Total synthesis of (±)-2-O-methylneovibsanin H

Article abstract of DOI:10.1021/ol801117e

(Chemical Equation Presented) The total synthesis of (±)-2-O- methylneovibsanin H was achieved in 12 steps. An acid-catalyzed, one-pot, four-step cascade reaction was key to the concise total synthesis, lending support to the proposed biosynthesis.

Full text of DOI:10.1021/ol801117e

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3441-3443
Total Synthesis of
(()-2-O-Methylneovibsanin H
Annette P.-J. Chen and Craig M. Williams*
School of Molecular and Microbial Sciences, UniVersity of Queensland,
Brisbane, 4072, Queensland, Australia
c.williams3@uq.edu.au
Received May 15, 2008
ABSTRACT
The total synthesis of (()-2-O-methylneovibsanin H was achieved in 12 steps. An acid-catalyzed, one-pot, four-step cascade reaction was key
to the concise total synthesis, lending support to the proposed biosynthesis.
Viburnum awabuki has yielded a plethora of rare and unusual
vibsane-type diterpenes as reported by Fukuyama1 and
Scheme 1. Neovibsanin H (1), Neovibsanin I (2),
others.2 Neovibsanin H (1),3 neovibsanin I (2),3 2-O-
methylneovibsanin H (3),4 and 2-O-methylneovibsanin I (4)4
(Scheme 1) constitute part of the highly functionalized six-
membered ring group of this intriguing family of natural
products. Fukuyama has proposed an acid-catalyzed biosyn-
thetic pathway for the formation of neovibsanins 1-4 starting
from vibsanin B (5), via plausable intermediates 6 and 7
(Scheme 1).4 With this consideration, 6 (or masked equiva-
lent), seems a suitable target to probe the biosynthetic
postulate and total synthesis of 1-4. In fact, Fukuyama has
made synthetic attempts in the neovibsanin area,5 targeting
molecules of type 6 as an advanced intermediate. However,
2-O-Methylneovibsanin H (3), and 2-O-Methylneovibsanin I (4)
Proposed Biosynthetic Pathway
(1) Fukuyama, Y.; Esumi, T. J. Org. Synth. Chem. (Jpn.) 2007, 65, 585.
(2) (a) Shen, Y.-C.; Prakash, C. V. S.; Wang, L.-T.; Chien, C.-T.; Hung,
M.-C. J. Nat. Prod. 2002, 65, 1052. (b) Shen, Y.-C.; Lin, C.-L.; Chien,
S.-C.; Khalil, A. T.; Ko, C.-L.; Wang, C.-H. J. Nat. Prod. 2004, 67, 74. (c)
Duh, C.-Y.; El-Gamal, A. A. H.; Wang, S.-K. Tetrahedron Lett. 2003, 44,
9321. (d) El-Gamal, A. A. H.; Wang, S. K.; Duh, C.-Y. J. Nat. Prod. 2004,
67, 333.
(3) Fukuyama, Y.; Minami, H.; Yamamoto, I.; Kodama, M.; Kawazu,
K. Chem. Pharm. Bull. 1998, 46, 545.
(4) Fukuyama, Y.; Kubo, M.; Minami, H.; Yuasa, H.; Matsuo, A.; Fujii,
T.; Morisaki, M.; Harada, K. Chem. Pharm. Bull. 2005, 53, 72.
(5) Esumi, T.; Zhao, M.; Kawakami, T.; Fukumoto, M.; Toyota, M.;
Fukuyama, Y. Tetrahedron Lett. 2008, 49, 2692.
no total syntheses of 1-4 or related family members have
been reported. Therefore, considering the attraction we have
10.1021/ol801117e CCC: $40.75
Published on Web 07/12/2008
2008 American Chemical Society

to this family of natural products,6–11 we extended our study
in this area, the results of which are now disclosed herein.
TBS protection of alcohol 86–8,12 followed by alkylation
with ethyl iodoacetate afforded, with poor stereocontrol, 9
and 10 in 37% and 24% yield, respectively. Attempts to react
9 with a range of metalated acetylides (including cerium),
to install a masked enone function, all failed to undergo 1,2-
addition, affording only recovered starting material 9 or
epimerized starting material 10. To circumvent the prob-
lematic two-carbon unit incorporation, reversion to a one-
carbon unit was investigated, and in this vein, only lithium
dithiazide13 was found to add successfully to give 12, albeit
in moderate yield. Mercury-mediated deprotection revealed
the aldehyde function, which was easily converted into the
desired enone function, affording the key intermediate 13
in 66% yield over two steps (Scheme 2).
Scheme 3
.
Preparation of Advanced Intermediate 17 via a
Four-Step, Acid-Induced Cascade
Scheme 2. Preparation of Intermediate 13
stepwise or concomitant solvolysis (i.e., allyl cation) and
nucleophilic attack by the solvent, and (4) Fischer esterifi-
cation. In addition to the succinct cascade is the remarkable
stereocontrol obtained at positions 2 and 5, most likely
inherent in the preexisting well-defined stereochemical
congestion in the starting material (i.e., 13).
Global reduction of 17 with lithium aluminum hydride was
easily accomplished. However, gobal oxidation to access 19
After some initial investigation of reaction conditions, it
was discovered that treatment of 13 with a gross excess of
concentrated sulfuric acid in anhydrous methanol afforded
methyl ester 17 and the corresponding position 2 epimer 18
(85:15, respectively)14 in 50% yield (Scheme 3).
Scheme 4
.
Final Sequence Leading to the Total Synthesis of
2-O-Methylneovibsanin H (3)
To arrive at methyl ester 17 in one synthetic manipulation
required 13 to negotiate four cascading steps: (1) TBS
deprotection giving primary alcohol 14, (2) Michael addition
of the primary alcohol function to the enone (i.e., 15), (3)
(6) Heim, R.; Wiedemann, S.; Williams, C. M.; Bernhardt, P. V. Org.
Lett. 2005, 7, 1327
.
(7) Tilly, D. P.; Williams, C. M.; Bernhardt, P. V. Org. Lett. 2005, 7,
5155
.
(8) Schwartz, B. D.; Tilly, D. P.; Heim, R.; Wiedemann, S.; Williams,
C. M.; Bernhardt, P. V. Eur. J. Org. Chem. 2006, 3181
(9) Gallen, M. J.; Goumont, R.; Clark, T.; Terrier, F.; Williams, C. M.
Angew. Chem., Int. Ed 2006, 45, 2929
(10) Gallen, M. J.; Williams, C. M. Org. Lett. 2008, 10, 713
(11) Schwartz, B. D.; Williams, C. M.; Anders, E.; Bernhardt, P. V.
Tetrahedron 2008, 64, 6482
(12) Porzelle, A.; Williams, C. M.; Schwartz, B. D.; Gentle, I. R. Synlett
.
.
.
.
2005, 2923
.
(13) Bauermeister, H.; Riechers, H.; Schomburg, D.; Washausen, P.;
Winterfeldt, E. Angew. Chem., Int. Ed. 1991, 30, 191.
(14) Compound 18 is tentatively assigned.
3442
Org. Lett., Vol. 10, No. 16, 2008

required some effort, and Dess-Martin periodinane per-
formed best. The remaining task to complete the synthesis
was installation of the 3,3-dimethylacroyl enol ester side
chain. In this instance the Davies15 protocol, which has been
slightly improved using microwave radiation,10 was utilized.
The one-pot side chain installation protocol we developed11
is not applicable in this case. The microwave reaction,
however, was found to be much more sluggish than previ-
ously observed with other substrates.10 Optimized conditions
required 15 h at 110 °C to obtain the target 3 and the cis-
isomer 20 [10% over three steps, E/Z ratio 3:2] (Scheme 4).
In conclusion, the total synthesis of (()-2-O-methyl-
neovibsanin H (3) is a further demonstration of the pivotal
role that cascade reactions, often based on biomimetic
rationale,16 play in the rapid construction of natural prod-
ucts.17 Furthermore, this body of work lends support to
Fukuyama’s proposed biosynthesis, opening the opportunity
to target closely related family members.
Acknowledgment. We thank the University of Queensland
and the Australian Research Council (DP0666855) for
financial support. NMR data of (()-2-O-methylneovibsanin
H (3) provided by Prof. Y. Fukuyama (Faculty of Pharma-
ceutical Sciences, Tokushima Bunri University) and NMR
collection of synthetic (()-2-O-Methylneovibsanin H (3) by
L. Lambert (Centre for Magnetic Resonance, University of
Queensland) are gratefully acknowledged. HPLC purification
provided by J. Johns (Queensland Institute of Medical
Research) is also gratefully acknowledged.
Supporting Information Available: Experimental details,
characterization data, and copies of 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Davies, H. M. L.; Loe, Ø.; Stafford, D. G. Org. Lett. 2005, 7,
5561. (b) Nikolai, J.; Loe, Ø.; Dominiak, P. M.; Gerlitz, O. O.; Autschbach,
J.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10763.
(16) Gravel, E.; Poupon, E. Eur. J. Org. Chem. 2008, 27.
(17) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134.
OL801117E
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