Stereoselectivity of the Honda-Reformatsky reaction in reactions with ethyl bromodifluoroacetate with α-oxygenated sulfinylimines

Article abstract of DOI:10.1021/jo500396p

The Reformatsky reaction of ethyl bromodifluoroacetate to α-oxygenated sulfinylimines is described. Using Honda-Reformatsky conditions, the reaction proceeds with double diastereodifferentiation, with the configuration of the sulfinyl group determining th

Full text of DOI:10.1021/jo500396p

Note
pubs.acs.org/joc
Stereoselectivity of the Honda−Reformatsky Reaction in Reactions
with Ethyl Bromodifluoroacetate with α‑Oxygenated Sulfinylimines
Clement Q. Fontenelle,† Matthew Conroy,† Mark Light,† Thomas Poisson,*,‡ Xavier Pannecoucke,‡
́
and Bruno Linclau*,†
†Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom
‡Normandie University, COBRA, UMR 6014 and FR 3038; University of Rouen, INSA Rouen, CNRS, 1 rue Tesnier
̀
e,
76821 Mont Saint-Aignan Cedex, France
S
* Supporting Information
ABSTRACT: The Reformatsky reaction of ethyl bromodi-
fluoroacetate to α-oxygenated sulfinylimines is described.
Using Honda−Reformatsky conditions, the reaction proceeds
with double diastereodifferentiation, with the configuration of
the sulfinyl group determining the stereochemical course of
the reaction. Excellent diastereoselectivities (>94:6) are ob-
tained for the matched cases. In contrast, reaction with sulfin-
ylimines derived from unsubstituted alkanals proceeded with virtually no diastereoselectivity.
he introduction of fluorine in molecules of interest to
Tmodulate their properties is a major strategy in many
application areas.1−3 These include the pharmaceutical and
agrochemical industries, around 20% of the commercially avail-
able pharmaceuticals and 30% of agrochemicals are fluori-
nated,4 and performance materials, such as liquid crystals.5
Given the abundance of amine-containing bioactive com-
pounds, their fluorination has received great attention.6−9 The
β-position of amino groups is often considered for fluorination
given the resulting effect on their pKa(H) value and lipophil-
icity.10,11 Fluorination will also have an impact on the amine
hydrogen-bonding properties and will induce potentially strong
conformational effects.12
found where 1 was reacted with imines derived from achiral
amines and α-oxygenated aldehydes: the benzyl imine derived
from glyceraldehyde acetonide was reported to react with a
∼4:1 syn-selectivity,27,28 while a complex C-glycosyl-derived
imine gave complete syn-selectivity.29
We were interested in investigating a short synthesis of the
motif A (Scheme 1), a versatile intermediate for the synthesis of
Scheme 1. Retrosynthetic Analysis Featuring a Reformatsky
Reaction
The conformational properties and biological activities of
β-amino acids have received great attention, including the
corresponding α,α-difluoro-β-amino acids.13−16 Their synthesis
using direct C−C bond formations with fluorinated building
blocks usually involve Reformatsky reaction of BrCF2COOEt
(1) to imine derivatives (or their equivalents).13 The synthesis
of enantioenriched α,α-difluoro-β-amino acid derivatives
using the Reformatsky reaction has been reported with
imines derived from chiral amines, such as the tert-butyl- and
p-toluenesulfinylimines7,17−21 and imines derived from (R)-
phenylglycinol.13,22−26 Excellent diastereoselectivities are obtained
with imines derived from aromatic aldehydes, while imines derived
from aliphatic substrates generally give lower selectivities.
The β-amino alcohol moiety is a well-known pharmacophore
in bioactive compounds, and the corresponding γ,γ-difluoro-β-
amino alcohols are thus of interest. Whereas nucleophilic
addition to sulfinylimines that contain an α-oxygenated chiral
center is a popular method for the diastereoselective synthesis
of β-amino alcohols,19 we are not aware of examples of
Reformatsky reactions (either with 1 or with BrCH2COOEt)
on these types of sulfinylimines. Only a few examples were
complex α,α-difluoro-β-amino acids and of 2,2-difluoro-3-
amino carbohydrate analogues, via a Reformatsky reaction as
shown in Scheme 1. The sulfinylimine auxiliaries were selected,
given they are accessible in both enantiomeric forms, and be-
cause of the absence of concomitant β-lactam formation upon
addition reaction. Addition reactions to substrates B using
various organometallic derivatives have been described to occur
with various levels of double diastereoselection, in which the
chirality of the auxiliary is usually dominant.20 Furthermore,
Ellman has recently described the addition of a benzyl zinc
reagent to either diastereomer of the tert-butanesulfinylimine
derived from (R)-glyceraldehyde acetonide, which for the matched
case proceeded with virtually complete stereoselectivity.30 Herein
we describe a study of the Reformatsky reaction using 1 with
Received: February 20, 2014
Published: April 18, 2014
© 2014 American Chemical Society
4186
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
a
α-oxygenated sulfinylimines B, in which the anticipated double
diastereoselection was investigated by combining both enantio-
meric sulfinylimine auxiliaries with all chiral aldehydes employed.
The imines were synthesized from the corresponding
aldehydes in good yields mainly using the Ti(OEt)4 proce-
dure (Table 1).31,32 As expected,33 no epimerization of the
Table 2. Optimisation of the Reaction
Table 1. Synthesis of the tert-Butanesulfinylimines
a
The prefix l (like) indicates that the sulfinyl group and the newly
formed amine stereocenter have the same absolute configuration (and
otherwise for ul (unlike)). The suffix R or S in the numbering refers to
b
the absolute configuration of the sulfinylimine auxiliary. Determined
c
d
by 19F NMR (crude reaction mixture) Isolated yield. Dilute aq HCl
e
f
activation. DCM was used as cosolvent. DMSO/TMSCl activation.
activation by DMSO/TMSCl35 failed to induce reaction (entry 5).
Pleasingly, using Et2Zn under Honda−Reformatsky conditions,
which employ the Wilkinson catalyst to promote Zn inser-
tion,36,37 a single diastereoisomer was obtained in 45% yield
(entry 6), which could be increased to 61% upon doubling the
amount of 1 (entry 7). Replacement of the Wilkinson catalyst by
NiCl2(PPh3)2 (entry 8)38 or of Et2Zn by Me2Zn (entry 9) was not
possible.
Next, the Reformatsky reaction was investigated on a range
of sulfinylimines (Table 3).
a
b
Isolated yield. Enantiomers were synthesized. See the Supporting
Information.
Reaction with the aliphatic sulfinylimines 3S and 4S was not
diastereoselective under the Honda−Reformaksky conditions
(entries 1 and 2). We also observed slight variations in diaste-
reoselectivity depending on the age of the Et2Zn and rate of its
addition (53:47 to 60:40), but always with the same major
diastereomer. The low dr was surprising, given the much higher
values obtained by Staas18 and Soloshonok (up to 86:14 even
in refluxing THF, using Zn)17 for similar sulfinylimines derived
from linear aliphatic aldehydes. However, Reformatsky reaction
of 5S, which has an α-benzyloxy substituent, proceeded with
much increased diastereoselectivity (entry 3). Interestingly, the
sterically hindered substrate 6S was unreactive under the
conditions used (entry 4). Pleasingly, the Reformatsky reaction
of substrate 7S (entry 5), derived from (R)-lactaldehyde and
the (S)-configured chiral auxiliary, proceeded with enhanced
diastereoselectivity compared to the benzyloxymethyl-derived
sulfinylimine 5S. In contrast, when the enantiomeric chiral
α-stereocenter was observed with chiral aldehydes. Imines 3−6
were synthesized as model compounds to enable comparison
with the stereoinduction exerted by the chiral auxiliaries with-
out the additional bias of an α-oxygenated substituent.
The Reformatsky reaction was first investigated by a short
optimization effort using sulfiminine 8S, which was predicted to
proceed with matched double diastereoselection.30 Promotion
by indium34 (Table 2, entry 1) gave no reaction, even at 60 °C.
The use of zinc was successful, and the desired product was
obtained in 46% yield and a 72:28 diastereoisomeric ratio (dr)
(entry 2). Modification of the stoichiometry afforded an im-
proved 61% yield and 85:15 dr (entry 3). The use of activated
zinc (dil HCl), and DCM as cosolvent enhanced the yield, but
proceeded with slightly lower dr (entry 4). The use of Et2O or
toluene as cosolvent gave similar results (not shown). Zn
4187
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
a
was determined by the configuration of the auxiliary and not by
the α-stereocenter. On that basis, the stereochemistry of the
other major and minor isomers was assigned.
Table 3. Scope of the Reaction
The relative stereochemistry determined for ul-11S was most
unexpected, given the precedence of both Staas and Solo-
shonok, who reported the other diastereomer as the major
product of the Reformatsky reaction on alkyl-derived sulfin-
ylimines. However, these Reformatsky reactions were per-
formed under different conditions (Zn, THF, reflux or room
temperature, versus ZnEt2/RhCl(PPh3)3, THF, 0 °C in our case),
and it should be remembered that the dr in our case was very low.
On the other hand, our results correspond to the stereoinduction
determined previously by Ellman for reactions of sulfinylimines
derived both from aliphatic aldehydes, and from (R)-glyceralde-
hyde acetonide, with benzylzinc reagents, including the matched/
mismatched stereoinduction.30 Their benzylzinc reagent was
synthesized from the corresponding benzyl chloride using ZnCl2/
Mg/LiCl (Knochel conditions39).
The stereoinduction by the α-oxygenated chiral center for 8S
can be deduced from the Cornforth-Evans (CE)/polar Felkin-
Anh (PFA) models TS-1 and TS-2 (Figure 1),40 which both
predict the observed Si-face attack. In contrast, the cyclic “Cram
model” TS-3,41 involving coordination of the imine nitrogen
and the α-alkoxy group, predicts Re-face attack.
Several models have been proposed to rationalize the induc-
tion by the sulfinylimine auxiliary.19−21 The cyclic Ellman tran-
sition state TS-4 has been suggested for the Reformatsky
reaction (Zn, refluxing THF) of 1 to sulfinylimines derived
from aromatic and aliphatic aldehydes17 and which successfully
explains the Staas and Soloshonok results17,18 (as well as for
Reformatsky reactions using BrCH2COOEt).42,43 However, given
that it predicts Re-face attack (for an (S)-configured sulfinylimine),
it is not consistent with our findings. Equally, TS-5,44,45 involving a
Zn-enolate, predicts the wrong facial selectivity. However, this
model correctly explained the facial selectivity of addition with allyl
zinc to an aryl sulfinylimine (in THF).43 In contrast, the Barrow
chelation model TS-6,46 involving chelation with both the SO
and the α-alkoxy groups and a rapid sulfinyl imine E/Z
isomerization, predicts the correct stereochemical outcome,
including the double diastereodifferentiation (though now due to
the avoidance of a sterically unfavorable interaction with the sulfinyl
group as opposed to involvement of TS-1/TS-2). The transition
state TS-7 proposed by Marek, also for reaction with allyl zinc
derivatives in THF, correctly predicts Si-face attack as well.47 This
model differs from TS-5 in that chelation is only involving the
imine nitrogen atom, with the SO dipole oriented anti-
periplanar to the imine lone pair. Both TS-7 and TS-5 (which
predict opposing facial selectivity) have been successfully used to
explain the outcome of additions of allylzinc to sulfin-
ylimines,43,47 which shows that the exact conditions, especially
the amount of coordinating species in solution, can influence the
facial selectivity. However, for a Reformatsky reaction the additional
pseudo-axial OEt-substituent could disfavor TS-7. Finally, an
open transition state TS-8 proposed by Davis48 also predicts
the observed Si-facial attack. This model was used by Ellman to
explain the stereochemical outcome of the aforementioned addition
of benzylzinc reagents to both aryl- and (R)-glyceraldehyde-derived
sulfinylimines (involving excess of coordinating ions and a co-
ordinating solvent).30
a
b
c
See Footnote a, Table 2. Isolated yield. Enantiomers were
synthesized. Shown as is to facilitate stereochemical analysis.
auxiliary was used (7R, entry 6), the diastereoselectivity was much
reduced, evidencing a double diastereodifferentiation effect. This
was also observed for the other chiral aldehydes derived from
glyceraldehyde and threose, for which the matched cases
proceeded with excellent diastereoselectivity (entries 7, 9, and 11).
The relative configuration of the major diastereomers
obtained from reaction of the aliphatic-derived 3S and the
α-alkoxy-derived 8S and 8R could be determined by X-ray
crystallographic analysis (see the Supporting Information). In
all cases, the ul-relative configuration was confirmed. Both
products ul-16S and ul-16R are derived from the same
glyceraldehyde enantiomer but with differently configured
chiral auxiliaries, and the different configuration of the formed
amine stereocenter clearly proved that the diastereoselection
The much-increased selectivities for substrates 5 and 7−10
compared to 3 and 4 suggest a chelation role of the α-oxygen-
containing substituent, which points to the Barrow transition state
TS-6. For the alkyl sulfinylimines 3 and 4, it is unlikely that the
4188
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
Figure 1. Models to explain the stereoinduction/double diastereodifferentiation.
(101 MHz, CDCl3) δ 169.8, 56.5, 36.1, 31.9, 29.6 (2C), 29.5, 29.3
(2C), 29.2, 25.5, 22.7, 22.3 (3C), 14.1 ppm; HRMS (MS+) for
C16H34NOS (M + H)+ calcd 288.2356, found 288.2356.
(SS,E)-N-(2-Benzyloxyethylidene)-2-methyl-2-propanesulfinamide
(5S).
required E/Z isomerization is occurring/complete, given there is
no chelating α-substituent to drive this process.
CONCLUSIONS
■
The Reformatsky reaction involving ethyl bromodifluoroacetate
was investigated both with sulfinylimines derived from alde-
hydes with a chiral α-oxygenated substituent as well as from
aliphatic aldehydes. Reformatsky reaction of the former pro-
ceeds with double diastereodifferentiation, with the configuration
of the chiral auxiliary determining the stereoinduction. The
stereochemical outcome is consistent with the Barrow model.
To benzyloxyacetaldehyde50 (0.250 g, 1.67 mmol) in CH2Cl2
(3.5 mL) were added (S)-2-methyl-2-propanesulfinamide (0.212 g,
1.75 mmol) and CuSO4 (0.558 g, 3.50 mmol). The resultant mixture
was stirred at rt for 15 h and then filtered over Celite to afford the
desired crude product. Purification over a short pad of silica eluting
with PE/EtOAc 75:25 yielded 5S (0.371 g, 1.46 mmol, 88%) as a
pale yellow oil: Rf 0.21 (hexane/ethyl acetate 70:30); [α]D +161.6 (c
0.09, CHCl3, 26 °C) [lit.51 (ent-5S) [α]D −212 (c 1.0, CHCl3,
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of tert-Butanesulfinyl-
imines (Table 1).30 To a mixture of aldehyde (1 equiv) and
sulfinamide (1.05 equiv) in CH2Cl2 was added Ti(OEt)4 (3−5 equiv).
After the mixture was stirred at rt overnight, water was added. Stirring
for a further 15 min was followed by filtration over a pad of MgSO4
and Celite. The filter cake was washed with EtOAc and the filtrate
concentrated under reduced pressure. The residue was purified via
filtration over a pad of silica to afford pure sulfinylimine (pale yellow oils).
(SS,E)-N-(Propylidene)-2-methyl-2-propanesulfinamide (3S).49
1
3
23 °C)]; H NMR (300 MHz, CDCl3) δ 8.14 (t, JHH 3.2 Hz, 1H),
7.40−7.29 (m, 5H), 4.65 (s, 2H), 4.45 (dd, 2JHH = 16.3, 3JHH = 3.2 Hz,
1H), 4.39 (dd, 2JHH = 16.3, 3JHH = 3.2 Hz, 1H), 1.23 (s, 9H) ppm; 13
C
NMR (101 MHz, CDCl3) δ 166.7, 137.2, 128.5, 128.0, 127.9, 73.3,
71.3, 57.0, 22.4 ppm. NMR spectra correspond to the reported data for
ent-5S.51
(SS,E)-N-[2-(Benzyloxy)-2-methylpropylidene]-2-methyl-2-pro-
panesulfinamide (6S).
Propionaldehyde (0.100 g, 1.72 mmol), (S)-2-methyl-2-propanesulfin-
amide (0.219 g, 1.81 mmol) and Ti(OEt)4 (1.18 g, 5.17 mmol) yielded
3S (0.201 g, 1.25 mmol, 72%) as a pale yellow oil: Rf 0.27 (hexane/
EtOAc 75:25); [α]D +338.4 (c 0.12, CHCl3, 26 °C) [lit.49 (ent-3S)
[α]D −328.5 (c 1.0, CHCl3, 23 °C)]; 1H NMR (300 MHz, CDCl3) δ
2-Benzyloxy-2-methylpropanal52 (0.120 g, 0.673 mmol), (S)-2-methyl-
2-propanesulfinamide (0.086 g, 0.707 mmol), and Ti(OEt)4 (0.768 g,
3.37 mmol) yielded 6S (0.149 g, 0.529 mmol, 79%) as a pale yellow
oil: Rf 0.47 (PE/Et2O 60:40); [α]D +210.6 (c 0.50, CHCl3, 22 °C); IR
3
3
3
8.11 (t, JHH = 4.3 Hz, 1H), 2.55 (dq, JHH = 7.4 Hz, JHH = 4.3 Hz,
3
2H), 1.20 (s, 9H), 1.20 (t, JHH = 7.4 Hz, 3H) ppm; 13C NMR
1
(neat) 2979 (w), 1622 (w), 1160 (m), 1087 (s), 1059 (m); H NMR
(75 MHz, CDCl3) δ 170.3, 56.5, 29.5, 22.3 (3C), 9.6 ppm. NMR
(400 MHz, CDCl3) δ 8.13 (s, 1H), 7.40−7.23 (m, 5H), 4.48 (d,
2JHH = 11.1 Hz, 1H), 4.45 (d, 2JHH = 11.1 Hz, 1H), 1.50 (s, 3H), 1.48
(s, 3H), 1.23 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 172.8, 138.4,
128.4, 127.5, 127.6, 78.1, 66.4, 56.9, 24.4, 24.0, 22.5 ppm; HRMS (MS+)
for C15H23NNaO2S (M + Na)+ calcd 304.1342, found 304.1338.
(RS,E)-N-[(2S)-2-(Benzyloxy)propylidene]-2-methyl-2-propanesul-
finamide (ent-7S).33
spectra correspond to the reported data for ent-3S.49
(SS,E)-N-(Dodecylidene)-2-methyl-2-propanesulfinamide (4S).
Dodecanal (0.30 mL, 0.249 g, 1.34 mmol), (S)-2-methyl-2-propane-
sulfinamide (0.170 g, 1.41 mmol), and Ti(OEt)4 (1.53 g, 6.70 mmol)
yielded 4S (0.366 g, 1.17 mmol, 87%) as a pale yellow oil: Rf 0.47
(hexane/EtOAc 75:25); [α]D +166.0 (c 0.21, CHCl3, 28 °C); IR
(neat) 2923 (s), 2854 (m), 1622 (m), 1457 (w), 1363 (w), 1087 (s);
1H NMR (400 MHz, CDCl3) δ 8.07 (t, 3JHH = 4.7 Hz, 1H), 2.52 (dt,
3JHH = 7.4 Hz, 3JHH = 4.7 Hz, 2H), 1.70−1.60 (m, 2H), 1.51−1.24 (m,
(2S)-2-Benzyloxypropanal52 (0.150 g, 0.914 mmol), (R)-2-methyl-2-
propanesulfinamide (0.122 g, 1.01 mmol), and Ti(OEt)4 (0.625 g,
2.74 mmol) yielded ent-7S (0.200 g, 0.748 mmol, 82%) as a pale
3
16H), 1.20 (s, 9H), 0.89 (t, JHH = 7.1 Hz, 3H) ppm; 13C NMR
4189
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
yellow oil: Rf 0.60 (hexane/EtOAc 50:50). [α]D −222 (c 0.52, EtOH,
(RS,E)-N-[(2S)-2,3-Cyclohexylidenedioxy)propylidene]-2-methyl-2-
propanesulfinamide (9R).
1
3
22 °C). H NMR (400 MHz, CDCl3) δ 8.07 (d, JHH = 4.6 Hz, 1H),
2
2
7.41−7.23 (m, 5H), 4.66 (d, JHH = 11.7 Hz, 1H), 4.54 (d, JHH
=
3
3
11.7 Hz, 1H), 4.35 (dq, JHH = 6.7 Hz, JHH = 4.6 Hz, 1H), 1.41 (d,
3JHH = 6.7 Hz, 3H), 1.22 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3)
δ 170.5, 137.6, 128.5, 127.9, 127.8, 76.3, 71.6, 56.9, 22.4, 18.7 ppm.
NMR spectra correspond to the reported data.33
(SS,E)-N-[(2S)-2-(Benzyloxy)propylidene]-2-methyl-2-propanesul-
finamide (ent-7R).
2,3-O,O-Cyclohexylidene-D-glyceraldehyde54 (1.00 g, 5.88 mmol),
(R)-2-methyl-2-propanesulfinamide (0.748 g, 6.17 mmol), and
Ti(OEt)4 (6.70 g, 29.4 mmol) yielded 9R (1.41 g, 5.16 mmol, 88%)
as a pale yellow oil: Rf 0.29 (hexane/EtOAc 70:30); [α]D −216.6
(c 0.49, CHCl3, 20 °C); IR (neat) 2934 (m), 2863 (m), 1625 (s), 1084
(s) cm−1. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 3JHH = 4.5 Hz, 1H),
4.83 (ddd, 3JHH = 7.2 Hz, 3JHH = 5.5 Hz, 3JHH = 4.5 Hz, 1H), 4.24 (dd,
(2S)-2-Benzyloxypropanal52 (0.150 g, 0.914 mmol), (S)-2-methyl-2-
propanesulfinamide (0.116 g, 0.959 mmol), and Ti(OEt)4 (0.833 g,
3.65 mmol) yielded ent-7R (0.173 g, 0.647 mmol, 71%) as a pale
yellow oil: Rf 0.40 (hexane/EtOAc 50:50); [α]D +67.3 (c 0.53, EtOH,
3
2
3
2JHH = 8.6 Hz, JHH = 7.2 Hz, 1H), 4.01 (dd, JHH = 8.6 Hz, JHH
=
5.5 Hz, 1H), 1.77−1.53 (m, 8H), 1.48−1.34 (m, 2H), 1.21 (s, 9H)
ppm; 13C NMR (101 MHz, CDCl3) δ 167.8, 111.6, 76.5, 66.8, 57.2,
36.0, 35.0, 25.0, 23.83, 23.80, 22.4 ppm; HRMS (MS+) for
C13H23NNaO3S (M + Na)+ calcd 296.1291, found 296.1296.
(SS,E)-N-[(2S)-2,3-Cyclohexylidenedioxy)propylidene]-2-methyl-2-
propanesulfinamide (9S).
1
3
22 °C); H NMR (400 MHz, CDCl3) δ 8.09 (d, JHH = 4.5 Hz, 1H),
2
2
7.43−7.28 (m, 5H), 4.67 (d, JHH = 11.6 Hz, 1H), 4.50 (d, JHH
=
3
3
11.6 Hz, 1H), 4.34 (dq, JHH = 6.6 Hz, JHH = 4.5 Hz, 1H), 1.43 (d,
3JHH = 6.6 Hz, 3H), 1.24 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3)
δ 170.4, 137.7, 128.5, 127.9, 127.8, 76.2, 71.5, 56.8, 22.5, 18.5 ppm;
NMR spectra correspond to the reported data.33
(RS,E)-N-[(2S)-2,3-(Isopropylidenedioxy)propylidene]-2-methyl-2-
propanesulfinamide (8R).
2,3-O,O-Cyclohexylidene-D-glyceraldehyde54 (1.00 g, 5.88 mmol),
(S)-2-methyl-2-propanesulfinamide (0.748 g, 6.17 mmol), and
Ti(OEt)4 (6.70 g, 29.4 mmol) yielded 9S (1.43 g, 5.23 mmol, 89%)
as a pale yellow oil: Rf 0.53 (PE/EtOAc 60:40); [α]D +193 (c 0.53,
EtOH, 22 °C). IR (neat) 2934 (m), 2359 (s), 1625 (m), 1364 (m),
1088 (s). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 3JHH = 4.2 Hz, 1H),
4.84 (ddd, 3JHH = 6.7 Hz, 3JHH = 5.1 Hz, 3JHH = 4.2 Hz, 1H), 4.22 (dd,
2,3-O,O-Isopropylidene-D-glyceraldehyde53 (0.500 g, 3.84 mmol),
(R)-2-methyl-2-propanesulfinamide (0.489 g, 4.03 mmol), and
Ti(OEt)4 (4.38 g, 19.2 mmol) yielded 8R (0.771 g, 3.30 mmol,
86%) as a pale yellow oil: Rf 0.21 (hexane/EtOAc 70:30); [α]D −198.6
(c 0.84, CHCl3, 26 °C); IR (neat) 2984 (m), 2873 (m), 1626 (s), 1060
(s) cm−1; 1H NMR (400 MHz, CDCl3) δ 8.02 (d, 3JHH = 4.5 Hz, 1H),
4.83 (ddd, 3JHH = 7.6 Hz, 3JHH = 5.5 Hz, 3JHH = 4.5 Hz, 1H), 4.25 (dd,
3
2
3
2JHH = 8.5 Hz, JHH = 6.7 Hz, 1H), 4.04 (dd, JHH = 8.5 Hz, JHH
=
5.1 Hz, 1H), 1.73−1.54 (m, 8H), 1.48−1.37 (m, 2H), 1.20 (s, 9H)
ppm; 13C NMR (101 MHz, CDCl3) δ 168.3, 111.5, 76.7, 67.0,
57.1, 36.1, 35.0, 25.0, 23.9, 23.9, 22.4 ppm; MS (ESI+) (m/z) 274
(M + H)+; HRMS (MS+) for C13H23NNaO3S (M + Na)+ calcd
296.1291, found 296.1297.
3
2
3
2JHH = 8.7 Hz, JHH = 7.6 Hz, 1H), 4.00 (dd, JHH = 8.7 Hz, JHH
=
5.5 Hz, 1H), 1.46 (s, 3H), 1.41 (s, 3H), 1.20 (s, 9H) ppm; 13C NMR
(101 MHz, CDCl3) δ 167.4, 111.0, 76.7, 67.1, 57.2, 26.4, 25.4,
22.3 ppm; HRMS (MS+) for C10H19NNaO3S (M + Na)+ calcd
256.0983, found 256.0978. NMR spectra correspond to the reported
data.30
(RS,E)-N-[(2R,3R)-4-(Benzyloxy)-2,3-(cyclohexylidenedioxy)-
butylidene]-2-methyl-2-propanesulfinamide (ent-10S).
(SS,E)-N-[(2S)-2,3-(Isopropylidenedioxy)propylidene]-2-methyl-2-
propanesulfinamide (8S).
SO3·pyridine (3.27 g, 20.5 mmol, 3.0 equiv), Et3N (3.34 mL,
23.9 mmol, 3.5 equiv), DMSO (8 mL), and CH2Cl2 (17 mL) were
combined and stirred at −20 °C for 0.5 h. The corresponding alcohol
([α]D −4.02 (c 1.3, CHCl3, 21 °C) [lit.55 +0.90 (c 1.3, CHCl3, 24 °C,
enantiomer)] (2.00 g, 6.84 mmol, 1 equiv), DMSO (8 mL), and DCM
were stirred at −20 °C in a separate flask, and to this solution was
added dropwise via cannula the solution of SO3. The resultant mixture
was allowed to stir below −10 °C for 1 h then at rt for 3 h. Quenching
with saturated aqueous NH4Cl solution and extraction with EtOAc
(2 × 15 mL) and Et2O (2 × 15 mL) was followed by drying over
MgSO4 and concentration in vacuo to afford a bright yellow oil.
Column chromatography (PE/EtOAc 75:25 to 70:30) afforded 1.63 g
(5.61 mmol, 82%) of the pure aldehyde 2h as a colorless oil: Rf 0.31
2,3-O,O-Isopropylidene-D-glyceraldehyde53 (1.05 g, 8.07 mmol),
(S)-2-methyl-2-propanesulfinamide (1.03 g, 8.47 mmol), and
Ti(OEt)4 (7.36 g, 32.3 mmol) yielded 8S (1.50 g, 6.43 mmol, 80%)
as a pale yellow oil: Rf 0.6 (PE/EtOAc 50:50); [α]D +248 (c 0.49,
EtOH, 23 °C); 1H NMR (300 MHz, CDCl3) δ 8.07 (d, 3JHH = 4.1 Hz,
1H), 4.85 (ddd, JHH = 6.8 Hz, JHH = 5.1 Hz, JHH = 4.1 Hz, 1H),
4.23 (dd, 2JHH = 8.5 Hz, 3JHH = 6.8 Hz, 1H), 4.05 (dd, 2JHH = 8.5 Hz,
3JHH = 5.1 Hz, 1H), 1.46 (s, 3H), 1.43 (s, 3H), 1.21 (s, 9H) ppm;
13C NMR (75 MHz, CDCl3) δ 168.0, 110.8, 76.9, 67.2, 57.0,
26.4, 25.4, 22.3 ppm. NMR spectra correspond to the reported
data.30
3
3
3
1
3
(PE/EtOAc 75:25); H NMR (300 MHz, CDCl3) δ 9.78 (d, JHH
=
1.6 Hz, 1H), 7.40−7.28 (m, 5H), 4.62 (s, 2H), 4.32−4.22 (m, 2H),
3
3
3.67 (dd, JHH = 4.5 Hz, JHH = 1.1 Hz, 2H), 1.75−1.54 (m, 8H),
4190
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
1.49−1.34 (m, 2H) ppm. The aldehyde was used immediately after
purification.
114.8 (t, 1JCF = 255.7 Hz), 62.8, 60.8 (dd, 2JCF = 25.7, 24.2 Hz), 56.5,
22.6, 22.4 (3C), 13.8, 10.0 ppm; 19F NMR (282 MHz, CDCl3)
2
3
2
4-O-Benzyl-2,3-O,O-cyclohexylidene-D-threose 2h obtained as
described above (800 mg, 2.76 mmol), (R)-2-methyl-2-propane-
sulfinamide (367 mg, 3.03 mmol), and Ti(OEt)4 (3.14 g, 13.8 mmol)
yielded ent-10S (900 mg, 2.29 mmol, 83%) as a pale yellow oil: Rf 0.7
(PE/EtOAc 50:50); [α]D −104 (c 0.67, EtOH, 23 °C); IR (neat) 2933
δ −110.4 (dd, JFF = 262.2 Hz, JHF = 7.5 Hz), −119.1 (dd, JFF
=
3
262.2 Hz, JHF = 17.2 Hz) ppm; MS (ESI+) (m/z) 349 (M + Na +
MeCN)+; HRMS (MS+) for C11H21F2NNaO3S (M + Na)+ calcd
308.1102, found 308.1106.
Minor Isomer: (3S,SS)-Ethyl 3-(tert-Butylsulfinamino)-2,2-difluoro-
pentanoate (l-11S).
1
(m), 2861 (m), 2359 (m), 2342 (m), 1084 (s); H NMR (400 MHz,
CDCl3) δ 8.09 (d, 3JHH = 4.7 Hz, 1H), 7.39−7.28 (m, 5H), 4.67−4.55
(m, 3H), 4.22 (ddd, 3JHH = 7.5 Hz, 3JHH = 5.6 Hz, 3JHH = 4.4 Hz, 1H),
2
3
2
3.68 (dd, JHH = 10.4 Hz, JHH = 4.4 Hz, 1H), 3.64 (dd, JHH
=
10.4 Hz, 3JHH = 5.6 Hz, 1H), 1.74−1.57 (m, 8H), 1.52−1.31 (m, 2H),
1.14 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 167.6, 137.7, 128.4
(2C), 127.8 (3C), 112.0, 79.0, 77.9, 73.6, 69.8, 57.1, 36.5, 36.1, 25.0,
23.9, 23.7, 22.3 (3C) ppm; MS (ESI+) (m/z) 416 (M + Na)+; HRMS
(MS+) for C21H31NNaO4S (M + Na)+ calcd 416.1866, found
416.1873.
Pale yellow oil: Rf 0.23 (hexane/EtOAc 70:30); [α]D +26.6 (c 0.51,
3
CHCl3, 19 °C); 1H NMR (400 MHz, CDCl3) δ 4.39 (q, JHH
=
3
7.1 Hz, 2H), 3.80−3.66 (m, 1H), 3.57 (d, JHH = 9.3 Hz, 1H), 1.91−
1.78 (m, 1H), 1.66−1.52 (m, 1H), 1.38 (t, 3JHH = 7.1 Hz, 3H), 1.24 (s,
9H), 1.06 (t, 3JHH = 7.4 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3)
δ 163.2 (t, 2JCF = 31.9 Hz), 114.7 (t, 1JCF = 256.4 Hz), 63.3, 60.4 (dd,
2JCF = 25.3, 23.8 Hz), 56.9, 22.7 (3C), 22.3, 13.8, 10.3 ppm; 19F NMR
(282 MHz, CDCl3) δ −109.9 (dd, 2JFF = 264.3, 3JHF = 7.5 Hz),−118.4
(SS,E)-N-[(2R,3R)-4-(Benzyloxy)-2,3-(cyclohexylidenedioxy)-
butylidene]-2-methyl-2-propanesulfinamide (ent-10R).
2
3
(dd, JFF = 264.3 Hz, JHF = 15.6 Hz) ppm; MS (ESI+) (m/z) 308
(M + Na)+; HRMS (MS+) for C11H21F2NNaO3S (M + Na)+ calcd
308.1102, found 308.1106.
Reaction with sulfinylimine 4S (150 mg, 0.522 mmol) yielded 12S
(53:47 dr). Chromatography (hexane/EtOAc 90:10→65:35) afforded
an inseparable mixture of diastereoisomers (125 mg, 0.304 mmol,
58%). Analytical samples of pure diastereoisomers were obtained by
HPLC (hexane/EtOAc 75:25).
4-O-Benzyl-2,3-O,O-cyclohexylidene-D-threose 2h obtained as de-
scribed above (900 mg, 3.1 mmol), (S)-2-methyl-2-propanesulfina-
mide (394 mg, 3.26 mmol), and Ti(OEt)4 (3.54 g, 15.5 mmol) yielded
ent-10R (1.03 g, 2.63 mmol, 85%) as a pale yellow oil: Rf 0.7
(PE/EtOAc 50:50); [α]D +156 (c 0.47, EtOH, 23 °C); IR (neat) 2934
Major Isomer: (3R,SS)-Ethyl 3-(tert-Butylsulfinamino)-2,2-difluoro-
tetradecanoate (ul-12S).
1
(m), 2862 (m), 2359 (m), 2342 (m), 1087 (s); H NMR (400 MHz,
CDCl3) δ 8.11 (d, 3JHH = 4.2 Hz, 1H), 7.39−7.28 (m, 5H), 4.67−4.59
(m, 3H), 4.28 (ddd, 3JHH = 7.5 Hz, 3JHH = 5.2 Hz, 3JHH = 4.2 Hz, 1H),
2
3
2
3.72 (dd, JHH = 10.6 Hz, JHH = 4.2 Hz, 1H), 3.68 (dd, JHH
=
10.6 Hz, 3JHH = 5.2 Hz, 1H), 1.76−1.57 (m, 8H), 1.48−1.35 (m, 2H),
1.20 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 167.2, 137.9, 128.4
(2C), 127.7 (3C), 111.9, 78.7, 77.8, 73.6, 69.7, 57.2, 36.5, 36.0, 25.0,
23.9, 23.7, 22.4 (3C) ppm; MS (ESI+) (m/z) 416 (M + Na)+; HRMS
(MS+) for C21H31NNaO4S (M + Na)+ calcd 416.1866, found
416.1864.
Pale yellow oil: Rf 0.19 (hexane/EtOAc 75:25); [α]D +43.9 (c 0.54,
CHCl3, 21 °C); IR (in CDCl3) 3206 (br w), 2924 (s), 2854 (s), 1774
1
2
(s), 1057 (s) cm−1; H NMR (400 MHz, CDCl3) δ 4.33 (dq, JHH
=
3
2
3
10.9, JHH = 7.2 Hz, 1H), 4.29 (dq, JHH3 = 10.9, JHH = 7.2 Hz, 1H),
3
3
3
3.79 (ddddd app. as ddtd, JHF = 16.1, JHH = 8.8, JHF = 8.6, JHH
=
3
3
8.6, JHH = 3.8 Hz, 1H), 3.10 (d, JHH = 8.8 Hz, 1H), 1.87−1.76 (m,
General Procedure for the Honda−Reformatski Reaction
(Table 3). A mixture of sulfinylimine (1 equiv) and RhCl(PPh3)3
(3 mol %) in THF (7.5 mL/mmol) was cooled to −20 °C. Compound
1 (3 equiv) was added immediately followed by dropwise addition of
Et2Zn (1.0 M in hexane, 2 equiv). The mixture was allowed to warm to
0 °C over 30 min, and stirring was continued for 1 h. Quenching with
satd NH4Cl was followed by extraction with EtOAc. The combined
organic layers were dried (MgSO4), filtered, and concentrated. Purifi-
cation by column chromatography gave the products as pale yellow
oils unless mentioned otherwise.
Reaction with sulfinylimine 3S (100 mg, 0.620 mmol) yielded 11S
(53:47 dr). Chromatography (PE/EtOAc 70:30) afforded an insepa-
rable mixture of diastereoisomers (114 mg, 0.400 mmol, 64%). Analyt-
ical samples of pure diastereoisomers were obtained by HPLC
(hexane/EtOAc 70:30).
1H), 1.73−1.59 (m, 1H), 1.59−1.22 (m, 18H), 1.36 (t, 3JHH = 7.1 Hz,
3H), 1.20 (s, 9H), 0.88 (t, JHH = 7.0 Hz, 3H) ppm; 13C NMR
3
2
1
(101 MHz, CDCl3) δ 163.3 (t, JCF = 33.0 Hz), 114.9 (t, JCF
=
255.4 Hz), 62.9, 59.4 (dd, 2JCF = 26.3 Hz, 2JCF = 23.4 Hz), 56.6, 31.9,
29.6 (4C), 29.3, 29.3 (2C), 25.2, 22.7, 22.5 (3C), 14.1, 13.9 ppm; 19F
2
3
NMR (282 MHz, CDCl3) δ −110.8 (dd, JFF = 261.1 Hz, JHF
=
2
3
8.6 Hz), −118.8 (dd, JFF = 261.1 Hz, JHF = 16.1 Hz) ppm; MS
(ESI+) (m/z) 475 (M + Na + MeCN)+; HRMS (MS+) for
C20H39F2NNaO3S (M + Na)+ calcd 434.2511, found 434.2516.
Minor Isomer: (3S,SS)-Ethyl 3-(tert-Butylsulfinamino)-2,2-difluoro-
tetradecanoate (l-12S).
Major Isomer: (3R,SS)-Ethyl 3-(tert-Butylsulfinamino)-2,2-difluoro-
pentanoate (ul-11S).
Pale yellow oil: Rf 0.17 (hexane/EtOAc 70:30); [α]D +61.9 (c 0.59,
3
CHCl3, 23 °C); 1H NMR (400 MHz, CDCl3) δ 4.38 (q, JHH
=
3
7.2 Hz, 2H), 3.86−3.72 (m, 1H), 3.56 (d, JHH = 9.5 Hz, 1H), 1.80−
1.68 (m, 1H), 1.63−1.49 (m, 2H), 1.41−1.24 (m, 17H), 1.37 (t,
3JHH = 7.2 Hz, 3H), 1.23 (s, 9H), 0.89 (t, 3JHH = 7.1 Hz, 3H) ppm; 13
C
=
NMR (101 MHz, CDCl3) δ 163.2 (t, 2JCF = 32.2 Hz), 114.7 (t, 1JCF
Pale yellow oil: Rf 0.20 (hexane/EtOAc 70:30); [α]D +62.9 (c 0.19,
CHCl3, 21 °C); IR (in CDCl3) 3207 (br), 2982 (m), 1773(s), 1062
2
256.1 Hz), 63.3, 58.9 (t, JCF = 24.9 Hz), 56.9, 31.9, 29.6 (2C), 29.5,
29.3 (2C), 29.1, 28.9, 25.4, 22.7 (3C), 22.7, 14.1, 13.9 ppm; 19F NMR
(s) cm−1; 1H NMR (400 MHz, CDCl3) δ 4.32 (dq, 2JHH = 10.7, 3JHH
=
2
3
7.2 Hz, 1H), 4.29 (dq, 2JHH = 10.7, 3JHH = 7.1 Hz, 1H), 3.81−3.66 (m,
1H), 3.15 (d, 3JHH = 8.9 Hz, 1H), 1.98−1.86 (m, 1H), 1.65−1.52 (m,
1H), 1.36 (t, 3JHH = 7.1 Hz, 3H), 1.20 (s, 9H), 1.14 (t, 3JHH = 7.4 Hz,
(282 MHz, CDCl3) δ −110.1 (dd, JFF = 264.3, JHF = 7.5 Hz, 1F),
−118.3 (dd, 2JFF = 264.3, 3JHF = 16.1 Hz, 1F) ppm; MS (ESI+) (m/z)
475 (M + Na + MeCN)+; HRMS (MS+) for C20H39F2NNaO3S
(M + Na)+ calcd 434.2511, found 434.2513.
3H) ppm; 13C NMR (101 MHz, CDCl3) δ 163.2 (t, JCF = 32.3 Hz),
2
4191
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
Reaction with sulfinylimine 5S (100 mg, 0.395 mmol) yielded 13S
(88:12 dr). Chromatography (hexane/EtOAc 75:25→65:35) afforded
an inseparable mixture of diastereoisomers (68 mg, 0.180 mmol, 46%).
Analytically Pure Sample of the Major Diastereoisomer (3R,SS)-
Ethyl 4-(Benzyloxy)-3-(tert-butylsulfinamino)-2,2-difluorobuta-
noate (ul-13S).
(ESI) (m/z) 455 (M + Na + MeCN)+; HRMS (ESI) for C18H27F2-
NNaO4S (M + Na)+ calcd 414.1521, found 414.1509.
Reaction with sulfinylimine ent-7R (100 mg, 0.374 mmol) yielded
ent-15R (54:46 dr). Chromatography (PE/Et2O 40:60→20:80) af-
forded ent-ul-15R (37 mg, 0.095 mmol, 25%) and ent-l-15R (31 mg,
0.079 mmol, 21%).
Major Isomer: (3R,4S,SS)-Ethyl 4-(Benzyloxy)-3-(tert-butylsulfin-
amino)-2,2-difluoropentanoate (ent-ul-15R).
Pale yellow oil obtained by HPLC (hexane/EtOAc 70:30): Rf 0.31
(hexane/EtOAc 40:60); [α]D +33.1 (c 0.62, CHCl3, 19 °C); IR (neat)
1
3209 (br w), 2982 (br w), 2871 (br w), 1771 (s), 1077 (s) cm−1. H
2
NMR (400 MHz, CDCl3) δ 7.38−7.25 (m, 5H), 4.56 (d, JHH
=
Pale yellow oil: Rf 0.38 (PE/Et2O 20:80); [α]D +30.0 (c 0.62, CHCl3,
23 °C); IR (neat) 3353 (w, br), 2979 (w), 1765 (m), 1079 (s), 1021
(s); H NMR (400 MHz, CDCl3) δ 7.36−7.24 (m, 5H), 4.60 (d,
2
3
11.6 Hz, 1H), 4.49 (d, JHH = 11.6 Hz, 1H), 4.15 (q, JHH = 7.2 Hz,
2H), 4.08−3.95 (m, 2H), 3.92−3.86 (m, 1H), 3.80−3.73 (m, 1H),
1.24 (t, J = 7.2 Hz, 3H), 1.23 (s, 9H) ppm; 13C NMR (101 MHz,
CDCl3) δ162.9 (t, 2JCF = 32.2 Hz), 137.2, 128.4 (2C), 127.84, 127.79
1
2
3
2JHH = 11.0 Hz, 1H), 4.33 (d, JHH = 11.0 Hz, 1H), 4.30 (d, JHH
=
=
3
3
9.1 Hz, 1H), 4.09−3.98 (m, 3H), 3.66 (dddd, JHF=12.8, JHH
1
2
9.1 Hz, 3JHF = 8.9 Hz, 3JHH = 0.9 Hz, 1H), 1.42 (d, 3JHH = 6.4 Hz, 3H),
(2C), 113.8 (t, JCF = 256.1 Hz), 73.6, 67.6, 62.9, 58.6 (t, JCF
=
24.9 Hz), 56.7, 22.4 (3C), 13.8 ppm; 19F NMR (376 MHz, CDCl3)
1.24 (s, 9H), 1.16 (t, JHH = 7.1 Hz, 3H) ppm; 13C NMR (101 MHz,
3
2
3
2
2
δ−112.7 (dd, JFF = 261.8 Hz, JHF 8.7 Hz), −115.7 (dd, JFF
=
CDCl3) δ 162.9 (dd, JCF = 33.7, 30.7 Hz), 137.5, 128.3 (2C), 127.8
261.8 Hz, JHF = 13.0 Hz) ppm; MS (ESI+) (m/z) 400 (M + Na)+;
HRMS (MS+) for C17H25F2NNaO4S (M + Na)+ calcd 400.1365,
found 400.1364.
3
1
3
(2C), 127.7, 113.8 (t, JCF = 255.4 Hz), 70.7, 70.4 (d, JCF = 2.9 Hz),
64.1 (dd, JCF = 27.8 Hz, 2JCF = 23.4 Hz), 62.7, 56.8, 22.5 (3C), 16.6,
2
13.7 ppm; 19F NMR (282 MHz, CDCl3) δ −109.9 (dd, JFF
=
2
257.9 Hz, 3JHF = 8.9 Hz), −114.7 (dd, 2JFF = 257.9 Hz, 3JHF = 12.8 Hz)
ppm; MS (ESI+) (m/z) 414 (M + Na)+; HRMS (MS+) for
C18H27F2NNaO4S (M + Na)+ calcd 414.1521, found 414.1526.
Minor Isomer: (3S,4S,SS)-Ethyl 4-(Benzyloxy)-3-(t-butylsulfinamino)-
2,2-difluoropentanoate (ent-l-15R).
Reaction with sulfinylimine ent-7S (100 mg, 0.374 mmol) yielded
ent-15S (94:6 dr). Chromatography (PE/Et2O 40:60→20:80) af-
forded ent-ul-15S (80 mg, 0.204 mmol, 54%) as a white solid and ent-
l-15S (4 mg, 0.010 mmol, 3%) as a pale yellow oil.
Major isomer: (3S,4S,RS)-ethyl 4-(benzyloxy)-3-(tert-butylsulfin-
amino)-2,2-difluoropentanoate (ent-ul-15S):
Pale yellow oil: Rf 0.22 (PE/Et2O 20:80); [α]D +37.7 (c 0.53, CHCl3,
23 °C); IR (neat) 3213 (w, br), 2981 (w), 1770 (m), 1097 (s), 1055
Rf 0.10 (PE/Et2O 40:60); mp 109−111 °C; [α]D −4.2 (c 0.14, CHCl3,
23 °C); IR (neat) 3213 (w, br), 2982 (w), 1771 (s), 1099 (s), 1054
1
(s); H NMR (400 MHz, CDCl3) δ 7.37−7.24 (m, 5H), 4.51 (d,
1
2
2JHH = 11.2 Hz, 1H), 4.39 (d, JHH = 11.2 Hz, 1H), 4.08−3.92 (m,
(s); H NMR (400 MHz, CDCl3) δ 7.37−7.25 (m, 5H), 4.57 (d,
2
2JHH = 11.1 Hz, 1H), 4.38 (d, JHH = 11.1 Hz, 1H), 4.05−3.85 (m,
3H), 3.76−3.68 (m, 1H), 3.68 (d, 3JHH = 9.3 Hz, 1H), 1.32 (d, 3JHH
=
3H), 3.80 (dq app. as quin, 3JHH = 6.3 Hz, 1H), 3.71 (d, 3JHH = 9.5 Hz,
1H), 1.44 (d, 3JHH = 6.3 Hz, 3H), 1.24 (s, 9H), 1.16 (t, 3JHH = 7.1 Hz,
6.1 Hz, 3H), 1.24 (s, 9H), 1.18 (t, 3JHH = 7.1 Hz, 3H) ppm; 13C NMR
2
2
(101 MHz, CDCl3) δ 162.7 (dd, JCF = 32.2 Hz, JCF = 30.7 Hz),
2
3H) ppm; 13C NMR (101 MHz, CDCl3) δ 163.0 (t, JCF = 32.2 Hz),
137.4, 128.3 (2C), 128.0 (2C), 127.8, 113.8 (t, 1JCF = 254.7 Hz), 73.9,
137.4, 128.3 (2C), 128.2 (2C), 127.9, 114.2 (t, 1JCF = 254.7 Hz), 74.9,
71.0, 62.8, 62.7 (dd, JCF = 23.4 Hz, 2JCF = 22.0 Hz), 57.1, 22.7 (3C),
2
2
16.6, 13.7 ppm; 19F NMR (282 MHz, CDCl3) δ −109.6 (dd, JFF
=
2
71.4, 63.3 (t, JCF = 23.4 Hz), 62.6, 57.0, 22.5 (3C), 16.4, 13.7 ppm;
2
3
19F NMR (282 MHz, CDCl3) δ −110.0 (dd, JFF = 262.2 Hz, JHF
=
262.2 Hz, 3JHF = 8.6 Hz), −117.3 (dd, 2JFF = 262.2 Hz, 3JHF = 17.2 Hz)
ppm; MS (ESI) (m/z) 455 (M + Na + MeCN)+; HRMS (MS+) for
C18H27F2NNaO4S (M + Na)+ calcd 414.1521, found 414.1524.
Reaction with sulfinylimine 8S (109 mg, 0.467 mmol) yielded ul-
16S as a single diastereoisomer. Chromatography (PE/EtOAc 70:30→
50:50) afforded ul-16S (103 mg, 0.288 mmol, 62%) as a white solid.
Major isomer: (3R,4S,SS)-ethyl 4,5-isopropylidenedioxy-3-(tert-
butylsulfinylamino)-2,2-difluoropentanoate (ul-16S):
2
3
8.6 Hz), −115.2 (dd, JFF = 262.2 Hz, JHF = 12.9 Hz). MS (ESI+)
(m/z) 414 (M + Na)+; HRMS (MS+) for C18H27F2NNaO4S
(M + Na)+ calcd 414.1521, found 414.1525.
Minor isomer: (3R,4S,RS)-ethyl-4-(benzyloxy)-3-(tert-butylsulfin-
amino)-2,2-difluoropentanoate (ent-l-15S):
Rf 0.20 (PE/Et2O 40:60); [α]D −33.5 (c 0.07, CHCl3, 23 °C); IR
1
(neat) 2980 (w), 1770 (m), 1108 (s), 1082 (s), 1026 (s); H NMR
2
(400 MHz, CDCl3) δ 7.38−7.25 (m, 5H), 4.56 (d, JHH = 11.1 Hz,
1H), 4.36 (d, 2JHH = 11.1 Hz, 1H), 4.31 (d, 3JHH = 10.5 Hz, 1H), 4.09
Rf 0.26 (PE/EtOAc 50:50); mp 88−90 °C; [α]D +30.3 (c 0.29, CHCl3,
23 °C); IR (neat) 3194 (w), 2986 (w), 1777 (m), 1761 (m), 1053 (s);
1H NMR (300 MHz, CDCl3) δ 4.38−4.11 (m, 5H), 3.96 (dddd,
(qd, 3JHH = 7.1 Hz, 2JHH = 6.7 Hz, 1H), 4.07 (qd, 3JHH = 7.1 Hz, 2JHH
=
6.7 Hz, 1H), 4.00 (qt, 3JHH = 6.3 Hz, 3JHH = 1.7 Hz, 1H), 3.74 (dddd,
3JHF=12.4 Hz, 3JHH = 10.5 Hz, 3JHF = 8.7 Hz, 3JHH = 1.8 Hz, 1H), 1.29
(d, 3JHH = 6.3 Hz, 3H), 1.27 (s, 9H), 1.20 (t, 3JHH = 7.1 Hz, 3H) ppm;
13C NMR (101 MHz, CDCl3) δ 137.7, 128.3 (2C), 127.8 (3C), 113.6
3
3
3
3JHF=17.4 Hz, JHH = 8.7 Hz, JHF = 8.2 Hz, JHH = 7.2 Hz, 1H), 3.54
(d, 3JHH = 8.7 Hz, 1H), 1.39 (s, 3H), 1.34 (t, 3JHH = 7.2 Hz, 3H), 1.29
(s, 3H), 1.21 (s, 9H) ppm; 13C NMR (75 MHz, CDCl3) δ 162.9 (t,
1
1
2JCF = 30.8 Hz), 113.8 (dd, JCF = 256.4 Hz, JCF = 252.5 Hz), 110.6,
1
3
2
(t, JCF = 257.6 Hz), 72.1 (d, JCF = 2.9 Hz), 71.1, 63.0 (t, JCF
=
2
2
24.9 Hz), 63.0, 57.2, 22.9 (3C), 16.6, 13.7 ppm (The CO signal was not
observed). 19F NMR (282 MHz, CDCl3) δ −108.0 (dd, 2JFF = 262.2 Hz,
3JHF = 8.7 Hz), −114.6 (dd, 2JFF = 262.2 Hz, 3JHF = 12.4 Hz) ppm; MS
73.6, 66.8, 63.0, 61.1 (dd, JCF = 22.6 Hz, JCF = 21.5 Hz), 57.1, 25.9,
24.9, 22.4 (3C), 13.7 ppm; 19F NMR (282 MHz, CDCl3) δ −110.0
2
3
2
(dd, JFF = 262.6 Hz, JHF = 8.2 Hz), −119.4 (dd, JFF = 262.6 Hz,
4192
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
3JHF = 17.4 Hz) ppm; MS (ESI+) (m/z) 421 (M + Na + MeCN)+;
HRMS (MS+) for C14H25F2NNaO5S (M + Na)+ calcd 380.1314,
found 380.1312.
−118.1 (dd, 2JFF = 262.2 Hz, 3JHF = 12.9 Hz) ppm; MS (ESI+) (m/z)
421 ((M + Na + MeCN)+, 100). HRMS (MS+) for C14H26F2NO5S
(M + H)+ calcd 358.1500, found 358.1498.
Minor Isomer: (3S,4S,SS)-Ethyl 4,5-Isopropylidenedioxy-3-(tert-
butylsulfinylamino)-2,2-difluoropentanoate (l-16S).
Reaction with sulfinylimine 9S (100 mg, 0.366 mmol) yielded
ul-17S (single diastereoisomer). Chromatography (PE/EtOAc
65:35→50:50) afforded ul-17S (75 mg, 0.189 mmol, 52%).
(3R,4S,SS)-Ethyl 4,5-cyclohexylidenedioxy-3-(tert-butylsulfinyl-
amino)-2,2-difluoropentanoate (ul-17S).
Isolated from an unselective reaction, pale yellow oil: [α]D +6.2
(c 0.17, CHCl3, 23 °C); IR (neat) 2991 (w), 1770 (s), 1137 (s), 1123
1
3
(s), 1107 (s); H NMR (300 MHz, CDCl3) δ 4.51 (ddd, JHH
=
3
3
7.1 Hz, JHH = 6.1 Hz, JHH = 2.2 Hz, 1H), 4.45−4.32 (m, 2H), 4.11
(dd, 2JHH = 8.2 Hz, 3JHH = 7.1 Hz, 1H), 4.14 (d, 3JHH = 10.4 Hz, 1H),
White solid: Rf 0.23 (PE 40−60 °C/EtOAc 50:50); mp 112−116 °C;
[α]D +28.3 (c 0.56, CHCl3, 23 °C); IR (neat) 3203 (br, w), 2937 (m),
1761 (m), 1092 (m), 1050 (s); 1H NMR (400 MHz, CDCl3) δ 4.37−
4.06 (m, 5H), 3.96 (dddd, 3JHF=17.2 Hz, 3JHF = 8.6 Hz, 3JHH = 8.5 Hz,
3
3
3
3
3.85 (dddd, JHF = 16.3 Hz, JHH = 10.4 Hz, JHF = 6.1 Hz, JHH
=
2.2 Hz, 1H), 3.80 (dd, 2JHH = 8.2 Hz, 3JHH = 6.1 Hz, 1H), 1.44 (s, 3H),
1.38 (t, 3JHH = 7.2 Hz, 3H), 1.33 (s, 3H), 1.26 (s, 9H) ppm; 13C NMR
3
3JHH = 7.3 Hz, 1H), 3.54 (d, JHH = 8.5 Hz, 1H), 1.70−1.45 (m, 8H),
2
1
(75 MHz, CDCl3) δ 162.7 (t, JCF = 31.4 Hz), 113.5 (dd, JCF = 261
1
3
3
Hz, JCF = 256 Hz), 110.2, 72.1 (d, JCF = 3.3 Hz), 66.1, 63.5, 59.4
1.44−1.28 (m, 2H), 1.35 (t, JHH = 7.1 Hz, 3H), 1.21 (s, 9H) ppm;
(t, JCF = 24.8 Hz), 57.3, 26.1, 24.4, 22.6 (3C), 13.7 ppm; 19F NMR
2
13C NMR (101 MHz, CDCl3) δ 162.8 (t, JCF = 30.7 Hz), 113.9 (dd,
2
2
3
1
1JCF = 256.1 Hz, JCF = 251.8 Hz), 111.3, 73.2, 66.5, 62.9, 61.1 (t,
(282 MHz, CDCl3) δ −107.0 (dd, JFF = 265.7 Hz, JHF = 6.1 Hz),
−117.9 (dd, 2JFF = 265.7 Hz, 3JHF = 16.3 Hz) ppm; HRMS (MS+) for
C14H25F2NNaO5S (M + Na)+ calcd 380.1314, found 380.1305.
Reaction with sulfinylimine 8R (150 mg, 0.643 mmol) yielded 16R
(88:12 dr). Chromatography (PE/EtOAc 75:25→70:30) afforded
ul-16R (120 mg, 0.336 mmol, 52%) and l-16R (15 mg, 0.042 mmol,
7%) as white solids.
2JCF = 22.0 Hz), 57.1, 35.6, 34.2, 24.9, 23.8, 23.6, 22.4 (3C), 13.8 ppm;
2
3
19F NMR (282 MHz, CDCl3) δ −109.5 (dd, JFF = 264.3 Hz, JHF
=
2
3
8.6 Hz), −118.9 (dd, JFF = 264.3 Hz, JHF = 17.2 Hz) ppm; MS
(ESI+) (m/z) 461 (M + Na + MeCN)+; HRMS (MS+) for
C17H30F2NO5S (M + H)+ calcd 398.1807, found 398.1804.
Reaction with sulfinylimine 9R (100 mg, 0.366 mmol) yielded 17R
(81:19 dr). Chromatography (PE/EtOAc 80:20→65:35) afforded
ul-17R (70 mg, 0.176 mmol, 48%) and l-17R (12 mg, 0.030 mmol,
8%) as white solids.
Major isomer: (3S,4S,RS)-ethyl 4,5-isopropylidenedioxy-3-(tert-
butylsulfinylamino)-2,2-difluoropentanoate (ul-16R):
Major isomer: (3S,4S,RS)-ethyl 4,5-cyclohexylidenedioxy-3-
(t-butylsulfinylamino)-2,2-difluoropentanoate (ul-17R):
Rf 0.50 (hexane/EtOAc 50:50); mp 84−86 °C; [α]D −62.5 (c 0.81,
CHCl3, 21 °C); IR (neat) 3313 (br w), 2985 (br m), 1771 (s), 1077
1
(s) cm−1; H NMR (400 MHz, CDCl3) δ 4.54−4.40 (m, 1H), 4.38−
2
3
4.25 (m, 3H), 4.15 (dd, JHH = 8.5 Hz, JHH = 7.8 Hz, 1H), 4.10 (dd,
2JHH = 8.5 Hz, JHH = 6.6 Hz, 1H), 3.91−3.77 (m, 1H), 1.45 (s, 3H),
3
Rf 0.21 (PE/EtOAc 65:35); mp 72−75 °C; [α]D −29.9 (c 0.68,
CHCl31, 21 °C); IR (neat) 3311 (br w), 2935 (m), 1770 (s), 1075 (s)
1.38 (s, 3H), 1.36 (t, 3JHH = 7.2 Hz, 3H), 1.24 (s, 9H) ppm; 13C NMR
2
1
3
cm−1; H NMR (400 MHz, CDCl3) δ 4.43 (t, JHH = 7.2 Hz, 1H),
(101 MHz, CDCl3) δ 162.7 (t, JCF = 30.7 Hz), 113.9 (dd, JCF
=
259.1 Hz, 1JCF = 254.7 Hz), 110.4, 70.8 (d, JCF = 2.9 Hz), 66.2, 63.0,
3
4.39−4.24 (m, 3H), 4.16−4.07 (m, 2H), 3.90−3.76 (m, 1H), 1.70−
57.9 (t, JCF = 25.6 Hz), 56.7, 26.2, 25.6, 22.5 (3C), 13.9 ppm; 19F
2
1.51 (m, 8H), 1.46−1.33 (m, 2H), 1.37 (t, 3JHH = 7.2 Hz, 3H), 1.25 (s,
2
3
9H) ppm; 13C NMR (101 MHz, CDCl3) δ 162.7 (t, JCF = 30.7 Hz),
2
NMR (282 MHz, CDCl3) δ −108.9 (dd, JFF = 262.2 Hz, JHF
=
2
3
1
3
8.6 Hz), −118.1 (dd, JFF = 262.2 Hz, JHF = 17.2 Hz) ppm; MS
(ESI+) (m/z) 421 ((M + Na + MeCN)+; HRMS (MS+) for
C14H26F2NO5S (M + H)+ calcd 358.1500, found 358.1494.
Minor isomer: (3R,4S,RS)-ethyl 4,5-isopropylidenedioxy-3-(tert-
butylsulfinylamino)-2,2-difluoropentanoate (l-16R):
113.9 (t, JCF = 259.1 Hz), 111.0, 70.5 (d, JCF = 2.9 Hz), 65.9, 63.0,
2
58.0 (t, JCF = 26.3 Hz), 56.7, 35.7, 35.4, 25.0, 23.9, 23.7, 22.5 (3C),
13.9 ppm; 19F NMR (282 MHz, CDCl3) δ −108.9 (dd, JFF
=
2
262.2 Hz, 3JHF = 8.6 Hz), −117.8 (dd, 2JFF = 262.2 Hz, 3JHF = 17.2 Hz)
ppm; MS (ESI+) (m/z) 461 (M + Na + MeCN)+; HRMS (MS+) for
C17H30F2NO5S (M + H)+ calcd 398.1807, found 398.1808.
Minor isomer: (3R,4S,RS)-ethyl 4,5-cyclohexylidenedioxy-3-(tert-
butylsulfinylamino)-2,2-difluoropentanoate (l-17R):
Rf 0.32 (hexane/EtOAc 50:50); mp 86−88 °C; [α]D −22.6 (c 0.06,
CHCl3, 22 °C); IR (neat) 3205 (br w), 2986 (br m), 1775 (s), 1065
1
(s) cm−1; H NMR (400 MHz, CDCl3) δ 4.43−4.22 (m, 3H), 4.14
(dd, 2JHH = 8.6 Hz, 3JHH = 6.4 Hz, 1H), 4.07−3.94 (m, 1H), 3.88 (dd,
3
3
2JHH = 8.6 Hz, JHH = 6.3 Hz, 1H), 3.65 (d, JHH = 9.0 Hz, 1H), 1.39
Rf 0.12 (PE/EtOAc 65:35); mp 122−124 °C; [α]D −39.0 (c 0.50,
CHCl31, 19 °C); IR (neat) 3204 (br w), 2937 (m), 1762 (s), 1053 (s)
3
(s, 3H), 1.38 (t, JHH = 7.2 Hz, 3H), 1.33 (s, 3H), 1.25 (s, 9H) ppm;
13C NMR (101 MHz, CDCl3) δ 162.6 (t, JCF = 30.8 Hz), 113.6 (dd,
2
2
3
cm−1; H NMR (400 MHz, CDCl3) δ 4.36 (dq, JHH = 10.7, JHH
=
1JCF = 257.5, 253.8 Hz), 110.5, 73.7 (d, 3JCF = 2.9 Hz), 67.1, 63.3, 61.0
7.2 Hz, 1H), 4.30 (dq, 2JHH = 10.7, 3JHH = 7.2 Hz, 1H), 4.25−4.18 (m,
1H), 4.15−4.08 (m, 1H), 3.98 (dddd app. ddt, 3JHF = 16.1, 3JHH = 9.1,
(t, JCF = 22.0 Hz), 57.2, 26.1, 25.1, 22.6 (3C), 13.8 ppm; 19F NMR
2
2
3
3
(282 MHz, CDCl3) δ −109.1 (dd, JFF = 262.2 Hz, JHF 8.6 Hz),
3JHF =3 JHH = 8.6 Hz, 1H), 3.83 (dd, JHH = 8.6, 6.3 Hz, 1H), 3.67 (d,
4193
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
3JHH = 9.1 Hz, 1H), 1.63−1.48 (m, 8H), 1.43−1.31 (m, 2H), 1.36 (t,
3JHH = 7.2 Hz, 3H), 1.23 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3)
δ 162.6 (t, 2JCF = 30.7 Hz), 113.7 (dd, 1JCF = 256.1 Hz, 1JCF 253.2 Hz),
111.2, 73.2 (br. s), 66.8, 63.2, 61.1 (t, 2JCF = 22.0 Hz), 57.1, 35.8, 34.4,
24.9, 23.8, 23.6, 22.6 (3C), 13.8 ppm; 19F NMR (282 MHz, CDCl3) δ
3JHF = 17.2 Hz) ppm; MS (ESI+) (m/z) 540 (M + Na)+;HRMS
(MS+) for C25H38F2NO6S (M + H)+ calcd 518.2382, found 518.2378.
Minor Isomer: (3S,4R,5R,SS)-Ethyl 6-(Benzyloxy)-3-(tert-butylsulfi-
nylamino)-4,5- (cyclohexylidenedioxy)-2,2-difluorohexanoate (ent-
l-18R).
−108.6 (dd, 2JFF = 262.8, 3JHF = 8.6 Hz), −118.3 (d, 2JFF = 262.2, 3JHF
=
16.1 Hz) ppm; MS (ESI+) (m/z) 461 (M + Na + MeCN; HRMS
(MS+) for C17H30F2NO5S (M + H)+ calcd 398.1807, found 398.1814.
Reaction with sulfinylimine ent-10S (2.06 g, 5.24 mmol) yielded
ent-ul-18S (single diastereoisomer). Chromatography (PE/EtOAc
75:25→60:40) afforded ent-ul-18S (1.81 g, 3.50 mmol, 67%).
(3S,4R,5R,RS)-Ethyl [6-(Benzyloxy)-3-(tert-butylsulfinylamino)-4,5-
(cyclohexylidenedioxy)-2,2-difluorohexanoate (ent-ul-18S).
Pale yellow oil: Rf 0.18 (PE/EtOAc 70:30); [α]D +28.3 (c 0.72,
CHCl3, 20 °C); IR (neat) 2936 (s), 2863 (w), 1773 (m), 1760 (m),
1057 (s); 1H NMR (400 MHz, CDCl3) δ 7.40−7.24 (m, 5H), 4.57 (s,
2
3
2
2H), 4.36 (dq, JHH = 10.7 Hz, JHH = 7.2 Hz, 1H), 4.31 (dq, JHH
=
10.7 Hz, 3JHH = 7.2 Hz, 1H), 4.30−4.23 (m, 1H), 4.09−3.95 (m, 2H),
3.83 (d, 3JHH = 9.2 Hz, 1H), 3.63 (dd, 2JHH = 10.0 Hz, 3JHH = 5.3 Hz,
2
3
1H), 3.58 (dd, JHH = 10.0 Hz, JHH = 4.9 Hz, 1H), 1.68−1.47 (m,
3
8H), 1.41−1.32 (m, 2H), 1.36 (t, JHH = 7.2 Hz, 3H), 1.15 (s, 9H)
ppm; 13C NMR (101 MHz, CDCl3) δ 162.8 (t, 2JCF = 31.1 Hz), 137.6,
Pale yellow oil: Rf 0.35 (PE/EtOAc 50:50); [α]D +43.2 (c 0.35,
CHCl3, 22 °C); IR (neat) 3244 (w), 2936 (m), 2360 (m), 1774 (m),
1
1
128.5 (2C), 128.0 (2C), 127.9, 113.8 (dd, JCF = 256.5 Hz, JCF
=
255.0 Hz), 111.4, 77.5, 76.0 (t, 3JCF = 2.6 Hz), 73.7, 71.1, 63.2, 60.7 (t,
2JCF = 22.7 Hz), 57.2, 36.4, 36.3, 25.0, 23.8, 23.7, 22.5 (3C), 13.8 ppm;
1
1759 (m), 1060 (s); H NMR (400 MHz, CDCl3) δ 7.40−7.27 (m,
3
3
5H), 4.62 (d, JHH = 6.4 Hz, 1H), 4.56 (s, 2H), 4.49 (ddd, JHH
=
19F NMR (282 MHz, CDCl3) δ −108.4 (d, JFF = 262.2 Hz), −116.8
2
3
3
2
8.8 Hz, JHH = 6.8 Hz, JHH = 4.4 Hz, 1H), 4.32 (dq, JHH = 10.7 Hz,
(d, 2JFF = 262.2 Hz) ppm; MS (ESI+) (m/z) 540 (M + Na)+; HRMS
(MS+) for C25H37F2NNaO6S (M + Na)+ calcd 540.2202, found
540.2192.
3JHH = 7.1 Hz, 1H), 4.28 (dq, 2JHH = 10.7 Hz, 3JHH = 7.1 Hz, 1H), 4.13
3
3
3
(dd, JHH = 8.5 Hz, JHH = 6.8 Hz, 1H), 3.99 (dddd, JHF = 17.2 Hz,
3JHH = 8.5 Hz, JHF = 7.5 Hz, JHH = 6.4 Hz, 1H), 3.88 (dd, JHH
=
=
=
3
3
2
3
2
3
8.8 Hz, JHH = 4.4 Hz, 1H), 3.38 (dd app. t, JHH = 8.8 Hz, JHH
ASSOCIATED CONTENT
3
■
8.8 Hz, 1H), 1.74−1.61 (m, 1H), 1.61−1.45 (m, 7H), 1.36 (t, JHH
S
7.1 Hz, 3H), 1.44−1.26 (m, 2H), 1.08 (s, 9H) ppm; 13C NMR
* Supporting Information
Characterization data for known compounds, copies of 19F
2
(101 MHz, CDCl3) δ 163.1 (t, JCF = 30.7 Hz), 136.9, 128.6 (2C),
128.1 (3C), 114.0 (dd, 1JCF = 257.6 Hz, 1JCF = 251.8 Hz), 111.6, 76.5,
NMR spectra of the crude Honda−Reformatsky reaction
1
76.2, 73.9, 71.1, 62.8, 61.7 (t, JCF = 22.0 Hz), 56.4, 36.3, 35.7, 24.9,
mixtures, and copies of H, 13C, and 19F NMR spectra of all
2
23.7, 23.6, 22.5 (3C), 13.8 ppm; 19F NMR (282 MHz, CDCl3) δ
novel compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
2
3
2
−110.8 (dd, JFF = 260.0 Hz, JHF = 7.5 Hz), −121.4 (dd, JFF
=
260.0 Hz, JHF = 17.2 Hz) ppm; MS (ESI+) (m/z) 540 (M + Na)+;
HRMS (MS+) for C25H38F2NO6S (M + H)+ calcd 518.2382, found
518.2377.
3
AUTHOR INFORMATION
Corresponding Authors
*Fax: +44 23 8059 7574. E-mail: thomas.poisson@insa-rouen.fr.
*E-mail: bruno.linclau@soton.ac.uk.
■
Reaction with sulfinylimine ent-10R (100 mg, 0.254 mmol) yielded
ent-18R (60:40 dr). Chromatography (PE/EtOAc 75:25→70:30)
afforded ent-ul-18R (41 mg, 0.079 mmol, 31%) and ent-l-18R (22 mg,
0.043 mmol, 17%).
Major Isomer: (3R,4R,5R,SS)-Ethyl-6-(Benzyloxy)-3-(tert-butyl-
sulfinylamino)-4,5- (cyclohexylidenedioxy)-2,2-difluorohexanoate
(ent-ul-18R).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The European Community (INTERREG IVa Channel Pro-
gramme, IS:CE-Chem, project 4061) is thanked for financial
support.
REFERENCES
■
(1) Kirsch, P. In Modern Fluororganic Chemistry; Wiley-VCH:
Weinheim, 2004.
Pale yellow oil: Rf 0.37 (PE/EtOAc 70:30); [α]D +50.8 (c 0.53,
CHCl3, 20 °C); IR (neat) 2936 (s), 2863 (w), 1773 (m), 1760 (m),
1073 (s); 1H NMR (400 MHz, CDCl3) δ 7.40−7.24 (m, 5H), 4.63 (d,
́ ́
(2) J.-P. Begue, D. Bonnet-Delpon In Bioorganic and Medicinal
Chemistry of Fluorine; John Wiley & Sons, Inc.: Hoboken, NJ, 2008.
(3) Jeschke, P. ChemBioChem 2004, 5, 570.
2
2JHH = 12.1 Hz, 1H), 4.59 (d, JHH = 12.1 Hz, 1H), 4.51−4.44 (m,
2
3
2
2H), 4.30 (dq, JHH = 10.7 Hz, JHH = 7.2 Hz, 1H), 4.26 (dq, JHH
=
(4) O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071−1081.
(5) Bremer, M.; Kirsch, P.; Klasen-Memmer, M.; Tarumi, K. Angew.
Chem., Int. Ed. 2013, 52, 8880−8896.
3
3
10.7 Hz, JHH = 7.2 Hz, 1H), 4.20 (d, JHH = 8.7 Hz, 1H), 4.05 (ddd,
3JHF = 17.2 Hz, JHH = 8.7 Hz, JHH = 7.5 Hz, 1H), 3.78 (dd, JHH
=
3
3
2
10.1 Hz, 3JHH = 4.2 Hz, 1H), 3.62 (dd, 2JHH = 10.1 Hz, 3JHH = 6.4 Hz,
(6) Acena, J. L.; Sorochinsky, A. E.; Soloshonok, V. A. Synthesis 2012,
44, 1591−1602.
3
1H), 1.77−1.47 (m, 8H), 1.44−1.30 (m, 2H), 1.33 (t, JHH = 7.2 Hz,
3H), 1.24 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 162.8 (t,
(7) Sorochinsky, A. E.; Soloshonok, V. A. J. Fluorine Chem. 2010,
131, 127−139.
2JCF = 33.7 Hz), 137.9, 128.3 (2C), 127.6 (3C), 114.0 (dd, JCF
=
1
259.1 Hz, 1JCF = 254.7 Hz), 110.8, 74.3, 74.2 (d, JCF = 2.9 Hz), 73.6,
3
(8) Fustero, S.; Sanz-Cervera, F. F.; Acena, J. L.; Sanchez-Rosello, M.
Synlett 2009, 525−549.
2
69.5, 62.9, 57.7 (t, JCF = 24.9 Hz), 56.7, 36.6, 36.1, 24.9, 23.8, 23.7,
22.5 (3C), 13.9 ppm; 19F NMR (282 MHz, CDCl3) δ −109.1 (dd,
(9) Salwicek, M.; Nyakatura, E. K.; Gerling, U. I. M.; Ye, S.; Koksch,
B. Chem. Soc. Rev. 2012, 41, 2135−2171.
3
2
2JFF = 257.9 Hz, JHF = 7.5 Hz), −117.9 (dd, JFF = 257.9 Hz,
4194
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195

The Journal of Organic Chemistry
Note
(10) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
(43) Fustero, S.; Herrera, L.; Lazaro, R.; Rodriguez, E.; Maestro, M.
A.; Mateu, N.; Barrio, P. Chem.Eur. J. 2013, 19, 11776−11785.
(44) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57,
6387−6389.
(45) Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12−13.
(46) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051−2054.
(47) Kolodney, G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I.
Angew. Chem., Int. Ed. 2007, 46, 9291−9294.
(48) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396−3397.
(49) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913−9914.
(50) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887−2896.
(51) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66,
8772−8778.
(52) Enders, D.; Berg, S. V.; Jandeleit, B. Org. Synth. 2002, 78, 177.
(53) Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6−13.
(54) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60,
585−587.
(55) Sishido, K.; Takahashi, K.; Oshio, Y.; Fukumoto, K.; Kametani,
T.; Honda, T. Heterocycles 1988, 27, 495−508.
̈
Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637−
̈
643.
(11) Morgenthaler, M.; Schweizer, E.; Hoffmann-Roder, A.; Benini,
̈
F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.;
Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Muller, K.
̈
ChemMedChem 2007, 2, 1100−1115.
(12) Lankin, D. C.; Chandrakumar, N. S.; Rao, S. N.; Spangler, D. P.;
Snyder, J. P. J. Am. Chem. Soc. 1993, 115, 3356−3357.
(13) March, T. L.; Johnston, M. R.; Duggan, P. J.; Gardiner, J. Chem.
Biodiversity 2012, 9, 2410−2440.
(14) Mikami, K.; Fustero, S.; Sanchez-Rosello, M.; Acena, J. L.;
Soloshonok, V.; Sorochinsky, A. Synthesis 2011, 3045−3079.
(15) Qiu, X.-L.; Qing, F.-L. Eur. J. Org. Chem. 2011, 3261−3278.
(16) Yoshinari, T.; Gessier, F.; Noti, C.; Beck, A. K.; Seebach, D.
Helv. Chem. Acta 2011, 94, 1908−1942.
(17) Soloshonok, V. A.; Ohkura, H.; Sorochinsky, A.; Voloshin, N.;
Markovsky, A.; Belik, M.; Yamazaki, T. Tetrahedron Lett. 2002, 43,
5445−5448.
(18) Staas, D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R. G.
J. Org. Chem. 2002, 67, 8276−8279.
(19) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869−8905.
(20) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600−3740.
(21) Choppin, S.; Ferreiro-Medeiros, L.; Barbarotto, M.; Colobert, F.
Chem. Soc. Rev. 2013, 42, 937−949.
(22) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion, J.-C. J. Org.
Chem. 1999, 64, 8461−8464.
(23) Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.; Watanabe, H.;
Kinoshita, T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org. Chem. 2004,
69, 1634−1645.
(24) Niida, A.; Tomita, K.; Mizumono, M.; Tanigaki, H.; Terada, T.;
Oishi, S.; Otaka, A.; Inui, K.-I.; Fuji, N. Org. Lett. 2006, 8, 613−616.
(25) Tarui, A.; Kondo, K.; Taira, H.; Sato, K.; Omote, M.; Kumadaki,
I.; Ando, A. Heterocycles 2007, 73, 203−208.
(26) March, T. L.; Johnston, M. R.; Duggan, P. J. Org. Lett. 2012, 14,
182−185.
(27) Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa, S.; Hashimoto, A.;
Iitaka, Y.; Kobayashi, Y. Tetrahedron Lett. 1988, 29, 5291−5294.
(28) Baldwin, J. E.; Lynch, G. P.; Schofield, C. Tetrahedron 1992, 48,
9085−9100.
(29) Dondoni, A.; Massi, A.; Sabbatini, S. Chem.Eur. J. 2005, 11,
7110−7125.
(30) Buesking, A. W.; Baguley, T. D.; Ellman, J. A. Org. Lett. 2011,
13, 964−967.
(31) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278−1284.
(32) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D. L.;
Zhang, H. J. Org. Chem. 1999, 64, 1403−1406.
(33) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948−9957.
(34) Poisson, T.; Belhomme, M.-C.; Pannecoucke, X. J. Org. Chem.
2012, 77, 9277−9285.
(35) Ivashkin, I.; Couve- Bonnaire, S.; Jubault, P.; Pannecoucke, X.
Org. Lett. 2012, 14, 2270−2273.
(36) Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2, 2549−
2551.
(37) Honda, T.; Wakabayashi, H.; Kanai, K. Chem. Pharm. Bull. 2002,
50, 307−308.
(38) Adrian, J. C., Jr.; Snapper, M. L. J. Org. Chem. 2003, 68, 2143−
2150.
(39) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P. Angew.
Chem., Int. Ed. 2010, 49, 4665−4668.
(40) Cee, V. J.; Cramer, C. J.; Evans, D. A. J. Am. Chem. Soc. 2006,
128, 2920−2930.
(41) (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74,
5828−5835. (b) Reetz, M. T.; Huellmann, M.; Seitz, T. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 477−480.
(42) Brinner, K.; Doughan, B.; Poon, D. J. Synlett 2009, 991−993.
4195
dx.doi.org/10.1021/jo500396p | J. Org. Chem. 2014, 79, 4186−4195