A flexible approach toward trans-fused polycyclic tetrahydropyrans. A synthesis of prymnesin and yessotoxin units

Article abstract of DOI:10.1021/ol048165q

(Chemical Equation Presented) Ru-catalyzed cycloisomerization and oxidative cyclization of bis-homopropargylic alcohols provide a rapid iterative approach to structural units of the ladder toxins.

Full text of DOI:10.1021/ol048165q

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4311-4313
A Flexible Approach toward trans-Fused
Polycyclic Tetrahydropyrans. A
Synthesis of Prymnesin and Yessotoxin
Units
Barry M. Trost* and Young Ho Rhee
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received September 10, 2004
ABSTRACT
Ru-catalyzed cycloisomerization and oxidative cyclization of bis-homopropargylic alcohols provide a rapid iterative approach to structural
units of the ladder toxins.
Cycloisomerization of bis-homopropargylic alcohols to di-
hydropyrans and their oxidative cyclization1 to δ-valerolac-
tones provide useful building blocks to the structurally
fascinating marine ladder toxins.2,3 An iterative approach4
to the construction of fused polycyclic compounds can
be envisioned as shown in Scheme 1. This strategy comple-
2-stannyldihyropyrans.5 Considering the BCD ring frag-
ment of yessotoxin (1)6 and the AB ring fragment of
prymnesin (2),7 we chose to investigate this strategy using
the readily available ynediol 3, which derives from the
diastereoselective Barbier addition of propargyl bromide
using zinc to the acetonide of (R)-glyceraldehyde (dr 8:1).8
Subjecting 3-7.5 mol % of the Ru complex 4 in DMF as
shown in eq 1 gave the dihydropyran 5a in 70% yield. None
of the seven-membered ring product was observed even
Scheme 1. An Iterative Approach to Fused Polycylic
Tetrahydropyrans
(1) (a) For a Ru-catalyzed divergent approach to dihydropyrans and
valerolactones, see: Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002,
124, 2528. (b) For Rh-catalyzed cycloisomerization of bis-homopropargylic
alcohols, see: Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125,
7482.
(2) For a review on the marine ladder toxins, see: Yasumoto, T.; Murata,
M. Chem. ReV. 1993, 93, 1897.
(3) (a) For other examples that utilize dihydropyrans as building blocks,
see: Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123 and references
therein. (b) For other examples that utilize valerolactones as building blocks,
see: Kadota, I.; Takamura, H.; Sato, K.; Yamamoto, Y. J. Org. Chem.
2002, 67, 3494 and references theirein.
(4) For other examples of iterative approaches, see: Marmsater, F. P.;
West, F. G. Chem. Eur. J. 2002, 8, 4347 and references theirein.
(5) Bowman, J. L.; McDonald, F. E. J. Org. Chem. 1998, 63, 3680.
(6) (a) Murata, M.; Kumagai, M.; Lee, J. S.; Yasumoto, T. Tetrahedron
Lett. 1987, 28, 5869. (b) Naoki, H.; Murata, M.; Yasumoto, T. Rapid
Commun. Mass Spectrom. 1993, 7, 179.
ments an iterative approach based upon a stoichiometric
tungsten-mediated process involving the intermediacy of
(7) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293.
10.1021/ol048165q CCC: $27.50
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though that would have involved attack by the less hindered
primary hydroxyl group.
of excellent diastereoselectivity (dr 9:1). Thus, both diaster-
eomers 7 and 8 are available in high diastereoselectivity.
Because the base equilibration and diastereoselective ketone
can be performed in one pot, any mixture of 7 and 8 can
now be transformed into diastereomer 8 of high selectivity,
requiring just four steps from starting alkyne 3.
As depicted in Scheme 1, diastereomer 8 conceptually can
diverge to the cycloisomer 11 (eq 3, path a) or the oxidatively
cyclized lactone 12 (eq 3, path b) by simple manipulation
Epoxidation of dihydropyran 5b proceeded diastereose-
lectively (4:1) to give 6 as the major diastereomer. Its lability
led to its in situ reaction with allenylmagnesium bromide to
give the trans hydroxy alkynes 7 and 8 in a 4:1 ratio in a
78% overall yield (eq 2).9 Stereoelectronic effects account
of the ligands on the Ru catalyst.1 Thus, subjecting terminal
alkyne 8 to the conditions of eq 1 provides the dihydropyran
11 in 70% yield with 6% of lactone 123b as a minor side
product. On the other hand, increasing the amount of the
N-hydroxysuccinimide and using a more electron-rich phos-
phine, p-anisylphosphine, provides the lactone 12 as the
major product in 60% yield with only 8% of the dihydro-
pyran 11.
The dihydropyran 11 corresponds to the B and C rings of
the ladder toxin yessotoxin (1). As previously, stereoelec-
tronic considerations predict that epoxidation of 11 would
give the â-epoxide10 predominantly, which indicates that an
iterative approach would necessitate a sequence as shown
in Scheme 2. This sequence has the advantage that neither
the stereochemistry of the epoxidation nor of the epoxide
ring opening is relevant because all stereoisomers funnel to
the same requisite diastereomer. Scheme 3 illustrates that
next iterative cycle. Epoxidation followed directly by addition
of allenylmagnesium bromide gave a mixture of diastereo-
mers that were not characterized.11 Subjecting the mixture
to PCC oxidation gave a good yield of ketone 14 predomi-
nantly as one diastereomer (dr 11:1). Base equilibration
followed by reduction either in two separate operations or
for the diastereoselectivity. Thus, this route provides good
access to diastereomer 7. For synthetic purposes, good access
to diastereomer 8 was also desirable. Direct epoxidation
methods to favor the opposite (i.e., R) epoxide diastereomer
proved fruitless. On the other hand, a very simple solution
evolved as shown in Scheme 2. The ketone 9 undergoes
Scheme 2. Diastereoselective Synthesis of 8
(8) Peng, Z.-H.; Li, Y.-L.; Wu, W.-L.; Liu, C.-X.; Wu, Y.-L. J. Chem.
Soc., Perkin Trans. 1 1996, 1057.
(9) (a) The structure of 7 and 8 was confirmed by conversion into the
corresponding acetates, which were easily separated by flash chromatog-
raphy. For detailed experimental procedure, see Supporting Information.
(b) The complete trans stereoselectivity in the propargylation step has been
established; see ref 1a.
(10) A similar facial selectivity in the epoxidation of trans-fused bicyclic
dihydropyrans has been reported; see: Rainier, J. D.; Allwein, S. P.
Tetrahedron Lett. 1998, 39, 9601.
facile base equilibration that strongly favors epimer 10 (dr
12:1). Simple LAH reduction then provides diastereomer 8
(11) The desired diastereomer 15 was formed as a minor diastereomer.
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Org. Lett., Vol. 6, No. 23, 2004

proved straightforward as shown in eq 4. Acetylide addition
followed by a Lewis acid promoted reductive dehydroxyla-
tion with triethylsilane14 gave bicycle 17 in 73% yield (over
two steps) as a single diastereomer.
Scheme 3. An Iterative Cycle for Preparation of the
Yessotoxin Fragment
In summary, we developed a highly flexible approach
toward trans-fused polycyclic tetrahydropyrans, structural
motifs commonly present in the ladder toxins and related
natural products. The ability of the Ru-catalyzed process to
provide either cycloisomerization to dihydropyrans or oxida-
tive cyclization to δ-valerolactones by minor modifications
of the catalyst imparts great flexibility in accessing the
different substitution patterns found on the pyrans. The ability
to create fused polycyclic in an iterative approach requiring
only four steps for each iteration should facilitate the partial
and total synthesis of this structurally and biologically
interesting class of of natural products.
in one pot gave comparable results to form hydroxy alkyne
15 in similar yield (dr 13:1).12 Ru-catalyzed cycloisomer-
ization completes the cycle. Thus, each iterative cycle
requires four steps. Starting from acyclic precursor 3 using
the Ru-catalyzed cycloisomerization three times, the tricycle
fragment corresponding to rings BC and D of yessotoxin is
available in nine steps and 11% overall yield.
Acknowledgment. We thank the National Institutes of
Health General Medicine Sciences (GM 13598) and the
National Science Foundation for their generous support of
our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California-
San Francisco supported by the NIH Division of Research
Resources.
The lactone 12 illustrates a different dimension of this Ru-
catalyzed methodology, the diastereoselective attachment of
a side chain as in ring A of prymnesin. Because the diene
side chain might be attached by a cross-coupling reaction
of a vinylmetal, which in turn would derive by hydrometa-
lation of an alkyne,13 diastereoselective introduction of an
alkyne onto lactone 12 is required. This transformation
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds and charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL048165Q
(13) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Cross-Coupling
Reactions. A Practical Guide; Miyaura, N., Ed.; Topics in Current
Chemistry; Springer: Berlin, 2002; Vol. 219.
(12) This epimerization-reduction protocol has previously been used
in other syntheses of trans-fused polycyclic tetrahydropyrans. (a) Marmsater,
F. P.; West, F. G. J. Am. Chem. Soc. 2001, 123, 5144. (b) Evans, P. A.;
Roseman, J. D.; Garber, L. T. J. Org. Chem. 1996, 61, 4880.
(14) Grewal, G.; Kalia, N.; Franck, R. W. J. Org. Chem. 1992, 57, 2084.
Org. Lett., Vol. 6, No. 23, 2004
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