Hydrogen bonding control in the oxidative cyclisation of 1,5-dienes

Article abstract of DOI:10.1016/S0040-4039(00)02225-5

The regioselective dihydroxylation of a series of functionalised polyenes is described. Under acidic conditions, the osmate ester derivatives obtained from oxidation with OsO₄/TMEDA undergo an intramolecular cyclisation reaction forming functionalised tetrahydrofurans with high stereoselectivity and in good yield. The generality of this method is illustrated with an application to the synthesis of a bis-tetrahydrofuran ring system.

Full text of DOI:10.1016/S0040-4039(00)02225-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 971–974
Hydrogen bonding control in the oxidative cyclisation of
1,5-dienes
a,
a
a,†
b
Timothy J. Donohoe, * Jonathan J. G. Winter, Madeleine Helliwell and Geoffrey Stemp
a
Department of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK
b
SmithKlineBeecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
Received 14 October 2000; accepted 5 December 2000
Abstract—The regioselective dihydroxylation of a series of functionalised polyenes is described. Under acidic conditions, the
osmate ester derivatives obtained from oxidation with OsO /TMEDA undergo an intramolecular cyclisation reaction forming
4
functionalised tetrahydrofurans with high stereoselectivity and in good yield. The generality of this method is illustrated with an
application to the synthesis of a bis-tetrahydrofuran ring system. © 2001 Elsevier Science Ltd. All rights reserved.
Recently we reported that the combination of osmium
tetroxide and TMEDA forms a reagent that is a willing
hydrogen bond acceptor. Oxidation of a series of cyclic
In fact, the two oxidations illustrated below show that
the directed dihydroxylation reaction is capable of con-
trolling not only regioselectivity, but also gives (syn)
1
2
3
allylic alcohols and amides with this reagent gives a
directed dihydroxylation reaction resulting in the for-
mation of syn stereoisomers that are difficult to access
by other means. We have also reported preliminary
results on the oxidation of allylic alcohols containing
more than one alkene unit and have shown that hydro-
gen bonding is a viable means of controlling regioselec-
stereoselectivity in both cyclic and acyclic systems.
Dihydroxylation of alkenes 1 and 3 under more standard
conditions (UpJohn- cat. OsO , NMO, acetone/water)
4
did not show any comparable regio- or stereoselectivity.
For example, the di-substituted alkene within compound
1 was oxidised exclusively (with no control of stereose-
lectivity) while the C-6,7 and C-10,11 alkenes within
compound 3 were oxidised in approximately equal pro-
portions (again with no control of stereoselectivity). The
results shown in Scheme 1 illustrate that this method is
particularly useful and unique for directing the oxidation
of multifunctional compounds.
1
tivity. As an extension of these studies we had cause to
oxidise a series of allylic trichloroacetamides using the
OsO /TMEDA combination (Scheme 1). As expected,
4
the reactions were regioselective forming the diol prod-
ucts derived from attack at the proximal alkene. In
each case the oxidation regime involved addition of the
transition metal and TMEDA in dichloromethane at
−
78°C, followed by hydrolysis of the resulting osmate
ester with acidic methanol.
We then attempted the regioselective oxidation of alke-
nes 5 and 7, fully expecting to achieve good yields of
Scheme 1. Reagents: (i) OsO (1 equiv.), TMEDA (1 equiv.), CH Cl , −78°C; then MeOH, HCl, rt.
4
2
2
*
Corresponding author. E-mail: t.j.donohoe@man.ac.uk
Author to whom correspondence regarding the crystal structures should be addressed.
†
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02225-5

9
72
T. J. Donohoe et al. / Tetrahedron Letters 42 (2001) 971–974
oxidative cyclisation of the intermediate osmate ester
complexes.
The oxidative cyclisation of other 1-trichloroacetamide-
2
,6-dienes was investigated and we discovered that the
cyclisation reaction was fairly general with yields rang-
ing from 44 to 63% (Scheme 3). The corresponding
4
allylic alcohols also cyclised to tetrahydrofurans, but in
5
yields that were 10–20% lower.
Scheme 2. Reagents: (i) OsO (1 equiv.), TMEDA (1 equiv.),
4
The structures of compounds 8 and 14 were proven by
CH Cl , −78°C; then MeOH, HCl, rt; (ii) (MeO) CMe , TFA.
2
2
2
2
6
X-ray crystallography on derivatives (Fig. 1).
Finally, we also oxidised the farnesyl derivative 15 and
isolated the cyclised product in good yield, 72%
(
Scheme 4). In order to manipulate the structure, and
illustrate the utility of the methodology, we then pro-
tected the secondary alcohol (Ac O) and cleaved the
2
7g
alkene (Lemieux) to furnish a lactol. This compound
was oxidised to the lactone 17 using Jones reagent.
Given the widespread occurrence of tetrahydrofurans in
nature, and that bis-tetrahydrofuran structures are the
key constituents of a variety of acetogenin natural
products, we expect that this methodology will prove to
be of use in synthesis.
These types of oxidative cyclisation have been reported
Scheme 3. Reagents: (i) OsO (1 equiv.), TMEDA (1 equiv.),
4
7
before, most notably with potassium permanganate
CH Cl , −78°C; then MeOH, HCl, rt; (ii) Ac O, Et N,
2
2
2
3
8
and chromium trioxide, although a single recent report
CH Cl .
2
2
detailed the oxidative cyclisation of geranyl and neryl
acetates with osmium tetroxide while this work was in
progress. It is fair to say that, generally, such cyclisa-
tions can give fairly low yields of tetrahydrofuran prod-
ucts, probably because of over oxidation of the
substrate/reaction products.
the corresponding dihydroxylated products (Scheme 2).
While the initial osmylation proceeded as expected to
give osmate esters, decomplexation of these esters gave
not diol products, but high yields of the tetra-
hydrofurans 6 and 8 that had resulted from a further
9
Figure 1.
Scheme 4. Reagents: (i) OsO (1 equiv.), TMEDA (1 equiv.), CH Cl , −78°C; then MeOH, HCl, rt; (ii) Ac O; (iii) OsO (cat.)
4
2
2
2
4
quinuclidine, NaIO ; (iv) CrO , H SO , acetone.
4
3
2
4

T. J. Donohoe et al. / Tetrahedron Letters 42 (2001) 971–974
973
Figure 2.
In terms of mechanism we are confident that the reac-
tion initiates with a regioselective dihydroxylation of
the polyene, controlled by hydrogen bonding (in some
cases we have been able to fully characterise the result-
ing osmate esters). For the cyclisation process we
invoke addition of the OꢀOsꢁO fragment across the
remote alkene bond as originally proposed by Baldwin
References
1. Donohoe, T. J.; Moore, P. R.; Waring, M. J.; New-
combe, N. J. Tetrahedron Lett. 1997, 38, 5027.
2. (a) Donohoe, T. J.; Blades, K.; Moore, P. R.; Winter, J.
J. G.; Helliwell, M.; Stemp, G. J. Org. Chem. 1999, 64,
980; (b) Donohoe, T. J.; Blades, K.; Winter, J. J. G.;
Stemp, G. Tetrahedron Lett. 2000, 41, 4701.
2
1
0
for KMnO4. This process would involve reduction of
Os(VI) to Os(IV), and the cyclisation is possible
because the reacting partners are intramolecular. Subse-
quent hydrolysis of the osmate ester in situ would
produce the diol product. At this time, we do not have
any evidence to indicate the nature of the other ligands
on osmium as it undergoes the oxidative cyclisation and
it could be the case that acid serves to promote what-
ever ligand exchange is necessary to allow cyclisation to
occur. Alternatively, acid could protonate the oxo lig-
ands thus making the metal a better electrophile and
more reactive in the cyclisation. If this addition mecha-
nism is correct then we would expect the cyclisation to
be stereospecific with respect to addition across the
alkene (and this is certainly borne out by the oxidation
of 11 and 13). It is also worth noting that there is a
clear stereoselectivity for formation of a cis-tetra-
hydrofuran (Fig. 2). The preference for production of
cis-tetrahydrofurans is explained via reaction through
transition structure A; the intact glycol osmium bonds
help to enforce the cis stereochemistry across the incip-
ient five-membered ring.
3
4
. Donohoe, T. J.; Waring, M. J.; Newcombe, N. J. Tetra-
hedron Lett. 1999, 40, 6881.
. Diene 5 was prepared from commercially available ger-
anyl amine. The remaining substrates were prepared from
the transposed allylic alcohol via the Overman rearrange-
ment (1, 3, 11 and 13) or from the structurally analogous
allylic alcohol via the Mitsunobu reaction (using phthal-
imide nucleophile) followed by deprotection (MeNH2)
and acylation (Cl CCOCl) (9 and 15).
3
5
. We hypothesise that the lower yields with allylic alcohols
are a consequence of migration of the initially formed
osmate esters and that these rearranged esters then
hydrolyse rather than cyclise.
6
. Compounds 8, 10, 14 and 16 showed similar NMR
spectra and their structures are assigned by analogy. All
new compounds displayed spectroscopic data consistent
1
13
with their structures and were fully characterised ( H/ C
NMR, mass spectrometry, IR and HRMS or microanaly-
sis).
Representative procedure: Farnesyl trichloroacetamide 15
(
61 mg, 0.17 mmol) was dissolved in CH Cl (15 mL) and
2 2
cooled to −78°C under an atmosphere of nitrogen. To
this mixture was added TMEDA (19 mg, 0.17 mmol),
then osmium tetroxide (42 mg, 0.17 mmol). The solution
turned a dark brown and was allowed to warm to rt over
This method of cyclisation should prove relatively easy
to study because we know that osmium(VI) is the active
oxidising agent and we also know which alkene is
oxidised first. Indeed, this ability to separate the initial
osmylation reaction from the cyclisation event should
prove invaluable in developing and understanding the
method further, particularly with regard to catalytic
variants. The good yields recorded in this paper bode
well for the introduction of an efficient and stereoselec-
tive oxidation protocol based on the use of osmium and
using hydrogen bonding as a controlling element.
2
h, then concentrated to dryness in vacuo. The resulting
brown oily solid was redissolved in methanol and conc.
HCl (two drops) was added. This mixture was then
stirred for 2 h until a yellow precipitate had formed, then
the mixture was partially concentrated in vacuo to a
brown liquid. This material was loaded onto a column of
silica gel and purified by flash column chromatography to
give 16 (50 mg, 72% yield). Compound 16 was protected
as the mono-acetate under standard conditions (excess
Et N and Ac O in CH Cl ) producing a colourless oil (41
3
2
2
2
−
1
mg, 74% yield); wmax(film)/cm 3348, 2973, 1717 and
Acknowledgements
1522; lH (300 MHz; CDCl ) 1.08 (3H, s), 1.30 (3H, s),
3
1.43–1.60 (2H, m), 1.60 (3H, s), 1.68 (3H, s), 1.80–2.10
(
6H, m), 2.10 (3H, s), 2.22 (1H, br s), 3.54 (1H, dd, J 5.7
We thank the EPSRC and SmithKline Beecham for
funding this work. AstraZeneca, Pfizer and GlaxoWell-
come are thanked for unrestricted support which aided
the project. We also thank R. C. D. Brown for useful
and 14.7), 3.82 (1H, ddd, J 1.8, 5.1 and 14.7), 3.92 (1H,
t, J 6.5), 5.02 (1H, dd, J 1.8 and 5.6), 5.12 (1H, dd, J 5.9
and 7.0), and 7.38 (1H, br s); l (75 MHz; CDCl ) 17.6,
C 3
20.8, 21.6, 22.4, 23.7, 25.6, 25.8, 35.2, 40.3, 42.0, 72.8,
75.6, 83.5, 84.6, 124.4, 131.4, 162.2 and 170.9.
discussions.
.

9
74
T. J. Donohoe et al. / Tetrahedron Letters 42 (2001) 971–974
M.; Keily, J.; Kenney, A. Chem. Commun. 2000, 1735.
7. (a) Klein, E.; Rojahn, W. Tetrahedron 1965, 21, 2353; (b)
Walba, D. M.; Wand, M. D.; Wilkes, M. C. J. Am.
Chem. Soc. 1979, 101, 4396; (c) Walba, D. M.; Edwards,
P. D. Tetrahedron Lett. 1980, 21, 3531; (d) Spino, C.;
Weiler, L. Tetrahedron Lett. 1987, 28, 731; (e) Walba, D.
M.; Przybyla, C. A.; Walker, C. B. J. Am. Chem. Soc.
8. Walba, D. M.; Stoudt, G. S. Tetrahedron Lett. 1982, 23,
727.
9. Piccialli, V. Tetrahedron Lett. 2000, 41, 3731. Oxidation
of 5 using 5 mol% OsO4 (Piccialli’s conditions) gave
compound 6 in 30% yield, illustrating the potential of this
method to be used with catalytic OsO4.
1
990, 112, 5624; (f) Kocienski, P. J.; Brown, R. C. D.;
Pommier, A.; Procter, M.; Schmidt, B. J. Chem. Soc.,
Perkin Trans. 1 1998, 9; (g) Brown, R. C. D.; Hughes, R.
10. Baldwin, J. E.; Crossley, M. J.; Lehtonen, E.-M. M. J.
Chem. Soc., Chem. Commun. 1979, 918.
.