A C-H oxidation approach for streamlining synthesis of chiral polyoxygenated motifs Dedicated to Professor Paul Wender for his pioneering and inspirational work on complexity generating organometallic reactions for streamlining complex molecule synthesis

Article abstract of DOI:10.1016/j.tet.2013.05.012

Chiral oxygenated molecules are pervasive in natural products and medicinal agents; however, their chemical syntheses often necessitate numerous, wasteful steps involving functional group and oxidation state manipulations. Herein a strategy for synthesizi

Full text of DOI:10.1016/j.tet.2013.05.012

Tetrahedron 69 (2013) 7771e7778
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A CeH oxidation approach for streamlining synthesis of chiral
polyoxygenated motifs
,
Dustin J. Covell a, M. Christina White b
*
a Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
b Department of Chemistry, Roger Adams Laboratory, University of Illinois Urbana, Urbana, IL 61801, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral oxygenated molecules are pervasive in natural products and medicinal agents; however, their
chemical syntheses often necessitate numerous, wasteful steps involving functional group and oxidation
state manipulations. Herein a strategy for synthesizing a readily diversifiable class of chiral building
blocks, allylic alcohols, through sequential asymmetric CeH activation/resolution is evaluated against the
state-of-the-art. The CeH oxidation routes’ capacity to strategically introduce oxygen into a sequence
and thereby minimize non-productive manipulations is demonstrated to effect significant decreases in
overall step-count and increases in yield and synthetic flexibility.
Received 11 March 2013
Received in revised form 3 May 2013
Accepted 6 May 2013
Available online 13 May 2013
Dedicated to Professor Paul Wender for his
pioneering and inspirational work on com-
plexity generating organometallic reactions
for streamlining complex molecule
synthesis
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
CeH oxidation
Allylic oxidation
Allylic alcohols
Enantioselective
Palladium
Sulfoxide
1. Introduction
resolution methods to interrogate the streamlining effect of such
processes for the construction of chiral polyoxygenated motifs.4
Polyoxygenation in natural products and medicinal agents is
ubiquitous and often confers specific biological function to small
molecules. Most traditional organic sequences for assembling such
motifs involve acid/base reactions to install the oxygenated func-
tionality as the hydrocarbon core is being constructed. Though re-
liable, these routes require significant synthetic overhead,
commonly in the form of protection/deprotection sequences, oxi-
dation state changes, and functional group manipulations (FGMs).
Our group and others have demonstrated that selective hydrocar-
bon CeH oxidation presents an alternative approach by directly
installing oxidation when it is most synthetically appropriate and
by significantly reducing the number of reactive functional groups
that must be carried through and consequently manipulated in
a sequence.1e3 Herein, we utilize an asymmetric branched allylic
CeH oxidation in combination with enzymatic and small molecule
Allylic alcohol motifs such as those shown in Scheme 1 are
prevalent, in part due to ease with which they can be further
elaborated. Such motifs are particularly challenging to construct
asymmetrically when the oxygen atom is remote from other
functionality, rendering stereochemical relay approaches un-
viable.5,6 Most often, these products are obtained through a kinetic
resolution of the racemic alcohol obtained by the addition of a vinyl
carbanion to an aldehyde.5h,i Additionally, Sharpless asymmetric
Scheme 1. The asymmetric branched allylic CeH oxidation reaction. R,R-Cr(salen)
F¼(R,R)-N,N0-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminochromium(III)
fluoride.
* Corresponding author. Tel.: þ1 217 333 6173; fax: þ1 217 244 8024; e-mail
address: white@scs.uiuc.edu (M.C. White).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.012

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D.J. Covell, M.C. White / Tetrahedron 69 (2013) 7771e7778
epoxidation (SAE) of linear allylic alcohols followed by two-step
sequences to install the vinyl moiety can be employed.5f,g,7 In
general, both of these strategies begin with preoxidized starting
materials that are elaborated toward the target through carbanion-
based reactions that, due to low chemoselectivities, demand
lengthy sequences of FGMs.
(45% ee, 72:28 er). Subsequent methanolysis and enzymatic reso-
lution via acylation of the minor enantiomer by commercially
available Novozyme 435Ô gives enantiopure (ꢀ)-3 in a total of four
steps and 47% overall yield. The CeH oxidation route significantly
reduces the overall step-count and improves the overall yield by
reducing FGMs and oxidation state changes (Scheme 2). Addition-
ally, we found that the CeH oxidation sequence requires only two
purifications, further enabling rapid access to these chiral building
blocks.15
Broad use of an enantioselective transformation requires that
either enantiomer of the desired product can be produced with
high enantioselectivity. Chiral Cr(salen)F 2 is readily available as
either the (R,R)- or (S,S)-enantiomer, and careful selection of
commercially available enzymes allows for enrichment of either
stereoisomer of the product.16 To demonstrate this, we used Pd(II)/
bis-sulfoxide 1/(S,S)-2 and resolution with the commercially
available protease Subtilisin Carlsberg to generate (þ)-3 in 99% ee
and nearly identical overall yield to the route previously described
for (ꢀ)-3 (Schemes 2 and 3). This matches the flexibility of other
catalyst-controlled approaches to these compounds, like the SAE,
which was utilized to make (þ)-3 in a total synthesis of the potent
biotoxin Azaspiracid A.13,14
Palladium(II)/sulfoxide catalysis has proven itself to be a general
platform for allylic CeH esterification,8aed amination,9b,c,eeg,j
alkylation,10aec and dehydrogenation11 of terminal olefins under
mildly acidic, oxidative conditions. We previously reported a Pd(II)-
bis-sulfoxide 1/chiral Cr(salen)F 2 catalyzed reaction for the
asymmetric branched allylic CeH oxidation (ABAO) of terminal
olefins (Scheme 1).4 This reaction proceeds under mild conditions
with high functional group tolerance and chemoselectivity (pri-
mary alcohols and internal olefins are well tolerated) to furnish
enantioenriched allylic alcohols in good yields. Although enantio-
selectivities are modest (43e63% ee) these represent the best to
date for CeH activation of this challenging olefin class.12 We hy-
pothesized that combining the ABAO with enzymatic and/or small-
molecule catalyst based resolutions would enable us to develop
streamlined routes to chiral allylic alcohols by circumventing the
FGMs of traditional carbanion based approaches. In addition, even
the modest enantioenrichment afforded by the ABAO would lead to
significant improvements in yield for subsequent resolution steps
as compared to racemic approaches (e.g., at 60% ee, 80:20 er, only
20% of the material is lost in a highly efficient resolution).
2. Results
We began our explorations by targeting a prototypical bis-
oxygenated chiral building block (ꢀ)-3,
a precursor to the
C19eC26 fragment of the potential cancer therapeutic Bistramide A
(Scheme 2).13a In the traditional carbanion-based route, diol 4 is
selectively protected at one terminus and then oxidized and sub-
jected to a HornereWadswortheEmmons olefination at the other
end to generate ester 5.13c,d After reduction of the ester, SAE affords
the epoxy alcohol in 93% ee.13e,f The primary alcohol is then con-
verted to a halogen, which is eliminated with zinc to afford the
desired allylic alcohol (ꢀ)-3 in a total of seven steps and 34% overall
yield.13a,14
Scheme 3. Stereoselective CeH oxidation approach to each enantiomer of allylic al-
cohol 3.
We next sought to compare the asymmetric CeH oxidation route
to chiral allylic alcohols to traditional resolution strategies. Ester
(ꢀ)-9 was synthesized en route to the potent flower inducing factor
9R-KODA (Scheme 4).17 In order to avoid a lengthy sequence of
FGMs, the carbanion based route started with ozonolysis of methyl
oleate (10) followed by direct vinylation of the resultant aldehyde in
the presence of an ester group. While the poor chemoselectivity of
this approach resulted in a significant diminishment in overall yield,
Scheme 2. CeH oxidation versus carbanion based route to (ꢀ)-3, a precursor of the
C19eC26 fragment of Bistramide A.
Alternatively, using an oxidation driven route, after simple
protection of commercially available 7, allylic CeH oxidation in-
stalls the oxygen functionality directly at the desired oxidation
state, with significant enrichment toward the desired enantiomer
Scheme 4. CeH oxidation versus carbanion based route for the synthesis of ester
(ꢀ)-9.

D.J. Covell, M.C. White / Tetrahedron 69 (2013) 7771e7778
7773
rapid access to (ꢁ)-9 was achieved. Subsequent enzymatic kinetic
resolution afforded enantiopure (ꢀ)-9 in only three steps, however,
with an overall yield of only 9%. Conversely, ABAO of commercially
this approach to chiral polyol synthesis through construction of the
densely functionalized furan core of Goniothalesdiol. Due to its
potent activity against mouse leukemia cells, a number of total
syntheses of Goniothalesdiol (15) and its epimers have been
undertaken.19bel Generally these routes begin with chiral pool
materials; however they lack the synthetic flexibility to rapidly
access derivatives of 15. One approach initially developed by Gracza
and co-workers to 15 proceeds through the tetrasubstituted furan
core 16.19b We recognized that an unprecedented Pd(II)/bis-
sulfoxide-catalyzed tandem ABAO/oxidative Heck sequence could
access this core structure rapidly (Scheme 6).20 Subsequent
Sharpless asymmetric dihydroxylation (SAD) would generate sep-
arable diastereomers, allowing us to obtain enantiopure material
for further reaction.21 Significantly, our de novo approach to 16 is
quite flexible, allowing us to selectively control the stereochemistry
at the 5, 6, and 7 positions of the core furan as well as easily vary the
nature of the aryl substituent at position 7. While previous syn-
theses have relied primarily on CeC bond forming reactions, this
plan involves a steady increase in complexity through hydrocarbon
oxidations.
available a-olefin 12 followed by methanolysis and enzymatic res-
olution yielded (ꢀ)-9 with an equivalent step-count and enantio-
purity, but with a five-fold increase in total yield (three steps, 53%
yield, 99% ee). High chemoselectivity and functional group tolerance
are general features of all of the Pd(II)/bis-sulfoxide-catalyzed allylic
CeH oxidations reported to date and render them well-suited
toward introduction of oxidized functionality late in synthetic
sequences.3ceg Importantly, this reaction sequence was run on gram
scale with virtually no diminishment in yield (49% versus 53%
overall yield).
Due to the large number of commercially available
a-olefin
starting materials, the CeH oxidation sequences presented so far
have begun with fully constructed carbon frameworks. We next
sought to evaluate cases in which the a-olefin is not available to
determine if a CeH oxidation route was still competitive with tra-
ditional approaches. Synthesis of allylic alcohol (ꢀ)-13 toward (þ)-
iso-6-cassine began from a commercially available, protected bro-
mide 14 (Scheme 5).18 Formation of a Grignard reagent from bro-
mide 14 followed by its addition into acrolein gave racemic alcohol
(ꢁ)-13 in one step.18b Again, this carbanion-based carbonyl alkyl-
ation reaction proceeds with poor chemoselectivity, giving a mix-
ture of 1,2 and 1,4 acrolein addition products. Enzymatic resolution
yielded the desired (ꢀ)-13 in two steps and 19% overall yield.18a
From the same commercially available bromide 14, a suitable
starting material for CeH oxidation can be obtained directly by
allylation, a CeC bond forming reaction without the chemo-
selectivity issues that limited the traditional route. Subjecting the
resultant olefin to the allylic CeH oxidation/methanolysis/enzy-
matic resolution sequence affords the desired enantiopure alcohol
(ꢀ)-13 in four steps and 46% overall yield, more than doubling the
yield of the traditional route. This is enabled by the ease of in-
stalling inert
a-olefin moieties through powerful allylation
methods and the selective nature of these CeH oxidation reactions.
Scheme 6. Enantioselective CeH oxidation approach to the core furan precursor
(ꢀ)-22 of the goniothalesdiol family. aSAD¼Sharpless asymmetric dihydroxylation.
Conditions: K2OsO4$2H2O (1 mol %), (DHQD)2PHAL (5 mol %), K2CO3 (3 equiv), NaHCO3
(3 equiv) K3Fe(CN)6 (3 equiv), MeSO2NH2 (1 equiv), t-BuOH/H2O/CH2Cl2 10:10:1,
0
ꢂC/rt.
We decided upon furan core (ꢀ)-22 as an interesting target for
this strategy because, to the best of our knowledge, 6-epi-Gonio-
thalesdiol has yet be synthesized or evaluated medicinally. Our
route began with the Pd(II)/bis-sulfoxide-catalyzed tandem ABAO/
oxidative Heck sequence. Asymmetric branched allylic CeH oxi-
dation (ABAO) reaction on methyl ester 17, followed by the addition
of phenyl boronic acid directly furnished ester 18 that was taken on
crude through hydrolysis and cyclization to give lactone 19 in 54%
yield (two steps) and 50% ee (75:25 er). Sharpless asymmetric
dihydroxylation (SAD) of 19 and subsequent ketal protection of the
resultant diol, gave 70% of diastereomerically and enantiomerically
pure (ꢀ)-20.22 Selenation/dehydroselenation of lactone (ꢀ)-20
Scheme 5. CeH Oxidation versus carbanion based route for the synthesis of (þ)-iso-6-
cassine precursor (ꢀ)-13.
We have demonstrated how the ABAO can be combined with
enzymatic resolution to afford enantiopure allylic alcohols rapidly
and in good yield. However, powerful, small-molecule catalyst-
controlled enantioselective transformations can also be used to
enrich the products of this CeH oxidation. We sought to explore
afforded unsaturated
g
-lactone (þ)-21 in 73% yield. Deprotection of
the acetonide followed by in situ triethylamine (NEt3) assisted cy-
clization afforded the desired tetrasubstituted pyran (ꢀ)-22 in
seven total steps and 22% overall yield. Previous CeC bond forming
routes to this core structure proceeded in 8 and 10 steps with 6 and

7774
D.J. Covell, M.C. White / Tetrahedron 69 (2013) 7771e7778
9% overall yields, respectively. This case study demonstrates the
streamlining potential of hydrocarbon oxidations for synthesizing
densely functionalized fragments.
re-dissolved in hexanes (50 mL) and extracted again with 5%
aq K2CO3 (3ꢃ10 mL) to remove residual hydroquinone. The organic
layer was again dried (MgSO4), filtered, and reduced in vacuo to
afford a clean mixture of allylic oxidation products and any
unreacted starting material from which the B/L, yield, and con-
versions were determined (1H NMR). Unless otherwise noted, this
material was taken forward without further purification, though
each substrate was isolated at least once for characterization pur-
poses. Reported yields and selectivities are an average of at least
3. Conclusions
In summary, we have established that the asymmetric branched
allylic CeH oxidation reaction4 can be combined with other enan-
tioselective transformations to afford enantiopure, polyoxygenated
allylic alcohols rapidly and in good yields. This CeH oxidation ap-
proach is demonstrated to be advantageous to commonly used
resolution and de novo synthetic strategies that require significant
numbers of protection/deprotection steps and functional group
manipulations. Strategies such as these, fueled by novel reactions,
have the greatest potential to both transform synthetic planning
and streamline chemical synthesis.24
two runs. Enantiomeric excess was determined by chiral GC (b-
cyclodextrin column), as compared to racemic standards generated
through our standard branched oxidation chemistry.8a,b Slight
variations in B/L ratios and ees were noted based on batch of Cr
catalyst.
4.2.2. General procedure for cleavage of allylic acetates. To a 25 mL
flask containing crude allylic acetate (1 mmol, assumed) were
added MeOH (5 mL, 0.2 M) and potassium carbonate (0.276 g,
2 mmol). The reaction mixture was vigorously stirred and moni-
tored via thin-layer chromatography (TLC). Upon completion, the
reaction mixture was transferred to a separatory funnel with
methylene chloride (50 mL). Water (15 mL) was added, and the
aqueous layer was extracted with methylene chloride (3ꢃ50 mL).
The combined organics were washed with brine (1ꢃ10 mL), then
dried (MgSO4), filtered, and reduced in vacuo. Products were then
purified by standard SiO2 chromatography. While the branched and
linear allylic alcohols were commonly separable, it was found that
carrying them forward as a mixture had no detrimental effect as the
subsequent resolution acylated the linear alcohol rapidly making
its separation from branched alcohol trivial. Individual product
yields and characterization are reported below.
4. Experimental section
4.1. General information
All commercially obtained reagents were used as received;
achiral gas chromatographic (GC) analyses were performed on
Agilent Technologies 6890N Series instrument equipped with FID
detectors using an HP-5 (5%-phenyl)-methylpolysiloxane column
(30 m, 0.32 mm, 0.25
yses were performed on an Agilent Technologies 5890A Series in-
strument equipped with an FID detector using a J&W Scientific
cyclodextrin column (30 m, 0.25 mm, 0.25 m). Thin-layer chro-
mm). Chiral gas chromatographic (GC) anal-
b
-
m
matography (TLC) was conducted with E. Merck silica gel 60 F254
precoated plates (0.25 mm) and visualized with UV, potassium
permanganate, and ceric ammonium molybdate staining. Flash
column chromatography was performed as described by Still et al.
using EM reagent silica gel 60 (230e400 mesh).23 1H NMR spectra
are reported in parts per million (ppm) using solvent as an internal
standard (CDCl3 at 7.26 ppm). Data reported as: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad; coupling
constant(s) in hertz (Hz); integration. Proton-decoupled 13C NMR
spectra were reported in parts per million (ppm) using solvent as an
internal standard (CDCl3 at 77.0 ppm). IR spectra were recorded as
thin films on NaCl plates on a PerkineElmer Spectrum BX and are
reported in frequency of absorption (cmꢀ1). High-resolution mass
spectra were obtained at the University of Illinois Mass Spectrom-
etry Laboratory.
4.2.2.1. (4R)-1-O-Benzyl-4-acetoxy-5-hexen-1,4-diol
3-OAc.
Following the general procedure for the asymmetric branched al-
lylic CeH oxidation afforded: Run 1: 226 mg, 0.910 mmol, 91%
yield; [B/L]¼4.7:1, [ee]¼44%. Run 2: 220 mg, 0.886 mmol, 89% yield;
[B/L]¼3.8:1, [ee]¼45% (
b
-cyclodextrin, 120 ꢂC isothermal, tR(R)¼
64.98 min, tR(S)¼66.64 min) [average yield: 90%]. This material was
taken forward without further purification. 1H NMR (500 MHz,
CDCl3)
5.28e5.15 (m, 3H), 4.50 (br s, 2H), 3.48 (t, J¼6.4 Hz, 2H), 2.06 (s, 3H),
1.75e1.60 (m, 4H); 13C NMR (125 MHz, CDCl3)
170.3, 138.4, 136.3,
d
7.37e7.27 (m, 5H), 5.77 (ddd, J¼17.2, 10.4, 6.2 Hz, 1H),
d
128.3, 127.6, 127.5, 116.7, 74.5, 72.9, 69.8, 30.8, 25.4, 21.2; IR (neat,
cmꢀ1) 3087.8, 3063.9, 3031.2, 2940.3, 2857.9, 1737.7, 1647.0, 1496.0,
1454.1; HRMS (ESI) m/z calculated for C15H20O3Na [MþNa]þ:
271.1310; found: 271.1302.
4.2. Experimental section
This material was then subjected to the standard procedure for
cleavage of the allylic acetate, which afforded allylic alcohol (ꢁ)-3
ready for subsequent resolution: Run 1: 185 mg, 0.897 mmol, 99%
yield; [B/L]¼4.7:1. Run 2: 181 mg, 0.877 mmol, 99% yield; [B/L]¼
3.8:1.
4.2.1. General procedure for asymmetric branched allylic
acetoxylation. A vial (8 mL borosilicate) was charged with the fol-
lowing: 1,2-bis(phenylsulfinyl)ethane palladium(II) acetate (1)
(10 mol %, 0.10 mmol, 50 mg); (1R,2R)-(ꢀ)-[1,2-cyclohexa
nediamino-N,N0-bis(3,5-di-tert-butylsalicylidene)]chromium(III)F
(R,R-2) (10 mol %, 0.10 mmol, 61.6 mg), 1,4-benzoquinone (2 equiv,
4.2.2.2. Methyl (9R)-9-acetoxyundec-10-eneoate 9-OAc. The
general procedure for the asymmetric branched allylic CeH oxi-
dation afforded: Run 1: 235 mg, 0.915 mmol, 92% yield; [B/L]¼5.1:1,
[ee]¼58%. Run 2: 224 mg, 0.876 mmol, 88% yield; [B/L]¼4.3:1, [ee]¼
55%. Run 3 (gram scale): 1.09 g, 4.250 mmol, 85% yield; [B/L]¼4.1:1,
ꢀ
2.0 mmol, 216 mg), an activated 4 A MS bead (w30 mg), and
a TeflonÓ stir bar. A separate vial (2 mL, borosilicate) was charged
with the following: substrate (1.0 mmol), AcOH (1.1 equiv, 63
and EtOAc (200 L). The liquids were transferred to the solids via
pipette and the vial rinsed with EtOAc (3ꢃ100 L). After carefully
mL),
m
m
[ee]¼57% (
b
-cyclodextrin, 120 ꢂC isothermal, tR(R)¼55.96 min,
stirring for 48 h at room temperature, the reaction mixture was
transferred to a separatory funnel with w3 mL EtOAc and diluted
with hexanes (200 mL). The organic layer was rinsed with satd
aq NaHSO3 (1ꢃ50 mL) and 5% aq K2CO3 (2ꢃ50 mL). Caution should
be taken when combining aqueous layers as carbon dioxide is
evolved. The combined aqueous layers were back extracted with
hexanes (100 mL). The combined organic layers were dried
(MgSO4), filtered, and reduced in vacuo. The resulting oil was
tR(S)¼57.30 min) [average yield: 90%]. This material was taken
forward without further purification. 1H NMR (500 MHz, CDCl3)
d
5.78 (ddd, J¼17.1, 10.5, 6.5 Hz, 1H), 5.24e5.14 (m, 3H), 3.66 (s, 3H),
2.29 (t, J¼8.0 Hz, 2H), 2.05 (s, 3H), 1.62e1.53 (m, 4H), 1.29 (br s, 8H);
13C NMR (125 MHz, CDCl3)
d 174.2, 170.3, 136.5, 116.5, 74.8, 51.4,
34.1, 34.0, 29.1, 29.0, 29.0, 24.9, 24.8, 21.2; IR (neat, cmꢀ1) 3089.1,
2932.9, 2858.2, 1742.0, 1436.3, 1371.5; HRMS (ESI) m/z calculated
for C14H24O4Na [MþNa]þ: 279.1572; found: 279.1564.

D.J. Covell, M.C. White / Tetrahedron 69 (2013) 7771e7778
7775
This material was then subjected to the standard procedure for
cleavage of the allylic acetate, which afforded allylic alcohol (ꢁ)-9
ready for subsequent resolution: Run 1: 188 mg, 0.877 mmol, 96%
yield; [B/L]¼5.1:1. Run 2: 179 mg, 0.835 mmol, 95% yield; [B/L]¼
4.3:1. Run 3 (gram scale): 879 mg, 4.101 mmol, 96% yield; [B/L]¼
4.1:1.
CDCl3) d 173.2, 170.2, 136.0, 133.0, 128.5, 128.0, 126.7, 126.6, 73.7,
51.7, 29.8, 29.5, 21.2; IR (neat, cmꢀ1) 3085.6, 3025.8, 2952.5,
2848.4,v1737.6, 1658.5, 1598.7, 1597.4, 1494.6; HRMS (ESI) m/z cal-
culated for C15H18O4Na [MþNa]þ: 285.1103; found 285.1092.
4.2.3. General procedure for resolution with Novozyme 435. To
a flame dried round bottom flask containing allylic alcohol to be re-
solved (1 equiv) were added vinyl acetate (0.6 M) and Novozyme 435
immobilized on polystyrene beads (33.3 mg/1 mmol). The reaction
mixture was stirred vigorously at room temperature for 36 h. Upon
completion, the solid supported enzyme was removed via filtration.
The solid support was rinsed thoroughly with diethyl ether and then
the filtrate reduced in vacuo and purified via standard SiO2 chroma-
tography. Enantioselectivities were determined by chiral gas chro-
matographic analysis on the acetylated derivative of each isolated
alcohol. It was found that the recovered solid supported enzyme
could be used up to five times with little diminishment in activity.
Individual yields and selectivities are reported below.
4.2.2.3. 2-((3R)-Pent-3-acetoxy-4-en-1-yl-3-ol)-1,3-dioxane 13-
OAc. Following the general procedure for the asymmetric branched
allylic CeH oxidation afforded: Run 1: 180 mg, 0.840 mmol, 84%
yield; [B/L]¼4.8:1:1, [ee]¼44%. Run 2: 178 mg, 0.831 mmol, 83%
yield; [B/L]¼4.3:1, [ee]¼46% (
b
-cyclodextrin, 110 ꢂC isothermal,
tR(R)¼22.21 min, tR(S)¼22.79 min) [average yield: 84%]. This ma-
terial was taken forward without further purification. 1H NMR
(500 MHz, CDCl3)
d
5.76 (ddd, J¼6.5, 10.5, 17.3 Hz, 1H), 5.24 (q,
J¼6.5 Hz, 1H), 5.23 (dm, J¼17.5 Hz, 1H), 5.16 (dm, J¼10.5 Hz, 1H),
4.53 (t, J¼5.0 Hz, 1H), 4.09 (m, 2H), 3.75 (dt, J¼3.0, 12.5 Hz, 2H),
2.12e2.02 (m, 1H), 2.06 (s, 3H), 1.78e1.58 (m, 4H), 1.33 (dm,
J¼13.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 170.2, 136.3, 116.7,
101.7, 74.3, 66.9, 30.7, 28.5, 25.8, 21.1; IR (neat, cmꢀ1) 3087.5, 2962.1,
2931.3, 2852.2, 2780.9, 2732.7, 2661.3, 1739.5, 1646.9, 1430.9,
1407.8; HRMS (ESI) m/z calculated for C11H18O4Na [MþNa]þ:
237.1103; found 237.1104.
4.2.3.1. (ꢀ)-(4R)-1-O-Benzyl-5-hexen-1,4-diol (ꢀ)-3. Following
the general procedure for Novozyme 435 resolution afforded: Run
1: 105 mg, 0.509 mmol, 57% yield; [B/L]¼>20:1, [ee]¼98%. Run 2:
100 mg, 0.485 mmol, 55% yield; [B/L]¼>20:1, [ee]¼99%. Enantio-
meric excess was determined on the acylated derivative of the final
This material was then subjected to the standard procedure for
cleavage of the allylic acetate, which afforded allylic alcohol (ꢁ)-13
ready for subsequent resolution: Run 1: 141 mg, 0.819 mmol, 97%
yield; [B/L]¼4.8:1. Run 2: 135 mg, 0.784 mmol, 94% yield; [B/L]¼
4.3:1.
product (ee determined on the acylated alcohol,
b-cyclodextrin,
120 ꢂC isothermal, tR(R)¼65.56 min, tR(S)¼67.14 min) [average
yield: 56%]. [
d
a
]
ꢀ2.86 (c 2.0, CHCl3). 1H NMR (500 MHz, CDCl3)
26
D
7.37e7.32 (m, 4H), 7.30e7.25 (m, 1H), 5.87 (ddd, J¼17.0, 10.5,
6.0 Hz, 1H), 5.25 (dt, J¼17.0, 1.5 Hz, 1H), 5.10 (dt, J¼10.5, 1.5 Hz, 1H),
4.52 (s, 2H), 4.13 (m, 1H), 3.52 (t, J¼6.0 Hz, 2H), 2.27 (d, J¼4.5 Hz,
4.2.2.4. (4R,E)-Methyl 4-acetoxy-6-phenylhex-5-enoate (18). The
general procedure for the asymmetric branched allylic CeH oxi-
dation was modified in the following way to generate allylic acetate
(18). A round bottom flask (25 mL) was charged with the following:
1,2-bis(phenylsulfinyl)ethane palladium(II) acetate (1) (10 mol %,
0.50 mmol, 250 mg); (1R,2R)-(ꢀ)-[1,2-cyclohexanediamino-N,N0-
bis(3,5-di-tert-butylsalicylidene)]chromium(III)F (R,R-2) (10 mol %,
0.50 mmol, 308 mg), 1,4-benzoquinone (2 equiv, 10.0 mmol, 1.08 g),
2H), 1.77e1.57 (m, 4H); 13C NMR (125 MHz, CDCl3)
d 141.0, 138.1,
128.3, 127.6, 127.6, 114.4, 72.9, 72.6, 70.2, 34.2, 25.7; IR (neat, cmꢀ1
)
3403.8, 3066.3, 3031.6, 2979.5, 2942.9, 2858.0, 2798.2, 1643.1.0,
1496.5, 1454.1; HRMS (ESI) m/z calculated for C13H18O2Na
[MþNa]þ: 229.1204; found: 229.1204.
4.2.3.2. Methyl (9R)-9-hydroxyundec-10-eneoate (ꢀ)-9. Follow-
ing the general procedure for Novozyme 435 resolution afforded:
Run 1: 119 mg, 0.555 mmol, 63% yield; [B/L]¼>20:1, [ee]¼99%. Run
2: 109 mg, 0.509 mmol, 61% yield; [B/L]¼>20:1, [ee]¼98%, Run 3
(gram scale): 523 mg, 2.441 mmol, 60% yield; [B/L]¼>20:1, [ee]¼
Ó
ꢀ
an activated 4 A MS bead (w30 mg), and a Teflon stir bar. A sep-
arate vial (2 mL, borosilicate) was charged with the following:
methyl hexenoate (1.0 equiv, 5.0 mmol, 0.704 mL), AcOH (1.1 equiv,
5.5 mmol, 0.315 mL), and EtOAc (0.50 mL). The liquids were
transferred to the solids via pipette and the vial rinsed with EtOAc
(4ꢃ0.50 mL). After carefully stirring for 48 h at room temperature,
to the reaction mixture were added phenyl boronic acid (1.5 equiv,
7.5 mmol, 0.914 g), AcOH (1 equiv, 5 mmol, 0.285 mL), and EtOAc
(12.5 mL). The reaction mixture was stirred at room temperature
until complete by TLC (w4 h) at which point the reaction mixture
was transferred to a separatory funnel with w5 mL EtOAc and di-
luted with hexanes (400 mL). The organic layer was rinsed with
satd aq NaHSO3 (1ꢃ50 mL) and 5% aq K2CO3 (2ꢃ50 mL). Caution
should be taken when combining aqueous layers as carbon dioxide is
evolved. The combined aqueous layers were back extracted with
hexanes (100 mL). The combined organic layers were dried
(MgSO4), filtered, and reduced in vacuo. The resulting oil was re-
dissolved in hexanes (150 mL) and extracted again with 5%
aq K2CO3 (3ꢃ25 mL) to remove residual hydroquinone. The organic
layer was again dried (MgSO4), filtered, and reduced in vacuo This
product was generally taken forward without further purification,
but was isolated and purified via silica gel chromatography for
characterization. [B/L]¼>20:1, [ee]¼50% (determined on the initial
99% (ee determined on the acylated alcohol,
b
-cyclodextrin, 120 ꢂC
25
isothermal, tR(R)¼55.92 min) [average yield: 62%]. [
a
]
ꢀ5.13 (c
D
1.0, CHCl3). 1H NMR (500 MHz, CDCl3)
d
5.86 (ddd, J¼16.9, 10.8,
6.0 Hz, 1H), 5.22 (d, J¼17.0 Hz, 1H), 5.10 (d, J¼10.5 Hz, 1H), 4.09 (p,
J¼5.5 Hz, 1H), 3.66 (s, 3H), 2.30 (t, J¼7.5 Hz, 2H),1.63e1.30 (m, 13H);
13C NMR (125 MHz, CDCl3)
d 174.2, 141.3, 114.4, 73.2, 51.4, 37.0, 34.1,
29.3, 29.1, 29.0, 25.2, 24.9; IR (neat, cmꢀ1) 3426.9, 2979.5, 2931.3,
2856.1, 1739.5, 1436.7; HRMS (ESI) m/z calculated for C12H22O3Na
[MþNa]þ: 237.1467; found: 237.1471.
4.2.3.3. 2-((3R)-Pent-4-en-1-yl-3-ol)-1,3-dioxane (ꢀ)-13. Follow
ing the general procedure for Novozyme 435 resolution afforded:
Run 1: 80 mg, 0.464 mmol, 57% yield; [B/L]¼>20:1:1, [ee]¼99%.
Run 2: 76 mg, 0.441 mmol, 56% yield; [B/L]¼>20:1, [ee]¼99% (ee
determined on the acylated alcohol,
b
-cyclodextrin, 110 ꢂC iso-
thermal, tR(R)¼22.31 min, tR(minor)¼22.93 min) [average yield:
24
57%]; [
a
]
D
ꢀ5.01 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d 5.86
(ddd, J¼5.6, 10.4, 17.3 Hz, 1H), 5.24 (dt, J¼1.6, 17.2 Hz, 1H), 5.10 (dt,
J¼1.2, 10.8 Hz, 1H), 4.58 (t, J¼4.4 Hz, 1H), 4.18e4.08 (m, 3H), 3.77
(app t, J¼11.6 Hz, 2H), 2.36 (d, J¼4.0 Hz, 1H), 2.08 (qt, J¼4.0, 12.4,
1H), 1.78e1.58 (m, 4H), 1.35 (d sep, J¼1.2, 13.6 Hz, 1H); 13C NMR
branched acetate product prior to oxidative Heck reaction, b-cy-
clodextrin, 110 ꢂC isothermal, tR(R)¼5.52 min, tR(S)¼5.83 min). 1H
NMR (500 MHz, CDCl3)
d
7.39 (d, J¼7.5 Hz, 2H), 7.34 (t, J¼7.5 Hz,
(125 MHz, CDCl3) d 141.0, 114.4, 102.1, 72.6, 66.9, 31.2, 31.1, 25.7; IR
2H), 7.31e7.25 (m, 1H), 6.64 (d, J¼16.0 Hz, 1H), 6.12 (dd, J¼7.5,
15.8 Hz, 1H), 5.46 (q, J¼6.5 Hz, 1H), 3.68 (s, 3H), 2.42 (dt, J¼2.0,
7.8 Hz, 2H), 2.13e2.07 (m, 2H), 2.10 (s, 3H); 13C NMR (125 MHz,
(neat, cmꢀ1) 3430.8, 3079.8, 2962.1, 2929.4, 2856.1, 2734.6, 1643.1,
1429.0, 1405.9; HRMS (ESI) m/z calculated for C9H16O3Na [MþNa]þ:
195.0995; found 195.0997.

7776
D.J. Covell, M.C. White / Tetrahedron 69 (2013) 7771e7778
4.2.4. General procedure for resolution with Subtilisin. Carls-
berg. The active enzyme for resolution was prepared as previously
described by Boren and co-workers.15 To a flame dried round bot-
tom flask containing allylic alcohol to be resolved (1 equiv) were
added isopropenyl valerate (1.5 equiv), active S. Carlsberg (36 mg/
1 mmol), sodium carbonate (1 equiv), and THF (0.5 M). The reaction
mixture was stirred vigorously at room temperature for 60 h. Upon
completion, the enzyme was removed via filtration. The enzyme
was rinsed thoroughly with diethyl ether and then the filtrate re-
duced in vacuo and purified via standard SiO2 chromatography.
Enantioselectivities were determined by chiral gas chromato-
graphic analysis on the acetylated derivative of each isolated al-
cohol. Individual yields and selectivities are reported below.
opaque, olefin (19) (0.941 g, 5 mmol, 1 equiv) was added in one
portion. CH2Cl2 (2.4 mL) was added to improve SM solubility and the
reaction mixture was stirred vigorously at 0 ꢂC for 1 h, then warmed
to room temperature and stirred until completion as indicated by
TLC (w5 h). Upon completion, sodium bisulfite (2 g) was added
slowly and the reaction mixture stirred for 1 h. The reaction mixture
was transferred to a separatory funnel and EtOAc (50 mL) was
added. The aqueous layer was extracted with additional EtOAc
(3ꢃ50 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated in vacuo. To the crude diol were added DMF
(8.4 mL, 0.6 M) and 2-methoxypropene (4.79 mL). The reaction
mixture was cooled to 0 ꢂC and p-TsOH$H2O (0.238 g, 1.25 mmol,
0.25 equiv) was added and the reaction mixture allowed to warm to
room temperature while stirring overnight. The reaction mixture
was then transferred to a separatory funnel and diluted with Et2O
(200 mL). The organic layer was washed with DI H2O (3ꢃ25 mL) and
brine (1ꢃ25 mL). The organic layer was then dried (MgSO4), filtered,
and reduced in vacuo. Residual DMF or 2-methoxypropene was
removed by addition of benzene and in vacuo concentration. The
crude oil was purified by silica gel chromatography in 10e40% Et2O/
Hexanes to afford a white solid (0.920 g, 3.52 mmol), 70% yield (two
steps), >20:1 dr, 99%ee (determined on Chiracel AD-RH, 35:75
4.2.4.1. (þ)-(4S)-1-O-Benzyl-5-hexen-1,4-diol
(þ)-3. Material
for this route was obtained by application of the general ABAO
procedure using (S,S)-2 as a chiral catalyst. Subsequent acetate
deprotection by the general procedure described afforded: Run 1:
180 mg, 0.873 mmol, 87% yield; [B/L]¼4.4:1, [ee]¼46%. Run 2:
187 mg, 0.906 mmol, 91% yield; [B/L]¼4.1:1, [ee]¼45%. Yields and
selectivities are over two steps. This material was then subjected to
the general procedure for resolution with S. Carlsberg to afford
chiral allylic alcohol: Run 1: 92 mg, 0.446 mmol, 52% yield, [B/L]¼>
20:1, [ee]¼99%. Run 2: 97 mg, 0.470 mmol, 54% yield; [B/L]¼>20:1,
[ee]. Enantiomeric excess was determined on the acylated de-
rivative of the final product (ee determined on the acylated alcohol,
CH3CN/H2O, tR(major)¼7.3 min, tR(minor)¼6.8 min). [
a
]
26 ꢀ94.9 (c
D
1.0, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.39e7.31 (m, 5H), 4.78 (d,
J¼8.5 Hz,1H), 4.60 (ddd, J¼4.0, 6.3, 7.5 Hz,1H), 4.10 (dd, J¼4.0, 8.3 Hz,
1H), 2.60 (ddd, J¼6.5,10.0,18.0 Hz,1H), 2.51 (ddd, J¼7.5, 9.5,17.4 Hz,
1H), 2.38e2.24 (m, 2H),1.56 (s, 3H),1.52 (s, 3H); 13C NMR (125 MHz,
b
-cyclodextrin, 120 ꢂC isothermal, tR(S)¼67.03 min) [average yield:
53%]. [
a]
26 þ2.85 (c 2.0, CHCl3).
CDCl3) d 176.5, 137.2, 128.8, 128.7, 126.7, 110.2, 83.4, 80.1, 78.7, 28.1,
D
27.1, 27.0, 22.9; IR (neat, cmꢀ1) 3066.3, 3031.6, 2985.3, 2935.1,
2980.8,1781.9,1604.5,1494.6,1456.0; HRMS (ESI) m/z calculated for
C15H19O4 [MþH]þ: 263.1283; found 263.1280. The absolute config-
uration of this molecule was determined on a crystal grown from
benzene of p-bromophenyl-20 synthesized through the same se-
quence. The cif file for this compound can be found as an additional
file of Supplementary data.
4.2.5. Synthesis of furan core (ꢀ)-22
4.2.5.1. (R,E)-5-Styryldihydrofuran-2(3H)-one (19). To crude 18
(5 mmol, assumed) in a round bottom flask (250 mL) were added
THF (18.75 mL), DI H2O (6.25 mL), and a TeflonÓ stir bar. The flask
was cooled to 0 ꢂC and LiOH$H2O (0.623 g, 15 mmol, 3.0 equiv) was
added in one portion. The ice bath was removed after 10 min and
the reaction monitored via TLC. Upon completion (w2e4 h) ben-
zene (150 mL) was added and the contents of the flask were
transferred to a 100 ꢂC oil bath and a DeaneStark trap and a reflux
condenser were added. The reaction mixture was brought to
a comfortable reflux and then allowed to stir overnight. After re-
moving the flask from the bath and allowing it to cool to room
temperature, the contents were transferred to a separatory funnel
and the organic layer washed with aq 1 M H3PO4 (3ꢃ25 mL). The
organic layer was then dried (MgSO4), filtered, and reduced in
vacuo. The resulting off white solid was purified via silica gel
chromatography (10e30% Et2O/hexanes) to afford a white sol-
id (0.504 g, 2.678 mmol, 54% (two steps)). 1H NMR (500 MHz,
4.2.5.3. (R)-5-((4R,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl)
furan-2(5H)-one ((þ)-21). To a clean, flame dried 25 mL recovery
flask charged with a Teflon stir bar and under an argon atmosphere
were added THF (5 mL) and hexamethyldisilazane (1.36 mmol,
0.288 mL, 1.1 equiv). The reaction mixture was cooled to ꢀ78 ꢂC,
and n-BuLi (1.30 mmol, 0.813 mL, 1.05 equiv) was added dropwise
via syringe. After stirring for 10 min, (ꢀ)-20 (1.24 mmol, 0.325 g,
1 equiv) in THF (1 mL, 0.15 mL rinse) was added slowly via cannula.
The reaction mixture was stirred a further 25 min, and then phe-
nylselenyl bromide (1.24 mmol, 0.293 g, 1 equiv) in THF (1.15 mL)
was added via cannula overw10 min. The reaction mixture was
stirred for an additional 5 min and then quenched at ꢀ78 ꢂC with
1 N HCl (5 mL). The reaction mixture was transferred to a separa-
tory funnel and diluted with Et2O (200 mL). The organic layer was
washed with satd aq NaHCO3 (2ꢃ10 mL). The organic layer was
then dried (Na2SO4), filtered, and concentrated in vacuo. Re-
producibility for the elimination step was significantly improved by
quickly purifying away fast running selenium containing species by
SiO2 chromatography in 5%e10%e20% Et2O/hexanes. To the mix-
ture of selenides (1.03 mmol, 0.425 g,1 equiv) in a clean, dry 100 mL
flask was added CH2Cl2 (20.6 mL, 0.05 M) and the reaction flask was
cooled to 0 ꢂC in an ice bath. Hydrogen peroxide (3.08 mmol,
0.346 mL of 30% solution, 3 equiv) was then added slowly via sy-
ringe. The reaction mixture was stirred at 0 ꢂC and conversion
monitored by TLC. Upon completion, the reaction mixture was
transferred to a separatory funnel and CH2Cl2 was added (200 mL).
The organic layer was then washed with DI H2O (2ꢃ20 mL) and
brine (20 mL). The organic layer was then dried (MgSO4), filtered,
and reduced in vacuo. The crude oil was purified by silica gel
chromatography in 10e40% Et2O/hexanes to afford a white solid
CDCl3)
d
7.40 (d, J¼7.5 Hz, 2H), 7.37e7.32 (m, 2H), 7.30e7.26 (m,1H),
6.69 (d, J¼16.0 Hz, 1H), 6.21 (dd, J¼6.5, 16.0 Hz, 1H), 5.13 (q,
J¼6.5 Hz,1H), 2.65e2.54 (m, 2H), 2.50 (app sextuplet, J¼9.0 Hz, 1H),
2.11 (ddd, J¼9.0, 12.5, 16.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d
176.9, 135.6, 132.9, 128.7, 128.4, 126.7, 126.4, 80.5, 28.8, 28.5; IR
(neat, cmꢀ1) 2989.1, 2950.6, 1762.6, 1722.1, 1454.1, 1415.5; HRMS
(ESI) m/z calculated for C12H13O2 [MþH]þ: 189.0916; found
189.0918.
4.2.5.2. (R)-5-((4R,5R)-2,2-Dimethyl-5-phenyl-1,3-dioxolan-4-yl)
dihydrofuran-2(3H)-one ((ꢀ)-20). To a clean, dry 100 mL recovery
flask were added sequentially the following: K2OsO4$2H2O (0.018 g,
0.05 mmol, 1 mol %), (DHQD)2PHAL (0.199 g, 0.25 mmol, 5 mol %),
K3Fe(CN)6 (4.94 g, 15 mmol, 3 equiv), K2CO3 (2.07 g, 15 mmol,
3 equiv), NaHCO3 (1.34 g, 15 mmol, 3 equiv), a TeflonÓ stir bar,
deionized water (24 mL), and tert-butanol (24 mL). The reaction
mixturewas stirred vigorously until both layers became translucent,
at which time MeSO2NH2 (0.476 g, 5 mmol, 1 equiv) was added and
the reaction mixture was cooled to 0 ꢂC. After the solution became

D.J. Covell, M.C. White / Tetrahedron 69 (2013) 7771e7778
7777
25
9542e9543; (f) Bigi, M. A.; Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2012, 134,
9721e9726; (g) Ren, Z.; Mo, F.; Dong, G. J. Am. Chem. Soc. 2012, 134,
16991e16994.
(0.237 g, 0.91 mmol), 73% yield (two steps). [
a
]
555.6 (c 1.0,
D
CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.48 (dd, J¼1.5, 6.0 Hz, 1H),
7.40e7.31 (m, 5H), 6.17 (dd, J¼2.5, 5.8 Hz,1H), 5.16 (dt, J¼2.0, 6.5 Hz,
1H), 5.02 (d, J¼8.0 Hz, 1H), 3.91 (dd, J¼6.5, 7.5 Hz, 1H), 1.56 (s, 3H),
3. Streamlining synthesis via late-stage CeH oxidation: (a) Nicolaou, K. C.; Yang,
Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Claiborne, C. F.; Renaud, J.;
Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J. Nature 1997, 367, 630e634;
(b) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno,
Y. J. Am. Chem. Soc. 1997, 119, 12976e12977; (c) Fraunhoffer, K. J.; Bachovchin, D.
A.; White, M. C. Org. Lett. 2005, 7, 223e226; (d) Covell, D. J.; Vermeulen, N. A.;
White, M. C. Angew. Chem., Int. Ed. 2006, 45, 8217e8220; (e) Stang, E. M.; White,
M. C. Nat. Chem. 2009, 1, 547e551; (f) Stang, E. M.; White, M. C. Angew. Chem.,
Int. Ed. 2011, 50, 2094e2097; (g) Vermeulen, N. A.; Delcamp, J. H.; White, M. C. J.
Am. Chem. Soc. 2010, 132, 11323e11328; For excellent reviews, see: (h) Hoff-
mann, R. W. Synthesis 2006, 21, 3531e3541; (i) Hoffmann, R. W. Elements of
Synthesis Planning; Springer: Heidelberg, Germany, 2009; For some examples of
late stage CeH hydroxylation see: (j) Wender, P. A.; Hilinski, M. K.; Mayweg, A.
V. W. Org. Lett. 2005, 7, 79e82; (k) Ref. 2a; (l) Ref. 2c; (m) Ref. 2f.
1.54 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 172.2, 153.8, 137.3, 128.6,
128.6, 127.0, 122.6, 110.6, 82.8, 82.7, 80.7, 27.1, 26.8; IR (neat, cmꢀ1
)
3089.4, 3033.5, 2989.1, 2935.1, 2894.6, 1783.8, 1758.8, 1602.6,
1496.5, 1456.0; HRMS (ESI) m/z calculated for C15H17O4 [MþH]þ:
261.1127; found 263.1123.
4.2.5.4. (3aS,5R,6S,6aS)-6-Hydroxy-5-phenyltetrahydrofuro[3,2-
b]furan-2(5H)-one((ꢀ)-22). To (þ)-21 (0.91 mmol, 0.237 g, 1 equiv)
in a clean, dry round bottom flask (50 mL) with a TeflonÓ stir bar
were added THF (9.1 mL) and 1 N HCl (5e10 drops). The reaction
mixture was heated to 45 ꢂC and monitored via TLC (70% EtOAc/
hexanes). Deprotection and cyclization would generally proceed to
completion under these conditions with prolonged stirring, but
could be expedited by the following procedure. After complete
acetonide deprotection by TLC, the flask was cooled to 0 ꢂC and
CH2Cl2 (9.1 mL) and NEt3 were added until a pH of w10 was ob-
tained. The flask was then allowed to warm to room temperature
and monitored via TLC. Upon completion (w4e6 h), the reaction
mixture was transferred to a separatory funnel and diluted with
further CH2Cl2. The organic layer was then washed with satd
aq NH4Cl solution (3ꢃ15 mL). The combined aqueous layers were
back extracted with EtOAc (3ꢃ50 mL) and then the combined or-
ganic layers were dried (MgSO4), filtered, and reduced in vacuo. The
resulting off white solid was purified via silica gel chromatography
4. Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448e6451.
5. For examples of asymmetric olefination of aldehydes, see: (a) Oppolzer, W.;
Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777e5780; (b) Brubaker, J. D.; Myers,
A. G. Org. Lett. 2007, 9, 3523e3525 and references therein; (c) Hargadena, G. C.;
Guiry, P. J. Adv. Synth. Catal. 2007, 349, 2407e2424 and references therein; For
chiral pool starting material derivatization: (d) Sheddan, N. A.; Mulzer, J. Org.
Lett. 2006, 8, 3101e3104; (e) Ichikawa, Y.; Yamaoka, T.; Nakano, K.; Kotsuki, H.
Org. Lett. 2007, 9, 2989e2992; For asymmetric epoxidation based examples,
see: (f) Babu, K. V.; Sharma, G. V. M. Tetrahedron: Asymmetry 2008, 19,
577e583; (g) Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2004, 15, 81e89;
For resolution examples, see: (h) Itoh, T.; Kudo, K.; Yokota, K.; Tanaka, N.;
^
Hayase, S.; Renou, M. Eur. J. Org. Chem. 2004, 2, 406e412; (i) Chenevert, R.;
Gravila, S.; Bolteb, J. Tetrahedron: Asymmetry 2005, 16, 2081e2086.
6. For elegant metal catalyzed enantioselective routes to chiral allylic esters and
alcohols see: (a) Kirsch, S. F.; Overman, L. E. J. Am. Chem. Soc. 2005, 127,
2866e2867; (b) Geurts, K.; Fletcher, S. P.; Feringa, B. L. J. Am. Chem. Soc. 2006,
128, 15572e15573; (c) Evans, P. A.; Grisin, A.; Lawler, M. J. J. Am. Chem. Soc. 2012,
134, 2856e2859.
7. For reviews of the Sharpless asymmetric epoxidation (SAE) and its applica-
tions see: (a) Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 7,
pp 7389e7436; (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, NY, 2000; p 231.
8. Pd-catalyzed allylic CeH oxidations: (a) Chen, M. S.; White, M. C. J. Am. Chem.
Soc. 2004, 126, 1346e1347; (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White,
M. C. J. Am. Chem. Soc. 2005, 127, 6970e6971; (c) Fraunhoffer, K. J.; Prabagaran,
N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006, 128, 9032e9033; (d) Del-
camp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076e15077; (e) Mis-
tudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda,
K. Angew. Chem., Int. Ed. 2006, 45, 481e485; (f) Pilarski, L. T.; Selander, N.; Bose,
D.; Szabo, K. J. Org. Lett. 2009, 11, 5518e5521; (g) Lin, B.-L.; Labinger, J. A.;
Bercaw, J. E. Can. J. Chem. 2009, 87, 264e271; (h) Thiery, E.; Aouf, C.; Belloy, J.;
Harakat, D.; Le Bras, J.; Muzart, J. J. Org. Chem. 2010, 75, 1771e1774; (i) Hen-
derson, W. H.; Check, C. T.; Proust, N.; Stambuli, J. P. Org. Lett. 2010, 12,
824e827; (j) Campbell, A. N.; White, P. B.; Guzei, I. A.; Stahl, S. S. J. Am. Chem.
Soc. 2010, 132, 15116e15119; (k) Check, C. T.; Henderson, W. H.; Wray, B. B.;
Eyden, M. J. V.; Stambuli, J. P. J. Am. Chem. Soc. 2011, 133, 18503e18505; (l) Alam,
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8778e8781.
9. Pd-catalyzed allylic CeH aminations: (a) Larock, R. C.; Hightower, T. R.; Hasvold,
L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584e3585; (b) Fraunhoffer, K. J.;
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2009, 131, 11701e11706; (g) Nahra, F.; Liron, F.; Prestat, G.; Mealli, C.; Mes-
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C. Tetrahedron 2010, 66, 4816e4826.
(10e50% EtOAc/Hexanes) to afford
a white solid (0.161 g,
26
0.731 mmol, 80%). [
CDCl3)
a]
ꢀ17.1 (c 1.0, CHCl3). 1H NMR (500 MHz,
D
d
7.44e7.34 (m, 5H), 5.23 (d, J¼2.5 Hz, 1H), 5.20 (td, J¼1.0,
5.0 Hz, 1H), 5.07 (d, J¼5.0 Hz, 1H), 4.64 (app t, J¼2.0 Hz, 1H), 2.86
(dd, J¼6.0, 18.8 Hz, 1H), 2.79 (d, J¼18.5 Hz, 1H), 1.36 (d, J¼2.5 Hz,
1H); 13C NMR (125 MHz, CDCl3)
d 175.4, 134.2, 128.9, 128.6, 126.6,
87.2, 82.8, 77.1, 75.8, 36.0; IR (neat, cmꢀ1) 3948.3, 2975.6, 2948.6,
2923.6, 2858.0, 1766.5, 1496.49, 1454.1; HRMS (ESI) m/z calculated
for C12H12O4Na [MþNa]þ: 243.0645; found 243.0633.
Acknowledgements
Financial support was provided by the NIH/NIGMS (2R01 GM
076153B) and generous gifts from Bristol-Myers Squibb and
Boehringer Ingelheim.
Supplementary data
Full experimental details for all compounds synthesized and
copies of 1H and 13C NMR spectra as well as chiral GC and HPLC
traces for chiral compounds as well as crystallographic data on p-
bromophenyl (ꢀ)-20. . Supplementary data associated with this
article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2013.05.012.
10. Pd-catalyzed allylic CeH alkylations: (a) Young, A. J.; White, M. C. J. Am. Chem.
Soc. 2008, 130, 14090e14091; (b) Young, A. J.; White, M. C. Angew. Chem., Int. Ed.
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Am. Chem. Soc. 2008, 130, 12901e12903; (d) Trost, B. M.; Thaisrivongs, D. A.;
Donckele, E. J. Angew. Chem., Int. Ed. 2012, 51, 1e5.
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