.; Luengo, J. I. J. Am. Chem. Soc. 1985, 107, 5572–
5573.
r
10.1021/ol3019488
Published on Web 09/10/2012
2012 American Chemical Society

sodium enolates derived from R-(allyloxy)propiophenone
occurred with remarkable ease (t1/2 < 0.1 and 2.4 h,
respectively, at ꢀ23 °C).
Scheme 2. Proposed Model Study
Scheme 1. Hypothesis for the Biosynthesis of Penostatin I (3)
and Penostatin F (4)
(ca. 1:1 meso þ d,l)7 was alkylated with tert-butyl bromo-
acetate (Bu4NþBrꢀ, PhH, reflux) to deliver the isomeric
dioxanones 14-trans/cis together with minor amounts
of their acyclic, hydroxy ester progenitors. This mixture
was driven to the desired products upon treatment with
TFA (PhH, reflux).8 Separation of these isomers (medium
pressure liquid chromatography on silica gel) provided
14-trans (>95% purity) and 14-cis (ca. 90% purity), the
relative configurations of which were assigned by analysis
of vicinal 3JH5,H6 coupling values.9
Lactone 14-trans10 was then subjected to Irelandꢀ
Claisen11 rearrangement to effect dioxanone-to-dihydro-
pyran reorganization12,13 (Scheme 3). In the event, the
intermediate silyl enol ether 15-trans rearranged smoothly
(PhMe, 100ꢀ110 °C8,14) to deliver the TBS ester 16-cis. It
should be noted that isolation of this latter, acid-sensitve
substance required the use of TMS-functionalized silica gel.15
(7) (a) Hekmatshoar, R.; Yavari, I.; Beheshtiha, Y. S.; Heravi, M. M.
Monatsh. Chem. 2001, 132, 689–691. (b) Trost, B. M.; Aponick, A.
J. Am. Chem. Soc. 2006, 128, 3931–3933.
(8) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71–74. In this
report, a single enantiomer of 14-trans was prepared by a route that
commenced with D-mannitol.
3
(9) The vicinal JH5,H6 values observed for 14-trans and 14-cis
(9.0 and 4.5 Hz, respectively) are in good agreement with those reported
for related structures by Burke and co-workers; see ref 12d.
(10) As a matter of experimental convenience, the higher purity lactone
14-trans (which gives 16-cis upon IrelandꢀClaisen rearrangement12,13) was
typically taken forward. Thus the ketones 7-cis and 8-cis were used in the
majority of the studies described here. However, the analogous series of
isomeric intermediates derived from 14-cis (i.e., 7-trans, 8-trans, 16-trans,
and 18-trans) have also been prepared and fully characterized; see the
Supporting Information for full details.
ꢀ
The implications of the Koreeda study vis-a-vis the
hypothesis proposed in Scheme 1 were intriguing. Might
it be the case that (the enolates corresponding to) 5 and 6,
present at low (but finite) concentration, undergo a pair of
biosynthetic, anionic oxy-Claisen rearrangements to give
rise to (the alkoxide precursors of) 3 and 4 at ambient
temperature? We reasoned that this possibility could be
addressed by interrogating the reactivity of the enolates
derived from the dihydropyrans 7 and 8 (Scheme 2). These
simplied analogs retain many of the key structural attri-
butes of 1 and 2 but have the advantage of being much
more readily accessible. The intent was to explore the
behavior of 7 or 8 under basic conditions to learn if the
enolate 9 or 10 would undergo [3,3]-sigmatropic rearran-
gementto produce the penostatin-like cyclooctadienone11
or12. We describe here the observations made through this
model study.
(11) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897–
5898.
(12) (a) Burke, S. D.; Armistead, D. M.; Schoenen, F. J. J. Org.
Chem. 1984, 49, 4320–4322. (b) Burke, S. D.; Armistead, D. M.; Fevig,
J. M. Tetrahedron Lett. 1985, 26, 1163–1166. (c) Burke, S. D.; Schoenen,
F. J.; Murtiashaw, C. W. Tetrahedron Lett. 1986, 27, 449–452. (d) Burke,
S. D.; Armistead, D. M.; Schoenen, F. J.; Fevig, J. M. Tetrahedron Lett.
1986, 27, 2787–2801. (e) Burke, S. D.; Schoenen, F. J.; Nair, M. S.
Tetrahedron Lett. 1987, 28, 4143–4146. (f) Burke, S. D.; Lee, K. C.;
Santafianos, D. Tetrahedron Lett. 1991, 32, 3957–3960. (g) Burke, S. D.;
Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett. 1991, 32, 3961–3964.
(h) Burke, S. D.; Piscopio, A. D.; Kort, M. E.; Matulenko, M. A.;
Parker, M. H.; Armistead, D. M.; Shankaran, K. J. Org. Chem. 1994, 59,
332–347.
€
(13) (a) Buchi, G.; Powell, J. E., Jr. J. Am. Chem. Soc. 1967, 89, 4559–
€
4560. (b) Buchi, G.; Powell, J. E., Jr. J. Am. Chem. Soc. 1970, 92, 3126–
3133. (c) Danishefsky, S.; Funk, R. L.; Kerwin, J. F., Jr. J. Am. Chem.
A straightforward, five-step sequence was employed
to prepare the substrates 7-cis and 8-cis (Scheme 3). The
stannylene ketal6 derivedfrom hexa-1,5-diene-3,4-diol (13)
Soc. 1980, 102, 6889–6891.
(14) Angle, S. R.; Breitenbucher, J. G.; Arnaiz, D. O. J. Org. Chem.
1992, 57, 5947–5955.
(15) For example, see ref 14 and Overman, L. E.; Angle, S. R. J. Org.
Chem. 1985, 50, 4021–4028 (the protocol used for the preparation of the
TMS-functionalized silica gel used here is described in the Supporting
Information).
ꢀ
(6) David, S.; Thieffry, A.; Veyrieres, A. J. Chem. Soc., Perkin Trans.
1 1981, 1796–1801.
Org. Lett., Vol. 14, No. 18, 2012
4739

The Weinreb amide 18-cis then emerged in moderate
overall yield from a two-step procedure that involved (i)
exposure of 16-cis to an excess (3 equiv) of the Vilsmeier
reagent16 and (ii) amidation of the resulting crude acid
chloride 17-cis under standard conditions. Finally, the
styrenyl- (7-cis) and phenyl- (8-cis) ketones were unevent-
fully produced upon acylation of either β-lithiostyrene17 or
phenylmagnesium bromide with the amide 18-cis.
Scheme 3. Preparation of the Model Substrates 7-cis and 8-cis
When ketone 7-cis was exposed to K2CO3 in MeOH for
90 min at 60 °C, the only isolable product was the
symmetric cycloheptadiene derivative 20 (Figure 1, Panel A),
derived from [2,3]-Wittig rearrangement18 of the enolate 9
(Panel B, entry 1). This product was again formed, this
time within minutes at room temperature, upon addition
of 7-cis to a solution of tetra-n-butylammonium hydroxide
(Bu4NþHOꢀ) in i-PrOH/MeOH (entry 2).
Figure 1. Oxyanionic rearrangements of enolates 9 and 10,
derived from 7-cis and 8-cis, respectively. (A) Rearrangement
of 9 via competitive [2,3]-Wittig (to 19) vs Claisen/Cope (to 23)
pathways. (B) Table of results. (C) Rearrangement of 10 via a
Claisen pathway.
We then attempted to trap the silyl enol ether derived
from 9 (M = Na) with the intent of subsequently examin-
ing its thermal reactivity. Deprotonation of 7-cis with
NaHMDS in THF at ꢀ78 °C followed by treatment with
TBSCl prior to workup again gave rise to 20, but now
along with a second unexpected product, the conjugated
cyclooctadienone 24 (Figure 1, Panel B, entry 3). Its
structure was established through extensive 1-D (1H and
the fortuitous positioning of the (E)-styrenyl appendage in
7-cis (Figure 1, Panel A). The cyclooctadienone 21 arising
from anionic oxy-Claisen rearrangement of 9 contains yet
another (all-carbon) vic-π,π subunit. It bears an aromatic
substituent at C119 and an electron-donating oxido at C3.20
[3,3]-Sigmatropic (anionic oxy-Cope20,21) rearrangement
of 21 gives the isomeric cyclooctadienone 22. The prototropic
1
13C) and 2-D (1Hꢀ H COSY, HMQC, and HMBC) NMR
experiments and analysis. Although this product was
formed as essentially a single diastereomer, we have not
unambiguously established its relative configuration.
Formation of 24 can be explained by the following
sequence, which is a pathway that is a consequence of
(19) Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett.
2003, 5, 3631–3634.
(20) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765–
4766.
(16) Wissner, A.;Grudzinskas,C. V.J. Org. Chem. 1978, 43, 3972–3974.
(17) Neumann, H.; Seebach, D. Tetrahedron Lett. 1976, 17, 4839–4842.
(18) Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084–2087.
(21) (a) Lee, E.; Shin, I.-J.; Kim, T.-S. J. Am. Chem. Soc. 1990, 112,
260–264. (b) Lee, E.; Lee, Y. R.; Moon, B.; Kwon, O.; Shim, M. S.; Yun,
J. S. J. Org. Chem. 1994, 59, 1444–1456.
4740
Org. Lett., Vol. 14, No. 18, 2012

shift indicated within 22 produces the isomeric and
presumably more stable dienolate 23. Silylative quenching
then gives rise to the observed dienol ether 24.22
entry 4). Notably, this rearrangement took place within
10 min at 0 °C.
In summary, as part of our studies designed to probe the
hypothesis that penostatin F (3) and penostatin I (4) arise
via spontaneous [3,3]-sigmatropic rearrangements of their
progenitors 1 and 2, respectively (Scheme 1), the homolo-
gous 2,6-disubstituted dihydropyran model substrates 7-cis
and 8-cis were prepared by five-step synthetic sequences
emanating from the dioxanone 14-trans. The rearrangements
of each were studied under a variety of basic conditions. The
observed formation of cyclooctadienone 12 via a rapid [3,3]-
sigmatropic (anionic oxy-Claisen) rearrangement serves as
evidence that the pathways shown in Scheme 1 that inter-
connect 1 with 3 and 2 with 4 are energetically viable.
In light of this proposed mechanism, we judged that the
product derived from anionic oxy-Claisen rearrangement
might be isolable ifthe styrenylunsaturation were removed
from 7-cis. Thus, the phenyl ketone 8-cis was subse-
quently studied (Figure 1, Panel C). Indeed, deproto-
nation of this compound with NaHMDS in THF
at ꢀ78 °C followed by warming gave rise to the cyclooc-
tadienone 12 as the major product23 (Figure 1, Panel B,
(22) We considered an alternative mechanism wherein 21 would arise
by [1,2]-migration of a CꢀC bond within 19. This type of reorganization
has been considered previously; see: Kirchner, J. J.; Pratt, D. V.;
Hopkins, P. B. Tetrahedron Lett. 1988, 29, 4229–4232. A control
experiment was performed in which 20 was reexposed to NaHMDS
under the conditions used to generate 24 from 7-cis. Following reaction
quench with TBSCl, none of 24 was observed, ca. 20% of 20 was
recovered, and a byproduct that was shown to be a monosilylated dimer
was isolated in ca. 19% yield, the structure of which was not fully
delineated.
Acknowledgment. This investigation was supported by
a grant awarded by the U.S. Department of Health and
Human Services (National Institute of General Medical
Sciences, GM-65597).
(23) The β,γ-unsaturated cyclooctadienone 12 was also seen to form
slowly upon exposure of 8-cis to aqeuous base (i.e., 0.1 M NaOH, THF,
rt, 20 d, ca. 7% conversion to 12). Under these conditions, the epimers
8-cis and 8-trans10 (ca. 0.9:1) were observed (1H NMR analysis) as the
major components of the crude mixture in addition to the rearrangement
product 12. This implies that enolate 10 was reprotonated (from both
diastereotopic faces) more rapidly than it underwent [3,3]-sigmatropic
rearrangement to 25. Moreover it suggests that 12 is more stable than
one of its isomeric R,β-unsaturated cyclooctadienone isomers under
these apparently equilibrating conditions.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and
13C NMR spectra for all isolated 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. 18, 2012
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