Studies in Marine Polypropionate Synthesis: Total Synthesis of (-)-Baconipyrone C

Article abstract of DOI:10.1021/ol000027n

(Equation Presented) An asymmetric total synthesis of the unusual siphonariid metabolite, (-)-baconipyrone C (3), is described. Key steps included a tin(II)-mediated aldol coupling for the preparation of the carboxylic acid 17 and two different boron-mediated aldol additions leading to alcohol 8. Ester formation using modified Yamaguchi conditions gave 24, leading on PMB deprotection to (-)-baconipyrone C.

Full text of DOI:10.1021/ol000027n

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1513-1516
Studies in Marine Polypropionate
Synthesis: Total Synthesis of
(−)-Baconipyrone C
Ian Paterson,* David Yu-Kai Chen, Jose´ Luis Acen˜a, and Alison S. Franklin
UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ip100@cus.cam.ac.uk
Received February 10, 2000
ABSTRACT
An asymmetric total synthesis of the unusual siphonariid metabolite, (−)-baconipyrone C (3), is described. Key steps included a tin(II)-
mediated aldol coupling for the preparation of the carboxylic acid 17 and two different boron-mediated aldol additions leading to alcohol 8.
Ester formation using modified Yamaguchi conditions gave 24, leading on PMB deprotection to (−)-baconipyrone C.
Siphonariids are pulmonate molluscs of the genus Sipho-
naria, which may represent an evolutionary link between
marine and terrestrial gastropods. A diverse range of
polyketides1 have been isolated from siphonariids, and these
appear to share a common biosynthetic origin to macrolide
and polyether antibiotics.2,3
a contiguous carbon skeleton as would be expected from
regular polyketide biosynthesis. In baconipyrones A (1) and
B (2), the γ-pyrone moiety is connected through an ester
In 1989, Faulkner and co-workers reported the isolation
of baconipyrones A-D (1-4) from Siphonaria baconi
collected from intertidal rock platforms near Melbourne,
Australia.4 The structure of baconipyrone B (2) was estab-
lished by X-ray analysis, while the structures of the other
baconipyrones were determined by comparison of spectral
data. The full absolute stereochemistry was not assigned.
The baconipyrones all contain a tetrasubstituted γ-pyrone
with a characteristic polypropionate side chain. In contrast
to other siphonariid metabolites, however, they do not contain
(1) For recent reviews, see: (a) Faulkner, D. J. Nat. Prod. Rep. 1996,
13, 75. (b) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998,
15, 477.
(2) Garson, M. J.; Goodman, J. M.; Paterson, I. Tetrahedron Lett. 1994,
35, 6929.
(3) (a) O’Hagan, D. Nat. Prod. Rep. 1989, 6, 205. (b) O’Hagan, D. The
Polyketide Metabolites; Horwood, Chichester, 1991.
(4) Manker, C. D.; Faulkner, D. J.; Stout, J. T.; Clardy, J. J. Org. Chem.
1989, 54, 5371.
linkage to a highly substituted â-hydroxy cyclohexanone,
whereas in baconipyrones C (3) and D (4), it is connected
through an ester to an acyclic â-hydroxy 1,5-diketone. It
10.1021/ol000027n CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/03/2000

Scheme 1
appears that 1 and 2 may be derived from 3 and 4,
Scheme 2
respectively, by means of an aldol-type cyclization. A
biosynthetic link with the structurally related siphonarins A
(5) and B (6),5a which contain a spiroacetal moeity, has also
been proposed.4,5b As part of our studies in the synthesis of
such marine polypropionates,6 we now report the first total
synthesis of (-)-baconipyrone C (3), which also serves to
firmly establish its absolute stereochemistry.
As outlined retrosynthetically in Scheme 1, disconnection
of the ester linkage in 3 reveals the γ-pyrone carboxylic acid
7 and the C2-symmetrical alcohol 8. The antipode of acid 7
was previously synthesized in the course of investigations
into the full stereostructures of the siphonarins and baconipy-
rones.7 The key step in the preparation of the γ-pyrone-
containing fragment 7 would be a syn aldol reaction between
ketone (R)-9 and aldehyde 10, where the latter would be
accessed via cyclization of the corresponding triketone 11.
The preparation of the alcohol 8 was envisaged using our
boron-mediated, asymmetric aldol methodology from the
ketone (R)-12 and the commercially available (E)-2-methyl-
2-pentenal (13).
As shown in Scheme 2, the synthesis of the C2-sym-
metrical 1,5-diketone 8 began with a syn aldol reaction
between the lactate-derived8 ketone (R)-12 and the enal 13.
Using our standard enolization conditions with (c-C6H11)2-
BCl and Et3N in Et2O,8a the desired aldol adduct 14 was
obtained with greater than 95% diastereoselectivity. Silyl
protection (TBSOTf) of 14, followed by reductive removal8b,9
of the R-benzyloxy substituent using SmI2, gave enantiopure
ethyl ketone 15 in 88% overall yield. In this way, the ketone
12 functions as an equivalent of 3-pentanone for performing
asymmetric aldol reactions.
The syn-configured ketone 15 could also be accessed more
rapidly (albeit in lower enantiomeric purity) by a reagent-
controlled, asymmetric aldol reaction of 3-pentanone itself.
Thus, an (-)-Ipc2BOTf-mediated aldol reaction10 with al-
dehyde 13, followed by silyl protection, gave 15 in 85% ee
and 56% yield. The remaining methyl-bearing stereocenter
was introduced by hydroboration of the trisubstituted alkene
in 15 using thexylborane.11 This occurred with greater than
95% facial selectivity and concomitant reduction of the
carbonyl group, giving the diols 16 (59%). Careful Swern
oxidation12,13 of 16, followed by deprotection of the TBS
ether, then completed the synthesis of 8 in 94% yield.
(5) (a) Hochlowski, J. E.; Coll, J. C.; Faulkner, D. J.; Biskupiak, J. E.;
Ireland, C. M.; Zheng, Q.-T.; He, C.-H.; Clardy, J. J. Am. Chem. Soc. 1984,
106, 6748. (b) A reexamination of S. baconi, as reported by Garson (ref
1b), failed to detect any baconipyrones, such that they may conceivably be
artifacts of the isolation process rather than biosynthetically related
metabolites to the siphonarins. This may also hold for other polypropionates
obtained from siphonariids, as with muamvatin (ref 6b) and the denticulatins
(ref 6c).
(6) (a) Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 801. (b)
Paterson, I.; Perkins, M. V. J. Am. Chem. Soc. 1993, 115, 1608. (c) Paterson,
I.; Perkins, M. V. Tetrahedron 1996, 52, 1811.
(7) Paterson, I.; Franklin, A. S. Tetrahedron Lett. 1994, 35, 6925.
(8) (a) Paterson, I.; Wallace, D. J.; Vela´zquez, S. M. Tetrahedron Lett.
1994, 35, 9083. (b) Paterson, I.; Wallace, D. J. Tetrahedron Lett. 1994, 35,
9087. (c) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639.
(9) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
(10) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663.
(11) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
1514
Org. Lett., Vol. 2, No. 11, 2000

Scheme 3
As shown in Scheme 3, the corresponding acid fragment
Completion of the synthesis of baconipyrone C required
a challenging esterification to be accomplished between
fragments 8 and 17 (Scheme 4). Initial attempts to form 24
employing the Steglich esterification protocol20 gave exclu-
sively the undesired N-acylurea derivative of 17. The Keck
modification21 of the Steglich method resulted in a 52% yield
of coupled products (entry a). However, this generated an
inseparable mixture of diastereomers, which appeared to be
in favor of the undesired C14-epimer 25. Similar results were
observed with the Yonemitsu variation22a of the Yamaguchi
esterification procedure (entry b).22b However, further in-
vestigations revealed that by modifying the Yonemitsu-
Yamaguchi protocol, the extent of epimerization could be
significantly reduced (entry c). By warming the reaction
mixture from -78 to 0 °C over a period of 10 min, followed
by rapid quenching with NaHCO3 solution, the desired ester
24 was obtained in 73% yield with less than 10% epimer-
ization detected. Finally, oxidative removal of the PMB ether
with DDQ in wet CH2Cl2 gave a 67% yield of baconipyrone
C (3) after chromatographic separation from a small amount
of diastereomer.
17 having a PMB ether at C11 was prepared by adaptation
and improvement of our earlier route.7 Cyclization of
triketone 11 (accessible in five steps from aldehyde 18)
employing the DMSO/(COCl)2 protocol of Yamamura and
co-workers14 gave γ-pyrone 19 in only moderate yield (54%).
However, the use of the alternative PPh3/CCl4 cyclization
conditions14 gave 19 in a much improved 88% yield.15
Debenzylation, followed by Dess-Martin oxidation16 of the
resulting alcohol 20, gave the sensitive chiral aldehyde 10,
which was reacted immediately with the preformed Sn(II)
Z-enolate of (R)-9.17 This gave a 74% yield of the desired
syn-syn aldol adduct 21, together with 6% of a mixture of
syn-anti and anti-anti isomers. A SmI2-promoted, Evans-
Tishchenko reduction18 with MeCHO then gave the acetate
22 as a single isomer. A three-step sequence of protecting
group manipulation then gave diol 23. Finally, careful Swern
oxidation12 of 23, followed by further oxidation with
NaClO2,19 led to the desired ketoacid 17 (96%).
(12) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(13) The double Swern oxidation was routinely performed by employing
oxalyl chloride (5 equiv), DMSO (10 equiv), and triethylamine (15 equiv).
After warming from -78 to -20 °C, the reaction mixture was quenched
with a mixture of anhydrous hexane/toluene (3:1), followed by filtration
through Celite, to obtain spectroscopically pure diketone. Other procedures
(Dess-Martin, TPAP) led to undesired cyclisations of mono-oxidized
products.
(14) (a) Yamamura, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1997, 70,
2025. (b) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1990, 31, 5491. (c) Arimoto, H.; Nishiyama, S.; Yamamura, S. Tetrahedron
Lett. 1990, 31, 5619.
The spectroscopic data (1H NMR, 13C NMR, IR, HRMS)
obtained for synthetic (-)-baconipyrone C were in agreement
with that recorded for natural material.4 The specific rotation
was measured as [R]20D ) -73.3 (c ) 0.77, MeOH), while
an authentic sample provided by Professor Faulkner had
[R]20 ) -82 (c 0.16, MeOH).4,23 The full absolute stereo-
D
chemistry of baconipyrones A-D (1-4) is therefore assigned
(15) This also avoided the presence of sulfur residues in the subsequent
hydrogenolysis of the benzyl group, which proved to be problematic due
to catalyst poisoning.
(16) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (c) Ireland, R.
E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(19) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(20) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(21) Keck, G. E.; Boden, E. P. J. Org. Chem. 1985, 50, 2394.
(22) (a) Hikotam, M.; Sakurai, Y.; Horita, K.; Yonemitsu, O. Tetrahedron
Lett. 1990, 31, 6367. (b) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(17) Paterson, I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233.
(18) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
Org. Lett., Vol. 2, No. 11, 2000
1515

Scheme 4
as represented in this paper, which is in agreement with that
Acknowledgment. We thank the EPSRC, the Cambridge
Commonwealth Trust, the Sim Foundation, King’s and
Corpus Christi Colleges, Ministerio de Educacio´n y Cultura
(Spain), the European Commission (Marie Curie Fellowship
to J.L.A.), and Merck, Sharp & Dohme for support. We also
thank Professor John Faulkner (Scripps Institution of Ocean-
ography) for his assistance in kindly providing an authentic
sample of baconipyrone C, along with copies of NMR
spectra, and Dr. Mary Garson (Queensland) for valuable
discussions.
established independently for the siphonarins.7,24
In conclusion, the first total synthesis of the unusual
siphonariid metabolite, (-)-baconipyrone C (3), has been
achieved in 17 steps with 13.9% overall yield from 18. The
efficient construction of the polypropionate skeleton using
the ketones (R)-9 and (R)-12 and appropriate aldol chemistry,
together with the special conditions required for esterification
to generate 24, are noteworthy.
(23) We repurified Professor Faulkner’s sample of natural baconipyrone
C and obtained a consistently higher specific rotation than that reported in
Supporting Information Available: Copies of NMR
spectra and experimental procedures for key compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
ref 4 ([R]20 ) -19.0 (c 0.90, MeOH)). It is possible that the original
D
measurement was adversely affected by an impurity or residual solvent.
Our measured [R]20D values for baconipyrone C are now also quite similar
to that recorded for the normethyl compound, baconipyrone D (4).
(24) Garson, M. J.; Jones, D. J.; Small, C. J.; Liang, J.; Clardy, J.
Tetrahedron Lett. 1994, 35, 6921.
OL000027N
1516
Org. Lett., Vol. 2, No. 11, 2000