A novel oxidative cyclisation onto vinyl silanes

Article abstract of DOI:10.1039/c0cc01342k

A novel osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendant vinyl silane affords THFs that contain silicon functionality at the ring junction. When the cyclisation occurs onto a vinyl benzyldimethylsilyl group, the resulting silyl group can act as a masked hydroxyl group and undergo a Fleming-Tamao type oxidation at a later stage to form the corresponding lactol. The scope of this reaction can also be extended beyond 1,2-diols and applied to the cyclisation of α-hydroxy-sulfonamides and α-hydroxy-amides.

Full text of DOI:10.1039/c0cc01342k

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A novel oxidative cyclisation onto vinyl silanesw
Timothy J. Donohoe,*a Paul C. M. Winship,a Ben S. Pilgrim,a Daryl S. Walterb and
a
Cedric K. A. Callensz
Received 11th May 2010, Accepted 17th August 2010
DOI: 10.1039/c0cc01342k
A novel osmium-catalysed oxidative cyclisation of 1,2-diols
bearing a pendant vinyl silane affords THFs that contain silicon
functionality at the ring junction. When the cyclisation occurs
onto a vinyl benzyldimethylsilyl group, the resulting silyl group
can act as a masked hydroxyl group and undergo a Fleming–
Tamao type oxidation at a later stage to form the corresponding
lactol. The scope of this reaction can also be extended
beyond 1,2-diols and applied to the cyclisation of a-hydroxy-
sulfonamides and a-hydroxy-amides.
Scheme 1 The osmium-catalysed oxidative cyclisation under Lewis
We have previously shown that vicinal diols and amino
alcohols derived from 1,5-dienes will cyclise in the presence
of a catalytic amount of osmium to form 2,5-cis-THFs and
pyrrolidines with excellent stereoselectivity.1,2 This oxidative
cyclisation required an acid and a catalytic amount of Os(VI),
which was provided by the in situ dihydroxylation of a
‘‘sacrificial alkene’’ (usually trans-cinnamic acid) by Os(VIII).
Recently this process was improved significantly by the
introduction of pyridine-N-oxide (PNO) as a reoxidant capable
of oxidizing Os(IV) to Os(VI) but not to unwanted Os(VIII), thus
eliminating the need for a sacrificial alkene.3 It was also found
that the addition of a catalytic amount of citric acid further
improved the reaction, presumably by stabilizing Os(VI) with
respect to disproportionation in acidic media.4
acid conditions.
the osmium-catalysed oxidative cyclisation is an inverse electron
demand [4+2] cycloaddition between the osmate ester, and
the pendant alkene (Scheme 1, transition structure 2).6
Consequently it was predicted that vinyl silanes, despite an
increase in steric bulk would provide sufficiently electron-rich
p-bonds to enable a successful oxidative cyclisation. Pleasingly,
we can report herein that a range of vinyl silanes will undergo
the osmium-catalysed oxidative cyclisation to form the
corresponding silyl substituted cis-THFs.7
Our initial investigations concentrated on the cyclisation of
terminal vinyl silane 6. This substrate was easily accessible by
the sequential dihydroxylation of commercially available
4-pentenal followed by subsequent Seyferth–Gilbert homo-
logation using the Bestmann–Ohira reagent (Scheme 2).
Regioselective hydrosilylation of the resulting terminal alkyne
furnished cyclisation precursor 6.8
More recently, it was discovered that replacing the Brønsted
acid promoter with a catalytic amount of Lewis acid [either
Zn(OTf)2 or Cu(OTf)2] resulted in higher yielding reactions
that proceeded nearly an order of magnitude faster than
before (Scheme 1).5 Under these improved conditions, the
osmium loading could be reduced to as little as 0.2 mol%.
Furthermore, these mildly acidic cyclisation reactions were
found to tolerate a range of acid sensitive functional groups
when a pH 6.5 phosphate buffer was incorporated. Under
these conditions, methoxymethyl ether (MOM), p-methoxy-
benzyl (PMB) and tert-butyl dimethyl silyl (TBS) protected
primary alcohols, and tert-butyl carbamate (Boc) protected
amines remained intact throughout the cyclisation.
Oxidative cyclisation of 6 using the recently-developed
Lewis acid conditions furnished the corresponding THF 7 in
96% yield (Scheme 3).y
Scheme
2 Synthesis of a cyclisation precursor. Reagents and
Attention turned to the possibility of performing the
cyclisation onto heteroatom-substituted pendant alkenes that
would have been unstable under previous acidic cyclisation
conditions. It is proposed that one of the key components of
conditions: (i) OsO4 (5.0 mol%), NMO, H2O/THF/tBuOH
(1 : 10 : 8), rt, then H3CCOC(N2)PO(OEt)2, K2CO3, MeOH, rt,
66% (over 2 steps); (ii) Cp*Ru(MeCN)3PF6 (2.0 mol%), HSiMe2Ph,
CH2Cl2, 0 1C to rt, 86%.
a Department of Chemistry, University of Oxford,
Chemistry Research Laboratory, Mansfield Road, Oxford,
OX1 3TA, UK. E-mail: timothy.donohoe@chem.ox.ac.uk
b GlaxoSmithKline, New Frontiers Science Park South, Harlow,
Essex, CM19 5AW, UK
w Electronic supplementary information (ESI) available: Experimental
procedures and NMR data. See DOI: 10.1039/c0cc01342k
z Author to whom correspondence regarding the X-ray crystal
structure should be addressed.
Scheme 3 Novel oxidative cyclisation onto a heteroatom-substituted
alkene.
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The cis 2,5-relationship was proven by X-ray crystal
structure analysis, which is consistent with the hypothesised
chelated transition structure 2 (Scheme 1).7,9 To our knowledge,
this is the first reported example of an oxidative cyclisation
onto a heteroatom-substituted alkene promoted by a metal–oxo
species. Attempts to apply previous cyclisation conditions to
the cyclisation of 6 [5.0 mol% K2OsO4ꢀ2H2O, PNO, citric
acid, acetone : water : trifluoroacetic acid (9 : 1 : 5)], reduced
the yield to 61%.
Using an analogous approach to that shown in Scheme 2, a
range of vinyl silanes were synthesised in 3 steps from
commercially available 4-enals (Scheme 4). Upon subjection
of these vinyl silanes to Lewis acid cyclisation conditions,
THFs 9, 11 and 13 were formed in excellent yields. Again, the
resulting THFs exhibited a cis 2,5-relationship as expected.10
The application of organosilanes as masked hydroxyl
groups has been widely reported in recent years.11 However,
our attempted oxidations of the 2-dimethylphenylsilyl THFs
were unsuccessful under Fleming–Tamao conditions, resulting
in either no reaction or over-oxidation to a lactone.12 At this
point, our attention turned to the cyclisation of vinyl silanes
bearing a benzyldimethylsilyl group which can be readily
oxidised using mild conditions.13 This transformation would
enable the silyl-substituted THFs formed in the oxidative
cyclisation to act as masked lactols. With this in mind, vinyl
benzyldimethylsilanes with different cyclisation initiators were
synthesised from the corresponding terminal alkynes [with
Cp*Ru(MeCN)3PF6, HSiBnMe2, CH2Cl2]. Pleasingly, 1,2-
diol 14, a-hydroxy sulfonamide 16 and a-hydroxy amide 18
all cyclised onto the vinyl benzyldimethylsilane in excellent
yields (Scheme 5).10
Scheme 5 Cyclisation of different initiators.
Scheme 6 Fleming–Tamao oxidation of protected THF.
expected lactol 21 as a mixture of isomers (Scheme 6).15
Despite this initial success, significant amounts of proto-
desilylation product 22 were still observed. In order to suppress
this side reaction, we adapted an approach originally reported
by Trost et al., whereby tetrabutylammonium fluoride was
added via syringe pump in order to maintain a low fluoride
concentration. This slow addition protocol, in combination
with anhydrous urea–hydrogen peroxide (UHP) led to the
formation of 21 in good yield (Table 1). Crucially, smaller
amounts of protodesilylation were observed.
Initial attempts to oxidise 15 using standard Fleming–
Tamao conditions resulted in immediate protodesilylation
(with retention) following the addition of tetrabutylammonium
fluoride (TBAF); this process afforded the corresponding
2,5-cis-THF in 78% yield.14 We propose that this unusually
fast rate of protodesilylation occurs due to the a-hydroxyl
group acting as either an intramolecular nucleophile for silicon
or a proton source. Therefore, it was found that subjecting
benzyl-protected THF 20 to the same Fleming–Tamao conditions
(the addition of tetrabutylammonium fluoride, followed by
aqueous hydrogen peroxide) led to the formation of the
With these optimised conditions available, oxidation of the
benzyl protected THFs 24 and 26 also provided the corres-
ponding lactols as mixtures of cyclic and open chain isomers.
Pleasingly, treatment of the lactol intermediates with PPTS in
MeOH/CH2Cl2 furnished the desired lactol ethers in good
yields as a mixture of diastereomers (Scheme 7).
An alternative approach to the formation of silyl-substituted
THFs was to dihydroxylate a vinyl silane precursor followed
by oxidative cyclisation onto
a pendant alkene. This
approach was taken with diol 28 which was formed by doubly
hydrosilylating commercially available 1,5-hexadiyne [with
Cp*Ru(MeCN)3PF6, HSiBnMe2, CH2Cl2], followed by mono-
dihydroxylation of the resulting diene [with OsO4 (5.0 mol%),
4-methylmorpholine N-oxide, water/tetrahydrofuran/tert-
butanol (1 : 10 : 8)]. In this case, the pendant alkene is also
a vinyl silane and the pseudo-trans-diaxial steric interaction
between the two benzyldimethylsilyl groups during cyclisation
might be expected to be unfavourable. Consequently, it was
unclear whether this interaction would cause the osmium-
mediated oxidative cyclisation to deviate from consistently
forming THFs with cis-selectivity or supress the cyclisation
altogether. Using a slightly higher catalyst loading, diol 28 was
subject to standard cyclisation conditions and furnished THF
29 in 51% yield after 24 h (Scheme 8). The relative stereo-
chemistry of the benzyldimethylsilyl groups was proven to be cis
by NOE enhancements on the corresponding mono-acetate.
Scheme 4 Cyclisations of a range of vinyl silanes.
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Table 1 Optimisation of the Fleming–Tamao oxidation
Entry
Reagents and conditions
Yield of 21 (%)
Yield of 2216 (%)
1
2
3
TBAF, THF, 40 1C, 0.5 h, then H2O2, MeOH, KHCO3, 40 1C, 1 h
TBAF, THF, 40 1C, 0.5 h then UHP, MeOH, KHCO3, 40 1C, 1 h
TBAF (over 30 min) THF, 40 1C, then UHP, MeOH, KHCO3, 40 1C, 1 h
43
64
74
32
24
15
Notes and references
y General experimental procedure: Potassium osmate dihydrate (mol%
as specified) was added to a solution of the cyclisation substrate
(1.0 eq.), PNO (2.0 eq.), citric acid (0.75 eq.) and zinc triflate
(0.50 eq.) in MeCN/H2O (3 : 2, 20 mL per mmol substrate) and the
resulting mixture was stirred at 60 1C until the reaction had gone to
completion by TLC. The reaction was quenched with Na2SO3 (0.1 g)
and after 30 minutes, water (20 mL) was added. The mixture was
extracted with EtOAc (3 ꢁ 25 mL) and washed with brine (20 mL).
The combined organic layers were dried over Na2SO4, filtered and the
solvent removed in vacuo to give the crude product which was purified
by flash column chromatography.
1 (a) T. J. Donohoe and S. Butterworth, Angew. Chem., Int. Ed.,
2005, 44, 4766; (b) T. J. Donohoe, G. H. Churchill, K. M.
P. Wheelhouse and P. A. Glossop, Angew. Chem., Int. Ed., 2006,
45, 8025.
2 This is in contrast to other metals where either stereoselectivity is
lower or stoichiometric quantities of metal are required. For
examples see: V. Piccialli, Synthesis, 2007, 2585–2607.
3 T. J. Donohoe, K. M. P. Wheelhouse, P. J. Lindsay-Scott,
P. A. Glossop, I. A. Nash and J. S. Parker, Angew. Chem., Int.
Ed., 2008, 47, 2872.
Scheme 7 Oxidation of the benzyldimethylsilyl group.
4 P. Dupau, R. Epple, A. A. Thomas, V. V. Fokin and
K. B. Sharpless, Adv. Synth. Catal., 2002, 344, 421.
5 T. J. Donohoe, P. C. M. Winship and D. S. Walter, J. Org. Chem.,
2009, 74, 6394.
Scheme 8 Double-silyl cyclisation.
6 For
a related inverse electron demand cycloaddition see:
L. Domingo, Eur. J. Org. Chem., 2000, 2265–2272.
7 The THF products in this paper are referred to as cis based upon
the relative stereochemistry of the two carbon substituents at C2
and C5. However, the mono-silyl-substituted THFs would be
officially designated trans under IUPAC nomenclature guidelines.
8 B. M. Trost and Z. T. Ball, J. Am. Chem. Soc., 2001, 123, 12726.
9 X-Ray crystallography data are available in the ESIw.
10 In each case, the relative stereochemistry proven by NOE
enhancements.
11 I. Fleming, R. Henning, D. C. Parker, H. E. Plaut and P. E.
J. Sanderson, J. Chem. Soc., Perkin Trans. 1, 1995, 317.
12 It is thought that the unexpected lactone product originates from a
Baeyer–Villiger type oxidation of the intermediate lactol.
13 B. M. Trost, Z. T. Ball and K. M. Laemmerhold, J. Am. Chem.
Soc., 2005, 127, 10028.
14 Protodesilylation of 15 gave a compound that was spectro-
scopically identical to 3, formed previously from the cyclisation
onto a terminal alkene (see ref. 5).
15 Acetylating the complex mixture of 21 provided the open chain
ketone as a single compound in 98%.
16 Protodesilylation again occurred with retention of stereochemistry
to afford a compound spectroscopically identical to the product
obtained upon doubly benzylating compound 3.
This result further demonstrates the stereochemical rigidity of
the osmium-mediated oxidative cyclisation.
To conclude, we have extended the scope of the osmium-
mediated oxidative cyclisation by performing the first such
cyclisations by metal–oxo species onto heteroatom-substituted
alkenes. This process is stereoselective for the formation of
silyl-substituted cis-THFs and proceeds with excellent yields.
We have also demonstrated the potential of benzyldimethylsilyl-
substituted THFs to act as masked lactols, which can be
oxidised under mild conditions at a later stage. Furthermore,
this methodology can be applied beyond 1,2-diols as cyclisation
initiators and has been extended to both a-hydroxy-sulfonamides
and a-hydroxy-amides.
We would like to thank the EPSRC/Pharma Organic
Synthetic Chemistry Studentships program and St John’s
College, Oxford for supporting this project and GlaxoSmithKline
for financial support. We would also like to thank the Oxford
Chemical Crystallography Service for instrumentation.
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7312 Chem. Commun., 2010, 46, 7310–7312
This journal is The Royal Society of Chemistry 2010