Oxazolidine synthesis by complementary stereospecific and stereoconvergent methods

Article abstract of DOI:10.1021/ol202068p

Complementary stereospecific and stereoconvergent reactions for enantioselective synthesis of 1,3-oxazolidines are reported. In the presence of a rhodium catalyst, reaction of enantioenriched butadiene monoxide with aryl imines is stereospecific (99% ee). Alternatively, the reaction of racemic butadiene monoxide, in the presence of a chiral palladium or nickel catalyst, provides an enantioselective synthesis of 1,3-oxazolidines (up to 94% ee). Synthesis of either the cis- or trans-1,3-oxazolidines is also accomplished under catalyst control.

Full text of DOI:10.1021/ol202068p

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5188–5191
Oxazolidine Synthesis by Complementary
Stereospecific and Stereoconvergent
Methods
Michael B. Shaghafi, Robin E. Grote, and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025,
United States
erjarvo@uci.edu
Received July 29, 2011
ABSTRACT
Complementary stereospecific and stereoconvergent reactions for enantioselective synthesis of 1,3-oxazolidines are reported. In the presence of
a rhodium catalyst, reaction of enantioenriched butadiene monoxide with aryl imines is stereospecific (99% ee). Alternatively, the reaction of
racemic butadiene monoxide, in the presence of a chiral palladium or nickel catalyst, provides an enantioselective synthesis of 1,3-oxazolidines
(up to 94% ee). Synthesis of either the cis- or trans-1,3-oxazolidines is also accomplished under catalyst control.
Oxazolidines are commonly utilized in synthesis as pro-
tected amino alcohols and are pharmacophores themselves,
embedded within the core of potent antitumor tetrahydro-
isoquinoline natural products including quinocarcin.1,2 Cata-
lytic enantioselective synthesis of 1,3-oxazolidines has been
reported, often featuring aminohydroxylation of styrenes as a
key design element.3 We report alternative highly enantio-
selective catalytic strategies for the assembly of oxazolidines.
High enantioselectivities are obtained through complemen-
tary stereospecific (substrate-controlled) and stereoconver-
gent (catalyst-controlled) methods, where the stereochemical
outcome of the transformation is determined by the rate of
isomerization of the requisite allylmetal intermediate. Devel-
opment of both stereospecific and stereoconvergent methods
provides flexibility for synthesis of bioactive compounds.
Formal cycloaddition reactions of vinyl epoxides and
electrophiles have been reported and most frequently employ
palladium-based catalysts.4 Inspired by racemic syntheses of
1,3-oxazolidines via formal cycloaddition reactions of imines
and vinyl epoxides,5 we hypothesized that metal complexes
known to catalyze allylic substitution reactions could provide
enantioselective variants of this transformation. We were
attracted to this strategy as allylmetal complexes afford a
unique opportunity to catalyze either stereoconvergent or
stereospecific reaction pathways by controlling rates of
isomerization of allylmetal intermediates. On the basis of
the stereochemical outcomes of allylic substitution reac-
tions, we anticipated that nickel and palladium catalysts
would provide stereoconvergent transformations, where
both enantiomers of vinyl epoxide would be converted
to one enantiomer of oxazolidine.6,7 In contrast, rhodium
(4) For enantioselective examples, see: (a) Larksarp, C.; Alper, H.
J. Am. Chem. Soc. 1997, 119, 3709. (b) Larksarp, C.; Alper, H. J. Org.
Chem. 1998, 63, 6229. (c) Trost, B. M.; Jiang, C. J. Am. Chem. Soc. 2001,
123, 12907. (d) Trost, B. M.; Jiang, C. Org. Lett. 2003, 5, 1563.
(5) Racemic synthesis of 1,3-oxazolidines from imines and vinyl
epoxides: (a) Shim, J.-G.; Yamamoto, Y. Heterocycles 2000, 52, 885–
895. (b) Shim, J.-G.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 1053.
(6) Ni, Stereoselective: (a) Shintani, R., Hayashi, T. Asymmetric
Synthesis. Modern Organonickel Chemistry; Tamaru, Y., Ed.; Wiley-VCH:
Germany, 2005; p 246 and references therein. Stereospecific: (b) Yatsumonji,
Y.; Ishida, Y.; Tsubouchi, A.; Takeda, T. Org. Lett. 2007, 9, 4603.
(7) Pd: (a) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1996,
96, 395. (b) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.
(c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543.
(1) A general review of the tetrahydroisoquinoline natural products
and analogs: Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102, 1669.
(2) (a) The oxazolidine moiety is necessary for antitumor activity of
quinocarcin, see: Williams, R. M.; Glinka, T.; Flanagan, M. E.; Gallegos,
R.; Coffman, H.; Pei, D. J. Am. Chem. Soc. 1992, 114, 733. (b) Tomita, F.;
Takahashi, K.; Tamaoki, T J. Antibiot. 1984, 37, 1268.
(3) For Cu(II) catalyzed aminohydroxylation of styrenes with ox-
aziridines to provide 1,3-oxazolidines, with up to 2.5:1 dr and 89% ee,
see: (a) Michaelis, D. J.; Ischay, M. A.; Yoon, T. P. J. Am. Chem. Soc.
2008, 130, 6610. (b) Michaelis, D. J.; Williamson, K. S.; Yoon, T. P.
Tetrahedron 2009, 5118.
r
10.1021/ol202068p
Published on Web 08/25/2011
2011 American Chemical Society

catalysts would produce oxazolidine products in a
stereospecific manifold and employ enantioenriched
vinyl epoxide.8,9 In addition to providing facile synthetic
access to 1,3-oxazolidines in high optical purity, this inves-
tigation contrasts the reactivity of allylrhodium, allylnickel,
and allylpalladium complexes.
monoxide (R)-2 was prepared in >99% ee utilizing
Jacobsen’s hydrolytic kinetic resolution reaction.12 Under
the optimized reaction conditions, employing an achiral
rhodium catalyst, enantioenriched vinyl epoxide reacted to
produce oxazolidines 3e and 3f in 99% ee (Table 1, entries 7
and 8). These results are consistent with our hypothesis that
racemization of the putative allylrhodium intermediates is
slow relative to heterocycle formation. The reaction was
found to provide retention at the stereogenic center derived
from the vinyl epoxide, consistent with double inversion. On
the basis of the reliable and facile access to either antipode of
enantiopure vinyl epoxide, this rhodium-catalyzed stereo-
specific transformation provides access to either enantiomer
of vinyl-substituted 1,3-oxazolidines with the highest levels
of enantiomeric excess reported to date.
Table 1. Scope of Rhodium-Catalyzed Oxazolidine Formationa
%
dr
Palladium and nickel complexes catalyze the dynamic
kinetic resolution (DKR) of allylic acetates, via rapid
isomerization of the allylpalladium and allylnickel com-
plexes.7a Therefore, we anticipated that these catalysts
would provide an analogous DKR of racemic vinyl ep-
oxide to provide enantioenriched oxazolidines.13 As pre-
viously mentioned, a palladium-catalyzed synthesis of racemic
1,3-oxazolidines from butadiene monoxide and imines was
reported;5 however, no enantioselective variant of the trans-
formation has been described.
We began our investigation of a stereoconvergent trans-
formation by examining catalysts prepared in situ from
Ni(cod)2 and chiral phosphines.14 Upon examining a series
of phosphine ligands and reaction conditions, we found
that 1,3-oxazolidines could be generated in good yield and
excellent diastereoselectivities from tosyl imine 1a and
racemic vinyl epoxide (()-2 (Table 2, entry 2). Addition
of the Lewis acid cocatalyst such as Ti(Oi-Pr)4 or TMSOTf
dramaticallyimproved the rateof the reaction, presumably
by facilitating oxidative addition.15 Addition of tetrabuty-
lammonium difluorotriphenylsilicate (TBAT) also signifi-
cantly improved the rateof the reaction, without impacting
enantioselectivity, allowing cooling of the reaction tem-
perature to ꢀ20 °C with a marked boost in enantioselec-
tivity (entry 3).16 Under the optimized reaction conditions,
entry imine
R0
R
epoxide product yieldb (cis:trans)c
1d
2d
3
1a SO2Tol
H
(()-2
(()-2
(()-2
3a
3b
3c
3d
3e
3f
e5
34
n.d.
n.d.
6:1
6:1
3:1
5:1
6:1
1b CH(Ph)2 H
1c PMP
1d PMP
1e PMP
1f PMP
H
86
4e
4-OCH3 (()-2
4-CH3 (()-2
60
5
6e
87
4-CI
4-CH3 (R)-2
(99% ee)
(R)-2
(99% ee)
(()-2
88
7e,f 1e PMP
3e
81
(99% ee)
83
8e,f 1f PMP
4-CI
3f
6:1
(99% ee)
a Conditions: 1.5 equiv (()-2, [1] = 0.20 M. b % Isolated yield of
3. % ee determined by chiral SFC chromatography. c cis:trans ratios
determined by 1H NMR. d THF used as solvent. e Two equivalents of
(()-2 used. f One equivalent by weight of molecular sieves used.
Todevelop a stereospecific synthesisof1,3-oxazolidines,
we first identified reaction conditions where rhodium
catalysts could affect formal cycloaddition of racemic
butadiene monoxide (()-2 with imines (Table 1). While
sulfonyl-protected imines did not provide the desired
product, the desired oxazolidine was furnished upon ex-
posure of p-methoxyphenyl imines to Rh(cod)2OTf as
catalyst. A series of catalyst precursors, ligands, and
solvents were examined.10 A combination of rhodium-
(biscyclooctadiene) triflate in dichloromethane as solvent
was found to be optimal, generating oxazolidine 3c in 86%
yieldwith6:1diastereoselectivity(entry 3). Themorestable
cis-oxazolidine was formed preferentially in favor of the
trans diastereomer.11 The optimal conditions were ob-
served to be general over a range of aryl imines. Substrates
containing electron-donating aswellas electron-withdraw-
ing groups were well-tolerated (entries 4ꢀ6).
(11) For relative stabilities, see: (a) Beckett, A. H.; Jones, G. R.
Tetrahedron 1977, 33, 3313. (b) Just, G.; Potvin, P.; Uggowitzer, P.
J. Org. Chem. 1983, 48, 2923. For a recent example see: (c) Tremblay,
M. R.; Wentworth, P., Jr.; Lee, G. E., Jr.; Janda, K. D. J. Comb. Chem.
2000, 2, 698.
(12) (a) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307. (b) Tokunaga, M.; Larrow, J. F.; Kakiuchi,
F.; Jacobsen, E. N. J. Am. Chem. Soc. 1997, 277, 936. (c) Nielsen,
L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 1360. (d) White, D. E.; Jacobsen, E. N. Tetra-
hedron: Asymm. 2003, 14, 3633.
The stereospecificity of the transformation was inves-
tigated using enantioenriched vinyl epoxide. Butadiene
(13) For DKR of 2 with carbodiimides, see ref 4.
(14) Monodentate phosphines provided only crotonaldehyde, result-
ing from β-hydride elimination. Bidentate ligands with bite angles
similar to dppe formed most efficient Ni catalysts for oxazolidine
formation.
(15) In the presence of a nickel complex and Lewis acid, crotonalde-
hyde (a product of β-hydride elimination) is observed by 1H NMR. In
the absence of Lewis acid, no reaction is observed.
(16) For select examples of additive effects in reactions involving
allylmetal intermediates, see the following. Rh: (a) Lautens, M.; Fagnou,
K. J. Am. Chem. Soc. 2001, 123, 7170. Ir: (b) Roggen, M.; Carreira,
E. M. J. Am. Chem. Soc. 2010, 132, 11917. Pd: (c) References 4c and 9b.
(8) For rhodium-catalyzed stereospecific addition of alcohols and
amines to vinyl epoxides: (a) Fagnou, K.; Lautens, M. Org. Lett. 2000, 2,
2319. For a complementary stereoselective example using an iridium
catalyst: (b) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig,
J. F. Org. Lett. 2007, 9, 3949.
(9) Examples of rhodium-catalyzed stereospecific allylic substitu-
tion: (a) Evans, P. A.; Leahy, D. K. Chemtracts 2003, 16, 567. (b) Evans,
P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (c) Evans, A. E.;
Robinson, J. E.; Moffett, K. K. Org. Lett. 2001, 3, 3269.
(10) Phosphine ligands (e.g., BINAP, dipamp) inhibit the reaction.
Org. Lett., Vol. 13, No. 19, 2011
5189

Table 2. Optimization of the Stereoselective 1,3-Oxazolidine Formation
entry
imine
catalyst
Ni(cod)2
ligand
% yielda
dr (cis:trans)b
% eec
1d
2d
3d,e
4f
5f
6f,g
1a
1a
4a
4a
4a
4a
C3-Tunephos
DIPAMP
20
87
88
92
80
96
g20:1
g20:1
g20:1
1:3
42
27
65
82
89
91
Ni(cod)2
Ni(cod)2
DIPAMP
Pd2dba3 CHCI3
C3-Tunephos
Josiphos-6
Josiphos-6
3
Pd2dba3 CHCI3
2:1
3
Pd2dba3 CHCI3
2:1
3
1
a % Isolated yield of 3a or 5a after column chromatography. b cis:trans determined by H NMR spectroscopy. c % ee of the major diastereomer
determined by chiral SFC chromatography. d Conditions: 2.0 equiv (()-2, [imine] = 0.20 M, THF. e Additives: 0.30 equiv Ti(Oi-Pr)4, 1.0 equiv TBAT;
ꢀ20 °C. f Conditions: 1.24 equiv (()-2, THF. g Diglyme used as solvent, 6.0 mol % ligand.
methansulfonyl imine 4a and vinyl epoxide (()-2 could be
smoothly converted to produce 1,3-oxazolidine product 5a
in excellent yield, g 95:5 cis:trans diastereoselectivity, and
65% ee.17 Upon garnering mechanistic insight into the
nickel-catalyzed transformation (vide infra), we concluded
that the modest enantioselectivity in this reaction results
from inefficient chirality transfer from the catalyst to
substrate.
We examined palladium catalysts for the reaction
with the objective of identifying a catalyst that would
provide higher enantioselectivities and avoid the need for
additives to maintain an acceptable reaction rate. Utilizing
For example, o-bromobenzaldehyde derived mesyl imine
4e produced the corresponding oxazolidine 5e in moderate
yield and good ee, demonstrating that oxidative addition
of Pd(0) takes place preferentially with vinyl epoxide (()-2
over an aryl bromide (entry 5).
Table 3. Enantioselective Synthesis of cis-1,3-Oxazolidinesa
Pd2(dba)3 CHCl3 as a precatalyst, we examined a variety
3
of bidentate phosphine ligands. Interestingly, we found
that diasterocontrol could be achieved through catalyst
selection. For example, a palladium-C3-Tunephos com-
plex provided trans-5a in excellent yield and good ee
(Table 2, entry 4). Notably, this is the less stable diaste-
reomer of the 1,3-disubstituted oxazolidine.11 Conversely,
complexes formed from ferrocenyl ligands, such as the
Walphos and Josiphos class of bidentate phosphines produced
cis-selective reactions (entries 5 and 6). Overall, the palladium-
catalyzed reaction proved to be superior in all aspects, except
diastereoselectivity, when compared to the nickel-catalyzed
system. For the first time 1,3-oxazolidines could be produced
in a catalytic enantioselective manner favoring either the cis- or
trans-diastereomer in good to excellent ee.18
%
dr
%
entry substrate
R
oxazolidine yieldb (cis:trans)c eed
1
2
3
4
5
4a
4b
4c
4d
4e
H
5a
5b
5c
5d
5e
96
99
96
97
67
2:1
3:1
2:1
2:1
2:1
91
94
91
89
86
4-Me
4-F
3,4-OMe
2-Br
a Conditions: 1.24 equiv (()-2. b % Isolated yield of 5 after column
chromatography. c cis:trans ratio determined by 1H NMR spectroscopy.
d % ee of the major diastereomer determined by chiral SFC.
Aryl imines with a variety of substituent patterns were
tolerated in the palladium-catalyzed reaction (Table 3).19
To refine our understanding of the transformation, we
undertook mechanistic studies designed to pinpoint the
origin of enantioselectivity. In the palladium-catalyzed
reaction, a dynamic kinetic resolution clearly occurs to
provide enantioenriched product in high yield, based on
the mass balance of the reaction. For the nickel-catalyzed
reactions, however, two mechanistic scenarios are consis-
tent with the observed results. The first scenario is a
dynamic kinetic resolution, such that both enantiomers
of the vinyl epoxide are consumed with similar rates (k1 =
k2), rapid η3-η1-η3 isomerization occurs to interconvert the
diastereomeric allylmetal intermediates (k3 > k4 and k5) and
(17) Under the optimized conditions with Ni catalyst a series of aryl
imine electrophiles reacted in up to 65% ee See Supporting Information.
(18) Palladium-catalyzed synthesis of trans-1,3-oxazolidines in up to
2.3:1 ratio as a racemic mixture: Chen, D.; Chen, X.; Du, T.; Kong, L.;
Zhen, R.; Zhen, S.; Wen, Y.; Zhu, G. Tetrahedron Lett. 2010, 51, 5131.
(19) Isoprene monoxide provided 98% yield and 62% ee. See Sup-
porting Information for details.
5190
Org. Lett., Vol. 13, No. 19, 2011

one diastereomer reacts preferentially (k4 > k5) to provide
high ee of the product (Scheme 1). This scenario mirrors the
mechanism of the palladium-catalyzed reaction.20 The alter-
native scenario is that the asymmetric catalyst performs a
kinetic resolution of the vinyl epoxide to preferentially con-
sume one enantiomer of the starting material (k1 > k2). In
the nickel-catalyzed transformations 1.5 equivalents of vinyl
epoxide are employed and the product is formed with
modest ee (82:18 er), making this mechanism viable.21
Stereoselectivity is determined during a later step in the
transformation.22
Table 4. Mechanistic Experiments Support Dynamic Kinetic
Resolution of Vinyl Epoxidea
Scheme 1. Possible Mechanistic Scenarios for Asymmetric In-
ductiona
% ee
entry
ligand
dppe
% yield 5ab
(major enantiomer)c
1
2
3
65
96
78
0
(S,S)-Dipamp
(R,R)-Dipamp
58 (R,R)
56 (S,S)
a Conditions: 1.2 equiv (R)-2, 30 mol % Ti(Oi-Pr), 1.0 equiv TBAT.
b % Yield of 5a after purification by column chromatography. c % ee of
the major diastereomer determined by chiral SFC.
a Dynamic kinetic resolution: k3 > k4 and k5; k4 > k5. Kinetic
resolution: k1 > k2; k4 > k3.
In summary, we demonstrate that both stereoselective
and stereospecific syntheses of 1,3-oxazolidines can be
accomplished by examining catalysts with differing rates
of allylmetal isomerization. Rhodium(I)-catalysis affords
stereochemical transfer from enantioenriched vinyl epox-
ide to 1,3-oxazolidine products in 99% ee and up to 7:1 cis:
trans diastereoselectivities. In contrast, asymmetric nickel
and palladium catalysts effect a dynamic kinetic resolution
of the racemic vinyl epoxide to provide enantioenriched
1,3-oxazolidines. Under the conditions developed in this
work, we observe efficient DKR with a palladium catalyst
system providing excellent yields and enantioselectivi-
ties. Taken as a whole, these methods provide mild,
complementary catalytic strategies for synthesis of cis- or
trans-oxazolidines.
To distinguish these two mechanistic scenarios for the
nickel-catalyzed reaction we performed experiments utiliz-
ing enantiopure vinyl epoxide in the presence of an achiral
bidentate phosphine ligand (dppe), under the standard
reaction conditions (Table 4, entry 1). Racemic product
was obtained, demonstrating that the allylnickel inter-
mediate indeed undergoes η3-η1-η3 isomerization, which,
in the presence of an achiral ligand, results in racemization
of the allylnickel intermediate. To determine whether the
chiral catalyst used in our enantioselective reaction is able
to undergo a similarly rapid isomerization that would
result in epimerization of the diastereomeric allylnickel
complexes, enantioenriched vinyl epoxide was used in
conjuction with chiral ligand (DIPAMP). The nickel-
catalyzed reaction using each enantiomer of DIPAMP
provided ees which are similar (Table 4, entries 2 and 3).
Most importantly, the opposite enantiomers of ligand
provided the opposite enantiomers of product, consistent
with a dynamic kinetic resolution wherein isomerization
of the diastereomeric allylnickel intermediates is faster
than subsequent reaction with imine (k3 > k4 and k5).
Acknowledgment. This work was supported by an NSF
CAREER Award (CHE-0847273) and University of
California Toxic Substances TSR&TP fellowship for
MBS. We thank Heraeus Metal Processing and Solvias
for donations of metal salts and ligands.
Supporting Information Available. Experimental pro-
cedures and spectroscopic and analytical data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) (a) Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am.
Chem. Soc. 1996, 118, 6297. (b) Trost, B. M.; Van Vranken, D. L.;
Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327. (c) Also see ref 8a.
(21) Several scenarios that involve a kinetic resolution of the vinyl
epoxide are possible. For a detailed discussion of such kinetic resolution
reactions, see: Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18,
249–330.
(22) Two possibilities are attack of the titanium alkoxide on imine
and allylic substitution by the sulfonamide. While we do not have
experimental evidence that distinguishes the two, given the high levels
of enantioselectivity, we favor reversible attack of the titanium alkoxide
on the imine, followed by faster allylic substitution of one diastereomer.
Org. Lett., Vol. 13, No. 19, 2011
5191