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

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

S_N2Ј 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 S_N2Ј

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

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 S_N2Ј 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 S_N2Ј 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 S_N2 pathway over

the S_N2Ј pathway (Table 1, entries 1–4). The reaction mix-

ture with several organometallic reagents (Mg, Cu or Zn)

gave 22, the S_N2 substitution product, and a mixture of 20a

and 21a, the S_N2Ј products. But the S_N2 pathway was by

far the major one whereas in the minor S_N2Ј 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 S_N2Ј 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 S_N2’ Reactions

For the exhaustive study of the S_N2Ј 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 S_N2Ј reaction with substrates 6,

7 and 8.

Entry

1

Conditions^[a]

syn/anti S_N2Ј/S_N2

6

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

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 S_N2Ј reactions with

substrates 8, 9 and 12.

Entry^[a]

R

S_N2Ј/S_N2 syn/anti^[b](products) Yield [%]^[c]

1

2

3

4

5

6

7

8

9

10

8

9

Me

Et

nBu

iPr

Ph

Me

Et

Bu

iPr

Me

98:2

96:4

98:2

44:56

96:4

99:1

98:2

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

–

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 S_N2Ј 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 S_N2 products in small but

traceable quantities arising from the starting Z olefin re-

sulted predominantly in the E isomer 22, which suggests

that the S_N2-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 S_N2Ј 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 S_N2Ј 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 S_N2Ј 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

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 S_N2Ј 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” S_N2Ј reaction with substrates 30 and 31.^[a]

syn/anti (products)

S_N2Ј/S_N2

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·SMe₂in Et₂O

at room temp. [b] Isolated yield after silica gel chromatography.

Entry

R

syn/anti (products)^[b]S_N2Ј/ S_N2

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 S_N2Ј 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 S_N2Ј reaction and minimize al-

The pronounced A^1,3strain expected for a cis-disubsti- lylic A^1,2and A^1,3strains. 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 A^1,3strain 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 A^1,3strain affected the course of the reaction. But,

6008

www.eurjoc.org

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 (S_N2Ј) 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

THF

toluene

THF

toluene

THF

83:17

91:9

89:11

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- Rh^I-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

www.eurjoc.org

6009

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann

coated with silica gel 60 (UV₂₅₄were 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, H₂flow

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^–1degcm²g^–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 S_N2Ј 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%). R_f= 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 S_N2Ј 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 S_N2’ 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

MgSO₄and 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 (C_quat), 80.3 (C_quat), 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

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%). R_f

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 (C_quat), desired product as a light-yellow solid. R_f= 0.27 (cyclohexane/

80.6/79.8 (rotamers, C_quat), 68.33 (CH₂), 62.7 (CH₂), 58.9 (CH), EtOAc, 8:2). Mp 62 °C. [α]²_D⁰= +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 (C_quat), 80.4 (C_quat), 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%). R_f= 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

(C_quat), 81.0 (C_quat), 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 MgSO₄and 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·OEt₂was 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 MgSO₄and

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 MgSO₄and 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%). R_f= 0.26 (cyclohexane/EtOAc, 8:2). [α]²_D⁰= +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 MgSO₄and

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 (C_quat), 79.9 (C_quat), 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

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, C_quat), 80.1/

79.7 (rotamers, C_quat), 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%). R_f= 0.78 (heptane/EtOAc, 6:4); m.p. 102 °C. [α]²_D⁰

(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, J_C,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 (C_quat),

79.8 (C_quat), 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, J_C,P= 12.4 Hz, C_quat), 134.4 (br. s, CH), 133.99

(d, J_C,P= 20.7 Hz, CH_Ar), 133.97 (d, J_C,P= 20.7 Hz, CH_Ar), 132.1

(br. s, CH_Ar), 130.7 (br. s, CH_Ar), 128.7 (CH_Ar), 128.5 (d, J_C,P

=

7.6 Hz, CH_Ar), 128.2 (CH_Ar), 125.8 (CH), 94.1 (C_quat), 79.8 (C_quat),

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. R_f

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, R_t: (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, C_quat), 80.0/79.7 (rotamers, C_quat), 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%). R_f= 0.73 (cyclohexane/EtOAc, 1:1); m.p. 96 °C. [α]²_D⁰

= –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, J_C,P= 27.0 Hz), 138.0 (d, J_C,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. R_f

132.1 (br. s), 134.4, 134.0 (d, J_C,P= 20.8 Hz) 133.8 (d, J_C,P

=

= 0.41 (cyclohexane/EtOAc, 8:2). IR (neat): ν = 2930, 1694, 1384,

˜

1363, 1255, 1174, 1089, 847, 767 cm^–^{1 1}H NMR (300 MHz,

20.6 Hz), 132.1 (br. s), 130.7 (br. s), 128.7 (d, J_C,P= 4.1 Hz), 128.50

(d, J_C,P= 6.5 Hz), 128.48 (d, J_C,P= 7.1 Hz), 128.2, 125.2, 123.6,

94.2/93.5 (rotamers, C_quat), 80.1/79.9 (rotamers, C_quat), 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, R_t: (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, C_quat), 80.0/79.7 (rotamers, C_quat), 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. R_f

= 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, C_quat), 80.0/79.7 (rotamers, C_quat), 64.7/64.3

6012

www.eurjoc.org

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]²_D⁰= +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 (C_quat), 82.8

(C_quat), 80.4 (C_quat), 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. R_f

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 Na₂SO₄and removed under reduced pressure. The residue was

purified by silica gel chromatography (heptane/EtOAc, 7:3) to yield

a colourless oil (101 mg, 43%). R_f= 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, C_quat), 80.0/79.7 (rotamers, C_quat), 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 (C_quat),

84.5 (C_quat), 80.9 (C_quat), 80.7 (C_quat), 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, C_quat), 79.9/79.7 (rotamers, C_quat), 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 Na₂SO₄and 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]²_D⁰= +37.6 (c = 1, CHCl₃). R_f=

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, C_quat), 79.8

(C_quat), 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, J_C,P= 28.0 Hz, C_quat), 138.1 (d, J_C,P= 12.7 Hz,

C_quat), 134.5 (CH_Ar), 134.5 (CH_Ar), 134.3 (CH_Ar), 133.9 (CH_Ar),

132.2 (CH_Ar), 130.9 (CH_Ar), 128.7 (CH_Ar), 128.6 (CH_Ar), 128.5

(CH_Ar), 128.2 (CH_Ar), 94.5 (C_quat), 86.0 (C_quat), 76.2 (C_quat), 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 Na₂SO₄and 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%). R_f= 0.40 (heptane/

carboxylate (23): Prepared by using the general procedure for the

directed allylic substitution. Colourless oil. R_f= 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

(C_quat), 152.2 (CO), 99.6/99.1 (C_quat), 94.3/93.8 (C_quat), 80.2/79.6

(C_quat), 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

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 H₂before 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. R_f= 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): (C_quat), 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, C_quat), 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

C_quat), 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 MgSO₄and 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). R_f= 0.52 (heptane/EtOAc, 6:4).

(90 mg, 85%). R_f

=

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 (C_quat), 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 (C_quat), 80.7

(C_quat), 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.). R_f= 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, C_quat), 79.9/79.5 (rotamers, C_quat), 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 MgSO₄and 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.

R_f= 0.41 (EtOAc). [α]²_D⁰= +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 MgSO₄and 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, J_C,P= 6.0 Hz, C_quat), 134.8 (d, J_C,P

= 10.9 Hz, CH_Ar), 134.1 (CH), 133.9 (CH_Ar), 133.9 (CH_Ar), 132.83/

6014

www.eurjoc.org

Eur. J. Org. Chem. 2010, 6005–6018

Synthesis of Chiral β-Branched α-Amino Acids

132.80 (rotamers, C_quat), 131.9 (CH_Ar), 131.8 (CH_Ar), 131.8 Methyl (2Z)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]acrylate (15):^[37]

(CH_Ar), 131.6 (CH_Ar), 130.9 (d, J_C,P= 11.6 Hz, CH_Ar), 130.2 (d, A solution of sodium periodate (4.3 g, 20.13 mmol, 30 mL) in

J_C,P= 8.6 Hz, CH_Ar), 128.3 (d, J_C,P= 12.5 Hz, CH_Ar), 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, C_quat), 80.2/79.7 (rotamers, C_quat), 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 NaHCO₃at 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. R_f= 0.32 (EtOAc). [α]²_D⁰= +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 (C_quat), 134.9 (CH_Ar),

134.8 (CH_Ar), 134.0/133.5 (rotamers, CH), 132.9 (C_quat), 132.0

(CH_Ar), 131.9 (CH_Ar), 131.8 (CH_Ar), 131.7 (CH_Ar), 131.0 (d, J_C,P

= 11.4 Hz, CH_Ar), 130.5 (CH_Ar), 128.4 (d, J_C,P= 12.0 Hz, CH_Ar),

(Z/E

= 88:12). R_f=

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 (C_quat), 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,

C_quat), 80.0

(C_quat), 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 MgSO₄and 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. R_f= 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 (C_quat), 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 MgSO₄and

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). R_f= 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 (C_quat), 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 MgSO₄and 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. R_f= 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 (C_quat), 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%). R_f= 0.66 (cyclohexane/

Eur. J. Org. Chem. 2010, 6005–6018

www.eurjoc.org

6015

T. Spangenberg, A. Schoenfelder, B. Breit, A. Mann

FULL PAPER

EtOAc, 1:1). [α]²_D⁰= +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, J_C,P= 2.2 Hz, CO), 140.6 (d, J_C,P= 26.8 Hz, C_quat), low oil. R_f= 0.50 (EtOAc, 100%). H NMR (300 MHz, CDCl₃): δ

138.0 (d, J_C,P= 11.1 Hz, C_quat), 134.2 (CH_Ar), 134.3 (d, J_C,P

19.1 Hz, CH_Ar), 134.1 (d, J_C,P= 2.7 Hz, CH_Ar), 133.9 (d, J_C,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, CH_Ar), 132.1 (CH), 130.8 (d, J_C,P= 2.7 Hz, CH_Ar), 128.7 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ

(CH_Ar), 128.6 (d, J_C,P= 7.0 Hz), 128.3 (CH_Ar), 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.

(C_quat), 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. R_f= 0.57 (heptane/EtOAc, 1:1).

[α]²_D⁰= –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, J_C,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

J_C,P= 27.0 Hz, C_quat), 137.7 (d, J_C,P= 11.6 Hz, C_quat), 134.2 a clear yellow liquid. R_f= 0.50 (heptane/EtOAc, 7:3). [α]²_D⁰= +13.1

1

(CH_Ar), 134.0 (d, J_C,P= 19.1 Hz, CH_Ar), 133.9 (d, J_C,P= 11.6 Hz,

CH_Ar), 133.7 (d, J_C,P= 11.6 Hz, CH_Ar), 132.1 (CH), 131.9 (CH_Ar),

(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, J_C,P= 2.7 Hz, CH_Ar), 128.5 (d, J_C,P= 3.6 Hz, CH_Ar), (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, J_C,P= 7.2 Hz, CH_Ar), 128.1 (CH_Ar), 127.2 (CH), 109.3 6.7 Hz, 3 H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 108.9 (C_quat),

(C_quat), 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 S_N2Ј reaction

(Table 4, entry 1) syn: 7.033 min (33), anti: 7.387 min; S_N2 (E):

8.410 min; S_N2 (Z): 8.200 min. After reduction: syn: 7.012 min,

anti: 6.962 min (36); S_N2-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: R_f= 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 (C_quat), 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: R_f= 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 NaHCO₃was 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 MgSO₄and 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, C_quat), 80.5/80.3 (rotamers, C_quat), 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. R_f= 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

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 S_N2Ј 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 MgSO₄and 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 S_N2Ј-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

R_f= 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 m³L). 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, H₂flow 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 S_N2 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: R_t= 15.803 min (anti product: R_t

= 15.887 min). From method B: R_t= 15.798 min (anti product: R_t

= 15.884 min). Compound 38: R_t= 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

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

Eur. J. Org. Chem. 2010, 6005–6018

Article Doi

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

DOI: 10.1002/ejoc.201000865

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201000865

Full text of DOI:10.1002/ejoc.201000865

Products guided by the article

R&D Labs maybe for 1258005-16-1

Relevant to this article

Hot Product