Synthesis of cis- and trans-2,5-disubstituted tetrahydrofurans by a tandem dihydroxylation-SN2 cyclization sequence

Article abstract of DOI:10.1021/ol051507n

(Chemical Equation Presented) Dihydroxylation of δ- and ε-mesyloxy α,β-unsaturated esters proceeds with in situ cyclization to afford 2,5-disubstituted and 2,3,5-trisubstituted tetrahydrofurans.

Full text of DOI:10.1021/ol051507n

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4819-4822
Synthesis of cis- and
trans-2,5-Disubstituted Tetrahydrofurans
by a Tandem Dihydroxylation-SN2
Cyclization Sequence
James A. Marshall* and Jesse J. Sabatini
Department of Chemistry, UniVersity of Virginia, P.O. Box 400319,
CharlottesVille Virginia 22904
jam5x@Virginia.edu
Received June 28, 2005
ABSTRACT
Dihydroxylation of
tetrahydrofurans.
δ- and E-mesyloxy r,â-unsaturated esters proceeds with in situ cyclization to afford 2,5-disubstituted and 2,3,5-trisubstituted
In connection with a projected synthesis of certain macro-
cyclic polyketide marine natural products of the amphidi-
nolide family,1 we examined the sequence outlined in
Scheme 1 for the preparation of the tetrahydrofuran 5.2
4, which would then be subjected to base treatment.
However, this latter step proved unnecessary as the cycliza-
tion took place in situ to afford hydroxy ester 5 as the major
isolable product. Evidently the basic medium of the dihy-
droxylation reaction was sufficient to effect the cyclization
step. In view of the widespread occurrence of 2,5-disubsti-
tuted tetrahydrofurans in bioactive natural products such as
Annonaceous acetogenins3 and polyether antibiotics,4 as well
as the aforementioned amphidinolides, we decided to survey
Scheme 1
(1) Kobayashi, J.; Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu, T.;
Hirota, H.; Sasaki, T. J. Antibiot. 1991, 44, 1259.
(2) Schaaf, G. M. PhD Thesis, University of Virginia, August, 2004.
(3) (a) Isolation: Oberlies, N. J.; Chang, C.; McLaughlin, J. L. J. Med.
Chem. 1997, 40, 2102. (b) Reviews: Figadere, B. Acc. Chem. Res. 1995,
28, 359. Hoppe R.; Scharf, H.-D. Synthesis 1995, 1447. Marshall, J. A.;
Hinkle, K. W.; Hagedorn, C. E. Isr. J. Chem. 1997, 37, 97. (d) Casiraghi,
G.; Zanardi, F.; Battistina, L.; Rassu, G.; Appendino, G. Chemtracts: Org.
Chem. 1998, 11, 803. Total synthesis: (e) Hoye, T. R.; Hanson, P. R.;
Kovelesky, A. C.; Ocain, T. D.; Zhuang, Z. J. Am. Chem. Soc. 1991, 113,
9369. (f) Naito, H.; Kawahara, E.; Maruta, K.; Naeda, M.; Sasaki, S. J.
Org. Chem. 1995, 60, 4419. (g). Sinha, S.; Sinha, A.; Yazbak, A.; Keinan,
E. J. Org. Chem. 1996, 61, 7640. (h) Hoye, T. R.; Ye, Z. J. Am. Chem.
Soc. 1996, 118, 1801. (i) Sinha, S. C.; Sinha, A.; Keinan, E. J. Am. Chem.
Soc. 1997, 119, 12014 (j) Emde, U.; Koert, U. Tetrahedron Lett. 1999, 40,
5979. (k) Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J. Org.
Chem. 2003, 68, 1771.
Toward that end, we treated the unsaturated mesylate 3 with
the Sharpless AD-mix â reagent, expecting to isolate the diol
(4) Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
10.1021/ol051507n CCC: $30.25
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other applications of this cascade sequence in order to probe
its generality.
We initiated these studies with the unsaturated alcohol 7,
prepared from epoxide 65 of 95% enantiopurity (see Supor-
ting Information) and allylmagnesium chloride/CuI in THF
(Scheme 2). Our first modification was to improve access
isomeric tetrahydrofurans could be detected in the NMR
spectra of the products or by TLC analysis. The stereochem-
istry of these tetrahydrofuran products was surmised from
the well-established steric preference of the AD-mix reagents
and the presumed SN2 nature of the cyclization reaction.9
Aldehyde 16 was prepared by a slight modification of the
sequence outlined in Scheme 1 (see Supporting Information).
Condensation with the Still-Gennari trifluoroethyl phos-
phonoacetate and propionate reagents effected conversion
to the (Z)-conjugated esters 17 and 20 (Scheme 4).10
Scheme 2
Scheme 4
to conjugated ester substrates for the cascade sequence. This
was achieved through use of an efficient Grubbs cross
metathesis reaction of olefin 7 with ethyl acrylate to afford
hydroxy ester 9.6 A methyl homologue 10 was prepared
directly through cross metathesis of unsaturated mesylate 8
with ethyl methacrylate.
The unsaturated mesylate derivative 19 was subjected to
the AD-mix R and â reagents to yield the tetrahydrofurans
23 and 25 (Scheme 5). Both reagents afforded essentially
The mesylate derivative 11 of alcohol 9 was subjected to
dihydroxylation with the Sharpless AD-mix R reagent,
whereupon the trans,syn tetrahydrofuran 12 was obtained
in high yield with excellent diastereoselectivity (Scheme 3).7
Scheme 5
Scheme 3
identical 1:1 mixtures of diastereomers. Evidently, dihy-
droxylation of the (Z)-unsaturated ester 19 is nonselective.
The 2-methyl homologue 22 proved more amenable. Dihy-
droxylation with the AD-mix R reagent afforded the tran-
s,anti tetrahydrofuran 24 as the major component of a 20:1
mixture of diastereomers and the cis,anti isomer 26 as the
major component of a 6:1 mixture of diastereomers from
the reaction with AD-mix â.
The methyl homologue 10 was likewise converted to the
tetrahydrofuran 13.8 The cis,syn isomer 14 was produced
from mesylate 11 through use of the AD-mix â reagent,
which also effected conversion of mesylate 10 to the
homologue 15. In each case barely detectable amounts of
We also examined sequences leading to the 3-hydroxy
tetrahydrofurans 32-35 (Scheme 7). One of the conjugated
(5) Epoxide 6 was obtained through Jacobsen kinetic resolution of the
racemate. Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 1360.
(6) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(9) As an added proof that the cyclization leads to a tetrahydrofuran rather
than a tetrahydropyran, we carried out the following conversion of hydroxy
ester 15:
(7) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(8) The stereochemistry of the dihydroxylation reaction was ascertained
through dihydroxylation of the TBS ether anlog of mesylate 10 with AD-
mix R and conversion of the derived diol to the O-methyl mandelate
derivative (see Supporting Information).
(10) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4404.
Org. Lett., Vol. 7, No. 22, 2005
4820

Scheme 6
Scheme 8
esters (31) required for these studies was prepared from the
alcohol 27 by cross metathesis with methyl acrylate and
subsequent mesylation (Scheme 6). Similar treatment of the
mesylate 28 and methyl methacrylate afforded the homolo-
gous ester mesylate 30.
Grubbs II catalyst to afford the dimer 42, a 5:1 mixture of
(E)- and (Z)-isomers (Scheme 9). Treatment with the
Scheme 7
Scheme 9
Dihydroxylation of the conjugated ester mesylate 31 with
AD-mix R afforded the cis,trans adduct 32 as a 5:1 mixture
of diastereomers whereas the trans,trans adduct 34 was
favored by 20:1 in the reaction of ester 31 with AD-mix â
(Scheme 7). Reactions of the methylated homologue 30 with
AD-mix R and â proceeded analogously to afford the
cis,trans and trans,trans adducts 33 and 35, but with
diminished selectivity reflecting the lower diastereoselectivity
of the dihydroxylation reaction.
The (Z)-isomer 39 of ester 30 was prepared by a sequence
involving ring-closing metathesis11 of the methacrylate 36
followed by methanolysis of the derived lactone 37 and
mesylation (Scheme 8). Exposure of mesylate 39 to AD-
mix R converted this ester to the trans,cis adduct 40, whereas
the cis,cis adduct 41 was obtained from the reaction with
AD-mix â. Once again the decreased selectivity of the AD-
mix reactions on the (Z)-esters resulted in poor diastereo-
selectivity
Sharpless AD-mix R reagent gave the all-cis fused bis-furan
43 in 54% yield (67% based on the available (E)-isomer).
The (Z)-isomer of olefin 42 would not be expected to yield
a fused bis-furan owing to the strain present in two trans
fused five-membered rings. The isomeric bis-furan 44 was
obtained similarly by treatment of the unsaturated dimesylate
42 with AD-mix â.
The sequence leading to attached bis-tetrahydrofurans is
summarized in Scheme 10. Unsaturated ester 45 was
prepared from 4-penten-1-ol by a Swern-Wittig sequence.
Dimerization of 45 was effected with the Grubbs I olefin
metathesis catalyst (RudCHPh(PCy3)2Cl2 affording triene
46 in 86% yield. Selective dihydroxylation of the central
nonconjugated double bond was effectively achieved by
exposure to AD-mix R NaHCO3 at 0 °C. A byproduct
resulting from internal 1,4-addition of the hydroxyl substit-
uents to the conjugated ester groups was also formed in
varying amounts. By using NaHCO3 to buffer the dihy-
droxylation, we were able to suppress but not eliminate its
formation. The diol 47 was converted to the mesylate 48,
which was subjected to a second exposure to AD-mix R to
effect dihydroxylation of the two conjugated double bonds.
A second line of investigation was briefly explored in
which two fused or attached tetrahydrofuran rings were
generated in the dihydroxylation reaction. For the first case,
the mesylate derivative 28 of alcohol 7 was subjected to the
(11) Furstner, A.; Thiel, O. R.; Ackermann, L.; Nolan, S. P.; Schanz, H.
J. J. Org. Chem. 2000, 65, 2204.
Org. Lett., Vol. 7, No. 22, 2005
4821

Scheme 10
Unlike the previous examples, the dihydroxylation product
The low diastereoselectivity observed with certain (Z)-
esters somewhat limits the generality of the methodology.
However, use of alternative dihydroxylation ligands7 could
provide a remedy for this limitation.
did not cyclize in situ and the tetrol 49 was isolated in
moderate yield. Upon exposure to refluxing pyridine, the
tetrol 49 cyclized to afford the bis-tetrahydrofuran 50.12
Surprisingly, attempts to effect cyclization with NaH in THF,
2,6-lutidine, or DBU at room temperature or above led to
lower yields of less pure tetrahydrofuran product.
In summary, the in situ Sharpless asymmetric dihydroxy-
lation-internal SN2 cyclization cascade of δ- and ꢀ-mesyloxy
R,â-unsaturated esters provides an efficient and convenient
route to 2,5-disubstituted and 2,3,5-trisubstituted tetrahydro-
furans of interest as possible segments of certain bioactive
natural products. The reactions proceed efficiently and with
moderate to high levels of enantioselectivity. Extensions to
fused and attached bis-tetrahydrofurans have also proved
effective. These latter ring systems constitute a key structural
element of Annonaceous acetogenin natural products.3,13
Acknowledgment. Support for this work was provided
by research grant R01 CA090383 from the National Cancer
Institute.
Supporting Information Available: Experimental pro-
1
cedures and H NMR spectra for all key compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051507N
(13) The vast majority of the syntheses reported for Annonaceous
acetogenins have employed various forms of acid-catalyzed alcohol-epoxide
cyclizations or catalyzed Re(VII) oxidative cyclizations3 to construct the
bis-tetrahydrofuran core unit. A recent exception is the allylsilane [3 + 2]
annulation approach. Tisley, J. M.; Roush, W. R. J. Am. Chem. Soc. 2005,
127, 10818.
(12) These conditions were employed for construction of one of the
tetrahydrofuran rings of the acetogenins asimicin and bullatacin by a “naked
carbon skeleton” approach. Avedission, H.; Sinha, S. C.; Yazbek, A.; Sinha,
A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org. Chem. 2000, 65, 6035.
4822
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