Diastereoselective anomeric oxygen to carbon rearrangements of silyl enol ether derivatives of lactols

Article abstract of DOI:10.1055/s-1998-1867

Lewis acid promoted oxygen to carbon rearrangement of anomerically linked silyl enol ethers gives a new and diastereoselective route to the corresponding 2-α-hydroxyketone substituted products.

Full text of DOI:10.1055/s-1998-1867

October 1998
SYNLETT
1093
Diastereoselective Anomeric Oxygen to Carbon Rearrangements of Silyl Enol Ether
Derivatives of Lactols.
Darren J. Dixon, Steven V. Ley* and Edward W. Tate.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
Received 17 July 1998
Abstract: Lewis acid promoted oxygen to carbon rearrangement of
anomerically linked silyl enol ethers gives a new and diastereoselective
route to the corresponding 2-α-hydroxyketone substituted products.
Compound 4 allows access to a wide range of anomerically-linked
carbonyl containing compounds, following the Weinreb protocol. Thus
the majority of the starting materials used in this study were simply
prepared by the addition of alkyllithium or Grignard reagents to 4 at
lowered temperature (-30°C) in tetrahydrofuran, in high isolated yield
(Scheme 3).
4
Of the many pyran and furan ring systems commonly found in natural
products, the vast majority contain carbon-linked substituents adjacent
to oxygen atoms. The problem of constructing these systems efficiently
and stereoselectively represents a significant challenge for synthetic
chemists, and a variety of different methods for direct introduction of
1
such functionality have been developed. In the previous
communication we described a new route to 2-alkyl substituted pyran
ring systems via anomeric oxygen to carbon rearrangement of alkynyl
2
tributylstannanes. Here we wish to report a further extension of this
anomeric rearrangement method to encompass silyl enol ethers as the
anomerically-linked carbon nucleophile.
The reactivity of silyl enol ethers towards oxonium ion intermediates
combined with the potential for further elaboration has lead to their use
for intermolecular displacement of anomeric leaving groups in pyran
3
ring systems. These features also make them attractive nucleophiles for
use in the anomeric rearrangement strategy, with the further possibility
for control at two new stereogenic centres (Scheme 1).
Scheme 3
In the first rearrangement study the phenyl ketone 5 was treated with an
excess of triethylamine and trimethylsilyl trifluoromethanesulfonate at
o
–78 C to give, after aqueous work-up, the silyl enol ether 8, which was
Scheme 1
used directly in the subsequent step. The cis-Z configuration of 8 was
1
unambiguously determined by
H nmr spectroscopy and nOe
In order to prepare the anomeric silyl enol ethers utilised in this work,
we have designed a rapid and flexible route into these starting materials.
This proceeds via initial quantitative reduction of a readily available δ-
lactone such as 1. Deprotonation of the product lactol 2 with potassium
experiments. Treatment of silyl enol ether 8 with an excess of tin
o
tetrachloride at –30 C resulted in a rapid rearrangement to a 3:1
5
separable pair of carbon linked products 9 and 10 in 86% combined
yield from 5 (Scheme 4).
o
bis(trimethyl)silylamide at –78 C in tetrahydrofuran, followed by
alkylation with α-bromo amide 3, affords the cis product 4 as a single
diastereoisomer (>95% de) in 88% isolated yield (Scheme 2).
Scheme 4
Scheme 2

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SYNLETT
Furthermore, it was also possible to achieve an improved selectivity of
4:1 using trimethylsilyl trifluoromethanesulfonate (10 mol%) as the
o
catalyst in dichloromethane at –30 C. Additional experiments
established that the rearrangement proceeds with slightly improved
o
selectivity at temperatures below –30 C, but that the yield was reduced
due to some decomposition of the starting material. Interestingly, only
two of the possible four diastereoisomeric products are formed in this
reaction, and just one (9) predominates. A combination of single crystal
X-ray crystallography and nOe studies allowed the unambiguous
assignment of all three stereocentres in each of the products. Complete
control (>95% de) at the ring junction is observed in both products due
to presumed preferential axial attack on a cyclic oxonium intermediate
species. We would suggest that the major product is formed by a process
under kinetic control, whereby the oxygen bearing the Lewis acid is
6
directed away from the bulk of the ring (Scheme 5).
Scheme 5
We have also shown that effective rearrangements can be achieved with
more complex silyl enol ethers. For example, silyl enol ether 11, formed
from phenylethynyl ketone 6 under the same conditions described
above, undergoes facile rearrangement on treatment with excess tin
o
tetrachloride at –30 C, to give
a 3:1 separable ratio of two
diastereoisomers 12 and 13 in 79% combined yield (Scheme 6).
Scheme 7
ether 21 by the usual protocol followed by exposure to the standard
rearrangement conditions gave the corresponding α-hydroxyketones 22
and 23 as a 3:1 mixture of diastereoisomers, in a combined yield of 84%
(Scheme 8).
Scheme 6
The methyl ketone silyl enol ether precursor 7 was then investigated in
the rearrangement sequence. Treatment of 7 with Hünig's base and
trimethylsilyl trifluoromethanesulfonate in dichloromethane at -78°C
afforded a mixture of exo and endo silyl enol ethers, with the kinetic exo
product 14 dominant (14:15, 6:1). This mixture underwent
a
synthetically useful rearrangement with excess tin tetrachloride at
o
–30 C to give an easily separable mixture of primary alcohol 16 and
secondary alcohols 17 and 18 in 90% combined yield. The primary/
secondary alcohol ratio mirrors the exo/endo ratio, indicating that no
significant isomerisation has occurred under the rearrangement
conditions (Scheme 7).
For the final example involving rearrangement on a pyran ring system,
the tert-butyl ketone 20 was synthesised in 50% yield by treatment of
ester 19 with tert-butyl lithium in pentane at –78 C. Formation of enol
o
Scheme 8

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This new rearrangement is not restricted to pyran ring systems. We have
extended the method to also encompass furan ring systems. Thus the
methyl ketone 24 was formed from the lactone by the reduction/
alkylation and Grignard addition route, in a similar manner to the pyran
systems described above. Following the same protocol as before, 24 is
converted to predominantly the exo silyl enol ether, and subjected to the
standard rearrangement conditions to give the two diastereoisomers of
primary alcohol 25 in a 1:1 ratio and in 56% combined yield (Scheme
References and Notes
(1) Levy, D.; Tang, C. The Chemistry of C-Glycosides, Pergamon,
1995, and references cited therein.
(2) See also Buffet, M. B.; Dixon, D. J.; Edwards, G. L.; Ley, S. V.;
Tate, E. W. Synlett, 1997, 1055.
(3) For some related examples see: i) Reetz, M. T.; Mallerstarke, H.
Ann. Chem., 1983, 10, 1726; ii) Toshima, K.; Miyamoto, N.;
Matsuo, G.; Nakata, M.; Matsumura, S. J. Chem. Soc. Chem.
Commun., 1996, 1379; iii) Uenishi, J.; Sohma, A.; Yonemitsu, O.
Chem. Lett., 1996, 595; iv) Craig, D.; Tierney, J. P.; Williamson,
C. Tetrahedron Lett., 1997, 38, 4153; and references cited therein.
7
9).
(4) Weinreb, S. M.; Nahm, S. Tetrahedron Lett., 1981, 22, 3815.
1
(5) Selected spectroscopic data for 9: H NMR (600MHz, CDCl ):
3
7.89-7.94 (m, 2H, Ph), 7.44-7.64 (m, 3H, Ph), 4.94 (dd, J = 6.7,
2.7 Hz, 1H, CHOH), 3.98-4.05 (m, 1H, OCHCHOH), 3.74-3.79
(m, 2H, OH and CH CH(CH )O), 0.79-1.89 (m, 19H, CH and
2
2
3
Scheme 9
13
8xCH ); C NMR (150MHz, CDCl ): 199.9 (C=O), 134.5,
2
3
133.5, 128.7, 128.5 (Ph-C), 76.3 (CHOH), 73.3 (CH CH(CH )O),
2
2
We believe that the methodology described above represents
a
70.9 (OCHCHOH), 31.6, 30.3, 29.1, 28.3, 27.0, 25.5, 22.7, 18.4
significant extension of our original concept of anomeric oxygen to
carbon rearrangements, being the first reported example of using
anomerically linked silyl enol ethers to effect C-glycosidation.
Furthermore, the formation of the carbon-carbon bonds at the anomeric
position occurs with concurrent stereocontrol at one or more stereogenic
centres.
(8xCH ), 14.0 (CH ).
2
3
(6) Re-exposure of
a
single diastereoisomer to identical
rearrangement conditions shows no evidence of equilibration to
the other diastereoisomer over an extended period, indicating that
the rearrangement proceeds under kinetic control.
(7) The minor side products observed in this reaction were tentatively
assigned as the rearrangement products of the endo enol ether.
Acknowledgements. We thank the EPSRC (to EWT and DJD) and the
Novartis Research Fellowship (to SVL) and Pfizer inc., Groton, U.S.A.
for further financial support.