A double donor-activated Ruthenium(VII) catalyst: Synthesis of enantiomerically pure THF-Diols

Article abstract of DOI:10.1002/anie.200903090

Chemical Equation Presented Double, double, no toll and trouble: Enantiomerically pure tetrahydrofurans are obtained with high position- and stereoselectivity through a ruthenium(Vll)-catalyzed oxidative cyclization of 5,6dihydroxy alkenes (see scheme TPAP = tetrapropylammonium perruthenate). A dual activation modifies the reactivity and increases the carbophilicity of the transition metal so that an otherwise unusual dioxygenation with perruthenate occurs.

Full text of DOI:10.1002/anie.200903090

Angewandte
Chemie
DOI: 10.1002/anie.200903090
Heterocycles
A Double Donor-Activated Ruthenium(VII) Catalyst: Synthesis of
Enantiomerically Pure THF-Diols**
Huan Cheng and Christian B. W. Stark*
Dedicated to Professor Hans-Ulrich Reissig on the occasion of his 60th birthday
Chiral tetrahydrofuran diols (THF-diols, Figure 1) represent
a characteristic structural motif in a range of biogenetically
unrelated natural product families.[1] The most prominent
Figure 1. General structure of THF-diols—a central motif in different
classes of biologically active compounds. R,R’=different substituents,
the asterisks indicate stereogenic centers.
Scheme 1. Envisaged ruthenium-catalyzed oxidative cyclization of 5,6-
dihydroxy alkenes to furnish enantiomerically pure THF-diols (path-
way A) and direct oxidative diene cyclization yielding diastereochemi-
cally pure THF-diols (pathway B). L=ligand.
classes are the polyether ionophores, the annonaceous
acetogenines, and some terpenoid metabolites.[2] In addition,
2,5-disubstituted THFs constitute the central repeating unit of
certain artificial ion channels.[3] Owing to the prevalence of
this structural motif in biologically active natural and non-
natural compounds, a number of methods for the stereose-
lective synthesis of THF-diols have been developed.[4] Stra-
tegically, the stereochemistry is often established in an initial
chemical transformation (e.g. by dihydroxylation or epoxida-
tion of a suitable olefinic precursor) followed by a separate
cyclization reaction. For instance, biomimetic[5] di- and
polyepoxide cyclizations have been established as a powerful
means for the construction of THF-diols[6] and related
polyethers.[7]
We recently described the development of ruthenium
tetroxide catalyzed[8] oxidative cyclization[9] reactions of 1,5-
dienes[10] and related substrate classes.[11] This methodology
allows for the efficient construction of THF-diols in high
yields (up to 98%) and with excellent control of relative
stereochemistry (generally > 95:5 d.r.;[12] pathway B in
Scheme 1). The aim of the present study was to investigate
a pathway to enantiomerically pure THF-diols[13] which
connects the establishment of stereogenic centers with the
ring-forming reaction. Thus, 5,6-dihydroxy olefins (Scheme 1,
pathway A) were identified as suitable precursors for the
desired enantiomerically pure heterocycles. The synthetic
strategy for this investigation is outlined in Scheme 1
(pathway A) in comparison to the direct oxidative cyclization
(pathway B in Scheme 1) producing diastereomerically pure
THF-diols. Based on our previous investigations,[10,11] we
focused on ruthenium catalysts. To our knowledge, ruthenium
catalysts have not been used for the oxidative cyclization of
related bishomoallylic alcohols. Other transition-metal-based
oxidants are known to promote similar reactions, however,
usually stoichiometric amounts of toxic oxidants have to be
used. Moreover, often moderate diastereoselectivities as well
as varying amounts of constitutional isomers and other
unwanted side products are obtained.[4e,f,8,14] In general, a
high degree of (chemo-)selectivity has to be attained for the
oxidative cyclization of this type of bishomoallylic alcohols:
The catalyst should neither oxidize any alcohols (mono or
vicinal diols) nor react with olefins in an intermolecular
fashion. On the other hand, for the envisaged heterocycliza-
[*] H. Cheng, Prof. Dr. C. B. W. Stark
Freie Universitꢀt Berlin, Institut fꢁr Chemie und Biochemie
Takustrasse 3, 14195 Berlin (Germany)
À
Prof. Dr. C. B. W. Stark
tion an intramolecular oxidative addition to the C C double
Universitꢀt Leipzig, Institut fꢁr Organische Chemie
Johannisallee 29, 04103 Leipzig (Germany)
Fax: (+49)341-97-36599
E-mail: cstark@uni-leipzig.de
Homepage: http://www.uni-leipzig.de/~stark/
bond is desired. This reaction has to occur under participation
of the oxygen atom of the proximal hydroxy group and should
possibly proceed stereoselectively. To meet these multilay-
ered requirements a double-activation concept[15]—for exam-
ple, by means of a ruthenium diester intermediate—was
regarded as particularly suitable.
[**] We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (STA 634/1-2) and the Otto-Rꢂhm-
Gedꢀchtnisstiftung for financial support of this research.
On the basis of these considerations, we tested a set of
mild ruthenium-based oxidants under different reaction
conditions (co-oxidant, solvent, temperature, etc.) for their
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903090.
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Table 1: TPAP-catalyzed oxidative cyclization of 5,6-dihydroxyalkenes.[a]
ability to promote the selective
oxidative cyclization of 5,6-dihy-
droxy alkenes. For this investigation
substrate 1 was chosen as a model
substrate (Table 1, Entry 1). Intri-
guingly, TPAP[16] (tetrapropylam-
monium perruthenate) one of the
mildest oxidation catalysts tested
provided the desired cyclization
product 2 in good yield. Impor-
tantly, the heterocyclic product
was obtained with high stereoselec-
tivity furnishing two new stereogen-
ic centers. Thus, the enantiomeri-
cally pure alcohol 1 was converted
into the desired THF-diol in enan-
tiomerically pure form with perfect
transfer of stereochemical informa-
tion (> 95:5 d.r., 99:1 e.r.; Table 1,
Entry 1). No other stereoisomers
could be detected.
Entry
Substrate
Product
Yield [%][b]
d.r.[c]
e.r.[d]
>95:5
99:1
1
2
63
68
>95:5
88:12
>95:5
>99:1
3
4
5
52
72
46
>95:5
98:2
>95:5
>99:1
>95:5
>99:1
6
7
8
37
62
65
TPAP is a well-established cata-
lyst for the highly chemoselective
oxidation of primary and secondary
alcohols to carbonyl products. Even
a number of bishomoallylic alcohols
(5-hydroxy alkenes) have cleanly
been converted into the corre-
sponding carbonyl compounds
without any addition or cyclization
>95:5
97:3
>95:5
>99:1
[16]
À
to the C C double bond.
This
>95:5
98:2
9
68
diametric reactivity indicates that
the
double-activation
concept
appears to be operative in the
observed cyclization reaction (see
below). Quite remarkably, even
under conditions closely resembling
those of the extraordinarily mild
Ley oxidation[16] using NMO (N-
>95:5
>99:1
10
11
47
28
>95:5
85:15[e]
methylmorpholine-N-oxide) as
a
co-oxidant smooth ring formation
took place.
[a] Reaction conditions: 5 mol% TPAP, 1.2 equiv NMO, wet CH2Cl2, room temperature, 1–24 h. Bz=
benzoyl, NPht=phthalimide, TBDPS=tert-butyldiphenylsilyl, Bn=benzyl. [b] Yield of isolated product
after chromatographic purification. [c] Diastereomeric ratio (d.r.) determined by NMR spectroscopy of
crude reaction mixtures. [d] Enantiomeric ratio (e.r.) determined by chiral HPLC with a Chiralpak AD-
Column. [e] The enantiomeric ratio (e.r.) of the starting material was 85:15.
We next investigated the gener-
ality of this reaction pathway and to
which extent the stereoselectivity
depends on the specific stereochem-
ical arrangement and substitution
pattern around the two reacting
À
subunits (diol and olefin) (Table 1). Therefore, a range of
starting materials were subjected to the optimized reaction
conditions using 5 mol% TPAP in wet CH2Cl2, tert-butanol,
or tert-amyl alcohol (see Table 1 and Supporting Information
for details). Generally, the 5,6-dihydroxy olefins underwent
smooth cyclization furnishing the desired THF-diols in good
to high yields. Most importantly, irrespective of the starting
material excellent stereoselectivities were obtained. With
respect to the olefin subunit, synthetically useful results were
achieved irrespective of the degree of substitution and
stereochemistry of the reacting double bond. Moreover, it is
worth mentioning that C C double bonds which are not in an
appropriate distance from the vicinal diol do not undergo an
intramolecular oxidative cycloaddition nor any intermolecu-
lar oxidation (Table 1, Entries 3 and 9). Thus, remote olefins
are compatible with the oxidative cyclization conditions
described. In addition, generation of a THF-ring is apparently
favored over an equally feasible formation of a six-membered
heterocycle (Table 1, Entry 3).
Mechanistically, we believe that the diol starting material
initially undergoes formation of a ruthenium(VII) monoester
similar to TPAP-catalyzed alcohol oxidations. For this first
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step two regioisomeric intermediates A and A’ (Scheme 2)
are conceivable, the ratio of which will primarily be controlled
by steric factors.[16] Instead of mediating an alcohol oxidation,
the high Lewis acidity of the metal center is assumed to drive
acyclic monoester—leads to a highly ordered and rigid
transition state which is in turn the basis for an effective
transfer of stereochemical information.
In summary, we have presented a new catalytic method
for the stereocontrolled oxidative cyclization of 5,6-dihy-
droxy alkenes to yield THF-diols in high diastereo- and
enantiopurity. Up to two new chiral centers are created in
these cyclization reactions. Our investigation describes the
first ruthenium-catalyzed oxidative cyclization of this class
of substrates and uncovers an unprecedented reactivity of
ruthenium(VII) catalysts. A mechanistic rationale and
preliminary experiments in support of this model are also
described. Thus, intramolecular donor activation changes
the transition metal into a more carbophilic and, in this
respect, more electrophilic species and hence allows for the
unusual perruthenate-mediated dioxygenation reaction.[17]
Received: June 8, 2009
Published online: February 1, 2010
Scheme 2. Mechanistic hypothesis for the ruthenium(VII)-catalyzed oxida-
tive cyclization of 5,6-dihydroxy alkenes. NMM=N-Methylmorpholine.
Keywords: cyclization · oxidation · ruthenium ·
.
[1] a) Polyether Antibiotics: Naturally Occurring Acid Ionophores
(Ed.: J. W. Westley), M. Dekker, New York, 1983, Vol. I
(“Biology”), Vol. II (“Chemistry”); b) R. Hoppe, H.-D. Scharf,
Synthesis 1995, 1447 – 1464; c) F. Q. Alali, X.-X. Liu, J. L.
McLaughlin, J. Nat. Prod. 1999, 62, 504 – 540; d) P. Metz, Top.
Curr. Chem. 2005, 244, 215 – 249.
[2] a) W. F. Tinto, S. McLean, W. F. Reynolds, C. A. G. Carter,
Tetrahedron Lett. 1993, 34, 1705 – 1708; b) B. Bian, I. A. van Al-
tena, Aust. J. Chem. 1998, 51, 1157 – 1165; c) B. Chen, K.
Kawazoe, T. Takaishi, M. Itoh, Y. Takeda, O. K. Kodzhimatov, O.
Ashurmetov, J. Nat. Prod. 2000, 63, 362 – 365.
[3] a) H. Wagner, K. Harms, U. Koert, S. Meder, G. Boheim, Angew.
Chem. 1996, 108, 2836 – 2839; Angew. Chem. Int. Ed. Engl. 1996,
35, 2643 – 2646; b) U. Koert, L. Al-Momandi, J. R. Pfeifer,
Synthesis 2004, 1129 – 1146.
[4] For reviews see: a) T. L. B. Boivin, Tetrahedron 1987, 43, 3309 –
3362; b) J. C. Harmange, B. Figadꢀre, Tetrahedron: Asymmetry
1993, 4, 1711 – 1754; c) U. Koert, Synthesis 1995, 115 – 132;
d) M. C. Elliott, E. Williams, J. Chem. Soc. Perkin Trans. 1 2001,
2303 – 2340; e) E. Keinan, S. C. Sinha, Pure Appl. Chem. 2002,
74, 93 – 105; f) J. Hartung, M. Greb, J. Organomet. Chem. 2002,
661, 67 – 84.
[5] a) Z. A. Hughes-Thomas, C. B. W. Stark, I. U. Bꢁhm, J. Staun-
ton, P. F. Leadlay, Angew. Chem. 2003, 115, 4613 – 4616; Angew.
Chem. Int. Ed. 2003, 42, 4475 – 4478; b) A. Bhatt, C. B. W. Stark,
B. M. Harvey, A. R. Gallimore, Y. A. Demydchuk, J. B. Spencer,
J. Staunton, P. F. Leadlay, Angew. Chem. 2005, 117, 7237 – 7240;
Angew. Chem. Int. Ed. 2005, 44, 7075 – 7078; c) A. R. Gallimore,
C. B. W. Stark, A. Bhatt, B. M. Harvey, Y. Demydchuk, V.
Bolanos-Garcia, D. J. Fowler, J. Staunton, P. F. Leadlay, J. B.
Spencer, Chem. Biol. 2006, 13, 453 – 460.
stereoselectivity · tetrahydrofurans
an intramolecular interaction with the neighboring hydroxy
group. Thus, both intermediates A and A’ will rapidly be
converted into the same cyclic ruthenium(VII) diester B
(Scheme 2). Within this key intermediate the doubly acti-
vated transition metal is now electrophilic and carbophilic
enough to undergo a [3+2]-cycloaddition to the proximal
À
C C double bond. Finally, hydrolysis liberates the THF-diol
product and a ruthenium(V) species which is reoxidized with
NMO to the active catalyst (Scheme 2).
Our mechanistic model rests upon the assumption that
only the ruthenium(VII) diester B (Scheme 2) exhibits an
À
appropriate reactivity to productively interact with the C C
double bond. This hypothesis is already supported by the fact
that olefins are generally compatible with TPAP-catalyzed
alcohol oxidations.[16] However, to seek further experimental
support to corroborate this assumption and to investigate
whether a covalent dual activation is indeed essential for the
oxidative cyclization, we prepared the monomethylether 23
and subjected this bishomoallylic alcohol to our standard
cyclization conditions (Scheme 3). Indeed, this simple struc-
tural alteration leads to a complete switch of mechanistic
pathways. Now, the secondary alcohol is oxidized cleanly to
the corresponding ketone 24 leaving the double bond
untouched. Therefore, this control experiment provides
support in favor of our proposed reaction mechanism and
the involvement of ruthenium(VII) diesters as reactive
intermediates (B in Scheme 2). In addition, it may be
speculated that a cyclic ruthenium diester—other than an
[6] a) J. C. Suhadolnik, T. R. Hoye, J. Am. Chem. Soc. 1985, 107,
5312 – 5313; b) H. Wagner, U. Koert, Angew. Chem. 1994, 106,
1939 – 1941; Angew. Chem. Int. Ed. Engl. 1994, 33, 1873 – 1875;
c) H. Wagner, M. Stein, U. Koert, Tetrahedron Lett. 1994, 35,
7629 – 7632; d) T. J. Beauchamp, J. P. Powers, S. D. Rychnovsky,
J. Am. Chem. Soc. 1995, 117, 12873 – 12874.
[7] I. Vilotijevic, T. F. Jamison, Science 2007, 317, 1189 – 1192.
[8] B. Plietker, Synthesis 2005, 2453 – 2472.
Scheme 3. Control experiment: use of a monomethylether.
[9] V. Piccialli, Synthesis 2007, 2585 – 2607.
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
[10] a) S. Roth, S. Gꢁhler, H. Cheng, C. B. W. Stark, Eur. J. Org.
[14] a) D. M. Walba, G. S. Stoudt, Tetrahedron Lett. 1982, 23, 727 –
730; b) E. J. Corey, D.-C. Ha, Tetrahedron Lett. 1988, 29, 3171 –
3174; c) R. M. Kennedy, S. Tang, Tetrahedron Lett. 1992, 33,
3729 – 3732; d) F. E. McDonald, T. B. Towne, J. Am. Chem. Soc.
1994, 116, 7921 – 7922; e) T. B. Towne, F. E. McDonald, J. Am.
Chem. Soc. 1997, 119, 6022 – 6028; f) Y. Morimoto, K. Muragaki,
T. Iwai, Y. Morishita, T. Kinoshita, Angew. Chem. 2000, 112,
4248 – 4250; Angew. Chem. Int. Ed. 2000, 39, 4082 – 4084; g) T. J.
Donohoe, S. Butterworth, Angew. Chem. 2005, 117, 4844 – 4846;
Angew. Chem. Int. Ed. 2005, 44, 4766 – 4768; h) T. J. Donohoe,
G. H. Churchill, K. M. P. Wheelhouse (nꢂe Gosby), P. A. Glos-
sop, Angew. Chem. 2006, 118, 8193 – 8196; Angew. Chem. Int. Ed.
2006, 45, 8025 – 8028.
[15] S. Roth, C. B. W. Stark, Chem. Commun. 2008, 6411 – 6413.
[16] W. P. Griffith, S. V. Ley, G. P. Whitcombe, A. D. White, J. Chem.
Soc. Chem. Commun. 1987, 1625 – 1627; S. V. Ley, J. Norman,
W. P. Griffith, S. P. Marsden, Synthesis 1994, 639 – 666; R. Lenz,
S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1997, 3291 – 3292; P.
Langer, J. Prakt. Chem. 2000, 342, 728 – 730.
Chem. 2005, 4109 – 4118; b) S. Gꢁhler, S. Roth, H. Cheng, A.
Rupp, L. O. Haustedt, C. B. W. Stark, Synthesis 2007, 2751 –
2754.
[11] a) S. Roth, C. B. W. Stark, Angew. Chem. 2006, 118, 6364 – 6367;
Angew. Chem. Int. Ed. 2006, 45, 6218 – 6221; b) S. Gꢁhler,
C. B. W. Stark, Org. Biomol. Chem. 2007, 5, 1605 – 1614.
[12] The resulting THF-diols can be desymmetrized enzymatically.
For a recent application of this strategy in natural product
synthesis, see: H. Gꢁksel, C. B. W. Stark, Org. Lett. 2006, 8,
3433 – 3436.
[13] For an enantioselective oxidative cyclization using chiral phase-
transfer catalysis, see: R. C. D. Brown, J. F. Keily, Angew. Chem.
2001, 113, 4628 – 4630; Angew. Chem. Int. Ed. 2001, 40, 4496 –
4498. For auxilary controlled diastereoselective oxidative cycli-
zations, see: a) D. M. Walba, C. A. Przybyla, C. B. Walker, J. Am.
Chem. Soc. 1990, 112, 5624 – 5625; b) P. J. Kocienski, R. C. D.
Brown, A. Pommier, M. Procter, B. Schmidt, J. Chem. Soc.
Perkin Trans. 1 1998, 9 – 39; c) A. R. L. Cecil, R. C. D. Brown,
Org. Lett. 2002, 4, 3715 – 3718; d) R. C. D. Brown, C. J. Bataille,
R. M. Hughes, A. Kenney, T. J. Luker, J. Org. Chem. 2002, 67,
8079 – 8085.
[17] For a TPAP-catalyzed oxidative cyclization of 1,5-dienes yield-
ing racemic THF-diols, see: V. Piccialli, T. Caserta, Tetrahedron
Lett. 2004, 45, 303 – 308.
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