Guidelines for β-lactam synthesis: Glycal protecting groups dictate stereoelectronics and [2+2] cycloaddition kinetics

Article abstract of DOI:10.1021/acs.joc.0c00510

The alkene-isocyanate cycloaddition method affords β- lactams from glycals with high regio- and stereoselectivity, but the factors that determine substrate reactivity are poorly understood. Thus, we synthesized a library of 17 electron-rich alkenes (glyca

Full text of DOI:10.1021/acs.joc.0c00510

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Article
Guidelines for #-Lactam Synthesis: Glycal Protecting Groups
Dictate Stereoelectronics and [2+2] Cycloaddition Kinetics
Anant S. Balijepalli, James H. McNeely, Aladin Hamoud, and Mark W. Grinstaff
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00510 • Publication Date (Web): 26 Aug 2020
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The Journal of Organic Chemistry
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Guidelines for β-Lactam Synthesis: Glycal Protecting Groups Dictate
Stereoelectronics and [2+2] Cycloaddition Kinetics
2,
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1,2,*
Anant S. Balijepalli1, † James H. McNeely , Aladin Hamoud , and Mark W. Grinstaff
†
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1.) Department of Biomedical Engineering, Boston University, Boston, MA, 02215
2.) Department of Chemistry, Boston University, Boston, MA, 02215
KEYWORDS: Glycals, Cycloaddition, Protecting Groups, Stereoelectronics, β-Lactams, Density Functional Theory (DFT)
Calculations
ABSTRACT: The alkene-isocyanate cycloaddition method affords β-lactams from glycals with high regio- and stereoselectivity,
but the factors that determine substrate reactivity are poorly understood. Thus, we synthesized a library of 17 electron-rich alkenes
(glycals) with varied protecting groups to systematically elucidate the factors that influence their reactivity towards the electron-
poor trichloroacetyl isocyanate. The experimentally determined reaction rates exponentially correlate with the computationally-
determined HOMO-LUMO gap and NBO (natural bond orbital) valence energies. The electron withdrawing ability of the protect-
ing groups, but not bulk, impacts the electron density of the glycal allyloxocarbenium system when oriented pseudo-axially (i.e.,
stereoelectronics). In this conformation, ring σC-O* orbitals oriented anti-periplanar to the allyloxocarbenium system decrease glycal
reactivity via negative hyperconjugation as protecting group electron withdrawal increases. Transition state calculations reveal that
protecting group stereoelectronics direct the reaction to proceed via an asynchronous one-step mechanism through a zwitterionic
species. The combined experimental and computational findings, along with experimental validation on an unknown glycal, pro-
vide insight on the reaction mechanism and the role of distant protecting groups in glycal reactivity. Together, these studies will aid
in the synthesis of new β-lactam antibiotics, β-lactamase inhibitors, and bicyclic carbohydrate-β-lactam monomers prepared by the
alkene-isocyanate method.
(Chart 1D) documented its importance as a key structural mo-
tif in monomers for ring-opening polymerization. Nylon-based
polymers are used widely in consumer products such as cloth-
ing, carpets, and automobile parts.16 Today, more structurally
complex β-lactam monomers are being synthesized including
those resembling naturally-occurring polypeptides17–19 and
INTRODUCTION
Lactams are an important class of functional group integral
to several key medicinal and material advances in the 20th
century.1–5 The discovery of penicillin, whose β-lactam ring is
essential for its inhibitory action against bacterial cell wall
synthesis, in 1928 led to the facile treatment of a wide array of
common bacterial ailments with a resulting significant in-
crease in life expectancy.1–3 β-lactam containing compounds
are aliphatic ring systems containing an amide bond. Many β-
lactam compounds are bicyclic structures whose properties
depend upon heteroatom substitution (Chart 1).3,6–8
such nylon
3
polymers (Chart 1E) are effective
antimicrobial19–23 and gene delivery24 agents. We recently de-
scribed a new class of carbohydrate polymers, prepared from
the anionic ring opening polymerization of a bicyclic sugar-β-
lactam monomer25,26 (Chart 1F), for use as cyropreservants27,
antimicrobial agents28, and as lectin agonists.29
For example, β-lactams fused to a sulfur-substituted five-
membered ring (i.e., penicillin derivatives) exhibit significant-
ly divergent antibiotic properties than when fused to an un-
saturated oxygen-substituted six-membered ring (i.e., ox-
acephem derivatives): the aminopenicillin amoxicillin is more
efficacious against S. aureus than P. aeruginosa while the
converse is observed for the slightly modified carboxypenicil-
lin carbenicillin.9,10 Current strategies to circumvent antibiotic
resistance include synthesizing β-lactam antibiotics with dif-
ferent ring sizes and heteroatom substitution1–4,11,12 as well as
preparing β-lactamase inhibitors such as the oxabicyclic clavu-
lanic acid.4,13–15 This avenue of research remains a high priori-
ty in light of the inevitable obsolescence of traditional antibi-
otics such as penicillin and amoxicillin.
Chart 1. Common β-lactam antibiotics, β-lactamase inhibitors, and lactam
monomers. (A): penicillin family; (B): clavulanic acid; (C): oxacephem
ring structure; (D): caprolactam; (E): nylon-3 monomer; (F): polyamidos-
accharide monomer.
In addition to the medicinal importance of the β-lactam
structure, the synthesis of Nylon 6 in 1938 via caprolactam
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Table 1. List of selected protected glycal substrates.
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2
3
4
5
Synthetic
scheme
Substrate
R1
R2
R3
1
2
-
-
Ac
Bn
Ac
Bn
Ac
Bn
6
7
8
9
3
-
Me
Me
Me
Scheme 1. Cycloaddition reaction of fully-protected glycal and trichloroa-
cetyl isocyanate (TCAI) yields bicyclic β-lactams with high stereoselectiv-
ity.
4
A
Et
Et
Et
5
A
TES
PMB
Troc
TES
PMB
Troc
TES
PMB
Troc
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β-lactams are commonly synthesized via the Staudinger
synthesis due to its versatility and relative accessibility.30–33
Depending on the steric and electronic properties of the sub-
stituents on either the ketene or the imine, the reaction may
vary in geometry of the initial attack by the imine and in the
subsequent isomerization of the zwitterionic intermediate.32,33
As a result, products are usually obtained as a cis/trans race-
mic mixture that, despite the readily available imine and ke-
tene precursors, presents a significant hurdle to the synthesis
of new enantiopure β-lactams.30–33 In addition to poor stereo-
chemical control, the ketene substrate is unstable in many cas-
es34,35 and must be generated in situ from an acyl chloride and
tertiary amine or from the Wolff rearrangement of α-
diazocarbonyl compounds.36 Alternative methods to synthesize
β-lactams include the expansion of aziridine rings37,38 and the
Kinugasa reaction39,40, but the starting materials for these
methods are not widely available commercially.
6
A
7
A
8
A
MOM MOM MOM
9
B1
B2
B2
B2
B2
B2
B2
B2
B2
Bn
Bn
Ac
Bn
Ac
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12
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17
TIPS
TIPS
TIPS
Ac
PMB
Bn
Bn
Bn
Bn
Bn
Bn
PMB
Bn
Bn
Bn
Bn
Bn
Bn
Me
Troc
Tr
DMT
glycals with combinations of common hydroxyl protecting
groups (Table 1) and TCAI (Scheme 1). The goals of this mul-
tifaceted study are to: 1) identify the protecting groups that are
stable to cycloaddition with TCAI; 2) measure the kinetics of
the cycloaddition reaction between protected glycals and
TCAI; and, 3) use conformer-weighted Kohn-Sham and natu-
ral bond orbital calculations to support our experimental ob-
servations and propose a model that identifies negative hyper-
conjugation as an important factor in glycal allyloxocarbenium
reactivity. We hypothesize that glycals with protecting groups
adopting a pseudo-axial (5H4) orientation possess a favorable
periplanar orientation of ring σC-O*, with respect to the al-
lyloxocarbenium system, thus facilitating negative hypercon-
jugation and modulation of its reactivity.
In contrast, the reaction of electron-deficient isocyanates
with electron-rich alkenes is a robust and relatively mild
method to synthesize β-lactams.39,41 Unlike the Staudinger
synthesis, this reaction offers less flexibility in the functionali-
ty of the starting reagents, with the majority of examples uti-
lizing activated isocyanates such as chlorosulfonyl isocyanate
(CSI), p-tolunesulfonyl isocyanate, trifluoroacetyl isocyanate,
and trichloroacetyl isocyanate (TCAI).39–43 Of note, while the
Staudinger synthesis is generally accepted to follow a step-
wise mechanism, findings from computational studies on
small model compounds (e.g., ethylene and isocyanic acid)
have led to proposals of both stepwise and concerted mecha-
nisms between sufficiently electron-rich alkenes and electron-
deficient isocyanates.44–47 Herein, we present a systematic
study to elucidate the influence of protecting group stereoelec-
tronics and solvents on the reaction kinetics of eighteen
RESULTS AND DISCUSSION
Scheme 2. Synthetic design for regioselectively and orthogonally protected glycals. Scheme A: protection of all 3 hydroxyl functionalities with the same
protecting group. Scheme B: regioselective protection by TIPS group followed by selective protection of the 3’- and 4’-OH; the silyl group was removed
and the 6’-OH either (1) oxidized and protected or (2) orthogonally protected.
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Chmielewksi and Kaluza studied the reactions of both CSI
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2
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4
5
6
7
8
and TCAI with protected glycals in order to yield oxabicyclic
β-lactam antibiotic structures including clavams and ox-
acephems.41,48–52 The authors pose several empirical observa-
tions including that cycloadducts between glycals and CSI
were susceptible to degradation at higher temperatures, non-
polar protecting groups afforded higher yields, side products
were formed due to a competing [4+2] cycloaddition reaction,
rearrangement of the transition state to a stable α, β-
unsaturated amide, and a high stereoselectivity towards trans-
substituted β-lactams with respect to the C-3 position.48,49. In
agreement with the observations noted by Chmielewksi, we
obtain enantiopure bicyclic β-lactam structures in higher yield
using tri-O-tert-butyldimethylsilyl (TBDMS) protected glycals
as opposed to tri-O-benzyl protected glycals.25 When extend-
ing this methodology to glycals with combinations of protect-
ing groups, however, we observed highly variable reaction
outcomes. Consequently, we undertook a comprehensive and
systematic experimental and computational study to: 1) deter-
mine the scope of reaction in terms of glycal composition; 2)
understand the advantages and limitations of the reaction; 3)
propose a mechanism; and, 4) develop a set of guidelines to
inform the future synthesis of β-lactams.
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The most commonly used protecting groups for the hydrox-
yl functionality span a wide range of steric bulk and electron
withdrawing ability that are likely to influence the outcome of
the cycloaddition reaction (Schemes 1 and 2, Table 1). For
example, O-trityl protecting groups are highly electron rich
and bulky enough to selectively protect the primary 6’ OH
functionality while O-acetyl protecting groups are compara-
Figure 2. Relationship between reaction rate and steric bulk (qualita-
tively ordered from lowest to highest). 3 – Tri-O-methyl, 4 – Tri-O-
ethyl, 1 – Tri-O-acetyl, 2 – Tri-O-benzyl, 6 – Tri-O-PMB, 7 – Tri-O-
Troc (no reaction), 5 – Tri-O-TES.
tively small and possess some electron withdrawing character,
due to the neighboring carbonyl. As shown in Scheme 2 and
Table 1, the 17 substrates include glycals protected by the
same protecting group at all 3 positions, glycals that are regi-
oselectively protected at the 6’ OH, and a glycal with a car-
boxylate at the 6’ carbon. While substrates such as 8, the tri-
O-methoxymethyl (MOM) protected glycals, possess less ste-
ric bulk and less electron withdrawing capacity, substrates
such as 7, the tri-O-2,2,2-trichloroethyl carbonate (Troc) pro-
tected glycals, are bulky and highly electron withdrawing.
In order to synthesize the library of regioselectively modi-
fied glycals (10-18), as shown in Scheme 2, we reacted the
commercially available D-glucal with the bulky triisopropylsi-
lyl chloride (TIPSCl) to selectively protect the 6’ OH position
followed by acetylation, p-methoxybenzylation, or benzylation
of the remaining positions to yield substrates 10-12, respec-
tively (yields 71-79%; see SI). After tetrabutylammonium
fluoride (TBAF) mediated desilylation, the 6’ OH position
(yield 89%) was either further protected orthogonally or oxi-
dized by TEMPO and benzyl protected (yields varied from 32
to 84%). Following purification, we dissolved the substrate in
300 µL of CD3CN (0.5 M) and added 2.0 eq of TCAI prior to
beginning the NMR study. Surprisingly, we were unable to
detect product formation for the protected oxidized glycal
(Substrate 9) as well as the tri-O-Troc glycal (Substrate 7)
over 4 days of monitoring. In addition, the tri-O-MOM glycal
(8), 6-O-trityl glycal (16), and 6-O-dimethoxytrityl (DMT)
glycal (17) were unstable to the reaction conditions as several
peaks in the 1H-NMR spectra were consistent with species
from a degradation reaction. In all cases, the relative composi-
tion of starting materials and products in the reaction mixture
were readily determined by NMR due to clear separation be-
1
Figure 1. Example H-NMR data during cycloaddition reaction at 15,
60, 100, and 200 minutes for 3,4,6-tri-O-ethyl-D-glucal. The H1 peak
corresponding to the starting material diminishes in intensity over time
at δ ≈ 6.33 ppm while the H1 peaks corresponding to the [2+2] product
(δ ≈ 5.98 ppm) and [4+2] product (δ ≈ 6.17 ppm) gradually increase in
intensity over time.
1
tween the respective peaks in the H-NMR spectra (Figure 1).
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We identified the C1 protons of the starting material as well as
tion at reaction completion). The consumption of starting ma-
those of the [2+2] and [4+2] products by 1H13C-HSQC (Figure
S1) and calculated the ratio of the integration of the C1 proton
terial in all reactions in acetonitrile followed first-order kinet-
ics (Figure S2) from which we extracted the reaction rate as
the decay constant.
1
2
3
4
5
6
7
8
9
Previous work in our group, in agreement with
Chmielewksi’s observations, indicated that bulky non-polar
protecting groups increase the reaction rate and [2+2] product
yield.25 To test this hypothesis, we experimentally determined
reaction rates of substrates 1-6, which each possess three iden-
tical protecting groups. The protecting group bulk was qualita-
tively ranked (e.g., acetyl < triethylsilyl) and compared to the-
se experimental rates and, as shown in Figure 2 (and Table 2),
no clear relationship is observed. For example, reactions with
glycals possessing large triethylsilyl groups proceed with near-
ly identical rate (0.0037 s-1) to glycals with methyl protecting
groups (0.0045 s-1). Moreover, glycals with the bulky Troc
protecting group did not react with TCAI unlike tri-O-acetyl
(less bulky) protected glycals that react with a rate of
0.000055 s-1.
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Given the poor relationship between protecting group bulk
and reaction rate, we reason that the rate acceleration observed
for certain bulky protecting groups is a consequence of their
reduced electron withdrawing ability. Electron withdrawing
substituents are known to significantly influence the stereo-
chemistry of Staudinger reaction products due to their effect
on the reaction rates during the step-wise mechanism.32,33 Ad-
ditionally, Jiao et. al reported that the Hammett constants of
the substituents on the imine and ketene in the Staudinger syn-
thesis predicted the cis/trans ratio.32 In order to empirically
test this hypothesis, we ranked five substrates with protecting
groups from the least to most electron withdrawing based on
the experimentally determined reaction rates in acetonitrile. As
shown in Figure 3, the reaction rate reduces by ~1000 fold
from ~0.05 s-1 for the less electron withdrawing 3,4-di-O-p-
methoxybenzyl-6-O-triisopropylsilyl protected (11) to
~0.00005 s-1 for the more electron withdrawing tri-O-acetyl
protected glycal (1). These data show that the protecting
groups at each position on the glycal, including the distant
6’OH influence the electronics of the alkene. Indeed, the sim-
Figure 3. Comparison of experimentally observed reaction rates of
glycals with protecting groups ordered from least electron withdraw-
ing to most electron withdrawing. 11: 3,4-di-O-PMB-6-TIPS-D-
glucal; 2: 3,4,6-tri-O-benzyl-D-glucal; 3: 3,4,6-tri-O-methyl-D-
glucal; 10: 3,4-di-O-acetyl-6-O-TIPS-D-glucal; 1: 3,4,6-tri-O-acetyl-
D-glucal.
of the starting material to the total integration of all compo-
nents to determine the percent of starting material remaining
in the mixture. Although other side products, and in certain
cases stereoisomers, were present in some reactions, these
were formed in negligible quantities (< 5% of total composi-
Table 2. Calculated HOMO energies for selected protected glycal substrates in both gas phase and acetonitrile solvent model
(n.r. = no reaction observed over 4 days).
εHOMO
εHOMO
(solvent)
(eV)
εLUMO-εHOMO
(gas phase)
(eV)
εLUMO-εHOMO
(solvent)
(eV)
(gas
phase)
(eV)
Reaction
rate (s-1)
Substrate Glycal (-D-glucal)
1
2
3
4
tri-O-acetyl
tri-O-benzyl
-6.959
-6.829
-6.584
-6.515
-6.378
4.741
4.363
4.243
4.117
4.743
4.498
4.429
4.292
0.000055
0.0069
-6.581
-6.461
-6.335
tri-O-methyl
tri-O-ethyl
0.0045
0.0057
5
6
7
tri-O-TES
tri-O-PMB
tri-O-Troc
-6.354
-6.443
-7.330
-6.439
-6.551
-7.074
4.136
4.225
5.112
4.353
4.465
4.988
0.0037
0.0088
n.r.
Benzyl di-O-benzyl-D-glucuronal
n.r.
9
-6.587
-6.774
-6.706
-6.717
4.369
4.556
4.620
4.631
3,4-di-O-acetyl-6-O-TIPS
0.00018
10
11
12
13
14
15
3,4-di-O-PMB-6-O-TIPS
3,4-di-O-benzyl-6-O-TIPS
3,4-di-O-benzyl-6-O-acetyl
3,4-di-O-benzyl-6-O-methyl
3,4-di-O-benzyl-6-O-Troc
-6.232
-6.464
-6.486
-6.384
-6.784
-6.549
-6.478
-6.599
-6.527
-6.714
4.014
4.246
4.268
4.166
4.566
4.463
4.392
4.513
4.441
4.628
0.056
0.031
0.0011
0.0031
0.00036
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same relationship with TCAI by varying the substrate energet-
ple modification of the 6’ OH to a TIPS protecting group in-
1
2
3
4
5
6
7
8
creases the reaction rate nearly 10-fold compared to the
peracetylated glycal (10 vs 1). In addition, strongly electron
withdrawing components at positions far from the alkene (e.g.,
6-O-Troc) significantly diminish its reactivity even with ben-
zyl protecting groups at 3’ and 4’ OH (15 vs 2; Table 2).
ic profile and holding temperature constant. Of the substrates
investigated, the tri-O-Troc protected glycal (7) and benzyl-
protected oxidized glycal (9) did not react with TCAI over 5
days of reaction monitoring. The low HOMO energy (-7.330
eV) of 7 is consistent with this observation. Interestingly, 9 did
not react with the isocyanate despite having a HOMO energy
~370 meV greater than that of 1, the tri-O-acetyl protected
glycal. In addition, the sterically hindered tri-O-TES protected
glycal (5, green) deviated significantly from the linear model,
with a reaction rate significantly slower than expected given
its high calculated HOMO value of -6.354 eV (discussed fur-
ther vide infra).
The reaction rate trends highlighted here resemble those ob-
served for glycosylation reactions, where protecting group
choices lead to empirically determined “armed”, “disarmed”,
and “superarmed” substrates.53–60 Like these glycosylation
reactions, the electron density of the ring oxygen plays a major
role in tuning reactivity; the allyloxocarbenium system is
modulated through participation in negative hyperconjugation
with neighboring periplanar σ* orbitals. In both cases, less
electron withdrawing protecting groups, such as benzyl pro-
tecting groups, destabilize the neighboring ring σ* orbital and
thereby prevent negative hyperconjugation from the allyloxo-
carbenium system.
9
10
11
12
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Although a linear relationship between HOMO-LUMO gap
and reaction rate is observed, we identified several modeling
limitations to address in order to improve our analyses. For
example, the modeled HOMO for certain protected glycals
such as tri-O-PMB and 3,4-di-O-PMB-6-O-TIPS (substrates 6
and 11) are delocalized (Figure S8, S12), with significant con-
tributions from the aryl protecting groups. Additionally, the
flexibility of side chains for each substrate gives rise to a large
number of conformers at each hydroxyl position. These con-
formers, many of which lie within 2 kcal/mol of the global
minimum energy structure, include protecting groups oriented
either pseudo-axially (5H4) or pseudo-equatorially (4H5) to the
glycal ring. The orientation of these protecting groups affects
the orientation of the ring σC-O* orbitals, and as a result, im-
pacts the alkene’s electronics. Protecting group orientation
plays a significant role in glycosylation reactions, and, for
example, rationalizes the deactivating effect of the 4,6-O-
benzylidene protecting group.58,60 Bols64 and Crich65, among
others propose that the fused ring system introduces a torsion-
To further investigate how protecting groups modulate
glycal electronics as well as understand the disparities in reac-
tion rates, we performed DFT calculations (PBE0/DEF2-
TZVP/D3BJ[/SMD(ACN)]) on the minimum energy structure
5
with H4 conformation (vide infra) of all 14 substrates (Figure
S3-S16). We extracted the highest occupied molecular orbital
energy (in some cases, the HOMO did not correspond to the
alkene; in this situation the π bond energy was extracted) in
eV. These calculations were also performed with an acetoni-
trile implicit solvation model. Table 2 lists the calculated
HOMO values in both gas phase and solvent. Importantly,
protecting groups at relatively distant positions from the al-
kene influence the HOMO energy and support our qualitative
ordering of the electron withdrawing ability as well as hyper-
conjugation between the ring oxygen and neighboring σ* or-
bitals. For example, when comparing substrate 15 and sub-
strate 12 with identical 3’- and 4’-OH benzyl protection, a
small change at the 6’-OH position from O-Troc protection to
O-TIPS protection affords a significant increase in HOMO
energy (372 meV; ~33% of the entire range of HOMO for all
substrates).
We note here that these HOMO energies are directly pro-
portional to the nucleophilicity indices described by
Domingo61, and as such the correlation we obtain in the
framework of FMO theory is expected to be similarly obtained
based on theoretical description in the framework of conceptu-
al DFT. Work is currently being performed to explore the re-
action pathways of these glycals in the context of molecular
electron density theory62.
A quantitative relationship between HOMO energies and
experimentally observed reaction rates exist that supports our
hypothesis that protecting groups influence alkene reactivity
via modulating negative hyperconjugation. As shown in Fig-
ure 4A, a logarithmic plot of the observed reaction rates vs.
the gas phase HOMO-LUMO gap calculations affords a linear
relationship (R2=0.75). When the implicit solvation model
HOMO-LUMO gap calculations are used (Figure 4B), this
linear relationship diminishes slightly (R2=0.61). Importantly,
reaction rates increase logarithmically with decreasing
HOMO-LUMO gaps, strongly resembling an Arrhenius rela-
tionship between reaction rate and activation energy. While
previous reports have established an Arrhenius relationship for
the [2+2] cycloaddition between CSI and fluorinated alkenes
with respect to temperature changes63, we demonstrate this
Figure 4. (A) Linear correlation between the logarithm of cycloaddi-
tion reaction rate and the corresponding HOMO-LUMO gap between
glycal and trichloroacetyl isocyanate (LUMO calculated to be -2.2178
eV) in gas phase. (B) Linear correlation between the logarithm of
cycloaddition reaction rate and the corresponding HOMO-LUMO gap
between glycal and trichloroacetyl isocyanate (LUMO calculated to
be -2.0858 eV) in an acetonitrile implicit solvation model. The resid-
ual of the lone outlier (tri-O-TES protected glycal) was found to ex-
ceed 3 standard deviations of the mean of residuals, supporting its
exclusion from the linear regression. Red circles – series of 6-O-TIPS
protected glycals; purple circles – series of 3,4-di-O-benzyl protected
6-O regioselectively protected glycals; green circle – tri-O-TES pro-
tected glycal.
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the coupling constant found for 9. Pederson and Bols similarly
reported a predominance of the pseudo-axial H4 orientation
with bulky silyl protecting groups, unlike traditional benzylic
ether or ester groups, leading to “superarmed” glycosyl do-
nors.58
5
Table 3. Experimentally determined vicinal coupling
constants between H4 and H5 as determined by H-
NMR. (n.d. = not determined)
1
2
3
4
5
6
7
8
1
3JH4H5
Substrate Glycal
(Hz)
To examine how protecting groups influence stereoelectron-
ics to affect the mechanism of the cycloaddition reaction, we
performed transition state calculations on the single minimum
energy 4H5 and 5H4 conformers of a subset of the glycals (1, 3,
4, 12, and 15). A summary of the energetic landscape is found
in Table 4 and Table SCX1 (see ESI). For each of the 5H4 con-
formers, the reaction is one-step, yet exhibits significant asyn-
chronicity, with the C-C bond forming prior to ring closure
with the C-N bond formation (see Figure 5 and Figure S20).
1
2
3
4
5
6
7
tri-O-acetyl
tri-O-benzyl
tri-O-methyl
tri-O-ethyl
tri-O-TES
7.3
8.2
8.3
8.5
n.d.
8.4
8.4
3.1
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
tri-O-PMB
tri-O-Troc
4
5
Our calculations additionally indicate that H5 and H4 con-
formers, present in all glycals at varying ratios, undergo differ-
ing reaction pathways.
benzyl
glucuronal
di-O-benzyl-D-
9
The transition state calculations on the 4H5 conformers for 1,
3, 4, 12, and 15 are summarized in the ESI. The calculated
activation barriers suggest that the cycloadditions involving
10
11
12
13
14
15
3,4-di-O-acetyl-6-O-TIPS
3,4-di-O-PMB-6-O-TIPS
3,4-di-O-benzyl-6-O-TIPS
3,4-di-O-benzyl-6-O-acetyl
3,4-di-O-benzyl-6-O-methyl
3,4-di-O-benzyl-6-O-troc
n.d.
n.d.
n.d.
8.3
4
the H5 conformers proceed much faster than the correspond-
5
ing H4 conformers. This gave us pause because it is incon-
sistent with the observed experimental stereoselectivity and
the orbital interactions predicted to drive the observed correla-
tion between kinetics and protecting group electron-
withdrawing ability.
8.3
8.4
4
Upon inspection of the transition state structures and reac-
al restriction, locking the glycal in the H5 orientation and dis-
favoring the formation of a flattened oxacarbenium ion.
5
4
tion pathways for the H4 and H5 conformers, however, an
explanation presents itself. First, the transition state geome-
4
5
To further probe these stereoelectronic factors, we identified
all conformers for a given glycal within ~30 eV from the min-
imum energy structure at the PBE0/DEF2-TZVP/
D3BJ/CPCM(ACN)//PBE0/D3BJ/DEF2-SVP//MMFF94 lev-
el. While the entire conformational window for substrates such
as tri-O-methyl (substrate 3) is comprised of only 16 conform-
ers, others with many degrees of freedom, such as 3,4-di-O-
benzyl-6-O-Troc (substrate 15) were limited to ~100 conform-
tries for the H5 conformers are at odds with the H4 geome-
5
tries. Particularly, while the H4 structures are expected for an
asynchronous one-step [2+2] cycloaddition, the 4H5 geometries
are characterized by C1-C2-C-N dihedral angles of ~80° (Fig-
ure S18). The near-orthogonal orientation of the π-π* partners
is unexpected for a concerted cycloaddition, and immediately
suggests a two-stage one-step mechanism via a highly asyn-
chronous TS or a two-step mechanism.
4
ers to make the calculations affordable. Glycals with H5 ori-
Indeed, after following the intrinsic reaction pathway start-
entation comprise a significant proportion of the selected con-
formers (not expected to contribute to reaction kinetics, vide
infra) in all cases except for the tri-O-TES protected glycal
(substrate 5), oxidized benzyl protected glycal (substrate 9),
and silyl-protected 6’ OH glycals (Table 2). To confirm these
4
ing from the H5 transition state for 3, we observe that the
product did not form after > 7000 steps (Figure 5). While we
were unable to locate the second transition state connecting
the intermediate with the product, our data indicate that it is
characterized by a very low enthalpic barrier (see ESI). Fur-
thermore, the reaction path curvatures following the formation
3
computational observations, we measured the JH4H5 coupling
constants to determine their relative orientation. According to
the Karplus equation, the vicinal coupling constant decreases
to a minimum as the torsion angle between protons passes
through 90o; 3JH4H5 is accordingly larger for glycals adopting a
4
of the C-C bond for the H5 conformers were very small. In-
spection of the normal modes (Figure S18) show that the se-
cond vibrational mode (17 cm-1) is best described as a rotation
around the forming C-C bond that moves the TCAI nitrogen
5
3
4H5 versus a H4 orientation. As shown in Table 3, the JH4H5
for all substrates with measurable coupling constants except 9
are of similar magnitude near 8 Hz, indicating a mixture be-
Table 4. Calculated transition state thermodynamic
5
quantities for minimum energy H4 conformer of se-
tween H5 (3JH4H5 = 11.8 Hz) and H4 (3JH4H5 = 2.0 Hz). Given
the low (0.6 kcal/mol) theoretical barrier between these two
conformations for 1, these states are expected to rapidly equil-
ibrate in solution.66 Spectral overlap with H4 and H5 prevent-
lected substrates
4
5
εHOMO
(eV)
εNBO
(kcal/mol)
Substrate ΔE‡ ΔH‡
ΔS‡
ΔG‡
3
15
12
4
12.3 13.4 -13.8 27.2 -6.714
10.6 10.4 -17.0 27.4 -6.478
-8.539
-8.424
-8.396
-8.391
-8.667
ed the measurement of JH4H5 for substrates 5, 10, 11, and 12
despite attempts to separate peaks using solvents such as
5
(CD3)2CO and CD3OH. The predominance of H4 within the
9.6
10.1 -15.4 25.5 -6.378
conformational windows determined computationally for 5
and 9 is supported experimentally in the case of 9, with a
3JH4H5 of only 3.1 Hz. In addition, our group previously found
3JH4H5 for a bulky persilylated glycal similar to 5 (tri-O-
TBDMS-D-glucal) to be 2.8 Hz25, which is in agreement with
3
10.9 11.4 -14.9 26.3 -6.515
12.5 12.8 -15.3 28.2 -6.829
1
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away from the C1 carbon, out-of-phase with the motion gov-
erned by the imaginary mode. Each of these observations sug-
1
gests that canonical transition state theory is not suitable to
2
3
describe the reaction pathways for the 4H5 conformers.
4
5
Singleton’s group studied the pathways of the reaction be-
tween ketenes with cyclopentadiene and cis-2-butene67,68
.
They note the following interesting observations that are di-
rectly relevant to the work described in this manuscript: 1) the
geometry of the transition state calculated for the cycloaddi-
tion of cis-2-butene with dichloroketene shares similar charac-
6
7
8
9
4
teristics with the H5 transition state structures calculated in
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
this work with an orthogonal approach of the two interacting
fragments at the CCSD(T)/6-311++G**/PCM(CH2Cl2) level
of theory; 2) An entropic barrier for the formation of the se-
cond C-C bond in the cycloaddition of dichloroketene with
cis-2-butene was proposed for which there was no enthalpic
barrier, but was termed an ‘entropic transition state’. This en-
tropic transition state was found to be rate-limiting based on
direct dynamics trajectories.
Figure 6. (A) Linear correlation between the logarithm of cycloaddition
reaction rate and the corresponding NBO valence energy gap between
glycal and trichloroacetyl isocyanate in implicit solvation model. (B)
Linear correlation between the logarithm cycloaddition reaction rate
adjusted for 5H4 population and the corresponding NBO valence gap
between glycal and trichloroacetyl isocyanate with tri-O-TES excluded.
Red circles – series of 6-O-TIPS protected glycals; purple circles –
series of 3,4-di-O-benzyl protected 6-O regioselectively protected
glycals; green circle – tri-O-TES protected glycal.
Spurred on by the success of Singleton’s group, we under-
took a detailed study of the dynamics of the reaction pathways
4
5
for the H5 and H4 conformers. While a full account of the
results will be given in a future publication, the preliminary
5
results support our previous assumption that only the H4 par-
ticipate in the [2+2] formation of β-lactams in these glycal-
TCAI systems. Of 100 sampled trajectories starting from the
The NBO energies are not eigenvalues of the Fock/KS matrix,
and as such, the orbital energies are non-physical. These ener-
gies correspond to eigenvalues of a hypothetical “Natural
Lewis Fock” matrix in which the true Fock matrix in the NBO
basis has all off-diagonal elements removed. The energies are
thus calculated primarily as a precursor to perturbative anal-
yses of interactions between filled “Lewis-type” and unfilled
“Non-Lewis type” NBOs.
4
transition state for the H5 conformer of 3, not a single one
resulted in the formation of the desired product, and greater
than 95% re-crossed to form the reactants (Figure S22). This
can be compared with a 23% product formation for the trajec-
tories started from the 5H4 transition state of 3. These results in
combination with the experimentally observed stereoselectivi-
5
ty of the reaction justify our focus on the H4 conformers go-
ing forward.
The NBO energies do, however, reflect certain important
properties of the electronic environment, and these properties
are expected to be highly relevant to our present study61,70: 1)
The natural atomic orbitals (NAOs) from which the NBOs are
constructed are sensitive to the partial charge of the parent
atom. It can thus be expected that the NAOs from which the
glycal alkene NBO is constructed will be slightly more diffuse
when electron-donating substituents are present at the 3 and 6
positions, thus destabilizing the NBO energy; 2) The NAOs
respond to steric pressure from the neighboring atoms during
the orthogonalization process. 3) The π→σ* negative hyper-
conjugation is re-introduced by including the second-order
perturbative delocalization energy between the NBOs.
In order to address the delocalization observed in our MO
calculations and the presence of multiple conformers (5H4
conformers are expected to react more favorably than 4H5 con-
formers), we calculated alkene natural bond orbital (NBO)
energies for all 5H4 conformers for all glycals within the
aforementioned conformational window69 and obtained a
Boltzmann-weighted NBO energy corrected for C1-C2 π → C3-
O σ* delocalization (see ESI Table SCY1 – Table SCY14).
Compared to the previous single conformer DFT calcula-
tions, these new Boltzmann-weighted calculations consider the
5
probability distribution of H4 conformers that influence al-
kene energy. As shown in Figure 6A, the correlation between
reaction rate and NBO π energy improves upon that obtained
with FMO energies (R2 = 0.72) when conformational sampling
was performed. In the case of the tri-O-TES protected glycal,
we rationalize that the observed deviation from the trend is
due to steric constraints arising from the bulk of the protecting
group at the C4 position. Additionally, we modified the exper-
imentally observed reaction rate to account for the percentage
of glycal adopting the reactive 5H4 conformation, as deter-
mined by our conformational analyses (see ESI methods).
With the removal of the tri-O-TES protected glycal and ad-
justment of the experimentally observed reaction rate, the cor-
relation further increases to R2 = 0.92, as shown in Figure 6B.
5
4
Figure 5. IRC of H4 (red) and H5 (green) conformers for glycal 3.
Transition state geometry is shown on the right with C1-N and C2-C
4
bond distances. Calculations for the H5 conformer were halted after
7000 steps with maximum delta of 1.3e-5.
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When comparing the tri-O-acetyl (12) to the 3,4-di-O-acetyl- reactions for four substrates in chloroform, acetonitrile, or
1
2
3
4
5
6
7
8
6-O-TIPS protected glycal (10), although the O-acetyl groups
enhance negative hyperconjugation from the allyloxocarbeni-
um system in both cases, there is an activating effect for 10, as
5
the bulky silyl group locks the glycal in the H4 conformation
thus inducing an antiperiplanar orientation of the σC3-O3* or-
bital with the π system. Additionally, while substrates 2 and 13
5
are comprised of similar H4/4H5 populations, the increased
electron donation from 2 leads to a ~7-fold rate acceleration
from 0.0011 s-1 to 0.0069 s-1 (Table 2). These data support our
hypothesis that protecting groups influence glycal reactivity
predominantly via π→σ* negative hyperconjugation and inter-
action with the ring oxygen, accounting for both the observed
steric and electronic effects.
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
As previously observed with the calculated HOMO energies
of substrates 1, 3, 4, 12, and 15, an increase in the calculated
NBO energy of the alkene of the minimum energy 5H4 con-
former is associated with a diminished energy barrier (ΔE‡)
for the proposed transition state (Table 4, Figure S21). While
this relationship serves as an important tool for validation, it
should be noted that NBO calculations are significantly less
costly than transition state calculations. Accordingly, an ad-
vantage of the NBO method utilized to obtain the correlation
identified in Figure 6B is the ability to quickly model the be-
havior of large populations of the 5H4 conformers of each
substrate.
Figure 8. Comparison between experimental and theoretical reaction rate
for 3,4,6-tri-O-benzyl-D-altral based on NBO calculations adjusted for
theoretical 5H4 conformer prevalence; (inset shows structure).
nitromethane to determine the effect of solvent polarity (i.e.,
dipole moment and dielectric constant) on reaction rate. These
three solvents are readily available in deuterated form and
while all polar, span a range of dielectric constant (chloro-
form, acetonitrile, or nitromethane ~5.5, 37.5, and 39.4, re-
spectively) and dipole moment (chloroform, acetonitrile, or
nitromethane ~1.01, 3.92, and 3.46 D, respectively). As shown
in Figure 7, each of the 4 glycals undergo faster reactions in
the more polar acetonitrile and nitromethane solvents com-
pared to chloroform. A slightly slower rate of reaction for 1, 2,
and 12 occurs in the lower dipole moment solvent of nitrome-
thane in comparison to acetonitrile (3.46 vs 3.92 D). Indeed,
the large dipole moment of acetonitrile likely stabilizes the
proposed asynchronous transition state and accelerates the
observed reaction rate. These findings are in agreement with
prior computational studies investigating the effect of solvent
on alkene-isocyanate cycloaddition rate.47
For a small set of glycal cycloadditions involving TCAI,
Chmielewski reported that reaction kinetics in chloroform are
slower than those in acetonitrile, yet increased when utilizing
nitromethane as a solvent.50 Thus, we conducted cycloaddition
Given that the stereoselectivity of the Staudinger synthesis
is determined at least in part by the Hammett constants of the
imine and ketene substituents32, we next investigated the rela-
tionship between the experimental cycloaddition [4+2] vs
[2+2] reaction selectivity and the theoretical NBO gap. Here,
we assume that the stereoelectronic effects governing the
[2+2] cycloaddition reaction similarly tune the energetics of
the [4+2] cycloaddition, although with differing magnitude.
The ratio between [4+2] and [2+2] products remains nearly
constant over the course of the reaction; ratios were extracted
after 24 h or when the starting material mol fraction was lower
than 10%. As shown in Figure S22, similar to the relationship
between protecting group bulk and reaction rate, no clear rela-
tionship exists between the observed selectivity and theoretical
NBO π energy calculation. These data imply that, as expected,
glycal reactivity does not bias reaction pathway and that the
[2+2] and [4+2] cycloaddition reactions are independent,
competing processes.
Figure 7. Reaction progress of cycloaddition reactions conducted in
deuterated acetonitrile, chloroform, and nitromethane as monitored by
1H-NMR. Starting material mol fraction at each time point was deter-
mined by comparing the integration of H1 to the integrations of the [2+2]
H1 and [4+2] H1 (determined by 1H13C-HSQC). The first-order rate
constants were obtained by plotting the logarithm of reaction progress vs
time and applying linear regression. The lines of fit shown on each graph
were obtained by applying this reaction rate to an exponential decay
function. As shown in insets: (A): 3,4-di-O-benzyl-6-O-triisopropylsilyl-
D-glucal (12); (B): 3,4,6-tri-O-benzyl-D-glucal (2); (C): 3,4,6-tri-O-ethyl-
D-glucal (4); (D): 3,4,6-tri-O-acetyl-D-glucal (1).
Importantly, in order to determine if our model can be used
to predict the reaction outcome of an unknown compound, we
identified and synthesized an additional glycal substrate with
potential antibiotic activity41, which possesses a β-lactam on
the β face of the pyranose. This inverted lactam stereoselectiv-
ity is achieved via the flipped orientation of the bulky 3’-OH
protecting group (O-benzyl) in a glycal readily obtained in 2
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steps from D-altrose, as we previously described.65 The JH4H5
3
1
2
3
4
5
6
7
8
for this glycal is 10.1 Hz indicating a predominance of pseu-
do-equatorially oriented 4’-OH and 6’-OH benzyl groups (4H5
conformation).66 Examination of the conformational scans for
this glycal, however, indicates a significant population (29%)
5
of H4 conformers that facilitates rate prediction according to
our previously modeled relationship. Indeed, the calculated
NBO energy gap for this substrate is 6.013 eV, corresponding
to a rate constant of 0.015 s-1. When accounting for the pre-
5
dominance of reactive H4 glycals in the reaction mixture, our
Scheme 3. Negative hyperconjugation explains how protecting groups
influence the NBO energy of the glycal alkene to dictate reaction rate.
Increased electron density of the alkene improves reaction rate by increas-
ing the enthalpic driving force of the cycloaddition reaction supported by
transition state ΔH‡ calculations.
calculations predict an experimental rate constant of 0.00435 s-
1. The experimentally determined reaction rate of this substrate
is 0.00466 s-1, corresponding to a percent error of 1.3% after
logarithmic transformation. Figure 8 shows a comparison be-
tween the experimental data and computationally predicted
data.
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
first, followed by ring closure from the isocyanate nitrogen to
glycal C-1. The predicted zwitterionic transition state is sup-
ported by observations that high dipole solvents, capable of
stabilizing charge, increase the reaction rate. Finally, the theo-
retical model successfully predicts the observed kinetics of a
new glycal [2+2] cycloaddition reaction. Together, our results
support the hypothesis that negative hyperconjugation from
the ring oxygen p-orbitals and the alkene π orbitals to ring σC-
O* orbitals significantly impacts glycal reactivity and that care-
ful selection of protecting groups either enhances or diminish-
es negative hyperconjugation to tune reactivity for predictable
β-lactam synthesis (Scheme 3). Specifically, allyloxocarbeni-
um reactivity increases with less electron-withdrawing groups
such as the benzyl and p-methoxybenzyl group at all three
positions. Highly electron-withdrawing acyl groups and car-
bonate groups, conversely, strongly deactivate the reactive
system. Our findings facilitate the informed synthesis of new
β-lactam antibiotics, β-lactamase inhibitors, and β-lactam
monomers derived from glycals.
CONCLUSIONS
The alkene-isocyanate cycloaddition displays sensitivity to
the stereoelectronic effects of protecting groups although, un-
like the literature describing this effect in other
cycloadditions71–73, does not involve directly delocalized or
conjugated systems. The influence of protecting groups has
been studied widely in reference to glycosylation reactions and
is in accordance with recent reports that side group orientation
plays a significant role in tuning reactivity.58,60,74,75 In particu-
lar, our findings align with those of Bols and coworkers that
bulky silyl groups increase the population of ring-flipped con-
formers with substituents in the axial position (5H4), thereby
modulating reactivity.74 For example, a single silyl group on
the 6’-OH of 11 and 12 increases the predominance of the
pseudo-axial conformation leading to a significant acceleration
in reactivity in parallel with higher calculated alkene energy.
Moreover, glycal orientation is only one part of protecting
group participation; the electronics of pseudo-axially oriented
protecting groups play a significant role in further tuning reac-
tivity. For example, glycals 10 and 12 exhibit highly disparate
reaction rates despite both possessing a silyl group at the 6’-
OH and a predominant 5H4 conformation as the O-acetyl group
is significantly more electron withdrawing than the O-benzyl
group. As protecting group effects hold across a variety of
glycosylation reactions, our results may be generally applica-
ble to other cycloaddition reactions involving the al-
lyloxycarbenium system, such as the [4+2] cycloaddition of
azodicarboxylates to glycals76 or 1,3-dipolar cycloaddition of
alkyl azides to glycals.77
EXPERIMENTAL SECTION
Materials and general methods
D-glucal, tri-O-benzyl-D-glucal, tri-O-acetyl-D-glucal, and 4,4-
dimethoxytrityl chloride were purchased from Carbosynth (San Die-
go, CA). Tri-O-methyl-D-glucal, benzyl bromide, and trimethylamine
were purchased from Alfa Aesar (Tewksbury, MA). 4-methoxybenzyl
chloride and trichloroacetyl isocyanate were purchased from TCI
America (Portland, OR). Deuterated chloroform, acetonitrile, and
nitromethane were purchased from Cambridge Isotopes (Tewksbury,
MA). All other reagents were purchased from Millipore Sigma (Bur-
lington, MA). All solvents were either purchased anhydrous over
molecular sieves or treated using a solvent drying system to remove
trace amounts of water. Reactions were monitored by thin-layer
chromatography (TLC) analysis, and stained by the solution of potas-
sium permanganate or acidic ceric ammonium molybdate. All 1H-
NMR and 13C-NMR spectra were taken with compounds dissolved in
CDCl3 [(D, 99.8%) + 0.05％ V/V TMS + Silver foil] and the TMS (0
ppm) was used as an internal standard for 1H-NMR spectra. Chemical
shifts (δ) are recorded in ppm, coupling constants (J) are reported in
Hz. Unless otherwise noted, all reactions were performed under an
argon atmosphere using anhydrous solvents and oven-dried glassware
and stir bars.
Reactivity studies with a library of 17 protected glycal sub-
strates demonstrate that the stereoelectronic influence of pro-
tecting groups and solvent stabilization of the reaction inter-
mediate dictate the [2+2] cycloaddition reaction kinetics of
glycals and isocyanates. Theoretical glycal HOMO to isocya-
nate LUMO gaps, calculated on global minimum energy struc-
tures, correlate positively and exponentially with the experi-
mentally observed reaction rates in accordance with an Arrhe-
nius model. When restricting glycal HOMO to the alkene con-
tribution using NBOs and accounting for conformational vari-
ability from protecting groups oriented pseudo-axially (both
computationally and experimentally), the correlation signifi-
cantly improves from R2=0.72 to R2=0.92. Transition state
calculations reveal that glycal conformation impacts the cy-
cloaddition reaction pathway and support a concerted, asyn-
NMR Spectroscopy
Samples were prepared to a concentration of 0.5 M (0.150 mmol)
in 300 µL of either CDCl3, CD3CN, or CD3NO2. 2.0 eq of trichloroa-
cetyl isocyanate was added to the solution and the combined solution
was quickly mixed and the time noted before adding to a clean, dry
NMR tube (Wilmad-LabGlass, Vineland, NJ). The sample was im-
5
1
chronous mechanism with glycals in the H4 conformation. In
mediately analyzed by H-NMR (500 MHz) (Varian, Palo Alto, CA)
all cases, the glycal C-2 to isocyanate carbon C-C bond forms
followed by time points distributed over 24-36 h. After 24 h or after
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90% of the starting material had been consumed, we obtained a
3,4,6-tri-O-triethylsilyl-D-glucal (5)
1H13C-HSQC in order to identify and quantify the ratio of the peaks
corresponding to H1 of the [2+2] and [4+2] products. All spectral data
was processed in MestreNova (Mestrelab Research, Escondido, CA)
by first calculating the baseline average by integration of the baseline
in 3 different regions without signal. This background average was
then subtracted from the integration of each relevant peak (starting
material H1, [2+2] H1, [4+2] H1). The subtracted values were added
and the percent integration of the starting material of this total value
was determined. The ratio of [4+2] to [2+2] products was determined
by finding the ratio between integrations of the subtracted integration
values after 24 h or after 90% of the starting material had been con-
sumed. To extract rate constants, the logarithm of the reaction pro-
gress was plotted against the reaction time and a linear fit equation
was obtained (R2 > 0.85 in all cases) whose slope is k, the reaction
rate.
1
2
3
4
5
6
7
8
3,4,6-tri-O-triethylsilyl-D-glucal was prepared as previously de-
scribed. D-glucal (400 mg, 2.74 mmol) and 6.6 eq of imidazole (1.23
g, 18.1 mmol) were dissolved to between 0.2 and 0.3 M glycal in
o
DMF (~10 mL), and cooled to 0 C. 3.3 eq of chlorotriethylsilane
(1.50 mL, 9.04 mmol) was added dropwise and the reaction was al-
lowed to warm to room temperature overnight. The reaction was
poured into 200 mL of a 0.1 M HCl solution, and extracted 3 times
with 50 mL of ether. The combined organic extracts were washed
with brine, dried over sodium sulfate, and evaporated to yield the
crude product. The crude product was purified by silica column
chromatography (15:1 hexanes:ethyl acetate) and fractions were con-
centrated and evaporated to yield the title compound as a pale oil.
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
D
1
(yield 1.04 g, 78%). [α]25 = -13 (0.3, CH3OH). H NMR (500 MHz,
CDCl3) δ 6.32 (d, J = 6.2 Hz, 1H, H1), 4.69 (dd, J = 6.2, 3.7 Hz, 1 H,
H2), 3.91 (d, J = 6.7 Hz, 1H, H3), 3.86-3.75 (m, 2H), 1.01-0.87 (m,
27 H, SiCH2CH3), 0.70-0.55 (m, 18H, SiCH2CH3). 13C{1H} NMR
(126 MHz, CDCl3) δ 143.2 (C1), 102.0 (C2), 80.0 (C5), 70.5 (C3),
68.2 (C4), 61.6 (C6), 6.9-6.4 (SiCH2CH3), 5.2-4.4 (SiCH2CH3).
HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd for C24H52O4Si3:
511.3071; found, 511.3136.
Synthetic methods
6-O-triisopropylsilyl-D-glucal was prepared as previously de-
scribed78. The crude product was purified by silica column chroma-
tography (4:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) and
the combined fractions were evaporated to dryness to yield 6-O-
triisopropylsilyl-D-glucal as a viscous, clear oil (yield 79%). Spectro-
scopic and mass characterization data matched those previously re-
ported.
3,4,6-tri-O-(p-methoxybenzyl)-D-glucal (6)
3,4,6-tri-O-(p-methoxybenzyl)-D-glucal was prepared as previous-
ly described. D-glucal (400 mg, 2.74 mmol) was dissolved to between
0.2 and 0.3 M in DMF (~10 mL), and cooled to 0 oC followed by the
addition of 3.6 eq of NaH (95% dry, 200 mg, 8.21 mmol). The reac-
tion was allowed to warm to room temperature over 30 minutes fol-
lowed by cooling to 0 oC. 3.3 eq of PMB-Cl (1.2 mL, 9.04 mmol) was
added dropwise and the reaction was allowed to warm to room tem-
perature overnight. The reaction was quenched with methanol, poured
into 200 mL of a 0.1 M HCl solution, and extracted 3 times with 50
mL of ether. The combined organic extracts were washed with brine,
dried over sodium sulfate, and evaporated to yield the crude product.
The crude product was purified by silica column chromatography (8:1
hexanes:ethyl acetate) and fractions were concentrated and evaporated
to yield the title compound as a clear oil that formed an amorphous
3,4-di-O-benzyl-6-O-triisopropylsilyl-D-glucal (12) was prepared
as previously described78. The crude product was purified by silica
column chromatography (19:1 hexanes:ethyl acetate to 17:1 hex-
anes:ethyl acetate) and the combined fractions were evaporated to
dryness to yield 3,4-di-O-benzyl-6-O-triisopropylsilyl-D-glucal as a
clear oil (yield 71%). Spectroscopic and mass characterization data
matched those previously reported.
3,4-di-O-benzyl-D-glucal was prepared as previously described79.
The crude product was purified by silica column chromatography (4:1
hexanes:ethyl acetate to 2:1 hexanes:ethyl acetate) and the combined
fractions were evaporated to dryness to yield 3,4-di-O-benzyl-D-
glucal as a clear oil that solidified into an amorphous white solid upon
o
D
white solid upon cooling to -20 C. (Yield 1.262 g, 91%). [α]25
=
1
+0.75 (0.25, CH3OH). H NMR (500 MHz, CDCl3) δ 7.30-7.23 (m,
4H, Ar H), 7.19-7.12 (m, 2H, Ar H), 6.92-6.80 (m, 6H, Ar H), 6.41
(dd, J = 6.1, 1.3 Hz, 1H, H1), 4.84 (dd, J = 6.1, 2.7 Hz, 1H, H2), 4.74
(d, J = 10.9 Hz, 1H, CH2Ar), 4.60-4.47 (m, 5H, CH2Ar), 4.17 (ddd, J
= 6.3, 2.7, 1.4 Hz, 1H, H3), 4.02 (ddd, J = 8.4, 5.1, 2.9 Hz, 1H, H5),
3.84-3.77 (m, 10H, ArOCH3 + H4), 3.76-3.69 (m, 2H, C6). 13C{1H}
NMR (126 MHz, CDCl3) δ 159.2 (ArCOCH3), 144.6 (C1), 130.5-
129.3 (ArCH), 113.8-113.8 (ArCH), 100.1 (C2), 76.8 (C5), 75.5 (C3),
74.1 (C4), 73.4-70.2 (CH2Ar), 68.2 (C6), 55.3 (ArOCH3). HRMS
ESI+ Q-TOF (m/z): [M+Na]+ calcd for C30H34O7: 529.2202; found,
529.2195.
o
storage at -20 C (yield 89%). Spectroscopic and mass characteriza-
tion data matched those previously reported.
3,4,6-tri-O-benzyl-D-altral was prepared as previously described80.
Clear to pale oil. (yield 47% over 5 steps). Spectroscopic and mass
characterization data matched those previously reported.
3,4,6-tri-O-ethyl-D-glucal (4)
3,4,6-tri-O-ethyl-D-glucal was prepared as previously described.
D-glucal (400 mg, 2.74 mmol) was dissolved to between 0.2 and 0.3
o
M in DMF (~10 mL), and cooled to 0 C followed by the addition of
3,4,6-tri-O-(2,2,2-trichloroethylcarbonate)-D-glucal
(7)
3.6 eq of NaH (95% dry, 200 mg, 8.21 mmol). The reaction was al-
lowed to warm to room temperature over 30 minutes followed by
cooling to 0 oC. 3.3 eq of iodoethane (720 µL, 9.04 mmol) was added
dropwise and the reaction was allowed to warm to room temperature
overnight. The reaction was quenched with methanol, poured into 200
mL of a 0.1 M HCl solution, and extracted 3 times with 50 mL of
ether. The combined organic extracts were washed with brine, dried
over sodium sulfate, and evaporated to yield the crude product. The
crude product was purified by silica column chromatography (10:1
hexanes:ethyl acetate) and fractions were concentrated and evaporated
D-glucal (400 mg, 2.74 mmol) was dissolved in 10 mL of pyridine
o
and cooled to 0 C. 3.3 eq of 2,2,2-trichloroethyl chloroformate (1.2
mL, 9.04 mmol) was added dropwise and the reaction was allowed to
warm to room temperature overnight. The reaction was poured into
200 mL of a 1 M HCl solution and extracted 3 times with 50 mL of
ethyl acetate. The combined organic extracts were washed again with
1 M HCl, a saturated solution of NaHCO3, brine, dried over sodium
sulfate, and evaporated to yield the crude product. The crude product
was purified by silica column chromatography (2:1 hexanes:ethyl
acetate) and fractions were concentrated and evaporated to yield the
title compound as a clear oil that formed a white amorphous solid
D
to yield the title compound as a clear oil. (Yield 390 mg, 62%). [α]25
= -0.8 (0.3, CH3OH). 1H NMR (500 MHz, CDCl3) δ 6.35 (dd, J = 6.1,
1.4 Hz, 1H, H1), 4.76 (dd, J = 6.1, 2.6 Hz, 1 H, H2), 3.95 (ddd, J =
6.4, 2.7, 1.5 Hz, 1H, H3), 3.91 (ddd, J = 8.5, 4.9, 3.2 Hz, 1H, H5),
3.81 (m, 1 H), 3.73-3.45 (m, 8H), 1.25-1.16 (m, 9H, Ethyl-CH3).
13C{1H} NMR (126 MHz, CDCl3) δ 144.3 (C1), 100.5 (C2), 76.9
(C5), 76.1 (C3), 74.8 (C4), 69.0-66.9 (CH2CH3), 15.7-15.1 (CH2CH3).
HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd for C12H22O4: 253.1416;
found, 253.1423.
o
D
upon cooling at -20 C. (Yield 1.10 g, 60%). [α]25 = +24 (0.2,
CH3OH). 1H NMR (500 MHz, CDCl3) δ 6.54 (dd, J = 6.1, 1.3 Hz, 1H,
H1), 5.4 (dddd, J = 5.4, 3.2, 1.3, 0.7, 1H, H3), 5.25 (dd, J = 7.4, 5.6
Hz, 1H, H4), 5.00 (dd, J = 6.2, 3.3 Hz, 1H, H2), 4.85-4.73 (m, 6H,
CH2CCl3), 4.57 (dd, J = 12.7, 6.8 Hz, 1H, H6-1), 4.50-4.41 (m, 2H,
H6-2 + H5). 13C{1H} NMR (126 MHz, CDCl3) δ 153.6-152.9 (CO3),
146.4 (C1), 97.6 (C2), 94.1 (CCl3), 77.2-77.0 (CH2CCl3), 73.1 (C5),
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The Journal of Organic Chemistry
71.6 (C3), 71.5 (C4), 65.4 (C6). HRMS ESI+ Q-TOF (m/z): [M+Na]+
calcd for C15H13Cl9O10: 690.7603; found, 690.7638.
M HCl solution and extracted 3 times with 50 mL of ethyl acetate.
The combined organic extracts were washed again with 1 M HCl, a
saturated solution of NaHCO3, brine, dried over sodium sulfate, and
evaporated to yield the crude product. The crude product was purified
by silica column chromatography (3:1 hexanes:ethyl acetate) and
fractions were concentrated and evaporated to yield the title com-
1
2
3
4
5
6
7
8
3,4,6-tri-O-methoxymethyl-D-glucal (8)
3,4,6-tri-O-methoxymethyl-D-glucal was prepared as previously
described. D-glucal (400 mg, 2.74 mmol) was dissolved to between
0.2 and 0.3 M in DMF (~10 mL), and cooled to 0 oC followed by the
addition of 3.6 eq of NaH (95% dry, 200 mg, 8.21 mmol). The reac-
tion was allowed to warm to room temperature over 30 minutes fol-
D
pound as a clear oil. (yield 467 mg, 73%). [α]25 = -3 (0.2, CH3OH).
1H NMR (500 MHz, CDCl3) δ 6.46 (d, J = 6.1 Hz, 1H, H1), 5.33-5.26
(m, 2H, H3 + H4), 4.78 (ddd, J = 6.2, 2.4, 1.2 Hz, 1H, H2), 4.12 (qt, J
= 5.1, 2.6 Hz, 1H, H5), 3.89 (d, J = 4.8 Hz, 2H), 2.05 (s, 3H, COCH3),
2.03 (s, 3H, COCH3), 1.05 (m, 21H, Si(i-Pr)3). 13C{1H} NMR (126
MHz, CDCl3) δ 170.5 (COCH3), 169.4 (COCH3), 146.0 (C1), 98.1
(C2), 76.8 (C5), 67.6 (C3), 67.3 (C4), 61.4 (C6), 21.1 (COCH3), 20.9
(COCH3), 17.9 (SiCH(CH3)2), 11.9 (SiCH(CH3)2). HRMS ESI+ Q-
TOF (m/z): [M+Na]+ calcd for C19H34O6Si: 409.2022; found
409.2024.
o
lowed by cooling to 0 C. 3.3 eq of MOM-Cl (700 µL, 9.04 mmol)
was added dropwise and the reaction was allowed to warm to room
temperature overnight. The reaction was quenched with methanol,
poured into 200 mL of a 0.1 M HCl solution, and extracted 3 times
with 50 mL of ether. The combined organic extracts were washed
with brine, dried over sodium sulfate, and evaporated to yield the
crude product. The crude product was purified by silica column
chromatography (3:1 hexanes:ethyl acetate) and fractions were con-
centrated and evaporated to yield the title compound as a clear oil.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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31
32
33
34
35
36
37
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41
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44
45
46
47
48
49
50
51
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55
56
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58
59
60
3,4-di-O-(p-methoxybenzyl)-6-O-triisopropylsilyl-D-
glucal (11)
D
1
(yield 591 mg, 77%). [α]25 = +19 (0.50, CH3OH). H NMR (500
MHz, CDCl3) δ 6.40 (dd, J = 6.3, 1.2 Hz, 1H, H1), 4.89-4.84 (m, 1H,
H2, OCH2O), 4.84-4.78 (m, 1H, OCH2O), 4.76-4.72 (m, 1H,
OCH2O), 4.71-4.64 (m, 3H, OCH2O), 4.17 (dddd, J = 9.3, 5.9, 3.1,
1.9 Hz, 1H, H5), 4.11 (ddt, J = 4.8, 2.3, 1.3 Hz, 1H, H3), 3.88-3.82
(m, 1H, H4), 3.82-3.77 (m, 2H, H6), 3.41-3.35 (m, 9H, OCH3).
13C{1H}NMR (126 MHz, CDCl3) δ 144.2 (C1), 100.0 (C2), 96.7-95.4
(OCH2O), 76.2 (C5), 73.0 (C4), 71.7 (C3), 65.9 (C6), 56.0-55.5
(OCH3). HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd for C12H22O7:
301.1263; found, 301.1257.
3,4-di-O-(p-methoxybenzyl)-6-O-triisopropylsilyl-D-glucal
was
prepared as previously described. 6-O-triisopropylsilyl-D-glucal (400
o
mg, 1.32 mmol) was dissolved in 10 mL of DMF and cooled to 0 C
followed by the addition of 2.4 eq of NaH (95% dry, 76 mg, 3.17
mmol). The reaction was allowed to warm to room temperature over
o
30 minutes followed by cooling to 0 C. 2.2 eq of PMB-Cl (400 µL,
2.90 mmol) was added dropwise and the reaction was allowed to
warm to room temperature overnight. The reaction was quenched
with methanol, poured into 200 mL of a 0.1 M HCl solution, and
extracted 3 times with 50 mL of ether. The combined organic extracts
were washed with brine, dried over sodium sulfate, and evaporated to
yield the crude product. The crude product was purified by silica
column chromatography (5:1 hexanes:ethyl acetate) and fractions
were concentrated and evaporated to yield the title compound as a
clear to pale oil. (yield 572 mg, 79%). [α]25D = -0.8 (0.3, CH3OH). 1H
NMR (500 MHz, CDCl3) δ 7.28 (ddd, J = 9.5, 4.5, 2.6 Hz, 4H, ArH),
6.92 – 6.84 (m, 4H, ArH), 6.39 (dd, J = 6.1, 1.4 Hz, 1H, H1), 4.82
(dd, J = 6.2, 2.7 Hz, 1H, H2), 4.75 (bq, 2H, ArCH2), 4.56 (q, 2H,
ArCH2), 4.18 (ddt, J = 4.3, 2.6, 1.5 Hz, 1H, H3), 4.05 – 3.97 (m, 2H,
H6), 3.90 (m, 2H, H4 + H5), 3.81 (s, 6H, ArOCH3), 1.22 – 1.01 (m,
Benzyl 3,4-di-O-benzyl-D-glucuronal (9)
Benzyl 3,4-di-O-benzyl-D-glucuronal was synthesized as previous-
ly described. 3,4-di-O-benzyl-D-glucal (400 mg, 1.22 mmol) and 1.1
eq of diacetoxyiodobenzene (434 mg, 1.35 mmol) were dissolved in 5
mL of DCM and 5 mL of H2O. The reaction mixture was cooled to 0
oC followed by the addition of 0.2 eq of TEMPO (38.1 mg, 0.24
mmol) and vigorous stirring with monitoring by TLC (permanganate,
UV, and bromocresol green). After 4 h, the starting material was
found to be consumed and a new spot with a double bond, UV ab-
sorbance, pH < 7, and lower Rf (0.1 in 2:1 hexanes:ethyl acetate)
appeared. The reaction was poured into 200 mL of 0.1 M HCl and
extracted 4 times with 50 mL of ethyl acetate. The combined organic
extracts were dried over magnesium sulfate, followed by sodium
sulfate, and the solvent was evaporated. The crude residue was then
dissolved in 20 mL of DMF, followed by the addition of KHCO3 (3 g,
30 mmol). After stirring at room temperature for 1 h, the solution was
21H, Si(i-Pr)3). 13C{1H} NMR (126 MHz, CDCl3)
δ 159.3
(ArCOCH3), 159.2 (ArCOCH3), 144.7 (C1), 130.7-129.4 (Ar), 113.8-
113.8 (Ar), 99.7 (C2), 78.2 (C5), 75.5 (C3), 73.7 (C4), 73.5 (ArCH2),
70.4 (ArCH2), 62.0 (ArCH2), 55.3 (OCH3), 18.0 (SiCH2CH3), 12.1-
12.0 (SiCH2CH3). HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd for
C31H46O6Si: 565.2961; found 565.2970.
o
cooled to 0 C and benzyl bromide was added to the solution drop-
3,4-di-O-benzyl-6-O-acetyl-D-glucal (13)
wise (3.42 mL, 28.8 mmol). The reaction was allowed to warm to
room temperature overnight and was poured into 250 mL of a 0.1 M
HCl solution followed by extraction 4 times with 50 mL of ether. The
combined organic extracts were further washed with a saturated Na-
HCO3 solution, brine, and dried over sodium sulfate. The crude prod-
uct was purified by silica column chromatography (gradient 10:1 to
6:1 hexanes:ethyl acetate) and fractions were concentrated and evapo-
rated to yield the title compound as a clear oil. (Yield 165 mg, 32%
over 2 steps). 1H NMR (500 MHz, CDCl3) δ 7.40-7.17 (m, 15H,
ArH), 6.66 (d, J = 6.3 Hz, 1H, H1), 5.06 (d, J = 12.3 Hz, 1H, ArCH2),
5.03 (ddd, J = 6.5, 5.0, 1.5 Hz, 1H, H2), 4.88 (d, J = 12.3 Hz, 1H,
ArCH2), 4.83 (dd, J = 3.1, 1.3 Hz, 1H, H5), 4.72-4.62 (m, 2H,
ArCH2), 4.43 (d, J = 11.6 Hz, 1H, ArCH2), 4.34 (d, J = 11.6, 1H,
ArCH2), 4.22 (td, J = 2.9, 1.5 Hz, 1H, H4), 3.86 (ddd, J = 4.6, 2.7, 1.2
Hz, 1H, H3). 13C{1H} NMR (126 MHz, CDCl3) δ 168.1 (COOBn),
145.1 (C1), 128.7-127.7 (Ar), 98.6 (C2), 73.3 (C4), 72.8 (C5), 72.0
3,4-di-O-benzyl-6-O-acetyl-D-glucal was prepared as previously
described. 3,4-di-O-benzyl- D-glucal (400 mg, 1.22 mmol) was dis-
o
solved in 8 mL of pyridine and cooled to 0 C. 2 mL of acetic anhy-
dride (21.1 mmol, 17 eq) was added dropwise and the reaction was
allowed to warm to room temperature over 3 h while monitoring by
TLC. Upon completion, the reaction was poured into 200 mL of a 1
M HCl solution and extracted 3 times with 50 mL of ethyl acetate.
The combined organic extracts were washed again with 1 M HCl, a
saturated solution of NaHCO3, brine, dried over sodium sulfate, and
evaporated to yield the crude product. The crude product was purified
by silica column chromatography (4:1 hexanes:ethyl acetate) and
fractions were concentrated and evaporated to yield the title com-
D
pound as a clear oil. (yield 380 mg, 84%). [α]25 = +3 (0.1, CH3OH).
1H NMR (500 MHz, CDCl3) δ 7.45 – 7.27 (m, 10H, ArH), 6.44 (dd, J
= 6.2, 1.3 Hz, 1H, H1), 4.96 (dd, J = 6.2, 2.7 Hz, 1H, H2), 4.90 (d, J =
11.4 Hz, 1H, ArCH2), 4.75 – 4.67 (m, 2H, ArCH2), 4.60 (d, J = 11.6
Hz, 1H, ArCH2), 4.43 (qd, J = 12.1, 4.1 Hz, 2H, H6), 4.27 (ddd, J =
6.0, 2.7, 1.3 Hz, 1H, H3), 4.14 (ddd, J = 8.3, 5.3, 2.7 Hz, 1H, H5),
3.83 (dd, J = 8.6, 6.0 Hz, 1H, H4), 2.08 (s, 3H, COCH3). 13C{1H}
NMR (126 MHz, CDCl3) δ 170.7 (COCH3), 144.4 (C1), 138.2-137.9
(Ar), 128.7,-127.8 (Ar), 100.1 (C2), 75.5 (C3), 75.1 (C5), 73.9 (C4),
73.9-70.5 (ArCH2), 62.8 (C6), 20.9 (COCH3). HRMS ESI+ Q-TOF
(m/z): [M+Na]+ calcd for C22H24O5: 391.1521; found 391.1508.
1
(ArCH2), 69.4 (ArCH2), 67.7 (C3), 67.0 (ArCH2). H and 13C spec-
troscopy data matched those previously reported79.
3,4-di-O-acetyl-6-O-triisopropylsilyl-D-glucal (10)
6-O-triisopropylsilyl-D-glucal (400 mg, 1.32 mmol) was dissolved
o
in 10 mL of pyridine and cooled to 0 C. 5 eq of acetic anhydride
(1.25 mL, 13.2 mmol) was added dropwise and the reaction was al-
lowed to warm to room temperature over 3 h while monitoring by
TLC. Upon completion, the reaction was poured into 200 mL of a 1
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Hz, 1H, H6). 13C{1H} NMR (126 MHz, CDCl3) δ 144.9 (C1), 143.9
3,4-di-O-benzyl-6-O-methyl-D-glucal (14)
(Ar) , 138.4-138.1 (Ar), 128.8-127.0 (Ar), 99.8 (C2), 86.5 (C-Tr),
77.0 (C5), 76.1 (C3), 74.7 (C4), 73.9 (ArCH2), 70.9 (ArCH2), 62.2
(C6). HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd for C39H36O4:
591.2511; found 591.2565.
1
2
3
4
5
6
7
8
3,4-di-O-benzyl- D-glucal (400 mg, 1.22 mmol) was dissolved in
10 mL of DMF and cooled to 0 oC followed by the addition of 1.3 eq
of NaH (95% dry, 38 mg, 1.59 mmol). The reaction was allowed to
warm to room temperature over 30 minutes followed by cooling to 0
oC. 1.3 eq of methyl iodide (100 µL, 1.61 mmol) was added dropwise
and the reaction was allowed to warm to room temperature overnight.
The reaction was quenched with methanol, poured into 150 mL of a
0.1 M HCl solution, and extracted 3 times with 30 mL of ether. The
combined organic extracts were washed with brine, dried over sodium
sulfate, and evaporated to yield the crude product. The crude product
was purified by silica column chromatography (6:1 hexanes:ethyl
acetate) and fractions were concentrated and evaporated to yield the
title compound as a clear to pale oil. (Yield 253 mg, 61%). [α]25D = -7
3,4-di-O-benzyl-6-O-dimethoxytrityl-D-glucal (17)
3,4-di-O-benzyl- D-glucal (400 mg, 1.22 mmol) and 0.1 eq of 4-
DMAP (15 mg, 0.12 mmol) was dissolved in 10 mL of pyridine and
o
cooled to 0 C followed by the addition of 1.2 eq of DMT-Cl (500
mg, 1.46 mmol). The reaction was allowed to warm to room tempera-
ture overnight. The reaction was then poured into 150 mL of a 1 M
HCl solution, and extracted 3 times with 30 mL of ether. The com-
bined organic extracts were washed again with 1 M HCl, a saturated
solution of NaHCO3, brine, dried over sodium sulfate, and evaporated
to yield the crude product. The crude product was purified by silica
column chromatography (12:1 hexanes:ethyl acetate) and fractions
were concentrated and evaporated to yield the title compound as a
9
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17
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19
20
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23
24
25
26
27
28
29
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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
1
(0.1, CH3OH). H NMR (500 MHz, CDCl3) δ 7.40 – 7.26 (m, 10H,
ArH), 6.42 (dd, J = 6.1, 1.3 Hz, 1H, H1), 4.88 (dd, J = 6.1, 2.7 Hz,
1H, H2), 4.86 (d, J = 11.4 Hz, 1H, ArCH2), 4.72 – 4.63 (m, 2H,
ArCH2), 4.58 (d, J = 11.7 Hz, 1H, ArCH2), 4.23 (ddd, J = 6.4, 2.6, 1.4
Hz, 1H, H3), 4.02 (ddd, J = 8.3, 5.2, 2.7 Hz, 1H, H5), 3.83 (dd, J =
8.8, 6.3 Hz, 1H, H4), 3.72 (dd, J = 10.6, 5.2 Hz, 1H, H6-1), 3.67 (dd,
J = 10.7, 2.7 Hz, 1H, H6-2), 3.40 (s, 3H, CH3). 13C{1H} NMR (126
MHz, CDCl3) δ 144.7 (C1), 138.4-138.2 (Ar), 128.4-127.6 (Ar),
100.1 (C2), 76.7 (C5), 75.8 (C3), 74.4 (C4), 73.8 (ArCH2), 70.9 (C6),
70.4 (ArCH2), 59.2 (CH3). HRMS ESI+ Q-TOF (m/z): [M+Na]+ calcd
for C21H24O4: 363.1572; found 363.1577.
D
1
clear oil. (Yield 404 mg, 53%). [α]25 = +4 (0.1, CH3OH). H NMR
(500 MHz, CDCl3) δ 7.58 – 7.51 (m, 2H, ArH), 7.45 – 7.19 (m, 15H,
ArH), 7.12 – 7.04 (m, 2H, ArH), 6.88 – 6.79 (m, 4H, ArH), 6.55 (dd,
J = 6.1, 1.4 Hz, 1H, H1), 4.93 (dd, J = 6.1, 2.5 Hz, 1H, H2), 4.80 (d, J
= 11.0 Hz, 1H, ArCH2), 4.69 (d, J = 11.6 Hz, 1H ArCH2), 4.59 (dd, J
= 25.2, 11.3 Hz, 2H ArCH2), 4.24 (ddt, J = 4.1, 2.5, 1.5 Hz, 1H, H3),
4.10 – 4.02 (m, 2H, H5+H4), 3.80 (2s, J = 1.1 Hz, 6H, OCH3), 3.60
(dd, J = 10.4, 1.7 Hz, 1H, H6-1), 3.51 – 3.43 (m, 1H, H6-2). 13C{1H}
NMR (126 MHz, CDCl3) δ 158.5 (ArCOCH3), 145.0 (C1), 138.4-
138.2 (Ar), 136.2-136.0 (Ar), 130.2-126.7 (Ar), 113.1 (o-Ar(OCH3)),
99.9 (C2), 85.9 (C-DMT), 77.1 (C5), 76.3 (C3), 74.7 (C4), 73.9
(ArCH2), 70.9 (ArCH2), 61.9 (C6), 55.2 (ArOCH3). HRMS ESI+ Q-
TOF (m/z): [M+Na]+ calcd for C41H40O6: 651.2723; found 651.2713.
3,4-di-O-benzyl-6-O-(2,2,2-trichloroethylcarbonate)-
D-glucal (15)
3,4-di-O-benzyl- D-glucal (400 mg, 1.22 mmol) was dissolved in
o
10 mL of pyridine and cooled to 0 C followed by the addition of 1.1
eq of 2,2,2-trichloroethyl chloroformate (190 µL, 1.34 mmol). The
reaction was allowed to warm to room temperature overnight. The
reaction was quenched with methanol, poured into 150 mL of a 1 M
HCl solution, and extracted 3 times with 30 mL of ethyl acetate. The
combined organic extracts were washed again with 1 M HCl, a satu-
rated solution of NaHCO3, brine, dried over sodium sulfate, and
evaporated to yield the crude product. The crude product was purified
by silica column chromatography (2:1 hexanes:ethyl acetate) and
fractions were concentrated and evaporated to yield the title com-
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
D
Supplemental figures, general experimental methods,
synthetic methods, spectra, and computational output
(PDF) are available (158 pages)
pound as a clear oil. (Yield 431 mg, 72%). [α]25 = +5 (0.2, CH3OH).
1H NMR (500 MHz, CDCl3) δ 7.44 – 7.31 (m, 10H, Ar), 6.44 (dd, J =
6.2, 1.3 Hz, 1H, H1), 4.98 (dd, J = 6.2, 2.8 Hz, 1H, H2), 4.91 (d, J =
11.4 Hz, 1H, ArCH2), 4.84 – 4.76 (m, 2H, CH2CCl3), 4.75 – 4.68 (m,
2H, ArCH2), 4.62 – 4.53 (m, 3H, ArCH2 + H6), 4.26 (ddd, J = 6.0,
2.8, 1.3 Hz, 1H, H3), 4.22 (ddd, J = 8.4, 5.6, 2.8 Hz, 1H, H5), 3.86
(dd, J = 8.3, 5.8 Hz, 1H, H4). 13C{1H} NMR (126 MHz, CDCl3) δ
153.9 (CO3), 144.3 (C1), 138.1-137.8 (Ar), 128.6-127.7 (Ar), 100.2
(C2), 94.4 (CCl3), 76.9 (CH2CCl3), 75.0 (C3), 74.7 (C5), 73.7 (C4),
73.6 (ArCH2), 67.1 (ArCH2). HRMS ESI+ Q-TOF (m/z): [M+Na]+
calcd for C23H23Cl3O6: 523.0458; found 523.0454.
AUTHOR INFORMATION
Corresponding Author
* mgrin@bu.edu
ORCID
Mark W. Grinstaff: 0000-0002-5453-3668
Anant S. Balijepalli: 0000-0003-4686-8123
Aladin Hamoud: 0000-0001-9928-2096
James H. McNeely:
3,4-di-O-benzyl-6-O-trityl-D-glucal (16)
3,4-di-O-benzyl-6-O-trityl-D-glucal was prepared as previously de-
scribed. 3,4-di-O-benzyl- D-glucal (400 mg, 1.22 mmol) and 0.1 eq of
4-DMAP (15 mg, 0.12 mmol) was dissolved in 10 mL of pyridine and
o
cooled to 0 C followed by the addition of 1.2 eq of TrCl (408 mg,
Author Contributions
1.46 mmol). The reaction was allowed to warm to room temperature
overnight. The reaction was then poured into 150 mL of a 1 M HCl
solution, and extracted 3 times with 30 mL of ether. The combined
organic extracts were washed again with 1 M HCl, a saturated solu-
tion of NaHCO3, brine, dried over sodium sulfate, and evaporated to
yield the crude product. The crude product was purified by silica
column chromatography (15:1 hexanes:ethyl acetate) and fractions
were concentrated and evaporated to yield the title compound as a
† - these authors contributed equally to this work. ASB syn-
thesized all compounds, performed all cycloaddition experiments,
performed all experimental data workup, and wrote the manu-
script. JHM performed all DFT and NBO calculations, transition
state calculations, and helped write and edit the manuscript. AH
helped synthesize compounds for characterization. MWG provid-
ed mentorship, writing, and editing of the manuscript.
D
viscous clear oil. (Yield 254 mg, 36%). [α]25 = +1.3 (0.2, CH3OH).
1H NMR (500 MHz, CDCl3) δ 7.55 – 7.02 (m, 25H, Ar), 6.54 (dd, J =
6.1, 1.4 Hz, 1H, H1), 4.92 (dd, J = 6.2, 2.6 Hz, 1H, H2), 4.78 (d, J =
11.1 Hz, 1H), 4.67 (d, J = 11.6 Hz, 1H), 4.57 (dd, J = 20.7, 11.3 Hz,
2H), 4.22 (ddt, J = 5.5, 2.5, 1.3 Hz, 1H, H3), 4.10 – 4.00 (m, 2H,
H5+H4), 3.59 (dd, J = 10.4, 2.2 Hz, 1H, H6), 3.45 (dd, J = 10.3, 4.0
ACKNOWLEDGMENT
This work was supported in part by BU and DOD USU
(HU0001810012). NMR facilities at Boston University are sup-
12
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The Journal of Organic Chemistry
Antimicrobial β-Peptides. J. Am. Chem. Soc. 2002, 124 (25),
7324–7330. https://doi.org/10.1021/JA0260871.
ported by the NSF (CHE-0619339). The authors would like to
1
2
3
4
5
6
7
8
acknowledge Daniel Burke for help in the synthesis of 6, 9, and
14 for characterization and Dr. Norman C. Lee for help in obtain-
ing HRMS spectra.
(20)
(21)
Mowery, B. P.; Lee, S. E.; Kissounko, D. A.; Epand, R. F.;
Epand, R. M.; Weisblum, B.; Stahl, S. S.; Gellman, S. H.
Mimicry of Antimicrobial Host-Defense Peptides by Random
Copolymers. J. Am. Chem. Soc. 2007, 129 (50), 15474–15476.
https://doi.org/10.1021/ja077288d.
Mowery, B. P.; Lindner, A. H.; Weisblum, B.; Stahl, S. S.;
Gellman, S. H. Structure−activity Relationships among Random
Nylon-3 Copolymers That Mimic Antibacterial Host-Defense
Peptides. J. Am. Chem. Soc. 2009, 131 (28), 9735–9745.
https://doi.org/10.1021/ja901613g.
Liu, R.; Chen, X.; Hayouka, Z.; Chakraborty, S.; Falk, S. P.;
Weisblum, B.; Masters, K. S.; Gellman, S. H. Nylon-3 Polymers
with Selective Antifungal Activity. J. Am. Chem. Soc. 2013, 135
(14), 5270–5273. https://doi.org/10.1021/ja4006404.
Karlsson, A. J.; Flessner, R. M.; Gellman, S. H.; Lynn, D. M.;
Palecek, S. P. Polyelectrolyte Multilayers Fabricated from
Antifungal β-Peptides: Design of Surfaces That Exhibit
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