Terminal olefins to chromans, isochromans, and pyrans via allylic C-H oxidation

Article abstract of DOI:10.1021/ja503322e

The synthesis of chroman, isochroman, and pyran motifs has been accomplished via a combination of Pd(II)/bis-sulfoxide C-H activation and Lewis acid co-catalysis. A wide range of alcohols are found to be competent nucleophiles for the transformation under uniform conditions (catalyst, solvent, temperature). Mechanistic studies suggest that the reaction proceeds via initial C-H activation followed by a novel inner-sphere functionalization pathway. Consistent with this, the reaction shows reactivity trends orthogonal to those of traditional Pd(0)-catalyzed allylic substitutions.

Full text of DOI:10.1021/ja503322e

Communication
Terminal Olefins to Chromans, Isochromans,
and Pyrans via Allylic C—H Oxidation
Stephen E Ammann, Grant T. Rice, and M. Christina White
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja503322e • Publication Date (Web): 01 Jul 2014
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Terminal Olefins to Chromans, Isochromans,
and Pyrans via Allylic C—H Oxidation
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Stephen E. Ammann, Grant T. Rice, M. Christina White*
Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana – Champaign, Urbana, Illinois
61801, United States
Supporting Information Placeholder
such oxygen heterocycle motifs are highly varied, and generally
necessitate the use of preoxidized starting materials.4 Prominently,
much work has focused on processes that proceed via Pd(II) oxy-
palladation or Pd(0) allylic substitution methods, in some cases
with high levels of asymmetric induction,5b,c 6b-d utilizing stereo-
chemically defined internal olefins as precursors.5,6
ABSTRACT: The synthesis of chroman, isochroman, and py-
ran motifs has been accomplished via a combination of palla-
dium(II)/bis-sulfoxide C—H activation and Lewis acid co-
catalysis. A wide range of alcohols were found to be compe-
tent nucleophiles for the transformation under uniform condi-
tions (catalyst, solvent, temperature). Mechanistic studies
suggest that the reaction proceeds via initial C-H activation
followed by a novel inner-sphere reductive elimination func-
tionalization pathway. Consistent with this, the reaction
shows orthogonal reactivity trends to traditional Pd(0)-
catalyzed allylic substitutions.
Table 1. Reaction Development
O
O
S
S
Ph
Ph
Pd(OAc)2
(10 mol%)
4
OH
5a
O
BQ (2 equiv.)
additive (10 mol%)
solvent, 45˚C
H
6a
Selective C—H oxidation reactions increasingly enable the
streamlining of synthetic routes due to their ability to introduce
oxygen and nitrogen functionality under conditions orthogonal to
those of traditional acid-base methods.1 In many cases, this is
because novel metal-promoted pathways are accessed to effect
electrophile and nucleophile activation. Herein we report a
Pd(II)/sulfoxide-catalyzed allylic C—H oxidation reaction that
proceeds under neutral and uniform conditions to provide access
to a wide range of oxygen heterocycles including chromans, iso-
chromans and pyrans.
Yield
[%]a
Entry
Additive
none
Catalyst
Solvent
Time
1
2
3
4
4
4
THF
THF
THF
72 h
24 h
16 h
18
0
DIPEA
B(C5F6)3
22
4
Cr(salen)Cl
Cr(salen)Cl
Cr(salen)BF4
Cr(TPP)Cl
Mn(salen)Cl
none
4
4
4
4
4
4
THF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
72 h
48
5
79d
47d
72d
6
7
8
45d,e
9
24
<5
9
Figure 1.
Bn
N
10
11b
12c
Cr(salen)Cl
Cr(salen)Cl
Cr(salen)Cl
Pd(OAc)2
OH
OH
H
O
H
H
O
H
4
4
O
N
O
O
O
O
67d
F
F
OH
opiod ! receptor
antagonist (2)
a Yields determined by 1HNMR with an internal standard (nitrobenzene).
b 2,6-dimethylbenzoquinone substituted for 1,4-benzoquinone. c 5 mol% 4.
d Average of two isolated yields. e 43% recovered starting material.
antihypertensive agent (1)
ficuspirolide (3)
This work
O
O
R
Palladium(II)/bis-sulfoxide catalyzed allylic C—H func-
tionalizations of terminal olefins have shown broad applicability
in synthetic methodology.7 We sought to apply a C—H activation
strategy toward a general method for the synthesis of cyclic ether
motifs starting from monooxygenated terminal olefin substrates.
However, nucleophiles used for allylic C—H functionalization
under the mild conditions of palladium sulfoxide catalysis have
uniformly possessed pKa’s under 6.7–9 Higher-basicity nucleo-
philes impede the catalytic cycle, either by deactivation of the Pd
catalyst or by failing to undergo deprotonation under the reaction
conditions whose only sources of base (the acetate counterion and
dihydroquinone generated upon palladium reoxidation) are weak
OH
O
S
S
Ph
Ph
O
O
R
Pd(OAc)2
4
R
R
R
L.A. co-catalyst
H
H
chromans
isochromans
pyrans
Oxygen-containing heterocycles comprise a class of com-
pounds that are widely sought-after for their significant biological
properties.2 Pyrans and benzopyran motifs, such as chromans and
isochromans, are pervasive structural elements in biologically
relevant small molecules (Figure 1), as displayed by antihyperten-
sive agent 1, opiod σ receptor antagonist 2, and Ficus Microcarpa
natural product ficuspirolide 3.3 Reported methods for accessing
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Page 2 of 5
and catalytic.7e With pKa’s ranging from ~ 10 for phenol to above
(< 5%) of product, supporting the hypothesis that the reaction
1
2
3
4
5
6
7
8
15 for aliphatic alcohols, alcohols represented a major hurdle for
allylic oxidations. Initial intermolecular experiments with terminal
olefins and excess phenols consistently showed no desired prod-
ucts. Inspired by our oxidative macrolactonization and diol form-
ing reactions, we envisioned rendering the reaction intramolecular
might promote alcohol complexation to the palladium, with con-
comitant acidification enabling deprotonation under neutral condi-
tions.8,9 Moreover, functionalization (C—O bond formation) may
proceed via an inner-sphere reductive elimination mechanism that
could have orthogonal scope to classic Pd(0) methods.8a,10
proceeds via a C—H cleavage/π-allylpalladium functionalization
pathway (entry 10). Consistent with the need for a π-acidic ligand
capable of binding to Pd for the Cr co-catalyst effect, the more
sterically bulky 2,6-dimethylbenzoquinone caused the reaction to
proceed with greatly diminished yield (entry 11).13 Significantly,
the loading of palladium catalyst 4 may be cut in half (5 mol%)
with only a minor decrease in yield if reaction times are extended
(entry 12).
We next examined the scope of this method for furnishing
the 2-vinyl-chroman motif. Gratifyingly, aromatic substitution
shows broad tolerance for both electron-donating substituents
(Table 2, products 6b, 6c, 6j) and electron-withdrawing substitu-
ents (products 6d-6i, 6k 6l). It is significant to note that even the
highly electron-withdrawing trifluoromethyl and nitro groups
furnish chroman products in good yields. This is in contrast to
what has been observed under Pd(0) allylic substitution conditions
where poor reactivity is observed with weakly nucleophilic phe-
nols (vide infra).14 Chloride- and bromide-substituents are well
tolerated under these oxidative conditions (products 6e-6g), and
serve as handles for further manipulation. Importantly, representa-
tive substrates were selected to illustrate tolerance for substitution
on the alkyl chain. The bulky ketal-substituted product 6m was
obtained in a 65% yield, serving as a masked ketone to access
chromanone motifs. Oxygen substitution on the alkyl chain fur-
nishes benzodioxan 6n; similarly, nitrogen substitution allows for
formation of dihydro-2,4-benzoxazine product 6o. Additionally,
we were gratified to find that the reaction may be scaled-up 50-
9
10
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Preliminary evaluation of standard Pd(II)/bis-sulfoxide
conditions using commercial catalyst 4 furnished chroman 6a in a
modest 18% yield from phenol 5a (Table 1, entry 1). Increasing
the concentration of weak base in solution via addition of catalytic
DIPEA shut down reactivity (entry 2).11 We have previously
demonstrated that catalytic amounts of both aza- and oxophilic
Lewis acids enhance the reactivity of allylic C—H functionaliza-
tions. Whereas the addition of catalytic amounts of B(C6F5)3 did
not increase the desired yield (entry 3),12 inclusion of the oxophi-
lic Lewis acid Cr(salen)Cl resulted in an increase in yield to 40%
(entry 4).7b,9,13 that was further enhanced in 1,2-dichloroethane
solvent (79% yield, entry 5). Use of a less-coordinating BF4 coun-
terion on the Cr Lewis acid diminished reactivity, however use of
an analogous, square planar porphyrin ligand results in nearly
identical yield of 6a (entry 6,7). Significantly, a Mn(salen)Cl co-
catalyst, previously shown to promote 4-catalyzed intermolecular
C—H aminations, also effected a promising improvement in yield
(entry 8).7b Removal of the co-catalyst from these optimized reac-
tion conditions resulted in a dramatic decrease in yield (entry 9).
Substitution of catalyst 4 for Pd(OAc)2 resulted in only trace yield
fold without any diminishment in yield (product 6a).
Table 3. Pd(II)/bis-sulfoxide/LA Catalyzed Isochroman and Pyran Formation
benzylic alcohols
O
O
S
S
Ph
Ph
R' R'
OH
R' R'
O
Table 2. Pd(II)/bis-sulfoxide/LA Catalyzed Chroman Formation
Pd(OAc)2 4
(10 mol%)
O
O
phenols
S
S
Ph
Ph
Cr(salen)Cl (10 mol%)
BQ (2 equiv.), DCE (0.3 M)
45˚C, 16h
R
R
Pd(OAc)2 4
7a-d
8a-da
OH
O
(10 mol%)
Cr(salen)Cl (10 mol%)
BQ (2 equiv.), DCE (0.3 M)
45˚C, 16h
Me Me
R
R
H
5a-o
6a-oa
O
O
O
O
Cl
F3C
O
O
O
8a: 76%
8b: 75%
8c: 65%
8d: 72%
Me
MeO
6a: 79%
6b: 84%
6c: 77%
aliphatic alcohols
O
O
5 mmol scale: 81%
S
S
Ph
Ph
Pd(OAc)2 4
R
R
R
O
O
O
(10 mol%)
OH
O
R
Cr(salen)Cl (10 mol%)
BQ (2 equiv.), DCE (0.3 M)
45˚C, 16h
F
Cl
Br
9a-d
10a-da
6d: 69%
Cl
6e: 81%
6f: 84%
O
O
O
O
O
O
O
O
O
Cl
F3C
O2N
10a: 72%
10b: 76%
10c: 86%
10d: 41%b
6g: 80%
6h: 81%
6i: 66%
a Average isolated yields of two runs at 0.1 mmol. b 1HNMR yield, 48% recovered 9d.
We hypothesized that such a chelation approach to nucleo-
phile activation may extend beyond phenols to other, significantly
less acidic alcohols such as benzylic and even aliphatic alcohols
(pKa = 15-16). We were delighted to discover that benzyl alcohol
7a is converted into 3-vinyl-2-isochroman 8a in good yield under
identical reaction conditions to those used for chroman synthesis
(Table 3). Electronic substitution of the aromatic ring is also well
tolerated, with chloride- and trifluoromethyl-substituted isochro-
mans produced in good yield (products 8b and 8d, respectively).
O
O
O
MeO
OMe
F
O
6j: 88%
6l: 72%
6k: 80%
O
O
O
N
O
O
O
Ts
6n: 67%b
6m: 65%b
6o: 57%b
a Average isolated yields of two runs at 0.1 mmol. b Reaction run for 72 h.
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Additionally, we were pleased to observe that bulky geminal di-
Scheme 2. Functionalization Step: Mechanistic Examination
A. Metal-assisted deprotonation/functionalization
1
2
3
4
5
6
7
8
methyl-substituted product 8c is furnished in 65% yield. Given
the facile nature of this reaction irrespective of the electronic na-
ture of the alcohol nucleophile, aliphatic alcohols may also func-
tion as nucleophiles to furnish pyran motifs. We were delighted to
find that the reaction of primary alcohols 9a-c proceeds under
identical conditions to those employed for phenols and benzyl
alcohols to furnish 2-vinylpyran products 10a-c in good yields.
While gem-disubstitution is beneficial for cyclization, it is not a
requirement for reactivity (Table 3, 10d).
Cr(salen)
Pd/bis-sulfoxide C—H cleavage
H
O
H
OH
R
O
PdLn
R
R
H
PdLn
metal-assisted deprotonation
Cr(salen)
O
O
R
O
PdLn
9
R
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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40
41
42
43
44
45
46
47
48
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Scheme 1. Mechanistic Experiments: Oxypalladation versus C—H Cleavage
outer-sphere
functionalization
inner-sphere
functionalization
II
I
PdLn
PdLn
A.
OH
OH
B.
O
O
O
CH3
R
R
R
S
S
Ph
Ph
OH
O
Pd(OAc)2 4
H
PdLn
olefin isomerization/
oxypalladation
C-H Activation
(10 mol%)
R
R
[Cr(salen)Cl (10 mol%)]
standard conditions
H
O
O
B.
/"
S
S
Ph
Ph
Pd(OAc)2 4
With Cr:
OH
11
O
! = 0.55
(10 mol%)
6i, R=NO2
"#$%&'(&
Cr(salen)Cl (10 mol%)
BQ (2 equiv.), DCE (0.3 M)
45˚C, 16h
$%&"
$"
6h, R=CF3
!"#"$%&&'"("$%$&"
)*"#"$%+,"
6a
not observed
C.
H/D
O
6b, R=Me
OH
above
Without Cr:
! = 0.63
"#$%)*$&'(&
6a, R=H
R
R
R = NO2
R = H
kD/kH = 3.3
= 1.8
H/D H/D
!"#"$%,-'"."$%$/"
)*"#"$%++"
6c, R=OMe
R = OMe
= 1.7
.$%&"
.$%&"
$"
$%&"
/"
*!)
The unexpectedly broad nucleophile scope prompted us to
examine the reaction mechanism. Benzopyrans have been gener-
ated via Pd(II)-mediated oxypalladation mechanisms from inter-
nal olefins, prompting us to evaluate an olefin isomeriza-
tion/oxypalladation mechanism (Scheme 1A).5 When internal
olefin 11 was subjected to the reaction conditions, minimal con-
version and, critically, no chroman product was observed (entry
B). Previous studies support that Pd(II)/bis-sulfoxide promotes
C—H cleavage from terminal olefins to furnish π-allylPd inter-
mediates and we sought to evaluate if such a mechanism operates
here.7b,8a,13 Isotope labelling studies were undertaken, where sepa-
rate rate constants were measured for reactions proceeding with
allylic hydrogen or deuterium. Interestingly, a range of isotope
effects were observed depending on the nature of the alcohol (en-
try C). With phenol nucleophiles of weak nucleophilicity and
modest acidity, isotope effects in the range of 1.7-1.8 were meas-
ured, whereas an isotope effect of 3.3 was measured for phenol 5i
with a significantly lower pKa. This is consistent with a scenario
where neither C—H cleavage nor deprotonation/functionalization
(C—O bond formation) are completely rate-determining and the
observed KIE reflects multiple steps.15
In considering the functionalization mechanism, metal as-
sisted alcohol deprotonation is necessary to acidify the O—H
bond and enable soft deprotonation with the weak acetate and/or
dihydroquinone base.16 Significantly, the course for functionaliza-
tion may be determined depending on the metal assisting in
deprotonation: π-allylPd coordination/deprotonation generates I,
the precursor for inner-sphere functionalization at the palladium,
whereas Cr(salen) assisted deprotonation would promote in an
outer-sphere delivery to the π-allylPd via II (Scheme 2A). To
evaluate the latter possibility, a Hammett analysis of the reaction
catalyzed by both Pd(II)/bis-sulfoxide 4 and Cr(salen)Cl was
compared to a second Hammett analysis of the background reac-
tion catalyzed only by 4 (Scheme 2B). The absence of a signifi-
cant change in rho values leads us to favor a mechanism whereby
deprotonation and functionalization occur at palladium.
Dissociation of the alkoxide from π-allylPd I followed by
an outer-sphere π-allylPd functionalization should have analogous
trends in reactivity to Pd(0)-mediated allylic substitution reactions
known to proceed via outer-sphere alkoxide functionalization of
π-allylPd.6,14,17 We examined the yields and initial rates of chro-
man formation for Pd(0)-mediated allylic substitution with elec-
tron-deficient and electron neutral substrates, and compared these
to the allylic C—H oxidation reaction (Scheme 3). When allylic
carbonate substrate 12a containing an electron-neutral phenol was
subjected to standard Pd(0) allylic substitution conditions, 2-
vinyl-chroman 6a was formed in good yield (84% yield); howev-
er, when para-nitrophenol or para-trifluoromethyl substrates
Scheme 3. Allylic C-H oxidation versus allylic substitution
C—H
Allylic
Substitution
Oxidation
O
O
OH
Pd2dba3
dppp
S
S
OH
Ph
Ph
Pd(OAc)2
R
R
Cr(salen)Cl
OC(O)2Me
12a: R=H
5a: R=H
5i: R=NO2
5h: R=CF3
H
12b: R=NO2
12c: R=CF3
6a: 84% yieldc
6i: 7% yielda
6h: 11% yieldb
6a: 79% yieldc
6i: 66% yieldb
O
6h: 81% yield
kNO2 / kH = 0.03
kCF3 / kH = 0.10
kNO2 / kH = 3.3
kCF3 / kH = 2.0
R
a 80% recovered starting material. b 78% recovered starting material.
(12b, 12c) were exposed to identical Pd(0) conditions, reactivity
was significantly retarded (7% and 11% yields, respectively,
Scheme 3). In both cases, this drop in reactivity correlates with a
significant decrease in reaction rate (kNO2 / kH = 0.03; kCF3 / kH =
0.10).14 In contrast, chroman yields for allylic C—H oxidation do
not show a significant dependence on the electronic properties of
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ford, M. S. Tetrahedron 2006, 62, 2439. (d) Giri, R.; Shi, B.-F.; Engle, K.
the alcohol, and the Hammett analysis of the Pd(II)/bis-
sulfoxide/Cr(salen)Cl catalyzed allylic C—H oxidation reaction
reveals that reaction rate is modestly enhanced by electron-
withdrawing groups on the phenol pro-nucleophile, presumably
reflecting a more facile deprotonation (kNO2 / kH = 3.3; (kCF3 / kH =
2.0) (Schemes 2 and 3).18 Such dramatic switches in reactivity and
reaction rate trends are unlikely to be due to the different mecha-
nisms for π-allylPd formation, therefore, we take this as further
evidence of a major deviation from the classical outer-sphere
functionalization model. Although we cannot definitively rule out
all outer-sphere functionalization pathways, on the basis of evi-
dence presented we view it as highly unlikely.19 Broad nucleo-
phile scope is likely a consequence of such a metal-chelation ap-
proach, serving as a “dampening effect” for the nucleophiles’
electronic character. We have previously provided evidence that
Pd(II)/sulfoxide-catalyzed C—H functionalizations with oxygen
nucleophiles (e.g. carboxylates) proceed via an inner-sphere re-
ductive elimination step.7a,8a,9 The mechanistic findings herein
constitute further evidence for such a pathway.
In summary, we have developed a general Pd(II)/bis-
sulfoxide-catalyzed allylic oxidation method to afford for the first
time direct access to chroman, isochroman, and pyran motifs start-
ing from terminal olefins. This operationally simple method (open
to air and moisture) proceeds with high substrate generality under
uniform conditions (catalyst, solvent, temperature). Its low sensi-
tivity to the electronic nature of the alcohol nucleophile along
with inverse electronic trends observed for reaction rate relative to
outer-sphere Pd(0)-catalyzed allylic substitutions, argues for an
allylic C—H functionalization mechanism proceeding via inner-
sphere palladium coordination/activation of the oxygen nucleo-
phile and subsequent reductive elimination. We anticipate that this
general strategy will help to broaden the scope of pro-
nucleophiles used in C—H functionalization reactions.
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4
5
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(7) (a) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am.
Chem. Soc. 2005, 127, 6970. (b) Reed, S. A.; White, M. C. J. Am. Chem.
Soc. 2008, 130, 3316. (c) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang, W.-H.;
Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 12901. (d) Young, A. J.; White,
M. C. J. Am. Chem. Soc. 2008, 130, 14090. (e) Rice, G.T.; White, M.C. J.
Am. Chem. Soc. 2009, 131, 11707. (f) Braun, M.-G.; Doyle, A. G. J. Am.
Chem. Soc. 2013, 135, 12990.
(8) (a) Fraunhoffer, K.J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J.
Am. Chem. Soc. 2006, 128, 9032. (b) Gade, N. R.; Iqbal, J. Tetrahedron
Lett. 2013, 54, 4225.
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(9) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2011, 133, 12584.
(10) For a seminal example of Pd-catalyzed inner-sphere acetoxylation of
cyclohexadiene, see: (a) Bäckvall, J.-E.; Byström, S. E.; Nordberg, R. E.
J. Org. Chem. 1984. 49, 4619.
(11) Reed, S. A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009,
131, 11701.
ASSOCIATED CONTENT
Experimentals, characterization data, and copies of 1H and 13
C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Strambeanu, I. I.; White, M. C. J. Am. Chem. Soc. 2013, 135, 12032.
(13) (a) Covell, D. J.; White, M. C. Angew. Chem. Int. Ed. 2008, 47, 6448.
(b) Hansen, K.B.; Leighton, J.L.; Jacobsen, E.N. J. Am. Chem. Soc. 1996.
118, 10924.
(14) Pd(0)-catalyzed functionalizations show diminished intermolecular
reactivity with electron deficient phenols: (a) Goux, C.; Massacret, M.;
Lhoste, P.; Sinou, D. Organometallics 1995, 14, 4585. (b) Goux, C.;
Lhoste, P.; Sinou, D. Synlett 1992, 725. (c) Fang, P.; Ding, C.-H.; Hou,
X.-L.; Dai, L.-X. Tetrahedron: Asymmetry 2010, 21, 1176.
(15) (a) Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51,
3066. (b) Bercaw, J.E.; Hazari, N.; Labinger, J.A.; Oblad, P.F. Angew.
Chem. Int. Ed. 2008, 47, 9941.
(16) For proposed metal-assisted deprotonation preceding reductive elimi-
nation in the Pd(0)-catalyzed etherification of aryl halides, see: Palucki,
M.; Wolfe, J. P.; Buchwald, S.L. J. Am. Chem Soc. 1996, 118, 10333.
(17) Trost, B.M.; Dirat, O.; Dudash Jr., J.; Hembre, E. J. Angew. Chem.
Int. Ed. 2001, 40, 3658.
(18) A KIE of 5.2 for aliphatic 9b, along with the fact that 9b shows a
more than two-fold rate increase when compared to phenol 5a, indicates
that a trend based purely on nucleophile pKa does not provide a complete
picture for all alcohols and different aspects of the nucleophilicity of alco-
hols must be considered.
AUTHOR INFORMATION
Corresponding Author
* white@scs.uiuc.edu
Funding Sources
Financial support was provided by the NIH/NIGMS (2R01 GM
076153B). SEA is the recipient of an NSF Graduate Research
Fellowship.
Notes
The authors declare no competing financial interest. GTR is
now a student at Duke Law School.
ACKNOWLEDGMENT
We thank Matt Kolaczkowski for help with substrate synthe-
sis. We thank Dr. Jennifer M. Howell for checking the experi-
mental procedure in Table 3, entry 8c.
(19) For example, attack of the protonated nucleophile onto the π-allylPd
electrophile followed by a deprotonation step would also be consistent
with electron-deficient phenols reacting at a faster rate.
REFERENCES
(1) (a) Crabtree, R. H. J. Chem Soc., Dalton Trans. 2001, 2437. (b) La-
binger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (c) Dick, A. R.; San-
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