A [3 + 3] annelation approach to (+)-rhopaloic acid B

Article abstract of DOI:10.1021/ol701553j

A general and enantiospecific [3 + 3] reaction toward functionalized pyrans is reported that has been employed in the first enantioselective synthesis of (+)-rhopaloic acid B.

Full text of DOI:10.1021/ol701553j

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3941-3943
A [3
+ 3] Annelation Approach to
(+)-Rhopaloic Acid B
Julien C. R. Brioche,† Katharine M. Goodenough,† David J. Whatrup,‡ and
Joseph P. A. Harrity*,†
Department of Chemistry, UniVersity of Sheffield, Brook Hill, Sheffield S3 7HF,
United Kingdom, and Synthetic Chemistry, GlaxoSmithKline, Tonbridge, Kent,
TN11 9AN, United Kingdom
j.harrity@sheffield.ac.uk
Received July 2, 2007
ABSTRACT
A general and enantiospecific [3
+ 3] reaction toward functionalized pyrans is reported that has been employed in the first enantioselective
synthesis of ( )-rhopaloic acid B.
+
The rhopaloic acids (Figure 1) are a class of novel norsester-
terpenes that were first isolated from the marine sponge
The interesting biological acitivty of these compounds
coupled with the paucity of material available from their
natural sources has inspired some significant synthetic effort
toward these molecules. Specifically, Snider developed a
short synthesis of racemic rhopaloic acid A that also provided
minor quantities of rhopaloic acid B methyl ester.3 Addition-
ally, enantioselective syntheses of rhopaloic acid A have been
reported by Ogasawara4 and Ohkata.5 The former required
some 30 steps from an enantiomerically pure dioxabicyclo-
[3.2.1]octane while the latter, shorter synthesis featured an
inefficient pyran-forming cyclization (30-40% yield). We
hoped to develop a new approach to the rhopaloic acids that
would deliver short, enantioselective routes to this family
of compounds.6 We report herein an unusual [3 + 3]
annelation approach to pyrans toward this end, and its
application in the first enantioselective synthesis of (+)-
rhopaloic acid B.
Figure 1. Rhopaloic acids.
(1) (a) Ohta, S.; Uno, M.; Yoshimura, M.; Hiraga, Y.; Ikegami, S.
Tetrahedron Lett. 1996, 37, 2265. (b) Yanai, M.; Ohta, S.; Ohta, E.; Ikegami,
S. Tetrahedron 1998, 54, 15607.
(2) Craig, K. S.; Williams, D. E.; Hollander, I.; Frommer, E.; Mallon,
R.; Collins, K.; Wojciechowicz, D.; Tahir, A.; Van Soest, R.; Andersen, R.
J. Tetrahedron Lett. 2002, 43, 4801.
(3) Snider, B. B.; He, F. Tetrahedron Lett. 1997, 38, 5453.
(4) Kadota, K.; Ogasawara, K. Heterocycles 2003, 59, 485.
(5) (a) Takagi, R.; Sasaoka, A.; Kojima, S.; Ohkata, K. Chem. Commun.
1997, 1887. (b) Takagi, R.; Sasaoka, A.; Nishitani, H.; Kojima, S.; Hiraga,
Y.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 925.
(6) For a recent enantioselective synthesis of related hippospongic acid
A and lead references see: Trost, B. M.; Machacek, M. R.; Tsui, H. C. J.
Am. Chem. Soc. 2005, 127, 7014.
Rhopaloeides sp. by Ohta and Ikegami,1 and subsequently
also from Hippospongia sp. by Andersen and co-workers.2
These compounds exhibit potent inhibition of the gastrulation
of starfish embryos, in vitro cytotoxicity toward human
myeloid K-562 cells, human MOLT-4 leukemia cells, and
murine L1210 cells, and RCE protease inhibitory activity.
† University of Sheffield.
‡ GlaxoSmithKline.
10.1021/ol701553j CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/31/2007

Recent studies in our laboratories have endeavored to
develop a series of [3 + 3] annelation processes for the
synthesis of piperidines by the addition of conjunctive
reagents to aziridines.7,8 Preliminary investigations high-
lighted that in situ generated Pd-trimethylenemethane [Pd-
TMM]9 could be employed to good effect in this regard,8a,b
and that the reaction was efficient for a range of 2-alkyl-
aziridines. It occurred to us that a similar strategy could be
employed to access functionalized pyrans.10 Specifically, as
outlined in Scheme 1, nucleophilic addition of Pd-TMM 1
to aziridines followed by a Pd-catalyzed cyclization.8e We
therefore decided to explore the scope of this approach with
respect to pyran synthesis.13
As outlined in entry 1 of Table 1, double deprotonation
of methallyl alcohol 5 followed by transmetallation provided
an organomagnesium reagent that underwent addition to
epoxide 6 in good yield. Moreover, subsequent treatment of
adduct 7 with a Pd-catalyst in the presence of Ti(OPr-i)4
facilitated ring closure to the desired pyran 8.14 Notably, the
inclusion of the Ti Lewis acid significantly promotes this
cyclization as longer reaction times (24 h as opposed to 1
h) and poorer conversions are observed in its absence. The
enantiospecificity of the stepwise annelation was confirmed
by the synthesis of pyran 14 (entry 3) while extension of
the methodology to include bicyclic pyrans was also
demonstrated by the synthesis of 17 (entry 4). Addition of
the in situ generated organomagnesium reagent to styrene
oxide 18 gave the expected mixture of regioisomers 19a/b
(entry 5);15 however, both were readily separated and cyclized
in good yield.
Scheme 1
to epoxide 2 would provide intermediate 3 that could cyclize
to generate the desired pyran 4. A point of concern at this
stage was the potential incompatibility of the hard alkoxide
nucleophile and the Pd π-allyl moiety.11 However, we were
encouraged by the elegant studies of Trost and co-workers
that highlighted the successful use of Sn- and In-based Lewis
acids in facilitating related cyclizations during [3 + 2]
annelations onto aldehydes and ketones.12
Table 1. [3 + 3] Annelation of Epoxidesa
Preliminary studies aimed at establishing this Pd-catalyzed
[3 + 3] annelation were disappointing. Employment of
standard conditions for the in situ generation of Pd-TMM
failed to provide the corresponding pyran (Scheme 2).
Scheme 2
Moreover, the employment of Bu3SnOAc or In(acac)3 Lewis
acid cocatalysts was unsuccessful in promoting the reaction
and starting epoxide was returned in all cases.
Our failure to observe the addition of Pd-TMM to
epoxides prompted us to consider an alternative strategy. In
this context, we had shown that an analogous, but stepwise,
[3 + 3] annelation process toward piperidines could be
realized by the addition of the dianion of methallyl alcohol
(7) For reviews of [3 + 3] approaches to heterocycle systems see: (a)
Harrity, J. P. A.; Provoost, O. Org. Biomol. Chem. 2005, 1349. (b) Hsung,
R. P.; Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005, 23.
(8) (a) Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.;
Harrity, J. P. A. Synlett 2001, 1596. (b) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286. (c) Moran, W. J.;
Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett. 2003, 5, 3427.
(d) Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A. J. Org.
Chem. 2005, 70, 207. (e) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A.
Org. Lett 2005, 7, 2993. (f) Pattenden, L. C.; Wybrow, R. A. J.; Smith, S.
A.; Harrity, J. P. A. Org. Lett. 2006, 8, 3089. (g) Provoost, O. Y.; Hedley,
S. J.; Hazelwood, A. J.; Harrity, J. P. A. Tetrahedron Lett. 2006, 47, 331.
a Organomagnesium reagent prepared by addition of TMEDA (2.1 equiv)
and nBuLi (2.1 equiv) to 5 followed by MgBr2 (2.1 equiv). 1.5 equiv of
this reagent added to epoxide. Entry 5: 2.5 equiv of Grignard used in this
case.
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Org. Lett., Vol. 9, No. 20, 2007

Scheme 3
Having established the validity of the [3 + 3] annelation
the rhopaloic acids. In the event, we decided to employ
hydroboration and found that Rh-catalyzed methodology17
provided the desired cis-24 in high yield, albeit with modest
diastereoselectivity.
strategy for the synthesis of functionalized pyrans, we turned
our attention to its application in the enantioselective
synthesis of (+)-rhopaloic acid B. Accordingly, the required
enantiopure epoxide 21 for the synthesis of the pyran core
was prepared by using Jacobsen’s kinetic resolution protocol
(Scheme 3).16 Addition of the Grignard reagent and subse-
quent cyclization proceeded without incident to provide pyran
23 in good overall yield. Diastereoselective functionalization
of the exomethylene group in 23 would set the stage for
elaboration of this intermediate to each specific member of
Installation of the farnesyl chain was carried out after
conversion of 24 to the corresponding iodide 25 and
alkylation with sulfone 26. Product sulfone 27 was found to
be contaminated by some unreacted 26 and so the crude
material was subjected to Pd-catalyzed reduction6,18 to
provide 28 in 73% yield over two steps. Finally, conversion
of the protected 2-hydroxyethyl chain to the required R,â-
unsaturated acid was carried out by cleavage of the silyl ether
with TBAF followed by Swern oxidation, Mannich meth-
ylenation, and Pinnick oxidation.
In conclusion, we have developed a stepwise [3 + 3]
annelation approach to functionalized pyrans and demon-
strated its employment in the enantioselective synthesis of
rhopaloic acid B. The employment of this strategy in the
synthesis of other members of the rhopaloic acids is
underway and will be reported in due course.
(9) For a review of Pd-TMM cycloadditions see: Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1986, 25, 1.
(10) For [3 + 3] approaches to pyrans see: (a) Hua, D. H.; Chen, Y.;
Sin, H.-S.; Maroto, M. J.; Robinson, P. D.; Newell, S. W.; Perchellet, E.
M.; Ladesich, J. B.; Freeman, J. A.; Perchellet, J.-P.; Chiang, P. K. J. Org.
Chem. 1997, 62, 6888. (b) Hsung, R. P.; Shen, H. C.; Douglas, C. J.;
Morgan, C. D.; Degen, S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690. (c)
Shen, H. C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C. D.;
Douglas, C. J.; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J.
M.; Liu, J.; Wei, L.-L.; Sklenicka, H. M.; Zehnder, L. R.; Zificsak, C. A.
J. Org. Chem. 2003, 68, 1729. (d) Epstein, O. L.; Rovis, T. J. Am. Chem.
Soc. 2006, 128, 16480.
(11) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2931.
(12) (a) Trost, B. M.; King, S. A. J. Am. Chem. Soc. 1990, 112, 408. (b)
Trost, B. M.; Sharma, S.; Schmidt, T. J. Am. Chem. Soc. 1992, 114, 7903.
(13) Addition of a related Grignard reagent to epoxides has been shown
to produce pyrans. However, this reagent is prepared in two steps in modest
yield. Moreover, the Grignard formation was found to be highly prone to
Wurtz coupling in our hands. van der Louw, J.; van der Baan, J. L.; Out,
G. J. J.; de Kanter, F. J. J.; Bickelhaupt, F.; Klumpp, G. W. Tetrahedron
1992, 48, 9901.
Acknowledgment. We thank the University of Sheffield
and GSK for financial support.
Supporting Information Available: Full experimental
details for the syntheses reported. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) For a recent example of transition metal-catalyzed cyclodehydration
and lead references see: Shibata, T.; Fujiwara, R.; Ueno, Y. Synlett 2005,
152.
(15) Morrison, J. D.; Atkins, R. L.; Tomaszewski, J. E. Tetrahedron Lett.
1970, 11, 4635.
(16) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 1307. (b) Romeril, S. P.; Lee, V.; Baldwin, J. E.; Claridge,
T. D. W.; Odell, B. Tetrahedron Lett. 2003, 44, 7757.
OL701553J
(17) This result was obtained by using aged catalyst. The employment
of freshly prepared Wilkinson’s catalyst resulted in a significantly slower
reaction, albeit with better levels of selectivity. For a mechanistic study
and lead references see: Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am.
Chem. Soc. 1992, 114, 6679.
(18) Hutchins, R. O.; Learn, K. J. Org. Chem. 1982, 47, 4380.
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