Asymmetric synthesis of umuravumbolide1

Article abstract of DOI:10.1021/ol006583z

(equation presented) This first asymmetric synthesis of enantiopure desacetylumuravumbolide and umuravumbolide via asymmetric reduction, allylboration, and ring-closing metathesis confirms their revised structures and configurations. A convenient procedure to upgrade the enantiopurity of α,β-acetylenic alcohols is also described.

Full text of DOI:10.1021/ol006583z

ORGANIC
LETTERS
2001
Vol. 3, No. 1
19-20
Asymmetric Synthesis of
Umuravumbolide1
M. Venkat Ram Reddy, John P. Rearick, Nyssa Hoch, and
P. Veeraraghavan Ramachandran*
Herbert C. Brown Center for Borane Research, Department of Chemistry,
Purdue UniVersity, West Lafayette, Indiana 47907-1393
chandran@purdue.edu
Received September 12, 2000
ABSTRACT
This first asymmetric synthesis of enantiopure desacetylumuravumbolide and umuravumbolide via asymmetric reduction, allylboration, and
ring-closing metathesis confirms their revised structures and configurations. A convenient procedure to upgrade the enantiopurity of r,â-
acetylenic alcohols is also described.
Several natural products containing 6-substituted 5,6-dihydro-
R-pyrones isolated from various plant species have been
established to be bioactive.2 They offer a wide range of
applications, such as plant growth inhibitors, pheromones,
and antifeedal, antifungal, antibacterial, and antitumor agents.2
Desacetylumuravumbolide (1a) and umuravumbolide (1b),3
isolated from Tetradenia riparia Lamiaceae from central and
southern Africa also belong to the above class of natural
products. Although they have not been examined for their
biological activity so far, several compounds from Lamiaceae
family have been shown to be an emetic to treat loss of
appetite.4 Unfortunately, the exact structure and configuration
of 1a and 1b were not known until recently.
an E-double bond on the side chain of the pyranone moiety
and also reported that they are optically inactive.3 Achenbach
and Witzke reported the synthesis of the racemic compounds
containing the E-double bond.5
Recently, Davies-Coleman and Rivett reinvestigated and
revised the structures of desacetylumuravumbolide and
umuravumbolide as 1a and 1b, respectively.6 They deter-
mined the absolute configurations on the basis of NMR and
CD studies and also reported the optical rotations of these
compounds.6 However, there has been no chemical synthesis
of these molecules to confirm their structure and/or stereo-
On the basis of infrared studies, Van Puyvelde and co-
workers erroneously reported that these compounds contain
(1) Contribution 8 from the Herbert C. Brown Center for Borane
Research.
(2) Davies-Coleman, M. T.; Rivett, D. E. A. Fortschr. Chem. Org.
Naturst. 1989, 55, 1.
(3) Van Puyvelde, L.; Dube, S.; Uwimana, E.; Uwera, C.; Dommisse,
R. A.; Esmans, E. L.; Van Schoor, O.; Vlietinck, A. J. Phytochemistry 1979,
18, 1215.
(4) Watt, J. M.; Brandwijk, M. G. The Medicinal and Poisnous Plants
of Southern and Eastern Africa; Livingstone: Edinburgh, 1962.
(5) Achenbach, H.; Witzke, J. Z. Naturforsch. B: Anorg. Chem. Org.
Chem. 1980, 35, 1459.
(6) Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry 1995, 38,
791.
10.1021/ol006583z CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/16/2000

chemistry. Herein we report the first asymmetric synthesis
of 1a and 1b involving two terpene-based borane reagents7
for asymmetric induction.
cation with acryloyl chloride, followed by ring-closing
metathesis using Grubbs ruthenium catalyst (10),14 provided
the lactenone 11 in 65% overall yield (Scheme 2).15
Repeated attempts to deprotect the TBDMS group with
Bu4NF provided very low yields of 1a, along with a mixture
of products. We achieved the deprotection in 94% yield by
utilizing triethylamine trihydrofluoride.16 Acetylation pro-
vided 98% yield of 1b (Scheme 2). The overall yield of 1b
starting with 4 is 15.4%.
Our approach required optically pure (S)-1-heptyn-3-ol (4).
Reduction of the corresponding acetylenic ketone 28 with
(S)-B-isopinocampheyl-9-borabicyclo[3.3.1]nonane (Alpine-
Borane)9 (3) provided (S)-4 in 75% yield and 74% ee.10
Recrystallizing the 3,5-dintrobenzoate of 4 and recovering
the alcohol by basic hydrolysis upgraded the enantiomeric
purity to G99% ee as determined by the HPLC analysis of
the 3,5-dinitrobenzoate on a CHIRALCEL OD-H column.11
Our successful synthetic strategy is outlined in Schemes 1
The configurations as determined by analogy for Alpine-
Borane reductions and allylborations with 7 and the signs
of rotations matched with those reported by Coleman and
Rivett.6 While the rotation of [R]25D ) -5.3 (c 1.3, CHCl3)
for 1a matched, the rotation of [R]25D ) +35 (c 1.8, CDCl3)
for 1b is higher than that reported ([R]25 ) +30 (c 2.1,
D
Scheme 1
CDCl3)).6
In conclusion, we have confirmed the structure and
configuration of desacetylumuravumbolide and umuravum-
bolide by synthesis via asymmetric reduction, allylboration,
and ring-closing metathesis as key steps. We have also
reported a convenient procedure to upgrade the % ee of R,â-
acetylenic alcohols.
Acknowledgment. Financial assistance from the Herbert
C. Brown Center for Borane Research is gratefully acknowl-
edged.
and 2. TBDMS protection of 4, followed by formylation,
provided the acetylenic aldehyde 5 in 50% overall yield. This
was converted to the required Z-olefinic aldehyde 6 in 65%
yield by hydrogenation under Lindlar catalysis.
Supporting Information Available: Experimental pro-
cedures for the preparation of 1 and the spectroscopic data
for compounds 1a, 1b, 5, 6, 8, and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL006583Z
Scheme 2
(7) Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500,
1.
(8) Ketone 2 was prepared via Jones oxidation of commercially available
1-heptyn-3-ol.
(9) (a) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano,
A. J. Am. Chem. Soc. 1980, 102, 867. (S)-Alpine-Borane provides S-alcohol.
(b) Alpine-Borane is the registered trademark of Aldrich Chemical Co.
(10) The reagent used was of 84% ee. Midland reported 92% ee with
optically pure reagent for a similar alcohol on the basis of 1H NMR analysis
in the presence of Eu(dcm)3.
(11) To confirm the efficacy of this upgradation procedure, we prepared
1-butyn-3-ol and 1-octyn-3-ol of 72% and 76% ee, respectively, by Alpine-
Borane (84% ee) reduction of the corresponding ketone and upgraded them
to 99% ee via the 3,5-dintrobenzoate.
(12) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla,
U. S. J. Am. Chem. Soc. 1990, 113, 2389.
(13) We did not observe any of the diastereomers by 1H NMR
spectroscopy. The configuration is based on analogy for allylborations with
7. This was confirmed by the rotation of the target molecule.
(14) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(15) The observed selectivity for the ring-closing metathesis reaction has
precedence. Wright, D. L. Curr. Org. Chem. 1999, 3, 211.
(16) Myers, A. G.; Gin, D. Y.; Rogers, D. H. J. Am. Chem. Soc. 1994,
116, 4697.
Allylboration of 6 with B-allyldiiso-2-caranylborane (7)12
provided enantiomerically pure 8 in 79% yield.13 Esterifi-
20
Org. Lett., Vol. 3, No. 1, 2001