1,2-diastereoselective C-C bond-forming reactions for the synthesis of chiral β-branched α-amino acids

Article abstract of DOI:10.1002/ejoc.201000865

S_N2′ sequences have been employed for the synthesis of β-branched α-amino acids using 1,2-diastereocontrol for forming C-C bonds. An oxazolidine fragment derived from Garner's aldehyde provides the handle for facial discrimination and acts as a

Full text of DOI:10.1002/ejoc.201000865

FULL PAPER
DOI: 10.1002/ejoc.201000865
1,2-Diastereoselective C–C Bond-Forming Reactions for the Synthesis of Chiral
β-Branched α-Amino Acids
Thomas Spangenberg,[a,b] Angèle Schoenfelder,[a] Bernhard Breit,*[b] and André Mann*[a]
Keywords: Amino acids / Diastereoselectivity / Allylic compounds / Nucleophilic substitution / Hydroformylation
SN2Ј sequences have been employed for the synthesis of β-
branched α-amino acids using 1,2-diastereocontrol for form-
ing C–C bonds. An oxazolidine fragment derived from Gar-
ner’s aldehyde provides the handle for facial discrimination
and acts as a masked amino acid functionality. This study
encompasses directed and non-directed allylic substitution
reactions. The stereocontrol of the oxazolidine appendage
during terminal olefin hydroformylation was also studied. Ef-
forts to understand the diastereochemical outcome of the re-
actions as well as synthetic applications are disclosed.
of seco-kainic acid. Another pathway that has been ex-
plored employed chiral bromoallenes that underwent SN2Ј
alkylation to produce anti-β-branched alkynyl amino
alcohol derivatives [Equation (2) in Figure 1].[7] More re-
cently, we applied the concept of “reagent-directing group”
to a 1,2-diastereoselective copper-mediated allylic substitu-
tion using the oxazolidine group derived from Garner’s al-
dehyde as a handle for facial discrimination and as a
masked amino acid functionality.[8–10] Indeed, hydrolytic
deprotections and oxidation of the primary alcohol func-
tion of the N-Boc-oxazolidine could restore the α-amino
acid function and therefore represent a new synthesis of β-
branched α-amino acids. Herein we disclose a full account
Introduction
Stereocontrol in the course of carbon–carbon bond-
forming reactions can be achieved either by reagent or sub-
strate control. The latter strategy is attractive if the sub-
strate is readily accessible in a few productive steps from
the chiral pool and amenable to diastereoselective transfor-
mations.[1–3] Following our interest in non-proteinogenic
amino acids, we envisaged the construction of β-substituted
α-amino acids from - or -serine using a suitable C–C
bond-forming reaction. Indeed, β-substituted α-amino ac-
ids are employed as building blocks for the synthesis of
wide ranges of natural products and biomolecules or as
probes to identify the mechanism of biological reactions.[4]
In addition, they have played a crucial role in the develop-
ment of therapeutic agents such as peptides and peptidomi-
metics, especially by inducing conformational constraints or
metabolic stability.[5]
Some years ago our group reported that α,β-unsaturated
esters 2 and 3 (the E and Z stereoisomers), obtained from
Garner’s aldehyde 1, were suitable substrates for the 1,4-
addition of organo-cuprates.[6] Indeed, the conjugate ad-
dition was high-yielding and the diastereoselectivity excel-
lent, favouring the formation of the syn adduct (syn/anti,
95:5) [see Equation (1) in Figure 1]. Interestingly, the E and
Z stereoisomers of enoate 2 both gave the syn adduct. At
the time these results were explained by a vinylogous Fel-
kin–Anh model. Then, after a few chemical manipulations,
the syn adducts were transformed into stereodefined 3-alk-
ylated glutamic acids. The work culminated in the synthesis
[a] Faculté de Pharmacie, UMR 7200, CNRS – Université de
Strasbourg, Laboratoire d’Innovation Thérapeutique,
74 route du Rhin, 67401 Illkirch, France
E-mail: andre.mann@pharma.u-strasbg.fr
[b] Institut für Organische Chemie und Biochemie, Albert-
Ludwigs-Universität Freiburg,
Figure 1. Diastereoselective approaches to β-branched α-amino ac-
ids.
Albertstrasse 21, 79104 Freiburg, Germany
E-mail: bernhard.breit@chemie.uni-freiburg.de
View this journal online at
wileyonlinelibrary.com
Eur. J. Org. Chem. 2010, 6005–6018
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6005

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann
FULL PAPER
focusing on the unique capability of the oxazolidine moiety dioxolane function in the course of the SN2Ј reaction. The
to drive the stereochemical outcome of the directed allylic chemical steps towards the starting substrates 6–9, 12, 18
substitution with organometallic reagents [see Equation (3) and 19 for the copper-mediated allylic substitution reaction
in Figure 1]. In addition, a methallyl adduct of Garner’s are depicted in Scheme 1. When E or Z stereoisomers were
aldehyde was submitted to hydroformylation to delineate involved the geometric purity of the compounds was en-
the influence of the oxazolidine fragment in hydrometalla- sured by HPLC.
tion and a subsequent carbonylative sequence which would
deliver a valuable glutamate analogue possessing a terminal
Results of the Studies of the SN2Ј Substitution Reaction
aldehyde ready for further manipulations [Equations (3)
and (4) in Figure 1].
Under standard conditions with leaving groups such as
OAc or Cl, the regioselectivity of the reaction was a con-
cern. Indeed, the sterically demanding oxazolidine group in
substrates 6 and 7 favoured the apparent SN2 pathway over
the SN2Ј pathway (Table 1, entries 1–4). The reaction mix-
ture with several organometallic reagents (Mg, Cu or Zn)
gave 22, the SN2 substitution product, and a mixture of 20a
and 21a, the SN2Ј products. But the SN2 pathway was by
far the major one whereas in the minor SN2Ј pathway a
trend for the syn adduct was still notable. This poor regiose-
lectivity could be overcome with a “reagent-directing/leav-
ing group”, ortho-(dihenylphosphanyl)benzoate (oDPPB),
which has the capability of precoordinating the copper rea-
gent to allow for intramolecular delivery of the organome-
tallic nucleophile. Under these conditions the desired regi-
ocontrol was nearly perfect for substrate 8; the SN2Ј path-
way was predominant and gave an excellent diastereomeric
ratio in favour of the anti adduct 20a (entry 5) using an
organo-copper reagent.
Results and Discussion
Synthesis of the Starting Substrates for SN2’ Reactions
For the exhaustive study of the SN2Ј reaction, several
strategic substrates were prepared by cognate chemistry.
Garner’s aldehyde 1 or the dioxolane 13, as starting materi-
als, underwent E- or Z-selective olefination reactions to
yield the enoates 2 or 3 and 14 or 15, respectively, as separa-
ble stereoisomers. Then DIBAl-H reduction afforded the
allylic alcohols 4 or 5 and 16 or 17, respectively. At first the
alcohol functions in 4 and 5 were converted into leaving
groups such as OAc (6) or Cl (7) and the directing/leaving
group ortho-(dihenylphosphanyl)benzoate (oDPPB) by
Steglich esterification (8 and 9). Also, starting from 1, al-
kyne derivative 12 was obtained by Bestmann–Ohira reac-
tion followed by alkylation[11] and Steglich esterification.
The substrates 18 and 19 were prepared to compare the
diastereochemical bias of the oxazolidine function with a
Table 1. Initial conditions for the SN2Ј reaction with substrates 6,
7 and 8.
Entry
1
Conditions[a]
syn/anti SN2Ј/SN2
6
6
7
7
8
MeMgBr, 50 mol-% CuCN, Et2O,
–78 °C
Me2Zn, CuCN·2LiCl, THF,
–30 °C
MeLi, CuI, BF3·Et2O, THF,
–30 °C
MeLi, CuBr·SMe2, ZnCl2, THF,
–70 °C
51:49
18:82
2
3
4
5
–
–
86:14
74:26
15:85
28:71
4:96
98:2
0.5 equiv. CuBr·SMe2/1.6 equiv.
MeMgBr, Et2O, room temp.
[a] Full conversions were observed for entries 1 and 3–5. Regio-
selectivities and diastereoselectivities were determined by GC
analysis.
Next, the chiral substrates 8 and 9 possessing opposite
alkene geometries were treated with different organometal-
lic reagents (Table 2, entries 1–9). With alkyl Grignard rea-
gents, the regioselectivity was controlled by the directing
group and the diastereochemical outcome was found to be
stereodivergent after correlation with the corresponding
isoleucines.[9] The E isomer gave rise to the valuable anti
Scheme 1. Preparation of substrates for the copper-mediated allylic
substitution reaction.
6006
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6005–6018

Synthesis of Chiral β-Branched α-Amino Acids
adducts in good diastereomeric ratios more or less indepen-
dently of the steric demand of the nucleophile (entries 1–
4). Conversely, the Z isomer led to syn diastereomers with
excellent diastereomeric excesses (entries 6–9). As a result
of a slower reductive elimination pathway, the phenyl Grig-
nard gave poor regioselectivity although the diastereoselectiv-
ity seems consistent with alkyl Grignard reagents (entry 5).
Table 2. Copper-mediated oDPPB-directed SN2Ј reactions with
substrates 8, 9 and 12.
Entry[a]
R
SN2Ј/SN2 syn/anti[b] (products) Yield [%][c]
1
2
3
4
5
6
7
8
9
10
8
8
8
8
8
9
9
9
9
Me
Et
nBu
iPr
Ph
Me
Et
Bu
iPr
Me
98:2
96:4
98:2
98:2
44:56
96:4
99:1
98:2
95:5
95:5
15:85 (20a/21a)
15:85 (20b/21b)
17:83 (20c/21c)
7:93 (20d/21d)
17:83
97:3 (20a/21a)
97:3 (20b/21b)
98:2 (20c/21c)
95:5 (20d/21d)
23
78
91
97
97
–
86
98
96
98
75
Scheme 2. Functionalization of the terminal olefin for the prepara-
tion of β-branched α-amino acids.
An interesting feature of the oDPPB leaving group is the
manipulation of the oxidation state of the phosphorus
atom. It has been shown that by switching the directing
group to the “off state” (oxidation of the phosphorus atom)
the opposite diastereomer could be obtained from the same
substrate.[15] Therefore stereodivergency may be possible
with little chemical effort (Figure 2). These results are based
on the following rational explanation: the entering nucleo-
phile approaches the phosphane oxide in an antiperiplanar
fashion rather than by syn attack as is the case for the di-
rected SN2Ј reaction. However, owing to the enhanced leav-
ing-group ability of the oDPPB oxide in substrates 30 and
31, the less nucleophilic dialkylzinc-derived copper reagent
was required to achieve good regiocontrol.[16]
12
[a] 0.1  RMgBr (2 equiv.) was added at a rate of 3 mL/h to a
solution of or precomplexed with 0.01  CuBr·SMe2
(0.5 equiv.) in Et2O at room temp. [b] The configurations of 20b–d
and 21b–d were assigned by analogy with 20a and 21a. [c] Isolated
yield after silica gel chromatography.
8
9
Note, detection of the formal SN2 products in small but
traceable quantities arising from the starting Z olefin re-
sulted predominantly in the E isomer 22, which suggests
that the SN2-type products do not result from a simple sub-
stitution pathway but probably from a copper–π-allyl com-
plex.[12,13] Next, to investigate the influence of the oxazolid-
ine group with respect to the geometry of the electrophile,
an SN2Ј reaction was performed using propargylic substrate
12 (Scheme 1). It was found that allene 23 was formed in a
good yield with an excellent regioselectivity. To the best of
our knowledge, the oDPPB-directed SN2Ј reaction with pri-
mary alkynes has no precedents (Table 2, entry 10).
The newly prepared adducts feature a terminal olefin
function that allows for several chemical transformations
such as reduction, cyclopropanation or oxidation. Exem-
plarily, 21a was transformed into different amino acid pre-
cursors. Thus, hydrogenation produced 24 in 95% yield, a
precursor for isoleucine, Wacker oxidation yielded 25 in
68% yield, a precursor for the fenugreek[14a,14b] amino acid
hydroxyisoleucine and cyclopropanation[14b] furnished 26
quantitatively, a precursor for the synthesis of the naturally
Figure 2. oDPPB on/off switch for SN2Ј stereodivergency.
Indeed, for 30 (the E isomer), a reversal of diastereoselec-
occurring β-branched α-amino acid 29 (Scheme 2). Cleav- tivity (syn ϾϾ anti) was observed with alkylzinc reagents
age of the acetonide with TFA in methanol produced 27 (Table 3, entries 1–3). This inversion of diastereoselectivity
and subsequent oxidation of the primary alcohol to the car- in 30 with respect to 8 confirms our expectations, and al-
boxylic acid with periodic acid and chromium(VI) oxide though Zn instead of Mg was used, a trend in the syn/anti
furnished the Boc-protected amino acid 28 in good overall ratio similar to that for the oDPPB-directed reaction was
yield. Cleavage of the Boc group under standard conditions observed. These data suggest that the incoming nucleophile
yielded the desired 29 quantitatively (dr 9:1).
indeed enters anti with respect to the leaving group. In con-
Eur. J. Org. Chem. 2010, 6005–6018
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6007

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann
FULL PAPER
trast, for substrate 31 (the Z isomer), the syn diastereomer Table 4. oDPPB-directed SN2Ј reactions of substrates 18 and 19.[a]
was formed as the major product even though the anti dia-
stereomer was expected (Table 3, entry 4).
Table 3. “Nondirected” SN2Ј reaction with substrates 30 and 31.[a]
syn/anti (products)
SN2Ј/SN2
Yield [%][b]
18
19
15:85 (32/33)
43:57
95:5
65:35
75
ND
[a] Conditions: 2 equiv. of 0.1  MeMgBr were added at 3 mL/h to
a solution of 0.01  18 or 19 and 0.5 equiv. of CuBr·SMe2 in Et2O
at room temp. [b] Isolated yield after silica gel chromatography.
Entry
R
syn/anti (products)[b] SN2Ј/ SN2
Yield [%][c]
1
2
3
4
30
30 nBu 85:15 (20c/21c)
30 iPr 85:15 (20d/21d)
31 nBu 99:1 (20c/21c)
Me 77:23 (20a/21a)
95:5
99:1
86:14
99:1
75
61
88
40
toxy-3-methylvaleric acid (34) as the major diastereomer
(syn/anti, 8:92).[18] The mixture of diastereomers was re-
duced with lithium aluminium hydride and acetonide for-
mation with 2,2-dimethoxypropane gave 36 in the same dia-
stereomeric ratio thereby enabling the relative assignment
of both syn and anti adducts (Scheme 3).[19]
[a] Conditions: In a dry flask under argon, CuCN·2LiCl (13 mg,
74.7 µmol) in anhydrous THF (0.5 mL) was introduced. The solu-
tion was stirred until the copper salt had dissolved and then it was
cooled to –30 °C by mean of a cryostat. A solution of alkylzinc in
toluene (2.4 equiv.) was added dropwise. The mixture was stirred
for 30 min at –30 °C (light yellow) and a solution of 30 or 31
(35 mg, 62.2 µmol) in THF (0.9 mL) was then added with a syringe
pump (rate 0.5 mL/h) at 0 °C. The mixture was stirred for 5 h at
0 °C and then overnight at room temp. (black solution). [b] The
configurations of 20b–d and 21b–d were assigned by analogy with
20a and 21a. [c] Isolated yield after silica gel chromatography.
At present we do not have convincing arguments to ex-
plain why, under substrate control, there is a discrepancy
between syn and anti attack of the directed and non-di-
rected allylic substitutions. Nonetheless, intrigued by this
divergence, we speculated that the N-Boc group could exert
a neighbouring-group participation effect.[17] To probe this
hypothesis, dioxolane analogues 18 and 19 were prepared in
isomerically pure form starting from -mannitol (see above;
Scheme 1). By using our previously optimized conditions
for the directed SN2Ј reactions of 8 and 9, we subjected 18
and 19 to the directed allylic substitution, as summarized
Scheme 3. Correlation of the relative stereochemistry of the dioxol-
ane derivatives.
Rationale for the Observed Results[20]
In the case of substrates 8 and 9, a directing/leaving
in Table 4. Strikingly, isomer E (18) shows a profile virtually group was used. For stereoelectronic reasons the reactive
identical to that of the N-Boc derivative with an anti/syn conformation should allow efficient overlap of the σ* or-
ratio of 85:15 and a regioselectivity of 95:5. However, for bital of the C–O bond to be broken and the π* orbital of
the Z isomer (19), the allylic substitution reaction was com- the alkene, that is, a dihedral angle of about 0°. Thus, for
pletely non-selective both regio- and diastereoselectively the E substrate 8 it is plausible that reactive conformations
(entry 2). From this result it would appear that the N-Boc A or AЈ account for the observed stereochemical outcome.
group plays an essential role during the allylic substitution Both conformations are in agreement with the stereoelec-
of the Z-oDPPB ester 9.
tronic requirements for the SN2Ј reaction and minimize al-
The pronounced A1,3 strain expected for a cis-disubsti- lylic A1,2 and A1,3 strains. Directed attack from the least
tuted alkene could be responsible for the higher diastereo- hindered Si alkene face provides the anti diastereomer pref-
selectivities observed for 9 but also a destabilizing effect of erentially for both conformations A and AЈ (Figure 3). In
the transient π-copper–allyl complex, as was the case for 19. the case of the Z substrate 9, conformation B with delivery
From this result it may be possible that the oxygen atoms in of the alkyl nucleophile to the sterically less-hindered Re
the N-Boc group coordinate the copper atom thereby al- face could explain the preferred formation of the syn dia-
lowing extra stabilization in the transition state. The relative stereomer. The pronounced A1,3 strain expected for a cis-
configuration of the major adduct 32 was unambiguously disubstituted alkene could be responsible for the higher dia-
assigned by GC comparison of the hydrogenated adduct 33 stereoselectivities observed for the Z-oDPPB ester 9. More-
with the synthetic material 36 obtained from -isoleucine. over, the fact that the Z-oxo derivative 19 displayed poor
Indeed, the latter underwent diazotization with isoamyl ni- regio- and diastereoselectivity indicates that the more pro-
trite in acetic acid to yield the corresponding (2S,3S)-2-ace- nounced A1,3 strain affected the course of the reaction. But,
6008
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6005–6018

Synthesis of Chiral β-Branched α-Amino Acids
as highlighted, the Boc group functioning as an additional (A) led to a significant increase in diastereoselectivity (en-
ligand for the copper atom during the reaction cannot be tries 2 and 3), however, the use of the more bulky phosphite
excluded (Figure 3).
B gave disappointing results with a lower diastereoselectiv-
ity (entries 4 and 5). Switching to phosphane ligands and
starting with triphenylphosphane (C) gave similar results as
ligand A (entry 6). Finally, the bulky phosphane ligand
phosphabarrelene[26] (D) was found to give the best dia-
stereocontrol and yield favouring the syn isomer 38
(syn/anti = 94:6, Table 5, entries 7 and 8). The relative con-
figuration was determined by correlation with the known
syn product formed by the addition of methyl cuprate to 2
(Scheme 1). Reduction of the latter ester with lithium alu-
minium hydride and 38 with sodium borohydride gave the
same primary alcohol 39.[27]
Table 5. Diastereoselective hydroformylation of N-Boc-oxazolidine
37.
Figure 3. Rationale for the diastereochemical outcome.
Finally, the oxazolidine residue has demonstrated its
capability to induce good-to-very-good 1,2-diastereocontrol
in the course of C–C bond-forming reactions. Whereas the
1,4-addition of cuprates gave only the syn product indepen-
dently of double-bond geometry, the directed copper-medi-
ated allylic substitution (SN2Ј) allowed the preparation of
both diastereomers selectively at the β-carbon next to the
oxazolidine. Accordingly, other C–C bond-forming reac-
tions were explored.
Entry
Ligand
Solvent
syn/anti
Yield [%]
[1[c]
2[a]
3[c]
4[a]
5[c]
6[c]
7[b]
8[c]
none
A
toluene
toluene
THF
toluene
THF
toluene
toluene
THF
83:17
91:9
89:11
87:13
87:13
90:10
94:6
63
71[d]
78
A
B
91,[c] 75[d]
93
B
C
65
Stereocontrol During the Hydroformylation of 37
D
76[d]
90
D
93:7
The influence of the oxazolidine appendage on dia-
stereocontrol was further evaluated with the methallylic
substrate 37 under hydroformylative conditions. Indeed, the
methallylic substrate 37 should undergo hydroformylation
exclusively at the less substituted C-terminus of the 1,1-di-
substituted alkene (Keulemans’ rule) and deliver solely the
linear aldehyde 38, but the influence of the stereogenic cen-
tre of the oxazolidine with respect to 1,2-stereoinduction
was unknown.[21] If successful, this sequence would secure
the introduction of the commonly encountered methyl
group at the β-carbon and deliver the valuable aldehyde
38.[22,23] Although it has been demonstrated that neigh-
bouring stereogenic centres generated moderate-to-good
1,2-diastereoselectivity in passive substrate control during
hydroformylation, the use of a proximal nitrogen-contain-
ing group has never been reported.[24] Olefin 37, the sub-
[a] Reactions were performed with 0.1 , 0.9 mol-% [Rh(CO)2-
(acac)] and 4 mol-% co-ligand. [b] Reactions were performed with
0.1 , 2 mol-% [Rh(CO)2(acac)] and 8% co-ligand. [c] In a parallel
autoclave: reactions were performed with 0.1 , 1.5 mol-%
[Rh(CO)2(acac)] and 6 mol-% co-ligand. [d] Isolated yield after sil-
ica gel chromatography.
To rationalize the formation of the syn preferred dia-
strate for hydroformylation, was obtained in five steps from stereomer, a model derived from the 1,2-diastereoselective
-serine by using known methods.[25] The most active hy- RhI-catalyzed hydroboration of olefins is suggested.[28]
droformylation catalysts are phosphane-modified rhodi- Complexation of the double bond with the catalyst would
um(I) complexes. The activity and selectivity of these cata- take place from the less hindered face of a conformation in
lysts depends largely on the selected P-donor ligands. For which the 1,3-allylic strain is minimized and the with-
this reason different types of phosphorus-containing li- drawing group (N-Boc) is antiperiplanar to the double
gands were screened. The results of our experiments are bond.
disclosed in Table 5. The hydroformylation was conducted
Furthermore, if 1,2-allylic strain is minimized, the coor-
in toluene or THF at 50 °C, the syngas pressure being fixed dination of the catalyst to the Boc residue may also contrib-
at 20 bar. By employing [Rh(CO)2(acac)] without a co-li- ute for the observed syn diastereocontrol. This sequence ac-
gand, moderate diastereoselectivity was observed (syn/anti counts for the substrate-directed hydroformylation (Fig-
= 83:17, Table 5, entry 1). Addition of triphenyl phosphite ure 4) and enables the preparation after some chemical
Eur. J. Org. Chem. 2010, 6005–6018
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6009

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann
coated with silica gel 60 (UV254 were used for thin-layer
FULL PAPER
)
transformations of the threo-3-methyl glutamate [e.g.,
(2S,3R)-3TMG from -serine], a synthon present in numer-
ous natural products.[29–31]
chromatography and were visualized by staining with KMnO4.
1H, 13C and 31P NMR spectra were recorded with Bruker 400/300/
200 spectrometers. Conditions are specified for each spectrum
(temperature of 25 °C unless specified). Chemical shifts (δ) are
given in ppm relative to the resonance of the solvent peak. Infrared
spectra were recorded with a Nicolet 380 FT-IR spectrometer. GC
analyses were conducted with a 6890N chromatograph from Ag-
ilent Technologies using a SUPLECOWAX-10 fused silica cap-
illary column (30 mϫ0.25 mmϫ0.25 µm film thickness). The inlet
temperature was set at 200 °C, gas carrier He (53.6 mL/min), pres-
sure 12.04 psi, flow 1 mL/min, detector FID 250 °C, H2 flow
30 mL/min, air flow 406 mL/min, He 1 mL/min (see below for re-
tention times and gradients). Elemental analyses were performed
at the Institut für Organische Chemie, Freiburg in Breisgau. High-
and low-resolution mass spectroscopy was conducted at the Uni-
versity of Strasbourg. Melting points were determined on a Gallen-
kamp melting point apparatus. Specific rotations were measured
with a Perkin–Elmer apparatus: values are given in 10–1 degcm2 g–1.
Figure 4. Proposed rationale for the observed syn diastereoselectiv-
ity.
Conclusions
A comprehensive study of 1,2-diastereoselective C–C
bond-forming reactions in the synthesis of chiral β-
branched α-amino acids has been performed. Copper-medi-
ated 1,2-diastereoselective oDPPB-directed allylic substitu-
tion with an oxazolidine group as the chiral auxiliary on
an open-chain substrate and primary leaving group readily
obtained from Garner’s aldehyde has been successfully per-
formed. By using this strategy very-good-to-excellent regio-
tert-Butyl (4S)-4-[(1E)-3-Methoxy-3-oxoprop-1-enyl]-2,2-dimethyl-
1,3-oxazolidine-3-carboxylate (2):[6b] A mixture of (R)-Garner’s al-
dehyde 1 (3.8 g, 16.6 mmol), trimethyl phosphonoacetate (6.6 mL,
33.2 mmol), tetrabutylammonium iodide (613 mg, 1.66 mmol) and
3  aqueous K2CO3 (8 mL, 23 mmol) was stirred at room temp.
for 16 h. The mixture was diluted with water (40 mL) and extracted
with EtOAc (3ϫ). The organic layer was washed with brine and
dried with Na2SO4. The solvents were removed under reduced pres-
selectivities in favour of the SN2Ј product were observed. sure and the residue was purified over silica gel chromatography
(heptane/EtOAc, 7:3) to yield the desired E isomer in a pure form
(4.87 g, 88%). Rf = 0.59 (hexane/Et2O, 7:3). H NMR (200 MHz,
60 °C, C6D6): δ = 6.88 (dd, J = 15, 7 Hz, 1 H), 5.95 (br. t, J =
15 Hz, 1 H), 4.63–4.49 (m, 0.5 H), 4.49–4.36 (m, 0.5 H), 4.10 (dd,
J = 9, 6 Hz, 1 H), 3.80 (dd, J = 9, 2 Hz, 1 H), 3.76 (s, 3 H), 1.56
(s, 3 H), 1.50 (s, 3 H), 1.42 (s, 9 H) ppm.
Notably, the geometry of the alkene is directly related to
the stereochemical outcome of the SN2Ј reaction. Thus, the
E stereoisomer led preferentially to the anti diastereomer in
good-to-very-good dr values and yields. Conversely, the Z
isomer furnished the syn SN2’ product in very-good-to-ex-
cellent dr values and yields. The resulting substitution prod-
ucts could be used for the preparation of naturally occur-
ring β-branched α-amino acids in a straightforward man-
ner. The selectivity of our substrates may be explained by a
model that involves a reactive conformation as a result of
minimization of allylic strain combined with an intramolec-
ular oDPPB-directed organometallic nucleophile delivery.
From non-directed allylic substitutions and reactions of di-
oxolane analogues it appears that the Boc group coordi-
nates the copper atom, enhancing the conformational sta-
bility of the Z substrate. Finally, a methallyl derivative of
Garner’s aldehyde underwent regio- and diastereoselective
hydroformylation to yield a useful orthogonally protected
glutamic acid derivative. From this detailed study it is clear
that the preparation of anti diastereomers of β-branched α-
amino acids still remains a challenging task.
1
tert-Butyl (4S)-4-[(1Z)-3-Methoxy-3-oxoprop-1-enyl]-2,2-dimethyl-
1,3-oxazolidine-3-carboxylate (3):[32] Into a dry flask under argon
was introduced successively bis(2,2,2-trifluoroethyl) (methoxycar-
bonyl)methylphosphonate (1.00 g, 3.14 mmol), 18-crown-6 com-
plexed with acetonitrile (6.6 g, 5.5 equiv.) and anhydrous THF
(48 mL). The mixture was cooled to –78 °C and a 0.5  solution
of KHMDS (6.36 mL, 5.18 mmol) in toluene was added dropwise.
After 15 min of stirring at –78 °C a solution of 1 (600 mg,
2.62 mmol) in anhydrous THF (6 mL) was added dropwise and the
reaction mixture was allowed to gradually reach 0 °C. The reaction
was quenched with a solution of saturated aqueous NH4Cl and
extracted with Et2O several times. The organic layer was dried with
MgSO4 and the solvent was removed under reduced pressure. The
residue was purified by flash chromatography (heptane/EtOAc, 8:2)
to yield the desired product (638 mg, 85%) as a white solid. 1H
NMR (300 MHz, 50 °C, CDCl3): δ = 6.27 (br. m, 1 H), 5.84 (br.
d, J = 11.2 Hz, 1 H), (br. t, J = 6.6 Hz, 1 H), 4.27 (br. t, J = 7.8 Hz,
1 H), 3.77 (dd, J = 3.1, 8.7 Hz, 1 H), 3.71 (s, 3 H, Me), 1.62 (s, 3 H,
Me), 1.55 (s, 3 H, Me), 1.43 (s, 9 H, tBu) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.60 (CO), 152.60/151.60 (rotamers, CO), 120.0
(CH), 119.4 (CH), 94.8 (Cquat), 80.3 (Cquat), 69.4/69.1 (rotamers,
CH2), 57.0/55.9 (rotamers, CH), 51.7 (CH3), 28.7 (tBu), 27.7/26.9
(rotamers, CH3), 25.2/24.1 (rotamers, CH3) ppm.
Experimental Section
General: All reagents were used as purchased from commercial sup-
pliers without further purification. The reactions were carried out
in oven- or flame-dried vessels and performed under argon. Sol-
vents were dried and purified by conventional methods prior to
use. Et2O and THF were freshly distilled from sodium/benzophe-
tert-Butyl (4S)-4-[(1E)-3-Hydroxyprop-1-enyl]-2,2-dimethyl-1,3-ox-
azolidine-3-carboxylate (4):[9] Into a dry round-bottomed flask un-
none and dichloromethane was distilled from CaH2. Flash column der argon was introduced the unsaturated ester
chromatography was performed with Merck silica gel 60 (0.040–
0.063 mm, 230–400 mesh). Merck aluminium-backed plates pre-
2
(300 mg,
1.05 mmol) and anhydrous THF (3 mL). The solution was cooled
to 0 °C using an ice bath and a solution of DIBAL-H (2.48 mL,
6010
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6005–6018

Synthesis of Chiral β-Branched α-Amino Acids
1.0  in THF) was added dropwise with stirring. After 1.5 h at 0 °C
the mixture was poured into MeOH (15 mL) followed after a few
minutes by a solution of sodium potassium tartrate (10 mL), water
and EtOAc. The heterogeneous mixture was stirred overnight. The
mixture was extracted with EtOAc and the organic layer was
washed with brine before being dried with MgSO4. The solvent was
removed under reduced pressure. Purification by flash chromatog-
raphy (heptane/EtOAc, 6:4) yielded 4 as a colourless oil (82%). Rf
The solution was stirred at room temp. and NEt3 (0.56 mL,
4 mmol) followed by MsCl (0.31 mL, 4 mmol) were added. The
mixture was stirred overnight and the organic layer was washed
successively with water and brine. The organic layer was removed
under reduced pressure. DMF (5 mL) and LiCl (340 mg, 8 mmol)
were added to the dry oily residue (0.66 g, 2 mmol). The mixture
was stirred at room temp. until no more starting material could be
detected by TLC (ca. 3 h). The solvent was removed under reduced
pressure and the residue was taken up in water and extracted sev-
1
= 0.40 (cyclohexane/EtOAc, 6:4). H NMR (300 MHz, CDCl3): δ
= 5.78–5.72 (m, 2 H), 4.41/4.31 (rotamers, br. m, 1 H), 4.16 (br. d, eral times with Et2O. The ethereal layer was washed with brine
J = 4.7 Hz, 2 H), 4.05 (dd, J = 8.9, 6.2 Hz, 1 H), 3.75 (dd, J = 8.8, before being dried with MgSO4. The solvent was removed under
2.2 Hz, 1 H), 1.60 (s, 3 H), 1.51 (s, 3 H), 1.46 (s, 9 H) ppm. 13C
reduced pressure and the residue was purified by silica gel column
NMR (75 MHz, CDCl3): δ = 152.4/152.1 (rotamers, CO), 131.5/
chromatography (heptane/Et2O, 7:3) to yield 320 mg (58%) of the
131.2 (rotamers, CH), 130.0/129.5 (rotamers, CH), 94.0 (Cquat), desired product as a light-yellow solid. Rf = 0.27 (cyclohexane/
80.6/79.8 (rotamers, Cquat), 68.33 (CH2), 62.7 (CH2), 58.9 (CH), EtOAc, 8:2). Mp 62 °C. [α]2D0 = +16.1 (c = 1, CHCl3). 1H NMR
28.6 (tBu), 27.4/26.8 (rotamers, CH3), 25.0/23.9 (rotamers,
CH3) ppm.
(300 MHz, 50 °C, CDCl3): δ = 5.75 (br. d, J = 3.8 Hz, 2 H), 4.33
(br. s, 1 H), 4.03 (m, 3 H), 3.73 (dd, J = 9.1, 2.2 Hz, 1 H), 1.60 (s,
3 H, Me), 1.51 (s, 3 H, Me), 1.46 (s, 9 H, tBu) ppm. 13C NMR
(300 MHz, 50 °C, CDCl3): δ = 152.2 (CO), 134.1 (CH), 128.1 (CH),
94.4 (Cquat), 80.4 (Cquat), 68.3 (CH2), 58.7 (CH), 44.5 (CH2), 28.8
(tBu), 27.2 (CH3), 24.4 (CH3) ppm. LRMS: m/z = 298.166 [M +
Na]+. HRMS (ESI + HCOOLi): calcd. for [M + Li]+ 282.1443;
found 282.1438.
tert-Butyl (4S)-4-[(1Z)-3-Hydroxyprop-1-enyl]-2,2-dimethyl-1,3-ox-
azolidine-3-carboxylate (5):[9] Into a dry round-bottomed flask un-
der argon was introduced the unsaturated ester
3 (300 mg,
1.05 mmol) and anhydrous THF (3 mL). The solution was cooled
to 0 °C using an ice bath and a solution of DIBAL-H (2.48 mL,
1.0  in THF) was added dropwise with stirring. After 1.5 h at 0 °C
the mixture was poured into MeOH (15 mL) followed after a few
minutes by a solution of sodium potassium tartrate (10 mL), water
and EtOAc. The heterogeneous mixture was stirred overnight. The
mixture was extracted with EtOAc and the organic layer was
washed with brine before being dried with MgSO4. The solvent was
removed under reduced pressure. Purification by flash chromatog-
raphy (heptane/EtOAc, 1:1) yielded 5 as a colourless oil (251 mg,
93%). Rf = 0.55 (cyclohexane/EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 5.85 (ddd, J = 10.5, 8.5, 6.5 Hz, 1 H), 5.53 (t, J =
10.5 Hz, 1 H), 4.90 (br. dd, J = 10.0, 6.5 Hz, 1 H), 4.42 (br. dd, J
= 12.0, 8.5 Hz, 1 H), 4.23 (br. s, 0.5 H), 4.14 (br. s, 0.5 H), 4.04
(dd, J = 6.0, 9.0 Hz, 1 H), 3.88 (m, 1 H), 3.69 (dd, J = 9.0, 1.5 Hz,
1 H), 1.57 (s, 3 H), 1.48 (s, 3 H), 1.45 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.5 (CO), 130.9 (CH), 130.2 (CH), 93.5
(Cquat), 81.0 (Cquat), 68.0 (CH2), 57.6 (CH2), 53.7 (CH), 28.4 (tBu),
27.6 (CH3), 24.8 (CH3) ppm.
Experimental Conditions for Table 1
Entry 1: Into a dry round-bottomed flask under argon was intro-
duced 6 (50 mg, 0.167 mmol) with CuCN (7.5 mg, 0.084 mmol) in
anhydrous diethyl ether (5 mL). The mixture was placed at –78 °C
and then a solution of 3.0  of MeMgBr (0.111 mL, 0.334 mmol)
was added dropwise. The colourless solution was allowed to reach
room temp. over a period of 2 h (the mixture goes yellow at 0 °C).
The reaction was quenched with saturated aqueous NH4Cl. The
aqueous layer was extracted three times with EtOAc. The organic
layer was dried with MgSO4 and evaporated under reduced pres-
sure. The crude mixture was directly injected into a GC apparatus.
Entry 3: Into a dry round-bottomed flask under argon was intro-
duced CuI (35 mg, 0.181 mmol) and anhydrous THF (0.9 mL). The
mixture was cooled to –30 °C and a 1.3  solution of MeLi in di-
ethyl ether (0.140 mL, 0.181 mmol) was added dropwise (colourless
solution). After 5 min of stirring at this temperature the mixture
was cooled to –70 °C and BF3·OEt2 was added (23 µL,
0.181 mmol). The solution turned yellow. Finally, after a few min-
utes of stirring at –70 °C a solution of 7 (50 mg, 0.181 mmol) in
anhydrous THF (0.9 mL) was added dropwise. The mixture was
allowed to reach room temp. The reaction was quenched with satu-
rated aqueous NH4Cl and the aqueous layer was extracted three
times with EtOAc. The organic layer was dried with MgSO4 and
evaporated under reduced pressure. The crude mixture was directly
injected into a GC apparatus.
tert-Butyl (4S)-4-[(1E)-3-(Acetyloxy)prop-1-enyl]-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (6): Into a dry flask under argon was in-
troduced
4 (200 mg, 0.78 mmol), anhydrous dichloromethane
(7.6 mL), NEt3 (0.32 mL, 2.33 mmol) and acetic anhydride
(0.22 mL, 2.33 mmol) at room temp. DMAP was added (10 mg,
0.10 mmol) and the reaction mixture was stirred overnight at room
temp. The solvent was removed under reduced pressure and the
residue was taken up in water and extracted with EtOAc (3ϫ). The
organic layer was dried with MgSO4 and the solvent was removed
under reduced pressure. The residual oil was purified over a silica
gel column (heptane/EtOAc, 8:2) to yield a colourless liquid
(0.175 mg, 78%). Rf = 0.26 (cyclohexane/EtOAc, 8:2). [α]2D0 = +11.7
Entry 4: Into a dry flask under argon was introduced CuBr·SMe2
(37.2 mg, 0.181 mmol) and anhydrous THF (0.36 mL). The suspen-
sion was cooled to –70 °C and a solution of 1.3  of MeLi in Et2O
(280 µL, 0.362 mmol) was added dropwise. The solution was then
allowed to reach 0 °C and was stirred for an additional 10 min
before cooling again to –70 °C. A 1  solution of ZnCl2 (181 µL,
0.181 mmol) was added dropwise. The mixture was stirred for
10 min at this temperature and 7 (50 mg, 0.181 mmol) was added.
The reaction was kept at –70 °C for 15 h and then 2 h at –40 °C.
The reaction was diluted with heptane and washed with saturated
aqueous NaHCO3. The organic layer was dried with MgSO4 and
evaporated under reduced pressure. The crude mixture was directly
injected into a GC apparatus.
1
(c = 1, CHCl3). H NMR (300 MHz, 50 °C, CDCl3): δ = 5.68 (br.
d, J = 4.3 Hz, 2 H), 4.51 (br. d, J = 4.1 Hz, 2 H), 4.27 (br. m, 1
H), 4.10–3.96 (m, 1 H), 3.68 (dd, J = 8.9, 2.4 Hz, 1 H), 1.99 (s, 3
H), 1.54 (s, 3 H), 1.45 (s, 3 H), 1.39 (s, 9 H) ppm. 13C NMR
(300 MHz, CDCl3): δ = 170 (CO), 151.9 (CO), 133.7 (CH), 126.0
(CH), 94.0 (Cquat), 79.9 (Cquat), 68.1 (CH2), 64.1 (CH2), 58.6 (CH),
28.4 (tBu), 26.9 (CH3), 24.1 (CH3), 20.8 (CH3) ppm. HRMS (ESI
positive, HCOOLi): calcd. for [M + Li]+ 306.1887; found 306.1893.
tert-Butyl
(4S)-4-[(1E)-3-Chloroprop-1-enyl]-2,2-dimethyl-1,3-ox-
azolidine-3-carboxylate (7): Into a dry flask under argon was intro-
duced 4 (0.53 g, 2 mmol) in anhydrous dichloromethane (32 mL).
Eur. J. Org. Chem. 2010, 6005–6018
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6011

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann
FULL PAPER
General Procedure for the Coupling of the Directing Group with the
Unsaturated Alcohols 4 and 5 to Form the Corresponding Esters 8
and 9: Into a dry round-bottomed flask under argon was intro-
duced the unsaturated alcohol 4 or 5 (285 mg, 1.11 mmol),
oDPPBA (340 mg, 1.11 mmol), DMAP (136 mg, 1.11 mmol), DCC
(229 mg, 1.11 mmol) and dry dichloromethane (5.6 mL, 0.2 ). The
cloudy mixture was stirred at room temp. overnight. Brine was
added and the mixture was extracted three times with dichloro-
methane. The organic layer was dried with MgSO4, filtered and
removed under reduced pressure. The residue was purified by flash
chromatography (heptane/EtOAc, 9:1).
with MgSO4, filtered and the solvent removed under reduced pres-
sure. The residue was purified by flash chromatography (heptane/
EtOAc, 9:1).
tert-Butyl (4S)-2,2-Dimethyl-4-[(1R)-1-methylprop-2-enyl]-1,3-ox-
azolidine-3-carboxylate (Major Diastereomer, 20a): Light-yellow
oil. R = 0.62 (heptane/EtOAc, 7:3). IR (neat): ν = 2926, 1694,
˜
f
1384, 1364, 1254, 1175, 1085, 1056, 543 cm–1. 1H NMR (300 MHz,
50 °C, CDCl3): δ = 5.78 (m, 1 H), 5.04 (m, 2 H), 3.87 (m, 3 H),
2.75 (br. m, 1 H), 1.61 (s, 3 H), 1.55 (s, 3 H), 1.49 (s, 9 H), 1.01 (d,
J = 7.2 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 152.9
(CO), 140.1 (CH), 115.8 (CH2), 94.3/93.8 (rotamers, Cquat), 80.1/
79.7 (rotamers, Cquat), 64.7/64.3 (rotamers, CH2), 61.7/61.5 (CH),
40.8/39.9 (rotamers, CH), 28.7 (tBu), 27.0/26.5 (rotamers, CH3),
24.7/23.2 (rotamers, CH3), 17.2/17.0 (rotamers, CH3) ppm. HRMS
(ESI positive): calcd. for [M + H]+ 256.1907; found 256.1901.
tert-Butyl
prop-1-enyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (8): White
solid (86%). Rf = 0.78 (heptane/EtOAc, 6:4); m.p. 102 °C. [α]2D0
(4S)-4-[(1E)-3-{[2-(Diphenylphosphanyl)benzoyl]oxy}-
=
+10.7 (c = 1, CHCl ). IR (neat): ν = 2981, 1688, 1361, 1248, 1098,
˜
3
1057, 961, 943, 758, 744, 521, 501 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 8.07 (m, 1 H), 7.44–7.25 (m, 12 H), 6.95 (m, 1 H),
5.71 (br. s, 2 H), 4.65 (d, J = 4.8 Hz, 2 H), 4.26–4.30 (2 br. s, 1 H),
4.03 (dd, J = 9.0, 6.3 Hz, 1 H), 3.72 (dd, J = 8.8, 2.6 Hz, 1 H), 1.6
(s, 3 H), 1.51 (s, 3 H), 1.42 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.5 (CO), 151.9 (CO), 140.7 (d, JC,P = 25.4 Hz,
tert-Butyl (4S)-2,2-Dimethyl-4-[(1S)-1-methylprop-2-enyl]-1,3-ox-
azolidine-3-carboxylate (Major Diastereomer, 21a): Light-yellow
oil. R = 0.61 (heptane/EtOAc, 7:3). IR (neat): ν = 2926, 1695,
˜
f
1374, 1364, 1254, 1175, 1084, 1054, 849 cm–1. 1H NMR (300 MHz,
50 °C, CDCl3): δ = 5.82 (m, 1 H), 5.08–5.02 (m, 2 H), 3.94–3.81
(m, 3 H), 2.75 (br. m, 1 H), 1.60 (s, 3 H), 1.49 (s, 9 H, tBu), 1.46
(s, 3 H), 1.01 (d, J = 7.18 Hz, 3 H) ppm. 13C NMR (75 MHz, 50 °C,
CDCl3): δ = 152.6 (CO), 141.1 (CH), 114.7 (CH2), 94.1 (Cquat),
79.8 (Cquat), 68.7 (CH2), 61.1 (CH), 39.9 (CH), 28.6 (tBu), 26.7 (br.
s, CH3), 24.0 (br. s, CH3), 14.2 (CH3) ppm. HRMS (ESI positive):
calcd. for [M + H]+ 256.1907; found 256.1903.
C
quat), 138.0 (d, JC,P = 12.4 Hz, Cquat), 134.4 (br. s, CH), 133.99
(d, JC,P = 20.7 Hz, CHAr), 133.97 (d, JC,P = 20.7 Hz, CHAr), 132.1
(br. s, CHAr), 130.7 (br. s, CHAr), 128.7 (CHAr), 128.5 (d, JC,P
=
7.6 Hz, CHAr), 128.2 (CHAr), 125.8 (CH), 94.1 (Cquat), 79.8 (Cquat),
68.0 (CH2), 64.9 (CH2), 58.7 (CH), 28.5 (tBu), 26.7 (CH3), 23.8
(CH3) ppm. 31P NMR (162 MHz, CDCl3):
δ = –4.53 ppm.
tert-Butyl (4S)-4-[(1R)-1-Ethylprop-2-enyl]-2,2-dimethyl-1,3-oxazol-
idine-3-carboxylate (Major Diastereomer, 20b): Light-yellow oil. Rf
C32H36NO5P (454.61): calcd. C 70.44, H 6.65, N 2.57; found C
70.6, H 6.94, N 2.38. Chiral HPLC: CHIRALCEL AD-H column
0.46 cmϫ25 cm, flow rate 0.8 mL/min (n-heptane/EtOH, 95/5),
UV 230 nm, Rt: (S)-E 10.25 min (100% E).
= 0.29 (cyclohexane/EtOAc, 8:2). IR (neat): ν = 2928, 1698, 1387,
˜
1
1365, 1259, 1176, 1091 cm–1. H NMR (300 MHz, 50 °C, CDCl3):
δ = 5.67–5.55 (m, 1 H), 5.13–5.00 (m, 2 H), 3.87–3.80 (m, 3 H),
2.46 (br. m, 1 H), 1.55 (s, 3 H), 1.48 (s, 9 H), 1.46 (s, 3 H), 1.26
(m, 2 H), 0.89 (t, J = 7.49 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.8/152.4 (rotamers, CO), 138.7 (CH), 117.7 (CH2),
94.2/93.2 (rotamers, Cquat), 80.0/79.7 (rotamers, Cquat), 64.7/64.3
(rotamers, CH2), 61.1/60.5 (rotamers, CH), 49.0/47.9 (rotamers,
CH), 28.6 (tBu), 26.9/26.3 (rotamers, CH3), 24.8 (CH2), 24.5/24.3
(rotamers, CH3), 12.3 (CH3) ppm. HRMS (ESI positive): calcd. for
[M + H]+ 270.2064; found 270.2052.
tert-Butyl
(4S)-4-[(1Z)-3-{[2-(Diphenylphosphanyl)benzoyl]oxy}-
prop-1-enyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (9): White
solid (97%). Rf = 0.73 (cyclohexane/EtOAc, 1:1); m.p. 96 °C. [α]2D0
= –70.0 (c = 1, CHCl ). IR (neat): ν = 2970, 1712, 1681, 1388, 1377,
˜
3
1268, 1253, 1105, 1065, 757, 744, 696, 526, 400 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.07 (m, 1 H), 7.44–7.25 (m, 12 H), 6.95
(m, 1 H), 5.58 (m, 2 H), 4.89–5.00 (2 br. s, 1 H), 4.68 (m, 2 H),
3.98 (dd, J = 6.3, 9.0 Hz, 2 H), 3.55 (br. s, 1 H), 1.60 (s, 3 H), 1.52
(s, 3 H), 1.43 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.5, 151.8, 140.6 (d, JC,P = 27.0 Hz), 138.0 (d, JC,P = 10.4 Hz),
tert-Butyl (4S)-4-[(1S)-1-Ethylprop-2-enyl]-2,2-dimethyl-1,3-oxazol-
idine-3-carboxylate (Major Diastereomer, 21b): Light-yellow oil. Rf
132.1 (br. s), 134.4, 134.0 (d, JC,P = 20.8 Hz) 133.8 (d, JC,P
=
= 0.41 (cyclohexane/EtOAc, 8:2). IR (neat): ν = 2930, 1694, 1384,
˜
1363, 1255, 1174, 1089, 847, 767 cm–1 1H NMR (300 MHz,
20.6 Hz), 132.1 (br. s), 130.7 (br. s), 128.7 (d, JC,P = 4.1 Hz), 128.50
(d, JC,P = 6.5 Hz), 128.48 (d, JC,P = 7.1 Hz), 128.2, 125.2, 123.6,
94.2/93.5 (rotamers, Cquat), 80.1/79.9 (rotamers, Cquat), 68.6/68.3
(rotamers), 61.0/60.6 (rotamers), 54.5/54.3 (rotamers), 28.5 (tBu),
27.5/26.6 (rotamers), 25.0/23.9 (rotamers) ppm. 31P NMR
(162 MHz, CDCl3): δ = –4.53 ppm. C32H36NO5P (454.61): calcd.
C 70.44, H 6.65, N 2.57; found C 70.21, H 6.67, N 2.53. Chiral
HPLC: CHIRALCEL AD-H column, 0.46 cmϫ25 cm, flow rate
0.8 mL/min (n-heptane/EtOH, 95:5), UV 230 nm, Rt: (S)-E
8.18 min (100% Z).
.
CDCl3): δ = 5.65 (m, 1 H), 5.14–5.00 (m, 2 H), 3.92–3.81 (m, 3 H),
2.39 (m, 1 H), 1.59 (s, 3 H), 1.53 (s, 9 H), 1.46 (s, 3 H), 1.18 (m, 2
H), 0.88 (t, J = 7.49 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 152.9/152.4 (rotamers, CO), 139.5 (CH), 117.2/116.7 (rotamers,
CH2), 94.2/93.6 (rotamers, Cquat), 80.0/79.7 (rotamers, Cquat), 65.7
(CH2), 61.0/60.9 (rotamers, CH), 49.73/49.66 (rotamers, CH), 29.6
(tBu), 27.2/26.4 (rotamers, CH3), 24.6 (CH2), 23.1/22.7 (rotamers,
CH3), 12.2 (CH3) ppm. HRMS (ESI positive): calcd. for [M +
H]+ 270.2064; found 270.2053.
General Procedure for Allylic Substitution Reactions: Into a dry
round-bottomed flask under argon was introduced 8 or 9 (80 mg,
0.146 mmol) in anhydrous Et2O (14.6 mL, 0.01 ) followed by
CuBr·SMe2 (15 mg, 0.073 mmol). The mixture was stirred at room
temp. until the copper salt had completely dissolved (ca. 10 min)
to yield a clear light-yellow solution. Then the alkylmagnesium bro-
mide in diethyl ether at 0.1  (3 mL) was added through a syringe
pump (rate 3 mL/h) at room temp. The mixture was stirred for
an additional 1 h and saturated aqueous NH4Cl was added and
extraction with EtOAc was performed. The organic layer was dried
tert-Butyl (4S)-4-[(1R)-1-Butylprop-2-enyl]-2,2-dimethyl-1,3-oxazol-
idine-3-carboxylate (Major Diastereomer, 20c): Light-yellow oil. Rf
= 0.50 (heptane/EtOAc, 7:3). IR (neat): ν = 2929, 1694, 1384, 1363,
˜
1
1254, 1174, 1090, 913, 847, 767 cm–1. H NMR (300 MHz, 50 °C,
CDCl3): δ = 5.64 (ddd, J = 16.8, 10.3, 9.6 Hz, 1 H), 5.11 (dd, J =
10.3, 2.1 Hz, 1 H), 4.98 (dd, J = 16.8, 2.1 Hz, 1 H), 3.87 (m, 3 H),
2.55 (br. m, 1 H), 1.54 (s, 3 H), 1.48 (s, 9 H), 1.46 (s, 3 H), 1.33–
1.26 (m, 6 H), 0.90 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 152.8/152.3 (rotamers, CO), 139.1 (CH), 117.5 (CH2),
94.2/93.7 (rotamers, Cquat), 80.0/79.7 (rotamers, Cquat), 64.7/64.3
6012
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6005–6018

Synthesis of Chiral β-Branched α-Amino Acids
(rotamers, CH2), 61.2/60.8 (rotamers, CH), 46.9/46.1 (rotamers,
CH), 31.3/31.1 (rotamers, CH2), 30.9, 28.6 (tBu), 26.9/26.3 (rota-
mers, CH3), 24.8/23.2 (rotamers, CH3), 22.8 (CH2), 14.1
(CH3) ppm. HRMS (ESI positive): calcd. for [M + H]+ 298.2377;
found 298.2375.
EtOAc, 7:3). [α]2D0 = +96.6 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3, 50 °C): δ = 4.46 (br. m, 1 H), 3.99–3.90 (m, 2 H), 2.21 (d,
J = 1.7 Hz, 1 H), 1.55 (br. s, 3 H), 1.42 (br. s, 12 H) ppm. 13C
NMR (75 MHz, CDCl3, 50 °C): δ = 151.5 (CO), 94.3 (Cquat), 82.8
(Cquat), 80.4 (Cquat), 70.3 (CH), 68.7 (CH2), 48.4 (CH), 28.4 (tBu),
26.1 (CH3), 24.7 (CH3) ppm.
tert-Butyl (4S)-4-[(1S)-1-Butylprop-2-enyl]-2,2-dimethyl-1,3-oxazol-
idine-3-carboxylate (Major Diastereomer, 21c): Light-yellow oil. Rf
tert-Butyl (S)-4-(3-Hydroxyprop-1-ynyl)-2,2-dimethyloxazolidine-3-
carboxylate (11):[34] Into a dry flask under argon was introduced
alkyne 10 (205 mg, 0.910 mmol) in anhydrous THF (5 mL). The
solution was cooled to –78 °C and a 1.42  solution of nBuLi in
hexanes (673 µL, 0.955 mmol) was added dropwise. The mixture
was stirred at –78 °C for 30 min and paraformaldehyde (273 mg,
9.100 mmol) was added in one portion. The mixture was allowed
to reach room temp. Saturated aqueous NH4Cl was added and the
mixture was extracted with DCM (3ϫ). The organic layer was dried
with Na2SO4 and removed under reduced pressure. The residue was
purified by silica gel chromatography (heptane/EtOAc, 7:3) to yield
a colourless oil (101 mg, 43%). Rf = 0.12 (heptane/EtOAc, 7:3). [α]
= 0.63 (heptane/EtOAc, 7:3). IR (neat): ν = 2928, 1694, 1385, 1363,
˜
1252, 1175, 1087, 912, 848, 767, 544 cm–1. 1H NMR (300 MHz,
50 °C, CDCl3): δ = 5.64–5.55 (m, 1 H), 5.10–4.98 (m, 2 H), 3.91–
3.79 (m, 3 H), 2.42 (m, 1 H), 1.58 (s, 3 H), 1.48 (s, 12 H), 1.34–
1.26 (m, 6 H), 0.87 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 152.4 (CO), 139.9 (CH), 117.0/116.4 (rotamers, CH2),
94.2/93.6 (rotamers, Cquat), 80.0/79.7 (rotamers, Cquat), 65.6 (CH2),
61.1 (CH), 47.5 (CH), 30.8 (CH2), 29.8/29.7 (rotamers, CH2), 28.6
(tBu), 27.2/26.4 (rotamers, CH3), 24.7/23.1 (rotamers, CH3), 22.8
(CH2), 14.1 (CH3) ppm. HRMS (ESI positive): calcd. for [M +
Na]+ 320.2196; found 320.2209.
20
1
= +100.4 (c = 1, CHCl3). H NMR (200 MHz, CDCl3, 50 °C):
D
tert-Butyl (4S)-4-[(1R)-1-Isopropylprop-2-enyl]-2,2-dimethyl-1,3-ox-
azolidine-3-carboxylate (Major Diastereomer, 20d): Light-yellow
δ = 4.57 (br. m, 1 H), 4.25 (br. d, J = 1.3 Hz, 2 H), 4.07–3.93 (m,
2 H), 2.21 (br. s, 1 H, OH), 1.60 (br. s, 3 H), 1.49 (br. s, 12 H) ppm.
13C NMR (50 MHz, CDCl3, 50 °C): δ = 151.8 (CO), 94.43 (Cquat),
84.5 (Cquat), 80.9 (Cquat), 80.7 (Cquat), 68.9 (CH2), 51.1 (CH2), 48.8
(CH), 28.6 (tBu), 26.5 (CH3), 25.0 (CH3) ppm.
oil. R = 0.65 (heptane/EtOAc, 7:3). IR (neat): ν = 2930, 1695,
˜
f
1382, 1253, 1175, 1098, 1054, 963, 850, 768 cm–1. 1H NMR
(300 MHz, 50 °C, CDCl3): δ = 5.64 (ddd, J = 16.8, 10.3, 10.1 Hz,
1 H), 5.12 (dd, J = 10.3, 2.4 Hz, 1 H), 5.00 Hz (dd, J = 16.8, 2.2 Hz,
1 H), 4.10 (br. m, 1 H), 3.92 (m, 2 H), 2.34 (br. m, 1 H), 1.56 (s, 3
H), 1.48 (s, 9 H), 1.45 (s, 3 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.89 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 152.2
(CO), 137.5/137.2 (rotamers, CH), 118.4 (CH2), 94.2/93.7 (rota-
mers, Cquat), 79.9/79.7 (rotamers, Cquat), 64.3/64.2 (rotamers, CH2),
59.3/59.1 (rotamers, CH), 53.5/52.3 (rotamers, CH), 29.8, 29.2/28.8
(rotamers, tBu), 26.7/26.0 (rotamers, CH3), 24.8, 23.2, 22.3 (CH3),
21.2 (CH3) ppm. HRMS (ESI positive): calcd. for [M + Na]+
306.2040; found 306.2033.
tert-Butyl (S)-4-{3-[2-(Diphenylphosphanyl)phenylcarbonyloxy]prop-
1-ynyl}-2,2-dimethyloxazolidine-3-carboxylate (12): Into a dry flask
under argon was introduced alcohol 11 (99 mg, 0.388 mmol) in
DCM (2 mL). oDPPBA (119 mg, 0.388 mmol), DCC (80 mg,
0.388 mmol) and DMAP (48 mg, 0.388 mmol) were added at room
temp. The mixture was stirred overnight and brine was added and
the mixture was extracted with DCM (3ϫ). The organic layer was
dried with Na2SO4 and the solvent was removed under reduced
pressure. The residue was purified by silica gel chromatography
(heptane/EtOAc, 8:2) to yield the desired product as a white solid
(187 mg, 90%); m.p. 110 °C. [α]2D0 = +37.6 (c = 1, CHCl3). Rf =
tert-Butyl (4S)-4-[(1S)-1-Isopropylprop-2-enyl]-2,2-dimethyl-1,3-ox-
azolidine-3-carboxylate (Major Diastereomer, 21d): Light-yellow
0.32 (petroleum ether/Et O, 7:3). IR (neat): ν = 2985, 2360, 1707,
˜
2
1689, 1364, 1250, 1092, 1057, 756, 695 cm–1. H NMR (300 MHz,
1
oil. R = 0.62 (heptane/EtOAc, 7:3). IR (neat): ν = 2929, 1694,
˜
f
1384, 1364, 1253, 1173, 1089, 912, 848, 767, 545 cm–1. 1H NMR
(300 MHz, 50 °C, CDCl3): δ = 5.81 (m, 1 H), 5.14–4.87 (m, 2 H),
4.14–3.70 (m, 3 H), 2.11 (m, 1 H), 1.69 (m, 1 H), 1.55 (s, 3 H), 1.50
(s, 3 H), 1.49 (s, 9 H), 0.89 (d, J = 7.0 Hz, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.1 (CO), 136.3/135.6 (rotamers, CH),
118.7/117.6 (rotamers, CH2), 94.0/93.4 (rotamers, Cquat), 79.8
(Cquat), 67.6/67.1 (rotamers, CH2), 59.0/58.9 (rotamers, CH), 55.8/
55.2 (rotamers, CH), 29.8 (CH), 29.0/28.6 (rotamers, tBu), 27.5/
26.8 (rotamers, CH3), 24.8, 23.3, 22.3, 21.3, 17.0 (CH3), 16.6
(CH3) ppm. HRMS (ESI positive): calcd. for [M + H]+ 284.2220;
found 284.2215.
CDCl3, 50 °C): δ = 8.12–8.06 (m, 1 H), 7.43–7.26 (m, 12 H), 7.01–
6.97 (m, 1 H), 4.78 (d, J = 1.8 Hz, 2 H), 4.59 (br. s, 1 H), 4.07–
3.97 (m, 2 H), 1.64 (br. s, 3 H), 1.52 (br. s, 3 H), 1.50 (br. s, 9
H) ppm. 13C NMR (50 MHz, CDCl3, 50 °C): δ = 165.9 (CO), 151.6
(CO), 141.2 (d, JC,P = 28.0 Hz, Cquat), 138.1 (d, JC,P = 12.7 Hz,
Cquat), 134.5 (CHAr), 134.5 (CHAr), 134.3 (CHAr), 133.9 (CHAr),
132.2 (CHAr), 130.9 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.5
(CHAr), 128.2 (CHAr), 94.5 (Cquat), 86.0 (Cquat), 76.2 (Cquat), 68.7
(CH2), 53.0 (CH2), 48.8 (CH), 28.6 (tBu), 26.4 (br., CH3), 24.9 (br.,
CH3) ppm. 31P NMR (121 MHz, CDCl3): δ = –3.8 ppm. HRMS
(ESI positive): calcd. for [M + H]+ 544.2247; found 544.2224.
tert-Butyl
(S)-4-(Buta-2,3-dien-2-yl)-2,2-dimethyloxazolidine-3-
(S)-2,2-Dimethyl-3-(tert-butoxycarbonyl)-4-ethynyloxazolidine
(10):[33] Into a dry flask under argon was introduced dimethyl (2-
oxopropyl)phosphonate (2.13 mL, 14.8 mmol) in anhydrous chlo-
roform (36 mL). The solution was cooled to 0 °C and under vigor-
ous stirring 4-acetamidobenzenesulfonyl azide (3.67 g, 15.3 mmol)
and potassium carbonate (2.1 g, 15.2 mmol) were added. The solu-
tion was stirred between 0 and 10 °C for 48 h. Then a solution of
1 (1.0 g, 4.46 mmol) in anhydrous methanol (36 mL) was added
dropwise at 0 °C. The mixture was stirred for 24 h at 0 °C with
additional potassium carbonate (0.96 g, 7.0 mmol). Saturated
aqueous NH4Cl was then added and the mixture was extracted
with chloroform. The organic layer was dried with Na2SO4 and the
solvents were removed under reduced pressure. The residue was
purified over silica gel column (pentane/Et2O, 9:1) to yield the de-
sired alkyne as a colourless oil (697 mg, 71%). Rf = 0.40 (heptane/
carboxylate (23): Prepared by using the general procedure for the
directed allylic substitution. Colourless oil. Rf = 0.59 (heptane/
Et O, 7:3). IR (neat): ν = 2925, 1698, 1375, 1364, 1088, 848 cm–1.
˜
2
1H NMR (300 MHz, 50 °C, CDCl3): δ = 4.74 (br. s, 2 H), 4.30 (br.
m, 1 H), 4.06 (dd, J = 8.8, 6.6 Hz, 1 H), 3.88 (dd, J = 8.8, 2.1 Hz,
1 H), 1.7 (t, J = 3.0 Hz, 3 H), 1.62 (br. s, 3 H), 1.50 (br. s, 3 H),
1.47 (br. s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 206.3/206.1
(Cquat), 152.2 (CO), 99.6/99.1 (Cquat), 94.3/93.8 (Cquat), 80.2/79.6
(Cquat), 77.5/77.0 (CH2), 67.7/67.1 (CH2), 59.9 (CH), 28.5 (tBu),
26.7/25.9 (CH3), 23.5/22.9 (CH3), 15.7/15.2 (CH3) ppm. HMRS
(ESI positive + HCOOLi): calcd. for [M + Li]+ 260.1833; found
260.1825.
tert-Butyl (4S)-2,2-Dimethyl-4-[(1S)-1-methylpropyl]-1,3-oxazolid-
ine-3-carboxylate (Major Diastereomer, 24): Into a suitable flask
Eur. J. Org. Chem. 2010, 6005–6018
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6013

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann
FULL PAPER
was introduced 21a (80 mg, 0.31 mmol) and EtOAc/MeOH (9 mL,
1:1). Then Pd(OH)2/C 20% (62 mg) was added. The flask was
purged with H2 before setting a pressure of 5 bar for 2 h at room
temp. The mixture was filtered through a plug of Celite. The sol-
vent was removed under reduced pressure and the residue was puri-
reduced pressure. The desired product was obtained as a white solid
(90 mg, 95%) and needed no further purification. Rf = 0.29 (hep-
1
tane/EtOAc, 7:3). H NMR (300 MHz, CDCl3): δ = 4.94 (br. d, J
= 6.9 Hz, 1 H), 3.70–3.43 (m, 3 H), 2.90 (br. s, 1 H), 1.41 (s, 9 H),
0.97 (br. s, 3 H), 0.60–0.30 (m, 3 H), 0.20–0.16 (m, 1 H), 0.03–0.04
(m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.9 (CO), 79.5
fied through a silica gel column (heptane/EtOAc, 9:1) to yield a
1
colourless oil (75 mg, 95%). H NMR (300 MHz, 50 °C, CDCl3): (Cquat), 64.1 (CH2), 58.0 (CH), 39.9 (CH), 28.5 (tBu), 17.1 (CH3),
δ = 4.40–4.27 (m, 3 H), 2.08 (br. m, 1 H), 1.63 (s, 3 H), 1.49 (s, 12 14.4 (CH), 5.3 (CH2), 2.8 (CH2) ppm. HRMS (ESI positive): calcd.
H), 1.33–1.24 (m, 1 H), 1.14–1.05 (m, 1 H), 0.83 (t, J = 8.9 Hz, 3
H), 0.75 (d, J = 8.3 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 152.8 (CO), 94.0/93.5 (rotamers, Cquat), 79.9/79.6 (rotamers,
for [M + Na]+ 252.1570; found 252.1557.
(2S,3S)-2-[(tert-Butoxycarbonyl)amino]-3-cyclopropylbutanoic Acid
(Major Diastereomer, 28):
A stock solution of H5IO6/CrO3
Cquat), 63.9 (CH2), 61.6/60.8 (rotamers, CH), 37.0/35.9 (rotamers,
(1.25 mL; H5IO6, 5 g, 0.22 mmol, CrO3, 10 mg, 0.1 mmol, MeCN
49.6 mL, H2O, 0.4 mL) was added dropwise to a solution of 27
(50 mg, 0.218 mmol) in MeCN (containing 0.75% of H2O;
2.75 mL) at 0 °C. After 2 h no further starting material could be
detected by TLC. The crude mixture was diluted in toluene and a
phosphate buffer (pH 5.8) was added. The organic phase was sepa-
rated and dried with MgSO4. The solvent was removed under re-
duced pressure and the residue was purified by silica gel column
chromatography (100% EtOAc) to yield the desired compound
CH), 28.6 (tBu), 26.8 (CH2), 26.8/26.2 (rotamers, CH3), 24.5/22.9
(rotamers, CH3), 14.2/13.8 (rotamers, CH3), 12.3 (CH3) ppm.
HRMS (ESI positive): calcd. for [M + 1]+ 258.2037; found
258.2060.
tert-Butyl (4S)-2,2-Dimethyl-4-[(1R)-1-methyl-2-oxopropyl]-1,3-ox-
azolidine-3-carboxylate (Major Diastereomer, 25): Into a round-
bottomed flask was introduced CuCl (33 mg, 0.329 mmol), PdCl2
(12 mg, 0.066 mmol) and DMF/H2O (0.4 mL, 10:1). The mixture
was stirred at room temp. for 2 h under O2 (the mixture turned
black). Then a solution of 21a (84 mg, 0.329 mmol) in DMF/H2O
(0.4 mL, 10:1) was added. The mixture was stirred overnight. A
solution of saturated aqueous NH4Cl was added and the mixture
was extracted with diethyl ether (3ϫ). The organic layer was dried
with MgSO4 and the solvent was removed under reduced pressure.
The resulting oil was purified through a silica gel column (heptane/
EtOAc, 9:1) to yield 60 mg of the desired product (68%) and 11 mg
of starting material (78% brsm). Rf = 0.52 (heptane/EtOAc, 6:4).
(90 mg, 85%). Rf
=
0.30 (heptane/EtOAc, 1:1). 1H NMR
(300 MHz, CDCl3): δ = 7.51 (br. s, 1 H), 5.22 (br. d, J = 8.7 Hz, 1
H), 4.40 (m, 1 H), 1.46 (s, 9 H), 1.07 (d, J = 6.9 Hz, 3 H), 0.67 (m,
1 H), 0.46 (m, 2 H), 0.25 (m, 1 H), 0.08 (m, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 177.1 (CO), 155.9 (CO), 80.1 (Cquat), 58.1
(CH), 41.6 (CH), 28.8 (tBu), 16.9 (CH3), 13.4 (CH), 4.4 (CH2), 3.2
(CH2) ppm. HRMS (ESI positive): calcd. for [M + Na]+ 266.1363;
found 266.1439.
(2S,3S)-2-Amino-3-cyclopropylbutanoic Acid (Major Diastereomer,
29):[14c] Into a dry flask under argon was introduced 28 (33 mg,
0.136 mmol) and anhydrous DCM (2.5 mL). Then trifluoroacetic
acid (188 µL, 2.448 mmol) was added at room temp. The mixture
was stirred overnight and then it was evaporated under reduced
pressure to yield the desired product as a TFA salt in a quantitative
yield (syn/anti, 10:90). 1H NMR (400 MHz, D2O/DMSO): δ = 3.87
(d, J = 4.7 Hz, 1 H), 1.28 (m, 1 H), 0.97 (d, J = 6.7 Hz, 3 H), 0.55
(m, 1 H), 0.36 (m, 2 H), 0.08 (m, 1 H), 0.00 (m, 1 H) ppm. 13C
NMR (100 MHz, D2O/DMSO): δ = 173.3 (CO), 59.7 (CH), 41.0
(CH), 17.3 (CH3), 14.4 (CH), 5.6 (CH2), 4.4 (CH2) ppm. LRMS
(ESI positive): calcd. for [M + H]+ 144.1; found 144.1.
IR (neat): ν = 2978, 2933, 1694, 1365, 1169 cm–1. 1H NMR
˜
(300 MHz, 50 °C, CDCl3): δ = 4.20 (br. m, 1 H), 3.99–3.78 (m, 2
H), 3.26 (br. m, 1 H), 2.16 (s, 3 H), 1.59 (s, 3 H), 1.47 (s, 9 H), 1.45
(s, 3 H), 1.12 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 211.3 (CO), 153.0 (CO, tBu), 94.3/93.7 (Cquat), 80.7
(Cquat), 64.6 (CH2), 57.8 (CH), 48.1 (CH), 30.0 (CH3), 28.7 (tBu),
27.1 (CH3), 24.3 (CH3), 10.7 (CH3) ppm. HRMS (ESI positive):
calcd. for [M + H]+ 272.1856; found 272.1869.
tert-Butyl (4S)-4-[(1S)-1-Cyclopropylethyl]-2,2-dimethyl-1,3-oxazol-
idine-3-carboxylate (Major Diastereomer, 26): Into a dry flask con-
taining 21a (118 mg, 0.462 mmol) was added at 0 °C a dry solution
of diazomethane (2.7 mmol, 12 mL) in Et2O. Then Pd(OAc)2
(1.5 mg) was added at 0 °C in one portion and gas evolution was
observed. After 10 min at 0 °C the solvent was removed under re-
duced pressure and the residue was purified through a silica gel
column (heptane/EtOAc, 9:1) to yield the desired product (124 mg,
quant.). Rf = 0.61 (heptane/EtOAc, 7:3). 1H NMR (300 MHz,
50 °C, CDCl3): δ = 4.07–3.88 (m, 3 H), 1.70 (m, 1 H), 1.61 (rota-
mers, 3 H), 1.49 (rotamers, 12 H), 0.98 (d, J = 7.0 Hz, 3 H), 0.87
(m, 1 H), 0.55–0.38 (m, 2 H), 0.24 (m, 1 H), 0.06 (m, 1 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 152.8/152.6 (rotamers, CO), 94.1/
93.6 (rotamers, Cquat), 79.9/79.5 (rotamers, Cquat), 64.2 (CH2), 61.5/
61.0 (rotamers, CH), 41.0/40.0 (rotamers, CH), 28.6 (tBu), 26.9/
26.1 (rotamers, CH3), 24.6/22.9 (rotamers, CH3), 15.2/14.9 (rota-
mers, CH3), 14.4 (CH), 4.2 (CH2), 3.7 (CH2) ppm. HRMS (ESI
positive): calcd. for [M + H]+ 270.2064; found 270.2064.
Oxidation of the oDPPB Esters 8 and 9: Into a round-bottomed
flask equipped with a magnetic stirring bar was introduced 8 or 9
(179 mg, 0.327 mmol) and dichloromethane (3.5 mL). Then at
room temp. a solution of hydrogen peroxide (35% in water, 313 µL,
3.275 mmol) was added. The mixture was stirred for 3 h and then
extracted with EtOAc. A spatula edge of manganese oxide was
added to the organic layer to eliminate any residual peroxide. The
organic was then dried with MgSO4 and removed under reduced
pressure. The residue was taken up in EtOAc and passed through
a silica gel column (EtOAc, 100%) to yield a waxy solid in quanti-
tative yields.
tert-Butyl (4S)-4-[(1E)-3-{[2-(Diphenylphosphoryl)benzoyl]oxy}prop-
1-enyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (30): Waxy solid.
Rf = 0.41 (EtOAc). [α]2D0 = +20.2 (c = 1, CHCl ). IR (neat): ν =
˜
3
2980, 1728, 1689, 1386, 1253, 1117, 722, 694, 538 cm–1. H NMR
1
tert-Butyl (1S,2S)-2-Cyclopropyl-1-(hydroxymethyl)propylcarbam- (400 MHz, CDCl3): δ = 7.84 (br. dd, J = 7.5, 3.6 Hz, 1 H), 7.64–
ate (Major Diastereomer, 27): Compound 26 (111 mg, 0.412 mmol)
was dissolved in dry MeOH (2 mL) and TFA (0.4 mL, 5.15 mmol)
was added at 0 °C. The mixture was stirred for 3 h at room temp.
and DCM and saturated aqueous Na2CO3. were added to the mix-
ture. The aqueous layer was extracted with DCM (3ϫ). The organic
layer was dried with MgSO4 and the solvent was removed under
7.55 (m, 5 H), 7.50–7.46 (m, 4 H), 7.42–7.39 (m, 4 H), 5.52 (m, 2
H), 4.37 (m, 2.5 H), 4.16 (br. m, 0.5 H), 3.95 (dd, J = 8.7, 6.2 Hz,
1 H), 3.64 (dd, J = 8.9, 2.1 Hz, 1 H), 1.54 (br. s, 3 H), 1.46 (br. s,
3 H), 1.35 (br. s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.8 (CO), 151.8 (CO), 136 (d, JC,P = 6.0 Hz, Cquat), 134.8 (d, JC,P
= 10.9 Hz, CHAr), 134.1 (CH), 133.9 (CHAr), 133.9 (CHAr), 132.83/
6014
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6005–6018

Synthesis of Chiral β-Branched α-Amino Acids
132.80 (rotamers, Cquat), 131.9 (CHAr), 131.8 (CHAr), 131.8 Methyl (2Z)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]acrylate (15):[37]
(CHAr), 131.6 (CHAr), 130.9 (d, JC,P = 11.6 Hz, CHAr), 130.2 (d, A solution of sodium periodate (4.3 g, 20.13 mmol, 30 mL) in
JC,P = 8.6 Hz, CHAr), 128.3 (d, JC,P = 12.5 Hz, CHAr), 125.4 (CH), MeOH/H2O (2:1) was added dropwise to a slurry of 1,2:5,6-di-O-
94.0/93.7 (rotamers, Cquat), 80.2/79.7 (rotamers, Cquat), 67.9 (CH2), isopropylidene--mannitol (4.00 g, 15.25 mmol) in MeOH/H2O
65.3 (CH2), 58.5 (CH), 28.4 (tBu), 27.4/26.6 (rotamers, CH3), 24.8/
(73 mL, 4:1) and 5% aqueous NaHCO3 at 0 °C. The mixture was
solution of
23.7 (rotamers, CH3) ppm. 31P NMR (162 MHz, CDCl3): δ = stirred for 2 h at this temperature and
a
30.99 ppm. HRMS (ESI positive): calcd. for [M + H]+ 562.2353;
found 562.2328.
Ph3PCH2CO2Me (14.78 g, 44.23 mmol, 34 mL) in MeOH was
added dropwise at 0 °C. The mixture was stirred for 24 h at 0 °C
and then extracted with DCM. The organic layer was dried with
MgSO4. The solvent was removed under reduced pressure and the
residue was taken up with a mixture of heptane/Et2O (4:1) and the
white solid was filtered off (triphenylphosphane oxide). The solvent
was removed under reduced pressure and the residue was purified
by silica gel column chromatography (heptane/EtOAc, 9:1) to yield
3.93 g (69%) of the desired product and 0.54 g (9%) of the E isomer
tert-Butyl
(4S)-4-[(1Z)-3-{[2-(Diphenylphosphoryl)benzoyl]oxy}-
prop-1-enyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (31): Waxy
solid. Rf = 0.32 (EtOAc). [α]2D0 = +56.0 (c = 1, CHCl3). IR (neat):
ν = 2957, 1722, 1694, 1283, 1254, 1191, 1121, 724, 693, 532 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 7.88 (br. m, 1 H), 7.66–7.58 (m,
5 H), 7.55–7.48 (m, 4 H), 7.45 (m, 4 H), 5.48 (t, J = 10.2 Hz, 1 H),
5.32 (br. m, 1 H), 4.69/4.64 (rotamers, br. m, 1 H), 4.49 (br. m, 2
H), 3.93 (dd, J = 8.7, 6.5 Hz, 1 H), 3.53 (br. m, 1 H), 1.56 (br. s, 3
H), 1.48 (br. s, 3 H), 1.37 (br. s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.9 (CO), 151.9 (CO), 136.1 (Cquat), 134.9 (CHAr),
134.8 (CHAr), 134.0/133.5 (rotamers, CH), 132.9 (Cquat), 132.0
(CHAr), 131.9 (CHAr), 131.8 (CHAr), 131.7 (CHAr), 131.0 (d, JC,P
= 11.4 Hz, CHAr), 130.5 (CHAr), 128.4 (d, JC,P = 12.0 Hz, CHAr),
(Z/E
= 88:12). Rf =
0.50 (heptane/EtOAc, 7:3). 1H NMR
(300 MHz, CDCl3): δ = 6.24 (dd, J = 11.6, 6.6 Hz, 1 H), 5.72 (dd,
J = 11.6, 1.6 Hz, 1 H), 5.35 (dq, J = 7.8, 1.6 Hz, 1 H), 4.24 (dd, J
= 8.1, 6.9 Hz, 1 H), 3.58 (s, 3 H), 3.47 (dd, J = 8.1, 6.9 Hz, 1 H),
1.30 (s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.0 (CO), 149.8 (CH), 120.3 (CH), 109.7 (Cquat), 73.7 (CH), 69.4
(CH2), 51.5 (CH3), 26.6 (CH3), 25.5 (CH3) ppm.
125.0/123.5 (rotamers, CH), 94.2/93.5 (rotamers,
Cquat), 80.0
(Cquat), 68.6/68.4 (rotamers, CH2), 61.5/61.2 (rotamers, CH2), 54.3 (2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]prop-2-en-1-ol (16):[37]
(CH), 28.52 (tBu), 27.5/26.6 (CH3), 25.1/24.0 (CH3) ppm. 31P
NMR (162 MHz, CDCl3): δ = 31.22 ppm. HRMS (ESI positive):
calcd. for [M + H]+ 562.2353; found 562.2328.
Into a dry flask under argon was introduced 14 (500 mg, 2.5 mmol)
and anhydrous DCM (12.5 mL). The solution was cooled to –78 °C
and a 1.0  solution of DIBAL-H in hexanes (6.25 mL, 6.25 mmol)
was added over a period of 30 min through a syringe pump. The
mixture was stirred for 2 h at –78 °C and quenched with water
(0.41 mL) at –78 °C. A saturated solution of sodium potassium tar-
trate (12.5 mL) was added, the mixture was allowed to reach room
temp. and then extracted with DCM (3ϫ). The organic layer was
dried with MgSO4 and removed under reduced pressure. The oily
residue was purified through a silica gel column (heptane/EtOAc,
1:1) to yield 380 mg (96%) of the desired product as a colourless
oil. Rf = 0.32 (cyclohexane/EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): δ = 5.93 (dt, J = 15.5, 4.9 Hz, 1 H), 5.69 (ddt, J = 15.4,
7.5, 1.5 Hz, 1 H), 4.51 (q, J = 7.2 Hz, 1 H), 4.13 (br. d, J = 4.5 Hz,
2 H), 4. 08 (dd, J = 8.3, 6.4 Hz, 1 H), 3.58 (t, J = 7.9 Hz, 1 H),
2.19 (br. s, 1 H), 1.41 (s, 3 H), 1.37 (s, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 133.8 (CH), 128.3 (CH), 109.5 (Cquat), 76.7
(CH), 69.5 (CH2), 62.5 (CH2), 26.8 (CH3), 26.0 (CH3) ppm.
General Procedure for Allylic Substitution Reactions with oDPPB
Oxides 30 and 31: Into a dry flask under argon was introduced
CuCN·2LiCl[34] (13 mg, 74.7 µmol) in anhydrous THF (0.5 mL).
The solution was stirred until the copper salt had dissolved and
then cooled to –30 °C by means of a cryostat. A solution of dialk-
ylzinc in toluene (2.4 equiv.) was added dropwise. The mixture was
stirred for 30 min at –30 °C (light yellow) and a solution of 30 or
31 (35 mg, 62.2 µmol) in THF (0.9 mL) was added through a sy-
ringe pump (rate 0.5 mL/h) at 0 °C. The mixture was stirred for 5 h
at 0 °C and then overnight at room temp. (black solution). Satu-
rated aqueous NH4Cl was added and the mixture was extracted
with EtOAc (3ϫ). The organic layer was dried with MgSO4 and
the solvents removed under reduced pressure. The residue was puri-
fied by silica gel chromatography (heptane/EtOAc, 9:1).
Methyl (2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]acrylate (14):[35]
A solution of sodium periodate (3.88 g, 18.12 mmol) in water
(40 mL) was added dropwise to a suspension of 1,2:5,6-di-O-iso-
propylidene--mannitol[36] (3.66 g, 13.94 mmol) in saturated aque-
ous NaHCO3 (60 mL) cooled to 0 °C. After 10 min at 0 °C the ice
bath was removed and the reaction was stirred for 2.5 h at room
temp. (TLC monitored). The mixture was cooled again to 0 °C and
potassium carbonate (78 g, 560 mmol) was added followed by di-
ethyl ethylphosphonate ester (10.2 mL, 57.2 mmol). After 10 min
at 0 °C the ice bath was removed and the mixture was stirred for
12 h at room temp. Water was added and the aqueous layer was
extracted with Et2O (5ϫ). The organic layer was dried with MgSO4
and removed under reduced pressure. The colourless oil was puri-
fied through a silica gel column (cyclohexane/EtOAc, 10:1) to yield
5.02 g of 14 as a colourless liquid (90%, E/Z = 95:5). Rf = 0.79
(cyclohexane/EtOAc, 1:1). 1H NMR (300 MHz, C6D6): δ = 6.84
(ddd, J = 15.5, 5.3, 1.4 Hz, 1 H), 6.13 (ddd, J = 15.5, 2.4, 1.5 Hz,
1 H), 4.21 (m, 1 H), 3.99 (q, J = 7.1 Hz, 2 H), 3.65 (m, 1 H), 3.25
(ddd, J = 7.2, 2.3, 1.0 Hz, 1 H), 1.27 (s, 3 H), 1.23 (s, 3 H), 0.96
(td, J = 7.1, 1.3 Hz, 3 H) ppm. 13C NMR (100 MHz, C6D6): δ =
165.7 (CO), 145.2 (CH), 122.3 (CH), 110.0 (Cquat), 75.1 (CH), 68.8
(CH2), 60.3 (CH2), 26.5 (CH3), 25.8 (CH3), 14.2 (CH3) ppm.
(2Z)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]prop-2-en-1-ol (17):[37]
Into a dry flask under argon was introduced 15 (1.00 g, 5.37 mmol)
and anhydrous DCM (27 mL). The solution was cooled to – 78 °C
and a 1.0  solution of DIBAL-H (13.42 mL, 13.42 mmol) in
DCM was added over 30 min through a syringe pump. The mixture
was stirred for 2 h at –78 °C and quenched with water (0.89 mL)
at –78 °C. A saturated solution of sodium potassium tartrate
(27 mL) was added and the mixture was allowed to reach room
temp. and then extracted with DCM (3ϫ). The organic layer was
dried with MgSO4 and evaporated under reduced pressure. The oily
residue was purified through a silica gel column (heptane/EtOAc,
1:1) to yield 822 mg (97%) of the desired product as a colourless
1
oil. Rf = 0.29 (heptane/EtOAc, 1:1). H NMR (300 MHz, CDCl3):
δ = 5.73 (m, 1 H), 5.48 (m, 1 H), 4.79 (q, J = 7.2 Hz, 1 H), 4.10
(m, 2 H), 4.02 (dd, J = 8.1, 5.9 Hz, 1 H), 3.49 (t, J = 7.8 Hz, 1 H),
3.01 (br. s, 1 H), 1.36 (s, 3 H), 1.33 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 133.5 (CH), 129.2 (CH), 109.5 (Cquat), 72.0
(CH), 69.6 (CH2), 58.3 (CH2), 26.8 (CH3), 26.0 (CH3) ppm.
(2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]prop-2-enyl 2-(Diphen-
ylphosphanyl)benzoate (18): The procedure was duplicated as men-
tioned in ref.[38] Colourless oil (97%). Rf = 0.66 (cyclohexane/
Eur. J. Org. Chem. 2010, 6005–6018
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6015

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann
FULL PAPER
EtOAc, 1:1). [α]2D0 = +22.1 (c = 1, CHCl3). 1H NMR (400 MHz,
ing dropwise water (0.8 mL) and then 15% aqueous NaOH
CDCl3): δ = 8.07 (m, 1 H), 7.41–7.25 (m, 12 H), 6.93 (m, 1 H), (2.4 mL) followed by water (0.8 mL). The white-yellow solid was
5.76 (m, 2 H), 4.66 (dt, J = 5.9, 1.1 Hz, 2 H), 4.48 (q, J = 6.8 Hz,
1 H), 4.07 (dd, J = 8.2, 6.2 Hz, 1 H), 3.56 (t, J = 7.8 Hz, 1 H), 1.43
(s, 3 H), 1.39 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
filtered off and washed with DCM. The solvent was removed under
reduced pressure and the residue was purified through a silica gel
column (heptane/EtOAc, 1:1) to yield 475 mg (74%) as a pale-yel-
1
166.44 (d, JC,P = 2.2 Hz, CO), 140.6 (d, JC,P = 26.8 Hz, Cquat), low oil. Rf = 0.50 (EtOAc, 100%). H NMR (300 MHz, CDCl3): δ
138.0 (d, JC,P = 11.1 Hz, Cquat), 134.2 (CHAr), 134.3 (d, JC,P
19.1 Hz, CHAr), 134.1 (d, JC,P = 2.7 Hz, CHAr), 133.9 (d, JC,P
=
=
= 3.67 (m, 1 H), 3. 49 (br. d, J = 7.5 Hz, 2 H), 3.28 (br. s, 2 H),
1.58 (m, 1 H), 1.50 (m, 1 H), 1.20 (m, 1 H), 0.92 (d, J = 7.5 Hz, 3
2.7 Hz, CHAr), 132.1 (CH), 130.8 (d, JC,P = 2.7 Hz, CHAr), 128.7 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
(CHAr), 128.6 (d, JC,P = 7.0 Hz), 128.3 (CHAr), 127.8 (CH), 109.5
= 76.3 (CH), 65.0 (CH2), 37.9 (CH), 25.4 (CH2), 15.0 (CH3), 11.5
(CH3) ppm. HRMS (ESI positive): calcd. for [M + Li]+ 125.1148;
found 125.1146.
(Cquat), 76.3 (CH), 69.3 (CH2), 64.7 (CH2), 26.8 (CH3), 25.9
(CH3) ppm. 31P NMR (162 MHz, CDCl3):
δ = –4.45 ppm.
C27H27O4P (446.47): calcd. C 72.63, H 6.1; found C 72.62, H 6.2.
(4S)-2,2-Dimethyl-4-[(1S)-1-methylpropyl]-1,3-dioxolane (36): Into a
dry flask under argon was introduced 35 (415 mg, 3.51 mmol), 2,2-
dimethoxypropane (5.2 mL, 42.14 mmol) and acetone (15 mL).
The mixture was stirred at room temp. and BF3·Et2O was added
(40 mL, 0.32 mmol). The yellow solution was stirred overnight at
(2Z)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]prop-2-enyl 2-(Diphen-
ylphosphanyl)benzoate (19): The procedure was duplicated as men-
tioned in ref.[37] Colourless oil. Rf = 0.57 (heptane/EtOAc, 1:1).
[α]2D0 = –22.1 (c = 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
8.06 (m, 1 H), 7.39–7.26 (m, 12 H), 6.94 (m, 1 H), 5.63 (m, 2 H), room temp. NEt3 (1.5 equiv.) was added until the yellow colour
4.84 (m, 2 H), 4.71 (m, 1 H), 4.04 (dd, J = 6.3, 1.9 Hz, 1 H), 3.49
(t, J = 7.7 Hz, 1 H), 1.42 (s, 3 H), 1.38 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.28 (d, JC,P = 2.2 Hz, CO), 140.4 (d,
disappeared (ca. 0.5 mL). The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(pentane/Et2O, 9:1) to yield the desired product (402 mg, 72%) as
JC,P = 27.0 Hz, Cquat), 137.7 (d, JC,P = 11.6 Hz, Cquat), 134.2 a clear yellow liquid. Rf = 0.50 (heptane/EtOAc, 7:3). [α]2D0 = +13.1
1
(CHAr), 134.0 (d, JC,P = 19.1 Hz, CHAr), 133.9 (d, JC,P = 11.6 Hz,
CHAr), 133.7 (d, JC,P = 11.6 Hz, CHAr), 132.1 (CH), 131.9 (CHAr),
(c = 1, CHCl3). H NMR (200 MHz, CDCl3): δ = 4.00–3.80 (m, 2
H), 3.56 (t, J = 7.4 Hz, 1 H), 1.62 (m, 2 H), 1.38 (s, 3 H, Me), 1.34
130.6 (d, JC,P = 2.7 Hz, CHAr), 128.5 (d, JC,P = 3.6 Hz, CHAr), (s, 3 H, Me), 1.15 (m, 1 H), 0.90 (t, J = 6.9 Hz, 3 H), 0.82 (d, J =
128.4 (d, JC,P = 7.2 Hz, CHAr), 128.1 (CHAr), 127.2 (CH), 109.3 6.7 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 108.9 (Cquat),
(Cquat), 71.7 (CH), 69.2 (CH2), 60.6 (CH2), 26.6 (CH3), 25.7
(CH3) ppm. 31P NMR (162 MHz, CDCl3): δ = –4.34 ppm. HRMS
(ESI positive): calcd. for [M + H]+ 447.1720; found 447.1712.
80.4 (CH), 67.9 (CH2), 38.3 (CH), 27.0 (CH3), 26.2 (CH2), 26.0
(CH3), 14.6 (CH3), 11.4 (CH3) ppm. Elemental analysis and
HRMS were not possible due to the very high volatility and non-
ionization of the compound. GC method (Table 4): Column: ini-
tially 50 °C for 3 min, 15 °C/min until 200 °C, isotherm for 5 min,
20 °C/min until 250 °C, isotherm for 10 min. For the SN2Ј reaction
(Table 4, entry 1) syn: 7.033 min (33), anti: 7.387 min; SN2 (E):
8.410 min; SN2 (Z): 8.200 min. After reduction: syn: 7.012 min,
anti: 6.962 min (36); SN2-reduced: 7.528 min. From -iLeu: syn:
7.027, anti 6.975 min (36).
(4S)-2,2-Dimethyl-4-[(1S)-1-methylprop-2-enyl]-1,3-dioxolane (Major
Diastereomer, 33): The procedure was duplicated as mentioned in
ref.[37] Major diastereomer: Rf = 0.63 (heptane/Et2O, 9:1). 1H NMR
(300 MHz, CDCl3): δ = 5.82 (ddd, J = 7.5, 7.2, 2.8 Hz, 1 H), 5.09
(d, J = 4.1 Hz, 1 H), 5.06 (s, 1 H), 3.99 (m, 2 H), 3.64 (m, 1 H),
2.31 (m, 1 H), 1.40 (s, 3 H), 1.34 (s, 3 H), 1.01 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.3 (CH), 115.3
(CH2), 109.2 (Cquat), 79.6 (CH), 67.6 (CH2), 41.1 (CH), 26.8 (CH3), tert-Butyl
2,2-Dimethyl-4-(1-methyl-3-oxopropyl)oxazolidine-3-
25.8 (CH3), 15.8 (CH3) ppm.
carboxylate (38): Major diastereomer: Rf = 0.43 (cyclohexane/
EtOAc, 7:3). IR (neat): ν = 2976, 2935, 1692, 1363, 1170,
˜
(2S,3S)-2-(Acetyloxy)-3-methylpentanoic Acid (34):[39] Isopentyl ni-
trite (1.51 mL, 11.3 mmol) was added dropwise to a solution of -
isoleucine (1.31 g, 10 mmol) and sodium acetate (820 mg, 10 mmol)
in acetic acid (14.3 mL) at 15 °C. The mixture was stirred for 2.5 d
at 15 °C. Acetic acid was removed under reduced pressure. Water
and Et2O were added. The aqueous layer was acidified with con-
centrated HCl to pH 1. The organic layer was separated and
washed with water. Then saturated aqueous NaHCO3 was added
and the aqueous layer was separated and acidified with concen-
trated HCl to pH 1. The aqueous layer was extracted with Et2O
(3ϫ), the organic layer was dried with MgSO4 and the solvent was
removed under reduced pressure to give a colourless oil (1.208 g,
1082 cm–1. 1H NMR (400 MHz, CDCl3): δ = 9.72 (br. s, 1 H), 3.90
(m, 2 H), 3.76 (d, J = 7.7 Hz, 1 H), 2.66 (m, 1 H), 2.60 (dd, J =
16.2, 3.7 Hz, 1 H), 2.20 (m, 1 H), 1.55 (s, 3 H), 1.46 (s, 9 H), 1.44
(s, 3 H), 0.92 (d, J = 7.32 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 202.5/202.0 (rotamers, CO), 153.3 (CO), 94.5/94.1 (rot-
amers, Cquat), 80.5/80.3 (rotamers, Cquat), 64.2 (CH2), 61.1 (CH),
46.2/45.8 (rotamers, CH2), 30.1 (CH), 28.5 (tBu), 26.8/26.4 (rota-
mers, CH3), 24.1/22.6 (rotamers, CH3), 17.2/16.9 (CH3) ppm.
C14H25NO4 (271.35): calcd. C 61.97, H 9.29, N 5.16; found C
61.69, H 9.39, N 4.99.
tert-Butyl 4-(3-Hydroxy-1-methylpropyl)-2,2-dimethyloxazolidine-3-
carboxylate (39)
1
69%, syn/anti = 8:92). H NMR (300 MHz, CDCl3): δ = 10.31 (br.
s, 1 H, OH), 4.91 (d, J = 4.4 Hz, 1 H), 2.11 (s, 3 H), 1.98 (m, 1 H),
1.54 (m, 1 H), 1.30 (m, 1 H), 0.97 (d, J = 6.9 Hz, 3 H), 0.90 (t, J
= 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.4 (CO),
171.3 (CO), 76.3 (CH), 36.7 (CH), 24.7 (CH2), 20.8 (CH3), 15.5
(CH3), 11.8 (CH3) ppm.
Method A: Sodium borohydride (52 mg, 1.387 mmol) was added in
one portion to a solution of 38 (80 mg, 0.295 mmol) in ethanol
(p.a.; 3 mL) at 0 °C. The mixture was stirred at this temperature
until the starting material disappeared (30 min). The solvent was
removed under reduced pressure and brine was added. Extraction
with EtOAc was performed and the organic layer was dried with
MgSO4. The solvent was removed under vacuum. Purification
through a silica gel column (cyclohexane/EtOAc, 7:3) afforded
35 mg (spot to spot reaction) of the desired products. Rf = 0.20
(2S,3S)-3-Methylpentane-1,2-diol (35):[40] Into a dry flask under ar-
gon was introduced LAH (828 mg, 21.8 mmol) and anhydrous
THF (10.9 mL). The mixture was placed at 0 °C and a solution of
34 (950 mg, 5.45 mg) in anhydrous THF (5.5 mL) was added drop-
wise. The ice bath was removed and the mixture was heated at
reflux for 5 h and then cooled to 0 °C. The work-up involved add-
1
(cyclohexane/EtOAc, 7:3). H NMR (CDCl3): δ = 3.94–3.58 (m, 5
H), 2.17–2.10 (m, 2 H), 1.82–1.71 (m, 1 H), 1.59 (br., s, 3 H), 1.44
6016
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6005–6018

Synthesis of Chiral β-Branched α-Amino Acids
(s, 12 H), 1.40–1.27 (br. s, 1 H), 0.91 (d, J = 7.2 Hz, 3 H) ppm. 13
NMR (CDCl3): δ = 153.0, 152.8, 90.0, 79.6, 64.9, 61.8, 61.4, 37.7,
32.4, 26.8, 26.3, 24.3, 22.8, 16.5 (Me) ppm.
C
Ed. Engl. 1967, 6, 195–206; d) M. G. Moloney, Nat. Prod. Rep.
2002, 19, 597–616.
[6] a) I. Jako, P. Uiber, A. Mann, M. Taddei, C. G. Wermuth, Tet-
rahedron Lett. 1990, 31, 1011–1014; b) I. Jako, P. Uiber, A.
Mann, C. G. Wermuth, T. Boulanger, B. Norberg, G. Evrard,
F. Durant, J. Org. Chem. 1991, 56, 5729–5733.
[7] For SN2Ј alkylation of bromoallenes obtained from Garner’s
aldehyde, see: a) F. D’Aniello, A. Mann, M. Taddei, C. G. Wer-
muth, Tetrahedron Lett. 1994, 35, 7775–7778; b) F. D’Aniello,
A. Schoenfelder, A. Mann, M. Taddei, J. Org. Chem. 1996,
61, 9631–9639; c) F. D’Aniello, A. Mann, A. Schoenfelder, M.
Taddei, Tetrahedron 1997, 53, 1447–1456.
Method B: Into a dry flask under argon were introduced CuI (801.
7 mg, 4.21 mmol) and anhydrous THF (10 mL). The suspension
was cooled to 0 °C before adding dropwise a 1.6  solution of
methyllithium in diethyl ether (5.2 mL, 8.42 mmol). A clear solu-
tion was obtained and then cooled to –78 °C for 15 min. A solution
of 2 (200 mg, 0.70 mmol) and TMSCl (0.538 mL, 4.21 mmol) in
dry THF (4 mL) was added dropwise to the slurry. The mixture
turned yellow and was allowed to reach room temp. A NH4OH/
NH4Cl (1:9) pH 8 buffer was added carefully to the solution. The
mixture was stirred for 15 min before extraction with Et2O. The
organic layer was dried with MgSO4 and the solvent was removed
under reduced pressure. The resulting oil was purified through a
silica gel column (cyclohexane/EtOAc, 9:1) to yield 110 mg of 40.
[8]
For SN2Ј-selective alkylation in the preparation of (E)-alkene
dipetide isosters, see: N. Fuji, K. Nakai, H. Habashita, H.
Yoshizawa, T. Ibuka, F. Garrido, A. Mann, Y. Chounan, Y.
Yamamoto, Tetrahedron Lett. 1993, 34, 4227–4230.
This work has been communicated in a preliminary form: T.
Spangenberg, A. Schoenfelder, B. Breit, A. Mann, Org. Lett.
2007, 9, 3881–3884.
For selected reviews, see: a) B. Breit, Y. Schmidt, Chem. Rev.
2008, 108, 2928–2951; b) S. R. Harutyunyan, T. den Hartog,
K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008,
108, 2824–2852.
[9]
1
Rf = 0.39 (cyclohexane/EtOAc, 7:3). H NMR (CDCl3): δ = 4.0–
[10]
3.7 (m, 3 H), 3.66 (s, 3 H), 2.6–2.4 (m, 1 H), 2.51 (dd, J = 15.6,
3.7 Hz, 1 H), 2.07 (dd, J = 11.2, 15.6 Hz, 1 H), 1.7–1.5 (br. s, 3 H),
1.47 (s, 12 H), 0.93 (d, J = 7.1 Hz, 3 H) ppm. Into a dry flask under
argon was introduced 40 (100 mg, 0.33 mmol) and anhydrous di-
ethyl ether (3.3 m3 L). The solution was placed in an ice bath and
LiAlH4 (14 mg, 0.36 mmol) was added. The mixture was stirred for
1.5 h at room temp. before adding sequentially H2O (0.014 mL),
15% aqueous NaOH and H2O (0.042 mL). The solution was fil-
tered through a pad of Celite® and toluene was added. The solvent
was removed under reduced pressure yielding quantitatively the de-
sired product. 1H NMR (CDCl3): δ = 3.94–3.58 (m, 5 H), 2.17–
2.10 (m, 2 H), 1.82–1.71 (m, 1 H), 1.59 (br. s, 3 H), 1.44 (s, 12 H),
1.40–1.27 (br. s, 1 H), 0.91 (d, J = 7.2 Hz, 3 H) ppm. GC method
(Table 5): GC analyses were conducted with a 6890N chromato-
graph from Agilent Technologies using a SUPLECOWAX-10
fused silica capillary column 30 mϫ0.25 mmϫ0.25 µm film thick-
ness. The inlet temperature was set at 250 °C, gas carrier He
(104 mL/min). Column: initially 140 °C for 10 min, 20 °C/min until
250 °C, isotherm for 8 min. Pressure 26.82 psi, flow 2 mL/min. De-
tector FID 250 °C, H2 flow 30 mL/min, air flow 400 mL/min, He
25 mL/min.
[11]
J. Y. L. Chung, J. T. Wasicak, Tetrahedron Lett. 1990, 31, 3957–
3960.
[12]
[13]
H. L. Goering, S. S. Kantner, J. Org. Chem. 1983, 48, 721–724.
The observed SN2 adducts were prepared from Garner’s alde-
hyde by Wittig olefination (E/Z = 1:3 with Ph3P=CHMe) and
were analysed for identification purposes in the crude reaction
mixture by GC-MS.
a) T. Kassem, J. Wehbe, V. Rolland-Fulcrand, M. Rolland, M.-
L. Roumestant, J. Martinez, Tetrahedron: Asymmetry 2001, 12,
2657; b) V. Rolland-Fulcrand, M. Rolland, M.-L. Roumestant,
J. Martinez, Eur. J. Org. Chem. 2004, 873; c) Y. Morimoto,
M. Takaishi, T. Kinoshita, K. Sakaguchi, K. Shibata, Chem.
Commun. 2002, 42; d) M. Suda, Synthesis 1981, 714–715.
a) B. Breit, P. Demel, C. Studte, Angew. Chem. Int. Ed. 2004,
43, 3786–3789; b) B. Breit, P. Demel, D. Grauer, C. Studte,
Chem. Asian J. 2006, 1, 586–597.
[14]
[15]
[16]
[17]
H. Leuser, S. Perrone, F. Liron, F. F. Kneisel, P. Knochel, An-
gew. Chem. Int. Ed. 2005, 44, 4627–4631.
A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93,
1307–1370.
Compound 39: From method A: Rt = 15.803 min (anti product: Rt
= 15.887 min). From method B: Rt = 15.798 min (anti product: Rt
= 15.884 min). Compound 38: Rt = 13.896 min (syn)/14.070 min
(anti).
[18]
[19]
U. Schmidt, M. Kroner, H. Griesser, Synthesis 1989, 832–835.
T. Ueki, M. Doe, R. Tanaka, Y. Morimoto, K. Yoshihara, T.
Kinoshita, J. Heterocycl. Chem. 2001, 38, 165–172.
For a review on “allyl 1,3 strain as a controlling factor in ster-
eoselective transformations”, see: R. W. Hoffmann, Chem. Rev.
1989, 89, 1841–1860.
For examples of non-directed 1,2-diastereoselective hydrofor-
mylations with methallylic systems, see: a) T. Doi, H. Komatsu,
K. Yamamoto, Tetrahedron Lett. 1996, 37, 6877–6880; b) B.
Breit, S. K. Zahn, Tetrahedron Lett. 1998, 39, 1901–1904; c) T.
Takahashi, S. Ebata, H. Yamada, Synlett 1998, 381–382; for
examples of directed 1,2 diastereoselective hydroformylations
with methallylic systems, see: d) B. Breit, Liebigs Ann./Recl.
1997, 1841–1851; e) B. Breit, Angew. Chem. Int. Ed. Engl. 1996,
35, 2835–2837.
[20]
[21]
Acknowledgments
This work was supported by the Ministère délégué à l’Enseigne-
ment Supérieur et à la Recherche (T. S.), by the Fonds der Chem-
ischen Industrie (B. B.) and the Krupp Award for Young University
Teachers (B. B.).
[1] M. S. Taylor, E. N. Jacobsen, Proc. Natl. Acad. Sci. USA 2004,
101, 5368–5373.
[2] S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem.
Int. Ed. Engl. 1985, 24, 1–76.
[3] E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive
Asymmetric Catalysis, Springer, New York, 1999, vols. 1–3.
[4] a) For a review, see: V. J. Hruby, G. Li, C. Haskell-Luevano,
M. D. Shenderovich, Biopolymers 1997, 43, 219–266; b) V. J.
Hruby, P. M. Balse, Curr. Med. Chem. 2000, 7, 945–970; c) S. E.
Gibson, N. Guillo, M. J. Tozer, Tetrahedron 1999, 55, 585–615.
[5] a) Y.-D. Wu, S. Gellman, Acc. Chem. Res. 2008, 41, 1231–1232;
b) S. M. Cowell, Y. S. Lee, J. P. Cain, V. J. Hruby, Curr. Med.
Chem. 2004, 11, 2785–2798; c) G. Nemethy, Angew. Chem. Int.
[22]
[23]
[24]
For a general review on hydroformylation reactions, see: B.
Breit, W. Seiche, Synthesis 2001, 1–36.
For synthetic and stereoselective hydroformylation reactions,
see: B. Breit, Acc. Chem. Res. 2003, 36, 264–275.
For an example with a protected form of kainic acid, see: M.
Rodriquez, C. Bassarello, G. Bifulco, L. Gomez-Paloma, A.
Mann, M. Marchetti, A. Schoenfelder, M. Taddei, Synlett
2005, 1581–1584.
a) Y. Yonezawa, K. Shimizu, F.-S. Yoon, C.-G. Shin, Synthesis
2000, 5, 634–636; b) S. Chandrasekhar, G. Chandrashekar, Tet-
rahedron: Asymmetry 2005, 16, 2209–2214.
[25]
[26]
B. Breit, E. Fuchs, Chem. Commun. 2004, 6, 694–695.
Eur. J. Org. Chem. 2010, 6005–6018
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6017

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann
FULL PAPER
[27] C. Flamant-Robin, Q. Wang, A. Chiaroni, N. A. Sasaki, Tetra-
hedron 2002, 58, 10475–10484.
[28] a) K. Burgess, J. Cassidy, M. J. Ohlmeyer, J. Org. Chem. 1991,
56, 1020–1027; b) K. Burgess, M. Ohlmeyer, J. Org. Chem.
1991, 56, 1027–1036.
[29] a) J. Wehbe, V. Rolland, M. L. Roumestant, J. Martinez, Tetra-
hedron: Asymmetry 2003, 14, 1123–1126; b) C. Mahlert, F.
Koop, J. Thirlway, J. Micklefield, M. A. Marahiel, J. Am.
Chem. Soc. 2007, 129, 12011–12018.
[30] M. V. D’Auria, V. Sepe, R. D’Orsi, F. Bellotta, C. Debitus, A.
Zampalla, Tetrahedron 2007, 63, 131–140.
[33]
P. Meffre, S. Hermann, P. Durand, G. Reginato, A. Riu, Tetra-
hedron 2002, 58, 5159–5162.
J. Y. L. Chung, J. T. Wasicak, Tetrahedron Lett. 1990, 31, 3957.
Dried at 120 °C under high vacuum for 2 h.
J. A. Marshall, J. D. Trometer, D. G. Cleary, Tetrahedron 1989,
45, 391–402.
[34]
[35]
[36]
[37] B. Breit, C. U. Grünanger, O. Abillard, Eur. J. Org. Chem. 2007,
15, 2497–2503.
[38] M. A. Jarosinski, W. K. Anderson, J. Org. Chem. 1991, 56,
4058–4062.
[39] R. W. Hoffmann, W. Helbig, Chem. Ber. 1981, 114, 2802–2807.
[40] U. Schmidt, M. Kroner, H. Griesser, Synthesis 1989, 832–835.
Received: June 16, 2010
[31] C. Milne, A. Powell, J. Jim, M. Al Nakeeb, C. P. Smith, J.
Micklefield, J. Am. Chem. Soc. 2006, 128, 11250–11259.
[32] L. Devel, L. Hamon, H. Becker, A. Thellend, A. Vidal-Cros,
Carbohydr. Res. 2003, 338, 1591–1601.
Published Online: September 20, 2010
6018
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6005–6018