Enantioselective nitroso-Diels-Alder reaction and its application for the synthesis of (-)-peracetylated conduramine A-I

Article abstract of DOI:10.1002/chem.200901331

Cu-catalyzed enantioselective nitroso-Diels-Alder reactions (NDA reactions) of 2-nitrosopyridine with various dienes are presented. The [CuPF ₆(MeCN)₄]/Walphos-CF₃ catalyst system is best suited to catalyze the NDA reactio

Full text of DOI:10.1002/chem.200901331

DOI: 10.1002/chem.200901331
Enantioselective Nitroso-Diels–Alder Reaction and Its Application for the
Synthesis of (ꢀ)-Peracetylated Conduramine A-1
Chandan Kumar Jana, Stefan Grimme, and Armido Studer*[a]
Abstract: CuI-catalyzed enantioselec-
tive nitroso-Diels–Alder reactions
(NDA reactions) of 2-nitrosopyridine
with various dienes are presented. The
ducts are obtained in quantitative yield
with very good to excellent enantiose-
lectivities. Based on DFT calculations,
a model to explain the stereochemical
outcome of the NDA reaction is pre-
sented. Finally, an efficient short syn-
thesis of (ꢀ)-peracetylated condurami-
ne A-1 by applying the enantioselective
NDA reaction as a key step is de-
scribed.
[CuPF6ACHTUNGTRENNUNG(MeCN)4]/Walphos-CF3 catalyst
Keywords: copper · density func-
tional calculations · Diels–Alder re-
action · enantioselective catalysis ·
natural products
system is best suited to catalyze the
NDA reaction of various dienes by
using 2-nitrosopyridine as a dienophile.
In most of the cases studied, cycload-
Introduction
Nitroso-Diels–Alder (DA) reactions have been intensively
used in organic synthesis.[1] Nitroso-DA adducts can reduc-
tively be transformed to the corresponding amino alcohols,
which are highly valuable building blocks for natural prod-
uct synthesis. Asymmetric nitroso-DA reactions have been
accomplished by using the chiral auxiliary approach. How-
ever, due to fast background reaction, it took a while to find
suitable conditions for conducting catalytic enantioselective
NDA reactions. To our knowledge, only very few reports on
successful enantioselective metal-catalyzed NDA reactions
appeared to date.[1e,2]
We have recently shown that racemic 5-substituted cyclo-
hexa-1,3-dienes undergo highly regiodivergent enantioselec-
tive nitroso-DA reactions by using a chiral CuI-Walphos-CF3
catalyst (Scheme 1).[3,4] It was hoped that the catalyst system
identified for the more complex regiodivergent process
should also perform well in enantioselective nitroso-Diels–
Alder reactions that lack the regioselectivity problem.
Herein we present a highly efficient catalyst for enantiose-
lective nitroso-DA reactions. Moreover, as a first application
Scheme 1. Catalytic enantioselective regiodivergent nitroso-Diels–Alder
reaction.
the synthesis of (ꢀ)-peracetylated conduramine A-1 is
shown.[5] Conduramine A-1 belongs to the aminoconduritols,
which are key structural moieties in many biologically active
molecules.
Results and Discussion
[a] Dr. C. K. Jana, Prof. Dr. S. Grimme, Prof. Dr. A. Studer
NRW Graduate School of Chemistry, Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt, Correnstrasse 40
48149 Mꢁnster (Germany)
Various CuI–bisphosphine complexes were screened as cata-
lysts for the enantioselective nitroso-DA reaction of cyclo-
hexa-1,3-diene with 2-nitrosopyridine (Table 1, Figure 1).
Reactions were performed in CH2Cl2 at low temperature by
Fax : (+49)281-83-36523
E-mail: studer@uni-muenster.de
using [CuPF6ACHTNUTRGNEUNG(MeCN)4] (10 mol%) as a catalyst precursor in
the presence of different chiral phosphine ligands. Enantio-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901331.
9078
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9078 – 9084

FULL PAPER
Table 1. Ligand screening.
Entry
Ligand
Yield [%]
ee [%][a]
1
2
3
4
5
6
(S)-Difluorphos
Walphos-CH3
(R)-Segphos
Walphos-CF3
(S)-Binap
99
99
90
99
99
99
ꢀ85
84
76
93
ꢀ55
(R)-Solphos
11
[a] A negative ee indicates formation of the enantiomer of 1.
Scheme 2. Enantioselective nitroso-Diels–Alder reaction with symmetri-
cal dienes.
sponding bicycles 3b and 3c, respectively. A CuI/Segphos
system reported by Yamamoto catalyzed the cycloaddition
of cyclohexa-1,3-diene with 6-methyl-2-nitrosopyridine,
which is more difficult to access than the 2-nitrosopyridine
used herein, in a similar selectivity (92% ee); however, for
cycloaddition with diene 2b an improved selectivity was ob-
tained with the CuI/Walphos-CF3 system reported herein as
compared to the CuI/Sephos catalyst (72% ee versus 91%
ee).[2b] The spirocyclopentadiene 4 underwent nitroso-DA
with high yield and good enantioselectivity (! 5, 95%,
90% ee). Alkyl substituents were tolerated at positions 2
and 3 of cyclohexa-1,3-diene as shown for the transforma-
tion of 6 to 7, which was formed in quantitative yield with
high enantioselectivity (95% ee). Perfect diastereoselectivity
and a high enantioselectivity was achieved for reaction of
diene 8 with 2-nitrosopyridine (! 9, 99%, d.r. >99:1, 93%
ee).
Figure 1. Various ligands that were tested.
selectivity was determined by HPLC. Good enantioselectivi-
ty was obtained when (S)-Difluorphos was used as ligand.
The cycloadduct 1 was isolated in quantitative yield with
85% enantiomeric excess (entry 1). A similar result (99%,
84% ee) was achieved with the Walphos-CH3 ligand
(entry 2). (R)-Segphos gave a slightly lower yield and a
lower selectivity (90%, 76% ee, entry 3), and the best result
was obtained by using the Walphos-CF3 ligand to provide
the cycloadduct in quantitative yield with 93% ee. Moderate
enantioselectivities were obtained with (S)-Binap (99%,
55% ee) and (R)-Solphos (99%, 11% ee) as ligands (en-
tries 5, 6).
We next studied the unsymmetrical cyclohexa-1,3-dienes
10a–d bearing a substituent at the 2-position (Table 2). Silyl
ether 10a reacted highly regioselectively, and 11a was isolat-
ed in quantitative yield with high ee (93%). Isomer 12a was
not identified. Perfect regioselectivity but slightly reduced
As a result of the initial ligand screening, all of the follow-
ing cycloadditions were performed in CH2Cl2 by using the
diene (1.1 equiv) and 2-nitrosopyridine in the presence of
Table 2. Enantioselective nitroso-Diels–Alder Reaction with 2-substitut-
ed cyclohexa-1,3-dienes.
10 mol% [CuPF6ACHTUNGTRENNUNG(MeCN)4]/Walphos-CF3. For most of the
reactions conducted, the product was formed with excellent
yield. Enantioselectivity was determined by HPLC (see the
Supporting Information).
Symmetrical 1,3-dienes were studied first. Cyclopenta-
diene 2a gave the adduct 3a in a quantitative yield with
high enantioselectivity (Scheme 2). The absolute configura-
tion was assigned by comparison of the optical rotation of
3a with the reported literature value of a similar com-
pound.[2b] Similar results were achieved with cyclohepta-1,3-
diene (2b) and cycloocta-1,3-diene (2c) to give the corre-
Diene
R
Yield [%]
(11a–d)
ee [%]
(11a–d)
Yield [%]
(12a–d)
n.i.[a]
n.i.[a]
66
ee [%]
(12a–d)
10a
10b
10c
10d
OTBS 99
Ph
OTf
nBu
93
88
81
87
–
–
99
33
97
98
<2
n.d.[b]
[a] n.i.=not identified. [b] n.d.=not determined.
Chem. Eur. J. 2009, 15, 9078 – 9084
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9079

A. Studer et al.
enantioselectivity was obtained for the 2-phenyl substituted
diene 10b. Regioselectivity was lower and reversed for enol
triflate 10c. Isomer 12c was isolated in 66% yield with ex-
cellent ee (98%). A lower ee (81%) was measured for the
minor isomer 11c. As expected, the alkyl-substituted diene
10d reacted with high regioselectivity. Hence for systems
bearing electron-donating groups at the 2-position of cyclo-
hexa-1,3-diene the nitroso-Diels–Alder reaction occurred
with perfect regioselectivity and moderate to high enantiose-
lectivity.
Structural assignment of the regioisomers in these studies
was based on careful 2D NMR spectroscopic analysis. More-
ꢀ
over, the N O bond in 11b was reductively cleaved and the
absolute configuration was assigned by NMR spectroscopic
analysis on the corresponding Mosher ester (see the Sup-
porting Information). The absolute configuration of all
other compounds in this table was assigned by analogy. In
addition, comparison of optical rotations of compounds 11a,
11b and 11d with literature values of analogous compounds
further supported our assignment.[2b]
As additional substrate we investigated 1-methylcyclo-
ACHTUNGTRENNUNGhexadiene 13. The minor isomer 14a was formed as a race-
mate whereas 14b was isolated with high ee (93%,
Scheme 3). Diene 15, which is important for the mechanistic
Figure 2. a) Fully optimized DFT structure of CuI/Walphos complexed
with 2-nitrosopyridine. b) ChemDraw presentation of substituted cyclo-
hexa-1,3-dienes (endo pathway) approaching the complexed dienophile.
the cyclohexadiene can approach the Cu-complexed nitroso
compound only from the north/east direction. The north/
west trajectory is well blocked by the ligand sphere. Based
on calculations conducted by Houk, nitroso-DA reactions
occur preferentially via the endo pathway.[8,9] Considering
these facts, we suggest the model depicted in Figure 2b to
explain the stereochemistry observed.
As shown in the experiment, substituents at the double
bond were tolerated in positions 1–3 of the cyclohexadiene
(Ra). However, a substituent at position 4 (Rb) of the cyclo-
hexadiene moiety interferes with the phenyl group of the
ligand while approaching the dienophile. Therefore, the
endo approach of 13 to Cu-complexed 2-nitrosopyridine to
give 14a was probably not accessible for steric reasons.
Isomer 14a, which was isolated as a racemate likely resulted
from thermal background reaction. For the same reason,
diene 15 does not fit our model and should react nonselec-
tively, as observed in the experiment. The absolute configu-
ration of regioisomer 14b could be predicted by our model.
Positions 5 and 6 of cyclohexa-1,3-dienes can bear substitu-
ents as shown for our divergent reactions[3] and also for the
transformation of diene 8. Moreover, the 5- and 6-substitut-
ed cyclohexadienes reacted with high diastereoselectivities
(anti-additions). The suggested model can also be applied to
explain the stereochemical outcome for the DA reaction of
nitrosopyridine with cyclopentadienes, cyclohepta-1,3-diene,
cycloocta-1,3-diene, and of azadiene 17.
Scheme 3. Enantioselective nitroso-Diels–Alder reaction with dienes 13,
15, and 17. Py=pyridine; Moc=methoxycarbonyl.
discussion below reacted slowly and adduct 16 was isolated
in 10% yield as a racemate. Pleasingly, N-protected azacy-
clohexadiene 17 upon reaction with nitrosopyridine provid-
ed the cyclic N,O-acetal 18 as a single regioisomer with ex-
cellent enantioselectivity in high yield. Importantly, adduct
18 can readily be transformed to diaminodideoxylyxopyra-
nose.[6]
To understand the stereoselectivity of the nitroso-DA re-
action with substituted cyclohexa-1,3-dienes the structure of
the CuI/Walphos-CF3 catalyst complexed with 2-nitrosopyri-
dine was studied theoretically by using DFT calculations
(Figure 2).[7] As can be seen from the minimized structure,
Finally, we applied the enantioselective nitroso-DA reac-
tion to the synthesis of (ꢀ)-peracetylated conduramine A-1
ꢀ
(Scheme 4). Reductive N O bond cleavage in
9 with
[10]
Mo(CO)6/NaBH4
and O-silylation afforded protected
amino alcohol 19 in a good yield (91%). Carbamoylation of
9080
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9078 – 9084

Enantioselective Nitroso-Diels–Alder Reaction
FULL PAPER
Elmer 241 & 341 polarimeter. TLC: Merck silica gel 60 F254 plates; de-
tection with UV light or by dipping into a solution of KMnO4 (1.5 g in
400 mL H2O, 5 g NaHCO3) or a solution of CeACHTUNGRTNE(UNG SO4)2·H2O (10 g), phos-
phormolybdic acid hydrate (25 g), and concd H2SO4 (60 mL) in H2O
(940 mL), followed by heating. Flash column chromatography (FC):
Merck or Fluka silica gel 60 (40–63 mm) at approximately 0.4 bar. HPLC:
Either a KNAUER instrument, that is a High Precision KNAUER
HPLC Pump, with Eurochrom V3.05 software, or a Hewlett–Packard
Binary Pump coupled to a Hewlett–Packard Series 1100 ChemStation for
LC were used. Column, eluent and retention times for HPLC analysis
that were used for the determination of enantiomer ratios are given
below with the details of the relevant experiment. IR: spectra were re-
corded on a Bruker IFS-28 spectrophotometer. MS: Mass spectra were
recorded on a Finnigan MAT 4200S, a Bruker Daltonics MicroTof, a
Waters Micromass Quatro LCZ (ESI); and peaks are given in m/z (% of
basis peak).
Scheme 4. Synthesis of (ꢀ)-peracetylated conduramine A-1 22.
General procedure for the enantioselective nitroso-Diels–Alder reaction
with (R,Rp)-Walphos-CF3
ACHTUNGRTEN(NUNG GP 1): (R,Rp)-Walphos-CF3 ligand (10 mol%)
and [CuI
AHCTUNGTRENNUNG
tube under an argon atmosphere. The catalyst was dried at RT for 15 min
under vacuum. The Schlenk tube was recharged with argon, anhydrous
CH2Cl2 (~6 mm with respect to ligand) was added to the mixture, and the
resulting solution was stirred under argon for 1 h at RT. The solution was
then cooled to ꢀ868C, a solution of 2-nitrosopyridine (1.0 equiv) in
CH2Cl2 (~15 mm) was added dropwise over 10 min, and the resulting
dark-blue solution was stirred for 15 min. A solution of the diene in
CH2Cl2 (~12 mm) was added slowly over 1 h at ꢀ868C. After completion
of addition, stirring was continued at ꢀ868C for 6 h. The mixture was
slowly warmed to ꢀ208C and was stirred for 12 h at that temperature.
The solvent was removed under reduced pressure, and the crude product
was subjected to silica gel chromatography to afford the products.
the amino group was performed by treatment of the corre-
sponding Mg amide with methyl chloroformate to give 20
(96%). The pyridyl group was cleaved after N-methylation
(MeOTf) and subsequent hydrolysis of the pyridinium salt
(! 21, 82%). The final steps, namely acetal and carbamate
cleavage followed by peracetylation to give protected
(ꢀ)-conduramine A-1 22 were elegantly performed as a
one-pot reaction by using acetyl chloride in combination
with NaI in MeCN ([a]D25 =ꢀ30.6, c=0.54, CHCl3; [a]2D5 (en-
antiomer)=+33, c=0.4, CHCl3).[5c]
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(3.5 mg, 9.3 mmol), CH2Cl2 (1.0 mL), 2-nitrosopyridine (10 mg, 93 mmol)
in CH2Cl2 (0.5 mL), cyclohexa-1,3-diene (10.0 mL, 101 mmol) in CH2Cl2
(0.5 mL) and SiO2 chromatography (pentane/MTBE 1:1) gave 1 as a col-
orless oil (17 mg, 93 mmol, 99%). Enantiomeric excess (93% ee) was de-
termined by chiral HPLC. Column: Chiralcel OD-H; solvent: cyclohex-
ane/iPrOH (95:05); flow: 1.0 mLminꢀ1; major enantiomer: tR =9.0 min,
Conclusions
We presented [CuPF6ACHTUNRGTNEG(UN MeCN)4]/Walphos-CF3 as an efficient
catalyst for enantioselective nitroso-DA reactions. In most
of the cases studied, the catalyst system introduced, deliv-
ered better selectivities compared to those reported by
using known catalysts. On the basis of DFT calculations a
model to explain the stereochemical outcome of the nitroso-
DA reaction was introduced. Finally, a first application of
the method in natural product synthesis was discussed.
minor enantiomer: tR =11.7 min. Rf =0.5 (pentane/MTBE 1:1); [a]D25
=
+192.2 (c=0.18, CHCl3); 1H NMR (300 MHz, CDCl3): d = 8.20–8.18
(m, 1H), 7.49 (ddd, J=1.8, 7.2, 8.3 Hz, 1H), 6.91–6.89 (m, 1H), 6.75
(ddd, J=0.9, 4.8, 7.2 Hz, 1H), 6.49–6.44 (m, 1H), 6.34–6.28 (m, 1H),
5.30–5.26 (m, 1H), 4.73–4.69 (m, 1H), 2.30–2.19 (m, 2H), 1.63–1.53 (m,
1H), 1.45–1.35 ppm (m, 1H);13C NMR (75 MHz, CDCl3): d=164.3,
147.4, 137.5, 132.1, 131.0, 116.7, 111.5, 69.9, 52.3, 24.4, 20.7 ppm; FTIR
(neat): n˜ = 3054, 2936, 2858, 1587, 1568, 1463, 1431, 1257, 1027, 953, 881,
781, 701 cmꢀ1
[M+H]+; found: 189.1046.
(1S,4R)-3-Pyridin-2-yl-2-oxa-3-azabicyclo
ing to GP 1: (R,Rp)-Walphos-CF3 (12.9 mg, 13.9 mmol), [CuI-
(CH3CN)4]PF6 (5.2 mg, 14 mmol), CH2Cl2 (1.5 mL), 2-nitrosopyridine
; HRMS (ESI): m/z: calcd for C11H12N2OH: 189.1033
Experimental Section
G
ACHTUNGTRNE[NUNG 2.2.1]hept-5-ene (3a): Accord-
General: All reactions involving air or moisture-sensitive reagents or in-
termediates were carried out in heat-gun-dried glassware under an argon
atmosphere. THF was freshly distilled from potassium under argon. Di-
ethyl ether (Et2O) was freshly distilled from K/Na under argon. Di-
chloromethane (CH2Cl2) was freshly distilled from phosphorus(V) oxide
(P2O5). Triethylamine (Et3N) was distilled from CaH2 and stored under
argon. All other solvents and reagents were purified according to stan-
dard procedures or were used as received from Aldrich, Acros or Fluka.
2-Nitrosopyridine,[11] diene 8,[12] 10a,[13] 10b–d[14] and 13[15] were synthe-
sized according to known procedures. 1H, 13C, GCOSY, GHSQC, and
1D-NOE NMR spectroscopy: Varian Unity plus 600 (at 298 K),
Varian 500 Inova (at 298 K), Bruker AMX 400 (at 300 K), Bruker
DPX 300 (at 300 K). Chemical shifts, d (in ppm), are reported relative to
TMS (d=0.0 ppm), which was used as the internal reference. Otherwise
the solvents residual proton resonance and carbon resonance (CHCl3,
AHCTUNGTRENNUNG
(15 mg, 0.14 mmol) in CH2Cl2 (1.0 mL, 0.2 mL/h), cyclopentadiene
(11 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and SiO2 chromatography (pen-
tane/MTBE 2:1) gave 3a as a yellow oil (23 mg, 99%). Enantiomeric
excess (91% ee) was determined by chiral HPLC. Column: Chiralcel
OD-H; solvent: cyclohexane/iPrOH 97:3; flow: 1.0 mLminꢀ1; major en-
antiomer: tR =19.3 min, minor enantiomer: tR =13.6 min. Rf =0.3 (pen-
tane/MTBE 2:1); 1H NMR (300 MHz, CDCl3): d=8.22–8.20 (m, 1H),
7.49 (ddd, J=8.3, 7.5, 1.8, 1H), 6.84–6.82 (m, 1H), 6.78 (ddd, J=7.2, 4.9,
0.8, 1H), 6.31–6.28 (m, 1H), 6.14–6.11 (m, 1H), 5.49 (m, 1H), 5.21–5.20
(m, 1H), 2.14 (dt, J=8.7, 1.8, 1H), 1.81 ppm (d, J=8.5, 1H); 13C NMR
(75 MHz, CDCl3): d=163.9, 147.5, 137.6, 135.3, 132.6, 117.2, 112.5, 83.0,
66.7, 48.3 ppm; FTIR (neat): n˜ = 3010, 2959, 2360, 2341, 1589, 1463,
1433, 1330, 1297, 1251, 929, 848, 799, 782, 735 cmꢀ1; HRMS (ESI): m/z:
calcd for C10H10N2OH: 175.0866 [M+H]+; found: 175.0871.
d(1H)=7.26 ppm,
128.0 ppm; CD3OD, d(1H)=3.31 ppm, d
calibration. Polarimetry: optical rotations were measured on a Perkin–
d
G
dACTHNGUTERNNUG
(13C)=
G
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Chem. Eur. J. 2009, 15, 9078 – 9084
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9081

A. Studer et al.
(2.3 mg, 6.2 mmol), CH2Cl2 (1.0 mL), 2-nitrosopyridine (6.7 mg, 62 mmol)
in CH2Cl2 (0.5 mL), cyclohepta-1,3-diene (8.0 mL, 74 mmol) in CH2Cl2
(0.5 mL) and SiO2 chromatography (pentane/MTBE 1:1) gave 3b as a
colorless oil (12 mg, 99%). Enantiomeric excess (91% ee) was deter-
mined by chiral HPLC. Column: Chiralcel OD-H; solvent: cyclohexane/
(12.9 mg, 13.9 mmol), [CuI
ACHTGNUTERNNU(G CH3CN)4]PF6 (5.2 mg, 14 mmol), CH2Cl2
(1.5 mL), 2-nitrosopyridine (15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), 2,2-
dimethyl-3a,7a-dihydro-1,3-benzodioxole (25 mg, 0.17 mmol) in CH2Cl2
(1.0 mL) and SiO2 chromatography (pentane/MTBE 5:1) gave 9 as white
powder (36 mg, 99%). Enantiomeric excess (93% ee) was determined by
chiral HPLC. Column: Chiralcel OD-H; solvent: cyclohexane/iPrOH
99:1; flow: 1.0 mLminꢀ1; major enantiomer: tR =12.8 min, minor enantio-
mer: tR =30.4 min. Rf =0.3 (pentane/MTBE 5:1); [a]2D5 =+91.8 (c=1.66,
CHCl3); 1H NMR (300 MHz, CDCl3): d=8.23–8.21 (m, 1H), 7.53 (ddd,
J=1.8, 7.5, 8.4, 1H), 6.96–6.93 (m, 1H), 6.83–6.79 (m, 1H), 6.38–6.32 (m,
1H), 6.25–6.20 (m, 1H), 5.64–5.60 (m, 1H), 4.90–4.86 (m, 1H), 4.69 (dd,
J=4.1,7.0, 1H), 4.62 (dd, J=4.5, 7.0, 1H), 1.34 ppm (s, 6H);13C NMR
(75 MHz, CDCl3): d=163.0, 147.5, 137.7, 130.9, 128.8, 117.4, 111.9, 110.7,
73.9, 73.6, 70.4, 55.4, 25.8, 25.6 ppm; FTIR (neat): n˜ =2989, 2939, 1585,
1570, 1462, 1431, 1373, 1257, 1204, 1162, 1092, 881, 776 cmꢀ1; HRMS
(ESI): m/z: calcd for C14H16N2O3H: 261.1234 [M+H]+; found: 261.1231.
iPrOH 99.5:0.5; flow: 1.0 mLminꢀ1
minor enantiomer: tR =22.3 min. Rf =0.5 (pentane/MTBE 1:1). [a]D25
; major enantiomer: tR =23.3 min,
=
+82.6 (c=0.3, CHCl3); 1H NMR (300 MHz, CDCl3): d=8.19–8.18 (m,
1H), 7.57–7.50 (m, 1H), 7.03–7.00 (m, 1H), 6.76–6.72 (m, 1H), 6.26–6.19
(m, 1H), 6.08–6.03 (m, 1H), 5.38–5.34 (m, 1H), 4.82–4.81 (m, 1H), 2.11–
1.90 (m, 3H), 1.79–1.71 (m, 1H), 1.66–1.60 (m, 1H), 1.51–1.35 ppm (m,
1H);13C NMR (75 MHz, CDCl3): d=163.8, 147.5, 137.8, 130.8, 126.2,
116.1, 111.0, 73.9, 56.8, 31.9, 27.4, 18.9 ppm; FTIR (neat): n˜ =3052, 2932,
2863, 1591, 1568, 1463, 1432, 1280, 1146, 908, 778, 733 cmꢀ1; HRMS
(ESI): m/z: calcd for C12H14N2OH: 203.1179 [M+H]+; found: 203.1156.
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(5.2 mg, 14 mmol), CH2Cl2 (1.5 mL), 2-nitrosopyridine (15 mg, 0.14 mmol)
in CH2Cl2 (0.5 mL), cycloocta-1,3-diene (21 mL, 0.17 mmol) in CH2Cl2
(1.0 mL) and SiO2 chromatography (pentane/MTBE 10:1) gave 3c as a
colorless oil (30 mg, 99%). Enantiomeric excess (93% ee) was deter-
mined by chiral HPLC. Column: Chiralcel OD-H; solvent: cyclohexane/
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(1.5 mL), 2-nitrosopyridine (15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), tert-
butyl-(cyclohexa-1,5-dienyloxy)dimethylsilane (35 mg, 0.17 mmol) in
CH2Cl2 (1.0 mL) and SiO2 chromatography (pentane/MTBE/Et3N
10:1:0.03) gave 11a as a yellow oil (44 mg, 99%). Enantiomeric excess
(93% ee) was determined by chiral HPLC. Column: Chiralcel OD-H;
solvent: cyclohexane/iPrOH 97:3; flow: 1.0 mLminꢀ1; major enantiomer:
tR =7.0 min, minor enantiomer: tR =13.9 min. Rf =0.3 (pentane/MTBE/
Et3N 10:1:0.03); [a]2D5 =+22.3 (c=1.43, CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.22–8.19 (m, 1H), 7.50 (ddd, J=1.8, 7.5, 8.3, 1H), 6.98–6.95
(m, 1H), 6.76 (ddd, J=0.9, 4.8, 7.2, 1H), 5.14 (dd, J=2.7, 6.6, 1H), 5.06
(dd, J=2.8, 1H), 4.84–4.81 (m, 1H), 2.26 (s, 2H), 1.83–1.71 (m, 1H),
1.47–1.36 (m, 1H), 0.80 (s, 9H), 0.01 (s, 3H), ꢀ0.25 ppm (s,
3H);13C NMR (75 MHz, CDCl3): d=164.5, 153.9, 147.5, 137.4, 116.8,
111.4, 100.5, 72.2, 58.4, 26.4, 25.5, 21.1, 18.0, ꢀ4.5, ꢀ5.6 ppm; FTIR
(neat): n˜ =2932, 2895, 2858, 1638, 1587, 1463, 1432, 1306, 1251, 1214, 915,
868, 779 cmꢀ1; HRMS (ESI): m/z: calcd for C17H26N2O2SiH: 319.1836;
found: 319.1838 [M+H]+.
iPrOH 99.5:0.5; flow: 1.0 mLminꢀ1
minor enantiomer: tR =20.8 min. Rf =0.2 (pentane/MTBE 10:1). [a]D25
; major enantiomer: tR =10.1 min,
=
ꢀ161.9 (c=0.92, CHCl3); 1H NMR (300 MHz, CDCl3): d=8.19–8.18 (m,
1H), 7.59–7.53 (m, 1H), 7.08 (d, J=8.4, 1H), 6.77–6.73 (m, 1H), 6.30
(dd, J=6.8, 10.1, 1H), 5.72 (dd, J=4.5, 10.1, 1H), 5.23 (m, 1H), 4.96 (m,
1H), 2.32–2.23 (m, 1H), 2.19–2.06 (m, 2H), 1.92–1.82 (m, 1H), 1.79–
1.61 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=162.9, 147.1, 138.2,
132.0, 126.0, 115.8, 110.3, 73.7, 54.7, 34.9, 32.1, 26.3, 22.5 ppm; FTIR
(neat): n˜ =3045, 2916, 1589, 1567, 1462, 1432, 1292, 1273, 1177, 789,
778 cmꢀ1; HRMS (ESI): m/z: calcd for C13H16N2OH: 217.1335 [M+H]+,
found: 217.1333.
Spiro[cyclopentane-1,7’-(1R,4S)-3-pyridin-2-yl-2-oxa-3-azabicyclo-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
R
ACHTUNGERTN[NUNG 2.2.2]oct-5-ene (11b):
diene (25 mg, 0.21 mmol) in CH2Cl2 (1.0 mL) and SiO2 chromatography
(pentane/MTBE 2:1) gave 5 as a yellow oil (30 mg, 95%). Enantiomeric
excess (90% ee) was determined by chiral HPLC. Column: Chiralcel
OD-H; solvent: cyclohexane/iPrOH 98:02; flow: 1.0 mLminꢀ1; major en-
antiomer: tR =7.9 min, minor enantiomer: tR =9.7 min. Rf =0.6 (pentane/
MTBE 2:1). [a]2D5 =+179.4 (c=0.71, CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.19–8.17 (m, 1H), 7.50–7.44 (m, 1H), 6.80–6.77 (m, 1H),
6.76–6.73 (m, 1H), 6.30–6.27 (m, 1H), 6.08 (dt, J=5.7, 1.9, 1H), 4.91 (m,
1H), 4.56 (m, 1H), 1.92–1.35 ppm (m, 8H); 13C NMR (75 MHz, CDCl3):
d=163.6, 147.4, 137.4, 136.2, 132.8, 116.7, 111.9, 88.1, 73.1, 68.1, 31.7,
31.3, 26.4, 26.2 ppm; HRMS (ESI): m/z: calcd for C14H16N2OH: 229.1335
[M+H]+, found: 229.1335.
AHCTUNGTRENNUNG
(15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), 2-phenylcyclohexa-1,3-diene
(26 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and SiO2 chromatography (pen-
tane/MTBE 8:1) gave 11b as a colorless oil (36 mg, 99%). Enantiomeric
excess (88% ee) was determined by chiral HPLC. Column: Chiralcel
OD-H; solvent: cyclohexane/iPrOH (99.5:0.5); flow: 1.0 mLminꢀ1; major
enantiomer: tR =23.8 min, minor enantiomer: tR =61.9 min. Rf =0.02
(pentane/MTBE 10:1); [a]2D5 =ꢀ198.3 (c=1.43, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.14–8.12 (m, 1H), 7.42–7.34 (m, 3H), 7.22–7.11
(m, 3H), 6.87–7.84 (m, 1H), 6.64–6.58 (m, 2H), 5.71–5.68 (m, 1H), 4.85–
4.81 (m, 1H), 2.38–2.21 (m, 2H), 1.66–1.57 (m, 1H), 1.43–1.35 ppm (m,
1H); 13C NMR (75 MHz, CDCl3): d=163.9, 147.4, 143.0, 137.6, 136.3,
128.5, 128.0, 125.6, 122.9, 116.9, 111.1, 70.3, 54.9, 24.7, 21.3 ppm; FTIR
(neat): n˜ =3054, 2935, 1586, 1462, 1431, 1249, 974, 959, 880, 780,
693 cmꢀ1; HRMS (ESI): m/z: calcd for C17H16N2OH: 265.1335; found:
265.1333 [M+H]+.
A
ACHTUNGTREN[NUGN 2.2.2]oct-5-ene
ACHTUNGTRENNUNG
(15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), 2,3-dimethyl-cyclohexa-1,3-diene
(18 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and SiO2 chromatography (pen-
tane/MTBE 5:1) gave 7 as a yellow oil (30 mg, 99%). Enantiomeric
excess (95% ee) was determined by chiral HPLC. Column: Chiralcel
OD-H; solvent: cyclohexane/iPrOH 99:1; flow: 1.0 mLminꢀ1; major en-
antiomer: tR =9.6 min, minor enantiomer: tR =38.1 min. Rf =0.25 (pen-
tane/MTBE 5:1); [a]2D5 =+97.2 (c=1.3, CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.27–8.20 (m, 1H), 7.52–7.47 (m, 1H), 6.92–6.89 (m, 1H),
6.77–6.69 (m, 1H), 5.00 (m, 1H), 4.51–4.50 (m, 1H), 2.21–2.12 (m, 2H),
1.75 (s, 3H), 1.62 (s, 3H), 1.59–1.52 (m, 1H), 1.44–1.34 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=164.6, 147.1, 137.6, 132.7, 130.7, 116.4,
111.3, 75.7, 57.8, 24.9, 21.3, 16.3, 14.4 ppm; FTIR (neat): n˜ =2934, 2856,
1588, 1463, 1431, 1293, 1254, 1141, 1064, 963, 879, 780 cmꢀ1; HRMS
(ESI): m/z: calcd for C13H16N2OH: 217.1335 [M+H]+; found: 217.1332.
Trifluoromethanesulfonic acid (1S,4R)-3-pyridin-2-yl-2-oxa-3-azabicyclo-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), trifluoromethanesulfonic acid cy-
clohexa-1,5-dienyl ester (38 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and SiO2
chromatography (pentane/MTBE 5:1) gave 46 mg (99%) of 11c and 12c
as a mixture of isomers. The isomer ratio was determined by chiral
HPLC (11c/12c 1:2). The diastereoisomers were separated by flash chro-
matography (pentane/MTBE 10:1) to give 11c (15 mg, 32%) and 12c
(30 mg, 64%).
(1S,2R,6R,7R)-4,4-Dimethyl-9-pyridin-2-yl-3,5,8-trioxa-9-azatricy-
11c: Enantiomeric excess (81% ee) was determined by chiral HPLC.
Column: Chiralcel OD-H; solvent: cyclohexane/iPrOH 99.5:0.5; flow:
clo[5.2.2.02,6]undec-10-ene (9): According to GP1: (R,Rp)-Walphos-CF3
9082
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9078 – 9084

Enantioselective Nitroso-Diels–Alder Reaction
FULL PAPER
1.0 mLminꢀ1; major enantiomer: tR =20.8 min, minor enantiomer: tR =
34.5 min. Rf =0.5 (pentane/MTBE 5:1); [a]2D5 =+25.7 (c=0.53, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.26–8.24 (m, 1H), 7.56 (ddd, J=1.8,
7.5, 8.3, 1H), 6.96–6.93 (m, 1H), 6.86 (ddd, J=0.9, 4.9, 7.5, 1H), 6.15 (dd,
J=3.0, 6.6, 1H), 5.50 (dd, J=3.0, 1H), 5.01–4.97 (m, 1H), 2.36–2.23 (m,
2H), 1.96–1.84 (m, 1H), 1.53–1.42 ppm (m, 1H);13C NMR (75 MHz,
CDCl3): d=163.1, 147.8, 147.9, 137.9, 118.6 (q, J=319 Hz), 118.1, 115.5,
(neat): n˜ = 3052, 2931, 1670, 1589, 1463, 1433, 1265, 1109, 850, 737 cmꢀ1
;
HRMS (ESI): m/z: calcd for C12H14N2OH: 203.1179 [M+H]+; found:
203.1181.
5-Pyridin-2-yl-2,3,3a,5,5a,6,7,8-octahydro-1H-4-oxa-5-aza-as-indacene
(16): According to GP1: (R,Rp)-Walphos-CF3 (12.9 mg, 13.9 mmol), [CuI-
AHCTUNERTGG(UNNN CH3CN)4]PF6 (5.2 mg, 14 mmol), CH2Cl2 (1.5 mL), 2-nitrosopyridine
(15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), bicyclopentyl-1,1’-diene (22 mg,
0.17 mmol) in CH2Cl2 (1.0 mL) and SiO2 chromatography (pentane/
MTBE 5:1) gave 16 as a yellow oil (4.0 mg, 11%). Rf =0.5 (pentane/
MTBE 5:1); 1H NMR (300 MHz, CDCl3): d=8.23–8.21 (m, 1H), 7.56–
7.50 (m, 1H), 7.11–7.08 (m, 1H), 6.68 (ddd, J=7.1, 5.0, 0.9, 1H), 4.89–
4.75 (m, 1H), 4.28–4.23 (m, 1H), 2.46–2.13 (m, 6H), 1.88–1.73 (m, 3H),
1.59–1.48 (m, 2H), 1.49–1.37 ppm (m, 1H); 13C NMR (75 MHz, CDCl3):
d=160.5, 147.9, 137.7, 133.1, 131.3, 114.6, 108.7, 77.3, 58.3, 30.6, 30.5,
27.6, 25.1, 21.5, 20.5 ppm; FTIR (neat): n˜ = 2960, 2869, 1593, 1564, 1464,
1434, 1361, 1298, 1259, 1176, 770, 736 cmꢀ1; HRMS (ESI): m/z: calcd for
C15H18N2OH: 243.1492 [M+H]+, found: 243.1490.
111.9, 71.7, 55.6, 24.8, 21.0 ppm; FTIR (neat): n˜
= 2944, 1650, 1588,
1463, 1433, 1247, 1211, 1138, 1112, 888, 870 cmꢀ1; HRMS (ESI): m/z:
calcd for C12H11F3N2O4SH: 337.0464 [M+H]+; found: 337.0471.
12c: Enantiomeric excess (98% ee) was determined by chiral HPLC.
Column: Chiralcel OD-H; solvent: cyclohexane/iPrOH 99.5:0.5; flow:
1.0 mLminꢀ1; major enantiomer: tR =13.2 min, minor enantiomer: tR =
19.2 min. Rf =0.4 (pentane/MTBE 5:1); [a]2D5 =+71.6 (c=1.5, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.21–8.19 (m, 1H), 7.55 (ddd, J=1.8,
7.4, 8.3, 1H), 6.98–6.95 (m, 1H), 6.84 (ddd, J=0.9, 4.9, 7.4, 1H), 6.13 (dd,
J=2.7, 6.6, 1H), 5.62–5.59 (m, 1H), 4.87–4.84 (m, 1H), 2.38–2.22 (m,
2H), 1.78–1.63 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=162.9,
147.4, 147.1, 137.9, 119.3, 118.6 (q, J=319.2 Hz), 117.8, 111.9, 71.8, 53.2,
24.9, 21.1 ppm; FTIR (neat): n˜ = 2944, 1588, 1463, 1431, 1211, 1138,
1108, 886, 840, 780 cmꢀ1; HRMS (ESI): m/z: calcd for C12H11F3N2O4SH:
337.0464 [M+H]+; found: 337.0467.
A
ACHTUNGTRNE[NUNG 2.2.2]oct-7-ene-5-carboxylic
AHCTUNGTRENNUNG
trosopyridine (15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), 2H-pyridine-1-car-
boxylic acid methyl ester (23 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and
A
ACHTUNGERTN[NUNG 2.2.2]oct-5-ene (11d):
SiO2 chromatography (pentane/MTBE 1:1) gave 18 as
a yellow oil
(32 mg, 94%). Enantiomeric excess (96% ee) was determined by chiral
HPLC. Column: Chiralcel OD-H; solvent: cyclohexane/iPrOH 99:1;
flow: 1.0 mLminꢀ1; major enantiomer: tR =30.9 min, minor enantiomer:
tR =41.6 min. Rf =0.3 (pentane/MTB 1:1); [a]2D5 =+146.6 (c=1.3, CHCl3);
1H NMR (600 MHz, CDCl3): d=8.20–8.14 (m, 1H), 7.52–7.490 (m, 1H),
6.91–6.87 (m, 1H), 6.81–6.79 (m, 1H), 6.56–6.51 (m, 1H), 6.34–6.30 (m,
1H), 6.21–6.05 (m, 1H), 5.47–5.43 (m, 1H), 3.91–3.89 (m, 1H), 3.73–3.70
(m, 3H), 3.29–3.25 ppm (m, 1H); 13C NMR (151 MHz, CDCl3): d=161.7,
161.6, 154.4, 153.5, 146.4, 146.3, 136.9, 136.8, 129.1, 128.6, 128.5, 128.2,
116.7, 110.7, 110.6, 74.9, 74.5, 51.9, 51.9, 51.4, 51.3, 43.6 ppm; FTIR
(neat): n˜ = 2955, 2250, 1709, 1590, 1433, 1395, 1339, 1293, 1124, 912, 867,
733 cmꢀ1; HRMS (ESI): m/z: calcd for C12H13N2O3H: 248.1030 [M+H]+,
found: 248.1022.
ACHTUNGTRENNUNG
(15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), 2-butylcyclohexa-1,3-diene
(23 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and SiO2 chromatography (pen-
tane/MTBE 7.5:1) gave 11d as a colorless oil (33 mg, 97%, ~2% other
isomer formed). Enantiomeric excess (87% ee) was determined by chiral
HPLC. Column: Chiralcel OD-H; solvent: cyclohexane/iPrOH
(99.5:0.5); flow: 1.0 mLminꢀ1; major enantiomer: tR =48.2 min, minor en-
antiomer: tR =41.8 min. Rf =0.4 (pentane/MTBE 5:1); [a]2D5 =+21.4 (c=
1.35, CHCl3); 1H NMR (300 MHz, CDCl3): d=8.20–8.18 (m, 1H), 7.50–
7.44 (m, 1H), 6.91–6.88 (m, 1H), 6.73 (ddd, J=0.8, 4.9, 7.2, 1H), 6.03–
6.00 (m, 1H), 5.10 (m, 1H), 4.71–4.68 (m, 1H), 2.28–2.14 (m, 2H), 2.01–
1.87 (m, 2H), 1.57–1.46 (m, 1H), 1.41–1.06 (m, 5H), 0.77 ppm (t, J=7.2,
3H);13C NMR (75 MHz, CDCl3): d=164.5, 147.3, 145.4, 137.4, 122.1,
116.5, 111.3, 70.7, 56.5, 34.2, 28.7, 25.3, 22.3, 21.1, 13.9 ppm; FTIR (neat):
[(3aR,4S,7R,7aR)-7-(tert-Butyldimethylsiloxy)-2,2-dimethyl-3a,4,7,7a-tet-
ꢀ
rahydro-1,3-benzodioxol-4-yl]-pyridin-2-yl-amine (19): The N O bond of
9
n˜
= 3050, 2958, 2931, 1587, 1568, 1463, 1432, 1252, 959, 881, 830,
was cleaved according to the previously reported procedure.[10]
779 cmꢀ1; HRMS (ESI): m/z: calcd for C15H20N2OH: 245.1648 [M+H]+;
[Mo(CO)6] (518 mg, 1.96 mmol) and NaBH4 (79 mg, 2.1 mmol) were
added to solution of (425 mg, 1.63 mmol) in MeOH/H2O 10:1
found: 245.1650.
a
9
rac-1-Methyl-3-pyridin-2-yl-2-oxa-3-azabicyclo
(1S,4R)-4-methyl-3-pyridin-2-yl-2-oxa-3-azabicyclo
According to GP1: (R,Rp)-Walphos-CF3 (12.9 mg, 13.9 mmol), [CuI-
ACHTUNGTRENNUNG(CH3CN)4]PF6 (5.2 mg, 14 mmol), CH2Cl2 (1.5 mL), 2-nitrosopyridine
(15 mg, 0.14 mmol) in CH2Cl2 (0.5 mL), 1-methylcyclohexa-1,3-diene
(16 mg, 0.17 mmol) in CH2Cl2 (1.0 mL) and SiO2 chromatography (pen-
tane/MTBE 5:1) gave 26 mg (92%) of 14a and 14b as a mixture of iso-
mers. The isomer ratio was determined by chiral HPLC (14a/14b 1:2.1).
The diastereoisomers were separated by flash chromatography (pentane/
MTBE 5:1) to get 14a (8 mg, 28%) and 14b (17 mg, 61%).
14a: Rf =0.4 (pentane/MTBE 5:1); 1H NMR (300 MHz, CDCl3): d=
8.21–8.19 (m, 1H), 7.55–7.49 (m, 1H), 6.95–6.92 (m, 1H), 6.79–6.74 (m,
1H), 6.33–6.29 (m, 1H), 6.25–6.22 (m, 1H), 5.33–5.31 (m, 1H), 2.34–2.24
(m, 1H), 2.06–1.98 (m, 1H), 1.68–1.58 (m, 1H), 1.53 (s, 3H), 1.48–
1.38 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=163.7, 146.8, 137.9,
135.2, 131.8, 116.5, 111.6, 75.0, 52.6, 30.9, 23.2, 22.1 ppm; FTIR (neat):
n˜ = 3051, 2973, 2932, 1588, 1462, 1432, 1379, 1197, 850, 782 cmꢀ1; HRMS
(ESI): m/z: calcd for C12H14N2OH: 203.1179 [M+H]+; found: 203.1184.
ACHTUNGTRENNUNG
(27 mL). The reaction mixture was heated to 658C and stirred for 10 h at
that temperature. The precipitate was removed by filtration through a
short pad of Celite, and the filtrate was concentrated in vacuo. The resi-
due was dissolved in CH2Cl2, washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was passed through a
short pad of silica gel (pentane/acetone 2:1) and concentrated in vacuo.
The resulting mass was dissolved in DMF (3 mL), treated successively
with TBSCl (353 mg, 2.35 mmol) and imidazole (320 mg, 4.70 mmol), and
stirred for 24 h at RT. A sat. aq NaHCO3 solution was added to the reac-
tion mixture, and the resulting solution was extracted with MTBE. The
combined organic layers were washed with brine, dried over MgSO4, con-
centrated under vacuum, and the residue was subjected to flash column
AHCTUNGTRENNUNG
chromatography (pentane/MTBE 4:1) to give 19 as
a colorless oil
(560 mg, 91%, over two steps). Rf =0.3 (pentane/MTBE 5:1); [a]D25
=
+4.2 (c=1.15, CHCl3); 1H NMR (300 MHz, CDCl3): d=8.11–8.01 (m,
1H), 7.39–7.33 (m, 1H), 6.58–6.54 (m, 1H), 6.42–6.37 (m, 1H), 5.95–5.94
(m, 2H), 4.95 (d, J=8.1, 1H), 4.53–4.49 (m, 1H), 4.32–4.21 (m, 3H), 1.42
(s, 3H), 1.32 (s, 3H), 0.93 (s, 9H), 0.14 (s, 3H), 0.13 ppm (s,
3H);13C NMR (75 MHz, CDCl3): d=157.9, 148.3, 137.3, 132.4, 130.7,
113.3, 108.6, 108.3, 79.5, 77.0, 69.1, 50.0, 26.9, 26.0, 24.8, 18.2, ꢀ4.6,
ꢀ4.6 ppm; FTIR (neat): n˜ = 2954, 2930, 1857, 1601, 1573, 1483, 1382,
1255, 1211, 1117, 1061, 897, 838, 776, 734 cmꢀ1; HRMS (ESI): m/z: calcd
for C20H32N2O3SiH: 377.2255 [M+H]+; found: 377.2249.
14b: Enantiomeric excess (93% ee) was determined by chiral HPLC.
Column: Chiralcel OD-H; solvent: cyclohexane/iPrOH (97:03); flow:
1.0 mLminꢀ1; major enantiomer: tR =22.1 min, minor enantiomer: tR =
14.4 min. Rf =0.3 (pentane/MTBE 5:1); [a]2D5 =ꢀ8.4 (c=0.25, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.29–8.28 (m, 1H), 7.56–7.50 (m, 1H),
6.98 (d, J=8.1, 1H), 6.94–6.89 (m, 1H), 6.61–6.57 (m, 1H), 5.93 (d, J=
8.1, 1H), 4.79–4.75 (m, 1H), 2.35–2.24 (m, 1H), 2.21–2.15 (m, 1H), 1.71
(s, 3H), 1.44–1.39ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=146.5,
137.2, 134.9, 130.4, 119.0, 116.4, 69.6, 60.0, 30.4, 26.6, 25.1 ppm; FTIR
[(3aR,4S,7R,7aR)-7-(tert-Butyldimethylsiloxy)-2,2-dimethyl-3a,4,7,7a-tet-
rahydro-1,3-benzodioxol-4-yl]-pyridin-2-yl-carbamic acid methyl ester
(20): A 3m solution of CH3MgCl in THF (0.57 mL, 1.7 mmol) was added
dropwise to a solution of 19 (541 mg, 1.43 mmol) in THF (8.0 mL) at RT,
Chem. Eur. J. 2009, 15, 9078 – 9084
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9083

A. Studer et al.
and the mixture was stirred for 10 min at that temperature. Methyl chlor-
oformate (0.34 mL, 4.3 mmol) was then added, and stirring was continued
at RT for 12 h. Then the reaction was quenched with H2O, and the result-
ing solution was extracted with CH2Cl2 (3ꢃ30 mL). The combined organ-
ic layers were washed with brine, dried over MgSO4, and concentrated in
vacuo; the residue was subjected to flash column chromatography (pen-
tane/MTB 2:1) to give 20 as a colorless oil (601 mg, 96%). Rf =0.2 (pen-
tane/MTBE 5:1); [a]2D5 =+19.8 (c=1.33, CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.41–8.39 (m, 1H), 7.71–7.65 (m, 1H), 7.50–7.44 (m, 1H),
7.10 (ddd, J=0.9, 4.8, 7.2, 1H), 5.78 (dt, J=2.4, 10.1, 1H), 5.62 (ddd, J=
1.8, 3.0, 10.1, 1H), 4.93–4.89 (m, 1H), 4.55–4.51 (m, 1H), 4.21–4.17 (m,
1H), 4.06 (dd, J=5.3, 7.0, 1H), 3.74 (s, 3H), 1.38 (s, 3H), 1.31 (s, 3H),
0.91 (s, 9H), 0.12 (s, 3H), 0.10 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=155.6, 154.2, 148.2, 137.6, 131.3, 128.2, 122.1, 121.3, 108.5, 80.4, 75.8,
71.5, 58.9, 53.0, 27.7, 26.0, 25.7, 18.3, ꢀ4.4, ꢀ4.7 ppm; FTIR (neat): n˜ =
2955, 2932, 2857, 1718, 1589, 1470, 1434, 1381, 1326, 1257, 1111, 1065,
Indranil Chatterjee for performing some experiments and Solvias AG for
donation of chiral ligands.
[1] Reviews: a) H. Waldmann, Synthesis 1994, 535–551; b) J. Streith, A.
Defoin, Synthesis 1994, 1107–1117; c) P. F. Vogt, M. Miller, Tetrahe-
dron 1998, 54, 1317–1348; d) H. Yamamoto, N. Momiyama, Chem.
Commun. 2005, 3514–3525; e) Y. Yamamoto, H. Yamamoto, Eur. J.
Org. Chem. 2006, 2031–2043; f) H. Yamamoto, M. Kawasaki, Bull.
Chem. Soc. Jpn. 2007, 80, 595–607.
[2] a) X. Ding, Y. Ukaji, S. Fujinami, K. Inomata, Chem. Lett. 2003, 32,
582–583; b) Y. Yamamoto, H. Yamamoto, J. Am. Chem. Soc. 2004,
126, 4128–4129; c) Y. Yamamoto, H. Yamamoto, Angew. Chem.
2005, 117, 7244–7247; Angew. Chem. Int. Ed. 2005, 44, 7082–7085.
[3] a) C. K. Jana, A. Studer, Angew. Chem. 2007, 119, 6662–6664; C. K.
Jana, A. Studer, Angew. Chem. 2007, 119, 6662–6664; Angew.
Chem. Int. Ed. 2007, 46, 6542–6544; b) C. K. Jana, A. Studer, Chem.
Eur. J. 2008, 14, 6326–6328.
836, 777, 733 cmꢀ1
; HRMS (ESI): m/z: calcd for C22H34N2O5SiNa:
457.2129 [M+Na]+, found: 457.2106.
((3aR,4S,7R,7aS)-7-Hydroxy-2,2-dimethyl-3a,4,7,7a-tetrahydro-1,3-benzo-
dioxol-4-yl)-carbamic acid methyl ester (21): Methyl trifluoromethanesul-
fonate (0.10 mL, 0.89 mmol) was added dropwise to a solution of 20
(0.35 g, 0.81 mmol) in CH2Cl2 (20 mL) at 08C, and the resulting solution
was stirred for 12 h at that temperature. Then the solvent was removed
under vacuum, and the residue was dissolved in MeOH (9.5 mL). A 2m
aq NaOH solution (4.7 mL) was added, and stirring was continued at
508C for 6 h. The solvents were removed, and the resulting residue was
extracted with EtOAc (3ꢃ30 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (pentane/acetone
2:1) to afford 21 as a colorless oil (160 mg, 82%). Rf =0.6 (pentane/ace-
tone 1:1); [a]2D5 =+41.1 (c=1.3, CHCl3); 1H NMR (300 MHz, CDCl3):
d=5.95–5.90 (m, 1H), 5.79 (ddd, J=1.5, 3.6, 9.7, 1H), 5.29–5.26 (m, 1H),
4.24–4.21 (m, 3H), 4.13–4.12 (m, 1H), 3.68 (s, 3H), 2.82 (brs, 1H), 1.44
(s, 3H), 1.34 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=156.7, 131.3,
129.9, 109.3, 79.4, 69.2, 52.4, 51.3, 27.1, 24.9 ppm; FTIR (neat): n˜ = 3333,
[4] Walphos ligand: T. Sturm, W. Weissensteiner, F. Spindler, Adv.
Synth. Catal. 2003, 345, 160–164.
[5] a) O. Werbitzky, K. Klier, H. Felber, Liebigs Ann. Chem. 1990, 267–
270; b) T. Hudlicky, H. F. Olivo, Tetrahedron Lett. 1991, 32, 6077–
6080; c) T. Hudlicky, H. Luna, H. F. Olivo, C. Andersen, T. Nugent,
J. D. Price, J. Chem. Soc. Perkin Trans. 1 1991, 2907–2917; d) R.
Leung-Toung, Y. Liu, J. M. Muchowski, Y.-L. Wu, Tetrahedron Lett.
1994, 35, 1639–1642.
[6] A. Defoin, C. Schmidlin, J. Streith, Tetrahedron Lett. 1984, 25,
4515–4518.
[7] Spin-restricted, dispersion-corrected (DFT-D[7a]) all-electron density
functional theory by using the PBE[7b] functional and polarized split-
valence (SV(P)[7c]) Gaussian AO basis sets. Calculations were per-
formed by using TURBOMOLE[7a] and the RI approximation[7e] for
the two-electron integrals; a) S. Grimme, J. Comput. Chem. 2006,
27, 1787–1799; b) J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev.
Lett. 1996, 77, 3865–3868; c) A. Schꢀfer, H. Horn, R. Ahlrichs, J.
Chem. Phys. 1992, 97, 2571–2577; d) TURBOMOLE Ver 5.9, R.
Ahlrichs et al. See http://www.turbomole.com; e) K. Eichkorn, O.
Treutler, H. ꢄhm, M. Hꢀser, R. Ahlrichs, Chem. Phys. Letters 1995,
240, 283–289.
2989, 2937, 1703, 1538, 1457, 1376, 1261, 1212, 1062, 912, 873, 732 cmꢀ1
;
HRMS (ESI): m/z: calcd for C11H17NO5Na: 266.1004 [M+Na]+; found:
266.0975.
Acetic acid (1R,4S,5R,6S)-5,6-diacetoxy-4-acetylamino-cyclohex-2-enyl
ester (22): Acetyl chloride (0.39 mL, 5.4 mmol) and NaI (0.81 g,
5.4 mmol) were added to a solution of 21 (88 mg, 0.36 mmol) in MeCN
(6 mL) at RT. The resulting mixture was stirred at 658C for 40 h. The re-
action was cooled to 08C and quenched with sat. aq NaHSO3 and
NaHCO3 solutions. Then the resulting mixture was extracted with
CH2Cl2 (3ꢃ20 mL), and the combined organic layers were washed with
brine, dried over MgSO4, and concentrated under vacuum. The residue
was purified by flash column chromatography (pentane/acetone 2:1) to
afford 22 as a colorless oil (65 mg, 57%). The physical data are in agree-
[8] A. G. Leach, K. N. Houk, J. Org. Chem. 2001, 66, 5192–5200.
[9] Because many reactions delivered the product in quantitative yield
and only one equivalent of 2-nitrosopyridine was used, the nitroso
compound did not oxidize the CuI catalyst to the corresponding CuII
species under the applied conditions, see: J. A. K. Howard, G. Ilya-
shenko, H. A. Sparkes, A. Whiting, A. R. Wright, Adv. Synth. Catal.
2008, 350, 869–882.
[10] S. Cicchi, A. Goti, A. Brandi, A. Guarna, F. De Sarlo, Tetrahedron
Lett. 1990, 31, 3351–3354.
[11] E. C. Taylor, C. P. Tseng, J. B. Rampal, J. Org. Chem. 1982, 47, 552–
555.
ment with those reported in the literature.[5a,c] Rf =0.2 (pentane/acetone
20
2:1); [a]2D5 =ꢀ30.6 (c=0.45, CHCl3), (lit:[5c] [a] for ent-22=+33 (c=0.4,
D
CHCl3)); 1H NMR (300 MHz, CDCl3): d=5.81 (m, 2H), 5.67 (d, J=8.4,
1H), 5.29–5.19 (m, 34H), 4.86–4.80 (m, 1H), 2.09 (s, 3H), 2.07 (s, 6H),
1.99 ppm (s, 3H);13C NMR (75 MHz, CDCl3): d=170.9, 170.1, 170.0,
169.8, 131.5, 125.1, 69.8, 69.7, 68.4, 47.9, 23.4, 21.0, 21.0 ppm; FTIR
(neat): n˜ = 1748, 1659, 1538, 1371, 1225, 1053, 1024, 733 cmꢀ1; HRMS
(ESI): m/z: calcd for C14H19NO7Na: 336.1054 [M+Na]+, found: 336.1047.
[12] N. C. C. Yang, M. J. Chen, P. Chen, J. Am. Chem. Soc. 1984, 106,
7310–7315.
[13] R. N. Buckle, P.-Y. Liu, E. W. D. Roberts, D. J. Burnell, Tetrahedron
1999, 55, 11455–11464.
[14] A. S. E. Karlstroem, M. Roenn, A. Thorarensen, J.-E. Bꢀckvall, J.
Org. Chem. 1998, 63, 2517–2522.
Acknowledgements
[15] P. K. Freeman, J. C. Danino, B. K. Stevenson, G. E. Clapp, J. Org.
Chem. 1990, 55, 3867–3875.
We thank the NRW Graduate School of Chemistry (stipend to C.K.J.)
and Novartis Pharma AG (Young Investigator Award to A.S.). We thank
Received: May 19, 2009
Published online: July 30, 2009
9084
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9078 – 9084