Carbanion stabilization by distal silyloxy groups. Origin of the high diastereoselectivity in the formation of quaternary centers with aryllead(IV) triacetate reagents

Article abstract of DOI:10.1021/ol026863+

(formula presented) Derivatives of methyl 5-hydroxy-2-oxo-1-cyclohexanecarboxylate react with aryllead(IV) reagents in high yield and with wide variation in diastereoselectivity. Ab initio calculations are consistent with a heretofore unrecognized attract

Full text of DOI:10.1021/ol026863+

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4121-4124
Carbanion Stabilization by Distal
Silyloxy Groups. Origin of the High
Diastereoselectivity in the Formation of
Quaternary Centers with Aryllead(IV)
Triacetate Reagents
Joseph P. Konopelski,* Jinzhen Lin, Philip J. Wenzel, Hongbo Deng,
Gregory I. Elliott, and Brian S. Gerstenberger
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Cruz, California 95064
joek@chemistry.ucsc.edu
Received September 6, 2002
ABSTRACT
Derivatives of methyl 5-hydroxy-2-oxo-1-cyclohexanecarboxylate react with aryllead(IV) reagents in high yield and with wide variation in
diastereoselectivity. Ab initio calculations are consistent with a heretofore unrecognized attraction between the carbanionic center of the
â-ketoester intermediate and the distal OSiR group. This attractive interaction stabilizes the silyl group in the axial conformation and leads
3
to the excellent trans diastereoselection in the formation of quaternary centers.
Steric effects dominate the conformational analysis and
reactivity of substituted neutral six-membered ring systems.
However, studies by Nagao et al.1 and Woerpel and co-
workers2 have established dominant stereoelectronic effects
in the conformational preferences of 4-silyloxycyclo-
hexanones and 4-alkoxy-1-oxocarbenium ions, respectively,
resulting in a pseudoaxial orientation of the C-4 substituent,
which greatly affects reaction stereochemistry. Herein we
present synthetic and computational evidence to suggest that
a conceptually similar and heretofore unrecognized inter-
action between a â-ketoester anion and a distal OSiR3 group
in arylation reactions mediated by aryllead(IV) triacetate
reagents3 accounts for the exceptional stereoselectivity in the
formation of quaternary centers4 under very mild conditions.
The diastereoselectivity difference between compounds 1a
and 1b in reactions with 2 (Scheme 15) were of particular
Scheme 1
interest, since conventional conformational energies (“A
values”)6,7 and mechanistic analysis7 suggest that the “larger”
tert-butyl substituent should have afforded higher selectivity
(1) (a) Nagao, Y.; Goto, M.; Ochiai, M.; Shiro, M. Chem. Lett. 1990,
1503-1506. (b) Nagao, Y.; Goto, M.; Ochiai, M. Chem. Lett. 1990, 1507-
1510.
(2) Romero, J. A. O.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168-169.
(3) Elliott, G. I.; Konopelski, J. P. Tetrahedron 2001, 57, 5683-5705.
(4) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388-401. (b) Fuji, K. Chem. ReV. 1993, 93, 2037-2066. (c) Martin,
S. F. Tetrahedron 1980, 36, 419-460.
10.1021/ol026863+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/26/2002

in the C-C bond formation reaction. Since our previous
work suggested that C-5 alkyl substituents behaved in the
predicted manner, we focused our attention on the preparation
and reaction of a series of methyl 5-hydroxy-2-oxo-1-
cyclohexanecarboxylate derivatives.
Table 1. Arylation Results for 5-Substituted â-Ketoesters
The production of these compounds, while not difficult,
was surprisingly diverse. Acetate 4 was obtained by treatment
of 1b with Ac2O in the presence of a catalytic amount of
FeCl3‚6H2O8 to produce a mixture of the desired â-ketoester
and the corresponding enol carboxylate product 5. The latter
could be converted easily to desired product by mild base
treatment, affording an overall yield of 89%. Pivalate 6 was
prepared in an analogous procedure in 96% yield from 1b;
in this case, the corresponding enol carboxylate was not
formed (Scheme 2).
product,
% yield
-∆Gf
(kcal/mol)
â-ketoester (R)
ArPb(OAc)3
dre
9:1 4.7
1a (tert-butyl)a,b
1b (OTBDMS)a,b
1b (OTBDMS)a
1b (OTBDMS)c
4 (OAc)d
6 (OPiv)d
7 (OTIPS)d
8 (OTBDPS)d
11 (OMe)d
12 (OBn)d
2
2
13
14
2
2
2
2
2
3a , 96
3b, 97
15, 98
16, 98
17, 64
18, 68
19, 92
20, 95
21, 96
22, 85
20:1 1.06
30:1 1.06
30:1 1.06
4:1 0.68
6:1
15:1 0.94
>99:1 0.56
4:1 0.55-0.75
6:1
Scheme 2
2
a Reactions consisted of 1 mmol of â-ketoester, 1.4 mmol of aryllead(IV)
reagent, and 3.3 mmol of pyridine at RT. b Taken from ref 5. c Taken from
ref 12. d Reactions consisted of 1 mmol of â-ketoester, 1.4 mmol of
aryllead(IV) reagent, and 4.5 mmol of pyridine at 40 °C. e dr ) diastereomer
ratio. f Taken from refs 6 and 7.
Table 1 gives the results of reactions between the
series of â-ketoesters and aryllead(IV) reagents 2,10 13,11 and
14.12 The presence of acetate, pivalate, carbon ethers, or the
tert-butyl group at the C-5 position produces modest
selectivities. Compound 1a is the most selective of this group,
as would be expected due to its large A value. Conversely,
a 5-OSiR3 group affords very high stereoselectivity and the
results do not correlate with the published A values.
Variations in selectivity can be seen with changes in
aryllead(IV) reagent (13 and 14 are more selective than 2 in
reaction with 1b) and in the identity of the silyloxy
substituent (8 > 1b > 7). In all cases, the major product
was determined to have a trans relationship between the aryl
group and the C5 substituent by NOE correlation of the aryl
group to the C5 proton, both of which are axial sub-
stituents.5
Silyl protected compounds 7 and 8 were prepared by
slightly different routes (Scheme 3). Compound 1b was
Scheme 3
A computational study was undertaken to understand the
interaction, if any, between the 5-OSiR3 group and the
â-ketoester anion that could account for these results. We
selected the 5-OSiH3 group (i.e., 23) as a model for the
silyloxy-substituted anions employed in our synthetic work
and performed a complementary series of calculations on
the anion formed from 11 (5-OCH3) for comparison. Three
conformations of each anion were considered: a C-5 group
as an axial substituent with rotation toward the carbanion
(axial-endo conformer), a C-5 group as an axial substituent
with rotation away from the carbanion (axial-exo conformer),
and a C-5 group as an equatorial substituent on the carbanion
(equatorial). Selected results are shown in Table 2; full results
are available in Supporting Information.
treated with 1% HCl in EtOH to afford the corresponding
5-hydroxyl compound 9 in 88% yield, which was subjected
to TIPSCl/imidazole to give 7 in 95% yield. Conversely, the
synthesis of 8 evolved from the reaction of known ketone
109 with NaH/dimethyl carbonate. Ethers 11 and 12 were
prepared from 4-hydroxycyclohexanone. Ketal formation
preceded alkylation of the free hydroxyl group.9 Ketal
removal and carbomethoxy group installation completed the
synthesis.
(5) Elliott, G. I.; Konopelski, J. P.; Olmstead, M. M. Org. Lett. 1999, 1,
1867-1870.
(6) Eliel, E. L.; Satici, H. J. Org. Chem. 1994, 59, 688-689.
(7) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley and Sons: New York, 1994; pp 696-697 and 900-90l.
(8) Danishefsky, S. J.; Mantlo, N. J. Am. Chem. Soc. 1988, 110, 8129-
8133.
(10) Kozyrod, R. P.; Pinhey, J. T. Org. Synth. 1984, 62, 24-30.
(11) Kozyrod, R. P.; Morgan, J.; Pinhey, J. T. Aust. J. Chem. 1985, 38,
1147-1153.
(9) Majewski, M.; MacKinnon, J. Can. J. Chem. 1994, 72, 1699-1704.
(12) Deng, H.; Konopelski, J. P. Org Lett. 2001, 3, 3001-3004.
4122
Org. Lett., Vol. 4, No. 23, 2002

The atomic and group charges do not change from one
computational method to another. We conclude that the
polarization of the silyl group allows for favorable intra-
molecular stabilization of the carbanionic charge. Thus,
5-OSiR3 compounds react through a unique ring con-
formation in which the axial C-5 substituent effectively
blocks the cis face of the â-ketoester anion, directing the
electrophilic lead(IV) reagent more dramatically toward trans
product formation than would be expected through the
normal mechanism. Larger alkyl groups on the silicon
atom afford increasing blockage and selectivity (8 vs 1b)
until the size of the alkyl groups precludes close contact with
the anionic center. We believe that this is the origin of the
lower selectivity of 7, which bears the very large OTIPS
group.15
Table 2. Computed Conformational Energies for Anions 11
and 23a,b
carbanion calculation axial-endo axial-exo
equatorial
11
6-31+G(d,p)
B3LYP
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
-0.9
-0.2
+1.64
+1.12
-5.1
-5.0
-3.3
-4.0
MP2c
MP3//MP2d
6-31+G(d,p)
B3LYP
MP2c
MP3//MP2d
23
+1.3 (+4.4) -1.6 (+1.2)
+1.5 (+5.0) -0.94 (+2.4)
+5.8
+4.7
+2.4
+2.2
a Values are in kcal/mol. b Values in parentheses are for the MP2 wave
function computed at the optimized geometry for that row; i.e., MP2//RHF
or MP2//B3LYP. c Insufficient disk space to compute the MP2 frequencies;
the B3LYP values were used. d MP3 wave function calculated at the MP2/
6-31+G(d,p) geometry.
The delocalized nature of a â-ketoester anion is well-
known. However, charge must be localized on carbon at the
transition state for the reaction to proceed. Bernasconi and
Wenzel16 have shown that this localization of charge raises
the TS energy above that of the delocalized anion. We
interpret the MP3//MP2 results as a favorable interaction
between the diffuse silicon atom and the carbanion, providing
stabilization via orbital interactions that compensate for the
destabilization of the transition state due to charge localiza-
tion.
Our basic calculations13 (first two rows for each com-
pound) are consistent with positive A values7 for the silyloxy
and methoxy groups. The equatorial conformer in anion 23
is lower in energy by 1.6 kcal/mol (RHF) to 0.94 kcal/mol
(B3LYP); the observed value for a neutral system is 0.74
kcal/mol for -OSiMe3. These computed values are enthalpy
differences: ∆H ) ∆Eelec + ∆zpe + ∆CvibT with both the
zero-point energy (zpe) and vibrational heat capacity ap-
propriately scaled.14 HoweVer, the axial-endo conformation
in 23, with the silyloxy oriented toward the carbanion, is
the lowest in energy when the effects of polarization are fully
deVeloped in the Moller-Plesset method for electron cor-
relation. These effects are clearly evident at both the MP2
and MP3 levels of calculation. By contrast, the calculations
on the carbanion of 11 at this level show no change in the
dominant conformation.
In conclusion, aryllead(IV) tricarboxylates have been
shown to be effective arylation agents for the formation of
sp2-sp3 bonds with a variety of carbon acids. The present
study indicates that extremely high and predictable dia-
stereoselectivity (>99:1) in the formation of highly func-
tionalized quaternary centers can be achieved under mild
conditions, providing new opportunities for stereoselective
synthesis. Computational data suggest that the origin of this
selectivity is a stabilizing effect between the carbanionic
center of the â-ketoesters and a distal OSiR3 group. Further
studies with aryllead(IV) reagents are ongoing in our
laboratory and will be reported in due course.
Figure 1 depicts the computed axial-endo conformation
for both anions. For 11, the distance between the anionic
Acknowledgment. We wish to thank NSF (CDA-
9724237) for funding the purchase of computer facilities.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.9; Gaussian,
Inc.: Pittsburgh, PA, 1998.
Figure 1. Calculated structures of the carbanions formed from 11
(left) and 23 (right) showing distances (Å) between the carbanionic
carbon and the methyl or silyl group. For 23, geometries around
the silicon atom are also given. (Carbon, gray; oxygen, red; silicon,
blue; hydrogen, white.)
(14) (a) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-
16513. (b) The enthalpy must be corrected for thermal effects to 298 K.
Since these calculations are relative to the center of mass, the vibrational
heat capacity is the only significant correction.
(15) For a review of the triisopropylsilyl group in organic chemistry,
see: Ru¨cher, C. Chem. ReV. 1995, 95, 1009-1064.
(16) (a) Bernasconi, C. F.; Wenzel, P. J. J. Am. Chem. Soc. 1994, 116,
5405-13. (b) Bernasconi, C. F.; Wenzel, P. J. J. Org. Chem. 2001, 66,
968-79.
center and the carbon of the C-5 substituent is invariant with
computational method. Anion 23, on the other hand, shows
significant variation in distance for the silicon atom to the
anionic center. In addition, the angles around the silicon atom
suggest partial rehybridization toward pentacoordinate ge-
ometry.
Org. Lett., Vol. 4, No. 23, 2002
4123

B.S.G. thanks NSF (REU Grant CHE-9987824). This work
was supported by the California DHS Cancer Research
Program (99-00632V-10129) and the American Cancer
Society (RGP-93-017-06-CDD). G.I.E. acknowledges a
Roche Bioscience (Palo Alto, CA) Fellowship in Synthetic
Organic Chemistry.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026863+
4124
Org. Lett., Vol. 4, No. 23, 2002