Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions

Article abstract of DOI:10.1021/jacs.5b12528

Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the S_N1-like, S_N2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (ρ = -2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 ± 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value.

Full text of DOI:10.1021/jacs.5b12528

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Article
Studies of the Mechanism and Origins of Enantioselectivity for the Chiral
Phosphoric Acid-Catalyzed Stereoselective Spi-roketalization Reactions
Yaroslav Ya Khomutnyk, Alonso J. Arguelles, Grace A.
Winschel, Zhankui Sun, Paul M. Zimmerman, and Pavel Nagorny
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12528 • Publication Date (Web): 07 Dec 2015
Downloaded from http://pubs.acs.org on December 11, 2015
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Journal of the American Chemical Society
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Studies of the Mechanism and Origins of Enantioselectivity
for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spi-
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Yaroslav Ya. Khomutnyk, Alonso J. Argüelles, Grace A. Winschel, Zhankui Sun, Paul M.
Zimmerman* and Pavel Nagorny*
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109
Spiroketalization, Acetalization, Chiral Phosphoric Acids, Brønsted Acid Catalysis, Mechanism, Computational Studies
ABSTRACT: Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enanti-
ocontrol for the asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to
differentiate between the SN1-like, SN2-like and covalent phosphate intermediate-based mechanisms. The chiral phosphoric
acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective
protonation/nucleophile addition thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction
kinetics revealed positive charge accumulation in the transition state (ρ = –2.9). A new computational reaction exploration
method along with the dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived
polar transition state (average lifetime = 519 ± 240 fs), which is consistent with the observed inverse KIE = 0.85. Based on
these studies, a transition state model explaining the observed stereochemical outcome was proposed. This model prediced
enantioselective formation of the observed enantiomer of the product in 92% ee, which matches the experimentally ob-
served value.
INTRODUCTION
Figure 1. Examples of natural products with challenging to
The transformations leading to formation of spiroketal
(spiroacetal) functionality represent a fundamentally
important class of organic reactions, discussion of which
can be found in the majority of the introductory organic
chemistry textbooks.1 A variety of natural products con-
tain the spiroketal functionality, and the presence of such
moiety is often crucial for their biological activity.1-3 Spi-
roketalization leads to the formation of a new stereogen-
ic center, and its configuration often defines the biologi-
cal properties of the molecule (Figure 1). The molecules
possessing only one stereogenic center arising from the
spiroketal moiety are well documented, and the absolute
configuration of such spiroketals may play an important
role in determining the biological properties of these
natural products. Thus, (R)-olean is a fruit fly sex phero-
mone that is known to act on male flies whereas its mir-
ror image, (S)-olean affects female fruit fly.2 Even in the
cases when numerous additional stereocenters are pre-
sent, the configuration of the spiroketal can be essential
for the properties and biological activity of the molecule
as it is the case for the cytotoxic natural product pecteno-
toxin 1, which was found to be more active than its ther-
modynamically more stable epimer, pectenotoxin 4.3
synthesize spiroketals
Chiral spiroketals:
MeO2C
O
O
OH
O
O
O
O
O
O
OH
O
HO
(R)-olean
(S)-olean
γ-rubromycin
O
OMe
Nonthermodynamic spiroketals:
n-Pr
Et
O
O
O
Me
O
O
O
chalcogran
conophthorin
Andrena bee
pheromone
H
Me
OH
HO2C
CO2H
O
O
Me
Me
Me
Me
spirofungin B
O
OH
R
R
Me
O
O
10
Me
10
Numerous studies investigated factors governing the
formation and stability of spiroketals. Typically, the sta-
bility of spiroketals is determined by both the steric and
stereoelectronic effects, and in the absence of significant
steric effects, stereoelectronic effects usually play the
O
O
7
H
O
7
O
O
OH
O
O
OH
OH
Me
O
pectenotoxin 1
Me
OH
O
Me Me
O
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natural product (cf. γ-rubromycin or olean, Figure 1).
determining role.4 The spiroketalization of dihy-
1
2
3
4
5
6
7
8
droxyketones (1, Scheme 1) may proceed through either
hydroxyacetals 2 or cyclic enol ethers 3 and may lead to
diastereomeric spiroketals 4 and 5. Diastereomer 5 is
more thermodynamically stable, and is typically the ma-
jor product under equilibrating conditions. The prefer-
ence for the formation of thermodynamic product 5 is
attributed to stereoelectronic effect arising from an addi-
tional n(O)→σ*(C–O) stabilizing interaction, which is
absent in the non-thermodynamic spiroketal 4. The ma-
jority of natural spiroketals possesses thermodynamical-
ly-favored configurations, which leads to the assumption
that their biosyntheses are under thermodynamic con-
trol. However, experimental evidence exists to suggest
that spiroketal biosyntheses could also happen under
enzymatic stereocontrol.5
Most current approaches to non-thermodynamic or chi-
ral spiroketals rely on substrate- or auxiliary-directed
methods to form the spiroketal stereocenter.8–10 The chi-
ral reagent-controlled formations of spiroketals are also
known, but significantly more rare.10c While the direct
chiral catalyst-controlled formation of chiral and non-
thermodynamic spiroketals would address the problems
specified above, until recently, such transformations11 as
well as the catalyst-controlled formation of O,O-acetals12
had been unknown. Among the various challenges asso-
ciated with the use of chiral catalysts, promoting the
formation of spiroketals without epimerization of the
formed stereocenter and controlling the reactivity of the
oxocarbenium ion intermediates could be highlighted as
the major challenges to overcome. Our group has long-
standing interests in hydrogen bond-donor catalysis and
its applications to acetalization reactions.11b,c,12g,13 Con-
temporaneously with the List and Coric,11a our group11b
recently demonstrated that both of these problems could
be avoided if chiral phosphoric acids are employed as the
catalysts for the cycloisomerization of cyclic enol ethers I
and III under the kinetic control. Correspondingly, this
article summarizes our work on chiral phosphoric acid-
catalyzed stereoselective spiroketalizations that could be
used to synthesize chiral and nonthermodynamic spiro-
ketal motifs (Figure 1). In addition, this article describes
the experimental and computational studies directed to
elucidate the mechanism and the origins of enantiocon-
trol for these reactions. Considering that many different
mechanistic pathways can be proposed for these trans-
formations, the described studies were designed to dif-
ferentiate between these pathways and to gain infor-
mation about the reactive intermediates. Thus, the cy-
clization of deuterated cyclic enol ethers, Hammett stud-
ies and secondary KIE studies were employed to differen-
tiate between the SN1-like, SN2-like and covalent phos-
phate intermediate-based mechanisms. These studies
suggest that the CPA-catalyzed cyclizations happen via
polar concerted mechanism that does not involve long-
lived oxocarbenium intermediates. A new computational
reaction exploration method along with molecular dy-
namics computational studies independently validated
this proposal and served to derive a transition state
model explaining the observed stereochemical outcome.
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Scheme 1.
A.
R
R
R
O
H-A
H-A
O
OH
O
OH
HO
OH
OH
3
2
1
H-A
H-A
R
R
O
O
O
O
4
5
thermodynamic
nonthermodynamic
B. n–σ*
no anomeric
stabilization
anomeric
stabilization
R
R
O
O
O
O
4
5
C.
OR
O
O
chiral acid
O
OR
OR
O
enantio-
selective
HO
HO
I
II
Kinetic Control
R
OR
R
O
O
R
O
chiral acid
O
diastereo-
selective
HO
HO
III
IV
A. Formation of thermodynamic and nonthermodynamic
spiroketals from dihydroxyketones (1) and cyclic enol
ethers (3). B. Stereoelectronic stabilization of thermody-
namic spiroketals. C. Catalyst-controlled spiroketalizations.
RESULTS AND DISCUSSION
Initial optimization studies. Although CPAs had
been previously employed to catalyze the formation of
chiral N,N-,14a-c,e N,O-,14d N,S-,14e,f and simple O,O-acetals,12
no examples of a successful chiral catalyst-controlled
enantioselective or diastereoselective spiroketalization
existed at the beginning of these studies. Despite these
encouraging precedents, the prospects of using chiral
Brønsted acids to promote catalyst-controlled spiroketal-
izations were unclear considering that spiroketals are
significantly more prone to epimerization under acidic
conditions. With this in mind, we surmised that the use of
cyclic enol ethers I or III as the spirocyclization precur-
sors was key in developing this transformation as the
mixed acetal precursors II and IV (Scheme 1) are too
Considering that natural spiroketals prevalently pos-
sess the thermodynamically most stable configuration,
the majority of synthetic approaches to natural spiro-
ketals rely on catalyst-promoted cyclization under equil-
ibrating conditions.6,7 At the same time, similar condi-
tions cannot be employed when a less stable nonthermo-
dynamic configuration is desired (cf. pectenotoxin 1, Fig-
ure 1). In those cases, the stereoselective synthesis of
spiroketals via direct acetalization becomes significantly
more challenging.8 Equally challenging is the enantiose-
lective synthesis of a spiroketal moiety, in which case the
ketal stereocenter is the only source of chirality in the
2
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similar to spiroketals in their ability to ionize under the ketalizations conducted in nonpolar hydrocarbon sol-
1
acidic conditions. The cycloisomerization of the enol
ethers I and III is easier to achieve under the epimeriza-
tion-free conditions, and the Deslongchamps and Pihko
groups had previously utilized weak acids such as acetic
acid (pKa = 4.7, H2O) to promote kinetic spiroketaliza-
tions.15 The same studies also indicate that the reactions
catalyzed by stronger trifluoroacetic acid (pKa = –0.25,
H2O) proceeded under the thermodynamic control. At
the same time, we surmised that the chiral phosphoric
acids have intermediate acidities (pKa ~ 2, H2O), and
would be excellent catalysts for kinetic spiroketaliza-
tions. In order to evaluate the feasibility of this proposal,
spiroketalization of substrate 6a into 8a was investigat-
ed (Table 1).11b Commercially available (S)-TRIP (7a)
was selected as the initial catalyst for the reaction opti-
mization (Table 1); however, our subsequent attempts to
identify a superior catalyst of this reaction were not suc-
cessful (cf. Table S1 in SI).
vents (entries 7–9) proceeded with higher enantioselec-
tivities and shorter reaction times. The observed solvent
effects emphasize the significance of non-covalent inter-
actions between the substrate and chiral phosphoric acid
for the productive reaction pathway. More polar, oxygen-
ated solvents (entries 2 and 3) can competitively form
hydrogen bonds with CPA, and thus reduce the complex-
ation with 6a. At the same time, the less polar solvents
favor enhanced hydrogen bonding and other types of
non-covalent interactions between 6a and 7a. Based on
these arguments, we surmised that the selectivity for the
formation of 8a can be further enhanced at lower reac-
tion temperature and if the hydrogen-bonding impurities
such as water are removed. Although lowering the reac-
tion temperature alone did not significantly affect the
enantioselectivity (entries 10 and 11), the addition of 4Å
MS combined with lowering the temperature to –35 ºC
resulted in the formation of 8a in 92% ee (entry 12).
2
3
4
5
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8
9
10
11
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Table 1. Initial evaluation of enantioselective spiroketalization
reaction conditions
Table 2. Investigation of enantioselective spiroketalization
substrate scope
R
Ar
O
O
P
O
O
O
O
(S)–
P
OH
Ph
OH
Ph
Ph
Ph
R
R
O O
O
(5 mol%)
R
7a
Ar
Ar = 2,4,6-(i-Pr)2C6H2
(5 mol%),
O
7a, R = 2,4,6-iPr3C6H2
R
O
OH
O
R
n
n
8a
6a
solvent, Ta
OH
R1
6
pentane, 4 Å MS
–35 or 0 ºC, 22 to 40 ha
8
R1
entry
solvent
T, ºC
time,b h
conversion
(yield), %
ee, %
rt
rt
rt
0.5
12 c
12
1
1
2
3
CH3CN
THF
100 (93)
30 (25)
7
Ar Ar
8ab
8cb
X-Ray
Ph Ph
O
8b
Ph
Ph
10
16
24
25
40
63
60
69
73
66
84
92
O
O
O
O
O
100 (98)
EtOAc
rt
rt
rt
rt
rt
4
5
6
7
8
benzene
100 (99)
100 (98)
100 (96)
100 (98)
100 (95)
Ar = 4-(MeS)Ph
81%, 93% ee
1
toluene
CCl4
96%, 92% ee
96%, 94% ee
1
Ph
8g
8d
8f
8h
Ph
Bn Bn
O
Bn
Bn
Ph Ph
O
hexanes
cyclohexane
0.5
0.5
0.5
4
O
O
O
O
O
O
pentane
pentane
rt
0
9
100 (97)
100 (97)
Me
10
88%, 74% ee
89%, 90% ee
82%, 75% ee
93%, 96% ee
–35
0
40
14
40
pentane
11
12
100 (96)
100 (97)
Cl
OMe
O
O
Bn
Bn
pentane, 4 Å MS
pentane, 4 Å MS
O
O
O
O
O
O
13
–35
100 (96)
8i
8j
8k
8l
aPhosphoric acids were washed with 6 M HCl after the purifica-
tion by the column chromatography. Unless specified otherwise,
reactions were performed on 0.1 mmol scale (0.02 M solution).
bTime required for the reactions to reach completion. cIncom-
plete conversion.
87%, 62% ee
92%, 4% ee
89%, 5% ee
72%, 54% ee
aReactions were performed on 0.1–0.05 mmol scale (0.02 M
solution), and the selectivities of these reactions were found to
be scale independent. Catalyst (R)-7a was used. bReactions
were conducted with catalyst (S)-7a.
In our attempts to optimize the selectivity for the for-
mation of 8a, we have encountered significant solvent
effects (Table 1). The reactions conducted in higher po-
larity solvents (entries 1–5) resulted in lower levels of
stereocontrol while the oxygenated solvents such as THF
and ethyl acetate significantly retarded the rate of cy-
clization (entries 2 and 3). At the same time, the spiro-
Enantioselective and Diastereoselective Spiro-
ketalizations. After the optimal reaction conditions
were identified, the scope of the enantioselective spiro-
ketalization was evaluated next (Table 2). In addition to
the previously evaluated 6a, the cyclic enol ethers 6b–6l
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were synthesized and subjected to the cyclizations lead- ed for these studies. Upon the spiroketalization, these
1
ing to 8b–8l. The introduction of p-MeS- substituents at
the aromatic rings of 6b and extension of the tether
length on 6c did not affect the reaction yield and selectiv-
ity of 8b and 8c. Similarly, the introduction of a fused
benzene ring into the side-chain (8d) or into the enol
ether ring (8e) was well tolerated, and the correspond-
ing products were obtained in excellent selectivities and
yields. At the same time, the cyclization of analogous sub-
strates 6g-6i containing less rigid Bn– substituents at
the tertiary alcohol consistently exhibited lower enanti-
oselectivities. Cyclization leading to 8h was found to be
more selective (88%, 74% ee) than a similar reaction
leading to 8i that lacks a methyl group on the aromatic
ring (87%, 62% ee). These results indicate that further
variations in the substrate backbone can potentially en-
hance the selectivity of the substrates lacking Ph– substi-
tution at the nucleophile. This is further reinforced by the
observation that primary alcohol-containing precursor
6l could be cyclized enantioselectively to 8l (72%, 54%
ee) while the reaction with a similar substrate 6j and 6k
lead to almost unselective formation of spiroketals 8j
and 8k.
substrates can provide anomerically stabilized thermo-
dynamic products such as 11 or less stable nonthermo-
dynamic spiroketals (10a–10f). Thus, to evaluate the
effect of chiral catalyst on the course of these cycliza-
tions, substrate 9a was subjected to the treatment with
(S)–7a, (R)–7a, as well as with achiral catalyst
(PhO)2PO2H. Remarkably, the treatment of glycal 9a with
catalyst (S)-7a (5 mol%) resulted in a highly diastere-
oselective cyclization, leading to nonthermodynamic spi-
roketal 10a (95:5 dr). At the same time, the exposure of
9a to (R)-7a as well as to (PhO)2PO2H provided ~1:1
mixtures of nonanomeric and anomeric products 10a
and 11a, clearly indicating that the chirality of the cata-
lyst is essential for the selective formation of 10a. Simi-
lar trends were observed for other substrates, and cata-
lyst (S)-7a was used for highly diastereoselective for-
mation of various non-thermodynamic spiroketals (10a–
10e) in good yields and diastereoselectivities. Interest-
ingly, the nature of protecting group at C3 was found to
play an important role, and unlike the formation of 10e,
the cyclization leading to 10f was not selective.
2
3
4
5
6
7
8
9
10
11
12
13
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The results summarized in Scheme 2 suggest that the
cyclizations catalyzed by 7a proceed under kinetic condi-
tions. The nonanomeric spiroketals 10 are clearly stable
to both enantiomers of acids 7a for the duration of the
reaction (i.e. 14 h). At the same time, if pure 10a is
treated with (S)-7a under the reaction conditions, a
complete epimerization to 11a was observed after 60 h.
Scheme 2. CPA-controlled formation of non-thermodynamic
spiroketals
catalyst,
RO
RO
RO
pentane
O
RO
HO
O
O
RO
RO
HO
O
HO
rt, 4 Å MSa
9a
10a
11a
O
HO
Mechanistic Considerations. The results above sug-
gest that 7a is the catalyst of choice for the asymmetric
spiroketalization of tertirary alcohol-containing sub-
strates 6 as well as for the diastereoselective cyclization
of chiral substrates 9 leading to nonanomeric spiroketals
10. Interestingly, the larger size of glycals 9 excluded the
requirement of using the tertiary alcohol-based nucleo-
philes and 7a could promote the cyclizations leading to
10 with primary and secondary alcohols as nucleophiles
in good-to-excellent selectivities. However, although the
aforementioned results provide some crude idea about
the scope and limitation of the method, the mechanistic
and stereochemical models explaining the origins of the
stereocontrol are essential for a more general use of the-
se and related transformations.
(S)–7a
(R)–7a
(PhO)2P(=O)OH
=
=
=
95 : 5, 87%b
48 : 52, 76%c
52 : 48, 89%c
R, R = C(CH3)2
Me
Me
Me
O
O
HO
O
O
HO
Me
O
O
HO
Me
Me
O
O
O
O
O
O
Me
Me
10b
10c
10d
(S)–7a, 73% yield
d.r. = 81:19b
(S)–7a, 85% yield
d.r. = 90:10b
(S)–7a, 86% yield
d.r. = 90:10b
Me
Me
O
O
AcO
O
O
Me
Me
O
O
MeO
O
O
10e
10f
(S)–7a, 92% yield
d.r. > 95:5b
(S)–7a, 42% yield
d.r. = 51:49b
aThe reactions with (S)-2a (5 mol%) and (R)-2a (5 mol%) were
performed for 14 h and the reactions with (PhO)2PO2H (10 mol%)
were performed for 2 h. Longer exposure to (PhO)2PO2H (10 mol%)
resulted in complete equilibration to thermodynamic spiroketals.
The cyclizations of 9a were performed at different scales without
significant variation in scale or selectivity. bYield of non-
thermodynamic spiroketal 10. cCombined yield of 10 and 11.
Despite the fact that CPA-catalyzed transformations
invoking oxocarbenium ion intermediates have received
significant attention in the recent years, very few at-
tempts to understand the mechanisms of such transfor-
mations and the factors governing the selectivity have
been made.16 The formation of stable oxocarbenium ion
intermediates has been proposed in the recent computa-
tional studies of N-triflyl phosphoramide-catalyzed cya-
nohydrin ether formation16a and CPA-catalyzed Petasis-
Ferrier rearrangements.16b However, instances when the
theoretical studies identified alternative mechanisms not
involving the formation of oxocarbenium ion intermedi-
ates have also been documented. Thus, the recent studies
of the acid-catalyzed enantioselective formation of pyr-
rolidines by the Toste group17 and piperidines by our
groups13d identified alternative pathways involving cova-
The results summarized in Table 2 indicate that chiral
catalyst could control the selectivity of the cyclization of
achiral substrates 6. However, considering that the chi-
rality of the substrate may completely override the
course of cyclization dictated by the catalyst, the effect of
the catalyst on the cyclization of chiral substrates had to
be addressed next (Scheme 2).11b Since the reactions of
carbohydrate-based oxocarbenium ions are highly sensi-
tive to stereoelectronic and steric effects, the conforma-
tionally locked D-glucal derivatives (i.e. 9a) were select-
lently
linked
thiophosphate
(or
phosphate)
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Scheme 3. Potential mechanism of CPA-catalyzed spiroketalizations
1
2
3
4
5
6
7
8
9
R
R
R
R
HO
1) Oxocarbenium intermediate
O
RO
RO
R
O
R
–
P
O
H
O
OH
anti- H-O
delivery
O
O
H
O
O
P
O
13a
OR
O
OR
O
RO
RO
P
H
O
14a
H
P
15a
O
OH
OR
OR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Protonation
O
RO
HO
R
O
H
R
–
O
P
syn- H-O
delivery
O
H
13b
RO
OH
H
R
O
12
14b
O
P
R
R
H
O
15b
RO
R
HO
R
R
P
O
RO
O
R
RO
OR
2) Mechanism involving anomeric phosphate intermediate
R
R
R
O
RO
RO
R
R
–
HO
O
P
O
O
H
16a
OH
anti- H-O
delivery
O
O
O
OR
O
H
P
O
O
O
RO
RO
H
15a
H
17a
P
OR
P
O
OH
RO
OR
syn-addition
O
HO
R
O
RO
O
16b
–
O
P
syn- H-O
delivery
17b
RO
OH
H
R
O
H
O
H
H
O
12
R
O
O
R
P
RO
HO
P
R
O
R
15b
RO
R
R
RO
OR
3) Concerted cyclization (no intermediate)
O
O
O
O
RO
RO
syn- H-O
delivery
O
RO
RO
–
R
H
O
P
P
R
H
OH
OH
O
O
H
HO
R
O
P
18
15b
12
RO
R
R
R
OR
intermediates rather than the corresponding high-energy
carbenium or oxocarbenium ion pairs. The oxocarbenium-
based mechanisms for the acid-catalyzed acetal formation
have indeed received widespread acceptance; however,
transformations of this type not involving oxocarbenium
ion intermediates have also been documented. Accordingly,
the Tan group observed an SN2-like concerted (rather than
SN1-like oxocarbenium-based) mechanism for the metha-
nol-promoted spirocyclization of glycal epoxides.18 In line
with these findings is the theoretical study of the thiourea-
catalyzed tetrahydropyranylation reaction by Schreiner
and Kotke, in which a concerted asynchronous addition of
alcohol nucleophiles rather than the formation of a discrete
oxocarbenium ion intermediate is proposed.19 Similarly, the
true nature of the glycosylation reaction intermediates has
been a subject of long-standing debates.20 Both the ionic
SN1-like and concerted SN2-like mechanisms are commonly
invoked to explain the outcome of the glycosylation reac-
tions, and there is strong evidence that non-ionic mecha-
nisms are operational in some instances. For example, the
Crich group has provided overwhelming evidence demon-
strating that 4,6-O-benzylidene-directed β-mannosylation
reactions proceed through covalently bound glycosyl tri-
flates rather than through the discrete glycosyl oxocarbeni-
um ion intermediates.21
With these prior observations in mind, we considered
several different mechanistic pathways for the CPA-
catalyzed enantioselective spiroketalization reaction
(Scheme 3). The reaction mechanisms proceeding through
oxocarbenium ion, covalently linked phosphate intermedi-
ate, and concerted mechanism with the concomitant C–H
and C–O bond formation were viewed as the most promi-
nent options. Both the counterion orientation and the rela-
tive stereochemistry of the forming C–H and C–O bonds are
crucial for understanding the origins of stereoinduction
and developing a stereochemical model. At the same time,
these important factors are typically omitted from the
mechanistic considerations. Thus, to our knowledge, no
information on the selectivity of the C–H/C–O bond addi-
tion has been available prior to this work. In theory, the
cyclization proceeding via an oxocarbenium ion intermedi-
ate can occur through two different modes. In the first
mode of cyclization, the formation of the C–H and C–O
bonds happen from the different faces of the molecule (i.e.
pathway proceeding through 13a/14a/15a). Alternatively,
the pathway proceeding through 13b/14b/15b and
5
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Journal of the American Chemical Society
Page 6 of 15
resulting in syn- protonation/C–O bond formation can be Diastereoselective Cyclizations Studies. With these
1
2
3
4
5
6
7
8
envisioned. Similarly, the reaction proceeding through the
anomeric phosphate intermediate conformations 16a or
16b can happen through the retentive or inversive (SN2-
like) mechanisms. The anti- relationship between the
formed C–H and C–O bonds is expected for the inversive
mechanism (i.e. 16a/17a/15a pathway), and the syn-
relationship between the formed C–H and C–O bonds is
expected for the retentive mechanism (16b/17b/15b
pathway). Unlike in the aforementioned mechanistic op-
tions that may lead to both the selective formation as well
as mixtures of syn- and anti- products, the concerted
mechanism, in which the phosphoric acid acts as the bi-
functional catalyst, could produce only syn- product 15b
(Scheme 3).
considerations in mind, we designed and conducted exper-
iments to distinguish between the diastereodivergent syn-
or anti- spiroketalization modes (Scheme 4).
To obtain this information, we generated deuterated
cyclic enol ethers 19–21 and subjected them to the cy-
clization in nonpolar solvents (i.e. toluene, dichloro-
methane and pentane) using (S)-7a, choroacetic acid,
CF3CO2H or p-TSA as the catalysts. The outcome of these
2
9
reactions was monitored using H(D) NMR (107 MHz). As
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
per our discussion above (i.e. Scheme 3), the cyclization of
19 may lead to syn- product 22a or anti- product 23a.
Similarly, the cyclization of 20 or 21 may provide syn-
diastereomers 22b and 22c or anti- diastereomers 23b
and 23c, respectively. Remarkably, only syn- products
22a–c were detected in the experiments with weaker ac-
ids (i.e. (S)-7a and ClCH2CO2H, entries 1–5); however, un-
selective formation of the syn- and anti- products was de-
tected for the p-TSA catalyzed reactions (entries 6 and 7).
The absence of the selectivity for the p-TSA catalyzed reac-
tions is attributed to rapid epimerization under the cy-
clization conditions. Thus, subjecting diastereomerically
pure 22b to p-TSA at –40 ºC resulted in rapid isomeriza-
tion to 1:1 mixture of 22b and 23b after 15 minutes. Fi-
Scheme 4. Diastereoselective spiroketalization of deuter-
ium-labeled substrates
O
H
D
O
O
D
D
H
O
O
HO
catalyst (5 mol%)a
Bn
Bn
Bn
or
22a
23a
Bn
Bn
Bn
19
or
24 h, solvent, 0 ºC
>98% conversion
D
H
O
O
O
D
H
D
O
O
R
R
nally,
a
substantial inverse kinetic isotope effect
23b, R = Ph
23c, R = H
22b, R = Ph
22c, R = H
R
R
HO
R
(KIE=0.85) was observed for the cyclization of 21c into
R
22c (cf. Eq. 1).
20, R = Ph
21, R= H
entry
catalyst
solvent
22a : 23a
22b : 23b
22c : 23c
D
O
O
(S)-7a (5 mol%)
2–3 h, pentane, 0 ºC
KIE = 0.85
OH
Ph
99 : 1
99 : 1
99 : 1
99 : 1
1
2
3
4
(S)–7a
(S)–7a
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
toluene
CH2Cl2
pentane
pentane
(1)
H
Ph
O
D
Ph
21c
22c
Ph
(S)–7a
ClCH2CO2Hb
ClCH2CO2Hb
p-TSAd
c
–
5
6
CH2Cl2
CH2Cl2
pentane
99 : 1
1 : 1
99 : 1
1 : 1
1 : 1
1 : 1
The relative configuration of 22a–22c was established
using NOE and 2D heteronuclear NMR studies, including
3JCH determination by SelEXSIDE,22 and some of the key
signals are depicted in Scheme 4 (cf. to Supporting infor-
mation for additional details). Despite the numerous stud-
ies on the spiroketalization mechanism and the wide-
spread use of spiroketals in organic synthesis, the results
in Scheme 4 represent the first documented evidence sug-
gesting that the kinetic spiroketalization of cyclic enol
ethers in nonpolar solvents proceeds via highly selective
syn- H/O addition. To investigate whether the syn- addi-
tion is more general and could be observed in intermolecu-
lar acetalization reactions, the reaction of D-labeled dihy-
dropyrane (24) and p-methoxybenzyl alcohol was investi-
gated next (Table 3). As for the spiroketalization studies
with deuterium-labeled cyclic enol ethers, the formation of
two diastereomeric products syn-25a and anti-25b is also
expected in this case. The phosphoric acids (S)-7a and 26,
chloroacetic acid and Schreiner’s thiourea 27 were select-
ed as the catalysts.
CF3CO2Hd
7
1 : 1
1 : 1
2H (D) NMR
22a
22a
23a
(S)-TRIP
p-TSA
23a
D
O
D
O
H
H2
C
H
R
H
H
O
O
R
22b, R = Ph
22c, R = H
22b, R = Ph
22c, R = H
R
R
3JCH ~ 1–2 Hz
NOE
aThe reactions were performed on 0.5–0.05 mmol scale, and each
experiment was reproduced twice. D(2H) NMR spectra were recorded
at 107 MHz using Varian VNMRS-700. The observed diastereoselec-
The formation of 25 promoted by these catalysts is ex-
pected to be irreversible (i.e. kinetic) under most condi-
tions since the THP-acetals possess significantly higher
stability than typical spiroketals. Interestingly, tetrahy-
dropyranylation reactions were found to be dissimilar to
spiroketalization reactions.
b
tivities were found to be conversion independent. 10 mol% of the
catalyst was employed. cNo reaction was observed. dThe racemization
reactions were found to be faster than the cyclization reactions under
these conditions.
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Journal of the American Chemical Society
Figure 2. Hammett analysis of (PhO)2PO2H-catalyzed spiroketal-
ization of 29.
Table 3. Acetalization with 3,4-dihydro-2H-pyran-5-d
1
2
3
4
5
6
7
8
9
H
O
OMe catalyst (5 mol%)a
D
D
O
HO
O
X
O
D
solvent, T, ºC
>98% conversion
H
(PhO)2PO2H (5 mol%)
toluene, 0 ºC
OPMB
OPMB
OH
O
24
O
anti-25b
syn-25a
30
29
X
A)
CF3
CF3
C6H2(iPr3)
O
45!
40!
35!
30!
25!
20!
15!
10!
5!
S
O
O
P
OH
OPh
P
PhO
–OCH3
CH3–
O
F3C
N
H
N
H
CF3
OH
26
27
C6H2(iPr3) (S)–7a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–H
–F
catalyst
solvent
entry
syn-25a : anti-25b
T, ºC
time, h
c o n v e r s i o n
rt
0
rt
rt
0
12
48
12
1
(S)–7a
1 : 1
1 : 1
1 : 1
CH2Cl2
%
2
26
pentane
Cl–
3
26
ClCH2CO2H
27
benzene
neat
4b
5c
48
42
–
1 : 1
0!
benzene
0"
10"
20"
30"
40"
50"
60"
70"
80"
time, min
B)
0.9!
0.6!
0.3!
0!
aThe reactions with were performed at 0.15-0.59 mmol scale, and
each experiment was reproduced twice. D(2H) NMR spectra were
recorded at 107 MHz on Varian 700. The observed diastereoselectivi-
ties were found to be conversion independent. bNo reaction was ob-
–OCH3
CH3–
)
H
/ K
–H
c
o b s
served with 10 mol% of the catalyst. 2 mol% of the catalyst 27 was
employed.
–F
( K
-0.3!
-0.6!
-0.9!
l o g
log(kobs/kH) = –2.9σ - 0.062!
R² = 0.98!
Thus, the reaction of p-methoxybenzyl alcohol with 24
produced a ~1:1 mixture of products with Brønsted acids
(S)-7a and 26 (entries 1–3), but no reaction was ob-
served with chloroacetic acid (entry 4). Similar results
were observed when unlabeled dihydropyrane was react-
ed with deuterium-enriched p-methoxybenzyl alcohol
(28) using diphenylphosphoric acid 26 as the catalyst (Eq.
2).
Cl–
"0.3&
"0.2&
"0.1&
0&
0.1&
0.2&
0.3&
σ (sigma)
(A) Rates of conversion with of 29 with (PhO)2PO2H (10 mol%)
in toluene at 0 ºC. (B) Hammett plot exhibits a linear correlation
for the electronically varied substrates 29 (ρ = –2.9).
Hammett Studies. The results above indicate that the
intramolecular and intermolecular acetalization reactions
proceed through different mechanisms. To further differ-
entiate between the outlined in Scheme 3 mechanistic op-
tions, a Hammett study was executed for the cyclization of
aromatic enol ether 29 leading to spiroketals 30 (Figure
2). Thus, the rate constants for the cyclization of substrates
29 with both electronwithdrawing (i.e. X = Cl–, F–) and
electrondonating (i.e. X = CH3O– and CH3–) substituents as
well as the unsubstituted substrate (X = H–) were meas-
ured at low conversions (Figure 2, A). The obtained
log(Kobs/KH) values for the electronically varied substrates
29 displayed an excellent linear correlation when plotted
against the corresponding known σ values (R2 = 0.98).
These results allowed for the measurement of ρ value to be
–2.9, which is consistent with a positive charge build up in
the transition state of the rate-limiting step (ρ < –1). It
should be noted that the obtained ρ value is lower than the
one expected for an SN1-like mechanism involving rate-
limiting formation of fully charged oxocarbenium ion in-
termediate. In this regard, the Tan group has investigated
the acid-catalyzed epimerization of kinetic D-glucal-
derived spiroketals structurally similar to 29 and obtained
ρ = –5.1, which is more in line with a rate-limiting ioniza-
tion step than the ρ value obtained in these studies.
H
O
catalyst 26
(5 mol%)
D
O
OMe
(2)
D
H
O
OPMB
12 h, toluene, r.t.
>98% conversion
OPMB
OD
28
anti-25b
~ 1 : 1 mixture
syn-25a
As before, the nonselective formation of both syn- and an-
ti- products was observed in this case. Tetrahydropyranyl-
ation of methanol catalyzed by thiourea catalyst 27 has
been investigated computationally and the concerted
asynchronous addition of methanol proceeding through a
polar transition state with oxyanion hole stabilization by
27 has been proposed (vide supra).19 Considering that a
concerted asynchronous addition of alcohol to dihydropy-
rane 24 should result in the selective formation of syn-
25a, we decided to investigate the outcome of the thiourea
(27)-catalyzed formation of 25 (Table 3, entry 5). Surpris-
ingly, thiourea (27)-catalyzed acetalization of 24 and p-
methoxybenzyl alcohol produced an equimolar mixture of
syn-25a and anti-25b in benzene. Since the formation of
syn-25a and anti-25b is not reversible under the reaction
conditions, the outcome of the experiments in Table 3 is
consistent with the formation of a relatively long-lived,
solvent-separated (rather than contact), oxocarbeni-
um/stabilized alkoxide ion pair. This ion pair could un-
dergo a non-selective association, and both faces of oxo-
carbenium ion are equally exposed to the reaction with the
oxyanion nucleophile.
The results of the aforementioned studies shed some
light on the mechanism of the CPA-catalyzed spiroketaliza-
tion reactions. Thus, the observed highly diastereoselec-
tive syn- H–O delivery, a significant inverse KIE = 0.85 for
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substrate 21c (Eq. 1) indicating that re-hybridization hap-
transformation was studied in depth using quantum chem-
ical calculations.
1
2
3
4
5
6
7
8
pens in the rate-limiting step, and positive charge accumu-
lation in the TS of the rate-limiting step observed in the
Hammett study all speak against the formation of the cova-
lent anomeric phosphate intermediates 16 (Scheme 3).
These is further reinforced by the fact that syn- H–O deliv-
ery is observed not only for the phosphoric acid catalysts,
but also for the chloroacetic acid. The relatively small
ρ value and diastereoselective syn- H–O delivery are also
not consistent with the long-lived oxocarbenium ion in-
termediates 13, but more in accord with a highly asyn-
chronous concerted mechanism proceeding through the
polarized TS 18 (Scheme 3). At the same time, the scenaria
with the formation of short-lived oxocarbeni-
um/phosphate contact ion pair 13b or phosphate 16 can-
not be completely ruled out with the obtained experi-
mental data. These distinctions, however, can be done
based on the DFT calculations and molecular dynamics
studies that would help to identify a pathway with the
lowest energy and provide information on the average
lifetime of the TS or intermediate involved. With these
considerations in mind we undertook studies described in
the next section.
Reactions mechanisms in relatively large systems with
many flexible degrees of freedom-such as the present cata-
lytic system-are especially difficult to characterize using
reaction path optimization tools. To overcome these chal-
lenging cases, the Zimmerman group developed the Grow-
ing String Method (GSM) to simultaneously search for re-
action paths and transition states.23a,c,d By restricting the
search to find a transition state within a series of struc-
tures along a minimum energy path from reactant to prod-
uct, GSM can efficiently locate transition states on highly
flat energy surfaces. When our tools were applied to the
asymmetric CPA-catalyzed formation of piperidines, an
accurate description of the reaction selectivity was ob-
tained, which invoked a two-step mechanism proceeding
through a chiral phosphate acetal intermediate.13d In the
piperidine formation mechanism and the present spiro-
ketalization, GSM is especially useful in locating challeng-
ing asynchronous and concerted transformations due to its
flexible treatment of the reaction pathway tangent vector
(see Computational Details). Prior to the use of GSM to
locate reaction pathways, a preliminary study of the di-
phenyl hydrogen phosphate-catalyzed spiroketalization of
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Computational Studies. Asymmetric spiroketalization
with chiral phosphoric acids may proceed through one or
more of the mechanisms depicted in Scheme 3, of which
the most classical one is mediated by an oxocarbenium
intermediate. Experimental analysis of the mechanism
provided strong evidence against anti-H-O delivery (to
yield 15a), but the mechanisms resulting in 15b could not
be ruled out. To gain further insight on the mechanism, the
a
simplified
enol
ether
leading
to
1,7-
dioxaspiro[5.5]undecane was performed using the Zim-
merman group’s combinatorial reaction discovery proce-
dure.23b,e The results suggested that the concerted pathway
could compete with the phosphate-mediate and SN1-like
mechanisms.
Figure 3. Concerted, asynchronous mechanism for the ring closure of 6,6 spiroketalization model system.a
aThe values in parenthesis correspond to the difference of the sum of Mulliken charges in the enol ether oxygen and electrophilic carbon
with respect to the starting complex. *Barriers not calculated.
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Journal of the American Chemical Society
Figure 4. Anomeric phosphate mechanism of the 6,6 spiroketalization model system.a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aThe energy of important stationary points are shown in kcal/mol. The values in parenthesis correspond to the difference of the sum of Mulliken
charges in the enol ether oxygen and electrophilic carbon with respect to the starting complex.
Following these preliminary results, more rigorous studies
were performed which involved an initial extensive explo-
ration of possible orientations of the catalyst-product
complex for three different systems: the diphenyl phos-
phoric acid 26-catalyzed 6,6-spiroketalization, the 26-
catalyzed 6,5-spiroketalization, and the chiral CPA 7a-
catalyzed 6,6-spiroketalization. Reaction path exploration
and exact transition state searches were performed using
GSM for each of the three types of mechanisms shown in
Scheme 3. The resultant intermediates and transition
states were corrected for thermodynamics and solvent
effects (pentane). Reported energies are solvent-phase
free energies with thermodynamic corrections at 298K
(diphenyl hydrogen phosphate catalyst system) and 238K
(7a catalyst system) from ωB97X-D/SMD/6-31G**.
strate alcohol to phosphate H-bonded complex, an initial
protonation of the enol ether occurs at the transition state
(TS1). Additionally, the transition state shows a chair-like
geometry involving the alcohol oxygen and the electro-
philic carbon, with a C-O distance of 2.70 Å. After the tran-
sition state, synchronous deprotonation and cyclization
occurs. The initial spiroketal is formed in a chair-boat con-
formation, which can readily rearrange to a more stable
nonthermodynamic chair-chair conformation and ulti-
mately, by a ring flip, to the most thermodynamically sta-
ble spiroketal. The Mulliken charges on the enol ether oxy-
gen and electrophilic carbon (provided in Figure 3) show a
significant build-up of positive charge at TS1 (ΔΣQ=0.247),
slightly smaller than the sum of charges of a bare oxo-
carbenium solvated in n-pentane (ΔΣQ=0.271, cf. SI). The
activation barrier for this transformation was 16.0
kcal/mol above to the catalyst-substrate complex, fully
consistent with a mechanism operative at or below room
temperature. It should be noted that the dual function of
the phosphoric acid as both Brønsted acid and Lewis base
is efficiently exploited in this mechanism, as evident in the
rate determining TS shown in Figure 3. Although the prod-
uct initially formed is predicted to be the nonthermody-
namic spiroketal, this is only relevant in conformationally
locked systems such as the glucal derivatives shown in
Scheme 2, since otherwise the thermodynamic spiroketal
is readily accessed by a ring-flip.
To discriminate between the three mechanisms of Scheme
3, the transformation leading to a 6,6-spiroketal (substrate
6a) was investigated first using a model diphenyl hydro-
gen phosphate catalyst. While this initial study did not use
a chiral catalyst, the lowest barrier pathway unveiled by
these simulations was further examined with the full cata-
lyst (vide infra). Before examining the phosphate mediated
and oxocarbenium pathways, 12 concerted pathways lead-
ing to thermodynamic and nonthermodynamic spiroketals
were investigated. The most favored pathway produces a
nonthermodynamic spiroketal (only one anomeric effect
present) that can readily convert to the more stable ther-
modynamic spiroketal, as shown in Figure 3. The reaction
pathway is concerted and asynchronous: from the sub-
The anomeric phosphate-mediated pathway was also
examined using the diphenyl catalyst model system, and
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different orientations of the catalyst were explored for this ure 5B shows the progression of product-forming trajecto-
1
2
3
4
5
6
7
8
mechanism. The attack of each phosphate oxygen was ex-
amined, and the lowest energy pathway relevant to this
mechanism is depicted in Figure 4. The initial orientation
of the catalyst is similar to the concerted pathway de-
scribed above, but the alcohol is not positioned such that
ring-closure can readily occur. The formation of the ano-
meric phosphate intermediate instead proceeds through a
concerted asynchronous mechanism. As initial protonation
of the enol ether creates an ionic transition state, and since
the alcohol moiety is further away from the electrophilic
site, attack of the hydrogen-bonded oxygen of the phos-
phate can form an axial bond. The formation of the phos-
phate intermediate has a 20.6 kcal/mol barrier (TS2), and
its syn displacement by the nucleophilic alcohol to afford
the spiroketal has a barrier of 20.7 kcal/mol (TS3, the anti-
phosphate displacement likely involves more than one
phosphate and was not modeled). Once the phosphate in-
termediate is formed, there is not a large preference to the
immediate formation of a thermodynamic compared to a
nonthermodynamic spiroketal. In fact, although Figure 4
shows the sequence for the formation of the thermody-
namic spiroketal, the phosphate could collapse to form a
nonthermodynamic spiroketal (TS4) with a 21.1 kcal/mol
barrier.
ries to the ring-closed structures. Of the 71 runs, which
resulted in product, an average time of 519 fs was required
to form the spiroketal. No persistent oxocarbenium species
were formed in any of the trajectories, including 7 trajec-
tories needed to be run to 1.5 ps in order to complete
product formation. This short timeframe is consistent with
the concerted asynchronous mechanism derived by GSM
without a stable intermediate along the pathway. Addi-
tionally, the trajectories show that the alcohol deprotona-
tion and ring closure occur synchronously, also in agree-
ment with the reaction path from GSM. This occurs due to
the activation of the alcohol by the Lewis basic anionic
oxygen of the catalyst, which quenches the positive charge
build-up on the alcohol oxygen by simultaneously depro-
tonating it while it forms the C-O bond.
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Having established
a concerted yet asynchronous
mechanism for spiroketalization with the model diphenyl
catalyst system, the reactions of substrate 6a and chiral
phosphoric acid 7a were studied next. Specifically, for-
mation of (R)-spiroketal was modeled to determine the
key interactions dictating the stereoselectivity of the reac-
tion. Analogous orientations of the catalyst in the diphenyl
phosphoric acid system were considered. To our delight,
we found a 1.5 kcal/mol difference between the lowest
computed activation barriers of the (R)-7a-catalyzed con-
certed spirocyclization and the (S)-7a-catalyzed, with the
(S)-catalyst chirality being favored (see Figure 6). Since
the (R) spiroketal was the designated simulation product,
this result is in agreement with the chirality of the product
formed in the experiment. Using a temperature of 238 K,
we proceeded to calculate the expected enantiomeric ex-
cess, which is given by
The difference of 4.6 kcal between the concerted and
anomeric phosphate mechanisms suggests that the phos-
phate mechanism is uncompetitive. To determine whether
the concerted mechanism was also operative for 5-
membered ring formation, reactions leading to a 6,5-
spiroketal (21c) were examined. The relevant stationary
points of the PES are shown in the SI. Not surprisingly, the
data shows the concerted mechanism (Ea = 13.8 kcal/mol)
is favored over the anomeric phosphate path (Ea = 22.9
kcal/mol for spiroketal formation by syn- displacement of
the phosphate intermediate). The build-up of positive
charge on the substrate and the asynchronicity of the
changes in bonding are similar to the 6,6-spiroketalization.
Finally, the KIE=0.96, calculated for the concerted mecha-
nism, was in qualitative agreement with the experimental-
ly measured value (KIE=0.85).
∆ꢀ!"
exp
− 1
+ 1
ꢀꢁ
ꢀꢀ =
∆ꢀ!"
ꢀꢁ
exp
where ΔGTS is the energy gap, ꢀ is the gas constant, and ꢀ is
the temperature in Kelvin. The computed enantiomeric
excess is of 92%, which exactly matches the experimental
result.11b
The study of an oxocarbenium-mediated mechanism
proved challenging because repeated efforts to optimize
stationary points for oxocarbenium intermediates resulted
in their collapse to the reactant or product structures. This
observation, however, makes sense in light of the proposed
concerted mechanism for spiroketalization, where the TS
itself is ionic (oxocarbenium-like). Given that an unstable
oxocarbenium-like structure is initially formed along the
concerted path, we turned to molecular dynamics to quan-
tify the lifetime of this structure. If a stable oxocarbenium
intermediate were possible, it should form after protona-
tion of the substrate and be identified by dynamics simula-
tions following the protonation TS. Therefore trajectories
were sampled using quasi-classical initial velocities start-
ing at the concerted TS structure to accurately mimic ex-
perimental conditions (see Computational Details). By
plotting the C-O distance against time for the product’s
new C-O connection, Figure 5A shows how most of the 100
MD runs proceed from the TS to the product. By removing
the trajectories that recrossed to the reactant species, Fig-
While this is a very promising result, it is only accurate
because the intrinsic errors in quantum chemical simula-
tion have largely cancelled one another out. This agree-
ment, however, has been seen in other applications of
quantum chemical methods to a number of stereoselective
transformations.24 The extensive study of the PES by care-
ful sampling of the driving coordinates and the end points
of the strings, which included 5 different approaches of the
catalyst to produce either thermodynamic (2 axial C-O
bonds) or nonthermodynamic (2 equatorial C-O bonds,
and both combinations of 1 axial and 1 equatorial C-O
bond) spiroketals as well as the fact that the comparison
between the lowest energy pathways for each catalyst chi-
rality gives the proper selectivity, gives us confidence in
our method and results.
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Figure 5. Results of the molecular dynamics calculations on the TS of the concerted pathway of the 6,6 spiroketalization of the model
system.
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Each line represents one of the 100 independent runs. A. The new ring’s C-O distance is plotted against time. B. The number of productive
(71), but yet uncollapsed TSs is plotted against time.
Figure 6. Comparison of the activation barriers for the (R) and (S)-7a catalyzed spiroketalization.a
aThe picture depicts the transition state structures. The values in parenthesis correspond to the difference of the sum of Mulliken charges in the enol
ether oxygen and electrophilic carbon with respect to the starting complex.
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Page 12 of 15
namic spiroketal and finally, by means of a ring-flip, to
1
2
3
4
5
6
7
8
the thermodynamic conformation. The relevant station-
ary points on the PES, disregarding the boat-chair spiro-
ketal and the later isomerization to a thermodynamic
product, are shown in Figure 6. While in this case the
conformation of the immediately formed spiroketal is not
vital (its equilibration to a more stable conformer is un-
impeded), in conformationally locked structures it would
be of importance. This mechanism shows how CPA catal-
ysis can be used to form nonthermodynamic spiroketals
with kinetic control. A major difference between the TS
structures, which explains the kinetic origin of the enan-
tioselectivity, is the interaction of the 2,4,6-
triisopropylphenyl groups at the 3 and 3’ position of 7a
with the phenyl rings of the tertiary alcohol of the sub-
strate. Figure 7 shows the quadrant-based frontal per-
spective commonly used in stereochemical models in-
volving CPAs and popularized by Himo25 and Terada26.
From this perspective, the diastereomeric relationship of
the substrate-(R)-TRIP (TSR) and substrate-(S)-TRIP
(TSS) spiroketalization TS is made clear. At the TS, the
substrate is arranged in a way where protonation of the
enol ether can take place, yet the positive charge being
built in the electrophilic carbon is stabilized by its inter-
action with the alcohol oxygen. This is best achieved
when the alcohol appendage adopts a chair-like geome-
try (Figure 7, top left diagram), in preparation for the
asynchronous cyclization, and the phenyl rings are not
located in the bulky quadrants near the catalytic site. To
achieve this, the dihydropyran core is arranged in a dif-
ferent orientation for TSR and TSS. The alcohol-
containing side chain in TSR adopts a less ideal chair-like
geometry due to unfavorable steric interactions between
the phenyl rings of the substrate and the ortho and para
substituents at the aryl groups of the CPA. This is reflect-
ed by a longer distance between the nucleophilic oxygen
and the electrophilic carbon (2.76 Å for TSR and 2.50 Å
for TSS) and a less directed angle for electronic interac-
tion (87° H-O-C angle for TSR and 117° for TSS). Figure 8
provides a perspective focusing on these key steric inter-
actions in TSR. Substitution of the phenyl rings at the
tertiary alcohol for more flexible benzyl groups is ex-
pected to relieve the steric congestion at TSR and result
in a decreased ee, as observed experimentally.
Figure 7. Comparison of concerted asynchronous mechanism
leading to the formation of a (R)-spiroketal involving (S)-7a
(TSS) and (R)-7a (TSR).
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Figure 8. Key steric interactions at TSR between the phenyl
groups at the alcohol appendage of the enol ether and the ortho
and para substituents of the aryl substituents of (R)-7a.
P
O
O
H
H
O
Ph
iPr
Ph
iPr
iPr
A description of the predicted mechanism and its asso-
ciated stereochemical model follows. In the first step of
the predicted concerted asynchronous mechanism, the
catalyst, irrespective of its chirality, is initially oriented
so that the phosphate oxygen hydrogen-bonds with the
tertiary alcohol, while the Brønsted acidic hydrogen is
aligned to add to the enol ether. As with the diphenyl
catalyst model system, protonation of the enol ether oc-
curs at the transition state for both catalyst chiralities.
Also coherent with the diphenyl system, there is consid-
erable build-up of positive charge on the substrate at the
TS when compared to the enol ether-catalyst complex, in
agreement with the experimental data on the mechanism
(Hammet and SKIE experiments). For both catalyst chi-
ralities, deprotonation of the nucleophilic oxygen and
spirocyclization occurs simultaneously following proto-
nation, as observed with diphenyl hydrogen phosphate
model system. The cyclization occurs through a six-
membered chair geometry to produce an initial boat-
chair spiroketal, that initially relaxes to a nonthermody-
CONCLUSION
This article describes the development of chiral phos-
phoric acid-catalyzed stereoselective spiroketalizations
as well as mechanistic and computational studies of the
mechanistic origins of catalysis. The commercially avail-
able TRIP catalysts were found to be effective promoters
of the enantioselective formation of chiral spiroketals
and diastereoselective formation of nonanomeric spiro-
ketals. The reactions were found to proceed under kinet-
ic control, where nonpolar solvents (i.e. pentane) and
anhydrous conditions (4 Å MS as additives) were found
to be essential for attaining high levels of stereocontrol.
The experimental studies were designed to differentiate
between the SN1-like, SN2-like and covalent phosphate
intermediate-based mechanisms. The chiral phosphoric
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We thank Dr. Yong Guan for the help with the synthesis of
substrates 20 and 21. We also thank David Braun for compu-
tational support.
acid-catalyzed spiroketalization of deuterium-labeled
1
2
cyclic enol ethers revealed a highly diastereoselective
syn-selective protonation/nucleophile addition thus rul-
ing out long-lived oxocarbenium intermediates. At the
same time, the intermolecular equivalent of these reac-
tions (i.e. tetrahydropyranylation with D3-labeled dihy-
dropyrane) was found to proceed unselectively, presum-
ably by a different (i.e. SN1-like) mechanism. Hammett
analysis of the reaction kinetics revealed positive charge
accumulation in the transition state of the rate-limiting
step (r = –2.9), and the KIE for the spiroketalization with
D-labeled substrates was determined to be 0.85. The fol-
lowing in-depth computational studies on the phosphoric
acid catalyzed spiroketalization mechanism suggest that
a single step asynchronous mechanism is responsible for
the observed experimental data. This mechanism fully
exploits the bifunctionality of the catalyst and is novel for
this type of transformations.15 The anomeric phosphate
pathway was shown to have higher energy barriers. Ad-
ditionally, molecular dynamics simulations resulted in
average lifetime of oxocarbenium structures average
lifetime to be 519 ± 240 fs, which do not support stable
ionic intermediate formation. The stereoselectivity of the
reaction was examined in a complete system, and the key
interactions which favor the experimentally observed
results were identified to be linked with the 3,3` aryl sub-
stituents of the CPA and the substituents at the alcohol
group of the substrate. This stereochemical model was
highly consistent with the observed experimental results
in terms of the selectivity and the levels of enantiocon-
trol, and his will allow the future catalyst design to over-
come the procedure limitations and expand its scope, as
well as the analysis of related reactions, such as intermo-
lecular chiral phosphoric acid catalyzed ace-
tal/aminal/hemiaminal ethers formation from enol
ethers. Finally, the applicability of the growing string
methods for the analysis of hydrogen-bond organocata-
lytic transformations involving large systems was
demonstrated, as was its usefulness in the proposal of
the underlying mechanism and in the explanation of the
stereocontrol observed.
3
4
5
6
7
8
9
DEDICATION
We dedicate this paper to prof. James D. White on the occa-
sion of his 80th birthday.
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ASSOCIATED CONTENT
The experimental procedures, detailed description of
computational studies, 1H, 2H and 13C NMR spectra and
HPLC traces are available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*nagorny@umich.edu, paulzim@umich.edu
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This work has been supported by the National Science Foun-
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ACKNOWLEDGMENT
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D
O
O
O
concerted
asynchronous
(S)–TRIP
D
O
KIE = 0.85
Hammett
ρ = –2.9
D
H
R
O
H
HO
O
R
syn- H-O delivery
> 99 : 1 dr
H
R
R
O
R
P
T1/2 = 520 fs
R
RO
OR
Empty
quadrant
Ph
Bulky
quadrant
Ph
O
H
O
Growing String Method +
Simultaneous Search for TS
and reaction paths
O
P
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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59
60
O
Bulky
quadrant
Empty
quadrant
H
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