Highly efficient stereocontrolled total synthesis of (+)-upial

Article abstract of DOI:10.1002/anie.200704423

(Chemical Equation Presented) Dual benefit:(+)-Upial, isolated from the sponge Dysidea fragilis (Kaneohe Bay, Hawaii), as a nonisoprenoid sesquiterpene aldehyde lactone, was efficiently synthesized. The key step involved an intramolecular carbonyl-ene rea

Full text of DOI:10.1002/anie.200704423

Angewandte
Chemie
DOI: 10.1002/anie.200704423
Natural Product Synthesis
Highly Efficient Stereocontrolled Total Synthesis of (+)-Upial**
Kazunori Takahashi, Masayuki Watanabe, and Toshio Honda*
(+)-Upial (1), isolated from the sponge Dysidea fragilis of
Kaneohe Bay (Hawaii), was found to be a nonisoprenoid
sesquiterpene aldehyde lactone containing the rare bicyclo-
[3.3.l]nonane skeleton.[1] Its structure was originally proposed
on the basis of spectroscopic analyses of the natural product
and the products of its degradation and chemical trans-
formations (Figure 1).[1] The absolute configuration of upial
Figure 2. Structures of natural products witha bicyclo[3.3.1]nonane
ring system.
structure of 1 for retrosynthetic disconnection, we focused on
formation of the bicyclo[3.3.1]nonane ring system and the
exo-methylene function simultaneously.Accordingly, either
the Sakurai reaction[6] or an intramolecular carbonyl–ene
reaction[7] were candidates for transformation of a corre-
sponding allyl silane derivative 7 possessing an appropriate
functional group, which could be converted into a carbonyl
function at the later stage of the synthesis (Scheme 1).
Moreover, the acetaldehyde unit of 1 could be introduced
to lactone 5 at the final stage of the synthesis, and lactone 5
could be secured from hydroxy-carbonyl compound 6.The
key aldehyde 7 would be obtained from a corresponding
alcohol 8 by oxidation.Installation of an allyl silyl group
would be achieved by coupling triflate 9 with (trimethyl-
silylmethyl)magnesium chloride in the presence of a palla-
dium catalyst.[8] Finally, 9 could readily be obtained from
ketone 10.
Figure 1. Structure of (+)-upial (1).
was unambiguously determined by the total synthesis of its
enantiomer starting from a readily accessible chiral source,
(À)-carvone.[2] Synthesis of the naturally occurring(+)-upial
was first achieved by Yamada and co-workers.[3] In the
synthesis, a double Michael reaction of an (E)-a,b-unsatu-
rated ester with the enolate of 6-methyl-3-methoxymethoxy-
2-cyclohexenone and subsequent fragmentation of the result-
ing adduct were the key reactions used to construct the basic
carbon framework.Snider and OꢀNeil also synthesized
racemic upial whereby oxidative free-radical cyclization of
4-(3-hexenyl)-1,3-cyclohexanedione was employed as a key
step.[4]
As a result of its architecturally intriguing bicyclic
skeleton, upial and related analogues 2–4 (Figure 2) have
received considerable attention from synthetic chemists over
the years.[5] The crucial step for the synthesis of 1 is the
stereocontrolled construction of a bicyclo[3.3.1]nonane ring
system with five stereogenic carbon centers as well as facile
introduction of the exo-methylene unit.
In view of these considerations, preparation of allyl silane
aldehyde 20 as the key precursor for a cyclization reaction was
Our own interest in 1 grew out of a desire to find an
entirely new route for its total synthesis.In analyzing the
[*] Dr. K. Takahashi, Dr. M. Watanabe, Prof. Dr. T. Honda
Faculty of Pharmaceutical Sciences
Hoshi University
Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501 (Japan)
Fax: (+81)3-3787-0036
E-mail: honda@hoshi.ac.jp
Homepage: http://www.hoshi.ac.jp/home/kyoiku/kyoushitsuh
gaid/6kyoushitsu.seizou.html
[**] This research was financially supported inpart by a grant for the
Open ResearchCenter Project and a grant-in-aid from the Ministry
of Education, Culture, Sports, Science, and Technology of Japan. We
also thank Central Glass Co., Ltd., for providing triflic anhydride.
Scheme 1. Retrosynthetic analysis of (+)-upial (1). FG=functional
group, PG=protecting group, Tf=trifluoromethanesulfonyl, TMS=tri-
methylsilyl.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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achieved as follows (Scheme 2): The optically active ketone
coupled with (trimethylsilylmethyl)magnesium chloride in
the presence of tetrakis(triphenylphosphine)palladium to
afford allyl silane derivative 18.Deprotection of the benzoyl
group of 18 using 3n NaOH gave the alcohol 19, which upon
oxidation with tetrapropylammonium perruthenate (TPAP)
afforded the desired aldehyde 20.[12]
11[9] was converted into silyl enol ether 12, which upon
reduction with lithium aluminum hydride afforded alcohol 13.
After protection of the hydroxy group of 13, the resulting
At this stage a study was carried out to determine the best
conditions for construction of the bicyclic system by using
either the Sakurai reaction or an intramolecular carbonyl–ene
reaction.Although difficulties were initially encountered with
the conversion of 20 into 21 (for example, attempted
cyclization with a Lewis acid such as zinc chloride, boron
trifluoride etherate, or tin(IV) chloride gave the desired
compound in only moderate yields), treatment of 20 with
0.2 mol% of para-toluenesulfonic acid (pTsOH) in refluxing
chloroform afforded the cyclization products 21, 22, and 23 in
85% yield in a ratio of 28:67:5 (Table 1).This result clearly
indicated that the cyclization would proceed through an
intramolecular carbonyl–ene reaction.When the reaction was
carried out with 10 mol% of pTsOH in refluxing chloroform
for 15 minutes, the desired compound 21 was isolated stereo-
selectivly in 96% yield (Table 1).[13] In this conversion, the
stereochemistry of the secondary hydroxy group of 21 was
again controlled by the presence of a vinyl group.The
stereochemistry of the product was unambiguously deter-
mined on the basis of 2D NMR spectroscopy and NOE
experiments.
It should also be noted that the presence of a trimethylsilyl
group seemed to be essential for the carbonyl–ene reaction.
Our preliminary experiment showed that a structurally
related model compound without a trimethylsilyl group did
not give any desired compound under similar reaction
conditions.
The stereochemistry of the hydroxy group of 21 was
inverted in two steps by oxidation with TPAP and subsequent
reduction of the resulting ketone 24 with sodium borohydride
reduction to give 25 (Scheme 3).
Scheme 2. Preparation of the key aldehyde (20). Bz=benzoyl,
DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide,
M.S.=molecular sieves, NMO=4-methylmorpholine N-oxide.
benzoate 14 was subjected to the improved Ito–Saegusa
oxidation[10] to give enone 15.Avinyl group was introduced at
the b-position of the enone moiety as a synthetic equivalent to
the carbonyl function because previous studies had shown
that an attempted preparation of allyl silane derivatives
bearing a cyano group or oxo function at this position did not
give the desired compounds.[11]
Accordingly, enone 15 was treated with vinylmagnesium
bromide in THF at À788C in the presence of copper(I)
cyanide to afford ketone 16 as an inseparable mixture of
diastereoisomers in a ratio of about 5:1 (98% yield).
Although the stereochemistry of the vinyl group could not
be determined at this stage, it was assumed that the major
product had an S configuration arising from an axial attack of
the vinyl group on enone 15.Significantly, the stereoselectiv-
ity of the conjugate addition of the vinyl group to 15 was
influenced by the presence of a methyl group on the side
chain.When a similar addition was carried out for the
compound without a methyl group on its side chain, the ratio
of products was found to be approximately 1:1.Ketone 16 was
treated with N-phenyltriflimide and sodium hexamethyl-
disilazide (NaHDMS), and the resulting triflate 17 was
Finally, the improved Lemieux–Johnson oxidation of 25
gave lactol 26.[14] In the oxidation, a site-selective di-
hydroxylation of the carbon–carbon double bond was
observed.Further oxidation of 26 with Fetizon reagent
provided the known lactone 27.The specific optical rotation
of 27 was identical to that reported in the literature[2]
(although its spectroscopic data were not mentioned).To
complete the total synthesis of the target compound 1, lactone
Table 1: Intramolecular carbonyl–ene reaction of aldehyde 20 with
pTsOH.
pTsOH [mol%]
t [h]
Total yield [%]
Ratio (21:22:23)
0.2
0.5
10
0.5
1.0
0.25
85
74
96
28:67:5
41:55:4
100[a]:0:0
[a] exo:endo ratio (96:4) was determined by 1H NMR spectroscopy.
132
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Chemie
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Scheme 3. Synthesis of (+)-upial (1). HMPA=hexamethylphosphor-
amide.
27 was alkylated with allyl iodide in the presence of lithium
diisopropylamide (LDA) to give allyl compound 28, which
upon Lemieux–Johnson oxidation afforded (+)-upial (1)
(Scheme 3).
[7] For recent reports on intramolecular carbonyl-ene reactions, see
a) A.Barbero, P.Castreno, C.Garcia, F.J.Pulido,
J. Org. Chem.
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M.Hiersemann, Org. Lett. 2006, 8, 1573 – 1576; g) A.Barbero,
In conclusion, we have established a concise total syn-
thesis of (+)-upial (1).The key step of this synthesis is an
intramolecular carbonyl–ene reaction, in which stereocon-
trolled construction of a bicyclo[3.3.1]nonane ring system
with five asymmetric carbon centers and facile introduction of
the exo-methylene unit were achieved in one step.In 15 steps,
this synthesis afforded the target compound 1 in 10.2%
overall yield from the readily accessible known starting
material 11.We believe that this synthetic strategy has great
potential application for the synthesis of a wide range of
natural products bearing such bicyclic systems.
F.J.Pulido, M.C.Sanudo,
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[10] a) Y.Ito, T.Hirao, T.Saegusa,
J. Org. Chem. 1978, 43, 1011 –
1013; b) R.C.Larock, T.R.Hightower, G.A.Kraus, P.Hahn, D.
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[11] Preparation of
a cyano derivative corresponding to 17
Received: September 26, 2007
Published online: November 12, 2007
was attempted; however, enone 15 was isolated instead
of a desired triflate as the reaction product.
Keywords: intramolecular reactions · natural products · silanes ·
.
terpenoids · total synthesis
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[4] B.B.Snider, S.V.OꢀNeil,
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