Possible reason for the unusual regioselectivity in nucleophilic ring opening of trisubstituted aziridines under mildly basic conditions

Article abstract of DOI:10.1021/jo5006685

2,2,3-Trisubstituted aziridines are known to undergo ring opening at the more substituted carbon under mildly basic conditions. However, the reason for the formation of the more sterically encumbered product has never been examined. Several trisubstituted aziridines, with different substitution patterns at the C-2 and C-3 carbons, were synthesized to change the electronics of the aziridine ring system. These changes had no effect on the regioselectivity of the ring-opening reaction. Using the B3LYP/6-31G* DFT basis set it was determined that the transition state for opening at the more substituted carbon proceeds at a lower energy than the transition state at the less substituted carbon.

Full text of DOI:10.1021/jo5006685

Article
pubs.acs.org/joc
Possible Reason for the Unusual Regioselectivity in Nucleophilic Ring
Opening of Trisubstituted Aziridines under Mildly Basic Conditions
Brandon T. Kelley, Patrick Carroll, and Madeleine M. Joullie*
́
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: 2,2,3-Trisubstituted aziridines are known to undergo ring
opening at the more substituted carbon under mildly basic conditions.
However, the reason for the formation of the more sterically encumbered
product has never been examined. Several trisubstituted aziridines, with
different substitution patterns at the C-2 and C-3 carbons, were synthesized
to change the electronics of the aziridine ring system. These changes had no
effect on the regioselectivity of the ring-opening reaction. Using the B3LYP/
6-31G* DFT basis set it was determined that the transition state for opening
at the more substituted carbon proceeds at a lower energy than the
transition state at the less substituted carbon.
aziridine ring. Nonetheless, some trisubstituted aziridines
display unique regioselectivity with ring opening at the more
substituted carbon. A unique characteristic of the reaction
profile is its stereospecificity, proceeding with inversion of
configuration.
INTRODUCTION
■
β-Substituted quaternary compounds (1; Figure 1) are present
in many products such as quaternary β-substituted amino acids,
which are important enzyme inhibitors and are incorporated in
peptides to modulate secondary and tertiary conformations.1
We have previously reported a stereospecific ring opening of a
trisubstituted aziridine (2) that displayed regioselectivity for the
more substituted carbon and applied it to the synthesis of a
variety of products (Figure 1). We have achieved the ring
opening of trisubstituted aziridines with a variety of
nucleophiles. Using trisubstituted aziridines and heteroatom
nucleophiles, tertiary moieties2 as well as 1,2-diamines3 were
synthesized in good yield. Trisubstituted aziridines were also
valuable in the total syntheses of ustiloxin D4−6 and phomopsin
B.7 The use of an ethynyl trisubstituted aziridine facilitated the
synthesis of ustiloxin D, resulting in its shortest synthesis to
date4,6 and making it amenable to the preparation of ustiloxin
analogues.8 Carbon nucleophiles were also used to make
quaternary centers and allenes.9 These ring openings occur
under non Lewis acidic conditions and occur regioselectively at
the more substituted carbon. The only instance where addition
at this carbon was not observed was with organocuprates, a
reaction that produced allenes (Figure 1).
The Bæyer strain and the electronegative atom enclosed in a
three-membered ring cause aziridines to undergo nucleophilic
ring opening even under mild conditions.10 The synthetic
utility of aziridines has been the topic of many reviews.11−18
However, nucleophilic attack on unsymmetrically substituted
aziridines can lead to two regioisomeric products. Under non
Lewis acidic conditions most nucleophiles attack preferentially
at the less substituted carbon, and this behavior is typically
attributed to sterics. Attack at the more substituted carbon can
be achieved by electronic bias either with Lewis acid catalysis or
with an aryl or other π bond containing substituent on the
Within the past decade, several other research laboratories
have used trisubstituted aziridines to advance their research
goals. Chandrasekaran and co-workers synthesized unsym-
metrical β-sulfonamido disulfides (4; Figure 2a) by ring
opening of aziridines with the use of benzyltriethylammonium
tetrathiomolybdate as a sulfur transfer reagent in the presence
of symmetrical disulfides.19 In the investigation of trisubstituted
aziridine 3 with benzyl disulfide in the presence of the
tetrathiomolybdate species, regioselective ring opening was
observed at the more substituted carbon (Figure 2a). Another
interesting reaction that has been applied to trisubstituted
aziridines is the C−C bond breakage of the ring.20−22
Trisubstituted aziridines bearing an electron-withdrawing
group on one or both carbons (5, Figure 2b) can undergo
C−C ring opening under Lewis acid catalysis to form
azomethine ylides (6). The zwitterion can undergo [3 + 2]
cycloaddition to form a new ring system (7; Figure 2b).23
The synthesis of chiral trisubstituted aziridines can include
many steps; thus, an asymmetric approach to these compounds
has been of much interest.24−40 The use of strong, chiral
Brønsted acids has been effective in transforming N-Boc imines
and α-diazocarbonyl compounds into trisubstituted aziridines.
Wulff41 (Figure 3a) and Maruoka42 (Figure 3b) both published
their respective asymmetric reactions where Wulff used the
axially chiral (R)-VANOL to achieve asymmetric induction, and
Maruoka employed the highly acidic N-triflyl phosphoramide
Received: March 22, 2014
Published: May 6, 2014
© 2014 American Chemical Society
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Figure 1. Recent applications of the nucleophilic ring opening of a trisubstituted aziridine with an array of nucleophiles to synthesize an assortment
of synthetic moieties in natural products and other structures.
Figure 2. (a) Applications of a trisubstituted aziridine in the synthesis
of β-substituted disulfides. (b) Lewis acid catalyzed C−C ring opening
of a trisubstituted aziridine to give an azomethine ylide that undergoes
a [3 + 2] cycloaddition.
developed by Yamamoto.43 Both approaches were effective
transformations of relatively simple substrates to chiral
trisubstituted aziridines. Recently a mild, versatile method for
the direct stereospecific conversion of structurally diverse
mono-, di-, tri-, and tetrasubstituted olefins to the correspond-
ing N-H or N-Me aziridines has been reported. The reaction
proceeds via a rhodium-catalyzed pathway free from external
oxidants. The transformation takes place by reacting the olefin
with O-(2,4-dinitrophenyl)hydroxylamine (DPH) and Du Bois’
catalyst, Rh2(esp)2, in 2,2,2-trifluoroethanol.44 This method will
allow trisubstituted aziridines to be rapidly accessed from
olefins, as opposed to the multistep approach that we used.
Figure 3. (a) Wulff’s approach to the asymmetric synthesis of
trisubstituted aziridines. (b) Maruoka’s approach to the asymmetric
RESULTS AND DISCUSSION
■
synthesis of trisubstituted aziridines. (c) Ess’s, Kurti’s, and Falck’s
̈
Carbon Nucleophiles. Expanding the ring-opening reac-
tions of trisubstituted aziridines with carbon nucleophiles was
of interest because, upon successful ring opening, a quaternary
center can be synthesized in a regioselective and stereospecific
stereospecific synthesis of unprotected mono-, di-, and trisubstituted
aziridines.
In order to investigate further the use of carbon nucleophiles,
the 2-nitrobenzenesulfonyl (Ns) group was replaced with the
tert-butylsulfonyl (Bus) group,45 as the nitro groups would not
be compatible with hard carbon nucleophiles. This protecting
group was chosen over the 4-toluenesulfonyl group (Ts)
because it can easily be removed under mildly acidic
́
manner. Joullie and co-workers have reported that cyanides are
effective nucleophiles in opening an ethynyl trisubstituted
aziridine at the more substituted carbon.9 While cyanides can
serve as surrogates for other useful functional groups, e.g.
malonates, their use as a carbon nucleophile is severely limited.
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conditions.46 However, tert-butylsulfonyl chloride is unstable;
therefore, the protecting group had to be synthesized. Using
intermediate 8,2 removal of the Ns group gave the free amine 9,
followed by reaction with tert-butylsulfinyl chloride, to produce
10 as a mixture of diastereomers. Oxidation of the sulfinyl
group to the sulfone (11) using m-CPBA was followed by ring
closure under Mitsunobu conditions to afford aziridine 12
(Scheme 1).
anisole as nucleophiles were unsuccessful in giving the addition
product. Only the previously reported enyne product2 was
isolated in trace quantities.
Investigation of Regioselectivity: Synthesis of Azir-
idines. To investigate the regioselectivity of the ring-opening
reaction, several unique trisubstituted aziridines were synthe-
sized, different from those that were used previously in natural
product syntheses (1450 and 166) and in the formation of fully
substituted carbon centers2 (14, 15, and 17) (Figure 4a).
Scheme 1. Synthesis of tert-Butylsulfonyl Aziridine 12
Upon treatment with numerous organometallic reagents
(Grignard, organolithium, aluminum, and cerium reagents)
only starting material and a trace amount of the enyne product,
which was a result of elimination from the C2 methyl, were
isolated. This finding was disappointing ,because on the basis of
a previous result of Grignard reagents with trisubstituted
epoxides47 the combination of Lewis basicity and nucleophil-
icity should have been sufficient to achieve ring opening.
In an effort to improve the reaction with organometallic
carbon nucleophiles, the Nicholas reaction48,49 was proposed.
Dicobalt octacarbonyl is a reagent that was originally used as an
alkyne protecting group,49 but in the Nicholas reaction dicobalt
octacarbonyl is used to activate propargylic leaving groups to
generate stabilized carbocations. If this reaction is applied to a
progargylic aziridine, the aziridine could react with dicobalt
octacarbonyl, losing 2 equiv of carbon monoxide, to produce a
Co2(CO)6−alkyne complex. If the complex were to be treated
with a protic or Lewis acid, a stabilized carbocation could be
generated. This carbocation could be trapped by a nucleophile
to generate an addition product. Upon reaction with an oxidant
the alkyne would be restored.
Figure 4. (a) Previous ethynyl aziridines used in ring-opening
reactions for the syntheses of natural products and quaternary centers.
(b) Aziridines of interest to investigate the regiochemistry of the ring
opening.
Aziridine 18 has an additional methylene carbon in the C-3
functional group. Aziridine 19 only has a methyl group on C-3,
and aziridine 20 has only methyl substituents. The reason for
synthesizing these compounds was to change the electronics of
the substituents to see whether they determined the
regioselectivity. In addition, aziridine 21 has a methyl-
substituted alkyne, and aziridine 22 has a ring activating
group on the less substituted carbon. This distinct aziridine is
still trisubstituted but with the phenyl on the less substituted
carbon. This structural modification should determine which
factor is the more important, the trisubstituted nature of the
aziridine or the activating group (Figure 4b). The aziridines
synthesized are shown in Figure 4.
The tert-butylsulfonyl aziridine 12 was complexed in good
yield (Scheme 2). The structure of the compound could not be
The synthesis of homologated aziridine 18 started from the
known Weinreb amide (23, Scheme 3).51−54 Attack of the
Weinreb amide with methyllithium afforded ketone 24, which
when treated with an ethynyl Grignard gave an inseparable
mixture of diastereomeric tertiary alcohols (25). The acid-labile
protecting groups were removed and the amine was reprotected
with the Ns group to yield compound 26. The diastereomeric
diols were separable by recrystallization, and diol 26 was
reprotected as the silyl ether 27. Under Mitsunobu conditions
the desired aziridine (18) was formed in acceptable yield
(Scheme 3). Although this aziridine was used in the
regioselective ring opening with pyrrolidine,3 the different
reaction conditions with the weaker phenol nucleophile could
lead to a mixture of regioisomeric products.
Scheme 2. Synthesis of Dicobalt Aziridine Complex 13
determined by NMR; therefore, it was confirmed by X-ray
(Supporting Information). It is important to note that
aziridines protected with Ts and Ns groups decomposed
upon reaction with dicobalt octacarbonyl.
Unfortunately, the Nicholas complex was unable to yield the
desired ring-opened product. It is not known whether the rate
of elimination is faster than nucleophilic addition, but protic
(HBF4) and Lewis (BF3·OEt2 and TiCl4) acids with phenol and
The syntheses of azirdines 19, 20, and 22 proceeded through
a similar synthetic sequence (Scheme 4). The synthesis of 19
started from the known ketone 30,55 which after Grignard
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Scheme 3. Synthesis of Homologated Aziridine 18
Scheme 5. Synthesis of Methyl Alkynyl Aziridine 21
Scheme 4. Synthesis of Diastereomeric Aziridines 19, 20,
and 22
group to give 42, and aziridine 21 was formed under
Mitsunobu conditions (Scheme 5).
Crystallographic Analysis of Unsymmetrical Aziri-
dines. Several X-ray structures of the aziridines were
determined to obtain the bond lengths and geometry around
the ring system (Table 1). In each of the aziridines, the C2−N
bond (the more substituted) is longer than the C3−N bond
(the less substituted), suggesting that the C2−N is the weaker
bond. The bond lengths may be explained by the donor−
acceptor interactions generated by the substitution pattern
across the ring system. A stereoelectronic effect between the
filled σC−H orbitals of the methyl groups and the empty σ*C−N
orbital of the C2−N bond of the aziridine would explain why
the more substituted bond is longer than the less substituted
bond. The C2 carbon has more substituents, either alkyl or
ethynyl, that can donate into the σ*C2−N bond. In comparison
to the less substituted C3−N bond, this increased donation
into the C2−N antibonding orbital would lengthen/weaken
this bond.
Using aziridine 20 as a representative, looking at the steric
environment, the methyl−C2−methyl bond angle is much
greater than that of a normal tetrahedral carbon at 116°
(Supporting Information, Table 41). This angle suggests that
even though the carbon is fully substituted the substituents are
not oriented in a manner that would block the carbon for back-
side attack in contrast with SN2 attack on a linear substrate.
Ring-Opening Reactions. After the desired aziridines were
synthesized, the next step was to determine if the changes
would provide different regioisomeric products under the
reaction conditions. The crystallographic information suggests
that the weaker C2−N bond would be broken under the
nucleophilic conditions. All of the trisubstituted aziridines
underwent ring opening in good yield to afford a single
regioisomer with attack at the more substituted carbon (Chart
1). The regioisomer of the products could be determined from
addition gave the tertiary alcohol 31 as a mixture of
diastereomers. The synthesis of aziridines 20 and 22 begin
from their respective methyl esters (28 and 29). Methyllithium
addition to the methyl esters gave the known tertiary alcohols
32 and 33.56 Removal of the carbamates followed by
reprotection with the Ns group gave sulfonamides 34−36.
Each sulfonamide was subjected to Mitsunobu conditions,
which gave a separable mixture of diastereomeric aziridines 19
and 37 and also aziridines 20 and 22 in good yield (Scheme 4).
The methyl alkynyl aziridine 21 was synthesized in six steps
from the known tertiary alcohol 38 (Scheme 5). The alcohol
was protected as the silyl ether with trimethylsilyl chloride to
give 39. Silyl ether protection was necessary for deprotonation
with n-butyllithium. The acetylide anion was quenched with
methyl iodide to give the methyl-substituted alkyne 40. The
alcohol was protected to avoid O-alkylation. Compound 40 was
treated with concentrated HCl to remove the protecting
groups, and the amine was reprotected with the Ns group to
give 41. The primary alcohol of 41 was protected with the TBS
1
the H NMR, where the sulfonamide N−H has a doublet
splitting pattern. In addition, the X-ray structure of 45 showed
the phenol bonded to the more substituted carbon of the
aziridine (Supporting Information).
In an effort to alter the substitution pattern around the
aziridine ring system, the known 2,2-gem-dimethyl-N-tosyl
aziridine 4857 was synthesized and subjected to the ring-
opening conditions. Upon treatment with 1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (TBD) and phenol a mixture of regioisomeric
products (49 and 50) was isolated in a 1:1 ratio. This result is
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a
Table 1. Crystallographic Analysis of Aziridines and Their Carbon−Nitrogen Bond Lengths
a
C2 is the more substituted carbon, C3 is the less substituted carbon, and N is the aziridine nitrogen. The bond distances are in angstroms. Aziridine
20 has four structures in the unit cell, but only one is reported. Aziridine 19 has two structures in the unit cell, but only one is reported.
first observed example of a mixture of regioisomers from an
unsymmetrical aziridine. Although a mixture of regioisomers
was isolated, the reaction displayed no preference for either
carbon of the ring system. This outcome contradicts the notion
that the longer, weaker bond is broken in the ring-opening
reaction.
Chart 1. Results of Aziridine Ring-Opening Reactions with a
Phenol Nucleophile
a
Additional Investigation of the Reaction Regioselec-
tivity. Although a better understanding of the aziridine ring
system was obtained through the X-ray structures, the unusual
regioselectivity of the ring-opening reaction was not explained.
The reaction provides a single stereoisomer with inverted
configuration. However, unsymmetrical aziridines are known to
undergo ring opening via a SET pathway.57,59−63 Upon ring
opening the more stable radical is formed and this radical
would be generated on the more substituted carbon of the
aziridine. While the possibility of this reaction type was low, an
experiment was done to rule out a radical ring opening
(Scheme 6).
No radical byproducts were observed when the radical trap
TEMPO was added to the reaction mixture, and the ring-
opened product isolated was a single stereoisomer whose
spectroscopic data matched those of the known compound.2
Scheme 6. Aziridine Ring-Opening Reaction in the Presence
a
of TEMPO
a
b
Conditions: phenol (2 equiv), TBD (2 equiv), PhCH3. A 1:1
mixture of product was isolated.
a
not the first instance in which aziridine 48 gave a mixture of
Conditions: phenol (2 equiv), TDB (2 equiv), TEMPO (2 equiv),
regioisomers upon nucleophilic ring opening,58 but this was our
PhCH3, 69% yield.
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To get a better analysis of the reaction, TBD and phenol were
replaced with potassium phenoxide. The TBD omission is
important as the guanidine base, TBD, can act as a hydrogen
bond donor and activate the aziridine for attack at the more
substituted carbon.64,65 When TBD was replaced with
potassium hydride (KH), the ring-opening reactions proceeded
in a similar manner (Scheme 7). For the trisubstituted aziridine
Table 2. Optimized Ground State and Transition State
Geometries, with the Transition State Energies and NBO
Charges of the Carbons, of Aziridine 48
a
Scheme 7. Ring-Opening Reactions using KH as a Base
a
Conditions: phenol (4 equiv), KH (4 equiv), 18-crown-6 (4 equiv),
b
c
d
THF. 80% isolated yield. 79% isolated yield. 75% isolated yield.
19 the only reaction observed was attack at the more
substituted carbon. This result could be explained by the
stabilization of the transition state of the alkynyl substituent.66
When aziridine 20 was used, a slight mixture of regioisomers
was observed. This observation was the first instance where a
trisubstituted aziridine gave a mixture of regioisomers.
However, attack at the more substituted carbon was the
major isomer. Aziridine 48 gave a mixture of regioisomers in a
1:2.5 ratio favoring attack at the less substituted carbon.
To examine the electronics of the ring-opening reaction,
density functional theory (DFT) molecular modeling calcu-
lations were performed. Using the Gaussian 09 program
package at the B3LYP/6-31G* basis set, ground state and
transition state calculations were performed to get the
optimized geometries along with the free energies and the
natural bond orbital (NBO) charges of the atoms involved in
the reactions. The charges of the atoms will allow for the
examination of the electronics of the aziridines and transition
states.66 The reactions were implicitly solvated in a self-
consistent reaction field (SCRF) of THF.
The computational model was designed to mimic the
experimental conditions of the potassium phenoxide ring-
opening conditions (Scheme 7). The ground state geometries
were determined for each aziridine, and in each geometry
optimization the more substituted carbon has a higher δ+
charge (Tables 2 and 3). This finding is consistent with our
previous work2 but cannot explain the regioselectivity. The
geometry optimization of aziridine 48 (Table 2) also has a large
δ+ charge at the more substituted carbon, but the ring-opening
reaction proceeds to give a mixture of regioisomers (Chart 1;
Scheme 7). A transition state model was optimized for
aziridines 19, 20, and 48, where the phenoxide attacks both
the more substituted and less substituted carbons. The
approach of the nucleophile was consistent with Walsh
orbitals.67,68 In a typical SN2 reaction, the approach of the
nucleophile is in line with the bond that is being broken, which
is not the case for the aziridine ring opening due to the bent
nature of the aziridine bonding system. This fact in conjunction
with our experimental results suggests a more favored attack
trajectory in contrast to the course of a typical SN2 reaction
(Tables 2 and 3).
Each of the geometries resembles an early transition state,
where the C−N bond of the aziridine is breaking before the
new C−O bond is formed. Within the transition state geometry
optimization, the δ− charges of the aziridine carbon change.
When the nucleophile approaches the carbon involved in the
reaction, the carbon increases in δ+ charge. This observation is
consistent for the six geometries, but the free energies for the
ring openings vary. The transition state energy for aziridine 19,
where the ring opening occurred at the more substituted
carbon, is ΔG⧧ = 16.23 kcal mol−1. The energy for ring opening
at the less substituted carbon is 20.22 kcal mol−1. This value
generates ΔΔG⧧ = 3.99 kcal mol−1. The large difference in the
transition state energies would lead to only one regioisomeric
product formed favoring the attack at the more substituted
carbon, since that has the lower transition state energy. This
difference was observed experimentally, where in Scheme 7,
only one regioisomeric product was observed. The ring-
opening transition state of aziridine 20 exhibited a similar trend.
The attack at the more substituted carbon has an energy of
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a
Table 3. (a) Optimized Ground State and Transition State Geometries, with the Transition State Energies and NBO Charges
of the Carbons, of Aziridines 19 and 20
a
The geometries were optimized with the B3LYP/6-31G* basis set in a SCRF of THF.
ΔG⧧ = 18.24 kcal mol−1. The attack at the less substituted
carbon has an energy of ΔG⧧ = 20.25 kcal mol−1. This energy
difference generates ΔΔG⧧ = 2.01 kcal mol−1 and a predicted
product distribution of 30:1 favoring attack at the more
substituted carbon. These data correlate well to the
experimental outcome of 15:1 in Scheme 7. A possible
explanation for the higher transition state energy for the attack
at the less substituted carbon is unfavorable electronics. In the
transition state optimizations for attack at the less substituted
carbon for aziridines 19 and 20 (Table 3) both carbons of the
aziridine have a δ+ charge. The positive charges in close
proximity could explain why attack at the less substituted
carbon is higher in energy. This higher energy is supported by
the transition state geometries of aziridine 48. The NBO
charges of the aziridine carbons in the transition state
geometries in Table 3 do not have the neighboring positive
charges. Consequently, the transition state energies for attack at
the more and less substituted carbon are ΔG⧧ = 21.50 and
20.66 kcal mol−1, respectively. This explanation generates
ΔΔG⧧ = 0.84 kcal mol−1 and a 4:1 product distribution
favoring attack at the less substituted carbon. The calculated
product ratio agrees with the experimentally observed 2.5:1
product ratio.
CONCLUSIONS
■
2,2,3-Trisubstituted aziridines undergo a regio- and stereo-
selective ring opening that occurs exclusively at the most
encumbered carbon with inversion of configuration. A
computational model designed to mimic the experimental
conditions allowed calculation of the ring-opening transition
state energies of three differently substituted aziridines. The
differences in transition state energies agreed with the
experimental product distribution. Unfavorable electronics at
the less substituted carbon and an alternate attack trajectory
could explain the unique preference for attack at the more
substituted carbon.
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3.50 (1H, m), 2.52 (1H, s), 1.63 (3H, s), 1.45 (9H, s), 0.91 (9H, s),
0.15 (3H, s), 0.14 (3H, s); 13C NMR (125 MHz, CDCl3) δ 85.2, 73.4,
71.5, 65.5, 60.6, 60.3, 28.2, 25.7, 24.3, 18.1, −5.7, −5.7; IR (film): 3280
(s), 2935 (s), 1716 (w), 1457 (s) cm−1; HRMS (EI) m/z calcd for
EXPERIMENTAL SECTION
■
1H and 13C NMR spectra were recorded at 500 and 125 MHz,
respectively, unless otherwise mentioned. 1H NMR chemical shifts are
reported in parts per million (ppm) from the solvent resonance
(CDCl3 7.27 ppm). The data are reported as follows: chemical shift,
number of protons, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, dd = doublet of doublets, br = broad, m = multiplet), and
coupling constants. Proton-decoupled 13C NMR chemical shifts are
reported in ppm from the solvent resonance (CDCl3 77.0 ppm). High-
resolution mass spectra (HRMS) were obtained on a Micromass
AutoSpec electrospray/chemical ionization spectrometer (GC-TOF).
Melting points (°C) were uncorrected. The reaction solvents PhCH3
and CH2Cl2 were all distilled over calcium hydride. THF was distilled
over sodium/benzophenone. Triethylamine was distilled over calcium
hydride, but all other reagents were used without further purification.
All Grignard and alkyllithium reagents were titrated with salicylalde-
hyde phenylhydrazone prior to use. All calculations were performed
using Gaussian 09. All geometries were optimized in a SCRF of THF.
(3R,4R)-4-Amino-5-((tert-butyldimethylsilyl)oxy)-3-methyl-
pent-1-yn-3-ol (9). The known sulfonamide 8 (2.16 g, 5.04 mmol)
was dissolved in anhydrous DMF (50 mL) and cooled to 0 °C under
argon. Cesium carbonate (2.46 g, 7.56 mmol) and thiophenol (1.54
mL, 15.1 mmol) were added sequentially to the solution, and the
reaction was monitored by TLC. The reaction was complete after 3 h.
The solution was diluted with EtOAc (100 mL) and partitioned with
saturated NaHCO3 (50 mL). The two layers were separated, and the
aqueous layer was extracted with EtOAc (100 mL). The combined
organic layers were washed with H2O (6 × 100 mL), after which the
organic layer was dried over Na2SO4, filtered, and concentrated. The
crude oil was purified by silica gel chromatography (10% EtOAc−90%
hexanes →100% EtOAc) to give the desired product as an amorphous
C16H33NO4SSiNa (M + Na)+ 386.1797, found 386.1788; [α]2D5
−16.9° (c 0.96, CHCl3).
=
(2S,3S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-(tert-butyl-
sulfonyl)-2-ethynyl-2-methylaziridine (12). Sulfoxide 11 (740 mg,
2.09 mmol) was dissolved in CH2Cl2 (21 mL) under argon and was
cooled to 0 °C. Triphenylphosphine (1.10 g, 4.18 mmol) and
diisopropyl azodicarboxylate (829 μL, 4.18 mmol) were added
sequentially to the solution. The reaction mixture was stirred overnight
at room temperature by allowing the ice bath to melt. The following
day, the reaction mixture was diluted with 20 mL of EtOAc and
quenched with 10 mL of 1 N NaOH. The heterogeneous solution was
stirred for 20 min to completely hydrolyze the diisopropyl
azodicarboxylate. The two layers were separated, and the aqueous
layer was extracted with EtOAc (2 × 20 mL). The combined organic
layers were washed with brine (10 mL). The organic layer was dried
over Na2SO4, filtered, and concentrated. The crude residue was
purified by silica gel chromatography (100% CH2Cl2), with triethyl-
amine-neutralized silica to afford aziridine 12 as a colorless oil (511
1
mg, 71%): Rf 0.73 (30% EtOAc in hexanes); H NMR (500 MHz,
CDCl3) δ 3.86 (1H, dd, J = 5.4, 5.4 Hz), 3.81 (1H, dd, J = 5.9, 5.9 Hz),
3.00 (1H, t, J = 5.7), 2.30 (1H, s), 1.90 (3H, s), 1.49 (9H, s), 0.91 (9H,
s), 0.09 (3H, s), 0.09 (3H, s); 13C NMR (125 MHz, CDCl3) δ 80.9,
71.2, 62.6, 60.7, 51.5, 41.9, 25.8, 24.1, 20.6, 18.2, −5.3, −5.4; IR (film):
3263 (s), 2955 (s), 2932 (s), 2858 (s), 1723 (s), 1472 (s) cm−1;
HRMS (EI) m/z calcd for C16H31NO3SSiNa (M + Na)+ 368.1692,
found 368.1684; [α]2D0 = +72.1° (c 2.57, CHCl3).
Cobalt Complex 13. Aziridine 12 (874 mg, 2.53 mmol) was
dissolved in dry CH2Cl2 under argon. Dicobalt octacarbonyl (1.00 g,
2.78 mmol) was added in one portion, and the reaction was monitored
by TLC. After completion, the reaction mixture was concentrated and
purified by silica gel chromatography (20% EtOAc−80% hexanes) to
yield complex 13 (1.36 g, 83%) as a red solid: Rf 0.50 (30% EtOAc−
1
white solid (988 mg, 81%); Rf 0.10 (70% EtOAc−30% hexanes); H
NMR (360 MHz, CDCl3) δ 3.73 (1H, dd, J = 5.7, 10.0 Hz), 3.53 (1H,
dd, J = 6.5, 10.0 Hz), 2.76 (1H, m), 2.57 (2H, bs), 2.32 (1H, s), 1.33
(1H, s), 0.77 (9H, s), −0.04 (3H, s), −0.05 (3H, s); 13C NMR (90
MHz, CDCl3) δ 86.2, 71.8, 69.9, 64.5, 59.0, 25.9, 25.5, 17.8, −5.9; IR
(film): 3371 (s), 2359 (s), 3309 (s), 2954 (s), 2930 (s), 2858 (s),
1586 (w), 1472 (s) cm−1; HRMS (EI) m/z calcd for C12H26NO2Si (M
+ H)+ 244.1733, found 244.1761; [α]D25 = 9.2° (c 0.95, CHCl3).
N-((2R,3R)-1-((tert-Butyldimethylsilyl)oxy)-3-hydroxy-3-
methylpent-4-yn-2-yl)-2-methylpropane-2-sulfinamide (10).
The amine 9 (1.22 g, 5.01 mmol) was dissolved in dry CH2Cl2 (50
mL) under argon and cooled to 0 °C. Dry triethylamine (3.5 mL, 25.1
mmol) and tert-butylsulfinyl chloride (931 μL, 7.52 mmol) were added
sequentially to the reaction mixture. The reaction was monitored by
TLC. After completion, the reaction was quenched with saturated
NaHCO3 (70 mL). The two layers were separated, and the aqueous
layer was extracted with EtOAc (4 × 50 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated. The
reaction was purified by silica gel chromatography (50% EtOAc−50%
hexanes) to give 10 as a yellow oil (1.62 g, 93%); Rf 0.60 (50%
1
70% hexanes); H NMR (500 MHz, CDCl3) δ 5.85 (1H, bs), 3.89
(1H, bs), 3.78 (1H, bs), 3.31 (1H, bs), 2.12 (3H, bs), 1.46 (9H, bs),
0.90 (9H, bs), 0.07 (6H, bs); 13C NMR (125 MHz, CDCl3) δ 199.2,
198.8, 94.0, 71.6, 61.8, 61.1, 56.8, 50.2, 25.8, 24.2, 22.5, 18.3, −5.5; IR
(film): 2956 (s), 2931 (s), 2858 (s), 2095 (s), 2029 (s), 2056 (s)
cm−1; HRMS (EI) m/z calcd for C22H31Co2NO9SSiNa (M + Na)+
654.0050, found 654.0073; mp 277−279 °C.
(R)-tert-Butyl 1-(tert-Butyldimethylsilyloxy)-4-oxopentan-3-
ylcarbamate (24). In a 1 L round-bottomed flask, (R)-tert-butyl
3,9,9,10,10-pentamethyl-4-oxo-2,8-diaoxa-3-aza-9-silaundecan-5-ylcar-
bamate (23; 17.5 g, 46.5 mmol) was dissolved in THF (120 mL)
under argon. The solution was cooled to −78 °C, and methyllithium
(22.0 mL; 1.6 M in diethyl ether) was added via cannula. The solution
was stirred at −78 °C under argon for 4 h. After completion, the
reaction mixture was quenched at −78 °C with 150 mL of saturated
NH4Cl. The solution was warmed to room temperature, and 20 mL of
water was added to dissolve the white solid. The aqueous layer was
extracted with diethyl ether (5 × 200 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated. The crude
residue was purified using silica gel chromatography (20% EtOAc−
80% hexanes) to afford (R)-tert-butyl 1-(tert-butyldimethylsilyloxy)-4-
oxopentan-3-ylcarbamate (24) as a yellow oil (13.51 g, 88%): 1H
NMR (500 MHz, CDCl3) δ 5.73 (1H, d, J = 5.1 Hz), 4.22 (1H, dd, J =
5.5 Hz, 5.0 Hz), 3.64 (2H, t, J = 5.5 Hz), 2.16 (3H, s), 2.02−1.98 (1H,
m), 1.91−1.84 (1H, m), 1.37 (9H, s), 0.82 (9H, s), −0.01 (6H, s); 13C
NMR (125 MHz, CDCl3) δ 207.2, 155.5, 79.3, 59.6, 58.6, 33.1, 28.2,
26.7, 25.7, 18.0, −5.8.3
1
EtOAc−50% hexanes); H NMR (500 MHz, CDCl3) δ 4.84 (1H, s),
4.19 (1H, dd, J = 4.1, 10.4 Hz), 4.01 (1H, dd, J = 8.5, 10.4 Hz), 3.45
(1H, d, J = 10.2 Hz), 3.32 (1H, m), 2.50 (1H, s), 1.63 (3H, s), 1.25
(9H, s), 0.92 (9H, s), 0.15 (3H, s), 0.14 (3H, s); 13C NMR (125 MHz,
CDCl3) δ 85.1, 72.9, 71.4, 64.9, 63.2, 56.3, 27.7, 25.6, 22.5, 17.8, −5.8,
−5.9; IR (film): 3311 (s), 2955 (s), 2930 (s), 2858 (s), 1472 (s) cm−1;
HRMS (EI) m/z calcd for C16H34NO3SSi (M + H)+ 348.2029, found
348.2045.
N-((2R,3R)-1-((tert-Butyldimethylsilyl)oxy)-3-hydroxy-3-
methylpent-4-yn-2-yl)-2-methylpropane-2-sulfonamide (11).
Sulfinyl compound 10 (1.62 g, 4.66 mmol) was dissolved in CH2Cl2
and cooled to 0 °C under argon. m-CPBA (77%; 1.36 g, 6.06 mmol)
was added in one portion, and the reaction was monitored by TLC.
After completion in 1 h, the reaction mixture was filtered through a
pad of Celite and concentrated. The reaction was purified by silica gel
chromatography (30% EtOAc−70% hexanes) to give the product 11
(1.67 g, 98%) as a colorless oil: Rf 0.50 (30% EtOAc−70% hexanes);
1H NMR (500 MHz, CDCl3) δ 4.62 (1H, s), 4.21 (1H, d, J = 10.5
tert-Butyl (3R)-1-(tert-Butyldimethylsilyloxy)-4-hydroxy-4-
methylhex-5-yn-3-ylcarbamate (25). In a 1 L round-bottomed
flask, the ketone 24 (7.26 g, 21.9 mmol) was dissolved in THF (62
mL) under argon. The solution was cooled to 0 °C, and
ethynylmagnesium bromide (136 mL; 0.5 M in tetrahydrofuran) was
added to the flask. The ice bath was removed, and the reaction was
stirred overnight. After completion, the reaction mixture was cooled to
Hz), 4.12 (1H, dd, J = 3.5, 10.5 Hz), 4.06 (1H, dd, J = 6.5, 10.5 Hz),
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0 °C and quenched with 125 mL of saturated NH4Cl. The reaction
mixture was warmed to room temperature to allow the white solid to
dissolve in enough water (10 mL). The aqueous layer was extracted
with diethyl ether (5 × 125 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The crude residue was
purified by silica gel chromatography (7% acetone−93% hexanes) to
afford tert-butyl (3R)-1-(tert-butyldimethylsilyloxy)-4-hydroxy-4-meth-
ylhex-5-yn-3-ylcarbamate (25) as a yellow oil that was a 1:1 mixture of
and quenched with 15 mL of 1 N NaOH. The heterogeneous solution
was stirred for 20 min to completely hydrolyze the diisopropyl
azodicarboxylate. The aqueous layer was extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with brine (10 mL).
The organic layer was dried over Na2SO4, filtered, and concentrated.
The crude residue was purified by silica gel chromatography (15%
EtOAc−85% hexanes), with triethylamine-neutralized silica to afford
the aziridine as a white solid (620 mg, 72%). The structure was
1
1
diastereomers (7.35 g, 94%). H NMR (500 MHz, CDCl3) δ 5.08
determined by X-ray analysis: H NMR (500 MHz, CDCl3) δ 8.21
(1H, d, J = 8.7 Hz), 4.97 (1H, d, J = 8.6 Hz), 4.63 (1H, m), 4.60 (1H,
m), 3.73 (6H, m), 2.45 (1H, s), 2.41 (1H, s), 2.08 (2H, m), 1.95 (2H,
m), 1.46 (3H, s), 1.45 (3H, s), 1.41 (18H, bs), 0.88 (9H, s), 0.87 (9H,
s), 0.05 (12H, s); 13C NMR (125 MHz, CDCl3) δ 156.4, 156.3, 86.1,
86.1, 79.6, 79.5, 73.0, 72.3, 70.6, 69.8, 60.6, 59.3, 57.5, 56.6, 33.8, 33.2,
28.3, 27.2, 26.4, 25.8, 18.1, 18.1, −5.5, −5.6.3
(1H, m), 7.74 (3H, m), 3.67 (2H, m), 3.45 (1H, dd, J = 5.2 Hz, 7.9
Hz), 2.55 (1H, s), 1.98−1.90 (1H, m), 1.70−1.64 (1H, m), 1.58 (3H,
s), 0.88 (9H, s), 0.04 (6H, s); 13C NMR (125 MHz, CDCl3) δ 148.4,
134.1, 133.5, 132.1, 131.0, 124.3, 80.7, 74.2, 60.3, 53.1, 42.9, 30.4, 25.9,
20.2, 18.3, −5.4.3
tert-Butyl ((2R)-3-Hydroxy-3-methylpent-4-yn-2-yl)-
carbamate (31). Ketone 30 (2.89 g, 15.4 mmol) was dissolved in
dry THF (74 mL) under argon and cooled to 0 °C. Ethynylmagne-
sium bromide (80 mL, 0.5 M in THF) was added to the solution and
was slowly warmed to room temperature and stirred overnight. Once
the reaction was complete, the mixture was cooled to 0 °C and
quenched with saturated NH4Cl (50 mL). The mixture was warmed to
room temperature, and 15 mL of H2O was added to dissolve the white
solid. The two layers were separated, and the aqueous layer was
extracted with Et2O (2 × 50 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The crude oil was
purified by silica gel chromatography (25% acetone−75% hexanes) to
give the product 31 as a colorless oil in a 1:1 mix of diastereomers
N-((3R,4R)-1,4-Dihydroxy-4-methylhex-5-yn-3-yl)-2-nitro-
benzenesulfonamide (26). A diastereomeric mixture of tertiary
alcohols 25 (304 mg, 0.851 mmol) was dissolved in THF (4 mL), and
1.5 mL of concentrated HCl was added dropwise to the solution. The
reaction mixture was stirred at room temperature for 2 h. The THF
was removed, and the water was azeotropically removed with MeCN
(5 × 10 mL). The crude mixture was redissolved in 4 mL of THF−
H2O (2:1), and sodium carbonate (451 mg, 4.225 mmol) was slowly
added to the solution. The pH was checked to ensure that the solution
was basic (pH 10), and 2-nitrobenzenesulfonyl chloride (189 mg,
0.851 mmol) was added. The reaction mixture was stirred at room
temperature overnight. The next day the reaction mixture was
partitioned between 10 mL of brine and 10 mL of EtOAc. The
aqueous layer was extracted with EtOAc (3 × 5 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated. The
mixture of diastereomers was purified by silica gel chromatography
(70% EtOAc−30% hexanes) to give the product (136 mg, 49%) as a
cloudy, yellow oil. The mixture of diastereomers was separated by
crystallization in chloroform, and the crystalline diastereomer N-
(3R,4R)-1,4-dihydroxy-4-methylhex-5-yn-3-yl)-2-nitrobenzenesulfona-
mide (26) was isolated as a white solid: 1H NMR (360 MHz, MeOH-
d4) δ 8.13 (1H, dd, J = 8.7 Hz, 6.1 Hz), 7.88 (1H, m), 7.78 (2H, dd, J
= 3.2 Hz, 5.9 Hz), 3.61 (2H, m), 3.52 (1H, m), 2.81 (1H, s), 2.11 (1H,
qd, J = 3.0 Hz, 7.4 Hz), 1.80 (1H, m); 13C NMR (90 MHz, MeOH-d4)
δ 149.3, 136.7, 134.8, 133.9, 131.8, 126.1, 86.9, 74.7, 70.8, 61.6, 59.8,
35.4, 28.3.3
N-(3R,4R)-1-(tert-Butyldimethylsilyloxy)-4-hydroxy-4-meth-
ylhex-5-yn-3-yl)-2-nitrobenzenesulfonamide (27). The tertiary
alcohol 26 (119 mg, 0.362 mmol) was suspended in CH2Cl2 (4 mL),
under argon, and was cooled to 0 °C. Triethylamine (252 μL, 1.810
mmol), tert-butyldimethylsilyl chloride (82 mg, 0.543 mmol), and 4-
dimethylaminopyridne (4 mg, 0.0362 mmol) were added to the
reaction mixture sequentially. The reaction mixture was stirred
overnight at room temperature by allowing the ice bath to melt.
The following day, the reaction was partitioned between 5 mL of H2O
and 5 mL of EtOAc. The aqueous layer was extracted with EtOAc (3 ×
10 mL). The combined organic layers were washed with 10 mL of
brine. The organic layers were dried over MgSO4, filtered, and
concentrated. The crude residue was purified by silica gel
chromatography (60% EtOAc−40% hexanes) to afford the product
27 as a thick oil (136 mg, 85%): 1H NMR (500 MHz, CDCl3) δ 8.13
(1H, m), 7.86 (1H, m), 7.73 (2H, m), 5.82 (1H, d, J = 8.6 Hz), 4.52
(1H, s), 3.82 (1H, m), 3.74 (1H, m), 3.62 (1H, m), 2.51 (1H, s), 2.23
(1H, qd, J = 4.3 Hz, 8.7 Hz), 1.93 (1H, m), 1.32 (3H, s), 0.91 (9H, s),
0.07 (6H, s); 13C NMR (125 MHz, CDCl3) δ 147.5, 134.7, 133.4,
132.8, 130.2, 125.1, 85.2, 74.0, 68.9, 60.4, 58.3, 34.5, 27.1, 25.7, 18.1,
−5.5.3
1
(3.10 g, 95%): Rf 0.43 (25% acetone−75% hexanes); H NMR (360
MHz, CDCl3) δ 4.81 (2H, m), 3.71 (2H, m), 3.55 (2H, s), 2.44 (1H,
s), 2.42 (1H, s), 1.44 (3H, s), 1.46 (3H, s), 1.40 (9H, s), 1.39 (9H, s),
1.27 (3H, d, J = 4.0 Hz), 1.25 (3H, d, J = 4.9 Hz), 1.21 (3H, d, J = 5.1
Hz), 1.20 (3H, d, J = 5.0 Hz); 13C NMR (125 MHz, CDCl3) δ 156.4,
156.2, 85.9, 85.1, 79.4, 79.8, 72.8, 72.5, 71.2, 54.9, 54.1, 28.3, 28.3,
27.1, 25.8, 17.6, 17.1, 16.1; IR (film): 3407 (s), 3310 (s), 2981 (s),
2936 (s), 1692 (s), 1509 (s) cm−1; HRMS (CI) m/z calcd for
C11H20NO3 (M + H)+ 214.1443, found 214.1446.
tert-Butyl (R)-(3-Hydroxy-3-methylbutan-2-yl)carbamate
(32). Methyl (tert-butoxycarbonyl)-D-alaninate (28; 3.16 g, 15.6
mmol) was dissolved in dry THF (52 mL) under argon and cooled
to −78 °C. Methyllithium (34 mL, 1.6 M in Et2O) was added to the
solution, and the reaction mixture was stirred and monitored by TLC.
After 2 h, the reaction was complete and the mixture quenched with
saturated NH4Cl (100 mL). The partition was warmed to room
temperature, and enough H2O (10 mL) was added to dissolve the
white solids. The two layers were separated, and the aqueous layer was
extracted with Et2O (150 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The crude oil was
purified by silica gel chromatography to give the tertiary alcohol 32
1
(2.48 g, 78%): Rf 0.42 (40% EtOAc−60% hexanes); H NMR (500
MHz, CDCl3) δ 4.87 (1H, d, J = 8.5 Hz), 3.55 (1H, m), 2.76 (1H, m),
1.40 (9H, s), 1.18 (3H, s), (3H, s), 1.09 (3H, d, J = 7.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 156.3, 79.2, 72.8, 54.4, 28.3, 27.9, 25.5, 16.0; IR
(film): 3440 (s), 2979 (s), 2934 (s), 1690 (s) cm−1; HRMS (ESI) m/z
calcd for C10H21NO3Na (M + Na)+ 226.1419, found 226.1421; [α]2D5
+1.8° (c 4.21, CHCl3).
=
tert-Butyl (R)-(2-Hydroxy-2-methyl-1-phenylpropyl)-
carbamate (33). The ester 29 (12.9 g, 48.5 mmol) was dissolved
in dry THF (145 mL) under argon and cooled to −78 °C.
Methyllithium (97 mL; 2.0 M in Et2O) was added via cannulation.
The reaction mixture was slowly warmed to 0 °C and monitored by
TLC. After completion, the reaction mixture was cooled to −78 °C
and quenched with saturated NH4Cl (200 mL). The mixture was
slowly warmed to room temperature, and enough H2O was added to
dissolve the white solid. The two layers were separated, and the
aqueous layer was extracted with Et2O (2 × 100 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated. The
crude product was purified by silica gel chromatography (10% → 20%
→ 30% EtOAc−hexanes) to give product 33 as a white solid (11.4 g,
89%): Rf 0.32 (30% EtOAc−70% hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.35−7.27 (5H, m), 5.55 (1H, d, J = 8.5 Hz), 4.52 (1H, bs),
(2R,3R)-3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-ethynyl-2-
methyl-1-(2-nitrophenylsulfonyl)aziridine (18). The viscous oil
27 (879 mg, 2.03 mmol) was dissolved in CH2Cl2 (21 mL) under
argon and was cooled to 0 °C. Triphenylphosphine (798 mg, 3.04
mmol) and diisopropyl azodicarboxylate (603 μL, 3.04 mmol) were
added sequentially to the solution. The reaction mixture was stirred
overnight at room temperature by allowing the ice bath to melt. The
following day, the reaction mixture was diluted with 30 mL of EtOAc
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1.73 (1H, bs), 1.41 (9H, bs), 1.34 (3H, bs), 1.06 (3H, bs); 13C NMR
(125 MHz, CDCl3) δ 155.8, 139.7, 128.2, 127.9, 127.5, 79.5, 72.8,
62.8, 28.3, 27.6, 27.5; IR (film): 3440 (s), 2978 (s), 1695 (s), 1496 (s)
cm−1; HRMS (EI) m/z calcd for C15H23NO3Na (M + Na)+ 288.1576,
found 288.1588; [α]2D0 = −21.2° (c 0.59, CHCl3); mp 113−115 °C.
N-((2R)-3-Hydroxy-3-methylpent-4-yn-2-yl)-2-nitrobenzene-
sulfonamide (34). Carbamate 31 (3.43 g, 16.1 mmol) was dissolved
in THF (64 mL), and concentrated HCl (17 mL) was added to the
solution. The reaction was monitored by TLC. After 1 h, the reaction
mixture was concentrated and azeotroped with MeCN to remove the
water. The crude amine was dissolved in THF/H2O (44 mL/22 mL),
and Na2CO3 (8.52 g, 80.4 mmol) and 2-nitrobenzenesulfonyl chloride
(3.56 g, 16.1 mmol) were added sequentially to the reaction mixture.
The reaction was monitored by TLC and stirred overnight. After
completion the reaction mixture was diluted with EtOAc (100 mL)
and partitioned with brine (30 mL). The aqueous layer was separated
and extracted with EtOAc (2 × 50 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated. The crude oil was
purified by silica gel chromatography (40% EtOAc−60% hexanes) to
give the product as a pale yellow oil as a 1:1 mix of diastereomers (4.41
7.48−7.43 (2H, m), 7.27−7.24 (1H, m), 7.10−7.09 (2H, m), 7.01−
6.98 (3H, m), 6.48 (1H, d, J = 9.5 Hz), 4.34 (1H, d, J = 9.5 Hz), 1.82
(1H, bs), 1.46 (3H, s), 1.02 (3H, s); 13C NMR (125 MHz, CDCl3) δ
147.1, 136.7, 134.3, 132.6, 132.2, 130.4, 128.1, 127.9, 127.7, 124.5,
72.7, 66.8, 27.7, 27.4; IR (film): 3533 (s), 3358 (s), 3097 (s), 3030 (s),
2979 (s), 1540 (s) cm−1; HRMS (EI) m/z calcd for C16H18N2O5SNa
(M + Na)+ 373.0834, found 373.0837; [α]2D2 = −267.8° (c 1.56,
CHCl3); mp 114−116 °C.
(2S,3R)-2-Ethynyl-2,3-dimethyl-1-((2-nitrophenyl)sulfonyl)-
aziridine (19). The tertiary alcohol 34 was dissolved in dry THF (27
mL) and cooled to 0 °C. Triphenylphosphine (1.54 g, 6.07 mmol) and
diisopropyl azodicarboxylate (1.19 mL, 6.07 mmol) were added
sequentially to the solution, and the reaction mixture was warmed to
room temperature. The reaction mixture was monitored by TLC and
stirred overnight. Upon completion, the reaction mixture was diluted
with EtOAc (30 mL), cooled to 0 °C, and quenched with 1 N NaOH
(20 mL). The two layers were separated, and the aqueous layer was
extracted with EtOAc (20 mL). The combined organic layers were
washed with brine and separated. The organic layer was dried over
Na2SO4, filtered, and concentrated. The crude oil was purified by silica
gel chromatography (100% CH2Cl2) to give the diastereomeric
1
g, 95%): Rf 0.68 (60% EtOAc−40% hexanes); H NMR (500 MHz,
1
CDCl3) δ 8.18−8.16 (2H, m), 7.90−7.88 (2H, m), 7.78−7.73 (4H,
m), 5.60 (1H, d, J = 9.5 Hz), 5.55 (1H, d, J = 9.0 Hz), 3.64−3.58 (1H,
m), 3.57−3.52 (1H, m), 2.73 (1H, s), 2.54 (1H, s), 2.40 (1H, s), 2.35
(1H, s), 1.52 (3H, s), 1.48 (3H, s), 1.21−1.18 (6H, m); 13C NMR
(125 MHz, CDCl3) δ 147.7, 134.8, 134.6, 133.7, 133.5, 133.0, 132.9,
130.7, 130.6, 125.4, 125.3, 84.4, 83.7, 74.1, 73.6, 70.4, 70.3, 59.3, 58.3,
26.6, 17.4, 16.6; IR (film): 3514 (s), 3363 (s), 3293 (s), 3097 (s), 2987
(s), 1535 (s), 1415 (s) cm−1; HRMS (CI) m/z calcd for C12H13N2O4S
(M − OH)+ 281.0596, found 281.0591.
aziridines 19 and 37 (726 mg, 64%): Rf 0.88 (100% CH2Cl2); H
NMR (500 MHz, CDCl3) δ 8.24 (1H, m), 7.75 (3H, m), 3.46 (1H, q,
J = 6.0 Hz), 2.56 (1H, s), 1.57 (3H, s), 1.34 (3H, d, J = 6.0 Hz); 13C
NMR (125 MHz, CDCl3) δ 147.8, 134.3, 134.1, 132.6, 130.8, 124.3,
80.4, 72.4, 50.6, 47.1, 21.3, 14.4; IR (film): 3285 (s), 3098 (s), 2984
(w), 2934 (w), 1545 (s) cm−1; HRMS (ESI) m/z calcd for
C12H13N2O4S (M + H)+ 281.0605, found 281.0596; [α]2D1 = +287.2°
(c 0.80, CHCl3); mp 94−96 °C.
(2R,3R)-2-Ethynyl-2,3-dimethyl-1-((2-nitrophenyl)sulfonyl)-
aziridine (37): Rf 0.82 (100% CH2Cl2); 1H NMR (500 MHz, CDCl3)
δ 8.23 (1H, bs), 7.76 (3H, bs), 3.46 (1H, q, J = 5.5 Hz), 2.56 (1H, s),
1.57 (3H, s), 1.34 (3H, d, J = 5.5 Hz); 13C NMR (125 MHz, CDCl3) δ
148.2, 134.1, 133.8, 132.3, 131.1, 124.3, 80.7, 74.1, 51.1, 42.5, 19.6,
12.4; IR (film): 3266 (s), 3101 (w), 2939 (w), 1699 (w), 1542 (s)
cm−1; HRMS (ESI) m/z calcd for C12H12N2O4SNa (M + Na)+
303.0413, found 303.0415; [α]2D3 +214.9° (c 1.04, CHCl3); mp
158−159 °C.
(R)-N-(3-Hydroxy-3-methylbutan-2-yl)-2-nitrobenzenesulfo-
namide (35). Carbamate 32 (1.49 g, 7.33 mmol) was dissolved in
THF (29 mL), and concentrated HCl (8 mL) was added to the
solution. The reaction was monitored by TLC. After 1 h, the reaction
mixture was concentrated and azeotroped with MeCN to remove the
water. The crude amine was dissolved in THF/H2O (20 mL/10 mL),
and Na2CO3 (3.88 g, 36.7 mmol) and 2-nitrobenzenesulfonyl chloride
(1.62 g, 7.33 mmol) were added sequentially to the reaction mixture.
The reaction mixture was monitored by TLC and stirred overnight.
After completion the reaction was diluted with EtOAc (50 mL) and
partitioned with brine (250 mL). The two layers were separated and
the aqueous layer was extracted with EtOAc (2 × 50 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated. The crude oil was purified by silica gel chromatography
(60% EtOAc−40% hexanes) to the product as a pale yellow oil (1.75
(R)-2,2,3-Trimethyl-1-((2-nitrophenyl)sulfonyl)aziridine (20).
Sulfonamide 35 (1.70 g, 5.88 mmol) was dissolved in THF (59 mL)
under argon and was cooled to 0 °C. Triphenylphosphine (2.31 mg,
8.82 mmol) and diisopropyl azodicarboxylate (1.73 mL, 8.82 mmol)
were added sequentially to the solution. The reaction mixture was
stirred overnight, at 50 °C. The following day, the reaction mixture
was diluted with 100 mL of EtOAc and quenched with 50 mL of 1 N
NaOH. The heterogeneous solution was stirred for 20 min to
completely hydrolyze the diisopropyl azodicarboxylate. The two layers
were separated, and the aqueous layer was extracted with EtOAc (2 ×
100 mL). The combined organic layers were washed with brine (50
mL). The organic layer was dried over Na2SO4, filtered, and
concentrated. The crude residue was purified by silica gel
chromatography (100% CH2Cl2), to afford the aziridine as a white
1
g, 83%): Rf 0.20 (30% EtOAc−70% hexanes); H NMR (500 MHz,
CDCl3) δ 8.15 (1H, m), 7.86 (1H, m), 7.75 (2H, m), 5.49 (1H, d, J =
8.5 Hz), 3.39 (1H, m), (1H, bs), 1.12 (3H, s), (3H, s), 1.05 (3H, d, J =
7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 147.7, 134.6, 133.5, 132.9,
130.7, 125.3, 72.3, 59.1, 27.1, 25.4, 16.4; IR (film): 3537 (s), 3368 (s),
2982 (s), 2937 (s), 1542 (s) cm−1; HRMS (ESI) m/z calcd for
C11H16N2O5SNa (M + Na)+ 311.0678, found 311.0677; [α]2D1
−140.9° (c 1.24, CHCl3).
=
1
solid (1.09 g, 69%): Rf 0.59 (40% EtOAc−60% hexanes); H NMR
(R)-N-(2-Hydroxy-2-methyl-1-phenylpropyl)-2-nitrobenze-
nesulfonamide (36). Carbamate 33 (11.4 g, 43.0 mmol) was
dissolved in THF (215 mL), and concentrated HCl (54 mL) was
added to the solution. The reaction was monitored by TLC. After 1 h,
the reaction mixture was concentrated and azeotroped with MeCN to
remove the water. The crude amine was dissolved in THF/H2O (144
mL/72 mL), and Na2CO3 (22.8 g, 215 mmol) and 2-nitro-
benzenesulfonyl chloride (9.52 g, 43.0 mmol) were added sequentially
to the reaction mixture. The reaction mixture was monitored by TLC
and stirred overnight. After completion the reaction mixture was
diluted with EtOAc (300 mL) and partitioned with brine (100 mL).
The two layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 100 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated. The crude oil was purified by
silica gel chromatography (30% EtOAc−70% hexanes) to give the
product as a pale purple solid (13.6 g, 90%): Rf 0.42 (30% EtOAc−
(500 MHz, CDCl3) δ 8.18 (1H, m), 7.71 (3H, m), 3.12 (1H, q, J = 6.0
Hz), 1.74 (3H, s), 1.34 (3H, m), 1.28 (3H, d, J = 5.5 Hz); 13C NMR
(125 MHz, CDCl3) δ 148.0, 135.0, 133.5, 132.2, 130.3, 124.1, 54.4,
50.7, 22.6, 20.4, 12.9; IR (film): 3283 (s), 2922 (s), 1542 (s) cm−1;
HRMS (EI) m/z calcd for C11H14N2O4SNa (M + Na)+ 293.0574,
found 293.0572; [α]2D2 = +295.5° (c 1.18, CHCl3); mp 77−79 °C.
(R)-2,2-Dimethyl-1-((2-nitrophenyl)sulfonyl)-3-phenylaziri-
dine (22). Sulfonamide 36 (12.9 g, 36.9 mmol) was dissolved in THF
(246 mL) under argon and was cooled to 0 °C. Triphenylphosphine
(14.5 g, 55.4 mmol) and diisopropyl azodicarboxylate (10.9 mL, 55.4
mmol) were added sequentially to the solution. The reaction mixture
was stirred for 3 h, and the reaction was complete as monitored by
TLC. The reaction mixture was diluted with 200 mL of EtOAc and
quenched with 100 mL of 1 N NaOH. The heterogeneous solution
was stirred for 20 min to completely hydrolyze the diisopropyl
azodicarboxylate. The two layers were separated, and the aqueous layer
was extracted with EtOAc (2 × 100 mL). The combined organic layers
1
70% hexanes); H NMR (500 MHz, CDCl3) δ 7.65−7.63 (1H, m),
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Article
were washed with brine (50 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated. The crude residue was purified by
silica gel chromatography (100% CH2Cl2), to afford the aziridine as a
IR (film): 3361 (s), 2924 (w), 1541 (s) cm−1; HRMS (EI) m/z calcd
for C13H16N2O6SNa (M + Na)+ 351.0627, found 351.0634; [α]2D1
+10.1° (c 1.17, CHCl3).
=
1
white solid (10.1 g, 82%): Rf 0.37 (30% EtOAc−70% hexanes); H
N-((2R,3R)-1-((tert-Butyldimethylsilyl)oxy)-3-hydroxy-3-
methylhex-4-yn-2-yl)-2-nitrobenzenesulfonamide (42). To a
solution of compound 41 (510 mg, 1.55 mmol) in CH2Cl2 (16 mL)
at 0 °C was added triethylamine (1.10 mL, 7.76 mmol), tert-
butyldimethylsilyl chloride (304 mg, 2.02 mmol), and 4-dimethylami-
nopyridine (19.0 mg, 0.155 mmol) sequentially. The reaction mixture
was stirred at 0 °C for 30 min and warmed to room temperature
overnight. The reaction mixture was partitioned between 50 mL of
EtOAc and 30 mL of H2O. The aqueous layer was extracted with
EtOAc (2 × 50 mL), and the combined organic layers were washed
with brine (30 mL). The organic layers were dried over MgSO4,
filtered, and concentrated. The residue was purified by silica gel
chromatography (30% EtOAc−70% hexanes) to afford 42 as a pale
yellow oil (691 mg, quantitative); Rf 0.40 (30% acetone−70%
hexanes): 1H NMR (500 MHz, CDCl3) δ 8.13−8.11 (1H, m),
7.87−7.85 (1H, m), 7.76−7.70 (2H, m), 5.73 (1H, d, J = 9.0 Hz), 4.22
(1H, s), 3.91−3.85 (2H, m), 3.54−3.50 (1H, m), 1.72 (3H, s), 1.31
(3H, m), 0.84 (9H, s), 0.02 (6H, s); 13C NMR (125 MHz, CDCl3) δ
147.5, 134.7, 133.5, 132.9, 130.3, 125.2, 81.8, 79.5, 77.2, 70.8, 64.8,
60.8, 27.8, 25.6, 17.9, 3.3, −5.9; IR (film): 3374 (s), 2928 (s), 2857
(s), 1541 (s) cm−1; HRMS (EI) m/z calcd for C19H29N2O6SSi (M −
H)− 441.1516, found 441.1517; [α]D21 = +51.5° (c 0.91, CHCl3).
(2S,3S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-2-methyl-1-
((2-nitrophenyl)sulfonyl)-2-(prop-1-yn-1-yl)aziridine (21). The
tertiary alcohol 42 was dissolved in dry THF (16 mL) and cooled to 0
°C. Triphenylphosphine (615 mg, 2.34 mmol) and diisopropyl
azodicarboxylate (464 μL, 2.34 mmol) were added sequentially to
the solution, and the reaction mixture was warmed to room
temperature. The reaction mixture was monitored by TLC and stirred
overnight. Upon completion, the reaction was diluted with EtOAc (30
mL), cooled to 0 °C, and quenched with 1 N NaOH (20 mL). The
two layers separated, and the aqueous layer was extracted with EtOAc
(2 × 20 mL). The combined organic layers were washed with brine
and separated. The organic layer was dried over Na2SO4, filtered, and
concentrated. The crude oil was purified by silica gel chromatography
(100% CH2Cl2) to give aziridine 21 (464 mg, 71%): Rf 0.50 (100%
NMR (500 MHz, CDCl3) δ 8.25−8.24 (1H, m), 7.75−7.73 (3H, m),
7.28−7.24 (3H, m), 7.14−7.13 (2H, m), 4.23 (1H, s), 1.93 (3H, s),
1.15 (3H, s); 13C NMR (125 MHz, CDCl3) δ 148.2, 134.4, 133.9,
133.8, 132.1, 130.4, 128.2, 127.7, 126.9, 124.3, 56.3, 55.7, 22.5, 20.3; IR
(film): 3093 (w), 2997 (w), 2932 (w), 1592 (w), 1544 (s) cm−1;
HRMS (EI) m/z calcd for C16H16N2O4SNa (M + Na)+ 355.0728,
found 355.0737; [α]2D2 = +100.4° (c 1.57, CHCl3); mp 94−96 °C.
tert-Butyl (R)-2,2-Dimethyl-4-((R)-2-((trimethylsilyl)oxy)but-
3-yn-2-yl)oxazolidine-3-carboxylate (39). To a solution of
compound 38 (1.04 g, 3.86 mmol) in CH2Cl2 (39 mL) at 0 °C
were added triethylamine (1.42 mL, 19.3 mmol), trimethylsilyl
chloride (588 μL, 4.63 mmol), and 4-dimethylaminopyridine (47.0
mg, 0.386 mmol) sequentially. The reaction mixture was stirred at 0
°C for 30 min and warmed to room temperature overnight. The
reaction mixture was partitioned between 75 mL of EtOAc and 75 mL
of H2O. The aqueous layer was extracted with EtOAc (3 × 100 mL),
and the combined organic layers were washed with brine (50 mL).
The organic layers were dried over MgSO4, filtered, and concentrated.
The residue was purified by silica gel chromatography (30% EtOAc−
70% hexanes) to afford 39 as a white amorphous solid (1.27 g, 95%):
1
Rf 0.51 (10% EtOAc−90% hexanes); H NMR (500 MHz, CDCl3) δ
54.21 (1H, bs), 4.03−3.93 (2H, m, rotamers), 2.44 (1H, s), 1.67 (3H,
bs), 1.49 (15H, s), 0.20 (9H, s); 13C NMR (125 MHz, CDCl3) δ
205.7, 80.3, 73.5, 72.3, 65.5, 65.1, 28.3, 1.9; IR (film): 2976 (s), 1702
(s), 1358 (s) cm−1; HRMS (EI) m/z calcd for C17H31NO4SiNa (M +
Na)+ 364.1920, found 364.1914; [α]D21 = +63.2,° (c 1.87, CHCl3).
tert-Butyl (R)-2,2-Dimethyl-4-((R)-2-((trimethylsilyl)oxy)pent-
3-yn-2-yl)oxazolidine-3-carboxylate (40). Compound 39 (1.27 g,
3.72 mmol) was dissolved in dry THF (37 mL), under argon, and was
cooled to −78 °C. n-Butyllithium (1.60 mL, 4.09 mmol) was added
dropwise, and the solution was stirred at −78 °C for 15 min. After this,
methyl iodide (277 μL, 4.46 mmol) was added and the reaction
mixture was stirred for 1 h and monitored by TLC. When the reaction
was complete, saturated NH4Cl (50 mL) was added to quench the
reaction. The two layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 50 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated. The reaction mixture
was purified by silica gel chromatography (50% EtOAc−50% hexanes)
to give the product 39 (708 mg, 54%) as a colorless oil: Rf 0.51 (10%
EtOAc−90% hexanes); 1H NMR (500 MHz, CDCl3) δ 4.21 (1H, bs),
4.03−3.93 (2H, m, rotamers), 2.44 (1H, s), 1.67 (3H, bs), 1.49 (15H,
s), 0.20 (9H, s); 13C NMR (125 MHz, CDCl3) δ 205.7, 80.3, 73.5,
72.3, 65.5, 65.1, 28.3, 1.9; IR (film): 2976 (s), 1702 (s), 1358 (s) cm−1;
HRMS (EI) m/z calcd for C17H31NO4SiNa (M + Na)+ 364.1920,
found 364.1914; [α]2D1 +63.2° (c 1.87, CHCl3).
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.27−8.25 (1H, m), 7.77−
7.72 (3H, m), 4.03 (1H, dd, J = 4.5, 10.8 Hz), 3.66 (1H, dd, J = 7.5,
10.5 Hz), 3.30 (1H, dd, J = 4.0, 7.5 Hz), 1.98 (3H, s), 1.86 (3H, s),
0.87 (9H, s), 0.05−0.04 (6H, s); 13C NMR (125 MHz, CDCl3) δ
148.0, 134.5, 133.9, 132.4, 130.9, 124.4, 81.1, 75.9, 61.9, 54.1, 47.9,
25.8, 22.2, 18.2, 3.8, −5.3, −5.4; IR (film): 3374 (s), 2928 (s), 2857
(s), 1541 (s) cm−1; HRMS (EI) m/z calcd for C19H29N2O5SSi (M +
H)+ 425.1566, found 425.1564; [α]D21 = +145.8° (c 0.91, CHCl3); mp
65−67 °C.
N-((3R,4R)-1-((tert-Butyldimethylsilyl)oxy)-4-methyl-4-phe-
noxyhex-5-yn-3-yl)-2-nitrobenzenesulfonamide (43). Aziridine
18 (31.4 mg, 0.0740 mmol) and phenol (14.0 mg, 0.148 mmol) were
placed in a flask and dissolved in dry PhCH3 (736 μL). 1,5,7-
Triazabicyclo[4.4.0]dec-5-ene (TBD; 21.0 mg, 0.148 mmol) was
added in one portion, and the reaction was monitored by TLC. After
completion, the reaction mixture was concentrated and purified by
silica gel chromatography (30% EtOAc−70% hexanes) to give the
product as an amorphous solid (32.3 mg, 84%): Rf 0.45 (30%
N-((2R,3R)-1,3-Dihydroxy-3-methylhex-4-yn-2-yl)-2-nitro-
benzenesulfonamide (41). Carbamate 40 (708 mg, 1.99 mmol) was
dissolved in THF (8 mL), and concentrated HCl (2 mL) was added to
the solution. The reaction was monitored by TLC. After 1 h, the
reaction mixture was concentrated and azeotroped with MeCN to
remove the water. The crude amine was dissolved in THF/H2O (6
mL/3 mL), and Na2CO3 (1.06 g, 9.96 mmol) and 2-nitro-
benzenesulfonyl chloride (441 mg, 1.99 mmol) were added
sequentially to the reaction mixture. The reaction mixture was
monitored by TLC and stirred overnight. After completion the
reaction was diluted with EtOAc (20 mL) and partitioned with brine
(10 mL). The two layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 20 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated. The crude oil was
purified by silica gel chromatography (30% EtOAc−70% hexanes) to
give the product as a white foam (510 mg, 78%): Rf 0.08 (30%
1
acetone−70% hexanes); H NMR (500 MHz, CDCl3) δ 8.14−8.12
(1H, m), 7.86−7.84 (1H, m), 7.64−7.59 (2H, m), 7.24−7.21 (2H, m),
7.08−7.05 (1H, m), 7.00−6.98 (2H, m), 5.71 (1H, d, J = 9.5 Hz),
4.12−4.08 (1H, m), 3.73−3.70 (1H, m), 3.60−3.55 (1H, m), 2.45
(1H, s), 2.35−2.29 (1H, m), 1.78−1.71 (1H, m), 1.53 (3H, s), 0.91
(9H, m), 0.05 (3H, s), 0.04 (3H, s); 13C NMR (125 MHz, CDCl3) δ
154.3, 147.5, 135.7, 132.8, 132.7, 130.7, 128.9, 125.0, 123.7, 122.1,
82.5, 78.3, 59.9, 59.5, 34.5, 25.9, 23.4, 18.3, −5.2, −5.3; IR (film): 3356
(w), 3284 (w), 2954 (s), 2927 (s), 1592 (s), 1540 (s) cm−1; HRMS
(ESI) m/z calcd for C25H34N2O6SSiNa (M + Na)+ 541.1805, found
541.1793; [α]2D3 = +20.7° (c 1.48, CHCl3).
1
acetone−70% hexanes); H NMR (500 MHz, CDCl3) δ 8.16−8.15
(1H, dd, J = 2.0 Hz), 7.89−7.88 (1H, dd, 1.5 Hz), 7.78−7.71 (2H, m),
3.88−3.84 (1H, m), 3.82−3.79 (1H, dd, J = 4.5, 12.0 Hz), 3.54−3.52
(1H, m), 1.72 (3H, s), 1.43 (3H, s); 13C NMR (125 MHz, CDCl3) δ
147.5, 134.6, 133.5, 130.5, 125.3, 82.5, 79.5, 70.6, 63.2, 62.0, 28.2, 3.5;
N-((2R,3R)-3-Methyl-3-phenoxypent-4-yn-2-yl)-2-nitroben-
zenesulfonamide (44). Aziridine 19 (30.8 mg, 0.110 mmol) and
5131
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phenol (21.0 mg, 0.220 mmol) were placed in a flask and dissolved in
dry PhCH3 (1.10 mL). 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD;
31.0 mg, 0.220 mmol) was added in one portion, and the reaction was
monitored by TLC. After completion, the reaction mixture was
concentrated and purified by silica gel chromatography (30% EtOAc−
70% hexanes) to give the product as a colorless oil (27.9 mg, 68%): Rf
Triazabicyclo[4.4.0]dec-5-ene (TBD; 31.0 mg, 0.148 mmol) was
added in one portion, and the reaction was monitored by TLC. After
completion, the reaction mixture was concentrated and purified by
silica gel chromatography (30% EtOAc−70% hexanes) to give the
product as an amorphous solid (44.5 mg, 78%): Rf 0.38 (30% EtOAc−
1
70% hexanes); H NMR (500 MHz, CDCl3) δ 8.14−8.12 (1H, m),
1
0.30 (30% EtOAc−70% hexanes); H NMR (500 MHz, CDCl3) δ
7.90−7.88 (1H, m), 7.66−7.60 (2H, m), 7.24−7.21 (2H, m), 7.06−
7.03 (1H, m), 6.97−6.96 (2H, m), 6.07 (1H, d, J = 8.5 Hz), 4.06−4.02
(1H, m), 3.95−3.91 (2H, m), 1.77 (3H, s), 1.55 (3H, s), 0.84 (9H, s),
−0.02 (3H, s), −0.05 (3H, s); 13C NMR (125 MHz, CDCl3) δ 154.5,
147.6, 136.9, 130.5, 128.7, 125.1, 123.3, 122.2, 85.8, 78.1, 77.4, 63.5,
62.5, 25.8, 24.3, 18.3, 3.6, −5.6; IR (film): 3385 (w), 2928 (s), 2856
(s), 1592 (s), 2964 (s), 1593 (s), 1542 (s) cm−1; HRMS (ESI) m/z
calcd for C25H35N2O6SSiNa (M + Na)+ 541.1805, found 541.1807;
[α]2D1 = −38.7° (c 0.925, CHCl3).
8.19−8.17 (1H, m), 7.89−7.87 (1H, m), 7.73−7.68 (2H, m), 7.25−
7.24 (2H, m), 7.09−7.07 (3H, m), 5.77 (1H, d, J = 9.0 Hz), 3.92−3.86
(1H, m), 2.45 (1H, s), 1.56 (3H, s), 1.36 (3H, d, J = 7.0 Hz); 13C
NMR (125 MHz, CDCl3) δ 154.5, 147.8, 135.2. 133.3, 132.9, 130.6,
128.9, 125.3, 123.7, 121.8, 82.2, 77.9, 58.7, 23.4, 16.9; IR (film): 3288
(s), 2921 (s), 1590 (s), 1541 (s) cm−1; HRMS (ESI) m/z calcd for
C18H18N2O5SNa (M + Na)+ 397.0833, found 397.0834; [α]2D2
−40.3° (c 1.31, CHCl3).
=
With Potassium Hydride. Potassium hydride (suspension in
mineral oil; 13.0 mg, 0.334 mmol) was placed in a vial and was
washed several times with hexanes (5 × 1 mL). After several washes,
the potassium hydride was placed under reduced pressure to remove
the residual hexanes and then suspended in dry THF (200 μL).
Phenol (31.0 mg, 0.334 mmol) dissolved in dry THF (250 μL) was
added dropwise to the suspension, and the solution was stirred until
effervescence stopped. Aziridine 19 (23.0 mg, 0.0835 mmol) and 18-
crown-6 (88.0 mg, 0.334 mmol) were dissolved in THF (450 μL) and
added to the solution. The reaction was monitored by TLC. After
completion the reaction was quenched with 1 M HCl (2 mL). The
two layers were separated, and the aqueous layer was extracted with
EtOAc (2 × 5 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The reaction mixture was purified
by silica gel chromatography (30% EtOAc−70% hexanes) to give the
product (25.0 mg, 80%) as an amorphous solid. The product ratio was
4-Methyl-N-(2-methyl-2-phenoxypropyl)benzenesulfon-
amide (49) and 4-Methyl-N-(2-methyl-1-phenoxypropan-2-
yl)benzenesulfonamide (50). Aziridine 48 (67.0 mg, 0.297
mmol) and phenol (56.0 mg, 0.595 mmol) were placed in a flask
and dissolved in dry PhCH3 (3.0 mL). 1,5,7-Triazabicyclo[4.4.0]dec-5-
ene (TBD; 83.0 mg, 0.595 mmol) was added in one portion, and the
reaction was monitored by TLC. After completion, the reaction was
concentrated and purified by silica gel chromatography (20% EtOAc−
80% hexanes) to give the product as an amorphous solid (58.3 mg,
1
64%): Rf 0.50 (30% EtOAc-hexanes); H NMR (500 MHz, CDCl3) δ
7.79−7.75 (4H, m), 7.35−7.33 (2H, m), 7.27−7.22 (4H, m), 7.19−
7.17 (2H, m), 7.11−7.09 (1H, m), 6.98−6.95 (1H, m), 6.86−6.85
(2H, m), 6.78−6.77 (2H, m), 5.11 (1H, m), 5.05 (1H, t, J = 5.5 Hz),
3.65 (2H, s), 3.07 (2H, s), 2.45 (3H, s), 2.35 (3H, s), 1.34 (6H, m),
1.26 (6H, m); 13C NMR (125 MHz, CDCl3) δ 158.2, 153.9, 143.4,
142.9, 139.9, 136.9, 129.7, 129.4, 129.1, 127.1, 126.9, 124.1, 123.8,
121.2, 114.4, 79.2, 74.3, 56.2, 52.8, 29.7, 24.8, 24.2, 21.5; IR (film):
3281 (s), 3062 (w), 3039 (w), 2979 (s), 2923 (s), 1597 (s) cm−1;
HRMS (ESI) m/z calcd for C17H21NO3SNa (M + Na)+ 342.1140,
found 342.1140.
1
determined by H NMR.
(R)-N-(3-Methyl-3-phenoxybutan-2-yl)-2-nitrobenzenesulfo-
namide (45). Aziridine 20 (41.2 mg, 0.152 mmol) and phenol (28.7
mg, 0.305 mmol) were placed in a flask and dissolved in dry PhCH3
(1.5 mL). 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD; 42.4 mg, 0.305
mmol) was added in one portion, and the reaction was monitored by
TLC. After completion, the reaction mixture was concentrated and
purified by silica gel chromatography (30% EtOAc−70% hexanes) to
give the product as a white solid (46.7 mg, 84%): Rf 0.38 (30%
With Potassium Hydride. Potassium hydride (suspension in
mineral oil; 26.6 mg, 0.663 mmol) was placed in a vial and was
washed several times with hexanes (5 × 1 mL). After several washes,
the potassium hydride was placed under reduced pressure to remove
the residual hexanes and then suspended in dry THF (400 μL).
Phenol (62.4 mg, 0.663 mmol) dissolved in dry THF (450 μL) was
added dropwise to the suspension, and the solution was stirred until
effervescence stopped. Aziridine 48 (37.3 mg, 0.166 mmol) and 18-
crown-6 (175 mg, 0.663 mmol) were dissolved in THF (850 μL) and
added to the solution. The reaction was monitored by TLC. After
completion the reaction mixture was quenched with 1 M HCl (2 mL).
The two layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 5 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The reaction mixture was purified
by silica gel chromatography (30% EtOAc−70% hexanes) to give the
products (39.8 mg, 75%) as an amorphous solid. The product ratio
1
EtOAc−hexanes); H NMR (500 MHz, CDCl3) δ 8.15 (1H, dd, 1.7,
7.3 Hz), 7.83 (1H, dd, 1.7, 6.3 Hz), 7.66 (2H, m), 7.23 (1H, t, J = 7.5
Hz), 6.86 (2H, d, J = 8.0 Hz), 5.83 (1H, d, J = 5.5 Hz), 3.65 (1H, m),
1.28 (3H, d, J = 7.0 Hz), 1.25 (3H, s), 1.19 (3H, s); 13C NMR (125
MHz, CDCl3) δ 153.9, 147.7, 135.3, 133.1, 132.7, 130.4, 129.0, 125.2,
123.9, 81.4, 59.3, 24.0, 23.1, 16.8; IR (film): 3383 (s), 3096 (s), 3071
(s), 3036 (w), 2964 (s), 1593 (s), 1541(s) cm−1; HRMS (ESI) m/z
calcd for C17H20N2O5SNa (M + Na)+ 387.0991, found 387.1006;
[α]2D1 = −14.4° (c 1.31, CHCl3); mp 96−98 °C.
With Potassium Hydride. Potassium hydride (suspension in
mineral oil; 35.8 mg, 0.893 mmol) was placed in a vial and was
washed several times with hexanes (5 × 1 mL). After several washes,
the potassium hydride was placed under reduced pressure to remove
the residual hexanes and then suspended in dry THF (500 μL).
Phenol (84.0 mg, 0.893 mmol) dissolved in dry THF (500 μL) was
added dropwise to the suspension, and the solution was stirred until
effervescence stopped. Aziridine 20 (60.3 mg, 0.223 mmol) and 18-
crown-6 (236 mg, 0.893 mmol) were dissolved in THF (1.2 mL) and
added to the solution. The reaction was monitored by TLC. After
completion the reaction mixture was quenched with 1 M HCl (2 mL).
The two layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 5 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated. The reaction mixture was purified
by silica gel chromatography (30% EtOAc−70% hexanes) to give the
products (64.2 mg, 79%) as a white solid. The product ratio was
1
was determined by H NMR.
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, tables, and CIF files giving X-ray crystallographic
data for 13, 17−22, 45, and 48, 1H and 13C NMR spectra, and
computational details. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
1
Corresponding Author
determined by H NMR.
N-((2R,3R)-1-((tert-Butyldimethylsilyl)oxy)-3-methyl-3-phe-
noxyhex-4-yn-2-yl)-2-nitrobenzenesulfonamide (46). Aziridine
21 (46.7 mg, 0.110 mmol) and phenol (21.0 mg, 0.220 mmol) were
placed in a flask and dissolved in dry PhCH3 (1.1 mL). 1,5,7-
*E-mail for M.M.J.: mjoullie@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
5132
dx.doi.org/10.1021/jo5006685 | J. Org. Chem. 2014, 79, 5121−5133

The Journal of Organic Chemistry
Article
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ACKNOWLEDGMENTS
■
We thank Drs. George Furst and Rakesh Kohli for assistance in
obtaining high-resolution NMR and mass spectral data,
respectively. We thank Drs. David Chenoweth and William
Dailey for useful suggestions and discussions with regard to the
aforementioned research. Financial support for this research
was provided by the NSF (CHE-0951394).
Devarajan, D.; Ess, D. H.; Kurti, L.; Falck, J. R. Science 2014, 343, 61.
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