Stereodivergent synthesis of alkenes by controllable syn-/anti-fragmentation of β-hydroxysulfonyl intermediates

Article abstract of DOI:10.1039/c9ob01563a

The reduction of the carbonyl group in acylated trifluoroethyl alkanesulfonates follows the Felkin-Ahn selectivity, and the so-formed diastereomeric β-hydroxysulfonyl intermediates undergo syn- and anti-fragmentation, depending on the reaction conditions. In effect, isomeric E- and Z-alkenes are formed in a stereodivergent manner, which mimics the mechanistic manifold of the Peterson olefination.

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Stereodivergent synthesis of alkenes by controllable
syn-/anti-fragmentation of β-hydroxysulfonyl intermediates
Received 00th January 20xx,
Accepted 00th January 20xx
Bartosz Górski, Dariusz Basiak, Łukasz Grzesiński and Michał Barbasiewicz*
DOI: 10.1039/x0xx00000x
Reduction of the carbonyl group in acylated trifluoroethyl
alkanesulfonates follows the Felkin-Ahn selectivity, and so-formed
diastereomeric β-hydroxysulfonyl intermediates undergo syn- and
anti-fragmentation, depending on the reaction conditions. In
effect, isomeric E- and Z-alkenes are formed in a stereodivergent
manner, which mimics mechanistic manifold of the Peterson
olefination.
Formation of the C=C bonds play a key role in construction of
the molecular frameworks, and numerous methods, based on
reactions of heteroorganic derivatives of phosphorus, silicon
and sulfur, have been developed.1 In the most prominent
variants, phosphonium (Wittig reaction) and phosphonate
(Horner-Wadsworth-Emmons reaction) precursors add to the
carbonyl compounds to produce four-membered ring
oxaphosphetanes, which spontaneously syn-fragment to the
olefins.2 A more diverse process can be realized with silyl-
stabilized carbanions (Peterson olefination), where
β-hydroxysilanes undergo controllable syn- and anti-
fragmentations. In effect, each of the diastereomeric
intermediates can be transformed into E- or Z-alkene,
depending on the reaction conditions.3 In turn one-pot Julia
olefination with heteroaryl sulfones usually runs by the initial
aldol-type addition, followed by Smiles rearrangement and
anti-fragmentation with release of SO2 and aryloxide
byproducts (Scheme 1, top).4 Recently, we systematically
studied5,6 another sulfur-based olefination reaction,
Scheme 1. One-pot Julia olefination with heteroaryl sulfones (top), and Hawkins
olefination with activated alkanesulfonates (bottom).
were only moderately successful, due to poor selectivity of the
initial aldol-type addition, and limited equilibration of adducts
formed with unstabilized alkanesulfonates.5 Therefore, to
improve the selectivity we considered alternative generation
of β-hydroxysulfonates by acylation and diastereoselective
reduction of the carbonyl group. A similar approach was
reported by Jørgensen8 on acylated benzothiazoyl sulfones,
which were selectively reduced to isomeric alcohols. Next,
Smiles rearrangement and anti-fragmentation of the
intermediates led to isomeric alkenes. Analogously, Warren9
applied the acylation-reduction approach to perform
E-selective Horner-Wittig reaction with phosphine oxides.
Importantly in the mentioned reports diastereomerically pure
intermediates were transformed into single isomer of the
olefins, following specific mechanism of the fragmentation
step. In the present report we demonstrate Felkin-Ahn
reduction of acylated trifluoroethyl alkanesulfonates, followed
by controllable syn- and anti-fragmentation of the
mechanistically
similar
to
the
phosphorus-based
transformations. The method, pioneered many years ago by
Hawkins,7 utilizes sulfonyl halides and esters, which add to the
carbonyl compounds, cyclize to four-membered ring
intermediates, and spontaneously syn-fragment to the olefins
(Scheme 1, bottom). Although yields of the olefinic products
were usually high, attempts at control of the E/Z-isomer ratio6
a.Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland,
e-mail: barbasiewicz@chem.uw.edu.pl, web page: www.aromaticity.pl
Electronic Supplementary Information (ESI) available: Experimental details,
spectroscopic data, and NMR spectra reproductions. See DOI: 10.1039/x0xx00000x
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intermediates to both isomers of the alkenes, that mimics (6:94) in 55% of yield (based on 1a, Scheme 2, bottom). The
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mechanistic manifold of the Peterson reaction.
stereochemical course of the reacDtiOonI: 10.c1o03n9f/iCrm9OeBd015o63uAr
expectations, concerning of the complementary fragmentation
In a preliminary experiment mixture of carbanion precursor mechanisms, where single diastereomer of the intermediate
1a5,6 and benzoyl chloride was treated with LiHMDS in THF translates into both isomers of the alkene.12 Amazingly, in
at -78 
C.10 After aqueous workup acylated product 2a was further studies we discovered yet another transformation of
isolated in a quantitative yield with excellent purity (see the acylated sulfonate 2a, in which carbonyl group remains intact,
Supporting Information for details). Next, we tested various but the SO2OCH2CF3 group is selectively cleavaged, giving
reducing agents of 2a, and identified a combination of ketone 6a. The chemoselective reduction-fragmentation of the
LiAlH4/LiCl‡ in THF at -78
C as optimal for the carbonyl sulfonyl group was performed using equimolar amount of
reduction, giving β-hydroxysulfonate 3a in 90% of yield with NBu4BH4 in DMF at 85
high diastereoselectivity (98:2, based on H NMR, Scheme 2,

C (Scheme 3, top).
1
top).
Scheme 2. Synthesis, LiAlH4 reductions, and further transformations of acylated
sulfonate 2a to the E-alkene (top), and to the Z-alkene (bottom). a The β-hydroxysulfinic
acid 4a decomposed on attempt of chromatographic purification on a silica gel.
The observed stereochemical course of the reaction followed
the Felkin-Ahn model of selectivity, where large
electronegative sulfonyl group is located perpendicularly to
the carbonyl moiety, as observed earlier by Jørgensen,8 and
Marcantoni and Bartoli.11 The produced S*,S*-isomer of the
alcohol 3a was known to selectively syn-fragment on
Scheme 3. Reductive cleavage of the sulfonyl group in acylated sulfonate 2a (top),
mechanistic studies (middle), and plausible reaction mechanism (bottom).
treatment with tert-BuOLi in THF at rt, giving E-1-phenyl-1-
nonene (E-5a).5 Indeed, when we repeated the three-step
sequence of acylationreductionfragmentation, with single
To elucidate mechanism of the formation of 6a we tested
β-hydroxysulfonate 3a and modified substrates 2b-d under the
same conditions (Scheme 3, middle). Reaction of alcohol 3a
gave only alkene E-5a instead of ketone that ruled out
reduction of the carbonyl group, as a first step of the
transformation. Thus, we assumed that in the polar aprotic
solvent (DMF) sulfonyl group is preferably attacked by the
borohydride, and nucleophilic substitution at the sulfur atom
releases ketone enolate (pathway 'a', Scheme 3, bottom), or
2,2,2-trifluoroethoxide ('pathway 'b', Scheme 3, bottom),13 as
a leaving group. To obtain more insights into the process we
tested ester derivative 2b and neo-pentyl sulfonate 2c. Basicity
considerations suggested that leaving group ability of ester
enolate in 2b, and neo-pentoxide in 2c should be reduced, as
compared with the parent structure of 2a. Interestingly, in our
hands only the first modification inhibited the reaction,
whereas sulfonate 2c gave ketone 6a in 64% of yield,
supporting mechanism, in which the C-S bond is preferentially
chromatographic purification of the final mixture, alkene 5a
was isolated as a predominant E isomer (98:2) in overall yield
85%, based on 1a. Interestingly, we observed also that
reduction of 2a with equimolar amount of LiAlH4 at -78 C,
followed by warming of the reaction mixture to rt, gives
β-hydroxysulfinic acid 4a, as a main product (Scheme 2,
bottom). Although stereochemical structure of 4a was not
unequivocally established, we assumed that the sulfonyl
reduction is a secondary process, which does not affect the
relative S*,S* configuration at the stereogenic centers,
controlled by the initial Felkin-Ahn attack on the carbonyl
group.§ Importantly formation of 4a paved the way to the
alternative fragmentation mechanism, inspired by the last step
of the one-pot Julia olefination (Scheme 1, top). We reckoned
that basic treatment of 4a with 5-chloro-1-phenyl-1H-tetrazole
can activate the hydroxyl group toward anti-fragmentation,§§
giving alkene of opposite configuration, as compared with
reaction of 3a. Indeed, using the activating agent and tert-
BuOK in THF, alkene 5a was formed as a predominant Z-isomer
cleavaged (pathway 'a'). However, reaction of -ketosulfone
2d was more difficult to interpret, suggesting a subtle balance
2 | J. Name., 2012, 00, 1-3
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between electrophilic properties of carbonyl and sulfonyl substrates we performed a series of 3-step (for alkenes) or
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DOI: 10.1039/C9OB01563A
groups, which seemed to be beyond the scope of the current 2-step (for ketones) transformations of alkanesulfonates 1a-e
,
studies.
with single chromatographic purification of the final products
Finally, after careful optimization of the reaction conditions of (see the Supporting Information for details). The results are
acylation, reduction and fragmentation for a broad palette of presented in Table 1.
Sulfonate
R1=
Acyl chloride
R2=
E-alkenes
Isolated yieldsa
Z-alkenes
Isolated yieldsa
Ketones
Isolated yieldsa
6b, 73%
6c, 68%
6d, 61%
6e, 66%
6f, 62%
Entry
E/Zb
97:3
E/Zb
8:92
8:92
48:52
26:74
‒
Me, 1b
Et, 1c
5b, 82%
5c, 73%
5d, 76%
5e,c 65%
5f, 66%
5g, 79%
5h, 61%
5i, 69%
5e,c 74%
5j, 39%
5k, 66%
5l, 46%
5m, 87%
5a, 85%
5n, 81%
5o, 82%
5p, 71%
53%
51%
39%
1
2
3
4
5
1-naphthyl
94:6
i-Pr, 1d
>99:1
87:13
97:3
n-C7H15
c-C6H11
34%
d
c-C6H11, 1e
Ph
>99:1
90:10e
90:10
97:3
>99:1
89:11
91:9
98:2
98:2
95:5
98:2
40%
35%
53%
62:38
8:92e
7:93
7:93
‒
10:90
12:88
8:92
6:94
16:84
37:63f
90:10f
6g, 70%
6h, 70%
6i, 73%
6e', 67%
6j, 53%
6
7
8
CH2=CHCH2CH2
n-C7H15
9
c-C6H11
tert-Bu
Ph(CH2)2
PhCH2
4-ClC6H4
Ph
1-naphthyl
4-MeC6H4
4-MeOC6H4
25%
d
10
11
12
13
14
15
16
41%
26%
53%
55%
50%
57%
59%
6k, 79%
6l, 59%
C7H15, 1a
6m, 83%
6a, 86%
6n, 66%
6o, 88%
6p, 72%
98:2
17
a
Table 1. Syntheses of isomeric alkenes and ketones by divergent reduction-fragmentation of acylated trifluoroethyl alkanesulfonates (1a-e) at 2.0 mmol scale. The yields were
based on 1a-e. b The E/Z-isomer ratio of alkenes was based on GC. c Alkene 5e was formed from two combination of substrates (entries 4 and 9). d Yield of alkene was <10 %. e The
approximate E/Z-isomer ratio was based on 13C NMR (isomers of 5h were inseparable by GC). f Selectivities of alkenes 5r,s produced under tetrazole activation conditions resulted
from use of β-hydroxysulfinic acids partially transformed to the E-alkenes (most likely by self-protonation and non-stereospecific decomposition via carbocations).
We observed that in most cases E-alkenes and ketones are In conclusion we presented chemoselective reductive
formed in good to very good yields, and best results are transformations of acylated trifluoroethyl alkanesulfonates.
obtained for a combination of linear-chain sulfonates (1a-c
)
Their reduction with LiAlH4 leads to β-hydroxysulfonates or
and aroyl chlorides (highlighted in yellow at the Table 1). In β-hydroxysulfinic acids, depending on the reaction conditions.
turn yields and selectivities of the Z-alkenes were lower, in In the following step the diastereomeric intermediates
particular for branched sulfonates (1d,e) and for branched acyl undergo base-induced syn- and anti-fragmentations to E- and
chlorides (e.g. cyclohexanecarbonyl chloride). Noteworthy, in Z-alkenes, respectively. The divergent transformations mimic
one-pot Julia olefination with heteroaromatic sulfones mechanistic manifold of the Peterson olefination, with
aromatic aldehydes preferably give E-alkenes,14 that is controllable switch between the fragmentation mechanisms.
attributed to a non-stereospecific elimination pathway.4,15 In In addition we observed that reduction of the substrates with
our studies 1-alkyl-2-arylethylenes 5a-c,m-p were formed as NBu4BH4 in DMF causes cleavage of the sulfonyl group, giving
predominant Z-isomers, and only for donor-substituted ketones.
benzoyl chlorides intermediate β-hydroxysulfinic acids
displayed limited stability and (prior to the tetrazole We are grateful to the National Science Center, Poland (grant
activation) underwent spontaneous non-stereospecific SONATA BIS DEC-2013/10/E/ST5/00030) for
decomposition to the E-alkenes, that altered selectivities in support.
entries 16 and 17.
a financial
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13 Synthesis of ketones from acylated benzothiazoVyilewsuAlrftoicnleeOsnline
was described in: M. W. Paixão, N. HolDuOb,I:C1.0V.10il3a9,/MC9.ONBie01ls5e6n3A
and K. A. Jørgensen, Angew. Chem. Int. Ed., 2009, 48, 7338;
B. Prüger, G. E. Hofmeister, C. B. Jacobsen, D. G. Alberg, M.
Nielsen and K. A. Jørgensen, Chem Eur. J., 2010, 16, 3783; R.
Bujok and M. Mąkosza, Synthesis, 2019, 51, DOI: 10.1055/s-
0037-1612423.
Conflicts of interest
There are no conflicts to declare.
Notes and references
‡ LiAlH4 reduction of 2a in THF at -78

C caused partial 14 J. B. Baudin, G. Hareau, S. A. Julia and O. Ruel, Tetrahedron
deprotonation of the substrate, which was recovered after
aqueous workup (16%). Presence of two-fold molar excess of
LiCl partially limited the process (to ca. 6%). See the Supporting
Information for details.
Lett., 1991, 32, 1175; J. B. Baudin, G. Hareau, S. A. Julia and
O. Ruel, Bull. Soc. Chim. Fr., 1993, 130, 336; J. B. Baudin, G.
Hareau, S. A. Julia and O. Ruel, Bull. Soc. Chim. Fr., 1993, 130
856.
,
15 R. Robiette and J. Pospíšil, Eur. J. Org. Chem., 2013, 2013
,
§ The assumption was supported by the fact that treatment of
3a with LiAlH4 with warming of the reaction mixture to rt
resulted in the same crude product 4a. Interestingly yield of Z-5a
prepared from 1a by a four step procedure (with the reduction
836.
carried out as two individual steps 2a3a4a) was even Graphical abstract
slightly higher (60%; 12:88), than obtained by a three-step
sequence, shown at Scheme 2, bottom (55%; 6:94).
§§ Reaction of 4a with 5-chloro-1-phenyl-1H-tetrazole was
carried out in the presence of two equivalents of strong base
(t-BuOK), so as both acidic groups (SO2H and OH) were
deprotonated. Therefore we reckoned that the activation
concerns more nucleophilic O-anion of the hydroxyl group, and
thus the following fragmentation process mimics the last step of
the one-pot Julia olefination. However, alternative activation of
the SO2H group was attempted by reaction of (neutral) 4a with
N,N'-dicyclohexylcarbodiimide (DCC) in CHCl3 at 0 Crt, which
resulted in the formation of alkene 5a of opposite (E)
configuration (52%; 95:5). In the latter case the most likely
scenario involves cyclization, followed by syn-fragmentation of
Text
Complementary fragmentation mechanisms of Hawkins and
one-pot Julia olefinations were applied for stereodivergent
synthesis of alkenes.
four-membered ring intermediate, as in case of 3a
.
1
2
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4 | J. Name., 2012, 00, 1-3
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