Practical synthesis of fluorous oxazolidinone chiral auxiliaries from α-amino acids

Article abstract of DOI:10.1021/jo051696n

A series of new fluorous-supported oxazolidinone chiral auxiliaries has been prepared using a versatile and general five-step pathway, starting from readily available chiral α-amino acids. The key feature of this synthesis is the efficient generation of a suitably active perfluoroalkyllithium species. By use of this protocol, the auxiliaries can be obtained in high enantiomeric purity and on multigram scales from L-phenylalanine and L-valine with overall yields as high as 55%. The new methodology also incorporates fluorous solid-phase extraction on the large scale, allowing bulk quantities (up to 25 g) of fluorous compounds to be purified from the crude reaction mixture.

Full text of DOI:10.1021/jo051696n

Practical Synthesis of Fluorous Oxazolidinone Chiral Auxiliaries
from r-Amino Acids
Jason E. Hein, Laina M. Geary, Ashley A. Jaworski, and Philip G. Hultin*
Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada
email: hultin@cc.umanitoba.ca
Received August 10, 2005
A series of new fluorous-supported oxazolidinone chiral auxiliaries has been prepared using a
versatile and general five-step pathway, starting from readily available chiral R-amino acids. The
key feature of this synthesis is the efficient generation of a suitably active perfluoroalkyllithium
species. By use of this protocol, the auxiliaries can be obtained in high enantiomeric purity and on
multigram scales from L-phenylalanine and L-valine with overall yields as high as 55%. The new
methodology also incorporates fluorous solid-phase extraction on the large scale, allowing bulk
quantities (up to 25 g) of fluorous compounds to be purified from the crude reaction mixture.
Introduction
transformations.8,9 However, these examples cover a
relatively narrow range of reaction conditions and sub-
strates. Many polymer-supported auxiliaries have af-
forded inconsistent yields and/or levels of stereoselectivity
compared to the analogous solution-phase reactions.8,9b,c,f,10
These problems are the result of incompatibilities be-
tween the polymer support and the conditions applied,
leading to side reactions or degradation of the polymer
or difficulties in drying and purifying the polymer-bound
materials.9c,11
In contrast, many fluorous supported compounds are
soluble in typical organic reaction solvents, and the
support itself is impervious to most common reagents.
After a reaction is complete, selective recovery of sup-
ported material is usually easily accomplished by fluorous
Fluorous techniques have been applied to many chemi-
cal transformations, offering a powerful alternative to
standard polymer-supported methods.1 Initially proposed
as a method of separating catalysts from process streams,2
fluorous chains have been developed as general supports
for organic reagents and for synthesis by Curran et al.1,3
In addition to their uses in organic synthesis, fluorous-
tagged molecules have been employed by several re-
searchers in proteomics,4 nucleotide research,5 chroma-
tography,6 and supercritical fluid chemistry.7
We identified the fluorous tag as the ideal support for
applications in stoichiometric asymmetric synthesis.
Polymer-supported chiral auxiliary systems have been
created and successfully applied to several asymmetric
(8) For a recent review see: Chung, C. W. Y.; Toy, P. H. Tetrahe-
dron: Asymmetry 2004, 15, 387-399.
* To whom correspondence should be addressed. Tel.: 204-474-9814.
Fax: 204-474-7608. E-mail: hultin@cc.umanitoba.ca.
(1) Gladysz, J. A.; Curran, D. P.; Horvath, I. T. Handbook of
Fluorous Chemistry; Wiley: New York, 2004.
(9) Selected examples: (a) Kotake, T.; Hayashi, Y.; Rajesh, S.;
Mukai, Y.; Takiguchi, Y.; Kimura, T.; Kiso, Y. Tetrahedron 2005, 61,
3819-3833. (b) Desimoni, G.; Faita, G.; Galbiati, A.; Pasini, D.;
Quadrelli, P.; Rancati, F. Tetrahedron: Asymmetry 2002, 13, 333-
337. (c) Faita, G.; Paio, A.; Quadrelli, P.; Rancati, F.; Seneci, P.
Tetrahedron 2001, 57, 8313-8322. (d) Winkler, J. D.; McCoull, W.
Tetrahedron Lett. 1998, 39, 4935-4936. (e) Phoon, C. W.; Abell, C.
Tetrahedron Lett. 1998, 39, 2655-2658. (f) Burgess, K.; Lim, D. Chem.
Commun. 1997, 785-786.
(2) (a) Horvath, I. T. Acc. Chem. Res. 1998, 31, 641-650. (b) Horvath,
I. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1009.
(3) (a) Curran, D. P. Actual. Chim. 2003, 67-71. (b) Curran, D. P.
Pharm. News 2002, 9, 179-188. (c) Curran, D. P. Pure and Applied
Chemistry 2000, 72, 1649-1653.
(4) Brittain, S. M.; Ficarro, S. B.; Brock, A.; Peters, E. C. Nature
Biotechnol. 2005, 23, 463-468.
(10) Hutchison, P. C.; Heightman, T. D.; Procter, D. J. J. Org. Chem.
2004, 69, 790-801.
(11) (a) Bew, S. P.; Bull, S. D.; Davies, S. G.; Savory, E. D.; Watkin,
D. J. Tetrahedron 2002, 58, 9387-9401. (b) Bew, S. P.; Bull, S. D.;
Davies, S. G. Tetrahedron Lett. 2000, 41, 7577-7581.
(5) Beller, C.; Bannwarth, W. Helv. Chim. Acta 2005, 88, 171-179.
(6) Glatz, H.; Blay, C.; Engelhardt, H.; Bannwarth, W. Chro-
matographia 2004, 59, 567-570.
(7) Prajapati, D.; Gohain, M. Tetrahedron 2004, 60, 815-833.
10.1021/jo051696n CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/21/2005
9940
J. Org. Chem. 2005, 70, 9940-9946

Fluorous Oxazolidinone Chiral Auxiliaries
SCHEME 1. General Pathway for the Synthesis of Fluorous Chiral Auxiliaries from r-Amino Acids
SCHEME 2. Nucleophilic Perfluoroalkyl Additiona
solid-phase extraction (FSPE).12 We have demonstrated
that coupling fluorous synthesis with chiral auxiliary
methods is both viable and broadly applicable in our
published studies of model aldol reactions,13 conjugate
radical additions,14 and 1,3-dipolar cycloadditions15 using
fluorous oxazolidinone chiral auxiliaries 1 and 2 derived
from L-phenylalanine.
In this paper we report simple, efficient, and scaleable
syntheses of a series of fluorous chiral auxiliaries 2-4.
Our procedure (Scheme 1) consists of five steps: N-
protection and carbonyl activation of the parent R-amino
acid producing A, perfluoroalkylation to give ketone B,
diastereoselective reduction to selectively generate anti
alcohol C, and finally cyclization to give oxazolidinone
D. In our initial studies, we created diastereomers 1a
and 1b, allowing us to determine that the cis geometry
was necessary for an effective auxiliary.13 We noted that
the possibility of epimerization existed at each stage of
the synthesis, a problem which obviously had to be
avoided. We also recognized the particular challenges
posed by the unique properties of highly fluorinated
carbanions, which had proven troublesome in our initial
synthesis of 1a and 1b.13
a Results from ref 13. bPercent conversion from 5a.
alkyl zinc species, and Grignards.17 Perfluoroalkyl cu-
prates and zinc reagents have afforded only modest yields
in addition reactions with esters.17,18 We therefore con-
centrated on the lithium and Grignard derivatives de-
rived from C8F17I.
We rapidly discovered that these organometallic spe-
cies could be difficult to prepare and handle. Ultimately,
the perfluoroalkyllithium reagent emerged as the best
option (Scheme 2), provided that reactions were con-
ducted with stringent control of addition rates, temper-
ature and reagent concentrations. Because the lithiated
species rapidly decomposed, even at low temperatures,16a
the transmetalation had to be carried out in situ through
addition of MeLi-LiBr to a solution of C8F17I and ester
5a.13 By use of the method, we were able to obtain 38%
of the required ketone 6, with only minimal amounts of
tertiary alcohol 7 formed by initial reaction of 5a with
MeLi, followed by perfluoroalkylation of the resulting
methyl ketone. The low yield reflected a combination of
degradation of the perfluoroalkyllithium reagent via
â-elimination,16a and competitive Wurtz-type coupling
with the iodide starting material.19 After considerable
experimentation, we concluded that we could not sup-
press this Wurtz coupling. By the use of larger excesses
of C8F17I, we were able to improve the conversion to 6
marginally; however, generation of tertiary alcohol 7 was
also enhanced under these conditions. The two fluorous
Results and Discussion
L-Phenylalanine, L-valine, and D - and L-phenylglycine
were selected as starting points for this study. We first
required an appropriately activated N-carbamoyl elec-
trophile (A), which could react with a perfluoroalkyl
nucleophile. An ester group was the simplest option.
Unlike the reaction of alkyl nucleophiles with esters,
addition of perfluoroalkyl nucleophiles usually generates
a stabilized, long-lived tetrahedral intermediate.16 This
intermediate does not undergo a second nucleophilic
addition, and thus the corresponding ketone (B) can be
obtained.
Perfluoroalkyl Addition to N-Carbamoyl Esters.
The most commonly applied nucleophilic perfluororga-
nometallic reagents are alkyl cuprates, alkyllithiums,
(12) (a) Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem. 2000, 65,
8866-8873. (b) Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121,
9069-9072.
(13) Hein, J. E.; Hultin, P. G. Synlett 2003, 635-638.
(14) Hein, J. E.; Zimmerman, J.; Sibi, M. P.; Hultin, P. G. Org. Lett.
2005, 7, 2755-2758.
(17) (a) Burton, D. J.; Lu, L. Top. Current Chem. 1997, 193, 45-89.
(b) Burton, D. J.; Yang, Z. Y. Tetrahedron 1992, 48, 189-275.
(18) Gopal, H.; Tamborski, C. J. Fluorine Chem. 1979, 13, 337-
351.
(19) Richter, B.; de Wolf, E.; van Koten, G.; Deelman, B.-J. J. Org.
Chem. 2000, 65, 3885-3893.
(15) Hein, J. E.; Hultin, P. G. Tetrahedron: Asymmetry 2005, 16,
2341-2347.
(16) (a) Uno, H.; Shiraishi, Y.; Suzuki, H. Bull. Chem. Soc. Jpn.
1989, 62, 2636-2642. (b) Gassman, P. G.; O’Reilly, N. J. Tetrahedron
Lett. 1985, 26, 5243-5246.
J. Org. Chem, Vol. 70, No. 24, 2005 9941

Hein et al.
TABLE 1. Perfluoroalkyl Addition to N-Protected
This reflected two factors. First, it was quite simple to
remove alcohol contamination from the ethyl and isopro-
pyl carbamates 5a and 5b on multigram scales, whereas
it was much harder to remove traces of benzyl alcohol
from the benzyl carbamate 5c. The use of highly purified
esters led to more efficient perfluoroalkylation. A problem
with solubility also affected the yields in some cases. The
ethyl carbamate 5a was only partly soluble in ether-
hexane mixtures at -78 °C (Table 1, entry 2). In contrast,
phenylglycine-derived ester 5e was quite soluble under
these conditions, and it reacted with RfLi in good net
yield. Overall, the shorter alkyl carbamates were more
practical, with the isopropyl carbamate 5b giving the best
results.
The use of a spacer in the fluorous nucleophile in-
creased the net conversion, but as is evident from the
data in Table 1 it also led to the formation of tertiary
alcohols. The ketone:alcohol ratio could be controlled to
some extent by adjusting the amount of the perfluoro-
alkyllithium reagent applied. The tertiary alcohols 9
predominated when a 3-fold excess of the perfluoroalkyl
species was employed (Table 1, entry 6, cf. entries 4 and
5). Unfortunately, it was not possible to favor the ketones
8 by using smaller amounts of the nucleophile without
sacrificing the overall conversion of the reaction.
Amino Esters
entry s.m.
R
R′
reaction RfI equiv yield (8:9)c
1
2
5a
5a
5b
5b
5b
5b
5c
5c
5d
5e
Bn (S) Et
Bn (S) Et
Bn (S) ipr
Bn (S) ipr
Bn (S) ipr
Bn (S) ipr
Bn (S) Bn
Bn (S) Bn
iPr (S) tBu
Ph (R) Et
A
B
A
B
B
B
A
B
B
B
3.0
2.0
3.0
1.5
2.0
3.0
3.0
2.0
1.5
1.5
42:36
18:2
30:17
39:19
47:32
12:68
15:5
10:0
42:21
35:34
3
4
5
6
7
8
9
10
a Mg powder, C6F13(CH2)2I, Et2O. b t-BuLi, C6F13(CH2)2I, 3:2
Hex:Ether, -78 °C f rt. c Percent conversion from the correspond-
ing electrophile.
materials 6 and 7 could be separated by column chro-
matography on silica, but these disappointing results led
us to change our fluorous nucleophile.
Fluoroalkyllithium species containing an ethylene
spacer, such as C6F13(CH2)2Li, behave much more like
typical organometallic reagents.1,20 The alkyl portion of
these compounds helps to insulate the reactive site,
allowing the resulting carbanion to be more nucleophilic
and less prone to â-elimination. A series of N-protected
amino esters 5a-e (Table 1) were synthesized via
literature procedures21 and subjected to perfluoroalky-
lation with both the lithiated and Grignard derivatives
of C6F13(CH2)2I.
The Grignard protocol required a 3-fold excess of the
fluorous iodide to give adequate conversion to the fluo-
rous products (Table 1, entries 1 and 3). In contrast, the
lithium reagent gave moderate to good yields of fluorous
materials for most of the esters tested using only 1.5-
2.0 equiv. The solvent in which the perfluoroalkyllithium
species was generated and used proved to be critical.
Reactions of C6F13(CH2)2Li with esters 5 in pure ether
at -78 °C afforded <10% yields of perfluoroalkyl adducts,
along with corresponding amounts of unreacted ester. By
use of a mixed ether/hydrocarbon solvent system analo-
gous to the conditions reported by Legros et al.,22 we were
able to improve the conversion to the desired perfluoro-
alkyl derivatives substantially. We assayed a series of
hexane:ether and pentane:ether mixtures ranging from
1:1 to 5:1 (v/v) for both the generation and reaction of
C6F13(CH2)2Li and found that 3:2 hexane:ether gave the
optimal results shown in Table 1.
The installation of the fluorous tag permitted us to use
FSPE to purify the products of these reactions. The
quenched reactions were evaporated, and the crude
residues were applied as concentrated solutions to short
pads of FluoroFlash.23 We found that not only could we
separate fluorous from nonfluorous (organic and inor-
ganic) materials but we could also separate products of
differing fluorine content simply by adjusting the polarity
of the eluting solvent. By use of this technique, (perfluo-
roalkyl)ketones 8a-e and bis(perfluoroalkyl)alcohols
9a-e could easily be purified and separated using only
three washes of the FSPE pad: 70:30 MeOH:H2O re-
moved organic and inorganic byproducts, 85:15 MeOH:
H2O removed ketones 8, and finally 100% MeOH released
the tertiary alcohols 9.
Perfluoroalkyl Addition to N-Carbamoyl Weinreb
Amides. To obtain the ketone selectively we turned to
Weinreb amides 10a-e, which were prepared using a
modification of the reported procedures. To form the
amides, the N-carbamoyl amino acids first had to be
activated. In preliminary experiments, carboxyl activa-
tion using mixed anhydride methods24 or CDMT25 led to
racemic products. This could be suppressed by stringent
temperature control at e-20 °C. However, under these
conditions the Weinreb amides could not be obtained in
sufficient purity for our purposes, necessitating further
purification by chromatography on silica.
The data in Table 1 show that the best overall yields
of perfluoroalkyl adducts were obtained using ester 5b.
We found that TBTU was the best coupling reagent,
promoting Weinreb amide formation at 0 °C without
epimerization. By use of this method, we have prepared
Weinreb amides 10a, c, d, and e on multigram scales
with no need for any further purification after simply
(20) Curran, D. P.; Hadida, S.; Kim, S.-Y.; Luo, Z. J. Am. Chem.
Soc. 1999, 121, 6607-6615.
(21) (a) Kruse, C. H.; Holden, K. G. J. Org. Chem. 1985, 50, 2792-
2794; (b) Edmonds, M. K.; Abell, A. D. J. Org. Chem. 2001, 66, 3747-
3752. (c) You, J.; Wro´blewski, A. E.; Verkade, J. G. Tetrahedron 2004,
60, 7877-7883. (d) Lewis, N.; McKillop, A.; Taylor, R. J. K.; Watson,
R. J. Synth. Commun. 1995, 25, 561-568.
(22) (a) Legros, J.; Crousse, B.; Bonnet-Delpon, D.; Begue, J.-P.
Tetrahedron 2002, 58, 3993-3998. (b) Legros, J.; Crousse, B.; Bourdon,
J.; Bonnet-Delpon, D.; Begue, J.-P. Tetrahedron Lett. 2001, 42, 4463-
4466.
(23) FluoroFlash perfluorooctylethylsilyl (C8F17CH2CH2Si) silica gel
was provided by Fluorous Technologies, Inc.
(24) Angelastro, M. R.; Peet, N. P.; Bey, P. J. Org. Chem. 1989, 54,
3913-3916.
(25) Luca, L. D.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66,
2534-2537.
9942 J. Org. Chem., Vol. 70, No. 24, 2005

Fluorous Oxazolidinone Chiral Auxiliaries
TABLE 2. Perfluoroalkyl Addition to N-Protected
TABLE 3. Diastereoselective Reduction via Chelation
Control
Weinreb Amides
entry
s.m.
R
R′
RfI equiv
yieldb
1
10a
10b
10a
10a
10a
10c
10d
10e
Bn (S)
Bn (S)
Bn (S)
Bn (S)
Bn (S)
iPr (S)
Ph (R)
Ph (S)
Et
Bn
Et
Et
Et
tBu
tBu
tBu
1.5
1.5
3.5
1.5
1.5
1.5
1.5
1.5
48%
30%
61%
68%
75%
55%
45%
35%
2
3
4c
5d
6d
7d
8d
entry
s.m.
R
R′
yield
anti:syn
1a,c
2b,c
3b
6
Bn (S)
Bn (S)
Bn (S)
Bn (S)
Bn (S)
iPr (S)
Ph (R)
Ph (R)
Ph (S)
Et
98%
98%
95%
99%
97%
97%
95%
90%
96%
3:1
5:1
6
Et
8a
8b
8c
8d
8e
8f
8g
Et
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
a t-BuLi, C6F13(CH2)2I, Ether:Hex, -78 °C f rt. b Percent
conversion from corresponding Weinreb amide. c n-BuLi used as
sacrificial base. d t-BuLi used as sacrificial base.
4b
iPr
Bn
tBu
Et
5b
6b
7b
8b
tBu
tBu
9b
extracting the products from the quenched reaction
mixtures with ether.
a NaBH4, EtOH, -78 °C f rt. b LiAl(OtBu)3, EtOH, -78 °C f
rt. c Results from ref 13.
As we observed with esters 5, the Weinreb amides
bearing smaller carbamate groups (Table 2, entries 1 vs
2) gave better results in the perfluoroalkylation reactions.
It was possible to obtain ketones 8a-g as the sole
perfluoroalkylated products, but an excess of the fluorous
iodide was still required to obtain acceptable yields (Table
2, entries 1 and 2 vs 3). This was unacceptable in our
overall plan, because the fluorous material was the most
expensive component of our synthesis. Nucleophilic ad-
dition to N-carbamoyl Weinreb amides of R-amino acids
reportedly can be improved by employing sacrificial bases
to deprotonate the carbamate N-H prior to introducing
the desired nucleophile.26 By pretreating Weinreb amide
10a with n-BuLi or t-BuLi (Table 2, entries 4 and 5), we
increased the yield of perfluoroketone 6c to 68 and 75%
respectively, using only 1.5 equiv of perfluoroalkyl iodide.
Similar results were obtained using L-valine-derived
Weinreb amide 10c, leading to ketone 8d. The reactions
of D - and L-phenylglycine-derived 10d and 10e (Table 2,
entries 7 and 8) afforded ketones 8f and 8g having optical
rotations near zero. This stood in marked contrast to the
results of entries 1-6 (Table 2), in which the products
showed significant optical activity. Determining the
enantiomeric purity of our products was thus our next
task.
SCHEME 3. Esterification of
(Perfluoroalkyl)Alcohols with (R)- and (S)-MTPAa
a Reaction conditions: MTPA, DCC, DMAP, Et2O, rt, 24 h.
8a-f were reduced with excellent anti stereoselectivity
(Table 3). Clearly, the fully fluorinated ketone 6 was able
to react with LiAlH(OtBu)3 by both chelated and non-
chelated pathways, leading to the observed product
mixture. We attribute this to weak Lewis basicity of the
carbonyl in 6 due to the strong electron-withdrawing
effects of the C8F17 group directly bonded to it. The
ethylene spacer separating the fluorocarbon moiety from
the carbonyl of ketones 8a-f attenuates this effect. It
should also be noted that the nature of the carbamate
group had no effect on the selectivity of the reduction,
indicating that steric bulk in this position does not
interfere with the required chelated transition state.
The enantiomeric excesses of alcohols 13a, d, e, f, and
g were determined by conversion to the corresponding
Diastereoselective Reduction and MTPA Deriva-
tives. Hoffmann et al.27 have shown that R-amino
ketones can be reduced diastereoselectively to give the
corresponding anti amino alcohols using a strongly
chelating reducing agent such as LiAlH(OtBu)3. Reduc-
tion of perfluoroalkyl ketone 6 using this reagent afforded
mixtures of the syn and anti diastereomers 11 and 12,
with only a slight preference for the chelation-controlled
pathway (Table 3, entries 1 vs 2). In contrast, ketones
(26) (a) So, R. C.; Ndonye, R.; Izmirian, D. P.; Richardson, S. K.;
Guerrera, R. L.; Howell, A. R. J. Org. Chem. 2004, 69, 3233-3235. (b)
Liu, J.; Ikemoto, N.; Petrillo, D.; Armstrong, J. D., III. Tetrahedron
Lett. 2002, 43, 8223-8226.
(27) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem.
2002, 67, 1045-1056.
(S)- and (R)-MTPA esters (Scheme 3). The H and 19F
1
NMR spectra of the products clearly indicated that
alcohols 13a and d, synthesized from L-phenylalanine
and L-valine, contained a single enantiomer (∼99%
J. Org. Chem, Vol. 70, No. 24, 2005 9943

Hein et al.
low yield, with no sign of the thiazolidinethione. We are
continuing to pursue this transformation, although we
note that to obtain the required syn geometry by this
process requires the use of the syn diastereomer of amino
alcohol 19.
We have already reported the use of fluorous oxazoli-
dinone 2 in several asymmetric transformations includ-
ing aldol reactions, 1,3-dipolar cycloadditions, and radical
conjugate additions.13,14,15 The new supported chiral
auxiliary reacted under standard solution phase condi-
tions, affording yields and stereoselectivities comparable
to those reported for corresponding nonfluorous oxazoli-
dinones.
FIGURE 1. (Perfluoroalkyl) oxazolidinones.
The greatest advantage of the fluorous oxazolidinones
lies in the use of FSPE, allowing us to recover fluorous
materials rapidly and efficiently. The auxiliaries were
easily acylated and employed in asymmetric transforma-
tions, each time using FSPE to obtain the desired
products from crude reaction mixtures. Because of this
characteristic, it was trivial to recover and reuse the
oxazolidinone following cleavage of the newly formed
exocyclic chiral material. In our study of 1,3-dipolar
cycloadditions we have demonstrated that auxiliary 2
could be recycled no fewer than five times with no
deleterious effect on the reactions.15 This also suggests
their potential use in multistep supported syntheses.
SCHEME 4. Synthesis of Oxazolidinethione 1e
enantiomeric excess (ee)). In contrast, alcohols 13e-g
(derived from D- or L-phenylglycine) proved to have very
low enantiomeric purities (37, ∼0, and ∼0% ee, respec-
tively). This was consistent with the low optical rotations
observed for their fluoroketone precursors 8e-g. Clearly,
the R center in these compounds had epimerized, sug-
gesting that the R position of phenylglycine is too acidic
to tolerate the conditions of the fluoroalkylation. These
phenylglycine-derived compounds prepared by this route
were clearly not of sufficient stereochemical purity to be
of use as chiral auxiliaries.
Synthesis and Application of the Fluorous Ox-
azolidinones. Hydroxycarbamates 13a-g were treated
with NaH in THF to give the corresponding mono-
(perfluoroalkyl) oxazolidinones 2 and 3 (Figure 1). Treat-
ing the bis(perfluoroalkyl) alcohols 9a-e under similar
conditions generated the disubstituted oxazolidinones 16,
17, and 18 (Figure 1). Alcohols 13a-d derived from
L-phenylalanine and L-valine produced diastereomerically
and enantiomerically pure oxazolidinones 2 and 3. The
syn geometry at C4 and C5 in these oxazolidinones was
evident from the vicinal H4-H5 coupling constants,
which were found to be 7.2 and 7.0 Hz in 2 and 3,
respectively. Nuclear Overhauser effect experiments
further established the syn geometry: anti oxazolidinone
1b showed <1% NOE between H4 and H5, whereas in
1a, 2, and 3, ∼5% NOE was observed between these
protons.
Conclusions
Our detailed experiments have led to an efficient five-
step sequence (presented in the Experimental Section)
requiring no conventional chromatography to produce
fluorous oxazolidinone and oxazolidinethione chiral aux-
iliaries from common R-amino acids. This route is dis-
tinguished by: TBTU-promoted formation of an N-car-
bamoyl amino acyl Weinreb amide to avoid epimerization;
perfluoroalkylation in hexane:ether mixtures, in the
presence of a sacrificial base, to install a spacer-linked
fluorous chain; chelation-controlled stereoselective reduc-
tion of the resulting ketone; and facile conversion to
either oxazolidinone or oxazolidinethione final products.
Purification consists of silica and fluorous solid-phase
extractions, with only two recrystallizations required. We
have performed the complete sequence on various scales,
up to the formation of 25 g of the target oxazolidinone in
a single batch.30 The process on these scales requires no
equipment other than typical laboratory glassware. These
fluorous auxiliaries are truly powerful tools for drug
discovery and high-throughput chemistry and are viable
alternatives to the standard supported or nonsupported
auxiliaries.
Crimmins et al. have found that oxazolidinethiones
offered some advantages over oxazolidinone chiral aux-
iliaries in particular applications.28 We therefore submit-
ted 13a to alkaline hydrolysis to produce amino alcohol
19 (Scheme 4), which was then treated with CS2 in the
presence of DIPEA, generating 1e (80%). We also briefly
examined the conversion of 19 to the corresponding
thiazolidinethione using a reported procedure (refluxing
CS2 in aqueous KOH),29 but this only afforded 1e in very
Experimental Procedures
General Protocol for Large-Scale Purification of Flu-
orous Materials Using FSPE: Purification and Separa-
tion of 2(S)-(Ethoxycarbonylamino)-6,6,7,7,8,8,9,9,10,10,
11,11,11-tridecafluoro-1-phenyl-undecan-3-one (8a) and
2(S)-(Ethoxycarbonylamino)-3,3-bis(1′H,1′H,2′H,2′H-per-
fluorooctyl)-1-pheny l-propan-3-ol (9a). The crude material
obtained after concentrating the reaction under vacuum (∼43
g) was thinned with a minimum volume of Et2O and applied
to a pad of dry Fluoroflash (4-6 × crude weight) in a fritted
glass funnel. The oily material was driven onto the solid phase
using compressed air. The pad was blown dry until no evidence
of the loading solvent remained and then washed with 70%
(28) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J.
Org. Chem. 2001, 66, 894-902.
(29) Delaunay, D.; Toupet, L.; Corre, M. L. J. Org. Chem. 1995, 60,
6604-6607.
9944 J. Org. Chem., Vol. 70, No. 24, 2005

Fluorous Oxazolidinone Chiral Auxiliaries
methanol in water (1.5-2.0 L) to remove organic and inorganic
impurities. Ketone 8a was selectively eluted from the solid
phase with 85% methanol in water (1-1.5 L). The solid phase
was then eluted with MeOH to obtain 9a.
evaporated to dryness. The crude material was then purified
by FSPE according to the general procedure to give 8a (28.88
g, 51.1 mmol, 68.2% yield).
2(S)-(Ethoxycarbonylamino)-6,6,7,7,8,8,9,9,10,10,11,
11,11-tridecafluoro-1-phenyl-undecan-3-one (8a). Rf 0.3
(9:1 hexanes/ethyl acetate); mp ) 57-60 °C; 1H NMR (300
MHz, CDCl3) δ 7.31-7.14 (m, 5H), 5.4 (br d, 1H, 3J ) 7.0 Hz),
Representative Procedure for the Synthesis of N-
Carbamoyl Weinreb Amides Using Isobutyl Chlorofor-
mate: 2(S)-N-(Ethoxycarbonyl)-N′-methoxy-N′-methyl-
phenylalaninamide (10a). 2(S)-N-(Ethoxycarbonyl) phenyl-
alanine (21.00 g, 89 mmol) was dissolved in CH2Cl2 (250 mL)
and cooled to -30 °C. DIPEA (16.96 mL, 97 mmol) was added
dropwise, and the solution was allowed to stir at -30 °C for
15 min. Isobutyl chloroformate (12.79 mL, 97 mmol) was added
dropwise while monitoring the reaction temperature with a
digital thermometer. The addition rate was carefully controlled
to keep the internal temperature between -30 and -25 °C.
Upon completion of the addition, stirring was continued at -30
°C for an additional 15 min, at which time DIPEA (20.81 mL,
119 mmol) was added dropwise. Solid N,O-dimethylhydroxy-
lamine hydrochloride (11.66 g, 119 mmol) was added in one
portion, followed by DMF (10 mL). The reaction was allowed
to warm to room temperature (rt) over 3 h and was then
quenched with 1 M HCl and diluted with CH2Cl2. The layers
were separated, and the organic layer was washed successively
with 1 M HCl, NaHCO3, and brine. The organic layer was dried
(MgSO4) and concentrated. The residual oil was eluted through
a pad of silica gel (4:1 hexanes/ethyl acetate) to produce 10a
(22.12 g, 79 mmol, 89% yield) as a clear oil.
Representative Procedure for the Synthesis of N-
Carbamoyl Weinreb Amides Using TBTU: 2(S)-N-(tert-
Butoxycarbonyl)-N′-methoxy-N′-methyl-valinamide (10c).
Solid (S)-N-(tert-butoxycarbonyl)-valinate (1.50 g, 6.90 mmol),
N,O-dimethoxyhydroxylamine hydrochloride (1.010 g, 10.36
mmol), and TBTU (3.33 g, 10.36 mmol) were combined. Dry
CH3CN (25 mL) was added, and the mixture was cooled to 0
°C. The solution was stirred at 0 °C for 10 min, and then
DIPEA (3.61 mL, 20.71 mmol) was added dropwise. The
solution turned yellow and quickly became opaque. The
reaction was allowed to warm to rt over 3 h. After this time,
the reaction was concentrated under vacuum, and the residue
was taken up in Et2O. The mixture was washed sequentially
with 1 M HCl, 1 M NaHCO3, and brine. The organic fraction
was dried with MgSO4 and evaporated to dryness. The
resulting crude yellow oil was applied to a 10-cm pad of silica
gel and eluted with 4:1 hexanes/ethyl acetate, providing 10c
(0.102 g, 0.346 mmol, 87% yield) as a clear oil.
Representative Procedure for the Application of a
Sacrificial Base in the Perfluoroalkylation of N-Car-
bamoyl Weinreb Amides Using Perfluoroalkyllithium
Reagents: 2(S)-(Ethoxycarbonylamino)-6,6,7,7,8,8,9,9,
10,10,11,11,11-tridecafluoro-1-phenyl-undecan-3-one (8a).
1H,1H,2H,2H-Perfluorooctyl iodide (26.6 mL, 112 mmol) was
dissolved in ether:hexane (3:2, 500 mL) and cooled to -78 °C.
t-BuLi (70.5 mL, 120 mmol) was added dropwise via cannula,
taking care to keep the reaction temperature below -60 °C.
In a separate flask 10a (21 g, 74.9 mmol) was dissolved in dry
Et2O, and the solution was cooled to -78 °C. t-BuLi (48.5 mL,
82 mmol) was then added to this solution, again adjusting the
addition rate to maintain a temperature below -60 °C. This
solution was then transferred via a cannula into the perfluo-
roalkyllithium solution. The reaction was then stirred at -78
°C for ∼15 min and was then allowed to warm to rt over 4 h.
The reaction was quenched with dilute aqueous NH4Cl, and
the solution was extracted with Et2O. The combined ether
extracts were washed with brine, dried with MgSO4, and
3
3
4.58 (ddd, 1H, J1 ) 7.5 Hz, J2 ) 7.0 Hz,3J3 ) 7.0 Hz), 4.09
(q, 2H, 3J ) 7.0 Hz), 3.04 (dd, 1H, 3J1 ) 13.8 Hz, 3J2 ) 7.0
Hz), 3.04 (dd, 1H, 3J1 ) 13.8 Hz, 3J2 ) 7.5 Hz), 2.75-2.69 (m,
1H, -CHHCH2C6F13), 2.60-2.53 (m, 1H, -CHHCH2C6F13),
3
2.43-2.23 (m, 2H, -CH2CH2C6F13), 1.20 (t, 3H, J ) 7.0 Hz);
13C NMR (75 MHz, CDCl3) δ 14.4 (-OCH2CH3), 24.9 (-CH2CH2-
C6F13), 31.8 (-CH2CH2C6F13), 37.8 (PhCH2-), 60.5 (BnCHN-
), 61.4 (-OCH2CH3), 127.4, 128.9, 129.0, 135.6 (-C6H5), 156.1
(-NHCOOEt), 206.4 (-COCH2CH2C6F13); 19F NMR (282 MHz,-
CDCl3) δ -81.25, -114.93, -122.36, -123.32, -123.93, -126.58;
[R]25D +15.0° (c 1.00, CHCl3). Anal. Calcd for formula C20H18F13-
NO3: C, 42.34; H, 3.20; N, 2.47. Found: C, 42.44; H, 3.43; N,
2.34.
2(S)-(tert-Butoxycarbonylamino)-7,7,8,8,9,9,10,10,
11,11,12,12,12-tridecafluoro-2-methyl-dodecan-4-one (8d).
1
Rf 0.4 (9:1 hexanes/ethyl acetate); mp ) 36-37 °C; H NMR
3
(300 MHz, CDCl3) δ 5.05 (d, 1H, J ) 8.2 Hz), 4.25 (dd, 1H,
3J1 ) 8.2 Hz, 3J2 ) 4.6 Hz, iPrCH-), 2.90-2.72 (m, 2H, -CH2-
CH2C6F13), 2.51-2.33 (m, 2H, -CH2CH2C6F13), 2.24-2.29 (m,
1H, (CH3)2CH-), 1.43 (s, 9H, (CH3)3C-), 1.01 (d, 3H, 3J ) 7.1
3
Hz, CH3CHCH3), 0.82 (d, 3H, J ) 7.0 Hz, CH3CHCH3); 13C
NMR (75 MHz, CDCl3) δ 16.9 (CH3CHCH3), 19.7 (CH3CHCH3),
25.0 (-CH2CH2C6F13), 28.3 ((CH3)3C-), 30.0 ((CH3)2CH-), 31.5
(-CH2CH2C6F13), 64.3 (iPrCHN-), 80.03 ((CH3)3C-), 156.4
(-NHCOOEt), 206.6 (-COCH2CH2C6F13); 19F NMR (282 MHz,-
CDCl3) δ -81.29, -114.69, -122.36, -123.34, -123.94, -126.61;
[R]25D +17.0° (c 1.06, CHCl3). Anal. Calcd for formula C18H22F13-
NO3: C, 39.50; H, 4.05; N, 2.56. Found: C, 39.64; H, 3.89; N,
2.55.
Representative Procedure for Diastereoselective Re-
ductions of (Perfluoroalkyl)ketones: (2S,3R)-2-(Ethoxy-
carbonylamino)-6,6,7,7,8,8,9,9,10,10,11,11,11-tridecafluoro-
1-phenyl-undecan-3-ol (13a). A solution of ketone 8a (21.0
g, 35.3 mmol) in anhydrous ethanol (2.0 L) at -78 °C was
treated with powdered LiAlH(OtBu)3 (26.9 g, 106 mmol). The
reaction was allowed to warm to rt over 16 h. It was then
quenched by gradual addition of 1 M HCl, and the solution
was stirred until it became translucent. The solution was then
concentrated under vacuum, and the crude residue was taken
up in distilled water and extracted with Et2O. The combined
ether extracts were dried with MgSO4 and evaporated to
dryness to give 13a (20 g, 33.5 mmol, 95% yield) as a white
powder. This material was used without further purification.
(2S,3R)-2-(Ethoxycarbonylamino)-6,6,7,7,8,8,9,9,10,
10,11,11,11-tridecafluoro-1-phenyl-undecan-3-ol (13a). Rf
1
0.37 (9:1 hexanes/ethyl acetate); mp ) 116-120 °C; H NMR
3
(300 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 4.67 (br d, 1H, J )
7.4 Hz), 4.10-4.01 (m, 2H), 3.96-3.88 (m, 1H), 3.75-3.70 (m,
1H), 3.24 (br s, 1H), 2.91 (dd, 1H, 3J1 ) 14.3 Hz, 3J2 ) 5.2 Hz),
2.77 (dd, 1H, 3J1 ) 14.3 Hz, 3J2 ) 9.5 Hz), 2.55-2.36 (m, 1H),
3
2.22-2.00 (m, 1H), 1.86-1.67 (m, 2H), 1.19 (t, 3H, J2 ) 7.0
Hz); 13C NMR (75 MHz, CDCl3) δ 14.4, 23.5, 27.8, 36.0, 57.4,
61.4, 73.0, 126.8, 128.7, 129.0, 137.3, 157.4; 19F (282 MHz,
CDCl3) δ -81.27, -114.95, -122.38, -123.38, -124.01, -126.60;
[R]25D -6.5° (c 1.00, CHCl3). Anal. Calcd for formula C20H20F13-
NO3: C, 42.19; H, 3.54; N, 2.46. Found: C, 42.59; H, 3.14; N,
2.65.
(3S,4R)-3-(tert-Butoxycarbonylamino)-7,7,8,8,9,9,
10,10,11,11,12,12,12-tridecafluoro-2-methyl-dodecan-4-
ol (13d). Rf 0.32 (9:1 hexanes/ethyl acetate); mp ) 101-107
°C; 1H NMR (300 MHz, CDCl3) δ 4.54 (d, 1H, 3J ) 9.0 Hz),
3.64-3.57 (m, 1H), 3.53-3.46 (m, 1H), 2.57-2.36 (m, 1H),
(30) We have made one attempt to perform the reaction sequence
using 200 g of C6F13(CH2)2I and 100 g of Weinreb amide 10a. A
significant exotherm occurred during the metalation of the perfluoro-
alkyl iodide, leading to decomposition of the perfluoroalkyllithium
reagent. On this occasion we were unable to control the exotherm, but
this difficulty can probably be overcome with the use of specialized
reaction vessels able to dissipate the heat more efficiently than can
standard round-bottom flasks.
3
3
2.20-1.98 (m, 1H), 1.90 (dqq, 1H, J1 ) 7.1 Hz, J2 ) 7.1 Hz,
3
3J3 ) 7.0 Hz), 1.79-1.55 (m, 2H), 1.42 (s, 9H), 0.93 (d, 3H, J
) 7.1 Hz), 0.89 (d, 3H, 3J ) 7.1 Hz); 13C NMR (75 MHz, CDCl3)
J. Org. Chem, Vol. 70, No. 24, 2005 9945

Hein et al.
δ 17.6, 18.2, 23.2, 27.6, 28.1, 28.4, 60.5, 71.4, 80.0, 157.2; 19F
(282 MHz, CDCl3) δ -81.49, -114.98, -122.54, -123.50,
2.49 (dd, 1H, 3J1 ) 13.7 Hz, 3J2 ) 10.0 Hz), 2.58-2.41 (m, 1H),
2.22-1.98 (br m, 4H), 1.85-1.70 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 22.6, 27.9, 38.4, 56.8, 72.7, 126.6, 128.8, 129.1, 138.6;
19F (282 MHz, CDCl3) δ -81.3, -114.7, -123.0, -123.3,
-124.08, -126.80; [R]25 -3.2° (c 0.760 CHCl3). Anal. Calcd
D
for formula C18H24F13NO3: C, 39.35; H, 4.40; N, 2.55. Found:
C, 38.94; H, 3.99; N, 2.38.
-123.9, -126.6; [R]25 -3.0 (c 1.01, CHCl3). Anal. Calcd for
D
Representative Procedure for Cyclization of Mono-
and Bis(perfluoroalkyl)alcohols: (4S,5R)-4-Benzyl-5-
(1′H,1′H,2′H,2′H-perfluorooctyl)-2-oxazolidinone (2). To
a stirred solution of 13a (20.00 g, 35.1 mmol) in THF (250 mL)
was added NaH (4.21 g, 105.3 mmol). The reaction was stirred
at rt for 12 h and then quenched (1M HCl) with vigorous
stirring. The solution was then evaporated to yield a crude
product (∼21 g). FSPE afforded 2 (17.12 g, 32.7 mmol, 93%
yield) as a white crystalline solid.
formula C17H16F13NO: C, 41.06; H, 3.24; N, 2.82. Found: C,
41.48; H, 2.96; N, 2.88.
(4S,5R)-4-Benzyl-5-(1′H,1′H,2′H,2′H-perfluorooctyl)-2-
oxazolidinethione (1e). Carbon disulfide (0.995 mL, 16.50
mmol) and 19 (5.47 g, 11.00 mmol) were dissolved in CH2Cl2
(500 mL) and cooled to 0 °C. DIPEA (3.83 mL, 22.00 mmol)
was added dropwise over 10 min. The reaction was allowed to
warm to rt overnight. A second charge of carbon disulfide
(0.199 mL, 3.30 mmol) was added, and the reaction was stirred
for an additional 24 h. After this time, the reaction appeared
complete by TLC. It quenched with saturated aqueous NH4-
Cl. The mixture was extracted with CH2Cl2, and the organic
fractions were pooled, dried (MgSO4), and concentrated under
vacuum. The crude material was then purified by FSPE to give
1e (4.76 g, 8.83 mmol, 80% yield) as a yellow solid. Rf 0.54
(4S,5R)-4-Benzyl-5-(1′H,1′H,2′H,2′H-perfluorooctyl)-2-
1
oxazolidinone (2). Mp ) 100-101 °C; H NMR (300 MHz,
CDCl3) δ 7.39-7.17 (m, 5H), 4.93 (br s, 1H), 4.69 (ddd, 1H,
3J1 ) 7.2 Hz, 3J2 ) 7.2 Hz, 3J3 ) 7.2 Hz), 4.05 (ddd, 1H, 3J1 )
3
3
3
7.2 Hz, J2 ) 7.2 Hz, J3 ) 7.2 Hz), 2.89 (dd, 1H, J1 ) 14.1
3
3
3
Hz, J2 ) 4.3 Hz), 2.71 (dd, 1H, J1 ) 14.1 Hz, J2 ) 7.9 Hz),
2.62-2.43 (m, 1H), 2.30-2.08 (m, 2H), 2.06-1.94 (m, 1H); 13
C
1
(2:1 hexanes/ethyl acetate); mp ) 124-130 °C; H NMR (300
(75 MHz, CDCl3) δ 21.1, 28.0, 36.3, 56.6, 78.3, 127.3, 128.9,
129.1, 136.1, 158.0; 19F (282 MHz, CDCl3) δ -81.32, -115.18,
-122.34, -123.23, -124.18, -126.91; [R]D ) -30.0° (c ) 1.0,
CHCl3). Anal. Calcd for formula C18H14F13NO2: C, 41.31; H,
2.70; N, 2.68. Found: C, 41.34; H, 2.64; N, 2.69.
MHz, CDCl3) δ 7.40-7.16 (m, 5H), 6.94 (br s, 1H), 4.94 (dd,
1H,3J1 ) 7.9 Hz, 3J2 ) 7.8 Hz), 4.28-4.21 (br m, 1H), 2.92
(dd, 1H, 3J1 ) 13.5 Hz, 3J2 ) 3.4 Hz), 2.77 (dd, 1H, 3J1 ) 13.5
Hz, 3J2 ) 11.5 Hz), 2.65-2.48 (br m, 1H), 2.33-2.13 (br m,
2H), 2.09-1.98 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 20.7,
28.3, 35.6, 60.2, 84.0, 127.7, 128.9, 129.6, 135.2, 188.6; 19F (282
MHz, CDCl3) δ -81.2, -114.9, -122.3, -123.3, -123.8,
(4S,5R)-4-iso-Propyl-5-(1′H,1′H,2′H,2′H-perfluorooctyl)-
2-oxazolidinone (3). Mp ) 96-99 °C; 1H NMR (300 MHz,
3
3
-126.5; [R]25 -40.0 (c 1.00, CHCl3). Anal. Calcd for formula
CDCl3) δ 6.90 (br s, 1H), 4.58 (ddd, 1H, J1 ) 10.6 Hz, J2 )
7.5 Hz, 3J3 ) 2.6 Hz), 3.6 (dd, 1H, 3J1 ) 7.5 Hz, 3J2 ) 7.5 Hz),
2.58-2.37 (m, 1H), 2.28-1.97 (m, 2H), 1.94-1.80 (m, 2H), 1.01
D
C18H14F13NOS: C, 40.08; H, 2.62; N, 2.60. Found: C, 40.40;
H, 2.40; N, 2.73.
3
3
(d, 3H, J ) 6.4 Hz), 0.93 (d, 3H, J ) 6.4 Hz); 13C (75 MHz,
CDCl3) δ 19.0, 19.7, 20.2, 27.7, 27.7, 28.2, 62.0, 78.7, 159.8;
19F (282 MHz, CDCl3) δ -81.12, -115.56, -122.12, -123.34,
-124.23, -126.83; [R]D ) -46.0° (c ) 0.43, CHCl3). Anal. Calcd
for formula C14H14F13NO2: C, 35.38; H, 2.97; N, 2.95. Found:
C, 35.12; H, 2.73; N, 2.68.
Acknowledgment. We are grateful to Fluorous
Technologies Inc. for the gift of FluoroFlash and C6F13-
(CH2)2I. The authors thank Dr. Frank Schweizer for
providing access to high-performance liquid chromatog-
raphy mass spectrometry. The work was funded by a
Discovery Grant from the Natural Sciences and Engi-
neering Research Council (NSERC) of Canada. A.A.J.
was the recipient of a Summer Undergraduate Research
Scholarship from NSERC, and L.M.G. acknowledges the
Province of Manitoba for a Graduate Fellowship.
(2S,3R)-2-Amino-6,6,7,7,8,8,9,9,10,10,11,11,11-trideca-
fluoro-1-phenyl-undecan-3-ol (19). KOH (28.4 g, 506 mmol)
and 13a (4.80 g, 8.43 mmol) were suspended in 60% EtOH in
water (500 mL) and stirred at rt until the solids dissolved.
The reaction was then heated to reflux for 4 h. The solution
was cooled, and 1 M NaOH was added until the mixture
became cloudy. The solution was extracted with Et2O, and the
combined organic fractions were dried (MgSO4) and evaporated
to dryness to yield 19 (4.05 g, 8.14 mmol, 97% yield) as a flaky
solid. This material was used without further purification. Rf
0.33 (4:1 hexanes/ethyl acetate); mp ) 72-80 °C; 1H NMR (300
MHz, CDCl3) δ 7.35-7.17 (m, 5H), 3.60-3.56 (br m, 1H), 3.14-
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all reported compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
3
3
3.08 (br m, 1H), 2.87 (dd, 1H, J1 ) 13.7 Hz, J2 ) 3.1 Hz),
JO051696N
9946 J. Org. Chem., Vol. 70, No. 24, 2005