Diastereoselective titanocene-catalyzed oxidative cyclization of bishomoallylic alcohols

Article abstract of DOI:10.1055/s-2001-16779

Bishomoallylic alcohols are converted in good yields and diastereoselectivity into tetrahydrofuranols and tetrahydropyranols by Cp₂TiCl₂/t-butyl hydroperoxide/activated 4? molecular sieves system.

Full text of DOI:10.1055/s-2001-16779

LETTER
1479
Diastereoselective Titanocene-Catalyzed Oxidative Cyclization of
Bishomoallylic Alcohols
Alessandra Lattanzi,* Giorgio Della Sala, Maurizio Russo, Arrigo Scettri
Dipartimento di Chimica, Università di Salerno 84081 Baronissi (Salerno), Italy
Fax +39(0)89-965296; E-mail: lattanzi@unisa.it
Received 8 May 2001
sterically hindered titanocene 2c [(±)Ethylen(4,5,6,7-tet-
rahydro-1-indenyl)dichlorotitanium(IV)], more sensitive
to moisture, was employed in the presence of activated 4Å
molecular sieves.
Abstract: Bishomoallylic alcohols are converted in good yields and
diastereoselectivity into tetrahydrofuranols and tetrahydropyranols
by Cp2TiCl2/t-butyl hydroperoxide/activated 4Å molecular sieves
system.
Key words: epoxidation, cyclization, metallocenes, tetrahydrofura-
nols, tetrahydropyranols
OH
Me
Me
OH
Me
OH
2, CH2Cl2
Ph
+
Me
Me
O
Me
Ph TBHP
H
H
Ph
O
Metallocenes are commonly used catalysts for C-C bond
forming reactions1, while only few examples have been
reported in oxidation processes2 and in particular a very
low conversion to products has been showed when em-
ployed in the epoxidation of unfunctionalised alkenes.
1a
3a
4a
2a=Cp2TiCl2
2b=CpTiCl3
2c=rac-(EBTHI)2TiCl2
Scheme 1
Very recently we have disclosed a synthetically useful
catalytic activity of metallocenes in the epoxidation of al-
lylic alcohols3 with t-butyl hydroperoxide (TBHP) and in
the asymmetric sulfoxidation of prochiral sulfides using
(R)-BINOL as chiral ligand4.
Table 1 Oxidation of 1a by 2/TBHP Systemsa
Prompted by these results we decided to investigate the
reactivity of bishomoallylic alcohols in the presence of
CpnTiXm/TBHP systems. This research was devoted to
the achievement of a new and efficient procedure for the
oxidative cyclization of bishomoallylic alcohols to tet-
rahydrofuranols and tetrahydropyranols.
Rhenium5, chromium6, thallium7, vanadium8 complexes
have been employed in some oxidative cyclizations of
bishomoallylic alcohols, affording the cyclic ethers with
aMolar ratios employed: 1a/2/TBHP/ 1/0.05/1.5. bIn this reaction ac-
tivated 4Å molecular sieves were added. cIsolated yields. dThe diaste-
the regio and diastereoselectivity dependent on the pattern reoisomeric ratios were determined by 1H NMR analysis.
of substitution of the alkenols and the oxidation system.
As these oxacyclic compounds are widely found in many
It was less reactive compared to 2a,b and the diastereose-
lectivity was marginally inverted.
natural products, such as polyether antibiotics9 and are
valuable building blocks in synthetic organic chemistry10
The blank experiment (entry 5) confirmed that molecular
sieves do not catalyze the oxidative cyclization but their
presence is beneficial (entry 6) as the reaction time was re-
markedly reduced (compare with entry 2) and almost all
the starting material consumed.
new methods for their synthesis are in demand.
Initially, we investigated the oxidation of model com-
pound 1-phenylhexenol 1a with catalytic amounts of
some commercial titanocene chlorides and TBHP as oxy-
gen donor.
The different steric hindrance and electronic properties of
the titanocene chlorides had a limited influence on the
outcome of the reaction. Comparable yields and diastere-
oselectivities were observed with 2a and 2b. However, in
view of its cheapness we felt it appropiate to carry on our
investigation using 2a in the presence of activated molec-
ular sieves.
When the reaction was carried out at room temperature
(entry 1) in catalytic mode (5%mol of Cp2TiCl2) com-
pound 1a was poorly converted to the tetrahydrofuranol
3a and the tetrahydropyranol 4a. The main product 3a was
isolated in high cis/trans ratio, 4a showed an appreciable
diastereoselectivity11, while no trace of epoxide was de-
tected. When refluxing the reaction mixture (entry 2) the
conversion was greatly improved and the cis/trans ratios
were maintained. Catalyst 2b afforded similar results. The
A screening of different solvents (Table 2) showed a de-
crease of the conversion to the ethers and the diastereo-
Synlett 2001, No. 9, 1479–1481 ISSN 0936-5214 © Thieme Stuttgart · New York

1480
A. Lattanzi et al.
LETTER
selectivity of tetrahydrofuranol 3a in apolar media (n- ingly, when (R3 = Ph) (entry 5) the trans tetra-
hexane, toluene). Halogenated solvents and in particular hydropyranol 4 was exclusively obtained. The electron-
CH2Cl2 seemed to be the most suitable to perform the poor terminal alkenol in entry 6 did not react at all under
transformation12.
the conditions applied. It is worth pointing out that lina-
lool (entry 7) was regioselectively converted only to the
cyclic ethers without traces of the allylic epoxidation
product.
Table 2 Effect of Solvent on the Oxidative Cyclization of 1aa
These findings indicate that the selectivity in the epoxida-
tion is dominated by the electron density of the double
bond.
From a mechanistic point of view, it seems reasonable
a reaction pathway that involves chloride/t-butyl hydro-
peroxide ligand exchange leading to the formation of
a titanocene t-butylperoxy complex as postulated by
Halterman in a previous report14.
aMolar ratios employed: 1a/2a/TBHP/ 1/0.05/1.5 and activated 4Å
molecular sieves (400mg). bSee note c in Table 1. cSee note d in Table
1.
The stereochemical outcome of the overall process can be
explain through the coordination of the unsaturated alco-
hol to the metal centre, followed by oxygen transfer to
give an epoxyalcohol intermediate in a diastereoselective
way, which then undergoes fast cyclization to five- and
six-membered products.
In order to evaluate the range of application of the system
Cp2TiCl2/TBHP/4Å ms in the oxidative cyclization, some
bishomoallylic alcohols13 were submitted to the condi-
tions reported in Scheme 2.
A confirmation to this proposition has been supported by
the following experiment.
R5
R3
R3
R4
OH
OH
R5
R4
+
OH
Me
OBz
Ph
Cp2TiCl2, TBHP R1
Me
OBz
Ph
TBHP, 40 °C, CH2Cl2
2a, m.s., 22h
20%
R2
R1
R4
R5
O
R2
R1
O
R2
H
40 °C, ms
CH2Cl2
O
Me
Me
6
R3
5
like/unlike
1/1
1
4
3
NaOH
MeOH
Ph
Scheme 2
OH
Me
Me
Table 3 Cp2TiCl2/TBHP/4Å Molecular Sieves Catalyzed Oxidative
Cyclization of Alcohols 1a
O
3a
cis/trans
1/1
Scheme 3
The model compound 1a was O-benzoylated and then
submitted to the same reaction conditions. After 22h a 1/
1 mixture of like and unlike epoxides 6 were isolated in
20% yield. This low conversion was not surprising be-
cause titanocene chlorides are known to be poor catalysts
for the epoxidation of unfunctionalized olefins2 and this
result clearly showed the decisive role of coordination in
favouring the epoxidation of the double bond. Then, the
hydrolysis of the epoxyester 6 yielded tetrahydrofuranol
3a in 1/1 cis/trans ratio pointing out the complete differ-
ent regio and stereochemical outcome of the reaction.
aSee note a in Table 2. bConversion estimated by 1H NMR. c1% mol
of 2a was used. dSee note c in Table 1.eSee note d in Table 1.
The level of diastereoselectivity observed for tetrahydro-
furanols 3 is dependent to a certain extent on the nature of
the substituent R1 proximal to the hydroxy group (first
three entries). When R1 = cyclohexyl good cis/trans ratios
were achieved for both the regioisomers. The reaction can
be carried out even with quite low catalyst loading
(1%mol) furnishing after a longer reaction time compara-
ble conversion and stereoselectivities (entry 4). Interest-
In conclusion, we have disclosed an interesting and pre-
paratively useful catalytic activity of titanocenes. The sys-
tem Cp2TiCl2/TBHP/4Å molecular sieves can be a mild
and selective alternative to the literature precedents for the
oxidative cyclization of bishomoallylic alcohols having
an electron rich double-bond. In particular, as regards rhe-
nium oxide reagents we wish to point out that Re2O7/
5a,b
H5IO6 system and ReO3(OCOCF3)5c are characterized
Synlett 2001, No. 9, 1479–1481 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Titanocene-Catalyzed Oxidative Cyclization of Bishomoallylic Alcohols
1481
(8) a) Fukuyama, T.; Vranesic, B.; Negri, D. P.; Kishi, Y.
by significant acidity so that a base such as pyridine or
2,6-lutidine is necessary in order to prevent the formation
of acid catalyzed (non oxidative) cyclohydration by-prod-
ucts.
Tetrahedron Lett. 1978, 2741. b) Hashimoto, M.; Kan, T.;
Yanagiya, M.; Shirahama, H.; Matsumoto, T. Tetrahedron
Lett. 1987, 28, 5665. c) Hartung, J.; Schmidt, P. Synlett 2000,
3, 367.
(9) Figadere, B. Acc. Chem. Res. 1995, 28, 359.
(10) Lord, M. D.; Negri, J. T.; Paquette, L. A. J. Org. Chem. 1995,
60, 191.
(11) Compound 1a is oxidatively cyclized to 3a and 4a by the
system VO(acac)2/TBHP8c (10%mol) in CH2Cl2 at r.t.
furnishing 4a within 48h in 19% yield and without
diastereoselection.
(12) Coordinating and polar solvents such as: THF, DMF, CH3CN,
diethyl ether were not investigated. We had previously
observed in the epoxidation of allylic alcohols using
titanocenes/TBHP system3 (unpublished results) that these
solvents led to a small conversion to epoxyalcohols (in some
cases they prevented the reaction to occur). A strong
coordination of the solvent to the catalytic complex might be
responsible of the suppressed reactivity.
Then, Re2O7 is economically less convenient than
Cp2TiCl2 and in general has to be used in more than
stoichiometric amounts. Furthermore, methyl trioxorheni-
um/H2O2 system5f has proven to be particular efficient for
the conversion of suitable hydroxy alkenes into tetrahy-
drofuran derivatives; however, no diastereoselectivity
was found in the formation of cis/trans isomers.
Acknowledgement
MURST and CNR are gratefully acknowledged for financial sup-
port.
(13) Typical experimental procedure: To a solution of dry
CH2Cl2 under argon atmosphere at r.t. are sequentially added:
2 (5%mol), activated 4Å ms (400mg) and the bishomoallylic
alcohol 1 (1 mmol). After stirring for 10 min, TBHP (1.5
mmol, 5.5 M solution in decane) is added and the reaction
mixture refluxed. The reaction was monitored by TLC. At the
end of the reaction the solvent is concentrated under vacuum
and the crude mixture is purified by silica gel column
chromatography by elution with light petroleum/diethyl ether
mixtures. The spectroscopic data of compounds 3 and 4
matched with ones reported in the literature: Michael, J. P.;
Nkwelo, M. M. Tetrahedron 1990, 46, 2549; Mischitz, M.;
Hackinger, A.; Francesconi, I.; Faber, K. Tetrahedron 1994,
50, 8661; Méou, A.; Bouanah, A.; Archelas, A.; Zhang, X. M.;
Guglielmetti, R.; Furstoss, R. Synthesis 1990, 752; Méou, A.;
Bouanah, A.; Archelas, A.; Zhang, X. M.; Guglielmetti, R.;
Furstoss, R. Synthesis 1990, 681; ref. 8c and 7.
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Article Identifier:
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1437-2096,E;2001,0,09,1479,1481,ftx,en;D12001ST.pdf
Synlett 2001, No. 9, 1479–1481 ISSN 0936-5214 © Thieme Stuttgart · New York