Enantioselective boronate additions to N-acyl quinoliniums catalyzed by tartaric acid

Article abstract of DOI:10.1021/ol2028702

Tartaric acid catalyzes the asymmetric addition of vinylboronates to N-acyl quinoliniums, affording highly enantioenriched dihydroquinolines. The catalyst serves to activate the boronate through a ligand-exchange reaction and generates the N-acyl quinolinium in situ from the stable quinoline-derived N,O-acetal.

Full text of DOI:10.1021/ol2028702

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6316–6319
Enantioselective Boronate Additions to
N-Acyl Quinoliniums Catalyzed by
Tartaric Acid
Tomohiro Kodama, Philip N. Moquist, and Scott E. Schaus*
Department of Chemistry and Center for Chemical Methodology and Library
Development (CMLD-BU), Life Sciences and Engineering Building, Boston University,
24 Cummington Street, Boston, Massachusetts 02215, United States
seschaus@bu.edu
Received October 24, 2011
ABSTRACT
Tartaric acid catalyzes the asymmetric addition of vinylboronates to N-acyl quinoliniums, affording highly enantioenriched dihydroquinolines.
The catalyst serves to activate the boronate through a ligand-exchange reaction and generates the N-acyl quinolinium in situ from the stable
quinoline-derived N,O-acetal.
Nucleophilic addition to quinolines is an effective
method to synthesize dihydroquinolines, useful synthons in
the construction of biologically active alkaloids.1 Shibasaki
reported the first catalytic, enantioselective addition to
quinoline, a Reissert-type reaction with trimethylsilylcya-
nide and a bifunctional phosphine-BINOLate catalyst.2
Alexakis performed a direct lithiation of quinolines in the
presence of a chiral diether catalyst.3 Recently, Takemoto
reported a Petasis-type reaction of quinolines with boronic
acids and a bifunctional thiourea catalyst.4 All of these
reactions require an in situ formation of an N-acyl quino-
linium generated by the addition of a chloroformate to
the quinoline electrophile. We hoped to utilize 2-ethoxy-
1-ethoxycarbonyl-1,2-dihydroquinolines (EEDQs) as
stable N-acyl quinolinium precursors to avoid the use
of chloroformates.5 Although EEDQs are reactive part-
ners in Petasis-like reactions,6 only one enantioselective
transformation of EEDQs has been reported.6c Herein,
we report the use of tartaric acid as a catalyst to perform
highly enantioselective additions of boronates to N-acyl
quinoliniums to form chiral dihydroquinolines.
Many of the seminal developments of asymmetric synthe-
sis and catalysis utilize tartaric acid derivatives as chiral
auxiliaries or catalysts.7 The Sharpless asymmetric epoxida-
tion,8 asymmetric allylborations,9 and asymmetric DielsÀ
Alder reactions10 are just a few examples of highly utilized
(5) (a) Belleau, B.; Martel, R.; Lacasse, G.; Menard, M.; Weinberg,
N. L.; Perron, Y. G. J. Am. Chem. Soc. 1968, 90, 823–824. (b) Belleau, B.;
Malek, G. J. Am. Chem. Soc. 1968, 90, 1651–1652. (c) Zacharie, B.;
Connolly, T. P.; Penney, C. L. J. Org. Chem. 1995, 60, 7072–7074.
(d) Hyun, M. H.; Na, M. S.; Min, C.-S. J. Chromatogr. A 1996, 732, 209–
214. (e) Hyun, M. H.; Kang, M. H.; Han, S. C. Tetrahedron Lett. 1999,
40, 3435–3438.
(6) (a) Batey, R. A.; MacKay, D. B.; Santhakumar, V. J. Am. Chem.
Soc. 1999, 121, 5075–5076. (b) Chang, Y. M.; Lee, S. H.; Nam, M. H.;
Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahedron Lett. 2005, 46, 3053–
3056. (c) Graham, T. J. A.; Shields, J. D.; Doyle, A. G. Chem. Sci. 2011,
2, 980–984.
(1) (a) Michael, J. P. Nat. Prod. Rep. 1995, 12, 77–89. (b) Rakotosou,
H.; Fabre, N.; Jacquemond-Collet, I.; Hannedouche, S.; Fouraste, I.;
Moulis, C. Planta Med. 1998, 64, 762–763. (c) Jacquemond-Collet, I.;
Hannedouche, S.; Fouraste, I.; Moulis, C. Phytochemistry 1999, 51,
1167–1169. (d) Houghton, P. J.; Woldemariam, T. Z.; Watanabe, Y.;
Yates, M. Planta Med. 1999, 65, 250–256. (e) Riva, R.; Guanti, G. Chem.
Commun. 2000, 36, 1171–1172.
(7) Gawronski, J.; Gawronski, K. In Tartaric and Malic Acids in
Synthesis: A Source Book of Building Blocks, Ligands, Auxiliaries and
Resolving Agents; Wiley-VCH: Weinheim, 1999.
(2) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 6327–6328.
(3) Amiot, F.; Cointeaux, L.; Silve, E. J.; Alexakis, A. Tetrahedron
2004, 60, 8221–8231.
(4) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007,
129, 6686–6687.
(8) (a) Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991;
Vol. 7, Chapter 3.2. (b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–
300.
r
10.1021/ol2028702
Published on Web 11/08/2011
2011 American Chemical Society

transformations employing the tartaric acid motif. Sur-
prisingly, tartaric acid itself has found little use as an
organocatalyst despite its ubiquitous nature and den-
sely functionalized structure.11 Instead, the role of
tartaric acid in asymmetric synthesis is most often as a
resolving agent.12
Table 2. Lewis Basic Solvents for the Asymmetric Addition of
Boronates to EEDQsa
Table 1. Asymmetric Addition of Boronates to EEDQsa
a Reactions were run with 0.20 mmol of 1, 0.3 mmol of 2, 0.02À0.04
mmol of 5, and 2.0 mmol of additive in solvent (1.0 mL) for 16 h at room
temperature under Ar, followed by aqueous workup and flash chroma-
tography on silica gel. b Yield of isolated product. c Enantiomeric ratios
determined by HPLC analysis using a chiral stationary phase. d Run for
48 h.
commercially available EEDQ 1 and diethyl styrylboro-
nate 2 afforded the desired product 3 in 24% yield and
54:46 er under these conditions (Table 1, entry 1). Switch-
ing to tartaric acid 5 and 10 mol % Yb(OTf)3 gave a similar
result (entry 2); however, omitting the Lewis acid cocata-
lyst led to increased enantioselectivity (entries 3 and 4). To
increase catalyst turnover, protic additives were employed
in the reaction (entries 5À7), and it was found 1 equiv of
CF3CH2OH increased the yield to 46% with a concomi-
tant increase in enantioselectivity of 81:19 er (entry 8).14
Use of 10 equiv of CF3CH2OH gave a 73% yield of 3 and
83:17 er (entry 11). Other tartaric acid derived catalysts,
such as the CAB-type catalyst 6 and diethyl tartrate 7, were
tested, but these catalysts did not perform well (entries 9
and 10). Takemoto and co-workers observed that the
enantioselectivity of their reaction depended on the
type of carbamate.4 Under the tartaric acid catalyzed
conditions, methyl and benzyl substituted carbamates
gave slightly lower selectivities and yields relative to
the ethyl carbamate (entries 12 and 13). The larger,
phenyl-substituted carbamate proved to be the least
effective N-acyl quinolinium precursor in this reaction
(entry 14).
a Reactions were run with 0.20 mmol of 1, 0.4 mmol of 2, 10 mol %
catalyst, and additive in solvent (1.0 mL) for 16 h at room temperature
under Ar, followed by flash chromatography on silica gel. b Yield of
isolated product. c Enantiomeric ratios determined by HPLC analysis
using a chiral stationary phase.
We began our studies using a Lewis acidÀBrønsted acid
catalyst system of 10 mol % tartramide 4 and 5 mol %
Yb(OTf)3, which was previously successful in catalyzing
the addition of boronates to 2H-chromene acetals.13 The
(9) (a) Haruta, R.; Ishiguro, M.; Ikeda, N.; Yamamoto, H. J. Am.
Chem. Soc. 1982, 104, 7667–7669. (b) Roush, W. R.; Walts, A. E.;
Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186–8190. (c) Hall, D. G. In
Boronic Acids;Preparations and applications in organic synthesis and
medicine: Wiley-VCH: Weinheim, 2005.
(10) (a) Narasaka, K.; Inoue, M.; Okada, N. Chem. Lett. 1986, 1109–
1112. (b) Furuta, K.; Miwa, Y.; Iwanaga, K.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 6254–6255. (c) Yamamoto, H.; Futatsugi, K.
Angew. Chem., Int. Ed. 2005, 44, 1924–1942.
(11) (a) Sugiura, M.; Tokudomi, M.; Nakajima, M. Chem. Commun.
2010, 46, 7799–7800. (b) Dominguez de Maria, P. ChemCatChem 2010,
2, 487–492.
(12) (a) Toda, F. Enantiomer Separation: Fundamentals and Practical
Methods; Kluwer Academic Publishers: Dordrecht, 2004. (b) Flack, H. D.
Acta Crystallogr. 2009, A65, 371–389.
(13) Moquist, P. N.; Kodama, T.; Schaus, S. E. Angew. Chem., Int.
Ed. 2010, 49, 7096–7100.
(14) For examples of ligand exchange catalysis: (a) Wu, T. R.; Chong,
J. M. J. Am. Chem. Soc. 2005, 127, 3244–3245. (b) Wu, T. R.; Chong,
J. M. J. Am. Chem. Soc. 2007, 129, 4908–4909. (c) Lou, S.; Schaus, S. E.
J. Am. Chem. Soc. 2008, 130, 6922–6923. (d) Barnett, D. S.; Moquist,
P. N.; Schaus, S. E. Angew. Chem., Int. Ed. 2009, 48, 8679–8682.
Org. Lett., Vol. 13, No. 23, 2011
6317

good yields and selectivities in NMP at low temperatures
(Table 3, entries 1 and 2), while electron-poor EEDQs
required slightly higher temperatures in HMPA (entries 3
and 4). The amido-substituted EEDQ afforded the dihy-
droquinoline 3f in 71% yield and 91:9 er (entry 5). The
higher reactivity of the electron-rich N-acyl quinolinium
precursors indicates the importance of stabilizing the
positive charge on the electrophilic iminium during the
rate-determining step. This trend of reactivity was also
observed in the tartaramide-catalyzed additions of boro-
nates to oxocarbeniums.13
Table 3. Tartaric Acid Catalyzed Addition of Boronates to
EEDQsa
Next, we expanded the scope of the reaction using
functionalized vinylboronates. Electron-donating groups
on the boronate gave good results using HMPA with
selectivities of >92:8 er (entries 6 and 9). Electron-with-
drawing boronates were also good partners in the reaction,
with a chlorine-substituted boronate affording product 3h
in 86% yield and 92.5:7.5 er (entry 7). The fluorine sub-
stituted boronate reacted slowly and was warmed to 4 °C
to afford 3l in 95:5 er (entry 11). The thiophene-derived
boronate gave 3i in an excellent selectivity of 96.5:3.5 er
(entry 8). Difunctionalized products 3mÀ3o were synthe-
sized in good yields and selectivity, and the reaction
appears tolerant of a variety of functionalizations on both
the boronate and EEDQ (entries 12À14).
a Reactions were run with 0.2 mmol of EEDQ, 0.3 mmol of boronate,
0.04 mmol of 5 and 2.0 mmol of Cl3CH2OH in NMP or HMPA (0.4 mL)
for 48 h under Ar, followed by aqueous workup and flash chromato-
graphy on silica gel. b Yield of isolated product. c Enantiomeric ratios
determined by HPLC analysis using a chiral stationary phase. d Entries
5, 10, 11, and 14 were run for 72 h. e Entries 6 and 8 were run for 24 h.
Scheme 1. Catalyst Resting State, Borate 9
Interestingly, increasing the Lewis basicity of the solvent
resulted in increased enantioselectivity and yield.15 Ethe-
real solvents THF and Et2O gave lower yields and selectiv-
ities than CH3CN (Table 2, entries 1 and 2). Reactions run
in DMF, tetramethylurea (TMU), and 1,3-dimethyl-2-
imidazolidinone (DMI) gave low yields but enantioselec-
tivities between 76:24 and 83:17 er (entries 3À5). Strongly
coordinating solvents, such as 1,3-dimethyl-tetrahy-
dropyrimidin-2-(1H)-one (DMPU), N-methylpyrroli-
dinone (NMP), and hexamethylphosphoramide (HMPA)
gave the best selectivity with HMPA, affording dihydro-
quinoline 3 in 96:4 er (entries 6À8). Increasing the amount
of tartaric acid to 20 mol % and lowering the temperature
of the reaction increased yields to 63% (entry 9 and 10).
Finally, a change to the slightly less acidic CCl3CH2OH
additive at À10 °C provided the optimal reaction condi-
tions and produced dihydroquinoline 3 in 96:4 er and 82%
yield (entry 12).
Mechanism studieswereundertakentoascertain therole
of the tartaric acid catalyst during the course of the
reaction. Although a double exchange reaction occurs
between catalyst 5 and boronate 2 the fate of the catalyst
after the reaction with the quinolinium remained unclear.
To understand whether the tartaric acid would remain free
in solution or bound to boron a series of experiments were
conducted. Triethyl borate and tartaric acid 5 were mixed
in HMPA for 5 min, and an aliquot of the solution was
injected into the ESI-MS (Scheme 1a). Monomeric borate
8 was notobserved inthe reaction, althoughitisprobablya
A substrate table was generated under the optimized
reaction conditions using HMPA and NMP as solvent.
First, we examined the effect of substitution at the 6-posi-
tion of EEDQ. Electron-donating groups on EEDQ gave
(16) (a) Henderson, W. G.; How, M. J.; Kennedy, G. R.; Mooney,
E. F. Carbohydr. Res 1973, 28, 1–12. (b) Chen, T. S. S.; Chang, C.; Floss,
H. G. J. Org. Chem. 1981, 46, 2661–2665. (c) Pizer, R.; Ricatto, P. J.
Inorg. Chem. 1994, 33, 4985–4990. (d) Pizer, R.; Ricatto, P. J.; Jacobson,
S. Inorg. Chem. 1995, 34, 1007–1008. (e) Yao, H.; Ji, M.; Ji, S.; Jiang, Y.;
Li, L.; An, Y. Inorg. Chem. Commun. 2007, 10, 440–442. (f) Hu, S.; Chen,
Y.; Zhu, H.; Zhu, J.; Yan, N.; Chen, X. J. Chromatogr. A 2009, 1216,
7932–7940.
(15) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560–1638.
6318
Org. Lett., Vol. 13, No. 23, 2011

fleeting intermediate in the reaction. Instead a mass was
observed for the dimeric tartaric acid adduct 9, a previously
reported tetracoordinated boron “ate” structure.16 To de-
termine whether boron “ate” 9 is catalytically viable, the
complex was formed in situ and used in the reaction
(Scheme 1b). Using 10 mol % 9under the optimized reaction
conditions, dihydroquinoline 3 was formed with similar
selectivity and yield as the original reaction conditions.
dioxaborolane 10. This exchange is likely facilitated
by the protic Cl3CH2OH additive.16 Next, activated
dioxaborolane 10 reacts with N,O-acetal 1 to form
the N-acyl quinolinium and boron “ate” intermediate 11.
Nucleophilic addition of the alkenyl group to the iminium
proceeds enantioselectively to furnish dihydroquinoline 3and
regenerate complex 9.
In summary, we have developed a nucleophilic bor-
onate addition reaction to stable EEDQs to form chiral
dihydroquinolines catalyzed by simple, inexpensive
tartaric acid. The reaction proceeds with high enan-
tioselectivity, good yield, and excellent functional
group tolerance. Mechanism studies indicated that
the tartaric acid activates the boronate via a double-
exchange reaction, and following the first catalytic
cycle the catalyst resting state is a tetracoordinated
boron “ate.” While often overlooked as a catalyst in
favor of its many derivatives, tartaric acid was found to
be a competent diol-exchange catalyst and the optimal
catalyst in this particular reaction. Further studies into
the application of tartaric acid in organocatalysis are
ongoing.
Scheme 2. Proposed Catalytic Cycle
Acknowledgment. This research was supported by the
NIH (R01 GM078240) and Dainippon Sumitomo Pharma
Co., Ltd. T.K. gratefully acknowledges support as a visit-
ing scientist from Dainippon Sumitomo Pharma Co., Ltd.
Our proposed catalytic cycle relies on the tetracoordi-
nated boron “ate” 9 as the resting state of the catalyst
(Scheme 2). The dimeric borate 9 undergoes a dispropor-
tionation with boronate 2 to form the activated alkenyl
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 23, 2011
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