Total syntheses of enokipodins A and B utilizing palladium-catalyzed addition of an arylboronic acid to an allene

Article abstract of DOI:10.1021/ol9001637

The enantioselective total syntheses of enokipodins A and B, α-cuparenone-type sesquiterpenoids with antimicrobial activity, have been achieved. The key step is the enantiospecific construction of the quaternary carbon center using a palladium-catalyzed a

Full text of DOI:10.1021/ol9001637

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1441-1443
Total Syntheses of Enokipodins A and
B Utilizing Palladium-Catalyzed Addition
of An Arylboronic Acid to An Allene
Masahiro Yoshida,* Yasunobu Shoji, and Kozo Shishido
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima,
1-78-1 Sho-machi, Tokushima, 770-8505, Japan
yoshida@ph.tokushima-u.ac.jp
Received January 26, 2009
ABSTRACT
The enantioselective total syntheses of enokipodins A and B, r-cuparenone-type sesquiterpenoids with antimicrobial activity, have been
achieved. The key step is the enantiospecific construction of the quaternary carbon center using a palladium-catalyzed addition of an arylboronic
acid to an allene followed by an Eschenmoser-Claisen rearrangement.
The enokipodins A (1) and B (2), isolated by Takahashi et
al. from a culture broth of an edible mushroom (Flammulina
Velutipes, “enokidake” in Japanese),1,2 are highly oxidized
R-cuparenone-type sesquiterpenoids that exhibit antimicrobial
activity against Cladosporium herbarum and Bacillus
subtilis.1b Owing to the sterically congested structures of
these compounds (Figure 1), which possess a quaternary
Figure 1. Structures for enokipodins A and B.
(1) (a) Ishikawa, N. K.; Yamaji, K.; Tahara, S.; Fukushi, Y.; Takahashi,
K. Phytochemistry 2000, 54, 777–782. (b) Ishikawa, N. K.; Fukushi, Y.;
Yamaji, K.; Tahara, S.; Takahashi, K. J. Nat. Prod. 2001, 64, 932–934
.
(2) For the total synthesis of the enokipodins A and B, see: (a) Srikrishna,
A.; Rao, M. S. Synlett 2004, 374–376. (b) Kuwahara, S.; Saito, M.
Tetrahedron Lett. 2004, 45, 5047–5049. (c) Kuwahara, S.; Saito, M. Biosci.
carbon stereocenter on the cyclopentane ring, they have
attracted considerable synthetic interest.3
Biotechnol. Biochem. 2005, 69, 374–381
.
Recently, we have developed a regiocontrolled addition
of arylboronic acids to allenic alcohols using a palladium or
platinum catalyst.4 The selectivity of the reaction can be
altered by the choice of the metal reagent and the base, with
the aryl-substituted allylic alcohol having an endo olefin
being obtained regio- and stereoselectively when the hy-
(3) For selected examples, see: (a) Natarajan, A.; Ng, D.; Yang, Z.;
Garcia-Garibay, M. A. Angew. Chem., Int. Ed. 2007, 46, 6485–6487. (b)
Spino, C.; Godbout, C.; Beaulieu, C.; Harter, M.; Mwene-Mbeja, T. M.;
Boisvert, L. J. Am. Chem. Soc. 2004, 126, 13312–13319. (c) Acherar, S.;
Audran, G.; Cecchin, F.; Monti, H. Tetrahedron 2004, 60, 5907–5912. (d)
Satoh, T.; Yoshida, M.; Takahashi, Y.; Ota, H. Tetrahedron: Asymmetry
2003, 14, 281–288. (e) Nakashima, H.; Sato, M.; Taniguchi, T.; Ogasawara,
K. Tetrahedron Lett. 2000, 41, 2639–2642. (f) Kosaka, T.; Bando, T.;
Shishido, K. Chem. Commun. 1997, 1167–1168
.
(4) Yoshida, M.; Matsuda, K.; Shoji, Y.; Gotou, T; Ihara, M.; Shishido,
(5) (a) Ziegler, F. E. Chem. ReV. 1988, 88, 1423–1452. (b) Martín Castro,
A. M. Chem. ReV. 2004, 104, 2939–3002.
K Org. Lett. 2008, 10, 5183–5186
.
10.1021/ol9001637 CCC: $40.75
Published on Web 02/26/2009
2009 American Chemical Society

droxopalladium complex and Et3N were used. Consequently,
we expected that a quaternary carbon center could be
stereoselectively created by a Claisen-type rearrangement5
of this resulting allylic alcohol (Scheme 1), and thus we
Scheme 3. Syntheses of 5 and 6
Scheme 1
.
Stereoselective Construction of a Quaternary Carbon
Center
applied this methodology toward the synthesis of 1 and 2.
Herein, the enantioselective total syntheses of enokipodins
A and B are described.
Our strategy for enokipodins A (1) and B (2) is shown in
the retrosynthetic analysis in Scheme 2. We anticipated
was treated with 5 mol % of [Pd2(OH)2(PPh3)4][BF4]2 and 5
equiv of Et3N in dioxane/H2O (20/1) at 60 °C,4 the desired
Scheme 2. Strategy for 1 and 2
Table 1. Palladium-Catalyzed Reaction of 5 with 6
entry
amine
temp (°C)
product
yield (%)
synthesizing enokipodins A (1) and B (2) from cyclopen-
tenone 3, according to Kuwahara’s protocol.2b,c The cyclo-
pentenone 3 could be obtained enantiospecifically via a
Claisen-type rearrangement of the allylic alcohol 4, which would
be prepared by the palladium-catalyzed addition of the arylbo-
ronic acid 6 to the optically active allenic alcohol 5.
The synthesis of the optically active allenic alcohol 5 and
the arylboronic acid 6 was conducted as shown in Scheme
3. Addition of the lithium acetylide 8 to benzaldehyde (7)
afforded the propargylic alcohol (()-9, which was oxidized
with MnO2 to give the ketone 10. Enantioselective reduction
of 10 with the (R)-CBS reagent6 and BH3 and subsequent
treatment of the resulting (+)-9 with LAH furnished the
optically active allenic alcohol 5 in 92% ee. The aryl bromide
12, prepared by bromination of the arene 11, was converted
to the arylboronic acid 6 by reaction with n-BuLi and
B(OiPr)3.
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
iPr2NEt
iPr2NH
pyridine
Et3Na
Et3Nb
60
80
100
80
80
80
4
4
4
4
4
13
4
4
61
68
60
53
47
92
56
42
80
80
a 0.5 equiv of Et3N was added. b 0.2 equiv of Et3N was added.
aryl-substituted allylic alcohol 4 was produced as the sole
product in 61% yield (entry 1). With the yields of 4 being
influenced by the reaction temperature (entries 2 and 3), the
best result was obtained when the reaction was carried out
at 80 °C (entry 2). Similar results were observed when other
amines such as iPr2NEt and iPr2NH were used (entries 4 and
5). Interestingly, the dehydrated diene 13 was predominant
With the key substrates in hand, we next examined the
palladium-catalyzed reaction of 5 with 6 (Table 1). When 5
(7) Although the reason for the pyridine effect is not clear, similar
reactivity to afford dienes has been observed in the presence of platinum
catalysts. See ref 4.
(6) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012.
1442
Org. Lett., Vol. 11, No. 6, 2009

in the presence of pyridine (entry 6).7 Even with decreased
amounts of Et3N (0.5 equiv and 0.2 equiv), the reactions
afforded the product 4 in moderate yields (entries 7 and 8).
These results suggest that the role of the amine is the
activation of the catalyst by coordination to the palladium
metal.4
To construct the quaternary asymmetric center, we next
attempted Claisen-type rearrangements of 4. The Eschen-
moser rearrangement5,8 successfully provided the corre-
sponding amide 14 in 80% yield, with an enantiomeric excess
of 91% (Scheme 4), indicating that the [3,3]-sigmatropic
15 with MeLi followed by the oxidative cleavage of the
double bond furnished the ketoaldehyde 16. The cyclopen-
tenone 3 was obtained quantitatively by the intramolecular
aldol condensation of 16 with K2CO3. Since the cyclopen-
tenone 3 has already been utilized as an intermediate in the
Kuwahara total synthesis,2b,c we followed their procedure
to complete our total synthesis. Thus, treatment of 3 with
MeI and NaH in THF-HMPA provided the dimethylated
product 17, which was hydrogenated and oxidized with CAN
to give enokipodin B (2) [mp 120-122 °C, [R]2D5 -52 (c
0.4, MeOH); lit.1a semisolid, [R]2D4 -63 (c 0.05, MeOH)].
Reduction of the benzoquinone moiety of 2 with Na2S2O4
produced enokipodin A (1) [mp 140-142 °C, [R]2D6 +42 (c
0.6, MeOH); lit.1a 138.5-138.9 °C, [R]2D3 +48 (c 0.5,
Scheme 4. Syntheses of 1 and 2
1
MeOH)]. The H and 13C NMR data of synthetic 1 and 2
were completely identical with those of the natural enoki-
podins A and B, respectively.
In conclusion, we have completed the enantioselective total
synthesis of enokipodins A and B, in which the enantiospe-
cific construction of the quaternary carbon center, using a
palladium-catalyzed addition of an arylboronic acid to an
allene followed by an Eschenmoser-Claisen rearrangement,
has been successfully accomplished. As the stereoselective
construction of molecules with quaternary carbon centers
represents a challenging area in organic synthesis,9 our
methodology would provide a new synthetic protocol.
Application of these results to the syntheses of other natural
products is now in progress.
Acknowledgment. This study was supported in part by a
Grant-in-Aid for the Encouragement of Young Scientists (B)
from the Japan Society for the Promotion of Science (JSPS)
and the Program for the Promotion of Basic and Applied
Research for Innovations in the Bio-oriented Industry
(BRAIN).
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9001637
rearrangement had proceeded in a highly enantiospecific
manner. Conversion of the amide 14 to the methyl ketone
(9) (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146.
(b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 389–
401.
(8) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. HelV. Chim. Acta
1964, 47, 2425–2429
.
Org. Lett., Vol. 11, No. 6, 2009
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