Palladium-catalyzed, asymmetric Baeyer-Villiger oxidation of prochiral cyclobutanones with PHOX ligands

Article abstract of DOI:10.1016/j.tet.2011.04.046

Described in this report is a general method for the conversion of prochiral 3-substituted cyclobutanones to enantioenriched γ-lactones through a palladium-catalyzed Baeyer-Villiger oxidation using phosphinooxazoline ligands in up to 99% yield and 81% ee. Lactones of enantiopurity ≥93% could be obtained through a single recrystallization step. Importantly, 3,3-disubtituted cyclobutanones produced enantioenriched lactones containing a β-quaternary center.

Full text of DOI:10.1016/j.tet.2011.04.046

Tetrahedron 67 (2011) 4352e4357
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed, asymmetric BaeyereVilliger oxidation of prochiral
cyclobutanones with PHOX ligands
*
Kimberly S. Petersen, Brian M. Stoltz
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Described in this report is a general method for the conversion of prochiral 3-substituted cyclobutanones
Received 28 February 2011
Received in revised form 11 April 2011
Accepted 13 April 2011
to enantioenriched g-lactones through a palladium-catalyzed BaeyereVilliger oxidation using phosphi-
nooxazoline ligands in up to 99% yield and 81% ee. Lactones of enantiopurity ꢀ93% could be obtained
through a single recrystallization step. Importantly, 3,3-disubtituted cyclobutanones produced enan-
Available online 23 April 2011
tioenriched lactones containing a b-quaternary center.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor F. Dean Toste on the
receipt of the 2011 Tetrahedron Young
Investigator Award
Keywords:
BaeyereVilliger oxidation
Phosphinooxazoline ligands
Asymmetric catalysis
Palladium
1. Introduction
substituent at the carbonyl carbon migrates to a peroxide oxygen atom
resulting in an ester or lactone. The reaction is highly regioselective
and stereospecific in that the more substituted alkyl substituent mi-
grates and there is retention of stereochemistry of the migrating
group. It is generally accepted that the reaction proceeds most
smoothly when the migrating carbon atom of Criegee adduct 2 is
antiperiplanar to both the OeO bond of the leaving group and the lone
pair of electrons of the hydroxy group. Thus it can be assumed that
interaction of the intermediate Criegee adduct 2 with a chiral catalyst
is necessary for asymmetric induction in the reaction (see 2b).
Catalytic asymmetric oxidation chemistry has had a profound
effect on modern organic synthesis. In particular, asymmetric epox-
idations(e.g., Sharpless, Jacobsen and Shi)1 and dihydroxylations (e.g.,
Sharpless)2 are powerful tools that deliver enantioenriched products
from prochiral starting materials with high levels of enantiose-
lectivity. Our laboratory has been interested in asymmetric oxidation
for some time and has developed a series of palladium-catalyzed
asymmetric oxidation reactions.3 Despite much progress in the field
over the past 30 years there are still many oxidation methods for
which no satisfactory catalytic asymmetric version exists.
OH
O
R'
O
A century after its discovery, the BaeyereVilliger oxidation remains
one of the most powerful methods to convert a ketone into an ester
proceeding by insertion of an oxygen atom into a CeC bond (Scheme
1).4 While much recent work has been devoted to developing catalytic
asymmetric variants of this reaction, the results, except for a few ex-
amples, have been modest with respect to enantioselectivity.5 By
contrast, bio-catalyzed BaeyereVilliger oxidations have been shown
to proceed with high levels of enantioselectivity (>95% ee).6 The
BaeyereVilliger reaction is believed to proceed by a two-step process
whereby the hydrogen peroxide or peracid initially adds to the car-
bonyl group to give a tetrahedral intermediate, the Criegee adduct 2.
This intermediate then undergoes a rearrangement in which an alkyl
O
R
O
2a
R'OOH
Criegee adduct
O
(chiral catalyst MLn)
L
L
R
R
1
3
M
O
O
O
R
2b
Scheme 1. BaeyereVilliger oxidation.
The first examples of catalytic, asymmetric BaeyereVilliger oxi-
dations were reported independently by Bolm and Strukul in 1994.7
Strukul and co-workers used a chiral platinum(II) complex in the
presence of hydrogen peroxide to selectively oxidize racemic cyclic
* Corresponding author. E-mail address: stoltz@caltech.edu (B.M. Stoltz).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.046

K.S. Petersen, B.M. Stoltz / Tetrahedron 67 (2011) 4352e4357
4353
ketones (up to 58% ee).7b Bolm and co-workers found that 2-
substituted cycloalkanones could be selectively oxidized in the
presence of a sacrificial aldehyde and a catalytic Cu/oxazoline com-
plex with molecular oxygen (up to 69% ee).7a The first catalytic,
asymmetric BaeyereVilliger oxidations of symmetric 3-substituted
material with 93% ee. One of these lactones, (R)-(ꢂ)-3-(40-chlor-
ophenyl)-g-butyrolactone (3b), can be further manipulated to
produce the GABAB receptor agonist (R)-(ꢂ)-baclofen.
2. Results and discussions
cyclobutanones (e.g., 1) to enantioenriched g-lactones (e.g., 3) pro-
ceeded in only modest selectivities (ꢁ65% ee).8 More recently, work
Prochiral 3-substituted cyclobutanones 1aef were prepared
through a [2þ2] cycloaddition of dichloroketene to the appropriate
alkene followed by dechlorination of the resulting 2,2-dichlor-
ocyclobutanones with zinc (Scheme 2).17
by Katsuki9 and then Malkov and Kocovsky has been toward the
development of a BaeyereVilliger oxidation of such cyclobutanones
using a chiral cationic palladium(II) complex and hydrogen peroxide/
urea adduct as the oxidant. Both procedures use phosphinopyridine
ligands (4e6, Fig. 1) and proceed with yields up to 100% and enan-
tioselectivies up to 81% ee. This oxidation is postulated to occur via
a metal/Criegee adduct, such as 2b. Finally, a variety of non-transition
metal catalyzed BaeyereVilliger oxidations have been developed.
Murahashi and Imada used chiral bisflavins to catalyze the asym-
metric BaeyereVilliger oxidation of prochiral cyclobutanones, such
as 1 to lactones, such as 3 with upto 74% ee.11 More recently, Ding and
collaborators performed the same transformation using chiral
ꢀ
ꢁ10
Cl
O
1a: R1 = Ph, R2 = H
O
O
R1
R2
Zn
Cl
1b: R1 = 4-Cl-Ph, R2 = H
1c: R1 = 4-CF3-Ph, R2 = H
1d: R1 = t-Bu, R2 = H
1e: R1 = Ph, R2 = Me
1f: R1= t-Bu, R2 = Me
R1
Cl
R1
R2 Cl
R2
1a 1f
Scheme 2. Preparation of meso cyclobutanones.
In order to optimize the reaction using PHOX ligands we first
examined the BaeyereVilliger oxidation of 3-phenylcyclobutanone
(1a, Table 1). Little difference in reactivity and selectivity was ob-
served by varying the palladium source (entries 1e5). Interestingly,
we found that tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3,
entry 4) was competent in the reaction suggesting that either a cat-
ionic Pd(II) species is responsible for the observed chemistry, or that
hydroxide or peroxide is serving as a ligand on palladium during the
course of the reaction, even when Clꢂ is present in the catalyst pre-
cursor.18 Based on these results we chose to focus on Pd(CH3CN)2Cl2
as the palladium source simply because of convenience. Silver is
necessary in the reaction as shown in entry 6, however silver tri-
fluoromethanesulfonimide (entry 8) gave results similar to silver
hexafluoroantimonate. With the optimized palladium and silver
sources we next focused on a ligand screen. The electronics of the
phosphorous made little difference in the reaction with both the
electron poor ligand 8 and the electron rich ligand 9 yielding lactone
3a in 76% and 64% ee, respectively (entries 12 and 14). However, the
Brønsted acids arriving at g
-lactones, such as 3 with up to 93% ee.12
Additionally, Miller and co-workers have shown in preliminary
results that chiral carboxylic acids can be used to desymmetrize
prochiral ketones with modest selectivities (30 and 42% ee).13
Phosphinopyridines
N
PPh2
N
PPh2
N
PPh2
4
5
6
CF3
PHOX
O
O
O
N
P
CF3
N
P
N
PPh2
Table 1
Screen of palladium source, silver source, and liganda
Pd source (5 mol%)
Ligand (6 mol%)
O
O
7
8
9
O
Ag source (10 mol%)
CF3
R
H2O2•urea
THF, – 40 °C
Ph
Ph
O
O
1a
3a
N
PPh2
N
PPh2
,
c
Entry
Pd source
Ligand
Silver source
Yieldb (%)
eed (%)
1
2
3
4
5
6
7
8
Pd(PhCN)2Cl2
Pd(nbd)Cl2
Pd(CH3CN)2Cl2
Pd2(dba)3
7
7
7
7
7
7
7
7
7
7
7
8
10
9
11
12
13
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
None
AgPF6
AgNTf2
AgOTf
AgClO4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
95b
98b
100b
96b
93b
0b
78
73
79
78
11
10
PdBr2
77
O
O
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
n.d.e
66
79b
100b
83b
94b
91c
93c
99c
97b
92b
39b
88b
N
PPh2
N
PPh2
76
66
70
9
13
12
HN
S
10
11
12
13
14
15
16
17
80 (93) f
76
Fig. 1. P,N-ligands.
81
64
56
64
Our interest in the development of enantioselective oxidation
processes along with our extensive experience with and collection
of P,N-type phosphinooxazoline (PHOX) ligands (7e13, Fig. 1)14 led
us to examine the palladium-catalyzed BaeyereVilliger oxidations
of cyclic ketones. We have recently demonstrated the utility of
PHOX ligands in palladium-catalyzed enantioselective decarbox-
ylative alkylation15 and protonation reactions.16 Herein, we report
the application of PHOX ligands in the palladium-catalyzed
BaeyereVilliger oxidation of meso cyclobutanones to produce
71
a
Reaction conditions: 0.1 mmol 1a, 0.005 mmol Pd source, 0.006 mmol ligand,
0.01 mmol silver source, and 0.13 mmol H2O2$urea in 0.5 mL THF for 24e100 h.
b
Yield determined by GC conversion.
Isolated yield on scale of 0.34 mmol of 1a.
Determined by chiral GC analysis and absolute configuration determined by
c
d
comparison of sign of rotation to published reports.
e
enantioenriched
g-lactones in up to 99% yield and 81% ee. Several of
n.d.¼not determined.
f
ee % after recrystallization from hexanes/Et2O.
these lactones (3a and 3b) were recrystallized in ꢀ66% yield to give

4354
K.S. Petersen, B.M. Stoltz / Tetrahedron 67 (2011) 4352e4357
substitution at the 4-position of the oxazoline ring was found to be
important, with aryl and heteroaryl alanine derived PHOX ligands
leading to product 3a with lower enantioselectivity (entries 15e17).
We also explored a number of other solvents (e.g., CH2Cl2, toluene,
and Et2O), however with the exception of 2-methyl THF these were
found to be inferior. Finally, lowering the temperature led to signif-
icant retardation of reaction rate. Fortuitously, the crystalline prod-
3. Conclusion
We have successfully employed PHOX ligands to effect a palla-
dium-catalyzed asymmetric BaeyereVilliger oxidation of prochiral
3-substituted cyclobutanones 1 to enantioenriched g-lactones 3 in
yields up to 99% and enantioselectivities up to 81% ee. Of note,
3,3-disubtituted cyclobutanones (1e and 1f) produced lactones with
uct,
g-lactone 3a, was easily recrystallized from diethyl ether and
a
b-quaternary center with moderate selectivity (3e and 3f). Fur-
hexanes to yield material with an ee of 93% in 66% yield.
thermore, we found that -lactones, such as 3a and 3b were easily
g
Under our optimized conditions we sought to explore the re-
action with other prochiral 3-substituted cyclobutanones (Table 2).
We were pleased to see that both aryl and aliphatic substituents
produced lactones in high yield and similar enantioselectivities.
recrystallized to material withenantiopurityof93% ee. Lactone3bcan
easily be manipulated to provide enantioenriched GABAB receptor
agonsist (R)-(ꢂ)-baclofen (14).22 Efforts to expand the scope and im-
prove the selectivity of the reaction are the focus of ongoing studies.
Importantly, (R)-(ꢂ)-3-(40-chlorophenyl)-
g-butyrolactone (3b),
which was obtained in 90% yield and 75% ee could easily be
recrystallized to yield material with 93% ee. Excitingly 3,3-dis-
ubtituted cyclobutanones were also competent substrates in the
4. Experimental
4.1. General
BaeyereVilliger oxidation producing lactones with a b-quaternary
center in moderate selectivities (3e and 3f, entries 4 and 5). The
substrate scope highlights the potential utility of this method in the
synthesis of biologically active molecules.
Unless stated otherwise, reactions were performed in oven-dried
or flame-dried glassware under a nitrogen atmosphere using dry,
deoxygenated solvents (distilled or passed over a column of acti-
vated alumina). Commercially obtained reagents were used as re-
ceived, unless specified otherwise. Low-temperature reactions were
controlled by a ThermoNeslab CB80 cryocool. Zinc/copper couple
was made as previously described.23 Thin-layer chromatography
(TLC) was conducted with E. Merck silica gel 60 F254 pre-coated
plates (0.25 mm) and visualized using a combination of UV light
(254 nm), p-anisaldehyde, potassium permanganate, or phospho-
Table 2
Substrate screena
Pd(CH3CN)2Cl2 (5 mol%)
(6 mol%)
O
O
7
O
AgSbF6 (10 mol%)
R1
*
H2O2•urea
THF, – 40 °C
R2
R2
R1
molybdic acid staining. SiliaFlashÒ P60 Academic Silica Gel (particle
1b–1f
3b–3f
ꢂ
size 40e63
m
m; pore diameter 60 A) was used for flash column
,
R1, R2
Yieldb (%)
eec d (%)
chromatography. Analytical chiral HPLC analyses were performed
with an Agilent 1100 Series HPLC instrument utilizing a Chiralcel AD
or OD-H column (4.6 mmꢃ25 cm) obtained from Daicel Chemical
Entry
,
e
1
2
3
4
5
1b/3b: R1¼4-ClePh, R2¼H
1c/3c: R1¼4-CF3ePh, R2¼H
1d/3d: R1¼t-Bu, R2¼H
1e/3e: R1¼Ph, R2¼Me
90
99
80
83
57
75 (93)d
65d
75c
Industries, Ltd with detection at either
l
¼210 or 254 nm. Chiral GC
52c
analysis was performed with an Agilent 6850 GC utilizing a Supleco
Chiraldex G-TA or Betadex (30 mꢃ0.25cm) column (1.0 mL/min
carrier gas flow). 1H, 13C, and 19F NMR spectra were recorded on
a Varian Mercury 300 (at 300 MHz, 75 MHz, and 282 MHz,
respectively) or a Varian Inova 500 (at 500 MHz and 125 MHz,
respectively) instrument and are reported as follows: chemical shift
f
1f/3f: R1¼t-Bu, R2¼Me
29
a
Reaction conditions: 0.34 mmol 1bef, 0.017 mmol Pd(CH3CN)2Cl2, 0.021 mmol
ligand, 0.034 mmol AgSbF6, and 0.445 mmol H2O2$urea in 1 mL THF for 24e100 h.
b
Isolated yield on 0.34 mmol scale of ketone.
Determined by chiral GC analysis.
Determined by chiral HPLC analysis.
ee % after recrystallization from hexanes/Et2O.
c
d
e
(d ppm) (multiplicity, coupling constant (Hz), integration). IR spectra
f
Determined by chiral HPLC analysis of the dibenzoate of the reduced diol (see
were recorded on a PerkineElmer Spectrum BXII spectrometer and
are reported in frequency of absorption (cmꢂ1). Optical rotations
were measured with a Jasco P-1010 polarimeter, using a 100 mm
path-length cell. High-resolution mass spectra were obtained from
the California Institute of Technology Mass Spectral Facility.
Experimental section).
The hydrochloride salt of (R)-(ꢂ)-baclofen (14, Scheme 3) is
a potent GABAB receptor agonist.19 The racemic form is commer-
cially available and used to treat spasticity and alcoholism, however
the (R)-isomer has been shown to be predominantly responsible for
the molecule’s bioactivity. The molecule has been the target of
many asymmetric syntheses. Several of these strategies start from
enantioenriched lactone 3b generated from either an enzymatic
BaeyereVilliger20 or from an enantioselective CeH insertion.21 We
4.2. Representative procedure for the synthesis of
cyclobutanones
Cl3CC(O)Cl
POCl3
O
O
Zn
have demonstrated that via our method we could generate g-lac-
Cl
Zn/Cu
Et2O
MeOH/NH4Cl
Ph
tone 3b in 93% ee and 72% yield after a single recrystallization.
Transformation of enantioenriched lactone 3b to (R)-(ꢂ)-baclofen
(14) can be completed as previously described.22
Ph Cl
Ph
1e
OEt
O
R
4.2.1. Cyclobutanone 1e. To a 100 mL 2-neck round-bottomed flask
ClH3N
equipped with a magnetic stir bar and a 25 mL addition funnel were
added a-methylstyrene (0.62 mL, 4.75 mmol), zincecopper couple
ref 20
O
O
R
(0.92 g, 7.12 mmol), and ether (10 mL). A solution of trichloroacetyl
chloride (0.79 mL, 7.12 mmol) and phosphorus oxychloride
(0.44 mL, 4.75 mmol) in ether (5 mL) was added dropwise via ad-
dition funnel over 20 min. A reflux condenser was added to the flask
and the resulting solution was heated at 40 ꢄC for 10 h. After cooling
to 23 ꢄC the mixture was filtered over Celite and washed with ether
(20 mL). The filtrate was then quenched with satd NaHCO3 and the
Cl
Cl
3b ee = 93%
14
Scheme 3. Synthesis of (R)-(ꢂ)-baclofen.

K.S. Petersen, B.M. Stoltz / Tetrahedron 67 (2011) 4352e4357
4355
layers separated. The aqueous layer is extracted with ether
(1ꢃ10 mL) and the combined organics are rinsed with brine, dried
over MgSO4, and concentrated under reduced pressure. The crude
material was purified by flash chromatography on silica gel (3 cmꢃ7
in silica, 5/7% EtOAc in hexanes) to afford 2,2-dichloro-3-phenyl-
cyclobutanone as a clear and colorless oil (780 mg, 72% yield).
In a 50 mL round-bottom flask equipped with a reflux condenser
is placed 2,2-dichloro-3-phenylcyclobutanone (775 mg, 3.38 mmol)
from above and activated zinc (885 mg 13.53 mmol) in a satd
methanolic NH4Cl solution (5 mL). The suspension is refluxed for
6 h, then cooled to 23 ꢄC, and filtered through Celite. The Celite is
rinsed with ether (20 mL) and organics are rinsed with H2O (10 mL),
satd NaHCO3 (10 mL), and brine (10 mL), dried over MgSO4 and
concentrated under reduced pressure. The crude material was pu-
rified byflash chromatographyon silica gel (3 cmꢃ7 in silica, 2/10%
EtOAc in hexanes) to afford cyclobutanone 1e as a clear and colorless
described above for 1e. The characterization data matches that in
literature.24
O
t-Bu
1f
4.2.6. Cyclobutanone 1f. Material was prepared from 2,3,3-tri-
methyl-1-butene in 4% overall yield as a clear and colorless oil
described above for 1e. The characterization data matches that in
literature.25
4.3. Representative procedure for the synthesis of g-lactones
oil (350 mg, 65% yield). 1H NMR (300 MHz, CDCl3)
3.48 (m, 2H), 3.13 (m, 2H), 1.62 (s, 3H); 13C NMR (126 MHz, CDCl3)
d
7.33 (m, 5H),
Pd(CH3CN)2Cl2 (5 mol%)
t-BuPHOX (6 mol%)
AgSbF6 (10 mol%)
O
O
O
d
206.6,148.3,128.6,126.3,125.6, 59.3, 34.0, 31.1; IR (neat film, NaCl)
3549, 3059, 3025, 2958, 2921, 2866, 1784, 1601, 1496, 1445, 1381,
H2O2•urea
THF, – 40 °C
t-Bu
n
t-Bu
1d
3d
1302,1186,1142,1080,1029, 764, 701 cmꢂ1; HRMS (EIþ) m/z calcd for
C11H12O [M]þ: 160.0888, found 160.0905.
O
4.3.1.
dium(II) (4.4 mg, 17
7 (8.1 mg, 21
mol) and the solution was stirred for 1 h at 23 ꢄC. To
another flask containing silver hexafluoroantimonate (11.7 mg,
34 mol) was added the above palladium(II) complex solution.
g
-Lactone 3d. To a solution of dichlorobis(acetonitrile)palla-
Ph
mmol) in THF (1 mL) was added ligand
1a
m
4.2.2. Cyclobutanone 1a. Material was prepared from styrene in
42% overall yield as a clear and colorless oil as described above for
1e. The characterization data matches that in literature.10
O
m
After stirring 1 h at 23 ꢄC the mixture was filtered through a pad of
Celite under Ar into a new flask containing cyclobutanone 1d
(43 mg, 0.34 mmol) and cooled to ꢂ40 ꢄC. To the cooled solution
was added urea$hydrogenperoxide (42 mg, 0.45 mmol) and the
mixture was further stirred at the temperature for 90 h. The mix-
ture was directly purified by flash chromatography on silica gel
1b
(2 cmꢃ7 in silica, 2/10% EtOAc in hexanes) to afford
g-lactone 3d
Cl
as a clear and colorless oil (39 mg, 80% yield). Observed 75% ee as
determined by chiral GC analysis (ChiraldexÒ GTA, 100 ꢄC, tR
(minor)¼52.4 min; tR (major)¼52.8 min). 1H NMR (500 MHz,
4.2.3. Cyclobutanone 1b. Material was prepared from 4-chlor-
ostyrene in 21% overall yield as a clear and colorless oil as described
above for 1e. The characterization data matches that in literature.10
CDCl3)
d 4.31 (m, 1H), 4.09 (m, 1H), 2.43 (m, 2H), 2.35 (m, 1H), 0.91
(s, 9H); 13C NMR (126 MHz, CDCl3)
d 177.4, 69.8, 45.9, 31.3, 30.1,
O
26.8; IR (neat film, NaCl) n 3537, 2962, 2873, 1780, 1477, 1419, 1400,
1369, 1175, 1033, 999, 987, 841 cmꢂ1; HRMS (EIþ) m/z calcd for
C8H14O2 [M]þ: 142.0994, found 142.0991.
O
1c
F3C
O
4.2.4. Cyclobutanone 1c. Material was prepared from 4-(tri-
fluoromethyl)styrene in 56% overall yield as a clear and colorless oil
Ph
3a
as described above for 1e. 1H NMR (500 MHz, CDCl3)
d
7.62 (d,
J¼8.1 Hz, 2H), 7.42 (d, J¼8.5 Hz, 2H), 3.75 (quintet, J¼8.1 Hz, 1H),
3.55 (m, 2H), 3.36 (m, 2H); 13C NMR (126 MHz, CDCl3)
205.4,147.5,
129.1 (q, J¼32.4 Hz), 126.9, 125.7 (q, J¼3.8 Hz), 124.1 (q, J¼271.8 Hz),
54.7, 28.4; 19F NMR (282 MHz, CDCl3)
n
4.3.2.
g-Lactone 3a. Material was prepared from 1a in 91% yield as
d
a white solid as described above for 3d. Observed 80% ee as de-
termined by chiral GC analysis (ChiraldexÒ GTA, 150 ꢄC, tR (minor)¼
35.4 min; tR (major)¼36.0 min). The characterization data matches
d
ꢂ62.5; IR (neat film, NaCl)
that in literature.10
[
a
]
ꢂ39.3 (c 0.99, CHCl3).
3560, 3049, 2980, 2928, 1791, 1619, 1425, 1387, 1327, 1165, 1123,
1069,1017, 834, 723 cmꢂ1; HRMS (EIþ) m/z calcd for C11H9OF3 [M]þ:
214.0606, found 214.0603.
D25
O
O
O
3b
t-Bu
Cl
1d
4.3.3.
g-Lactone 3b. Material was prepared from 1b in 90% yield as
a white solid as described above for 3d. Observed 75% ee as de-
4.2.5. Cyclobutanone 1d. Material was prepared from 3,3-di-
methyl-1-butene in 32% overall yield as a clear and colorless oil as
termined by chiral HPLC analysis (ChiralpakÒ AD, 4% 2-propanol/

4356
K.S. Petersen, B.M. Stoltz / Tetrahedron 67 (2011) 4352e4357
hexanes, 1 mL/min, 210 nm, tR (minor)¼29.8 min; tR (major)¼
2-propanol/hexanes, 1 mL/min, 254 nm, tR (major)¼6.4 min; tR
(minor)¼7.2 min).
31.4 min). The characterization data matches that in literature.12
O
4.4. Procedure for the recrystallization of
g-lactones
O
4.4.1. -Lactone 3a. Lactone 3a (152 mg, 77% ee) was dissolved in
g
3c
warm Et2O (w4 mL). This solution was then diluted with warm
hexanes (w20 mL) and the solutionwas allowed to cool to 23 ꢄC then
stored at 0 ꢄC for 8 h. The mother liquor was decanted and the solids
were rinsed with cold Et2O (1ꢃ3 mL) and hexanes (3ꢃ5 mL). Solids
were dried to yield white crystals in 66% yield (101 mg, 93% ee).
CF3
4.3.4.
g-Lactone 3c. Material was prepared from 1c in 79% yield as
4.4.2.
g-Lactone 3b. Lactone 3b (116 mg, 71% ee) was dissolved in
an off white solid as described above for 3d. Observed 74% ee as
determined by chiral HPLC analysis (ChiralpakÒ AD, 4% 2-propanol/
hexanes, 1 mL/min, 254 nm, tR (minor)¼19.3 min; tR (major)¼
20.1 min). The characterization data matches that in literature.26
warm Et2O (w2 mL). This solution was then diluted with warm
hexanes (w20 mL) and the solution was allowed to cool to 23 ꢄC
then stored at 0 ꢄC for 8 h. The mother liquor was decanted and the
solids were rinsed with cold Et2O (1ꢃ3 mL) and hexanes (3ꢃ5 mL).
Solids were dried to yield white crystals in 72% yield (83 mg,
93% ee).
O
O
Ph
Me
Acknowledgements
3e
This publication is based on work supported by Award No. KUS-
11-006-02, made by King Abdullah University of Science and
Technology (KAUST).
4.3.5.
g-Lactone 3e. Material was prepared from 1e in 83% yield as
a clear and colorless oil as described above for 3d. Observed 51% ee
as determined by chiral GC analysis (BetaDex, 145 ꢄC, tR (minor)¼
45.1 min; tR (major)¼45.9 min). The characterization data matches
that in literature.12
References and notes
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O
O
t-Bu
Me
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3f
3. (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725e7726; (b)
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4.3.6.
a clear and colorless oil as described above for 3d. 1H NMR
(500 MHz, CDCl3)
4.30 (d, J¼9.1 Hz, 1H), 3.87 (d, J¼9.1 Hz, 1H),
2.64 (d, J¼17.5 Hz, 1H), 2.10 (d, J¼17.5 Hz, 1H), 1.18 (s, 3H), 0.94 (s,
9H); 13C NMR (126 MHz, CDCl3)
177.4, 75.7, 45.5, 38.1, 34.0, 25.7,
g-Lactone 3f. Material was prepared from 1f in 57% yield as
d
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€
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d
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1022, 847
n
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157.1229, found 157.1180.
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O
O
t-Bu
t-Bu
benzoyl chloride
DMAP, NEt
LiAlH
O
HO
O
OH
O
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t-Bu
O
ꢀ
ꢁ
3f
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Observed 29% ee as determined by chiral HPLC analysis of the
derived dibenzoate. To a mixture of lactone 3f (3 mg, 0.03 mmol)
in Et2O (1 mL) was added LiAlH4 (11 mg, 0.30 mmol) and the
mixture was refluxed for 4 h. After cooling to 23 ꢄC the reaction
mixture was diluted with Et2O (5 mL) and 1 N HCl (5 mL). The
layers were separated and the aqueous layer was re-extracted
with Et2O (2ꢃ5 mL). The combined organic phases were rinsed
with brine (5 mL), dried over MgSO4, and concentrated under
reduced pressure. The crude diol was dissolved in NEt3 (0.5 mL)
and DMAP (3 mg, 0.02 mmol) and benzoyl chloride (35 mL,
0.3 mmol) were added. After stirring 4 h the reaction mixture was
directly purified by flash chromatography on silica gel (2 cmꢃ4
in silica, 2/20% EtOAc in hexanes) to yield the dibenzoate as
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