Synthesis of β-Ketosulfonamides Derived from Amino Acids and Their Conversion to β-Keto-α,α-difluorosulfonamides via Electrophilic Fluorination

Article abstract of DOI:10.1021/acs.joc.7b02179

β-Ketosulfonamides derived from Boc or Cbz-protected amino acids bearing hydrophobic side chains were prepared in good to excellent yield by treating N-allyl, N-alkyl methanesulfonamides with n-BuLi, followed by reaction of the resulting carbanion with me

Full text of DOI:10.1021/acs.joc.7b02179

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Cite This: J. Org. Chem. XXXX, XXX, XXX-XXX
Synthesis of β‑Ketosulfonamides Derived from Amino Acids and
Their Conversion to β‑Keto-α,α-difluorosulfonamides via
Electrophilic Fluorination
Jacob Soley,† Edmond Chiu,† Ryan Chung,‡ Jeremy Green,§ Jason E. Hein,‡ and Scott D. Taylor*,†
†Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada
‡University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada
§Vertex Pharmaceuticals, 50 Northern Avenue, Boston, Massachusetts 02210, United States
S
* Supporting Information
ABSTRACT: β-Ketosulfonamides derived from Boc or Cbz-
protected amino acids bearing hydrophobic side chains were
prepared in good to excellent yield by treating N-allyl, N-alkyl
methanesulfonamides with n-BuLi, followed by reaction of the
resulting carbanion with methyl esters of N-protected L-amino
acids. The analogous reaction using the dianion derived from
an N-alkyl methanesulfonamide proceeded in much lower
yield. Electrophilic fluorination of the β-ketosulfonamides using Selectfluor in the presence of CsF in DMF at room temperature
for 15−60 min provided β-keto-α,α-difluorosulfonamides in good to excellent yields. The allyl protecting group could be
removed in good yield using cat. Pd(PPh)3)4 and dimethyl barbituric acid. When the fluorination reaction was performed with
Cs2CO3 as base, β-ketosulfonamides derived from Val, Leu or Ile gave the expected β-keto-α,α-difluorosulfonamides, while β-
ketosulfonamides derived from Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,α-difluorosulfonamides.
As part of a research program on the development of
inhibitors of medicinally significant proteases, we wished to
prepare a series of N-ethyl or, preferably, N-methyl β-keto-α,α-
difluorosulfonamides derived from hydrophobic amino acids.
Here we report the synthesis of β-ketosulfonamides (3) (Figure
2) derived from α-amino acids by reaction of monoanions of N-
INTRODUCTION
■
β-Keto-α,α-difluoro esters,1 amides,2 and phosphonates3 have
been the subjects of study for many years mainly due to their
applications as probes and inhibitors of enzymes. For example,
certain β-keto-α,α-difluoroamides have been shown to be up to
1000 times more potent inhibitors of serine proteases, such as
pepsin,2a renin,2b elastase,2c and chymase,2d than their non-
fluorinated counterparts. Studies indicate that β-keto-α,α-
difluoroamides inhibit these enzymes by forming covalent
adducts with active site residues.2c
Surprisingly, only a single report has appeared that has
described the synthesis and in vitro biological activity of a β-
keto-α,α-difluorosulfonamide.4 In 2007, Vannada et al. reported
the synthesis of compound 1 (Figure 1), a hydrolytically stable
analog of compound 2, which is a highly potent inhibitor of
MtbA, an enzyme involved in the biosynthesis of mycobactins
in Mycobacterium tuberculosis.
Figure 2. Compounds prepared in this study.
alkyl, N-allylmethanesulfonamides with N-protected amino acid
methyl esters. These β-ketosulfonamides were converted into
the corresponding β-keto-α,α-difluorosulfonamides (4) (Figure
2) by electrophilic fluorination of 3 using Selectfluor in the
presence of CsF. We also report that when the fluorination
reaction was performed using Cs2CO3, compounds of type 5
were obtained as the dominant products, and the formation of
these compounds was dependent upon the side chain of the
amino acid.
Figure 1. Compound 1, a hydrolytically stable analog of MtbA
inhibitor 2.
Received: August 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02179
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Scheme 1. Synthesis of β-ketosulfonamides 9−11
Table 1. Formation of β-Ketosulfonamides from N,N-Disubstituted Methanesulfonamides and N-Protected Amino Acid Methyl
Esters
a
entry
sulfonamide
amino acid ester
product
yield (%)
er
1
2
3
4
5
6
7
8
9
7
8 (R2 = CH2CH2Ph, R3 = Boc)
13 (R2 = CH(CH3)2, R3 = Boc)
14 (R2 = CH2Ph, R3 = Boc)
11
21
22
23
24
25
26
27
28
92
97
93
84
74
65
71
83
68
>99:1
>99:1
12
12
12
12
12
12
12
12
b
ND
15 (R2 = CH3, R3 = Boc)
99:1
96:4
99:1
16 (R2 = CH2CH2SCH3, R3 = Boc)
17 (R2 = CH(CH3)2, R3 = Z)
18 (R2 = CH(CH3)CH2CH3, R3 = Z)
19 (R2 = CH2CH(CH3)2, R3 = Z)
b
ND
b
ND
b
20 (R2 = CH2Ph(p-OtBu), R3 = Z)
ND
a
b
Enantiomeric ratio (er) determined using chiral HPLC. ND = not determined.
The low yields that were obtained using the dianion
approach prompted us to examine whether the reaction of a
monoanion of an N,N-dialkyl methanesulfonamide with methyl
esters of N-protected amino acids would provide β-
ketosulfonamides in higher yield. We chose N-allyl, N-
ethylmethanesulfonamide (7, Scheme 1) as a model substrate
for these studies anticipating that the allyl group could be
removed later via a Tsuji−Trost reaction without affecting the
N-protecting group on the amino acid portion of the product.
Hence, 3.2 equiv of the monoanion of 7, generated using n-
BuLi at −78 °C, was reacted with 8 at −78 °C. After 1 h, TLC
indicated that the reaction was complete, and compound 11
was isolated in a 92% yield. This process also worked well using
N-methyl, N-allylmethanesulfonamide (12) and other methyl
esters of Boc- and Z-protected amino acids (Table 1), though
the reactions with the Z derivatives proceeded in slightly lower
yields. However, sulfonamide 12 and products 25, 26, and 28
exhibited very similar mobility on silica gel making purification
by chromatography challenging, contributing to the slightly
lower yields for these three compounds. We were able to
determine the enantiomeric ratios (er) of some of the
compounds in Table 1 using chiral HPLC which were found
to be between 96:4 and 99:1.
RESULTS AND DISCUSSION
■
We initially envisaged preparing compounds of type 3 by
reacting the dianion of N-alkyl-methanesulfonamides with the
methyl esters of N-protected amino acids (Scheme 1), as this
approach to β-ketosulfonamides has been reported to be
successful when employing a methyl ester of a benzoic acid
derivative as the electrophile.4 N-Ethylmethanesulfonamide (6)
and L-Boc-hPheOMe (8) were employed as model substrates.
The conditions developed by Thompson et al.5 were used for
dianion formation except the literature procedure was modified
to account for the additional carbamate proton in 8. Thus,
sulfonamide 6 in THF was subjected to 2.2 equiv LDA at −78
°C, then allowed to warm to −30 °C over 45 min, and then
cooled to −78 °C. A 3-fold molar excess of this mixture was
reacted with 8 at −78 °C in THF, and the mixture was allowed
to warm to rt and reacted for 8 h. After workup, β-
ketosulfonamide 9 was obtained in a 19% yield. When 4.2
equiv of the dianion was used, compound 9 was obtained in a
30% yield. Using more than 4.2 equiv of the dianion, generated
using LDA or n-BuLi, or maintaining the reaction at −78 or
−30 °C or generating the dianion at 0 °C followed by its
reaction with 8 at 0 °C resulted in similar or lower yields of 9.
In contrast, the reaction of the dianion of 6 with
methylbenzoate gave compound 10 in a 90% yield (Scheme 1).
Compound 1 was prepared by Vannada et al.4 in an 87%
yield by subjecting a nonfluorinated, protected β-ketosulfona-
B
DOI: 10.1021/acs.joc.7b02179
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Scheme 2. Conditions Examined for the Fluorination of 21
Table 2. Formation of β-Keto-α,α-difluorosulfonamides from β-Ketosulfonamides
entry
R1
R2
R3
R4
base
product
yield (%)
1
2
Me
Me
Et
allyl
allyl
allyl
H
Boc
Z
CH(CH3)2
CsF
CsF
CsF
TBAF
CsF
CsF
CsF
CsF
CsF
CsF
30
32
33
34
35
36
37
38
39
40
84
93
CH(CH3)2
3
Boc
Boc
Boc
Boc
Z
CH2CH2Ph
CH2CH2Ph
CH2Ph
85
a
4
Et
74
5
Me
Me
Me
Me
Me
Me
allyl
allyl
allyl
allyl
allyl
allyl
84
76
90
82
74
0
6
CH3
7
CH(CH3)CH2CH3
CH2CH(CH3)2
CH2Ph(p-OtBu)
CH2CH2SCH3
8
Z
9
Z
10
Boc
a
68% yield using CsF.
mide precursor to 1.6 equiv NaH in dry THF at 0 °C for 20
min followed by cannulation of the mixture into a solution of 2
equiv of Selectfluor in CH3CN at −10 °C and allowing the
mixture to warm to 0 °C over 2 h. We examined these
conditions for fluorinating compound 21 except the number of
equiv of NaH and Selectfluor was increased to account for the
carbamate proton in 21. The reaction proved to be surprisingly
sluggish, and, after 24 h, unreacted 21 still remained. Upon
workup, the monofluorinated product 29 (Scheme 2) was
obtained in a 70% yield, while the difluorinated compound 30
was obtained in only 5% yield.
Efforts to improve the yield of 30 focused on examining
alternative bases and solvents for the fluorination reaction. We
reasoned that the fluorination reaction should not require a
strong base such as NaH, as we estimated the pKa of the α-
protons in 21 to be 10−12.6 Thus, compound 21 was subjected
to 2.5 equiv of either DBU, Cs2CO3, CsF, or TBAF in dry
MeOH, CH3CN, or DMF for 15 min followed by the addition
of 3 equiv Selectfluor, and the reaction was monitored by 19F-
NMR and TLC. Reactions performed using DBU as base
proceeded sluggishly, and, after 24 h, the mixture consisted of
mainly unreacted starting material and monofluorinated
compound 29 (δf ≈ −184 ppm), and only a small amount of
the difluorinated compound 30 (δF ≈ −107 ppm) was formed.
With Cs2CO3 as base and DMF or CH3CN as solvent, all of 21
was consumed after 15−30 min, and 19F-NMR revealed the
presence of mainly compound 30 along with a variety of
unidentified impurities as evidenced by a significant number of
small peaks between −104 and −150 ppm. Among these
impurity peaks in the 19F-NMR spectrum was a doublet at
approximately −122 ppm corresponding to compound 31
(Figure 3).7 The formation of 31 indicates that fragmentation
of the C−C bond between the carbonyl and CF2 groups in 30
was occurring.8 The reaction in MeOH was slightly slower but
cleaner, and after 1 h no starting sulfonamide remained, and
19F-NMR revealed mainly product 30 along with about 10%
compound 29 as well as a small amount of impurities including
compound 31.
Figure 3. A byproduct formed during the electrophilic fluorination of
β-ketosulfonamides.
With CsF or TBAF as base, the reaction proceeded sluggishly
in CH3CN or MeOH. However, in DMF, all of 21 was
consumed within 15 min (for TBAF) or 60 min (with CsF),
and a mixture of 29 and 30 was obtained with 30 accounting
for approximately 75% of the product and very few impurities
were present. Since the reaction products remained unchanged
after 2 h, we performed the reaction in DMF again except the
amount of CsF or TBAF and Selectfluor was increased to 4
equiv. Under these conditions, all of 21 was consumed within
15 min using TBAF or within 45 min using CsF, though the
CsF reaction gave the difluorinated 30 almost exclusively. After
aqueous workup and chromatographic purification, compound
30 was obtained in a 78% yield using TBAF and an 84% yield
using CsF. These conditions were applied to other β-
ketosulfonamides (Table 2). All of the β-keto-α,α-difluor-
osulfonamides were obtained in good yield with the exception
of the methionine derivative 24 which gave a complex mixture
of products probably due to a reaction between the sulfide
moiety and Selectfluor.9 It was also found that the fluorination
reaction could be carried out on the crude substrates with only
a slight reduction in yield. For example, fluorination of crude 25
and 26 (obtained after aqueous workup followed by drying
(Na2SO4), filtration, and subjecting the residue to high vacuum
for several hours) using our usual procedure gave compounds
32 and 37 in yields of 86%. In contrast to compounds 25 and
26, compounds 32 and 37 were easily separated from
sulfonamide 12 by column chromatography. Fluorination of
the unprotected sulfonamide 9 (entry 4) was also accomplished
in good yield, though it was found that the reaction proceeded
in higher yield using TBAF as opposed to CsF.
C
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Removal of the allyl group from the β-keto-α,α-difluor-
osulfonamides was examined using compounds 30 and 35.
Little or no deallylation occurred using 2.5−10 equiv of either
N-methylbarbituric acid (NMBA), morpholine, or benzenesul-
finic acid in the presence of 10 mol % Pd(PPh3)4 in methylene
chloride either a room temperature or reflux. Nevertheless,
deallylation was achieved using 10 mol % Pd(PPh3)4, 5 equiv of
DMBA, and dry CH3CN in a Schlenk tube at 100 °C for 24 h
(Scheme 3) to give compounds 41 and 42 in yields of 81% and
using 4 equiv of Cs2CO3 and 4 equiv of Selectfluor at room
temperature for 30−60 min, 19F-NMR spectra of the reaction
mixtures indicated that the desired difluorinated compounds
(30, 32, 37, and 38) were the dominant products, though
various unidentified byproducts, as well as compound 31, were
also formed. However, when these conditions were applied to
β-ketosulfonamides derived from hPhe (11), Phe (22), Ala
(23), and Tyr (28), the expected difluorinated products (33,
35, 36, and 39) were not the major products. In the case of
tyrosine derivative 28, a complex mixture of products was
obtained. However, with substrates 11, 22, and 23, compounds
44−46 were the major products,13 which were isolated in yields
of 35−64% (Scheme 5).
Scheme 3. Deallylation of Compounds 30 and 35
Scheme 5. Products Formed When the Fluorination
Reaction Is Performed on Compounds 11, 22, and 23, Using
4 equiv of Cs2CO3
76%, respectively.10 The er of compounds 30 and 32 were
found to be 99:1. However, the er of compound 41 was
determined to be 3:2, indicating that considerable loss of
stereochemical integrity occurred during deallylation.
In the 13C NMR spectra of the β-keto-α,α-difluorosulfona-
mides described in Table 2 and Scheme 3, the carbonyl carbon
appears as a triplet at approximately 195 ppm (J = 24.3 Hz) in
CDCl3 and DMSO-d6. This indicates that these compounds
exist mainly in their keto form and not as their hydrates in these
solvents, as the hydrated carbon would have appeared much
further upfield.11 The 19F-NMR spectra of these compounds, in
CDCl3 or DMSO-d6 at room temperature, show a large AB
quartet centered at approximately −108 ppm. For some of the
compounds, smaller AB quartets that have chemical shifts very
similar to the large AB quartet are also apparent. For example,
with compound 41, a small AB quartet accounts for
approximately 15% of the total peak area in DMSO-d6 at
room temperature. The 19F-NMR spectra of compound 41 in
DMSO-d6 and DMSO-d6/12% D2O are identical suggesting
that the hydrate is not responsible for the minor AB quartet.12
At 80 °C in DMSO-d6, only a single AB quartet is evident in
the 19F-NMR spectrum suggesting that the minor quartets
observed at room temperature are due to rotamers. Although
Unlike the products listed in Table 2, compounds 44−46
exist exclusively as their hydrates in CDCl3 as evidenced by the
lack of a triplet at 195 ppm and the presence of a triplet at 79
ppm (J = 20.2 Hz) in their 13C NMR spectra. Thus, the
electron-withdrawing CN moiety destabilizes the adjacent
carbonyl group which promotes formation of the hydrate.
Possible mechanisms for the formation of compounds 43−
46 are presented in Scheme 6. We propose that upon
difluorination of the α-carbon, the C−H proton adjacent to
the β-carbonyl becomes more acidic and can be removed by
Cs2CO3 (or CsF in the case of the tyrosine derivative 39) to
give intermediate 47 (pathway 1). Fluorination of 47 produces
compound 48 which undergoes elimination of fluoride to give
imine 49. Compound 49 can tautomerize to the conjugated
ketone 50, or, if tautomerization is not favorable, it will form
hydrate 51. An alternative mechanism can also be envisaged
where removal of the N−H proton occurs after difluorination
of the methylene carbon to give amide 52. Fluorination of 52
on the Boc-protected nitrogen provides compound 53
(pathway 2). Elimination of fluoride from 53 gives compound
49. The observation that compounds of type 50 or 51 were not
obtained when the fluorination reaction was performed on β-
ketosulfonamides derived from Val, Leu, and Ile suggests to us
that pathway 1 may be the more plausible pathway as
fluorination of intermediate 47 may be difficult with the
more sterically demanding Val, Leu, and Ile derivatives. One
would expect that the steric effect of the side chain would have
less impact on the fluorination of intermediate 52.
1
the H- or 13C NMR spectra of 41 in DMSO-d6 do not reveal
the presence of multiple conformers in solution, we are unable
to offer any other explanation, other than the presence of
rotamers, to account for the additional peaks in the 19F-NMR
spectrum.
During the fluorination of tyrosine derivative 28, using the
conditions described above in Table 2, a small amount of
compound 43 was isolated in addition to compound 39
(Scheme 4). When the reaction was allowed to proceed for 10
h, compounds 39 and 43 were isolated in yields of 34% and
31%, respectively. Letting the reaction proceed for 24 h resulted
in lower yields for both products.
When the fluorination reaction was performed on β-
ketosulfonamides derived from Val, Leu. and Ile (21, 25−27)
The driving force behind the formation of tautomerized
product 43 is most likely the formation of a conjugated system
that allows delocalization of the lone pair of electrons of the
phenolic oxygen into the carbonyl (Figure 4). Unlike
compounds 44−46, compound 43 does not exist as its hydrate
partly because electron delocalization into the carbonyl group
makes the carbonyl carbon less electropositive than the
corresponding carbon in compounds 44−46.
Scheme 4. Formation of Compound 43
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Scheme 6. Possible Mechanisms for the Formation of Compounds of Type 50 and 51
All 13C NMR spectra were proton decoupled. Chemical shifts (δ)
for 1H NMR spectra run in CDCl3 are reported in ppm relative to the
standard tetramethylsilane (TMS). Chemical shifts for 13C NMR
spectra run in CDCl3 are reported in ppm relative to the solvent
residual carbon (δ 77.0 for central peak). Chemical shifts (δ) for 19F
NMR spectra run in CDCl3 or DMSO-d6 are reported in ppm relative
1
to CFCl3 (δ 0.0, external standard). Chemical shifts (δ) for H NMR
spectra run in or DMSO-d6/D2O mixtures are reported in ppm relative
to DMSO residual solvent protons (δ 2.5). Chemical shifts for 13C
NMR spectra run in DMSO-d6 or DMSO-d6/D2O mixtures are
reported in ppm relative to the solvent residual carbon (δ 39.5). The
samples for high-resolution positive ion electrospray ionization mass
spectrometry (HRMS-ESI+) (ion trap) were prepared in 1:1 CH3CN/
H2O + 0.2% formic acid.
Figure 4. Delocalization of the lone pair of electrons of the phenolic
oxygen into the carbonyl group in compound 43.
CONCLUSION
■
A series of β-ketosulfonamides derived from amino acids were
prepared in good yield by reacting the monoanion of N-alkyl,
N-allylmethanesulfonamides with N-protected amino acid
methyl esters. The corresponding reaction with the dianion
of N-ethylmethanesulfonamide proceeded in much lower yield.
The β-ketosulfonamides were converted into the corresponding
β-keto-α,α-difluorosulfonamides by electrophilic fluorination
using Selectfluor in the presence of CsF. The allyl protecting
group can be removed in good yield using cat. Pd(PPh)3)4 and
dimethyl barbituric acid; however, significant racemization
occurred during deallylation. When the fluorination reaction
was performed with Cs2CO3 as base, β-ketosulfonamides
derived from Val, Leu, or Ile gave the expected β-keto-α,α-
difluorosulfonamides, while β-ketosulfonamides derived from
Ala, Phe, or hPhe gave the hydrates of the imino β-keto-α,α-
difluorosulfonamides. Studies to incorporate the β-keto-α,α-
difluorosulfonamides into peptides and the biological properties
of the resulting peptides are in progress.
Chiral HPLC analyses were performed using a Chiralpak AS-RH
column (250 × 4.6 mm) with CH3CN/0.1%TFA in H2O as eluent.
N-Allyl-N-ethylmethanesulfonamide (7). To a solution of N-
ethylmethanesulfonamide (6, 1.00 g, 9.16 mmol, 1 equiv) in dry
acetone (10 mL) were added allyl bromide (0.79 mL, 9.16 mmol, 1
equiv) and anhydrous K2CO3 (2.53 g, 18.3 mmol, 2 equiv), and the
mixture stirred for 24 h. After 24 h another 0.25 equiv of ally bromide
was added, and the mixture stirred for an additional 6 h. Water (30
mL) was added, and the solution extracted with CH2Cl2 (3 × 30
mL)). The organic layer was dried (Na2SO4) and concentrated.
Purification by FC (flash chromatography) (20% EtOAc, 80% hexane)
1
gave compound 7 as a colorless liquid (0.89 g, 60% yield). H NMR
(300 MHz, CDCl3): δ 5.68−5.85 (1H, m), 5.23 (1H, dd, J = 1.2, 17.1
Hz), 5.18 (1H, dd, J = 1.2, 11.2 Hz), 3.77 (2H, d, J = 6.1 Hz), 3.21 (2
H, q, J = 7.3 Hz), 2.79 (3H, s), 1.12 (3H, t, J = 7.3 Hz); 13C{1H}
NMR (CDCl3, 75 MHz): δ 133.0, 118.9, 49.3, 41.7, 39.3, 13.8;
HRMS-ESI+ (m/z) calcd for C6H14NO2S (M + H)+, 164.07398;
found, 164.07394.
tert-Butyl (1-(N-Ethylsulfamoyl)-2-oxo-5-phenylpentan-3-yl)-
carbamate (9). To a flame-dried round-bottom flask under Ar was
added dry diisopropyl amine (0.68 mL, 4.9 mmol, 9.8 equiv). The
mixture was cooled to −78 °C, and then n-BuLi (2.78 mL of a 1.6 M
solution in hexane, 4.45 mmol, 8.9 equiv) was added. After being
stirred for 10 min at 0 °C, this solution was cooled to −78 °C and
treated with sulfonamide 6 (0.198 mL, 2.10 mmol, 4.2 equiv) in dry
THF (4 mL), added over a period of 10 min. The reaction mixture was
allowed to warm −30 °C over a period of 45 min and was then cooled
to −78 °C and treated with a solution of Boc-hPheOMe (8, 0.146 g,
0.500 mmol) in dry THF (4 mL) added in a fast stream. The solution
was allowed to warm to rt and followed by TLC. After 8 h the mixture
was cooled to 0 °C and quenched with sat. aqueous NH4Cl. The
mixture was extracted with ether (3 × 20 mL). The combined organic
extracts were washed with brine and water, dried (Na2SO4), filtered,
and concentrated in vacuo to give a yellow oil. Purification using FC
EXPERIMENTAL SECTION
■
General. All reagents and solvents were purchased from
commercial suppliers and used without purification unless stated
otherwise. Methyl esters of the Boc or Z-protected amino acids were
either purchased or prepared via reaction of the corresponding Boc or
Z-protected amino acids with SOCl2 in dry MeOH14 or via reaction of
their cesium salts with methyl iodide in dry DMF.15
Dimethylformamide (DMF) was distilled from calcium hydride
under reduced pressure and stored over activated 4 Å molecular sieves.
Tetrahydrofuran (THF) was distilled from sodium metal in the
presence of benzophenone under nitrogen. Acetonitrile was distilled
from calcium hydride (CaH2) under nitrogen. Diisopropylamine was
distilled from sodium metal. Methanol was distilled from Mg turnings
and stored over activated 4 Å molecular sieves.
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(30% EtOAc, 70% hexane) provided compound 9 as an amorphous
white solid (0.057 g, 30% yield). H NMR (CDCl3, 300 MHz): δ
(d, 1H, J = 8.6 Hz), 4.29 (1H, dd, J = 4.6, 8.8 Hz), 4.23 (1H, d, J =
14.3 Hz), 4.03 (1H, d, J = 14.3 Hz), 3.78 (2H, d, J = 6.1 Hz), 2.83
(1H, s), 2.35−2.26 (1H, m), 1.42 (9H, s), 0.99 (3H, d, J = 6.8 Hz),
0.81 (3H, s, J = 6.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 199.0,
155.9, 132.5, 119.2, 80.3, 65.1, 58.1, 53.1, 34.5, 28.6, 28.2, 19.8, 16.8;
HRMS-ESI+ (m/z) calcd for C11H21N2O5S (M − C4H9 + 2H)+,
293.1166; found, 293.1164.
tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-3-oxo-1-phenylbutan-
2-yl)carbamate (22). Obtained as an amorphous white solid (0.370,
93% yield) after FC (25% EtOAc, 75% hexane) from ester 14 (0.279,
1.00 mmol) and sulfonamide 12 (0.521 g, 3.2 mmol). 1H NMR
(CDCl3, 300 MHz): δ 7.46−7.21 (3H, m), 7.17 (2H, d, J = 6.6 Hz),
5.82−5.69 (1H, m), 5.26 (1H, d, J = 18.5 Hz), 5.24 (1H, d, J = 9.5
Hz), 5.10 (1H, d, J = 6.9 Hz), 4.53−4.46 (1H, m), 4.17 (1H, d, J =
13.8 Hz), 4.03 (1H, d, J = 13.8 Hz), 3.74 (2H, d, J = 5.8 Hz), 3.20
(1H, dd, J = 5.8, 14.4 Hz), 2.90 (1H, d, J = 9.0, 14.3 Hz), 2.18 (3H, s),
1.37 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.8, 155.5, 136.3,
132.4, 129.3, 128.8, 127.1, 119.3, 80.2, 61.3, 57.9, 53.1, 36.4, 34.4, 28.2;
HRMS-ESI+ (m/z) calcd for C19H29N2O5S (M + H)+, 397.1792;
found, 397.1787
1
7.29−7.08 (5H, m), 5.22 (1H, bt), 5.13 (1H, d, J = 7.1 Hz), 4.43−4.31
(1H, m), 4.28 (1H, d, J = 14.4 Hz), 4.01 (1H, d, J = 14.4 Hz), 3.11
(2H, overlapping dq, J = 6.8 Hz), 2.25−2.10 (1H, m), 1.88−1.71 (1H,
m), 1.44 (9H, s), 1.18 (3H, t, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 75
MHz): δ 200.1, 155.9, 140.2, 128.6, 128.4, 126.4, 80.8, 59.6, 58.2, 38.7,
31.8, 31.6, 28.3, 15.2; HRMS-ESI+ (m/z) calcd for C18H32N3O5S (M +
NH4)+, 402.2057; found, 402.2051.
N-Ethyl-2-oxo-2-phenylethane-1-sulfonamide (10). To a flame-
dried flask under Ar was added dry diisopropylamine (0.770 mL, 5.50
mmol, 3.3 equiv) and THF (6 mL) and then cooled to 0 °C. n-BuLi
(1.6 M in hexane, 3.25 mL, 5.20 mmol, 3.1 equiv) was added, and the
mixture stirred at 0 °C for 30 min. A solution of sulfonamide 6 (0.200
g, 1.67 mmol, 1 equiv) in THF (6 mL) was added, and the mixture
was stirred for 1 h at 0 °C. A solution of methyl benzoate (0.231 mL,
1.84 mmol, 1.1 equiv) in THF (2 mL) was added, and the mixture
stirred for 1 h at 0 °C. The reaction was quenched with sat. aqueous
NH4Cl (15 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were washed with brine, dried (Na2SO4),
filtered, and concentrated in vacuo to give a pale yellow solid.
Purification using FC (75% EtOAc, 25% hexane) provided compound
10 as an amorphous white solid (0.340 g, 90% yield). 1H NMR
(CDCl3, 300 MHz): δ 7.96 (2H, d, J = 8.3 Hz), 7.62 (1H, t, J = 6.8
Hz), 7.48 (2H, overlapping dd, J = 7.3 Hz), 4.94 (1H, bt, J = 5.4 Hz),
4.42 (2H, s), 3.27−3.14 (2H, m), 1.21 (3H, t, J = 7.8 Hz); 13C{1H}
NMR (CDCl3, 75 MHz): δ 190.2, 135.6, 134.5, 129.0, 57.3, 38.8, 15.3;
HRMS-ESI+ (m/z) calcd for C10H14NO3S (M + H)+, 228.06890;
found, 228.0688.
tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-3-oxobutan-2-yl)-
carbamate (23). Obtained as an amorphous white solid (0.658,
84% yield) after FC (10% EtOAc, 90% benzene) from ester 15 (0.500
1
g, 2.46 mmol) and sulfonamide 12 (1.28 g, 8.61 mmol). H NMR
(CDCl3, 300 MHz): 5.56−5.81 (m, 1H), 5.15−5.32 (m, 3H), 4.19−
4.35 (m, 2H), 4.06 (one-half of a doublet of doublets, 1H, J = 13.9
Hz), 3.74 (d, 2H, J = 5.6 Hz), 2.80 (s, 3H), 1.39 (s, 9H), 1.33 (d, 3H, J
= 7.1 Hz); 13C{1H} NMR (CDCl3, 75 MHz): 199.7, 155.3, 132.3,
119.1, 80.2, 57.1, 55.9, 53.0, 34.3, 28.1, 16.3; HRMS-ESI+ (m/z) calcd
for C13H25N2O5S (M + H)+, 321.1475; found, 321.1479.
N-allyl-N-methylmethanesulfonamide (12). To a solution of N-
methylmethanesulfonamide (10.9 g, 100 mmol, 1 equiv) in dry DMF
(50 mL) was added allyl bromide (11.2 mL, 130 mmol, 1.3 equiv) and
anhydrous K2CO3 (27.6 g, 200 mmol, 1 equiv). The mixture was
stirred for 18 h. Water was added (100 mL), and the mixture was
extracted with Et2O (3 × 150 mL). The organic layer was washed with
water (3 × 100 mL), sat. brine (1 × 100 mL), then concentrated by
rotary evaporation. The resulting yellow liquid was purified by vacuum
distillation to give sulfonamide 12 as a colorless liquid (13.3 g, 89%
tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-5-(methylthio)-2-oxo-
pentan-3-yl)carbamate (24). Obtained as an amorphous white solid
(1.12 g, 74% yield) after FC (33% EtOAc, 67% hexane) from ester 16
1
(0.970 g, 3.68 mmol) and sulfonamide 12 (1.90 g, 12.8 mmol). H
NMR (CDCl3, 300 MHz): 5.8−5.65 (m, 1H), 5.41 (d, 1H, J = 7.4
Hz), 5.24 (1H, d, J = 16.4 Hz), 5.19 (1H, d, J = 9.5 Hz), 4.32−4.44
(1H, m), 4.21 (1H, d, J = 13.8 Hz), 4.08 (1H, d, J = 13.8 Hz), 3.73 (d,
1H, J = 5.8 Hz), 2.79 (s, 3H), 2.45−2.55 (m, 2H), 2.10−2.23 (1H, m),
2.03 (3H, s), 1.77−1.90 (m, 1H), 1.39 (s, 9H); 13C{1H} NMR
(CDCl3, 75 MHz): 199.0, 155.6, 132.3, 119.3, 80.5, 59.4, 57.5, 53.0,
34.4, 30.1, 29.7, 28.2, 15.4; HRMS-ESI+ (m/z) calcd for
C15H32N3O5S2 (M + NH4)+, 398.1778; found, 398.1773.
Benzyl (1-(N-Allyl-N-methylsulfamoyl)-4-methyl-2-oxopentan-3-
yl)carbamate (25). Obtained as an amorphous white solid (1.12 g,
65% yield) after FC (30% EtOAc, 70% hexane) from ester 17 (2.00 g,
8.02 mmol) and sulfonamide 12 (4.18 g, 28.0 mmol). 1H NMR
(CDCl3, 300 MHz): δ 7.31 (5H, s), 5.77−5.68 (1H, m), 5.52 (1H, d, J
= 9.0 Hz), 5.27−5.19 (2H, m), 5.09 (2H, s), 4.40 (1H, dd, J = 4.2, 9.0
Hz), 4.21 (1H, s, J = 13.8 Hz), 4.02 (1H, d, J = 13.8 Hz), 3.75 (3H, d,
J = 5.8 Hz), 2.79 (3H, s), 2.34−2.27 (1H, m), 0.99 (3H, d, J = 6.9 Hz)
0.80 (3H, d, J = 6.4 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.6,
156.5, 136.1, 132.4, 128.6, 128.3, 128.1, 119.2, 67.2, 65.5, 58.2, 53.0,
34.3, 28.8, 19.8, 16.7; HRMS-ESI+ (m/z) calcd for C18H27N2O5S (M +
H)+, 383.1635; found, 383.1627.
Benzyl (1-(N-Allyl-N-methylsulfamoyl)-4-methyl-2-oxohexan-3-
yl)carbamate (26). Obtained as an amorphous white solid (1.00 g,
71% yield) after FC (33% EtOAc, 67% hexane) from ester 18 (1.00 g,
3.57 mmol) and sulfonamide 12 (1.87 g, 12.5 mmol). 1H NMR
(CDCl3, 300 MHz): δ 7.34 (5H, s), 5.85−5.69 (1H, m), 5.37 (1H, bd,
J = 9.0 Hz), 5.27 (1H, d, J = 17.5 Hz), 5.25 (1H, d, J = 9.5 Hz), 5.11,
(2H, s), 4.42 (1H, dd, J = 4.2, 9.0), 4.22 (1H, d, J = 14.3 Hz), 4.02
(1H, d, J = 14.3 Hz), 3.78 (2H, d, J = 5.8 Hz), 2.82 (3H, s), 1.40−1.25
(1H, m), 1.16−1.00 (1H, m), 1.00 (3H, d, J = 6.4 Hz), 0.89 (3H, t, J =
7.4 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.6, 156.4, 136.1,
132.4, 128.6, 128.3, 128.1, 119.3, 67.2, 65.4, 58.4, 35.6, 34.3, 24.1, 16.1,
11.5; HRMS-ESI+ (m/z) calcd for C19H29N2O5S (M + H)+, 397.1792;
found, 397.1785.
1
yield). Bp. = 67−70 °C (0.30 mmHg). The H NMR spectrum was
identical to that reported in the literature.16 1H NMR (300 MHz,
CDCl3): δ 5.74−5.89 (m, 1H), 5.27 (1H, dd, J = 1.6, 17.0 Hz), 5.24
(1H, dd, J = 1.6, 10.1 Hz), 3.72 (2H, d, J = 6.3 Hz), 2.79 (3H, s).
General Procedure for Preparing β-Ketosulfonamides 11
and 21−28. To a solution of sulfonamide 7 or 12 (3.2 equiv) in dry
THF (5.7 mL/mmol) at −78 °C was added n-BuLi (1.6 M solution in
in hexane, 3.5 equiv) dropwise over 2 min. The mixture was stirred at
−78 °C for 45 min. A solution of the protected amino acid (1.0 equiv)
in dry THF (5 mL/mmol) was added over 10 min. The mixture was
stirred at −78 °C for 1 h. A sat. aqueous solution of NH4Cl was added,
and the mixture extracted with CH2Cl2. The organic layer was dried
(Na2SO4) and concentrated in vacuo. Purification by FC (EtOAc,
hexane or EtOAc, benzene) gave pure 11 and 21−28. In most
instances unreacted sulfonamide 7 or 12 could be isolated and reused.
tert-Butyl (1-(N-Allyl-N-ethylsulfamoyl)-2-oxo-5-phenylpentan-3-
yl)carbamate (11). Prepared as an amorphous white solid (0.189 g,
92% yield) after FC (20% EtOAc, 80% hexane) from ester 8 (0.146 g,
0.500 mmol) and sulfonamide 7 (0.261 g, 1.60 mmol). 1H NMR
(CDCl3, 300 MHz): δ 7.32−7.14 (5H, m), 5.38−5.25 (1H, m), 5.30−
5.20 (3H, m), 4.35−4.27 (1H, m), 4.25 (1H, d, J = 13.7 Hz), 3.95
(1H, d, J = 13.7 Hz), 3.83 (1H, d, J = 6.1 Hz), 3.27 (2H, q, J = 7.1
Hz), 2.71−2.64 (1H, m), 2.33−2.20 (1H, m), 1.94−1.80 (1H, m),
1.45 (9H, s), 1.16 (3H, t, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 75
MHz): δ 199.2, 155.6, 140.6, 133.1, 128.6, 128.5, 126.3, 119.0, 80.4,
60.0, 59.2, 50.1, 42.6, 32.2, 31.7, 28.3, 14.0; HRMS-ESI+ (m/z) calcd
for C21H36N3O5S (M + NH4)+, 442.2370; found, 442.2365.
tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-4-methyl-2-oxopentan-
3-yl)carbamate (21). Obtained as an amorphous white solid (1.45 g,
97% yield) after FC (25% EtOAc, 75% hexane) from ester 13 (1.00 g,
4.32 mmol) and sulfonamide 12 (2.25 g, 15.1 mmol). 1H NMR
(CDCl3, 300 MHz): δ 5.83−5.72 (1H, m), 5.29−5.21 (2H, m), 5.19
Benzyl (1-(N-Allyl-N-methylsulfamoyl)-5-methyl-2-oxohexan-3-
yl)carbamate (27). Obtained as an amorphous white solid (0.330 g,
83% yield) after FC (25% EtOAc, 75% hexane) from ester 19 (0.279 g,
F
DOI: 10.1021/acs.joc.7b02179
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.00 mmol) and sulfonamide 12 (0.521 g, 3.00 mmol). 1H NMR
(CDCl3, 300 MHz): δ 7.32 (5H, s), 5.79−5.65 (1H, m), 5.25 (1H, d, J
= 17.8 Hz), 5.23 (1H, d, J = 9.9 Hz), 5.10 (2H, s), 4.42 (1H, m), 4.25
(1H, d, J = 13.7 Hz), 4.02 (1H, d, J = 13.7 Hz), 3.75 (2H, d, J = 5.6
Hz); 2.79 (3H, s), 1.74−1.61 (2H, m), 1.45 (1H, m), 0.92 (6H, d, J =
3.2 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 199.7, 156.3, 136.1,
132.4, 128.6, 128.3, 128.1, 119.3, 67.2, 59.3, 57.5, 53.0, 39.3, 34.4, 24.8,
23.2, 21.3; HRMS-ESI+ (m/z) calcd for C19H32N3O5S (M +
NH4)+,414.2057; found, 414.2048.
Benzyl (4-(N-Allyl-N-methylsulfamoyl)-1-(4-(tert-butoxy)phenyl)-
3-oxobutan-2-yl)carbamate (28). Obtained as an amorphous white
solid (0.887 g, 68% yield) after FC (33% EtOAc, 67% hexane) from
ester 20 (1.0 g, 2.59 mmol) and sulfonamide 12 (1.23 g, 8.29 mmol).
1H NMR (CDCl3, 300 MHz): δ 7.38−7.24 (5H, m), 7,.02 (2H, d, J =
8.3 Hz), 6.89 (2H, d, J = 8.3 Hz), 5.82−5.67 (1H, m), 5.53 (1H, d, J =
7.3 Hz), 5.25 (1H, d, J = 17.1 Hz), 5.23 (1H, d, J = 9.5 Hz), 5.15 (2H,
s), 4.64−4.55 (1H, m), 4.13 (1H, d, J = 13.9 Hz), 4.00 (1H, d, J = 13.9
Hz), 3.72 (2H, d, J = 5.9 Hz), 3.15 (1H, dd, J = 5.6, 14.2 Hz), 2.91
(1H, dd, J = 8.3, 14.2 Hz), 2.27 (3H, s), 1.30 (9H, s); 13C{1H} NMR
(CDCl3, 75 MHz): δ 198.4, 156.0, 154.5, 136.0, 132.2, 130.6, 129.7,
128.6, 128.3, 128.1, 124.4, 119.3, 78.5, 67.2, 61.7, 58.1, 53.0, 35.8, 34.3,
28.8; HRMS-ESI+ (m/z) calcd for C26H38N3O6S (M + NH4)+,
520.2476; found, 520.2467.
tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-1-fluoro-4-methyl-2-ox-
opentan-3-yl)carbamate (29). NaH (60% dispersion in mineral oil,
0.030 g, 0.746 mmol, 2.6 equiv) was suspended in dry hexane (5 mL)
under argon atmosphere. This was allowed to settle, and the hexane
was removed by syringe. Residual hexane was removed by
resuspending in dry THF (5 mL), allowing the mixture to settle,
removing THF by syringe twice, and then suspending the resulting
solid in dry THF (5 mL). This mixture was cooled to 0 °C, and
compound 21 (0.100 g, 0.287 mmol, 1 equiv) was added and stirred
for 20 min. After 20 min the mixture was cannulated into a flask
containing Selectfluor (0.305 g, 0.862 mmol, 3.0 equiv) in acetonitrile
(5 mL) under argon atmosphere at −10 °C with stirring. This mixture
was allowed to warm to room temperature overnight (20 h), then
quenched with water (50 mL), and extracted three times with diethyl
ether (50 mL). The combined organic layers were dried with sodium
sulfate, filtered, and concentrated. Purification using FC (15% EtOAc,
85% hexane then 35% EtOAc, 65% hexane) provided compound 29 as
a colorless oil (mixture of diastereomers, 0.074 g, 70% yield). 1H NMR
(CDCl3, 500 MHz): δ 5.80 (d, 2H, J = 48 Hz), 5.76−5.85 (m, 2H),
5.29−5.33 (m, 4H), 5.20 (d, 1H, J = 8.5 Hz), 5.05 (d, 1H, 8.7 Hz),
4.71 (d, 1H, J = 8.9 Hz), 4.63 (dd, 1H, J = 6.2 Hz, 6.5 Hz), 3.95 (dd,
2H, J = 5.7 Hz, 15 Hz), 3.81−3.89 (m, 2H), 2.94 (s, 3H), 2.93 (s, 3H),
2.43 (bs, 1H), 2.21−2.26 (m, 1H), 1.45 (s, 18H), 1.05 (d, 3H, J = 6.7
Hz), 1.02 (d, 3H, J = 6.7 Hz), 0.89 (d, 3H, J = 6.7 Hz), 0.83 (d, 3H, J
= 6.7 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 198.3 (d, J = 19.0 Hz),
197.4 (d, J = 19.9 Hz), 155.7, 155.6, 132.0, 131.9, 119.8, 119.7, 100.1
(d, J = 71.0 Hz), 98.1 (d, J = 70.1 Hz), 80.4, 80.4, 62.6, 61.1, 53.4, 53.3,
34.8, 34.8, 28.9, 28.7, 28.2, 19.9, 19.8, 16.8, 16.3; 19F NMR (CDCl3,
282 Hz): δ −184.4 (d, 1F, J = 47.9 Hz), −185.5 (d, 1F, J = 50.8 Hz);
HRMS-ESI+ (m/z) calcd for C15H28FN2O5S+: 367.1698 found:
367.1697.
s), 1.06 (3H, d, J = 6.8 Hz), 0.84 (3H, d, J = 6.8 Hz); 13C{1H} NMR
(CDCl3, 75 MHz): δ 195.4 (t, J = 26.3 Hz), 155.3, 131.8, 120.2, 115.6
(t, J = 297.6), 80.3, 61.0, 53.7, 35.0, 28.9, 28.1, 19.9, 16.0; 19F NMR
(CDCl3, 282 MHz): δ −106.5 (d, J = 246.6 Hz), −106.9 (d, J = 246.6
Hz), −108.0 (d, J = 246.6 Hz), −108.8 (d, J = 246.6 Hz); HRMS-ESI+
(m/z) calcd for C15H27F2N2O5S (M + H)+, 385.1603; found,
385.1603.
N-Allyl-1,1-difluoro-N-methylmethanesulfonamide (31). To a
solution of sulfonamide 12 (2.1 mL, 15.7 mmol, 2 equiv) in dry
THF (50 mL) in a flame-dried round-bottom flask under argon at −78
°C was added n-BuLi (2.5 M in hexanes, 6.30 mL, 15.7 mmol, 2 equiv)
dropwise, and the mixture was stirred for 40 min. Methylbenzoate
(0.93 mL, 7.30 mmol, 1 equiv) was added, and the resulting yellow
solution stirred for 2 h at −78 °C and then quenched with sat. aqueous
NH4Cl (10 mL). Water (50 mL) was added, and then the mixture was
extracted with methylene chloride (3 × 50 mL). The combined
organic layers were dried with Na2SO4, filtered, and concentrated in
vacuo. Purification by FC (10% EtOAc, 90% hexane then 30% EtOAc,
70% hexane) yielded N-allyl-N-methyl-2-oxo-2-phenylethane-1-sulfo-
namide as a colorless oil (1.43g, 77%). 1H NMR (CDCl3, 300 MHz):
δ 8.03 (d, 2H, J = 8.3 Hz), 7.63 (t, 1H, J = 7.5 Hz), 7.51 (t, 2H, J =
7.82 Hz), 5.70−5.84 (m, 1H), 5.25−5.31 (m, 2H), 4.59 (s, 3H), 3.78
(d, 2H, J = 6.4 Hz), 2.87 (s, 3H); 13C{1H} NMR (CDCl3, 75 MHz): δ
189.5, 135.8, 134.4, 132.6, 129.4, 128.9, 119.1, 57.8, 53.3, 34.6; HRMS-
ESI (m/z) calcd for C12H16NO3S (M + H)+, 254.0845; found,
254.0844. To a solution of CsF (0.607 g, 4 mmol, 4 equiv) in dry
DMF (12 mL) was added N-allyl-N-methyl-2-oxo-2-phenylethane-1-
sulfonamide (0.253 g, 1 mmol, 1 equiv) and Selectfluor (1.42 g, 4
mmol, 4 equiv). The resulting mixture was stirred at room temperature
overnight, then aqueous sodium hydroxide (6 M, 10 mL) was added,
and the mixture was stirred 15 min. The reaction was diluted with
water (50 mL) and extracted three times with diethyl ether (30 mL).
The combined organic layers were washed three times with water (50
mL), then dried (Na2SO4), filtered, and concentrated in vacuo.
Purification by FC (5% Et2O, 95% pentane then 10% Et2O, 90%
1
pentane) yielded compound 31 as a colorless oil (0.118 g, 63%). H
NMR (CDCl3, 300 MHz): δ 6.18 (t, 1H, J = 53.8 Hz), 5.70−5.84 (m,
1H), 5.26−5.31 (m, 2H), 3.91 (d, 2H, J = 6.4 Hz); 13C{1H} NMR
(CDCl3, 75 MHz): δ 132.0, 119.9, 114.7 (t, J = 278 Hz), 53.2, 34.7;
19F NMR (CDCl3, 282 MHz) δ 121.7 (d, 2F, J = 53.4 Hz); HRMS-ESI
(m/z) calcd for C5H9F2LiNO2S (M + H)+, 192.0477; found, 192.0477.
Benzyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-4-methyl-2-
oxopentan-3-yl)carbamate (32). Obtained as a colorless liquid
(0.511 g, 93% yield) after FC (30% EtOAc, 70% hexane) from
compound 25 (0.500 g, 1.31 mmol). 1H NMR (CDCl3, 300 MHz): δ
7.35 (5H, s), 5.84−5.70 (1H, m), 5.32−5.27 (3H, m), 5.11 (2H, s),
4.92 (1H, dd, J = 3.7, 9.3 Hz), 3.92 (2H, bs), 2.96 (3H, s), 2.43−2.33
(1H, m), 1.05 (3H, d, J = 6.6 Hz), 0.82 (3H, d, J = 6.8 Hz); 13C{1H}
NMR (CDCl3, 75 MHz): δ 195.0 (t, J = 24.7 Hz), 156.0, 136.0, 131.7,
128.6, 128.3, 128.2, 120.3, 119.6 (t, J = 297 Hz), 67.4, 61.5, 53.7, 35.0,
29.1, 19.9, 16.0; 19F NMR (CDCl3, 282 MHz): δ −106.6 (d, J = 246.6
Hz), −107.3 (d, J = 244.8 Hz), −108.1 (d, J = 246.6 Hz), −108.5 (d, J
= 244.8 Hz); HRMS-ESI+ (m/z) calcd for C18H25F2N2O5S (M + H)+,
419.1447; found, 419.1446.
tert-Butyl (1-(N-Allyl-N-ethylsulfamoyl)-1,1-difluoro-2-oxo-5-phe-
nylpentan-3-yl)carbamate (33). Obtained as a colorless oil (0.185 g,
85% yield) after FC (20% EtOAc, 80% hexane) from compound 11
(0.200 g, 0.471 mmol). H NMR (CDCl3, 300 MHz): δ 7.28−7.16
(5H, m), 5.87−5.70 (1H, m), 5.29 (1H, d, J = 17.8 Hz), 5.27 (1H, d, J
= 8.3 Hz), 5.16 (1H, d, J = 6.6 Hz), 4.88 (1H, m), 3.96 (2H, bd, J =
5.4 Hz), 3.42 (1H, dd, J = 6.6, 7.1 Hz), 2.80−2.60 (2H, m), 2.36−2.20
(1H, m), 1.94−1.79 (1H, m), 1.44 (9H, s), 1.19 (3H, t, J = 7.1 Hz);
13C{1H} NMR (CDCl3, 75 MHz): δ 195.2 (t, J = 24.8 Hz), 155.0,
140.3, 132.5, 128.6, 128.5, 126.3, 120.0, 115.3 (t, J = 297.1 Hz), 80.5,
56.2, 50.4, 42.9, 32.6, 31.5, 28.2, 13.8; 19F NMR (CDCl3, 282 MHz):
−107.3 (d, J = 244.8 Hz), −107.4, (d, J = 243.1 Hz), −108.6 (d, J =
243.1 Hz), −108.9 (d, J = 244.8 Hz); HRMS-ESI+ (m/z) calcd for
C21H31F2N2O5S (M + H)+, 461.1916; found, 461.1917.
General Procedure for Preparing β-Keto-α,α-difluorosulfo-
namides 30 and 32−40. To a solution of the β-ketosulfonamides in
dry DMF (0.04 mL/mg β-ketosulfonamide) was added 4 equiv CsF
(for N-allyl-β-ketosulfonamides) or 4 equiv TBAF (1 M in THF, for
28), and the mixture stirred for 15 min. Four equiv of Selectfluor was
added, and the mixture stirred for 30−60 min. The mixture was diluted
with water then extracted with Et2O (3×). The combined organic
layers were washed with saturated brine, then dried (Na2SO4), and
concentrated by rotary evaporation. FC of the residue (EtOAc, hexane
or EtOAc, benzene) provided the purified products.
1
tert-Butyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-4-methyl-
2-oxopentan-3-yl)carbamate (30). Obtained as a colorless liquid
(0.926 g, 84% yield) after FC (20% EtOAc, 80% hexane) from
1
compound 21 (1.00 g, 2.87 mmol). H NMR (CDCl3, 300 MHz): δ
5.83−5.71 (1H, m), 5.32 (d, J = 14.7 Hz), 5.06 (1H, d, J = 9.3 Hz),
4.83 (1H, d, J = 9.3 Hz), 3.95 (1H, bs), 2.42−2.34 (1H, m), 1.45 (9H,
tert-Butyl (1-(N-Ethylsulfamoyl)-1,1-difluoro-2-oxo-5-phenylpen-
tan-3-yl)carbamate (34). Obtained as a white solid (0.078 g, 74%
G
DOI: 10.1021/acs.joc.7b02179
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The Journal of Organic Chemistry
Article
yield) after FC (15% EtOAc, 85% hexane) from compound 9 (0.096 g,
0.250 mmol). H NMR (CDCl3, 300 MHz): δ 7.38−7.10 (5H, m),
182.2 (t, J = 22.7 Hz), 159.0, 154.0, 140.6, 135.9, 132.7, 131.8, 128.5,
128.3, 127.0, 126.7, 122.8, 120.1, 117.6 (t, J = 295.4 Hz), 79.7, 67.7,
53.8, 35.1, 28.9; 19F-NMR (CDCl3, 282 MHz): δ −107.3 (d, J = 244.8
Hz); −108.4 (J = 244.8 Hz), −108.6 (d, J = 248.3 Hz); HRMS-ESI+
(m/z) calcd for C26H33F2N2O6S (M + H)+, 539.2022; found,
539.2023.
General Procedure for the Deallylation of Compounds 30
and 35. To a solution of 30 or 35 and DMBA (5 equiv) in dry
acetonitrile (0.05 mL/mg 30 or 35) in a pressure tube was added
Pd(PPh3)4 (0.1 equiv). The mixture was heated to 100 °C for 24 h.
After cooling, the mixture was diluted with EtOAc and washed with
sat. NaHCO3 (3×), water (1×), and sat. brine (1×), dried (Na2SO4),
and concentrated by rotary evaporation. The residue was purified by
FC (EtOAc, hexane).
1
6.19 (1H, s), 5.05 (1H, d, J = 7.6 Hz), 4.78−4.73 (1H, bt, J = 7.1 Hz),
3.35−3.10 (2H, m), 2.84−2.61 (2H, m), 2.32−2.18 (1H, m), 1.89−
1.71 (1H, m), 1.43 (9H, s), 1.43 (3H, t, J = 7.1 Hz); 13C{1H} NMR
(CDCl3, 75 MHz): δ 195.8 (t, J = 23.7 Hz), 155.9, 139.5, 128.7, 128.4,
126.6, 115.3 (t, J = 299.1 Hz), 81.5, 56.5, 39.3, 31.8, 28.1, 15.5; 19F
NMR (CDCl3, 282 MHz): −108.3 (d, J = 244.8 Hz), −109.4, (d, J =
244.8 Hz); HRMS-ESI+ (m/z) calcd for C18H30F2N3O5S (M + NH4)+,
438.1869; found, 438.1862.
tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-4,4-difluoro-3-oxo-1-
phenylbutan-2-yl)carbamate (35). Obtained as a pale yellow
amorphous solid (0.724 g, 84% yield) after FC (15% EtOAc, 85%
hexane) from compound 22 (0.800 g, 2.00 mmol).1H NMR (CDCl3,
300 MHz): δ 7.36−7.24 (3H, m), 7.16 (2H, d, J = 6.8 Hz), 5.83−5.73
(1H, m), 5.29 (2H, d, J = 13.2 Hz), 5.12−4.85 (2H, m), 3.92 (2H, bs),
3.30 (1H, bd, J = 13.9 Hz), 2.97 (3H, s), 3.00−2.79 (1H, m), 1.53
(9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 194.5 (t, J = 24.3 Hz),
154.7, 135.1, 131.7, 129.4, 128.7, 127.2, 120.2, 115.8 (t, J = 297.6 Hz),
80.5, 57.0, 53.7, 36.5, 35.0, 28.1; 19F NMR (CDCl3, 282 MHz): δ
−107.1 (d, J = 244.8 Hz), −107.2 (d, J = 244.8 Hz), −108.1 (d, J =
244.8 Hz), −108.3 (d, J = 244.8 Hz); HRMS-ESI+ (m/z) calcd for
C15H19F2N2O5S (M − (CH3)3 + 2H)+, 377.0977; found, 377.0976.
tert-Butyl (4-(N-Allyl-N-methylsulfamoyl)-4,4-difluoro-3-oxobu-
tan-2-yl)carbamate (36). Obtained as a white solid (0.131 g, 76%
yield) after FC (20% EtOAc, 80% benzene) from compound 23
tert-Butyl (1,1-Difluoro-4-methyl-1-(N-methylsulfamoyl)-2-oxo-
pentan-3-yl)carbamate (41). Prepared via deallylation of compound
30 (050 g, 0.142 mmol) using the general procedure. Obtained as a
white amorphous solid (0.042 g, 75% yield) after FC (20% EtOAc,
1
80% hexane). H NMR (CDCl3, 300 MHz): δ 6.02 (1H, bs), 4.98
(1H, d, J = 8.6 Hz), 4.73 (1H, dd, J = 2.9, 7.6 Hz), 2.92 (3H, d, J = 3.9
Hz), 2.43−2.31 (1H, m), 1.42 (9H, s), 1.08 (3H, d, J = 6.6 Hz), 0.85
(3H, d, J = 6.8 Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 195.5 (t, J =
22.7 Hz), 156.1, 115.2 (t, J = 297.0 Hz), 81.2, 61.4, 30.1, 28.6, 28.1,
19.9, 16.1; 19F NMR (CDCl3, 282 MHz): δ −107.3 (d, J = 246.6 Hz),
−108.6 (d, J = 246.6 Hz); 19F NMR (DMSO-d6, 282 MHz, 23 °C): δ
−105.8 (d, J = 249.6 Hz), −106.0 (d, J = 245.0 Hz), −110.2 (d, J =
246.1 Hz), −110.8 (d, J = 245.3 Hz); 19F NMR (DMSO-d6, 282 MHz,
80 °C): δ −105.5 (d, J = 148.0 Hz), −108.8 (d, J = 148.0 Hz); HRMS-
ESI+ (m/z) calcd for C12H23F2N2O5S (M + H)+, 345.1290; found,
345.1290.
tert-Butyl (4,4-Difluoro-4-(N-methylsulfamoyl)-3-oxo-1-phenyl-
butan-2-yl)carbamate (42). Prepared via deallylation of compound
35 (0.050 g, 0.140 mmol) using the general procedure. Obtained as a
white amorphous solid (0.041 g, 75% yield) after FC (30% EtOAc,
70% hexane). Crystals used for X-ray crystallography were obtained by
recrystallization from heptane (mp = 113−115 °C) 1H NMR (CDCl3,
300 MHz): δ 7.36−7.24 (3H, m), 7.16 (2H, d, J = 6.8 Hz), 6.10 (1H,
bs), 5.10−5.01 (1H, m), 4.92 (1H, d, J = 6.3 Hz), 3.30 (1H, dd, J =
3.4, 17.1 Hz), 2.94−2.77 (4H, m), 1.36 (9H, s); 13C{1H} NMR
(CDCl3, 75 MHz): δ 195.1 (t, J = 23.2 Hz), 155.6, 134.4, 129.2, 129.0,
127.6, 115.5 (t, J = 298.1 Hz), 83.4, 57.6, 36.0, 30.0, 28.1; 19F NMR
(CDCl3, 282 MHz): δ −106.8 (d, J = 246.6 Hz), −108.2 (d, J = 246.6
Hz); HRMS-ESI+ (m/z) calcd for C16H23F2N2O5S (M + H)+,
393.1290; found, 393.1290.
1
(0.155 g, 0.484 mmol). H NMR (CDCl3, 300 MHz): δ 5.80−5.68
(1H, m), 5.29 (1H, d, J = 15.7 Hz), 5.28 (1H, d, J = 11.2 Hz), 5.09
(1H, s), 4.81 (1H, dq, J = 7.0, 7.0 Hz), 3.90 (2H, bs), 2.95 (3H, s),
1.41 (s, 1.5H, one-half of the doublet corresponding to CH-CH3), 1.39
(12H, s, 9H from (CH3)3-C overlapping with one-half of the doublet
corresponding to CH-CH3); 13C{1H} NMR (CDCl3, 75 MHz): δ
196.0 (t, J = 24.3 Hz), 154.7, 131.8, 120.2, 115.7 (t, J = 297.1 Hz),
80.4, 53.7, 52.3, 35.0, 28.2, 17.1; 19F NMR (CDCl3, 282 MHz): δ
−106.3, (d, J = 251.7 Hz), −106.7 (d, J = 246.6 Hz), −108.2 (d, J =
246.6 Hz), −108.8 (d, J = 253.5 Hz); HRMS-ESI+ (m/z) calcd for
C9H15F2N2O5S (M - (CH3)3 + 2H)+, 301.0662; found, 301.0663.
Benzyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-4-methyl-2-
oxohexan-3-yl)carbamate (37). Obtained as a colorless oil (0.196
g, 90% yield) after FC (15% EtOAc, 85% hexane) from compound 26
(0.200 g, 0.504 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.33 (5H, s),
5.80−5.71 (1H, m), 5.40−5.25 (3H, m), 5.10 (2H, s), 4.90 (1H, dd, J
= 4.4, 9.3 Hz), 3.91 (1H, bs), 2.95 (3H, s), 2.10 (1H, bs), 1.38−1.21
(1H, m), 1.06−0.95 (4H, m), 0.86 (3H, t, J = 7.1 Hz); 13C{1H} NMR
(CDCl3, 75 MHz): δ 195.1 (t, J = 24.3 Hz), 156.0, 136.1, 131.8, 128.6,
128.3, 128.2, 120.2, 115.7 (t, J = 297.1 Hz), 67.3, 61.7, 53.7, 35.7, 35.0,
23.3, 16.2, 11.3; 19F NMR (CDCl3, 282 MHz): −106.2 (d, J = 246.6
Hz), −106.9 (d, J = 246.6 Hz), −108.1 (d, J = 246.6 Hz), −108.3 (d, J
= 246.6 Hz); HRMS-ESI+ (m/z) calcd for C19H27F2N2O5S (M + H)+,
433.1603; found, 433.1604.
Benzyl (4-(N-Allyl-N-methylsulfamoyl)-1-(4-(tert-butoxy)phenyl)-
4,4-difluoro-3-oxobut-1-en-2-yl)carbamate (43). Prepared using the
same procedure described for compound 39 except the reaction was
conducted for 10 h. Obtained as an amorphous white solid (0.040 g,
31% yield) after FC (5% EtOAc, 95% benzene) from compound 28
(0.100 g, 0.231 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.60 (s, 1H),
7.56 (2H, d, J = 8.7 Hz), 7.31 (5H, bs), 6.94 (2H, d, J = 8.7 Hz), 6.52
(1H, bs), 5.82−5.70 (1H, m), 5.28 (1H, dd, J = 1.0, 17.5 Hz), 5.27
(1H, dd, J = 1.0, 11.1 Hz), 5.13 (2H, bs), 3.92 (2H, bs), 2.96 (3H, s),
1.39 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ 182.2 (t, J = 22.7
Hz), 159.0, 154.0, 140.6, 135.9, 132.7, 131.8, 128.5, 128.3, 127.0,
126.7, 122.8, 120.1, 117.6 (t, J = 295.4 Hz), 79.7, 67.7, 53.8, 35.1, 28.9;
19F NMR (CDCl3, 282 MHz): δ −101.9; HRMS-ESI+ (m/z) calcd for
Benzyl (1-(N-Allyl-N-methylsulfamoyl)-1,1-difluoro-5-methyl-2-
oxohexan-3-yl)carbamate (38). Obtained as a colorless oil (0.180
g, 82% yield) after FC (15% EtOAc, 85% hexane) from compound 27
(0.200 g, 0.504 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.32 (5H, s),
5.87−5.69 (1H, m), 5.38−5.25 (3H, m), 5.10 (2H, s), 5.03−4.18 (1H,
m), 3.91 (2H, bs), 2.95 (3H, s), 1.84−1.60 (2H, m), 1.49−1.30 (1H,
m), 0.98 (3H, d, J = 5.4 Hz), 0.93 (3H, d, J = 5.6 Hz); 13C{1H} NMR
(CDCl3, 75 MHz): δ 195.6, (t, J = 23.7 Hz), 155.6, 135.9, 131.7, 128.4,
128.1, 128.0, 120.1, 115.7, (t, J = 297.1, Hz), 67.1, 55.3, 53.6, 39.6,
34.9, 24.8, 23.1, 20.9; 19F NMR (CDCl3, 282 MHz): −106.8 (d, J =
246.6 Hz), −107.6, (d, J = 246.6 Hz), HRMS-ESI+ (m/z) calcd for
C19H27F2N2O5S (M + H)+, 433.1603; found, 433.1603.
Benzyl (4-(N-Allyl-N-methylsulfamoyl)-1-(4-(tert-butoxy)phenyl)-
4,4-difluoro-3-oxobutan-2-yl)carbamate (39). Obtained as a pale
yellow semisolid (0.040 g, 74% yield) after FC (5% EtOAc, 95%
benzene then 10% EtOAc, 90% benzene) from compound 28 (0.050
g, 0.100 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.24−7.38 (m, 5H),
7.02 (2H, d, J = 8.3 Hz), 5.82−5.70 (1H, m), 5.05−5.35 (1H, m), 3.92
(2H, bs), 3.28 (1H, dd, J = 4.9, 14.7 Hz), 2.97 (3H, s), 2.88 (1H, dd, J
= 7.8, 14.4 Hz), 1.32 (9H, s); 13C{1H} NMR (CDCl3, 75 MHz): δ
C26H31F2N2O6S (M + H)+, 537.1865; found, 537.1865.
General Procedure for the Preparation of Compounds 44−
46. These compounds were prepared using the general procedure
described above for the synthesis of β-keto-α,α-difluorosulfonamides
32, 33, and 35-44 except 4 equiv of Cs2CO3 was used, and the
reactions were allowed to stir for 30−60 min after the addition of
Selectfluor.
tert-Butyl (E)-(1-(N-Allyl-N-ethylsulfamoyl)-1,1-difluoro-2,2-dihy-
droxy-5-phenylpentan-3-ylidene)carbamate (44). Obtained as an
amorphous white solid (0.036 g, 64% yield) after FC (20% EtOAc,
1
80% hexane) from compound 11 (0.050 g, 0.118 mmol). H NMR
(CDCl3, 300 MHz): δ 8.76 (1H, s), 7.32−7.16 (5H, m), 5.88−5.71
(1H, m), 5.31 (1H, d, J = 17.3 Hz), 5.30 (1H, d, J = 7.7 Hz), 4.28 (1H,
H
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The Journal of Organic Chemistry
Article
s), 4.10−3.90 (1H, m), 3.53−3.36 (1H, m), 3.90−3.75 (1H, m), 2.66−
2.52 (2H, m), 2.41−2.38 (1H, m), 1.55 (9H, s), 1.20 (3H, t, J = 7.0
Hz); 13C{1H} NMR (CDCl3, 75 MHz): δ 165.3, 148.5, 140.1, 132.2,
128.5, 128.4, 126.2, 120.7 (t, J = 296.5 Hz), 119.9, 83.1, 79.5 (t, J =
21.6 Hz), 50.2, 42.8, 34.8, 28.8, 27.9, 13.6; 19F NMR (CDCl3, 282
MHz): δ −107.2 (d, J = 243.1 Hz), −108.1 (d, J = 243.1 Hz); HRMS-
ESI+ (m/z) calcd for C21H30F2N2O6NaS (M + Na)+, 499.1685; found,
499.1686.
REFERENCES
■
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1
75% hexane) from compound 22 (0.050 g, 0.126 mmol). H NMR
(CDCl3, 300 MHz): δ 8.35 (1H, s), 7.40−7.21 (5H, m), 5.89−5.73
(1H, m), 5.34 (2H, two overlapping doublets with J ∼ 11.5 Hz), 4.2−
3.7 (1H, bs), 3.98 (2H, s), 3.62 (1H, d, J = 14.1 Hz), 3.36 (2H, d, J =
14.1 Hz), 3.02 (3H, s), 1.44 (9H, s); 13C{1H} NMR (CDCl3, 75
MHz): δ 165.3, 148.2, 132.1, 131.7, 130.7, 128.7, 127.7, 121.7 (t, J =
297.1 Hz), 120.2, 82.80, 79.5 (t, J = 26.2 Hz), 53.6, 38.6, 35.0, 27.8;
19F NMR (CDCl3, 282 MHz): δ −105.7; HRMS-ESI+ (m/z) calcd for
(3) (a) Cox, R. J.; Gibson, J. S.; Martin, M. B. M. ChemBioChem
2002, 3, 874−886. (b) Cox, R. J.; Gibson, J. S.; Hadfield, A. T.
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V. P. Org. Biomol. Chem. 2015, 13, 7437−7444. (e) Derbanne, M.;
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C15H19F2N2O6S(M − C4H9 + 2H)+, 393.0926; found, 393.0933.
tert-Butyl (E)-(4-(N-Allyl-N-methylsulfamoyl)-4,4-difluoro-3,3-di-
hydroxybutan-2-ylidene)carbamate (46). Obtained as an amorphous
white solid (0.041 g, 35% yield) after FC (30% EtOAc, 70% hexane)
1
from compound 23 (0.100 g, 0.312 mmol). H NMR (CDCl3, 300
MHz): δ 8.70 (1H, bs), 5.82−5.69 (1H, m), 5.28 (2H, bd, J = 13.4
Hz), 4.37 (1H, s), 3.92 (1H, bs), 2.95 (3H, s), 1.73 (3H, s), 1.48 (9H,
s); 13C{1H} NMR (CDCl3, 75 MHz): δ 160.5, 148.7, 131.7, 121.7 (t, J
= 295.1 Hz), 120.1, 83.1, 76.8 (t, J = 21.7 Hz), 53.6, 34.9, 27.9, 21.0;
19F NMR (CDCl3, 282 MHz): δ −106.3 (bd, J = 243.3 Hz), −107.4
(d, J = 243.1 Hz); HRMS-ESI+ (m/z) calcd for C13H22F2N2O6LiS (M
+ Li)+, 379.1321; found, 379.1320.
(7) Compound 31 was identified by synthesis of an authentic sample.
See the SI.
(8) Ladame et al. (ref 3c) have reported that β-keto-α,α-
difluorophosphonates readily undergo C−C bond fragmentation
between the carbonyl and CF2 carbons under basic conditions.
Their studies indicate that the decomposition reaction afforded :CF2, a
highly reactive carbene. The formation of :CF2 may account for the
significant number of small peaks that appear between −104 and −150
ppm in the 19F-NMR spectra during some of the reactions described
here.
(9) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.;
Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192−212 We also
attempted the fluorination of the methionine derivative (compound
24) using our usual conditions except N-fluorobenzenesulfonimide
(NFSi) was used in place of Selectfluor. No reaction had occurred
after 8 h..
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02179.
X-ray crystal structure of compound 42 (CIF)
Spectral data (1H, 13C, 19F-NMR) for all new
compounds, 19F-NMR spectra of compound 41 at 80
°C (PDF)
(10) The X-ray structure of compound 42 was obtained (see the SI).
(11) Ni, C.; Zhang, L.; Hu, J. J. J. Org. Chem. 2009, 74, 3767.
(12) It is possible that these compounds would exist, either in part or
entirely, as their hydrates in a purely aqueous environment. The low
solubility of these compounds in aqueous solution prevented us from
determining this.
(13) Compound 31 as well as other minor unidentified impurities
were also evident in the 19F NMR spectra of the crude reaction
mixture.
(14) Siedel, W.; Sturm, K.; Geiger, R. Chem. Ber. 1963, 96, 1436−
1439.
(15) Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.; Kulesha, I.
D.; Tzougraki, C.; Meienhofer, J. J. Org. Chem. 1977, 42, 1286−1290.
(16) King, J. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.; Klassen, D. F.
J. Am. Chem. Soc. 1992, 114, 3028−3033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s5taylor@uwaterloo.ca
ORCID
Ryan Chung: 0000-0001-7242-1195
Jeremy Green: 0000-0003-4544-6412
Jason E. Hein: 0000-0002-4345-3005
Scott D. Taylor: 0000-0001-5449-5940
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Natural Sciences and
Engineering Research Council of Canada (NSERC) Discovery
Grant to S.D.T. (RGPIN-2017-04233) and an NSERC Engage
Grant (EGP-437470-2012) to S.D.T. and Vertex Pharmaceut-
icals. J.S. thanks NSERC for a postgraduate scholarship. We
thank Luc Farmer, Simon Giroux, and Dylan Jacobs of Vertex
Pharmaceuticals for helpful discussions during the early stages
of this work. We also thank Luke Vanderzwet for assitance
during the early stages of this work.
I
DOI: 10.1021/acs.joc.7b02179
J. Org. Chem. XXXX, XXX, XXX−XXX