Aminooxylation Horner-Wadsworth-Emmons Sequence for the Synthesis of Enantioenriched γ-Functionalized Vinyl Sulfones

Article abstract of DOI:10.1021/acs.joc.5b02556

An operationally simple protocol for the synthesis of γ-hydroxy vinyl sulfones has been developed using a proline-based aldehyde aminooxylation, followed by a vinyl sulfone forming Horner-Wadsworth-Emmons olefination. The adducts, formed in high enantiopurity, were subsequently converted to γ-azido vinyl sulfones, and azide-alkyne click chemistry enabled the synthesis of vinyl sulfone-based triazoles as potential nonpeptidic cysteine protease inhibitors. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02556

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Article
Aminooxylation Horner-Wadsworth-Emmons sequence for the
synthesis of enantioenriched gamma-functionalized vinyl sulfones
William Doherty, and Paul Evans
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02556 • Publication Date (Web): 27 Jan 2016
Downloaded from http://pubs.acs.org on January 28, 2016
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Aminooxylation Horner-Wadsworth-Emmons sequence for the synthesis of
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enantioenriched γ-functionalized vinyl sulfones
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W. Doherty and P. Evans*
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Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin,
Dublin 4, Ireland.
(1) L-proline, PhNO
(2) (EtO)2POCH2SO2Ph,
(1) MsCl
(2) NaN3
Et3N, LiBr
R
R
R
SO2Ph
SO2Ph
O
1 step
up to 51% yield
up to 99% ee
OH
N3
building blocks for
protease inhibitors
access to both
enantiomers
ABSTRACT: An operationally simple protocol for the synthesis of γ-hydroxy vinyl sulfones
has been developed using a proline-based aldehyde aminooxylation, followed by a vinyl
sulfone forming Horner-Wadsworth-Emmons olefination. The adducts, formed in high
enantiopurity, were subsequently converted to γ-azido vinyl sulfones and azide-alkyne click
chemistry enabled the synthesis of vinyl sulfone-based triazoles as potential non-peptidic
cysteine protease inhibitors
.
INTRODUCTION
Vinyl sulfones are useful functionalized building blocks which have frequently been used in
the assembly of target molecules.1,2 Additionally, since the mid-90s certain members of this
wider family are recognized to be potent enzyme inhibitors (see Figure 1 for representative
vinyl sulfone cysteine protease inhibitors).3 In relation to the latter, we became interested
in developing a means to access chiral γ-functionalized vinyl sulfones in order to prepare
targets not directly available from chiral pool amino acid-based starting materials so that,
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ultimately, we can study their anti-parasitic behaviour.4 This type of compound has been
prepared in racemic and enantioenriched/pure form via sequences involving several steps.
As a rule, these routes are focused on a single target and, therefore, do not readily provide
access to the enantiomeric series, or readily incorporate alternative structural
characteristics.5
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SO2Ph
Ph
SO2Ph
N
HN
Ph
O
O
N
N
N
N
N
H
NH
NMe
K777 (1): Drug candidate
2: Reversible cruzain inhibitor
for Chagas' disease
Figure 1. Representative vinyl sulfone-based enzyme inhibitors
In 2003, Zhong, MacMillan and Hayashi independently6 published their findings concerning
the enamine-based7 asymmetric α-aminooxylation of a range of aldehydes using proline and
nitrosobenzene (as an electrophilic oxygen source), in order to form α-aniloxy aldehydes of
the type 4. These aldehydes, bearing an electronegative group in the α-position, are
complex in terms of structure. However, the material from the crude reaction mixture
participated in typical aldehyde chemistry (borohydride-based reduction, reductive
amination etc.). In terms of stereochemistry, for aliphatic aldehydes, L-proline afforded the
R-enantiomeric series.8 Shortly after these initial reports, Zhong demonstrated that the
aminooxylation could be telescoped in one-pot with a Horner-Wadsworth-Emmons (HWE)
olefination, generating γ-aniloxy-α,β-unsaturated ketones (eg. 5) in good overall yield and
excellent enantioselectivity (Scheme 1).9 During these processes it was reported that the
weak N-O bond was conserved and that the products could be reduced either by
hydrogenolysis, or copper-mediated conditions providing the corresponding
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enantioenriched secondary alcohols (eg. 6). Since the original report, this sequence has
been utilized by several groups for the preparation of carbonyl compounds bearing γ-
stereogenic centres.10 However, to date, this process has not been transferred to sulfones.
Described here is a simple protocol to access enantioenriched γ-hydroxy and γ-amino vinyl
sulfones.
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Scheme 1. Zhong’s aminooxylation-HWE reaction sequence
RESULTS AND DISCUSSION
For the initial study, octanal 7 was selected for optimisation. As shown in Table 1, use of
Zhong’s one-pot reaction conditions in the presence of sulfonyl phosphonate 8 gave the
trans-γ-hydroxy vinyl sulfone 9 in only very low yield (Entry 1). None of the anticipated
aniloxy adduct (of the type 5, Scheme 1) was detected and when the reaction period for the
HWE phase was reduced negligible amounts of sulfone-based material was produced.11
Although the yield was disappointing the enantiomeric excess of the adduct E-9 proved high
and was consistent with literature reports for this type of reaction.6,9,10 As Entry 2 indicates
only a slight improvement in chemical yield was observed when Masamune-Roush,12,10d (or
Rathke’s13 MgBr2-based conditions - not shown) for the HWE reaction were employed. We
6b
then opted to change the solvent for the aminooxylation, moving to MacMillan’s CHCl3
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and Hayashi’s MeCN6c at 0 °C rather than room temperature. In both instances this change
in reaction medium and temperature resulted in a slower initial reaction (i.e. 2 to 2.5 hours)
and better overall yields were obtained, particularly using Rathke’s mild HWE conditions,13
which were optimized to 51% when 7 was distilled prior to the reaction (Entries 3 and 4). In
relation to the chemical yield we were concerned that some material remained at the
aniloxy intermediate, therefore the reported copper-mediated process for N-O bond
heterolysis (CuSO4·5H2O in MeOH)6 was performed on the crude reaction mixture following
HWE olefination. This did not result in any increase in yield. A traditional sodium hydride
based HWE reaction gave E-9 in 42% yield (Entry 5).5h We also attempted a Z-selective Ando
HWE olefination14 using phosphonate 10 and literature conditions deviating slightly from
our optimal procedure (Entry 6). However, in this instance only moderate yields and poor Z-
selectivity was observed. Nonetheless, the separation of the geometric isomers by column
chromatography was facile and optically active Z-9 was fully characterized.
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Table 1. The aminooxylation vinyl sulfone forming HWE reaction for the preparation of 9
We then applied our optimized reaction conditions, with L- and D-proline, to a small range
of aldehydes (Scheme 2). Using propanal 11 and the optimum conditions identified from
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the study included in Table 1, both enantiomers of 14 were isolated in moderate yields and
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excellent enantioselectivities.
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Scheme 2. Substrate scope for the aminooxylation-HWE sequence
Use of the branched aldehyde 3 similarly provided (R)- and (S)-15. 4-Phenylbutanal 12 and
the ω-amino functionalized aldehyde 13 gave (R)- and (S)-16 and 17 in slightly poorer yields
than their alkyl counterparts but pleasingly the enantiomeric excess of the adducts was
comparable. In order to demonstrate the utility of the γ-hydroxy-α,β-unsaturated sulfones,
further conversions of the initial adducts were considered. As shown in Scheme 3, (R)- and
(S)-16 engage in selective reductions. Magnesium(0) in the presence of catalytic amounts of
Hg(II) leads to a reductive cleavage of the C-S bond to form (R)- and (S)-18 in moderate
yield.15 Use of typical hydrogenation conditions in order to generate a remote stereocentre
provided (R)- and (S)-19 in essentially quantitative yield.5c In both instances no erosion of
enantiopurity was detected.
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Scheme 3. Complementary reductions of (R)- and (S)-16
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The stereocontrolled conversion of the allylic hydroxyl group into an azido group was
considered next. Under direct Mitsunobu-type conditions16 none of the hoped for γ-azido
vinyl sulfone was observed due to issues with vinylic to allylic sulfone isomerization1f and
decomposition. However, as shown in Scheme 4, following a mesylation-based sequence17
both enantiomers of 9, 16 and 17 were converted with inversion into the corresponding
azides 20, 21 and 22. No issue with double bond isomerization, or the loss of optical purity
was observed during the course of the reactions. In the case of (S)-21, single crystal X-ray
diffraction supported the structural assignment.18
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Scheme 4. Synthesis of γ-azido vinyl sulfones and single crystal X-ray structure image of
(S)-21 (Ortep plots to 50% probability)
With the γ-azido vinyl sulfones in hand, their copper(I) catalyzed azide-alkyne click reaction
(CuAAC)19 with phenylalanine derived alkyne 23 (prepared from the corresponding aldehyde
via a Corey-Fuchs alkynylation)20 was considered. 1,4-Disubstituted-1,2,3-triazoles are
recognized to be proteolytically stable motifs that effectively mimic peptide bonds; they are
therefore of significant interest from a biological standpoint (for example compound 2,
Figure 1).21,22
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Both enantiomers of azide 21 were reacted with phenylalanine-based alkyne 23 using DMF
as the solvent under otherwise standard conditions to provide triazoles 25 and 26 as single
diastereoisomers (Scheme 5). These vinyl sulfone-containing homophenylalanine analogues
can be considered to be non-peptidic bioisosteres21 of compounds of type 1. Furthermore,
triazoles 27 and 28, similarly obtained from R- and S-22 can be viewed as Boc-protected
lysine analogues. This methodology therefore alleviates the reliance on naturally occurring
amino acid residues for incorporation into the γ-position of vinyl sulfone based protease
inhibitors.
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Scheme 5. The CuAAC reaction for the synthesis of 1,4-disubstituted 1,2,3-triazole-based
vinyl sulfone peptidomimetics
In summary, we have developed a straight-forward synthesis of γ-oxygen, or nitrogen-
substituted vinyl sulfones, whereby, the desired enantiomer can be accessed in good
enantiomeric excess. The reaction conditions were conducted in an aerobic atmosphere
without the need for dry solvents and, in contrast to previous reports,9,10 avoid an additional
N-O bond cleavage step. To highlight the utility of this reaction we have shown that these
compounds can easily be converted to the corresponding azides using mesylation/azide
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displacement chemistry and found application in the synthesis of diastereomeric triazoles
which are potential cysteine protease inhibitor scaffolds. Chemoselective reduction of the
azido group is currently under investigation in our laboratory in order to access γ-amino
vinyl sulfones.
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EXPERIMENTAL SECTION
General Directions. 1H and 13C NMR spectra were recorded at 500 MHz and 400 MHz
system spectrometers and coupling constants J are quoted in Hertz. 1H and 13C NMR
1
chemical shift assignments are based on two-dimensional NMR experiments including H -
1H gCOSY, DEPT, HSQC and HMBC. High resolution mass spectra were carried out on a mass
spectrometer with a TOF analyzer. Infrared spectra were recorded on a FT-IR spectrometer.
Optical rotation data are quoted in units of 10‒1degcm2g‒1. Chiral phase HPLC was
performed under the conditions provided and enantiomeric excess was calculated on the
basis of the average between the 210 and 230 nm wavelength traces. Reagents were
obtained from commercial suppliers and were used without further purification.
Dichloromethane was used as received except for the Corey-Fuchs dibromination reaction
where it was dried over activated 4Å molecular sieves. Tetrahydrofuran was freshly distilled
from sodium-benzophenone ketyl radical under nitrogen.
General Procedure for Aminooxylation-Horner-Wadsworth-Emmons (AO-HWE) reaction
Note: the AO-HWE reactions do not require anhydrous/inert conditions or dry solvents.
At 0 °C, to a stirred solution of aldehyde (1.2 equiv.) and nitrosobenzene (1.0 equiv.) in
MeCN (0.2 M based on aldehyde) was added proline (0.2 equiv.) and the reaction mixture
was stirred at 0 °C for 2 hours after which time the reaction turned from clear turquoise
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green to opaque orange indicating consumption of nitrosobenzene. Meanwhile, at room
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temperature in
a
separate flask, to
a
stirred solution of diethyl
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9
[(phenylsulfonyl)methyl]phosphonate 8 (2.0 equiv.) and LiBr (2.0 equiv.) in MeCN (0.5 M)
was added Et3N (2.0 equiv.) and the reaction mixture was stirred for 10 minutes. Note: this
reaction can be set up once the AO reaction has reached completion i.e. turned orange. The
contents of the AO flask were then transferred to the HWE flask using a Pasteur pipette.
The AO flask was then rinsed with MeCN (1-4 mL depending on reaction scale) and the
resulting clear orange solution was stirred for 24 hours at room temperature. The reaction
mixture was quenched with HCl (1 M, 10-20 mL depending on scale of the reaction) to give a
dark clear burgundy solution and the mixture was extracted with CH2Cl2 (20-40 mL
depending on scale of the reaction). The layers were separated and the aqueous layer was
re-extracted with CH2Cl2 (10-20 mL) after which the aqueous layer was very pale yellow or
colourless. The combined organic layers were washed with brine (10-20 mL), dried over
MgSO4, filtered and solvent was removed in vacuo to the crude product as a thick burgundy
oil. Purification by column chromatography gave γ-hydroxy vinyl sulfones as orange/yellow
solids, or orange/yellow oils.
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(R,E)-1-(Phenylsulfonyl)non-1-en-3-ol (R)-E-9.5a,d AO flask: Octanal 7 (0.22 mL, 1.41 mmol,
1.2 equiv.), nitrosobenzene (129 mg, 1.20 mmol, 1.0 equiv.) and L-proline (28 mg, 0.24
mmol, 0.2 equiv.) in MeCN (6 mL) were stirred for 2 h at 0 °C. HWE flask: Diethyl
[(phenylsulfonyl)methyl]phosphonate 8 (701 mg, 2.40 mmol, 2.0 equiv.), LiBr (230 mg, 2.65
mmol, 2.2 equiv.) and Et3N (0.33 mL, 2.37 mmol, 2.0 equiv.) in MeCN (5 mL + 1 mL rinse).
After aqueous workup, purification by column chromatography (c-Hex/EtOAc; 6:1) gave γ-
hydroxy vinyl sulfone (R)-9 as a pale yellow solid (161 mg, 47%). M.p. 58-62 °C; Lit.5c 64-65
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°C. Rf = 0.5 (c-Hex/EtOAc; 1:1). IR (film) νmax = 3062, 2927, 2858, 1628, 1446, 1306, 1180,
1146, 1086, 968 cm‒1. H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3H, CH3) 1.20-1.46
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(m, 8H, CH2) 1.50-1.62 (m, 2H, CH2) 1.81 (s (br), 1H, OH) 4.35-4.42 (m, 1H, CH) 6.60 (dd, J =
15.0, 2.0 Hz, 1H, CH) 6.99 (dd, J = 15.0, 4.0 Hz, 1H, CH) 7.54 (t, J = 7.5 Hz, 2H, ArH) 7.62 (t, J =
7.5 Hz, 1H, ArH) 7.89 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3)
22.5 (CH2) 25.1 (CH2) 29.0 (CH2) 31.6 (CH2) 36.4 (CH2) 70.4 (CH) 127.6 (CH) 129.3 (CH) 129.6
(CH) 133.4 (CH) 140.3 (C) 148.1 (CH) ppm. [α]D = ‒31 (c = 1.0, CHCl3). HPLC Analysis (Chiralcel
OJ-H column) Heptane/Ethanol; 95:5 (1.0 mL/min): tr minor (S)-9 = 22.9 min, tr major (R)-9 =
24.5 min; 97% ee.
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(S,E)-1-(Phenylsulfonyl)non-1-en-3-ol (S)-E-9.5a,d AO flask: Octanal 7 (0.22 mL, 1.41 mmol,
1.2 equiv.), nitrosobenzene (125 mg, 1.17 mmol, 1.0 equiv.) and D-proline (29 mg, 0.25
mmol, 0.2 equiv.) in MeCN (6 mL) were stirred for 2 hours at 0 °C. HWE flask: Diethyl
[(phenylsulfonyl)methyl]phosphonate 8 (694 mg, 2.37 mmol, 2.0 equiv.), LiBr (212 mg, 2.44
mmol, 2.1 equiv.) and Et3N (0.33 mL, 2.37 mmol, 2.0 equiv.) in MeCN (5 mL + 1 mL rinse).
After aqueous workup, purification by column chromatography (c-Hex/EtOAc; 6:1) gave γ-
hydroxy vinyl sulfone (S)-9 as a pale yellow solid (169 mg, 51%). [α]D = +39 (c = 1.0, CHCl3);
Lit.5c [α]D = +44.4 (c = 1.0, CHCl3). HPLC Analysis (Chiralcel OJ-H column) Heptane/Ethanol;
95:5 (1.0 mL/min): tr major (S)-9 = 23.5 min, tr minor (R)-9 = 25.4 min; 97% ee.
Diphenyl
[(phenylsulfonyl)methyl]phosphonate
10.
Diethyl
[(phenylsulfonyl)methyl]phosphonate 8 (502 mg, 1.71 mmol, 1.0 equiv.) was melted in a 5
mL round bottom flask with a heat gun. To this was added PCl5 (913 mg, 4.38 mmol, 2.6
equiv.) and the reaction mixture was heated at 85 °C for 18 hours. Vacuum distillation (120
°C; ca. 1 mm Hg) to remove POCl3 and PCl5 gave the residual crude dichloride as a black tar
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which was dissolved in toluene (1 mL) and cooled to 0 °C. A toluene solution (1 mL) of
phenol (323 mg, 3.43 mmol, 2.0 equiv.) and Et3N (0.60 mL, 4.25 mmol, 2.5 equiv.) was then
added to the above solution. The reaction mixture stirred for 1.5 hours at room
temperature and the resulting brown mixture was diluted with EtOAc (10 mL). The solution
was filtered and washed with EtOAc (5 mL). The filtrate was washed with 1 M NaOH (3 × 10
mL), sat. aq. NH4Cl (10 mL), brine (10 mL), dried over MgSO4 and filtered. Solvent was
removed in vacuo to give a crude brown oil. Purification by column chromatography (c-
Hex/EtOAc; 3:1) gave phosphonate 10 as a white powdery solid (257 mg, 39%). M.p. 69-72
°C. Rf = 0.1 (c-Hex/EtOAc; 3:1). IR (film): νmax 1590, 1490, 1448, 1326, 1282, 1213, 1185,
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1
1160, 1110, 1086, 1025, 952 cm‒1. H NMR (400 MHz, CDCl3): δ = 4.05 (d, JPH = 17.0 Hz, 2H,
CH2) 7.14 (d, J = 7.5 Hz, 4H, ArH) 7.19 (t, J = 7.5 Hz, 2H, ArH) 7.31 (t, J = 7.5 Hz, 4H, ArH) 7.57
(t, J = 7.5 Hz, 2H, ArH) 7.67 (t, J = 7.5 Hz, 1H, ArH) 8.04 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 53.3 (d, JPC = 141.5 Hz, CH2) 120.6 (d, JPC = 4.5 Hz, CH) 125.8 (d, JPC
=
1.5 Hz, CH) 128.5 (CH) 129.3 (CH) 129.9 (d, JPC = 1.0 Hz, CH) 134.4 (CH) 139.8 (C) 149.6 (d, JPC
= 8.5 Hz, C) ppm. 31P NMR (162 MHz, CDCl3): δ = 3.9 ppm. HRMS (ES+): C19H17O5PNaS (MNa+)
calcd. 411.0432; found 411.0446. Anal. calcd. C19H17O5PS: C, 58.76; H, 4.41; found C, 58.61;
H. 4.26.
(R,Z)-1-(Phenylsulfonyl)non-1-en-3-ol (R)-Z-9. AO flask: Octanal 7 (65 μL, 0.42 mmol, 1.2
equiv.), nitrosobenzene (38 mg, 0.35 mmol, 1.0 equiv.) and L-proline (8 mg, 0.07 mmol, 0.2
equiv.) in MeCN (2 mL) were stirred for 2 hours at 0 °C. HWE flask: At ‒78 °C, diphenyl
[(phenylsulfonyl)methyl]phosphonate 10 (269 mg, 0.69 mmol, 2.0 equiv.), NaI (105 mg, 0.70
mmol, 2.0 equiv.) and DBU (0.11 mL, 0.74 mmol, 2.1 equiv.) were stirred in THF (4 mL). The
contents of the AO-flask were transferred (0.5 mL MeCN rinse) and the reaction mixture
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stirred overnight warming slowly to room temperature. After 24 hours, the reaction
mixture was quenched with sat. aq. NH4Cl solution (5 mL) and extracted with EtOAc (2 × 10
mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4,
filtered and solvent was removed in vacuo to give the crude product. Purification by column
chromatography (c-Hex/EtOAc; 6:1) gave (R)-E-9 (19 mg, 19%); Rf = 0.5 (c-Hex/EtOAc; 1:1).
Further elution gave (R)- Z-9 as a yellow oil (9 mg, 9%). Rf = 0.4 (c-Hex/EtOAc; 1:1). IR (film):
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νmax 2927, 2858, 1626, 1446, 1375, 1306, 1147, 1084 cm‒1. H NMR (500 MHz, CDCl3): δ =
0.89 (t, J = 7.0 Hz, 3H, CH3) 1.20-1.48 (m, 8H, CH2) 1.49-1.70 (m, 2H, CH2) 2.47 (s (br), 1H,
OH) 5.20 (app. q, J = 7.0 Hz, 1H, CH) 6.24 (dd, J = 11.5, 8.0 Hz, 1H, CH) 6.30 (d, J = 11.5 Hz,
1H, CH) 7.57 (t, J = 7.5 Hz, 2H, ArH) 7.65 (t, J = 7.5 Hz, 1H, ArH) 7.93 (d, J = 7.5 Hz, 2H, ArH)
ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1 (CH3) 22.6 (CH2) 25.0 (CH2) 29.1 (CH2) 31.7 (CH2)
36.6 (CH2) 66.4 (CH) 127.4 (CH) 129.4 (CH) 130.4 (CH) 133.7 (CH) 140.9 (C) 148.1 (CH) ppm.
HRMS (EI+): C15H22O3S (M+) calcd. 282.1290; found 282.1283. [α]D = ‒4 (c = 0.3, CHCl3). HPLC
Analysis (Chiralcel OJ-H column) Heptane/Ethanol; 95:5 (1.0 mL/min): tr major (R)-Z-9 = 24.9
min, tr minor (S)-Z-9 = 26.6 min; 98% ee.
(S,Z)-1-(Phenylsulfonyl)non-1-en-3-ol (S)-Z-9. AO flask: Octanal 7 (18 μL, 0.12 mmol, 1.2
equiv.), nitrosobenzene (11 mg, 0.10 mmol, 1.0 equiv.) and D-proline (2 mg, 0.02 mmol, 0.2
equiv.) in MeCN (0.5 mL) were stirred for 2 hours at 0 °C. HWE flask: At ‒78 °C, diphenyl
[(phenylsulfonyl)methyl]phosphonate 10 (70 mg, 0.18 mmol, 1.8 equiv.), NaI (31 mg, 0.21
mmol, 2.0 equiv.) and DBU (27 μL, 0.18 mmol, 1.8 equiv.) were stirred in THF (2 mL). The
contents of the AO-flask were transferred (0.5 mL MeCN rinse). After aqueous workup as
above, purification by column chromatography (c-Hex/EtOAc; 6:1) gave (S)-E-9 (5 mg, 17%);
Rf = 0.5 (c-Hex/EtOAc; 1:1). Further elution gave (S)-Z-9 as a yellow oil (3 mg, 10%). Rf = 0.4
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(c-Hex/EtOAc; 1:1). [α]D = +3 (c = 0.3, CHCl3). HPLC Analysis (Chiralcel OJ-H column)
Heptane/Ethanol; 95:5 (1.0 mL/min): tr minor (R)-Z-9 = 25.3 min, tr major (S)-Z-9 = 26.3 min;
97% ee.
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(R,E)-4-(Phenylsulfonyl)but-3-en-2-ol (R)-14.5a,d AO flask: Propanal 11 (0.10 mL, 1.39
mmol, 1.2 equiv.), nitrosobenzene (128 mg, 1.20 mmol, 1 equiv.) and L-proline (28 mg, 0.24
mmol, 0.2 equiv.) were stirred in MeCN (6 mL) for 2 hours at 0 °C. HWE flask: Diethyl
[(phenylsulfonyl)methyl]phosphonate 8 (683 mg, 2.34 mmol, 2.0 equiv.), LiBr (207 mg, 2.38
mmol, 2.0 equiv.) and Et3N (0.33 mL, 2.37 mmol, 2.0 equiv.) in MeCN (5 mL + 1 mL rinse).
After aqueous workup, purification by column chromatography (c-Hex/EtOAc; 1:1) gave γ-
hydroxy vinyl sulfone (R)-14 as an orange solid (124 mg, 49%). M.p. = 79-83 °C; Lit.5c 94-95
°C. Rf = 0.2 (c-Hex/EtOAc; 1:1). IR (film): νmax = 3487, 3064, 2981, 1626, 1586, 1450, 1282,
1197, 1141, 1083, 1037, 985 cm‒1. 1H NMR (400 MHz, CDCl3): δ = 1.35 (d, J = 6.5 Hz, 3H, CH3)
1.90 (s (br), 1H, OH) 4.55 (qdd, J = 6.5, 3.5, 2.0 Hz, 1H, CH) 6.60 (dd, J = 15.0, 2.0 Hz, 1H, CH)
6.99 (dd, J = 15.0, 3.5 Hz, 1H, CH) 7.54 (t, J = 7.5 Hz, 2H, ArH) 7.63 (t, J = 7.5 Hz, 1H, ArH) 7.89
(d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.5 (CH3) 66.5 (CH) 127.7 (CH)
129.28 (CH) 129.29 (CH) 133.4 (CH) 140.2 (C) 148.7 (CH) ppm. [α]D = ‒34 (c = 1.0, CHCl3).
HPLC Analysis (Chiralcel OJ-H column) Heptane/Ethanol; 90:10 (1.0 mL/min): tr minor (S)-14
= 24.4 min, tr major (R)-14 = 25.9 min; 99% ee.
(S,E)-4-(Phenylsulfonyl)but-3-en-2-ol (S)-14.5a,d AO flask: Propanal 11 (0.10 mL, 1.39 mmol,
1.2 equiv.), nitrosobenzene (127 mg, 1.19 mmol, 1.0 equiv.) and D-proline (27 mg, 0.23
mmol, 0.2 equiv.) in MeCN (6 mL) were stirred for 2 hours at 0 °C. HWE flask: Diethyl
[(phenylsulfonyl)methyl]phosphonate 8 (685 mg, 2.34 mmol, 2.0 equiv.), LiBr (210 mg, 2.42
mmol, 2.0 equiv.) and Et3N (0.33 mL, 2.37 mmol, 2.0 equiv.) in MeCN (5 mL + 1 mL rinse).
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After aqueous workup, purification by column chromatography (c-Hex/EtOAc; 1:1) gave γ-
hydroxy vinyl sulfone (S)-14 as an orange solid (115 mg, 46%). [α]D = +32 (c = 1.0, CHCl3);
Lit.5c [α]D = +42.9 (c = 1.0, CHCl3). HPLC Analysis (Chiralcel OJ-H column) Heptane/Ethanol;
90:10 (1.0 mL/min): tr major (S)-14 = 24.4 min, tr minor (R)-14 = 26.0 min; 97% ee.
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(R,E)-4-Methyl-1-(phenylsulfonyl)pent-1-en-3-ol (R)-15.5a,d AO flask: Isovaleraldehyde 3
(156 mg, 1.81 mmol, 1.2 equiv.), nitrosobenzene (162 mg, 1.51 mmol, 1.0 equiv.) and L-
proline (36 mg, 0.31 mmol, 0.2 equiv.) in MeCN (9 mL) were stirred for 2 hours at 0 °C. HWE
flask: Diethyl [(phenylsulfonyl)methyl]phosphonate 8 (883 mg, 3.02 mmol, 2.0 equiv.), LiBr
(265 mg, 3.05 mmol, 2.0 equiv.) and Et3N (0.42 mL, 3.01 mmol, 2.0 equiv.) in MeCN (7 mL +
2 mL) rinse. After aqueous workup, purification by column chromatography (CH2Cl2/EtOAc;
9:1) gave γ-hydroxy vinyl sulfone (R)-15 as an orange solid (183 mg, 50%). M.p. 55-59 °C;
Lit.5c 60-62 °C. Rf = 0.4 (CH2Cl2/EtOAc; 9:1). IR (film): νmax 3508, 3063, 2964, 2874, 1628,
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1447, 1306, 1144, 1086, 1029, 972 cm‒1. H NMR (500 MHz, CDCl3): δ = 0.91 (d, J = 7.0 Hz,
3H, CH3) 0.95 (d, J = 7.0 Hz, 3H, CH3) 1.82-1.95 (m, 2H, CH + OH) 4.18-4.23 (m, 1H, CH) 6.62
(d, J = 15.0 Hz, 1H, CH) 7.00 (dd, J = 15.0, 4.0 Hz, 1H, CH) 7.54 (t, J = 7.5 Hz, 2H, ArH) 7.62 (t, J
= 7.5 Hz, 1H, ArH) 7.89 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.2
(CH3) 18.3 (CH3) 33.7 (CH) 74.9 (CH) 127.6 (CH) 129.3 (CH) 130.6 (CH) 133.4 (CH) 140.4 (C)
146.9 (CH) ppm. [α]D = ‒50 (c = 1.0, CHCl3). HPLC Analysis (Chiralcel OJ-H column)
Heptane/Ethanol; 90:10 (1.0 mL/min): tr minor (S)-15 = 17.3 min, tr major (R)-15 = 18.3 min;
98% ee.
(S,E)-4-Methyl-1-(phenylsulfonyl)pent-1-en-3-ol (S)-15.5a,d AO flask: Isovaleraldehyde 3
(155 mg, 1.80 mmol, 1.2 equiv.), nitrosobenzene (161 mg, 1.50 mmol, 1.0 equiv.) and D-
proline (36 mg, 0.31 mmol, 0.2 equiv.) in MeCN (9 mL) were stirred for 2 hours at 0 °C. HWE
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flask: Diethyl [(phenylsulfonyl)methyl]phosphonate 8 (886 mg, 3.03 mmol, 2.0 equiv.), LiBr
(261 mg, 3.01 mmol, 2.0 equiv.) and Et3N (0.42 mL, 3.01 mmol, 2.0 equiv.) in MeCN (7 mL +
2 mL rinse). Purification by column chromatography (CH2Cl2/EtOAc; 9:1) gave γ-hydroxy
vinyl sulfone (S)-15 as an orange solid (178 mg, 49%). [α]D = +49 (c = 1.0, CHCl3); Lit.5c [α]D =
+45.3 (c = 1.0, CHCl3). HPLC Analysis (Chiralcel OJ-H column) Heptane/Ethanol; 90:10 (1.0
mL/min): tr major (S)-15 = 17.2 min, tr minor (R)-15 = 18.5 min; 98% ee.
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(R,E)-5-Phenyl-1-(phenylsulfonyl)pent-1-en-3-ol (R)-16. AO flask: 4-Phenylbutanal23 12
(518 mg, 3.50 mmol, 1.2 equiv.), nitrosobenzene (312 mg, 2.91 mmol, 1.0 equiv.) and L-
proline (68 mg, 0.59 mmol, 0.2 equiv.) in MeCN (14 mL) were stirred for 2 hours at 0 °C.
HWE flask: Diethyl [(phenylsulfonyl)methyl]phosphonate 8 (1.71 g, 5.85 mmol, 2.0 equiv.),
LiBr (527 mg, 6.07 mmol, 2.1 equiv.) and Et3N (0.82 mL, 5.88 mmol, 2.0 equiv.) in MeCN (10
mL + 4 mL rinse). After aqueous workup, purification by column chromatography
(CH2Cl2/EtOAc; 9:1) gave γ-hydroxy vinyl sulfone (R)-16 as a powdery yellow solid (383 mg,
43%). M.p. 92-96 °C. Rf = 0.4 (CH2Cl2/EtOAc; 9:1). IR (film): νmax 3444, 3057, 2933, 1626,
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1446, 1397, 1299, 1282, 1145, 1102, 1086, 1023 cm‒1. H NMR (500 MHz, CDCl3): δ = 1.80-
1.91 (m, 2H, OH + CH2) 1.95 (dddd, J = 13.5, 9.0, 7.0, 4.5 Hz, 1H CH2) 2.68-2.80 (m, 2H, CH2)
4.34-4.41 (m, 1H, CH) 6.61 (dd, J = 15.0, 2.0 Hz, 1H, CH) 7.00 (dd, J = 15.0, 4.0 Hz, 1H, CH)
7.16 (d, J = 7.0 Hz, 2H, ArH) 7.20 (t, J = 7.0 Hz, 1H, ArH) 7.29 (t, J = 7.0 Hz, 2H, ArH) 7.54 (t, J =
7.5 Hz, 2H, ArH) 7.62 (t, J = 7.5 Hz, 1H, ArH) 7.87 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (125
MHz, CDCl3): δ = 31.4 (CH2) 37.6 (CH2) 69.5 (CH) 126.2 (CH) 127.7 (CH) 128.4 (CH) 128.6 (CH)
129.3 (CH) 129.9 (CH) 133.5 (CH) 140.2 (C) 140.7 (C) 147.9 (CH) ppm. HRMS (ES+):
C17H18O3NaS (MNa+) calcd. 325.0874; found 325.0888. [α]D = ‒38 (c = 1.0, CHCl3). Anal. calcd.
C17H18O3S: C, 67.52; H, 6.00; found C, 67.73; H, 5.93. HPLC Analysis (Chiralcel OJ-H column)
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Heptane/Ethanol; 80:20 (1.0 mL/min): tr major (R)-16 = 22.2 min, tr minor (S)-16 = 31.3 min;
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(S,E)-5-Phenyl-1-(phenylsulfonyl)pent-1-en-3-ol (S)-16. AO flask: 4-Phenylbutanal23 12
(505 mg, 3.41 mmol, 1.2 equiv.), nitrosobenzene (307 mg, 2.87 mmol, 1.0 equiv.) and D-
proline (66 mg, 0.57 mmol, 0.2 equiv.) in MeCN (14 mL) were stirred for 2 hours at 0 °C.
HWE flask: Diethyl [(phenylsulfonyl)methyl]phosphonate 8 (1.66 g, 5.68 mmol, 2.0 equiv.),
LiBr (501 mg, 5.77 mmol, 2.0 equiv.) and Et3N (0.80 mL, 5.74 mmol, 2.0 equiv.) in MeCN (10
mL + 4 mL rinse). After aqueous workup, purification by column chromatography
(CH2Cl2/EtOAc; 9:1) gave γ-hydroxy vinyl sulfone (S)-16 as a powdery yellow solid (332 mg,
38%). [α]D = +50 (c = 1.0, CHCl3). HPLC Analysis (Chiralcel OJ-H column) Heptane/Ethanol;
80:20 (1.0 mL/min): tr minor (R)-16 = 22.2 min, tr major (S)-16 = 30.9 min; 96% ee.
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tert-Butyl (6-oxohexyl)carbamate 13.24 Under nitrogen, at room temperature, to a stirred
solution of tert-butyl (6-hydroxyhexyl)carbamate25 (1.65 g, 7.59 mmol, 1.0 equiv.) and
TEMPO (120 mg, 0.77 mmol, 0.1 equiv.) in CH2Cl2 (35 mL) was added BAIB (2.70 g, 8.38
mmol, 1.1 equiv.) and the reaction was monitored by TLC. After 4 hours stirring, a further
portion of TEMPO (127 mg, 0.81 mmol, 0.1 equiv.) was added followed by a further portion
of BAIB (546 mg, 1.70 mmol, 0.2 equiv.) to drive the reaction to completion. After a further
3 hours stirring, the reaction mixture was diluted with CH2Cl2 (50 mL) and quenched with
sodium thiosulfate sat. aq. solution (50 mL). The layers were separated and the aqueous
layer was extracted with CH2Cl2 (50 mL). The combined organic layers were washed with
NaHCO3 sat. aq. solution (50 mL), brine (50 mL), dried over MgSO4, filtered and solvent was
removed in vacuo to give the crude product. Purification by column chromatography
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(CH2Cl2 → CH2Cl2/EtOAc; 9:1) gave aldehyde 13 as a pale clear orange/yellow oil (0.92 g,
56%). Rf = 0.4 (CH2Cl2/EtOAc; 9:1). Data is consistent with that reported in the literature.24
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(R,E)-tert-Butyl [5-hydroxy-7-(phenylsulfonyl)hept-6-en-1-yl]carbamate (R)-17. AO flask:
tert-Butyl (6-oxohexyl)carbamate 13 (689 mg, 3.20 mmol, 1.2 equiv.), nitrosobenzene (286
mg, 2.67 mmol, 1.0 equiv.) and L-proline (66 mg, 0.57 mmol, 0.2 equiv.) in MeCN (16 mL)
were stirred for 2 hours at 0 °C. HWE flask: Diethyl [(phenylsulfonyl)methyl]phosphonate 8
(1.56 g, 5.34 mmol, 2.0 equiv.), LiBr (469 mg, 5.40 mmol, 2.0 equiv.) and Et3N (0.75 mL, 5.38
mmol, 2.0 equiv.) in MeCN (12 mL + 4 mL rinse). After aqueous workup, purification by
column chromatography (c-Hex/EtOAc; 1:1) gave γ-hydroxy vinyl sulfone (R)-17 as an orange
oil which gradually solidified as an orange crystalline solid (415 mg, 42%). M.p. 68-72 °C. Rf
= 0.2 (c-Hex/EtOAc; 1:1) IR (film): νmax 3388, 2977, 1689, 1523, 1447, 1367, 1306, 1146, 1086
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cm‒1. H NMR (500 MHz, CDCl3): δ = 1.35-1.53 (m, 13H, CH2 + CH3) 1.54-1.62 (m, 1H, CH2)
1.63-1.75 (m, 1H, CH2) 2.64 (s (br), 1H, OH) 3.07-3.14 (m, 2H, CH2) 4.35-4.41 (m, 1H, CH) 4.60
(s (br), 1H, NH) 6.62 (dd, J = 15.0, 2.0 Hz, 1H, CH) 6.97 (dd, J = 15.0, 3.5 Hz, 1H, CH) 7.54 (t, J
= 7.5 Hz, 2H, ArH) 7.62 (t, J = 7.5 Hz, 1H, ArH) 7.88 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (125
MHz, CDCl3): δ = 21.7 (CH2) 28.4 (CH3) 29.9 (CH2) 35.4 (CH2) 39.7 (CH2) 70.0 (CH) 79.4 (C)
127.7 (CH) 129.3 (CH) 129.8 (CH) 133.4 (CH) 140.4 (C) 148.0 (CH) 156.4 (CO) ppm. HRMS
(ES+): C18H27NO5NaS (MNa+) calcd. 392.1508; found 392.1490. [α]D = ‒18 (c = 1.0, CHCl3).
Anal. calcd. C18H27NO5S: C, 58.51; H, 7.37; N, 3.79; found C, 58.34; H, 7.29; N, 3.61. HPLC
Analysis (Chiralcel IA column) Heptane/Ethanol; 80:20 (1.0 mL/min): tr minor (S)-17 = 13.1
min, tr major (R)-17 = 15.1 min; 98% ee.
(S,E)-tert-Butyl [5-hydroxy-7-(phenylsulfonyl)hept-6-en-1-yl]carbamate (S)-17. AO flask:
tert-Butyl (6-oxohexyl)carbamate 13 (265 mg, 1.23 mmol, 1.2 equiv.), nitrosobenzene (111
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mg, 1.04 mmol, 1.0 equiv.) and D-proline (26 mg, 0.23 mmol, 0.2 equiv.) in MeCN (6 mL)
were stirred for 2 hours at 0 °C. HWE flask: Diethyl [(phenylsulfonyl)methyl]phosphonate 8
(595 mg, 2.04 mmol, 2.0 equiv.), LiBr (190 mg, 2.19 mmol, 2.1 equiv.) and Et3N (0.29 mL,
2.08 mmol, 2.0 equiv.) in MeCN (5 mL + 1 mL rinse). After aqueous workup, purification by
column chromatography (c-Hex/EtOAc; 1:1) gave γ-hydroxy vinyl sulfone (S)-17 as an orange
oil which gradually solidified as an orange crystalline solid (144 mg, 38%). [α]D = +18 (c =
1.0, CHCl3). HPLC Analysis (Chiralcel IA column) Heptane/Ethanol; 80:20 (1.0 mL/min): tr
major (S)-17 = 13.0 min, tr minor (R)-17 = 15.1 min; 98% ee.
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(R)-5-Phenylpent-1-en-3-ol (R)-18.26 At room temperature, to a vigorously stirred solution
of vinyl sulfone (R)-16 (86 mg, 0.28 mmol, 1.0 equiv.) in MeOH (1.7 mL) was added oven
activated magnesium turnings (26 mg, 1.07 mmol, 3.8 equiv.) followed by HgCl2 (a small
spatula tip). The resulting green/black mixture was stirred for 3 hours and quenched with
sat. aq. NH4Cl solution (5 mL). The mixture was extracted with Et2O (2 × 10 mL) and the
combined ethereal layers were washed with brine (10 mL), dried over MgSO4, filtered and
solvent was removed in vacuo to give the crude product. Purification by column
chromatography (CH2Cl2) gave allylic alcohol (R)-18 as a clear light yellow liquid (24 mg,
52%). Rf = 0.5 (CH2Cl2). IR (film): νmax 3362, 2927, 1603, 1496, 1454, 1041, 991 cm‒1. 1H NMR
(500 MHz, CDCl3): δ = 1.56 (s (br), 1H, OH) 1.80-1.92 (m, 2H, CH2) 2.65-2.79 (m, 2H, CH2) 4.13
(app. q, J = 6.0 Hz, 1H, CH) 5.14 (d, J = 10.5 Hz, 1H, CH2) 5.25 (d, J = 17.0 Hz, 1H, CH2) 5.90
(ddd, J = 17.0, 10.5, 6.0 Hz, 1H, CH) 7.16-7.23 (m, 3H, ArH) 7.25-7.31 (m, 2H, ArH) ppm. 13C
NMR (125 MHz, CDCl3): δ = 31.6 (CH2) 38.5 (CH2) 72.5 (CH) 114.9 (CH2) 125.8 (CH) 128.39
(CH) 128.44 (CH) 141.0 (CH) 141.8 (C) ppm. [α]D = +7 (c = 1.0, CHCl3). Lit.26a [α]D = ‒5.8 (c =
1.3, CHCl3).
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(S)-5-Phenylpent-1-en-3-ol (S)-18.26 In a procedure identical to the above desulfonylation:
Vinyl sulfone (S)-16 (101 mg, 0.33 mmol, 1.0 equiv.), MeOH (2 mL), oven activated
magnesium turnings (25 mg, 1.03 mmol, 3.1 equiv.) and HgCl2 (a small spatula tip). After
aqueous workup, purification by column chromatography (CH2Cl2) gave allylic alcohol (S)-18
as a clear light yellow liquid (27 mg, 50%). [α]D = -6 (c = 1.0, CHCl3), Lit.26b [α]D = +4.9 (c =
2.2, CHCl3). Note: Some ambiguity concerning absolute stereochemistry26a-c for correct
assignment see Helmchen and co-workers.26d
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(R)-1-Phenyl-5-(phenylsulfonyl)pentan-3-ol (R)-19. Vinyl sulfone (R)-16 (61 mg, 0.20 mmol,
1.0 equiv.) was stirred with 10% w/w Pd/C (22 mg, 0.021 mmol, 0.1 equiv.) in EtOH (6 mL)
under an atmosphere of hydrogen (1 atm.) for 24 hours. The reaction mixture was filtered
through Celite and the cake washed with EtOAc (3 × 10 mL). Solvent was removed in vacuo
to give the alkane compound (R)-19 as a white powdery solid (61 mg, >95%). M.p. 108-111
°C. Rf = 0.4 (CH2Cl2/EtOAc; 9:1). IR (film): νmax 3305, 2929, 1445, 1305, 1265, 1148, 1082,
1
1039 cm‒1. H NMR (500 MHz, CDCl3): δ = 1.72-1.85 (m, 4H, CH2 + OH) 1.97 (dddd, J = 13.5,
9.5, 6.0, 3.5 Hz, 1H, CH2) 2.65 (dt, J = 14.0, 8.0 Hz, 1H, CH2) 2.75 (dt, J = 14.0, 7.5 Hz, 1H, CH2)
3.20 (ddd, J = 14.0, 10.0, 6.0 Hz, 1H, CH2) 3.30 (ddd, J = 14.0, 10.0, 5.0 Hz, 1H, CH2) 3.72 (app.
dtd, J = 9.5, 6.0, 3.5 Hz, 1H, CH) 7.16 (d, J = 7.0 Hz, 2H, ArH) 7.19 (t, J = 7.0 Hz, 1H, ArH) 7.25-
7.29 (m, 2H, ArH) 7.56 (t, J = 7.5 Hz, 2H, ArH) 7.65 (t, J = 7.5 Hz, 1H, ArH) 7.90 (d, J = 7.5 Hz,
2H, ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 30.1 (CH2) 31.9 (CH2) 39.0 (CH2) 53.0 (CH2)
69.3 (CH) 126.0 (CH) 128.0 (CH) 128.3 (CH) 128.5 (CH) 129.3 (CH) 133.7 (CH) 139.1 (C) 141.3
(C) ppm. HRMS (ES+): C17H20O3NaS (MNa+) calcd. 327.1031; found 327.1034. [α]D = ‒10 (c =
1.0, CHCl3).
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(S)-1-Phenyl-5-(phenylsulfonyl)pentan-3-ol (S)-19. In a procedure identical to the above
hydrogenation: Vinyl sulfone (S)-16 (63 mg, 0.21 mmol, 1.0 equiv.), 10% w/w Pd/C (22 mg,
0.02 mmol, 0.1 equiv.) in EtOH (6 mL) under an atmosphere of hydrogen (1 atm.) for 24
hours. The product (S)-19 was isolated as a white powdery solid (63 mg, >95%). [α]D = +9 (c
= 1.0, CHCl3).
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(R,E)-1-(Phenylsulfonyl)non-1-en-3-yl methanesulfonate. At 0 °C, under nitrogen, to a
stirred solution of alcohol (R)-E-9 (101 mg, 0.36 mmol, 1.0 equiv.) and Et3N (0.20 mL, 1.43
mmol, 4.0 equiv.) in CH2Cl2 (4 mL) was added MsCl (0.11 mL, 1.42 mmol, 4.0 equiv.) in a
dropwise fashion and the reaction mixture was stirred overnight warming gradually to room
temperature. The reaction mixture was quenched with 1 M HCl (5 mL) and the layers were
separated. The aqueous layer was back-extracted with CH2Cl2 (2 × 10 mL) and the combined
organic layers were washed with brine (10 mL). The organic layer was dried over MgSO4,
filtered and solvent was removed in vacuo to give the crude product. Purification by column
chromatography (CH2Cl2) gave (R,E)-1-(phenylsulfonyl)non-1-en-3-yl methanesulfonate as a
clear pale yellow oil (109 mg, 85%). Rf = 0.2 (CH2Cl2). IR (film): νmax 3062, 2931, 2859, 1638,
1
1447, 1321, 1175, 1149, 1087, 970, 914 cm‒1. H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 6.5
Hz, 3H, CH3) 1.21-1.44 (m, 8H, CH2) 1.73-1.86 (m, 2H, CH2) 2.99 (s, 3H, CH3) 5.23 (app. q, J =
5.5 Hz, 1H, CH) 6.63 (d, J = 15.0 Hz, 1H, CH) 6.93 (dd, J = 15.0, 5.5 Hz, 1H, CH) 7.57 (t, J = 7.5
Hz, 2H, ArH) 7.65 (t, J = 7.5 Hz, 1H, ArH) 7.89 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (125
MHz, CDCl3): δ = 14.0 (CH3) 22.5 (CH2) 24.5 (CH2) 28.7 (CH2) 31.4 (CH2) 34.5 (CH2) 38.9 (CH3)
78.6 (CH) 127.8 (CH) 129.5 (CH) 132.7 (CH) 133.8 (CH) 139.6 (C) 141.4 (CH) ppm. HRMS (ES+):
C16H24O5NaS2 (MNa+) calcd. 383.0963; found 383.0954. [α]D = +10 (c = 1.0, CHCl3). Anal.
calcd. C16H24O5S2: C, 53.31; H, 6.71; found C, 53.41; H, 6.60.
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(S,E)-1-(Phenylsulfonyl)non-1-en-3-yl methanesulfonate. In a procedure identical to the
above mesylation: alcohol (S)-E-9 (232 mg, 0.82 mmol, 1.0 equiv.), Et3N (0.46 mL, 3.30
mmol, 4.0 equiv.) and MsCl (0.26 mL, 3.36 mmol, 4.1 equiv.) in CH2Cl2 (8 mL). After aqueous
workup, purification by column chromatography (CH2Cl2) gave (S,E)-1-(Phenylsulfonyl)non-
1-en-3-yl methanesulfonate as a clear pale yellow oil (267 mg, 90%). [α]D = ‒10 (c = 1.0,
CHCl3).
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(S,E)-[(3-Azidonon-1-en-1-yl)sulfonyl]benzene (S)-20. At 0 °C, to a stirred solution of
mesylate (R)-S1 (249 mg, 0.69 mmol, 1.0 equiv.) in DMF (7 mL) was added sodium azide (93
mg, 1.43 mmol, 2.1 equiv.). Stirring was continued for 3 hours at 0 °C after which time
water (5 mL) was added to the flask and the mixture was extracted with Et2O (3 × 15 mL).
The combined ethereal layers were washed with brine (15 mL), dried over MgSO4, filtered
and solvent was removed in vacuo to give the crude product. Purification by column
chromatography (CH2Cl2) gave azide (S)-20 as a clear colourless liquid (169 mg, 80%). Note:
the allylic azides were found to isomerize/oligomerize/polymerize over time and were
therefore used soon after preparation or stored under nitrogen in a freezer at ‒20 °C. Rf =
1
0.7 (CH2Cl2). IR (film): νmax 2930, 2859, 2108, 1447, 1322, 1149, 1086 cm‒1. H NMR (500
MHz, CDCl3): δ = 0.88 (t, J = 6.5 Hz, 3H, CH3) 1.21-1.44 (m, 8H, CH2) 1.66 (app. q, J = 7.5 Hz,
2H, CH2) 4.10 (app. q, J = 6.5 Hz, 1H, CH) 6.57 (d, J = 15.0 Hz, 1H, CH) 6.86 (dd, J = 15.0, 5.5
Hz, 1H, CH) 7.56 (t, J = 7.5 Hz, 2H, ArH) 7.65 (t, J = 7.5 Hz, 1H, ArH) 7.90 (d, J = 7.5 Hz, 2H,
ArH) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.0 (CH3) 22.5 (CH2) 25.4 (CH2) 28.8 (CH2) 31.5
(CH2) 33.8 (CH2) 61.5 (CH) 127.7 (CH) 129.4 (CH) 132.2 (CH) 133.7 (CH) 139.9 (C) 142.8 (CH)
ppm. HRMS (ES+): C15H21N3O2NaS (MNa+) calcd. 330.1252; found 330.1260. [α]D = +11 (c =
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1.0, CHCl3). Anal. calcd. C15H21N3O2S: C, 58.61; H, 6.89; N, 13.67; found C, 58.48; H, 6.83; N,
13.62.
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(R,E)-[(3-Azidonon-1-en-1-yl)sulfonyl]benzene (R)-20. In a procedure identical to the above
azide displacement: Mesylate (S)-S1 (242 mg, 0.67 mmol, 1.0 equiv.), sodium azide (90 mg,
1.38 mmol, 2.1 equiv.) in DMF (7 mL). After aqueous workup, purification by column
chromatography (CH2Cl2) gave azide (R)-20 as clear colourless oil (168 mg, 81%). [α]D = ‒14
(c = 1.0, CHCl3).
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(S,E)-[3-Azido-5-(phenylsulfonyl)pent-4-en-1-yl]benzene (S)-21. In a procedure identical to
the above mesylation: Alcohol (R)-16 (265 mg, 0.88 mmol, 1.0 equiv.), Et3N (0.49 mL, 3.52
mmol, 4.0 equiv.) and MsCl (0.27 mL, 3.49 mmol, 4.0 equiv.) in CH2Cl2 (9 mL). After aqueous
workup, purification by column chromatography (CH2Cl2) gave the intermediate mesylate as
a yellow viscous oil which crystallized over 3 hours as a pale yellow crystalline solid (300 mg,
90%). Rf = 0.2 (CH2Cl2). In a procedure identical to the above azide displacement: the
intermediate mesylate (300 mg, 0.79 mmol, 1.0 equiv.), sodium azide (106 mg, 1.63 mmol,
2.1 equiv.) in DMF (8 mL). After aqueous workup, purification by column chromatography
(c-Hex/CH2Cl2; 1:9) gave azide (S)-21 as clear viscous colourless oil which crystallized
overnight as a white crystalline solid (231 mg, 89%). M.p. 70-74 °C. Rf = 0.6 (CH2Cl2). IR
1
(film): νmax 2924, 2106, 1447, 1321, 1148, 1086 cm‒1. H NMR (500 MHz, CDCl3): δ = 1.95
(app. q, J = 7.5 Hz, 2H, CH2) 2.69 (dd, J = 14.5, 8.0 Hz, 1H, CH2) 2.75 (dd, J = 14.5, 7.0 Hz, 1H,
CH2) 4.06 (app. q, J = 6.0 Hz, 1H, CH) 6.57 (d, J = 15.0 Hz, 1H, CH) 6.87 (dd, J = 15.0, 6.0 Hz,
1H, CH) 7.15 (d, J = 7.5 Hz, 2H, ArH) 7.21 (t, J = 7.5 Hz, 1H, ArH) 7.29 (t, J = 7.5 Hz, 2H, ArH)
7.55 (t, J = 7.5 Hz, 2H, ArH) 7.64 (t, J = 7.5 Hz, 1H, ArH) 7.89 (d, J = 7.5 Hz, 2H, ArH) ppm. 13
C
NMR (125 MHz, CDCl3): δ = 31.6 (CH2) 35.3 (CH2) 60.6 (CH) 126.5 (CH) 127.8 (CH) 128.4 (CH)
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128.7 (CH) 129.4 (CH) 132.6 (CH) 133.7 (CH) 139.81 (C) 139.84 (C) 142.3 (CH) ppm. HRMS
(ES+): C17H17N3O2NaS (MNa+) calcd. 350.0939; found 350.0955. [α]D = +1 (c = 1.0, CHCl3).
Anal. calcd. C17H17N3O2S: C, 62.36; H, 5.23; N, 12.83; found C, 62.15; H, 5.03; N, 12.68.
Crystals suitable for single crystal X-Ray diffraction were grown from the slow evaporation of
a CH2Cl2 solution of (S)-21.
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(R,E)-[3-Azido-5-(phenylsulfonyl)pent-4-en-1-yl]benzene (R)-21. In a procedure identical to
the above mesylation: Alcohol (S)-16 (260 mg, 0.86 mmol, 1.0 equiv.), Et3N (0.48 mL, 3.44
mmol, 4.0 equiv.) and MsCl (0.27 mL, 3.49 mmol, 4.1 equiv.) in CH2Cl2 (9 mL). After aqueous
workup, purification by column chromatography (CH2Cl2) gave the intermediate mesylate as
a yellow viscous oil which crystallized over 3 hours as a pale yellow crystalline solid (313 mg,
>95%). Rf = 0.2 (CH2Cl2). In a procedure identical to the above azide displacement: the
intermediate mesylate (313 mg, 0.82 mmol, 1.0 equiv.), sodium azide (108 mg, 1.66 mmol,
2.0 equiv.) in DMF (8 mL). After aqueous workup, purification by column chromatography
(c-Hex/CH2Cl2; 1:9) gave azide (R)-21 as clear viscous colourless oil which crystallized
overnight as a white crystalline solid (219 mg, 81%). [α]D = ‒1 (c = 1.0, CHCl3).
(S,E)-tert-Butyl [5-azido-7-(phenylsulfonyl)hept-6-en-1-yl]carbamate (S)-22. In a procedure
identical to the above mesylation: Alcohol (R)-17 (112 mg, 0.30 mmol, 1.0 equiv.), Et3N (0.19
mL, 1.36 mmol, 4.5 equiv.) and MsCl (0.10 mL, 1.29 mmol, 4.3 equiv.) in CH2Cl2 (3 mL). After
aqueous workup, purification by column chromatography (CH2Cl2/EtOAc; 9:1) gave the
intermediate mesylate as a viscous yellow oil which crystallized gradually over time as a
yellow crystalline solid (116 mg, 86%). Rf = 0.2 (CH2Cl2/EtOAc; 9:1). In a procedure identical
to the above azide displacement: The intermediate mesylate (116 mg, 0.26 mmol, 1.0
equiv.), sodium azide (35 mg, 0.54 mmol, 2.1 equiv.) in DMF (2.5 mL). After aqueous
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workup, purification by column chromatography (CH2Cl2/EtOAc; 9:1) gave azide (S)-22 as
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clear colourless liquid (94 mg, 92%). Rf = 0.5 (CH2Cl2/EtOAc; 9:1). IR (film): νmax = 3392, 2977,
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2934, 2109, 1703, 1518, 1447, 1366, 1149, 1086 cm‒1. H NMR (500 MHz, CDCl3): δ = 1.35-
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1.55 (m, 13H, CH2 + CH3) 1.61-1.74 (m, 2H, CH2) 3.06-3.16 (m, 2H, CH2) 4.10 (app. q, J = 6.0
Hz, 1H, CH) 4.52 (s (br), 1H, NH) 6.58 (d, J = 15.0 Hz, 1H, CH) 6.85 (15.0, 5.5 Hz, 1H, CH) 7.57
(t, J = 7.5 Hz, 2H, ArH) 7.65 (t, J = 7.5 Hz, 1H, ArH) 7.90 (d, J = 7.5Hz, 2H, ArH) ppm. 13C NMR
(125 MHz, CDCl3): δ = 22.8 (CH2) 28.4 (CH3) 29.7 (CH2) 33.5 (CH2) 40.2 (CH2) 61.5 (CH) 79.3
(C) 127.8 (CH) 129.4 (CH) 132.5 (CH) 133.7 (CH) 139.9 (C) 142.4 (CH) 155.9 (CO) ppm. HRMS
(ES+) C18H26N4O4NaS (MNa+) calcd. 417.1572; found 417.1552. [α]D = +25 (c = 2.0, CHCl3).
Anal. calcd. C18H26N4O4S: C, 54.80; H, 6.64; N, 14.20; found C, 54.58; H, 6.61; N, 13.80.
(R,E)-tert-Butyl [5-azido-7-(phenylsulfonyl)hept-6-en-1-yl]carbamate (R)-22.
In
a
procedure identical to the above mesylation: Alcohol (S)-17 (110 mg, 0.30 mmol, 1.0
equiv.), Et3N (0.19 mL, 1.36 mmol, 4.5 equiv.) and MsCl (0.10 mL, 1.29 mmol, 4.3 equiv.) in
CH2Cl2 (3 mL).
After aqueous workup, purification by column chromatography
(CH2Cl2/EtOAc; 9:1) gave the intermediate mesylate as a viscous yellow oil which crystallized
gradually over time as a yellow crystalline solid (109 mg, 82%). Rf = 0.2 (CH2Cl2/EtOAc; 9:1).
In a procedure identical to the above azide displacement: The intermediate mesylate (109
mg, 0.24 mmol, 1.0 equiv.), sodium azide (35 mg, 0.54 mmol, 2.2 equiv.) in DMF (2.5 mL).
After aqueous workup, purification by column chromatography (CH2Cl2/EtOAc; 9:1) gave
azide (R)-22 as clear colourless liquid (84 mg, 87%). [α]D = ‒29 (c = 2.0, CHCl3).
(S)-Benzyl (1-(methoxy(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate.27 At 0 °C,
24 (2.01 g, 6.72 mmol, 1.0 equiv.) was stirred with DIPEA (1.4 mL, 8.04 mmol, 1.2 equiv.) in
CH2Cl2 (50 mL) for 10 mins. DIC (1.05 mL, 6.71 mmol, 1.0 equiv.) was added and the mixture
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was stirred for 10 mins. N,O-dimethylhydroxylamine hydrochloride (651 mg, 6.67 mmol, 1.0
equiv.) was then added and the reaction mixture was stirred overnight warming slowly to
room temperature. The mixture was filtered and the filtrate washed with 1 M HCl (20 mL),
brine (20 mL), dried over MgSO4, filtered and solvent was removed in vacuo to give the
crude product. Purification by column chromatography (c-Hex/EtOAc; 2:1) gave the
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Weinreb amide (1.84 g, 80%) as a golden syrup. Rf = 0.5 (c-Hex/EtOAc; 1:1). IR (film): νmax
=
1
3303, 2939, 1719, 1657, 1529, 1497, 1455, 1391, 1254, 1049 cm‒1. H NMR (400 MHz,
CDCl3): δ = 2.91 (dd, J = 13.5, 7.0 Hz, 1H, CH2) 3.08 (dd, J = 13.5, 6.0 Hz, 1H, CH2) 3.17 (s, 3H,
CH3) 3.67 (s, 3H, CH3) 4.96-5.06 (m, 2H, CH2 + CH) 5.09 (d, J = 12.5 Hz, 1H, CH2) 5.44 (s (br),
1H, NH) 7.15 (d, J = 7.0 Hz, 2 H, ArH) 7.19-7.38 (m, 8H, ArH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 32.1 (CH3) 38.7 (CH2) 52.1 (CH) 61.5 (CH3) 66.8 (CH2) 126.9 (CH) 128.0 (CH) 128.1 (CH)
128.4 (CH) 128.5 (CH) 129.4 (CH) 136.26 (C) 136.35 (C) 155.8 (CO) 171.9 (CO) ppm. HRMS
(ES+) C19H22N2O4Na (MNa+) calcd 365.1477; found 365.1469. [α]D = +20 (c = 0.1, CH2Cl2).
(S)-Benzyl (1-oxo-3-phenylpropan-2-yl)carbamate.28 Under nitrogen, at ‒78 °C, to a
vigorously stirred solution of LiAlH4 (2.37 g, 62.5 mmol, 5.0 equiv.) in dry THF (60 mL) was
added the above Weinreb amide (4.29 g, 12.5 mmol, 1.0 equiv.) as a solution in dry THF (20
mL) rapidly via syringe. The mixture was stirred for 5 minutes after which a pressure
equalising dropping funnel with 1M KHSO4 (20 mL) was attached to the flask. Cautiously,
this solution was added one drop at a time (under nitrogen) until excess LiAlH4 was
consumed, after which the rest of the contents of the dropping funnel were added over 5
minutes. Water was then added (30 mL) followed by EtOAc (100 mL) and the solution was
warmed to room temperature stirring vigorously. The contents of the flask were
transferred to a separating funnel and the layers were separated. The aqueous layer was
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extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with 1M HCl
(2 × 50 mL), sat. aq. NaHCO3 (50 mL), water (50 mL) and brine (50 mL). The organic layer
was dried over MgSO4, filtered and solvent was removed in vacuo to give aldehyde (3.45 g,
>95%) as a white solid. M.p. = 70-73 °C. Rf = 0.2 (c-Hex/EtOAc; 3:1). IR (film): νmax = 3336,
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3032, 2953, 2864, 1741, 1690, 1537, 1453, 1263, 1064 cm‒1. H NMR (400 MHz, CDCl3): δ =
3.13 (d, J = 6.5 Hz, 2H, CH2) 4.50 (app. q, J = 6.5 Hz, 1H, CH) 5.10 (s, 2H, CH2) 5.32 (d, J = 6.5
Hz, 1H, NH) 7.13 (d, J = 7.0 Hz, 2H, ArH) 7.21-7.39 (m, 8H, ArH) 9.62 (s, 1H, CHO) ppm. 13C
NMR (100 MHz, CDCl3): δ = 35.5 (CH2) 61.2 (CH) 67.2 (CH2) 127.3 (CH) 128.3 (CH) 128.4 (CH)
128.7 (CH) 128.9 (CH) 129.4 (CH) 135.5 (C) 136.2 (C) 156.0 (CO) 198.9 (CHO) ppm. HRMS
(ES+) C17H17NO3Na (MNa+) calcd. 306.1106; found 306.1111. [α]D = +29 (c = 0.1, CH2Cl2).
(S)-Benzyl (4,4-dibromo-1-phenylbut-3-en-2-yl)carbamate. Under N2 at room temperature,
CBr4 (2.01 g, 6.06 mmol, 2.0 equiv.) was stirred in anhydrous CH2Cl2 (20 mL). To this was
added Ph3P (3.20 g, 12.20 mmol, 4.0 equiv.) and the red solution was stirred for 10 min. The
above aldehyde (856 mg, 3.02 mmol, 1.0 equiv.) was added as a solution in dry CH2Cl2 (10
mL) to give a deep burgundy coloured solution. TLC analysis confirmed consumption of
starting material after 1 minute after which silica was added to the flask, solvent was
removed in vacuo (30 °C water bath temperature) and the material was purified by column
chromatography (c-Hex/EtOAc; 7:1) to give dibromide (701 mg, 53%) as a white crystalline
solid. Note: the success of this reaction depends on the strict short reaction time after
addition of the aldehyde. Longer reaction times lead to substantial decomposition and
diminished yields. M.p. = 103-107 °C Rf = 0.5 (c-Hex/EtOAc; 3:1). IR (film): νmax = 3330, 2928,
1692, 1535, 1453, 1441, 1343, 1264, 1232, 1083, 1042, 1022, 803, 743 cm‒1. H NMR (400
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NH) 5.08 (s, 2H, CH2) 6.40 (d, J = 7.5 Hz, 1H, CH) 7.13-7.18 (m, 2H, ArH) 7.22-7.39 (m, 8H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 39.6 (CH2) 54.9 (CH) 66.9 (CH2) 91.6 (CBr2) 127.0
(CH) 128.1 (CH) 128.2 (CH) 128.5 (CH) 128.7 (CH) 129.5 (CH) 136.0 (C) 136.2 (C) 137.9 (CH)
155.3 (CO) ppm. HRMS (ES+) C18H17NO2Na79Br81Br (MNa+) calcd. 461.9503; found 461.9524.
[α]D = +12 (c = 0.1, CH2Cl2).
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(S)-Benzyl (1-phenylbut-3-yn-2-yl)carbamate 23. Under nitrogen, at ‒78 °C, to a stirred
solution of the above dibromide (230 mg, 0.52 mmol, 1.0 equiv.) in dry THF (5 mL) was
added freshly titrated29 n-BuLi in hexanes (1.53 M, 1.1 mL, 1.68 mmol, 3.2 equiv.) dropwise
over 10 minutes after which time the reaction mixture went black. The reaction mixture
was then warmed to 0 °C and stirred at for 30 minutes. The reaction mixture was then
quenched with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine, dried over MgSO4, filtered and solvent was removed in
vacuo to give the crude product. Purification by column chromatography (c-Hex/EtOAc; 7:1)
gave alkyne 23 as a white waxy solid (94 mg, 64%). M.p. = 61-64 °C. Rf = 0.4 (c-Hex/EtOAc;
3:1). IR (film): νmax = 3405, 3296, 3032, 2931, 1701, 1524, 1497, 1455, 1335, 1283, 1246,
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1028 cm‒1. H NMR (400 MHz, CDCl3): δ = 2.30 (d, J = 2.5 Hz, 1H, CH) 2.96 (dd, J = 13.5, 7.0
Hz, 1H, CH2) 3.02 (dd, J = 13.5, 5.5 Hz, 1H, CH2) 4.70-4.82 (m, 1H, CH) 4.92 (s (br), 1H, NH)
5.10 (s, 2H, CH2) 7.20-7.39 (m, 10H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 41.5 (CH2)
44.3 (CH) 67.0 (CH2) 72.6 (CH) 82.4 (C) 127.0 (CH) 128.1 (CH) 128.2 (CH) 128.4 (CH) 128.5
(CH) 129.8 (CH) 136.0 (C) 136.2 (C) 155.2 (CO) ppm. HRMS (ES+) C18H17NO2Na (MNa+) calcd.
302.1157; found 302.1148. [α]D = ‒25 (c = 0.1, CH2Cl2). Anal. calcd. C18H17NO2: C, 77.40; H,
6.13; N, 5.01; found C, 77.02, H, 6.31, N, 4.73.
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[(S)-2-phenyl-1-(1-((S,E)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl)-1H-1,2,3-
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triazol-4-yl)ethyl]carbamate 25. To a stirred solution of azide (S)-21 (30 mg, 0.09 mmol, 1.0
equiv.), alkyne 23 (27 mg, 0.10 mmol, 1.05 equiv.) and CuSO4·5H2O (6 mg, 0.02 mmol, 0.25
equiv.) in DMF (1 mL) was added sodium ascorbate (14 mg, 0.07 mmol, 0.75 equiv.) and the
green reaction mixture was stirred for 3 days at room temperature. Solvent was removed in
vacuo and the residue was re-dissolved in EtOAc (10 mL) and washed with water (5 mL). The
aqueous layer was back-extracted with EtOAc (3 × 10 mL) and the combined organic layers
were washed with brine (10 mL), dried over MgSO4, filtered and solvent was removed in
vacuo to give the crude product. Purification by column chromatography (c-Hex/EtOAc; 2:1)
gave triazole 25 as a white powdery solid (42 mg, 76%). M.p. 110-115 °C. Rf = 0.4 (c-
Hex/EtOAc; 1:1). IR (film): νmax = 3056, 2926, 1686, 1510, 1446, 1305, 1285, 1227, 1145,
1085 cm‒1. 1H NMR (400 MHz, CDCl3): δ = 2.16-2.44 (m, 3H, CH2) 2.45-2.54 (m, 1H, CH2) 3.14
(dd, J = 13.0, 9.0 Hz, 1H, CH2) 3.36 (dd, J = 13.0, 5.5 Hz, 1H, CH2) 5.00-5.17 (m, 4H, CH + CH2)
5.61 (d, J = 8.0 Hz, 1H, NH) 6.05 (d, J = 15.0 Hz, 1H, CH) 6.92 -7.06 (m, 6H, CH + ArH) 7.15-
7.24 (m, 5H, ArH) 7.28-7.37 (m, 6H, ArH) 7.53 (t, J = 7.5 Hz, 2H, ArH) 7.63 (t, J = 7.5 Hz, 1H,
ArH) 7.80 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.4 (CH2) 35.4 (CH2)
41.6 (CH2) 49.3 (CH) 59.7 (CH) 66.9 (CH2) 120.8 (CH) 126.7 (CH) 126.8 (CH) 127.8 (CH) 128.0
(CH) 128.2 (CH) 128.4 (CH) 128.46 (CH) 128.53 (CH) 128.8 (CH) 129.4 (CH) 129.5 (CH) 132.7
(CH) 133.9 (CH) 136.3 (C) 137.0 (C) 138.9 (C) 139.3 (C) 141.9 (CH) 147.5 (C) 155.6 (CO) ppm.
HRMS (ES+) C35H34N4O4NaS (MNa+) calcd. 629.2198; found 629.2180. [α]D = +12 (c = 1.0,
CHCl3).
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[(S)-2-phenyl-1-(1-((R,E)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl)-1H-1,2,3-
triazol-4-yl)ethyl]carbamate 26. In a procedure identical to the above click reaction: Azide
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(R)-21 (30 mg, 0.09 mmol, 1.0 equiv.), alkyne 23 (27 mg, 0.10 mmol, 1.05 equiv.),
CuSO4·5H2O (6 mg, 0.02 mmol, 0.25 equiv.) and sodium ascorbate (13 mg, 0.07 mmol, 0.7
equiv.) in DMF (1 mL). After aqueous workup, purification by column chromatography (c-
Hex/EtOAc; 2:1) gave triazole 26 as a white powdery solid (44 mg, 79%). M.p. 157-161 °C. Rf
= 0.4 (c-Hex/EtOAc; 1:1). IR (film): νmax = 2925, 1713, 1518, 1454, 1315, 1245, 1148, 1085,
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1043 cm‒1. H NMR (400 MHz, CDCl3): δ = 2.17-2.28 (m, 1H, CH2) 2.29-2.41 (m, 2H, CH2)
2.44-2.54 (m, 1H, CH2) 3.11 (dd, J = 13.5, 8.5 Hz, 1H, CH2) 3.36 (dd, J = 13.5, 6.0 Hz, 1H, CH2)
5.04-5.17 (m, 4H, CH + CH2) 5.63 (d, J = 7.5 Hz, 1H, NH) 6.05 (dd, J = 15.0, 1.5 Hz, 1H, CH)
6.93-7.05 (m, 6H, CH + ArH) 7.11-7.23 (m, 4H, ArH) 7.26-7.38 (m, 7H, ArH) 7.52 (t, J = 7.5 Hz,
2H, ArH) 7.63 (t, J = 7.5 Hz, 1H, ArH) 7.80 (d, J = 7.5 Hz, 2H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 31.4 (CH2) 35.3 (CH2) 41.7 (CH2) 49.3 (CH) 59.7 (CH) 66.9 (CH2) 120.5 (CH) 126.7
(CH) 126.8 (CH) 127.8 (CH) 128.0 (CH) 128.2 (CH) 128.4 (2 × CH) 128.5 (CH) 128.8 (CH) 129.4
(CH) 129.5 (CH) 132.8 (CH) 133.9 (CH) 136.3 (C) 137.0 (C) 138.9 (C) 139.3 (C) 141.9 (CH)
147.6 (C) 155.6 (CO) ppm. HRMS (ES+) C35H34N4O4NaS (MNa+) calcd. 629.2198; found
629.2171. [α]D = ‒21 (c = 1.0, CHCl3).
Benzyl [(S)-1-(1-((S,E)-7-((tert-butoxycarbonyl)amino)-1-(phenylsulfonyl)hept-1-en-3-yl)-
1H-1,2,3-triazol-4-yl)-2-phenylethyl]carbamate 27. In a procedure identical to the above
click reaction: Azide (S)-22 (37 mg, 0.09 mmol, 1.0 equiv.), alkyne 23 (27 mg, 0.09 mmol, 1.0
equiv.), CuSO4·5H2O (5 mg, 0.02 mmol, 0.2 equiv.) and sodium ascorbate (12 mg, 0.06 mmol,
0.6 equiv.) in DMF (1 mL). After aqueous workup, purification by column chromatography
(c-Hex/EtOAc; 1:1) gave triazole 27 as a white powdery solid (47 mg, 74%). M.p. 156-159 °C.
Rf = 0.2 (c-Hex/EtOAc; 1:1). IR (film): νmax = 3376, 3056, 2930, 1692, 1522, 1447, 1245, 1147,
1084, 1041 cm‒1. 1H NMR (400 MHz, CDCl3): δ = 0.97-1.51 (m, 13H, CH2 + CH3) 1.91-2.07 (m,
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