Synthesis of the proposed structures of Prevezol C

Article abstract of DOI:10.1021/ol400754e

The first enantioselective synthesis of the proposed relative structures of Prevezol C is reported in 11 linear steps from readily available materials. The unusual syn bromohydrin was installed via a multistep sequence culminating in a diastereoselective

Full text of DOI:10.1021/ol400754e

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis of the Proposed Structures
of Prevezol C
Anna E. Leung, Michael Blair, Craig M. Forsyth, and Kellie L. Tuck*
School of Chemistry, Monash University, Clayton, Vic. 3800, Australia
Kellie.Tuck@monash.edu
Received March 20, 2013
ABSTRACT
The first enantioselective synthesis of the proposed relative structures of Prevezol C is reported in 11 linear steps from readily available materials.
The unusual syn bromohydrin was installed via a multistep sequence culminating in a diastereoselective geminal dibromide reduction.
Discrepancies in the spectral data of the synthetic materials and the natural sample have led to the conclusion that the proposed structures are
incorrect.
Almost a decade ago, the family of novel diterpenes
known as the prevezols was isolated from the organic
extracts of the red alga Laurencia obtusa, found on the
coastal rocks of Preveza in the Ionean Sea, Greece.1,2 Five
prevezols were discovered (Prevezols AÀE),1,2 and their
structures were elucidated using spectral data analysis and
molecular modeling studies.1,2 The carbon skeletons of
these natural products were unprecedented in the litera-
ture. All of the prevezols feature an unusual syn bromo-
hydrin motif, which piqued our interest and prompted us
to select Prevezol C as a synthetic target. Roussis and co-
workers were unable to assign the relative stereochemistry
of Prevezol C due to a lack of observed NOE correlations
between the two rings (rings A and B);2 consequently, two
diastereomers and their enantiomers were proposed for the
natural product (compounds 1 and 2, Figure 1).2
misassignment of natural products have been published in
recent years.3À5 For several years, our group has been
exploring the total synthesis of Prevezol C in the hope of
unambiguously determining the absolute structure of the
natural product. To the best of our knowledge none of the
prevezols have been synthesized.
Despite the advances in spectroscopic strategies for the
structural elucidation of natural products, total synthesis
is often required in order to unambiguously determine
the absolute structures. Several excellent reviews of the
Figure 1. Proposed structures of Prevezol C (1 and 2).
Herein, we report the first total asymmetric synthesis of
both of the proposed diastereomers of Prevezol C
(compounds 1 and 2). This convergent synthesis utilizes a
novel strategy for incorporation of the challenging syn
bromohydrin motif, which may be exploited to facilitate
the synthesis of other compounds which possess syn
orientated bromohydrins.
(1) Mihopoulos, N.; Vagias, C.; Mikros, E.; Scoullos, M.; Roussis, V.
Tetrahedron Lett. 2001, 42, 3749–3752.
(2) Iliopoulou, D.; Mihopoulos, N.; Vagias, C.; Papazafiri, P.;
Roussis, V. J. Org. Chem. 2003, 68, 7667–7674.
(3) Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44,
1012–1044.
(4) Maier, M. E. Nat. Prod. Rep. 2009, 26, 1105–1124.
(5) Amagata, T. 2.18 - Misassigned Structures: Case Examples from
the Past Decade. In Comprehensive Natural Products II; (Eds.-in-Chief)
Lew, M., Hung-Wen, L., Eds.; Elsevier: Oxford, 2010; pp 581À621.
Previous work within our group has culminated in the
enantioselective synthesis of 2-epi-Prevezol C 3, an anti
bromohydrin (Scheme 1).6 Comparison of the 13C NMR
r
10.1021/ol400754e
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spectra of 2-epi-Prevezol C and the natural product
showed excellent correlation between the B rings. Unfor-
tunately all attempts to form the syn bromohydrin from
the triol 7 were unsuccessful.6
tolerant of the reaction sequence and easily removed.9
Protection of hydroxyl ketone 12 with dimethylisopropyl-
silyl trifluoromethanesulfonate and 2,6-lutidine in DCM
at À78 °C provided the required DMIPS ketone 11
(Scheme 3). Formation of the required gem-dibromide
was inspired by the work of Takeda and co-workers on
the synthesis of gem-dihalides from ketones or aldehydes,
via the corresponding hydrazones, using LiOtBu/CuBr2.10
Takeda’s two-step procedure was modified to provide the
gem-dibromide 10:10 DMIPS ether 11 was treated with
para-toluenesulfonylhydrazide in methanol to afford the
corresponding tosyl hydrazone 13,fromwhichgem-dibromide
10 was readily accessed (Scheme 3).
Scheme 1. Diastereoselective Alkyation in the Synthesis
of 2-epi-Prevezol C 3, and the Triol 76
Scheme 2. Retrosynthesis of Prevezol C 1
We envisioned that the natural product 1 could be
accessed via a stereoselective reduction of the diterpene
8, which might be obtained via a substrate-controlled,
diastereoselective alkylation reaction between ketone 4
and allylic iodide 9 (Scheme 2), using similar conditions
to those established for 2-epi-Prevezol C 3.6 We then
turned our attention to establishing methodology for the
synthesis of syn bromohydrins with quaternary oxygen-
ated centers.7 It was anticipated that the crucial syn
bromohydrin motif could be installed prior to the alkyla-
tion reaction, via a diastereoselective hydrodebromination
of the geminal dibromide 10 which might be accessed from
ketone 11 (Scheme 2).
The hydroxyl ketone 12 was synthesized in two steps
from (À)-limonene oxide, following published procedures
for the corresponding enantiomer.8 After several protect-
ing groups for the tertiary alcohol were investigated, the
dimethylisopropylsilyl ether was selected since it was both
Scheme 3. Synthesis of gem-Dibromide 10
(6) Blair, M.; Forsyth, C. M.; Tuck, K. L. Tetrahedron Lett. 2010, 51,
4808–4811.
(7) Secondary syn bromohydrins have been synthesized by Stoltz and
co-workers and Dubois and co-workers; see: (a) White, D. E.; Stewart,
I. C.; Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2007, 130, 810–811.
ꢀ
ꢀ
(b) Deka, V.; Dubois, J.; Thoret, S.; Gueritte, F.; Guenard, D. Org. Lett.
2003, 5, 5031–5034. In both cases a mixture of the syn and anti
bromohydrins were obtained by the reduction of a bromoketone pre-
cursor. Tertiary bromohydrins have been synthesized by Williams and
co-workers in the synthesis of alkaloid intermediates; see: (c) Williams,
C. M.; Mander, L. N.; Bernhardt, P. V.; Willis, A. C. Tetrahedron 2005,
61, 3759–3769. The addition of a deprotonated arylacetylene to a
brominated ketone gave the desired syn diastereomer as the major
product.
(8) (a) Blair, M.; Tuck, K. L. Tetrahedron: Asymmetry 2009, 20,
2149–2153. (b) Royals, E. E.; Leffingwell, J. C. J. Org. Chem. 1966, 31,
1937–1944. (c) Blair, M.; Andrews, P. C.; Fraser, B. H.; Forsyth, C. M.;
Junk, P. C.; Massi, M.; Tuck, K. L. Synthesis 2007, 10, 1523–1527.
(9) Attempts to perform the subsequent synthetic steps without first
protecting the tertiary alcohol were unsuccessful. Several alternative
protecting groups were investigated: they were either too labile under the
reaction conditions used or unable to be removed when required.
The dehalogenation of gem-dihalocyclopropanes has
been well documented in the literature,11 and various
reagents have been reported for this purpose. However,
(10) Takeda, T.; Sasaki, R.; Yamauchi, S.; Fujiwara, T. Tetrahedron
1997, 53, 557–566.
(11) For a general review on the use of gem-dihalocyclopropanes in
ꢀ
organic synthesis, see: Fedorynski, M. Chem. Rev. 2003, 103, 1099–1132.
B
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using published procedures, a mixture of stereoisomers is
obtained. Furthermore, to the best of our knowledge there
are no reports of chemistry of this kind concerning larger
cyclic systems. A diethyl phosphiteÀtriethylamine system
has been reported by Ohshiro and co-workers to result
only in partial dehalogenation of gem-dibromocyclopro-
panes, providing the monobromocyclopropane selectively.12
We applied these conditions to a TBS protected analogue
of the gem-dibromide 10, but no reaction was observed.9
Oshima and co-workers report the monodehalogenation
of gem-dibromocyclopropanes with a tributyltin hydride/
triethyl borane system,13 but the toxicity of tributyltin
hydride prompted us to investigate the use of tris-
(trimethylsilyl)silane, (TMS)3SiH, as an alternative redu-
cing agent. While the reduction of monobromides using
(TMS)3SiH is well documented by Chatgilialoglu and co-
workers,14 use of this reagent for the diastereoselective
monoreduction of gem-bromides has not been reported.
We rationalized that a system such as this, applied to the
monodehalogenation of gem-dibromide 10, might afford
the desired diastereoselectivity as follows: the carbon-
centered radical formed by abstraction of bromide by the
silyl radical equilibrates faster than hydride is delivered,
and the less hindered approach of the bulky (TMS)3SiH is
anti to the bulky DMIPS ether to provide the syn isomer
selectively (Scheme 4). Pleasingly, reduction of the gem-
dibromide 10 with 1.05 equiv of (TMS)3SiH in refluxing
benzene, with AIBN as a radical initiator, afforded a single
diastereomer exclusively (Scheme 4).15 The configuration
of the brominated center was assigned via analysis of the
(which was inseparable from any unreacted ketone 4) in
modest yields, but as a single diastereomer. The newly
formed asymmetric center was assigned via analysis of the
R-methine resonance in the 1H NMR spectrum, the cou-
pling constants of which were consistent with an axially
positioned proton. The observed diastereoselectivity was
justified by proposed 1,3-diaxial interactions between the
sterically demanding TBS ether and the incoming electro-
phile. Attempts to promote the complete consumption of
the TBS ketone 4, using an excess of allylic iodide 9 and/or
KHMDS, gave rise to complicated mixtures of products,
and so the diterpene 16 was typically isolated with the
ketone 4 impurity. Fortunately, after global deprotection
of the silyl ethers with an excess of TBAF, the diterpene
diol 8 was easily separated from any impurities (Scheme 5).
The diterpene diol 8 was then treated with sodium bor-
ohydride in a THF/methanol mixture to provide the
2S,3R,6S,9S,10R,13S,14S diastereomer17 1 of the pro-
posed structure of Prevezol C exclusively. The stereochem-
istry of the newly formed asymmetric center was assigned
as S, based on analysis of the coupling constants of the
hydroxymethine resonance, and was later confirmed by
X-ray crystallography (Scheme 5). The observed diaster-
eoselectivity was postulated to arise from coordination of
sodium borohydride tothe R-hydroxyl group, encouraging
hydride delivery syn to this moiety.
Scheme 4. Diastereoselective Monodehalogenation of
gem-Dibromide 10 to syn Bromohydrin 14
1
bromomethine proton resonance in the H NMR spec-
trum, which appears asa doublet of doublets withcoupling
constants of 12.4 and 4.0 Hz, indicative of axialÀaxial and
axialÀequatorial coupling (see Supporting Information
(SI)). The stereochemistry was later confirmed by X-ray
crystallography (Scheme 5).
In preparation for the key alkylation reaction, the syn
bromohydrin 14 was subjected to an allylic chlorination
reaction employing modified Massanet conditions;16
a
subsequent Finkelstein reaction using sodium iodide in
dry acetone provided the required allylic iodide 9, which
was typically used directly in the subsequent alkylation
reaction due to its instability (Scheme 5). TBS ketone 4 (see
SI) was treated with freshly prepared KHMDS and then
allylic iodide 9 to afford the requisite diterpene core 16
1
The H and 13C NMR spectra of diterpene 1 were
markedly different from the data for the natural product
(see SI). We thus concluded that the natural product must
have an alternative structure and turned our attention to
the synthesis of the other proposed diastereomer, Prevezol
C 2. Employing the previously established alkylation con-
ditions, and the enantiomer of ketone 4, ketone 17 (see SI),
the requisite diterpene core 18 was prepared diastereose-
lectively, though this material was inseparable from any
unreacted ketone 17 (Scheme 6). Global deprotection of
the silyl ethers using TBAF, followed by diastereoselective
(12) Hirao, T.; Masunaga, T.; Ohshiro, Y.; Agawa, T. J. Org. Chem.
1981, 46, 3745–3747.
(13) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 143–147.
(14) (a) Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.; Giese,
B.; Kopping, B. J. Org. Chem. 1991, 56, 678–683. (b) Chatgilialoglu, C.
ꢀ
Chem.;Eur. J. 2008, 14, 2310–2320. (c) Chatgilialoglu, C.; Lalevee, J.
Molecules 2012, 17, 527–555. (d) Chatgilialoglu, C.; Ferreri, C.; Gimisis,
T. Tris(trimethylsilyl)silane in Organic Synthesis. In The Chemistry
of Organic Silicon Compounds; John Wiley & Sons, Ltd: 2003; pp
1539À1579.
1
(15) This reaction must be carefully followed by H NMR spectro-
scopy: if excess (TMS)3SiH is used, the over-reduced species is obtained.
The anti bromohydrin was not observed in the 1H NMR spectra of the
crude or purified product.
(16) Moreno-Dorado, F. J.; Guerra, F. M.; Manzano, F. L.; Aladro,
F. J.; Jorge, Z. D.; Massanet, G. M. Tetrahedron Lett. 2003, 44, 6691–
6693.
(17) Numbered in accordance with Roussis and co-workers; see:
Iliopoulou, D.; Mihopoulos, N.; Vagias, C.; Papazafiri, P.; Roussis,
V. J. Org. Chem. 2003, 68, 7667–7674.
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C

Scheme 5. Diastereoselective Alkylation and Subsequent
Transformations To Form Prevezol C 1
Scheme 6. Diastereoselective Alkylation and Subsequent
Transformations To Form Prevezol C 2
stereoselective manner. A novel synthetic strategy was
employed to install the challenging syn bromohydrin
functionality. Continuous efforts toward structural deter-
mination of Prevezol C are underway and will be reported
in due course.
reduction of the ketone using sodium borohydride, pro-
vided the 2S,3R,6S,9R,10S,13R,14R diastereomer17 2 of
the proposed structure of Prevezol C (Scheme 6). The
absolute structure of 2 was confirmed by X-ray crystal-
Acknowledgment. The authors acknowledge the sup-
port of the School of Chemistry, Monash University and
Monash University. A.E.L. gratefully acknowledges re-
ceipt of a Faculty of Science Dean’s Postgraduate Re-
search Scholarship.
1
lography (Scheme 6). The H and 13C NMR spectra of
diterpene 2 were also markedly different from the data for
the natural product (see SI). Having confirmed the abso-
lute structures of 1 and 2 via X-ray crystallography, these
NMR deviations call into question the validity of the
structural assignment of Prevezol C.
Supporting Information Available. Experimental pro-
cedures and NMR and X-ray crystallography data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have accomplished the first total
synthesis of the proposed structures of Prevezol C, in a
The authors declare no competing financial interest.
D
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