An expeditious synthesis of bruguierol A

Article abstract of DOI:10.1021/jo8021204

A very simple strategy for the construction of 2,3-benzofused 8-oxabicyclo[3.2.1]octane derivatives is reported. This new process is based on a platinum-catalyzed tandem intramolecular hydroalkoxylation-hydroarylation reaction of aryl- substituted pentyno

Full text of DOI:10.1021/jo8021204

An Expeditious Synthesis of Bruguierol A†
Francisco J. Fan˜ana´s,* Amadeo Ferna´ndez, Deniz C¸ evic, and
Fe´lix Rodr´ıguez*
FIGURE 1. Structures of bruguierols A-C.
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique
Moles”, Unidad Asociada al CSIC, UniVersidad de OViedo,
Julia´n ClaVer´ıa 8, 33006-OViedo, Spain
SCHEME 1. Retrosynthetic Analysis
fjfV@unioVi.es; frodriguez@unioVi.es
ReceiVed September 26, 2008
derivative(R)-2atoyieldthebenzofused8-oxabicyclo[3.2.1]octane
skeleton.3 It was envisaged that the precursor (R)-2a would be
readily synthesized from commercially available (S)-epichlo-
rydrin (Scheme 1).
As previously stated, our approach to bruguierol A was guided
by the perception that the formation of the oxabicyclo[3.2.1]octane
skeleton could be readily achieved by a tandem intramolecular
hydroalkoxylation-hydroarylation reaction of the chiral non-
racemic alkynol derivative (R)-2a. This hypothesis was sup-
ported by our experience on this kind of reaction performed on
hexynol derivatives.4 However, the extension of this reaction
to pentynol derivatives analogous to (R)-2a had not been
evaluated. So, before starting the total synthesis of our target
natural product we decided to check the catalytic tandem
intramolecular hydroalkoxylation-hydroarylation reaction of
pentynol derivatives. It should be noted that although both the
hydroalkoxylation and the hydroarylation reactions are known
transformations, the development of a method where a single
catalyst promotes both reactions in a one-pot process would be
highly interesting.
As shown in Scheme 2, the treatment of pentynol derivatives
2 with 5 mol % of PtCl4 in dichloromethane at room temperature
readily afforded the tricyclic compounds 3 in high yield and as
single diastereoisomers. The reaction was shown to proceed with
both secondary and tertiary alcohols 2. The scope of this reaction
is limited by the fact that only alkynols 2 containing electron-
rich aromatic rings worked efficiently. In those cases where the
starting materials 2 contained simple phenyl groups the hy-
droarylation reaction did not progress, and we isolated the
corresponding enol ethers proceeding from the first hydroalkox-
ylation reaction of the triple bond. However, this limitation did
not affect our plan for the synthesis of bruguierol A as this
natural product contains an electron-rich aromatic ring. In fact,
A very simple strategy for the construction of 2,3-benzofused
8-oxabicyclo[3.2.1]octane derivatives is reported. This new
process is based on a platinum-catalyzed tandem intramo-
lecular hydroalkoxylation-hydroarylation reaction of aryl-
substituted pentynol derivatives. This reaction has been
applied in the key step of the total synthesis of bruguierol
A, allowing the synthesis of this natural product in a very
straightforward manner.
As part of investigations on mangroves for the search for
new natural products, in 2005 Sattler and co-workers isolated
and characterized from the stem of Bruguiera gymmorrhiza tree
a new family of compounds termed bruguierols A-C (Figure
1).1 The structure of these natural products is characterized by
a 2,3-benzofused 8-oxabicyclo[3.2.1]octane core. Additionally,
the aromatic ring is substituted with one (bruguierol A) or two
hydroxyl groups (bruguierols B and C). Among the three,
bruguierol C was shown to exhibit activity against both Gram-
positive and Gram-negative bacteria. Thus, the development of
a flexible strategy to access these natural products or analogues
could be highly interesting in finding new broad spectrum
antibiotics. The biological profile combined with the interesting
structural features and the potential to exploit methods developed
within our group make the bruguierols ideal synthetic targets.2
Here we describe a new and simple strategy that allows the
stereoselective synthesis of bruguierol A, 1. The method could
be easily adapted to the synthesis of the other bruguierols or
analogues.
(3) For an excellent paper on the synthesis of 8-oxabicyclo[3.2.1]octane
systems, see: Marson, C. M.; Campbell, J.; Hursthouse, M. B.; Malik, K. M. A.
Angew. Chem., Int. Ed. 1998, 37, 1122.
(4) Barluenga, J.; Ferna´ndez, A.; Satru´stegui, A.; Die´guez, A.; Rodr´ıguez,
F.; Fan˜ana´s, F. J. Chem. Eur. J. 2008, 14, 4153.
The synthetic plan relied on a late stage tandem intramolecular
hydroalkoxylation-hydroarylation reaction of the pentynol
(5) For recent works where platinum complexes have been used as catalysts
in hydroalkoxylation reactions of unsaturated carbon-carbon bonds, see: (a)
Die´guez-Va´zquez, A.; Tzschucke, C. C.; Lam, W. Y.; Ley, S. V. Angew. Chem.,
Int. Ed. 2008, 47, 209. (b) Nakamura, I.; Chan, C. S.; Araki, T.; Terada, M.;
Yamamoto, Y. Org. Lett. 2008, 10, 309. (c) Bhuvaneswari, S.; Jeganmohan,
M.; Cheng, C.-H. Chem. Eur. J. 2007, 13, 8285. (d) Barluenga, J.; Die´guez, A.;
Ferna´ndez, A.; Rodr´ıguez, F.; Fan˜ana´s, F. J. Angew. Chem., Int. Ed. 2006, 45,
2091. (e) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907. (f) Fu¨rstner, A.;
Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024. (g) Nakamura, I.; Mizushima,
Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022. (h) Qian, H.; Han, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536. (i) Lucey, D. W.;
Atwood, J. D. Organometallics 2002, 21, 2481.
† This article is dedicated to Professor Jose´ Barluenga.
(1) Han, L.; Huang, X.; Sattler, I.; Moellmann, U.; Fu, H.; Lin, W.; Grabley,
S. Planta Med. 2005, 71, 160.
(2) As far as we know only a total synthesis of the enantiomer of bruguierol
A and a total synthesis of bruguierol C have been published. For the synthesis
of bruguierol A, see: (a) Ramana, C. V.; Salian, S. R.; Gonnade, R. G. Eur. J.
Org. Chem. 2007, 5483. For the synthesis of bruguierol C, see: (b) Solorio,
D. M.; Jennings, M. P. J. Org. Chem. 2007, 72, 6621.
932 J. Org. Chem. 2009, 74, 932–934
10.1021/jo8021204 CCC: $40.75 2009 American Chemical Society
Published on Web 11/21/2008

SCHEME 2. 2,3-Benzofused 8-Oxabicyclo[3.2.1]octane
Derivatives 3 by Catalytic Tandem
SCHEME 4. Synthesis of Bruguierol A from
(S)-Epichlorydrin
Hydroalkoxylation-Hydroarylation Reaction of Pentynol
Derivatives 2
with the Grignard reagent 9 to give the chlorydrin derivative
10 in 92% yield. Further reaction of this alcohol with methyl-
lithium furnishes the new epoxide 11 in 92% yield. The reaction
of this epoxide with propargylmagnesium bromide provides the
desired pentynol derivative (R)-2a in 90% yield as a single
regioisomer with an enantiomeric ratio of >95:5 as determined
by the Mosher method. The pentynol derivative (R)-2a was
subjected to the intramolecular hydroalkoxylation-hydroarylation
reaction by using PtCl4 as catalyst in dichloromethane at room
temperature. Under these conditions the protected bruguierol
A (1S,3R)-3a was obtained in 94% yield. Last, treatment of
(1S,3R)-3a with TBAF in THF afforded the natural product
bruguierol A in 96% yield. The spectral data and optical rotation
of synthetic bruguierol A were in agreement with those of the
natural sample.
SCHEME 3. Proposed Mechanism for the Formation of
2,3-Benzofused 8-Oxabicyclo[3.2.1]octanes 3 from Alkynols 2
In conclusion, a very short and efficient total synthesis of
bruguierol A has been accomplished from commercially avail-
able (S)-epichlorydrin (5 steps, ca. 69% overall yield). This
synthesis favorably competes with the previous approach in
terms of all usual empirical indices.7 We have also demonstrated
the power of the catalytic tandem intramolecular hydroalko-
xylation-hydroarylation reaction for the construction of 2,3-
benzofused 8-oxabicyclo[3.2.1]octane systems. Clearly, the
strategy described here could be readily adapted to the total
synthesis of other bruguierols and novel analogues.
compound 3a, which is a precursor of racemic bruguierol A,
could be easily obtained in 93% yield (Scheme 2).
A mechanism that explains the formation of compounds 3
from pentynol derivatives 2, supported by our previous studies
in the field,4 is shown in Scheme 3. The reaction is initiated by
coordination of the platinum catalyst to the triple bond of the
starting alkynol 2 to form intermediate 4. This coordination
favors an intramolecular addition of the hydroxyl group to the
internal carbon of the triple bond (5-exo addition) to generate
5. Protodemetalation of the latter affords the enol ether 6 and
releases the catalytic species.5,6 Once enol ether 6 is formed, it
enters the second catalytic cycle. Thus, after an initial coordina-
tion of the catalyst to the double bond of the enol ether 6, the
oxocarbenium ion intermediate 7 is formed. Further nucleophilic
attack of the aryl group affords the intermediate 8 that after a
rearomatization and a protodemetalation step leads to the final
product 3, regenerating the catalytic species.
Experimental Section
Representative Procedure for the 5-exo Hydroalkoxylation-
Hydroarylation Reaction: Synthesis of (1S,3R)-3a.
Alkynol (R)-2a (1 mmol) was added to an orange solution of
PtCl4 (16.7 mg, 0.05 mmol) in dichloromethane (2 mL) at room
temperature. The resulting mixture was stirred until complete
conversion of the starting alkynol (1 h; monitored by TLC). The
solvent was removed at reduced pressure and the residue obtained
was purified by flash column chromatography on silica gel (hexane:
ethyl acetate 7:1) to yield pure compound (1S,3R)-3a as a colorless
After establishing the feasibility of the catalytic tandem
intramolecular hydroalkoxylation-hydroarylation reaction for
the synthesis of 2,3-benzofused 8-oxabicyclo[3.2.1]octane sys-
tems, we turned our attention to the synthesis of bruguierol A
from commercially available (S)-epichlorydrin (Scheme 4). The
first reaction implies the ring opening of the epoxide by reaction
oil. Rf 0.55 (hexane:ethyl acetate 5:1). [R]D -30.1 (c 6 × 10-3
,
1
CH2Cl2). H (300 MHz, CDCl3) δ 6.98 (d, J ) 8.3 Hz, 1H; H8),
6.58 (dd, J ) 8.3, 2.2 Hz, 1H; H7), 6.53 (d, J ) 2.2 Hz, 1H; H5),
J. Org. Chem. Vol. 74, No. 2, 2009 933

4.68 (ddd, J ) 7.1, 5.1, 1.3 Hz, 1H; H3), 3.29 (dd, J ) 16.4, 5.1
Hz, 1H; H4a), 2.43 (d, J ) 16.4 Hz, 1H; H4b), 2.30-2.14 (m, 1H;
1H; H4b), 2.26–2.18 (m, 1H; H10a), 1.98 (ddd, J ) 11.5, 9.5, 3.1
Hz, 1H; H9a), 1.83 (dd, J ) 11.5, 7.4 Hz, 1H; H9b), 1.75-1.63 (m,
1H; H10b), 1.70 (s, 3H; H). 13C NMR (75 MHz, CDCl3) δ 24.8,
32.4, 39.5, 45.0, 76.3, 82.7, 115.0, 117.7, 126.0, 135.4, 138.1, 156.6.
HRMS calcd for C12H14O2 190.0994, found 190.0992.
H
10a), 1.98 (ddd, J ) 11.7, 9.7, 2.7 Hz, 1H; H9a), 1.82 (dd, J )
11.4, 7.1 Hz, 1H; H9b), 1.77-1.59 (m, 1H; H10b), 1.68 (s, 3H), 0.87
t
(s, 9H; Bu-Si), 0.17 (s, 6H; 2 × Me-Si). 13C NMR (75 MHz,
CDCl3) δ -4.5, 18.1, 22.8, 25.6, 30.4, 37.5, 42.9, 74.2, 80.2, 117.4,
120.3, 123.6, 133.1, 136.9, 154.1. HRMS calcd for C18H28O2Si
304.1859, found 304.1857.
Acknowledgment. Financial support for this work was
provided by the Ministerio de Educacio´n y Ciencia of Spain
(CTQ2007-61048/BQU).
Deprotection of (1S,3R)-3a: Synthesis of Bruguierol A (1).
Supporting Information Available: Experimental proce-
dures and 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.
JO8021204
Bu4NF (1 mmol) was added to a solution of (1S,3R)-3a (1 mmol)
in wet THF (20 mL) at room temperature. The mixture was stirred
until complete conversion of the starting material (30 min;
monitored by TLC). Water (20 mL) was added, and the mixture
was extracted with diethyl ether (3 × 10 mL). The combined
organic layers were dried over anhydrous Na2SO4. The solvent was
removed and the crude was purified by flash column chromatog-
raphy on silica gel (hexane:diethyl ether 1:2) to yield pure
compound 1 (Bruguierol A) as a white solid. Mp 129.6-133.1 °C.
Rf 0.33 (hexane:ethyl acetate 2:1). [R]D +14.5 (c 7 × 10-3, CHCl3)
(6) Some other metallic complexes have been reported to catalyze the
intramolecular hydroalkoxylation of alkynes. For selected recent examples see
the following references. Palladium: (a) Trost, B. M.; Weis, A. H. Angew. Chem.,
Int. Ed. 2007, 46, 7664. Silver: (b) Pale, P.; Chuche, J. Eur. J. Org. Chem.
2000, 1019 Gold: (c) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour, C.;
Geneˆt, J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112. Ruthenium: (d)
Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528. Rhodium: (e)
Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482. Iridium: (f) Genin,
E.; Antoniotti, S.; Michelet, V.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2005, 44,
4949. Tungsten: (g) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc.
2000, 122, 4304. (h) Barluenga, J.; Die´guez, A.; Rodr´ıguez, F.; Fan˜ana´s, F. J.
Angew. Chem., Int. Ed. 2005, 44, 126. (i) Barluenga, J.; Die´guez, A.; Rodr´ıguez,
F.; Fan˜ana´s, F. J.; Sordo, T.; Campomanes, P. Chem. Eur. J. 2005, 11, 5735.
(7) Ramana’s synthesis of the enantiomer of bruguierol A (see ref 2a) requires
at least 10 steps (from geranyl acetate) and the global yield is approximately
1.5%.
{lit.1 [R]D +14.3 (c 6 × 10-3, CHCl3)}. H (300 MHz, CDCl3) δ
1
6.98 (d, J ) 8.4 Hz, 1H; H8), 6.58 (dd, J ) 8.4, 2.5 Hz, 1H; H7),
6.50 (d, J ) 2.5 Hz, 1H; H5), 4.71 (ddd, J ) 7.0, 5.1, 1.5 Hz, 1H;
H3), 3.28 (dd, J ) 16.5, 5.1 Hz, 1H; H4a), 2.42 (d, J ) 16.5 Hz,
934 J. Org. Chem. Vol. 74, No. 2, 2009