Stereospecific syntheses of 2-alkyl and 2-phenyl substituted 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acids

Article abstract of DOI:10.1055/s-2001-16757

Stereospecific syntheses of 2-methyl-, 2-ethyl-, 2-cyclohexyland 2-phenyl- substituted 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acids were developed. The key steps for the formation of the stereogenic centers involved the utilization of Evans' 4-benzyl-2-oxazolidinone chiral auxiliary. These compounds were designed to replace the N-terminal tyrosine residue in opioid peptides.

Full text of DOI:10.1055/s-2001-16757

PAPER
1639
Stereospecific Syntheses of 2-Alkyl and 2-Phenyl Substituted 3-(2,6-Dimethyl-
4-hydroxyphenyl)propanoic Acids
S
tereospecific Syn
itheses
x
i
ted 3-(
n
L
u
A
cid
,
s
*1 Peter W. Schiller*
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec,
Canada, H2W 1R7
Fax +1(514)9875513; E-mail: schillp@ircm.qc.ca
Received 9 February 2001; revised 19 May 2001
In view of this remarkable result, it was of interest to re-
Abstract: Stereospecific syntheses of 2-methyl-, 2-ethyl-, 2-cyclo-
place the amino group of the N-terminal L-Dmt residue in
opioid peptides with other, somewhat larger aliphatic or
aromatic groups (ethyl, cyclohexyl and phenyl) to probe
hexyl- and 2-phenyl- substituted 3-(2,6-dimethyl-4-hydroxyphe-
nyl)propanoic acids were developed. The key steps for the
formation of the stereogenic centers involved the utilization of
Evans' 4-benzyl-2-oxazolidinone chiral auxiliary. These com- the receptor-binding site. Stereospecific syntheses of
pounds were designed to replace the N-terminal tyrosine residue in
opioid peptides.
(2S)-2-ethyl-3-(4-hydroxy-2,6-dimethylphenyl)propano-
ic acid (Edp), (2R)-2-cyclohexyl-3-(4-hydroxy-2,6-dime-
Key words: amino acids, tyrosine analogues, asymmetric synthe-
sis, chiral auxiliaries, Heck reaction
thylphenyl)propanoic acid (Cdp) and (2R)-2-phenyl-3-(4-
hydroxy-2,6-dimethylphenyl)propanoic acid (Pdp) were
therefore developed, and are described in the present pa-
per.
For decades it has been assumed that a positively charged
nitrogen in opioid compounds is a necessary requirement
for binding to their receptors. The quaternary ammonium
group on the ligand was assumed to engage either in an
ionic interaction with a negatively charged receptor
moiety2 (e.g., side chain of an Asp residue) or in chelation
by multiple aromatic receptor residues.3 In a recent study,
both somatostatin-derived cyclic hexapeptides lacking a
positive charge and a neutral des-amino analogue of a cy-
clic -casomorphin analogue were shown to be opioid
antagonists with moderate receptor binding affinity.4
Subsequently, we prepared an analogue of the potent en-
kephalin-derived peptide H-Dmt-D-Ala-Gly-Phe-Leu-
NH2 (Dmt = 2’,6’-dimethyltyrosine) in which the N-termi-
nal amino group was replaced with the neutral and almost
isosteric methyl group.5 A Dmt1-containing enkephalin
analogue was chosen as parent peptide because substitu-
tion of Dmt for Tyr1 in opioid peptides is known to gener-
The syntheses of (2S)-Mdp 10a and (2S)-Edp 10b are
shown in Scheme 1. 3,5-Dimethylphenol 1 was iodinated
using a literature procedure7 to give 3,5-dimethyl-4-io-
dophenol 2, which was protected as the Boc derivative 3.
Heck coupling8 of 3 with methyl acrylate then afforded
alkene 4. The trans configuration of 4 was established by
measurement of the coupling constant (16.4 Hz) of the
two alkene protons. Subsequent catalytic hydrogenation,
followed by basic hydrolysis afforded acid 6. Incorpora-
tion of Evans’ chiral auxiliary (S)-(–)-4-benzyl-2-oxazoli-
dinone was performed in the standard manner9 to yield 7.
Asymmetric methylation10 or ethylation then furnished 8a
or 8b as single diastereomers after purification by flash
chromatography. Removal of the chiral oxazilidinone
auxiliary and Boc group then gave (2S)-Mdp 10a or (2S)-
Edp 10b.
We initially attempted to prepare (2R)-Cdp by a synthetic
route analogous to that used for the preparation of (2S)-
Mdp and (2S)-Edp. Oxazolidinone 7 in THF was treated
with NaHMDS at –78 °C for an hour, followed by treat-
ment with cyclohexyl iodide at –78 °C. The mixture was
allowed to warm up to –25 °C for 3 hours. No desired in-
corporation product was obtained. It had previously been
shown that 3-bromocyclohexene reacted smoothly with
lithium enolate, while bromo- or iodocyclohexane failed
to give any desired product.11 Preparation of the sodium
enolate of 7 by treatment with NaHMDS at –78 °C and
subsequent reaction with bromocyclohexene did give the
desired product 11, which can be transformed to (2R)-Cdp
by catalytic hydrogenation and subsequent removal of the
chiral auxiliary and Boc group (Scheme 2). However, the
yield of 11 was very low (15%), probably due to steric
hindrance and lack of reactivity of bromocyclohexene to-
wards the enolate. Therefore, it is not practical to synthe-
size Cdp by this approach.
ally result in significantly enhanced
and
opioid
receptor binding affinities.6 The substitution of the amino
group in this enkephalin analogue with a methyl group
was achieved by replacing L-Dmt1 with (2S)-2-methyl-3-
(4-hydroxy-2,6-dimethylphenyl)propanoic acid [(2S)-
Mdp], for which a stereospecific synthesis was developed
and described in a preliminary publication.5 The resulting
compound, (2S)-Mdp-D-Ala-Gly-Phe-Leu-NH2, turned
out to be a quite potent opioid antagonist and a some-
what less potent antagonist, indicating that a positively
charged N-terminal amino group is not an absolute re-
quirement for the binding of this opioid peptide to and
receptors, but it is required for signal transduction.
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
1437-210X,E;2001,0,11,1639,1644,ftx,en;M00801SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1640
Y. Lu, P. W. Schiller
PAPER
OH
OR
OBoc
iii
i
(61%)
(79%)
I
1
2 R = H
3 R = Boc (98%)
ii
COOMe
4
iv
OBoc
OBoc
OR
viii
vi
COOR
COXc
COOH
5 R = Me
6 R = H (88%)
R
v
R'
7 R = H (87%)
8 a R = Me (71%)
b R = Et (65%)
vii
a R' = Me b R' = Et
9 R = Boc
10 R = H (96%)
ix
Xc = (S)-4-benzyl-2-oxazolidinone
Scheme 1 Reagents and conditions: i. KI, KIO3, MeOH, HCl; ii. (Boc)2O, Et3N, DMAP, H2O–THF, r.t.; iii. CH2=CHCOOMe, Pd(OAc)2,
Et3N, (o-MePh)3P, CH3CN, reflux; iv.H2, Pd/C, 70 psi, 60 °C, EtOAc; v. 1 N NaOH–THF; vi.Et3N, PvCl, Et2O, –78 °C to 0 °C, then treated
with n-BuLi, Xc, THF, –78 °C to 0 °C; vii. NaHMDS, THF, MeI or EtI, –78 °C to –25 °C; viii. LiOH, H2O2, THF–H2O; ix. TFA, CH2Cl2, r.t.
An alternative approach for the synthesis of Cdp is depict- The performed synthesis of (2R)-Pdp 20b was analogous
ed in Scheme 3. 3,5-Dimethyl-4-iodophenol 2 was pro- to that of (2R)-Cdp, using phenylacetic acid instead of cy-
tected as its TBDMS derivative 12. Subsequent metal- clohexylacetic acid (Scheme 3). The compound was easi-
halogen exchange with n-butyllithium, followed by the ly prepared with reaction yields similar to those obtained
addition of DMF afforded aldehyde 13. Reduction of 13 in the synthesis of (2R)-Cdp.
with sodium borohydride yielded alcohol 14. The attempt-
ed transformation of the alcohol to bromide 15 using
A non-stereospecific synthesis of (R,S)-Mdp has been re-
ported.12 However, the substitution of such a racemic
Ph3P/CBr4 did not occur in satisfactory yield. However,
compound for Tyr1 in opioid peptides is unsatisfactory for
the reaction proceeded smoothly and cleanly with PBr3
two reasons. Firstly, it may not be possible to separate the
resulting diastereomeric peptides and, therefore, a conclu-
sive biological activity determination in terms of agonist
and pyridine in ether to give the desired bromide 15.
Evans’4-benzyl-2-oxazolidinone chiral auxiliary was in-
corporated into commercially available cyclohexyl acetic
or antagonist properties would not be possible. Secondly,
acid 16a in the usual manner to afford 17a. Oxazolidinone
even in cases where the diastereomeric peptides could be
separated, it would still be necessary to make the stere-
ochemical assignments, which would obviously require a
stereospecific synthesis of (2S)- or (2R)-Mdp.
17a in THF was treated with NaHMDS at –78 °C for half
an hour, followed by the addition of bromide 15 at –78 °C,
and subsequent warming up to –25 °C. To our delight, the
desired product 18a was obtained in 75% yield. The ox-
In conclusion, convenient asymmetric syntheses of the
azolidinone chiral auxiliary and TBDMS protecting group
Dmt analogues (2S)-Mdp, (2S)-Edp, (2R)-Cdp and (2R)-
were removed to afford Cdp 20a.
OH
OBoc
OBoc
OBoc
iii, iv
i
ii
COOH
COXc
COXc
COXc
7
Cdp
11
Xc = (S)-4-benzyl-2-oxazolidinone
Scheme 2 Reagents and conditions: i. NaHMDS, THF, 3-bromocyclohexene, –78 °C to –25 °C; ii. H2, Pd/C; iii. LiOH, H2O2, THF–H2O; iv.
TFA, CH2Cl2, r.t.
Synthesis 2001, No. 11, 1639–1644 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereospecific Syntheses of 2-Substituted 3-(2,6-Dimethyl-4-hydroxyphenyl)propanoic Acids
1641
ed, washed, and dried. The solvent was removed in vacuo to afford
3 as a white solid (328 mg, 98%).
OTBDMS
OTBDMS
i
iii
1H NMR (400 MHz, CDCl3): = 6.89 (s, 2 H), 2.45 (s, 6 H), 1.53
(s, 9 H).
2
13C NMR (100.6 MHz, CDCl3): = 151.7, 150.5, 143.3, 119.7,
83.7, 29.7, 27.7, 19.7.
HRMS (EI): m/z calcd for C13H17IO3 [M]+: 348.0222. Found:
R
R
12 R = I (97%)
13 R = CHO
14 R = OH (76%)
15 R = Br (97%)
ii
iv
348.0209.
O
O
Methyl (E)-3-(4-tert-Butoxycarbonyloxy-2,6-dimethylphenyl)-
2-propenoate (4)
X
COOH
v
X
N
O
16 a X = Cy, b X = Ph
A mixture of 3 (3.48 g, 10 mmol), methyl acrylate (2.70 mL, 30
mmol), tri-o-tolylphosphine (161 mg, 0.53 mmol), Et3N (2.79 mL,
20 mmol) and palladium(II) acetate (45 mg, 0.20 mmol) in MeCN
(50 mL) was refluxed for 24 h. The mixture was then cooled down
to r.t. and filtered through Celite. The solvent was removed in vacuo
and the residue was diluted with H2O (20 mL). The aqueous phase
was extracted with EtOAc (3 20 mL). The combined organic ex-
tracts were washed with brine and dried (MgSO4). Purification by
flash chromatography (EtOAc–hexanes, 1:15) afforded 4 as a col-
orless oil (1.9 g, 61%).
1H NMR (400 MHz, CDCl3): = 7.76 (d, 1 H, J = 16.4 Hz), 6.87 (s,
2 H), 6.03 (d, 1 H, J = 16.4 Hz), 3.80 (s, 3 H), 2.32 (s, 6 H), 1.54 (s,
9 H).
13C NMR (100.6 MHz, CDCl3): = 167.1, 151.9, 150.3, 142.7,
138.4, 131.7, 123.8, 120.9, 83.7, 51.7, 27.7, 21.2.
Bn
17 a X = Cy (72%)
b X = Ph (83%)
vi
OR
O
O
N
O
X
TBDMSO
COOH
Bn
X
18 a X = Cy (79%)
b X = Ph (77%)
a X = Cy, b X = Ph
19 R = TBDMS
20 R = H (84%)
viii
HRMS (EI): m/z calcd for C17H22O5 [M]+: 306.1467. Found:
306.1471.
Scheme 3 Reagents and conditions: i. TBDMSCl, imidazole, DMF;
ii. n-BuLi, THF, DMF, –78 °C to r.t.; iii. NaBH4, MeOH; iv. PBr3, py-
ridine, Et2O; v. Et3N, PvCl, Et2O, –78 °C to 0 °C, then treated with n-
BuLi, Xc, THF, –78 °C to 0 °C; vi. NaHMDS, THF, 15, –78 °C to
–25 °C; vii. LiOH, H2O2, THF–H2O; viii. 1 N HCl/MeOH; Cy = Cy-
clohexyl, Ph = Phenyl
Methyl 3-(4-tert-Butoxycarbonyloxy-2,6-dimethyl-phenyl)-
propanoate (5)
An argon purged reaction vessel was charged with 4 (1.0 g, 3.3
mmol) and Pd/C (10%, 0.2 g) in EtOAc (50 mL). The reaction ves-
sel was then carefully pressurized to 70 psi with H2 and heated at 60
°C for 5 h. The mixture was cooled down to r.t., vented with Ar, and
filtered through Celite. The filtrate was collected and concentrated
to yield 5 as a white solid, which was used directly without further
purification.
Pdp were developed. The incorporation of these Dmt an-
alogues into opioid peptides is under way. It is expected
that the substitution of the N-terminal amino function with
the various alkyl- and phenyl groups will not only affect
the opioid activity profile of the resulting peptides but
may also improve their bio-availability due to their in-
creased lipophilic character.
3-(4-tert-Butoxycarbonyloxy-2,6-dimethylphenyl)propanoic
Acid (6)
Crude 5 (0.62 g, 2 mmol) was dissolved in a mixture of 1 N NaOH
and THF (5 mL/5 mL) and stirred at r.t. until TLC showed the dis-
appearance of the starting material. THF was removed in vacuo.
The pH of the aqueous layer was adjusted to 2–3 by adding 1 N HCl,
and then extracted with EtOAc (3 15 mL). The combined organic
extracts were washed with brine and dried (MgSO4). The solvent
was removed to furnish 6 as a white solid.
1H NMR (400 MHz, CDCl3): = 6.81 (s, 2 H), 2.92–2.98 (m, 2 H),
2.45–2.51 (m, 2 H), 2.31 (s, 6 H), 1.53 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): = 179.2, 152.2, 148.8, 137.6,
134.4, 120.8, 83.4, 33.1, 27.7, 24.3, 19.8.
Mass spectra were recorded on a Micromass Autospec TOF mass
spectrometer. 1H and 13C NMR spectra were recorded on a Varian
Unity 400 spectrometer and referenced with respect to the residual
signals of the solvent. THF and Et2O were distilled from sodium
benzophenone ketyl, and Et3N from CaH2. Anhyd CH2Cl2 and DMF
were purchased from Aldrich and were used without further drying.
All other reagents were purchased from Aldrich. Products were pu-
rified by flash chromatography on silica gel (40 m; Baker). A Vari-
an HPLC system consisting of a programmable solvent delivery
system 9010 and a variable wavelength detector 9050 was used for
the diastereomeric purity determinations.
HRMS (EI): m/z calcd for C16H22O5 [M]+: 294.1467. Found:
294.1464.
(4S)-4-Benzyl-3-[3-(4-tert-butoxycarbonyloxy-2,6-
4-Iodo-3,5-dimethyl-O-tert-butoxycarbonyl-phenol (3)
dimethylphenyl)propanoyl]-1,3-oxazolan-2-one (7)
Et3N (0.35 mL, 2.5 mmol) was added to 3,5-dimethyl-4-iodophenol
(248 mg, 1.0 mmol) in a mixture of H2O and THF (10 mL/10 mL)
at r.t. Di-tert-butyl dicarbonate [(Boc)2O] (262 mg, 1.2 mmol) was
then introduced, followed by 4-(dimethylamino)pyridine (DMAP)
(12 mg, 0.1 mmol). The mixture was stirred at r.t. for 30 min. THF
was removed under reduced pressure. The residue was partitioned
between EtOAc, 1 N HCl and brine. The organic layer was separat-
To a stirred solution of 6 (0.59 g, 2 mmol) in anhyd Et2O (20 mL)
at –78 °C was added Et3N (0.29 mL, 2.1 mmol), followed by piv-
aloyl chloride (0.26 mL, 2.1 mmol). The resulting solution was
stirred at 0 °C for 1 h and then re-cooled to –78 °C. Meanwhile, a
solution of (4S)-4-(benzyl)-2-oxazolidinone (354 mg, 2 mmol) in
freshly distilled THF (10 mL) was cooled to –78 °C and treated
slowly with a 1.6 M solution of n-BuLi in hexanes (1.37 mL, 2.2
Synthesis 2001, No. 11, 1639–1644 ISSN 0039-7881 © Thieme Stuttgart · New York

1642
Y. Lu, P. W. Schiller
PAPER
mmol). The resulting solution was stirred at –78 °C for 15 min and
then added via cannula into the solution of the mixed anhydride.
The mixture was stirred at –78 °C for 15 min, and at 0 °C for 30 min.
Sat. NH4Cl (5 mL) was added to quench the reaction. THF was re-
moved in vacuo and the residue was extracted with EtOAc (3 20
mL). The combined organic extracts were washed with brine and
dried (MgSO4). Purification by flash chromatography (EtOAc–hex-
anes, 1:5) furnished 7 as a white solid (733 mg, 81%).
13C NMR (100.6 MHz, CDCl3): = 177.7, 155.9, 138.6, 128.1,
115.8, 40.2, 33.0, 20.5, 16.8.
HRMS (FAB): m/z calcd for C12H16O3 [M]+: 208.1099. Found:
208.1095.
(2S)-1-[(4S)-4-Benzyl-2-oxo-1,3-oxazolan-3-yl]-3-(4-tert-
butoxycarbonyloxy-2,6-dimethylbenzyl)-2-ethylpropan-1-one
(8b)
The synthesis of 8b (65% yield) was analogous to that of 8a except
that EtI was used instead of MeI.
[ ]D20 +46.2° (c 1.03, CH2Cl2).
1H NMR (400 MHz, CDCl3): = 7.20–7.33 (m, 5 H), 6.81 (s, 2 H),
4.67–4.70 (m, 1 H), 4.15–4.23 (m, 2 H), 3.30–3.34 (dd, 1 H, J = 3.2,
13.2 Hz), 2.94–3.07 (m, 4 H), 2.75–2.81 (dd, 1 H, J = 9.6, 13.2 Hz),
2.34 (s, 6 H), 1.53 (s, 9 H).
HPLC diastereomeric analysis (4.6 mm 25.0 cm Vydac 218TP54
column, 50–95% gradient of MeOH, 1 mL/min, 220 nm) showed
>99:1 diastereomeric purity (tR 25.85 min).
13C NMR (100.6 MHz, CDCl3): = 172.7, 153.4, 152.3, 148.9,
137.8, 135.3, 134.6, 129.5, 129.1, 127.4, 120.8, 83.4, 66.3, 55.3,
37.9, 34.5, 27.7, 24.1, 20.0.
HRMS (EI): m/z calcd for C26H31NO6 [M]+: 453.2151. Found:
453.2153.
[ ]D20 +114.0° (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): = 7.17–7.32 (m, 5 H), 6.75 (s, 2 H),
4.34–4.39 (m, 1 H), 4.20–4.28 (m, 1 H), 3.93–3.96 (m, 1 H), 3.80–
3.84 (m, 1 H), 3.22–3.26 (dd, 1 H, J = 3.6, 13.2 Hz), 2.98–3.03 (dd,
1 H, J = 9.6, 13.6 Hz), 2.81–2.86 (dd, 1 H, J = 6.4, 13.6 Hz), 2.61–
2.67 (dd, 1 H, J = 10.0, 13.2 Hz), 2.32 (s, 6 H), 1.87–1.90 (m, 1 H),
1.57–1.65 (m, 1 H), 1.51 (s, 9 H), 0.98 (t, 3 H).
13C NMR (100.6 MHz, CDCl3): = 176.7, 152.9, 152.0, 148.8,
138.6, 135.4, 133.3, 129.4, 128.9, 127.2, 120.6, 83.2, 65.8, 56.0,
42.7, 37.9, 32.1, 27.7, 25.7, 20.4, 11.7.
(2S)-1-[(4S)-4-Benzyl-2-oxo-1,3-oxazolan-3-yl]-3-(4-tert-
butoxycarbonyloxy-2,6-dimethylphenyl)-2-methylpropan-1-
one (8a)
To a solution of 7 (590 mg, 1.3 mmol) in anhyd THF (10 mL) at
–78 °C was added slowly 1.0 M sodium bistrimethylamide in THF
(1.44 mL, 1.44 mmol). The resulting mixture was stirred at –78 °C
for 1 h. MeI (0.40 mL, 6.5 mmol) in THF (5 mL) was introduced
slowly at –78 °C, and the mixture was stirred at –25 °C for 3 h. Sat.
NH4Cl (5 mL) was then added to quench the reaction. The volatiles
were removed under reduced pressure and the residue was taken up
in CH2Cl2. The combined organic extracts were washed with aq. po-
tassium bisulfate solution (10%) and dried (MgSO4). Purification
by flash chromatography (EtOAc–hexanes, 1:10) afforded 8a as a
white foamy solid (0.43 g, 71%).
HRMS (FAB): m/z calcd for C28H36NO6 [M+H]+: 482.2542. Found:
482.2531.
(2S)-2-Ethyl-3-(4-hydroxy-2,6-dimethylphenyl)propanoic Acid
[(2S)-Edp] (10b)
The preparation of 10b (96% yield) from 8b was analogous to that
of 10a from 8a.
[ ]D20 +55.6° (c 1.00, CH2Cl2).
1H NMR (400 MHz, CD3COCD3): = 6.50 (s, 2 H), 2.88–2.94 (m,
1 H), 2.66–2.71 (m, 1 H), 2.44–2.51 (m, 1 H), 2.23 (s, 6 H), 1.61–
1.70 (m, 1 H), 1.44–1.52 (m, 1 H), 0.89 (t, 3 H).
13C NMR (100.6 MHz, CDCl3): = 181.0, 153.3, 138.4, 128.3,
115.0, 47.4, 31.4, 24.8, 20.4, 12.2.
HPLC diastereomeric analysis (4.6 mm 25.0 cm Vydac 218TP54
column, 50–95% gradient of MeOH, 1 mL/min, 220 nm) showed
>99:1 diastereomeric purity (tR 23.90 min).
[ ]D20 +110.1° (c 1.12, CH2Cl2).
1H NMR (400 MHz, CDCl3): = 7.17–7.31 (m, 5 H), 6.77 (s, 2 H),
4.43–4.49 (m, 1 H), 4.17–4.22 (m, 1 H), 3.93–4.04 (m, 2 H), 3.19–
3.24 (dd, 1 H, J = 3.2, 13.6 Hz), 2.99–3.05 (dd, 1 H, J = 8.0, 14.0
Hz), 2.80–2.85 (dd, 1 H, J = 7.2, 14.0 Hz), 2.67–2.73 (dd, 1 H, J =
10.0, 13.6 Hz), 2.32 (s, 6 H), 1.51 (s, 9 H), 1.24 (d, 3 H, J = 6.8 Hz).
13C NMR (100.6 MHz, CDCl3): = 177.1, 152.9, 152.1, 148.9,
138.7, 135.4, 133.4, 129.5, 128.9, 127.3, 120.7, 83.3, 65.9, 55.8,
37.8, 36.4, 32.9, 27.7, 20.5, 17.3.
HRMS (EI): m/z calcd for C13H18O3 [M]+: 222.1256. Found:
222.1263.
4-Iodo-3,5-dimethyl-O-tert-butyldimethylsilyl-phenol (12)
To a solution of 2 (2.48 g, 10.0 mmol) and imidazole (1.7 g, 25
mmol) in anhyd DMF (5 mL) at r.t. was added tert-butyldimethyl-
silyl chloride (1.96 g, 13 mmol). The solution was stirred at r.t. for
1 h and H2O (5 mL) was then added to the reaction mixture. The sol-
vent was removed under high vacuum and the residue was taken up
in CH2Cl2. The combined CH2Cl2 extracts were washed with brine
and dried (MgSO4). The solvent was removed to provide 12 as a
white sticky solid (3.51 g, 97%), which was used directly in the next
reaction without further purification.
HRMS (FAB): m/z calcd for C27H34NO6 [M+H]+: 468.2386. Found:
468.2384.
(2S)-2-Methyl-3-(4-hydroxy-2,6-dimethylphenyl)propanoic
Acid [(2S)-Mdp] (10a)
1H NMR (400 MHz, CDCl3): = 6.59 (s, 2 H), 2.41 (s, 6 H), 0.98
(s, 9 H), 0.19 (s, 6 H).
MS (FAB, NBA): m/z = 362 (M+, 100%).
The oxazolidinone chiral auxiliary of 8a (468 mg, 1 mmol) was re-
moved in the standard manner,13 except that Et2O was used instead
of CH2Cl2 to extract the oxazolidinone chiral auxiliary, to give 9a.
The crude 9a was dissolved in a mixture of TFA–CH2Cl2 (5 mL/5
mL) at 0 °C and the solution was then stirred at r.t. until TLC indi-
cated the disappearance of the starting material. The solvent was re-
moved in vacuo, and the residue was purified by flash
chromatography (EtOAc–hexanes, 1:1) to give 10a as a white solid
(200 mg, 96%).
4-tert-Butyldimethylsilyloxy-2,6-dimethylphenyl)methanol (14)
n-BuLi (2.1 mL, 3.3 mmol) was added dropwise into a solution of
crude 12 (1.09 g, 3.0 mmol) in THF (15 mL) at –78 °C, and the mix-
ture was stirred for 1 h. DMF (1.16 mL, 15 mmol) was introduced
slowly, and the mixture was then warmed up slowly to r.t. After 30
min at r.t., a few drops of H2O were added to quench the reaction.
The solvent was removed and the residue was taken up in EtOAc.
The organic extracts were washed with H2O and brine, and dried
(MgSO4). Removal of the solvent provided in quantitative yield the
[ ]D20 +45.9° (c 0.93, CH2Cl2).
1H NMR (400 MHz, CD3COCD3): = 6.5 (s, 2 H), 2.94–3.00 (m, 1
H), 2.61–2.68 (m, 2 H), 2.24 (s, 6 H), 1.08 (d, 3 H, J = 6.8 Hz).
Synthesis 2001, No. 11, 1639–1644 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Stereospecific Syntheses of 2-Substituted 3-(2,6-Dimethyl-4-hydroxyphenyl)propanoic Acids
1643
crude aldehyde 13 as a yellow oil, which was used directly in the
der isocratic conditions, 1 mL/min, 220 nm) showed >99:1 diaste-
subsequent reduction step.
reomeric purity (tR 34.79 min).
[ ]D20 –23.5° (c 0.98, CH2Cl2).
NaBH4 (110 mg, 3 mmol) was added to a solution of crude 13 in
MeOH (20 mL) at 0 °C. The mixture was allowed to warm up to r.t.,
and was stirred for 30 min. Sat. NH4Cl was then added to the reac-
tion mixture. The solvent was removed and the residue was taken
up in EtOAc, washed with H2O and brine, and dried (MgSO4). Pu-
rification by flash chromatography (EtOAc–hexanes, 1:10) afford-
ed the desired product as a light yellow solid (606 mg, 76%).
1H NMR (400 MHz, CDCl3): = 6.51 (s, 2 H), 4.63 (s, 2 H), 2.35
(s, 6 H), 0.96 (s, 9 H), 0.18 (s, 6 H).
13C NMR (100.6 MHz, CDCl3): = 154.9, 138.8, 129.7, 119.7,
58.9, 25.6, 19.5, 18.1, –4.4.
1H NMR (400 MHz, CDCl3): = 7.19–7.25 (m, 3 H), 6.91–6.93 (m,
2 H), 6.43 (s, 2 H), 4.53–4.58 (m, 1 H), 4.33–4.39 (m, 1 H), 3.97–
4.01 (m, 1 H), 3.87–3.90 (dd, 1 H, J = 2.8, 9.2 Hz), 3.05–3.12 (m, 1
H), 2.85–2.90 (dd, 1 H, J = 4.0, 13.6 Hz), 2.78–2.82 (dd, 1 H, J =
3.2, 13.6 Hz), 2.33 (s, 6 H), 2.06–2.11 (m, 1 H), 1.60–1.76 (m, 5 H),
1.11–1.26 (m, 5 H), 0.92 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): = 176.7, 153.4, 153.0, 138.4,
135.4, 129.2, 128.8, 128.7, 127.0, 119.7, 65.2, 54.7, 46.6, 41.8,
37.5, 30.9, 30.1, 29.3, 26.3, 25.7, 20.4, 18.1, –4.41, –4.45.
HRMS (FAB, NBA): m/z calcd for C33H48NO4Si [M+1]+: 550.3353.
Found: 550.3374.
HRMS (EI): m/z calcd for C15H26O2Si [M]+: 266.1702. Found:
266.1709.
(2R)-2-Cyclohexyl-3-(4-tert-butyldimethylsilyloxy-2,6-di-
methylphenyl)propanoic Acid (19a)
The removal of the oxazolidinone chiral auxiliary of 18a (550 mg,
1.0 mmol) was performed using the same procedure as for 9a.
Crude 19a was used in the next reaction without further purifica-
tion.
4-(Bromomethyl)-3,5-dimethyl-tert-butyldimethyl-silyloxy-
phenol (15)
To a solution (–5 °C) of 14 (1.6 g, 6 mmol) in Et2O (8 mL) contain-
ing pyridine (97 L, 1.2 mmol) was added dropwise a solution of
PBr3 (0.57 mL, 6 mmol) in Et2O. The mixture was stirred at 0 °C for
30 min, warmed up slowly to r.t., and then poured into a mixture of
ice and brine. The layers were separated and the aqueous layer was
washed with Et2O. The combined Et2O extracts were washed with
sat. NaHCO3 and brine, and dried (MgSO4). Removal of the solvent
provided the desired bromide as a colorless oil (1.91 g, 97%).
1H NMR (400 MHz, CDCl3): = 6.49 (s, 2 H), 4.55 (s, 2 H), 2.34
(s, 6 H), 0.95 (s, 9 H), 0.18 (s, 6 H).
13C NMR (100.6 MHz, CDCl3): = 155.7, 138.2, 126.8, 119.8,
30.3, 25.6, 19.4, 18.2, –4.4.
(2R)-2-Cyclohexyl-3-(4-hydroxy-2,6-dimethylphenyl)-
propanoic Acid [(2R)-Cdp] (20a)
Crude 19a was dissolved in 1 N HCl/MeOH and the resulting clear
solution was stirred at r.t. for 2 h. After removal of MeOH, the res-
idue was taken up in EtOAc and the solution was washed with H2O
and brine, and dried (MgSO4). The solvent was removed and the de-
sired product was obtained as a white solid (230 mg, 84%).
[ ]D20 +33.7° (c 0.97, EtOAc).
1H NMR (400 MHz, CDCl3): = 6.46 (s, 2 H), 2.78–2.92 (m, 2 H),
2.43–2.47 (m, 1 H), 2.19 (m, 6 H), 1.07–1.99 (m, 11 H).
13C NMR (100.6 MHz, CDCl3): = 181.8, 153.1, 138.2, 128.1,
115.1, 51.5, 40.5, 30.9, 30.6, 28.8, 26.3, 26.2, 20.2.
HRMS (FAB, NBA): m/z calcd for C17H25O3 [M + 1]+: 277.18036.
HRMS (EI): m/z calcd for C15H25OSiBr [M]+: 328.0858. Found:
328.0850.
(4R)-4-Benzyl-3-(2-cyclohexylacetyl)-1,3-oxazolan-2-one (17a)
The incorporation of the oxazolidinone chiral auxiliary into 16a
(2.5 g, 17.6 mmol) was done using a procedure analogous to that de-
scribed for the preparation of 7. Recrystallization of the crude prod-
uct from EtOAc–hexanes gave 17a as a white solid (3.8 g, 72%).
Found: 277.18010.
(4R)-4-Benzyl-3-(2-phenylacetyl)-1,3-oxazolan-2-one (17b)
The incorporation of the oxazolidinone chiral auxiliary into 16b
(2.04 g, 15 mmol) was performed using a procedure analogous to
that described for 17a. Compound 17b was obtained as a white solid
(3.6 g, 83%)
[ ]D20 –62.7° (c 1.00, CH2Cl2).
1H NMR (400 MHz, CDCl3): = 7.18–7.33 (m, 5 H), 4.63–4.69 (m,
1 H), 4.11–4.19 (m, 2 H), 3.20–3.31 (dd, 1 H, J = 3.2, 13.2 Hz),
2.70–2.89 (m, 3 H), 1.62–1.91 (m, 6 H), 0.96–1.33 (m, 5 H).
13C NMR (100.6 MHz, CDCl3): = 172.6, 153.4, 135.3, 129.4,
128.9, 127.3, 66.0, 55.2, 42.7, 38.0, 34.3, 33.10, 33.05, 27.6, 26.18,
26.11, 26.10.
[ ]D20 –104.4° (c 1.06, CH2Cl2).
1H NMR (400 MHz, CDCl3): = 7.13–7.36 (m, 10 H), 4.66–4.70
(m, 1 H), 4.16–4.25 (m, 4 H), 3.26–3.30 (dd, 1 H, J = 3.2, 13.2 Hz),
2.73–2.79 (dd, 1 H, J = 9.2, 13.2 Hz).
13C NMR (100.6 MHz, CDCl3): = 171.03, 153.3, 134.98, 133.4,
129.7, 129.3, 128.8, 128.4, 127.2, 127.1, 65.9, 55.1, 41.4, 37.5.
MS (FAB, NBA): m/z calcd for C18H24NO3 [M+1]+: 302.17563.
Found: 302.17510.
(2R)-1-[(4R)-4-Benzyl-2-oxo-1,3-oxazolan-3-yl]-2-cyclohexyl-3-
(4-tert-butyldimethylsilyloxy-2,6-dimethylphenyl)propan-1-one
(18a)
HRMS (EI): m/z calcd for C18H17NO3 [M]+: 295.1208. Found:
295.1203.
To a solution of 17 (1.39 g, 4.63 mmol) in freshly distilled THF (20
mL) at –78 °C was added sodium bis(trimethylsilyl)amide in THF
(1.0 M, 5.1 mL, 5.1 mmol) and the mixture was stirred at –78 °C for
30 min. A solution of bromide 15 (1.6 g, 4.86 mmol) in THF (5 mL)
was then added dropwise. The mixture was allowed to warm up to
–25 °C, and then stirred for 30 min. The reaction was quenched by
the addition of sat. NH4Cl. The volatiles were removed and the res-
idue was taken up in CH2Cl2, washed with a 10% NaHSO4 and dried
(MgSO4). Purification by flash chromatography (EtOAc–hexanes,
1:10) afforded 18a as a white solid (2.01 g, 79%).
(2R)-1-[(4R)-4-Benzyl-2-oxo-1,3-oxazolan-3-yl]-3-(4-tert-
butyldimethylsilyloxy-2,6-dimethylphenyl)-2-phenylpropan-1-
one (18b)
Using the procedure analogous to that described for 18a, compound
18b was obtained as a white solid (5.1 g, 77%).
HPLC diastereomeric analysis (4.6 mm 25.0 cm Vydac 218TP54
column, 50–95% gradient of MeOH, followed by 95% MeOH un-
der isocratic conditions, 1 mL/min, 220 nm) showed >99:1 diaste-
reomeric purity (tR 32.57 min).
[ ]D20 –169.1° (c 1.26, CH2Cl2).
HPLC diastereomeric analysis (4.6 mm 25.0 cm Vydac 218TP54
column, 50–95% gradient of MeOH, followed by 95% MeOH un-
Synthesis 2001, No. 11, 1639–1644 ISSN 0039-7881 © Thieme Stuttgart · New York

1644
Y. Lu, P. W. Schiller
PAPER
1H NMR (400 MHz, CDCl3): = 7.27–7.36 (m, 8 H), 7.05–7.07 (m,
2 H), 6.50 (s, 2 H), 5.46 (t, 1 H, J = 7.6 Hz), 4.60–4.65 (m, 1 H),
3.99–4.06 (m, 2 H), 3.53 (dd, 1 H, J = 7.6, 14.0 Hz), 3.03–3.11 (m,
2 H), 2.69–2.74 (dd, 1 H, J = 8.4, 13.2 Hz), 2.23 (s, 6 H), 0.99 (s, 9
H), 0.18 (s, 3 H), 0.17 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): = 173.9, 153.5, 152.7, 138.39,
138.37, 135.0, 129.4, 128.9, 128.6, 128.5, 128.4, 127.4, 127.2,
119.7, 65.4, 55.2, 47.9, 37.6, 33.7, 31.6, 25.7, 22.6, 20.2, 18.1, 14.1,
–4.41, –4.44.
Acknowledgement
This work was supported by operating grants from the Medical Re-
search Council of Canada (MT-5655) and the U.S. National Institu-
te on Drug Abuse (DA-04443). We thank Grazyna Weltrowska for
excellent technical assistance.
References
(1) Present address: Research Center for Materials Science,
Nagoya University, Chikusa, Nagoya 464-8602, Japan.
(2) Rees, D. C.; Hunter, J. C. In Comprehensive Medicinal
Chemistry; Emmet, J. C., Ed.; Pergamon: New York, 1990,
805.
(3) Befort, K.; Tabbara, L.; Bausch, S.; Chavkin, C.; Evans, C.;
Kieffer, B. Mol. Pharmacol. 1996, 49, 216.
(4) Schiller, P. W.; Berezowska, I.; Nguyen, T. M.-D.; Schmidt,
R.; Lemieux, C.; Chung, N. N.; Falcone-Hindley, M. L.;
Yao, W.; Liu, J.; Iwama, S.; Smith, A. B. III.; Hirschmann,
R. J. Med. Chem. 2000, 43, 551.
(5) Lu, Y.; Weltrowska, G.; Lemieux, C.; Chung, N. N.;
Schiller, P. W. Bioorg. Med. Chem. Lett. 2001, 11, 323.
(6) Hansen, D. W.; Stapelfeld, A.; Savage, M. A.; Reichmann,
M.; Hammond, D. L.; Haaseth, R. C.; Mosberg, H. I. J. Med.
Chem. 1992, 35, 684.
(7) Hünig, S.; Schwartz, H. Liebigs Ann. Chem. 1956, 599, 131.
(8) Dygos, J. H.; Yonan, E.; Scaros, M. G.; Goodmonson, O. J.;
Getkman, D. P.; Periana, R. A.; Beck, G. R. Synthesis 1992,
741.
(9) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc.
1992, 114, 9434.
(10) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737.
HRMS (FAB, NBA): m/z calcd for C33H42NO4Si [M+1]+:
544.28832. Found: 544.28660.
(2R)-3-(4-tert-Butyldimethylsilyloxy-2,6-dimethylphenyl)-2-
phenylpropanoic Acid (19b)
The oxazolidinone chiral auxiliary of 18b (460 mg, 0.85 mmol) was
removed using the procedure described for 9a. Crude 19b was used
in the next reaction without further purification.
(2R)-2-Phenyl -3-(4-hydroxy-2,6-dimethylphenyl)propanoic
Acid [(2R)-Pdp] (20b)
Using the procedure described for 20a, compound 20b was ob-
tained as a white solid (192 mg, 84%).
[ ]D20 –146.2° (c 0.91, EtOAc).
1H NMR (400 MHz, CDCl3): = 7.21–7.29 (m, 5 H), 6.45 (s, 2 H),
3.73–3.76 (t, 1 H), 3.38–3.43 (dd, 1 H, J = 6.4, 14.4 Hz), 2.95–3.01
(dd, 1 H, J = 8.0, 14.4 Hz), 2.07 (s, 6 H).
13C NMR (100.6 MHz, CDCl3): = 179.5, 153.4, 138.5, 138.3,
128.5, 128.1, 127.7, 127.5, 114.9, 51.5, 33.2, 20.1.
HRMS (FAB, NBA): m/z calcd for C17H19O3 [M+1]+: 271.13342.
Found: 271.13300.
(11) Thottathil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M. K.
Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140.
(12) Salvadori, S.; Balboni, G.; Guerrini, R.; Tomatis, R.;
Bianchi, C.; Bryant, S. D.; Cooper, R. S.; Lazarus, L. H. J.
Med. Chem. 1997, 40, 3100.
(13) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
Synthesis 2001, No. 11, 1639–1644 ISSN 0039-7881 © Thieme Stuttgart · New York