Asymmetric synthesis of γ-lactones through reaction of sulfoxonium ylides, aldehydes, and ketenes

Article abstract of DOI:10.1016/j.tetlet.2014.05.130

A method for the enantioselective synthesis of γ-lactones through the reaction of enantioenriched sulfoxonium ylides, aldehydes, and ketenes was developed. Enantioenriched (98% ee) aminosulfoxonium ylide was subjected to reaction with a variety of aldehydes (both aromatic and aliphatic) and disubstituted ketenes, leading to the formation of α,β-substituted γ-lactones in moderate to very good diastereoselectivity (dr up to 95:5) and with enantiomeric excesses of up to 79% ee. Best levels of enantioselectivity were observed in the reactions of enantioenriched aminosulfoxonium ylide with isobutyraldehyde and various alkylarylketenes.

Full text of DOI:10.1016/j.tetlet.2014.05.130

Accepted Manuscript
Asymmetric Synthesis of γ-Lactones through Reaction of Sulfoxonium Ylides,
Aldehydes and Ketenes
Nicholas J. Peraino, Han-Jen Ho, Mukulesh Mondal, Nessan J. Kerrigan
PII:
S0040-4039(14)00963-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.130
TETL 44721
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
30 April 2014
29 May 2014
30 May 2014
Please cite this article as: Peraino, N.J., Ho, H-J., Mondal, M., Kerrigan, N.J., Asymmetric Synthesis of γ-Lactones
through Reaction of Sulfoxonium Ylides, Aldehydes and Ketenes, Tetrahedron Letters (2014), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2014.05.130
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Asymmetric Synthesis of γ-Lactones through
Reaction of Sulfoxonium Ylides, Aldehydes
and Ketenes
Leave this area blank for abstract info.
Nicholas J. Peraino, Han-Jen Ho, Mukulesh Mondal
and Nessan J. Kerrigan.
Department of Chemistry, Oakland University, USA
A method for the enantioselective synthesis of γ-lactones through the reaction of enantioenriched sulfoxonium ylides,
aldehydes and ketenes was developed. Enantioenriched (98% ee) aminosulfoxonium ylide was subjected to reaction with a
variety of aldehydes (both aromatic and aliphatic) and disubstituted ketenes, leading to the formation of α,β-substituted γ-
lactones in moderate to very good diastereoselectivity (dr up to 95:5) and with enantiomeric excesses of up to 79% ee.

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Asymmetric Synthesis of γ-Lactones through Reaction of
Sulfoxonium Ylides, Aldehydes and Ketenes
Nicholas J. Peraino, Han-Jen Ho, Mukulesh Mondal and Nessan J. Kerrigan*
Department of Chemistry, Oakland University, 2200 N. Squirrel Rd, Rochester, MI 48309-4477, USA; E-mail: kerrigan@oakland.edu
Abstract—A method for the enantioselective synthesis of γ-lactones through the reaction of enantioenriched sulfoxonium ylides, aldehydes
and ketenes was developed. Enantioenriched (98% ee) aminosulfoxonium ylide was subjected to reaction with a variety of aldehydes (both
aromatic and aliphatic) and disubstituted ketenes, leading to the formation of α,β-substituted γ-lactones in moderate to very good
diastereoselectivity (dr up to 95:5) and with enantiomeric excesses of up to 79% ee. Best levels of enantioselectivity were observed in the
reactions of enantioenriched aminosulfoxonium ylide with isobutyraldehyde and various alkylarylketenes.
rights reserved
© 2014 Elsevier Science. All
Keywords: disubstituted ketenes; ketoketenes; sulfoxonium ylide; oxosulfonium ylide; γ-lactone; diastereoselective; enantioselective;
asymmetric synthesis; aldehydes
4
,6-8
be obtained in the formation of γ-lactones (Scheme 2).
The asymmetric synthesis of γ-lactones is a very
challenging task, and few successful intermolecular
Based on this mechanism, we reasoned that γ-lactones
could be formed in enantioselective fashion, provided a
suitable enantioenriched aminosulfoxonium salt could be
identified. In this letter, we detail our preliminary findings
and report that indeed good enantioselectivity in γ-lactone
synthesis can be achieved through such a reaction
manifold.
1
approaches to this problem have been reported. One of the
2
best solutions is the SmI -reductive coupling of ephedrinyl
acrylates and aldehydes, introduced by Fukuzawa and co-
2
workers in 1997. However, as is usual for chiral
auxiliaries, an additional step was necessary in order to
attach the auxiliary to the substrate. In recent years we
have had success in developing nucleophile-catalyzed
reactions of ketenes, and we anticipated that an approach
involving ketene chemistry might lead to a versatile entry
to γ-lactones, without the need for the use of excess
3
amounts of expensive reagents. In 2013 we showed that
aminosulfoxonium ylides could engage aldehydes and
ketenes in a sequential one-pot approach to γ-lactones
(Scheme 1).
4
,5
Scheme 1. Diastereoselective synthesis of γ-lactones from reaction of
aminosulfoxonium ylide, aldehydes and ketenes.
We proposed that the reaction involved a [3,3]-
sigmatropic rearrangement of
intermediate, which allowed for high diastereoselectivity to
a
sulfurane oxide

2
Tetrahedron Letters
Scheme 2. Proposed mechanism for the formation of γ-lactone.
We began our investigations by evaluating
aminosulfoxonium salt 1a. (S)-1a was obtained through a 4
step procedure from commerically available methylphenyl
9
,10
sulfoxide, as outlined in Scheme 3.
Methylphenyl
sulfoxide was converted to the sulfoximine derivative by
reaction with sodium azide under acidic conditions. After
racemic methylphenyl sulfoximine was obtained, it was
1
0
resolved with (+)-(S)-10-camphorsulfonic acid.
The
enantioenriched methylphenyl sulfoximine was then
subjected to methylation using formic acid and
9
formaldehyde (the Eschweiler-Clarke reaction). The final
step involved the use of trimethyloxonium fluoroborate to
Scheme 4. Optimization of asymmetric reaction.
methylate
dimethylamino)methylphenyl oxosulfonium fluoroborate
in enantioenriched form (98% ee).
the
sulfoximine
and
access
the
(
a
Table 2. Substrate scope of the γ-lactone-forming reaction.
1
2
3
R
b
Entry
R
R
Yield
dr
ee
Lactone
(
%)
76
6
c
1
i-Pr
i-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
41
65
28
51
31
25
28
62
50
0
87:13
92:8
5a
5b
5c
5d
5e
5e
5f
2
3
4
5
2-NO
2
Ph i-Bu
2-MePh
Ph
i-Bu
i-Bu
Et
95:5
14
10
65
66
79
3
73:27
80:20
77:23
87:13
90:10
i-Pr
d
6
i-Pr
Et
7
i-Pr
Me
3 2 4 3
Scheme 3. (i) NaN , H SO , CHCl ; (ii) (+)-(S)-10-camphorsulfonic acid;
8
2-NO
4-NO
i-Pr
2
Ph Me
5g
5h
(iii) formic acid, formaldehyde; (iv) trimethyloxonium fluoroborate.
9
2
Ph Ph
Ph
34
With the desired enantioenriched sulfoxonium salt in
hand, we proceeded to evaluate its effectiveness in
reactions with isobutyraldehyde and
10
1
1
2-NO
2
2
Ph Me
Ph Me
31
48
21
7
5i
1
1
12
4-NO
5j
isobutylphenylketene. These reactants were chosen as we
had previously determined that the reaction of racemic
aminosulfoxonium ylide, generated from the corresponding
tetrafluoroborate salt by treatment with n-BuLi, proceeded
with very good diastereoselectivity (dr 88:12) and in
a
b
Ylide 2a generated from 1a by treatment with n-BuLi in all cases.
c
d
2
Yields are isolated yields. MgCl used as an additive. CuI used as an
additive.
4
In general, best yields of γ-lactone were obtained with
aromatic aldehydes (up to 65%), as had been previously
noted in our communication on the racemic variant of
4
this reaction. This is presumably due to the more
moderate yield (32%). We then proceeded to evaluate the
influence of (S)-1a on enantioselectivity in γ-lactone
formation (Scheme 4). When n-BuLi was used as a base,
+
and hence Li as the counterion (M ), good
reactive intermediate E that is formed when an aromatic
substituent is present at the β-position of the α,β-
unsaturated sulfurane oxide intermediate E, leading to a
preference for [3,3]-sigmatropic rearrangement rather
than competing intermolecular side reactions (e.g. aldol
reactions). When an aliphatic aldehyde is utilized, the
lower reactivity of intermediate E, with an aliphatic
enantioselectivity (60% ee) and diastereoselectivity was
obtained.
additive, a slight improvement in enantioselectivity was
obtained (76% ee). We speculate that the improvement in
this particular case is due to increased chelation
2
In addition, when MgCl was used as an
(organization) in the transition state. In subsequent
substrate scope experiments (Table 2), we evaluated both
sets of conditions in order to establish optimal
enantioselectivity. In most cases, it was found that best
substituent
present at the β-position of the α,β-
unsaturated sulfurane oxide intermediate E, slows [3,3]-
sigmatropic rearrangement, leading to an increase in
competing intermolecular side reactions, such as aldol
reactions. Not surprisingly, moderate yields (up to 41%)
were obtained with aliphatic aldehydes (entry 1, and
entries 5-7). A limitation of the methodology was found
+
results were obtained with the simple system of M = Li
(base = n-BuLi), without any need for an additive.

Tetrahedron Letters
when diphenylketene was tested in a reaction with
3
isobutyraldehyde (Entry 10). In that case, no γ-lactone
product was formed. This is most likely due to the
enolate in E being too stabilized, in combination with
the α,β-unsaturated sulfurane oxide of E lacking
sufficient electrophilicity at the β-position (see Scheme
5
).
Scheme 6. Proposed transition state for [3,3]-rearrangement of
intermediate E.
Optimal transfer of chirality was observed for those
reactions involving an α-branched aliphatic aldehyde
(
7
isobutyraldehyde), where enantiomeric excesses of 65-
9% ee were observed. Configurationally stable
sulfurane oxides are known, and so we speculate that
high enantioselectivity may be achieved through the
rigid transition state depicted in Scheme 6, where the
phenyl substitutent blocks approach by the enolate
moiety to the re face of the α,β-unsaturated sulfurane
1
3
oxide. Chelation of the enolate O-atom and the N of
the -NMe group by the metal (M = Li or MgCl) may
also provide important transition state organization for
the achievement of high enantioselectivity and
diastereoselectivity. The more reactive aromatic
2
Scheme 5. Intermediate E substitution pattern trends for formation of γ-
lactone 5.
Diastereoselectivity in γ-lactone reaction may be
rationalized by a [3,3]-sigmatropic rearrangement of
sulfurane oxide E, involving a six-membered chair-like
transition state, where the larger (higher priority)
2
aldehydes (e.g., 4-NO PhCHO) gave significantly lower
enantioselectivity (3-34% ee). These lower levels of
enantioselectivity may be interpreted in terms of a more
reactive intermediate (E), with an earlier less
organized/less defined transition state (lower energy
barrier to rearrangement), and correspondingly lower
discrimination between competing diastereomeric
transition states. Alternatively, intermediate E may be
in equilibrium with enediolate and α,β-unsaturated
sulfurane oxide H, leading to lower enantioselectivity
via competing acyclic transition states (Scheme 7).
Berry pseudorotation of pentacoordinate sulfurane oxide
intermediates (particularly of E) might also be a factor
1
3
substituents (R
pseudoequatorial positions (Scheme 6). We propose that
and R ) preferentially occupy
7
2
the O-enolate and –NMe substituents occupy apical
positions at sulfur (in a trigonal bipyramidal geometry),
which is consistent with the reported arrangement of
cyclic sulfurane oxides bearing electronegative
8
,12
substituents.
observed when a sterically bulky substituent (e.g., R =
i-Pr, 2-MePh, 2-NO Ph) was located at the β-position of
Best levels of diastereoselectivity were
1
2
the α,β-unsaturated sulfurane oxide intermediate E (e.g.
entry 2 vs entry 4). [3,3]-sigmatropic rearrangement of
intermediate E, where the enolate is mainly in the E-
isomeric form, would provide the trans-diastereomer
1
4
in the low enantioselectivity observed in some cases.
Indeed, lactone 5h (34% ee) was accompanied by
sulfinamide byproduct as a racemate.
(anti-diastereomer) of the γ-lactone. The identity of the
major diastereomer (for the analogous racemic series)
had previously been confirmed to be the trans-isomer by
4
X-ray crystal structure analysis. We define the trans-
diastereomer of the γ-lactone as the isomer with the
highest priority groups at each stereogenic center on
opposite sides of the the γ-lactone ring.
Scheme 7. Possible mechanism for erosion of enantioselectivity.
In summary, we have developed a novel route to
enantioenriched γ-lactones that is efficient (sequential
one-pot reaction of three components), operationally
1
5,16
simple, and economically attractive.
While
enantioselectivity is modest in many cases, the highest
enantiomeric excess of 79% represents a promising lead

4
Tetrahedron Letters
for future investigations using other, as yet untested,
chiral non-racemic sulfoxonium salts. Future studies
will also focus on the development of catalytic
asymmetric variants of the methodology described
herein.
R.; Shroeck, C. W.; Shanklin, J. R. J. Am. Chem. Soc. 1973,
5, 7424–7431.
Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 6, 909-
12.
Preparation of ketenes: (a) Hodous, B. L.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 10006-10007. (b) Baigrie, L. M.;
Seiklay, H. R.; Tidwell, T. J. Am. Chem. Soc. 1985, 107,
9
1
0
1
9
1
Acknowledgments
5
2
391-5396. (c) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc.
002, 124, 1578–1579. (d) Wilson, J. E.; Fu, G. C. Angew.
Chem., Int. Ed. 2004, 43, 6358-6360.
We thank the National Science Foundation (Grant Nos.
CHE-1213638 to N.J.K., CHE-0821487 for NMR
facilities at Oakland University, and CHE-1048719 for
LC-MS facilities at Oakland University).
12 Ohno, F.; Kawashima, T.; Okazaki, R. J. Am. Chem. Soc.
1996, 118, 697-698.
13
(a) Drabowicz, J.; Martin, J. C. Pure & Appl. Chem. 1996,
8, 951-956. (b) Drabowicz, J.; Martin, J. C. Phosphorus,
Sulfur, and Silicon 1993, 74, 439-440.
6
References and notes
1
1
4
Berry, R. S. J. Chem. Phys. 1960, 32, 933-938.
5 Experimental procedure for preparation of (−)-5a: (S)-
Dimethylamino)methylphenyl oxosulfonium fluoroborate 1a
1
(a) Seitz, M.; Reiser, O. Curr. Opinion in Chem. Biol. 2005,
, 285-292. (b) Spielvogel, D. J.; Buchwald, S. L. J. Am.
(
9
was placed under high vacuum for 0.5 h. After drying, the
sulfoxonium salt 1a (68 mg, 0.25 mmol) was suspended in
anhydrous THF (1.5 mL) and stirred at −78 °C. n-
Butyllithium (2.5 M in hexane, 0.1 mL, 0.25 mmol) was
added dropwise at −78 °C and the solution was stirred for 45
Chem. Soc. 2002, 124, 3500-3501. (c) Ohkuma, T.;
Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31, 5509-
5
3
512. (d) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997,
6, 2283-2316. (e) Harcken, C.; Brückner Angew. Chem., Int.
Ed. 1997, 36, 2750-2752. (f) Whitehead, D. C.; Yousefi, R.;
Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132,
min. MgCl
solution under
2
(0.50 mmol) was then added to the reaction
positive pressure of nitrogen.
a
3
298-3300. (g) Steward, K. M.; Gentry, E. C.; Johnson, J. S.
Transmetallation was assumed complete after 15 min.
Isobutyraldehyde (0.25 mmol) was added dropwise and the
reaction was stirred for another 1.5 h at −78 °C. Finally,
isobutylphenylketene solution (0.25 mmol in 0.5 mL THF)
was added to the reaction via syringe pump over 1 h. After
stirring for a further 4 h at −78 °C, the reaction was gradually
allowed to warm to room temperature overnight in the
cooling bath. The total reaction time was ca. 20 h. The
reaction was quenched with water (10 mL) and extracted with
ether (3 × 10 mL). The combined organics were dried with
J. Am. Chem. Soc. 2012, 134, 7329-7332. (h) Burstein, C.;
Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205-6208.
Fukuzawa, S.-i.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am.
Chem. Soc. 1997, 119, 1482-1483.
(a) Ibrahim, A. A.; Nalla, D.; Van Raaphorst, M.; Kerrigan,
N. J. J. Am. Chem. Soc. 2012, 134, 2942-2945. (b) Chen, S.;
Salo, E. C.; Wheeler, K. A.; Kerrigan, N. J. Org. Lett. 2012,
2
3
1
4, 1784-1787. (c) Mondal, M.; Ibrahim, A. A.; Wheeler, K.
A.; Kerrigan, N. J. Org. Lett. 2010, 12, 1664-1667. (d)
Ibrahim, A. A.; Wei, P.-H.; Harzmann, G. D.; Kerrigan, N. J.
J. Org. Chem. 2010, 75, 7901-7904.
4
MgSO and filtered. The crude product was purified by
passing through a plug of neutral silica, eluting with a 2%
EtOAc:hexane solvent system. The solvent was removed
under reduced pressure to afford (−)-5a as a colorless oil (26
mg, 41%), with a dr of 87:13 as determined by GC-MS
4
5
Mondal, M.; Ho, H.-J.; Peraino, N. J.; Gary, M. A.; Wheeler,
K. A.; Kerrigan, N. J. J. Org. Chem. 2013, 78, 4587-4593.
(a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997,
1
9
7, 2341-2372. (b) Johnson, A. W.; LaCount, R. B. J. Am.
analysis (and confirmed by H NMR analysis) of the crude
product.
Chem. Soc. 1961, 83, 417-423. (c) Corey, E. J.; Chaykovsky,
M. J. Am. Chem, Soc. 1965, 87, 1353-1364. (d) Johnson, C.
R.; Janiga, E. R.; Haake, M. J. Am. Chem. Soc. 1968, 90,
1
6 Characterization data for (−)-5a: HPLC analysis: 76% ee
[
Daicel Chiralpak AS-H column; 1 mL/min; solvent system:
% isopropanol in hexane; retention times: 20.6 min (major),
2
3
3
890-3891. (e) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341-
47.
2
3
17.9 min (minor)]; [α ] = −15.7 (c = 0.15, CH
2
Cl
2
); IR (thin
D
-1 1
6
7
8
Marino, J. P.; Neisser, M. J. Am. Chem. Soc. 1981, 103,
687-7689.
Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.;
McIntosh, M. C. Tetrahedron 2002, 58, 2905-2928.
(a) Martin, J. C.; Perozzi, E. F. J. Am. Chem. Soc. 1974, 96,
film): 1766 cm ; H (400 MHz, CDCl , TMS) for the major
3
7
diastereomer: δ 7.38-7.31 (m, 5H), 4.21 (dd, J = 6.6 Hz, 9.3
Hz, 1H), 4.11 (dd, J = 5.8 Hz, 9.3 Hz, 1H), 2.64 (app q, J =
6.2 Hz, 1H), 2.07-1.99 (m, 1H), 1.97-1.86 (m, 2H), 1.72-1.63
1
3
(
m, 1H), 0.89-0.87 (m, 6H), 0.81-0.79 (m, 6H); C NMR
3
155-3168. (b) Rongione, J. C.; Martin, J. C. J. Am. Chem.
(100 MHz, CDCl ) for the major diastereomer: δ 180.3,
3
Soc. 1990, 112, 1637-1638. (c) Lau, P. H. W.; Martin, J. C. J.
Am. Chem. Soc. 1977, 99, 5490-5491.
(a) Johnson, C. R.; Haake, M.; Schroeck, C. W. J. Am. Chem.
Soc. 1970, 92, 6594–6598. (b) Johnson, C. R.; Schroeck, C.
W. J. Am. Chem. Soc. 1973, 95, 7418-7423. (c) Johnson, C.
1
2
40.3, 128.7, 127.6, 127.4, 67.5, 53.9, 53.5, 38.7, 26.6, 24.6,
4.4, 24.4, 22.0, 19.0; MS (EI 70eV): 260, 204, 161, 117, 91
+
+
9
m/z; (M + H) HRMS m/z calcd for C17
found: 261.1854.
25 2
H O : 261.1855;
Supplementary Material
Electronic
Characterization data and procedures for the preparation of
γ-lactones 5a-5j, NMR spectra for 5a and 5f.
Supplementary
Information
available: