Citric acid mediated catalytic osmylation/oxidative cleavage of electron deficient olefins: A vinyl sulfone study

Article abstract of DOI:10.1016/j.tetlet.2015.05.044

The first broad catalytic dihydroxylation of enantiopure cyclic vinyl sulfones followed by oxidative cleavage of the resulting acyloin provides linear termini-differentiated polyketide fragments. This mild vinyl sulfone cleavage provides an effective alternative to the current ozonolysis protocol.

Full text of DOI:10.1016/j.tetlet.2015.05.044

Tetrahedron Letters 56 (2015) 4151–4154
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Citric acid mediated catalytic osmylation/oxidative cleavage
of electron deficient olefins: a vinyl sulfone study
⇑
Thomas P. Bobinski, Philip L. Fuchs
Department of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN 47907, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The first broad catalytic dihydroxylation of enantiopure cyclic vinyl sulfones followed by oxidative cleav-
age of the resulting acyloin provides linear termini-differentiated polyketide fragments. This mild vinyl
sulfone cleavage provides an effective alternative to the current ozonolysis protocol.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 13 April 2015
Revised 8 May 2015
Accepted 11 May 2015
Available online 22 May 2015
Keywords:
Acyloin
Osmium catalysis
Electron deficient olefins
Vinyl sulfone
Polyketide
Oxidative cleavage
Introduction
assembly of aplyronine A by Yamada,10 2-methoxyethoxymethyl
(
MEM) ether utilized in anti-fungal soraphen A
analogs11 and
1a
Efforts toward optimization of vinyl sulfone polyketide meth-
ods for the synthesis of natural products illustrate the effectiveness
of five-, six-, and seven-membered cyclic vinyl sulfones to assem-
ble contiguous chiral centers.1 The vinyl sulfone polypropionate
methodology has been utilized to provide cyclic vinyl sulfones
for use as termini differentiated polyketide precursors primarily
1-ethoxyethyl ether included in an examination of the C16–C22
1
2
13
part of irumamycin
all react in the presence of ozone.
Ozonolysis has also been responsible for unwanted oxidation of
14
secondary alcohols on select cyclic vinyl sulfones to ketones.
The aforementioned considerations demand alternative experi-
mental methods for oxidative cleavage. Mild, more versatile meth-
ods would be highly desirable.
2
via ozonolysis.
Ozonolysis of electron-rich olefins is widely used and fully doc-
umented, as electron-rich olefins are an estimated 10,000 times
more reactive to ozone than electron-deficient olefins.3 Oxidative
cleavage of electronically deactivated and/or sterically hindered
Results and discussion
Osmium tetroxide addition to electron-deficient alkenes is typ-
ically slow because of diminished reactivity.
4
olefins has proven historically quite difficult. Griesbaum and
5
Fuchs reported the first ozonolysis of vinyl triflates, vinyl nitriles,
Phenyl vinyl sulfones bear a tetrahedral sulfone moiety which is
1
,2
1
5
and vinyl sulfones,
respectively, in the 1990s. Ozonolysis of
highly sterically shielded (A value >2.5) in addition to being
electronically deficient. These features are clearly apparent in the
regio- and enantiospecific Jacobsen epoxidation of the terminal
olefin of 6- and 7-membered 1,3-dienyl phenyl sulfones (>99% de
and ee), leading to the genesis of our polypropionate method.1
Earlier strategies for dealing with the oxidative inertness of vinyl
sulfonesoriginally involvedreductivecleavage of the sulfonemoiety
via treatment with BuMgCl/Pd(II)OTf, or Na amalgam. The
resulting electron-neutral olefin can then be readily cleaved, but
the transformation sacrifices the inherent olefin dissymmetry.
Previous reports on osmium catalyzed dihydroxylation of vinyl
seven-membered vinyl sulfones was more extensively studied for
the synthesis of polypropionate fragments of apoptolidin and
6
–8
aplyronine A.
6–18
While ozonolysis of vinyl sulfones has been established as an
effective method, it has limitations in the construction of polyke-
tide fragments. Many frequently used protecting groups are
incompatible with ozolytic cleavage conditions. Methoxymethyl
1
9
20
(
MOM) ether used in the total synthesis of lepranthin by
9
Miyashita, methylthiomethyl (MTM) ether employed in the
21
⇑
Corresponding author. Tel.: +1 765 494 5242.
E-mail address: pfuchs@purdue.edu (P.L. Fuchs).
sulfones are scarce and highly substrate dependant. Backvall
2
2
and Fuchs
reported osmium catalyzed dihydroxylation of
http://dx.doi.org/10.1016/j.tetlet.2015.05.044
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

4
152
T. P. Bobinski, P. L. Fuchs / Tetrahedron Letters 56 (2015) 4151–4154
torsionally-activated vinyl sulfones
a
to bridged tetrahydrofurans
osmium catalyzed dihydroxylation conditions (Table 1). Entry 1
2
4
in yields of 57% for a system with no substituents and 90% with
two substituents in the syn position to the oxo bridgehead. In addi-
tion Fuchs reported a 90% yield on a cyclic vinyl sulfone with all
three substituents occupying the same face of the molecule.
Citric acid has been shown to improve the rates and the yields
of cis-dihydroxylations of various electron-deficient alkenes
represents the results of the Upjohn protocol as a point of depar-
ture. Consistent with scheme 1, no reaction ensued. It was postu-
lated that substrate insolubility could be an issue in 10:1
2
H O/acetone. Entry 2 employed a THF/water (4:1) system
2
5
employed by Cho, in the total synthesis of (+)-trans-dihydronar-
ciclasine. The homogenous reaction solution showed no product
2
3
(
Scheme 1). In addition to acting as a pH buffer by retarding for-
mation of insoluble Os(VIII) dioxoosmate iii, citric acid strongly
binds to OsO to form i. Studies on the effects of citric acid buffered
4
Table 1
osmium catalyzed dihydroxylation on cyclic vinyl sulfones are
herein examined.
Survey of osmium catalyzed dihydroxylation of vinyl sulfones
Addition of citric acid to improve the catalytic osmylation sys-
tem led to a greater understanding of the dihydroxylation mecha-
nism as it applies to vinyl sulfone substrates (Scheme 1). As
previously mentioned, addition of citric acid to osmium tetroxide
gives rise to monoglycolate (i). Red-Ox addition of monoglycolate
to the vinyl sulfone substrate provides mixed (bis)glycolate (ii)
Os(VI) species. Rate-limiting hydrolysis of the mixed (bis)glycolate
ii affords the desired acyloin and Os(VI) monoglycolate iv. When
the osmylation is performed under homogeneous conditions the
co-oxidant N-methylmorpholine N-oxide (NMO) and base N-
methylmorpholine (NMM) have access to all intermediates in the
O
O
S
O
HO
OH
OH
Si O
Si O
1
2
Entry Reaction conditions
%
Recovered
a
Yield SM (%)
catalytic cycle. Alternatively (bis)glycolate iiÁH
2
O can be deproto-
nated by NMM equilibrating to dioxoosmate iii thereby causing
cessation of the catalytic cycle.
(
%)
1
2
3
4
5
6
7
NMO (1.05 equiv), OsO
O/acetone (0.35 M), rt, 6 h
NMO (2.0 equiv), OsO4 (1 mol %), 4:1 THF/H O
(0.05 M), rt, 24 h
NMO (1.10 equiv), MeSO
2 mol %), 10:1 acetone/H
NMO (1.10 equiv), OsO (1 mol %), citric acid
0.20 equiv), 4:1 THF/H O (0.07 M), rt ? 80 °C, 24 h
Citric acid (1.05 equiv), NMO (1.10 equiv), K
1 mol %), 4:1 MeCN/H O (0.1 M), rt, 24 h
Citric acid (2.05 equiv), NMO (1.10 equiv), K
0.10 equiv), 4:1 MeCN/H O (0.1 M), rt, 24 h
Citric acid (3.05 equiv), NMO (1.10 equiv), K
4
(0.7 mol %), 10:1
0
100
100
65
H
2
Addition of citric acid assists catalyst turnover by preventing
formation of the catalytically unreactive dioxoosmate dianion spe-
cies iii, which is formed upon deprotonation of hydrated (bis)gly-
0
2
2
NH
2
(1.10 equiv), OsO
O (0.1 M), rt, 24 h
4
35
40
56
65
73
(
2
colate iiÁH
2
O at higher pH. The strong electron withdrawing
4
60
ability of the sulfone contributes to the acidity of symmetric
hydrated (bis)glycolate species, which forms in the absence of
citric acid, increasing the concentration of symmetric dioxoosmate
and arresting the cycle at high pH. Proximal acidic moieties act as a
(
2
OsO
OsO
OsO
4
4
4
35b
2
2
(
2
b
615
(
2
buffer in hydrated (bis)glycolate iiÁH
2
O preventing buildup of diox-
oosmate iii. The equilibrium favors increased concentration of
hybrid (bis)glycolate ii allowing continuation of the cycle
0c
2
(0.10 equiv), 4:1 MeCN/H O (0.1 M), rt, 24 h
2
a
b
c
%
%
Yield after column chromatography.
by NMR analysis.
Conversion of starting material monitored by disappearance of UV activity on
(Scheme 1).
In an effort to find an optimum procedure, cyclic vinyl sulfone 1,
6
a pivotal aplyronine A intermediate, was subjected to a variety of
TLC.
O
R1
S O
O
O Os
HO2C
R3
R2
O
HO2C OH
O
R4
O
O
CO2H
Vinylsulfone
i
CO2H
HO2C
Citric Acid
H2O
H
N
proximal
acidic
O
Os
moiety
O
O
S
O
O
O
S
O
O
O
O
O
NMM
HO2C
R1
HO HO2C
O
Osmium
Tetroxide
R1
O
Os
H O
2
O
2 R3
R2 R3
O
N
O
Os
HO
O
−
H O
R
O
O
2
O
O
R4
ii
R4
CO H
ii·H2O
CO2H
2
O
PhSO2H
NMO
O
2−
H2O
CO2H
R1
S
O
O
HO2C
O
O
O
Os
O
iii
O
O
Os
R1
O
O
2
3
O
R R
O
2R3
O
O
iv
R
R4
CO2H
OH
CO2H
R4
Acyloin
1
2
3
4
Scheme 1. Citric acid assisted osmylation of cyclic vinyl sulfones. R , R , R , R = H = Me = OH = OTBS = i-Pr.

T. P. Bobinski, P. L. Fuchs / Tetrahedron Letters 56 (2015) 4151–4154
4153
(
2) after 24 h by TLC visualization. At this point it was asserted that
an additive would be necessary to effect the transformation. Entry
utilized methylsulfonamide based upon the Kerr observation of
40% conversion. Heating to 80 °C leads to no further consumption
of starting material as evidenced by proton NMR. In entry 5 an
increase to 1.05 equiv of citric acid raised the conversion to 56%,
but again the reaction did not go to completion. Over the course
of the survey it was found that potassium osmate dihydrate was
easier to handle and acetonitrile improved the homogeneity of
the reaction. The Sharpless protocol used a maximum of 2 equiv
of citric acid but using this amount for our substrate returned a
remaining 15% starting material (entry 6). We theorized that, due
to the possible increased acidity of vinyl sulfone, osmium adducts
formed in the catalytic cycle (Scheme 1), were being deprotonated
by the NMM amine co-product and/or solvent preventing full
3
dihydroxylation of an electron deficient dihydrofuran in the total
synthesis of (+)-Isatisine A.26 After 24 h the reaction showed 35%
conversion by proton NMR, but an additional 24 h of reaction time
showed no further conversion. We next reasoned that the insight-
ful mechanistic work of Sharpless which featured the use of citric
acid to stimulate reaction rates would bear fruit. Entry 4 utilizes a
substoichiometric amount of citric acid previously employed to
23
successfully dihydroxylate
phates, and c,d-unsaturated sulfones. The reaction ceased after
a,b-unsaturated esters, amides, phos-
23
Table 2
Citric acid assisted osmylation and termini differentiated oxidative cleavage of vinyl sulfones
Entry
1
Vinyl sulfone
Osmylation producta (%)
Cleavage productb (%)
O
HO
O
S
O
na
4
8
0%
3
O
MeO
O
O
HO
O
O
HO
S
OH
2
3
6
7
OH
not isolated
85%
5
OH
O
O
O
HO
O
S
O
Si
O
Si
O
O
Si
O
10
9%
9
5%
9
HO
9
8
O
OH
O
O
HO
Si
O
O
S
Si
OH
O
OMe
4
OH
O
11
Si
O
97%
2
1
73%
O
OH
O
HO
Si
O
O
S
O
OH
TBSO
OMe
5
6
7
O
OH
1
4
Si
O
13
4%
8
7%
9
1
2
O
O
O
O
HO
HO
O
O
S
O
OMe
O
17
5%
1
9
6
7%
8
1
5
O
O
O
O
S
O
O
O
O
O
O
2
0
O
c
O
19
6%
71%/ 76%
8
1
8
a
b
c
K
2
OsO
Pb(OAc)
PhI(OAc)
4
Á2H
(1.5 equiv), MeOH, rt, 5–45 min.
, MeOH (0.1 M), 60 °C, 18 h.
2 2
O (0. 01 equiv), NMO (2.5 equiv), citric acid (3.0 equiv), 4:1 MeCN/H O, rt, 16–24 h.
4
2

4
154
T. P. Bobinski, P. L. Fuchs / Tetrahedron Letters 56 (2015) 4151–4154
conversion. Apparently increasing the amount of citric acid to
equiv (entry 7) provided an equilibrium concentration high
Acknowledgements
3
enough to neutralize the free amine, thereby establishing a reason-
able rate for the osmylation. Complete disappearance of starting
material was demonstrated by TLC monitoring and the absence
We thank Arlene Rothwell and Dr. Karl Wood from Purdue
University for MS data and Purdue University for support of this
research.
1
of sulfone signals in the aromatic region of the H NMR.
The Purdue group has archived a diverse inventory of cyclic
vinyl sulfone polyketide precursors. A selection of these was cho-
sen to explore the optimized citric acid mediated osmylation.
Since this study was initiated by real-world need for aldehyde-
bearing compounds, lead tetraacetate27–29 (Pb(IV)OAc) was chosen
for oxidative cleavage of the acyloin intermediates. An excellent
review by Schmidt and Clark30 provides a comprehensive survey
of reagents for the cleavage of diols and acyloins.
Supplementary data
Supplementary data (characterization data and procedures)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.05.044.
References and notes
Compound 3 (Entry 1, Table 2) was chosen as an initial example
with the fewest variables. The acyloin product (4) is well known and
1. El-Awa, A.; Noshi, M. N.; du Jourdin, X. M.; Fuchs, P. L. Chem. Rev. 2009, 109,
2315.
2
3
.
.
El-Awa, A.; du Jourdin, X. M.; Fuchs, P. L. J. Am. Chem. Soc. 2007, 129, 9086.
Pryor, W. A.; Giamalva, D.; Church, D. F. J. Am. Chem. Soc. 1983, 105, 6858.
provided spectra identical to literature values.3
1–34
Oxidative cleav-
3
5
age of the acyloin was previously achieved by Eguchi, Masatomi
and Brégeault. Previous studies by the Fuchs group showed
facially accessible cyclic vinyl sulfones reactive to osmylation, but
facially occluded cyclic vinyl sulfones yielded little product.
Compound 5 Entry 2 contains a trans stereodiad that was an aply-
4. Griesbaum, K.; Greinert, R. Chem. Ber. 1990, 123, 6858.
5. Noshi, M. N.; El-Awa, A.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2007, 129,
3
6
1
1242.
Hong, W. P.; Noshi, M. N.; El-Awa, A.; Fuchs, P. L. Org. Lett. 2011, 13, 6342.
7. Chochrek, P.; Wicha, J. J. Org. Chem. 2007, 72, 5276.
Noshi, M. N.; El-Awa, A.; Fuchs, P. L. J. Org. Chem. 2008, 73, 3274.
9. Takada, H.; Nagumo, S.; Yasui, E.; Mizukami, M.; Miyashita, M. Heterocycles
011, 83, 293.
6.
1
7
26
8.
5
,37
ronine A intermediate.
The crude epimeric acyloin 6 was sub-
2
jected to the Criegee oxidation without further purification to
yield lactol 7. The aplyronine A strategy sought to employ cyclic
vinyl sulfone stereotetrads as precursors to linear dipropionate seg-
ments. Compound 8 (Entry 3) provided target epimeric hydroxy lac-
tol 9 in excellent yields with subsequent cleavage giving 99% yield of
10. Suenaga, K.; Ishigaki, T.; Sakakura, A.; Kigoshi, H.; Yamada, K. Tetrahedron Lett.
1995, 36, 5053.
1
1
1
1. Bettina, B.; Gerhard, H.; Michael, K.; Anthony, C. O. S.; Dietmar, S.; Marius, S.
Am. Chem. Soc. 1997, 658, 249.
2. Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.; Oishi, T. Tetrahedron Lett.
1988, 29, 6449.
3. Bis(2-chloroethoxy)methyl Ether (BOM), tetrahydropyranyl Ether (THP),
tetrahydrothiopyranyl ether, 4-methoxy tetrahydropyranyl ether, 4-
1
0. Changing the proximity of the protecting group on Entry 4
afforded desired acyloin 2 epimers in 73% yield. Criegee oxidation
provided termini-differentiated epimeric lactol 11 in near-quantita-
tive yield. Compound 12 (Entry 5) is an intermediate prepared for
the synthesis of isopropyl discodermolide analogs.3 Criegee oxida-
methoxytetrahydro-thiopyranyl
ether,
tetrahydrofuranyl
ether,
and
tetrahydrothio-furanyl ether, are also susceptible to ozonolysis Greene, T.
W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th ed.; John Wiley
and Sons Inc, 2007; pp 992–996.
8
1
4. du Jourdin, Mollat. Org. Lett. 2009, 11, 543.
tion again smoothly afforded termini-differentiated lactol 14 via 13.
15. Eliel, E. L.; Kandasamy, D. J. Org. Chem. 1976, 41, 3899.
16. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296.
Early aplyronine A intermediate 15,5,7 contains an enantiomer-
1
1
7. Hentemann, M.; Fuchs, P. L. Org. Lett. 1999, 1, 355.
8. Ebrahimian, G. R.; du Jourdin, X. M.; Fuchs, P. L. Org. Lett. 2012, 14, 2630.
ically pure epoxide and provides enantiopure acyloin 16 with the
epoxide intact (Entry 6). Criegee oxidation next afforded termini-
19. Bialecki, M.; Vogel, P. Helv. Chim. Acta 1995, 78, 325.
0. Arjona, O.; Menchaca, R.; Plumet, J. J. Org. Chem. 2001, 66, 2400.
2
differentiated epoxide cleavage product 17. Entry 7, an enantiop-
ure bicyclic cytochalasin C intermediate (18),3
9–42
21. Lofstrom, C. M. G.; Ericsson, A. M.; Bourrinet, L.; Juntunen, S. K.; Backvall, J. E. J.
Org. Chem. 1995, 60, 3586.
22. Jiang, W. L.; Lantrip, D. A.; Fuchs, P. L. Org. Lett. 2000, 2, 2181.
23. Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K. B. Adv. Synth.
Catal. 2002, 344, 421.
accommodates
dihydroxylation to 19 and subsequently gives intact acetonide 20
upon oxidative cleavage (Table 2). To address concerns about
Pb(IV) toxicity iodobenzene diacetate,3
5,43
was also shown to be
2
2
2
2
2
2
3
3
4. Vanrheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973.
5. Shin, I.-J.; Choi, E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007, 46, 2303.
6. Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2010, 75, 6830.
7. Criegee, R. Ber. Dtsch. Chem. Ges. 1931, 64, 260.
an efficient oxidative cleavage reagent (Entry 7, case 2).
Conclusions
8. Criegee, R. Angew. Chem. 1940, 53, 321.
9. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189.
0. Schmidt, A.-K. C.; Stark, C. B. W. Synthesis 2014, 46, 3283.
1. Sundén, H.; Engqvist, M.; Casas, J.; Ibrahem, I.; Córdova, A. Angew. Chem., Int.
Ed. 2004, 43, 6532.
We have shown that this two-stage osmylation/cleavage proto-
col is effective on a range of stereorich cyclic vinyl sulfones. Entries
1
–5 illustrate tolerance of multiple substitution patterns not previ-
32. El-Qisairi, A. K.; Qaseer, H. A. J. Organomet. Chem. 2002, 659, 50.
3
3
3
3. Zhang, W.; Shi, M. Chem. Commun. 2006, 1218.
4. William, J. M.; Kuriyama, M.; Onomura, O. Tetrahedron Lett. 2014, 55, 6589.
5. Ohno, M.; Oguri, I.; Eguchi, S. J. Org. Chem. 1999, 64, 8995.
ously subject to osmylation. Sterically biased vinyl sulfones such as
entries 6 and 7 afford isolable diastereo- and enantiopure acyloins.
The inherent dissymmetry of the sulfone-substituted olefin in con-
cert with the presence or absence of a free alcohol moiety dictates
formation of either the lactol or lactone product. This method sub-
stantially increases the scope of polypropionate construction via
vinyl sulfones. Citric acid assisted catalytic osmylation/oxidation
is a superior, mild, protection group friendly and convenient alter-
native for ozonolysis in the vinyl sulfone polypropionate strategy.
It is highly probable that the modified Sharpless conditions
used in this study will be applicable for other electronically-
deficient olefins.
36. El Aakel, L.; Launay, F.; Atlamsani, A.; Bregeault, J.-M. Chem. Commun. 2001,
2218.
3
3
3
7. Noshi, M. N. PhD Thesis, Purdue University, 2009.
8. du Jourdin, Mollat. Org. Lett. 2008, 11, 543.
9. Anderson, M. B.; Ranasinghe, M. G.; Palmer, J. T.; Fuchs, P. L. J. Org. Chem. 1988,
53, 3125.
4
4
4
0. Anderson, M. B.; Fuchs, P. L. J. Org. Chem. 1990, 55, 337.
1. Scarpetti, D.; Fuchs, P. L. J. Am. Chem. Soc. 1990, 112, 8084.
2. Lamothe, M.; Anderson, M. B.; Fuchs, P. L. Synth. Commun. 1991, 21, 1675.
43. Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010, 12, 1552.