Oxidative cyclization of diols derived from 1,5-dienes: Formation of enantiopure cis-tetrahydrofurans by using catalytic osmium tetroxide; formal synthesis of (+)-cis-solamin

Article abstract of DOI:10.1002/anie.200500513

(Chemical Equation Presented) High yields and high levels of stereocontrol are observed in the oxidative cyclization of vicinal diols using catalytic amounts of a transition metal (see scheme; TFA = trifluoroacetic acid). The product stereochemistry is co

Full text of DOI:10.1002/anie.200500513

Communications
Asymmetric Catalysis
Oxidative Cyclization of Diols Derived from
1,5-Dienes: Formation of Enantiopure
cis-Tetrahydrofurans by Using Catalytic
Osmium Tetroxide; Formal Synthesis of
(+)-cis-Solamin**
Timothy J. Donohoe* and Sam Butterworth
In 1965, Klein and Rojahn discovered that treatment of 1,5-
hexadiene with KMnO4 afforded cis-2,5-bis(hydroxymethyl)-
tetrahydrofuran.[1] The mechanism of the reaction was a
matter of some debate but eventually was considered to be a
concerted cyclization of a metal–glycolate complex across a
distal alkene.[2] This mechanism is consistent with the fact that
the addition across both alkenes is stereospecific (syn) and
also that stereoselective formation of cis-tetrahydrofurans is
observed. Since the original reports using KMnO4, several
[*] Prof. T. J. Donohoe, Dr. S. Butterworth
Department of Chemistry
University of Oxford, Chemistry Research Laboratory
Mansfield Road, Oxford, OX13TA (UK)
Fax: (+44)186-527-5708
E-mail: timothy.donohoe@chem.ox.ac.uk
[**] We thank the EPSRC andMerck for supporting this project.
AstraZeneca, Pfizer, Novartis, andMerck are thankedfor unre-
stricted funding. R. C. D. Brown is thanked for providing the NMR
spectra of compound 19.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500513
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Angewandte
Chemie
other metals have been shown to mediate this type of
cyclization, including ruthenium[3] and, more recently,
osmium.[4]
We recently described the development of the oxidative
cyclization of 1,5-dienes using catalytic amounts of OsO4
(5 mol%) under acidic conditions (see 1!2, Scheme 1).[5]
This sequence is remarkable for its high yields, especially
during the oxidation of mono- and disubstituted alkenes,
which tend to give overoxidation products with manganese
and ruthenium oxidants.
suggests that the 1,2-diol forms a chelated osmate ester in situ
(see intermediate A, Scheme 1) that then cyclizes as before.
Naturally, we were intrigued by the oxidation state of the
osmium center in A, because the diene cyclization protocol
provides Osvi directly and the diol cyclization route commen-
ces with Osviii [7]
. Therefore, we examined the role of additives
in the cyclization of 3 (Table 1) and found that a range of
Table 1: Oxidation of (+)-3!(ꢀ)-2.
Entry
Sacrificial alkene[a]
t [h]
Conversion [%][b]
1
2
3
4
5
none
none
cyclohexene (5)
cyclohexene (5)
isoprene (5)
6
30
6
30
6
30
85 (55)
40
100 (83)
45
[a] Equivalents given in brackets. [b] Yieldof isolatedproduct given in
brackets.
sacrificial alkenes improved the yield (5 equiv were best). It is
possible that this second alkene is able to generate Osvi in situ
(from Osviii) by a dihydroxylation reaction and thus acts to
increase the amount of active Osvi catalyst in the reaction
mixture.
Scheme 1. Oxidative cyclization of 1,5-dienes. Reagents and
conditions: a) OsO4 (5 mol%), Me3NO (4 equiv), camphor sulfonic
acid(6 equiv), CH 2Cl2. Bn=benzyl.
A major obstacle to the application of this sequence in
synthesis is the fact that racemic mixtures are produced.
Attempts to introduce asymmetric induction into this reaction
by the addition of chiral amine ligands failed, presumably
because the pH values of the solutions were too low to enable
efficient coordination of the amines to the osmium center.
However, we now report a reaction sequence that overcomes
this hurdle, allows the formation of tetrahydrofuran (THF)
systems with complete control over both the relative and
absolute stereochemistries, and uses catalytic amounts of a
transition metal. We have discovered that vicinal diols derived
from 1,5-dienes will cyclize to form the THF ring system when
they are subjected to oxidative cyclization conditions (see 3!
2, Scheme 2). This cyclization reaction becomes a powerful
methodology because the starting diols can be obtained from
1,5-dienes in a regio- and stereoselective manner by using, for
example, the Sharpless asymmetric dihydroxylation (AD)
reaction.[6] We have proven unambiguously by HPLC analysis
that there is no loss of stereochemical integrity during the
cyclization process.
Although we could find no advantage to using cyclo-
hexene rather than isoprene, the choice of sacrificial alkene
becomes important in the purification as the product occa-
sionally coelutes with the diol derived from this second
alkene.
This investigation is related to the oxidative cyclization of
bishomoallylic alcohols using ReVII reagents (to give trans-
tetrahydrofurans)[8] and diols using CrVI reagents[9] (the yields
for this process are low), which have both been used
successfully in synthesis.[10] However, both sets of conditions
use stoichiometric amounts of the metal reagent to accom-
plish these transformations, and the advantages of catalytic
metal oxidants are clear.
Next, we examined the oxidative cyclization of a range of
diols derived from 1,5-dienes (Scheme 3). The diol starting
materials were made by a regio- and stereoselective dihy-
droxylation of a diene by using the Sharpless AD reaction—
although there are other viable routes to the diol precursors.
The cyclization was shown to be tolerant of a variety of
different substitution patterns on the alkene, diol unit, and
even the backbone (Scheme 3). The yields were good and the
products from the diol cyclizations were identical, as shown
by NMR spectroscopic analysis, to a (racemic) compound
formed by the cyclization of the corresponding 1,5-diene
under the conditions shown in Scheme 1. As expected, the
sequence is highly selective in each case for the formation of
cis-tetrahydrofurans. Moreover, the enantiomeric purity of
the diol was transferred completely to the THF product.
We then sought to exemplify this new cyclization reaction
in synthesis. Our target was cis-solamin, which is an annona-
ceous acetogenin with potent biological activity (e.g., cis-
solamin displays cytotoxicity and hemolytic activity).[11,12]
Brown and co-workers[12] recently reported a clever synthesis
of this molecule, whereby KMnO4 was used to oxidatively
cyclize a 1,5-diene precursor that was loaded with a chiral
The cyclization of diol 3 gave 2, which was identical to the
product obtained from the corresponding diene. This result
Scheme 2. Two-step procedure for the formation of enantiopure cis-
THF rings. Reagents andconditions: a) AD-mix- b; b) OsO4 (5 mol%),
Me3NO (4 equiv), trifluoroacetic acid(TFA; 6 equiv), acetone/H 2O, RT.
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Communications
cally identical to the product reported by Brown and co-
workers. This investigation constitutes a formal synthesis of
the target as 19 can be converted into (+)-cis-solamin in four
steps and 56% yield by using a literature precedent.[12] This
osmium-catalyzed oxidation methodology compares well with
the permanganate-based alternative (e.g., 15!18: obtained
in five steps and 46% overall yield from the method of Brown
and co-workers[12] compared with three steps and 70% overall
yield from our new approach).
To conclude, we present herein a new catalytic oxidation
reaction that promotes the cyclization of vicinal diols onto a
proximal alkene with a high level of stereocontrol. The diol
precursors are readily prepared as single enantiomers, which
means that the oxidation products (tetrahydrofurans) can also
be accessed in enantiopure form. This method is simple to
perform, high yielding, and tolerant of substitution on the
THF backbone. The usefulness of this method has been
proved in a short and extremely efficient (formal) synthesis of
(+)-cis-solamin.
Received: February 10, 2005
Revised: April 14, 2005
Published online: June 29, 2005
Scheme 3. Oxidative cyclization of various diols. Reagents and
Keywords: asymmetric catalysis · natural products · osmium ·
oxidation · stereoselectivity
conditions: a) OsO4 (5 mol%), Me3NO (4 equiv), TFA (6 equiv),
acetone/H2O, RT. Isoprene (5 equiv) was used as an additive in each
entry, except for 4 in which cyclohexene was used.
.
[1] E. Klein, W. Rojahn, Tetrahedron 1965, 21, 2353.
[2] J. E. Baldwin, M. J. Crossley, E.-M. M. Lehtonen, J. Chem. Soc.
Chem. Commun. 1979, 918; D. M. Walba, M. D. Wand, M. C.
Wilkes, J. Am. Chem. Soc. 1979, 101, 4396.
auxiliary to control the absolute stereochemistry of the
product.
This literature route was used to prepare compound 15 in
four steps (Scheme 4). The ester group was then reduced and
a regioselective AD reaction was performed on hydroxy-
substituted diene 16 to yield 17 in 86% yield from 15 and with
> 90% ee. The key oxidative cyclization reaction of 17
worked well and gave THF product 18 in 81% yield. This
product was subsequently transformed into tosylate 19
(> 90% ee as determined by HPLC), which was spectroscopi-
[3] P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org.
Chem. 1981, 46, 3936; V. Piccialli, N. Cavallo, Tetrahedron Lett.
2001, 42, 4695; V. Piccialli, T. Caserta, Tetrahedron Lett. 2004, 45,
303.
[4] M. de Champdore, M. Lasalvia, V. Piccialli, Tetrahedron Lett.
1998, 39, 9781; T. J. Donohoe, J. J. G. Winter, M. Helliwell, G.
Stemp, Tetrahedron Lett. 2001, 42, 971.
[5] T. J. Donohoe, S. Butterworth, Angew. Chem. 2003, 115, 978;
Angew. Chem. Int. Ed. 2003, 42, 948.
[6] For a review, see: H. C. Kolb, M. S. VanNieuwenhze, K. B.
Sharpless, Chem. Rev. 1994, 94, 2483.
[7] Preliminary studies have shown that the vicinal diol must be
intact for cyclization to occur: monoprotected derivatives of 4
and bishomoallylic alcohols gave no THF products under these
cyclization conditions.
[8] S. H. Tang, R. M. Kennedy, Tetrahedron Lett. 1992, 33, 5299;
F. E. McDonald, T. B. Towne, J. Am. Chem. Soc. 1994, 116, 7921;
F. E. McDonald, T. B. Towne, C. C. Schultz, Pure Appl. Chem.
1998, 70, 355.
[9] D. M. Walba, G. S. Stoudt, Tetrahedron Lett. 1982, 23, 727.
[10] E. J. Corey, D.-C. Ha, Tetrahedron Lett. 1988, 29, 3171; Y.
Morimoto, K. Muragaki, T. Iwai, Y. Morishita, T. Kinoshita,
Angew. Chem. 2000, 112, 4248; Angew. Chem. Int. Ed. 2000, 39,
4082; for a review of Re reagents used in oxidative cyclization
reactions, see: E. Keinan, S. C. Sinha, Pure Appl. Chem. 2002, 74,
93.
[11] C. Gleye, P. Duret, A. Laurens, R. Hocquemiller, A. CavØ, J. Nat.
Prod. 1998, 61, 576; H. Makabe, Y. Hattori, A. Tanaka, T.
Orltani, Org. Lett. 2002, 4, 1083; J. Defretin, C. Gleye, D. Cortes,
X. Franck, R. Hocquemiller, B. Figadere, Lett. Org. Chem. 2004,
1, 316.
Scheme 4. The synthesis of cis-solamin. Reagents andconditions:
a) diisobutylaluminum hydride; b) AD-mix-a,(DHQ)2PHAL; c) OsO4
(5 mol%), Me3NO (4 equiv), TFA (6 equiv), isoprene (5 equiv),
acetone/H2O, RT; d) Bu2SnO, p-toluenesulfonyl chloride (TsCl),
benzene. (DHQ)2PHAL=hydroquinine 1,4-phthalazinediyl diether.
[12] A. R. L. Cecil, Y. Hu, M. J. Vincent, R. Duncan, R. C. D. Brown,
J. Org. Chem. 2004, 69, 3368.
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Angew. Chem. Int. Ed. 2005, 44, 4766 –4768