Enantioselective total and formal syntheses of paroxetine (PAXIL) via phosphine-catalyzed enone α-arylation using arylbismuth(V) reagents: a regiochemical complement to Heck arylation

Article abstract of DOI:10.1016/j.tet.2006.05.092

Exposure of dihydropyridinone 1 to the arylbismuth(V) reagent (p-F-Ph)₃BiCl₂ in the presence of substoichiometric quantities of tributylphosphine (10 mol %) results in aryl transfer to the transiently generated (β-phosphonio)enolate to provide the α-arylated enone 2. This transformation, which represents a regiochemical complement to the Mizoroki-Heck arylation, is used strategically in concise formal and enantioselective total syntheses of the blockbuster antidepressant (-)-paroxetine (PAXIL).

Full text of DOI:10.1016/j.tet.2006.05.092

Tetrahedron 62 (2006) 10594–10602
Enantioselective total and formal syntheses of paroxetine (PAXIL)
via phosphine-catalyzed enone a-arylation using arylbismuth(V)
reagents: a regiochemical complement to Heck arylation
*
Phillip K. Koech and Michael J. Krische
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, United States
Received 20 January 2006; revised 5 May 2006; accepted 6 May 2006
Available online 10 August 2006
Abstract—Exposure of dihydropyridinone 1 to the arylbismuth(V) reagent (p-F-Ph)3BiCl2 in the presence of substoichiometric quantities of
tributylphosphine (10 mol %) results in aryl transfer to the transiently generated (b-phosphonio)enolate to provide the a-arylated enone 2.
This transformation, which represents a regiochemical complement to the Mizoroki–Heck arylation, is used strategically in concise formal
and enantioselective total syntheses of the blockbuster antidepressant (ꢀ)-paroxetine (PAXIL).
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
evoking a surprisingly diverse array of strategies for its asym-
metric synthesis. To date, approaches to the asymmetric
synthesis of paroxetine encompass the physical resolution
of racemates,10 enzyme-catalyzed asymmetric transforma-
tions,11 chiral auxiliary-based approaches,12 asymmetric
deprotonation using chiral bases,13 catalytic enantioselective
transformations,14 as well as the use of naturally occurring
chiral starting materials.15 We envisioned a concise approach
to (ꢀ)-paroxetine based on phosphine-catalyzed a-arylation
of N-benzyl dihydropyridinone 1, which may be prepared
from commercially available N-benzyl glycine ethyl ester
in only three steps.16 The resulting a-arylated enone 2 repre-
sents an attractive synthetic intermediate en route to (ꢀ)-
paroxetine, as closely related a-aryl enones are amenable
to a range of relevant catalytic enantioselective transforma-
tions. These include asymmetric conjugate addition, asym-
metric 1,2-reduction, as well as asymmetric protonation by
way of the enol silane (Scheme 1).17,18
Nucleophilic or Lewis base catalysis represents a major sub-
set of organocatalytic transformations.1 As part of an ongo-
ing program in this area, we have developed a family of
catalytic transformations that exploit the unique reactivity
of enolates derived upon phosphine-conjugate addition to
a,b-unsaturated carbonyl compounds.2–5 These studies en-
compass a catalytic method for the regiospecific a-arylation
of enones and enals, wherein transiently generated (b-phos-
phonio)enolates or oxaphospholenes are captured by arylbis-
muth(V) reagents.5–7 The scope of this process complements
corresponding palladium-catalyzed enolate arylations,8 as
strongly basic reagents are not required for enolate genera-
tion. Further, the use of enones as enolate precursors enables
regiospecific enolate generation. In this account, the syn-
thetic utility of the phosphine-catalyzed enone a-arylation
is highlighted through its strategic use in concise formal
and enantioselective total syntheses of the blockbuster anti-
depressant (ꢀ)-paroxetine (PAXIL).
F
O
F
O
O
O
O
Bu3P (cat)
BiAr3Cl2
Paroxetine, a GlaxoSmithKline product marketed as Paxil/
Seroxat, is an enantiomerically enriched trans-3,4-disubsi-
tuted piperidine used for the treatment of depression, obses-
sive compulsive disorder, and panic disorder.9 As one of
the leading prescription drugs worldwide, paroxetine has
received considerable attention from synthetic chemists,
BnN
HN
BnN
(-)-Paroxetine
2
1
O
Enantioselective 1,2-Reduction
Ar
Enantioselective Protonation (via enol silane)
BnN
Enantioselective Conjugate Addition
2, Ar = p-fluorophenyl
* Corresponding author. Fax: +1 512 471 8696; e-mail: mkrische@mail.
utexas.edu
Scheme 1. Retrosynthesis of (ꢀ)-paroxetine via enone a-arylation.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.092

P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
10595
1.1. Formal synthesis of ( )-paroxetine (PAXIL)
Here, a potentially effective strategy involves asymmetric
protonation17,18 of enol silanes 6a or 6b, which are derived
in a single manipulation from enones 2a and 2b by way of
conjugate reduction with trapping of the resulting enolate
in situ using trimethylsilyl chloride or tert-butyldimethylsilyl
chloride, respectively.19 However, enol silane 6a did not react
upon exposure to Yamamoto’s BINOL/SnCl4 reagent,17a–c
perhaps due to the presence of the Lewis basic N-benzyl
amine. Treatment of the carbamoyl-protected enone 6b to
the BINOL/SnCl4 reagent gave the desired a-aryl ketone
3b in 80% yield, but with very low levels of optical enrich-
ment (10% ee). Yanagisawa’s recently reported silver
fluoride-catalyzed asymmetric protonation gave a more
promising result, providing the a-aryl ketone 3b in 90% yield
and 39% ee (Scheme 4).17d
Preparation of the arylation substrate, dihydropyridinone 1,
is achieved readily in accordance with the literature proce-
dure.16 The requisite bismuth reagent (p-F-Ph)3BiCl2 is
prepared by treating p-F-PhMgBr with BiCl3 followed by
oxidation of the resulting triarylbismuth(III) compound
with elemental chlorine.5,6 Gratifyingly, exposure of dihy-
dropyridinone 1 to (p-F-Ph)3BiCl2 (110 mol %) in the pres-
€
ence of tributylphosphine (10 mol %) and Hunig’s base
(100 mol %) at ambient temperature in CH2Cl2/tBuOH
(9:1) provides the a-arylated dihydropyridinone 2 in 79%
1
isolated yield as a single regioisomer, based on H NMR
analysis (Scheme 2).
F
PBu3 (10 mol%)
(p-F-Ph)3BiCl2 (110 mol%)
O
O
The difficulties encountered in preparing optically enriched
aminoketones 3a or 3b led usto consider alternativesynthetic
routes. Accordingly, oxazaborolidine-catalyzed asymmetric
1,2-reduction of enones 2a and 2b was explored.21 The
N-benzyl-protected enone 2a gave the corresponding allylic
alcohol in 35% yield and 70% ee. It was speculated that the
presence of the Lewis basic N-benzyl amine of 2awas incom-
patible with the Lewis acidic oxazaborolidine catalyst, re-
sulting in diminished yields and selectivities. Gratifyingly,
oxazaborolidine-catalyzed asymmetric 1,2-reduction of the
corresponding N-carbamoyl-protected enone 2b provides al-
lylic alcohol 7a in 95% yield and 96% ee. The allylic alcohol
7a was converted to the diphenyl phosphate 8a and was sub-
jected to conditions for anti-selective copper-mediated SN20
allylicsubstitution22 using(i-PrO)Me2SiCH2Clasahydroxy-
methyl anion equivalent.23 The silicon containing product
of allylic substitution 9 was obtained in 96% yield and was
subjected to Tamao oxidation to provide the homo-allylic
alcohol 10 in 70% yield. As revealed by chiral stationary
phase HPLC analysis, compound 10 is obtained in 92% ee.
The high fidelity of chirality transfer supports an anti-SN20
mechanism for allylic substitution and the slight decrease
in enantiomeric excess is attributed to competitive SN2
substitution. Stereoselective substrate-directed catalytic
homogeneous hydrogenation of the homo-allylic alcohol
10 was accomplished using Crabtree’s conditions24,25 to pro-
vide the corresponding saturated alcohol in 69% yield as
i-Pr2NEt (100 mol%)
CH2Cl2-t-BuOH (9:1)
BnN
BnN
°
25 C
1
2, 79% Yield
Scheme 2. Catalytic a-arylation of dihydropyridinone 1.
Subsequent efforts focused on the conversion of aryl enone
2a to N-benzyl aminoalcohol 5, which has been converted
to paroxetine in two steps.10i,11e,13b,c,15 Conjugate reduction
of 2a using L-Selectride provides the corresponding saturated
a-aryl ketone 3a in 87% yield.19 Ketone olefination using
Ph3P]CHOMe20 affords the enol ether 4 in 65% yield as
1
a single alkene geometrical isomer, as determined by H
NMR. Acid hydrolysis of enol 4 followed by NaBH4 reduc-
tion of the resulting aldehyde provides N-benzyl aminoalco-
hol 5 in 63% yield over the two-step sequence as a single
1
diastereomer, as determined by H NMR. Aminoalcohol 5
exhibits spectral properties identical in all respects to previ-
ously reported material that has been converted to paroxetine
in two steps.10i,11e,13b,c,15 Hence, the preparation of 5 from
dihydropyridinone 1 represents a formal synthesis of (ꢁ)-
paroxetine (Scheme 3).
1.2. Enantioselective total synthesis of (L)-paroxetine
(PAXIL)
Having completed a formal racemic synthesis of paroxetine,
efforts toward an enantioselective total synthesis were made.
1
a single diastereomer, as determined by H NMR analysis.
F
F
HO
F
O
F
O
O
O
X
2 steps
a
c,d
BnN
BnN
BnN
HN
(Literature)
(+/-)-Paroxetine
3a, X = O
4, X = CHOCH3
5
2a
b
Scheme 3. Conversion of arylation product 2a to (ꢁ)-paroxetine. Conditions: (a) L-Selectride, THF, ꢀ78 ꢂC, 87%; (b) Ph3PCH2OMeCl, NaHMDS, THF, 0 ꢂC,
65%; (c) 0.1 M H2SO4, THF, 50 ꢂC; (d) NaBH4, EtOH, 25 ꢂC, 63% over two steps.
F
F
F
O
(R2)3SiO
O
b
c
RN
R1N
R1N
2a, R = Bn
2b, R = CO2Me
6a, (R1 = Bn, R2 = TBS)
6b, (R1 = CO2Me, R2 = TMS)
3a (R1 = Bn)
3b (R1 = CO2Me)
a
Scheme 4. Attempted asymmetric protonation of enol silanes 6a and 6b. Conditions: (a) MeOCOCl, CH2Cl2, 25 ꢂC, 86%; (b) Li(s-Bu)3BH, THF, ꢀ78 ꢂC, then
R3SiCl, 74% (from 2a using TBSCl) and 86% (from 2b using TMSCl); (c) AgF (cat.), R-BINAP (cat.), DCM/MeOH (20:1), 90%, 39% ee (refers to the
conversion of 6b to 3b).

10596
P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
F
F
F
O
F
O
O
O
OR
e,f,g
a
c
MeO2CN
MeO2CN
7a, R = H
MeO2CN
R
HN
9, R = SiMe2(i-PrO)
10, R = OH
(-)-Paroxetine
2b
b
d
8a, R = PO(OPh)2
Scheme 5. Enantioselective total synthesis of (ꢀ)-paroxetine. Conditions: (a) (S)-Me-CBS (cat.), BH3$SMe2, CH2Cl2, ꢀ20 ꢂC, 95%, 96% ee; (b) (PhO)2P(O)Cl,
DMAP (cat.), Pyr, CH2Cl2, 25 ꢂC, 89%; (c) (i-PrO)Me2SiCH2Cl, Mg, 25 ꢂC, then CuCN, THF, ꢀ30 to 0 ꢂC, 96%; (d) KF, H2O2, DMF, 25 ꢂC, 70%, 92% ee;
(e) [Ir(COD)(PCy3)Pyr]PF6, CH2Cl2, 25 ꢂC, 69%; (f) DIAD, PPh3, sesamol, THF, 0–50 ꢂC, 76%; (g) KOH, (HOCH2)2, 100 ꢂC, then HCl, 92%.
F
F
O
F
O
O
O
OR
O
SnBu3
O
O
b
d
RN
CbzN
CbzN
7b, R = H
8b, R = PO(OPh)2
12
11
2a, R = Bn
2c, R = CO2Bn
a
c
Scheme 6. Enantioselective total synthesis of (ꢀ)-paroxetine. Conditions: (a) BnOCOCl, CH2Cl2, 25 ꢂC, 89%; (b) NaBH4, CeCl3$7H2O, CH3OH, 25 ꢂC, 76%;
(c) (PhO)2P(O)Cl, DMAP (cat.), Pyr, CH2Cl2, 25 ꢂC, 86%; (d) stannane 11, n-BuLi, THF, ꢀ78 ꢂC, then CuBr$DMS, THF, ꢀ78 to ꢀ10 ꢂC, 27%.
The alcohol was converted to the phenolic ether in 76%
yield through its reaction with sesamol under Mitsunobu’s
conditions.26 Finally, deprotection of methyl carbamate
was achieved under basic conditions27 and the free amine
was treated with anhydrous HCl to provide (ꢀ)-paroxetine
as the hydrochloride salt in 92% yield. (ꢀ)-Paroxetine hydro-
chloride obtained in this manner exhibits spectral properties
identical in all respects to previously reported material
(Scheme 5).10–15
3. Experimental
3.1. General
All reactions were performed under an atmosphere of argon,
unless otherwise indicated. Anhydrous solvents were trans-
ferred by an oven-dried syringe and degassed with argon
prior to use. Flasks were flame-dried and cooled under
argon. Tetrahydrofuran (THF) was distilled from sodium/
benzophenone ketyl. Dichloromethane (DCM) was distilled
from calcium hydride. Methanol (MeOH) was distilled
from magnesium turnings and iodine. Other solvents and
chemical reagents obtained from commercial sources were
used without further purification, unless otherwise noted.
The literature procedures used to prepare dihydropyridinone
1 from N-benzyl glycine ethyl ester are described in Ref. 16.
Finally, it is noteworthy that a more concise approach to
(ꢀ)-paroxetine is potentially achieved via direct anti-
selective copper-mediated SN20 allylic substitution using
a sesamol-based phenoxymethyl anion. Stimulated by this
prospect, the tributylstannylmethyl ether 11 was prepared
from sesamol and tributyl(iodomethyl)stannane.28 Allylic
substitution using the phenoxymethyl anion derived cuprate
with allylic phosphate 8b gave the desired phenolic ether in
27% yield. This low yield is attributed to the instability of
the intermediate a-alkoxy organolithium reagent, and the
resulting organocuprate, with respect to a-elimination, as
suggested by the recovery of sesamol. Hence, this strategy
was not implemented in the synthesis of (ꢀ)-paroxetine
(Scheme 6).
Analytical thin-layer chromatography (TLC) was carried out
by using 0.2-mm commercial silica gel plates (DC-Fertig-
platten Kieselgel 60 F254, EMD Chemicals). Solvents for
chromatography are listed as volume/volume ratios. Infrared
spectra were recorded on a Perkin–Elmer 1420 spectro-
meter. Samples were prepared as films through evaporation
from dichloromethane or chloroform solution on sodium
chloride plates. High-resolution mass spectra (HRMS)
were obtained on a Karatos MS9 by using chemical ioniza-
tion in the positive ionization mode. Accurate masses are
reported for the molecular ion (M+1) or a suitable fragment
ion. Melting points were determined on a Thomas Hoover
Uni-melt apparatus in open capillaries and were uncor-
rected. Enantiomeric purity was determined by chiral
stationary phase HPLC analysis. Optical rotations were
measured by using an Atago Polax-2L polarimeter. Concen-
trations are reported in units of g/100 mL.
2. Conclusion
In summary, the phosphine-catalyzed a-arylation of enones
was used strategically in concise formal and total enan-
tioselective syntheses of the blockbuster antidepressant
(ꢀ)-paroxetine (PAXIL). This methodology complements
related Pd-catalyzed enolate arylations in several regards.
The use of enones as latent enolates enables regiospecific
enolate generation and preservation of the enone moiety in
the product facilitates subsequent elaboration of the arylated
products. Future studies will focus on the invention of related
reagents for aryl transfer under the conditions of nucleophilic
catalysis.
Proton NMR (1H NMR) spectra were recorded with a Varian
Gemini (300 MHz) spectrometer, a Varian Gemini
(400 MHz) spectrometer, and a Inova (500 MHz) spectrom-
eter. Chemical shifts (d) are expressed as parts per million

P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
10597
relative to trimethylsilane (d¼0.00 ppm), referenced to the
residual protic solvent. Coupling constants are reported in
hertz. Carbon-13 NMR (13C NMR) spectra were recorded
on a Varian Gemini 300 (75 MHz) spectrometer, a Varian
Gemini 400 (100 MHz) spectrometer, and a Inova 500
(125 MHz) spectrometer. Chemical shifts (d) are expressed
as parts per million relative to trimethylsilane (d¼0.0 ppm),
referenced to the center of the triplet at d¼77.0 ppm for
deuteriochloroform and d¼39.5 ppm for deuteriodimethyl-
sulfoxide (DMSO). 13C NMR analyses were run routinely
with broadband decoupling.
(100 MHz, CDCl3): d 191.1, 162.7 (d, J¼247.5 Hz), 154.7,
143.3, 137.2, 135.8, 130.3 (d, J¼7.7 Hz), 128.5, 128.2
(d, J¼6.9 Hz), 115.1 (d, J¼21.5 Hz), 67.8, 51.9, 43.6.
IR (film): 3033, 2956, 2829, 1688, 1601, 1509, 1430,
1350, 1231, 1160, 1100, 814 cmꢀ1. HRMS: Calcd for
C19H17NO3F [M+1] 326.1192, found 326.1195.
3.2.4. Aryl ketone 3a. To a solution containing 2a (0.71 g,
2.53 mmol, 100 mol %) in dry THF (15 mL) at ꢀ78 ꢂC
was added L-Selectride (1 M in THF, 2.6 mL, 2.53 mmol,
100 mol %) dropwise. The mixture was stirred at ꢀ78 ꢂC for
1 h, at which point aqueous NH4Cl (10% solution, 20 mL)
was added. The reaction mixture was transferred to a separa-
tory funnel and was extracted with CH2Cl2 (3ꢃ30 mL). The
combined organic extracts were dried (MgSO4), filtered, and
evaporated to afford an oily residue. Purification by column
chromatography (SiO2, 9:1 to 3:2 hexane/ethyl acetate)
gives compound 3a (0.609 g, 2.15 mmol) in 87% yield as
3.2. Preparation of compounds 2a–12
3.2.1. Aryl enone 2a. To 100 mL flask charged with tris-
(4-fluorophenyl)bismuth dichloride (12.3 g, 21.7 mmol,
110 mol %) and 1 (3.7 g, 19.7 mmol, 100 mol %) was added
CH2Cl2/tBuOH (9:1) (36 mL, 0.5 M), followed by tributyl-
phosphine (0.5 mL, 1.98 mmol, 10 mol %) and diisopropy-
lethylamine (3.4 mL, 19.7 mmol, 100 mol %). The reaction
mixture was allowed to stir at room temperature until com-
plete consumption of starting material was observed by
TLC (3 h), at which point the reaction mixture was evapo-
rated onto silica gel. Purification by column chromatography
(SiO2, 9:1 to 3:2 hexane/ethyl acetate) gives the title com-
pound 2a (4.39 g, 15.6 mmol) in 79% yield as an off white
solid. Mp 66.5–68.5 ꢂC. 1H NMR (400 MHz, CDCl3):
d 7.35 (m, 6H), 7.03 (m, 4H), 3.70 (s, 2H), 3.43 (d, J¼
3.42 Hz, 2H), 3.33 (s, 2H). 13C NMR (100 MHz, CDCl3):
d 194.1, 162.5 (d, J¼247.5 Hz), 145.2, 137.4, 136.3,
130.8, 130.2 (d, J¼8.5 Hz), 129.1, 128.5, 127.6, 114.9 (d,
J¼21.5 Hz), 61.8, 61.7, 52.6. IR (film): 3063, 3029, 2918,
2803, 2750, 1683, 1601, 1509, 1349, 1223, 1160, 823,
1
a pale yellow oil. H NMR (300 MHz, CDCl3): d 7.33 (m,
5H), 7.11 (m, 2H), 7.03 (m, 2H), 3.64 (s, 2H), 3.53 (t,
J¼10.0 Hz, 1H), 3.36 (dd, J¼14.1, 1.8 Hz, 1H), 3.06
(dm, J¼9.2 Hz, 1H), 2.93 (d, J¼13.8 Hz, 1H), 2.58 (m,
1H), 2.21 (m, 2H). 13C NMR (100 MHz, CDCl3): d 205.2,
162.2 (d, J¼246.2 Hz), 136.9, 133.65, 130.2 (d, J¼
8.4 Hz), 129.0, 128.4, 127.4, 115.3 (d, J¼11.5 Hz), 64.4,
62.5, 54.3, 51.9, 32.7. IR (film): 3062, 3029, 2949, 2801,
1722, 1604, 1511, 1454, 1224, 1098, 833, 740, 700 cmꢀ1
.
HRMS: Calcd for C18H19NOF [M+1] 284.14507, found
284.14541.
3.2.5. Aryl ketone 3b. A mixture of silver fluoride (2 mg,
0.016 mmol, 10 mol %) and (R)-BINAP (5.8 mg, 9.0 mmol,
6 mol %) was dissolved in methanol (0.2 mL) and stirred at
room temperature for 10 min in the dark, at which point
CH2Cl2 (2 mL) was added and the solution was stirred for
another 10 min. The solution was cooled to ꢀ78 ꢂC and 6b
(50 mg, 0.155 mmol, 100 mol %) in CH2Cl2 (2 mL) was
added dropwise. The mixture was warmed to ꢀ30 ꢂC and
stirred at this temperature for 72 h, at which point the mixture
was evaporated to dryness. Purification via column chroma-
tography (SiO2, 4:1 to 1:1 hexane/ethyl acetate) gives the
title compound 3b (35 mg, 0.014 mmol) in 90% yield as a
colorless oil. Chiral HPLC (Daicel Chiralpak OJ-H column,
699 cmꢀ1
.
282.12942, found 282.12898.
HRMS: Calcd for C18H17NOF [M+1]
3.2.2. Aryl enone 2b. Methylchloroformate (2 mL,
24.9 mmol, 200 mol %) was added dropwise to a solution
containing 2a (3.5 g, 12.4 mmol, 100 mol %) in CH2Cl2
(20 mL) at room temperature. The reaction mixture was
stirred at this temperature for 18 h, at which point the reaction
mixture was evaporated onto silica gel and purified via col-
umn chromatography (SiO2, 4:1 to 1:1 hexane/ethyl acetate)
to give the title compound 2b (2.64 g, 10.5 mmol) in 86%
yield as a white solid. Mp 110–111 ꢂC. 1H NMR
(400 MHz, CDCl3): d 7.32 (dd, J¼8.6, 5.5 Hz, 2H), 7.05
(t, J¼8.6 Hz, 3H), 4.45 (d, J¼2.1 Hz, 2H), 4.29 (s, 2H), 3.77
(s, 3H). 13C NMR (100 MHz, CDCl3): d 191.2, 162.1 (d, J¼
247.5 Hz), 155.3, 143.4, 137.2, 130.1 (d, J¼3.1 Hz), 130.2
(d, J¼7.7 Hz), 115.1 (d, J¼21.5 Hz), 53.0, 51.9, 43.6. IR
(film): 3053, 2981, 2863, 1723, 1673, 1606, 1463, 1403,
1351, 1236, 1103, 953, 842, 809 cmꢀ1. HRMS: Calcd for
C13H13NO3F [M+1] 250.0879, found 250.0882.
85:15 hexanes/i-PrOH, l¼254 nm, 0.5 mL minꢀ1, tmajor
¼
1
67.0 min, tminor¼97.7 min, ee¼39%). H NMR (500 MHz,
DMSO-d6 at 100 ꢂC): d 7.19 (dd, J¼8.6, 5.5 Hz, 2H), 7.10
(t, J¼11.1 Hz, 2H), 4.14 (A part of AB pattern, d,
J¼17.4 Hz, 1H), 4.05 (B part of AB pattern, d, J¼17.4 Hz,
1H), 3.85 (m, 2H), 3.63 (s, 3H), 3.56 (m, 2H), 2.21 (m,
13
2H). C NMR (125 MHz, DMSO-d6 at 100 ꢂC): d 203.9,
160.7 (d, J¼243.1 Hz), 154.7, 133.3 (d, J¼3.5 Hz), 129.2
(d, J¼8.1 Hz), 114.2 (d, J¼1.3 Hz), 53.2, 51.9, 41.7, 29.1.
IR (film): 2956, 1700, 1602, 1511, 1449, 1404, 1223, 835,
770 cmꢀ1
.
252.1036, found 252.1038.
HRMS: Calcd for C13H15NO3F [M+1]
3.2.3. Aryl enone 2c. Benzylchloroformate (1.21 g,
7.1 mmol, 200 mol %) and 2a (1.0 g, 3.5 mmol, 100 mol %)
were reacted according to the procedure described for 2b.
The crude product was purified via column chromatography
(SiO2, 4:1 to 1:1 hexane/ethyl acetate) to give compound 2c
(1.03 g, 3.16 mmol) in 89% yield as a white solid. Mp
3.2.6. Enol ether 4. To a vigorously stirred suspension of
methoxymethyltriphenylphosphonium chloride20 (500 mg,
1.76 mmol, 100 mol %) in dry THF (18 mL) was added a
solution of NaHMDS (2 M in THF, 3.5 mL, 7.06 mmol,
400 mol %) dropwise. The resulting red solution was stirred
at this temperature for 2 h, at which point 3a (500 mg,
1.76 mmol, 100 mol %) in THF (3 mL) was added dropwise
1
80–81 ꢂC. H NMR (400 MHz, CDCl3): d 7.37 (m, 5H),
7.31 (dd, J¼8.9, 5.5 Hz, 2H), 7.04 (t, J¼8.9 Hz, 2H), 5.19
(s, 2H), 4.47 (d, J¼3.8 Hz, 2H), 4.32 (s, 2H). 13C NMR

10598
P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
over 10 min. The reaction mixturewas allowed to stir at room
temperature for 20 h, at which point aqueous NH4Cl (1 M,
30 mL) was added. The resulting mixture was extracted
with diethyl ether (3ꢃ15 mL) and the combined organic ex-
tracts were dried (MgSO4), filtered and evaporated to give
a yellow oil. Purification of the residue via column chroma-
tography (SiO2, 9:1 to 4:1 hexane/ethyl acetate) givesthe title
compound 4 (350 mg, 11.2 mmol) in 65% yield as a yellow
3.2.8. Enol silane 6a. To a solution containing 2a (0.1 g,
0.35 mmol, 100 mol %) in dry THF (2 mL) at ꢀ78 ꢂC was
added L-Selectride (1 M in THF, 0.36 mL, 0.35 mmol,
100 mol %) dropwise. The mixture was stirred at this tem-
perature for 1 h, at which point TBSCl (59 mg, 0.39 mmol,
110 mol %) in THF (1 mL) was added dropwise. The reac-
tion mixture was allowed to stir at this temperature for an
addition 1 h and then left to warm to room temperature.
Removal of the volatiles in vacuo affords an oily residue,
which upon purification by column chromatography (SiO2,
9:1 hexane/ethyl acetate) gives 6a (104 mg, 2.62 mmol) in
1
oil. H NMR (300 MHz, CDCl3): d 7.34 (m, 5H), 7.19 (m,
2H), 6.99 (t, J¼8.9 Hz, 2H), 5.14 (s, 1H), 3.83 (d,
J¼12.3 Hz, 1H), 3.70 (A part of AB pattern, J¼13.0 Hz,
1H), 3.50 (B part of AB pattern, J¼13.0 Hz, 1H), 3.42 (s,
3H), 3.16 (d, J¼10.3 Hz, 1H), 2.90 (d, J¼11.6 Hz, 1H),
2.60 (d, J¼12.3 Hz, 1H), 2.21 (td, J¼11.3, 2.7 Hz, 1H),
1.98 (m, 1H), 1.78 (m, 1H). 13C NMR (75 MHz, CDCl3):
d 161.4 (d, J¼244.4 Hz), 143.2, 137.9, 137.7, 129.8 (d,
J¼7.6 Hz), 129.4, 128.1, 126.9, 117.5, 114.9 (d,
J¼21.1 Hz), 63.0, 59.4, 52.8, 51.6, 43.9, 32.7. IR (film):
3029, 2933, 2846, 2798, 1677, 1603, 1509, 1222, 1129,
835, 699 cmꢀ1. HRMS: Calcd for C20H22NOF [M+1]
311.16854, found 311.16756.
1
74% yield as a colorless oil. H NMR (300 MHz, CDCl3):
d 7.34 (m, 7H), 6.95 (t, J¼8.7 Hz, 2H), 3.63 (s, 2H), 2.99
(s, 2H), 2.63 (t, J¼5.6 Hz, 2H), 2.43 (m, 2H), 0.74 (s, 9H),
ꢀ0.19 (s, 6H). 13C NMR (75 MHz, CDCl3): d 161.1 (d,
J¼243.5 Hz), 140.8, 130.1 (d, J¼7.6 Hz), 129.3, 128.3,
114.6 (d, J¼21.1 Hz), 62.2, 56.3, 50.1, 29.2, 25.5, 17.9,
ꢀ4.2. IR (film): 2928, 2856, 1669, 1601, 1509, 1471,
1222, 837, 780 cmꢀ1. HRMS: Calcd for C24H33NOFSi
[M+1] 398.2315, found 398.2313.
3.2.9. Enol silane 6b. Aryl enone 2b (200 mg, 0.80 mmol,
100 mol %), L-Selectride (1 M in THF, 0.8 mL, 0.80 mmol,
3.2.7. Aminoalcohol 5. A solution of the enol ether 4 (50 mg,
0.16 mmol, 100 mol %) in THF (3 mL) was treated with
0.1 M aqueous H2SO4 (2.4 mL, 0.24 mmol, 150 mol %).
The solution was allowed to reflux for a 12 h period, at which
point the heating batch was removed and the reaction was
allowed to reach room temperature. Saturated aqueous
NaHCO3 (10 mL) was added, and the resulting mixture
was extracted with diethyl ether (3ꢃ5 mL). The combined
organic extracts were dried (MgSO4), filtered and evaporated
to provide the crude aldehyde (34 mg, 0.11 mmol) in 72%
100 mol %),
and
chlorotrimethylsilane
(0.12 mL,
0.880 mmol, 110 mol %) were reacted according to the pro-
cedure described for 8a. The crude product was purified via
Kugelrohr distillation to give 6b (230 mg, 0.71 mmol) in
1
86% yield as a colorless oil. H NMR (300 MHz, CDCl3):
d 7.32 (dd, J¼8.2 Hz, 2H), 6.98 (t, J¼8.7 Hz, 2H), 3.91 (s,
2H), 3.73 (s, 3H), 3.60 (s, 2H), 2.43 (s, 2H), ꢀ0.04 (s,
9H). 13C NMR (75 MHz, CDCl3): d 203.0, 161.2 (d,
J¼245.0 Hz), 155.8, 140.8, 135.2, 129.8 (d, J¼7.6 Hz),
114.5 (d, J¼21.4 Hz), 52.6, 46.8, 41.0, 28.5, 0.3. IR (film):
2957, 1707, 1601, 1510, 1448, 1410, 1253, 1226, 1106,
844, 767 cmꢀ1. HRMS: Calcd for C16H23NO3FSi [M+1]
324.1431, found 324.1437.
1
yield as a yellow oil. H NMR (300 MHz, CDCl3): d 9.45
(d, J¼1.8 Hz, 1H), 7.34 (m, 5H), 7.28 (m, 2H), 7.02 (t,
J¼8.5 Hz, 2H), 3.62 (s, 2H), 3.18 (dm, J¼11.4 Hz, 1H),
2.99 (dm, J¼11.4 Hz, 1H), 2.90 (dm, J¼18.4 Hz, 1H), 2.77
(dd, J¼9.0, 7.0 Hz, 1H), 2.12 (t, J¼11.1 Hz, 2H), 1.89 (m,
2H). 13C NMR (75 MHz, CDCl3): d 203.0, 161.6 (d,
J¼244.7 Hz), 138.6, 137.8, 129.1, 128.8 (d, J¼7.9 Hz),
128.3, 127.2, 115.5 (d, J¼21.4 Hz), 63.1, 54.4, 53.5, 53.0,
43.1, 34.1. IR (film): 2938, 2806, 1721, 1603, 1510, 1465,
1224, 1160, 833, 699 cmꢀ1. HRMS: Calcd for C19H21NOF
[M+1] 298.1607, found 298.1601.
3.2.10. Allylic alcohol 7a. To a dry 50 mL flask, a solution of
(S)-2-methyl-CBS-oxazaborolidine catalyst (1 M in toluene,
0.4 mL, 0.04 mmol, 10 mol %) and a solution of borane
dimethyl sulfide complex (2 M in THF, 2 mL, 4.0 mmol,
100 mol %) were added successively at room temperature.
The resulting solution was cooled to ꢀ20 ꢂC and 2b (1.0 g,
4.0 mmol, 100 mol %) in dichloromethane (18 mL) was
added dropwise over 1 h, the reaction mixture was stirred
at this temperature for 1 h. Methanol (15 mL) was added
dropwise to the reaction mixture and the reaction mixture
was allowed to warm to room temperature. The solution
was evaporated to dryness. Purification of the residue via col-
umn chromatography (SiO2, 9:1 to 1:1 hexane/ethyl acetate)
gives 7a (0.96 g, 3.85 mmol) in 95% yield as a white solid.
Mp 104–105 ꢂC. [a]D25 +70 (c 1.6, CH2Cl2). Chiral HPLC
(Daicel Chiralpak OJ-H column, 70:30 hexanes/i-PrOH,
l¼254 nm, 0.5 mL minꢀ1, tmajor¼35.2 min, tminor¼39.2 min,
ee¼96%). 1H NMR (500 MHz, DMSO-d6 at 100 ꢂC): d 7.52
(dd, J¼8.9, 5.5 Hz, 2H), 7.10 (t, J¼12.0 Hz, 2H), 6.08 (t,
J¼3.5 Hz, 1H), 4.79 (d, J¼6.6 Hz, 1H), 4.46 (m, 1H), 4.23
(dd, J¼19.0, 2.7 Hz, 1H), 3.86 (dd, J¼13.3, 3.8 Hz, 1H),
3.84 (dt, J¼17.2, 2.0 Hz, 1H), 3.65 (s, 3H), 3.34 (dd,
J¼13.3, 3.3 Hz, 1H). 13C NMR (125 MHz, DMSO-d6 at
100 ꢂC): d 161.0 (d, J¼244.1 Hz), 155.1, 136.4, 135.2 (d,
J¼3.05 Hz), 127.2 (d, J¼8.1 Hz), 122.6, 114.2 (d,
J¼20.8 Hz), 63.0, 51.5, 47.9, 42.9. IR (film): 3412, 2957,
This crude aldehyde was dissolved in ethanol (2 mL) and
treated with NaBH4 (6 mg, 0.16 mmol, 100 mol %), and
the reaction mixture was stirred at room temperature for
1 h. The reaction mixture was treated with 2 N aqueous
sodium hydroxide (10 mL) and extracted with CH2Cl2
(3ꢃ5 mL), the combined organic extracts were dried over
MgSO4, filtered, and evaporated in vacuo to give an oily
residue. Purification of the residue via column chromato-
graphy (SiO2, 9:1 to 3:2 hexane/ethyl acetate) gives the title
compound 5 (30 mg, 0.10 mmol) in 63% yield over two
steps as a colorless oil. 1H NMR (400 MHz, CDCl3):
d 7.34 (m, 5H), 7.17 (m, 2H), 6.98 (t, J¼8.6 Hz, 2H),
3.60 (A part of AB pattern, J¼13.2 Hz, 1H), 3.56 (B part
of AB pattern, J¼13.2 Hz, 1H), 3.37 (dd, J¼11.3, 3.0 Hz,
1H), 3.21 (m, 2H), 2.98 (d, J¼11.0 Hz, 1H), 2.33 (m,
1H), 1.98 (m, 3H), 1.79 (m, 3H). IR (film): 3427, 2934,
2848, 2799, 1604, 1510, 1222, 1130, 836, 739, 700 cmꢀ1
.
HRMS: Calcd for C19H23NOF [M+1] 300.17637, found
300.17487.

P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
10599
2921, 2851, 1693, 1601, 1511, 1470, 1448, 1411, 1231, 1130,
1062, 818, 767 cmꢀ1. HRMS: Calcd for C18H17NOF [M+1]
250.0879, found 250.0880.
62.2, 57.7, 53.0. IR (film): 3408, 3061, 3029, 2917, 2804,
1602, 1509, 1454, 1230, 1162, 1054, 822, 699. HRMS:
Calcd for C18H19NOF [M+1] 284.14506, found 284.14320.
3.2.11. Allylic alcohol 7b. To a solution containing
CeCl3$7H2O (1.09 g, 2.71 mmol, 100 mol %) and 2c
(0.88 g, 2.71 mmol, 100 mol %) in methanol (20 mL) was
added NaBH4 (0.10 g, 2.7 mmol, 100 mol %) in small por-
tions over 2 min at room temperature. The mixture was
allowed to stir for 5 min, at which point water (30 mL)
was added and the reaction mixture was extracted with
CH2Cl2 (3ꢃ20 mL). The organic extracts were combined,
dried over MgSO4, filtered, and concentrated in vacuo to
afford an oily residue. Purification via column chromato-
graphy (SiO2, 3:1 hexane/ethyl acetate) gives 7b (0.68 g,
2.07 mmol) in 76% yield as a white solid. Mp 106–108 ꢂC.
1H NMR (500 MHz, DMSO-d6 at 100 ꢂC): d 7.53 (dd,
J¼8.8, 5.5 Hz, 2H), 7.36 (m, 5H), 7.11 (t, J¼8.9 Hz, 2H),
6.09 (t, J¼3.5 Hz, 1H), 5.15 (s, 2H), 4.86 (t, J¼5.4 Hz,
1H), 4.49 (m, 1H), 4.29 (dd, J¼19.1, 3.7 Hz, 1H), 3.92
(dd, J¼13.2, 3.7 Hz, 1H), 3.89 (d, J¼16.5 Hz, 1H), 3.39
(dd, J¼13.2, 3.1 Hz, 1H). 13C NMR (125 MHz, DMSO-d6
at 100 ꢂC): d 161.0 (d, J¼244.1 Hz), 154.5, 136.6, 136.4,
135.2 (d, J¼3.05 Hz), 127.8, 127.2 (d, J¼7.6 Hz), 127.1,
126.9, 122.6, 114.2 (d, J¼21.4 Hz), 71.6, 63.0, 47.9, 43.0.
IR (film): 3414, 3033, 2915, 1691, 1510, 1432, 1360,
1229, 1125, 1070, 819, 698 cmꢀ1. HRMS: Calcd for
C19H19NO3F [M+1] 328.1349, found 328.1349.
3.2.13. Diphenyl phosphate 8a. Chlorodiphenylphosphate
(0.9 mL, 4.2 mmol, 150 mol %) was added dropwise to
a solution containing 7a (0.71 g, 2.8 mmol, 100 mol %), pyr-
idine (0.45 mL, 5.6 mmol, 200 mol %), and DMAP (0.51 g,
4.2 mmol, 150 mol %) at room temperature. After stirring
for 2 h at this temperature, the reaction mixture was trans-
ferred to a separatory funnel, washed with aqueous CuSO4
(2 M, 3ꢃ20 mL), dried (MgSO4), filtered, and evaporated
to afford an oily residue. Purification via column chromato-
graphy (SiO2, 9:1 to 4:1 dichloromethane/ethyl acetate)
gives 8a (1.21 g, 2.42 mmol) in 89% yield as a white solid.
Mp 99–100 ꢂC. [a]D23 +36 (c 3.33, CH2Cl2). 1H NMR
(300 MHz, CDCl3): d 7.34 (m, 4H), 7.18 (m, 6H), 6.94 (t, J¼
8.4 Hz, 2H), 6.88 (d, J¼7.94 Hz, 2H), 6.22 (s, 1H), 5.62 (s,
1H), 4.55 (dd, J¼14.6, 2.8 Hz, 2H), 3.91 (d, J¼18.2 Hz,
1H), 3.76 (s, 1H), 3.61 (s, 2H), 3.50 (d, J¼14.6 Hz, 1H).
13C NMR (75 MHz, CDCl3): d 162.5 (d, J¼247.3 Hz),
155.9, 150.4, 150.0, 133.4, 129.0 (d, J¼16.0 Hz), 127.8,
127.7, 125.2, 125.1, 119.8, 119.7, 115.4 (d, J¼21.4 Hz),
71.7, 52.7, 46.4, 43.5. IR (film): 3063, 3033, 2962, 2840,
1706, 1590, 1512, 1488, 1446, 1410, 1283, 1232, 1190,
1130, 1009, 956, 825, 767 cmꢀ1. HRMS: Calcd for
C25H24NO7FP [M+1] 500.1274, found 500.1278.
3.2.14. Diphenyl phosphate 8b. Chlorodiphenylphosphate
(0.5 mL, 2.31 mmol, 150 mol %), 7b (500 mg, 1.54 mmol,
100 mol %), pyridine (0.25 mL, 3.08 mmol, 200 mol %),
and DMAP (0.28 g, 2.3 mmol, 150 mol %) were reacted
according to the procedure described for 8a. The crude prod-
uct was purified via column chromatography (SiO2, 9:1
to 4:1 dichloromethane/ethyl acetate) to give 8b (0.74 g,
1.323 mmol) in 86% yield as a white solid. Mp 59–61 ꢂC.
1H NMR (300 MHz, CDCl3): d 7.24 (m, 17H), 6.91 (t,
J¼8.4 Hz, 2H), 6.88 (d, J¼7.94 Hz, 2H), 6.20 (s, 1H),
5.62 (s, 1H), 5.2 (s, 1H), 4.60 (dd, J¼14.4, 3.0 Hz, 2H),
3.92 (d, J¼19.5 Hz, 1H), 3.76 (s, 1H), 3.52 (dd, J¼14.1,
2.4 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 162.5 (d,
J¼247.3 Hz), 155.3, 150.4, 150.0, 136.3, 133.4, 129.0 (d,
J¼16.0 Hz), 128.4, 127.8, 127.7, 125.2, 125.0, 119.8,
115.4 (d, J¼21.4 Hz), 71.7, 67.4, 46.4, 43.6. IR (film):
3065, 2951, 1706, 1590, 1511, 1489, 1429, 1283, 1230,
1190, 1010, 957, 825, 766, 689 cmꢀ1. HRMS: Calcd for
C31H28NO6FP [M+1] 560.163, found 560.1638.
3.2.12. Allylic alcohol derived from 2a. To a solution of 2a
(0.1 g, 0.355 mmol, 100 mol %) in CH2Cl2 (3.5 mL) and
isopropyl alcohol (30 mL, 0.355 mmol, 100 mol %) at
ꢀ20 ꢂC was added dropwise a solution of BH3$SMe2 (2 M
in THF, 0.45 mL, 0.889 mmol, 250 mol %). The mixture
was allowed to stir at ꢀ20 ꢂC for 1 h, at which point a solution
containing both (S)-2-methyl-CBS-oxazaborolidine (2 M in
toluene, 36 mL, 0.035 mmol, 10 mol %) and BH3$SMe2
(2 M in THF 30 mL) was added in one portion. The reaction
mixture was allowed to stir at ꢀ20 ꢂC for 30 min. The tem-
perature was increased to ꢀ15 ꢂC over 45 min, at which
point MeOH (10 mL) was added carefully and the reaction
mixture allowed to stir for an additional 15 min. The reac-
tion mixture was placed in heating bath at 50 ꢂC and
CH2Cl2 and BH3$SMe2 were removed via distillation. To
the remaining solution was added MeOH (5 mL) and the
resulting mixture was allowed to stir at 65 ꢂC for 1 h (to
cleave the N–B complex). The heating bath was removed
and reaction mixture was allowed to reach ambient temper-
ature. The solvent was removed in vacuo and the resulting
residue was purified via column chromatography (SiO2,
3:2 to 1:1 hexane/ethyl acetate) to provide the allylic alcohol
(36 mg, 0.13 mmol) in 35% yield as a white solid. Mp 76–
77 ꢂC. Chiral HPLC (Daicel Chiralpak OJ-H column, 98:2
hexanes/i-PrOH, l¼254 nm, 1 mL minꢀ1, tmajor¼43.9 min,
3.2.15. Silane 9. To a slurry of CuCN (0.43 g, 4.81 mmol,
200 mol %) in THF (10 mL) was added a solution of
(i-PrO)Me2SiCH2MgCl (1 M in THF, 4.80 mL, 4.81 mmol,
200 mol %) at ꢀ18 ꢂC (ice/NaCl). After stirring at this tem-
perature for 40 min, the reaction mixture was cooled to
ꢀ50 ꢂC and 8a (1.20 g, 2.40 mmol, 100 mol %) in THF
(10 mL) was added dropwise. The reaction mixture was
allowed to warm to 0 ꢂC over 40 min, at which point aqueous
NH4Cl (10% solutions, 40 mL) was added. The resulting
mixture was extracted with CH2Cl2 (3ꢃ10 mL) and the
combined organic extracts were dried (MgSO4), filtered,
and evaporated to afford an oily residue. Purification of the
residue via column chromatography (SiO2, 3:2 hexane/ethyl
acetate) gives 9 (0.84 g, 2.306 mmol) in 96% yield as a color-
1
tminor¼31.7 min, ee¼70%). H NMR (400 MHz, CDCl3):
d 7.48 (dd, J¼8.7, 5.5 Hz, 2H), 7.33 (m, 5H), 6.99 (t,
J¼8.9 Hz, 2H), 6.09 (t, J¼3.5 Hz, 1H), 6.02 (dd, J¼4.8,
3.4 Hz, 1H), 4.37 (s, 1H), 3.65 (s, 2H), 3.35 (dd, J¼17.4,
4.4 Hz, 1H), 3.04 (dd, J¼10.6, 2.0 Hz, 1H), 2.84 (d, J¼
17.4 Hz, 1H), 2.75 (br s, 1H), 2.49 (dd, J¼11.6, 2.0 Hz,
1H). 13C NMR (100 MHz, CDCl3): d 162.1 (d, J¼246.0 Hz),
137.6, 137.0, 135.2 (d, J¼3.1 Hz), 129.0, 128.3, 127.3,
127.1 (d, J¼7.7 Hz), 124.5, 115.2 (d, J¼21.5 Hz), 66.1,
1
less oil. [a]2D3 +72 (c 3.6, CH2Cl2). H NMR (300 MHz,

10600
P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
CDCl3): d 7.29 (m, 2H), 6.99 (t, J¼8.7 Hz, 2H), 5.76 (s, 1H),
4.28 (m, 1H), 3.95 (m, 2H), 3.87 (d, J¼18.8 Hz, 1H), 3.71 (s,
3H), 3.28 (dd, J¼13.2, 3.3 Hz, 1H), 2.87 (s, 1H), 1.12 (2d,
J¼6.2 Hz, 6H), 0.68 (2d, J¼10.8 Hz, 1H), 0.55 (2s, 1H),
0.09 (s, 6H). 13C NMR (75 MHz, CDCl3): d 162.1 (d,
J¼246.0 Hz), 156.6, 141.6, 135.9, 127.6 (d, J¼7.3 Hz),
119.5, 115.1 (d, J¼21.1 Hz), 64.9, 52.4, 46.3, 43.8, 32.3,
25.8, 19.5, ꢀ0.78. IR (film): 3081, 2956, 2889, 1706,
1601, 1510, 1448, 1412, 1375, 1335, 1250, 1231, 1191,
1118, 1025, 958, 880, 836, 813 cmꢀ1. HRMS: Calcd for
C19H27NO3FSi [Mꢀ1] 364.1744, found 364.1745.
HRMS: Calcd for C14H19NO3F [M+1] 268.1349, found
268.1350.
The saturated alcohol (100 mg, 0.37 mmol, 100 mol %) was
dissolved in THF (3 mL) and PPh3 (120 mg, 0.45 mmol,
120 mol %) was added. The solution was cooled to 0 ꢂC
and DIAD was added dropwise. The solution was allowed
to stir at 0 ꢂC for 10 min, at which point sesamol (100 mg,
0.75 mmol, 200 mol %) in THF (1 mL) was added dropwise
and the reaction mixture was allowed to stir for another
10 min at 0 ꢂC. The reaction mixture was heated to 50 ꢂC
and was allowed to stir at this temperature for 2 h, at which
point the reaction mixture was allowed to reach ambient tem-
perature. The reaction mixture was evaporated to dryness,
and the residue was dissolved in CH2Cl2 (5 mL). In order
to remove excess sesamol, the organic layer was washed with
aqueous NaOH (2 M, 2ꢃ10 mL) and the aqueous extracts
were back-extracted with CH2Cl2 (10 mL). The combined
organic layers were dried (MgSO4), filtered and evaporated
onto silica gel. Purification via column chromatography
(SiO2, 4:1 hexane/ethyl acetate) gives the phenolic ether
(110 mg, 2.84 mmol) in 76% yield as a pale yellow oil.
3.2.16. Homo-allyl alcohol 10. To a solution of 9 (0.82 g,
2.24 mmol, 100 mol %) in DMF (12 mL) at room tempera-
ture were added potassium fluoride (0.52 g, 8.98 mmol,
400 mol %) and 30% aqueous hydrogen peroxide (3 mL,
26.9 mmol, 1200 mol %). The reaction mixture was allowed
to stir at room temperature for 18 h, at which point H2O
(60 mL) was added. The resulting mixture was extracted
with diethyl ether (3ꢃ20 mL), and the combined organic ex-
tracts were washed with saturated aqueous Na2S2O3 (20 mL)
dried (MgSO4), and evaporated to afford a colorless oil.
Purification via column chromatography (SiO2, 4:1 to 1:1
hexane/ethyl acetate) gives 10 (0.41 g, 1.54 mmol) in 70%
yield as a colorless oil. [a]2D3 +84 (c 3.06, CH2Cl2). Chiral
HPLC (Daicel Chiralpak OJ-H column, 90:10 hexanes/
1
[a]2D3 ꢀ13 (c 1.5, CH2Cl2). H NMR (500 MHz, DMSO-d6
at 100 ꢂC): d 7.27 (dd, J¼8.6, 5.6 Hz, 2H), 7.06 (t,
J¼8.9 Hz, 2H), 6.9 (d, J¼8.5 Hz, 1H), 6.40 (d, J¼2.4 Hz,
1H), 6.18 (dd, J¼8.3, 2.4 Hz, 1H), 5.89 (s, 2H), 4.31 (dd,
J¼13.4, 3.0 Hz, 1H), 4.09 (dt, J¼13.3, 2.0 Hz, 1H), 3.64 (s,
3H), 3.41 (m, 2H), 2.89 (td, J¼12.8, 2.8 Hz, 1H), 2.82 (t,
J¼11.6 Hz, 1H), 2.70 (td, J¼5.8 Hz, 1H), 2.05 (m, 1H),
1.73 (dd, J¼13.2, 3.1 Hz, 1H), 1.67 (qd, J¼12.1, 4.4 Hz,
i-PrOH, l¼254 nm, 0.4 mL minꢀ1, tmajor¼31.0 min, tminor
¼
45.9 min, ee¼92%). 1H NMR (500 MHz, DMSO-d6 at
100 ꢂC): d 7.43 (dd, J¼8.8, 2.1 Hz, 2H), 7.12 (t, J¼8.9 Hz,
2H), 6.00 (t, J¼2.4 Hz, 1H), 4.27 (s, 1H), 4.18 (m, 2H),
3.82 (dt, J¼19.1, 2.8 Hz, 1H), 3.65 (s, 3H), 3.32 (dt,
J¼10.6, 3.8 Hz, 1H), 3.18 (m, 2H), 2.83 (dd, J¼4.2,
13
1H). C NMR (125 MHz, DMSO-d6 at 100 ꢂC): 160.5 (d,
J¼242.6 Hz), 154.7, 153.6, 147.4, 141.0, 139.7 (d, J¼
3.0 Hz), 128.6 (d, J¼8.1 Hz), 114.5 (d, J¼21.4 Hz), 107.3,
105.9, 100.4, 97.6, 69.0, 51.6, 46.4, 43.5, 42.9, 40.6, 32.9.
IR (film): 3008, 2916, 1701, 1510, 1488, 1450, 1412, 1276,
1223, 1185, 1132, 1037, 937, 832, 765 cmꢀ1. HRMS: Calcd
for C21H23NO5F [M+1] 388.1560, found 388.1561.
13
2.1 Hz, 1H). C NMR (125 MHz, DMSO-d6 at 100 ꢂC):
d 161.0 (d, J¼2.44.1 Hz), 155.3, 135.7 (d, J¼3.0 Hz),
135.0, 126.9 (d, J¼8.1 Hz), 121.9, 114.4 (d, J¼21.4 Hz),
60.3, 51.5, 43.1, 41.5. IR (film): 3426, 3056, 2954, 2876,
1686, 1601, 1510, 1448, 1412, 1375, 1228, 1131, 1091,
1039, 953, 836, 814, 768, 735 cmꢀ1. HRMS: Calcd for
C14H17NO3F [M+1] 266.1192, found 266.1199.
To a reaction vessel charged with the phenolic ether (50 mg,
0.13 mmol, 100 mol %) and KOH (94 mg, 1.68 mmol %,
1300 mol %) were added ethylene glycol (1.5 mL), and wa-
ter (0.6 mL). The mixture was heated to 100 ꢂC for 20 h
and then cooled to room temperature, diluted with water
(10 mL), and extracted with CH2Cl2 (3ꢃ5 mL). The com-
bined organic layers were washed with H2O (2ꢃ5 mL), dried
(MgSO4), filtered, and evaporated to provide an oily residue.
The residue was dissolved in ether (5 mL) and the resulting
solution was treated with 4 M HCl in dioxane (5 mL) to
give a white solid. The white solid was filtered, washed
with ether, and dried to afford (45 mg, 0.12 mmol) paroxetine
hydrochloride in 92% yield. Mp 132–134 ꢂC. Lit10i 136–
3.2.17. Conversion of 10 to paroxetine hydrochloride. A
solution containing 10 (300 mg, 1.13 mmol, 100 mol %) in
CH2Cl2 (11 mL) was cooled to ꢀ78 ꢂC, evacuated and filled
with Ar(g). This process was repeated twice. The solution
was allowed towarm to room temperature and Crabtree’s cat-
alyst (45 mg, 0.056 mmol, 5 mol %) was added as a solid in
one portion. The mixture was purged with H2(g) for 5 min
and allowed to stir under 1 atm of hydrogen for 20 h. The
reaction mixture was evaporated onto silica gel. Purification
via column chromatography (SiO2, 4:1 to 3:2 hexane/ethyl
acetate) gives the saturated alcohol (210 mg, 0.78 mmol) in
69% yield. [a]2D3 ꢀ40 (c 2.0, CH2Cl2). 1H NMR (500 MHz,
DMSO-d6 at 100 ꢂC): d 7.23 (dd, J¼7.9, 6.1 Hz, 2H), 7.06
(t, J¼8.9 Hz, 2H), 4.30 (dd, J¼13.3, 2.5 Hz, 1H), 4.09 (d,
J¼5.6 Hz, 1H), 4.07 (d, J¼15.7 Hz, 1H), 3.64 (s, 3H), 3.18
(m, 1H), 3.02 (m, 1H), 2.83 (t, J¼13.0 Hz, 1H), 2.66 (t,
J¼11.4 Hz, 1H), 2.53 (td, J¼11.6, 3.2 Hz, 1H), 1.72 (m,
2H), 1.57 (qd, J¼12.6, 4.4 Hz, 1H). 13C NMR (125 MHz,
DMSO-d6 at 100 ꢂC): d 160.3 (d, J¼244.1 Hz), 154.7,
139.8 (d, J¼3.0 Hz), 128.5 (d, J¼7.6 Hz), 114.3 (d, J¼
21.4 Hz), 60.8, 51.5, 46.7, 43.6, 43.0, 42.8, 33.2. IR (film):
3435, 3009, 2918, 2853, 1697, 1603, 1510, 1476, 1451,
1
138 ꢂC. [a]D23 ꢀ85 (c 1.0, CH3OH). Lit10i ꢀ86.5. H NMR
(400 MHz, CDCl3): d 7.20 (dd, J¼8.2, 5.5 Hz, 2H), 7.00 (t,
J¼8.5 Hz, 2H), 6.61 (d, J¼8.2 Hz, 1H), 6.32 (d, J¼
2.73 Hz, 1H), 6.10 (dd, J¼8.5, 2.4 Hz, 1H), 5.88 (s, 2H),
3.73 (dd, J¼21.5, 14.4 Hz, 2H), 3.60 (d, J¼8.2 Hz, 1H),
3.48 (dd, J¼9.9, 4.4 Hz, 1H), 3.17 (t, J¼10.9 Hz, 1H), 2.04
(m, 1H), 2.90 (t, J¼11.3 Hz, 1H), 2.64 (m, 1H), 2.38 (q,
J¼13.3 Hz, 2H), 2.03 (d, J¼6.3 Hz, 1H). IR (film): 3401,
2925, 1605, 1510, 1224, 1185, 1037, 831 cmꢀ1
.
3.2.18. Phenolic ether 12. To a stirred solution of 11
(240 mg, 0.54 mmol, 300 mol %) in THF (3 mL) at ꢀ78 ꢂC
1413, 1279, 1223, 1159, 1129, 1064, 1014, 832, 767 cmꢀ1
.

P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
10601
1982, 82, 15; (b) Barton, D. H. R.; Finet, J.-P. Pure Appl.
Chem. 1987, 59, 937; (c) Abramovitch, R. A.; Barton,
D. H. R.; Finet, J.-P. Tetrahedron 1988, 44, 3039; (d) Finet,
J.-P. Chem. Rev. 1989, 89, 1487.
was added n-BuLi (2.5 M in hexanes, 0.18 mL, 0.45 mmol,
250 mol %) dropwise. The reaction mixture was allowed to
stir at ꢀ78 ꢂC for 1 h, at which point CuBr$SMe2
(110 mg, 0.54 mmol, 300 mol %) in Me2S (0.5 mL) was
added dropwise. The reaction mixture was allowed to stir
an additional 30 min at ꢀ78 ꢂC, at which point 8b
(100 mg, 0.18 mmol, 100 mol %) in Me2S (0.5 mL) was
added. The reaction mixture was allowed to continue stirring
at ꢀ78 ꢂC for an additional 1 h period, at which point the
reaction mixture was allowed to warm to ꢀ10 ꢂC and aque-
ous NH4Cl (10% solution, 10 mL) was added. The aqueous
layer was extracted with CH2Cl2 (3ꢃ5 mL) and the com-
bined organic extracts were dried (MgSO4), filtered, and
evaporated to afford an oily residue. Purification of the
residue via column chromatography (SiO2, 3:2 hexane/ethyl
acetate) gives the title compound 12 (22 mg, 0.05 mmol)
7. For related chemistry involving aryllead(IV) reagents, see:
Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001 and refer-
ences therein.
8. (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108; (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc.
˚
1997, 119, 12382; (c) Ahman, J.; Wolfe, J. P.; Troutman,
M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 1918; (d) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 1999, 121, 1473; (e) Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360.
9. For a review, see: Gunasekara, N. G.; Noble, S.; Benfield, P.
Drugs 1998, 55, 85.
1
in 27% yield. H NMR (500 MHz, DMSO-d6 at 100 ꢂC):
10. For physical resolution of racemates, see: (a) Christensen, J. A.;
Squires, R. F. German Patent 2,404,113, 1974; Chem. Abstr.
1974, 81, 152011q; (b) Stemp, J. A.; Miller, D.; Martin, R. T.
Eur. Patent 0190496, 1985; Chem. Abstr. 1987, 106, 18361;
(c) Faruk, E. A.; Martin, R. T. EP Patent 223,334, 1986;
Chem. Abstr. 1987, 107, 96594; (d) Willcocks, K.; Barnes,
R. D.; Rustidge, D. C.; Tidy, D. J. D. J. Labelled Compd.
Radiopharm. 1993, 33, 783; (e) Engelstoft, M.; Hansen, J. B.
Acta Chem. Scand. 1996, 50, 164; (f) Istvan, B.; Laszlo, C.;
Laszlo, D.; Kalman, H.; Istvan, H.; Janos, K.; Andras, N.;
Eva, W. P.; Juhaszida, D.; Judit, N. B. U.S. Patent 6,657,062,
1997; Chem. Abstr. 1998, 128, 127941; (g) Sugi, K.; Itaya,
N.; Katsura, T.; Igi, M.; Yamakazi, S.; Ishibashi, T.; Yamaoka,
T.; Kawada, Y.; Tagami, Y. Eur. Patent 0812827, 1997;
Chem. Abstr. 1998, 128, 75308; (h) Kreidl, J.; Czibula, L.;
Nemes, A.; Deutschne, J. I.; Werkne Papp, E.; Nagyne Bagdy,
J.; Dobay, L.; Hegedus, I.; Harsanyi, K.; Borza, I. WO Patent
9801424, 1998; Chem. Abstr. 1998, 128, 127941; (i) Czibula,
d 7.45 (dd, J¼8.8, 5.5 Hz, 2H), 7.29 (s, 5H), 7.13 (t,
J¼8.8 Hz, 2H), 6.68 (d, J¼8.4 Hz, 1H), 6.41 (d, J¼2.4 Hz,
1H), 6.22 (dd, J¼8.5, 2.3 Hz, 1H), 6.10 (t, J¼3.4 Hz, 1H),
5.89 (s, 2H), 5.08 (AB pattern, J¼12.6 Hz, 2H), 4.33
(d, J¼13.3 Hz, 2H), 3.90 (d, J¼19.2 Hz, 1H), 3.72
(d, J¼5.1 Hz, 2H), 3.29 (d, J¼3.4 Hz, 2H), 3.20 (s, 1H).
13C NMR (125 MHz, DMSO-d6 at 100 ꢂC): 161.2 (d,
J¼244.6 Hz), 154.5, 153.5, 147.4, 141.0, 136.5, 135.4,
134.1, 127.7, 127.1, 127.1 (d, J¼8.1 Hz), 126.8, 123.2,
114.6 (d, J¼21.4 Hz), 107.3, 106.0, 100.4, 97.7, 68.1,
65.8, 43.1, 41.8, 36.9. IR (NaCl): 3033, 2962, 2877,
1701, 1602, 1508, 1465, 1431, 1260, 1224, 1184, 1129,
1037, 814 cmꢀ1. HRMS: Calcd for C27H25NO5F [M+1]
462.1717, found 462.1711.
Supplementary data
€
ꢀ
ꢀ
L.; Nemes, A.; Sebok, F.; Szantay, C., Jr.; Mak, M. Eur. J.
Scanned images of 1H NMR and 13C NMR spectra. Supple-
mentary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2006.05.092.
Org. Chem. 2004, 3336.
11. For enzyme-catalyzed asymmetric transformations, see: (a)
Zepp, C. M.; Gao, Y.; Heefner, D. L. U.S. Patent 5,258,517,
1993; Chem. Abstr. 1993, 120, 217289; (b) Curzons, A. D.;
Powell, L. W.; Keay, A. M. WO Patent 9322284, 1993;
Chem. Abstr. 1993, 120, 163991; (c) Yu, M. S.; Jacewicz, V.
W.; Shapiro, E. WO Patent 9853824, 1998; Chem. Abstr.
1998, 128, 151093; (d) Gledhill, L.; Kell, C. M. WO Patent
9802556, 1998; Chem. Abstr. 1998, 128, 151093; (e) Yu,
M. S.; Lantos, I.; Yu, P. Z.-Q. J.; Cacchio, T. Tetrahedron
References and notes
1. For selected monographs encompassing Lewis base catalysis,
see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
40, 3726; (b) Berkessel, A.; Groerger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005.
2. For phosphine-catalyzed regioretentive allylic substitutions
of Morita–Baylis–Hillman acetates, see: (a) Cho, C.-W.;
Kong, J. R.; Krische, M. J. Org. Lett. 2004, 6, 1337; (b)
Cho, C.-W.; Krische, M. J. Angew. Chem., Int. Ed. 2004,
43, 6689.
3. For phophine-catalyzed cycloallylation of tethered enone-
allylic cabonates, see: Jellerichs, B. G.; Kong, J. R.; Krische,
M. J. J. Am. Chem. Soc. 2003, 125, 7758.
4. For phophine-catalyzed intramolecular [3+2] cycloaddition of
acetylenic esters to enones, see: (a) Wang, J. C.; Ng, S. S.;
Krische, M. J. J. Am. Chem. Soc. 2003, 125, 3682; (b) Wang,
J.-C.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 5855.
5. For phophine-catalyzed a-arylation of enones using hyper-
valent bismuth reagents, see: Koech, P. K.; Krische, M. J.
J. Am. Chem. Soc. 2004, 126, 5350.
ꢀ
Lett. 2000, 41, 5647; (f) Gonzalo, G. D.; Brieva, R.; Sanchez,
V. M.; Bayod, M.; Gotor, V. J. Org. Chem. 2001, 66, 8947.
12. For chiral auxiliary-based approaches, see: (a) Amat, M.;
Hildago, J.; Bosch, J. Tetrahedron: Asymmetry 1996, 7, 1591;
(b) Adger, B. M.; Potter, G. A.; Fox, M. E. WO Patent
9724323, 1997; Chem. Abstr. 1997, 127, 149075; (c)
Murthy, K. S. K.; Rey, A. W. U.S. Patent 5,962,689, 1999;
WO Patent 9907680, 1999; Chem. Abstr. 1999, 130, 182361;
(d) Amat, M.; Bosch, J.; Hildago, J.; Canto, M.; Perez, M.;
Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J.
J. Org. Chem. 2000, 65, 3074; (e) Cossy, J.; Mirguet, O.;
Pardo, D. G.; Desmurs, J.-R. Tetrahedron Lett. 2001, 42,
7805; (f) Cossy, J.; Mirguet, O.; Pardo, D. G.; Desmurs, J.-R.
New J. Chem. 2003, 27, 475; (g) Yamada, S.; Jahan, I.
Tetrahedron Lett. 2005, 46, 8673.
13. For asymmetric deprotonation using chiral bases, see: (a)
Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc.
2001, 123, 1004; (b) Greenhalgh, D. A.; Simpkins, N. S.
6. For selected reviews encompassing the use of arylbismuth
reagents, see: (a) Freedman, L. D.; Doak, G. O. Chem. Rev.

10602
P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
Synlett 2002, 2074; (c) Gill, C. D.; Greenhalgh, D. A.;
Simpkins, N. S. Tetrahedron 2003, 59, 9213.
14. For catalytic enantioselective transformations, see: (a) Taylor,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204;
(b) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 11253.
15. For naturally occurring chiral starting materials, see: (a) Cossy,
J.; Mirguet, O.; Pardo, D. G.; Desmurs, J.-R. Tetrahedron Lett.
2001, 42, 5705; (b) Cossy, J.; Mirguet, O.; Pardo, D. G.;
Desmurs, J.-R. Eur. J. Org. Chem. 2002, 35, 3543.
19. Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41, 2194.
20. Wittig, G.; Boell, W.; Krueck, K. H. Chem. Ber. 1962, 95, 2514.
21. For a review, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int.
Ed. 1998, 37, 1986.
22. For anti-selective copper-mediated SN20 allylic substitution of
allylic phosphates, see: (a) Chong, J. M.; Belelie, J. L. J. Org.
Chem. 2001, 66, 5552; (b) Chong, J. M.; Belelie, J. L. J. Org.
Chem. 2002, 67, 3000; (c) Calaza, M. I.; Hupe, E.; Knochel,
P. Org. Lett. 2003, 5, 1059; (d) Dieter, R. K.; Gore, V. K.;
Chen, N. Org. Lett. 2004, 6, 763.
16. (a) Chen, L. C.; Wang, E.-C.; Lin, J.-H.; Wu, S.-S. Heterocycles
1984, 22, 2769; (b) Moretto, A. F.; Liebeskind, L. S. J. Org.
Chem. 2000, 65, 7445.
17. Forenantioselective protonation of enol silanes related to 2, see:
(a) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc.
1994, 116, 11179; (b) Ishihara, K.; Nakamura, S.; Kaneeda, M.;
Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854; (c)
Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H.
J. Am. Chem. Soc. 2003, 125, 24; (d) Yanagisawa, A.; Touge,
T.; Arai, T. Angew. Chem., Int. Ed. 2005, 44, 1546.
18. For selected reviews encompassing enantioselective proton-
ation of enol silanes, see: (a) Fehr, C. Angew. Chem., Int. Ed.
1996, 35, 2567; (b) Yanagisawa, A.; Ishihara, K.; Yamamoto,
H. Synlett 1997, 411; (c) Duhamel, L.; Duhamel, P.;
Plaquevent, J.-C. Tetrahedron: Asymmetry 2004, 15, 3653.
23. (a) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4245; (b)
Tamao, K.; Ishida, N.; Kumada, M. Org. Synth. 1990, 69, 96;
(c) Matsuumi, M.; Ito, M.; Kobayashi, Y. Synlett 2002, 1508.
24. Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
25. For reviews encompassing substrate-directed hydrogenation,
see: (a) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26,
190; (b) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307.
26. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Shi, Y.-N.; Hughes,
D. L.; McNamara, J. M. Tetrahedron Lett. 2003, 44, 3609.
27. Gilligan, P. J.; Cain, G. A.; Christos, T. E.; Cook, L.;
Drummond, S.; Johnson, A. L.; Kergaye, A. A.; McElroy,
J. F.; Rohrbach, K. W.; Schmidt, K. W.; Tam, S. M. J. Med.
Chem. 1992, 35, 4344.
28. Mikami, T.; Harada, M.; Naraka, K. Chem. Lett. 1999, 425.