Stereodivergent access to cis- and trans-3,5-disubstituted 1,4-thiazane 1-oxides by cyclization of homochiral β-amino sulfoxides and sulfones. the preparation of isomeric ant venom alkaloids

Article abstract of DOI:10.1021/ol4023003

Intramolecular conjugate additions of homochiral (E)-1-alkenyl 2-aminoalkyl sulfoxides and sulfones were investigated. The relative position of the 3,5-substituents of the resulting 1,4-thiazane oxides was found to be dependent on the oxidation state of the sulfur atom, demonstrating a simple and highly stereodivergent synthetic protocol. Selected cis- and trans-3,5-disubstituted 1,4-thiazane dioxides were converted to cis- and trans-2,5-disubstituted pyrrolidines, known ant venom alkaloids.

Full text of DOI:10.1021/ol4023003

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4434–4437
Stereodivergent Access to Cis- and Trans-
3,5-Disubstituted 1,4-Thiazane 1‑Oxides
by Cyclization of Homochiral β‑Amino
Sulfoxides and Sulfones. The Preparation
of Isomeric Ant Venom Alkaloids
€
Stefan C. Soderman and Adrian L. Schwan*
Department of Chemistry, University of Guelph, Guelph, ON, Canada N1G 2W1
schwan@uoguelph.ca
Received July 15, 2013
ABSTRACT
Intramolecular conjugate additions of homochiral (E)-1-alkenyl 2-aminoalkyl sulfoxides and sulfones were investigated. The relative position of
the 3,5-substituents of the resulting 1,4-thiazane oxides was found to be dependent on the oxidation state of the sulfur atom, demonstrating a
simple and highly stereodivergent synthetic protocol. Selected cis- and trans-3,5-disubstituted 1,4-thiazane dioxides were converted to cis- and
trans-2,5-disubstituted pyrrolidines, known ant venom alkaloids.
Chiral 3,5-disubstituted 1,4-thiazane S-oxides represent
an important class of biologically active heterocycles.1ꢀ5
Cycloalliin (2), a natural product found in Allium plants,
displays numerous medicinal benefits including antioxi-
dant activity,5 enhanced fibrinolysis in humans,3 reduced
serum triacylglycerol levels in rats,4 and anticancer activity
(Figure 1).6,7 3,5-Disubstituted thiazane S-oxide 3 (Figure 1)
has antibiotic properties, inhibiting dihydrodipicolinate
synthase in E. coli.2,8
single examples or low yielding mixtures of diastereomeric
sulfoxides.9,10 Sulfones are more readily accessible,11 but
cyclization protocols prior to the oxidation often fail to
deliver ring substituents with good stereoselectivity.9,12
On the other hand, cyclization chemistry via conjugate
addition to alkenyl sulfones and sulfoxides tends to hold
more promise. In the sulfoxide manifold, cycloalliin13
and homocycloalliin14 were obtained as a single cis-3,5-
disubstituted diastereomer by cyclization of the acyclic
isomer, but reactions took at least four days. Low yields
and isomeric mixtures were obtained when conditions
were changed15 or when cis-isoalliin16 was cyclized. Sulfone
Attempts to access 3,5-disubstituted 1,4-thiazane S-oxides
by oxidation of thiomorpholine derivatives provide only
(1) Ichikawa, M.; Mizuno, I.; Yoshida, J.; Ide, N.; Ushijima, M.;
Kodera, Y.; Hayama, M.; Ono, K. J. Agric. Food Chem. 2006, 54, 9811.
(2) Mitsakos, V.; Dobson, R. C. J.; Pearce, F. G.; Devenish, S. R.;
Evans, G. L.; Burgess, B. R.; Perugini, M. A.; Gerrard, J. A.; Hutton,
C. A. Bioorg. Med. Chem. Lett. 2008, 18, 842.
(9) Sakai, K.; Yoneda, N. Chem. Pharm. Bull. 1981, 29, 1554.
(10) Carson, J. F.; Boggs, L. M.; Lundin, R. E. J. Org. Chem. 1970,
35, 1594.
(3) Agarwal, R. K.; Dewar, H. A.; Newell, D. J.; Das, B. Athero-
sclerosis 1977, 27, 347.
(4) Yanagita, T.; Han, S.-y.; Wang, Y. u.-M.; Tsuruta, Y.; Anno, T.
Nutrition 2003, 19, 140.
(11) Hutton, C. A.; Jaber, R.; Otaegui, M.; Turner, J. J.; Turner, P.;
White, J. M.; Bacskay, G. B. J. Chem. Soc., Perkin Trans. 2 2002, 1066.
(12) Paradisi, M. P.; Zecchini, G. P.; Torrini, I.; Lucente, G.
J. Heterocycl. Chem. 1990, 27, 1661.
(5) Xiao, H.; Parkin, K. L. J. Agric. Food Chem. 2002, 50, 2488.
(6) Singh, V.; Belloir, C.; Siess, M.-H.; Le, B. A.-M. Nutr. Cancer
2006, 55, 178.
(7) Arulselvan, P.; Wen, C.-C.; Lan, C.-W.; Chen, Y.-H.; Wei, W.-C.;
Yang, N.-S. PLoS One 2012, 7, e44658.
(13) Carson, J. F.; Ludin, R. E.; Lukes, T. M. J. Org. Chem. 1966, 31,
1634.
(14) Kubec, R.; Cody, R. B.; Dane, A. J.; Musah, R. A.; Schraml, J.;
Vattekkatte, A.; Block, E. J. Agric. Food Chem. 2010, 58, 1121.
(15) Carson, J. F.; Lundin, R. E.; Boggs, L. M. J. Org. Chem. 1969,
34, 1996.
(8) Turner, J. J.; Gerrard, J. A.; Hutton, C. A. Bioorg. Med. Chem.
2005, 13, 2133.
(16) Carson, J. F.; Boggs, L. E. J. Org. Chem. 1966, 31, 2862.
r
10.1021/ol4023003
Published on Web 08/27/2013
2013 American Chemical Society

analogs of isoalliin (1) delivered 3,5-disubstituted 1,4-thiazane
S,S-dioxides in low yields with poor diastereoselection
after five days.17 More recently, a series of 3-substituted
and 3,5-disubstituted 1,4-thiazane dioxides were prepared
by the reaction of amines with divinyl sulfones,18 which
included a cyclization to create a second stereogenic center.
Overall, the stereoselective intramolecular cyclizations
of vinylic β-amino sulfoxides and sulfones remain, in
general, underexplored and sometimes inefficientreactions
in organic chemistry. Herein we report the diastereo-
selective synthesis of trans-3,5-disubstituted thiazane S-
monoxides and cis-3,5-disubstituted thiazane S,S-dioxides
from an intramolecular asymmetric aza-Michael reac-
tion of the corresponding enantiopure trans-1-alkenyl
2-aminoalkyl sulfoxides and sulfones, respectively. The value
of the chemistry is demonstrated by the stereodivergent
synthesis of cis- and trans-2,5-disubstituted pyrrolidine
alkaloids isolated from the venom extract of Myrmicaria
melanogaster.19
with that of the cis-disubstituted thiazane obtained from
the cyclization of isoalliin (1), which possesses anti SꢀO/
CꢀR0 stereochemistry. A selection of other sulfoxides 5
with syn stereochemistry also provided trans-3,5-disubsti-
tuted heterocycles as single diastereomers in excellent
yields, whether the starting material was introduced as
an amine (Table 1, entries 5, 7, 8) or as the ammonium
trifluoroacetate salt (Table 1, entries 2ꢀ4, 6). To the best of
our knowledge these are the first examples of an intra-
molecular aza-Michael reaction of an (E)-1-alkenyl
2-aminoalkyl sulfoxide with syn stereochemistry. In con-
trast, a β-amino sulfoxide (5h, Table 1, entry 9) with anti
stereochemistry provided the complementary trans-3,5-
disubstituted heterocycle over an extended reaction time,
consistent with isoalliin and its analog.13,14 The data in
Table 1 suggest the sulfinyl configuration alone directs the
stereochemistry of the R group.
β-Amino sulfoxides 5 with t-Bu, c-hexenyl, or phenyl-
ethyl R groups failed to cyclize after prolonged heating
under various reaction conditions. Therefore, we prepared
several (E)-1-alkenyl 2-aminoalkyl sulfones (7), anticipat-
ing them to be superior Michael acceptors.23,24 Using
similar conditions, sulfones 7 were converted to cis-3,5-
disubstituted thiazanes 8, possessing substituent stereo-
chemistry different from that of trans-3,5-thiazane sulf-
oxides 6aꢀg. Entry 1 of Table 2 displays near-complete
reversalinselectivity from thatof entries 1 and 2 ofTable1;
a similar relationship is seen for entries 7 of the tables.
Simply oxidizing the sulfoxides 5 to the corresponding
sulfone 6 prior to cyclization can shift the 3,5-substituent
orientation of the thiazanes from trans to cis!
Figure 1. Bioactive β-amino sulfoxides (A = CO2H; E = CO2Me).
Sulfones 7 with sterically demanding phenylethyl and
t-Bu substituents at the electrophilic carbon cyclized effi-
ciently to give cis-3,5-disubstituted thiazane dioxides in
good yields with dr’s ≈ 9:1 (Table 2, entries 2ꢀ3, 6). Ph
and t-Bu substituted thiazane 8e was formed as a single
diastereomer, likely owing to the large steric bulk of the
substituents (Table 2, entry 5). 1-Cyclohexenyl sulfone 7d
cyclized to bicyclic thiazane 8d with its tertiary hydrogens
in an all-cis orientation (Table 2, entry 4).25
The observed stereochemical dependence of the cycliza-
tion on the sulfur oxidation state can be attributed to
differences in conjugate addition reactivity and to the dis-
similar H-bonding propensities between sulfoxides and
sulfones.26 Sulfoxides are among the strongest H-bond
accepting functional groups, while sulfones are comparatively
weak.26,27 Sulfoxides exhibit strong intramolecular H-bonds
with hydroxyl groups even at temperatures >170 °C,28ꢀ30
while the analogous sulfones do not.29,30 It is suggested here
Scheme 1. Doubly Diasteroselective Preparation of Chiral
syn-(E)-1-Alkenyl 2-Aminoalkyl Sulfoxides (ref 20)
Our recently disseminated doubly diastereoselective
sulfenate alkylation chemistry permits facile access to syn
oriented Boc-protected (E)-1-alkenyl 2-aminoalkyl sulfox-
ides 4 (Scheme 1).20 Numerous cyclization attempts
of sulfoxide 4a (R = Me, R0 = Bn)20 failed to provide
any cyclic products, likely due to the electronic and steric
hindrance of the Boc group.21 Therefore cyclizations of the
deprotected free amine were pursued. Amine 5a could be
cyclized to the corresponding trans-3,5-substituted thia-
zane 6a as a single diastereomer by treatment with Et3N in
MeOH at reflux.22 The stereochemistry of 6a contrasts
(23) Podlech, J. J. Phys. Chem. A 2010, 114, 8480.
(24) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(25) Subjecting the pure major diastereomer 8c and the pure minor
isomer of 8f to prolonged cyclization conditions did not change the dr,
indicating that the cyclization reaction is not reversible.
(26) Patai, S., Rapoport, Z., Stirling, C., Eds. The Chemistry of
Sulfones and Sulfoxides; John Wiley & Sons: New York, 1988.
(27) Hunter, C. A. Angew. Chem., Int. Ed. 2004, 43, 5310.
(28) Chasar, D. W. J. Org. Chem. 1976, 41, 3111.
(17) Carson, J. F.; Boggs, L. E.; Lundin, R. J. Org. Chem. 1968, 33,
3739.
(18) Pal, T. K.; Dey, S.; Pathak, T. J. Org. Chem. 2011, 76, 3034.
(19) Jones, T. H.; Voegtle, H. L.; Miras, H. M.; Weatherford, R. G.;
Spande, T. F.; Garraffo, H. M.; Daly, J. W.; Davidson, D. W.; Snelling,
R. R. J. Nat. Prod. 2007, 70, 160.
(20) Soderman, S. C.; Schwan, A. L. J. Org. Chem. 2013, 78, 1638.
(21) The authors adopt the syn and anti notation to designate the
[RS,SC/SS,RC] and [RS,RC/SS,SC] configurations, respectively, of the
chiral sulfoxide.
(29) Kingsbury, C. A.; Auerbach, R. A. J. Org. Chem. 1971, 36, 1737.
(30) Kingsbury, C. A.; Day, V. W.; Day, R. O. J. Org. Chem. 1980,
45, 5255.
(22) See Supporting Information for a table of optimization conditions.
Org. Lett., Vol. 15, No. 17, 2013
4435

Table 1. Trans-Selective Cyclizations of (E)-1-Alkenyl
2-Aminoalkyl Sulfoxides
Table 2. Cis-Selective Cyclizations of (E)-1-Alkenyl
2-Aminoalkyl Sulfones
a All dr’s assigned by NMR analysis of the crude reaction mixture.
No minor isomers were evident. The relative stereochemistry of ring
substituents was determined by analysis of 1H NMR coupling constants
and 2D NMR acquisitions and NOE experiments. b Reaction did not go
to completion. Yield reported is of isolated material based on 100%
consumption of 5. c Yield is 91% based on consumed 5g. d Yield is 94%
based on consumed 5h. e Reaction mixture was refluxed for 42 h.
a 1 equiv of Et3N was used unless otherwise noted. b All dr’s assigned
as indicated for Table 1. c Cyclization reaction was done on an ∼5:1
(uncyclized/cyclized) mixture, because partial cyclization was observed
following Boc removal. d Product was isolated from unreacted 7 (∼5%).
Yield based on consumed 7 ∼83%. e Compound was reacted as the TFA
salt. 2 equiv of Et3N were employed.
that the cyclization reactions of the sulfones proceed by way
of a six-membered transition state (labeled A, Scheme 2)
wherein both R and R0 assume pseudoequatorial positions.
A similar chair transition state for the cyclizations of syn
β-amino sulfoxides (Table 1, entries 1ꢀ8) would not
deliver the observed trans-3,5-disubstituted thiazanes 6.
However, if pseudotwist-boat conformation B is adopted
in the transition state, the trans-3,5-disubstituted hetero-
cycles 6 can be accessed. Twist-boat B features a stabilizing
hydrogen bond interaction between the sulfinyl oxygen
andaminefunctionalities, whichprecludestheunfavorable
1,4-flagpole interaction present in the twist-boat confor-
mation of related ring systems, while the R0 and R sub-
stituents remain remote from one another. The sluggish
cyclization of sulfoxide 5h (e.g., Table 1, entry 9) can be
explained by the weaker activating sulfoxide group if
geometry A is operable. Alternatively, the R and R0 groups
of 6hare expectedtoundergoa steric clash ifB is part of the
reaction pathway. MeOH is also anticipated to be in-
volved; further investigations are underway.
Jones et al. isolated 14 alkaloids from venom extracts of
the ant Myrmicaria melanogaster,19 two of which include
chiral trans- and cis-2,5-disubstituted pyrrolidines 15 and
20 (Scheme 3). The authors did not elucidate the absolute
configuration at either stereocenter. Alkaloids of the same
structural family have been isolated from frog skin
extracts31 and extracts of the venoms from other ant
species.32 In Nature, alkaloids 15 and 20 are sprayed from
a venom gland of M. melanogaster to ward off predators.19
Scheme 2. Possible Transition State Geomteries for Cyclization
Reactions
Structurally similar 2,5-substituted pyrrolidines have
shown potent insecticidal activity toward arthropods32
while other such compounds have demonstrated high
biological activity.33 The biological study of insect venoms
has led to the discovery of new therapeutic agents.34
Coldham and Leonori have prepared venom alkaloids
15 and 20 in good optical purity using a sequence of
stereoselective Cu(I)-promoted allylation and crotylation
reactions as key steps.35 However, the crotylation provides
a disubstituted pyrrolidine intermediate in low yield (32%)
and poor dr (1.8:1 = cis/trans). Further, (ꢀ)-sparteine,
the ligand used for the allylation reaction, is no longer
available from major suppliers36 and is a preparative
challenge.37,38
(33) (a) Santarem, M.; Vanucci-Bacque, C.; Lhommet, G. J. Org. Chem.
2008, 73, 6466. (b) van Esseveldt, B. C. J.; Vervoort, P. W. H.; van, D. F. L.;
€
Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 1791. (c) Gartner, M.; Weihofen,
(31) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005,
R.; Helmchen, G. Chem.;Eur. J. 2011, 17, 7605.
(34) Dossey, A. T. Nat. Prod. Rep. 2010, 27, 1737.
(35) Coldham, I.; Leonori, D. J. Org. Chem. 2010, 75, 4069.
68, 1556.
(32) Jones, T. H.; Blum, M. S.; Escoubas, P.; Ali, T. M. M. J. Nat.
Prod. 1989, 52, 779.
4436
Org. Lett., Vol. 15, No. 17, 2013

the 6f so that hydrogenation/hydrogenolysis of 13 could
be later performed in a single step. MCPBA oxidation
of Cbz protected thiazane 11 afforded sulfone 12 which
Scheme 3. Stereodivergent Synthesis of Trans and Cis Isomeric
Ant Venom Alkaloids
was then converted to pyrroline 13 in acceptable yield
41
€
using newly developed RambergꢀBacklund conditions.
Initial hydrogenation/hydrogenolysis attempts on 13 with
a Pd/C/H2 catalyst system resulted in pyrrolidine formation
with a large erosion of diastereoselectivity.42 The use of a
Pt/C/H2 catalyst system converted 13 to pyrrolidine 14
in excellent yield with only a slight erosion of dr to the cis
diastereomer. The trans pyrrolidine 14 could not be sepa-
rated from the minor cis isomer so it was carried on to
the next step. Cbz protected pyrrolidine 14 was deblocked
with Pd/C/H2 and then converted to the TFA salt 15 in
excellent yield for the two steps without any change of the
dr. Optical rotation of the free amine (2R,5R)-2-butyl-5-
propylpyrrolidine (15) suggested it was obtained in high
optical purity.35
The synthesis of 20 required immediate MCPBA oxida-
tion of the original ∼9:1 mixture of 10 which delivered
an excellent yield of sulfone 16. Subsequent deprotection
of 16 with TFA to give free amine 7g proceeded efficiently.
The cyclization of 7g occurred as per Table 2 (entry 7).
The major cis diastereomer was separated from the trans
isomer by flash chromatography. Protection of 8g with
€
Cbz affording 17 was followed by RambergꢀBacklund
treatment to give an acceptable yield of pyrroline 18.
For hydrogenation/hydrogenolysis, the Pt/C/H2 catalyst
system converted 18 to pyrrolidine 19 with no loss of dr.
Pyrrolidine 19 was deblocked with the Pd catalyst and
isolated (2S,5R)-2-butyl-5-propylpyrrolidine (20) as its
TFA salt in excellent overall yield. The success of the two
syntheses and the data of Tables 1 and 2 indicate that the
enantiomers of 15 and 20 can also be prepared if one
employs L-norvaline as a source of the homochiral iodide.
To summarize, this investigation demonstrates a novel
stereodivergent synthesis of trans- or cis-3,5-disubstituted
1,4-thiazane oxides achieved by simply changing the oxida-
tion state of the sulfur atom. Transition states are offered to
account for the observed selectivity. The utility of this
chemistry permitted the stereodivergent diastereoselective
synthesis of two isomeric ant venom alkaloids from iden-
tical starting materials. The mechanistic origins of the
experimentally observed cyclization stereoselectivities are
currently under investigation.
Our synthesis of alkaloids 15 and 20 commenced with
the diastereoselective alkylation of lithium (E)-1-hexene-
sulfenate (from butylthiirane S-oxide) with amino iodide 9
derived from D-norvaline, to give β-amino sulfoxide 10
in good yield and diastereoselectivity (Scheme 3).20,39,40
For the synthesis of 15, the major isomer of sulfoxide 10
was deprotected withTFA toprovide free amine 5f in good
yield and subsequent cyclization provided thiazane 6f
(entry 7, Table 1). The Cbz group was chosen to protect
Acknowledgment. The authors gratefully acknowledge
NSERC of Canada for funding this research and for
providing PGS funding for S.C.S.
(36) Coady, D. J.; Engler, A. C.; Horn, H. W.; Bajjuri, K. M.;
Fukushima, K.; Jones, G. O.; Nelson, A.; Rice, J. E.; Hedrick, J. L.
ACS Macro Lett. 2011, 1, 19.
(37) Smith, B. T.; Wendt, J. A.; Aube, J. Org. Lett. 2002, 4, 2577.
(38) Wendt, J. A.; Aube, J. Tetrahedron Lett. 1996, 37, 1531.
(39) 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.
(40) Soderman, S. C.; Schwan, A. L. Org. Lett. 2011, 13, 4192.
(41) Soderman, S. C.; Schwan, A. L. J. Org. Chem. 2012, 77, 10978.
(42) Coquerel, Y.; Rodriguez, J. ARKIVOC 2008, 227.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds, includ-
ing selected NOESY data and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 17, 2013
4437