Synthesis of the putative structure of tridachiahydropyrone

Article abstract of DOI:10.1021/ol050236d

(Chemical Equation Presented) A short total synthesis of the putative structure of the marine natural product tridachiahydropyrone as a single enantiomer is described. Novel steps include a cuprate addition and cyclization to form a cyclohexanone ring and

Full text of DOI:10.1021/ol050236d

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1581-1584
Synthesis of the Putative Structure of
Tridachiahydropyrone
David W. Jeffery,† Michael V. Perkins,*,† and Jonathan M. White‡
School of Chemistry, Physics and Earth Sciences, Flinders UniVersity,
G.P.O. Box 2100, Adelaide, S.A. 5001, Australia, and School of Chemistry,
The UniVersity of Melbourne, Melbourne, Vic. 3010, Australia
mike.perkins@flinders.edu.au
Received February 4, 2005
ABSTRACT
A short total synthesis of the putative structure of the marine natural product tridachiahydropyrone as a single enantiomer is described. Novel
steps include a cuprate addition and cyclization to form a cyclohexanone ring and formation of the bicyclic pyrone with P2O5 on Celite. The
spectroscopic data obtained for compound 1 do not match those reported for tridachiahydropyrone; therefore, revision of the assigned natural
product structure is warranted.
Tridachiahydropyrone was isolated in 1996 by Gavagnin et
al.1 from the sacoglossan mollusc, Tridachia crispata. The
structure was assigned as compound 1 (Figure 1) by
extensive NMR spectroscopic analysis, and the relative
stereochemistry was assigned by NOE experiments; however,
the absolute configuration was not determined. This com-
pound is structurally interesting, possessing an unusual fused
bicyclic pyrone. This ring system is accessible by our recently
reported2,3 methodology for the convergent total synthesis
of enantiopure tridachione marine natural products. We now
wish to describe the first, unambiguous total synthesis of
compound 1 with the reported structure of tridachiahydro-
pyrone, as a single enantiomer.
to be formed by cyclization of the enone oxygen onto the
acid moiety of ketoacid 3, followed by dehydration. Pyrone
2 could then be O-methylated to yield compound 1 (Scheme
1). Ketoacid 3 can be seen to come from the deprotection/
oxidation of cyclohexenone 4, which in turn arises from trans
methylation and elimination of cyclohexenol 5. Addition of
cuprate 6 to enone 7, using the tandem conjugate addition-
cyclization procedure we have previously described,2,3
produces enol 5.
We began with enone 7, obtained as previously described,3
and synthesized cuprate precursor 8 (Scheme 2) on the basis
The retrosynthesis of compound 1 is analogous to that
reported3 for a model system, where pyrone 2 is proposed
† Flinders University.
‡ The University of Melbourne.
(1) Gavagnin, M.; Mollo, E.; Cimino, G.; Ortea, J. Tetrahedron Lett.
1996, 37, 4259-4262.
(2) Jeffery, D. W.; Perkins, M. V. Tetrahedron Lett. 2004, 45, 8667-
8671.
Figure 1. Structure reported1 for tridachiahydropyrone.
(3) Jeffery, D. W.; Perkins, M. V.; White, J. M. Org. Lett. 2005, 7, 407-
409.
10.1021/ol050236d CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/16/2005

Scheme 1
Scheme 3
of literature precedent.4 The known5 R,â-unsaturated acid 9
was stereospecifically brominated (Br2, CH2Cl2, -78 °C)4
to afford crystalline dibromide 10 (74%, crude), and the crude
material was subjected to decarboxylative anti elimination
conditions (NaHCO3, DMF, 65 °C)6 to yield volatile (Z)-
vinyl bromide 11 (72%).
line 13 (89%, crude), followed by decarboxylative elimina-
tion, yielded volatile (E)-vinyl bromide 8 (73%).8 Purification
of the liquid products was performed by distillation under
reduced pressure. This somewhat circuitous route gave
isomerically pure vinyl bromide 8 in reasonable yield (27%,
six steps) and was amenable to scale-up.
With substantial quantities of cuprate precursor 8 in
hand, we explored the conditions necessary for successful
cuprate formation, subsequent 1,4 addition, and cyclization.
Initially, problems were associated with the thermal instabil-
ity of the derived organolithium solution. This obstacle was
overcome by the use of a precooled cannula as described
below. The use of various copper salts was also attempted,
but CuCN (Aldrich) proved to be the most reliable. The final
conditions we employed enabled the synthesis of 5 repro-
ducibly, in 50-65% yield, exclusively as the enol tautomer
(Scheme 3).
Scheme 2
Treatment of a colorless solution of vinyl bromide 8 in
THF with t-BuLi at -100 °C resulted in a bright yellow
solution, with the color being indicative of the lithium-
halogen exchange. This yellow organolithium solution was
transferred quickly via a precooled cannula (-78 °C) into a
CuCN/Et2O slurry at -78 °C, and the mixture was allowed
to warm to -50 °C. The formation of a colorless, homoge-
neous solution after several minutes at -50 °C was diag-
nostic of successful preparation of cuprate 6. Addition of
enone 7 in Et2O caused an immediate bright yellow colora-
tion, and the reaction was stirred at -50 °C for 1 h (to ensure
complete addition) and 0 °C for 1 h (to ensure complete
cyclization) before being quenched (90% NH4Cl/10%
Treatment of (Z)-bromide 11 with t-BuLi7 in Et2O at -78
°C (Scheme 2), followed by transferral of the organolithium
solution into solid CO2 and subsequent acidification, yielded
the corresponding (Z)-R,â-unsaturated acid 12 (94%). An
iteration of the above bromination procedure to give crystal-
(4) Kim, H.; Lee, S.-K.; Lee, D.; Cha, J. K. Synth. Commun. 1998, 28,
729-735.
(5) Villa, M.-J.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1994, 1569-
1572.
(6) Norris, W. P. J. Org. Chem. 1959, 24, 1579-1580.
(7) Care was needed with the amount of t-BuLi used; otherwise, the
crude product was contaminated with pivalic acid. To overcome this, the
t-BuLi was standardized prior to use by titration against N-pivaloyltoluidine
(Suffert, J. J. Org. Chem. 1989, 54, 509-510.).
(8) All new compounds gave spectroscopic data in agreement with the
assigned structures and copies of the NMR spectra, and spectral data for
all new compounds are available in Supporting Information.
1582
Org. Lett., Vol. 7, No. 8, 2005

1
Table 1. Comparison of H and 13C NMR for Tridachiahydro-
pyrone1 and Synthetic 1 (Significant Differences in Bold)
tridachiahydropyronea
synthetic 1b
Figure 2. X-ray crystal structure of alcohol 14.
carbon
no.
δ 1Hc
δ 13Cc
δ 1Hc
δ 13Cc
NH4OH), filtered through Celite, and purified by SiO2 flash
chromatography. The addition of the cuprate was highly
selective for syn addition product 5.
1
2
3
4
5
6
7
8
165.97
87.88
195.79
46.56
145.33
115.74
121.28
134.42
53.45
133.42
130.37
37.24
28.72
22.59
22.47
13.71
21.21
21.72
14.62
7.40
164.17
88.94
192.83
46.17
145.80
112.14
121.45
133.59
58.82
132.54
128.05
36.90
28.94
22.24
22.30
13.38
25.40
21.67
14.31
6.46
Subsequent trans (axial) methylation2,3 (Scheme 3) pro-
ceeded with concurrent â-elimination of the OTBS group to
afford cyclohexenone 4 (77%, stereochemistry confirmed by
NOE experiments) with high selectivity for the trans product
5.44
5.48
1
(>40:1 trans:cis, determined by H NMR). Apparently, the
9
3.91
2.91
extra steric bulk of the vinyl side-chain had a large directing
influence when compared to the simple methyl group in the
model (9:1 trans:cis).3 Cyclohexenone 4 was deprotected9 to
give crystalline alcohol 14 (93%, Scheme 3). Compound 14
gave small, weakly diffracting crystals, but a crystal structure
of sufficient quality to indicate the three-dimensional struc-
ture was obtained and showed the relative stereochemistry
of the molecule as depicted in Figure 2.
10
11
12
13
14
15
16
17
18
19
20
OMe
5.51
1.90
1.64
0.88
0.88
1.53
1.20
1.63
1.75
1.63
3.96
5.39
1.80
1.63
0.82
0.82
1.47
1.35
1.75
1.75
1.60
3.94
This crystal structure highlights several important factors.
The conjugate addition gave the Felkin-Anh-like product,10
with induction coming from the γ-methyl in enone 7. The
side chain alkene has an (E)-configuration, and NaH/MeI
methylation gave the product where the side chain and the
methyl group are trans. Alcohol 14 was acid sensitive and
cyclized readily in CDCl3 to undesired pyrone 15 (Scheme
3). Alcohol 14 could be further manipulated provided that
acidic conditions were avoided.
55.08
54.69
a Bruker AMX 500 MHz NMR spectrometer. b Varian Gemini 300 MHz
NMR spectrometer. Assignments assisted by 1H-1H COSY, 1H-13C
HMBC and HMQC (Inova 600 MHz NMR spectrometer). c Chemical shifts
in ppm referenced to CHCl3 (δ 7.26) for proton resonances and to CDCl3
(δ 77.0) for carbon resonances.
Dess-Martin oxidation11 of alcohol 14 to crystalline
aldehyde 16 (ca. 100%, crude, Scheme 4) proceeded with
no detectable epimerization of the aldehyde R-stereocenter,
as did NaClO2 oxidation,12 with modified product isolation,13
affording ketoacid 3 (88%). Treatment of acid 3 in CH2Cl2
with Eaton’s reagent (P2O5-MeSO3H),14 as previously
described,3 yielded a mixture of products, none of which
involved the desired cyclization. This was apparent from the
presence of the enone vinyl proton singlet at ca. 6.3 ppm
and the loss of the side-chain vinyl proton triplet at ca. 5.1
ppm in the 1H NMR spectrum of the crude product. Clearly,
the acidic conditions were not compatible with the presence
of the side-chain alkene.
Scheme 4
A modification involved supporting P2O5 on oven-dried
Celite,15 followed by the addition of acid 3 in CH2Cl2 and
stirring at room temperature (Scheme 4). This method
(9) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J.
Am. Chem. Soc. 2001, 123, 9535-9544.
(10) Chounan, Y.; Ono, Y.; Nishii, S.; Kitahara, H.; Ito, S.; Yamamoto,
Y. Tetrahedron 2000, 56, 2821-2831.
(11) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(12) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron Lett. 1980,
37, 2091-2096.
Org. Lett., Vol. 7, No. 8, 2005
1583

afforded pyrone 2 (56%), predominantly as the keto tautomer,
after filtration and purification. Treatment of pyrone 2 with
CH2N2 in Et2O gave a 1.3:1 mixture of readily separable
R-pyrone 17 (45%) and γ-pyrone 1 (36%). The structures
of 17 and 1 were confirmed by extensive NMR studies, and
strong NOEs were observed between H-9 and H-17 in both
17 and 1, confirming the trans relationship of the side chain
and methyl group.
crystalline, pyrone 1 failed to solidify and also decomposed
in CDCl3 (or CHCl3) over time, partly reverting to the parent
pyrone 2. We therefore conclude that the previously assigned
structure of tridachiahydropyrone is not correct and warrants
revision. It appears that tridachiahydropyrone is a diastere-
omer of compound 1.
In summary, we have applied our methodology for the
synthesis of tridachione marine natural products to the
formation of compound 1 with the reported structure of
tridachiahydropyrone as a single enantiomer. We utilized a
conjugate addition-cyclization approach, with the novel,
bicyclic pyrone formation being accomplished under P2O5-
mediated cyclization conditions. We are exploring alternative
possibilities in an attempt to determine the true structure of
tridachiahydropyrone.
The reported spectra of tridachiahydropyrone1 were com-
pared with those of synthetic 1. The 13C NMR spectra were
significantly different, with a large disparity in the chemical
shifts of C-9 and C-17. There was also a 1.0 ppm difference
1
between the chemical shift of H-9 in the H NMR spectra
of the synthetic material and the natural product (Table 1).
Visual comparison of copies of 1H and 13C NMR spectra of
the natural product16 and the synthetic material 1 confirmed
these differences.
While the EI mass spectra were virtually identical, the UV/
vis absorbances (in MeOH) were slightly different (1 λmax
262 nm, (ꢀ 9020); tridachiahydropyrone λmax 271 nm, (ꢀ
10 840)), as were the optical rotations (1 [R]D -542 (c 0.26,
CHCl3); tridachiahydropyrone [R]D -476 (c 0.49, CHCl3)).
Finally, while tridachiahydropyrone was reported to be
Acknowledgment. We wish to thank the Australian
Research Council for funding and Flinders University for
its support and facilities. We are also grateful to Dr. M.
Gavagnin for the copies of tridachiahydropyrone spectra and
for useful discussions.
Supporting Information Available: Copies of NMR
spectra for all new compounds (and tridachiahydropyrone),
data for all new compounds (including CIF for 14), and
experimental procedures for compounds 1-5 and 17. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Mulzer, J.; Mantoulidis, A.; Ohler, E. J. Org. Chem. 2000, 65,
7456-7467.
(14) Eaton, P. E.; Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 38,
4071-4073.
(15) Puglisi, C. J.; Elsey, G. M.; Prager, R. H.; Skouroumounis, G. K.;
Sefton, M. A. Tetrahedron Lett. 2001, 42, 6937-6939.
1
(16) Copies of the original H and 13C NMR spectra of tridachiahydro-
pyrone were obtained for comparison.
OL050236D
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Org. Lett., Vol. 7, No. 8, 2005