An asymmetric, bifunctional catalytic approach to non-natural α-amino acid derivatives

Article abstract of DOI:10.1021/jo070472x

(Chemical Equation Presented) A catalytic, asymmetric process for the synthesis of 1,4-benzoxazinones from o-benzoquinone imides and ketene enolates is reported. Addition of Lewis acids (Zn(OTf)₂, In(OTf)₃, and in particular Sc(OTf)<

Full text of DOI:10.1021/jo070472x

An Asymmetric, Bifunctional Catalytic Approach
SCHEME 1. Bifunctional Catalytic System To Promote
4+2] Cycloaddition (Nu ) BQd or BQ)
[
to Non-Natural r-Amino Acid Derivatives
Daniel H. Paull, Ethan Alden-Danforth, Jamison Wolfer,
Cajetan Dogo-Isonagie, Ciby J. Abraham, and
Thomas Lectka*
Department of Chemistry, New Chemistry Building, Johns
Hopkins UniVersity, 3400 North Charles Street, Baltimore,
Maryland 21218
lectka@jhu.edu
ReceiVed March 6, 2007
SCHEME 2. Simple Derivatization To Yield r-Amino Acid
Derivatives
A catalytic, asymmetric process for the synthesis of 1,4-
benzoxazinones from o-benzoquinone imides and ketene
Asymmetric, bifunctional catalytic systems that promote
inverse electron demand hetero-Diels-Alder reactions are
virtually unknown, excepting an initial communication from our
enolates is reported. Addition of Lewis acids (Zn(OTf)
2
,
In(OTf) , and in particular Sc(OTf) ) creates a bifunctional
3
3
4
catalytic system that dramatically increases the reaction rate
and the yield of these non-natural amino acid precursors
while preserving the remarkable enantioselectivity inherent
to the reaction. Cocatalyst Sc(OTf) increases the yield by
3
up to 42% while producing products in >99% ee.
lab. We report a system in which a chiral nucleophile generates
dienophile activity while an achiral Lewis acid enhances diene
electrophilicity. These catalysts, working in tandem, promote
the enantioselective reaction of ketene enolates with o-benzo-
quinone imides to produce optically active 1,4-benzoxazinones
(4, Scheme 1) with greatly improved yield and excellent
enantiomeric excess (>99% ee).
5
The use of asymmetric, bifunctional catalytic systems for the
efficient synthesis of optically active compounds is an especially
active area of research in modern asymmetric catalysis. Systems
As previously described, these 1,4-benzoxazinone products
are readily converted into R-amino acid derivatives by in situ
methanolysis and a simple oxidation by ceric ammonium nitrate
(CAN) in an acetonitrile/water mixture. This process affords
the respective R-amino acid derivatives in good yield and in
virtually enantiomerically pure form (Scheme 2).
1
that attempt to mimic enzymatic efficiency by the simultaneous
activation of both substrates via the partnership of a Lewis acid
2
and a Lewis base are particularly attractive. The cooperative
action of these dynamic catalysts promotes respectively elec-
trophilicity and nucleophilicity in reactive partners. One obstacle
is that, theoretically, most Lewis acid/base pairs should self-
quench, yet when the right pair is combined, for example, a
hard metal ion and a softer base, reaction rates may increase
considerably.3
We had previously determined that the in situ methanolysis
proceeds quantitatively; mass loss must occur during the
formation of the 1,4-benzoxazines and may be a function of
the sluggishness of the cycloaddition reaction. A faster reaction
might therefore limit byproduct formation and increase the yield
of the desired product. We reasoned that a Lewis acid might
coordinate to the quinone imide, rendering it more electrophilic
without detriment to the nucleophilic catalyst, thereby increasing
the reaction rate and, subsequently, the chemical yield.
(
1) (a) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128 (51), 16438-16439.
b) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc.
(
2
007, 129 (4), 768-769.
(
2) (a) DiMauro, E. F.; Mamai, A.; Kozlowski, M. C. Organometallics
(3) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533-3539.
(4) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski, J. W.; Lectka,
T. J. Am. Chem. Soc. 2006, 128 (41), 13370-13371.
(5) Wolfer, J.; Bekele, T.; Abraham, C. J.; Dogo-Isonagie, C.; Lectka,
T. Angew. Chem., Int. Ed. 2006, 45 (44), 7398-7400.
2
003, 22, 850-855. (b) France, S.; Shah, M. H.; Weatherwax, A.; Wack,
H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206-1215. (c)
Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 10, 1491-
1
508.
10.1021/jo070472x CCC: $37.00 © 2007 American Chemical Society
5
380
J. Org. Chem. 2007, 72, 5380-5382
Published on Web 06/08/2007

TABLE 1. Metal Cocatalyst Effect on the [4+2] Cycloaddition
Reaction
TABLE 2. The Effect of Sc(OTf)3 Cocatalyst
no metal
10 mol % Sc(OTf)3
entry
MLn
% ee
% yielda
% ee % yielda
% yielda,b
entry
R1
% ee
1
2
3
4
5
6
Sc(OTf)3
Zn(OTf)2
In(OTf)3
AI(OTf)3
Cu(OTf)2
no metal
>99
>99
>99
>99
>99
>99
81
73
68
57
34
69c
1
2
3
4
5
6
7
8
4a Me
4b Me
4c Et
4d i-Pr
4e Ph
4f Bn
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
91
92
86
84
92
81
87
90
d
d
71
62
c
59
c,e
e
66
63
83
86
b
63
c
e
e
a
4g p-MeO-Ph
4h CH2Phthalimide >99
Reactions run with the quinone imide (0.12 mmol), dihydrocinnamoyl
chloride (0.12 mmol), H u¨ nig’s base (0.12 mmol), BQd (0.012 mmol), and
metal triflate (0.012 mmol), followed by addition of MeOH; percent yield
a
Reactions run with quinone imide (0.12 mmol), acid chloride (0.12
mmol), H u¨ nig’s base (0.12 mmol), and BQd (3a, 0.012 mmol), followed
by addition of MeOH; percent yield is for both steps. Reactions employed
cocatalyst Sc(OTf)3 (0.012 mmol). Previously reported yield, ref 5.
b
is for both steps. Previously reported yield, ref 5.
b
c
For guidance, we drew on our previous experience with
bifunctional catalytic systems, which focused on the cooperative
action of Lewis acids and cinchona alkaloid based nucleophilic
catalysts. One study screened Lewis acids for their ability to
activate imino esters toward nucleophilic attack by cinchona
alkaloid derived zwitterionic ketene enolates.2b This work
identified several Lewis acids that worked well in tandem with
our chiral nucleophilic catalyst, narrowing a range of metal co-
catalysts to complexes of Al(III), Zn(II), Sc(III), and In(III). In
another study, these same metals were found to activate o-benzo-
quinone diimides and improve their reaction with chiral ketene
d
Reactions employed BQ (3b, 0.012 mmol) instead of BQd and yielded
the opposite enantiomer. e Reactions required slow addition of a solution
of acid chloride over 6 h.
cycloaddition reaction (Table 2). The yields of the scandium
cocatalyzed reactions are universally high. Generally, the
addition of Sc(OTf)3 increased the reaction yields by an average
of 28%, and up to a 42% increase (Table 2, entry 4). Only two
reactions displayed less than a 29% increase: the reactions
involving p-methoxyphenylacetyl chloride and 3-phthalimi-
dopropionyl chloride each benefited from a scandium cocatalyst
by a modest 5% increase in yield. However, these were by far
the highest yielding no-metal reactions (Table 2, entries 7 and
).
Each reaction shown in Table 2 (entries 1 and 3-8) gave
the (R)-enantiomer in virtually enantiomerically pure form. The
S)-enantiomer can be obtained in similarly high enantioselec-
4
enolates. Though each reaction set prefers a different metal
complex, both reports demonstrated that the Lewis acid acts
through coordination with the respective electrophilic substrate.
On the basis of previous success, we tested the ability of these
metals to enhance the reaction between o-benzoquinone imides
and ketene enolates. We examined the effect of a metal
cocatalyst on the overall yield of a standard reaction. Several
metal triflates were screened in the reaction of the dichloroben-
zoquinone imide (1) and dihydrocinnamoyl chloride (Table 1).
Cocatalyst Sc(OTf)3 provided a nearly 30% increase in yield
relative to no metal. The strong Lewis acid activity of Sc(OTf)3
is expected because of its hard character and electron-delocal-
izing triflate group. Scandium has found considerable use in
catalysis of Diels-Alder-type reactions, and is particularly
known for catalyzing hetero-Diels-Alder cycloadditions. The
scandium complex promoted a faster, cleaner reaction than the
other metals tested, thereby making it the best overall Lewis
acid for this cycloaddition reaction.
Zinc(II) triflate was the second most efficient metal cocatalyst,
effecting a 16% increase in yield, and indium promoted a more
modest increase. It is not surprising that copper(II) triflate was
detrimental to the reaction; copper is known to have an affinity
for amines, and it is possible that this is an example of the self-
quenching catalytic system discussed previously. Most impor-
tantly, there was no erosion of ee when any of these metal
complexes were used as cocatalysts.
8
8
(
tivity and yield for every cycloaddition reaction when catalyst
pseudoenantiomer BQ (3b) is utilized (Table 2, entry 2). This
sense of induction is consistent with other asymmetric reactions
that have employed these cinchona alkaloids to catalytically
9
derive chiral ketene enolates. Importantly, the addition of the
scandium cocatalyst did not degrade or change the enantiose-
lectivity. In fact, in every chiral reaction assayed, the other
enantiomer was not detected by chiral phase HPLC. The
bifunctional catalytic system, employing scandium as a cocata-
lyst, provided faster, cleaner reactionssthey were generally
complete in less than half the time required for their no-metal
counterparts. By coordinating with the quinone imide function-
ality, scandium renders it more electrophilic and more suscep-
tible to nucleophilic attack by the catalytically derived chiral
ketene enolate; thus, scandium creates the bifunctional catalytic
system proposed in Scheme 3.
6
7
In conclusion, we have demonstrated an asymmetric, bifunc-
tional catalytic method that vastly improves the yield and
accessibility of non-natural R-amino acid precursors, 1,4-
Having established that the Sc(OTf)3 cocatalyst was the best
overall Lewis acid, we decided to screen several acid chloride
substrates to study the scope of scandium’s influence on the
(
8) Absolute configurations were determined previously by correlation
to several known R-amino acid derivatives; see ref 5.
9) (a) Bekele, T.; Shah, M. H.; Wolfer, J.; Abraham, C. J.; Weatherwax,
(
A.; Lectka, T. J. Am. Chem. Soc. 2006, 128 (6), 1810-1811. (b) France,
S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37
(8), 592-600. (c) France, S.; Weatherwax, A.; Lectka, T. Eur. J. Org. Chem.
2005, 475-479. (d) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.;
Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124 (23), 6626-6635.
(
6) Silvero, G.; Ar e´ valo, M. J.; Bravo, J. L.; AÄ valos, M.; Jim e´ nez, J. L.;
L o´ pez, I. Tetrahedron 2005, 61 (30), 7105-7111.
7) Kobayashi, S. Eur. J. Org. Chem. 1999, 15-27.
(
J. Org. Chem, Vol. 72, No. 14, 2007 5381

SCHEME 3. Proposed Mechanism of Bifunctional Catalysis
R ) CO-Ph-p-NO
-78 °C and monitored by TLC. When the reaction was complete,
it was quenched with methanol (3 mL) and allowed to warm to
room temperature overnight. The solvent was removed in vacuo
and the crude residue was purified by column chromatography to
(
2
)
yield pale yellow crystalline solid 4h: yield 90%; % ee >99; mp
1
8
(
8 °C; [R]
D
102.4° (c 0.9467, CHCl
3
); H NMR (CDCl
3
) δ 9.37
s, 0.85H), 9.10 (s, 0.15H), 8.01 (m, 2H), 7.85 (m, 2H), 7.42 (m,
2
2
1
1
H), 7.38 (2H), 6.85 (s, 1H), 6.29 (s, 1H), 4.93 (m, 1H), 4.24 (m,
H), 3.93, (m, 2.6H), 3.73 (s, 0.4H) ppm; 13C NMR (CDCl
) δ
3
72.5, 169.4, 168.2, 152.5, 148.5, 139.8, 134.8, 134.4, 131.4, 129.2,
28.7, 128.0, 123.9, 123.4, 122.9, 120.2, 64.4, 63.5, 54.5 ppm; IR
-
1
(solvent) 3193, 1774, 1719, 1672 cm ; HPLC (OD, 20% i-PrOH/
hexanes, 1.0 mL/min) (R) 17.00, (S) 47.04; HRMS (ESI+) calcd
+
2 3 8
for C25H17Cl N O Na 580.0285, found 580.0282.
Representative Procedure for Arylacetyl Chloride Reactions,
(R)-Methyl 2-(N-(4,5-Dichloro-2-hydroxyphenyl)-4-nitrobenza-
mido)-2-(4-methoxyphenyl)acetate (4g). A solution of p-meth-
oxyphenylacetyl chloride (0.12 mmol in 2 mL THF) was added
via syringe pump over 6 h, at -78 °C, to a reaction flask containing
benzoylquinidine (3a, 0.012 mmol), scandium(III) triflate (0.012
mmol, where indicated), H u¨ nig’s base (0.12 mmol), and quinone
imide (1, 0.12 mmol) in 3 mL of THF. The reaction was stirred at
-
78 °C and monitored by TLC. When the reaction was complete,
it was quenched with methanol (3 mL) and allowed to warm to
room temperature overnight. The solvent was removed in vacuo
and the crude residue was purified by column chromatography to
benzoxazines, in virtually enantiomerically pure form. The
catalyst used here, Sc(OTf)3, reduces reaction times and
increases chemical yield of the [4+2] cycloaddition by ef-
ficiently activating the quinone imide. Combined with methods
yield white crystalline solid 4g: yield 87%; % ee >99; mp 88 °C;
1
[R]
D
-10.9° (c 1.14, CHCl
3
); H NMR (CDCl
3
) δ 9.72 (s, 1H),
5
previously reported, the system presented here opens the door
8
2
.07 (m, 2H), 7.47 (m, 2H), 6.98 (m, 2H), 6.84 (s, 1H), 6.78 (m,
to a wide range of amino acids, both natural and non-natural,
with selectable enantiomers, in exceptional enantioselectivity
and high yields. The improved scope of this remarkably
enantioselective methodology now provides unhindered access
to this important class of chiral compounds that are otherwise
difficult to synthesize.
13
H), 6.35 (s, 1H), 6.23 (s, 1H), 3.91 (s, 3H), 3.76 (s, 3H) ppm;
C
NMR (CDCl ) δ 175.7, 169.9, 160.7, 154.1, 148.5, 140.6, 134.2,
3
132.6, 130.9, 128.2, 125.1, 123.3, 122.7, 122.4, 119.6, 114.7, 64.3,
-
1
55.4, 54.2) ppm; IR (CH
2 2
Cl ) 3207, 1715, 1662 cm ; HPLC
(
Whelk-01, 10% i-PrOH/hexanes, 1.0 mL/min) (R) 42.77, (S) 27.01;
+
HRMS (ESI+) calcd for C23
5
2 2 7
H18Cl N O Na 527.0383, found
27.0379.
Experimental Section
Acknowledgment. T.L. thanks the NIH (Grant GM064559),
the Sloan and Dreyfus Foundations, and Merck & Co. for
support.
Representative Procedure for Aliphatic Acid Chloride Reac-
tions, (R)-Methyl 2-(N-(4,5-Dichloro-2-hydroxyphenyl)-4-ni-
trobenzamido)-3-(1,3-dioxoisoindolin-2-yl)propanoate (4h). A
solution of quinone imide (1, 0.12 mmol in 1 mL THF) was added
dropwise, at -78 °C, to a reaction flask containing benzoylquinidine
Supporting Information Available: General procedures for the
synthesis of catalysts, quinone imide, and compound characteriza-
tion. This material is available free of charge via the Internet at
http://pubs.acs.org.
(
3a, 0.012 mmol), scandium(III) triflate (0.012 mmol, where
indicated), H u¨ nig’s base (0.12 mmol), and 3-phthalimidopropionyl
chloride (0.12 mmol) in 3 mL of THF. The reaction was stirred at
JO070472X
5
382 J. Org. Chem., Vol. 72, No. 14, 2007