Memory of chirality approach to the enantiodivergent synthesis of chiral benzo[ d ]sultams

Article abstract of DOI:10.1021/ol401557v

The "memory of chirality" stereodivergent synthesis of polyfluorobenzo[d]sultams has been developed. The interest of this protocol resides in the possibility of using the chirality of a starting sulfonamide single enantiomer to synthesize the target sulta

Full text of DOI:10.1021/ol401557v

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3686–3689
Memory of Chirality Approach to the
Enantiodivergent Synthesis of Chiral
Benzo[d]sultams
Francesca Foschi,† Aaron Tagliabue,‡ Voichita Mihali,‡ Tullio Pilati,† Ilir Pecnikaj,‡
and Michele Penso*,†
CNR-Institute of Molecular Science and Technologies (ISTM), Via Golgi 19,
ꢀ
I-20133 Milano, Italy, and Dipartimento di Chimica, Universita degli Studi di Milano,
Via Golgi 19, I-20133 Milano, Italy
michele.penso@istm.cnr.it
Received June 3, 2013
ABSTRACT
The “memory of chirality” stereodivergent synthesis of polyfluorobenzo[d]sultams has been developed. The interest of this protocol resides in
the possibility of using the chirality of a starting sulfonamide single enantiomer to synthesize the target sultams in both absolute configurations,
by using different base systems, under homogeneous conditions.
The “memory of chirality” (MOC) strategy, widely used
in asymmetric synthesis, has been extensively applied by
Kawabata1 and other authors2 to the synthesis of
several enantiopure compounds. In particular, Kawabata
applied MOC protocols to the enantioselective synthesis of
R,R-disubstituted R-amino acids, through intramolecular
alkylation,1g,j,q,r conjugate addition,1h,s carbonyl migration,1c
and Dieckman condensation1e or intermolecular alkyla-
tion,1i,lꢀn aldol condensation,2b and conjugate addition2a
of readily available optically active R-amino acid deriva-
tives, without any external source of chirality.3 The for-
mation of long-lifetime conformers, which derive their
† CNR-Institute of Molecular Science and Technologies.
‡
ꢀ
Universita degli Studi di Milano.
(1) (a) Yoshimura, T.; Kinoshita, T.; Yoshioka, H.; Kawabata, T. Org.
Lett. 2013, 15, 864–867. (b) Watanabe, H.; Yoshimura, T.; Kawakami, S.;
Sasamori, T.; Tokitoh, N.; Kawabata, T. Chem. Commun. 2012, 48, 5346–
5348and references therein. (c) Teraoka, F.; Fuji, K.; Ozturk, O.; Yoshi-
mura, T.; Kawabata, T. Synlett 2011, 543–546. (d) Kawabata, T. ACS
Symp. Ser. 2009, 1009, 31–56. (e) Watanabe, T.;Kawabata, T. Heterocycles
2008, 76, 1593–1606. (f) Moriyama, K.; Sakai, H.; Kawabata, T. Org. Lett.
2008, 10, 3883–3886. (g) Kawabata, T.; Moriyama, K.; Kawakami, S.;
Tsubaki, K. J. Am. Chem. Soc. 2008, 130, 4153–4157. (h) Kawabata, T.;
Majmudar, S.; Tsubaki, K.; Monguchi, D. Org. Biomol. Chem. 2005, 3,
1609–1611. (i) Kawabata, T.; Chen, J.; Suzuki, H.; Fuji, K. Synthesis 2005,
1368–1377. (j) Kawabata, T.; Kawakami, S.; Majmudar, S. J. Am. Chem.
Soc. 2003, 125, 13012–13013. (k) Kawabata, T.; Fuji, K. Memory of
Chirality: Asymmetric Induction Based on the Dynamic Chirality of
Enolates. In Topics in Stereochemistry; Denmark, S. E., Ed.; John Wiley &
Sons, Inc.: Hoboken, NJ, 2003; Vol. 23. (l) Kawabata, T.; Suzuki, H.; Nagae,
Y.; Fuji, K. Angew. Chem., Int. Ed. 2000, 39, 2155–2157. (m) Kawabata, T.;
Chen, J.; Suzuki, H.; Nagae, Y.; Kinoshita, T.; Chancharunee, S.; Fuji, K.
Org. Lett. 2000, 2, 3883–3885. (n) Fuji, K.; Kawabata, T. Chem.ꢀEur. J.
1998, 4, 373–376. (o) Kawabata, T.; Fuji, K. J. Syn. Org. Chem. Jpn. 1994,
52, 589–595. (p) Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. Soc.
1991, 113, 9694–9696. (q) Kawabata, T.; Matsuda, S.; Kawakami, S.;
Monguchi, D.; Moriyama, K. J. Am. Chem. Soc. 2006, 128, 15394–15395.
(r) Kawabata, T.; Wirth, T.; Yahiro, K.; Suzuki, H.; Fuji, K. J. Am. Chem.
Soc. 1994, 116, 10809–10810. (s) Yoshimura, T.; Takuwa, M.; Tomohara,
K.; Uyama, M.; Hayashi, K.; Yang, P.; Hyakutake, R.; Sasamori, T.;
Tokitoh, N.; Kawabata, T. Chem.ꢀEur. J. 2012, 18, 15330–15336.
(2) For recent references see: (a) Sasmal, A.; Taniguchi, T.; Wipf, P.;
Curran, D. P. Can. J. Chem. 2013, 91, 1–5. (b) Ghorai, M. K.; Ghosh, K.;
Yadav, A. K.; Nanaji, Y.; Halder, S.; Sayyad, M. J. Org. Chem. 2013, 78,
2311–2326. (c) Patil, N. T. Chem. Asian J. 2012, 7, 2186–2194. (d)
Mondal, S.; Nechab, M.; Vanthuyne, N.; Bertrand, M. P. Chem.
Commun. 2012, 48, 2549–2551. (e) Campolo, D.; GaudelꢀSiri, A.;
Mondal, S.; Siri, D.; Besson, E.; Vanthuyne, N.; Nechab, M.; Bertrand,
M. P. J. Org. Chem. 2012, 77, 2773–2783. (f) Mai, T. T.; Viswambharan,
B.; Gori, D.; Kouklovsky, C.; Alezra, V. J. Org. Chem. 2012, 77, 8797–
8801. (g) Farran, D.; Archirel, P.; Toupet, L.; Martinez, J.; Dewynter, G.
Eur. J. Org. Chem. 2011, 2043–2047.
(3) MOC approach, according to Carlier et al., “... can be defined as a
formal substitution at an sp3 stereogenic center that proceeds stereo-
specifically, even though the reaction proceeds by trigonalization of that
center, and despite the fact that no other permanently chiral elements are
present in the system”. Zhao, H.; Hsu, D. C.; Carlier, P. R. Synthesis
2005, 1–16.
r
10.1021/ol401557v
Published on Web 07/05/2013
2013 American Chemical Society

chirality from the presence of a stereogenic element, has
been invoked to explain the MOC phenomenon. For
instance, enolates of optically pure R-amino acid deriva-
tives bearing two different N-substituents may present
a stereogenic CꢀN axis and, therefore, behave as chiral
nonracemic compounds. Moreover, in the majority of the
literature cases, the configuration of the R-alkylation
products of the above enolates is closely related to the
absolute configuration of the starting R-amino acids, and
the retention products are obtained. Kawabata reported
also the enantioselective synthesis of both enantiomers of
R-quaternary-R-amino acids, modulated by changing the
organometallic bases.1q Furthermore, a few examples of
“product chirality switching” modulated by the reaction
conditions are known,4 and examples of application of this
principle to dendrimers,5 peptides,6 and to helical bio-
organic systems,7 such as proteins and DNA’s, have recently
reported.
N-alkylation/cyclization, through the intermediate N-alkyl
amidoester 2, under phase transfer catalysis (PTC) condi-
tions; (b) a quantitative cyclization to the nonalkylated
sultam 4 with 1,8-diazabicycloundec-7-ene (DBU) as a
base, under homogeneous conditions, followed by (c)
PTC N-alkylation of the intermediate 4. Experiments per-
formed on enantiopure methyl N-(pentafluorobenzene)-
sulfonyl-L-phenyl-glycinate 5a under PTC conditions by
varying the alkylating agent, the solvent, or PT catalyst gave
only minor or no enantioselectivity.10 On the basis of these
results, we turned our attention toward the homogeneous
conditions for the cyclization of 5a. As already reported,9
when excess DBU was used as a base in acetonitrile (Table 1,
entry 1) the NH sultam 7a was isolated in quantitative
yield and in racemic form. Thus, to improve the enantio-
meric ratio, both solvent and base effects were investigated
(Table 1). A first interesting result (entry 2) was reached by
using DME as a solvent at 25 °C and 7a was isolated with er
68:32 in favor of the (ꢀ)-enantiomer (the retention R-isomer,
as demonstrated hereafter); THF gave a minor er (entry 3),
whereas other common solvents of different polarity
(DMSO, DMF, DCM, toluene, chlorobenzene) induced
complete racemization. Furthermore, a series of bases similar
to DBU regarding structural characteristics and/or basic
strength11 were examined by using DME as a solvent
(entries 4ꢀ8). Among bicyclic bases, only MTBD (entry 6)
was partially effective, giving a er comparable to that ob-
tained with DBU, but in longer reaction times. Surprisingly,
BTMG (entry 8) completely reversed the enantioselectivity in
favor of the (þ)-isomer (the inversion S-isomer).
Scheme 1. Synthesis of Racemic Tetrafluorobenzo[d]sultams 3
Herewereport the MOC enantiodivergent cyclization of
R-arylglycine (polyfluorobenzo)sulfonamides to the corre-
sponding benzo[d]sultams, which have been obtained
in both their absolute configurations by using different
base systems. Sultams, and their fused counterparts, have
stimulated vast interest8 due to their bioactivity and med-
icinal use as antiviral, anticancer, antimicrobial, antima-
larial, antileukemic, etc. and exhibit broad inhibitory
properties against a variety of enzymes. Besides, fused
sultams have found interesting applications in organic
synthesis as protecting groups, chiral auxiliaries, and
directed metalation groups (DMGs).8
Recently, we have described a novel strategy for the
preparation of racemic N-substituted 3-aryl-3-carboxy-
tetrafluorobenzo[d]sultam 3 (Scheme 1).9 Starting from
the corresponding N-sulfonyl-2-amino esters 1, we pro-
posed two alternative synthetic pathways: (a) a one-pot
Table 1. Synthesis of Sultam 7a under Homogeneous Conditionsa
entry
baseb
solvent
t (h)
yield (%)c
er (%)d
1
2
3
4
5
6
7
8
DBU (24.3)
DBU
MeCN
DME
THF
16
8
98
98
95
94
98
56
90
95
0
68:32
62:38
57:43
52:48
69:31
52:48
10:90
DBU
8
DBN (23.9)
TBD (25.98)
MTBD (25.4)
TMG (23.3)
BTMG (23.56)
DME
DME
DME
DME
DME
16
16
20
16
90
a Base and Solvent Variation. Reaction conditions. 5a (1 mmol), base
(4 mmol), solvent (4 mL), 25 °C. b DBN = 1,5-diazabicyclo(4.3.0)non-5-
ene; TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene; MTBD = 7-methyl-1,5,
7-triazabicyclo[4.4.0]dec-5-ene; TMG = 1,1,3,3-tetramethyl-guanidine;
BTMG = 2-tert-butyl-1,1,3,3-tetramethylguanidine. In parentheses,
pka value in acetonitrile of the conjugate acid. c Isolated yields.
d Enantiomeric ratio (R:S) determined by chiral HPLC.
(4) (a) Li, G.; Wang, Z.; Lu, R.; Tang, Z. Tetrahedron Lett. 2011, 52,
3097–3101. (b) Liu, Z.; Shi, M. Tetrahedron: Asymmetry 2009, 20, 119–
123. (c) Burguete, M. I.; Collado, M.; Escorihuela, J.; Luis, S. V. Angew.
Chem., Int. Ed. 2007, 46, 9002–9005.
(5) Hofacker, A. L.; Parquette, J. R. Angew. Chem., Int. Ed. 2005, 44,
1053–1057.
(6) Peacock, A. F. A.; Stuckey, J. A.; Pecoraro, V. L. Angew. Chem.,
Int. Ed. 2009, 48, 7371–7374.
(7) Miyake, H.; Tsukube, H. Chem. Soc. Rev. 2012, 41, 6977–6991.
(8) Majumdar, K. C.; Mondal, S. Chem. Rev. 2011, 111, 7749–
7773and references therein.
(9) Penso, M.; Albanese, D.; Landini, D.; Lupi, V.; Tagliabue, A.
J. Org. Chem. 2008, 73, 6686–6690.
(10) For details see Supporting Information.
(11) Lemaire, C. F.; Aerts, J. J.; Voccia, S.; Libert, L. C.; Mercier, F.;
Goblet, D.; Plenevaux, A. R.; Luxen, A. J. Angew. Chem., Int. Ed. 2010,
49, 3161–3164.
Org. Lett., Vol. 15, No. 14, 2013
3687

The ring-closing reaction of methyl ester 5a was con-
ducted at 25 °C by using molar amounts of DBU in
association with catalytic or molar quantities of an addi-
tional base, looking forward additive-DBU-substrate
interactions capable of inducing the formation of a chiral
adduct, which could evolve enantioselectively toward the
desired benzosultam. Under the applied reaction condi-
tions, the stereoselectivity of the reaction was not influ-
enced by the presence of any added base, with the sub-
stantial exception of BTMG.
Table 2. Enantiodivergent Cyclization of Substituted R-Aryl
(Polyhalobenzene)sulfonamidesa
entry
methb
t (h)
productc
yield (%)
er (%)d
1
5a
R
I
3
96
6
R-7a
S-7a
9a
97
96
45
47
40e
33e
94
88
81
35e
99
70e
96
93
87
92
93
94
93
89
83:17
10:90
50:50
50:50
53:47
46:54
78:22
18:82
97:3
2
3
8a
R
I
4
16
16
48
16
48
96
96
96
168
72
96
72
144
20
72
12
24
9a
5
8b
R
I
R-9b
S-9b
R-9c
S-9c
6
Figure 1. Synthesis of sultam 7a under homogeneous conditions
using the basic system DBU/BTMG (2 mol equiv): influence of
the bases ratio on the er. Isolated yields are in the range 97 ( 2%.
7
8c
R
I
8
9
8d
R
I
R-9d
S-9d
R-9e
S-9e
R-12a
S-12a
R-12b
S-12b
R-12c
S-12c
R-12d
S-12d
10
11
12
13
14
15
16
17
18
19
20
2:98
In fact, the runs carried out by varying the ratio of the
basic system DBU/BTMG (Figure 1) evidenced a strong
synergistic effect between the two bases on the enantios-
electivity, that is, the er value increased by increasing
the amount of BTMG, up to a maximum (er 84:16) with
a 7:93 DBU/BTMG molar ratio; as reported, by using only
BTMG as a base (Table 1, entry 8), the enantioselectivity is
drastically reversed in favor of (þ)-7a (er 10:90, right side
of Figure 1).
8e
R
I
89:11
3:97
11a
11b
11c
11d
R
I
76:24
9:91
R
I
74:26
12:88
74:26
10:90
74:26
15:85
R
I
R
I
The influence of the R-proton acidity on the ring-closing
stereoselectivity was analyzed by applying both the opti-
mized protocols (methods R and I in Table 2, note a) to the
(S)-R-aryl (pentafluorobenzene)sulfonamido esters 8aꢀe
series (Table 2). When compounds 8a,b (entries 3ꢀ6),
bearing an electronwithdrawing group, were used exten-
sive racemization occurred under both the basic condi-
tions. On the contrary, the presence of an electrondonating
group in compounds 8cꢀe produced good er, the stronger
the EDG the higher the er value (entries 7ꢀ12). Both
methods were then applied to (S)-R-phenyl sulfonamides
11aꢀd (Table 2), bearing different halogenated sulfonami-
do-aromatic rings. In all cases, the yields of sultams 12aꢀd
are good; er values of the inversion sultams (entries 14, 16,
18, 20) are interesting, whereas the retention products
(entries 13, 15, 17, 19) have er values somewhat inferior
than that found for R-7a.
As regards the mechanism (Scheme 2) we suppose that
the NꢀH proton, much more acidic than ester R-CꢀH,
is first deprotonated by the sterically demanding base,
BTMG, forming the tight ion-pair A. The less sterically
demanding DBU (path a) favors the enol formation
through an intermolecular H-bond from the less crowded
side forming the intermediate B that, in turn, cyclizes
to the retention sultam. In the presence of BTMG
a Variation of R-Aryl and Arylsulfonamido Moieties. b Reaction
conditions. Method R: sulfonamide 5a,8,11 (1 mmol), BTMG/DBU
(2 mol) in 85:15 molar percentage, DME (4 mL), 25 °C. Method I:
sulfonamide 5a,8,12 (1 mmol), BTMG (4 mmol), DME (4 mL). c The
stereochemical descriptor of the main enantiomer is indicated. d The er
was determined by chiral HPLC. e Partial conversion of substrate 8.
alone (path b), the enol formed from the ion-pair A,
through an intramolecular H-bond, is forced to the more
crowded conformation C, which evolves to the inversion
sultam.
As reported in the literature, MOC conditions are
ineffective on symmetrically N,N-disubstituted substrates,
therefore all MOC reactions were carried out using com-
pounds having two different substituents on the nitrogen.
To explain the reactivity of our starting NH-sulfonamido
esters, we supposed that the very stable tight ion-pair
formed by BTMG and the substrate (intermediate A in
Scheme 2) mimics an unsymmetrically N,N-disubstituted
sulfonamide hence, stabilizing a specific conformation of
the formed enol.
To determine the absolute stereochemistry of the main
enantiomer, sultams R-7a and S-7d (Scheme 3) were
N-alkylated under SL-PTC conditions to the correspond-
ing compounds 6a,b,d that, in turn, were subjected to
3688
Org. Lett., Vol. 15, No. 14, 2013

Scheme 2. Hypothesized Model that Fits with the Results: Method R (path a) and Method I (path b)
enantiomer to synthesize the target polyfluorobenzo[d]-
sultams in both absolute configurations by choosing the
organic base system, which is the determining factor to
direct the cyclization toward either enantiomer. A further
feature of this protocol is the use, as starting compound, of
an R-amino acid derivative bearing a monosubstituted
NH-sulfonamide function, so opening the possibility to
study the synthesis under MOC conditions of several
amino acid derivatives, without the need of introducing
two different N-activating groups.
Scheme 3. PTC Synthesis and Preferential Crystallization of
Sultams 6
Acknowledgment. This research was carried out within
the framework of the National Project “Nuovi metodi
catalitici stereoselettivi e sintesi stereoselettiva di molecole
funzionali” and is supported by MIUR (Rome) and CNR
(Italy).
preferential crystallization.11 The Rx analysis12 of the
optically pure enantiomers R-6a,b and S-6d confirms that
method R producesmainlythe corresponding sultamswith
retention of the starting configuration, whereas method I
gives the inversion sultams.13
In conclusion, the MOC stereodivergent synthesis here
described uses the chirality of a starting sulfonamide single
Supporting Information Available. Full experimental
procedures, analyses, and characterization data for all
new compounds. X-ray crystallographic data (CIF) for
compounds R-6a,b and S-6d. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) CCDC 920402 (R-6a), CCDC 920404 (R-6b), and CCDC 920403
(S-6d) contains supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(13) The absolute configuration of 9aꢀe and 12aꢀe was tentatively
assigned by analogy to that of 7a and 7d.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 14, 2013
3689