Preparation of 2,4-disubstituted cyclopentenones by enantioselective iridium-catalyzed allylic alkylation: Synthesis of 2′-methylcarbovir and TEI-9826

Article abstract of DOI:10.1002/chem.200800495

A broadly applicable synthesis of chiral 2- or 2,4-substituted cyclopent-2-enones has been developed by combining asymmetric iridium-catalyzed allylic alkylation reactions and ruthenium-catalyzed ring-closing meta-thesis. Enantiomeric excesses (ee values)

Full text of DOI:10.1002/chem.200800495

DOI: 10.1002/chem.200800495
Preparation of 2,4-DisubstitutedCyclopentenones by Enantioselective
Iridium-Catalyzed Allylic Alkylation: Synthesis of 2’-Methylcarbovir and
TEI-9826
[a]
Pierre Dübon, Mathias Schelwies, andGünter Helmchen*
Dedicated to Professor Volker Jäger on the occasion of his 65th birthday
Abstract: A broadly applicable synthe-
sis of chiral 2- or 2,4-substituted cyclo-
pent-2-enones has been developed by
combining asymmetric iridium-cata-
lyzed allylic alkylation reactions and
ruthenium-catalyzed ring-closing meta-
thesis. Enantiomeric excesses (ee
values) in the range of 95–99% ee have
been achieved. This method offers a
straightforward access to biologically
active prostaglandins of the PGA type.
As an example, an enantioselective
synthesis of the prostaglandin-analogue
13,14-dihydro-15-deoxy-D7-prostaglan-
din-A1-methyl ester (TEI-9826) has
been carried out. Furthermore, the car-
bonucleoside 2’-methylcarbovir has
been prepared from O-protected 4-hy-
droxymethyl-2-methyl-cyclopent-2-en-
Keywords: allylic alkylation · car-
bocyclic nucleosides · cyclopente-
nones · iridium · phosphoramidites
A
U
Introduction
Many natural products and pharmaceuticals containing a cy-
clopentane moiety show interesting biological activity. For
example, alkylidene cyclopentenones, such as the prosta-
glandins D7-PGA1 methyl ester or 15-deoxy-D12,14-PGJ2
(Figure 1), display anti-inflammatory, antiviral or antitumor-
al activities.[1] Stereoselective synthesis of these compounds
remains a topic of active investigation in organic chemis-
try.[2]
Recently, we have communicated a new enantioselective
method, which offers a straightforward access to 4- and 2,4-
disubstituted cyclopentenones.[3] These compounds are of
special interest as intermediates for the synthesis of 2,4-di-
Figure 1. Examples of biologically active cyclopentenones.
substituted cyclopentenones such as phomapentenone A or
of 2-substituted carbocyclic nucleosides, as will be illustrated
later.[4] The simpler 4-substituted cyclopentenones, which
are also accessible by using the reported method, can serve
as precursors in the synthesis of the cyclopentenones that
are shown in Figure 1. Further functionalization of a 2,4-di-
sition by reaction with a nucleophile or at the 5-position by
reaction with an electrophile (Scheme 1).[5]
A
[a] P. Dübon, M. Schelwies, Prof. Dr. G. Helmchen
Organisch-Chemisches Institut der Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544205
Scheme 1. Possibilities for the functionalization of 2,4-disubstituted cyclo-
pentenones.
E-mail: g.helmchen@oci.uni-heidelberg.de
6722
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Chem. Eur. J. 2008, 14, 6722 – 6733

FULL PAPER
Herein, we present applications of our method in the syn-
theses of the prostaglandin analogue TEI-9826 (Figure 1)
and the carbocyclic nucleoside 2’-methylcarbovir. TEI-9826
is available by aldol condensation from 4-n-octyl-cyclopent-
A
ability of the method to the synthesis of prostaglandins. The
targeted carbonucleoside was accessed from a 2,4-disubsti-
tuted cyclopentenone (Scheme 2).
Scheme 4. Allylic substitution by using a malonic amide of the Weinreb
type as a pronucleophile.
Scheme 2. A cyclopentenone as a precursor for 2’-methylcarbovir.
The sodium enolate of the Weinreb-type amide 1 was em-
ployed as pronucleophile (Scheme 4). Reaction conditions
typical for malonates were used (conditions D according to
Our synthesis of cyclopentenones is schematically de-
scribed in Scheme 3, and it involves the following concepts:
1) The chirality center C-4 is constructed with high enantio-
selectivity by iridium-catalyzed asymmetric allylic alkyla-
tion[6] by using the enolate of the Weinreb-type amide 1 as a
novel nucleophile.[7] 2) Demethoxycarbonylation and a sub-
sequent acylation by addition of an alkenylmagnesium
halide yields a second olefinic moiety. 3) The cyclopente-
none is prepared by ring-closing metathesis (RCM).[8] The
combination of an allylic substitution and a RCM reaction
has already proven to be a very powerful tool in natural-
product synthesis.[9]
Table 1. Iridium-catalyzed allylic alkylation of carbonates 2a–d with
Weinreb-type amide 1 according to Scheme 4.
Entry Sub
strate
L*
t
Yield
3/4[c]
ee[d] [%](absolute
configuration)
[h][a] 3+4 [%][b]
1
2a
2a
L1
L2
L1
L2
L1 18
L2 5.5
189
0.5
3
>98:2
>98:2
94:6
94:6
83:17 96 (R)
84:16 99 (R)
86:14 97.5 (R)
66:34 98 (R)
96 (R)
98 (R)
95 (R)
95 (R)
2[e]
3[e]
4
88
83
76
89
62
85
69
2b[f]
2b[f]
2c[f]
2
5
6
2c[f]
7[e]
8
2dL1
2dL2
6
1.5
[a] Reaction time. [b] Yield of the isolated mixture of the regioisomeric
products 3 and 4. [c] Determined by 1H NMR spectroscopy. [d] Deter-
mined by HPLC on a chiral column. In all cases the branched com-
pounds 3 were obtained as 1:1 mixtures of diastereoisomers. All absolute
configurations refer to the starred (*) chiral center in Scheme 4. Com-
pounds 4 were racemic. [e] 2 mol% of iridium was used. [f] The substrate
contained approximately 3% of the Z diastereoisomer.[15]
reference [6a]). If not otherwise stated, the reactions were
Scheme 3. Retrosynthetic concept.
carried out with 2 mol% of [IrCl(cod)]2 in combination with
A
the ligands L1 and L2. Recently reported salt-free condi-
tions, which gave excellent results for malonates,[12] were not
suitable for the malonic amide 1, which is expected to be
less acidic than a malonic ester. The allylic carbonates 2a–d
were prepared by standard procedures; amide 1 was avail-
able in a single step by reaction of methyl 3-chloro-3-oxo-
Results andDiscussion
Iridium-catalyzed allylic alkylation: This reaction was intro-
duced in 1997. Today enantioselectivities >90% ee (ee=en-
antiomeric excess) can be achieved routinely.[6] The com-
monly applied catalyst is prepared from a mixture of
propionate with N,O-di
N
N
triethylamine.
A
G
The results obtained for the allylic substitutions depicted
in Scheme 4 are displayed in Table 1. The reactions general-
ly proceeded in good yield and with high enantio- and regio-
selectivity. Selectivities were similar to those obtained with
dimethyl sodiomalonate, that is, the enantiomeric excesses
were found to be in the range 95–99% ee and the regiose-
lectivities in the range of 83:17 to 98:2. An exception is the
reaction with substrate 2d, which proceeded with low regio-
selectivity (70:30) upon the use of ligand L2, as was previ-
diene) and a chiral phosphora-
midite by reaction with base,
which effects C H activation.
The phosphoramidite ligands
used here (L1 and L2 ) were in-
troduced by Feringa[10] and
Alexakis.[11]
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6723

G. Helmchen et al.
ously found with malonates as nucleophiles;[6f] however, in
combination with the less bulky ligand L1, selectivities were
significantly better. Regioselectivities were determined by
1H NMR spectroscopy; the requisite pure linear regioiso-
A
using standard procedures. The enantioselectivities of 3a–d
were determined by HPLC on a Daicel column.
The branched products 3 were obtained as 1:1 mixtures of
diastereoisomers. Their separation was not possible, except
in the case of malonic amide 3d of which both diastereoiso-
mers were sufficiently stable for separation by HPLC.
Scheme 5. Conversion of amides 3 to chiral cyclopentenones 7a–f.
The TBDPS-protected product (+)-(2R,3R)-3d was crys-
talline and its absolute and relative configuration was deter-
mined by X-ray crystal structure analysis.[13] For the other
products, absolute configurations were assigned according to
a rule that has been found to hold without exception so
far.[6a,14]
Scheme 6. LDA (LDA=lithium diisopropylamide) was used
as the base[22] for the aldol reaction of 7d with methyl 6-for-
mylhexanoate to yield the anti aldol product 8 in 58% yield.
The relative configuration of 8 was determined by compari-
son of coupling constants between Ha and Hb (8.4 Hz) with
values reported for similar compounds by Kobayashi et al.[22]
Coupling constants of Ja,b ꢀ3 and 8.4–9.6 Hz are typical for
syn and anti aldol products, respectively. For the subsequent
elimination, a procedure of Kobayashi et al. was applied,[22]
which involved conversion of the alcohol 8 to the mesylate
9, which was subsequently treated with neutral Al2O3 to
give TEI-9826 (10) in 77% yield over two steps. This kind
of elimination is known as a syn-specific reaction and yield-
ed the (E)-olefin.[23] The overall yield of TEI-9826 (10) from
7d was 45%.
Preparation of the 2,4-disubstituted cyclopentenones 7–12:
Mixtures of the regioisomers 3 and 4 were converted into
the 2,4-disubstituted cyclopentenones in three steps
(Scheme 5, Table 2) as follows: Demethoxycarbonylation of
3 and 4 by saponification/decarboxylation gave amides 5 in
yields of >80%. In the following step, amides 5 were con-
verted into enones 6 by Grignard reactions under previously
described conditions.[16] Finally, RCM with Grubbs II cata-
lyst[17] yielded 2,4-disubstituted cyclopentenones 7a–f. In this
step, impurities resulting from the linear regioisomers 4
were easily removed by column chromatography. After
RCM, the enantiomeric excesses were checked by HPLC
again and no racemization was found. With the exception of
the extremely volatile enone 7c, the overall yields exceeded
50%.
Synthesis of 2’-methylcarbovir: Carbonucleosides often dis-
play conformers different from those of the corresponding
nucleosides. One reason is the lack of an anomeric effect.
As a remedy for this problem, medicinal chemists are devis-
ing carbocyclic nucleosides that are locked in conformations
which are considered to be important for biological activi-
ty.[24] 2’-Substituted carbocyclic nucleosides constitute one
class of conformationally locked compounds, and according-
ly are interesting targets for synthesis.[25] The 2,4-disubstitut-
ed cyclopentenone 7 f appears to be well suited as a precur-
sor for these compounds. We have tested this approach by
carrying out an asymmetric synthesis of 2’-methylcarbovir, a
compound previously synthesized by Crimmins et al.[25b] who
used an auxiliary-controlled aldol reaction and RCM as key
steps.
Enone 7c commands particular interest because it has
been identified as a volatile flavor ingredient of dried
fish.[18] Both enantiomers were prepared and their olfactory
properties characterized (Table 3).
Synthesis of the prostaglandin analogue TEI-9826 (10): The
prostaglandin analogue TEI-9826 (10) shows activity against
cisplatin-resistant tumors.[19] Furthermore, a new antitumor
mechanism has been proposed for this compound.[20] Synthe-
ses of the racemate and of one of the pure enantiomers
(98% ee), obtained by resolution, have been described.[21]
The transformation of cyclopentenone 7d into TEI-9826
has already been described by Monneret et al.[21c] However,
no experimental details have been published. Accordingly,
we repeated this work with (À)-(S)-7d as described in
Our synthesis of 2’-methylcarbovir from 7 f required five
steps and is described in Schemes 7 and 8. In the first step,
(S)-7 f was reduced with DIBAL (diisobutylaluminum hy-
dride) to give the cis-alcohol 11 accompanied by a small
6724
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Chem. Eur. J. 2008, 14, 6722 – 6733

Enantioselective Iridium-Catalyzed Allylic Alkylation
Table 2. Synthesis of cyclopentenones according to Scheme 5.
FULL PAPER
A Pd-catalyzed allylic amina-
tion was planned as the next
step (Scheme 8). This is a stan-
dard step in carbonucleoside
synthesis that has been carried
out often before. However, it
usually gives rise to mixtures of
isomers: 1) The formation of re-
gioisomers with respect to N-9
and N-7 of the purine has been
observed frequently with vari-
ous nucleobases, such as 2-
Entry
Starting material
R1
R2[c]
Yield [%][a]
Product
ee [%][b]
1
(R)-3a
Ph
H
66
97
2
3
(R)-3a
(R)-3b
Ph
Ph
55
96
95
amino-6-chloropurine,
which
was used here.[25a,b,26] 2) The for-
mation of isomers with respect
to the cyclopentene moiety has
also been described. Cis and
trans isomers[27] and 1,2- and
1,4-regioisomers have been en-
countered.[27,28]
Me
Me
44[c]
In our synthesis, the allylic
carbonate 13 was reacted with
2-amino-6-chloropurine. The re-
gioisomers 14 and 15 were
formed in an 86:14 ratio. The
mixture was treated with pyridi-
ne·HF to effect deprotection,
and the resultant alcohols 16
and 17 were separated. The rel-
ative and absolute configura-
tions of both isomers were con-
firmed by X-ray crystal struc-
ture analysis (see below).[13] The
final transformation of 16 into
2’-methylcarbovir (18) by treat-
ment with NaOH proceeded in
82% yield. NMR spectroscopic
data of 18 were in accordance
with data published by Crim-
mins et al.[25b] However, the op-
4
5
(R)-3c
(R)-3c
n-octyl
n-octyl
H
56
50
96
Me
n.d.[d]
6[e]
(R)-3d
CH2Oꢀ
Me
56
98
[a] Starting from 3 and 4. [b] Determined by HPLC on a chiral column; in each case both enantiomers were
prepared. [c] Volatile compound. [d] n.d.=not determined. [e] Saponification with LiOH.
Table 3. Olfactory characterization of (S)- and (R)-7c.[a]
Substance
Fragrance description
(À)(S)-7c
Ethereal, herbaceous and nutty in the direction of ha-
zelnut, sweeter in tonality but also significantly weaker
in strength compared with its enantiomer
(95.5% ee)
(+)(R)-7c
(93% ee)
More intense in odor strength compared with its enan-
tiomer, and more pronounced tobacco and leathery
character with haylike facets, besides also ethereal, her-
baceous, and sweet
[a] Carried out by Givaudan SA (Dr. P. Kraft), Dübendorf, Switzerland.
amount of the trans-diastereoisomer 12. Pure 11 and 12
were obtained by column chromatography in 80 and 15%
yields, respectively. Alcohol 11 was transformed into the car-
bonate 13 (86%) in the standard manner.
Scheme 6. Conversion of cyclopentenone 7d to prostaglandin analogue
TEI-9826 (10). Ms=methanesulfonyl.
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G. Helmchen et al.
Conclusion
We have presented a short and flexible route to 2,4-disubsti-
tuted cyclopentenones. Key steps were an iridium-catalyzed
allylic substitution and a ruthenium-catalyzed ring-closing
metathesis reaction. Cyclopentenones 7a–f were synthesized
in excellent enantiomeric excesses and in good yields. The
first asymmetric synthesis of 2,4-dimethylcyclopentenone 7c
and the flavor description of both enantiomers of this com-
pound are reported. Furthermore, the prostaglandin ana-
logue TEI-9826 and the carbonucleoside 2’-Methylcarbovir
were synthesized by starting from cyclopentones 7d and 7 f,
respectively.
Scheme 7. Synthesis of carbonate 13 (ꢀ=Si(tBuPh2), Py=pyridine).
A
tical rotation of [a]2D0 =+10.4 (c=0.11 in MeOH) is com-
pletely different from the reported value. To reliably deter-
mine the ee and to reconfirm the optical rotation measured
by us, the enantiomer of 18 was also prepared. The enantio-
meric excess of 18 was determined to be 97.5% ee; accord-
ingly, our synthesis had proceeded without racemization.
Compound 16 displays a pseudoequatorial conformation
in the solid state (Figure 2), which is very similar to that of
the cyclopentene moiety of Carbovir.[29] However, the struc-
tures differ considerably with respect to the torsion angle
Experimental Section
General: 1H NMR spectra were recorded at RT on Bruker AC-300
(300 MHz) or Bruker Avance 500 (500 MHz) spectrometers. Chemical
shifts are reported in d units relative to CHCl3 (dH =7.26 ppm). 13C NMR
spectra were recorded on Bruker AC-300 (75 MHz) or Bruker Avance
500 (125 MHz) spectrometers. Chemical shifts are reported in d units rel-
ative to CHCl3 (dC =77.16 ppm (central line of the triplet)). The follow-
ing abbreviations were used throughout: s=singlet, d=doublet, t=trip-
let, q=quartet, m=multiplet. The assignments of signals for compounds
2–18 were confirmed by 1H,1H-COSY, 1H,13C-COSY and DEPT spectra.
Optical rotations were measured with a Perkin–Elmer 341Polarimeter in
a 1dm thermostated cuvette by using a mercury lamp. Concentration c is
given in g per 100 mL. HRMS were recorded on a JEOL JMS-700 instru-
ment. Elemental analyses were carried out at the Organisch-Chemisches
Institut, Universität Heidelberg. Enantiomeric excesses were determined
by chiral HPLC on a HP 1100 instrument. The following columns from
Daicel were used: Chiralpak AD-H (250”4.6 mm, 5 mm) with guard car-
tridge AD-H (10”4 mm, 5 mm) and Chiralcel OD-H (250”4.6 mm,
5 mm) with guard cartridge OD-H (10”4 mm, 5 mm). For preparative
HPLC a Gilson-305 pump coupled with a Knauer UV detector 2600 and
a silica-gel column (Latek, 5m, 21”250 mm) were used.
À
around the C-1’ N-9 bond.
THF was dried over sodium benzophenone ketyl, and the water content
was determined by Karl Fischer titration. 1,5,7-Triazabicyclo[4.4.0]dec-5-
G
ene (TBD) was stored in a dessicator over KOH; alternatively, small
amounts were stored under argon in a Schlenk tube. Magnesium turnings
used for the preparation of Grignard reagents were activated by addition
of a drop of 1,2-dibromoethane. IUPAC names were generated with the
program ACD/Lab 6.0 from Advanced Chemistry Development Inc.
Figure 2. X-ray crystal structures of the isomers 16 (right) and 17 (left).
Scheme 8. Synthesis of 2’-methylcarbovir from cyclopentene 13.
6726
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Chem. Eur. J. 2008, 14, 6722 – 6733

Enantioselective Iridium-Catalyzed Allylic Alkylation
FULL PAPER
Methyl 3-[methoxy
A
had been stirred for 2 h at RT (monitored by TLC: Rf(2b)=0.41(petro-
G
leum ether/ethyl acetate 5:1)), and a workup was carried out. 1H NMR
spectroscopic analysis of the crude product was used for determination of
the ratio of the regioisomers (3b/4b 94:6). The crude product was sub-
jected to flash chromatography on silica (50 g, petroleum ether/ethyl ace-
tate 5:1) to yield a mixture of 3b and 4b (980 mg, 76%) as a colorless
triethylamine (32.59 g, 366.2 mmol) in dry CH2Cl2 (55 mL) was added
dropwise to a cold (08C) solution of methyl 3-chloro-3-oxopropanoate
(25.00 g, 183.1 mmol) and N,O-dimethylhydroxylamine hydrochloride
(17.86 g, 183.1 mmol) in dry CH2Cl2 (450 mL) under an argon atmos-
phere. The resulting yellow solution was stirred for 1h at 0 8C and for
12 h at RT. Conversion was then complete (monitored by TLC), and the
mixture was extracted with water (200 mL). The aqueous layer was re-ex-
tracted with CH2Cl2 (3”200 mL) and the combined organic layers were
washed with brine (400 mL), dried over Na2SO4, and concentrated in
vacuo to give a brown oil as the crude product. Distillation (748C,
0.1mbar) yielded amide 1 (18.9 g, 64%) as a colorless oil. Rf(1)=0.21
oil. Rf
(3b)=0.10 (petroleum ether/ethyl acetate 5:1); 1H NMR
N
(300 MHz, CDCl3): mixture of branched diastereoisomers in ratio 52:48;
d=5.77 (ddd, J=17.4, 10.2, 7.7 Hz, 2H; 2”CH=CH2), 5.13–4.95 (m, 4H;
2”CH=CH2), 3.72–3.65 (m, 14H; 4”OCH3, 2”CHCO2CH3), 3.20 (s,
3H; NCH3), 3.16 (s, 3H; NCH3), 3.08–2.93 (m, 2H; 2”CHCH3), 1.09 (d,
J=6.8 Hz, 3H; CHCH3), 1.05 ppm (d, J=6.8 Hz, 3H; CHCH3);
13C NMR (75 MHz, CDCl3): mixture of branched diastereoisomers; d=
169.3, 169.2, 169.1, 169.0 (4s; 4”C=O), 140.5, 140.4 (2d; 2”CH=CH2),
115.3, 115.2 (2t; 2”CH=CH2), 61.5 (2q; 2”NOCH3), 54.1, 53.8, 52.4,
52.3 (2d, 2q; 2”CHCO2CH3, 2”CO2CH3), 38.0, 37.7 (2d; 2”CHCH3),
32.5 (2q; 2”NCH3), 18.4, 18.1 ppm (2q; 2”CHCH3); elemental analysis
calcd (%) for C10H17NO4: C 55.80, H 7.96, N 6.51; found: C 55.46, H
7.92, N 6.61; HPLC (Daicel AD-H column, n-hexane/iPrOH 99:1, 208C,
210 nm): tr((R)-3b)=36/43, tr((S)-3b)=41/47 min, 95% ee for each dia-
stereoisomer.
(CH2Cl2/methanol 100:1); H NMR (300 MHz, CDCl3): d=3.69, 3.66 (2s,
6H; OCH3), 3.46 (s, 2H; CH2), 3.17 ppm (s, 3H; NCH3); 13C NMR
(75 MHz, CDCl3): d=167.8, 167.2 (2s; C=O), 61.4, 52.3 (2q; OCH3), 39.7
(t; CH2), 32.2 ppm (q; NCH3); elemental analysis calcd (%) for
C6H11NO4: C 44.72, H 6.88, N 8.69; found: C 44.97, H 7.00, N 8.40.
General procedure
amide 1 (1.3 mmol) was added dropwise to a stirred suspension of NaH
(95%, 1.3 mmol) in dry THF (4.0 mL) to give solution A. A solution of
[IrCl(cod)]2 (13.4 mg, 20.0 mmol) and L1 or L2 (40 mmol) in anhydrous
A
THF (1.0 mL, content of water <50 mgmLÀ1, Karl Fischer titration) was
treated with tetrahydrothiophene (THT) (18 mL, 0.20 mmol) and TBD
(11.1 mg, 80.0 mmol), and the mixture was stirred for 2 h under an argon
atmosphere. Then, allylic carbonate (1.0 mmol), CuI (38 mg, 0.20 mmol),
and solution A were successively added and the mixture was stirred for
the time stated in Table 1; conversion was monitored by TLC. After com-
plete conversion had been reached, diethyl ether (5 mL) and saturated
NH4Cl solution (5 mL) were added, and the aqueous phase was extracted
with diethyl ether (2”20 mL). The combined organic phases were
washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated
in vacuo. The crude product was analyzed with respect to the ratio of
Methyl (3R)-2-{[methoxy
(3c): GP1 was carried out with [IrCl
ACHTREUNG
AHCTREUNG
(S,S,aS)-L1 (207 mg, 0.384 mmol), TBD (107 mg, 0.770 mmol), THT
(169 mL, 1.92 mmol), CuI (366 mg, 1.92 mmol), NaH (95%, 300 mg,
12.5 mmol), 2c (2.2 g, 9.6 mmol), 1 (2.01g, 12.5 mmol), and dry THF
(38 mL). Complete conversion was reached after the reaction mixture
had been stirred for 18 h at RT (monitored by TLC), and a workup was
carried out. The ratio of the regioisomers (3c/4c 83:17) was determined
1
by H NMR spectroscopic analysis of the crude product. The crude prod-
uct was subjected to flash chromatography on silica (petroleum ether/
ethyl acetate 3:1) to yield 3c and 4c (2.63 g, 89%) as a colorless oil. Rf-
1
branched and linear products by H NMR spectroscopy and then subject-
ed to flash column chromatography (silica, petroleum ether/ethyl ace-
tate).
A
CDCl3): mixture of branched epimers in a ratio of 61:39; d=5.70–5.54
(m, 1H; 2”CH=CH2), 5.12–5.01 (m, 2H; 2”CH=CH2), 3.71–3.61 (m,
1H; 2”CHCOOCH3), 3.71(s, 3H; OCH 3), 3.69 (s, 3H; OCH3), 3.69 (s,
3H; OCH3), 3.65 (s, 3H; OCH3), 3.20 (s, 3H; NCH3), 3.15 (s, 3H;
NCH3), 2.91–2.75 (m, 1H; 2”CH), 1.36–1.12 (m, 14H; 2”CH2(n-octyl)),
0.91–0.82 ppm (m, 3H; 2”CH3(n-octyl)); 13C NMR (75 MHz, CDCl3): mix-
ture of branched epimers; d=169.5, 169.1 (2s; 2”C=O), 138.9 (d; 2”
CH=CH2), 117.2 (t; 2”CH=CH2), 61.6, 61.6 (2q; OCH3), 53.7, 53.1(2d;
2”CHCOOCH3), 52.3, 52.2 (2q; 2”OCH3), 44.1(d; 2”CH), 32.9 (t;
CH2(n-octyl)), 32.6 (q; 2”NCH3), 32.5 (t; 2”CH2(n-octyl)), 32.0 (t; 2”
CH2(n-octyl)), 29.7, 29.7 (t; 2”CH2(n-octyl)), 29.6, 29.4 (t; 2”CH2(n-octyl)), 27.3,
27.2 (t; 2”CH2(n-octyl)), 22.8 (t; 2”CH2(n-octyl)), 14.2 ppm (q; 2”CH3(n-octyl));
elemental analysis calcd (%) for C17H31NO4: C: 65.14, H: 9.97, N: 4.47;
found: C 65.29, H 9.89, N 4.49; HPLC (3c; Daicel AD-H column, n-
hexane/iPrOH 99:1, 208C, 220 nm): tr((R)-3c)=26/28, tr((S)-3c)=27/
32 min.
Methyl (3R)-{[methoxy
ACHTREUNG
(3a): GP1 was carried out with [IrCl
AHCTREUNG
(S,S,aS)-L2 (59.9 mg, 0.100 mmol), TBD (42 mg, 0.30 mmol), THT
(44 mL, 0.50 mmol), CuI (95 mg, 0.50 mmol), NaH (95%, 139 mg,
5.50 mmol), 2a (961mg, 5 mmol), 1 (886 mg, 5.50 mmol) and dry THF
(15 mL). Complete conversion was reached after the reaction mixture
had been stirred for 0.5 h at RT (monitored by TLC Rf(2a)=0.47 (petro-
G
leum ether/ethyl acetate 3:1)) and a workup was carried out. 1H NMR
spectroscopic analysis of the crude product was used for the determina-
tion of the ratio of the regioisomers (3a/4a >98:2). The crude product
was subjected to flash chromatography on silica (petroleum ether/ethyl
acetate 4:1) to yield 3a (1.22 g, 88%) containing <2% of 4a, as a color-
less oil. Rf
(3a)=0.12 (petroleum ether/ethyl acetate 3:1); 1H NMR
H
(300 MHz, CDCl3): mixture of branched diastereoisomers in a ratio of
51:49; d=7.29–7.14 (m, 5H; 2”Ar), 6.02–5.93 (m, 1H; 2”CH=CH2),
5.13–5.03 (m, 2H; 2”CH=CH2), 4.36–4.33 (m, 1H; 2”CH), 4.21–4.18
(m, 1H; 2”CH), 3.72 (s, 3H; COOCH3), 3.70 (s, 3H; NOCH3), 3.59 (s,
3H; COOCH3), 3.44 (s, 3H; NOCH3), 3.19 (s, 3H; NCH3), 2.93 ppm (s,
3H; NCH3); 13C NMR (75 MHz, CDCl3): mixture of branched diastereo-
isomers; d=168.7, 168.5, 168.4, 168.0 (4s; C=O), 140.7, 140.6, 138.6,
138.4 (4s; Ar), 128.6, 128.6, 128.3, 128.2, 127.0, 126.9 (6d; Ar), 116.4 (t;
2”CH=CH2), 61.7, 61.6 (2q; NOCH3), 53.4, 53.1(2d; CH), 52.5, 52.3
(2q; COOCH3), 49.4, 49.4 (2d; CH), 32.6, 32.4 ppm (2q; NCH3); elemen-
tal analysis calcd (%) for C15H19NO4: C 64.97, H 6.91, N 5.05; found: C
64.85, H 6.93, N 5.12; HPLC (Daicel AD-H column, n-hexane/iPrOH
95:5, 208C, 210 nm): tr((3S)-3a)=28/37, tr((3R)-3a)=33/47 min, 98% ee
for both diastereoisomers.
Methyl (3R)-3-({[tert-butyl
yl)amino]carbonyl}pent-4-enoate (3d): GP1 was carried out with [IrCl-
(cod)]2 (33.5 mg, 50.0 mmol), (S,S,aS)-L1 (54.0 mg, 0.100 mmol), TBD
(27.8 mg, 0.200 mmol), THT (44 mL, 0.50 mmol), CuI (95 mg, 0.50 mmol),
NaH (95%, 139 mg, 5.50 mmol), 2d (1.89 g, 4.9 mmol), (935 mg,
A
(meth-
AHCTREUNG
AHCTREUNG
1
5.80 mmol), and dry THF (17 mL). Complete conversion was reached
after the reaction mixture had been stirred for 6 h at RT (monitored by
TLC: Rf(2d)=0.43 (petroleum ether/ethyl acetate 5:1)) and a workup
H
1
was carried out. H NMR spectroscopic analysis of the crude product was
used for determination of the ratio of the regioisomers, (3d/4d 86:14).
The crude product was subjected to flash chromatography on silica (30 g,
petroleum ether/ethyl acetate 5:1) to yield a mixture of 3d and 4d
(1.96 g, 85%) as a colorless oil. For the branched epimers a ratio of (+)-
(2S,3R)-3d/(+)-(2R,3R)-3d 47:53 was determined by 1H NMR spectros-
copy. Compounds (+)-(2S,3R)-3d, (+)-(2R,3R)-3d, and 4d were separat-
ed by HPLC (petroleum ether/ethyl acetate 5:1, Latek, 250”21 mm, 5 m
silica, 20 mLminÀ1, 50 bar), and their absolute and relative configurations
were determined by X-ray crystal structure analysis of (2R,3R)-3d.
Methyl (3R)-2-{[methoxy
ACHTREUNG
A
ACHTREUNG
(S,S,aS)-L2 (36.0 mg, 60 mmol), TBD (16.7 mg, 120 mmol), THT (26.5 mL,
0.300 mmol), CuI (57.1mg, 0.300 mmol), NaH (95%, 168 mg,
6.60 mmol), 2b (780 mg, 6.00 mmol), 1 (1.06 g, 6.60 mmol), and dry THF
(12 mL). Complete conversion was reached after the reaction mixture
Chem. Eur. J. 2008, 14, 6722 – 6733
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6727

G. Helmchen et al.
Compound (+)-(2S,3R)-3d: Colorless oil; Rf
G
tate 5:1)) indicated complete consumption of the substrate. After workup
as described above, the crude product was subjected to flash chromatog-
raphy on silica (20 g, petroleum ether/ethyl acetate 5:1) to yield a mix-
ture of the regioisomers 3b and 4b (3b/4b 40:60, 371mg, 86%) as a col-
orless oil. Separation of the mixture by flash chromatography on silica
(20 g, petroleum ether/ethyl acetate 5:1) yielded analytically pure 4b
ether/ethyl acetate 5:1); [a]D20 =+42 (c=0.99 in CHCl3, 99% ee according
to HPLC after decarboxylation); 1H NMR (500 MHz, CDCl3): d=7.65–
7.62 (m, 4H; Ar), 7.43–7.35 (m, 6H; Ar), 5.98 (ddd, J=17.2, 10.0, 9.4 Hz,
1H; CH=CH2), 5.11 (d, J=17.3 Hz, 1H; CH=CH2), 5.08 (d, J=10.2 Hz,
1H; CH=CH2), 4.37 (d, J=9.2 Hz, 1H; CHCO2CH3), 3.82–3.77 (m, 2H;
OCH2), 3.72, 3.65 (2s, 6H; 2”OCH3), 3.18 (s; NCH3), 3.10–3.04 (m, 1H;
(110 mg, 26%) as a colorless oil. Rf(4b)=0.10 (petroleum ether/ethyl
G
CHCH=CH2), 1.06 ppm (s, 9H; C
A
acetate 5:1); 1H NMR (300 MHz, CDCl3): d=5.60–5.30 (m, 2H; CH=
CH), 3.75–3.67 (m, 1H; CH), 3.70, 3.68 (2s, 6H; 2 OCH3), 3.20 (s, 3H;
NCH3), 2.60–2.53 (m, 2H; CH2), 1.63 ppm (dd, J=6.1, 1.3 Hz, 3H;
CHCH3); 13C NMR (75 MHz, CDCl3): d=170.2, 169.9 (2s; 2”C=O),
128.2, 127.2 (2d; CH=CH), 61.5, 52.4 (2q; 2”OCH3), 48.9 (d;
CHCO2CH3), 32.6 (q; NCH3), 31.9 (t; C-2), 18.0 ppm (q; CHCH3);
HRMS (EI): m/z: calcd for C10H17NO4: 215.1158; found: 215.1168 [M]+;
elemental analysis calcd (%) for C10H17NO4: C 55.80, H 7.96, N 6.51;
found: C 55.58, H 8.00, N 6.62; HPLC(Daicel AD-H column, n-hexane/
d=169.5 (s; C=O), 136.3 (d; CH=CH2), 135.7 (d; Ar), 133.6, 133.6 (2s;
2”Ar), 129.8, 129.8, 127.8, (3d; Ar), 118.0 (t, CH=CH2), 65.2 (t, OCH2),
61.5, 52.4 (2q, 2”OCH3), 48.3 (d; CHCO2CH3), 46.4 (d; CHCH=CH2),
32.5 (q; NCH3), 27.0 (q;
C
A
(FAB): m/z: calcd for C26H36NO5Si: 470.2363 [M+H]+; found: 470.2334;
elemental analysis calcd (%) for C26H35NO5Si: C 66.49, H 7.51, N 2.98;
found: C 66.29, H 7.37, N 3.04.
Compound (+)-(2R,3R)-3d: Pure (+)-3d crystallized as colorless poly-
G
hedral crystals; m.p. 63–668C; [a2D0 =+30.9 (c=1.02 in CHCl3, 95.5% ee
according to HPLC after decarboxylation); 1H NMR (500 MHz, CDCl3):
d=7.66–7.61(m, 4H; Ar), 7.43–7.34 (m, 6H; Ar), 5.97 (ddd, J=17.2,
10.2, 9.3 Hz, 1H; CH=CH2), 5.12 (d, J=17.1 Hz, 1H; CH=CH2), 5.09 (d,
J=10.3 Hz, 1H; CH=CH2), 4.23 (d, J=8.4 Hz, 1H; CHCO2CH3), 3.78
(dd, J=10.1, 4.5 Hz, 1H; OCHaHb), 3.73 (dd, J=10.0, 5.0 Hz, 1H;
OCHaHb), 3.67, 3.66 (2s, 6H; 2”OCH3), 3.17 (s; NCH3), 3.10 (ddd, J=
iPrOH 99:1, 208C, 210 nm): tr
A
Methyl (4E)-2-{[methoxy(methyl)amino]carbonyl}tridec-4-enoate (4c):
AHCTREUNG
Malonic amide 1 (97 mg, 0.60 mmol) was transformed into a solution of
the sodium salt as described above in the procedure for the preparation
of 4a. The solution was added to a solution of [Pd2(dppf)Cl2]·CH2Cl2
E
(8.2 mg, 20 mmol) and carbonate 2c (114 mg, 0.50 mmol) in dry THF
(0.75 mL), and the reaction mixture was stirred at RT for 2 h. After
workup as described above, the crude product was subjected to flash
chromatography on silica (petroleum ether/ethyl acetate 5:1) to yield 4c
13.6, 9.0, 4.7 Hz, 1H; CHCH=CH2), 1.05 ppm (s, 9H;
13C NMR (125 MHz, CDCl3): d=169.3, 169.2 (2s, 2”C=O), 136.4 (d;
CH=CH2), 135.8, 135.7 (2d; Ar), 133.7, 133.5, (2s, 2”Ar), 129.8, 129.8,
127.8, (3d; Ar), 117.6 (t; CH=CH2), 65.1(t; OCH 2), 61.5, 52.2 (2q; 2”
OCH3), 49.3 (d; CHCO2CH3), 45.7 (d; CHCH=CH2), 32.7 (q; NCH3),
(116 mg, 74%) as a colorless, analytically pure oil. Rf(4c)=0.13 (petro-
E
leum ether/ethyl acetate 5:1); 1H NMR (300 MHz, CDCl3): d=5.56–5.31
(m, 2H; CH=CH), 3.69, 3.68 (2s, 6H; OCH3), 3.76–3.61(m, 1H; CH),
3
3
27.0 (q; C
N
(CH3)3); HRMS (FAB): m/z: calcd for
3.20 (s, 3H; NCH3), 2.57 (dd, J=6.3, 6.3 Hz, 2H; CH2), 1.95 (dt, J=6.6,
6.6 Hz, 2H; CH2(n-octyl)), 1.37–1.17 (m, 12H; CH2(n-octyl)), 0.87 ppm (t, 3J=
7.0 Hz, 3H; CH3(n-octyl)); 13C NMR (75 MHz, CDCl3): d=170.2, 169.9 (2s;
C=O), 133.9, 125.9 (2d; CH=CH), 61.5, 52.3 (2q; OCH3), 48.9 (d; CH),
32.6 (q; NCH3), 32.5 (t; CH2), 32.0, 31.9, 29.6, 29.5, 29.4, 29.3, 22.8 (7t;
CH2(n-octyl)), 14.2 ppm (q; CH3(n-octyl)); elemental analysis calcd (%) for
C17H31NO4: C 65.14, H 9.97, N 4.47; found: C 65.11, H 9.88, N 4.77;
HPLC (Daicel AD-H column, 99:1 n-hexane/iPrOH, 208C, 220 nm): tr-
Methyl (4E)-2-{[methoxy(methyl)amino]carbonyl}-5-phenylpent-4-enoate
N
(4a): Malonic amide 1 (209 mg, 1.30 mmol) was added to a suspension of
NaH (95%, 33 mg, 1.3 mmol) in dry THF (3.5 mL) in a flame-dried
Schlenk tube at RT under an argon atmosphere. The mixture was stirred
for 10 min to form a clear solution, which was added to a solution of [Pd-
AHCTREUNG
A
(diphenyl)silyl]oxy}-2-{[methoxy
U
U
U
cene; 22 mg, 40 mmol), and carbonate 2a (192 mg, 1.00 mmol) in dry
THF (2.5 mL), which had been prepared in a second flame-dried Schlenk
tube under an argon atmosphere. The reaction mixture was stirred for
ACHTREUNG
product in the preparation of 3d (see above). 1H NMR (500 MHz,
CDCl3): d=7.69–7.66 (m, 4H; Ar), 7.43–7.36 (m, 6H; Ar), 5.76–5.65 (m,
2H; CH=CH), 4.16 (d, J=2.5 Hz, 2H; CH2O), 3.82 (t, J=6.6 Hz, 1H;
CHCO2CH3), 3.71, 3.68 (2s, 6H; 2”OCH3), 3.20 (s, 3H; NCH3), 2.71–
2.62 (m, 2H; CH2), 1.06 ppm (s, 9H; tBu); 13C NMR (125 MHz, CDCl3):
d=170.0, 169.6 (2s, 2”C=O), 135.5 (d; Ar), 133.7 (s; Ar), 131.7 (d; CH=
CH), 129.6, 127.7 (2d; 2” C, Ar), 126.5 (d; CH=CH), 64.1(t; O CH2),
61.4, 52.3 (2q; 2”OCH3), 48.4 (d; CHCO2CH3), 32.4 (q; NCH3), 31.4 (t;
90 min at RT until TLC analysis (Rf(2a)=0.41(petroleum ether/ethyl
T
acetate 5:1)) indicated complete consumption of the substrate. Diethyl
ether (10 mL) and a saturated aqueous solution of NH4Cl (10 mL) were
added, and the phases were separated. The aqueous layer was extracted
with diethyl ether (2”20 mL), and the combined organic phases were
washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated
in vacuo. The crude product was purified by flash chromatography on
silica (petroleum ether/ethyl acetate 5:1) to yield 4a (170 mg, 61%) as an
CH2), 26.8 (q; C
E
A
for C26H35NO5Si: 469.2284; found: 469.2272 [M]+; elemental analysis
calcd (%) for C26H35NO5Si: C 66.49, H 7.51, N 2.98; found: C 66.21, H
7.51, N 3.12.
analytically pure colorless oil. Rf
tate 5:1); H NMR (300 MHz, CDCl3): d=7.15–7.33 (m, 5H; Ph-H), 6.46
A
1
(d, J=15.8 Hz, 1H; Ph-CH), 6.17 (dt, J=15.6, 7.4 Hz, 1H; Ph-CH=CH),
3.84 (d, J=7.4 Hz, 1H; CHCO2CH3), 3.70, 3.67 (2s, 6H; 2”OCH3), 3.19
(s, 3H; NCH3), 2.86–2.71ppm (m, 2H, CH 2); 13C NMR (75 MHz,
CDCl3): d=170.0, 169.7 (2s; 2”C=O), 137.3 (s; Ph-C), 132.7 (d; Ph-CH),
128.6, 127.4, 126.4, 126.3 (4d; 3”Ph-C, Ph-CH=CH), 61.5, 52.5 (2q; 2”
OCH3), 48.7 (d; CHCO2CH3), 32.6 (q; NCH3), 32.3 ppm (t; CH2); ele-
mental analysis calcd (%) for C15H19NO4: C 64.97, H 6.91, N 5.05; found:
C 64.78, H 6.97, N 5.07; HPLC (Daicel AD-H column, n-hexane/iPrOH
(+)-(3S)-N-methoxy-N-methyl-3-phenylpent-4-enamide (5a): A solution
of 3a (containing <2% of 4a) (1.90 g, 6.88 mmol) and aqueous NaOH
(2n, 22 mL) in methanol (65 mL) was stirred for 4 h at RT and was then
acidified to pH 1with aqueous HCl (2 n) and extracted with CH2Cl2 (3”
50 mL). The combined organic phases were washed with brine (50 mL),
dried over Na2SO4, filtered and concentrated in vacuo to give a yellowish
oil. A small amount of 2,6-di-tert-butyl-4-methylphenol (<0.1mg) was
added as radical inhibitor, and the mixture was heated at 2108C (oil bath
temperature). TLC analysis (Rf(carboxylic acid)=0.00 (petroleum ether/
ethyl acetate 3:1)) indicated complete decarboxylation after 20 min.
Flash chromatography on silica (30 g, petroleum ether/ethyl acetate 3:1)
95:5, 208C, 210 nm): tr
ACHTREUNG
Methyl (4E)-2-{[methoxy
AHCTREUNG
Malonic amide 1 (419 mg, 2.60 mmol) was transformed into a solution of
the sodium salt as described above in the procedure for preparation of
gave amide 5a (1.3 g, 87%) as a colorless oil. Rf(5a)=0.19 (petroleum
G
4a. This solution was added to a solution of [Pd
A
ether/ethyl acetate 3:1); a2D5 =+1.1 (c=0.62 in MeOH); 1H NMR
(300 MHz, CDCl3): d=7.27–7.16 (m, 5H; Ar), 6.08–5.96 (m, 1H; CH=
CH2), 5.08–5.02 (m, 2H; CH=CH2), 4.01–3.94 (m, 1H; CH), 3.57 (s, 3H;
NOCH3), 3.11 (s, 3H; NCH3), 2.93–2.76 ppm (m, 2H; CH2); 13C NMR
(CDCl3, 75 MHz): d=172.7 (s; C=O), 143.4 (s; Ar), 140.9 (d; CH=CH2),
dene acetone) (20.7 mg, 20.0 mmol), dppe (dppe=1,2-bis(diphenyphos-
phino)ethane) (15.9 mg, 40.0 mmol), and carbonate 2b (260 mg,
2.00 mmol) in dry THF (2 mL). The reaction mixture was stirred at RT
overnight until TLC analysis (Rf(2b)=0.57, (petroleum ether/ethyl ace-
U
6728
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6722 – 6733

Enantioselective Iridium-Catalyzed Allylic Alkylation
FULL PAPER
128.6, 127.9, 126.6 (3d; Ar), 114.7 (t; CH=CH2), 61.4 (q; NOCH3), 45.0
(d; CH), 37.6 (t; CH2), 32.3 ppm (q; NCH3); elemental analysis calcd
(%) for C13H17NO2: C 71.21, H 7.81, N 6.39; found: C 71.27, H 7.83, N
6.55.
HPLC (Daicel AD-H column, n-hexane/iPrOH 99.5:0.5, 208C, 230 nm):
tr((S)-5d)=33.5, tr((R)-5d)=37.5 min.
(5S)-5-Octylhepta-1,6-dien-3-one (6d): A solution of amide 5c (1.2 g,
4.7 mmol), contaminated with the linear regioisomer, in dry THF
(30 mL) was cooled to À788C and then treated dropwise with a 1m solu-
(+)-(3S)-N-methoxy-N,3-dimethylpent-4-enamide (5b):
A mixture of
esters 3b and 4b (843 mg, 3.92 mmol), obtained by iridium-catalyzed al-
lylic alkylation according to Table 1, entry 4 (3b/4b 94:6), was saponified
as described for ester 3a. The decarboxylation was conducted by heating
at 1608C for 2 h. Flash chromatography on silica (30 g, petroleum ether/
ethyl acetate 5:1) yielded 5b (517 mg, 84%) as colorless, analytically
tion of bromo(vinyl)magnesium in THF (12.2 mL). The reaction mixture
G
was stirred for 1h and then allowed to warm to 0 8C. After further 2 h,
TLC analysis indicated complete consumption of 5c. The mixture was
added dropwise to a cold (08C) saturated aqueous solution of NaHSO4
(50 mL). The mixture was extracted with diethyl ether (3”50 mL), and
the combined organic phases were washed with brine (100 mL), dried
over Na2SO4, filtered and concentrated in vacuo to give a yellow oil. This
was subjected to flash chromatography on silica (petroleum ether/ethyl
acetate 15:1) to yield diene 6d (0.86 g, 82%), contaminated with the
pure oil. R
f(5b)=0.13 (petroleum ether/ethyl acetate 5:1); [a]2D0 =+1.3
R
(c=1.30 in MeOH); 1H NMR (300 MHz, CDCl3): d=5.81(ddd, J=17.3,
10.4, 6.8 Hz, 1H; CH=CH2), 5.03 (ddd, J=17.1, 1.5, 1.5 Hz, 1H; CH=
CH2), 4.95 (ddd, J=10.4, 1.3, 1.3 Hz, 1H; CH=CH2), 3.67 (1s, 3H;
OCH3), 3.18 (s, 3H; NCH3), 2.81–2.72 (m, 2H; CHCH3), 2.49 (dd, J=
15.1, 7.0 Hz, 1H; CHaHbCO), 2.36 (dd, J=15.2, 7.6 Hz, 1H; CHaHbCO),
1.06 ppm (d, J=6.8 Hz, 3H; CHCH3); 13C NMR (CDCl3, 75 MHz): d=
173.5 (s; C=O), 143.4 (d; CH=CH2), 113.1 (t; CH=CH2), 61.4 (q; OCH3),
38.7 (t; CH2CO), 33.9 (d; CHCH3), 32.3 (q; NCH3), 19.9 ppm (q;
CHCH3); HRMS (EI): m/z: calcd for C8H15NO2: 157.1103, found:
157.1108 [M]+; elemental analysis calcd (%) for C8H15NO2: C 61.12, H
9.62, N 8.91; found: C 60.86; H 9.54; N 9.17.
linear regioisomer, as a yellowish oil. Rf(6d)=0.64 (petroleum ether/
E
ethyl acetate 5:1); 1H NMR (300 MHz, CDCl3): d=6.35 (dd, J=16.6,
10.3 Hz, 1H; (CO)CH=CH2), 6.19 (dd, J=17.6, 1.2 Hz, 1H; (CO)CH=
CH2), 5.80 (dd, J=10.4, 1.4 Hz, 1H; (CO)CH=CH2), 5.67–5.34 (m, 1H;
CH=CH2), 5.00–4.94 (m, 2H; CH=CH2), 2.67–2.54 (m, 3H; CH, CH2),
1.42–1.17 (m, 14H; CH2(n-octyl)), 0.87 ppm (t, 3J=6.5 Hz, 3H; CH3(n-octyl));
13C NMR (75 MHz, CDCl3): d=200.1(s; C =O), 141.6 (d; CH=CH2),
137.1 (d; (CO)CH=CH2), 128.1 (t; (CO)CH=CH2), 114.8 (t; CH=CH2),
45.2 (t; CH2), 39.8 (d; CH), 34.8, 32.0, 29.7, 29.7, 29.4, 27.2, 22.8 (7t;
CH2(n-octyl)), 14.2 ppm (q; CH3(n-octyl)); elemental analysis calcd (%) for
C15H26O: C 81.02, H 11.79; found: C 80.81, H 11.64.
(3S)-N-Methoxy-N-methyl-3-octylpent-4-enamide (5c):
A mixture of
esters 3 and 4c (2.0 g, 6.4 mmol), obtained from the iridium-catalyzed al-
lylic alkylation according to Table 1, entry 5 (3c/4c 83:17), was saponified
as described for ester 5a. The decarboxylation was conducted by heating
at 2108C for 20 min. Purification of the brown crude product by flash
chromatography on silica (100 g, petroleum ether/ethyl acetate 5:1) yield-
ed amide 5c (1.4 g 88%), still contaminated by the corresponding linear
(5S)-2-Methyl-5-octylhepta-1,6-dien-3-one (6e): A solution of a Grignard
reagent was prepared from activated magnesium turnings (56.0 mg,
2.34 mmol), 2-bromopropene (254 mg, 2.23 mmol), and THF (3.5 mL).
This was cannulated into a cooled (À788C) solution of 5c (200 mg,
0.780 mmol), contaminated with the linear regioisomer, in THF (35 mL).
The mixture was stirred at À788C for 1h and at 0 8C for 2 h. TLC analy-
sis indicated complete consumption of 5c. A solution of saturated aque-
ous NaHSO4 (10 mL) was added, and the mixture was extracted with di-
ethyl ether (3”50 mL). The combined organic phases were dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was subjected
to flash chromatography on silica (40 g, petroleum ether/ethyl acetate
10:1) to yield the dienone 6e, contaminated with the linear regioisomer,
regioisomer, as a yellowish oil. Rf(5c)=0.27 (petroleum ether/ethyl ace-
N
tate 5:1); 1H NMR (300 MHz, CDCl3): d=5.72–5.57 (m, 1H; CH, CH=
CH2), 5.06–4.95 (m, 2H; CH=CH2), 3.72–3.65 (m, 3H; OCH3), 3.20–3.16
(m, 3H; NCH3), 2.66–2.25 (m, 3H; CH, CH2), 1.34–1.13 (m, 14H;
CH2(n-octyl)), 0.87 ppm (t, J=6.9 Hz, 3H; CH3(n-octyl)); 13C NMR (75 MHz,
CDCl3): d=173.6 (C=O), 142.0 (d; CH=CH2), 114.8 (t; CH=CH2), 61.4
(q; OCH3), 40.1(t; CH 2), 37.6 (d; CH), 34.8 (q; NCH3), 32.0, 29.8, 29.7,
29.6, 29.4, 27.3, 22.8 (7t; CH2(n-octyl)), 14.3 ppm (q; CH3(n-octyl)); elemental
analysis calcd (%) for C15H29NO2: C 70.54, H 11.45, N 5.48; found: C
70.72, H 11.54, N 5.56.
as a colorless oil (160 mg, 87%). Rf(6e)=0.61(petroleum ether/ethyl
E
acetate 5:1); [a]2D0 =+44.6 (c=0.73 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=6.01–5.89 (m, 1H; C=CH2), 5.78–5.73 (m, 1H; C=CH2), 5.68–
5.54 (m, 1H; CH=CH2), 5.61(ddd, J=17.7, 8.0, 1.2 Hz, 1H; CH=CH2),
(+)-(3S)-3-({[tert-Butyl
ACHTREUNG
pent-4-enamide (5d):
A
5.00–4.91(m, 2H; CH =CH2), 2.76–2.51(m, 3H; CH , CH), 1.87–1.83 (m,
2
4.62 mmol), obtained by iridium-catalyzed allylic alkylation according to
Table 1, entry 7 (3d/4d 85:15), in THF (10 mL) was added to an aqueous
solution of LiOH (1m, 10 mL) and the resulting mixture was stirred at
RT for 18 h. The solution was acidified to pH 2 with aqueous 2n HCl,
and the aqueous phase was extracted with CH2Cl2 (3”50 mL). The com-
bined organic phases were dried over Na2SO4, filtered, and concentrated
in vacuo. A small amount (<0.1mg) of 2,6-di- tert-butyl-4-methylphenol
was added to the crude product as a radical inhibitor and then the mix-
ture was heated to 2008C (oil bath temperature) for 30 min until TLC
analysis indicated complete decarboxylation. Purification of the dark
crude product by flash chromatography on silica (50 g, petroleum ether/
ethyl acetate 5:1) yielded (+)-(3S)-5d (1.34 g, 70%) as a slightly yellow,
3H; CH3), 1.39–1.16 (m, 14H; 7”CH2(n-octyl)), 0.87 ppm (t, J=6.0 Hz, 3H;
CH3(n-octyl)); 13C NMR (75 MHz, CDCl3): d=201.6 (s; C=O), 145.2 (s; C=
CH2), 141.9 (d; CH=CH2), 124.6 (t; C=CH2), 114.7 (t; CH=CH2), 43.0 (t;
CH2), 40.3 (d; CH), 34.8, 32.0, 29.7, 29.6, 29.4, 27.2, 22.8 (7t; CH2(n-octyl)),
17.8 (q; CH3),14.3 ppm (q; CH3(n-octyl)); HRMS (EI): m/z: calcd for
C16H28O: 236.2140; found: 236.2137 [M]+.
(+)-(5S)-5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-methylhepta-1,6-
R
dien-3-one (6 f): A solution of a Grignard reagent was prepared from ac-
tivated magnesium turnings (780 mg, 32.0 mmol), 2-bromopropene (3.9 g,
32 mmol) and THF (20 mL). This was transferred by cannula into a
cooled (À788C) solution of pure (+)-5d (5.08 g, 12.4 mmol) in THF
(35 mL). After the reaction mixture had been stirred for 1h, the mixture
was allowed to warm to 08C and was stirred for another 2 h; TLC analy-
analytically pure oil. Rf(5d)=0.18 (petroleum ether/ethyl acetate 5:1);
N
1
[a]2D0 =+14.2 (c=1.02 in CHCl3, 97.5% ee according to HPLC); H NMR
(500 MHz, CDCl3): d=7.68–7.65 (m, 4H; Ar), 7.44–7.36 (m, 6H; Ar),
5.81(ddd, J=17.4, 10.0, 7.6 Hz, 1H; CH=CH2), 5.09 (d, J=17.1 Hz, 1H;
CH=CH2), 5.05 (d, J=10.3 Hz, 1H; CH=CH2), 3.71(dd, J=9.8, 4.9 Hz;
1H; OCHaHb), 3.67 (s, 3H; OCH3), 3.62 (dd, J=9.8, 6.4 Hz, 1H;
OCHaHb), 3.17 (s, 3H; NCH3), 2.94–2.88 (m, 1H; CHCH=CH2), 2.75
(dd, J=15.4, 5.1 Hz, 1H; CH2C=O), 2.54 (dd, J=14.2, 8.3 Hz, 1H;
CH2C=O), 1.06 ppm (s, 9H; tBu-H), 13C NMR (CDCl3, 125 MHz): d=
173.5 (s; C=O), 138.9 (d; CH=CH2), 135.8 (d; Ar), 133.8 (s; Ar), 129.7,
127.8 (2d; Ar), 116.0 (t; CH=CH2), 66.8 (t; OCH2), 61.3 (q; OCH3), 42.1
sis (Rf(5d)=0.18 (petroleum ether/ethyl acetate 5:1)) indicated complete
N
consumption of the starting material. An aqueous solution of NaHSO4
(10%, 100 mL) was added. The resultant mixture was extracted with di-
ethyl ether (3”100 mL), and the combined organic phases were dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography on silica (100 g, petroleum ether/ethyl
acetate 5:1) to yield (+)-(6d) as a colorless oil (4.58 g, 94%). Rf(6 f)=
T
0.59 (petroleum ether/ethyl acetate 5:1); [a]2D0 =+12.3 (c=0.73 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.67–7.62 (m, 4H; Ar), 7.45–
7.34 (m, 6H; Ar), 5.95 (s, 1H; CCH3=CH2), 5.81–5.68 (m, 2H; CH=CH2,
CCH3=CH2), 5.08–5.02 (m, 2H; CH=CH2), 3.67 (dd, J=9.9, 5.2 Hz, 1H;
OCHaHb), 3.57 (dd, J=9.9, 6.4 Hz, 1H; OCHaHb), 3.05 (dd, J=15.7,
5.4 Hz, 1H; CH2C=O), 2.95–2.84 (m, 1H; CHCH=CH2), 2.69 (dd, J=
(d; CHCH=CH2), 33.5 (t; CH2C=O), 32.2 (q; NCH3), 27.0 (q; C(CH3)3),
C
19.5 ppm (s;
C(CH3)3); HRMS (FAB): m/z: calcd for C24H34NO3Si:
C
C24H33NO3Si: C 70.03, H 8.08, N 3.40; found: C 69.94, H 8.10, N 3.44;
Chem. Eur. J. 2008, 14, 6722 – 6733
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6729

G. Helmchen et al.
15.7, 8.0 Hz, 1H; CH2C=O), 1.85 (s, 3H; CH3), 1.05 ppm (s, 9H; tBu);
13C NMR (75 MHz, CDCl3): d=201.2 (s; C=O), 144.9 (s; CCH3=CH2),
138.8 (d; CH=CH2), 135.7 (d; Ar), 133.7 (s; Ar), 129.8, 127.8 (2d; Ar),
124.7 (t; CCH3=CH2), 116.0 (t; CH=CH2), 66.6 (t; OCH2), 42.3 (d;
ethyl acetate 5:1)) indicated complete consumption of the starting mate-
rial. The mixture was added dropwise to an aqueous solution of NaHSO4
(10%, 50 mL), which was kept at 08C to avoid possible side reactions.[30]
The mixture was extracted with diethyl ether (3”20 mL), and the com-
bined organic phases were dried over Na2SO4, filtered, and concentrated
in vacuo to give crude 6c, a colorless, volatile liquid. This was dissolved
in CH2Cl2 (15 mL), Grubbs II catalyst (42 mg, 50 mmol) was added, and
the vigorously stirred mixture was heated at reflux for 2 h under an
argon atmosphere, until TLC analysis indicated complete consumption of
the starting material. The reaction flask was connected by a wide glass
tube to a second flask. The reaction mixture was cooled to À408C, the
system evacuated and the solvent was removed, over a period of ca. 3 h,
by cooling the second flask to À1968C. The resulting solvent-free crude
product was subjected to the same procedure by vaporization at RT and
condensation at À1968C to remove the catalyst. Ketone (À)-7c (144 mg,
52%) was obtained as a colorless, highly volatile liquid with a character-
istic odor. The analytical data agreed with the data for the racemic com-
CHCH=CH2), 38.9 (t; CH2C=O), 27.0 (q; C
N
N
17.8 ppm (q; CH3); HRMS (FAB): m/z: calcd for C25H33O2Si: 393.2250;
found: 393.2229 [M+H+]; elemental analysis calcd (%) for C25H32O2Si:
C 76.48, H 8.22; found: C 76.37, H 8.33.
(À)-(4S)-4-Phenylcyclopent-2-en-1-one (7a):
(88 mg, 0.40 mmol) in dry THF (1mL) was cooled to À788C. Then, a so-
lution of bromo(vinyl)magnesium in THF (1.2 mL, 1m) was added
slowly. After the reaction mixture had been stirred for 1h, it was allowed
to warm to 08C. After 2 h, TLC analysis (Rf(5a)=0.15 (petroleum ether/
A solution of (+)-5a
ACHTREUNG
AHCTREUNG
ethyl acetate 3:1)) indicated complete consumption of 5a. The mixture
was added dropwise to an aqueous solution of NaHSO4 (10 mL, 5%) at
08C. The mixture was extracted with diethyl ether (3”15 mL), and the
combined organic phases were washed with brine (30 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to give a colorless oil as the
crude product (6a). This was treated with a solution of Grubbs II catalyst
(8.0 mg, 10 mmol) in CH2Cl2 (3 mL) and the resultant mixture was stirred
and heated at reflux for 2 h under an argon atmosphere. The solvent was
removed in vacuo to give a dark-brown residue that was subjected to
pound published by Ahlbrecht and Daacke.[31] Rf
(7c)=0.38, (petroleum
A
ether/ethyl acetate 5:1); [a]2D0 =À164 (c=0.82 in MeOH, 95.5% ee ac-
cording to HPLC); 1H NMR (300 MHz, CDCl3): d=7.19 (dd, J=2.2,
1.0 Hz, 1H; C=CH), 2.92–2.79 (m, 1H; CH), 2.61 (dd, J=18.8, 6.3 Hz,
1H; CH2), 1.94 (dd, J=18.8, 1.9 Hz, 1H; CH2), 1.75 (dd, J=1.7, 1.5 Hz,
3H; CH3), 1.15 ppm (d, J=7.1Hz, 3H; CH 3); 13C NMR (CDCl3,
75 MHz): d=210.3 (s; C=O), 163.7 (d; C=CH), 141.0 (s; C=CH), 43.1(t;
CH2), 33.4 (d; CH), 20.4, 10.1 ppm (2q; 2”CH3); HRMS (EI): m/z: calcd
for C7H10O: 110.0732; found: 110.0723 [M]+; HPLC (Daicel AD-H
column, n-hexane/iPrOH 99:1, 78C, 220 nm): tr((À)-(S)-7c)=16.5, tr((+)-
(R)-7c)=17.6 min.
flash chromatography on silica (15 g, Rf(6a)=0.26, petroleum ether/ethyl
G
acetate 10:1) to yield 7a (48 mg, 76%) as slightly yellow oil. Rf(7a)=
E
0.07 (petroleum ether/ethyl acetate 10:1); [a]2D4 =À284 (c=0.51in CHCl ,
3
97% ee according to HPLC); 1H NMR (300 MHz, CDCl3): d=7.67 (dd,
J=5.6, 2.6 Hz, 1H; (C=O)CH=CH), 7.36–7.13 (m, 5H; Ar), 6.32 (dd, J=
5.6, J=2.1Hz, 1H; (C =O)CH=CH), 4.19–4.15 (m, 1H; CH), 2.90 (dd,
J=18.9, 6.9 Hz, 1H; CH2b), 2.32 ppm (dd, J=18.9, 2.5 Hz, 1H; CH2a),
13C NMR (75 MHz, CDCl3): d=210.0 (s; C=O), 166.7 (d; CH=), 141.6
(s; Ar), 134.2 (d; CH=), 129.1, 127.4, 127.3 (3d; Ar), 46.9 (d; CH),
44.1ppm (t; CH 2); HRMS (EI): m/z: calcd for C11H10O: 158.0732; found:
158.0746 [M+]; HPLC (Daicel AD-H column, n-hexane/iPrOH 99.7:0.3,
258C, 210 nm): tr((+)-7a)=108.4 min, tr((À)-7a)=118.1 min.
(À)-(4S)-4-Octylcyclopent-2-en-1-one
(7d):
Diene
6d
(800 mg,
3.60 mmol), contaminated with the linear regioisomer, was dissolved in
dry CH2Cl2 (100 mL), and Grubbs II catalyst (90 mmol, 76 mg) was
added. Under an argon atmosphere, the stirred solution was heated at
reflux for 2 h (monitored by TLC). The solvent was removed in vacuo to
give a dark-brown residue, which was subjected to flash chromatography
on silica (5:1petroleum ether/ethyl acetate) to yield enone 7d (0.49 g,
70%) as slightly brown oil. Side products formed from the linear regio-
isomer were separated off in this step, but they were not isolated. Rf-
(À)-(4S)-2,4-Diphenylcyclopent-2-en-1-one (7b): A solution of bromo(1-
phenylvinyl)magnesium in THF (2m, 1.43 mL) was added dropwise to a
cooled (À788C) solution of amide (+)-5a (250 mg, 1.14 mmol) in dry
THF (3 mL). After the reaction mixture had been stirred for 1h, it was
A
CHCl3, 96% ee according to HPLC); 1H NMR (300 MHz, CDCl3): d=
7.63 (dd J=5.6, 2.4 Hz, 1H; (C=O)CH=CH), 6.13 (dd, J=5.7, 2.0 Hz,
allowed to warm to 08C. After a further 2 h, TLC analysis (Rf(6b)=0.57,
E
petroleum ether/ethyl acetate 5:1) indicated complete consumption of
5a. The reaction mixture was added dropwise to a cold (08C) saturated
aqueous solution of NaHSO4 (50 mL). The resultant mixture was extract-
ed with diethyl ether (3”50 mL), and the combined organic phases were
washed with brine (100 mL), dried over Na2SO4, filtered, and concentrat-
ed in vacuo to give 6b as a yellow oil. This was treated with a solution of
Grubbs II catalyst (21mg, 29 mmol) in CH2Cl2 (15 mL) and the resulting
solution was vigorously stirred and heated at reflux for 2 h under an
argon atmosphere. The mixture was then stirred overnight at RT until
TLC analysis indicated complete consumption of the starting material.
The solvent was removed in vacuo to give a dark-brown residue, which
was subjected to flash chromatography on silica (petroleum ether/ethyl
acetate 5:1) to yield cylopentenone 7b (175 mg, 63% over 2 steps) as a
À
1H; (C=O)CH=CH), 2.96–2.86 (m, 1H; =C CH), 2.52 (dd, J=18.8,
6.3 Hz, 1H; CH2b), 1.99 (dd, J=18.8, 2.1 Hz, 1H; CH2a), 1.68–1.45 (m,
1H; CH2(n-octyl)), 1.44–1.19 (m, 13H; CH2(n-octyl)), 0.87 ppm (t, J=6.5 Hz,
3H; CH3); 13C NMR (75 MHz, CDCl3): d=210.2 (s; C=O), 168.8, 137.7
(2d; CH=CH) 41.6 (d; CH), 41.2 (t; CH2), 34.9, 31.2, 29.7, 29.6, 29.4, 27.8
22.8 (7t; CH2(n-octyl)), 14.2 ppm (q; CH3); HRMS (EI): m/z: calcd for
C13H22O: 194.1671; found: 194.1657 [M+]; HPLC (Daicel AD-H column,
n-hexane/iPrOH 99.8:0.2, 78C, 220 nm): tr((+)-7d)=36.3, tr((À)-7d)=
38.9 min.
(À)-(4S)-2-Methyl-4-octylcyclopent-2-en-1-on (7e): Under an argon at-
mosphere, a stirred solution of dienone 6e (120 mg, 0.510 mmol), conta-
minated with the linear regioisomer, and Grubbs II catalyst (11.1 mg,
10.0 mmol) in CH2Cl2 (15 mL) was heated at reflux for 3.5 h. The solvent
was removed in vacuo to give a dark-brown residue, which was subjected
to flash chromatography on silica (20 g, petroleum ether/ethyl acetate
5:1) to yield 69 mg (65%) of cyclopentenone 7e as a slightly yellow oil;
the linear regioisomer was separated off in this step but it was not isolat-
white powder. Rf(7b)=0.43 (petroleum ether/ethyl acetate 5:1); m.p. 63–
U
1
648C; [a]D24=À94 (c=0.50 in CHCl3); H NMR (300 MHz, CDCl3): d=
7.83–7.74 (m, 3H; Ar, C=CH), 7.45–7.18 (m, 8H; Ar), 4.18 (ddd, J=7.0,
5.4, 2.6 Hz, 1H; PhCH), 3.14 (dd, J=19.0, 7.1 Hz, 1H; CH2b), 2.58 ppm
(dd, J=19.0, 2.6 Hz, 1H; CH2a); 13C NMR (75 MHz, CDCl3): d=207.2
(s; C=O), 160.7 (d; C=CH), 143.0, 142.1, 131.3, 129.2, 128.9, 128.7, 127.4,
127.4 (8d; Ar, C=CH), 45.8 (t; CH2), 43.9 ppm (d; CH); elemental analy-
sis calcd (%) for C17H14O: C 87.15, H 6.02; found: C 86.96, H 6.13;
HPLC (Daicel AD-H column, n-hexane/iPrOH 95:5, 208C, 254 nm):
tr((+)-7b)=20.7, tr((À)-7b)=26.9 min].
ed. Rf
C
À
CH), 2.78–2.71(m, 1H; =C CH), 2.55 (dd, J=18.5, 6.5 Hz, 1H; CH2a),
2.00 (dd, J=18.5, 2.0 Hz, 1H; CH2b), 1.76–1.74 (m, 3H; CH3), 1.54–1.20
(m, 14H; CH2(n-octyl)), 0.88 ppm (t, J=6.4 Hz, 3H; CH3(n-octyl)); 13C NMR
(75 MHz, CDCl3): d=210.0 (s; C=O), 162.4 (d; C=CH), 141.3 (s; C=
CH), 41.5 (d; CH), 39.0 (t; CH2), 35.3, 32.0, 29.8, 29.6, 29.4, 27.8, 22.8
(7t; CH2(n-octyl)), 14.2 (q; CH3(n-octyl)), 10.2 ppm (q; CH3); HRMS (EI): m/
z: calcd for C14H24O: 208.1824; found: 208.1819 [M]+.
(À)-(4S)-2,4-Dimethylcyclopent-2-en-1-one (7c): A Grignard reagent was
prepared from magnesium (194 mg, 8.00 mmol), 2-bromopropene
(968 mg, 8.00 mmol), and Et2O (8 mL). The solution was transferred by
cannula into a cooled (À788C) solution of (+)-5b (393 mg, 2.50 mmol) in
Et2O (8 mL). After the reaction mixture had been stirred at À788C for
(À)-(4S)-4-({[tert-Butyl
C
1h and at 0 8C for 2 h, TLC analysis (Rf
A
A
6730
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6722 – 6733

Enantioselective Iridium-Catalyzed Allylic Alkylation
FULL PAPER
10.60 mmol) and Grubbs II catalyst (90.0 mg, 106 mmol) in CH2Cl2
(50 mL) was heated at reflux for 16 h under an argon atmosphere (moni-
(11t; C-3, C-4, C-5, C-6, C-13, C-14, C-15, C-16, C-17, C-18, C-19),
14.2 ppm (q; C-20). HRMS (FAB): m/z: calcd for C22H39O6S: 431.2467;
found: 431.2482 [M+H]+.
tored by TLC: Rf(6 f)=0.59 (petroleum ether/ethyl acetate 5:1)). The sol-
A
vent was removed in vacuo to give a dark-brown residue, which was sub-
jected to flash chromatography on silica (200 g, petroleum ether/ethyl
acetate 5:1) to yield 7 f as slightly yellow oil. The product was dissolved
in hot methanol and water was added until saturation. Upon cooling of
the solution to 58C, (À)-7 f was obtained as colorless polyhedral crystals
(À)-(12R)-TEI-9826 (10):
A suspension of the mesylate 9 (60 mg,
0.14 mmol) and neutral alumina (150 mg) in dry CH2Cl2 (5 mL) was
stirred at RT; additional portions of alumina, 130, 90, and 50 mg, were
added after 2, 4, and 6 h, respectively. After 18 h, the reaction mixture
was filtered through a pad of Celite, which was washed with ethyl ace-
tate. The filtrate was concentrated in vacuo, and the residue was subject-
ed to flash chromatography on silica (petroleum ether/ethyl acetate 5:1)
to yield TEI-9826 (10) (44 mg, 94%) as a yellowish oil. Rf(10)=0.35 (pe-
troleum ether/ethyl acetate 5:1); [a]2D4 =À121 (c=0.58 in CHCl3);
1H NMR (500 MHz, CDCl3): d=7.53 (dd, J=6.0, 2.0 Hz, 1H; 11-H), 6.51
(t, J=7.8 Hz, 1H; 7-H), 6.32 (dd, J=6.0, 2.0 Hz, 1H; 10-H), 3.66 (s, 3H;
OCH3), 3.48–3.43 (m, 1H; 12-H), 2.32–2.18 (m, 4H; 2-H, 6-H), 1.85–1.75
(m, 1H; CH2), 1.68–1.58 (m, 2H; CH2), 1.55–1.45 (m, 3H; CH2), 1.42–
1.34 (m, 2H; CH2), 1.33–1.18 (m, 12H; CH2), 0.87 ppm (t, J=7.1Hz,
3H; 20-H); 13C NMR (125 MHz, CDCl3): d=197.1, 174.2 (2s; C-1, C-9),
162.1 (d; C-11), 138.3 (s; C-8), 135.3 (d; C-7), 134.9 (d; C-10), 51.6 (q;
OCH3), 43.5 (d; C-12), 34.0, 32.6, 31.2, 29.9, 29.6, 29.4, 29.1, 29.0, 28.5,
26.0, 24.9, 22.8 (12t; C-2, C-3, C-4, C-5, C-6, C-13, C-14, C-15, C-16, C-
17, C-18, C-19), 14.2 ppm (q; C-20); elemental analysis calcd (%) for
C21H34O3: C 75.41, H 10.25; found: C 75.07, H 10.22; HPLC (Daicel AD-
H column, 96:4 n-hexane/iPrOH, 208C, 220 nm): tr((+)-10)=18.7, tr((À)-
10)=20.6 min.
(3.29 g, 85%). Rf(7 f)=0.37 (petroleum ether/ethyl acetate 5:1); m.p. 52–
G
548C; [a]2D0 =À106 (c=1.01 in CHCl3, 97.5% ee according to HPLC);
1H NMR (500 MHz, CDCl3): d=7.65–7.60 (m, 4H; Ar), 7.47–7.36 (m,
6H; Ar), (m, 1H; CH=), 3.71(dd, J=9.8, 5.9 Hz, 1H; OCHaHb), 3.66
(dd, J=9.8, 6.4 Hz, 1H; OCHaHb), 3.00 (brm, 1H; CHCH=), 2.47 (dd,
J=18.6, 6.4 Hz, 1H; CH2C=O), 2.20 (dd, J=19.1, 1.9 Hz, 1H; CH2C=O),
1.78 (s, 3H; CH3), 1.04 ppm (s, 9H; tBu-H); 13C NMR (75 MHz, CDCl3):
d=209.5 (s; C=O), 159.3 (d; CH=), 142.8 (s; CH=C), 135.7, 135.7 (2d;
Ar), 133.5, 133.4 (2s; Ar), 129.9, 129.9, 127.9 (3d; Ar), 66.0 (t; OCH2),
41.6 (d; CHCH=), 37.9 (t; CH2C=O), 26.9 (q; C(CH3)3), 19.4 (s; C-
G
A
365.1937; found: 365.1943 [M+H+]; elemental analysis calcd (%) for
C23H28O2Si: C 75.78, H 7.74; found: C 75.52, H 7.73; HPLC (Daicel OD-
H
column, n-hexane/iPrOH 90:10, 208C, 220 nm): tr((À)-7 f)=10.5,
tr((+)-7 f)=14.0 min.
(À)-(12R)-Methyl 7-hydroxy-9-oxoprost-10-en-1-oate (8): A solution of
iPr2NH (0.24 mL, 1.7 mmol) in dry THF (5 mL) was treated with nBuLi
(0.88 mL, 1.6m in hexane). The resulting solution of LDA was cooled to
À788C, then enone 7d (248 mg, 1.27 mmol) was added. The mixture was
stirred for 10 min at À788C, and then freshly prepared methyl 6-formyl-
hexanoate (269 mg, 1.70 mmol) was added dropwise. After 2 h at À788C,
TLC analysis indicated complete conversion, and the solution was
poured into a cold (08C), vigorously stirred mixture of diethyl ether
(50 mL) and saturated aqueous NH4Cl (25 mL). The organic layer was
separated, and the aqueous layer was extracted with diethyl ether (3”
50 mL). The combined extracts were dried over MgSO4, filtered and con-
centrated in vacuo. The crude product was purified by flash chromatogra-
phy on silica (petroleum ether/ethyl acetate 5:1) to yield alcohol 8
(265 mg, 58%) as a colorless oil. Rf(8)=0.24 (petroleum ether/ethyl ace-
tate 5:1); [a]2D4 =À81( c=0.85 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=7.68 (dd, J=5.4, 2.4 Hz, 1H; 11-H), 6.13 (dd, J=5.9, 2.0 Hz, 1H; 10-
H), 3.80 (s, 1H; OH), 3.68–3.65 (m, 1H; 7-H), 3.66 (s, 3H; OCH 3), 2.67–
Diastereomeric 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-methylcyclo-
A
pent-2-en-1-ols (11, 12): DIBAL (1m in n-hexane, 4.0 mL, 4.0 mmol) was
added to a solution of (À)-7 f (1.29 g, 3.54 mmol) in dry THF (80 mL) at
À758C under an argon atmosphere. After the reaction mixture had been
stirred for 35 min, TLC analysis indicated complete conversion. Water
(1.6 mL) and silica (8 g) were added, and the mixture was allowed to
warm to RT. The mixture was filtered through Celite and washed with
ethyl acetate. The solvent was removed in vacuo and the residue was sub-
jected to flash chromatography on silica (100 g, petroleum ether/ethyl
acetate 10:1 to 3:1). The stereoisomeric products were isolated as color-
less oils, (À)-11 (1.04 g, 80%) and (À)-12 (0.23 g, 15%).
Compound (À)-(1R,4S)-11: Rf(11)=0.27 (petroleum ether/ethyl acetate
3:1); [a]2D0 =À40.6 (c=0.66 in MeOH); 1H NMR (500 MHz, CDCl3): d=
7.67–7.64 (m, 4H; Ar), 7.45–7.37 (m, 6H; Ar), 5.36 (s, 1H; CH=), 4.38
(m, 1H; CHOH), 3.61–3.55 (m, 2H; OCH2), 2.74–2.70 (m, 1H;
A
ACHTREUNG
2.61(m, 1H; 12-H), 2.31(t,
J=7.4 Hz, 2H; 2-H), 2.00 (dd, J=8.4, 2.0 Hz,
2.41(ddd, J=14.6, 7.5, 7.5 Hz, 1H; CH2CHOH), 2.35 (d, J=9.8 Hz, 1H;
OH), 1.84 (s, 3H; CH3), 1.61 ppm (ddd, J=13.8, 2.6, 2.6 Hz, 1H;
CH2CHOH), 1.05 ppm (s, 9H; tBu); 13C NMR (75 MHz, CDCl3): d=
144.4 (s; CH=C), 135.9, 135.8 (2d; Ar), 133.5, 133.4 (2s; Ar), 129.9 (d,
Ar), 128.7 (d; CH=), 127.9, 127.8 (2d; Ar), 78.9 (d; CHOH), 66.6 (t;
1H; 8-H), 1.68–1.21 (m, 22H; 3-H, 4-H, 5-H, 6-H, 13-H, 14-H, 15-H, 16-
H, 17-H, 18-H, 19-H), 0.88 ppm (t, J=6.4 Hz, 3H; 20-H); 13C NMR
(125 MHz, CDCl3): d=213.0 (s; C-9), 174.3 (s; C-1), 168.7 (d; C-11),
133.0 (d; C-10), 72.3 (d; C-7), 56.2 (d; C-8), 51.6 (q; C-1’), 45.1(d; C-12),
35.5, 34.1, 34.1, 31.2, 29.9, 29.6, 29.4, 29.2, 27.1, 25.3, 25.1, 22.8 (12t ; C-2,
C-3, C-4, C-5, C-6, C-13, C-14, C-15, C-16, C-17, C-18, C-19), 14.2 ppm
(q; C-20); elemental analysis calcd (%) for C21H36O4: C 71.55, H 10.31;
found: C 71.62, H 10.31.
OCH2), 45.8 (d; CHCH=), 38.1(t; CH2CHOH), 27.0 (q; C(CH3)3), 19.4
E
(s;
C(CH3)3), 14.0 ppm (q; CH3); HRMS (FAB): m/z: calcd for
C
calcd (%) for C23H30O2Si: C 75.36, H 8.25; found: C 75.07, H 8.29.
(À)-(12R)-Methyl 7-[(methylsulfonyl)oxy]-9-oxoprost-10-en-1-oate (9):
A solution of alcohol 8 (120 mg, 0.340 mmol) and dry Et3N (0.47 mL,
3.4 mmol) in dry CH2Cl2 (3 mL) was cooled to 08C and freshly distilled
MsCl (0.20 mL, 2.5 mmol) was added. The mixture was allowed to warm
to RT and was stirred overnight (monitored by TLC). It was then poured
into a stirred mixture of ethyl acetate (10 mL) and saturated aqueous
NaHCO3 (5 mL). The mixture was extracted with diethyl ether (3”
20 mL), and the organic layer was dried over MgSO4 and concentrated in
vacuo. The residue was subjected to flash chromatography on silica (30 g,
petroleum ether/ethyl acetate 5:1) to yield mesylate 9 (120 mg, 82%) as
Compound (À)-(1S,4S)-12: [a]2D0 =À96 (c=1.08 in MeOH); 1H NMR
(500 MHz, CDCl3): d=7.67–7.63 (m, 4H; Ar), 7.44–7.36 (m, 6H; Ar),
5.51(s, 1H; CH =), 4.63–4.60 (m, 1H; CHOH), 3.52 (d, J=6.4 Hz; 2H;
OCH2), 3.00–2.96 (m, 1H; CHCH=), 2.07 (ddd, J=13.9, 7.3, 4.2 Hz, 1H;
CH2CHOH), 1.82 (ddd, J=13.9, 8.0, 3.7 Hz, 1H; CH2CHOH), 1.79 (s,
3H; CH3), 1.04 ppm (s, 9H; tBu); 13C NMR (75 MHz, CDCl3): d=143.3
(s; CH=C), 135.8, 135.7 (2d; Ar), 134.1, 134.0 (2s; Ar), 130.3 (d; CH=),
129.7, 129.7, 127.7 (3d; Ar), 79.7 (d; CHOH), 67.8 (t; OCH2), 46.1(d;
CHCH=), 37.9 (t; CH2CHOH), 27.0 (q; C
N
N
a yellowish oil. Rf(9)=0.12, (petroleum ether/ethyl acetate 5:1); [a]D24
=
13.8 ppm (q; CH3); HRMS (FAB): m/z: calcd for C23H29OSi: 349.1988;
found: 349.1964 [M+HÀH2O]+; elemental analysis calcd (%) for
C23H30O2Si: C 75.36, H 8.25; found: C 75.50, H 8.22.
1
À53 (c=0.8 in CHCl3); H NMR (300 MHz, CDCl3): d=7.68 (dd, J=5.8,
2.4 Hz, 1H; 11-H), 6.11 (dd, J=5.8, 1.7 Hz, 1H; 10-H), 5.04–4.95 (m,
1H; 7-H), 3.66 (s, 3H; OCH3), 3.04–2.99 (m, 1H; 8-H), 3.00 (s, 3H;
SCH3), 2.57–2.52 (m, 1H; 12-H), 2.30 (t, J=7.4 Hz, 2H; 2-H), 1.85–1.16
(m, 22H; 3-H, 4-H, 5-H, 6-H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H, 19-
H), 0.88 ppm (t, J=6.8 Hz, 3H; 20-H); 13C NMR (75 MHz, CDCl3): d=
209.4 (s; C-9), 173.1 (s; C-1), 168.4 (d; C-11), 133.4 (d; C-10), 82.4 (d; C-
(À)-(1R,4S)-4-({[tert-Butyl
C
À
À
7), 54.7 (d; C-12), 51.7 (d; C OCH3), 44.2 (d; C-8), 38.6 (q; C SCH3),
34.5 (1t; C-2), 34.0, 32.0, 31.2, 29.8, 29.6, 29.4, 28.8, 27.4, 25.7, 24.8, 22.8
Chem. Eur. J. 2008, 14, 6722 – 6733
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6731

G. Helmchen et al.
lution of NH4Cl was added (100 mL) to the reaction mixture. The phases
were separated and the aqueous phase was extracted with CH2Cl2 (2”
100 mL). The combined organic phases were washed with a saturated
aqueous solution of CuSO4 (100 mL) and brine (100 mL). The organic
phase was dried over Na2SO4, and the solvent was removed in vacuo.
The crude product was purified by flash chromatography on silica (30 g,
petroleum ether/ethyl acetate 5:1) to yield (À)-13 (2.60 g, 86%) as a col-
orless oil. Rf(13)=0.56 (petroleum ether/ethyl acetate 5:1); [a]2D0 =À61
(c=0.46 in MeOH, 98% ee); 1H NMR (500 MHz, CDCl3): d=7.68–7.64
(m, 4H; Ar), 7.45–7.34 (m, 6H; Ar), 5.63–5.61(m, 1H; CH =), 5.47–5.43
(m, 1H; CHOCO2CH3), 3.78 (s, 3H; OCH3), 3.63–3.52 (m, 2H; OCH2),
2.85–2.75 (m, 1H; CHCH=), 2.54 (ddd, J=14.3, 7.8, 7.8 Hz, 1H;
CH2CHOCO2CH3), 1.74 (s, 3H; CCH3), 1.60 (ddd, J=14.3, 4.7, 4.7 Hz,
1H; CH2CHOCO2CH3), 1.06 ppm (s, 9H; tBu); 13C NMR (75 MHz,
CDCl3): d=156.0 (s; C=O), 139.0 (s; CH=C), 135.8, 135.7, (2d; Ar),
134.1, 134.0 (2s; Ar), 132.4 (d; CH=), 129.7, 127.8 (2d; Ar), 85.4 (d;
CHOCO2CH3), 68.0 (t; OCH2), 54.7 (q; OCH3), 46.2 (d; CHCH=), 34.3
Compound (+)-(1S,4R)-16: Crystallization of (+)-16 by slow evaporation
from ethanol at RT yielded colorless, plate-shaped crystals. [a]2D0 =+3.0
(c=0.28 in MeOH); m.p. 180–1848C; 1H NMR (300 MHz, CDCl3): d=
7.85 (s, 1H; HC=N), 5.76–5.73 (m, 1H; CH=C), 5.32–5.25 (m, 1H;
CH2CHN), 5.13 (s, 2H; NH2), 3.85 (dd, J=10.5, 2.7 Hz, 1H; OCHaHb),
3.74 (dd, J=10.6, 3.3 Hz, 1H; OCHaHb), 3.80–3.67 (m, 1H; OH), 3.08–
3.02 (m, 1H; CHCH2OH), 2.81(ddd,
J=14.5, 9.5, 9.5 Hz, 1H;
CH2CHN), 2.14 (ddd, J=14.5, 5.6, 5.6 Hz, 1H; CH2CHN), 1.53 ppm (s,
3H; CH3); 13C NMR (75 MHz, CDCl3): d=158.6, 153.1, 151.9 (3s;
purine), 142.4 (d; purine), 138.3 (s; purine), 132.7 (d; CH=), 126.1 (s;
CH=C), 65.3 (t; OCH2), 64.4 (d; CH2CHN), 46.4 (d; CHCH2OH), 33.0
(t; CH2CHN), 13.8 ppm (q; CH3); HRMS (FAB): m/z: calcd for
C12H1535ClN5O: 280.0965; found: 280.0967 [M+H+].
Compound (À)-(1S,2S)-17: Crystallization of (À)-17 by slow evaporation
at RT from methanol yielded colorless needles. [a]2D0 =À25.4 (c=0.18 in
MeOH); m.p. 192–1948C; 1H NMR (300 MHz, CDCl3): d=7.55 (s, 1H;
HC=N), 6.01(s, 1H; CH =), 5.28 (s, 2H; NH2), 5.20 (d, J=6.4 Hz, 1H;
CCHN), 3.50–3.30 (m, 2H; OH, OCH2), 3.05–2.94 (m, 1H; OCH2), 2.93–
2.80 (m, 1H; CHCH2OH), 2.45 (dddd, J=16.6, 7.5, 2.8, 1.7 Hz, 1H;
CH2CH=), 2.15–2.03 (m, 1H; CH2CH=), 1.75 ppm (s, 3H; CH3);
13C NMR (75 MHz, CDCl3): d=159.0, 154.0, 152.1 (3s; purine), 141.4 (d;
purine), 136.7 (s; CH=C), 133.3 (d; CH=), 126.0 (s; C-purine), 63.2 (d;
CHN), 60.9 (t; OCH2), 47.4 (d; CHCH2OH), 29.8 (t; CH2CH=),
14.9 ppm (q; CH3); HRMS (FAB): m/z: calcd for C12H1535ClN5O:
280.0965; found: 280.0934 [M+Na+].
(t; CH2CHOCO2CH3), 27.0 (q; C
N
N
CH3); HRMS (FAB): m/z: calcd for C23H29OSi: 349.1988; found:
349.1995 [M+HÀMeOCOOH]+; elemental analysis calcd (%) for
C25H32O4Si: C 70.72, H 7.60; found: C 70.79, H 7.66.
(À)-9-[(1R,4S)-4-({[tert-Butyl
C
6-chloropurine (596 mg, 3.50 mmol) in dry DMSO (10 mL) was added to
a
solution of (À)-13 (1.247 g, 2.93 mmol) and [Pd
A
(+)-2-Amino-9-[(1R,4S)-4-(hydroxymethyl)-2-methylcyclopent-2-en-1-
yl]-1,9-dihydro-6H-purine-6-one (2’-Methylcarbovir) (18): A solution of
(+)-(1S,4R)-16 (40.5 mg, 0.145 mmol) in aqueous NaOH (0.5m, 2 mL)
was heated at reflux for 30 min, when conversion was complete (moni-
tored by TLC) saturated aqueous NaHCO3 (2 mL) was added. The mix-
ture was concentrated in vacuo, and the residue was subjected to flash
chromatography on silica (15 g, CH2Cl2/methanol 95:5) to yield (+)-
(1R,4S)-2’-methylcarbovir (18) (31mg, 82%) as a colorless solid. With
the exception of the optical rotation, the analytical data matched the
data provided by Crimmins et al.[25b] Rf(18)=0.02, (CH2Cl2/methanol
95:5); m.p. >2508C; [a]D20 =+10.4 (c=0.11 in MeOH) (lit.:[25b] [a]D =
À61.0 (c=0.31in MeOH)); 1H NMR (300 MHz, [D6]DMSO): d=10.58
(s, 1H; NH), 7.59 (s, 1H; HC =N), 6.44 (s, 2H; NH2), 5.70 (dd, J=2.8,
1.2 Hz, 1H; CCH=), 5.22–5.16 (m, 1H; CCHN), 4.68 (t, J=5.2 Hz, 1H;
OH), 3.43 (dd, J=5.5, 5.5 Hz, 2H; OCH2), 2.82–2.73 (m, 1H;
CHCH2OH), 2.58 (ddd, J=13.7, 8.9, 8.8 Hz, 1H; CH2CHN), 1.65 (ddd,
J=13.7, 5.8, 5.8 Hz, 1H; CH2CHN), 1.48 ppm (s, 3H; CH3); 13C NMR
(75 MHz, [D6]DMSO): d=156.8, 153.5, 151.1, 137.7 (4s), 135.3 (d;
purine), 132.1 (d; CH=), 116.4 (s; CH=C), 64.3 (t; OCH2), 60.8 (d;
CHN), 46.3 (d; CHCH2OH), 34.7 (t; CH2CHN), 13.4 ppm (q; CH3);
HRMS (FAB): m/z: calcd for C12H16N5O2: 262.1304; found: 262.1325
[M+H]+; HPLC (Daicel AD-H column, 60:40 n-hexane/iPrOH, 308C,
0.300 mmol) in dry THF (12 mL) at RT under an argon atmosphere. The
mixture was stirred at RT until conversion was complete (18 h; monitored
by TLC, Rf(13)=0.67, CH2Cl2/methanol 9:1). Water (20 mL) was added
and the mixture was extracted with ethyl acetate (4”30 mL). The organic
phase was dried over Na2SO4, and the solvent was removed in vacuo.
The crude product was subjected to flash chromatography on silica
(170 g, CH2Cl2/methanol 99:1) to yield a mixture of the regioisomers 14
and 15 (1.10 g, 72% combined yield) in a ratio of 86:14 (determined by
1H NMR spectroscopy).
An analytically pure fraction of the major product (À)-14 was obtained
by preparative HPLC (column: Latek, 250”21mm, 5 m silica; CH2Cl2/
methanol 99.5:0.5, 20 mLminÀ1, 50 bar) as a colorless foam. The analyti-
cal data refers to this sample. [a]2D0 =À49.5 (c=0.49 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.67–7.62 (m, 5H; Ar), 7.46–7.34 (m, 6H; Ar),
5.76–5.75 (m, 1H; CH=), 5.38 (ddd, J=8.6, 6.8, 1.0 Hz, 1H; CH2CHN),
5.01(s, 2H; NH ), 3.74–3.62 (m, 2H; OCH2), 3.02–2.93 (m, 1H; C
G
U
N
R
T
G
U
H
A
HCH=),
G
U
N
E
R
G
N
T
H
A
2
2.72 (ddd, J=13.9, 8.6, 8.6 Hz, 1H; CH2CHN), 1.71 (ddd, J=13.6, 6.6,
6.6 Hz, 1H; CH2CHN), 1.55 (s, 3H; CH3), 1.06 ppm (s, 9H; tBu);
13C NMR (75 MHz, CDCl3): d=159.0, 154.0, 151.3 (3s; purine), 140.9 (d;
purine), 137.8 (s; Ar), 135.7 (d; Ar), 133.6 (s; Ar), 133.1 (d; CH=), 129.9,
127.9 (2d; Ar), 125.7 (s; =CCH3), 67.2 (t; OCH2), 62.1(d; CH 2CHN),
46.5 (d; CHCH=), 35.4 (t; CH2CHN), 27.1(q;
C (CH3)3), 19.4 (s;
A
254 nm): tr
A
N
A
N
C28H33ClN5OSi: 518.2143; found: 518.2163 [M+H+]; elemental analysis
calcd (%) for C28H3235ClN5OSi: C 64.91, H 6.23, N 13.52, Cl 6.84; found:
C 64.61, H 6.21, N 13.25, Cl 6.89.
(+)-[(1S,4R)-4-(2-Amino-6-chloro-9H-purine-9-yl)-3-methylcyclopent-2-
en-1-yl]methanol (16) and( À)-[(1S,2S)-2-(2-amino-6-chloro-9H-purin-9-
yl)-3-methylcyclopent-3-en-1-yl]methanol (17): A solution of the mixture
of 14 and 15 (604 mg, 1.17 mmol), described above, in dry THF (25 mL)
was treated with a solution of HF in pyridine (ca. 70% HF/30% pyridine,
2.3 mL, 2.5 g, ꢀ90 mmol HF) in a Teflon flask. Conversion was complete
after the reaction mixture had been stirred for 2.5 h at RT (monitored by
TLC: Rf(15)=0.52, CH2Cl2/methanol 95:5). Aqueous Na2CO3 (2m,
20 mL) was added dropwise. The mixture was extracted with ethyl ace-
tate (3”30 mL), and the organic phase was dried over Na2SO4. The sol-
vent was removed in vacuo and the crude product was subjected to flash
chromatography on silica (8 g, CH2Cl2/methanol 95:5) to yield a mixture
of the regioisomers 16 and 17 (233 mg, 72%). The isomers were separat-
ed by preparative HPLC (50 mg per run; column: Latek, 250”21mm,
5 m silica; CH2Cl2/methanol 97:3, 20 mLminÀ1, 50 bar). Both compounds
were obtained as colorless solids: (+)-16 (163 mg, 50%) and (À)-17
(32 mg, 11%).
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB
623), the Degussa-Stiftung, and the Studienstiftung des deutschen Volkes.
We thank Dr. P. Kraft (Givaudan AG, Dübendorf, Switzerland) for the
olfactory characterization of (+)- and (À)-7c and Dr. F. Rominger (Uni-
versität Heidelberg) for the crystal structure analyses. Furthermore, we
thank S. Dreisigacker, S. Holm, and M. Krauter for experimental assis-
tance and Prof. K. Ditrich (BASF AG) for enantiomerically pure 1-aryl-
A
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6722 – 6733

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[13] Crystal data for (2R,3R)-3d: C26H35NO5Si; M=469.64; orthorombic;
space group P212121; a=7.9338(1), b=10.1467(1), c=33.4027(1) Š;
a=90.0, b=90.0, g=90.08; V=2688.98(4) Š3; Z=4; m=
0.121 mmÀ1; 28291reflections collected, 6166 unique (R int =0.0520),
5151 observed [I>2s(I)], R1=0.045, wR2=0.111, flack 0.08(12).
Crystal data for 16: C12H14ClN5O; M=279.73; orthorombic; space
group C2221; a=10.5535(9), b=10.9127(9), c=44.623(4) Š; a=90.0,
b=90.0, g=90.08; V=5139.0(8) Š3; Z=16; m=0.30 mmÀ1; 26958 re-
flections collected, 6398 unique (Rint =0.0520), 5917 observed [I>
2s(I)]. R1=0.059, wR2=0.113, flack 0.08(6). Crystal data for 17:
C12H14ClN5O; M=279.73; orthorombic; space group P212121; a=
7.7318(2), b=9.5740(3), c=17.9875(5) Š; a=90.0, b=90.0, g=
90.08; V=1331.51(7) Š3; Z=4; m=0.29 mmÀ1; 13356 reflections col-
lected, 3030 unique (Rint =0.0425), 2512 observed [I>2s(I)]. R1=
0.038, wR2=0.072, flack 0.04(6). CCDC-664433 (3d), 653304 (16),
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Received: March 17, 2008
Published online: June 23, 2008
Chem. Eur. J. 2008, 14, 6722 – 6733
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6733