A tandem C-H insertion-acetal cleavage sequence: Stereocontrolled synthesis of substituted tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2005.08.082

A short sequence involving Rh(II) mediated carbene insertion followed by Lewis acid promoted reductive acetal cleavage with Et₃SiH provides a stereoselective method for the construction of 2,3,5-trisubstituted tetrahydrofuran rings.

Full text of DOI:10.1016/j.tetlet.2005.08.082

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7175–7178
A tandem C–H insertion—acetal cleavage sequence:
stereocontrolled synthesis of substituted tetrahydrofurans
Amel Garbi,a John G. Mina,a Patrick G. Steel,a,* Tim Longstaff a and Sadie Vileb
aDepartment of Chemistry, University of Durham, Science Laboratories, South Road Durham DH1 3LE, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 13 July 2005; revised 10 August 2005; accepted 17 August 2005
Available online 6 September 2005
Abstract—A short sequence involving Rh(II) mediated carbene insertion followed by Lewis acid promoted reductive acetal cleavage
with Et3SiH provides a stereoselective method for the construction of 2,3,5-trisubstituted tetrahydrofuran rings.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Substituted tetrahydrofuran ring systems are a common
structural unit found in many bioactive natural prod-
ucts. Consequently, the development of strategies for
the stereocontrolled synthesis of substituted tetra-
hydrofurans is an area of considerable ongoing interest.1
In particular, the 3-hydroxy-2,5-disubstituted tetra-
hydrofuran skeleton is found in a number of natural prod-
ucts isolated from various marine sources (Fig. 1).2
These exhibit a broad range of biological profiles and
therefore have been the targets of a number of synthetic
programmes.
an acetal template followed by a reductive Lewis acid
mediated ring opening, that provides access to this core
structure (Scheme 1). Whilst both components of this
sequence have been the subject of a number of studies,
this combination represents a new strategy for the
stereocontrolled access to these valuable heterocycles.3–5
In preliminary experiments, the desired acetal template
could be constructed by the condensation of diol 5a with
pyruvic acid according to the procedure of Newman.6
Consistent with the simple principles of anomeric
stabilisation, the acetal 6a adopted a conformation plac-
ing the carboxylate group preferentially in the axial
position.7 The formation of the mixed anhydride and
In this letter, we describe a tandem reaction sequence,
involving an intramolecular C–H insertion reaction on
OH
OAc
OAc
O
O
Br
Br
Br
1
2
O
O
HO
H
O
OH
O
C H
5
11
O
OH
O
OH
3
4
Figure 1.
Keywords: Rhodium; C–H insertion; Reductive cleavage; Acetal; Tetrahydrofuran.
*
Corresponding author. Tel.: +44 01913342131; fax: +44 01913844737; e-mail: p.g.steel@durham.ac.uk
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.082

7176
A. Garbi et al. / Tetrahedron Letters 46 (2005) 7175–7178
O
OH
O
N2
insertion
reduction
R2
R1
R2
R1
O
R2
O
HO
R1
O
O
O
Scheme 1.
R1 R2
O
O
R1 R2
N2
R1
CH3
R1
i or ii.
iii.
O
iv.
CH3
O
O
O
O
O
OH
OH
R2
R2
CH3
HO2C
5
6
7
8
Entry
R 1
Me
Ph
H
R2
6
7
8
a
b
c
d
e
f
Me
H
38%
73%
---a
79%
84%
82%
85%
75%
70%
79%
27%
45%
15%
50%
20%
11%
33%
Ph
H
PhCH2
70%
68%
---a
4-NO2C6H4
H
H
4-NO 2C6H4
g
4-AcNHC6H4
H
---b
a Minor epimer isolated from the reaction mixture (6b:6c 3.5:1; 6e:6f 4:1). b. Obtained from 6b by nitration, reduction and
acetylation (63%)
Scheme 2. Reagents and conditions: (i) CH3COCO2H, PhH, Dowex 50WX8, D; (ii) CH3COCO2Me, BF3ÆOEt2, MeCN then NaOH, THF, H2O; (iii)
EtO2CCl, Et3N, THF, ꢀ15 ꢁC, then CH2N2, Et2O/THF, ꢀ5 ꢁC; (iv) Rh2(OAc)4, DCM, rt.
subsequent treatment with diazomethane then afforded
the desired diazoketone 7a. Slow addition of this to a
solution of Rh2(OAc)4 in DCM gave the desired bicyclic
acetal 8a, albeit in low yield (Scheme 2). Attempts to
optimise this result were complicated by the volatility
of this acetal and the lack of a chromophore for easy
analysis of reaction progress.
and the axial 4-H. Treatment of 9bx with Et3SiH and
BF3ÆOEt2 at 0 ꢁC afforded the tetrahydrofurans 10bx
and 11bx as a 3:7 mixture of isomers at C-2. These reac-
tions are believed to proceed via nucleophilic attack on
an intermediate oxocarbenium with the balance of reten-
tive and invertive pathways being controlled by factors
including the life-time of the initial ion pair and steric
hindrance to the approach of the nucleophile.8 Attempts
to control this selectivity through the use of DIBAL-H,
which is believed to reduce acetals via a retentive ring
opening mechanism via a coordinated complex, were
not successful, affording a complicated mixture of prod-
ucts. Similarly, variation of Lewis acid or reaction tem-
perature did not provide a significant enhancement in
selectivity. Consequently, we explored the effect of steric
bulk at C3 and prepared a range of simple derivatives to
probe the effect of controlling additions to the interme-
diate oxocarbenium ion. Satisfyingly, the use of a TBS
ether in the presence of TiCl4 as Lewis acid enabled
the ring opening reaction to be achieved in high yield
and high selectivity affording the 2,3-anti-3,5-syn prod-
uct 11 in good yields and selectivities (P95:65). The ste-
reochemistry was established by NOE experiments on
the corresponding acetates 10by and 11by (Scheme 3).
Consequently, the synthesis was repeated using 2-phen-
ylpropane-1,3-diol, and in this case it proved more
efficient to utilise the sequence reported by Wardrop
involving acetalisation of pyruvate ester and subsequent
hydrolysis. With the corresponding diazoketone 7b in
hand, attempts to optimise the insertion sequence
explored the reaction variables including catalyst,
solvent, concentration and the rate of addition. From
these studies it proved possible to achieve the insertion
reaction with the dioxanes with equatorial substituents
at C-4 in modest but reproducible yields of 35–45%
(Scheme 2). Variation of the electronic effect of the aryl
group had limited effect on the process. Attempts to
extend this result to the C-4 epimers (7c and 7f) were
considerably less efficient, presumably reflecting an
unfavourable conformation of the dioxane template.
Initial attempts to undertake Lewis acid promoted ace-
tal ring opening using the bicyclic ketone 8b failed,
and consequently this was reduced with NaBH4 to give
the endo alcohol 9bx as a single diastereoisomer. The
formation of the endo alcohol was confirmed by NOE
experiments on the corresponding acetate, which
showed strong correlations between the acetate CH3
This result can be rationalised by coordination of Lewis
acid to the more accessible oxygen atom to generate a
five-membered ring oxocarbenium ion. Subsequent
delivery of the hydride occurs to the ꢀinside faceꢁ of
this oxocarbenium ion in such a conformation that
both substituents reside in a pseudoequatorial orienta-
tion. Importantly, this approach maintains a staggered

A. Garbi et al. / Tetrahedron Letters 46 (2005) 7175–7178
7177
OR'
OR'
OR'
O
iv. or v.
CH3
i. ii. iii.
CH3
+
HO
O
R
HO
O
R
O
O
O
O
H
H
R
R
H
H
8
9
10
11
x R' = H; y R' = Ac; z R' = TBS
Scheme 3. Reagents and conditions: (i) NaBH4, MeOH (9b 87%, 9d 70%, 9e 84%, 9g 80%); (ii) AcCl, Et3N, DMAP, DCM (9by 75%); (iii) TBSOTf,
2,6-lutidine, DCM (9bz 60%, 9dz 85%, 9ez 65%, 9gz 89%); (iv) Et3SiH, BF3ÆOEt2, ꢀ78 ꢁC (10bx:11bx 7:3, 60%); (v) Et3SiH, TiCl4, ꢀ78 ꢁC (10bz:11bz
5:95, 77%; 10dz:11dz 5:95, 80%; 10ez:11ez 3:97, 79%; 10gz:11gz 13:87, 50%).
R
H
OR
OR
H
R
O
O
HO
HO
H
O
O
OTBS
H
H
R
R
OTBS
H
Scheme 4.
2. (1) Capon, R. J.; Barrow, R. A.; Rochfort, S.; Jobling, M.;
Skene, C.; Lacey, E.; Gill, J. H.; Friedel, T.; Wadsworth,
D. Tetrahedron 1998, 54, 2227–2242; (2) Norte, M.;
Fernandez, J. J.; Ruano, J. Z. Tetrahedron 1989, 45,
5987–5994; (3) Suzuki, T.; Koizumi, K.; Suzuki, M.;
Kurosawa, E. Chem. Lett. 1983, 1643–1644; (4) Quinoa,
E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53, 3642–
3644.
3. For recent overviews on intramolecular C–H insertion
processes see: Sulikowski, G. A.; Cha, K. L.; Sulikowski,
M. M. Tetrahedron: Asymmetry 1998, 9, 3145–3169;
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds:
from Cyclopropanes to Ylides; Wiley: Chichester, 1998;
Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861–2903; Doyle, M. P. Chiral dirhodium(II) carboxam-
idates for catalytic asymmetric synthesis. In Methodologies
in Asymmetric Catalysis; 2004; Vol. 880; pp 1–13.
4. For examples of the application of reductive cleavage of
bicyclic acetals as a route to heterocyclic systems see:
Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990,
46, 4595–4612; Kotsuki, H. Synlett 1992, 97–106; Rych-
novsky, S. D.; Dahanukar, V. H. Tetrahedron Lett. 1996,
37, 339–342; Fujiwara, K.; Amano, A.; Tokiwano, T.;
Murai, A. Tetrahedron 2000, 56, 1065–1080; Bogaczyk, S.;
Brescia, M. R.; Shimshock, Y. C.; DeShong, P. J. Org.
Chem. 2001, 66, 4352–4355; Barrero, A. F.; Roldan, E.;
Santiago, J. L. R.; Chahboun, R. Synlett 2003, 2313–2316;
Crimmins, M. T.; Siliphalvanh, P. Org. Lett. 2003, 5,
4641–4644.
arrangement between the C-1CH and C-2 OSiR3 in
3
the transition state structure and leads to the observed
2,3-anti stereochemistry.9 The alternative conformation
leading to attack anti to the C–OSi bond is additionally
disfavoured by steric interactions between the C-5 sub-
stituent and the bulky OTBS group (Scheme 4).
Having established the basic methodology, we then
probed the effect of different groups at C-5 of the
bicyclic acetal on both the insertion and ring fragmenta-
tion steps. Both aryl and alkyl groups work equally
efficiently. Whilst an electron withdrawing group on
the aryl ring or the alternative stereochemistry at this
C-4 of the acetal lowered the efficiency of the insertion
process neither variation has significant effect on the
stereochemical outcome of the ring cleavage reaction.
In all cases, the sequence produces the 2,3-anti-3,5-syn
tetrahydrofuran with good levels of stereocontrol.
In conclusion, we have demonstrated a short stereoselec-
tive sequence for the synthesis of 2,3,5 substituted
tetrahydrofurans.10 Work towards extending this meth-
odology to produce other stereochemistries and its
application towards the synthesis of target structures
containing this motif are in progress and will be
reported in due course.
5. Concurrent with our early endeavours, Wardrop reported
an identical C–H insertion approach en route to the
synthesis of the squalestatin and sordidin skeleton: War-
drop, D. J.; Velter, A. I.; Forslund, R. E. Org. Lett. 2001,
3, 2261–2264; Wardrop, D. J.; Forslund, R. E. Tetra-
hedron Lett. 2002, 43, 737–739; Wardrop, D. J.; Forslund,
R. E.; Landrie, C. L.; Velter, A. I.; Wink, D.; Surve, B.
Tetrahedron: Asymmetry 2003, 14, 929–940.
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for finan-
cial support of this work (CASE award to A.G.), the
EPSRC Mass Spectrometry Service for accurate mass
determinations, Dr. A. M. Kenwright for assistance with
NMR experiments and Dr. M. Jones for mass spectra.
6. Newman, M. S.; Chen, C. H. J. Org. Chem. 1973, 38,
1173–1177.
7. Kirby, A. J. The Anomeric Effect and Related Stereoelec-
tronic Effects at Oxygen; Springer: New York, 1983.
8. Yamamoto, Y.; Nishii, S.; Yamada, J. J. Am. Chem. Soc.
1986, 108, 7116–7117; Denmark, S. E.; Almstead, N. G. J.
Am. Chem. Soc. 1991, 113, 8089–8110; Mori, I.; Ishihara,
K.; Flippin, L. A.; Nozaki, K.; Yamamoto, H.; Bartlett,
References and notes
1. Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301–
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A. Garbi et al. / Tetrahedron Letters 46 (2005) 7175–7178
P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107–
219 ([MH]+, 100%), 201 (25%), 187 (62%), 173 (60%),
157 (9%), 130 (62%), 117 (19%), 104 ([PhCHCH2]+, 34%),
91([PhCH] +, 17%), 77 ([Ph]+, 12%). HRMS (ES+):
218.0865 (C13H14O3 requires 218.0941). 2-[40-(tert-Butyl-
dimethylsilanyloxy)-50-methyltetrahydrofuran-20-yl]-2-phen-
ylethanol 10bz, 11bz: To a solution of the TBDMS
protected alcohol (9bz) (70 mg, 0.21mmol) in CH 2Cl2
(15 mL), triethylsilane (Et3SiH, 0.05 mL, 0.315 mmol,
1.5 equiv) was added at ꢀ78 ꢁC followed by the dropwise
addition of a 1M solution of titanium tetrachloride
(TiCl4) in CH2Cl2 (0.030 mL, 0.252 mmol, 1.2 equiv).
The reaction mixture was stirred at ꢀ78 ꢁC. After 8 h,
the solvent was evaporated in vacuo and without any
work up, the crude residue, containing a mixture of two
tetrahydrofuran isomers (11bz, 10bz) in a 95:5 ratio, was
purified by flash chromatography (cyclohexane/EtOAc:
9:1) to give the title tetrahydrofurans as an inseparable
mixture (54 mg, 77%). Data for major isomer 11bz mmax
(ATR): 3480–3000 (br OH) 2980–2850 (CH–OSi),
1245+835 (Si–CH3), 1111, 1044, 881,835, 730, 699,
667 cmꢀ1. dH (500 MHz): 7.32–7.17 (5H, m, Ar–CH),
4.44 (1H, ddd, J = 8.8, 6.5, 6.2 Hz, 5-H), 4.02 (1H, dd,
J = 11.0, 6.2 Hz, 20-H), 3.90–3.82 (2H, m, 20-H+3-H),
3.66 (1H, qd, J = 6.2, 6.2 Hz, 2-H), 3.07 (1H, ddd, J = 6.2,
6.2, 6.2 Hz, 10-H), 2.27 (1H, br s, OH), 2.07 (1H, ddd,
J = 12.4, 6.5, 6.2 Hz, 4-Ha), 1.76 (1H, ddd, J = 12.4, 8.8,
6.8 Hz, 4-Hb), 1.13 (3H, d, J = 6.2 Hz, CH3), 0.86 (9H, s,
SiC(CH3)3), 0.36+0.30 (6H, 2·s, Si(CH3)2). dC
(125.7 MHz): 139.5, 129.0, 128.7, 127.1, 80.5 (C-2), 78.4
(C-5), 77.9 (C-3), 64.2 (C-20), 51.7 (C-10), 37.5 (C-4), 25.9
(SiC(CH3)3), 18.4 (CH3), 18.2 (SiC(CH3)3), ꢀ4.5
(Si(CH3)2), ꢀ4.7 (Si(CH3)2). m/z (ES+): 359.2 (M+Na,
100%). HRMS (ES+) found: 359.2024 (C19H32O3SiNa
requires 359.2018).
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10. Typical experimental procedures: 1-methyl-4-phenyl-2,8-
dioxabicyclo[3.2.1]octan-7-one 8b: To
a solution of
rhodium acetate dimer (Rh2[OAc]4) (22.1mg, 0.05 mmol)
in CH2Cl2 (50 mL, 1mmol/L, 2 mol %), a solution of
diazoketone (6b) (0.615 g, 2.5 mmol) in CH2Cl2 (100
mmol/L) was added dropwise over 24 h via a syringe
pump at room temperature. When the addition was
complete, silica gel was added and the reaction mixture
was concentrated. The residue was then immediately
purified by flash chromatography (cyclohexane/EtOAc:
9/1), to give the title ketone (8b) (0.245 g, 45%) as a white
solid. Mp: 78–80 ꢁC. mmax (ATR) : 3000–2838, 1763
(C@O), 1259, 1183, 1086, 1021, 862, 799, 759, 699,
668 cmꢀ1. dH (400 MHz): 7.35–7.15 (3H, m, Ar–CH),
7.07 (2H, d, J = 7.0 Hz, Ar–CH), 4.83 (1H, dd, J = 7.1,
3.3 Hz, 5-H), 4.25–4.15 (2H, m, 3-Hax, 3-Heq), 3.80 (1H,
ddd, J = 10.2, 7.7, 3.3 Hz, 4-H), 2.50 (1H, dd, J = 18.7,
7.1Hz, 6-H a), 2.35 (1H, d, J = 18.7 Hz, 6-Hb), 1.4 (3H, s,
CH3). dC (100.5 MHz): 210.7 (CO), 136.3, 129.1, 127.6,
127.2, 98.2 (C-1), 76.1 (C-5), 64.1 (C-3), 42.2 (C-6), 36.4
(C-4), 18.1 (CH3). m/z (CI, NH3): 236 ([MH+NH3]+, 50%),