The asymmetric aminohydroxylation route to GABOB and homoserine derivatives

Article abstract of DOI:10.1016/j.tet.2008.11.037

The 4-nitrophenyl ether is an efficient directing group in the asymmetric aminohydroxylation reaction of homoallylic ether derivatives. Either regioisomeric product can be obtained with useful levels of enantioselectivity allowing for the short enantiosel

Full text of DOI:10.1016/j.tet.2008.11.037

Tetrahedron 65 (2009) 831–843
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The asymmetric aminohydroxylation route to GABOB and homoserine derivatives
,
Michael Harding a, Jennifer A. Bodkin a, Fatiah Issa a, Craig A. Hutton b c, Anthony C. Willis d,
,d,
Malcolm D. McLeod a
*
a School of Chemistry, University of Sydney, Sydney NSW 2006, Australia
b School of Chemistry, University of Melbourne, VIC 3010, Australia
c Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, VIC 3010, Australia
d Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The 4-nitrophenyl ether is an efficient directing group in the asymmetric aminohydroxylation reaction of
homoallylic ether derivatives. Either regioisomeric product can be obtained with useful levels of enan-
tioselectivity allowing for the short enantioselective synthesis of GABOB and homoserine derivatives. A
model based on substrate-catalyst interactions is presented to explain the regio- and enantioselectivity
of the aminohydroxylation reactions.
Received 29 September 2008
Received in revised form 26 October 2008
Accepted 13 November 2008
Available online 18 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric aminohydroxylation
Amino acid
Osmium
Asymmetric catalysis
Regioselective
1. Introduction
The osmium-catalysed asymmetric aminohydroxylation (AA) of
alkenes has become a powerful tool for the synthesis of the vicinal
amino alcohol functional array and has been applied to the con-
struction of numerous biologically important targets.1 Despite this
success, the levels of regio- and enantioselectivity obtained for
some alkene substitution patterns are not always synthetically
useful.
Scheme 1. Proposed synthesis of GABOB 1 and homoserine 2 derivatives from but-3-
en-1-ol.
Research within our laboratory2–4 and by other groups5–7 has
shown that the interaction of substrate and catalyst plays a pivotal
role in controlling selectivity in the AA reaction. In a previous
study3 we demonstrated that the AA reaction of the 4-nitrophenyl
ether of but-3-en-1-ol granted selective access to either regioiso-
meric product, providing synthetic access to the unusual amino
acids, (3R)-(ꢀ)-4-amino-3-hydroxybutyric acid (GABOB) 1 and
homoserine 2 in protected form (Scheme 1). In this paper we
provide complete experimental details of this work and extend this
study to propose an explanation based on substrate-catalyst in-
teractions for the observed changes in AA regioselectivity.
2. Results and discussion
2.1. Synthesis of GABOB in protected form
Our initial goal was the synthesis of the unusual amino acid
GABOB 1, which has been identified as a key fragment of the
microsclerodermins, a family of marine cyclic peptides possessing
anti-tumour and anti-fungal activity.8 It is also an agonist of the
g
-amino-butyric acid (GABA) receptor and is used in the treatment
of epilepsy and hypertension.9
The proposed synthesis required aminohydroxylation of pro-
tected but-3-en-1-ol 3a–g to give the terminal amine regioisomers
4a–g (Table 1). Although the selective AA of styrenes to give ter-
minal alcohol products is well documented in the literature,10 ox-
idation to afford the terminal amine regioisomer usually occurs
with lower levels of selectivity.10a The oxidation of other terminal
* Corresponding author at present address: Research School of Chemistry, Aus-
tralian National University, Canberra, ACT 0200, Australia. Tel.: þ612 6125 3504;
fax: þ612 6125 8114.
E-mail address: m.mcleod@rsc.anu.edu.au (M.D. McLeod).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.037

832
M. Harding et al. / Tetrahedron 65 (2009) 831–843
Table 1
The (DHQD)2AQN-mediated synthesis of terminal amine regioisomers 4a–g
R2OCONH2
R1O
NH
OR2
(DHQD)2AQN (5 mol%)
K2OsO4.2H2O (4 mol%)
HO
HN
O
R1O
3a-g
4a-g
R1O
1,3-dichloro-5,5-dimethyl
hydantoin, NaOH
H2O, PrOH
OH
OR2
5a-g
O
Entry Substrate R1
R2
Ratioa (4/5) Yield of 4 (%) eeb (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3e
3a
3b
3c
3d
3e
3e
3f
4-MeO-Ph
3,4-Di-MeO-Ph
4-Br-Ph
tBu
tBu
tBu
tBu
tBu
Me
6/1
5/1
8/1
7/1
9/1
9/1
56
53c
66
61
73
61
61
53c
63
62
67
61
48
56
71
65
63
73
73
79
79
78
76
75
81
72f
77
65
4-Me-Ph
4-NO2-Ph
4-NO2-Ph
4-MeO-Ph
3,4-Di-MeO-Ph
4-Br-Ph
4-Me-Ph
4-NO2-Ph
4-NO2-Ph
TMSEd 5/1
TMSE 5/1
TMSE 7/1
TMSE 7/1
TMSE 10/1
TMSE 9/1
9
10
11
12e
13
14
2,6-Di-Me-4-NO2-Ph TMSE 9/1
TBDPSg
TMSE 9/1
3g
a
Determined by integration of the 300 MHz 1H NMR spectrum of crude reaction
mixture.
b
Determined by chiral HPLC.
c
d
e
f
Chlorination occurs to afford the 2-chloro-4,5-dimethoxyphenyl ether products.
TMSE¼2-(trimethylsilyl)ethyl.
(DHQ)2AQN ligand used.
Product formed with (S)-configuration.
TBDPS¼tert-butyldiphenylsilyl.
g
Figure 1. Sharpless ligands.
alkene substrates also typically proceeds with poor regio- or
enantioselectivity.1l,11
Table 2
Mosher’s ester analysis of terminal amine regioisomer 4e
Previous work has demonstrated that aryl ethers are effective
directing groups in the AA of structurally related unsaturated ester
derivatives and AQN ligands were expected to favour the terminal
amine regioisomer.2–4 Initial studies used 4-methoxyphenyl but-3-
en-yl ether 3a12 as substrate and tert-butyl carbamate10a as the
nitrogen source in concert with the (DHQD)2AQN ligand (Fig. 1).13
The reaction afforded a 6:1 mixture14 of the two regioisomeric
products 4a and 5a (R2¼tBu), from which the amino alcohol 4a
could be isolated in 56% yield with an enantiomeric excess of 71%
(Table 1, entry 1).15
Different aromatic ethers (3a–f) and nitrogen sources were
surveyed in an effort to improve the selectivity in this AA trans-
formation. In all cases (Table 1, entries 2–13) the major product 4a–f
was that formed from addition of nitrogen to the terminal end of the
alkene. The highest regioselectivities were observed with the 4-
nitrophenyl ether 3e (entries 5, 6,11 and 12) and moderately higher
enantioselectivity was obtained using the sterically undemanding
methyl carbamate3 (entry 6) or 2-(trimethylsilyl)ethyl (TMSE) car-
bamate16 (entries 7–13). Thus, the best results were obtained when
the 4-nitrophenyl ether was employed with TMSE carbamate to give
a 67% isolated yield of regioisomer 4e (R2¼TMSE) in 81% ee.
The absolute configuration of 4e (R2¼TMSE) was confirmed by
the formation of (S) and (R)-Mosher’s esters, 6 and 7, respectively
(Table 2). Application of the modified Mosher’s method17 displayed
a pattern of anisotropic shielding consistent with a (2R)-configu-
ration for alcohol 4e. Thus the facial selectivity of the amino-
hydroxylation reaction is consistent with the face selectivity rule
for the Sharpless asymmetric dihydroxylation reaction18 with the
dihydroquinidine derived ligand (DHQD)2AQN effecting attack on
the lower face of the double bond, as shown, to afford the product
4e of (R)-configuration. The product of opposite configuration was
successfully prepared using the pseudoenantiomeric dihy-
droquinine derived ligand (DHQ)2AQN (Table 1, entry 12).
Signal
d
(S)-MTPA ester
d
(R)-MTPA ester
d(S) d(R)
ꢀ
TMS
0.03
0.96
4.14
4.61
3.47a
5.41
0.04
0.97
4.16
4.75
3.51a
5.41
ꢀ0.01
ꢀ0.01
ꢀ0.02
ꢀ0.14
ꢀ0.04
0.00
þ0.05
þ0.19
þ0.07
þ0.02
CH2TMS
COOCH2
NH
H1
H2
H3
H4
H20, H60
H30, H50
2.18b
4.10a
6.91
8.20
2.13b
3.91b
6.84
8.18
a
Chemical shift estimate for partially overlapping or obscured multiplets.
Chemical shift of central point for complex two proton multiplet.
b
The substrate-catalyst interactions responsible for the observed
regio- and enantioselectivity of the (DHQD)2AQN-mediated ami-
nohydroxylation of substrate 3e, to give terminal amine 4e, are
depicted in Scheme 2. This proposal builds on a similar study of
substrate-catalyst interaction in the AA of structurally related un-
saturated ester substrates that also contain homoallyl ether func-
tionality.2 Key features of the putative substrate-catalyst
interaction are:
ꢁ a di-apical arrangement of the nitrogen atoms about osmium in
the distorted trigonal bipyramidal osmium-ligand complex;19
ꢁ a geometry of the ligand based on the X-ray crystal structure of
the (DHQ)2AQN ligand (see Fig. 2 below);20
ꢁ a face-to-face interaction of the 4-nitrophenyl ether with the
anthraquinone unit of the catalyst,21 with the but-3-en-1-yl

M. Harding et al. / Tetrahedron 65 (2009) 831–843
833
substituent in a low energy extended conformation and the
terminal alkene carbon approaching the apical imido-sub-
stituent on osmium, and;
ꢁ a syn addition of the imidotrioxoosmium species to the
Re-face of the alkene to give the terminal amine 4e of (R)-
configuration.
Scheme 3. Conformational preferences (C2–C1–O–C10) of phenyl ether substrates 3e
and 3f.
Scheme 2. Proposed substrate-catalyst interaction for the (DHQD)2AQN-mediated
synthesis of terminal amine regioisomer 4e (R3¼Teoc). The AQN spacer unit located
behind the 4-nitrophenyl ether substrate 3e is shown in grey for clarity.
The 4-nitrophenyl (PNP) ether product 4e proved to be an ef-
fective building block for the synthesis of a protected form of
GABOB 10 (Scheme 4). The crystalline amino alcohol 4e could be
optically enriched to 96% ee with 75% recovery by recrystallisa-
tion. Subsequent protection of the secondary alcohol as its TBS
ether 8 was carried out in 86% yield. The phenyl ether was then
removed using a two-stage procedure23 involving reduction of the
nitro group and acetylation, followed by oxidative cleavage with
The results obtained for 2,6-dimethyl-4-nitrophenyl ether 3f
(Table 1, entry 13) and tert-butyldiphenylsilyl (TBDPS) ether 3g
(entry 14) lend support to the proposed binding mode. The 2,6-
dimethyl substitution of substrate 3f favours a near 90ꢂ twist of the
aromatic ring relative to the 4-nitrophenyl ether analogue (Scheme
3).22 This twist suggests a face-to-face interaction between the
phenyl ether of the substrate and the anthraquinone spacer as the
methyl substituents render a phenyl ether edge to anthraquinone
face interaction unfavourable. For the 4-nitrophenyl ether 3e, the
relatively small energy difference between the planar and twisted
conformations22 could also allow face-to-face interactions with the
catalyst.
Interestingly, silyl ether 3g proved moderately effective,
affording isomer 4g with good regioselectivity but lower enantio-
selectivity (Table 1, entry 14). In this instance the steric bulk of the
TBDMS ether prefers to occupy the region over the flat anthraqui-
none spacer unit rather than the relatively congested region adja-
cent to the methoxyquinoline rings.
Scheme 4. Synthesis of GABOB derivative 10. PNP¼4-nitrophenyl; Teoc¼2-(trimethyl-
silyl)ethoxycarbonyl;
piperidine 1-oxyl.
TBS¼tert-butyldimethylsilyl;
TEMPO¼2,2,6,6-tetramethyl-
Figure 2. Structure of one (DHQ)2AQN molecule with labelling of selected atoms. Anisotropic displacement ellipsoids show 30% probability levels. Hydrogen atoms are drawn as
circles with small radii.

834
M. Harding et al. / Tetrahedron 65 (2009) 831–843
CAN. Primary alcohol 9 was obtained in 62% yield (two steps).
Finally, a one-step oxidation of the alcohol to the carboxylic acid
using TEMPO24 afforded the protected GABOB derivative 10 in 85%
yield.
2.2. Synthesis of homoserine in protected form
The application of phthalazine-derived ligands for the AA of
aromatic ethers, 3 (R1¼Ar), was also investigated with the expec-
tation of obtaining primary alcohol 5 as the major regioisomer.2 The
use of 4-methoxyphenyl ether 3a in concert with phthalazine-de-
rived ligand (DHQD)2PHAL and TMSE carbamate afforded a 1:1.9
mixture14 of the two regioisomeric products 4a and 5a (Table 3,
entry 1).5 The major primary alcohol 5a was afforded with 85% ee.15
Scheme 5. Confirmation of primary alcohol 5e (R2¼TMSE) absolute configuration by
chemical correlation. Teoc¼2-(trimethylsilyl)ethoxycarbonyl; CDI¼1,10-carbonyl-
diimidazole.
Table 3
The (DHQD)2PHAL mediated synthesis of terminal alcohol regioisomer 5a–g
is consistent with an interaction of the aromatic ether with the
face-to-face methoxyquinoline units of the catalyst depicted in
Scheme 6.25,26 The buten-3-yl substituent adopts a folded confor-
mation27 with the terminal alkene carbon approaching the equa-
torial oxo-substituent on osmium. Addition to the Re-face of the
alkene gives the primary alcohol product of (R)-configuration.
Entry Substrate R1
R2
Ratioa (4/5) Yield of 5 (%) eeb (%)
1
2
3
4
5d
6
7
8
3a
3c
3d
3e
3e
3e
3f
4-MeO-Ph
4-Br-Ph
4-Me-Ph
4-NO2-Ph
4-NO2-Ph
4-NO2-Ph
TMSEc 1/1.9
TMSE 1/3.5
TMSE 1/1.5
TMSE 1/12
TMSE 1/12
48
48
45
65
64
71
53f
48f
85
92
86
95
96e
96
67
79
tBu
1/6
2,6-Di-Me-4-NO2-Ph TMSE 5/1
TBDPSg
TMSE 5/1
3g
a
Determined by integration of the 300 MHz 1H NMR spectrum of crude reaction
mixture.
b
Determined by chiral HPLC.
Scheme 6. Proposed substrate-catalyst interaction for the (DHQD)2PHAL-mediated
synthesis of primary alcohol regioisomer 5e (R3¼Teoc). The substrate 4e phenyl ether,
located above and behind the PHAL spacer, is shown in grey and with 4-nitro sub-
stituent removed for clarity.
c
d
e
f
TMSE¼2-(trimethylsilyl)ethyl.
(DHQ)2PHAL ligand used.
Product formed with (S)-configuration.
Yield of 4.
g
TBDPS¼tert-butyldiphenylsilyl.
In contrast to the effective direction observed for 4-nitrophenyl
ether 3e (Table 3, entries 4–6), the reaction of 2,6-dimethyl-4-
nitrophenyl ether substrate 3f (entry 7) and the sterically de-
manding silyl ether, 3g (entry 8),5 gave opposite regioselectivity,
favouring the isomer 4 in a lower ee. In the case of the 2,6-di-
methyl-4-nitrophenyl ether substrate 3f (entry 7), the dimethyl
substituents induce a near 90ꢂ twist of the aromatic ring relative to
the 4-nitrophenyl ether counterpart (Scheme 3).22 This twist of the
phenyl ring would be expected to disrupt the normal mode of
binding to the PHAL-derived catalyst due to the increased steric
interaction between the now orthogonal aromatic ether with the
methoxyquinoline rings. In contrast, the twisted conformation of
the 2,6-dimethyl-4-nitrophenyl ether is well aligned to engage in
face-to-face contact with the PHAL spacer of this ligand, leading to
production of the terminal amine regioisomer. The silyl ether 3g,
proved reasonably effective, affording isomer 4g with moderate
regio- and enantioselectivity (entry 8).5 As observed for the an-
thraquinone ligands (Table 1) the steric bulk of the TBDMS ether
prefers to occupy the region over the flat phthalazine spacer unit
rather than the relatively congested region adjacent to the
methoxyquinoline rings.
Variation of aromatic ether was investigated in an attempt to
optimise the process (Table 3, entries 2–4). The 4-bromo- and
4-methyl-phenyl ethers afforded 5 with higher levels of optical
purity. However, as before, the best results were obtained with the
4-nitrophenyl ether, which gave 12:1 regioselectivity providing
compound 5e in an isolated yield of 65% and with 95% ee (entry 4).
The use of the pseudoenantiomeric (DHQ)2PHAL ligands gave the
enantiomeric product with identical efficiency (entry 5). The sub-
stitution to tert-butyl carbamate gave similar isolated yield and
enantioselectivity but lower regioselectivity (entry 6).
The absolute configuration of primary alcohol (R)-5e (R2¼TMSE)
was confirmed by chemical correlation (Scheme 5). Deprotection of
the 4-nitrophenyl ether was achieved by the method of Fukase23 to
give Teoc-protected diol 11 (95% ee, [
enantiomeric diol ent-11 ([
ꢀ10.8 (c 1.7, CH2Cl2)) was in-
dependently prepared from
a]
D þ10.9 (c 1.3, CH2Cl2)). The
a
]
D
L-aspartic acid dimethyl ester hydro-
chloride, by protection to afford carbamate 12 followed by ester
reduction. The facial selectivity of the aminohydroxylation reaction
is consistent with the face selectivity rule for the Sharpless asym-
metric dihydroxylation reaction18 with the dihydroquinidine de-
rived ligand (DHQD)2PHAL effecting attack on the lower face of the
double bond, as shown, to afford the product 5e of (R)-configura-
tion (Table 3).
The primary alcohol ent-5e obtained from the AA reaction of the
4-nitrophenyl ether 3e with (DHQ)2PHAL could be efficiently
transformed to a protected homoserine derivative (Scheme 7). The
one-step oxidation of alcohol ent-5e with TEMPO afforded the
amino acid 13 in 84% yield.24
The observed regio- and enantioselectivity observed in the
(DHQD)2PHAL mediated AA of substrate 3 to give primary alcohol 5

M. Harding et al. / Tetrahedron 65 (2009) 831–843
835
Both PHAL and AQN ligands adopt a similar overall conforma-
tion, with close correlation of key torsions between the alkaloid and
spacer units. The aryl ether torsion of the AQN ligand (C10–O2–
C21–C34, av 1.5ꢂ) was of the same magnitude as the corresponding
torsion within the PHAL ligand (av 4.6ꢂ). The alkyl ether torsion
(C1–C10–O2–C21, av 75ꢂ) was of similar magnitude to the PHAL
ligand (av 86ꢂ). In this instance the slightly larger torsion observed
for the PHAL ligands may arise due to buttressing of the DHQD
alkaloid unit ethyl substituent with the PHAL spacer and the re-
duced steric interaction of the C10–H of the alkaloid unit with the
adjacent PHAL nitrogen lone pair when compared with the AQN
C34–H atom. Changes in bond lengths and angles also result in
a small increase in distance (C10–C35) between alkaloid oxy-
methine carbon atoms of 0.36 Å for the AQN ligand relative to its
PHAL counterpart.
Overall, only small changes in ligand conformation are observed
upon changing from AQN to PHAL ligands. Although the foregoing
discussion cannot account for effects such as crystal packing forces
or conformational mobility of ligands in solution, the analysis
suggests that gross structural change in catalyst conformation is
not responsible for the reversal in regioselectivity in changing from
AQN to PHAL-derived ligands. Rather, changes in regioselectivity
arise from changes to substrate-catalyst interaction resulting from
differences in the nature of the spacer unit as depicted in Schemes 2
and 6.
Scheme 7. Synthesis of homoserine derivative 13. PNP¼4-nitrophenyl; Teoc¼2-(tri-
methylsilyl)ethoxycarbonyl; TEMPO¼2,2,6,6-tetramethylpiperidine 1-oxyl.
2.3. Asymmetric aminohydroxylation of 4-nitrophenyl (E)-
pent-3-enyl ether
To further explore the scope of this directing effect the AA of 4-
nitrophenyl (E)-pent-3-enyl ether substrate 14 was briefly explored
(Table 4). The experiments used the optimal 4-nitrophenyl ether as
directing group and either tert-butyl- or TMSE-carbamate as ni-
trogen source. Aminohydroxylation with the AQN derived catalysts
(Table 4, entries 1–4) resulted in moderate regioselectivity (2–
4:1)14 favouring the 2-amino product 15 with good levels of
enantioselectivity (80–84% ee).15 This corresponds to a lower level
of regioselectivity when compared with aminohydroxylation of the
terminal alkene substrate 3e. In contrast, the PHAL mediated AA
gave good levels of regiocontrol (8–10:1) in favour of 3-amino
product 16, which is similar to that observed for terminal alkene
substrate 3e. In this case the enantioselectivity of the trans-
formation was somewhat lower than that observed for substrate
3e. Although of limited scope, the study of (E)-1,2-disubstituted
alkene 14 shows that PHAL catalysts in general give higher levels of
regio- and enantioselectivity that the AQN counterparts and high-
lights the subtle interplay of substrate and catalyst characteristic of
the aminohydroxylation reaction.
3. Conclusion
In conclusion this work demonstrates that the 4-nitrophenyl
ether is an efficient directing group in the asymmetric amino-
hydroxylation reaction of homoallylic ether derivatives, providing
either regioisomeric product with useful levels of enantiose-
lectivity. This finding has been applied to the short enantioselective
synthesis of protected GABOB 10 and homoserine 13. The substrate-
catalyst interactions responsible for the observed regio- and
enantioselectivity of the AA reactions have been proposed.
Table 4
The ligand mediated aminohydroxylation of (E)-1,2-disubstituted alkene 14. PNP¼4-
nitrophenyl
4. Experimental
4.1. General details
Melting points were determined using a Reichert heating stage
with microscope and are uncorrected. Infrared absorption spectra
were obtained using a Perkin–Elmer 1600 Fourier Transform In-
frared spectrometer as a thin film between 0.5 cm sodium chloride
Entry Ligand
R1
tBu
tBu
Ratioa (15/16) Yield major (%) ee majorb (%)
1
2
3
4
5
6
(DHQD)2AQN
3.7/1
2.6/1
75
56
48
43
56
38
84
(DHQ)2AQN
(DHQD)2AQN
(DHQ)2AQN
(DHQD)2PHAL TMSE
(DHQ)2PHAL TMSE
80c
84
TMSEd 2.6/1
plates. Absorption maxima are expressed in wavenumbers (cmꢀ1
)
TMSE
2.3/1
1/8
1/10
81c
89
and the appearance of bands are expressed as s¼strong,
m¼medium, w¼weak and br¼broad. 1H Nuclear magnetic reso-
nance spectra were recorded using a Bruker AC200 (200.1 MHz),
Bruker AVANCE DPX200 (200 MHz), Bruker AVANCE DPX300
(300.1 MHz) or Bruker DPX400 (400.1 MHz) spectrometer at 300 K.
Data is expressed as parts per million downfield shift from tetra-
methylsilane with either tetramethylsilane or chloroform as an
91c
Determined by integration of the 300 MHz 1H NMR spectrum of the crude re-
action mixture.
a
b
Determined by chiral HPLC. Absolute configuration assigned by analogy with 4e
and 5e (R2¼TMSE).
c
Product formed with (R,R)-configuration.
TMSE¼2-(trimethylsilyl)ethyl.
d
internal standard and is reported as chemical shift (d), relative in-
tegral, multiplicity (s¼singlet, d¼doublet, t¼triplet, m¼multiplet
with descriptor br¼broad), coupling constant (J in hertz) and as-
signment. 13C Nuclear magnetic resonance spectra were recorded
2.4. X-ray crystal structure analysis of (DHQ)2AQN
The X-ray structure of the (DHQ)2AQN ligand was solved from
crystals grown in acetonitrile solution (Fig. 2).20 Two molecules of
(DHQ)2AQN were observed in the asymmetric unit. As no previous
crystal structure of the AQN derived ligands exists, the structure
provides a useful guide to ligand conformation in the active cata-
lyst. The structure also permits comparison with the previously
reported structure of the (DHQD)2PHAL ligand25 to identify the
structural changes associated with changing from AQN to PHAL
spacer units, albeit for ligands with different alkaloid units.
using a Bruker AC200 (50.3 MHz), Bruker AVANCE DPX200
(50 MHz), Bruker AVANCE DPX300 (75.5 MHz) or Bruker DPX400
(100.4 MHz) spectrometer with complete proton decoupling at
300 K. The chemical shifts are reported relative to chloroform and
are expressed as chemical shift (d). FIDs were manipulated prior to
Fourier transformation applying an exponential line broadening
function to improve the signal to noise ratio. Low resolution elec-
tron impact mass spectra were recorded on either an AEI model
Kratos MS902 double focusing mass spectrometer with an

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M. Harding et al. / Tetrahedron 65 (2009) 831–843
accelerating voltage of 8000 V and using electron impact (EI) ion-
isation mode at 70 eV, or a Finnegan PolarisQ ion trap mass spec-
trometer using electron impact ionisation mode at 40 or 70 eV.
High resolution electron impact mass spectra were recorded on
a VC Autospec mass spectrometer operating at 70 eV. Low resolu-
tion electrospray (ESIþ) mass spectra were recorded on a Finnegan
LCQ mass spectrometer. High resolution electrospray mass spectra
were recorded on a Bruker ApexII Fourier Transform Ion Cyclotron
Resonance mass spectrometer with a 7.0 T magnet, fitted with an
off-axis Analytica electrospray source (University of New South
Wales, Sydney) or a Finnegan MAT 900XL (University of Queens-
land, Brisbane). Major fragments are quoted as x (assignment),
where x is the mass to charge ratio. High resolution mass spectra
were recorded at a nominal resolution of 8000–9000. Chiral Ana-
lytical High Performance Liquid Chromatography (HPLC) was car-
ried out on a Waters Gradient system consisting of two 510 pumps,
a 490E programmable multiwavelength detector at 220, 254 and
270 nm, a 410 differential refractometer, and a U6K injector. All
retention times are reported at 270 nm and calculations were based
on peak areas at 270 nm. Data was acquired and processed using
Millenium software (Version 3.05.01). Separation was carried out
reaction mixture by 300 MHz 1H NMR identified a 6:1 ratio of the
regioisomers 4a and 5a. Purification by flash chromatography (40%
ethyl acetate/hexane) afforded the major regioisomer 4a (45 mg,
56%; 71% ee, Chiralcel OD-H, 15% isopropyl alcohol/hexane; tR: 15.6
major, 17.3 minor). [
a]
D ꢀ1.6 (c 2.0, CH2Cl2); Rf 0.29 (40% ethyl ace-
tate/hexane); 1H NMR (300 MHz, CDCl3):
d
6.82 (4H, s, ArH), 5.02
(1H, br s, NH), 4.12–4.05 (2H, m, H4), 3.98 (1H, m, H2), 3.76 (3H, s,
OCH3), 3.34 (1H, m, H1A), 3.15 (1H, m, H1B), 2.85 (1H, br s, OH),1.93–
1.87 (2H, m, H3),1.44 (9H, s, tBu); 13C NMR (75 MHz, CDCl3):
d 156.8,
154.0,152.7,115.5,114.7, 79.6, 69.8, 66.2, 55.7, 46.6, 33.9 28.4; IR (thin
film): 3381 (br s, OH), 2975, 2932 (m, CH), 1693 (s, C]O) cmꢀ1; MS
(ESIþ): m/z 334 ([MþNa]þ, 100), 278 (37), 212 (16); HRMS (ESIþ):
calcd for C16H25NO5Na ([MþNa]þ) 334.1630, found 334.1629.
4.2.3. (R)-2-(Trimethylsilyl)ethyl 2-hydroxy-4-(4-
methoxyphenoxy)butylcarbamate 4a (R2¼TMSE)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-methoxybenzene 3a28 (46 mg, 0.260 mmol),
(DHQD)2AQN and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 5:1 ratio of
the regioisomers 4a and 5a. Purification by flash chromatography
(40% ethyl acetate/hexane) afforded the major regioisomer 4a
(56 mg, 61%; 79% ee, Chiralpak AD-H, 8% isopropyl alcohol/hexane;
using the indicated solvents on
a Daicel Chiralcel OD-H
(25 cmꢃ4.6 mm ID, 5
m
m
m particle size) or a Daicel Chiralpak AD-H
m particle size) column with a flow rate of
(25 cmꢃ4.6 mm ID, 5
tR: 26.2 major, 30.0 minor). [
a
]
D þ10.0 (c 0.2, CH2Cl2); Rf 0.31 (40%
0.5 mL/min. Optical rotations
a
were measured using an Optical
ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3):
d
6.82 (4H, s,
Activity PolAAr 2001 Automatic polarimeter with the sodium D line
(589 nm) at ambient temperature. Optical rotations were recorded
in dichloromethane, chloroform or methanol and run in a 0.25 dm
ArH), 5.13 (1H, br s, NH), 4.19–4.03 (4H, m, H4, COOCH2), 3.99 (1H,
m, H2), 3.76 (3H, s, OCH3), 3.39 (1H, m, H1A), 3.18 (1H, m, H1B), 2.61
(1H, br s, OH), 1.94–1.88 (2H, m, H3), 0.97 (2H, m, CH2TMS), 0.03
cell. Specific rotations [
a
]
are expressed in units of dmꢀ1 gꢀ1 cm3
(9H, s, TMS); 13C NMR (75 MHz, CDCl3):
d 157.6, 154.1, 152.6, 115.5,
D
and concentrations (c) are reported as g solute/100 cm3 solution.
Analytical thin layer chromatography was performed using alu-
minium backed precoated silica gel plates (Merck Kieselgel 60 F254).
Compounds were visualised by short wave ultra-violet fluores-
cence or by staining with acidified ethanolic solution of anisalde-
114.7, 69.8, 66.2, 63.3, 55.7, 46.8, 33.8, 17.7, ꢀ1.5; IR (thin film): 3365
(br s, OH), 2953 (s, CH), 1693 (s, C]O) cmꢀ1; MS (ESIþ): m/z 378
([MþNa]þ, 100); HRMS (ESIþ): calcd for C17H29NO5SiNa ([MþNa]þ)
378.1713, found 378.1706.
hyde,
alkaline
potassium
permanganate
solution
or
4.2.4. (R)-2-(Trimethylsilyl)ethyl 1-hydroxy-4-(4-methoxy-
phenoxy)butan-2-ylcarbamate 5a (R2¼TMSE)
phosphomolybdic acid and ceric sulfate in sulfuric acid. Flash
chromatography was performed using Merck Kieselgel 60 (230–
400 mesh) with the indicated solvents. Solvent compositions are
mixed v/v as specified.
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-methoxybenzene 3a28 (46 mg, 0.260 mmol),
(DHQD)2PHAL and 2-(trimethylsilyl)ethyl carbamate. Analysis of
the crude reaction mixture by 300 MHz 1H NMR identified a 1:1.9
ratio of the regioisomers 4a and 5a. Purification by flash chroma-
tography (40% ethyl acetate/hexane) afforded the major
regioisomer 5a as a colourless oil (44 mg, 48%; 85% ee, Chiralpak
4.2. Experimental procedures and data
4.2.1. General procedure for the AA reaction
To a solution of carbamate (0.7801 mmol) in propan-1-ol
(0.65 mL) at ambient temperature was added an aqueous solution
of sodium hydroxide (0.4 M, 0.780 mmol). To this mixture was
added 1,3-dichloro-5,5-dimethylhydantoin (0.520 mmol) followed
by a solution of ligand (0.0130 mmol) in propan-1-ol (1.3 mL). The
solution was sonicated to ensure homogeneity. To the reaction
mixture was added a solution of substrate 3 (0.260 mmol) followed
by potassium osmate dihydrate (0.0104 mmol). The reaction was
left to stir at ambient temperature for 18 h and quenched upon
addition of sodium sulfite (2.03 mmol). The mixture was then di-
luted with water (4 mL) and extracted with ethyl acetate
(3ꢃ10 mL). The combined organic extract was washed with brine
(10 mL), dried (NaSO4) and concentrated under reduced pressure to
afford the crude product. The crude product was subject to analysis
by 300 MHz 1H NMR to determine the ratio of the regioisomers 4
and 5, followed by purification by flash chromatography (ethyl
acetate/hexane) to afford the target compounds.
AD-H, 8% isopropyl alcohol/hexane; tR: 22.2 major, 20.0 minor). [a]
D
þ9.1 (c 1.1, CH2Cl2); Rf 0.27 (40% ethyl acetate/hexane); 1H NMR
(300 MHz, CDCl3):
d 6.81 (4H, s, ArH), 5.16 (1H, br s, NH), 4.13 (2H,
m, COOCH2), 4.01 (2H, t, J 5.8 Hz, H4), 3.94–3.84 (1H, m, H2), 3.75
(3H, s, OCH3), 3.73–3.68 (2H, m, H1), 2.34 (1H, br s, OH), 2.09–1.91
(2H, m, H3), 0.96 (2H, m, CH2TMS), 0.02 (9H, s, TMS); 13C NMR
(75 MHz, CDCl3):
d 157.0, 154.1, 152.5, 115.5, 114.7, 65.7, 65.3, 63.3,
55.7, 51.2, 31.0, 17.7, ꢀ1.5; IR (thin film): 3350 (br m, OH), 2953 (m,
CH), 1695 (s, C]O) cmꢀ1; MS (ESIþ): m/z 378 ([MþNa]þ, 100);
HRMS (ESIþ): calcd for C17H29NO5SiNa ([MþNa]þ) 378.1713, found
378.1705.
A second fraction afforded the minor regioisomer 4a as a col-
ourless oil (24 mg, 26%; 70% ee, Chiralpak AD-H, 8% isopropyl al-
cohol/hexane; tR: 25.8 major, 29.8 minor).
4.2.5. (R)-tert-Butyl 4-(2-chloro-4,5-dimethoxyphenoxy)-2-
hydroxybutylcarbamate 4b (R2¼tBu)
The reaction was conducted under standard conditions using 4-
(but-3-enyloxy)-1,2-dimethoxybenzene 3b29 (54 mg, 0.260 mmol),
(DHQD)2AQN and tert-butyl carbamate. Analysis of the crude re-
action mixture by 300 MHz 1H NMR identified a 5:1 ratio of the
regioisomers 4b and 5b. Purification by flash chromatography (55%
ethyl acetate/hexane) afforded the major regioisomer 4b (49 mg,
4.2.2. (R)-tert-Butyl 2-hydroxy-4-(4-methoxyphenoxy)-
butylcarbamate 4a (R2¼tBu)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-methoxybenzene 3a28 (46 mg, 0.260 mmol),
(DHQD)2AQN and tert-butyl carbamate. Analysis of the crude

M. Harding et al. / Tetrahedron 65 (2009) 831–843
837
53%; 65% ee, Chiralcel OD-H, 5% isopropyl alcohol/hexane; tR: 38.6
major, 43.7 minor). [
ꢀ4.6 (c 1.2, CH2Cl2); Rf 0.12 (40% ethyl ac-
etate/hexane); 1H NMR (200 MHz, CDCl3):
(30% ethyl acetate/hexane) afforded the major regioisomer 4c as
a colourless oil (66 mg, 63%; 76% ee, Chiralcel OD-H, 2.5% isopropyl
a]
D
d
6.87 (1H, s, ArH), 6.58
alcohol/hexane; tR: 82.1 major, 93.1 minor). [
a
]D ꢀ1.6 (c 0.5, CH2Cl2);
(1H, s, ArH), 5.06 (1H, br s, NH), 4.17 (2H, m, H4), 4.03 (1H, ddt, J 6.3,
Rf 0.55 (50% ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3):
d
7.38
6.3, 3.4 Hz, H2), 3.86 (3H, s, OCH3A), 3.82 (3H, s, OCH3B), 3.42–3.33
(2H, m, ArH), 6.78 (2H, m, ArH), 5.03 (1H, br s, NH), 4.21–4.05 (4H, m,
H4, COOCH2), 4.00 (1H, m, H2), 3.40 (1H, ddd, J 14.1, 6.2, 3.3 Hz, H1A),
3.19 (1H, m, H1B), 2.04–1.80 (3H, m, H3, OH), 0.98 (2H, m, CH2TMS),
(1H, m, H1A), 3.24–3.12 (1H, m, H1B), 2.53 (1H, br s, OH), 1.97 (2H,
t
m, H3), 1.44 (9H, s, Bu); 13C NMR (75 MHz, CDCl3):
d 157.3, 148.9,
148.5, 144.4, 113.9, 100.7, 80.1, 70.6, 68.7, 57.0, 56.7, 47.0, 34.2, 28.8
0.04 (9H, s, TMS); 13C NMR (75 MHz, CDCl3):
d 157.7, 132.3, 116.3,
(one carbon obscured or overlapping); IR (thin film): 3388 (br s, OH,
113.2, 69.5, 65.5, 63.5, 47.0, 33.8, 17.8, ꢀ1.5 (one carbon obscured or
35
NH), 1701 (s, C]O) cmꢀ1; MS (ESIþ): m/z 773 (2{C17
H
ClNO6}þNa,
overlapping); IR (thin film): 3360 (br m, OH), 2951 (s, CH), 1690 (s,
26
35
81
10), 398 ([{C17
H
ClNO6}þNa]þ, 100); HRMS (ESIþ): calcd for
C]O) cmꢀ1; MS (ESIþ): m/z 428 ([C16
H
26
BrNO4SiþNa]þ, 100), 426
26
35
79
79
C17
H
26
ClNO6Na ([MþNa]þ) 398.1346, found 398.1340.
([C16
H
26
BrNO4SiþNa]þ, 89); HRMS (ESIþ): calcd for C16
H BrNO4
26 -
SiNa ([MþNa]þ) 426.0712, found 426.0713.
4.2.6. (R)-2-(Trimethylsilyl)ethyl 4-(2-chloro-4,5-dimethoxy-
phenoxy)-2-hydroxybutylcarbamate 4b (R2¼TMSE)
4.2.9. (R)-2-(Trimethylsilyl)ethyl 4-(4-bromophenoxy)-1-
The reaction was conducted under standard conditions using 4-
(but-3-enyloxy)-1,2-dimethoxybenzene 3b29 (54 mg, 0.260 mmol),
(DHQD)2AQN and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 5:1 ratio of
the regioisomers 4b and 5b. Purification by flash chromatography
(55% ethyl acetate/hexane) afforded the major regioisomer 4b
(58 mg, 53%; 78% ee, Chiralcel OD-H, 15% isopropyl alcohol/hexane;
hydroxybutan-2-ylcarbamate 5c (R2¼TMSE)
The reaction was conducted under standard conditions using 1-
bromo-4-(but-3-enyloxy)benzene 3c30 (59 mg, 0.260 mmol),
(DHQD)2PHAL and 2-(trimethylsilyl)ethylcarbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 1:3.5 ratio
of the regioisomers 4c and 5c. Purification by flash chromatography
(40% ethyl acetate/hexane) afforded the major regioisomer 5c as
a colourless oil (50 mg, 48%; 92% ee, Chiralpak AD-H, 8% isopropyl
tR: 27.5 major, 30.5 minor). [
a]
ꢀ9.9 (c 1.9, CH2Cl2); Rf 0.30 (55%
D
ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3):
d
6.87 (1H, s,
alcohol/hexane; tR: 23.8 major, 19.4 minor). [
CH2Cl2); Rf 0.24 (40% ethyl acetate/hexane); 1H NMR (200 MHz,
CDCl3): 7.37 (2H, m, ArH), 6.77 (2H, m, ArH), 5.05 (1H, br s, NH), 4.13
a
]
D
þ12.6 (c 1.3,
ArH), 6.58 (1H, s, ArH), 5.16 (1H, br s, NH), 4.23–4.10 (4H, m, H4,
COOCH2), 4.05 (1H, m, H2), 3.86 (3H, s, OCH3A), 3.82 (3H, s, OCH3B),
3.25 (1H, m, H1A), 3.22 (1H, m, H1B), 2.97 (1H, br s, OH), 2.02–1.94
(2H, m, H3), 0.98 (2H, m, CH2TMS), 0.03 (9H, s, TMS); 13C NMR
d
(2H, m, COOCH2), 4.03 (2H, t, J 5.9 Hz, H4), 3.90 (1H, m, H2), 3.78–
3.64 (2H, m, H1), 2.17–1.93 (3H, m, H3, OH), 0.94 (2H, m, CH2TMS),
(75 MHz, CDCl3):
d
157.7, 148.5, 148.1, 144.0, 113.5, 100.3, 70.1, 68.3,
0.03 (9H, s, TMS); 13C NMR (75 MHz, CDCl3):
d 157.6, 157.0, 132.3,
63.3, 56.6, 56.3, 46.7, 33.7, 17.7, ꢀ1.5 (one carbon overlapping
116.3, 113.2, 65.3, 63.4, 50.9, 30.9, 17.7, ꢀ1.5 (one carbon obscured or
or obscured); IR (thin film): 3381 (br s, OH), 2953 (s, CH), 1705
overlapping); IR (thin film): 3337 (br m, OH), 2953 (m, CH), 1684 (s,
37
81
(s, C]O) cmꢀ1; MS (ESIþ): m/z 864 ([2{C18
H
30
ClNO6Si}þNa]þ,
C]O) cmꢀ1; MS (ESIþ): m/z 428 ([C16
H
26
BrNO4SiþNa]þ, 77), 426
35
37
35
79
6), 862 ([C18
H
ClNO6SiþC18
H
ClNO6SiþNa]þ, 18), 860 ([2{C18
H
-
([C16H
26
BrNO4SiþNa]þ, 75), 262 (28), 260 (27); HRMS (ESIþ): calcd
30
30
30
37
79
ClNO6Si}þNa]þ, 20), 444 ([C18
H
ClNO6SiþNa]þ, 43), 442
for C16
H
BrNO4SiNa ([MþNa]þ) 426.0712, found 426.0721.
30
26
35
35
([C18
H
ClNO6SiþNa]þ, 100); HRMS (ESIþ): calcd for C18
H
ClNO6
-
A second fraction afforded the minor regioisomer 4c as a col-
ourless oil (15 mg, 14%; 55% ee, Chiralpak AD-H, 8% isopropyl al-
cohol/hexane; tR: 25.9 major, 30.7 minor).
30
30
SiNa ([MþNa]þ) 442.1429, found 442.1413.
4.2.7. (R)-tert-Butyl 4-(4-bromophenoxy)-2-hydroxybutyl-
carbamate 4c (R2¼tBu)
4.2.10. (R)-tert-Butyl 2-hydroxy-4-(4-methylphenoxy)-
The reaction was conducted under standard conditions using 1-
bromo-4-(but-3-enyloxy)benzene 3c30 (59 mg, 0.260 mmol),
(DHQD)2AQN and tert-butyl carbamate. Analysis of the crude re-
action mixture by 300 MHz 1H NMR identified an 8:1 ratio of the
regioisomers 4c and 5c. Purification by flash chromatography (30%
ethyl acetate/hexane) afforded the major regioisomer 4c (62 mg,
66%; 63% ee, Chiralcel OD-H, 5% isopropyl alcohol/hexane; tR: 26.5
butylcarbamate 4d (R2¼tBu)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-methylbenzene 3d31 (42 mg, 0.260 mmol),
(DHQD)2AQN and tert-butyl carbamate. Analysis of the crude re-
action mixture by 300 MHz 1H NMR identified a 7:1 ratio of the
regioisomers 4d and 5d. Purification by flash chromatography (30%
ethyl acetate/hexane) afforded the major regioisomer 4d as a col-
ourless oil (47 mg, 61%; 73% ee, Chiralcel OD-H, 5% isopropyl alcohol/
major, 30.3 minor). [
a]
D ꢀ1.9 (c 1.7, CH2Cl2); Rf 0.57 (50% ethyl ace-
tate/hexane); 1H NMR (300 MHz, CDCl3):
d
7.36 (2H, m, ArH), 6.77
hexane; tR: 28.4 major, 30.0 minor). [
a]
D ꢀ4.4 (c 1.0, CH2Cl2); Rf 0.21
(2H, m, ArH), 4.98 (1H, br s, NH), 4.17–4.03 (2H, m, H4), 3.97 (1H, m,
(30% ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3):
d
7.07 (2H,
H2), 3.34 (1H, dd, J 13.9, 2.6 Hz, H1A), 3.13 (1H, dd, J 14.1, 7.1 Hz, H1B),
m, ArH), 6.81 (2H, m, ArH), 4.97 (1H, br s, NH), 4.19–4.03 (2H, m, H4),
3.98 (1H, ddd, J 12.5, 6.8, 3.4 Hz, H2), 3.35 (1H, dd, J 14.1, 3.2 Hz, H1A),
3.14 (1H, dd, J 14.1, 7.1 Hz, H1B), 2.58 (1H, br s, OH), 2.28 (3H, s,
t
1.99–1.86 (2H, m, H3), 1.45 (9H, s, Bu); 13C NMR (75 MHz, CDCl3):
d
157.7 (C), 156.9 (C), 132.3 (CH), 116.3 (CH), 113.1 (C), 79.9 (C), 69.4
t
(CH), 65.4 (CH2), 46.8 (CH2), 33.8 (CH2), 28.4 (CH3); IR (thin film):
ArCH3), 1.96–1.86 (2H, m, H3), 1.45 (9H, s, Bu); 13C NMR (75 MHz,
3373 (br m, OH), 2976, 2932 (m, CH),1699 (s, C]O) cmꢀ1; MS (ESIþ):
CDCl3): d 156.8, 156.4, 130.3, 129.9, 114.4, 79.7, 69.9, 65.6, 46.7, 33.9,
81
79
m/z 384 ([C15
H
22
BrNO4þNa]þ, 21), 382 ([C15
H
22
BrNO4þNa]þ, 18),
28.4, 20.4; IR (thin film): 3366 (br m, OH), 2976, 2928, 2876 (m, CH),
1686 (s, C]O) cmꢀ1; MS (ESIþ): m/z 318 ([MþNa]þ, 100); HRMS
(ESIþ): calcd for C16H25NO4Na ([MþNa]þ) 318.1681, found 318.1670.
304 (100); HRMS (ESIþ): calcd for C15
384.0609, found 384.0603; calcd for C15
382.0630, found 382.0622.
H
BrNO4Na ([MþNa]þ)
81
22
79
H
BrNO4Na ([MþNa]þ)
22
4.2.11. (R)-2-(Trimethylsilyl)ethyl 2-hydroxy-4-(4-methylphenoxy)-
butylcarbamate 4d (R2¼TMSE)
4.2.8. (R)-2-(Trimethylsilyl)ethyl 4-(4-bromophenoxy)-2-
hydroxybutylcarbamate 4c (R2¼TMSE)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-methylbenzene 3d31 (42 mg, 0.260 mmol),
(DHQD)2AQN and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 7:1 ratio of
the regioisomers 4d and 5d. Purification by flash chromatography
(35% ethyl acetate/hexane) afforded the major regioisomer 4d as
The reaction was conducted under standard conditions using 1-
bromo-4-(but-3-enyloxy)benzene 3c30 (59 mg, 0.260 mmol),
(DHQD)2AQN and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 7:1 ratio of
the regioisomers 4c and 5c. Purification by flash chromatography

838
M. Harding et al. / Tetrahedron 65 (2009) 831–843
a colourless oil (55 mg, 62%; 75% ee, Chiralpak AD-H, 8% isopropyl
alcohol/hexane; tR: 16.5 major, 19.0 minor). [
ꢀ14.4 (c 0.8,
CH2Cl2); Rf 0.30 (35% ethyl acetate/hexane); 1H NMR (200 MHz,
CDCl3): 7.07 (2H, m, ArH), 6.79 (2H, m, ArH), 5.05 (1H, br s, NH),
acetate/hexane); 1H NMR (300 MHz, CDCl3):
d 8.19 (2H, m, ArH),
6.96 (2H, m, ArH), 5.18 (1H, br s, NH), 4.30–4.17 (2H, m, H4), 4.02
(1H, m, H2), 3.69 (3H, s, OCH3), 3.41 (1H, m, H1A), 3.22 (1H, m, H1B),
2.36 (1H, br s, OH), 2.06–1.87 (2H, m, H3); 13C NMR (50 MHz,
a
]
D
d
4.21–4.08 (4H, m, H4, COOCH2), 4.00 (1H, m, H2), 3.41 (1H, ddd, J
14.0, 6.4, 3.4 Hz, H1A), 3.19 (1H, m, H1B), 2.92 (1H, br s, OH), 2.28
(3H, s, ArCH3), 1.97–1.88 (2H, m, H3), 0.99 (2H, m, CH2TMS), 0.04
CDCl3): d 163.7, 155.7, 141.0, 125.9, 114.5, 68.7, 65.6, 52.4, 47.2, 33.7;
IR (thin film): 3331 (br s, OH), 2951 (w, CH), 1724 (s, C]O) cmꢀ1
;
MS (ESI): m/z 285 ([MþH]þ, 25), 227 (19); HRMS (ESIþ): calcd for
(9H, s, TMS); 13C NMR (50 MHz, CDCl3):
d 157.6 (C), 156.3 (C), 130.4
C12H17N2O6 ([MþH]þ) 285.1087, found 285.1081.
(C), 129.9 (CH), 114.4 (CH), 69.9 (CH2), 65.7 (CH2), 63.3 (CH2), 46.8
(CH), 33.8 (CH2), 20.4 (CH3), 17.7 (CH2), ꢀ1.5 (CH3); IR (thin film):
3354 (br m, OH), 2953 (m, CH), 1697 (s, C]O) cmꢀ1; MS (ESIþ): m/z
362 ([MþNa]þ, 100); HRMS (ESIþ): calcd for C17H29NO4SiNa
([MþNa]þ) 362.1764, found 362.1760.
4.2.15. (R)-2-(Trimethylsilyl)ethyl 2-hydroxy-4-(4-nitrophenoxy)-
butylcarbamate 4e (R2¼TMSE)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-nitrobenzene 3e32 (434 mg, 2.25 mmol),
(DHQD)2AQN and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by300 MHz 1H NMR identified a 10:1 ratio of
the regioisomers 4e and 5e. Purification by flash chromatography
(40% ethyl acetate/hexane) afforded the major regioisomer 4e
(558 mg, 67%; 81% ee, Chiralcel OD-H,15% isopropyl alcohol/hexane;
tR: 14.3 major, 15.4 minor). The product was recrystallised from
tetrahydrofuran/hexane (1:3; 24 mL) to give the product 4e as white
needles (447 mg, 54%; 96% ee, Chiralcel OD-H, 8% isopropyl alcohol/
4.2.12. (R)-2-(Trimethylsilyl)ethyl 1-hydroxy-4-(4-
methylphenoxy)butan-2-ylcarbamate 5d (R2¼TMSE)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-methylbenzene 3d31 (42 mg, 0.260 mmol),
(DHQD)2PHAL and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 1:1.5 ratio
of the regioisomers 4d and 5d. Purification by flash chromatography
(30% ethyl acetate/hexane) afforded the major regioisomer 5d as
a colourless oil (40 mg, 45%; 86% ee, Chiralpak AD-H, 8% isopropyl
hexane; tR: 39.4 major, 46.6 minor). Mp 92–93 ꢂC; [
CH2Cl2); Rf 0.29 (40% ethyl acetate/hexane); 1H NMR (300 MHz,
CDCl3): 8.17 (2H, m, ArH), 6.94 (2H, m, ArH), 5.12 (1H, m, NH), 4.29–
a
]D þ2.7 (c 2.2,
alcohol/hexane; tR: 18.2 major, 16.4 minor). [
a
]
D þ9.1 (c 1.1, CH2Cl2);
d
Rf 0.38 (40% ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3):
d
7.08
4.13 (4H, m, H4, COOCH2), 4.00 (1H, m, H2), 3.39 (1H, m, H1A), 3.21
(1H, m, H1B), 2.87 (1H, br s, OH), 2.05–1.87 (2H, m, H3), 0.97 (2H, m,
(2H, m, ArH), 6.78 (2H, m, ArH), 5.15 (1H, br s, NH), 4.14 (2H, m,
COOCH2), 4.04 (2H, t, J 5.8 Hz, H4), 3.91 (1H, m, H2), 3.76–3.68 (2H,
m, H1), 2.28 (3H, s, ArCH3), 2.14–1.93 (3H, m, H3, OH), 0.96 (2H, m,
CH2TMS), 0.03 (9H, s, TMS); 13C NMR (50 MHz, CDCl3):
d 163.8,157.8,
141.5,125.8,114.4, 68.5, 65.6, 63.5, 47.1, 33.6,17.7, ꢀ1.6; IR (thin film):
3398 (br s, OH), 2953, 2894 (m, CH),1701 (s, C]O) cmꢀ1; MS (ESIþ):
m/z 762 ([2MþNa]þ,100), 393 ([MþNa]þ, 83); HRMS (ESIþ): calcd for
C16H26N2O6SiNa ([MþNa]þ) 393.1458, found 393.1449.
CH2TMS), 0.03 (9H, s, TMS); 13C NMR (75 MHz, CDCl3):
d 157.0,156.3,
130.4,130.0,114.4, 65.3, 65.1, 63.3, 51.2, 30.9, 20.4,17.7, ꢀ1.5; IR (thin
film): 3331 (br m, OH), 2953, 2897 (m, CH),1689 (s, C]O) cmꢀ1; MS
(ESIþ): m/z 362 ([MþNa]þ, 100); HRMS (ESIþ): calcd for
C17H29NO4SiNa ([MþNa]þ) 362.1764, found 362.1757.
4.2.16. (S)-2-(Trimethylsilyl)ethyl 2-hydroxy-4-(4-nitrophenoxy)-
butylcarbamate ent-4e (R2¼TMSE)
A second fraction afforded the minor regioisomer 4d as a col-
ourless oil (25 mg, 28%; 64% ee, Chiralpak AD-H, 8% isopropyl al-
cohol/hexane; tR: 21.4 major, 24.2 minor).
The reaction was conducted under standard conditions using
1-(but-3-enyloxy)-4-nitrobenzene 3e32 (50 mg, 0.260 mmol),
(DHQ)2AQN and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 9:1 ratio of
the regioisomers ent-4e and ent-5e. Purification by flash chroma-
tography (40% ethyl acetate/hexane) afforded the major regioisomer
ent-4e (59 mg, 61%; 72% ee, Chiralcel OD-H, 15% isopropyl alcohol/
hexane; tR: 13.7 minor, 14.8 major).
4.2.13. (R)-tert-Butyl 2-hydroxy-4-(4-nitrophenoxy)-
butylcarbamate 4e (R2¼tBu)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-nitrobenzene 3e32 (50 mg, 0.260 mmol),
(DHQD)2AQN and tert-butyl carbamate. Analysis of the crude re-
action mixture by 300 MHz 1H NMR identified a 9:1 ratio of the
regioisomers 4e and 5e. Purification by flash chromatography (40%
ethyl acetate/hexane) afforded the major regioisomer 4e (62 mg,
73%; 73% ee, Chiralcel OD-H, 15% isopropyl alcohol/hexane; tR: 13.5
4.2.17. (R)-tert-Butyl 1-hydroxy-4-(4-nitrophenoxy)butan-2-
ylcarbamate 4e (R2¼tBu)
The reaction was conducted under standard conditions using
1-(but-3-enyloxy)-4-nitrobenzene 3e32 (30 mg, 0.154 mmol), (DH-
QD)2AQN and tert-butyl carbamate. Analysis of the crude reaction
mixture by 300 MHz 1H NMR identified a 1:6 ratio of the
regioisomers 4e and 5e. Purification by flash chromatography (5%
methanol/dichloromethane) afforded the major regioisomer 5e
(36 mg, 71%; 96% ee, Chiralcel OD-H, 12% isopropyl alcohol/hexane;
major, 14.7 minor). [
a]
þ5.1 (c 1.1, CH2Cl2); Rf 0.20 (30% ethyl ac-
D
etate/hexane); 1H NMR (200 MHz, CDCl3):
d
8.17 (2H, m, ArH), 6.94
(2H, m, ArH), 5.01 (1H, br t, J 5.7 Hz, NH), 4.31–4.14 (2H, m, H4), 3.98
(1H, m, H2), 3.34 (1H, ddd, J 14.3, 6.2, 3.3 Hz, H1A), 3.22–3.08 (1H,
m, H1B), 3.02 (1H, br s, OH), 1.98–1.84 (2H, m, H3), 1.44 (9H, s, tBu);
13C NMR (75 MHz, CDCl3):
d 164.2, 157.4, 142.0, 126.3, 114.9, 80.5,
69.3, 66.1, 47.3, 34.2, 28.7; IR (thin film): 3396 (br s, OH, NH), 1686
(s, C]O) cmꢀ1; MS (ESIþ): m/z 349 ([MþNa]þ, 100); HRMS (ESIþ):
calcd for C15H22N2O6Na ([MþNa]þ) 349.1376, found 349.1374.
tR: 20.3 major, 19.1 minor). [
a
]
þ29 (c 1.8, CH2Cl2); Rf 0.063 (30%
D
ethyl acetate/hexane); 1H NMR (200 MHz, CDCl3):
d
8.17 (2H, m,
2ArH), 6.94 (2H, m, 2ArH), 4.96 (1H, d, J 8.4 Hz, NH), 4.15 (2H, t, J
6.3 Hz, H4), 3.88 (1H, m, H2), 3.80–3.61 (2H, m, H1), 2.66 (1H, br s,
t
4.2.14. (R)-Methyl 2-hydroxy-4-(4-nitrophenoxy)butylcarbamate
4e (R2¼Me)
OH), 2.12–1.97 (2H, m, H3), 1.40 (9H, s, Bu); 13C NMR (75 MHz,
CDCl3):
d 164.1, 156.5, 141.9, 126.2, 114.8, 80.2, 66.3, 65.6, 50.5, 31.4,
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-nitrobenzene 3e32 (50 mg, 0.260 mmol),
(DHQD)2AQN and methyl carbamate. Analysis of the crude reaction
mixture by 300 MHz 1H NMR identified a 9:1 ratio of the
regioisomers 4e and 5e. Purification by flash chromatography (35%
ethyl acetate/hexane) afforded the major regioisomer 4e (45 mg,
61%; 79% ee, Chiralcel OD-H, 15% isopropyl alcohol/hexane; tR: 32.0
28.6; IR (thin film): 3398 (br s, OH, NH), 2975 (CH), 1703 (s,
C]O) cmꢀ1;MS (ESIþ):m/z 349 ([MþNa]þ, 48%); HRMS (ESIþ):calcd
for C15H22N2O6Na 349.1376, found 349.1377.
4.2.18. (R)-2-(Trimethylsilyl)ethyl 1-hydroxy-4-(4-nitrophenoxy)-
butan-2-ylcarbamate 3e (R2¼TMSE)
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-nitrobenzene 3e32 (50 mg, 0.260 mmol),
major, 38.1 minor). [
a]
þ2.1 (c 1.0, CH2Cl2); Rf 0.27 (35% ethyl
D

M. Harding et al. / Tetrahedron 65 (2009) 831–843
839
(DHQD)2PHAL and 2-(trimethylsilyl)ethyl carbamate. Analysis of
the crude reaction mixture by 300 MHz 1H NMR identified a 1:12
ratio of the regioisomers 4e and 5e. Purification by flash chroma-
tography (45% ethyl acetate/hexane) afforded the major
regioisomer 5e (63 mg, 65%, 95% ee, Chiralpak AD-H, 12% isopropyl
(trimethylsilyl)ethyl carbamate. Analysis of the crude reaction
mixture by 300 MHz 1H NMR identified a 5:1 ratio of the
regioisomers 4f and 5f. Purification by flash chromatography (30%
ethyl acetate/hexane) afforded the major regioisomer 4f as a pale
yellow oil (55 mg, 53%; 67% ee, Chiralpak AD-H, 12% isopropyl
alcohol/hexane; tR: 14.0 major, 15.1 minor).
alcohol/hexane; tR: 30.8 minor, 39.7 major) [
CH2Cl2); Rf 0.29 (40% ethyl acetate/hexane); 1H NMR (300 MHz,
CDCl3): 8.18 (2H, m, ArH), 6.94 (2H, m, ArH), 5.03 (1H, br d, J
a]
ꢀ27.5 (c 1.3,
D
d
4.2.22. (R)-2-(Trimethylsilyl)ethyl 4-(tert-butyldiphenylsilyloxy)-2-
hydroxybutylcarbamate 4g (R2¼TMSE)
7.3 Hz, NH), 4.18–4.09 (4H, m, H4, COOCH2), 3.93 (1H, m, H3), 3.79–
3.66 (2H, m, H2), 2.31 (1H, br s, OH), 2.18–1.93 (2H, m, H2), 0.94 (2H,
The reaction was conducted under standard conditions using
(but-3-enyloxy)(tert-butyl)diphenylsilane 3g33 (81 mg, 0.260 -
mmol), (DHQD)2AQN and 2-(trimethylsilyl)ethyl carbamate. Anal-
ysis of the crude reaction mixture by 300 MHz 1H NMR identified
a 9:1 ratio of the regioisomers 4g and 5g. Purification by flash
chromatography (35% ethyl acetate/hexane) afforded the major
regioisomer 4g as a pale yellow oil (71 mg, 56%; 65% ee, Chiralpak
m, CH2TMS), 0.01 (9H, s, TMS); 13C NMR (75 MHz, CDCl3):
d 163.6,
156.9, 141.7, 125.9, 114.5, 65.9, 65.1, 63.4, 50.5, 31.0, 17.7, ꢀ1.5; IR
(thin film): 3396 (br m, OH), 2953, 2894 (m, CH), 1693 (s,
C]O) cmꢀ1; MS (ESIþ): m/z 393 ([MþNa]þ, 12), 227 (100); HRMS
(ESIþ): calcd for C16H26N2O6SiNa ([MþNa]þ) 393.1458, found
393.1439.
AD-H, 2% isopropyl alcohol/hexane; tR: 35.2 major, 39.6 minor). [a]
D
4.2.19. (S)-2-(Trimethylsilyl)ethyl 1-hydroxy-4-(4-nitrophenoxy)-
butan-2-ylcarbamate ent-5e (R2¼TMSE)
ꢀ3.2 (c 1.0, CH2Cl2); Rf 0.30 (30% ethyl acetate/hexane); 1H NMR
(300 MHz, CDCl3): d 7.66 (4H, m, ArH), 7.45–7.40 (6H, m, ArH), 5.08
The reaction was conducted under standard conditions using 1-
(but-3-enyloxy)-4-nitrobenzene 3e32 (575 mg, 2.98 mmol),
(DHQ)2PHAL and 2-(trimethylsilyl)ethyl carbamate. Analysis of the
crude reaction mixture by 300 MHz 1H NMR identified a 1:12 ratio
of the regioisomers ent-4e and ent-5e. Purification by flash chro-
matography (45% ethyl acetate/hexane) afforded the major
regioisomer ent-5e (706 mg, 64%, 96% ee, Chiralpak AD-H, 25%
isopropyl alcohol/hexane; tR: 19.6 major, 27.0 minor).
(1H, br s, NH), 4.16 (2H, m, COOCH2), 3.99 (1H, m, H2), 3.88 (2H, t, J
5.5 Hz, H4), 3.37 (1H, m, H1A), 3.14 (1H, m, H1B), 1.85–1.59 (2H, m,
t
H3), 1.06 (9H, s, Bu), 0.98 (2H, m, CH2TMS), 0.04 (9H, s, TMS) (OH
overlapping or obscured); 13C NMR (75 MHz, CDCl3):
d 157.3, 135.5,
132.8, 129.9, 127.8, 71.1, 63.1, 46.7, 35.7, 26.8, 19.0, 17.8, ꢀ1.5 (one
carbon overlapping or obscured); IR (thin film): 3346 (br m, OH),
2956, 2893 (s, CH), 1703 (s, C]O) cmꢀ1; MS (ESIþ): m/z 510
([MþNa]þ,100); HRMS (ESIþ): calcd for C26H41NO4Si2Na ([MþNa]þ)
510.2472, found 510.2465.
4.2.20. 2-(But-3-enyloxy)-1,3-dimethyl-5-nitrobenzene 3f
The reaction was conducted under standard conditions using
(but-3-enyloxy)(tert-butyl)diphenylsilane 3g33 (81 mg, 0.260
mmol), (DHQD)2PHAL and 2-(trimethylsilyl)ethyl carbamate.
Analysis of the crude reaction mixture by 300 MHz 1H NMR iden-
tified a 5:1 ratio of the regioisomers 4g and 5g. Purification by flash
chromatography (35% ethyl acetate/hexane) afforded the major
regioisomer 4g as a pale yellow oil (61 mg, 48%; 79% ee, Chiralpak
AD-H, 2% isopropyl alcohol/hexane; tR: 35.2 major, 39.6 minor).
To a stirred solution of but-3-en-1-ol (1.00 g, 13.9 mmol) in
tetrahydrofuran (35 mL) at room temperature was added 2,6-di-
methyl-4-nitrophenol (3.01 g, 18.0 mmol) and triphenylphosphine
(3.92 g, 14.9 mmol). Following addition of diethyl azodicarboxylate
(3.06 mL, 19.4 mmol), the mixture was heated at reflux for 30 min
then cooled and concentrated to afford a brown oil. Purification by
flash chromatography (15% ethyl acetate/hexane) afforded pure
ether 3f as a colourless oil (2.21 g, 72%). Rf 0.40 (15% ethyl acetate/
hexane); 1H NMR (200 MHz, CDCl3):
d
7.80 (2H, s, ArH), 5.90 (1H, m,
4.2.23. (S)-((R)-4-(4-Nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)-
carbonylamino)butan-2-yl)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate ((S)-MTPA derivative) 6
H3), 5.20–5.05 (2H, m, H4), 3.83 (2H, t, J 6.6 Hz, H1), 2.54 (2H, qt, J
6.7, 1.3 Hz, H2), 2.27 (6H, s, ArMe); 13C NMR (75 MHz, CDCl3):
d
161.5, 143.4, 134.3, 132.4, 124.2, 117.5, 71.9, 34.8, 16.6; IR (thin
Alcohol 4e (R2¼TMSE, 10 mg, 0.0270 mmol) and (S)-3,3,3-tri-
fluoro-2-methoxy-2-phenylpropanoic acid (8.2 mg, 0.0350 mmol)
were stirred in dichloromethane (1.0 mL) at room temperature.
film): 2979, 2959, 2927 (w, CH), 1519 (s, C]C), 1346 (s, NO2) cmꢀ1
;
ꢁ
MS (EI): m/z 222 (45), 221 (Mþ , 30), 55 (100); HRMS (EI): calcd for
ꢁ
C12H15NO3 (Mþ ) 221.1052, found 221.1051.
To this solution was added N,N0-dicyclohexylcarbodiimide (57
mL,
1 M, 0.0567 mmol) and 4-(dimethylamino)pyridine (0.3 mg,
0.0027 mmol). The mixture was sonicated at 0 ꢂC for 5 h, during
which time a white precipitate formed. The mixture was filtered
through Celite and concentrated. Purification by flash chromatog-
raphy (25% ethyl acetate/hexane) afforded pure (S)-MTPA de-
rivative 6 as a pale yellow oil (12 mg, 76%). 1H NMR (300 MHz,
4.2.21. (R)-2-(Trimethylsilyl)ethyl 4-(2,6-dimethyl-4-
nitrophenoxy)-2-hydroxybutylcarbamate 4f (R2¼TMSE)
The reaction was conducted under standard conditions using
substrate 3f (58 mg, 0.260 mmol), (DHQD)2AQN and 2-(trime-
thylsilyl)ethyl carbamate. Analysis of the crude reaction mixture by
300 MHz 1H NMR identified a 9:1 ratio of the regioisomers 4f and
5f. Purification by flash chromatography (30% ethyl acetate/hexane)
afforded the major regioisomer 4f as a pale yellow oil (50 mg, 48%;
77% ee, Chiralcel OD-H, 12% isopropyl alcohol/hexane; tR: 14.0
CDCl3):
d
8.20 (2H, m, H30, H50), 7.48–7.28 (5H, m, Ph), 6.91 (2H, m,
H20, H60), 5.41 (1H, m, H2), 4.61 (1H, m, NH), 4.14 (2H, m, COOCH2),
4.18–4.01 (2H, m, H4), 3.53–3.41 (2H, m, H1), 3.49 (3H, s, OMe),
2.23–2.13 (2H, m, H3), 0.96 (2H, m, CH2TMS), 0.03 (9H, s, TMS).
major, 15.2 minor). [
a]
þ0.4 (c 1.1, CH2Cl2); Rf 0.18 (30% ethyl ac-
D
etate/hexane); 1H NMR (300 MHz, CDCl3):
d
7.91 (2H, s, ArH), 5.11
4.2.24. (R)-((R)-4-(4-Nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)-
carbonylamino)butan-2-yl)-3,3,3-trifluoro-2-methoxy-2-
phenylpropanoate ((R)-MTPA derivative) 7
(1H, br s, NH), 4.19–3.95 (5H, m, H4, H2, COOCH2), 3.42 (1H, m,
H1A), 3.26 (1H, m, H1B), 2.51 (1H, br s, OH), 2.35 (6H, s, ArCH3),1.99–
1.92 (2H, m, H3), 0.98 (2H, m, CH2TMS), 0.03 (9H, s, TMS); 13C NMR
Alcohol 4e (10 mg, 0.0270 mmol) and (R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoic acid (8.2 mg, 0.0350 mmol) were
stirred in dichloromethane (1.0 mL) at room temperature. To this
(75 MHz, CDCl3):
d 161.0, 157.7, 143.6, 132.3, 124.3, 70.0, 69.4, 63.5,
47.2, 34.7, 17.7, 16.5, ꢀ1.5; IR (thin film): 3412 (br m, OH), 2953 (m,
CH), 1701 (s, C]O) cmꢀ1; MS (ESIþ): m/z 421 ([MþNa]þ, 15); HRMS
(ESIþ): calcd for C18H30N2O6SiNa ([MþNa]þ) 421.1771, found
421.1759.
The reaction was conducted under standard conditions using
substrate 4f (58 mg, 0.260 mmol), (DHQD)2PHAL and 2-
solution was added N,N0-dicyclohexylcarbodiimide (57
m
L, 1 M,
0.0567 mmol)
and
4-(dimethylamino)pyridine
(0.3 mg,
0.0027 mmol). The mixture was sonicated at 0 ꢂC for 5 h, during
which time a white precipitate formed. The mixture was filtered
through Celite and concentrated. Purification by flash

840
M. Harding et al. / Tetrahedron 65 (2009) 831–843
chromatography (25% ethyl acetate/hexane) afforded pure (R)-
MTPA derivative 7 as a pale yellow oil (12 mg, 76%). 1H NMR
4.2.27. (R)-3-(tert-Butyldimethylsilyloxy)-4-((2-(trimethylsilyl)-
ethoxy)carbonylamino)butanoic acid 10
To a solution of alcohol 9 (31 mg, 0.0852 mmol) and TEMPO
(1.3 mg, 0.0083 mmol) in acetonitrile (1 mL) and pH 6.7 potassium
phosphate buffer (0.6 mL) was added simultaneously an aqueous
(300 MHz, CDCl3):
d
8.18 (2H, m, H30, H50), 7.49–7.27 (5H, m, Ph),
6.84 (2H, m, H20, H60), 5.41 (1H, m, H2), 4.75 (1H, m, NH), 4.16 (2H,
m, COOCH2), 4.01–3.81 (2H, m, H4), 3.55–3.47 (2H, m, H1), 3.51 (3H,
s, OMe), 2.19–2.07 (2H, m, H3), 0.97 (2H, m, CH2TMS), 0.04 (9H, s,
TMS).
solution of NaClO2 (84
dium hypochlorite (10
m
m
L, 2 M, 0.168 mmol) and a solution of so-
L, 1.4 M, 14 M). After stirring for 15 h at
m
35 ꢂC the reaction mixture was adjusted to pH 3 upon addition of
citric acid. The reaction was diluted with water (5 mL) and the
aqueous layer was extracted ethyl acetate (3ꢃ10 mL). The com-
bined organic extract was washed with brine (5 mL), dried (NaSO4)
and concentrated under reduced pressure to leave the crude
product as a pale brown oil. Purification by flash chromatography
(5% methanol/dichloromethane) gave the product 10 as a colourless
4.2.25. (R)-2-(Trimethylsilyl)ethyl 2-(tert-butyldimethylsilyloxy)-4-
(4-nitrophenoxy)butylcarbamate 8
To a solution of alcohol 4e (R2¼TMSE, 216 mg, 0.583 mmol) in
dimethylformamide (2.0 mL) at ambient temperature was added
tert-butyldimethylsilyl chloride (263 mg, 1.75 mmol) followed by
imidazole (159 mg, 2.33 mmol) and 4-dimethylaminopyridine
(21 mg, 0.172 mmol). The reaction mixture was heated to 40 ꢂC.
After 14 h the reaction was quenched upon addition of a saturated
aqueous solution of sodium hydrogen carbonate (5 mL). Ethyl ac-
etate (10 mL) was added and the organic layer was separated. The
aqueous layer was then extracted with ethyl acetate (2ꢃ10 mL) and
the combined organic extract was washed with water (10 mL),
brine (10 mL), dried (NaSO4) and concentrated under reduced
pressure to leave a brown oil, which was purified by flash chro-
matography (10% ethyl acetate/hexane). The product 8 was isolated
oil (27 mg, 85%). [
a
]
D þ9.3 (c 0.6, MeOH); Rf 0.29 (40% ethyl acetate/
hexane); 1H NMR (300 MHz, MeOH-d4):
d
6.75 (1H, m, NH), 4.25–
4.12 (3H, m, H3, COOCH2), 3.23 (1H, m, H4A), 3.09 (1H, m, H4B), 2.51
(1H, dd, J 14.9, 4.3 Hz, H2A), 2.33 (1H, dd, J 14.9, 7.9 Hz, H2B), 1.01
t
(2H, m, CH2TMS), 0.90 (9H, s, Bu), 0.12 (3H, s, SiMeA), 0.10 (3H, s,
SiMeB), 0.07 (9H, s, TMS); 13C NMR (50 MHz, MeOH-d4):
d 175.2 (C),
159.3 (C), 70.1 (CH), 63.9 (CH2), 47.6 (CH2), 41.8 (CH2), 26.3 (CH3),
18.9 (CH2), 18.7 (C), ꢀ1.5 (CH3), ꢀ4.4 (CH3), ꢀ4.8 (CH3); IR (thin
film): 3339 (w, NH), 2953, 2895, 2858 (m, CH), 1710 (s, C]O) cmꢀ1
;
as a pale yellow oil (281 mg, 99%). [
(10% ethyl acetate/hexane); H NMR (200 MHz, CDCl3): 8.18 (2H,
a
]
D þ16.0 (c 2.6, CH2Cl2); Rf 0.27
MS (ESIþ): m/z 422 ([MꢀHþ2Na]þ, 41), 400 ([MþNa]þ, 100); HRMS
(ESIþ): calcd for C16H35NO5Si2Na ([MþNa]þ) 400.1952, found
400.1965.
1
d
m, ArH), 6.93 (2H, m, ArH), 4.86 (1H, m, NH), 4.20–4.00 (5H, m, H4,
H2, COOCH2), 3.30–3.23 (2H, m, H1), 2.05–1.85 (2H, m, H3), 0.97
(2H, m, CH2TMS), 0.87 (9H, m, tBu), 0.07, (3H, s, SiMeA), 0.03 (9H, s,
4.2.28. (R)-2-(Trimethylsilyl)ethyl 1,4-dihydroxybutan-2-
ylcarbamate 11
TMS), ꢀ0.02 (3H, s, SiMeB); 13C NMR (50 MHz, CDCl3):
d
163.8,
156.9, 141.5, 125.9, 114.3, 67.8, 64.8, 63.1, 46.3, 33.8, 25.7, 17.9, 17.7,
ꢀ1.6, ꢀ4.6, ꢀ4.9; IR (thin film): 3342 (br w, NH), 2953, 2930, 2894,
2856 (m, CH), 1718 (s, C]O) cmꢀ1; MS (ESIþ): m/z 991 ([2MþNa]þ,
10), 940 (16), 507 ([MþNa]þ, 100), 457 (21), 341 (23); HRMS (ESIþ):
calcd for C22H40N2O6Si2Na ([MþNa]þ) 507.2323, found 507.2321.
A suspension of p-nitrophenyl ether 5e (R2¼TMSE, 135 mg,
0.364 mmol) and palladium on charcoal (20 mg) in ethyl acetate
(3 mL) was submitted to an atmosphere of hydrogen gas. After
complete consumption of starting material was observed by TLC,
acetic anhydride (1 mL) was added and the reaction was stirred for
1 h. The mixture was then filtered through a 1 cm pad of CeliteÒ
and the residue was washed with ethyl acetate (1 mL). The com-
bined filtrate was evaporated under reduced pressure to leave
a pale brown oil. The crude product was dissolved in acetonitrile/
water (10:1; 3.3 mL), cooled to 0 ꢂC and ammonium cerium(IV)
nitrate (395 mg, 0.721 mmol) was added. After 10 min the reaction
was quenched upon addition of a saturated aqueous solution of
sodium thiosulfate (5 mL). The mixture was extracted with ethyl
acetate (3ꢃ10 mL) and the combined organic extract was washed
with brine (10 mL), dried (NaSO4) and concentrated under reduced
pressure to leave a brown oil. The crude product was purified by
flash chromatography (10% methanol/dichloromethane) to give the
4.2.26. (R)-2-(Trimethylsilyl)ethyl 2-(tert-butyldimethylsilyloxy)-4-
hydroxybutylcarbamate 9
A suspension of p-nitrophenyl ether 8 (140 mg, 0.290 mmol)
and palladium on charcoal (15 mg) in ethyl acetate (2 mL) was
submitted to an atmosphere of hydrogen gas. After complete con-
sumption of starting material was observed by TLC, acetic anhy-
dride (1 mL) was added and the reaction was stirred for 1 h. The
mixture was then filtered through a 1 cm pad of CeliteÒ and the
residue was washed with ethyl acetate (1 mL). The combined fil-
trate was evaporated under reduced pressure to leave a pale brown
oil. The crude product was dissolved in acetonitrile/water (10:1;
3.3 mL) cooled to 0 ꢂC and ammonium cerium(IV) nitrate (238 mg,
0.434 mmol) was added. After 15 min the reaction was quenched
upon addition of a saturated aqueous solution of sodium thiosulfate
(5 mL). The mixture was extracted with ethyl acetate (3ꢃ10 mL)
and the combined organic extract was washed with brine (10 mL),
dried (NaSO4) and concentrated under reduced pressure to leave
a brown oil. The crude material was purified by flash chromatog-
raphy (30% ethyl acetate/hexane) to give the desired product 9 as
diol product 11 as a pale yellow oil (18.5 mg, 20%). [
CH2Cl2); Rf 0.44 (90% ethyl acetate/hexane); 1H NMR (300 MHz,
CDCl3): 5.33 (1H, br d, J 6.4 Hz, NH), 4.13 (2H, m, COOCH2), 3.84
a
]
D þ10.9 (c 1.3,
d
(1H, m, H2), 3.72–3.59 (4H, m, H1, H4), 3.16 (2H, br s, OH), 1.80 (1H,
m, H3A), 1.64 (1H, m, H3B), 0.96 (2H, m, CH2TMS), 0.03 (9H, s, TMS);
13C NMR (75 MHz, CDCl3):
d 157.6, 65.0, 63.5, 58.7, 50.0, 34.6, 17.7,
ꢀ1.5; IR (thin film): 3339 (br m, OH), 2953, 2895 (m, CH), 1689 (s,
C]O) cmꢀ1; MS (ESIþ): m/z 272 ([MþNa]þ, 17), 250 ([MþH]þ, 11),
222 (15), 204 (15); HRMS (ESIþ): calcd for C10H23NO4SiNa
([MþNa]þ) 272.1294, found 272.1289.
a colourless oil (65 mg, 62%). [
ethyl acetate/hexane); H NMR (300 MHz, CDCl3): 4.86 (1H, br s,
a
]
D þ6.5 (c 1.1, CH2Cl2); Rf 0.45 (40%
1
d
NH), 4.15 (2H, br t, J 8.4 Hz, COOCH2), 3.99 (1H, quin, J 5.9 Hz, H2),
3.74 (2H, t, J 5.9 Hz, H4), 3.33–3.16 (2H, m, H1), 2.03 (1H, br s, OH),
1.82–1.64 (2H, m, H3), 0.97 (2H, t, J 8.3 Hz, CH2TMS), 0.89 (9H, s,
tBu), 0.09 (6H, s, SiMe2), 0.03 (9H, s, TMS); 13C NMR (75 MHz,
4.2.29. (S)-2-(Trimethylsilyl)ethyl 1,4-dihydroxybutan-2-
ylcarbamate ent-11
To a solution of L-aspartic acid, 1,4-dimethyl ester, hydrochloride
CDCl3):
d
157.0 (C), 69.6 (CH), 63.1 (CH2), 59.5 (CH2), 46.3 (CH2), 36.7
(452 mg, 2.29 mmol) and triethylamine (0.64 mL, 4.60 mmol) in
dichloromethane (11 mL) was added carbonyldiimidazole (745 mg,
4.60 mmol) and the reaction was stirred for 30 min followed by the
addition of 2-(trimethylsilyl)ethanol (0.66 mL, 4.60 mmol). After
14 h the reaction was quenched upon addition of a saturated
aqueous solution of sodium hydrogen carbonate (20 mL). Ethyl
(CH2), 25.8 (CH3), 18.0 (C), 17.8 (CH2), ꢀ1.5 (CH3), ꢀ4.6 (CH3), ꢀ4.8
(CH3); IR (thin film): 3352 (br s, OH), 2953, 2894, 2856 (s, CH), 1705
(s, C]O) cmꢀ1; MS (ESIþ): m/z 386 ([MþNa]þ,100), 336 (24); HRMS
(ESIþ): calcd for C16H37NO4Si2Na ([MþNa]þ) 386.2159, found
386.2149.

M. Harding et al. / Tetrahedron 65 (2009) 831–843
841
ꢁ
acetate (20 mL) was added and the organic layer was separated. The
aqueous layer was then extracted with ethyl acetate (2ꢃ10 mL) and
the combined organic extract was washed with water (10 mL),
brine (10 mL), dried (NaSO4) and concentrated under reduced
pressure to leave a colourless oil, which was purified by flash
chromatography (20% ethyl acetate/hexane) to give the N-((2-(tri-
1510, 1339 (s, NO2) cmꢀ1; MS (EI): m/z 207 (Mþ , 100), 191 (10);
ꢁ
HRMS (EI): calcd for C11H13NO3 (Mþ ) 207.0895, found 207.0893.
4.2.32. tert-Butyl (2R,3R)-3-hydroxy-5-(4-nitrophenoxy)pentan-2-
ylcarbamate 15 (R1¼tBu)
The reaction was conducted under standard conditions using
substrate 14 (100 mg, 0.48 mmol), (DHQD)2AQN and tert-butyl
carbamate. Analysis of the crude reaction mixture by 300 MHz 1H
NMR identified a 3.7:1 ratio of the regioisomers 15 and 16. Purifi-
cation by flash chromatography (40% ethyl acetate/hexane) affor-
ded the major regioisomer 15 as a pale yellow oil (124 mg, 75%; 84%
ee, Chiralpak AD-H, 20% isopropyl alcohol/hexane; tR: 21.8 major,
25.8 minor). Data for ent-15 (R1¼tBu) below.
methylsilyl)ethoxy)carbonyl)-L-aspartic acid, dimethyl ester 12 as
a colourless oil (180 mg). This was dissolved in tetrahydrofuran
(4 mL) and added via cannula to a suspension of lithium borohy-
dride (76 mg, 3.50 mmol) in tetrahydrofuran (4 mL). After 12 h the
reaction was quenched upon addition of a saturated aqueous so-
lution of sodium hydrogen carbonate (10 mL). Ethyl acetate (10 mL)
was added and the organic layer was separated. The aqueous layer
was then extracted with ethyl acetate (2ꢃ10 mL) and the combined
organic extract was washed with water (10 mL), brine (10 mL),
dried (NaSO4) and concentrated under reduced pressure to leave
a colourless oil, which was purified by flash chromatography (7%
methanol/dichloromethane) to give the (S)-2-(trimethylsilyl)ethyl
4.2.33. tert-Butyl (2S,3S)-3-hydroxy-5-(4-nitrophenoxy)pentan-2-
ylcarbamate ent-15 (R1¼tBu)
The reaction was conducted under standard conditions using
substrate 14 (200 mg, 0.97 mmol), (DHQ)2AQN and tert-butyl car-
bamate. Analysis of the crude reaction mixture by 300 MHz 1H
NMR identified a 2.6:1 ratio of the regioisomers ent-15 and ent-16.
Purification by flash chromatography (40% ethyl acetate/hexane)
afforded the major regioisomer ent-15 as a pale yellow oil (185 mg,
56%; 80% ee, Chiralpak AD-H, 20% isopropyl alcohol/hexane; tR:
1,4-dihydroxybutan-2-ylcarbamate ent-11 as
(135 mg, 24%). [
ꢀ10.8 (c 1.7, CH2Cl2).
a colourless oil
a]
D
4.2.30. (S)-4-(4-Nitrophenoxy)-2-((2-(trimethylsilyl)ethoxy)-
carbonylamino)butanoic acid 13
To a solution of alcohol ent-5e (R2¼TMSE, 524 mg, 1.42 mmol)
and TEMPO (22 mg, 0.141 mmol) in acetonitrile (7.1 mL) and pH 6.7
potassium phosphate buffer (5.3 mL) was added simultaneously an
aqueous solution of sodium chlorite (1.42 mL, 2 M, 2.84 mmol) and
25.5 major, 21.7 minor). [
a
]
D ꢀ25.3 (c 1.5, CHCl3); Rf 0.34 (40% ethyl
acetate/hexane); 1H NMR (300 MHz, CDCl3):
d
8.16 (2H, m, ArH),
6.94 (2H, m, ArH), 4.75 (1H, br s, NH), 4.30–4.17 (2H, m, H5), 3.79
(1H, dt, J 8.9, 3.9 Hz, H3), 3.69 (1H, br s, H2), 2.40 (1H, br s, OH),
a solution of sodium hypochlorite (20
mL, 1.4 M, 28
mmol). After
2.02–1.88 (2H, m, H4), 1.43 (9H, s, tBu), 1.21 (3H, d, J 6.8 Hz, H1); 13
C
stirring for 17 h at 35 ꢂC the reaction mixturewas taken to pH 3 upon
addition of citric acid. The reaction was diluted with water (5 mL)
and the aqueous layer was extracted ethyl acetate (3ꢃ15 mL). The
combined organic extract was washed with brine (5 mL) and con-
centrated under reduced pressure to leave the crude product, which
was redissolved in water/diethyl ether (1:1; 50 mL) and the aqueous
layer was taken to pH 10 upon addition of sodium hydroxide (2 M).
The ether layer was separated and the aqueous layer extracted with
diethyl ether (2ꢃ10 mL). The aqueous layer was then converted to
pH 3 upon addition of an aqueous solution of hydrochloric acid and
extracted withethyl acetate(3ꢃ15 mL). Thecombined organicswere
washed with brine (15 mL), dried (NaSO4) and concentrated under
reducedpressure to leave the product 13 as a paleyellowoil(455 mg,
NMR (75 MHz, CDCl3): d 163.8 (C), 156.4 (C), 141.5 (C), 125.9 (CH),
114.4 (CH), 79.8 (C), 72.1 (CH), 66.0 (CH2), 50.8 (CH), 33.5 (CH2), 28.3
(CH3), 18.1 (CH3); IR (thin film): 3400 (br s, OH), 2975, 2931 (w, CH),
1691 (s, C]O) cmꢀ1; MS (ESIþ): m/z 363 ([MþNa]þ, 100), 285 (18),
241 (30); HRMS (ESIþ): calcd for C16H24N2O6Na ([MþNa]þ)
363.1532, found 363.1514.
A second fraction afforded the minor regioisomer ent-16 as
a pale yellow oil (30 mg, 9%; ee not determined). [
CHCl3); Rf 0.17 (40% ethyl acetate/hexane); 1H NMR (300 MHz,
CDCl3): 8.18 (2H, m, ArH), 6.94 (2H, m, ArH), 4.81 (1H, d, J 8.5 Hz,
a
]
D ꢀ23.4 (c 0.53,
d
NH), 4.14 (2H, t, J 6.2 Hz, H1), 3.90 (1H, m, H4), 3.71 (1H, m, H3),
2.11–2.00 (3H, m, H2, OH), 1.40 (9H, s, tBu), 1.24 (3H, d, J 6.3 Hz, H5);
13C NMR (75 MHz, CDCl3):
d 163.8 (C), 156.4 (C), 141.6 (C), 125.9
84%). [
methane); 1H NMR (200 MHz, MeOH-d4):
(2H, m, ArH), 4.49–4.39 (1H, m, H2), 4.27–4.08 (4H, m, H4, COOCH2),
2.46–2.09 (2H, m, H3), 0.95 (2H, m, CH2TMS), 0.02 (9H, s, TMS); 13
NMR (50 MHz, MeOH-d4): 176.9, 166.8, 144.4, 128.3, 117.3, 67.8,
65.7, 53.7, 33.6, 20.1, 0.0 (one carbon obscured or overlapping); IR
(thin film): 3330 (br s, OH), 2953 (m, CH), 1712 (s, C]O) cmꢀ1; MS
(ESIþ): m/z 407 ([MþNa]þ, 75), 241 (100); HRMS (ESIþ): calcd for
C16H24N2O7SiNa ([MþNa]þ) 407.1251, found 407.1246.
a
]
ꢀ6.4 (c 1.4, MeOH); Rf 0.30 (10% methanol/dichloro-
(CH), 114.5 (CH), 79.6 (C), 69.4 (CH), 66.1 (CH2), 53.0 (CH), 32.1
(CH2), 28.3 (CH3), 20.5 (CH3); IR (thin film): 3404 (br s, OH), 2974,
2931 (w, CH), 1683 (s, C]O) cmꢀ1; MS (ESIþ): m/z 363 ([MþNa]þ,
100), 285 (41), 241 (63); HRMS (ESIþ): calcd for C16H24N2O6Na
([MþNa]þ) 363.1532, found 363.1516.
D
d
8.19 (2H, m, ArH), 7.08
C
d
4.2.34. 2-(Trimethylsilyl)ethyl (2R,3R)-3-hydroxy-5-(4-
nitrophenoxy)pentan-2-ylcarbamate 15 (R1¼TMSE)
The reaction was conducted under standard conditions using
substrate 14 (100 mg, 0.48 mmol), (DHQD)2AQN and 2-(trime-
thylsilyl)ethyl carbamate. Analysis of the crude reaction mixture by
300 MHz 1H NMR identified a 2.6:1 ratio of the regioisomers 15 and
16. Purification by flash chromatography (40% ethyl acetate/hex-
ane) afforded the major regioisomer 15 as a pale yellow oil (90 mg,
48%; 84% ee, Chiralpak AD-H, 20% isopropyl alcohol/hexane; tR:
15.6 major, 19.4 minor). Data for ent-15 (R1¼TMSE) below.
A second fraction afforded the minor regioisomer 16 as a pale
yellow oil (35 mg, 19%; 34% ee, Chiralpak AD-H, 20% isopropyl al-
cohol/hexane; tR: 14.5 major, 11.9 minor). Data for ent-16
(R1¼TMSE) below.
4.2.31. (E)-1-Nitro-4-(pent-3-enyloxy)benzene 14
To a stirred solution of (E)-pent-3-en-1-ol34 (0.990 g, 11.5 mmol)
in tetrahydrofuran (41 mL) at room temperature was added
p-nitrophenol (1.65 g, 11.9 mmol) and triphenylphosphine (3.92 g,
14.9 mmol). Following addition of diethyl azodicarboxylate
(2.53 mL, 16.1 mmol), the mixture was heated at reflux for 30 min
then cooled and concentrated to afford a brown oil. Purification by
flash chromatography (10% ethyl acetate/hexane) afforded pure
ether 14 as a colourless oil (1.20 g, 50%). Rf 0.50 (10% ethyl acetate/
hexane); 1H NMR (300 MHz, CDCl3):
d 8.19 (2H, m, ArH), 6.94 (2H,
m, ArH), 5.65–5.43 (2H, m, H3, H4), 4.05 (2H, t, J 6.8 Hz, H1), 2.50
(2H, q, J 6.8 Hz, H2), 1.69 (3H, d, J 6.0 Hz, H5); 13C NMR (75 MHz,
4.2.35. 2-(Trimethylsilyl)ethyl (2S,3S)-3-hydroxy-5-(4-nitro-
phenoxy)pentan-2-ylcarbamate ent-15 (R1¼TMSE)
CDCl3): d 164.1 (C), 141.4 (C), 128.4 (CH), 125.9 (CH), 114.4 (CH), 68.6
(CH2), 32.2 (CH2), 18.0 (CH3) (one carbon obscured or overlapping);
IR (thin film): 3026 (w, CH]CH), 2951, 2922 (w, CH), 1595 (s, C]C),
The reaction was conducted under standard conditions using
substrate 14 (100 mg, 0.48 mmol), (DHQ)2AQN and 2-

842
M. Harding et al. / Tetrahedron 65 (2009) 831–843
(trimethylsilyl)ethyl carbamate. Analysis of the crude reaction
mixture by 300 MHz 1H NMR identified a 2.3:1 ratio of the
regioisomers ent-15 and ent-16. Purification by flash chromatog-
raphy (40% ethyl acetate/hexane) afforded the major regioisomer
ent-15 as a pale yellow oil (79 mg, 43%; 81% ee, Chiralpak AD-H, 20%
Supplementary data
CIF file for the (DHQ)2AQN crystal structure. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2008.11.037.
isopropyl alcohol/hexane; tR: 19.3 major, 15.9 minor). [
1.4, CHCl3); Rf 0.36 (40% ethyl acetate/hexane); 1H NMR (300 MHz,
CDCl3): 8.15 (2H, m, ArH), 6.93 (2H, m, ArH), 4.94 (1H, d, J 8.7 Hz,
NH), 4.30–4.09 (4H, m, H5, COOCH2), 3.85–3.65 (2H, m, H2, H3),
2.55 (1H, br s, OH), 1.97 (2H, m, H4), 1.22 (3H, d, J 6.7 Hz, H1), 0.95
(2H, m, CH2TMS), 0.02 (9H, s, TMS); 13C NMR (75 MHz, CDCl3):
a
]
D ꢀ18.9 (c
References and notes
d
1. (a) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2007, 72, 9936; (b) Fer-
na´ndez de la Pradilla, R.; Lwoff, N.; Viso, A. Tetrahedron Lett. 2007, 48, 8141; (c)
Curtis, K. L.; Evinson, E. L.; Handa, S.; Singh, K. Org. Biomol. Chem. 2007, 5, 3544;
(d) Shuter, E. C.; Duong, H.; Hutton, C. A.; McLeod, M. D. Org. Biomol. Chem.
2007, 5, 3183; (e) Kim, G.; Kim, N. Tetrahedron Lett. 2007, 48, 4481; (f) Kurosawa,
W.; Kobayashi, H.; Kan, T.; Fukuyama, T. Tetrahedron 2004, 60, 9615; (g) Singh,
S.; Han, H. Tetrahedron Lett. 2004, 45, 6349; (h) Crowley, B. M.; Mori, Y.;
McComas, C. C.; Tang, D.; Boger, D. L. J. Am. Chem. Soc. 2004, 126, 4310; (i)
Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 8112; (j) Zhang,
H.-X.; Xia, P.; Zhou, W.-S. Tetrahedron 2003, 59, 2015; (k) Dong, L.; Miller, M. J.
J. Org. Chem. 2002, 67, 4759; (l) Yang, C.-G.; Wang, J.; Tang, X.-X.; Jiang, B. Tet-
rahedron: Asymmetry 2002, 13, 383; (m) Cao, B.; Park, H.; Joullie, M. M. J. Am.
Chem. Soc. 2002, 124, 520; (n) Boger, D. L.; Kim, S. H.; Mori, Y.; Weng, J.-H.;
Rogel, O.; Castle, S. L.; McAtee, J. J. J. Am. Chem. Soc. 2001, 123, 1862; (o) Masse,
C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org. Chem. 2000, 2513; (p)
Masse, C. E.; Morgan, A. J.; Panek, J. S. Org. Lett. 2000, 2, 2571; (q) Panek, J. S.;
Masse, C. E. Angew. Chem., Int. Ed. 1999, 38, 1093.
d
163.8 (C), 157.0 (C), 141.3 (C), 125.8 (CH), 114.3 (CH), 71.3 (CH), 65.8
(CH2), 63.1 (CH2), 50.8 (CH), 33.4 (CH2), 18.1 (CH3), 17.6 (CH2), ꢀ1.6
(CH3); IR (thin film): 3425 (br s, OH), 2952, 2896 (w, CH), 1691 (s,
C]O) cmꢀ1; MS (ESIþ): m/z 407 ([MþNa]þ, 100), 357 (19), 241
(100); HRMS (ESIþ): calcd for C17H28N2O6SiNa ([MþNa]þ) 407.1614,
found 407.1617.
A second fraction afforded the minor regioisomer ent-16 as
a pale yellow oil (35 mg,19%; 25% ee, Chiralpak AD-H, 20% isopropyl
alcohol/hexane; tR: 11.9 major, 14.6 minor). Data below.
2. Bodkin, J. A.; Bacskay, G. B.; McLeod, M. D. Org. Biomol. Chem. 2008, 6, 2544.
3. Harding, M.; Bodkin, J. A.; Hutton, C. A.; McLeod, M. D. Synlett 2005, 2829.
4. Davey, R. M.; Brimble, M. A.; McLeod, M. D. Tetrahedron Lett. 2000, 41, 5141.
5. Han, H.; Cho, C.-W.; Janda, K. D. Chem.dEur. J. 1999, 5, 1565.
6. Morgan, A. J.; Masse, C. E.; Panek, J. S. Org. Lett. 1999, 1, 1949.
7. Chuang, C.-Y.; Vassar, V. C.; Ma, Z.; Geney, R.; Ojima, I. Chirality 2002, 14, 151 and
erratum: Chirality 2002, 14, 757.
8. (a) Qureshi, A.; Colin, P. L.; Faulkner, D. J. Tetrahedron 2000, 56, 3679; (b)
Schmidt, E. W.; Faulkner, D. J. Tetrahedron 1998, 54, 3043; (c) Bewley, C. A.;
Debitus, C.; Faulkner, D. J. J. Am. Chem. Soc. 1994, 116, 7631.
9. See Jung, M. E.; Shaw, T. J. Am. Chem. Soc. 1980, 102, 6304 and references cited
therein.
10. (a) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207; (b) O’Brien, P.;
Osborne, S. A.; Parker, D. D. J. Chem. Soc., Perkin Trans. 1 1998, 2519; (c) O’Brien,
P.; Osborne, S. A.; Parker, D. D. Tetrahedron Lett. 1998, 39, 4099.
11. (a) Bushey, M. L.; Haukaas, M. H.; O’Doherty, G. A. J. Org. Chem. 1999, 64, 2984;
(b) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 3899; (c) Demko, Z. P.;
Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221; (d) Feldman, K. S.; Sa-
unders, J. C.; Wrobleski, M. L. J. Org. Chem. 2002, 67, 7096.
12. The aromatic ethers were prepared from the corresponding phenol and but-3-
ene-1-ol under Mitsunobu conditions: Ramachandran, P. V.; Chandra, J. S.;
Reddy, M. V. R. J. Org. Chem. 2002, 67, 7547.
13. Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 448.
14. Determined by integration of the 300 MHz 1H NMR spectrum of crude reaction
mixture.
15. Determined by chiral HPLC using Chiralpak AD or Chiralcel OD-H columns.
16. Reddy, K. L.; Dress, K. R.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 3667.
17. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991,
113, 4092.
18. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
*
19. Theoretical investigations (B3LYP/f/6-31G ) of the ligand-osmium binding
in model systems show that the di-apical nitrogen geometry is approximately
4.6 kcal molꢀ1 more stable than alternate binging modes; See Ref. 2.
20. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 701980. Copies of the data can be ob-
tained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: þ44 (0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.uk). The
CIF file is reported as Supplementary data.
4.2.36. 2-(Trimethylsilyl)ethyl (3R,4R)-4-hydroxy-1-(4-
nitrophenoxy)pentan-3-ylcarbamate 16 (R1¼TMSE)
The reaction was conducted under standard conditions using
substrate 14 (100 mg, 0.48 mmol), (DHQD)2PHAL and 2-(trime-
thylsilyl)ethyl carbamate. Analysis of the crude reaction mixture by
300 MHz 1H NMR identified a 1:8 ratio of the regioisomers 15 and
16. Purification by flash chromatography (40% ethyl acetate/hex-
ane) afforded the major regioisomer 16 as a pale yellow oil (103 mg,
56%; 89% ee, Chiralpak AD-H, 20% isopropyl alcohol/hexane; tR: 14.1
major, 11.6 minor). Data for ent-16 (R1¼TMSE) below.
A second fraction afforded the minor regioisomer 15 as a pale
yellow oil (12.5 mg, 7%; 33% ee, Chiralpak AD-H, 20% isopropyl al-
cohol/hexane; tR: 15.0 major, 18.1 minor).
4.2.37. 2-(Trimethylsilyl)ethyl (3S,4S)-4-hydroxy-1-(4-
nitrophenoxy)pentan-3-ylcarbamate ent-16 (R1¼TMSE)
The reaction was conducted under standard conditions using
substrate 14 (100 mg, 0.48 mmol), (DHQ)2PHAL and 2-(trime-
thylsilyl)ethyl carbamate. Analysis of the crude reaction mixture by
300 MHz 1H NMR identified a 1:10 ratio of the regioisomers ent-15
and ent-16. Purification by flash chromatography (40% ethyl ace-
tate/hexane) afforded the major regioisomer ent-16 as a pale yellow
oil (71 mg, 38%; 91% ee, Chiralpak AD-H, 20% isopropyl alcohol/
hexane; tR: 11.6 major, 14.2 minor). [
a
]
D ꢀ29.8 (c 1.7, CHCl3); Rf 0.22
(40% ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3):
d
8.17 (2H,
m, ArH), 6.94 (2H, m, ArH), 5.00 (1H, d, J 9.4, NH), 4.17–4.06 (4H, m,
H1, COOCH2), 3.92 (1H, m, H4), 3.76 (1H, m, H3), 2.16–2.07 (3H, m,
H2, OH), 1.24 (3H, d, J 6.3 Hz, H5), 0.93 (2H, m, CH2TMS), 0.01 (9H, s,
TMS); 13C NMR (75 MHz, CDCl3):
d 163.7 (C), 157.2 (C), 141.5 (C),
125.9 (CH), 114.5 (CH), 69.3 (CH), 66.0 (CH2), 63.3 (CH2), 53.4 (CH),
32.2 (CH2), 20.5 (CH3), 17.7 (CH2), ꢀ1.5 (CH3); IR (thin film): 3400
(br s, OH), 2952, 2897 (w, CH), 1691 (s, C]O) cmꢀ1; MS (ESIþ): m/z
407 ([MþNa]þ, 100), 357 (23), 241 (55); HRMS (ESIþ): calcd for
C17H28N2O6SiNa ([MþNa]þ) 407.1614, found 407.1597.
21. The face-to-face interaction of these electron deficient aromatic units can be
rationalised by the Hunter and Sanders model of
p–p interactions: Hunter, C.
A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112, 5525. For a further discussion of
the nature of this interaction see Ref. 2.
22. The planar conformation (C2–C1–O–C10 constrained dihedral angle 0ꢂ, local
maximum) of the 2,6-dimethyl-4-nitrophenyl ether (R1¼2,6-di-Me-4-NO2-Ph,
entry 7) is þ4.95 kcal molꢀ1 higher in energy (MM2/Chem3D Pro) than the
corresponding twisted conformation (C2–C1–O–C10 dihedral angle 84ꢂ, local
minimum). The planar conformation (C2–C1–O–C10 dihedral angle 0ꢂ, local
minimum) of the 4-nitrophenyl ether (R1¼4-NO2-Ph) is 1.07 kcal molꢀ1 lower
in energy (MM2/Chem3D Pro) than the corresponding twisted conformation
(C20–C10–O–C5 dihedral angle 85ꢂ, local minimum).
A second fraction afforded the minor regioisomer ent-15 as
a pale yellow oil (6.9 mg, 4%; 8% ee, Chiralpak AD-H, 20% isopropyl
alcohol/hexane; tR: 18.2 major, 15.1 minor).
23. Fukase, K.; Yasukochi, T.; Nakai, Y.; Kusumoto, S. Tetrahedron Lett. 1996,
37, 3343.
Acknowledgements
24. Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 2564.
25. The geometry of the ligand was based on the reported (DHQD)2PHAL crystal
structure: see Ref. 26.
26. Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.; Davis, W. D.; Hartung,
J.; Jeong, K.-S.; Ogino, Y.; Shibata, T.; Sharpless, K. B. J. Org. Chem. 1993, 58, 844.
Dr. Kelvin Picker, School of Chemistry, University of Sydney, is
acknowledged for assistance with HPLC. We thank the Australian
Research Council (DP0342590), the Australian National University
and The University of Sydney for financial support.

M. Harding et al. / Tetrahedron 65 (2009) 831–843
30. Samanta, D.; Faure, N.; Rondelez, F.; Sarkar, A. Chem. Commun. 2003, 1186.
843
27. In this binding mode substrate adopts an s-cis conformation about the allylic
C–C single bond. This conformation (C10–C20–C30–C40 dihedral angle 0ꢂ) is
0.45 kcal molꢀ1 (MM2/Chem 3D Pro) higher in energy than the corresponding ex-
tended conformation (C10–C20–C30–C40 dihedral angle 119ꢂ). A similar conformation
has been proposed for the Sharpless AD reaction of homoallyl aryl ethers: see Ref. 28.
28. Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805.
29. Hoffmann, N.; Pete, J.-P. J. Org. Chem. 1997, 62, 6952.
31. De Keukeleire, D.; He, S.-L.; Blakemore, D.; Gilbert, A. J. Photochem. Photobiol., A:
Chem. 1994, 80, 233.
32. Rammler, D. H.; Haugland, R.; Shavitz, R. Anal. Biochem. 1973, 52, 180.
33. Boeckman, R. K., Jr.; Charette, A. B.; Asberom, T.; Johnston, B. H. J. Am. Chem. Soc.
1991, 113, 5337.
34. Knight, J. A.; Diamond, J. H. J. Org. Chem. 1959, 24, 400.