Synthesis of enantiomerically pure amino acids containing 2,5- disubstituted THF rings in the molecular backbone

Article abstract of DOI:10.1002/(sici)1099-0690(199911)1999:11<2977::aid-ejoc2977>3.0.co;2-3

N- and C-protected derivatives of 2,5-disubstituted trans-and cis-THF amino acids 6 and 7 were prepared in enantiomerically pure form from L- alanine. Felkin-Anh-controlled reduction of the ketone 9 was achieved with a 85:15 diastereoselectivity. Epoxidat

Full text of DOI:10.1002/(sici)1099-0690(199911)1999:11<2977::aid-ejoc2977>3.0.co;2-3

FULL PAPER
Synthesis of Enantiomerically Pure Amino Acids Containing 2,5-Disubstituted
THF Rings in the Molecular Backbone
Anna Schrey,[a] Frank Osterkamp,[a] Alrun Straudi,[a] Corry Rickert,[a] Holger Wagner,[a]
Ulrich Koert,*[a] Bernhard Herrschaft,[a] and Klaus Harms[b]
Keywords: β-Turn mimetic / Conformational analysis / Synthesis design / Tetrahydrofuran / THF amino acid
N- and C-protected derivatives of 2,5-disubstituted trans-
and cis-THF amino acids and were prepared in corresponding N- and C-protected 2,5-disubstituted trans-
enantiomerically pure form from
alcohols 11 and 12, which were further transformed into the
6
7
L
-alanine. Felkin–Anh-
and cis-THF amino acids. Conformational studies show that
the cis-THF diamide 34 is a β-turn mimetic in the solid state
and in CDCl3 solution.
controlled reduction of the ketone 9 was achieved with a
85:15 diastereoselectivity. Epoxidation of 10 and subsequent
intramolecular epoxide opening gave the trans- and cis-THF
Combining the cation-binding ability of ether subunits
with the synthetic and conformational potential of amino
acids has caused great interest in the synthesis of amino
acids containing ether functionalities in the side chain and/
or the molecular backbone. Examples of naturally occur-
ring ether amino acids are neuraminic acid and muraminic
acid.
Figure 1. Naturally ocurring ether amino acids
Most contributions to the field of synthetic ether amino
acids start from carbohydrates. Sugar amino acids were de-
veloped by Kessler et al.[1] (1, 2), Lansbury et al.[2] (3), as
well as by Dondoni et al.[3] (4). Wessel et al.[4a] and Ichi-
kawa et al.[4b] have reported the synthesis of sacchar-
ideϪpeptide hybrids based on sugar amino acids. Sugar-
derived THF amino acids of type 5[1] have been synthesized
by several groups.[5] THF peptides made out of 5 show re-
markable secondary structures.[6]
Figure 2. Sugar-derived synthetic THP and THF amino acids
Our approach to THF amino acids such as 6 and 7
chooses naturally occurring α-amino acids as a chiral pool
source.[7] N-Tosylalanine chloride 8 was allowed to react
with butenylmagnesium bromide to yield the ketone 9 in
64% yield.[8] Conversion of the Grignard reagent to an
Figure 3. trans- and cis-THF amino acids 6 and 7
organocopper species prior to the reaction with the acid
chloride improved the yield to 94%. The acid chloride was
found to be a superior starting material than the lithium
salt of N-tosylalanine, which gave yields in the 40% range
only. -Selectride reduction of 9 (Cram stereoselectivity
85:15) and separation of the major epimer by crystallisation
lead to the desired alcohol 10 in 83% yield.[8] After epoxid-
ation of the terminal double bond in 10, followed by an
intramolecular 5-exo opening of the resulting epoxy-func-
[a]
Institut für Chemie der Humboldt-Universität zu Berlin,
Hessische Straße 1Ϫ2, D-10115 Berlin, Germany
Fax: (internat.) ϩ 49-(0)30/2093-7266
E-mail: koert@lyapunov.chemie.hu-berlin.de
Fachbereich Chemie der Philipps-Universität,
[b]
Hans-Meerwein-Straße, D-35032 Marburg, Germany
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
Eur. J. Org. Chem. 1999, 2977Ϫ2990
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1111Ϫ2977 $ 17.50ϩ.50/0
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U. Koert et al.
FULL PAPER
tion the trans-THF alcohol 11 and the cis-THF alcohol 12
could be obtained in 38% and 42% yield, respectively.
Scheme 1. Synthesis of N-Ts THF alcohols 11 and 12: (a) H2C ϭ
CHCH2CH2MgBr, Et2O, Ϫ78°C to room temp., 12 h, 64% or
CuCN · 2 LiCl, H2CϭCHCH2CH2MgBr, THF, Ϫ70°C 1 h, to
0°C, 5 min, 94% (b) -selectride, THF, Ϫ100 to Ϫ60°C, 3 h, 83%.
(c) i: MCPBA, CH2Cl2, room temp., 12 h; ii: p-TsOH, CH2Cl2,
room temp., 3 h; 38% 11, 40% 12; -selectride ϭ lithium tri-sec-
butylborohydride, MCPBA
ϭ meta-chloroperbenzoic acid, p-
TsOH ϭ para-toluenesulfonic acid
Attempts to achieve a stereoselective epoxidation of 10
[VO(acac)2/tBuOOH[9] or Jacobsen conditions[10]] failed,
mainly due to problems of low conversion. Therefore,
Sharpless asymmetric dihydroxylation was examined as a
stereoselective entry into the cis or trans series (Scheme 2).
Scheme 2. Preparation of the alkenes 15, 16a, and 17 and asymme-
tric dihydroxylation into the diols 18 and 19: (a) TMSCl, Et3N,
The sulfonamide alcohol 10 gave no turnover under stand- CH2Cl2, 94%; (b) paraformaldehyde, CSA, toluene, DeanϪStark
ard AD conditions.[11] While the sulfonamide NH and the
trap, 65% 16a and 32% 16b; treatment of 16b with CSA in CH2Cl2
afforded 16a in 98% yield; (c) 2,2-dimethoxypropane, CSA, room
hydroxyl group may act as a concurrent coordination site
for the catalyst, we decided to block these positions. Ac-
cording to this idea, the TMS ether 15 and the two oxazoli-
dines 16a and 17 were prepared. During the formation of
16a the seven-membered ring compound 16b was formed as
a side product.
temp., 2 h, 92%; CSA ϭ camphersulfonic acid
Table 1. Asymmetric dihydroxylations of alkenes 15, 16a, and 17
AD-mix
Yield (%)
18/19
The results of the asymmetric dihydroxylations of the
substrates 15, 16a, and 17 are summarized in Table 1. The
TMS ether 15 showed a clear case of double stereodifferen-
tiation: the AD-mix α gave a 42:58 ratio (mismatched case)
of the diols 18a and 19a while the AD-mix β produced a
85:15 ratio (matched case). Almost no double stereodiffer-
entiation was observed during the asymmetric dihydroxyl-
15
α
β
α
β
α
β
88
94
88
94
97
90
42:58
85:15
73:27
37:63
80:20
22:78
15
16a
16a
17
17
ations of compounds 16a and 17. The corresponding diols pound 20. The structural assignment of 20 was achieved by
18 and 19 were obtained in good yields and selectivities in X-ray crystal-structural analysis.
the range between 2:1 and 4:1.
The oxidation of the N-tosyl-protected THF alcohols 11
The mixture of the diols 18 and 19 was transformed into and 12 into the corresponding aldehydes was examined next
the corresponding epoxides by reaction with NaH/tosyl- (Scheme 4). While the trans-alcohol 11 could be cleanly oxi-
imidazole (Scheme 3).[12] Treatment of the epoxides with dized into the trans-aldehyde 21 using DessϪMartin con-
acid resulted in the cleavage of the silyl ether in 15 and of ditions,[13] the cis-alcohol 12 was transformed via the corre-
the oxazolidines in 16a and 17 followed by intramolecular sponding aldehyde into the hemiaminal 22 as a single dia-
epoxide opening and formation of the THF alcohols 11 and stereomer. The structural assignment of 22 was possible by
12. Both epimers 11 and 12 were separated by column chro- X-ray crystal-structural analysis.
matography. In the case of the formaldehyde-derived oxazo-
The hemiaminal formation of the N-tosyl-protected com-
lidines 18b/19b the cis isomer provided the bicyclic com- pound in the cis series can be explained by the relative
2978
Eur. J. Org. Chem. 1999, 2977Ϫ2990

Enantiomerically Pure Amino Acids Containing 2,5-Disubstituted THF Rings
FULL PAPER
Scheme 4. Oxidation of a 1:1 mixture of the THF alcohols 11 and
12: (a) DessϪMartin oxidation, 40% 21 and 40% 22; Swern oxida-
tion, 31% 21 and 66% 22; X-ray structure of 22
Scheme 3. Conversion of the diols 18 and 19 into the THF alcohols
11 and 12: (a) i: NaH, tosylimidazole, THF; ii: 1 equiv. CSA,
CH2Cl2, room temp., 2 h; (b) i: NaH, tosylimidazole, THF; ii: epo-
xide purification by column chromatography; iii: 0.1 equiv. CSA,
CH2Cl2, room temp., 12 h; (c) i: NaH, tosylimidazole, THF; ii:
HOAc/H2O 4:1, 40°C, 30 min; CSA ϭ camphersulfonic acid
acidic NH of the sulfonamide. Therefore, a change of the
N-protective group to tert-Butoxycarbonyl (Boc) with a less
acidic NH was undertaken (Scheme 5). The deprotection of
the N-tosyl group of 11 and 12 could be achieved with Na
in liq. NH3. The resulting amino-THF alcohols were Boc-
protected to give the trans-N-Boc-THF alcohol 23 and the
the cis-N-Boc-THF alcohol 26, respectively. Oxidation of
the alcohols 23 and 26 by a two-step procedure (Swern oxi-
dation followed by NaClO2 oxidation) yielded the N-Boc-
protected THF amino acids 24 and 27. Figure 4 shows the
results of X-ray crystal structural analyses of compounds
24 and 27. The corresponding benzyl esters 25 and 28,
which are useful building blocks for THF peptide synthesis
in solution, were prepared by reaction of the carboxylic ac-
ids with benzyl bromide.
N-Fmoc-protected amino acids are standard building
blocks for solid-phase peptide synthesis. For this reason,
the N-Fmoc protected THF amino acids 30 (trans) and 32
(cis) were prepared by analogy to the N-Boc series
(Scheme 6).
Inspection of molecular models indicated that the cis-
THF amino acid 7 could function as a β-turn inducer in
peptides. Turns are defined as sites in a peptide structure
where the peptidic chain reverses its overall direction.[14]
Scheme 5. Conversion of the THF alcohols 11 and 12 into the Boc-
protected THF amino acid derivatives: (a) i: Na, NH3, Ϫ40°C,
10 min; ii: Boc2O, NaOH, MeOH; (b) i: dimethyl sulfoxide, oxalyl
chloride, Et3N; ii: NaClO2, NaH2PO4, tBuOH; (c) BnBr, Et3N, ace-
Following Venkatachalam,[15] β-turns are classified into dif- tone; Boc ϭ tert-butoxycarbonyl
Eur. J. Org. Chem. 1999, 2977Ϫ2990
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U. Koert et al.
FULL PAPER
Scheme 6. Conversion of the THF alcohols 11 and 12 into the
Fmoc-protected THF amino acid derivatives: (a) i: Na, NH3,
Ϫ40°C, 10 min; ii: Fmoc-succinimide, NaHCO3, MeCN/H2O, 12 h
room temp.; (b) i: dimethyl sulfoxide, oxalyl chloride, Et3N; ii:
NaClO2, NaH2PO4, tBuOH;. Fmoc ϭ 9-fluorenylmethoxycarbonyl
Figure 4. A: solid-state conformation of the trans-THF amino acid
derivative 24 obtained by X-ray crystal-structural analysis; B: solid-
state conformation of the cis-THF amino acid derivative 27 obtai-
ned by X-ray crystal-structural analysis
Scheme 7. Synthesis of the THF diamide 34: (a) MeNH2 · HCl,
EDC, HOBT, EtNiPr2, THF, room temp., 18 h; (b) i: TFA, CH2Cl2,
room temp., 4 h; ii: PhCOCl, NaHCO3, THF/H2O, room temp.,
1 h; EDC
ϭ N-(3-dimethylaminopropyl)-NЈ-ethylcarbodiimide,
HOBT ϭ 1-hydroxy-1H-benzotriazole, TFA ϭ trifluoroacetic acid
ferent conformational types depending on the torsion angle
values for Φ1, Ψ1, Φ2, and Ψ2 (Figure 5a). According to equilibrium of different conformers. In addition the tem-
Kabsch and Sander, the αCi to αCi ϩ 3 distance must be perature dependence of the NH shifts (Ϫ4.6 and Ϫ5.2 ppb/
[16]
˚
shorter than 7 A.
To explore the β-turn forming poten- K respectively) revealed the absence of any intramolecular
hydrogen bond in this solvent. Due to solubility reasons,
tial of 7 the dipeptide 34 was synthesized (Scheme 7).
An X-ray crystal-structural analysis of 34 was under- no conformational studies could be accomplished in water.
taken. The solid-state conformation of 34 showed indeed a Further work, with elongated peptide chains containing po-
β-turn type conformation with a 10-membered-ring hydro- lar amino acids should allow us to study the effect of THF
gen bond (Figure 5b). One highly ordered molecule of water amino acids on peptide secondary structures under physio-
was found in the solid state.
logical conditions.
The solution structure of 34 was investigated by NMR
In conclusion, a synthetic route towards enantiomerically
studies. Interproton distances derived from quantified pure cis- and trans-2,5-disubstituted THF amino acids has
NOESY crosspeaks were used as input for MD Simu- been elaborated. While the work presented here concen-
lations. The calculations were done with “Insight Discover trates on -alanine as the starting point, other THF amino
97” (MSI, San Diego, CA) using the force field cvff. In acids with side chains other than methyl should be access-
CDCl3 a preferred conformation was found that displayed ible along this route by using other α-amino acids as the
the same 10-membered-ring hydrogen bond as in the solid chiral pool source. The THF amino acids are interesting
state (Figure 5c). In contrast, the NOESY spectrum of a candidates as peptidomimetics or for the assembly of arti-
2 m [D6]DMSO solution of 34 was consistent with a fast ficial ion channels.
2980
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Enantiomerically Pure Amino Acids Containing 2,5-Disubstituted THF Rings
FULL PAPER
Finnigan MAT 95. Ϫ All reactions were performed under an inert
atmosphere of argon in oven- or flame-dried glassware. Dry sol-
vents: THF, Et2O, benzene, and toluene were distilled from sodium
benzophenone. All commercially available reagents were used with-
out purification unless otherwise noted. Ϫ All reactions were moni-
tored by thin-layer chromatography (TLC) carried out on Merck
F-254 silica glass plates visualized with UV light and/or heat-gun
treatment with 5% phosphomolybdic acid in ethanol or 1) 2% anis-
aldehyde in ethanol and 2) 20% H2SO4. Ϫ Column chromatogra-
phy was performed with Merck silica gel 60 (70Ϫ200 mesh and
230Ϫ400 mesh). Ϫ PE: Light petroleum ether, b.p. 40Ϫ60°C.
MTBE: tert-butyl methyl ether.
X-ray Structure Determination of 20, 22, 24, 27, and 34: Com-
pounds 22 and 24 were measured on a four-circle diffractometer
CAD4 (EnrafϪNonius, Delft), 27 was measured on a four-circle
diffractometer STADI4 (Stoe, Darmstadt). The intensity data col-
lection of 20 was performed on a IPDS one-circle diffractometer
(Stoe, Darmstadt). The crystal-structure analyses were performed
with the program packages SHELXS-86/SHELXL-93[17] and
SHELXS-97.2/SHELXL-97.2;[18] for details see Table 2. Further
crystallographic data, excluding structure-factor listings, have been
deposited at the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC-111903 (20), -103321 (22), -
103320 (24), -111904 (27), and -103321 (34). Copies of the data can
be obtained free of charge on application to CCCD, 12 Union
Road, Cambridge CB21EZ, UK [Fax: (internat.) ϩ 44-1223/336-
033, E-mail: deposit@ccdc.cam.ac.uk].
(2S)-2-N-Tosylamino-6-hepten-3-one (9): Magnesium turnings
(8.10 g, 333 mmol) were covered with Et2O (30 mL). 2 mL of a
solution of 4-bromo-1-butene (16.9 mL, 22.5 g, 167 mmol) in Et2O
(80 mL) was added. The reaction initiated exothermically after a
short period of induction. The remainder of the bromide solution
was added dropwise. The dropping funnel was rinsed with Et2O
(40 mL) and the reaction mixture was refluxed for 15 min. The cold
Grignard solution was transferred via cannula into a 250 mL drop-
ping funnel and added at Ϫ78°C within 75 min to a mechanically
stirred solution of acid chloride 8 (20.8 g, 79.3 mmol) in Et2O
(800 mL). During the addition a yellowish solid precipitated. The
reaction was allowed to warm to room temperature overnight and
then quenched at 0°C by the addition of aqueous HCl (1 ,
200 mL). The layers were separated and the aqueous layer was ex-
tracted with MTBE (3 ϫ 300 mL). The combined organic layers
were washed with saturated NaHCO3 solution (2 ϫ 200 mL) and
with saturated NaCl solution (300 mL). After drying with MgSO4
and removal of the solvent in vacuo, the crude product was purified
by column chromatography (PE/MTBE 1:1, 600 g of silica) to yield
14.3 g of the ketone 9 (50.8 mmol, 64%) as colorless crystals. m.p.
94Ϫ98°C. Ϫ Rf ϭ 0.43 (PE/MTBE 1:1). Ϫ [α]D ϭ ϩ 54.4, [α]578 ϭ
ϩ 57.8, [α]546 ϭ ϩ 68.2, [α]436 ϭ ϩ 142.9, [α]365 ϭ ϩ 288.2 (c ϭ
1.03, CHCl3, T ϭ 20°C). Ϫ IR (KBr): ν˜ ϭ 3262 cmϪ1 s (NH),
2979/2937/2920 m (CH), 1715 s (CϭO), 1426 m, 1404 m, 1339 s,
1168 s, 1092 m, 995 w, 963 w, 908 w, 618 m, 594 m, 561 m, 548 m.
Figure 5. A: general β-turn structure; B: solid-state conformation
of the cis-THF dipeptide 34 obtained by X-ray structural analysis;
C: solution conformation (CDCl3) of the cis-THF dipeptide 34 ob-
tained by NMR studies and MD calculations
1
Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.24 (d, J ϭ 7.2 Hz, 3 H, 1-
H3), 1.95Ϫ2.58 (m, 4 H, 4-H2 and 5-H2), 2.34 (s, 3 H, TsCH3), 3.84
(q, J ϭ 7.2 Hz, 1 H, 2-H), 4.78Ϫ4.89 (m, 2 H, 7-H2), 5.47Ϫ5.67
(m, 2 H, NϪH and 6-H), 7.21 (d, J ϭ 8.2 Hz, 2 H, Ts), 7.64 (d,
J ϭ 8.2 Hz, 2 H, Ts). Ϫ 13C NMR (50 MHz, CDCl3): δ ϭ 18.9 (C-
1), 21.5 (TsCH3), 27.2 (C-5), 38.0 (C-4), 57.1 (C-2), 115.6 (C-7),
136.1 (C-6), 127.1, 129.7, 136.8 and 143.6 (Ts), 207.2 (CϭO). Ϫ
C14H19NO3S (281.37): calcd. C 59.76, H 6.81, N 4.98; found C
59.46, H 7.02, N 4.91.
Experimental Section
General: All b.p.s and m.p.s are uncorrected values. Ϫ IR: Bruker
IFS 88. Ϫ NMR: Bruker ARX-200, AC-300, DPX-300, AMX-500
and AMX-600. For 1H NMR, CDCl3 as solvent δH ϭ 7.25,
[D6]DMSO as solvent δH ϭ 2.50, [D4]MeOH as solvent δH ϭ 4.78;
for 13C NMR, CDCl3 as solvent δC ϭ 77.0, [D6]DMSO as solvent
δC ϭ 39.5, [D4]MeOH as solvent δC ϭ 49.0. Ϫ Elemental analysis:
CHN Rapid (Heraeus), CHNS-932 Analysator (Leco). Ϫ HRMS:
Preparation of Ketone
9 by Cuprate Addition: LiCl (13.9 g,
328 mmol) and CuCN (14.5 g, 162 mmol) were dried in vacuo at
Eur. J. Org. Chem. 1999, 2977Ϫ2990
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U. Koert et al.
FULL PAPER
Table 2. Crystal data for compounds 20, 22, 24, 27, and 34
20
22
24
27
34
Empiric formula
Molecular mass
C15H21NO4S
311.39
C14H19NO4S
297.36
C12H21NO5
259.30
C12H21NO5
259.30
C15H22N2O4
294.35
ρ [gcmϪ3
]
1.366
1.393
1.190
1.149
1.252
Z
4
4
2
2
4
Temperature [K]
Crystal system
Space group
Radiation [pm]
Monochrom.
Crystal size [mm]
a [pm] ϭ
1702)
193(2)
293(2)
298(2)
120(2)
rhombic (222)
P212121 (no. 19)
Mo-Kα (71.069)
planar graph.
0.85ϫ0.39ϫ0.39
807.99(13)
1296.90(15)
1445.10(18)
rhombic (222)
P212121 (no. 19)
Cu-Kα (154.178)
planar graph.
0.70ϫ0.50ϫ0.40
845.5(1)
monoclinic (2)
P21 (no. 4)
Cu-Kα (154.178)
planar graph.
0.35ϫ0.20ϫ0.20
762.3(1)
monoclinic (2)
P21 (no. 4)
Mo-Kα (71.069)
planar graph.
1.60ϫ0.83ϫ0.08
862.69(7)
925.1(2)
rhombic (222)
P212121 (no. 19)
Mo-Kα (71.069)
planar graph.
0.42ϫ0.30ϫ0.19
935.3(1)
b [pm] ϭ
1165.6(1)
1438.3(1)
991.3(1)
962.4(1)
1050.0(1)
1590.0(2)
c [pm] ϭ
978.9(1)
α [o] ϭ
β [o] ϭ
95.90(1)
106.459(8)
γ [o] ϭ
Fooo
664
280
632
Volume [106 pm3]
Scan range [o]
Type
1514.3(4)
2.82 < Θ < 27.35
ω-scan
2.00 < Θ < 32.50
ω.2Θ-scan
h: Ϫ9/9,
k: Ϫ13/13,
l: Ϫ16/16
2.00 < Θ < 30
ω.2Θ-scan
h: Ϫ8/10,
k: Ϫ11/0,
l: Ϫ10/0
2.17 < Θ < 27.46
ω.2Θ-scan
h: Ϫ11/11,
k: 0/12,
2.53 < Θ < 28.06
Θ-scan
h: Ϫ12/12,
k: 0/13,
l: 0/20
h: Ϫ10/10,
k: 0/16,
l: 0/18
l: Ϫ12/12
Data; restraints; parameters 3352; 0; 275
Absorption correction
2331; 0; 191
1143; 0; 174
3672; 1; 212
empirical
3460; 0
Θ-scans
Atom form factors
International Tables for Crystallography, vol. C, 1995 (Tables 4.2.6.8 and 6.1.1.4),
Kluwer Academic Press, Dordrecht, Boston, London
Full-matrix least squares based on F2
Refinement
Final R indices [I > 2σ(I)]
Final R indices (all data)
GoF
R1 ϭ 0.0330
wR2 ϭ 0.0838
1.015
R1 ϭ 0.0538
wR2 ϭ 0.1588
1.133
R1 ϭ 0.0492
wR2 ϭ 0.1324
1.092
R1 ϭ 0.0382
wR2 ϭ 0.1107
1.051
Ϫ2.2(15) ഠ 0
Ϫ0.127/0.122 e
R1 ϭ 0.0303
wR2 ϭ 0.0772
1.044
Flack parameter
Ϫ0.02(6) ഠ 0
0.8(7)
Difference electron density Ϫ0.241/0.157 e
Ϫ0.341/0.202 e
Ϫ0.235/0.202 e
Ϫ0.133/0.176 e
(min/max) [10Ϫ6 pmϪ3
]
250°C for 5 h, cooled down and flushed with argon. Magnesium
turnings (5.0 g, 200 mmol) were covered with THF (50 mL). Some
drops of C2H4Br2 and after it 4-bromo-1-butene (10.0 mL, 13.3 g,
99 mmol) in THF (100 mL) were added dropwise keeping the reac-
tion solution gently boiling. After completed addition, the mixture
was refluxed for 1 h. The previously dried LiCl and CuCN were
iPrOH (4:1, 100 mL). The layers were separated and the aqueous
layer was extracted with CHCl3/iPrOH (4:1, 3 ϫ 100 mL). The
combined organic layers were dried with MgSO4 and the solvents
were removed in vacuo. The nonpolar impurities were removed by
filtration over 200 g of silica (PE/MTBE 1:1 to PE/MTBE 1:2). The
minor epimer was removed by recrystallisation from 30 mL of PE/
covered with THF (200 mL) and the Grignard solution was added MTBE (1:2). Thus, 5.15 g (18.2 mmol, 83%) of the alcohol 10 was
at Ϫ40°C via cannula. The color of the pale-green salt suspension
turned chocolate brown. Acid chloride 8 (12.3 g, 44.3 mmol) in
obtained as colorless crystals. m.p. 68°C. Ϫ Rf ϭ 0.11 (PE/Et2O,
1:1). Ϫ [α]D ϭ Ϫ13.0, [α]578 ϭ Ϫ13.3, [α]546 ϭ Ϫ15.4, [α]436
ϭ
THF (150 mL) was added dropwise at Ϫ70°C. After stirring for Ϫ28.1, [α]365 ϭ Ϫ46.0 (c ϭ 1.00, CHCl3, T ϭ 20°C). Ϫ IR (KBr):
1 h, the cooling bath was replaced by an ice bath and the reaction
was allowed to warm to 0°C within 5 min and then quenched with
saturated NH4Cl solution (250 mL). Water was added to redissolve
ν˜ ϭ 3499 cmϪ1 s (OH), 3287 m (NH), 2974/2943 m (CH), 1450 w,
1332 m, 1319 m, 1162 s, 1146 s, 1090 s, 815 m, 678 s, 555 s. Ϫ H
NMR (300 MHz, CDCl3): δ ϭ 0.95 (d, J ϭ 6.7 Hz, 3 H, 1-H3),
1
the white precipitate and stirring was continued for 30 min at 0°C. 1.41Ϫ1.48 (m, 2 H, 4-H2), 1.93Ϫ2.18 (m, 2 H, 5-H2), 2.32 (d, J ϭ
The layers were separated and the aqueous layer was extracted with
MTBE (3 ϫ 100 mL). The combined organic layers were washed
with saturated NaCl solution (100 mL) and dried with MgSO4. The
solvents were removed in vacuo. Recrystallisation (MTBE) af-
forded 11.7 g (41.5 mmol, 94%) of ketone 9.
5.1 Hz, 1 H, OH), 2.37 (s, 3 H, TsCH3), 3.14Ϫ3.28 (m, 1 H, 2-H),
3.34Ϫ3.41 (m, 1 H, 3-H), 4.87Ϫ4.98 (m, 2 H, 7-H2), 5.08 (d, J ϭ
8.5 Hz, 1 H, NH), 5.63Ϫ5.74 (m, 1 H, 6-H), 7.24 (d, J ϭ 8.1 Hz,
2 H, Ts), 7.72 (d, J ϭ 8.3 Hz, 2 H, Ts). Ϫ13C NMR (75 MHz,
CDCl3): δ ϭ 18.5 (C-1), 21.5 (TsCH3), 29.8 (C-5), 32.8 (C-4), 53.7
(C-2), 74.1 (C-3), 115.1 (C-7), 138.1 (C-6), 127.0, 129.7 and 143.4
(Ts). Ϫ C14H21NO3S (283.39): calcd. C 59.34, H 7.47, N 4.94;
found C 59.22, H 7.35, N 4.84.
(2S,3S)-2-N-Tosylamino-6-hepten-3-ol (10): The ketone 9 (6.175 g,
21.96 mmol) was dissolved in THF (100 mL) and cooled to
Ϫ100°C. A 1  solution of -selectride in THF (44.0 mL,
44.0 mmol) was precooled to Ϫ78°C and added dropwise within
(2S,5S,1ЈS)-5-Hydroxymethyl-2-[1Ј-(N-tosylamino)ethyl]-
30 min to the reaction mixture. The reaction mixture was warmed tetrahydrofuran (11) and (2S,5R,1ЈS)-5-Hydroxymethyl-2-[1Ј-(N-
to Ϫ60°C over 3 h and quenched with 200 mL of dropwise added
AcOH/H2O 1:1. After stirring for 3 h at room temperature, the
solvents were removed in vacuo. Remaining water and acid was
tosylamino)ethyl]tetrahydrofuran (12): m-CPBA (60%, 13.9 g,
48.3 mmol) was dissolved in CH2Cl2 (300 mL). The organic layer
of this mixture was added to a solution of the alcohol 10 (6.80 g,
removed azeotropically with toluene (2 ϫ 100 mL). The crude 24.2 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred
product was dissolved in saturated NaHCO3 (100 mL) and CHCl3/
2982
overnight at room temperature. It was washed successively with
Eur. J. Org. Chem. 1999, 2977Ϫ2990

Enantiomerically Pure Amino Acids Containing 2,5-Disubstituted THF Rings
FULL PAPER
saturated Na2SO3 solution (300 mL), saturated NaHCO3 solution
(300 mL), saturated NaCl solution (300 mL) and dried with
MgSO4. The solution was concentrated to 150 mL, para-tolu-
2.39 (s, 3 H, TsCH3), 3.29 (ddq, J ϭ 8.7, 1.9 and 6.6 Hz, 1 H, 2-
H), 3.44 (dt, J ϭ 6.6 and 1.9 Hz, 1 H, 3-H), 4.65 (d, J ϭ 8.7 Hz, 1
H, NϪH), 4.81Ϫ4.92 (m, 2 H, 7-H2), 5.60 (ddt, J ϭ 18.1, 9.1 and
enesulfonic acid (207 mg, 1.2 mmol) was added, and the solution 6.6 Hz, 1 H, 6-H), 7.26 (d, J ϭ 8.7 Hz, 2 H, Ts), 7.73 (d, J ϭ 8.3
was stirred for 3 h at room temperature. It was washed with satu-
rated NaHCO3 solution (150 mL) and with saturated NaCl solu-
tion (150 mL). The aqueous layers were extracted with CH2Cl2
(50 mL). The combined organic layers were dried with MgSO4. The
solvent was evaporated in vacuo. The crude product was filtered
over 500 g of silica gel (MTBE). Column chromatography (MTBE/
DCM, 4:1, 500 g of silica) afforded 2.78 g (9.3 mmol, 38%) of the
trans-alcohol 11 and 2.87 g (9.6 mmol, 40%) of the cis-alcohol 12
as colorless solids. Ϫ trans-THF Alcohol 11: m.p. 85Ϫ89°C
(MTBE). Ϫ Rf ϭ 0.27 (MTBE/CH2Cl2 4:1). Ϫ [α]D ϭ ϩ6.0,
[α]578 ϭ ϩ6.3, [α]546 ϭ ϩ6.7, [α]436 ϭ ϩ6.2 (c ϭ 0.91, CHCl3, T ϭ
20°C). Ϫ IR (KBr): ν˜ ϭ 3506 and 3109 cmϪ1 (NH and OH), 2977/
2912/2875 m (CH), 1493 m, 1468 m, 1441 w, 1318 m, 1146 s, 1090
s, 1052 s, 949 s, 815 m, 665 m, 546 s. Ϫ1H NMR (300 MHz,
CDCl3): δ ϭ 1.02 (d, J ϭ 6.7 Hz, 3 H, 2Ј-H3), 1.56Ϫ1.98 (m, 4 H,
3-H2 and 4-H2), 2.30 (br. s, 1 H, OH), 2.41 (s, 3 H, TsCH3), 3.23
(dp, J ϭ 4.3 and 7.0 Hz, 1 H, 1Ј-H), 3.42 (dd, J ϭ 6.2 and 11.3 Hz,
1 H, CHHOH), 3.56 (dd, J ϭ 3.5 and 11.6 Hz, 1 H, CHHOH),
3.80 (ddd, J ϭ 4.4, 6.0 and 7.8 Hz, 1 H, 2-H), 3.94 (ddt, J ϭ 3.2,
8.0 and 6.1 Hz, 1 H, 5-H), 4.80 (d, J ϭ 7.3 Hz, 1 H, NϪH), 7.29
(d, J ϭ 8.1 Hz, 2 H, Ts), 7.73Ϫ7.76 (m, 2 H, Ts). Ϫ 13C NMR
(75 MHz, CDCl3): 18.9 (C-2Ј), 21.5 (TsCH3), 27.4 and 28.7 (C-4
and C-3), 52.7 (C-1Ј), 64.8 (CH2OH), 80.1 (C-5), 81.9 (C-2), 127.1,
129.6, 138.1 and 143.2 (Ts). Ϫ C14H21NO4S (289.39): calcd. C
56.17, H 7.07, N 4.68; found C 56.15, H 6.84, N 4.65. Ϫ cis-THF
Alcohol 12: m.p. 95Ϫ96°C (MTBE). Ϫ Rf ϭ 0.35 (MTBE/CH2Cl2,
4:1). Ϫ [α]D ϭ ϩ2.8, [α]278 ϭ ϩ3.2, [α]546 ϭ ϩ3.5, [α]436 ϭ ϩ4.4,
[α]365 ϭ ϩ5.1 (c ϭ 0.99, CHCl3, T ϭ 19°C). Ϫ IR (KBr): ν˜ ϭ 3494
cmϪ1 s, 3361 br. s and 3181 br. m (NH and OH), 2975/2955/2941/
2905/2878 m (CH), 1596 m, 1494 w, 1474 s, 1456 s, 1404 m, 1380
m, 1367 m, 1328 s, 1209 m, 1188 m, 1159 s, 1148 s, 1111 s, 1087 s,
1053 s, 1040 s, 1018 m, 995 m, 980 m, 955 s, 887 m, 867 m, 822 s,
708 m, 666 s, 550 s, 474 m, 459 m. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 1.06 (d, J ϭ 6.7 Hz, 3 H, 2Ј-H3), 1.64Ϫ1.91 (m, 4 H, 3-H2 and
4-H2), 2.20 (br. s, 1 H, OϪH), 2.41 (s, 3 H, TsCH3), 3.19Ϫ3.36 (m,
1 H, 1Ј-H), 3.47 (dd, J ϭ 4.9 and 11.6 Hz, 1 H, CHHOH), 3.70
(dd, J ϭ 2.9 and 11.6 Hz, 1 H, CHHOH), 3.79 (dt, J ϭ 4.0 and
6.7 Hz, 1 H, 2-H), 3.89Ϫ4.09 (m, 1 H, 5-H), 5.43 (d, J ϭ 7.5 Hz,
1 H, NϪH), 7.28 (d, J ϭ 8.2 Hz, 2 H, Ts), 7.76 (d, J ϭ 8.3 Hz, 2
H, Ts). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 19.3 (C-2Ј), 21.4
(TsCH3), 26.8 and 28.5 (C-3 and C-4), 53.2 (C-1Ј), 64.7 (CH2OH),
79.9 (C-5), 82.3 (C-2), 127.0, 129.5, 138.4 and 143.1 (Ts). Ϫ
C14H21NO4S (289.39): calcd. C 56.17, H 7.07, N 4.68; found C
55.95, H 7.06, N 4.49.
Hz, 2 H, Ts). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 0.4 (TMS), 19.2
(C-1), 21.5 (TsCH3), 29.7 (C-5), 32.8 (C-4), 51.8 (C-2), 74.8 (C-3),
114.7 (C-7), 127.0, 129.6 (Ts), 138.0 and 138.6 (Ts and C-6), 143.3
(Ts). Ϫ C17H29NO3SiS (355.57): calcd.C 57.43, H 8.22, N 3.94, S
9.02; found C 57.34, H 8.22, N 3.81, S 9.03.
(4S,5S)-5-(3Ј-Butenyl)-4-methyl-N-tosyl-1,3-oxazolidine (16a) and
(6S,7S)-7-(3Ј-Butenyl)-6-methyl-N-tosyl-1,3,5-dioxazolepine (16b):
Alcohol 10 (14.1 g, 49.8 mmol), paraformaldehyde (4.49 g,
149.5 mmol) and camphorsulfonic acid (580 mg, 2.49 mmol) in
toluene (300 mL) were heated on a DeanϪStark trap for 1 h. The
reaction mixture was washed with saturated NaHCO3 solution
(100 mL) and saturated NaCl solution (100 mL) and dried with
Na2SO4. The solvent was removed in vacuo. Column chromatogra-
phy (PE/MTBE 3:1, 150 g of silica) yielded 4.41 g of the acetal 16a
and 10.4 g of 1:1 mixture of the acetals 16a and 16b. The latter
fraction was dissolved in CH2Cl2 (100 mL), camphorsulfonic acid
(cat.) was added and the reaction mixture was stirred overnight.
The solution was washed with saturated NaHCO3 solution (50 mL)
and with saturated NaCl solution (50 mL) and dried with Na2SO4.
Column chromatography (PE/MTBE, 3:1, 250 g of silica) afforded
additional 9.71 g of five-membered acetal 16a and 0.27 g
(0.83 mmol, 2%) of seven-membered acetal 16b as a colourless oil.
Overall yield: 14.20 g of 16a (47.8 mmol, 96%), colorless oil, Rf ϭ
0.30 (PE/MTBE, 3:1). Ϫ [α]D ϭ ϩ110.2, [α]578 ϭ ϩ115.1, [α]546
ϭ
ϩ132.1, [α]436 ϭ ϩ237.6, [α]365 ϭ ϩ406.6 (c ϭ 0.94, CHCl3, T ϭ
1
27°C). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.02Ϫ1.20 (m, 1 H),
1.20Ϫ1.45 (m, 1 H) and 1.75Ϫ2.02 (m, 2 H, 1Ј-H2, 2Ј-H2), 1.30 (d,
J ϭ 7.0 Hz, 3 H, 4-CH3), 2.39 (s, 3 H, TsCH3), 3.16 (p, J ϭ 7.1 Hz,
1 H, 4-H), 3.42 (dt, J ϭ 4.5 and 8.4 Hz, 1 H, 5-H), 4.60 (d, J ϭ
7.6 Hz, 1 H, 2-H), 4.82Ϫ4.98 (m, 2 H, 4Ј-H2), 5.13 (d, J ϭ 7.7 Hz,
1 H, 2-H), 5.62 (ddt, J ϭ 7.3, 10.3 and 18.0 Hz, 1 H, 3Ј-H), 7.29
(d, J ϭ 9.3 Hz, 2 H, Ts), 7.70 (d, J ϭ 9.2 Hz, 2 H, Ts). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 19.0 (4-CH3), 21.4 (TsCH3), 29.5 (C-
2Ј), 31.1 (C-1Ј), 59.1 (C-4), 79.1 (C-5), 85.0 (C-2), 115.0 (C-4Ј),
127.8 and 129.6 (Ts), 134.4 (C-3Ј), 137.2 and 143.9 (Ts). Ϫ
C15H21NO3S (295.40): calcd. C 60.99, H 7.17, N 4.74, S 10.85;
found C 60.99, H 6.94, N 4.88, S 10.85.
(6S,7S)-7-(3Ј-Butenyl)-6-methyl-N-tosyl-1,3,5-dioxazolepine (16b):
Rf ϭ 0.18 (PE/MTBE, 3:1). Ϫ [α]D ϭ ϩ113.8, [α]578 ϭ ϩ118.2,
[α]546 ϭ ϩ134.9, [α]436 ϭ ϩ235.7, [α]365 ϭ ϩ387.4 (c ϭ 1.18,
1
CHCl3, T ϭ 27°C). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.23 (d,
J ϭ 6.5 Hz, 3 H, 6-CH3), 1.09Ϫ1.45 (m, 2 H, 1Ј-H2), 1.85Ϫ2.23
(m, 2 H, 2Ј-H2), 2.40 (s, 3 H, TsCH3), 3.25 (dt, J ϭ 2.2 and 9.3 Hz,
1 H, 7-H), 3.60 (dq, J ϭ 7.2 and 10.3 Hz, 1 H, 6-H), 4.36 (d, J ϭ
7.1 Hz, 1 H, 2-H), 4.52 (d, J ϭ 12.9 Hz, 1 H, 4-H), 4.85Ϫ5.01 (m,
3 H, 2-H, 4Ј-H2), 5.56Ϫ5.77 (m, 1 H, 3Ј-H), 5.64 (d, J ϭ 12.9 Hz,
4-H), 7.25 (d, J ϭ 8.1 Hz, 2 H, Ts), 7.82 (d, J ϭ 8.3 Hz, 2 H, Ts).
(2S,3S)-2-N-Tosylamino-3-trimethylsilyloxy-6-heptene (15): To
a
solution of alcohol 10 (1.00 g, 3.53 mmol) in CH2Cl2 (25 mL) were
added at 0°C TMSCl (0.9 mL, 7.57 mmol) and NEt3 (2.0 mL,
14.1 mmol). Stirring was continued for 15 min. (0°C to room tem-
perature). Saturated aqueous NaHCO3 solution (10 mL) was added
and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (5 mL), the combined organic layers were washed
with saturated NaCl solution (20 mL) and dried with Na2SO4. The
solvent was removed in vacuo. Column chromatography (cyclohex-
ane/MTBE 4:1, 50 g of silica) afforded 1.19 g of the TMS ether 15
(3.36 mmol, 94%) as a colorless oil, Rf ϭ 0.38 (cyclohexane/MTBE,
Ϫ
13C NMR (75 MHz, CDCl3): δ ϭ 19.2 (6-CH3), 21.5 (TsCH3),
29.6 (C-2Ј), 32.7 (C-1Ј), 57.9 (C-6), 74.3 (C-7), 86.2 (C-4), 97.8 (C-
2), 115.4 (C-4Ј), 128.2 and 129.1 (Ts), 136.9 (C-3Ј), 137.5 and 143.4
(Ts). Ϫ C16H23NO4S (325.42): calcd. C 59.05, H 7.12, N 4.30, S
9.85; found C 59.11, H 7.34, N 4.18, S 9.87.
(4S,5S)-5-(3Ј-Butenyl)-2,2,4-trimethyl-N-tosyl-1,3-oxazolidine (17):
Alcohol 10 (6.00 g, 21.2 mmol), 2,2-dimethoxypropane (26 mL,
4:1). Ϫ [α]D ϭ ϩ0.6, [α]578 ϭ ϩ0.7, [α]546 ϭ ϩ1.0, [α]436 ϭ ϩ2.5, 212 mmol), and camphorsulfonic acid (49 mg, 0.22 mmol) were
[α]365 ϭ ϩ5.2 (c ϭ 0.97, CHCl3, T ϭ 27°C). Ϫ 1H NMR
stirred at room temperature for 2 h and subsequently warmed in
(300 MHz, CDCl3): δ ϭ 0.06 (s, 9 H, TMS-H3), 0.99 (d, J ϭ 6.4 Hz, vacuo (40°C, 337 mbar) to remove MeOH. The reaction mixture
3 H, 1-H3), 1.25Ϫ1.45 (m, 2 H, 4-H2), 1.93Ϫ2.18 (m, 2 H, 5-H2), was washed with saturated NaHCO3 solution (25 mL) and satu-
Eur. J. Org. Chem. 1999, 2977Ϫ2990
2983

U. Koert et al.
FULL PAPER
rated NaCl solution (25 mL). The combined aqueous layers were 18.5 (C-1), 21.5 (TsCH3), 28.8 and 29.4 (C-4, C-5), 51.9 (C-2), 66.1
extracted with MTBE (25 mL). The combined organic layers were (C-7), 71.9 (C-6), 75.2 (C-3), 127.0, 129.6, 138.4 and 143.3 (Ts). Ϫ
dried with Na2SO4. The solvent and residual DMP were removed HRMS (ESI): C17H31NO5SSi: calcd. 412.1590 [M ϩ Na]ϩ; found
in vacuo. Column chromatography (PE/Et2O 10:1, then PE/MTBE
1:2) afforded 287 mg of the starting material (1.01 mmol, 5%) and
6.29 g of 17 (19.5 mmol, 92%) as a colorless solid, m.p. 62°C. Ϫ
Rf ϭ 0.26 (PE/MTBE, 10:1). Ϫ [α]D ϭ Ϫ32.4, [α]578 ϭ Ϫ34.0,
[α]546 ϭ Ϫ38.3, [α]436 ϭ Ϫ63.9, [α]365 ϭ Ϫ97.2 (c ϭ 1.05, CHCl3,
T ϭ 27°C). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.39 (d, J ϭ
6.8 Hz, 3 H, 4-CH3), 1.58 (s, 3 H, 2-CH3) and 1.62 (s, 3 H, 2-CH3),
1.39Ϫ1.62 (m, 2 H, 1Ј-H2), 1.85Ϫ2.29 (m, 2 H, 2Ј-H2), 2.44 (s, 3
H, TsCH3), 3.22 (p, J ϭ 7.0 Hz, 1 H, 4-H), 3.72 (ddd, J ϭ 5.0, 7.5
and 8.5 Hz, 1 H, 5-H), 4.89Ϫ5.09 (m, 2 H, 4Ј-H2), 5.77 (ddt, J ϭ
18.6, 11.4 and 7.3 Hz, 1 H, 3Ј-H), 7.28 (2d, J ϭ 9.5 and 10.3 Hz,
2 H, Ts), 7.74 (d, J ϭ 9.2 Hz, 2 H, Ts). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 20.0 (4-CH3), 21.4 (TsCH3), 26.8 (C-2Ј), 29.7 and 29.8
(2-CH3), 32.0 (C-1Ј), 59.9 (C-4), 81.1 (C-5), 97.7 (C-2), 115.1 (C-
4Ј), 138.6 (C-3Ј), 127.2, 129.4, 137.5 and 143.4 (Ts). Ϫ C17H25NO3S
(323.45): calcd. C 63.13, H 7.79, N 4.33; found C 62.86, H 7.47,
N 4.30.
412.1590 [M ϩ Na]ϩ.
(4S,5S,3ЈR)-5-(3Ј,4Ј-Dihydroxybutyl)-4-methyl-N-tosyl-1,3-
oxazolidine (18b): Acetal 16a (227 mg, 0.768 mmol), AD-mix-β
(1.18 g), MsNH2 (68 mg, 1.08 mmol). Column chromatography
(MTBE) yielded 239 mg of a 1.7:1 mixture of the alcohols 18b/
19b (0.73 mmol, 94%), as a colorless oil; ds ratio determined by
comparison of the integrals over OϪH (δ ϭ 2.24/2.41). Ϫ Rf ϭ
1
0.16 (AcOEt). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.31 (d, J ϭ
6.3 Hz, 3 H, 4-CH3), 0.96Ϫ1.64 (m, 4 H, 1Ј-H2 and 2Ј-H2), 2.01
(br. s, 1 H, OH), 2.24 (s, 0.63 H, OH), 2.41 (s, 3 H, TsCH3),
3.13Ϫ3.34 (m, 2 H, 4-H and 4Ј-H), 3.36Ϫ3.61 (m, 3 H, 5-H, 3Ј-H
and 4Ј-H), 4.59 (d, J ϭ 7.0 Hz, 0.63 H, major epimer, 2-H), 4.60
(d, J ϭ 7.0 Hz, 0.37 H, minor epimer, 2-H), 5.15 (d, J ϭ 7.0 Hz, 1
H, 2-H), 7.31 (d, J ϭ 8.1 Hz, 2 H, Ts), 7.70 (d, J ϭ 8.3 Hz, 2 H,
Ts). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 18.9 (4-CH3), 21.5
(TsCH3), 27.9 (C-2Ј), 29.3 (C-1Ј), 59.3 (C-4), 66.5 (C-4Ј), 71.5 (C-
3Ј), 79.9 (C-5), 85.9 (C-2), 127.9, 128.8, 134.4 and 144.1 (Ts). Ϫ
HRMS (ESI): C15H23NO5S: calcd. 352.1195 [M ϩ Na]ϩ; found
352.1193 [M ϩ Na]ϩ.
General Procedure for the Asymmetric Dihydroxylations of Alkenes
15, 16a, and 17: AD-Mix (1.54 g/mmol) and MsNH2 (1.4 equiv.)
were added to a solution of the alkene in tBuOH/H2O (1:1, 10 mL/
mmol) at 0°C. The suspension was stirred overnight. Na2S2O3 (1 g/
mmol) was added and the reaction mixture was stirred for 1 h at
room temperature. The layers were separated and the aqueous layer
was extracted with ethyl acetate (3 ϫ). The combined organic layers
were washed with saturated NH4Cl solution and with saturated
NaCl solution and dried with Na2SO4. The solvent was removed
in vacuo and the residue was purified by column chromatography.
(4S,5S,3ЈS)-5-(3Ј,4Ј-Dihydroxybutyl)-4-methyl-N-tosyl-1,3-ox-
azolidine (19b): Acetal 16a (465 mg, 1.57 mmol), AD-mix-α
(2.42 g), MsNH2 (139 mg, 2.20 mmol). Column chromatography
(MTBE) yielded 458 mg of a 2.7:1 mixture of the alcohols 19b/
18b (1.39 mmol, 88%) as a colorless oil, ds ratio determined by
comparison of the integrals over OϪH (δ ϭ 2.14/2.50). Ϫ Rf ϭ
1
0.16 (AcOEt). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.30 (d, J ϭ
6.3 Hz, 3 H, 4-CH3), 0.94Ϫ1.64 (m, 4 H, 1Ј-H2 and 2Ј-H2), 2.09
(br. s, 1 H, OH), 2.14 (s, 0.27 H, OH), 2.41 (s, 3 H, TsCH3), 2.50
(s, 0.73 H, OH), 3.12Ϫ3.34 (m, 2 H, 4-H and 4Ј-H), 3.42Ϫ3.64 (m,
3 H, 5-H, 3Ј-H and 4Ј-H), 4.59 (d, J ϭ 7.0 Hz, 0.27 H, 2-H), 4.60
(d, J ϭ 7.0 Hz, 0.73 H, 2-H), 5.15 (d, J ϭ 7.0 Hz, 1 H, 2-H), 7.31
(d, J ϭ 8.2 Hz, 2 H, Ts), 7.70 (d, J ϭ 8.2 Hz, 2 H, Ts). Ϫ 13C
NMR (75 MHz, CDCl3): δ ϭ 19.0 (4-CH3), 21.6 (TsCH3), 27.9 (C-
2Ј), 29.0 (C-1Ј), 59.1 (C-4), 66.5 (C-4Ј), 71.5 (C-3Ј), 79.9 (C-5), 85.6
(C-2), 127.9, 128.8, 134.4 and 144.2 (Ts). Ϫ HRMS (ESI):
C15H23NO5S: calcd. 352.1195 [M ϩ Na]ϩ; found 352.1196 [M ϩ
Na]ϩ.
(2R,5S,6S)-6-N-Tosylamino-5-trimethylsilyloxyheptan-1,2-diol
(18a): TMS ether 15 (1.50 g, 4.22 mmol), AD-mix-β (6.50 g),
MsNH2 (372 mg, 5.91 mmol). Column chromatography (PE/
MTBE 1:1, then MTBE) yielded 1.69 g of a 5.7:1 mixture of the
alcohols 18a/19a [contains MTBE (9%), 3.97 mmol, 94%] as a col-
orless oil. 20 mg of the diol mixture was silylated using TMSCl/
NEt3 for ds determination by comparison of the integrals over
1
NϪH. Ϫ Rf ϭ 0.39 (CHCl3/MeOH, 10:1). Ϫ H NMR (300 MHz,
CDCl3): δ ϭ 0.06 (s, 9 H, TMS), 0.89 (d, J ϭ 6.8 Hz, 3 H, 1-H3),
1.25Ϫ1.55 (m, 3 H) and 1.52Ϫ1.74 (m, 1 H, 4-H2 and 5-H2), 2.39
(s, 3 H, TsCH3), 3.25Ϫ3.75 (m, 7 H, 2-H, 3-H, 6-H, 7-H, 2 ϫ OH),
5.42 (d, J ϭ 8.7 Hz, NH, minor epimer), 5.55 (d, J ϭ 8.7 Hz, NH,
major epimer), 7.28 (d, J ϭ 8.1 Hz, 2 H, Ts), 7.76 (d, J ϭ 8.1 Hz,
2 H, Ts). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 0.1 (TMS), 16.7 (C-
1), 21.3 (TsCH3), 28.3 and 29.8 (C-4, C-5), 58.2 (C-2), 66.4 (C-7),
72.1 (C-6), 75.1 (C-3), 126.8, 129.5, 138.1 and 143.0 (Ts). Ϫ HRMS
(ESI): C17H31NO5SSi: calcd. 412.1590 [M ϩ Na]ϩ; found 412.1601
[M ϩ Na]ϩ.
(4S,5S,3ЈR)-5-(3Ј,4Ј-Dihydroxybutyl)-2,2,4-trimethyl-N-tosyl-1,3-
oxazolidine (18c): Acetonide 17 (500 mg, 1.55 mmol), AD-mix-β
(2.38 g), MsNH2 (136 mg, 2.16 mmol). Column chromatography
(AcOEt) yielded 574 mg of a 3.5:1 mixture of the alcohols 18c/19c
[contains AcOEt (13%), 1.40 mmol, 90%] as a colorless oil; ds ratio
determined by comparison of the integrals over OϪH (δ ϭ 2.63/
1
2.93). Ϫ Rf ϭ 0.25 (AcOEt). Ϫ H NMR (300 MHz, CDCl3): δ ϭ
1.32 (d, J ϭ 6.4 Hz, 3 H, 4-CH3), 1.30Ϫ1.77 (m, 4 H, 1Ј-H2 and
2Ј-H2), 1.53 (s, 3 H, 2-CH3) and 1.55 (s, 3 H, 2-CH3), 2.32 (br. s,
1 H, OH), 2.38 (s, 3 H, TsCH3), 2.63 (s, 0.76 H, OH), 2.93 (s, 0.24
H, OH), 3.25Ϫ3.42 (m, 2 H, 4-H and 4Ј-H), 3.49Ϫ3.75 (m, 3 H,
5-H, 3Ј-H and 4Ј-H), 7.25 (d, J ϭ 8.7 Hz, 2 H, Ts), 7.67 (d, J ϭ
8.3 Hz, 2 H, Ts). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 19.6 (4-CH3),
21.3 (TsCH3), 26.7 (C-2Ј), 28.9 and 29.4 (2-CH3), 29.5 (C-1Ј), 59.9
(C-4), 66.4 (C-4Ј), 71.7 (C-3Ј), 81.6 (C-5), 97.2 (C-2), 127.1, 129.4,
138.2 and 143.2 (Ts). Ϫ HRMS (ESI): C17H27NO5S: calcd.
380.1508 [M ϩ Na]ϩ; found 380.1525 [M ϩ Na]ϩ.
(2RS,5S,6S)-6-N-Tosylamino-5-trimethylsilyloxyheptan-1,2-diol
(18a/19a): TMS ether 15 (1.50 g, 4.22 mmol), AD-mix-α (6.50 g),
MsNH2 (372 mg, 5.91 mmol). Column chromatography (PE/
MTBE 1:1, then MTBE) yielded 1.56 g of a 1.4:1 mixture 19a/18a
[contains MTBE (9%), 3.69 mmol, 88%] as a colorless oil. 20 mg
of the diol mixture was silylated using TMSCl/NEt3 for ds determi-
nation by comparison of the integrals over NϪH. Ϫ Rf ϭ 0.39
(CHCl3/MeOH, 10:1). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 0.06
(s, 9 H, TMS), 0.91 (d, J ϭ 6.6 Hz, 3 H, 1-H3), 1.21Ϫ1.57 (m, 3
H) and 1.57Ϫ1.74 (m, 1 H, 4-H2 and 5-H2), 2.40 (s, 3 H, TsCH3), (4S,5S,3ЈS)-5-(3Ј,4Ј-Dihydroxybutyl)-2,2,4-trimethyl-N-tosyl-1,3-
2.46 (br. s 1 H, OH), 2.61 (br. s, 1 H, OH), 3.25Ϫ3.64 (m, 5 H, 2- oxazolidine (19c): Acetonide 17 (500 mg, 1.55 mmol), AD-mix-α
H, 3-H, 6-H, 7-H), 5.00 (d, J ϭ 8.7 Hz, 0.58 H, NH), 5.04 (d, J ϭ (2.38 g), MsNH2 (136 mg, 2.16 mmol). Column chromatography
8.7 Hz, 0.42 H, NH), 7.27 (d, J ϭ 7.9 Hz, 2 H, Ts), 7.73 (d, J ϭ (AcOEt) yielded 536 mg of a 4:1 mixture of the alcohols 19c/18c
8.1 Hz, 2 H, Ts). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 0.3 (TMS),
(1.50 mmol, 97%) as a colorless oil; ds ratio determined by com-
2984
Eur. J. Org. Chem. 1999, 2977Ϫ2990

Enantiomerically Pure Amino Acids Containing 2,5-Disubstituted THF Rings
FULL PAPER
parison of the integrals over OϪH (δ ϭ 2.60/2.85). Ϫ Rf ϭ 0.25
Oxidation of 1:1 Mixture of N-Tosyl THF Alcohols 11 and 12 to
(2S,5S,1ЈS)-5-[1Ј-(Tosylamino)ethyl]tetrahydrofuran-2-carbaldehyde
(AcOEt). Ϫ [α]D ϭ ϩ12.9, [α]578 ϭ ϩ13.8, [α]546 ϭ ϩ15.5, [α]436 ϭ
1
ϩ24.6, [α]365 ϭ ϩ33.4 (c ϭ 0.93, CHCl3, T ϭ 27°C). Ϫ H NMR (21)
and
[3.2.1.]octan-2-ol (22). ؊ (A) Swern Oxidation: DMSO (3.76 mL,
1.40Ϫ1.74 (m, 4 H, 1Ј-H2 and 2Ј-H2), 1.54 (s, 3 H, 2-CH3) and 1.57 4.14 g, 52.9 mmol) in CH2Cl2 (20 mL) was added dropwise to a
(s, 3 H, 2-CH3), 2.26 (br. s, 1 H, OH), 2.39 (s, 3 H, TsCH3), 2.60 solution of oxalyl chloride (2.37 mL, 3.36 g, 26.5 mmol) in CH2Cl2
(s, 0.20 H, OH), 2.85 (s, 0.80 H, OH), 3.26Ϫ3.45 (m, 2 H, 4-H and (60 mL) at Ϫ60°C. After stirring for 5 min, a 1:1 mixture of al-
4Ј-H), 3.49Ϫ3.85 (m, 3 H, 5-H, 3Ј-H and 4Ј-H), 7.26 (d, J ϭ 8.7 Hz, cohols 11 and 12 (3.96 g, 13.2 mmol) in CH2Cl2 (20 mL) was ad-
2 H, Ts), 7.69 (d, J ϭ 8.3 Hz, 2 H, Ts). Ϫ 13C NMR (75 MHz, ded. The solution was allowed to stir for 20 min at Ϫ60°C, then
(1R,2R,4S,5S)-4-Methyl-N-tosyl-8-oxa-3-azabicyclo-
(300 MHz, CDCl3): δ ϭ 1.33 (d, J ϭ 6.3 Hz, 3 H, 4-CH3),
CDCl3): δ ϭ 19.7 (4-CH3), 21.4 (TsCH3), 26.7 (C-2Ј), 28.6 and 29.1
(2-CH3), 29.5 (C-1Ј), 59.8 (C-4), 66.5 (C-4Ј), 71.6 (C-3Ј), 81.4 (C-
NEt3 (17 mL, 13.4 g, 132 mmol) was added and stirring was con-
tinued for 5 min at Ϫ60°C. The mixture was warmed to 0°C and
5), 97.3 (C-2), 127.1, 129.5, 138.3 and 143.2 (Ts). Ϫ HRMS (ESI): water (20 mL) was added dropwise. The layers were separated and
C17H27NO5S: calcd. 380.1508 [M ϩ Na]ϩ; found 380.1519 [M ϩ
the aqueous layer was extracted with CH2Cl2 (3 ϫ 10 mL). The
combined organic layers were washed with saturated NH4Cl solu-
tion (50 mL), saturated NaCl solution (50 mL) and dried with
Na2SO4. The solvent was removed in vacuo. Column chromatogra-
phy (MTBE, 200 g of silica) afforded aldehyde 21 (1.21 g,
4.07 mmol, 31%) as a colorless oil and hemiaminal 22 (2.6 g,
8.81 mmol, 66%) as colorless crystals. Ϫ (B) Dess؊Martin Oxi-
dation: To a solution of a 1:1 mixture of alcohols 11 and 12 (4.46 g,
14.9 mmol) in CH2Cl2, pyridine (13 mL, 13.3 g, 168 mmol) and
periodinane (7.94 g, 18.6 mmol) were added at 0°C. The mixture
was allowed to stir overnight. Saturated NaHCO3 solution
(100 mL) was added, the layers were separated and the organic
layer was washed with saturated NH4Cl solution (50 mL), saturated
NaCl solution (50 mL) and dried with Na2SO4. The solvent was
removed in vacuo. Column chromatography (MTBE, 40 g of silica)
afforded aldehyde 21 (1.78 g, 5.97 mmol, 40%) and hemiaminal 22
(1.76 g, 5.92 mmol, 40%).
Na]ϩ.
Conversion of the Diols 18a/19a into the THF Alcohols 11/12: NaH
was added to a solution of the mixture of the diols 18a/19a in dry
THF (5 mL/mmol) at 0°C and the suspension was stirred for
30 min. Tosylimidazole was added. The suspension became clear
for a moment and then a colorless solid precipitated. The ice bath
was removed and the reaction was stirred for a further 3 h. Water
(1 mL/mmol) was added, the layers separated and the aqueous
layer extracted with MTBE (3 ϫ). The combined organic layers
were washed with saturated NH4Cl solution, saturated NaCl solu-
tion and dried with Na2SO4. The solvent was removed in vacuo.
The crude epoxide was dissolved in CH2Cl2 (0.07 mmol/mL). Cam-
phorsulfonic acid (1 equiv.) was added and the reaction mixture
was stirred for 2 h at room temp. The solution was washed with
saturated NaHCO3 solution, with saturated NaCl solution and
dried with MgSO4. The solvents were removed in vacuo. Purifi-
cation and separation of the epimers were done by column chroma-
tography (PE/MTBE 1:2, then 1:5, then MTBE).
(2S,5S,1ЈS)-5-[1Ј-(Tosylamino)ethyl]tetrahydrofuran-2-carbaldehyde
(21): Rf ϭ 0.31 (MTBE). [α]D ϭ Ϫ13.5, [α]578 ϭ Ϫ13.9, [α]546
ϭ
Ϫ16.5, [α]436 ϭ Ϫ32.0, [α]365 ϭ Ϫ58.0 (c ϭ 1.29, CHCl3, T ϭ
18°C). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.97 (d, J ϭ 6.7 Hz,
1
Conversion of the Diols 18b/19b into THF Alcohol 11 and Acetal
20: The epoxide (preparation vide supra) was purified by column
chromatography (PE/MTBE, 1:1) to remove residual tosylimida-
zole and then dissolved in CH2Cl2 (0.15 mmol/mL). CSA (0.1
equiv.) was added and the reaction was stirred overnight. The solu-
tion was washed with saturated NaHCO3 solution and with satu-
rated NaCl solution and dried with Na2SO4. The solvent was re-
moved in vacuo. The acetal 20 and the trans-alcohol 11 were sepa-
rated by column chromatography (PE/MTBE 1:2, then MTBE).
3 H, 2Ј-H3), 1.72Ϫ2.15 (m, 4 H, 3,4-H2), 2.35 (s, 3 H, CH3-Ts),
3.19Ϫ3.30 (m, 1 H, 1Ј-H), 3.87Ϫ3.92 (m, 1 H) and 4.13Ϫ4.18 (m,
1 H, 2,5-H), 4.85 (d, J ϭ 8.1 Hz, 1 H, NϪH), 7.23 (d, J ϭ 8.1 Hz,
2 H, Ts), 7.69 (d, J ϭ 8.3 Hz, 2 H, Ts), 9.49 (d, J ϭ 1.5 Hz, 1 H,
CHO). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 18.8 (C-2Ј), 21.5 (Ts-
CH3), 27.0 and 27.4 (C-3 and C-4), 52.3 (C-1Ј), 83.1 and 83.2 (C-
2,5), 126.9, 129.6, 137.9 and 143.4 (Ts), 201.9 (CϭO). Ϫ HRMS
(EI): C14H19NSO4 calcd. 297.1035; found 297.1033.
(1R,6S,7S)-6-Methyl-N-tosyl-3,10-dioxa-5-azabicyclo[5.2.1]decane
(20): Colorless crystals, m.p. 122°C (MTBE). Ϫ Rf ϭ 0.50 (MTBE/
CH2Cl2 4:1). Ϫ [α]D ϭ ϩ72.3, [α]578 ϭ ϩ75.9, [α]546 ϭ ϩ86.4,
[α]436 ϭ ϩ150.0, [α]365 ϭ ϩ244.1 (c ϭ 2.41, CHCl3, T ϭ 19°C). Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 1.02 (d, J ϭ 7.1 Hz, 3 H, 1Ј-
H3), 1.83Ϫ2.23 (m, 4 H, 8-H2 and 9-H2), 2.37 (s, 3 H, TsCH3), 3.58
(dd, J ϭ 1.0 and 13.2 Hz, 1 H, 2-H), 3.69 (dd, J ϭ 1.8, 13.2 Hz, 1
H, 2-H), 3.84 (dq, J ϭ 1.0 and 7.1 Hz, 1 H, 6-H), 4.04Ϫ4.06 (m, 1
H, 7-H), 4.12Ϫ4.15 (m, 1 H, 1-H), 4.45 (d, J ϭ 12.4 Hz, 1 H, 4-
H), 5.39 (d, J ϭ 12.4 Hz, 1 H, 4-H), 7.24 (d, J ϭ 8.6 Hz, 2 H, Ts),
7.65 (d, J ϭ 8.4 Hz, 2 H, Ts). Ϫ 13C NMR (75 MHz, CDCl3): 16.6
(C-1Ј), 21.4 (TsCH3), 27.1 and 28.5 (C-8 and C-9), 55.0 (C-6), 65.7
(C-2), 76.5 (C-4), 79.5 (C-7), 82.0 (C-1), 126.9, 129.5, 138.1 and
143.2 (Ts). Ϫ C15H21NO4S (311.40): calcd. C 57.86, H 6.80, N 4.50,
S 10.30; found C 57.72, H 6.86, N 4.35, S 10.28.
(1R,2R,4S,5S)-4-Methyl-N-tosyl-8-oxa-3-azabicyclo[3.2.1]octan-2-
ol (22): m.p. 164°C (MTBE/PE). Ϫ Rf ϭ 0.58 (PE/MTBE, 2:1).
[α]D ϭ Ϫ7.7, [α]578 ϭ Ϫ8.0, [α]546 ϭ Ϫ9.7, [α]436 ϭ Ϫ20.1, [α]365
ϭ
Ϫ44.2 (c ϭ 0.64, CHCl3, T ϭ 18°C). Ϫ IR (KBr): ν˜ ϭ 3522 cmϪ1
s (OH), 2993 sh, 2978 m, 2963 m, 2879 w (CH), 1452 m, 1407 m,
1378 m, 1335 s, 1326 s, 1179 m, 1160 s (CϪO), 1124 m, 1060 s, 995
s, 981 s, 963 m, 670 s, 562 m, 544 s. Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 1.31 (d, J ϭ 6.8 Hz, 3 H, 4-CH3), 1.30Ϫ1.43 (m, 2 H) and
1.67Ϫ1.82 (m, 2 H, 6-H2, 7-H2), 2.36 (s, 3 H, Ts), 3.14 (d, J ϭ
6.9 Hz, 1 H, OH), 3.48 (q, J ϭ 6.9 Hz, 1 H, 4-H), 4.06 (d, J ϭ
6.5 Hz, 1 H, 5-H), 4.23 (d, J ϭ 6.4 Hz, 1 H, 1-H), 4.83 (dd, J ϭ
1.2 and 6.8 Hz, 1 H, 2-H), 7.21 (d, J ϭ 8.1 Hz, 2 H, Ts), 7.68 (d,
J ϭ 8.3 Hz, 2 H, Ts). Ϫ 13C NMR (75 MHz, CDCl3): 20.0 (C-1Ј),
21.5 (TsCH3), 26.9 (C-6), 27.3 (C-7), 55.0 (C-4), 77.2, 78.7 and 79.2
(C-1, C-2 and C-5), 127.0, 129.6, 137.8 and 143.5 (Ts). Ϫ
C14H19NO4S (297.37): calcd. C 56.55 H 6.44, N 4.71; found C
56.43, H 6.47, N 4.60.
Conversion of the Diols 18c/19c into the THF Alcohols 11/12: A
solution of the epoxide (preparation vide supra) in AcOH/H2O
(4:1, 0.2 mmol/mL) was stirred for 30 min at 40°C. The solvents
were removed in vacuo and the crude products were dried azeo-
tropically with toluene (2 ϫ). The epimers were separated by col-
umn chromatography (PE/MTBE 1:2, then 1:5, then MTBE).
(2S,5S,1ЈS)-2-{1Ј-[(tert-Butoxycarbonyl)amino]ethyl}-5-(hydroxy-
methyl)tetrahydrofuran (23): To a solution of the trans-alcohol 11
(3.20 g, 10.1 mmol) in THF (15 mL) and liquid NH3 (150 mL) was
added sodium (552 mg, 24.2 mmol) in small portions at Ϫ40°C
Eur. J. Org. Chem. 1999, 2977Ϫ2990
2985

U. Koert et al.
FULL PAPER
until the arising blue color persisted for more than 10 s. After stir-
(C-2), 155.8 (CϭO, Boc), 202.2 (CϭO). Ϫ The aldehyde was con-
ring for 10 min, the reaction was quenched by adding dropwise verted directly to the corresponding acid. Therefore, a solution of
glacial acetic acid (2 mL). The NH3 was allowed to evaporate. The
crude product was dried in vacuo for 1 h and dissolved in methanol
NaH2PO4 · 2 H2O (7.61 g, 48.8 mmol) and NaClO2 (5.52 g,
61.0 mmol) in water (80 mL) was added to a solution of the trans-
(250 mL). Boc2O (2.21 g, 10.1 mmol) was added in one portion. aldehyde (1.49 g, 6.10 mmol) and amylene (32.4 mL, 305 mmol) in
12 mL of 1  aqueous NaOH (12 mmol) were added dropwise. Stir- tBuOH (100 mL) at room temperature. The mixture was stirred
ring was continued for 10 min at room temperature, when Boc2O overnight at room temperature. tBuOH was removed in vacuo and
(1.10 g, 5.10 mmol) and 6 mL of 1  aqueous NaOH were added. MTBE (100 mL) was added. The reaction mixture was acidified
After stirring for additional 10 min, the latter addition procedure with 2  aqueous HCl (25 mL, 50 mmol) at 0°C. The layers were
was repeated. Then, the solvents were removed in vacuo and the
crude product was partitioned between CH2Cl2 (100 mL) and satu-
rated NaHCO3 solution (100 mL). The layers were separated and
the aqueous layer was extracted with CH2Cl2 (5 ϫ 20 mL). The
combined organic layers were washed with saturated NaCl solution
(100 mL) and dried with Na2SO4. The solvent was removed in va-
cuo. Column chromatography (PE/MTBE 1:3, 100 g of silica) af-
separated and the aqueous layer was extracted with MTBE
(5 ϫ 50 mL). The organic layers were combined and the solvent
was removed in vacuo. For purification, the crude product was dis-
solved in a solution of K2CO3 (8.43 g, 61 mmol) in water (200 mL).
The carboxylic salt solution was washed with MTBE (2 ϫ 50 mL),
covered with MTBE (50 mL) and acidified under vigorous stirring
at 0°C with 2  aqueous HCl (61 mL, 122 mmol). The layers were
forded 334 mg of starting material 11 (1.1 mmol, 11%) and 2.21 g separated and the aqueous layer was extracted with MTBE
(9.0 mmol, 89%) of the N-Boc-protected alcohol 23 as a colorless
oil. Ϫ Rf ϭ 0.35 (PE/MTBE 1:3). Ϫ [α]D ϭ Ϫ12.9, [α]578 ϭ Ϫ13.1,
(5 ϫ 500 mL). The combined organic layers were washed with satu-
rated NaCl solution (50 mL) and dried with Na2SO4. After evapor-
[α]546 ϭ Ϫ15.7, [α]436 ϭ Ϫ31.2, [α]365 ϭ Ϫ54.8 (c ϭ 1.34, CHCl3, ation of the solvent in vacuo, 1.40 g (5.40 mmol, 89%) of the car-
T ϭ 25°C). Ϫ IR (neat): ν˜ ϭ 3445 and 3348 cmϪ1 m (NH and boxylic acid 24 was obtained as a colorless solid. An analytical
OH), 2975/2934 m (CH), 1693 br. s, 1525 m, 1454 m, 1391 m, 1367
sample was recrystallized from MTBE/PE to give colorless crystals,
m, 1247 m, 1171 s, 1097 m, 1044 m. Ϫ 1H NMR (500 MHz, m.p. 67°C. Ϫ Rf ϭ 0.29 (CHCl3/MeOH/AcOH, 100:10:1). Ϫ [α]D ϭ
CDCl3): δ ϭ 1.17 (d, J ϭ 6.8 Hz, 3 H, 2Ј-H3), 1.43 [s, 9 H,
Ϫ2.9, [α]278 ϭ Ϫ3.2, [α]546 ϭ Ϫ3.7, [α]436 ϭ Ϫ6.5, [α]365 ϭ Ϫ10.2
C(CH3)3], 1.66Ϫ1.74 (m, 3 H, 3-H and 4-H axial and OϪH), (c ϭ 1.84, EtOH, T ϭ 19°C). Ϫ IR (KBr): ν˜ ϭ 3853Ϫ2739 cmϪ1
1.74Ϫ1.93 ( m, 2 H, 3-H and 4-H equatorial), 3.47 (dd, J ϭ 11.5 mb (OH), 3298 s (NH), 3002/2931/2938/2892 s (CH), 2606 m, 2533
and 6.4 Hz, 1 H, CHHOH), 3.62Ϫ3.70 (m, 1 H, 1Ј-H), 3.63 (dd, m, 1728 s, 1636 s, 1481 m, 1461 m, 1417 s, 1369 s, 1327 m, 1249
J ϭ 11.5 and 3.2 Hz, 1 H, CHHOH), 3.86 (ddd, J ϭ 8.4, 5.3 and
3.0 Hz, 1 H, 2-H), 4.11 (ddt, J ϭ 3.2, 7.8 and 6.2 Hz, 1 H, 5-H),
m, 1228 s, 1159 s, 1115 s, 1090 s, 1056 m, 1011 m, 998 m, 956 m,
915 m. Ϫ 1H NMR (600 MHz, [D4]methanol): δ ϭ 1.13 (d, J ϭ
4.66 (br. s, 1 H, NϪH). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 19.2 6.8 Hz, 3 H, 2Ј-CH3), 1.44 [s, 9 H, C(CH3)3], 1.70 (dddd, J ϭ 7.5,
(C-2Ј), 27.6 and 28.9 (C-3 and C-4), 28.4 [C(CH3)3], 47.0 (C-1Ј), 7.6, 8.7, 12.5 Hz, 1 H, 4-H axial), 1.98 (dddd, J ϭ 5.9, 7.6, 8.1,
65.0 (CH2OH), 79.1 [C(CH3)3], 80.0 (C-5), 82.0 (C-2), 155.9 (Cϭ
O, Boc). Ϫ NMR spectra were assigned using homo- and heteronu-
clear correlation spectroscopy (1H-1H and 13C-1H COSY) and two-
dimensional NOE spectroscopy (1H-1H NOESY). Ϫ C12H23NO4
12.7 Hz, 1 H, 3-H axial), 1.98 (dddd, J ϭ 5.5, 6.7, 8.1, 12.3, Hz, 1
H, 4-H equatorial), 2.30 (dddd, J ϭ 5.5, 8.1, 8.7, 12.3 Hz, 1 H, 3-
H equatorial), 3.62 (dq, J ϭ 4.8 and 6.8 Hz, 1 H, 1Ј-H), 4.05 (ddd,
J ϭ 4.8, 6.7, 7.5 Hz, 1 H, 5-H), 4.49 (dd, J ϭ 5.9 and 8.1 Hz, 1 H,
(245.32): calcd. C 58.75, H 9.45, N 5.71; found C 58.61, H 9.36, 2-H). Ϫ NϪH not visible because of H/D exchange. Ϫ 13C NMR
N 5.80.
(125 MHz, [D4]methanol): 17.5 (C-2Ј), 28.1 [C-4, C(CH3)3], 30.6
(C-3), 49.8 (C-1Ј), 77.4 (C-2), 79.0 [C(CH3)3], 83.6 (C-5), 157.5 (Cϭ
O, Boc), 176.4 (COOH). Ϫ NMR spectra were assigned using
homo- and heteronuclear correlation spectroscopy (1H-1H and 13C-
1H COSY) and two-dimensional NOE spectroscopy (1H-1H
NOESY), the coupling constants were determined by WIN-DAISY
simulation. Ϫ C12H21NO5 (259.30): calcd. C 55.58, H 8.16, N 5.40;
found C 55.30, H 8.25, N 5.48.
(2S,5S,1ЈS)-5-{1Ј-([tert-Butyloxycarbonyl)amino]ethyl}tetrahydro-
furan-2-carboxylic Acid (24): A solution of DMSO (2.51 mL,
2.76 g, 35.3 mmol) in CH2Cl2 (20 mL) was added to a solution of
oxalyl chloride (1.5 mL, 2.24 g, 17.6 mmol) in CH2Cl2 (60 mL) at
Ϫ60 to Ϫ55°C. The reaction mixture was stirred for 5 min at
Ϫ60°C. Then, a solution of the alcohol 23 (2.71 g, 11.0 mmol) in
CH2Cl2 (20 mL) was added dropwise. After stirring for further
15 min, NEt3 (11.2 mL, 8.15 g, 80.5 mmol) was added and the reac-
tion mixture was stirred for an additional 5 min. The reaction mix-
Benzyl (2S,5S,1ЈS)-5-{1Ј-[(tert-Butoxycarbonyl)amino]ethyl}tetra-
hydrofuran-2-carboxylate (25): NEt3 (9.7 mL, 7.07 g, 69.4 mmol)
ture was allowed to warm to 2°C during 10 min. Then, water was added to a solution of trans-acid 24 (4.00 g, 15.4 mmol) in
(10 mL) was added. The layers were separated and the aqueous
phase was extracted with CH2Cl2 (5 ϫ 10 mL). The combined or-
ganic layers were washed with saturated NaCl solution (100 mL)
and dried with Na2SO4. The solvent was removed in vacuo. Col-
acetone (150 mL) at 0°C. After stirring for 1 h, benzyl bromide
(8.3 mL, 11.9 g, 69.4 mmol) was added dropwise and stirring was
continued overnight. The solvent was removed in vacuo and the
residue was redissolved in MTBE (50 mL) and water (50 mL). The
umn chromatography (PE/MTBE 3:1, 50 g of silica) afforded 2.59 g layers were separated and the aqueous layer was extracted with
of the corresponding trans-aldehyde, (10.6 mmol, 97%) as a color- MTBE (2 ϫ 20 mL). The combined organic layers were washed
less oil. (2S,5S,1ЈS)-5-{1Ј-[(tert-Butoxycarbonyl)amino]ethyl}tetra- with saturated NaHCO3 solution (20 mL) and saturated NaCl solu-
hydrofuran-2-carbaldehyde: Rf ϭ 0.41 (PE/MTBE, 1:3). Ϫ 1H
tion (20 mL) and dried with Na2SO4. Column chromatography
NMR (300 MHz, CDCl3): δ ϭ 1.22 (d, J ϭ 6.9 Hz, 3 H, 2Ј-H3), (PE/MTBE 3:1, 400 g of silica) afforded 4.18 g of the benzyl ester
1.43 [s, 9 H, C(CH3)3], 1.71Ϫ1.78 (m, 1 H, 4-H axial), 1.91Ϫ2.01 25 (12.0 mmol, 71%) as a colorless solid, m.p. 72Ϫ73°C (MTBE/
(m, 2 H, 4-H equatorial, 3-H axial), 2.26Ϫ2.36 (m, 1 H, 3-H equa- PE). Ϫ Rf ϭ 0.38 (PE/MTBE, 3:1). [α]D ϭ Ϫ2.2, [α]578 ϭ Ϫ2.2,
torial), 3.66Ϫ3.86 (m, 1 H, 1Ј-H), 3.98 (ddd, J ϭ 3.1, 5.8 and [α]546 ϭ Ϫ3.0, [α]436 ϭ Ϫ4.4, [α]365 ϭ Ϫ8.2 (c ϭ 0.27, CHCl3, T ϭ
8.6 Hz, 1 H, 5-H), 4.34 (ddd, J ϭ 1.8, 6.6 and 8.1 Hz, 1 H, 2-H),
19°C). Ϫ IR (KBr): ν˜ ϭ 3469 cmϪ1 br. w and 3378 m (NH), 3068
4.62 (br. s, 1 H, NϪH), 9.63 (d, J ϭ 1.8 Hz, 1 H, CHO). Ϫ 13C br. w, 3035, 3008 (CHPh), 2983 m (CH), 1758 s, 1686 s, 1520 s,
NMR (75 MHz, CDCl3): δ ϭ 19.1 (C-2Ј), 27.1 and 27.9 (C-3 and 1454 m, 1390 m, 1371 m, 1366 m, 1251 m, 1186 s, 1171 s, 1107 s,
1
C-4), 28.4 [C(CH3)3)], 48.7 (C-1Ј), 80.8 [C(CH3)3], 83.0 (C-5), 83.5
1070 s, 1029 m, 613 m. Ϫ H NMR (600 MHz, CDCl3): δ ϭ 1.20
2986
Eur. J. Org. Chem. 1999, 2977Ϫ2990

Enantiomerically Pure Amino Acids Containing 2,5-Disubstituted THF Rings
FULL PAPER
(d, J ϭ 6.8 Hz, 3 H, 2Ј-CH3), 1.44 [s, 9 H, C(CH3)3], 1.71 (dddd, was stirred for additional 5 min. The reaction mixture was allowed
J ϭ 7.4, 7.5, 8.9, 12.5 Hz, 1 H, 4-H axial), 1.95 (dddd, J ϭ 5.5, to warm to room temperature during 30 min. A saturated NaHCO3
6.8, 8.4, 12.5 Hz, 1 H, 4-H equatorial), 1.98 (dddd, J ϭ 5.5, 7.4,
solution (40 mL) was added, the layers were separated and the
8.4, 12.7 Hz, 1 H, 3-H equatorial), 2.24 (dddd, J ϭ 5.5, 8.1, 8.9, aqueous phase was extracted with CH2Cl2 (2 ϫ 10 mL) and MTBE
12.7 Hz, 1 H, 3-H axial), 3.71 (dq, J ϭ 3.2 and 6.8 Hz, 1 H, 1Ј-H),
4.11 (ddd, J ϭ 3.2, 6.8, 7.5 Hz, 1 H, 5-H), 4.55 (dd, J ϭ 5.5 and
8.1 Hz, 1 H, 2-H), 5.13 (d, J ϭ 12.3 Hz, 1 H, PhCHH), 4.63Ϫ4.64
(m, 1 H, NϪH), 5.15 (d, J ϭ 12.3 Hz, 1 H, PhCHH), 7.30Ϫ7.38
(5 ϫ 10 mL). The combined organic layers were dried with
Na2SO4. The solvent was removed in vacuo. The crude product
was directly converted into the carboxylic acid. Therefore, amylene
(10.8 mL, 7.20 g, 102 mmol), NaH2PO4 · 2 H2O (2.54 g, 16.3
(m, 5 H, Ph). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 19.1 (C-2Ј), mmol) and NaClO2 (1.84 g, 20.4 mmol) were added to a solution
27.7 (C-4), 28.3 [C(CH3)3], 30.0 (C-3), 48.8 (C-1Ј), 66.4 (CH2ϪPh), of the aldehyde (1.49 g, 6.10 mmol) in tBuOH (40 mL) at room
77.1 (C-2), 79.1 [C(CH3)3], 83.1 (C-5), 128.1, 128.3, 128.5, 135.6 temperature. The mixture was stirred overnight at room tempera-
(Ph), 155.8 (CϭO, Boc), 173.3 (COOBn). Ϫ NMR spectra were
ture. tBuOH was removed in vacuo and water (100 mL) was added.
assigned using homo- and heteronuclear correlation spectroscopy The mixture was extracted with MTBE (5 ϫ 30 mL), acidified with
(1H-1H and 13C-1H COSY) and two-dimensional NOE spec-
2  HCl to pH ϭ 3 and extracted with MTBE (2 ϫ 20 mL). The
combined organic layers were washed with ice water and dried with
troscopy (1HϪ1H NOESY); coupling constants were determined
by WIN-DAISY simulation. Ϫ C19H27NO5 (349.42): calcd. C 65.31 MgSO4. Column chromatography (CHCl3/MeOH 10:1, 25 g of sil-
H 7.79, N 4.01; found C 65.25, H 7.79, N 4.11.
ica) afforded 343 mg (1.342 mmol, 65%) of the carboxylic acid 27
as a colorless solid. An analytical sample was recrystallized from
MTBE/PE to give colorless crystals, m.p. 125°C (MTBE/PE). Ϫ
Rf ϭ 0.13 (CHCl3/MeOH, 15:1). Ϫ [α]D ϭ ϩ44.3, [α]578 ϭ ϩ46.3,
[α]546 ϭ ϩ53.0, [α]436 ϭ ϩ93.6, [α]365 ϭ ϩ155.4 (c ϭ 1.24, EtOH,
T ϭ 25°C). Ϫ IR (KBr): ν˜ ϭ 3433 cmϪ1 s (OH), 3070 w (NH),
2975 s, 2932 m, 2877 w, 1698 s (CϭO), 1614 w, 1526 m, 1366 s,
1246 m, 1171 s (CϪO), 1056 s, 1027 s, 1008 s, 866 w, 822 s, 759 s.
(2S,5R,1ЈS)-2-{1Ј-[(tert-Butoxycarbonyl)amino]ethyl}-5-(hydroxy-
methyl)tetrahydrofuran (26): To a solution of the cis alcohol 12
(3.0 g, 10.0 mmol) in THF (15 mL) and liquid NH3 (150 mL) was
added sodium (470 mg, 20.0 mmol) in small portions and the solu-
tion was stirred for 30 min at Ϫ40°C. Additional sodium (120 mg,
5.01 mmol) was added, until the arising blue color persisted for
more than 10 s. After stirring for 10 min, the reaction was
quenched by adding dropwise glacial acetic acid (3 mL). The NH3
was allowed to evaporate. The crude product was dried in vacuo
for 1 h and dissolved in methanol (150 mL). Boc2O (2.18 g,
10.0 mmol) was added in one portion. 12 mL of 1  aqueous
NaOH was added dropwise. Stirring was continued for 10 min at
room temperature, when once again Boc2O (2.18 g, 10.0 mmol) and
12 mL of 1  aqueous NaOH were added. After stirring for ad-
ditional 30 min, the solvents were removed in vacuo and the crude
product was partitioned between CH2Cl2 (100 mL) and saturated
NaHCO3 solution (100 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (5 ϫ 30 mL). The com-
bined organic layers were washed with saturated NaCl solution
(100 mL) and dried with Na2SO4. The solvent was removed in va-
cuo. Column chromatography (PE/MTBE 1:3, 150 g of silica) af-
forded 630 mg of starting material 12 (2.1 mmol, 21%) and 1.94 g
of the N-Boc protected cis-alcohol 26 (7.91 mmol, 79%) as a color-
1
Ϫ H NMR (600 MHz, [D4]methanol): δ ϭ 1.18 (d, J ϭ 6.8 Hz, 3
H, 2Ј-CH3), 1.44 [s, 9 H, C(CH3)3], 1.66 (dddd, J ϭ 8.1, 9.1, 10.4,
12.3 Hz, 1 H, 4-H axial), 1.93 (dddd, J ϭ 3.3, 6.2, 7.8, 12.5 Hz, 1
H, 4-H equatorial), 2.09 (dddd, J ϭ 12.7, 3.3, 4.0, 8.1 Hz, 1 H, 3-
H equatorial), 2.30 (dddd, J ϭ 7.8, 9.0, 10.4, 12.7 Hz, 1 H, 3-H
axial), 3.65 (dq, J ϭ 3.2 and 6.8 Hz, 1 H, 1Ј-H), 3.98 (ddd, J ϭ
3.3, 6.2, 9.1 Hz, 1 H, 5-H), 4.42 (dd, J ϭ 4.0, 9.0 Hz, 1 H, 2-H). Ϫ
NϪH not visible because of H/D exchange. Ϫ 13C-NMR (75 MHz,
[D4]methanol): δ ϭ 19.5 (C-2Ј), 25.5 (C-4), 28.6 [C(CH3)3], 32.0
(C-3), 49.4 (C-1Ј), 79.0, 80.4 [C-2, C(CH3)3], 85.8 (C-5), 158.9 (Cϭ
O, Boc), 177.9 (COOH). Ϫ NMR spectra were assigned using
homo- and heteronuclear correlation spectroscopy (1H-1H and 13C-
1H COSY) and two-dimensional NOE spectroscopy (1H-1H
NOESY); coupling constants were determined by WIN-DAISY
simulation. Ϫ HRMS (CI): C12H21NO5 (259.30): calcd. 260.1498
[M ϩ H]ϩ; found 260.2377 [M ϩ H]ϩ.
less oil. Ϫ Rf ϭ 0.37 (PE/MTBE, 1:3). Ϫ [α]D ϭ Ϫ3.1, [α]578
ϭ
Benzyl (2R,5S,1ЈS)-5-{1Ј-[(tert-Butoxycarbonyl)amino]ethyl}tetra-
hydrofuran-2-carboxylate (28): NEt3 (2.29 mL, 1.67 g, 16.5 mmol, 5
equiv.) was added to a solution of the cis-acid 27 (858 mg,
3.31 mmol) in acetone (30 mL) at 0°C. After stirring for 1 h, benzyl
bromide (1.97 mL, 2.83 g, 16.5 mmol, 5 equiv.) was added and stir-
ring was continued overnight. The solvent was removed in vacuo
and the residue was redissolved in MTBE (10 mL) and water
(10 mL). The layers were separated and the aqueous layer was ex-
tracted with MTBE (2 ϫ 5 mL). The combined organic layers were
washed with saturated NaHCO3 solution (5 mL), saturated NaCl
solution (5 mL) and dried with Na2SO4. Column chromatography
(PE/MTBE 3:1, 100 g of silica) afforded 740 mg of the benzyl ester
28 (2.12 mmol, 64%) as a colorless solid, m.p. 82°C (MTBE/PE).
Ϫ Rf ϭ 0.25 (PE/MTBE, 2:1). [α]D ϭ Ϫ1.5, [α]578 ϭ Ϫ1.6, [α]546 ϭ
Ϫ1.9, [α]436 ϭ Ϫ3.6, [α]365 ϭ Ϫ5.8 (c ϭ 0.75, CHCl3, T ϭ 18°C).
Ϫ IR (KBr): ν˜ ϭ 3279 cmϪ1 s (NH), 2975 s (CH), 2931 m (CH2),
1736 m (CϭO), 1518 m, 1454 m (CϪO), 1390 w, 1365 m [C(CH3)3],
1295 w, 1245 w, 1170 m (CϪO), 865 w. Ϫ 1H NMR (600 MHz,
Ϫ3.9, [α]546 ϭ Ϫ3.2, [α]436 ϭ Ϫ4.3 (c ϭ 1.34, CHCl3, T ϭ 21°C).
Ϫ IR (neat): ν˜ ϭ 3335 cmϪ1 s (NH and OH), 2975 s (CH3), 2933
s (CH2), 2875 s (NH), 1693 s (CϭO), 1530 s (COϪNHR), 1454 s
(COR), 1391 m [C(CH3)3], 1335 m, 1249 s (OH), 1171 s (CϪO),
1104 m, 1047 m. Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ 1.08 (d, J ϭ
6.7 Hz, 3 H, 2Ј-H3), 1.42 [s, 9 H, C(CH3)3], 1.67Ϫ1.73 (m, 1 H, 3-
H axial), 1.82Ϫ2.01 (m, 3 H, 4-H2 and 3-H equatorial), 2.15 (s, 1
H, OH), 3.45 (dd, J ϭ 10.6 and 7.0 Hz, 1 H, CHHOH), 3.59 (dq,
J ϭ 6.7 and 2.7 Hz, 1 H, 1Ј-H), 3.65Ϫ3.73 (m, 2 H, CHHOH and
2-H), 3.99Ϫ4.03 (m, 1 H, 5-H), 4.62 (d, J ϭ 8.4 Hz, 1 H, NϪH).
Ϫ
13C NMR (125 MHz, CDCl3): δ ϭ 18.1 (C-2Ј), 26.3 (C-3), 28.3
[C(CH3)3], 28.8 (C-4), 50.3 (C-1Ј), 64.0 (CH2OH), 79.4 [C(CH3)3],
80.3 (C-5), 83.4 (C-2), 156.6 (CϭO, Boc). Ϫ C12H23NO4 (245.32):
calcd. C 58.75, H 9.45, N 5.71; found C 58.61, H 9.36, N 5.80.
(2R,5S,1ЈS)-5-{1Ј-[(tert-Butoxycarbonyl)amino]ethyl}tetrahydro-
furan-2-carboxylic Acid (27): A solution of DMSO (1.1 mL, 1.2 g,
15.3 mmol) in CH2Cl2 (10 mL) was added to a solution of oxalyl
chloride (0.9 mL, 1.3 g, 10 mmol) in CH2Cl2 (40 mL) at Ϫ60 to CDCl3): δ ϭ 1.25 (d, J ϭ 6.8 Hz, 3 H, 2Ј-CH3), 1.38 [s, 9 H,
Ϫ55°C. The reaction mixture was stirred for 20 min at Ϫ60°C.
Then a solution of the alcohol 26 (0.50 g, 2.04 mmol) in CH2Cl2
(10 mL) was added dropwise. After stirring for further 20 min,
NEt3 (4.3 mL, 3.1 g, 31 mmol) was added and the reaction mixture
C(CH3)3], 1.75 (m, 1 H, 4-H axial), 1.87 (m, 1 H, 4-H equatorial),
2.08 (m, 1 H, 3-H equatorial), 2.24 (m, 1 H, 3-H axial), 3.75 (m, 1
H, 1Ј-H), 4.03 (dd, J ϭ 7.4 and 7.5 Hz, 1 H, 5-H), 4.50 (dd, J ϭ
3.5 and 9.1 Hz, 1 H, 2-H), 5.16 (d, J ϭ 12.2 Hz, 1 H, CHHϪPh),
Eur. J. Org. Chem. 1999, 2977Ϫ2990
2987

U. Koert et al.
FULL PAPER
5.22 (d, J ϭ 12.3 Hz, 1 H, CHHϪPh), 5.95 (d, J ϭ 7.0 Hz, 1 H, ganic solvents were evaporated. For purification, the crude product
NϪH), 7.30 (m, 5 H, Ph). Ϫ 13C NMR (125 MHz, CDCl3): 18.7
was dissolved in MTBE, and extracted with saturated NaHCO3
(C-2Ј), 27.1 (C-4), 28.5 [C(CH3)3], 30.9 (C-3), 48.1 (C-1Ј), 66.8 solution (100 mL). The aqueous layer was covered with MTBE and
(CH2ϪPh), 76.6 (C-2), 78.8 [C(CH3)3], 84.4 (C-5), 128.3, 128.4, acidified with HCl (conc.) to pH ϭ 2. The layers were separated.
128.6, 135.5 (Ph), 156.2 (CϭO, Boc), 173.8 (COOBn). Ϫ NMR
spectra were assigned using homo- and heteronuclear correlation tion (100 mL) and dried with Na2SO4. The solvent was removed in
spectroscopy (1H-1H and 13C-1H COSY) and two-dimensional
vacuo. Thus, 0.45 g (1.18 mmol, 38%) of the acid 30 was obtained
NOE spectroscopy (1H-1H NOESY). Ϫ C19H27NO5 (349.42): as a colorless oil. Ϫ Rf ϭ 0.33 (CHCl3/MeOH/AcOH, 200:10:1). Ϫ
The organic layer was washed with saturated aqueous NaCl solu-
calcd. C 65.31 H 7.79, N 4.01; found C 65.34, H 7.69, N 3.82.
[α]D ϭ Ϫ14.6, [α]578 ϭ Ϫ15.1, [α]546 ϭ Ϫ17.4, [α]436 ϭ Ϫ30.9,
[α]365 ϭ Ϫ49.4 (c ϭ 1.02, CHCl3, T ϭ 19°C). Ϫ IR (neat): ν˜ ϭ
3438 cmϪ1 (NH and OH), 3018/2981/2951/2878 (CH), 1716 (Cϭ
O). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.17 (d, J ϭ 8.6 Hz, 3 H,
2Ј-CH3), 1.57Ϫ1.65 (m, 1 H, 4-H), 1.89Ϫ2.01 (m, 2 H, 4-H and 3-
H), 2.15Ϫ2.37 (m, 1 H, 3-H), 3.35Ϫ3.80 (m, 1 H, 1Ј-H), 3.90Ϫ4.08
(m, 1 H, 5-H), 4.10Ϫ4.19 (m, 1 H, Fmoc), 4.35Ϫ4.49 (m, 3 H, 2-
H, Fmoc), 4.81 (d, J ϭ 8.3 Hz, 1 H, NϪH), 7.18Ϫ7.70 (m, 8 H,
Fmoc). Ϫ 13C NMR (300 MHz, CDCl3): δ ϭ 19.1 (C-2Ј), 28.1, 30.1
(C-3 and C-4), 47.3 (CHϪCH2O), 49.4 (C-1Ј), 66.4 (CH2O, Fmoc),
77.2 (C-2), 83.3 (C-5), 120.0, 124.9, 127.0, 127.7, 141.4, 143.8, 156.9
(Fmoc), 176.7 (CϭO). Ϫ C22H23NO5 (381.16): calcd. C 69.28, H
6.08, N 3.67; found C 69.18, H 6.06, N 3.64.
(2S,5S,1ЈS)-2-{1Ј-[(Fluorenylmethoxycarbonyl)amino]ethyl}-5-
(hydroxymethyl)tetrahydrofuran (29): To a solution of the trans-al-
cohol 11 (1.7 g, 5.6 mmol) in THF (10 mL) and liquid NH3
(100 mL) was added sodium (259 mg, 11 mmol) in small portions
at Ϫ40°C until a persistent blue-colored solution was obtained.
After stirring for 10 min, the reaction was quenched by dropwise
addition of glacial acetic acid (2 mL). The NH3 was allowed to
evaporate. The crude product was dried in vacuo for 1 h and dis-
solved in acetonitrile (5 mL) and saturated NaHCO3 solution
(5 mL). Fmoc-succinimide (3.8 g, 11 mmol) was added in one por-
tion. After stirring overnight, the acetonitrile was removed and the
aqueous layer was extracted with MTBE (5 ϫ 20 mL). The com-
bined organic layers were washed with 0.1  HCl (100 mL), satu-
(2S,5R,1ЈS)-2-{1Ј-[(Fluorenylmethoxycarbonyl)amino]ethyl}-5-
rated NaCl solution (100 mL) and dried with Na2SO4. The solvent (hydroxymethyl)tetrahydrofuran (31): To a solution of the cis-al-
was removed in vacuo. Column chromatography (PE/MTBE, 5:1 cohol 12 (1.7 g, 5.6 mmol) in THF (10 mL) and liquid NH3
to 1:1) afforded 1.14 g (3.11 mmol, 56%) of 29 as colorless crystals. (100 mL) was added sodium (259 mg, 11 mmol) in small portions
m.p. 110°C. Ϫ Rf ϭ 0.15 (MTBE/PE, 2:1). Ϫ [α]D ϭ Ϫ58.2, at Ϫ40°C until a persistent blue-colored solution was obtained.
[α]578 ϭ Ϫ58.2, [α]546 ϭ Ϫ58.8, [α]436 ϭ Ϫ64.1, [α]365 ϭ Ϫ72.5, After stirring for 10 min, the reaction was quenched by dropwise
(c ϭ 0.47, CHCl3, T ϭ 19°C). Ϫ IR (KBr): ν˜ ϭ 3439 cmϪ1 (NH addition of glacial acetic acid (2 mL). The NH3 was allowed to
and OH), 3019/2977/2878 (CH), 1715 (CϭO). Ϫ 1H NMR
evaporate. The crude product was dried in vacuo for 1 h and dis-
(300 MHz, CDCl3): δ ϭ 1.12 (d, J ϭ 6.8 Hz, 3 H, 2Ј-CH3), solved in acetonitrile (5 mL) and saturated NaHCO3 (5 mL).
1.50Ϫ1.63 (m, 2 H, 3-H2), 1.83Ϫ1.87 (m, 2 H, 4-H2), 2.15 (m, 1 Fmoc-succinimide (3.8 g, 11 mmol) was added in one portion.
H, OH), 3.36Ϫ3.42 (m, 1 H, CHHOH), 3.53Ϫ3.56 (m, 1 H,
CHHOH), 3.68 (m, 1 H, 1Ј-H), 3.79 (m, 1 H, 2-H), 3.98Ϫ4.00 (m, ous layer was extracted with MTBE (5 ϫ 20 mL). The combined
1 H, 5-H), 4.11Ϫ4.16 (m, 1 H, Fmoc), 4.34Ϫ4.36 (d, J ϭ 6.8 Hz, organic layers were washed with 0.1  HCl (100 mL), saturated
2 H, Fmoc), 4.92 (m, 1 H, NϪH), 7.17Ϫ7.69 (m, 8 H, Fmoc). Ϫ NaCl solution (100 mL) and dried with Na2SO4. The solvent was
13C NMR (300 MHz, CDCl3): δ ϭ 19.2 (CϪ2Ј), 27.6, 28.9 (C-3
removed in vacuo. Column chromatography (PE/MTBE, 5:1 to 2:1)
und C-4), 47.4 (CHϪCH2O, Fmoc), 49.5 (C-1Ј), 64.9 (CH2OH), afforded 1.52 g (4.14 mmol, 44%) of 31 as colorless solid. Ϫ Rf ϭ
66.4 (CH2O, Fmoc), 80.2 (C-5), 81.8 (C-2), 120.0, 125.0, 127.0, 0.23 (MTBE/PE, 2:1). Ϫ [α]D ϭ ϩ4.0, [α]578 ϭ ϩ4.3, [α]546 ϭ ϩ5.0,
127.7, 141.3, 144.0, 156.3 (Fmoc). Ϫ C22H25NO4 (367.18): calcd. [α]436 ϭ ϩ10.7, [α]365 ϭ ϩ22.4 (c ϭ 1.00, CHCl3, T ϭ 19°C). Ϫ
After stirring overnight the acetonitrile was removed and the aque-
C 71.91, H 6.86, N 3.81; found C 71.96, H 6.95, N 3.85.
IR: ν˜ ϭ 3437 cmϪ1 (NH and OH), 3011/2977/2951/2878 (CH),
1709 (CϭO). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.08 (d, J ϭ
6.4 Hz, 3 H, 2Ј-CH3), 1.57Ϫ1.65 (m, 2 H, 3-H2), 1.72Ϫ1.79 (m, 2
H, 4-H2), 1.83Ϫ1.91 (m, 1 H, OH), 3.35Ϫ3.40 (dd, J ϭ 4.5 and
12.1 Hz, CHHOH), 3.62Ϫ3.66 (m, 1 H, CHHOH), 3.69Ϫ3.75 (m,
2 H, 2-H and 1Ј-H), 3.93Ϫ3.94 (m, 1 H, 5-H), 4.11Ϫ4.15 (m, 1 H,
Fmoc), 4.25Ϫ4.39 (m, 2 H, Fmoc), 5.16 (d, J ϭ 8.3 Hz, 1 H,
NϪH), 7.18 Ϫ7.68 (m, 8 H, Fmoc). Ϫ 13C NMR (300 MHz,
CDCl3): δ ϭ 18.6 (C-2Ј), 27.0, 28.9 (C-3 and C-4), 47.3
(CHϪCH2O), 50.7 (C-1Ј), 64.2 (CH2O, Fmoc), 66.6 (CH2OH),
80.2 (C-5), 83.1 (C-2), 119.9, 125.1, 127.0, 127.6, 141.3, 144.0, 156.9
(Fmoc). Ϫ C22H25NO4 (367.18): calcd. C 71.82, H 6.96, N 3.78;
found C 71.96, H 6.95, N 3.85.
(2S,5S,1ЈS)-2-{1Ј-[(-Fluorenylmethoxycarbonyl)amino]ethyl}tetra-
hydrofuran-2-carboxylic Acid (30): A solution of DMSO (0.89 mL,
980 mg, 12 mmol) in CH2Cl2 (15 mL) was added to a solution of
oxalyl chloride (0.54 mL, 790 mg, 6.2 mmol) in CH2Cl2 (40 mL) at
Ϫ60 to Ϫ55°C. The reaction mixture was stirred for 5 min at
Ϫ60°C and a solution of the alcohol 29 (1.14 g, 3.10 mmol) in
CH2Cl2 (10 mL) was added dropwise. After stirring for 15 min,
NEt3 (4.31 mL, 3.13 g, 31.0 mmol) was added and the reaction
mixture was stirred for additional 5 min. The reaction mixture was
allowed to warm to 2°C during 10 min and saturated NaHCO3
solution (20 mL) was added. The layers were separated and the
aqueous phase was extracted with CH2Cl2 (5 ϫ 10 mL). The com-
bined organic layers were washed with saturated NaCl solution
(100 mL) and dried with Na2SO4. The aldehyde was converted di-
rectly to the corresponding acid. A solution of NaH2PO4·2 H2O
(3.40 g, 24.8 mmol) and NaClO2 (2.81 g, 31.0 mmol) in water
(14 mL) was added to a solution of the trans-aldehyde (1.14 g,
(2S,5R,1ЈS)-2-{1Ј-[(Fluorenylmethoxycarbonyl)amino]ethyl}tetra-
hydrofuran-2-carboxylic Acid (32): A solution of DMSO (1.19 mL,
1.31 g, 16.5 mmol) in CH2Cl2 (20 mL) was added to a solution of
oxalyl chloride (0.71 mL, 1.02 g, 6.2 mmol) in CH2Cl2 (50 mL) at
Ϫ60 to Ϫ55°C. The reaction mixture was stirred for 5 min at
3.10 mmol) in tBuOH (14 mL) and amylene (16.5 mL, 10.9 g, Ϫ60°C and a solution of the alcohol 31 (1.52 g, 4.16 mmol) in
155 mmol) at room temperature. After stirring overnight, the reac-
tion mixture was acidified with saturated oxalic acid solution to
pH ϭ 2. The layers were separated and the aqueous layer was ex-
CH2Cl2 (10 mL) was added dropwise. After stirring for 15 min,
NEt3 (5.74 mL, 4.19 g, 41.4 mmol) was added and the reaction
mixture was stirred for additional 5 min. The reaction mixture was
tracted with MTBE (5 ϫ 20 mL). The combined organic layers allowed to warm to 2°C during 10 min and saturated NaHCO3
were washed with saturated NaCl solution (100 mL) and the or-
2988
solution (20 mL) was added. The layers were separated and the
Eur. J. Org. Chem. 1999, 2977Ϫ2990

Enantiomerically Pure Amino Acids Containing 2,5-Disubstituted THF Rings
FULL PAPER
aqueous phase was extracted with CH2Cl2 (5 ϫ 10 mL). The com-
bined organic layers were washed with saturated aqueous NaCl
solution (100 mL) and dried with Na2SO4. The aldehyde was con-
(2R,5S,1ЈS)-5-{1Ј-[(Benzoyl)amino]ethyl}tetrahydrofuran-2-
carboxylic Acid Methyl Amide (34): A solution of methyl amide
33 (250 mg, 0.918 mmol) in CH2Cl2 (5 mL) was treated with TFA
(1.2 mL) and allowed to stir for 4 h at room temperature. The solu-
verted directly to the corresponding acid.
A solution of
NaH2PO4 · 2 H2O (4.55 g, 33.3 mmol) and NaClO2 (3.77 g, tion was concentrated in vacuo and residual TFA was removed by
41.7 mmol) in water (19 mL) was added to a solution of the cis- codistillation with toluene (2 ϫ 10 mL). The crude ammonium salt
aldehyde (1.52 g, 4.16 mmol) in tBuOH (19 mL) and amylene was dissolved in THF (5 mL), saturated aqueous NaHCO3 solution
(22.1 mL, 14.6 g, 209 mmol) at room temperature. After stirring (2 mL) and water (2 mL). Benzoyl chloride (0.21 mL, 0.26 g,
overnight at room temperature, the reaction mixture was acidified
with saturated oxalic acid solution to pH ϭ 2. The layers were
separated and the aqueous layer was extracted with MTBE
(5 ϫ 20 mL). The combinined organic phases were washed with
saturated NaCl (100 mL) and the organic solvents were evaporated.
For purification, the crude product was dissolved in MTBE, and
1.8 mmol) was added at 0°C. The solution was allowed to stir for
1 h at room temperature before the organic solvent was removed in
vacuo. The aqueous layer was extracted with EtOAc (2 ϫ 15 mL),
washed with saturated NaCl solution (20 mL) and dried with
Na2SO4. Concentration in vacuo and column chromatography
(EtOAc, 20 g of silica) yielded 34 ϫ 0.3 H2O (232 mg, 0.822 mmol,
extracted with saturated aqueous NaHCO3 solution (100 mL). The 90%) as white solid. Crystals of 34 ϫ H2O suitable for X-ray-struc-
aqueous layer was covered with MTBE and acidified with HCl
(conc.) to pH ϭ 2 and the layers were separated. The organic layer
was washed with saturated NaCl solution (100 mL) and dried with
Na2SO4. The solvent was removed in vacuo. Thus, 0.71 g
(1.86 mmol, 45%) of the acid 32 was obtained as a white solid. m.p.
tural analysis were obtained by slow evaporation of a solution of
34 in acetone. Ϫ m.p.* 86Ϫ88°C (acetone). Ϫ Rf ϭ 0.21 (EtOAc).
Ϫ [α]D ϭ ϩ107.3, [α]578 ϭ ϩ112.8, [α]546 ϭ ϩ129.5, [α]436
ϭ
ϩ233.9, [α]365 ϭ ϩ405.5 [c ϭ 0.96* (CHCl3); T ϭ 20°C]. Ϫ IR
(KBr): ν˜ ϭ 3480 cmϪ1 m, 3410 m (NH), 3310 s (NH), 3010 w,
2980/2940/2900 w (CH), 1665 s (CϭO), 1630 s, 1575 m, 1560 m,
142°C. Ϫ Rf ϭ 0.30 (CHCl3/MeOH/AcOH, 200:10:1). Ϫ [α]D
ϩ22.3, [α]578 ϭ ϩ23.5, [α]546 ϭ ϩ26.7, [α]436 ϭ ϩ45.7, [α]365
ϭ
1
ϭ
1495 w, 1445 w. Ϫ H NMR (600 MHz, CDCl3): δ ϭ 1.24 (d, J ϭ
ϩ73.8 (c ϭ 1.02, CHCl3, T ϭ 19°C). Ϫ IR: ν˜ ϭ 3300 cmϪ1 (NH 6.8 Hz, 3 H, 2Ј-H3), 1.47 (mc, 1 H, 4-HA), 2.01 (dddd, J ϭ 2.1, 5.4,
and OH), 3100/2990/2900/2800 (CH), 1750 (CϭO). Ϫ 1H NMR 7.4, 12.4 Hz, 1 H, 4-HB), 2.22 (dddd, J ϭ 7.5, 8.6, 11.5, 12.6 Hz, 1
(300 MHz, CDCl3): δ ϭ 1.17 (d, J ϭ 6.8 Hz, 3 H, 2Ј-CH3), 1.56 H, 3-HA), 2.35 (ddd, J ϭ 2.5, 7.5, 12.7 Hz, 1 H, 3-HB), 2.90 (d,
(m, 1 H, 4-H), 1.93Ϫ2.07 (m, 1 H, 4-H), 2.19Ϫ2.40 (m, 2 H, 3- J ϭ 4.8 Hz, 3 H, NMe), 3.87 (dt, J ϭ 5.8, 9.0 Hz, 1 H, 5-H), 4.26
H2), 3.71Ϫ3.73 (m, 1 H, 1Ј-H), 3.83Ϫ3.88 (m, 1 H, 5-H), 4.22 (t, (ddq, J ϭ 6.8, 8.9, 8.9 Hz, 1 H, 1Ј-H), 4.39 (dd, J ϭ 2.6, 8.8 Hz, 1
J ϭ 7.0 Hz, 1 H, Fmoc), 4.47Ϫ4.55 (m, 3 H, 2-H, Fmoc),
H, 2-H), 6.50 (d, J ϭ 8.9 Hz, 1 H, N1ЈH), 7.44 (mc, 2 H, 2 ϫ m-
5.30Ϫ5.33 (d, J ϭ 8.5 Hz, 1 H, NϪH), 7.26Ϫ7.77 (m, 8 H, Fmoc), ArH), 7.51 (mc, 1 H, p-ArH), 7.82 (mc, 2 ϫ o-ArH), 8.10 (br. s,
8.7 (br. s, 1 H, COOH). Ϫ 13C NMR (300 MHz, CDCl3): δ ϭ 17.7
(C-2Ј), 28.4, 31.1 (C-3 and C-4), 47.2 (CHϪCH2O, Fmoc), 51.5 (C-
1 H, NHMe). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 17.7 (C-2Ј), 25.9
(NϪCH3), 28.7 (C-4), 30.7 (C-3), 50.4 (C-1Ј), 79.0 (C-2), 85.3 (C-
1Ј), 67.1 (CH2O, Fmoc), 77.2 (C-2), 86.3 (C-5), 120.0, 125.1, 127.1, 5), 127.0, 128.5, 131.5 and 134.4 (phenyl), 168.3 and 174.3
127.7, 141.3, 143.8, 156.9 (Fmoc), 175.8 (CϭO). Ϫ HRMS(EI): (2 ϫ CONH). Ϫ C15H20N2O3 ϫ H2O* (293.34): calcd. C 61.21 H
C22H23NO5: calcd. 381.1576 [Mϩ], found 381.1559 [Mϩ].
7.53 N 9.52; found C 61.73 H 7.45 N 9.46. *Analytical data from
34 ϫ H2O.
(2R,5S,1ЈS)-5-{1Ј-[(tert-Butoxycarbonyl)amino]ethyl}tetrahydro-
furan-2-carboxylic Acid Methyl Amide (33): A solution of acid 27
(1.00 g, 3.86 mmol), methyl amine hydrochloride (390 mg,
5.78 mmol) and HOBt ϫ H2O (945 mg, 6.17 mmol) in THF
(20 mL) was treated at 0°C with EtN(iPr)2 (0.67 mL, 0.50 g,
3.87 mmol) and with EDC (814 mg, 4.25 mmol). After 50 min Et-
N(iPr)2 (0.67 mL, 0.50 g, 3.87 mmol) was added again. The solu-
tion was allowed to stir for 18 h at room temperature before the
solvent was removed in vacuo. The residue was dissolved in EtOAc
(50 mL) and washed with saturated aqueous NaHCO3 solution
(20 mL), 5% aqueous citric acid (2 ϫ 10 mL), saturated NaCl solu-
tion (20 mL) and dried with Na2SO4. Concentration in vacuo and
recrystallization from MTBE afforded 33 (665 mg, 2.44 mmol,
63%) as a white solid, m.p. 156°C. Ϫ Rf ϭ 0.33 (MTBE). Ϫ [α]D ϭ
Conformational Analysis of 34 in CDCl3 Solution: Interproton dis-
tances of 34 were obtained from a 600-MHz NOESY experiment
with a mixing time of 500 ms. The peak volumes were integrated
on both sides of the diagonal. The integrals between geminal pro-
tons served as a reference for calibration.
Table 3. NOESY data from 34 in CDCl3
˚
Crosspeak
Rel. integral
Distance [A]
(1)
(2)
(3)
(4)
(5)
1Ј-H ϫ 4-HA
3-HA ϫ 5-H
17.1
7.0
2.2
2.6
1Ј-H ϫ NHMe 10.4
2.4
1.74
reference
ϩ61.6; [α]578 ϭ ϩ64.3; [α]546 ϭ ϩ73.0; [α]436 ϭ ϩ123.6; [α]365
ϭ
3-HA ϫ 3-HB
4-HA ϫ 4-HB
58.0
84.2
ϩ192.6 (c ϭ 0.99, CHCl3, T ϭ 20°C). Ϫ IR (KBr): ν˜ ϭ br. 3330
cmϪ1 m (NH), 3300 s (NH), 3010 w, 2970 m/2940 w/2875 w (CH),
1695 s (CϭO), 1650 s, 1545 s, 1460 w, 1410 w, 1390 w, 1365 w, 1335
m, 1320 w, 1275 w, 1250 m, 1195 w, 1170 m, 1085 m, 1055 w, 1045
1
w. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.10 (d, J ϭ 6.4 Hz, 3 H,
2Ј-H3), 1.46 [s, 9 H, C(CH3)3], superimposes 1.45Ϫ1.55 (m, 1 H, 4-
HA), 1.90Ϫ2.02 and 2.16Ϫ2.39 (m, 1 H and m, 2 H, 3-H2 and 4-
HB), 2.83 (d, J ϭ 6.4 Hz, 3 H, NMe), 3.62Ϫ3.77 (m, 2 H, 5-H, 1Ј-
H), 4.41 (dd, J ϭ 3.5, 8.4 Hz, 1 H, 2-H), 4.71 (br. d, J ϭ 8.1 Hz,
1 H, NHBoc), 8.06 (br. s, 1 H, NHMe). Ϫ 13C NMR (75 MHz,
CDCl3): δ ϭ 17.6 (C-2Ј), 25.6 (NϪCH3), 28.3 [C(CH3)3], 28.7 (C-
4), 30.6 (C-3), 51.4 (C-1Ј), 79.0 (C-2), 79.7 [C(CH3)3], 85.7 (C-5),
156.8 (BocϪCO), 174.2 (CONH). Ϫ C13H24N2O4 (272.344): calcd.
C 57.33, H 8.88, N 10.29; found C 57.08, H 8.55, N 10.07.
Figure 6. Selected NOESY crosspeaks found for 34 in CDCl3 and
used as input for the MD calculations
Eur. J. Org. Chem. 1999, 2977Ϫ2990
2989

U. Koert et al.
FULL PAPER
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1.0 fs and minimization of the frozen structures at 200 K steepest
descent Ǟ conjugate gradient Ǟ BFGS) with a dieelectric constant
of 1.00 and the distances 1Ϫ3 (Table 2) as experimental restraints
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M. D. Smith, D. D. Long, D. G. Marquess, T. D. W. Clar-
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˚
(calculated value ± 0.4 A) we found the structure displayed in Fig-
[7] [7a]
ure 5c) to be the minimum. The calculated structure was fully con-
sistent with all NOESY-derived distances. The 600-MHz 1H-NMR,
75-MHz APT spectrum and the aliphatic region of the NOESY
spectrum of 34 in CDCl3 solution are included as Supporting Infor-
mation.
H. Wagner, K. Harms, U. Koert, S. Meder, G. Boheim, An-
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[7b]
1996, 35, 2643Ϫ2645 Ϫ
An excellent review about the syn-
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`
Figadere, Tetrahedron: Asymmetry 1993, 4, 1711Ϫ1754.
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This work was supported by the Deutsche Forschungsgemein-
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2990
Eur. J. Org. Chem. 1999, 2977Ϫ2990