Synthetic versatility in C-H oxidation: A rapid approach to differentiated diols and pyrans from simple olefins

Article abstract of DOI:10.1021/ja206013j

Conventionally, C-H oxidation reactions are used to install functional groups. The use of C-H oxidation to transform simple starting materials into highly versatile intermediates, which enable rapid access to a range of complex target structures, is a new area with tremendous potential in synthesis. Herein we report a Pd(II)/sulfoxide-catalyzed allylic C-H oxidation to form anti-1,4-dioxan-2-ones from homoallylic oxygenates. These versatile building blocks are rapidly elaborated to differentiated syn-1,2-diols, stereodefined amino-polyols, and syn-pyrans, structures ubiquitous in medicinally important complex molecules found in Nature. We also demonstrate that a C-H oxidation approach to the synthesis of these motifs is orthogonal and complementary to other state-of-the-art methods.

Full text of DOI:10.1021/ja206013j

ARTICLE
pubs.acs.org/JACS
Synthetic Versatility in CꢀH Oxidation: A Rapid Approach to
Differentiated Diols and Pyrans from Simple Olefins
Paul E. Gormisky and M. Christina White*
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
S Supporting Information
b
ABSTRACT: Conventionally, CꢀH oxidation reactions are used to install
functional groups. The use of CꢀH oxidation to transform simple starting
materials into highly versatile intermediates, which enable rapid access to a
range of complex target structures, is a new area with tremendous potential in
synthesis. Herein we report a Pd(II)/sulfoxide-catalyzed allylic CꢀH oxidation
to form anti-1,4-dioxan-2-ones from homoallylic oxygenates. These versatile
building blocks are rapidly elaborated to differentiated syn-1,2-diols, stereo-
defined amino-polyols, and syn-pyrans, structures ubiquitous in medicinally
important complex molecules found in Nature. We also demonstrate that a
CꢀH oxidation approach to the synthesis of these motifs is orthogonal and complementary to other state-of-the-art methods.
’ INTRODUCTION
’ DESIGN PRINCIPLES
Selective CꢀH oxidation reactions have emerged as powerful
methods for rapidly introducing functional groups onto pre-
formed carbon skeletons,1 often enabling a significant streamlin-
ing of the synthesis of complex molecules.2 Tremendous
untapped opportunity also exists to use CꢀH oxidation as a means
of transforming simple starting materials into versatile synthetic
intermediates en route to more complex products (Figure 1).3 Ideally,
these pluripotent intermediates could rapidly be transformed into a
range of structurally and functionally diverse products of high
synthetic value. Herein we describe the realization of this concept
for the straightforward synthesis of anti-1,4-dioxan-2-ones from
simple olefins using Pd(II)/sulfoxide catalysis. These highly versatile
synthetic intermediates are rapidly elaborated to varied motifs pre-
valent in biologically active, oxygenated natural products: differen-
tiated syn-1,2-diol functionality, polyfunctionalized acyclic structures,
and syn-pyran skeletons.
In addition to being present in some classes of natural
products,4 dioxanones are a particularly valuable target because
of their potential for high synthetic versatility. Enolization of
anti-dioxanones is known to promote skeletal rearrangement
with relay of stereochemistry to furnish syn-pyrans.5 Further-
more, the development of a method for selective cleavage of the
dioxanone CꢀO bonds (ethereal vs acyl) would enable efficient
installation of differentially protected syn-1,2-diol functionality.6 In
considering CꢀH activation platforms to access dioxanones, Pd-
(II)/sulfoxide catalysis presents unique opportunties for efficiency
and selectivity.7ꢀ9 Given our success in using tethered nucleophiles
for diastereoselective allylic CꢀH aminations,8a,d we postulated that
an intramolecular process would provide rapid access to stereo-
chemically defined 1,4-dioxan-2-ones via allylic CꢀH oxidation of
readily available chiral homoallylic alcohols with a carboxylic acid
tether. Moreover, given the proven levels of broad functional group
tolerance and high chemoselectivity for R-olefins versus more
electron-rich π-systems, a palladium(II)/sulfoxide catalyzed allylic
CꢀH oxidation reaction would provide complementary reactivity
to other olefin oxidation methods. The terminal olefin in these
products may also be utilized for iterative CꢀH oxidation se-
quences, providing a new approach for retrosynthetic simplification
of polyfunctionalized targets.10 The ability to selectively transform
simple homoallylic oxygenates to differentiated diols, polyfunctio-
nalized acyclic structures, or stereochemically defined pyrans pre-
sents a unique opportunity to use CꢀH oxidation as a means of
rapidly constructing diverse and biologically privileged oxygenated
motifs.
Received: March 25, 2011
Published: July 11, 2011
Figure 1. Rapid access to complex structures via allylic CꢀH oxidation.
r
2011 American Chemical Society
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’ RESULTS AND DISCUSSION
Table 2. Optimization of the Intramolecular CꢀH Oxidation
Reaction Development. Despite the success of using car-
boxylic acid nucleophiles for intermolecular allylic CꢀH ester-
ifications with a wide range of substrates,7 we were surprised to
find that substrates having oxygenation in the homoallylic
position afforded only poor yields of 1,2-dioxygenation products
with poor regioselectivities (Table 1, linear(L)/branched(B)
ratio). This low reactivity persists even when p-nitrobenzoic acid
(previously shown to be the most effective nucleophile in
intermolecular CꢀH esterifications) is used as a functionaliza-
tion reagent and is unaffected by changing the nature of the
homoallylic ether substituent (Table 1, R = CH2CO2Me or Bn,
entries 3 and 5, respectively). This result stands in stark contrast
to the same reaction with alkyl homoallylic substitution, which
proceeds in good yield (73%) and outstanding regioselectivity
Pd
isolated
yield
dr
entry
additive
quinone
catalyst
(anti:syn)a
1
2
3
4
5
6
none
DIPEA
Cr(salen)CI BQ
BQ
1
1
1
1
38
46
83
0
9:1
7:1
9:1
nd
BQ
none
none
2,6-Me2BQ
BQ
Pd(OAc)2
>5
nd
Cr(salen)CI BQ
none
1
0
nd
a Diastereomeric ratio determined by H NMR of the crude reaction
after workup. DIPEA = diisopropylethylamine.
Table 1. Intermolecular CꢀH Esterification with Homo-
allylic Oxygen Substitution
We hypothesize that homoallylic oxygen substituents may che-
late to the palladium and occupy a requisite site for inner-sphere
functionalization thereby forcing functionalization to proceed via
an outer-sphere pathway. In support of this, the large amount of
linear regioisomer formed (Table 1, entries 1 and 3) is consistent
with an outer-sphere, non-BQ dependent functionalization
pathway.8b,c,12
We postulated that, by tethering the carboxylic acid nucleo-
phile to the homoallylic oxygen substituent, a productive Pd-
carboxylate chelate would be formed, which, upon BQ activation,
would lead to the desired CꢀO bond formation. In addition to
overcoming reactivity and selectivity issues inherent to the
intermolecular process, we considered that such an intramole-
cular process would also expand the synthetic utility of this
method beyond formation of 1,2-dioxygenation patterns. We
therefore examined the reaction of 2-((2-methylhex-5-en-3-yl)
oxy)acetic acid 5a, containing a carboxylic tether, which could
fulfill these goals (Table 2). Under standard allylic CꢀH oxida-
tion conditions,7b dioxanone 6a was produced in improved yield
(38%), compared to intermolecular oxidation, and good diaster-
eoselectivity favoring the anti-stereoisomer (Table 2, entry 1).
We next examined diisopropylethylamine (DIPEA) and
Cr(salen)Cl as catalytic additives due to their known ability to
promote functionalization of carboxylic acid and carbamate
nucleophiles without attenuating CꢀH cleavage.8b,c,13 While
addition of 10 mol % DIPEA provided only a modest increase
in yield (entry 2), 10 mol % Cr(salen)Cl markedly improved the
yield to 83% with identical stereoselectivity (entry 3).14 Inter-
estingly, Cr(salen)Cl did not improve reactivity in the inter-
molecular CꢀH esterification system (Table 1, entries 2 and 4).
We also performed a series of experiments to probe if this
reaction, like the intermolecular version,7b proceeds via a serial
ligand catalysis mechanism. Use of 2,6-dimethyl-1,4-benzoqui-
none (2,6-Me2BQ), a sterically encumbered quinone, which
does not coordinate well to the π-allylPd intermediate, failed
to produce the dioxanone (Table 2, entry 4). Moreover,
Pd(OAc)2 in the absence of a bis-sulfoxide ligand also failed to
furnish significant quantities of the desired product (entry 5).
Finally, Cr and oxidant alone fail to promote the reaction (entry
6).15 These experimental findings are consistent with the re-
storation of a serial ligand catalysis mechanism in the
isolated L:Bc E/Z
yieldb 3/4 (3)d (4)e
dr
a
entry
R
R0
additive
1
2
3
4
5
CH2CO2Me Ac
CH2CO2Me Ac
none
Cr(salen)CI
11
10
16
>5
>5
1:2
>20:1 16:1
>20:1 >20:1 N/A
CH2CO2Me p-NO2Bz none
1:2
nd
nd
nd
nd
nd
>20:1
nd
CH2CO2Me p-NO2Bz Cr(salen)CI
Bn
p-NO2Bz none
nd
a AcOH (4.0 equiv) or p-NO2BzOH (1.5 equiv) used as the acid
nucleophile. b Average of 2 runs at 0.5 mmol. c Linear(L)/Branched(B)
ratio determined by GC of the crude reaction after workup. d E/Z ratio
determined by GC of the crude reaction after workup. e Diastereomeric
ratio determined by GC of the crude reaction after workup. BQ =
p-benzoquinone, salen = l,2-cyclohexanediamine-N,N0-bis(3,5-di-tert-
butylsalicylidine).
(>20:1 B:L) favoring the branched product, albeit with no
diastereoselectivity.2a Intermolecular CꢀH esterification is
thought to proceed via a serial ligand catalysis mechanism
involving Pd(II)/sulfoxide promoted allylic CꢀH cleavage to
generate a π-allylPd-carboxylate followed by a benzoquinone
(BQ) mediated CꢀO bond forming event from within the
sphere of the metal (eq 1).7b,11
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Table 3. Scope of the Intramolecular CꢀH Oxidation
Table 4. Chemoselectivity of the Intramolecular CꢀH
Oxidation
a Average of 2 runs at 0.3 mmol. b Diastereomeric ratio determined by
GC of the crude reaction after workup. c Average of 2 runs at 10 mmol.
1
d Diastereomeric ratio determined by H NMR of the crude reaction
after workup.
intramolecular CꢀH esterification reaction where both sulfoxide
and quinone ligands working sequentially with the palladium are
required to furnish the CꢀH oxidation product.
a Average of 2 runs at 0.3 mmol. b Diastereomeric ratio determined by
GC of the crude reaction after workup.
Scope. We next evaluated a series of substrates to examine the
effects of neighboring substituents (R group, Table 3) on
reactivity and selectivity. Proximal aryl moieties are well tolerated
(entry 2). Reactions with unbranched substrates proceeded in
good yield but with diminished stereoselectivity (entry 3);
whereas a substrate with a bulky quaternary alkyl substituent
gave poor yields but excellent diastereoselectivity (entry 4).
Despite the apparent sensitivity to sterics, tertiary centers are
well tolerated (entries 5 and 6). Notably, competing methods for
forming these diol products would require setting the geometry
of a trisubstituted olefin.16 Additionally, R-stereocenters influ-
ence the magnitude of the diastereoselectivity (entries 7 and 8),
but the overall diastereomeric outcome of the reaction favoring
the anti-dioxanone is relayed exclusively from the stereocenter
bearing the carboxylic acid tether. Significantly, these reactions
feature a high level of operational simplicity. The reactions are
run with no precautions taken to exclude O2 or water, and the
analytical scales directly translate to preparative scales with no
diminishment in yield or selectivity (10 mmol scale, 80% yield,
entry 1). Moreover, the major anti-dioxanone diastereomer can
generally be isolated in pure form using standard chromatogra-
phy techniques.
(SAD).17 When multiple olefins are present in a molecule, SAD
generally selects for the more electron-rich olefin with variable
chemoselectivity. For example, SAD of a terminal diene to
generate the vinylic diol products produced from CꢀH oxida-
tion gives mixtures of regioisomeric diols.17b Consequently,
SAD is often not used to install diols when multiple olefins
are present and alternate, lengthy routes must be devised,
reducing overall synthetic efficiency.18 In contrast, the allylic
CꢀH oxidation reaction gives complete selectivity for the
terminal olefin allowing a diol to be installed in the presence
of tetrasubstituted, trisubstituted, and trans- and cis-disubstitut-
ed olefins (Table 4).
Differentiated 1,2-Diols. We first sought to use this intramo-
lecular CꢀH esterification reaction to develop a streamlined
route to differentiated, chiral syn-1,2-diols(Scheme1), compounds,
which generally require extensive functional group manipula-
tions to access. In order achieve this goal, we needed to (1)
evaluate the feasibility of generating optically enriched dioxa-
nones using this method and (2) develop a novel deprotection
sequence for converting the chemically inequivalent oxygens in
the dioxanone products to differentiated, chiral syn-1,2-diols.
Starting from a simple aldehyde, asymmetric allylation affords an
enantioenriched homoallylic alcohol. Alkylation with bromoace-
tic acid followed by CꢀH oxidation catalyzed by Pd(II)/bis-
Chemoselectivity. The CꢀH oxidation approach to these
1,2-dioxygenated motifs also provides orthogonal and comple-
mentary selectivity to the Sharpless asymmetric dihydroxylation
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Scheme 1. Access to Differentiated syn-1,2-Diolsa
this sequence, are found in several classes of natural products,20
such as bengazole A (a potent antifungal agent) and AAL Toxin
TA. Traditional approaches to these polyoxidized motifs often
rely on chiral relay strategies, making the synthesis of multiple
stereoisomeric compounds challenging. This sequence highlights
the power of diastereoselective CꢀH oxidation and amination
reactions, when used in combination with powerful reagent
controlled alkylation methodology, to facilitate the synthesis of
a wide assortment of diastereomers with varied oxygen and
nitrogen motifs.
syn-Pyrans. Efficient generation of dioxanones via CꢀH
oxidation additionally allows for rapid structural diversification
from topologically simple starting materials. 1,4-Dioxan-2-ones
undergo stereoselective IrelandꢀClaisen5d rearrangements to
form syn-pyran skeletons.5,21 We present two case studies
illustrating the utility and advantages of CꢀH oxidation for the
synthesis of syn-pyrans. First, bifunctional pyrans like (ꢀ)-16 are
powerful building blocks used in a number of natural product
syntheses. For example, dioxanone 14, readily formed via CꢀH
oxidation, undergoes facile rearrangement to give dihydropyran
15 (Scheme 3). Hydrogenation, reduction of the ester, benzyla-
tion, and desilylation gives (ꢀ)-16, an intermediate in the
synthesis of SCH 351448.22 Our intramolecular CꢀH oxidation
not only sets a stereocenter selectively, which is relayed to the
pyran 2-position, but the tether can also be incorporated into the
final product, eliminating extraneous masking or directing
groups.
a Conditions: (a) 10% 1, 10% Cr(salen)Cl, BQ (2.0 equiv), dioxane,
45 °C (72% of >20:1 anti-diastereomer; 83%, 9:1 crude dr); (b) (1)
LiOH (2.0 equiv), 3:1 THF/H2O, 0 °C, (2) TBSOTf (3.0 equiv), 2,6-
lutidine (6.0 equiv), CH2C12, 0 °C, (3) MeI (3.0 equiv), K2CO3 (3.0
equiv), DMF, RT (89%, 3 steps); (c) SmI2 (3.0 equiv), ethylene glycol
(1.2 equiv), THF/HMPA, RT (61%, 12% rsm); (d) BOMCl (1.5
equiv), iPr2NEt (1.75 equiv), CH2C12, 0 °C to RT (79%).
sulfoxide 1 gives anti-dioxanone (ꢀ)-6a with no erosion in
enantioenrichment. The anti-dioxanone is rapidly unmasked
via base-promoted lactone opening to generate a hydroxyacid,
which can be protected to afford (ꢀ)-9. The R-alkoxy ester
moiety in (ꢀ)-9 is then cleaved under mild reducing conditions
using SmI219 to furnish a free alcohol, which may be protected as
desired. Benzyloxymethyl protection gave differentiated diol
(ꢀ)-10, a compound that is challenging to obtain via other
oxidation methods, like the Sharpless asymmetric dihydroxyla-
tion (SAD), which directly affords unprotected syn-1,2-diol
motifs.
Polyoxidized Motifs via Iterative CꢀH Oxidation. The R-
olefin moiety of the differentiated syn-1,2-diol products (e.g.,
(ꢀ)-10) can be used as a functional handle to iterate this and
other allylic CꢀH oxidation processes for the purpose of rapidly
constructing densely functionalized chains from simple starting
materials (Scheme 2).10 A hydroborationꢀoxidation sequence
affords an intermediate aldehyde that can undergo asymmetric
allylation to generate a homoallylic alcohol as one diastereomer.
After carbamate formation to yield (ꢀ)-11, a masked syn-1,2-
amino alcohol moiety can be installed in good yields via Pd(II)/
bis-sulfoxide 1 catalyzed allylic CꢀH amination.8a Amino-poly-
ols like (ꢀ)-12, which are generated in optically pure form via
Scheme 3. Synthesis of a Useful Bifunctional Pyrana
Scheme 2. Iterative CꢀH Oxidation for the Synthesis of
Polyoxidized Motifsa
a Conditions: (a) NaH (3.0 equiv), BrAcOH (1.1 equiv), THF/DMF 0
°C to RT (70%); (b) 10% 1, 10% Cr(salen)Cl, BQ (2.0 equiv), dioxane,
65 °C (83%, 3:1 crude dr, mixture of diastereomers taken forward); (c)
(1) LiHMDS (2.0 equiv), 1:1 v/v TMSCl/Et3N, THF, ꢀ78 °C then
reflux in toluene, (2) MeI (3.0 equiv), K2CO3 (3.0 equiv), DMF, RT
(83%); (d) 10% wt of 5% Pd/C, H2 (1 atm), EtOAc, RT (68% of >20:1
syn-diastereomer, 3:1 crude dr); (e) LiAlH4 (2.0 equiv), THF, 0 °C; (f)
BnBr (2.0 equiv), NaH (2.0 equiv), DMF, 0 °C to RT; (g) 3 M HCl,
EtOH, RT (74%, 3 steps).
Particularly in the context of complex molecule synthesis,
CꢀH oxidation methods must be effective in the presence of
dense functionality. Scheme 4 shows the rapid synthesis of
highly oxygenated dioxanone (+)-18 and subsequent rearrange-
ment to dihydropyran (+)-19. Reduction of the ester, benzyl
protection, and hydrolysis of the acetonide give diol (+)-20, an
intermediate in the synthesis of ent-goniodomin A, a potent
antifungal agent.23 This route compares favorably to the re-
ported synthesis of this pyran (7 versus 10 steps from commer-
cial material) and demonstrates the ability of CꢀH oxidation to
enable the rapid construction of densely functionalized pyran
skeletons.
a Conditions: (a) (1) BH3-Me2S (2.4 equiv), THF; 2-methyl-2-butene
(4.7 equiv); 7, 0 to 45 °C; 3.0 M NaOH, 30% wt H2O2, (2) PCC (1.3
equiv), CH2C12, RT (74%, 2 steps); (b) (+)-Ipc2B-allyl, Et2O, ꢀ78 °C;
3.0 M NaOH, 30% wt H2O2 (95%); (c) NsNCO (1.5 equiv), THF, RT
(90%); (d) 10% 1, 5% l,2-bis(phenylsulfinyl)ethane, PhBQ (1.05
equiv), THF, 45 °C (65%, 1.6:1 crude dr).
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Scheme 4. Synthesis of a Densely Functionalized Pyrana
Crabtree, R. H. J. Am. Chem. Soc. 2010, 132, 12550. (h) Dick, A. R.; Hull,
K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (i) Zhang, Y.-H.;
Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
(2) For examples of late-state CꢀH oxidations in total synthesis, see:
(a) Stang, E. M.; White, M. C. Nat. Chem. 2009, 1, 547. (b) Hinmann, A.;
DuBois, J. J. Am. Chem. Soc. 2003, 125, 11510. (c) Davies, H. M. L.; Dai,
X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485. (d) Kim, J.;
Ashenhurst, J. A.; Movassaghi, M. Science 2009, 324, 238. (e) Nicolaou,
K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. K.;
Claibourne, C. F.; Reynaud, J.; Couladouros, E. A.; Paulvannan, K.;
Sorenson, E. J. Nature 1994, 367, 630. (f) Wender, P. A.; Jesudason,
C. D.; Nakhira, H.; Tamura, N.; Tebe, A. L.; Ueno, Y. J. J. Am. Chem. Soc.
1997, 119, 12976.
(3) For an example of CꢀH activation/Cope rearrangement for
forming carbocyclic skeletons, see: (a) Davies, H. M. L.; Jin, Q. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5472. (b) Hansen, J.; Gregg, T. M.;
Ovalles, S. R.; Lian, Y.; Autschbach, J.; Davies, H. M. L. J. Am. Chem. Soc.
2011, 133, 5076.
a Conditions: (a) NaH (3.0 equiv), BrAcOH (1.1 equiv), THF/DMF
0 °C to RT (54%); (b) 10% 1, 10% Cr(salen)Cl, BQ (2.0 equiv),
dioxane, 65 °C (56% of >20:1 dr anti-diastereomer; 73%, 3:1 crude dr);
(c) (1) LiHMDS (2.0 equiv), 1:1 v/v TMSCl/Et3N, THF, ꢀ78 °C then
reflux in toluene, (2) MeI (3.0 equiv), K2CO3 (3.0 equiv), DMF, RT
(82%); (d) LiAlH4 (2.0 equiv), THF, 0 °C; (e) BnBr (2.0 equiv), NaH
(2.0 equiv), DMF, 0 °C to RT; (f) 1 N HCl, THF, RT (60%, 3 steps).
(4) Washida, K.; Abe, N.; Sugiyama, Y.; Hirota, A. Biosci. Biotechnol.
Biochem. 2009, 73, 1355.
(5) (a) Burke, S. D.; Armistead, D. M.; Schoenen, F. J.; Fevig, J. M.
Tetrahedron 1986, 42, 2787. For the dioxanone to pyran approach
previously applied to total synthesis, see:(b) Burke, S. D.; Sametz, G. M.
Org. Lett. 1999, 1, 71. (c) Burke, S. D.; Piscopio, A. D.; Kort, M. E.;
Matulenko, M. A.; Parker, M. H.; Armistead, D. M.; Shankaran, K. J. Org.
Chem. 1994, 59, 332. For the seminal report of the IrelandꢀClaisen
rearrangement, see:(d) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc.
1972, 94, 5897.
(6) For an example of the synthesis of differentiated cyclic 1,2-
diols, see: Lim, S. M.; Hill, N.; Myers, A. G. J. Am. Chem. Soc. 2009,
131, 5763.
(7) For CꢀH esterification, see: (a) Chen, M. C.; White, M. C.
J. Am. Chem. Soc. 2004, 126, 1346. (b) Chen, M. S.; Prabagaran, N.;
Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970. (c)
Fraunhoffer, K. F.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 9032.
(8) For CꢀH amination, see: (a) Fraunhoffer, K. J.; White, M. C.
J. Am. Chem. Soc. 2007, 129, 7274. (b) Reed, S. A.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 3316. (c) Reed, S. A.; Mazzotti, A. R.; White, M. C.
J. Am. Chem. Soc. 2009, 131, 11701. (d) Rice, G. T.; White, M. C. J. Am.
Chem. Soc. 2009, 131, 11707.
(9) For CꢀH alkylation, see: (a) Young, A. J.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 14090.(b) Young, A. J.; White, M. C. Angew.
Chem., Int. Ed. 2011, 50, 6824. (c) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang,
W.-H.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 12901.
’ CONCLUSION
We have developed a novel approach to differentiated poly-
oxygenated motifs and bifunctional syn-pyrans from homoallylic
alcohols using Pd(II)/bis-sulfoxide CꢀH oxidation catalysis.
This work underscores the power of selective CꢀH oxidation
reactions for installing versatile functionality that enables rapid
access to functionally and topologically diverse structures from
simple starting materials.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures, compound characterization data, and NMR spectra for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(10) For examples of an iterative approach to polyol synthesis, see:
(a) Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587.
(b) Iwata, M.; Yazaki, R.; Suzuki, Y.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 18244. (c) Menz, H.; Krisch, S. F. Org. Lett. 2009,
11, 5634. (d) Hassan, A.; Lu, Y.; Krische, M. J. Org. Lett. 2009, 11, 3112.
(11) An analogous intermediate has been proposed for the
Pd(OAc)2-catalyzed 1,4-diacetoxylation of 1,3-dienes, and stereochem-
ical evidence supports an inner-sphere CꢀO bond forming process. See:
B€ackvall, J. E.; Bystr€om, S. E.; Nordberg, R. E. J. Org. Chem. 1984,
49, 4619.
Corresponding Author
white@scs.uiuc.edu
’ ACKNOWLEDGMENT
Financial support was provided by NIH/NIGMS
(GM07615). P.E.G. is the recipient of the University of Illinois
Synthetic Organic and NSF Graduate Research Fellowships. We
thank TCI and Aldrich Chemical Co. for generous gifts of the
commercial bis-sulfoxide/Pd(OAc)2 catalyst (1). We also thank
Mr. Marinus Bigi for checking the experimental procedure in
Table 3, entry 1.
(12) For example, intermolecular CꢀH amination, thought to
proceed via outer-sphere CꢀN bond formation, forms predominantly
the linear regioisomer and is tolerant of homoallylic oxygen function-
ality. See ref 8b.
(13) For a detailed exploration of the role of Cr(salen)X in allylic
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