Synthesis of the active form of loxoprofen by using allylic substitutions in two steps

Article abstract of DOI:10.1021/ol802949c

High regioselectivity for allylic substitution of the cyclopentenyl picolinate 5 with benzylcopper reagent was attained with ZnBr₂, and the finding was applied to the p-BrC₆H₄CH₂ reagent. The cyclopentene moiety in the product was reduced to the cyclopentane, and the p-BrC₆H₄ was converted to the "Cu"C₆H₄ for the second allylic substitution with picolinate 8 to furnish the title compound after oxidative cleavage of the resulting olefin moiety.

Full text of DOI:10.1021/ol802949c

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1103-1106
Synthesis of the Active Form of
Loxoprofen by Using Allylic
Substitutions in Two Steps
Tomonori Hyodo, Yohei Kiyotsuka, and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received December 23, 2008
ABSTRACT
High regioselectivity for allylic substitution of the cyclopentenyl picolinate 5 with benzylcopper reagent was attained with ZnBr2, and the
finding was applied to the p-BrC6H4CH2 reagent. The cyclopentene moiety in the product was reduced to the cyclopentane, and the p-BrC6H4
was converted to the “Cu”C6H4 for the second allylic substitution with picolinate 8 to furnish the title compound after oxidative cleavage of
the resulting olefin moiety.
Copper-assisted substitution of secondary allylic esters
with alkyl reagents usually produces anti SN2′ products
with efficient regioselectivity and chirality transfer.1
However, substitution with aryl and alkenyl anions has
suffered from insufficient regioselectivity due to the low
nucleophilicity. To improve the inconvenience, we have
reported the picolinoxy leaving group (2-PyCO2-), with
which aryl and alkenyl copper reagents afforded the anti
SN2′ products highly efficiently (Scheme 1).2 The electron
withdrawal by the pyridyl unit and the chelation of the
group to MgBr2 are responsible for the activation of the
group. To demonstrate the new allylation system, we chose
the active form of anti-inflammatory loxoprofen, i.e., 4,3
as a target,4 for which we envisioned substitution of
picolinate 8 and aryl copper reagent 9 as delineated in
Scheme 2. In addition, we studied substitution of the
picolinate 5 with benzylic copper reagent 6 for synthesis
Scheme 1
.
Allylic Substitution with the Picolinoxy Leaving
Group
(1) (a) Negishi, E.; Liu, F. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 1.
(b) Negishi, E. Handbook of Organopalladium Chemistry for Organic
Synthesis; Wiley-VCH: Weinheim, 2002; Vol. 1. (c) Kar, A.; Argade, N. P.
Synthesis 2005, 2995–3022. (d) Krause, N.; Gerold, A. Angew. Chem., Int.
Ed. 1997, 36, 186–204.
(2) (a) Kiyotsuka, Y.; Acharya, H. P.; Katayama, Y.; Hyodo, T.;
Kobayashi, Y. Org. Lett. 2008, 10, 1719–1722. (b) Kiyotsuka, Y.;
Kobayashi, Y. Tetrahedron Lett. 2008, 49, 7256–7259.
10.1021/ol802949c CCC: $40.75
Published on Web 02/05/2009
2009 American Chemical Society

Table 1. Reaction of rac-5a with BnMgBr
equiv of
BnMgX
equiv of
CuBr·Me2S
equiv of
ZnBr2
ratioa of
11a:12a:13a:rac-5a
combined
yield, %b
entry
temp, °C
time, h
1
2
3
4
5
6
7
8
BnMgBr,2.0
BnMgBr,2.0
BnMgBr,2.1
BnMgBr,2.1
BnMgCl,2.1
BnMgCl,2.1
BnMgBr,2.0
BnMgBr,2.0
1
2.1
2.1
1.0
1.0
1.0
1.0
0.5
0.5
0
0 to rt
0 to rt
14
14
1
1
1
1
1
1
84:0:16:0
66:0:20:14
90:10:0:0
100:0:0:0
95:5:0:0
100:0:0:0
88:12:0:0
100:0:0:0
1
nd
nd
82
81
97
100
nd
nd
3.0
0
0
0
0
0
0
0
3.0c
0
3.0
0
3.0
Determined by H NMR spectroscopy. Zero (0) indicates the case that signals were not seen in the expanded H NMR spectra. b nd, not determined.
c Complete regioselectivity was also obtained with 1.0 and 2.1 equiv of ZnBr2, whereas use of 6.3 equiv of ZnBr2 produced a mixture of 11a and 13a in a
84:16 ratio.
a
of the bromide 7, a precursor of the reagent 9, because
the regioselectivity of the previous method to obtain
alcohol 7 (R ) H) is somewhat low.5
The reaction was carried out at 0 °C in THF/Et2O (3-7:
Since allylic picolinate 5 and p-bromobenzylcopper reagent
1). When reaction was not completed after 1 h, reaction was
6 in the first substitution were new types that had not been
continued at higher temperature (rt) for 14 h. Ratios of the
studied in our early investigation with the acyclic picolinates
anti SN2′ product 11a, regioisomer 12a, alcohol 13a, and/or
and aryl coppers,2 we first studied the reaction using a
racemic picolinate rac-5a possessing the TBS group (R )
6
(Bn)2 were determined by 1H NMR spectroscopy, and yield
1
of product 11a was calculated on the basis of the H NMR
TBS) and three benzylcopper reagents derived from BnMgBr
ratio of the isolated (and weighted) mixture of 11a, 12a, and/
(2.0-2.1 equiv) and varied quantities of CuBr·Me2S (2.0,
or (Bn)2.7 As summarized in Table 1, copper reagents derived
1.0, and 0.5 equiv) according to the previous results with
from BnMgBr (2.0-2.1 equiv) and CuBr·Me2S (1.0 and 0.5
ArMgBr/CuBr·Me2S (eq 1).
equiv), respectively, afforded 11a as a major product (entries
3 and 7), whereas a copper reagent derived from BnMgBr/
CuBr·Me2S in 2.0/2.1 equiv was less reactive at 0 °C and
produced alcohol 13a competitively at rt (entry 1). Although
the observed regioselectivities of 11a in the former two
entries were in good level (88-90%), separation of regio-
isomer 12a by chromatography was unsuccessful. To im-
prove the selectivity, we postulated an activation of the
picolinoxy moiety by ZnX2, which would be stronger than
MgBr2 generated in situ from the reagents. Indeed, addition
of ZnBr2 (3.0 equiv) brought the regioselectivity to a
substantially complete level for BnMgBr/CuBr·Me2S in 2/1
Scheme 2. Construction of 4
(3) Naruto, S.; Terada, A. Chem. Pharm. Bull. 1983, 31, 4286–4294.
(4) Preparation by separation of the stereoisomers: (a) Naruto, S.; Terada,
A. Chem. Pharm. Bull. 1983, 31, 4319–4323. (b) Mandai, T.; Yamakawa,
T. Synlett 2000, 862–864.
(5) Ito, M.; Matsuumi, M.; Murugeshi, M. G.; Kobayashi, Y. J. Org.
Chem. 2001, 66, 5881–5889.
(6) Probably produced by the Wurtz-type coupling during the Griganrd
preparation from BnBr and Mg and/or by oxidative coupling of the
remaining reagent during the workup.
(7) The trans stereochemistry of the products 11a and 12a was
determined by correlation to the corresponding alcohols, which were
synthesized by the previous CuCN-catalyzed substitution of the monoacetate
of 4-cyclopenten-1,3-diol with BnMgBr.5
1104
Org. Lett., Vol. 11, No. 5, 2009

and 2/0.5 equiv (entries 4 and 8), though that in 2/2 equiv
was not improved (entry 2). Among other molar ratios of
ZnBr2 examined, 1 and 2 equiv were similarly effective (cf.,
footnote c of Table 1).8
p-BrC6H4CH2MgBr/CuBr·Me2S. The substrate (∼100% ee
by chiral HPLC) was synthesized by a method delineated in
Scheme 3 starting with (1R)-monoacetate 16, obtained by
lipase-catalyzed hydrolysis of the corresponding diacetate
followed by recrystallization.9 Allylic substitution of (1R)-
5a with the copper reagent derived from p-BrC6H4CH2MgBr
(2.0 equiv) and CuBr·Me2S (1.0 equiv) proceeded smoothly
under the above conditions (0 °C, 1 h) to afford 7a (R )
TBS) regioselectively, which was isolated as a mixture with
(p-XC6H4CH2)2 (X ) Br and H). The mixture was treated
with Bu4NF, and the alcohol separated by chromatography
was resilylated to 7a for the further reaction (92% from (1R)-
5a).
A copper reagent derived from BnMgCl (2.1 equiv) and
CuBr·Me2S (1.0 equiv) in the presence of ZnBr2 (3.0 equiv)
afforded 11a as well (entry 6; see entry 5 for the result
obtained in the absence of ZnBr2). These results with
BnMgCl are informative in a case where benzylic magnesium
bromides are hardly accessible from ArCH2Br and Mg due
to the rapid homocoupling reaction. In addition, ZnCl2 in
place of ZnBr2 retarded the reaction with the copper reagents
derived from BnMgCl/CuBr·Me2S in 2.1/1.0 and 2.0/0.5
equiv at 0 °C, and further reaction at rt produced a mixture
of 11a and 13a, though complete regioselectivity was
observed (data not shown).
Next, the reaction conditions of entry 4 of Table 1 were
applied to substrates rac-5b-f, which possess protective
groups other than the TBS group (Table 2). In all cases ZnBr2
assisted exclusive production of the anti SN2′ products
11b-f. Interestingly, the native selectivity obtained without
ZnBr2 (ratios in parentheses) was dependent on the protective
group: low selectivity with the electron-donating groups
(TBDPS and Bn in entries 1 and 2) as in the case of the
TBS group and high selectivity with the electron-withdrawing
group (Ac and Piv in entries 4 and 5). In addition, entries 4
and 5 show a chemoselectivity indicating the picolinoxy
group is the better leaving group compared to the AcO and
PivO groups (see ref 8).
Scheme 3
.
Synthesis of the Key Intermediate 7a through the
Picolinate (1R)-5a
Table 2. Effect of Substituent on the Regioselectivitya
Allylic picolinate 8, another key substrate, was prepared
by a method shown in Scheme 4. Wittig reaction of aldehyde
19, obtained from lactate 18 (natural form) in two steps, with
an ylide derived from [Ph3PEt]+Br- and NaN(TMS)2 af-
forded cis olefin 20 exclusively in 65% overall yield.
Removal of the THP group in MeOH was successful.
Unfortunately, removal of MeOH co-extracted with volatile
21 by evaporation resulted in substantial loss of 21. To avoid
the loss ethylene glycol was used as a solvent. The alcohol
21 extracted was free of the glycol for the next esterification
with 2-PyCO2H to afford picolinate 8 (96% ee (by chiral
HPLC)) in 66% yield from 20.
ratiob c d of
combined
yield, %e
,
,
entry
1
substrate
R1
11:12
rac-5b
TBDPS
99:1
(60:40)
99:1
(66:34)
100:0
(95:5)
100:0
(99:1)
100:0
(100:0)
nd
nd
nd
nd
95
83
82
76
90
82
2
3
4
5
rac-5c
rac-5d
rac-5e
rac-5f
Bn
PMB
Ac
Scheme 4. Synthesis of Picolinate 8
Piv
a Reactions with BnMgBr (2.1 equiv) and CuBr·Me2S (1.0 equiv) were
carried out in the presence of ZnBr2 (3.1 equiv) in THF/Et2O (3-7:1) at 0
°C for 1 h. b Determined by 1H NMR spectroscopy. Zero (0) indicates the
1
case that signals for 12 were not seen in the expanded H NMR spectra.
c The corresponding alcohol and the starting compound were not obtained.
d The ratios obtained without ZnBr2 are shown in parentheses. e nd, not
determined.
With the above results in mind, we chose (R)-5a (R )
TBS) as a substrate in the first allylic substitution with
Org. Lett., Vol. 11, No. 5, 2009
1105

Scheme 5. Latter Stage of the Synthesis Furnishing the Target Compound 4
The cyclopentene part of 7a was reduced with NBSH10
to afford 22 in good yield (Scheme 5). Unfortunately,
attempted preparation of the Grignard reagent 23 several
times afforded varying concentrations of 23. Alternatively,
22 was lithiataed with t-BuLi, and the resulting lithium anion
24 was converted to the copper reagent by transmetalation
with MgBr2 and then with CuBr·Me2S. The reagent thus
prepared was subjected to reaction with picolinate 8 to
produce 10a, which underwent ozonolysis to afford, after in
situ reduction, alcohol 25 in 64% yield from 8. Oxidation
of alcohol 25 to acid 26 was carried out successfully by using
NaClO2/TEMPO (cat.).11,12 Finally, removal of the TBS
group furnished 4 in 58% yield: [R]33D +77 (c 0.94, EtOH);
In summary, substitution of the cyclopentenyl picolinates
and benzylic reagents was studied to find the substantial role
of ZnBr2 for the anti SN2′ preference, and the finding was
applied to stereoselective synthesis of the active form of
loxoprofen.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture, Japan.
Supporting Information Available: Experimental pro-
cedures and spectral data of compounds described herein.
This material is available free of charge via the Internet at
http://pubs.acs.org.
cf. lit.4b [R]20 +72 (c 0.15, EtOH).
D
OL802949C
(8) No substitution took place with the acetate corresponding to the
picolinate rac-5a under the conditions of entry 4.
(9) Sugai, T.; Mori, K. Synthesis 1988, 19–22.
(10) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507.
(11) Xie, J.-H.; Zhou, Z.-T.; Kong, W.-L.; Zhou, Q.-L. J. Am. Chem.
Soc. 2007, 129, 1868–1869.
(12) Jones reagent and NaIO4 catalyzed by RuCl3 afforded a mixture of
acid 26 and the corresponding acetophenone as a byproduct.
1106
Org. Lett., Vol. 11, No. 5, 2009