Iridium-catalyzed asymmetric allylic amination with polar amines: Access to building blocks with lead-like molecular properties

Article abstract of DOI:10.1002/adsc.201000721

The combination of an air-stable iridium catalyst and the dipolar aprotic solvent dimethyl sulfoxide (DMSO) allowed, for the first time, the systematic exploitation of highly polar, functionalized amines in asymmetric allylic substitutions: low molecular

Full text of DOI:10.1002/adsc.201000721

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DOI: 10.1002/adsc.201000721
Iridium-Catalyzed Asymmetric Allylic Amination with Polar
Amines: Access to Building Blocks with Lead-Like Molecular
Properties
Paolo Tosatti,a Joachim Horn,a Amanda J. Campbell,b David House,b
Adam Nelson,a,* and Stephen P. Marsdena,*
a
School of Chemistry, University of Leeds, Leeds LS2 9JT, U.K.
Fax : (+44)-0113-343-6565; e-mail: s.p.marsden@leeds.ac.uk or a.s.nelson@leeds.ac.uk
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
b
Received: September 21, 2010; Published online: December 5, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000721.
Abstract: The combination of an air-stable iridium
catalyst and the dipolar aprotic solvent dimethyl
sulfoxide (DMSO) allowed, for the first time, the
systematic exploitation of highly polar, functional-
ized amines in asymmetric allylic substitutions: low
molecular weight, sp3-rich chiral building blocks
were obtained with physicochemical properties that
will be valuable in the synthesis of lead-like small
molecules.
ACHTUNGTRENaNGNU mides and carbamates (including their activated de-
rivatives).[4–9] Extensive studies have led to the optimi-
zation of the reaction, and the elucidation of its mech-
anism.[8b,10] The most active catalyst can be generated
in situ from [IrACHTUNRGTNEUNG(cod)Cl]2 (cod=1,5-cyclooctadiene), a
chiral phosphoramidite[11] and a base[10n] (typically
DABCO, TBU or n-PrNH2), but the formation of the
catalytically competent iridacycle is very sensitive to
the presence of either water or oxygen.[3b,10d] High
enantioselectivity has been observed in low-polarity
solvents (typically THF) and, although rapid reactions
have been observed in more polar solvents (e.g.,
DMF, EtOH, MeCN), the enantioselectivity of the re-
Keywords: allylic compounds; allylic substitution;
asymmetric catalysis; iridium; lead-like compounds
Controlling the molecular properties of lead com-
pounds is essential to reduce attrition rates in drug
discovery.[1] High lipophilicity and molecular weight
are both associated with high attrition rates, and are
almost inevitably further inflated during lead optimi-
zation.[1a–d] Low numbers of aromatic rings[1e] and high
fractions of sp3-hybridized carbons[1f] are favourable
lead-like properties, and polar, chiral, low molecular
weight compounds are consequently attractive start-
ing points for drug discovery.[1] Huge progress has
been made in asymmetric synthesis over the past 30
years, but procedures appropriate for parallel synthe-
sis have rarely been developed and validated for
polar, highly functionalized substrates.[2]
Iridium-catalyzed allylic amination is a valuable re-
action for the enantioselective synthesis of allylic
amines,[3] and has been widely exploited in target syn-
thesis.[4] A wide range of nitrogen nucleophiles has
been exploited in the reaction including amines, am-
Figure 1. Physicochemical properties of nucleophiles in iridi-
um-catalyzed allylic amination reactions: data is provided
for all nucleophiles that have been previously used (ꢀ) and
[13]
*
monia (and its equivalents), heteroarylamines, sulfon- the nucleophiles exploited in this study ( ).
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Paolo Tosatti et al.
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action is generally compromised.[3b,10d] Thus, although the precatalyst, <5% conversion was observed in all
a wide range of nitrogen nucleophiles have been ex- cases (entries 7, 9 and 11). These results are consistent
ploited, emphasis has been placed on rather lipophilic with previous attempts at Ir-catalysed allylic substitu-
substrates (Figure 1).
We sought to develop a procedure for iridium-cata- cific combination of [IrCAHTNUGTRNE(NUG dbcot)Cl]2 and DMSO was ef-
tion in this solvent.[6a] Remarkably, however, the spe-
lyzed allylic substitution reactions to allow polar, fective with all of the amines 3a–c, and the required
highly functionalized amines to be exploited as nucle- products 4, 5 and 6A were obtained as single re-
ophiles. Crucially, it was important to avoid the re- gioisomers in good yield and with excellent enantio-
quirement for an inert atmosphere to allow the proce- or diastereoselectivity (entries 8, 10 and 12).
dure to be conducted in parallel format. Therefore, a
Interestingly, the reaction was significantly faster in
recently developed air-stable metallacycle catalyst, DMSO than in THF: with the amine 3c, the product
[12]
formed from [Ir
[a,e]cyclooctatraene), a chiral phosphoramidite and a DMSO (entry 12) compared with 66% yield after 24 h
base, that avoids the need for Schlenk techniques, was in THF (entry 6). We also tested other polar sol-
of great interest to our study.[10d] vents[14] in combination with [Ir
(dbcot)Cl]2, but
(dbcot)Cl]2
(dbcot=dibenzo- 6A was obtained in 81% yield after just 3.5 h in
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Initial studies focused on reactions involving cin- DMSO proved to be the most effective and, in addi-
namyl methyl carbonate 2a and the polar amines 3a–c tion, is inexpensive, non-toxic, readily available and
(Table 1). In THF, the reaction gave poor results, with compatible with highly polar substrates that are val-
moderate yields for methyl serinate 3c and very low uable in medicinal chemisry. With [IrACTHNUTRGNEN(UG dbcot)Cl]2, re-
or no conversion for histamine 3a and glycinamide 3b. sults were broadly comparable in the presence and
Speculating that this may be due to the limited solu- absence of inert atmosphere, and thus subsequent re-
bility of these nucleophiles in THF, we investigated actions were performed without recourse to a protec-
the use of DMSO as solvent but, with [IrACHTNURGTNEUNG(cod)Cl]2 as tive atmosphere.
Table 1. Solvent and pre-catalyst comparison using polar amines.
Entry
3
X
Solvent
4–6
Yield [%]
ee[a] or dr[b]
1
2
3a
3a
3b
3b
3c
3c
3a
3a
3b
3b
3c
3c
cod
dbcot
cod
dbcot
cod
dbcot
cod
dbcot
cod
dbcot
cod
THF
THF
THF
THF
THF
THF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
4
4
5
5
6A
6A
4
4
5
<5[c]
<5[c]
<5[c]
27
n.d.[f]
n.d.
n.d.
ee 80%
n.d.
dr 93:7
n.d.
ee 97%
n.d.
ee 91%
n.d.
3[d]
4[d]
5[d]
6[d]
7
<5[c]
66
<5[c]
66
8
9[d]
10[d]
11[d]
12[d,e]
<5[c]
83
5
6A
6A
<5[c]
81
dbcot
dr 93:7
[a]
Determined by chiral HPLC.
Diastereoisomeric ratio of the isolated product (determined by 500 MHz H NMR spectroscopy).
Conversion after 24 h determined by 500 MHz H NMR analysis of the crude mixture.
K3PO4 (1.3 equiv.) was used as additive.
Reaction time 3.5 h.
[b]
[c]
[d]
[e]
[f]
1
1
n.d.=not determined.
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Iridium-Catalyzed Asymmetric Allylic Amination with Polar Amines
Using these optimized conditions, we determined were obtained as single regioisomers, with generally
the effect of the relative configurations of the catalyst high enantio- or diastereoselectivity. The highly polar
and the amino acid-derived nucleophile on the out- and functionalised nucleophile serinol afforded the
come of the substitution. Accordingly, the Ir-catalyzed product 10 in high yield and with excellent enantiose-
reactions between an allylic carbonate (2a or 2b) and lectivity. The reaction was notably successful with
l- or d-configured amino acid derivatives were inves- both regioisomers of mono-N-Boc protected 2,3-dia-
tigated (Table 2). With an l-configured amino acid minopropionic acid methyl ester (11–14) as well as
and (S,S,aS)-1, the products 6–9A were obtained in otherwise unprotected amino esters (15–23). In addi-
good to excellent yield and stereoselectivity. In con- tion, the structure of the allylic carbonate 2 could be
trast, in the other diastereomeric series, increased re- widely varied, and good yields were obtained employ-
action times were required, and slightly lower, though ing carbonates with aryl (2a), heteroaryl (2b), n-alkyl
still synthetically useful, yields and diastereoselectivi- (2c) and substituted alkyl (2g–i) R1 substituents. The
ties were observed. Although a significant matched/ reaction was, however, significantly slower with a sec-
mismatched effect was observed, the stereochemical alkyl R1 group (as in 2d and 2e) such that completion
outcome of the reaction was largely controlled by the was not reached even after 20 h; with R1 =t-Bu (as in
configuration of the chiral ligand. Again, no trace of 2f), the starting materials were recovered. The scope
linear regioisomers was observed. The approach al- of the reactions was broad: free alcohols (6, 7, 9, 10
lowed both diastereomeric series of products to be and 18–23), indoles (15) and imidazoles (16), as well
prepared with complementary stereoselectivity, dem- as protected alcohols (as in 22 and 23) or amines (as
onstrating that significant epimerisation of nucleo- in 11–14 and 21) were tolerated.
phile or the product did not occur under the reaction
conditions.
The relative and absolute configurations of the
products 9A and 22 were assigned by X-ray crystallo-
We further determined the scope of the reaction graphic analysis,[15] confirming that the sense of ste-
using a range of allylic carbonates and polar amino reochemical control exerted by the chiral ligand was
acid derivatives (Table 3). The expected products the same as has been observed in other Ir-catalysed
allylic aminations using ligand 1.[4]
In summary, we have developed a simple and relia-
Table 2. Matched and mismatched effects using chiral amino
acid derivatives.[a]
ble method for the asymmetric amination of allylic
carbonates using a wide range of polar amine nucleo-
philes which is amenable to operation in parallel
format, and does not require an inert atmosphere.
The unique combination of DMSO as solvent and
[IrACTHNUTRGNEG(NU dbcot)Cl]2 as precatalyst was essential to the suc-
cess and generality of the reaction. The range of
highly functionalised amines validated included
amino acid derivatives with free hydroxy, carbamate,
amide and unprotected N-heterocyclic functionalities.
Crucially, the method allows a wide range of polar
amines to be exploited as nucleophiles, systematically
expanding the physicochemical properties of the
products into useful drug-like space for the first time,
whilst still allowing the introduction of small lipophil-
ic groups (Figure 1). The method allows the direct
construction of highly-functionalised products valua-
ble in the synthesis of diverse chiral scaffolds with
lead-like molecular properties, which will be reported
in due course.
Experimental Section
General Procedure for Allylic Amination with
[IrACTHNUTRGNE(NUG dbcot)Cl]2 and (S,S,aS)-1 in DMSO
[a]
Diastereoisomeric ratio of the isolated products deter-
mined by 500 MHz H NMR spectroscopy.
(R,R,aR)-1 was used as chiral ligand.
To a solution of [IrACTHGUNTERNNU(G dbcot)Cl]2 (4.3 mg, 0.005 mmol) and
chiral phosphoramidite (S,S,aS)-1 (5.4 mg, 0.010 mmol) in
DMSO (0.5 mL) was added n-butylamine (1.0 mL,
1
[b]
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Paolo Tosatti et al.
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Table 3. Scope of the reaction.[a]
[a]
Diastereoisomeric ratio of the isolated products determined by 500 MHz
1H NMR spectroscopy.
No added K3PO4 (free amine was used).
[b]
[c]
[d]
[e]
Determined by chiral HPLC.
2.6 equiv. of K3PO4 were used with l-His-OMe·2HCl.
1
Conversion after 24 h determined by H NMR analysis of the crude mixture
(19ꢀ75%; 20ꢀ65%).
1
0.010 mmol) via microsyringe under air. The reaction vessel
was sealed with a screw cap and the mixture heated at 508C
for 30 min to allow the formation of the active catalyst spe-
cies. After this time, the allylic carbonate (0.25 mmol), the
nucleophile (0.33 mmol) and potassium phosphate
(0.33 mmol, when necessary) were added and the resulting
mixture was heated at 558C in a closed vessel. Upon com-
pletion, the mixture was allowed to reach room temperature
and the solvent evaporated (by means of a GeneVac centri-
fugal evaporator) to give a crude product. The regioselectiv-
ity of the reaction was determined by H NMR analysis of
the crude product. The desired product was finally purified
by flash chromatography.
Acknowledgements
EPSRC and GlaxoSmith
ACHTUNGTRNEKNUNG line are gratefully acknowledged
for financial support to this study (EP/E020712/1). The au-
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Iridium-Catalyzed Asymmetric Allylic Amination with Polar Amines
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