An asymmetric, SmI2-mediated approach to γ-butyrolactones using a new, fluorous-tagged auxiliary

Article abstract of DOI:10.1016/j.tet.2008.08.110

A new, fluorous-tagged chiral auxiliary has been developed for the asymmetric, SmI₂-mediated coupling of aldehydes and α,β-unsaturated esters. γ-Butyrolactones are obtained in moderate to good isolated yield and in high enantiomeric excess. The fluorous tag allows the auxiliary to be conveniently recovered by fluorous solid-phase extraction (FSPE) and reused.

Full text of DOI:10.1016/j.tet.2008.08.110

Tetrahedron 64 (2008) 11876–11883
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An asymmetric, SmI2-mediated approach to g-butyrolactones using a new,
fluorous-tagged auxiliary
,
Johannes C. Vogel a, Rebecca Butler b, David J. Procter a
*
a School of Chemistry, University of Manchester, Manchester M13 9PL, UK
b Novartis, Horsham, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Accepted 12 August 2008
Available online 20 September 2008
A new, fluorous-tagged chiral auxiliary has been developed for the asymmetric, SmI2-mediated coupling
of aldehydes and -unsaturated esters. -Butyrolactones are obtained in moderate to good isolated
yield and in high enantiomeric excess. The fluorous tag allows the auxiliary to be conveniently recovered
by fluorous solid-phase extraction (FSPE) and reused.
a
,b
g
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Samarium
Radicals
Asymmetric
Fluorous
Lactones
1. Introduction
aldehydes and a,b-unsaturated esters to give g-butyrolactones in
high enantiomeric excess. The fluorous tag allows the auxiliary to
be conveniently recovered by fluorous solid-phase extraction
(FSPE)10 and reused.
Samarium(II) iodide (SmI2) continues to be used widely in or-
ganic synthesis.1 This mild, single-electron reductant has been used
to mediate a broad range of radical and anionic transformations
ranging from functional group interconversions to complex car-
bon–carbon bond-forming sequences.1 The reductive coupling of
carbonyl compounds with olefins represents one of the most im-
portant classes of SmI2 carbon–carbon bond-forming reaction. In
1986, Fukuzawa2 and Inanaga3 described the SmI2-mediated, in-
2. Results and discussion
Our auxiliary design is inspired by Braun’s (R)-2-hydroxy-1,2,2-
triphenyl-1,2-diol (HYTRA) auxiliary that has found application in
a number of asymmetric reactions.11 To our knowledge the use of
termolecular coupling of aldehydes and ketones with
a,b-un-
saturated esters to give substituted -butyrolactones. In 1997,
g
O
O
R1
R2
R3
Fukuzawa reported a useful, asymmetric variant in which acrylates
and crotonates derived from ephedrine are coupled with aldehydes
and ketones.4 We have applied Fukuzawa’s approach in a short
O
R1 R2
SmI2, THF
ROH
R3
OR*
O
asymmetric synthesis of an antifungal,
g-butyrolactone natural
product.5 We have also adapted Fukuzawa’s methodology in the
development of a solid-phase asymmetric catch and release ap-
O
Ph
Ph
H
H
Fukuzawa 1997
aldehydes/ketones
43–99% ee
Lin 2000
ketones
O
N
proach to g-butyrolactones using acrylates and crotonates linked to
O
O
resin through an ephedrine chiral linker.6 Lin7 and Dai8 have also
reported the use of new chiral auxiliaries in asymmetric, SmI2-
76–99% ee
O
43–88% GC yield
43–99% yield
OBn
O
mediated approaches to g-butyrolactones (Fig. 1).
i–Pr
N
Here, we describe the design and synthesis of a new, fluorous-
i–Pr
MeO
tagged9 auxiliary for the asymmetric, SmI2-mediated coupling of
Procter 2003
aldehydes/ketones
66–96% ee
Dai 2006
N
aldehydes
O
80–99% ee
37–73% yield
87–90% yield
* Corresponding author. Tel.: þ44 161 275 1425; fax: þ44 161 275 4939.
E-mail address: david.j.procter@manchester.ac.uk (D.J. Procter).
Figure 1. Asymmetric, SmI2-mediated approaches to
g
-butyrolactones.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.110

J.C. Vogel et al. / Tetrahedron 64 (2008) 11876–11883
11877
i–PrMgCl,n–BuLi
C8F17
OH
Ph
THF, 0 °C
S
OTBDMS
Ph
5
Braun's (R)-2-hydroxy-
1,2,2-triphenyl-1,2-diol
auxiliary
4
Ph
Ph OH
then
Weinreb amide 2
0 °C, rt, FSPE
5
O
PhMgBr, THF
0 °C, rt, FSPE
61 % over 3
steps
RF
C8F17
OH
Ph
S
OH
1
5
2
Ph
Ph OH
RF = perfluoroalkyl group
Ph OH
1
C8F17
S
OTBDMS
Ph
TBAF, THF, rt
5
1
FSPE, 91%
6
Figure 2. Design of a new, fluorous-tagged auxiliary.
Ph OH
Scheme 2. Synthesis of the fluorous-tagged auxiliary 1.
the 1,2,2-triphenyl-1,2-diol auxiliary in radical reactions has not
been reported. We chose to attach the fluorous tag using a spacer
unit located at the 4-position of a 2-phenyl ring thus minimizing
the effect of the linker and tag on the proposed asymmetric
transformations. Our initial goal, therefore, was the diaster-
eoselective synthesis of tagged auxiliary 1 (Fig. 2).
The synthesis of the fluorous-tagged auxiliary 1 began with the
preparation of Weinreb amide 2 from (R)-mandelic acid (in-
expensive in either enantiomeric form) in three steps (Scheme 1).12
OH
X-ray crystal
structure of 7
1. PhMgBr,THF
0 °C to rt, 98%
2. 1,4-dibromobenzene
Mg, I2 cat., THF
0 °C to rt,70%
Ph
2
OH
7
Br
3. TBAF,THF, rt, 95%
1. SOCl2, MeOH
0 °C to Δ
2. HN(CH3)OMeHCl
Scheme 3. Indirect confirmation of the stereochemistry in 1.
O
O
AlMe3, CH2Cl2
0 °C to Δ
Ph
OH
R–mandelic acid
MeO
Ph
HO
N
3. TBDMSOTf, NEt3
CH2Cl2,0 °C
64% overall
OTBDMS
O
2
C8F17
trans–crotonic anhydride
or acryloyl chloride
S
O
R
5
1
Ph
DMAP, NEt3
CH2Cl2, rt, FSPE, 78%
8 R = Me, 78%
9 R = H, 65%
1. 4-Bromobenzaldehyde
NaH, THF, rT
2. Rh/C,H2, EtOH, 60 °C
Ph OH
C8F17
Ph3P
Br
S
5
Br
Scheme 4. Loading of auxiliary 1.
3.
Br
SH
3
4
C8F17
NaH, 3 h, 0 °C, FSPE
auxiliary 1 was first converted to the crotonate and acrylate esters,
8 and 9, respectively (Scheme 4).
58% overall
Scheme 1. En route to the fluorous-tagged auxiliary 1.
The SmI2-mediated coupling of 8 and 9 with a range of alde-
hydes was then studied (Table 1). Couplings of crotonate 8 with
a range of aldehydes proceeded in moderate to good yield and with
excellent diastereo- and enantioselectivity (97–99% ee) to give
cis-lactones 10–14. Reductive couplings of acrylate 9 also pro-
ceeded to give lactones 15–17 in good yield but with slightly lower
enantioselectivity (82–88% ee). The tagged auxiliary 1 was re-
covered from the crude product mixtures by FSPE (approx. 70%)
and reused. We have previously observed that lower enantiose-
lectivities are often obtained with acrylate substrates bearing an
ephedrine auxiliary6 (Table 1).
To form the spacer and the phase tag unit, 4-bromobenzalde-
hyde was reacted with phosphonium bromide 3 to give almost
exclusively the cis-alkene. Rhodium on carbon-mediated hydro-
genation of the double bond and reaction with commercially
available 1H,1H,2H,2H-perfluorodecane thiol and NaH gave the
tagged thioether 4 in good overall yield after rapid purification by
FSPE. For the remainder of the synthesis, FSPE was used to conve-
niently purify all intermediates. The fluorous tag therefore has an
additional role in that it facilitates the synthesis of the auxiliary by
allowing purification of intermediates without recourse to con-
ventional chromatography.
Interestingly, the successful use of cyclopropane carbox-
aldehyde in the reductive coupling to give 14 appears to confirm
Lithium magnesiate exchange13 reaction of 4 and subsequent
coupling with Weinreb amide 2 gave phenylketone 5. Addition of
PhMgBr then gave protected auxiliary 6 as a single diastereoisomer
in 61% overall yield for three steps. Finally, deprotection of 6 gave
the new, fluorous-tagged auxiliary 1 in excellent yield (Scheme 2).
The stereochemistry of 1 was confirmed indirectly by the se-
quential addition of phenylmagnesium bromide and 4-bromo-
phenylmagnesium bromide to 2, followed by TBAF deprotection of
the resultant secondary alcohol to give 7. X-ray crystallographic
analysis was used to confirm the stereochemical configuration of 7
and, by analogy, the configuration of 1 (Scheme 3).
that the reaction proceeds by reduction of the
a,b-unsaturated
ester to give either a dianionic intermediate 18 or a radical-an-
ionic intermediate 19 that adds to the aldehyde.2 For cyclopro-
pane carboxaldehyde, the alternative mechanism involving
reduction of the aldehyde to give a ketyl-radical anion 20 would
be expected to lead to fragmentation of the cyclopropane ring
(Scheme 5).14
Couplings of ketones and nitrones using the tagged auxiliary 1
were less successful. For example, in preliminary experiments
coupling of acetophenone with acrylate 9 gave lactone 21 in ex-
cellent yield but in only 46% ee. Similarly, coupling of nitrone 22
We next investigated the use of the fluorous-tagged diol auxil-
15
with 8, adapting the conditions of Vallee and Skrydstrup,16 gave
´
iary in the asymmetric synthesis of
mediated coupling of aldehydes and
g
a,b
-butyrolactones via the SmI2-
-unsaturated esters. Tagged
g-lactam 23 in 73% yield and 45% ee (Scheme 6).

11878
J.C. Vogel et al. / Tetrahedron 64 (2008) 11876–11883
Table 1
3. Conclusions
SmI2-mediated couplings using auxiliary 1
O
We have developed a new, fluorous-tagged chiral auxiliary
for the asymmetric, SmI2-mediated coupling of aldehydes and
-unsaturated esters. -Butyrolactones are obtained in moderate
to good isolated yield and in high enantiomeric excess. For cou-
plings using crotonate substrates, near perfect diastereocontrol is
achieved. The fluorous tag allows the auxiliary to be conveniently
recovered by fluorous solid-phase extraction (FSPE) and reused.
O
O
R2
C8F17
S
O
Ph OH
O
R1
5
a,
b
g
SmI2,t–BuOH
O
+
1
8 R1 = Me
9 R1 = H
Ph
THF, –15 °C
R2
R1
O
O
O
O
O
O
4. Experimental
4.1. General
O
13
11
12
10
a,b
51%, 98% ee
a,b
a,b
a,b
60%, 97% ee
82%,99% ee
75%, 98% ee
All solvents were dried and distilled prior to use if not stated
otherwise. All glasswares were dried before use either by heating
with a heat gun under vacuum or by drying in an oven at 110 ꢀC. Thin
layer chromatography (TLC) was carried out using silica plates and
mixtures of petroleum ether (40–60 ꢀC) and ethyl acetate. TLC plates
were visualised using UV or by staining with 0.5% potassium per-
manganate in 2.5% aqueous sodium hydrogen carbonate and drying
with a heat gun. 1H and 13C NMR were recorded in CDCl3 on a Fourier
transform spectrometer operating at 500 MHz for 1H and 125 MHz
for 13C spectra. The results are quoted in parts per million downfield
from the Me4Si standard and given in the following format for 1H
NMR:(i)numberofequivalentnuclei(byintegration);(ii)multiplicity
(s, d, t, q, quintet, sextet, etc.); (iii) coupling constants quoted in hertz;
(iv) assignment. For 13C NMR the chemical shift in parts per million
and the assignment are quoted. Proton spectra are referenced to re-
sidual CHCl3 at 7.27 ppm and carbon spectra to CDCl3 at 77.4 ppm.
Mass spectra were recorded at the University of Manchester. Infrared
spectra were obtained using a Fourier transform spectrometer. Op-
tical rotations were measured in chloroform (CHCl3) and the values
quoted in 10ꢁ1 deg cm2 gꢁ1. In a typical fluorous solid-phase extrac-
tion (FSPE), a crude product mixture containing tagged and non-
tagged organic compounds was loaded onto the fluorous silica by
usingaminimumamountoforganicsolvent(lessthan20%ofsilicagel
volume). Elution with fluorophobic solvent mix, such as 80% MeCN/
H2O or MeOH/H2O, removes non-fluorinated compounds from the
column. The column was then eluted with a fluorophilic solvent such
as MeCN or methanol, which removes tagged compounds from the
column. The fluorous silica gel could often be reused. RF¼C8F17.
O
O
O
O
O
O
O
O
17
16
15
14
a
a
a
a,b
74%, 88% ee
77%, 86% ee
60%, 82% ee
69%, 99% ee
a
Enantiomeric excesses were determined by chiral GC.
No other diastereoisomers were observed in the crude 1H NMR.
b
(a)
(b)
Sm
R1
O
O
Sm
20
R2
Sm
R1
or
O
O
O
R2
18
19
R*
R*
O
O
Sm
R2 = c–Pr
– products of radical
ring–opening
R*
R1
O
Scheme 5. Two possible mechanisms (R
*
¼ tagged chiral auxiliary).
O
O
Ph
Me
O
SmI2,t–BuOH
THF, –15 °C
21 92%
O
(46% ee)
4.1.1. (R)-(ꢁ)-Methyl mandelate12
R = H
Ph
Bn
(R)-(ꢁ)-Mandelic acid (10.0 g, 0.066 mol) was dissolved in
methanol (80 ml) in a dry two-necked round-bottomed flask fitted
with a condenser under N2 atmosphere. The mixture was cooled to
0 ꢀC using an ice bath. Thionyl chloride (1.16 g, 0.014 mol) was then
added to the reaction mixture once it had cooled to the desired
temperature. Subsequently the reaction was heated under reflux.
After 80 min, the reaction was quenched by adding water (80 ml).
The layers were separated and the aqueous layer was washed with
diethyl ether (4ꢂ100 ml). The combined organic layers were then
washed with saturated aqueous sodium hydrogen carbonate solu-
tion. Subsequently the organic layer was dried (Na2SO4) and con-
centrated in vacuo. The resultant crude mixture was then purified
by chromatography (80:20 ethyl acetate to petroleum ether as el-
uent) to give (R)-(ꢁ)-methyl mandelate (9.39 g, 0.057 mol, 86%) as
a white crystalline solid. Data was in agreement with that in the
Me
O
C8F17
+
1 (70%)
S
R
5
8 R = Me
9 R = H
Ph
Ph OH
O
SmI2, H2O
23 73%
R = Me
N
+
(45% ee)
THF, –78 °C to rT
then HCO2H, 40 °C
O
Bn
N
i–Pr
22
1 (70%)
Scheme 6. Preliminary couplings of a ketone and a nitrone.
The low enantioselectivities obtained in preliminary studies
literature. 1H NMR (500 MHz, CDCl3)
d 3.58 (1H, br s, OH), 3.78 (3H,
using ketone and nitrone substrates and tagged auxiliary 1 suggest
that these reactions may proceed via a different mechanism to
those involving aldehydes. Our current understanding is that aux-
iliary 1 gives high diastereocontrol in couplings that proceed via
mechanisms of type (a), but currently gives low diastereocontrol in
couplings of type (b) (Scheme 5).
s, OCH3), 5.20 (1H, s, PhCH(OH)CO2CH3), 7.3–7.5 (5H, m, 5ꢂArH).
4.1.2. (2R)-N-methoxy-N-methyl-(2-hydroxy-2-phenyl)-
acetamide12
HN(CH3)OMe hydrochloride (11.0 g, 0.113 mol) was dissolved in
CH2Cl2 (120 ml) in a dry three-necked round-bottomed flask fitted

J.C. Vogel et al. / Tetrahedron 64 (2008) 11876–11883
11879
with a condenser under a nitrogen atmosphere and cooled to 0 ꢀC
using an ice bath. Trimethylaluminium (56.5 ml, 2 M in hexane,
0.113 mol) was then slowly added using a syringe pump (flow rate:
70 ml/20 min). Once the addition was complete, the reaction mix-
ture was allowed to warm to room temperature and stirred for 2 h.
Subsequently, (R)-(ꢁ)-methyl mandelate (9.39 g, 0.057 mol) dis-
solved in CH2Cl2 (80 ml) was added dropwise by syringe pump
(flow rate: 70 ml/20 min). Following the addition, the solution was
heated under reflux overnight. The reaction mixture was then
poured into a 1:1 mixture of ice (125 ml) and aqueous hydrochloric
acid (125 ml, 1 M). The resultant yellow solid was dissolved using
concentrated hydrochloric acid (37%) and the aqueous layer was
washed with CH2Cl2 (2ꢂ200 ml). The combined organic layer was
dried (Na2SO4) and concentrated in vacuo. Chromatography using
an eluent system of 10:90 ethyl acetate to petroleum ether gave (2R)-N-
methoxy-N-methyl-(2-hydroxy-2-phenyl)acetamide (8.36 g, 0.043 mol,
76%) as a white, crystalline solid. Data was in agreement with that
through silica gel and concentration in vacuo gave 1-bromo-4-(5-
bromopentyl)benzene (9.45 g, 0.031 mol, 99%) as a yellow oil. 1H
NMR (500 MHz, CDCl3)
d 1.32 (2H, m, ArCH2CH2CH2), 1.47 (2H,
pentet, J¼7.8 Hz, CH2CH2Br), 1.73 (2H, pentet, J¼7 Hz, ArCH2CH2),
2.43 (2H, t, J¼7.8 Hz, CH2Br), 3.25 (2H, t, J¼7 Hz, ArCH2), 6.90 (2H, d,
J¼8.2 Hz, 2ꢂArH), 7.24 (2H, d, J¼8.2 Hz, 2ꢂArH); 13C NMR
(125 MHz, CDCl3)
d 27.8 (ArCH2CH2CH2), 30.5 (CH2CH2Br), 32.7
(ArCH2CH2), 33.8 (CH2Br), 35.2 (Ar–CH2), 119.5 (ArC–Br), 130.3
(2ꢂArCH), 131.4 (2ꢂArCH), 141.3 (ArC); m/z (CIþ mode) 306 (Mþ2
,
19%), 186 (100%), 171 (72%), 108 (20%), 89 (23%); found: (M),
303.9468. C11H14Br2 requires M, 303.9457; nmax (ATR) 2924 (]C–
H), 2855 (C–H), 1712 cmꢁ1 (C]C).
4.1.6. 1-Bromo-4-[5-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
heptadecafluorodecylsulfanyl)pentyl]benzene (4)
NaH (0.45 g, 11.2 mmol) was suspended in THF (13 ml) and the
suspension cooled to 0 ꢀC. 1H,1H,2H,2H-Perfluorodecane-1-thiol
(2.98 ml, 10.2 mmol) in THF (13 ml) was then added slowly with
vigorous stirring. The reaction was left to stir for 1 h, followed by
the addition of 1-bromo-4-(5-bromopentyl)benzene (4.00 g,
12.2 mmol) in THF (14 ml). The reaction mixture was then allowed
to warm to room temperature and left for 2 h before quenching
with water (40 ml). The aqueous layer was washed with Et2O
(3ꢂ40 ml) and the combined organic layer was dried (Na2SO4) and
concentrated in vacuo. The crude product was then purified using
fluorous solid-phase extraction (FSPE) to give 4 (7.67 g, 10.9 mmol,
in the literature. 1H NMR (500 MHz, CDCl3)
d 3.23 (6H, s, NCH3 and
OCH3), 4.30 (1H, br s, OH), 5.37 (1H, s, PhCH(OH)), 7.30–7.50 (5H, m,
5ꢂArH).
4.1.3. (2R)-tert-Butyldimethylsilanyloxy-N-methoxy-N-methyl-2-
phenylacetamide (2)12
(2R)-N-methoxy-N-methyl-(2-hydroxy-2-phenyl)acetamide (0.681 g,
3.50 mmol) and NEt3 (0.580 ml, 4.20 mmol) in CH2Cl2 (10 ml) were
cooled to 0 ꢀC. tert-Butyldimethylsilyl trifluoromethanesulfonate
(0.88 ml, 3.85 mmol) was then added and the mixture was left to
stir for 1 h. The reaction was quenched using aqueous, saturated
NaHCO3 (10 ml) and the aqueous layer was washed with CH2Cl2
(3ꢂ10 ml). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified using col-
umn chromatography (10:90 ethyl acetate and petroleum ether as
the eluent) to give 2 (0.996 g, 3.22 mmol, 92%) as a colourless oil.
Data was in agreement with that in the literature. 1H NMR
89%) as a white, waxy solid. 1H NMR (500 MHz, CDCl3)
d 1.35 (2H,
m, ArCH2CH2CH2CH2CH2S), 1.58 (4H, m, ArCH2CH2CH2CH2CH2S),
2.25 (2H, m, SCH2CH2RF), 2.48 (4H, two overlapping t, J¼7.8, 7.3 Hz,
CH2S and ArCH2), 2.64 (2H, m, SCH2CH2RF), 6.97 (2H, d, J¼8.3 Hz,
2ꢂArH), 7.32 (2H, d, J¼8.6 Hz, 2ꢂArH); 13C NMR (125 MHz, CDCl3)
d
22.6 (CH2), 28.3 (ArCH2CH2CH2), 29.7 (CH2CH2S), 30.9
(ArCH2CH2), 31.9 (SCH2CH2RF), 32.1 (SCH2CH2RF and CH2), 35.2
(ArCH2), 118.2 (ArC–Br), 130.1 (2ꢂArCH), 131.3 (2ꢂArCH), 141.3
(ArC–CH2S); m/z (EIþ mode) 704 (MHþ2 , 60%), 535 (90%), 224 (97%),
169 (100%), 145.1 (100%); found: (M), 704.0033. C21H18BrF17S re-
quires M, 704.0036; nmax (IR, neat) 2933 (C–H), 2858 (C–H), 1213
(500 MHz, CDCl3) d 0.01 (3H, s, SiCH3), 0.02 (3H, s, SiCH3), 0.81 (9H,
s, 3ꢂSiC(CH3)), 3.03 (3H, s, NCH3), 3.39 (3H, br s, OCH3), 5.49 (1H, s,
PhCH(OH)), 7.18–7.35 (5H, m, 5ꢂArH).
(strong, C–F) cmꢁ1
.
4.1.4. (Z)-1-Bromo-4-(5-bromopentyl-1-enyl)benzene
4-Bromobutyltriphenylphosphoniumbromide3(10.9 g, 0.023 mol)
was suspended in THF (50 ml) under nitrogen atmosphere. NaH
(0.547 g, 0.023 mol) was added to the mixture and the reaction was
stirred for 30 min. 4-Bromobenzaldehyde (3.50 g, 0.108 mol,
1 equiv) in THF (20 ml) was then added and the reaction mixture
stirredovernight. The mixturewasquenchedwith water(70 ml) and
the aqueous layer washed with petroleum ether (3ꢂ70 ml). The
combined organic layers were dried (Na2SO4) and concentrated in
vacuo. Purification by column chromatography (10:90 ethyl acetate
and petroleum ether as the eluent) gave (Z)-1-bromo-4-(5-bromo-
pentyl-1-enyl)benzene (4.39 g, 0.014 mol, 76%) as a colourless oil. 1H
4.1.7. (1R)-{4-[5-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluoro)decylsulfanylpentylphenyl]}-2-(tert-
butyldimethylsilanyloxy)-2-phenylethanone (5)
n-BuLi (12.7 ml, 1.99 M in hexane, 26.0 mmol) in THF (39 ml)
was added slowly to a solution of i-PrMgCl (6.53 ml, 13.0 mmol) in
THF (39 ml) at 0 ꢀC. The mixture was allowed to stir for 15 min at
0 ꢀC. Bromide 4 (7.67 g, 10.9 mmol) in THF (39 ml) was then added
to the reaction mixture and the solution was stirred for 30 min,
followed by dropwise addition of 2 (4.04 g, 13 mmol) in THF
(39 ml). The reaction mixture was then allowed to warm to room
temperature and was stirred for 2 h. The reaction was quenched
with aqueous, saturated NH4Cl (156 ml) and the aqueous layer
washed with Et2O (3ꢂ75 ml), dried (Na2SO4) and concentrated in
vacuo. The crude product was thus purified using FSPE to give 5 as
NMR (500 MHz, CDCl3)
d
2.05 (2H, pentet, J¼7 Hz, CH]
CHCH2CH2CH2Br), 2.45 (2H, m, CH]CHCH2CH2CH2Br), 3.40 (2H, t,
J¼6.7 Hz, CH2Br), 5.69 (1H, dt, J¼11.4 Hz, 7.4 Hz, ArCH]CH), 6.44
(1H, d, J¼11.4 Hz, ArCH]CH), 7.17 (2H, d, J¼8.6 Hz, 2ꢂArH), 7.5 (2H,
a clear oil that was used without further purification. [
a
]D¼þ8.2ꢀ
d, J¼8.6 Hz, 2ꢂArH); 13C NMR (125 MHz, CDCl3)
d
27.1 (CH2CH2Br),
(c¼0.018, CHCl3); 1H NMR (500 MHz, CDCl3)
d 0.00 (3H, s, SiCH3),
32.8 (CH]CHCH2), 33.1 (CH2Br), 120.6 (PhCH]CH), 127.1
(PhCH]CH), 129.4 (ArC–Br), 130.2 (2ꢂArCH), 131.0 (ArC–CH]CH),
136.1 (2ꢂArCH); m/z (EIþ mode) 304 (Mþ2 100%), 224 (10%), 197
(10%), 116 (23%); found: (M), 301.9303. C11H12Br2 requires M,
301.9300; nmax (ATR) 3010 (]C–H), 2947 (C–H), 1484 cmꢁ1 (C]C).
0.08 (3H, s, SiCH3), 0.89 (9H, s, 3ꢂSiC(CH3)), 1.37 (2H, m,
ArCH2CH2CH2), 1.57–1.65 (4H, m, ArCH2CH2CH2CH2CH2S), 2.35 (2H,
m, SCH2CH2RF), 2.52 (2H, t, J¼7.6 Hz, CH2S), 2.61 (2H, t, J¼7.5 Hz,
ArCH2), 2.71 (2H, m, SCH2CH2RF), 5.72 (1H, s, PhCH(OTBDMS)), 7.13
(2H, d, J¼8.2 Hz, 2ꢂArH), 7.23 (1H, m, ArH), 7.33 (2H, m, 2ꢂArH),
7.50 (2H, d, J¼8.2 Hz, 2ꢂArH), 7.93 (2H, d, J¼8.2 Hz, 2ꢂArH); 13C
4.1.5. 1-Bromo-4-(5-bromopentyl)benzene
NMR (125 MHz, CDCl3)
d
ꢁ5.1 (SiCH3), ꢁ4.9 (SiCH3), 18.4 (SiC(CH3)),
(Z)-1-Bromo-4-(5-bromopentyl-1-enyl)benzene (9.45 g, 0.031 mol)
was suspended in ethanol (100 ml) and rhodium on carbon
(0.472 g, 5% w/w) was added. The reaction mixture was then heated
under an atmosphere of hydrogen gas at 40 ꢀC overnight. Filtration
22.6 (SCH2CH2RF), 25.8 (3ꢂSiC(CH3)), 25.7 (ArCH2CH2CH2), 28.3
(CH2CH2S), 29.1 (ArCH2CH2), 30.5 (CH2S), 31.9 (SCH2CH2RF), 35.8
(ArCH2), 80.5 (PhCH(OTBDMS)), 125.7 (2ꢂArCH), 127.6 (ArCH),
128.1 (2ꢂArCH), 128.5 (2ꢂArCH), 130.2 (2ꢂArCH), 132.1 (ArC), 139.1

11880
J.C. Vogel et al. / Tetrahedron 64 (2008) 11876–11883
(ArC), 148.0 (ArC–C]O), 198.6 (C]O); m/z (ESþ mode) 897 (MNaþ,
90%); found: (MNaþ), 897.2056. C35H39O2F17NaSSi requires M,
897.2061; nmax (neat) 2858 (C–H), 1676 (C]O), 1678 (C]O),
Bromobenzene (2.01 ml, 0.019 mol) was added slowly with vig-
orous stirring. The reaction was allowed to warm to room tem-
perature and stirred for 2 h. An aliquot of the phenyl Grignard
solution (9.74 ml, 0.95 M in THF, 9.26 mmol) was then added
dropwise to a solution of 2 (1.91 g, 6.17 mmol) in THF (57 ml) at
0 ꢀC. The solution was left to stir for 1.5 h and then quenched with
aqueous, saturated NH4Cl (60 ml). The aqueous layer was washed
with ethyl acetate (3ꢂ60 ml) and the combined organic layers
were dried (Na2SO4) and concentrated in vacuo. The crude product
was purified using column chromatography (5:95 ethyl acetate to
petroleum ether as the eluent) to give (2R)-tert-butyldimethylsi-
lyloxy-1,2-diphenylethanone (1.41 g, 4.32 mmol, 70%) as a clear,
1212 cmꢁ1
.
4.1.8. (1R,2S)-{4-[5-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluoro)decylsulfanyl pentyl]-phenyl}-2-(tert-
butyldimethylsilanyloxy)-1,2-diphenylethanol (6)
Magnesium turnings (0.283 g, 11.8 mmol) and a small crystal of
iodine were suspended in THF (10 ml). The suspension was cooled
to 0 ꢀC and bromobenzene (1.11 ml, 10.5 mmol) was added slowly
with vigorous stirring. The reaction was allowed to warm to room
temperature. In a separate, dry round-bottomed flask, crude 5
(5.41 g, 6.20 mmol) in THF (55 ml) was cooled to 0 ꢀC and the
freshly prepared solution of phenylmagnesium Grignard added.
The solution was allowed to warm to room temperature and stirred
for 2 h. The reaction was then quenched with aqueous, saturated
NH4Cl (50 ml) and the aqueous layer was washed with Et2O
(3ꢂ50 ml). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The crude product was purified using FSPE
to give 6 (4.89 g, 5.13 mmol, 62% over two steps) as a clear, viscous
viscous oil. [
a
]D¼þ79.7ꢀ (c¼0.018, CHCl3); 1H NMR (500 MHz,
CDCl3)
d
0.00 (3H, s, SiCH3), 0.08 (3H, s, SiCH3), 0.89 (9H, s,
3ꢂSiC(CH3)), 5.74 (1H, s, PhCH(OTBDMS)), 7.25 (2H, m, 2ꢂArH),
7.34 (3H, m, 3ꢂArH), 7.45 (1H, m, ArH), 7.53 (2H, d, J¼7.8, ArH),
8.00 (2H, dd, J¼8.4, 1.2 Hz, 2ꢂArH); 13C NMR (125 MHz, CDCl3)
d
ꢁ5.1 (SiCH3), ꢁ5.0 (SiCH3), 18.3 (SiC), 25.7 (3ꢂSiC(CH3)), 80.4
(CH), 125.7 (2ꢂArCH), 127.7 (ArCH), 128.1 (2ꢂArCH), 128.5
(2ꢂArCH), 128.6 (2ꢂArCH), 132.9 (ArCH), 134.4 (ArC), 138.9 (ArC),
199.1 (C]O); m/z (CIþ mode) 327 (Mþ, 100), 269 (12%), 221 (43%),
195 (18%), 105 (10%), 90 (14%), 73 (20%); found: (M), 326.1688.
C20H26O2Si requires M, 326.1697; nmax (ATR) 2931 (]C–H), 2856,
oil. [
a
]D¼þ9.6ꢀ (c¼0.018, CHCl3); 1H NMR (500 MHz, CDCl3)
ꢁ0.02
d
(3H, s, SiCH3), 0.00 (3H, s, SiCH3), 0.78 (9H, s, 3ꢂSiC(CH3)), 1.40–1.45
(2H, m, ArCH2CH2CH), 1.57–1.70 (4H, m, ArCH2CH2CH2CH2CH2S),
2.46 (2H, m, SCH2CH2RF), 2.56 (2H, t, J¼7.6 Hz, CH2S), 2.62 (2H, t,
J¼7.3 Hz, ArCH2), 2.83 (2H, t, J¼8.5 Hz, SCH2CH2RF), 5.55 (1H, s,
PhCH(OTBDMS)), 6.96 (2H, d, J¼7.9 Hz, ArH), 7.17–7.23 (8H, m,
8ꢂArH), 7.46 (2H, m, ArH), 7.81 (2H, d, J¼7.9 Hz, ArH); 13C NMR
1681 (C]O), 1255, 1117, 616 cmꢁ1
.
4.1.11. (1R,2R)-1-(4-Bromophenyl)-2-(tert-butyldimethylsilanoxy)-
1,2-diphenylethanol
Magnesium turnings (0.100 g, 4.17 mmol) and a small crystal of
iodine were suspended in THF (5 ml). The suspension was cooled to
0 ꢀC and 1,4-dibromobenzene (0.921 g, 3.90 mmol) dissolved in
THF (3 ml) was added slowly with vigorous stirring and the re-
action allowed to warm to room temperature. (2R)-tert-Butyldi-
methylsilyloxy-1,2-diphenylethanone (0.774 g, 2.37 mmol) in THF
(8 ml) was cooled to 0 ꢀC and the solution of freshly prepared
Grignard (7.3 ml) was added. The solution was allowed to warm to
room temperature and stirred for 2 h. The reaction was then
quenched using aqueous, saturated NH4Cl (10 ml). The layers were
separated and the aqueous layer was washed with Et2O (3ꢂ10 ml).
The combined organic layers were dried (Na2SO4) and concentrated
in vacuo. Purification by column chromatography (5:95 ethyl ace-
tate and petroleum ether as the eluent) gave (1R,2R)-1-(4-bromo-
phenyl)-2-(tert-butyldimethyl-silanoxy)-1,2-diphenylethanol (0.799 g,
(125 MHz, CDCl3)
d
ꢁ5.4 (SiCH3), ꢁ4.3 (SiCH3), 17.9 (SiC(CH3)), 22.6
(SCH2CH2RF), 25.6 (3ꢂSiC(CH3)), 28.3 (ArCH2CH2CH2), 29.2
(CH2CH2S), 30.8 (ArCH2CH2), 31.9 (SCH2CH2RF), 32.3 (CH2S), 35.1
(ArCH2), 80.1 (PhCH(OTBDMS)), 80.9 (COH), 126.3–128.7 (15ꢂArCH,
ArC), 139.7 (ArC), 140.2 (ArC), 145.9 (ArC); m/z (ESꢁ mode) 953 (Mþ,
24%); found: (MNaþ), 975.2539. C41H45O2F17NaSSi requires M,
975.2530; nmax (neat) 3546 (O–H), 2931 (]C–H), 2857 (C–H), 1213,
1067 cmꢁ1
.
4.1.9. (1R,2S)-[4-(5-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluoro)decyl sulfanylpentyl)-phenyl]-1,2-
diphenylethane-1,2-diol (1)
Silyl ether 6 was dissolved in THF (49 ml) and tert-buty-
lammonium fluoride (7.64 ml, 2 M in THF) was added. After 5 min
the reaction was quenched with water (50 ml) and the aqueous
phase washed with Et2O (3ꢂ50 ml). The combined organic layers
were washed with brine (3ꢂ50 ml), dried (Na2SO4) and concen-
trated in vacuo. The crude product was then purified using FSPE to
1.659 mmol, 70%) as a white solid. [
a
]D¼24.8ꢀ (c¼0.99, CHCl3); mp
94–98 ꢀC (MeOH); 1H NMR (500 MHz, CDCl3)
d
ꢁ0.28 (3H, s, SiCH3),
0.00 (3H, s, SiCH3), 0.79 (9H, s, 3ꢂSiC(CH3)), 5.49 (1H, s, PhCH), 7.10–
7.19 (9H, m, 9ꢂArH), 7.23 (1H, dd, J¼8.5, 1.5 Hz, ArH), 7.54 (2H, d,
J¼8.5 Hz, ArH), 7.65 (2H, d, J¼8.8 Hz, ArH); 13C NMR (125 MHz,
give 1 (4.16 g, 46.7 mmol, 91%) as a viscous oil. [
a
]D¼þ23.1ꢀ
(c¼0.018, CHCl3); 1H NMR (500 MHz, CDCl3)
d
1.25–1.27 (2H, m,
CDCl3)
d
ꢁ5.2 (SiCH3), ꢁ4.2 (SiCH3), 18.0 (SiC), 25.7 (3ꢂSiC(CH3)),
ArCH2CH2CH2), 1.48 (4H, m, ArCH2CH2CH2CH2CH2S), 2.27 (2H, m,
SCH2CH2RF), 2.40–2.43 (4H, m, ArCH2CH2CH2CH2CH2S), 2.62 (2H, t,
J¼8.2 Hz, SCH2CH2RF), 5.49 (1H, s, PhCH(OH)), 6.82 (2H, d, J¼8.2 Hz,
ArH), 6.95 (4H, m, 4ꢂArH), 7.09 (2H, m, ArH), 7.21 (2H, m, ArH), 7.30
(2H, m, ArH), 7.58 (2H, d, J¼7.9 Hz, ArH); 13C NMR (125 MHz, CDCl3)
79.9 (PhCH), 80.8 (COH), 121.0 (ArC), 126.4 (ArCH), 126.7 (ArCH),
127.2 (ArCH),127.5 (ArCH), 127.6 (ArCH),128.7 (ArCH),129.0 (ArCH),
130.9 (ArCH), 139.2 (ArC), 142.6 (ArC), 144.9 (ArC); m/z (ESꢁ mode)
481 (Mꢁ, 90%), 403 (10%); found: (Mꢁ), 481.1196. C26H30O2BrSi
requires M, 481.1204; nmax (neat) 2923 (Nujol), 1584, 1085 cmꢁ1
.
d
22.6 (SCH2CH2RF), 28.5 (ArCH2CH2CH2), 29.3 (CH2CH2S), 30.9
(ArCH2CH2), 31.9 (SCH2CH2RF), 35.2 (CH2S), 35.4 (ArCH2), 78.0
(PhCH(OH)), 80.7 (COH), 126.2 (2ꢂArCH), 127.1 (2ꢂArCH), 127.3
(ArCH), 127.4 (2ꢂArCH), 127.6 (ArCH), 127.7 (2ꢂArCH), 128.2
(2ꢂArCH), 128.4 (2ꢂArCH), 139.0 (ArC), 140.8 (ArC), 140.9 (ArC),
145.2 (ArC); MS m/z (ESꢁ mode) 837 (Mꢁ, 80%), 731 (22%), 439
(23%), 269 (100%); found: (MNaþ), 861.1680. C35H31O2F17NaS re-
quires M, 861.1666; nmax (neat) 3367 (br, O–H), 2923 (]C–H), 2853
4.1.12. (1R,2R)-1-(4-Bromophenyl)-1,2-diphenylethanol (7)
(1R,2R)-1-(4-Bromophenyl)-2-(tert-butyldimethylsilanoxy)-
1,2-diphenylethanol (0.700 g, 1.45 mmol) was dissolved in THF
(7 ml) under nitrogen atmosphere. tert-Butylammonium fluoride
(2.17 ml, 2.0 M in THF) was added to the reaction, stirred for 5 min
and then quenched with water (10 ml). The aqueous phase was
washed with Et2O (3ꢂ10 ml) and the combined organic layers were
washed with brine (3ꢂ10 ml), dried (Na2SO4) and concentrated in
vacuo. The crude product was then purified by column chromatog-
raphy (10:90 ethyl acetate and petroleum ether as the eluent) to give
(C–H), 1460, 1041 cmꢁ1
.
4.1.10. (2R)-tert-Butyldimethylsilyloxy-1,2-diphenylethanone
Magnesium turnings (0.518 g, 0.0216 mol) and a small crystal of
iodine were suspended in THF (20 ml) and cooled to 0 ꢀC.
7 (0.51 g, 1.37 mmol, 95%) as a white solid. [
a
]D¼142.3ꢀ (c¼0.99,
CHCl3); mp 142–145 ꢀC (MeOH); 1H NMR (500 MHz, CDCl3)
d 5.45

J.C. Vogel et al. / Tetrahedron 64 (2008) 11876–11883
11881
(1H, s, PhCH), 6.94 (2H, d, J¼7.3 Hz, 2ꢂArH), 7.00–7.10 (9H, m,
4.2. General procedure
9ꢂArH), 7.42 (3H, m, 3ꢂArH); 13C NMR (125 MHz, CDCl3)
d 77.9
(PhCH), 80.8 (COH), 121.4 (ArC), 126.2 (ArCH), 127.0 (ArCH), 127.6
(ArCH), 127.8 (ArCH), 127.9 (ArCH), 128.0 (ArCH), 129.1 (ArCH), 131.4
(ArCH), 138.7 (ArC), 143.0 (ArC), 144.3 (ArC); m/z (ESꢁ mode) 481
(Mꢁ, 90%), 403 (10%); Found: (Mꢁ), 481.1196. C26H30O2BrSi requires
SmI2-mediated coupling of aldehydes with 8 or 9 to give
-butyrolactones.
g
To a solution of samarium(II) iodide (0.1 M in THF, 2.2 equiv)
under nitrogen atmosphere at ꢁ15 ꢀC was added dropwise
a mixture of aldehyde (1 equiv), t-BuOH (6 equiv) and 8/9 (1 equiv)
dissolved in THF. The dark blue reaction was stirred for 5 h. The
reaction was quenched with aqueous, saturated NaCl solution
(5 ml) and the aqueous phase was washed with Et2O (3ꢂ5 ml).
The combined organic layers were dried (Na2SO4) and concen-
trated in vacuo. The crude was purified by FSPE to give the lactone
product.
M, 481.1204; nmax (neat) 3427 (br, O–H), 2923 (C–H), 704 cmꢁ1
.
4.1.13. Crotonic acid (1S,2R)-1-{4-[5-(4,4,5,5,6,6,7,7,8,8,9,
9,10,10,11,11,11-heptadecafluoro-undecylsulfanyl)-
pentyl]-phenyl}-1,2-diphenyl (8)
(1R,2S)-[4-(5-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluoro)
decylsulfanylpentyl)-phenyl]-1,2-diphenylethane-1,2-diol 1 (0.73 g,
0.87 mmol), triethylamine (0.17 ml, 1.1 mmol), 4-N-dimethylami-
nopyridine (cat.) and trans-crotonic anhydride (0.175 ml, 1.1 mmol)
in CH2Cl2 (8 ml) were stirred overnight. The product mixture was
washed with aqueous, saturated NaHCO3 (3ꢂ10 ml). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo. The
crude product was purified by FSPE to give 8 (0.599 g, 0.66 mmol,
For the synthesis of the racemic lactone standards for de-
termination of enantiomeric excess using chiral GC, methyl acrylate
and methylcrotonate were used in the above procedure.
4.2.1. (4R,5S)-5-Isopropyl-4-methyl dihydrofuran-2-one6 (10)
See general procedure: the reaction of isobutyraldehyde
(0.017 ml, 0.18 mmol, 1 equiv) with 8 (0.165 g, 0.18 mmol, 1 equiv)
gave, after FSPE, (4R,5S)-5-isopropyl-4-methyl dihydrofuran-2-one
10 (19.1 mg, 75%, 98% ee) as a clear oil. Data is in agreement with
78%) as a white solid. [
a
]D¼90.9ꢀ (c¼0.018, CHCl3); mp 143–145 ꢀC
(MeOH); 1H NMR (500 MHz, CDCl3)
d 1.27–1.29 (2H, m,
ArCH2CH2CH2), 1.50 (4H, m, ArCH2CH2CH2CH2CH2S), 1.75 (3H, dd,
J¼6.6, 1.9 Hz, C(O)CH]CHCH3), 2.29 (2H, m, SCH2CH2RF), 2.42–2.47
(4H, m, ArCH2CH2CH2CH2CH2S), 2.64 (2H, m, SCH2CH2RF), 5.73 (1H,
dd, J¼15.4, 1.9 Hz, C(O)CH]CHCH3), 6.59 (1H, s, PhCH), 6.80–6.87
(3H, m, 2ꢂArH, C(O)CH]CHCH3), 6.97 (2H, m, ArH), 7.03 (2H, m,
ArH), 7.08 (2H, m, ArH), 7.18 (2H, m, ArH), 7.26 (2H, m, ArH), 7.46
that in the literature. 1H NMR (500 MHz, CDCl3)
d 0.91 (3H, d,
J¼6.6 Hz, CH3CHCH3), 1.00 (3H, d, J¼7.0 Hz, CH3CHCH2), 1.09 (3H,
d, J¼6.5 Hz, CH3CHCH3), 1.86–1.93 (1H, m, CH(CH3)2), 2.21 (1H, dd,
J¼16.9 Hz, 1.1 Hz, 1H from CH2C]O), 2.53–2.58 (1H, m,
CHCH2C]O), 2.74 (1H, dd, J¼16.9 Hz, 7.4 Hz, 1H from CH2C]O),
3.94 (1H, dd, J¼10.2 Hz, 4.8 Hz, CHO).
(2H, d, J¼8.2 Hz, ArH); 13C NMR (125 MHz, CDCl3)
d 18.0
(CH3CH]CHC(O)O), 22.6 (SCH2CH2RF), 28.3 (ArCH2CH2CH), 29.2
(CH2CH2S), 30.8 (ArCH2CH2), 32.1 (SCH2CH2RF), 32.2 (CH2S), 35.2
(ArCH2), 78.3 (PhCH), 80.3 (COH), 122.2 (OC(O)CH]CHCH3), 126.3
(ArCH), 126.5 (ArCH), 127.2 (ArCH), 127.3 (ArCH), 127.4 (ArCH), 127.8
(ArCH), 128.2 (ArCH), 128.5 (ArCH), 136.2 (ArC), 140.4 (ArC), 141.1
(ArC), 144.9 (ArC), 145.9 (OC(O)CH]CHCH3), 165.2 (OC]O); m/z
(ESþ mode) 929 (MNa, 100%), 928 (45%), 924 (20%); found: (MNaþ),
929.1931. C39H35O3F17NaS requires M, 929.1928; nmax (neat) 2929,
4.2.2. (S)-5-tert-Butyl-4-methyl dihydrofuran-2-one6 (11)
See general procedure: the reaction of pivaldehyde (0.02 ml,
0.18 mmol, 1 equiv) with 8 (0.165 g, 0.15 mmol, 1 equiv) gave,
after FSPE, (4R,5S)-tert-butyl-4-methyl dihydrofuran-2-one 11
(17.2 mg, 60%, 97% ee) as a clear oil. Data is in agreement with
that in the literature. 1H NMR (500 MHz, CDCl3)
d 1.08 (9H, s,
C(CH3)3), 1.14 (3H, d, J¼7.1 Hz, CH3CH), 2.20 (1H, dd, J¼16.6,
1.6 Hz, 1H from CH2C]O), 2.64–2.69 (1H, m, CHCH2C]O), 2.76
(1H, dd, J¼16.6, 7.6 Hz, 1H from CH2C]O), 4.09 (1H, d, J¼4.9 Hz,
CHO).
1685 (C]O), 1204 (C–F) cmꢁ1
.
4.1.14. Acrylic acid (1S,2R)-1-{4-[5-(4,4,5,5,6,6,7,7,8,8,9,
9,10,10,11,11,11-heptadecafluoro-undecylsulfanyl)-
pentyl]-phenyl}-1,2-diphenyl (9)
4.2.3. (4R,5S)-5-Cyclohexyl-4-methyl dihydrofuran-2-one6 (12)
See general procedure: the reaction of cyclohexyl carbox-
aldehyde (0.02 ml, 0.15 mmol, 1 equiv) with 8 (0.135 g, 0.15 mmol,
1 equiv) gave, after FSPE, (4R,5S)-5-cyclohexyl-4-methyl dihy-
drofuran-2-one 12 (17.5 mg, 82%, 99% ee) as a clear oil. Data is in
agreement with that in the literature. 1H NMR (500 MHz, CDCl3)
(1R,2S)-[4-(5-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadeca-
fluoro)decylsulfanylpentyl)-phenyl]-1,2-diphenylethane-1,2-diol 1
(0.13 g, 0.16 mmol), triethylamine (0.03 ml, 0.25 mmol) and
acryloyl chloride (0.02 ml, 0.22 mmol) in CH2Cl2 (2 ml) was stirred
overnight. The reaction mixture was diluted with CH2Cl2 (5 ml) and
washed with aqueous, saturated NaHCO3 (3ꢂ5 ml). The combined
organic layers were dried (Na2SO4) and concentrated in vacuo.
Purification using FSPE gave 9 (0.094 g, 0.11 mmol, 65%) as a white
d
0.83–0.92 (1H, m, 1H of CH2 of cyclohexane ring), 0.95 (3H, d,
6.9 Hz, CH3CH), 0.99–1.00 (1H, m, 1H of CH2 of cyclohexane ring),
1.07–1.22 (2H, m, CH2 of cyclohexane ring), 1.53–1.58 (3H, m, CH2
and 1H of CH2 of cyclohexane ring), 1.62–1.71 (4H, m, 2ꢂCH2 of
cyclohexane ring),1.96–2.00 (1H, m, 1H of CH2 of cyclohexane ring),
2.12 (1H, dd, J¼16.9 Hz,1.1 Hz, 1H from CH2C]O), 2.47–2.50 (1H, m,
CHCH2C]O), 2.65 (1H, dd, J¼16.9, 7.4 Hz, 1H from CH2C]O), 3.95
(1H, dd, J¼9.8, 4.7 Hz, CHO).
solid. [
a
]D¼81.9ꢀ (c¼0.018, CHCl3); mp 147–150 ꢀC (MeOH); 1H
NMR (500 MHz, CDCl3) d 1.27–1.31 (2H, m, ArCH2CH2CH2), 1.50 (4H,
m, ArCH2CH2CH2CH2CH2S), 2.29 (2H, m, SCH2CH2RF), 2.43–2.47
(4H, m, ArCH2CH2CH2CH2CH2S), 2.64 (2H, m, SCH2CH2RF), 5.80 (1H,
d, J¼10.7 Hz, C(O)CH]CHH), 6.00 (1H, dd, J¼17.0, 10.7 Hz,
C(O)CH]CH2), 6.25 (1H, d, J¼17.0 Hz, C(O)CH]CHH), 6.64 (1H, s,
PhCH), 6.87 (2H, m, ArH), 6.98 (2H, m, ArH), 7.04 (2H, m, ArH), 7.11
(2H, m, ArH), 7.20 (2H, m, ArH), 7.27 (2H, m, ArH), 7.47 (2H, d,
4.2.4. (4R,5S)-5-n-Butyl-4-methyl dihydrofuran-2-one6 (13)
See general procedure: the reaction of valeraldehyde (0.02 ml,
0.18 mmol, 1 eq.) with 8 (0.165 g, 0.18 mmol, 1 equiv) gave, after
FSPE, (4R,5S)-5-n-butyl-4-methyl dihydrofuran-2-one 13 (14.4 mg,
51%, 98% ee) as a clear oil. Data is in agreement with that in the
J¼7.9 Hz, ArH); 13C NMR (125 MHz, CDCl3)
d 22.6 (SCH2CH2RF), 28.3
(ArCH2CH2CH2), 29.2 (CH2CH2S), 30.8 (ArCH2CH2), 32.1
(SCH2CH2RF), 32.2 (CH2S), 35.2 (ArCH2), 78.7 (PhCH), 80.2 (COH),
126.3 (ArCH), 126.5 (ArCH), 127.3 (ArCH),127.4 (ArCH), 127.8 (ArCH),
127.9 (ArCH), 128.0 (C(O)CH]CH2), 128.2 (ArCH), 128.4 (ArCH),
131.6 (C(O)CH]CH2), 135.9 (ArC), 140.3 (ArC), 141.2 (ArC), 144.6
(ArC), 164.9 (OC]O); m/z (ESþ mode) 915 (MNa, 65%), 914 (100%),
921 (10%); found: (MNaþ), 915.1755. C38H33O3F17NaS requires M,
literature. 1H NMR (500 MHz, CDCl3)
d
0.93 (3H, t, J¼7.3 Hz,
CH3CH2), 0.93 (3H, d, J¼7.0 Hz, CHCH3), 1.36–1.42 (3H, m, CH2),
1.45–1.58 (2H, m, CH2), 1.61–1.70 (1H, m, 1H of CH2), 2.21 (1H, dd,
J¼16.9, 3.9 Hz, 1H from CH2C]O), 2.54–2.63 (1H, m, CHCH2C]O),
2.70 (1H, dd, J¼16.9, 7.8 Hz, 1H from CH2C]O), 4.41–4.46 (1H,
m, CHO).
915.1771; nmax (neat) 2929, 1701 (C]O), 1204 (C–F) cmꢁ1
.

11882
J.C. Vogel et al. / Tetrahedron 64 (2008) 11876–11883
4.2.5. (4R,5S)-5-Cyclopropyl-4-methyl dihydrofuran-
2(3H)-one (14)
See general procedure: the reaction of cyclopropane carbox-
aldehyde (0.007 ml, 0.0933 mmol, 1 equiv) with
ꢁ78 ꢀC and the solution added to SmI2 (6.40 ml, 1.0 M in THF,
0.64 mmol) at ꢁ78 ꢀC. The reaction was kept at ꢁ78 ꢀC for 4 h
and subsequently allowed to warm to room temperature and left
overnight. The reaction was quenched with saturated Na2S2O3
solution (5 ml), the aqueous layer was washed with Et2O
(3ꢂ5 ml) and the combined organic layers were washed with
saturated, aqueous NaCl solution (3ꢂ5 ml), dried (Na2SO4), fil-
tered and concentrated in vacuo. The resultant crude mixture was
dissolved in THF (3 ml) and formic acid (0.1 ml) was added. The
reaction was stirred for 3 h at 40 ꢀC and quenched with saturated,
aqueous NaHCO3 solution (5 ml). The aqueous layer was washed
with Et2O (3ꢂ5 ml) and the combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The crude mixture was
purified by FSPE to give cis-1-benzyl-5-isopropyl-4-methyl-
pyrrolidin-2-one (0.0152 g, 0.0658 mmol, 73%, 45% ee) as a clear
8 (0.0845 g,
0.0933 mmol, 1 equiv) gave, after FSPE, (4R,5S)-5-cyclopropyl-4-
methyldihydrofuran-2(3H)-one 14 (9.0 mg, 69%, 99% ee) as a clear
oil. 1H NMR (500 MHz, CDCl3)
d 0.29 (1H, m, 1H of cyclopropyl CH2),
0.46 (1H, m, 1H of cyclopropyl CH2), 0.64 (1H, m, 1H of cyclopropyl
CH2), 0.71 (1H, m, 1H of cyclopropyl CH2), 1.00 (1H, m, CH of
cyclopropyl), 1.19 (3H, d, J¼6.9 Hz, CH3), 2.29 (1H, m, 1H from
CH2C]O), 2.68 (2H, m, 1H from CH2 and CHCH3), 3.94 (1H, dd,
J¼9.1, 6.0 Hz, CHO); 13C NMR (125 MHz, CDCl3)
d 0.0 (CH2 of
cyclopropyl), 1.8 (CH2 of cyclopropyl), 8.4 (CH of cyclopropyl), 12.9
(Me), 31.8 (CHMe), 35.2 (C(O)CH2), 86.8 (CHO), 175.1 (C]O); m/z
(ESþ mode) 141 (MHþ, 70%), 123 (10%), 109 (10%), 83 (15%), 69
(15%); found: (M), 140.0836. C8H12O2 requires M, 140.0832; nmax
oil. 1H NMR (500 MHz, CDCl3)
d
0.88 (3H, d, J¼7.0 Hz, CHCH3),
(neat) 2938, 1712 (C]O) cmꢁ1
.
0.97 (3H, d, J¼7.2 Hz, CHCH3), 1.03 (3H, d, J¼6.9 Hz, CHCH3), 1.97
(1H, m, CH(CH3)2), 2.18 (1H, m, C(O)CHH), 2.34–2.44 (2H, m,
C(O)CHH, CHMe), 3.22 (1H, dd, J¼7.9, 2.4 Hz, CHN), 3.83 (1H, d,
J¼15.1 Hz, PhCHH), 5.20 (1H, d, J¼15.1 Hz, PhCHH), 7.14 (2H, d,
J¼7.2 Hz, 2ꢂArH), 7.19 (1H, m, ArH), 7.25 (2H, m, 2ꢂArH); 13C
4.2.6. (S)-5-tert-Butyl dihydrofuran-2-one6 (15)
See general procedure: the reaction of pivaldehyde (0.02 ml,
0.18 mmol, 1 equiv) with 9 (0.134 g, 0.15 mmol, 1 equiv) gave, after
FSPE, (S)-5-tert-butyl dihydrofuran-2-one 15 (17.2 mg, 60%, 82% ee)
as a clear oil. Data is in agreement with that in the literature. 1H
NMR (125 MHz, CDCl3)
d 15.2 (Me), 18.0 (CHCH3 of i-Pr), 21.4
(CHCH3 of i-Pr), 29.1 (CHMe), 32.7 (CH(CH3)2), 38.8 (C(O)CH2),
45.7 (PhCH2), 64.4 (CHN), 127.4 (ArCH), 127.9 (2ꢂArCH), 128.6
(2ꢂArCH), 136.8 (ArC), 175.6 (C]O); m/z (CIþ mode), 232 (Mþ,
100%), 187 (20%), 90 (10%); found: (Mþ), 232.1692. C15H22ON re-
quires M, 232.1696; nmax (neat) 2932 (C–H), 2360, 1734,
NMR (500 MHz, CDCl3)
d
0.95 (9H, s, 3ꢂ(CH3)C), 1.94–2.02 (1H, m,
1H from CH2), 2.08–2.16 (1H, m, 1H from CH2), 2.50–2.55 (2H, m,
CH2C]O), 4.19 (1H, dd, J¼6.9 Hz, 8.8 Hz, CHO).
4.2.7. (S)-5-Cyclohexyl dihydrofuran-2-one6 (16)
1423 cmꢁ1
.
See general procedure: the reaction of cyclohexane carbox-
aldehyde (0.02 ml, 0.18 mmol, 1 equiv) with 9 (0.134 g, 0.15 mmol,
1 equiv) gave, after FSPE, (S)-5-cyclohexyl dihydrofuran-2-one 16
(23.3 mg, 77%, 86% ee) as clear oil. Data is in agreement with that in
Acknowledgements
We thank the University of Manchester and Novartis (student-
ship to J.C.V.) and Dr. Glynn Williams for preliminary studies on the
synthesis of 1.
the literature. 1H NMR (500 MHz, CDCl3)
d 1.00–1.06 (2H, m, CH2),
1.16–1.29 (2H, m, CH2), 1.51–1.57 (2H, m, CH2), 1.65–1.72 (2H, m,
CH2), 1.76–1.80 (2H, m, CH2), 1.90–1.98 (2H, m, 1H from
CH2CH2C]O and 1H from CH2), 2.25 (1H, apparent sextet, J¼6.7 Hz,
1H from CH2CH2C]O), 2.50–2.54 (2H, m, CH2C]O), 4.14 (1H, dt,
J¼7.4, 8.0 Hz, CHO).
References and notes
1. For recent reviews on the use of samarium(II) iodide in organic synthesis: (a)
Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307–338; (b) Molander, G. A.;
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4.2.8. (5S)-5-Cyclopentyl dihydrofuran-2(3H)-one (17)
See general procedure: the reaction of cyclopentane carbox-
aldehyde (0.001 ml, 0.0952 mmol, 1 equiv) with
9 (0.085 g,
0.0952 mmol, 1 equiv) gave, after FSPE, (5S)-5-cyclopentyl dihy-
drofuran-2(3H)-one (10.8 mg, 74%, 88% ee) as a clear oil. 1H NMR
(500 MHz, CDCl3)
CH2), 2.23 (1H, m, 1H of CH2), 2.47 (2H, m, CH2C]O), 4.25 (1H, m,
CHO); 13C NMR (125 MHz, CDCl3)
25.4 (CH2 of cyclopentyl), 25.5
d 1.20–1.99 (10H, m, cyclopentyl group, 1H of
d
(CH2 of cyclopentyl), 27.1 (CH2CH2C]O), 29.1 (CH of cyclopentyl),
29.2 (CH2 of cyclopentyl), 29.4 (CH2 of cyclopentyl), 44.8 (CH2C]O),
84.9 (CHO), 177.5 (C]O); m/z (Clþ mode) 155 (MHþ, 100%), 136
(10%), 108 (10%), 84 (25%), 64 (10%); found: (M), 154.0986. C9H14O2
requires M, 154.0988; nmax (neat) 2976, 1724 (C]O) cmꢁ1
.
4.2.9. (5S)-5-Methyl-5-phenyl dihydrofuran-2(3H)-one6 (21)
See general procedure: the reaction of acetophenone (0.013 ml,
0.011 mmol, 1 equiv) with 9 (0.0978 g, 0.011 mmol, 1 equiv) gave,
after FSPE (5S)-5-methyl-5-phenyldihydrofuran-2(3H)-one 21
(17.2 mg, 97%, 46% ee) as a clear oil. Data is in agreement with that
´
Zhang, W. Tetrahedron 2003, 59, 4475–4489.
10. Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069–9072.
11. For examples of the use of Braun’s auxiliary, see: (a) Braun, M.; Mai, B.; Ridder,
D. Eur. J. Org. Chem. 2001, 16, 3155–3160; (b) Braun, M. Angew. Chem., Int. Ed.
1996, 35, 519–522; (c) Sacha, H.; Waldmueller, D.; Braun, M. Chem. Ber. 1994,
127, 1959–1968; (d) Braun, M. Angew. Chem. 1987, 99, 24–37; (e) Devant, R.;
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in the literature. 1H NMR (500 MHz, CDCl3)
d 1.66 (3H, s, CH3C),
2.31–2.62 (4H, m, CH2CH2C]O), 7.21–7.31 (5H, m, ArH).
4.2.10. (4R,5R)-1-Benzyl-5-isopropyl-4-methylpyrrolidin-
2-one (23)
N-Benzyl-N-[(1Z)-2-methylpropylidene]amine oxide 22 (0.040 g,
0.22 mmol),
8 (0.0825 g, 0.091 mmol) and degassed water
(0.06 ml, 3.19 mmol) were dissolved in THF (3 ml), pre-cooled to

J.C. Vogel et al. / Tetrahedron 64 (2008) 11876–11883
11883
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6211–6214; (c) Molander, G. A.; McKie, J. A. J. Org. Chem.1991, 56, 4112–4120; (d)
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