Stereoselective cyanosilylation reactions in hindered cyclic ketones

Article abstract of DOI:10.1055/s-2004-829534

An efficient, mild and inexpensive protocol for the stereoselective construction of cyanohydrins in hindered, and in some cases, multifunctional cyclic ketones has been established.

Full text of DOI:10.1055/s-2004-829534

LETTER
1631
Stereoselective Cyanosilylation Reactions in Hindered Cyclic Ketones
Stereoselective
C
yanos
a
ilylation
R
r
k
in
H
inderedCyclic
G
K
etones . Moloney,* Muhammad Yaqoob
The Department of Chemistry, Central Research Laboratory, The University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
Fax +44(1865)275674; E-mail: mark.moloney@chem.ox.ac.uk
Received 28 March 2004
this case.18 In a model study, we found that cyanosilyla-
tion of b-ketoesters 3a and 3b using TMSCN and ZnI2 at
room temperature and in the absence of solvent19 gave ex-
cellent yields of two inseparable diastereomeric products
4a (83%, 4:1 ratio) and 4b (83%, 4:1 ratio), respectively
after 24 hours stirring (Scheme 1). These adducts were
stable to chromatography and the presence of the nitrile
function was indicated by IR analysis (2230 cm–1);20 no
evidence for elimination to the corresponding TMS ether
was apparent. Significantly, application of these mild con-
ditions to more heavily substituted cyclopentanones 5a
and 5b gave high yields of the products 6a, 7a (97%, 3:1
ratio of separable diastereomers)21 and 6b, 7b (60%,
mostly one diastereomer 6b but of unassigned stereo-
chemistry at C-3, Scheme 2).22 Of value was our addition-
al finding that the sense of the diastereoselectivity of these
processes could be established by careful NOE analysis,
provided long mixing times were used, as indicated by
the presence/absence of enhancements from adjacent
protons to the TMS residue (Figure 1). Thus, the major
diastereomer to be formed was the one in which cyanide
preferentially approached from the less hindered exo-face
of the cyclic system, i.e. syn- to the ester function. Of
interest was the fact that reaction of cyclohexenone 8
under these conditions gave the product 9 of 1,2-addition
exclusively in 42% yield (Scheme 3), consistent with
earlier findings.7
Abstract: An efficient, mild and inexpensive protocol for the
stereoselective construction of cyanohydrins in hindered, and in
some cases, multifunctional cyclic ketones has been established.
Key words: cyanohydrin, diastereoselectivity, ketones
We have recently reported some our work for the prepara-
tion of the left1–3 and middle fragments4 of the synthesis
of the novel antibiotic, antiviral and cytotoxic compound,
oxazolomycin (1), and in order to address the remaining
right hand side, required methodology which would per-
mit the homologation of tetramic acid 2 at C-6, to generate
an a-hydroxyaldehyde function or its synthetic equiva-
lent. Enantiopure tetramic acid 2 is readily available using
our previously published methodology by chemoselective
Dieckmann cyclisation of an appropriately modified
serine derivative,5 and we had earlier shown that ketone
extension using Wittig reagents is possible under forcing
conditions, leading to benzoindolone products.6 The den-
sity of functionality, along with the hindered bicyclic
structure and acidity at C-7 of tetramic acid 2 clearly make
homologation at C-6 a demanding step, but we report here
that this can be achieved under mild conditions using the
inexpensive TMSCN–ZnI2 reagent combination at room
temperature and in the absence of solvent.
Since its original report,7 cyanosilylation has been widely
used for reactions to aldehydes and simple ketones, and
although effective conversions require appropriate Lewis
acid catalysis,8,9 highly efficient enantioselective reac-
tions have been shown to be possible.10 Developments in
this area continue apace.11–14 However, a recent report
noted that, although TMSCN has been rarely used for less
reactive ketones, and in particular those deactivated with
a-heteroatoms, indium tribromide catalyst can be used in
these cases to great effect; however, even under these con-
ditions, sterically hindered systems exhibited lower
yields.15,16 In order to develop cyanosilylation methodol-
ogy for our purposes, we needed to investigate its applica-
tion to hindered cyclic ketones which also possessed
acidic protons; this is an area which has been largely
ignored, except for one recent report,17 as well as a proce-
dure reported more than 20 years ago in which a cyanohy-
drin was used for in situ protection of b-dicarbonyls in a
reduction reaction; the cyanohydrins were not isolated in
Figure 1
Encouraged by these results, we examined the reaction of
tetramic acid 2, but found that the reaction required ele-
vated temperature, and after 24 hours at 60–90 °C, high
yields (>90%) of the product 10 in a diastereomeric ratio
of 2:1 could be obtained, but unfortunately in this case,
NOE analysis was unproductive, and direct stereochemi-
cal assignment was therefore not possible (Scheme 4).
This compound was stable, with its keto tautomeric struc-
ture evident from the presence of C(7)H/C(7)Me coupling
in both stereoisomers (d = 2.7 and 1.3 ppm, J = 7.7 Hz in
one diastereomer and d = 3.0 and 1.4 ppm, J = 7.5 Hz in
the other). However, the stereochemistry at C-6 was
SYNLETT 2004, No. 9, pp 1631–1633
2
2.
0
7.
2
0
0
4
Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829534; Art ID: D07804ST
© Georg Thieme Verlag Stuttgart · New York

1632
M. G. Moloney, M. Yaqoob
LETTER
Scheme 1
Scheme 2
assigned on the basis of the results indicated above, and as a result of a kinetically preferred process; similar selec-
from NOE analysis on derivative 13 (see below); that the tivity in the case of reductions in this system has been
C-7 position is epimeric was established as indicated observed.25
below. Thus, cyanide is most likely to have added to the
exo-face of the bicyclic system in a thermodynamically
In summary, we report here an efficient methodology for
the construction of cyanohydrins from hindered and
controlled process. An attempt to achieve more robust
heavily functionalised ketones under mild and inexpen-
protection of the TMS ether of 10 as the corresponding O-
sive conditions. Furthermore, diastereomeric assignment
has been shown to be possible, using NOE and NOESY
acetyl derivative gave the mixture of products 11 and 12
in 60% and 20% yields, respectively. Similarly, attempted
techniques, by using long mixing times to probe the large
OMEM protection by direct treatment with MEMCl and
distances involved. These results suggest that the syn-
i-Pr2NEt in CH2Cl2 gave ketene aminal 13 as a single
thetic scope and utility of the cyanosilylation reaction
remains to be more fully exploited.
diastereomer in 33% yield, or initial deprotection (KF,
THF) followed by reaction with MEMCl and i-Pr2NEt
gave a 30% yield of a mixture of 14 and 15. The fact that
13 was obtained as single diastereomer, assigned by NOE
analysis as indicated in Scheme 4, indicates that the dia-
stereomeric mixture of lactam 10 is therefore epimeric at
C-7.23
Acknowledgment
We gratefully acknowledge the Lady Noon Foundation for a
scholarship (MY) and the EPSRC Chemical Database Service at
Daresbury.26
References
(1) Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z.
Current Drug Discovery Technologies 2004, 1, submitted.
(2) Bulger, P. G.; Moloney, M. G.; Trippier, P. C. Org. Biomol.
Chem. 2003, 1, 3726.
(3) Bulger, P. G.; Moloney, M. G.; Trippier, P. C. Synlett 2002,
1871.
Scheme 3
(4) Wang, Z.; Moloney, M. G. Tetrahedron Lett. 2002, 43,
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(5) Andrews, M. D.; Brewster, A. G.; Crapnell, K. M.; Ibbett, A.
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(6) Andrews, M. D.; Brewster, A. G.; Chuhan, J.; Ibbett, A. J.;
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to alternative nucleophiles. For example, lithiated ben-
zothiazole has found application for one-carbon exten-
sions of a range of electrophilic functional groups, giving
valuable synthetic intermediates.24 However, we found
that this reagent with tetramic acid 2 gave low yielding
(ca. 11%) and non-specific reactions at each possible car-
bonyl site, to give products 16, 17 and 18 (Scheme 4),
consistent with its high nucleophilicity. NOE analysis
indicated C-6 endo-attack of the nucleophile, presumably
(10) North, M. Tetrahedron: Asymmetry 2003, 14, 147.
Synlett 2004, No. 9, 1631–1633 © Thieme Stuttgart · New York

LETTER
Stereoselective Cyanosilylation Reactions in Hindered Cyclic Ketones
1633
Scheme 4
(11) Shen, Y. C.; Feng, X. M.; Li, Y.; Zhang, G. L.; Jiang, Y. Z.
Tetrahedron 2003, 59, 5667.
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(20) All new compounds gave satisfactory spectroscopic and
high-resolution mass spectrometric or analytical data.
(21) These diastereomers were readily distinguishable by 1H
NMR spectroscopy: for 6a at d = 2.9 and 3.4 ppm (J = 13.6
Hz) and for 7a, the benzylic resonances appeared as a dd at
d = 2.5 and 3.6 ppm (J = 13.2 Hz).
(14) Shen, Y. C.; Feng, X. M.; Li, Y.; Zhang, G. L.; Jiang, Y. Z.
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(19) A typical experimental procedure is as follows: to the ketone
(2–3 mmol) was added freshly distilled TMSCN (3 equiv,
distilled over CaH2) and ZnI2 (3–5 mg, dried over P2O5) and
the mixture was stirred at r.t. (or 90 °C for tetramic acid 2)
for 24 h (6 h for compound 9). The crude product was
immediately purified by flash chromatography using a
petroleum ether–EtOAc eluant.
(22) The reaction of 5b differs from the earlier cases, since it
exists exclusively as the enol tautomer, and product 6b/7b
was not stable.
(23) Additional support for the fact that lactam 10 was epimeric
at C-7 came from a consideration of 13C NMR values: the
13C nitrile resonances for the two disatereomers of 4a were
at d = 120.16 and 118.99 ppm, for 4b were at d = 122.32 and
119.32 ppm, and for 6a and 7a were at d = 119.08 and 118.86
ppm. For cyanohydrin 10, the corresponding values were
114.8 and 114.9 ppm, and for the single diastereomers 11
and 13, the values were 115.0 and 116.2 ppm.
(24) Chikashita, H.; Ishibaba, M.; Ori, K.; Itoh, K. Bull. Chem.
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Synlett 2004, No. 9, 1631–1633 © Thieme Stuttgart · New York