Total synthesis of ±-5,14-bis-epi-spirovibsanin A

Article abstract of DOI:10.1021/ol702827x

The total synthesis of ±-5,14-bis-epi-spirovibsanin A was achieved in 18 steps. Physical data obtained from ±-5,14-bis-epi-spirovibsanin A lends strong support to the proposed connectivity and relative stereochemistry of spirovibsanin A.

Full text of DOI:10.1021/ol702827x

ORGANIC
LETTERS
2
008
Vol. 10, No. 5
13-715
Total Synthesis of
)-5,14-bis-epi-Spirovibsanin A
7
(±
Michael J. Gallen and Craig M. Williams*
School of Molecular and Microbial Sciences, UniVersity of Queensland,
Brisbane 4072, Queensland, Australia
c.williams3@uq.edu.au
Received November 21, 2007
ABSTRACT
The total synthesis of (±)-5,14-bis-epi-spirovibsanin A was achieved in 18 steps. Physical data obtained from (±)-5,14-bis-epi-spirovibsanin A
lends strong support to the proposed connectivity and relative stereochemistry of spirovibsanin A.
1
Spirovibsanin A (1) (Figure 1), isolated by Fukuyama from
Viburnum awabuki, is an unusual member of the vibsane-
type diterpene family.1 A unique feature of this polyoxy-
genated compact molecule is the bicyclo[3.3.1]nonane spiro-
γ-lactone, to which we were attracted due to our familiarity
with this system (i.e., 2).5
diastereomer. Regioselective conversion of 7 into hydroxy-
ketone 8, via DMDO oxidation of the silyl enol ether,
-4
2
Later work by Fukuyama divulged the related natural
products 15-O-methylneovibsanin F (3) and 14-epi-15-O-
6
methylneovibsanin F (4), which surprisingly differ only in
configuration at position 14. From our perspective this fact
casts doubt over the stereochemical assignment at position
1
4 of 1, and considering bicyclo[3.3.1]nonanes of type 2
(albeit epimeric at positon 6) were in hand, we embarked
on a total synthesis campaign in the racemic series.
Key to this endeavor was intermediate 10, which was
succinctly accessed via a novel keto transposition/carbonyl-
7
-9
ation sequence. Treating rac-enone 6, obtained from 5,
with HCl in methanol gave bicyclic ketone 7 as the sole
(
1) Kubo, M.; Fujii, T.; Hioki, H.; Tanaka, M.; Kawazu, K.; Fukuyama,
Y. Tetrahedron Lett. 2001, 42, 1081.
2) Fukuyama, Y.; Kubo, M.; Minami, H.; Yuasa, H.; Matsuo, A.; Fujii,
T.; Morisaki, M.; Harada, K. Chem. Pharm. Bull. 2005, 53, 72.
3) Fukuyama, Y.; Minami, H.; Matsuo, A.; Kitamura, K.; Akizuki, M.;
Kubo, M.; Kodama, M. Chem. Pharm. Bull. 2002, 50, 368.
4) Fukuyama, Y.; Kubo, M.; Fujii, T.; Matsuo, A.; Minoshima, Y.;
Minami, H.; Morisaki, M. Tetrahedron 2002, 58, 10033.
5) Gallen, M. J.; Goumont, R.; Clark, T.; Terrier, F.; Williams, C. M.
Angew. Chem. Int. Ed. 2006, 45, 2929.
6) Synthetic studies towards 15-O-methylneovibsanin F (3) and 14-epi-
5-O-methylneovibsanin F (4) will be reported in due course.
7) Heim, R.; Wiedemann, S.; Williams, C. M.; Bernhardt, P. V. Org.
Lett. 2005, 7, 1327.
(
(
(
(
(
1
(
Figure 1. Spirovibsanin A (1) and related family members.
1
0.1021/ol702827x CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/02/2008

proceeded smoothly. Moffatt-Swern oxidation gave the keto
transposed diosphenol 9. Palladium-catalyzed carbonylation
of the corresponding triflate then gave rise to ester 10 in
14% overall yield from 5 (eight steps) (Scheme 1).
Scheme 1. Preparation of Intermediate 10.
Figure 2. X-ray crystal structure of lactone 14 at the 30% ellipsoid
probability.
specificity is most likely a result of large steric shielding of
the R face by the dimethylmethoxy substituent at position
6. Dihydroxylation of 12 afforded diol 13, which underwent
intramolecular transesterification on treatment with base
giving lactone 14 in 80% yield over two steps (Scheme 2).
The X-ray crystal structure of 14 elaborated the connectivity
of the newly formed spirolactone and confirmed the undes-
ired diastereomer of 12 (see Figure 2).
Lactone 14 was converted into the corresponding mesylate
15, which was subsequently deprotected with trimethylsilyl
Conjugate addition of commercial (1,3-dioxolan-2-yl-
methyl)magnesium bromide to ester 10 occurred stereose-
lectively affording enol 11 in 70% yield. O-Allylation of 11
followed by a Claisen rearrangement afforded only the
undesired (â) C-allylated diastereomer. This unavoidable
Scheme 3. Preparation of Advanced Intermediate 17.
Scheme 2. Preparation of Intermediate 14.
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Org. Lett., Vol. 10, No. 5, 2008

enlactones 19 and 20. All attempts to directly eliminate the
mesylate function (i.e., 17 and 18) failed. The final step
required an exo- to endo-cyclic double bond isomerization.
An acid-catalyzed (i.e., TsOH) process has been reported
Scheme 4. Total Synthesis of (()-5,14-bis-epi-spirovibsanin
A 22
1
4
by J a¨ ger for this type of transformation as have the use of
15
palladium (0) catalysts. To our satisfaction, however, slight
modification of the J a¨ ger protocol (i.e., PPTS rather than
TsOH) unveiled the desired material as a mixture of isomers
[i.e., 21 (Z)/22 (E)], separable by HPLC (Scheme 4).
In conclusion, considering the stereochemical incertitude
over spirovibsanin A (1), a total synthesis campaign arriving
at (()-5,14-bis-epi-spirovibsanin A (22) was warranted.
1
13
Comparison of H NMR and C NMR data of both 1 and
22 gives strong support to Fukuyama’s proposed connectivity
and relative stereochemistry. This work identifies an efficient
route to vibsane type family members containing R stereo-
chemistry at position 14, for example, 15-O-methylneovib-
6
sanin F (3).
Acknowledgment. We thank the University of Queen-
sland and the Australian Research Council (DP0666855) for
financial support. NMR data of spirovibsanin A (1) provided
by Prof. Y. Fukuyama (Faculty of Pharmaceutical Sciences,
Tokushima Bunri University), NMR collection of 21 and 22
by Dr. L. Lambert (Centre for Magnetic Resonance, Uni-
versity of Queensland) and experimental data provided by
Prof. V. J a¨ ger (Institute for Organic Chemistry, University
of Stuttgart) are gratefully acknowledged. HPLC and X-ray
crystal structure analysis provided by J. Johns (Queensland
Institute of Medical Research) and Prof. P.V. Bernhardt
(School of Molecular and Microbial Sciences, University of
Queensland) respectively, is also gratefully acknowledged.
trifluoromethanesulfonate10 affording aldehyde 16 in 50%
yield over two steps. Modifying the procedure of Davies,
1
1
the crotonate side chain was installed as a mixture of E- and
Z-isomers in a ratio of 7:3 (55%) (Scheme 3).
Based in part on the work of J a¨ ger, a one-pot microwave -
Supporting Information Available: Experimental pro-
cedures, selected characterization data and copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
12
13
mediated Finkelstein/elimination reaction gave the exo-cyclic
(
8) Tilly, D. P.; Williams, C. M.; Bernhardt, P. V. Org. Lett. 2005, 7,
155.
9) Schwartz, B. D.; Tilly, D. P.; Heim, R.; Wiedemann, S.; Williams,
C. M.; Bernhardt, P. V. Eur. J. Org. Chem. 2006, 3181.
10) Fujioka, H.; Okitsu, T.; Sawama, Y.; Murata, N.; Li, R.; Kita, Y. J.
Am. Chem. Soc. 2006, 128, 5930.
OL702827X
5
(
(13) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(14) Guntrum, E.; Kuhn, W.; Sp o¨ nlein, W.; J a¨ ger, V.; G u¨ ther, H. J.
Synthesis 1986, 921.
(
(
(
11) Davies, H. M. L.; Loe, Ø.; Stafford, D. G. Org. Lett. 2005, 7, 5561.
12) J a¨ ger, V.; G u¨ ther, H. J. Tetrahedron Lett. 1977, 18, 2543.
(15) Rudler, H.; Harris, P.; Parlier, A.; Cantagrel, F.; Denise, B.;
Bellassoued, M.; Vaissermann, J. J. Organometallic Chem. 2001, 624, 186.
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