Enantioselective Synthesis of 2,3-Disubstituted Benzomorpholines: Analogues of Lignan Natural Products

Article abstract of DOI:10.1021/acs.joc.6b02265

The enantioselective synthesis of 2,3-disubstituted benzomorpholines, analogues of 1,4-benzodioxane natural products, has been achieved via addition of electron-rich aromatic donors to acyl-iminium ions derived from benzomorpholine aminols. Subsequent mod

Full text of DOI:10.1021/acs.joc.6b02265

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Enantioselective synthesis of 2,3-disubstituted benzo-
morpholines – analogues of lignan natural products
Eun-Kyung Jung, Lisa I. Pilkington, and David Barker
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02265 • Publication Date (Web): 28 Oct 2016
Downloaded from http://pubs.acs.org on October 28, 2016
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Enantioselective synthesis of 2,3ꢀdisubstituted benzoꢀmorpholines – analogues of lignan
natural products
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EunꢀKyung Jung, Lisa I. Pilkington and David Barker*
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School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Corresponding author email: d.barker@auckland.ac.nz
Abstract: The enantioselective synthesis of 2,3ꢀdisubstituted benzomorpholines, analogues of 1,4ꢀbenzodioxane
natural products, has been achieved via addition of electronꢀrich aromatic donors to acylꢀiminium ions derived
from benzomorpholine aminols. Subsequent modification of the benzomorpholine scaffold allows side chains
mimicking those found in 1,4ꢀbenzodioxane lignans to be added. Antiproliferative testing of the prepared
analogues showed promising results against MDAꢀMBꢀ231 and HCT116 cancer cell lines.
1,4ꢀBenzodioxane neolignans are a subclass within the lignan family of natural products that exhibit potent
biological effects, including antimicrobial, hepaprotective and antiproliferative activities.1–5 Naturally occurring
compounds all contain a 2ꢀarylꢀ1,4ꢀbenzodioxane core structure with various oxygenated substituents.6 The
eusiderin family is the largest group of 1,4ꢀbenzodioxane lignans (eg. eusiderin A 1) whilst isoamericanol A 2,
the wellꢀknown lignanꢀhybrid silybin A and lignan 3 are other examples that have a hydroxymethyl group at Cꢀ9
(Figure 1).1,2 In particular, silybin A, one of the components of silymarin (milk thistle extract), has shown
inhibitory activity against hepatotoxicants.7,8 Biosynthetically, 1,4ꢀbenzodioxane neolignans are formed by the
oxidative dimerisation of two phenylpropanoid units through phenoxy radical coupling.9
Figure 1. Natural products and target azaꢀlignan.
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Previously, we have developed an enantioselective and flexible synthetic method to produce 1,4ꢀbenzodioxane
lignans such as eusiderin A 1, isoamericanol A 2 and the rodgersinines.1ꢀ3 Unfortunately, naturally occurring
1,4ꢀbenzodioxane lignans are known to have poor aqueous solubility which limits their therapeutic
application.10–12
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We wished to prepare 3ꢀaryl benzomorpholine analogues 4 of these natural products to explore the solubility of
these compounds and the effect of exchanging an oxygen with a substituted amino group. There are limited
examples of the preparation of 2,3ꢀdisubstituted benzomorpholines13–16 and few of these are diastereoꢀ or
enantioselective.17–20 Our approach was designed around the addition of various electron rich aromatic
nucleophiles to an acylꢀiminium ion derived from benzomorpholine aminol 5. To date there are very few
examples of the morpholine21,22 and benzomorpholine23 ring systems participating in acylꢀiminium chemistry.24
Aminol 5 would be prepared from chiralꢀpool derived, suitably protected, glycerol 6 and aminophenol 7
derivatives (Scheme 1).
Scheme 1. Retrosynthetic analysis
The synthesis began with enantiopure glycerol derivative, which was prepared by selective protection of diol 8
to give either benzyl ether 9 or SiiPr3 (TIPS) 10 over three high yielding steps (Scheme 2). Mitsunobu reaction
of alcohols 9 and 10, which have previously been shown to undergo inversion with high enantospecificity,2 with
NꢀCbz 1125 or NꢀBoc 1226 protected aminophenols gave highly enantioentriched aryl ethers 13, 14 and 15 all in
high yields. Deprotection of the PMB group in ethers 13ꢀ15 gave primary alcohols 16ꢀ18, which were oxidised
using DessꢀMartin periodinane (DMP) to give cyclic benzomorpholine aminols 19ꢀ21 as a separable mixture of
diastereomers.
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Scheme 2. Synthesis of benzomorpholine aminol.
Having prepared aminols 19ꢀ21, we then wished to add a range of electronꢀrich aromatics that mimic the aryl
groups found in natural lignans. NꢀAcyl iminium ions are commonly formed using either Lewis acids or
Brønsted acids. We began with benzomorpholine aminol 21 containing NꢀBoc and OꢀTIPS groups to find
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optimized conditions using 1,3,5ꢀtrimethoxybenzene (Table 1). Using BF3·OEt2 induced decomposition of
starting materials whilst 10 mol % AuOTf28 resulted in successful aryl addition however the Boc and TIPS
groups were removed, giving amino alcohol 22 in low yield. The use of Brønsted acids methanesulfonic acid
and sulfuric acid improved the yield, especially when acetic acid was used as solvent.29,30 When catalytic
sulfuric acid was used, in spite of the better yield compared to the use of AuOTf, deprotection of both TIPS and
BOC group occurred with acetate 23 and alcohol 22 being obtained in 17% and 7% yield, respectively.
Increasing the amount of sulfuric acid (8 eq.) gave acetate 23 and alcohol 22 in improved yields of 69% and
30%, respectively. It is assumed that the acetate is formed due to the acidic deprotection of the TIPS group and
the resultant formation of an acetylating agent TIPS acetate which then reacts with the free primary alcohol. We
then applied these conditions to NꢀCbz, OꢀBn aminol 19 and NꢀBoc and OꢀBn aminol 20. Both aminols 19 and
20 gave aryl addition products 24 and 25, respectively, in near quantitative yield with cleavage of the NꢀBoc in
25 observed. Conveniently, the deprotected Boc group allowed functionalization of the benzomorpholine
nitrogen position at a later stage.
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Table 1. Optimisation of aryl addition conditions.
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yield
(%)
Aminol
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acid
solvent
Products
BF3·OEt2
(2 eq.)
CH2Cl2
NR
11
ꢀ
AuOTf
CH2Cl2
AcOH
21
22
(10 mol%)
H2SO4
17/7
21
22/23
(30 mol%)
H2SO4 (8 eq.)
H2SO4 (8 eq.)
H2SO4 (8 eq.)
AcOH
AcOH
AcOH
69/30
97
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19
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22/23
24
97
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Having found optimized conditions, the nucleophile scope was investigated with various electron rich aromatic
donors (Table 2). Benzomorpholine aminols 19, 20 and 21 gave a variety of 3ꢀarylꢀbenzomorpholines 26ꢀ32 as
single diastereoisomers all with the more stable 2,3ꢀtrans configuration. This was determined by analysis of the
J2,3 coupling constant; all compounds with a NꢀCbz group had J = ~2 Hz which indicates a transꢀdiaxial
configuration. In cases where the aryl group was a 2,4,6ꢀtrimethoxyphenyl then additional steric interactions
between the Cbz and aryl substituents led the compound to adopt a transꢀdiequatorial conformation (J = ~8 Hz).
After removal of the NꢀCbz group (see below) all compounds adopted the more favoured transꢀdiequatorial
conformation (J = ~8 Hz). When investigating the nucleophilic scope of the reaction the only unsuccessful
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example was when using syringol (2,6ꢀdimethoxyphenol), which upon reaction with aminols 19ꢀ21 gave a
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complex mixture of 3ꢀarylꢀbenzomorpholines, most likely due to competing directing effects.
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Table 2. Nucleophile scope of reaction
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R1
R2
product
yield (%)
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Cbz
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MeO
MeO
N
Br
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Bn
Bn
Cbz
Cbz
Cbz
Boc
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94
50
Bn
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TIPS
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With an adaptable route to Nꢀacyl iminium addition determined, addition of side chains to benzomorpholines
was explored. The first aim was to add an allylic alcohol which found in a number of benzodioxane lignans,
such as isoamericanol A 2. Attempted formylation of NꢀCbz/OꢀBn aryl benzomorpholines 24, using lithiation
was unsuccessful. Further studies with NꢀCbz/OꢀBn benzomorpholine 24 concluded that selective reduction or
deprotection of the Cbz group were similarly unsuccessful. To obtain a deprotected amine, the NꢀBocꢀOꢀBn
aminol 20 was chosen due to removal of the Boc group under optimized acidic conditions. After methylation of
benzomorpholine 25 the bromide was successfully converted to aldehyde 32 in 93% yield, via lithiation and
addition of DMF. A Wittig reaction with aldehyde 32 gave the unsaturated ester, which was reduced to give
allylic alcohol 33 (Scheme 3).
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Scheme 3. Synthesis of allylic and saturated side chains
Exhaustive hydrogenation of 33 using hydrogen and Pd/C removed the benzyl ether and reduced the alkene,
giving compound 34 in 51% yield, which is an azaꢀanalogue of lignan 3.31 Attempted selective removal of the
Oꢀbenzyl group in the presence of the allylic alcohol under various conduction was unfortunately unsuccessful.
In an attempt to successfully obtain the natural allylic alcohol side chain, we revised our strategy to use the
previously prepared acetate 23. Compound 23 was subjected to a four step procedure (Nꢀmethylation, ester
hydrolysis, TIPS protection and formylation) to obtain aldehyde 35 which was then converted to allylic alcohol
36 (Scheme 3). Finally, removal of the TIPS group from 36 gave the desired compound 37, an analogue of
lignans such as isoamericanol A 2.
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We then explored alternative sidechain additions using Suzuki reactions on benzomorpholine bromides. The
Suzuki coupling reaction between 31 and transꢀpropꢀ1ꢀenylboronic acid 38 gave alkene 39, from which the
acetyl protecting group was hydrolysed to give analogue 40 (Scheme 4). Additionally, Suzuki coupling reaction
between 25 and 26 with boronic acid 41 gave biaryls 42 and 43, respectively. Hydrogenolysis of benzyl and Cbz
protecting groups in 42 gave alcohol 44 in 67% yield.
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Scheme 4. Synthesis of alternative analogues
Following the synthesis of the 3ꢀaryl benzomorpholine analogues, their antiproliferative activity was
investigated against two human cell lines, MDAꢀMBꢀ231, a breast cancer cell line and HCT116, a human colon
cancer cell line and their IC50 values determined. In particular, biarylꢀbenzomorpholine 44 showed promising
activity, with an IC50 values of 0.65 ꢁM and 0.82 ꢁM against MDAꢀMBꢀ231 and HCT116 cell lines,
respectively. Biarylꢀbenzomorpholine 44 is a novel scaffold which could be further explored for its
antiproliferative activity. Further studies to compare the solubility and bioactive of these biaryl compounds to
their oxygen counterparts are currently being investigated.
In conclusion, we report methods to enantioselectively synthesize functionalised 2,3ꢀdisubstituted
benzomorpholines. Aryl addition to benzomorpholine aminols via an Nꢀacyl iminium intermediate was
promoted under Brønsted acid conditions to generate a variety of 3ꢀarylꢀbenzomorpholines as single
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diastereomers. We then utilized these compounds to the synthesis of a number of azaꢀlignan analogues. The
route used to prepare these analogues is adaptable to the preparation of numerous other compounds, with
modification of the aryl groups and side chain easily achievable.
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Experimental Section
General Procedures
All reactions were carried out with ovenꢀdried glassware and under a nitrogen atmosphere in dry, freshly
distilled solvents unless otherwise noted. Diisopropylethylamine was distilled from CaH2 and stored over
activated 4Å molecular sieves. NMR spectra were recorded on a 300 MHz or 400 MHz spectrometer. Chemical
shifts are reported relative to the solvent peak of chloroform (δ 7.26 for 1H and δ 77.16 ± 0.06 for 13C). 1H NMR
data is reported as position (δ), relative integral, multiplicity (s, singletl; d, doublet; dd, doublet of doublets; ddd,
doublet of doublet of doublets; dt, doublet of triplets; t, triplet; td, triplet of doublets; tt, triplet of triplets; m,
multiplet), coupling constant (J, Hz), and the assignment of the atom. 13C NMR data are reported as position (δ)
and assignment of the atom. NMR assignments were performed using COSY, HSQC and HMBC experiments.
Highꢀresolution mass spectroscopy (HRMS) was carried out by either chemical ionisation (CI) or electrospray
ionization (ESI) on a MicroTOFꢀQ mass spectrometer. Unless noted, chemical reagents were used as purchased.
Compounds 8 and 10 were prepared using previously reported methods.2
(R)ꢀ1ꢀ(Benzyloxy)ꢀ3ꢀ((4′ꢀmethoxybenzyl)oxy)propanꢀ2ꢀol 9. To a solution of diol 8 (1.0 g, 4.71 mmol) and
Ag2CO3 (2.60 g, 9.42 mmol) in toluene (35 mL) under an atmosphere of nitrogen, in the absence of light at
room temperature, was added BnBr (0.84 mL, 7.07 mmol) slowly, and the mixture stirred for 20 h. The solvent
was removed in vacuo and the crude product was purified by flash chromatography (3:1 hexanes, ethyl acetate)
to give the title compound 9 (1.07 g, 75%) as a pale yellow oil. RF = 0.43 (2:1 hexane, ethyl acetate); [α]D +2.34
(c = 1.19, CHCl3); δH (500 MHz; CDCl3; Me4Si) 2.52 (1H, d, J = 4.2 Hz, OH), 3.47–3.56 (4H, m, 1ꢀCH2, 3ꢀ
CH2), 3.79 (3H, s, OMe), 3.97–4.02 (1H, m, 2ꢀH), 4.47 (2H, s, OCH2Ar), 4.54 (2H, s, OCH2Ph), 6.86 (3H, d, J
= 8.6 Hz, 3′ꢀH), 7.24 (1H, d, J = 8.6 Hz, 2′ꢀH), 7.28–7.35 (5H, ArꢀH, Bn); δC (125 MHz; CDCl3) 55.4 (4′ꢀ
OCH3), 69.6 (Cꢀ2), 71.0 (Cꢀ1), 71.4 (Cꢀ3), 73.1 (OCH2Ar), 73.5 (OCH2Ph), 114.0 (Cꢀ3′), 127.8, 128.4 (ArꢀCH),
129.4 (Cꢀ2′), 130.1 (Cꢀ1′), 138.0 (ArꢀC), 159.3 (Cꢀ4′); IR: (film)/cmꢀ1; 3448, 2861, 1708, 1610, 1490, 1454,
1417, 1388, 1364, 1326, 1301, 1245, 1205, 1174, 1088, 1028, 952, 815, 735; HRMS (ESI+) Found (MNa+):
325.1418; C18H22NaO4 requires 325.1410.
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Benzyl (5ꢀbromoꢀ2ꢀhydroxyphenyl)carbamate 11. To a solution of 2ꢀaminoꢀ4ꢀbromophenol (4.0 g, 21 mmol)
and Amberlyst® 15 (1.6 g, 40% w/w) in CH3CN (60 mL) under an atmosphere of nitrogen at room temperature
was added benzyl chloroformate (3.64 mL, 26 mmol) slowly, and the mixture stirred for 4 h. The solution was
filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (4:1
hexanes, ethyl acetate) to give the title compound 11 (3.5 g, 51%) as a brown solid. RF = 0.65 (2:1 hexane, ethyl
acetate); M.P.: 164–166 °C; δH (500 MHz; CDCl3; Me4Si) 5.23 (2H, s, OCH2Ph), 6.79 (1H, d, J = 8.6 Hz, 3ꢀH),
6.93 (1H, br s, OH), 7.05 (1H, br s, NH), 7.11 (1H, dd, J = 8.6, 2.4 Hz, 4ꢀH), 7.35–7.42 (5 H, ArꢀH), 7.56 (1H,
d, J = 2.4 Hz, 6ꢀH); δC (125 MHz; CDCl3) 68.1 (OCH2Ph), 112.8 (Cꢀ5), 119.2 (Cꢀ3), 123.5 (Cꢀ6), 126.8 (Cꢀ1),
127.8 (Cꢀ4), 128.5, 128.6, 128.7 (ArꢀCH), 135.4 (ArꢀC), 145.6 (Cꢀ2), 154.6 (C=O); IR: (film)/cmꢀ1; 3431, 3203,
3031, 1703, 1611, 1593, 1538, 1454, 1423, 1381, 1349, 1299, 1272, 1215, 1189, 1121, 1078, 1054, 1025, 969,
882, 866, 800, 736; HRMS (ESI+) Found (MNa+): 345.9859; C14H1281BrNNaO3 requires 345.9874. Found
(MNa+): 343.9881; C14H1279BrNNaO3 requires 343.9893.
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tertꢀButyl (5ꢀbromoꢀ2ꢀhydroxyphenyl)carbamate 12. To a solution of 2ꢀaminoꢀ4ꢀbromophenol (2.0 g, 11
mmol) and Amberlyst® 15 (0.8 g, 40% w/w) in EtOH (30 mL) under an atmosphere of nitrogen was added diꢀ
tertꢀbutyl dicarbonate (4.89 mL, 21 mmol). The mixture was heated to 45 °C and stirred for 2 h. The solution
was filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (4:1
hexanes, ethyl acetate) to give the title compound 12 (2.5 g, 83%) as a brown solid. RF = 0.62 (2:1 hexane, ethyl
acetate); M.P.: 143–145 °C; δH (500 MHz; CDCl3; Me4Si) 1.52 (9H, s, (CH3)3), 6.77 (1H, d, J = 8.6 Hz, 3ꢀH),
6.86 (1H, br s, OH), 7.06 (1H, dd, J = 8.6, 2.4 Hz, 4ꢀH), 7.51 (1H, d, J = 2.4 Hz, 6ꢀH), 7.97 (1H, br s, NH); δC
(125 MHz; CDCl3) 28.3 (C(CH3)3), 82.4 (C(CH3)3),112.6 (Cꢀ5), 118.9 (Cꢀ3), 123.4 (Cꢀ6), 127.3 (Cꢀ1), 127.4
(Cꢀ4), 145.6 (Cꢀ2), 154.4 (C=O); IR: (film)/cmꢀ1; 3388, 3257, 2978, 1689, 1594, 1522, 1455, 1419, 1392, 1366,
1352, 1306, 1277, 1252, 1227, 1193, 1151, 1123, 1056, 1028, 883, 857, 808, 766. 747; HRMS (ESI+) Found
(MNa+): 312.0023; C11H1481BrNNaO3 requires 312.0030. Found (MNa+): 310.0040; C11H1479BrNNaO3 requires
310.0049.
General Procedure for the Mitsunobu synthesis of aryl ethers
To a solution of alcohol 9 or 10 (3.54 mmol) in toluene (30 mL), under an atmosphere of nitrogen, was added
PPh3 (5.59 mmol) and resultant mixture was stirred for 10 min. A solution of phenol 11 or 12 (2.79 mmol) in
toluene (15 mL) was then added dropwise and the mixture was stirred at 0 °C for 20 min. DIAD (5.59 mmol)
was added, the solution was allowed to warm to room temperature and stirred for 3 days. Following this, the
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solvent was removed in vacuo. The crude product was purified by flash chromatography to give the aryl ether
13ꢀ15.
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(S)ꢀBenzyl (2′ꢀ(1ꢀ(benzyloxy)ꢀ3ꢀ((4′′ꢀmethoxybenzyl)oxy)propanꢀ2ꢀyl)oxy)ꢀ5′ꢀbromophenyl)carbamate 13.
Using the general procedure, alcohol 9 gave the title product 13 (1.48 g, 82%) as a brown oil: RF = 0.66 (2:1
hexanes, ethyl acetate); [α]D +0.47 (c = 0.21, CHCl3); δH (500 MHz; CDCl3; Me4Si) 3.56–3.66 (4H, m, 1ꢀCH2,
3ꢀCH2), 3.79 (3H, s, OMe), 4.18–4.21 (1H, m, 2ꢀH), 4.44 (2H, s, OCH2Ar), 4.51 (2H, s, OCH2Ph), 5.15 (2H, s,
OCH2Ph), 6.81–6.83 (3H, m, 3′′ꢀH, 3′ꢀH), 7.01 (1H, dd, J = 8.6, 2.4 Hz, 4′ꢀH), 7.16 (1H, d, J = 8.6 Hz, 2′′ꢀH),
7.28–7.44 (10 H, ArꢀH), 8.29 (1H, br s, NH), 8.36 (1H, br, s, 6′ꢀH); δC (125 MHz; CDCl3) 55.3 (4′′ꢀOCH3), 67.2
(OCH2Ph), 68.7 (Cꢀ3), 69.2 (Cꢀ1), 73.1 (OCH2Ar), 73.5 (OCH2Ph), 81.0 (Cꢀ2), 113.8 (Cꢀ3′′), 116.3 (Cꢀ5′),
119.9 (Cꢀ3′), 121.5 (Cꢀ6′), 125.2 (Cꢀ4′), 127.7 (ArꢀCH), 127.8 (ArꢀCH), 128.3 (ArꢀCH), 128.4 (ArꢀCH), 128.5
(ArꢀCH), 128.6 (ArꢀCH), 129.4 (Cꢀ2′′), 129.5 (Cꢀ1′′), 132.3 (Cꢀ2′), 136.2 (ArꢀC), 137.4 (ArꢀC), 145.2 (Cꢀ2′),
152.5 (C=O), 159.4 (Cꢀ4′′); IR: (film)/cmꢀ1; 3262, 3032, 2863, 1732, 1594, 1515, 1470, 1454, 1417, 1366,
1295, 1248, 1217, 1082, 1046, 906, 877, 821, 737, 697; HRMS (ESI+) Found (MNa+): 630.1297;
C32H3281BrNNaO6 requires 630.1291. Found (MNa+): 628.1312; C32H3279BrNNaO6 requires 628.1305.
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tertꢀButyl (S)ꢀ(2′ꢀ((1ꢀ(benzyloxy)ꢀ3ꢀ((4′′ꢀmethoxybenzyl)oxy)propanꢀ2ꢀyl)oxy)ꢀ5′ꢀbromophenyl)carbamate
14. Using the general procedure, alcohol 9 gave the title product 14 (1.27 g, 93%) as a brown oil: RF = 0.60 (2:1
hexanes, ethyl acetate); [α]D +0.51 (c = 0.19, CHCl3); δH (500 MHz; CDCl3; Me4Si) 1.49 (9H, s, (CH3)3), 3.58–
3.69 (4H, m, 1ꢀCH2, 3ꢀCH2), 3.80 (3H, s, OMe), 4.20–4.23 (1H, m, 2ꢀH), 4.51 (2H, s, OCH2Ar), 4.58 (2H, s,
OCH2Ph), 6.81 (1H, d, J = 8.6 Hz, 3′ꢀH), 6.86 (2H, d, J = 8.6 Hz, 3′′ꢀH), 6.98 (1H, dd, J = 8.6, 2.4 Hz, 4′ꢀH),
7.22 (2H, d, J = 8.6 Hz, 2′′ꢀH), 7.28–7.34 (5 H, ArꢀH), 8.01 (1H, br s, NH), 8.36 (1H, br, s, 6′ꢀH); δC (125
MHz; CDCl3) 28.4 (C(CH3)3), 55.3 (4′′ꢀOCH3), 68.6 (Cꢀ3), 69.1 (Cꢀ1), 73.1 (OCH2Ar), 73.5 (OCH2Ph), 80.6
(C(CH3)3), 80.8 (Cꢀ2), 113.9 (Cꢀ3′′), 116.2 (Cꢀ5′), 119.7 (Cꢀ3′), 121.5 (Cꢀ6′), 124.9 (Cꢀ4′), 127.7 (ArꢀCH), 127.8
(ArꢀCH), 128.5 (ArꢀCH), 129.4 (Cꢀ2′′), 129.6 (Cꢀ1′′), 132.7 (Cꢀ1′), 137.6 (ArꢀC), 145.3 (Cꢀ2′), 152.8 (C=O),
159.4 (Cꢀ4′′); IR: (film)/cmꢀ1; 3020, 2970, 1743, 1593, 1515, 1454, 1366, 1231, 1217, 1156, 906, 732; HRMS
(ESI+) Found (MNa+): 596.1423; C29H3481BrNNaO6 requires 596.1446. Found (MNa+): 594.1440;
C29H3479BrNNaO6 requires 594.1462.
tertꢀButyl
(R)ꢀ(5′ꢀbromoꢀ2′ꢀ((3ꢀ((4′′ꢀmethoxybenzyl)oxy)ꢀ1ꢀ((triisopropylsilyl)oxy)propanꢀ2ꢀ
yl)oxy)phenyl)carbamate 15. Using the general procedure, alcohol 10 gave the title compound 15 (2.71 g,
87%) as a brown oil: RF = 0.78 (2:1 hexanes, ethyl acetate); [α]D +1.72 (c = 0.29, CHCl3); δH (500 MHz;
CDCl3; Me4Si) 1.02 (18H, d, J = 6.0 Hz, Si(CH(CH3)2)3, 1.03–1.07 (3H, m, Si(CH(CH3)2)3, 1.50 (9H, s,
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(CH3)3), 3.63 (1H, dd, J = 10.4, 5.6 Hz, 3ꢀHa), 3.67 (1H, dd, J = 10.4, 4.4 Hz, 3ꢀHb), 3.79 (3H, s, OMe), 3.87
(1H, dd, J = 10.4, 4.8 Hz, 1ꢀHa), 3.92 (1H, dd, J = 10.4, 4.8 Hz, 1ꢀHb), 4.21–4.25 (1H, m, 2ꢀH), 4.52 (2H, s,
OCH2Ar), 6.84 (1H, d, J = 8.4 Hz, 3′ꢀH), 6.86 (2H, d, J = 8.8 Hz, 3′′ꢀH), 6.99 (1H, dd, J = 8.4, 2.4 Hz, 4′ꢀH),
7.23 (2H, d, J = 8.8 Hz, 2′′ꢀH), 7.66 (1H, br s, NH), 8.34 (1H, br, s, 6′ꢀH); δC (125 MHz; CDCl3) 11.9
(Si(CH(CH3)2)3), 17.9 (Si(CH(CH3)2)3, 28.3 (C(CH3)3), 55.4 (4′′ꢀOCH3), 62.5 (Cꢀ1), 68.3 (Cꢀ3), 73.1 (OCH2Ar),
80.5 (C(CH3)3), 81.3 (Cꢀ2), 113.9 (Cꢀ3′′), 115.2 (Cꢀ5′), 117.6 (Cꢀ3′), 121.1 (Cꢀ6′), 124.9 (Cꢀ4′), 129.4 (Cꢀ2′′),
129.7 (Cꢀ1′′), 131.8 (Cꢀ1′), 145.3 (Cꢀ2′), 152.5 (C=O), 159.9 (Cꢀ4′′); IR: (film)/cmꢀ1; 3434, 2941, 2866, 1729,
1592, 1513, 1462, 1416, 1391, 1367, 1302, 1230, 1154, 1126, 1049, 996, 954, 919, 881, 849, 803, 772, 751;
HRMS (ESI+) Found (MNa+): 662.2295; C31H4881BrNNaO6Si requires 662.2312. Found (MNa+): 660.2312;
C31H4879BrNNaO6Si requires 660.2326.
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General Procedure for removal of PMB group
To a stirred solution of ethers 13ꢀ15 (0.59 mmol) in a mixture of CH2Cl2 (20 mL) and water (20 mL) was added
DDQ (0.71 mmol) and the mixture stirred at room temperature for 18 h. The resulting solution was washed with
portions of sat. aq. NaHCO3 (40 mL) until the washings were colourless. The organic layer was dried (MgSO4)
and the solvent was removed in vacuo. The crude product was purified by flash chromatography to yield the
primary alcohols 16ꢀ18.
Benzyl (R)ꢀ(2′ꢀ((1ꢀ(benzyloxy)ꢀ3ꢀhydroxypropanꢀ2ꢀyl)oxy)ꢀ5′ꢀbromophenyl)carbamate 16. Using the
general procedure, ether 13 gave the title compound 16 (0.21 g, 85%) as a brown oil: RF = 0.47 (2:1 hexanes,
ethyl acetate); [α]D ꢀ5.26 (c = 0.27, CHCl3); δH (500 MHz; CDCl3; Me4Si) 2.01 (1H, br s, OH), 3.63 (1H, dd, J
= 10.6, 5.4 Hz, 1ꢀHa), 3.67 (1H, dd, J = 10.2, 4.4 Hz, 1ꢀHb), 3.85 (2H, d, J = 4.4 Hz, 3ꢀCH2), 4.19–4.25 (1H, m,
2ꢀH), 4.49 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.55 (1H, d, J = 12.2 Hz, OCHaHbPh), 5.16 (1H, d, J = 12.0 Hz,
OCHaHbPh), 5.19 (1H, d, J = 12.0 Hz, OCHaHbPh), 6.85 (1H, d, J = 8.6 Hz, 3′ꢀH), 7.06 (1H, dd, J = 8.6, 2.4
Hz, 4′ꢀH), 7.28–7.39 (10 H, ArꢀH), 8.04 (1H, br s, NH), 8.35 (1H, s, 6′ꢀH) ; δC (125 MHz; CDCl3) 62.4 (Cꢀ3),
67.2 (OCH2Ph), 68.9 (Cꢀ1), 73.7 (OCH2Ph), 81.2 (Cꢀ2), 116.3 (Cꢀ5′), 118.9 (Cꢀ3′), 122.0 (Cꢀ6′), 125.5 (Cꢀ4′),
127.8 (ArꢀCH), 127.9 (ArꢀCH), 128.4 (ArꢀCH), 128.5 (ArꢀCH), 128.6 (ArꢀCH), 128.7 (ArꢀCH), 131.7 (Cꢀ1′),
136.2 (ArꢀC), 137.4 (ArꢀC), 145.2 (Cꢀ2′), 152.3 (C=O); IR: (film)/cmꢀ1; 3427, 3032, 2931, 1728, 1594, 1520,
1472, 1454, 1415, 1368, 1293, 1252, 1214, 1043, 1027, 873, 799, 738.
HRMS (ESI+) Found (MNa+): 510.0733; C24H2481BrNNaO5 requires 510.0713. Found (MNa+): 508.0750;
C24H2479BrNNaO5 requires 508.0730.
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tertꢀButyl (R)ꢀ(2′ꢀ((1ꢀ(benzyloxy)ꢀ3ꢀhydroxypropanꢀ2ꢀyl)oxy)ꢀ5′ꢀbromophenyl)carbamate 17. Using the
general procedure, ether 14 gave the title compound 17 (0.26 g, 82%) as a brown oil: RF = 0.45 (2:1 hexanes,
ethyl acetate); [α]D +0.51 (c = 0.20, CHCl3); δH (500 MHz; CDCl3; Me4Si) 1.50 (9H, s, (CH3)3), 2.39 (1H, br s,
OH), 3.64 (1H, dd, J = 10.6, 4.2 Hz, 1ꢀHa), 3.68 (1H, dd, J = 10.2, 5.4 Hz, 1ꢀHb), 3.87 (2H, d, J = 4.4 Hz, 3ꢀ
CH2), 4.22–4.25 (1H, m, 2ꢀH), 4.56 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.62 (1H, d, J = 12.2 Hz, OCHaHbPh),
6.83 (1H, d, J = 8.6 Hz, 3′ꢀH), 7.02 (1H, dd, J = 8.6, 2.4 Hz, 4′ꢀH), 7.30–7.36 (5 H, ArꢀH), 7.77 (1H, br s, NH),
8.31 (1H, br, s, 6′ꢀH); δC (125 MHz; CDCl3) 28.3 (C(CH3)3), 62.4 (Cꢀ3), 69.0 (Cꢀ1), 73.6 (OCH2Ph), 80.9
(C(CH3)3), 81.2 (Cꢀ2), 115.8 (Cꢀ5′), 118.4 (Cꢀ3′), 121.9 (Cꢀ6′), 125.1 (Cꢀ4′), 127.8 (ArꢀCH), 128.0 (ArꢀCH),
128.6 (ArꢀCH), 132.2 (Cꢀ1′), 137.7 (ArꢀC), 145.2 (Cꢀ2′), 152.8 (C=O); IR: (film)/cmꢀ1; 3433, 2978, 2932,
1724, 1592, 1516, 1454, 1414, 1392, 1367, 1295, 1232, 1201, 1152, 1102, 1048, 1026, 917, 848, 735; HRMS
(ESI+) Found (MNa+): 476.0867; C21H2681BrNNaO5 requires 476.0869. Found (MNa+): 474.0884;
C21H2679BrNNaO5 requires 474.0887.
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tertꢀButyl (R)ꢀ(5′ꢀbromoꢀ2′ꢀ((3ꢀhydroxyꢀ1ꢀ((triisopropylsilyl)oxy)propanꢀ2ꢀyl)oxy)phenyl)carbamate 18.
Using the general procedure, ether 15 gave the title compound 18 (0.39 g, 89%) as a brown oil: RF = 0.67
(2:1hexanes, ethyl acetate); [α]D +0.33 (c = 0.30, CHCl3); δH (500 MHz; CDCl3; Me4Si) 1.04 (18 H, d, J = 6.0
Hz, Si(CH(CH3)2)3, 1.07–1.13 (3H, m, Si(CH(CH3)2)3, 1.50 (9H, s, (CH3)3), 2.37 (1H, t, J = 6.4 Hz, OH), 3.91
(1H, dd, J = 10.4, 4.4 Hz, 1ꢀHa), 3.94 (1H, dd, J = 10.4, 5.8 Hz, 1ꢀHb), 3.96 (2H, d, J = 6.4 Hz, 3ꢀCH2), 4.29–
4.33 (1H, m, 2ꢀH), 6.83 (1H, d, J = 8.6 Hz, 3′ꢀH), 7.04 (1H, dd, J = 8.6, 2.4 Hz, 4′ꢀH), 7.33 (1H, br s, NH), 8.28
(1H, br, s, 6′ꢀH); δC (125 MHz; CDCl3) 11.9 (Si(CH(CH3)2)3), 17.9 (Si(CH(CH3)2)3, 28.4 (C(CH3)3), 62.5 (Cꢀ3),
63.2 (Cꢀ1), 80.5 (C(CH3)3), 80.7 (Cꢀ2), 114.9 (Cꢀ5′), 116.0 (Cꢀ3′), 121.8 (Cꢀ6′), 124.9 (Cꢀ4′), 131.3 (Cꢀ1′), 145.0
(Cꢀ2′), 152.5 (C=O); IR: (film)/cmꢀ1; 3426, 2942, 2866, 1731, 1593, 1518, 1464, 1461, 1392, 1367, 1232, 1203,
1156, 1050, 919, 881, 850, 733; HRMS (ESI+) Found (MNa+): 542.1716; C23H4081BrNNaO5Si requires
542.1734. Found (MNa+): 540.1734; C23H4079BrNNaO5Si requires 540.1751.
General Procedure for the synthesis of benzomorpholine aminols
To a stirred solution of alcohol 16ꢀ18 (0.18 mmol) in CH2Cl2 (15 mL) was added DMP (0.28 mmol) and stirred
at room temperature for 2 h. Sat. aq. Na2S2O5 solution (10 mL) was added followed by sat. aq. NaHCO3 solution
(10 mL). The organic layer was separated and the aqueous layer further extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried (MgSO4) and the solvent removed in vacuo.
The crude product was purified by flash chromatography to yield the aminols 19ꢀ21 as separate, but undefined,
diastereomers.
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Benzyl
(2S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀhydroxyꢀ2,3ꢀdihydroꢀ4Hꢀbenzo[b][1,4]oxazineꢀ4ꢀ
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carboxylate 19a and 19b. Using the general procedure, alcohol 16 gave the title products 19a (0.039 g, 45%)
as a white solid and 19b (0.037 g, 41%) as a yellow oil. 19a: RF = 0.72 (2:1 hexanes, ethyl acetate) ; [α]D ꢀ5.39
(c = 0.46, CHCl3); M.P.: 130–133 °C; δH (500 MHz; CDCl3; Me4Si) 3.28 (1H, d, J = 4.4 Hz, OH), 3.85 (2H, d,
J = 5.4 Hz, 9ꢀCH2), 4.11 (1H, td, J = 5.4, 1.2 Hz, 2ꢀH), 4.63 (2H, s, OCH2Ph), 5.28 (1H, d, J = 12.2 Hz,
OCHaHbPh), 5.32 (1H, d, J = 12.2 Hz, OCHaHbPh), 6.04 (1H, d, J = 4.4, 1.2 Hz, 3ꢀH), 6.82 (1H, d, J = 8.6 Hz,
8ꢀH), 7.10 (1H, dd, J = 8.6, 2.4 Hz, 7ꢀH), 7.27–7.43 (10 H, ArꢀH), 8.24 (1H, br, s, 5ꢀH); δC (125 MHz; CDCl3)
68.6 (OCH2Ph), 68.8 (Cꢀ9), 73.8 (Cꢀ3), 73.9 (OCH2Ph), 74.9 (Cꢀ2), 113.8 (Cꢀ6), 118.4 (Cꢀ8), 124.7 (Cꢀ5), 125.4
(Cꢀ4a), 127.3 (Cꢀ7), 127.9 (ArꢀCH), 128.1 (ArꢀCH), 128.3 (ArꢀCH), 128.5 (ArꢀCH), 128.6 (ArꢀCH), 128.8 (Arꢀ
CH), 135.1 (ArꢀC), 137.3 (ArꢀC), 144.1 (Cꢀ8a), 151.7 (C=O); IR: (film)/cmꢀ1; 3431, 2926, 1935, 1711, 1599,
1489, 1391, 1302, 1257, 1211, 1144, 1050, 1026, 910, 871, 809, 739; HRMS (ESI+) Found (MNa+): 508.0559;
C24H2281BrNNaO5 requires 508.0557. Found (MNa+): 506.0577; C24H2279BrNNaO5 requires 506.0574. 19b: RF
= 0.66 (2:1 hexanes, ethyl acetate); [α]D ꢀ21.13 (c = 1.11, CHCl3); δH (500 MHz; CDCl3; Me4Si) 3.25 (1H, d, J
= 4.6 Hz, OH), 3.55 (1H, dd, J = 10.4, 5.2 Hz, 9ꢀHa), 3.65 (1H, dd, J = 10.4, 5.2 Hz, 9ꢀHb), 4.28 (1H, q, J = 5.2
Hz, 2ꢀH), 4.49 (2H, s, OCH2Ph), 5.24 (1H, d, J = 12.2 Hz, OCHaHbPh), 5.30 (1H, d, J = 12.2 Hz, OCHaHbPh),
5.97 (1H, t, J = 4.6 Hz, 3ꢀH), 6.83 (1H, d, J = 8.6 Hz, 8ꢀH), 7.11 (1H, dd, J = 8.6, 2.4 Hz, 7ꢀH), 7.27–7.41 (10
H, ArꢀH), 8.03 (1H, br, s, 5ꢀH); δC (125 MHz; CDCl3) 68.2 (Cꢀ9), 68.6 (OCH2Ph), 73.7 (OCH2Ph), 75.0 (Cꢀ3),
76.8 (Cꢀ2), 113.7 (Cꢀ6), 118.9 (Cꢀ8), 125.4 (Cꢀ5), 125.7 (Cꢀ4a), 127.6 (Cꢀ7), 127.7 (ArꢀCH), 127.9 (ArꢀCH),
128.3 (ArꢀCH), 128.5 (ArꢀCH), 128.7 (ArꢀCH), 128.8 (ArꢀCH), 135.3 (ArꢀC), 137.5 (ArꢀC), 144.5 (Cꢀ8a), 151.9
(C=O); IR: (film)/cmꢀ1; 3431, 2926, 1935, 1711, 1599, 1489, 1391, 1302, 1257, 1211, 1144, 1050, 1026, 910,
871, 809, 739; HRMS (ESI+) Found (MNa+): 508.0563; C24H2281BrNNaO5 requires 508.0557. Found (MNa+):
506.0583; C24H2279BrNNaO5 requires 506.0574.
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tertꢀButyl
(2S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀhydroxyꢀ2,3ꢀdihydroꢀ4Hꢀbenzo[b][1,4]oxazineꢀ4ꢀ
carboxylate 20a and 20b Using the general procedure, alcohol 17 gave the title products 20a (0.12 g, 42%) as a
white solid and 20b (0.16 g, 58%) as a yellow oil. 20a: RF = 0.77 (2:1 hexanes, ethyl acetate); [α]D +3.79 (c =
0.58, CHCl3); M.P.: 133–135 °C; δH (500 MHz; CDCl3; Me4Si) 1.58 (9H, s, (CH3)3), 3.20 (1H, d, J = 4.8 Hz,
OH), 3.86 (2H, d, J = 5.2 Hz, 9ꢀCH2), 4.11 (1H, td, J = 5.2, 1.2 Hz, 2ꢀH), 4.64 (2H, s, OCH2Ph), 5.97 (1H, dd, J
= 4.8, 1.2 Hz, 3ꢀH), 6.82 (1H, d, J = 8.6 Hz, 8ꢀH), 7.08 (1H, dd, J = 8.6, 2.2 Hz, 7ꢀH), 7.30–7.37 (5 H, ArꢀH),
8.17 (1H, br, s, 5ꢀH); δC (125 MHz; CDCl3) 28.3 (C(CH3)3), 69.0 (Cꢀ9), 73.5 (Cꢀ3), 73.9 (OCH2Ph), 75.0 (Cꢀ2),
83.4 (C(CH3)3), 113.4 (Cꢀ6), 118.4 (Cꢀ8), 124.8 (Cꢀ5), 125.2 (Cꢀ4a), 126.8 (Cꢀ7), 127.9 (ArꢀCH), 128.0 (Arꢀ
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CH), 128.6 (ArꢀCH), 137.4 (ArꢀC), 144.0 (Cꢀ8a), 151.5 (C=O); IR: (film)/cmꢀ1; 3460, 2977, 2933, 1702, 1598,
1486, 1454, 1369, 1326, 1255, 1156, 1121, 1018, 855, 811, 740; HRMS (ESI+) Found (MNa+): 474.0704;
C21H2481BrNNaO5 requires 474.0712. Found (MNa+): 472.0719; C21H2479BrNNaO5 requires 472.0730. 20b: RF
= 0.60 (2:1 hexanes, ethyl acetate); [α]D ꢀ34.16 (c = 0.52, CHCl3); δH (500 MHz; CDCl3; Me4Si) 1.54 (9H, s,
(CH3)3), 3.34 (1H, br, s, OH), 3.58 (1H, dd, J = 10.4, 5.4 Hz, 9ꢀHa), 3.67 (1H, dd, J = 10.4, 5.4 Hz, 9ꢀHb), 4.26
(1H, m, 2ꢀH), 4.55 (2H, s, OCH2, Bn), 5.89 (1H, t, J = 3.6 Hz, 3ꢀH), 6.83 (1H, d, J = 8.6 Hz, 8ꢀH), 7.08 (1H, dd,
J = 8.6, 2.4 Hz, 7ꢀH), 7.28ꢀ7.37 (5 H, ArꢀH, Bn), 7.93 (1H, d, J = 2.4 Hz, 5ꢀH); δC (125 MHz; CDCl3) 28.2
(C(CH3)3), 68.5 (Cꢀ9), 73.7 (OCH2, Bn), 74.9 (Cꢀ3), 77.1 (Cꢀ2), 83.3 (C(CH3)3), 113.6 (Cꢀ6), 118.7 (Cꢀ8), 125.6
(Cꢀ5), 126.4 (Cꢀ4a), 127.1 (Cꢀ7), 127.7 (ArꢀC, Bn), 127.9 (ArꢀC, Bn), 128.5 (ArꢀC, Bn), 137.5 (ArꢀC, Bn),
144.7 (Cꢀ8a), 152.5 (C=O); IR: (film)/cmꢀ1; 3460, 2977, 2933, 1702, 1598, 1486, 1454, 1369, 1326, 1255,
1156, 1121, 1018, 855, 811, 740; HRMS (ESI+) Found (MNa+): 474.0707; C21H2481BrNNaO5 requires
474.0712. Found (MNa+): 472.0725; C21H2479BrNNaO5 requires 472.0730.
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tertꢀButyl
(2S)ꢀ6ꢀbromoꢀ3ꢀhydroxyꢀ2ꢀ(((triisopropylsilyl)oxy)methyl)ꢀ2,3ꢀdihydroꢀ4Hꢀ
Using the general procedure, alcohol 18 gave the title
benzo[b][1,4]oxazineꢀ4ꢀcarboxylate 21a and 21b
.
products 21a (0.82 g, 55%) as a colourless oil and 21b (0.15 g, 45%) as a pale yellow oil. 21a: RF = 0.84 (2:1
hexanes, ethyl acetate); [α]D +7.03 (c = 0.24, CHCl3); δH (500 MHz; CDCl3; Me4Si) 1.09 (18 H, d, J = 4.8 Hz,
Si(CH(CH3)2)3, 1.12–1.14 (3H, m, Si(CH(CH3)2)3, 1.58 (9H, s, (CH3)3), 3.45 (1H, br, s, OH), 3.99 (1H, ddd, J =
5.6, 4.2, 1.4 Hz, 2ꢀH), 4.08 (1H, dd, J = 10.4, 4.2 Hz, 9ꢀHa), 4.12 (1H, dd, J = 10.4, 5.6 Hz, 9ꢀHb), 6.06 (1H, dd,
J = 4.4, 1.4 Hz, 3ꢀH), 6.78 (1H, d, J = 8.6 Hz, 8ꢀH), 7.08 (1H, dd, J = 8.6, 2.4 Hz, 7ꢀH), 8.20 (1H, br, s, 5ꢀH); δC
(125 MHz; CDCl3) 11.8 (Si(CH(CH3)2)3), 17.9 (Si(CH(CH3)2)3, 28.3 (C(CH3)3), 62.7 (Cꢀ9), 73.4 (Cꢀ3), 75.6 (Cꢀ
2), 83.0 (C(CH3)3), 113.2 (Cꢀ6), 118.2 (Cꢀ8), 125.1 (Cꢀ5), 125.2 (Cꢀ4a), 126.8 (Cꢀ7), 144.2 (Cꢀ8a), 151.3
(C=O); IR: (film)/cmꢀ1; 3447, 2943, 2867, 1719, 1486, 1465, 1369, 1255, 1155, 1123, 1058, 908, 882, 806, 735;
HRMS (ESI+) Found (MNa+): 540.1567; C23H3881BrNNaO5Si requires 540.1578. Found (MNa+): 538.1577;
C23H3879BrNNaO5Si requires 538.1595. 21b: RF = 0.83 (2:1 hexanes, ethyl acetate); [α]D ꢀ28.95 (c = 0.23,
CHCl3); δH (500 MHz; CDCl3; Me4Si) 1.04 (18 H, d, J = 4.8 Hz, Si(CH(CH3)2)3, 1.07–1.10 (3H, m,
Si(CH(CH3)2)3, 1.57 (9H, s, (CH3)3), 3.30 (1H, d, J = 4.4 Hz, OH), 3.74 (1H, dd, J = 10.4, 6.8 Hz, 9ꢀHa), 3.88
(1H, dd, J = 10.4, 4.4 Hz, 9ꢀHb), 4.18ꢀ4.23 (1H, ddd, J = 6.8, 4.4, 1.0 Hz, 2ꢀH), 5.96 (1H, dd, J = 4.4, 1.0 Hz, 3ꢀ
H), 6.79 (1H, d, J = 8.6 Hz, 8ꢀH), 7.07 (1H, dd, J = 8.6, 2.4 Hz, 7ꢀH), 8.03 (1H, br, s, 5ꢀH); δC (125 MHz;
CDCl3) 11.8 (Si(CH(CH3)2)3), 17.9 (Si(CH(CH3)2)3, 28.2 (C(CH3)3), 62.1 (Cꢀ9), 74.1 (Cꢀ3), 78.1 (Cꢀ2), 83.2
(C(CH3)3), 113.3 (Cꢀ6), 118.5 (Cꢀ8), 125.0 (Cꢀ5), 126.1 (Cꢀ4a), 126.8 (Cꢀ7), 144.3 (Cꢀ8a), 152.2 (C=O); IR:
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(film)/cmꢀ1; 3447, 2943, 2867, 1719, 1486, 1465, 1369, 1255, 1155, 1123, 1058, 908, 882, 806, 735; HRMS
(ESI+) Found (MNa+): 540.1566; C23H3881BrNNaO5Si requires 540.1578. Found (MNa+): 538.1582;
C23H3879BrNNaO5Si requires 538.1595.
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General Procedure for the aryl addition to benzomorpholine aminols
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To a stirred solution of aminol 19ꢀ21 (0.050 mmol) in AcOH (5 mL) was added conc. H2SO4 (8 equiv.) and the
resultant solution was stirred at room temperature for 5 min. Aromatic nucleophile (1.2 equiv.) was added and
the solution was stirred for 2 h. Sat. aq. NaHCO3 solution (3 mL) was added. The layers were separated and the
aqueous layer further extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried (MgSO4)
and the solvent removed in vacuo. The crude product was purified by flash chromatography to yield the 3ꢀ
arylbenzomorpholines 22ꢀ32.
((2R,3S)ꢀ6ꢀBromoꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀyl)methanol
22
and ((2R,3S)ꢀ6ꢀbromoꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀyl)methyl
acetate 23. Using the general procedure, aminol 21 gave the title products 22 (0.043 g, 31%) as a yellow oil and
23 (0.10 g, 69%) as yellow oil. 22: RF = 0.52 (2:1 hexanes, ethyl acetate); [α]D ꢀ32.33 (c = 0.16, CHCl3); δH
(500 MHz; CDCl3; Me4Si) 3.58 (1H, dd, J = 12.6, 5.4 Hz, 9ꢀHa), 3.67 (1H, dd, J = 12.6, 3.0 Hz, 9ꢀHb), 3.79
(6H, s, 2′, 6′ꢀMeO), 3.83 (3H, s, 4′ꢀMeO), 4.41 (1H, ddd, J = 8.6, 5.4, 3.0 Hz, 2ꢀH), 4.82 (1H, d, J = 8.6 Hz, 3ꢀ
H), 6.16 (2H, s, 3′, 5′ꢀH), 6.77 (1H, d, J = 2.2 Hz, 5ꢀH), 6.80 (1H, d, J = 8.6 Hz, 8ꢀH), 6.81 (1H, dd, J = 8.6, 2.2
Hz, 7ꢀH); δC (125 MHz; CDCl3) 48.2 (Cꢀ3), 55.4 (4′ꢀMeO), 55.9 (2′, 6′ꢀMeO), 63.2 (Cꢀ9), 75.6 (Cꢀ2), 91.3 (Cꢀ
3′, Cꢀ5′), 105.6 (Cꢀ1′), 113.3 (Cꢀ6), 118.3 (Cꢀ5), 119.6 (Cꢀ8), 121.6 (Cꢀ7), 135.2 (Cꢀ4a), 143.9 (Cꢀ8a), 159.7 (Cꢀ
2′, Cꢀ6′), 161.6 (Cꢀ4′); IR: (film)/cmꢀ1; 3374, 2925, 2856, 1737, 1593, 1496, 1457, 1364, 1228, 1153, 1123,
1203, 1034, 814, 739; HRMS (ESI+) Found (MNa+): 434.0407; C18H2081BrNNaO5 requires 434.0399. Found
(MNa+): 432.0420; C18H2079BrNNaO5 requires 432.0417. 23: RF = 0.79 (2:1 hexanes, ethyl acetate); [α]D ꢀ22.18
(c = 0.73, CHCl3); δH (500 MHz; CDCl3; Me4Si) 2.02 (3H, s, OAc), 3.77 (6H, s, 2′, 6′ꢀMeO), 3.82 (3H, s, 4′ꢀ
MeO), 4.09 (1H, dd, J = 10.4, 5.2 Hz, 9ꢀHa), 4.13 (1H, dd, J = 10.4, 3.2 Hz, 9ꢀHb), 4.64 (1H, ddd, J = 8.6, 5.2,
3.2 Hz, 2ꢀH), 4.84 (1H, d, J = 8.6 Hz, 3ꢀH), 6.13 (2H, s, 3′ꢀH and 5′ꢀH), 6.78 (1H, d, J = 2.2 Hz, 5ꢀH), 6.79 (1H,
d, J = 8.6 Hz, 8ꢀH), 6.80 (1H, dd, J = 8.6, 2.2 Hz, 7ꢀH); δC (125 MHz; CDCl3) 20.9 (OCH3, OAc), 48.2 (Cꢀ3),
55.4 (4′ꢀMeO), 55.8 (2′, 6′ꢀMeO), 64.2 (Cꢀ9), 73.3 (Cꢀ2), 91.2 (Cꢀ3′, Cꢀ5′), 105.3 (Cꢀ1′), 113.5 (Cꢀ6), 118.3 (Cꢀ
5), 119.5 (Cꢀ8), 121.6 (Cꢀ7), 135.2 (Cꢀ4a), 143.9 (Cꢀ8a), 159.8 (Cꢀ2′, Cꢀ6′), 161.7 (Cꢀ4′), 170.8 (CO, OAc); IR:
(film)/cmꢀ1; 3370, 2939, 1740, 1592, 1495, 1457, 1367, 1227, 1208, 1153, 1125, 1037, 952, 900, 813; HRMS
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(ESI+) Found (MNa+): 476.0500; C20H2281BrNNaO6 requires 476.0505. Found (MNa+): 474.0516;
C20H2279BrNNaO6 requires 474.0523.
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Benzyl
(2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ2,3ꢀdihydroꢀ4Hꢀ
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benzo[b][1,4]oxazineꢀ4ꢀcarboxylate 24. Using the general procedure, aminol 19 gave title product 24 (0.031 g,
97%) as a yellow oil. RF = 0.66 (2:1 hexanes, ethyl acetate); [α]D +29.36 (c = 0.53, CHCl3); δH (500 MHz;
CDCl3; Me4Si) 3.44 (6H, s, 2′, 6′ꢀMeO), 3.59 (1H, dd, J = 11.6, 3.0 Hz, 9ꢀHa), 3.63 (1H, dd, J = 11.6, 6.0 Hz, 9ꢀ
Hb), 3.79 (3H, s, 4′ꢀMeO), 4.22 (1H, ddd, J = 9.6, 6.0, 3.0 Hz, 2ꢀH), 4.51 (1H, d, J = 12.0 Hz, OCHaHbPh), 4.58
(1H, d, J = 12.0 Hz, OCHaHbPh), 5.04 (1H, d, J = 12.2 Hz, OCHaHbPh), 5.06 (1H, d, J = 12.2 Hz, OCHaHbPh),
5.70 (1H, d, J = 9.6 Hz, 3ꢀH), 6.00 (2H, s, 3′ꢀH, 5′ꢀH), 6.88 (1H, d, J = 8.6 Hz, 8ꢀH), 7.10–7.12 (3H, m, 7ꢀH and
ArꢀH), 7.26–7.31 (8 H, ArꢀH), 7.96 (1H, d, J = 2.2 Hz, 5ꢀH); δC (125 MHz; CDCl3) 52.8 (Cꢀ3), 55.2 (2′, 6′ꢀ
MeO), 55.3 (4′ꢀMeO), 67.6 (OCH2Ph), 69.9 (Cꢀ9), 73.5 (OCH2Ph), 79.8 (Cꢀ2), 90.5 (Cꢀ3′, Cꢀ5′), 107.1 (Cꢀ1′),
113.9 (Cꢀ6), 118.7 (Cꢀ8), 126.3 (Cꢀ5), 127.6 (Cꢀ7), 127.7, 127.9, 128.0, 128.3, 128.4 (ArꢀCH), 132.9 (Cꢀ4a),
136.0 (ArꢀC), 138.0 (ArꢀC), 148.6 (Cꢀ8a), 153.5 (C=O), 159.1 (Cꢀ2′, Cꢀ6′), 161.0 (Cꢀ4′); IR: (film)/cmꢀ1; 2936,
1706, 1591, 1488, 1454, 1416, 1388, 1326, 1299, 1253, 1223, 1204, 1150, 1057, 1026, 951, 907, 866, 811, 735;
HRMS (ESI+) Found (MNa+): 658.1242; C33H3281BrNNaO7 requires 658.1240. Found (MNa+): 656.1262;
C33H3279BrNNaO7 requires 656.1254.
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(2R,3S)ꢀ2ꢀ((Benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazine 25. Using the general procedure, aminol 20 gave the title product 25 (0.026 g, 97%) as a
yellow oil. RF = 0.62 (2:1 hexanes, ethyl acetate); [α]D ꢀ70.36 (c = 0.39, CHCl3); δH (500 MHz; CDCl3; Me4Si)
3.53 (1H, dd, J = 10.4, 5.0 Hz, 9ꢀHa), 3.56 (1H, dd, J = 10.4, 3.2 Hz, 9ꢀHb), 3.72 (6H, s, 2′, 6′ꢀMeO), 3.82 (3H,
s, 4′ꢀMeO), 4.46 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.49 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.65 (1H, ddd, J =
8.4, 5.0, 3.2 Hz, 2ꢀH), 4.85 (1H, d, J = 8.4 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀH), 6.77 (1H, dd, J = 8.8, 2.2 Hz, 7ꢀ
H).6.78 (1H, d, J = 2.0 Hz, 5ꢀH), 6.80 (1H, d, J = 8.8 Hz, 8ꢀH), 7.21–7.29 (5H, ArꢀH); δC (125 MHz; CDCl3)
48.4 (Cꢀ3), 55.4 (4′ꢀMeO), 55.7 (2′ꢀMeO and 6′ꢀMeO), 70.4 (Cꢀ9), 73.4 (OCH2Ph), 75.1 (Cꢀ2), 91.0 (Cꢀ3′, Cꢀ5′),
106.2 (Cꢀ1′), 113.0 (Cꢀ6), 118.4 (Cꢀ5), 119.2 (Cꢀ8), 121.4 (Cꢀ7), 127.4, 127.5, 128.2 (ArꢀCH), 135.4 (Cꢀ4a),
138.3 (ArꢀC), 144.1 (Cꢀ8a), 159.8 (Cꢀ2′, Cꢀ6′), 161.4 (Cꢀ4′); IR: (film)/cmꢀ1; 3397, 2936, 2835, 1591, 1494,
1454, 1419, 1333, 1274, 1225, 1204, 1152, 1126, 1060, 1037, 953, 906, 813, 735; HRMS (ESI+) Found
(MNa+): 524.0865; C25H2681BrNNaO5 requires 524.0870. Found (MNa+): 522.0881; C25H2679BrNNaO5 requires
522.0887.
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Benzyl
(2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀ(3′,4′ꢀdimethoxyphenyl)ꢀ2,3ꢀdihydroꢀ4Hꢀ
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benzo[b][1,4]oxazineꢀ4ꢀcarboxylate 26. Using the general procedure, aminol 19 gave title product 26 (0.022 g,
61%) as a yellow oil. RF = 0.77 (2:1 hexanes, ethyl acetate); [α]D +19.33 (c = 0.15, CHCl3); δH (500 MHz;
CDCl3; Me4Si) 3.50 (1H, dd, J = 10.2, 7.3 Hz, 9ꢀHa), 3.64 (1H, dd, J = 10.2, 5.6 Hz, 9ꢀHb), 3.68 (3H, s, 3′ꢀ
MeO), 3.81 (3H, s, 4′ꢀMeO), 4.45 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.49 (1H, d, J = 12.2 Hz, OCHaHbPh),
4.74 (1H, ddd, J = 7.3, 5.6, 2.4 Hz, 2ꢀH), 5.24 (1H, d, J = 12.0 Hz, OCHaHbPh), 5.26 (1H, d, J = 12.0 Hz,
OCHaHbPh), 5.75 (1H, d, J = 2.4 Hz, 3ꢀH), 6.71 (1H, d, J = 8.4 Hz, 5′ꢀH), 6.72 (1H, d, J = 2.0 Hz, 2′ꢀH), 6.75
(1H, d, J = 8.8 Hz, 8ꢀH), 6.77 (1H, dd, J = 8.4, 2.0 Hz, 6′ꢀH), 7.07 (1H, dd, J = 8.8, 2.2 Hz, 7ꢀH), 7.27–7.34 (10
H, ArꢀH), 8.11 (1H, br, s, 5ꢀH); δC (125 MHz; CDCl3) 53.6 (Cꢀ3), 55.7 (4′ꢀMeO), 55.8 (3′ꢀMeO), 68.3
(OCH2Ph), 69.0 (Cꢀ9), 73.7 (OCH2Ph), 76.0 (Cꢀ2), 110.1 (Cꢀ5′), 111.1 (Cꢀ2′), 113.3 (Cꢀ6), 118.6 (Cꢀ8), 119.0
(Cꢀ6′), 125.7 (Cꢀ5), 127.5 (Cꢀ7), 127.8, 127.9, 128.1, 128.4, 128.5, 128.6 (ArꢀCH), 130.3 (Cꢀ1′), 130.4 (Cꢀ4a),
135.0 (ArꢀC), 137.5 (ArꢀC), 144.1 (Cꢀ8a), 148.5 (Cꢀ4′), 148.9 (Cꢀ3′), 153.6 (C=O); IR: (film)/cmꢀ1; 2929, 2860,
1714, 1596, 1517, 1489, 1454, 1417, 1389, 1208, 1142, 1027, 862, 807, 751; HRMS (ESI+) Found (MNa+):
628.1104; C32H3081BrNNaO6 requires 628.1134. Found (MNa+): 626.1128; C32H3079BrNNaO6 requires
626.1149.
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(2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀ(4′ꢀhydroxyꢀ3′ꢀmethoxyphenyl)ꢀ2,3ꢀdihydroꢀ4Hꢀ
benzo[b][1,4]oxazineꢀ4ꢀcarboxylate 27. Using the general procedure, aminol 19 gave the title product 27
(0.023 g, 56%) as a yellow oil. RF = 0.48 (2:1 hexanes, ethyl acetate); [α]D +23.68 (c = 0.46, CHCl3); δH (500
MHz; CDCl3; Me4Si) 3.49 (1H, dd, J = 10.2, 7.4 Hz, 9ꢀHa), 3.64 (1H, dd, J = 10.2, 5.4 Hz, 9ꢀHb), 3.67 (3H, s,
3′ꢀMeO), 4.45 (1H, d, J = 12.0 Hz, OCHaHbPh), 4.47 (1H, d, J = 12.0 Hz, OCHaHbPh), 4.72 (1H, ddd, J = 7.4,
5.4, 2.0 Hz, 2ꢀH), 5.23 (1H, d, J = 12.2 Hz, OCHaHbPh), 5.26 (1H, d, J = 12.2 Hz, OCHaHbPh), 5.52(1H, br s,
OH), 5.72 (1H, d, J = 2.0 Hz, 3ꢀH), 6.68 (1H, dd, J = 8.4, 2.0 Hz, 6′ꢀH), 6.73 (1H, d, J = 2.0 Hz, 2′ꢀH), 6.74 (1H,
d, J = 8.6 Hz, 8ꢀH), 6.76 (1H, d, J = 8.4 Hz, 5′ꢀH), 7.07 (1H, dd, J = 8.6, 2.4 Hz, 7ꢀH), 7.26–7.33 (10 H, ArꢀH),
8.10 (1H, s, 5ꢀH); δC (125 MHz; CDCl3) 53.6 (Cꢀ3), 55.8 (3′ꢀMeO), 68.3 (OCH2Ph), 69.0 (Cꢀ9), 73.8
(OCH2Ph), 76.1 (Cꢀ2), 109.5 (Cꢀ6′), 113.0 (Cꢀ6), 114.5 (Cꢀ2′), 118.6 (Cꢀ8), 119.8 (Cꢀ5′), 125.8 (Cꢀ5), 127.6 (Cꢀ
7), 127.8, 127.9, 128.1, 128.4, 128.5, 128.6 (ArꢀCH), 129.8 (Cꢀ1′), 129.8 (Cꢀ4a), 135.9 (ArꢀC), 137.3 (ArꢀC),
144.2 (Cꢀ8a), 145.2 (Cꢀ4′), 146.5 (Cꢀ3′), 153.6 (C=O); IR: (film)/cmꢀ1; 3451, 2979, 2916, 1736, 1722, 1514,
1484, 1366, 1299, 1256, 1229, 1216, 1140, 1090, 1042, 906, 807, 740; HRMS (ESI+) Found (MNa+):
614.0971; C31H2881BrNNaO6 requires 614.0977. Found (MNa+): 612.0988; C31H2879BrNNaO6 requires
612.0992.
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Benzyl
(2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀ(2′,4′ꢀdihydroxyphenyl)ꢀ2,3ꢀdihydroꢀ4Hꢀ
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benzo[b][1,4]oxazineꢀ4ꢀcarboxylate 28. Using the general procedure, aminol 19 gave the title product 28
(0.018 g, 39%) as a yellow oil. RF = 0.37 (2:1 nꢀhexanes, ethyl acetate); [α]D ꢀ0.53 (c = 0.19, CHCl3); δH (500
MHz; CDCl3; Me4Si) 3.43 (1H, dd, J = 10.2, 7.6 Hz, 9ꢀHa), 3.65 (1H, dd, J = 10.2, 5.4 Hz, 9ꢀHb), 4.42 (1H, d, J
= 11.8 Hz, OCHaHbPh), 4.46 (1H, d, J = 11.8 Hz, OCHaHbPh), 4.84 (1H, ddd, J = 7.6, 5.4, 1.8 Hz, 2ꢀH), 5.02
(2H, br s, OH), 5.22 (1H, d, J = 12.0 Hz, OCHaHbPh), 5.34 (1H, d, J = 12.0 Hz, OCHaHbPh), 5.75 (1H, d, J =
1.8 Hz, 3ꢀH), 6.21 (1H, dd, J = 8.6, 2.4 Hz, 5′ꢀH), 6.38 (1H, d, J = 2.4 Hz, 3′ꢀH), 6.81 (1H, d, J = 8.8 Hz, 8ꢀH),
7.06 (1H, d, J = 8.6 Hz, 6′ꢀH), 7.09 (1H, dd, J = 8.8, 2.4 Hz, 7ꢀH), 7.26–7.36 (10 H, ArꢀH), 7.56 (1H, s, 5ꢀH); δC
(125 MHz; CDCl3) 47.8 (Cꢀ3), 69.2 (Cꢀ9), 69.4 (OCH2Ph), 73.7 (OCH2Ph), 75.6 (Cꢀ2), 104.2 (Cꢀ3′), 107.6 (Cꢀ
5′), 112.6 (Cꢀ6), 115.9 (Cꢀ1′), 118.6 (Cꢀ8), 126.7 (Cꢀ5), 127.8 (ArꢀCH), 127.9 (Cꢀ6′), 128.3 (Cꢀ7), 128.4, 128.5,
128.7, 128.8 (ArꢀCH), 130.4 (Cꢀ4a), 134.8 (ArꢀC), 137.8 (ArꢀC), 144.0 (Cꢀ8a), 152.8 (C=O), 156.9 (Cꢀ4′),
157.0 (Cꢀ3′); IR: (film)/cmꢀ1; 3352, 2924, 2849, 1685, 1604, 1489, 1396, 1303, 1259, 1147, 960, 740, 697.
HRMS (ESI+) Found (MNa+): 600.0817; C30H2681BrNNaO6 requires 600.0820. Found (MNa+): 598.0834;
C30H2679BrNNaO6 requires 598.0836.
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Benzyl
(2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀ(3′,4′ꢀdihydroxyphenyl)ꢀ2,3ꢀdihydroꢀ4Hꢀ
benzo[b][1,4]oxazineꢀ4ꢀcarboxylate 29. Using the general procedure, aminol 19 gave the title product 29
(0.013 g, 36%) as a yellow oil. RF = 0.34 (2:1 nꢀhexanes, ethyl acetate); [α]D +19.36 (c = 0.25, CHCl3); δH (500
MHz; CDCl3; Me4Si) 3.48 (1H, dd, J = 9.8, 7.4 Hz, 9ꢀHa), 3.61 (1H, dd, J = 9.8, 5.4 Hz, 9ꢀHb), 4.43 (1H, d, J =
12.0 Hz, OCHaHbPh), 4.47 (1H, d, J = 12.0 Hz, OCHaHbPh), 4.67 (1H, ddd, J = 7.4, 5.4, 2.2 Hz, 2ꢀH), 5.20
(1H, d, J = 12.4 Hz, OCHaHbPh), 5.26 (1H, d, J = 12.4 Hz, OCHaHbPh), 5.29 (2H, br s, OH), 5.67 (1H, d, J =
2.2 Hz, 3ꢀH), 6.66 (1H, dd, J = 8.6, 2.0 Hz, 6′ꢀH), 6.68 (1H, d, J = 2.0 Hz, 2′ꢀH), 6.71 (1H, d, J = 8.6 Hz, 5′ꢀH),
6.73 (1H, d, J = 8.8 Hz, 8ꢀH), 7.09 (1H, dd, J = 8.8, 2.0 Hz, 7ꢀH), 7.27–7.33 (10 H, ArꢀH), 8.11 (1H, s, 5ꢀH); δC
(125 MHz; CDCl3) 53.6 (Cꢀ3), 68.3 (OCH2Ph), 68.9 (Cꢀ9), 73.7 (OCH2Ph), 76.0 (Cꢀ2), 113.0 (Cꢀ6), 113.9 (Cꢀ
2′), 115.6 (Cꢀ5′), 118.6 (Cꢀ8), 119.5 (Cꢀ6′), 125.7 (Cꢀ5), 127.5 (Cꢀ7), 127.8, 127.9, 128.1, 128.4, 128.5 and
128.6 (ArꢀCH), 130.8 (Cꢀ4a), 130.8 (Cꢀ1′), 135.6 (ArꢀC), 137.5 (ArꢀC), 143.2 (Cꢀ4′), 143.5 (Cꢀ3′), 144.1 (Cꢀ8a),
153.6 (C=O); IR: (film)/cmꢀ1; 3351, 2923, 1712, 1598, 1521, 1490, 1454, 1390, 1256, 1207, 1144, 1045, 908,
869, 810, 744; HRMS (ESI+) Found (MNa+): 600.0813; C30H2681BrNNaO6 requires 600.0820. Found (MNa+):
598.0827; C30H2679BrNNaO6 requires 598.0836.
(2R,3S)ꢀ2ꢀ((Benzyloxy)methyl)ꢀ6ꢀbromoꢀ3ꢀ(2′,4′ꢀdimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazine
30. Using the general procedure, aminol 20 gave the title product 30 (0.012 g, 94%) as a yellow oil; RF = 0.65
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(2:1 hexanes, ethyl acetate); [α]D ꢀ14.19 (c = 0.16, CHCl3); δH (500 MHz; CDCl3; Me4Si) 3.57 (1H, dd, J =
10.4, 4.2 Hz, 9ꢀHa), 3.60 (1H, dd, J = 10.4, 5.6 Hz, 9ꢀHb), 3.77 (6H, s, 2′, 6′ꢀMeO), 3.80 (3H, s, 4′ꢀMeO), 4.34 –
4.38 (1H, m, 2ꢀH), 4.50 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.53 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.69 (1H, d, J
= 6.6 Hz, 3ꢀH), 6.44 (1H, d, J = 2.2 Hz, 3′ꢀH), 6.46 (1H, dd, J = 8.2, 2.2 Hz, 5′ꢀH), 6.71 (1H, d, J = 2.4 Hz, 5ꢀ
H), 6.73 (1H, d, J = 8.8, 2.4 Hz, 7ꢀH), 6.75 (1H, d, J = 8.8 Hz, 8ꢀH), 7.22 (1H, dd, J = 8.2 Hz, 6′ꢀH); δC (125
MHz; CDCl3) 48.1 (Cꢀ3), 55.4 (4′ꢀMeO), 55.5 (2′ꢀMeO), 70.0 (Cꢀ9), 77.0 (Cꢀ2), 98.6 (Cꢀ3′), 104.6 (Cꢀ5′), 113.2
(Cꢀ6), 117.1 (Cꢀ5), 118.2 (Cꢀ8), 120.1 (Cꢀ1′), 121.0 (Cꢀ7), 128.3 (Cꢀ6′), 134.9 (Cꢀ4a), 142.0 (Cꢀ8a), 158.1 (Cꢀ
2′), 160.2 (Cꢀ4′), 127.6, 128.1, 128.3 (ArꢀCH); IR: (film)/cmꢀ1; 3374, 2923, 1738, 1604, 1495, 1454, 1417,
1366, 1259, 1231, 1206, 1090, 1069, 1019, 795, 736; HRMS (ESI+) Found (MNa+): 494.0780;
C24H2481BrNNaO4 requires 494.0764. Found (MNa+): 492.0793; C24H2479BrNNaO4 requires 492.0781.
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((2R,3S)ꢀ6ꢀBromoꢀ3ꢀ(2′,4′ꢀdimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀyl)methyl acetate 31
Using the general procedure, aminol 21 gave the title product 31 (0.027 g, 50%) as a yellow oil. RF = 0.44 (2:1
hexanes, ethyl acetate); [α]D ꢀ12.40 (c = 0.52, CHCl3); δH (500 MHz; CDCl3; Me4Si) 2.04 (3H, s, OAc), 3.80
(3H, s, 2′ꢀMeO), 3.81 (3H, s, 4′ꢀMeO), 4.11 (1H, dd, J = 12.0, 3.6 Hz, 9ꢀHa), 4.16 (1H, dd, J = 12.0, 6.0 Hz, 9ꢀ
Hb), 4.27 (1H, ddd, J = 6.8, 6.0, 3.6 Hz, 2ꢀH), 4.68 (1H, d, J = 6.8 Hz, 3ꢀH), 6.46 (1H, d, J = 2.2 Hz, 3′ꢀH), 6.49
(1H, dd, J = 8.2, 2.2 Hz, 5′ꢀH), 6.74 (1H, d, J = 2.4 Hz, 5ꢀH). 6.76 (1H, d, J = 8.8 Hz, 8ꢀH), 6.76 (1H, d, J = 8.8,
2.4 Hz, 7ꢀH), 7.22 (1H, dd, J = 8.2 Hz, 6′ꢀH); δC (125 MHz; CDCl3) 20.8 (OCH3, OAc), 47.9 (Cꢀ3), 55.4 (4′ꢀ
MeO), 55.5 (2′ꢀMeO), 63.8 (Cꢀ9), 76.3 (Cꢀ2), 98.6 (Cꢀ3′), 104.9 (Cꢀ5′), 113.4 (Cꢀ6), 117.2 (Cꢀ5), 118.1 (Cꢀ8),
119.1 (Cꢀ1′), 121.2 (Cꢀ7), 128.7 (Cꢀ6′), 135.0 (Cꢀ4a), 142.0 (Cꢀ8a), 158.1 (Cꢀ2′), 160.9 (Cꢀ4′), 170.8 (CO,
OAc); IR: (film)/cmꢀ1; 3377, 2965, 2835, 1741, 1607, 1496, 1465, 1234, 1207, 1159, 1125, 1039, 907, 797, 731;
HRMS (ESI+) Found (MNa+): 446.0399; C19H2081BrNNaO5 requires 446.0399. Found (MNa+): 444.0416;
C19H2079BrNNaO5 requires 444.0417.
(2R,3S)ꢀ2ꢀ((Benzyloxy)methyl)ꢀ6ꢀbromoꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazine. To a stirred solution of aryl benzomorpholine 25 (0.04 g, 0.080 mmol) in acetone (12
mL) was added K2CO3 (0.11 g, 0.80 mmol) and the resultant solution was stirred at room temperature for 10
min. Methyl iodide (0.05 mL, 0.80 mmol) was added and the resultant mixture was stirred vigorously at 40 °C
for 3 days. Water (10 mL) was added, the layers were separated and the aqueous layer further extracted with
ethyl acetate (3 × 10 mL). The combined organic extracts were dried (MgSO4) and the solvent removed in
vacuo. The crude product was purified by flash chromatography (9:1 hexanes, ethyl acetate) to yield the title
product (0.03 g, 73%) as a yellow oil. RF = 0.71 (2:1 hexanes, ethyl acetate); [α]D +5.38 (c = 0.37, CHCl3); δH
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(500 MHz; CDCl3; Me4Si) 2.55 (3H, s, NꢀCH3), 3.53 (1H, dd, J = 10.4, 5.0 Hz, 9ꢀHa), 3.56 (1H, dd, J = 10.4,
3.2 Hz, 9ꢀHb), 3.65 (6H, s, 2′ꢀMeO, 6′ꢀMeO), 3.82 (3H, s, 4′ꢀMeO), 4.48 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.52
(1H, d, J = 12.2 Hz, OCHaHbPh), 4.60 (1H, ddd, J = 8.4, 5.0, 3.2 Hz, 2ꢀH), 4.94 (1H, d, J = 8.4 Hz, 3ꢀH), 6.10
(2H, s, 3′, 5′ꢀH), 6.66 (1H, dd, J = 8.8, 2.2 Hz, 7ꢀH), 6.67 (1H, d, J = 2.2 Hz, 5ꢀH), 6.73 (1H, d, J = 8.8 Hz, 8ꢀH),
7.23–7.29 (5H, ArꢀH); δC (125 MHz; CDCl3) 34.2 (NꢀCH3), 53.4 (Cꢀ3), 55.3 (4′ꢀMeO), 55.7 (2′ꢀMeO and 6′ꢀ
MeO), 70.8 (Cꢀ9), 73.3 (OCH2Ph), 75.8 (Cꢀ2), 90.8 (Cꢀ3′ and Cꢀ5′), 105.7 (Cꢀ1′), 113.5 (Cꢀ5), 114.1 (Cꢀ6),
117.0 (Cꢀ8), 118.3 (Cꢀ7), 127.4, 127.8, 128.2 (ArꢀCH), 138.3 (ArꢀC), 139.2 (Cꢀ4a), 144.3 (Cꢀ8a), 160.1 (Cꢀ2′,
Cꢀ6′), 161.2 (Cꢀ4′); IR: (film)/cmꢀ1; 2936, 2846, 1731, 1592, 1508, 1454, 1436, 1418, 1364, 1325, 1229, 1204,
1152, 1119, 1062, 1037, 992, 953, 815, 737; HRMS (ESI+) Found (MNa+): 538.1004; C26H2881BrNNaO5
requires 538.1027. Found (MNa+): 536.1023; C26H2879BrNNaO5 requires 536.1043.
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(2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ4ꢀmethylꢀ3ꢀ(2,4,6ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazineꢀ6ꢀcarbaldehyde 32. To a solution of (2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ6ꢀbromoꢀ4ꢀmethylꢀ
3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazine (0.027 g, 0.052 mmol) in THF (3 mL) at ꢀ78
°C under an atmosphere of nitrogen was added tꢀbutyllithium (1.6 M in pentane, 0.23 mL, 0.31 mmol). After 30
sec, dry DMF (0.08 mL, 1.04 mmol) was added and the mixture stirred at ꢀ78 °C for 30 min, allowed to warm to
room temperature and stirred for a further 1 h. Sat. aq. NH4Cl (3 mL) was added and the aqueous mixture
extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were dried (MgSO4) and the solvent
removed in vacuo. The crude product was purified by flash chromatography (4:1 hexanes, ethyl acetate) to yield
the title product 33 (0.024 g, 99%) as a yellow oil. RF = 0.39 (2:1 hexanes, ethyl acetate); [α]D +1.58 (c = 0.57,
CHCl3); δH (500 MHz; CDCl3; Me4Si) 2.65 (3H, s, NꢀCH3), 3.56 (1H, dd, J = 10.4, 5.4 Hz, 9ꢀHa), 3.60 (1H, dd,
J = 10.4, 3.2 Hz, 9ꢀHb), 3.65 (6H, s, 2′ꢀMeO, 6′ꢀMeO), 3.82 (3H, s, 4′ꢀMeO), 4.49 (1H, d, J = 12.2 Hz,
OCHaHbPh), 4.52 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.75 (1H, ddd, J = 8.4, 5.4, 3.2 Hz, 2ꢀH), 4.97 (1H, d, J =
8.4 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀH), 6.98 (1H, d, J = 8.2 Hz, 8ꢀH), 7.12 (1H, d, J = 2.0 Hz, 5ꢀH), 7.14 (1H, dd, J
= 8.2, 2.0 Hz, 7ꢀH). 7.24–7.29 (5H, ArꢀH), 9.81 (1H, CHO); δC (125 MHz; CDCl3) 34.5 (NꢀCH3), 53.0 (Cꢀ3),
55.3 (4′ꢀMeO), 55.7 (2′, 6′ꢀMeO), 70.7 (Cꢀ9), 73.4 (OCH2Ph), 76.2 (Cꢀ2), 90.9 (Cꢀ3′, Cꢀ5′), 105.4 (Cꢀ1′), 109.6
(Cꢀ5), 115.9 (Cꢀ8), 122.0 (Cꢀ7), 127.5, 127.8, 128.2 (ArꢀCH), 131.0 (Cꢀ6), 138.1 (Cꢀ4a), 138.2 (ArꢀC), 150.1
(Cꢀ8a), 160.1 (Cꢀ2′, Cꢀ6′), 161.2 (Cꢀ4′), 191.9 (CHO); IR: (film)/cmꢀ1; 2937, 2860, 1736, 1592, 1509, 1455,
1365, 1229, 1203, 1154, 1120, 1032, 812, 736; HRMS (ESI+) Found (MNa+): 486.1879; C27H29NNaO6 requires
486.1887.
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(E)ꢀ3′′ꢀ((2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
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benzo[b][1,4]oxazinꢀ6ꢀyl)acrylate. To a solution of aldehyde 32 (0.028 g, 0.060 mmol) in dry toluene (6 mL)
under an atmosphere of nitrogen at room temperature, was added triphenylcarbethoxymethylenephosphorane
(0.032 g, 0.091 mmol). The solution was heated at reflux for 4 days and the solvent was removed in vacuo. The
crude product was purified by flash chromatography (4:1 hexanes, ethyl acetate) to yield the title product (0.018
g, 57%) as a yellow oil. RF = 0.5 (2:1 hexanes, ethyl acetate); [α]D +3.13 (c = 0.16, CHCl3); δH (500 MHz;
CDCl3; Me4Si) 1.33 (3H, t, J = 7.2 Hz, OCH2CH3), 2.60 (3H, s, NꢀCH3), 3.55 (1H, dd, J = 10.4, 5.2 Hz, 9ꢀHa),
3.58 (1H, dd, J = 10.4, 3.2 Hz, 9ꢀHb), 3.65 (6H, s, 2′ꢀMeO, 6′ꢀMeO), 3.82 (3H, s, 4′ꢀMeO), 4.24 (2H, q, J = 7.2
Hz, OCH2CH3), 4.48 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.52 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.73 (1H, ddd, J
= 8.4, 5.2, 3.2 Hz, 2ꢀH), 4.93 (1H, d, J = 8.4 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀH), 6.28 (1H, d, J = 15.8 Hz, 2′′ꢀH),
6.76 (1H, d, J = 2.0 Hz, 5ꢀH), 6.81 (1H, dd, J = 8.2, 2.0 Hz, 7ꢀH). 6.87 (1H, d, J = 8.2 Hz, 8ꢀH), 7.22–7.30 (5H,
ArꢀH), 7.63 (1H, d, J = 15.8 Hz, 3′′ꢀH); δC (125 MHz; CDCl3) 14.4 (OCH2CH3), 34.4 (NꢀCH3), 53.4 (Cꢀ3), 55.3
(4′ꢀMeO), 55.7 (2′, 6′ꢀMeO), 70.7 (Cꢀ9), 73.3 (OCH2Ph), 76.0 (Cꢀ2), 90.9 (Cꢀ3′, Cꢀ5′), 106.5 (Cꢀ1′), 110.1 (Cꢀ
5), 114.7 (Cꢀ2′′), 116.1 (Cꢀ8), 117.9 (Cꢀ7), 127.4 (Cꢀ6), 127.5, 128.0, 128.2 (ArꢀCH), 138.0 (Cꢀ4a), 138.3 (Arꢀ
C), 145.6 (Cꢀ3′′), 146.7 (Cꢀ8a), 160.1 (Cꢀ2′, Cꢀ6′), 161.2 (Cꢀ4′), 167.8 (CO); IR: (film)/cmꢀ1; 2970, 2919, 1741,
1600, 1453, 1365, 1231, 1217, 1203, 1121, 906, 800. HRMS (ESI+) Found (MNa+): 556.2319; C31H35NNaO7
requires 556.2306.
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(E)ꢀ3′′ꢀ((2R,3S)ꢀ2ꢀ((Benzyloxy)methyl)ꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazinꢀ6ꢀyl)propꢀ2′′ꢀenꢀ1′′ꢀol 33. To a solution of ethyl (E)ꢀ3′′ꢀ((2R,3S)ꢀ2ꢀ((benzyloxy)methyl)ꢀ
4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ6ꢀyl)acrylate (0.018 g, 0.034
mmol) in CH2Cl2 (4 mL) at ꢀ78 °C, under an atmosphere of nitrogen, was added DIBALꢀH (1.0 M in
cyclohexane, 0.11 mL, 0.10 mmol) and the resultant solution was stirred at ꢀ78 °C for 1 h. A saturated solution
of Rochelle salt (3 mL) was added and the aqueous mixture extracted with ethyl acetate (3 × 3 mL). The
combined organic extracts were washed with brine (3 mL), dried (MgSO4) and the solvent removed in vacuo.
The crude product was purified by flash chromatography (1:1 hexanes, ethyl acetate) to yield the title product
33 (0.015 g, 91%) as a yellow oil. RF = 0.16 (2:1 hexanes, ethyl acetate); [α]D +2.27 (c = 0.26, CHCl3); δH (500
MHz; CDCl3; Me4Si) 2.60 (3H, s, NꢀCH3), 3.54 (1H, dd, J = 10.4, 5.0 Hz, 9ꢀHa), 3.58 (1H, dd, J = 10.4, 3.4 Hz,
9ꢀHb), 3.65 (6H, s, 2′, 6′ꢀMeO), 3.82 (3H, s, 4′ꢀMeO), 4.29 (2H, dd, J = 6.0, 1.2 Hz, 1′′ꢀH), 4.48 (1H, d, J =
12.0 Hz, OCHaHbPh), 4.52 (1H, d, J = 12.0 Hz, OCHaHbPh), 4.72 (1H, ddd, J = 8.0, 5.0, 3.4 Hz, 2ꢀH), 4.92
(1H, d, J = 8.0 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀH), 6.22 (1H, dt, J = 15.8, 6.0 Hz, 2′′ꢀH), 6.54 (1H, d, J = 15.8 Hz,
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3′′ꢀH), 6.66 (1H, dd, J = 8.2, 2.0 Hz, 7ꢀH), 6.67 (1H, d, J = 2.0 Hz, 5ꢀH), 6.84 (1H, d, J = 8.2 Hz, 8ꢀH), 7.23–
7.30 (5H, ArꢀH); δC (125 MHz; CDCl3) 34.5 (NꢀCH3), 53.6 (Cꢀ3), 55.3 (4′ꢀMeO), 55.7 (2′, 6′ꢀMeO), 64.2 (Cꢀ
1′′), 70.9 (Cꢀ9), 73.3 (OCH2Ph), 76.0 (Cꢀ2), 90.9 (Cꢀ3′, Cꢀ5′), 106.1 (Cꢀ1′), 109.2 (Cꢀ5), 115.3 (Cꢀ7), 116.0 (Cꢀ
8), 125.3 (Cꢀ2′′), 127.3, 127.5, 128.2 (ArꢀCH), 130.2 (Cꢀ6), 132.7 (Cꢀ3′′), 136.0 (Cꢀ4a), 138.5 (ArꢀC), 144.6 (Cꢀ
8a), 160.1 (Cꢀ2′, Cꢀ6′), 161.0 (Cꢀ4′); IR: (film)/cmꢀ1; 3419, 2928, 2856, 1727, 1605, 1512, 1420, 1322, 1228,
1205, 1152, 1118, 955, 814, 735; HRMS (ESI+) Found (MNa+): 514.2189; C29H33NNaO6 requires 514.2200.
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3′′ꢀ((2R,3S)ꢀ2ꢀ(Hydroxymethyl)ꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazinꢀ6ꢀyl)propanꢀ1′′ꢀol 34. To a solution of alcohol 33 (0.013 g, 0.027 mmol) in MeOH (3
mL) was added 10 % Pd/C (0.003 g, 20% w/w) and the mixture stirred under an atmosphere of hydrogen for 1
h. The mixture was filtered through Celite® washed with methanol (3 × 3 mL) and the solvent removed in
vacuo. The crude product was purified by flash chromatography (1:1 hexanes, ethyl acetate) to yield the title
product 34 (0.005 g, 51%) as a yellow oil. RF = 0.13 (1:2 hexanes, ethyl acetate); [α]D +4.55 (c = 0.02, CHCl3);
δH (500 MHz; CDCl3; Me4Si) 1.87–1.93 (2H, m, 2′′ꢀH), 2.57 (3H, s, NꢀCH3), 2.63 (2H, t, J = 7.6 Hz, 3′′ꢀH),
3.56 (1H, dd, J = 12.2, 5.6 Hz, 9ꢀHa), 3.63 (1H, dd, J = 12.2, 3.2 Hz, 9ꢀHb), 3.70 (2H, t, J = 6.4 Hz, 1′′ꢀH), 3.73
(6H, s, 2′, 6′ꢀMeO), 3.83 (3H, s, 4′ꢀMeO), 4.54 (1H, ddd, J = 8.6, 5.6, 3.2 Hz, 2ꢀH), 4.86 (1H, d, J = 8.6 Hz, 3ꢀ
H), 6.15 (2H, s, 3′, 5′ꢀH), 6.44 (1H, dd, J = 8.2, 2.0 Hz, 7ꢀH), 6.48 (1H, d, J = 2.0 Hz, 5ꢀH), 6.78 (1H, d, J = 8.2
Hz, 8ꢀH); δC (125 MHz; CDCl3) 32.2 (Cꢀ3′′), 34.3 (NꢀCH3), 34.6 (Cꢀ2′′), 53.4 (Cꢀ3), 55.3 (4′ꢀMeO), 55.9 (2′, 6′ꢀ
MeO), 62.6 (Cꢀ1′′), 63.7 (Cꢀ9), 76.1 (Cꢀ2), 91.1 (Cꢀ3′, Cꢀ5′), 105.5 (Cꢀ1′), 111.8 (Cꢀ5), 115.5 (Cꢀ8), 116.0 (Cꢀ7),
135.2 (Cꢀ6), 137.6 (Cꢀ4a), 142.5 (Cꢀ8a), 160.1 (Cꢀ2′, Cꢀ6′), 161.3 (Cꢀ4′); IR: (film)/cmꢀ1; 3405, 2929, 2846,
1736, 1603, 1591, 1514, 1457, 1416, 1362, 1229, 1152, 1122, 1041, 908, 815, 733; HRMS (ESI+) Found
(MNa+): 426.1880; C22H29NNaO6 requires 426.1887.
((2R,3S)ꢀ6ꢀBromoꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀ
yl)methyl acetate. To a stirred solution of aryl benzomorpholine 23 (0.041 g, 0.091 mmol) in acetone (15 mL)
was added K2CO3 (0.13 g, 0.91 mmol) and the resultant solution was stirred at room temperature for 10 min.
Methyl iodide (0.06 mL, 0.91 mmol) was added and the resultant mixture was stirred vigorously at 40 °C for 4
days. Water (10 mL) was added. The layers were separated and the aqueous layer further extracted with ethyl
acetate (3 × 10 mL). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo. The
crude product was purified by flash chromatography (9:1 hexanes, ethyl acetate) to yield the title product (0.033
g, 79%) as a yellow oil: RF = 0.68 (2:1 hexanes, ethyl acetate); [α]D +13.46 (c = 0.05, CHCl3); δH (500 MHz;
CDCl3; Me4Si) 2.05 (3H, s, OAc), 2.56 (3H, s, NꢀCH3), 3.71 (6H, s, 2′, 6′ꢀMeO), 3.82 (3H, s, 4′ꢀMeO), 4.08
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(1H, dd, J = 12.0, 3.4 Hz, 9ꢀHa), 4.12 (1H, dd, J = 12.0, 5.2 Hz, 9ꢀHb), 4.63 (1H, ddd, J = 8.6, 5.2, 3.4 Hz, 2ꢀH),
4.94 (1H, d, J = 8.6 Hz, 3ꢀH), 6.12 (2H, s, 3′, 5′ꢀH), 6.68 (1H, dd, J = 8.4, 2.4 Hz, 7ꢀH), 6.69 (1H, d, J = 2.4 Hz,
5ꢀH), 6.72 (1H, d, J = 8.4 Hz, 8ꢀH); δC (125 MHz; CDCl3) 20.7 (OCH3, OAc), 34.1 (NꢀCH3), 53.1 (Cꢀ3), 55.3
(4′ꢀMeO), 55.7 (2′, 6′ꢀMeO), 64.7 (Cꢀ9), 73.8 (Cꢀ2), 90.9 (Cꢀ3′, Cꢀ5′), 104.8 (Cꢀ1′), 113.7 (Cꢀ5), 114.4 (Cꢀ6),
117.1 (Cꢀ7), 118.4 (Cꢀ8), 138.9 (Cꢀ4a), 143.1 (Cꢀ8a), 160.1 (Cꢀ2′, Cꢀ6′), 161.5 (Cꢀ4′), 170.8 (CO); IR:
(film)/cmꢀ1; 3013, 2907, 1736, 1594, 1442, 1366, 1229, 1217, 1205, 1107, 897; HRMS (ESI+) Found (MNa+):
490.0668; C21H2481BrNNaO6 requires 490.0668. Found (MNa+): 488.0684; C21H2479BrNNaO6 requires
488.0679.
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((2R,3S)ꢀ6ꢀBromoꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀ
yl)methanol. To a stirred solution of ((2R,3S)ꢀ6ꢀbromoꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazinꢀ2ꢀyl)methyl acetate (0.032 g, 0.069 mmol) in MeOH (7 mL) was added NaOH (0.022 g,
0.55 mmol) and the resultant solution was stirred at room temperature for 2 h. The resulting solution was added
to water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extracts were dried
(MgSO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography (9:1
hexanes, ethyl acetate) to yield the title product (0.027 g, 93%) as a yellow oil: RF = 0.17 (2:1 hexanes, ethyl
acetate); [α]D +24.81 (c = 0.26, CHCl3); δH (500 MHz; CDCl3; Me4Si) 2.55 (3H, s, NꢀCH3), 3.58 (1H, dd, J =
12.0, 5.6 Hz, 9ꢀHa), 3.65 (1H, dd, J = 12.0, 3.4 Hz, 9ꢀHb), 3.73 (6H, s, 2′, 6′ꢀMeO), 3.83 (3H, s, 4′ꢀMeO), 4.41
(1H, ddd, J = 8.6, 5.6, 3.4 Hz, 2ꢀH), 4.92 (1H, d, J = 8.6 Hz, 3ꢀH), 6.14 (2H, s, 3′, 5′ꢀH), 6.67 (1H, dd, J = 8.4,
2.4 Hz, 7ꢀH), 6.68 (1H, d, J = 2.4 Hz, 5ꢀH), 6.71 (1H, d, J = 8.4 Hz, 8ꢀH); δC (125 MHz; CDCl3) 34.0 (NꢀCH3),
53.1 (Cꢀ3), 55.3 (4′ꢀMeO), 55.9 (2′, 6′ꢀMeO), 63.5 (Cꢀ9), 76.2 (Cꢀ2), 91.0 (Cꢀ3′, Cꢀ5′), 104.9 (Cꢀ1′), 113.6 (Cꢀ
5), 114.4 (Cꢀ6), 116.9 (Cꢀ8), 118.3 (Cꢀ7), 138.9 (Cꢀ4a), 143.3 (Cꢀ8a), 160.0 (Cꢀ2′, Cꢀ6′), 161.7 (Cꢀ4′); IR:
(film)/cmꢀ1; 3437, 2931, 2860, 1738, 1601, 1509, 1456, 1365, 1228, 1205, 1153, 1123, 1037, 814; HRMS
(ESI+) Found (MNa+): 448.0538; C19H2281BrNNaO5 requires 448.0555. Found (MNa+): 446.0559;
C19H2279BrNNaO5 requires 446.0574.
(2R,3S)ꢀ6ꢀBromoꢀ4ꢀmethylꢀ2ꢀ(((triisopropylsilyl)oxy)methyl)ꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ
2Hꢀbenzo[b][1,4]oxazine. To a solution of ((2R,3S)ꢀ6ꢀbromoꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀ
dihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀyl)methanol (0.025 g, 0.058 mmol) and 1H-imidazole (0.01 g, 0.12 mmol) in
DMF (5 mL) under an atmosphere of nitrogen at room temperature was added TIPSCl (0.015 mL, 0.071 mmol)
dropwise, and the mixture stirred for 2 days. Water (5 mL) was added and the aqueous mixture extracted with
diethyl ether (3 × 5 mL). The combined organic extracts were washed with water (3 × 5 mL) and brine (5 mL),
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dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by flash chromatography
(19:1 hexanes, ethyl acetate) to yield the title product (0.031 g, 91%) as a yellow oil: RF = 0.86 (2:1 nꢀhexanes,
ethyl acetate); [α]D +1.40 (c = 0.43, CHCl3); δH (500 MHz; CDCl3; Me4Si) ) 1.01 (18 H, d, J = 6.0 Hz,
Si(CH(CH3)2)3, 1.02–1.04 (3H, m, Si(CH(CH3)2)3, 2.58 (3H, s, NꢀCH3), 3.64 (6H, s, 2′, 6′ꢀMeO), 3.72 (1H, dd,
J = 10.6, 5.6 Hz, 9ꢀHa), 3.75 (1H, dd, J = 10.6, 3.2 Hz, 9ꢀHb), 3.81 (3H, s, 4′ꢀMeO), 4.38 (1H, ddd, J = 6.8, 5.6,
3.2 Hz, 2ꢀH), 4.97 (1H, d, J = 6.8 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀH), 6.64 (1H, d, J = 1.8 Hz, 5ꢀH), 6.64 (1H, dd, J
= 8.0, 1.8 Hz, 7ꢀH), 6.65 (1H, d, J = 8.0 Hz, 8ꢀH); δC (125 MHz; CDCl3) 12.0 (Si(CH(CH3)2)3), 17.9
(Si(CH(CH3)2)3, 34.6 (NꢀCH3), 52.9 (Cꢀ3), 55.3 (4′ꢀMeO), 55.5 (2′, 6′ꢀMeO), 64.1 (Cꢀ9), 77.1 (Cꢀ2), 90.7 (Cꢀ3′,
Cꢀ5′), 106.6 (Cꢀ1′), 113.0 (Cꢀ5), 113.7 (Cꢀ6), 116.6 (Cꢀ8), 118.0 (Cꢀ7), 139.3 (Cꢀ4a), 143.5 (Cꢀ8a), 160.0 (Cꢀ2′,
Cꢀ6′), 160.9 (Cꢀ4′); IR: (film)/cmꢀ1; 2925, 2856, 1739, 1601, 1509, 1464, 1418, 1367, 1230, 1203, 1154, 1123,
1060, 988, 880, 815; HRMS (ESI+) Found (MNa+): 604.1862; C28H4281BrNNaO5Si requires 604.1892. Found
(MNa+): 602.1889; C28H4279BrNNaO5Si requires 602.1908.
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(2R,3S)ꢀ4ꢀMethylꢀ2ꢀ(((triisopropylsilyl)oxy)methyl)ꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazineꢀ6ꢀcarbaldehyde
35.
To
a
solution
of
(2R,3S)ꢀ6ꢀbromoꢀ4ꢀmethylꢀ2ꢀ
(((triisopropylsilyl)oxy)methyl)ꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazine (0.018 g,
0.031 mmol) in THF (3 mL) at ꢀ78 °C under an atmosphere of nitrogen was added tꢀbutyllithium (1.6 M in
pentane, 0.14 mL, 0.19 mmol). After 30 sec, dry DMF (0.05 mL, 0.62 mmol) was added and the mixture stirred
at ꢀ78 °C for 30 min, allowed to warm to room temperature and stirred for a further 1 h. Sat. aq. NH4Cl (3 mL)
was added and the aqueous mixture extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were
dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography (4:1
hexanes, ethyl acetate) to yield the title product 35 (0.013 g, 83%) as a yellow oil: RF = 0.64 (2:1 hexanes, ethyl
acetate); [α]D +1.02 (c = 0.39, CHCl3); δH (500 MHz; CDCl3; Me4Si) ) 1.02 (18 H, d, J = 6.0 Hz,
Si(CH(CH3)2)3, 1.04–1.06 (3H, m, Si(CH(CH3)2)3, 2.68 (3H, s, NꢀCH3), 3.63 (6H, s, 2′, 6′ꢀMeO), 3.74 (1H, dd,
J = 10.6, 5.2 Hz, 9ꢀHa), 3.79 (1H, dd, J = 10.6, 3.2 Hz, 9ꢀHb), 3.81 (3H, s, 4′ꢀMeO), 4.53 (1H, ddd, J = 6.2, 5.2,
3.2 Hz, 2ꢀH), 5.03 (1H, d, J = 6.2 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀH), 6.91 (1H, d, J = 8.0 Hz, 7ꢀH), 7.09 (1H, d, J =
1.8 Hz, 7ꢀH), 7.12 (1H, d, J = 8.0, 1.8 Hz, 8ꢀH), 9.81 (1H, CHO); δC (125 MHz; CDCl3) 11.9 (Si(CH(CH3)2)3),
17.9 (Si(CH(CH3)2)3, 34.8 (NꢀCH3), 52.3 (Cꢀ3), 55.3 (4′ꢀMeO), 55.5 (2′, 6′ꢀMeO), 63.9 (Cꢀ9), 77.8 (Cꢀ2), 90.7
(Cꢀ3′, Cꢀ5′), 106.4 (Cꢀ1′), 109.3 (Cꢀ5), 115.3 (Cꢀ8), 122.0 (Cꢀ7), 130.8 (Cꢀ6), 138.3 (Cꢀ4a), 150.2 (Cꢀ8a), 160.0
(Cꢀ2′, Cꢀ6′), 161.1 (Cꢀ4′), 192.0 (CHO); IR: (film)/cmꢀ1; 2360, 1741, 1455, 1364, 1215, 904, 735; HRMS
(ESI+) Found (MNa+): 552.2738; C29H43NNaO6Si requires 552.2752.
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Ethyl
(E)ꢀ3′′ꢀ((2R,3S)ꢀ4ꢀmethylꢀ2ꢀ(((triisopropylsilyl)oxy)methyl)ꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀ
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dihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ6ꢀyl)acrylate. To a solution of aldehyde 35 (0.011 g, 0.021 mmol) in dry
toluene (5 mL) under an atmosphere of nitrogen at room temperature, was added
triphenylcarbethoxymethylenephosphorane (0.011 g, 0.032 mmol). The solution was heated at reflux for 4 days
and the solvent was removed in vacuo. The crude product was purified by flash chromatography (4:1 hexanes,
ethyl acetate) to yield the title compound (9 mg, 73%) as a green oil: RF = 0.4 (2:1 hexanes, ethyl acetate); [α]D
+2.08 (c = 0.22, CHCl3); δH (500 MHz; CDCl3; Me4Si) ) 1.01 (18 H, d, J = 4.4 Hz, Si(CH(CH3)2)3, 1.02–1.04
(3H, m, Si(CH(CH3)2)3, 1.33 (3H, t, J = 7.2 Hz, OCH2CH3), 2.63 (3H, s, NꢀCH3), 3.64 (6H, s, 2′, 6′ꢀMeO), 3.73
(1H, dd, J = 10.6, 5.2 Hz, 9ꢀHa), 3.78 (1H, dd, J = 10.6, 4.2 Hz, 9ꢀHb), 3.81 (3H, s, 4′ꢀMeO), 4.24 (2H, q, J =
7.2 Hz, OCH2CH3), 4.49 (1H, ddd, J = 6.6, 5.2, 4.2 Hz, 2ꢀH), 4.98 (1H, d, J = 6.6 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀ
H), 6.28 (1H, d, J = 15.6 Hz, 2′′ꢀH), 6.76 (1H, d, J = 8.0 Hz, 8ꢀH), 6.77 (1H, dd, J = 8.0, 1.2 Hz, 7ꢀH), 6.80
(1H, d, J = 1.2 Hz, 5ꢀH), 7.63 (1H, d, J = 15.6 Hz, 3′′ꢀH); δC (125 MHz; CDCl3) 11.9 (Si(CH(CH3)2)3), 14.5
(OCH2CH3), 17.9 (Si(CH(CH3)2)3, 34.7 (NꢀCH3), 52.8 (Cꢀ3), 55.3 (4′ꢀMeO), 55.6 (2′, 6′ꢀMeO), 64.1 (Cꢀ9), 77.6
(Cꢀ2), 90.8 (Cꢀ3′, Cꢀ5′), 106.5 (Cꢀ1′), 109.6 (Cꢀ8), 114.4 (Cꢀ2′′), 115.7 (Cꢀ7), 117.9 (Cꢀ5), 127.7 (Cꢀ6), 138.0
(Cꢀ4a), 146.1 (Cꢀ3′′), 146.9 (Cꢀ8a), 160.0 (Cꢀ2′, Cꢀ6′), 161.0 (Cꢀ4′), 167.7 (CO); IR: (film)/cmꢀ1; 2919, 2863,
1736, 1631, 1594, 1512, 1463, 1369, 1254, 1221, 1154, 1123, 1200, 1060, 1037, 814; HRMS (ESI+) Found
(MNa+): 622.3152; C33H49NNaO7Si requires 622.3171.
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(E)ꢀ3ꢀ((2R,3S)ꢀ4ꢀMethylꢀ2ꢀ(((triisopropylsilyl)oxy)methyl)ꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazinꢀ6ꢀyl)propꢀ2′′ꢀenꢀ1′′ꢀol 36. To
a
solution of ethyl (E)ꢀ3′′ꢀ((2R,3S)ꢀ4ꢀmethylꢀ2ꢀ
(((triisopropylsilyl)oxy)methyl)ꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ6ꢀyl)acrylate
(8.8 mg, 0.015 mmol) in CH2Cl2 (4 mL) at ꢀ78 °C under an atmosphere of nitrogen was added DIBALꢀH (1.0 M
in cyclohexane, 0.05 mL, 0.044 mmol) and the resultant solution was stirred at ꢀ78 °C for 1 h. A saturated
solution of Rochelle salt (3 mL) was added and the aqueous mixture extracted with ethyl acetate (3 × 3 mL).
The combined organic extracts were washed with brine (3 mL), dried (MgSO4) and the solvent removed in
vacuo. The crude product was purified by flash chromatography (1:1 hexanes, ethyl acetate) to yield the title
product 36 (5 mg, 65%) as a yellow oil: RF = 0.21 (2:1 hexanes, ethyl acetate); [α]D +2.08 (c = 0.05, CHCl3); δH
(500 MHz; CDCl3; Me4Si) ) 1.01 (18 H, d, J = 4.2 Hz, Si(CH(CH3)2)3, 1.02–1.04 (3H, m, Si(CH(CH3)2)3, 2.63
(3H, s, NꢀCH3), 3.64 (6H, s, 2′, 6′ꢀMeO), 3.73 (1H, dd, J = 10.4, 5.4 Hz, 9ꢀHa), 3.77 (1H, dd, J = 10.4, 4.4 Hz, 9ꢀ
Hb), 3.70 (3H, s, 4′ꢀMeO), 4.28 (2H, dd, J = 6.0, 1.2 Hz, 1′′ꢀH), 4.48 (1H, ddd, J = 6.8, 5.4, 4.4 Hz, 2ꢀH), 4.95
(1H, d, J = 6.8 Hz, 3ꢀH), 6.11 (2H, s, 3′, 5′ꢀH), 6.22 (1H, dt, J = 15.8, 6.0 Hz, 2′′ꢀH), 6.54 (1H, d, J = 15.8 Hz,
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3′′ꢀH), 6.63 (1H, dd, J = 8.0, 1.2 Hz, 7ꢀH), 6.64 (1H, d, J = 1.2 Hz, 5ꢀH), 6.76 (1H, d, J = 8.0 Hz, 8ꢀH); δC (125
MHz; CDCl3) 11.9 (Si(CH(CH3)2)3), 17.9 (Si(CH(CH3)2)3, 34.7 (NꢀCH3), 53.0 (Cꢀ3), 55.3 (4′ꢀMeO), 55.6 (2′,
6′ꢀMeO), 64.2 (Cꢀ9), 64.2 (Cꢀ1′′), 77.2 (Cꢀ2), 90.9 (Cꢀ3′, Cꢀ5′), 106.8 (Cꢀ1′), 108.5 (Cꢀ5), 115.0 (Cꢀ7), 115.5 (Cꢀ
8), 125.0 (Cꢀ2′′), 129.8 (Cꢀ6), 132.8 (Cꢀ3′′), 137.8 (Cꢀ4a), 144.8 (Cꢀ8a), 160.0 (Cꢀ2′, Cꢀ6′), 160.8 (Cꢀ4′); IR:
(film)/cmꢀ1; 3370, 2938, 2870, 1591, 1513, 1465, 1418, 1205, 1154, 1126, 911, 812, 730; HRMS (ESI+) Found
(MNa+): 580.3061; C31H47NNaO6Si requires 580.3065.
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(E)ꢀ3′′ꢀ((2R,3S)ꢀ2ꢀ(Hydroxymethyl)ꢀ4ꢀmethylꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀ
benzo[b][1,4]oxazinꢀ6ꢀyl)propꢀ2′′ꢀenꢀ1′′ꢀol 37. To a stirred solution of the silyl ether 36 (0.005 g, 0.01 mmol)
in THF (3 mL), at 0 °C was added 1M TBAF in THF (0.047 mL, 0.047 mmol) dropwise and mixture stirred for
3 h. Saturated aqueous NaHCO3 solution (3 mL) was added and the organic layer separated. The aqueous layer
was further extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were washed with brine (3
mL), dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by flash
chromatography (1:2 hexanes, ethyl acetate) to give the title compound 37 (2 mg, 57%) as a yellow gum, RF =
0.18 (1:2 hexanes, ethyl acetate); [α]D +6.25 (c = 0.02, CHCl3); δH (500 MHz; CDCl3; Me4Si) ) 2.60 (3H, s, Nꢀ
CH3), 3.58 (1H, dd, J = 11.6, 5.6 Hz, 9ꢀHa), 3.65 (1H, dd, J = 11.6, 3.2 Hz, 9ꢀHb), 3.73 (6H, s, 2′, 6′ꢀMeO), 3.83
(3H, s, 4′ꢀMeO), 4.29 (2H, dd, J = 6.0, 1.2 Hz, 1′′ꢀH), 4.54 (1H, ddd, J = 8.6, 5.6, 3.2 Hz, 2ꢀH), 4.89 (1H, d, J =
8.6 Hz, 3ꢀH), 6.15 (2H, s, 3′, 5′ꢀH), 6.24 (1H, dt, J = 15.8, 6.0 Hz, 2′′ꢀH), 6.54 (1H, d, J = 15.8 Hz, 3′′ꢀH), 6.66
(1H, dd, J = 8.0, 1.2 Hz, 7ꢀH), 6.68 (1H, d, J = 1.2 Hz, 5ꢀH), 6.81 (1H, d, J = 8.0 Hz, 8ꢀH); δC (125 MHz;
CDCl3) 34.2 (NꢀCH3), 53.2 (Cꢀ3), 55.2 (4′ꢀMeO), 55.9 (2′, 6′ꢀMeO), 63.8 (Cꢀ9), 64.3 (Cꢀ1′′), 76.2 (Cꢀ2), 91.1
(Cꢀ3′, Cꢀ5′), 105.4 (Cꢀ1′), 109.4 (Cꢀ5), 115.3 (Cꢀ7), 115.7 (Cꢀ8), 125.6 (Cꢀ2′′), 130.5 (Cꢀ6), 132.5 (Cꢀ3′′), 137.6
(Cꢀ4a), 142.3 (Cꢀ8a), 160.1 (Cꢀ2′, Cꢀ6′), 161.3 (Cꢀ4′); IR: (film)/cmꢀ1; 3423, 2954, 2922, 2853, 1738, 1603,
1514, 1462, 1366, 1260, 1217, 1228, 1091, 1017, 798; HRMS (ESI+) Found (MNa+): 424.1719; C22H27NNaO6
requires 424.1719.
((2R,3S)ꢀ3ꢀ(2′,4′ꢀDimethoxyphenyl)ꢀ6ꢀ((E)ꢀpropꢀ1′′ꢀenꢀ1′′ꢀyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀ
yl)methyl acetate 39. To a solution of bromo benzomorpholine 31 (0.023 g, 0.054 mmol) in DME (5 mL) was
added 2 M K2CO3 (0.18 mL, 0.36 mmol), transꢀpropꢀ1ꢀenylboronic acid 38 (0.009 g, 0.11 mmol) and Pd(PPh3)4
(0.013 g, 0.011mmol). The resultant mixture was stirred vigorously at 90 °C for 24 h. The mixture was cooled,
water (5 mL) added, the organic layer was separated and the aqueous phase further extracted with diethyl ether
(3 × 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (MgSO4),
and the solvent removed in vacuo. The crude product was purified by flash chromatography (3:1 hexanes, ethyl
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acetate) to give the title compound 39 (0.011 g, 51%) as a yellow oil: RF = 0.45 (2:1 hexanes, ethyl acetate); δH
(500 MHz; CDCl3; Me4Si) 1.83 (3H, dd, J = 6.6, 1.8 Hz, 3′′ꢀ H), 2.03 (3H, s, OAc), 3.80 (6H, s, 2′, 4′ꢀMeO),
4.13 (1H, dd, J = 12.0, 3.6 Hz, 9ꢀHa), 4.16 (1H, dd, J = 12.0, 6.0 Hz, 9ꢀHb), 4.30 (1H, ddd, J = 6.6, 6.0, 3.6 Hz,
2ꢀH), 4.69 (1H, d, J = 6.6 Hz, 3ꢀH), 6.04 (1H, dd, J = 15.8, 6.6 Hz, 2′′ꢀ H), 6.26 (1H, dd, J = 15.8, 1.8 Hz, 1′′ꢀ
H), 6.46 (1H, d, J = 2.4 Hz, 3′ꢀH), 6.49 (1H, dd, J = 8.2, 2.4 Hz, 5′ꢀH), 6.61 (1H, d, J = 2.2 Hz, 5ꢀH). 6.63 (1H,
dd, J = 8.6, 2.2 Hz, 7ꢀH), 6.80 (1H, d, J = 8.6 Hz, 8ꢀH), 7.26 (1H, d, J = 8.2 Hz, 6′ꢀH); δC (125 MHz; CDCl3)
18.3 (Cꢀ3′′), 20.9 (OCH3, OAc), 48.4 (Cꢀ3), 55.5 (2′, 4′ꢀMeO), 64.1 (Cꢀ9), 76.5 (Cꢀ2), 98.6 (Cꢀ3′), 104.9 (Cꢀ5′),
112.1 (Cꢀ5), 116.7 (Cꢀ8), 116.8 (Cꢀ7), 119.3 (Cꢀ1′), 123.5 (Cꢀ2′′), 128.8 (Cꢀ6′), 130.8 (Cꢀ1′′), 131.7 (Cꢀ6),
133.4 (Cꢀ4a), 142.2 (Cꢀ8a), 158.1 (Cꢀ2′), 160.9 (Cꢀ4′), 170.8 (CO, OAc); IR: (film)/cmꢀ1; 3384, 2933, 2846,
1739, 1607, 1466, 1366, 1229, 1208, 1127, 1041, 905, 803, 729; HRMS (ESI+) Found (MNa+): 406.1616;
C22H25NNaO5 requires 406.1625.
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((2R,3S)ꢀ3ꢀ(2′,4′ꢀDimethoxyphenyl)ꢀ6ꢀ((E)ꢀpropꢀ1′′ꢀenꢀ1′′ꢀyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀ
yl)methanol 40. To a stirred solution of acetate 39 (0.010 g, 0.026 mmol) in MeOH (4 mL) was added NaOH
(0.011 g, 0.26 mmol) and the resultant solution was stirred at room temperature for 2 h. The resulting solution
was added to water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic extracts were
dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by flash chromatography (9:1
hexanes, ethyl acetate) to yield the title product 40 (7 mg, 78%) as a yellow oil: RF = 0.28 (2:1 hexanes, ethyl
acetate); [α]D +5.68 (c = 0.09, CHCl3); δH (500 MHz; CDCl3; Me4Si) 1.83 (3H, dd, J = 6.6, 1.8 Hz, 3′′ꢀ H), 3.64
(1H, dd, J = 12.0, 5.6 Hz, 9ꢀHa), 3.68 (1H, dd, J = 12.0, 3.2 Hz, 9ꢀHb), 3.82 (3H, s, 4′ꢀMeO), 3.84 (3H, s, 2′ꢀ
MeO), 4.04 (1H, ddd, J = 8.0, 5.6, 3.2 Hz, 2ꢀH), 4.70 (1H, d, J = 8.0 Hz, 3ꢀH), 6.04 (1H, dd, J = 15.8, 6.6 Hz,
2′′ꢀ H), 6.26 (1H, dd, J = 15.8, 1.8 Hz, 1′′ꢀ H), 6.49 (1H, d, J = 2.0 Hz, 3′ꢀH), 6.53 (1H, dd, J = 8.6, 2.0 Hz, 5′ꢀ
H), 6.62 (1H, d, J = 2.0 Hz, 5ꢀH). 6.68 (1H, dd, J = 8.0, 2.0 Hz, 7ꢀH), 6.82 (1H, d, J = 8.0 Hz, 8ꢀH), 7.33 (1H, d,
J = 8.6 Hz, 6′ꢀH); δC (125 MHz; CDCl3) 18.5 (Cꢀ3′′), 47.7 (Cꢀ3), 55.5 (4′ꢀMeO), 55.7 (2′ꢀMeO), 62.7 (Cꢀ9),
79.8 (Cꢀ2), 98.7 (Cꢀ3′), 104.9 (Cꢀ1′), 105.2 (Cꢀ5′), 112.1 (Cꢀ5), 116.6 (Cꢀ8), 116.8 (Cꢀ7), 123.5 (Cꢀ2′′), 130.7
(Cꢀ1′′), 129.1 (Cꢀ6′), 131.6 (Cꢀ6), 133.7 (Cꢀ4a), 142.7 (Cꢀ8a), 158.0 (Cꢀ2′), 160.7 (Cꢀ4′); IR: (film)/cmꢀ1; 3370,
2919, 2856, 1737, 1608, 1586, 1503, 1461, 1365, 1258, 1208, 1156, 1120, 1029, 963, 921, 827, 742; HRMS
(ESI+) Found (MNa+): 364.1506; C20H23NNaO4 requires 364.1519.
(2R,3S)ꢀBenzyl
2ꢀ((benzyloxy)methyl)ꢀ3ꢀ(3′,4′ꢀdimethoxyphenyl)ꢀ6ꢀ(3′′,4′′,5′′ꢀtrimethoxyphenyl)ꢀ2Hꢀ
benzo[b][1,4]oxazineꢀ4(3H)ꢀcarboxylate 42. To a solution of bromo benzomorpholine 26 (0.026 g, 0.044
mmol) in DME (6 mL) was added 2 M K2CO3 (0.15 mL, 0.28 mmol), arylboronic acid 41 (0.018 g, 0.086
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mmol) and Pd(PPh3)4 (0.011 g, 0.009 mmol). The resultant mixture was stirred vigorously at 90 °C for 72 h. The
mixture was cooled, water (5 mL) added, the organic layer was separated and the aqueous phase further
extracted with diethyl ether (3 × 5 mL). The combined organic extracts were washed with water (5 mL) and
brine (5 mL), dried (MgSO4), and the solvent removed in vacuo. The crude product was purified by flash
chromatography (2:1 hexanes, ethyl acetate) to give the title compound 42 (0.015 g, 52%) as a yellow oil: RF =
0.28 (2:1 hexanes, ethyl acetate); [α]D +42.62 (c = 0.30, CHCl3); δH (500 MHz; CDCl3; Me4Si) 3.59 (1H, dd, J =
9.8, 7.2 Hz, 9ꢀHa), 3.68 (3H, s, 3′ꢀMeO), 3.71 (1H, dd, J = 9.8, 5.5 Hz, 9ꢀHb), 3.81 (3H, s, 4′ꢀMeO), 3.86 (6H, s,
3′′ꢀMeO, 5′′ꢀMeO), 3.87 (3H, s, 4′′ꢀMeO), 4.51 (2H, s, OCH2Ph), 4.81 (1H, ddd, J = 7.2, 5.5, 1.8 Hz, 2ꢀH), 5.26
(1H, d, J = 12.2 Hz, OCHaHbPh), 5.31 (1H, d, J = 12.2 Hz, OCHaHbPh), 5.82 (1H, d, J = 1.8 Hz, 3ꢀH), 6.68 (2H,
s, 2′′ꢀH and 6′′ꢀH), 6.72 (1H, d, J = 8.2 Hz, 5′ꢀH), 6.80 (1H, d, J = 2.0 Hz, 2′ꢀH), 6.85 (1H, dd, J = 8.2, 2.0 Hz,
6′ꢀH), 6.94 (1H, d, J = 8.6 Hz, 8ꢀH), 7.18 (1H, dd, J = 8.6, 2.4 Hz, 7ꢀH), 7.28–7.34 (10 H, ArꢀH), 8.11 (1H, s, 5ꢀ
H); δC (125 MHz; CDCl3) 53.7 (Cꢀ3), 55.7 (3′ꢀMeO), 55.8 (4′ꢀMeO), 56.2 (3′′, 5′′ꢀMeO), 60.9 (4′′ꢀMeO), 68.1
(OCH2Ph), 69.3 (Cꢀ9), 73.8 (OCH2Ph), 76.1 (Cꢀ2), 104.3 (Cꢀ2′′, Cꢀ6′′), 110.4 (Cꢀ2′), 111.1 (Cꢀ5′), 117.3 (Cꢀ8),
119.2 (Cꢀ6′), 121.9 (Cꢀ5), 123.4 (Cꢀ7), 124.5 (Cꢀ4a), 127.8, 127.9, 128.0, 128.3, 128.5, 128.6 (ArꢀCH), 130.7
(Cꢀ1′), 134.4 (Cꢀ6), 135.8 (ArꢀC), 136.8 (Cꢀ1′′), 137.4 (Cꢀ4′′), 137.6 (ArꢀC), 144.5 (Cꢀ8a), 148.5 (Cꢀ4′), 148.9
(Cꢀ3′), 153.4 (Cꢀ3′′, Cꢀ5′′), 153.9 (C=O); IR: (film)/cmꢀ1; 2923, 2860, 1706, 1577, 1516, 1495, 1456, 1402,
1257, 1127, 1028, 819, 754; HRMS (ESI+) Found (MNa+): 714.2665; C41H41NNaO9 requires 714.2674.
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(2R,3S)ꢀ2ꢀ((Benzyloxy)methyl)ꢀ3ꢀ(2′,4′,6′ꢀtrimethoxyphenyl)ꢀ6ꢀ(3′′,4′′,5′′ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ
2Hꢀbenzo[b][1,4]oxazine 43. To a solution of bromo benzomorpholine 25 (0.029 g, 0.059 mmol) in DME (8
mL) was added 2 M K2CO3 (0.2 mL, 0.39 mmol), arylboronic acid 41 (0.025 g, 0.12 mmol) and Pd(PPh3)4
(0.014 g, 0.012 mmol). The resultant mixture was stirred vigorously at 90 °C for 72 h. The mixture was cooled,
water (10 mL) added, the organic layer was separated and the aqueous phase further extracted with diethyl ether
(3 × 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried
(MgSO4), and the solvent removed in vacuo. The crude product was purified by flash chromatography (2:1
hexanes, ethyl acetate) to give the title compound 43 (0.013 g, 38%) as a brown oil: RF = 0.21 (2:1 hexanes,
ethyl acetate); [α]D ꢀ63.54 (c = 0.19, CHCl3); δH (500 MHz; CDCl3; Me4Si) 3.58 (1H, dd, J = 10.4, 5.0 Hz, 9ꢀ
Ha), 3.60 (1H, dd, J = 10.4, 3.4 Hz, 9ꢀHb), 3.74 (6H, s, 2′, 6′ꢀMeO), 3.83 (3H, s, 4′ꢀMeO), 3.87 (3H, s, 4′′ꢀMeO),
3.89 (6H, s, 3′′, 5′′ꢀMeO), 4.49 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.52 (1H, d, J = 12.2 Hz, OCHaHbPh), 4.77
(1H, ddd, J = 8.6, 5.0, 3.4 Hz, 2ꢀH), 4.89 (1H, d, J = 8.6 Hz, 3ꢀH), 6.13 (2H, s, 3′, 5′ꢀH), 6.73 (2H, s, 2′′, 6′′ꢀH),
6.93 (1H, d, J = 1.8 Hz, 5ꢀH), 6.94 (1H, dd, J = 8.4, 1.8 Hz, 7ꢀH), 7.01 (1H, d, J = 8.4 Hz, 8ꢀH), 7.22–7.29 (5H,
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ArꢀH); δC (125 MHz; CDCl3) 48.9 (Cꢀ3), 55.4 (4′ꢀMeO), 55.7 (2′, 6′ꢀMeO), 56.1 (3′′, 5′′ꢀMeO), 60.9 (4′′ꢀMeO),
70.6 (Cꢀ9), 73.3 (OCH2Ph), 75.5 (Cꢀ2), 91.0 (Cꢀ3′, Cꢀ5′), 104.0 (Cꢀ2′′, Cꢀ6′′), 106.5 (Cꢀ1′), 116.4 (Cꢀ5), 117.3
(Cꢀ8), 118.4 (Cꢀ7), 127.3, 127.5, 128.2 (ArꢀCH), 133.7 (Cꢀ4a), 134.3 (Cꢀ6), 137.0 (Cꢀ1′′), 137.5 (Cꢀ4′′), 138.4
(ArꢀC), 145.1 (Cꢀ8a), 153.3 (Cꢀ3′′, Cꢀ5′′), 159.8 (Cꢀ2′, Cꢀ6′), 161.3 (Cꢀ4′); IR: (film)/cmꢀ1; 3370, 2937, 2839,
1729, 1603, 1591, 1579, 1496, 1454, 1416, 1275, 1228, 1126, 814, 736; HRMS (ESI+) Found (MNa+):
610.2404; C34H37NNaO8 requires 610.2411.
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((2R,3S)ꢀ3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ6ꢀ(3,4,5ꢀtrimethoxyphenyl)ꢀ3,4ꢀdihydroꢀ2Hꢀbenzo[b][1,4]oxazinꢀ2ꢀ
yl)methanol 44. To a solution of biarylꢀbenzomorpholine 42 (0.015 g, 0.022 mmol) in MeOH (3 mL) was
added 10% Pd/C (0.003 g, 20% w/w) and the mixture stirred under an atmosphere of hydrogen for 1 h. The
mixture was filtered through Celite® washed with methanol (3 × 3 mL) and the solvent removed in vacuo. The
crude product was purified by flash chromatography (1:1 hexanes, ethyl acetate) to yield the title product 44 (7
mg, 67%) as a yellow gum: RF = 0.48 (1:2 hexanes, ethyl acetate); [α]D +71.02 (c = 0.01, CHCl3); δH (500
MHz; CDCl3; Me4Si) 3.56 (1H, dd, J = 10.4, 5.4 Hz, 9ꢀHa), 3.75 (1H, dd, J = 10.4, 3.4 Hz, 9ꢀHb), 3.88 (3H, s,
4′′ꢀMeO), 3.90 (6H, s, 3′, 4′ꢀMeO), 3.91 (6H, s, 3′′, 5′′ꢀMeO), 4.04 (1H, ddd, J = 7.8, 5.4, 3.4 Hz, 2ꢀH), 4.38
(1H, d, J = 7.8 Hz, 3ꢀH), 6.72 (2H, s, 2′′, 6′′ꢀH), 6.87 (1H, d, J = 2.0 Hz, 5ꢀH), 6.89 (1H, d, J = 8.4 Hz, 5′ꢀH),
6.91 (1H, dd, J = 8.4, 2.0 Hz, 7ꢀH), 6.96 (1H, d, J = 8.4 Hz, 8ꢀH), 6.97 (1H, d, J = 2.0 Hz, 2′ꢀH), 6.99 (1H, dd, J
= 8.4, 2.0 Hz, 6′ꢀH); δC (125 MHz; CDCl3) 54.9 (Cꢀ3), 55.9 (3′ꢀMeO), 56.0 (4′ꢀMeO), 56.2 (3′′, 5′′ꢀMeO), 60.9
(4′′ꢀMeO), 62.2 (Cꢀ9), 79.8 (Cꢀ2), 104.1 (Cꢀ2′′, Cꢀ6′′), 110.5 (Cꢀ2′), 111.3 (Cꢀ5′), 113.4 (Cꢀ5), 116.7 (Cꢀ8),
117.7 (Cꢀ7), 120.3 (Cꢀ6′), 131.0 (Cꢀ1′), 133.9 (Cꢀ4a), 135.4 (Cꢀ6), 137.1 (Cꢀ1′′), 137.2 (Cꢀ4′′), 143.1 (Cꢀ8a),
149.2 (Cꢀ4′), 149.6 (Cꢀ3′), 153.4 (Cꢀ3′′, Cꢀ5′′); IR: (film)/cmꢀ1; 3458, 3349, 2926, 2835, 2342, 1738, 1579, 1497,
1460, 1421, 1371, 1264, 1234, 1128, 1027, 910, 733; HRMS (ESI+) Found (MNa+): 490.1835; C26H29NNaO7
requires 490.1836.
Supporting Information
NMR spectra for all novel compounds is supplied. Details of the biological testing is also provided. This
material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgements
We thank the University of Auckland Faculty Research Development Fund for funding this project
References
(1)
Pilkington, L. I.; Barker, D. J. Org. Chem. 2012, 77, 8156.
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