Asymmetric synthesis and structural assignment of (-)-α-conhydrine

Article abstract of DOI:10.1016/S0957-4166(02)00066-6

The first asymmetric synthesis of the conium alkaloid (-)-α-conhydrine is reported. Starting from a protected glycol aldehyde hydrazone as chiral precusor, a short route based on our α-alkylation/1,2-addition methodology has been developed. After cleavage of the auxiliary and simultaneous deprotection, the concluding ring closure is accomplished under reductive amination conditions. The title compound is obtained in moderate overall yield and in excellent diastereo- and enantiomeric excess (d.e., e.e. >96%). Single-crystal X-ray crystallography as well as ¹H NMR NOE experiments confirm the expected relative and absolute (2R,7S)-configuration of the product.

Full text of DOI:10.1016/S0957-4166(02)00066-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 285–291
Asymmetric synthesis and structural assignment of
(−)-a-conhydrine
Dieter Enders,* Bert Nolte, Gerhard Raabe and Jan Runsink
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule, Professor-Pirlet Straße 1,
52074 Aachen, Germany
Received 5 February 2002; accepted 8 February 2002
Abstract—The first asymmetric synthesis of the conium alkaloid (−)-a-conhydrine is reported. Starting from a protected glycol
aldehyde hydrazone as chiral precusor, a short route based on our a-alkylation/1,2-addition methodology has been developed.
After cleavage of the auxiliary and simultaneous deprotection, the concluding ring closure is accomplished under reductive
amination conditions. The title compound is obtained in moderate overall yield and in excellent diastereo- and enantiomeric excess
1
(d.e., e.e. >96%). Single-crystal X-ray crystallography as well as H NMR NOE experiments confirm the expected relative and
absolute (2R,7S)-configuration of the product. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
novsky and Mulley.3 Fodor et al. optimized the
procedure by performing the required resolution in a
previous step of the synthesis.4 The stereoselective syn-
thesis of the unnatural (+)-b-conhydrine 2 was achieved
by Husson’s amino nitrile methodology,5 followed in
recent years by a number of other auxiliary-supported
syntheses6 or ex chiral pool approaches, which were
also adapted for its (−)-enantiomer, ent-2.7 However,
much less attention has been given to the enantioselec-
tive synthesis of (−)-a-conhydrine ent-1.
Since the isolation of the naturally occuring (+)-a-con-
hydrine 1 from seeds and leaves of the poisonous plant
Conium maculatum L.1 in 1856 and the elucidation of
its structure in 1933,2 many synthetic studies towards
this hydroxylated piperidine alkaloid and its
diastereomers 2 and ent-2 have been carried out (Fig.
1).
One of the first successful attempts towards the synthe-
sis of (+)-a-conhydrine 1 was carried out by Mali-
2. Results and discussion
HN
HN
R
S
Herein, we wish to report on the first asymmetric
synthesis of (−)-a-conhydrine ent-1 employing our
SAMP/RAMP hydrazone methodology in key steps.8,9
H3C
H3C
S
R
OH
OH
(+)-α-conhydrine 1
(−)-α-conhydrine (ent)-1
2.1. Asymmetric synthesis of (−)-a-conhydrine, ent-1
HN
HN
S
R
Retrosynthetic analysis of the piperidine core unit fur-
nishes an open chain amino aldehyde precursor 3,
which can be employed in a reductive amination-
induced ring closure (Scheme 1). The disubstituted 1,2-
amino alcohol subunit can be obtained by
diastereoselective nucleophilic 1,2-addition of a g-
metallated acetal-protected butanal 4 to the a-substi-
tuted glycol aldehyde SAMP hydrazone 5.10 The use of
this class of hydrazones as versatile chiral synthons for
the synthesis of miscellaneous substituted 1,2-amino
H3C
H3C
R
S
OH
OH
(+)-β-conhydrine 2
(−)-β-conhydrine (ent)-2
Figure 1. (+)-a-Conhydrine 1 and its stereoisomers.
* Corresponding
author.
Tel.:
+49(0241)8094676;
+49(241)8092127; e-mail: enders@rwth-aachen.de
fax:
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00066-6

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D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 285–291
cially available (Z)-butenediol, which is first protected
O
before ozonolytic cleavage to the aldehyde and con-
cluding condensation with the SAMP hydrazine to
13.11c
HN
O
NH2
H3C
H3C
OH
PGO
ent-1
3
As depicted in Scheme 3, treatment of hydrazone 13
with LDA at low temperature gave the intermediate
lithium azaenolate, which was trapped at the same
temperature with ethyl iodide to form the a-substituted
species 14 in moderate yield and good diastereomeric
excess. After isolation by flash column chromatography
the product was employed in the highly diastereoselec-
tive 1,2-addition to the carbonꢀnitrogen double bond11
(d.e. >96%). Due to its light- and air-sensitivity the
hydrazine 15 had to be isolated immediately by flash
chromatography and could thus be obtained in high
yield. Because of the incomplete asymmetric induction
in the alkylation leading to 14 a minor diastereomer
was expected, but NMR spectroscopic investigations
showed no significant signals. We assume that the
undesired isomer was separated during the purification
procedure. Removal of the remaining part of the auxil-
iary was facilitated by a reductive nitrogenꢀnitrogen
bond cleavage with BH3THF complex in refluxing
THF.15 After completion the reaction mixture was
treated with hydrochloric acid to destroy the excess
borane. In addition, complete deprotection of the inter-
mediate amine took place. Besides the acid-catalyzed
silyl ether cleavage, acetal hydrolysis occurred and the
resulting amino aldehyde underwent spontaneous
cyclization to the corresponding imine. The solvents
were evaporated and the remaining residue was dis-
solved in EtOH without further purification. Finally,
NaBH4 reduction completed the reductive amination to
(−)-a-conhydrine (ent-1) in moderate yield over three
steps; an overall yield of 21% starting from glycol
aldehyde hydrazone 13 was achieved with both
diastereomeric and enantiomeric excess greater than
N
H
O
N
OCH3
O
H3C
+
M
PGO
5
4
N
N
OCH3
H3C
X
+
H
PGO
6
7
Scheme 1. Retrosynthetic analysis of (−)-a-conhydrine ent-1.
alcohol units has already been reported by our group.11
Introduction of the short alkyl chain can be achieved
by a-alkylation with 6 of a protected glycol aldehyde
SAMP hydrazone 7 which already has the two het-
eroatoms of the target molecule installed in the
skeleton.
The required acetal-containing organolithium reagent
12 was prepared by halogen–metal exchange reaction
from the corresponding iodoacetal 11, following the
procedure of Negishi and Bailey12 (Scheme 2).
In turn, iodoacetal 11 is easily available from 4-bromo-
butyric acid ester 8 by DIBAL-H reduction to the
aldehyde 9 followed by acetalization to 10.13 The subse-
quent Finkelstein reaction in THF with lithium iodide
led to the desired iodide 11.14
1
96%, as determined by H and 13C NMR.
The enantiopure TBS-protected glycol aldehyde SAMP
hydrazone 13 is readily available in high yield by a
three-step sequence in a multigram scale from commer-
HN
N
N
OCH3
H3C
21%
OH
H
DIBAL-H, Et2O,
−78°C
O
O
TBSO
d.e.,e.e. >96%
ent-1
13
Br
Br
OEt
H
99%
8
9
iii, iv
55%
43%
i
− H2O
HO
OH,
OCH3
Toluen, p-TSA, ∆
90%
N
H
N
O
O
N
O
ii
LiI, THF, ∆
HN
OCH3
O
Br
I
O
H3C
TBSO
14 d.e. 89%
88%
68%
H3C
O
11
10
TBSO
15
d.e. >96%
t-BuLi, Et2O,
−78°C→0°C
O
Li
Scheme 3. Asymmetric synthesis of (−)-a-conhydrine (ent-1).
Reagents and conditions: (i) LDA, THF, −78°C, then EtI,
−78°C; (ii) 12, THF, −78°C, then NaHCO3 (aq.); (iii)
BH3·THF, THF, D, then 3 M HCl (aq.), CH2Cl2, rt; (iv)
NaBH4, EtOH, rt.
O
12
Scheme 2. Synthesis of nucleophile 12.

D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 285–291
287
Either the 1,2-addition of the oxo-functionalized nucleo-
phile 12 established an unexpected (2S)-configuration
or during the reaction sequence starting from (S,R)-
hydrazine 15 to the title compound an undesired epimer-
ization to the (2S,7S)-configured product occurs. Both
explanations are quite unsatisfying, because numerous
examples proved the proposed mechanism for the 1,2-
addition supported by the SAMP auxiliary11,16 and the
improbable complete epimerization of one of the stereo-
genic centers. Moreover, a comparison of the reported
melting points and optical rotations values gave a
striking indication for the existence of the proposed
product ent-1 (Table 2). The ease of a clear distinction
between the higher melting a-isomer and the lower
melting b-isomer is evident. In fact, the similar optical
rotation values prevent an exact assigment of the respec-
tive enantiomers. A few groups reported IR spectro-
scopic data of conhydrine species,17 but a striking
similarity was only shown again by those of (+)-a-conhy-
drine 1 described by Fodor.4
2.2. Structural assignment
Unfortunately, the spectroscopic data obtained from
ent-1 were not in accord with those published in the
literature for the enantiomer 1. Especially most of the
1
described H and 13C NMR data did not show enough
1
similarity. Only two H NMR data sets of (+)-a-conhy-
drine 1 has been reported.4,6 But, only Fodor described
similar chemical shifts.
As shown in Table 1, a comparison of the reported 13C
chemical shifts gave a significant matching with data of
the b-isomers (Table 1). Therefore, in combination with
a negative optical rotation value of ent-1 the formation
of the (2S,7S)-configured (−)-b-conhydrine ent-2 was
assumed (see Fig. 1, Table 2).
However, the proposed configuration generated by the
SAMP auxiliary according to the mechanism is (2R,7S).
Table 1. Reported 13C NMR data of (+)-a-conhydrine 1,
(+)-b-conhydrine 2 and (−)-b-conhydrine ent-2 in com-
parison to ent-1
Thereupon we started further investigations to confirm
the expected configuration of ent-1. At first, we focused
our efforts on the determination of the relative configu-
ration of the key intermediate, hydrazine 15. Applying
our methodology for the synthesis of disubstituted oxa-
zolidin-2-ones, we trapped the resulting lithium hydra-
zide of the 1,2-addition of nucleophile 12 to hydrazone
14 with methyl chloroformate (MocCl) (Scheme 4).11c
The resulting methyl carbamate 16 was transformed to
the desired 4,5-disubstituted oxazolidin-2-one 18 by
fluoride-induced cyclization and reductive nitrogenꢀ
nitrogen single bond cleavage effected by reaction with
lithium in liquid ammonia. Our goal was to provide a
more rigid system which would allow NOE experiments
for structural determination of the 1,2-amino alcohol
subunit. As is summarized in Scheme 4, irradiation of the
C(4) proton of 18 gave a significant enhancement of the
resonance at the C(5) proton. Other observed interac-
tions between these nuclei and the methylene protons of
substituents attached at the 4 and 5 ring positions are less
strong. Both observations indicate the proposed cis
configuration of 18. In addition, the determination of the
coupling constant of the annular protons 3JCHO/NCH with
7.6 Hz provides another strong evidence for the cis
13C NMR data in ppma
ent-1
10.6, 24.4, 25.1, 25.5, 26.5, 47.0, 60.3, 75.7
(+)-a-Conhydrine 1
Comins6
10.5, 24.3, 25.8, 26.9, 44.0, 54.5, 70.5b
b-Conhydrines
Comins6
Couty7b
Husson5
10.2, 24.5, 26.4, 29.1, 46.6, 61.1, 75.4 2b
10.5, 24.8, 26.8, 26.9, 29.5, 46.9, 61.3, 75.9 ent-2
10.2, 24.5, 26.3, 26.4, 29.1, 46.6, 61.1, 75.4 2
a Measured in CDCl3.
b One signal is missing.
Table 2. Reported melting points and optical rotation val-
ues of (+)-a-conhydrine 1, (+)-b-conhydrine 2 and (−)-
b-conhydrine ent-2 in comparison to ent-1
Mp [°C]a
[h]b
3
stereochemistry. In the oxazolidin-2-one ring JCHO/NCH
ent-1
118
−8.6
of the cis isomer is in general higher (6–9 Hz) than the
trans isomer (4–6 Hz).18 The determined cis configuration
of 18 confirms the (S,R)-absolute configuration of the
two vicinal stereogenic centers generated by the a-alkyl-
ation/1,2-addition sequence starting from the glycol
aldehyde SAMP hydrazone 13.
(+)-a-Conhydrine 1
Galinovsky3
Comins6
Fodor4
121
–
120
119–121
+9.6
+9.0
+8.6
+8.9
Masaki7c
On the other hand, one major intention of our investiga-
tions towards the absolute configuration of (−)-a-conhy-
drine ent-1 was to prove the racemization-free reaction
pathway starting from hydrazine 15. We obtained suit-
able crystals of the title compound by recrystallization
from ether at room temperature. The X-ray crystallo-
graphic analysis confirmed unambiguously the relative
anti configuration (Fig. 2). In combination with the
negative optical rotation the proposed absolute configu-
ration (2R,7S) is confirmed.
b-Conhydrines
Comins6
2
–
+8.0
–
Beak17 (9)-2
Couty7b ent-2
68–70
67
72
−34.1c
+8.6
Husson5
2
a Partly recrystallized from different solvents and uncorrected.
b Measured in EtOH.
c Measured in CHCl3.

288
D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 285–291
OCH3
dent ways. Further investigations towards other 2-(a-
hydroxyalkyl)piperidine analogs of (−)-a-conhydrine by
introduction of various alkyl substituents in the a-alkyl-
ation of hydrazone 13 are now in progress.
O
N
H
i
N
N
OCH3
H3CO
N
O
75%
H3C
TBSO
H3C
TBSO
O
14
16
4. Experimental
4.1. General
d.e. >96%
d.e. = 89%
ii
OCH3
O
Melting points were determined on a Tottoli melting
point apparatus and are uncorrected. IR spectra were
recorded on a Perkin–Elmer 1750 FT-IR spectrometer.
1H and 13C NMR spectra were recorded at 300 or 500
MHz and 75 or 125 MHz, respectively, on Varian VXR
300, Varian Gemini 300 or Varian Unity spectrometers.
3JH,H coupling constants were expressed in Hz. All
measurements were performed in CDCl3 and chemical
shifts are expressed in ppm (l) with tetramethylsilane
as an internal standard. Mass spectra (MS) were
obtained on a Varian MAT 212 or Finnigan SSQ 7000.
Optical rotations were measured on a Perkin–Elmer P
241 polarimeter. Microanalyses were performed on
Heraeus CHN-O-Rapid, Elementar Vario EL. In case
of sensitive compounds high resolution mass spectra
(HR-MS) were obtained on a Finnigan MAT 95.
O
O
S
NH
R
O
O
iii
N
O
N
O
41%, 2 steps
H3C
H3C
18
O
d.e., e.e. >96%
17
H
N
O
H
H
+
O
4
3JCHO/NCH = 7.6 Hz
H
H
5
cis
H
H
H3C
O
O
Scheme 4. Confirmation of the proposed relative configura-
tion by NOE experiments and determination of the coupling
constant JCHO/NCH of oxazolidin-2-one 18. Reagents and
3
4.2. Synthesis of (−)-a-conhydrine (ent-1)
conditions: (i) 12, THF, −78°C, then MocCl, −78°C; (ii)
TBAF, THF, rt; (iii) Li/NH3, −33°C.
4.2.1. (2S,2S)-(−)-(E)-N-[2-(tert-Butyldimethylsilyloxy)-
but-1-ylidene]-N-(2-methoxymethylpyrrolidin-1-yl)-
amine, 14. A solution of 13 (2.87 g, 10 mmol) in dry
THF (5 mL) was slowly added to a solution of 2.0
equiv. LDA (freshly prepared from a solution of n-
butyllithium (1.6 m) in hexane (12.5 mL, 20 mmol) and
diisopropylamine (2.9 mL, 20.5 mmol) in dry THF (20
mL) at −78°C. After stirring at –78°C for 15 h, ethyl
iodide (2.40 mL, 30 mmol) was added at −100°C. The
solution was stirred for 1 h at –100°C and then allowed
to warm to room temperature within 20 h. The reaction
mixture was quenched with saturated NH4Cl solution
(15 mL). The aqueous phase was extracted with Et2O
(3×10 mL), and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4 and
concentrated in vacuo. After the isomer ratio was deter-
mined, flash column chromatography of the residue on
silica gel eluting with pentane–Et2O (4:1, 1 vol% of
Et3N) gave 14 (940 mg, 43%, 70% conversion). Rf
(silica, pentane–Et2O 4:1): 0.9. d.e.=89% (1H, 13C
NMR). [h]2D4 −78.0 (c 1.03, CHCl3). 1H NMR (300
MHz): l 0.04 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3), 0.89
(s, 9H, C(CH3)3), 0.92 (d, J=7.4, 3H, CH3CH2), 1.52–
1.64 (m, 2H, CH3CH2), 1.77–2.00 (m, 4 H, CH2CH2),
2.79 (q, J=8.2, 1H, NCHH), 3.26–3.57 (m, 4H,
CH2OCH3, NCHCH2, NCHH), 3.36 (s, 3H, OCH3),
4.10 (q, J=6.5, 1H, CHOSi), 6.40 (d, J=6.5, 1H,
CHN). 13C NMR (75 MHz): l −4.72 (SiCH3), −4.17
(SiCH3), 9.80 (CH2CH3), 18.27 (C(CH3)3), 22.17
(NCH2CH2), 25.94 (C(CH3)3), 26.60 (NCHCH2), 29.98
(CH2CH3), 49.65 (NCH2), 59.21 (OCH3), 63.20
(NCH), 74.58 (CH2OCH3), 74.97 (CHOSi), 139.18
Figure 2. Crystal structure and confirmed absolute configura-
tion of ent-1.
3. Conclusion
In summary, we succeeded in accomplishing the asym-
metric synthesis of (−)-a-conhydrine ent-1. The target
molecule was obtained in moderate overall yield and
excellent diastereo- and enantiomeric excess. We were
able to confirm the proposed (2R,7S) absolute configu-
ration of the isolated product by NMR spectroscopic
methods and by X-ray crystallography in two indepen-

D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 285–291
289
+
’
(NꢁCH). MS (EI): m/z (%) 314 (7, M ), 285 (12,
mixture was quenched with aqueous HCl (3 M, 2 mL)
and conc. NH3 was added to a basic pH value. H2O (18
mL) and CH2Cl2 (20 mL) was added and after separa-
tion of the organic layer the aqueous portion was
extracted with CH2Cl2 (4×10 mL). The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The isomer ratio was deter-
mined and flash column chromatography of the residue
on silica gel eluting with CH2Cl2–MeOH (1:1) gave
ent-1 (140 mg, 55%). Rf (AcOEt–MeOH–conc. NH3
4:4:0.25): 0.3. d.e., e.e.=>96% (1H, 13C NMR). [h]D27
+
+
’
’
M −CH3CH2), 270 (18), 269 (100, M −CH2OCH3),
257 (16, M −tBu), 173 (7), 115 (8), 75 (6), 73 (21), 70
(5). IR (CHCl3): w 2957, 2930, 2882, 2857, 2827, 1599,
1463, 1387, 1361, 1341, 1253, 1198, 1092, 1043, 1004,
939, 909, 837, 794, 777, 673. Anal. calcd for
C16H34N2O2Si: C, 61.10; H, 10.90; N, 8.91. Found: C,
61.34, H, 11.07; N, 9.00%.
+
’
4.2.2. (1R,2S,2S)-(−)-N-[2-(tert-Butyldimethylsilyloxy)-
1-(3-[1,3]dioxolan-2-yl-propyl)-butyl]-N-(2-methoxy-
methyl-pyrrolidin-1-yl)-amine, 15. Iodide 12 (1.94 g, 8
mmol) was dissolved in dry Et2O (4 mL) and a solution
of tert-butyllithium (1.6 M, 2.0 equiv.) in hexane (10
mL, 16.0 mmol) was slowly added at −78°C. After
stirring for 30 min at –78°C, the solution was allowed
to warm to room temperature and stirred for an addi-
tional hour. The resulting mixture was cooled again to
−78°C and dissolved in dry THF (20 mL). A solution
of hydrazone 14 (630 mg, 2.0 mmol) in dry THF (2
mL) was slowly added and the reaction mixture was
stirred at –78°C for 16 h. After stirring for 1 h at −20°C
the reaction was quenched with saturated NaHCO3
solution (15 mL). The aqueous phase was extracted
with Et2O (3×10 mL), and the combined organic layers
were washed with brine, dried over anhydrous Na2SO4
and concentrated in vacuo. Flash column chromatogra-
phy of the residue on silica gel eluting with pentane–
Et2O (1:1) gave 15 (760 mg, 88%). Rf (silica,
pentane–Et2O 1:1): 0.5. d.e. >96% (13C NMR). [h]D24
1
−8.6 (c 0.68, EtOH). Mp 118°C. H NMR (500 MHz):
l 0.98 (t, J=7.5, 3H, CH2CH3), 1.22–1.53 (m, 5H,
CH2CH3, NCH2CHHCH2), 1.60 (m, 2H, NCH2CHH,
NCHCHH), 1.86 (m, 1H, NCHCHH), 2.56 (d/t, J=
10.7/2.7, 1H, NCH), 2.72 (t/d, J=12.0/2.7, 1H,
NCHH), 3.05 (br s, 2H, NH; OH), 3.12 (m, 1H,
NCHH), 3.42 (m, 1H, CHO). 13C NMR (125 MHz): l
10.61
(CH2CH3),
24.40
(NCHCH2),
25.13
(NCHCH2CH2), 25.52 (CH2CH3), 26.47 (NCH2CH2),
46.99 (NCH2), 60.29 (NCH), 75.71 (OCH). MS (EI):
+
’
m/z (%) 143 (1, M ), 85 (5), 84 (100), 56 (13), 55 (6).
IR (CHCl3): w 3289 (NH), 3112 (OH), 2974, 2953, 2927,
2852, 2805, 2739, 2679, 1726, 1476, 1448, 1350, 1252,
1235, 1214, 1151, 1128, 1106, 1085, 1059, 1035, 1005,
978, 953, 894, 853, 811, 754, 596. Anal. calcd for
C8H17NO: C, 67.09; H, 11.96; N, 9.78. Found: C, 66.89,
H, 12.02; N, 9.93%.
4.3. Synthesis of oxazolidin-2-one 18
1
−44.0 (c 1.11, CHCl3). H NMR (300 MHz): l 0.06 (s,
4.3.1. (5S,4R)-(+)-4-([1,3]-Dioxolan-2-yl-propyl)-5-ethyl-
oxazolidin-2-one, 18. Iodide 12 (1.16 g, 4.8 mmol) was
dissolved in dry Et2O (2.5 mL) and cooled to −78°C a
solution of tert-butyllithium (1.6 M, 2.0 equiv.) in
hexane (6 mL, 9.6 mmol) was slowly added. After 30
min stirring at that temperature, the solution was
allowed to warm to room temperature and stirred for
an additional hour. The resulting mixture was cooled
again to −78°C and dissolved in dry THF (16 mL). A
solution of hydrazone 14 (520 mg, 1.66 mmol) in dry
THF (2 mL) was slowly added and the reaction mixture
was stirred at –78°C for 16 h and allowed to warm up
to −30°C. After cooling to −78°C MocCl (1.23 mL,
16.6 mmol, 10.0 equiv.) was added rapidly. reaction
mixture was stirred at –78°C for 15 h, then allowed to
warm to room temperature and quenched with satu-
rated NaHCO3 solution (15 mL). The aqueous phase
was extracted with Et2O (3×15 mL), the combined
organic layers were washed with brine, dried over anhy-
drous Na2SO4 and concentrated in vacuo. After filtra-
tion through silica gel washing with pentane–Et2O the
crude product was first concentrated in vacuo and then
dissolved in dry THF (5 mL). A solution of TBAF (1
M) in THF (5 mL, 5.0 mmol) was added at room
temperature. The mixture was stirred for 1 day at room
temperature and then concentrated in vacuo at 35°C.
The residue was filtered through silica gel, washed with
pentane–Et2O and concentrated in vacuo. The crude
product was dissolved in THF (10 mL) and added to a
solution of Li (116 mg, 16.6 mmol, 10.0 equiv.) in NH3
(40 mL) at −78°C. The solution was allowed to warm
to −33°C and stirred at –33°C for 40 min. The reaction
6H, Si(CH3)2), 0.88 (t, J=7.4, 3H, CH2CH3), 0.90 (s,
9H, C(CH3)3), 1.35–2.10 (m, 10H, NCHHCH2CH2,
NCHCH2CH2CH2), 1.44 (m, 2H, CH2CH3), 2.51 (m,
1H, NCHH), 3.28–3.88 (m, 6H, NCHH, NCHCH2O,
NCHCH2CH2CH2, CHOSi), 3.34 (s, 3H, OCH3), 3.85
(m, 2H, OCH2CH2O), 3.96 (m, 2H, OCH2CH2O), 4.86
(t, J=4.9, 1H, CH(OCH2)2). 13C NMR (75 MHz): l
−4.57 (SiCH3), −4.08 (SiCH3), 11.19 (CH2CH3), 18.09
(C(CH3)3), 20.85, 20.91 ((CH2O)2CHCH2CH2), 23.27
(NCH2CH2), 25.97 (C(CH3)3), 26.04 (NCHCH2), 29.26
(NCHCHOSi), 30.44 (CH2CH3), 34.52 ((CH2O)2-
CHCH2CH2CH2), 56.62 (NCH2), 59.00 (CH2OCH3),
62.95 (NCHCH2), 64.79 ((CH2O)2CH), 74.32 (CHOSi),
74.73 (CH2OCH3), 104.63 ((CH2O)2CH). MS (EI): m/z
+
’
(%) 430 (6, M ), 258 (15), 257 (100), 114 (6), 85 (6), 73
(14), 70 (9). IR (film): w 3298, 2954, 2927, 2856, 1742,
1464, 1373, 1241, 1129, 1103, 1048, 837, 776. HR-MS
+
’
calcd for C22H46N2O4Si : 430.3227. Found: 430.3226.
4.2.3. (−)-a-Conhydrine ent-1. Hydrazine 15 (760 mg,
1.76 mmol) was dissolved in dry THF (4 mL) at room
temperature and treated by slow addition of a solution
of BH3·THF (1 M, 10.0 equiv.) in THF (17.6 mL, 17.6
mmol). After heating under reflux for 15 h, the reaction
mixture was allowed to cool to room temperature and
carefully quenched with aqueous HCl (3 M, 18 mL).
After addition of CH2Cl2 (16 mL) and stirring for 4 h
at room temperature, the solvents were removed in
vacuo. The residue was dissolved in EtOH (20 mL) and
NaBH4 (684 mg, 18 mmol, 10.0 equiv.) were slowly
added at room temperature. After 2 h the reaction

290
D. Enders et al. / Tetrahedron: Asymmetry 13 (2002) 285–291
mixture was quenched with NH4Cl (2.5 g). NH3 was
removed at room temperature and the residue was
extracted with CH2Cl2 (3×10 mL). The combined
organic layers were washed with brine, dried over anhy-
drous Na2SO4 and concentrated in vacuo. After the
isomer ratio was determined, flash column chromatog-
raphy of the residue on silica gel eluting with Et2O–
MeOH (1:1) gave 18 (180 mg, 48%). Rf (Et2O): 0.3. d.e.,
e.e. >96% (1H, 13C NMR). [h]D26 +8.8 (c 0.97, CHCl3).
1H NMR (400 MHz): l 1.04 (tr, J=7.4, 3H, CH2CH3),
1.35–1.80 (m, 8 H, CH2CH2CH2, CH2CH3), 3.75 (m,
1H, CHN), 3.83 (m, 2H, OCH2CH2O), 3.95 (m, 2H,
OCH2CH2O), 4.50 (m, 1H, CHO), 4.84 (t, J=4.5, 1H,
CH(OCH2)2), 6.63 (s, 1H, NH). 13C NMR (100 MHz):
l 10.69 (CH2CH3), 20.65 ((CH2O)2CHCH2CH2), 22.66
(CH2CH3), 29.93 (NCHCH2), 33.56 ((CH2O)2CHCH2),
55.78 (NCH), 65.10, 65.12 ((CH2O)2CH), 81.96
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft (Sonderforschungsbereich 380) and the
Fonds der Chemischen Industrie. For the donation of
chemicals we thank the companies Aventis, BASF AG,
Bayer AG, Degussa AG, and Wacker Chemie. We also
thank Dr. Chunhu Hu for the collection of diffraction
data and Marco Schmitz for his contributions to the
experimental part of this work.
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,
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CCDC 178847 contains the supplementary crystallo-
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