Enders SAMP-hydrazone as traceless auxiliary in the asymmetric 1,4-addition of cuprates to enones

Article abstract of DOI:10.1002/adsc.201000412

Conjugate additions of Gilman cyanocuprates to (5)-N-amino-2- (methoxymethyl)pyrrolidine (SAMP)-hydrazones 4, 5 derived from cyclic and acyclic α,β-unsaturated ketones were investigated. A protocol utilizing copper(II) sulfate/ammonium chloride was evolved, which allowed cleavage of SAMP (S)-1 under the hydrolysis and work-up conditions, followed by recovery of the auxiliary with ethylenediaminetetraacetic acid (EDTA). The enantioselectivity of cuprate additions was dominated for cyclic SAMP-hydrazones 4 by the cuprate alkyl substituent and the ring size, in the case of acyclic arylidene SAMP-hydrazones 5, however, by the nature of the aryl substituent. Electron-donating substituents gave poor enantiomeric excesses, whereas electron-withdrawing groups provided excellent ee values of 98-99%. The configuration of the new stereocenter was determined to be (R). Moreover, a reaction sequence was developed which integrates a tandem 1,4-addition/ methylation and traceless hydrolytic cleavage of the auxiliary (S)-1 in a one-pot reaction, resulting in enantiomerically pure methyl ketones 11-13, each of them with > 99% ee.

Full text of DOI:10.1002/adsc.201000412

FULL PAPERS
DOI: 10.1002/adsc.201000412
Endersꢀ SAMP-Hydrazone as Traceless Auxiliary in the
Asymmetric 1,4-Addition of Cuprates to Enones
Karsten Sammet,a Christoph Gastl,a Angelika Baro,a Sabine Laschat,a,*
Peter Fischer,a and Ina Fettiga
a
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax : (+49)-711-685-64285; e-mail: sabine.laschat@oc.uni-stuttgart.de
Received: May 26, 2010; Published online: September 8, 2010
Dedicated to Prof. Franz Effenberger on the occasion of his 80th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000412.
Abstract: Conjugate additions of Gilman cyanocup- aryl substituent. Electron-donating substituents gave
rates to (S)-N-amino-2-(methoxymethyl)pyrrolidine poor enantiomeric excesses, whereas electron-with-
(SAMP)-hydrazones 4, 5 derived from cyclic and drawing groups provided excellent ee values of 98–
acyclic a,b-unsaturated ketones were investigated. A 99%. The configuration of the new stereocenter was
protocol utilizing copper(II) sulfate/ammonium chlo- determined to be (R). Moreover, a reaction sequence
ride was evolved, which allowed cleavage of SAMP was developed which integrates a tandem 1,4-addi-
(S)-1 under the hydrolysis and work-up conditions, tion/methylation and traceless hydrolytic cleavage of
followed by recovery of the auxiliary with ethylene- the auxiliary (S)-1 in a one-pot reaction, resulting in
diaminetetraacetic acid (EDTA). The enantioselec- enantiomerically pure methyl ketones 11–13, each of
tivity of cuprate additions was dominated for cyclic them with>99% ee.
SAMP-hydrazones 4 by the cuprate alkyl substituent
and the ring size, in the case of acyclic arylidene Keywords: asymmetric synthesis; chiral auxiliaries;
SAMP-hydrazones 5, however, by the nature of the conjugate addition; cuprates; SAMP-hydrazones
Introduction
compounds to 4a.[7] However, to the best of our
knowledge 1,4-additions of organometallic carbon nu-
Since their introduction in 1976 Endersꢂ (S)- and (R)- cleophiles such as cuprates to a,b-unsaturated hydra-
N-amino-2-(methoxymethyl)pyrrolidines, SAMP (S)-1 zones have not been reported in the literature. Due
(Scheme 1) and RAMP (R)-1, belong to the most ver- to their functional group tolerance and their possible
satile and successful chiral auxiliaries, which have utilization in tandem reactions, stoichiometric cuprate
been employed in asymmetric syntheses.[1,2] Among additions are still highly attractive[8–10] despite the tre-
the broad range of carbonyl compounds forming the mendous achievements in Cu- and Rh-catalyzed con-
corresponding chiral hydrazones with (S)- or (R)-1, jugate additions.[11,12] However, the latter do not give
enones are much less exploited. For example, Toko- reliable yields and enantioselectivities in each case[13]
ACHTUNGTRENNUNGroyama used the stereoselective a’-alkylation of cyclo- and were only rarely combined with electrophilic
hexenone-derived SAMP-hydrazone 4a for the prepa- trapping of the intermediate enolate.[14] Furthermore,
ration of the clerodane diterpenoid (À)-methyl ko- Rh-catalyzed conjugate additions are limited to aryl-
valenate.[3] Palacios published the synthesis of a,b-un- and vinylboronic acids,[12] whereas alkyl groups
saturated hydrazones by Wittig reaction of functional- cannot be transferred. These findings motivated us to
ized ylides and phosphane oxides[4] and Pearson study the application of Endersꢂ SAMP-hydrazone
employed a,b-unsaturated hydrazones for the prepa- methodology to conjugate cuprate additions to a vari-
ration of chiral tricarbonyl iron diene complexes.[5] ety of a,b-unsaturated carbonyl compounds. The re-
Besides the use of the C=N bond in 4a as a dipolaro- sults are reported below.
phile in asymmetric [3+2]cycloadditions[6] Enders
studied in 1993 conjugate additions of stannyllithium
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dꢂAngelo and co-workers in Michael additions of
chiral imines to methyl vinyl ketone.[16] Later Hall
evolved a synthesis of a-exomethylene-g-lactones
where the auxiliary is either cleaved directly under
the reaction conditions or during work-up[17] and Glo-
rius further developed this strategy for catalytic hy-
drogenations of pyridines.[18] Noteworthy, Enders
much earlier used this concept in the SAMP-mediated
synthesis of 1,4-dihydropyridines by tandem Michael
addition of acetoacetate to benzylidene acetone deriv-
atives and subsequent cyclization, although the term
“traceless auxiliary” was never mentioned.[19] Very re-
cently, “traceless auxiliaries” have been applied by
Tius for allene ether Nazarov cyclizations[20] and by
Kolesinska for peptide couplings.[21] Also ortho-diphe-
nylphosphanylbenzoate (o-DPPB)-directed allylic
substitutions with cuprates developed by Breit can be
considered in this category.[22,23]
In order to initiate our studies on SAMP-mediated
conjugate additions in more detail, a series of cyclic
and acyclic a,b-unsaturated SAMP-hydrazones 4a–c
and 5a–f were prepared by heating the corresponding
enones with (S)-1 in benzene under Dean–Stark con-
ditions (for details see Experimental Section). SAMP-
hydrazones 4 and 5, which were obtained as E/Z-mix-
tures in 73% to 90% and 83% to quantitative yield
(Table 1 and Table 2), respectively, were reacted in
Et2O at À788C with a slight excess of various Gilman
cuprates R2CuLi·LiCN (R=Me, Et, n-Bu, t-Bu) in
the presence of the additive LiBr, and the reaction
mixture was allowed to warm to 158C overnight.
Cleavage of the hydrazone moiety to regenerate the
carbonyl functionality depended on the type of
SAMP-hydrazone, and thus two different work-up
protocols using hydrolytic cleavage conditions have
been worked out. Cyclic SAMP-hydrazones 4 were
Scheme 1. 1,4-Addition of Gilman cuprate Bu2CuLi·LiCN to
SAMP-hydrazones 4a and 5a.
Results and Discussion
In
a preliminary experiment six-membered ring treated with a saturated aqueous NH4Cl solution at
SAMP-hydrazone 4a[1c,2f,3] was treated with Gilman room temperature for 1 h, followed by addition of a
cuprate Bu2CuLi·LiCN in Et2O at À788C followed by 0.4M CuSO4·5H2O solution in H2O/MeOH (1:1)
hydrolysis with a saturated NH4Cl solution and aque- (Table 1). Acyclic SAMP-hydrazones 5 were treated
ous work-up (Scheme 1). Surprisingly, the reaction sequentially with a half-saturated aqueous NH4Cl so-
did not give the expected b-substituted hydrazone 6a, lution and a 0.4M CuSO4·5H2O solution in MeOH
but 3-butylcyclohexanone 8a was isolated in 50% for 2 h at room temperature (Table 2).[24] Upon addi-
yield with 52% ee. This result suggested that the a,b- tion of CuSO4 under both conditions an immediate
À
unsaturated hydrazone is still intact during the C C color change from dark yellow to wine red was ob-
bond formation and thus exerts some stereocontrol served, which is caused by the formation of
on the reaction. The conversion of 4-phenylbut-3-en- (SAMP)2CuSO4 complex 10 (lmax =260 nm).[25] The
2-one (3a)-derived SAMP-hydrazone 5a with the obtained product mixtures were chromatographed on
Gilman cuprate under identical conditions yielded the silica gel to yield the b-alkylated ketones 8 and 9
crude b-substituted hydrazone 7a in 98%.[15] After (Table 1 and Table 2), while complex 10 remained as
chromatographic purification on silica gel, however, an insoluble residue on top of the column packing.
only (4R)-4-phenyloctan-2-one (9a) was isolated in After dissolving complex 10 in DMSO, EDTA was
87% with the high enantiomeric excess of 90%.
added resulting in the formation of the
CATHNUGTREN(NUNG EDTA)2CuSO4 complex (lmax =243 nm) as being visi-
From these results we anticipated that SAMP (S)-1
might be useful as a “traceless auxiliary” for this kind ble by immediate color change to green. Extraction
of asymmetric conjugate additions. The concept of with Et2O allowed the recycling of SAMP (S)-1 in
“traceless auxiliaries” has been first introduced by 83% isolated yield and >95% purity.
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Endersꢂ SAMP-Hydrazone as Traceless Auxiliary in the Asymmetric 1,4-Addition
Table 1. Asymmetric 1,4-addition of cuprates R2CuLi·LiCN to a,b-unsaturated SAMP-hydrazones 4.[a,b]
Entry
Hydrazone
n
E:Z
Yield [%]
85
Product
R
Yield [%]
% ee
1
2
3
4
5
6
4a
4a
4a
4a
4b
4c
1
1
1
1
0
2
63:37
63:37
63:37
63:37
63:37
96:4
8b
8c
8a
8d
8e
8f
Me
Et
n-Bu
t-Bu
n-Bu
n-Bu
78
97
65
62
87
92
12
32
54
8
18
64
73
90
[a]
Enantioselectivities were determined by capillary GC on a chiral stationary phase.
The configuration of 8 was assigned to be (R) based on comparison with literature data (see Supporting Information).
[b]
Table 2. Asymmetric 1,4-addition of cuprates R2CuLi·LiCN to a,b-unsaturated SAMP-hydrazones 5.[a,b]
Entry
Hydrazone
Ar
E:Z
Yield [%]
quant.
Product
R
Yield [%]
% ee
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
78:22
78:22
78:22
78:22
78:22
62:38
85:15
79:21
71:29
9b
9c
9a
9d[c]
9e
9f
9g
9h
9i
Me
Et
74
27
56
88
69
65
35
80
81
85
93
98
2
18
22
99
98
54
n-Bu
t-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
4-Me-C6H4
4-MeO-C6H4
4-NO2-C6H4
4-Cl-C6H4
2-furyl
99
quant.
85
83
quant.
[a]
Enantioselectivities were determined by HPLC on a chiral stationary phase (entries 1–8) or capillary GC on a chiral sta-
tionary phase (entry 9).
The configuration of 9 was assigned to be (R) based on comparison with literature data (see Supporting Information).
(S)-configuration due to priority rules.
[b]
[c]
Table 1 reveals for cyclohexenone-derived SAMP- ring size of hydrazones 4a–c influenced the enantiose-
hydrazone 4a that the cuprate substituent R affected lectivity, which is enhanced from the five-membered
the enantioselectivities of organocuprate additions. to the seven-membered ring system (entries 3, 5, 6).
With increasing chain length of the alkyl groups the
Organocuprate addition and subsequent hydrolytic
ee values increased from 12% ee for R=Me to 54% cleavage of auxiliary (S)-1 provided substituted ke-
ee for R=n-Bu (entries 1–3). In contrast, the addition tones 9 with improved enantioselectivities as com-
of the branched cuprate (R=t-Bu) to 4a afforded an pared to 8 (Table 2). The effect of cuprate substituent
almost racemic ketone 8d (entry 4). Additionally, the R on the enantioselectivity is smaller for hydrazone
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5a than for derivative 4a (entries 1–3), but again the
tert-butyl group led to a nearly racemic product
(entry 4). With regard to 1,4-additions of n-
Bu2CuLi·LiCN to various arylidene acetone-derived
hydrazones 5b–f, however, the electronic character of
the aryl moiety plays a prominent role. The electron-
rich aryl substituents (MeC6H4 and MeOC6H4) de-
creased the ee values significantly, for example, 18%
ee and 22% ee for 4-(methylphenyl)- and 4-(methoxy-
phenyl)octan-2-one 9e and 9f (entries 5 and 6) rela-
tive to 4-phenyloctan-2-one 9a (98% ee, entry 3). In
agreement with these results the electron-rich furyl
substituent in SAMP-hydrazone 5f caused a de-
creased enantioselectivity of 54% ee for ketone 9i
(entry 9). In contrast, cuprate addition to SAMP-hy-
drazones 5d and 5e with electron-poor aryl moieties
afforded the corresponding 4-(nitrophenyl)- and 4-
(chlorophenyl)-substituted octanones 9g and 9h with
excellent selectivities of 98–99% ee (entries 7 and 8).
In order to explain the preferred formation of the
(R)-enantiomers we propose the following mechanis-
tic rationale (Scheme 2). Despite the bimetallic acti-
À
À
vation via Li N and Cu C=C interactions, the SAMP
auxiliary directs the attack of the cuprate moiety R to
the Re-face of cyclic hydrazones 4 or the Si-face of ar-
ylhydrazones 5 leading to the (R)-configurated prod-
uct in both cases.[26]
Scheme 3. Cuprate addition to SAMP-hydrazone 5a, methyl-
ation and cleavage of the auxiliary in one reaction.
tion of intermediate A in Et2O failed completely. Al-
ready in 1979 Smith reported the poor reactivity of
cuprate-derived enolates particularly when Et2O was
used as the solvent.[27] Therefore, we considered a sol-
vent exchange prior to the alkylation reaction al-
though this might cause epimerization of the azaeno-
late and leading to competing a- and a’-alkylation.[27]
As shown in Scheme 3, SAMP-hydrazone 5a was
treated with Bu2CuLi·LiCN in Et2O at À788C for
45 min. After removal of Et2O at À58C,[28] residue A
was redissolved in THF and treated with MeI in the
presence of HMPA at À58C for 1 h followed by
Cu(II)-mediated hydrolytic auxiliary cleavage as de-
scribed above.
Scheme 2. Proposed transition states of the cuprate addi-
tions. For better visibility the cuprates are shown as mono-
meric species.
A mixture of a-methyl-, a,a’-dimethyl- and a,a’,a’-
trimethyl-substituted 4-phenyloctan-2-ones 11–13 was
In Cu- and Rh-catalyzed 1,4-additions electrophilic isolated in 81% yield in a ratio of 11:12:13=46:27:27.
trapping of the intermediate enolate is rarely possi- 1H NMR spectroscopy of compound 13 revealed the
ble.[14] We were therefore interested to see whether trans configuration. A characteristic doublet of quar-
the cuprate addition to SAMP-hydrazones can be tets at d=2.90 ppm with coupling constants J=10.1
combined with an a-alkylation of the formed inter- and 6.9 Hz was found for the signal of the proton at
mediate azaenolate A (Scheme 3).
C-4, which is in good agreement with the H-3 proton
Thus, we developed a methodology which enabled signal at d=2.87 ppm (dq, J=10.0 Hz, 7.0 Hz) report-
a sequence of asymmetric cuprate addition to SAMP- ed for the structurally related methyl (2RS,3SR)-2-
hydrazones, a-alkylation and subsequent traceless methyl-3-phenylbutanoate.[29] In contrast, in the case
cleavage of the auxiliary SAMP to liberate the origi- of derivatives 11 and 12 the H-4 proton signal inter-
nal carbonyl function in one reaction. For this pur- fered with that of H-3 and a multiplet was observed.
pose, 2-(methoxymethyl)-N-[(1E)-1-methyl-3-phenyl- Considering the fact that auxiliary (S)-1 resulted in
prop-2-enylidene]pyrrolidin-1-amine (5a) was used the (R)-configuration at C-4, the newly generated ste-
(Scheme 3). Initial attempts to achieve the a-alkyla- reogenic center at C-3 should be (S). The alkylation
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Endersꢂ SAMP-Hydrazone as Traceless Auxiliary in the Asymmetric 1,4-Addition
Prominence diode array detector, ELSD-LT low tempera-
products 11–13 were obtained in high enantioselectiv-
ities of >99%, as determined by HPLC in compari-
son with the corresponding racemic products. In all
cases, only one enantiomer was detected, demonstrat-
ing that the auxiliary seemed to control also the a-al-
kylation despite the solvent change.
ture evaporative light scattering detector, CBM-20 A Promi-
nence communications bus module and CTO-20AC Promi-
nence column oven. Separation of enantiomers: Chiralcel
OJ-H (250ꢄ4.6 mm) (Chiral Technologies Europe). Optical
rotation values [a]2D5 were measured on a Polarimeter 241
(Perkin–Elmer). All reactions were performed in dried
glassware. Cyclohept-2-enone was prepared according to
ref.[31–34] The syntheses of arylidene acetones 3 are described
in the Supporting Information.
Conclusions
In summary, we applied successfully Endersꢂ SAMP-
hydrazone method to the enantioselective conjugate
addition of Gilman cuprates to a,b-unsaturated car-
bonyl compounds. SAMP-hydrazones 4 and 5, which
were accessible by heating cyclic and acyclic enones
with SAMP (S)-1 in benzene, were treated with vari-
General Procedure for the Synthesis of SAMP-
Hydrazones (4, 5)
A solution of enone 2 or 3 (12.2 mmol) and (S)-1 (1.98 g,
15.2 mmol) in benzene (40.0 mL) was heated at reflux for 5–
17 h. The condensate was passed through molecular sieves
ous cuprates and under Cu(II)-mediated hydrolysis 4 ꢅ until TLC indicated complete conversion. The reaction
mixture was cooled to room temperature, filtered and the
filtrate was concentrated. The residue was purified by flash
chromatography on SiO2 and lyophilized under high
vacuum. GC analyses were not possible due to decomposi-
tion on the HP-5 column.
conditions the hydrazone moiety was cleaved to give
the b-alkylated ketones 8 and 9 with an (R)-config-
ured new stereocenter at C-4. Particularly for aryl-
substituted enones high enantioselectivities can be ob-
tained. Recycling of SAMP in 83% yield and >95%
purity was realized. It should be emphasized that the
hydrolytic cleavage does not require strongly oxidiz-
ing conditions such as the recently reported H2O2/
SeO2 procedure by Smith.[30] Furthermore, we devel-
(+)-(2S)-N-[(1E)-Cyclopent-2-en-1-ylidene]-2-(methoxy-
methyl)pyrrolidin-1-amine (4b): Chromatography on SiO2
(EtOAc/MeOH/NEt3 =86:9:5, then MeOH) gave 4b as an
orange oil (E/Z=63:37 by 1H NMR); yield: 1.73 g
(8.91 mmol, 73%); purity: >95% (1H NMR); Rf =0.56;
oped a procedure that combines cuprate addition to 1H NMR (500 MHz, CDCl3): d=1.49–2.10 (3 m, 5H, 4-H, 5-
H, 5’-HA), 2.10–2.59 (3 m, 5H, 2’-H, 3’-HA, 4’-H, 5’-HB),
3.04–3.71 (m, 3H, 3’-HB, CH2OCH3), 3.35* (s, 3H, OCH3),
3.36 (s, 3H, OCH3), 6.28 (dt, J=5.7 Hz, J=2.0 Hz, 1H, 3-
H), 6.54–6.75 (m, 1H, 2-H); 13C NMR (125 MHz, CDCl3):
d=22.5 (C-5), 26.6 (C-4), 28.0 (C-4’), 31.3 (C-3’), 54.0 (C-5’),
59.2 (OCH3), 66.6 (C-2’), 75.7 (CH2OCH3), 133.0 (C-3),
145.8 (C-2), 171.3 (C-1) [* denotes signal of the (Z)-isomer];
acyclic SAMP-hydrazone 5a, a-alkylation of the
formed azaenolate species and traceless cleavage of
the chiral auxiliary in one reaction. Also in this case,
SAMP acts as a traceless auxiliary, which led to prod-
ucts with high enantioselectivities >99%.
˜
FT-IR (ATR): n=2922 (s), 2872 (s), 2825 (s), 1650 (w), 1458
(m), 1353 (w), 1281 (w), 1196 (m), 1097 (s), 969 (m), 914
Experimental Section
(m), 740 (m) cmÀ1
; UV/Vis (acetonitrile): lmax =273.0,
198.0 nm; MS (EI, 70 eV): m/z (%)=194 (10) [M]+, 151
(16), 149 (100) [MÀCH2OCH3]+, 125 (17), 80 (9)
[MÀpyrrolidine]+; HR-MS (ESI): m/z=195.1483, calcd. for
C11H18N2O [M+H]+: 195.1492; anal. calcd. for C11H18N2O
(194.27): C 68.01, H 9.34, N 14.42; found: C 66.60, H 9.56, N
14.45; [a]25: +212.3 (c 1.0, CH2Cl2).
General
Melting points were measured on a Bꢀchi SMP-20 apparatus
and are uncorrected. NMR spectra were recorded on a
Bruker ARX 500 spectrometer with TMS as an internal
standard. FT-IR spectra were recorded on a Vektor 22 spec-
trometer (Bruker) with MKII Golden Gate Single Reflec-
tion Diamant ATR-System. UV/Vis spectra were recorded
on a Lambda 2 spectrometer (Perkin–Elmer) using quartz
glass cuvettes. GC was performed on a Hewlett–Packard
HP 6890 with HP-5 column (30 mꢄ0.32 mm) and on a
Thermo-Finnigan Trace GC Ultra with a Optima-5-MS
column (30 mꢄ0.25 mm). Separation of enantiomers: HR-
GC Mega 2 series, HT system (Fisons Instruments) with H2
(0.4 bar) as carrier gas. Chromatography was performed on
silica gel 60 (grain size 40–63 mm) (Fluka) using columns of
different size. TLC: TLC-plates silica gel 60 F254 (Merck).
Glove box: MB 150-GI (M. Braun) with Ar and N2 as inert
gas. MS/HR-MS were measured on MAT 95, MAT 711 and
micrOTOF Q (Finnigan and Varian) spectrometers. Analyt-
ical HPLC: HPLC apparatus (Shimadzu) with DGU-20 A5
Prominence degasser, LC-20AT Prominence liquid chroma-
tograph, SIL-20 A Prominence auto sampler, SPD-M20 A
(+)-(2SD)-N-[(1E)-Cyclohept-2-en-1-ylidene]-2-(methoxy-
methyl)pyrrolidin-1-amine (4c): Chromatography on SiO2
(EtOAc/NEt3 =95:5, then MeOH) gave 4c as a yellow oil
(E/Z=96:4 by 1H NMR); yield: 2.45 g (11.0 mmol, 90%);
purity: >95% (1H NMR); Rf =0.62; 1H NMR (500 MHz,
CDCl3): d=1.61–2.07 (3 m, 5H, 4-H, 5-H, 5’-HA), 2.16–2.80
(4 m, 5H, 2’-H, 3’-HA, 4’-H, 5’-HB), 3.23–3.50 (m, 7H, 3’-HB,
6-H, CH2OCH3, 7-H), 3.34* (s, 3H, OCH3), 3.35 (s, 3H,
OCH3), 5.90–6.17 (m, 1H, 3-H), 6.40 (d, J=11.5 Hz, 1H, 2-
H); 13C NMR (125 MHz, CDCl3): d=22.7 (C-5), 24.0 (C-4),
26.7 (C-4’), 26.9 (C-3’), 28.9 (C-6), 36.0 (C-7), 55.6 (C-5’),
59.2 (OCH3), 66.8 (C-2’), 75.8 (CH2OCH3), 126.7 (C-3),
136.4 (C-2), 161.1 (C-1) [* denotes signal of the (Z)-isomer];
˜
FT-IR (ATR): n=2921 (s), 2851 (s), 1620 (m), 1455 (s), 1384
(w), 1348 (m), 1279 (w), 1194 (m), 1127 (s), 1098 (s), 1067
(m), 1047 (m), 1010 (w), 969 (m), 916 (m), 855 (m), 721 (w)
cmÀ1
; UV/Vis (acetonitrile): lmax =308.0, 231.0 nm; MS
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(ESI): m/z=223 [M+H]+, 191, 128, 114 [pyrrolidine]+, 108
[MÀpyrrolidine]+, 94; HR-MS (ESI): m/z=223.1801, calcd.
for C13H22N2O [M+H]+: 223.1805; anal. calcd. for
C13H22N2O (222.33): C 70.23, H 9.97, N 12.60; found: C
69.75, H 9.85, N 12.22; [a]2D5: +863.8 (c 1.0, CH2Cl2).
3H, OCH3), 3.37 (s, 3H, OCH3), 6.74 (d, J=16.5 Hz, 1H, 2-
H), 6.87 (d, J=16.4 Hz, 1H, 3-H), 7.29 (d, J=8.6 Hz, 2H,
2’’-H, 6’’-H), 7.38 (d, J=8.4 Hz, 2H, 3’’-H, 5’’-H); 13C NMR
(125 MHz, CDCl3): d=14.9 (C-1’), 23.1 (C-4’), 27.1 (C-3’),
55.5 (C-5’), 59.3 (OCH3), 67.0 (C-2’), 75.7 (CH2OCH3), 128.4
(C-3’’, C-5’’), 128.9 (C-2’’, C-6’’), 131.3 (C-3), 133.5 (C-1’’),
135.3 (C-4’’), 135.4 (C-2), 156.9 (C-1) [* denotes signal of
(+)-(2S)-2-(Methoxymethyl)-N-[(1E,2E)-1-methyl-3-(4-
methoxyphenyl)prop-2-enylidene]pyrrolidin-1-amine
(5c):
˜
the (Z)-isomer]; FT-IR (ATR): n=2963 (m), 2920 (s), 2872
Chromatography on SiO2 (CHCl3/EtOAc/NEt3 =79:16:5,
then MeOH) gave 5c as an orange oil (E/Z=62:38 by
1H NMR); yield: 3.52 g (12.2 mmol, quant.); purity: >95%
(s), 2827 (m), 1715 (m), 1667 (w), 1490 (s), 1446 (m), 1088
(s), 965 (s), 810 (s) cmÀ1; UV/Vis (acetonitrile): lmax =346.0,
276.0, 192.0 nm; MS (EI, 70 eV): m/z (%)=292 (20) [M]+,
249 (32), 247 (100) [MÀCH2OCH3]+, 178 (24)
[MÀpyrrolidine]+, 137 (28); HR-MS (ESI): m/z=293.1408,
calcd. for C16H21ClN2O [M+H]+: 293.1415; anal. calcd. for
C16H21ClN2O (292.80): C 65.63, H 7.23, N 9.57, Cl 12.11;
found: C 65.68, H 7.11, N 8.76, Cl 12.03; [a]2D0: +1094.6 (c
1.0, CH2Cl2).
1
(1H NMR); Rf =0.56; H NMR (500 MHz, CDCl3): d=1.62–
2.70 (5 m, 6H, 3’-H, 4’-H, 5’-H), 2.11 (s, 3H, 1’-H), 2.17* (s,
3H, 1’-H), 3.05–3.86 (3 m, 3H, 2’-H, CH2OCH3), 3.35* (s,
3H, CH2OCH3), 3.36 (s, 3H, CH2OCH3), 3.81 (s, 3H,
OCH3), 3.82* (s, 3H, OCH3), 6.81–6.95 (m, 3H, 2-H, 3’’-H,
5’’-H), 7.21–7.51 (m, 3H, 3-H, 2’’-H, 6’’-H); 13C NMR
(125 MHz, CDCl3): d=14.7 (C-1’), 22.9 (C-4’), 27.0 (C-3’),
55.3 (OCH3), 55.4 (C-5’), 59.2 (CH2OCH3), 66.8 (C-2’), 75.5
(CH2OCH3), 114.2 (C-3’’, C-5’’), 127.1 (C-2’’, C-6’’), 130.0
(C-1’’), 131.7 (C-3), 134.2 (C-2), 158.8 (C-1), 160.2 (C-4’’) [*
(+)-(2S)-N-[(1E,2E)-3-(2-Furyl)-1-methylprop-2-enyli-
dene]-2-(methoxymethyl)pyrrolidin-1-amine (5f): Chroma-
tography on SiO2 (EtOAc/MeOH/NEt3 =86:9:5, then
MeOH) afforded 5f as a red-brown oil (E/Z=71:29 by
1H NMR); yield: 3.03 g (12.2 mmol, quant.); purity: >95%
˜
denotes signal of the (Z)-isomer]; FT-IR (ATR): n=2923
(s), 2873 (s), 2834 (m), 1736 (w), 1666 (w), 1459 (m), 1108
(s), 965 (s) cmÀ1; UV/Vis (acetonitrile): lmax =292.0, 223.0,
192.0 nm; MS (EI, 70 eV): m/z (%)=288 (30) [M]+, 243
(100) [MÀCH2OCH3]+, 174 (36) [MÀpyrrolidine]+, 133 (42);
HR-MS (ESI): m/z=289.1913, calcd. for C17H24N2O2 [M+
H]+: 289.1911; anal. calcd. for C17H24N2O2 (288.38): C 70.80,
H 8.39, N 9.71; found: C 70.81, H 8.21, N 9.18; [a]2D5: +772.7
(c 1.0, CH2Cl2).
(+)-(2S)-2-(Methoxymethyl)-N-[(1E,2E)-1-methyl-3-(4-ni-
trophenyl)prop-2-enylidene]pyrrolidin-1-amine (5d): Chro-
matography on SiO2 (CHCl3/EtOAc/NEt3 =79:16:5, then
MeOH) gave 5d as a red oil (E/Z=85:15 by 1H NMR);
yield: 2.88 g (9.49 mmol, 85%); purity: >95% (1H NMR);
Rf =0.64; 1H NMR (500 MHz, CDCl3): d=1.57–2.70 (5 m,
6H, 3ꢂ-H, 4ꢂ-H, 5ꢂ-H), 2.12 (s, 3H, 1’-H), 2.20* (s, 3H, 1’-H),
2.90–3.62 (3 m, 3H, 2’-H, CH2OCH3), 3.33* (s, 3H, OCH3),
3.38 (s, 3H, OCH3), 6.79 (d, J=16.4 Hz, 1H, 2-H), 7.04 (d,
J=16.4 Hz, 1H, 3-H), 7.57 (d, J=8.7 Hz, 2H, 2’’-H, 6’’-H),
8.18 (d, J=8.8 Hz, 2H, 3’’-H, 5’’-H); 13C NMR (125 MHz,
CDCl3): d=14.8 (C-1’), 23.2 (C-4’), 27.1 (C-3’), 55.9 (C-5’),
59.3 (OCH3), 66.7 (C-2’), 75.6 (CH2OCH3), 124.1 (C-3’’, C-
5’’), 129.4 (C-2’’, C-6’), 131.1 (C-3), 135.5 (C-2), 143.4 (C-1’’),
147.4 (C-4’’), 155.1 (C-1) [* denotes signal of the (Z)-
1
(1H NMR); Rf =0.72; H NMR (500 MHz, CDCl3): d=1.62–
2.70 (5 m, 6H, 3’-H, 4’-H, 5’-H), 2.06 (s, 3H, 1’-H), 2.13* (s,
3H, 1’-H), 3.24–3.53 (2 m, 3H, 2’-H, CH2OCH3), 3.35* (s,
3H, OCH3), 3.36 (s, 3H, OCH3), 6.34–7.43 (m, 3H, 3’’-H,
4’’-H, 5’’-H), 6.62 (d, J=16.4 Hz, 1H, 3-H), 6.82 (d, J=
16.4 Hz, 1H, 2-H); 13C NMR (125 MHz, CDCl3): d=14.7
(C-1’), 23.1 (C-4’), 27.0 (C-3’), 55.4 (C-5’), 59.3 (OCH3), 66.8
(C-2’), 75.6 (CH2OCH3), 109.0 (C-3’’), 111.7 (C-4’’), 119.4
(C-3), 129.1 (C-2), 142.6 (C-5’’), 156.9 (C-1), 157.0 (C-2’’) [*
˜
denotes signal of the (Z)-isomer]; FT-IR (ATR): n=2967
(m), 2921 (s), 2872 (s), 2827 (m), 1716 (w), 1624 (w), 1447
(m), 1261 (m), 1198 (m), 1095 (s), 1013 (s), 960 (s) cmÀ1
;
UV/Vis (acetonitrile): lmax =343.0, 299.0, 196.0 nm; MS (EI,
70 eV):
m/z
(%)=248
(34)
[M]+,
203
(100)
[MÀCH2OCH3]+, 134 (49) [MÀpyrrolidine]+, 93 (17), 65
(14); anal. calcd. for C14H20N2O2 (248.32): C 67.71, H 8.12, N
11.28; found: C 67.72, H 8.13, N 11.40; [a]2D5: +1339.0 (c 1.0,
CH2Cl2).
General Procedure for the Asymmetric 1,4-Addition
of Cuprates to SAMP-Hydrazones with Cleavage of
the Auxiliary
˜
isomer]; FT-IR (ATR): n=2968 (s), 2922 (s), 2874 (s), 2828
(m), 1716 (w), 1643 (w), 1593 (s), 1516 (s), 1447 (m), 1340
(s), 1107 (s), 1094 (s), 966 (m) cmÀ1; UV/Vis (acetonitrile):
lmax =399.0, 285.0, 196.0 nm; MS (EI, 70 eV): m/z (%)=303
(13) [M]+, 260 (40), 258 (100) [MÀCH2OCH3]+, 189 (14)
[MÀpyrrolidine]+, 183 (24), 125 (18); HR-MS (ESI): m/z=
304.1659, calcd. for C16H21N3O3 [M+H]+ 304.1656; anal.
calcd. for C16H21N3O3 (303.36): C 63.35, H 6.98, N 13.85;
found: C 62.71, H 6.79, N 13.88; [a]2D5: +1184.9 (c 1.0,
CH2Cl2).
Method for hydrazones (4): A solution of the organolithium
compound (3.09 mmol) was slowly added dropwise to a sus-
pension of CuCN (138 mg, 1.54 mmol) and LiBr (1.07 g,
12.3 mmol) in Et2O (16.0 mL) at À788C. [In the case of
methyllithium, TMSCl (3.09 mmol) was slowly added after
30 min and the reaction mixture stirred further for 40 min].
After stirring for 70 min,
a solution of hydrazone 4
(1.03 mmol) in Et2O (16.0 mL) was added dropwise at
À788C. Then the reaction mixture was allowed to warm to
10–158C overnight. The reaction was quenched with a satu-
rated solution of NH4Cl (20 mL) and stirred for a further
1 h at room temperature prior to addition of CH2Cl2
(15 mL). The reaction mixture was hydrolyzed with H2O
(20 mL), MeOH (20 mL) and CuSO4·5H2O (4.00 g,
16.0 mmol). After vigorous stirring for 1 h, the mixture was
extracted with CH2Cl2 (2ꢄ100 mL). The combined organic
layers were dried (MgSO4), concentrated (408C/>80 mbar)
(+)-(2S)-2-(Methoxymethyl)-N-[(1E,2E)-1-methyl-3-(4-
chlorophenyl)prop-2-enylidene]pyrrolidin-1-amine
(5e):
Chromatography on SiO2 (CHCl3/EtOAc/NEt3 =79:16:5,
then MeOH) gave 5e as an orange oil (E/Z=79:21 by
1H NMR); yield: 2.63 g (8.98 mmol, 83%); purity: >95%
1
(1H NMR); Rf =0.52; H NMR (500 MHz, CDCl3): d=1.62–
2.73 (5 m, 6H, 3’-H, 4’-H, 5’-H), 2.10 (s, 3H, 1’-H), 2.17* (s,
3H, 1’-H), 3.16–3.53 (3 m, 3H, 2’-H, CH2OCH3), 3.36* (s,
2286
asc.wiley-vch.de
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 2281 – 2290

Endersꢂ SAMP-Hydrazone as Traceless Auxiliary in the Asymmetric 1,4-Addition
and the crude products were purified by flash chromatogra-
phy on SiO2. Traces of SiO2 were removed by filtration
through Celite.
Method for hydrazones (5): A solution of the organolithi-
um compound (2.32 mmol) was slowly added dropwise to a
suspension of CuCN (104 mg, 1.16 mmol) and LiBr (807 mg,
9.29 mmol) in Et2O (16.0 mL) at À788C. (In the case of
methyllithium, TMSCl (2.32 mmol) was slowly added after
30 min and the reaction mixture stirred further for 40 min).
Recycling of the Auxiliary SAMP (S)-1
The Cu(II)-SAMP-complex 10 [from the addition of n-
Bu2CuLi · LiCN to 4c (1.35 mmol); UV/Vis (DMSO): lmax
260.0, 227.0 nm], which remained on the silica gel, was
transferred from the column into a flask, dissolved in
DMSO (50 mL) and filtered. With stirring a solution of diso-
dium EDTA dihydrate (3.00 g, 8.06 mmol) in H2O (150 mL)
=
was added to the filtrate [UV/Vis (DMSO/H2O 1:2): lmax
=
243.0 nm] and the reaction mixture was extracted with Et2O
(2ꢄ300 mL). The combined organic layers were washed
with H2O (2ꢄ1.0 L) and dried (MgSO4). After removal of
the solvent under vacuum (408C/>100 mbar), SAMP (S)-1
was isolated as a colorless oil; yield: 146 mg (1.12 mmol,
83%); purity: >95% (1H NMR); 1H NMR (500 MHz,
CDCl3): d=1.50–1.99 (3 m, 4H, 3-H, 4-H), 2.11–2.47 (2 m,
2H, 5-H), 3.00–3.60 (ABX system, 3H, CH2OCH3, 2-H),
3.11 (s, 2H, NH2), 3.38 (s, 3H, OCH3); 13C NMR (125 MHz,
CDCl3): d=21.0 (C-3), 26.3 (C-4), 59.2 (OCH3), 60.2 (C-5),
68.4 (C-2), 75.8 (CH2OCH3); MS (ESI) for [(SAMP)2Cu]2+:
After stirring for 70 min,
a solution of hydrazone 5
(0.774 mmol) in Et2O (16.0 mL) was added dropwise at
À788C. The stirred reaction mixture was allowed to warm
to 10–158C overnight prior to addition of CH2Cl2 (15 mL)
and Et2O (30 mL). The reaction mixture was concentrated
and
a half-saturated NH4Cl solution (40 mL), MeOH
(40 mL) and CuSO4·5H2O (4.00 g, 16.0 mmol) were succes-
sively added. After vigorous stirring for 2 h, the reaction
mixture was concentrated to the half volume and extracted
with CH2Cl2 (2ꢄ100 mL). The combined organic layers
were dried (MgSO4), concentrated (408C/>80 mbar) and
the crude products were purified by flash chromatography
on SiO2. Traces of SiO2 were removed by filtration through
Celite.
m/z=323
[M]2+,
297
[(MÀ2CH2)+2H]2+,
279
[(MÀCH2OCH3)+H]2+, 154, 114. The spectroscopic data
are in accordance with those in the literature.[1c]
(+)-(3R)-Butylcyclohexanone [(R)-8a]:[35] Chromatogra-
phy on SiO2 (pentane/Et2O=1:1) gave 8a as a pale yellow
oil; yield: 48 mg (0.311 mmol, 65%); purity: 91% (GC);
Rf =0.57; 1H NMR (500 MHz, CDCl3): d=0.89 (t, J=
6.8 Hz, 3H, 4’-H), 1.23–1.38 (m, 7H, aliphatic), 1.60–1.70
(m, 1H, aliphatic), 1.71–1.81 (m, 1H, aliphatic), 1.90 (dddd,
J=1.1 Hz, J=1.1 Hz, J=4.6 Hz, J=13.8 Hz, 1H, 2-HA),
1.96–2.07 (m, 2H, 5-H), 2.25 (dddd, J=1.1 Hz, J=6.4 Hz,
J=12.2 Hz, J=20.1 Hz, 1H, 6-HA), 2.31–2.38 (m, 1H, 6-HB),
2.39–2.45 (m, 1H, 2-HB); 13C NMR (125 MHz, CDCl3): d=
14.1 (C-4’), 22.8 (C-2’), 25.4 (C-3ꢂ), 28.9 (C-5), 31.4 (C-1’),
36.4 (C-4), 39.1 (C-3), 41.6 (C-6), 48.3 (C-2), 212.3 (C-1);
GC (column HP-5, 168CminÀ1 gradient from 80–3008C):
tR =4.51 min; [a]D25: +40.3 (c 0.50, CHCl3) ([a]2D5: À74.8 [c
1.3, CHCl3) (S)-enantiomer[36]]; separation of enantiomers
by GC [column Bondex un a (20 mꢄ0.25 mm), 0.4 bar H2;
temperature program: 408C, 5 min isothermal, 0.58C minÀ1
gradient to 878C, then isothermal]: tR1 =89.54 min (major
enantiomer), tR2 =90.83 min (minor enantiomer), 54%ee.
(À)-(4R)-4-Phenyloctan-2-one [(R)-9a]:[37,38] Chromatog-
raphy on SiO2 (pentane/Et2O=2:1) gave 9a as a pale yellow
oil; yield: 85 mg (0.416 mmol, 56%); purity: 97% (GC);
Rf =0.44; 1H NMR (500 MHz, CDCl3): d=0.82 (t, J=
7.1 Hz, 3H, 8-H), 1.02–1.32 (m, 4H, 6-H, 7-H), 1.50–1.66
(m, 2H, 5-H), 2.01 (s, 3H, 1-H), 2.71 (dd, J=7.4 Hz, J=
16.2 Hz, 2H, 3-H), 3.06–3.12 (m, 1H, 4-H), 7.13–7.21 (m,
3H, 2ꢂ-H, 4’-H, 6’-H), 7.24–7.31 (m, 2H, 3’-H, 5’-H);
13C NMR (125 MHz, CDCl3): d=14.0 (C-8), 22.6 (C-7), 29.6
(C-6), 30.7 (C-1), 36.2 (C-5), 41.3 (C-4), 51.0 (C-3), 126.3 (C-
4’), 127.5 (C-2’, C-6’), 128.5 (C-3’, C-5’), 144.6 (C-1ꢂ), 208.1
(C-2); GC (column HP-5, 168CminÀ1 gradient from 80–
3008C): tR =6.37 min; [a]2D5: À6.9 (c 0.50, CH2Cl2); separa-
tion of enantiomers by HPLC (column Chiralcel OJ-H, flow
0.2 mLminÀ1, hexane/2-propanol 98.5:1.5, l=220 nm UV):
General Procedure for the Tandem 1,4-Addition/
Methylation Reaction
Method for hydrazone 5a: A 1.6M solution (1.45 mL) of n-
BuLi (2.32 mmol) in n-hexane was slowly added dropwise to
a suspension of CuCN (104 mg, 1.16 mmol) and LiBr
(807 mg, 9.29 mmol) in Et2O (16.0 mL) in a dried Schlenk
flask at À788C. After stirring for 70 min, a solution of hy-
drazone 5a (200 mg, 0.774 mmol) in Et2O (16.0 mL) was
added dropwise and the reaction mixture was stirred for a
further 45 min, whereby the temperature should not exceed
À788C. The supernatant solution was placed in a separate
Schlenk flask and the solvent was removed in a stream of ni-
trogen at À58C. The residue was dissolved in THF
(10.0 mL) and
a solution of MeI (0.097 mL, 220 mg,
1.55 mmol) in HMPA (1.5 mL) was added dropwise. After
stirring for 1 h at À58C, MeOH (0.5 mL) was added. The re-
action mixture was then stirred for 22 h at À58C and 19 h at
room temperature prior to addition of CH2Cl2 (15 mL) and
Et2O (30 mL). After concentration (408C/>80 mbar), a
half-saturated NH4Cl solution (40 mL), MeOH (40 mL) and
CuSO4·5H2O (4.00 g, 16.0 mmol) were added. After vigo-
rous stirring for 2 h at room temperature, the reaction mix-
ture was concentrated to the half volume and extracted with
CH2Cl2 (2ꢄ100 mL). The combined organic layers were
dried (MgSO4) and concentrated (408C/300 mbar). The resi-
due was dissolved in Et2O (50 mL), washed with H2O
(250 mL) and a 2% solution of Na2S2O3 (100 mL). It was
dried (MgSO4), concentrated and purified by flash chroma-
tography on SiO2. Products (3S,4R)-11, (4S,5R)-12 and -13
were isolated in 81% yield in a ratio of 11:12:13=46:27:27.
(+)-(3S,4R)-3-Methyl-4-phenyloctan-2-one [(3S,4R)-11]:
Chromatography (pentane/Et2O=5:1) gave a colorless oil;
yield: 63 mg (0.288 mmol, 37%); purity: >95% (1H NMR);
Rf =0.36; 1H NMR (500 MHz, CDCl3): d=0.77 (t, J=
7.5 Hz, 3H, 8-H), 0.80 (d, J=6.3 Hz, 3H, CH3), 0.87–1.09
(m, 2H, 6-H), 1.10–1.29 (m, 2H, 7-H), 1.46–1.59 (m, 2H, 5-
H), 2.19 (s, 3H, 1-H), 2.68–2.80 (m, 2H, 3-H, 4-H), 7.09–
7.15 (m, 2H, 2’-H, 6’-H), 7.18–7.24 (m, 1H, 4’-H), 7.27–7.32
t
R1 =38.37 min (minor enantiomer), tR2 =40.42 min (major
enantiomer), 98% ee, being with utmost probability the (R)-
enantiomer [comparison with (R)-9c]; [a]2D6: À29.9 (c 2.0,
CHCl3)[39]).
Adv. Synth. Catal. 2010, 352, 2281 – 2290
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2287

Karsten Sammet et al.
FULL PAPERS
(m, 2H, 3’-H, 5’-H); 13C NMR (125 MHz, CDCl3): d=13.9 References
(C-8), 15.8 (CH3), 22.5 (C-7), 29.2 (C-1), 29.7 (C-6), 34.4 (C-
5), 48.6 (C-3), 53.4 (C-4), 126.4 (C-4’), 128.3 (C-2’, C-6’),
128.4 (C-3’, C-5’), 142.5 (C-1’), 213.2 (C-2); [a]2D5: +20.3 (c
0.30, CH2Cl2); separation of enantiomers by HPLC [column
Chiralcel OJ-H, flow 0.1 mLminÀ1, hexane/2-propanol 98:2,
l=214 nm (UV), no minor enantiomer]: tR =65.73 min,
>99% ee. For a complete characterization see rac-11 (Sup-
porting Information).
[1] a) D. Enders, H. Eichenauer, Angew. Chem. 1976, 88,
579–581; Angew. Chem. Int. Ed. Engl. 1976, 15, 549–
551; b) D. Enders, H. Eichenauer, Tetrahedron Lett.
1977, 191–194; c) D. Enders, H. Eichenauer, Chem.
Ber. 1979, 112, 2933–2960.
[2] Reviews: a) R. Brehme, D. Enders, R. Fernandez, J. M.
Lassaletta, Eur. J. Org. Chem. 2007, 5629–5660; b) D.
Enders, W. Bettray, in: Asymmetric Synthesis – The Es-
sentials, (Eds.: M. Christmann, S. Brꢁse), Wiley-VCH,
Weinheim, 2007, pp 23–28; c) D. Enders, W. Bettray,
in: Asymmetric Synthesis with Chemical and Biological
Methods, (Eds.: D. Enders, K.-E. Jaeger), Wiley-VCH,
Weinheim, 2007, pp 38–75; d) D. Enders, M. Boudou,
J. Gries, in: New Methods for the Asymmetric Synthesis
of Nitrogen Heterocycles, (Eds.: J. L. Vicario, D. Badia,
L. Carillo), Research Signpost, Trivandrum, India,
2005, pp 1–31; e) M. M. Alam, Synlett 2003, 1755–
1756; f) A. Job, C. F. Janeck, W. Bettray, R. Peters, D.
Enders, Tetrahedron 2002, 58, 2253–2329; g) D. Enders,
C. Thiebes, Pure Appl. Chem. 2001, 73, 573–578; h) D.
Enders, J. Adam, D. Klein, T. Otten, Synlett 2000,
1371–1384; i) D. Enders, M. Bolkenius, J. Vꢆzquez, J.-
M. Lassaletta, R. Fernꢆndez, J. Prakt. Chem. 1998, 340,
281–285; j) D. Enders, B. Bockstiegel, W. Gatzweiler,
U. Jegelka, B. Duecker, L. Wortmann, Chimica Oggi
1997, 15, 20–22; k) D. Enders, W. Bettray, J. Schankat,
J. Wiedemann, in Enantioselective Synthesis of b-
Amino Acids, (Ed.: E. Juaristi), Wiley-VCH, New
York, 1997, pp 187–210; l) D. Enders, W. Bettray, Pure
Appl. Chem. 1996, 68, 569–580; m) D. Enders, Acros
Organics Acta 1995, 1, 37–38.
(+)-(4S,5R)-4-Methyl-5-phenylnonan-3-one [(4S,5R)-12]:
Chromatography (pentane/Et2O=5:1) gave a colorless oil;
yield: 39 mg (0.169 mmol, 22%); purity: >95% (1H NMR);
Rf =0.56; 1H NMR (500 MHz, CDCl3): d=0.76 (t, J=
7.5 Hz, 3H, 9-H), 0.78 (d, J=6.4 Hz, 3H, CH3), 0.91–1.06
(m, 2H, 7-H), 1.09 (t, J=7.6 Hz, 3H, 1-H), 1.11–1.28 (m,
2H, 8-H), 1.41–1.55 (m, 2H, 6-H), 2.38–2.60 (m, 2H, 2-H),
2.71–2.82 (m, 2H, 4-H, 5-H), 7.09–7.15 (m, 2H, 2ꢂ-H, 6’-H),
7.15–7.25 (m, 1H, 4’-H), 7.25–7.32 (m, 2H, 3’-H, 5’-H);
13C NMR (125 MHz, CDCl3): d=7.7 (C-1), 13.9 (C-9), 16.2
(CH3), 22.5 (C-8), 29.8 (C-7), 34.4 (C-6), 35.9 (C-2), 48.7 (C-
4), 52.3 (C-5), 126.3 (C-4’), 128.3 (C-2ꢂ, C-6’), 128.4 (C-3’, C-
5’), 142.8 (C-1’), 215.7 (C-3) ppm; [a]2D5: +45.1 (c 0.30,
CH2Cl2); separation of enantiomers by HPLC [column Chir-
alcel OJ-H, flow 0.1 mLminÀ1, hexane/2-propanol 98:2, l=
214 nm (UV), no minor enantiomer]: tR =62.92 min,>
99%ee. For a complete characterization see rac-12 (Support-
ing Information).
(+)-(4S,5R)-2,4-Dimethyl-5-phenylnonan-3-one [(4S,5R)-
13]: Chromatography (pentane/Et2O=5:1) afforded a color-
less oil; yield: 42 mg (0.170 mmol, 22%); purity: >95%
1
(1H NMR); Rf =0.65; H NMR (500 MHz, CDCl3): d=0.75
(t, J=7.3 Hz, 3H, 9-H), 0.76 (d, J=6.4 Hz, 3H, 4-CH3),
0.97–1.06 (m, 2H, 7-H), 1.12 (d, J=3.2 Hz, 3H, 1-H), 1.14
(d, J=3.1 Hz, 3H, 2-CH3), 1.16–1.29 (m, 2H, 8-H), 1.40–
1.53 (m, 2H, 6-H), 2.67–2.82 (m, 2H, 2-H, 4-H), 2.90 (dq,
J=10.1 Hz, J=6.9 Hz, 1H, 5-H), 7.09–7.16 (m, 2H, 2’-H, 6’-
H), 7.18–7.24 (m, 1H, 4’-H), 7.27–7.33 (m, 2H, 3’-H, 5’-H);
13C NMR (125 MHz, CDCl3): d=13.9 (C-9), 16.8 (4-CH3),
18.1 (C-1), 18.2 (2-CH3), 22.5 (C-8), 29.8 (C-7), 34.5 (C-6),
41.2 (C-2), 48.7 (C-4), 50.7 (C-5), 126.3 (C-4’), 128.3 (C-2’,
C-6’), 128.4 (C-3’, C-5’), 143.1 (C-1’), 218.7 (C-3); [a]2D5:
+75.9 (c 0.30, CH2Cl2); separation of enantiomers by HPLC
[column Chiralcel OJ-H, flow 0.1 mLminÀ1, hexane/2-propa-
nol 98:2, l=214 nm (UV), no minor enantiomer]: tR =
49.36 min, >99%ee. For a complete characterization see
rac-13 (Supporting Information).
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Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft, the Ministerium fꢀr Wissenschaft, Forschung und
Kunst des Landes Baden-Wꢀrttemberg (Landesgraduierten
fellowship for C. G.), and the Fonds der Chemischen Indus-
trie. We would like to thank Catrin Hermann for preliminary
experiments.
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