Efficient access to 2,5-substituted tetrahydrofurans via a one-pot cyclization of di- and triepoxides

Article abstract of DOI:10.1016/j.tetlet.2008.09.053

The one-pot addition and cyclization of 1,5-diepoxyhexane with a range of organolithium species provides efficient access to 2,5-substituted tetrahydrofurans (THFs), common structural motifs found in a range of natural products and pharmaceutical ingredients. Extension of this reaction to triepoxides has also been demonstrated to access adjacently linked bis-THF motifs in a single step.

Full text of DOI:10.1016/j.tetlet.2008.09.053

Tetrahedron Letters 49 (2008) 6784–6786
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient access to 2,5-substituted tetrahydrofurans via a one-pot cyclization
of di- and triepoxides
*
Gordon J. Florence , Romain Cadou
EaStCHEM and Centre for Biomolecular Sciences, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The one-pot addition and cyclization of 1,5-diepoxyhexane with a range of organolithium species pro-
vides efficient access to 2,5-substituted tetrahydrofurans (THFs), common structural motifs found in a
range of natural products and pharmaceutical ingredients. Extension of this reaction to triepoxides has
also been demonstrated to access adjacently linked bis-THF motifs in a single step.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 August 2008
Revised 2 September 2008
Accepted 10 September 2008
Available online 13 September 2008
Substituted tetrahydrofuran (THF) ring systems are common
structural motifs found in a wide variety of natural product fami-
lies. From a biosynthetic perspective,1 their formation arises from
the isomerization of intermediate hydroxy epoxide precursors in
secondary metabolites such as the marine macrolide amphidino-
lide E (1, Fig. 1)2 and the bis-THF acetogenin rollidecin C (2).3
The wide variety of biologically active THF-containing natural
products have also inspired the pharmaceutical sector to incorpo-
rate this privileged structural motif in potential drug candidates.
For instance Uriach Pharma have prepared a range of 2,5-substi-
tuted THFs,4 such as 3, which display platelet aggregation factor
activity. Due to the importance of these frameworks, they have
been the target of considerable synthetic studies giving rise to
numerous and elegant methodologies for their preparation.5 How-
ever, the potential of directly accessing the 2,5-substituted THF
motif from the controlled opening of 1,5-diepoxyhexanes remains
a relatively unexplored synthetic tactic. In 1950, Wiggins and
Wood reported the cyclization of 1,5-diepoxyhexane under meth-
anolysis or aminolysis conditions to give the tetrahydrofuran and
piperidine products, respectively.6 The latter has seen application
in the synthesis of azasugar derivatives.7 In contrast, the addition
of carbon-based nucleophiles has garnered limited attention, apart
from the 2001 report by Le Merrer and co-workers,8 where a range
of C-aryl-arabinose analogs were prepared by the addition of aryl-
OH
O
HO
HO
O
O
1: amphidinolide E
OH
O
C12H25
O
O
O
2: rollidecin C
OH
O
Ac
O
N
.I-
C15H31
N
O
Et
3
platelet agregation factor from Uriach Pharma
Figure 1. 2,5-Substituted THF motifs in natural products and pharmaceutical
agents.
Herein, we report on our work on the development of a one-pot
addition and cyclization of 1,5-diepoxyhexane to 2,5-substituted
THFs and the extension of this methodology to the synthesis of
adjacently linked bis-THF motifs from 1,5,9-triepoxydecane.
We initially focussed our studies on identifying appropriate
reaction conditions to affect successful mono-addition followed
by 5-exo cyclization using rac/meso diepoxyhexane 4 (prepared
from 1,5-hexadiene by mCPBA epoxidation,9 73% yield), as detailed
in Table 1. As a benchmark, addition of allyl cuprate to 4, followed
by treatment of the crude monoaddition adduct with K2CO3 in
MeOH gave the corresponding diastereomeric syn/anti THFs 5
and 6 in a moderate 48% yield as an inseparable mixture (entry
1). The major byproduct of the reaction was the corresponding
diols resulting from double addition to the diepoxide. In an effort
to improve upon this result and facilitate the cyclization of the pre-
sumed intermediate epoxy alcohol in situ, BF3ꢀOEt2 was added
lithium derivatives to a Bn-protected D-mannitol-derived diepox-
ide. However, applications beyond modified carbohydrate motifs
remain unexplored, particularly in the context of natural product
synthesis, where practical access to such frameworks would be
advantageous, building in the THF motif and latent functionality
at an early stage with the advantage of minimizing protecting
group manipulations.
* Corresponding author. Tel.: +44 1334 463834; fax: +44 1334 463808.
E-mail address: gjfl@st-andrews.ac.uk (G. J. Florence).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.053

G. J. Florence, R. Cadou / Tetrahedron Letters 49 (2008) 6784–6786
6785
Table 1
Development of reaction conditions using rac/meso diepoxyhexane 4
O
O
R-Met
4
R
OH
R
OH
rac/meso
O
O
Met = MgBr, Li
O
O
4
( )-5: R= CH2CH=CH2
( )-7: R=
CTMS
( )-6: R= CH2CH=CH2
( )-8: R=
CTMS
(
R,R)-Co(II)salen
(21%)
rac/meso
C
C
AcOH, THF, H2O
Entry
1
R–Met
Conditions
Product
Yielda (%)
MgBr
MgBr
(i) Cul,THF,ꢁ78 to 0 °C;
5 + 6
48
O
O
(ii) K2CO3 MeOH
(2R,5R)-17
>95% ee by chiral GC
2
Cul, BF3ꢀOEt2, THF,ꢁ78 to 0 °C
—
Scheme 1. Preparation of C2-symmetric 1,5-diepoxyhexane 17.
3
BF3ꢀOEt2, THF,ꢁ78 to 40 °C
7 + 8
76
TMS
Li
a
Isolated yield of combined diastereomers after column chromatography.
HKR conditions, provided (2R,5R)-diepoxyhexane 17 in 21% yield
with >95% ee on multigram scale.13
which led only to decomposition (entry 2). The incompatibility of
the organocuprate reagents with Lewis acids led us to return to
the use of organolithium species in combination with BF3ꢀOEt2.
Thus, addition of the lithium anion of TMS-acetylene (1.2 equiv,
from deprotonation with n-BuLi) in the presence of BF3ꢀOEt2
(1.5 equiv) to 4 in THF (ꢁ78 to ꢁ40 °C over 1.5 h) gave the corre-
sponding THFs 7 and 8 in an excellent 76% yield (entry 3).
With optimal conditions developed for the addition and cycliza-
tion with TMS-acetylene to rac/meso diepoxyhexane 4, we next
investigated the addition of a range of lithium acetylide species,
as detailed in Table 2. In all instances (entries 2–5) addition of
1.2 equiv of the lithium acetylide in the presence of BF3ꢀOEt2 to 4
gave the corresponding pairs of diastereomeric THF products 7–
16 in good to excellent yields (62–80%).10
For this one-pot protocol to have utility in the context of com-
plex molecule synthesis, reliable access to the requisite C2-sym-
metric diepoxyhexane, in either enantiomeric form, was
required.11 This was conveniently achieved using the Jacobsen
hydrolytic kinetic resolution (HKR) reaction,12 as outlined in
Scheme 1. Thus, treatment of rac/meso diepoxide 4, with activated
(R,R)-Co(III)salen(OAc) complex, using a modification of Jamison’s
With (2R,5R)-diepoxyhexane 17 in hand, we turned our atten-
tion to its use in the preparation of enantiomerically pure THFs
and extending the scope and generality of the addition/cycliza-
tion reaction to include alkyl- and vinyllithium species, as de-
tailed in Table 3. Under our optimized conditions, addition of
the lithium anions of TMS-acetylene and 1-octyne proceeded
smoothly to provide the corresponding 2,5-syn THFs 18 and
19 as single diastereomers, respectively (entries
1 and 2).
Table 3
One-pot addition and cyclization of C2-symmetric diepoxyhexane (2R,5R)-17
1.2 eq reagent, 1.2 eq
1.5 eq BF3 OEt2, THF,
n
-BuLi
.
R
OH
-78 → -40 °C, 1.5 h
O
O
O
60-75%
2,5-syn THF
(2R
,5
R
)-17
Entry
1
Reagent
Product
Yielda (%)
TMS
OH
75
65
62
60
TMS
O
18
C6H13
Table 2
OH
OH
2
3
C6H13
One-pot addition and cyclization with alkynes
O
19
O
O
n-BuLi
O
21
4
rac/meso
1.2 eq alkyne, 1.2 eq
1.5 eq BF3 OEt2, THF,
n
-BuLi
.
OH
TBSO
SnBu3
-78 → -40 °C, 1.5 h
4
TBSO
O
22
20
R
R
OH
OH
a
Yield of sole diastereomeric product after column chromatography.
O
O
( )-7: R= TMS
( )-8 R= TMS
( )-9: R= CH2OBn
( )-10: R= CH2OBn
( )-12: R= CH2OTBS
( )-14: R= C6H13
( )-16: R= Ph
( )-11: R= CH2OTBS
( )-13: R= C6H13
( )-15: R= Ph
R
Li
R
Yielda (%)
76
addition
Entry
1
Alkyne
Product
O
O
O
Li
O
7 + 8
TMS
BF3
BF3
2
3
4
BnOCH2
TBSOCH2
C6H13
9 + 10
73
65
62
80
5-exo
cyclization
HO
11 + 12
13 + 14
15 + 16
O
5
2
R
OH
H
H
O
21
2,5-syn
5
Ph
a
Combined yield of diastereomers after column chromatography.
Scheme 2. Confirmation of relative stereochemistry and proposed mechanism.

6786
G. J. Florence, R. Cadou / Tetrahedron Letters 49 (2008) 6784–6786
Table 4
Acknowledgments
Addition and double cyclization of 1,5,9-triepoxydecane 25
This work was supported by the Royal Society (University Re-
search Fellowship to GJF), the EPSRC/EaStChem (studentship to
RC), and AstraZeneca (unrestricted support to GJF). We also thank
the EPSRC National Mass Spectrometry Service Centre, Swansea for
mass spectral analysis.
O
O
O
23
1.2 eq reagent, 1.2 eq
n-BuLi
.
59-75%
2 eq BF3 OEt2, THF,
-78 → -20 °C, 5 h
OH
R
References and notes
O
O
24: R=
25: R= C CTMS
26: R= C CC6H13
n
-Bu
1. Hill, A. M. Nat. Prod. Rep. 2006, 23, 256–320.
2. Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451–460.
3. Bermejo, A.; Figadère, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes,
D. Nat. Prod. Rep. 2005, 22, 269–303.
4. Bartroli, J.; Carceller, E.; Merlos, M.; Garcia-Rafanell, J.; Forn, J. J. Med. Chem.
1991, 34, 373–386.
Entry
1
Reagent
Product
Yielda (%)
70
n-BuLib
24
5. For a recent review on the stereoselective synthesis of tetrahydrofurans and
references therein, see: Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
6. Wiggins, L. F.; Wood, D. J. C. J. Chem. Soc. 1950, 1566–1575.
7. (a) Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. 1994, 35, 3293–
3296; (b) Concellón, J. M.; Rivero, I. A.; Rodríguez-Solla, H.; Concellón, C.;
España, E.; García-Granda, S.; Díaz, M. R. J. Org. Chem. 2008, 73, 6048–6051.
8. Rigolet, S.; McCort, I.; Le Merrer, Y. Tetrahedron Lett. 2002, 43, 8129–8132.
9. Baylon, C.; Heck, M.-P.; Mioskowski, C. J. Org. Chem. 1999, 64, 3354–3360.
10. All new compounds gave spectroscopic data in agreement with assigned
structures. A typical procedure for the one-pot cyclization: to a solution of 1-
2
25
26
75
59
TMS
3
C6H13
a
Combined yield of diastereomeric mixtures after column chromatography.
1.2 equiv of n-BuLi was added as the reagent.
b
octyne (235
lL, 1.58 mmol) in THF (7 mL) at ꢁ78 °C was added n-butyllithium
Gratifyingly, the addition of both n-butyllithium and the lithium
species derived from vinylstannane 20,14 again proceeded
smoothly to provide the corresponding 2,5-syn THF products
21 and 22 in good yields (entries 3 and 4).
The 2,5-syn relationship in the THF products was confirmed by
NOE analysis of 21, which showed a diagnostic NOE from H2 to H5
(Scheme 2). This observation is consistent with a mechanism
whereby Lewis acid activation of either terminal epoxide promotes
the 1° opening with the organolithium species, which is then fol-
lowed by an intramolecular 5-exo tet cyclization giving rise to
the 2,5-syn substitution in the THF products.
In a further extension of the present study, we considered the
feasibility of applying the one-pot addition/cyclization conditions
to 1,5,9-triepoxydecane 23 (prepared as a mixture of diastereo-
mers from 1,5,9-decatriene by mCPBA epoxidation, 79% yield)15
to access adjacently linked bis-THFs, as shown in Table 4. Gratify-
ingly, only slight modifications to our optimized conditions were
required in order to obtain the addition/ double cyclization prod-
ucts 24, 25, and 26 in excellent yields as diastereomeric mixtures
(entries 1–3).
In summary, we have developed and applied a highly efficient
one-pot addition cyclization reaction for the synthesis of 2,5-syn
tetrahydrofurans. This protocol allows rapid access to this privi-
leged motif in a single step from C2-symmetric 1,5-diepoxyhex-
ane 17, and can incorporate a range of functional groups for
further elaboration in the context of natural product synthesis.
In a further extension, we have shown that adjacently linked
bis-THFs can be prepared in a similar manner from 1,5,9-trisep-
oxides. Current studies are focused on the synthetic application
of this protocol in the context of the synthesis of amphidinolide
E and acetogenins, which will be reported in due course.
1.6 M in hexane (1.0 mL, 1.60 mmol). After 30 min (2R,5R)-1,5-diepoxyhexane
17 (150 mg, 1.31 mmol) in THF (3 mL) was added dropwise at ꢁ78 °C, followed
by the dropwise addition of BF3ꢀEt2O (240
lL, 1.97 mmol). The mixture was
warmed up to ꢁ40 °C over 1.5 h and was quenched with NH4Cl (10 mL). The
aqueous phase was extracted with dichloromethane (3 ꢂ 10 mL), and the
organic phases were combined, dried over MgSO4, filtered, and evaporated
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (30% EtOAc/hexanes) to give the 19 as
a
colorless oil (190 mg, 65%). Rf 0.30 (30% EtOAc/hexanes) ½a D20
ꢃ
+20.4 (c 1.3,
CHCl3); IR (thin film, cmꢁ1) 3394, 2924, 2857, 2212, 1457, 1376, 1046; 1H NMR
(300 MHz, CDCl3) 4.02–3.96 (2H, m), 3.67–3.62 (1H, dd, J = 11.6, 3.2 Hz), 3.46–
3.40 (1H, dd, J = 11.6, 5.1 Hz), 2.65 (1H, br s), 2.37 (2H, dt, J = 5.1, 2.7 Hz), 2.08
(1H, tt, J = 7.1, 2.4 Hz), 1.97–1.82 (2H, m), 1.80–1.72 (2H, m), 1.44–1.39 (2H, m),
1.32–1.19 (6H, m), 0.82 (3H, t, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3) 82.4, 80.3,
78.1, 76.4, 65.3, 31.5, 30.6, 29.1, 28.7, 27.3, 25.6, 22.7, 18.9, 14.2; HRMS (ESI)
calculated for C14H28O2N [M+NH4]+ 242.2115; found: 242.2114.
11. For a multi-step synthesis of either enantiomer of diepoxyhexane from
D-
mannitol, see: Machinaga, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 1386–1393.
12. (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936–
938; (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.;
Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315.
13. O’Brien, K. C.; Colby, E. A.; Jamison, T. F. Tetrahedron 2005, 61, 6243–6248.
Under our optimized conditions, (2R,5R)-diepoxyhexane was isolated via
vacuum transfer in 21% yield (>95% ee by chiral GC). Our standard procedure
for the HKR reaction of rac/meso 4: To a solution of (R,R)Co(II) salen complex
(420 mg, 0.69 mmol) in toluene (15 mL) was added acetic acid (85
1.39 mmol), and the mixture was stirred open to air for 30 min. After
removal of the solvent under reduced pressure, solution of 1,5-
diepoxyhexane 4 (5.30 g, 46.5 mmol) in THF (10 mL) was added. The solution
was then cooled to 0 °C, and water (670 L, 37.2 mmol) was added dropwise.
lL,
a
l
After 16 h at rt, the mixture was filtered through a silica pad with Et2O (50 mL).
The solvent was removed under reduced pressure, and (2R,5R)-diepoxyhexane
17 was collected as a colorless oil (1.11 g, 21%) by vacuum transfer (0.5 mmHg,
rt). Rf 0.52 (40% EtOAc/hexanes); ½a D20
ꢃ
+20.4 (c 1.3, CHCl3), Lit.11 a 2D0
½ ꢃ +18.5 (c
2.22, CHCl3); 1H NMR (300 MHz, CDCl3) 2.99–2.97 (2H, m, H-2), 2.77 (2H, app t,
J = 4.9 Hz, H-1a), 2.51–2.49 (2H, dd, J = 4.9, 2.7 Hz, H-1b), 1.75–1.65 (4H, m,
H-3); 13C NMR (75 MHz, CDCl3) 51.6, 47.1, 28.7.
14. Trost, B. M.; Chung, J. Y. J. Am. Chem. Soc. 1985, 107, 4586–4588.
15. Kakuchi, T.; Nonokawa, R.; Umeda, S.; Satoh, T.; Yokota, K. Macromolecules
2000, 33, 246–247.