Isoxazolinium salts in asymmetric synthesis. 1. Stereoselective reduction induced by a 3′-alkoxy stereocentre. A new approach to polyfunctionalized β-amino acids

Article abstract of DOI:10.1515/znb-2004-0414

A new approach to optically active N-methylamino acids is presented, relying on stereoselective reduction of N-methylisoxazolinium salts with a dioxyethyl side-chain. The diastereoselectivity of the reduction step is studied systematically, in comparison with that of respective isoxazolines. A two-step transformation of isoxazolinium salts - with NaBH₃(OAc) and subsequent catalytic hydrogenation as well as a one-pot reduction by catalytic hydrogenation led to high (95:5 and 87:13) diastereomeric ratios of protected erythro-N-methylaminopentanetriols. The hydroxyethyl side-chain is elaborated by oxidation to afford the β-N-methylamino acid 37, exemplifying the potential of this strategy.

Full text of DOI:10.1515/znb-2004-0414

Isoxazolinium Salts in Asymmetric Synthesis.
1. Stereoselective Reduction Induced by a 3’-Alkoxy Stereocentre.
A New Approach to Polyfunctionalized β-Amino Acids* [1, 2]
Marco Hennebo¨hle, Pierre-Yves Le Roy, Matthias Hein, Rudolf Ehrler, and Volker Ja¨ger
Institut fu¨r Organische Chemie, Universita¨t Stuttgart, Pfaffenwaldring 55,
D-70569 Stuttgart, Germany
Reprint requests to Prof. Dr. Volker Ja¨ger. Fax: +49(0)711-6854321.
E-mail: jager.ioc@po.uni-stuttgart.de
Z. Naturforsch. 59b, 451 – 467 (2004); received February 2, 2004
Dedicated to Professor Ulrich Schmidt on the occasion of his 80th birthday
A new approach to optically active N-methylamino acids is presented, relying on stereoselective
reduction of N-methylisoxazolinium salts with a dioxyethyl side-chain. The diastereoselectivity of
the reduction step is studied systematically, in comparison with that of respective isoxazolines. A
two-step transformation of isoxazolinium salts – with NaBH3(OAc) and subsequent catalytic hy-
drogenation as well as a one-pot reduction by catalytic hydrogenation led to high (95:5 and 87:13)
diastereomeric ratios of protected erythro-N-methylaminopentanetriols. The hydroxyethyl side-chain
is elaborated by oxidation to afford the β-N-methylamino acid 37, exemplifying the potential of this
strategy.
Key words: Isoxazolinium Salts, Methylamino Alcohols, Diastereoselective Reduction,
Homoserine, β-Amino Acids
Introduction
House cyclization with suitable olefinic side-chains
present [14]. Other strategies followed involved di-
astereoselective nitroaldol additions [15] and ring-
opening of epoxypentenols obtained by asymmetric
Sharpless epoxidation of divinylcarbinol [16].
The development of concise approaches for access
to amino/imino polyols and acids continues to stim-
ulate efforts of synthetically oriented chemists. Con-
cerning amino acids, the synthesis of structures with
multiple other functions and/or branched units at the
α- or β-position has attracted wide-spread interest, due
to extraordinary properties and challenging problems
to be overcome [3 – 7]. In many of these studies addi-
tions to the C=N bond of imines or imine derivatives,
both linear and cyclic, have been used, mostly involv-
ing chiral substrates or chiral N-bound auxiliaries [8].
The isoxazoline route has occasionally been drawn
upon for the synthesis of hydroxy amino or imino
acids [9, 10, 17 – 20]. Reductions with often high and
predictable diastereoselectivity of isoxazolines occur
by means of lithium aluminium hydride [9], but this
cannot be applied to the case of isoxazoline-3-esters
or -carboxylic acids [17d, 20]. On the other hand,
catalytic hydrogenation of such esters has proceeded
with little or no selectivity [9, 17b– d, 19, 20]. In or-
der to avoid the accompanying ester reduction, car-
boxy group acid equivalents have been used [9], such
as the oxazolinyl group [17a], p-anisyl [17c], 2,5-
dimethoxyphenyl [17c], and 2-furyl [17c, 18], with the
latter giving most satisfactory results [9a– c, 17c, 21].
Diol units protected as acetals are particularly suited
Our own work in this field has been concerned with
various routes to amino/imino polyols and acids, no-
tably with the use of isoxazoline intermediates [9, 10],
with imines derived from optically active aldehy-
des [11, 12], or additions to nitrones [13, 14] (from
oxime cyclizations [13]) which may undergo Cope-
* Presented in part at the 6th Conference on Iminium to that purpose, first because of their inertness towards
Salts (ImSat-6), Stimpfach-Rechenberg (Germany), Septem-
ber 16 – 18, 2003.
LiAlH4 (and other strong nucleophiles and bases), and
second, because thereby one may introduce optical
c
0932–0776 / 04 / 0400–0451 $ 06.00 ꢀ 2004 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

452
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
activity and induce asymmetric induction in addition
steps [11, 17d– e, 18, 20, 22, 23].
Unfortunately, the C=N bond of isoxazolines is
rather unreactive towards attack of nucleophiles other
than hydride from LiAlH4. With strongly basic nu-
cleophiles such as phenyllithium, mixtures of prod-
ucts are obtained [24], and with hindered strong base
such as lithium diisopropylamide deprotonation occurs
[9, 10e – f, 17b, 17f, 24]. Activation of isoxazolines to-
wards addition of strongly basic C-nucleophiles is pos-
sible, however, according to the seminal findings of
Uno, Terakawa, and Suzuki, by means of boron tri-
fluoride etherate [25]. Alkyl, aryl, hetaryl, and allyl-
lithium or respective Grignard compounds react well
and with high stereoselectivity; the limit was seen
with phenylethinyllithium, t-butyllithium, phenylmag-
nesium bromide and lithium dimethylcuprate which
failed to react [25a].
Another mode to activate isoxazolines towards ad-
dition of even weak nucleophiles should consist in N-
alkylation, to produce N-alkylisoxazolinium salts, a
class of compounds actually known since 1955 [26].
Few examples of nucleophilic additions to these – pre-
sumably highly reactive – N-oxyiminum salts have
been reported [27– 30], for example with sodium
borohydride [27], methyl- and phenylmagnesium bro-
mide [27], aqueous base or methoxide [29], and
diphenyl phosphite [30]. Systematic studies on the po-
tential utility of isoxazolinium salts in asymmetric syn-
thesis are lacking though.
With the ready availability of isoxazolines, built
from alkenes and nitrile oxides, and with the rich
chemistry and manifold transformations to acyclic
structures in mind, isoxazolinium salts appear as
promising candidates for extending this strategy: with
nucleophilic additions stereoselective access to N-
methylisoxazolidines might be found, and subsequent
N-O reduction should provide syntheses of branched
γ-amino alcohols. Further elaboration of the termini
with R and R’ would be open, leading to a great variety
of polyfunctional, heavily substituted target structures
such as branched amino sugars or amino acids (α-, β-,
γ- etc.). The strategy for uses of isoxazolinium salts
in asymmetric amino acid synthesis is summarized in
Scheme 1.
Scheme 1.
chains and induction from the 1’-stereocentre. It also
discloses a new access to β-amino acids by oxi-
dation of the (former) 5-position, as specified by a
synthesis of (protected) D-erythro-4,5-dihydroxy-3-
methylaminopentanoic acid 37.
Results and Discussion
Preparation of isoxazolines and N-methylisoxazo-
linium tetrafluoroborates
The isoxazolines were prepared by 1,3-dipolar cy-
cloaddition of respective olefins and nitrile oxides ob-
tained in situ from oximes via hydroximoyl chlorides,
using standard procedures, see Scheme 2, 3.
The nitrile oxide derived from 2-O-benzyl-L-
glyceraldehyde 1 [31] via the hydroximoyl chloride
3 [17c – e, 20] smoothly underwent cycloaddition with
ethylene, forming the isoxazoline 4 in 88 – 90% yield.
The free hydroxy group was benzylated to provide
a model substrate 5 with protected O-functions in
The following report is the first part of our stud-
ies outlining stereoselective transformations of isox-
azolinium salts [2]; it deals with the stereoselec-
tivity of C=N reductions both of isoxazolines and
N-methylisoxazolinium salts with (di)oxyethyl side- Scheme 2.
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
453
Scheme 5.
Scheme 3.
Scheme 6.
Scheme 4.
an acyclic side-chain (Scheme 2). Derivatives with
acetal-protected side-chains 9 and 13 were obtained
starting from the respective acetone or cyclohexanone
bis(acetals) of D-mannitol, via the aldehydes 6 and
10, the oximes 7 and 11, and the chlorooximes 8 and
12 (Scheme 3).
N-Methylation of the isoxazolines 4, 5, 9 and 13 was
effected with trimethyloxonium tetrafluoroborate in
dichloromethane at room temperature following work
of Cerri et al. [27a] (Schemes 4, 5). The isoxazolinium
salts 14-17 were obtained in high yield in analytically
pure form; in some cases stable, crystalline products
were isolated. Remarkably, functional groups such as
acetal moieties or even a free hydroxy group proved
compatible with these reaction conditions.
Scheme 7.
Table 1. Diastereoselective reduction of isoxazolines 9 and
13.
Entry Isoxaz- Reducing
oline Agent
Solvent Temp.
d. r.
Yield
(◦C) 20/21 or 22/23 (%)a
(erythro/threo)
1
2
3
4
9
LiAlH4
Et2O
45:55
44:56
20:80
35:65
(98)
(81)
(51)
(97)
13 LiAlH4
13 iBu2AlH
13 NaBH4,
Et2O
hexane
25
0
Reduction of isoxazolines with 3-dioxyethyl
side-chains
MeOH −30
NiCl2·6H2O
13 H2, Pd/C
13 H2, Rh/Al2O3 MeOH
Employing lithium aluminium hydride, the reduc-
tion of isoxazolines with 5- and/or 4-substituents pro-
ceeds with often excellent stereoselectivity [9, 17, 32].
Catalytic hydrogenations usually are rather unselective
[9, 17, 19, 32], unless special combinations of 3- and 5-
substituents are present [9, 17d, e, 20]. Asymmetric in-
duction from stereocentres in the 3-side-chain of isoxa-
zolines had not been screened, so representative model
compounds 4, 9 and 13 were chosen for reductions
5
6
MeOH
25
25
45:55
20:80
(100)
(97)
a
Spectroscopically pure; not purified further.
isoxazoline 4 with a 2’-OH group was performed, hop-
ing for a chelate effect. This proceeded in good yield
(as usual), but in a non-selective way (d. r. of amino
alcohols: 18:19 = 53:47), see Scheme 6.
In order to avoid the presumed levelling effect
with different reagents. First, LiAlH4 reduction of the of such OH groups, substrates 9 and 13 with ace-
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

454
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
Scheme 8.
tal side-chains were used and various reagents tried,
see Scheme 7 and Table 1. Again, with LiAlH4 non-
selective reaction was seen (entries 1, 2 in Table 1).
Since the cyclohexylidene acetal proved more stable
during work-up, the isoxazoline 13 was preferred for
most further studies. As seen from the selection of re-
sults collected in Table 1, excellent yields of amino
alcohols 22/23 were obtained from reduction with
“nickel boride” (NaBH4/NiCl2 · 6H2O) and catalytic
hydrogenations. The highest diastereomeric ratios of
80:20 were achieved both with diisobutylaluminium
hydride (entry 3) and the rhodium-catalyzed reaction
(entry 6).
Scheme 9.
15, with an acyclic 3-side-chain, treated this way led to
diastereomeric mixtures 28/29 and 30/31, respectively,
with similar ratios (76:24 from 14, 73:27 from 15); the
free hydroxy group in 14 thus had little or no effect
(Scheme 9).
The cyclohexylidene acetal 17 gave somewhat bet-
ter results (d. r. 32:33 = 81:19) under these conditions
and was chosen for a more detailed study with a vari-
ety of hydride-delivering reagents, see Scheme 10 and
Table 2.
As seen from these results, many reagents are suited
to this purpose, concerning yield of isoxazolidines
32/33. Except for the case of diisobutylaluminium hy-
dride (entry 6), the erythro isomer 32 was the prepon-
derant one throughout, with highest selectivity found
for sodium triacetoxyborohydride– rapid reaction even
at −78 ◦C, with a diastereomeric ratio of 95:5.
A remaining problem was how to unambiguously
assign the relative configuration to these isoxazolidine
pairs. This was not possible from 1H or 13C NMR
In order to assign the configuration to these diastere-
omeric amino alcohols, a mixture of 22/23 (d. r. 35:65)
was transformed to the N-Z derivatives 24/25, which
were separated by MPLC. The major isomer 25 was
converted into homoserinolactone 27 by acetal hydrol-
ysis, oxidative diol cleavage and N-deprotection (see
Scheme 8). Comparison of the specific rotation of this
with literature data [43] established the configuration
of the aminomethylidene centre as (R). The reductions
of 13 therefore had furnished the threo isomer as the
preponderant one. In hydrogenations of isoxazolines
usually N-O cleavage occurs first, the new stereocen-
tre is formed with C=N reduction of the intermediate
β-hydroxyimine [9, 10d, 17, 20, 32], an acyclic species
less amenable to steric induction.
1
data; the differences were too small both with H and
13C NMR shifts (∆δ 0 – 0.41 and 0−1.9, respectively)
as well as with coupling constants J3,1’ (∆J ≤ 1 Hz).
Fortunately, the N-methylisoxazolidine 32 (major iso-
mer) on alkylation with trimethyloxonium tetrafluo-
roborate gave a crystalline ammonium salt 34, from
which the relative configuration – erythro – could be
established by X-ray crystal structure analysis [33], see
Scheme 10. The course of dominant hydride addition
then is presumed to be anti to the oxygen substituent at
Reduction of isoxazolinium salts;
stereochemical course
In contrast to the case of isoxazolines, isoxazolinium C-1’, just as seen with the conformation present in the
salts 14 –17 smoothly underwent reduction on treat- crystal (Fig. 1), in perfect agreement with the Felkin-
ment with sodium borohydride in ethanol, to afford the Anh-Houk model of such transition states of carbonyl
corresponding isoxazolidines. The substrates 14 and additions [34].
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
455
Scheme 10.
Table 2. Reduction of the isoxazolinium salt 17 with hy-
drides.
Entry Reagent
a
Solvent Temp. Reaction d. r. Yieldb,c
(◦C)
20 1 d
time
32/33
81:19
84:16
(%)
1
2
3
4
5
6
7
8
NaBH4
NaBH4
catecholborane THF
LiBHEt3
LiBH(iBu)3
(iBu)2AlH
LiAlH(OtBu)3 THF
NaAlH2(OR)2 THF
(Red-Al)
EtOH
84
EtOH −30 7 h
65
−78 ca. 1 min 90:10 (79)
THF
THF
THF
−78 ca. 1 min 76:24 84
−78 ca. 1 min 82:18 (73)
−78 ca. 1 min 37:63
−78 ca. 1 min 65:35
83
78
84
Fig. 1. Conformation of 34 in the crystal and presumed stere-
ochemical course of predominant hydride addition to the pre-
cursor 17.
−78 15 min
61:39
9
NaBH(OAc)3 THF
0
ca. 1 min 93: 7
81
86
10 NaBH(OAc)3 THF
−78 ca. 1 min 95: 5
From 13C NMR of crude product or after chromatography; b yield
a
relates to analytically pure material, otherwise put in brackets;c fur-
ther reagents tested: Zn(BH4)2 gave low recovery of products (24%)
with good d. r. (90:10); LiBH4, NaBH(OMe)3 led to decomposition.
Further transformation of these isoxazolidines to the
corresponding N-methylamino alcohols was studied
next, see Scheme 11.
Scheme 11.
As expected, hydrogenation with palladium on car-
bon readily afforded the respective diastereomers 35 (Scheme 12). Again, a variety of reagents and condi-
and 36 which, of course, tempted to look at direct tions was tested, with a selection of results gathered in
conversion of isoxazolinium salt to amino alcohols Table 3.
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

456
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
Scheme 13. (i) 1. Z-Cl, Et3N, CH2Cl2, 0 ◦C to r. t., 2 h, 92%
of N-Z-35; 2. H5IO4/CrO3, CH3CN; 3. H2 (1 bar), Pd/C,
MeOH; 4. HCl (gas), crystallization, 53% from N-Z-35.
Scheme 12.
Table 3. Amino alcohols 35 and 36 from isoxazolinium salts
17.
duced by an alkoxy stereocentre in the 3-side-chain.
Thus, a basis is laid for the vast field of additions of
C-nucleophiles to these substrates, which hitherto have
constituted a rather inconspicuous class of compounds.
Results of such extensions and applications in synthe-
sis will be forwarded.
Entry Reagent(s)
Temp. d. r.a
Yieldb
(◦C)
35/36 (%)
1
2
3
4
5
H2, Pd/C, MeOH
H2, Rh/C, MeOH
H2, Rh/Al2O3, MeOH
r. t.
r. t.
r. t.
80:20 73
87:13 68
88:12 (72)
86:14 (81)
95: 5
NiCl2 ·6H2O/NaBH4, MeOH −78
1. NaBH(OAc)3, THF
2. H2, Pd/C, MeOH
−78
>95: 5 82
Experimental Section
a From 13C NMR of crude product; b yields refer to isolated, analyt-
ically pure material, otherwise put in brackets.
For general experimental details see ref. [14]. Reagents
NaBH(OAc)3 (ca. 95%, Fluka); Me3OBF4 (Fluka, Aldrich);
Pd/C (10%, Degussa); iBu2AlH (1.0 M in THF, Aldrich);
catecholborane (1.0 M in THF, Aldrich); LiBH4 (Fluka);
LiBHEt3 (1.0 M in THF, Aldrich); LiBH(iBu)3 (1.0 M
in THF, Aldrich); LiAlH(OtBu)3 (1.1 M in THF, Fluka);
The conditions successful with isoxazolidines –
Pd/C catalyst – worked likewise, but with unsatisfac-
tory diastereoselectivity (entry 1 in Table 13). With
rhodium catalysts the d. r. of the products 35/36 was
improved somewhat from 80:20 to 88:12 (entries 2, 3).
The “nickel boride” reagent [35] (entry 4) was simi-
larly effective, and probably would be the best choice
for large-scale preparative runs. The best method in
terms of diastereoselectivity, however, was the two-
NaAlH2(OCH2CH2OMe)2 (3.5
M in toluene, Fluka);
NaBH(OMe)3 (Janssen); NaBH(OAc)3 (ca. 95%, Fluka)
were purchased and used without further purification.
CAUTION: Hydroximoyl chlorides are strong skin irri-
tants!
step reduction with NaBH(OAc)3 with subsequent cat- (1’R)-3-(1’-O-Benzyloxy-2’-hydroxyethyl)-4,5-dihydro-1,2-
oxazole (4)
alytic hydrogenation (entry 5 in Table 3).
a) 2-O-Benzyl-L-glyceraldoxime (2) [20, 31]
Completion of a new β-amino acid synthesis
A solution of K2CO3 (19.5 g, 141 mmol) and HONH3Cl
(8.55 g, 94.2 mmol) in water (150 ml) at 0 C was added
◦
One of the incentives of these studies, new ap-
proaches to (branched) amino acids, was put to prac-
tice with the conversion of the amino alcohol 35 to the
corresponding amino acid 37. After N-protection, the
Zhao modification of the Jones oxidation [36] was ap-
plied and indeed gave spectroscopically pure resinous
amino acid product 37. Analytically pure material was
obtained in the form of the hydrochloride 37·HCl, a
crystalline product which also permitted to carry out
an X-ray structure determination [37].
dropwise to a stirred solution of the aldehyde 1 [31] (8.65 g,
ca. 47 mmol) in methanol (150 ml). The mixture warmed up
overnight and was rota-evaporated (15 Torr); the cloudy so-
lution was extracted with CH2Cl2 (4 × 80 ml), the organic
solutes were dried (MgSO4) and the solvent was removed in
vacuo (10−3 Torr). The oxime 2 was obtained as a colorless
analytically pure oil; yield 8.23 g (90% from 2-O-benzyl-
threitol [2d, 31]; E/Z-mixture 86:14 (from NMR), [α]D20
=
57.9 (c = 1.04, EtOH); [α]2D0 = −62.4 (c = 1.51, EtOH). – IR
(film): ν = 3300 (b, OH), 2915, 2860, 1490, 1445, 1090, 930,
735, 695 cm−1. – 1H NMR (200.1 MHz, CDCl3; E/Z mixture
75:25); major isomer (E): δ = 3.66 (m, 3-H, 3’-H, OH), 4.05
(dM of ABM, J3,2 = 4.6 Hz, J1,2 = 7.3 Hz, 2-HM), 4.40,
4.57 (A,B of AB, J = 11.6 Hz, CH2Ph), 7.28 (m, C6H5),
7.36 (d, J2,1 = 7.3 Hz, 1-H), 9.68 (bs, NOH). – Minor isomer
In summary, isoxazolinium salts are readily avail-
able by 1,3-dipolar cycloaddition of alkenes and nitrile
oxides via isoxazolines. In contrast to isoxazolines,
they display high reactivity towards nucleophiles, as
exemplified here with hydride reagents, and they ac-
cept these (hydride) in a highly stereoselective way in- (Z): δ = 4.40, 4.56 (A,B of AB, J = 11.5 Hz, CH2Ph), 4.77
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
457
(m, 2-H), 6.77 (d, J2,1 = 6.0 Hz, 1-H); other signals coincid- with ether (3×100 ml). The combined organic solutes were
ing with those of the major isomer. – 13C NMR (50.3 MHz, dried (MgSO4) and evaporated (15 Torr), leaving a yellow-
CDCl3; E/Z mixture 75:25); major isomer (E): δ = 63.21 ish oil (6.97 g). This was filtered through silica (column
(t, C-3), 71.16 (t, CH2Ph), 76.74 (d, C-2), 127.92, 127.97, 3 cm × 15 cm) by means of petrol ether/ethyl acetate (3:7),
128.37 (3d, C6H5), 137.06 (s, i-C6H5), 149.31 (d, C-1). – the solvents were removed (15 Torr), and the resulting yel-
Minor isomer (Z): δ = 62.07 (t, C-3), 72.09 (t, CH2Ph), low oil (6.61 g) was submitted to MPLC (column type C,
73.49 (d, C-2), 127.92, 127.97, 128.37 (3d, C6H5), 137.06 eluent as above). After concentrating the solvents in vacuo
(s, i-C6H5), 150.98 (d, C-1). – C10H13NO3 (195.2): calcd. (10−3 Torr), a colorless oil of the isoxazoline 4 (5.52 g, 75%
C 61.53, H 6.71, N 7.17; found C 61.79, H 7.09, N 7.10.
from 3, 63% from oxime 2) was recovered which solidified
overnight.
b) 2-O-Benzyl-L-glycerohydroximoyl chloride (3)
M. p. 33 ◦C; [α]D20 = −116 (c = 1.15, CHCl3). – IR (KBr):
ν = 3253 (OH), 1452 (C=N), 1434, 1104, 1087, 1066, 1048,
1019, 854 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 2.39
(sb, 1 H, OH), 2.91 – 3.05 (m, 2 H, 4-H), 3.76 – 3.83 (m,
According to ref. [38] a solution of the oxime 2 (8.16 g,
41.8 mmol) in abs. DMF (150 ml) was treated with N-
chlorosuccinimide (NCS; 6.14 g, 48.0 mmol). First at room
temp. ca. one fourth of NCS was added and the reaction was
started by blowing in 20 ml of gaseous HCl (taken from the
vapour of a bottle with conc. hydrochloric acid). The rest
of NCS was added portionwise within 20 min and the so-
lution was stirred for another 1.5 h at room temp.; there was
slight warming of the mixture which took a light-green color.
For work-up, the mixture was put on ice water (400 ml), ex-
tracted with ether (4 × 100 ml) and partitioned against ice
water (100 ml). After drying (MgSO4) the solvent was re-
moved on a rotary evaporator (15 Torr), leaving a colorless
oil (9.84 g) which contained some DMF (ca. 3%) and ether
(ca. 15%) according to 1H NMR; this crude product was used
for the next step. – Yield 8.08 g (corrected), 84%.
ꢀ
ꢀ
2 H, 2’-H), 4.24 – 4.35 (m, 2 H, 5-H), 4.43 (dd, J1 ,2 A = 4.9,
J1 ,2 B = 5.8 Hz, 1 H, 1’-H), 4.52, 4.60 (A, B von AB, 2JAB
=
ꢀ
ꢀ
11.7 Hz, 2 H, CH2C6H5), 7.27 – 7.40 (m, 5 H, C6H5). –
13C NMR (125.8 MHz, CDCl3): δ = 34.4 (t, C-4), 63.5 (t,
C-2’), 68.6 (t, C-5), 71.6 (t,CH2C6H5), 74.7 (d, C-1’), 128.1,
128.6 (2 d, o-, m-, p-C of C6H5 – only 2 of the expected 3
signals could be seen), 137.2 (s, i-C of C6H5), 157.8 (s, C-3).
- C12H15NO3 (221.3): calcd. C 65.14, H 6.83, N 6.33; found
C 64.96, H 6.77, N 6.36.
(1R’)-3-(1’,2’-Dibenzyloxyethyl)-4,5-dihydro-1,2-oxazole
(5)
Silver oxide (1.03 g, 4.44 mmol) was added in portions
to a solution of the isoxazoline 4 (983 mg, 4.44 mmol) and
benzyl bromide (1.15 g, 6.72 mmol) in ether (20 ml). After
standing at room temp for 1 h., the suspension was heated
to reflux. After 2 d TLC analysis still showed the presence
of starting material, therefore more benzyl bromide (760 mg,
4.44 mmol) and Ag2O (1.03 g, 4.44 mmol) were added. Af-
ter 5 d the reaction was virtually complete (TLC), Ag salts
were filtered off and the precipitate rinsed with abs. ether.
After rota-evaporation (15 Torr) of the organic solution, an
orange oil (2.21 g) was recovered and filtered through sil-
ica (column 3 cm×14 cm; petrol ether/EtOAc 1:1) to afford
2.13 g of an orange oil. MPLC separation (column type C,
petrol ether/EtOAc 85:15) as above gave a colorless, analyt-
ically pure oil of the isoxazoline (1.11 g, 80%), solidifying
overnight.
Analytically pure hydroximoyl chloride 3 was obtained,
when extraction was performed with tert-butyl methyl ether
(3 × 60 ml for a 12 mmol run) [17d, 20]; 91% from 2-
O-benzyl-L-threitol (3 steps). [α]2D0 = −79.7 (c = 0.78,
MeOH). – IR (film): ν = 3300 (b, OH), 1653, 1631, 1497,
1455, 1100, 1056, 1028, 984 cm−1. – 1H NMR (200.1 MHz,
CDCl3): δ = 2.57 (s, 1 H, OH), 3.76 (“dd”, J2,3a = 5.4,
J3a,b = 11.7 Hz, 1 H, 3-Ha), 3.87 (“dd”, J2,3b = 6.7, J3a,3b
=
11.7 Hz, 1 H, 3-Hb), 4.30 (“dd”, J2,3a = 5.4, J2,3b = 6.7 Hz,
1 H, 2-H), 4.42, 4.66 (A,B of AB, JA,B = 11.4 Hz, 2 H,
CH2Ph), 7.30 – 7.40 (m, 5 H, C6H5). – 13C NMR (50.3 MHz,
CDCl3): δ = 62.7 (C-3), 71.6 (CH2Ph), 79.8 (C-2), 128.0
(p-C), 128.2 (o-C), 128.4 (m-C), 136.7 (i-C), 139.2 (C-1). –
C10H12NO3Cl (229.7): calcd. C 52.30, H 5.27, N 6.09; found
C 51.91, H 5.37, N 5.92.
M. p. 24 – 25 ◦C. – [α]D20 = −51.8 (c = 0.97, CH2Cl2). –
IR (KBr): ν = 1454 (C=N), 1101, 1083, 1066, 862 cm−1. –
c) Isoxazoline (4)
1H NMR (500.1 MHz, CDCl3): δ = 2.92 − 2.96 (m, 2 H,
At 0 ◦C ethylene was bubbled into a solution of the 4-H); 3.69 (dd, J1 ,2 A = 5.5, J2 A,2 B = 10.3 Hz, 2’-HA),
2
ꢀ
ꢀ
ꢀ
ꢀ
2
ꢀ
ꢀ
ꢀ
ꢀ
hydroximoyl chloride 3 (crude, 9.79 g, content ca. 82%, 3.73 (dd, J1 ,2 B = 5.9, J2 A,2 B = 10.3 Hz, 2’-HB) – sum
35.0 mmol) in toluene (abs., 150 ml). While keeping a slow 2 H; 4.23 – 4.33 (m, 2 H, 5-H), 4.51 – 4.61 (m, 5 H, 1’-H,
stream of ethylene in the vessel, a solution of triethylamine 2 CH2C6H5), 7.25 – 7.38 (m, 10 H, 2 C6H5). – 13C NMR
in toluene (38.5 ml of a 1.00 M solution, 38.5 mmol) was (125.8 MHz, CDCl3): δ = 34.1 (t, C-4), 68.6 (t, C-5), 70.6 (t,
added dropwise within 43 h (Dosimat, ca. 0.015 ml/min). C-2’), 71.5 (t, CH2C6H5), 73.1 (d, C-1’), 73.4 (t, CH2C6H5),
For work-up 1 N HCl (300 ml) was added, the organic 127.75, 127.79, 127.9, 128.0, 128.42, 128.44 (6 d, o-, m-, p-
layer was removed and the aqueous phase was extracted C of 2 C6H5), 137.5, 137.7 (2 s, i-C of 2 C6H5), 157.9 (s,
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

458
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
C-3). – C19H21NO3 (311.4): calcd. C 73.29, H 6.80, N 4.50; 10.9 Hz, 5-HA), 4.63 – 4.67 (m, 5-HB), 4.64, 4.70 (A, B of
found. C 73.15, H 6.85, N 4.55.
AB, 2JA,B = 11.5 Hz, CH2C6H5) – sum 4 H; 4.89 – 4.91 (m,
1 H, 1’-H), 7.24 – 7.36 (m, 10 H, 2 C6H5). Due to incomplete
resolution not all couplings could be identified. – 13C NMR
(125.8 MHz, CDCl3): δ = 38.1 (t, C-4), 40.5 (q, NCH3), 69.1
(t, C-2’), 70.6 (t, C-5), 74.0, 74.1 (2 t, 2 CH2C6H5), 74.5 (d,
C-1’), 128.5, 128.6, 128.9, 128.99, 129.03, 129.1 (6 d, o-,
m-, p-C of 2 C6H5), 136.6, 137.4 (2 s, i-C of 2 C6H5), 168.2
(s, C-3). – C20H24BF4NO3 (413.2): calcd. C 58.13, H 5.85,
N 3.39; found C 58.14, H 5.95, N 3.35.
General Procedure A, N-methylation of 2-isoxazolines to
form N-methylisoxazolinium tetrafluoroborates
In analogy to Gandolfi’s procedure [27a, c] 1.1 eq of
trimethyloxonium tetrafluoroborate at room temp. was added
to a stirred solution of the isoxazoline (0.5 to 15 mmol runs)
in CH2Cl2 (5 – 30 ml). The mixture was stirred overnight,
then rota-evaporated (room temp./15 Torr) to leave the crude
salt. For details of isolation and characterization see individ-
ual compounds. – In many cases the crude product was used
for reduction.
(1’S)-3-(1’,2’-Isopropylidenedioxyethyl)-4,5-dihydro-1,2-
oxazole (9)
a) 2,3-O-Isopropylidene-D-glyceraldoxime (7): prepared
according to the literature [39, 40].
(1’R)-3-(1’-Benzyloxy-2-hydroxyethyl)-2-methyl-4,5-di-
b) 2,3-O-Isopropylidene-D-glycerohydroximoyl chloride
(8): Obtained as described for 3; oxime 7 (3.90 g,
26.9 mmol), NCS (3.95 g, 29.6 mmol), DMF, moist HCl
vapour (20 ml). The crude product was a colorless solid,
yield 4.41 g, 89% after correction for impurities (DMF 2.6%,
ether 0.3%); spectroscopic data in agreement with those
given in ref. [39]. The chlorooxime was used for the next
step without further purification.
hydro-1,2-oxazolium tetrafluoroborate (14)
General Procedure: Isoxazoline 4 (455 mg, 2.01 mmol),
Me3OBF4 (327 mg, 2.21 mmol), CH2Cl2 (abs., 5 ml). The
crude product, a colorless oil, was dissolved in EtOH and
◦
cooled to −30 C which made a cloudy oil separate. After
decanting carefully, the oil was concentrated (10−3 Torr) to
give the salt 14 as an analytically pure, colorless oil; yield
602 mg (91%).
c) Isoxazoline 9: Prepared as described for 4; hy-
droximoyl chloride 8 (4.39 g, content 97%, 23.7 mmol),
ether (300 ml), saturation with ethylene, triethylamine in
ether (26.1 ml of 1 N solution, 26.1 mmol), addition rate
0.02 ml/min. After purification by MPLC, the isoxazoline 9
was isolated as a colorless, analytically pure oil; yield 3.38 g
(83%; 74% from oxime 7).
[α]2D0 = −9.8 (c = 1.18, MeOH). – IR (Film): ν =
3539 (OH), 1679 (C=N), 1068, 927, 755 cm−1. – H NMR
1
(500.1 MHz, CD3OD): δ = 3.93 − 3.99 (m, 2 H, 4-H); 4.09
5
ꢀꢀ
(t, J4,1 = 2.0 Hz, NCH3), 4.10 – 4.17 (m, 2’-H) – sum 5
H; 4.88 – 5.00 (m, 4 H, 5-H, CH2C6H5), 5.10 – 5.12 (m, 1 H,
1’-H), 7.56 – 7.68 (m, 5 H, C6H5). – 13C NMR (125.8 MHz,
CD3OD): δ = 39.4 (t, C-4), 41.2 (q, NCH3), 63.5 (t, C-2’),
72.3, 75.3 (2 t, C-5, CH2C6H5), 77.6 (d, C-1’), 130.3, 130.4,
130.5 (3 d, o-, m-, p-C of C6H5), 138.6 (s, i-C of C6H5),
170.3 (s, C-3). – C13H18BF4NO3 (323.1): calcd. C 48.33,
H 5.62, N 4.34; found C 48.27, H 5.84, N 4.17.
[α]2D0 = −5.8 (c = 2.56, CHCl3). – IR (Film): ν = 2989,
1456 (m, C=N), 1373, 1259, 1216, 1153, 1062, 872 cm−1. –
1H NMR (500.1 MHz, CDCl3): δ = 1.41, 1.46 (2 s, each
3 H, C(CH3)2), 2.98 – 3.12 (2 dddd, 2J4A,4B = 10.2, J4A,5A
=
=
4
J4B,5B = 11.1, J4A,5B = J4B,5A = 9.4, J4A,1 =4 J4B,1
ꢀ
ꢀ
0.8 Hz, 2 H, 4-H), 4.01 (dd, J1 ,2 A = 6.0, 2J2 A,2 B = 8.7 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
2
(1’R)-3-(1’,2’-Dibenzyloxyethyl)-2-methyl-4,5-dihydro-1,2-
oxazolium tetrafluoroborate (15)
ꢀ
ꢀ
ꢀ
ꢀ
1 H, 2’-HA), 4.23 (dd, J1 ,2 B = 6.8, J2 A,2 B = 8.7 Hz,
1 H, 2’-HB), 4.32 – 4.40 (2 “ddd”, J4A,5A = J4B,5B = 11.1,
2
J4A,5B = J4B,5A = 9.4, J5A,5B = 8.0 Hz, 2 H, 5-H), 4.97
The General Procedure A was followed: Isoxazoline 5
(136 mg, 0.44 mmol), Me3OBF4 (71 mg, 0.48 mmol),
CH2Cl2 (abs., 5 ml). The resulting crude product, a color-
less oil, was treated as described for 14; isoxazolinium salt
15 (168 mg, 93%), analytically pure, colorless oil.
4
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(ddt, J4,1 = 0.8, J1 ,2 A = 6.0, J1 ,2 B = 6.8 Hz, 1 H, 1’-
H). – 13C NMR (125.8 MHz, CDCl3): δ = 25.5, 26.6 (2 q,
C(CH3)2), 34.4 (t, C-4), 67.5 (t, C-2’), 69.2 (t, C-5), 71.5
(d, C-1’), 110.7 (s, C(CH3)2), 158.6 (s, C-3). – C8H13NO3
(171.2): calcd. C 56.13, H 7.65, N 8.18; found C 56.01,
H 7.62, N 8.09.
[α]2D0 = 0.0 (c = 1.12, CH2Cl2) (reproducible value; prod-
ucts prepared from 15 again showed optical activity, vide in-
fra). – IR (Film): ν = 1681 (C=N), 1605 (w), 1455, 1365,
(1’S)-3-(1’,2’-Cyclohexylidenedioxyethyl)-4,5-dihydro-1,2-
oxazole (13)
1055, 927 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ =
5
ꢀꢀ
3.57 − 3.63 (m, 2 H, 4-H), 3.67 (t, J4,1 = 2.0 Hz, 3 H,
2
ꢀ
ꢀ
ꢀ
ꢀ
NCH3); 3.76 (dd, J1 ,2 A = 5.6, J2 A,2 B = 10.5 Hz, 2’-
a) 2,3-O-Cyclohexylidene-D-glyceraldoxime (11): Pre-
HA), 3.80 (dd, J1 ,2 B = 4.4, J2 A,2 B = 10.5 Hz, 2’-HB) – pared according to ref. [41] from 1,2:5,6-di-O-cyclohexyl-
2
ꢀ
ꢀ
ꢀ
ꢀ
2
sum 2 H; 4.47, 4.49 (A, B of AB, JA,B = 11.9 Hz, 2 H, idene-D-mannitol by periodate cleavage and oximation of
CH2C6H5); 4.60 (ddd, J4A,5A, J4B,5A
,
2J5A,5B = 7.6, 9.4, the aldehyde 10. – 36.5 mmol run, yield of colorless, oily
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
459
oxime 11, 11.8 g (87%, E/Z 65:35). – [α]2D0 = 55.0 (c = 1.35, (1’S)-3-(1’,2’-Cyclohexylidenedioxyethyl)-2-methyl-4,5-
CHCl3). – Spectroscopic data in agreement with literature dihydro-1,2-oxazolium tetrafluoroborate (17)
data [17f, 41].
The General Procedure A was followed; isoxazoline 13
(2.60 g, 12.3 mmol), Me3OBF4 (2.00 g, 13.5 mmol), CH2Cl2
(30 ml, abs.). The crude product was a brownish solid, which
on re-crystallization from ethanol gave analytically pure, col-
orless crystals of the isoxazolinium salt 17 (3.25 g, 84%). –
b) 2,3-O-Cyclohexylidene-D-glycerohydroximoyl chlo-
ride (12): As described above for 8, the oxime 11 (7.46 g,
40.3 mmol) in DMF (150 ml, abs.) with NCS (5.92 g,
44.3 mmol) and moist HCl vapor (20 ml) gave crude 12
(8.75 g, 96% yield corrected for impurities DMF (2.5%) and
ether (0.7%). The product was used without further purifica-
tion in the subsequent cycloaddition step.
c) Isoxazoline 13: Prepared in analogy to 9 as described
above. Hydroximoyl chloride 12 (8.71 g, content 96.8%,◦ca.
38.4 mmol), toluene (250 ml), ethylene saturation at 0 C,
triethylamine in toluene (42.2 ml of 1.00 M solution, addi-
tion time 47 h with rate 0.015 ml/min. The crude product
8.12 g of a yellow oil, was purified by chromatography (col-
umn 7 cm×20 cm, petrol ether/EtOAc 7:3) to afford analyt-
ically pure, colorless, crystalline 13 (7.56 g, 93%, 74% from
oxime 11).
◦
M. p. 105 – 106 C. – [α]2D0 = −12.9 (c = 0.96, CH2Cl2). –
IR (KBr): ν = 2939 (s), 2858 (m), 2361 (w), 1634 (w,
C=N+), 1450 (m), 1368 (m), 1335 (w), 1289 (m), 1237 (m),
1163 (s), 1057 (vs), 923 (s), 848 (w), 830 (w) cm−1. –
1H NMR (500.1 MHz, CDCl3): δ = 1.35 − 1.76 (m, 10 H,
C(CH2)5), 3.68 – 3.85 (m, 2 H, 4-H), 3.88 (t, 5J4,1 = 2.1 Hz,
ꢀꢀ
3 H, NCH3), 4.33 (dd, J1 ,2 A = 4.1, 2J2 A,2 B = 10.1 Hz, 1 H,
ꢀ
ꢀ
ꢀ
ꢀ
2
ꢀ
ꢀ
ꢀ
ꢀ
2’-HA), 4.42 (dd, J1 ,2 B = 6.9, J2 A,2 B = 10.1 Hz, 1 H,
ꢀ
ꢀ
2’-HB), 4.78 – 4.92 (m, 2 H, 5-H), 5.25 (dd, J1 ,2 A = 4.1,
J1 ,2 B = 6.9 Hz, 1 H, 1’-H). – 13C NMR (125.8 MHz,
CDCl3): δ = 23.6, 23.9, 24.8, 33.7, 35.6 (5 t, C(CH2)5), 36.6
(t, C-4), 39.4 (q, NCH3), 66.5 (t, C-2’), 69.5 (d, C-1’), 70.5 (t,
C-5), 113.4 (s, C(CH2)5), 166.7 (s, C-3). – C12H20BF4NO3
(313.1): calcd. C 46.03, H 6.44, N 4.47; found C 45.93,
H 6.44, N 4.45.
ꢀ
ꢀ
M. p. 45 ◦C. – [α]2D0 = −3.7 (c = 0.50, CH2Cl2); [α]2D0
=
−4.1 (c = 0.60, CH2Cl2) [2b]. – IR (KBr): ν = 2920,
2840, 1440 (C=N), 1150, 1090, 910, 850 cm−1. – 1H NMR
(500.1 MHz, CDCl3): δ = 1.40 − 1.64 (m, 10 H, C(CH2)5),
2.98 – 3.13 (m, 2 H, 4-H), 3.99 (dd, J1 ,2 A = 6.0, 2J2 A,2 B
=
=
(2S,3R)/(2S,3S)-3-Amino-1,2-O-cyclohexylidene-1,2,5-
pentanetriol (22/23; L-erythro/D-threo) from isoxazoline
13 by LiAlH4 reduction
ꢀ
ꢀ
ꢀ
ꢀ
2
ꢀ
ꢀ
ꢀ
ꢀ
8.6 Hz, 1 H, 2’-HA), 4.22 (dd, J1 ,2 B = 6.8, J2 A,2 B
8.6 Hz, 1 H, 2’-HB), 4.32 – 4.40 (m, 2 H, 5-H), 4.97 (dd,
J1 ,2 A = 6.0, J1 ,2 B = 6.8 Hz, 1 H, 1’-H). – 13C NMR
(125.8 MHz, CDCl3): δ = 23.8, 24.0, 25.0, 34.1, 34.6 (5 t,
C(CH2)5), 35.9 (t, C-4), 66.8 (t, C-2’), 68.8 (t, C-5), 70.7
(d, C-1’), 111.0 (s, C(CH2)5), 158.4 (s, C-3). – C11H17NO3
(211.3): calcd. C 62.54, H 8.11, N 6.63; found C 62.74,
H 8.11, N 6.62.
ꢀ
ꢀ
ꢀ
ꢀ
According to ref. [17a, 32] the isoxazoline 13 (100 mg,
0.47 mmol) in ether (5 ml, abs.) was added to a suspension of
LiAlH4 (37 mg, 0.95 mmol) in ether (5 ml, abs.) and stirred
under nitrogen at room temp. for 1.5 h. Hydrolysis was ef-
fected with water (0.04 ml). NaOH solution (0.03 ml, 20%),
and again water (0.13 ml) [42], then CH2Cl2 (10 ml) was
added and stirring was continued for 30 min. The aqueous
phase was extracted with CH2Cl2 (2×10 ml), the combined
organic solutes were dried (MgSO4) and rota-evaporated to
leave a colorless, somewhat impure hygroscopic oil of the
amino alcohols 22/23 (83 mg, “81%”, d. r. 44:56), which was
transformed to analytically pure Z-derivatives 24/25 (vide
infra).
(1’S)-3-(1’,2’-Isopropylidenedioxyethyl)-2-methyl-4,5-
dihydro-1,2-oxazolium tetrafluoroborate (16)
See General Procedure A: isoxazoline 9 (125 mg,
0.73 mmol), Me3OBF4 (119 mg, 0.80 mmol), CH2Cl2
(10 ml, abs.). The crude product, a brown oil (233 mg)
was triturated as above, to yield slightly impure (NMR;
cf. elemental analysis) 16 as a yellowish oil (148 mg,
[α]2D0 = 0.3 (c = 0.27, CH2Cl2). – IR (film): ν =
“86%”). – [α]2D0 = −7.8 (c = 0.90, MeOH). – IR (Film): 3357, 2934, 1592, 1106, 1066, 1041 cm−1. – 1H NMR
ν = 2992, 2944, 1635 (C=N), 1380, 1208, 1148, 1056, 928, (250.1 MHz, CDCl3, 22/23 = 44 : 56): 22 (erythro): δ =
837 cm−1. – 1H NMR (500.1 MHz, CD3OD): δ = 1.89, 2.87 (ddd, J = 9.1, 6.2, 4.1 Hz, 3-H), 3.63 (“dd”, J = 8,
1.98 (2 s, each 3 H, C(CH3)2); 4.14 – 4.42 (m, 4-H), 4.33 (t, 6.4 Hz, 1-Ha), other signals coinciding with those of major
5
ꢀꢀ
ꢀ
ꢀ
J4,1 = 1.9 Hz, NCH3) – sum 5 H; 4.73 (dd, J1 ,2 A = 4.7, isomer. – 23 (threo): δ = 1.30 − 1.78 (m, 4-H, C(CH2)5),
2
2
ꢀ
ꢀ
ꢀ
ꢀ
J2 A,2 B = 9.6 Hz, 1 H, 2’-HA), 4.91 (dd, J1 ,2 B = 7.3, 2.35 (sb, NH2, OH), 3.05 “ddd”, J = 10.1, 5.0, 3.4 Hz, 3-
J2 A,2 B = 9.6 Hz, 1 H, 2’-HB), 5.22 – 5.31 (m, 2 H, 5- H), 3.71 – 4.07 (m, 1-H, 2-H, 5-H). – 13C NMR (62.9 MHz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
H), 5.81 (dd, J1 ,2 A = 4.7, J1 ,2 B = 7.2 Hz, 1 H, 1’-H). – CDCl3, 22/23 = (44 : 56); 22 (erythro): δ = 34.5, 34.8, 36.0
13C NMR (125.8 MHz,): δ = 25.4, 26.6 (2 q, C(CH3)2), 38.6 (3 t, C-4, C(CH2)5), 54.5 (d, C-3), 60.6 (t, C-5), 66.0 (t, C-
(t, C-4), 40.4 (q, NCH3), 68.5 (t, C-2’), 72.1 (d, C-1’), 72.5 1), 79.4 (d, C-2), 109.4 (s, C(CH2)5); other signals overlap-
(t, C-5), 114.4 (s, C(CH3)2), 170.3 (s, C-3). – C9H16BF4NO3 ping with those of major isomer. 23 (threo): δ = 23.4, 23.7,
(273.0): calcd. C 39.59, H 5.91, N 5.13; found C 37.96, 24.8, 34.3, 34.5, 35.8 (6 t, C-4, C(CH2)5), 53.4 (d, C-3), 60.9
H 5.91, N 5.09.
(t, C-5), 64.7 (t, C-1), 78.8 (d, C-2), 109.3 (s, C(CH2)5). –
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

460
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
C11H21NO3 (215.3): calcd. C 61.37, H 9.83, N 6.51; found treated with NiCl2 · 6H2O (569 mg, 2.40 mmol) and NaBH4
◦
C 59.80, H 9.38, N 6.16.
(227 mg, 6.00 mmol; added in portions) at −30 C. The
solution immediately turned black; after 10 min methanol
was cautiously rota-evaporated. The residual mixture was
treated with conc. ammonia (36 ml) and CH2Cl2 (36 ml)
and stirred with air contact, until the organic phase had taken
a yellow-brown color. After separation of the layers, the
aqueous phase was extracted with CH2Cl2 (2 × 36 ml); the
combined organic solutes were dried (Na2SO4) and concen-
trated (15 Torr). The product, a brown-yellow oil (251 mg,
“97%”) consisted of a mixture of amino alcohols 22/23 (ery-
thro/threo= 35 : 65) and ca. 10% of unidentified impurities.
13C NMR data were in accordance with those of 22/23 given
above.
(+)-(2S,3R)- and (−)-(2S,3S)-3-Benzyloxylcarbonylamino-
1,2-O-cyclohexylidene-1,2,5-pentanet riol (24 and 25; D-
erythro and L-threo)
The mixture of erythro/threo-amino alcohols 22/23
(242 mg, 1.30 mmol; d. r. = 44 : 56) was dissolved in diox-
ane/water (10 ml, 7:3) and treated with benzyl chloroformate
(333 mg, 1.95 mmol), then NaHCO3 (218 mg, 2.60 mmol)
was added in portions. After stirring at room temp. for
1 d CH2Cl2 (50 ml) was added and the organic phase
was washed with water and bicarbonate solution (50 ml
of each) and dried (MgSO4). After rota-evaporation the re-
maining oil was separated by MPLC (column type B, eluent
CH2Cl2/MeOH 98:2; flow 20 ml/min at 13 bar).
b) N-Z-Amino alcohols 24 (L-erythro) and 25 (D-threo):
Preparation as above; amino alcohol mixture 22/23 (251 mg,
crude product obtained above), Z-Cl (200 mg, 1.17 mmol),
Et3N (118 mg, 1.17 mmol). MPLC separation afforded col-
orless, analytically pure samples of 24 (L-erythro; 101 mg,
25%) and 25 (D-threo; 187 mg, 46%). – L-erythro isomer
24: [α]2D0 = 43.0 (c = 0.345, CH2Cl2). – L-threo isomer 25:
[α]2D0 = −24.1 (c = 0.840, CH2Cl2). – C19H27NO (349.4):
calcd. C 65.31, H 7.79, N 4.01; found for 24: C 65.25, H 7.52,
N 3.88; found for 25: C 65.08, H 7.86, N 3.90. – Spectro-
scopic data in complete agreement with those reported above.
Erythro isomer 24: colorless oil, 112 mg, 25%, [α]D20
=
42.9 (c = 1.70, CH2Cl2). – IR (film): ν = 3335, 2936, 1699,
1506, 1252, 1096 cm−1. – H NMR (250.1 MHz, CDCl3):
1
δ = 1.40 − 1.91 (m, 12 H, 4-H, C(CH2)5), 3.23 (sb, 1 H,
OH), 3.56 – 3.60 (m, 2 H, 5-H), 3.68 (“dd”, 2J = 8.0, J1a,2
=
7.1 Hz, 1-Ha), 3.92 (m, 1 H, 3-H), 4.03 (“dd”, 2J = 8.0,
J1b,2 = 6.8, 1 H, 1-Hb), 4.17 (“ddd” as “dt”, J2,3 = 1.9 Hz,
1 H, 2-H), 5.06 (d, J3,NH = 9.9 Hz, NH), 5.06, 5.15 (A, B
of AB, 2J = 12.2 Hz, CO2CH2Ph), together 3 H, 7.26 – 7.45
(m, 5 H, C6H5). – 13C NMR (62.9 MHz, CDCl3): δ = 23.6,
23.9, 25.0, 35.9, 36.7 (5 t, C(CH2)5), 34.2 (t, C-4), 48.1 (d,
C-3), 58.4 (t, C-5), 66.1, 67.2 (t, C-2, CO2CH2Ph), 76.8 (d,
C-2), 109.9 (s, C(CH2)5), 128.0, 128.2, 128.6 (3 d; o-, m-,
p-C of C6H5), 136.1 (s, i-C of C6H5), 157.6 (s, CO2CH2Ph).
c) (+)-D-N-Benzyloxycarbonylhomoserinolactone 26:
The Z-aminotriol derivative 25 (115 mg, 0.33 mmol)
was dissolved in THF and treated with hydrochloric acid
(10%, 0.5 ml) for 5 h at room temp. Then NaIO4 (77 mg,
0.36 mmol) was added and the mixture continued stirring
for 1.5 d. After addition of saturated NaCl (20 ml), the
mixture was extracted with ether (3 × 20 ml), the organic
solutes were dried (MgSO4) and concentrated in vacuo.
The remainders were taken up in acetic acid (3 ml) and
CrO3 (36 mg, 0.36 mmol) was added in 3 portions within
3 h. After another 4.5 h, the volatiles were removed by
rota-evaporation and the remaining oil was filtered through
silica (7 g, column 2 cm × 3 cm) by means of EtOAc
(40 ml). The solvent was evaporated to give a yellow oil,
which was dried (10−2 Torr/KOH) and chromatographically
purified (MPLC, column type B, eluent petrol ether/EtOAc
1:1, 12 bar, flow rate 40 ml/min). The Z-aminolactone 26
was obtained as an analytically pure, colorless solid (11 mg,
14%).
Threo isomer 25: colorless oil, 173 mg, 38%, [α]D20
=
−24.0 (c = 1.50, CH2Cl2). – IR (film): ν = 3328, 2936,
1695, 1537, 1252, 1100, 1070, 1042 cm−1. – 1H NMR
(250.1 MHz, CDCl3): δ = 1.22 − 1.61 (m, 11 H, 4-Ha,
C(CH2)5), 1.83 – 1.97 (m, 1 H, 4-Hb), 3.10 (very br, 1 H,
OH), 3.68 (m, 2 H, 5-H), 3.79 (“dd”, 2J = 8.6, J1a,2 = 5.6 Hz,
1 H, 1-Ha), 3.89 (m, 1 H, 3-H), 4.03 (“dd”, 2J = 8.6, J1b,2
=
6.7 Hz, 1 H, 1-Hb), 4.14 (“ddd” als “q”, J2,3 = 5.3 Hz, 1 H, 2-
H), 5.10 (s, 2 H, CO2CH2Ph), 5.19 (d, J3,NH = 9.0 Hz, 1 H,
NH), 7.26 – 7.43 (m, 5 H, C6H5). – 13C NMR (62.9 MHz,
CDCl3): δ = 23.7, 23.9, 25.0, 34.4, 35.9 (5 t, C(CH2)5),
33.1 (t, C-4), 50.6 (d, C-3), 58.7 (t, C-5), 66.1, 67.1 (t, C-1,
CO2CH2Ph), 77.1 (d, C-2), 110.3 (s, C(CH2)5), 128.1, 128.2,
128.5 (3 d; o-, m-, p-C of C6H5), 136.2 (s, Cipso), 157.1 (s,
CO2CH2Ph). – C19H27NO5 (349.4): calcd. C 65.31, H 7.79,
N 4.01; found for 24 (erythro) C 64.85, H 7.85, N 3.99; found
for 25 (threo) C 65.16, H 7.88, N 4.08.
M. p. 126 – 128 ◦C; m. p. [17f] 121 – 122 ◦C. – [α]2D0 = 3.5
(c = 0.90, CHCl3); [α]D20 = 1.11(c = 2.00, CHCl3) [17f]. –
IR (CCl4): 3240, 1732, 1499, 1172, 1063, 1019 cm−1. –
1H NMR (250.1 MHz, CDCl3): δ = 2.21 (“ddt”, 2J = 24.0,
3J = 11.6, 3J = 8.9 Hz, 1 H, 3-Ha), 2.79 (m, 1 H, 3-Hb), 4.25
(ddd, 3J = 11.2, 3J = 9.3, 3J = 5.8 Hz, 1 H, 2-H), 4.35 – 4.50
D-(+)Homoserinolactone hydrobromide 27
a) Amino alcohols 22/23 from isoxazoline 13 by reduction (m, 2 H, 4-H), 5.13 (“s”, 2 H, CO2CH2Ph), 5.34 (bs, 1 H,
with NaBH4/NiCl2 · 6H2O: In analogy to ref. [35] the isox- NH), 7.30 – 7.39 (m, 5 H, C6H5). – 13C NMR (62.9 MHz,
azoline 13 (253 mg, 1.20 mmol) in methanol (36 ml) was CDCl3): δ = 30.4 (t, C-3), 50.5 (d, C-2), 65.8, 67.3 (2 t, C-4,
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
461
CO2CH2Ph), 128.2, 128.3, 128.6 (3 d, o-, m-, p-C of C6H5), oils of 28 (erythro; 221 mg, 53%) and 29 (50 mg, 12%) were
135.8 (s, i-C of C6H5), 156.0 (s, NCO2CH2Ph), 174.9 (s, obtained.
Erythro isomer 28: [α]2D0 = 70.2 (c = 0.465, CH2Cl2). –
C-1). – C12H13NO (235.2): calcd. C 61.27, H 5.57, N 5.95;
found C 61.41, H 5.69, N 5.67.
IR (Film): ν = 3419 (OH), 2876, 1454, 1067, 740 cm−1. –
1H NMR (500.1 MHz, CDCl3): δ = 2.17 (“dddd”, J3,4A
=
d) D-Homoserinolactone hydrobromide (27·HBr): Z-
Protected homoserinolactone 26 {73 mg, 0.33 mmol; sam-
ple with [α]2D0 = +1.11 (c = 2.00 in CHCl3), m. p. 121 –
122 ◦C, analytically pure} was treated with HBr/glacial
acetic acid (0.5 ml), causing immediate gas evolution. Af-
ter 6 ◦h ether (5 ml) was added, the mixture was cooled to
2
3.8, J4A,4B = 12.6, J4A,5A = 8.7, J4A,5B = 6.1 Hz, 1 H,
2
4-HA), 2.42 (ddt, J3,4B = J4B,5B = 8.7, J4A,4B = 12.6,
J4B,5A = 6.1 Hz, 1 H, 4-HB), 2.66 (s, 3 H, NCH3), 3.12 (dt,
ꢀ
J3,4A = 3.7, J3,4B = J3,1 = 7.9 Hz, 1 H, 3-H), 3.31 (ddd,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J3,1 = 7.5, J1 ,2 A = 6.1, J1 ,2 B = 3.3 Hz, 1 H, 1’-H), 3.75
2
ꢀ
ꢀ
ꢀ
ꢀ
−20 C and the precipitate (hydrobromide) filtered off. Af- (dd, J1 ,2 A = 6.2, J2 A,2 B = 11.6 Hz, 1 H, 2’-HA); 3.82
(dt, J4A,5A =2 J5A,5B = 8.4, J4B,5A = 6.1 Hz, 5-HA), 3.86
ter washing with ice-cold ether and drying in vacuo (P2O5,
2
10−3 Torr), pale-orange crystals of 27·HBr (43 mg, 72%)
ꢀ
ꢀ
ꢀ
ꢀ
(dd, J1 ,2 B = 3.3, J2 A,2 B = 11.6 Hz, 2’-HB) – sum 2 H;
◦
◦
2
were isolated. – M. p. 241 C, m. p. [43] 242 – 244 C. – 4.01 (ddd, J4A,5B = 6.1, J4B,5B = 9.0, J5A,5B = 8.1 Hz,
2
[α]2D7 = 19.5 (c = 1.02, H2O); [α]2D7 (lit. [43] = 21 (c = 1.0,
1 H, 5-HB), 4.54, 4.67 (A, B of AB, JAB = 11.6 Hz,
2 H, CH2C6H5), 7.28 – 7.37 (m, 5 H, C6H5). – 13C NMR
H2O). – IR (KBr): 2990 (b), 2870 (b), 1775 (C=O), 1210,
1022 cm−1. – H NMR (400.1 MHz, D2O; mixture of lac- (125.8 MHz, CDCl3): δ = 31.4 (t, C-4), 45.2 (q, NCH3),
1
63.0 (t, C-2’), 65.3 (t, C-5), 70.4 (d, C-3), 72.5 (t, CH2C6H5),
79.0 (d, C-1’), 128.3, 128.4, 128.9 (3 d, o-, m-, p-C of C6H5),
tone and hydroxy amino acid ca. 75:25, insufficient res-
olution); lactone 27·HBr: δ = 2.27, 2.63 (m, 2 H, 3-H),
4.29, 4.46 (m, 2 H, 4-H), 4.5 (s, b; OH, NH, 3-H). – Acid: 138.3 (s, i-C of C6H5).
Threo isomer 29: [α]2D0 = −56.9 (c = 0.45, CH2Cl2). –
δ = 1.9 − 2.1 (m, 2 H, 3-H), 3.61, 3.95 (m, 2 H, 4-H). –
13C NMR (100.6 MHz, D2O, d6-acetone; 75:25 mixture);
lactone 27·HBr: δ = 26.9 (C-3), 48.8 (C-2), 67.6 (C-4); acid:
δ = 32.0 (C-3), 52.2 (C-2), 58.4 (C-4); C=O not identified. –
C4H9BrNO2 (182.0): calcd. C 26.40, H 4.43, N 7.70; found
C 25.78, H 4.21, N 7.48.
IR (Film): ν = 3408 (OH), 2876, 1454, 1060 (vs),
740 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 2.15
2
(“ddt”, J3,4A = J4A,5B = 6.2, J4A,4B = 12.5, J4A,5A
=
8.4 Hz, 1 H, 4-HA), 2.36 (ddt, J3,4B = J4B,5B = 8.4,
2J4A,4B = 12.5, J4B,5A = 5.7 Hz, 1 H, 4-HB), 2.72 (s, 3 H,
ꢀ
NCH3), 3.13 (dt, J3,4A = J3,1 = 6.2, J3,4B = 8.4 Hz, 1 H,
General Procedure B, reduction of isoxazolinium salts (pre-
pared from isoxazolines) with NaBH4 to yield isoxazolidines;
two-step/one-pot procedure
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3-H); 3.58 (“ddd”, J3,1 = 6.5, J1 ,2 A = 4.4, J1 ,2 B = 5.2 Hz,
1’-H), 3.61 (dd, J1 ,2 A = 4.4, 2J2 A,2 B = 11.7 Hz, 2’-HA) –
ꢀ
ꢀ
ꢀ
ꢀ
2
sum 2 H; 3.80 – 3.84 (m, 1 H, 2’-HB), 3.88 (dt, J4A,5A
=
J5A,5B = 8.3, J4B,5A = 5.7 Hz, 1 H, 5-HA), 4.00 (dt, J4A,5B
=
To a solution of the isoxazoline (1 – 10 mmol) in abs.
CH2Cl2 (5 – 30 ml) at room temp. Me3OBF4 (1.1 eq) was
added; after stirring overnight the solvent was removed
(15 Torr), the remainders are dissolved in abs. ethanol and
treated with 2 eq of NaBH4 with stirring overnight. For
work-up the mixture was hydrolyzed with 5% aqueous citric
acid and water. After removal of ethanol (rota-evaporation at
15 Torr) the mixture was extracted with EtOAc (4×20 ml),
the solutes were partitioned against sat. NaCl (30 ml) and
dried (MgSO4). For further product purification see individ-
ual compounds.
2
6.4, J4B,5B
= J5A,5B = 8.2 Hz, 1 H, 5-HB), 4.65, 4.69
2
(A, B of AB, JAB = 11.6 Hz, 2 H, CH2C6H5), 7.28 –
7.39 (m, 5 H, C6H5). The OH signal was not identified. –
13C NMR (125.8 MHz, CDCl3): δ = 31.0 (t, C-4), 45.4 (q,
NCH3), 61.8 (t, C-2’), 65.3 (t, C-5), 69.0 (d, C-3), 72.5 (t,
CH2C6H5), 79.4 (d, C-1’), 127.8, 127.9, 128.5 (3 d, o-, m-,
p-C of C6H5), 138.2 (s, i-C of C6H5). – C13H19NO3 (237.3):
calcd. C 68.50, H 8.07, N 5.90; found for erythro isomer 28
C 65.05, H 8.04, N 5.81; found for threo isomer 29 C 64.95,
H 8.07, N 5.79.
Reduction of 14 (prepared from 4, 0.74 mmol as above)
◦
(3R,1’R)/(3S,1’R)-3-(1’-Benzyloxy-2’-hydroxyethyl)-2-me-
thyltetrahydro-1,2-oxazole (28, erythro and 29, threo)
with NaBH(OAc)3 (2.2 mmol) as described for 17 at 0 C
gave a 83:17 mixture of 28/29. – [α]2D0 = 45.5 (c = 1.12,
CH2Cl2). – Found: C 65.43, H 8.12, N 5.88.
General Procedure B; isoxazoline 4 (420 mg, 1.90 mmol),
CH2Cl2 (5 ml, abs.), Me3OBF4 (308 mg, 2.08 mmol); isox-
azolinium salt 14 dissolved in ethanol (5 m◦l), reduction with
NaBH4 (143 mg, 3.78 mmol), 3 h at 0 C, 3 h at room
temp. Work-up gave a colorless oil of 28/29 (79:21 from
(3R,1’R)- and (3S,1’R)-3-(1’,2’-Dibenzyloxyethyl)-2-methyl-
tetrahydro-1,2-oxazole (30, erythro and 31, threo)
General Procedures A and B were followed. – Isoxazoline
HPLC and NMR), which was filtered through silica (col- 5 (264 mg, 0.85 mmol), Me3OBF4 (138 mg, 0.93 mmol),
umn 2 cm × 12 cm, petrol ether/EtOAc 3:7) and separated CH2Cl2 (5 ml, abs.); reduction with NaBH4 (64 mg,
by MPLC (column type C, petrol ether/EtOAc 1:9). After re- 1.69 mmol) in EtOH (8 ml, abs.). TLC analysis showed the
moval of the solvent (10−3 Torr) analytically pure, colorless reduction to be complete after 2 h; work-up then gave a
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

462
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
yellowish oil (286 mg, d. r. 72:28). The mixture was filtered then reduced according to General Procedure B. Isoxazo-
through silica (column 2 cm ×8 cm, petrol ether/EtOAc 8:2) line 13 (1.46 g, 6.91 mmol), Me3OBF4 (1.12 g, 7.57 mmol),
and the resulting colorless oil (172 mg) was separated by CH2Cl2 (30 ml, abs.); then reduction with NaBH4 (523 mg,
MPLC (column type C, petrol ether/EtOAc 1:1). After sol- 13.8 mmol) in EtOH (60 ml, abs.); yellow oil of 32/33
vent removal (10−3 Torr) colorless, analytically pure com- (1.46 g, d. r. 81:19). Purification: The crude product was fil-
pounds 30 (erythro, oil, 122 mg, 44%) and 31 (threo, oil, tered through silica (column 2 cm × 17 cm, solvent petrol
45 mg, 16%) were obtained.
ether/EtOAc 1:1), affording 1.45 g of a slightly yellow oil af-
ter solvent removal. MPLC separation (column type C, elu-
ent petrol ether/EtOAc 1:1) gave the erythro isoxazolidine 32
(1.07 g, 68%) and the threo isomer 33 (256 mg, 16%), both
as colorless, analytically pure oils.
Erythro isomer 30: [α]2D0 = 42.6 (c = 0.55, CH2Cl2). –
IR (film): ν = 2954, 2868, 1454, 1097, 1062, 1028,
737 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 2.25
(“dddd”, J3,4A = 4.7, 2J4A,4B = 12.4, J4A,5A = 8.5, J4A,5B
=
Erythro isomer 32: [α]2D0 = −31.9 (c = 0.73, CH2Cl2). –
IR (Film): ν = 2936, 2861, 1163, 1101, 1038, 927 cm−1. –
1H NMR (500.1 MHz, CDCl3): δ = 1.35 − 1.65 (m,
10 H, C(CH2)5), 2.30 (“dddd”, J3,4A = 3.6, 2J4A,4B = 12.6,
J4A,5A = 8.7, J4A,5B = 6.2 Hz, 1 H, 4-HA), 2.44 (dddd,
6.3 Hz, 1 H, 4-HA), 2.33 (ddt, J3,4B = J4B,5B = 8.5,
2J4A,4B = 12.4, J4B,5A = 6.0 Hz, 1 H, 4-HB), 2.60 (s,
ꢀ
3 H, NCH3), 3.09 (ddd, J3,4A = 4.7, J3,4B = 8.3, J3,1
=
ꢀ
ꢀ
ꢀ
6.8 Hz, 1 H, 3-H), 3.48 (ddd, J3,1 = 6.8, J1 ,2 A = 4.9,
ꢀ
ꢀ
ꢀ
ꢀ
J1 ,2 B = 3.4 Hz, 1 H, 1’-H), 3.66 (dd, J1 ,2 A = 4.9,
2
2
ꢀ
ꢀ
ꢀ
ꢀ
J2 A,2 B = 10.4 Hz, 1 H, 2’-HA); 3.73 (dd, J1 ,2 B = 3.4,
J3,4B = 8.1, J4A,4B = 12.6, J4B,5A = 6.0, J4B,5B = 8.9 Hz,
1 H, 4-HB), 2.63 (s, 3 H, NCH3), 2.94 (dt, J3,4A = 3.6,
J2 A,2 B = 10.4 Hz, 2’-HB), 3.76 (dt, J4A,5A =2 J5A,5B = 8.3,
2
ꢀ
ꢀ
J4B,5A = 6.1 Hz, 5-HA) – sum 2 H; 3.96 (dt, J4A,5B = 6.2,
ꢀ
ꢀ
ꢀ
J3,4B = J3,1 = 8.2 Hz, 1 H, 3-H), 3.83 (dd, J1 ,2 A = 5.3,
J4B,5B =2J5A,5B = 8.3 Hz, 1 H, 5-HB), 4.53, 4.56 (A, B of
2
ꢀ
ꢀ
J2 A,2 B = 8.4 Hz, 1 H, 2’-HA); 3.90 (“ddd”, J4A,5A = 8.7,
2
J4B,5A = 6.0, 2J5A,5B = 8.0 Hz, 5-HA), 3.94 (ddd, J3,1 = 8.2,
AB, JAB = 12.1 Hz, 2 H, CH2C6H5), 4.59, 4.73 (A, B of
ꢀ
AB, 2JAB = 11.7 Hz, 2 H, CH2C6H5), 7.22 – 7.37 (m, 10 H,
2 C6H5). – 13C NMR (125.8 MHz, CDCl3): δ = 30.6 (t, C-
4), 44.8 (q, NCH3), 65.0 (t, C-5), 67.7 (d, C-3), 70.1 (t, C-2’),
72.5, 73.3 (2 t, 2 CH2C6H5), 78.8 (d, C-1’), 127.5, 127.6,
127.9, 128.1, 128.28, 128.32 (6 d, o-, m-, p-C of 2 C6H5),
138.3, 138.5 (2 s, i-C of 2 C6H5).
ꢀ
ꢀ
ꢀ
ꢀ
J1 ,2 A = 5.3, J1 ,2 B = 6.1 Hz, 1’-H) – sum 2 H; 4.04 (ddd,
2
J4A,5B = 6.2, J4B,5B = 9.0, J5A,5B = 8.0 Hz, 1 H, 5-HB),
2
ꢀ
ꢀ
ꢀ
ꢀ
4.10 (dd, J1 ,2 B = 6.1, J2 A,2 B = 8.4 Hz, 1 H, 2’-HB). –
13C NMR (125.8 MHz, CDCl3): δ = 23.8, 24.0, 25.2, 34.8,
36.7 (5 t, C(CH2)5), 30.7 (t, C-4), 44.8 (q, NCH3), 64.9 (t,
C-5), 67.7 (t, C-2’), 69.5 (d, C-3), 76.4 (d, C-1’), 109.8 (s,
C(CH2)5).
Threo isomer 31: [α]2D0 = −29.4 (c = 0.38, CH2Cl2). –
IR (film): ν = 2956, 2866, 1454, 1097, 1058, 1028,
737 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 2.00
(ddt, J3,4A = J4A,5B = 6.7, 2J4A,4B = 12.2, J4A,5A = 8.3 Hz,
1 H, 4-HA), 2.30 (ddt, J3,4B = J4B,5B = 8.2, 2J4A,4B = 12.2,
Threo isomer 33: [α]2D0 = 82.2 (c = 0.81, CH2Cl2). –
IR (Film): ν = 2935, 2861, 1163, 1105, 1041, 928 cm−1. –
1H NMR (500.1 MHz, CDCl3): δ = 1.39 − 1.66 (m,
10 H, C(CH2)5), 1.89 (“dddd”, J3,4A = 6.5, 2J4A,4B = 12.3,
J4B,5A = 5.5 Hz, 1 H, 4-HB), 2.74 (s, 3 H, NCH3), 2.98 – 3.03
J4A,5A = 8.7, J4A,5B = 5.8 Hz, 1 H, 4-HA), 2.33 (ddt, J3,4B
8.6, J4A,4B = 12.3, J4B,5A = 6.0, J4B,5B = 8.6 Hz, 1 H, 4-
=
2
2
ꢀ
ꢀ
ꢀ
ꢀ
(m, 1 H, 3-H), 3.56 (dd, J1 ,2 A = 5.0, J2 A,2 B = 10.1 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1 H, 2’-HA), 3.60 (ddd, J3,1 = 7.3, J1 ,2 A = 5.0, J1 ,2 B
=
=
HB), 2.78 (s, 3 H, NCH3), 2.80 – 2.85 (m, 1 H, 3-H), 3.66 (dd,
2
J1 ,2 A = 6.8, 2J2 A,2 B = 8.3 Hz, 1 H, 2’-HA), 3.83 (“dddd”,
ꢀ
ꢀ
ꢀ
ꢀ
3.3 Hz, 1 H, 1’-H), 3.68 (dd, J1 ,2 B = 3.3, J2 A,2 B
10.1 Hz, 1 H, 2’-HB), 3.82 (dt, J4A,5A
ꢀ
ꢀ
ꢀ
ꢀ
2
4J3,5A = 0.5, J4A,5A = 8.7, J4B,5A = 6.0, J5A,5B = 8.2 Hz,
2
= J5A,5B = 8.2,
1 H, 5-HA), 3.96 (ddd, J4A,5B = 5.8, J4B,5B = 8.6, 2J5A,5B
=
J4B,5A = 5.4 Hz, 1 H, 5-HA), 3.94 (dt, J4A,5B = 6.6, J4B,5B
=
2J5A,5B = 8.0 Hz, 1 H, 5-HB), 4.51, 4.57 (A, B of AB,
2JAB = 12.1 Hz, 2 H, CH2C6H5), 4.67, 4.74 (A, B of AB,
2JAB = 11.6 Hz, 2 H, CH2C6H5), 7.25 – 7.37 (m, 10 H,
2 C6H5). – 13C NMR (125.8 MHz, CDCl3): δ = 32.4 (t, C-
4), 46.1 (q, NCH3), 64.9 (t, C-5), 68.5 (d, C-3), 70.6 (t, C-2’),
72.9, 73.5 (2 t, 2 CH2C6H5), 80.7 (d, C-1’), 127.5, 127.7,
127.9, 128.3, 128.4 (5 d, o-, m-, p-C of 2 C6H5) 138.1, 138.6
(2 s, i-C of 2 C6H5). – C20H25NO3 (327.4): calcd. C 73.37,
H 7.70, N 4.28; found for 30: C 73.17, H 7.75, N 4.24; found
for 31: C 73.25, H 7.78, N 4.29.
8.2 Hz, 1 H, 5-HB), 4.04 (dd, J1 ,2 B = 6.4, 2J2 A,2 B = 8.3 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1 H, 2’-HB), 4.13 (ddd, J3,1 = 7.7, J1 ,2 A = 6.8, J1 ,2 B
=
6.4 Hz, 1 H, 1’-H). – 13C NMR (125.8 MHz, CDCl3):
δ = 23.8, 24.0, 25.1, 34.8, 36.4 (5 t, C(CH2)5), 31.6 (t, C-
4), 45.1 (q, NCH3), 64.9 (t, C-5), 66.5 (t, C-2’), 69.7 (d, C-
3), 76.8 (d, C-1’), 110.3 (s, C(CH2)5). – C12H21NO3 (227.3):
calcd. C 63.41, H 9.31, N 6.16; found for 32: C 63.51, H 9.38,
N 6.14; found for 33 C 63.49, H 9.33, N 6.08.
Isoxazolidines 32 (erythro) and 33 (threo) from 17 by sodium
triacetoxyborohydride reduction
(3S,1’S)- and (3R,1’S)-3-(1’,2’-Cyclohexylidenedioxyethyl)-
2-methyltetrahydro-1,2-oxazole (32, erythro and 33, threo)
A solution of the isoxazolinium salt 17 (295 mg,
◦
Starting with the isoxazoline 13, the isoxazolinium salt 0.94 mmol) in THF (5 ml, abs.) was added at −78 C to a
17 was prepared according to General Procedure A and suspension of NaBH(OAc)3 (420 mg, ca. 1.88 mmol) in THF
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
463
(10 ml, abs.). TLC analysis showed complete consumption of celite, the cake was rinsed with methanol, and the combined
17 after ca. 1 min. For work-up hydrolysis was effected by solutions were put to dryness (10−3 Torr). Thus, a colorless,
addition of aqueous citric acid (5%, 5 ml) and water (20 ml). analytically pure oil of 35 (176 mg, 95%) was obtained. –
The mixture was extracted with EtOAc (4 × 20 ml); the so- [α]2D0 − 30.4 (c = 1.30, CH2Cl2). – IR (film): ν = 3316 (b;
lution then was washed with aqueous NaHCO3 (saturated, NH, OH), 2935, 2861, 1449, 1366, 1103, 1039, 936 cm−1. –
20 ml) and dried (MgSO4). After rota-evaporation a slightly 1H NMR (250.1 MHz, CDCl3): δ = 1.41 − 1.63 (m, 10 H,
yellow oil resulted, consisting of a 95:5 mixture of diastere- C(CH2)5), 1.65 - 1.74 (m, 2 H, 4-H), 2.47 (s, 3 H, NHCH3),
omers 32/33. The product was purified on silica (column 2.66 - 2.74 (m, 1 H, 3-H), 3.13 (sb, 2 H, OH, NHCH3), 3.73
2
2 cm × 15 cm, eluent petrol ether/EtOAc 1:1) and the sol- (dd, J1A,1B = 8.3, J1A,2 = 6.3 Hz, 1 H, 1-HA), 3.79 – 3.86
vent was removed in vacuo (10−3 Torr) to leave 32/33 as an (m, 2 H, 5-H), 4.07 (dd, 2J1A,1B = 8.3, J1B,2 = 6.7 Hz, 1 H, 1-
analytically pure oil (184 mg, 86%), with spectroscopic data HB), 4.26 (dt, J1A,2 = J1B,2 = 6.5, J2,3 = 4.7 Hz, 1 H, 2-H). –
in full agreement with those described above. – Data of 32/33 13C NMR (62.9 MHz, CDCl3): δ = 23.8, 24.0, 25.1, 34.4,
mixture (95:5 from 13C NMR): [α]D20 = −25.9 (c = 1.08, 36.0 (5 t, C(CH2)5), 30.5 (t, C-4), 33.9 (q, NHCH3), 62.5
CH2Cl2). – C12H21NO3 (227.3): calcd. C 63.41, H 9.31, (d, C-3), 62.6 (t, C-5), 66.2 (t, C-1), 75.4 (d, C-2), 109.6 (s,
N 6.16, found C 63.42, H 9.37, N 6.15.
C(CH2)5). – C12H23NO3 (229.3): calcd. C 62.85, H 10.11,
N 6.11; found C 62.80, H 10.11, N 6.04.
(3S,1’S)- 3-(1’,2’-Cyclohexylidenedioxyethyl)-2,2-dimethyl-
tetrahydro-1,2-oxazolium-tetrafluoroborate (34)
(2S,3R)-1,2-O-Cyclohexylidene-3-methylamino-1,2,5-
pentanetriol (36; threo)
To a solution of the isoxazolidine 32 (124 mg, 0.55 mmol)
in abs. CH2Cl2 (5 ml) at room temp. Me3OBF4 (89 mg,
0.60 mmol) was added and the mixture was stirred for 16 h.
After removal of the solvent (15 Torr) a colorless solid
(187 mg) remained, which was recrystallized from ethanol
to afford colorless, analytically pure 34 (152 mg, 85%; m. p.
Following the Typical Procedure given above, the threo
isoxazolidine 33 (122 mg, 0.54 mmol) was hydrogenated
using Pd/C (10%, 50 mg) in methanol (5 ml) for 1 d at
3 bar. Work-up gave the amino alcohol 36 (121 mg, 98%),
an analytically pure, colorless oil. – [α]2D0 = 12.8 (c = 1.46,
CH2Cl2). – IR (film): ν = 3321 (br; NH, OH), 2935, 2860,
1448, 1366, 1163, 1104, 1039, 933 cm−1. – 1H NMR
(250.1 MHz, CDCl3): δ = 1.40 − 1.78 (m, 12 H, 4-H,
◦
170 – 171 C). Another recrystallization from ethanol fur-
nished crystals of 34 (m. p. 172 ◦C) suitable for crystal struc-
ture analysis [33].
[α]2D0 = −29.4 (c = 0.81, CH2Cl2). – IR (KBr): ν =
C(CH2)5), 2.49 (s, 3 H, NHCH3), 2.73 (ddd, J2,3 = 8.3, J3,4A
,
2935, 1468, 1112, 1068 cm−1. – 1H NMR (500.1 MHz,
J3,4B = 3.6, 7.1 Hz, 1 H, 3-H), 3.52 (sb, 2 H, OH, NHCH3),
3.62 (dd, 2J1A,1B = 8.1, J1A,2 = 7.0 Hz, 1 H, 1-HA), 3.72 –
3.90 (m, 2 H, 5-H), 4.04 (dd, 2J1A,1B = 8.1, J1B,2 = 6.2 Hz,
1 H, 1-HB), 4.21 (ddd, J1A,2 = 7.0, J1B,2 = 6.2, J2,3 = 8.3 Hz,
1 H, 2-H). [Due to incomplete resolution not all couplings
were identified]. – 13C NMR (62.9 MHz, CDCl3): δ = 23.8,
24.0, 25.1, 35.0, 36.5 (5 t, C(CH2)5), 29.4 (t, C-4), 33.1 (q,
NHCH3), 61.8 (t, C-5), 62.7 (d, C-3), 66.8 (t, C-1), 76.5
(d, C-2), 109.9 (s, C(CH2)5). – C12H23NO3 (229.3): calcd.
C 62.85, H 10.11, N 6.11; found C 62.82, H 10.07, N 5.99.
2
CD3OD): δ = 2.69 (ddt, J3,4A = J4A,5A = 7.5, J4A,4B
=
=
13.1, J4A,5B = 4.0 Hz, 1 H, 4-HA), 2.77 (ddt, J3,4B
J4B,5B = 8.6, J4A,4B = 13.1, J4B,5A = 9.9 Hz, 1 H, 4-HB),
2
ꢀ
ꢀ
3.40, 3.52 (2 s, 3 H each, N(CH3)2), 3.68 (dd, J1 ,2 A = 6.4,
2
ꢀ
ꢀ
ꢀ
ꢀ
J2 A,2 B = 9.1 Hz, 1 H, 2’-HA); 4.23 (dd, J1 ,2 B = 7.3,
J2 A,2 B = 9.1 Hz, 2’-HB), 4.24 (ddd, J3,4A = 7.4, J3,4B
2
ꢀ
ꢀ
=
ꢀ
8.7, J3,1 = 1.3 Hz, 3-H) – sum 2 H; 4.39 – 4.43 (m, 5-HA),
2
4.45 (ddd, J4A,5B = 4.0, J4B,5B = 8.8, J5A,5B = 7.6 Hz,
ꢀ
ꢀ
ꢀ
5-HB) – sum 2 H; 4.70 (“ddd”, J3,1 = 1.3, J1 ,2 A = 6.3,
J1 ,2 B = 7.4 Hz, 1 H, 1’-H). – 13C NMR (125.8 MHz,
CD3OD): δ = 25.4, 25.6, 26.7, 35.7, 37.0 (5 t, C(CH2)5),
27.7 (t, C-4), 52.6, 56.4 (2 q, N(CH3)2), 68.5 (t, C-2’), 71.7
(d, C-1’), 72.1 (t, C-5), 80.7 (d, C-3), 114.0 (s, C(CH2)5). –
C13H24BF4NO3 (329.1): calcd. C 47.44, H 7.35, N 4.26;
found C 47.47, H 7.33, N 4.18.
ꢀ
ꢀ
(2S,3S)-3-(N-Benzyloxycarbonyl-N-methylamino)-1,2-O-
cyclohexylidene-1,2,5-pentanetriol (N-Z-35)
To a solution of the amino alcohol 35 ◦(erythro; 378 mg,
1.65 mmol) in abs. CH2Cl2 (15 ml) at 0 C benzyl chloro-
formate (326 mg, 1.82 mmol) in abs. CH2Cl2 (2 ml) was
added, followed by triethylamine (183 mg, 1.81 mmol) in
abs. CH2Cl2 (2 ml). The mixture was allowed to warm
to room temp.; after 2 h water (50 ml) was added and
the mixture was extracted with CH2Cl2 (4 × 20 ml). The
(2S,3S)-1,2-O-Cyclohexylidene-3-methylamino-1,2,5-penta-
netriol (35, erythro) by catalytic hydrogenation of the isoxa-
zolidine 32; Typical Procedure
Under nitrogen, to a solution of the isoxazolidine 32 organic layer was washed with saturated NaCl solution
(186 mg, 0.82 mmol) in methanol (5 ml) palladium on car- (20 ml), dried (MgSO4), and evaporated. The resulting col-
bon (10%, 60 mg) was added and the mixture hydrogenated orless oil (669 mg) was purified on silica (column 3 cm ×
(3 bar) for 3 d at room temp. The mixture was filtered through 18 cm, eluent petrol ether/EtOAc 1:1); after solvent removal
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

464
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
(10−3 Torr) colorless, analytically pure N-Z-35 (553 mg,
92%) was isolated.
1H NMR (500.1 MHz, CD3OD): δ = 1.41 − 1.72 (m,
10 H, C(CH2)5), 2.48 – 2.54 (m, 2 H, 2-H), 2.75 (s, 3 H,
NCH3), 3.44 – 3.48 (m, 1 H, 3-H), 3.82 (dd, J4,5A = 5.8,
2J5A,5B = 9.1 Hz, 1 H, 5-HA), 4.13 (dd, J4,5B = 7.0,
[α]2D0 = −15.8 (c = 0.66, CH2Cl2). – IR (film): ν = 3464
(OH), 2936, 1697 (NC=O), 1450, 1403, 1331, 1283, 1160,
1
1100, 1044 cm−1. – H NMR (250.1 MHz, CD3OD), mix-
2J5A,5B = 9.1 Hz, 1 H, 5-HB), 4.50 (ddd, J3,4 = 3.2, J4,5A
=
5.8, J4,5B = 7.0 Hz, 1 H, 4-H). – 13C NMR (62.9 MHz,
CD3OD): δ = 26.2, 26.4, 27.6, 36.4, 38.1 (5 t, C(CH2)5),
32.6 (q, NCH3), 34.1 (t, C-2), 61.1 (d, C-3), 67.8 (t, C-5),
75.4 (d, C-4), 113.5 (s, C(CH2)5), 179.1 (s, C-1).
ture of rotamers (59:41): δ = 1.28 − 1.63 (C(CH2)5), 1.78 –
2.04 (4-H), 2.82 (NCH3, minor rotamer), 2.86 (NCH3, ma-
jor rotamer), 3.40 – 4.28 (1-H, 2-H, 3-H, 5-H), 5.05 – 5.19
(CO2CH2Ph), 7.26 – 7.39 (C6H5). – 13C NMR (62.9 MHz,
CD3OD) mixture of rotamers (59:41). Major rotamer: δ =
26.3, 26.5, 27.7, 37.3, 38.86 (5 t, C(CH2)5), 31.9 (q,
NHCH3), 33.1 (t, C-4), 58.4 (d, C-3), 61.3 (t, C-5), 69.4, 69.9
(2 t, C-1, CH2C6H5), 79.41 (d, C-2), 112.9 (s, C(CH2)5),
130.2, 130.55, 131.0 (3 d, o-, m-, p-C von C6H5), 139.6
(s, i-C von C6H5), 160.1 (s, CO2CH2Ph). – Minor rotamer:
δ = 33.5 (t, C-4), 38.90 (t, C(CH2)5), 56.3 (d, C-3), 61.2 (t,
C-5), 69.1, 70.0 (2 t, C-1, CH2C6H5), 79.44 (d, C-2), 130.5,
130.63 (2 d, o-, m-, p-C von C6H5), 139.4 (s, i-C von C6H5),
159.7 (s, CO2CH2Ph); other signals overlapped by those of
the major rotamer. – C20H29NO5 (363.5): calcd. C 66.09,
H 8.04, N 3.85; found C 66.01, H 8.01, N 3.75.
b) Hydrochloride 37·HCl: The amino acid 37 (156 mg)
was dissolved in CH2Cl2 (5 ml, abs.) and moist HCl gas
(from supernatant vapour phase of a bottle with conc. HCl)
introduced with a syringe until the salt precipitated. The mix-
ture was rota-evaporated (15 Torr), leaving a brownish solid
(177 mg) which was recrystallized from acetone/water to af-
ford colorless, analytically pure crystals of 37·HCl (119 mg,
53% from N-Z-35). A sample of this proved suitable for
crystal structure ana◦lysis [37].
M. p. 178 – 181 C (dec.). – [α]2D0 = −32.3 (c = 1.02,
MeOH). – IR (KBr): ν = 3435 (br; NH, OH), 2954 (b),
2851, 2791, 2733, 1724 (C=O), 1585, 1365, 1211, 1098,
1049, 938 cm−1. – 1H NMR (500.1 MHz, CD3OD): δ =
2
(3S,4S)-4,5-Cyclohexylidenedioxy-3-methylamino-penta-
noic acid (37) and hydrochloride 37·HCl
1.41 − 1.71 (m, 10 H, C(CH2)5), 2.67 (dd, J2A,2B = 18.1,
J2A,3 = 7.5 Hz, 1 H, 2-HA); 2.78 (s, NCH3), 2.80 (“dd”,
2J2A,2B = 18.3, J2B,3 = 4.2 Hz, 2-Hb) – sum 4 H; 3.67
(“ddd”, J2A,3 = 7.6, J2B,3 = 4.3, J3,4 = 2.9 Hz, 1 H, 3-
a) Amino acid 37: According to ref. [36] a solution of
H5IO6/CrO3 (0.44 M of H5IO4) was prepared from H5IO6
(10.0 g, 43.9 mmol) and CrO3 (20.2 mg, 0.20 mmol) in ace-
tonitrile (100 ml, with 0.75% v/v of water) and applied to the
oxidation of the alcohol 35. The latter (309 mg, 0.85 mmol)
was dissolve◦d in aqueous acetonitrile (10 ml, 0,75% v/v) and
cooled to 0 C; then within 10 min the solution of the oxi-
dant (5.8 ml, 2.55 mmol of HIO6) was added. After 2 h the
pH of the mixture was brought to 5 by adding a solution
of Na2HPO4 (0.42 M), then it was extracted with toluene
(3 × 20 ml). The organic phase was washed with aqueous
NaCl (half saturated, 2×5 ml), NaHSO3 (0.42 M, 5 ml), and
NaCl (saturated, 5 ml) and dried over MgSO4. After concen-
tration (15 Torr) a colorless resin (N-Z-acid, 271 mg) was
obtained which was taken up in methanol (10 ml). Into this
solution under N2 Pd/C (10%, 120 mg) was placed, then hy-
drogen was introduced (1 bar) and the mixture was hydro-
genated on stirring for 1 d, then filtered (celite, washed with
methanol) and rota-evaporated. From this a brownish resin
(164 mg, “79%”) was obtained which according to NMR
analysis consisted of pure amino acid 37. Since the elemental
analysis indicated some impurities, purification and full char-
acterization was done with the hydrochloride 37·HCl, vide
infra.
2
H), 3.82 (dd, J4,5A = 5.5, J5A,5B = 9.3 Hz, 1 H, 5-HA),
2
4.17 (dd, J4,5B = 7.2, J5A,5B = 9.3 Hz, 1 H, 5-HB), 4.56
(ddd, J3,4 = 3.0, J4,5A = 5.5, J4,5B = 7.1 Hz, 1 H, 4-H). –
13C NMR (75.5 MHz, CD3OD): δ = 24.8, 25.0, 26.2, 34.7,
36.5 (5 t, C(CH2)5), 31.2 (t, C-2), 31.9 (q, NCH3), 58.9
(d, C-3), 66.4 (t, C-5), 74.1 (d, C-4), 112.4 (s, C(CH2)5),
174.3 (s, C-1). – C12H22ClNO4 (279.8): calcd. C 51.52,
H 7.93, N 5.01, Cl 12.67; found C 51.39, H 7.92, N 4.89,
Cl 12.64.
Acknowledgements
The authors thank Ms. Sonja Henkel and Dr. Wolfgang
Frey for providing crystal structure analyses, and Priv.-Doz.
Dr. Peter Fischer and Mr. Joachim Rebell for NMR spec-
tra. We are also grateful to Dr. Albrecht Lieberknecht, Dipl.-
Ing.(FH) Helmut Griesser, Dr. Lubos Remen, and Yaser
Bathich, M.Sc., for technical help and advice. This work
was supported by Rhoˆne Poulenc S. A., Lyon (fellowship to
Pierre-Yves Le Roy), the French ministry of defense (VSNA
of Pierre-Yves Le Roy), Fonds der Chemischen Industrie,
and Volkswagen-Stiftung, Hannover.
[1] Synthesis via Isoxazolines, 25; for part 24 see M. Kle-
ban, P. Hilgers, J. Greul, R. Kugler, J. Li, S. Picasso,
P. Vogel, V. Ja¨ger, ChemBioChem 2, 365 (2001).
[2] Taken in part from: a) R. Ehrler, Dissertation, Univer-
sita¨t Wu¨rzburg (1985); b) Matthias Hein, Dissertation,
Universita¨t Stuttgart (1996); c) P.-Y. Le Roy, Disserta-
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
465
tion, Universita¨t Stuttgart (1997); d) M. Hennebo¨hle,
Dissertation, Universita¨t Stuttgart (2002).
of 1,3-Dipolar Cycloaddition Chemistry Towards Het-
erocycles and Natural Products, Vol. 59, p. 361, Wiley,
London, New York (2002).
[3] Reviews: U. Scho¨llkopf, Pure Appl. Chem. 55, 1799
(1983); M. J. Jung, in G. C. Barrett (ed.): Chemistry
and Biochemistry of the Amino Acids, p. 227, Chap-
man and Hall, London (1985); R. M. Williams, Synthe-
sis of Optically Active α-Amino Acids, Ch. 5, p. 208,
in J. E. Baldwin, P. D. Magnus (eds): Organic Chem-
istry Series, Vol. 7, Pergamon Press, Oxford (1989);
R. O. Duthaler, Tetrahedron 50, 1539 (1994); P. Wipf,
Chem. Rev. 95, 2115 (1995).
[4] a-Branched a-amino acids: H. Heimgartner, Angew.
Chem. 103, 271 (1991); Angew. Chem. Int. Ed. 30,
238 (1991); C. J. Moody, P. T. Gallagher, A. P. Light-
foot, A. M. Z. Slawin, J. Org. Chem. 64, 4419 (1999),
and references given therein.
[5] β-Amino Acids: a) U. Schmidt, M. Kroner,
H. Griesser, Synthesis, 832 (1989); b) E. Juaristi,
D. Quintana, B. Lamatsch, D. Seebach, J. Org. Chem.
56, 2553 (1991); c) E. Juaristi (ed.): Enantioselective
Synthesis of β-Amino Acids, Wiley-VCH, New York
(1977); d) D. J. Hill, M. J. Mio, R. B. Prince, T. S.
Hughes, J. S. Moore, Chem. Rev. 101, 3893 (2001);
e) R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem.
Rev. 101, 3219 (2001); f) A. R. Minter, A. A. Fuller,
A. K. Mapp, J. Am. Chem. Soc. 125, 6846 (2003).
[6] Lactacystin: a) P. O’Brien, Angew. Chem. 111, 339
[10] See also: a) C. Grundmann, P. Gru¨nanger, The Ni-
trile Oxides, Springer Verlag, Berlin (1977); b) A. P.
Kozikowski, Acc. Chem. Res. 17, 410 (1984); c) S. A.
Lang (Jr.), Y.-I. Lin, Isoxazoles and their Benzo
Derivatives, in A. R. Katritzky, C. W. Rees (eds): Com-
prehensive Heterocyclic Chemistry, Vol. 6, Perga-
mon Press, Oxford (1984); d) D. P. Curran, Adv. Cy-
cloadd. 1, 129 (1988); e) K. B. G. Torssell, Nitrile
Oxides, Nitrones, and Nitronates in Organic Synthe-
sis; Novel Strategies in Synthesis, VCH, Weinheim
(1988); f) P. Caramella, P. Gru¨nanger, Nitrile Oxides
and Imines, in A. Padwa (ed.): 1,3-Dipolar Cycload-
dition Chemistry, Vol. 1, p. 291, Wiley, New York
(1988); g) S. Kanemasa, O. Tsuge, Heterocycles 30,
719 (1990); h) P. Gru¨nanger, P. Vita-Finzi, Isoxa-
zoles, in E. C. Taylor, A. Weissberger (ed.): The Chem-
istry of Heterocyclic Compounds, Vol. 49, Part. 1,
p. 417, Wiley, Toronto (1991); i) S. Shatzmiller, 2-
Isoxazolines, in H. Suchitzky (ed.): Progress in Het-
erocyclic Chemistry, Vol. 4, Pergamon Press, Oxford
(1992); j) D. Sutharchana, R. Murugan, Isoxazoles,
in A. R. Katritzky, C. W. Rees, E. F. V. Scriven (eds):
Comprehensive Heterocyclic Chemistry II, Vol. 3,
S. 222, Pergamon Press, Oxford (1996).
(1999); Angew. Chem. Int. Ed. 38, 326 (1999); b) C. E. [11] T. Franz, M. Hein, U. Veith, V. Ja¨ger, K. Peters,
Masse, A. J. Morgan, J. Adams, J. S. Panek, Eur. J. Org.
Chem. 2513 (2000); c) T. Nagamitsu, T. Sunazuka,
H. Tanaka, A. B. Smith, S. Omura, J. Am. Chem. Soc.
118, 3584 (1996).
H. G. von Schnering, Angew. Chem. 106, 1308 (1994);
Angew. Chem. Int. Ed. 33, 1298 (1994); N. Meunier,
U. Veith, V. Ja¨ger, J. Chem. Soc., Chem. Commun. 331
(1996); U. Veith, O. Schwardt, V. Ja¨ger, Synlett, 1181
(1996).
[7] Cf. Myriocin: T. Fujita, K. Inone, S. Yamamoto, T. Iku-
moto, S. Sasaki, J. Antibiot. 47, 216 (1994).
[12] See also: K. Weinges, H. Blackholm, Chem. Ber.
113, 3098 (1980); H. Kunz, D. Schazenbach, Angew.
Chem. 101, 1042 (1989); Angew. Chem. Int. Ed. 28,
1068 (1989); C. Cativiela, M. D. Diaz-de-Villegas,
J. A. Ga´lvez, Tetrahedron: Asymmetry 5, 261 (1994).
[13] V. Ja¨ger, L. Bierer, H.-Q. Dong, A. M. Palmer,
D. Shaw, W. Frey, J. Heterocyclic Chem. 37, 455
(2000).
[8] D. Enders, U. Reinhold, Tetrahedron: Asymmetry 8,
1895 (1997); R. Bloch, Chem. Rev. 98, 1407 (1998);
N. Risch, M. Arend in G. Helmchen, R. W. Hoffmann,
J. Mulzer, E. Schaumann (eds): Methods of Organic
Chemistry (Houben-Weyl-Mu¨ller), 4th ed., Vol. E21b,
p. 1833, Thieme, Stuttgart (1995).
[9] a) V. Ja¨ger, H. Grund, V. Buß, W. Schwab, I. Mu¨ller,
R. Schohe, R. Franz, R. Ehrler, Bull. Soc. Chim. Belg.
92, 1039 (1983); b) V. Ja¨ger, I. Mu¨ller, R. Schohe,
M. Frey, R. Ehrler, B. Ha¨fele, D. Schro¨ter, Lect. Het-
erocycl. Chem. 8, 79 (1985); c) V. Ja¨ger, R. Franz,
W. Schwab, B. Ha¨fele, D. Schro¨ter, D. Scha¨fer,
W. Hu¨ mmer, E. Guntrum, B. Seidel, Studies in Or-
[14] A. M. Palmer, V. Ja¨ger, Eur. J. Org. Chem. 1293 (2001).
¨
[15] V. Ja¨ger, R. Ohrlein, V. Wehner, H. Griesser, A. Men-
¨
zel, Synthesis, 1691 (1999); V. Ja¨ger, R. Ohrlein,
V. Wehner, P. Poggendorf, B. Steuer, J. Raczko,
H. Griesser, F.-M. Kieß, A. Menzel, Enantiomer 4, 205
(1999).
ganic Chemistry, Vol. 35 in J. Kova´c, P. Za´lupsky (eds): [16] B. Ha¨fele, D. Schro¨ter, V. Ja¨ger, Angew. Chem. 98,
Chemistry of Heterocyclic Compounds, p. 58, Else-
vier, Amsterdam (1988); d) V. Ja¨ger, R. Mu¨ller, T. Lei-
bold, M. Hein, M. Schwarz, M. Fengler, L. Jaroskova,
M. Pa¨tzel, P.-Y. Le Roy, Bull. Soc. Chim. Belg. 103,
491 (1994); e) P. Colinas, V. Ja¨ger, Nitrile Oxides, in
A. Padwa, W. H. Pearson (eds): Synthetic Applications
89 (1986); Angew. Chem. Int. Ed. 25, 87 (1986);
V. Ja¨ ger, W. Hu¨mmer, Angew. Chem. 102, 1182
(1990); Angew. Chem. Int. Ed. 29, 1171 (1990);
B. Kirschbaum, U. Stahl, V. Ja¨ger, Bull. Soc. Chim.
Belg. 103, 425 (1994); V. Ja¨ger, T. Gracza, E. Dubois,
T. Haseno¨hrl, W. Hu¨mmer, U. Kautz, B. Kirschbaum,
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

466
M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
A. Lieberknecht, L. Remen, D. Shaw, U. Stahl,
Soc. Jpn. 66, 2730 (1993); b) cf. rediscoveries: K. S.-
L. Huang, E. H. Lee, M. M. Olmstead, M. J. Kurth, J.
Org. Chem. 65, 499 (2000); ref. [5f]; F. J. Freire Cas-
tro, M. M. Vila, P. R. Jenkins, M. L. Sharma, G. Tustin,
J. Fawcett, D. R. Russel, Synlett 6, 798 (1999); c) cf.
K. E. Rodriques, A. Basha, J. B. Summers, D. W.
Brooks, Tetrahedron Lett. 29, 3455 (1988); R. A. Volk-
man, in B. M. Trost, I. Fleming (eds): Comprehensive
Organic Synthesis, Vol. 1, p. 386, Pergamon, Oxford
(1991).
O. Stephan, Organic Synthesis via Organometallics
(OSM 5), p. 331, in G. Helmchen (ed.): Proceed-
ings of the Fifth Symposium, Heidelberg, Sep 26 –
28 (1996), F. Vieweg & Sohn Verlagsges., Braun-
schweig/Wiesbaden (1997); A. Palmer, V. Ja¨ger, Syn-
lett 10, 1405 (2000).
[17] a) V. Buß, Dissertation, Universita¨t Gießen (1979);
b) W. Schwab, Dissertation, Universita¨t Gießen (1978);
c) R. Franz, Dissertation, Universita¨t Wu¨rzburg (1985);
d) R. Mu¨ller, Dissertation, Universita¨t Wu¨rzburg
(1992); e) T. Leibold, Dissertation, Universita¨t
Stuttgart (1995); f) R. Ehrler, Dissertation, Universita¨t
Wu¨rzburg (1986); g) cf. ref. [9].
[18] a) P. J. Zimmermann, Dissertation, Universita¨t Stuttgart
(2000); b) P. J. Zimmermann, I. Blanarikova, V. Ja¨ger,
Angew. Chem. 112, 936 (2000); Angew. Chem. Int. Ed.
39, 910 (2000); c) J.-Y. Lee, Dissertation, Universita¨t
Stuttgart (planned).
[26] A. H. Blatt, N. Gross, J. Am. Chem. Soc. 77, 5424
(1955); A. Belly, C. Pe´trus, F. Pe´trus, Bull. Soc. Chim.
Fr. 1390 (1973).
[27] a) A. Cerri, C. De Micheli, R. Gandolfi, Synthesis 710
(1974); b) A. P. Kozikowski, H. Ishida, J. Am. Chem.
Soc. 102, 4265 (1980); c) D. Cristina, M. De Am-
ici, C. De Micheli, R. Gandolfi, Tetrahedron 37, 1349
(1981); d) N. P. Peet, E. W. Huber, R. A. Farr, Tetrahe-
don 47, 7537 (1991).
[19] G. Drehfahl, H. Ho¨rhold, Chem. Ber. 97, 159 (1964);
T. Kusumi, H. Kakisawa, S. Suzuki, K. Harada,
C. Kashima, Bull. Chem. Soc. Jpn. 51, 1261 (1978);
T. Kametani, S.-P. Huang, S. Yokohama, Y. Suzuki,
M. Ihara, J. Am. Chem. Soc. 102, 2060 (1980);
T. Kametani, A. Nakayama, Y. Nakayama, T. Ikuta,
R. Kubo, E. Goto, T. Honda, K. Fukumoto, Hete-
[28] S. Shatzmiller, E. Shalom, R. Lidor, E. Tartkovski,
Liebigs Ann. Chem. 906 (1983).
[29] J. L. Olive´, R. Jacquier, C. Pe´trus, F. Pe´trus, Bull. Soc.
Chim. Fr. 1651 (1974); A. Belly, C. Pe´trus, F. Pe´trus,
Bull. Soc. Chim. Fr. 1025 (1974).
[30] S. Shatzmiller, B.-Z. Dolitzky, R. Meirowich, R. Nei-
dlein, C. Weik, Liebigs Ann. Chem. 161 (1991).
rocycles 16, 53 (1981); G. Zimmermann, W. Hass, [31] a) V. Wehner, Dissertation, Universita¨t Wu¨rzburg
H. Faasch, H. Schmalle, W. A. Ko¨nig, Liebigs Ann.
Chem. 2165 (1985); W. A. Ko¨nig, H. Hahn, R. Rath-
mann, W. Hass, A. Keckeisen, H. Hagenmaier, C. Bor-
mann, W. Dehler, R. Kurth, H. Za¨hner, Liebigs Ann.
Chem. 407 (1986); W. Hass, W. A. Ko¨nig, Liebigs
Ann. Chem. 1615 (1982); A. G. M. Barrett, D. Dhanak,
S. A. Lebold, M. A. Russell, J. Org. Chem. 56, 1894
(1991).
(1990); b) B. Steuer, V. Wehner, A. Lieberknecht,
V. Ja¨ ger, Org. Synth. 74, 1 (1996); c) V. Ja¨ger,
V. Wehner, Angew. Chem. 101, 512 (1989); Angew.
Chem. Int. Ed. 28, 469 (1989).
[32] V. Ja¨ger, V. Buß, W. Schwab, Tetrahedron Lett. 34,
3133 (1978); V. Ja¨ger, V. Buß, Liebigs. Ann. Chem.
101 (1980).
[33] W. Frey, M. Hennebo¨hle, V. Ja¨ger, Z. Kristallogr. NCS,
in press.
[20] R. Mu¨ller, T. Leibold, M. Pa¨tzel, V. Ja¨ger, Angew.
Chem. 106, 1305 (1994); Angew. Chem. Int. Ed. 33, [34] J. Mulzer in G. Helmchen, R. W. Hoffmann, J. Mulzer,
1295 (1994); C. Schaller, P. Vogel, V. Ja¨ger, Carbohydr.
Res. 314, 25 (1998).
[21] For uses of 2-furyl as carboxyl equivalent see, f. e.:
a) G. Alvaro, G. Martelli, D. Savoia, A. Zoffoli, Syn-
thesis 1773 (1988); b) see ref. [4] (Moody).
[22] Cf. ref. [11] (synthesis of the statine family).
[23] Cf. use of styryl as latent carboxyl in related oxime
ether additions: ref. [4] (Moody); cf. also complemen-
tary strategy to elaborate a carboxyl group at the (for-
mer) 5-position of the isoxazoline by reduction to the
diol and subsequent oxidative cleavage, ref. [5f].
[24] V. Ja¨ger, H. Grund, Angew. Chem. 88, 27 (1976);
Angew. Chem. Int. Ed. 15, 50 (1976); V. Ja¨ger,
W. Schwab, Tetrahedron Lett. 3129 (1978); H. Grund,
V. Ja¨ ger, Liebigs Ann. Chem. 80 (1980); V. Ja¨ger,
V. Buß, W. Schwab, Liebigs Ann. Chem. 122 (1980).
[25] a) H. Uno, T. Terekawa, and H. Suzuki, Bull. Chem.
E. Schaumann (eds): Houben-Weyl-Mu¨ller, Methods
of Organic Chemistry, Vol. E21a, Stereoselective Syn-
thesis, p. 75, Thieme, Stuttgart (1995); A. Mengel,
O. Reiser, Chem. Rev. 99, 1191 (1999).
[35] R. Annzunziata, M. Cinquini, F. Cozzi, A. Gilardi,
A. Restelli, J. Chem. Soc., Perkin Trans I, 2289
(1985); J. Ipaktschi, Chem. Ber. 117, 856 (1984); S. K.
Armstrong, S. Warren, E. W. Collington, A. Naylor,
Tetrahedron Lett. 32, 4171 (1991); H. I. Schlesinger,
H. C. Brown, A. E. Finholt, J. R. Gilbreath, H. R.
Hoekstra, E. K. Hyde, J. Am. Chem. Soc. 75, 215
(1953).
[36] M. Zhao, J. Li, Z. Song, R. Desmond, D. M. Tschaen,
E. J. J. Grabowski, P. J. Reider, Tetrahedron Lett. 39,
5323 (1998).
[37] M. Hennebo¨hle, W. Frey, V. Ja¨ger, Z. Kristallogr. NCS,
in press.
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM

M. Hennebo¨hle et al. · Isoxazolinium Salts in Asymmetric Synthesis. 1. Reduction
467
[38] K.-C. Liu, B. R. Shelton, R. K. Howe, J. Org. Chem.
45, 3916 (1980).
[41] H. Yin, R. W. Franck, S.-L. Chen, G. J. Quigley, L. To-
dardo, J. Org. Chem. 57, 644 (1992).
[39] B. Ha¨fele, Diplomarbeit, Universita¨t Wu¨rzburg (1983);
B. Ha¨fele, Dissertation, Universita¨t Wu¨rzburg (1987).
[40] R. W. Hoffmann, G. Eichler, A. Endesfelder, Liebigs
Ann. Chem. 2000 (1983).
[42] L. F. Fieser, M. Fieser, Reagents for Organic Synthesis,
Vol. 1, p. 584, Wiley, New York (1967).
[43] M. D. Armstrong, J. Am. Chem. Soc. 70, 1756 (1948).
Brought to you by | University of California
Authenticated
Download Date | 11/30/15 10:06 AM