A ceric ammonium nitrate based oxidative cleavage pathway for the asymmetric aldol adducts of oxadiazinones derived from (1R,2S)-N-p-methoxybenzylnorephedrine

Tetrahedron: Asymmetry 28 (2017) 1154–1162

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A ceric ammonium nitrate based oxidative cleavage pathway for the asymmetric aldol adducts of oxadiazinones derived from (1R,2S)-N-p-methoxybenzylnorephedrine Austin R. Leise, Nicole Comas, Doug Harrison, Dipak Patel, Eileen G. Whitemiller, Jennifer Wilson, Jacob Timms, Ian Golightly, Christopher G. Hamaker, Shawn R. Hitchcock ⇑ Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA

a r t i c l e

i n f o

Article history: Received 14 July 2017 Revised 27 July 2017 Accepted 2 August 2017

a b s t r a c t An N4-p-methoxybenzyloxadiazinone has been prepared from (1R,2S)-norephedrine through a process of reductive amination, N-nitrosation, reduction, and cyclization. The oxadiazinone was acylated and employed in the asymmetric aldol addition reaction with aromatic and aliphatic aldehydes to yield aldol adducts in isolated yields ranging from 54% to 90%. Selected aldol adducts were treated with ceric ammonium nitrate in aqueous acetonitrile to afford the desired b-hydroxycarboxylic acids through a tandem process of oxidative cleavage of the N4-p-methoxybenzyl group and acidic hydrolysis of the N3-acyl side chain. The b-hydroxycarboxylic acids were recovered in high diastereomeric purity as determined by 500 MHz 1H NMR spectroscopy and the absolute configuration was confirmed by polarimetry. The chiral auxiliary unit, the 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone), was converted into its corresponding 3,6-dihydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone) through an oxidative pathway promoted by the ceric ammonium nitrate. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction The asymmetric aldol addition reaction, mediated by chiral auxiliaries such as the Evans’ auxiliary 1, remains as a highly valuable synthetic tool for the preparation of b-hydroxycarbonyl compounds.1 Recently, Tokuyama et al. employed the Evans’ oxazolidinone aldol methodology in the synthesis of the natural products ( )-SCH 64874 and of Hirstullomycin.2a In addition, Revu and Prasad reported on the total synthesis of the bis-silyl ether of (+)-epi-Aetheramide A via the Evans’ oxazolidinone chemistry.2b The success of the oxazolidinones in numerous asymmetric synthetic applications3 inspired our efforts in the development of 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones (oxadiazinones) 2 as chiral auxiliaries (Scheme 1). Oxadiazinones are 6-member ring aza-analogues of the Evans’ auxiliary, and have been successfully employed in asymmetric aldol addition reactions.4 The observed diastereoselectivities of the oxadiazinone mediated asymmetric aldol reactions range from fair to excellent, depending on the N4-substituent and the aldehyde substrate. The asymmetric induction is proposed to originate from

⇑ Corresponding author. Tel.: +1 309 438 7854; fax: +1 309 438 5538. E-mail address: [email protected] (S.R. Hitchcock). http://dx.doi.org/10.1016/j.tetasy.2017.08.003 0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

the presence of the stereogenic N4-nitrogen substituent. The importance of the N4-position is based on the observed diastereoselectivities for the asymmetric aldol reaction which ranged from 3:1 to 99:1 when the N4-substituent was a methyl group, and ranged from 10:1 to 99:1 when the N4-substituent of the oxadiazinone 7a–c was a more sterically demanding group (Scheme 2). Unfortunately, the difficulty of the hydrolytic cleavage of the aldol fragment from the N3-position of the oxadiazinones 8a–c increased as the size of the N4-position increased. Hydrolysis under acidic or basic conditions afforded compromised yields of the desired b-hydroxycarboxylic acid in addition to endocyclic ring opening of the oxadiazinone, retro-aldol products (recovered aldehyde, etc.), and degradation products. Attempts to use the Evans methodology for the cleavage of the aldol fragment with lithium hydroperoxide (via LiOH/H2O2) failed to generate the desired cleavage products in useful chemical yields. In the context of the failed hydrolyses, it became apparent that the hydrolysis had to overcome if the oxadiazinones were to have any utility as useful chiral auxiliaries. It had been proposed that the steric volume of the N4-substituent led to enhanced stereoselection, but also increased the difficulty of the hydrolysis. The solution to this dilemma emerged in the form of concept of employing a labile protecting group. Ideally, the protecting group would have the

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O O

O N

1

H

O

H

N

1b. NaH, CH 2 Cl2

CH 3

4

CH3

O

O

1a. CH3 CH2 COCl

N

Ph

CH 3

Ph

O 3

1a. TiCl4 1b. TEA, -78 to 0 oC

N N

Ph

CH 3

2

1c. R'CHO, -78 oC

CH 3 3

Evans, 1 O O

O

OH

N

Ph

4

O

R'

N

6M H2 SO4

2 +

CH 3

HO

R' CH 3

CH3

CH 3

OH

5

4 Scheme 1. Oxadiazinone chemistry.

O OH Ph

O N

O NH2

N

Ph

4

CH3

H

N

Ph

4

CH3

norephedrine, 6

OH R'

N

O

R

O

CH 3

OH

HO

hydrolysis

R

R' CH3

CH 3

7a: R = -CH(CH3 )2 7b: R = -CH2 Ph 7c: R = -cyclo-C 6 H13

O

acidic/basic

5 compromised yield

8a-c dr: 10:1 to 99:1

Scheme 2. Norephedrine based oxadiazinones.

The N-nitrosamine was reduced with lithium aluminum hydride to generate the beta-hydroxyhydrazine 10 in 90% yield after chromatography. Cyclization with triphosgene afforded the N4-p-methoxybenzyloxadiazinone 11 in 90% yield after chromatography and recrystallization. The oxadiazinone was then acylated at the N3-position with propanoic acid (EDC, DMAP) to yield 12 in 48% yield after flash chromatography and recrystallization. With the requisite material in hand, oxadiazinone 12 was dissolved in THF and treated with titanium tetrachloride in THF and cooled to 10 C. The reaction mixture was then reacted with Hünig’s base, and a variety of aromatic and aliphatic aldehydes to yield the aldol adducts that were purified by flash chromatography (Table 1). The crude diastereoselectivities ranged from good to excellent as determined by 500 MHz 1H NMR spectroscopy, and the absolute stereochemistry was confirmed by X-ray crystallography (Fig. 1). The mechanism of addition is proposed to follow the pathway as experimentally and computationally evaluated for a titanium mediated non-Evans type aldol addition reaction.1c At this stage, the

necessary steric bulk to allow for high diastereoselectivity, but could also be cleaved under conditions that would also allow for the facile cleavage of the N3-aldol fragment. Thus, the p-methoxybenzyl group5 was selected as a suitable substituent for the N4-position that could be removed by the addition of ceric ammonium nitrate in an acidic environment that would facilitate the hydrolysis of the aldol side chain. Herein, we report on our efforts to synthesize and apply an N4-p-methoxybenzyl oxadiazinone in the asymmetric aldol addition reaction, and cause a tandem deprotection/hydrolysis reaction. 2. Results and discussion The requisite N4-p-methoxybenzyl-N3-propanoyloxadiazinone was prepared by reductive amination of (1R,2S)-norephedrine 6 with p-anisaldehyde and sodium borohydride, followed by N-nitrosation by treatment with sodium nitrite and aqueous hydrochloric acid. The resultant N-nitrosamine 9 was purified by flash chromatography to yield the product in 95% yield (Scheme 3).

OH

1. p-MeOC 6H 4CHO; NaBH 4

6

NO N

Ph

2. NaNO2 , HCl, THF

OH

LiAlH4 , THF

PMB

N

Ph

90%

CH 3

95%

9

10

CH 2 Cl2 90%

O Ph

PMB

CH 3 10

O (Cl3CO) 2C=O, Et3 N

NH 2

O N N

CH 3 11

H PMB

EDC, DMAP CH2 Cl2 48%

O Ph

N

O

N OMe CH 3 12

Scheme 3. Synthesis of the N4-p-methoxybenzyl-N3-propanoyl.

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A. R. Leise et al. / Tetrahedron: Asymmetry 28 (2017) 1154–1162 Table 1 The asymmetric aldol addition reaction with oxadiazinone 12

O 1

O 3 N

O

N

Ph

4

O PMB

O

1a. TiCl4 , THF; i-Pr 2NEt 1b. RCHO

Ph

CH3

O N N

a

R CH3 PMB

CH3

12

b

OH

13a-i

Entry

Aldehyde, RCHO

Number

Crude d.r.a

1 2 3 4 5 6 7 8 9 10

C6H5CHO p-ClC6H4CHO p-BrC6H4CHO o-BrC6H4CHO m-NO2C6H4CHO 2-C10H7CHO C6H5CH@CHCHO CH3(CH2)2CHO (CH3)2CHCH2CHO CH3(CH2)6CHO

13a 13b 13c 13d 13e 13f 13g 13h 13i 13j

95:5 95:5 95:5 95:5 95:5 95:5 85:15 94:6 91:9 95:5

Yieldb 76 69 77 89 87 54 65 84 90 90

Diastereoselectivity determined by 500 MHz 1H NMR spectroscopy. Yields determined after purification by chromatography.

hydrolytic cleavage of the N3-aldol adduct side chain was pursued. A central problem in the hydrolysis of oxadiazinone products was the difficulty of the hydrolysis when increasing the size of the N4-substituent, the stereocontrol element. To circumvent this intrinsic limitation, the oxidative removal of the N4-substituent via ceric ammonium nitrate was initiated. If successful, this proposed pathway would cause the removal of the N4-p-methoxybenzyl group from the N4-position, thereby removing any steric encumberment and facilitating the acidic hydrolysis. Thus, aldol adducts 13c and 13i were subjected to the oxidative conditions to test the hypothesis of the improved hydrolysis (Scheme 4).

We found that the process yielded the target b-hydroxycarboxylic acid 15a and 15b in 85% and 90% recovered yield, respectively (Scheme 4). The diastereomeric purity of the starting purified oxadiazinone aldol adducts 13c and 13i was greater than 95:5 as determined by the 500 MHz 1H NMR spectroscopy. The diastereomeric purities of the recovered cleaved aldol products 15a and 15b were also determined to be greater than 95:5 based on the absence of diastereomeric peaks in their respective 500 MHz 1H NMR spectra. The absolute configuration of 15a, and 15b by analogy, was determined by comparison of the specific rotation of the present 15a {[a]23 21.8 (c 0.75, CH2Cl2), D =

Figure 1. X-ray crystal structure of oxadiazinone 13g with the thermal ellipsoids set at 50% probability.

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O

O

O

OH

N

R

N

Ph

O O

Ce(NH 4) 2 (NO3 )6

CH 3

CH 3CN, H 2O

CH 3

CHO N N

Ph

O

H +

OH

HO

+

R

H

CH 3

CH3

OCH 3

13c: R = -p-ClC 6H 4 13i: R = -CH2 CH(CH 3) 2

OCH 3 15a: R = -p-ClC 6H 4 (85%) 15b: R = -CH2 CH(CH 3) 2 (90%)

14 not observed

O O

O H

N N

Ph

16

O

Ce(NH4 )2 (NO3 )6 CH 3CN, H2 O

PMB

H + 16

N

Ph

41%

CH 3

N

CH 3 17

11

Scheme 4. Oxidative cleavage/hydrolysis of oxadiazinones 13c and 13i.

O

R

O Ce+4

O Ph

N

R

O

O

N OCH 3

O

Ce+3 N

O

N

Ph

-H

O

H2 O, -H

O

O OCH3

H

R

N

Ph

18

Ce +4

N

O

O

O -H

H

N

CH3 21

H

O

proton transfer

Ph

Ce+4

N

Ph

Ce+3

O H

CH 3

O O

R

N

CH 3

R

N

O

Ce +3

19 not observed

O

OCH 3

CH 3 H 17

O

O

N

CH3 H

13c [R = -CH(CH3 )CH(OH)C6 H4 Cl]

R N

Ph

OCH3

CH 3

Ph

Ce +3

Ce +4

20 loss of stereochemistry

R

O

N

O

N

H

O

H2 O Ph

CH 3

N

O

H

N

+

OH

HO CH 3

CH 3 16 (isolated)

22

Cl

15 (isolated)

Scheme 5. Proposed mechanism for the tandem deprotection/oxidation/hydrolysis process.

[a]23 16.7 (c 0.78, CHCl3)} versus its literature value D = {[a]20 16.2 (c 0.9, CH2Cl2)}, {[a]20 15.9 (c 0.8, CH2Cl2)}.6a,b D = D = In addition to the aldol products, the oxidation by-product p-anisaldehyde 16 was also observed by 500 MHz 1H NMR spectroscopy. However, the expected oxadiazinone 14 was not observed [no diagnostic CH3- doublet (d  0.9 ppm) observed in the 1H NMR spectrum]. There was a concern that oxadiazinone 14 might have undergone oxidative degradation in the presence of the ceric ammonium nitrate. To test this, N4-unsubstituted oxadiazinone 11 was directly treated with ceric ammonium nitrate to afford the (R)-5-methyl-6-phenyl-3,6-dihydro-2H-1,3,4oxadiazinone in 41% yield, the apparent product of a secondary oxidation. Based on the collected evidence, the proposed mechanism for the overall transformation from the aldol adduct to the cleaved product is believed to involve a conventional deprotection of the N4-nitrogen position resulting in the loss of the p-methoxybenzyl

group (Scheme 5).7 This would lead to putative intermediate 20, an entity that was not observed, and presumably underwent further ceric ammonium nitrate mediated oxidation to generate iminium ion 22. This type of oxidation is not unprecedented as it has been previously observed in the synthesis of a piperidine-2,6-dione using the related reagent DDQ.8 This intermediate can undergo intramolecular proton transfer to facilitate the hydrolysis of the N3-substituent without the steric encumbrance of the N4-p-methoxybenzyl substituent. 3. Conclusion The utility of the p-methoxybenzyl group as a stereochemical control element and as a labile protecting group that allows for the direct cleavage of the N3-acyl fragment has been demonstrated. The diastereoselectivities ranged from 75:25 to 95:5 as determined by 1H NMR spectroscopy. Treatment of the aldol adducts with ceric

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A. R. Leise et al. / Tetrahedron: Asymmetry 28 (2017) 1154–1162

ammonium nitrate afforded the desired b-hydroxy carboxylic acids in good yield and with high diastereoselectivity and enantioselectivity. The oxidative conditions caused the N3-unsubstituted oxadiazinone to undergo oxidation to give the corresponding (R)-5-methyl-6-phenyl-3,6-dihydro-2H-1,3,4-oxadiazinone. 4. Experimental 4.1. General remarks Chemical reagents were used as purchased. Methylene chloride was purchased as an anhydrous reagent. All reactions were conducted in flame-dried or oven dried glassware under a nitrogen atmosphere. 4.1.1. Chromatography Crude reaction mixtures were purified by flash chromatography using an automated flash chromatograph. The stationary phase was 40 g normal phase silica gel cartridges. The collected fractions were analyzed by thin layer chromatography with tlc plates coated with fluorescent indicator F254, and visualized with UV light. 4.1.2. Polarimetry Samples were prepared using volumetric glassware and then transferred by pipet into in an 8  100 mm cell. Specific rotation data was collected on a JASCO P-1010 digital polarimeter operating at 589 nm. 4.1.3. NMR spectroscopy All 1H and 13C NMR spectra were recorded in deuterated chloroform (CDCl3) or dimethylsulfoxide (DMSO-d6) using an NMR spectrometer operating at 500 MHz (or 400 MHz) for 1H NMR spectra and operating at 125 MHz (or 100 MHz), respectively. Chemical shifts were reported in parts per million (d scale), and coupling constant (J values) are listed in Hertz (Hz). Tetramethylsilane (TMS) was used as internal standard (d = 0 ppm).

reaction was stirred for 3 h, and then diluted with 1 M NaOH (50 mL) and ethyl acetate (150 mL) and stirred for a further 45 min. After this time, the reaction mixture was transferred to a separatory funnel and the layers were separated. The organic layer was treated with 1 M NaOH (2  50 mL), brine (25 mL), separated, and dried (MgSO4). The organic layer was filtered, and the solvents were removed by rotary evaporation to afford the target N-pmethoxybenzylnorephedrine. The 500 MHz 1H NMR spectrum suggested the material was >95% pure. This material was then converted to the corresponding N-nitrosamine by dissolution in THF (50 mL) and 3 M HCl (25 mL, 75 mmol), followed by the portionwise addition of sodium nitrite (3.8 g, 55 mmol). The reaction was stirred overnight and the THF solvent was removed by rotary evaporation. The reaction mixture was reconstituted in ethyl acetate (100 mL) and extracted with 1 M HCl (2  25 mL) and brine (25 mL). The organic layer was filtered and the solvents were removed by rotary evaporation. This process afforded an amber oil that was purified by flash chromatography (silica gel, 4:1, hexanes/ethyl acetate). This overall process afforded 14.2 g of the product (95%). As evidenced by the 1H NMR spectrum of the nitrosamine, the product was obtained as a mixture of E- and Z-diastereomers. Only the major diastereomer is reported. [a]23 D = +100.4 (c 0.58, CHCl3). H NMR (500 MHz, CDCl3): d 1.46 (d, J = 7.0 Hz, 3H), 2.41 (br s, 1H), 3.79 (s, 3H), 4.25 (qd, J = 7.0, 5.1 Hz, 1H), 4.37 (d, J = 14.5 Hz, 1H), 4.75 (d, J = 14.5 Hz, 1H), 5.09 (d, J = 5.1 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 7.24–7.34 (m, 5H) ppm. 13C NMR (125 MHz, CDCl3): d 15.1, 47.4, 55.3, 64.0, 77.0, 114.2, 125.7, 126.3, 128.1, 128.5, 129.6, 140.9, 159.2 ppm. IR (neat): 3401, 1612, 1454, 1249, 1177, 1033, 910, 732, 702 cm 1. ESI-HRMS calc’d for C17H21N2O3 (M+H)+: 301.1552. Found 301.1549.

OH Ph

NH2

OCH3

N CH3

4.1.4. Infrared spectroscopy Infrared spectra were recorded using NaCl plates. Infrared spectral values were reported in reciprocal centimeters (cm 1) and were measured as a neat liquid, nujol mull, or as a neat liquid film from an evaporated CDCl3 solution. 4.1.5. Electrospray ionization high resolution mass spectrometry (ESI-HRMS) Samples were prepared in concentrations of 5–25 ppm in HPLC grade methanol/water/formic acid (1:1:0.01). Analytical data was collected using a ThermoScientific Q-Exactive ESI mass spectrometer.

OH Ph

N

O

OCH3

N CH3

4.2. (1R,2S)-N-p-Methoxybenzyl-N-nitroso-norephedrine 9 In a flame dried, nitrogen purged 1 L flask equipped with a stir bar was added (1R,2S)-norephedrine (7.56 g, 50.0 mmol), ethanol absolute (100 mL), and MgSO4 (1 g). To this mixture was added p-anisaldehyde (6.1 mL, 50 mmol). The reaction was stirred overnight and sodium borohydride (2.9 g, 150 mmol) was added. The

4.3. (1R,2S)-2-(1-(p-Methoxybenzyl)hydrazinyl)-1-phenyl-1propanol 10 In a flame dried, nitrogen purged 3 L round bottom flask equipped with a stir bar and fitted with a Claisen adapter that was fitted with a 205 mL addition funnel with pressure equalizing side-arm, and a condenser, was placed lithium aluminum hydride (3.79 g, 100 mmol) and THF (1 L). This heterogeneous mixture was heated to a gentle reflux. The N-nitrosamine (14.2, 47.3 mmol) was dissolved in THF (150 mL), added to the additional funnel, and the mixture was added dropwise over a period of 30 min. After the addition was complete, the reaction stirred for 3 h. The reaction was then cooled to room temperature, placed into an ice bath, and then quenched by the dropwise addition of 1 M NaOH (100 mL). The THF was removed by rotary evaporation and the mixture was reconstituted in ethyl acetate (200 mL), treated with 1 M NaOH (2  80 mL), brine (80 mL), separated, and dried (MgSO4). The solvents were removed by rotary evaporation to yield the target hydrazine as a yellow oil (12.3 g, 42.8 mmol) in 90%. The 1 crude hydrazine was characterized: [a]23 D = +62.2 (c 0.92, CHCl3). H NMR (500 MHz, CDCl3): d 0.90 (d, J = 6.7 Hz, 3H), 2.96 (dq, J = 6.7, 2.1 Hz, 1H), 3.57 (d, J = 13.1 Hz, 1H), 3.81 (s, 3H), 3.83 (d, J = 13.1 Hz, 1H), 5.26 (d, J = 2.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 7.19–7.23 (m, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.31 (t, J = 8.3 Hz, 2H), 7.35–7.38 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 2.99, 55.3, 63.4, 64.1, 78.3, 126.1, 126.7, 128.0, 129.6, 130.1, 142.8,

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159.2 ppm. IR (neat): 3340, 1611, 1174, 1053, 733, 702 cm 1. ESI-HRMS calc’d for C17H23N2O2 (M+H)+: 287.1754. Found 287.1746. O O

N

H

OCH3

N

Ph

CH3

the title compound in 48%. Mp = 93–95 °C. [a]23 10.1 (c 1.02, D = CHCl3). 1H NMR (500 MHz, CDCl3): d 0.75 (d, J = 6.9 Hz, 3H), 1.16 (t, J = 7.3 Hz, 3H), 2.87 (dq, J = 17.8, 7.3 Hz, 1H), 3.00 (dq, J = 17.8, 7.3 Hz, 1H), 3.57 (dq, J = 6.9, 4.6 Hz, 1H), 3.83 (s, 3H), 4.09 (d, J = 12.3 Hz, 1H), 4.27 (d, J = 12.3 Hz, 1H), 6.06 (d, J = 4.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.3 Hz, 2H), 7.29 (tt, J = 7.3, 2.2 Hz, 1H), 7.33–7.37 (m, 2H), 8.53 (d, J = 8.6 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 9.02, 12.3, 31.2, 51.1, 55.3, 58.6, 114.3, 124.8, 127.2, 128.1, 128.6, 130.6, 135.9, 148.6, 159.7, 174.8 ppm. IR (CDCl3): 1778, 1727, 1249, 1031, 735, 700 cm 1. ESI-HRMS calc’d for C21H25N2O+4 (M+H)+: 369.1809. Found 369.1806.

4.4. (5S,6R)-4-(p-Methoxybenzyl)-5-methyl-6-phenyl-2H-1,3,4oxadiazin-2-one 11

4.6. Experimental procedure for the asymmetric aldol addition products 13a–j

In a 500 mL flame dried round bottom flask was placed the b-hydroxyhydrazine (5.10 g, 17.8 mmol) and dichloromethane (200 mL), and a stir bar. The reaction was stirred until it became homogeneous, at which point triethylamine (7.50 mL, 53.5 mmol). The reaction was cooled to 0 °C and triphosgene (1.77 g, 5.95 mmol) was add portion-wise. The reaction mixture was poured into a separatory funnel and the organic layer was treated with HCl (2  25 mL), and brine (25 mL). The organic layer was separated, dried (MgSO4), gravity filtered, and the solvents were removed by rotary evaporation. The crude product was purified by flash chromatography (65:35 hexanes/ethyl acetate) on silica gel. This process afforded 5.03 g of product (90%). Multiple runs were conducted with comparable yields. Mp = 130–133 °C. 1 [a]23 D = +62.7 (c 1.01, CHCl3). H NMR (500 MHz, CDCl3): d 0.89 (d, J = 6.9 Hz, 3H), 3.23 (qd, J = 6.9, 2.9 Hz, 1H), 3.81 (s, 3H), 4.00 (d, J = 12.5 Hz, 1H), 4.15 (d, J = 12.5 Hz, 1H), 5.81 (d, J = 2.9 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 6.94 (br s, 1H), 7.28–7.32 (m, 4H), 7.35– 7.39 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 11.7, 53.5, 55.3, 62.2, 74.6, 114.2, 125.2, 127.6, 127.9, 128.5, 130.4, 136.5, 152.3, 159.5 ppm. IR (CDCl3): 3237, 1698, 1254, 1120, 735, 700 cm 1. ESI-HRMS calc’d for C18H20N2O3Na (M+Na)+: 335.1367. Found 335.1360.

In a flame dried, nitrogen-purged 100 mL round bottom flask equipped with a magnetic stir bar was placed the N3-propanoyloxadiazinone 12 (0.500 g, 1.35 mmol) and anhydrous THF (7 mL). Titanium tetrachloride (TiCl4, 0.30 mL, 2.7 mmol) was added to the reaction mixture at room temperature. This process generated a yellow-orange solution that stirred for 30 min. The reaction was then cooled to 10 °C and Hünig’s base (0.47 mL, 2.7 mmol), was then added dropwise by syringe. This caused the solution to turn into a deep burgundy color; this solution was stirred for another 45 min. The desired aldehyde was added (2.0 mmol) and the reaction was stirred for four hours and then quenched by the addition of brine (10 mL).

O O Ph

N

O

OCH3

N CH3

4.5. (5S,6R)-4-(p-Methoxybenzyl)-5-methyl-6-phenyl-3-propanoyl-2H-1,3,4-oxadiazin-2-one 12 In a flame-dried, nitrogen purged 1 L round bottom flask equipped with a stir bar was placed 9 (8.56 g, 27.4 mmol) and the dichloromethane (120 mL). 1-Ethyl-3-(3-dimethylaminopropyl carbodiimide (EDC, 5.84 g, 30.2 mmol) and dimethylaminopyridine (DMAP, 0.84 g, 6.9 mmol) were then added to the reaction mixture. Finally, propanoic acid (1.75 mL, 28.8 mmol) was added and the reaction mixture was stirred overnight. The reaction was diluted with dichloromethane (100 mL) and treated with 1 M HCl (2  30 mL). The layers were separated and the organic layer was treated with brine (30 mL), dried (MgSO4), filtered, and the solvents removed by rotary evaporation. The crude product was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 85:15). The collected product was further purified by recrystallization from ethyl acetate and hexanes to yield 4.84 g (13.1 mmol) of

O

O

O

synthesis

of

the

OH

N N

Ph

CH3

CH3

OCH3

4.6.1. (5S,6R)-3-((2S,3S)-3-Hydroxy-2-methyl-3phenylpropanoyl)-4-(4-methoxybenzyl)-5-methyl-6-phenyl1,3,4-2H-oxadiazin-2-one 13a The material was purified by flash chromatography (silica gel; 7:3, hexanes/ethyl acetate) and was recovered as a clear oil (0.48 g, 1.0 mmol) and afforded a yield of 76%. [a]23 5.9 (c D = 0.16, CHCl3). 1H NMR (500 MHz, CDCl3): d 0.73 (d, J = 7.4 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H), 3.03 (br s, 1H), 3.38 (dq, J = 7.0, 4.6 Hz, 1H), 3.83 (s, 3H), 4.05 (d, J = 12.2 Hz, 1H), 4.14 (d, J = 12.2 Hz, 1H), 4.15 (qd, J = 7.0, 3.4 Hz, 1H), 5.16 (d, J = 3.0 Hz, 1H), 6.07 (d, J = 4.6 Hz, 1H), 6.94 (d, J = 8.7 Hz, 2H) 7.18 (d, J = 7.5 Hz, 2H), 7.23–7.38 (m, 8H), 7.44 (d, J = 8.4 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 10.8, 12.3, 47.0, 51.2, 55.3, 58.5, 73.3, 78.1, 114.3, 124.7, 126.2, 127.0, 127.3, 128.2, 128.7, 130.6, 135.7, 141.5, 148.6, 159.8, 177.8 ppm. IR (neat): 1729, 1613, 1378, 1175, 1008 cm 1. ESI-HRMS calc’d for C28H31N2O5 (M+H)+: 475.2228. Found 475.2230. O O Ph

O

OH

N N CH3

CH3

Cl OCH3

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4.6.2. (5S,6R)-3-((2S,3S)-3-(p-Chlorophenyl)-3-hydroxy-2methyl-propanoyl)-4-(4-methoxy benzyl)-5-methyl-6-phenyl1,3,4-2H-oxadiazin-2-one 13b The material was purified by flash chromatography (silica gel; 75:25, hexanes/ethyl acetate) and was recovered as a clear oil (0.48 g, 0.94 mmol) and afforded a yield of 69%. [a]23 7.7 (c D = 0.18, CHCl3). 1H NMR (500 MHz, CDCl3): d 0.67 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 7.0 Hz, 3H), 3.03 (s, 1H), 3.33 (dq, J = 7.0, 4.7 Hz, 1H), 3.76 (s, 3H), 4.02 (qd, J = 7.0, 3.0 Hz, 2H), 4.14 (d, J = 12.4 Hz, 1H), 5.06 (d, J = 2.9 Hz, 1H), 6.02 (d, J = 4.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 7.3 Hz, 2H), 7.27–7.25 (m, 3H), 7.27–7.31 (m, 4H), 7.37 (d, J = 8.7 Hz, 2H) ppm. 13C (CDCl3, 125 MHz): d 10.4, 12.4, 46.7, 51.3, 55.3, 58.6, 72.5, 78.3, 114.3, 124.8, 126.9, 127.5, 128.2, 128.3, 128.7, 130.6, 133.0, 139.9, 148.7, 159.8, 177.6 ppm. IR (nujol): 3504, 3018, 1770, 1722, 1249, 1007 cm 1. ESI-HRMS calc’d for C28H29ClN2O5Na+ (M+Na)+: 531.1657. Found 531.1652.

6.87 (d, J = 8.7 Hz, 2H), 7.08 (td, J = 7.7, 1.7 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 7.23 (tt, J = 7.2, 1.3 Hz, 1H), 7.27–7.31 (m, 3H), 7.39 (d, J = 8.7 Hz, 2H), 7.46 (dd, J = 8.0, 1.3 Hz, 1H), 7.58 (dd, J = 7.7, 1.7 Hz, 1H) ppm. 13C NMR (500 MHz, CDCl3): d 10.2, 12.5, 43.3, 51.5, 55.3, 58.7, 72.2, 76.8, 114.4, 121.8, 124.8, 126.8, 127.2, 128.2, 128.7, 128.9, 129.1, 130.6, 132.7, 135.7, 139.7, 148.0, 159.8, 179.2 ppm. IR (nujol): 3530, 3019, 1764, 1736, 1248 cm 1. ESI-HRMS calc’d for C28H30BrN2O+5 (M+H)+: 553.1333. Found 553.1331. O O

O

OH NO2

N N

Ph

CH3

CH3 O O

O N N

Ph

CH3

Br

CH3

OCH3

4.6.3. (5S,6R)-3-((2S,3S)-3-(p-Bromophenyl)-3-hydroxy-2methyl-propanoyl)-4-(4-methoxy benzyl)-5-methyl-6-phenyl1,3,4-2H-oxadiazin-2-one 13c The material was purified by flash chromatography (80:20 hexanes/ethyl acetate) to afford a yield of 77% of the target compound as a clear oil. [a]23 = 9.65 (c 1.69, CHCl3). 1H NMR (500 MHz, CDCl3): d 0.68 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.9 Hz, 3H), 3.02 (br s, 1H), 3.33 (qd, J = 7.1, 4.7 Hz, 1H), 3.76 (s, 3H), 4.01 (dq, J = 7.1. 3.0 Hz, 1H), 4.02 (d, J = 12.2 Hz, 1H), 4.15 (d, J = 12.2 Hz, 1H), 5.05 (d, J = 2.7 Hz, 1H), 6.03 (d, J = 4.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H), 7.22–7.31 (m, 5H), 7.38 (d, J = 8.7 Hz, 2H), 7.40 (d, 8.5 Hz, 2H) ppm. 13C (CDCl3, 125 MHz): d 10.4, 12.4, 46.7, 51.3, 55.4, 58.6, 72.5, 78.3, 114.3, 121.2, 124.8, 126.9, 127.9, 128.3, 128.7, 130.5, 131.3, 135.6, 140.5, 148.7, 159.8, 177.6 ppm. IR (nujol mull): 3489, 1772, 1719, 1248, 1174, 1009, 851 cm 1. ESI-HRMS calc’d for C28H30BrN2O+5 (M+H)+: 553.1333. Found 553.1326.

4.6.5. (5S,6R)-3-((2S,3S)-3-Hydroxy-2-methyl-3-(m-nitrophenyl) propanoyl)-4-(4-methoxy benzyl)-5-methyl-6-phenyl-1,3,4-2Hoxadiazin-2-one 13e The material was purified by flash chromatography (silica gel; 4:1, hexanes/ethyl acetate), and was recovered as a clear oil that formed a foam (0.614 g, 1.18 mmol, 87% yield) after rotary evaporation. Melting Point: 63–65 °C. [a]23 12.2 (c 1.06, CHCl3). D = 1 H NMR (500 MHz, CDCl3): d 0.69 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H), 3.27 (br s, 1H), 3.37 (qd, J = 7.0, 4.5 Hz, 1H), 3.76 (s, 3H), 4.05 (qd, J = 7.0, 2.4 Hz, 1H), 4.08 (d, J = 12.4 Hz, 1H), 4.22 (d, J = 12.4 Hz, 1H), 5.16 (d, J = 2.4 Hz, 1H), 6.06 (d, J = 4.5 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 7.2 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.60 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1 H, 7.70 (d, J = 7.6 Hz, 1H), 8.05 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.25 (s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 10.2, 12.5, 46.6, 51.5, 55.4, 58.7, 72.0, 78.5, 114.3, 121.3, 122.4, 124.8, 125.2, 126.8, 128.3, 128.8, 129.1, 130.6, 132.3, 135.5, 143.7, 148.3, 148.8, 159.9, 177.4 ppm. IR (CDCl3): 3452, 1721, 1531, 1351, 1249, 1175 cm 1. ESI-HRMS calc’d for C28H30N3O+7 (M+H)+: 520.2078. Found 520.2070. O O

O

O

OH

Br

Ph O Ph

OCH3

OH

N N CH3

O N N

CH3 CH3

OH

CH3 OCH3

OCH3

4.6.4. (5S,6R)-3-((2S,3S)-3-(o-Bromophenyl)-3-hydroxy-2methylpropanoyl)-4-(4-methoxy benzyl)-5-methyl-6-phenyl1,3,4-2H-oxadiazin-2-one 13d The crude product was extracted and purified via flash chromatography (85:15 hexanes/ethyl acetate ratio was used as the mobile phase) to yield 0.674 g (89%) of product as a white crystalline solid. Mp: 67–69 °C. [a]23 45.7 (c 1.01, CHCl3). 1H NMR D = (500 MHz, CDCl3): d 0.73 (d, J = 7.0 Hz, 1H), 1.05 (d, J = 7.2 Hz, 1H), 3.35 (qd, J = 7.0, 4.6 Hz, 1H), 3.76 (s, 1H), 3.81 (d, J = 2.0 Hz, 1H), 4.08 (d, J = 12.7 Hz, 1H), 4.21 (qd, J = 7.2, 2.1 Hz, 1H), 4.22 (d, J = 12.7 Hz, 1H), 5.31 (t, J = 1.7 Hz, 1H), 6.03 (d, J = 4.6 Hz, 1H),

4.6.6. (5S,6R)-3-((2S,3S)-3-Hydroxy-2-methyl-3naphthylpropanoyl)-4-(4-methoxybenzyl)-5-methyl-6-phenyl1,3,4-2H-oxadiazin-2-one 13f The material was purified by flash chromatography (silica gel, 4:1 hexanes/ethyl acetate). This process yielded the purified title compound 0.3875 g representing a 54% isolated yield. [a]23 16.4 (c 1.01, CHCl3). 1H NMR (500 MHz, CDCl3): d 0.64 D = (d, J = 7.0 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 3.16 (br s, 1H), 3.27 (dq, J = 7.0, 4.6 Hz, 1H), 3.71 (s, 3H), 3.91 (d, J = 12.5 Hz, 1H), 4.05 (d, J = 12.5 Hz, 1H), 4.17 (qd, J = 7.0, 3.1 Hz, 1H), 5.23 (d, J = 3.1 Hz, 1H), 5.94 (d, J = 4.6 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H),

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7.08 (d, J = 7.30 Hz, 2H), 7.16–7.27 (m, 3H), 7.30–7.37, (m, 4H), 7.45 (dd, J = 8.4, 1.7 Hz, 1H), 7.84 (s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 10.8, 12.4, 26.9, 51.3, 55.5, 73.3, 78.2, 114.3, 124.4, 124.8, 125.0, 125.8, 126.1, 127.1, 128.0, 128.2, 128.7, 132.9, 133.3, 135.7, 139.2, 148.8, 159.8, 177.7 ppm. IR (nujol): 3460, 1713, 1248, 1003, 723 cm 1. ESI-HRMS calc’d for C32H33N2O5 (M+H)+: 525.2384. Found 525.2381. O O

O

O

O

OH

N N

Ph

CH3

CH3

OCH3

OH

N N

Ph

CH3

CH3

OCH3

4.6.7. (5S,6R)-3-((2S,3R,E)-3-Hydroxy-2-methyl-5-phenyl-4pentenoyl)-4-(4-methoxy benzyl)-5-methyl-6-phenyl-1,3,4oxadiazin-2-one 13g The material was purified by flash chromatography (silica gel, 4:1 hexanes/ethyl acetate), and then recrystallized from ethyl acetate and hexanes. This process yielded 0.324 g of product as a white crystalline solid (65%). Mp = 132–134 °C. [a]23 D = +0.7 (c 2.4, CHCl3). 1 H NMR (500 MHz, CDCl3): d 0.69 (d, J = 6.9 Hz, 3H), 1.17 (d, J = 7.1 Hz, 3H), 2.98 (s, 1H), 3.32 (dq, J = 6.9, 4.6 Hz, 1H), 3.76 (s, 3H), 3.99 (qd, J = 6.9, 3.8 Hz, 1H), 4.02 (d, J = 12.3 Hz, 1H), 4.23 (d, J = 12.3 Hz, 1H), 4.62 (s, 1H), 6.01 (d, J = 4.4 Hz, 1H), 6.15 (d, J = 5.5 Hz, 1H), 6.18 (d, J = 5.5 Hz, 1H), 6.65 (dd, J = 16.01, 1.3 Hz, 1H), 6.85–6.88, (m, 2H), 7.12 (d, J = 7.1 Hz, 2H), 7.14–7.17 (m, 1H), 7.21–7.34, (m, 7H), 7.38 (d, J = 8.5 Hz, 2H). 13C (CDCl3, 125 MHz): d 11.5, 12.4, 45.3, 51.4, 55.4, 58.6, 72.7, 78.2, 114.3, 124.8, 126.5, 127.1, 127.6, 128.2, 128.5, 128.7, 129.0, 130.5, 131.2, 135.7, 136.8, 148.9, 159.8, 117.4 ppm. IR (neat): 3491, 1769, 1721, 1248, 1173, 1032, 751, 698 cm 1. ESI-HRMS calc’d for C30H33N2O+5 (M+H)+: 501.2384. Found 501.2379. O O Ph

O

O

OH

N N CH3

CH3 OCH3

4.6.8. (5S,6R)-3-((2S,3R)-3-Hydroxy-2-methylhexanoyl)-4-(4methoxybenzyl)-5-methyl-6-phenyl-1,3,4-oxadiazin-2-one 13h The title compound was purified by flash chromatography (silica gel, 4:1 hexanes/ethyl acetate) to yield 0.505 g (84%) of the target material as a yellow oil. [a]23 0.02 (c 1.0, CHCl3). 1H D = NMR (500 MHz, CDCl3): d 0.68 (d, J = 7.0 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H), 1.24–1.33 (m, 2H), 1.40– 1.50 (m, 2H), 2.74 (s, 1H), 3.27–3.34 (m, 1H), 3.75 (s, 3H), 3.78 (qd, J = 7.1, 2.4 Hz, 1H), 3.83–3.89 (m, 1H), 4.02–4.06 (m, 1H), 4.20 (d, J = 12.6 Hz, 1H), 6.00 (d, J = 4.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 7.20–7.23 (m, 1H), 7.27–7.30 (m, 2H), 7.37 (d, J = 8.7 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): 10.5, 12.5, 14.0, 19.3, 36.0, 44.4, 51.2, 55.3, 58.6, 71.2, 78.2, 114.3, 124.8, 127.0, 128.2, 128.7, 130.6, 135.7, 148.7, 159.8, 178.4 ppm. IR (neat): 3437, 3020, 1773, 1719, 1247 cm 1. ESI-HRMS calc’d for C25H32N2O5Na+ (M+Na)+: 463.2203. Found 463.2193.

4.6.9. (5S,6R)-3-((2S,3R)-3-Hydroxy-2,5-dimethylhexanoyl)-4(4-methoxybenzyl)-5-methyl-6-phenyl-1,3,4-oxadiazin-2-one 13i The title compound was purified by flash chromatography (silica gel, 4:1 hexanes/ethyl acetate) to yield 0.554 g (90%) of the target material as a clear oil. [a]25D = +0.6 (c 1.15, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.69 (d, J = 6.9 Hz, 3H), 0.87 (apparent triplet, J = 6.7 Hz, 6H), 1.13 (d, J = 7.1 Hz, 3H), 1.15–1.26 (m, 1H), 1.42– 1.49 (m, 1H), 1.69–1.79 (m, 1H), 2.71 (s, 1H), 3.33 (dq, J = 6.9 Hz, 2.3 Hz, 1H), 3.76 (s, 3H), 3.97–3.99 (m, 1H), 4.05 (d, J = 12.3 Hz, 1H), 4.23 (d, J = 12.3 Hz, 1H), 6.03 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 8.7, 2H), 7.12 (d, J = 7.1 Hz, 2H), 7.23 (t, J = 14.5 Hz, 1H), 7.29 (t, J = 14.5 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): 10.7, 12.5, 22.0, 23.6, 24.7, 43.0, 44.8, 51.3, 55.3, 58.7, 69.5, 78.2, 114.3, 124.8, 127.0, 128.2, 128.7, 130.6, 135.7, 148.7, 159.8, 178.4 ppm. IR (neat): 3500, 1732, 1614, 1249, 1176 cm 1. ESI-HRMS calc’d for C26H35N2O+5 (M+H)+: 455.2541, found 455.2531. O O Ph

O

OH

N N

CH3

CH3

OCH3

4.6.10. (5S,6R)-3-((2S,3R)-3-Hydroxy-2-methyldecanoyl)-4-(pmethoxybenzyl)-5-methyl-6-phenyl-1,3,4-oxadiazin-2-one 13j The title compound was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 80:20) to produce 0.558 g (1.12 mmol) of material for a 82% isolated yield as a yellow oil. [a]25D = +2.5 (c 1.38, CHCl3). 1H NMR (400 MHz, CDCl3): d 0.69 (d, J = 7.1 Hz, 3H), 0.81 (t, J = 7.1 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H), 1.18–1.36 (m, 10H), 1.39–1.52 (m, 2H), 2.74 (br s, 1H), 3.32 (qd, J = 7.1, 4.7 Hz, 1H), 3.76 (s, 3H), 3.80 (qd, J = 7.1, 3.8 Hz, 1H), 3.83–3.88 (m, 1H), 4.04 (d, J = 12.5 Hz, 1H), 4.22 (d, J = 12.5 Hz, 1H), 6.02 (d, J = 4.6 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 7.21–7.24 (m, 1H), 7.29 (t, J = 8.1 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H). 13C NMR (125 MHz, CDCl3): 10.5, 12.5, 14.1, 22.7, 26.1, 29.3, 29.6, 31.8, 33.9, 44.4, 51.1, 55.3, 58.6, 71.5, 78.2, 114.3, 124.8, 127.0, 128.2, 128.7, 130.6, 135.7, 148.7, 159.8, 178.5 ppm. IR (neat): 3520, 1728, 1248, 1174, 910, 732 cm 1. ESI-HRMS calc’d for C29H41N2O+5 (M+H)+: 497.3010, found 497.3007. O

OH

HO CH3

Cl

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A. R. Leise et al. / Tetrahedron: Asymmetry 28 (2017) 1154–1162

4.6.11. (2S,3S)-3-Hydroxy-2-methyl-3-phenylpropanoic acid 15a Aldol adduct 13c (0.2715 g, 0.533 mmol) was dissolved in acetonitrile (5 mL). To this solution was added a solution of ceric ammonium nitrate (5 equiv, 1.46 g, 2.67 mmol) in H2O (10 mL). The reaction was stirred for 4 h and the pH was checked (pH = 2 by litmus paper). The reaction mixture was diluted with saturated NaHCO3 (50 mL) and 6 M NaOH (4 mL) (pH = 12 by litmus). The solution was transferred to a separatory funnel and washed with diethyl ether (3  30 mL). The aqueous solution was treated with 2 M HCl (20 mL) rendering the solution acidic (pH = 2). This solution was extracted with ether (2  40 mL), the organic layers were combined, dried (MgSO4), and the solvents were removed by rotary evaporation. This yielded the crude product as a yellow oil (0.097 g, 0.45 mmol) in 85% crude yield. This crude material was determined to be > 92% pure by 500 MHz 1H NMR spectroscopy. [a]23 16.7 (c 0.78, CHCl3), [a]23 21.8 (c 0.75, CH2Cl2). D = D = 1 H NMR (500 MHz, CDCl3): d 1.15 (d, J = 7.2 Hz, 3H), 2.81 (qd, J = 7.2, 3.9 Hz, 1H), 5.15 (d, J = 3.9 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.6 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): 10.3, 46.0, 72.7, 127.4, 128.9, 133.5, 139.5, 180.2 ppm. IR (neat): 3412, 1706, 1598, 1216, 1092, 829 cm 1. ESI-HRMS calc’d for C10H11ClO3Na+ (M+Na)+: 237.0289. Found: 237.0286.

4.8. (6R)-5-Methyl-6-phenyl-3,6-dihydro-2H-1,3,4-oxadiazin-2one 16a The N3-methyl oxadiazinone 14 (0.5138 g, 1.64 mmol) was dissolved in acetonitrile (10 mL). In a separate flask, the ceric ammonium nitrate (4.35 equiv, 3.92 g, 7.15 mmol) was dissolved in water (35 mL). Once both solutions were homogeneous, the reactants were combined and the reaction mixture stirred for 1 hr. The reaction was then diluted with sodium bicarbonate (60 mL) and ethyl acetate (60 mL). The layers were separated and the organic layer was washed with brine (2  25 mL), dried (MgSO4), and the solvents were removed. The crude product was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 8:2). The title compound was isolated as a yellow oil (0.128 g, 0.677 mmol, 41%). [a]24D = 192.5 (c 1.08, CHCl3). 1H NMR (500 MHz, CDCl3): d 1.93 (s, 3H), 3.39 (s, 3H), 5.65 (s, 1H), 7.32– 7.37 (m, 2H), 7.42–7.45 (m, 3H), 8.01 (br s, 1H) ppm. 13C NMR (125 MHz, CDCl3): d 19.2, 79.9, 127.8, 129.3, 130.0, 133.7, 148.1, 149.2 ppm. IR (neat): 3439, 1724, 1666, 1265, 1144, 1049 cm 1. ESI-HRMS calc’d for C10H11N2O+2 (M+H)+: 191.0815. Found: 191.0813. Acknowledgement

O

OH

The authors thank the Department of Chemistry at Illinois State University for financial support.

HO CH3

References

4.7. (2S,3R)-3-Hydroxy-2,5-dimethylhexanoic acid 15b Aldol adduct 13i (0.353 g, 0.777 mmol) was dissolved in acetonitrile (10 mL). To this solution was added a solution of ceric ammonium nitrate (5 equiv, 2.13 g, 3.88 mmol) in H2O (10 mL). The reaction was stirred for 4 h and the pH was checked (pH = 2 by litmus paper). The reaction mixture was diluted with saturated NaHCO3 (20 mL) and 6 M NaOH (20 mL) (pH = 12 by litmus). The solution was transferred to a separatory funnel and washed with diethyl ether (2  30 mL). The aqueous solution was treated with 2 M HCl until the solution acidic (pH = 2). This solution was extracted with ether (2  40 mL), the organic layers were combined, dried (MgSO4), and the solvents were removed by rotary evaporation. This yielded the crude product as a yellow oil (0.111 g, 0.69 mmol) in 90% crude yield. This crude material was determined to be >92% pure by 500 MHz 1H NMR spectroscopy. Recrystallization from hexanes and diethyl ether afforded 0.0505 g (41%) of the product as an off-white crystalline solid. Mp = 78–80 °C. [a]22D = +30.3 (c 0.28, CH2Cl2). 1H NMR (500 MHz, CDCl3): d 0.93 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.16– 1.21 (m, 1H), 1.21 (d, J = 7.3 Hz, 3H), 1.48 (ddd, J = 13.7, 9.7, 5.3 Hz, 1H), 2.57 (qd, J = 7.3, 3.5 Hz, 1H), 4.05 (dt, J = 9.6, 3.5 Hz, 1H), 6.4 (br s, 2H) ppm. 13C NMR (125 MHz, CDCl3): 10.4, 21.8, 23.4, 24.7, 42.7, 44.5, 69.8, 181.3 ppm. IR (neat): 3401, 1707, 1215, 1089 cm 1. ESI-HRMS calc’d for C8H16O3Na+ (M+Na)+: 183.0992. Found: 183.0896. O O Ph

N N CH3

H

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