Diastereoselective alkylations of a protected cysteinesulfenate

Article abstract of DOI:10.1021/jo901021r

(Chemical Equation Presented) To further understand stereoselection in the alkylation of sulfenate anions, a protected cysteinesulfenate was generated in THF solution at low temperature. Introduction of a reactive alkylating agent brings about a cysteinyl

Full text of DOI:10.1021/jo901021r

pubs.acs.org/joc
addition-elimination chemistry,7-9 desilylation methods10,11
Diastereoselective Alkylations of a Protected
Cysteinesulfenate
and selected specialized protocols.12,13
Adrian L. Schwan,* Marcus J. Verdu, Suneel P. Singh,
Jennifer S. O’Donnell, and Amir Nasser Ahmadi
Department of Chemistry, University of Guelph, Guelph,
Ontario, Canada, N1G 2W1
schwan@uoguelph.ca
Received May 26, 2009
FIGURE 1. Sulfenates and related structures.
The growth in the number of sulfenate preparations has
been mirrored by an increase in studies pertaining to stereo-
selective sulfur functionalization reactions. Calling on the
prochiral nature of the sulfur’s lone pairs, Madec and Poli14
reported the enantioselective palladium-catalyzed prepara-
tion of aryl sulfoxides in the presence of chiral ligands. With
the assistance of internal chirality, diastereoselective alkyla-
tion reactions have also been achieved.4,13,15,16 On the basis
of these latter results, we investigated diastereoselective
alkylations of protected cysteinesulfenate derivative 3,
wherein the substituents on the amino acid R-carbon may
be positioned to influence the alkylations. Exploration of
this chemistry will enhance our knowledge of factors that
govern sulfenate reactivity and selectivity.
This study may also assist in understanding the role of
reactive cysteinesulfenate residues in proteins, which have
been implicated as catalysts for a number of enzymes17
including nitrile hydratase.18 In addition, cysteinesulfenate
alkylation chemistry is expected to amplify the available
synthetic procedures to analogues of Allium-based naturally
occurring sulfoxides.19,20
To further understand stereoselection in the alkylation of
sulfenate anions, a protected cysteinesulfenate was gen-
erated in THF solution at low temperature. Introduction
of a reactive alkylating agent brings about a cysteinyl
sulfoxide in 51-75% yield, with diastereomeric ratios at
the sulfinyl group ranging from 83:17 to 95:5. An intern-
ally complexed lithium counterion is proposed to account
for the stereoselectivity.
Sulfenate anions (1)1 represent the conjugate base of sulfenic
acids (2) (Figure 1).2 Like sulfenic acids, the anions are inher-
ently unstable and their study is based principally on their
reactivity. In recent years, a variety of routes have been devel-
oped for the generation of sulfenate anions including oxidation
reactions,3 base induced retro-Michael fragmentations,4-6
(11) Keerthi, K.; Gates, K. S. Org. Biomol. Chem. 2007, 5, 1595–1600.
(12) (a) Refvik, M. D.; Froese, R. D. J.; Goddard, J. D.; Pham, H. H.;
Pippert, M. F.; Schwan, A. L. J. Am. Chem. Soc. 1995, 117, 184–192. (b)
Schwan, A. L.; Lear, Y. Sulfur Lett. 2000, 23, 111–119. (c) Schwan, A. L.;
Roche, M. R.; Gallagher, J. F.; Ferguson, G. Can. J. Chem. 1994, 72, 312–
324. (d) Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.; Suzuki, T.;
Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003, 68, 5550–
5558. (e) Maezaki, N.; Yagi, S.; Maeda, J.; Yoshigami, R.; Tanaka, T.
Heterocycles 2004, 62, 263–277. (f ) Maezaki, N.; Yoshigami, R.; Maeda, J.;
Tanaka, T. Org. Lett. 2001, 3, 3627–3629.
(13) Maezaki, N.; Yagi, S.; Ohsawa, S.; Ohishi, H.; Tanaka, T. Tetra-
hedron 2003, 59, 9895–9906.
(14) Maitro, G.; Vogel, S.; Sadaoui, M.; Prestat, G.; Madec, D.; Poli, G.
Org. Lett. 2007, 9, 5493–5496.
(15) Sandrinelli, F.; Perrio, S.; Averbuch-Pouchot, M.-T. Org. Lett. 2002,
4, 3619–3622.
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hedron: Asymmetry 2002, 13, 1961–1964.
(17) Kovacs, J. A. Chem. Rev. 2004, 104, 825–848.
(1) O’Donnell, J.; Schwan, A. J. Sulfur Chem. 2004, 25, 183–211.
(2) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. Curr.
Org. Chem. 2007, 11, 1034–1052.
(3) (a) Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997, 62, 8626–
8627. (b) Sandrinelli, F.; Boudou, C.; Caupene, C.; Averbuch-Pouchot,
M.-T.; Perrio, S.; Metzner, P. Synlett 2006, 3289–3293. (c) Sandrinelli, F.;
Fontaine, G.; Perrio, S.; Beslin, P. J. Org. Chem. 2004, 69, 6916–6919. (d)
Boudou, C.; Berges, M.; Sagnes, C.; Sopkova-de Oliveira Santos, J.; Perrio,
S.; Metzner, P. J. Org. Chem. 2007, 72, 5403–5406.
(4) Lohier, J.-F.; Foucoin, F.; Jaffres, P.-A.; Garcia, J. I.; Sopkova-de
Oliveira Santos, J.; Perrio, S.; Metzner, P. Org. Lett. 2008, 10, 1271–1274.
(5) Caupene, C.; Boudou, C.; Perrio, S.; Metzner, P. J. Org. Chem. 2005,
70, 2812–2815.
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7449–7454. (b) Maitro, G.; Vogel, S.; Prestat, G.; Madec, D.; Poli, G. Org.
Lett. 2006, 8, 5951–5954.
(7) O’Donnell, J. S.; Schwan, A. L. Tetrahedron Lett. 2003, 44, 6293–
6296.
(8) Furukawa, N.; Konno, Y.; Tsuruoka, M.; Ogawa, S. Heteroat. Chem.
1992, 3, 495–503.
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Chem. Lett. 1989, 1501–1504.
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M.; Odaka, M. J. Biol. Chem. 2008, 283, 36617–36623. (b) Heinrich, L.; Li,
Y.; Vaissermann, J.; Chottard, J.-C. Eur. J. Inorg. Chem. 2001, 1407–1409.
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Soc. 2006, 128, 11211–11221.
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(20) One unoptimized example of this work has been reported previously,
see ref 7. Herein we significantly expand upon that contribution, with
optimizations, more examples, complete characterizations, and alkylation
models.
(10) Foucoin, F.; Caupene, C.; Lohier, J.-F.; Santos, J. S. d. O.; Perrio, S.;
Metzner, P. Synthesis 2007, 1315–1324.
DOI: 10.1021/jo901021r
r
Published on Web 08/11/2009
J. Org. Chem. 2009, 74, 6851–6854 6851
2009 American Chemical Society

Schwan et al.
JOCNote
In a previous communication, we introduced the use of
sulfinyl acrylates as a source of sulfenate anions through
addition-elimination reactions with nucleophiles.7 This was
viewed as a safe choice given the alkaline protocols for
accessing some sulfenates and the base sensitivity of pro-
tected cysteinyl sulfoxides.
TABLE 1. Sulfenate Anion Trapping, Using Various Electrophiles
The logical means to prepare the requisite cysteinesulfinyl
acrylate 5 would be through conjugate addition of Boc-Cys-
OEt (derived from (R)-(þ)-cysteine) to methyl propiolate and
oxidation. Similar reactions of protected cysteine derivatives
have been reported in the past as problematic, since the
products are obtained in low yields and unwanted byproducts
are formed.21 We have demonstrated an alternative approach
to 2-Z-carbomethoxyethenyl cysteinyl sulfides such as Z-4,22
but still sought an efficient preparation of E-4 or E-5.
For direct access to the E-isomer of 5 without the inter-
mediacy of E-4, we evaluated the chemistry employed by
Aversa to generate cysteinesulfenic acids.23 That protocol
generates a sulfenic acid that in our case would conveniently
add in a syn fashion to create exclusively E-5. We evaluated
that chemistry and could access E-5 in approximately 60%
yield over three steps, but the process incurred consumption
of excess and expensive methyl propiolate and diethyl iso-
propylidenemalonate.
RX
PhCH2Br
product
yielda
drb
1
2
3
4
5
6
7
8
9
6/7a
6/7b
6/7c
6/7d
6/7e
6/7f
6/7g
6/7h
6/7i
60 (65)
69 (75)
66 (72)
48 (52)
61 (66)
68 (74)
49 (53)
67 (73)
53 (58)
47 (51)
54 (60)
92:8
92:8
92:8
91:9
89:11
89:11
89:11
95:5
93:7
83:17c
83:17c
p-MeC6H4CH2Br
p-BrC6H4CH2Br
m-MeOC6H4CH2Br
m-O2NC6H4CH2Br
p-NCC6H4CH2Br
o-NCC6H4CH2Br
o-BrC6H4CH2Br
o-HC(O)C6H4CH2Br
MeI
10
11
6/7j
6/7k
Allyl bromide
a
First value is the yield based on the sulfur-containing substrate.
Parenthesized value is the yield based on the limiting reagent. bDr values
based on peak integrations unless otherwise noted. See text and the
Supporting Information for additional detail. Dr calculated by NMR
c
Revisiting the conjugate addition of thiol to methyl pro-
piolate, several experiments were performed to optimize the
addition reaction for E-selectivity and to improve the yield of
E-4. A key finding was that short reaction times were vital.
Hence, this reaction was terminated after 3-5 min and taken
directly to MCPBA oxidation. The overall two-step prepara-
tion could be achieved in 60% yield (1.2:1 dr) in one after-
noon without the need for excess amounts of expensive
coreactants.24
Several nucleophiles were evaluated for release of cystei-
nesulfenate 3 from E-5, but only thiolates proved successful,
presumably because of their highly nucleophilic and weakly
basic nature. From those experiments, lithium cyclohexa-
nethiolate was adopted as the nucleophile. Other optimiza-
tions provided the following experimental protocol for the
release and alkylation of cysteinesulfenate 3. A prepared
solution of 0.90-0.95 equiv of lithium cyclohexanethiolate
was added to sulfoxide E-5 at -78 °C.25 After 1 min, the
electrophile was added, and the reaction was allowed to stir
for 16 h, while warming slowly to rt. Direct concentration
and flash chromatography provided diastereomeric mixtures
of sulfoxides with chemical yields as shown in Table 1.26 The
yields are fair-to-good and are thought to be reflective of the
sensitivity and lability of the cysteine-based substrates at all
stages of the reaction sequence.
spectroscopy.
The dr values of cysteinyl benzyl sulfoxides 6/7a-i were
measured by HLPC on a CHIRACEL-OJ chiral HPLC
column. Authentic samples of each diastereomer were ob-
tained by MCPBA oxidation of the corresponding sulfide
and were used to establish separations and retention times.
The assigned structures were fully consistent with their
infrared and H and 13C NMR spectra. Recrystallization
of the diastereomeric mixtures gave major sulfoxide 6 in pure
form (HPLC and elemental analysis).
1
The configuration of the sulfinyl stereocenter of the major
diastereomer was assigned to be R on the following basis. As
indicated, all the benzyl sulfoxides could be separated on a
CHIRACEL-OJ chiral HPLC column and the major isomer
always eluted second under consistent elution conditions.
Allyl and methyl sulfoxides 6/7j/k could not be assessed by
HPLC, but crystals of 6k were grown and successfully
analyzed by X-ray crystallography, wherein the sulfinyl
configuration was established to be R.27
The benzyl sulfoxides did not provide suitable crystals for
X-ray analysis, so chemical adaptations were performed. A
92:8 mixture of 6a/7a was reduced to the alcohol with LiBH4/
THF and the Boc group was removed with TFA/CH2Cl2.
The resulting amino alcohols 8 were obtained as a diastere-
omeric mixture (ca. 92:8), whose 600 MHz 1H NMR spectra
could be assigned to those spectra reported in the literature
for (RC,RS) and (RC,SS) examples of 8, previously prepared
through sulfoxidation of the corresponding RC-sulfide 9.28
To complete the comparison, recrystallization of a diastereo-
mericmixture a8provided the major diastereomer only, which
gave an optical rotation of þ16.2, matching that reported
(21) Crisp, G. T.; Millan, M. J. Tetrahedron 1998, 54, 637–648.
(22) O’Donnell, J. S.; Singh, S. P.; Metcalf, T. A.; Schwan, A. L. Eur. J.
Org. Chem. 2009, 547–553.
(23) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. J. Org.
Chem. 2005, 70, 1986–1992.
(24) Full experimental detail including a reaction equation are part of the
Supporting Information.
(25) The use of excess base brought about lower yields and increased
byproducts including protected dehydroalanine and dibenzyl sulfoxides,
when the alkylation was performed with a benzyl bromide.
(26) To confirm the sulfoxides were kinetic products arising directly from
alkylation chemistry, selected sulfoxides were thermolyzed to determine if
the observed dr value were caused by (a) selective thermal breakdown of one
diasteromer or (b) thermal conversion of one isomer to the other. No
evidence in support of either of these processes was observed. See: Rich,
D. H.; Tam, J. P. J. Org. Chem. 1977, 42, 3815–3820.
(27) Singh, S. P.; Verdu, M. J.; Lough, A. J.; Schwan, A. L. Acta
Crystallogr. 2009, E65, o1385–o1386.
(28) Petra, D. G. I.; Kamer, P. C. J.; Spek, A. L.; Schoemaker, H. E.;
van Leeuwen, P. W. N. M. J. Org. Chem. 2000, 65, 3010–3017.
6852 J. Org. Chem. Vol. 74, No. 17, 2009

Schwan et al.
JOCNote
SCHEME 1. Configurational Assignment of Sulfoxides 6a/7a
TABLE 2. Influence of 12-Crown-4 on the Diastereoselectivity of Benzy-
lations of Sulfenate 3
equiv of 12-crown-4a
dr b
1
2
3
4
5
6
0
92:8
91:9
90:10
88:12
86:14
85:15
0.3
0.6
1
1.5
2.5
a
12-Crown-4 was introduced immediately after sulfenate generation.
bDr values based on peak integrations. See text and the Supporting
Information for additional detail.
SCHEME 2. Possible Sulfenate Conformations
These results provide evidence that the lithium counterion
is indeed an important component of the stereoselection step
and directs further scrutiny to conformational isomers 3-A/
3-B of Scheme 2. Both conformations hold the potential to
add electrophiles at their axial or equatorial positions. The
population of complex 3-B is believed to be insignificant due
to an unfavorable interaction of the ester and carbamate
groups in adjacent equatorial positions. Focusing on 3-A, the
ester group in the axial form further inhibits the already
undesirable axial alkylation, allowing preferential equatorial
alkylation. Indeed the (RC,RS) configuration of the product
is consistent with equatorial alkylation of 3-A (Scheme 2).
Some of the highest dr values were observed with ortho-
substituted benzyl bromides, where the alkylation reaction is
expected to encounter additional steric encumbrances.
The diastereoselectivity of the benzylation reactions re-
presents a significant contribution to the growing field of
asymmetric sulfenate functionalization. The ratios are com-
petitive or superior to a number of S-alkylations in the
literature.13,15,16 The chemistry creates products comple-
mentary to those accessed through cysteinesulfenic acid
addition chemistry,23 and the functionalization occurs with
superior stereoselectivity.
for the (RC,RS) isomer of 8 previously obtained (þ16).28 Based
on Scheme 1, it follows that the sulfinyl configuration of the
major isomer of the 6a/7a isomeric pair is R.
The key features uniting all of the sulfoxides are their
chemical shift trends in both their 1H and 13C NMR spectra.
1
In the H NMR spectra of every sulfoxide, the NH peak
of the major isomer of 6 was 0.04-0.15 ppm downfield
from that of the minor isomer. Moreover, in the 13C NMR
spectra, the amino acid R and β carbon atoms of the
major diastereomer resonated downfield by 0.11-0.81 and
0.55-1.59 ppm, respectively, in every example. It has pre-
viously been established that like isomers of cysteinyl sulf-
oxides demonstrate consistent trends for related NMR
spectroscopic data.29,30
Following the lead of Perrio, who invoked internal com-
plexation of the lithium counterion,15 it is suggested that
sulfenate 3 adopts a chair conformation from which the
diastereoselection arises. The chair conformations of 3 may be
held through either lithium complexation (3-A/3-B, Scheme 2)
or by way of internal hydrogen bonding (3-C/3-D).
To investigate if the lithium plays a prominent role in the
coordination of the intermediate, several alkylations of 3
with benzyl bromide were performed in the presence of
varying amounts of 12-crown-4 (12-c-4), which was antici-
pated to sequester the lithium counterion.31 The reaction
afforded the same major diastereomer (RC,RS) as previous
alkylations, but progressively lower dr values were observed
as the 12-c-4 concentration was increased (Table 2). The
interpretation is that under the reaction conditions, 12-c-4
competitively strips sulfenate 3 of some its stoichiometric
lithium leaving the uncomplexed sulfenate to alkylate with
reduced stereoselectivity.
As a final note, it is worth mentioning that the 1H NMR
spectra of the crude sulfoxide-containing reaction mixtures
displayed chemical shifts of some hydrogen atoms that
strayed as far as 0.6 ppm from the chemical shifts of the
pure products. While puzzling for a period of time, this
observation was eventually found to be a result of the
sulfoxide coordinating to lithium in CDCl3 solution.32 This
complexation is consistent with the high affinity that some
amino acids have for alkali metals,33 but it also parallels the
behavior of cysteinesulfenate 3, whose anionic form is expected
to demonstrate an even higher affinity for lithium ion. Given
the competitiveness for the lithium ion that cysteinesulfenate 3
shares with 12-c-4, this and related sulfenates should be
further explored for their strong affinity for alkali metals.
Further, the cysteinesulfenato34 and related complexes17,35
(32) This conclusion was established by introducing LiBr to pure sulf-
oxide and obtaining similar NMR spectra comparable to those of the crude
mixtures in CDCl3.
(33) (a) Aziz, E. F.; Ottosson, N.; Eisebitt, S.; Eberhardt, W.; Jagoda-
Cwiklik, B.; Vacha, R.; Jungwirth, P.; Winter, B. J. Phys. Chem. B 2008, 112,
12567–12570. (b) Deeying, N.; Sagarik, K. Biophys. Chem. 2007, 125, 72–91.
(c) Feng, W. Y.; Gronert, S.; Lebrilla, C. J. Phys. Chem. A 2003, 107, 405–
410. (d) Talley, J. M.; Cerda, B. A.; Ohanessian, G.; Wesdemiotis, C.
Chem.;Eur. J. 2002, 8, 1377–1388. (e) Feng, W. Y.; Gronert, S.; Lebrilla,
C. B. J. Am. Chem. Soc. 1999, 121, 1365–1371.
(29) Aversa, M. C.; Bonaccorsi, P.; Faggi, C.; Lamanna, G.; Menichetti,
S. Tetrahedron 2005, 61, 11902–11909.
(30) Nakamura, S.; Goto, K.; Kondo, M.; Naito, S.; Tsuda, Y.; Shishido,
K. Bioorg. Med. Chem. Lett. 1997, 7, 2033–2036.
(31) Power, P. P. Acc. Chem. Res. 1988, 21, 147–153.
(34) Park, H.; Yang, J. S.; Jun, M.-J. Bull. Korean Chem. Soc. 2002, 23,
500–502.
(35) Kung, I.; Schweitzer, D.; Shearer, J.; Taylor, W. D.; Jackson, H. L.;
Lovell, S.; Kovacs, J. A. J. Am. Chem. Soc. 2000, 122, 8299–8300.
J. Org. Chem. Vol. 74, No. 17, 2009 6853

Schwan et al.
JOCNote
explored in organometallic studies have arisen through oxida-
tion of thiolato ligands. The chemistry herein may serve as
an alterative synthetic strategy for this important area of
chemistry.
To summarize, protected cysteinesulfenate 3 has been
shown to alkylate with high diastereoselectivity, possibly
through an internal complexation with the lithium counter-
ion. From this result, we plan to create new sulfenates and
electrophiles based on an amino acid foundation in order to
fully evaluate the identity and role of the substituent groups
in governing this important alkylation process.
were recovered as a white solid after flash chromatography
(EtOAc/hexanes 90:10 to 50:50) as a mixture of diastereomers
(dr 92:8). Recrystallization from EtOAc/hexanes yielded the
major diastereomer. Major diastereomer: mp 126-127 °C;
D
1
[R]25 -69.0 (c 0.45, CHCl3); H NMR (400 MHz, CDCl3) δ
7.35 (m, 5H), 5.79 (br d, J = 7.6 Hz, 1H), 4.68 (br d, J = 3.2 Hz,
1H), 4.21 (q, J = 7.1 Hz, 2H), 4.07 (ABq, J = 11.6 Hz, 2H), 3.11
(ABX, JAX = 7.8 Hz, JBX = 3.6 Hz, JAB = 13.0 Hz, 2H), 1.42 (s,
9H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ
170.3, 155.2, 130.0, 129.2, 129.0, 128.5, 80.2, 61.9, 58.9, 51.9,
50.1, 28.2, 14.0; IR (CH2Cl2) cm-1 3270, 2979, 1734, 1715, 1497,
1367, 1216, 1166, 1026; HPLC (10% iPrOH/hexanes, 0.4 mL/
min flow rate, OJ-H column) 23.1 min. Anal. Calcd for
C17H25NO5S: C, 57.44; H, 7.03. Found: C, 57.66; H, 7.17.
Minor diastereomer: partial 1H NMR (400 MHz, CDCl3) δ
5.73 (br d, J = 6.6 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 169.9, 155.1, 130.0, 129.4, 128.8, 128.3,
80.1, 61.8, 57.9, 52.6, 49.5, 28.1, 13.9; HPLC (10% iPrOH/
hexanes, 0.4 mL/min flow rate, OJ-H column) 20.4 min.
Experimental Section
General Preparation of Sulfoxides via Sulfenate Anion Alkyla-
tion. A solution of cyclohexyl mercaptan (0.95 equiv) and
n-BuLi (0.92 equiv) in anhydrous THF (2 mL), under N2 gas,
was stirred at rt for 5 min and was then cooled to -78 °C. The
CySLi solution was transferred via syringe into the solution of
the R,β-unsaturated sulfoxide E-5 (1 equiv) with stirring in
anhydrous THF (10 mL) at -78 °C, under N2 gas. The reaction
was stirred for 1 min and electrophile (RX, 2 equiv) was added.
If the electrophile was a solid, it was dissolved in THF (1 mL)
then added. The reaction was left to stir overnight, slowly
warming to room temperature. The solution was evaporated
under vacuum or concentrated by N2 gas and the residue was
purified by flash chromatography. Yields are based on n-BuLi
as the limiting reagent.
Acknowledgment. The authors wish to thank the Natural
Sciences and Engineering Research Council of Canada for
partial funding of this research. Acknowledgment is also
made to the Donors of the American Chemical Society
Petroleum Research Fund for partial support of this re-
search. J.S.O. thanks the Ontario Government for Science
and Technology Graduate Fellowship.
Sample Procedure and Data for Boc-Cys((O)-Bn)-OEt (6a/
7a). Sulfoxide E-5 (327 mg, 0.934 mmol) in anhydrous THF (10
mL) was treated with a CySH (112 μL, 0.888 mmol)/n-BuLi (102
μL, 0.859 mmol) solution, followed by the addition of benzyl
bromide (222 μL, 1.87 mmol). Sulfoxides 6a/7a (200 mg, 65%)
Supporting Information Available: Detailed descriptions of
experimental procedures and characterization of compounds
and 1H NMR and 13C NMR spectra of compounds 6 (37 pages).
This material is available free of charge via the Internet at http://
pubs.acs.org.
6854 J. Org. Chem. Vol. 74, No. 17, 2009