Trans-2,5-disubstituted tetrahydrofurans via addition of carbon nucleophiles to the strained bicyclic acetal 2,7-dioxabicyclo[2.2.1] heptane

Article abstract of DOI:10.1021/ol901613k

(Figure Presented) Addition of allyltributylstannane to 2,7-dioxabicyclo[2.2.1]heptane in the presence of TiCI₄ produces 5-allyl-2-(hydroxymethyl)tetrahydrofuran with a transieis ratio of 93:7. The frans-selectivity is also observed in addition

Full text of DOI:10.1021/ol901613k

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3958-3961
Trans-2,5-Disubstituted Tetrahydrofurans
via Addition of Carbon Nucleophiles to
the Strained Bicyclic Acetal
2,7-Dioxabicyclo[2.2.1]heptane
Gregory K. Friestad* and Hye Jin Lee
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
gregory-friestad@uiowa.edu
Received July 14, 2009
ABSTRACT
Addition of allyltributylstannane to 2,7-dioxabicyclo[2.2.1]heptane in the presence of TiCl4 produces 5-allyl-2-(hydroxymethyl)tetrahydrofuran
with a trans/cis ratio of 93:7. The trans-selectivity is also observed in additions of various other carbon nucleophiles.
Disubstituted tetrahydrofurans and bis(tetrahydrofurans) are
prominent structural features in annonaceous acetogenins, a
broad class of lipophilic natural products that includes a
number of potent cytotoxins such as bullatacin, asimicin, and
squamocin (Figure 1).1 Such compounds exhibit potent
induction of apoptosis. Recently, photoactive analogues of
asimicin and squamocin have been prepared; a fluorescent
analogue of squamocin lacking the butenolide portion was
shown to specifically target mitochondria, implicating the
tetrahydrofuran motif in a selective recognition event that
may be of relevance to potential antitumor agents.2 With
such interest in their biological properties, tetrahydrofurans
require synthetic methods for their rapid and diastereose-
lective assembly.3
Key steps in the many valuable approaches to tetrahydro-
furans include single or tandem cyclizations of hydroxy
epoxides and haloalkanols,4 oxidative cyclization of alkenes
or polyenes,5 intramolecular Prins reaction,6 olefin metath-
(2) (a) Han, H.; Sinha, M. K.; D’Souza, L. J.; Keinan, E.; Sinha, S. C.
Chem.sEur. J. 2004, 10, 2149–2158. (b) Derbre´, S.; Roue´, G.; Poupon,
E.; Susin, S. A.; Hocquemiller, R. ChemBioChem 2005, 6, 979–982.
(3) Review: Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290.
(4) (a) Fukuyama, T.; Vranesic, B.; Negri, D. P.; Kishi, Y. Tetrahedron
Lett. 1978, 19, 2741–2744. (b) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996,
118, 1801–1802. (c) Marshall, J. A.; Hann, R. K. J. Org. Chem. 2008, 73,
6753–6757. (d) Kang, B.; Mowat, J.; Pinter, T.; Britton, R. Org. Lett. 2009,
11, 1717–1720.
Figure 1. Tetrahydrofurans and bis(tetrahydrofurans) with a trans-
2,5-dialkyl substitution pattern, highlighted in red in the structures
above, are common among annonaceous acetogenins.
(5) (a) Brovetto, M.; Seoane, G. J. Org. Chem. 2008, 73, 5776–5785. (b)
Caserta, T.; Piccialli, V.; Gomez-Paloma, L.; Bifulco, G. Tetrahedron 2005,
61, 927–939. (c) Klein, E.; Rojahn, W. Tetrahedron 1965, 21, 2353–2358.
(6) (a) Petasis, N. A.; Lu, S.-P. J. Am. Chem. Soc. 1995, 117, 6394–
6395. (b) Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.;
Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223–226.
inhibition of mitochondrial complex 1 (NADH/ubiquinone
oxidoreductase), an effect which has been linked with
(1) Bermejo, A.; Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–303.
10.1021/ol901613k CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

esis,7 metal-catalyzed allylic substitution,8 radical cycliza-
tion,9 reductive cyclizations of carbonyl compounds,10 and
a variety of [3 + 2]-annulations.11
to be the least predictable”.16 A number of recent efforts
have addressed this limitation,17 and new methods continue
to warrant further development.
In developing potential solutions to the foregoing stereo-
control problem, our attention was drawn to two studies
of bicyclic acetals. In 1999, Veyrieres reported a highly
diastereoselective allylsilane addition reaction upon a 2,7-
dioxabicyclo[2.2.1]heptane ring system (Figure 3a).18 The
The C-glycosidic disconnection of oxacyclic compounds,
i.e., addition to cyclic oxocarbenium ions (Figure 2a),12
Figure 3. Reactivity of bicyclic acetals. (a) Reaction of an
anhydropyranose with a C-nucleophile; the tetrahydropyran product
is disfavored. (b) Relative rates of hydrolysis of 1 and acetaldehyde
dimethyl acetal differ by a factor of 104.
Figure 2. Stereocontrol by the 5-substituent in addition of C-
nucleophiles to 5-membered cyclic oxocarbenium ions.
tetrahydrofuran product was not accompanied by the tet-
rahydropyran regioisomer.19 The preparation and reactivities
of bicyclic acetal 1 (Figure 3b) were examined by Hall and
co-workers, revealing rapid rates of acid-catalyzed hydrolysis
(krel ) 2.5 × 104 versus acyclic acetaldehyde dimethyl
acetal).20 Ring strain activation of the pathway to oxocar-
benium ion intermediates is implied.21 The acetals in bicyclic
ring systems depicted in Figure 3 bear an internally tethered
leaving group, a feature absent from the Reissig and Woerpel
precedents (Figure 2). These considerations inspired the
hypothesis that C-C bond forming reactions upon the 2,7-
dioxabicyclo[2.2.1]heptane ring system might address the
longstanding stereocontrol problem highlighted in Figure 2.
We now report tests of this hypothesis, using reactions of
bicyclic acetal 1 with various C-nucleophiles in the presence
of Lewis acids.
represents a simple yet powerful strategy in which C-C bond
construction and stereoselection are achieved concurrently.
Thus, there have been numerous studies of the fundamental
stereochemical behavior of five-membered cyclic oxocarbe-
nium ions, notably by Reissig13 and Woerpel14 (Figure 2).
Woerpel concluded about trans-2,5-disubstituted tetrahydro-
furans that “controlling this array has been challenging”,15
and Reissig noted that efforts to access this substitution
pattern by allylsilane additions to oxocarbenium ions “seem
(7) (a) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 4876–4877. (b) Schneider, M. F.; Lucas, N.; Velder, J.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 257–259. (c) Louie, J.; Bielawski,
C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312–11313. (d) Liu,
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8168. (b) Lee, E.; Song, H. Y.; Kim, H. J. J. Chem. Soc., Perkin Trans. 1
1999, 3395–3396. (c) Sibi, M. P.; Patil, K.; Rheault, T. R. Eur. J. Org.
Chem. 2004, 372–384.
(16) See page 3894 of ref 13.
(17) For a review, see ref 3. Selected recent examples: (a) Donohoe,
T. J.; Williams, O.; Churchill, G. H. Angew. Chem., Int. Ed. 2008, 47, 2869–
2871. (b) Pilli, R. A.; Riatto, V. B. J. Braz. Chem. Soc. 2008, 19, 583–599.
(c) Menendez Perez, B.; Schuch, D.; Hartung, J. Org. Biomol. Chem. 2008,
6, 3532–3541. (d) Fernandez de la Pradilla, R.; Castellanos, A.; Osante, I.;
Colomer, I.; Sanchez, M. I. J. Org. Chem. 2009, 74, 170–181. (e) Menendez
Perez, B.; Hartung, J. Tetrahedron Lett. 2009, 50, 960–962. (f) Jalce, G.;
Franck, X.; Figadere, B. Eur. J. Org. Chem. 2009, 378–386. (g) Ward,
A. F.; Wolfe, J. P. Org. Lett. 2009, 11, 2209–2212.
(10) (a) Mitchell, T. A.; Zhao, C.; Romo, D. Angew. Chem., Int. Ed.
2008, 47, 5026–5029. (b) Mead, K. T.; Pillai, S. K. Tetrahedron Lett. 1993,
34, 6997–7000.
(11) Review: (a) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293–
1316. Selected examples: (b) Parsons, A. T.; Johnson, J. S. J. Am. Chem.
Soc. 2009, 131, 3122–3123. (c) Mertz, E.; Tinsley, J. M.; Roush, W. R. J.
Org. Chem. 2005, 70, 8035–8046. (d) Gansa¨uer, A.; Rinker, B.; Pierobon,
M.; Grimme, S.; Gerenkamp, M.; Mu¨ck-Lichtenfeld, C. Angew. Chem., Int.
Ed. 2003, 42, 3687–3690.
(18) (a) Jaouen, V.; Jegou, A.; Lemee, L.; Veyrieres, A. Tetrahedron
1999, 55, 9245–9260. (b) More substituted cases may be less selective:
Kovensky, J.; Sinay, P. Eur. J. Org. Chem. 2000, 3523–3525; correction
Eur. J. Org. Chem. 2000, 4125.
(12) Reviews: (a) Overman, L. E.; Pennington, L. D. J. Org. Chem.
2003, 68, 7143–7157. (b) Postema, M. H. D. Tetrahedron 1992, 48, 8545–
8599. For selected examples, see: (c) Jasti, R.; Rychnovsky, S. D. J. Am.
Chem. Soc. 2006, 128, 13640–13648. (d) Sawant, K. B.; Jennings, M. P. J.
Org. Chem. 2006, 71, 7911–7914. (e) Denmark, S. E.; Yang, S.-M. J. Am.
Chem. Soc. 2004, 126, 12432–12440.
(19) For relevant computational studies, see: Nokami, T.; Werz, D. B.;
Seeberger, P. H. HelV. Chim. Acta 2005, 88, 2823–2831.
(20) (a) Hall, H. K. Jr.; DeBlauwe, F. J. Am. Chem. Soc. 1975, 97, 655–
656. (b) Hall, H. K., Jr.; DeBlauwe, F.; Carr, L. J.; Rao, V. S.; Reddy,
G. S. J. Polym. Sci. Polym. Symp. 1976, 56, 101–115.
(13) Schmitt, A.; Reissig, H.-U. Eur. J. Org. Chem. 2000, 3893–3901.
(14) (a) Smith, D. M.; Woerpel, K. A. Org. Biomol. Chem. 2006, 7,
1195–1201. (b) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.;
Woerpel, K. A. J. Am. Chem. Soc. 2005, 127, 10879–10884.
(15) See page 10881 of ref 14b.
(21) Enhanced reactivity of 1 suggests that the range of conditions
suitable for initiation of its reactions (i.e., combinations of Lewis acids and
nucleophiles) might be broader than for other types of acetals.
Org. Lett., Vol. 11, No. 17, 2009
3959

Racemic bicyclic acetal 1 was prepared from alkene 2,22
TiCl4 gave a promising trans/cis ratio of 82:18 (entry 4),
and a series of other Lewis acids were moderately effective
(entries 5-8). With allyltributylstannane as the nucleophile,
the selectivities generally increased (entries 9-12) with the
exception of SnCl4. In this initial screen, AlCl3 and InCl3
gave the highest ratios but were accompanied by incomplete
conversion (entries 10 and 12). Thus, TiCl4 was chosen for
further development of this reaction.
which was subjected to OsO4-catalyzed dihydroxylation to
afford diol 3 (Scheme 1).23 According to Hall’s method,20
a
Scheme 1
Next, the effects of temperature and solvent were assessed
for the allylstannane addition to 1 in the presence of TiCl4
(Table 2). Inverse dependence of selectivity on temperature
Table 2. Effects of Temperature and Solvent on TiCl4-Mediated
Allyltributylstannane Additions to Bicyclic Acetal 1a
entry
T (°C)
solvent
trans/cisc
1
2
3
-78
-42
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
benzene
toluene
(CH2Cl)2
(CH2Cl)2
93:7b
90:10
84:16b
89:11b
75:25
77:23
89:11
88:12
solution of 3 in dioctyl phthalate was heated in the presence
of catalytic TsOH at ca. 1 mmHg, producing first ethanol
and then 1, collected in a liquid nitrogen-cooled trap. Simple
vacuum distillation through a standard short-path condenser
afforded pure 1 in 40% yield.24 This material was stored in
the refrigerator and used over a few weeks time without
significant degradation.
Using allyltrimethylsilane as the C-nucleophile, an initial
survey of the reactivity of 1 in the presence of Lewis acids
showed facile production of allyl tetrahydrofuran 4a25 (Table
1). There were sharp distinctions in the trans/cis diastereomer
ambient
ambient
ambient
ambient
ambient
-23
4d
5d
6d
7d
8d
a Conditions: see entry 9, Table 1. b Isolated yields: entry 1, 84%; entry
3, 76%, entry 4, 57%. Conversion was complete in all cases. c Ratio
determined by GC. d 0.4 equiv of TiCl4.
was observed, with excellent selectivity available at -78 °C
(entries 1-3). Diminished TiCl4 (0.4 equiv) was not detri-
mental to selectivity but lowered the yield (entries 3 and 4).
At ambient temperature in benzene and toluene, the reaction
exhibited lower selectivity than in dichloromethane (entries
4-6), whereas in dichloroethane there was a slight improve-
ment (entry 7). When operation at low temperatures is
undesirable, the conditions of entry 7 offer an alternative.
With conditions enabling high selectivity established,
scope became of interest, so the TiCl4-mediated reaction
Table 1. Survey of the Effects of Lewis Acids in Allylsilane
and Allylstannane Additions to Bicyclic Acetal 1a
entry
Lewis acid
M
trans/cisc
1
2
3
4
5
6
7
8
TMSOTf
BF3·OEt2
Cu(OTf)2
TiCl4
AlCl3
SnCl4
Zn(OTf)2
InCl3
TiCl4
AlCl3
SnCl4
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
SnBu3
SnBu3
SnBu3
SnBu3
50:50b
50:50b
50:50
82:18b
70:30
77:23
65:35
59:41
90:10
94:6d
64:36
94:6d
(22) Bakina, E.; Wu, Z.; Rosenblum, M.; Farquhar, D. J. Med. Chem.
1997, 40, 4013–4018.
(23) Diol 3 has also been prepared in enantiomerically enriched form.
Raifeld, Y. E.; Nikitenko, A. A.; Arshava, B. M.; Mikerin, I. E.; Zilberg,
L. L.; Vid, G. Y.; Lang, S. A., Jr.; Lee, V. J. Tetrahedron 1994, 50, 8603–
8616.
(24) Hall reported a yield of 85% of 1 using lower pressure and
mechanical stirring. See ref 20b.
(25) Compounds 4a, 4b, and 4e were identified by comparison to
literature data. (a) 4a: Pilli, R. A.; Riatto, V. B. Tetrahedron: Asymmetry
2000, 11, 3675–3686. (b) 4b: Freifeld, I.; Holtz, E.; Dahmann, G.; Langer,
P. Eur. J. Org. Chem. 2006, 3251–3258. Bunn, B. J.; Cox, P. J.; Simpkins,
N. S. Tetrahedron 1993, 49, 207–218. Iqbal, J.; Pandey, A.; Chauhan,
B. P. S. Tetrahedron 1991, 47, 4143–4154. (c) 4e: Chakraborty, T. K.;
Reddy, V. R.; Sudhakar, G.; Kumar, S. U.; Reddy, T. J.; Kumar, S. K.;
Kunwar, A. C.; Mathur, A.; Sharma, R.; Gupta, N.; Prasad, S. Tetrahedron
2004, 60, 8329–8339.
9
10
11
12
InCl3
a Conditions: 0.1 M solution of 1 (1 mmol) in CH2Cl2, allylmetal reagent
(1.5 mmol), Lewis acid (1 mmol); workup with saturated aqueous NaHCO3.
b Isolated yields: entry 1, 69%; entry 2, 91%; entry 4, 72%. Conversion
was complete unless otherwise noted. c Ratio determined by GC. d Reaction
was incomplete.
(26) (a) Mori, I.; Ishihara, K.; Flippin, L. A.; Nozaki, K.; Yamamoto,
H.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 6107–6115.
(b) Denmark, S. E.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089–
8110. (c) Sammakia, T.; Smith, R. S. J. Am. Chem. Soc. 1994, 116, 7915–
7916.
(27) For discussions of the role of ion-pairing on stereocontrol in
additions to cyclic oxocarbenium ions, see: (a) Krumper, J. R.; Salamant,
W. A.; Woerpel, K. A. Org. Lett. 2008, 10, 4907–4910. (b) Shenoy, S. R.;
Woerpel, K. A. Org. Lett. 2005, 7, 1157–1160. (c) Zhang, Y.; Reynolds,
N. T.; Manju, K.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 9720–9721.
ratio depending on the Lewis acid. In the presence of
TMSOTf, BF3·OEt2, and Cu(OTf)2 there was no selectivity
(entries 1-3), congruent with precedent. On the other hand,
3960
Org. Lett., Vol. 11, No. 17, 2009

at low temperature was applied to a series of commercially
available C-nucleophiles (Scheme 2). Excellent trans-
mirror the prior observations of poor selectivity, as high-
lighted in Figure 2. This appears to be the case for TMSOTf,
BF3·OEt2, and Cu(OTf)2, which afford nonselective addition
(entries 1-3 of Table 1). The other entries of Table 1 exhibit
dramatic dependence of selectivity upon the identity of the
Lewis acid, implying direct involvement of the Lewis acid
in the configuration-determining step of the addition mech-
anism.
Scheme 2
The departure from precedent in the trans-selective reac-
tions of 1 may be explained by invoking a competition
between A and intimate ion pair B26,27 (Figure 4) for the
nucleophile; the latter could react stereospecifically with
inversion of configuration.28 Relative populations of free ion
and intimate ion pair may be expected to be impacted both
by intramolecular tethering of the leaving group, and by the
identity of the Lewis acid. Such a scenario implies that those
Lewis acids affording higher selectivities (TiCl4, AlCl3, and
InCl3) avoid the SN1-like stereorandom process29 by increas-
ing the reactivity and/or proportion of ion pair B.
In summary, addition of C-nucleophiles to 2,7-diox-
abicyclo[2.2.1]heptane affords access to trans-2,5-disubsti-
tuted tetrahydrofurans, a structural subunit common in
biologically active natural products. The preparative potential
of the selectivity pattern established here merits further
investigation, including adaptations to enantiomerically pure
substances.
Acknowledgment. We thank the University of Iowa for
support of this work through the UI MPSFP program and
through a UI Faculty Scholar Award (G.K.F.). We thank
Professor J. Vilarrasa (Barcelona) for helpful communica-
tions.
selectivity (dr 95:5) was observed with the silyl enol ether
derivative of methyl acetate, leading to 4b25 bearing ester
functionality for flexible applications in total synthesis.
From a mechanistic standpoint, if the reaction is SN1-like
(free oxocarbenium ion A, Figure 4), there should be little
impact of the Lewis acid on selectivity, and the results would
Supporting Information Available: Preparative details
and characterization data for 1 and 4a-e.This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901613K
(28) For related mechanistic features, see: (a) Braun, M.; Kotter, W.
Angew Chem., Int. Ed. 2004, 43, 514–517. Also see: (b) Reisman, S. E.;
Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 7198–7199.
(29) The SN1-like mechanism has been invoked for both TMSOTf and
BF3·OEt2 in the reaction of acyclic chiral acetals with allylsilane reagents.
(a) Matsutani, H.; Ichikawa, S.; Yaruva, J.; Kusumoto, T.; Hiyama, T. J. Am.
Chem. Soc. 1997, 119, 4541–4542. (b) Manju, K.; Trehan, S. Chem.
Commun. 1999, 1929–1930.
Figure 4
. Intermediates of Suggested Relevance to Competitive
Nonselective and Stereospecific Additions to Bicyclic Acetal 1.
Org. Lett., Vol. 11, No. 17, 2009
3961