A diastereocontrolled route to (R)-(-)-baclofen using a cyclopentanoid chiral building block

Article abstract of DOI:10.3987/com-02-s73

A diastereoselective route to the key intermediate lactone leading to a GABA_B receptor agonist (R)-(-)-baclofen has been developed starting from (+)-4-cumyloxycyclopent-2-en-1-one via the 4-arylcyclopentenone intermediate.

Full text of DOI:10.3987/com-02-s73

HETEROCYCLES, Vol. 59, No. 2, 2003, pp. 785 - 791, Received, 10th October, 2002
A DIASTEREOCONTROLLED ROUTE TO (R)-(–)-BACLOFEN USING
A CYCLOPENTANOID CHIRAL BUILDING BLOCK
Masato Hayashi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578,
Japan; E-mail: konol@mail.cc.tohoku.ac.jp
Abstract – A diastereoselective route to the key intermediate lactone leading to a
GABAB receptor agonist (R)-(–)-baclofen has been developed starting from (+)-
4-cumyloxycyclopent-2-en-1-one via the 4-arylcyclopentenone intermediate.
We have recently developed a preparation of enantiopure 4-cumyloxycyclopent-2-en-1-one (2) in both
enantiomeric forms from a diastereomeric mixture of the 3,5-dioxygenated cyclopentene (1) by
employing enzymatic kinetic resolution as the key step1 (Scheme 1).
O
Ph
O
Ph
O
Ph
Ref. 1
and
OAc
O
O
(–)-2
1
(+)-2
Scheme 1
Owing to the 4-cumyloxy functionality, the chiral enone (2) allowed a cuprate-mediated 1,4-addition in a
highly diastereoselective manner to give exclusively the trans-3,4-disubstituted cyclopentenones of
which stereochemistry was proved by the synthesis of stereo-defined natural products having a d-lactone
chromophore.2 Moreover, the observed stereochemical behavior has been reflected in the
diastereocontrolled synthesis of a variety of natural products.3 Since the trans-3,4-disubstituted
cyclopentanones generated from the cyclopentene precursor (2) possess a b-cumyloxy functionality, it
is readily assumed that the cyclopentanones afford the corresponding 4-substituted cyclopentenones by
elimination of the b-alkoxy functionality if racemization does not occur. We therefore sought the optimal

conditions for the elimination of the b-alkoxy functionality without suffering racemization and found that
the expected reaction did take place keeping original chiral integrity when the 4-substituent is an aryl.4
We show here an example of the diastereoselective synthesis of the enantiopure 4-aryl enone ((+)-6)
leading to the key intermediate lactone ((–)-3) for the synthesis of a GABAB receptor agonist (R)-(–)-
baclofen (4)5,6 (Scheme 2).
Cl
Cl
O
Ph
present
study
known
–
Cl
+
H N
3
CO H
2
O
O
(–)-3
O
(R)-(–)-baclofen 4
(+)-2
Scheme 2
The 1,4-addition of the cuprate to the enone ((+)-2) proceeded smoothly under the Kuwajima conditions.7
Thus, on exposure to the cuprate generated in situ from 4-chlorophenylmagnesium bromide6c in THF
containing hexamethylphosphoric triamide (HMPA) in the presence of copper (I) iodide and
chlorotrimethylsilane, the enantiopure enone ((+)-2) afforded the trans-3,4-disubstituted cyclopentanone
((+)-5) selectively as the single diastereomer after hydrolysis of the silyl enolate product under acidic
conditions. After extensive experimentation under both acidic and basic conditions, it was found that the
b-elimination took place without causing any racemization under acidic conditions using acetic acid.
Thus, on stirring in acetic acid at 60 °C for 20 h, the 3,4-disubstituted cyclopentanone ((+)-5) afforded
the enantiopure 4-arylcyclopent-2-en-1-one ((–)-6) in excellent yield. The present transformation implies
the replacement of a 4-cumyloxy functionality on the cyclopentanone ((+)-2) by an aryl functionality
with retention of the stereochemistry in a formal sense. The overall yield of the 4-arylcyclopentenone
((–)-6) from the 4-cumyloxycyclopentenone ((+)-2) was 79% in two steps.
In order to confirm the stereochemistry as well as to find utilization of the product, the enone ((+)-6) was
transformed into the known lactone ((–)-3) from which ((R)-(–)-baclofen 4) has been obtained in four
steps.6d Thus, the enone ((–)-6) was first reduced with sodium borohydride in the presence of cerium (III)
chloride8 to give the cyclopentenol (7) as a 3:1 mixture of two epimers. It is interesting to note that the 4-
aryl substituent in the cyclopentenone ((–)-6) did not exhibit a significant diastereocontrolled effect
under these reduction conditions since we have observed high diastereoselectivity (>99 de) in the
reaction of the cyclopentanone (2) having a 4-cumyloxy functionality under the same conditions.1,3 For

the present purpose, the reduction product without separation was sequentially ozonized, reduced with
sodium borohydride and cleaved with sodium periodate in the same flask to afford the hemiacetal
mixture (10) as a 1.7:1 mixture via the transient intermediates, the triol (8) and the hydroxy aldehyde (9).
Finally, the hemiacetal mixture 10) was refluxed with Fetizon reagent9 in toluene to give the lactone ((S)-
(–)-3) of which spectral and physical data were identical in all respects with those reported.6d The overall
yield of the lactone ((S)-(–)-3) from the arylenone ((–)-6) was 71% in three steps, thus, in 56% from the
starting 4-cumyloxycyclohexenone ((+)-2) in five steps (Scheme 3).
Cl
AcOH, 60 °C
Cl
Cl
O
O
Ph
NaBH4-CeCl3
ArMgBr, CuI
(+)-2
TMS-Cl, HMPA
MeOH
(88%)
THF, acid workup
(100%)
O
OH
7
(–)-6
5
Cl
Cl
Cl
Cl
O3, MeOH
–78 °C, then
NaBH4, then
OH
O
OH
Fetizon
oxidation
O
(94%)
NaIO4, aq.THF
(75%)
O
HO
OH
OH
O
10
8
9
(–)-3
Scheme 3
In conclusion, we have succeeded in replacing the 4-cumyloxy functionality on cyclopentanone by an
aryl functionality retaining the original chiral integrity in a formal sense. The stereochemistry observed
has been confirmed by developing an alternative route to a GABAB receptor (R)-(–)-baclofen.
EXPERIMENTAL
The melting points were determined on a Yanagimoto hot-stage and are uncorrected. IR spectra were
1
13
recorded on a JASCO-IR 700 spectrophotometer. H NMR (300 MHz) and C NMR (75 MHz) spectra
were recorded in CDCl3 on a Varian Gemini-2000 (300 MHz) spectrometer. Enantiomeric purities were
determined on a Gilson Model-307 instrument equipped with a column with a chiral stationary phase.
(3S,4R)-3-(4-Chlorophenyl)-4-cumylooxycyclopentan-1-one ((+)-5): To a stirred solution of CuI
(660 mg, 3.47 mmol) and HMPA (3.3 mL) in THF (10 mL) was added a solution of 4-
chlorophenylmagnesium bromide in THF (1 M in THF, 6.9 mL, 6.9 mmol) followed by a solution of
chlorotrimethylsilane (TMS-Cl) in THF (0.67 mL, 4.62 mmol in THF 3.3 mL) at –78 °C and, after

stirring for 20 min at the same temperature, the temperature was raised to 0 °C and, after 1 min, cooled
again to –78 °C and the stirring was continued for 30 min at the same temperature. To this mixture was
then added a mixture of the enone (+)-(2)) (500 mg, 2.31 mmol) and trimethylchlorosilane (0.67 mL,
4.62 mmol) in THF 3.3 mL at the same temperature. After stirring at the same temperature for 30 min,
the reaction was quenched by addition of 10% diluted hydrochloric acid and extracted with ether. The
extract was washed successively with brine and 5% aqueous NaHCO3, dried (MgSO4), evaporated under
reduced pressure, and the residue was chromatographed (SiO2, elution with AcOEt-hexane 1:10 v/v) to
give the cyclopentanone ((+)-5) (629 mg, 89.6%) as colorless needles: mp 46-48 °C (from hexane),
[a]D29 +45.5° (c 0.95, CHCl3). IR (film): n = 1744 cm–1. 1H NMR (CDCl3): d = 1.34 (s, 3H), 1.47 (s, 3H),
2.22-2.31 (m, 2H), 2.46 (dd,1H, J = 18.3, 6.5 Hz), 2.72 (ddd,1H, J = 18.8, 10.0, 1.0 Hz), 3.32 (td, 1H, J =
9.2, 7.1 Hz), 3.82 (dd, 1H, J = 14.8, 7.4 Hz), 6.99 – 7.16 (m, 9H). 13C NMR (CDCl3): d = 27.62, 28.93,
31.42, 43.73, 47.06, 49.07, 76.45, 116.60, 124.26, 125.88, 126.46, 127.00, 127.85, 128.02, 128.46,
128.78, 129.21, 132.44, 139.26, 144.98, 214.59. MS: m/z = 328 (M+). HRMS: Calcd for C20H21O2Cl (M+)
= 328.1230. Found: 328.1278.
(4R)-4-(4-Chlorophenyl)cyclopent-2-en-1-one ((–)-6): A solution of the ketone ((+)-5) (679 mg, 2.07
mmol) in AcOH (12 mL) was stirred at 60 °C for 20 h. After cooling, the mixture was diluted with
AcOEt and the solution was washed successively with brine, saturated aqueous NH4Cl and brine, and
dried on MgSO4. The solution was evaporated under reduced pressure and and the residue was
chromatographed (SiO2, elution with AcOEt-hexane 1:15 v/v) to give the cyclopentenone ((–)-6) (350
mg, 88.2%) as colorless needles: mp 41-42 °C (from hexane), [a]D29 –308° (c 1.37, CHCl3). IR (film):
n = 1711 cm–1. 1H NMR (CDCl3): d = 2.28 (dd, 1H, J = 18.9, 2.5 Hz), 6.34 (dd,1H, J = 7.8, 2.1 Hz), 7.09
13
(td, 1H, J = 8.5, 2.1 Hz), 7.27 – 7.66 (m, 4H). C NMR (CDCl3): d = 43.83, 45.99, 128.60, 129.25,
133.17, 134.49, 140.06, 166.07, 209.55. MS: m/z = 192 (M+). HRMS: Calcd for C11H9OCl (M+) =
192.0342. Found: 192.0366. Optical purity = >99%ee by HPLC (CHIRALCEL OJ, elution with i-PrOH-
hexane 1:19 v/v).
4-(4-Chlorophenyl)cyclopent-2-en-1-ol (7): To a stirred solution of the enone (–)-(6) (100 mg, 0.52
mmol) and CeCl3-7H2O (214 mg, 0.57 mmol) in MeOH (2.6 mL) was added NaBH4 (20 mg, 0.52 mmol)
at 0 °C. After stirring at the same temperature for 30 min, the reaction was quenched by addition of
acetone and the mixture was extracted with AcOEt. The extract was washed with brine, dried (MgSO4),
evaporated under reduced pressure, and and the residue was chromatographed (SiO2, elution with
AcOEt-hexane 1:8 v/v) to give the cyclopentenol (7) (101 mg, 100%) as colorless crystals: mp 83-85 °C
(from hexane). IR (film): n = 3287 cm–1. 1H NMR (CDCl3): d = 1.53 (dt, 0.75H, J = 13.7, 5.6 Hz), 1.73 –

1.83 (m, 1H), 2.04 (ddd, 0.25H, J = 14.3, 6.9, 5.6 Hz), 2.28 (ddd, 0.25H, J = 14.2, 8.0, 2.7 Hz), 2.83 (dt,
0.75H, J = 15.2, 6.9 Hz), 3.76 (m, 0.75 H), 4.11 (ddd, 0.25 H, J = 7.7, 6.9, 5.9, 2.1 Hz), 4.93 (t,0.75H, J
= 5.5 Hz), 5.03 – 5.05 (m, 0.25H), 5.91 (dt, 0.75H, J = 5.5, 1.5 Hz), 5.97 – 6.06 (m, 1.5 H), 7.04 – 7.28
(m, 4H). MS: m/z = 194 (M+). HRMS: Calcd for C11H11OCl (M+) = 194.0498. Found: 194.0468.
4-(4-Chlorophenyl)-2-hydroxy-2H-2,3,4,5-tetrahydrofuran (10): To a stirred solution of the
cyclopentenol (7) (211 mg, 1.09 mmol) in MeOH (11 mL) was introduced ozone at –78 °C for 10 min.
After evacuation of the ozone by bubbling argon, to this mixture was added NaBH4 (412 mg, 10.9 mmol)
at the same temperature and, after 30 min, the reaction was quenched by addition of acetone and the
mixture was diluted with AcOEt. The solution was washed with brine, dried (MgSO4), extracted with
AcOEt, and evaporated under reduced pressure to leave the crude triol (8).
The crude triol (8) was dissolved in THF (5.5 mL) and the solution was stirred with aqueous NaIO4 (1.17
g, 5.45 mmol in H2O 5.5 mL) at rt for 2 h. The mixture was extracted with AcOEt and the extract was
washed successively with brine and saturated NaHCO3, dried (MgSO4) and the residue was
chromatographed (SiO2, elution with AcOEt-hexane 1:6 v/v) to give the lactol (10) (163 mg, 75.3%) as
colorless crystals: mp 47-49 °C (from hexane). IR (film): n = 3346 cm–1. 1H NMR (CDCl3): d = 1.95 (ddd,
0.4H, J = 13.6, 10.7, 3.0 Hz), 1.73 – 1.83 (m, 1H), 2.07 (dddd, 0.6H, J = 12.9, 9.0, 4.9, 1.1 Hz), 2.35 (dd,
0.6H, J = 12.9, 7.4 Hz), 2.63 (ddd, 0.4H, J = 13.9, 9.4, 5.0 Hz), 3.36 – 3.93 (m, 3H), 4.20 (t, 0.4 H, J =
8.1 Hz), 4.42 (t,0.6H, J = 7.8 Hz), 5.85 (dt, 1H, J = 8.0, 2.7 Hz ), 7.15 – 7.31 (m, 4H). MS: m/z = 198
(M+). HRMS: Calcd for C10H11O2Cl (M+) = 198.0448. Found: 198.0430.
4-(4-Chlorophenyl)tetrahydrofuran-2-one ((–)-3): A suspension of the lactol (10) (68 mg, 0.34
mmol) and Fetizon reagent (375 mg, 0.68 mmol) in toluene (3.4 mL) was refluxed for 1 h. After cooling,
the suspension was filtered through a Celite pad and the filtrate was evaporated under reduced pressure
and the residue was chromatographed (SiO2, elution with AcOEt-hexane 1:5 v/v) to give the lactone ((–)-
3) (26 mg, 93.6%) as colorless needles: mp 73-75 °C (from hexane), [a]D29 –51.8° (c 1.38, CHCl3){lit.6k:
[a]D25 –51° (c 0.5, CHCl3)}. IR (film): n = 1774 cm–1. 1H NMR (CDCl3): d = 2.63 (dd, 1H, J = 17.4, 8.8
Hz), 2.94 (dd, 1H, J = 17.6, 8.8 Hz), 3.77 (q, 1H, J = 8.2 Hz), 4.24 (dd, 1 H, J = 9.1, 7.7 Hz), 4.66 (dd,
1H, J = 9.1, 7.7 Hz), 4.66 (dd, 1H, J = 9.2, 7.8 Hz), 7.25 – 7.27 (m, 4H). 13C NMR (CDCl3): d = 35.27,
40.15, 73.49, 128.04, 129.06, 133.22, 137.99, 170.06. MS: m/z = 196 (M+). MS: m/z = 198 (M+).
HRMS: Calcd for C10H9O2Cl (M+) = 196.0291. Found: 1968.0274. The spectral data were identical with
those reported.6r

ACKNOWLEDGEMENTS
The authors thank the Ministry of Education, Culture, Sports, Science and Technology, Japan for support
of this research. We also thank Professor Yoshiharu Iwabuchi, Pharmaceutical Institute, Tohoku
University, for his kind suggestion.
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