Total synthesis and determination of the absolute configuration of (+)-intricatetraol

Article abstract of DOI:10.1002/anie.200603806

(Chemical Equation Presented) A victory for synthesis: The total synthesis of the marine triterpene polyether (+)-intricatetraol (1) has revealed its absolute configuration, which could not be determined even by spectroscopic methods. The approach feature

Full text of DOI:10.1002/anie.200603806

Communications
DOI: 10.1002/anie.200603806
Natural Products Synthesis
Total Synthesis and Determination of the Absolute Configuration of
(+)-Intricatetraol**
Yoshiki Morimoto,* Tatsuya Okita, Mamoru Takaishi, and Takeshi Tanaka
Intricatetraol (1), a member of a family of squalene-derived
method for the synthesis of the vicinal bromochloro function-
ality,[4] which also occurs in the marine polyhalogenated
monoterpene halomon (2), a promising anticancer agent,[5]
has never been developed. Herein we report the total
assignment of the configuration of (+)-intricatetraol (1) as 3
through the first asymmetric total synthesis of this natural
product. The synthesis features the enantioselective construc-
tion of the vicinal bromochloro functionality through a
pathway in which the configuration is secured.
triterpene polyethers named oxasqualenoids,[1] was isolated
Suzuki et al. suggested structure 4, which disregards the
configuration at C3 (C22), as a possibility on the basis of the
hypothetical biogenesis,[2] and recently we[6] and Ujihara[7]
independently confirmed this assignment. Our retrosynthetic
from the red alga Laurencia intricata by Suzuki et al. in 1993.
A crude fraction containing intricatetraol (1) as the major
component exhibited cytotoxic activity against P388 “leuke-
mia cells” with an IC50 value of 12.5 mgmLꢀ1.[2] The structural
analysis was mainly carried out by NMR spectroscopic
methods. Although it was found that the molecule has C2
symmetry, the cis configuration within the tetrahydrofuran
ring, the R configuration at C11 (C14), the relative config-
urations at C6 and C7 (C18 and C19), C10 and C11 (C14 and
C15), and at bromine-bonded C3 (C22) remained to be
determined.
There are many other types of oxasqualenoids; however,
it is often difficult to determine their configurations even by
highly advanced spectroscopic methods, especially for the
acyclic portions that include stereogenic quaternary carbon
centers, such as C6–C7 (C18–C19) and C10–C11 (C14–C15) in
1. These difficulties have prompted attempts to determine the
configurations of oxasqualenoids by chemical synthesis.[3]
Furthermore, the presence of the vicinal bromochloro
functionality in 1 makes the problem of stereochemical
assignment even more inaccessible. An enantioselective
[*] Prof. Dr. Y. Morimoto, T. Okita, M. Takaishi, T. Tanaka
Department of Chemistry
Scheme 1. Retrosynthetic analysis of the target compound 4. A D=
asymmetric dihydroxylation, AE=asymmetric epoxidation.
Graduate School of Science, Osaka City University
Sumiyoshi-ku, Osaka 558–8585 (Japan)
Fax: (+81)6-6605-2522
E-mail: morimoto@sci.osaka-cu.ac.jp
[**] We thank Dr. M. Suzuki, University Malaysia Sabah, for kindly
providing us with an authentic sample of natural intricatetraol and
its spectra. This research was supported by the Novartis Foundation
(Japan) for the Promotion of Science, the Saneyoshi Scholarship
Foundation, and Grants-in-Aid for Scientific Research on Basic
Research (C) from the JSPS and on Priority Areas 17035071 from the
MEXT.
analysis of the target compound 4 is depicted in Scheme 1. We
envisaged that it would be efficient to dimerize by olefin
metathesis the functionalized fragment 5, which represents
half of the molecule, because of the C2 symmetry of the
natural product. The R or S configuration at the carbon atom
attached to bromine in 5 could be introduced through epoxide
chemistry. The desired trihydroxytetrahydrofuran 6 might be
constructed by the stereospecific and stereoselective oxacyc-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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lization of the diepoxyalcohol 8 under alkaline conditions.[8]
The required stereocenters in 8 would be introduced into
commercially available trans,trans-farnesyl acetate (9) by
established methods of asymmetric oxidation.
zoquinone (DDQ) [12] provided a 3:7 mixture of regioisomeric
benzoate esters, which upon reduction with lithium aluminum
hydride gave the deprotected diol 18.
Selective mesylation of the secondary hydroxy group in
the diol 18 followed by treatment of the mesylate with
potassium carbonate yielded the epoxide 19 (Scheme 3).[13]
The epoxide-opening reaction of 19 with dilithium tetrabro-
monickelate in THF proceeded regioselectively to produce
the secondary bromide 20 with inversion of configuration at
the less hindered carbon atom.[14] It has been reported that
dilithium tetrabromonickelate reacts with epoxides through
an SN2 mechanism. We confirmed that the bromohydrin 20 is
reconverted into the starting epoxide 19 upon treatment with
a base. Chlorination[15] of the bromohydrin 20 and subsequent
deprotection of the alcohols protected as MOM ethers
afforded the fully functionalized half fragment 21 with a cis
tetrahydrofuran ring, as confirmed by the observation of an
NOE between the hydrogen atoms indicated in structure 21.
In the chlorination of bromohydrin 20 with thionyl
chloride in DMPU, the major (chlorination) and minor
(dehydration) products 21 and 23 were formed in a 2:1 ratio
(Scheme 4). We also prepared the regioisomeric bromohydrin
22 by treating the epoxide 19 with magnesium bromide
etherate.[16] When the bromohydrin 22 was subjected to the
same chlorination conditions, products 21 and 23 were formed
in almost the same ratio as in the reaction of 20. Therefore, it
seems that the chlorination proceeds via a common bromo-
nium-ion intermediate E, as described previously for a similar
chlorination by Mioskowski and co-workers.[4a]
The protection of the chiral diol 10 (> 95% ee)[9] as a p-
methoxybenzylidene acetal (7:3 mixture) and subsequent
deacetylation afforded the allylic alcohol 11[10] (Scheme 2).
Katsuki–Sharpless asymmetric epoxidation of 11 in the
presence of (+)-diethyl l-tartrate (l-(+)-DET) provided the
epoxyalcohol 12. Asymmetric epoxidation of the alkene 12 by
the method of Shi and co-workers[11] with ketone 13 as the
chiral catalyst then gave the diepoxyalcohol 14. Treatment of
the diepoxyalcohol 14 with 1m aqueous solution of lithium
hydroxide and 1,4-dioxane (1:1) under reflux furnished the
desired trihydroxytetrahydrofuran product 15 with high
stereospecificity. It was thought from our previous studies[3g,8]
that the reaction proceeds through a Payne rearrangement, 5-
exo-tet formation of the ether ring, and an intermolecular
attack of hydroxide ion on the epoxide in the more stable
conformer C. In this reaction, the bicyclic ether 16 was also
formed as a by-product. Compound 16 could be generated
from the less stable conformer D by an intramolecular attack
of the tertiary alkoxide on the epoxide ring. Selective tert-
butyldimethylsilyl (TBDMS) protection of the primary hy-
droxy group in the triol 15, methoxymethyl (MOM) protec-
tion of the remaining hydroxy groups, deprotection of the silyl
ether, Parikh–Doering oxidation of the alcohol, and Wittig
methylenation of the resulting aldehyde afforded the terminal
alkene 17 in good overall yield. Oxidation of the p-methoxy-
benzylidene acetal 17 with 2,3-dichloro-5,6-dicyano-1,4-ben-
Scheme 2. Reagents and conditions: a) p-MeOC6H4CH(OMe)2, pyridinium p-toluenesulfonate, CH2Cl2, 08C!RT, 16 h; b) K2CO3, MeOH, RT, 7 h,
99% (2 steps); c) tBuOOH, Ti(OiPr)4, l-(+)-DET, M.S. (4 Š), CH2Cl2, ꢀ208C, 21 h, 95% (d.r.>20:1); d) 13, oxone, Bu4NHSO4, CH2(OMe)2/
CH3CN/H2O, pH 10.5, 08C, 2.5 h, 87% (d.r. >6:1); e) aq. LiOH (1m), 1,4-dioxane, 1008C, 7 h; f) TBDMSCl, Et3N, 4-(dimethylamino)pyridine,
CH2Cl2, RT, 26 h, 96%; g) MOMCl, iPr2NEt, CH2Cl2, 08C!RT, 36 h, 96%; h) Bu4NF, THF, 08C!RT, 15 h, 100%; i) SO3·pyridine, Et3N, DMSO/
=
CH2Cl2, 08C, 30 min, 100%; j) Ph3P CH2, THF, 08C, 1 h, 90%; k) DDQ, H2O, CH2Cl2, RT, 2 h; l) LiAlH4, THF, 08C, 1.5 h, 96% (2 steps).
DMSO=dimethyl sulfoxide, MP=p-methoxyphenyl.
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catalyst 24 (Scheme 3; Cy = cyclohexyl).[17] Although catalytic
hydrogenation of the alkene 25 under standard conditions
afforded the dehalogenated product by overreduction, dii-
mide reduction[18] provided the target compound 3 without
dehalogenation. The respective spectra of the synthetic
compound 3 ([a]2D3 = + 51.3 (c = 0.41, CHCl3)), prepared
from the R alcohol 10, were identical to those of the natural
product ([a]D20 = + 53.0 (c = 0.625, CHCl3)).[2,6,7] Thus, it was
found that the hitherto unknown absolute configuration of
(+)-intricatetraol (1) is shown by the structural formula 3.[19]
In conclusion, we have completed the first asymmetric
total synthesis of the marine bromochloro-functionalized
triterpene polyether (+)-intricatetraol (1). Our synthesis
features the enantioselective construction of the unique
vicinal bromochloro functionality in an approach that may
be applied to the synthesis of other bromochloro compounds,
such as halomon (2), and an efficient olefin-metathesis
strategy that takes the intrinsic molecular symmetry of the
natural product into consideration. The total synthesis
resulted in the assignment of the absolute configuration of
intricatetraol (1), which is difficult to determine by other
means. Further contributions to structure elucidation by
organic synthesis are in progress.
Received: September 15, 2006
Revised: October 16, 2006
Published online: December 27, 2006
Keywords: asymmetric synthesis · configuration determination ·
.
halogen compounds · polyethers · terpenoids
Scheme 3. Reagents and conditions: a) methanesulfonyl chloride, pyri-
dine, CH2Cl2, 08C!RT, 14 h; then K2CO3, MeOH, RT, 3 h, 90%;
b) Li2[NiBr4], THF, RT, 56 h, 76%; c) K2CO3, MeOH, RT, 1 h, 92%;
d) SOCl2, DMPU, 08C, 30 min; e) HCl, MeOH, RT, 66 h, 55%
(2 steps); f) 24, CH2Cl2, 408C, 7 h, 86%; g) (KOCON)2, AcOH, MeOH,
RT, 70 h, 56%. DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidi-
none.
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[19] For further discussion on the possibility of other diastereomers,
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