Expanding the scope of the organocatalytic addition of fluorobis(phenylsulfonyl)methane to enals: Enantioselective cascade synthesis of fluoroindane and fluorochromanol derivatives

Article abstract of DOI:10.1002/adsc.201300703

Highly enantioselective cascade reactions for the synthesis of fluoroindanes and chromanols derivatives are described. The cascade reactions consisted of either a double Michael reaction or Michael- hemiacetal formation via the addition of fluorobis( phenylsulfonyl)methane (FBSM) to enals. The final products were obtained in good yields with excellent stereoselectivities.

Full text of DOI:10.1002/adsc.201300703

FULL PAPERS
DOI: 10.1002/adsc.201300703
Expanding the Scope of the Organocatalytic Addition of Fluoro-
bis(phenylsulfonyl)methane to Enals: Enantioselective Cascade
Synthesis of Fluoroindane and Fluorochromanol Derivatives
Young Sug Kim,+a,b Sun Min Kim,+a,b Bing Wang,a,c Xavier Companyꢀ,a Jing Li,c
a
d
e
b,
ˇ
ˇ
Albert Moyano, Seoyoung Im, Zdenek Tosner, Jung Woon Yang, *
and Ramon Riosa,f,*
a
Department de Quꢁmica Orgꢂnica, Universitat de Barcelona, Martꢁi Franquꢃs 1-11, 08028 Barcelona, Spain
Department of Energy Science, Sungkyunkwan University, Suwon 440-746, Korea
b
E-mail: jwyang@skku.edu
c
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University Tianjin, Tianjin 30007,
Peopleꢄs Republic of China
Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea
Laboratory of NMR Spectroscopy, Charles University in Prague, Faculty of Science, Albertov 6, 128 43 Praha 2, Czech
d
e
Republic
f
School of Chemistry, University of Southampton, Southampton, SO171BJ, U.K.
E-mail: R.Rios-Torres@southampton.ac.uk
+
These authors contributed equally to this work.
Received: August 4, 2013; Revised: November 7, 2013; Published online: January 20, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300703.
Abstract: Highly enantioselective cascade reactions final products were obtained in good yields with ex-
for the synthesis of fluoroindanes and chromanols cellent stereoselectivities.
derivatives are described. The cascade reactions con-
sisted of either a double Michael reaction or Mi-
chael–hemiacetal formation via the addition of fluo- Keywords: enantioselectivity; fluorine; indanes; Mi-
robis(phenylsulfonyl)methane (FBSM) to enals. The chael reaction; organocatalysis
Introduction
enantioselective construction of complex molecules
from readily available precursors via simple synthetic
Since the rediscovery of proline as a catalyst for aldol routes.[4] For example, a variety of tandem organoca-
reactions by List, Barbas, and Lerner in 2000[1] and talytic reactions for cyclopropanation[5] and aziridina-
the subsequent development of iminium catalysis by tion,[6] as well as Michael–aldol,[7] Michael–Michael,[8]
MacMillan,[2] organocatalysis has emerged as a power- and Michael–a-alkylation reactions[9] have been de-
ful tool in organic synthesis.[3]
veloped with excellent results.
Over the past few years, several research groups
The success of fluorination to improve molecular
have worked to develop new and powerful methodol- properties has been convincingly demonstrated in
ogies for the syntheses of complex molecules in high a wide range of applications. In many cases, the small,
yields with excellent enantioselectivity in a metal-free highly electronegative fluorine atom is introduced fol-
environment. Moreover, combining two or more orga- lowing a particular rationale, based on our under-
nocatalytic reactions into a single protocol has been standing of the effects of fluorination.[10] In the area
introduced as a challenging goal to alleviate the need of life sciences, well-known effects that include en-
for costly protecting groups and time-consuming pu- hancement of metabolic stability, conformational sta-
rification procedures with individual reaction steps. bilization, and modifications of reactive functional
To address these issues, tandem, domino, cascade, or groups give rise to enhanced central nervous system
multicomponent one-pot organocatalytic reactions (CNS) penetration or lipophilicity. Importantly, these
have been utilized for the efficient diastereo- and effects cannot be considered individually as usually
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Young Sug Kim et al.
Intrigued by the highly enantioselective synthesis of
fluorine compounds[16] and encouraged by our previ-
ous experience in the synthesis of fluorine com-
pounds[17] and organocatalytic domino reactions,[18] we
envisioned an organocatalytic domino reaction that
would extend the synthetic applicability of our previ-
ously developed FBSM addition to enals.
Results and Discussion
Scheme 1. The formal fluoromethylation was reported in
2009.
First, we focused on the development of a new Mi-
chael–Michael domino process, extending the synthet-
ic utility of FBSM addition to enals.
a number of molecular properties are influenced si-
Taking into account the underlying mechanism of
multaneously.[11] For example, fluorination of an this addition (Scheme 2), we realized that several syn-
amine-containing compound to increase its metabolic thetic protocols could be possible if the generated en-
stability leads to a decrease in pKa(H) and an increase amine intermediate 6 (via conjugated addition of
in its lipophilicity, and thus, may induce strong confor- FBSM to the a,b-unsaturated iminium ion) attacked
mational effects. For this reason, the development of an appropriate electrophile. The indane core would
new enantioselective methodologies that can deliver result from the domino Michael–Michael reaction se-
fluorinated compounds, a common moiety in drug quence via the strategy shown in Scheme 2.
candidates, would be of great interest not only for
academia but also for the chemical industry.
To determine the feasibility of this cascade process,
we initially examined the efficacy of chiral organoca-
In the realm of organocatalysis, several methodolo- talysts I–III for the addition of FBSM 2 to enal-enone
gies to access fluorine compounds have been devel- 1a in toluene at room temperature. The results are
oped such as a-fluorination[12] or a-trifluoromethyla- summarized in Table 1.
tion of aldehydes.[13] In 2009, Rios, Wang, and Cꢀrdo-
Among the chiral pyrrolidine catalysts I–III, proline
va independently developed an organocatalytic gave a complicated mixture (Table 1; entry 1), and no
formal b-fluoromethylation of enals catalyzed by sec- reaction occurred when diarylprolinol TMS ether II
ondary amines with fluorobis(phenylsulfonyl)methane was employed as the organocatalyst (Table 1; entry 2).
(FBSM),[14] resulting in the formation of fluorinated Gratifyingly, diphenylprolinol TMS ether III signifi-
aldehydes with excellent results (Scheme 1).[15]
cantly increased both the chemical yield and enantio-
Scheme 2. Proposed catalytic cycle.
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Expanding the Scope of the Organocatalytic Addition
Table 1. Screening of reaction parameters.[a]
Entry
Fluorine source
Catalyst
Solvent
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
2
2
2
2
2
3
I
II
III
III
III
III
toluene
toluene
toluene
CH2Cl2
MeOH
toluene
C.M.
0
95
80
0
–
–
–
–
>20:1
>20:1
–
–
>99
>99
–
C.M.
–
[a]
General reaction conditions: 1a (0.3 mmol), 2 or 3 (0.25 mmol), catalyst I–III (20 mol%), benzoic acid as additive
(20 mol%), solvent (2.0 mL), room temperature.
[b]
[c]
[d]
Isolated yield.
Determined by H NMR of the crude mixture.
1
Determined by chiral-phase HPLC analysis. C.M.=complicated mixture.
selectivity of the desired product (Table 1; entry 3). and specific NMR spectroscopy experiments (see the
To improve the catalytic activity, the reaction condi- Supporting Information).
tions were further optimized by examining the solvent
The Michael–Michael tandem reaction led to tri-
and the fluorinating agent. Switching the solvent from substituted indane derivative 4, which featured
toluene to CH2Cl2 or MeOH gave the desired prod- a trans,trans substitution pattern (Figure 1).[20]
ucts in 80% and 0% yields, respectively (Table 1; en-
We have demonstrated that reductive desulfonyla-
tries 4 and 5). Treatment with 2-fluoro-1,3-benzodi- tion of 4a could be achieved with the Mg-MeOH-
thiole-1,1,3,3-tetraoxide 3[19] as the fluorinating agent NiBr2 system to deliver fluorinated compound 5a in
with enal-enone 1a under the optimized conditions 71% yield (Scheme 3).
generated a complicated mixture (Table 1; entry 6).
Next, we decided to study a related Michael–hemi-
After identifying suitable conditions for the Mi- acetal formation cascade reaction for the synthesis of
chael–Michael cyclization, we next explored the scope fluorochromanol derivatives. Kim[21] and Wang[22]
of this transformation, and the results are shown in have recently reported the use of ortho-
Table 2. A variety of aromatic a,b-unsaturated alde- hydroxycinnamACTHNUTRGNEaUNG ldehydes as suitable starting materials
hydes with different tethered Michael acceptors, in- for easy access to chiral chromanols via an iminium-
cluding a,b-unsaturated ketone (Table 2; entries 1–3) catalyzed Michael addition, followed by intramolecu-
and ester, were well tolerated in the intramolecular lar hemiACTHNUGRTENUNGacetal formation. Kim demonstrated the nu-
Michael–Michael cascade reaction. Extremely high cleophilic addition of malonates, nitroalkanes, and
levels of diastereoselectivity (>20:1) and enantiose- boronic acids to ortho-hydroxycinnamaldehydes 8
lectivity (99% ee) were obtained when enones were with excellent results.
used (Table 2, entries 1–4), regardless of the nature of
A proposed catalytic cycle for the Michael–hemia-
the substituents on the aromatic rings. With substrates cetal formation cascade reaction of ortho-hydroxycin-
bearing an unsaturated ester as electron-withdrawing namaldehyde 8 and FBSM 2 with chiral organocata-
group somewhat lower diastereo- and enantioselectiv- lyst III, similar to the mechanism suggested by the
ities were obtained (Table 2; entries 5 and 6).
Kim group, is shown in Scheme 4.
The stereochemical assignment of adduct 4a was
The sequence of reactions begins with the activa-
made on the basis of a uniform reaction mechanism tion of the cinnamaldehyde by the organocatalyst to
form iminium ion 9. Subsequently, the iminium ion
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Table 2. Reaction scope with substrate 1.[a]
Entry
R
Product
X
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
–
4a
4b
4c
4d
4e
4 f
Me
Me
Me
Ph
OEt
OEt
65
69
58
57
65
75
>20:1
>20:1
>20:1
>20:1
5:1
>99
>99
>99
>99
94
3-F
4-MeO
3-F
–
3-F
5:1
94
[a]
General reaction conditions: 1 (0.3 mmol), 2 (0.25 mmol), catalyst III (20 mol%), benzoic acid as additive (20 mol%), sol-
vent (2 mL), room temperature.
[b]
[c]
[d]
Isolated yield.
Determined by H NMR of the crude mixture.
1
Determined by chiral-phase HPLC analysis.
action, as previously reported by Wang, is the genera-
tion of aminal 10 from iminium ion 9 through the ad-
dition of a hydroxy group to the a,b-unsaturated imi-
nium ion, thereby trapping the organocatalyst and de-
creasing the rate of the desired reaction.
We screened different reaction conditions in order
to optimize the yield of the reaction and to avoid the
formation of 10 (see the Supporting Information). To
our delight, when ortho-hydroxycinnamaldehyde 8
was treated with FBSM 2 in the presence of catalyst
III with benzoic acid as an additive in toluene at
room temperature, the desired fluorinated chromanol
13 was produced in moderate to good yield and with
Figure 1. Relative configuration ascertained by nOe experi-
ments.
quickly reacts with FBSM through a 1,4-addition excellent enantioselectivity.
pathway to give enamine intermediate 11. After de-
To explore the substrate scope of this transforma-
protonation of the hydroxy group of ortho-hydroxy- tion, various ortho-hydroxycinnamaldehydes were ex-
cinnamaldehyde by the resulting enamine species 11 amined (Table 3). The reaction proceeded well with
and subsequent hydrolysis, cyclization provides the an
electron-withdrawing
substituent
(Table 3;
chroman-2-ol 13 and regenerates the organocatalyst. entry 4), electron-donating substituents (Table 3;
An important possible side product in this type of re- entry 5) or with different halogen substituents
(Table 3; entries 2, 3, 6–9). The desired products 15
were obtained in moderate to good yields (50–75%)
with excellent enantioselectivities (92–96% ee) and
good diastereoselectivities, regardless of the electronic
nature and sites of substituents on the aromatic ring.
A slight decrease in enantioselectivity (89% ee) was
observed with 3,5-dichlorocinnamaldehyde as the sub-
strate.
Moreover, we expanded this protocol for large-
scale preparation of compound 15a. The reaction of
ortho-hydroxycinnamaldehyde was repeated on
Scheme 3. Desulfonylation of 4a.
a 1.00 g (6.75 mmol) scale [27 times larger than the
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Expanding the Scope of the Organocatalytic Addition
Scheme 4. Proposed catalytic cycle for the Michael–hemiacetal formation cascade reaction.
Table 3. Reaction scope with substrate 14.[a]
Entry
R
Product
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
9
–
5-Cl
5-Br
5-NO2
5-Me
3-Br
4-Br
3,5-dichloro
3,5-dibromo
15a
15b
15c
15d
15e
15f
15g
15h
15i
75
67
63
56
66
65
50
55
71
4:1
5:1
4:1
7:1
3:1
4:1
5:1
7:1
6:1
92
92
93
94
96
94
95
89
95
[a]
General reaction conditions: 14 (0.25 mmol), 2 (0.25 mmol), catalyst III (20 mol%), benzoic acid as additive (20 mol%),
solvent (1 mL), room temperature.
[b]
[c]
[d]
Isolated yield.
Determined by H NMR of the crude mixture.
1
Determined by chiral-phase HPLC analysis.
experiments described in Table 3], giving the product
15a in 71% yield without any loss of enantioselectivity
(92% ee) and diastereomeric ratio (4:1 dr) (see the
Supporting Information).
As a brief demonstration of the utility of the devel-
oped methodology, we performed a simple oxidation
of hemiacetal 15a with PCC to furnish the corre-
sponding lactone 16a in 84% yield. Next, we proceed
to eliminate the 1,1’-bisACTHNURGTNE(UNG sulfone) moiety by reductive
desulfonylation with the Mg-MeOH-NiBr2 system,
which was further reductively ring-opened to give the
fluorinated product 17a in 67% yield (Scheme 5).
Scheme 5. Derivatization of 15a.
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Young Sug Kim et al.
83 mg (65%); dark yellow solid; [a]2D5: À194 (c 0.5, CHCl3,
96% ee); 1H NMR (400 MHz, CDCl3): d=10.18 (br, 1H),
7.93 (m, 2H), 7.73 (m, 1H), 7.63 (m, 5H), 7.73 (m, 1H),
7.43 (m, 2H), 7.73 (m, 1H), 7.22 (m, 1H), 7.14 (m, 1H),
7.00 (m, 2H), 4.89 (m, 1H), 4.30 (m, 1H), 3.76 (m, 1H),
3.59 (m, 1H), 3.18 (m, 1H), 2.30 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=208.1, 200.0, 171.1, 143.9, 137.4,
135.3, 134.8, 131.4, 131.4, 130.7, 128.9, 128.5, 127.3, 124.0,
114.4, 110.8, 60.3, 55.2, 55.2, 50.1, 46.2, 46.1, 41.9, 30.9;
19F NMR (376 MHz, CDCl3): d=À130.44; HR-MS (ESI):
m/z=532.1252, calcd. for C26H27FNO6S2 (M+NH4)+:
532.1264; enantiomeric excess: 99%, determined by HPLC
(Daicel Chiralpak IA, i-PrOH/hexane=10/90, UV 220 nm,
flow rate 1 mLminÀ1): major 35.7 min, minor 57.5 min.
AHCTUNGTREG(NNNU 1R,2R,3S)-5-Fluoro-3-[fluorobis(phenylsulfonyl)-
methyl]-1-(2-oxopropyl)-2,3-dihydro-1H-indene-2-carbalde-
hyde (4b): yield: 92 mg (69%); yellow foam; [a]2D5: À216 (c
1
0.5, CHCl3, 96% ee); H NMR (400 MHz, CDCl3): d=10.15
Figure 2. ORTEP drawing of compound 16a.
(br, 1H), 7.91–7.26 (m, 1H), 7.01 (m, 1H), 6.83 (m, 1H),
6.69 (m, 1H), 4.83 (m, 1H), 4.31 (m, 1H), 3.76 (m, 1H),
3.59 (m, 1H), 3.10 (m, 1H), 2.31 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=207.7, 199.7, 187.1, 136.1, 135.4,
134.9, 134.5, 131.4, 130.6, 128.9, 128.6, 114.8, 114.6, 111.1,
110.9, 55.8, 55.7, 49.8, 45.7, 45.5, 41.7, 30.2; 19F NMR
In order to elucidate the absolute configuration of
compound 16a, an X-ray diffraction analysis was per-
formed, shown in Figure 2.[23] From the X-ray struc-
ture of 16a, the single stereogenic center was unam- (376 MHz, CDCl3): d=À113.68, À130.75; HR-MS (ESI):
m/z=550.1155, calcd. for C26H26F2NO6S2 (M+NH4)+:
biguously established as having the (R)-configuration.
550.1170; enantiomeric excess: 99%, determined by HPLC
The use of the (S)-configured catalyst III leads to the
expected configuration of the product based on the
(Daicel Chiralpak IA, i-PrOH/hexane=10/90, UV 220 nm,
flow rate 1 mLminÀ1): major 28.9 min, minor 46.4 min.
proposed mechanism outlined in Scheme 4.
AHCTUNGTREG(NNUN 1S,2R,3R)-1-[Fluorobis(phenylsulfonyl)methyl]-5-me-
thoxy-3-(2-oxopropyl)-2,3-dihydro-1H-indene-2-carbalde-
hyde (4c): yield: 79 mg (58%); yellow foam; [a]2D5: À173 (c
Conclusions
1
0.5, CHCl3, 96% ee); H NMR (400 MHz, CDCl3): d=10.15
(br, 1H), 7.92 (m, 2H), 7.73 (m, 1H), 7.60 (m, 5H), 7.43 (m,
2H), 6.91 (m, 1H), 6.64 (m, 1H), 6.52 (m, 1H), 4.83 (m,
1H), 4.28 (m, 1H), 3.76 (s, 3H), 3.59 (m, 1H), 3.53 (m, 1H),
3.17 (m, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3):
d=208.0, 200.0, 160.2, 145.6, 135.2, 134.7, 131.4, 131.4, 130.6,
130.5, 128.8, 128.5, 126.9, 126.8, 113.9, 108.7, 55.8, 55.7, 55.3,
49.9, 45.8, 45.6, 41.8, 30.3; 19F NMR (376 MHz, CDCl3): d=
À130.18; HR-MS (ESI): m/z=562.1372, calcd. for
C27H29FNO7S2 (M+NH4)+: 562.1364; enantiomeric excess:
99%, determined by HPLC (Daicel Chiralpak IA, i-PrOH/
hexane=10/90, UV 220 nm, flow rate 1 mLminÀ1): major
40.1 min, minor 50.9 min.
In summary, we have developed new cascade reac-
tions for the synthesis of indanes and chromanols. Ex-
cellent stereoselectivities and moderate to good yields
were observed in the addition of FBSM to enals via
the Michael–Michael cascade reaction to afford in-
danes, as well as in the Michael–hemiacetal formation
cascade reaction to afford chromanols. Importantly,
these cascade reactions provide access to fluoro-sub-
stituted indane or chromanol derivatives in a one-pot
process.
AHCTUNGTREG(NNNU 1R,2R,3S)-5-Fluoro-3-[fluorobis(phenylsulfonyl)-
methyl]-1-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-indene-2-
carbaldehyde (4d): yield: 85 mg (57%); yellow foam; [a]2D5:
Experimental Section
1
À190 (c 0.4, CHCl3, 99% ee); H NMR (400 MHz, CDCl3):
d=10.27 (br, 1H), 8.07–8.04 (m, 2H), 7.92–7.88 (m, 2H),
7.80–7.45 (m, 11H), 7.12–7.05 (m, 1H), 6.90 (dd, J1 =2.3,
J2 =8.7 Hz, 1H), 6.74 (td, J1 =8.6, J2 =2.3 Hz, 1H), 4.89 (t,
J=6.4 Hz, 1H), 4.40 (t, J=5.0 Hz, 1H), 4.17 (dd, J1 =18.5,
J2 =9.9 Hz, 1H), 4.01–3.96 (m, 1H), 3.62 (dd, J1 =18.5, J2 =
3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=199.9, 199.1,
164.6, 137.5, 136.6, 135.4, 135.0, 133.5, 131.5, 131.4, 130.7,
130.7, 129.0, 128.7, 128.6, 128.2, 114.8, 114.6, 111.3, 111.1,
56.1 (d, JC,F =6.1 Hz), 45.8 (d, JC,F =17.2 Hz), 45.3, 42.1 (d,
General Procedure for the Michael/Michael Cascade
Reaction
Catalyst III (16 mg, 0.05 mmol), fluorobis(phenylsulfonyl)-
methane 2 (79 mg, 0.25 mmol), and benzoic acid (6.1 mg,
0.05 mmol) were added in 2 mL of toluene to a vial. Next,
substrate 1 (0.30 mmol, 1.2 equiv.) was added and the reac-
tion mixture was stirred at room temperature over 3 days.
The crude product was purified by column chromatography
on silica gel eluting with hexanes/ethyl acetate to afford the
final compound 4.
J
C,F =1.9 Hz); 19F NMR (376 MHz, CDCl3): d=À112.6 (m,
1F) À130.3 (s, 1F); HR-MS (ESI): m/z=612.6827, calcd. for
C31H28F2NO6S2 (M+NH4)+: 612.6834; enantiomeric excess:
99%, determined by HPLC (Daicel Chiralpak IB, i-PrOH/
ACHTUNGTRENNUNG
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Expanding the Scope of the Organocatalytic Addition
hexane=10/90, UV 220 nm, flow rate 1 mLminÀ1): major
24.5 min, minor 39.4 min.
Ethyl 2-{(1R,2R,3S)-3-[fluorobis(phenylsulfonyl)methyl]-
85.05 (d, J=171.5 Hz), 60.13 (d, J=1.75 Hz), 49.64, 45.43 (d,
J=19.25 Hz), 39.92, 29.98 (d, J=92.56 Hz); 19F NMR
(376 MHz, CDCl3): d=À21.87 (td, J1 =94, J2 =23.03 Hz);
HR-MS (ESI+): m/z=234.1272,calcd. for [M+H]+
C14H15O2F: 234.1056.
2-formyl-2,3-dihydro-1H-inden-1-yl}acetate
(4e):
yield:
88 mg (65%); yellow scum; [a]2D5: À134 (c 0.5, CHCl3, 94%
1
ee); H NMR (400 MHz, CDCl3): d=10.12 (m, 1H), 7.99–
7.93 (m, 2H), 7.84–7.71 (m, 2H), 7.63–7.58 (m, 2H), 7.53–
7.48 (m, 2H), 7.08–7.03 (m, 1H), 7.01–6.97 (m, 1H), 6.74– General Procedure for the Michael/Hemiacetal
6.68 (m, 1H)„ 5.15–5.10 (m, 1H), 5.0–4.95 (m, 1H), 4.85–
4.75 (m, 1H), 4.47–4.40 (m, 2H), 3.08 (dd, J1 =17.2, J2 =
5.2 Hz, 1H), 2.92 (dd, J1 =17.2, J2 =8.7 Hz, 1H) 1.48 (t, J=
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=200.7, 171.5,
147.2, 135.7, 135.3, 134.6, 131.5, 131.4, 130.1, 130.0, 130.0,
129.4, 128.8, 128.5, 114.8, 114.5, 110.6, 110.4, 61.1, 52.1 (d,
Formation Cascade Reaction
In a vial, catalyst III (16 mg, 0.05 mmol), fluorobis(phenyl-
sulfonyl)methane 2 (79 mg, 0.25 mmol), and benzoic acid
(6.1 mg, 0.05 mmol) were added in 1 mL of toluene. Next,
substrate 14 (0.25 mmol, 1.0 equiv.) was added and the reac-
tion mixture was stirred at room temperature over 3 days.
The crude product was purified by column chromatography
on silica gel eluting with hexanes/ethyl acetate to afford the
final compound 15.
J
C,F =6.5 Hz), 46.4 (d, JC,F =17.8 Hz), 42.9 (d, JC,F =2.3 Hz),
35.3, 14.1; 19F NMR (376 MHz, CDCl3): d=À113.2 (m),
129.5 (d, JH,F =9.9 Hz); HR-MS (ESI): m/z=563.1009, calcd.
for C27H25F2O7S2 (M+H)+: 563.1004; enantiomeric excess:
99%, determined by HPLC (Daicel Chiralpak IA, i-PrOH/
hexane=10/90, UV 220 nm, flow rate 1 mLminÀ1): minor
27 min, major 35 min.
(4S)-4-[Fluorobis(phenylsulfonyl)methyl]chroman-2-ol
(15a): yield: 87 mg (75%); white solid; [a]2D5: +21.16 (c 0.5,
1
CHCl3, 93% ee); H NMR (400 MHz, CDCl3): d=8.10–8.06
(m, 2H), 7.78–7.73 (m, 1H), 7.65–7.55 (m, 2H), 7.50–7.30
(m, 2H), 7.25–7.15 (m, 2H), 7.04–6.96 (m, 1H), 6.90–6.75
(m, 2H), 6.36 (t, J=7.6 Hz, 1H), 5.84 (q, J=3 Hz, 1H),
4.50–4.40 (m, 1H), 3.25–3.15 (m, 1H), 2.82–2.76 (m, 1H);
13C NMR (100 MHz, CDCl3): d=152.4, 135.0, 134.4, 131.6,
131.6, 130.1 128.6 128.5, 121.5, 121.0, 118.4, 118.3, 116.9,
116.9, 90.4, 34.2 (d, JC,F =14.9 Hz), 27.5 (d, JC,F =6.9 Hz);
19F NMR (376 MHz, CDCl3): d=À127.0 (d, JH,F =13.9 Hz);
HR-MS (ESI): m/z=463.0672, calcd. for C22H20FO6S2 (M+
H)+: 463.0680; enantiomeric excess: 93%, determined by
HPLC (Daicel Chiralpak IA, i-PrOH/hexane=10/90, UV
220 nm, flow rate 1 mLminÀ1): major 28 min, minor 34 min.
(4S)-6-Chloro-4-[fluorobis(phenylsulfonyl)methyl]chro-
man-2-ol (15b): yield: 83 mg (67%); pale yellow solid; [a]2D5:
Ethyl 2-{(1R,2R,3S)-5-fluoro-3-[fluorobis(phenylsulfonyl)-
methyl]-2-formyl-2,3-dihydro-1H-inden-1-yl}acetate
(4f):
yield: 105 mg (75%); white scum; [a]2D5: À142 (c 0.5, CHCl3,
94% ee); 1H NMR (400 MHz, CDCl3): d=10.12 (m, 1H),
7.96–7.92 (m, 2H), 7.76–7.70 (m, 2H), 7.62–7.54 (m, 4H),
7.42–7.32 (m, 2H), 7.24–6.90 (m, 4H), 4.94–4.90 (m, 1H),
4.46–4.42 (m, 1H), 3.80 (s, 3H), 3.79–3.70 (m, 1H), 3.34 (dd,
J1 =17.3, J2 =10.7 Hz, 1H), 3.05 (dd, J1 =17.3, J2 =4.1 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=199.9, 173.2, 143.6,
137.4, 135.3, 134.8, 131.4, 131.4, 130.7, 128.9, 128.5, 127.3,
124.0, 117.0, 114.4, 55.4 (d, JC,F =6.1 Hz), 51.9, 46.4 (d, JC,F
=
16.9 Hz), 43.0, 40.1; 19F NMR (376 MHz, CDCl3): d=À129.2
(d, JH,F =10 Hz); HR-MS (ESI): m/z=531.0945, calcd. for
C26H24FO7S2 (M+NH4)+: 531.0942; enantiomeric excess:
94%, determined by HPLC (Daicel Chiralpak IA, i-PrOH/
hexane=10/90, UV 220 nm, flow rate 1 mLminÀ1,): major
27 min, minor 34 min.
1
+31.16 (c 0.5, CHl3, 94% ee); H NMR (500 MHz, CDCl3):
d=8.1–8.14 (m, 2H), 7.74–7.8 (m, 1H), 7.6–7.65 (m, 2H),
7.51 (tt, J1 =7.5, J2 =1.5 Hz, 1H), 7.3–7.35 (m, 2H), 7.24–
7.27 (m, 1H), 7.19–7.24 (m, 1H), 6.93 (dd, J1 =9, J2 =3 Hz,
1H), 6.74 (broad s, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.83–5.87
(m, 1H), 4.39–4.47 (m, 1H), 3.19–3.26 (m, 1H), 2.96 (broad
s, 1H), 2.82 (dddd, J1 =14, J2 =7.5, J3 =3, J4 =1 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=151.3, 136.8, 136.2, 135.4,
Procedure for the Desulfonylation of 4a
To a well stirred solution of aldehyde (120 mg, 0.23 mmol)
in anhydrous MeOH (5 mL), Mg turnings (195 mg,
8.1 mmol) and a catalytic amount of NiBr2 were added at
08C under an argon atmosphere. After 12 h, the reaction
mixture was filtered through Celite. The residue was washed
thoroughly with MeOH. The filtrates were pooled, and the
liquid was concentrated under reduced pressure. The result-
ing residue was dissolved in EtOAc, washed with saturated
NH4Cl solution, dried over anhydrous Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure to
a residue, which was purified by column chromatography on
silica gel using a gradient eluent system (hexanes/ethyl ace-
tate=8:1 to 5:1).
135.2, 132.0, 130.0, 129.7, 129.4 129.3, 128.9, 128.8 (d, JC,F
=
4.3 Hz), 126.0, 119.8, 118.9, 90.6, 34.1 (d, JC,F =14.9 Hz), 27.3
(d, JC,F =6.6 Hz); 19F NMR (470 MHz, CDCl3): d=À127.17
(d, JH,F =22.1 Hz); HR-MS (FAB+): m/z=496.0217, calcd.
for C26H27ClFNO6S2: 496.0218; enantiomeric excess: 92%,
determined by HPLC (Daicel Chiralpak IA, i-PrOH/
hexane=15/85, UV 220 nm, flow rate 1 mLminÀ1): major
22 min, minor 27 min.
(4S)-6-Bromo-4-[fluorobis(phenylsulfonyl)methyl]chro-
man-2-ol (15c): yield: 85 mg (63%); pale yellow solid; [a]2D5:
+35.24 (c 0.5, CHCl3, 92% ee); 1H NMR (500 MHz,
CDCl3): d=8.09–8.12 (m, 2H), 7.74–7.79 (m, 1H), 7.6–7.64
(m, 2H), 7.52 (tt, J1 =7.5, J2 =1.5 Hz, 1H), 7.29–7.34 (m,
2H), 7.23–7.28 (m, 1H), 7.2–7.22 (m, 1H), 7.06 (d, J1 =9,
J2 =3 Hz, 1H), 6.88 (broad s, 1H), 6.67 (d, J=9 Hz, 1H),
5.82–5.87 (m, 1H), 4.38–4.47 (m, 1H), 3.28 (broad s, 1H),
3.17–3.25 (m, 1H), 2.81 (dddd, J1 =14, J2 =7.5, J3 =3, J4 =
1 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=151.9, 136.7,
136.1, 135.4, 135.3, 132.3, 132.2, 131.9, 129.9, 128.9, 120.3,
ACHTUNGTRENNUNG(1S,2S,3S)-5-Fluoro-3-(fluoromethyl)-1-(2-oxopropyl)-2,3-
dihydro-1H-indene-2-carbaldehyde (5a): yield: 38 mg
(71%); brownish liquid; [a]2D5: À16.20 (c 1.0, CHCl3);
1H NMR (700 MHz, CDCl3): d=9.95 (s, 1H), 7.28–7.12 (m,
4H), 4.70 (d, J=4.9 Hz, 1H), 4.64 (d, J=4.9 Hz, 1H), 3.97–
3.82 (m, 2H), 3.12–3.06 (m, 1H), 2.83–2.78 (m, 2H), 2.23 (s,
3H); 13C NMR (175 MHz, CDCl3): d=207.34, 201.34,
143.87, 139.96 (d, J=5.25 Hz), 128.09, 127.76, 124.25, 123.89,
119.4, 113.6, 90.6, 34.1 (d, JC,F =14.9 Hz), 27.3 (d, JC,F
=
Adv. Synth. Catal. 2014, 356, 437 – 446
ꢅ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
443

FULL PAPERS
Young Sug Kim et al.
6.8 Hz); 19F NMR (470 MHz, CDCl3): d=À127.08 (d, JH,F
=
7.25–7.28 (m, 1H), 7.2–7.24 (m, 1H), 6.93 (d, J=2 Hz, 1H),
6.67 (ddd, J1 =8.5, J2 =2.5, J3 =1 Hz, 1H), 6.37 (dd, J1 =8.5,
J2 =2 Hz, 1H), 5.83 (q, J=3 Hz, 1H), 4.35–4.45 (m, 1H),
3.16–3.24 (m, 2H), 2.79 (dddd, J1 =14, J2 =7.5, J3 =3, J4 =
1 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=153.5, 137.1,
136.3, 135.8, 135.3, 134.5, 131.8, 130.9, 130.8, 130.3, 130.1,
129.6, 128.9 (d, JC,F =12.3 Hz), 124.2, 122.5, 121.5, 116.3,
90.8, 34.1 (d, JC,F =15.1 Hz), 27.5 (d, JC,F =6.9 Hz); 19F NMR
(470 MHz, CDCl3): d=À66.96; HR-MS (ESI): m/z=
564.9589, calcd. for C22H18BrFO6S2Na (M+Na)+: 564.9592;
enantiomeric excess: 95%, determined by HPLC (Daicel
Chiralpak IA, i-PrOH/hexane=15/85, UV 220 nm, flow rate
1 mLminÀ1): major 18 min, minor 25 min.
22.1 Hz); HR-MS (ESI): m/z=541.9692, calcd. for
C22H18BrFNO6S2 (FAB+): 541.9692; enantiomeric excess:
92%, determined by HPLC (Daicel Chiralpak IA, i-PrOH/
hexane=15/85, UV 220 nm, flow rate 1 mLminÀ1): major
24 min, minor 28 min.
(4S)-4-[Fluorobis(phenylsulfonyl)methyl]-6-nitrochroman-
2-ol (15d): yield: 71 mg (56%); pale yellow solid; [a]2D5:
+46.68 (c 0.5, CHCl3, 94% ee); 1H NMR (500 MHz,
CDCl3): d=8.11 (d, J=8.5 Hz, 2H), 7.83–7.86 (dd, J1 =9,
J2 =2.5 Hz, 1H), 7.79 (t, J=7.5 Hz, 1H), 7.71–7.76 (m, 1H),
7.61–7.66 (m, 2H), 7.44 (t, J=7.5 Hz, 1H), 7.32–7.37 (m,
2H), 7.17–7.24 (m, 2H), 6.88 (d, J=9 Hz, 1H), 5.95 (broad
s, 1H), 4.47–4.57 (m, 1H), 3.16–3.26 (m, 1H), 2.89–2.97 (m,
1H); 13C NMR (125 MHz, CDCl3): d=159.5, 140.8, 136.7,
136.4, 135.9, 135.7, 131.9, 130.1, 130, 126.2, 126.1, 125.6,
(4S)-6,8-Dichloro-4-[fluorobis(phenylsulfonyl)methyl]-
chroman-2-ol (15h): yield: 73 mg (55%); white solid; [a]2D5:
1
35.36 (c 0.5, CHCl3, 89% ee); H NMR (500 MHz, CDCl3):
d=8.08–8.13 (m, 2H), 7.96–8.01 (m, 2H), 7.75–7.8 (m, 1H),
7.59–7.64 (m, 3H), 7.52 (tt, J1 =7.5, J2 =1.5 Hz, 1H), 7.36–
7.4 (m, 2H), 7.27–7.33 (m, 2H), 7.05 (d, J=2.5 Hz, 1H),
6.73–6.76 (m, 1H), 5.95 (broad s, 1H), 4.4–4.5 (m, 1H), 3.4
(broad s, 1H), 3.17–3.27 (m, 1H), 2.85 (dddd, J1 =14.25, J2 =
7.75, J3 =3, J4 =1 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=
147.6, 136.8, 136.1, 135.8, 135.5, 135.3, 131.9 (d, JC,F =2 Hz),
130.3, 129.9, 129.6, 129.6, 128.8 (d, JC,F =8.4 Hz), 128 (d,
119.6, 118.0, 91.3, 34.5 (d, JC,F =15.3 Hz), 28.0 (d, JC,F
=
=
6.8 Hz); 19F NMR (470 MHz, CDCl3): d=À127.66 (d, JH,F
20.7 Hz); HR-MS (ESI): m/z=530.0356, calcd. for
C22H18FNO8S2 (M+Na)+: 530.0356; enantiomeric excess:
92%, determined by HPLC (Daicel Chiralpak IA, i-PrOH/
hexane=15/85, UV 220 nm, flow rate 1 mLminÀ1): major
28 min, minor 36 min.
(4S)-4-[Fluorobis(phenylsulfonyl)methyl]-6-methylchro-
man-2-ol (15e): yield: 79 mg (66%); dark yellow solid; [a]2D5:
+25.16 (c 0.5, CHCl3, 93% ee); 1H NMR (500 MHz,
CDCl3): d=8.1–8.14 (m, 2H), 7.73–7.78 (m, 1H), 7.58–7.63
(m, 2H), 7.43 (tt, J1 =7.5, J2 =1.5 Hz, 1H), 7.24–7.28 (m,
2H), 7.15–7.2 (m, 2H), 6.75–6.79 (m, 1H), 6.68 (d, J=
8.5 Hz, 1H), 6.54 (broad s, 1H), 5.81 (q, J=3 Hz, 1H), 4.37–
4.47 (m, 1H), 3.21–3.29 (m, 1H), 2.77 (dddd, J1 =14, J2 =7.5,
J3 =3, J4 =1 Hz, 1H), 1.79 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=145.8, 132.5, 131.8, 130.5, 129.7, 127.2, 125.6,
125.5, 125.4, 125.3, 125.1, 124.0, 123.8, 113.6, 112.0, 85.9, 29.7
(d, JC,F =14.8 Hz). 23.0 (d, JC,F =6.9 Hz), 15.9; 19F NMR
(470 MHz, CDCl3): d=À127.74 (d, JH,F =23.5 Hz); HR-MS
(ESI): m/z=476.0764, calcd. for C23H21FO6S2 (FAB+):
476.0764; enantiomeric excess: 92%, determined by HPLC
(Daicel Chiralpak IA, i-PrOH/hexane=15/85, UV 220 nm,
flow rate 1 mLminÀ1): major 31 min, minor 38 min.
J
J
C,F =12 Hz), 125.7, 124.1, 120.5, 118.2, 116.1, 91.2, 34.3 (d,
C,F =14.9 Hz), 27.35 (d, JC,F =6.4 Hz); 19F NMR (470 MHz,
CDCl3): d=À66.95; HR-MS (ESI): m/z=529.9828, calcd.
for C22H17Cl2FO6S2 (FAB+): 529.9828; enantiomeric excess:
89%, determined by HPLC (Daicel Chiralpak IA, i-PrOH/
hexane=15/85, UV 220 nm, flow rate 1 mLminÀ1): major
15 min, minor 19 min.
(4S)-6,8-Dibromo-4-[fluorobis(phenylsulfonyl)methyl]-
chroman-2-ol (15i): yield: 110 mg (71%); white solid; [a]2D5:
1
33.48 (c 0.5, CHCl3, 95% ee); H NMR (500 MHz, CDCl3):
d=8.09–8.13 (m, 2H), 7.96–8.01 (t, J=2.5 Hz, 1H), 7.60–
7.65 (m, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.29–7.4 (m, 5H), 6.9–
6.92 (m, 1H), 5.93–5.98 (m, 1H), 4.41–4.56 (m, 1H), 3.35
(broad s, 1H), 3.2–3.29 (m, 1H), 2.8–2.87 (m, 1H);
13C NMR (125 MHz, CDCl3): d=148.9, 136.8, 136.1, 135.5,
135.4, 135.2, 132.1, 131.9, 131.6, 131.5, 130.3, 129.9, 129.6,
128.9, 120.9, 113.5, 113.3, 91.3, 34.3 (d, JC,F =14.8 Hz), 27.4
(d, JC,F =6.1 Hz); 19F NMR (470 MHz, CDCl3): d=À66.91;
HR-MS (ESI): m/z=619.8797, calcd. for C22H17Br2FO6S2
(FAB+): 619.8798; enantiomeric excess: 95%, determined by
HPLC (Daicel Chiralpak IA, i-PrOH/hexane=15/85, UV
220 nm, flow rate 1 mLminÀ1): major 16 min, minor 19 min.
(4S)-8-Bromo-4-[fluorobis(phenylsulfonyl)methyl]chro-
man-2-ol (15f): yield: 88 mg (65%); pale yellow solid; [a]2D5:
1
À74.40 (c 0.5, CHCl3, 94% ee); H NMR (500 MHz, CDCl3):
d=8.03–8.08 (m, 2H), 7.72–7.77 (m, 2H), 7.56–7.61 (m,
3H), 7.48 (tt, J1 =7.5, J2 =1 Hz, 1H), 7.37–7.41 (m, 2H),
7.27–7.29 (m, 1H), 7.21–7.26 (m, 2H), 6.9–6.93 (m, 1H),
6.28 (t, J=8 Hz, 1H), 5.91 (q, J=3 Hz, 1H), 4.43–4.51 (m,
1H), 3.13–3.2 (m, 1H), 2.77 (ddd, J1 =14.25, J2 =7.75, J3 =
2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=149.4, 136.9,
136.1, 135.8, 135.3, 134.8, 132.9, 131.7, 130.3, 130.2, 129.6,
128.8 (d, JC,F =6.9 Hz), 121.6, 119.3, 112.6, 91.3, 34.5 (d,
Procedure for the Oxidation of 15a
PCC (323 mg, 1.5 mmol) was added to a well stirred solution
of hemiacetal 15a (231 mg, 0.5 mmol) in anhydrous CH2Cl2
(5 mL, 0.1M) at room temperature. After 3 h, the reaction
mixture was filtered through Celite. The resulting residue
was dissolved in CH2Cl2, washed with saturated NH4Cl solu-
tion, dried over anhydrous Na2SO4, and filtered. The filtrate
was concentrated under reduced pressure to a residue,
which was purified by column chromatography on silica gel
eluting with hexanes/ethyl acetate (4:1) to afford 16a as
a white solid.
J
C,F =15.1 Hz), 27.9 (d, JC,F =6.8 Hz); 19F NMR (470 MHz,
CDCl3): d=À67.1; HR-MS (ESI): m/z=564.9589, calcd. for
C22H18BrFO6S2Na (M+Na)+: 564.9592; enantiomeric
excess: 94%, determined by HPLC (Daicel Chiralpak IA, i-
PrOH/hexane=15/85, UV 220 nm, flow rate 1 mLminÀ1):
major 20 min, minor 26 min.
(4S)-7-Bromo-4-[fluorobis(phenylsulfonyl)methyl]chro-
man-2-ol (15g): yield: 67 mg (50%); pale yellow solid; [a]2D5:
1
À24.76 (c 0.5, CHCl3, 95% ee); H NMR (500 MHz, CDCl3):
(S)-4-[Fluorobis(phenylsulfonyl)methyl]chroman-2-one
d=8.07–8.11 (m, 2H), 7.74–7.78 (m, 2H), 7.59–7.64 (m,
2H), 7.55 (tt, J1 =7.5, J2 =1.5 Hz, 1H), 7.3–7.35 (m, 2H),
(16a): yield: 193 mg (84%) white solid; [a]2D5: +53.08 (c 0.5,
1
CHCl3, 93% ee); H NMR (500 MHz, CDCl3): d=7.8–7.87
444
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Adv. Synth. Catal. 2014, 356, 437 – 446

FULL PAPERS
Expanding the Scope of the Organocatalytic Addition
(m, 2H), 7.71 (t, J=7.5 Hz, 1H), 7.48–7.54 (m, 5H), 7.27– References
7.3 (m, 2H), 7.22–7.26 (m, 1H), 7.05–7.08 (m, 1H), 6.96 (dd,
J1 =8, J2 =1 Hz, 1H), 6.9 (td, J1 =7.5, J2 =1 Hz, 1H), 4.45
(dd, J1 =12.5, J2 =9.5 Hz, 1H), 4.01 (d, J=18 Hz), 3.1 (ddd,
J1 =18, J2 =9.5, J2 =2.5 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=164.66, 152.92, 135.66, 135.43, 135.26, 135.03,
131.39 (d, J=3.9 Hz), 131.16 (d, J=2.1 Hz), 130.82, 130.29
(d, J=2.1 Hz), 129.05, 128.77, 124.19, 117.92, 114.79, 37.86
(d, J=18.1 Hz), 29.3 (d, J=7.5 Hz); 19F NMR (470 MHz,
CDCl3): d=À158.37 (td, J1 =28.2, J2 =11.84 Hz); HR-MS
(EI+): m/z=460.0447, calcd. for C22H18FO6S2 (M+H)+:
460.0451.
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Procedure for the Desulfonylation of 16a
Mg turnings (391 mg, 16.2 mmol) and NiBr2 (11.8 mg,
0.054 mmol) were added to a well stirred solution of lactone
(250 mg, 0.54 mmol) in anhydrous MeOH (20 mL) at À208C
under an argon atmosphere. After 1 h, the reaction mixture
was filtered through Celite, and the residue was washed
thoroughly with MeOH. The filtrates were pooled, and the
liquid was concentrated under reduced pressure. The result-
ing residue was dissolved in EtOAc, washed with saturated
NH4Cl solution, dried over anhydrous Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure to
a residue, which was purified by column chromatography on
silica gel eluting with hexanes/ethyl acetate (12:1) to give
17a as a colorless liquid.
Methyl (S)-4-fluoro-3-(2-hydroxyphenyl)butanoate (17a):
yield: 77 mg (67%); colorless liquid); [a]2D5: +27.48 (c 0.5,
1
CHCl3, 93% ee); H NMR (500 MHz, CDCl3): d=7.07–7.2
(m, 2H), 6.91 (t, J=7.5 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H),
6.85 (s, 1H), 4.62–4.7 (m, 1H), 4.53–4.61 (m, 1H), 3.76–3.89
(m, 1H), 3.66 (s, 3H), 3.0 (dd, J1 =17, J2 =5 Hz, 1H), 2.77
(dd, J1 =16.5, J2 =9 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d=174.31, 153.96, 128.63, 128.03, 121.38, 117.39, 86.06,
84.69, 52.3, 36.29 (d, J=4 Hz), 35.86 (d, J=19.5 Hz);
19F NMR (470 MHz, CDCl3): d=À158.37 (td J1 =28.2, J2 =
11.8 Hz); HR-MS (FAB+): m/z=235.0746, calcd. for
C11H13FO3Na [M+Na]+: 235.0747.
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Acknowledgements
A.M. and R.R. thank the Spanish Ministry of Science and In-
novation (MICINN) for financial support (Project AYA2009-
13920-C02-02). X.C. thanks MICINN for a predoctoral fel-
lowship. B.W. is grateful to the China Scholarship Council
for a fellowship. J.W.Y. thanks the NRF Nano·Material Tech-
nology Development Program (2012M3A7B4049652) and
the NRF Basic Science Research Program (2009-0094023)
for financial support. This work has been done under the
auspices of COST Action CM0905 (ORCA). R.R. is thankful
for financial support from European Regional Development
Fund (ERDF) (AI-Chem & InterReg IVb).We would like to
thank the referee for a comment that pointed out our atten-
tion to determine the relative configuration of compound 4a.
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ꢅ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 437 – 446