Highly diastereoselective radical cyclisations of chiral sulfinimines

Article abstract of DOI:10.1039/c3cc45452e

Chiral amines are formed by the highly diastereoselective intramolecular addition of alkyl and aryl radicals onto chiral mesityl sulfinimines.

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Highly Diastereoselective Radical Cyclisations of Chiral Sulfinimines
Elise M. Rochette,a William Lewis,a Al G. Dossetterb and Robert A. Stockman*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
We initially decided to investigate the intramolecular
45 radical addition of an Ellmanꢀtype tertꢀbutylsulfinimine, as
our previous work on aziridine synthesis with carbenoidꢀtype
reagents9 had shown that these larger tertꢀbutanesulfiminines
gave higher stereoselectivity than the tolyl variants (Table 1).
5
Chiral amines are formed by the highly diastereoselective
intramolecular addition of alkyl and aryl radicals onto chiral
mesityl sulfinimines.
Chiral amines are an important class of compounds, and
find uses in the fields of drug discovery, materials synthesis
10 and natural product synthesis. Of the many methods for the
synthesis of chiral amines,1 the addition of nucleophiles to
chiral sulfinimines is often the most reliable, simple and
general method.2 Whilst there have been a large number of
reports on the addition of anionic nucleophiles to both the
conditions
O
S
X
N
R
O
HN
S
1a X = Br, R = tBu
1b X = I, R = tBu
1c X = I, R = mesityl
N
2a-c
R
H
H
N
B
H
15 Ellman
tertꢀbutanesulfinimines
and
Davis
pꢀ
3
toluenesulfinimines,2 relatively little work has been disclosed
on the use of radical addition to these motifs. Following on
from a few reports throughout the past decade on their SmI2ꢀ
mediated radical dimerisation or coupling with carbonyls3 and
20 addition of cyclic etherꢀstabilised radicals to sulfinimines,4
recently Garcia Ruano reported the first general study on
intermolecular radical addition to Ellmanꢀtype sulfiminines.5
Their study looked at addition of alkyl radicals to (mainly)
aryl tertꢀbutanesulfinyl aldimines activated by complexation
25 with the strong Lewisꢀacid boron trifluoride. They showed
that radical addition gave the same type of 1,2 addition
products as Grignard addition, with yields in the range of 32ꢀ
98% and notably high diastereoselectivity (90ꢀ>96% de),
although a large excess (typically 10 eq) of alkyl iodide
30 radical precursor was used. Prompted by this disclosure, we
herein detail our preliminary investigations into the
intramolecular radical reactions of chiral mesitylsulfinimines.
Our work in this area was prompted by our onꢀgoing
interest in the chemistry of sulfinimines,6 and by pioneering
35 reports by Malacria7 and Clive8 on radical additions to imine
derivatives. Clive found Oꢀtrityl oximes to be good substrates
for radical cyclisation, whilst Malacria described a single
Table 1 Initial studies into radical cyclisation of sulfinimines
Yield
2
entry Substrate Initiator Propagator
Temp
dr
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1c
1c
1c
1c
AIBN
AIBN
AIBN
AIBN
AIBN
Bu3SnH
80 °C,
ꢀ
ꢀ
ꢀ
ꢀ
(Me3Si)3SiH 80 °C,
ꢀ
ꢀ
Bu3SnH
Bu3SnH
80 °C,
80 °C,
50% >98:2
(Me3Si)3SiH 80 °C,
ꢀ
ꢀ
Et3B / O2 Bu3SnH
40 °C,
80 °C,
40 °C,
61% >98:2
22% >98:2
33% >98:2
AIBN
3
3
Et3B / O2
All reactions carried out in benzene for 2 hours.
Thus we initially investigated the intramolecular cyclisation
50 of compound 1a, which contained bromide radical
a
precursor, tethered to a tertꢀbutanesulfinimine. After initial
failure using AIBN with tributyltin hydride10 or
tris(trimethylsilyl)silane, we then looked at using the aryl
iodide radical precursor 1b. However, again we were not able
55 to promote the radical cyclisation, although deiodination of
the aryl iodide was observed. We thus surmised that a more
electron rich sulfinimine might be more reactive towards
radical addition: both Malacria and Clive’s precedents used
such electron rich imine derivatives. We therefore turned to
60 mesitylsilfinimines. Initially introduced by Davis,11 we have
found that they offer selectivity near that of the hindered tertꢀ
butanesulfinimines, but offer complementary reactivity in
Grignard additions, giving high diastereoselectivities in an
openꢀtransitions state addition.12 Furthermore, the mesityl
65 group can be more easily removed, which can be useful for
particularly sensitive substrates such as Nꢀsulfinyl
example
of
radical
addition
to
Davisꢀtype
pꢀ
toluenesulfinimines, which gave moderate diastereoselectivity
40 in the presence of the Lewis Acid MAD (Scheme 1).
O
O
S
N
S
Bu3SnH, AIBN
MAD, PhH, rt
Br
NH
*
60% yield, 66% de
Scheme 1. Malacria’s report of radical cyclisation. Absolute
configuration of diastereomers was not reported.
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aziridines.10,11 We recently reported a convenent oneꢀpot
systems.
procedure for the synthesis of mesitylsulfinimines in >99% ee
using a phenyl alanineꢀbased template,13 and thus they are also
readily available substrates. It is interesting to note that this is
different to the course taken by Garcia and coꢀworkers, who
also faced the issue of low reactivity.5 Working independently
to us, they instead utilised activation of the tert-
butanesulfinimines with boron trifluoride in order to increase
their reactivity towards radical addition, as well as using an
10 excess of radical precursor, in their intermolecular radical
addition protocol. The stereoselctivity of our radical
cyclisation follows the same sense of induction as Garcia
noted, as confirmed by the Xꢀray crystal structure of adduct
2c (Figure 1).
45
50
55
5
Figure 2. Xꢀray crystal structure14 of 5b.
15
Initially, we looked at inclusion of an oxygen in the tether,
and the length of the tether (Scheme 2). It was found that
60 phenolꢀderivative 4a cyclised in similar yield to the allꢀ
carbon analogue explored previously. Increasing the chain
length to form a sixꢀmembered ring (5b) also worked, albeit in
slightly reduced yield. The sixꢀring 5b was found to be
crystalline, and thus we were able to confirm the sense of
65 induction in the cyclisation is consistant in the formation of
the fiveꢀmembered ring 2c and the sixꢀmembered ring 5b
system (Figure 3). We found the mesityl sulfinimine group of
5a was easily removed in nearꢀquantitative yield by treatment
with 4M HCl (Scheme 3).
20
Figure 1. Xꢀray crystal structure14 of 2c.
With mesitylsulfinimine 1c in hand, we then explored a
25 range of radical initiators and propagators (Table 1). We were
very happy to find that the mesitylsulfinimines were able to
undergo radical cyclisation under a range of conditions, in
each case giving the product 2c with complete
diastereoselectivity, despite the elevated temperatures of these
30 reactions. We were also pleased to find that tinꢀfree
conditions could be used, using the Malacria / Curran15 Nꢀ
heterocyclic carbene borane complex 3 as a hydrogen atom
donor with either triethyl borane / oxygen or AIBN as
initiator, although attempts to use the more common and
35 commercially available tris(trimethylsilyl)silane propagator
were not fruitful.
70
O
O
4 M HCl
98%
O
HN
NH2 .HCl
S
Mes
6
5a
75
Scheme 3. Removal of mesitylsulfinyl group.
We then looked at aliphatic precursors. The simple Nꢀtosyl
tethered system 7a was prepared, but upon reaction it was not
found to undergo radical cyclisation (Scheme 4). Rather,
80 elimination of the terminal iodide to form alkene 8a was
observed. Cyclohexane derivative 7b, which is not able to
undergo an elimination, was successful in the cyclisation
reaction, giving spirocycle 8b in a good 73% yield as a single
diasteromer (Xꢀray structure, Figure 3).
O
O
Conditions
A or B
Mes
O
S
I
N
O
HN
S
4a
5a
85
A: 63%, >98%de
B: 18%
Mes
O
Mes
O
Mes
I
S
N
S
Conditions
A or B
NH
O
O
Conditions
A or B
N
N
Ts
Ts
A: 51%
B: 19%
I
8a
7a
N
O
90
HN
O
S
4b
S
Mes
Mes
5b
A: 48%, >98% de
B: 41%
Mes
O
Mes
S
O
S
NH
I
N
Conditions: A: Bu3SnH, AIBN, PhH, reflux
Conditions
A or B
B: Et3B/O2, NHC-borane 3, PhH, 40 °C
Scheme 2. Investigation of tether length and heteroatom inclusion.
95
A: 73%, de>98%
B: 59%, de>98%
8b
7b
40
Having found success with the mesitylsulfinyl group, we
then turned our attention to investigating chain length,
inclusion of heteroatoms in the chain, and the use of more
substituted aryl groups, heteroaryl groups, and allꢀalkyl
Conditions: A: Bu3SnH, AIBN, PhH, reflux
B: Et3B/O2, NHC-borane 3, PhH, 40 °C
100
Scheme 4. Investigation of aliphatic radical presursors
2
|
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DOI: 10.1039/C3CC45452E
Figure 4. Xꢀray crystal structure14 of 10b.
AstraZeneca (ER) and EPSRC (RAS, EP/E055346) are
30 acknowledged for funding.
Notes and references
a School of Chemistry, University of Nottingham, Nottingham, NG7 2RD,
UK. E-mail: Robert.stockman@nottingham.ac.uk
b AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK:
35 † Electronic Supplementary Information (ESI) available: [Full
experimental details]. See DOI: 10.1039/b000000x/
1. T. C. Nugent (Ed), Chiral Amine Synthesis: Developments and
Applications, WileyꢀVCH: Chichester, UK, 2010.
Figure 3. Xꢀray crystal structure14 of 8b. Structure shown is one of
three independent molecules of compound 8b in the asymmetric unit.
2. For a recent comprehensive review on sulfinimines in synthesis, see:
M. T. Robak, M. A. Herbage and J. A. Ellman, Chem. Rev., 2010,
110, 3600.
Finally we investigated two electronꢀrich aryl bromides as
radical cyclisation precursors (9a and 9b, Scheme 4). In each
case, we found that the reaction was able to proceed, albeit
with modest yield. No other sideꢀproducts or starting material
was isolated from these reactions. Both products were formed
as single diastereoisomers. In the case of thiophene adduct
10 10b, the absolute configuration was confirmed by Xꢀray
crystallography (Figure 4), and we assumed the absolute
stereochemistry of 10a would be that shown by analogy with
10b.
5
3. B. Wang and Y. Wang, Org. Lett., 2009, 11, 3410; B. Wang and R.ꢀ
H. Liu, Eur. J. Org. Chem., 2009, 2845; R. Wang, K. Fang, B.ꢀF.
Sun, M.ꢀH. Xu, and G.ꢀQ. Lin, Synlett, 2009, 2301; R.ꢀC. Liu, K.
Fang, B. Wang, B. F. Sun, M.ꢀH. Xu and G.ꢀQ. Lin, J. Org. Chem.,
2008, 73, 3307; R.ꢀC. Liu, J.ꢀH. Wei, B.ꢀG. Wei and G.ꢀQ. Lin,
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Fang, K. Izumi, M.ꢀH. Xu and G.ꢀQ. Lin, J. Am. Chem. Soc., 2005,
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J. L. GarcíaꢀRuano and I. Alonso, Org. Lett., 2013, 15, 1658.
6. For our most recent work in the area of sulfinimine reactivity see: G.
Procopiou, W. Lewis, G. Harbottle and R. A. Stockman, Org. Lett.,
2013, 15, 2030.
7. E. Lacôte and M. Malacria, C. R. Acad. Sci. Paris, 1998, 191.
8. D. L. J. Clive, M. P. Pham and R. Subedi, J. Am. Chem. Soc., 2007,
129, 2713.
O
O
Bu3SnH, AIBN,
O
S
O
O
Br
9a
N
Mes
PhH, reflux
O
HN
S
22%, >98% de
10a
Mes
S
O
Mes
S
N
Bu3SnH, AIBN,
Br
O
S
Mes
PhH, reflux
9. T. MoragasꢀSola, I. Churcher and R. A. Stockman, Org. Biomol
Chem., 2011, 9, 5034.
10. For an excellent workꢀup procedure for tributyl tin hydride reactions,
see: D. C. Harrowven, D. P. Curran, S. L. Kostiuk, I. L. WallisꢀGuy,
S, Whiting, K, J. Stenning, B, Tang, E. Packard and L. Nansona,
Chem. Commun., 2010, 46, 6335.
NH
S
25%, >98% de
9b
10b
Scheme 4. Cyclisation of electronꢀrich aryl bromides
15
11. F. A. Davis, T. Ramachandar and Y. Wu, J. Org. Chem., 2003, 68,
6894.
12. C. Roe, T. MoragasꢀSola, L. SasrakuꢀNeequye, H. Hobbs, I.
Churcher, D. MacPherson and R. A. Stockman, Chem. Commun.,
2011, 4791.
In conclusion, we have found that Sꢀmesitylsulfinimines are
able radical acceptors, and undergo radical cyclisations with
exquisite control of diastereoselectivity. The product chiral
sulfinamines are easily deprotected to give chiral amines
13. C. Roe, H. Hobbs and R. A. Stockman, Chem. Eur. J., 2011, 17,
2704; L. SasrakuꢀNeequaye, D. MacPherson and R. A. Stockman,
Tetrahedron Lett. 2008, 49, 1129.
14. Ellipsoids shown at 50% probability. Crystalꢀdata notes can be found
in the electronic supplementary information.
15. A. Solovyev, SꢀH. Ueng, J. Monot, L. Fensterbank, M. Malacria, E.
lacôte, D.P. Curran, Org. Lett., 2010, 12, 2998; SꢀH. Ueng, L.
Fensterbank, M. Malacria, E. lacôte, D.P. Curran, Org. Lett., 2010,
12, 3002.
20 which have fused aryl/aliphatic and spiro aliphatic ring
systems, making them interesting as chiral building blocks for
screening collection enhancement.16 Further studies are
underway in our laboratories to fully explore the scope and
limitations of this unusually diastereoselective radical
25 cyclisation methodology, which will be reported in due
course.
16. For interesting discussions on “LeadꢀOrientedꢀSynthesis” and threeꢀ
dimensionality in screening compounds and drug discovery see: F.
Lovering, Med. Chem. Commun., 2013, 4, 515; P. MacLellan, A.
Nelson, Chem. Commun., 2013, 49, 24, 238; A. Nadin, C.
Hattotuwagama and I. Churcher, Angew. Chem. Int Ed., 2012, 51,
1114; W. P. Walters, J. Green, J. R. Weiss and M. A. Murcko, J.
Med. Chem., 2011, 54, 6405; F. Lovering, J. Bikker and C. Humbler,
J. Med. Chem., 2009, 52, 6752.
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O
I
O
Bu3SnH, AIBN
O
S
PhH, reflux
N
Mes
O
HN
S
Mes
63%, >98%de
Cyclisation of aryl and alkyl radicals with tethered chiral mesitylsulfinimines is
found to proceed with exquisite diastereoselectivity.