Facile synthesis of versatile enantioenriched α-substituted hydroxy esters through a Bronsted acid catalyzed kinetic resolution

Article abstract of DOI:10.1021/ol400207t

An efficient synthesis of enantioenriched α-substituted γ-hydroxy esters via a kinetic resolution event is described. Bulky racemic esters in the presence of a chiral Bronsted acid selectively lactonize to yield a recoverable enantioenriched hydroxy ester and lactone. These esters are highly versatile building blocks that can readily be converted to synthetically useful materials.

Full text of DOI:10.1021/ol400207t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Facile Synthesis of Versatile
Enantioenriched r‑Substituted Hydroxy
Esters through a Brønsted Acid Catalyzed
Kinetic Resolution
Ghassan Qabaja, Jennifer E. Wilent, Amanda R. Benavides, George E. Bullard, and
Kimberly S. Petersen*
Department of Chemistry and Biochemistry, University of North Carolina at
Greensboro, Greensboro, North Carolina 27402, United States
kspeters@uncg.edu
Received January 23, 2013
ABSTRACT
An efficient synthesis of enantioenriched R-substituted γ-hydroxy esters via a kinetic resolution event is described. Bulky racemic esters in the
presence of a chiral Brønsted acid selectively lactonize to yield a recoverable enantioenriched hydroxy ester and lactone. These esters are highly
versatile building blocks that can readily be converted to synthetically useful materials.
Enantioenriched R-substituted γ-hydroxy esters such as
(ꢀ)-1 are versatile molecules with two distinct functional
group handles for further manipulation. Previous synthe-
ses of these molecules are nearly nonexistent, likely due to
the propensity of nonbulky esters tolactonize orepimerize.
Select examples include a hydroboration/oxidation of an
R-substituted allylic ester prepared by an asymmetric Cu-
catalyzed SN20-addition1 and an organocatalyzed Friedelꢀ
Crafts alkylation of an R,β-unsaturated ester/aldehyde
followed by reduction.2 Stabilization of these versatile build-
ing blocks through the use of a bulky ester and a facile enantio-
selective synthesis would likely lead to the widespread use of
these molecules in the preparation of important biological
molecules including natural products or drug candidates.
Enzyme catalyzed enantioselective transesterifications
are attractive reactions.3 However, primary alcohols are
often particularly problematic in the process. Our strategy
for the preparation of enantioenriched primary alcohol
containing building blocks such as (ꢀ)-1 takes advantage
of the different rates of intramolecular tranesterification
of the enantiomers of (()-1 in the presence of a chiral
Brønstedacid catalyst(Scheme 1). By using bulky esterswe
reduce the inherent instability of the substrates so that
lactonization is slowed and will only occur in the presence
of a strongly activating acid catalyst. The two enantiomers
can then be separated via the selective lactonization of one
of the enantiomers over the other. This kinetic resolution
leads to a generalized and scalable process for the pre-
paration of stable enantioenriched hydroxy ester building
blocks.
The useofchiralBrønsted acidsisarapidly growing field
of organocatalysis.4 In the proposed lactonization reac-
tion, we envisioned that the chiral acid would serve to
activate substrates through either a hydrogen bonding
ꢀ
(1) den Hartog, T.; Macia, B.; Minnard, A. J.; Feringa, B. L. Adv.
Synth. Catal. 2010, 999–1013.
(2) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
4370–4371.
(3) Select reviews: (a) Ghanem, A. Tetrahedron 2007, 63, 1721–1754.
(b) Santaniello, E.; Ferraboschi, P.; Grisenti, P. Enzyme Microb. Tech-
nol. 1993, 15, 367–382.
(4) (a) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006,
348, 999–1010. (b) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc.
Rev. 2011, 40, 4539–4549.
r
10.1021/ol400207t
XXXX American Chemical Society

Table 1. Initial Optimizationa
Scheme 1. Kinetic Resolution of Hydroxy Ester with Chiral
Acid Catalyst
temp time
%
ee%, ee%,
entry catalyst solvent
(°C)
(h) conv 1a
2a
s
1
3
4
5
6
7
8
9
9b
9
9
9
9
9
9
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
5
6
3
0
0
n/a
2
5
12
6
1
0
n/a n/a
3
5
18
75
71
23
40
42
41
2
0
0
n/a
n/a
1
4
5
19
24
24
24
24
24
48
48
48
4
0
0
5
5
17
8
32
29
31
68
41
event or full Brønsted acid catalysis (through coordination
to the carbonyl and/or the alcohol). Typical catalysts are
based on thiourea, TADDOL, or BINOL (Figure 1) and
have been used in a variety of enantioselective transfor-
mations.5 In particular, there have been several recent
examples using chiral phosphoric acids in kinetic resolu-
tion processes.6
6
5
4
7
5
58
57
64
0
25
15
19
8
5
9
5
10
11
12
13
14
15
5
n/a n/a
Et2O
5
2
0
10
45
68
32
49
n/a
4
hexanes
toluene
toluene
toluene
5
47
50
67
47
39
73
>98
71
rt
ꢀ5
14
15
19
48
ꢀ20 720
a Typical reaction conditions: 0.06 mmol of (()-1a, 0.001 mmol of
catalyst, in 10 mL of solvent at set temperature and time. Conversion
and % ee’s determined by GC analysis with a chiral support unless
indicated otherwise. b Catalyst 9 washed with HCl before use.7
Gratifyingly, when 2,20-aryl substituted BINOL-derived
phosphoric acids were examined we began to see selectivity
in the process (Table 1, entries 5ꢀ8), with the triisopropyl
phenyl catalyst 9 being the most selective. At 40% conver-
sion, lactone (ꢀ)-2a was found to have an ee of 68% and
the recovered starting material (ꢀ)-1a had an ee of 57%
giving a selectivity factor of 25.8 Next, we performed a
limited solvent screen. Predictably, nonpolar solvents such
astoluene (Table 1, entry9) and hexanes(Table1, entry 12)
performed at similar rates and selectivities to CH2Cl2,
while polar aprotic solvents such as THF (Table 1,
entry 10) and Et2O (Table 1, entry 11) were ineffective,
presumably due to interruption of hydrogen bonding
between the catalyst and substrate. Varying the tem-
perature of the reaction had little difference on the
selectivity factor of the reaction; however, the reaction
time was significantly affected (Table 1, entries 13ꢀ15).
Using optimized conditions (Table 1, entries 7 and 9)
we consistently were able to achieve selectivity factors of
∼20 and with test substrate 1a.9
Figure 1. Chiral hydrogen bonding catalysts.
Initial optimization of the process focused on R-methyl
hydroxy tert-butyl ester (()-1a (Table 1). Hydroxy ester
(()-1a was cooled to 5 °C in dichloromethane and treated
with a variety of chiral hydrogen bonding acid catalysts,
monitoring lactonization by gas chromatography. TAD-
DOL (3) and thiourea based acids 4 (Table 1, entries 1 and
2) were not effective at catalyzing the lactonization of
hydroxy ester (()-1a. Camphor sulfonic acid (5) and
unsubstituted BINOL phosphoric acid 6 were both ca-
pable of inducing lactonization; however, they did not
produce either lactone 2a or recovered hydroxy ester 1a
with any enantioenrichment (Table 1, entries 3 and 4).
(7) For a discussion on the impact of trace metals in chiral phosphoric
acids, see: Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew.
Chem., Int. Ed. 2010, 49, 3823–3826.
(8) (a) The selectivity factor (s) was determined using the equation
s = krel(fast/slow) = ln[(1 ꢀ c)(1 ꢀ ees)]/ln[(1 ꢀ c)(1 þ ees)], where c =
conversion and ees is the ee of the recovered starting material. This
equation was developed by Kagan; see: Kagan, H. B.; Fiaud, J. C. In
Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley & Sons: New York, 1988;
Vol. 18, pp 249ꢀ330. (b) The absolute configuration of stereocenter in
(ꢀ)-2a was determined based on comparison of optical rotation to
literature values (see Supporting Information), and that of (ꢀ)-1a was
determined by comparison of the optical rotation of lactone formed by
treatment of (ꢀ)-1a with TFA (see Scheme 4 and Supporting Information).
(9) Use of enant-9 gave recovered hydroxy ester (þ)-1a.
(5) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566–1568. (b) Huang, Y.; Unni, A. K.; Thadani,
A. N.; Rawal, V. H. Nature 2003, 424, 146. (c) Sigman, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 1998, 120, 4901–4902. (d) Uraguchi, D.; Terada,
M. J. Am. Chem. Soc. 2004, 126, 5356–5357. (e) Vachal, P.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 10012–10014.
(6) Select recent examples: (a) Mandai, H.; Murota, K.; Mitsudo, K.;
Suga, S. Org. Lett. 2012, 14, 3486–3489. (b) Lu, G.; Birman, V. B. Org.
Lett. 2011, 13, 356–358.
B
Org. Lett., Vol. XX, No. XX, XXXX

Regrettably, the lactonization of prochiral diol 12 to
lactone 13 in the presence of chiral catalyst 9 was not as
successful. While the yield was still good (65%), the
selectivity was diminished (ee = 35%), likely due to the
increased rate of the reaction.11 Both lactones (ꢀ)-11
and 13 contain an all-carbon quaternary stereocenter
that would be difficult to install using other methodol-
ogies. Studies are currently underway to employ lac-
tone (ꢀ)-11 in the synthesis of a biologically important
molecule.
Table 2. Substrate Scopea
temp time
%
ee%, ee%,
Scheme 2. Desymmetrization of Prochiral Substrates
entry substrate solvent (°C)
(h) conv
1
2
s
1
2
3
4
5
6
7
1b
1c
1d
1e
1f
CH2Cl2
5
8
68
50
56
71
67
63
53
21
14
52
50
85
86
83
24
27
37
1.4
1.5
3.9
CH2Cl2 35
144
72
hexanes
toluene
5
5
40
26b 2.3
n/a 6.1
CH2Cl2 rt
CH2Cl2
24
1g
1h
5
72
50
7.9
CH2Cl2 5frt 232
66b 16.7
a Typical reaction conditions: 0.06 mmol of (()-1, 0.001 mmol of 9,
in 10 mL of solvent at set temperature and time. Conversion and % ee’s
determined by GC analysis with a chiral support column unless indi-
cated otherwise. b Ee determined by HPLC analysis with a chiral support
column.
With our optimum conditions in hand we set out to
explore the scope of the reaction (Table 2). We first
explored other ester functionalities. The smaller isopropyl
ester 1b showed drastically reduced selectivity and reaction
time (Table 2, entry 1, s = 1.4). However the bulkier 2,4-
dimethyl-3-pentanol ester 1c was prohibitively slow and
needed heat to progress to lactone while showing little
selectivity (Table 2, entry 2, s = 1.5). Thus, we focused on
the initial tert-butyl esters.
Hydroxy esters with bulky R-substituents such as iso-
propyl 1d (Table 2, entry 3, s = 3.9) or phenyl 1e (Table 2,
entry 4, s = 2.3) were found to be poor substrates in the
resolution; however substrates with small to moderately
sized R-substitution such as ethyl 1f (Table 2, entry 5, s =
6.1) proceeded through the resolution with moderate to
good selectivities. Most excitingly, easily manipulated
R-allyl substrate 1g (Table 2, entry 6, s = 7.9) yielded pro-
duct with good enantioselectivity and the di-R-substi-
tuted substrate 1h (Table 2, entry 7, s = 16.7) produced
an enantioenriched hydroxy ester with a challenging all-
carbon quaternary center.
We next sought to show the utility of the kinetic resolu-
tion process on a larger, more synthetically relevant scale
than for the initial screenings (Scheme 3). Starting with 300
mg of (()-1a we obtained 102 mg (34% isolated yield) of
(ꢀ)-1a with an enantiopurity of 93% using only 0.5 mol %
of the catalyst. The R-quaternary substrate (()-1h (200
mg) produced 76 mg (38% yield) of (ꢀ)-1h with an
enantiopurity of 94%.12
Enantioenriched hydroxy esters of the type described
here are highly versatile building blocks that are suitable
for either incorporation directly intoa biologicallyrelevant
molecule or conversion into a multitude of other small
molecules (Scheme 4). Commercially available lactone 2a
is easily prepared by treatment of (ꢀ)-1a with acid in high
Scheme 3. Scale
The desymmetrization of prochiral substrates, an im-
portant variant of kinetic resolutions, is not limited by the
inherent yield constraints of classical kinetic resolutions.10
Gratifyingly, symmetric substrates such as 10 or 12 were
compatible with the reaction conditions yielding enan-
tioenriched lactones (ꢀ)-11 and 13 (Scheme 2). Prochiral
diester 10 was converted to enatioenriched ester (ꢀ)-11
in excellent yield (90%) and selectivity (ee = 98%).
ꢀ
(10) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005,
105, 313–354.
Org. Lett., Vol. XX, No. XX, XXXX
C

and can easily be converted to lactam 16. Oxidation of
alcohol (ꢀ)-1a generated carboxylic acid 17, and reduction
afforded diol 18. These newly formed enantioenriched
molecules can then be manipulated further and incor-
porated into more complex molecules. In particular
diol 18 has been used in numerous natural product
syntheses.13
Scheme 4. Easy Access to Enantioenriched Building Blocks
In summary, we report an efficient and generalized
procedure for the preparation of enantioenriched R-sub-
stituted hydroxy esters through a kinetic resolution. This
process is easily scalable and requires catalyst load-
ings as low as 0.5 mol %. Generation of all-carbon qua-
ternary centers in high enantioselectivities is readily
achieved. Current work is directed toward expanding
the scope of this reaction and examining the mechanism
in more detail.
Acknowledgment. We thank the University of North
Carolina at Greensboro for financial support and Dr.
Franklin J. Moy (UNCG) and Dr. Brandie M. Ehrman
(UNCG) for assistance with NMR and mass spectrometry
data analysis.
yield and no loss of enantioselectivity. Amino ester 15 was pre-
pared in three steps with minimal loss of enantioselectivity
(11) Reaction was complete after 12 h at 5 °C.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) The absolute configuration of the stereocenter in (ꢀ)-1h was
determined based on comparison to literature values of recovered
lactone (ꢀ)-2h (see Supporting Information).
(13) Select recent examples: (a) Liu, H.; El-Salfiti, M.; Chai, D. I.;
Auffret, J.; Lautens, M. Org. Lett. 2012, 14, 3648–3651. (b) Francais, A.;
Leyva, A.; Etxebarria-Jardi, G.; Ley, S. V. Org. Lett. 2010, 12, 340–343.
(c) Lautens, M.; Stammers, T. A. Synthesis 2002, 1993–2012.
The authors declare no competing financial interest.
D
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