Enantioselective Synthesis of α-Allyl Amino Esters via Hydrogen-Bond-Donor Catalysis

Article abstract of DOI:10.1021/jacs.9b05556

We report a chiral-squaramide-catalyzed enantio- and diastereoselective synthesis of α-allyl amino esters. The optimized protocol provides access to N-carbamoyl-protected amino esters via nucleophilic allylation of readily accessible α-chloro glycinates. A variety of useful α-allyl amino esters were prepared, including crotylated products bearing vicinal stereocenters that are inaccessible through enolate alkylation, with high enantioselectivity (up to 97% ee) and diastereoselectivity (>10:1). The reactions display first-order kinetic dependence on both the α-chloro glycinate and the nucleophile, consistent with rate-limiting C-C bond formation. Computational analysis of the uncatalyzed reaction predicts an energetically inaccessible iminium intermediate, and a lower energy concerted S_N2 mechanism.

Full text of DOI:10.1021/jacs.9b05556

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Communication
Enantioselective Synthesis of #-Allyl Amino
Esters via Hydrogen-Bond Donor Catalysis
Andrew J. Bendelsmith, Seohyun Chris Kim, Masayuki Wasa, Stephane P. Roche, and Eric N. Jacobsen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05556 • Publication Date (Web): 07 Jul 2019
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Enantioselective Synthesis of α-Allyl Amino Esters via Hydrogen-
Bond-Donor Catalysis
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Andrew J. Bendelsmith,†,‡ Seohyun Chris Kim,†,‡ Masayuki Wasa,‡ Stéphane P. Roche,§ Eric N. Jacob-
sen*,‡
‡ Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
§ Department of Chemistry & Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, United States
Supporting Information Placeholder
the ready accessibility of N-carbamoyl -chloro amino esters as α-imino
ester equivalents.14,15 The products resulting from the proposed nucleo-
philic allylation protocol would possess readily cleavable carbamate pro-
tecting groups, facilitating further manipulations.16 Herein, we report
the highly enantioselective and diastereoselective synthesis of α-allyl
amino esters via anion-abstraction catalyzed addition of allylsilane and
allylstannane nucleophiles to N-carbamoyl-α-chloro amino esters.
ABSTRACT: We report a chiral-squaramide-catalyzed enantio- and di-
astereoselective synthesis of α-allyl amino esters. The optimized proto-
col provides access to N-carbamoyl-protected amino esters via nucleo-
philic allylation of readily accessible α-chloro glycinates. A variety of use-
ful α-allyl amino esters were prepared—including crotylated products
bearing vicinal stereocenters that are inaccessible through enolate alkyl-
ation—with high enantioselectivity (up to 97% ee) and diastereoselec-
tivity (> 10:1). The reactions display first-order kinetic dependence on
both the α-chloro glycinate and the nucleophile, consistent with rate-
limiting C–C bond formation. Computational analysis of the uncata-
lyzed reaction predicts an energetically inaccessible iminium intermedi-
ate, and a lower energy concerted SN2 mechanism.
Scheme 1. Approaches to the Asymmetric Catalytic Synthesis of α-Allyl
Amino Esters
Among the many classes of unnatural amino acids devised by syn-
thetic chemists, α-allyl amino acids have proven particularly valuable in
a wide variety of contexts.1-6 The alkenyl functional handle in these
building blocks can be elaborated for site-selective protein modifica-
tion,1,2 preparation of glycopeptides,3 or generation of peptide staples4
and macrocycles. Noteworthy applications include construction of all-
carbon analogs of disulfide-bridged macrocyclic peptides such as oxyto-
cin,5 and thioether-bridged lantibiotics such as nisin.6
As a result of their broad utility, α-allyl amino acids have been targets
of widespread synthetic effort.7-13 Among catalytic approaches, the
phase-transfer-catalyzed (PTC) allylation of Schiff base, ester enolates
was pioneered by O’Donnell8 (Scheme 1A) and advanced to the current
state-of-the-art by Maruoka through the discovery of highly effective, C2
symmetric, quaternary ammonium salt catalysts.9 This methodology
provides access to unbranched α-allyl amino esters, but the preparation
of branched products via PTC is generally not possible. Approaches in-
volving transition-metal π-allyl intermediates have also been developed,
but preparing branched products is hampered by requiring substitution
to occur on a hindered electrophilic partner.10 More effective ap-
proaches require the preparation of glycine allyl esters or allyl ammo-
nium salts, which undergo enantioselective Claisen11 or [2,3]-sigma-
tropic rearrangements,12 respectively.
We selected the allylation of α-chloro glycinate 1-Cbz with 2-methal-
lyltrimethylsilane as a model reaction for catalyst optimization (Figure
1). An extensive survey of chiral dual-hydrogen-bond-donors revealed
that arylpyrrolidinosquaramides 4a-g17 catalyzed the formation of 2a
with promising levels of enantiocontrol. As observed previously in reac-
tions involving stabilized cationic intermediates, enantioselectivity was
strongly responsive to the polarizability of the arene substituent on the
pyrrolidine.18 Such effects have been ascribed to stabilizing  interac-
tions between the catalyst and positively charged intermediates and/or
transition states, in which the diastereomeric transition state leading to
the major product is stabilized preferentially. However, arene polariza-
bility alone does not account for the effects on reaction enantioselectiv-
ity in the allylation reaction (Figure 1B).19 The point of attachment of
the arene to the pyrrolidine is also important, with arenes bearing sub-
The use of nucleophilic allylating agents allows stereocontrolled con-
struction of β-branched α-allyl amino acid derivatives, as elegantly
demonstrated by Lectka and Jørgensen in Lewis-acid-catalyzed allyla-
tions of N-tosyl α-imino esters using chiral copper complexes (Scheme
1B).13 Inspired by this precedent, we envisioned a new approach involv-
ing nucleophilic allylation of α-halo amino esters catalyzed by chiral hy-
drogen-bond-donor catalysts (Scheme 1C). This strategy benefits from
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stitution ortho to the pyrrolidine group affording lower enantioselectiv-
enantioselectivities but substantially improved rates and product yields
than the bis-trifluoromethyl derivative 4d’.
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ity. Such sensitivity to the spatial disposition of the aryl group is con-
sistent with a highly ordered network of attractive non-covalent interac-
tions in the enantioselectivity-determining transition state assembly.18
Table 1. Reaction Scopea
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a
Figure 1. (A) Yield and enantioselectivity of 2a for a series of 2-ar-
ylpyrrolidine- and 2-aryl-2-methylpyrrolidine-substituted catalysts.
Yields were determined by H NMR by integration against an internal
standard. (B) Relationship between the enantiomeric ratio of 2a and the
polarizability of the arene substituents on the catalysts 4a–4g (R2 = H,
blue series) and 4a’–4e’ (R2 = Me, red series).
Conditions: substrate (0.5 mmol), catalyst (0.0125 mmol), nucleo-
phile (1.0 mmol), 3 Å MS (60 mg), DCM (2 mL), under N2, initially
cooled to –78 °C and stirred at –30 °C, 36 h. Enantiomeric excess deter-
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mined by HPLC. Diastereomeric ratio determined by H NMR of the
crude product, yield reflects isolation of major diasteromer. b –5 °C. c cat-
alyst (0.05 mmol), nucleophile (2.0 mmol), DCM (5 mL), –50 °C, 72
d
h. catalyst (0.05 mmol), nucleophile (1.5 mmol), DCM (5 mL), –
30 °C, 72 h. (E)-trimethyl(2-methylbut-2-en-1-yl)silane and (E)-cro-
tylstannane employed as the nucleophiles. Yields and enantioselectivi-
ties in parentheses are of crystallized products.
e
Further evidence for the importance of the conformational properties
of the arylpyrrolidine in enantioinduction was provided through the
evaluation of 2-aryl-2-methyl-substituted pyrrolidine-derived catalysts.
Dual H-bond-donor catalysts bearing such fully substituted arylpyrroli-
dine derivatives have been found to exist predominantly as the amide
(Z)-rotamer, whereas the unsubstituted analogs exist as rotameric mix-
tures.20 In the model allylation reaction, catalysts bearing fully substi-
tuted arylpyrrolidines (R2 = Me, 4a’–4e’, Figure 1B, red circles) all in-
duce higher enantioselectivities than the corresponding unsubstituted
catalysts (R2 = H 4a–4e, Figure 1B, blue squares). A dependence of ee
on arene group polarizability and positioning was observed with the fully
substituted arylpyrrolidine catalysts similar to that of the unsubstituted
catalysts. At this stage it may be concluded that the properties of the ar-
ylpyrrolidine have a strong influence on reaction enantioselectivity, but
that full elucidation of the bases for these effects and their relative im-
portance will require a sophisticated multiparameter analysis.21 Finally,
optimization of the aniline-derived portion of the catalyst revealed that
the more electron deficient dicyano derivative 5d’ afforded comparable
The scope of the α-allyl amino ester synthesis was investigated with
optimal catalyst 5d’ (Table 1).22 Consistently high yields and excellent
enantioselectivities were obtained with several different 2-substituted al-
lylsilane nucleophiles. 2-Arylallyltrimethylsilanes with electronically
neutral or donating substituents furnished the corresponding products
2b–g in 90-96% ee. -Branched-α-allyl amino esters were produced with
high diastereoselectivities and enantioselectivities using 2,3-disubsti-
tuted allylsilanes as nucleophilic reacting partners (Table 1, 2i–l). As
noted above, these products are generally inaccessible using electro-
philic allylation reagents in traditional enolate allylations.9,10 The enan-
tio- and diastereoselectivies of branched products 2i-l and 2n are gener-
ally higher than those obtained with previously reported catalytic asym-
metric methods.13 Additional benefits of this method include a larger
range of reported nucleophiles, as well as products containing easily
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cleavable N-protecting groups. In contrast, allylsilane nucleophiles lack-
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ing 2-substituents were completely unreactive under the catalytic condi-
tions, an observation consistent with the fact that allyltrimethylsilane (N
= 1.68)23 is substantially less nucleophilic than 2-methylallylsilane (N =
4.41).24 The more nucleophilic allyltributylstannanes (N = 5.46 for the
parent compound)23 were evaluated and found to be effective reacting
partners, allowing construction of α-allyl amino esters 2m–o with high
yields and enantioselectivities. Reoptimization of the reaction condi-
tions and carbamate protecting group was necessary for reactions em-
ploying stannane nucleophiles; in particular the Fmoc-protected analog
of 1 was found to provide improved enantioselectivities (e.g., 93 vs 74%
ee with prenylstannane nucleophile). Crotylstannanes underwent reac-
tion to furnish the branched product 2n. Both the (E)- and (Z)-cro-
tyltributylstannane afforded the syn diastereomer predominantly (8:1
with the (E)-isomer, 4:1 with the (Z)-isomer). A similar outcome was
observed using silane nucleophiles leading to product 2i, indicating that
the allylation reactions proceed through open transition states. Reaction
of prenyl tributylstannane with 1-Fmoc generated the reverse-prenyl
amino ester 2o in 93% ee.
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Scheme 2. Gram-scale reactions
The new catalytic protocol proved to be readily adaptable to the pre-
parative-scale synthesis of α-allyl amino esters. For example, using either
the -chloro amino ester 1-Cbz or 1-Fmoc and appropriate allylsilane
or allylstannane nucleophiles, the -branched products 2i and 2o were
generated on gram scale (Scheme 2). The reaction of 2,3-dimethylal-
lylsilane with 1-Cbz could be conducted at relatively high concentra-
tions (0.5 M in DCM) with 1.5 equiv. of the nucleophile and 1 mol%
catalyst with no compromise in enantioselectivity relative to the smaller
scale reaction. The addition of prenylstannane to 1-Fmoc could not be
conducted at higher concentration due to the limited solubility of 1-
Fmoc in DCM, but the catalyst loading could be lowered to 5 mol%
while preserving the high enantioselectivity of the reaction.
Figure 2: (A) Proposed catalytic cycle. Observed first order dependence
on 1-Cbz and Nuc indicate that nucleophilic addition is the rate-deter-
mining step. (B) Concerted SN2 and stepwise SN1 mechanisms require
different mechanisms for enantioinduction. (C) Computational evalua-
tion of the uncatalyzed reaction predicts that the SN1 pathway is much
higher in energy than the SN2 pathway. All DFT calculations were per-
formed at the B3LYP-D3(BJ)/6-311+G(d,p) level of theory including
solvent corrections PCM(DCM). For a fuller discussion of the compu-
tational study, see SI.
While the direct generation of carbamate-protected amino esters pro-
vides amino acid derivatives in conveniently protected form, we were
naturally concerned about the likely incompatibility of the alkenyl group
in the allylated products with typical protocols for Cbz group removal.
Indeed, under standard hydrogenolysis conditions, compound 2i under-
went competitive reduction of the alkene. However, reduction with tri-
ethylsilane under Pd(OAc)2 catalysis left the alkenyl group intact and
afforded the corresponding free amine in 87% yield with no measurable
racemization.25
A simplified catalytic cycle for the new allylation reaction is outlined
in Figure 2A. The catalytic mechanism is proposed to involve three fun-
damental steps: 1) complexation of the electrophile 1-Cbz to catalyst
5d’, 2) substitution involving C–Cl bond breaking and C–C bond for-
mation, and 3) trimethylsilyl elimination from the -silyl cation to form
product 2a and TMSCl. The detailed mechanism of the substitution
step and the role of the catalyst in promoting it are of greatest interest,
since that process results in formation of the new C–C bond and is en-
antiodetermining. Although enantioselective anion-binding catalysis
has been applied successfully to many reactions proceeding via N-acyli-
minium ion intermediates,18b,26 several considerations led us to question
whether such species are involved in the system under consideration
here. α-Chloro carbonyl compounds such as 1 are generally activated to-
ward SN2 substitution pathways and deactivated toward dissociative SN1
mechanisms.27 Optimal enantioselectivities are obtained using DCM as
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solvent in the allylations of 1 (Figure S7). In contrast, nonpolar ethereal
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or aromatic solvents are generally required to achieve high enantioselec-
tivities in ion-pairing catalysis promoted by chiral H-bond donors. In-
deed, DCM has been found to promote solvent separation of ion pairs
in these systems, resulting in severe diminution of enantioinduction.28
AUTHOR INFORMATION
Corresponding Author
jacobsen@chemistry.harvard.edu
Two plausible mechanisms for the substitution step are outlined in
Figure 2B. If a stepwise SN1 is operant, anion abstraction would precede
C–C bond formation with the intermediacy of a discrete, highly electro-
philic iminium ion intermediate. The unexpected solvent effect noted
above might be reconciled with a secondary attractive interaction hold-
ing the ion-pair together, such as the iminium–Cl H-bond depicted in
Figure 2B (right). If the reaction proceeds through a concerted, stereo-
specific nucleophilic displacement, a dynamic kinetic resolution with
rapid racemization of the -chloro glycinate would be required to ac-
count for the observed high yields and enantioselectivies. Such a racemi-
zation could occur via chloride dissociation, bimolecular chloride dis-
placement, or sequential tautomerization pathways. The catalytic reac-
tion was determined to obey a second-order rate law, with first-order de-
pendence on both the -chloro glycinate and allylsilane concentrations,
consistent with either a concerted SN2 mechanism or rate-determining
allylation of an iminium intermediate in an SN1 pathway.
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Author Contributions
† These authors contributed equally.
9
Notes
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The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the NIH (GM043214), by an NSF pre-
doctoral fellowship to A.J.B., and by a Samsung Scholarship Foundation
predoctoral fellowship to S.C.K. We thank Dr. Adam Trotta (Harvard
University) for helpful discussions, Mr. Richard Liu for valuable experi-
mental assistance, and Dr. Shao-Liang Zheng (Harvard University) for
determination of the X-ray crystal structures.
Clear differentiation of the two mechanisms and determination of the
basis for enantioinduction will require considerable further study and
are under active investigation. However, a preliminary computational
analysis of the uncatalyzed transformation predicts that the concerted
SN2 substitution proceeds through a substantially lower-energy pathway
than the stepwise SN1 mechanism.29,30 The global ground state was iden-
tified as a dipole-dipole interaction complex between 1 and Nuc. Six
staggered SN2 transition states were located with activation barriers < 20
kcal/mol, with the lowest at 12.7 kcal/mol (Figure 2C). In contrast, the
iminium–chloride ion-pair implicated in the SN1 mechanism was 31.6
kcal/mol above the ground state. Recognizing that nucleophile addition
is rate-determining and therefore must involve a discrete activation bar-
rier, the concerted SN2 pathway is thus computed to be more than 18.9
kcal/mol lower in energy than the SN1 pathway.31,32
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In summary, an enantio- and diastereoselective synthesis of α-allyl
amino esters was accomplished via allylation of α-chloro glycine esters
with a chiral squaramide hydrogen-bond donor as an anion-abstraction
catalyst. Using either allylsilane or allylstannane nucleophiles, 15 repre-
sentative α-allyl amino esters were constructed in high enantio- (up to
97% ee) and diastereoselectivities (> 10:1 dr). The silane addition reac-
tion was carried out on gram-scale at 0.5 M concentration using 1 mol%
catalyst. Experimental observations, kinetic data, and DFT calculations
all point to an energetically inaccessible acyliminium ion intermediate
and a relatively favorable, concerted SN2 mechanism for the substitution
step. Our current efforts are directed toward elucidating the racemiza-
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covalent interactions involved in the selectivity-determining transition
state. We anticipate that a full mechanistic understanding of the origin
of selectivity in the allylation of 1 could enable extension of the method-
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(6) Ghalit, N.; Reichwein, J. F.; Hilbers, H. W.; Breukink, E.; Rijkers, D. T. S.;
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of amino acid derivatives by catalytic phase-transfer alkylations. Tetrahedron
Supporting Information
The Supporting Information is available free of charge on the ACS Pub-
lications website at DOI:
Experimental and Characterization Data of Catalyst and Substrate Syn-
theses (PDF)
Procedures and Analytical Data for the Enantioselective Reactions
(PDF)
Details of Kinetic Studies (PDF)
Computational Studies (PDF)
Crystallographic Data for 2l (CIF)
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ter undergoing elimination to the dehydroalanine derivative.
1
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Synthesis by Chiral Phase-Transfer Catalysis. Chem. Rev. 2003, 103, 3013-3028.
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(29) Computations were carried using DFT at the B3LYP-D3BJ/6-
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(30) Given the observed solvent sensitivity and likely importance of attractive
non-covalent interactions, we used the polarization continuum model (PCM)
with a DCM dielectric and Grimme’s dispersion correction with Becke-Johnson
damping (D3BJ). (a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent
and accurate ab initio parametrization of density functional dispersion correction
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Scalmani, G.; Frisch, M. J. Continuous surface charge polarizable continuum
models of solvation. I. General formalism. J. Chem. Phys. 2010, 132, 114110.
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(31) Given that the rate-limiting step is known to be 1st-order in nucleophile
and therefore associative based on the kinetic analysis, electronic energies (E)
rather than free energies (G) are provided. Inappropriate entropic contribu-
tions from comparing computed associative (SN2) and dissociative (SN1) path-
ways are thereby avoided. As expected, the energy difference between the two
pathways is smaller if free energies are compared, but the SN2 pathway is still sub-
stantially lower in energy: G‡ for SN2 = 13.7 kcal/mol, G‡ for SN1 >24.1
kcal/mol, Grxn = –33.0 kcal/mol.
(32) Using a water PCM, we found the SN2 pathway to be favored by an even
greater margin, 22.8 kcal/mol, providing a strong indication that the high energy
predicted for the iminium ion intermediate was not simply an artifact of compar-
ing unbenchmarked covalent and ionized energies in a solvent PCM.
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