One-pot catalytic asymmetric cascade synthesis of cycloheptane derivatives

Article abstract of DOI:10.1002/chem.200701918

A regiospecific, highly chemo-, diastereo-, and enantioselective one-pot catalytic cascade synthesis of cycloheptane derivatives is presented. In this chiralamine-catalyzed asymmetric process, six new bonds and five new stereocenters were formed with excellent stereocontrol (> 25:1 d.r. and 98- >99 ee).

Full text of DOI:10.1002/chem.200701918

FULL PAPER
DOI: 10.1002/chem.200701918
One-Pot Catalytic Asymmetric Cascade Synthesis ofCycloheptane
Derivatives
Jan Vesely,[a] Ramon Rios,[a] Ismail Ibrahem,[a] Gui-Ling Zhao,[a] Lars Eriksson,[b] and
Armando Córdova*[a]
The manuscript is dedicated to Prof. Jan-Erling Bäckvall on the occasion of his 60th birthday
Abstract: A regiospecific, highly chemo-, diastereo-, and enantioselective one-pot
catalytic cascade synthesis of cycloheptane derivatives is presented. In this chiral-
amine-catalyzed asymmetric process, sixnew bonds and five new stereocenters
were formed with excellent stereocontrol (>25:1 d.r. and 98– >99 ee).
Keywords: asymmetric catalysis
cascade reaction · chiral amines ·
·
cycloaddition
derivatives
·
cycloheptane
Introduction
over, the products derived from these reactions may have a
functionality that allows for a subsequent cascade reaction
to obtain further diversification or another valuable com-
pound. For example, Enders and co-workers elegantly com-
bined a chiral amine-catalyzed, three-component, domino
reaction with a Lewis acid catalyzed intermolecular Diels–
Alder reaction in one-pot for the syntheses of complextricy-
clic compounds.[7p] Hence, organocatalytic domino reactions
may also be applicable for the challenge of developing a
simple, one-pot, multicomponent, catalytic asymmetric syn-
thesis of functional cycloheptanes.
Highly functionalized seven-membered carbocycles are a
common structural motif in a multitude of natural and un-
natural bioactive targets, such as the perhydroazulenes, the
guanacastepene diterpenes, or the scabronines.[1–4] Thus, the
development of efficient methods for the asymmetric syn-
thesis of complexcycloheptanes is an important ongoing re-
search area.[1–4] For example, asymmetric metal catalyzed
[4+3][2b,c] and [5+2][3] cycloadditions or ring-expanding allyl-
ation reactions[4] for the synthesis of functional seven-mem-
bered carbocycles have been reported. Moreover, Harmata
and co-workers recently reported the first catalytic enantio-
selective [4+3] cycloaddition with a chiral amine catalyst.[2a]
The asymmetric synthesis of functional carbocycles can
also be accomplished by the use of domino reaction process-
es.[5] One way to assemble complexmolecules by domino re-
actions is to employ asymmetric organocatalysis.[6] In partic-
ular, chiral amines have been used successfully in such pro-
cesses based on the direct activation of carbonyl compounds
by forming enamine and iminium intermediates.[7] More-
Based on our previous research, we envisaged a one-pot
procedure to construct oxygen- and nitrogen-functionalized
seven-membered carbocyclic frameworks (chiral tricyclic
bis-isoxazolidines) A, which contain five stereogenic centers,
with high stereocontrol [Eq. (1)]. The assembly of the func-
tional cycloheptanes should be feasible by employing a
chiral-amine-catalyzed, one-pot, three-component intermo-
lecular [3+2] cycloaddition[8] starting from simple aldehyde
and hydroxylamine substrates B–D via transition state I,[8f]
followed directly by a two-component, intramolecular [3+2]
cycloaddition of the nitrone intermediate formed between F
and hydroxyl amine E.[9] We visualized that the polycyclic
framework with a seven membered carbocycle A would pre-
dominate over the polycyclic framework with a sixmem-
bered carbocycle A’ due to a combination of steric and sub-
stitution effects of the [3+2] cycloaddition mode G-1 as
compared to mode G-2 of the chiral dipole intermediate-
[a] Dr. J. Vesely, Dr. R. Rios, I. Ibrahem, G.-L. Zhao,
Prof. Dr. A. Córdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax: ( +46)8-154908
E-mail: acordova@organ.su.se
[b] Prof. Dr. L. Eriksson
AHCTREUNG
Department of Structural Chemistry, The Arrhenius Laboratory,
Stockholm University, 106 91 Stockholm (Sweden)
stereo-, and enantioselective, one-pot, organocatalytic cas-
cade synthesis of functional cycloheptane derivatives.
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 2693 – 2698
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2693

smoothly assembled ent-4a with
a cycloheptane core as the only
product with >25:1 d.r. and
55% ee. The other isolated ma-
terials were starting materials
and nitrone intermediates de-
rived from the acceptor alde-
hyde and the aldehyde adduct
from the first cycloaddition
step. Thus, the reaction was re-
giospecific and no six-mem-
bered carbocycle was formed.
Encouraged by this result, we
performed
with chiral
a
catalyst screen
amines 6–11
(Table 1). To our delight, chiral-
protected diarylprolinol 10[11]
catalyzed the formation of the
opposite enantiomer of func-
tional cycloheptane derivative
4a in 42% yield with excellent
diastereo- and enantioselectivi-
ty (>25:1 d.r. and 99% ee;
entry 6).
Moreover,
chiral
amine 10 catalyzed the asym-
metric formation of 4a in tolu-
ene with excellent stereoselec-
tivity (entry 8). Based on these
results, we decided to investi-
gate the enantioselective, one-
pot, domino double [3+2] cy-
cloaddition reactions between
enal 1, aldehydes 2 and hydrox-
ylamines 3 catalyzed by amine
10 in more detail. (Table 2).
The organocatalytic cascade
syntheses were regiospecific
and highly chemo- and enantio-
selective. 1H NMR analysis of
the crude reaction mixtures de-
termined that only one predom-
Scheme 1. One-pot organocatalytic cascade synthesis of cycloheptane derivatives, plausible transition state I,
[3+2] cycloaddition mode G-1, and [3+2] cycloaddition mode G-2. The figures were prepared with molecular
ꢀ
ꢀ
mechanics by using frozen C and O distances.
inant
diastereoisomer
was
formed (>25:1 d.r.). The corre-
sponding cycloheptane deriva-
tives 4 were isolated in good yields for a four-step procedure
(nitrone formation!cycloaddition!nitrone formation!cy-
cloaddition; 23–68% yield). In this process, sixnew bonds
and five new stereocenters were formed with excellent ste-
reocontrol. The one-pot reaction procedure also allowed for
the variation of both enals 2 and hydroxylamines 3. For ex-
ample, the cascade reaction between enal 1, cinnamic alde-
hyde (2h), 4-chlorophenyl hydroxylamine (3b), and phenyl
hydroxylamine (3a) gave functional cycloheptane derivative
4j as the only product in 51% yield with >25:1 d.r. and
99% ee (entry 10). Notably, changing the order of addition
of the hydroxylamines 3b and 3a (first 3a then 3b) gave the
functional carbocycle 4k in 43% yield as a nearly enantio-
Results and Discussion
In an initial experiment, we reacted a,b-unsaturated alde-
hyde 1, benzaldehyde 2a, and hydroxyl amine 3a to give tri-
cyclic bis-isoxazolidene ent-4a in the presence of a catalytic
amount of (S)-proline (5) (Table 1, entry 1). The reaction
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Chem. Eur. J. 2008, 14, 2693 – 2698

Asymmetric Synthesis of Cycloheptanes
FULL PAPER
Table 1. Catalyst screen for the one-pot catalytic reaction between 1a,
2a and 3a.[a]
(entry 12). Nitrones derived from aliphatic aldehydes were
also excellent substrates for the cascade reaction. For exam-
ple, benzyl-protected 4m was furnished in 68% yield with
>25:1 d.r. and 98% ee (entry 13). Notably, the one-pot reac-
tion followed by highly diastereoselective dihydroxylation
allowed for the formation of seven new stereocenters with
excellent stereocontrol [Eq (2)]. Thus, compounds 12h and
12l were isolated in 90 and 67% yield with >25:1 d.r., re-
spectively. We also prepared the optically pure cycloheptane
amino aldehyde derivative 13l in 95% yield, which is an ex-
cellent precursor for further diversification and the synthesis
of valuable amino acid derivatives or amino alcohols.
Entry
Catalyst
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
5
6
7
8
9
10
11
10
24
0
0
0
0
42
>25:1
–
–
–
ꢀ55[e]
–
–
–
–
99
n.d.
99[f]
–
>25:1
n.d.
traces
29[f]
>25:1[f]
[a] For a general procedure and the analytical data of 4a see the Experi-
mental Section. [b] Isolated yield of the pure product 4a after silica-gel
column chromatography. [c] Determined by NMR analyses of the crude
reaction mixture. [d] Determined by chiral-phase HPLC analysis. [e] ent-
4a was formed. [f] Toluene was used as the solvent.
The relative and absolute configuration of the functional
bis-isoxazolidine compounds 4 with a seven-membered car-
bocycle core was established by X-ray analysis of a single
crystal of cycloheptane derivative 4j (Figure 1).[12]
Based on the relative and absolute configuration of 4j, we
propose the following reaction
scheme for the stereochemical
Table 2. Scope of the one-pot organocatalytic cascade synthesis of functional cycloheptane derivatives.[a]
outcome of the domino reac-
tion. Thus, efficient shielding of
the Si-face of the chiral imini-
um intermediate 10 by the
bulky aryl groups of 10 leads to
stereoselective Re-facial endo-
addition to the activated olefin
via the initial plausible transi-
Entry
R1
R2
R3
Prod.
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
42
42
35
23
36
49
45
48
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
99
98
99
99
99
>99
99
98
4-BrC6H4
4-CNC6H4
4-NO2C6H4
Ph
4-MeOC6H4
4-MeOC6H4
tion state
I
depicted in
Scheme 1. This is in accordance
with previous chiral-amine-cat-
alyzed [3+2] cycloadditions.[8]
Next, the ring closure occurs
through a regiospecific intramo-
lecular endo-addition via the
[3+2] cycloaddition mode G-1.
In the case of (S)-proline, the
opposite facial attack occurs in
the first [2+3] cycloaddition
leading to formation of ent-4.
Ph
Ph
9
4-ClC6H4
Ph
4i
41
>25:1
99
10
11
12
13
Ph
Ph
4j
51
43
44
68
>25:1
>25:1
>25:1
>25:1
99
99
99
98
Ph
4-ClC6H4
Ph
Ph
4k
4l
4m
Ph
PhCH2
Ph
[a] For a general procedure and the analytical data of compounds 4 see the Experimental Section. [b] Isolated
yield of the pure products 4 after silica-gel column chromatography. [c] Determined by NMR analyses of the
crude reaction mixture. [d] Determined by chiral-phase HPLC analysis.
Conclusion
merically pure compound (>25:1 d.r. and 99% ee,;
In summary, we report an un-
entry 11). Moreover, aldehydes such as 2-heptenal were ex-
cellent substrates and the corresponding cycloheptane deriv-
ative 4l was obtained with >25:1 d.r. and 99% ee
precedented example of a regiospecific and highly chemose-
lective one-pot organocatalytic cascade synthesis of bis-oxa-
zolidines with a functionalized seven membered carbocycle
Chem. Eur. J. 2008, 14, 2693 – 2698
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2695

A. Córdova et al.
was added to a stirred solution of aldehyde 2 (0.375 mmol, 1.5 equiv) in
CHCl3 (1 mL). The reaction was stirred at room temperature for 1 h and
then catalyst 10 (0.05 mmol, 20 mol%) and a,b-unsaturated aldehyde 1
(0.25 mmol, 1.0 equiv) were added. The reaction mixture was stirred at
room temperature for 16 h followed by addition of the same or another
N-hydroxyarylamine (0.25 mmol, 1.0 equiv) and the reaction was stirred
for 4 h at room temperature. Next, the crude reaction mixture was puri-
fied directly by column chromatography to afford the functional cyclo-
heptane product 4.
Data for 4a: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.72–7.69 (m,
2H), 7.53–7.16 (m, 7H), 7.05–6.84 (m, 6H), 4.78 (br d, J=9.2 Hz, 1H),
4.77 (d, J=10.0 Hz, 1H), 4.52 (t, J=10.4 Hz, 1H), 3.86 (dd, J=2.8,
6.8 Hz, 1H), 2.33–2.01 (m, 4H), 1.86–1.77 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d= 153.7, 152.3, 141.7, 129.4, 129.1, 128.9, 128.2,
127.5, 122.7, 121.2, 115.4, 113.9, 79.3, 77.0, 74.3, 66.0, 62.0, 33.3, 29.1,
25.3 ppm; [a]D =++235.1 (c=1.0 in CHCl3); HRMS (ESI): m/z calcd for
[M+H]+ (C26H26N2O2): 399.2067; found: 399.2079. The enantiomeric
excess was determined by HPLC with an AD column (n-hexane:
iPrOH=93:7, l=250 nm), 0.5 mLminꢀ1; tR =major enantiomer 16.8 min,
minor enantiomer 13.8 min.
Figure 1. ORTEP picture of the crystalline cycloheptane compound 4j.
Data for 4b: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.72–7.58 (m,
4H), 7.36–7.20 (m, 5H), 7.05–6.82 (m, 5H), 4.77 (d, J=9.6 Hz, 1H), 4.73
(d, J=9.6 Hz, 1H), 4.51 (t, J=10 Hz, 1H), 3.83 (dd, J=6.8 Hz, J’=
2.0 Hz, 1H), 2.39–2.00 (m, 5H), 1.95–1.80 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d= 153.3, 152.0, 140.6, 132.3, 129.0, 128.9, 128.8,
122.7, 121.9, 121.3, 115.1, 113.7, 79.3, 76.8, 73.5, 65.8, 61.6, 33.1, 28.8,
25.0 ppm; [a]D =+180.7 (c=0.5 in CHCl3); HRMS (ESI):m/z calcd for
[M+Na]+ (C26H25BrN2O2): 499.0992; found: 499.1002. The enantiomeric
excess was determined by HPLC with an AD column (n-hexane:
core. The reaction is efficiently catalyzed by simple chiral
pyrrolidine derivatives and provides a direct entry to nearly
diastereo- and enantiomerically pure cycloheptane deriva-
tives, wherein the formation of five new bonds and five ste-
reocenters is controlled. Mechanistic studies, synthetic appli-
cations of this transformation, and the development of other
enantioselective domino transformations based on this con-
cept are ongoing in our laboratory.
iPrOH=90:10, l=250 nm), 1.0 mLminꢀ1
;
tR =major enantiomer
13.7 min, minor enantiomer 9.0 min.
Data for 4c: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.81 (d, J=
3.6 Hz, 2H), 7.35–7.18 (m, 6H), 7.05–6.81 (m, 6H), 4.81 (d, J=10.4 Hz,
1H), 4.77 (m, 1H), 4.55 (t, J=11.2 Hz, 1H), 3.82 (m, 1H), 2.40–2.00 (m,
4H), 1,90–1.70 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=152.9,
151.8, 147.3, 133.1, 129.0, 128.9, 128.0, 122.9, 121.5, 118.5, 115.2, 113.6,
112.0, 79.4, 76.9, 73.6, 66.0, 61.6, 33.0, 28.8, 24.9 ppm; [a]D =+73.5 (c=
0.5 in CHCl3). HRMS (ESI): m/z calcd, for [M+Na]+ (C27H25N3O2):
446.1839, found: 446.1847. The enantiomeric excess was determined by
HPLC with an OD-H column (n-hexane: iPrOH=90:10, l=250 nm),
Experimental Section
General. Chemicals and solvents were either purchased puriss p. A. from
commercial suppliers or purified by standard techniques. Catalyst 10 was
synthesized according to literature procedures.[11] For thin-layer chroma-
tography (TLC), silica gel plates Merck 60 F254 were used and com-
pounds were visualized by irradiation with UV light and/or by treatment
with a solution of phosphomolybdic acid (25 g), Ce
and conc. H2SO4 (60 mL), in H2O (940 mL) followed by heating or by
treatment with solution of p-anisaldehyde (23 mL), conc. H2SO4
0.5 mLminꢀ1
32.5 min.
;
tR =major enantiomer 19.6 min, minor enantiomer
(SO4)2·H2O (10 g),
Data for 4d: Yellow oil; 1H NMR (400 MHz, CDCl3): d=8.37 (d, J=
8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.35–7.10 (m, 3H), 7.05–6.96 (m,
3H), 6.91–6.86 (m, 4H), 4.86 (d, J=9.2 Hz, 1H), 4.79 (d, J=9.2 Hz, 1H),
4.55 (t, J=10 Hz, 1H), 3.82 (dd, J=6.8 Hz, J’=2.0 Hz, 1H), 2.40–2.00
(m, 4H), 1,90–1.70 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=152.4,
151.8, 149.3, 129.7, 129.2, 129.0, 128.9, 128.1, 124.5, 122.9, 121.6, 115.1,
113.6 79.5, 76.9, 73.3, 66.0, 61.6 33.0, 28.7, 24.9 ppm; [a]D =+87.6 (c=1.0
in CHCl3); HRMS (ESI): m/z calcd for [M+Na]+ (C26H25N3O4) 466.1737,
found 466.1722. The enantiomeric excess was determined by HPLC with
a
(35 mL), and acetic acid (10 mL), in ethanol (900 mL) followed by heat-
ing. Flash chromatography was performed over silica gel Merck 60 (parti-
1
cle size 0.040–0.063 mm), H and 13C NMR spectra were recorded on Var-
ian AS 400. Chemical shifts are given in d relative to tetramethylsilane
(TMS), the coupling constants J are given in Hz. The spectra were re-
corded in CDCl3 as solvent at room temperature, TMS served as internal
1
standard (d=0 ppm) for H NMR measurements, and CDCl3 was used as
an OD-H column (n-hexane: iPrOH=90:10, l=250 nm), 0.5 mLminꢀ1
tR =major enantiomer 23.6 min, minor enantiomer 29.9 min.
;
internal standard (d=77.0 ppm) for 13C NMR measurements. HPLC was
carried out using a Waters 2690 Millennium with photodiode array detec-
tor. Optical rotations were recorded on a Perkin Elmer 241 Polarimeter
(l=589 nm, 1 dm cell at 258C). High-resolution mass spectra were re-
corded on a Bruker MicrOTOF spectrometer.
Data for 4e: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.65–7.63 (m,
2H), 7.52–7.48 (m, 3H), 7.24–7.09 (m, 4H), 6.97–6.85 (m, 4H), 4.77 (br
d, J=9.6 Hz, 1H), 4.66 (d, J=10.4 Hz, 1H), 4.46 (t, J=10.0 Hz, 1H),
3.79 (dd, J=1.6 Hz, 6.4 Hz, 1H), 2.30–2.01 (m, 4H), 1.87–1.75 ppm (m,
3H); 13C NMR (100 MHz, CDCl3): d=152.2, 150.9, 141.0, 129.5, 129.1,
128.8, 128.5, 127.9, 127.4, 126.2, 116.7, 115.3, 79.4, 77.1, 74.4, 65.8, 62.0,
33.2, 29.0, 25.2 ppm; [a]D =+57.3 (c=0.5 in CHCl3); HRMS (ESI): m/z
calcd for [M+H]+ (C26H24Cl2N2O2): 466.1288, found: 467.1294. The enan-
tiomeric excess was determined by HPLC with an AD column(n-hexane:
Typical experimental procedure for the catalyst screen: N-Hydroxyaryl-
amine 3a (0.375 mmol, 1.5 equiv) was added to a stirred solution of alde-
G
hyde 2a (0.375 mmol, 1.5 equiv) in CHCl3 (1 mL). The reaction was
stirred at room temperature for 1 h and then the catalyst (0.05 mmol,
20 mol%) and a,b-unsaturated aldehyde 1 (0.25 mmol, 1.0 equiv) were
added. The reaction mixture was stirred at room temperature for 16 h
followed by addition of N-hydroxyarylamine 3a (0.25 mmol, 1.0 equiv)
and the reaction was stirred for 24 h at room temperature. Next, the
crude reaction mixture was purified directly by column chromatography
to afford cycloheptane derivative 4a.
iPrOH=90:10, l=250 nm), 1.0 mLminꢀ1
;
tR =major enantiomer
17.1 min, minor enantiomer 11.1 min.
Data for 4 f: White solid; 1H NMR (400 MHz, CDCl3): d=7.56–7.53 (m,
2H), 7.23–6.86 (m, 10H), 4.76 (d, J=9.6 Hz, 1H), 4.61 (d, J=10.0 Hz,
1H), 4.45 (t, J=9.6 Hz, 1H), 3.87 (s, 3H), 3.76 (dd, J=2.0, 6.4 Hz, 1H),
2.29–2.01 (m, 4H), 1.87–1.75 ppm (m, 3H); 13C NMR (100 MHz, CDCl3):
Typical experimental procedure for the one-pot cascade synthesis of cy-
cloheptane derivatives: N-Hydroxyarylamine 3 (0.375 mmol, 1.5 equiv)
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Chem. Eur. J. 2008, 14, 2693 – 2698

Asymmetric Synthesis of Cycloheptanes
FULL PAPER
d=159.8, 152.3, 150.9, 132.7, 129.2, 129.1, 128.8, 128.5, 127.8, 126.2, 116.7,
115.4, 114.9, 79.3, 77.0, 74.0, 65.5, 62.0, 55.5, 33.2, 29.0, 25.2 ppm; [a]D =+
143.1 (c=1.0 in CHCl3); HRMS (ESI):m/Z calcd for [M+Na]+
(C27H26Cl2N2O3): 519.1213; found: 519.1238. The enantiomeric excess was
determined by HPLC with an OD-H column (n-hexane: iPrOH=90:10,
l=250 nm), 1.0 mLminꢀ1; tR =major enantiomer 8.5 min, minor enantio-
mer 11.0 min.
Data for 4g: White solid; 1H NMR (400 MHz, CDCl3): d=7.63–7.59 (m,
2H), 7.28–7.15 (m, 5H), 7.05–6.83 (m, 7H), 4.77 (br d, J=9.2 Hz, 1H),
4.72 (d, J=10.4 Hz, 1H), 4.51 (t, J=6.4 Hz, 1H), 3.87 (s, 3H), 3.83 (dd,
J=2.0, 6.8 Hz, 1H), 2.30–2.00 (m, 4H), 1.86–1.75 ppm (m, 3H);
13C NMR (100 MHz, CDCl3): d=159.6, 153.8, 152.4, 133.4, 129.1, 128.9,
128.6, 122.7, 121.2, 115.4, 114.8, 114.1, 79.3, 77.1, 73.9, 65.8, 62.0, 55.5,
33.3, 29.1, 25.3 ppm; [a]D =+143.1 (c=1.0 in CHCl3); HRMS (ESI) m/z:
calcd. for [M+Na]+ (C27H28N2O3): 451.1992; found: 451.2002. The enan-
tiomeric excess was determined by HPLC with an AD column. (n-
hexane: iPrOH=93:7, l=250 nm), 0.5 mLminꢀ1; tR =major enantiomer
43.4 min, minor enantiomer 23.3 min.
33.1, 32.1, 31.5, 30.9, 29.1, 25.2, 22.3, 14.0 ppm; [a]D =+75.5 (c=1.3 in
CHCl3); HRMS (ESI): m/z calcd for [M+H]+(C26H32N2O2) 405.2537;
found: 405.2548. The enantiomeric excess was determined by HPLC with
an OD-H column (n-hexane: iPrOH=90:10, l=230 nm), 0.5 mLminꢀ1
tR =major enantiomer 12.6 min, minor enantiomer 15.6 min.
;
Synthesis of4m : Catalyst 10 (0.05 mmol, 20 mol%) and a?b unsaturated
aldehyde 1 (0.25 mmol) were added to a small vial containing nitrone de-
rived from benzylamine and banzaldehyde (0.25 mmol, 1.0 equiv.) in
CHCl3 (1.0 mL) . The reaction was stirred at room temperature for 3
days. Then hydroxylphenyl amine (0.25 mmol) was added and the reac-
tion was stirred at room temperature for 4 h. The crude was purified by
column chromatography to afford the desired product. Yellow oil;
1H NMR (400 MHz, CDCl3): d=7.60–7.00 (m, 15H), 4.79 (d, J=9.2 Hz,
1H), 4.73 (t, J=9.2 Hz, 1H), 4.32 (d, J=10.8 Hz, 1H), 4.25 (d, J=
13.6 Hz, 1H), 4.02 (d, J=13.6 Hz, 1H), 4.79 (dd, J=1.6 Hz, 6.4 Hz, 1H),
2.20–1.40 ppm
(m, 7H); 13C NMR (100 MHz, CDCl3): d=152.4, 139.5,
R
137.9, 128.9, 128.9, 128.6, 128.3, 128.1, 127.9, 126.9, 122.5, 115.3, 76.9,
75.5, 63.6, 62.6, 62.3, 33.1, 29.7, 29.1, 25.7 ppm; [a]D =+45.5 (c=0.5 in
CHCl3); HRMS (ESI): m/z calcd for [M+H]+(C27H28N2O2) 413.2224;
found: 413.2221. The enantiomeric excess was determined by HPLC with
Data for 4h: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.55–7.50 (m,
2H), 7.42–7.38 (m, 2H), 7.34–7.20 (m, 7H), 7.14–7.11 (m, 1H), 7.00–6.88
(m, 4H), 6.54 (dd, J=4.4 Hz, J’=16.0 Hz, 1H), 4.81 (d, J=7.2 Hz, 1H),
4.45–4.37 (m, 2H), 4.02 (dd, J=6.8 Hz, J’=2.0 Hz, 1H), 2.30–2.13 (m,
an OD-H column. (n-hexane: iPrOH=93:7, l=230 nm), 0.5 mLminꢀ1
tR =major enantiomer 13.6 min, minor enantiomer 23.2 min.
;
3H), 2.06–1.70 ppm
(m, 4H); 13C NMR (100 MHz, CDCl3): d=153.8,
G
Typical dihydroxylation procedure: In a round-bottomed flask, com-
pound 4h or 4l (0.25 mmol) was dissolved in an acetone/water (8:1) mix-
ture (1.0 mL). Next, a catalytic amount of OsO4 (2.5% mol%) and N-
methyl morpholine N-oxide (0.75 mmol) were added. The reaction mix-
ture was stirred at room temperature overnight. The crude product was
purified by column chromatography (pentane/EtOAc mixtures) to afford
the desired product 12.
Data for 12h: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.50–7.10
(m,11H), 7.00–6.90 (m, 4H), 5.12 (s, bs, 1H), 4.78 (d, J=10 Hz, 1H),
4.32–4.18 (m, 3H), 4.04 (d, J=6.4 Hz, 1H), 2.30–1.20 ppm (m, 7H);
13C NMR (100 MHz, CDCl3): d=152.5, 152.4, 141.4, 129.1, 128.7, 128.6,
127.8, 125.9, 122.4, 121.7, 115.3, 114.5, 78.9, 78.2, 72.1, 70.7, 64.2, 61.7,
33.4, 31.9, 25.1, 22.6 ppm; [a]D =+64.5 (c=1.0 in CHCl3); HRMS (ESI):
m/z calcd for [M+Na]+ (C28H30N2O4): 459.2278; found: 459.2259.
Data for 12l: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.30–6.90 (m,
10H), 4.79 (m., 1H), 4.40–4.00 (m, 5H), 2.20–1.10 (m, 15H), 0.87 ppm(t,
J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=152.4, 152.4, 130.8,
129.0, 128.8, 128.2, 115.4, 114.4, 78.7, 74.8, 72.2, 70.1, 68.1, 64.1, 60.4, 36.7,
31.9, 30.3, 29.3, 23.7, 22.7, 14.0 ppm; [a]D =+21.5 (c=0.2 in CHCl3);
HRMS (ESI): m/z calcd for [M+Na]+ (C26H34N2O4): 461.2411, found:
461.2410.
152.2, 136.3, 132.6, 130.1, 128.9, 128.8, 128.8, 128.1, 126.6, 122.5, 121.4,
115.2, 114.3, 78.4, 77.2, 73.2, 62.1, 61.9, 33.1, 29.1, 25.2 ppm; [a]D =+
260.5 (c=1.0 in CHCl3); HRMS (ESI): m/z calcd for [M+H]+
(C28H28N2O2) 425.2224; found: 425.2228. The enantiomeric excess was de-
termined by HPLC with an OD-H column. (n-hexane: iPrOH=90:10,
l=250 nm), 0.5 mLminꢀ1; tR =major enantiomer 9.6 min, minor enantio-
mer 12.3 min.
Data for 4i: Yellow solid; 1H NMR (400 MHz, CDCl3): d=8.33–8.30 (m,
1H), 8.18–8.15 (m, 1H), 7.55–7.48 (m, 3H), 7.42–7.36 (m, 2H), 7.29–7.20
(m, 3H), 7.13–7.08 (m, 2H), 7.00–6.84 (m, 3H), 6.53 (dd, J=7.6 Hz,
16.0 Hz, 1H), 4.81 (d, J=7.2 Hz, 1H), 4.44–4.37 (m, 2H), 4.01 (dd, J=
1.6 Hz, 6.4 Hz, 1H), 2.28–2.15 (m, 3H), 2.10–1.68 ppm
(m, 4H). 13C NMR
U
(100 MHz, CDCl3): d=153.9, 152.3, 135.4, 132.1, 131.8, 131.4, 131.0,
129.8, 129.1, 129.0, 128.9, 128.2, 125.7, 122.8, 122.5, 122.1, 121.6, 115.4,
114.4, 78.5, 77.4, 73.1, 62.3, 62.1, 33.2, 29.2, 25.3 ppm; [a]D =+129.4 (c=
1.0 in CHCl3);. HRMS (ESI): m/z calcd for [M+Na]+ (C28H27BrN2O2):
525.1148; found: 525.1157. The enantiomeric excess was determined by
HPLC with an AD column (n-hexane: iPrOH=93:7, l=250 nm),
1.0 mLminꢀ1
44.8 min.
;
tR =major enantiomer 51.6 min, minor enantiomer
Data for 4j: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.55–7.15 (m,
10H), 6.95–6.83 (m, 5H), 6.52 (dd, J=8.4 Hz, J’=16.0 Hz, 1H), 4.81 (d,
J=10 Hz, 1H), 4.41–4.34 (m, 2H), 4.01 (dd, J=6.8 Hz, J’=2.0 Hz, 1H),
2.30–1.65 ppm (m, 7H); 13C NMR (100 MHz, CDCl3): d=152.4, 152.1,
136.1, 132.8, 129.7, 128.9, 128.8, 128.7, 128.2, 126.6, 126.3, 122.6, 115.6,
115.2, 78.5, 77.2, 73.6, 62.1, 61.9, 33.1, 29.0, 25.1 ppm; [a]D =+125 (c=1.0
in CHCl3); HRMS (ESI): m/z calcd for [M+Na+](C28H27ClN2O2)
481.1653, found 481.1655. The enantiomeric excess was determined by
HPLC with an OD-H column (n-hexane: iPrOH=90:10, l=250 nm),
0.5 mLminꢀ1; tR =major enantiomer 8.5 min, minor enantiomer 13.9 min.
Typical experimental procedure for aldehyde formation: In a round-bot-
tomed flask, diol 12 (0.2 mmol) was dissolved in a THF:water (1:1, 2 mL)
mixture. Next, NaIO4 (1.0 mmol) was added and the reaction was stirred
at room temperature overnight. The crude product was purified by
column chromatography (pentane:EtOAc mixtures) to afford the desired
product 13.
Data for 13l: Yellow oil; 1H NMR (400 MHz, CDCl3): d=9.96 (d, J=
4.0 Hz, 1H), 7.20–6.90 (m, 10H), 4.83 (d, J=9.2 Hz, 1H), 4.34–4.20 (m,
2H). 4.1 (d, J=6.4 Hz, 1H), 2.40–2.30 (m, 2H), 2.00–1.00 ppm (m, 5H);
13C NMR (100 MHz, CDCl3): d= 202.1, 152.5, 151.9, 129.1, 128.9, 122.7,
122.0, 115.3, 113.7, 78.4, 76.4, 62.3, 58.1, 32.8, 31.9, 24.7, 22.7 ppm; [a]D =
+33.1 (c=1.0 in CHCl3); HRMS (ESI): m/z calcd for [M+Na]+
(C21H22N2O3) 373.1523, found 373.1540.
Data for 4k: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.55–7.15 (m,
10H), 6.95–6.83 (m, 5H), 6.52 (dd, J=8.4 Hz, J’=16.0 Hz, 1H), 4.80 (d,
J=9.6 Hz, 1H), 4.41–4.35 (m, 2H), 3.97 (dd, J=6.8 Hz, J’=2.0 Hz, 1H),
2.30–1.65 ppm (m, 7H); 13C NMR (100 MHz, CDCl3): d=153.8, 150.9,
136.2, 132.7, 130.0, 128.9, 128.8, 128.2, 127.5, 126.6, 121.5, 116.5, 114.3,
78.3, 77.2, 73.3, 62.2, 61.8, 33.1, 29.0, 25.2 ppm; [a]D =+147.5 (c=1.0 in
CHCl3); HRMS (ESI): m/z calcd for [M+H+](C28H27ClN2O2) 459.1847,
found 459.1834. The enantiomeric excess was determined by HPLC with
Acknowledgements
an OD-H column. (n-hexane: iPrOH=90:10, l=250 nm), 0.5 mLminꢀ1
tR =major enantiomer 21.3 min, minor enantiomer 24.4 min.
;
We gratefully acknowledge the Swedish National Research Council,
Wenner-Gren Foundation, Magnus Bergvall Foundation, and Carl Tryg-
ger Foundation for financial support. A.C. is grateful recipients of the
city of Stockholm inventor award.
Data for 4l: Yellow oil; 1H NMR (400 MHz, CDCl3): d=7.30–6.80 (m,
10H), 6.10–6.00 (m, 1H), 5.80–5.70 (m, 1H), 4.80 (d, J=9.6 Hz, 1H),
4.34–4.19 (m, 2H) 3.94 (dd, J=6.4 Hz, 1.6 Hz, 1H), 2.25–1.20 (m, 13H),
0.97 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=154.1, 152.4,
134.7, 130.7, 128.8, 128.6, 122.4, 121.1, 115.2, 114.3, 78.1, 73.1, 62.4, 61.6,
Chem. Eur. J. 2008, 14, 2693 – 2698
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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[12] CCDC 649366 (4j) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Received: December 5, 2007
Published online: January 28, 2008
2698
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Chem. Eur. J. 2008, 14, 2693 – 2698