The synthesis and development of 2,5-disubstituted tetrahydrofurans as potential scaffolds for diversity-oriented synthesis

Article abstract of DOI:10.1016/j.tetlet.2012.02.100

The synthesis of 2,5-disubstituted tetrahydrofurans from donor silylmethylcyclopropanes (without bearing an acceptor function) is described. Their further elaboration via a wide range of synthetic transformations is presented to highlight the potential of this method and the resulting THFs as potential scaffolds for diversity-oriented synthesis.

Full text of DOI:10.1016/j.tetlet.2012.02.100

Tetrahedron Letters 53 (2012) 2392–2395
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Tetrahedron Letters
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The synthesis and development of 2,5-disubstituted tetrahydrofurans as
potential scaffolds for diversity-oriented synthesis
⇑
Adrian P. Dobbs , Jonathan Dunn
School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 2,5-disubstituted tetrahydrofurans from donor silylmethylcyclopropanes (without bear-
ing an acceptor function) is described. Their further elaboration via a wide range of synthetic transforma-
tions is presented to highlight the potential of this method and the resulting THFs as potential scaffolds
for diversity-oriented synthesis.
Received 6 December 2011
Revised 10 February 2012
Accepted 23 February 2012
Available online 3 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Silylmethylcyclopropane
Donor cyclopropane
2,5-Disubstituted tetrahydrofuran
Flemming oxidation
The 2,5-disubstituted tetrahydrofuran (THF) motif is found
widely throughout nature, notably appearing in highly topical and
active Annonaceous acetogenins and many polyether-containing
compounds and antibiotics. Robust routes to access this structural
motif, and particularly ones which also incorporate functionality
for additional elaboration are currently of great interest. Herein
we report one such route, and several subsequent transformations
of the resultant 2,5-disubstituted THF, illustrating its potential as a
novel scaffold for diversity-orientated synthesis.
We have had a long standing interest in organosilicon chemistry,
and particularly utilising the b-effect of silicon to stabilise adjacent
carbocations during a reaction.1–5 As part of this, we reported
the reaction of silylmethylcyclopropanes with glyoxals in the pres-
ence of a Lewis acid, to give 2,5-disubstituted tetrahydrofurans
(Scheme 1).6 Depending upon the exact nature of the reaction con-
ditions, it was possible to obtain either the cis or trans-substitution
the opportunity for the introduction of a variety of functional groups
and also the means to couple the THF to another molecule. It is gen-
erally accepted that ketones are slow to react under standard Wittig
reaction conditions, but far more reactive in the Horner–Wadsworth–
Emmons reaction, which also has the practical advantage that the
phosphorus by-products are relatively water soluble. Deprotona-
tion of triethyl phosphonoacetate with sodium hydride in diethyl
ether followed by addition of the trans-diastereoisomer of THF 1
gave the alkene in an excellent 96% yield as a 1:1.2 mixture of alkene
geometric isomers 2 (Scheme 2). Separation of the isomers was
achieved by column chromatography. NOE studies confirmed that
no epimerisation of the C-5 proton had occurred and the relative
stereochemistry of the THF ring remained trans but identification
of the different alkene geometries was inconclusive, and thus it
was impossible to state whether the E/Z isomer was the major one.
pattern. It was envisaged that the presence of the
a-ketone and
the silicon moiety would render this a useful scaffold for diversity-
oriented synthesis. Therefore, we have investigated the potential
of this scaffold for further elaboration and our findings are reported
herein.
SnCl4
SiiPr3
Ph
First we investigated transformations involving the keto func-
tionality; all are novel transformations of this particular scaffold.
CH2Cl2, 0 °C
O
O
H
H
H
O
O
i
+
Pr3Si
Ph
H
85%
(i) Horner–Wadsworth–Emmons reactions
It was envisaged that the a-ketone could be converted into the
trisubstituted alkene using a Wittig or related reaction, presenting
SnCl4
O
SiiPr3
Ph
CH2Cl 2, -78 °C
O
H
81% (1.6:1)
⇑
Corresponding author. Tel.: +44 0207 882 5251; fax: +44 0207 882 7427.
E-mail address: a.dobbs@qmul.ac.uk (A.P. Dobbs).
Scheme 1. Synthesis of 2,5-disubstituted tetrahydrofurans.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.02.100

A. P. Dobbs, J. Dunn / Tetrahedron Letters 53 (2012) 2392–2395
2393
Ph
SiMe2Ph
O
O
1
Ph
SiMe2Ph
O
EtO2C
EtO2C
P(OEt)2
O
Et2O, 0 °C to rt
CO 2Et
96%
NaH
2
Et2O, 0 °C
O
P(OEt)2
Scheme 2. The Horner–Wadsworth–Emmons reaction employing a-ketotetrahydrofurans.
MgCl
SiiPr3
Ph
SiiPr3
Ph
O
O
THF, 14 h, rt
85%, dr 2.5 : 1
OH
O
O
3
4
M
b)
a)
O
O
O
H
H
O
O
CH2
H2C
H
Ph
Ph
CH2
Nu
Nu
Nu
Ph
Scheme 3. Grignard addition to a-ketotetrahydrofurans under possible (a) chelation or (b) Felkin–Anh control.
(ii) Nucleophilic addition
yield (Scheme 4). Given that it would be possible to form both E-
and Z-enolates 4, it was unsurprising that the product 5 was ob-
tained as two (inseparable) diastereoisomers (1.5:1).
Nucleophilic addition of an organometallic reagent to the ke-
tone was next investigated. Addition of allylmagnesium chloride
to the trans THF diastereoisomer 3 gave the desired tertiary alcohol
4 in 85% yield (Scheme 3) as a mixture of diastereoisomers (2.5:1).
The higher proportion of one diastereoisomer over the other is be-
lieved to be the result of chelation control of the addition7 through
the THF oxygen, favouring the anti arrangement of the C-5 proton
and hydroxy group in the product.
(iv) Reduction of the carbonyl group
Reduction of the ketone occurred readily using sodium borohy-
dride with both the dimethylphenyl 1 and triisopropyl 3 contain-
ing THFs, giving the 2-hydroxymethyl THFs 6 and 7 in excellent
yields. The secondary alcohol 7 could be converted into the ester
8 in moderate yield using acetic anhydride (Scheme 5). It is inter-
esting to note that the products obtained both from the reduction
with sodium borohydride and from the nucleophilic addition with
allylmagnesium chloride were obtained in the same diastereo-
meric ratio (2.5:1), even though sodium borohydride is considered
to be a far weaker chelating agent.8
The direct reduction of the ketone to the methylene moiety was
also attempted. The one-step Clemmensen reduction using amal-
gamated zinc (prepared by stirring a 5% mercuric chloride solution
with metallic zinc for 1 h) resulted in the decomposition of the
starting material. The Salvador-modified ultrasound-assisted
Clemmensen reduction9 using zinc in acetic acid also led to degra-
dation of the starting THF (Scheme 6).
(iii) Enolate formation
In addition to forming a new C–C bond at the carbonyl carbon
atom, it should also be possible to form a new C–C bond at the
a-position to the carbonyl group via the corresponding enolate.
The presence of only one enolisable proton would remove any che-
mo- or regioselectivity issues, and would generate a quaternary
centre in the product. When reacting 3 with LDA in THF at
À78 °C and quenching with MeI, only decomposition of the start-
ing material was observed. However, employing sodium hydride
as the base with 3 at room temperature and again quenching with
MeI resulted in formation of the methyl substituted THF 5 in 76%
It was considered possible that the THF was incompatible with
the strongly acid reaction conditions. As an alternative, non-acidic
route, it was proposed to reduce the ketone to the alcohol and fol-
low this with a Barton-McCombie radical deoxygenation. Conver-
sion of the diastereomeric mixture of alcohols derived from the
NaBH4 reduction into the methyl xanthate 9 was achieved with
carbon disulfide, methyl iodide and sodium hydride in tetrahydro-
furan at 0 °C. Treatment of the methyl xanthate with tri-n-butyltin
hydride and AIBN in toluene at reflux gave the 2,5-disubstituted
THF 10 in an overall yield of 50% from the ketone (Scheme 7).
NOE results confirmed the THF was still the single trans-diastereo-
isomer across the ring. Thus, even though the initial cyclisation is
currently limited to the use of highly reactive glyoxalates as the
aldehyde component, this sequence permits access to the cyclisa-
tion products of simpler, less reactive aldehydes.
Ph
SiiPr3
O
3
O
Na H
THF, rt
Me I
Ph
SiiPr3
Ph
SiiPr3
O
THF, rt
76%
O
Me
H
4
O
O
5
Na
Scheme 4. Enolate formation and subsequent C–C bond formation in
-ketotetrahydrofurans.
a

2394
A. P. Dobbs, J. Dunn / Tetrahedron Letters 53 (2012) 2392–2395
NaBH4, MeOH
Ph
SiPhMe2
Ph
HO
SiPhMe2
O
O
0 °C to rt
O
1
6
86%, dr 2.5 : 1
O
O
O
SiiPr3
Ph
HO
SiiPr3
Ph
SiiPr3
NaBH4, MeOH
Ph
O
3
O
O
DMAP , CH2Cl2
57%, dr 2.6 : 1
°
0
C to rt
O
O
8
7
77%, dr 2.6 : 1
O
Scheme 5. Reduction of a ketone moiety to the corresponding alcohol, and subsequent esterification.
that the entire procedure could be carried out in one pot with per-
acetic acid as the oxidant, although the authors have noted that the
bromine-based method should be avoided if a ketone functionality
Zn(Hg),
HCl (conc)
was present.11 No product was isolated from the reaction of the
a-
reflux
PhH, 12 h
Ph
SiMe2Ph
Ph
SiMe2Ph
keto THF with mercuric acetate and peracetic acid (Scheme 8a),
although the reaction mixture showed the presence of several
phenylmercury species indicating that the electrophilic aromatic
substitution had occurred. Suspecting that the presence of the ke-
tone was the problem, removal by reduction followed by benzyl
protection of the resulting alcohol gave THF 11 as a mixture of dia-
O
O
Zn
O
AcOH/H2O
1
sonication
Scheme 6. Attempted Clemmensen reductions.
stereoisomers. Desilylation of the protected
a-hydroxy-THF now
proceeded well (Scheme 8b) and in high yield, to give a mixture
of diastereoisomers 12.12 Fortunately, purification by column chro-
matography gave a pure sample of one diastereoisomer, in 32%
yield; the remaining mass balance comprised the other inseparable
diastereomers. We are currently examining further uses for the
alcohol moiety in these compounds.
In summary, we have demonstrated that 2-keto-5-silylmethyl
substituted tetrahydrofurans are versatile building blocks for a
variety of transformations and offer a unique opportunity for the
rapid generation of molecular complexity. These are currently un-
der investigation for a variety of applications, including in natural
product synthesis and will be reported in due course.
In addition to the many transformations available via the ke-
tone, it is also entirely feasible to modify the THF adducts via the
silicon moiety. Indeed, when devising our route to THFs, the incor-
poration of the silicon moiety was always to fulfil a dual role: to
stabilise any build of positive charge at the b-carbon during the
cyclisation step (via the b-effect) and to act as a masked alcohol
in the THF product,10 while remaining chemically inert throughout
a range of other transformations, as already demonstrated.
Fleming reported several methods for the conversion of the
phenyldimethylsilyl group using Br+, Hg2+ and H+ as electrophiles;
the advantages of mercuridesilylation or bromodesilylation being
NaB H4, MeOH
CS2, MeI, NaH
SiPhMe2
Ph
SiPhMe2
Ph
HO
O
O
°
THF 0 °C
0
C to rt
H
H
H
H
O
69%,
1
86%, dr 2.5 : 1
dr 2.5 : 1
Ph
SiPhMe2
Bu3SnH, AIBN
Ph
SiPhMe2
O
O
S
H
H
H
H
reflux, PhH
84%
O
9
10
MeS
Scheme 7. Reduction and subsequent radical deoxygenation.
Hg(OAc)2
Ph
Ph
SiPhMe2
Ph
OH
(a)
(b)
O
1
O
AcOOH/AcOH
O
O
i) NaBH4, MeOH,
0
oC to rt
Hg(OAc)2
Ph
Ph
BnO
SiPhMe2
SiMe2Ph
OH
O
1
O
O
12
AcOOH/AcOH
ii) BnBr, NaH,
THF, rt, 16 h
O
BnO
11
32% + other diastereomers
77% over two steps
Scheme 8. Oxidative removal of the silicon moiety.

A. P. Dobbs, J. Dunn / Tetrahedron Letters 53 (2012) 2392–2395
2395
( )-(5-(Benzyloxy(phenyl)methyl)tetrahydrofuran-2-yl)methanol 12.11
To stirred solution of ((5-(benzyloxy(phenyl)methyl)tetrahydrofuran-2-
Acknowledgments
a
yl)methyl)dimethyl(phenyl)silane (0.12 g, 0.31 mmol) in peracetic acid
(30% wt sol. in acetic acid, 3 mL) was added in one portion mercury(II)
acetate (0.11 g, 0.35 mmol). The reaction was stirred for 2 h then washed with
water (10 mL), sat. NaS2O3 (10 mL) and sat. NaHCO3 (10 mL). The aqueous layer
was extracted with CH2Cl2 (3 Â 10 mL) and the organic fractions were
combined, washed with brine (10 mL), dried (MgSO4), filtered and
concentrated in vacuo to yield the impure product as a white solid (0.19 g).
Purification by flash column chromatography [silica gel, gradient elution 50%
hexane/diethyl ether – 100% diethyl ether] isolated a single diastereoisomer of
the title compound (0.03 g, 0.10 mmol, 32%) as a colourless viscous oil; Rf 0.14
We wish to thank the following: EPSRC (studentship to J.D.) and
the EPSRC National Mass Spectrometry Service, Swansea, UK for
running high resolution mass spectra.
References and notes
1. Dobbs, A. P.; Martinovic´, S. Tetrahedron Lett. 2002, 43, 7055.
2. Dobbs, A. P.; Guesné, S. J. J.; Martinovic´, S.; Coles, S. J.; Hursthouse, M. B. J. Org.
Chem. 2003, 68, 7880.
[80% diethyl ether/hexane]; m
max(film)/cmÀ1 3439 (O–H), 3062, 3030, 2870,
1495, 1454, 1062 (C–O); dH (400 MHz; CDCl3) 1.55–1.67 (3H, m, overlapping
signals CH2 C-4 and CHaHb C-3 THF), 1.73–1.82 (1H, m, CHaHb C-3 THF), 2.16
(1H, br s, OH), 3.43 (1H, app dd, J = 11.1 and 5.1, CHaHbOH), 3.66 (1H, app br d,
J = 11.7, CHaHbOH), 4.04–4.10 (1H, m, CH C-2 THF), 4.24–4.31 (2H, m,
overlapping signals CH C-5 THF and HCOBn), 4.34 (1H, d, J = 12.1 PhCHaHbO),
4.56 (1H, d, J = 12.1, PhCHaHbO), 7.24–7.39 (10H, m, Ar); dC (100.6 MHz; CDCl3)
27.3 (CH2, C-3 THF), 28.9 (CH2, C-4 THF), 65.0 (CH2, CH2OH), 70.6 (CH2,
PhCH2O), 80.1 (CH, C-2 THF), 82.5 (CH, C-5 THF), 84.0 (CH, HCOBn), 127.6 (p-CH
Ar), 127.9 (2 Â o-CH Ar), 128.0 (2 Â o-CH Ar), 128.2 (p-CH Ar), 128.4 (2 Â m-CH
Ar), 128.5 (2 Â m-CH Ar), 138.5 (ipso-C Ph), 139.0 (ipso-C Ph); LRMS (EI+, m/z):
298 ([M]+, 1%), 197 (26), 101 (23), 91 (100), 57 (28); HRMS (ESP, m/z) 316.1902
[M+NH4]+, C19H26O3N requires 316.1907.
3. Dobbs, A. P.; Guesné, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003, 1740.
4. Dobbs, A. P.; Parker, R. J.; Skidmore, J. Tetrahedron Lett. 2008, 49, 827.
5. Chio, F. K.; Warne, J.; Gough, D.; Penny, M. J.; Green (néeMartinovic´), S.; Coles,
S. J.; Hursthouse, M. B.; Jones, P.; Hassall, L.; McGuire, T. M.; Dobbs, A. P.
Tetrahedron 2011, 67, 5107.
6. Dunn, J.; Motevalli, M.; Dobbs, A. P. Tetrahedron Lett. 2011, 52, 6974–6977.
7. Still, W. C.; McDonald, J. H. Tetrahedron Lett. 1980, 21, 1031.
8. Calo, V.; Nacci, A. Tetrahedron Lett. 1998, 39, 3825.
9. Salvador, J. A. R.; Melo, M.; Neves, A. S. C. Tetrahedron Lett. 1993, 34, 357.
10. Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
11. Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J. Chem. Soc.
Perkin Trans. 1 1995, 317.
12. Representative procedures for the preparation of the 2,5-disubstituted THFs
and the sodium borohydride mediated reduction have already been
published.6