Asymmetric catalytic C-H activation applied to the synthesis of syn-aldol products

Article abstract of DOI:10.1021/ol006671j

(formula presented) Rh₂(R-DOSP)₄-catalyzed decomposition of methyl phenyldiazoacetate in the presence of tetraalkoxysilanes results in the asymmetric synthesis of syn-aldol products. This catalytic asymmetric intermolecular C-H activ

Full text of DOI:10.1021/ol006671j

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4153-4156
Asymmetric Catalytic C−H Activation
Applied to the Synthesis of Syn-Aldol
Products
Huw M. L. Davies* and Evan G. Antoulinakis
Department of Chemistry, State UniVersity of New York at Buffalo, Box 603000,
Buffalo, New York 14260-3000
hdaVies@acsu.buffalo.edu
Received September 29, 2000
ABSTRACT
Rh2(R-DOSP)4-catalyzed decomposition of methyl phenyldiazoacetate in the presence of tetraalkoxysilanes results in the asymmetric synthesis
of syn-aldol products. This catalytic asymmetric intermolecular C−H activation proceeds by means of a rhodium−carbene-induced C−H insertion.
The metal-catalyzed decomposition of diazo compounds has
been extensively used in organic synthesis.1 In recent years
it has become clear that diazo compounds containing both
electron-withdrawing (EWG) and electron-donating groups
(EDG) (1) are especially useful because reactions of the
systems that contain only an EWG.1 Furthermore, by using
either Rh2(R-DOSP)4 (2) or Rh2(S-DOSP)4 as the catalyst
with such systems (1), highly enantioselective cyclopro-
panations can also be achieved.4,5
Recently, a new and general transformation for diazo
compounds 1 has been discovered. These diazo compounds
are capable of undergoing efficient asymmetric intermolecu-
lar C-H insertions.6,7 This reaction is used as a catalytic
(4) (a) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.; Fall, M. J. J.
Am. Chem. Soc. 1996, 118, 6897. (b) Davies, H. M. L.; Bruzinski, P. R.;
Fall, M. J. Tetrahedron Lett. 1996, 37, 4133. (c) Doyle, M. P.; Zhou, Q.-
L.; Charnsangavej, C.; Longoria, M. A.; McKervey, M. A.; Garcia, C. F.
Tetrahedron Lett. 1996, 37, 4129 (d) Davies, H. M. L.; Stafford, D. G.;
Doan, B. D.; Houser, J. H. J. Am. Chem. Soc. 1998, 120, 3326. (e) Davies,
H. M. L.; Kong, N. X.; Churchill, M. R. J. Org. Chem. 1998, 63, 6586. (f)
Davies, H. M. L.; Nagashima, T.; Klino, J., III. Org. Lett. 2000, 2, 823.
(5) For general reviews, see: (a) Davies, H. M. L. Aldrichimica Acta
1997, 30, 105. (b) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459.
(6) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(b) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
(c) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1,
383. (d) Davies, H. M. L.; Hansen, T.; Hopper, D.; Panaro, S. A. J. Am.
Chem. Soc. 1999, 121, 6509. (e) Axten, J. M.; Ivy, R.; Krim, L.; Winkler,
J. D. J. Am. Chem. Soc. 1999, 121, 6511. (f) Davies, H. M. L.; Stafford, D.
G.; Hansen, T.; Churchill, M. R.; Keil, K. M. Tetrahedron Lett. 2000, 41,
2035. (g) Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725. (h) Davies, H.
M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063.
(7) For a general review, see: Davies, H. M. L.; Antoulinakis, E. G. J.
Organomet. Chem., in press.
carbenoids derived from such systems are highly chemo-
selective.2 Highly diastereoselective cyclopropanations are
routinely achieved with such systems3 even though poor
diastereoselectivity is a recurring problem in diazoacetate
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley-Interscience: New
York, 1998; pp 112-162.
(2) Davies, H. M. L.; Panaro, S. A. Tetrahedron 2000, 56, 4871.
(3) (a) Davies, H. M. L.; Church, L. A.; Clark, T. J.; Chee, E. H.
Tetrahedron Lett. 1989, 30, 4653. (b) Davies, H. M. L.; Rusiniak, L.
Tetrahedron Lett. 1998, 39, 8811.
10.1021/ol006671j CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/01/2000

asymmetric method for the C-H activation of alkanes.6a,h
One novel application of this chemistry is for the asymmetric
synthesis of syn-aldol products8 by reaction of aryldiazo-
acetates with allyl silyl ethers (Scheme 1).6c The Rh2(R-
exclusively at the methylene adjacent to the oxygen, and only
one insertion occurring on each substrate molecule with all
substrates tested.
The C-H insertion occurs preferentially at a methylene
site as illustrated in Scheme 3. A competition reaction
Scheme 1
Scheme 3
DOSP)4-catalyzed reaction of p-chlorophenyldiazoacetate
with trans-disubstititued allyl silyl ethers occurs with high
diastereoselectivity and moderate enantioselectivity.6c In this
Letter we report that tetraalkoxysilanes are exceptional
reactants for this type of C-H insertion, which greatly
expands the synthetic utility of this novel transformation.
Even though our original study with allyl silyl ethers
resulted in effective C-H insertions, it also indicated that
the reaction was of limited scope.6c Highly diastereoselective
C-H insertions were obtained only when trans-allyl silyl
ethers were used as substrates. To broaden the scope of this
chemistry beyond allyl silyl ethers, the reaction with tetra-
alkoxysilanes as substrates was explored. The presence of
four active methylene sites per molecule was expected to
enhance the C-H insertion chemistry. All of the reactions
were carried out in 2,2-dimethylbutane as solvent, which is
a good inert solvent for C-H insertion.6h Rh2(R-DOSP)4 (1
mol %) catalyzed decomposition of phenyldiazoacetate 3 in
the presence of tetraethoxysilane (4a) at room temperature
was very promising (Scheme 2).9 The C-H insertion product
between tetramethoxysilane (6) and tetraethoxysilane (4a)
leads to the formation of a single C-H insertion product,
5a, arising from exclusive insertion into tetraethoxysilane
(4a). The reaction with tetramethoxysilane (6) alone as the
trapping agent does not generate any C-H insertion product.
A second competition reaction between tetraethoxysilane (4a)
and tetraisopropoxysilane (7) again resulted in only a single
product, 5a, arising from exclusive C-H insertion into
tetraethoxysilane (4a). The reaction with tetraisopropoxy-
silane (7) alone as the trapping agent results in the formation
of C-H insertion product 8 in only 10% yield and 69% ee.
Scheme 2
(8) For reviews of catalytic enantioselective aldol reactions, see: (a)
Nelson, S. G. Tetrahedron Asymmetry 1998, 9, 357. (b) Carreira, E. M. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer, Berlin: 1999; Vol. III, pp 997-1066.
(9) General Procedure for C-H Insertion Reactions: A flame dried
50 mL round-bottom flask equipped with a magnetic stir bar and a rubber
septum was charged with silane (3.0 mmol), Rh2(R-DOSP)4 (14 mg, 7.5 ×
10-3 mmol), and degassed 2,2-dimethybutane (0.5 mL) and stirred under
argon at room temperature to give a green solution. A 10 mL gastight syringe
was charged with the diazo compound (0.75 mmol) in degassed 2,2-
dimethylbutane (7.5 mL) to give a 0.10 M diazo solution. Addition via
syringe pump was initiated at a rate of 3.75 mL/h (2 h addition time). After
the diazo addition was complete the reaction mixture was allowed to stir
for an additional hour and then the solvent and excess silyl ether were
removed in vacuo. Purification by flash chromatography on silica gel
(petroleum ether:ether, 9:1) gave the product as a clear oil. Diastereomeric
ratios were determined by 500 MHz 1H NMR of the crude reaction mixtures.
Diastereomeric ratios of >90% de could not be determined accurately from
the 1H NMR of the crude reaction mixtures and the products were not
sufficiently stable for analysis by GCMS. Enantiomeric excess (ee) was
determined by HPLC using a Chiralcel OD column and 2-propanol (0.8%
or 1.0%) in hexane as the eluent.
5a was formed in 70% yield, >90% de, and 95% ee. Similar
transformations with likewise high diastereo- and enantio-
selectivities were also possible with tetrapropoxysilane (4b)
and tetrabutoxysilane (4c). The chemoselectivity of these
reactions was extremely high, with insertion occurring
4154
Org. Lett., Vol. 2, No. 26, 2000

These reactions are excellent examples of the general trend
in these C-H insertions where there is a delicate balance
between steric and electronic effects.6,7 The C-H insertions
at sites (3°) that would most stabilize a buildup of positive
charge in the transition state are favored electronically, but
the carbenoid is unable to successfully approach these
sterically crowded sites. On the other hand, primary sites
are very sterically accessible; however, they are unreactive
toward C-H insertion, presumably because C-H bonds at
primary sites are stronger than those at secondary or tertiary
sites.
lacking the aryl ring, and this allows for broader possible
applications of this unusual reaction in synthesis.
The relative and absolute stereochemistry of the C-H
insertion product 5b was readily determined by hydrolysis
of the silyl group of 5b to give the alcohol 13, whose
enantiomer is known in the literature (Scheme 6).11 Syn
Scheme 6
An interesting opportunity that is available with this
chemistry is the formation of novel siloxy protecting groups
that are not generally obtained by the standard approach to
alcohol silylation. Two further examples are shown in
Scheme 4. Reaction of phenyldiazoacetate 3 with dimethyl-
stereochemistry was assigned by comparison of J values for
Ha, which was observed to be 6.2 Hz, to that reported in the
literature for the syn-isomer, 6.3 Hz. Absolute stereochem-
istry was determined to be (2R,3S), when using Rh2(R-
DOSP)4 (2), by comparison of the sign of optical rotation
of 13 ([R]24D +86.9, c ) 0.70, CHCl3, 92% ee), which was
found to be opposite that of the literature value ([R]20D -84.2,
c ) 0.87, CHCl3, 88% ee) for the (2S,3R) isomer. Similar
absolute and relative12 stereochemistries were assigned to
the other C-H insertion products, assuming a similar mode
of C-H insertion for all the substrates.
Scheme 4
The predictive model6h that has been used to determine
the stereoselectivity of these C-H insertions is illustrated
in Figure 1 using insertion into tetraethoxysilane with the
dimethoxysilane (9a) generated the C-H insertion product
10a in 93% ee. Similarly, reaction of 3 with diphenyl-
dimethoxysilane (9b) generated the C-H insertion product
10b in 94% ee.
The success of the intermolecular C-H insertion depends
on the unique characteristics of rhodium carbenoids contain-
ing both electron donor and acceptor groups.6g,h,7,10 The major
future challenge facing this chemistry will be to broaden the
range of carbenoids that have this donor/acceptor charac-
teristic in order to diversify the synthetic opportunities.
Vinyldiazoacetate 11 is also effective in this chemistry,
resulting in the formation of C-H insertion product 12 with
high enantioselectivity (97% ee) but moderate yield (32%)
(Scheme 5). Thus, it is possible to obtain syn-aldol products
Figure 1. Predictive model for C-H insertion.
Scheme 5
Rh2(R-DOSP)4 catalyst as an example. The catalyst is
considered to behave as if it is D2-symmetric with two
blocking groups on each face of the catalyst.4a,5 The approach
of the substrate occurs over the EWG (CO2Me) of the
rhodium carbenoid. While the hydrogen undergoing the
(10) Davies, H. M. L.; Hodges, L. M.; Matasi, J. J.; Hansen, T.; Stafford,
D. G. Tetrahedron Lett. 1998, 39, 4417.
(11) Ahn, M.; Tanaka, K.; Fuji, K. J. Chem. Soc., Perkin Trans. 1 1998,
2, 185.
(12) Hydrolysis of products 5a-c, 10a, 10b, and 12 gave their corre-
sponding alcohols which all gave similar J values (4.8-6.7 Hz) for Ha,
indicating a syn relative stereochemistry for all the insertion products.
Org. Lett., Vol. 2, No. 26, 2000
4155

insertion is thought to approach side-on (14), the large
(OSi(OEt)3) group has been postulated to be pointing up,
away from the catalyst, in the least sterically demanding
position. The medium-sized (Me) group would then be
pointing out, away from the carbenoid, while the smallest
group (H) would face in toward the catalyst. The C-H
insertion is thought to occur in a concerted, nonsynchronous
mode, with buildup of positive charge on the carbon which
bears the hydrogen undergoing insertion (15).5b,6h When this
model is applied to the alkoxysilanes, it correctly predicts
the observed stereochemistry (Scheme 2).
In summary, these studies considerably enhance the utility
of the intermolecular C-H insertions of aryldiazoacetates.
â-Hydroxy esters are formed with high diasteroselectivity
and enantioselectivity. A major future challenge will be to
broaden the range of carbenoids that exhibit this exceptional
chemoselectivity.
Acknowledgment. This work was supported by the
National Science Foundation (CHE 972612).
OL006671J
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Org. Lett., Vol. 2, No. 26, 2000