Enantioselective access to multi-cyclic α-amino phosphonates via carbene-catalyzed cycloaddition

89 Pages·2017·6.66 MB·English

Electronic Supplementary Material (ESI) for Organic Chemistry Frontiers.
This journal is © the Partner Organisations 2018
Supporting Information
Enantioselective access to multi-cyclic -amino
phosphonates via carbene-catalyzed cycloaddition
reactions between enals and six-membered cyclic imines
Jun Sun,a† Chengli Mou,b† Changyi Liu,a Ruoyan Huang,a Shupeng Zhang,a Pengcheng Zheng,*a
a,c
Yonggui Robin Chi*

aLaboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green
Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District,
Guiyang 550025, China.
bSchool of Pharmacy, Guiyang College of Traditional Chinese Medicine, Huaxi District, Guiyang 550025,
China.
cDivision of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang
Technological University, Singapore 637371, Singapore
E-Mail: [email protected]
[email protected]

Ⅰ
. General information ........................................................................................................ 2
Ⅱ
. Preparation of substrates ............................................................................................... 3
Ⅲ
. Reaction condition optimization ..................................................................................... 4
Ⅳ
. Proposed mechanism. ................................................................................................... 5
Ⅴ
. General procedure. ........................................................................................................ 6
Ⅵ
. Stereochemistry determination via X-ray crystallographic analysis .............................. 7
Ⅶ
. In vitro antibacterial bioassay ......................................................................................... 8
Ⅷ
. Characterization of intermediates & products .............................................................. 10
Ⅸ
. NMR spectra of intermediates & products ................................................................... 22
Ⅹ
. HPLC spectra of products ............................................................................................ 68
Ⅰ
. General information
Commercially available materials purchased from J&K or Aladdin were used as
received. THF was distilled over sodium. Unless otherwise specified, all reactions were
carried out under an atmosphere of nitrogen in 10 mL dry Schlenk tube. Proton nuclear
1
magnetic resonance ( H NMR) spectra were recorded on a Bruker (400 MHz)
spectrometer or on a JEOL-ECX-500 (500 MHz) spectrometer. Chemical shifts were
recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ 0.00) or chloroform (δ
1
= 7.26, singlet). H NMR splitting patterns are designated as singlet (s), doublet (d), triplet
(t), quartet (q), dd (doublet of doublets); m (multiplets), and etc. All first-order splitting
patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns
that could not be easily interpreted are designated as multiplet (m) or broad (br). Carbon
13
nuclear magnetic resonance ( C NMR) spectra were recorded on a Bruker (101 MHz)
19
spectrometer or on a JEOL-ECX-500 (126 MHz) spectrometer. Fluorine ( F) nuclear
19
magnetic resonance ( F NMR) spectra were recorded on a Bruker (376 MHz)
31
spectrometer or on a JEOL-ECX-500 (471 MHz) spectrometer. Phosphorus ( P) nuclear
31
magnetic resonance ( P NMR) spectra were recorded on a Bruker (162 MHz)
spectrometer or on a JEOL-ECX-500 (202MHz) spectrometer. The melting points (m.p.) of
the title compounds were determined when left untouched on an XT-4-MP apparatus from
Beijing Tech. Instrument Co. (Beijing, China). High resolution mass spectral analysis
(HRMS) was performed on a quadrupole/electrostatic field orbitrap mass spectrometer.
Absolute configuration of the products was determined by X-ray crystallography. HPLC
analyses were measured on Waters systems with Empower3 system controller, Alliance
column heater, and 2998 Diode Array Waters 2489 UV/Vis detector. Chiralcel brand chiral
columns from Daicel Chemical Industries were used with models AD-H, or OD-H in 4.6 x
250 mm size. The racemic products used to determine the er values were synthesized
using racemic catalyst. Optical rotations were measured on a Insmark IP-digi Polarimeter
o
in a 1 dm cuvette at 26 C. The concentration (c) is given in g/100 mL. Analytical thin-layer
chromatography (TLC) was carried out on Merck 60 F254 pre-coated silica gel plate (0.2
mm thickness). Visualization was performed using a UV lamp.
Ⅱ
. Preparation of substrates
α-Iminophosphonates 2 were synthesized from salicylaldehyde by the combination of
1
slightly modified literature procedures.

Following a known literature report: to a solution of salicylaldehyde (15 mmol) in
dimethylacetamide (100 mL) at 0 °C was carefully added freshly prepared
chlorosulfonamide (40 mmol) in small portions and the resulting solution was stirred for 12
h. The reaction was quenched carefully with ice-cold water (100 mL) and the mixture was
transferred to a separating funnel containing dichloromethane (200 mL). The aqueous
layer was separated and extracted with dichloromethane (3×50 mL), and the combined
organic layers were washed with saturated sodium bicarbonate solution (100 mL), dried
over sodium sulfate, filtered through a short pad of silica using dichloromethane as eluent
and concentrated in vacuo. The residue was heated to 180 °C under vacuum to remove
volatile impurities to get benzoxathiazine-2,2-dioxide (2-2).
To a suspension of the corresponding benzoxathiazine-2,2-dioxide (25 mmol) and the
corresponding dialkylphosphite (30 mmol) in toluene (50 mL) was added triethylamine
(2.5mmol). The solution was stirred and refluxed in toluene for 24 h until disappearance of
benzoxathiazine-2,2-dioxide. The solution was allowed to cool to room temperature and
purification was performed by a silica gel column eluted with dichloromethane to give pure
product.
To a solution of the above product (1.0 mmol) in dichloromethane was added freshly
prepared manganese dioxide (10 mmol) (the manganese dioxide must be freshly
prepared, or the reaction yield will be low). The solution was stirred and refluxed at 50 °C
for 4-8 h. The solution was allowed to cool to room temperature and purification was
performed by a silica gel column eluted with dichloromethane to give pure product 2.
Ⅲ
. Reaction condition optimization
a
Table 1. Screening of different carbene catalysts, bases and solvents.

b c
entry NHC base solvent yield er
1 A Cs CO THF < 5 --
2 3
2 B Cs CO THF < 5 --
2 3
3 C Cs CO THF 34 98:2
2 3
4 D Cs CO THF 73 99:1
2 3
5 E Cs CO THF < 5 --
2 3
6 D K CO THF 60 99:1
2 3
7 D NaOAc THF 93 > 99:1
8 D DBU THF 34 97:3
9 D DMAP THF < 5 --
10 D NaOAc EtOAc 58 > 99:1

11 D NaOAc CH Cl 32 99:1
2 2
a
General conditions (unless otherwise specified): 1a (0.12mmol), 2a (0.1 mmol), NHC
o b
(0.005 mmol), base (0.02 mmol), 4 (0.12 mmol), THF (2.0 mL), 30 C, 12 h. Isolated
c
yield of 3a. Er was determined via HPLC on chiral stationary phase.
Ⅳ
. Proposed mechanism.

Figure 1. Proposed mechanism
Ⅴ
. General procedure.
1. General procedure for the synthesis 3 from cyclic six-membered ring
α-iminophosphonates substrates 2.

To a dry Schlenk reaction tube equipped with a magnetic stir bar was added 1 (0.12
mmol), aldehydes 2 (0.1 mmol), triazolium salt D (2.5 mg, 0.005 mmol), oxidant 4 (49 mg,
0.12 mmol) and NaOAc (1.6 mg, 0.02 mmol). The schlenk tube was then closed with
septum, evacuated and refilled with N , freshly distilled anhydrous THF (2 mL) was added.
2
o
The mixture was stirred at 30 C for 12 h. After completion of the reaction monitored by
TLC, solvent was removed under reduced pressure and the residue was purified via
column chromatography on silica gel with Hexane/EtOAc (2: 1) as eluent to afford the
products 3.

2. General procedure for the synthesis 5.

To a solution of 3u (130 mg) in EtOAc (5 mL) was added Pd/C(5%w, 6 mg), then the
mixture was degassed and refilled with H2(balloon) for 3 times, then the mixture was
stirred at rt under H (balloon) for 6h, then the mixture was filtered off and the residue was
2
purified via column chromatography on silica gel with Hexane/EtOAc (2: 1) as eluent to
afford the product 5 (120 mg).
Ⅵ
. Stereochemistry determination via X-ray crystallographic

analysis
The absolute stereochemistry of 3e was determined by the X-ray diffraction. This
crystal was deposited in the Cambridge Crystallographic Data Centre and assigned as
CCDC: 1854098.

Refrences:
[1]. Z. Yan, B. Wu, X. Gao, M.-W. Chen, Y.-G. Zhou, Org. Lett., 2016, 18, 692.
Ⅶ
. In vitro antibacterial bioassay
The target compounds were dissolved in 150 L DMSO and diluted with sterile distilled
water containing 0.1 % Tween-20 (4 mL) to prepare 1000 and 500 g/mL stock solution.
Their antibacterial activities against Xanthomonas oryzae pv. oryzae was evaluated by the
turbidimeter test. 1 mL of stock solution was added to 4 mL nutrient broth liquid medium
NB (3 g of beef extract, 5 g of peptone, 1 g of yeast powder, 10 g of glucose, and 1000 mL
of distilled water, pH 7.0 - 7.2) in tubes. Then, to the tube, 40 μL NB containing bacteria
o
was added and incubated with continuous shaking at 180 rpm for 36 h at 30±1 C. The
test concentration was fixed at 200 and 100 g/mL. The data of bacterial growth was
reported by measuring the optical density at 600 nm (OD ) with a spectrophotometer.
600
DMSO in sterile distilled water containing 0.1 % Tween-20 served as the negative control,
whereas Bismerthiazol served as positive control. The inhibitory rate of bacterial culture
growth was calculated according to the following formula:
Inhibition rate (%) = (CK-T)/CK×100
“CK” means the value of corrected optical density of bacterial growth on untreated NB
(negative control), and “T” means the value of corrected optical density of bacterial growth
on treated NB.
Table 2. Antibacterial activity
Antibacterial activity of the title compounds
Antibacterial activity of the title compounds
a
X. oryzoe pv. oryzae inhibition rate [%]
Compound
100 g/mL 200 g/mL
3a 10.4±7.2 17.1±4.4
3b 19.2±3.2 32.9±3.8
3c 16.3±6.5 20.9±6.7
3d 17.1±4.8 46.0±1.9
3e 45.6±3.8 80.0±2.5
3f 27.7±6.3 31.7±3.7
3g 22.0±6.3 0
3h 9.7±7.3 2.1±6.4
3i 21.8±6.1 0
3j 6.4±5.7 8.6±3.9
3k 0 0
3l 69.3±3.8 88.8±3.1
3m 0 0
3n 0 o
3o 0 10.6±6.7
3p 23.5±3.6 18.2±4.2
3q 0 6.9±3.9
3r 0 0
3s 0 0
3t 0 0
3u 25.3±2.4 32.6±5.3
b
Bismerthiazol 45.4±1.9 73.6±1.4
c
Negative control 0 0
a b
Average of three replicates. Commercial bactericide, used as the positive control.
c
DMSO was used as the negative control.
Ⅷ
. Characterization of intermediates & products
Diethyl (6-methoxy-2,2-dioxidobenzo[e][1,2,3]oxathiazin-4-yl)phosphonate (2q)
o
Light yellow solid, m.p. 45-46 C 350 mg, 35% yield.
O
1
O H NMR (400 MHz, CDCl ) δ 8.00 (d, J = 2.9 Hz, 1H), 7.29 (dd, J
O S 3
= 9.1, 2.9 Hz, 1H), 7.23 (dd, J = 9.1, 1.3 Hz, 1H), 4.43 - 4.30 (m,
N
4H), 3.88 (s, 3H), 1.42 (td, J = 7.1, 0.6 Hz, 6H).
O
P 13C NMR (101 MHz, CDCl ) δ 172.5 (d, J = 199.1 Hz), 157.0 (s),
H CO O 3
3 O
148.2 (d, J = 8.6 Hz), 125.2 (s), 120.0 (d, J = 3.2 Hz), 116.1 (d, J =
24.1 Hz), 113.3 (s), 65.5 (d, J = 7.0 Hz), 56.1 (s), 16.3 (d, J = 6.0 Hz).
31
P NMR (162 MHz, CDCl ) δ 0.92 (s).
3
+
HRMS (ESI, m/z): Mass calcd for C H O NPS [M+H] , 350.0458; found 350.0468.
12 17 7

Diethyl (R)-(6,6-dioxido-8-oxo-10-phenyl-8,11-dihydro-11aH-benzo[e]pyrido[1,2-c]
[1,2,3]oxathiazin-11a-yl)phosphonate (3a)
o
O White solid, m.p. 127-128 C, 45 mg, 97% yield.
O
O S O [] 28 = -31.2 (c 1.0 CHCl ).
D 3
N 1
H NMR (400 MHz, CDCl ) δ 7.67 - 7.60 (m, 2H), 7.60 - 7.55 (m,
3
1H), 7.55 - 7.40 (m, 5H), 7.32 - 7.27 (m, 1H), 6.40 (d, J = 2.9 Hz,
O P O Ph 1H), 4.25 - 4.04 (m, 3H), 4.01 - 3.87 (m, 1H), 3.80 - 3.65 (m, 1H),
O
3.39 (ddd, J = 34.3, 17.2, 2.9 Hz, 1H), 1.24 (t, J = 7.0 Hz, 3H), 1.10
(t, J = 7.0 Hz, 3H).
13
C NMR (101 MHz, CDCl ) δ 162.3 (s), 150.4 (s), 148.4 (d, J = 4.7 Hz), 136.2 (s), 131.3
3
(d, J = 2.8 Hz), 130.8 (s), 129.2 (s), 127.5 (d, J = 2.2 Hz), 126.8 (d, J = 4.0 Hz), 126.6 (s),
125.4 (s), 119.8 (d, J = 2.3 Hz), 118.5 (s), 66.4 (d, J = 152.6 Hz), 64.7 (d, J = 3.8 Hz), 64.6
(d, J = 3.6 Hz), 36.5 (d, J = 2.4 Hz), 16.3 (d, J = 5.5 Hz), 16.1 (d, J = 5.4 Hz).
31
P NMR (162 MHz, CDCl ) δ 17.57 (s).
3
+
HRMS (ESI, m/z): Mass calcd for C H O NPS [M+H] , 464.0927; found 464.0918.
21 23 7
Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel AD-H; IPA/hexanes =
30/70, 0.8 mL/min, 254 nm), Rt (minor) = 10.5 min, Rt (major) = 17.0 min; er = 99.2:0.8).
1 2