Stereoselective synthesis of highly functionalized α-diazo-β- ketoalkanoates via catalytic one-pot mukaiyama-aldol reactions

Article abstract of DOI:10.1021/ol902872y

(Chemical Equation Presented) Methyl diazoacetoacetate undergoes zinc triflate catalyzed condensation with a broad selection of aldehydes to produce δ-siloxy-α-diazo-β-ketoalkanoates in good yield, and δ-hydroxy-α-diazo-β-ketoalkanoates are formed with high diastereoselectivity in reactions with α-diazo-β-ketopentanoate promoted by dibutylboron triflate.

Full text of DOI:10.1021/ol902872y

ORGANIC
LETTERS
2010
Vol. 12, No. 4
796-799
Stereoselective Synthesis of Highly
Functionalized r-Diazo-ꢀ-ketoalkanoates
via Catalytic One-Pot Mukaiyama-Aldol
Reactions
Lei Zhou and Michael P. Doyle*
Department of Chemistry and Biochemistry, UniVersity of Maryland, College Park,
Maryland 20742
mdoyle3@umd.edu
Received December 12, 2009
ABSTRACT
Methyl diazoacetoacetate undergoes zinc triflate catalyzed condensation with a broad selection of aldehydes to produce δ-siloxy-r-diazo-ꢀ-
ketoalkanoates in good yield, and δ-hydroxy-r-diazo-ꢀ-ketoalkanoates are formed with high diastereoselectivity in reactions with r-diazo-ꢀ-
ketopentanoate promoted by dibutylboron triflate.
Diazoacetoacetate derivatives are among the most commonly
used substrates in catalytic diazo decomposition reactions.1,2
Their relative stability compared to diazoacetates or vinyl-
diazoacetates, and their enhanced reaction selectivities
compared to diazoacetates, are among their advantages for
organic synthesis.1 Traditionally these diazo compounds have
been prepared by multistep synthesis involving diazo transfer
as the final step.3,4 Alternative methods that involve base-
mediated condensation of diazo compounds with various
electrophiles5,6 have not been generalizable because they
require stoichiometric amounts of base and often occur under
relatively harsh reaction conditions.
(3) Review :Regitz, M.; Maas, G. Diazo Compounds; Properties and
Synthesis; Academic Press: Orlando, FL, 1986
.
(4) (a) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem.
Soc. 1993, 115, 8669–8680. (b) Doyle, M. P.; Westrum, L. J.; Wolthuis,
W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am.
Chem. Soc. 1993, 115, 958–964. (c) Clemens, R. J.; Hyatt, J. A. J. Org.
Chem. 1985, 50, 2431–2435. (d) Clark, J. S.; Middleton, M. D. Org. Lett.
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; John Wiley & Sons: New York, 1998
.
(2) Reviews: (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem.
ReV., DOI: 10.1021/cr900239n. (b) Merlic, C. A.; Zechman, A. L. Synthesis
2003, 1137–1156. (c) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV.
2003, 103, 2861–2904. (d) Davies, H. M. L.; Antoulinakis, E. G. Org. React.
2001, 57, 1–326. (e) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A.
Chem. Soc. ReV. 2001, 30, 50–61. (f) Doyle, M. P. Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; John Wiley & Sons: New York, 2000.
(g) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1797–
1815. (h) Maas, G. Top. Curr. Chem. 1987, 137, 77–253. (i) Burke, S. D.;
2002, 4, 765–768
.
(5) Review: Zhao, Y.; Wang, J. Synlett 2005, 2886–2892
.
(6) (a) Wenkert, E.; McPherson, C. A. J. Am. Chem. Soc. 1972, 94,
8084–8090. (b) Moody, C. J.; Morfitt, C. N. Synthesis 1998, 1039–1042.
(c) Kanemasa, S.; Araki, T.; Kanai, T.; Wada, E. Tetrahedron Lett. 1999,
40, 5059–5062. (d) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285–
1287. (e) Sa, M. M.; Silveira, G. P.; Bortoluzzi, A. J.; Padwa, A.
Tetrahedron 2003, 59, 5441–5447. (f) Erhunmwunse, M. O.; Steel, P. G.
J. Org. Chem. 2008, 73, 8675–8677. (g) Dong, C.; Mo, F.; Wang, J. J.
Grieco, P. A. Org. React. 1979, 26, 361–475
.
Org. Chem. 2008, 73, 1971–1974.
10.1021/ol902872y  2010 American Chemical Society
Published on Web 01/26/2010

We have reported an efficient Mukaiyama-aldol reaction
between methyl 2-diazo-3-(trialkylsilanoxy)-3-butenoate and
both aromatic and aliphatic aldehydes catalyzed by scan-
dium(III) triflate,7 and more recently, a process improvement
in this reaction using zinc triflate has been described.8
Although methyl 2-diazo-3-(trialkylsilanoxy)-3-butenoate is
produced directly from methyl diazoacetoacetate under a
standard set of conditions (R3SiOTf, Et3N),9 we set out to
examine if the Mukaiyama-aldol reactions between aldehydes
and readily accessible diazoacetoacetates, rather than methyl
2-diazo-3-(trialkylsilanoxy)-3-butenoate, using catalytic
amounts of Lewis acid under mild conditions could be
achieved. Calter and Zhu previously described a stoichio-
metric version in which ethyl diazoacetoacetate underwent
condensation with aldehydes in the presence of stoichiometric
amounts of TiCl4 at -78 °C,10 and they also showed that
this condensation could be performed in a two-step process
from ethyl diazoacetoacetate (i: TMSOTf, Et3N in CH2Cl2,
-78 °C; ii: ArCHO, BF3·OEt2, -78 °C). We now report a
more efficient and general Lewis acid catalyzed one-pot
Mukaiyama-aldol reaction between diazoacetoacetates and
aldehydes with low catalyst loading of inexpensive zinc
triflate. On the basis of the same strategy but not indicated
in prior reports, we also report a highly diastereoselective
boron-mediated Mukaiyama-aldol reaction with the use of
R-diazo-ꢀ-ketopentanoate.
the presence of zinc triflate (3 mol %) at room temperature
(Scheme 1).
Recognizing that the regioselectivity for addition might
be dependent on the base employed, a weaker base, 2,6-
lutidine,11 was used in place of triethylamine for the reaction
with methyl diazoacetoacetate outlined in Scheme 1. Under
these conditions, the one-pot Mukaiyama-aldol reaction
proceeded to produce the 1,2-addition product in 90%
isolated yield to the virtual exclusion of the 1,4-addition
product. Reactions performed at 0 °C or room temperature,
however, produced up to 20% of the 1,4-addition product.
Table 1. One-Pot Mukaiyama-Aldol Reactions between Methyl
Diazoacetoacetate and R,ꢀ-Unsaturated Aldehydesa
Scheme 1
We first screened reaction conditions for the one-pot
Mukaiyama-aldol reaction. Reaction between methyl diaz-
oacetoacetate (2) and trans-p-methoxycinnamaldehyde in the
presence of a catalytic amount of zinc triflate, triethylamine
(3.0 equiv), and TBS triflate (1.2 equiv) at -78 °C yielded
both 1,2- and 1,4-addition products in a 5:1 molar ratio
(Scheme 1). This result is identical to that obtained from
the reaction of methyl 3-tert-butyldimethylsilanyloxy-2-
diazobut-3-enoate and trans-4-methoxycinnamaldehyde in
a Methyl diazoacetoacetate 2 (1.0 mmol), 2,6-lutidine (3.3 equiv), and
aldehyde (1.1 equiv) were added sequentially to zinc triflate (3 mol %) in
5 mL of dry DCM. After cooling to -78 °C, TBSOTf (1.25 equiv) was
added dropwise. The mixture was stirred at -78 °C then warmed to room
temperature over 16 h. b Yields were obtained by mass following flash
column chromatography. c Trace amounts of 1,4-addition product were
observed.
(7) Doyle, M. P.; Kundu, K.; Russell, A. E. Org. Lett. 2005, 7, 5171–
5174.
Examination of the scope of the reaction with a variety of
R,ꢀ-unsaturated aldehydes (1), the results for which are
presented in Table 1, showed the production of 1,2-addition
(8) Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008, 10, 1605–
1608.
(9) Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc.
1996, 118, 10774–10780.
(10) (a) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett.
1997, 38, 3837–3840. (b) Calter, M. A.; Zhu, C. J. Org. Chem. 1999, 64,
1415–1419.
(11) For prior use of 2,6-lutidine, see: Evans, D. A.; Downey, C. W.;
Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706–8707.
Org. Lett., Vol. 12, No. 4, 2010
797

products in very good yields (Table 1). R,ꢀ-Unsaturated
ketones do not react with methyl diazoacetoacetate under
the same conditions and, with substrates such as 2-cyclo-
hexenone, undergo preferential silyl enolization. That methyl
diazoacetoacetate reacted with TBS triflate in the presence
of 2,6-lutidine at low temperature to yield the vinyl ether,
methyl 3-tert-butyl-dimethylsilanyloxy-2-diazobut-3-enoate,
was confirmed by observing the transformation at low
entry 1i resulted in the production of 3i in nearly the same
yield (91% versus 93%) as when 3 mol % zinc triflate was
used. For the aliphatic aldehydes (1l and 1m), the standard
conditions (zinc triflate and 2,6-lutidine or zinc triflate and
triethylamine) led to less than full conversions over 16 h, so
scandium(III) triflate (3.0 mol %) and triethylamine (1.5
equiv) were used and resulted in complete conversion,
providing the desired products in good yields (Table 2). Even
the enolizable aldehyde (1l) underwent this reaction protocol
with excellent results.
1
temperature by H NMR (see Supporting Information for
details).
Table 3. One-Pot Mukaiyama-Aldol Reaction between Methyl
Table 2. One-Pot Mukaiyama-Aldol Reactions between Methyl
2-Diazo-3-oxo-pentanoate and Aromatic/Vinyl Aldehydesa
Diazoacetoacetate and Aromatic/Aliphatic Aldehydesa
a Reactions were performed as described in Table 1.
Diastereocontrol in Mukaiyama-aldol reactions is a uni-
versal problem whose solutions have been the subject of
numerous investigations.12 Using the Mukaiyama-aldol
protocol with methyl 2-diazo-3-oxo-pentanoate (4) under the
same conditions as those reported in Tables 1 and 2, we
discovered that the condensation products were produced as
a mixture of two diastereomers (anti/syn ∼ 2:1)13 in good
yields (Table 3). Similar results were obtained with the use
of stoichiometric TiCl4 (80% yield, syn:anti ) 77:23).
Although a number of approaches have been used to increase
(12) Representative examples: (a) Ollevier, T.; Bouchard, J.-E.; Desyroy,
V. J. Org. Chem. 2008, 73, 331–334. (b) Jankowska, J.; Paradowska, J.;
Rakiel, B.; Mlynarski, J. J. Org. Chem. 2007, 72, 2228–2231. (c) Boeckman,
R. K., Jr.; Pero, J. E.; Boehmier, D. J. J. Am. Chem. Soc. 2006, 128, 11032–
11033. (d) Kong, K.; Romo, D. Org. Lett. 2006, 8, 2909–2912. (e)
Jankowska, J.; Mlynarski, J. J. Org. Chem. 2006, 71, 1317–1321. (f) Jung,
M. E.; van den Heuvel, A. Org. Lett. 2003, 5, 4507–4707. (g) Hassfield, J.;
Christmann, M.; Kalesse, M. Org. Lett. 2001, 3, 3561–3564.
a Reactions were performed as described in Table 1. b Reaction catalyzed
by 1 mol % of Zn(OTf)2 gave the product 3i in 91% yield. c Sc(OTf)3 (3
mol %) and triethylamine (1.5 equiv) were used.
(13) The diastereomeric ratio was determined from 1H NMR integration
of the tertiary C-H bonded directly to the OTBS group. The coupling
constant J of the tertiary C-H: anti (threo) J ) 8.8-9.6 Hz, syn (erythro)
J ) 6.4-7.6 Hz.
This methodology was extended to aromatic and aliphatic
aldehydes. As shown in Table 2, reactions between methyl
diazoacetoacetate and aromatic aldehydes afforded the ad-
dition products in excellent yields and suggest the overall
generality of this protocol. Product yields were at least as
high as those reported for scandium(III) triflate catalyzed
reactions of some of these same aldehydes with methyl
2-diazo-3-(trialkylsilanoxy)-3-butenoate that were previously
reported by our group.7 Using 1.0 mol % zinc triflate with
(14) (a) Ghosh, A. K.; Shevlin, M. Modern Aldol Reactions; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 63-125. (b) Markert,
M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2009, 131, 16642–
16643. (c) Han, S. B.; Hassan, A.; Krische, M. J. Synthesis 2008, 17, 2669–
2679. (d) Nishiyama, H.; Shiomi, T. Top. Curr. Chem. 2007, 279, 105–
137. (e) Enders, D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857–7870. (f)
MacMillan, D. W. C. Nature 2008, 455, 304–308. (g) Bertelsen, S.;
Jorgensen, K. A. Chem. Soc. ReV. 2009, 38, 2178–2189.
798
Org. Lett., Vol. 12, No. 4, 2010

diastereoselectivity in aldol reactions,12,14 we selected di-n-
butylboryl triflate and diisopropylethylamine because of their
demonstrated ability to effect enolization at low tempera-
ture15 and because of the success of Evans and co-workers16
in using this combination to generate mainly Z-enol boronates
that subsequently react with aldehyde to afford syn-aldol
products.17
aromatic/vinyl/aliphatic aldehydes (1.0 equiv) at 0 °C af-
forded the syn-aldol product in good yields with very high
diastereoselectivity (Table 4). For the investigated aldehydes,
the syn/anti is above 96:4. For the reaction with benzalde-
hyde, the same yield and diastereoselectivity were obtained
when the reaction was performed at 0 °C as when the reaction
was performed at -78 °C. With triethylamine used in place
of Hunig’s base with entries 1c, 1i, and 1 m, 6c, 6i, and 6m
were obtained in lower yields (6c 60%, 6i 59%, 6m 51%)
but with nearly the same diastereoselectivities (6c, 99:1; 6i,
99:1; 6 m, 93:7).
Table 4. Boron-Mediated Aldol Reaction between Methyl
2-Diazo-3-oxo-pentanoate and Aldehydesa
Scheme 2
Consistent with the prior report of Calter and Zhu,10b
rhodium acetate catalyzed diazo decomposition produces the
corresponding O-H insertion product in excellent yield. This
reaction was explored with Mukaiyama-aldol adduct 6i
(Scheme 2). The tetrahydrofuran derivative 7 was formed
as a ∼5:3 diastereomeric mixture with the isomer having
the methylcarboxylate group trans to the benzene ring
predominating.
In summary, we have developed an efficient one-pot aldol
reaction between diazoacetoacetate with a wide spectrum of
aldehydes using catalytic amounts of zinc triflate, and we
also report a highly diastereoselective di-n-butylboryl-
mediated aldol reaction with the use of substituted diazoac-
etoacetate. This methodology can be used for the efficient
construction of highly substituted diazo compounds. The
synthetic utility of the Mukaiyama aldol adduct has been
demonstrated with the diazo decomposition/O-H insertion
reaction, and we anticipate additional uses of this methodol-
ogy with the synthesis of more complex R-diazo-ꢀ-ketoal-
kanoates than previously possible. Efforts are continuing to
develop the full synthetic potential of this methodology.
a Methyl 2-diazo-3-oxo-pentanoate 4 (2.0 mmol), N,N-diisopropylethy-
lamine (2.0 equiv), and di-n-butylboron triflate (1.1 equiv) were added
sequentially to 5 mL of dry DCM. After stirring at 0 °C for 15 min, aldehyde
(1.0 equiv) was added. The mixture was stirred at 0 °C for 3 h. b The
diastereomer ratio was determined by the integral ratio by 1H NMR of the
tertiary C-H bonded to the OH group and/or the integral ratio of 1H NMR
signals for the methyl group. c Yields were obtained by mass following
flash column chromatography.
To enhance the diastereoselectivity, a boron-mediated
Mukaiyama-aldol reaction was performed. As shown in Table
4, the reaction between methyl 2-diazo-3-oxo-pentanoate (4),
(n-Bu)2BOTf (1.1 equiv), Hunig’s base (2.0 equiv), and
Acknowledgment. We gratefully acknowledge the finan-
cial support provided by the National Institutes of Health
(GM46503).
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503–7509.
(16) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099–3111.
(17) (a) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.;
Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441–3442. (b) Abiko, A. Acc.
Chem. Res. 2004, 37, 387–395.
OL902872Y
Org. Lett., Vol. 12, No. 4, 2010
799