Highly selective glycine phase-transfer catalysis using fluoroanthracenylmethyl cinchonidine catalysts

Article abstract of DOI:10.1016/j.tetlet.2005.03.185

Fluoroanthracenylmethyl cinchonidine phase-transfer catalysts have been produced and explored for asymmetric glycine alkylation. The fluoroanthracenylmethyl precursors were made from aryloxazolidinones and aldehydes using an efficient electrophilic substi

Full text of DOI:10.1016/j.tetlet.2005.03.185

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3839–3842
Highly selective glycine phase-transfer catalysis using
fluoroanthracenylmethyl cinchonidine catalysts
Merritt B. Andrus,* Zhifeng Ye and Jiuqing Zhang
Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, UT 84602, USA
Received 7 March 2005; accepted 28 March 2005
Available online 16 April 2005
Abstract—Fluoroanthracenylmethyl cinchonidine phase-transfer catalysts have been produced and explored for asymmetric glycine
alkylation. The fluoroanthracenylmethyl precursors were made from aryloxazolidinones and aldehydes using an efficient electro-
philic substitution with phosphorous pentoxide. The cinchonidine catalysts promote highly selective glycine alkylation under mild
conditions. The 1,8-difluoroanthracenyl-10-methyl catalyst 6 (10 mol %) in toluene/THF with 50% aqueous KOH (À20 °C) pro-
moted benzylation of glycine 1 to give 2 in 86% yield, 98% ee. Other electrophiles also gave excellent selectivity and reactivity.
Ó 2005 Elsevier Ltd. All rights reserved.
Phase-transfer catalysis (PTC) continues to develop as a
practical method for asymmetric synthesis. The process
is particularly attractive for glycine alkylation, conju-
gate addition, and epoxide formation.1 PTC has numer-
ous attractive features including the use of inexpensive,
cinchona alkaloid catalysts, which are readily available
in enantiomeric antipodes, simple hydroxide bases for
in situ enolate formation, and mild conditions per-
formed in either liquid–liquid or liquid–solid mode over
an extended temperature range. The formation of C–C
bonds through a direct alkylation is a significant syn-
thetic challenge with only a few successes based on cata-
lytic methods.2 PTC amino acid synthesis is facilitated
by the benzophenone imine tert-butyl glycine 1 (Scheme
1), pioneered by OꢀDonnell, due to its extended enolate
conjugation and relatively low pKa value (18.7,
DMSO).3 While there are many successful catalysts for
this substrate, the development of generally applicable,
readily available catalysts that can operate under mild
conditions, remain elusive. We now report a new class
of fluorinated anthracenylmethyl cinchonidine derived
catalysts that promote glycine alkylation with very high
reactivity and selectivity under mild conditions with a
wide range of electrophiles.
O
O
R*4N+
N
N
Ph
Ph
O-t-Bu
O-t-Bu
base
BnBr
Ph
Ph
Bn
1
2
3 Ar= phenyl
4
5
N+
9-anthracenyl
9
Ar
2,3,4-trifluorophenyl
O
N
F
F
F
F
F
8
F
6
F
7
Scheme 1.
Cinchonidine derived catalysts 3–5 (Scheme 1), bases,
and reaction condition variations have shown steady
improvement in selectivity for the production of S-2.3
Non-natural chiral bis-binaphthyl catalysts, that require
12 synthetic steps, have also demonstrated success
among others.3f,4 Asymmetric PTC reactions are re-
ported to follow an interfacial-type mechanism, where
Keywords: Phase-transfer catalysis; Alkylation; Cinchona alkaloid;
Organocatalysis.
*
Corresponding author. Tel.: +1 801 4228171; fax: +1 801 4220153;
e-mail: mbandrus@chem.byu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.185

3840
M. B. Andrus et al. / Tetrahedron Letters 46 (2005) 3839–3842
enolate formation occurs at the solvent interface
boundary layer and alkylation of the ammonium-eno-
late ion pair in the organic layer is the rate-limiting
step.5 The placement of a benzyl group on the quinucli-
dine nitrogen creates a well-defined binding site for the
enolate between the quinoline and the ethyl moieties 3.
Benzylation of 1 gives 2 in 75% yield (66% ee) with
C9-OH 3.3a The 9-methylanthracene 4, developed inde-
pendently by Corey and Lygo accentuates the steric con-
straints and provides a larger region for non-bonded
interaction leading to significant increases in selectivity.
In methylene chloride at À78 °C with CsOHÆH2O under
solid–liquid phase conditions, benzylation of 1 gives
87% yield (94% ee)3c with 4 (C9-Oallyl) and at 20 °C
in toluene (C9-OH) with 50% aqueous KOH, 2 was pro-
duced in 63% yield (89% ee).3d The report of Park and
Jew using various fluorinated benzyl cinchonidine cata-
lysts, including 5,3g demonstrates an important added
benefit to both reactivity and selectivity. Electronegative
fluoro substituents can contribute to the overall electron
deficiency of the positively charged catalyst enhancing
the degree of ion pairing with the enolate. This effect
is expected to facilitate both phase-transfer and enhance
non-bonded interactions leading to improved selectivity.
The steric advantage of the larger anthracenyl function-
ality is now combined with the beneficial electronic char-
acteristics of fluorine substitution. Catalysts with
specific fluoro substituents 6–8 were made and tested
for glycine alkylation.
(PPA),5 the desired 10-methylanthracene 13 was
obtained in only low to moderate yield (5–50%). Phos-
phorous pentoxide (P2O5) proved to be a more
reliable reagent for this challenging electron-deficient
electrophilic aromatic substitution step.7 When used in
o-dichlorobenzene (130 °C), 1,8-difluoro-10-methylan-
thracene 13 was obtained in 74% isolated yield. The
corresponding methyl bromide 14 was then generated
using NBS (N-bromosuccinimide) with AIBN (azo-
bis-isobutyronitrile) catalysis in benzene. Dihydrocin-
chonidine 15 was reacted with 14 to generate the quater-
nary ammonium bromide and treatment with allyl
bromide in the presence of base produced the desired
catalyst 6. Catalysts 7 and 8 were made following the
same 7-step route starting with oxazoline 9 and 4-fluoro-
benzaldehyde and the corresponding 3,5-difluorophen-
yloxazoline reacted with 4-fluorobenzaldehyde. The
intermediates were obtained with comparable yields
and the key electrophilic substitution steps using phos-
phorus pentoxide with the deactivated substrates were
equally efficient (69% and 71%, respectively).
Benzylation of glycine 1 was explored using the new cata-
lysts (10 mol %) in toluene–chloroform (7:3) with 50%
aqueous KOH initially at À20 °C (Table 1). Reaction
with the Corey/Lygo catalyst 4 at À20 °C gave 2 in
88% isolated yield under these conditions (95% ee). With
1,8-difluoro 6, the selectivity improved to 98% ee. 1,6-
difluoro 7 showed improved reactivity, 23 h versus
50 h, however the selectivity dropped to 95% ee. Triflu-
oro catalyst 8 did not show improved reactivity or selec-
tivity. At lower temperature, À40 °C, 6 gave comparable
yield and selectivity with a greatly slowed rate, 120 h.
Use of this catalyst 6 at 0 °C gave a similar yield in only
12 h with reduced selectivity (96% ee) and at rt, product
was obtained in 92% yield (91% ee) in only 8 h.
Following a modified route reported by Newman and
Kannan,6 m-fluoro phenyloxazolines 9 was o-metallated
and reacted with 2-fluorobenzaldehyde (Scheme 2).
Treatment of the reaction mixture with HCl gave lac-
tone 10 in 84% isolated yield. Hydrogenation with palla-
dium on carbon catalyst gave the diphenylmethyl
intermediate 11 in quantitative yield and treatment with
excess methyllithium provided the methyl ketone 12.
Following the reported use of polyphorphoric acid
The 1,8-difluoro catalyst 6 was explored under more
convenient, environmentally benign conditions using
toluene–THF mixture with 50% aqueous KOH (Table
2). With a 7:3 ratio of toluene–THF at À20 °C, 2 was
produced in 16 h with 82% yield and 97% ee. Using 1:1
toluene–THF, the reaction was completed in 8 h,
and the yield and selectivity remained high. 9:1 ratio
O
1) H2
Pd/C
O
n-BuLi
CHO
O
N
100%
F
/ HCl
F
9
84%
F
F
10
Table 1. Catalyst variation for glycine PTC
O
O
O
P2O5
o-DCB
R*4N+
N
Ph
N
Ph
2) MeLi
O-t-Bu
O-t-Bu
50% KOH/H2O
BnBr, tol/CHCl3 7:3
-20 ˚C
Ph
Bn
Ph
79%
F
76%
1
F
F
12
F
2
11
Catalyst
Temp (°C)
Time (h)
Yield (%)
Eea (%)
4
6
7
8
6
6
6
À20
À20
À20
À20
À40
0
44
50
23
54
120
12
8
88
88
92
86
87
88
92
95
98
95
92
98
96
91
N
Br
14
OH
N
NBS, AIBN
6
PhH, ∆
1) EtOH/DMF/CHCl3 75%
2) allylBr, KOH 69%
85%
13
F
F
23
Scheme 2.
a Enantiomeric excess determined by chiral HPLC (Chiracel OJ).

M. B. Andrus et al. / Tetrahedron Letters 46 (2005) 3839–3842
Table 2. Solvent variations for PTC alkylation
3841
-
Ph
O
O
N
N
N
6 10 mol%
Ph
N
Ph
O-t-Bu
E+
O-t-Bu
O
50% KOH/H2O
BnBr, tol/THF -20˚C
Ph
Bn
S-
2
E+
Ph
1
O-
H
2
N+
Tol/THF ratio
Time (h)
Yield (%)
Ee (%)
7:3
1:1
9:1
1:9
1:0
0:1
7:3
7:3
16
8
82
83
95
81
97
96
96
95
A
F
24
7
6
F
1
-or-
base
-
Ph
98a
98b
N
26
55
86
81
N
O
E+
a Performed at À40 °C.
R-
2
O-
H
b 5 mol % of catalyst was used.
E+
N+
affected the rate, 24 h, but not the yield or selectivity.
Lower temperature, À40 °C, required 26 h for comple-
tion and the selectivity was again excellent (98% ee).
Use of 5 mol % 6 greatly slowed the reaction rate to 55 h.
F
B
F
Figure 1. Transition state of the E-enolate from 1.
The new 1,8-difluoro catalyst 6 was applied to various
allylic, propargyl, and alkyl electrophiles at À40 °C (Ta-
ble 3). Allyl bromide reacted with excellent yield and
selectivity, 98% ee in 11 h. Methallyl bromide reacted
at a slower rate, but also gave 2 with 98% ee. Methyl io-
dide also gave 2 with high selectivity, however the yield
was reduced to 66%. TMS propargyl bromide reacted in
11 h, again with excellent yield and selectivity.
S-2 product as indicated. The other face of the enolate
is exposed in pathway B leading to the minor enantio-
mer R-2. In this case, the p-interaction is lost and the
electrophile trajectory is occluded by the anthracenyl
group of the catalyst. The presence of the fluoro substitu-
ents accentuates the electron deficiency of the ammo-
nium ion. This effect shortens the distance between the
enolate oxygen and the ammonium ion of the catalyst
in the tight ion pair, enhancing non-bonded interactions
leading to improved selectivity.
The tight-ion pair model of Corey can be used to rationa-
lize the stereoinduction (Fig. 1).3e The quinoline and
the ethyl group form a defined binding region for the
glycine enolate where the enolate oxygen points directly
at the less hindered face of the ammonium ion. The ex-
tended p-conjugation of the enolate and the imine adopt
a face to face p-interaction with the quinoline and the
tert-butyl group of the ester is placed over the anthra-
cene moiety in the favored pathway A. Alkylation,
opposite from the isoquinoline, generates the observed
New fluoroanthracenyl cinchonidinium catalysts were
produced that demonstrate enhanced reactivity and
selectivity for PTC glycine alkylation. Phosphorous
pentoxide mediates intramolecular electrophilic substi-
tution with the deactivated intermediates allowing for
specific placement of fluoro groups. Convenient li-
quid–liquid conditions with aqueous KOH in toluene–
THF are used at moderate temperatures to achieve high
reactivity and selectivity with a wide range of electro-
philes. These favorable results bode well for the use of
these catalysts with other substrates under PTC
conditions.
Table 3. PTC alkylation with electrophiles
O
O
N
6 10 mol%
Ph
N
Ph
O-t-Bu
O-t-Bu
50% KOH/H2O
RX, tol/THF -40˚C
Ph
R
Ph
1
2
Acknowledgements
RX
Time (h)
11
Yield (%)
87
Ee (%)
98
We are grateful for the support provided by the Ameri-
can Chemical Society Petroleum Research Fund—AC
(41552-AC1) and Brigham Young University.
Br
Br
28
21
11
90
66
92
98
97
98
CH3I
Supplementary data
Br
1H NMR and optical rotation data for all compounds
are provided. Supplementary data associated with this
TMS

3842
M. B. Andrus et al. / Tetrahedron Letters 46 (2005) 3839–3842
3038; (i) Kumar, S.; Ramachandran, U. Tetrahedron:
Asymmetry 2003, 14, 2539–2545.
article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.03.185.
4. (a) Ooi, T.; Uematsu, Y.; Kameda, M.; Maruoka, K.
Angew. Chem. Int. Ed. 2002, 41, 1551–1554; (b) Shi, M.;
Kazuta, K.; Satoh, Y.; Masaki, Y. Chem. Pharm. Bull.
1994, 42, 2625–2628; (c) Shibuguchi, T.; Fukuta, Y.;
Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 9539–9543; (d) Shirakawa,
S.; Yamamoto, K.; Kitamura, M.; Ooi, T.; Maruoka, K.
Angew. Chem. Int. Ed. 2005, 44, 625–628; (e) Kita, T.;
Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagasawa, K.
Angew. Chem. Int. Ed. 2002, 41, 2832–2834.
References and notes
1. (a) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–3028;
(b) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961–998;
(c) OꢀDonnell, M. J. Acc. Chem. Res. 2004, 37, 506–517; (d)
Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004, 37, 518–
526.
2. (a) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 62–63; (b) Andrus, M. B.; Hicken, E. J.; Stephens, J. S.
Org. Lett. 2004, 6, 2289–2292.
5. (a) Hughes, D. L.; Dolling, U. H.; Ryan, K. M.; Schoene-
wadt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52,
4745; (b) Lipkowitz, K. B.; Cavanaugh, M. W.; Baker, B.;
OꢀDonnell, M. J. J. Org. Chem. 1991, 56, 5181–5192; (c)
Starks, C. M. In Phase-Transfer Catalysis; Halpern, M. E.,
Ed.; ACS Symposium Series 659; The American Chemical
Society: Washington D.C., 1997, pp 10–28.
6. (a) Newman, M. S.; Kannan, J. Org. Chem. 1979, 44, 3388–
3390; (b) Newman, M. S.; Kannan, V. K. Bull. Soc. Chim.
Belg. 1979, 88, 871–872.
7. For related intramolecular electrophilic cyclizations of
methyl ketones using strong acid see: (a) Sainsbury, M.;
Mahon, M. F.; Williams, C. S.; Naylor, A.; Scopes, D. I. C.
Tetrahedron 1991, 47, 4195–4210; (b) Sainsbury, M.;
Williams, C. S.; Naylor, A.; Scopes, D. I. C. Tetrahedron
Lett. 1990, 31, 2763–2766.
3. (a) OꢀDonnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353–2354; (b) OꢀDonnell, M. J.; Delgado,
F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998,
39, 8775–8778; (c) Corey, E. J.; Xu, F.; Noe, M. C. J. Am.
Chem. Soc. 1997, 119, 12414–12415; (d) Lygo, B.; Wain-
wright, P. G. Tetrahedron Lett. 1997, 38, 8595–8598; For a
related unsaturated ester see: (e) Corey, E. J.; Bo, Y.;
Busch-Petersen, J. J. Am. Chem. Soc. 1998, 120, 13000–
13001; (f) Ooi, T.; Kameda, K.; Maruoka, K. J. Am. Chem.
Soc. 1999, 121, 6519–6520; (g) Jew, S.; Yoo, M.; Jeong, B.;
Park, I. Y.; Park, H. Org. Lett. 2002, 4, 4245–4248; (h)
Park, H.; Jeong, B.; Yoo, M.; Lee, J.; Park, M.; Lee, Y.;
Kim, M.; Jew, S. Angew. Chem. Int. Ed. 2002, 41, 3036–