1-Silyl-2,6-diketones: Versatile intermediates for the divergent synthesis of five- and six-membered carbocycles under radical and anionic conditions

Article abstract of DOI:10.1021/ol0613517

1-Silyl-2,6-diketones, readily prepared by addition of (silylmethyl)metal reagents to 1,5-lactols followed by oxidation of the resultant diols, can be efficiently transformed into 3-hydroxycyclohexanones, cyclohex-2-enones, or 1-(silylmethyl)cyclopentane-1,2-diols under nucleophilic, basic, or single electron-transfer reduction conditions, respectively. The latter cyclitols can be further transformed into 2-methylenecyclopentanols or 1-(hydroxymethyl) cyclopentane-1,2-diols by Peterson elimination or Tamao-Fleming oxidation, respectively.

Full text of DOI:10.1021/ol0613517

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3935-3938
1-Silyl-2,6-diketones: Versatile
Intermediates for the Divergent
Synthesis of Five- and Six-Membered
Carbocycles under Radical and Anionic
Conditions
Jose L. Chiara,* AÄ ngela Garc´ıa, Esther Sesmilo, and Tatiana Vacas
Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la CierVa, 3,
E-28006 Madrid, Spain
jl.chiara@iqog.csic.es
Received June 2, 2006
ABSTRACT
1-Silyl-2,6-diketones, readily prepared by addition of (silylmethyl)metal reagents to 1,5-lactols followed by oxidation of the resultant diols, can
be efficiently transformed into 3-hydroxycyclohexanones, cyclohex-2-enones, or 1-(silylmethyl)cyclopentane-1,2-diols under nucleophilic, basic,
or single electron-transfer reduction conditions, respectively. The latter cyclitols can be further transformed into 2-methylenecyclopentanols
or 1-(hydroxymethyl)cyclopentane-1,2-diols by Peterson elimination or Tamao−Fleming oxidation, respectively.
R-Silyl carbonyl compounds are highly versatile reagents that
can be utilized in a wide range of useful synthetic transfor-
mations.1 The particular reactivity of these compounds
originates in the relative weakness of the C-Si bond, which
is activated by the electron-withdrawing carbonyl group and
the pronounced propensity of the silyl group to migrate to
neighboring oxygen. Thus, R-silyl carbonyl compounds
rearrange stereoselectively to silyl enol ethers under thermal
conditions or in the presence of Lewis acids or metal
catalysts.2 R-Silyl aldehydes and R-silyl ketones are espe-
cially useful in the stereoselective synthesis of disubstituted
and trisubstituted olefins3 and in a wide variety of regio-
and diastereoselective electrophilic substitution reactions in
which the silyl group acts as a “traceless” directing group.4
However, despite this synthetic potential, the widespread use
of R-silyl carbonyl compounds has been limited by their high
propensity to suffer protiodesilylation and thermal rearrange-
ment.
(2) (a) Brook, A. G.; MacRae, D. M.; Limburg, W. W. J. Am. Chem.
Soc. 1967, 89, 5493-5. (b) Lutsenko, I. F.; Baukov, Y. I.; Dudukina, O.
V.; Kramarova, E. N. J. Organomet. Chem. 1968, 11, 35-48. For a recent
theoretical study on this rearrangement, see: (c) Takahashi, M.; Kira, M.
J. Am. Chem. Soc. 1999, 121, 8597-8603.
(3) (a) Hudrlik, P. F.; Peterson, D. J. Am. Chem. Soc. 1975, 97, 1464-
1468. (b) Utimoto, K.; Obayashi, M.; Nozaki, H. J. Org. Chem. 1976, 41,
2940-2941. (c) Hudrlik, P. F.; Hudrlik, A. M.; Misra, R. N.; Peterson, D.;
Withers, G. P.; Kulkarni, A. K. J. Org. Chem. 1980, 45, 4444-4448. (d)
Hudrlik, P. F.; Kulkarni, A. K. J. Am. Chem. Soc. 1981, 103, 6251-6253.
(e) Fu¨rstner, A.; Kollegger, G.; Weidmann, H. J. Organomet. Chem. 1991,
414, 295-305. (f) Barrett, A. G. M.; Hill, J. M.; Wallace, E. M. J. Org.
Chem. 1992, 57, 386-389. (g) Trost, B. M.; Ball, Z. T.; Kang, E.-J. Org.
Lett. 2005, 7, 4911-4913.
(1) (a) Landais, Y. Science of Synthesis 2002, 4, 757-771. (b) Larson,
G. L. AdV. Silicon Chem. 1996, 3, 105-271. (c) Colvin, E. W. In
ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 11, pp 317-
354. (d) Colvin, E. Silicon Reagents in Organic Synthesis; Academic
Press: London, U.K., 1988.
10.1021/ol0613517 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/08/2006

Due to our interest in the synthesis of carbocyclic
polyhydroxylated natural products and analogues,5 we de-
cided to explore the potential and versatility of 1-silyl-2,6-
diketones in carbocyclization reactions performed under
anionic and radical conditions. To our knowledge, R-silyl
ketones have never been used in intramolecular carbon-
carbon bond-forming processes. With this study, we intended
to develop a new synthetic strategy that could allow an
efficient access to a series of key intermediates for the
preparation of carbafuranoses, carbapyranoses, and natural
inhibitors of glycosidases with a C7 aminocyclitol ring.6 The
general synthetic plan is depicted in Scheme 1. Alicyclic
Scheme 2
Scheme 1
methylene (that flanked by the trialkylsilyl and carbonyl
groups)4c to form an intermediate R-trialkylsilyl enolate,
which could participate in an intramolecular Peterson ole-
fination reaction to afford cyclic enone E. Alternatively, the
intramolecular reductive coupling reaction of diketone C
would provide the cyclic pinacol F with a (trialkylsilyl)-
methyl substituent. The functionality present in this com-
pound endows it with a valuable synthetic versatility. Thus,
F could be subjected to a Peterson elimination reaction to
give allylic alcohol G, which can undergo a diversity of
further synthetic transformations. Alternatively, oxidation of
F under Tamao-Fleming conditions would afford branched
triol H.
We have successfully reduced this plan to practice using
the D-glucose-derived hemiacetal 1 as starting material. Thus,
treatment of 1 with PhMe2SiCH2MgCl afforded the open
chain diol 2 as a 2:1 mixture of diastereoisomers in almost
quantitative yield (Scheme 2).7 Swern oxidation of 2 cleanly
gave diketone 3, which, not surprisingly, proved to be
1-trialkylsilyl-2,n-diketones C could be readily accessed from
cyclic hemiacetal A by reaction with a ((trialkylsilyl)methyl)-
metal reagent and subsequent oxidation of the resultant diol.
Desilylative aldol cyclization of C, promoted by an appropri-
ate nucleophile, would produce â-hydroxy ketone D regi-
oselectively. Treatment of C with an appropriate base instead
would selectively remove a proton from the more acidic
Table 1. Carbocyclization of Crude Diketone 3 under Anionic
Conditions
(4) (a) Kuwajima, I.; Inoue, T.; Sato, T. Tetrahedron Lett. 1978, 4887-
4890. (b) McNamara, J. M.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 7371-
7372. (c) Inoue, T.; Sato, T.; Kuwajima, I. J. Org. Chem. 1984, 49, 4671-
4674. (d) Johnson, W. S.; Edington, C.; Elliott, J. D.; Silverman, I. R. J.
Am. Chem. Soc. 1984, 106, 7588-7591. (e) Fiorenza, M.; Mordini, A.;
Papaleo, S.; Pastorelli, S.; Ricci, A. Tetrahedron Lett. 1985, 26, 787-788.
(f) Matsuda, I.; Sato, S. J. Organomet. Chem. 1986, 314, 47-52. (g) Enders,
D.; Adam, J.; Klein, D.; Otten, T. Synlett 2000, 1371-1384.
(5) (a) Chiara, J. L.; Storch de Gracia, I.; Garcia, A.; Bastida, A.; Bobo,
S.; Martin-Ortega, M. D. ChemBioChem 2005, 6, 186-191. (b) Chiara, J.
L.; Garcia, A.; Cristobal-Lumbroso, G. J. Org. Chem. 2005, 70, 4142-
4151. (c) Chiara, J. L.; Garcia, A. Synlett 2005, 2607-2610. (d) Chiara, J.
L.; Storch de Gracia, I.; Bastida, A. Chem. Commun. 2003, 1874-1875.
(e) Storch de Gracia, I.; Bobo, S.; Martin-Ortega, M. D.; Chiara, J. L. Org.
Lett. 1999, 1, 1705-1708. (f) Bobo, S.; Storch de Gracia, I.; Chiara, J. L.
Synlett 1999, 1551-1554. (g) Storch de Gracia, I.; Dietrich, H.; Bobo, S.;
Chiara, J. L. J. Org. Chem. 1998, 63, 5883-5889. (h) Chiara, J. L. In
Carbohydrate Mimics: Concepts and Methods; Chapleur, Y., Ed.; Wiley-
VCH: New York, 1998; Chapter 7, pp 123-156 and references cited therin.
(6) For a recent review on this important family of compounds, see:
Mahmud, T. Nat. Prod. Rep. 2003, 20, 137-166.
entry
conditions
products (yield, %)a
1
2
3
CsF (3 equiv), MeCN, 0 °C, 4 h
LiCl (0.5 equiv), DMF, rt, 15 h
BF3‚OEt2 (2 equiv), CH2Cl2,
-78 °C, 7 h
4 (57), 5 (9), 7 (5), 8 (3)
4 (50), 5 (6), 8 (5)
4 (20), 8 (80)
4
SnCl4, (1.2 equiv), CH2Cl2,
-78 °C, 2.5 h
4 (47), 5 (14), 8 (17)
5
6
BEMP (0.5 equiv), THF, 0 °C, 5 h 4 (75), 7 (6), 8 (5)
KHMDS (1 equiv), THF, -78 °C, 4 (7), 6 (25), 7 (55)
3.5 h
7
LiHMDS (1 equiv), THF, -78 °C, 6 (9), 7 (76), 8 (8)
24 h
a Overall isolated yield from diol 2.
3936
Org. Lett., Vol. 8, No. 18, 2006

Scheme 3. Proposed Mechanistic Pathways for the Carbocyclization of 3 under Nucleophilic and Basic Conditions
unstable on silica gel and, accordingly, was used for ensuing
steps without purification.8 First, we tried to perform the
carbocyclization of 3 under anionic conditions. For this
purpose, we assayed the series of reagents and conditions
shown in Table 1, some of which have been previously
employed for intermolecular C-C bond forming processes
of R-silyl ketones.9 Both nucleophilic (entries 1 and 2) and
Lewis acidic conditions (entries 3 and 4) promoted the
regioselective desilylative aldol carbocyclization of 3 af-
fording a separable mixture of diastereoisomeric â-hydroxy
cyclohexanones 4/510,11 in moderate yield and with moderate
stereoselectivity (dr ) 3.4-8.3). In the case of BF3‚OEt2,
however, the major product was the protiodesilylated dike-
tone 8.12 No other carbocyclic regioisomeric aldol products
could be detected in any of the crude reaction mixtures (1H
NMR analysis).13 More interesting results were obtained
under basic reaction conditions. Thus, treatment of 3 with
substoichiometric amounts of the phosphazene base BEMP14
furnished â-hydroxy cyclohexanone 4 stereoselectively in
75% overall yield from 2 (entry 5). In contrast, deprotonation
of 3 with KHMDS yielded a mixture of cyclohexenone 715
and O-silylated â-hydroxy cyclohexanone 610 as major
products (entry 6). Treatment with LiHMDS instead maxi-
mized formation of 7 (76% overall yield from 2) at the
expense of 6.
The distinct outcomes observed for the nonionic BEMP
base and the metalated HMDS bases suggest different
mechanistic scenarios in each case (Scheme 3). Thus, the
BEMP-promoted aldol carbocyclization probably takes place
through nucleophilic activation of the silyl group16 to afford
enolate I, while the anionic bases are expected to produce
the regioselective deprotonation of 3, as previously explained,
to give an R-trialkylsilyl Z-enolate (J).17 Both enolates cyclize
stereoselectively via chairlike transition states. In the case
of J, an intermediate aldol product K is produced containing
a cis-â-silyl alkoxide, which partitions18 between Brook
rearrangement followed by protonation of the ensuing enolate
to give 6, and Peterson elimination to afford 7. As expected,
the Brook rearrangement is more efficient for the potassium
than for the lithium alkoxide.18
(7) For a similar transformation, see: Glanzer, B. I.; Gyorgydeak, Z.;
Bernet, B.; Vasella, A. HelV. Chim. Acta 1991, 74, 343-369.
(8) Flash chromatography (SiO2, EtOAc/hexanes 1:8 with 1% v/v Et3N)
of crude 3 afforded only a 42% yield of 3 along with protiodesilylated
diketone 8 (17%) and a 5:1 diastereoisomeric mixture of cyclohexanones 4
and 5, respectively (27%).
Compounds 4 and 7 are key intermediates for the prepara-
tion of carbapyranoses15a,19 and a number of important C7
aminocyclitol natural products6,11,15b including valiolamine,
valienamine and its derivatives, such as acarbose, the
validamycins, salvostatin, and the synthetic drug voglibose.
(9) For intermolecular cross-aldol reactions of R-silyl ketones promoted
by LDA, n-Bu4NF, BF3‚OEt2, TiCl4, or SnCl4, see: (a) Inoue, T.; Sato, T.;
Kuwajima, I. J. Org. Chem. 1984, 49, 4671-4674. (b) Kuwajima, I.; Inoue,
T.; Sato, T. Tetrahedron Lett. 1978, 4887-4890. Promoted by CsF: (c)
Fiorenza, M.; Mordini, A.; Papaleo, S.; Pastorelli, S.; Ricci, A. Tetrahedron
Lett. 1985, 26, 787-788. For intermolecular cross-aldol reactions of R-silyl
esters promoted by LiCl, see: (d) Miura, K.; Nakagawa, T.; Hosomi, A.
Synlett 2005, 1917-1921.
(14) BEMP: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine. (a) Schwesinger, R.; Schlemper, H. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1167-1169. (b) Schwesinger, R.; Willaredt, J.;
Schlemper, H.; Keller, M.; Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127,
2435-2454 and references therein.
(15) (a) Paulsen, H.; von Deyn, W. Liebigs Ann. Chem. 1987, 125-
131. (b) Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3651-3658.
(16) For recent examples of nucleophilic activation of silylated nucleo-
philes by phosphazene bases, see: Ueno, M.; Hori, C.; Suzawa, K.; Ebisawa,
M.; Kondo, Y. Eur. J. Org. Chem. 2005, 1965-1968.
(17) Ketones with large substituents form preferentially Z-enolates under
these conditions. See: Heathcock, C. H. Modern Synthetic Methods;
Scheffold, R., Ed.; VCH: New York, 1992; Vol. 6, pp 1-102.
(18) Moser, W. H. Tetrahedron 2001, 57, 2065-2084.
(19) For a review, see: Suami, T.; Ogawa, S. AdV. Carbohydr. Chem.
Biochem. 1990, 48, 21-90.
(10) The stereochemistry of the carbocyclic products was unambiguously
established through 1H NMR and 1D and 2D NOESY studies (see the
Supporting Information for details).
(11) The structures of 4 and 5 were further confirmed by comparison of
their physical and spectroscopic data with those described in the literature:
(a) Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3642-3650. (b) Mahmud,
T.; Xu, J.; Choi, Y. U. J. Org. Chem. 2001, 66, 5066-5073.
(12) (a) Ohtake, H.; Ikegami, S. Org. Lett. 2000, 2, 457-460. (b) Ohtake,
H.; Li, X.-L.; Shiro, M.; Ikegami, S. Tetrahedron 2000, 56, 7109-7122.
(13) Minor amounts (<10%) of three elimation products were isolated
in some of the reactions included in Table 1 (see the Supporting Information
for details).
Org. Lett., Vol. 8, No. 18, 2006
3937

Compared to previous approaches11,12,15 to those key inter-
mediates, our new method allows the divergent direct
preparation of both compounds from a common intermediate
in a shorter and more efficient route.
Scheme 5
We studied next the preparation of five-membered cyclitols
from diketone 3 via an intramolecular pinacol coupling
reaction (Scheme 4). This transformation was more ef-
Scheme 4
of 9 under Fleming conditions21 afforded the asymmetrically
protected polyhydroxylated meso cyclopentane 13 in excel-
lent yield.
In conclusion, alicyclic 1-trialkylsilyl-2,6-diketones are
versatile intermediates for the divergent preparation of a
variety of saturated and unsaturated five- and six-membered
cyclitols in a very efficient way, displaying a great potential
for inclusion in synthetic schemes oriented to the generation
of skeletal diversity.22
Acknowledgment. Financial support from the Ministry
of Science and Technology of Spain (project BQU2000-
1501-C02-01), Fundacio´n Ramo´n Areces, and Comunidad
de Madrid (predoctoral fellowships to A.G and E.S.,
respectively) are gratefully acknowledged.
ficiently performed starting from diol 2 and using our
previously developed5d,g,h one-pot methodology of Swern
oxidation followed by reductive coupling promoted by SmI2.
Under these conditions, a chromatographically separable
5.7:1 mixture of diastereoisomeric cis-cyclopentanediols 910
and 10,10 respectively, was obtained in moderate overall yield
together with a minor amount of diol 11,10 a deoxy analogue
of 9 resulting from the reductive elimination of the primary
benzyloxy group prior to the pinacol coupling step. To our
knowledge, this is the first example of a radical C-C bond
forming reaction involving an R-silyl carbonyl compound.
It is worth mentioning that this intramolecular diketone
reductive coupling is astonishingly fast, taking less than 5
min at -30 °C to go to completion.20
Supporting Information Available: Complete experi-
mental procedures and characterization data for compounds
2-13. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0613517
(20) This probably reflects a particularly facile single electron-transfer
reduction of the â-silyl carbonyl group. It has been proposed that â-silyl
alkyl radicals are stabilized by hyperconjugation involving the SOMO orbital
of the radical center and the HOMO of the proximal C-Si bond: Bernardi,
F.; Bottoni, A.; Fossey, J.; Sorba, J. Tetrahedron 1986, 42, 5567-5580.
(21) For a review, see: Jones, G. R.; Landais, Y. Tetrahedron 1996, 52,
7599-7662.
Compound 9 was further transformed into methylenecy-
clopentitol 12 via Peterson elimination reaction under either
acidic or basic conditions (Scheme 5). In addition, oxidation
(22) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302,
613-618.
3938
Org. Lett., Vol. 8, No. 18, 2006