Synthesis of diaminosuberic acid derivatives via ring-closing alkyne metathesis

Full text of DOI:10.1021/jo001734x

3584
J . Org. Chem. 2001, 66, 3584-3589
Notes
Syn th esis of Dia m in osu ber ic Acid
Der iva tives via Rin g-Closin g Alk yn e
Meta th esis
Begon˜a Aguilera,† Larissa B. Wolf,‡ Piotr Nieczypor,‡
Floris P. J . T. Rutjes,*,§ Herman S. Overkleeft,†
J an C. M. van Hest,§ Hans E. Schoemaker,| Bing Wang,|
J ohannes C. Mol,‡ Alois Fu¨rstner, Mark Overhand,†
Gijs. A. van der Marel,† and J acques H. van Boom*,†
F igu r e 1.
Leiden Institute of Chemistry, Leiden University,
Einsteinweg 55, 2300 RA Leiden, The Netherlands, Institute
of Molecular Chemistry,University of Amsterdam, Nieuwe
Achtergracht 129, 1018 WS Amsterdam, The Netherlands,
Department of Organic Chemistry, University of Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands, DSM
Research, Life Science Products, PO Box 18, 6160 MD
Geleen, The Netherlands, and Max Planck Institut fu¨r
Kohlenforschung, Mulheim a/ d Ruhr, Germany
DAS via reduction of the double bond. Not surprisingly,
the higher conformational freedom of the alkyl chain of
DAS in comparison with disulfide linkages appeared an
incentive for the development of conformationally re-
stricted cystine isosteres.7 In pursuing a similar goal, we
here report the synthesis of the constrained analogues 3
and 4 (Figure 1) containing an Z-alkene or alkyne
functionality, respectively.
Recently,8 an efficient ring-closing alkyne metathesis
(RCAM) reaction using the tungsten-alkylidyne complex
(tBuO)3WtCtBu (5)9 as the precatalyst has been intro-
duced to produce cycloalkynes from the corresponding
Me-terminated dialkynes. In the process of creating
macrocyclic rings, RCAM has the advantage over RCM
that the formation of geometrical isomers is circum-
vented. Having developed an efficient and reliable bio-
catalytic method for the synthesis of unsaturated amino
acids in both enantiomerically pure forms,10 we envisaged
that application of tailor-made acetylene-containing amino
acids in a tungsten-catalyzed RCAM strategy would give
access to cystine isosteres 3 and 4.
Enantiopure (S)-2-tert-butoxycarbonylamino-hex-4-
ynoic acid (S)-(6) was condensed in a two-step procedure
with either 1,2-ethanediol, 1,2-, or 1,3-benzenedimethanol
to afford (Scheme 1) the corresponding tethered adducts
(S,S)-10, (S,S)-11, and (S,S)-12, in satisfactory overall
yields. RCAM of the latter individual compounds medi-
ated by the tungsten catalyst 5 (6 mol %, chlorobenzene,
3 h, 80 °C) led to the cyclic acetylenes (S,S)-13, (S,S)-14,
and (S,S)-15 in 48, 66, and 84% yield, respectively. Small
amounts of cyclodimeric products were also detected. The
substantial increase in yield of 15 may be attributed
either to the larger ring size or to a more favorable
boom@chem.leidenuniv.nl
Received December 13, 2000
In tr od u ction
The side chains of cysteine residues in peptides and
proteins are often involved in disulfide linkages (viz.
cystine (1) in Figure 1). The presence of one or more
covalent disulfide bridge(s) is important for the structural
and functional properties of many polypeptides. Cystine
isosteres have been developed to improve the stability of
biologically active peptides since disulfide bonds are
chemically and metabolically labile. The most frequently
exploited isostere is the dicarba analogue (2S,7S)-2,7
-diaminosuberic acid (DAS, 2)1 which has been synthe-
sized by several groups.2-6 A straightforward approach
to DAS proceeds via ring-closing alkene metathesis
(RCM). As shown independently by three groups,6 RCM
of two suitably tethered 2-amino-4-pentenoic acid deriva-
tives led to mixtures of the corresponding (E)- and (Z)-
cycloalkenes, which were conveniently transformed into
† Leiden University. Tel +31-71-5274274. Fax +31-71-5274307.
‡ University of Amsterdam.
§ University of Nijmegen.
| DSM Research.
Max Planck Institut fu¨r Kolenforschung.
(1) (a) Walker, R.; Yamanaka, T.; Sakakibara, S. Proc. Natl. Acad.
Sci. U.S.A. 1974, 71, 1901. (b) Nutt, R. F.; Veber, D. F.; Saperstein, R.
J . Am. Chem. Soc. 1980, 102, 6539.
(7) For a previous synthesis of unsaturated and bis-hydroxylated
(S,S)-2,7-diaminosuberic acid derivatives, see: Kremminger, P.; Und-
heim, K. Tetrahedron 1997, 53, 6925.
(2) (a) Hiebl, J .; Blanka, M.; Guttman, A.; Kollmann, H.; Leitner,
K.; Mayrhofer, G.; Rovenszky, F.; Winkler, K. Tetrahedron 1998, 54,
2059. (b) Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J .
Org. Chem. 1980, 45, 3078.
(3) (a) Lange, M.; Fisher, P. M. Helv. Chim. Acta 1998, 81, 2053.
(b) Williams, R. M.; Yuan, C. G. J . Org. Chem. 1992, 57, 6519. (c)
Callahan, J . F.; Khatana, S. S.; Bhatnagar, P. K. Synth. Commun.
2000, 30. 1213.
(4) Mazo´n, A.; Najera, C.; Ezquerra, J .; Pedregal, C. Tetrahedron
Lett. 1995, 36, 7697.
(5) Hiebl, J .; Kollmann, H.; Rovenszky, F.; Winkler, K. J . Org. Chem.
1999, 64, 1947.
(8) Fu¨rstner, A.; Seidel, G. Angew. Chem., Int. Ed. 1998, 37, 1734.
(b) Fu¨rstner, A., Mathes, C.; Lehmann, C. W. J . Am. Chem. Soc. 1999,
121, 9453. (c) Bunz, U. H. F.; Kloppenburg, L. Angew. Chem., Int. Ed.
Engl. 1999, 38, 478. (d) Fu¨rstner, A.; Rumbo, A. J . Org. Chem. 2000,
65, 2608. (e) Fu¨rstner, A.; Grela K. Angew. Chem., Int. Ed. 2000, 39,
1234. For the first examples of alkyne metathesis reaction with a
defined alkylidyne catalyst, see: (f) Wengrovius, J . H.; Sancho, J .;
Schrock, R. R. J . Am. Chem. Soc. 1981, 103, 3932. (g) Schrock, R. R.
Polyhedron 1995, 14, 3177.
(9) (a) Listemann, M. L.; Schrock, R. R. Organometallics 1985, 4,
74. (b) Akiyama, M.; Chisholm, M. H.; Cotton, F. A.; Extine, M. W.;
Haitko, D. A.; Little, D.; Fanwick, P. E. Inorg. Chem. 1979, 18, 2266.
(10) Sonke, T.; Kaptein, B.; Boesten, W. H. J .; Broxterman, Q. B.;
Kamphuis, J .; Formaggio, F.; Toniolo, C.; Rutjes, F. P. J . T.; Schoe-
maker, H. E. In Stereoselective Biocatalysis; Patel, R. N., Ed.; Marcel
Dekker: New York, 2000; pp 23-58.
(6) (a) O’Leary, D. J .; Miller, S. J .; Grubbs, R. H. Tetrahedron Lett.
1998, 39, 1689. (b) Williams, R. M.; Liu, J . J . Org. Chem. 1998, 63,
2130. (c) Gao, Y.; Lane-Bell, P.; Vederas, J . C. J . Org. Chem. 1998, 63,
2133.
10.1021/jo001734x CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/19/2001

Notes
J . Org. Chem., Vol. 66, No. 10, 2001 3585
Sch em e 1
Sch em e 2
To incorporate the diamino dicarboxylic acids 2, 3, or
4 into peptides, the availability of orthogonally protected
derivatives is required. For instance, the orthogonally
protected adduct 22 was prepared from (R)-2-tert-butoxy-
carbonylamino-hex-4-ynoic acid (R)-6 in four steps by a
slight modification of the route reported by Williams et
al.6b (Scheme 3). Thus, tungsten mediated cyclization of
22 gave cycloalkyne 23 in 66% yield, showing that all
protective groups were compatible with the RCAM pro-
cess. Catalytic hydrogenation of 23 and subsequent
protection of the resulting amine with an Fmoc group
finally furnished the orthogonally protected (2R,7R)-2,7-
diaminosuberic acid derivative 24 in 76% yield.
In summary, the ring closing alkyne metathesis reac-
tion of 2-amino-4-hexynoic acid derivatives catalyzed by
5 proved to be a useful tool for the synthesis of several
cystine isosters. The methodology allows the asymmetric
preparation of saturated and unsaturated cystine isos-
teres as the free diamino dicarboxylic acids or in orthogo-
nally protected form. While the availability of both
enantiomers of the starting amino acids ensures access
to all possible diastereomers, selective reduction of the
triple bond allows the synthesis of geometrically pure
conformationally restricted DAS derivatives. Adaptation
of this approach to the synthesis of orthogonally protected
derivatives of 3 and 4 will be reported in due course.
orientation of the alkylidene functionalities in adduct 12
in comparison to 10 and 11. To investigate if no epimer-
ization took place during the ring closure conditions, we
also prepared the meso-derivative (S,R)-10. To this end,
enantiopure (S)-6 and (R)-6 were tethered with ethylene
glycol following a two-step procedure as described for the
synthesis of (S,S)-7. Subjection of (S,R)-10 to the tungsten-
mediated cyclization conditions gave (S,R)-13. Compari-
son of the 13C NMR data of compounds (S,S)- and (S,R)-
13 showed in each case a single set of peaks indicating,
within the limits of the 13C spectra, that no epimerization
had taken place.11 Additionally, starting from (R)-2 -tert-
butoxycarbonylamino-hex-4-ynoic acid, adducts (R,R)-11
and (R,R)-12 were synthesized and cyclized under the
action of the tungsten catalyst 5. Thus, cyclic compounds
(R,R)-14 and (R,R)-15 were obtained in a similar yield
as their enantiomers.
At this stage, the cyclic alkynes were transformed
(Scheme 2) into several cystine isosteres. Lindlar reduc-
tion of cycloalkyne (S,S)-13 followed by cleavage of the
ester linkages and deprotection of the Boc protecting
groups with TFA provided Z-alkene 3. In addition,
saponification of (S,S)-13 with LiOH followed by cleavage
of the Boc groups gave the acetylenic cystine isostere 4
in good overall yield. Alternatively, as an illustration that
this approach can provide access to several diastereoi-
somers of diaminosuberic acid derivatives, exhaustive
catalytic hydrogenation of (R,R)-14 gave 18,2a and sub-
sequent removal of the Boc protecting groups furnished
(2R,7R)-2,7-diaminosuberic acid, the analytical data of
which were in full accord with those previously reported.3b
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise indicated, all reagents
were obtained from commercial suppliers and were used without
further purification. Solvents were dried according to established
procedures by distillation from an appropriate drying agent
under an inert atmosphere. Reactions involving air- or moisture-
sensitive reagents or intermediates were performed under argon
in glassware that had been flame-dried. Flash chromatography
was performed using Merck silica gel 60 (230-400 mesh). ESI
mass spectra were collected by constant infusion of the sample
dissolved in methanol/water with 1% HOAc. ESI is a soft
ionization technique, resulting in protonated, sodiated species
in positive ionization mode and deprotonated, chlorated or [M
+ acetic acid]- in negative ionization mode.
Gen er a l P r oced u r e I: Syn th esis of Mon oester s. N,N′-
Dicyclohexylcarbodiimide (1.3 equiv) was added to a solution of
(S)-6 (or (R)-6 when appropriate), the diol tether (3-5 equiv),
and DMAP (0.14 equiv) in CH2Cl2 (0.04 M) at 0 °C. The reaction
mixture was allowed to warm slowly and stirred overnight at
room temperature. The solid was filtered off, and the solvent
was concentrated under reduced pressure. EtOAc was added to
(11) A 13C NMR spectrum of a 1:1 mixture of (S,S)- and (S,R)-13
was measured in CDCl3 and compared with the 13C NMR spectra of
the reaction products (S,S)- and (S,R)-13. While the 13C NMR spectrum
of the 1:1 mixture showed a double set of peaks, only a single set of
peaks was observed in the 13C NMR spectra of (S,S)- and (S,R)-13,
indicating (within the detection limit of the 13C NMR (e5%)) that no
epimerization took place under the reaction conditions. The 13C NMR
spectra of (S,S)-, (S,R)-13, and the mixture of both compounds are
available as Supporting Information.

3586 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
Sch em e 3
the reaction mixture, the solid was filtered off again, and the
solvent concentrated. The crude product was purified by column
chromatography (20% f 100% ether/petroleum ether).
Gen er a l P r oced u r e II: Syn th esis of Diester s. A solution
of DMAP (3 equiv), DMAP‚HCl (2 equiv), and N,N′-dicyclohexy-
lcarbodiimide (2 equiv) in CH2Cl2 (10 mL/mmol DMAP) was
refluxed for 10 min. A solution of (S)-6 (1 equiv) (or (R)-6 when
appropriate) and the monoester compound (obtained following
the general procedure I) in CH2Cl2 (16 mL/mmol compound) was
added to the reaction mixture and stirred under reflux for 16 h.
The reaction mixture was washed with 1 M HCl/H2O (1:5) and
saturated aqueous NaHCO3/H2O (1:5). The organic layer was
dried (MgSO4) and concentrated and the crude product purified
by column chromatography (20% f 100% ether/petroleum
ether).
Gen er a l P r oced u r e III: Rin g-Closin g Alk yn e Meta th e-
sis (RCAM) Rea ction . The reaction was performed under an
argon atmosphere. To a solution of 5 (6% mol) in dry C6H5Cl
(0.02 M final concentration) was added the diyne dissolved in
C6H5Cl, and the reaction mixture was stirred at 80 °C for 1-3
h. The solvent was then concentrated, and the crude product
was purified by column chromatography (20% f 100% ether/
petroleum ether).
organic layers were dried (MgSO4) and evaporated. The residue
was dissolved in acetone (700 mL), concentrated HCl (7.8 mL,
0.2 mol) was added, and the reaction mixture was stirred for 3
h. The resulting solid was filtered off to give 2-a m in o-4-
h exyn oic a cid a m id e as a white powder (13.5 g, 0.083 mol,
66% overall yield). Decomp (HCl salt) >243 °C, 1H NMR (400
MHz, D2O) δ 1.79 (t, J ) 2.4 Hz, 3H), 2.53-2.55 (m, 2H), 3.55
(t, J ) 5.8 Hz, 1H). 13C NMR (100 MHz, D2O) δ 5.4, 24.3, 54.4,
73.7, 85.3, 173.5. HRMS (EI) calculated for C6H11N2O 126.0793,
found 126.0790.
E n zym a t ic R esolu t ion of 2-Am in o-4-h exyn oic Acid
Am id e. A solution of the HCl salt of the racemic amide (12 g,
0.073 mol) in distilled H2O (80 mL) was brought to pH 9.2 with
KOH, followed by addition of an 80 mM solution of MnSO4 until
a 1 mM concentration was reached. The H2O was added until a
volume of 120 mL was reached. Then whole E. coli DH5a/
pTrpLAP cells10 (48 mg) in a HEPES buffer (1 mL) were added.
The reaction mixture was shaken at 40 °C for 24 h. The reaction
mixture was brought to pH 6 by carefully adding H2SO4. The
enzyme was filtered off the solution, and by adding NaOH the
pH was brought at 8-9; then benzaldehyde (4.09 mL, 0.036 mol)
was added, and the reaction mixture was stirred vigorously for
2 h. The resulting suspension was extracted with CH2Cl2 (3 ×),
and the combined organic layers containing the Schiff base of
the (R)-amide were dried (MgSO4), filtrated, and concentrated.
The residue was dissolved in acetone, concentrated HCl (2.8 mL,
0.036 mmol) was added dropwise, and the mixture was stirred
for 2 h. The solid was filtered off to give the HCl-salt of (R)-2-
a m in o-4-h exyn oic a cid a m id e as a white solid (4.01 g, 0.024
mol, 33%): ee 99% (HPLC, Crownpak CR(+)), [R]D ) +10.5 (c
) 1, H2O). Anal. Calcd for C6H11N2OCl: C 44.32, H 6.82, N 17.23.
Found: C 44.11, H 6.76, N 17.11.
r a c-2-Am in o-4-h exyn oic Acid Am id e. A solution of diphe-
nylketimine12 (29.5 g, 0.125 mol) in THF (500 mL) was treated
with NaH (5.00 g, 0.125 mol) and LiI (0.53 g, 0.013 mol). After
stirring for 20 min, a solution of 1-bromo-2-butyne (20.0 g, 0.15
mol) in THF (100 mL) was slowly added over a period of 1 h.
After refluxing for 48 h, the mixture was cooled and evaporated,
and the residue was dissolved in saturated aqueous NH4Cl (400
mL). This solution was extracted with ether (3 × 400 mL), and
the combined organic layers were dried (MgSO4) and evaporated
to give the crude product (45.3 g) as a white solid, which was
directly subjected to the next reaction. Rf ) 0.63 (50% ether in
The aqueous layer containing the (S)-acid was lyophilized and
the residue was purified over a strongly acidic (Dowex 50W) ion
exchange column to give (S)-2-a m in o-4-h exyn oic a cid as a
white solid (4.0 g, 0.032 mol, 43%): ee 99% (HPLC, Crownpak
1
petroleum ether). H NMR (400 MHz, CDCl3) δ 1.72 (t, J ) 2.5
Hz, 3H), 2.83-2.66 (m, 2H), 3.73 (s, 3H), 4.25 (dd, J ) 5.2, 8.2
Hz, 1H), 7.22-7.63 (m, 8H), 7.65 (d, J ) 7.2 Hz, 2H).
1
CR(+)), mp 238-240 °C. [R]D ) -35.3 (c ) 1 in H2O). H NMR
A solution of the crude product in ether (500 mL) was treated
carefully with a 1 M aqueous solution of HCl (125 mL, 0.125
mol) at 0 °C. After vigorously stirring for 16 h, the layers were
separated, and the ether layer was evaporated to give the HCl
salt of the crude amino methyl ester. This was immediately
dissolved in H2O (200 mL), NH4OH (300 mL of a 25% solution
in H2O) was added, and the reaction mixture was stirred for 3
h. The mixture was evaporated and the residue dissolved in H2O
(400 mL). The pH was raised to 9 by adding 1 M aqueous NaOH,
benzaldehyde (9.77 mL, 0.095 mol) was added, and the reaction
mixture was vigorously stirred for 4 h. The resulting Schiff base
was extracted with CH2Cl2 (3 × 300 mL), and the combined
(400 MHz, D2O) δ 1.77 (t, J ) 2.3 Hz, 3H), 2.76-2.77 (m, 2H),
3.83-3.85 (m, 1H). 13C NMR (100 MHz, D2O) δ 5.2, 23.6, 56.1,
74.7, 84.3, 175.9. Anal. Calcd for C6H9NO2: C 56.68, H 7.13, N
11.02, O 25.07. Found: C 56.33, H 6.95, N 10.77.
(R)-2-Am in o-4-h exyn oic Acid . The (R)-amino acid amide
(2.00 g, 0.024 mol) was dissolved in a phosphate buffer (pH 8,
40 mL), lyophilized whole cells of Rhodoccocus erythropolis NCIB
11540 (0.4 g) were added, and the mixture was shaken at 37 °C
for 3 h. The reaction was monitored with TLC. After complete
conversion, the mixture was centrifuged to separate the solvent
from the enzyme. The water layer was lyophilized and the
residue was purified with ion exchange chromatography (Dowex
50W) to obtain (R)-2-a m in o-4-h exyn oic a cid (1.44 g, 0.012 mol,
(12) O’Donnell, M. J .; Wojciechowski, K. Synthesis 1984, 313.

Notes
J . Org. Chem., Vol. 66, No. 10, 2001 3587
92%) as a white solid: ee 99% (HPLC, Crownpak CR(+)), [R]D
) +42.8 (c ) 1 in H2O).
1H NMR (CDCl3, 400 MHz) δ 1.43 (s, 18H), 1.68 (s, 6H), 2.61
(m, 4H), 4.43 (m, 2H), 5.32 (m, 6H), 7.39 (m, 4H). 13C NMR
(CDCl3, 100 MHz) 3.29, 22.94, 28.15, 52.30, 64.44. 72.78, 79.26,
79.94, 128.31, 128.65, 129.54, 129.63, 133.88, 155.02, 170.66.
HRMS (FAB +) m/z (M + 1)+: calculated for C30H41N2O8
557.2863, found 557.2858.
(S)-2 -ter t-Bu toxyca r bon yla m in o-h ex-4-yn oic Acid (S)-
6. (S)-2-amino-4-hexynoic acid (500 mg, 3.93 mmol) was dissolved
in a mixture of water (10 mL), dioxane (20 mL) and NaOH (10
mL). Di-tert-butyl dicarbonate (1.2 equiv, 4.72 mmol) was added
at 0 °C and stirring was continued at room temperature for 3 h.
The dioxane was partially removed under reduced pressure,
EtOAc (10 mL) was added and the water layer was acidified
with KHSO4 0.1 M to pH≈ 4. The aqueous layer was extracted
with EtOAc (4 × 20 mL). The combined organic layers were dried
(MgSO4) and concentrated. After purification of the crude
product by column chromatography (95% ether, 5% AcOH),
compound (S)-6 (705 mg, 79%) was obtained as an amorphous
solid. Rf ) 0.10 (95% ether, 5% AcOH). mp 132-133 °C. [R]D)
+3.55 (c )1, CH2Cl2). 1H NMR (400 MHz, CDCl3) δ 1.23 (s, 9H),
1.78 (t, 3H, J ) 2.5 Hz), 2.74-2.67 (m, 2H), 4.43-4.42 (m, 1H),
5.29-5.28 (m, 1H), 10.27 (s, 1H). 13C NMR (100 MHz, CDCl3) δ
3.37, 22.65, 28.15, 52.01, 72.68, 79.35, 80.32, 155.35, 175.63.
HRMS (EI): calculated for C11H17NO4 227.1158, found 227.1165.
(R)-2 -ter t-Bu toxyca r bon yla m in o-h ex-4-yn oic Acid (R)-
6. Compound (R)-6 was obtained following the same procedure
as described for (S)-6 starting from of (R)-2-amino-4-hexynoic
acid (500 mg, 3.93 mmol) in 81% yield. All the other physical
data were in accord with those reported for (S)-6. [R]D) -3.52
(c )1, CH2Cl2).
(S)- 2-ter t-Bu toxycar bon ylam in o-h ex-4-yn oic Acid 3-((S)-
2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oyloxym eth yl)ben -
zyl Ester ((S,S)-12). Compound 12 was prepared following the
general procedure II starting from (S)-6 (1 equiv, 0.22 mmol,
50 mg) and 9 (76 mg, 0.22 mmol). Yield 97 mg (80%). Rf ) 0.53
1
(70% ether/petroleum ether). [R]D ) -10.1. (c ) 1, CH2Cl2). H
NMR (CDCl3, 400 MHz) δ 1.44 (s, 18H), 1.71 (t, 6H, J ) 2.5
Hz), 2.64 (m, 4H), 4.45 (t, 2H, J ) 4.2 Hz), 5.32 (m,6H), 7.33 (m,
4H). 13C NMR (CDCl3, 100 MHz) 3.34, 22.95, 28.17, 52.26, 66.69,
72.81, 79.25, 79.97, 127.69, 127.95, 128.71, 135.72, 155.06,
170.83. HRMS (FAB +) m/z (M + 1)+: calculated for C30H41N2O8
557.2863, found 557.2872.
((6S,11S)-11-ter t-Bu t oxyca r b on yla m in o-5,12-d ioxo-1,4-
d ioxa cyclod od ec-8-yn -6-yl)ca r ba m ic Acid ter t-Bu tyl Ester
((S,S)-13). It was prepared following the general procedure III
starting from (S,S)-10 (161 mg, 0.34 mmol). Yield 68 mg (48%).
Rf ) 0.15 (70% ether/petroleum ether). [R]D ) +77.7 (c ) 1, CH2-
Cl2). 1H NMR (CDCl3, 400 MHz) δ 1.44 (s, 18H), 2.47 (dd, 2H, J
) 6.2 Hz, J ) 14.9 Hz), 2.79 (m, 2H), 4.38 (m, 2H), 4.47 (m,
2H), 4.57 (m, 2H), 5.22 (d, 2H, J ) 7.6 Hz). 13C NMR (CDCl3,
100 MHz) δ 23.55, 23.79, 28.13, 52.82, 61.96, 77.86, 80.15,
154.69, 170.72. HRMS (FAB +) m/z (M + 1)+: calculated for
(S)-2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oic Acid , 2-Hy-
d r oxyeth yl Ester (7). Compound 7 was obtained following
general procedure I starting from (S)-6 (100 mg, 0.44 mmol) and
ethylene glycol (4 equiv, 1.76 mmol, 98 µL). Yield 101 mg (89%).
Rf ) 0.13 (70% ether/petroleum ether). [R]D ) +15.4 (c ) 1, CH2-
C
20H31N2O8 427.2080, found 427.2082.
((6R,11S)-11-ter t-Bu t oxyca r b on yla m in o-5,12-d ioxo-1,4-
d ioxa cyclod od ec-8-yn -6-yl)ca r ba m ic Acid ter t-Bu tyl Ester
((S,R)-13). It was prepared following the general procedure III
starting from (S,R)-10. Yield 61%. 1H NMR (CDCl3, 300 MHz)
δ 1.45 (s, 18H), 2.50 (dd, 2H, J ) 4.1 Hz, J ) 14.9 Hz), 2.79 (dd,
2H, J ) 3.1 Hz, J ) 14.9 Hz), 4.32 (m, 2H), 4.49 (bs, 2H), 4.62
(m, 2H), 5.34 (d, 2H, J ) 7.6 Hz). 13C NMR (CDCl3, 100 MHz) δ
23.58, 23.83, 28.17, 52.92, 62.35, 77.90, 80.15, 154.75, 170.62.
((8S,13S)-13-ter t-Bu t oxyca r b on yla m in o-7,14-d ioxo-1,6-
d ioxa -[1.6.4]ben zocyclotetr a d ec-10-yn -8-yl)ca r ba m ic Acid
ter t-Bu tyl Ester ((S,S)-14). Compound 14 was prepared fol-
lowing the general procedure III starting from (S,S)-11 (151 mg,
0.27 mmol). Yield 87 mg (66%). Rf ) 0.46 (70% ether/petroleum
ether). [R]D ) +9.0. (c ) 1, CH2Cl2). 1H NMR (CDCl3, 400 MHz)
δ 1.39 (s, 18H), 2.48 (dd, 2H, J ) 4.9 Hz, J ) 15.4 Hz), 2.79 (m,
2H), 4.45 (bs, 2H), 5.23 (m, 6H), 7.38 (s, 4H). 13C NMR (CDCl3,
100 MHz) δ 22.98, 28.12, 52.69, 65.50, 77.25, 80.08, 129.29,
131.64, 133.82, 155.50, 170.72. HRMS (FAB +) m/z (M + 1)+:
calculated for C26H35N2O8 503.2393, found 503.2390.
((5S,10S)-10-ter t-Bu toxyca r bon yla m in o-4,11-d ioxo-3,12-
d ioxa -bicyclo[12.3.1]octa d eca -1(18),14,16-tr ien -7-yn -5-yl)-
ca r ba m ic Acid ter t-Bu tyl Ester ((S,S)-15). Compound 15 was
prepared following the general procedure III starting from (S,S)-
12 (95 mg, 0.17 mmol). Yield 70 mg (84%). Rf ) 0.48 (70% ether/
petroleum ether). [R]D ) -71.2. (c ) 1, CH2Cl2). 1H NMR (CDCl3,
400 MHz) δ 1.45 (s, 18H), 2.68 (m, 2H), 2.80 (m, 2H), 4.49 (m,
2H), 4.82 (d, 2H, J ) 12.6 Hz), 5.34 (d, 2H, J ) 8.3 Hz), 5.69 (d,
2H, J ) 12.6 Hz), 7.28 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ
22.89, 28.18, 51.85, 66.23, 77.82, 80.09, 125.55, 127.63, 128.27,
136.68, 155.03, 170.28. HRMS (FAB +) m/z (M + 1)+: calculated
for C26H35N2O8 503.2393, found 503.2361.
(Z)-(2S,7S)-2,7-Dia m in o-oct-4-en ed ioic Acid TF A Sa lt (3).
(S,S)-13 (72 mg, 0.17 mmol) was dissolved in EtOAc:MeOH (6:
1, 3.5 mL). Quinoline (1 equiv, 0.17 mmol, 20 µL) was added
followed by the Lindlar catalyst (29 mg). The reaction mixture
was stirred under H2 atmosphere at room temperature. After
48 h, an additional amount of Lindlar catalyst (29 mg) and
quinoline (1 equiv, 0.17 mmol, 20 µL) were added, and stirring
was continued for 48 h under H2. Then, the mixture was filtered
over Hyflo. The filtrate was washed with HCl 0.25 M (3 × 10
mL) and water, dried (MgSO4) and concentrated. The crude
product was suspended in MeOH (9.5 mL), LiOH (0.1 M in
water, 2.2 equiv, 0.37 mmol, 3.7 mL) was added, and the mixture
stirred at room temperature for 48 h. After this time, the reaction
mixture was covered with a layer of EtOAc and acidified to pH
≈ 4 with KHSO4 0.1 M. The aqueous phase was extracted with
EtOAc (3 × 10 mL). The combined organics were dried (MgSO4)
and concentrated. The residue was purified by column chroma-
1
Cl2). H NMR (CDCl3, 400 MHz) δ 1.43 (s, 9H), 1.75 (t, 3H, J )
2.5 Hz), 2.58 (s, 1H), 2.62 (m, 2H), 3.79 (m, 2H), 4.24 (m, 1H),
4.36 (m, 2H), 5.33 (d, 1H, J ) 6.8 Hz), 13C NMR (CDCl3, 100
MHz) δ 3.33, 22.77, 28.15, 52.45, 60.65, 66.88, 73.04, 79.30,
80.20, 155.31, 171.10. HRMS (FAB +) m/z (M + 1)+: calculated
for C13H22NO5 272.1498, found 272.1496.
(S)-2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oic Acid , 2-Hy-
d r oxym eth ylben zyl Ester (8). Compound 8 was obtained
following general procedure I starting from (S)-6 (100 mg, 0.44
mmol) and 1,2-benzenedimethanol (3 equiv, 182 mg, 1.31 mmol).
Yield 120 mg (79%). Rf ) 0.35 (70% ether/petroleum ether). [R]D
) -5.5 (c ) 1, CH2Cl2). 1H NMR (CDCl3, 400 MHz) δ 1.42 (s,
9H), 1.69 (t, 3H, J ) 2.5 Hz), 2.61 (m, 2H), 4.41 (m, 1H), 4.75 (s,
2H), 5.32 (m, 3H), 7.40 (m, 4H). 13C NMR (CDCl3, 100 MHz) δ
3.28, 22.74, 28.13, 52.35, 62.44, 64.89, 72.85, 79.34, 80.07, 127.78,
128.58, 128.78, 129.70, 133.01, 139.39, 155.18, 170.84. HRMS
(FAB +) m/z (M + 1)+: calculated for C19H26NO5 348.1811, found
348.1803.
(S)-2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oic Acid , 3-Hy-
d r oxym eth ylben zyl Ester (9). Compound 9 was obtained
following the general procedure I starting from (S)-6 (100 mg,
0.44 mmol) and 1,3-benzenedimethanol (4 equiv, 244 mg, 1.76
mmol). Yield 103 mg (67%). Rf ) 0.25 (70% ether/petroleum
ether). [R]D ) -5.2 (c ) 0.5, CH2Cl2). 1H NMR (CDCl3, 400 MHz)
δ 1.42 (s, 9H), 1.69 (t, 3H, J ) 2.5 Hz), 2.61 (m, 2H), 4.42 (m,
1H), 4.75 (s, 2H), 5.33 (m, 3H), 7.35 (m, 4H). 13C NMR (CDCl3,
100 MHz) δ 3.34, 22.90, 28.17, 52.27, 64.76, 66.93, 72.83, 79.29,
80.02, 126.43, 126.73, 127.12, 128.61, 135.60, 141.32, 155.12,
170.89. HRMS (FAB +) m/z (M + 1)+: calculated for C19H26
NO5 348.1811, found 348.1821.
-
(S)- 2-ter t-Bu toxycar bon ylam in o-h ex-4-yn oic Acid 2-((S)-
2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oyloxy)eth yl Ester
((S,S)-10). Compound 10 was prepared following the general
procedure II starting from (S)-6 (1 equiv, 0.39 mmol, 88 mg)
and 7 (100 mg, 0.39 mmol). Yield 177 mg (95%). Rf ) 0.67 (70%
ether/petroleum ether). 1H NMR (CDCl3, 400 MHz) δ 1.42 (s,
18H), 1.72 (t, 6H, J ) 2.4 Hz), 2.61 (m, 4H), 4.34 (m, 6H), 5.27
(m, 2H). 13C NMR (CDCl3, 100 MHz) δ 3.30, 22.87, 28.13, 52.12,
62.67. 72.74, 79.16, 79.91, 154.98, 170.71. HRMS (FAB +) m/z
(M + 1)+: calculated for C24H37N2O8 481.2550, found 481.2540.
(S)- 2-ter t-Bu toxycar bon ylam in o-h ex-4-yn oic Acid 2-((S)-
2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oyloxym eth yl)ben -
zyl Ester ((S,S)-11). Compound 11 was prepared following the
general procedure II starting from (S)-6 (1 equiv, 0.31 mmol,
71 mg) and 8 (108 mg, 0.31 mmol). Yield 172 mg (99%). Rf )
0.67 (70% ether/petroleum ether). [R]D ) +3.5. (c ) 1, CH2Cl2).

3588 J . Org. Chem., Vol. 66, No. 10, 2001
Notes
tography (petroleum ether-EtOAc 2:1 to EtOAc-MeOH 5:1) to
13C NMR (CDCl3, 50 MHz) δ 3.19, 20.72, 22.75, 28.03, 52.29,
66.45, 70.33, 72.88, 79.16, 79.82, 114.79, 115.36, 121.58, 125.07,
125.86, 128.01, 128.28, 128.49, 128.83, 134.53, 136.05, 145.17,
152.21, 155.06, 155.30, 170.77. HRMS (FAB +) m/z (M + 1)+:
calculated for C26H29N2O9 513.1873, found 513.1877.
1
give 16 (41 mg, 56%). H NMR (D2O, 200 MHz) δ 1.42 (s, 18H),
2.43 (m, 4H), 3.96 (m, 1H), 5.51 (m, 1H).13C NMR (CD3OD, 50
MHz) δ 28.43, 30.68, 80.29, 128.39, 157.59, 175.54. To a solution
of 16 (9 mg, 0.022 mmol) in CH2Cl2 (0.25 mL) was added TFA
(0.25 mL), and the reaction mixture was stirred at room
temperature for 10 min. Then, it was concentrated to dryness
and coevaporated with toluene (2 × 5 mL) to give (S,S)-3 (9 mg,
(R)-2-[3-((R)-2-ter t-Bu t oxyca r b on yla m in o-h ex-4-yn oy-
loxym eth yl)ben zyloxycar bon ylam in o]h ex-4-yn oic Acid (21).
To a solution of 20 (1.3 equiv, 2.25 mmol 1.15 g) in dry DMF (9
mL) were added of (R)-2-amino-4-hexynoic acid (1.7 mmol, 215
mg) and DIPEA (2.6 equiv, 4.5 mmol, 780 µL), and the reaction
mixture was stirred at room temperature for 48 h. Then, it was
diluted with EtOAc (50 mL) and acidified with KHSO4 0.1 M
until pH≈4. The aqueous phase was extracted with EtOAc (4 ×
50 mL). The combined organics were dried (MgSO4) and con-
centrated to dryness. The residue was purified by column
chromatography (petroleum ether-EtOAc 4:1 to EtOAc-MeOH
10:1) to give compound 21 (820 mg, 96%). Unreacted carbonate
20 was also recovered (178 mg). Rf ) 0.19 (petroleum ether/
EtOAc 2:1 2% AcOH). [R]D ) +6.2. (c ) 0.8, CH2Cl2). 1H NMR
(CDCl3, 200 MHz) δ 1.39 (s, 9H), 1.67 (s, 6H), 2.66 (m, 4H), 4.41
(m, 2H), 5.08 (m, 4H), 5.40 (d, 1H, J ) 8.7 Hz), 5.74 (d, 1H),
7.27 (s, 4H), 9.29 (bs, 1H). 13C NMR (CDCl3, 50 MHz) δ 3.25,
22.54, 22.85, 28.06, 52.23, 52.59, 66.39, 72.82, 73.00, 79.00, 79.19,
80.03, 86.92, 127.37, 127.65, 128.56, 135.59, 136.62, 155.21,
155.76, 170.83, 173.41. HRMS (EI): calculated for C26H32N2O8
500.2158, found 500.2169.
1
94%). [R]D ) +18.0. (c ) 0.2, H2O). H NMR (D2O, 400 MHz) δ
2.71 (t, 4H, J ) 5.8 Hz), 3.95 (t, 2H, J ) 5.8 Hz), 5.66 (t, 2H, J
) 5.1 Hz). 13C NMR (D2O, 50 MHz) δ 28.80, 54.09, 127.87,
173.63. MS (ESI) m/z ) 263 (M+ 2 H+ + Ac-)
(2S,7S)-2,7-Dia m in o-oct -4-yn ed ioic Acid TF A Sa lt (4).
Compound (S,S)-13 (90 mg, 0.21 mmol) was suspended in
MeOH-H2O (1:1 v/v, 14 mL), LiOH (0.1 M in water, 2.1 equiv,
0.44 mmol, 4.43 mL) was added, and the mixture was stirred at
room temperature for 72 h. After this time, the reaction mixture
was covered with a layer of EtOAc and acidified to pH ≈ 4 with
KHSO4 0.1 M. The aqueous phase was extracted with EtOAc (3
× 10 mL). The combined organics were dried (MgSO4) and
concentrated. The crude was purified by column chromatography
(petroleum ether-EtOAc 2:1 to EtOAc-MeOH 10:1) to give
1
compound 17 (73 mg, 87%). H NMR (CD3OD, 400 MHz) δ 1.42
(s, 9H), 1.46 (s, 9H), 2.45-2.48 m, 4H), 4.22-4.17 (m, 2H). 13C
NMR (CD3OD, 50 MHz) δ 24.49, 28.53, 55.45, 79.29, 80.02,
156.89. Compound 17 (41 mg, 0.1 mmol) was treated with a
mixture TFA-CH2Cl2 (1:1 v/v, 1 mL) at room temperature for
10 min. Then, the reaction mixture was concentrated and
coevaporated with toluene (2 × 5 mL) to give (S,S)-4 (42 mg,
98%). [R]D ) -3.8. (c ) 1.2, H2O). 1H NMR (D2O, 400 MHz) δ
2.85 (m, 4H), 3.93 (t, 2H, J ) 4.2 Hz).13C NMR (D2O, 50 MHz)
(R)-2-ter t-Bu toxyca r bon yla m in oh ex-4-yn oic Acid 3-((R)-
1-ter t-bu toxyca r bon yl-p en t-3-yn ylca r ba m oyloxym eth yl)-
ben zyl Ester (22). To a solution of 21 (320 mg, 0.64 mmol) in
CH2Cl2 (0.33 mL) was added a solution of tert-butyl 2,2,2-
trichloroacetimidate (3 equiv, 1.92 mmol, 419 mg) in cyclohexane
(0.66 mL) followed by BF3‚Et2O (1 M in CH2Cl2, 0.16 equiv, 102
µL), and the reaction mixture was stirred at 20 °C for 5 h. Then,
more tert-butyl 2,2,2-trichloroacetimidate (2 equiv, 1.28 mmol,
280 mg) was added, and stirring was continued for 3 h. The solid
was filtered off, and the solvent was concentrated. A cold mixture
of CH2Cl2:petroleum ether (1:1 v/v, 2 mL) was added, the
precipitated solid was filtered again, and the solvent was
concentrated. The crude mixture was purified by column chro-
matography (petroleum ether-acetone 6:1) to give compound 22
δ 21.06, 52.36, 78.25, 171.58. MS (ESI) m/z ) 261 (M + 2H+
+
Ac-)
(2R,7R)-Dia m in osu ber ic Acid (R,R-2). To a solution of
(R,R)-14 (83.0 mg, 0.17 mmol) in EtOAc (4.0 mL) Pd/C (8.0 mg)
was added. After stirring under an atmosphere of H2 for 4 h,
the reaction mixture was flushed with N2 and filtered over Hyflo.
Purification of the crude product by flash chromatography (95%
ether, 5% AcOH) furnished 182a (68.0 mg, 99%). Rf ) 0.05 (70%
ether/petroleum ether). 1H NMR (400 MHz, CD3OD) δ 1.50-
1.30 (m, 22H), 1.70-1.50 (m, 2H), 1.85-1.70 (m, 2H), 4.05-4.04
(m, 2H). 13C NMR (100 MHz, CDCl3) δ 26.50, 28.75, 32.66, 54.86,
80.48, 158.18, 176.35. A solution of 18 (68.0 mg, 0.17 mmol) in
CH2Cl2 (2.0 mL) and TFA (2.0 mL) was stirred for 16 h at
ambient temperature. After evaporation of the solvents, the
crude product was purified with ion exchange chromatography
(dowex 50 × 4W eluted 2 M NH4OH) which afforded (R,R)-2 (15
mg, 44%). [R]D ) -26.8 (c ) 1, 2 M HCl) [lit. for (2S,7S)-2,7-
diaminosuberic acid [R]D) +24.8 (c ) 0.25, H2O)3b]. 1H NMR
(400 MHz, D2O, HCl) δ 1.53-1.45 (m, 2H), 2.00-1.91 (m, 2H),
4.05 (t, 1H, J ) 6.3 Hz). 13C NMR (100 MHz, D2O, HCl) δ 26.54,
32.11, 55.57, 174.88.
(295 mg, 83%). Rf ) 0.76 (70% ether/petroleum ether). [R]D
)
+10.0. (c ) 1, CH2Cl2). 1H NMR (CDCl3, 200 MHz) δ 1.42 (s,
9H), 1.48 (s, 9H), 1.65 (s, 6H), 2.63 (m, 4H), 4.31 (m, 1H), 4.40
(m, 1H), 5.19 (m, 4H), 5.33 (d, 1H, J ) 8.7 Hz), 5.61 (d, 1H, J )
8.0 Hz), 7.30 (s, 4H). 13C NMR (CDCl3, 50 MHz) δ 3.31, 22.87,
23.08, 27.75, 28.12, 52.25, 52.98, 66.41, 66.74, 79.90, 82.21,
127.54, 127.72, 127.81, 128.63, 135.06, 136.54, 155.43, 169.53,
170.84. HRMS (FAB +) m/z (M + 1)+: calculated for C30H41N2O8
557.2863, found 557.2830.
(6R,11R)-11-ter t-Bu toxyca r bon yla m in o-4,12-d ioxo-3,13-
d ioxa -5-a za -bicyclo[13.3.1]n on a d eca -1(18),15(19),16-tr ien -
8-yn e-6-ca r boxylic Acid ter t-Bu tyl Ester (23). Following the
general procedure for alkyne metathesis, compound 23 was
obtained from 22 (217 mg, 0.39 mmol). Yield 128 mg (66%). Rf
) 0.67 (70% ether/petroleum ether). [R]D ) +22.4. (c ) 1, CH2-
Cl2). 1H NMR (CDCl3, 200 MHz) δ 1.45 (s, 9H), 1.47 (s, 9H),
2.44-2.94 (m, 4H), 4.25 (m, 1H), 4.45 (m, 1H), 4.83 (m, 2H), 5.55
(m, 2H), 5.84 (d, 1H), 7.33 (m, 4H). 13C NMR (CDCl3, 50 MHz)
δ 22.51, 27.79, 28.15, 51.44, 53.02, 65.24, 66.79, 78.13, 79.95,
82.86, 125.86, 126.25, 127.41, 128.13, 136.02, 138.14, 154.88,
155.28, 169.35, 170.75. HRMS (FAB +) m/z (M + 1)+: calculated
for C26H35N2O8 503.2393, found 503.2375.
(2R,7R)-2-ter t-Bu toxyca r bon yla m in o-7-(9H-flu or en -9-yl-
m eth oxyca r bon yla m in o)octa n ed ioic Acid 8-ter t-Bu tyl Es-
ter (24). Compound 23 (45 mg, 0.08 mmol) was dissolved in dry
MeOH (6 mL), and Pd/C (15 mg) was added. The mixture was
stirred under H2 atmosphere overnight at room temperature.
After that, the reaction mixture was filtered over Hyflo and
concentrated. The residue was dissolved in water (1 mL), and
Na2CO3 (2 equiv, 0.16 mmol, 17 mg) and NaHCO3 (4 equiv, 0.32
mmol, 27 mg) were added. Fmoc-OSu (2 equiv, 0.16 mmol, 54
mg) dissolved in 1,4-dioxane (1 mL) was added dropwise at 0
°C. The reaction mixture was stirred at room temperature for 3
h. Then, it was diluted with EtOAc (10 mL) and acidified with
KHSO4 0.1 M until pH 4, and the aqueous phase was extracted
with EtOAc (3 × 10 mL). The combined organics were dried
(MgSO4) and concentrated. The residue was purified by column
(R)-2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oic Acid 3-Hy-
d r oxym eth ylben zyl Ester (19). Compound 19 was prepared
following the general procedure I starting from (R)-6 (885 mg,
3.9 mmol) and 1,3-benzenedimethanol (5 equiv, 19.5 mmol, 2.7
g). Yield 1.05 g (77%). Rf ) 0.26 (70% ether/petroleum ether).
1
[R]D ) +5.6 (c ) 1, CH2Cl2). H NMR (CDCl3, 200 MHz) δ 1.32
(s, 9H), 1.59 (s, 3H), 2.52 (m, 2H), 3.68 (bs, 1H), 4.30 (m, 1H),
4.51 (s, 2H), 5.04 (m, 2H), 5.44 (d, 1H, J ) 8.7 Hz) 7.18 (m, 4H).
13C NMR (CDCl3, 50 MHz) δ 3.31, 22.81, 28.11, 52.25, 64.50,
66.93, 72.81, 79.24, 79.99, 126.39, 126.66, 126.99, 128.51, 135.45,
141.43, 155.10, 170.84. HRMS (FAB +) m/z (M + 1)+: calculated
for C19H26NO5 348.1811, found 348.1841.
(R)-2-ter t-Bu toxyca r bon yla m in o-h ex-4-yn oic Acid 3-(4-
Nitr o-p h en oxyca r bon yloxym eth yl)ben zyl Ester (20). To a
solution of 19 (134 mg, 0.38 mmol) in DMF (5 mL), bis(4-
nitrophenyl) carbonate (2.5 equiv, 0.96 mmol, 292 mg), and
DIPEA (1.5 equiv, 0.57 mmol, 100 µL) were added, and the
reaction mixture was stirred for 16 h at room temperature. Then,
it was poured over EtOAc (50 mL), washed with KOH 0.01 N (7
× 25 mL) and brine (25 mL), dried (MgSO4), and concentrated.
The residue was purified by column chromatography petroleum
ether-EtOAc 5:1 to give 20 (177 mg, 91%). Rf ) 0.80 (70% ether/
petroleum ether). [R]D ) +7.5. (c ) 1, CH2Cl2). 1H NMR (CDCl3,
200 MHz) δ 1.37 (s, 9H), 1.61 (s, 3H), 2.61 (m, 2H), 4.38 (m,
1H), 5.22 (m, 4H), 5.39 (d, 1H, J ) 8.7 Hz), 7.29-8.19 (m, 8H).

Notes
J . Org. Chem., Vol. 66, No. 10, 2001 3589
chromatography (petroleum ether-EtOAc 3:1 f EtOAc-MeOH
10:1) to give compound 24 (35 mg, 76%). [R]D ) -2.0. (c ) 0.6,
CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 1.79 (s, 9H),
1.63 (m, 2H), 1.79 (m, 2H), 2.63 (m, 4H), 4.22 (m, 3H), 4.42 (m,
2H), 5.26 (bs, 1H), 5.49 (bs, 1H), 7.29-7.79 (m, 8H). 13C NMR
(CDCl3, 50 MHz) δ 24.78, 27.85, 28.24, 29.57, 32.43, 46.98, 54.23,
55.14, 66.87, 79.76, 119.78, 125.06, 126.91, 127.51, 141.10,
143.71, 155.95, 171.66. HRMS (EI m/z (M + Na)+: calculated
for C32H42N2O8Na 605.2838, found 605.2847.
acknowledged for providing research grants to L.B. Wolf
and B. Aguilera.
Su p p or t in g In for m a t ion Ava ila b le: Copies of the 13C
spectra of compounds (S)-6, (S)-7, (S)-8, (S)-9, (S,S)-10, (S,S)-
11, (S,S)-12, (S,S)-13, (S,R)-13, 1:1 mixture of (S,S)- and (S,R)-
13, (S,S)-14, (S,S)-15, (S,S)-16, (S,S)-17, (S,S)-3, (S,S)-4, 19,
20, 21, 22, 23, 24. This material is available free of charge via
the Internet at http://pubs.acs.org.
Ack n ow led gm en t. DSM Research and the Spanish
Ministry of Education, Culture and Sport are kindly
J O001734X