Atropo- and Diastereoselective Construction of Tetracyclic Biphenylazepinium Salts Derived from Aminoalcohols: Use as Catalysts in Enantioselective Asymmetric Epoxidation

Article abstract of DOI:10.1021/acs.joc.5b01157

A range of new biphenylazepinium salt organocatalysts effective for asymmetric epoxidation has been developed incorporating an additional substituted oxazolidine ring, and providing improved enantiocontrol in alkene epoxidation over the parent structure. Starting from enantiomerically pure aminoalcohols, tetracyclic iminium salts were obtained as single diastereoisomers through an atroposelective oxazolidine formation.

Full text of DOI:10.1021/acs.joc.5b01157

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Atropoꢀ and diastereoꢀ selective construction of tetracyclic biphenylazepinium salts
derived from aminoalcohols: Use as catalysts in enantioselective asymmetric
epoxidation
a
a
a
b
Philip C. Bulman Page, * Christopher A. Pearce, Yohan Chan, Phillip Parker, Benjamin R.
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b
c
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Buckley, Gerasimos A. Rassias, and Mark R. J. Elsegood
a
School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK
b
Chemistry Department, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
c
Department of Chemistry, University of Patras, 26504 Patras, Greece
p.page@uea.ac.uk
Abstract
A range of new biphenylazepinium salt organocatalysts effective for asymmetric epoxidation has
been developed incorporating an additional substituted oxazolidine ring, and providing improved
enantiocontrol in alkene epoxidation over the parent structure. Starting from enantiomerically pure
aminoꢀalcohols, tetracyclic iminium salts were obtained as single diastereoisomers through an
atroposelective oxazolidine formation.
Introduction
1
Epoxides are versatile building blocks widely used in synthesis. The past thirty years have seen the
development of many methodologies capable of efficient asymmetric epoxidation of various types of
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3
4
alkene. Dioxiranes, and oxaziridinium salts, first reported by Lusinchi, and generated in situ from
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the corresponding iminium salts or amines, have proven to be two of the most effective types of
organocatalyst for asymmetric oxygen transfer to weakly nucleophilic substrates such as
unfunctionalized alkenes. Over the past ten years we have developed a range of enantiopure iminium
salts effective as organocatalysts for highly enantioselective asymmetric epoxidation in the presence
of Oxone as stoicheiometric oxidant. We have reported that the most reactive and selective iminium
salt catalysts discovered to date are based on (S,S)ꢀacetonamine derivative 1 and a biphenyl
backbone such as 2, 3 and 4, or a binaphthyl backbone such as 5. For example, iminium species 2a
catalyses the oxidation of 1ꢀphenylcyclohexene to its corresponding epoxide in less than 4 minutes
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inducing up to 60% enantioselectivity, while catalyst 5a affords the same epoxide in 91% ee after 15
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min. The use of alternative oxidants, such as bleach or hydrogen peroxide, has also been explored,
and the successful development of nonꢀaqueous conditions using tetraphenylphosphonium
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monoperoxysulfate (TPPP) has allowed us to access highly enantioenriched epoxides (up to 99%
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ee).
BPh4
O
BPh4
O
R
R
H N
2
O
N
N
O
O
O
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2a R= H
3a R= H
2b R= Me
3b R= Me
BPh4
O
BPh4
O
R
N
R
N
O
O
4
a R= H
5a R= H
4b R= Me
5b R= Me
Figure 1. Iminium salt catalysts for asymmetric epoxidation
A potential issue concerning cyclic biaryl structures is their ability to rotate through the aryl/aryl
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bond generating two interconverting atropoisomers. Using biaryl azepine 6 as a model substrate,
Wallace showed that asymmetric introduction of an alkyl group at C(7) could induce a strong
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conformational preference for one atropoisomer. Lacour has used derivatization at the 3,3’ꢀ
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positions on the aromatic rings to prevent such interconversion, as in 3a/3b. We have shown that
the introduction of an axial substituent at the C(7) position by nucleophilic addition to 2a to create a
new chiral centre adjacent to the iminium nitrogen, followed by reoxidation, generates ‘second
generation’ iminium salt catalysts such as 2b, 3b, 4b and 5b, which provide increased enantiocontrol
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in the epoxidation of alkene substrates.
Meyers’ bicyclic lactam methodology has been widely used in the stereoselective construction of
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fiveꢀ, sixꢀ and sevenꢀmembered ring nitrogen heterocycles from enantiopure amino alcohols.
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Particularly of interest to us, the methodology has been applied to prepare a range of axially chiral
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biaryl lactams such as 7. We postulated that structurally related iminium salts such as 8 might
impart increased levels of enantioselectivity when used as an asymmetric epoxidation catalyst by
imparting additional rigidity and structural elements in the transition state compared to catalysts such
as 4.
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Results and Discussion
Our initial hypothesis was that the 7,5ꢀfused bicyclic lactam subꢀstructure 7 could be used to
generate amine 9, a suitable precursor to iminium species 8, by reduction of the lactam unit (Scheme
1
). However, reduction of compound 7 is known to lead to aminoꢀalcohol 10 using literature
18
procedures. We have previously shown that oxidation of such azepines occurs preferentially at the
least substituted adjacent position, ruling out the possibility to use this pathway, because 10 would
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not be oxidized to 11. We therefore devised an alternative pathway based upon a biaryl coupling of
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9
a suitably functionalized oxazolidinone using an adaptation of Fagnou’s methodology by Wallace
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(Scheme 1). Synthesis of the cyclization precursor 12 would be achieved by SuzukiꢀMiyaura
coupling of a suitably functionalized aminoꢀalcohol 14 with 2ꢀacetylphenylboronic acid to give 13,
and subsequent hydrolysis of the oxazolidinone protecting group. Cyclocondensation of 12 to form
the iminium species 11 would result in concomitant cyclization to the oxazolidine 9 by
intramolecular attack of the hydroxyl group. We have previously observed diastereoselective
formation of oxazolidines in a related binaphthyl system when generating iminium species bearing
21
an alcohol moiety. Finally, oxidation of 9 under our standard conditions would give iminium salt
catalyst 8.
This methodology would allow the use of a wide variety of enantiomerically pure aminoꢀalcohol
precursors. Accordingly, alkylation of (R)ꢀphenyl oxazolidinone 15 with 2ꢀiodobenzylbromide
afforded Nꢀsubstituted oxazolidinone 14 in 98% yield. NꢀBenzyl oxazolidinone 14 was coupled with
1
7a
2ꢀacetylphenyl boronic acid under conditions used by Levacher.
Hydrolysis of the crude
oxazolidinone 13 was completed with aqueous sodium hydroxide in dichloromethane; the solvent
was removed and tertꢀbutylmethyl ether (TBME) added. The resulting solution of aminoalcohol 12
was treated with aqueous HCl to generate the desired tetracyclic amine 9 via 11 as a single
diastereoisomer in 12% yield over the three steps. Finally, the iminium salt 8 was generated by
oxidation of the amine using NBS in chloroform in 80% yield.
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Scheme 1
We tested iminium salt 8 for its efficacy as an epoxidation catalyst, using 1ꢀphenylcyclohexene as
our test substrate under our standard Oxone oxidative conditions. Catalyst 8 gave 100% conversion
within thirty minutes, imparting a fair 55% ee for 1ꢀphenylcyclohexene oxide (Scheme 2).
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Scheme 2
While this result established a new subꢀstructure of iminium salts active for the catalytic asymmetric
epoxidation of alkenes, the overall yield of this synthetic route, particularly in the conversion of 14
into 9, coupled with the problematic purification of the unstable oxazolidinone 13 led us to seek an
alternative.
We reasoned that a change of aminoalcohol protecting group from oxazolidinone to a much more
readily hydrolysed oxaminal might improve the process, and so targeted dimethyloxazolidine 18
(
Scheme 3). Reductive amination of 2ꢀiodobenzaldehyde with (R)ꢀphenyl glycinol 16 gave the Nꢀ
benzyl amino alcohol 17 in 81% yield. Protection of the aminoalcohol functionality with
dimethoxypropane gave the oxazolidine 18 in 96% yield.
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Scheme 3
Oxazolidine 18 was coupled with 2ꢀacetylphenylboronic acid under the conditions described above.
Attempted purification using column chromatography on silica gel of the crude coupled product led
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to the isolation of a mixture of two inseparable compounds. Upon inspection of the H NMR
spectrum of the mixture, the two products were identified as the desired Suzuki adduct 19 and the
target tetracyclic 6,6,7,5 material 9 as a single diastereoisomer.
Following our conjecture that silica gel had effected a deprotection to expose the aminoalcohol,
which then condensed in situ with the pendent ketone generating the desired tetracycle, we subjected
the crude reaction mixture from the Suzuki coupling to silica gel in chloroform over 15 h (Scheme
3), so generating tetracycle 9 as a single diastereoisomer in a somewhat improved 40% yield. The
absolute configuration of 9 was confirmed by single crystal Xꢀray analysis. The tetracylic tertiary
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amine 9 was readily converted into iminium salt 8 in 80% yield. To test the need for the
protection/deprotection steps, a Suzuki coupling between unprotected aminoꢀalcohol 17 and 2ꢀ
acetylphenylboronic acid was attempted.
Anticipating the deactivation of the palladiumꢀphosphine catalyst by the aminoalcohol, we expected
to observe poor conversion. To our delight, however, we observed the Suzuki coupling followed by
in situ intramolecular cyclization, generating the 6,6,7,5ꢀtetracyclic core 9 as a single
diastereoisomer in 40% yield (Scheme 4).
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Scheme 4
The phenyl substituted azepinium bromide salt 8 was thus obtained in just four steps in 26% overall
yield from (R)ꢀphenyl glycinol 16. A number of aminoalcohols ꢀ (S)ꢀalaninol, (S)ꢀvalinol, and (R)ꢀ &
(S)ꢀphenylalaninol ꢀ were subjected to the same reaction sequence to prepare a selection of potential
catalysts with different substituents at the oxazolidine ring, to give the cyclized products 8 and 28ꢀ
3
1, each again generated as single diastereoisomers (Table 1; Figure 2).
Table 1. Isolated yields of the key intermediates in generating six tetracyclic iminium salt catalysts
I
NH
HO
R
R = (S)ꢀMe
83% (20)
16% (21)
81% (17)
90% (22)
86% (23)
22% (24)
47% (25)
40% (9)
74% (28)
81% (29)
80% (8)
i
R = (S)ꢀ Pr
R = (R)ꢀPh
R = (R)ꢀBn
R = (S)ꢀBn
60% (26)
30% (27)
82% (30)
75% (31)
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BPh4
N
BPh4
N
BPh4
N
O
O
O
28
13% overall yield
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8
6% overall yield
27% overall yield
0
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4
4% overall yield
19% overall yield
Figure 2. New iminium salts
Single crystal Xꢀray structure determination carried out on the (R)ꢀphenyl 9 and (S)ꢀbenzyl 27
derivatives (Figure 3) show the cisꢀrelationship between the methyl groups and the oxazolidine ring
phenyl and benzyl substituents derived from the parent aminoalcohols, the pseudoꢀequatorial
placement of these phenyl and benzyl substituents, the axial orientation of the methyl groups, and the
chirality of the atropoisomeric biaryl units.
(
aR,3R,13bS)ꢀamine 9
(aS,3S,13bR)-amine 27
Figure 3. Single crystal Xꢀray structural determination of 9 and 27
The stereoselectivity of the cyclization of the aminoalcohol functionality in the intermediate iminium
species 11 may be driven by preferred placement of the smaller methyl substituent in the pseudoꢀ
17a
axial orientation (Scheme 5), perhaps through an equilibrium process.
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Scheme 5
Catalysts 8 and 28-31 were tested for catalytic activity under our standard conditions using oxone as
oxidant, and compared to the simple biphenyl azepinium catalyst 2a (Table 2).
a
Table 2. Asymmetric Epoxidation of a range of alkenes by catalysts 8 and 28-31
c, d
b, c
f
Epoxide
Catalyst Conversion/%
ee/%
Major enantiomer
2
a
100
100
100
100
100
100
100
100
100
100
34
60
55
30
30
64
64
32
76
46
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41
64
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(–)ꢀ1S,2S
(+)1R,2R
(–)ꢀ1S,2S
(–)ꢀ1S,2S
(+)1R,2R
(–)ꢀ1S,2S
(+)1S,2R
(–)1R,2S
(–)1R,2S
(+)1S,2R
(–)1R,2S
(+)1S,2R
(+)1S,2R
(–)1R,2S
8
2
2
8
9
30
3
1
a
2
8
3
3
0
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2a
8
20
3
3
0
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a
90
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98
15
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(–)1S,2S
(+)1R,2R
(+)1R,2R
(–)1S,2S
(–)1S
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95
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100
100
100
(+1R
3
3
0
1
(+)1R
(–)1S
a
Epoxidation conditions: Iminium salt catalyst (5 mol%), Oxone® (2 equiv.). Na CO (4 equiv.), MeCN:H O 1:1 (5 ml),
2
3
2
b
0
ºC, 1ꢀ6 h. Enantiomeric excesses were determined by chiral GC chromatography on a Chiraldex BꢀDM column by
c
comparison of the two epoxide peak areas. Conversions were evaluated from the chiral GC–FID spectra by comparison
d
e
of the alkene and epoxide peak areas. Enantiomeric excess determined by Chiral HPLC on a Chiracel ODꢀH column.
1
f
Conversions were evaluated from the HꢀNMR spectra by integration of alkene and epoxide signals. Absolute
configurations of the major enantiomers were determined by comparison of both optical rotation and GCꢀFID of samples
of known configuration.
Catalysts 8, 30, and 31 provide greater enantioselectivity in the oxidation of 1ꢀphenylcyclohexene
than catalysts 28 and 29, and this pattern is repeated for the other alkene substrates tested. Observed
enantioselectivities are comparable with or superior to the simple azepinium catalyst 3a. Highest
enantioselectivities were observed with the cyclic cisꢀalkene dihydronaphthalene substrates, where
catalysts 8, 30, and 31 outperformed catalyst 2a by a considerable margin.
Conclusion
To conclude, we have successfully developed a new subꢀstructure of iminium salt catalyst containing
a 6,6,7,5ꢀring tetracyclic core. The synthesis of these novel iminium salts can be completed within
four steps in good yields from the corresponding aminoꢀalcohols. We have postulated that the
cyclization occurs through one favoured atropoisomer, giving rise to a favoured diastereoisomer in
all the iminium salt catalysts generated, that where the methyl group is pseudoꢀaxial. Catalysts 8, 30
and 31 generally provide enantioselectivities better than or equal to the parent azepinium catalyst 2a.
Experimental Section
General Experimental Detail
1
13
All infrared spectra were obtained using; thin films on sodium chloride plates. All H and C NMR
spectra were measured at 400.13 and 100.62 MHz respectively, or at 500.21 and 125.79 MHz
respectively, in deuteriochloroform solution unless otherwise stated, using TMS (tetramethylsilane)
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as the internal reference. Mass spectra were recorded utilizing electron–impact (EI), fast atom
bombardment (FAB) or electrospray (ESI) techniques and an ion trap mass analyser. Optical rotation
values were measured at
λ=589 nm, corresponding to the sodium D line, at the temperatures
indicated. All chromatographic manipulations used silica gel as the adsorbent. Reactions were
monitored using thin layer chromatography (TLC) on aluminium–backed plates coated with F254
silica gel. TLC plates were visualized by UV irradiation at a wavelength of 254 nm, or stained by
exposure to an ethanolic solution of phosphomolybdic acid (acidified with concentrated sulfuric
acid), followed by charring where appropriate. Reactions requiring anhydrous conditions were
carried out using glassware dried overnight at 150 ºC, under a nitrogen atmosphere unless otherwise
stated. Reaction solvents were used as obtained commercially unless otherwise stated. Light
petroleum (b.p. 40–60 ºC) was distilled from calcium chloride prior to use. Ethyl acetate was
distilled over calcium chloride. Dichloromethane was distilled over calcium hydride.
Tetrahydrofuran and diethyl ether were distilled under a nitrogen atmosphere from the
sodium/benzophenone ketyl radical. Acetone was dried over 4Å Linde molecular sieve, and distilled
under a nitrogen atmosphere. Enantiomeric excesses were determined by chiral HPLC using a
Chiracel OD and ODꢀH columns with an ultra–violet absorption detector set at 254 nm, by chiral GC
using a Chiraldex BꢀDM column and a flame ionization detector, or by proton nuclear magnetic
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resonance
spectroscopy
in
the
presence
of
europium
(III)
tris[3–
(heptafluropropylhydroxymethylene)–(+)–camphorate] as the chiral shift reagent.
General procedure A: Reductive amination using 2-iodobenzaldehyde and aminoalcohols
The amino alcohol and 2ꢀiodobenzaldehyde (1.1 equiv.) were dissolved in methanol (10 mL per g of
aminoalcohol) and agitated over 5 to 16 h. The mixture was cooled to 0 °C, sodium
cyanoborohydride (1.1 equiv.) added, and the mixture stirred at ambient temperature for 16 h.
Saturated aqueous ammonium chloride (1 mL per g of aminoalcohol) was added and the solvent
removed under reduced pressure. The residue was dissolved in tertꢀbutyl methyl ether (10 mL per g
of aminoalcohol) and the solution washed with saturated brine and dried over magnesium sulphate.
The solvents were removed and the crude oil purified by column chromatography using
2 2
CH Cl /MeOH (100:0ꢀ95:5) as eluent to yield the desired secondary amine.
General procedure B: Suzuki coupling between 2-iodobenzyl aminoalcohols and 2-acetyl
phenylboronic acid
The aminoalcohol and 2ꢀacetyl phenylboronic acid (3 equiv.) were dissolved in toluene (10 mL per g
of aminoalcohol) and ethanol (1 mL per g of aminoalcohol) and saturated aqueous potassium
carbonate (1 mL per g of aminoalcohol) added. The mixture was degassed with nitrogen over 30
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min. Pd(PPh
3
)
4
(10 mol%) was added and the mixture degassed for a further 15 min. The mixture
was stirred at reflux under a nitrogen atmosphere with monitoring by HPLC; once complete
consumption of the starting material was observed, the mixture was allowed to cool to ambient
temperature and filtered through a plug of celite. The organic layer was separated, washed with
water, dried over magnesium sulphate, and the solvents were removed under reduced pressure. The
residue was dissolved in chloroform (10 mL per g of aminoalcohol and silica gel (0.5 g per g of
aminoalcohol) added. The mixture was stirred for 15 hours at room temperature to achieve
cyclization. The suspension was filtered through a plug of celite and the solvent removed under
reduced pressure. The residue was purified using flash chromatography on silica gel using ethyl
acetate:heptane (1ꢀ5%) as eluent.
0
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8
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General procedure C: Oxidation of tertiary cyclic amines using N-bromosuccinimide
The amine was dissolved in chloroform (5 mL per g of amine) and the mixture cooled to 0 °C. Nꢀ
Bromosuccinimide (2 equiv.) was added. The reaction mixture was removed from the ice bath and
stirred for 15ꢀ20 min with monitoring by HPLC/TLC. Upon completion, water (10 mL per g of
amine) was added, and the organic layer separated and dried over magnesium sulphate. The solvent
was removed under reduced pressure to yield the corresponding bromide salt. The residue was
dissolved in ethanol (50 mL per g of bromide salt) and a solution of sodium tetraphenylborate (1
equiv.) in the minimum amount of acetonitrile to enable dissolution added. The solvents were
removed under reduced pressure and the residue was recrystallized from ethanol to yield the desired
tetracyclic imnium tetraphenylborate salts.
General procedure for the formation of racemic epoxides for ee determinations
The alkene was dissolved in dichloromethane (10 mL per g of alkene) and cooled to 0 ºC. mꢀCPBA
(
2 equiv.) was added as a solution in dichloromethane (10 mL per g of alkene). The mixture was
allowed to attain ambient temperature and stirred until complete consumption of the substrate was
observed by TLC. Saturated aqueous NaHCO (20 mL per g of alkene) was added and the layers
separated. The organic layer was washed with NaOH (1.0 M, 20 mL per g of alkene), and dried
MgSO ). The solvents were removed under reduced pressure and the product purified by column
3
(
4
chromatography, eluting with ethyl acetate/light petroleum (1:99).
General procedure for catalytic asymmetric epoxidation of simple alkenes mediated by
iminium salts using Oxone
Oxone (2 equiv.) was added to an ice cooled solution of Na CO , (4 equiv.) in water (8 mL per g of
2
3
Na CO ), and the resulting foaming solution stirred for 5ꢀ10 min. The iminium salt (10 mol%) was
2
3
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added as a solution in acetonitrile (4 mL per g of Na
2 3
CO used), followed by the alkene substrate,
also as a solution in acetonitrile (4 mL per g of Na CO used). The mixture was stirred at 0 °C until
2
3
the alkene substrate was completely consumed as observed by TLC. The mixture was dissolved in
iceꢀcooled diethyl ether (20 mL per 100 mg substrate), and the same volume of water added. The
aqueous phase was washed four times with diethyl ether, and the combined organic layers were
washed with saturated brine and dried over magnesium sulphate. Filtration and evaporation of the
solvents gave a yellow/brown residue, which was purified by column chromatography, eluting with
ethyl acetate/light petroleum (1:99).
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3
-(2’-Iodobenzyl)-4R-phenyloxazolidin-2-one 14
R)ꢀ(–)ꢀ4ꢀphenylꢀ2ꢀoxazolidinone (0.20 g, 1.23 mmol, 1.0 equiv.) was dissolved in THF (2 mL) at
(
room temperature under a nitrogen atmosphere. NaHMDS (2M in THF, 0.68 mL, 1.35 mmol, 1.1
equiv.) was added and the reaction mixture stirred for 30 min. A solution of 2ꢀiodobenzylbromide
(0.40 g, 1.35 mmol, 1.1 equiv.) in THF (2 mL) was added and the reaction monitored by HPLC. On
complete consumption of the starting material, saturated aqueous potassium carbonate (10 mL per g
of oxazolidinone) and tertꢀbutyl methyl ether (20 mL per g of oxazolidinone) were added. The
organic layer was separated, washed with brine (10 mL per g of oxazolidinone), dried over
anhydrous magnesium sulphate, and the solvents removed under reduced pressure to yield the
ꢀ1
desired alkylated oxazolidinone (0.46 g, 1.21 mmol, 98%);
ν
max(film) /cm 2960, 1749, 1428, 1240,
20
1
1
081, 1012, 751, 668. [
α]
D
−7.8 ° (c 1.0, CH Cl ), H NMR (400 MHz; CDCl ) δH 4.00 (1 H, d, J
2
2
3
1
5.6 Hz), 4.17 (1 H, dd. J 5.6, 8.4 Hz), 4.56 (1 H, dd, J 5.2, 9.2 Hz), 4.63 (1 H, t, J 8.3 Hz), 4.80 (1
H, d, J 15.4 Hz), 6.97 (1 H, td, J 1.5, 7.5 Hz), 7.14 ꢀ 7.20 (3 H, m), 7.29 (1 H, td, J 1.2, 7.5 Hz), 7.35
1
3
ꢀ
7.40 (3 H, m), 7.79 (1 H, dd, J 1.2, 7.9 Hz). C NMR (100 MHz; CHCl ) δC 50.7, 59.3, 70.1, 99.0,
3
+
1
27.2, 128.6, 129.2, 129.4, 129.7, 130.0, 137.8, 137.9, 140.0, 158.4; m/z found for [M+H]
+
380.0145; [C16
H
14NO
2
I+H] requires 380.0142.
2
-(2’-Iodobenzylamino)-2(R)-phenylethanol 17
(R)ꢀPhenylglycinol (1.32 g, 9.60 mmol, 1.1 equiv.) in MeOH (25 mL), 2ꢀiodobenzaldehyde (2.20 g,
9
.50 mmol, 1.0 equiv.) and NaBH
3
CN (0.60 g, 9.60 mmol, 1.1 equiv.) were treated using general
20
procedure A to yield the desired product (2.77 g, 7.80 mmol, 81%); [
α]
−49.7 ° (c 1.0, CH Cl ).
D 2 2
1
3 H
H NMR (400 MHz; CDCl ) δ 3.58 (1 H, dd, J 8.6, 10.8 Hz), 3.66 (1 H, d, J 13.2 Hz), 3.73 (1 H,
dd, J 4.4, 10.8 Hz), 3.78 (1 H, d, J 13.2 Hz), 3.81 (1 H, dd, J 4.4, 8.4 Hz), 6.93ꢀ6.98 (1 H, m), 7.26ꢀ
13
7
.40 (7 H, m), 7.80ꢀ7.83 (1 H, m); C NMR (100 MHz; CHCl
3
)
δ
C
55.8, 64.0, 67.0, 100.0, 127.5,
+
1
27.9, 128.4, 128.8, 129.1, 130.2, 139.8, 140.3, 142.2; m/z found for [M+H] : 354.0363;
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+
15
[C H16INO+H] requires 354.0355.
3-(2’-Iodobenzyl)-2,2-dimethyl-(4R)-phenyloxazolidine 18
2R)ꢀ2ꢀ(2’ꢀIodoꢀbenzylamino)ꢀ2ꢀphenylꢀethanol 17 (650 mg, 1.84 mmol, 1 equiv.) was dissolved in
(
toluene (10 mL). Dimethoxypropane (2.25 mL, 18.40 mmol, 10 equiv.) and pꢀTSA (70.0 mg, 0.37
mmol, 0.2 equiv.) were added, and the mixture heated under reflux using a DeanꢀStark apparatus.
The reaction was monitored by TLC and the azeotropic removal of solvents. Upon completion, the
mixture was allowed to reach ambient temperature. Saturated brine (3 x 20 mL) was added and the
0
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4
organic phase separated, dried over MgSO , and the solvents removed under reduced pressure.
Purification using column chromatography on silica gel (washed with 4% TEA) using
ethylacetate/light petroleum (10%) as eluent yielded the desired acetal as a yellow lowꢀmelting solid
ꢀ1
(694 mg, 1.76 mmol, 96%); νmax(film) /cm 3420, 2972, 1455, 1362, 1255, 1187, 1054, 1011, 753,
2
0
1
7
00; [
1 H,d, J 14.4 Hz), 3.75 (1 H, t, J 8.0 Hz), 3.88 (1 H, d, J 14.8 Hz), 4.08 (1 H, t, J 7.6 Hz), 4.21 (1 H,
t, J 7.2 Hz), 6.75 (1 H, dt, J 1.6, 7.6 Hz), 7.09ꢀ7.14 (2 H, m), 7.15ꢀ7.20 (2 H, m), 7.32ꢀ7.36 (2 H, m),
D 3 3 H
α] −60.2 (c 1.19, CHCl ); H NMR (400 MHz; CDCl ) δ 1.34 (3 H, s), 1.37 (3 H, s), 3.67
(
1
3
7.43 (1 H, dd, J 1.6, 7.6 Hz), 7.61 (1 H, dd, J 1.2, 8.0 Hz); C NMR (100 MHz; CHCl
3 C
) δ 21.6,
2
8.7, 56.8, 67.8, 72.1, 96.4, 99.6, 127.5, 127.7, 128.1, 128.2, 128.5, 131.3, 139.1, 140.5, 141.2; m/z
+
+
found for M : 393.0583; [C18H20INO] requires 393.0590.
(
aR,3R,13bS)-13b-Methyl-3-phenyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepine 9
First method: from oxazolidinone 14
(4R)ꢀ3ꢀ(2’ꢀIodoꢀbenzyl)ꢀ4ꢀphenylꢀoxazolidinꢀ2ꢀone 14 (0.46 g, 1.21 mmol) was dissolved in toluene
5 mL) and ethanol (7.5 mL). 2ꢀAcetyl phenylboronic acid (0.20 g, 1.21 mmol, 1 equiv.) and
saturated aqueous potassium carbonate (5 mL) were added. The mixture was degassed with nitrogen
over 30 min. Pd(PPh (0.07 g, 0.06 mmol, 5 mol%) was added, and the mixture was degassed with
(
3 4
)
nitrogen for a further 15 min. The mixture was stirred under reflux under a nitrogen atmosphere with
monitoring by HPLC. Once complete consumption of the starting material was observed, the mixture
was allowed to cool to ambient temperature. The mixture was filtered through a plug of celite, and
the solvents were removed under reduced pressure. tertꢀButyl methyl ether (10 mL) and water (5
mL) were added to the residue. The organic layer was separated, washed with water (5 mL), and
4
dried over MgSO . The solvents were removed under reduced pressure, and the residue dissolved in
ethanol (5 mL) and aqueous NaOH (2M, 5 mL) added. The mixture was heated under reflux for 16 h
to remove the protecting goup, then allowed to cool to ambient temperature. The organic solvent was
removed under reduced pressure, the residue was dissolved in tertꢀbutyl methyl ether (5 mL), and
aqueous HCl (5M, 1 mL) added. The mixture was stirred for 30 min to achieve cyclization, and the
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organic layer separated, dried over magnesium sulphate and the solvents removed under reduced
pressure. The residue was purified using flash chromatography on silica gel using ethyl
acetate:heptane (1 – 5%) as eluent to give the desired product (0.049 g, 0.15 mmol, 12%).
Second method: from oxazolidine 18
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(4R)ꢀ3ꢀ(2ꢀIodoꢀbenzyl)ꢀ2,2ꢀdimethylꢀ4ꢀphenylꢀoxazolidine 18 (0.69 g, 1.76 mmol) was dissolved in
toluene (10 mL) and ethanol (15 mL). 2ꢀAcetyl phenylboronic acid (0.29 g, 1.76 mmol, 1 equiv.) and
saturated aqueous potassium carbonate (10 mL) were added. The mixture was degassed with
3 4
nitrogen over 30 min. Pd(PPh ) (0.10 g, 0.09 mmol, 5 mol%) was added, and the mixture degassed
with nitrogen for a further 15 min. The mixture was stirred under reflux under a nitrogen atmosphere
for 4 h. The mixture was allowed to cool to ambient temperature, filtered through a plug of celite,
and the solvents were removed under reduced pressure. tertꢀButyl methyl ether (10 mL) and water (5
mL) were added to the residue. The organic layer was separated, washed with water (5 mL) and
4
dried over MgSO . The solvents were removed under reduced pressure, and the residue dissolved in
chloroform (10 mL) and silica gel added. The mixture was stirred at room temperature for 30 min
and the suspension filtered through a pad of celite. The solvent was removed under reduced pressure
and the residue purified using flash chromatography on silica gel using ethyl acetate:heptane (1ꢀ5%)
as eluent to give the desired product (0.23 g, 0.70 mmol, 40%).
Third method: from amino alcohol 17
(2R)ꢀ(2’ꢀIodobenzylamino)ꢀ2ꢀphenylethanol 17 (2.29 g, 6.50 mmol) and 2ꢀacetyl phenylboronic
acid (3.20 g, 19.5 mmol, 3 equiv.) were treated using general procedure B to yield the desired
ꢀ1
product (0.85 g, 2.60 mmol, 40%);
ν
max(film) /cm 2963, 1449, 1260, 1153, 1038, 897, 802, 758,
2
0
1
7
40, 701. [
α]
D
–15.6° (c 1.0, CH
2
Cl
2
). H NMR (400 MHz; CDCl
3
)
δ
H
1.11 (3 H, s), 3.09 (1 H, d, J
10.8 Hz), 3.58 (1 H, d, J 10.8 Hz), 3.86 (1 H, dd, J 7.6, 9.2 Hz), 3.94 (1 H, dd, J 6.0, 9.6 Hz), 4.37 (1
H, t, J 6.8 Hz), 7.25 (1 H, d, J 6.8 Hz), 7.30ꢀ7.37 (2 H, m), 7.38ꢀ7.45 (3 H, m), 7.46ꢀ7.53 (6 H, m),
1
3
7
.86ꢀ7.92 (1 H, m); C NMR (100 MHz; CHCl
3 C
) δ 30.6, 52.5, 69.3, 72.8, 97.3, 125.8, 127.6, 127.8,
127.9, 128.00, 128.04, 128.1, 128.5, 128.8, 129.1, 128.2, 135.3, 137.0, 139.1, 140.4, 142.1; m/z
+
+
found for M 327.1626; [C23H21NO] requires 327.1623.
2S-(2’-Iodobenzylamino)-propan-1-ol 20
S)ꢀAlaninol (1.3 mL, 16.38 mmol) and 2ꢀiodobenzaldehyde (3.8 g, 16.38 mmol, 1 equiv.) were
(
dissolved in toluene (100 mL) in a roundꢀbottomed flask fitted with a DeanꢀStark apparatus. Acetic
acid (0.5 mL) was added and the solution heated under reflux for 16 h. The reaction mixture was
allowed to reach room temperature and the solvents were removed under reduced pressure. The
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residue was dissolved in methanol (50 mL), NaBH
3
CN (1.23 g, 19.66 mmol, 1.2 equiv.) and acetic
acid (1 mL) were added, and the solution was stirred for 16 h. Saturated aqueous NH Cl (20 mL)
4
was added, and the aqueous layer washed with Et O (3 x 20 mL). The combined organic layers were
2
washed with a saturated solution of aqueous NH Cl (20 mL). The aqueous layers were combined and
4
the pH of the solution was brought to 8ꢀ9 using a saturated solution of Na CO . The resulting
2
3
0
1
2
3
4
5
6
7
8
9
0
1
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8
9
0
solution was extracted using dichloromethane (3 x 20 mL) and the combined organic layers were
washed with water and brine, dried over MgSO
4
, filtered, and the solvents removed to yield the
ꢀ1
product (4.0 g, 13.75 mmol, 83%);
ν
max(film) /cm 3324, 2956, 1563, 1435, 1045, 1011, 750, 648.
20
1
D 2 2 3 H
[α] +10.8 ° (c 1.0, CH Cl ). H NMR (500 MHz; CDCl ) δ 1.08 (3 H, d, J 6.0 Hz), 2.78ꢀ2.85 (1
H, m), 3.29 (1 H, dd, J 7.0, 11.0 Hz), 3.58 (1 H, dd, J 4.0, 11.0 Hz), 3.74 (1 H, d, J 13.5 Hz), 3.87 (1
H, d, J 13.5 Hz), 6.94 (1 H, dt, J 1.5, 7.5 Hz), 7.30 (1 H, dt, J 1.0, 7.5 Hz), 7.35 (1 H, dd, J 1.5, 7.5
1
3
Hz), 7.81 (1 H, dd, J 1.2, 8.0 Hz). C NMR (125 MHz; CHCl
3
)
δ
C
17.1, 53.9, 55.6, 65.6, 99.8,
+
+
128.4, 129.0, 129.8, 139.6, 142.2; m/z found for [M+H] : 292.0204; [C10
H
14NOI+H] requires
2
92.0198.
2S-(2’-Iodobenzylamino)-3-methyl-butan-1-ol 21
S)ꢀValinol (2.56 g, 24.8 mmol) in MeOH (50 mL), 2ꢀiodobenzaldehyde (6.33 g, 27.3 mmol, 1.1
equiv.) and NaBH CN (1.71 g, 27.3 mmol, 1.1 equiv.) were treated using general procedure A to
yield the product (1.30 g, 4.09 mmol, 16%);
(
3
ꢀ1
ν
max(film) /cm 3321, 2956, 1563, 1464, 1435, 1045,
2
0
1
1
011, 750, 648. [
α]
−16.7 ° (c 1.5, CHCl ). H NMR (400 MHz; CDCl ) δH 0.93 (3 H, d, J 6.8
D
3
3
Hz), 0.99 (3 H, d, J 6.8 Hz), 1.81 (1 H, sextet, J 6.8 Hz), 2.41 (1 H, dt, J 4.0, 6.4 Hz), 3.40 (1 H, dd J
.8, 10.8 Hz), 3.68 (1 H, dd, J 4.0, 10.8 Hz), 3.78 (1 H, d, J 13.2 Hz), 3.88 (1 H, d, J 13.2 Hz), 6.97
(1 H, dt, J 2.0, 7.6 Hz), 7.32 (1 H, dt, J 1.2, 7.2 Hz), 7.36 (1 H, dd, J 1.6, 7.6 Hz), 7.83 (1 H, dd, J
6
1
3
0
.8, 8.0 Hz); C NMR (100 MHz; CHCl ) δC 18.7, 19.8, 29.1, 56.0, 60.6, 64.1, 100.0, 128.6, 129.2,
3
+
+
1
30.1, 139.7, 142.5; m/z found for [M+H] 320.0511; [C12
H
18INO+H] requires 320.0511.
2
R-(2’-Iodobenzylamino)-3-phenyl-propan-1-ol 22
(2R)ꢀ2ꢀAminoꢀ3ꢀphenylpropanꢀ1ꢀol (2.92 g, 19.6 mmol) in MeOH (50 mL), 2ꢀiodobenzaldehyde
3
(3.00 g, 21.5 mmol, 1.1 equiv.) and NaBH CN (1.35 g, 21.5 mmol, 1.1 equiv.) were treated using
ꢀ1
general procedure A to yield the product (6.47 g, 17.6 mmol, 90%); νmax(film) /cm 3441, 2359,
20
1
1
652, 1635, 1113, 743, 699, 668. [
2 H, qd, J 7.2, 14.0 Hz), 2.93ꢀ3.00 (1 H, m), 3.38 (1 H, dd, J 5.2, 10.8 Hz), 3.71 (1 H, dd, J 4.0, 10.8
Hz), 3.80 (2 H, s), 6.95 (1 H, dt, J 1.6, 7.6 Hz), 7.14ꢀ7.18 (2 H, m), 7.19ꢀ7.24 (2 H, m), 7.25ꢀ7.31 (3
D 3 3 H
α] +20.0° (c 1.5, CHCl ). H NMR (400 MHz; CDCl ) δ 2.81
(
1
3
3 C
H, m), 7.79 (1 H, dd, J 1.2, 8.0 Hz); C NMR (100 MHz; CHCl ) δ 38.4, 55.7, 59.5, 62.6, 100.0,
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1
26.7, 128.5, 128.8, 129.2, 129.4, 129.9, 138.4, 139.7, 142.0; m/z found for [M+H] 368.0506;
+
[
C H NOI+H] requires 368.0510.
1
6
18
2
S-(2’-Iodobenzylamino)-3-phenyl-propan-1-ol 23
(
2S)ꢀ2ꢀAminoꢀ3ꢀphenylpropanꢀ1ꢀol (2.92 g, 19.6 mmol) in MeOH (50 mL), 2ꢀiodobenzaldehyde
(3.00 g, 21.5 mmol, 1.1 equiv.) and NaBH CN (1.35 g, 21.5 mmol, 1.1 equiv.) were treated using
general procedure A to yield the product (6.19 g, 16.9 mmol, 86%);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
ꢀ1
ν
max(film) /cm 3450, 2358,
). H NMR (400 MHz; CDCl 2.81 (2 H,
qd, J 7.2, 14.0 Hz), 2.93ꢀ3.00 (1 H, m), 3.38 (1 H, dd, J 5.2, 10.8 Hz), 3.70 (1 H, dd, J 3.6, 10.8 Hz),
.80 (2 H, s), 6.95 (1 H, dt, J 2.0, 8.0 Hz), 7.14ꢀ7.18 (2 H, m), 7.19ꢀ7.24 (2 H, m), 7.26ꢀ7.31 (3 H,
20
1
1
645, 1112, 745, 670, 668. [
α]
D
−22.8° (c 1.3, CHCl
3
3 H
) δ
3
1
3
m), 7.79 (1 H, dd, J 1.2, 8.0 Hz); C NMR (100 MHz; CHCl
3
)
δ
C
38.4, 55.7, 59.5, 62.7, 100.0,
+
1
26.7, 128.5, 128.8, 129.1, 129.4, 129.9, 138.4, 139.7, 142.0; m/z found for [M+H] 368.0506;
+
[C16H18INO+H] requires 368.0510.
(
aS,3S,13bR)-3,13b-Dimethyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepine 24
(2S)ꢀ2ꢀ(2’ꢀIodoꢀbenzylamino)ꢀpropanꢀ1ꢀol 20 (1.05 g, 3.60 mmol) and 2ꢀacetyl phenylboronic acid
1.77 g, 10.8 mmol, 3 equiv.) were treated using general procedure B to yield the product (0.21 g,
(
ꢀ1
20
D
0
.80 mmol, 22%);
ν
max(film) /cm 3377, 2966, 1448, 1365, 1217, 1161, 1097, 1046, 756, 738. [
α]
1
−
69.2 ° (c 0.96, CHCl ); H NMR (400 MHz; CDCl ) δH 0.98 (3 H, s), 1.22 (3 H, d, J 6.0 Hz), 2.85ꢀ
3
3
2.94 (1 H, m), 3.01 (1 H, d, J 10.8 Hz), 3.68 (1 H, dd, J 7.6, 9.6 Hz), 3.86 (1 H, d, J 11.2 Hz), 4.20 (1
1
3
H, dd, J 6.4, 7.6 Hz), 7.32ꢀ7.46 (7 H, m), 7.74ꢀ7.79 (1 H, m); C NMR (100 MHz; CHCl
3 C
) δ 15.9,
3
0.5, 52.9, 59.7, 71.7, 97.5, 121.8, 125.9, 127.6, 127.7, 128.1, 128.7, 129.0, 129.3, 134.9, 136.9,
+
+
142.4; m/z found for [M+H] 266.1542; [C18H19NO+H] requires 266.1539.
(
aS,3S,13bR)-13b-Methyl-3-isopropyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepine 25
(2S)ꢀ2ꢀ(2’ꢀIodobenzylamino)ꢀ3ꢀmethylꢀbutanꢀ1ꢀol 21 (1.30 g, 4.09 mmol) and 2ꢀacetyl
phenylboronic acid (2.01 g, 12.3 mmol, 3 equiv.) were treated using general procedure B to yield the
ꢀ1
product (0.54 g, 1.90 mmol, 47%); νmax(film) /cm 3419, 2954, 2871, 1459, 1365, 1213, 1160, 1043,
20
1
7
56, 730. [
D 3 3 H
α] – 98.8 ° (c 1.21, CHCl ). H NMR (400 MHz; CDCl ) δ 0.96 (3 H,s), 0.99 (6 H, d,
J 6.8 Hz), 1.88 (1 H, octet, J 6.8 Hz), 2.82 (1 H, q, J 6.0 Hz), 3.24 (1 H, d, J 11.2 Hz), 3.74 (1 H, d, J
1
1.2 Hz), 3.86 (1 H, dd, J 6.0, 8.0 Hz), 4.02 (1 H, dd, J 7.0, 8.0 Hz), 7.34ꢀ7.37 (2 H, m), 7.38ꢀ7.43 (3
13
H, m), 7.44ꢀ7.48 (2 H, m), 7.69ꢀ7.74 (1 H, m); C NMR (100 MHz; CHCl
3
)
C
δ 17.1, 19.6, 30.2,
30.5, 54.3, 65.8, 70.1, 98.2, 125.2, 127.6, 127.90, 127.91, 128.0, 128.3, 129.1, 135.8, 137.4, 140.5,
+
+
1
42.1; m/z found for [M+H] : 294.1857 [C20
H
23NO+H] requires 294.1852.
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6
(
aR,3R,13bS)-13b-Methyl-3-benzyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepine 26
(2R)ꢀ2ꢀ(2’ꢀIodobenzylamino)ꢀ3ꢀphenylꢀpropanꢀ1ꢀol 22 (1.00 g, 2.70 mmol) and 2ꢀacetyl
phenylboronic acid (1.34 g, 8.20 mmol, 3 equiv.) were treated using general procedure B to yield the
ꢀ1
product (0.51 g, 1.60 mmol, 60%); (
ν
max(film) /cm 2926, 1493, 1452, 1365, 1215, 1158, 1069,
2
0
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1043, 761, 738, 700. [
α]
−130.1° (c 0.99, CHCl
); H NMR (500 MHz; CDCl
)
δ
H
0.93 (3 H, s),
D
3
3
2
7
7
δ
1
3
.60ꢀ2.67 (1 H, m), 2.99ꢀ3.06 (2 H, m), 3.09 (1 H, d, J 11 Hz), 3.66 (1 H, d, J 11 Hz), 3.75 (1 H, t, J
.5 Hz), 3.93 (1 H, dd, J 6.5, 8.0 Hz). 7.11ꢀ7.16 (3 H, m), 7.18ꢀ7.24 (3 H, m), 7.24ꢀ7.27 (1 H, m),
1
3
.27ꢀ 7.32 (2 H, m), 7.32ꢀ7.39 (3 H, m), 7.63 (1 H, dd, J 1.5, 7.5 Hz); C NMR (125 MHz; CHCl
3
)
C
30.6, 39.7, 53.5, 66.2, 69.9, 98.1, 125.4, 126.4, 127.5, 127.8, 128.0, 128.5, 129.0, 129.1, 129.2,
+
+
35.0, 137.1, 138.8, 140.1, 142.0; m/z found for [M+H] : 342.1853; [C24H23NO+H] requires
42.1858.
(
aS,3S,13bR)-13b-Methyl-3-benzyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepine 27
2S)ꢀ2ꢀ(2’ꢀIodobenzylamino)ꢀ3ꢀphenylpropanꢀ1ꢀol 23 (1.00 g, 2.70 mmol) and 2ꢀacetyl
phenylboronic acid (1.34 g, 8.20 mmol, 3 equiv.) were treated using general procedure B to yield the
(
ꢀ1
product (0.27 g, 0.80 mmol, 30%);
ν
max(film) /cm 2926, 1493, 1452, 1365, 1215, 1158, 1069, 1043,
20
1
7
2
61, 738, 700. [
α]
+130.9° (c 1.10, CHCl ). H NMR (400 MHz; CDCl ) δH 1.01 (3 H, s), 2.68ꢀ
D
3
3
.76 (1 H, m), 3.07ꢀ3.19 (3 H, m), 3.75 (1 H, d, J 10.8 Hz), 3.83 (1 H, t, J 7.6 Hz), 4.02 (1 H, dd, J
6.2, 7.6 Hz), 7.20ꢀ7.26 (3 H, m), 7.27ꢀ7.33 (3 H, m), 7.34ꢀ7.41 (3 H, m), 7.42ꢀ7.48 (3 H, m), 7.68ꢀ
1
3
7
1
.72 (1 H, m); C NMR (100 MHz; CHCl
3
)
δ
C
30.7, 39.7, 53.6, 66.3, 70.0, 98.2, 125.5, 126.5,
+
27.6, 127.9, 128.0, 128.6, 129.1, 129.2, 129.3, 135.0, 137.1, 138.9, 140.1, 142.1; m/z [M+H] :
+
342.1853; [C24
H
23NO+H] requires 342.1858.
(aS,3S,13bR)-3,13b-Dimethyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepin-5-ium
tetraphenylborate salt 28
Compound 24 (0.21 g, 0.80 mmol) in dichloromethane (2 mL) and Nꢀbromosuccinimide (0.29 g,
1
.60 mmol, 2 equiv.) were treated using general procedure C to yield the product (0.20 g, 0.59 mmol,
ꢀ1
20
74%); νmax(film) /cm 2965, 1704, 1652, 1558, 1259, 1184, 1102, 1017, 763, 615. [
α]
107.6 ° (c
D
1
1
0.3, CHCl
3
); H NMR (500 MHz; d6ꢀacetone)
δ
H
1.56 (3 H, s), 1.90 (3 H, d, J 6.8 Hz), 4.48 (1 H,
dd, J 2.9, 9.5 Hz), 4.54 (1 H, dd, J 5.3 & 9.5 Hz), 4.96ꢀ5.03 (1 H, m), 6.74ꢀ6.78 (4 H, m), 6.91 (8 H,
t, J 7.4 Hz), 7.31ꢀ7.35 (8 H, m), 7.71 (1 H, dt, J 1.5, 7.5 Hz), 7.76 (1 H, dt, J 1.4, 7.5 Hz), 7.84ꢀ7.89
(2 H, m), 7.91 (1 H, dd, J 1.1, 7.6 Hz), 8.10 (1 H, dt, J 1.2, 7.4 Hz), 8.16ꢀ8.20 (2 H, m), 9.67 (1 H,
13
s); C NMR (125 MHz; d6ꢀacetone)
δ
C
19.7, 23.4, 65.8, 71.5, 100.4, 122.3, 124.6, 126.0 (q, 3 Hz),
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29.9, 131.4, 131.5, 131.7, 132.6, 134.6, 136.0, 137.0, 137.9, 139.3, 143.1, 164.4, 164.8, 165.1,
+
65.5, 165.7; m/z found for iminium cation: 264.1385; C H NO requires 264.1383.
18
18
(aS,3S,13bR)-13b-Methyl-3-isopropyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepin-5-ium
tetraphenylborate salt 29
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 25 (0.54 g, 1.90 mmol) in dichloromethane (2 mL) and Nꢀbromosuccinimide (0.68 g,
3
.80 mmol, 2 equiv.) were treated using general procedure C to yield the product (0.57 g, 1.50 mmol,
ꢀ1
8
1%);
ν
max(film) /cm 3055, 2998, 1639, 1596, 1579, 1559, 1479, 1425, 1377, 1184, 1031, 734.
20
1
[
α
]
D
+236.8 ° (c 2.0, CHCl
3
); H NMR (500 MHz; d6ꢀacetone)
δ
H
1.24 (3 H, d, J 7.0 Hz), 1.26 (3
H, d, J 7.0 Hz), 1.54 (3 H, s), 2.64 (1 H, sextet, J 7.0 Hz), 4.47 (1 H, dd, J 5.0, 10.0 Hz), 4.60 (1 H,
tt, J 1.5, 6.5 Hz), 4.72 (1 H, dd, J 2.0, 10.0 Hz), 6.79 (4 H, t, J 7.2 Hz), 6.93 (8 H, t, J 7.5 Hz), 7.33ꢀ
7
.37 (8 H, m), 7.73 (1 H, td, J 1.5, 7.5 Hz), 7.77 (1 H, td, J 1.5, 7.5 Hz), 7.83ꢀ7.87 (2 H, m), 7.92 (1
H, dd, J 1.5, 7.5 Hz), 8.09 (1 H, td, J 1.5, 7.5 Hz), 8.14 (1 H, dd, J 1.5, 7.5 Hz), 8.18 (1 H, d, 7.5 Hz),
13
9
1
C
.50 (1 H, s); C NMR (125 MHz; d6ꢀacetone) δ 17.8, 19.2, 22.2, 31.9, 67.4, 73.6, 100.3, 122.0,
24.3, 125.6, 125.73, 125.75, 125.77, 125.80, 129.7, 131.0, 131.2, 131.4, 132.4, 134.4, 135.6,
+
136.75, 136.76, 137.6, 139.2, 142.7, 164.1, 164.5, 164.9, 165.3, 166.2; m/z found for M (iminium
+
cation) 292.1704; [C20
H
22NO] requires 292.1701.
(aR,3R,13bS)-13b-Methyl-3-phenyl-2,3-dihydro-13bH-dibenz[c,e]oxazolo[3,2-a]azepin-5-ium
tetraphenylborate salt 8
Compound 9 (0.43 g, 1.32 mmol) in dichloromethane (2 mL) and Nꢀbromosuccinimide (0.47 g, 2.64
mmol, 2 equiv.) were treated using general procedure C to yield the product as a pair of
ꢀ1
diastereoisomers (0.27 g, 0.66 mmol, 50%);
ν
max(film) /cm 3055, 1709, 1641, 1596, 1579, 1557,
20
1
1
479, 1426, 1361, 1222, 731, 703. [
α]
D
– 9.2 ° (c 1.3, acetone). H NMR (500 MHz; d6ꢀacetone)
δH 1.65 (3 H, s), 4.85 (1 H, dd, J 5.0, 10.0 Hz), 4.89 (1 H, dd, J 6.5, 10.0 Hz), 5.79 (1 H, dt, J 1.0, 5.8
Hz), 6.72ꢀ6.77 (4 H, m), 6.88 (8 H, t, J 7.5 Hz), 7.28ꢀ7.34 (8 H, m), 7.57ꢀ7.60 (3 H, m), 7.68ꢀ7.72 (2
H, m), 7.72ꢀ7.75 (2 H, m), 7.80 (1 H, dt, J 1.5, 7.5 Hz), 7.90 (2 H, dt, J 1.5, 7.5 Hz), 7.95 (1 H, dd, J
13
1
.0, 8.0 Hz), 8.05 (1 H, dt, J 1.5, 8.0 Hz), 8.16 (1 H, d, J 7.5 Hz), 9.27 (1 H, d, J 1.5 Hz); C NMR
(125 MHz; d6ꢀacetone) δC 21.4, 71.08, 71.15, 99.8, 121.4, 124.0, 125.1 (q, J 3Hz), 128.6, 128.8,
1
29.1, 129.9, 130.4, 130.6, 130.7, 130.9, 131.8, 135.6, 136.2 (q, J 1 Hz), 137.4, 142.5, 163.5, 163.9,
+
+
1
64.3, 164.7, 165.7. m/z found for M (iminium cation) 326.1549; [C23H20NO] requires 326.1545.
(aR,3R,13bS)-13b-Methyl-3-benzyl-2,3-dihydro-13bHdibenz[c,e]oxazolo[3,2-a]azepin-5-ium;
tetraphenylborate salt 30
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2
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2
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2
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3
3
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5
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6
Compound 26 (0.26 g, 0.80 mmol) in dichloromethane (2 mL) and Nꢀbromosuccinimide (0.29 g,
1
.60 mmol, 2 equiv.) were treated using general procedure C to yield the product (0.28 g, 0.66 mmol,
ꢀ1
82%); νmax(film) /cm 3051, 3013, 1642, 1598, 1581, 1557, 1481, 1426, 1381, 1183, 1031, 1016,
2
0
1
7
3
5
7
67, 755, 716, 714. [
α]
– 30.3 ° (c 1.4, CHCl ); H NMR (500 MHz; d6ꢀacetone) δH 1.59 (3 H, s),
D 3
.61 (2 H, dq, J 7.5, 13.5 Hz), 4.49 (1 H, dd, J 5.0, 10.0 Hz), 4.66 (1 H, dd, J 1.5, 10.0 Hz), 5.06ꢀ
.13 (1 H, m), 6.76 (4 H, t, J 7.0 Hz), 6.91 (8 H, t, J 7.0 Hz), 7.30ꢀ7.35 (8 H, m), 7.44ꢀ7.52 (5 H, m),
.70 (1 H, td, J 1.5, 7.5 Hz), 7.71 (1 H, dd, J 1.5, 8.0 Hz), 7.75 (1 H, td, J 1.5, 7.5 Hz), 7.82 (1 H, td,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J 1.0, 8.0 Hz), 7.85 (1 H, td, J 1.5, 7.5 Hz), 7.89 (1 H, dd, J 1.5, 8.0 Hz), 8.08 (1 H, td, J 1.5, 7.5 Hz),
1
3
8
.16 (1 H, d, J 7.5 Hz), 8.91 (1 H, s); C NMR (125 MHz; d6ꢀacetone) δC 23.3, 40.2, 70.1, 70.5,
100.9, 122.2, 124.4, 125.5, 125.98, 126.00, 126.02, 126.04, 128.9, 130.0, 130.3, 130.9, 131.4, 131.5,
1
1
31.7, 132.7, 134.6, 135.3, 136.0, 137.04, 137.05, 138.0, 139.2, 143.0, 134.4, 164.8, 165.2, 165.5,
+
+
65.8; m/z found for M (iminium cation) 340.1707; [C24H22NO] requires 340.17014.
(aS,3S,13bR)-13b-Methyl-3-benzyl-2,3-dihydro-13bHdibenz[c,e]oxazolo[3,2-a]azepin-5-ium,
tetraphenylborate salt 31
Compound 27 (0.51 g, 1.60 mmol) in dichloromethane (5 mL) and Nꢀbromosuccinimide (0.57 g,
3
7
6
.20 mmol, 2 equiv.) were treated using general procedure C to yield the product (0.62 g, 1.20 mmol,
ꢀ1
5%);
ν
max(film) /cm 3445, 2358, 1714, 1654, 1616, 1558, 1454, 1404, 1257, 1182, 1104, 744, 701,
2
0
1
68; [
α]
+15.0 ° (c 1.07, CHCl ); H NMR (400 MHz; d6ꢀacetone) δH 1.58 (3 H, s), 3.58 (2 H,
D
3
dq, J 7.6, 13.6 Hz), 4.45 (1 H, dd, J 5.2, 10.0 Hz), 4.62 (1 H, dd, J 1.2, 10.0 Hz), 4.98ꢀ5.06 (1 H, m),
.76 (4 H, t, J 7.2 Hz), 6.90 (8 H, t, J 7.6 Hz), 7.30ꢀ7.36 (8 H, m), 7.43ꢀ7.52 (5 H, m), 7.67 (1 H, dd,
6
J 1.2, 7.6 Hz), 7.70 (1 H, td, J 1.6, 7.6 Hz), 7.75 (1 H, td, J 1.6, 7.6 Hz), 7.80 (1 H, td, J 1.2, 7.6 Hz),
7.85 (1 H, td, J 1.6, 8.0 Hz), 7.88 (1 H, dd, J 1.6, 7.6 Hz), 8.06 (1 H, td, J 1.2, 8.0 Hz), 8.14 (1 H, d, J
13
7
.2 Hz), 8.84 (1 H, s); C NMR (125 MHz; d6ꢀacetone) δC 23.4, 40.3, 70.1, 70.5, 101.0, 122.4,
1
24.5, 125.5, 126.10, 126.12, 126.15, 126.18, 129.0, 130.1, 130.4, 131.0, 131.5, 131.6, 131.8, 132.8,
+
134.7, 135.5, 137.13, 137.15, 139.3, 143.1, 164.3, 164.8, 165.8, 165.9; m/z found for M (iminium
+
cation) 340.1701; [C24
H
22NO] requires 340.1701.
24
1-Phenylcyclohexene oxide
ꢀ1
Isolated as a colourless oil: νmax(neat)/cm 3083, 1602, 1495, 1445, 1359, 1248, 1174, 1133, 1078,
1
1
030, 993, 974; H NMR (300 MHz; CDCl
3
)
δ
H
1.20ꢀ1.33 (1 H, m), 1.51ꢀ1.62 (3 H, m), 1.97ꢀ2.05 (2
H, m), 2.16ꢀ2.18 (1 H, m), 2.24ꢀ2.31 (1 H, m), 3.10 (1 H, t, J = 2.0 Hz), 7.26ꢀ7.41 (5 H, m).
2
4
1
-Phenyldihydronaphthalene oxide
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ꢀ
1
Isolated as a colourless crystalline solid:
νmax(neat)/cm 3087, 1601, 1493, 1284, 1176, 1158, 1094,
1
1
2
7
072, 1028; H NMR (300 MHz; CDCl ) δH 2.10 (1 H, td, J = 15.5 Hz, 5.6 Hz) 2.48ꢀ2.59 (1 H, m),
3
.76 (1 H, dd, J = 15.5 Hz, 5.5 Hz) 2.96ꢀ3.07 (1 H, m), 3.70 (1 H, d, J = 3.0 Hz), 7.09ꢀ3.29 (4 H, m),
.45ꢀ7.60 (5 H, m). HPLC conditionsꢀhexane/2ꢀpropanol (90:10), oven temp 20 °C, column Chiracel
r
ODꢀH 01 250 × 4.6 mm, 5 ꢁm particle size, flow rate 1 mL/min, 254 nm: t ꢀ4.51 min (–)ꢀ(1S,2R),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
.94 min (+)ꢀ(1R,2S).
24
(E)-Stilbene oxide
ꢀ
1
Isolated as a colourless crystalline solid: νmax(neat)/cm 3081, 1776, 1602, 1485, 1336, 1155, 1074,
1
1042, 953; H NMR (400 MHz; CDCl
3
)
δ
H
3.87 (2 H, s), 7.29ꢀ7.39 (10 H, m);
δ
C
(75 MHz; CDCl
3
)
6
3.3, 126.0, 128.6, 129.3, 137.6. HPLC conditionsꢀhexane/2ꢀpropanol (80:20), oven temp 20 °C,
column Chiracel ODꢀH 01 250 × 4.6 mm, 5 ꢁm particle size, flow rate 1 mL/min, 254 nm: t
min (–)ꢀ(1S,2S), 6.54 min (+)ꢀ(1R,2R).
r
ꢀ4.98
8
Dihydronaphthalene oxide
ꢀ1
Isolated as a colourless oil:
ν
max(neat)/cm 3058, 3028, 2931, 2850, 1602, 1492, 1314, 1129, 1088,
1
1031, 965; H NMR (400 MHz; CDCl
3
)
δ
H
1.65ꢀ1.84 (1 H, m), 2.33ꢀ2.42 (1 H, m), 2.52 (1 H, dd, J
=
15.5 Hz, 5.5 Hz), 2.67ꢀ2.85 (1 H, m), 3.71ꢀ3.80 (1 H, m), 3.81ꢀ3.89 (1 H, m), 7.05 (1 H, d, J = 7.2
Hz), 7.18ꢀ7.35 (2 H, m), 7.40 (1 H, d, J = 7.1 Hz).
8
Triphenylethylene oxide
ꢀ1
Isolated as a colourless crystalline solid:
νmax(neat)/cm 3061, 3031, 2956, 2924, 2857, 1604, 1595,
1
1
498, 1471, 1448, 1262, 1220, 741, 699; H NMR (400 MHz; CDCl
(15H, m). HPLC conditionsꢀhexane/2ꢀpropanol (90:10), oven temp 20 °C, column Chiracel ODꢀH
1 250 × 4.6 mm, 5 ꢁm particle size, flow rate 1 mL/min, 254 nm: t – 4.26 min (+)ꢀ(S), 7.47 min (–
ꢀ(R).
3 H
) δ 4.42 (1 H, s), 7.13ꢀ 5.50
0
r
)
Crystallography
For 9 and 27 diffraction data were collected at 150(2)K and corrections were made for absorption,
Lorentz, and polarization factors. Both structures were solved by direct methods and were routine in
nature. The absolute structures could not be determined reliably from the diffraction data, so were set
from unchanging chiral centres. For 9: C H NO, M = 327.41, monoclinic, P2 , a = 8.4016(5), b =
23
21
1
3
9.9253(6), c = 10.5431(7) Å, β = 97.2928(9)°, V = 872.06(9) Å , Z = 2, colourless crystal, 0.32
×
3
3
–1
0
.29
×
0.10 mm , Dcalc = 1.247 g/cm ,
ꢀ
(MoꢀK
α
) = 0.076 mm , 9089 data measured, Rint = 0.020,
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9
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
wR
2
= 0.090 for all 4258 unique data, R1 = 0.037 for 3932 data with F ≥ 2
σ
(F ). For 27: C24
H23NO,
M = 341.43, monoclinic, P2
1
, a = 8.5648(4), b = 9.8551(5), c = 11.1777(5) Å, β = 98.4207(7)°, V =
3
3
3
933.30(8) Å , Z = 2, colourless crystal, 0.52
×
0.38
×
0.36 mm , D = 1.247 g/cm ,
ꢀ
(MoꢀK
= 0.119 for all 5541 unique data, R1 = 0.044 for
(F ). CCDC 1400420ꢀ1400421 contain supplementary crystallographic data
These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge, CB2
EZ, UK. Fax +44 1223 336033, eꢀmail: deposit@ccdc.cam.ac.uk.).
α) =
calc
–1
0
.073 mm ,11151 data measured, Rint = 0.022, wR
2
2
2
4
987 data with F ≥ 2
cif format.
σ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in
1
Acknowledgments
This investigation has enjoyed the support of Loughborough University, the EPSRC, the University
of East Anglia, and the ERDF (ISCEꢀChem & INTERREG IVa programme 4061). We are indebted
to the Royal Society for an Industry Fellowship (to PCBP) and the EPSRC national mass
spectrometry service at the University of Wales, Swansea.
Supporting Information
1
13
Supporting Information: H and C NMR spectra; Displacement ellipsoid plots of 9 and 27. This
material is available free of charge via the Internet at http://pubs.acs.org/.
References
1
)
(a) Behrens, C.H.; Sharpless, K. B. Aldrichimica Acta 1983, 16, 67; (b) Gorzynski Smith, J.
Synthesis 1984, 629; (c) Katsuki, T. Coord. Chem. Rev. 1995, 140, 189; (d) Paquette, L. A.;
Gao, Z.; Ni, Z.; Smith, G. F. J. Am. Chem. Soc. 1998, 120, 2543; (e) Amano, S.; Ogawa, N.;
Ohtsuka, M.; Chinda, N. Tetrahedron 1999, 55, 2205; (f) Wong, O. A.; Shi, Y. Chem. Rev.
2
008, 108, 3958.
2)
See for example: (a) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis,
Ojima, I., Ed.; VCH: New York, 1993; (b) Katsuki, T. In Comprehensive Asymmetric
Catalysis, Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds., Springer: Berlin, 1999, Vol. 2, p
621.; (c) Jacobsen, E. N.; Wu, M.H. In Comprehensive Asymmetric Catalysis, Jacobsen, E.
N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2, p 649; (d) Julia, S.;
Masana, J.; Vega, J. C. Angew. Chem. Int. Ed. Engl. 1980, 19, 929; (e) Allen, J. V.;
Bergeron, S.; Griffiths, M. J.; Mukherjee, S.; Roberts, S. M.; Williamson, N. M.; Wu, L. E. J.
Chem. Soc., Perkin Trans. 1 1998, 3171; (f) Katsuki, T.; Sharpless, K. B. J. Am. Chem Soc.
1
980, 102, 5974; (g) Michaelson, R. C; Palermo, R. E.; Sharpless, K. B. J Am. Chem. Soc.
22
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Page 23 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
977, 99, 1990; (h) Groves, J. T.; Nemo, T. E.; Myers, R. S. J. Am. Chem. Soc., 1979, 101,
032; (i) Groves, J. T.; Myers, R. S. J. Am. Chem. Soc., 1983, 105, 5791; (j) Cavallo, L.;
1
Jacobsen, H. Inorg. Chem. 2004, 43, 2175; (k) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.;
Katsuki, T. Tetrahedron Lett. 1990, 31, 7345; (l) Kawai, H.; Okusu, S.; Yuan, Z.; Tokunaga,
E.; Yamano, A.; Shiro, M.; Shibata, M. Angew. Chem. Int. Ed. 2013, 52, 2221.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3)
See for example; (a) Tu, Y.; Wang, Z.ꢀX.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806; (b)
Wang, Z.ꢀX.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62, 2328; (c) Wang, Z.ꢀX.; Shi,
Y. J. Org. Chem. 1998, 63, 3099; (d) Wang, Z.ꢀX.; Shi, Y. J. Org. Chem. 1997, 62, 8622; (e)
Cao, G. A.; Wang, Z.ꢀX.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425; (f) Zhu, Y.; Tu,
Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819; (g) Yong, T.; Wang, Z. X.; Frohn, M.;
He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475; (h) Warren, J. D.; Shi, Y. J.
Org. Chem. 1999, 64, 7675; (i) Frohn, M.; Zhou, X.; Zhang, J.ꢀR.; Tang, Y.; Shi, Y. J. Am.
Chem. Soc. 1999, 121, 7718; (j) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40, 8721; (k) Shu,
L.; Shi, Y. J. Org. Chem. 2000, 65, 8807; (l) Tian, H.; She, X.; Xu, J.; Shi, Y. Org. Lett.
2001, 3, 1929; (m) Tian, H.; She, X.; Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435;
(n) Wu, X.ꢀY.; She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792; (o) Denmark, S. E.; Wu,
Z. Synlett 1999, 847; (p) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; DePue, J. S.; Wilde, R.
G. J. Org. Chem. 1995, 60, 1391; (q) Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002,
6
7, 3479; (r) Yang, D.; Yip, Y.ꢀC.; Tang, M.ꢀW.; Wong, M.ꢀK.; Zheng, J.ꢀH.; Cheung, K.ꢀK.
J. Am. Chem. Soc. 1996, 118, 491; (s) Yang, D.; Wang, X. C.; Wong, M.ꢀK.; Yip, Y.ꢀC.;
Tang, M.ꢀW. J. Am. Chem. Soc. 1996, 118, 11311; (t) Yang, D.; Wong, M.ꢀK.; Yip, Y.ꢀC.;
Wang, X. C.; Tang, M.ꢀW.; Zheng, J.ꢀH.; Cheung, K.ꢀK. J. Am. Chem. Soc. 1998, 120, 5943;
(u) Yang, D.; Yip, M. C.; Tang, M. M.; Wong, M. K.; Cheung, K. K. J. Org. Chem. 1998, 63,
9888; (v) Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621; (w) Armstrong, A.;
Ahmed, G.; DominguezꢀFernandez, B.; Hayter, B. R.; Wailes, J. S. J. Org. Chem. 2002, 67,
8
610; (x) Curci, R.; Fiorentino, M.; Serio, M. R. Chem. Commun. 1984, 155.
4)
Picot, A.; Milliet, P.; Lusinchi, X. Tetrahedron Lett. 1976, 17, 1573; Milliet, P.; Picot, A.;
Lusinchi, X. Tetrahedron Lett. 1976, 17, 1577.
5
)
(a) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett., 1987, 28, 6061; (b) Hanquet, G.;
Lusinchi, X.; Milliet, P. Tetrahedron Lett. 1988, 29, 3941; (c) Bohé, L.; Hanquet, G.;
Lusinchi, M.; Lusinchi, X. Tetrahedron Lett. 1993, 34, 7271; (d) Bohé, L.; Lusinchi, M.;
Lusinchi, X. Tetrahedron, 1999, 55, 141; (e) Lacour, J.; Monchaud, D.; Marsol, C.
Tetrahedron Lett. 2002, 43, 8257; (f) Bohé, L.; Kammoun, M. Tetrahedron Lett. 2002, 43,
8
03; g) Bohé, L.; Kammoun, M. Tetrahedron Lett. 2004, 45, 747; (h) Aggarwal, V. K.;
Wang, M. F. Chem. Commun. 1996, 191; (i) Armstrong, A.; Ahmed, G.; Garnett, I.;
23
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Page 24 of 27
1
2
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Gioacolou, K. Synlett 1997, 1075; (j) Armstrong, A.; Ahmed, G.; Garnett, I.; Gioacolou K.;
Wailes, J. S. Tetrahedron 1999, 55, 2341; (k) Gluszynska, A.; Mackowska, I.;
Rozwadowska, M. D.; Sienniak, W. Tetrahedron: Asymmetry 2004, 15, 2499; (l) Biscoe, M.
R.; Breslow R. J. Am. Chem. Soc. 2005, 127, 10812; (m) Minakata, S.; Takemiya, A.;
Nakamura, K.; Ryu, I.; Komatsu, M. Synlett, 2000, 1810; (n) Wong, M.ꢀK.; Ho, L.ꢀM.;
Zheng, Y.ꢀS.; Ho, C.ꢀY.; Yang, D. Org. Lett. 2001, 16, 2587; (o) Crosthwaite, J. M.; Farmer,
V. A.; Hallett, J. P.; Welton, T. J. Mol. Catal. A 2008, 279, 148; (p) Novikov, R.; Lacour, J.
Tetrahedron: Asymmetry 2010, 21, 1611; (q) Novikov, R.; Vachon, J.; Lacour, J. Chimia,
2007, 61, 236; (r) Vachon, J.; Lauper, C.; Ditrich, K.; Lacour, J. Tetrahedron: Asymmetry
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
006, 17, 2334; (s) Vachon, J.; Rentsch, S.; Martinez, A.; Marsol, C.; Lacour, J. Org. Biomol.
Chem. 2007, 5, 501; (t) Novikov, R.; Bernardinelli, G.; Lacour, J. Adv. Synth. Catal. 2009,
351, 596.
6
)
(a) Gonçalves, M.ꢀH.; Martinez, A.; Grass, S.; Bulman Page, P. C.; Lacour, J. Tetrahedron
Lett. 2006, 47, 5297; (b) Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem. Soc.
2000, 122, 8317; (c) Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem. Soc.
2
002, 124, 11223; (d) Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc. 2003,
1
25, 7596; (e) Ho, C.ꢀY.; Chen, Y.ꢀC.; Wong, M.ꢀK.; Yang, D. J. Org. Chem. 2005, 70, 898.
7)
Farah, M. M.; Page, P. C. B.; Buckley, B. R.; Blacker, A. J.; Elsegood, M. R. J. Tetrahedron
013, 69, 758.
2
8
)
(a) Page, P. C. B.; Buckley, B. R.; Farah, M. M.; Blacker, A. J. Eur. J. Org. Chem. 2009,
3413; (b) Page, P. C. B.; Bartlett, C. J.; Chan, Y.; Day, D. P.; Parker, P.; Buckley, B. R.;
Rassias, G. A.; Slawin, A. M. Z.; Allin, S. M.; Lacour, J.; Pinto, A. J. Org. Chem. 2012, 77,
6
128.
(a) Bulman Page, P. C.; Parker, P.; Buckley, B. R.; Rassias, G. A.; Bethell, D. Tetrahedron,
009, 65, 2910; (b) Buckley, B. R.; Chan, Y.; Dreyfus, N.; Elliott, C. E.; Marken, F.; Page, P.
9)
2
C. B. Green Chem. 2012, 14, 2221 and references therein; (c) Buckley, B. R.; Elliott, C. E.;
Chan, Y.; Dreyfus, N.; Bulman Page, P. C. Synlett, 2013, 2266 and references therein.
Campestrini, S.; Di Furia, F.; Labat, G.; Novello, F. J. Chem. Soc. Perkin Trans. 2 1994, 10,
1
0)
2
175.
11)
(a) Page, P. C. B.; Buckley, B. R.; Barros, D.; Blacker, J. A.; Marples, B. A.; Elsegood, M. R.
J. Tetrahedron. 2007, 63, 5386; (b) Bartlett, C. J.; Day, D. P.; Chan, Y.; Allin, S. M.;
McKenzie, M. J.; Slawin, A. M. Z.; Bulman Page, P. C. J. Org. Chem. 2012, 77, 772; (c)
Bulman Page, P. C.; Appleby, L. F.; Chan, Y.; Day, D.; Buckley, B. R.; Slawin, A. M. Z.;
Allin, S. M.; McKenzie, M. J. J. Org. Chem. 2013, 78, 8074; (d) Page, P. C. B.; Chan, Y.;
Day, D. P.; Eur. J. Org. Chem., 2014, 8029.
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1
2
3
4
5
6
7
8
9
1
2)
(a) Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning,
M. Angew. Chem. Int. Ed. 2005, 44, 5384; (b) Baudoin, O. Eur. J. Org. Chem. 2005, 4223;
(c) Wallace, T. W. Org. Biomol. Chem. 2006, 4, 3197.
1
3)
4)
Wallace, T. W; Pira, S. L.; Graham, J. P. Org. Lett. 2009, 11, 1663.
1
Novikov, R.; Bernardinelli, G.; Lacour, J. Adv. Synth. Catal. 2008, 350, 1113.
Bulman Page, P. C.; Bartlett, C. J.; Chan, Y.; Day, D.; Parker, P.; Buckley, B. R.; Rassias, G.
A.; Slawin, A. M. Z.; Allin, S. M.; Lacour, J.; Pinto, A. J. Org. Chem. 2012, 77, 6128.
(a) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1; (b) Amat, M.; Canto, M.; Llor, N.;
Ponzo, V.; Perez, M.; Bosch, J. Angew. Chem., Int. Ed. 2002, 41, 335; (c) Amat, M.; Canto,
M.; Llor, N.; Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15)
1
6)
(d) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem. 2003, 68, 1919; (e)
Ennis, M. D.; Hoffman R. L.; Ghazal, N. B.; Old, D. W.; Mooney, P. A. J. Org. Chem. 1996,
6
1, 5813; (f) Allin, S. M.; James, S. L.; Elsegood, M. R. J.; Martin, W. P. J. Org. Chem.
2
002, 67, 9464; (g) Houpis, J. N.; Molina, A.; Reamer, R. A.; Joseph, J. E.; Volante, R. P.;
Reider, P. J. Tetrahedron Lett. 1993, 34, 2593; (h) Penhoat, M.; Leleu, S.; Dupas, G.;
Papamicaël, C.; Marsais, F.; Levacher, V. Tetrahedron Lett. 2005, 46, 8385; (i) Husain, S.
M.; Heim, M. T.; Schepmann, D.; Wünsch, B. Tetrahedron: Asymmetry, 2009, 20, 1383; (j)
Penhoat, M.; Bohn, P.; Dupas, G.; Papamicaël, C.; Marsais, F.; Levacher, V. Tetrahedron:
Asymmetry, 2006, 17, 281; (k) Husain, S. M.; Fröhlich, R.; Wünsch B. Tetrahedron:
Asymmetry, 2008, 19, 1613; (l) Bouet, A.; Oudeyer, S.; Dupas, G.; Marsais, F.; Levacher, V.
Tetrahedron: Asymmetry, 2008, 19, 2396.
1
7)
(a) Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517; (b) Ried, W.; Conte,
R. Chem. Ber. 1971, 104, 1573; (c) Edwards, D. J.; Pritchard, R. G.; Wallace, T. W.
Tetrahedron Lett. 2003, 44, 4665; (d) Edwards, D. J.; House, D.; Sheldrake, H. M.; Stone, S.
J.; Wallace, T. W. Org. Biomol. Chem. 2007, 5, 2658; (e) Postikova, S.; Sabbah, M.;
Wightman, D.; Nguyen, I. T.; Sanselme, M.; Besson, T.; Brière, J.ꢀF.; Oudeyer, S.; Levacher,
V. J. Org. Chem. 2013, 78, 8191.
1
8)
(a) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656; (b) Meyers, A. I.; Sowning,
S. V.; Weiser, M. J. J. Org. Chem. 2001, 66, 1413; (c) Husain, S. M.; Fröhlich, R.;
Schepmann, D.; Wünsch, B. J. Org. Chem. 2009, 74, 2788; (d) Wallace, T. W; Pira, S. L.;
Graham, J. P. Org. Lett. 2009, 11, 1663.
1
9)
0)
(a) Campeau, L.ꢀC.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126,
9186; (b) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849; (c) Lafrance, M.; Lapointe, D.;
Fagnou, K. Tetrahedron, 2008, 64, 6015.
2
Cheetham, C. A.; Massey, R. S.; Pira, S. L.; Pritchard, R. G.; Wallace, T. W. Org. Biomol.
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5
6
Chem. 2011, 9, 1831.
2
1)
2)
Bulman Page, P. C.; Farah, M. M.; Buckley, B. R.; Blacker, A. J.; Lacour, J. Synlett, 2008,
1381.
2
APEX 2 and SAINT (2006), software for CCD diffractometers. Bruker AXS Inc., Madison,
USA.
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
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8
9
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7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
23)
(a) Sheldrick, G. M. Acta Cryst., 2015, C71, 3; (b) Sheldrick, G. M. SHELXTL user manual,
version 6.12. Bruker AXS Inc., Madison, WI, USA, 2001.
Bulman Page, P. C.; Rassias, G. A.; Bethell, D.; Schilling, M. B. J. Org. Chem. 1998, 63,
2774.
2
4)
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
27
ACS Paragon Plus Environment