Global Diastereoconvergence in the Ireland-Claisen Rearrangement of Isomeric Enolates: Synthesis of Tetrasubstituted α-Amino Acids

Article abstract of DOI:10.1021/jacs.0c11480

A dual experimental/theoretical investigation of the Ireland-Claisen rearrangement of tetrasubstituted α-phthalimido ester enolates to afford α-tetrasubstituted, β-trisubstituted α-amino acids (generally >20:1 dr) is described. For trans allylic olefins, the Z- and E-enol ethers proceed through chair and boat transition states, respectively. For cis allylic olefins, the trend is reversed. As a result, the diastereochemical outcome of the reaction is preserved regardless of the geometry of the enolate or the accompanying allylic olefin. We term this unique convergence of all possible olefin isomers global diastereoconvergence. This reaction manifold circumvents limitations in present-day technologies for the stereoselective enolization of α,α-disubstituted allyl esters. Density functional theory paired with state-of-the-art local coupled-cluster theory (DLPNO-CCSD(T)) was employed for the accurate determination of quantum mechanical energies.

Full text of DOI:10.1021/jacs.0c11480

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Global Diastereoconvergence in the Ireland−Claisen Rearrangement
of Isomeric Enolates: Synthesis of Tetrasubstituted α‑Amino Acids
Tyler J. Fulton,∥ Alexander Q. Cusumano,∥ Eric J. Alexy, Yun E. Du, Haiming Zhang, K. N. Houk,*
and Brian M. Stoltz*
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ABSTRACT: A dual experimental/theoretical investigation of the
Ireland−Claisen rearrangement of tetrasubstituted α-phthalimido
ester enolates to afford α-tetrasubstituted, β-trisubstituted α-amino
acids (generally >20:1 dr) is described. For trans allylic olefins, the
Z- and E-enol ethers proceed through chair and boat transition
states, respectively. For cis allylic olefins, the trend is reversed. As a
result, the diastereochemical outcome of the reaction is preserved
regardless of the geometry of the enolate or the accompanying
allylic olefin. We term this unique convergence of all possible olefin
isomers global diastereoconvergence. This reaction manifold circum-
vents limitations in present-day technologies for the stereoselective
enolization of α,α-disubstituted allyl esters. Density functional
theory paired with state-of-the-art local coupled-cluster theory
(DLPNO-CCSD(T)) was employed for the accurate determination of quantum mechanical energies.
both diastereomeric series of rearrangement products, the
utilization of allylic esters with highly enantioenriched or
enantiopure α-stereocenters is required and each substrate
requires optimization of the chiral base. Crimmins and co-
workers utilized a chiral auxiliary approach to prepare chiral,
nonracemic α-methyl-β-hydroxy allylic esters toward the
synthesis of briarane natural products (Figure 1B).5 In this
approach, enolization selectivity is imparted by chelation and
steric approach control to provide Ireland−Claisen rearrange-
ment products with generally excellent diastereoselectivity.
More recently, Zakarian and co-workers investigated the
diastereodivergent Ireland−Claisen rearrangement of tetrasub-
stituted α-alkoxy ester enolates toward the synthesis of α-
alkoxy carboxylic acids (Figure 1C).6 While the chelation-
controlled, kinetic Z-selective enolization of α-alkoxy esters has
been well established,7 Zakarian and co-workers found that an
E-selective enolization could be achieved with a judicious
choice of base and solvent based on prior research from
Langlois and co-workers.8 While a variety of α-alkoxy
carboxylic acid products were obtained with good to excellent
diastereoselectivity, the level of control over enolate geometry
INTRODUCTION
■
For over 40 years, the Ireland−Claisen rearrangement has been
a mainstay for the construction of a diversity of carbon−carbon
bonds in organic synthesis.1 The ubiquity of the Ireland−
Claisen rearrangement can be attributed to the relative ease of
accessing the requisite allylic ester and the robust and
predictable stereochemical outcome of the rearrangement.
Consequently, the Ireland−Claisen rearrangement has been an
indispensable tool for the construction of sterically encum-
bered vicinal stereogenic centers. Despite the utility of the
Ireland−Claisen rearrangement, one longstanding challenge
has been the implementation of fully substituted acyclic allyl
ester enolates derived from α,α-disubstituted esters. This is
presumably a consequence of the difficulty in controlling the
enolate geometry in tetrasubstituted ester-derived systems.
The Ireland−Claisen rearrangement typically proceeds
through a predictable and well-defined chair-like transition
state; thus, E- and Z-enolate geometries lead to diastereomeric
products, necessitating a highly selective enolization protocol
for efficient diastereoselection.
Few examples of fully substituted, acyclic enolates in highly
diastereoselective Ireland−Claisen rearrangements have been
reported to date.2 Zakarian and co-workers established the first
effective protocol for the selective enolization of chiral α,α-
disubstituted esters utilizing chiral Koga-type3 bases to impart
E/Z enolization selectivity (Figure 1A).4 Although this
protocol enables the selective generation of either E- or Z-
tetrasubstituted ester enolates under mild conditions to access
Received: November 1, 2020
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A

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investigation of the Ireland−Claisen rearrangement of
tetrasubstituted α-phthalimido ester enolates toward the
synthesis of non-natural tetrasubstituted α-amino acid
derivatives bearing vicinal stereogenic centers (Figure 1D).
RESULTS AND DISCUSSION
■
Quantum Mechanical Evaluation of the Diastereo-
convergent Ireland−Claisen Rearrangement. Quantum
mechanics (QM) calculations were carried out in order to
probe the energetic requirements for a diastereoconvergent
transformation. A multilevel approach was employed in which
geometries, thermodynamic corrections, and solvation free
energies are obtained via density functional theory (DFT) with
final electronic energies obtained from calculations with
domain-based local pair natural orbital coupled-cluster theory
(DLPNO-CCSD(T)). Reported energies are relative Gibbs
free energies in kcal/mol calculated at 298.15 K with the
DLPNO-CCSD(T)/cc-pVTZ/SMD(toluene)//B3LYP-
D3(BJ)/6-31G(d) level of theory. Throughout the text, signed
ΔΔG⧧ values defined as ΔG⧧(boat) − ΔG⧧(chair) are
provided. All computations were carried out using the
ORCA program.9 Full computational details as well as
comparisons between DFT and coupled-cluster methods are
included in the Supporting Information.
In a fully simplified model system, i.e. the trimethylsilyl enol
ether derived from allyl acetate (1), an energetic preference of
2.6 kcal/mol is observed for the chair-like (TS1) over the boat-
like transition state (TS2) (Figure 2A, D entry 1). A
diastereoconvergent rearrangement will occur in the case of
E/Z mixtures of tetrasubstituted enolates when the sum of the
interactions between the substituents for one enolate geometry
overcomes the intrinsic preference for a chair-like transition
state to the extent that the boat-like transition state is
significantly favored. The groups of Houk, Neier, and Aviyente
described a preference for a boat-like transition state in the
Ireland−Claisen rearrangement of cyclohexenyl esters which
was attributed to steric interactions between the enolate and
cyclohexenyl fragments.10 In the case of acylic, tetrasubstituted
enol ethers, these interactions are diminished.
We examined stereoconvergence in the Ireland−Claisen
rearrangement in the context of the synthesis of valuable
tetrasubstituted α-amino acid building blocks. The α-
phthalimido group was chosen as a stable, easily removed,
bis-protected α-amine.11 Introduction of the α-phthalimido
group imparts a minimal effect on the chair/boat selectivities,
with a preference for the chair-like (TS3/TS5) over boat-like
transition state (TS4/TS6) for both E- and Z-silyl enol ethers
((E/Z)-3) of 3.4 and 2.4 kcal/mol, respectively (Figure 2B, D
entry 2). While introduction of substitution in the form of a
phenyl group at the terminus of the allylic olefin slightly
increases the preference for the chair-like transition state from
(Z)-5 to 4.2 kcal/mol, the boat-like transition state is 1.0 kcal/
mol lower in energy than the chair-like transition state from
enol ether (E)-5 (Figure 2B, D entry 3).12 This reversal in
preference for chair-like versus boat-like transition state for the
α-phthalimido E-silyl enol ethers is further exacerbated with
additional substitution of the silyl enol ether. In fact, the boat-
like transition state (TS14) derived from the corresponding α-
phenyl-α-phthalimido E-silyl enol ether ((E)-8) is computed
to be 3.8 kcal/mol lower in energy than its chair counterpart
(TS13) (Figure 2B, D entry 4).
Figure 1. Stereoselective Ireland−Claisen rearrangements of fully
substituted acyclic α,α-disubstituted esters.
is highly substrate dependent, particularly for E-selective
enolization.
We address the limitations of enolate geometry control by
developing a system wherein both enolate geometries converge
to a single diastereomer of the product, rendering the
enolization selectivity inconsequential (Figure 1D). This was
accomplished in the context of tetrasubstituted amino acid
synthesis wherein intramolecular interactions of an α-
phthalimide group with an E-phenyl-substituted allyl olefin
serves to overturn the inherent preference for the chair-like
transition state from the E-silyl enol ether (ΔΔG⧧ = −3.8 kcal/
mol). In contrast, these interactions reinforce the energetic
preference for the chair-like transition state from the Z-silyl
enol ether (ΔΔG⧧ = 5.5 kcal/mol). Consequently, in the case
of a Z-phenyl-substituted allyl olefin, the E-silyl enol ether
rearranges via a chair-like transition state, while from the Z-silyl
enol ether a boat-like transition state is favored.
The ability to incorporate an enantioenriched allylic
stereogenic center in the Ireland−Claisen rearrangement
allows for the transfer of chirality with generally excellent
stereochemical fidelity. We demonstrate that chirality transfer
is conserved within the divergent transition state preference
from E- and Z-silyl enol ethers. In this study, we detail the
computational design and modeling and experimental
In contrast, high levels of selectivity for the chair-like
transition state are anticipated for the fully substituted Z-silyl
B
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Figure 2. ΔΔG⧧ (in kcal/mol) defined as ΔG⧧(boat) − ΔG⧧(chair): (A) innate preference for chair-like TS; (B) effect of substitution pattern on
diastereoconvergence in the Ireland−Claisen rearrangement; (C) probing α-alkyl substitution; (D) diastereoconvergence, compound labels, and
a
tabulated relative free energies. Aabsolute stereochemistry drawn arbitrarilyopposite enantiomeric series than TS-B/D.
a
Table 1. Initial Investigation into Enolization Conditions
Table 2. Enolate Trapping Experiments
b
c
entry
base
yield 15a (%)
dr
yield (%)
d
1
2
3
LiHMDS, Me2NEt
LiHMDS
KHMDS
92
90
90
>20:1
>20:1
>20:1
entry
base
A
B
d
1
2
3
LiHMDS, Me2NEt
LiHMDS
KHMDS
16
43
55
23
27
24
a
Conditions: 1.00 mmol of 14, toluene (10 mL), base (2.00 mmol).
b
c
d
1
Isolated yields. Determined by H NMR analysis. Me2NEt (2.00
a
Conditions: 1.00 mmol of 16, toluene (10 mL), base (2.00 mmol).
mmol).
b
c
d
Isolated yields. Determined by 1H NMR analysis. Me2NEt (2.00
mmol).
enol ether ((Z)-8), with the chair-like transition state (TS11)
favored over the boat-like transition state (TS12) by 5.5 kcal/
mol (Figure 2B, D entry 4). As a result, for the fully substituted
system, the diastereoselectivity of the ensuing Ireland−Claisen
rearrangement is anticipated to be independent of the E/Z
selectivity in the enolization and trapping of the requisite
tetrasubstituted silyl enol ether. Note that the diastereocon-
vergent effect is significantly less pronounced when the α-
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Figure 3. Origins of diastereoselectivity in the diastereoconvergent Ireland−Claisen rearrangement of (E/Z)-8. Relative free energies are given in
kcal/mol. The surfaces depicted are solvent-excluded surfaces from van der Waals radii with a probe radius of 1.4 Å.
phenyl group is substituted for an α-ethyl substituent (Figure
2C, D entry 5).13
enolization conditions (vide supra). These trapping experi-
ments failed due to the inability to form or isolate the resulting
enol ethers; however, moderate yields of allyl enol carbonate
isomers A and B were obtained with allyl chloroformate as an
O-acylating reagent (Table 2). In each enolization and O-
acylation control, a mixture of two isomeric enol carbonates
was generated in varying E/Z ratios. Despite variable yields and
selectivities, these results demonstrate that, under each set of
nonequilibrating enolization conditions, a mixture of enolates
is generated. These yields do not necessarily reflect the true
enolization selectivity due to the difficulty of O-acylation of the
in situ generated enolate. Although the reaction yield and
diastereoselectivity of the Ireland−Claisen rearrangement of
cinnamyl ester 14 is consistent for various enolization
methods, our study proceeded with 1:1 LiHMDS/Me2NEt
as the standard enolization procedure, as in practice this
affords the cleanest reaction profile and most homogeneous
reaction mixturenecessitating only an acid/base extraction
to afford the rearranged products in high purity in most cases.
Origins of Stereoselectivity in Diastereoconvergent
Mechanism. The invariance of olefin geometry of the in situ
generated trimethylsilyl enol ethers in the diastereomeric
selectivity of the subsequent Ireland−Claisen rearrangement to
15a suggests that a diastereoconvergent mechanism is indeed
occurring. Kinetic enolization of 14 with LiHMDS/Me2NEt
and trapping with TMSCl affords a mixture of E/Z silyl enol
ethers (Z)-8 and (E)-8. Upon warming from −78 °C, Z-enol
ether (Z)-8 undergoes a [3,3]-sigmatropic rearrangement
Initial Experimental Investigations. An Ireland−Claisen
rearrangement of the computationally modeled α-phthalimido
cinnamyl ester 14 leads to >20:1 diastereoselection with
several different enolization conditions (Table 1). Enolization
conditions of 1:1 LiHMDS/Me2NEt (entry 1) were originally
developed by Gosselin, Zhang, and co-workers14 for the highly
selective enolization of α,α-disubstitued aryl ketones. Addi-
tionally, Stoltz and Zhang demonstrated that these conditions
can be applied to the selective enolization and trapping of a
variety of acyclic α-aryl substituted carboxylic acid derivatives,
including α-ethyl-α-phenyl tert-butyl, phenyl, and ethyl
esters.15 Enolization with LiHMDS (entry 2) and KHMDS
(entry 3) without additives results in identical yields and
diastereoselectivity. Notably, phthalimide-protected amino
acid 15a is obtained without column chromatography and
the relative stereochemistry was confirmed unambiguously by
X-ray crystallography, matching the computationally predicted
outcome.16
Direct observation of and quantification of the ratio of
enolate geometries formed in situ proved challenging due to
the facile nature of the rearrangement at low temperature and
heterogeneous reaction mixture. Thus, the analogous dihydro-
α-phthalimide-substituted ester 16 was examined as a
surrogate to 14 that is incapable of undergoing rearrangement.
A variety of kinetic enolate trapping reagents (e.g., TMSCl,
TMSOTf, Ts2O, Tf2O) were studied employing the same
D
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Figure 4. Geometric perturbations resulting from the out-of-plane
rotation of the phthalimide moiety. Surfaces depicted are solvent-
excluded surfaces from van der Waals radii with a probe radius of 1.4
Å.
preferentially through the chair-like transition state TS11
(ΔΔG⧧ = 5.5 kcal/mol), while the E-enol ether (E)-8
rearranges predominantly via the boat-like transition state
TS14 (ΔΔG⧧ = −3.8 kcal/mol), yielding tetrasubstituted
product 9 as a single diastereomer. With barrier heights of 19.6
and 19.9 kcal/mol for the rearrangement of (Z)-8 and (E)-8,
respectively, no appreciable resolution of the E/Z-silyl enol
ether mixture is anticipated. Furthermore, these barrier heights
are consistent with the experimentally observed reaction times
considering gradual warming from −78 to 20 °C.
An initial inspection of TS11−TS14 reveals a commonality
in which the planar phthalimide motif of the enolate fragment
is rotated out of the plane defined by the olefin of the enolate
(Figure 3). On examination of the generality of this effect, the
E- and Z-olefin isomers of both the simplified trisubstituted
analogue 17 and tetrasubstituted enolate 18, corresponding to
the enolate fragments encountered in TS11−TS14, were
optimized as the enolate anion (Figure 4). Indeed, a similar
torsion around the N−C(olefin) bond is observed. The
simplified trisubstituted enolates (E)-17 and (Z)-17 present
optimal dihedral angles, defined between the planar enolate
and phthalimide groups, of 55° and 53°, respectively. The
rotation is further accentuated with the introduction of an aryl
substituent as in the case of α-phenyl tetrasubstituted enolates
(E)-18 and (Z)-18 with dihedral angles of 85° and 66°,
respectively (Figure 4). As is observed in TS11−TS14, the α-
phenyl substituent remains nearly coplanar with the enolate
fragment. This perturbation is likely the result of the steric/
electrostatic repulsion between the phthalimide oxygen and
enolate oxygen atoms presenting a larger destabilizing force in
comparison to the electronic stabilization gained through
Figure 5. Global stereoconvergence in the Ireland−Claisen rearrange-
ment of Z- and E-cinnamyl compounds 14 and 19. Relative free
energies are given in kcal/mol.
further conjugation with the enolate π system as achieved with
coplanarity.
When one considers that the planar enolate and allyl
fragments adopt a nearly parallel orientation in the transition
state, the out-of-plane phthalimide substituent of the enolate
scaffold is well poised to interact with substitution on the allyl
fragment. Hence, the phthalimide group plays a key role in
determining the stereochemical outcome of the reaction.
Specifically, in the case of Z-silyl enol ether (Z)-8, eclipsing
interactions between the equatorial, out-of-plane phthalimide
group and the phenyl ring of the cinnamyl fragment are
encountered in the boat-like transition state (TS12), resulting
in a distortion of the transition state geometry. This adverse
NPhth−Ph(cinnamyl) eclipsing interaction is largely relieved
in the chair-like transition state (TS11). Hence, a substantial
preference for the chair-like transition state (TS11) of 5.5
kcal/mol is afforded. In contrast, in the pericyclic transition
states derived from E-silyl enol ether (E)-8, the phthalimide
occupies an axial orientation. As a result, the chair-like
transition state (TS13) bears the costly NPhth−Ph(cinnamyl)
eclipsing interaction, which is greatly reduced in the boat-like
transition state (TS14). The net interactions are substantial
enough in magnitude to not only overcome the inherent
preference for a chair-like transition state but also favor the
boat-like transition state by 3.8 kcal/mol.
E
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total, the diastereoselectivity of the transformation is invariant
to any combination of the E/Z geometry of both olefins of the
in situ generated silyl enol ether. We term this effect global
diastereoconvergencei.e. all possible stereoisomers derived
from permutations of stereochemical elements of the reagent
lead to the formation of a single stereoisomer of the product.
To the best of our knowledge, this constitutes the first example
of a globally diastereoconvergent Ireland−Claisen rearrange-
ment of an acyclic, tetrasubstituted silyl enol ether.
A powerful feature of the Ireland−Claisen rearrangement is
its ability to relay stereochemical information from a chiral
center in the substrate to the absolute stereochemistry of the
rearranged product.18 In contrast to previous achiral examples,
the approach of a chiral cinnamyl fragment from either the Re
or Si face of the enol ether gives rise to diastereomeric
transition states. For a mixture of E/Z silyl enol ethers this
gives rise to eight unique transition states, which we modeled
with regard to enantioenriched α-phthalimido ester 21 (Figure
6).
Analogous to our previous discussion, the Z- and E-silyl enol
ethers derived from 21 preferentially rearrange via chair-like
(TS21) and boat-like (TS28) transition states, respectively.
While the NPhth−Ph(cinnamyl) eclipsing interaction drives
the chair/boat selectivity in each silyl enol ether geometry,
differentiation between the two diastereotopic chair-like (TS21
and TS23) and boat-like (TS26 and TS28) transition states
must be achieved for effective chirality transfer. This
component of the stereoselectivity arises in the energetic
differences between axial and equatorial orientations of the
methyl group (Figure 6). For the relevant chair-like transition
states (TS21 and TS23) derived from the Z-enol ether of 21,
the 1,3-diaxial interactions imposed from the methyl group
occupying an axial orientation carry an energetic penalty of 4.3
kcal/mol. Likewise, for the pair of boat-like transition states in
the rearrangement of the E-enol ether (TS26 and TS28) a
preference of 1.4 kcal/mol is found for the equatorial
orientation of the methyl group. As a result, the system
exhibits diastereoconvergence with respect to chirality transfer.
To experimentally demonstrate this, we synthesized the
enantioenriched α-phthalimido ester from the requisite
alcohol, in turn prepared via a Corey−Bakshi−Shibata
(CBS) reduction. Indeed, nonselective enolization, trapping
as the TMS enol ether, and warming to 20 °C afforded the
desired α,α-disubstituted acid. The crude acid was sub-
sequently transformed to methyl ester 22, which was isolated
in 86% yield over two steps, with >20:1 dr and with complete
retention of the enantiomeric excess (95% ee) (Figure 6).
Substrate Scope of the Diastereoconvergent Ire-
land−Claisen Rearrangement. A variety of differentially
substituted α-aryl, α-phthalimido esters were examined in the
Ireland−Claisen rearrangement to explore the scope of this
transformation (Table 3). The reaction was highly compatible
with a broad scope of differentially substituted esters, affording
tetrasubstituted amino acid derivatives bearing an adjacent
tertiary stereogenic center with generally >20:1 diastereose-
lectivity. Additionally, the rearrangement could be performed
with the standard substrate 14 on a 5.00 g (12.6 mmol) scale
with identical yield and diastereoselectivity. In some cases, the
carboxylic acid products were transformed into the corre-
sponding methyl ester to circumvent challenges in substrate
acid/base purification or decomposition of the parent
carboxylic acid. With respect to the α-aryl group, a variety of
both electron-rich and electron-deficient aryl rings were
Figure 6. Chirality transfer in the diastereoconvergent Ireland−
Claisen rearrangement. Relative free energies (in kcal/mol) of the
eight possible stereochemically distinct transition states for the
rearrangement of the E- and Z-silyl enol ethers derived from 21.
To further highlight the role that the phthalimide moiety has
in the stereocontrol of the rearrangement, control calculations
were carried out in which the α-phthalimide of (E/Z)-8 is
replaced with an ethyl group (see the Supporting Information
for details). An analysis analogous to that of TS11−TS14
revealed that the magnitude of ΔΔG⧧ of the chair/boat
selectivity is reduced for both enolate geometries. Critically,
with the α-phthalimide replaced with an α-ethyl substituent,
the key diastereoconvergence of the transformation is lost, as
the chair-like transition state is favored for both E- and Z-silyl
enol ethers by 1.5 and 1.2 kcal/mol, respectively.17 Hence, in
addition to being individually less selective (calculated
maximum dr values of 13:1 and 8:1), the overall
diastereoselectivity is highly reliant on the E/Z selectivity of
the initial enolization conditions.
On the basis of our working stereochemical model, if the
NPhth−Ph(cinnamyl) eclipsing interaction is indeed the
dominant element of stereocontrol, then inversion of the
axial/equatorial positioning of the phenyl group of the
cinnamyl fragment, i.e. employing the Z-cinnamyl ester (19),
leads to an inversion in the chair/boat transition state
preference for both of the corresponding E- and Z-silyl enol
ethers. In this case, the double inversion in stereoselectivity
affords the diastereomer of product 15a identical with that
obtained from E-cinnamyl ester 14.
With respect to the E-cinnamyl system, a global inversion in
the chair/boat transition state preference for both E/Z silyl
enol ethers is predicted (Figure 5). The Z-silyl enol ether (Z)-
20 preferentially rearranges through a boat-like transition state
(TS19) (ΔΔG⧧ = −1.0 kcal/mol), while for E-silyl enol ether
(E)-20, the chair-like transition state (TS20) is preferred
(ΔΔG⧧ = 5.2 kcal/mol). As anticipated, the Ireland−Claisen
rearrangement of Z-cinnamyl ester 19 affords the same
diastereomeric outcome as that with E-cinnamyl ester 14. In
F
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a
Table 3. Scope of the α,α-Disubstituted α-Phthalimido Ester Ireland−Claisen Rearrangement
a
Reactions were performed on a 1.00 mmol scale unless specified otherwise; yields are of isolated products. Diastereomeric ratios were determined
by 1H NMR spectroscopy. In some cases, the crude products were converted to the corresponding methyl ester for isolation (see the Supporting
Information for details). The relative configuration was assigned by single-crystal X-ray diffraction of 15a; all others are assigned by analogy.
b
c
Reaction performed on a 5.00 g (12.6 mmol) scale. Rearrangement performed at 40 °C.
tolerated in excellent yields. Chloro and methoxy ortho-
substitutions were also well tolerated in the rearrangement,
affording highly sterically encumbered amino acid derivatives
29 and 30 in excellent yields with >20:1 dr. Variation of the
G
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was observed with (S)-cyclohex-2-en-1-ol derived ester 49.
The relative and absolute stereochemistry of cyclohexene 50
was determined by single-crystal X-ray diffraction.
Derivatizations of the Ireland−Claisen Rearrange-
ment Product. Derivatization of the Ireland−Claisen
rearrangement product 15a afforded a range of densely
functionalized small molecules (Figure 8). A Curtius rearrange-
ment in t-BuOH provided the bench-stable, differentially
protected aminoacetal 51 in 82% yield. Iodolactonization
afforded lactone 52 in an excellent 91% yield as a single
diasteromer with the relative configuration being confirmed by
single-crystal X-ray diffraction. Ozonolysis with reductive
quenching provided cyclized product 53 in 11:1 dr and 86%
yield. Methyl esterification with MeI/K2CO3 generated ester
54 in an excellent 90% yield. Removal of the phthalimide
proved challenging under standard hydrazine-mediated proto-
cols due to competitive olefin reduction and slow phthalhy-
drazide removal. A modified Ganem protocol19 reported by
Davies20 effected semireduction of the phthalimide. Methyl
esterification followed by AcOH-mediated phthalide removal
afforded α-amino acid methyl ester 55.
Figure 7. Ireland−Claisen rearrangement of tetrasubstituted α-
phthalimido esters with alkyl-substituted allyl esters.
CONCLUSIONS
■
We have computationally modeled and experimentally
developed a globally diastereoconvergent Ireland−Claisen
rearrangement of α-phthalimido esters that is invariant to the
geometry of the silyl enol ether and allylic ester olefin. A local
coupled-cluster theory (DLPNO-CCSD(T)) and DFT multi-
level approach was employed for the accurate determination of
quantum mechanical energies. The scope of the rearrangement
is broad with respect to aryl and heteroaryl substitution, and a
variety of α-phthalimide-protected α-tetrasubstituted amino
acids bearing a vicinal tertiary stereogenic center are isolated
with generally excellent (>20:1) diastereoselection in good to
excellent yields. Additionally, transfer of chirality with
stereodefined α-phthalimido esters affords rearrangement
products with excellent retention of chiral information. A
range of densely substituted small molecules can be readily
prepared from the representative rearrangement product 15a.
Further examination of the Ireland−Claisen rearrangement in
other classes of tetrasubstituted silyl enol ethers is currently
under way.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11480.
■
Figure 8. Derivatizations of the Ireland−Claisen rearrangement
product 15a.
sı
allylic olefin aryl group was also well tolerated, providing
differentially substituted β-aryl groups in high yield and
diastereoselection. Methyl ortho-substitution was also well
tolerated, affording carboxylic acid 37 as a single diasteromer
in 79% yield. In addition to these substrates, a variety of
different heterocycles were incorporated, affording rearrange-
ment products in generally >20:1 dr and moderate to excellent
yield.
While a broad scope of rearrangement products could be
prepared by utilizing this diastereoconvergent methodology,
alkyl-substituted allylic esters proved to be challenging
substrates (Figure 7). The E-hexenyl ester 45 afforded methyl
ester 46 in 2.3:1 dr. A modest improvement in diastereose-
lectivity is observed with Z-pentenyl ester 47 which was
isolated as methyl ester 48 in 3.7:1 dr. On the other hand,
excellent diastereoselectivity and enantioretention (>99% ee)
Computational details, materials and methods, list of
abbreviations, Ireland−Claisen Rearrangements of α-
phthalidomido esters, Ireland−Claisen rearrangement of
(Z)-3-phenylallyl 2-(1,3-dioxoisoindolin-2-yl)-2-phenyl-
acetate (19), Ireland−Claisen rearrangements of Sub-
strates Relevant to Figure 2, product derivatizations,
preparation of allyl esters, investigation of enolization
selectivity, X-ray crystallographic data for 15a, 50, and
52, and NMR and IR spectra of new compounds (PDF)
QM energies (XLSX)
Cartesian coordinates of the calculated structures (ZIP)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
H
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Article
AUTHOR INFORMATION
REFERENCES
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■
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Corresponding Authors
K. N. Houk − Department of Chemistry and Biochemistry,
University of California, Los Angeles, California 90095,
United States; orcid.org/0000-0002-8387-5261;
Email: houk@chem.ucla.edu
Brian M. Stoltz − The Warren and Katharine Schlinger
Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United
States; orcid.org/0000-0001-9837-1528; Email: stoltz@
caltech.edu
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Tyler J. Fulton − The Warren and Katharine Schlinger
Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United
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Alexander Q. Cusumano − The Warren and Katharine
Schlinger Laboratory for Chemistry and Chemical
Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States
Eric J. Alexy − The Warren and Katharine Schlinger
Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United
States
Yun E. Du − The Warren and Katharine Schlinger Laboratory
for Chemistry and Chemical Engineering, Division of
Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, California 91125, United States
Haiming Zhang − Small Molecule Process Chemistry,
Genentech, Inc., South San Francisco, California 94080,
United States; orcid.org/0000-0002-2139-2598
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11480
Author Contributions
∥T.J.F. and A.Q.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Stereoselective Route to a Fumagillin and Ovalicin Synthetic
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■
We thank the NIH-NIGMS (R01GM080269), NSF Grant
CHE-1764328, the Gordon and Betty Moore Foundation, and
Caltech for financial support. We thank the Caltech High
Performance Computing Center for support. E.J.A. thanks the
National Science Foundation for a predoctoral fellowship. We
thank Dr. David VanderVelde (Caltech) for NMR expertise.
Dr. Scott Virgil (Caltech Center for Catalysis and Chemical
Synthesis) is thanked for instrumentation and SFC assistance.
Dr. Michael Takase (Caltech) and Lawrence Henling
(Caltech) are acknowledged for X-ray analysis. We acknowl-
edge the X-ray Crystallography Facility in the Beckman
Institute at Caltech and a Dow Next Generation Instrumenta-
tion Grant. Alexandra Beard (Caltech) is acknowledged for
initial studies on phthalimide removal strategies. This manu-
script is dedicated to our friend and colleague Professor
Michael Krout (Bucknell University).
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Computational Study of Factors Controlling the Boat and Chair
I
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Article
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(12) Experimentally, this reaction did not provide the desired
product (see the Supporting Information for details):
.
(13) Experimentally, a 2.7:1 dr is obtained (see the Supporting
Information for details):
.
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(16) Similar products in the opposite diasteromeric series have been
prepared previously by iridium/phase transfer catalysis: Su, Y.-L.; Li,
Y.-H.; Chen, Y.-G.; Han, Z.-Y. Ir/PTC Cooperatively Catalyzed
Asymmetric Umpolung Allylation of α-imino Ester Enabled Synthesis
of α-quaternary Amino Acid Derivatives Bearing Two Vicinal
Stereocenters. Chem. Commun. 2017, 53, 1985−1988.
(17) Experimentally, a 2.9:1 dr is obtained (see the Supporting
Information for details):
.
(18) For relevant reviews on the Ireland−Claisen rearrangement,
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J
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