Stereoselective thallium-induced ring contraction of glycals

Article abstract of DOI:10.1039/a807128d

Various glycals, treated with TI(NO₃)₃·3H₂O under mild conditions in an acetonitrile-methanol solvent mixture, underwent ring contraction in a stereoselective fashion, affording stable acetal products.

Full text of DOI:10.1039/a807128d

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108 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 108±109$
Stereoselective Thallium-induced Ring Contraction
of Glycals$
Dana H. Braithwaite, Cedric W. Holzapfel* and D. Bradley G. Williams
Department of Chemistry and Biochemistry, Rand Afrikaans University, P.O. Box 524,
Auckland Park, 2006, South Africa
Various glycals, treated with Tl(NO3)3 Á3H2O under mild conditions in an acetonitrile±methanol solvent mixture,
underwent ring contraction in a stereoselective fashion, affording stable acetal products.
Chiral 2,5-disubstituted furanoids are found in a variety of
natural products, including the many natural nucleosides
(and their synthetic analogues). Important compounds
bearing this moiety are nonactin1 (an ionophoric antibiotic),
furanomycin2 (an a-amino acid) and showdomycin3 (a C-
glycosyl nucleoside antibiotic).
2,5-Disubstituted furanoids have been prepared via
a number of routes. These include the introduction of a
substituent at the anomeric position of a glycofuranoside,4
furanoid ring synthesis from simple starting materials,5
and the use of hexose carbohydrates.6 Despite the elegance
Scheme 1
of many of these procedures, most are directed towards a
single compound and are not general in their applicability.
Herein, we describe the application of a ring contraction
identical conditions worked out for the ethers 1a (see
Experimental section) to yield acetal 2c (55%). Similarly,
glycals 1d and 1e a€orded the corresponding furanoid
products (2d, 47% and 2e, 41%).
protocol7 that is general in nature for the preparation of a
variety of 2,5-disubstituted furanoid compounds, including
a precursor to the antibiotic (‡)-furanomycin. In addition,
Ring contractions of derivatives of D-arabinal, 3a and 3b
this study addressed the e€ects of stereochemistry on the
(Scheme 2) did not display the stereoselectivity observed
ring contraction.
Oxythallation of ole®ns has been recognised as a powerful
with the hexose glycals. Here, the ring contracted products
were isolated as a/b mixtures (which could be separated).
tool in synthesis, and has been used in the preparation
The isomer ratio was found to be substrate dependent.
Similar results were obtained with derivatives of D-xylal,
of highly functionalised molecules.7 The organothallium
intermediate is subject to a variety of reactions due to the
3c and 3d (Scheme 2). These results indicated that the
substituent on C-5 in the hexose sugar played a de®nitive
role in determining the stereochemical outcome of the ring
lability of the C±TlIII bond and the reduction potential of
the TlIII±TlI couple.8 The facility with which the reduction
occurs allows the occurrence of Wagner±Meerwein-type
contraction reactions.
rearrangements, which have been put to use in the synthesis
of, for example, 11-desoxyprostaglandins.9 The ®rst results
of the TlIII-induced ring contraction of carbohydrate deriva-
tives were reported a decade ago.7 We set out to expand
on this methodology and to gain an understanding of the
roles that various chiral centres play in the ring-contraction
step.
Our ®rst attempts at a ring-contraction reaction of glucal
1a employed the exact conditions as previously described.7
It was found that slightly better results could be obtained
when using methanol, at 0 8C followed by heating, as
the solvent instead of acetonitrile. Subsequent experiments
Scheme 2
proved that a solvent comprising a 9:1 ratio of acetonitrile±
Finally, this methodology was applied to the prepara-
methanol facilitated the reaction and allowed the isolation
tion of a late precursor in the synthesis of furanomycin.
of an enantiomerically pure 2,5-trans-disubstituted acetal 2a
L-Rhamnal
6 (prepared from L-rhamnose by standard
in a yield of 50% (Scheme 1). A similar reaction was carried
out on galactal 1b, a€ording the furanoid C-glycoside 2b in
a yield of 45%.
chemistry)10 was treated with Tl(NO3)3Á3H2O under our
optimal conditions to furnish (60%) the anticipated trans-
furanoid acetal 7 (Scheme 3). This product was subsequently
deprotected (quantitative) and deoxygenated11 (78%) to
a€ord the desired unsaturated acetal 9. This compound has
previously been employed to prepare (‡)-furanomycin.12
The stereoselective outcome of the reactions described in
Schemes 1 and 3 seems to rely exclusively on the stereo-
chemistry of the substituent at C-5. This substituent has a
preference for the equatorial position, rendering the 4H5
conformation (10) the more stable (Scheme 4). It is through
this conformation that reaction occurs. Attack of the TlIII
from the b-face would lead to intermediate 11a, while attack
from the a-face would lead to intermediate 11b. The intra-
molecular SN2-type reaction13 of the ring oxygen atom
We were encouraged by these results and wished to
expand the scope of this reaction to glycal esters since the
further manipulation of esters is more readily accomplished
than that of the corresponding ethers. Again it was estab-
lished that a 9:1 acetonitrile±methanol solvent ratio pro-
vided the best results. Thus, tri-O-acetyl-D-glucal 1c (Scheme
1) was treated with 1.5 equivalents of Tl(NO3)3Á3H2O under
*To receive any correspondence (e-mail: dbgw@na.rau.ac.za).
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1999 109
Scheme 4
103.3, 82.1, 81.1, 78.3, 77.9, 63.1, 55.4, 54.1, 20.8; HRMS for
M
OMe, found m/z 303.1076, calc. for C14H19O8 303.1080.
Acetal 4a-ꢀ.Ð36% yield; [ꢀ]D 22.9 (c 1.15, CHCl3); IR (CHCl3)
Scheme 3
1750 cm 1; ꢁH (200 MHz, CDCl3) 5.51 (dd, 1H, J ˆ 5.0 and 4.2 Hz),
5.34 (ddd, 1H, J ˆ 7.1, 6.8 and 5.0 Hz), 4.53 (d, 1H, J ˆ 7.7 Hz),
4.08 (dd, 1H, J ˆ 9.3 and 7.1 Hz), 4.00 (dd, 1H, J ˆ 7.7 and
4.2 Hz), 3.82 (dd, 1H, J ˆ 9.3 and 6.8 Hz), 3.40 (s, 3H), 3.33 (s,
3H), 2.10 (s, 3H), 3.01 (s, 3H); ꢁC 169.9, 169.4, 101.7, 77.9, 71.7,
requires an equatorial placement of the thallium atom.
While 11b is set up for such a reaction (leading to the
observed 2,5-trans-tetrahydrofuran product), 11a requires
a ring ¯ip to the higher energy chair conformation (sub-
sequent reaction would lead to the 2,5-cis-tetrahydrofuran
product, which is not observed) before this reaction is
theoretically possible. It is possible that intermediate 11a is
indeed formed but that this intermediate decomposes into
other products.
In conclusion, we have described an ecient application
of Tl(NO3)3 Á3H2O to the ring contraction of various hexose
and pentose glycals. The modest yields (41±71%) obtained
are the result of competing reactions (e.g. ring opening
and/or ring ketone formation), but were acceptable in the
light of the easy access to the starting materials. This work
indicated that the ring contraction remains more or less
independent of changes in stereochemistry at C-3 or C-4
of both hexose and pentose sugars, and is more directly
in¯uenced by stereochemistry at C-5. The methodology is
amenable to the use of readily removable protecting groups
and, under the correct conditions, a€ords stable, enantio-
merically pure products. Our protocol shows signi®cant
potential for the rapid elucidation of glycals into natural
products, as con®rmed by the preparation of an advanced
synthetic precursor of (‡)-furanomycin.
71.3, 69.2, 54.7, 53.2, 21.5; HRMS for
231.0868, calc. for C10H15O6 231.0869.
M
OMe, found m/z
Acetal 7.Ð60% yield; [ꢀ]D ‡ 21.4 (c 0.95, CHCl3); IR (CHCl3)
1746 cm 1; ꢁH (200 MHz, CDCl3) 5.29 (dd, 1H, J ˆ 4.2 and 3.5 Hz),
4.86 (dd, 1H, J ˆ 4.2 and 2.9 Hz), 4.42 (d, 1H, J ˆ 6.1 Hz), 4.06
(dd, 1H, J ˆ 6.1 and 3.5 Hz), 3.97 (qd, 1H, J ˆ 6.1 and 2.9 Hz),
3.40 (s, 6H), 2.06 (br s, 6H), 1.30 (d, 3H, J ˆ 6.1 Hz); ꢁC 170.3,
170.0, 103.4, 82.3, 81.1, 79.4, 78.4, 55.3, 54.0, 20.9, 18.2; HRMS for
M
OMe, found m/z 245.1025, calc. for C11H17O6 245.1025.
We express our gratitude to AECI and the FRD (South
Africa) for ®nancial support.
Received, 14th September 1998; Accepted, 6th November 1998
Paper E/8/07128D
References
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Experimental
General procedure for ring contraction reactions: The glycal was
dissolved in a 9:1 mixture of acetonitrile and methanol (250 mg
in 10 ml) and the solution was cooled to 0 8C. Tl(NO3)3 Á3H2O (1.5
equivalents) in the acetonitrile±methanol mixture (half of the
volume used above) was added and the mixture was stirred at 0 8C
until the brown colour disappeared. The solution was then heated
under re¯ux until precipitation of the thallium salts occurred
(usually ca. 12 h). The mixture was ®ltered through Celite and
concentrated in vacuo to approximately one third of the original
volume. An equal volume of chloroform was added and the crude
product was adsorbed onto silica gel and subjected to column
chromatography.
Selected Data. Acetal 2c.Ð55% yield; [ꢀ]D ‡ 32.3 (c 1.03,
CHCl3); IR (CHCl3) 1747 cm 1; ꢁH (200 MHz, CDCl3) 5.36 (dd,
1H, J ˆ 3.8 and 2.9 Hz), 5.09 (dd, 1H, J ˆ 4.0 and 2.9 Hz), 4.41 (d,
1H, J ˆ 5.8 Hz), 4.21 (m, 3H), 4.10 (dd, 1H, J ˆ 5.8 and 3.8 Hz),
3.41 (s, 3H), 3.40 (s, 3H), 2.07 (br s, 9H); ꢁC 170.6, 169.9, 169.7,
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