Catalytic, enantioselective alkylations of N,O-acetals

Full text of DOI:10.1021/jo982421t

2168
J . Org. Chem. 1999, 64, 2168-2169
Ta ble 1. Rea ction s of N,O-Aceta ls a n d Va r iou s
Ca ta lytic, En a n tioselective Alk yla tion s of
N,O-Aceta ls
Nu cleop h iles Ca ta lyzed by Com p lex 2
Dana Ferraris, Travis Dudding, Brandon Young,
William J . Drury III, and Thomas Lectka*
Department of Chemistry, J ohns Hopkins University,
3400 North Charles Street, Baltimore, Maryland 21218
yield
(%)
ee
(%)
Received December 10, 1998
entry
acetal
Nu
Xa
Ts
Ts
Ts
Mds
Mds
Ns
R
product
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1b
1c
1d
1e
1f
1f
1f
1g
1h
1d
4a
H
H
H
H
Et
Et
H
H
H
H
H
Ac
Et
93
85
81
87
92
89
89
78
73
75
86
88
85
95
90
76
94
90
87
85
96
89
70c
50
42
87
5a
5b
5c
5d
5d
5e
5f
5g
5h
5i
Over the past few years, asymmetric alkylation reactions
of acetals have attained a prominent position in organic
synthesis.1 Methods employing either chiral acetals or
promoters are well-known; however, those utilizing a sub-
stoichiometric quantity of catalyst on either achiral or
racemic acetals are few,2 and procedures employing N,O-
acetals remain unknown. We anticipated that the asym-
metric alkylation of N,O-acetals could efficiently lead to
useful chiral amines and amino acid derivatives, especially
in cases where the corresponding imines are less easily
accessed (eq 1). However, in order for an asymmetric variant
4bb
4c
4a b
4a b
4a b
4a
Ms
4a
SES
SES
SES
Ac
Ac
Ns
4bb
4c
4a
4a
4d
5j
5j
5k
a
Abbreviations: Ts ) p-toluenesulfonyl, Mds ) 2,6-dimethyl-
4-methoxybenzenesulfonyl, Ns ) p-nitrobenzenesulfonyl, Ms )
methanesulfonyl, SES ) trimethylsilylethanesulfonyl. Enantio-
meric excesses were determined by CHIRALCEL OD chiral HPLC
b
column unless otherwise noted. Reaction carried out in refluxing
CH2Cl2. c Enantiomeric excesses determined by 1H NMR in the
presence of Pr(hfc)3 chiral shift reagent.
procedure.5 We discovered that a unique transilylation
reaction starts off the catalytic, enantioselective alkylation;
other mechanistic investigations of our process reveal novel
features that may lend general significance to alkylations
of acetals by enol silanes.
to be successful, the Lewis acid catalyst must effectively
serve a dual role, namely to dissociate RO- and subsequently
to activate the intermediate imine toward enantioselective
addition. When X is an electron-withdrawing group, we have
found that racemic hemiacetals 1a -1h possessing a flexible
range of N-protecting groups become stable, convenient
precursors to useful enantioenriched products.3 We describe
the first high-yielding (73-93%) asymmetric alkylations (ee’s
up to 96%) of conveniently prepared N,O-acetals using our
versatile chiral Cu(I)-based Lewis acid catalyst 2. We also
summarize a process to synthesize several non-natural
amino acids4 in high yield using readily available precursors
via an in situ generation of N,O-acetals in a one-pot
When a solution of 1a and catalyst 2 (6 mol %) was mixed
at 0 °C with 2 equiv of enol silane 4a for 5 h, compound 5a
was produced in 93% yield and 95% ee (Table 1, entry 1).6
Although substrate 1a (X ) Ts, R ) H) is a highly crystalline
and stable starting material, removal of the tosyl group in
a subsequent step requires long reaction times and highly
acidic conditions.7 We envisaged that other more easily
removable sulfonamido protecting groups could be substi-
tuted for the tosyl group to provide complementary depro-
tection procedures. For example, acetal 1b, containing a 2,6-
dimethyl-4-methoxybenzenesulfonyl (Mds)8 group, reacts
with enol silane 4a in the presence of 6 mol % 2 to yield 5d
(87% yield, 94% ee, entry 4). It is noteworthy that the nature
of the leaving group in substrate 1c (OH vs OEt) does not
significantly lower the yield or selectivity of product 5d
(entry 5). Similarly, the 4-nitrophenylsulfonamido (Ns)9
acetal 1d affords product 5e in 87% ee and 89% yield (entry
6). Excellent selectivity (up to 96% ee) can also be achieved
(1) For reviews, see: Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry
1990, 1, 477-511. (b) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043-
1054. For mechanistic work on alkylation of acetals: (c) Sammakia, T.;
Smith, R. S. J . Am. Chem. Soc. 1994, 116, 7915-7916. (d) Sammakia, T.;
Smith, R. S. J . Am. Chem. Soc. 1992, 114, 10998-10999.
(2) Hoveyda et al. have developed a Ni-catalyzed alkylation reaction of
allylic acetals as formal equivalents for conjugate addition reactions: (a)
Gomez-Bengoa, E.; Heron, N. M.; Didiuk, M. T.; Luchaco, C. A.; Hoveyda,
A. H. J . Am. Chem. Soc. 1998, 120, 7649-7650. For reviews of achiral
R-amidoalkylation reactions, see: (b) Zaugg, H. E. Synthesis 1984, 85-110.
(c) Zaugg, H. E. Synthesis 1984, 181-212. For amido alkylation using
stoichiometric quantities of Lewis acid, see: (d) Mooiweer, H. H.; Ettema,
K. W. A.; Hiemstra, H.; Spekamp, W. N. Tetrahedron 1990, 46, 2991-2998.
(e) Renaud, P.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1986, 25, 843-
844. (f) Shono, T.; Matsumura, Y.; Tsubata, K. J . Am. Chem. Soc. 1981,
103, 1172-1175.
(3) Our recent work has focused on the use of chiral, transition metal-
phosphine complexes 2 to catalyze the addition of carbon-based nucleophiles
4 to imino esters 3 (X ) Ts) with high diastereo- and enantioselectivity to
yield protected amino acids 5: (a) Ferraris, D.; Young, B.; Dudding, T.;
Lectka, T. J . Am. Chem. Soc. 1998, 120, 4548-4549. (b) Ferraris, D.; Young,
B.; Cox, C.; Drury, W. J ., III; Dudding, T.; Lectka, T. J . Org. Chem. 1998,
63, 6090-6091. (c) Drury, W. J ., III; Ferraris, D.; Cox, C.; Young, B.; Lectka,
T. J . Am. Chem. Soc. 1998, 120, 11006-11007. The drawbacks of this
synthetic methodology are the purification and hydrolytic lability of the
imine 3 as well as the deprotection of the tosyl group after alkylation.
(4) Williams, R. M. Synthesis of Optically Active a-Amino Acids; Perga-
mon: New York, 1989.
(5) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett. 1995, 51,
5773-5776.
(6) General procedure for conduction of alkylation reactions: The catalyst
was made by dissolving (R)-Tol-BINAP (15 mg, 0.022 mmol) and
2
CuClO4•(CH3CN)2 (7 mg, 0.021 mmol) in CH2Cl2. To the tosyl acetal 1a (100
mg, 0.37 mmol) in CH2Cl2 (2 mL) was added the solution of catalyst 2. This
reaction mixture was cooled to 0 °C, and the enol silane 4a (142 mg, 0.74
mmol) was added to the reaction mixture over a period of 30 min. The
reaction was stirred at room temperature or heated to reflux until
completion as shown by TLC (30% EtOAc/hexanes). The reaction was
partitioned with water (3 mL) and CH2Cl2 (3 mL). The organic layer was
dried with MgSO4 and the solvent removed in vacuo. The crude residue
(200 mg) was subjected to column chromatography on silica gel to yield
128 mg of the final product (93% yield, 95% ee).
(7) Li, G.; Sharpless, K. B. Acta Chem. Scand. 1996, 50, 649-651.
(8) Fujino, M.; Wakimasu, M.; Kitada, C. Chem. Pharm. Bull. 1981, 10,
2825-2831.
(9) Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53, 15787-15798.
10.1021/jo982421t CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/18/1999

Communications
J . Org. Chem., Vol. 64, No. 7, 1999 2169
by using the trimethylsilylethanesulfonamido (SES)10 sub-
stituent on the N,O-acetal to form products 5g, 5h , and 5i
(entries 8-10). A slight loss in selectivity is noted when the
steric bulk of the sulfonamido group is diminished, as shown
in the alkylation of 1e (X ) Ms; 85% ee, entry 7). However,
the decrease in selectivity is more pronounced in the
alkylations of amide acetals 1g and 1h , affording product
5j in modest ee (entries 11 and 12). These results confirm
that the sulfonyl group is an important factor in determining
enantioselectivity.
Sch em e 1. P r op osed Mech a n ism of N,O-Alk yla tion
To demonstrate the flexibility of the alkylation reaction,
we tested a number of nucleophiles representing several
classes. For example, allylsilane 4b11 reacts with both
substrates 1a and 1f to afford products 5b and 5h in
excellent yield and selectivity (entries 2 and 9). Ketene acetal
4c also reacts well with these substrates to yield compounds
5c and 5i in 76% and 70% ee, respectively (entries 3 and
10). Once again, an array of sulfonamido groups including
SES,10 Mds,8 and Ns9 were highlighted. In the deprotection
step, compounds 5d , 5e, and 5g can be converted to amine
hydrochloride 6a in yields ranging from 75 to 87% with no
detectable racemization (eq 2).12 In fact, we used this
are not well-precedented to act as silylating reagents.14 This
anomaly prompted us to determine mechanistic details of
the enol silane reaction through 1H NMR experiments. For
example, when acetal 1a was dissolved in CD2Cl2 along with
1 equiv of enol silane 4a , an immediate change in the 1H
NMR spectrum occurred. The enol silane resonances disap-
peared, and those characteristic of acetophenone developed.
A second equiv of enol silane 4a was then added to the
mixture, and the reaction was monitored; no product forma-
tion was noted even after extended periods of time. After
addition of the catalyst 2, however, resonances due to
product began to appear.15 Interestingly, peaks due to the
intermediate imine 316 were not observed, nor were those
for the N-trimethylsilylated product 7 (Scheme 1). In our
previous work, imine 3 (X ) Ts) reacts with enol silane 4a
in the presence of catalyst 2 to produce 7 exclusively (Scheme
1)3 that retains its silyl group through aqueous workup. In
fact, product 7 will only partially desilylate in the presence
of 1:1 THF/H2O even after several hours but can be desilyl-
ated immediately upon treatment with fluoride or standard
column chromatography on silica gel. In the reaction of N,O-
acetal 1a with enol silane 4a no silylated product is observed
by 1H NMR or TLC. This finding leads us to suggest that
adventitious water, silanol, or an LnCu‚ROH species is
protonating the product immediately after alkylation,17 as
shown in a possible mechanism (Scheme 1). Not surprisingly,
only 1 equiv of enol silane 4a is needed to alkylate N,O-
acetals 1c and 1d in which O-silylation cannot take place.
Further studies on the scope and mechanism of the asym-
metric reactions of N,O-acetals are underway and will be
reported in due course.
methodology for the multigram synthesis of L-3-nitroben-
zoylalanine (6b, eq 2) in 48% overall yield from 1d (entry
13) using only 1 mol % 2. This compound is currently of
interest as an inhibitor of enzymes that metabolize trypo-
tophan, including kynurenine-3-hydroxylase and kynureni-
nase.13 In an effort to further simplify the synthesis of
protected amino acids 5a -5j, an efficient one-pot procedure
was developed. The condensation of ethyl glyoxylate and
p-toluenesulfonamide was done in CH2Cl2 over a 6 h period
in the presence of catalyst 2 (6 mol %). The reaction mixture
was then cooled to 0 °C, and 2 equiv of nucleophile 4a was
added. After 2 h, the reaction was subjected to aqueous
workup, and the product was isolated in 89% yield and 95%
ee. A one-pot procedure was also implemented for the
synthesis of compound 5g (76% yield, 93% ee).
To our surprise, the use of 1 equiv of enol silane 4a with
N,O-acetal 1a did not lead to product 5a with 6 mol % 2;
however, when 2 equiv was used, product 5a was formed in
good yield. Although silyl ketene acetals can be quenched
through silyl transfer reactions with alcohols, enol silanes
Ack n ow led gm en t. T.L. thanks the NSF Career pro-
gram for support and Eli Lilly for a Grantee Award. D.F.
thanks J HU for a Marks Fellowship.
Su p p or tin g In for m a tion Ava ila ble: General procedures for
the conduct of catalytic reactions, spectroscopic details for all new
compounds, and proof of absolute configuration.
(10) (a) Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. J . Am. Chem.
Soc. 1990, 112, 3475-3482. (b) Weinreb, S. M.; Demko, D. M.; Lessen, T.
A. Tetrahedron Lett. 1986, 42, 2099-2103.
J O982421T
(11) Narayanan, B. A.; Bunnelle, W. H. Tetrahedron Lett. 1987, 28, 6261-
6264.
(14) (a) Kita, Y.; Shibata, N.; Miki, T.; Takemura, Y.; Tamura, O. Chem.
Pharm. Bull. 1992, 40(1), 12-20. (b) Onaka, M.; Ohno, R.; Izumi, Y.
Tetrahedron Lett. 1989, 30, 747-750.
(12) All deprotection products 6a were converted to L-benzoylalanine
upon acidic hydrolysis. The hydrolysis products were identical in every way
to the literature compound; see: Gulobev, A. S.; Sewald, N.; Burger, K.
Tetrahedron 1996, 52, 14757-14776. See Supporting Information for details.
(13) (a) Botting, N. P. Chem. Rev. 1995, 95, 1-412. (b) Pellicciari, R.;
Natalini, B.; Constantino, G. J . Med. Chem. 1994, 37, 647-655.
(15) See the Supporting Information for details.
(16) Imine 3 has been fully characterized by Wienreb et al.: Tschaen,
D. M.; Turos, E.; Weinreb, S. M. J . Org. Chem. 1984, 49, 5058-5064.
(17) For acid-catalyzed siloxane formation, see: Grubb, W. T. J . Am.
Chem. Soc. 1954, 76, 3408-3414.