The diastereoselective alkylation of arenesulfenate anions using homochiral electrophiles

Article abstract of DOI:10.1021/ol201508e

A series of Boc-protected β-amino sulfoxides were prepared by the reaction of arenesulfenate anions with chiral Boc-protected β-amino iodides. The stereoselective substitution reaction is believed to arise through precoordination of the sulfenate counteri

Full text of DOI:10.1021/ol201508e

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4192–4195
The Diastereoselective Alkylation of
Arenesulfenate Anions Using Homochiral
Electrophiles
€
Stefan C. Soderman and Adrian L. Schwan*
Department of Chemistry, University of Guelph, Guelph, Ontario, Canada N1G 2W1
schwan@uoguelph.ca
Received June 5, 2011
ABSTRACT
A series of Boc-protected β-amino sulfoxides were prepared by the reaction of arenesulfenate anions with chiral Boc-protected β-amino iodides.
The stereoselective substitution reaction is believed to arise through precoordination of the sulfenate counterion with the nitrogen lone pair of the
electrophile.
Sulfenic acid anions (sulfenates), which are defined by
the structure CꢀSꢀOꢀMþ,1 have emerged as useful reac-
tive nucleophiles in organic chemistry. Their prochiral
nature makes them potential sources of asymmetric sulfur
compounds upon functionalization. Sulfenates hold sig-
nificant unexplored reactivity, and their use for sulfoxide
synthesis is counter to the paradigms of sulfide oxidation
and nucleophilic attack at sulfur for the formation of
asymmetric sulfinyl containing compounds.2,3
A number of recent studies have confirmed that S-func-
tionalization of sulfenates can occur with enantio- or
diastereoselectivity. For instance, Madec, Poli and co-
workers have demonstrated enantioselective sulfoxide for-
mation through transition metal catalyzed CꢀS bond
formation.1b,4 The Perrio group has established examples
of diastereoselective alkylation with cyclophane5 or
carbon stereogenicity6 in the sulfenate structure. A con-
ceptually new protocol calls on chiral phase transfer
catalysis for access to stereoenriched sulfoxides.7 Tanaka
and co-workers demonstrated the value of proximal
oxygen atoms within a chiral sulfenate for diastereoselec-
tive alkylation reactions.8 The Schwan group has recently
published work concerning diastereoselective alkylations
of a protected cysteinesulfenate,9 which provides a com-
plementary protocol to cysteinesulfenic acid addition
chemistry.10
To our knowledge there has only been one report of the
use of a chiral electrophile for the formation of asymmetric
sulfinyl containing compounds.11 Using (R)- and (S)-con-
figured sulfonium salts as alkylating agents, methyl and
ethyl sulfoxides wereobtainedin yields up to44% and with
modest enantioselectivity (ee = 24%), through chemistry
proposed to involve a sulfurane intermediate (Scheme 1).
Given the increased recognition of sulfenates as a source of
(1) (a) O’Donnell, J. S.; Schwan, A. L. J. Sulfur Chem. 2004, 25, 183.
(b) Maitro, G.; Prestat, G.; Madec, D.; Poli, G. Tetrahedron: Asymmetry
2010, 21, 1075.
(6) Sandrinelli, F.; Perrio, S.; Averbuch-Pouchot, M.-T. Org. Lett.
2002, 4, 3619.
(7) Gelat, F.; Jayashankaran, J.; Lohier, J.-F.; Gaumont, A.-C.;
(2) O’Mahony, G. E.; Kelly, P.; Lawrence, S. E.; Maguire, A. R.
Arkivoc 2011, No. (i), 1.
(3) Stingl, K. A.; Tsogoeva, S. B. Tetrahedron: Asymmetry 2010, 21,
1055.
Perrio, S. Org. Lett. 2011, 13, 3170.
(8) Maezaki, N.; Yagi, S.; Ohsawa, S.; Ohishi, H.; Tanaka, T.
Tetrahedron 2003, 59, 9895.
(9) Schwan, A. L.; Verdu, M. J.; Singh, S. P.; O’Donnell, J. S.;
Ahmadi, A. N. J. Org. Chem. 2009, 74, 6851.
(10) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.
Curr. Org. Chem. 2007, 11, 1034.
(4) (a) Maitro, G.; Prestat, G.; Madec, D.; Poli, G. J. Org. Chem.
2006, 71, 7449. (b) Maitro, G.; Vogel, S.; Prestat, G.; Madec, D.; Poli, G.
Org. Lett. 2006, 8, 5951. (c) Maitro, G.; Vogel, S.; Sadaoui, M.; Prestat,
G.; Madec, D.; Poli, G. Org. Lett. 2007, 9, 5493. (d) Bernoud, E.; Le,
D. G.; Bantreil, X.; Prestat, G.; Madec, D.; Poli, G. Org. Lett. 2010, 12,
320.
(5) Lohier, J.-F.; Foucoin, F.; Jaffres, P.-A.; Garcia, J. I.; Sopkova-de
Oliveira Santos, J.; Perrio, S.; Metzner, P. Org. Lett. 2008, 10, 1271.
(11) Kobayashi, M.; Manabe, K.; Umemura, K.; Matsuyama, H.
Sulfur Lett. 1987, 6, 19.
r
10.1021/ol201508e
Published on Web 07/18/2011
2011 American Chemical Society

Table 1. Preliminary Alkylation Attempts of p-Toluenesulfe-
nate (1) with Electrophile 3
Scheme 1. A Past Attempt of Stereoselective Alkylation of a
Sulfenate Using a Chiral Electrophile (An = 1-Anthraquinoyl;
Xꢀ = d-Camphorsulfonate)
asymmetric sulfinyl containing compounds,6,9,5,1b,8,12 we
now report the use of homochiral iodides as electrophiles
to induce chirality at sulfur. The value of chiral sulfoxides
in organic synthesis is well documented.13
MþNucꢀ
solvent
THF
dr
yield (%)
Liþ ꢀOMe
Naþ ꢀOMe
Kþ ꢀOMe
Liþ ꢀSC6H11
Naþ ꢀSC6H11
Liþ ꢀOMe
Liþ ꢀBu
90:10
78:22
58:42
91:9
52
88
57
46
83
61
87
61
Our group has previously established that the lithium
counterion is important in the diastereoselectivity during
cysteinesulfenate benzylation. This is proposed to occur by
internal coordination to the amino acid nitrogen,9 in
accord with a related system of the Perrio group.6 This
concept suggested that a bimolecular precoordination may
be important to achieving diastereoselective alkylations.
As such, the first foray into this chemistry involved the use
of nitrogen and carboxyl protected serinyl iodides. Un-
fortunately, only dehydroalanines were obtained when a
series of iodides was reacted with lithium p-toluenesulfe-
nate (1-Li), the latter generated from methyl (Z)-2-p-
tolylsulfinylacrylate (2).14 Attribution of this reactivity
mode to the high acidity of the R-hydrogen of protected
iodides and hence their proclivity for elimination led us toa
different set of electrophiles. Specifically, iodides derived
from common amino acids by way of carboxyl reduction,
nitrogen protection, and hydroxyl-to-iodide conversion15
were explored.
Focusing on the use of Boc protection,16 some of our
preliminary experiments using nitrogen protected (S)-2-
amino-3-phenylpropyl iodide (3), derived from L-phenyla-
lanine, and p-toluenesulfenate (1) are indicated in Table 1.
The β-sulfinyl acrylate ester was dissolved in THF, chilled
to ꢀ78 °C, treated with a nucleophile, and stirred for 15
min to allow sulfenate generation. The Boc protected
amino iodide (3) in THF was then added at ꢀ78 °C to
the sulfenate solution. The reaction mixture was stirred for
3 h at ꢀ78 °C and then allowed to slowly warm to room
temperature. Boc-protected amino sulfoxide4 was isolated
and subjected to flash chromatography to obtain a chemi-
cal yield. The diastereomeric ratios were determined using
an HPLC equipped with a Daicel OJ-H column.
THF
THF
THF
THF
70:30
78:22
91:9
THF/12-c-4a
THF
Liþ ꢀBu
THF/MeOHb
68:32
a 4 equiv of 12-crown-4 were added to the alkylation mixture. b 0.2
equiv of MeOH was introduced after sulfenate formation.
importance of the lithium counterion for high dr, but
sodium typically provided the superior chemical yield.
The introduction of 12-crown-4 and the consequent atte-
nuated dr are suggestive of an important role for the
lithium counterion in the stereochemical outcome. Finally,
the use of BuLi to release p-toluenesulfenate from the
sulfinyl acrylate provided the best de with a surprisingly
high yield. The introduction of MeOH after sulfenate
formation reduced the dr and yield significantly. The
interpretation is not that BuLi is necessarily a superior
reagent for the generation of 1-Li, but rather that it ensures
the absenceofhydroxylicspecies which may be attenuating
diastereoselectivity and yield.
It has long been recognized that more reactive electro-
philes, such as benzyl bromides and methyl iodides, alky-
late sulfenates most efficiently.1a To achieve high yields of
sulfoxide with less reactive materials, an excess of an
electrophile is often required. Although we adopted only
a 2-fold excess of a chiral electrophile, the generally high
yields of alkylation came as a surprise, especially since
iodide 3 exhibits significant steric hindrance on the carbon
β to the iodide. As such we performed a competition
experiment with equal molar amounts of 3 and PhCH2Br.
With 1-Li as the limiting reagent to mimic pseudo-first-
order conditions, benzylation was observed as the only
alkylation event. However, in a similar competition using
nBu-I vs 3, alkylation with 3 proved ca. four times faster,
even though a steric bias should prefer butylation. Some
mode of precoordination of the heteroatom(s) of 3 is
presumably an accelerating influence in favor in its alkyla-
tion, and this is expected to be a key contributor to the
observed stereoselectivity (vide infra). Moreover, the result
is also evocative in that electrophiles with heteroatoms
proximal to the carbon leaving group bond may accelerate
sulfenate reactivity, heretofore an unobserved result in
sulfenate chemistry.18
Various modes of sulfenate generation and counterion
identity were explored.17 The data in Table 1 reveal the
(12) Caupene, C.; Boudou, C.; Perrio, S.; Metzner, P. J. Org. Chem.
2005, 70, 2812.
(13) (a) Carmen, C. M.; Hernandez-Torres, G.; Ribagorda, M.;
Urbano, A. Chem. Commun. 2009, 6129. (b) Wojaczynska, E.;
Wojaczynski, J. Chem. Rev. 2010, 110, 4303.
(14) O’Donnell, J. S. PhD Thesis. University of Guelph, 2005.
(15) (a) Caputo, R.; Cassano, E.; Longobardo, L.; Palumbo, G.
Tetrahedron Lett. 1995, 36, 167. (b) Mosa, F.; Thirsk, C.; Vaultier,
M.; Maw, G.; Whiting, A. Org. Synth. 2008, 85, 219.
(16) Boc was selected due to its demonstrated success with cysteinyl
sulfoxides. See ref 9.
(17) The chemistry employed does not tolerate a wide selection of
solvents, and variations within the narrow realm of options were of no
benefit.
Org. Lett., Vol. 13, No. 16, 2011
4193

Table 2. Reactions of Sulfenate 1-Li with Various Chiral Elec-
trophiles
Table 3. Reactions of Various Sulfenates with Chiral Amino
Iodides 3 and ent-3
a Product drawn and numbered is major isomer obtained. b Major
isomer listed first.
a Product drawn and numbered is major isomer obtained. b Major
isomer listed first. c Reaction was performed with LiOMe as the nucleo-
phile. d E-acrylate was employed as the starting material.
Given the optimized conditions for the alkylation, atten-
tion was turned to changing the amino acid R group.
Electrophiles of both configurations were employed and
yields ranged from 71% to 92%, with dr’s consistently
approaching or exceeding 9:1, with the exception of R =
Ph (ca. 3:1, Table 2).
in transition state A for the SC-iodide and the sulfur to
carbon bondforming reaction occursthroughattackofthe
carbon bearing the iodide (Figure 1). In the proposed transi-
tion state, it is anticipated that the leaving iodide would be
nearly eclipsing the equatorial substituent of the stereo-
genic carbon. Given the stereochemistry of the electro-
phile, transition state A holds the electrophile’s R group
axial, and the H isequatorial, thereby minimizing the effect
of the eclipsing interaction. In such an arrangement, the
selectivity of the alkylation occurs by placing the sulfur’s
R1 group in an equatorial position away from the axial R
group of the electrophile, avoiding a 1,3-diaxial interac-
tion. The stereoselectivity of the alkylation arises since the
RC-iodide requires an adaptation of A where the R group
on the chiral carbon creates an unfavorable eclipsing
interaction with the iodide. Hence the transition state
adopted for RC-iodide alkylation is the enantiomer of A.
Further evaluation of the scope of diastereomeric alky-
lation focused on the identity of the sulfenate. Benzene-
and 2-naphthalenesulfenates delivered comparable alkyla-
tion chemistry with electrophile 3. The lower yield of 13
may be due to chemoselectivity problems wherein the
nBuLi reacts with the bromine of the 2-bromophenyl
group. To improve the yield, we reverted to LiOMe for
more directed sulfenate release and obtained 71% yield
with a reduced 83:17 dr. Alkanesulfenates, exemplified by
entry 6 in Table 3, did not get alkylated by iodide 3.19 In all
cases presented in Tables 2 and 3, the major diastereomer
could be obtained in pure form after one or two recrys-
tallizations. The absolute configurations of the products
were established by comparison to literature optical rota-
tion values.20,21
To account for the observed stereochemistry, one could
invoke a lithium to nitrogen precomplex as indicated
(18) A related phenomenon has been observed wherein a proximal
heteroatom enhances the yield of zinc sulfenate addition to an alkyne.
See: Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.; Suzuki, T.;
Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003, 68, 5550.
(19) Alkanesulfenates generated by this method generally decompose
as the temperature approaches rt. See ref 14.
(20) (a) Lewanowicz, A.; Lipinski, J.; Siedlecka, R.; Skarzewski, J.;
Baert, F. Tetrahedron 1998, 54, 6571. (b) Garcia Ruano, J. L.; Alcudia,
A.; Del Prado, M.; Barros, D.; Maestro, M. C.; Fernandez, I. J. Org.
Chem. 2000, 65, 2856.
(21) The absolute configurations of 10 (RS, SC) and ent-10 (SS,RC)
were assigned based on the identical match to the known literature
values for 10 (þ115.0; see ref 20a). Other rotations were consistent with
the general trends of (RS,SC)-amino sulfoxides and (SS,RC)-amino
sulfoxide as indicated in ref 20a. Further corroboration comes with
the rotation value of the (RS,RC) isomer of 8 (ref 20b).
Figure 1. Orientations and interactions for the alkylation of the
sulfenate sulfur.
4194
Org. Lett., Vol. 13, No. 16, 2011

Alternatively, a primary H-bonding interaction may be
preferred as in transition state B, with a secondary require-
ment for Li complexation to the Boc oxygen. Such an
arrangement would also be consistent with the observed
products, and both transition states call upon involvement
of the lithium counterion as demanded by the results from
the 12-crown-4 experiment.
against oxidation of amino sulfanes.23a,c,26 The key difference
is that the stereocenter influences oxygen delivery in the
oxidation protocol, whereas, in this chemistry, the chirality
influences carbonꢀsulfur bond formation of an already
monoxidized sulfur. Although the diastereoselective oxida-
tion of enantiopure amino sulfides has been utilized exten-
sively as a general method for amino sulfoxide formation, the
existing protocols do not deliver dr’s as consistently high as
reported herein. The potential preference of sulfenate chem-
istry for this purpose is particularly realized when compared
to an example where two chiral influences are required to
deliver dr’s as high as 93.5:6.5 in 59% yield.26d
To summarize, it has been shown that aromatic sulfe-
nateanionscan be alkylatedby chiralβ-aminoiodideswith
high diastereoselectivity. Moreover, the reaction is stereo-
specific when considered from the perspective of the elec-
trophilic (R)- and (S)-iodides. The alkylation chemistry
demonstrates a conceptually novel mode for the creation
of sulfur stereogenicity. Based on the examples shown, the
S-functionalization of the prochiral sulfenates holds the
potential to be superior to sulfur oxidation for the prepara-
tion of β-amino sulfoxides. An internal complexation of the
lithium counterion with the electrophile’s nitrogen is pro-
posed to play a key role in the stereoselection.
To address the question as to whether H-bonding is
involved or not, the N-methylated analog of 3 was selected
as an electrophile that would permit alkylation without
opportunity for H-bonding. However, attempts to convert
Boc-protected (S)-2-(methylamino)-3-phenylpropyl alco-
hol to its iodide led to decomposition of the Boc unit and
oxazoline formation. As an alternative that maintains
some structural similarities, L-prolinol was converted to
its corresponding iodide (15). The reaction of 1-Li with 15
provided 61% of amino sulfoxide 16, with a dr of 95:5
(Scheme 2). A single crystal X-ray structure analysis con-
firmed the configuration of the major isomer to be (RS,
SC),22 consistent with the stereochemistry of other alkyla-
tions with SC-amino iodides. The high diastereoselectivity
indicates that H-bonding is not a significant requirement
for diastereoselection and that complexing to the heteroa-
tom lone pair should be adequate to direct the stereochem-
istry in this and the other examples.
It should also be noted that a new family of sulfenate
electrophiles has been uncovered; the electrophile exhi-
bits increased reactivity based on the nature of remote
substitution, rather than on the degree of substitution
or identity of the leaving group at the electrophilic
carbon. We are exploring the substitution chemistry of
a larger set of electrophiles and sulfenates to establish
the scope of the chemistry and other influences on the
stereoselectivity.
Scheme 2. Alkylation of Lithium p-toluenesulfenate (1-Li) with
L-Prolinyl Iodide (15)
Acknowledgment. The authors thank Dr. J. S. O’Don-
nell and Ms. S. Joyce (nee Britton) (Univ. of Guelph) for
helpful experiments and Dr. Alan Lough (Univ. of
Toronto) for the crystallographic work. Acknowledgment
is also made to the Donors of the American Chemical
Society Petroleum Research Fund and to the Natural
Sciences and Engineering Research Council of Canada
for partial support of this research. S.C.S. also thanks
NSERC for a postgraduate scholarship.
Chiral β-amino sulfoxides have found utility as chiral
ligands,23 as effective organocatalysts24 and in the synthesis
of biologically or medicinally important compounds.25
Although various methods are available for their synthesis,20b
the sulfenate chemistry presented herein should be evaluated
(22) There is 7% disorder in the crystal due to the presence of the
minor isomer in the recrystallized sample (post HPLC analysis). See
Supporting Information. The crystal structure has been deposited at the
CCDC (# CCDC 827867).
Supporting Information Available. Experimental pro-
cedures and characterization data for products; X-ray
crystal structure data including .cif file. This material is
available free of charge via the Internet at http://pubs.acs.
org.
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