Enantioselective synthesis of -aminophosphonates via organocatalytic sulfenylation and [2,3]-sigmatropic sulfimide rearrangement

Article abstract of DOI:10.1055/s-0030-1260309

β,γ-Unsaturated α- aminophosphonates are prepared in enantiomerically enriched form via organocatalytic aldehyde -sulfenylation/ olefination followed by oxaziridine-mediated sulfimidation and sulfimide [2,3]-sigmatropic rearrangement. Subsequent N-deprote

Full text of DOI:10.1055/s-0030-1260309

LETTER
2347
Enantioselective Synthesis of a-Aminophosphonates via Organocatalytic
Sulfenylation and [2,3]-Sigmatropic Sulfimide Rearrangement
E
a
nantioselective
S
l
ynthesi
a
s
of
a
-Ami
n
nophosphonate
s
Armstrong,*a Neil Deacon,a Craig Donaldb
Department of Chemistry, Imperial College London, South Kensington, SW7 2AZ, UK
E-mail: A.Armstrong@imperial.ac.uk
b
AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK
Received 25 July 2011
[X = P(O)(OEt)2]. In this paper we report the successful
realisation of this strategy.
Initially, we applied our previously successful17a one-pot
sulfenylation–olefination conditions to the phosphonate
Abstract: b,g-Unsaturated-a-aminophosphonates are prepared in
enantiomerically enriched form via organocatalytic aldehyde a-
sulfenylation/olefination followed by oxaziridine-mediated sulfim-
idation and sulfimide [2,3]-sigmatropic rearrangement. Subsequent
N-deprotection and amino acid coupling are also accomplished.
synthesis. However, the target 8a
[R = Et,
Key words: asymmetric catalysis, amination, rearrangement, orga-
X = P(O)(OEt)2] was obtained only in trace yields (<5%).
The olefination step was therefore examined in detail
starting from isolated samples of the aldehyde rac-4a
(R = Et). Extensive screening of solvent, temperature, re-
action time, and reagent excess gave only modest results.
However, application of a method reported by Belakhov
et al.18 which used substoichiometric amounts of n-butyl-
lithium and reverse addition (aldehyde added to anion)
gave the target phosphonate in 47% yield. Increasing the
amount of n-butyllithium to a full equivalent provided the
target in 87% yield. Utilising these olefinating conditions
in the one-pot sulfenylation–olefination procedure, in the
first instance, gave again a low yield of 27%, but using
2 equivalents of diphosphonate 6 and 2 equivalents of n-
butyllithium gave the target in good yield (88%) and ee
(87%). With a successful one-pot sulfenylation and olefi-
nation in hand the scope was tested with a diverse range
of aldehydes bearing alkyl, alkenyl, aromatic, and protect-
nocatalysis, oxaziridine
a-Amino phosphonates have emerged as important mo-
lecular targets, due to their bioactivity against protease en-
zymes which relies on their ability to mimic the
tetrahedral transition state of amino acids undergoing hy-
drolysis. This has led to the application of amino phospho-
nate derivatives as antibacterial1 and antifungal agents.2,3
Syntheses of these compounds4 are dominated by tran-
sition-metal-based
catalytic
hydrogenation5
and
hydrophosphonylation6–8 reactions. There are also exam-
ples of asymmetric organocatalytic hydrophosphonyla-
tion reactions, for instance, Jacobsen’s9 thiourea-
catalysed hydrophosphonylation of aldimines and
Toru’s10 cinchona alkaloid hydrophosphonylation of a va-
riety of aryl-substituted aldimines. However, there remain
a few biologically relevant amino phosphonates that are
not available through current methodologies. b,g-Unsat-
urated amino phosphonates are one such class whose
asymmetric synthesis is limited to a few examples.11,12 To
the best of our knowledge there is no general methodolo-
gy to access these phosphonates asymmetrically from a
broad range of substrates.
Ar
Ar
N
OTMS
H
SHex
2 Ar = 3,5-(CF3)2C6H3
O
O
R
R
1
N
4
N
N
Jørgensen and co-workers13,14 have developed a syntheti-
cally useful, organocatalytic a-sulfenylation of aldehydes.
Marrying this chemistry with work from this group on
amination of sulfur using the oxaziridine 915 led to the
strategy of organocatalytic sulfenylation, in situ olefina-
tion, and [2,3]-sigmatropic sulfimide rearrangement
(Scheme 1) to access a range of vinyl glycines 10
(X = CO2Et) in good yield and high enantioselectivity.16,17
Exchanging the phosphonoacetate 5 (X = CO2Et) for a
diphosphonate 6 [X = P(O)(OEt)2] (Scheme 1) was envis-
aged to give the analogous amino phosphonates 11
SHex
3
NBoc
O
SHex
X
(EtO)2(O)P
EtO2C
CO2Et
9
5 or 6
R
X
7 or 8
n-BuLi
Boc
N–
NHBoc
X
[2,3]-sigmatropic
rearrangement
+
HexS
R
desulfurisation
10 or 11
R
X
5, 7, and 10 X = CO2Et: previous work
6, 8, and 11 X = P(O)(OEt)2: this work
SYNLETT 2011, No. 16, pp 2347–2350
Advanced online publication: 13.09.2011
x
x
.x
x
.2
0
1
1
Scheme 1
DOI: 10.1055/s-0030-1260309; Art ID: D23911ST
© Georg Thieme Verlag Stuttgart · New York

2348
A. Armstrong et al.
LETTER
to afford 11a in 56% isolated yield. Further increasing the
concentration to 0.5 M and using 1.2 equivalents of ox-
aziridine 9 gave the target in 63% yield. These optimised
conditions were then applied to the enantiomerically en-
riched sulfides 8a–f (Table 3).
Table 1 One-Pot Sulfenylation–Olefination with a Diverse Range
of Aldehydes
2 (20 mol%)
3, toluene, r.t., 3 h
SHex
O
R
R
P(O)(OEt)2
then 6 (2 equiv)
n-BuLi (2 equiv)
THF, –78 °C, 30 min
then 0 °C, 2 h
1a–f
8a–f
The majority of the examples gave good yields. High E
selectivity was observed (Z isomer not seen by 1H NMR)
and there was only minor loss of enantiomeric excess in
the rearrangement process. The product configuration is
assumed based on the expectation of a suprafacial con-
certed [2,3]-sigmatropic rearrangement, as in the ester se-
ries.16,17 Two of the substrates gave low yields (Table 3,
entries 2 and 5). In the case of R = Me, we were able to
isolate side products 15 (30%) and 16 (30%), both pre-
sumably originating from the sulfonium ion 14, which
could be formed via elimination from the intermediate
sulfimide 13 (Scheme 2).
Entry
1
R
Yield of 8 (%)a ee (%)b
1
2
3
4
5c
6
1a
1b
1c
1d
1e
1f
Et
8a 88
8b 79
8c 73
8d 68
8e 72
8f 65
87
78
84
84
82
82
Me
i-Pr
Bn
All
(CH2)2OTBS
While the products 11 were obtained in reasonable ee, we
wished to improve their enantiomeric purity further. Ad-
ditionally, we aimed to demonstrate that these motifs
could be incorporated into peptide mimetics. Therefore,
two of the amino phosphonates (11a and 11c) were depro-
a Isolated yield of E isomer after flash chromatography.
b Determined by HPLC on chiral stationary phase.
c Sulfenylation required 24 h.
ed alcohol functional groups (Table 1). In all cases, very
high E-selectivity was observed (>95:5).
Table 2 Synthesis of Amino Phosphonate 11 and Sulfoxide Side
Product 12
With a successful route to enantiomerically enriched sul-
fides 8 in hand our attention turned towards the amination
at sulfur. While no direct precedent existed, it was hoped
that this would lead, in line with the ester series, to a spon-
taneous [2,3]-sigmatropic rearrangement to furnish the
amino phosphonate 11 (Scheme 1). Interestingly, in con-
trast to the high levels of chemoselectivity in the earlier
work,15a,16,17a initial results showed significant levels of
oxygen transfer from the oxaziridine 9 to sulfide 8a, giv-
ing rise to the unwanted sulfoxide side product 12. To op-
timise this process in favour of amination, variation of
solvent, temperature, concentration, and reaction time
were investigated (Table 2). Desulfurisation with triethyl
phosphite was carried out in the same reaction pot to aid
1H NMR analysis of the crude reaction mixture.
NHBoc
P(O)(OEt)2
11
SHex
9
P(O)(OEt)2
then
P(OEt)3
O
HexS
rac-8a
P(O)(OEt)2
12
Entry Solvent
Temp
(°C)
Concn Time 11/12a
Conv.
(%)a
(M)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.3
0.3
(h)
1
2
MeCN
MeCN
CH2Cl2
CH2Cl2
PhMe
25
–40
25
3
55:45
69:31
39:61
86:14
34:66
71:29
40:60
0:100
50:50
71:29
47:53
59:41
86:14
87:13
99
91
95
44
84
19
81
33
84
15
77
44
55
80
3
3
3
In the first instance the reactions were carried out in a
range of solvents at both room temperature and at reduced
temperature (Table 2, entries 1–10). In all cases higher
temperature gave better conversion but poorer chemose-
lectivity, as we have noted previously.15c This relationship
was further studied by investigating a range of tempera-
tures with dichloromethane (Table 2, entries 3, 4, 11, and
12). Dichloromethane at –78 °C gave the best selectivity;
increasing the temperature to –40 °C caused a significant
decrease in chemoselectivity. Increased concentration
(Table 2, entry 13) and reaction time (Table 2, entry 14)
were both found to improve conversion without having an
adverse effect on selectivity.
4
–78
25
3
5
3
6
PhMe
–78
25
3
7
MeOH
MeOH
THF
3
8
–78
25
3
9
3
10
11
12
13
14
THF
–78
0
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
–40
–78
–78
3
In further, preparative experiments, desulfurisation was
effected using triphenylphosphine instead of triethylphos-
phite to aid product purification. The sulfide rac-8a was
again submitted to the optimal amination conditions of en-
try 14 (Table 2) using the new desulfurisation conditions
3
24
a Estimated by 1H NMR integration.
Synlett 2011, No. 16, 2347–2350 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of a-Aminophosphonates
2349
Table 3 Synthesis of Amino Phosphonates 11 under Optimized Conditions
O
NBoc
EtO2C
CO2Et
NHBoc
SHex
9 (1.2 equiv)
CH2Cl2 (0.5 M)
24 h, –78 °C
then Ph3P, MeOH
R
P(O)(OEt)2
11a–f
R
P(O)(OEt)2
8a–f
Entry
8
R
ee of 8 (%)
8a 87
Yield of 11 (%)a
11a21 64
11b 38
ee of 11 (%)b
1
2
3
4
5
6
8a20
Et
85
79
75
79
79
76c
8b
8c
8d
8e
8f
Me
i-Pr
Bn
All
8b 79
8c 81
11c 68
8d 84
11d 69
8e 82
11e 35
(CH2)2OTBS
8f 83
11f 75
a Isolated yield after flash chromatography.
b Deduced by formation of Mosher’s amides19 and inspection of 19F and 1H NMR.
c The silyl protecting group was removed during the formation of this Mosher’s amide.
Boc deprotection was then effected with TFA (Scheme 3).
Importantly, in both cases the peptide diastereomers 19
and 20 were readily separable by column chromatogra-
phy, providing an effective means for removing the minor
aminophosphonate diastereoisomer.
Boc
N –
H
Hex
S+
+
S
Hex
P(O)(OEt)2
P(O)(OEt)2
13
14
In conclusion, we have developed a concise route to enan-
tiomerically enriched b,g-unsaturated a-amino phospho-
nates by coupling an organocatalytic sulfenylation and
olefination procedure to a stereoselective [2,3]-sigmatro-
pic rearrangement. This methodology has provided rapid
access to biologically relevant amino acid mimetics.
These products have also been shown to undergo coupling
to amino acids which also allows purification to afford a
single diastereomer. This strategy, in principle, will also
furnish alternative amino acid mimetics by varying the
coupling partner in the olefination step. Efforts in this area
are currently ongoing in this laboratory as well as further
investigation into manipulation of the phosphonopeptide
products.
SHex
HexS OMe
MeOH
+
P(O)(OEt)2
P(O)(OEt)2
15
16
Scheme 2
NHBoc
1) 4 M HCl, dioxane
2) N-Boc phenylalanine 17
DCC, HOBt, CH2Cl2
P(O)(OEt)2
R
11a R = H
11c R = Me
O
Ph
NHBoc
P(O)(OEt)2
TFA–CH2Cl2
(1:1)
HN
Acknowledgment
R
18a 64%
18c 48%
We gratefully acknowledge AstraZeneca and the EPSRC for fun-
ding and L. Challinor for preliminary results.
O
O
Ph
Ph
References and Notes
HN
HN
NH2
NH2
P(O)(OEt)2
+
(1) Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med.
Chem. 1986, 29, 29.
(2) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M.
J. Med. Chem. 1989, 32, 1652.
P(O)(OEt)2
R
R
20a 10%
20c 3%
19a 60%
19c 49%
(3) Peyman, A.; Stahl, W.; Wagner, K.; Ruppert, D.; Budt, K. H.
Bioorg. Med. Chem. Lett. 1994, 4, 2601.
Scheme 3
(4) Reviews: (a) Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C.
Tetrahedron 2009, 65, 17. (b) Ma, J. A. Chem. Soc. Rev.
2006, 35, 630. (c) Orsini, F.; Sello, G.; Sisti, M. Curr. Med.
Chem. 2010, 17, 264. (d) Kudzin, Z. H.; Kudzin, M. H.;
Drabowicz, J.; Stevens, C. V. Curr. Org. Chem. 2011, 15,
tected with HCl in dioxane and coupled with N-Boc-
phenylalanine using DCC and HOBt to give the corre-
sponding dipeptides 18 in good yield over the two steps.
Synlett 2011, No. 16, 2347–2350 © Thieme Stuttgart · New York

2350
A. Armstrong et al.
LETTER
2015. (e) Albrecht, L.; Albrecht, A.; Krawczyk, H.;
Jørgensen, K. A. Chem. Eur. J. 2010, 16, 28.
and concentrated in vacuo. The crude was purified on silica
eluting with EtOAc–PE (1:1).
(5) Schmidt, U.; Oehme, G.; Krause, H. Synth. Commun. 1996,
26, 777.
(6) Saito, B.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007,
129, 1978.
(7) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem.
1995, 60, 6656.
(8) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem. Int. Ed.
1997, 36, 1237.
(9) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
4102.
(10) Nakamura, S.; Nakashima, H.; Yamamura, A.; Shibata, N.;
Toru, T. Adv. Synth. Catal. 2008, 350, 1209.
(11) Akiyama, T.; Morita, H.; Bachu, P.; Mori, K.; Yamanaka,
M.; Hirata, T. Tetrahedron 2009, 65, 4950.
(12) Bhadur, P. S.; Zhang, Y. P.; Zhang, S.; Song, B. A.; Yang,
S.; Hu, D. Y.; Chen, Z.; Xue, W.; Jin, L. H. Chirality 2009,
21, 547.
Typical Data for Compound 8a
Colourless oil (0.566 g, 88%). IR (film): nmax = 2962 (s),
2924 (s), 2839 (m), 1624 (m), 1460 (m), 1390 (m), 1248 (s),
1166 (m), 1100 (m), 1054 (s), 1028 (s), 962 (s), 856 (m), 823
(m), 791 (m), 750 (m) cm–1. 1H NMR (400 MHz, CDCl3):
d = 6.51 (1 H, ddd, J = 20.7, 16.9, 9.2 Hz, SCHCHCHP),
5.60 (1 H, dd, J = 20.0, 17.2 Hz, SCHCHCHP), 4.14–4.05
(4 H, m, POCH2CH3), 3.17 (1 H, td, J = 7.7, 9.2 Hz, SCH),
2.43–2.37 (2 H, m, SCHCH2), 1.73–1.59 (2 H, m, SCH2),
1.60–1.47 (2 H, m, SCH2CH2), 1.34 (6 H, t, J = 7.1 Hz,
POCH2CH3), 1.35–1.22 [4 H, m, S(CH2)2CH2CH2], 1.00
(3 H, t, J = 7.4 Hz, SCHCH2CH3), 0.89 [3 H, t, J = 7.0 Hz,
S(CH2)5CH3] ppm. 31P NMR (162 MHz, CDCl3): d = 17.801
(s)ppm. 13C NMR (100 MHz, CDCl3): d = 152.3 (d, J = 4.5
Hz) 116.2 (d, J = 186.5 Hz), 61.7 (d, J = 5.5 Hz), 50.0 (d,
J = 23.5 Hz), 31.4, 30.6, 29.3, 28.6, 26.7, 22.5, 16.4, 14.0.
11.8. MS (CI): m/z = 323 [MH+], 340 [MNH4 ]. HRMS:
+
(13) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005,
127, 18296.
(14) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem. Int. Ed. 2005, 44, 794.
m/z calcd for C15H32O3SP: 323.1810, D = 1.2 ppm; found:
323.1806 [MH+]. The enantiomers were separated by HPLC
over an AD-H column eluting with 2% 2-PrOH in hexane
[tR = 15 min(major) and 18 min(minor)]; a sample of 87% ee
gave [a]24D –40 (c 1, CHCl3).
(15) (a) Armstrong, A.; Cooke, R. S. Chem. Commun. 2002, 904.
(b) Armstrong, A.; Jones, L. H.; Knight, J. D.; Kelsey, R. D.
Org. Lett. 2005, 7, 713. (c) Armstrong, A.; Edmonds, I. D.;
Swarbrick, M. E. Tetrahedron Lett. 2003, 44, 5335.
(16) Armstrong, A.; Challinor, L.; Cooke, R. S.; Moir, J. H.;
Treweeke, N. R. J. Org. Chem. 2006, 71, 4028.
(17) (a) Armstrong, A.; Challinor, L.; Moir, J. H. Angew. Chem.
Int. Ed. 2007, 46, 5369. (b) For quaternary vinyl glycine
synthesis using the analogous selenimide rearrangement,
see: Armstrong, A.; Emmerson, D. G. Org. Lett. 2011, 13,
1040.
(21) Typical Procedure for Amination–Rearrangement–
Desulfurisation
The starting phosphonate (0.62 mmol) in CH2Cl2 (0.6 mL)
was added to oxaziridine 9 (216 mg, 0.74 mmol) in CH2Cl2
(0.6 mL) dropwise at –78 °C. The reaction was stirred for 24
h. To this was added Ph3P (210 mg, 0.81 mmol) and MeOH
(0.1 mL); the reaction was stirred for a further 30 min before
being allowed to warm to r.t. The reaction was then concen-
trated in vacuo. The crude was purified on silica eluting with
EtOAc–PE (1:1).
Typical Data for Compound 11a
(18) Belakhov, V.; Dovgolevsky, E.; Rabkin, E.; Shulami, S.;
Shoham, Y.; Baasov, T. Carbohydr. Res. 2004, 339, 385.
(19) Hammerschmidt, F.; Hanbauer, M. J. Org. Chem. 2000, 65,
6121.
(20) Typical Procedure for One-Pot Sulfenylation–
Olefination
Clear and colourless oil (127 mg, 64%). IR (film): nmax =
3436 (w), 3156 (w), 2982 (w), 2933 (w), 2361 (w), 2253 (w),
1712 (w), 1496 (w), 1373 (w), 1247 (w), 1166 (w), 1031 (w),
969 (w), 909 (s), 735 (s), 650 (m), 546 (w) cm–1. 1H NMR
(400 MHz, CDCl3): d = 5.81 (1 H, m, PCHCHCH), 5.51 (1
H, m, PCHCH), 4.94 (1 H, br, NH), 4.62 (1 H, br, PCH),
4.19–4.10 [4 H, m, P(OCH2CH3)2], 2.15–2.05 (2 H, m,
PCHCHCHCH2), 1.47 [9 H, s, C(CH3)3], 1.33 [6 H, dt,
J = 1.7, 7.1 Hz, P(OCH2CH3)2], 1.01 (3 H, t, J = 7.4 Hz,
PCHCHCHCH2CH3). 13C NMR (100 MHz, CDCl3): d =
135.8 (d, J = 11.6 Hz, CH), 121.5 (CH), 80.2 (CCH3), 62.9
(d, J = 6.7 Hz, CH2), 62.7 (d, J = 6.6 Hz, CH2), 50.2 (CH),
48.6 (CH), 28.3 (CH3), 25.4 (CH2), 16.4 (t, J = 7.0 Hz, CH3),
Hexane sulfanyl triazole 317 (480 mg, 2.6 mmol) was added
to a solution of aldehyde (2.0 mmol) and catalyst 2 (238 mg,
0.4 mmol) in toluene (1.34 mL). The reaction was allowed to
stir for 3 h before addition of THF (7 mL). The mixture was
then added dropwise to a prepared solution of tetraethyl
methylenediphosphonate (1 mL, 4 mmol) and n-BuLi (1.8
mL, 2.22 M, 4 mmol) in THF (7 mL) at –78 °C. After 30 min
the reaction was allowed to warm to 0 °C. The reaction was
stirred until completion (approx. 1 h). The reaction was
taken up in EtOAc (70 mL) and washed with NaHCO3 (sat.),
H2O, and NaCl (sat.) The organics were dried with MgSO4
+
13.2 (CH3). MS (CI): m/z = 322 [MH+] 339 [MNH4 ].
HRMS: m/z calcd for C14H29NO5P: 322.1783, D = 2.2 ppm;
found: 322.1790 [MH+]; a sample of 85% ee gave [a]24D –9
(c 1, CHCl3).
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