This is the peer reviewed version of the following article Synthesis 2017, 49 (1), 76-86
which has been published in final form
https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0036-1588606

Light-triggered Enantioselective Organocatalytic Mannich-type Reaction
Hamish B. Hepburna
Giandomenico Magagnanoa
Paolo Melchiorre*a,b
a

ICIQ – Institute of Chemical Research of Catalonia
Barcelona Institute of Science and Technology,
Països Catalans 16, 43007 - Tarragona, Spain

b

the
Av.

ICREA – Pg. LLuís Companys 23, 08010 - Barcelona, Spain

pmelchiorre@iciq.es

Dedicated to Professor Dieter Enders on the occasion
of his 70th birthday

Received:
Accepted:
Published online:
DOI:

Abstract Disclosed herein is a photochemical organocatalytic strategy for the direct enantioselective Mannich-type reaction of 2-alkyl-benzophenones and cyclic
imines. The chemistry exploits the light-triggered enolization of 2-alkyl-benzophenones to generate transient hydroxy-o-quinodinomethanes. These fleeting
intermediates can be stereoselectively intercepted by imines upon activation with a chiral organic catalyst, derived from natural cinchona alkaloids. The developed
method uses mild conditions, simple sources of illumination and easily available substrates and catalysts, affording enantioenriched chiral amines that are difficult to
synthesize by other approaches.
Key words: enantioselective catalysis, organocatalysis, Mannich-type reaction, photochemistry, synthetic methods.

The possibility of generating highly reactive hydroxyl-o-quinodimethanes A through the photoexcitation of 2-alkyl benzophenones 1 has
been reported as far back as 1961.1 Transient intermediates A2 can serve as suitable dienes for a range of [4+2] cycloadditions with
electron-poor alkenes 2 (Figure 1a).3 The resulting Diels-Alder processes afford synthetically valuable benzannulated carbocyclic products
3. The mechanism of formation of A has been well-studied and characterized (Figure 1b).4 Irradiation of the 2-alkyl benzophenone 1
triggers the formation of a singlet excited state S1-B that, upon intersystem crossing, decays to a triplet state T1-B. Following 1,5-hydrogen
transfer, the diradical intermediate (Z)-C is generated, which then undergoes rotation to afford the highly reactive enol (E)-A. Chemical
trapping of A by a dienophile 2 provides straightforward access to stereochemically dense cyclic derivatives 3.
The photoenolization/Diels-Alder sequence, in racemic fashion, has been extensively used by chemists.2,5 However, developing an
enantioselective catalytic variant has proven a difficult target. Asymmetric catalytic approaches are greatly complicated by the high
reactivity and fleeting nature of the photoenols A, which make it difficult for a chiral catalyst to channel the process through a
stereocontrolled pathway. One effective asymmetric method used a stoichiometric amount of a chiral complexing agent to selectively bind
a purposely designed 2-alkyl carbonyl compound.6 But methods that use substoichiometric chiral catalysts remained unprecedented until
recently, when our research group reported an organocatalytic strategy for successfully trapping A in a stereoselective fashion.7 Our
approach relied on the use of a chiral organic catalyst which could effectively activate the dienophilic maleimide D (Figure 1c).

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1a;
Figure 1 a) The classical photoenolization/Diels-Alder strategy; EWG = electron withdrawing group. b) The photoenolization mechanism of 2-methylbenzophenone 1a
ISC: intersystem crossing. c) Our precedent organocatalytic approach for activating maleimide B toward the stereoselective trap of hydroxy-o-quinodimethanes A. d)
The proposed trap of photoenol A with an imine C activated by a chiral organic catalyst; PG: protecting group.

Building upon this precedent, we wondered whether organocatalysis8 could offer other effective tools to stereoselectively trap
photogenerated hydroxy-o-quinodimethanes A with different dienophiles. Specifically, we considered imines E as suitable candidates for
the interception of A (Figure 1d). Although no literature precedent exists for even the racemic version of such transformation, we were
motivated by the notions that imines are primed to organocatalytic activations9 and can generally participate in hetero-Diels Alder
processes.10 Herein, we document how this idea was translated to experimental reality.
We started out our investigations studying the reaction between the commercially available 2-methylbenzophenone 1a and a variety of
N-protected benzaldimines 2. These processes were conducted in the presence of 20 mol% of the phosphoric acid 5a11a or the cinchonabased thiourea 5b11b (Figure 2), two chiral organic catalysts with an established ability to activate imine substrates while inducing high
level of stereoselectivity.11 We also tested the catalytic profile of 5c, since it provided the best results in our previous study on the
stereocontrolled trapping of photoenol A with maleimides of type D (Figure 1c).7 The experiments were performed over 14 hours, in
toluene, at ambient temperature, and under irradiation by a single black-light-emitting diode (black LED, λmax = 365 nm).

Figure 2 Initial explorations aimed at identifying the model reaction and a suitable imine substrate.

Benzaldimines bearing commonly used N-protecting groups, including N-Boc, N-tosyl, and N-PMP imines (Boc = tert-butyloxycarbonyl;
tosyl = toluenesulfonyl; PMP = p-methoxyphenyl), did not lead to the formation of any product, and were recovered untouched. The lack
of reactivity of linear imines prompted us to evaluate the behavior of benzoxathiazine-2,2-dioxide 2a. Indeed, it has been recently reported
that the cyclic nature of 2a, by constraining the C=N bond in a Z geometry, makes it a highly reactive substrate prone to undergo
nucleophilic additions12 and hetero-Diels-Alder reactions.13 This reactivity profile provides a rationale for the capability of 2a, in the
presence of catalyst 5a-c, to successfully trap the fleeting hydroxy-o-quinodimethane A, generated from 1a (Figure 2). These observations
come about with an unanticipated reactivity, since an unconventional formal Mannich-type reaction of the photoenol with 2a was
observed instead of the expected [4+2] manifold. The light-triggered process led to the exclusive formation of the adduct 3a, while no
traces of the cyclic product 4 were detected.
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Having identified a suitable substrate combination, we next focused on obtaining a high level of stereocontrol, since the light-triggered
Mannich-type processes catalyzed by 5a, 5b, and 5c offered minimal level of enantioinduction, if any (product 3a formed as a racemate or
with 8% ee, Figure 2). We undertook the evaluation of a large and diverse set of chiral organic catalyst structures (full details can be found
in the Supporting Information), which identified the dimeric cinchona alkaloid derivative (DHQ)2PHAL 6a, commonly employed as a ligand
for Sharpless asymmetric dihydroxylation,14 as a promising candidate (Table 1). Indeed, the commercially available catalyst 6a afforded
the amine product 3a in 58% yield and with an enantiomeric excess as high as 60% in toluene (entry 1). Evaluation of the standard reaction
parameters revealed that the use of a non-polar solvent such as cyclohexane increased the level of stereoselectivity up to 72% ee (entry
2).
1:
Table 1 Optimization Studiesa

entry

catalyst

3a yield (%)

e.e. (%)

1b

6a (DHQ)2PHAL

58

60

2

6a (DHQ)2PHAL

38

72

3

6b

36

72

4

6c

37

25

5

6d

18

67

6

6e

36

70

7

6f

40

59

8

(DHQ)2PYRc

75

0

9

none

25

0

10d

6a (DHQ)2PHAL

82e

72

11d

(DHQD)2PHALf

68

46

a

Reactions performed using 20 mol% of catalyst 6, 2 equiv. of 1a and [2a]0 = 0.025 M in cyclohexane; yield determined by 1H NMR analysis of the crude mixture using
2
trichloroethylene as the internal standard; ee determined by UPC2 analysis on a chiral stationary phase. b Reaction performed in toluene. c The structure of (DHQ)2PYR catalyst,
bearing a pyrimidine linker instead of a phthalazine core, is reported in the Supporting Information. d Reaction time: 48 hours. e Yield of isolated 3a after chromatography
purification. f Reaction performed using the pseudoenantiomeric catalyst (DHQD)2PHAL to furnish ent-3a
3a.
3a

We then wondered if the stereoselectivity of the reaction could be improved by structurally modifying the dimeric cinchona scaffold of
catalyst 6a. Unfortunately, extensive modifications of both the phthalazine linker and the cinchona moiety at a variety of sites did not bring
about any improvement in enantioinduction (a representative selection is shown in Table 1, further details can be found in the Supporting
Information). Still, these studies established the key role played by both the methoxy group on the quinoline ring (R2 group in Table 1,
compare catalysts 6a and 6c in entries 2 and 4) and the two contiguous nitrogen atoms within the phthalazine linker (compare catalysts
6a and (DHQ)2PYR in entries 2 and 8) in dictating the stereoselectivity.
A final cycle of optimization using the commercial catalyst (DHQ)2PHAL 6a revealed that the adduct 3a could be isolated with high chemical
yield and with 72% ee when extending the reaction time to 48 hours (entry 10, 82% yield). This level of enantioselectivity is striking when
considering the substantial rate of background reaction observed in the absence of catalyst (entry 9).15,16 The use of the
pseudoenantiomeric (DHQD)2PHAL catalyst, derived from hydroquinidine, provided access to the antipode of the Mannich-type product
ent-3a, albeit with a reduced enantiomeric excess (46% ee, entry 11).
We next sought to explore the scope of both substrates in the asymmetric organocatalytic photenolization/Mannich-type reaction
sequence, using the reaction conditions detailed in entry 10 of Table 1. As shown in Scheme 1, there appears to be significant tolerance for
structural and electronic variations of the benzophenone derivatives 1 to enable access to a variety of amine products 3. Substitution on
the non-enolizable aromatic ring of 1 with both electron-donating and electron-withdrawing groups is well tolerated. The reaction
proceeds well with substrates bearing substituents at the meta- and para- positions (products 3b-3h), while an ortho-substitution pattern
negatively affects the stereoselectivity (product 3i). The presence of a substituent at the benzylic R2 position of 1 brings about the
formation of two contiguous stereogenic centers (product 3j), albeit with a low diastereoselectivity. Substitution of the enolizable phenyl
ring led to a decreased stereocontrol (product 3k) while providing a high chemical yield. Not all 2-methylbenzophenones 1 are suitable
for the reaction; substrates featuring extended π-systems (1l, 1m) or sterically encumbered substitution patterns (1n) remained
unreacted. Crystals from compound 3e were suitable for X-ray crystallographic analysis,17 which established the stereochemical outcome
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of the Mannich-type reaction and the absolute configuration of the newly-formed stereogenic center. From a synthetic perspective, it is
interesting that, although the amine products 3 are generally obtained in moderate enantioselectivity, the optical purity can be easily
increased by simple crystallization, as demonstrated for compound 3d (96% ee).

Scheme 1: Survey of the benzophenones 1 that can participate in the photochemical organocatalytic Mannich-type reaction. Reactions performed using 100 µmol of
2a, 50 µmol of 1 and 20 mol% of catalyst 6a in cyclohexane (2 mL). Yields and the enantiomeric excesses of the isolated products 3 are indicated below each entry
(average of two runs per substrate). a Ee value obtained after a single crystallization.

As for the cyclic imines 2 that can participate in the light-triggered organocatalytic Mannich-type reaction (Scheme 2), different alkyl
substituents are well tolerated at the ortho-, meta-, and para- positions (with respect to the oxygen), affording products 7a-d in good yields
and moderate enantioselectivity. The presence of an electron-donating group negatively influences the reactivity of the imine, resulting in
a lower isolated yield while maintaining a good stereoselectivity (product 7e). Electron-withdrawing groups provide the products 7f-h in
good yields but with a reduced enantioselectivity.

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Scheme 2: Survey of the cyclic aromatic imines 2 that can participate in the photochemical organocatalytic Mannich-type reaction. Reactions performed using 100
µmol of 2, 50 µmol of 1a and 20 mol% of catalyst 6a in cyclohexane (2 mL). Yields and the enantiomeric excesses of the isolated products 7 are indicated below each
entry (average of two runs per substrate). a Reaction time: 72 hours.

Mechanistically, several aspects of this photo-mediated process deserve comment. The most peculiar trait is that no traces of the expected
cycloaddition adducts 4 (see Figure 2) were detected during our studies. Given the well-established tendency of both photogenerated
hydroxy-o-quinodimethanes2,3,5 and cyclic imines of type 213 to engage in hetero-Diels-Alder pathways, the occurrence of a [4+2]cycloaddition manifold, followed by the spontaneous collapse of the hemiaminal 4, is likely. A similar hetero-Diels-Alder/ring-opening
sequence has been recently proposed (and supported by calculations) as the underlying mechanism of the light-driven carboxylation
of ketones 1 proceeding via the trapping of the photoenol A with CO2.18
As for the mechanism of stereocontrol, we initially thought that (DHQ)2PHAL 6a could interact with the transient photoenol (E)-A. This
idea was motivated by our precedent studies7 demonstrating that the quinuclidine core within the cinchona-based catalyst 5c could reduce
the formation of the photoenol derived from 1a by means of an electron transfer mechanism. To evaluate whether the cinchona moiety in
6a could participate in a similar pathway, we conducted laser flash photolysis studies. These investigations, detailed in the Supporting
Information, showed that the absorption at 450 nm of the transient photoenol A (half lifetime 7 ms in toluene), generated upon laser
excitation of 1a, was not significantly affected by the presence of 6a.16 Overall, our observations suggest that the chiral catalyst 6a controls
the stereochemical outcome of the reaction by solely interacting with the imine substrate 1.19 Additional studies are underway in our
laboratories to shed further light upon the mechanism governing the stereoinduction of the light-triggered Mannich-type reaction.
In conclusion, we have documented the possibility to stereoselectively trap hydroxyl-o-quinodimethane A, generated upon light excitation
of 2-alkyl benzophenones 1, with cyclic imines 2. This process, which has no precedents in the racemic regime too, leads to the formation
of chiral amines 3 via a formal Mannich-type reaction manifold. The developed method uses mild conditions, simple sources of illumination
and the commercially available (DHQ)2PHAL as catalyst, which can induce a good level of stereoselectivity. Further studies are ongoing to
provide a deeper mechanistic understanding while identifying additional dieneophiles that may serve to stereoselectively trap the
photoenol A.
The experimental section has no title; please leave this line here.
Commercial grade reagents and solvents were purchased at the highest commercial quality and used without further purification, unless otherwise stated.
Cyclohexane was purchased from Sigma Aldrich and was sparged with argon for 30 minute before use. (DHQ)2PHAL 6a was purchased from Sigma Aldrich.
Cyclic imines 220 and benzophenones7 were prepared according to procedures reported in the literature. Chromatographic purification of products was
accomplished using force-flow chromatography (FC) on silica gel (35-70 mesh). For thin layer chromatography (TLC) analysis throughout this work, Merck
precoated TLC plates (silica gel 60 GF254, 0.25 mm) were used, using UV light as the visualising agent.
The NMR spectra were recorded at 500 MHz for 1H or at 125 MHz for 13C, respectively. The chemical shifts (δ) for 1H and 13C are given in ppm relative to
residual signals of the solvents (CHCl3 @ 7.27 ppm 1H NMR, 77.00 ppm 13C NMR). Coupling constants are given in Hz. The following abbreviations are used
to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad signal. High-resolution mass spectra (HRMS) were obtained
from the ICIQ High Resolution Mass Spectrometry Unit on Waters GCT gas chromatograph coupled time-of-flight mass spectrometer (GC/MS-TOF) with
electron ionization (EI) or MicroTOF II (Bruker Daltonics): HPLC-MS-TOF (ESI). X-ray data were obtained from the ICIQ X-Ray Unit using a Bruker-Nonius
diffractometer equipped with an APPEX 2 4K CCD area detector. Optical rotations were measured on a Polarimeter Jasco P-1030 and are reported as follows:
[α]D rt (c in g per 100 mL, solvent). FT-IR measurements were carried out on an Agilent Technologies Cary 630 FTIR spectrometer. Melting points were
measured on a Mettler Toledo MP70 melting point system and are uncorrected. Studies with millisecond transient absorption spectroscopy (TAS) were
performed using an excitation source of Nd:YAG (neodymium-doped yttrium aluminium garnet) tuned with an optical parametric oscillator (OPO) from

page 5 of 12

Opolette as a pump source. This laser produces 6 ns pulses of 1 mJ at a wavelength of 355 nm. The system is completed with two monochromators with
double grating at the VIS an IR, and a digital recorder DSP-DAU from RAMDSP. A photodetector amplifiers and a software control complete the TAS system.
Determination of Enantiomeric Purity: UPC2 and HPLC analyses on chiral stationary phase were performed on a Waters Acquity and an Aglient 1200
series instrument, respectively. Traces were compared to racemic samples prepared by running the reaction in the absence of catalyst.
Light Source: The light source used for illuminating the reaction vessel consisted of a single black LED (3.6 W, EOLD-365-525 LED, UV, 5 mm, λ max= 365
nm) produced by OSA OPTO Light and purchased from Farnell (http://www.farnell.com/).
General Procedure for the light-triggered enantioselective organocatalytic Mannich-type reaction: A 5 mL glass vial was charged with the imine 2
(50 µmol) and the catalyst (DHQ)2PHAL 6a (10 µmol, 0.2 equiv., 7.8 mg). The vial was capped with a septum and purged with vacuum/argon cycles (x 3).
The benzophenone 2 (2 equiv.) was dissolved in degassed cyclohexane (2 mL) and added to the vial. The vial was flushed with argon, closed with a Tefloncoated cap, sealed with parafilm and placed into a single black LED plate (λ = 365 nm, intensity = 6.5 ±0.5 mW/cm2, as controlled by an external power
supply; the setup is further detailed in the Supporting Information). Stirring at ambient temperature was maintained for 48 hours, and then the irradiation
was stopped. The reaction was then diluted with methylene chloride (1 mL) and passed through a pad of silica. The volatiles were removed in vacuum and
the residue was purified by flash column (FC) chromatography to give the amine product 3 in the stated yield and enantiomeric purity. The experiment was
repeated and the results are an average of two runs.
Experimental Note A: when colleting the final amine products 3/7 after chromatography, in vacuo concentration should be made from a non-polar solution,
such as hexane. This secures the resultant product to be obtained as a crystalline solid. If the final product is concentrated from a polar solution instead, such
as CH2Cl2 or CHCl3, this would provide a gummy solid, which may need further mechanical handling to form a crystalline solid.
Experimental Note B: The amine products 3/7 have generally a low solubility in non-polar solvent. To ensure consistent UPC2 analysis of the enantiomeric
excess, it is necessary to dissolve the whole sample in a 7:3 hexane:iPrOH solution and then taking a aliquot for analysis.
(R)-(2-((2,2-Dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (3a)
The title compound 3a was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The
crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3a (15.5 mg, 82%, average of two runs) as a white solid.
Rf = 0.32 (9:1
hexane/EtOAc); melting point (mp) = 55-57 °C (upon recrystallized from hexane).
IR (ATR): 3103, 1636 (C=O), 1595, 1369, 1263, 1178, 1111, 938, 755, 705 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.81 (2H, dt, J = 8.4, 1.5 Hz, ArH), 7.64 (1H, ddt, J = 8.8, 7.1, 1.3 Hz, ArH), 7.61-7.58 (2H, m, ArH), 7.49 (2H, ddt, J = 8.7, 7.5, 1.4
Hz, ArH), 7.44 (1H, dt, J = 7.8, 1.1 Hz, ArH), 7.41-7.37 (2H, m, ArH), 7.32 (1H, dddd, J = 8.2, 7.4, 1.7, 0.8 Hz, ArH), 7.20 (1H, td, J = 7.6, 1.3 Hz, ArH), 7.11 (1H, d,
J = 7.6 Hz, NH), 7.06 (1H, dd, J = 8.2, 1.2 Hz, ArH), 5.15 (1H, ddd, J = 12.0, 7.6, 4.6 Hz, CHNH), 3.53 (1H, dd, J = 13.7, 4.6 Hz, CH2CHNH), 3.25 (1H, dd, J = 13.7,
11.5 Hz, CH2CHNH).
13C NMR (125.6 MHz, CDCl ) δ 199.4 (C=O), 151.2 (C), 137.6 (C), 137.3 (C), 136.7 (C), 133.8 (CH), 131.8 (CH), 131.2 (CH), 130.9 (2 x CH), 130.7 (CH), 129.4
3
(CH), 128.5 (2 x CH), 126.5 (CH), 126.3 (CH), 125.1 (CH), 122.4 (C), 119.1 (CH), 58.7 (CH), 37.7 (CH2).

HRMS (ESI) Exact mass calculated for C21H17NO4SNa [M+Na]+: 402.0770, found: 402.0776.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 251 nm: τminor = 5.60 min, τmajor = 5.77 min (72% ee). [α]D28 = +18.9 (c = 1.0, CHCl3, 72% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(4-methoxyphenyl)methanone (3b)
The title compound 3b was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (4-methoxyphenyl)(o-tolyl)methanone 1b (22.6
mg, 100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3b (13.5 mg, 66%, average of two runs) as a white solid. Rf = 0.21
(9:1 hexane/EtOAc); mp = 50-52 °C (hexane).
IR (ATR): 2923, 1627 (C=O), 1590, 1485, 1453, 1419, 1373, 1257, 1169, 746 cm-1.
1H NMR (500 MHz, CDCl ) δ 7.63-7.55 (2H, m, ArH), 7.45 (1H, dd, J = 7.5, 1.2 Hz, ArH), 7.42-7.35 (4H, m, ArH), 7.33 (1H, tdd, J = 7.4, 1.6, 0.7 Hz, ArH), 7.29
3
(1H, dt, J = 7.7, 1.3 Hz, ArH), 7.22-7.16 (2H, m, ArH), 7.12 (1H, d, J = 7.4 Hz, NH), 7.06 (1H, dd, J = 8.3, 1.3 Hz, ArH), 5.15 (1H, ddd, J = 11.8, 7.4, 4.6 Hz, NHCH),
3.86 (3H, s, OCH3), 3.52 (1H, dd, J = 13.7, 4.6 Hz, NHCHCH2), 3.24 (1H, dd, J = 13.7, 11.5 Hz, NHCHCH2).
13C

NMR (125.6 MHz, CDCl3) δ 199.2 (C=O), 159.8 (C), 151.1 (C), 138.6 (C), 137.6 (C), 136.6 (C), 131.8 (CH), 131.2 (CH), 130.7 (CH), 129.44 (CH), 129.41
(CH), 126.4 (CH), 126.3 (CH), 125.1 (CH), 124.0 (CH), 122.5 (C), 120.6 (CH), 119.1 (CH), 114.5 (CH), 58.7 (CH), 55.5 (CH3), 37.7 (CH2).

HRMS (ESI) Exact mass calculated for C22H20NO5S [M+H]+: 410.1063, found: 410.1057.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/i-PrOH to 60:40 CO2/i-PrOH for 9 minutes with curve of
“6”, λ= 285 nm: τminor = 6.37 min, τmajor = 6.82 min (73% ee). [α]D28 = +13.5 (c = 0.8, CHCl3, 73% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(4-tert-butylphenyl)methanone (3c)
The title compound 3c was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (4-tert-butylphenyl)(o-tolyl)methanone 1c (25.2
mg, 100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3c (16 mg, 74%, average of two runs) as a white solid. Rf = 0.36
(9:1 hexane/EtOAc); mp = 70-72 °C (hexane).
IR (ATR): 2919,1634 (C=O), 1599, 1487, 1456, 1370, 1187, 1106, 937, 751 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.78-7.73 (2H, m, ArH), 7.61-7.55 (2H, m, ArH), 7.51-7.47 (2H, m, ArH), 7.47-7.43 (1H, m, ArH), 7.41-7.35 (2H, m, ArH), 7.32
(1H, dddd, J = 8.2, 7.3, 1.6, 0.7 Hz, ArH), 7.24 (1H, d, J = 7.6 Hz, NH), 7.19 (1H, td, J = 7.6, 1.3 Hz, ArH), 7.06 (1H, dd, J = 8.2, 1.3 Hz, ArH), 5.14 (1H, ddd, J = 11.9,
7.6, 4.6 Hz, NHCH), 3.51 (1H, dd, J = 13.7, 4.6 Hz, NHCHCH2), 3.21 (1H, dd, J = 13.7, 11.5 Hz, NHCHCH2), 1.36 (9H, s, C(CH3)3).
13C NMR (125.6 MHz, CDCl ) δ 199.0 (C=O), 157.9 (C), 151.2 (C), 137.9 (C), 136.5 (C), 134.6 (C), 131.6 (CH), 131.1 (CH), 131.0 (2 x CH), 130.5 (CH), 129.4
3
(CH), 126.4 (CH), 126.3 (CH), 125.5 (2 x CH), 125.1 (CH), 122.5 (C), 119.1 (CH), 58.6 (CH), 37.7 (CH2), 35.3 (C), 31.0 (3 x CH3).

HRMS (ESI) Exact mass calculated for C25H25NO4SNa [M+Na]+: 458.1398, found: 458.1396.

page 6 of 12

The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 261 nm: τminor = 5.90 min, τmajor = 6.07 min (77% ee). [α]D28 = +30.0 (c = 0.5, CHCl3, 77% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(4-bromophenyl)methanone (3d)
The title compound 3d was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (4-bromophenyl)(o-tolyl)methanone 1d (27.5 mg,
100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3d (18 mg, 79%, average of two runs) as a white solid. Rf = 0.30 (9:1
hexane/EtOAc); mp = 88-90 °C (hexane).
IR (ATR): 2922, 1645 (C=O), 1578, 1453, 1423, 1369, 1262, 1183, 1166, 750 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.69-7.66 (2H, m, ArH), 7.65-7.58 (4H, m, ArH), 7.43-7.37 (3H, m, ArH), 7.33 (1H, dddd, J = 8.1, 7.3, 1.6, 0.7 Hz, ArH), 7.21 (1H,
td, J = 7.6, 1.3 Hz, ArH), 7.06 (1H, dd, J = 8.3, 1.2 Hz, ArH), 6.92 (1H, d, J = 7.7 Hz, NH), 5.15 (1H, ddd, J = 11.9, 7.7, 4.5 Hz, NHCH), 3.52 (1H, dd, J = 13.7, 4.5 Hz,
CH2), 3.24 (1H, dd, J = 13.7, 11.5 Hz, CH2).
13C NMR (125.6 MHz, CDCl3) δ 198.3 (C=O), 151.2 (C), 137.1 (C), 136.9 (C), 136.1 (C), 133.3 (2 x CH), 132.1 (CH), 131.9 (2 x CH), 131.5 (CH), 130.5 (CH),
129.5 (CH), 129.3 (C), 126.6 (CH), 126.4 (CH), 125.2 (CH), 122.4 (C), 119.1 (CH), 58.7 (CH), 37.7 (CH2).

HRMS (ESI) Exact mass calculated for C21H17BrNO4S [M+H]+: 458.0064, found: 458.0056.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 262 nm: τmajor = 6.44 min, τminor = 6.84 min (77% ee). [α]D28 = +10.5 (c = 1.0, CHCl3, 77% ee).
Recrystallation from 7:3 hexane/iso-propanol gave racemic crystals while the enantioenriched compound 3d (96% ee) was recovered from the mother
liquor.

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(4-fluorophenyl)methanone (3e)
The title compound 3e was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (4-fluorophenyl)(o-tolyl)methanone 1e (21 mg,
100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3e (15.5 mg, 82%, average of two runs) as a white solid. Rf = 0.31
(9:1 hexane/EtOAc); mp = 119-121 °C (hexane).
IR (ATR): 2922, 1643 (C=O), 1593, 1486, 1455, 1424, 1363, 1183, 1110, 751 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.85 (2H, dd, J = 8.9, 5.4 Hz, ArH), 7.59 (2H, m, ArH), 7.42-7.37 (3H, m, ArH), 7.33 (1H, dddd, J = 8.2, 7.4, 1.7, 0.7 Hz, ArH), 7.237.13 (3H, m, ArH), 7.09-7.02 (2H, m, ArH), 5.15 (1H, ddd, J = 11.9, 7.7, 4.5 Hz, CHNH), 3.52 (1H, dd, J = 13.7, 4.6 Hz, CH2CHNH), 3.23 (1H, dd, J = 13.7, 11.5
Hz, CH2CHNH).
13C NMR (125.6 MHz, CDCl3) δ 197.8 (C=O), 166.2 (d, J = 257 Hz, C), 151.2 (C), 137.3 (C), 136.7 (C), 133.7 (CH), 133.6 (d, J = 2.9 Hz, C), 133.5 (CH), 131.9
(CH), 131.3 (CH), 130.4 (CH), 129.5 (CH), 126.4 (d, J = 26.2 Hz, 2 x CH), 125.1 (CH), 122.4 (CH), 119.1 (CH), 115.8 (d, J = 22.1 Hz, 2 x CH), 58.7 (CH), 37.7 (CH2).
19F

NMR (376 MHz, CDCl3) δ -103.4 (tt, J = 8.3, 5.4 Hz).

HRMS (ESI) Exact mass calculated for C21H17FNO4S [M+H]+: 398.0857, found: 398.0854.
The enantiomeric excess was determined by UPC2 analysis on a Waters Cel2 column, 100:0 CO2/MeCN to 60:40 CO2/MeCN for 9 minutes with curve of “6”,
λ= 254 nm: τminor = 4.63 min, τmajor = 4.75 min (75% ee). [α]D28 = +16.2 (c = 1.0, CHCl3, 75% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(3-methoxyphenyl)methanone (3f)
The title compound 3f was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (3-methoxyphenyl)(o-tolyl)methanone 1f (22.6 mg,
100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3f (15 mg, 73%, average of two runs) as a white solid. Rf = 0.22 (9:1
hexane/EtOAc); mp = 53-55 °C (hexane).
IR (ATR): 2922, 1635 (C=O), 1576, 1483, 1454, 1373, 1269, 1183, 1166, 751 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.63-7.58 (2H, m, ArH), 7.47-7.43 (1H, m, ArH), 7.43-7.34 (4H, m, ArH), 7.33 (1H, dddd, J = 8.2,7.3, 1.7, 0.7 Hz, ArH). 7.29 (1H,
dt, J = 7.7, 1.3 Hz, ArH), 7.24-7.15 (2H, m, ArH), 7.12,(1H, d, J = 7.6 Hz, NH), 7.06 (1H, dd, J = 8.3, 1.2 Hz, ArH), 5.15 (1H, ddd, J = 11.9, 7.6, 4.6 Hz, NHCH), 3.86
(3H, s, OCH3), 3.52 (1H, dd, J = 13.7, 4.6 Hz, NHCHCH2), 3.24 (1H, dd, J = 13.7, 11.6 Hz, NHCHCH2).
13C

NMR (125.6 MHz, CDCl3) δ 199.2 (C=O), 159.7 (C), 151.2 (C), 138.6 (C), 137.6 (C), 136.6 (C), 131.8 (CH), 131.1 (CH), 130.7 (CH), 129.44 (CH), 129.41
(CH), 126.4 (CH), 126.3 (CH), 125.1 (CH), 124.0 (CH), 122.4 (C), 120.6 (CH), 119.1 (CH), 114.5 (CH), 58.7 (CH), 55.5 (CH3), 37.7 (CH2).

HRMS (ESI) Exact mass calculated for C22H19NO5SNa [M+Na]+: 432.0876, found: 432.0878.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/i-PrOH to 60:40 CO2/i-PrOH for 9 minutes with curve of
“6”, λ= 257 nm: τminor = 5.87 min, τmajor = 6.06 min (69% ee). [α]D28 = +27.34 (c = 0.5, CHCl3, 69% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(3-chlorophenyl)methanone (3g)
The title compound 3g was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (3-chlorophenyl)(o-tolyl)methanone 1g (23 mg,
100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3g (14.5 mg, 70%, average of two runs) as a white solid. Rf = 0.33
(9:1 hexane/EtOAc); mp = 39-41 °C (hexane).
IR (ATR): 2922, 1645 (C=O), 1567, 1484, 1452, 1419, 1372, 1257, 1184, 747 cm-1.
1H

NMR (500 MHz, CDCl3) δ 7.79 (1H, t, J = 1.9 Hz, ArH), 7.68 (1H, dt, J = 7.8, 1.3 Hz, ArH), 7.64-7.58 (3H, m, ArH), 7.48-7.37 (4H, m, ArH), 7.33 (1H, dddd, J
= 8.1, 7.3, 1.6, 0.7 Hz, ArH), 7.21 (1H, td, J = 7.6, 1.3 Hz, ArH), 7.06 (1H, dd, J = 8.3, 1.2 Hz, ArH), 6.77 (1H, d, J = 7.7 Hz, NH), 5.26 (1H, ddd, J = 11.9, 7.7, 4.5 Hz,
NHCH), 3.52 (1H, dd, J = 13.7, 4.5 Hz, NHCHCH2), 3.26 (1H, dd, J = 13.7, 11.5 Hz, NHCHCH2).

page 7 of 12

13C NMR (125.6 MHz, CDCl ) δ 198.0 (C=O), 151.2 (C), 139.0 (C), 137.0 (C), 136.9 (C)¸134.9 (C), 133.7 (CH), 132.2 (CH), 131.6 (CH), 130.7 (CH), 130.6 (CH),
3
129.9 (CH), 129.5 (CH), 128.9 (CH), 126.6 (CH), 126.4 (CH), 125.2 (CH), 122.3 (C), 119.1 (CH), 58.7 (CH), 37.7 (CH2).

HRMS (ESI) Exact mass calculated for C21H16ClNO4SNa [M+Na]+: 436.0381, found: 436.0384.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 254 nm: τminor = 5.79 min, τmajor = 5.99 min (72% ee). [α]D28 = +17.3 (c = 0.7, CHCl3, 72% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(3-bromophenyl)methanone (3h)
The title compound 3h was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (3-bromophenyl)(o-tolyl)methanone 1h (27.5 mg,
100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3h (17 mg, 74%, average of two runs) as a white solid. Rf = 0.34 (9:1
hexane/EtOAc); mp = 60-62 °C (hexane).
IR (ATR): 2921, 1645 (C=O), 1558, 1485, 1449, 1418, 1373, 1256, 1185, 739 cm-1.
1H NMR (500 MHz, CDCl ) δ 7.94 (1H, t. J = 1.8 Hz, ArH), 7.76 (1H, ddd, J = 8.0, 2.0, 1.1 Hz, ArH), 7.72 (1H, ddd, J = 7.8, 1.7, 1.1 Hz, ArH), 7.65-7.59 (2H, m,
3
ArH), 7.45-7.30 (5H, m, ArH), 7.21 (1H, td, J = 7.6, 1.3 Hz, ArH), 7.06 (1H, dd, J = 8.3, 1.2 Hz, ArH), 6.76 (1H, d, J = 7.7 Hz, NH), 5.16 (1H, ddd, J = 11.9, 7.7, 4.5
Hz, NHCH), 3.52 (1H, dd, J = 13.7, 4.5 Hz, NHCHCH2), 3.26 (1H, dd, J = 13.7, 11.5 Hz NHCHCH2).
13C NMR (125.6 MHz, CDCl3) δ 197.9 (C=O), 151.2 (C), 139.2 (C), 137.0 (C), 136.9 (C), 136.6 (CH), 133.6 (CH), 132.2 (CH), 131.6 (CH), 130.6 (CH), 130.1
(CH), 129.5 (CH), 129.4 (CH), 126.7 (CH), 126.4 (CH), 125.2 (CH), 122.8 (C), 122.3 (C), 119.1 (CH), 58.7 (CH), 37.7 (CH2).

HRMS (ESI) Exact mass calculated for C21H16BrNO4SNa [M+Na]+: 479.9876, found: 479.9861.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 254 nm: τmajor = 6.07 min, τminor = 6.30 min (71% ee). [α]D28 = +7.9 (c = 1.0, CHCl3, 71% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(2,3-dimethoxyphenyl)methanone (3i)
The title compound 3i was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (2,3.dimethoxyphenyl)(o-tolyl)methanone 1i (25.6
mg, 100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3i (17 mg, 77%, average of two runs) as a white solid. Rf = 0.19
(9:1 hexane/EtOAc); mp = 45-47 °C (hexane).
IR (ATR): 2924, 1652 (C=O), 1576, 1473, 1423, 1373, 1311, 1263, 1165, 750 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.58-7.46 (3H, m, ArH), 7.38-7.29 (3H, m, ArH), 7.22 (1H, td, J = 7.6, 1.3 Hz, ArH), 7.15 (1H, dd, J = 8.4, 7.2 Hz, ArH), 7.12-7.07
(2H, m, ArH), 7.05 (1H, dd, J = 8.2, 1.2 Hz, ArH), 6.40 (1H, d, J = 7.5 Hz, NH), 5.19 (1H, ddd, J = 11.7, 7.6, 4.3 Hz, NHCH), 3.88 (3H, s, OCH3), 3.73 (1H, dd, J =
13.7, 4.3 Hz, NHCHCH2), 3.48 (3H, s, OCH3), 3.43 (1H, dd, J = 13.7, 11.6 Hz, NHCHCH2).
13C NMR (125.6 MHz, CDCl3) δ 200.4 (C=O), 152.9 (C), 151.2 (C), 147.9 (C), 139.5 (C), 136.3 (C), 134.2 (C), 131.9 (CH), 131.8 (CH), 130.7 (CH), 129.4 (CH),
126.8 (CH), 126.6 (CH), 125.2 (CH), 124.0 (CH), 122.5 (C), 121.4 (CH), 119.0 (CH), 116.0 (CH), 61.0 (CH3), 58.7 (CH), 56.0 (CH3), 38.0 (CH2).

HRMS (ESI) Exact mass calculated for C23H21NO6SNa [M+Na]+: 462.0982, found: 462.0983.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 254 nm: τmajor = 5.70 min, τminor = 5.88 min (39% ee). [α]D28 =+22.1 (c = 0.7, CHCl3, 39% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)ethyl)phenyl)(phenyl)methanone (3j)
The title compound 3j was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (2-ethyl)(phenyl)methanone 1j (21.0 mg, 100 µmol).
The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3j (13 mg, 66%, average of two runs) as an inseparable mixture of diastereomers
(1.3:1 d.r.) and as a white solid. Rf = 0.30 (9:1 hexane/EtOAc).
IR (ATR): 2922, 1652, (C=O), 1448, 1378, 1314, 1268, 1189, 1102, 927, 758 cm-1.
Major diastereoisomer: 1H NMR (500 MHz, CDCl3) δ 7.88-7.76 (2H, m, ArH), 7.68-7.56 (1H, m, ArH), 7.54-7.43 (3H, m, ArH), 7.41-7.29 (3H, m, ArH), 7.257.15 (3H, m, ArH), 7.01 (1H, dd, J = 8.2, 1.2 Hz, ArH), 5.54 (1H, d, J = 6.5 Hz, NH), 5.11 (1H, dd, J = 6.4, 4.3 Hz, NHCH), 4.15-4.06 (1H, m, NHCHCH), 1.28 (3H,
d, J = 2.9 Hz, CH3).
13C NMR (125.6 MHz, CDCl3) δ 199.0 (C=O), 151.6 (C), 140.7 (C), 137.9 (C)¸137.7 (C), 130.9 (CH), 130.5 (2 x CH), 129.7 (CH), 129.43 (CH), 129.2 (CH), 128.7
(CH), 128.6 (2 x CH), 127.0 (CH), 126.5 (CH), 125.5 (CH), 121.9 (C), 119.1 (CH) , 62.1 (CH), 38.8 (CH), 14.4 (CH3).

Minor diastereoisomer: 1H NMR (500 MHz, CDCl3) δ 7.78-7.70 (2H, m, ArH), 7.65-7.58 (2H, m, ArH), 7.53-7.43 (3H, m, ArH), 7.40-7.29 (3H, m, ArH), 7.21
(1H, tdd, J = 7.5, 1.6, 0.7 Hz, ArH), 7.07-6.99 (2H, m, ArH), 6.13 (1H, d, J = 7.8 Hz, NH), 4.91 (1H, t, J = 7.8 Hz, NHCH), 3.93 (1H, app p, J = 7.1 Hz, NHCHCH),
1.58 (3H, d, J = 7.0 Hz, CH3),
13C NMR (125.6

MHz, CDCl3) δ 199.2 (C=O), 151.7 (C), 141.6 (C), 138.1 (C), 137.0 (C), 133.7 (CH), 131.5 (CH), 130.8 (2 x CH), 129.8 (CH), 129.42 (CH), 128.4
(2 x CH), 128.2 (CH), 127.5 (CH), 126.3 (CH), 124.9 (CH), 122.6 (C), 119.2 (CH), 62.2 (CH), 39.0 (CH), 20.5 (CH3).

HRMS (ESI) Exact mass calculated for C22H19NO4SNa [M+Na]+: 416.0927, found: 416.0926.
The enantiomeric excess of the major diastereoisomer was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/MeOH to 60:40 CO2/MeOH
for 9 minutes with curve of “6”, λ= 249 nm: τmajor = 5.62 min, τminor = 6.20 min (68% ee). The enantiomeric excess of the minor diastereoisomer was
determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/MeOH to 60:40 CO2/MeOH for 9 minutes with curve of “6”, λ= 250 nm: τminor = 5.64 min,
τmajor = 6.08 min (60% ee). [α]D28 = +15.4 (c = 0.8, CHCl3, 1.3:1 dr, 68% ee).

(R)-(2-((2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)-4-(trifluoromethyl)phenyl)(phenyl)methanone (3k)

page 8 of 12

The title compound 3k was prepared according to the general procedure using 2a (9.2 mg, 50 µmol) and (2-methyl-4(trifluoromethyl)phenyl)(phenyl)methanone 1k (26.4 mg, 100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 3k (18.8
mg, 84%, average of two runs) as a white solid. Rf = 0.31 (9:1 hexane/EtOAc); mp = 167-169 °C (hexane).
IR (ATR): 3252, 2929, 1658 )C=O), 1484, 1424, 1374, 1164, 1121, 1075, 1075, 756 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.84- 7.77 (3H, m, ArH), 7.70-7.63 (2H, m, ArH), 7.57-7.48 (3H, m, ArH), 7.36-7.30 (2H, m, ArH), 7.23-7.18 (1H, m ArH), 7.087.02 (1H, m, ArH), 6.69 (1H, d, J = 7.7 Hz NH), 5.15 (1H, ddd, J = 11.8, 7.7, 4.8 Hz, CHNH), 3.53 (1H, dd, J = 13.8, 4.4 Hz, CH2CHNH), 3.30 (1H, dd, J = 13.8, 11.4
Hz, CH2CHNH).
13C NMR (125.6 MHz, CDCl ) δ 198.3 (C=O), 151.1 (C), 140.9 (C), 137.4 (C), 136.5 (C), 134.5 (CH), 133.2 (q, J =33.1 Hz, C), 130.8 (2 x CH), 130.5 (CH), 129.7
3
(CH), 128.8 (2 x CH), 128.2 (q, J = 3.8 Hz, CH), 126.4 (CH), 125.3 (CH), 123.5 (q, J = 3.8 Hz, CH), 123.4 (q, J = 272.8 Hz, CF3), 121.9 (C), 119.2 (CH), 58.5 (CH),
37.7 (CH2).
19F

NMR (376 MHz, CDCl3) δ -63.0 (s, CF3).

HRMS (ESI) Exact mass calculated for C22H16F3NNaO4S [M+Na]+: 470.0644, found: 470.0649.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/i-PrOH to 60:40 CO2/i-PrOH for 9 minutes with curve of
“6”, λ= 251 nm: τminor = 4.59 min, τmajor = 4.78 min (37% ee). [α]D28 =+1.4 (c = 0.93, CHCl3, 37% ee).

(R)-(2-((6-methyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7a)
The title compound 7a was prepared according to the general procedure using 2b (9.9 mg, 50 µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The
crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7a (15.6 mg, 79%, average of two runs) as a white solid. Rf = 0.30 (9:1 hexane/EtOAc);
mp = 50-52 °C (hexane).
IR (ATR): 2921, 1651 (C=O), 1488, 1404, 1372, 1266, 1173, 1114, 847, 762 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.82- 7.77 (2H, m, ArH), 7.63 (1H, ddt, J = 8.7, 7.4, 1.3 Hz, ArH), 7.61-7.55 (1H, m, ArH), 7.50-7.46 (2H, m, ArH), 7.44-7.41 (1H,
m ArH), 7.40-7.35 (1H, m, ArH), 7.15-7.13 (1H, m, ArH), 7.12-7.07 (1H, m, Hz, ArH), 6.99 (1H, d, J = 7.6 NH), 6.93 (1H, d, J = 8.4 Hz, ArH), 6.97 (1H, d, J = 8.6
Hz, ArH), 5.09 (1H, ddd, J = 12.0, 7.6, 4.6 Hz, CHNH), 3.51 (1H, dd, J = 13.7, 4.6 Hz, CH2CHNH), 3.22 (1H, dd, J = 13.7, 11.5 Hz, CH2CHNH), 2.32 (3H, s, CH3).
13C NMR (125.6 MHz, CDCl3) δ 199.4 (C=O), 149.1 (C), 137.6 (C), 137.3 (C), 136.7 (C), 134.8 (C), 133.8 (CH), 131.7 (CH), 131.2 (CH), 130.9 (2 x CH), 130.6
(CH), 130.0 (CH), 128.5 (2 x CH), 126.6 (CH), 126.4 (CH), 122.0 (C), 118.8 (CH), 58.7 (CH), 37.7 (CH2), 20.9 (CH3).

HRMS (ESI) Exact mass calculated for C22H19NNaO4S [M+Na]+: 416.0927, found: 416.0932.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/MeOH to 60:40 CO2/MeOH for 9 minutes with curve of “6”,
λ= 251 nm: τminor = 5.46 min, τmajor = 5.69 min (64% ee). [α]D28 =+7.2 (c = 0.98, CHCl3, 64% ee).

(R)-(2-((7-methyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7b)
The title compound 7b was prepared according to the general procedure using 2c (9.9 mg, 50 µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The
crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7b (15.6 mg, 79%, average of two runs) as a white solid. Rf = 0.32 (9:1 hexane/EtOAc);
mp = 54-56 °C (hexane).
IR (ATR): 3115, 1637 (C=O), 1596, 1431, 1367, 1317, 1268, 1180, 1111, 782 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.82- 7.77 (2H, m, ArH), 7.62 (1H, ddt, J = 8.7, 7.4, 1.3 Hz, ArH), 7.60-7.54 (2H, m, ArH), 7.49-7.45 (2H, m, ArH), 7.43-7.40 (1H,
m ArH), 7.39-7.35 (1H, m, ArH), 7.23 (1H, d, J = 8.0, ArH), 7.03 (1H, d, J = 7.5 Hz, NH), 7.01- 6.97 (1H, m, ArH), 6.87-6.83 (1H, m, ArH), 5.09 (1H, ddd, J = 11.8,
7.5, 4.5 Hz, CHNH), 3.49 (1H, dd, J = 13.7, 4.5 Hz, CH2CHNH), 3.20 (1H, dd, J = 13.7, 11.5 Hz, CH2CHNH), 2.34 (3H, s, CH3).
13C NMR (125.6 MHz, CDCl3) δ 199.4 (C=O), 151.0 (C), 139.9 (C), 137.6 (C), 137.3 (C), 136.7 (C), 133.8 (CH), 131.7 (CH), 131.2 (CH), 130.9 (2 x CH), 130.6
(CH), 128.5 (2 x CH), 126.4 (CH), 126.1 (CH), 126.0 (CH), 119.4 (C), 119.3 (CH), 58.5 (CH), 37.7 (CH2), 20.9 (CH3).

HRMS (ESI) Exact mass calculated for C22H19NNaO4S [M+Na]+: 416.0927, found: 416.0928;
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/MeOH to 60:40 CO2/MeOH for 9 minutes with curve of “6”,
λ= 251 nm: τminor = 5.70 min, τmajor = 5.97 min (64% ee). [α]D28 =+6.2 (c = 0.76, CHCl3, 64% ee).

(R)-(2-((8-methyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7c)
The title compound 7c was prepared according to the general procedure using 2d (9.9 mg, 50 µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The
crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7c (12.4 mg, 63%, average of two runs) as a white solid. Rf = 0.31 (9:1 hexane/EtOAc);
mp = 104-106 °C (hexane).
IR (ATR): 2921, 1636 (C=O), 1594, 1457, 1370, 1263, 1189, 1151. 1069, 758 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.83- 7.77 (2H, m, ArH), 7.62 (1H, ddt, J = 8.7, 7.1, 1.3 Hz, ArH), 7.60-7.55 (2H, m, ArH), 7.49-7.45 (2H, m, ArH), 7.44-7.41 (1H,
m ArH), 7.39-7.35 (1H, m, ArH), 7.20 (1H, d, J = 7.6 Hz, NH), 7.18-7.14 (1H, m, ArH), 7.10- 7.03 (2H, m, ArH), 5.12 (1H, ddd, J = 11.8, 7.6, 4.6 Hz, CHNH), 3.49
(1H, dd, J = 13.7, 4.6 Hz, CH2CHNH), 3.22 (1H, dd, J = 13.7, 11.5 Hz, CH2CHNH), 2.30 (3H, s, CH3).
13C NMR (125.6 MHz, CDCl ) δ 199.4 (C=O), 149.7 (C), 137.6 (C), 137.3 (C), 136.8 (C), 133.8 (CH), 131.7 (CH), 131.2 (CH), 130.9 (2 x CH), 130.8 (CH), 130.6
3
(CH), 128.5 (2 x CH), 128.4 (C), 126.4 (CH), 124.4 (CH), 123.8 (CH), 122.2 (C), 58.8 (CH), 37.9 (CH2), 15.6 (CH3).

HRMS (ESI) Exact mass calculated for C22H19NNaO4S [M+Na]+: 416.0927, found: 416.0911.
The enantiomeric excess was determined by HPLC analysis on a Daicel IC3 column, 85:15 hexane/i-PrOH, flow rate = 0.8 mL, λ= 254 nm: τmajor = 17.95 min,
τminor = 21.51 min (67% ee). [α]D28 = -0.38 (c = 0.80, CHCl3, 67% ee).

page 9 of 12

(R)-(2-((6-tert-butyl-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7d)
The title compound 7d was prepared according to the general procedure using 2e (12.0 mg, 50 µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The
crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7d (13.1 mg, 60%, average of two runs) as a white solid. Rf = 0.38 (9:1 hexane/EtOAc);
mp = 47-49 °C (hexane).
IR (ATR): 2959, 1646 (C=O), 1489, 1367, 1267, 1186, 1120, 929, 813, 767 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.83- 7.79 (2H, m, ArH), 7.65-7.60 (1H, m, ArH), 7.59-7.57 (2H, m, ArH), 7.50-7.45 (2H, m, ArH), 7.43 (1H, dt, J = 7.7, 1.1 Hz,
ArH), 7.40-7.36 (1H, m, ArH), 7.32 (1H, ddd, J = 8.6, 2.4, 0.7, Hz, ArH), 7.30 (1H, m, ArH), 7.06 (1H, d, J = 7.6, Hz, NH), 6.97 (1H, d, J = 8.6 Hz, ArH), 5.10 (1H,
ddd, J = 12.0, 7.6, 4.6 Hz, CHNH), 3.52 (1H, dd, J = 13.7, 4.7 Hz, CH2CHNH), 3.23 (1H, dd, J = 13.7, 11.4 Hz, CH2CHNH), 1.30 (9H, s, C(CH3)3).
13C NMR (125.6 MHz, CDCl3) δ 199.4 (C=O), 148.9 (C), 148.1 (C), 137.7 (C), 137.4 (C), 136.7 (C), 134.8 (CH), 131.7 (CH), 131.1 (CH), 130.9 (2 x CH), 130.5
(CH), 128.5 (2 x CH), 126.6 (CH), 126.4 (CH), 122.8 (CH), 121.5 (C), 118.5 (CH), 58.9 (CH), 37.8 (CH2), 34.5 (C), 31.3 (3 x CH3).

HRMS (ESI) Exact mass calculated for C25H24NO4S [M+H]+: 434.1432, found: 434.1421.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 260 nm: τminor = 4.92 min, τmajor = 5.20 min (62% ee). [α]D28 = +12.3 (c = 0.62, CHCl3, 62% ee).
(R)-(2-((7-methoxy-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7e)
The title compound 7e was prepared according to the general procedure (but with a reaction time of 72 hours rather than 48 hours) using 2f (10.7 mg, 50
µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7e (7.8 mg, 38%,
average of two runs) as a white solid. Rf = 0.24 (9:1 hexane/EtOAc); mp = 59-61 °C (hexane).
IR (ATR): 2922, 1636 (C=O), 1575, 1505, 1372, 1268, 1184, 1152, 1092, 746 cm-1.
1H NMR (500 MHz, CDCl ) δ 7.84- 7.79 (2H, m, ArH), 7.69-7.56 (3H, m, ArH), 7.53-7.47 (2H, m, ArH), 7.47-7.43 (1H, m, ArH), 7.42-7.37 (1H, m ArH), 7.293
7.26 (1H, m, ArH), 7.08 (1H, d, J = 7.6 Hz NH), 6.77 (1H, dd, J = 8.7, 2.6 Hz), 5.59 (1H, d, J = 2.6 Hz), 5.09 (1H, ddd, J = 11.8, 7.6, 4.5 Hz, CHNH), 3.82 (3H, s CH3),
3.49 (1H, dd, J = 13.6, 4.5 Hz, CH2CHNH), 3.22 (1H, dd, J = 13.6, 11.4 Hz, CH2CHNH).
13C NMR (125.6 MHz, CDCl3) δ 199.4 (C=O), 148.9 (C), 148.1(C), 137.7 (C), 137.3 (C), 136.7 (C), 133.8 (CH), 131.7 (CH), 131.1 (CH), 130.9 (2 x CH), 130.5
(C), 128.5 (2 x CH), 126.6 (CH), 126.4 (CH), 122.8 (CH), 121.5 (C), 118.5 (CH), 58.9 (CH), 37.7 (CH2), 31.3 (CH3).

HRMS (ESI) Exact mass calculated for C22H19NNaO5S [M+Na]+: 432.0876 , found: 432.0881
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 250 nm: τminor = 5.77 min, τmajor = 6.03 min (69% ee). [α]D28 = +5.7 (c = 0.50, CHCl3, 69% ee).

(R)-(2-((6-fluoro-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7f)
The title compound 7f was prepared according to the general procedure (but with a reaction time of 72 hours rather than 48 hours) using 2g (10.1 mg, 50
µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7f (8.5 mg, 43%, average
of two runs) as a white solid. Rf = 0.31 (9:1 hexane/EtOAc); mp = 55-57 °C (hexane).
IR (ATR): 3063, 1935 (C=O), 1487, 1418, 1373, 1257, 1190, 1157, 929, 763 cm-1.
1H

NMR (500 MHz, CDCl3) δ 7.87-7.74 (2H, m, ArH), 7.66-7-55 (3H, m, ArH), 7.52-7.46 (2H, m, ArH), 7.46-7.42 (1H, m, ArH), 7.42-7.37 (1H, m ArH), 7.18
(1H, d, J = 7.6 Hz, NH), 7.12 - 7.07 (1H, m, ArH), 7.06-6.99 (1H, m ArH), 7.01- 6.97 (1H, m, ArH), 5.12 (1H, ddd, J = 11.9, 7.6, 4.6 Hz, CHNH), 3.45 (1H, dd, J =
13.6, 4.6 Hz, CH2CHNH), 3.24 (1H, dd, J = 13.6, 11.5 Hz, CH2CHNH).
13C

NMR (125.6 MHz, CDCl3) δ 196.7 (C=O), 156.4 (d, J = 245.0 Hz, C), 144.3 (d, J = 2.5 Hz, C), 134.7 (C), 134.4 (C), 133.5 (C), 131.1 (CH), 129.1 (CH), 128.3
(CH), 128.1 (2 x CH), 128.0 (CH), 126.7 (2 x CH), 123.8 (CH), 121.1 (d, J = 6.9 Hz, C), 117.7 (d, J = 8.3 Hz, CH), 113.6 (d, J = 23.6 Hz, CH), 110,2 (d, J = 24.9 Hz,
CH), 55.7 (d, J = 1.7 Hz, CH), 34.7 (CH2).
19F

NMR (376 MHz, CDCl3) δ -116.3 (dt, J = 8.9, 6.3 Hz, F).

HRMS (ESI) Exact mass calculated for C21H16FNNaO4S [M+Na]+: 420.0676, found: 420.0682.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 251 nm: τminor = 4.95 min, τmajor = 5.21 min (54% ee). [α]D28 = +0.65 (c = 0.59, CHCl3, 54% ee).

(R)-(2-((6-chloro-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7g)
The title compound 7g was prepared according to the general procedure using 2h (10.9 mg, 50 µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The
crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7g (14.5 mg, 70%, average of two runs) as a white solid. Rf = 0.32 (9:1 hexane/EtOAc);
mp = 63-65 °C (hexane).
IR (ATR): 2922, 1645 (C=O), 1539, 1473, 1373, 1259, 1187, 1165, 1113, 769 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.82- 7.77 (2H, m, ArH), 7.66-7.59 (2H, m, ArH), 7.58-7.55 (1H, m, ArH), 7.51-7.46 (2H, m, ArH), 7.45-7.43 (1H, m ArH), 7.427.35 (1H, m, ArH), 7.31-7.27 (2H, ArH), 7.00 (2H, d, J = 8.8 Hz), 5.11 (1H, ddd, J = 12.0, 7.7, 4.7 Hz, CHNH), 3.48 (1H, dd, J = 13.6, 4.7 Hz, CH2CHNH), 3.22 (1H,
dd, J = 13.6, 11.6 Hz, CH2CHNH).
13C NMR (125.6 MHz, CDCl ) δ 199.6 (C=O), 149.8 (C), 137.5(C), 137.2 (C), 136.2 (C), 134.0 (CH), 131.9 (CH), 131.1 (CH), 131.0 (2 x CH), 130.8 (CH), 130.3
3
(C), 129.5 (CH), 128.5 (2 x CH), 126.6 (CH), 126.3 (CH), 124.0 (C), 120.5 (CH), 58.4 (CH), 37.5 (CH2).

HRMS (ESI) Exact mass calculated for C21H16ClNNaO4S [M+Na]+: 436.0381, found: 436.0394.
The enantiomeric excess was determined by UPC2 analysis on a Waters Amy1 column, 100:0 CO2/EtOH to 60:40 CO2/EtOH for 9 minutes with curve of “6”,
λ= 251 nm: τminor = 5.28 min, τmajor = 5.63 min (47% ee). [α]D28 = +5.8 (c = 0.89, CHCl3, 47% ee).

page 10 of 12

(R)-(2-((7-bromo-2,2-dioxido-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)methyl)phenyl)(phenyl)methanone (7h)
The title compound 7h was prepared according to the general procedure using 2i (13.0 mg, 50 µmol) and 2-methylbenzophenone 1a (18 µL, 100 µmol). The
crude product was purified by FC (95:5 hexane/EtOAc) to afford amine 7h (17.2 mg, 75%, average of two runs) as a white solid. Rf = 0.33 (9:1 hexane/EtOAc);
mp = 119-121 °C (hexane).
IR (ATR): 3063, 1635 (C=O), 1595, 1477, 1363, 1268, 1184, 1122, 907, 763 cm-1.
1H NMR (500 MHz, CDCl3) δ 7.82- 7.77 (2H, m, ArH), 7.63 (1H, ddt, J = 8.7, 7.1, 1.3 Hz, ArH), 7.61-7.57 (1H, m, ArH), 7.57-7.53 (1H, m, ArH), 7.50-7.45 (2H,
m ArH), 7.43 (1H, dd, J = 7.7, 1.5 Hz, ArH), 7.40-7.36 (1H, m, ArH), 7.32 (1H, dd, J = 8.4, 2.0, Hz, ArH), 7.25-7.22 (1H, m, ArH), 7.21 (1H, d, J = 2.0, Hz, NH),
6.97 (1H, d, J = 8.6 Hz, ArH), 5.08 (1H, ddd, J = 12.0, 7.6, 4.6 Hz, CHNH), 3.47 (1H, dd, J = 13.7, 4.6 Hz, CH2CHNH), 3.21 (1H, dd, J = 13.7, 11.5 Hz, CH2CHNH).
13C NMR (125.6 MHz, CDCl3) δ 199.5 (C=O), 151.5 (C), 137.5 (C), 137.2 (C), 136.3 (C), 133.9 (CH), 131.9 (CH), 131.2 (CH), 130.9 (2 x CH), 130.8 (CH), 128.5
(2 x CH), 128.3 (CH), 127.6 (CH), 126.6 (CH), 122.2 (CH), 122.2 (C), 121.5 (C), 58.4 (CH), 37.6 (CH2).

HRMS (ESI) Exact mass calculated for C21H16BrNNaO4S [M+Na]+: 479.9876, found: 479.9875.
The enantiomeric excess was determined by UPC2 analysis on a Waters Cel1 column, 100:0 CO2/MeOH to 60:40 CO2/MeOH for 9 minutes with curve of “6”,
λ= 250 nm: τminor = 4.68 min, τmajor = 4.79 min (53% ee). [α]D28 = +1.8 (c = 0.81, CHCl3, 53% ee).

Acknowledgment
Financial support was provided by the ICIQ Foundation, MINECO (project CTQ2013-45938-P and Severo Ochoa Excellence Accreditation 2014-2018, SEV2013-0319), the AGAUR (2014 SGR 1059), and the European Research Council (ERC 278541 - ORGA-NAUT). H.H. thanks the Marie Curie COFUND action
(2015-1-ICIQ-IPMP) for a postdoctoral fellowship. G.M. thanks ICIQ-LMU (SEV-2013-0319) for a predoctoral fellowship. The authors thank Dr. Luca
Dell’Amico for preliminary investigations and insightful discussions, and Sara Cuadros and Dr. Javier Perez for assistance with the transient absorption
spectroscopic experiments.

Supporting Information
YES (this text will be updated with links prior to publication)

Primary Data
NO (this text will be deleted prior to publication)

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6766; b) Luo. Y.; Hepburn, H. B.; Chotsaeng, N.; Lam, H. W. Angew. Chem. Int. Ed. 2012, 51, 8309–8313. For an early example of using the corresponding
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(13) For an example of imine 2a participating in an enantioselective catalytic hetero-Diels-Alder reaction, see: Liu, Y.; Kang, T.-R.; Liu, Q.-Z.; Chen, L.-M.;
Wang, Y.-C.; Liu, J.; Xie, Y.-M.; Yang, J.-L.; He, L. Org. Lett. 2013, 15, 6090–6093.
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(15) In addition to the rate acceleration provided by catalyst 6a, the observed level of stereoselectivity can be rationalized on the basis of solubility issues.
Indeed, under the reaction conditions (initial concentration of cyclic imine 2a is 0.025M in cyclohexane) the substrate 2a is only partially soluble.
This condition secures a low amount of electrophile in the organic solvent interacting with the (fully soluble) chiral catalyst 6a.
(16) In analogy with our precedent study on the stereoselective trapping of the photoenol A with maleimides promoted by the cinchona-derived catalyst
5c (Ref. 7), we evaluated the possibility for the chiral amine 6a to attenuate the rate of the racemic background process by reducing the concentration
of A in solution. Flash photolysis quenching studies of the transient photoenol A at the millisecond resolution, detailed in the Supplementary
Information, established that the amine 6a does not influence the formation of A.
(17) Crystallographic data for compound 3e has been deposited with the Cambridge Crystallographic Data Centre, accession numbers CCDC 1497811.
Other entries were assigned by analogy.

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(18) Masuda, Y.; Ishida, N.; Murakami, M. J. Am. Chem. Soc. 2015, 137, 14063–14066.
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Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc. 2010, 132, 3298–3300; b) Yousefi, R.; Whitehead, D. C.; Mueller, J. M.; Staples, R. J.; Borhan, B.
Org. Lett. 2011, 13, 608–611; c) Nicolaou, K. C.; Simmons, N. L.; Ying, Y.; Heretsch, P. M.; Chen, J. S. J. Am. Chem. Soc. 2011, 133, 8134–8137; d) Wilking,
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4183; g) Zhang, T.; Qiao, Z.; Wang, Y.; Zhong, N.; Liu, L.; Wang, D.; Chen, Y.-J. Chem. Commun. 2013, 49, 1636–1638; h) Di Iorio, N.; Champavert, F.;
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