Synthesis of D- and L-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-5- hydroxymethylproline and tripeptides containing them

Article abstract of DOI:10.1021/jo049637h

Enantiomerically pure (-)-(1R,4R,5R,6S)- and (+)-(1S,4S,5S,6R)-7-(tert- butoxycarbonyl)-5,6-exoisopropylidenedioxy-7-azabicyclo[2.2.1]hept-2-one ((-)-3 and (+)-3) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrrole and 2-bromo

Full text of DOI:10.1021/jo049637h

Syn th esis of D- a n d L-2,3-tr a n s-3,4-cis-
4,5-tr a n s-3,4-Dih yd r oxy-5-h yd r oxym eth ylp r olin e a n d Tr ip ep tid es
Con ta in in g Th em
Antonio J . Moreno-Vargas,*,†,‡ Inmaculada Robina,‡ Elena Petricci,† and Pierre Vogel†
Laboratoire de Glycochimie et de Synthe`se Asyme´trique, Swiss Federal Institute of Technology (EPFL),
BCH, CH-1015 Lausanne-Dorigny, Switzerland, and Departamento de Qu´ımica Orga´nica de la
Facultad de Qu´ımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
ajmoreno@us.es
Received March 4, 2004
Enantiomerically pure (-)-(1R,4R,5R,6S)- and (+)-(1S,4S,5S,6R)-7-(tert-butoxycarbonyl)-5,6-exo-
isopropylidenedioxy-7-azabicyclo[2.2.1]hept-2-one ((-)-3 and (+)-3) have been obtained from the
Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrrole and 2-bromo-1-(p-toluenesulfonyl)acetylene,
including the Alexakis optical resolution of ketone (()-3 via formation of cyclic aminals with (1R,2R)-
diphenylethylenediamine. Compounds (-)-3 and (+)-3 were converted into D- and L-2,3-trans-3,4-
cis-4,5-trans-N-(tert-butoxycarbonyl)-5-hydroxymethyl-3,4-isopropylidenedioxyprolines (-)-4 and (+)-
4, respectively. Applying the Boc and Fmoc strategies of peptide synthesis, these compounds were
used to construct two tripeptides containing the D- or L-2,3-trans-3,4-cis-4,5-trans-3,4-dihydroxy-
5-hydroxymethylproline.
In tr od u ction
To discover new peptide-based drugs, many structur-
ally rigid non-peptide scaffolds have been designed.
Insertion of these moieties in appropriate sites, a common
approach to restrict the conformational degrees of free-
dom in small peptides, produces the specific three-
dimensional structures required for binding to their
receptors.1 Hydroxylated prolines have been shown to
significantly influence polypeptide secondary structure
in antibiotics.2 Dihydroxyprolines are present in adhesive
proteins produced by marine organisms.3 It should be
recalled that the properties of peptides, and especially
their water solubility, are modified by their degree of
hydroxylation. Additional hydroxyl groups do not affect
the general structure of the peptide containing them.4
The incorporation of 3- or 4-hydroxyproline and of 3,4-
dihydroxyproline moieties into fucopeptides that mimic
F IGURE 1.
the structure of sialyl Lewis X increases the interaction
with E-selectin.5 Also, L-proline and derivatives6 have
shown to be efficient organocatalysts in asymmetric aldol
reactions. All these observations have stimulated the
synthesis of several polyhydroxylated proline deriva-
tives.7
† Swiss Federal Institute of Technology (EPFL).
‡ Universidad de Sevilla.
(1) (a) Recent Advances in Peptidomimetics; Aube´, J ., Guest Ed.;
Tetrahedron Symposia-in-Print, No. 83; Pergamon Press: Oxford,
2000; Tetrahedron 2000, 56 (50). (b) Robinson, J . A. Synlett 2000, 429.
(c) Smith, A. B.; Favor, D. A.; Sprengeler, P. A.; Guzman, M. C.; Carrol,
P. J .; Furst, G. T.; Hirschmann, R. Bioorg. Med. Chem. 1999, 7, 9. (d)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789. (e) Giannis, A.; Kolter, T. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1244.
(2) (a) Morris, S. A.; Schwartz, R. E.; Sesin, D. F.; Masurekar, P.;
Hallada, T. C.; Schwartz, D. M.; Bartizal, K.; Hensens, O. D.; Zink, D.
L. J . Antibiot. 1994, 47, 755. (b) Waite, J . H.; Tanzer, M. L. Science
1981, 212, 1038. (c) Bann, J . G.; Bachinger, H. P. J . Biol. Chem. 2000,
275, 24466.
(5) (a) Lin, C.-C.; Shimazaki, M.; Heck, M.-P.; Aoki, S.; Wang, R.;
Kimura, T.; Ritze`n, H.; Takayama, S.; Wu, S.-H.; Weitz-Schmidt, G.;
Wong, C.-H. J . Am. Chem. Soc. 1996, 118, 6826. (b) Lin, C.-C.; Kimura,
T.; Wu, S. H.; Weitz-Schmidt, G.; Wong, C.-H. Bioorg. Med. Chem. Lett.
1996, 6, 2755.
(6) (a) Northrup, A. B.; MacMillan, D. W. C. J . Am. Chem. Soc. 2002,
124, 6798. (b) Cordova, A.; Notz, W.; Barbas, C. F., III. J . Org. Chem.
2002, 67, 301. (c) Tang, Z.; J iang, F.; Yu, L.-T.; Cui, X.; Gong, L.-Z.;
Mi, A.-Q.; J iang, Y.-Z.; Wu, Y.-D. J . Am. Chem. Soc. 2003, 125, 5262.
(7) (a) El-Ashry, E. H.; El Nemr, A. Carbohydr. Res. 2003, 338,
2265-2290. (b) Garc´ıa, A. L. L.; Correia, C. R. D. Tetrahedron Lett.
2003, 44, 1553. (c) Madhan, A.; Venkateswara, R. Tetrahedron Lett.
2003, 44, 5641. (d) Taylor, C. M.; Barker, W. D.; Weir, C. A.; Park, J .
H. J . Org. Chem. 2002, 67, 4466. (e) Long, D. D.; Frederiksen, S. M.;
Marquess, D. G.; Lane, A. L.; Watkin, D. J .; Winkler, D. A.; Fleet, G.
W. J . Tetrahedron Lett. 1998, 39, 6091. (f) Weir, C. A.; Taylor, C. M.
J . Org. Chem. 1999, 64, 1554.
(3) (a) Taylor, C. M.; Weir, C. A. J . Org. Chem. 2000, 65, 1414. (b)
Taylor, S. W.; Waite, J . H.; Ross, M. M.; Shabanowitz, J .; Hunt, D. F.
J . Am. Chem. Soc. 1994, 116, 10803. (c) Waite, J . H.; Housley, T. J .;
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(4) Strausberg, R. L.; Link, R. P. TIBTECH 1990, 8, 53.
10.1021/jo049637h CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/29/2004
J . Org. Chem. 2004, 69, 4487-4491
4487

Moreno-Vargas et al.
SCHEME 110a
SCHEME 2
Our research group has developed the “naked sugar”
methodology8 which transforms furan into enantiomeri-
cally pure intermediates 19a and 2,9b as examples. The
latter has been converted into a large variety of sugars
and rare analogues.9 As part of our studies on the
chemistry of 7-azabicyclo[2.2.1]heptanes,10 we report
herein the synthesis of enantiomerically pure 7-azanor-
bornanones (+)-3 and (-)-3, two new compounds that are
expected to become key intermediates for the synthesis
of products of biological interest (“naked aza-sugar”
chemistry). They can be easily transformed into the new
polyhydroxyproline derivatives (-)-4 and (+)-4. We shall
also show that the latter can be used in the synthesis of
peptides containing them.
Resu lts a n d Discu ssion
We previously reported the synthesis of enantiomeri-
cally pure â-hydroxysulfone 810a via optical resolution of
alcohol 5 using camphanic acid as chiral auxiliary
(Scheme 1). Desulfonylation of hydroxysulfone (-)-8 was
attempted in different ways. When Bu3SnH/AIBN in
toluene at reflux was employed, the starting material was
recovered. Using SmI2/HMPA in THF at room tempera-
ture, the desired desulfonylated compound (-)-9 was
obtained in 39% yield. However, the use of Na(Hg) (5%)
in dry MeOH-THF at -15 °C increased the yield of (-)-9
up to 75%. The symmetric byproduct 1011 was formed in
10% yield (Scheme 2). Desulfonylation of â-hydroxysul-
fones by applying these conditions corresponds to the
second step of the J ulia olefination,12 and usually, olefins
are obtained in good yields. Swern oxidation of alcohol
(-)-9 led to 7-azanorbornanone derivative (-)-3 in 91%
yield. Starting from the enantiomerically pure alcohol
(+)-8, the corresponding enantiomerically pure 7-azan-
orbornanone (+)-3 was easily synthesized in the same
way.
Recently, we reported the facile optical resolution of
7-azanorbornenone 1110c and 7-oxanorbornenone 113 via
formation of cyclic aminals with commercially available
(1R,2R)-diphenylethylenediamine.14 We thus envisaged
the synthesis of enantiomerically pure ketone (-)-3
starting from (-)-11 by dihydroxylation of its alkene unit
using OsO4/NMO in acetone/H2O (Scheme 3). To our
surprise, the reaction never met with success: a complex
mixture of products was obtained instead of the expected
diol. We then decided to resolve (()-3 with the Alexakis
method.14 The diastereoisomeric aminals (+)-12 and (-)-
13 are thus formed in nearly quantitative yield by
reaction of racemic (()-3 with (1R,2R)-diphenylethylene-
diamine in CH2Cl2 containing MS 4 Å (20 °C, 24 h). The
aminals (+)-12 and (-)-13 could be only separated by
flash chromatography on silica gel (∆RF ) 0.25) doped
with triethylamine (4%). The diastereomerically pure
aminals were then hydrolyzed by treatment with 0.1 M
H3PO4-THF affording enantiomerically pure (+)-3 and
(8) For reviews on the “naked sugars” methodology and applications,
see: (a) Vogel, P. Curr. Org. Chem. 2000, 4, 455. Vogel, P. In
Glycoscience, Chemistry and Biology; Fraser-Reid, B., Tatsuta, K.,
Thiem, J ., Eds.; Springer-Verlag: Berlin, 2001; Vol. II, Chapter 4.4, p
1023. (b) Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett 1990,
173. (c) Vogel, P.; Auberson, Y.; Bimwala, M.; de Guchteneere, E.;
Vieira, E.; Wagner, J . In Trends in Synthetic Carbohydrate Chemistry;
Horton, D., Hawkins, L. D., McGarvey, G. L., Eds.; ACS Symposium
Series 386; American Chemical Society: Washington, D.C., 1989; p
197.
(9) (a) Vieira, E.; Vogel, P. Helv. Chim. Acta 1983, 66, 1865. (b)
Wagner, J .; Vieira, E.; Vogel, P. Helv. Chim. Acta 1988, 71, 624.
(10) (a) Moreno-Vargas, A. J .; Schu¨tz, C.; Scopelliti, R.; Vogel, P. J .
Org. Chem. 2003, 68, 5632. (b) Moreno-Vargas, A. J .; Vogel, P.
Tetrahedron Lett. 2003, 44, 5069. (c) Moreno-Vargas, A. J .; Vogel, P.
Tetrahedron: Asymmetry 2003, 14, 3173.
(13) Foster, A.; Kovac, T.; Mosimann, H.; Renaud, P.; Vogel, P.
Tetrahedron: Asymmetry 1999, 10, 567.
(14) Alexakis, A.; Frutos, J . C.; Mangeney, P. Tetrahedron: Asym-
metry 1993, 4, 2431.
(11) Hodgson, D. M.; Maxwell, C. R.; Miles, T. J .; Paruch, E.;
Matthews, I. R.; Witherington, J . Tetrahedron 2004, 60, 3611.
(12) J ulia, M. Pure Appl. Chem. 1985, 57, 763.
4488 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of 3,4-Dihydroxy-5-hydroxymethylprolines
SCHEME 3
SCHEME 4
(-)-3 in almost quantitative yield. The chiral diamine
was also recovered nearly quantitatively.13
Finally, we explored the possibility of incorporating
polyhydroxylated prolines into peptides with the goal to
generate highly water soluble and conformationally
restricted peptides. We first carried out the incorporation
of polyhydroxylated proline (+)-4 into a tripeptide fol-
lowing the Boc strategy for peptide synthesis. The
coupling of (+)-4 with glycine benzyl ester in the presence
of PyBOP (benzotriazolyloxytrispyrrolidinophosphonium
hexafluorophosphate) as condensating reagent followed
by deprotection of the Boc group using 20% TFA in CH2-
Cl2 gave 17 in 63% overall yield (Scheme 5). The coupling
of 17 with N-Boc-L-phenylalanine presented some dif-
ficulties: (1) the hindered nature of the secondary amine,
(2) the rigidity of the cyclic system, and (3) the inductive
effect of the oxy substituents of the pyrrolidine ring make
the trihydroxyproline derivative 17 a poor nucleophile.
When PyBOP was used as promoter, only traces of the
desired tripeptide were detected. Using BOPCl,17 a more
powerful condensating reagent than PyBOP, the corre-
sponding tripeptide was isolated in 25% yield. Finally,
the use of PyAOP18 (azabenzotriazolyloxytrispyrro-
lidinophosphonium hexafluorophosphate) was necessary
to isolate tripeptide 19 in a good yield (72% after
deprotection of the Boc group using 20% TFA in CH2-
Cl2).
This resolution method is much more convenient than
the one reported earlier10a for (()-8, and enantiomerically
pure ketones (+)-3 and (-)-3 are readily obtained.
To demonstrate the potential of 7-azanorbornanone
derivatives (+)-3 and (-)-3 as suitable building blocks
in the synthesis of new pyrrolidine-based scaffolds, we
studied the opening of the bicyclic moiety following the
chemistry developed previously in our group with oxa-
analogues.15 Treatment of (-)-3 with 4 equiv of Et3N and
N-[(ter t-bu t yl)dim et h ylsilyl]-N-m et h ylt r iflu or oa cet -
amide gave the silyl enol ether (-)-14 in 86% yield
(Scheme 4). Ozonolysis of (-)-14 at -78 °C in MeOH/
CH2Cl2, followed by reduction of the ozonide and the
aldehyde intermediate with NaBH4 (-78 to +20 °C), gave
(-)-4 in 88% yield. To our delight and contrary to the
result obtained with the oxa-analogue,15 the acidic work-
up (pH 2-3) of the latter reaction mixture did not lead
to the lactonization of (-)-4.
To confirm the relative configuration of (-)-4 and to
determine if any epimerization occurred at C-5 during
the ozonolysis and further reductive workup processes,
we carried out the reduction of acid (-)-4 employing
borane dimethyl sulfide complex in THF under reflux
1
which gave diol 15 in 59% yield. The H and 13C NMR
spectra showed the Cs symmetry of this compound. The
2,5-syn configuration was unambiguously assigned for
(-)-4 and 15 by the NMR data (Experimental Section).
Deprotection of 15 under acidic conditions gave the
known16 meso-2,5-dihydroxymethyl-3,4-dihydroxypyrro-
lidine hydrochloride 16 in quantitative yield.
We have also carried out the incorporation of polyhy-
droxylated proline (-)-4 into a tripeptide following the
(17) (a) For a review in coupling methods for N-alkyl amino acids,
see: Humphrey, J . M.; Chamberlin, R. A. Chem. Rev. 1997, 97, 2243.
(b) For the use of BOPCl in difficult couplings, see: Halab, L.; Lubell,
W. D. J . Am. Chem. Soc. 2002, 124, 2474.
(15) Bimwala, R. M.; Vogel, P. Helv. Chim. Acta 1989, 72, 1825.
(16) Ikota, N. Tetrahedron Lett. 1992, 33, 2553.
(18) Albericio, F.; Bofill, J . M.; El-Faham, A.; Kates, S. A. J . Org.
Chem. 1998, 63, 9678.
J . Org. Chem, Vol. 69, No. 13, 2004 4489

Moreno-Vargas et al.
SCHEME 5
cooled to -15 °C. Then, the solution was filtered through
Celite, concentrated in vacuo, and purified by column chro-
matography on silica gel (ether/petroleum ether, 1:1 f 3:1),
eluting first 10 (34 mg, 10%) and second (-)-9 (266 mg, 75%)
as a white solid and a colorless oil, respectively. Data for (-)-
9: [R]D -8 (c 1.0, CH2Cl2); 1H NMR (400 MHz, DMSO-d6, 363
Fmoc strategy for peptide synthesis. The coupling of (-)-4
with L-valine benzyl ester in the presence of PyBOP gave
the corresponding dipeptide in only 40% yield. However,
when PyAOP was used as promoter the yield was
increased significantly as the corresponding dipeptide
was obtained in 66% yield after deprotection of the Boc
and acetonide groups with 80% CF3COOH in H2O.
Removal of the protective groups such as Boc and
acetonide, allows the peptide elongation to continue
without the use of acidic conditions thanks to the Fmoc
strategy. Subsequent coupling reaction of 20 with Fmoc-
L-alanine, using PyAOP/DIEA as activating reagent, gave
the corresponding tripeptide 21 in 70% yield. Tripeptide
21 was characterized as unprotected compound 22, after
deprotection of the Fmoc group under standard conditions
(Et2NH/CH2Cl2), in nearly quantitative yield. The cou-
pling reaction was accomplished without protection of the
triol moiety of the dipeptide 20.
3
K) δ 4.90 (br s, 1 H), 4.71 (d, 1 H, J ) 5.6 Hz), 4.24 (d, 1 H),
3
3
4.07 (dt, 1 H), 3.99 (d, J ) 5.9 Hz), 3.97 (d, J ) 4.8 Hz), 2.02
(ddd, 1 H, 3J ) 9.8 Hz, 2J ) 13.0 Hz), 0.86 (dd, 1 H); 13C NMR
(100.5 MHz, DMSO-d6, 363 K) δ 152.5, 108.3, 80.1, 77.3, 75.9,
66.2, 61.0, 58.4, 32.4, 27.2, 24.6, 23.4; HRCIMS m/z 286.1650,
calcd for C14H23NO5 + H 286.1654. Anal. Calcd for C14H23
-
NO5: C, 58.95; H, 8.07; N, 4.91. Found: C, 58.76; H, 8.30; N,
4.70.
(1R,2R,3S,4S,4′R,5′R)- a n d (1S,2S,3R,4R,4′R,5′R)-4′,5′-
Diph en ylspir o[2,3-exo-isopr opyliden edioxy-7-ter t-bu toxy-
ca r bon yl-7-a za bicyclo[2.2.1]h ep t-2,2′-im id a zolin e] (+)-12
a n d (-)-13. (R,R)-Diphenylethylenediamine (158 mg, 0.74
mmol) was added under N2 to a solution of ketone (()-3 (195
mg, 0.71 mmol) in dry CH2Cl2 (3 mL) containing 4 Å molecular
sieves. The reaction mixture was stirred for 24 h. Et3N (0.5
mL) was added, and the molecular sieves were eliminated by
filtration. The filtrate was concentrated and the resultant
residue purified by flash chromatography (ether/petroleum
ether:Et3N, 10:15:1 f 15:10:1) affording first 12 (150 mg, 44%)
and then 13 (141 mg, 42%), both as syrups. Da ta for (+)-12:
[R]D +73 (c 1.65, CHCl3); 13C NMR (75.4 MHz, CDCl3-Et3N,
298 K, δ ppm, mixture of rotamers 1.2:1) (major rotamer) δ
155.0, 141.3, 139.6, 128.1-126.9 (10 C), 111.0, 81.7, 80.8, 78.6,
79.6, 70.2, 69.2, 66.3, 59.2, 43.0, 28.3, 25.5, 24.1, (minor
rotamer) δ 154.9, 141.3, 139.4, 128.1-126.9 (10 C), 111.0, 81.5,
81.4, 78.7, 79.7, 70.2, 69.3, 67.5, 58.3, 42.7, 28.3, 25.5, 24.1;
HRCIMS m/z found 477.2626, calcd for C28H35N3O4 477.2628.
Da ta for (-)-13: [R]D -38 (c 1.65, CHCl3); 13C NMR (75.4 MHz,
CDCl3-Et3N, 298 K, mixture of rotamers 3.5:1) (major rota-
mer) δ 154.7, 141.8, 138.8, 128.7-126.1 (10 C), 110.8, 83.4,
81.3, 79.6, 78.6, 71.8, 69.2, 67.8, 58.4, 41., 28.4, 25.6, 24.3;
(minor rotamer) δ 154.7 (CO), 141.0, 140.9, 128.7-126.1 (10
C), 110.8, 82.9, 81.6, 79.5, 78.5, 79.5, 71.3, 69.3, 67.1, 59.7,
42.6, 28.3, 25.6, 24.3; HRCIMS m/z 477.2620, calcd for
Con clu sion
In summary, by following reaction schemes of the
“naked sugars” methodology, we have performed the
syntheses of previously unreported D- and L-3,4-diol-5-
hydroxymethylproline derivatives starting from pyrrole.
The method implies an efficient optical resolution of the
(()-7-tert-butoxycarbonyl-5,6-exo-isopropylidenedioxy-7-
azabicyclo[2.2.1]hept-2-one ((()-3). We have demon-
strated that the new polyfunctional prolines can be used
to prepare peptides containing them, using either the
Fmoc or the Boc strategy for the peptide synthesis. Work
is undergoing to use our new proline derivatives as
tridimensional scaffolds using not only their amino acid
moiety but also their 5-hydroxymethyl group (primary
alcohol) and 3,4-cis-diol moiety.
C
28H35N3O4 477.2628.
(-)-7-ter t-Bu toxycar bon yl-5,6-exo-isopr opyliden edioxy-
Exp er im en ta l Section
(()-7-ter t-Bu toxycar bon yl-5,6-exo-isopr opyliden edioxy-
7-a za bicyclo[2.2.1]h ep ta n e-2-en d o-ol ((-)-9) a n d 7-ter t-
Bu toxyca r bon yl-5,6-exo-isop r op ylid en ed ioxy-7-a za bicy-
clo[2.2.1]h ep t-2-en e (10).11 To a solution of alcohol (-)-8 (548
mg, 1.24 mmol) in anhydrous MeOH (20 mL)-THF (20 mL)
cooled at -15 °C was added finely crushed 5% sodium mercury
amalgam (4.7 g, 12.4 mmol) in one portion under N2 atmo-
sphere. The mixture was vigorously stirred for 30 min and
7-a za bicyclo[2.2.1]h ep t-2-on e ((-)-3). Meth od a . See the
Supporting Information. Meth od b. A solution of (-)-13 (50
mg, 0.10 mmol) in 0.1 M H3PO4-THF (2:1, 9 mL) was stirred
for 30 min at 20 °C. Then, the mixture was diluted with H2O
and extracted with ether. The combined extracts were dried
(MgSO4), and the solvent was evaporated. The residue was
purified by flash chromatography (ether/petroleum ether, 2:1)
affording (-)-3 (27 mg, 91%) as white solid: mp ) 85-87 °C;
4490 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis of 3,4-Dihydroxy-5-hydroxymethylprolines
1
[R]D -51.9 (c 1.11, CH2Cl2); H NMR (400 MHz, CDCl3, 313
added N-Boc-L-phenylalanine (23 mg, 0.085 mmol), diisopro-
pylethylamine (51 µL, 0.284 mmol), and PyAOP (45 mg, 0.085
mmol). The solution was stirred for 1 h and evaporated to
dryness, and the crude was purified by flash chromatography
(ether/petroleum ether, 2:1 f ether) to give 18 (31 mg, 0.051
mmol, 72% yield) as a white solid. Compound 18 was charac-
terized as the unprotected tripeptide 19.
3
3
K) δ 4.67 (d, 1H, J ) 5.4 Hz), 4.41 (d, 1 H, J ) 5.4 Hz), 4.37
2
(d, 1 H), 4.34 (s, 1 H), 2.40 (dd, 1 H, J ) 17.8 Hz), 1.80 (d, 1
H), 1.47 (s, 12 H), 1.2 (s, 3 H); 13C NMR (100.5 MHz, CDCl3,
313 K) δ 206.2, 154.1, 113.4, 81.8, 80.8, 78.0, 68.0, 59.2, 39.3,
28.2, 25.6, 24.4; HREIMS m/z 283.1422, calcd for C14H21NO5
283.1420.
(-)-7-ter t-Bu t oxyca r b on yl-2-[[(ter t-b u t yl)d im et h ylsi-
lyl]oxy]-5,6-exo-isop r op ylid en ed ioxy-7-a za bicyclo[2.2.1]-
h ep t-2-en e ((-)-14). Et3N (68 mL, 0.92 mmol) and N-[(tert-
butyl)dimethylsilyl]-N-methyltrifluoroacetamide (64 mL, 0.46
mmol) were added to a stirred solution of (-)-3 (66 mg, 0.46
mmol) in dry DMF under Ar. The mixture was heated to 60
°C for 6 h. The solution was evaporated at 50 °C/0.05 Torr,
and the residue was purified by column chromatography on
silica gel (petroleum ether/AcOEt, 1:6) to give (-)-14 (79 mg,
86%) as a colorless oil: [R]D -38.2 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3, 298 K, mixture of rotamers) δ 4.86, 4.79 (2
H-L-P h e-L-Th yp -Gly-OBn (19). Tripeptide 18 (24 mg,
0.039 mmol) was dissolved in TFA (20%)-DCM (2 mL), and
the mixture was stirred for 30 min. Then, the solution was
concentrated and the crude coevaporated with Et3N. The
residue was purified by flash chromatography (CH2Cl2/MeOH,
30:1) to give 19 (16 mg, 0.032 mmol, 82%) as a colorless oil:
1
[R]D +36.2 (c 0.65, CH3OH); H NMR (400 MHz, CD3OD, 298
K, mixture of rotamers) (major rotamer) δ 7.41-7.20 (m, 10
3
3
H), 5.21 (s, 2 H), 4.81 (dd, 1 H, J ) 5.8 Hz, J ) 2.2 Hz), 4.70
3
(br d, 1 H), 4.32 (t, 1 H, J ) 3.9 Hz), 4.25 (d, 1 H), 4.10 (d, 1
H, 2J ) 17.5 Hz), 4.05 (d, 1 H), 3.88 (dd, 1 H, 2J ) 11.5 Hz,
3
3J ) 4.8 Hz), 3.70 (dd, 1 H, J ) 3.1 Hz), 3.67 (dd, 1 H, J )
3
3
br s, 1 H), 4.55, 4.46 (2 br s, 1 H), 4.46 (d, 1 H, J ) 5.4 Hz),
3
2
4.38 (d, 1 H), 4.26, 4.15 (2 br s, 1 H), 1.43, (s, 12 H), 1.30 (s, 3
H), 0.89, 0.88 (2 br s, 9 H), 0.15, 0.12 (2 s, 6 H); 13C NMR (100.5
MHz, CDCl3, 298 K, mixture of rotamers) δ 162.9, 161.7, 155.0,
154.9, 116.2, 116.1, 104.5, 103.1, 83.0, 82.5, 80.3, 80.0, 80.2,
65.4, 64.7, 63.4, 62.8, 28.7, 26.7, 25.9, 25.7, 25.6, 18.5, -4.4,
-4.5, -4.6, -4.7; CIMS m/z 398 [20, (M + H)+]. Anal. Calcd
for C20H35NSiO5: C, 60.42; H, 8.87; N, 3.52. Found: C, 60.22;
H, 8.96; N, 3.46.
8.2 Hz, J ) 5.8 Hz), 2.99 (dd, 1 H, J ) 13.2 Hz), 2.85 (dd, 1
H), 1.28, 1.26 (2 s, 3 H each), (minor rotamer) δ 7.41-7.20 (m,
3
3
10 H), 5.21 (s, 2 H), 4.85 (dd, 1 H, J ) 5.7 Hz, J ) 2.7 Hz),
3
4.68 (d, 1 H), 4.66 (d, 1 H), 4.42 (t, 1 H, J ) 4.9 Hz), 4.06 (d,
1 H, 2J ) 17.6 Hz), 3.99 (d, 1 H), 3.91-3.89 (m, 1 H), 3.32 (dd,
2
3
1 H), 3.24 (dd, 1 H, J ) 11.9 Hz, J ) 5.3 Hz), 3.14 (dd, 1 H,
2J ) 12.8 Hz, J ) 7.4 Hz), 2.81 (dd, 1 H, J ) 6.5 Hz), 1.47,
1.33 (2 s, 3 H each).13C NMR (100.5 MHz, CD3OD, mixture of
rotamers) (major rotamer) δ 177.3, 174.6, 171.8, 139.7-128.7
(12 C), 114.2, 85.8, 83.3, 70.9, 68.9, 68.3, 62.3, 56.3, 43.1, 42.6,
28.5, 26.2, (minor rotamer) δ 177.6, 174.3, 171.6, 139.0-128.7
(12 C), 114.2, 84.9, 83.8, 70.4, 68.9, 67.9, 64.3, 55.9, 43.7, 43.1,
28.4, 26.2; HRCIMS m/z 512.2401, calcd for C27H33N3O7 + H
512.2397.
3
3
D-2,3-tr a n s-3,4-cis-4,5-tr a n s-N-(ter t-Bu toxyca r bon yl)-5-
h yd r oxym eth yl-3,4-isop r op ylid en ed ioxyp r olin e (Boc-D-
Th yp (CMe2)-OH)19 ((-)-4). Compound (-)-14 (98 mg, 0.24
mmol) was dissolved in anhydrous CH2Cl2/MeOH (1:1, 4 mL)
and cooled to -78 °C. A stream of O3 (3% in O2, 50 mL/h) was
bubbled through the solution for 25 min until persistence of a
blue color. Then NaBH4 (37 mg, 0.96 mmol) was added and
the mixture allowed to warm to 20 °C under stirring. After 2
h at 20 °C, the solution was diluted with CH2Cl2 and washed
with a saturated aqueous solution of citric acid. The organic
layer was separated, concentrated, and purified by column
chromatography on silica gel (CH2Cl2/MeOH, 10:1 f 4:1) to
give (-)-4 (69 mg, 88%) as a syrup:. [R]D -44 (c 0.8, CHCl3);
1H NMR (400 MHz, DMSO-d6, 373 K) δ 4.67 (dd, 1 H, 3J )
Ack n ow led gm en t. We are grateful to the Swiss
National Science Fondation (Grant No. 200020-10002/
1), the “Office Fe´de´ral de l’Education et de la Science”
(Bern, COST D13/0001/99), and the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica of Spain (Grant
No. BQU-2001-3779) for generous support. We thank
also the EPFL for support of a exchange program
(Socrates EPFL-Seville).
3
5.9 Hz, J ) 1.5 Hz), 4.64 (d, 1 H), 4.14 (br s, 1 H), 3.92 (t, 1
2
3
H), 3.72 (dd, 1 H, J Ha,Hb ) 11.4 Hz, J ) 4.3 Hz), 3.44 (dd, 1
H, 3J ) 3.2 Hz), 1.40 (s, 9 H), 1.38, 1.29 (2 s, 3 H each); 13C
NMR (100.5 MHz, DMSO-d6, 373 K) δ 173.9, 153.2, 110.2, 83.0,
81.7, 77.6, 68.4, 66.0, 60.8, 27.2, 26.1, 24.3; CIMS m/z 318 [5,
(M + H)+], m/z 217 [20, (M - Boc + 2H)+].
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all the new compounds. Experimental data for
preparation of compounds 15-17 and 20-22. 1H and 13C NMR
data with detailed signal assignments, detailed MS data,
complete list of R values, and IR data for all the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Boc-L-P h e-L-Th yp (CMe2)-Gly-OBn (18). To a solution of
compound 18 (26 mg, 0.071 mmol) in dry DMF (1.5 mL) were
(19) To use the nomenclature of peptides, the abbreviation H-D-
Thyp-OH was chosen for the trihydroxyproline moiety in analogy to
the D-hydroxyproline (H-D-Hyp-OH).
J O049637H
J . Org. Chem, Vol. 69, No. 13, 2004 4491