Catalytic asymmetric synthesis of cyclic sulfamides from conjugated dienes

Article abstract of DOI:10.1021/ol303469a

This paper describes the catalytic asymmetric diamination of alkyl dienes using N,N′-di-tert-butylthiadiaziridine 1,1-dioxide in the presence of Pd(0) and a chiral phosphoramidite ligand to give cyclic sulfamides in high yield and high ee. The diamination is also amenable to gram scale.

Full text of DOI:10.1021/ol303469a

ORGANIC
LETTERS
2013
Vol. 15, No. 4
796–799
Catalytic Asymmetric Synthesis of Cyclic
Sulfamides from Conjugated Dienes
Richard G. Cornwall, Baoguo Zhao, and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States
yian@lamar.colostate.edu
Received December 18, 2012
ABSTRACT
This paper describes the catalytic asymmetric diamination of alkyl dienes using N,N0-di-tert-butylthiadiaziridine 1,1-dioxide in the presence of
Pd(0) and a chiral phosphoramidite ligand to give cyclic sulfamides in high yield and high ee. The diamination is also amenable to gram scale.
Vicinal diamines are found throughout biologically
active molecules and are important chiral control agents
in asymmetric synthesis.1 The synthesis of vicinal diamines
through the metal-promoted diamination of olefins pre-
sents an attractive and efficient strategy to access these
important functional motifs, and various methods have
been reported.1ꢀ10 We have previously reported Pd(0)-11 and
Cu(I)-catalyzed12 methods for the regioselective diamination
of conjugated dienes using N,N0-di-tert-butyldiaziridinone
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r
10.1021/ol303469a
Published on Web 01/30/2013
2013 American Chemical Society

(1) (Figure 1) as nitrogen source.13 Asymmetric variations
of these reactions have also been disclosed.14,15 A related
analogue, N,N0-di-tert-butylthiadiaziridine 1,1-dioxide (2),16
has also shown to be an effective nitrogen source in the syn-
thesis of cyclic sulfamides using Pd(0),17 CuCl,18,19 or CuBr19
as catalyst. The resulting cyclic sulfamides are important
functional motifs present in medicinal and biologically active
molecules including HIV protease inhibitors, anti-inflam-
matory agents, antibacterials, blood pressure regulators,
enzyme inhibitors, and treatments for Alzheimer’s disease
(Figure 2).20 Cyclic sulfamides have also shown promise as
chiral auxiliaries (Figure 2).21 Due to their biological and
synthetic importance, an asymmetric synthesis of cyclic
sulfamides is highly desirable. Commonly used methods
employ multistep syntheses from chiral amino acids,22 or
more recently, the asymmetric hydrogenation of thiadiazole
Figure 1. Nitrogen sources for diamination.
(12) (a) Yuan, W.; Du, H.; Zhao, B.; Shi, Y. Org. Lett. 2007, 9, 2589.
(b) Zhao, B.; Peng, X.; Cui, S.; Shi, Y. J. Am. Chem. Soc. 2010, 132,
11009. (c) Zhao, B.; Peng, X.; Zhu, Y.; Ramirez, T. A.; Cornwall, R. G.;
Shi, Y. J. Am. Chem. Soc. 2011, 133, 20890.
(13) For a leading review on diaziridinones, see: Heine, H.W. In
The Chemistry of Heterocyclic Compounds; Hassner, A., Ed.; John Wiley &
Sons: New York, 1983; p 547.
(14) For Pd(0)-catalyzed asymmetric diamination of conjugated
dienes, see: (a) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
2007, 129, 11688. (b) Xu, L.; Shi, Y. J. Org. Chem. 2008, 73, 749.
(15) For Cu(I)-catalyzed asymmetric diamination of conjugated
dienes, see: (a) Du, H.; Zhao, B.; Yuan, W.; Shi, Y. Org. Lett. 2008,
10, 4231. (b) Zhao, B.; Du, H.; Shi, Y. J. Org. Chem. 2009, 74, 8392.
(16) For preparation of N,N0-di-tert-butylthiadiaziridine 1,1-dioxide
(2), see: (a) Timberlake, J. W.; Alender, J.; Garner, A. W.; Hodges, M. L.;
Figure 2. Cyclic sulfamides as biologically active molecules and
chiral auxiliaries.
1,1-dioxides, which are synthesized via reaction of R-hydroxy
aryl ketones with sulfamide.23 Herein we wish to report the
direct synthesis of optically active cyclic sulfamides via the
catalytic asymmetric diamination of conjugated dienes with
N,N0-di-tert-butylthiadiaziridine 1,1-dioxide (2).
€
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olefins using 2, see: Wang, B.; Du, H.; Shi, Y. Angew. Chem., Int. Ed.
2008, 47, 8224.
Using trans-nona-1,3-diene as test substrate, thiadiaziri-
dine 2 as nitrogen source, and catalysts generated from
Pd2(dba)3 and a chiral ligand, the reactivity and selectivity
of diamination was investigated (Scheme 1). No reaction
was observed using bidentate ligand R-BINAP (L1).24 Of
the ligands screened,25ꢀ28 BINOL-based phosphoramidite
ligands displayed the most promising selectivity, and di-
amination was found to be highly regioselective for the
internal double bond of the diene. Somewhat surprisingly,
ligands L514a and L6,29 which were found to induce high
(18) For CuCl-catalyzed diamination of activated terminal double
bonds using 2, see: Zhao, B.; Yuan, W.; Du, H.; Shi, Y. Org. Lett. 2007,
9, 4943.
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and 2, see: Cornwall, R. G.; Zhao, B.; Shi, Y. Org. Lett. 2011, 13, 434.
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Org. Lett., Vol. 15, No. 4, 2013
797

Table 1. Catalytic Asymmetric Diamination of Conjugated
Dienes to Form Cyclic Sulfamidesa
Scheme 1. Initial Screening for Asymmetric Diamination
selectivity for catalytic asymmetric diaminations using 1,
exhibited lower selectivity in the current system. On the
contrary, (R,R,R) ligand L7 was found to be optimal for
both yield and selectivity providing the corresponding cyclic
sulfamide in 76% yield and 90% ee, whereas ent-L7 had
previously displayed poor reactivity using 1. As also shown
in Scheme 1, (R,S,S) ligand L8 displayed decreased selec-
tivity from that of L7, indicating that a matched relationship
between the BINOL and amine portions of the ligand are
important for high asymmetric induction. In both cases, the
product configuration is determined by the BINOL skeleton
and not the amine portion of the ligand. H8ꢀBINOL-
derived phosphoramidite ligand L9 also resulted in high ee,
yielding the opposite enantiomer of the product sulfamide.
With optimal ligand in hand, the substrate scope was
subsequently investigated. As shown in Table 1, a variety
of alkyl-substituted conjugated (E)-dienes30 can be effi-
ciently diaminated in 66ꢀ98% yield and 90ꢀ93% ee with
2.5 mol % Pd2(dba)3 and 10 mol % L7 in toluene at 65 °C
for3 h. Alkylchains can contain silyl (Table1, entry6), and
aryl groups (Table 1, entries 7ꢀ9) as well as ethers (Table 1,
entries 10ꢀ12). Double bondsin the alkyl groupsremained
unreacted in geometrically pure form (Table 1, entries 13
and 14). The catalytic asymmetric diamination is also
amenable to gram scale and catalyst loading can be further
reduced to 1.4 mol % Pd2(dba)3 (Table 1, entry 8). In all
a All reactions were carried out withdiene 3(0.20 mmol), 2(0.30 mmol),
Pd2(dba)3 (0.005 mmol), and L7 (0.02 mmol) in toluene (0.10 mL) under Ar
at 65 °C for 3 h, unless otherwise stated. b For entries 4 and 7, the absolute
configurations (R,R) were determined by comparison of the optical rota-
tions with reported ones after complete deprotection to the free diamine
(refs 12b, 14a). For all other entries, the absolute configurations were not
determined and the stereochemistry indicated represents relative stereo-
chemistry. c Isolated yield. d The ee was determined by chiral HPLC
(Chiralpak IC column) after removal of the t-Bu groups, unless other-
wise stated. e The ee was determined without removal of the t-Bu groups.
f Reaction was carried out with diene 3h (6.96 mmol), 2 (9.03 mmol),
Pd2(dba)3 (0.10 mmol), and L7 (0.46 mmol) in toluene (3.5 mL) under Ar
at 65 °C for 3 h. g Reaction time, 6 h. h The ee was determined by chiral
HPLC (Chiralpak IA column).
cases, the reaction occurs with high regioselectivity toward
the internal double bond (Figure 3) and other regioisomers
were barely detectable by 1H NMR analysis if there was any.
The diamination most likely proceeds through a concerted
reaction mechanism analogous to the previously reported
catalytic cycle using 1 (Scheme 2).11a,c Insertion of the
chiral Pd(0) complex into the NꢀN bond of 2 forms
four-membered Pd(II) complex 5, which coordinates
to diene 3 to give complex 6. The migratory insertion of 6
leads to π-allyl Pd complex 7. Upon reductive elimination,
(28) For leading references on phosphoramidite ligands L7ꢀL9, see:
(a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem., Int.
Ed. 1996, 35, 2374. (b) Sewald, N.; Wendisch, V. Tetrahedron: Asym-
metry 1998, 9, 1341. (c) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries,
A. H. M.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865. (d)
Shintani, R.; Park, S.; Duan, W.-L.; Hayashi, T. Angew. Chem., Int. Ed.
2007, 46, 5901.
(29) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 8590.
(30) No diamination product was observed when cis-1,3-pentadiene
was subjected to the reaction conditions.
798
Org. Lett., Vol. 15, No. 4, 2013

cyclic sulfamide 4 is formed with regeneration of the chiral
Pd(0) catalyst.
Scheme 3. Representative Deprotection of Cyclic Sulfamides
dienes using Pd2(dba)3 and chiral phosphoramidite ligand
L7 as catalyst and N,N0-di-tert-butylthiadiaziridine 1,1-
dioxide (2) as nitrogen source. Various alkyl-substituted
conjugated dienes are smoothly diaminated in high yields
and high selectivities, providing cyclic sulfamides with
two adjacent chiral centers and the pendent vinyl group
allows possible further functionalization. The reaction
is amenable to gram scale and can produce the resulting
cyclic sulfamides in multigram quantity. The resulting
cyclic sulfamides can be deprotected via removal of the
t-Bu groups and the corresponding free diamines can
also be obtained without loss of ee. Cyclic sulfamides
are valuable moieties in biologically relevant mole-
cules and the described process provides a viable route
to access a broad range of diverse analogues for future
study.
Figure 3. X-ray structure of 4f.
Scheme 2. Proposed Catalytic Cycle for the Asymmetric
Diamination of Dienes Using 2
Acknowledgment. We are grateful for generous finan-
cial support from the National Institutes of General
Medical Sciences, National Institutes of Health (grant
no. GM083944-05). R.G.C. thanks Eli Lilly for a grad-
uate student fellowship.
As shown in Scheme 3, removal of the t-Bu groups is
accomplished in a mixture of CF3CO2H-hexanes at room
temperature, allowing possible further derivatization of
the nitrogens. Complete removal of the t-Bu groups and
the sulfone moiety in one step is also realized in aqueous
HBr at elevated temperature to unmask the free diamine.31
In summary, we have developed the direct and efficient
synthesis of chiral cyclic sulfamides from conjugated
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(31) Pansare, S. V.; Rai, A. N.; Kate, S. N. Synlett 1998, 623.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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