Conversion of L-cysteine into D-α-amino acids and related transformations

Article abstract of DOI:10.1002/ejoc.201100247

Naturally configured cysteine is converted into 4-substituted thiazolidines via the 4-carbaldehyde corresponding to the serine derived Garner's aldehyde. The key transformation is the conversion into 5-thiazolidinones by ¹O₂ oxidatio

Full text of DOI:10.1002/ejoc.201100247

FULL PAPER
DOI: 10.1002/ejoc.201100247
Conversion of
L
-Cysteine into
D
-α-Amino Acids and Related Transformations
Rudolf O. Duthaler*[a] and Bernhard Wyss[a]
Keywords: Amino acids / Synthetic methods / Chiral pool / Cysteine / Singlet oxygen
Naturally configured cysteine is converted into 4-substituted
thiazolidines via the 4-carbaldehyde corresponding to the
serine derived Garner’s aldehyde. The key transformation is
the conversion into 5-thiazolidinones by 1O2 oxidation, and
fragmentation of the primary 5-hydroperoxides under in situ
acetylating conditions. Whereas the reagent couple trimeth-
ylsilyl halides/phenol selectively cleaves the N-Boc group,
LiOH/H2O2 transforms the thiol lactones into lactones by an
unknown mechanism, and, subsequently, also cleaves the
acetonide affording N-Boc-protected -amino acids without
D
loss of optical activity. This sequence tolerates unsaturated
residues with sensitive allylic functions. In some cases,
double bond isomerization is, however, observed. The
thiazolidine intermediates can be cleaved with 3-nitro-2-
pyridinesulfenyl chloride, giving reactive mixed disulfides.
Introduction
α-Amino acids are important natural products in terms
of occurrence, biological function, building components for
other natural products, and metabolism. In addition to the
large number of naturally occurring representatives, artifi-
cial structures are designed and synthesized for various pur-
poses, notably also as pharmaceuticals. Not surprisingly,
many synthetic strategies have been developed with empha-
sis on stereoselectivity because, with few exceptions, α-
amino acids are chiral.[1] An appealing possibility that is
often used relies on transformations of proteinogenic α-
amino acids, most of which are readily available in the l-
configuration. A useful synthon for the d-configured
enantiomers a is (S)-serine (1), which can be converted by
transformation of the carboxylic acid into the desired side
chain R (Ǟb), and oxidation of the hydroxymethyl side
chain to the carboxylic acid (Scheme 1).[1b] A versatile and
configurationally stable intermediate that can be used for
conversion into intermediates b is Garner’s aldehyde 2,[2,3]
which is most conveniently prepared by LiAlH4 mediated
reduction of the corresponding Weinreb N-methoxy-N-
methyl amide.[2b]
Scheme 1. Conversion of (S)-serine (1) into (R)-α-amino acids a.
(4 equiv.) with bulk amounts of 2-methyl-2-butene (used in
a 1:4 ratio as solvent as a radical trap) for the conversion
into acid a.[3a]
Some time ago we speculated that (R)-cysteine (3) might
offer advantages with respect to the final oxidation, because
it was known that N-acylated thiazolidine derivatives d can
be oxidized at C(5) by various methods, giving hemiacetal-
like structures e (Scheme 2). Pioneering work was done by
Woodward, who introduced a 5-hydrazino residue with azo-
dicarboxylate in his cephalosporin synthesis.[4] Transforma-
tion into the 5-acetoxy derivative was achieved with
Pb(OAc)4. Later Baldwin and co-workers introduced a 5-
benzoyloxy group using benzoyl peroxide.[5] Problems were,
however, encountered with the Pummerer rearrangement of
sulfoxide f.[6] In contrast to conventional Ac2O treat-
ment,[6a] reaction with silyl triflates induced rearrangement
to e, but this was accompanied by elimination.[6b,6c] The
Potentially problematic steps of this sequence are, in the
case of Garner’s aldehyde 2, selective acetonide cleavage
without affecting the tert-butyl carbamate, and, in general,
the oxidation of alcohol b to the carboxylate a with a ra-
cemisation-prone aldehyde intermediate c. If applicable, the
reagents of choice are Dess–Martin periodinane (2 equiv.) –
a potentially dangerous reagent – for the conversion of b
into aldehyde c, followed by NaClO2 (7 equiv.)/Na[H2PO4]
1
most elegant method is oxidation with O2, which was de-
scribed by Ando and co-workers.[7] With a catalytic amount
of a sensitizing dye, daylight, and air, a 5-hydroperoxy
group is smoothly generated. In situ reduction with a sulf-
ide or phosphane gives hemiacetal e.
[a] Global Discovery Chemistry, Novartis Pharma AG,
Post Box, 4002 Basel, Switzerland
E-mail: duthalersteinlin@vtxmail.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100247.
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cleavage of the N-Boc-thiazolidine ring with 3-nitro-2-pyr-
idinesulfenyl chloride.
Results and Discussion
As previously described,[9a] cysteine hydrochloride (3)
was transformed into thiazolidine 5 upon treatment with
dimethoxypropane in boiling acetone. The N-tert-butyl car-
bamoylation to give 6 was effected with a slight excess of
di-tert-butyl dicarbonate (Boc2O) in pyridine with cooling
during addition of the reagent.[10] To assess the optical pu-
rity of 6, the known methyl ester 7[4a] was prepared by
methylation with 3-methyl-1-tolyltriazene.[11] Conversion
into N-methoxy-N-methyl amide 8 could be effected by ac-
tivation of acid 7 with N,N-dicyclohexylcarbodiimide
(DCC). Alternatively, conversion into the acid chloride with
1-chloro-1-dimethylamino-2-methylpropene[12] followed by
treatment with N-methoxy-N-methylamine/pyridine was
also successful. The use of thionyl chloride or oxalyl chlo-
ride was not suitable for conversion into the acid chloride,
nor was formation of a mixed anhydride with isobutyl chlo-
roformate/N-methylmorpholine. Reduction of 8 to aldehyde
4 was performed with LiAlH4 in ether. Purification by dis-
tillation gave 4 with 95–98% ee (Scheme 4). Occasionally,
loss of optical purity was observed during distillation. Alde-
hyde 4 can readily be racemized with Et3N in boiling
dichloromethane, thus also giving access to racemic refer-
ence compounds for the determination of optical purity. Af-
ter our initial report,[8] several authors prepared aldehyde 4
either following our route or with minor modifications.[13]
Scheme 2. Oxidation of (R)-cysteine-derived N-acylthiazolidines d.
Following these lines, we have transformed l-cysteine (3)
into the protected aldehyde 4, which, like Garner’s serine
aldehyde 2,[2] can be transformed into various 4-substituted
1
thiazolidines g (Scheme 3). The O2 oxidation gives hydro-
peroxides h, which are reduced to hemiacetals i with tri-
phenyl phosphane. As opposed to the aldehydes c – inter-
mediates in the route from serine (1, Scheme 1) – these
masked aldehydes are configurationally stable and can be
oxidized readily to the thiol lactones j. These 5-thiazolidi-
nones j can be obtained directly from the hydroperoxides
h by treatment with acetic anhydride/triethylamine at low
temperatures. Deprotection under acidic conditions finally
gives the target α-amino acids a. This sequence was success-
fully applied to a series with olefinic residues R, thus giving
access to (R)-configured β,γ-unsaturated amino acids.[8]
This manuscript describes these transformation in full de-
tail, adds additional methods for the final deprotection,
exemplifies the method with an exceptionally delicate exam-
ple with an allylic mono-phosphate function, and includes
further transformations of intermediates, for example, the
Scheme 4. Synthesis of 4-formylthiazolidine 4 from (R)-cysteine
(3). Reagents and conditions: (a) 2,2-dimethoxypropane/acetone,
reflux, 20 h, 82%; (b) (Boc)2O (1.1 equiv.)/pyridine, –23 °C to room
temp., 2–3 d, 78%; (c) 3-methyl-1-(p-tolyl)triacene/CH2Cl2, 20 °C,
69%; (d) DCC/N-methoxy-N-methylamine/EtOAc, room tempera-
ture, 4 d, 74%; (e) LiAlH4/Et2O, 5 °C, 95%; (f) Et3N/CH2Cl2, re-
flux, 18 h.
Scheme 3. Conversion of cysteine aldehyde 4 into (R)-α-amino
acids a.
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Conversion of l-Cysteine into d-α-Amino Acids
As a model system, we decided to introduce an unsatu- transformed in dry methanol/chlorotrimethylsilane into
rated chain at C(4) of thiazolidine 4. Wittig olefination with methyl ester hydrochloride 19 (87%). Both, amino acid 18
ethyl triphenylphosphonium bromide and butyllithium gave and ester 19, were converted into N-Boc methyl ester 20
the (Z)-propenyl derivative 9 containing 10% of the (E)- with 94% ee, and 98.8% ee, respectively. More demanding
isomer 10, in 80% yield. Crystallization gave isomerically was cleavage of the 5-thiazolidinone ring without losing the
pure 9 (27%) and a 7:1 mixture of 9 and 10 (32%; tert-butyl carbamate. Treatment with LiOH in THF/water
Scheme 5). According to analysis by chiral capillary GLC gave the desired product 22 but only with 78% ee. With the
and NMR [in the presence of the chiral shift reagent (2,2,2- more nucleophilic LiOH/H2O2 couple,[20] we stumbled on
trifluoro-1-anthracen-9-yl)ethanol (TFAE)[14]] the optical an unexpected and puzzling conversion of thiol lactone 14
1
purity remained intact. Treatment with O2 converted thia- into lactone 21, which was isolated in 56% yield in addition
zolidine 9 into hydroperoxide 11, which was stable in solu- to starting material 14 (13%) and 4% of desired 22, which
tion up to 0 °C, and various amounts of sulfoxide 12 (see was isolated as the methyl ester 20 in 99% ee. Prolonged
Table 1 below). The mechanism of this rather clean conver- exposure of lactone 21 to LiOH/H2O2 afforded 22 in 65%
sion has been studied by Ando and co-workers.[7] When a yield and 98% optical purity.[18,19] Similar to thiol-lactone
solution of 9 and a catalytic amount of a sensitizing dye 14, the N-Boc-group of lactone 21 could be cleaved with
were exposed to daylight and air, formation of hydroperox- bromotrimethylsilane and phenol.[17] The product 23, which
ide 11 could be detected by TLC. Preparative runs were best
performed at –78 °C in a cylindrical vessel with a water-
cooled and insulated insert for a halogen lamp. About
0.25 wt-% meso-tetraphenylporphyrin was found to be suf-
ficient sensitizer. Suitable solvents were tetrahydrofuran
(THF), tert-butyl methyl ether, and toluene (Table 1). In
dichloromethane, formation of sulfoxide 12 prevailed.
Other dyes – bengal rose or methylene blue – in ethanol
were found to be unsuitable. In situ reduction gave hemi-
acetal 13, which was isolated in 66% yield together with
23% of 12. The target 5-thiazolidinone 14 should be obtain-
able directly from hydroperoxide 11 by fragmentation (for-
mal water elimination), which is a well-documented process
for other hydroperoxides.[15] Whereas most documented
conditions, including acylation with various acid chlorides
or imidazolides,[15b] and also cobalt-catalysis,[15g] failed,
treatment with acetic anhydride/triethylamine[15d] at –78 °C
was successful, affording 14 with 66% yield based on thia-
zolidine 9. However, the use of acetic anhydride with other
bases, e.g., pyridine or diisopropylethylamine, was not suc-
cessful. According to NMR analysis with the chiral shift
reagent TFAE,[14] the optical purity of 14 was at least 95%.
Complete racemization of 14 in dichloromethane contain-
ing 5% Et3N occurred in 65 h at room temperature. At
0 °C, the optical purity dropped to 25% within 24 h. Only
a slow loss of optical activity was observed with Et3N/
CH2Cl2 at –25 °C (86% ee after 48 h), and racemization
was negligible at –78 °C or with diisopropylethylamine at
0 °C (24 h). Thiol lactone 14 of comparable quality could
also be obtained in 81% yield by oxidation of hemi-thioace-
tal 13 under Swern conditions.[16] The remaining task – de-
protection to give the free amino acid or suitably protected
derivatives – was solved in various ways (Scheme 5). Treat- bromide/BuLi, THF, 5–10 °C, 80%; (b) O2/meso-tetraphenylpor-
Scheme 5. Synthesis and transformations of (R)-4-propenylthiazol-
idine 9. Reagents and conditions: (a) ethyl triphenylphosphonium
phyrin (cat.)/light, THF, –78 °C; (c) Ph3P, room temp., 66%; (d)
Ac2O/Et3N, –78 °C, (66%); (e) DMSO/oxalyl chloride/Et(iPr)2N,
CH2Cl2, –70 °C to room temp., 81%; (f) TMSBr/phenol, CH2Cl2,
0 °C, 98%; (g) TMSCl/phenol, CH2Cl2, 0 °C, 96%; (h) 10%
ment of 14 with either bromo- or chlorotrimethylsilane and
phenol in dichloromethane at 0 °C[17] cleanly cleaved only
the tert-butyl carbamate to give the crystalline hydrobro-
mide 15 (98%) or the hydrochloride 16 (96%). The free base
17 could be liberated with aqueous Na2CO3 in 70% yield.
The 5-thiazolidinone ring was slowly cleaved in 1 n hydro-
chloric acid, giving the hydrochloride salt of amino acid 18.
Ion exchange chromatography (Dowex 50Wϫ8, H+) gave
Na2CO3, 70%; (i) 1 n HCl, room temp., 18 days, ion exchange
resin, 64%; (j) TMSCl/MeOH, 6 d, 87%; (k) (i) Boc2O/NaHCO3,
H2O/dioxane; (ii) CH2N2/ether; (l) Boc2O/NaHCO3, H2O/dioxane;
(m) LiOH/H2O2, THF/H2O, 0 °C, 30 min, 56%; (n) methanol,
room temp., 3 d, 99%; (o) (i) Boc2O/NaHCO3, H2O/dioxane (Ǟ
22, 74%); (ii) HOBT/DCC, BnNH2, DMF, room temp., 3 h, 71%;
free 18 in 64% yield.[18,19] Similarly, the hydrochloride was (p) Me2AlNHBn, toluene, room temp., 57%.
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R. O. Duthaler, B. Wyss
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was isolated in 80% yield, was, however, more labile than
either 15 or 16. Thus, an NMR sample in CD3OD was
cleaved quantitatively to the hydrobromide of 18 in three
days. In D2O, this cleavage was almost instantaneous, and
was much faster than the corresponding deprotection of the
thiol-analogue 15 in 1 n hydrochloric acid (see above).[21]
Hydrobromide 18 could be protected as the tert-butyl car-
bamate to give 22 (74%), and coupled through standard N-
hydroxy-benztriazol (HOBT)/DCC methodology with ben-
zylamine to give amide 24 in 71% yield. The same deriva-
tive was also obtained directly from thiol lactone 14 by
treatment with N-benzyl-dimethylaluminum amide.[22]
In addition to the transformations described above for 5-
thiazolidinone 14 (Scheme 5), it was also of interest to find
methods for cleaving either the parent thiazolidine 9 or the
C(5)-hydroxylated derivative 13, which is an aldehyde
equivalent. Of special value would be removal of the aceto-
nide without affecting the tert-butyl carbamate. This has
been achieved under strictly controlled and optimized con-
ditions either with trifluoroacetic acid in wet dichlorometh-
ane,[13a] or with 1 equiv. p-toluenesulfonic acid in meth-
anol.[13b] An interesting alternative is the use of meth-
oxycarbonyl-sulfenyl chloride in acetate-buffered N,N-di-
methylformamide (DMF)/water, followed by reductive di-
sulfide cleavage with trimethylphosphane in wet THF.[13d]
We were, on the other hand, intrigued by the versatility of
3-nitro-2-pyridinesulfenyl protection/activation of cysteine
residues.[23] The reagent 3-nitro-2-pyridinesulfenyl chloride
(25)[24] cleaves other thiol protecting groups such as p-meth-
Scheme 6. Cleavage of thiazolidine 9 and 5-hydroxylated deriva-
tives. Reagents and conditions: (a) 3-nitro-2-pyridinesulfenyl chlo-
ride, EtOH/NaHCO3, 0 °C, 5.5 h; (b) trioctylphosphane/dioxane –
water, room temp. 30 min, 78%; (c) Ac2O/pyridine, room temp.,
18 h, 84%; (d) tert-butylchlorodimethylsilane/imidazol, DMF,
room temp., 18 h, 85%; (e) 1-chloro-1-dimethylamino-2-methylpro-
pene, CH2Cl2, 0 °C, 18 h, 78%; (f) CH3OH, room temp., 2 h, 54%.
oxybenzyl and tert-butyl cleanly,[24b,25] and is also expected case). The effect of the substituent R is also evident in the
to cleave the C–S bonds of acetonides such as 9 and 13 propensity of the 5-thiazolidinones j to undergo racemiza-
(Scheme 6). The target disulfide 26 could indeed be ob- tion. The methyl ester (Table 1, entry 2) was isolated only
tained from 9 in moderate yield in ethanol in the presence in racemic form, the tert-butyl ester (Table 1, entry 3) shows
of solid NaHCO3 to quench hydrochloric acid formed by low optical activity, and the bulky Weinreb amide (Table 1,
solvolysis. An excess of sulfenyl chloride 25 is required be- entry 4) was obtained in optically pure form. With triethyl-
cause a side reaction is formation of the ethyl sulfenate de- amine in dichloromethane at reflux, this β-dicarbonyl deriv-
rived from chloride 25. Other solvents (CF3CH2OH, ative retained 70% of its optical activity after 24 h, whereas
AcOH) or ethanol alone gave lower yields of 26, and other the propenyl-substituted analogue 14 (Table 1, entry 6)
products were formed when dichloromethane or DMF were underwent racemization even at 0 °C (see above, Scheme 5).
used as solvent. Reduction with trioctylphosphane in diox- Solvent effects were studied with the propenylthiazolidine
ane/water readily gave mercaptan 27. When applied to hem- (Table 1, entries 6–9). High yield of C(5) oxidation (to give
iacetal 13, an intractable mixture was formed under the 13, 14) and low sulfoxide formation (to give 12) was ob-
conditions described above. Therefore, the hydroxyl group served in toluene and tert-butyl methyl ether (Table 1, en-
was protected as either acetate 28 or tert-butyldimethylsilyl tries 7 and 8); THF (Table 1, entry 6) was intermediate, and,
ether 29. The labile chloride 30 could be readily prepared in dichloromethane, only sulfoxide 12 was isolated (Table 1,
1
with Ghosez’s chlorenamine reagent.[12] Solvolysis of 30 in entry 9). Interestingly, O2 attack on the allylic positions
methanol gave the methyl ether 31, which was accompanied was never observed, not even for the allylsilanes 34 and 35
by 15% of the N-Boc-cleaved product. Whereas the acetate (Table 1, entries 11 and 12), which should be especially sen-
was unreactive, sulfenyl chloride 25 cleaved silyl ether 29 sitive towards allylic oxidation.[26] The 5-thiazolidinones j
cleanly to give the masked aldehyde 32. The corresponding were generally obtained in higher yield by the direct conver-
methoxy derivative 33 was, however, obtained in low yield sion of primary hydroperoxides h with Ac2O/Et3N, than by
only.
the two-step sequence with reduction to hemiacetal i and
The scope and limitations of this 1O2-mediated oxidation Swern oxidation (Table 1, columns 4 vs. 5). Amino acids
is outlined in Figure 1 and Table 1. In general, bulkier 4- with relatively complex side-chains can be prepared
substituents (R) facilitate this reaction, and rather moderate (Table 1, entries 19–21). To avoid acetylation and oxidation,
yields are observed for the parent compound (R = H; respectively, alcohol functions required protection (Table 1,
Table 1, entry 1) and R = CH2OH (Table 1, entry 5; NaBH4 entry 16). However, whereas some base-sensitive functions
reduction of aldehyde 4 gave racemic thiazolidine g in this such as a primary allyl bromide, were tolerated (Table 1,
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Conversion of l-Cysteine into d-α-Amino Acids
entry 17), double bond isomerizations were observed when Table 1. The 1O2-mediated oxidation of N-(tert-butoxycarbonyl)-
thiazolidines [THF, meso-tetraphenylporphyrin (cat.)/O2/light,
–78 °C]; see Figure 1 for structures.
the acidity of the allylic protons reached a limit (governed
by stereo-electronic effects). Thus, the 4-ethynyl derivative
Entry
g
i [%][a]
k [%][b]
j [%][c]
j [%][d]
is smoothly oxidized as seen by the high yielding conversion
into hemiacetal i (Table 1, entry 13), however, Ac2O/Et3N
treatment was accompanied by isomerization to allene 37,
which was isolated as a dimer in low yield. Similarly, an
acryl ester side-chain survived reduction to i, but iso-
merized to 38 upon exposure to Ac2O/Et3N (Table 1, entry
14). Gratifyingly, this isomerization was not a problem for
the methacryl analogue 39 (Table 1, entry 15). In the case
of an allylic nitrile (Table 1, entry 18), the expected product,
which was isolated in moderate yield (42%), was ac-
companied by the formation of isomer 42 (10%). It is still
1
2
3
40[e]
57
74
23[e]
7
8
73[f]
71[g]
72[h]
4[f]
49
58
4
86
4
5[f]
6
53[f]
66 (13)
9
9
9
9
23 (12)
70 (14)
53 (14)
65 (14)
68 (14)
7
8
9
10
11
12
81 (13)[e] 4 (12)[e]
84 (13)[i] 4 (12)[i]
0[j]
75
56[j]
34
35
71 (36)
77
91
85
possible that some of these rather delicate 5-thiazolidinones 13
38 (37)
62 (38)
65
14
15
16
17
18
19
20
21
can be prepared from the hemiacetals i by using milder oxi-
dation methods that avoid the need for strong bases.
39
40
63[k]
47
61 (41)[k]
57
42 (10% 42)
80
66
62
60
47
73
[a] In situ reduction of hydroperoxide with [(Ph)3P]. [b] The polar
sulfoxides have often not been isolated. [c] In situ treatment of hy-
droperoxide with Ac2O/Et3N. [d] Overall yield after Swern oxi-
dation of hemiacetal i. [e] In toluene. [f] Racemic. [g] Probably of
low optical purity: [α]D = –18.0 (c = 0.3, CHCl3). [h] Optically pure:
[α]D = –145 (c = 0.58, CHCl3). [i] In tBuOMe. [j] In CH2Cl2. [k]
After Me3Si ether cleavage.
ate that is specific for the N-methyl-d-aspartate (NMDA)
receptor subtype. The main therapeutic use envisaged was
treatment of epileptic seizures and prevention of ischemic
brain damage after strokes.[27] A promising compound still
considered an experimental drug is (E)-(R)-2-amino-4-
methyl-5-phosphono-3-pentenoic acid (43; CGP-40116),[28]
1
which could also be prepared from cysteine (3) using O2-
mediated oxidation of the corresponding thiazolidine g
(Table 1, entry 19). It has been found that, for mono-phos-
phate processing enzymes, directly connected phosphonates
(non-isosteric analogs shortened by one atom) are as good
or even better than the isosteric methylene-phosphon-
ates.[29] In this context, we were interested in establishing
the potency of the non-isosteric phosphate analogue 44 as a
NMDA antagonist in comparison to phosphonate 43. The
synthesis of the former is depicted in Scheme 7.
Aldehyde 4 was converted with ethyl 2-(triphenylphos-
phoranylidene)propionate[30] into ester 39 (73%), which was
reduced with diisobutylaluminum hydride (DIBAL-H) to
allyl alcohol 45 (96%). For the following oxidation, the
alcohol function was protected as the trimethylsilyl ether
1
40. The key sequence with O2 addition, in situ treatment
of the intermediate thiazolidine-5-hydroperoxide (general
structure h, cf. Scheme 3) with Ac2O/Et3N, and acidic cleav-
age of the silyl ether, afforded the 5-thiazolidinone 41 in
61% yield together with acetate 46 (6%). To simplify depro-
Figure 1. Compound structures for Table 1. Compounds with num-
bers are described in the Exp. Section (with the exception of side
products 37, 38, and 42).
This method has been developed to prepare analogues of tection, the thiol-lactone 46 was converted into lactone 47
(R)-2-amino-5-phosphonopentanoic acid (AP5), a competi- (69%) with LiOH/H2O2. O-Phosphorylation with di-tert-
tive antagonist of the excitatory neurotransmitter l-glutam- butyl-N,N-diethylphosphoramidite/tetrazole[31] gave phos-
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R. O. Duthaler, B. Wyss
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1
12% substrate concentration; competing O2-mediated oxi-
dations have not been observed so far, not even for very
reactive allylsilanes. In general, the optical purity is re-
tained, but aldehyde 4 and 5-thiazolidinones j are prone to
base-catalyzed racemization. In some extreme cases, in situ
treatment of hydroperoxides h with Ac2O/Et3N at –78 °C
leads to either full or partial double bond isomerization.
However, reduction of such hydroperoxides h with tri-
phenylphosphane leads to the formation of hemiacetals i
with unchanged double-bond position. From such interme-
diates, the target 5-thiazolidinones j might still be obtain-
able with mild oxidation methods. For the deprotection to
(R)-configured α-amino acids, selective methods allow
cleavage of either the N-Boc group or the acetonide. Rather
sensitive and complex d-amino acids, such as 44 (β,γ-unsat-
urated, and with an allylic phosphate) can be prepared. 3-
Nitro-2-pyridinesulfenyl chloride in ethanol/NaHCO3 selec-
tively cleaves the thiazolidine ring of the parent compounds
g, and of hemiacetals i after O-derivatization with electron-
donating protecting groups.
Experimental Section
Scheme 7. Synthesis of phosphonoylpentenoic acid 44 from cyste-
ine. Reagents and conditions: (a) Ph3P=C(CH3)CO2Et/CH2Cl2,
room temp. 3 d, 73%; (b) DIBAL-H/ Et2O, 4 °C, 35 min, 96%; (c)
(CH3)3SiCl/imidazole/DMF, room temp., 3 d, 51%; (d) (1) O2/
meso-tetraphenylporphyrin (cat.)/light, THF, –78 °C, 18 h; (2)
Ac2O/Et3N, –78 °C, 3 h; (3) 1 n HCl (61%, 6% of 46); (e) LiOH/
H2O2, THF/H2O, 0 °C, 3 h, 69%; (f) Et2NP(OtBu)2/tetrazole, room
temp., 20 min., 82%; (g) MCPBA/THF, 0 °C, 38 min. (73%, 2.5%
of 48); (h) pTsOH/CH2Cl2/THF, room temp., 60 min, ion exchange
chromatography, 87%.
General: All reagents and solvents were purchased from commer-
cial suppliers and used without further purification. Oxidations
with 1O2 were performed in a cylindrical glass vessel with a double-
jacketed cylindrical insert holding the halogen lamp (100 W), with
the outer jacket evacuated for insulation, the inner set-up was used
for water cooling of the light bulb. Two side arms served for bub-
bling O2 through the reactant solution through a Teflon® tube. For
cooling, the apparatus was immersed in a Dewar vessel filled with
dry-ice/acetone. Stirring was performed magnetically. Precoated sil-
ica gel 60 F-254 plates (Merck) were used for TLC, with detection
by UV, I2-vapor, KMnO4, or phosphomolybdenic acid/Ce(SO4)2.
phite 48 (82%), which was oxidized with 3-chloroperben-
zoic acid (MCPBA) to phosphate 49 (73%). As a side-prod- Chromatography was performed with Merck 60 (40–63 μm) silica
gel. A Carlo–Erba Strumentazione HRGC 5300 chromatograph
was used for Capillary GLC with Chirasil-Val-III columns (50 m,
0.32 mm diameter, Alltech Applied Science Labs, Deerfield, IL
60015, Serial No 986L). Considerable variation in retention time
(tR) and separation was observed for different columns. Optical
Rotations ([α]D) were recorded with a Perkin–Elmer Polarimeter
241 at ambient temperatures in a 1 mL cuvette (10 cm). NMR spec-
tra were recorded with a Bruker AC-250 or a Bruker-AM-300 spec-
trometer. In general, the integration corresponds to the number of
protons of the signal assignment.
uct arising from acidic mono-cleavage of phosphite 48, 2–
3% of the H-phosphonate 50 was formed. Removal of all
protecting groups was effected with p-toluenesulfonic acid
monohydrate (pTsOH) in dichloromethane/THF, which is a
method originally developed for tert-butyl carbamate cleav-
age.[32] By ion exchange chromatography, pTsOH was sepa-
rated and the target α-amino acid 44 was isolated in 87%
yield as the acidic zwitterion. In a ligand binding assay,
measuring displacement of radio-labeled glutamate,[28b] the
affinity of phosphate 44 (IC50 = 449 nM) was found to be
substantially lower than phosphonate 43 (IC50 = 8 nM).
(4R)-2,2-Dimethylthiazolidine-4-carboxylic Acid Hydrochloride (5):
A suspension of l-cysteine hydrochloride monohydrate (3, Fluka,
100 g, 0.569 mol, 99.7% ee) in acetone (2.3 L) and 2,2-dimeth-
oxypropane (500 mL, 4.076 mol) was boiled under reflux for 20 h.
The resulting suspension was filtered hot, and the collected solid
was washed with acetone and dried under reduced pressure at
30 °C, affording 5 (92.2 g, 82%) as a white solid. Evaporation of
the filtrate to 60 mL gave a second crop of 5 (13.3 g, 11%). This
material was used without further purification; m.p. 153–156 °C.
[α]D = –85 (c = 0.5, MeOH). NMR (250 MHz, D2O): δ = 1.78 and
1.79 [2ϫ s, (CH3)2C(2)], 3.50 (dd, J = 18, 10 Hz) and 3.65 (dd, J
= 18, 11 Hz) [2 H-C(5)], 4.82 [dd, J = 10, 11 Hz, H-C(4)] ppm.
Conclusions
(R)-Cysteine of natural l-configuration can readily be
transformed into 4-substituted N-(tert-butoxycarbonyl)-2,2-
dimethylthiazolidines of high optical purity. A key interme-
diate is aldehyde 4, which is the sulfur analogue of Garner’s
serine aldehyde 2. The oxidation to 5-thiazolidinones j relies
1
on O2 addition and either reduction to a hemiacetal i, or
acetic anhydride mediated water elimination from the pri-
(4R)-3-(tert-Butoxycarbonyl)-2,2-dimethylthiazolidine-4-carboxylic
Acid (6): To a mixture of 5 (105 g, 0.532 mol) and pyridine
mary 5-hydroperoxide h. Compared with other conversions
1
with O2, this is a rather fast process that tolerates up to (500 mL), di-tert-butyl dicarbonate (Fluka; 127.5 g, 0.584 mol,
4672
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Conversion of l-Cysteine into d-α-Amino Acids
1.1 equiv.) was added within 5 min under argon and with cooling
to –23 °C. After stirring at room temp. for 2.5 d, toluene (1.2 L)
was added and the solution was extracted with ice-cold 2 n NaOH
(3ϫ 600 mL). The alkaline extracts were washed with toluene (3ϫ
700 mL) and hexane (500 mL) before being acidified at 8 to 15 °C
with citric acid to pH 3. Extraction with CH2Cl2 (500 mL, then 2ϫ
400 mL), and washing of the organic phases with 10% brine (2ϫ
300 mL), drying with Na2SO4, and evaporation, gave the crude ma-
terial (136.2 g). Crystallization from hexanes (550 mL) afforded
carbamate 6 (109.2 g, 78%); m.p. 111–112 °C. [α]D = –82.7 (c =
0.75, CHCl3). The optical purity was determined for methyl ester
7 below. 1H NMR (300 MHz, CDCl3, 2 rotamers, 1:1 ratio): δ =
1.40 and 1.45 [2ϫ br. s, (CH3)3CO], 1.60 [br, (CH3)2C(2)], 3.0–3.4
[m, 2H-C(5)], 4.85 and 4.95 [2ϫ m, H-C(4)], 8.9–10.6 (br, CO2
H) ppm.
cooling. Stirring at 0 °C was continued for 20 min, then solids were
removed by filtration and washing with diethyl ether. The filtrate
was washed with 0.1 n HCl (130 mL), 10% NaHCO3 (130 mL),
and twice with saturated brine. Drying with Na2SO4, evaporation
of solvent, and distillation of the residue (kugelrohr; 150–170 °C,
0.4 Torr) gave 4 (11.7 g, 95%). [α]D = –99.1 (c = 0.94, CHCl3).
GC-Analysis (Chirasil-Val; 50 m; 125 °C; carrier 50 kPa): 22.3 min
(100%, optically pure). 1H NMR (250 MHz, CDCl3; 2 rotamers,
ratio 1:1): δ = 1.43 and 1.52 [2ϫ s, (CH3)3CO], 1.80 and 1.86 [2ϫ
s, (CH3)2-C(2)], 3.04–3.80 [m, 2H-C(5)], 4.55 and 4.71 [2ϫ m, H-
C(4)], 9.60 [s, HCO-C(4)] ppm.
Racemization: A sample (0.49g) was dissolved in CH2Cl2 and, after
the addition of Et3N (1 mL), the mixture was heated under reflux
for 18 h. Washing with 1 n HCl (2ϫ 25 mL), drying (Na2SO4), and
evaporation gave the crude oil (0.51 g). [α]D = –3.9 (c = 0.77,
CHCl3). GC-Analysis (Chirasil-Val; 50 m; 125 °C; carrier 50 kPa):
21.4 (47.4%) and 21.7 min (49.1%, 2% ee).
3-tert-Butyl 4-Methyl (4R)-2,2-Dimethylthiazolidine-3,4-dicarboxyl-
ate (7): To a solution of 3-methyl-1-(p-tolyl)triazene[11] (CA Reg.
No. 21124-13-0; 4.44 g, 29.77 mmol) in dichloromethane (200 mL),
a solution of acid 6 (7.77 g, 29.77 mmol) in dichloromethane
(100 mL) was added from a dropping funnel in 20 min at 15 to
20 °C. The mixture was stirred at room temperature for 3 h. Ice
was added, and the mixture was washed with 2 n HCl (2ϫ 80 mL),
10% NaHCO3 (2ϫ 80 mL), and with 10% brine (2ϫ 80 mL). The
organic phase was dried (Na2SO4) and evaporated, and the residue
(7.34 g) was distilled (micro distillation apparatus, 125 °C,
0.3 mbar) to afford ester 7 (5.65 g, 69%). [α]D = –59 (c = 1, CHCl3).
GC-Analysis (Chirasil-Val; 50 m; 120 °C; carrier: 50 kPa): 37.0 min
(100%, optically pure). 1H NMR (300 MHz, CDCl3; 2 rotamers,
ratio 1:1): δ = 1.41 and 1.50 [2ϫ s, (CH3)3CO], 1.77, 1.79, 1.81,
1.86 [4ϫ s, (CH3)2C(2)], 3.10 (br d, J = 10.5 Hz) and 3.28 (dd, J =
10.5, 6.5 Hz) [2 H-C(5)], 3.77 (s, OCH3), 4.80 and 4.97 [2ϫ m, H-
C(4)].
tert-Butyl (R)-2,2-Dimethyl-4-[(Z)-propenyl]thiazolidine-3-carboxyl-
ate (9): To a stirred suspension of ethyltriphenylphosphonium bro-
mide (47.81 g, 129 mmol) in anhydrous THF (500 mL), butyllith-
ium (1.6 m in hexanes, 78 mL, 124.8 mmol) was added with cooling
(5–9 °C), under argon, within 10 min. Stirring at 5 °C was contin-
ued for 10 min before a solution of aldehyde 4 (24.27 g, 9.9 mmol)
in THF (100 mL) was added from a dropping funnel within 20 min
at 5–9 °C to the orange reaction solution. After stirring at low tem-
perature for 40 min, the reaction was quenched by the addition of
1 m phosphate buffer (pH 7, 400 mL). After 18 h at room temp. the
white precipitate was removed by filtration and washed with ethyl
acetate (3ϫ 100 mL). The aqueous phase was separated, extracted
with ethyl acetate (2ϫ 150 mL), the organic phases were dried with
Na2SO4, and solvents were removed by evaporation at reduced
pressure. The residue was treated with hexanes/ethyl acetate (19:1),
and the insoluble material was removed by filtration. After washing
with hexanes/ethyl acetate (19:1), the filtrate was evaporated and
the residue was purified by chromatography on silica gel (1 kg; hex-
anes/ethyl acetate, 29:1) to afford a mixture of isomeric olefins 9
and 10 (20.48 g, 80%) containing approximately 90% of the major
(Z)-isomer 9. Solids that separated spontaneously and upon ad-
dition of pentane to the liquid fraction were recrystallized twice
from methanol/water to give the (Z)-isomer 9 (6.98 g, 27%), con-
taining 0.3% (E)-isomer 10; m.p. 34.0–34.5 °C. [α]D = 48.9 (c =
0.45, CHCl3). C13H23NO2S (257.39): calcd. C 60.66, H 9.01, N
5.44, S 12.46; found C 61.04, H 9.13, N 5.15, S 11.64. 1H NMR
(300 MHz, CDCl3): δ = 1.45 [s, (CH3)3CO], 1.71 (dd, J = 7, 1.7 Hz,
CH3CH=), 1.78 and 1.80 [2ϫ s, (CH3)2-C(2)], 2.58 (dd, J = 11.5,
2 Hz) and 3.26 (dd, J = 11.5, 6 Hz) [2 H-C(5)], 5.11 [m, 3 main
peaks, H-C(4)], 5.5 (dqd, J = 11, 7, 1 Hz, CH3CH=), 5.68 (ddq, J
= 11, 8.5, 1.7 Hz, CH3CH=CH) ppm; addition of the chiral shift
tert-Butyl (4R)-4-(Methoxymethylcarbamoyl)-2,2-dimethylthiazolid-
ine-3-carboxylate (8): To an ice-cooled solution of acid 6 (40 g,
0.152 mol) and N-methoxy-N-methylamine (10 g, 0.164 mol) in
ethyl acetate (500 mL) a solution of dicyclohexylcarbodiimide
(33.3 g, 0.162 mol) in ethyl acetate (200 mL) was added from a
dropping funnel within 50 min. The mixture was stirred at room
temperature for 4 d, while at day 1 and day 2 further N-methoxy-N-
methylamine (1 g, 16.4 mmol) and dicyclohexylcarbodiimide (3.4 g,
16.5 mmol) were added. The mixture was filtered, the filtrate evap-
orated, and the residue was dissolved in hexanes (300 mL), and
filtered hot. Crystallization of the residue of the evaporated filtrate
from a mixture of methanol (100 mL) and water (90 mL) gave
amide 8 (27.45 g, 59%); m.p. 99–99.5 °C. [α]D = –64.1 (c = 1.25,
CHCl3). Chromatography (330 g of silica gel; hexanes/EtOAc, 2:1)
and crystallization from methanol/water gave a further 6.98 g
(15 %) of product 8; m.p. 99.5–100 °C. [α]D = –63.6 (c = 1.48,
CHCl3). C13H24N2O4S (304.40) calcd. C 51.30, H 7.95, N 9.20, S agent TFAE[14] showed no signals for the l-enantiomer, for exam-
10.53; found C 51.29, H 8.02, N 9.40, S 10.58. GC-Analysis (Chira-
sil-Val; 50 m; 130 to 200 °C; 2 °C/min; carrier 50 kPa): 29.1 min
(100%, optically pure). 1H NMR (300 MHz, CDCl3; 2 rotamers,
ratio 1:1): δ = 1.41 and 1.50 [2ϫ s, (CH3)3CO], 1.80, 1.83, 1.90,
ple, in contrast to the racemic reference, only one signal was ob-
served for the tert-butyl ester. Kugelrohr distillation of the mother
liquors under high vacuum afforded further product 9 (8.14 g,
32%) containing 12.3% (E)-isomer 10. Capillary GC (Chirasil-Val;
and 1.91 [4ϫ s, (CH3)2-C(2)], 2.98 (dd, J = 12.5, 4 Hz) and 3.35 50 m; 120 °C; carrier 50 kPa): tR = 30.7 (12.3 %, 10), 34.4 min
(dd, J = 12.5, 7.5 Hz) [2 H-C(5)], 3.22 (2ϫ s, NCH3), 3.38 and 3.42
(2ϫ s, OCH3), 5.05 and 5.20 [2ϫ m, H-C(4)] ppm.
(86.9%, 9); racemic reference: tR = 30.2 [1.6%, (S)-10], 30.5 [2.0%,
(R)-10], 33.8 [48.2%, (S)-9], 34.1 min [48.1%, (R)-10].
tert-Butyl (4R)-4-Formyl-2,2-dimethylthiazolidine-3-carboxylate (4):
To an ice-cooled solution of amide 8 (15.2 g, 50 mmol) in dry di-
tert-Butyl (4R,5S)-5-Hydroxy-2,2-dimethyl-4-[(Z)-propenyl]thiazol-
idine-3-carboxylate (13): A solution of thiazolidine 9 (8.5 g,
ethyl ether (175 mL), LiAlH4 (1.27 g, 33.5 mmol) was added under 33.07 mmol, 6.1% trans-isomer 10) and meso-tetraphenylporphyrin
argon. After stirring at 0 to 5 °C for 20 min, the mixture was di-
luted with diethyl ether (200 mL) before dropwise addition
(15 min.) of a solution of KHSO4 (3 g) in water (10 mL) under ice-
(20 mg) in THF (85 mL) was cooled to –78 °C, and oxygen was
bubbled through under irradiation with a 100 W halogen lamp for
18 h. TLC (hexanes/ethyl acetate, 4:1) showed complete conversion
Eur. J. Org. Chem. 2011, 4667–4680
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4673

R. O. Duthaler, B. Wyss
FULL PAPER
into hydroperoxide 11. Triphenylphosphane (8.68 g, 33.07 mmol)
was added, and the temperature was allowed to reach room tem-
perature. After 40 min. solvent was evaporated under reduced pres-
sure and the residue was subjected to column chromatography on
silica gel (450 g; hexanes/ethyl acetate, 4:1) to give 13 (1.58 g, 17%),
which still contained some sensitizer, followed by purer 13 (4.42 g,
49%). C13H23NO3S (273.39): calcd. C 57.11, H 8.48, N 5.12, S
11.73; found C 57.01, H 8.58, N 4.95, S 11.75. MS: m/z = 273 [M+],
258 [M+ – 15], 216 [M+ – 57]. [α]D = +152.7 (c = 1.91, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.46 [s, (CH3)3CO], 1.75 (dd, J = 7,
1.7 Hz, H3CCH=), 1.81 and 1.97 [2ϫ s, (CH3)2-C(2)], 2.25 [d, J =
4 Hz, HO-C(5)], 4.95 [d, J = 4 Hz, H-C(5)], 5.15–5.3 [m, 2 main
peaks, H-C(4)], 5.38 (ddq, J = 10.5, 9, 1.7 Hz, H3CH=CH), 5.59
(dq, J = 10.5, 7 Hz, H3C-CH=) ppm. Further elution with hexanes/
ethyl acetate (1:1) afforded the sulfoxide tert-butyl (R)-2,2-di-
methyl-1-oxo-4-[(Z-propenyl)thiazolidine-3-carboxylate (12; 2.11 g,
23%) as a single epimer. MS: m/z = 273 [M+], 240, 217 [M+ – 56],
(350 mL). This solution was washed with 0.5N HCl (2ϫ 100 mL)
and with 10% brine (100 mL). Drying with Na2SO4 and evapora-
tion of solvents gave a residue (1.4 g), which was purified on silica
gel (57 g; hexane/ethyl acetate, 10:1) to afford 14 {1.114 g, 81%;
[α]D = –215.8 (c = 1.8, CHCl3)}, followed by starting material 13
(146 mg, 10%).
(R)-2,2-Dimethyl-4-(Z)-propenylthiazolidin-5-one (17): To a solu-
tion of thiazolidinone 14 (2.0 g, 7.38 mmol) in anhydrous CH2Cl2
(8 mL), trimethylsilyl bromide (1.9 mL, 14.76 mmol) was added
dropwise at 0 °C, followed by the addition of phenol (4 m in
CH2Cl2, 10.66 mL, 42.6 mmol). After stirring at 0 °C for 5 h, vola-
tiles were evaporated under reduced pressure from the white sus-
pension. Diethyl ether (50 mL) was added and the suspension was
stirred at room temp. for 30 min. The suspension was filtered, and
the solids were washed three times with diethyl ether. Drying in a
vacuum desiccator gave hydrobromide 15 (1.822 g, 98%). [α]D
=
–40 (c = 0.33, EtOH). 1H NMR (300 MHz, CD3OD): δ = 1.86 (dd,
J = 7, 1.7 Hz, H3C-CH=), 2.03 [s, (CH3)2-C(2)], 5.45 (ddq, J = 11,
9, 1.7 Hz, H3C-CH=CH), 5.56 [dd, J = 9, 1 Hz, H-C(4)], 6.25 (dqd,
J = 11, 7, 1 Hz, H3C-CH=) ppm. 13C NMR (62.9 MHz, D2O): δ
= 203.6 [C(5)], 143.1 (H3C-CH=), 120.4 (H3C-CH=CH), 75.6
[C(2)], 66.2 [C(4)], 31.2 [(CH3)2-C(2)], 17.0 (H3C-CH=) ppm.
1
173 [M+ – 100]. H NMR (250 MHz, CDCl3): δ = 1.44 (s, (CH3)3-
CO], 1.57 and 1.79 [2ϫ s, (CH3)2-C(2)], 1.69 (dd, J = 7, 1.6 Hz,
H3CCH=), 2.72 (dd, J = 13, 8.5 Hz), and 3.10 (dd, J = 13, 6 Hz)
[2 H-C(5)], 5.2–5.45 [m, H-C(4) and H3C-CH=CH], 5.56 (dq, J =
11, 7 Hz, H3C-CH=) ppm.
tert-Butyl (R)-2,2-Dimethyl-5-oxo-4-[(Z)-propenyl]thiazolidine-3-
carboxylate (14)
Crude hydrochloride 16 (185 mg), obtained analogously from 14
with trimethylsilyl chloride/phenol in CH2Cl2 (see below[17]) was
partitioned between ethyl acetate (20 mL) and 10% aqueous
Na2CO3 (20 mL). The aqueous phase was separated and extracted
with ethyl acetate (20 mL), the organic phases were washed with
10% brine (3 ϫ 10 mL), dried (Na2SO4), and the solvent was evap-
orated under reduced pressure. Kugelrohr distillation (120 °C, 0.4
mbar) of the residue (117 mg) gave 17 (108 mg, 70%). MS: m/z =
171 [M+], 143 [M+ – 28]. 1H NMR (250 MHz, CDCl3): δ = 1.67
and 1.82 [2ϫ s, (CH3)2-C(2)], 1.79 (dd, J = 7, 1.7 Hz, H3C-CH=),
2.31 (br d, J = 9 Hz, NH), 4.55 [br. t, J = 9 Hz, H-C(4)], 5.31 (ddq,
J = 10.5, 8, 1.7 Hz, H3C-CH=CH), 5.93 (dqd, J = 10.5, 7, 1 Hz, 1
H, H3C-CH=) ppm.
Method a. From Hydroperoxide 11: A solution of thiazolidine 9
(8.36 g, 32.53 mmol, 0.5% trans-isomer) and meso-tetraphenylpor-
phyrin (25 mg) in THF (100 mL) was cooled to –78 °C, and oxygen
was bubbled through under irradiation with a 100 W halogen lamp
for 18 h. TLC (hexanes/ethyl acetate, 4:1) showed complete conver-
sion into hydroperoxide 11. Et3N (10 mL) and acetic anhydride
(10 mL) were added at –78 °C, and stirring was continued for 3.5 h.
The reaction mixture was added with stirring to 0.5 n HCl
(350 mL), and extracted with ethyl acetate (2ϫ 200 mL). The or-
ganic phase was washed with saturated brine, dried (Na2SO4), and
the solvents were evaporated under reduced pressure. The residue
(9.2 g) was purified by chromatography on silica gel (250 g; hex-
anes/ethyl acetate, 10:1) to give a red product 14 (6.2 g), which was
treated with Tonsil (3 g) in hexanes (200 mL). Filtration and evapo-
ration of the solvent gave white crystalline 14 (6.176 g, 70%).
Recrystallization from methanol/water gave pure 14 (5.89 g, 66%);
m.p. 74–75 °C. [α]D = –242.6 (c = 0.452, CHCl3). C13H21NO3S
(271.37): calcd. C 57.54, H 7.80, N 5.16, S 11.82; found C 57.74,
H 7.83, N 5.06, S 11.77. Capillary GC (Chirasil Val; 50 m; 130 °C;
(Z)-(R)-2-Aminopent-3-enoic Acid (18): Crude hydrobromide 15
(200 mg, 0.794 mmol) was dissolved in 1 n HCl (6 mL). After 13 d
at room temperature, lyophilization gave the hydrobromide of 18
(127 mg). Part of this material (114 mg) was subjected to a column
of ion exchange resin (Dowex 50Wϫ8 H+; 200–400 mesh; 4.5 g).
After elution with water, the product was eluted with 1% aqueous
ammonia. Lyophilization gave 18 (53 mg, 64%). [α]D = –283 (c =
0.27, AcOH). C5H9NO2 (115.13): calcd. C 52.16, H 7.88, N 12.17;
found C 52.20, H 7.93, N 12.14. MS (FAB): m/z = 116 [M + H+].
1H NMR (300 MHz, D2O): δ = 1.79 [dd, J = 7.0, 1.7 Hz, 3H-C(5)],
4.61 [dd, J = 10.0, 0.8 Hz, H-C(2)], 5.46 [ddq, J = 11.5, 10.0,
1.7 Hz, H-C(3)], 6.02 [dqd, J = 11.5, 7.0, 0.8 Hz, H-C(4)] ppm.
et
carrier 50 kPa): tR = 34.26 (trans), 36.14 (cis) min, no separation
of enantiomers. MS: m/z = 243 [M+ – 28]. IR (CHCl ): ν = 1695
˜
3
(strong), 1655 (weak) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.45
[s, (CH3)3CO], 1.81 (d, J = 7 Hz, further high order splitting, H3C-
CH=), 1.99 and 2.05 [2ϫs, (CH3)2C(2)], 5.3–5.4 [m, H-C(4),
H3CH=CH-], 5.75–5.85 (m, H3CCH=) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 198.0 [C(5)], 151.7 [N-C(O)-O], 129.8
(H3C-CH=), 127.2 (H3CCH=CH-), 81.2 [(CH3)3CO], 73.1 [C(2)],
67.9 [C(4)], 32.0 and 30.9 [(CH3)2C(2)], 28.3 [(CH3)3CO], 13.6
(H3C-CH=) ppm.
Methyl (Z)-(R)-2-(tert-Butoxycarbonylamino)pent-3-enoate (20):
For analytical purposes, part of the above material was dissolved
in 10% aqueous NaHCO3 (10 mL/mmol) and an equal amount of
dioxane. Di-tert-butyl dicarbonate (Boc2O, 2 equiv.) was added and
the mixture was stirred vigorously for 30 min. Addition to 2 n HCl
was followed by extraction with ethyl acetate (3ϫ). The organic
phase was washed with 10% brine, dried (Na2SO4), and the sol-
vents were evaporated under reduced pressure. The crude residue
was dissolved in diethyl ether and treated with an excess of ethereal
diazomethane. Evaporation of solvent after quenching of excess
diazomethane with acetic acid, and chromatography on silica gel
(hexanes/ethyl acetate, 4:1) gave 20. [α]D = –140.2 (c = 0.51,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 1.45 [s, (CH3)3CO], 1.83
[dd, J = 7.0, 1.7 Hz, 3H-C(5)], 3.74 (s, OCH3), 4.95–5.20 [m, H-
C(2), NH], 5.26 [ddq, J = 11.5, 10.0, 1.7 Hz, H-C(3)], 5.80 [dqd, J =
Method b. From Hemithioacetal 13: To a solution of oxalyl chloride
(0.49 mL, 5.73 mmol) in CH2Cl2 (25 mL), DMSO (0.81 mL,
11.5 mmol) was added by using a syringe at –60 to –70 °C within
2 min, followed by the dropwise addition of a solution of 13 (1.37 g,
5 mmol) in CH2Cl2 (25 mL) at the same temperature within 20 min.
The mixture was stirred at –70 °C for 15 min before ethyldiidoprop-
ylamine (8.6 mL, 50 mmol) was added within 10 min, keeping the
temperature below –60 °C. The mixture was allowed to reach room
temperature, and was stirred for 2 h before dilution with CH2Cl2
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Conversion of l-Cysteine into d-α-Amino Acids
11.5, 7.0, 0.8 Hz, H-C(4)] ppm. Capillary GC (Chirasil-l-Val; 50 m; solvents gave an additional 20 mg (2%) of lactone 21, followed by
100 °C; carrier 80 kPa) racemic reference: tR = 42.48 [cis(R)], 43.38
[cis(S)], 46.97 [trans(R)], 48.57 [trans(S)] min; 94% ee.
34 mg (4%) of methyl ester 20 in better than 99% ee according to
capillary GC analysis (see above).
(Z)-(R)-2-(tert-Butoxycarbonylamino)pent-3-enoic Acid (22): To a
solution of lactone 21 (186 mg, 0.729 mmol) in THF (11 mL) and
water (4 mL), 30% H2O2 (0.44 mL) was added at 0 °C, followed by
LiOH·H2O (33.6 mg, 0.802 mmol). After stirring at 0 °C for 2 h,
the mixture was diluted with ethyl acetate (150 mL), washed with
0.1 n NaS2O3 (150 mL), and water. From the organic phase, start-
ing material 21 (28 mg, 15%) was recovered. The aqueous phase
was acidified to pH 1 with 2 n HCl and extracted with ethyl acetate
(3ϫ 50 mL). The residue of the organic phase (220 mg) contained
elemental sulfur, which was separated from the product by filtration
and by several chromatographic columns on silica gel. A final col-
umn with 9 g of silica gel (hexanes/ethyl acetate, 1:1, 1% AcOH)
gave acid 22 (102 mg, 65%). [α]D = –123 (c = 1.29, CHCl3). 1H
NMR (400 MHz, [D6]DMSO): δ = 1.38 [s, (CH3)3CO], 1.69 [dd, J
= 7, 1.7 Hz, 3H-C(5)], 4.69 [t, J = 9 Hz, H-C(2)], 5.35 [dd, J = 11,
9 Hz, H-C(3)], 5.63 [dq, J = 11, 7 Hz, H-C(4)], 7.24 (d, J = 9 Hz,
NH), 12.43 (br., CO2H) ppm. 13C NMR (75.4 MHz, [D6]-
DMSO): δ = 172.8 [C(1)], 155.2 [HNC(O)O], 128.3 [C(4)], 125.4
[C(3)], 78.1 [(CH3)3CO], 51.3 [C(2)], 28.2 [(CH3)3CO], 13.3
[C(5)] ppm. Part of this material was esterified as above with ethe-
real diazomethane, giving methyl ester 20 in 98% ee.
Methyl (Z)-(R)-2-Aminopent-3-enoate Hydrochloride (19): To a
solution of thiazolidinone 14 (2.0 g, 7.38 mmol) in CH2Cl2 (8 mL),
trimethyl chlorosilane (1.87 mL, 14.76 mmol) was added at 0 °C,
followed by a solution of phenol (4 m in CH2Cl2, 10.66 mL,
42.64 mmol).[17] After stirring for 5 h at 0 °C, trimethyl chlorosilane
(1.9 mL) was added and stirring was continued overnight. Another
portion of trimethyl chlorosilane (1.9 mL) and phenol solution (4 m
in CH2Cl2, 5.33 mL) were added, and stirring at 0 °C was contin-
ued for 5 h. Addition of reagents was repeated and, after stirring
for 30 min, volatiles were removed at 25 °C under reduced pressure.
Diethyl ether (100 mL) was added, and the resulting suspension
was stirred for 30 min. Filtration, washing with diethyl ether (3ϫ),
and drying under high vacuum gave hydrochloride 16 (1.48 g, 96%)
as a white powder. Part of this material (50 mg) was taken up in
anhydrous methanol (1 mL) and trimethyl chlorosilane (0.1 mL).
After stirring at room temp. for 6 d, solvents were evaporated under
reduced temperature to give ester 19 (35 mg, 87%). [α]D = –174 (c
1
= 0.44, MeOH). H NMR (250 MHz, D2O): δ = 1.87 [dd, J = 7,
1.7 Hz, 3H-C(5)], 3.90 (s, OCH3), 5.10 [d, J = 10 Hz, H-C(2)], 5.51
[ddq, J = 11, 10, 1.7 Hz, H-C(3)], 6.20 [dq, J = 11, 7 Hz, H-
C(4)] ppm. For analysis by capillary GC, an analytical probe of the
above material was derivatized with Boc2O/NaHCO3 in dioxane/
water as described above, affording the tert-butyl carbamate 20 in
98.8% ee.
(R)-2,2-Dimethyl-5-oxo-4-[(Z)-propenyl]oxazolidinium
Bromide
(23): To a solution of lactone 21 (306 mg, 1.2 mmol) in anhydrous
CH2Cl2 (4 mL), trimethylbromosilane (0.31 mL, 2.4 mmol) was
added at 5 °C, followed by a solution of phenol (452 mg, 4.8 mmol)
in CH2Cl2 (1.2 mL). After stirring for 3.5 h at 0–5 °C, volatiles were
evaporated from the suspension and the residue was taken up in
diethyl ether (40 mL). Filtration, washing with diethyl ether and
drying at room temp. in a desiccator afforded hydrobromide 23
(226 mg, 80%). 1H NMR (250 MHz, CD3OD, immediate measure-
ment): δ = 1.74 (dd, J = 7, 1.7 Hz, H3C-CH=), 2.40 and 2.50 [2ϫ
br. s, 1.8 H, (CH3)2C(2)], 5.43 (dd, J = 11, 9 Hz, H3CH=CH), 5.56
tert-Butyl
(R)-2,2-Dimethyl-5-oxo-4-[(Z)-propenyl]oxazolidine-3-
carboxylate (21): To a solution of thiazolidinone 14 (1.003 g,
3.7 mmol) in THF (56 mL) and water (20 mL), 30% H2O2 (2.2 mL)
was added dropwise under cooling (6–7 °C), followed by LiOH
monohydrate (3.7 mmol). The mixture was stirred for 30 min at
0 °C, then the reaction was quenched by adding 0.1 n Na2S2O3
(20 mL), immediately followed by partition between ethyl acetate
(100 mL) and water (100 mL). The aqueous phase was extracted
with ethyl acetate (2ϫ100 mL), and the organic phase was washed
with water (60 mL) and brine, to separate the phases. After ad-
ditional washing with saturated brine (2ϫ 60 mL) the organic
phase was dried (Na2SO4), and volatiles were evaporated under re-
duced pressure. Chromatography of the residue (773 mg) on silica
gel (35 g; hexanes/ethyl acetate, 10:1) afforded starting material 14
(131 mg, 13%). [α]D = –229 (c = 0.675, CHCl3), corresponding to
94% optical purity (no signal from the other enantiomer was de-
tected by 1H NMR analysis by addition of TFAE, see above). Fur-
ther elution gave lactone 21 (528 mg, 56%); m.p. 101.5–102.5°.
[α]D = –75.6 (c = 0.71, CHCl3). C13H21NO4 (255.31): calcd. C
61.16, H 8.29, N 5.49; found C 61.15, H 8.52, N 5.41. MS: m/z =
255 [M+], 240 [M+ – 15], 199 [M+ – 56]. 1H NMR (300 MHz,
CDCl3): δ = 1.45 [s, (CH3)3CO], 1.76 [s, (CH3)2-C(2)], 1.83 (d, J =
7 Hz, H3C-CH=), 4.9–5.2 [m, H-C(4)], 5.32 (tq, J = 11, 1.7 Hz,
H3C-CH=CH), 5.86 (dq, J = 11, 7 Hz, H3C-CH=) ppm. 13C NMR
(62.89 MHz, CDCl3): δ = 169.6 [C(5)], 151.2 [NC(O)O], 130.3
(H3C-CH=), 125.5 (H3C-CH=CH), 96.5 [(CH3)3CO], 81.3 [C(2)],
54.8 [C(4)], 28.3 [(CH3)3CO], 27.7 and 26.0 [(CH3)2-C(2)], 13.4
(H3C-CH=) ppm.
[d, J = 9 Hz, H-C(4)], 5.97 (dq, J = 11, 7 Hz, H3C-CH=) ppm. 13
C
NMR (62.9 MHz, CD3OD): δ = 170.2 [C(5)], 135.9 (H3C-CH=),
122.3 (H3CH=CH), 101.8 [C(2)], 60.0 [C(4)], 26.7 and 22.6 [2ϫ m,
(CD3)2-C(2)], 14.5 (H3C-CH=) ppm.
(Z)-(R)-2-Aminopent-3-enoic Acid Hydrobromide (18)
(a) NMR Experiment: The above NMR solution was measured af-
ter 3 d. 1H NMR (250 MHz, CD3OD): δ = 1.27 [m, (CD3)2C-
(OCD3)2], 1.83 (dd, J = 7, 1.7 Hz, H3C-CH=), 4.83 [d, J = 9 Hz,
H-C(2)], 5.42 (ddq, J = 11, 9, 1.7 Hz, H3C-CH=CH), 6.04 (dq, J
= 11, 7 Hz, H3C-CH=) ppm. 13C NMR (62.9 MHz, CD3OD): δ =
171.5 [C(1)], 136.4 (H3C-CH=), 122.5 (H3C-CH=CH), 51.9 [C(2)],
14.7 [C(5)] ppm. 1H NMR (250 MHz, D2O, immediate measure-
ment): δ = 1.67 (dd, J = 7, 1.7 Hz, H3C-CH=), 2.09 (s, 5 H,
acetone), 4.75 [d, J = 9 Hz, H-C(2)], 5.32 (ddq, J = 11, 9, 1.7 Hz,
H3CH=CH), 5.97 (dq, J = 11, 7 Hz, H3C-CH=) ppm.
(b) Preparative Experiment: Deprotected lactone 23 (109 mg,
0.462 mmol) was dissolved in CD3OD (0.7 mL). After 3 d at room
temperature, NMR analyses indicated complete cleavage of the
acetonide. Evaporation of solvent gave hydrobromide 18 (90.0 mg,
99%). The two NMR samples were transformed into N-Boc methyl
ester 20 and subjected to capillary GC analysis as described above:
99% ee, ca. 2% trans-isomer.
The aqueous phase was carefully acidified under cooling with 2 n
HCl (20 mL) and extracted with ethyl acetate (3ϫ100 mL). The
organic phases were washed with 10% brine (3ϫ 60 mL), dried
(Na2SO4), and solvents were evaporated under reduced pressure.
The residue (117 mg) was redissolved in ethyl acetate and treated
with an excess of ethereal diazomethane. Chromatography (silica
gel; hexanes/ethyl acetate, 6:1) of the residue after evaporation of
(Z)-(R)-2-(tert-Butoxycarbonylamino)pent-3-enoic Acid Benzyl
Amide (24)
(a) From Aminobutenoate 18: To a solution/suspension of the hy-
drobromide of 18 (90 mg, 0.459 mmol) in dioxane (9 mL) and 10%
Eur. J. Org. Chem. 2011, 4667–4680
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4675

R. O. Duthaler, B. Wyss
FULL PAPER
aqueous NaHCO3 (9 mL), di-tert-butyl dicarbonate (Boc2O)
(200 mg, 0.918 mmol) was added at room temp. After 18 h stirring,
tert-Butyl [(Z)-(R)-1-(Mercaptomethyl)but-2-enyl]carbamate (27):
To a solution of disulfide 26 (100 mg, 0.27 mmol) in dioxane
the mixture was taken up in water (20 mL), 10% NaHCO3, and (2.7 mL) and water (0.3 mL), tri-n-octyl phosphane (156 μL,
ethyl acetate (20 mL). The aqueous phase was separated and ex-
tracted with ethyl acetate (2ϫ 25 mL) then the organic phases were
washed with 10% NaHCO3 (2ϫ 20 mL). The aqueous phases were
cooled with ice before careful acidification to pH 1 with 2 n HCl.
Extraction with ethyl acetate (3ϫ 50 mL), washing with 10% brine
(3ϫ 30 mL), drying (Na2SO4), and evaporation of solvents gave
0.35 mmol) was added by using a syringe. After stirring at room
temperature for 30 min, dichloromethane (60 mL) was added and,
after drying with Na2SO4, volatiles were removed under reduced
pressure. Chromatography of the residue (250 mg) on silica gel
(10 g; hexanes/ethyl acetate, 10:1) afforded mercaptan 27 (46 mg,
1
78%). H NMR (250 MHz, CDCl3): δ = 1.37 (t, J = 8.5 Hz, SH),
the crude material (95 mg). Chromatography on silica gel (10 g; 1.46 [s, (CH3)3CO], 1.73 [dd, J = 7, 1.7 Hz, 3H-C(4)], 2.65 (ddd, J
hexanes/ethyl acetate, 1:1 with 1% AcOH) gave carbamate 22
(73 mg, 74%) (see above) with 97.6% ee according to capillary GC
analysis of its methyl ester derivative 20 (1.8% trans-isomer, see
above). Part of this material (35 mg, 0.163 mmol) was dissolved in
DMF (2 mL) and treated with HOBT (30 mg, 13% water,
0.195 mmol) and DCC (50.5 mg, 0.2445 mmol) for 1 h at room
temperature. After the addition of further amount of reagents
(15 mg of HOBT, 25 mg of DCC) stirring was continued for 30 min
before the addition of benzylamine (53 μL, 0.489 mmol) to the sus-
pension. After 3 h at room temp, the mixture was taken up in di-
ethyl ether (35 mL) and 0.1 n HCl (50 mL) and the separated aque-
ous phase was extracted with diethyl ether (40 mL). The organic
phases were washed with 10% brine (2ϫ 30 mL), the organic phase
was dried (Na2SO4) and the solvent was evaporated to afford the
crude material (131 mg). Chromatography (9 g of silica gel; hex-
anes/ethyl acetate, 2:1) gave amide 24 (33 mg, 71%). [α]D = –54.6
= 13, 8.5, 6 Hz) and 2.74 (ddd, J = 13, 8.5, 5 Hz) (HS-CH2-), 4.45–
4.65 [m, H-C(1)], 4.6–4.8 (m, NH), 5.29 [ddq, J = 11, 8.5, 1.7 Hz,
H-C(2)], 5.69 [dqd, J = 11, 7, 1 Hz, H-C(3)] ppm. MS: m/z = 170
(M+ – 47, HSCH2), 161 [M+ – 56], 114, 70.
tert-Butyl (4R,5S)-5-Acetoxy-2,2-dimethyl-4-[(Z)-propenyl]thiazol-
idine-3-carboxylate (28): To a solution of thiazolidine 13 (546 mg,
2 mmol) in pyridine (4 mL), acetic anhydride (4 mL) was added at
0 °C. The solution was stirred for 18 h at room temperature, then
solvents and reagents were removed by evaporation at 50 °C under
reduced pressure. Traces of pyridine were removed by co-evapora-
tion with hexanes (2ϫ 150 mL). Chromatography of the residue on
silica gel (25 g; hexanes/ethyl acetate, 10:1) gave acetate 28 (529 mg,
1
84%). H NMR (300 MHz, CDCl3): δ = 1.48 [s, (CH3)3CO], 1.73
(br. d, J = 7 Hz, H3C-CH=), 1.81 and 1.89 [2ϫ br. s, (CH3)2-C(2)],
2.13 [s, CH3C(O)O-C(5)], 5.05–5.35 [m, H-C(4)], 5.41 (ddq, J = 11,
9, 1.7 Hz, H3C-CH=CH), 5.53–5.70 (m, H3C-CH=), 5.70 [s, H-
C(5)] ppm. 13C NMR (62.9 MHz, CDCl3): δ = 169.9 [CH3-
C(O)O], 152.4 [NC(O)O], 129.0 (H3C-CH=), 127.2 (br., H3C-
CH=CH), 81.3 and 80.4 [C(2), C(5)], 67.2 [C(4)], 32.8 and 30.0
[br., (CH3)2-C(2)], 28.5 [(CH3)3CO], 21.4 [CH3-C(O)O], 13.3 (H3C-
CH=) ppm. MS: m/z = 315 [M+], 300 [M+ – 15], 259 [M+ – 56].
(c = 0.39, CHCl3). MS: m/z = 304 [M+], 248 [M+ – 56], 231 [M+
–
73]. 1H NMR (250 MHz, CDCl3): δ = 1.42 [s, (CH3)3CO], 1.80 [dd,
J = 7, 1.7 Hz, 3H-C(5)], 4.46 (m, 2 peaks, 2 H, PhCH2NH), 4.92
[t, J = 9 Hz, H-C(2)], 5.15–5.35 (m, NH), 5.48 [ddq, J = 11, 9,
1.7 Hz, H-C(3)], 5.83 [dq, J = 11, 7 Hz, H-C(4)], 6.2–6.4 (m, NH),
7.1–7.4 (m, PhH) ppm.
tert-Butyl (4R,5S)-5-(tert-Butyldimethylsilanyloxy)-2,2-dimethyl-4-
[(Z)-propenyl]thiazolidine-3-carboxylate (29): To a solution of 5-hy-
droxythiazolidine 13 (546 mg, 2 mmol) in anhydrous DMF (3 mL),
imidazole (204 mg, 3 mmol) and tert-butylchlorodimethylsilane
(362 mg, 2.4 mmol) were added at room temperature. After stirring
(b) From Thiolactone 14: To a solution of thiolactone 14 (100 mg,
0.369 mmol) in toluene (2 mL, freshly distilled from Na) a solution
of N-benzyl-dimethylaluminum amide (1.7 m in CH2Cl2, 0.33 mL)
[22]
was added by syringe. The mixture was stirred for 18 h at room
temperature before additional aluminum amide (0.33 mL) was for 18 h, water (150 mL) was added, and the mixture was extracted
added. After 2 h, the mixture was diluted with ethyl acetate and
washed with 10% aqueous tartaric acid (30 mL). The aqueous
phase was extracted with ethyl acetate (30 mL and 2ϫ20 mL), and
the organic phases were washed with 10% tartaric acid solution
(25 mL) and with 10% brine (3ϫ 30 mL). The organic phase was
dried (Na2SO4) to give a residue (104 mg), which was purified by
with hexanes (3ϫ100 mL). The combined organic phases were
washed with saturated brine (2ϫ 80 mL), dried (Na2SO4), and vol-
atiles were evaporated under reduced pressure. Chromatography on
silica gel (50 g; hexanes/ethyl acetate, 10:1) of the residue (700 mg)
gave silyl ether 29 (659 mg, 85%). H NMR (300 MHz, CDCl3): δ
= 0.11 and 0.13 [2ϫ s, (CH3)2Si], 0.91 [s, (CH3)3C-Si], 1.45 [s,
1
chromatography (10 g silica gel; hexanes/ethyl acetate, 2:1) to give (CH3)3CO], 1.72 (dd, J = 7, 1.7 Hz, H3C-CH=), 1.77 and 1.92 [2ϫ
amide 24 (64 mg, 57%). [α]D = –57 (c = 0.54, CHCl3).
br. s, (CH3)2-C(2)], 4.87 [s, H-C(5)], 5.0–5.2 [br., 2 peaks, H-C(4)],
5.37 (ddq, J = 11, 10.5, 1.7 Hz, H3C-CH=CH), 5.54 (dq, J = 11,
7 Hz, H3C-CH=) ppm. MS: m/z = 372 [M+ – 15], 330 [M+ – 57],
316 [M+ – 15 – 56], 272 [M+ – 15 – Boc].
tert-Butyl [(Z)-(R)-1-(3-Nitropyridin-2-yl-disulfanylmethyl)but-2-
enyl]carbamate (26): To a solution of thiazolidine 9 (257 mg,
1.0 mmol) in ethanol (4 mL), NaHCO3 (252 mg, 3.0 mmol) was
added, followed by 3-nitro-2-pyridinesulfenyl chloride (25; 286 mg,
1.5 mmol[24a]) at 0 °C. After stirring for 5.5 h at 0 °C (during which
time generation of some CO2 was observed), the mixture was fil-
tered and the insoluble (mostly inorganic) material was washed
with ethyl acetate. Chromatography of the residue (456 mg) of the
filtrate (18 g silica gel; hexanes/ether, 1:1) afforded 2-ethoxysul-
fanyl-3-nitropyridine (40 mg), mixed fractions (145 mg), and 26
tert-Butyl (4R,5R)-5-Chloro-2,2-dimethyl-4-[(Z)-propenyl]thiazolid-
ine-3-carboxylate (30): To a solution of 5-hydroxythiazolidine 13
(1.4 g, 5.128 mmol, 13% trans isomer) in anhydrous CH2Cl2
(14 mL), 1-chloro-1-dimethylamino-2-methylpropene (2.17 mL,
15.4 mmol[12]) were added at 0 °C within 3 min (syringe). The mix-
ture was stirred at 0 °C for 18 h then added to pH 7 phosphate
buffer (1 m, 100 mL), cooled to 0 °C. Extraction with ethyl acetate
(200 mL), drying (Na2SO4), and evaporation of volatiles under re-
1
(217 mg, 58%). H NMR (250 MHz, CDCl3): δ = 1.45 [s, (CH3)3-
1
duced pressure gave crude 30 (1.16 g, 78%). H NMR (250 MHz,
CO], 1.73 [dd, J = 7, 1.6 Hz, 3H-C(4)], 3.03 (dd, J = 13, 5 Hz) and
3.19 (dd, J = 13, 6 Hz) (CH2-SS), 4.65 [m, 5 peaks, H-C(1)], 5.42
[ddq, J = 11, 8, 1.6 Hz, H-C(2)], 5.64 [dqd, J = 11, 7, 1 Hz, H-
C(3)], 5.97 (br. d, J = 6 Hz, 0.9 H) and 6.17 (br. d, J = 6 Hz, 0.1
H) (NH), 7.40 [dd, J = 8, 4.5 Hz, H-C(5Ј)], 8.55 [dd, J = 8, 1.5 Hz,
CDCl3): δ = 1.48 [s, (CH3)3CO], 1.76 (d, J = 7 Hz, H3C-CH=),
1.80 and 2.06 [2ϫ s, (CH3)2-C(2)], 5.20 [s, H-C(5)], 5.35–5.55 [m,
H-C(4), H3CH=CH], 5.55–5.7 (m, H3C-CH=) ppm. MS: m/z = 255
[M+ – Cl], 199 [M+ – 56 – Cl].
H-C(4Ј)], 8.97 [br. d, J = 4.5 Hz, H-C(6Ј)]. MS: m/z = 315 [M+
–
tert-Butyl (4R,5S)-5-Methoxy-2,2-dimethyl-4-[(Z)-propenyl]thiazol-
idine-3-carboxylate (31): Chloride 30 (1.16 g, 3.98 mmol) was dis-
56], 298 [M+ – 73], 254, 216 [M+ – 155].
4676
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4667–4680

Conversion of l-Cysteine into d-α-Amino Acids
solved in CH3OH (5 mL). After stirring at room temperature for
2 h, this solution was added to pH 7 phosphate buffer (1 m, 50 mL).
Extraction with ethyl acetate (100 mL and 50 mL), drying of the
organic phase (Na2SO4), evaporation of solvent, and chromatog-
raphy on silica gel (50 g; hexanes/ethyl acetate, 10:1) afforded 31
room temperature and stirred for 1.5 h at this temperature. Alde-
hyde 4 (5.0 g, 20.41 mmol) dissolved in THF (10 mL) was then
added within 10 min at –30 to –50 °C. After stirring for 30 min at
–15 to –30 °C, the mixture was left overnight at room temperature,
then added to saturated NH4Cl (100 mL), and extracted three times
with ethyl acetate. The combined organic phases were washed with
10% brine, dried (Na2SO4), and volatiles were evaporated. The resi-
(615 mg, 54%). MS: m/z = 255 [M+ – OCH3], 216, 211, 199 [M+
–
1
OCH3 – 56], 172 [M+ – OCH3 – 73], 155 [M+ – OCH3 – Boc]. H
NMR (250 MHz, CDCl3): δ = 1.45 [s, (CH3)3CO], 1.72 (d, J = due (14.1 g) was co-evaporated with CH2Cl2 at normal pressure
7 Hz, H3C-CH=), 1.80 and 1.82 [2ϫ s, (CH3)2-C(2)], 3.33 [s, until a clear solution resulted. Addition of diethyl ether under ice-
H3CO-C(5)], 4.46 [s, H-C(5)], 5.41 (ddq, J = 11, 9, 1.7 Hz, cooling led to the formation of a resinous precipitate. The mother
H3CH=CH), 5.45–5.65 (m, H3C-CH=) ppm. Further elution liquor was decanted and filtered (paper filter), solvents were evapo-
gave (4R,5S)-5-methoxy-2,2-dimethyl-4-[(Z)-propenyl]thiazolidine
(114 mg, 15%). MS: m/z = 187 [M+], 172 [M+ – 15], 155 [M+ – 32].
1H NMR (250 MHz, CDCl3): δ = 1.63 and 1.66 [2ϫ s, (CH3)2-C-
(2)], 1.79 (dd, J = 7, 1.7 Hz, H3C-CH=), 1.95–2.2 (br., NH), 3.33
rated, and the residue (7.5 g) was subjected to column chromatog-
raphy (3120 g silica gel; hexanes/toluene, 7:3 followed by toluene)
to afford fractions of pure cis-isomer 34 (793 mg), followed by a
mixture of 34 and its trans-isomer 35 (8%). Kugelrohr distillation
[s, H3CO-C(5)], 4.41 [dd, J = 10, 4 Hz, H-C(4)], 5.08 [d, J = 4 Hz, of 34 (0.01 mbar, 120–150 °C) gave pure 34 (770 mg, 11%). [α]D
=
H-C(5)], 5.40 (ddq, J = 11, 10, 1.7 Hz, H3C-CH=CH), 5.70 (dq, J +149.2 (c = 1.35, CHCl3). C16H31NO2SSi (329.57): calcd. C 58.31,
= 11, 7 Hz, H3C-CH=) ppm.
H 9.48, N 4.25, S 9.73, Si 8.52; found C 58.62, H 9.49, N 4.18, S
9.78, Si 8.50. MS: m/z = 329 [M+], 273 [M+ – 56]. 1H NMR
(300 MHz, CDCl3): δ = 0.02 [s, (CH3)3Si], 1.45 [s, (CH3)3CO], 1.39
(dd, J = 13, 6 Hz) and 1.86 (dd, J = 13, 10 Hz) [(CH3)3Si-CH2-],
1.77 and 1.79 [2ϫ s, (CH3)2-C(2)], 2.55 (dd, J = 11.5, 2 Hz) and
3.25 (dd, J = 11.5, 6 Hz) [2 H-C(5)], 5.06 [br. dd, J = 8.5, 6 Hz, H-
C(4)], 5.56 [dddd, J = 11, 10, 6, 1 Hz, (CH3)3Si-CH2-CH=], 5.60
[dd, J = 11, 8.5 Hz, further split by small couplings, (CH3)3Si-CH2-
CH=CH-] ppm.
tert-Butyl
{(Z)-(R)-1-[(S)-(tert-Butyldimethylsilanyloxy)-(3-nitro-
pyridin-2-yl-disulfanyl)methyl]but-2-enyl}carbamate (32): To a solu-
tion of 5-(silyloxy)thiazolidine 29 (212 mg, 0.548 mmol) in ethanol
(4 mL), NaHCO3 (138 mg, 1.64 mmol) and sulfenyl chloride 25
(157 mg, 0.822 mmol) were added at 0 °C. The mixture was stirred
at 0 °C for 3 h before more reagents (138 mg of NaHCO3, 157 mg
of 25) were added. After 2 h, further portions of NaHCO3 (138 mg)
and sulfenyl chloride 25 (157 mg) were added. The mixture was left
at 0–8 °C before filtration and washing with ethyl acetate.
Chromatography of the residue of the filtrate (520 mg) on silica
gel (hexanes/ethyl acetate, 4:1) gave 32 (228 mg, 88%). 1H NMR
(250 MHz, CDCl3): δ = 0.0 and 0.09 [2ϫ s, (CH3)2-Si], 0.73 [s,
(CH3)3C-Si], 1.24 [s, (CH3)3CO], 1.68 [dd, J = 7, 1.7 Hz, 3H-C(4)],
4.6–4.9 [m, H-C(1)], 4.95 (d, J = 3 Hz, -SCHO-), 5.26 (d, J = 8 Hz,
NH), 5.37 [ddq, J = 11, 9, 1.7 Hz, H-C(2)], 5.66 [dq, J = 11, 7 Hz,
H-C(3)], 7.21 [dd, J = 8, 4.5 Hz, H-C(5Ј)], 8.36 [dd, J = 8, 1.5 Hz,
H-C(4Ј)], 8.80 [dd, J = 4.5, 1.5 Hz, C(6Ј-H)] ppm.
tert-Butyl (4R,5S)-5-Hydroxy-2,2-dimethyl-[(Z)-3-(trimethylsilanyl)-
propenyl]thiazolidine-3-carboxylate (36): A solution of allylsilane 34
(197 mg, 0.598 mmol) and meso-tetraphenylporphyrin (1 mg) in
THF (5 mL) was cooled to –78 °C, and oxygen was bubbled
through, while being irradiated with a 100 W halogen lamp for 2 h.
TLC (hexanes/ethyl acetate, 4:1) showed almost complete conver-
sion into the hydroperoxide. Triphenylphosphane (157 mg,
0.598 mmol) was added and the temperature was allowed to reach
room temperature. After 20 min at room temperature, additional
triphenylphosphane (50 mg) was added, and the mixture was left
overnight. Solvent was evaporated under reduced pressure and the
residue (458 mg) was subjected to column chromatography on silica
gel (12 g; hexanes/ethyl acetate, 4:1) to give 36 (146 mg, 70%). MS:
m/z = 327 [M+ – 18], 271 [M+ – 18 – 56]. 1H NMR (300 MHz,
CDCl3): δ = 0.0 [s, (CH3)3Si-], 1.42 [s, (CH3)3CO], 1.75 and 1.92
[2ϫ s, (CH3)2-C(2)], 1.8–1.9 [m, (CH3)3Si-CH2-], 2.10 (br, OH),
4.92 [br. s, H-C(5)], 5.18 [br. d, H-C(4)], 5.29 [dd, J = 10.5, 9 Hz,
split by further small couplings, (CH3)3Si-CH2-CH=CH-], 5.54 [td,
J = 10.5, 7 Hz, (CH3)3Si-CH2-CH=] ppm.
tert-Butyl {(Z)-(R)-1-[(S)-Methoxy-(3-nitropyridin-2-yl-disulfanyl)-
methyl]but-2-enyl}carbamate (33): To a solution of 5-methoxythi-
azolidine (31; 0.348 mmol) in ethanol (2 mL), NaHCO3 (88 mg,
1.044 mmol) and sulfenyl chloride 25 (99.4 mg, 0.522 mmol) were
added at 0 °C. After stirring at 0 °C for 2 h, additional freshly pre-
pared 25 (99 mg) was added, and stirring was continued for 15 min.
Ethyl acetate (30 mL) was added, and the suspension was filtered.
The filtrate was evaporated, and the residue (281 mg) was purified
by chromatography on silica gel (hexane/ether, 1:1), followed by
two chromatographic columns of the mixed fractions. A total of
tert-Butyl (R)-4-[(E)-2-(Ethoxycarbonyl)propenyl]-2,2-dimethylthi-
azolidine-3-carboxylate (39): To a solution of ethyl (2-triphenyl-
phosphoranylidene)propionate[30] (6.96 g, 19.2 mmol) in CH2Cl2
(155 mL), a solution of aldehyde 4 (4.65 g, 19 mmol) in CH2Cl2
was added at room temperature within 15 min. After stirring for
18 h, additional ethyl (2-triphenylphosphoranylidene)propionate
(3.48 g, 9.6 mmol) was added, and stirring was continued until TLC
analysis indicated total consumption of 4 (3 d). The mixture was
33 mg (23%) of disulfide 33 was isolated. MS: m/z = 345 [M+
–
1
56], 328 [M+ – 73], 214. H NMR (250 MHz, CDCl3): δ = 1.43 [s,
(CH3)3CO], 1.88 [dd, J = 7, 1.7 Hz, 3H-C(4)], 3.57 (s, CH3O), 4.59
(d, J = 4 Hz, -SCHOCH3), 5.0–5.5 [m, NH, H-C(1), H-C(2)], 5.78
[dq, J = 11, 7 Hz, H-C(3)], 7.38 [dd, J = 8, 4.5 Hz, H-C(5Ј)], 8.52
[dd, J = 8, 1.5 Hz, H-C(4Ј)], 8.93 [dd, J = 4.5, 1.5 Hz, H-
C(6Ј)] ppm.
tert-Butyl (R)-2,2-Dimethyl-4-[(Z)-3-(trimethylsilanyl)propenyl]thi- cooled to 0 °C then 10% NaH2PO3 (154 mL) was added. After
azolidine-3-carboxylate (34): To
a
suspension of methyltri-
stirring at 0 °C for 20 min, the phases were separated. The aqueous
phase was extracted twice with CH2Cl2, the organic phases were
dried (Na2SO4), and the solvent was evaporated. Chromatography
of the residue (9.4 g) on silica gel (335 g; hexanes/ethyl acetate, 7:1)
gave 1.37 g of material contaminated with some (Z)-isomer, fol-
lowed by 39 (4.53 g, 73%). [α]D = –34 (c = 1.18, CHCl3). NMR
(300 MHz, CDCl3): δ = 1.30 (t, J = 7 Hz, CH3CH2O), 1.42 [s,
(CH3)3CO], 1.80 and 1.92 [2ϫ s, (CH3)2C(2)], 1.92 (br. s, CH3-C=),
2.66 (dd, J = 12.5, 1.5 Hz) and 3.27 (dd, J = 12.5, 6 Hz) [2 H-C(5)],
phenylphosphonium bromide (8.2 g, 22.96 mmol) in absolute THF
(40 mL), n-butyllithium (1.6 m in hexane, 16 mL, 25.5 mmol) was
added within 20 min at 4–7 °C under argon. After stirring for 1 h
at room temperature, (iodomethyl)trimethylsilane (3.4 mL, 4.9 g,
23 mmol) was added within 10 min at 0 °C. Stirring at room tem-
perature for 1.5 h resulted in the formation of two liquid phases.
Butyllithium (1.6 m in hexane, 16 mL) was added by using a syringe
at –35 to –55 °C and the inhomogeneous mixture was warmed to
Eur. J. Org. Chem. 2011, 4667–4680
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4677

R. O. Duthaler, B. Wyss
FULL PAPER
4.12–4.25 (m, CH3CH2O), 4.96–5.12 [m, H-C(4)], 6.83 (d, J = 7 Hz, tert-Butyl (R)-4-[(E)-3-Hydroxy-2-methylpropenyl]-2,2-dimethyl-5-
H-C=) ppm. GC-Analysis (Chirasil-Val 50 m; 130–160 °C; carrier oxo-oxazolidine-3-carboxylate (47): To a solution of thiazolidinone
100 kPa): 33.9 min (100%); racemic reference: 33.4 (46%), 33.6 min
(54%).
41 (851 mg, 2.83 mmol) in THF (43 mL) and water (15 mL), hydro-
gen peroxide (30%, 2.3 mL) was added dropwise, followed by
LiOH·H2O (119 mg, 2.83 mmol) under ice cooling (exothermic, 0–
6 °C). The mixture was stirred for 3 h at 0 °C, before addition to
10% NaHSO3 (200 mL). Extraction with ethyl acetate (3ϫ
100 mL), washing with saturated brine, drying with Na2SO4, and
evaporation of solvents under reduced pressure gave the crude
product (800 mg), chromatography of which (silica gel; hexanes/
ethyl acetate, 2:1) afforded the starting material 41 (86 mg, 10%)
and lactone 47 (558 mg, 69%). MS: m/z = 267 [M+ – 18], 167 [M+ –
18 – 100]. 1H NMR (250 MHz, CDCl3): δ = 1.44 [s, (CH3)3CO],
1.77, 1.78, and 1.83 [3ϫ s, CH3-C=, (CH3)2-C(2)], 4.09 (br. s, HO-
CH2), 4.85–5.15 [m, H-C(4)], 5.31 (br. d, J = 9 Hz, H-C=) ppm.
tert-Butyl
(R)-4-[(E)-3-Hydroxy-2-methylpropenyl]-2,2-dimethyl-
thiazolidine-3-carboxylate (45): To a solution of 39 (32.91 g,
100 mmol) in anhydrous diethyl ether (950 mL), a solution of diiso-
butylaluminum hydride (1 m in hexane, 250 mL, 250 mmol) was
added from a dropping funnel within 25 min under cooling (3–
10 °C). Stirring at 4 °C was continued for 10 min before the ad-
dition of ethyl acetate (315 mL), followed by the careful addition
of 2 n NaOH (63 mL) at 3–9 °C within 20 min. After stirring for
2 h at room temperature, anhydrous Na2SO4 was added to the sus-
pension. Filtration, evaporation of solvents from the filtrate, and
chromatography of the residue (silica gel; hexanes/ethyl acetate, 3:1)
afforded 45 (27.6 g, 96%), an analytical sample of which was ob-
tained by crystallization from MeOH/H2O and kugelrohr distil-
lation (0.2 mbar, 200 °C). [α]D = +4.78 (c = 2, CHCl3). MS (FAB):
m/z = 287 [M+], 269 [M+ – 18], 213 [M+ – 18 – 56]. Analysis calcd.
for C 58.50, H 8.77, N 4.87, S: 11.16; found C 58.52, H 8.80, N
tert-Butyl (R)-4-[(E)-3-(Di-tert-butoxyphosphoryloxy)-2-methylprop-
enyl]-2,2-dimethyl-5-oxo-oxazolidine-3-carboxylate (49): To a solu-
tion of alcohol 47 (558 mg, 1.96 mmol) in anhydrous THF (30 mL,
freshly distilled from Na), di-tert-butyl N,N-diethylphosphoramid-
ite (1.46 g, 5.88 mmol, freshly prepared and distilled according to
Perich and Johns[31]) was added, followed by tetrazole (549 mg, 7.84
mmol, crystallized from anhydrous acetonitrile). The reaction was
monitored by TLC (hexanes/ethyl acetate, 1:1) on silica gel plates,
which had previously been wetted with 10% Et3N in MeOH and
dried with a heat gun. After stirring at room temp. for 20 min, ethyl
acetate (200 mL) was added and the solution was washed with 10%
NaHCO3. The aqueous phase was extracted with ethyl acetate (2ϫ
100 mL). Drying with Na2SO4, evaporation of solvents at reduced
pressure, and chromatography of the residue (1.8 g) on silica gel
(80 g; hexanes/ethyl acetate, 10:1, containing 1% of Et3N), gave
phosphite 48 (749 mg, 82%) {31P NMR (101 MHz, CDCl3, 1H-
decoupled): δ = 132 (s) ppm}. To a solution of 48 (748 mg) in THF
(30 mL), 3-chloroperbenzoic acid (656 mg, 85%, 3.23 mmol) dis-
solved in THF (20 mL) was added within 5 min at 0 °C. After stir-
ring for 30 min, further peracid (328 mg, 85%, 1.62 mmol) in THF
(10 mL) was added within 3 min. TLC after 5 min showed complete
conversion of phosphite 48. At 0 °C, 10% NaHSO3 (100 mL) was
added and the mixture was extracted with diethyl ether (150 mL
and 2ϫ 80 mL). The organic phases were washed with 10%
NaHCO3 (2ϫ 70 mL), and the aqueous phases were extracted with
diethyl ether (2ϫ 50 mL). Drying of the organic phases (Na2SO4),
evaporation of the solvent under reduced pressure, and chromatog-
raphy of the residue (844 mg) on silica gel (75 g; hexanes/ethyl acet-
ate, 1:1, containing 1% of Et3N) afforded phosphate 49 (689 mg,
1
4.79, S 10.96. H NMR (300 MHz, CDCl3): δ = 1.41 (t, J ≈ 6 Hz,
HOCH2, exchangeable with D2O), 1.45 [s, (CH3)3CO], 1.75 (d, J =
1 Hz, CH3-C=), 1.78 and 1.81 [2ϫ s, (CH3)2-C(2)], 2.56 (dd, J =
11.5, 2 Hz) and 3.24 (dd, J = 11.5, 6.5 Hz) [2 H-C(5)], 4.02 (d, J
≈ 6 Hz, HOCH2), 5.0–5.1 [m, 3 peaks, H-C(4)], 5.71 (dq, J = 8.5,
1 Hz, H-C=) ppm.
tert-Butyl (R)-2,2-Dimethyl-4-[(E)-2-methyl-3-(trimethylsilanyloxy)-
propenyl]thiazolidine-3-carboxylate (40): To
a solution of 45
(2.573 g, 8.97 mmol) in DMF (8 mL), imidazole (916 mg,
13.45 mmol) and trimethylchlorosilane (1.36 mL, 10.76 mmol) were
added at ambient temperature. After stirring at room temp. for 3 d,
the mixture was diluted with diethyl ether (420 mL) and extracted
with 10% citric acid/ice. The organic layer was washed three times
with 10% brine, dried with Na2SO4, and solvents were removed
by evaporation under reduced pressure. The residue (2.615 g) was
purified by chromatography on Florisil (150 g; hexanes/ethyl acet-
ate, 4:1) to afford silyl ether 40 (1.668 g, 51%). 1H NMR
(250 MHz, CDCl3): δ = 1.0 [s, (CH3)3SiO], 1.31 [s, (CH3)3CO], 1.58
(d, J = 1 Hz, CH3-C=), 1.65 and 1.68 [2ϫ s, (CH3)2C(2)], 2.45 (dd,
J = 11.5, 2 Hz) and 3.12 (dd, J = 11.5, 6 Hz) [2 H-C(5)], 3.87 [br. s,
CH2-OSi(Me)3], 4.83–5.03 [m, 3 peaks, H-C(4)], 5.56 (dq, J = 9,
1 Hz, H-C=) ppm.
tert-Butyl (R)-4-[(E)-3-Hydroxy-2-methylpropenyl]-2,2,dimethyl-5-
oxothiazolidine-3-carboxylate (41):
A solution of 40 (1.65 g,
1
73%). H NMR (250 MHz, CDCl3): δ = 1.44 (br. s, 9 H), 1.50 (s,
4.596 mmol) and meso-tetraphenylporphyrin (20 mg) in THF
(100 mL) was irradiated for 18 h at –78 °C, while oxygen was
bubbled through. TLC analysis (hexanes/ethyl acetate, 4:1) showed
that all starting material had been transformed into the hydroper-
oxide. Triethylamine (10 mL) and acetic anhydride (10 mL) were
added at –78 °C and stirring was continued for 3 h. The reaction
mixture was poured into 1 n HCl (300 mL) and extracted with ethyl
acetate (150 mL). Extraction with 1 n HCl (80 mL) was repeated
and the aqueous phases were extracted with ethyl acetate (100 mL).
18 H), 1.78 (s, 6 H) and 1.88 (s, 3 H) [3ϫ (CH3)3CO, CH3-C=,
(CH3)2C(2)], 4.37 (d, J = 6 Hz, PO-CH2), 4.9–5.1 [m, H-C(4)], 5.35
(dq, J = 9, 1 Hz, CH3-C=) ppm. 31P NMR (101 MHz, CDCl3, 1H-
decoupled): δ = –10.0 ppm (s). In addition, H-phosphonate 50
(20 mg, 2.5%) was eluted afterwards. 1H NMR (250 MHz, CDCl3):
δ (selected peaks) = 6.9 (d, J = 690 Hz, 1 H, H-PO3) ppm. 31P
1
NMR (101 MHz, CDCl3, H-decoupled): δ = 2 ppm (s).
(E)-(R)-2-Amino-4-methyl-5-phosphonooxypent-3-enoic Acid (44):
The combined organic phases were washed with 10% brine (2ϫ Phosphate 49 (666 mg, 1.438 mmol) was dissolved in 14 mL of a
100 mL), dried (Na2SO4) and the solvents were removed under re-
duced pressure. The residue was dried under high vacuum at 40 °C
to remove acetic anhydride. Chromatography of the residue (1.4 g)
on silica gel (70 g; hexanes/ethyl acetate, 2:1), afforded thiazolidi-
none 41 (853 mg, 61%) and acetate 46 (90 mg, 6%). H NMR of
41 (250 MHz, CDCl3): δ = 1.43 [s, (CH3)3CO], 1.50–1.65 (br., 1 H,
HO-CH2), 1.80 (d, J = 1 Hz, CH3-C=), 2.0 and 2.03 [2ϫ s, (CH3)2-
stock solution prepared by dissolving p-toluenesulfonic acid mono-
hydrate (38 g) in dichloromethane (40 mL) and THF (75 mL).[32]
After stirring at room temp. for 60 min, solvents were removed at
room temp. by evaporation under reduced pressure. The residue
(4.9 g) was dissolved in water and applied to a column of ion ex-
change resin (50 g of Dowex 50W ϫ8/H+). Elution with water gave
fractions with p-toluenesulfonic acid followed by fractions contain-
1
C(2)], 4.03 (br. s, CH2OH), 5.38 [d, J = 9 Hz, H-C(4)], 4.41 (dq, J ing the product as the acidic zwitterion of 44 (283 mg, 87%). [α]D
= 9, 1 Hz, H-C=) ppm. = –114.3 (c = 0.6, H2O). C6H12NO6P·0.5H2O: calcd. C 30.77, H
4678
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4667–4680

Conversion of l-Cysteine into d-α-Amino Acids
[12]
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For (R)-18, the optical rotation {[α]D = –283 (c = 0.27, AcOH)}
matches literature values: [α]D = +275 (c = 0.16, AcOH)[19b]
and [α]D = +297.9 (c = 0.3, AcOH),[19f] both for (S)-18. In the
case of (R)-22 {[α]D = –123 (c = 1.52, CHCl3)} a small differ-
ence might be due to a different solvent {[α]D = +103 (c = 2,
CH3OH),[19c] [α]D = +98.6 (c = 1.52, CH3OH),[19e] both (S)-
22}. The difference for (R)-20 {[α]D = –140.2 (c = 0.51,
5.55, N 5.98, P 13.25; found C 30.87, H 5.60, N 5.94, P 13.06.
1
HRMS: m/z [M – H]– calcd. 224.03295; found 224.0330. H NMR
(400 MHz, D2O): δ = 1.77 [d, J = 1 Hz, CH3-C(4)], 4.28 [d, J =
7 Hz, 2H-C(5)], ca. 4.73 [covered by solvent peak, H-C(2)], 5.51
[dq, J = 9.5, 1 Hz, H-C(3)] ppm. 13C NMR (62.9 MHz, D2O): δ =
174.3 [C(1)], 146.1 [d, J = 6 Hz, C(4)], 117.7 [C(3)], 71.3 [d, J =
5 Hz, C(5)], 53.7 [C(2)], 16.1 [CH3-C(4)] ppm. 31P NMR
(101.3 MHz, 1H-decoupled, D2O): δ = 0.014 ppm. For HSQC data,
see the Supporting Information.
[14]
[15]
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra and capillary GC traces.
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[16]
[17]
[18]
CHCl3)} is, however, larger {[α]D
= –50.9 (c = 0.75,
CH3OH),[19e] (R)-20}.
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signals of CH(2) of 18 hydrobromide at higher field [δ =
4.83 ppm (1H), 51.9 ppm (13C)]. Interestingly, the protons of
the acetonide methyl groups of 23 are exchanged by deuterium
in CD3OD. In methanol, partially deuterated dimethoxy-pro-
pane is formed, whereas acetone is the product in water. The
optical purity of 18 obtained from lactone 21 via 23 and
derivatization to 20 is 99%.
[20]
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[23]
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Received: February 23, 2011
Published Online: July 7, 2011
4680
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4667–4680