Diastereoselectivity in the formation of quaternary centers with aryllead(IV) tricarboxylates

Article abstract of DOI:10.1021/ol991143x

(formula presented) The formation of quaternary centers utilizing the reaction of aryllead(IV) tricarboxylates with β-ketoesters has been investigated. A series of substituted methyl 2-oxo-1-cyclohexanecarboxylates served as substrates for the evaluation

Full text of DOI:10.1021/ol991143x

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1867-1870
Diastereoselectivity in the Formation of
Quaternary Centers with Aryllead(IV)
Tricarboxylates
,†
Gregory I. Elliott,† Joseph P. Konopelski,* and Marilyn M. Olmstead‡
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Cruz, California 95064, and Department of Chemistry,
UniVersity of California, DaVis, California 95616
joek@chemistry.ucsc.edu
Received October 11, 1999
ABSTRACT
The formation of quaternary centers utilizing the reaction of aryllead(IV) tricarboxylates with â-ketoesters has been investigated. A series of
substituted methyl 2-oxo-1-cyclohexanecarboxylates served as substrates for the evaluation of diastereoselectivity in the sp2−sp3 bond forming
reaction with p-methoxyphenyllead tricarboxylates. Selectivities ranged from poor to excellent depending on the substituent. A comparison to
iodonium salts is discussed.
Quaternary center formation1 continues to provide challenges
to the synthetic organic chemist, and many ingenious
solutions to this problem have emerged. As part of our total
synthesis of the marine natural product diazonamide A,2 we
have explored the chemistry of aryllead(IV) tricarboxylates
as effective arylation reagents for the formation of sp2-sp3
bonds with carbon acids. Herein, we report our investigations
on the effects of variations in the substituents, temperature,
and base employed in the diastereoselective aryllead tricar-
boxylate reaction with substituted methyl 2-oxo-1-cyclo-
hexanecarboxylates.
available synthetic methods allow for the widest range of
substitutions on the aromatic nucleus. Second, these re-
agents contain only one aryl group (i.e., ArPb(OC(O)R)3)
that is transferred efficiently to the active methylene com-
ponent. Thus, the lead-based reagents are quite economical,
especially if a more elaborate and/or expensive aryl group
is required. Third, aryllead tricarboxylates afford C-arylation
products only.4 Finally, the mechanism of aryllead tricar-
boxylate arylation reactions has been shown to not involve
radicals.5
The stereochemistry of aryllead reactions has not been
extensively investigated. Pinhey et al. have reported diastereo-
selectivity for the arylation of two compounds,6 and Moloney
et al. have done the same for a single compound.7 We began
our studies with the reaction of 5-substituted methyl 2-oxo-
Arylation reactions mediated by organolead reagents have
been extensively studied by Pinhey.3 We found the reagents
particularly attractive for our total synthesis venture for a
number of reasons. First, they are easily prepared and the
(4) N-Arylation afforded by copper catalysis. See: (a) Lo´pez-Alvarado,
P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org. Chem. 1996, 61, 5865-70. (b)
Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org. Chem. 1995,
60, 5678-82. (c) Barton, D. H. R.; Donnelly, D. M. X.; Finet, J.-P.; Guiry,
P. J. J. Chem. Soc., Perkin Trans. 1 1991, 2095-02.
† University of California, Santa Cruz.
‡ University of California, Davis. Author to whom correspondence
concerning X-ray crystallography should be addressed.
(1) (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37,
388-401. (b) Fuji, K. Chem. ReV. 1993, 93, 2037-66. (c) Martin, S. F.
Tetrahedron 1980, 36, 419-60.
(5) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1993, 1673-
6.
(2) (a) Konopelski, J. P.; Hottenroth, J. M.; Mo´nzo-Oltra, H.; Ve´liz, E.
A.; Yang, Z.-C. Synlett 1996, 609-11. (b) Hang, H. C.; Drotleff, E.; Elliott,
G. I.; Ritsema, T. A.; Konopelski, J. P. Synthesis 1999, 398-400.
(3) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353-82.
(6) (a) Pinhey, J. T.; Rowe, B. A. Aust. J. Chem. 1980, 33, 113-20.
Our sample of 3b was spectroscopically identical to that described by Pinhey
in this article. (b) Morgan, J.; Pinhey, J. T.; Rowe, B. A. J. Chem. Soc.,
Perkin Trans. 1 1997, 1005-8.
10.1021/ol991143x CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/04/1999

1-cyclohexanecarboxylates 1a-d8 with p-methoxyphenyllead
triacetate 29 (Table 1). Excellent isolated yields are obtained
all three compounds to be identical to the solid-phase
depiction of 3a.
Temperature, counterion, and carboxylate variations are
shown in Table 2. All reactions in this study were performed
Table 1. Arylation Results for 5-Substituted â-Ketoesters 1a
Table 2. Arylation Results at Varying Conditions of 1ba
entry
R
R′
temp, °C
base
% yield of 3b dre
Ab
B
C
D
E
H
C(O)CH3
C(O)CH3
C(O)CH3
C(O)CH3
C(O)C6H5
C(O)CHCl2
60
25
70
4
25
25
25
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
none
61
66
59c
48d
62
6:1
9:1
6:1
10:1
9:1
9:1
H
H
H
H
H
F
G
65
60
Na C(O)CH3
9:1
a All reactions consisted of 1 mmol of 1b, 1.1 mmol of 2, and 3.3 mmol
of pyridine. b Taken from ref 6a. c No starting material remained at the end
of this reaction. d Starting material isolated (47%). e Diastereomer ratio.
a All reactions consisted of 1 mmol of 1, 1.4 mmol of 2, and 3.3 mmol
of pyridine at room temperature.
at the optimum reagent-to-substrate ratio of 1.4:1.0. Selec-
tivities range from poor for ketal 1d to excellent for protected
alcohol 1c.10
The stereochemistry of the final product was determined
with the aid of a single-crystal X-ray structure determination
of 3a (Figure 1b).11 This stereochemistry is the opposite of
with a reagent-to-substrate ratio of 1.1:1.0 so that the
persistence of starting material and/or byproducts could be
ascertained. In most cases reactions are quite clean, with
unreacted starting material (15-20%) and desired product
being the only identifiable materials in the mixture.12 Pinhey
has already reported that the formation of 3b at 60 °C affords
a diastereomeric ratio of 6:1 (entry A). The reaction at room
temperature (entry B) yields a 9:1 ratio of isomers. Lower
temperatures (entry D) afford a slightly greater selectivity
at the expense of yield, with the remaining mass consisting
of starting material. Conversely, higher temperatures (entry
C) lead to a slightly decreased yield and decreased selectivity,
with more byproduct formation and no recovered starting
material. Substitution of benzoate ligands onto the lead for
the kinetically labile acetates affords no stereochemical
advantage, nor does use of the more electron withdrawing
dichloroacetate ligand (entries E and F13). Finally, we were
intrigued with Pinhey’s results on the use of preformed
anions of â-ketoesters (sodium or potassium salts) in a THF/
pyridine mixed solvent system.14 In our hands, however, the
reaction proceeded in CHCl3 without any loss of yield or
diastereoselectivity with no added pyridine (entry G).
The major product of the preceding reactions is explained
by the generally accepted mechanism for electrophilic
Figure 1. (a) Depiction of solution structures of 3b (R ) tert-
butyl) and 3c (R ) OTBDMS), with NOE enhancement. (b) Solid-
state structure of 3a obtained from crystallography.
that proposed by Pinhey for 3b.6a However, we were able to
establish an NOE enhancement for the C5 proton of
compounds 3b and 3c when the ortho protons of the
p-methoxyphenyl group were irradiated and visa-versa
(Figure 1a). This establishes the solution conformation of
(10) General Procedure for Arylations. â-Ketoester (1 mmol) is stirred
in CHCl3 (5 mL) at room temperature. To this solution, pyridine (3.3 mmol)
is added and the solution allowed to stir for 10 min. A solution of aryllead
tricarboxylate (1.4 mmol) in CHCl3 (5 mL) is added. The resulting solution
is allowed to stir for 48 h at room temperature. The reaction is quenched
with the addition of H2SO4 (2 M solution, 3 mL) and stirred for an addition
5 min. The reaction mixture is passed through Celite to remove solid
material, the organic layer is separated, and the aqueous layer is extracted
with CHCl3 (3 × 5 mL). The organic layer is dried over sodium sulfate
and concentrated in vacuo. Column chromatography affords the desired
product. All new compounds have been fully characterized by infared and
(7) Dyer, J.; Keeling, S.; Moloney, M. G. Chem. Commun. 1998, 461-
2.
(8) Compound 1d has been described. See: Konopelski, J. P.; Deng,
H.; Schiemann, K.; Keane, J. M.; Olmstead, M. M. Synlett 1998, 1105-7.
Compound 1c has been fully characterized by infrared 500 MHz 1H and
13C spectra and elemental analysis.
1
(9) Kozyrod, R. P.; Pinhey, J. T. Org. Synth. 1984, 62, 24-30.
500 MHz H and 13C spectra and elemental analysis.
1868
Org. Lett., Vol. 1, No. 11, 1999

addition to â-ketoester enolates.15 The stabilized enolate
allows for a more product-like transition state in which the
differences between the possibilities (Aq for axial arylation
and Eq for equatorial arylation) are accentuated. As shown
in Figure 2, the transition state leading to (Aq) possesses a
giving the best selectivity (Table 3, entry 3e). The yield of
this reaction was poor, however, with no recovered starting
material. We suggest that this lone example of poor mass
recovery of a room-temperature reaction is due to over-
oxidation at the C3 center, with concomitant formation of
water-soluble materials. This side reaction may originate
from an increase in acidity of the C3 proton due to
complexation of the â-ketoester functionality with lead as a
Lewis acid. The high diastereoselectivity may also arise
through this mechanism; that is, by an equilibration of the
final product under the reaction conditions. Alternatively,
one diastereomer could oxidize more rapidly, resulting in a
significant increase in the amount of that isomer relative to
that of the least reactive isomer. These details also must await
further mechanistic studies. By contrast, the yield of product
3g is low, but starting material makes up the remainder of
material isolated. This low yield is most likely attributed to
enhanced steric interactions in that system.
Figure 2. Transition states for axial and equatorial attack of the
enolate of 1 on aryllead(IV) tricarboxylate reagent.
Recently, the use of mixed diaryliodonium salts for the
arylation of malonates has been reported.17 This interesting
methodology allows for the selective transfer of the most
electron deficient aryl group in a mixed diaryliodonium
reagent.18 For example, Oh et al.17 showed that phenyl
transferred at a rate 10 times greater than that of p-
methoxyphenyl to malonates and â-ketoesters when using
the mixed iodonium salt to afford desired products in good
yield. We elected to explore the limits of this reaction in
comparison to our organolead chemistry by preparing the
4,4′-dimethoxydiphenyliodonium salts19 and attempting the
arylation of the â-ketoesters 3. However, we were never able
to isolate more than a few percent of desired material from
the complex mixture that was formed under a variety of
reaction conditions. Thus, it would appear that the organolead
reagents are superior to the corresponding iodonium salts
for the transfer of electron rich aryl groups. Finally,
preliminary experiments using inductively coupled plasma
mass spectrometry (ICP-MS20) indicate residual lead levels
chairlike structure that minimizes torsional and eclipsing
strain, whereas the transition state leading to Eq possesses a
twist-boat structure with significantly more eclipsing interac-
tions between adjacent centers. Higher temperatures would
be expected to minimize these differences, lower tempera-
tures to accentuate them. Disubstitution at C5 negates any
preferred conformation and gives poor stereoselectivity
(Table 1, entry 3d). Changes in the ligand system of the lead
reagent or the method of carbocyclic anion formation seem
to have little effect (Table 2, compare entries B, E, F, and
G). Thus, to a first approximation, the aryllead reagent reacts
as any other electrophile with the stabilized enolate of 1.
However, this simple steric argument does not explain the
high degree of selectivity exhibited in the formation of 3c.
Literature values for conformational energies16 would suggest
a much higher selectivity for the production of 3b (R ) tert-
butyl) than for 3c (R ) OTBDMS). A final explanation for
this result must await further mechanistic study.
Table 3 shows the results obtained when the 3-, 4-, 5-,
and 6-methyl derivatives of methyl 2-oxo-1-cyclohexanecar-
boxylate are employed as substrates. The selectivities ranged
from moderate to excellent, with the 3-methyl derivative
(11) Crystals of 3a are triclinic, a ) 7.981(13), b ) 8.737(15), and c )
12.26(2) Å, R ) 80.61(2), â ) 73.49(2), and γ ) 66.55(2)°, space group
P1, Z ) 2, F ) 1.223 g/cm3 for C16H20O4. A total of 2897 independent
reflections were measured with graphite-monochromated Mo KR radiation
at 297(2) K on a Bruker SMART diffractometer in the θ range of 1.74-
26.00°. The structure was solved by using direct methods and refined to a
final R value of 5.32%. The primary program used was SHELXS-97, 1997,
by G. M. Sheldrick.
Table 3. Arylation Results for Substituted â-Ketoesters 1a
(12) Each entry in Table 1 was performed at the 1.1:1 ratio. Yields of
desired product ranged from 66 to 74%, with the remaining mass consisting
of starting material.
(13) Prepared as an intermediate in the synthesis of reagent 2. See ref 9
for details.
(14) (a) Kopinski, R. P.; Pinhey, J. T.; Rowe, B. A. Aust. J. Chem. 1984,
37, 1245-54. (b) Morgan, J.; Pinhey, J. T.; Rowe, B. A. J. Chem. Soc.,
Perkin Trans. 1 1997, 1005-8.
(15) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
John Wiley and Sons: New York, 1994; pp 900-1.
(16) See ref 15, p 696.
entry
R
% yield 3
diastereomer ratio
e
f
a
g
3-Me
4-Me
5-Me
6-Me
16b
65
74
23
15:1
3:1
7:1
(17) Oh, C. H.; Kim, J. S.; Jung, H. H. J. Org. Chem. 1999, 64, 1338-
40.
(18) (a) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998, 120,
13523-24. (b) See ref 17.
9:2
(19) (a) Beringer, F. M.; Falk, R. A.; Karnol, M.; Lillien, I.; Masullo,
G.; Mausner, M.; Sommer, E. J. Am. Chem. Soc. 1959, 81, 342-51. (b)
Beringer, F. M.; Drexler, M.; Gindler, E. M.; Lumpkin, C. C. J. Am. Chem.
Soc. 1953, 75, 2705-08.
a All reactions consisted of 1 mmol of 1, 1.1 mmol of 2, and 3.3 mmol
of pyridine at room temperature. b No starting material remained at the end
of this reaction.
(20) Gwiazda, R.; Woolard, D.; Smith, D. J. Anal. Atom. Spectrom. 1998,
13, 1233-38.
Org. Lett., Vol. 1, No. 11, 1999
1869

to be in the 40 ppm range for compounds 3a, 3b, and 3c
following our standard isolation procedure. Since no care
was taken to minimize the ambient lead contamination, these
results must be considered maximum levels in the samples
and, in fact, could be much lower.
In conclusion, we have shown that aryllead tricarboxylates
afford excellent yields of arylated products under mild
conditions. Diastereoselectivities can be excellent in certain
cases. These selectivities can be largely understood by
invoking the accepted mechanism of reaction between cyclic
â-ketoester enolates and electrophiles, although anomalies
exist. The use of aryllead reagents is preferred for the
introduction of electron rich aryl groups over the corre-
sponding diaryliodonium salts, and lead contamination of
the organic sample is minimal. Further studies of organolead
reagents are ongoing in our laboratory and will be presented
in due course.
for support of this work. In addition, we gratefully acknowl-
edge a Roche Biosciences (Palo Alto, CA) Fellowship in
Synthetic Organic Chemistry for G.I.E. Purchase of the 500
MHz NMR used in these studies was supported by funds
from the Elsa U. Pardee Foundation and the National Science
Foundation (BIR-94-19409). Finally, we are grateful to our
colleagues Professor Paul A. Wender (Stanford) and Profes-
sor Rebecca Braslau (UCSC) for very helpful discussion and
Steve Reaney and Professor Don Smith (UCSC Environ-
mental Toxicology) for lead analysis.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and X-ray crystal
structure data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. We wish to thank the American
Chemical Society-Petroleum Research Fund (32051-AC1)
OL991143X
1870
Org. Lett., Vol. 1, No. 11, 1999