Stereospecific synthesis of chiral tertiary alkyl-aryl ethers via Mitsunobu reaction with complete inversion of configuration

Article abstract of DOI:10.1016/S0040-4039(03)00728-7

Mitsunobu reaction of chiral tertiary alcohol (S)-2 with phenol 3 provides the desired ether (R)-1 in moderate yields at elevated temperatures (80-100°C). The S_N2 displacement pathway is evident by complete inversion of the (S)-alcohol to (R)-e

Full text of DOI:10.1016/S0040-4039(03)00728-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3609–3611
Stereospecific synthesis of chiral tertiary alkyl-aryl ethers via
Mitsunobu reaction with complete inversion of configuration
Yao-Jun Shi,* David L. Hughes and James M. McNamara
Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065 USA
Received 3 January 2003; revised 14 March 2003; accepted 18 March 2003
Abstract—Mitsunobu reaction of chiral tertiary alcohol (S)-2 with phenol 3 provides the desired ether (R)-1 in moderate yields
at elevated temperatures (80–100°C). The SN2 displacement pathway is evident by complete inversion of the (S)-alcohol to
(R)-ether. © 2003 Elsevier Science Ltd. All rights reserved.
The Mitsunobu reaction has become a useful tool in
organic synthesis since its discovery in 1967.1 In this
series, the coupling of primary or secondary alcohols
with a phenol in the presence of diethyl azodicarboxyl-
ate (DEAD)/triphenyl phosphine (TPP) is widely used
for the synthesis of alkyl-aryl ethers.2 Specifically, when
a chiral secondary alcohol is employed, the reaction
usually undergoes an SN2 displacement with inversion
of configuration.3 Mitsunobu reactions of tertiary alco-
the Mitsunobu reaction of chiral tertiary alcohol (S)-28
with phenol 3 as shown in Scheme 1.
Initially, when the Mitsunobu reaction was carried out
under the usual conditions by mixing diisopropyl azodi-
carboxylate (DIAD), alcohol (S)-2, phenol 3, and TPP
in THF at 0°C and then aged at either 0°C or ambient
temperature, desired 1 was not detected. However,
when the mixture was heated at 50°C for 16 h, a trace
amount of the product 1 was observed by HPLC. In
order to further raise the reaction temperature,9 the
reaction solvent was switched to toluene. When the
reaction mixture was heated at 100°C for 14 h, the
alcohol (S)-2 totally disappeared and the desired 1 was
obtained in 47% yield along with the dehydrated side
product methyl tiglate (4). At this reaction temperature,
using NMP instead of toluene, the yield dropped to
18%. However, an improved yield (54%) was realized
by slow addition of neat or a toluene solution of DIAD
to a toluene solution of the reaction mixture at 100°C.10
To verify the expected SN2 displacement pathway, chi-
ral HPLC assays were carried out by sampling the
reaction mixture during and after the reaction. The
hols with
a phenol, however, have rarely been
reported.4 Furthermore, there is no precedence of Mit-
sunobu reactions of chiral tertiary alcohols with phe-
nols relating to the inversion of configuration on the
chiral tertiary center.5
In conjunction with our recent process development,
chiral ether (R)-1 is the key intermediate in the synthe-
sis of an investigational drug candidate. Although the
target (R)-1 could be obtained by chiral HPLC separa-
tion of the racemic ether [( )-1],6 an efficient synthesis
of the target (R)-1 is highly desired. After initial
attempts using classical resolution of its corresponding
acid by various chiral amines proved fruitless, we
explored asymmetric routes.7 One selected approach is
Scheme 1.
Keywords: Mitsunobu reaction; tertiary alcohols; alkyl aryl ether; SN2 displacement; inversion.
* Corresponding author. Tel.: 732-594-6306; fax: 732-594-5170; e-mail: y-j shi@merck.com
–
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00728-7

3610
Y.-J. Shi et al. / Tetrahedron Letters 44 (2003) 3609–3611
results showed the formation of the desired (R)-1 with
>99% ee with respect to starting material (S)-2 (>99%
ee) throughout the reaction. Thus, complete inversion
at hydroxy carbon occurred, revealing that the Mit-
sunobu reaction underwent the typical SN2 displace-
ment pathway (Scheme 1).2b,c,3
were examined. The results (entries 6 and 7) indicate
that there is minimal steric effect. This was further
confirmed when 2,6-dimethoxyphenol was used in the
reaction affording the desired ether in 53% yield.
Steric effects on the alcohol component were observed
when the diethyl analogy 20 was used, where reaction
with phenol 3 was very sluggish, yielding the dehy-
drated product as the major product. In comparison,
the reaction of dimethyl analogy 22 with phenol 3
afforded the desired 23 in 59% yield, which is compara-
ble to the yield obtained using alcohol (S)-5 (Scheme
4).
Additional evaluation of the reaction was conducted
using the alcohol (S)-5 at various temperatures and in a
different order of addition of reagents as depicted in
Scheme 2. At various temperatures (60, 80, 100, and
130°C),9 the reactions were conducted by slow addition
of a solution made from alcohol (S)-5 and DIAD in
toluene (or chlorobenzene for 130°C).11 The reaction at
60°C was slow and incomplete. The results obtained
from 80 and 100°C were comparable and superior to
one obtained at 130°C in terms of the reaction profile.
In addition, benzyl tiglate (7) was obtained as the major
side product for all reactions. The SN2 displacement
pathway was confirmed again by chiral HPLC assays
showing a complete conversion of alcohol (S)-5 to ether
(R)-6.
In conclusion, we have demonstrated an unprecedented
Mitsunobu reaction of a chiral tertiary alcohol with
phenols undergoing clean SN2 displacement to provide
the desired tertiary alkyl-aryl ethers in moderate yields.
The reaction is sensitive to the steric bulk of the chiral
alcohol, whereas the phenolic component is insensitive
to both steric and electronic effects.
The reaction was further probed using phenols with
various electronic and steric effects and is shown in
Scheme 3. The results are summarized in Table 1.
Table 1. Mitsunobu reaction with various phenols
Entry
Phenols
R1
R2
(R)-ethers
Yield12
In Table 1 the data from entries 1–5 reflects the elec-
tronic effects of a substituent group at 4-position of
phenols towards the reaction. There is little difference
among donating groups (-OBn, -OMe and -Me) and
withdrawing groups (-NO2 and -CN), although slightly
lower yields are observed from the latter groups (entries
4 and 5 versus entries 1 and 3). In addition, steric
effects via introduction of an ortho group to the phenol
1
2
3
4
5
6
7
3
8
9
10
11
12
13
H
H
H
H
H
CH3
OCH3
OBn
H
CH3
NO2
CN
H
6
56
51
58
51
52
55
54
14
15
16
17
18
19
H
Scheme 2.
Scheme 3.
Scheme 4.

Y.-J. Shi et al. / Tetrahedron Letters 44 (2003) 3609–3611
3611
Acknowledgements
alyzed cross-coupling of chiral alcohol (S)-2 and 4-(ben-
zyloxy)phenyl bromide were unsuccessful. However, the
copper-promoted cross-coupling of (S)-2 with 4-(benzyl-
oxy)phenylboronic acid has afforded a low yield of (S)-1
with compete retention of configuration that was con-
firmed by chiral HPLC assay (unpublished results of
Conlon, D. A.; Drahus, A. L. and Shi, Y.-J. in our
laboratories). For the copper-promoted arylation of phe-
nols with arylboronic acid, see: Evans, D. A.; Katz, J. L.;
West, T. R. Tetrahedron Lett. 1998, 39, 2937.
The authors would like to thank Ms. M. Biba for her
assistance during the chiral assay development work
and Dr. R. Desai for kindly providing us both (R)-1
and (S)-1 for HPLC comparison.
References
8. (a) The chiral alcohol (S)-2 is activated by the a-ester
moiety, see: Bordwell, F. G.; Brannen, W. T., Jr. J. Am.
Chem. Soc. 1964, 5, 4645 and references cited therein; (b)
For synthesis of chiral alcohol (S)-2, see: Tan, L.; Chen,
C.-y.; Frey, L.; King, A. O.; Tillyer, R. D.; Xu, F.; Zhao,
D.; Grabowski, E. J. J.; Reider, P. J.; O’Shea, P.; Dag-
neau, P.; Wang, X. Tetrahedron 2002, 58, 7403.
1. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967,
40, 2380.
2. Reviews of the Mitsunobu reaction: (a) Mitsunobu, O.
Synthesis 1981, 1; (b) Hughes, D. L. Org. Reactions 1992,
42, 335; (c) Hughes, D. L. Org. Prep. Proc. Int. 1996, 28,
127.
9. For temperature effects on the Mitsunobu reaction, see
3. Dirlam, N. L.; Moore, B. S.; Urban, F. J. J. Org. Chem.
1987, 52, 3587.
Ref. 2b.
10. The order of addition of reagents was critical, see Ref.
2b.
4. For intermolecular reactions: (a) Bittner, S.; Assaf, Y.
Chem. Ind. (London) 1975, 281; (b) Subramanian, R. S.;
Balasubramanian, K. K. Synth. Commun. 1989, 19, 1255;
(c) Subramanian, R. S.; Balasubramanian, K. K. Tetra-
hedron Lett. 1989, 30, 2297; (d) Brunner, H.; Hankofer,
P.; Treittinger, B. Chem. Ber. 1990, 1029. For intramolec-
ular reactions: (d) Reisch, J.; Voerste, A. A. W. J. Chem.
Soc., Perkin Trans. 1 1994, 3251.
5. The SN2 displacement of tertiary hydroxy centers with
different nucleophiles: (a) SOCl2/pyridine, Mu¨ller, P.;
Rossier, J.-C. J. Chem. Soc., Perkin Trans. 2 2000, 2232
and references cited therein; (b) DAST, Wachtmeister, J.;
Mu¨hlman, A.; Classon, B.; Samuelsson, B. Tetrahedron
1999, 55, 10761 and references cited therein.
6. Racemic ether ( )-1 was made from alkylation of 4-(ben-
zyloxy)phenol with methyl 2-bromobutyrate followed by
a-methylation with methyl iodide and subsequent chiral
HPLC separation afforded enantiomerically pure (R)-1
and (S)-1 (communication with Dr. R. Desai in our
laboratories).
11. A typical procedure: A solution of chiral alcohol (S)-2
(0.76 g, 5.76 mmol) and DIAD (1.40 ml, 7.12 mmol) was
made in toluene (4.0 ml) and then slowly added to a
mixture of phenol 3 (1.30 g, 6.49 mmol) and TPP (1.87 g,
7.12 mmol) in toluene (8.0 ml) at 100°C over 4 h via a
syringe pump. It was kept at 100°C until the disappear-
ance of (S)-2 (2-5 h) was observed and then cooled to
room temperature. Solvents were removed in vacuo and
the residue was chromatographed on silica gel eluting
with ethyl acetate/hexanes (1:14) to afford 1.04 g of the
ether (R)-1 as a colorless oil in 57% yield. (R)-1 was
obtained in >99% ee as determined by chiral assay [Chi-
ralCell OJ-RH, 150×4.6 mm, eluent (A): H2O (0.1%
H3PO4), eluent (B): MeCN, gradient (25°C): A/B from
40/60 to 20/80 over 20 min, 1.0 ml/min, 210 nm, retention
time: 9.84 min for (R)-1 and 13.38 min for (S)-1].
12. The typical procedure was used (Ref. 11) and the isolated
products were identified by NMR (1H and 13C) and
LCMS.
7. Attempts to synthesis chiral ether (S)-1 using the Pd-cat-