Side-chain-functionalized dipeptides derived from 6,5-fused bicyclic thiazolidinlactams

Article abstract of DOI:10.1002/ejoc.200390133

Condensation of D-arabinuronolactone (2) with L-cysteine methyl ester yields the bicyclic thiazolidinlactam 3 as a single diastereoisomer with the new bridgehead stereocenter in the (S) configuration. Regioselective activation of the a-hydroxy group leads to the triflate 4 without requiring protecting groups on the residual hydroxy groups. Subsequent azide exchange, reduction, and Boc protection, yields the epimeric dipeptide mimetics 6 and 7. Compound 3 forms the single acetonide 9, which permits the regioselective alkylation of the γ-hydroxy group of the bicyclic framework. Subsequent deprotection and exchange of the α-hydroxy functionality against a Boc-protected amino group (13) demonstrates the regioselective side-chain modification of bicyclic dipeptides. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390133

FULL PAPER
Side-Chain-Functionalized Dipeptides Derived from 6,5-Fused Bicyclic
Thiazolidinlactams
Peter Tremmel,[a] Jörg Brand,[b] Volker Knapp,[b] and Armin Geyer*[a]
Keywords: Peptidomimetics / Heterocycles / Lactams / Structure elucidation / Amino acids
Condensation of
D-arabinuronolactone (2) with
L-cysteine
acetonide 9, which permits the regioselective alkylation of
methyl ester yields the bicyclic thiazolidinlactam 3 as a single the γ-hydroxy group of the bicyclic framework. Subsequent
diastereoisomer with the new bridgehead stereocenter in the
(S) configuration. Regioselective activation of the α-hydroxy
group leads to the triflate 4 without requiring protecting
groups on the residual hydroxy groups. Subsequent azide ex-
change, reduction, and Boc protection, yields the epimeric
dipeptide mimetics 6 and 7. Compound 3 forms the single
deprotection and exchange of the α-hydroxy functionality
against a Boc-protected amino group (13) demonstrates the
regioselective side-chain modification of bicyclic dipeptides.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
Results and Discussion
Amino acids that are derived from sugar precursors com-
bine the polyfunctional character of carbohydrates with the
polyamide backbone of peptides.[1] Furanoid or pyranoid
sugar amino acids restrict the dynamics about peptide tor-
sional angles and, as a consequence, the monocyclic amino
acids can stabilize structural motifs in peptides.[2] Fused
rings exert an even stronger local structural control by
freezing several torsions within bi- or oligocyclic frame-
works.[3] The peptide mimetics described here combine the
molecular diversity of sugars with the rigidity of fused het-
erocyclic rings. The synthesis of 7,5-fused ring systems and
their structural properties within oligopeptides have been
described recently.[4] Here we investigate the possibility of
constraining the relative ring sizes further and we describe
the regioselective modification of hydroxy groups. The
,-,[5] ,-,[6] and ,-configured[7] dipeptides that are con-
strained within hexahydrothiazolo[3,2-a]pyridin-5-one ring
systems find application as active-site inhibitors of enzymes.
The uronic acid derived dipeptides described here bear ad-
ditional functional groups that mimic the side chains of ser-
ine and threonine. Regioselective alkylation of the hydroxy
groups introduces alternative amino acid side chains and
opens access to different dipeptide mimetics that are de-
rived from a common precursor.
Synthesis
Periodate cleavage of -glucurono-3,6-lactone (1) yields
-arabinurono-2,5-lactone (2),[8] which combines with -
cysteine methyl ester to give the bicyclic thiazolidinlactam
3 (Scheme 1). The annulation reaction is spontaneous in
water containing a few percent of pyridine.[4] The yield of
this two-step reaction is limited by the preparation of the
oily sugar lactone 2, which was not isolated but immediately
condensed with -cysteine methyl ester in a highly diaster-
eoselective reaction. The different nucleophilicities of the
hydroxy groups of 3 regulate the third selective reaction
step, which is the formation of triflate 4 with 1.1 equiv. of
triflic anhydride. Crystals of 4 were grown from ethyl acet-
ate and the (S) configuration at the bridgehead stereocenter
was proven by X-ray structural analysis.
[a]
Institut für Organische Chemie, Universität Regensburg,
93040 Regensburg, Germany
Fax: (internat.) ϩ 49-941/943-4627
E-mail: armin.geyer@chemie.uni-regensburg.de
[b]
Fakultät für Chemie, Universität Konstanz,
Scheme 1. a) NaIO4, 0.05  Na2HPO4, 0 °C to room temp.; b)
HCl·H-Cys-OMe, H2O/pyridine (10:1) (65 % both steps); c) Tf2O,
CH2Cl2/pyridine (10:1), Ϫ30 °C to room temp. (78%)
78457 Konstanz, Germany
Fax: (internat.) ϩ 49-7531/88-3140
878
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0305Ϫ0878 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 878Ϫ884

Side-Chain-Functionalized Dipeptides
FULL PAPER
The triflate is displaced with inversion of configuration
by an azido group in CH2Cl2 to yield 5 (Scheme 2). Altern-
atively, the reaction of 4 with sodium azide can be per-
formed with a comparable yield in DMF as solvent without
the necessity of adding a crown ether. The SN2-type reac-
tion is accompanied by an inversion of the α-stereocenter
in contrast to the double inversion Ϫ and thus overall reten-
tion of configuration Ϫ that was observed in the case of the
7,5-membered rings and explained by the destabilized axial
orientation of the azido group.[4c] Such destabilization is ab-
sent in the more planar 6,5-membered fused rings, and the
6-H proton is found on the same side of the six-membered
ring as the bridgehead proton 8a-H as determined from the
ROESY spectrum of 5 (Figure 1). Subsequent reduction of
5 with hydrogen sulfide is accompanied by the epimeriz-
ation of the α-carbon atom. The two diastereoisomeric
amines were protected with Boc anhydride and then separ-
ated by flash chromatography to yield the ,-configured
dipeptide 6 and the ,-dipeptide 7. Reduction of the azide
5 with Na2S2O3, TMSCl, and NaI in acetonitrile at room
temperature for 30 min,[9] followed by Boc protection of the
amine, gave 6 without formation of the diastereoisomer 7.
The transformation of 3 to azide 5 can be performed by
a one-pot reaction in an overall 62% yield without isolation
of the intermediate triflate 4, which reduces the number of
synthetic steps from the commercial sugar lactone to the
fully protected dipeptide to only four. Similarly, the trans-
formation of 4 to the Boc-protected dipeptides can be per-
formed without requiring workup of the intermediate.
The carboxy terminus of 7 (or 6) is deprotected upon
Figure 1. ROESY spectrum (600 MHz, 300 K, 4 kHz pulsed spin
lock, 200 ms mixing time) of the azide 5 in [D6]DMSO; the small
3J coupling constants within the six-membered ring, namely 3J6,7 ϭ
5.2, 3J7,8 Ͻ 2, and 3J8,8a ϭ 1.5 Hz, are caused by the relative gauche
arrangement of the four ring protons; the strongest NOE is ob-
served between the neighbouring protons 8-H and 8a-H; the in-
tense NOE between protons in the positions 6 and 8a proves that
both protons are found on the same side of the ring; the full assign-
ment is given in the Exp. Sect.
saponification with LiOH, and HCl/Et2O sets the amino by serving as anchoring points for encoded amino acid side
terminus free. Coupling products are then obtained under chains. For example, Hirschmann et al. showed that an O-
the standard conditions of peptide synthesis. Only the tri- benzyl group attached to a sugar scaffold can mimic the
peptide 8 is presented here, which has interesting conforma- phenylalanine side chain.[10] The regioselective modification
tional properties as discussed below.
of one of the two hydroxy groups of 3 forms the basis for
Synthetic strategies towards bicyclic peptidomimetics the synthesis of a wide range of side-chain-modified dipept-
start generally from two amino acids of which the side ides. Various peptidomimetics are then accessible form the
chain functionalities are consumed in the formation of the common precursor 3. Branching of the synthetic strategy
bicyclic ring.[3] In a similar manner, the strategy presented after the synthesis of the fused ring system is another ad-
here consumes the aldehyde functionality of the uronic acid vantage of the uronic acid based synthesis over amino acid
in the formation of the fused rings. The two remaining hy- based strategies, in which each new bicyclic dipeptide re-
droxy groups allow for subsequent synthetic modifications quires a new amino acid precursor; examples of syntheses
of more than one bicyclic peptide from a common pre-
cursor remain exceptions.[11] Compound 3 forms a single
acetonide (9, Scheme 3) that permits the differentiation be-
tween the 7-OH and the 8-OH groups and, hence, 9 be-
comes the key intermediate for the regioselective modifica-
tion of the side chain.
Benzylation of 9, followed by deprotection of the aceton-
ide, yielded the monoalkylated derivative 10. The reaction
sequence of triflation (Ǟ 11) and azide exchange yielded
the azide 12, which was transformed by reduction and Boc
protection into the crystalline ,-dipeptide 13 in an 87%
yield. Additionally, the epimeric ,-dipeptide (11%) was
separated by flash chromatography.
The side products (14 and 15) formed in the two low-
yielding steps were separated and characterized. Both result
Scheme 2. a) NaN3, CH2Cl2, 15-crown-5, room temp. (92%); b)
H2S, H2O/pyridine (1:2), then Boc2O, DIPEA, CH2Cl2
from eliminations and yield dehydro amino acids. The side
879
Eur. J. Org. Chem. 2003, 878Ϫ884

P. Tremmel, J. Brand, V. Knapp, A. Geyer
FULL PAPER
Scheme 3. a) acetone, Hϩ (89%); b) i. BnBr, NaH, DMF, ii. TFA/
H2O/EtOH (34%); c) Tf2O, DMAP, CH2Cl2/pyridine (10:1) (38%);
d) NaN3, 15-crown-5, CH2Cl2 (83%); e) H2S, H2O/pyridine (1:2),
then Boc2O, DIPEA, CH2Cl2 (87%)
product 14 from the benzylation reaction is separable from
10 after cleavage of the acetonide group. Only the stereoiso-
mer that retains the configuration of the former bridgehead
stereocenter is observed. This was an unexpected reaction,
because the thioproline sulfur atom does not act as a nucle-
ophile in reactions with other electrophiles. Therefore, we
expect that a change in the reaction conditions will permit
a better differentiation between the secondary hydroxy
group and the thiazolidin lactam sulfur atom. A second side
product resulting from elimination is observed upon the
triflation of 10. The DMAP present in the reaction mixture
leads to the formation of 15, which was not formed from
the reaction conducted in the absence of DMAP as shown
by the high yield of triflate 4.
Figure 2. Crystal structures of the protected dipeptides 6 and 7
Structural Analysis
The crystal structures of 6 and 7 are shown in Figure 2.
The planarized six-membered rings keep both hydroxy sub-
stituents in pseudoaxial orientations with OϪCϪCϪO tor-
sional angles of ca. 180° for 7 and 8 and ca. Ϫ150° for 6
and 13 (Figure 3).
Figure 3. Crystal structure of side-chain-functionalized 13
Thiazabicycloalkane amino acids like the β-turn dipept-
ide (BTD)[12] 7, its diastereoisomer 6, or the O-alkylated 13,
mimic dipeptides consisting of the amino acids i and iϩ1. a wider range. Surprisingly, the largest variation of ϕi is
The 6,5-fused heterocyclic rings lock three sequential pep- found in the two molecules in the asymmetric unit in the
tide backbone torsions ψi, ωi, and ϕiϩ1 (ϕ
COϪNϪCαϪCO, NϪCOϪCαϪN,
ϭ
ϭ
crystal structure of 8. The carboxy termini (torsion ψiϩ1
assume extended conformations with the exception of 6,
)
ω
ϭ
ψ
CαϪCOϪNϪCα).[13] Torsion Ψi is constrained within an which is flipped by 180°. Conformational mobility is ex-
extended conformation and the observed values for ϕiϩ1 are pected for this exocyclic torsion in solution. NMR spectro-
the ones expected for (thio)proline (Table 1). The amino scopy corroborates the ring conformations found in the
3
and carboxy terminal torsions of the bicyclic ring ϕi and solid state; the J coupling constants are listed in the Exp.
ψiϩ1 assume preferred orientations, although varying over Sect.
880
Eur. J. Org. Chem. 2003, 878Ϫ884

Side-Chain-Functionalized Dipeptides
FULL PAPER
MeOH (50 mL) was added after 1 h causing a white precipitate to
form. The suspension was stirred for another 12 h at room temp.,
the precipitate was filtered off, and the solvent was evaporated.
The residue was dissolved in H2O/pyridine (10:1, 110 mL). After
addition of -cysteine methyl ester (5.0 g, 29.1 mmol), the solution
was stirred at room temp. for 4 d. The solvent was evaporated and
Table 1. Representative torsion angles of the solid-state structures;
compounds 6 and 13 represent ,-configured dipeptides while all
others mimic ,-dipeptides; structures 8 (1) and 8 (2) are the two
molecules in the asymmetric unit of the crystal; the values for BTD
were taken from the literature (ref.[12b]
)
ϕi
ψi
ϕiϩ1
ψiϩ1
the residue was dissolved in MeOH. Compound
3 (4.87 g,
18.5 mmol, 65%) was obtained as a colorless solid after flash chro-
6
13
7
8 (1)
8 (2)
BTD
105.0°
156.3°
Ϫ110.9°
Ϫ151.9°
Ϫ78.1°
Ϫ104.3°
175.1°
178.7°
Ϫ142.3°
Ϫ148.0°
Ϫ164.3°
Ϫ157.0°
Ϫ96.6°
Ϫ96.0°
Ϫ76.3°
Ϫ70.1°
Ϫ77.2°
Ϫ66.5°
30.1°
Ϫ169.9°
Ϫ172.3°
144.3°
matography with CHCl3/MeOH (3:1) (Rf ϭ 0.65). 1H NMR
3
(600 MHz, [D6]DMSO): δ ϭ 5.60 (d, J8-OH,8 ϭ 5.1 Hz, 1 H, 8-
3
3
OH), 5.40 (d, J7-OH,7 ϭ 3.5 Hz, 1 H, 7-OH), 5.31 (d, J6-OH,6
ϭ
3
6.1 Hz, 1 H, 6-OH), 5.16 (d, J8a,8 ϭ 2.6 Hz, 1 H, 8a-H), 4.87 (dd,
162.4°
3J3,2proS ϭ 5.4, J3,2proR ϭ 7.6 Hz, 1 H, 3-H), 4.07 (dd, J6,6-OH
ϭ
3
3
Ϫ197.0°
3
6.0, J6, 7 ϭ 3.6 Hz, 1 H, 6-H), 4.01 (m, 1 H, 7-H), 3.93 (m, 1 H,
8-H), 3.63 (s, 3 H, OCH3), 3.30 (m, 1 H, 2-HproR), 3.03 (dd,
3J2proS,3 ϭ 5.28, Jgem ϭ 11.44 Hz, 1 H, 2-HproS) ppm. 13C NMR:
2
δ ϭ 170.51, 169.02 (C-5, CO2), 71.03 (C-7), 66.93 (C-6), 66.77 (C-
8), 64.64 (C-8a), 60.35 (C-3), 52.22 (OCH3), 31.23 (C-2) ppm.
[α]2D4 ϭ Ϫ214 (c ϭ 1, MeOH). FAB-MS: m/z ϭ 264 [M ϩ H]ϩ, 527
[2 M ϩ H]ϩ. C9H13NO6S (263.27): calcd. C 41.06, H 4.98, N 5.32;
found C 40.23, H 5.05, N 5.18.
Conclusion
A straightforward synthetic strategy yields 6,5-fused car-
bodipeptides in ,- (major) and ,-configured (minor) di-
astereoisomers, respectively. No side-chain protection is
necessary during the synthesis or in the subsequent peptide
coupling steps. Selective synthetic transformations of hy-
droxy groups, excellent solubility, and a tendency to form
crystals, make these carbohydrate-derived dipeptides a
Analytical Data of the Ethyl Ester 3a: 1H NMR (600 MHz,
3
[D6]DMSO): δ ϭ 5.60 (d, J8-OH,8 ϭ 5.0 Hz, 1 H, 8-OH), 5.38 (d,
3
3J7-OH,7 ϭ 3.5 Hz, 1 H, 7-OH), 5.30 (d, J6-OH,6 ϭ 6.2 Hz, 1 H, 6-
OH), 5.17 (d, 3J8a, 8 ϭ 2.9 Hz, 1 H, 8a-H), 4.85 (dd, 3J3,2proS ϭ 5.3,
3J3,2proR ϭ 7.9 Hz, 1 H, 3-H), 4.1 (m, 3 H, CH2CH3, 6-H), 4.01 (m,
1 H, 7-H), 3.93 (m, 1 H, 8-H), 3.30 (m, 1 H, 2-HproR), 3.01 (dd,
2
3
promising new class of peptidomimetics. The dipeptide ana- 3J2proS,3 ϭ 5.0, Jgem ϭ 11.2 Hz, 1 H, 2-HproS), 1.19 (t, JEt
ϭ
7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 170.0, 169.0 (C-5,
CO2), 70.1 (C-7), 66.6 (C-6), 66.5 (C-8), 64.3 (C-8a), 60.6
logs described here are derived from a single bicyclic pre-
cursor that is accessible in large quantities and that can
serve as a starting point for the synthesis of dipeptides with
diverse side-chain functionalities.
(CH2CH3), 60.1 (C-3), 30.9 (C-2), 13.6 (CH2CH3) ppm. [α]2D4
ϭ
Ϫ151 (c ϭ 1, MeOH). FAB-MS: m/z ϭ 278 [M ϩ H]ϩ, 300 [M ϩ
Na]ϩ. C10H15NO6S (277.29): calcd. C 40.23, H 5.05, N 5.18; found
C 43.32, H 5.45, N 5.05.
Experimental Section
Methyl (3R,6S,7R,8S,8aS)-7,8-Dihydroxy-5-oxo-6-(trifluoro-
methanesulfonyloxy)hexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-
carboxylate (4): Compound 3 (950 mg, 3.6 mmol) was dissolved in
pyridine (50 mL) and CH2Cl2 (5 mL). At a reaction temperature of
Ϫ40 °C a catalytic amount of DMAP was added together with
General Remarks: Solvents were purified according to standard
procedures. Flash chromatography was performed on J. T. Baker
silica gel 60 (0.040Ϫ0.063 mm) at a pressure of 0.4 bar. Thin layer
chromatography was performed on Merck silica gel plastic plates, Tf2O (900 µL, 5.4 mmol) in CH2Cl2 (1.5 mL). The reaction mixture
60F254; compounds were visualized by treatment with a solution of was maintained at Ϫ40 °C for 30 min, then at room temperature
(NH4)6Mo7O24·4H2O (20 g) and Ce(SO4)2 (0.4 g) in 10% sulfuric for 30 min, and then poured onto ice (50 mL). The product was
acid (400 mL) and heating at 150 °C. Optical rotations were meas- extracted with ethyl acetate (1 ϫ 100 mL, 2 ϫ 50 mL) and the
ured with a PerkinϪElmer polarimeter 241 in a 1-dm cell at 22 °C. combined organic phases were dried (MgSO4). After flash chroma-
NMR spectra were recorded with a Bruker AC 400 or a Bruker
DRX 600. TMS, or the resonance of the residual solvent
([D6]DMSO: δ ϭ 2.49 ppm), was used as internal standard. Dias-
tography (ethyl acetate/toluene, 4:1), compound 4 (1.14 g,
2.9 mmol, 81%) (Rf ϭ 0.72) was obtained. 1H NMR (400 MHz,
3
[D6]DMSO): δ ϭ 6.47 (d, J ϭ 3.7 Hz, 1 H, OH), 6.18 (br. s, 1 H,
3
3
terotopic proton pairs that could not be assigned stereochemically OH), 5.32 (d, J6,7 ϭ 3.5 Hz, 1 H, 6-H), 5.20 (d, J8a,8 ϭ 2.4 Hz, 1
1
3
3
are characterized as highfield (h) and lowfield (l) in the H NMR
H, 8a-H), 4.95 (dd, J3,2h ϭ 5.7, J3,2l 7.5 Hz, 1 H, 3-H), 4.36 (m,
data. FAB mass spectra were acquired with a Finnigan MAT 312
1 H, 7-H), 4.11 (m, 1 H, 8-H), 3.69 (s, 3 H, OCH3), 3.40 (dd,
3
2
in the positive mode, using NBA as the matrix. CCDC-183964 (4), 2Jgem ϭ 11.5, J2l,3 ϭ 7.7 Hz, 1 H, 2-Hl), 3.11 (dd, Jgem ϭ 11.4,
-154782 (6), -183443 (7), -183963 (8), and -183444 (13) contain the
supplementary crystallographic data for this paper. These data can (C-5, CO2), 82.37 (C-6), 69.73 (C-7), 66.84 (C-8), 64.54 (C-8a),
3J2h, 3 ϭ 5.5 Hz, 1 H, 2-Hh) ppm. 13C NMR: δ ϭ 169.70, 160.66
be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (internat.)
ϩ 44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
60.62 (C-3), 52.49 (OCH3), 31.30 (C-2) ppm. PI-DCI-MS: m/z ϭ
413 [M ϩ NH4]ϩ. C10H12F3NO8S2 (395.34): calcd. C 30.38, H 3.06,
N 3.54; found C 30.00, H 3.08, N 2.95.
Methyl (3R,6R,7R,8S,8aS)-6-Azido-7,8-dihydroxy-5-oxohexahydro-
5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (5): NaN3 (700 mg,
10.8 mmol) and 15-crown-5 (2 mL, 8.2 mmol) were added to a solu-
Methyl (3R,6S,7R,8S,8aS)-6,7,8-Trihydroxy-5-oxohexahydro-5H-
[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (3): γ-Glucuronolactone
(5.0 g, 28.4 mmol) and NaIO4 (7.9 g, 36.9 mmol, 1.3 equiv.) were tion of triflate 4 (2.00 g, 3.05 mmol) in CH2Cl2 (200 mL). The reac-
dissolved in aqueous Na2HPO4 (0.05 , pH ϭ 7.5, 50 mL). An ice tion mixture was stirred at room temp for 14 h and then H2O
bath was used to keep the reaction temperature below 30 °C.
(20 mL) was added. The aqueous phase was extracted twice with
Eur. J. Org. Chem. 2003, 878Ϫ884
881

P. Tremmel, J. Brand, V. Knapp, A. Geyer
FULL PAPER
ethyl acetate and the combined organic phases were dried
(MgSO4). Flash chromatography (ethyl acetate/toluene, 3:1) yielded
the azide 5 (1.34 g, 4.65 mmol, 92%) (Rf ϭ 0.43).
3
3
3.96 (dd, J6,NH ϭ 9.4, J6,7 ϭ 6.8 Hz, 1 H, 6-H), 3.75 (m, 1 H, 8-
3
H), 3.66 (s, 3 H, OCH3), 3.61 (m, 1 H, 7-H), 3.24 (dd, J2l,3 ϭ 7.3,
3
3
3J2l,2h ϭ 11.2 Hz, 1 H, 2-Hl), 3.06 (dd, J2h,3 ϭ 2.9, J2h,2l
ϭ
11.4 Hz, 1 H, 2-Hh), 1.39 (s, 9 H, CH3 tBu) ppm. 13C NMR: δ ϭ
170.20, 166.93 (C-5, CO2), 155.73 (COtBu), 77.96 (Cq tBu), 73.56
(C-7), 73.27 (C-8), 63.04 (C-8a), 61.23 C-3), 56.83 (C-6), 52.43
One-Pot Synthesis of 5: Compound 3 (1 mmol) was dissolved in
pyridine/CH2Cl2 (3:2, 5 mL) and cooled to Ϫ40 °C. DMAP (cata-
lytic amount) was added followed by Tf2O (0.2 mL, 1.22 mmol) in
CH2Cl2 (0.5 mL). The solution was stirred at Ϫ40 °C for 45 min,
at Ϫ20 °C for 45 min, and then at room temp. for 45 min. The
solution was then cooled to Ϫ10 °C before NaN3 (100 mg,
1.54 mmol) and 15-crown-5 (300 µL, 334 mg, 1.52 mmol) were ad-
ded. After 1 h at this temperature, the solution was stirred for 3 d
at room temp. The red-brown solution was concentrated and dis-
solved in H2O/ethyl acetate (1:2, 30 mL). The aqueous phase was
extracted with ethyl acetate (2 ϫ 20 mL). The combined organic
phases were dried (MgSO4) and 5 (177 mg, 0.62 mmol, 62%) was
obtained as a clear syrup after flash chromatography (ethyl acetate/
toluene, 3:1) (Rf ϭ 0.43). 1H NMR (600 MHz, [D6]DMSO): δ ϭ
5.90 (d, 3J7-OH,7 ϭ 4.7 Hz, 1 H, 7-OH), 5.73 (d, 3J8-OH,8 ϭ 4.57 Hz,
1 H, 8-OH), 5.22 (dd, 3J3,2l ϭ 6.9, 3J3,2h ϭ 2.82 Hz, 1 H, 3-H), 5.04
(OCH3), 31.27 (C-2), 28.20 (CH3 tBu) ppm. M.p. 172 °C. [α]2D4
ϭ
Ϫ86 (c ϭ 1, CHCl3). FAB-MS: m/z ϭ 363 [M ϩ H]ϩ. C14H22N2O7S
(362.40): calcd. C 46.40, H 6.12, N 7.73; found C 46.46, H 6.15,
N 7.67.
1
Analytical Data of 7: H NMR (600 MHz, [D6]DMSO): δ ϭ 6.34
3
3
(d, JNH,6 ϭ 9.7 Hz, 1 H, NH). 5.74 (d, J8-OH,8 ϭ 4.7 Hz, 1 H, 8-
3
3
OH), 5.62 (d, J7-OH,7 ϭ 3.8 Hz, 1 H, 7-OH), 5.15 (d, J8,8a
ϭ
2.6 Hz, 1 H, 8-H), 4.84 (dd, 3J2,3 ϭ 7.3, 3J2Ј,3 ϭ 5.9 Hz, 1 H, 3-H),
4.44 (dd, J6,NH ϭ 9.7, J6,7 ϭ 2.9 Hz, 1 H, 6-H), 3.92Ϫ3.96 (m, 2
H, 7-H, 8-H), 3.64 (s, 3 H, OCH3), 3.31 (dd, J2,2Ј ϭ 11.4, J2,3
3
3
2
3
ϭ
7.6 Hz, 1 H, 2-Hl), 3.02 (dd, J2,2Ј ϭ 11.4, J2Ј,3 ϭ 5.6 Hz, 1 H, 2-
Hh), 1.39 (s, 9 H, CH3 tBu) ppm. 13C NMR: δ ϭ 170.41, 166.54
(C-5, CO2), 155.67 (COtBu), 78.11 (Cq tBu), 70.94 (C-7) 66.16 (C-
8), 64.51 (C-8a), 60.64 (C-3), 52.16 (OCH3), 50.97 (C-6), 31.12 (C-
2), 28.10 (CH3 tBu) ppm. [α]2D4 ϭ Ϫ96.1 (c ϭ 1, CHCl3). FAB-MS:
m/z ϭ 363 [M]ϩ. C14H22N2O7S (362.40): calcd. C 46.40, H 6.12, N
7.73; found C 46.38, H 6.14, N 7.71.
2
3
3
3
(d, J8a,8 ϭ 1.5 Hz, 1 H, 8a-H), 4.13 (d, J6,7 ϭ 5.2 Hz, 1 H, 6-H),
3.75 (m, 1 H, 8-H), 3.68 (s, 3 H, OCH3), 3.60 (m, 1 H, 7-H), 3.26
3
2
3
(dd, J2l,3 ϭ 7.0, Jgem ϭ 11.3 Hz, 1 H, 2-Hl), 3.10 (dd, J2h,3
ϭ
2
2.9, Jgem ϭ 11.30 Hz, 1 H, 2h-H) ppm. 13C NMR: δ ϭ 169.82,
165.12 (C-5, CO2), 73.76 (C-7), 71.55 (C-8), 64.15 (C-6), 62.86 (C-
8a), 61.38 (C-3), 52.52 (OCH3), 31.18 (C-2) ppm. [α]2D4 ϭ Ϫ57.3
(c ϭ 1, CHCl3). FAB-MS: m/z ϭ 289 [M ϩ H]ϩ, 577 [2 M ϩ H]ϩ.
C9H12N4O5S (288.28): calcd. C 37.50, H 4.20, N 19.44; found C
37.24, H 4.40, N 18.18.
Analytical Data of Methyl {[(3R,6S,7R,8S,8aS)-(6-tert-Butoxy-
carbonylamino-7,8-dihydroxy-5-oxohexahydro-5H-[1,3]thiazolo[3,2-
a]pyridin-3-yl)carbonyl]amino}acetate (8): 1H NMR (600 MHz,
[D6]DMSO): δ ϭ 8.30 (t, 3JGlyNH,Hα ϭ 6.2 Hz, 1 H, Gly-NH), 6.31
3
3
(d, JBocNH,6ϭ 9.1 Hz, 1 H, BocNH), 5.71 (d, J8-OH,8 ϭ 4.7 Hz, 1
3
H, 8-OH), 5.57 (d, 3J7-OH,7 ϭ 3.5 Hz, 1 H, 7-OH), 5.17 (d, J8a,8 ϭ
Methyl (3R,6S,7R,8S,8aS)-6-tert-Butoxycarbonylamino-7,8-dihy-
droxy-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate
(6) and Methyl (3R,6R,7R,8S,8aS)-6-tert-Butoxycarbonylamino-7,8-
dihydroxy-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-
carboxylate (7): Azide 5 (1.15 g, 4 mmol) was dissolved in pyridine/
H2O (2:1, 150 mL). H2S was bubbled through the solution for
10 min, and then the mixture was stirred at room temp. for 14 h.
The solvent was evaporated and the crude product was dissolved
in CH2Cl2. Boc2O (1.2 g, 5.5 mmol) and DIPEA (0.7 mL,
4.0 mmol) were added and the reaction mixture was stirred at room
temp. for 14 h. The solution was concentrated under vacuum and
the products isolated by flash chromatography (ethyl acetate/tolu-
ene, 10:1) to yield 6 (950 mg, 2.62 mmol, 66%) (Rf ϭ 0.56) and 7
(310 mg, 0.86 mmol, 22%) (Rf ϭ 0.43).
3
3
1.8 Hz, 1 H, 8a-H), 4.88 (dd, J3,2l ϭ 7.3, J3,2h ϭ 5.6 Hz, 1 H, 3-
3
3
H), 4.38 (dd, J6,NHBoc ϭ 9.7, J6,7 ϭ 2.9 Hz, 1 H, 6-H), 3.93 (m,
1 H, 7-H), 3.90 (m, 1 H, 8-H), 3.88 (dd, 2JHα,HαЈ ϭ 17.6, 3JHγ,NH ϭ
5.9 Hz, 1 H, Gly-Hγl ), 3.82 (dd, JHα,HαЈ ϭ 17.6, 3JHα,NH ϭ 5.9 Hz,
2
1 H, Gly-Hhα), 3.62 (s, 3 H, OCH3), 3.21 (dd, 2Jgem ϭ 11.4, 3J2l,3
ϭ
7.6 Hz, 1 H, 2-Hl), 2.99 (dd, Jgem ϭ 11.2, J2h,3 ϭ 5.0 Hz, 1 H, 2-
Hh), 1.38 (s, 9 H, CH3 tBu) ppm. 13C NMR: δ ϭ 170.08, 169.98,
166.21 (C-5, CO2, CONH), 155.66 (COtBu), 78.14 (Cq tBu), 70.47
(C-7), 66.32 (C-8), 64.79 (C-8a), 61.17 (C-3), 51.70 (OCH3), 50.96
(C-6), 40.57 (Gly-Cα), 31.28 (C-2), 28.14 (CH3 tBu) ppm. PI-DCI-
MS: m/z ϭ 437 [M ϩ NH4]ϩ.
2
3
Ethyl (3R,6S,7R,8S,8aS)-8-Hydroxy-6,7-isopropylidene-5-oxohexa-
hydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (9): Ethyl ester
3a (1.6 g, 5.77 mmol) was dissolved in acetone (50 mL) and the
reaction vessel was cooled in an ice bath. Concentrated sulfuric
acid (0.5 mL) was added and the reaction mixture was stirred for
15 min at 0 °C and then 45 min at room temp. The precipitate that
formed during neutralization with sodium carbonate was isolated
and subjected to flash-chromatography (ethyl acetate/toluene, 5:1)
to give 9 (1.63 g, 5.14 mmol, 89%) (Rf ϭ 0.53) as a yellow solid.
Alternative Preparation of 6: Azide 5 (100 mg, 0.35 mmol) and NaI
(80 mg, 0.53 mmol 1.5 equiv.) were dissolved in dry MeCN (5 mL)
and the solution stirred for 5 min before TMSCl (70 µL,
0.53 mmol) was added; a red-brown suspension was formed. After
30 min at room temp., 10% Na2S2O3 was added dropwise until a
yellow color was observed. The solvent was evaporated and the dry
residue was dissolved in dry CH2Cl2. While cooling in an ice bath,
DIPEA (70 µL) and Boc2O (115 mg, 0.53 mmol, 1.5 equiv.) were
added. After stirring the solution for 3 d at room temp., the solvent
was evaporated and the residue was dissolved in ethyl acetate/H2O
(2:1, 30 mL). The aqueous phase was extracted with ethyl acetate
(2 ϫ 20 mL) and the combined organic phases were dried (MgSO4).
Compound 6 (56 mg, 0.15 mmol, 44.5%) was obtained as a yellow
solid after flash chromatography (ethyl acetate/toluene, 5:1) (Rf ϭ
0.53).
3
1H NMR (600 MHz, [D6]DMSO): δ ϭ 5.79 (d, J8-OH,8 ϭ 5.0 Hz,
1 H, 8-OH), 5.21 (dd, J3,2h ϭ 2.6, 3J3,2l ϭ 6.5 Hz, 1 H, 3-H), 4.99
3
3
3
(s, 1 H, 8a-H), 4.44 (d, J6,7 ϭ 6.5 Hz, 1 H, 6-H), 4.41 (dd, J7,6
ϭ
3
6.5, J7,8 ϭ 2.9 Hz, 1 H, 7-H), 4.11 (m, 2 H, CH2CH3), 3.93 (m, 1
3
2
H, 8-H), 3.13 (dd, J2l,3 ϭ 6.8, Jgem ϭ 11.4 Hz, 1 H, 2-Hl), 3.06
(dd, J2h,3 ϭ 2.6, Jgem ϭ 11.2 Hz, 1 H, 2-Hh), 1.39 (s, 3 H, CH3),
3
2
3
1.31 (s, 3 H, CH3), 1.18 (t, JEt ϭ 7.0 Hz, 3-H, CH2CH3) ppm. 13
C
NMR: δ ϭ 169.21, 164.73 (C-5, CO2), 109.67 (CIqsopr), 75.89 (C-6),
73.24 (C-7), 67.51 (C-8), 61.40 (CH2CH3), 61.24 (C-8a), 61.16 (C-
Analytical Data of 6: H NMR (600 MHz, [D6]DMSO): δ ϭ 6.84 3), 30.46 (C-2), 26.20, 24.34 (CH3Isopr), 13.88 (CH2CH3) ppm.
1
3
3
(d, JNH,6 ϭ 9.1 Hz, 1 H, NH), 5.61 (d, J8-OH,8 ϭ 4.8 Hz, 1 H, 8-
[α]2D4 ϭ Ϫ85.9 (c ϭ 1, CHCl3). FAB-MS: m/z ϭ 318 [M ϩ H]ϩ.
3
3
OH), 5.44 (d, J7-OH,7 ϭ 5.3 Hz, 1 H, 7-OH), 5.15 (dd, J3,2l 7.0, C13H19NO6S (317.36): calcd. C 47.52, H 5.65, N 4.62; found C
3J3,2h ϭ 2.6 Hz, 1 H, 3-H), 5.06 (d, J8a,8 ϭ 1.2 Hz, 1 H, 8a-H), 49.21, H 5.82, N 4.23.
3
882
Eur. J. Org. Chem. 2003, 878Ϫ884

Side-Chain-Functionalized Dipeptides
Ethyl (3R,6S,7R,8S,8aS)-8-Benzyloxy-6,7-dihydroxy-5-oxohexahy- 3.8 Hz, 1 H, 7-OH), 5.27 (d, J8a,8 ϭ 2.1 Hz, 1 H, 8a-H), 5.24 (d,
FULL PAPER
3
3
3
dro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (10): Alcohol 9
(1.2 g, 3.8 mmol) was dissolved in DMF (50 mL), followed by the H, 3-H), 4.77 (d, Jgem ϭ 12.0 Hz, 1 H, PhCH2), 4.70 (d, Jgem
3J6,7 ϭ 3.2 Hz, 1 H, 6-H), 5.00 (dd, J3,2h ϭ 5.3, J3,2t ϭ 7.6 Hz, 1
2
2
ϭ
addition of benzyl bromide (1.5 mL, 12.6 mmol). The reaction
vessel was cooled in an ice bath, NaH (70 mg, 2.9 mmol) was ad-
11.7 Hz, 1 H, PhCH2), 4.42 (m, 1 H, 7-H), 4.1 (m, 2 H, CH2CH3),
3.40 (dd, 2Jgem ϭ 11.4, 3J2l,3 ϭ 7.6 Hz, 1 H, 2-Hl), 3.14 (dd, 2Jgem ϭ
3
3
ded, the mixture was stirred for 30 min, and then the ice bath was 11.4, J2h,3 ϭ 5.3 Hz, 1 H, 2-Hh), 1.19 (t, JEt ϭ 7.0 Hz, 3 H,
removed. Twice more, NaH (40 mg, 1.7 mmol) was added in inter-
vals of 30 min. The solvent was evaporated, then toluene was added
and evaporated. The dried residue was dissolved in ethyl acetate/
H2O (4:1, 250 mL). The aqueous phase was extracted twice with
ethyl acetate and the combined organic phases were dried (MgSO4).
At this stage, separation of 10 from the side product was not pos-
sible by flash chromatography (ethyl acetate/toluene, 4:5) (Rf ϭ
0.5). The acetonide was cleaved using TFA (15 mL) in EtOH
(10 mL) and H2O (0.7 mL). The solvent was evaporated after 15 h
at room temp. and flash chromatography (ethyl acetate/toluene,
5:1) of the residue yielded 10 (470 mg, 1.28 mmol, 34%) (Rf ϭ 0.36)
CH2CH3) ppm. 13C NMR: δ ϭ 169.05, 160.62 (C-5, CO2), 137.58,
128.41, 127.99, 127.82 (Ph), 82.23 (C-6), 74.37 (C-8), 73.36
(CH2Ph), 67.77 (C-7), 63.12 (C-8a), 61.35 (CH2CH3), 60.34 (C-3),
31.44 (C-2), 13.92 (CH2CH3) ppm. FAB-MS: m/z ϭ 500 [M ϩ H]ϩ,
522 [M ϩ Na]ϩ. C18H20F3NO8S2 (499.48): calcd. C 43.28, H 4.04,
N 2.80; found C 43.53, H 4.30, N 2.75.
Analytical Data of the Side Product Ethyl (3R,8S,8aS)-8-Benzyloxy-
5-oxo-6-(trifluoromethanesulfonyloxy)-2,3,8,8a-tetrahydro-5H-
[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (15): 1H NMR (600 MHz,
3
[D6]DMSO): δ ϭ 7.30 (m, 6 H, Ph), 5.29 (d, J8a,8 ϭ 2.9 Hz, 1 H,
3
3
8a-H), 5.26 (dd, J3,2l ϭ 6.5, J3,2h ϭ 1.8 Hz, 1 H, 3-H), 4.72 (d,
1
and the side product 14 (115 mg, 0.25 mmol, 7%) (Rf ϭ 0.43). H
2Jgem ϭ 11.4 Hz, 1 H, CH2Ph), 4.69 (d, Jgem ϭ 11.4 Hz, 1 H,
2
NMR (600 MHz, [D6]DMSO): δ ϭ 7.35 (m, 5 H, Ph), 5.57 (d,
CH2Bn), 4.39 (dd, J8,8a ϭ 3.2, 3J8,7 ϭ 6.5 Hz, 1 H, 8-H), 4.15 (m,
3
3
3J7-OH,7 ϭ 3.8 Hz, 1 H, 7-OH), 5.45 (d, J6-OH,6 ϭ 5.9 Hz, 1 H, 6-
2 H, CH2Et), 3.34 (dd, Jgem ϭ 11.4, J2l,3 ϭ 6.8 Hz, 1 H, 2-Hl),
2
3
3
3
OH) 5.24 (d, J8a,8 ϭ 2.6 Hz, 1 H, 8a-H), 4.91 (dd, J3,2h ϭ 5.0,
3.22 (dd, Jgem ϭ 11.4, J2h,3 ϭ 2.1 Hz, 1 H, 2-Hh), 1.19 (t, JEt
ϭ
2
3
3
3J3,2l 7.6 Hz, 1 H, 3-H), 4.69 (m, 2 H, PhCH2), 4.17 (m, 1 H, 7-H),
4.11 (m, 2 H, CH2CH3), 4.05 (dd, J6,6-OH ϭ 5.9, J6,7 ϭ 3.5 Hz, 1
7.0 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 168.69, 154.78 (5-CO,
CO2), 141.31 (C-6), 137.76 (C-Ph), 128.47 (C-7), 128.32, 127.80,
127.65 (Ph), 72.15 (CH2Ph), 69.06 (C-8), 63.79 (C-8a), 61.60
(CH2CH3), 61.24 (C-3), 32. 87 (C-2), 13.83 (CH2CH3) ppm.
3
3
3
3
H, 6-H), 3.99 (dd, J8,8a ϭ 2.6, J8,7 ϭ 4.7 Hz, 1 H, 8-H), 3.31 (m,
1 H, Hl), 3.05 (dd, Jgem ϭ 11.4, J2h,3 ϭ 5.0 Hz, 1 H, 2-Hh),1.19
2
3
(t, JEt ϭ 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 169.85,
3
168.92 (C-5, CO2), 138.09, 128.27, 127.66, 127.63 (Ph), 74.61 (C-
8), 72.71 (PhCH2), 68.75 (C-7), 67.37 (C-6), 63.32 (C-8a), 60.99
Ethyl
(3R,6R,7R,8S,8aS)-6-Azido-8-benzyloxy-7-hydroxy-5-oxo-
hexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (12): Com-
pound 11 (200 mg, 0.4 mmol) was dissolved in CH2Cl2 (30 mL) and
then NaN3 (50 mg, 0.77 mmol) and 15-crown-5 (100 µL,
0.51 mmol) were added and the mixture was stirred at room temp.
for 16 h. H2O (10 mL) was added and the aqueous phase was ex-
tracted twice with CH2Cl2. The combined organic phases were
dried (MgSO4) and flash chromatography (toluene/ethyl acetate,
(CH2CH3), 60.06 (C-3), 31.39 (C-2), 13.97 (CH2CH3) ppm. [α]2D4
ϭ
Ϫ197.4 (c ϭ 1, CHCl3). FAB-MS: m/z ϭ 368 [M ϩ Hϩ], 390 [M
ϩ Na]ϩ. C17H21NO6S (367.42): calcd. C 55.57, H 5.76, N 3.81;
found C 56.30, H 5.57, N 3.90.
Analytical Data of the Minor Product
1
Ethyl 2-[(2S,3S,4R,5S)-3-Benzyloxy-2-benzylsulfanyl-4,5-dihydroxy-
2:1) yielded 12 (130 mg, 0.33 mmol, 83%) (Rf ϭ 0.37) as an oil. H
6-oxopiperidin-1-yl]acrylate (14): 1H NMR (600 MHz, [D6]DMSO): NMR (600 MHz, [D6]DMSO): δ ϭ 7.35 (m, 5 H, Ph), 6.06 (d, 3J7-
δ ϭ 7.30 (m, 10 H, Ph), 6.24 (s, 1 H, 3-Hl), 5.74 (s, 1 H, 3-Hh),
ϭ 5.0 Hz, 1 H, 7-OH), 5.22 (dd, J3,2l ϭ 7.0, J3,2h ϭ 2.6 Hz,
3
3
OH,7
3
3
3
2
5.48 (d, J4-OH,4 ϭ 3.8 Hz, 1 H, 4-OH), 5.25 (d, J5-OH,5 ϭ 5.3 Hz, 1 H, 3 H), 5.17 (d, J8a,8 ϭ 2.1 Hz, 1 H, 8a-H), 4.71 (d, Jgem
ϭ
3
2
1 H, 5-OH), 5.09 (d, J2,3 ϭ 4.4 Hz, 1 H, 2-H), 4.65 (m, 2 H, 11.7 Hz, 1 H, CH2Ph), 4.62 (d, Jgem ϭ 12.0 Hz, 1 H, CH2-Ph),
3
3
PhCH2), 4.37 (pt, J5,5-OH/7 ϭ 4.4 Hz, 1 H, 5-H), 4.1 (m, 3 H, 7-
4.31 (d, J6,7 ϭ 5.9 Hz, 1 H, 6-H), 4.13 (m, 2 H, CH2CH3), 3.80
H, CH2CH3), 3.89 (pt, 3J3,2/4 ϭ 4.4 Hz, 1 H, 3-H), 3.85 (d, 2Jgem ϭ (m, 1 H, 7-H), 3.75 (pt, J8,8a/7 ϭ 2.6 Hz, 1 H, 8-H), 3.23 (dd,
3
12.9 Hz, 1 H, PhCH2S), 3.76 (d, Jgem ϭ 12.6 Hz, 1 H, PhCH2S), 2Jgem ϭ 11.4, J2l, 3 ϭ 7.0 Hz, 1 H, 2-Hl), 3.13 (dd, Jgem ϭ 11.4,
2
3
2
1.17 (t, 3JEt ϭ 7.3 Hz, 3 H, CH2CH3) ppm. 13C NMR: δ ϭ 171.27, 3J2h,3 ϭ 2.6 Hz, 1 H, 2-Hh), 1.19 (t, JEt ϭ 7.0 Hz, 3 H, CH2CH3)
3
163.14 (C-6, CO2), 138.16, 137.94 137.76 (Ph, C-2), 128.85, 128.44, ppm. 13C NMR: δ ϭ 169.11, 164.70 (C-5, CO2), 137.85, 128.26,
128.25, 127.72, 127.66, 127.06 (Ph), 123.36 (C-3 acrylic ester), 79.63 127.62, 127.53 (Ph), 79.39 (C-8), 71.69 (CH2Ph), 71.06 (C-7), 64.06
(C-3), 72.22 (OCH2Ph), 69.62 (C-4), 67.62 (C-5), 65.80 (C-2), 60.83
(C-6), 61.82 (C-8a), 61.37 (CH2CH3) 61.20 (C-3), 31.55 (C-2), 13.97
(CH2CH3), 36.03 (SCH2Ph), 13.90 (CH2CH3) ppm. [α]2D4 ϭ Ϫ53.2 (CH2CH3) ppm. [α]2D4 ϭ Ϫ49.6 (c ϭ 1, CHCl3). FAB-MS: m/z ϭ
(c ϭ 1, CHCl3). FAB-MS: m/z ϭ 480 [M ϩ Na]ϩ, 502 [M ϩ 2 Naϩ 393 [M ϩ H]ϩ, 415 [M ϩ Na]ϩ, 565 [M ϩ 2 Na ϩ I]ϩ.
Ϫ Hϩ]ϩ, 630 [M ϩ 2 Na ϩ I]ϩ.
Ethyl (3R,6R,7R,8S,8aS)-8-Benzyloxy-6-tert-butoxycarbonylamino-
Ethyl (3R,6S,7R,8S,8aS)-8-benzyloxy-7-hydroxy-5-oxo-6-(trifluoro- 7-hydroxy-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carb-
methanesulfonyloxy)hexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-
carboxylate (11): Compound 10 (450 mg, 1.2 mmol) and DMAP
(9 mg) were dissolved in CH2Cl2 (50 mL). The solution was cooled
to Ϫ30 °C and Tf2O (300 µL, 1.8 mmol, 1.5 equiv.) was added. The
solution was cooled to Ϫ50 °C and pyridine (3 mL) was added.
The mixture was warmed to room temperature, stirred for 2 h, and
then the solvent was evaporated. The residue was dissolved in ethyl
acetate (100 mL) and H2O (20 mL), and the aqueous phase was
extracted twice with ethyl acetate and the combined organic phases
oxylate (13): Azide 12 (90 mg, 0.23 mmol) was dissolved in pyrid-
ine/H2O (2:1, 23 mL). H2S was bubbled through the solution for
10 min and then the reaction mixture was stirred at room temp. for
16 h. The solvent was evaporated and the residue dissolved in
CH2Cl2 (30 mL). Boc2O (100 mg, 0.46 mmol) and DIPEA (40 µL)
were added and the solution was stirred for 16 h at room temp.,
before being concentrated in vacuo. The product was isolated by
flash chromatography (toluene/ethyl acetate, 2:1) to yield 13
(93 mg, 0.2 mmol, 87%) (Rf
ϭ
0.4). 1H NMR (600 MHz,
3
were dried (MgSO4). Flash chromatography (toluene/ethyl acetate, [D6]DMSO): δ ϭ 7.30 (m, 5 H, Ph), 7.03 (d, JNHBoc,6 ϭ 9.1 Hz, 1
5:1) yielded 11 (228 mg, 0.46 mmol, 38%) (Rf ϭ 0.26) and the side
H, BocNH), 5.61 (d, 3J7-OH,7 ϭ 5.9 Hz, 7-OH), 5.10 (m, 2 H, 3, 8a),
4.69 (d, 2J gem ϭ 11.7 Hz, 1 H, CH2Ph), 4.56 (d, 2Jgem ϭ 12.0 Hz, 1
H, CH2Ph), 4.10 (m, 2 H, CH2CH3), 4.05 (pt, 3J6,7/NHBoc ϭ 8.2 Hz,
product 15 (217 mg, 0.45 mmol, 37%) (Rf ϭ 0.54). 1H NMR
(600 MHz, [D6]DMSO): δ ϭ 7.35 (m, 5 H, Ph), 6.61 (d, 3J7-OH,7
Eur. J. Org. Chem. 2003, 878Ϫ884
ϭ
883

P. Tremmel, J. Brand, V. Knapp, A. Geyer
FULL PAPER
rahedron Lett. 1999, 40, 477Ϫ478. [4b] A. Geyer, F. Moser, Eur.
1 H, 6-H), 3.84 (m, 1 H, 7-H), 3.69 (m, 1 H, 8-H), 3.20 (dd, 2Jgem ϭ
[4c]
3
2
11.4, J2t,3 ϭ 7.3 Hz, 1 H, 2-Hl), 3.10 (d, Jgem ϭ 11.2 Hz, 1 H, 2-
J. Org. Chem. 2000, 1113Ϫ1120.
P. Tremmel, A. Geyer, J.
Am. Chem. Soc. 2002, 124, 8548Ϫ8549.
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3
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ppm. 13C NMR: δ ϭ 169.47, 166.64 (C-5, CO2), 155.80 (COtBu),
138.01, 128.20, 127.52, 127.48 (Ph), 82.24 (C-8), 77.88 (Cq tBu),
71.32 (CH2Ph), 70.68 (C-7), 61.65 (C-8a), 61.24 (CH2CH3), 61.11
(C-3), 57.26 (C-6), 31.74 (C-2), 28.23 (CH3 tBu), 13.98 (CH3CH3)
ppm. FAB-MS: m/z ϭ 467 [M ϩ H]ϩ, 489 [M ϩ Na]ϩ.
C22H30N2O7S (466.55): calcd. C 56.63, H 6.48, N 6.00; found C
56.64, H 6.77, N 6.15.
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Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged.
The authors thank Dr. M. Zabel (Universität Regensburg) for the
crystal structure analyses of 4 and 8.
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