Synthesis of a protected 3,4-dihydroxyproline from a pentose sugar

Article abstract of DOI:10.1021/ol990763v

Formula presented D-Ribonolactone (6) was transformed into N-((fluorenylmethoxy)carbonyl)-3,4.bis.O-(tert-butyldimethylsilyl)-D-2,3-cis-3, 4-cis-3,4-dihydroxyproline (13) in nine chemical steps. This represents a potentially general strategy for the synth

Full text of DOI:10.1021/ol990763v

ORGANIC
LETTERS
1999
Vol. 1, No. 5
787-789
Synthesis of a Protected
3,4-Dihydroxyproline from a Pentose
Sugar
Claudette A. Weir and Carol M. Taylor*
Department of Chemistry, UniVersity of Auckland, PriVate Bag 92019,
Auckland, New Zealand
cm.taylor@auckland.ac.nz
Received June 24, 1999
ABSTRACT
D-Ribonolactone (6) was transformed into N-((fluorenylmethoxy)carbonyl)-3,4-bis-O-(tert-butyldimethylsilyl)-D-2,3-cis-3,4-cis-3,4-dihydroxyproline
(13) in nine chemical steps. This represents a potentially general strategy for the synthesis of 3,4-dihydroxyprolines, utilizing the pentose
sugar series as starting materials.
3,4-Dihydroxyproline (DHP) contains the three stereogenic
centers C2, C3, and C4; there are eight possible stereoiso-
mers. Three members of the L-series have been isolated from
natural sources.1 The L-2,3-cis-3,4-trans isomer (1; Figure
1) was isolated from the cell wall hydrolysates of the diatom
an adhesive protein produced by the marine mussel Mytilus
edulis.4
Interest in these molecules, and related pyrrolidines, stems
largely from their ability to inhibit glycosidase enzymes.5
Our focus, however, is on the role of dihydroxyprolines in
peptide structure and function. To properly investigate
structure-activity relationships (SARs), we required an
efficient synthesis of DHP, which would afford access to
all stereoisomers.
All eight stereoisomers, or related aza sugars, have been
synthesized previously.6 As a synthetic target, DHP is
deceptively challenging: although a small molecule, it is
densely functionalized and rich in stereochemistry. Previous
synthetic strategies can be divided broadly into two groups:
Figure 1. 3,4-Dihydroxyprolines from natural sources.
(4) Taylor, S. W.; Waite, J. H.; Ross, M. M.; Shabanowitz, J.; Hunt, D.
G. J. Am. Chem. Soc. 1994, 116, 10803-10804.
NaVicula pelicullosa almost 30 years ago.2 In 1980, the L-2,3-
trans-3,4-trans isomer (2) was isolated from the acid
hydrolysates of the toxic mushroom Amanita Virosa.3 In
1994, the L-2,3-trans-3,4-cis isomer 3 was identified as the
sixth residue in the repeating decapeptide sequence of Mefp1,
(5) (a) Ganem, B. Acc. Chem. Res. 1996, 29, 340-347. (b) Sears, P.;
Wong, C. H. Chem. Commun. 1998, 1161-1170. (c) Sinnott, M. L. Chem.
ReV. 1990, 90, 1171-1202.
(6) For some recent examples, with comprehensive references to earlier
work, see: (a) Huang, Y.; Dalton, D. R.; Carroll, P. J. J. Org. Chem. 1997,
62, 372-376. (b) Pohlit, A. M.; Correia, C. R. D. Heterocycles 1997, 45,
2321-2325. (c) Schumacher, K. K.; Jiang, J.; Joullie´, M. M. Tetrahedron:
Asymmetry 1998, 9, 45-53. (d) Deming, T. J.; Fournier, M. J.; Mason, T.
L.; Tirrell, D. A. J. Macromol. Sci. Pure Appl. Chem. 1997, A34, 2143-
2150. (e) Defoin, A.; Sifferlen, T.; Streith, J. Synlett 1997, 1294-1296. (f)
Zanardi, F.; Battistini, L.; Nespi, M.; Rassu, G.; Spanu, P.; Cornia, M.;
Casiraghi, G. Tetrahedron: Asymmetry 1996, 7, 1167-1180.
(1) Mauger, A. B. J. Nat. Prod. 1996, 59, 1205-1211.
(2) Nakajima, T.; Volcani, B. E. Science 1969, 164, 1400-1401.
(3) Buku, A.; Faulstich, H.; Wieland, T.; Dabrowski, J. Proc. Natl. Acad.
Sci. U.S.A. 1980, 77, 2370-2371.
10.1021/ol990763v CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/30/1999

those which lead to DHP’s with 3,4-cis relative stereochem-
istry and those which culminate in a 3,4-trans arrangement
of hydroxy groups. Our mandate was to devise a reaction
sequence which would permit the stereospecific synthesis
of each isomer.
By selection of the appropriate pentose sugar (Table 1), it
ought to be possible to prepare any isomer of DHP.
Table 1. Dihydroxyprolines from Pentoses
We have recently reported a synthesis of an L-2,3-trans-
3,4-cis-DHP (5) from D-gulonolactone (4; Scheme 1)7 by
DHP isomer
pentose precursor
L-2,3-cis-3,4-cis
L-ribose
L-2,3-cis-3,4-trans
L-2,3-trans-3,4-cis
L-2,3-trans-3,4-trans
D-2,3-cis-3,4-cis
L-arabinose
L-lyxose
L-xylose
Scheme 1
D-ribose
D-2,3-cis-3,4-trans
D-2,3-trans-3,4-cis
D-2,3-trans-3,4-trans
D-arabinose
D-lyxose
D-xylose
We chose D-2,3-cis-3,4-cis-DHP as our test case, because
D-ribonolactone is commercially available. The synthesis of
protected amino acid 13 is outlined in Scheme 3.10 The
primary alcohol of compound 6 was protected as its
triphenylmethyl (trityl) ether.11 Formation of tert-butyldi-
methylsilyl ethers from the two secondary alcohols, at C2
and C3, was accomplished under standard conditions12 to
give 7.
adapting the methodology of Fleet et al.8 This first-generation
approach has two drawbacks: it involves the excision of one
carbon atom with concomitant destruction of a stereogenic
center, and the use of an acetonide (or indeed, any cyclic
protecting group) limits the strategy to DHP’s with a 3,4-
cis relative stereochemistry.
To overcome these limitations, we decided to use the
pentose family of sugars as our source of chirality. Protection
of the 1,2-diol required the use of “independent” protecting
groups for each secondary alcohol. Our retrosynthetic
analysis, as outlined in Scheme 2, does not specify stereo-
Fleet and Son have previously reported that reductive
opening of silyl-protected hydroxylactones with LiAlH4 can
be accompanied by silyl migration.12b On the basis of their
experience, we employed LiBH4, which effected reduction
slowly but cleanly to give compound 8 as the sole product.
Diol 8 was converted to bis(mesylate) 9 by adding a
solution of the diol in pyridine, dropwise, to a premixed
solution of methanesulfonyl chloride and catalytic DMAP
in pyridine. Heating bis(mesylate) 9 in neat benzylamine (1.5
mL of benzylamine/g of substrate), at 80 °C for 60 h, led to
formation of pyrrolidine 10.
Scheme 2
Replacement of the N-benzyl substituent by the Fmoc
group (Fmoc ) (fluorenylmethoxy)carbonyl) was performed
for two reasons: to increase stabilility toward oxidation (vide
supra) and to provide a suitable protecting group for
downstream applications in peptide chemistry. Hydrogenoly-
sis of 10 gave the corresponding secondary amine.
Significantly, the trityl group was stable to these reaction
conditions.13 The crude amine was treated directly with
fluorenylmethyl chloroformate in toluene to give 11 in an
efficient manner.
chemistry intentionally. We believe that the disconnections
apply regardless. P1, P2, and P3 are protecting groups.
Pyrrolidine I can be envisaged to arise from the suitably
functionalized precursor II, using the double-displacement
chemistry of Fleet. Compound II can be derived from
appropriately protected γ-lactone III via a reductive ring
opening. Lactones of general structure III (P2 ) P3 ) H)
can be obtained by bromine oxidation of aldopentoses,9
represented by the generic structure IV.
Bessodes et al. had previously reported the selective
cleavage of a trityl ether in the presence of tert-butyldi-
(10) All new compounds in Scheme 3 gave satisfactory 1H and 13C NMR
and HRMS data.
(11) Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J.;
McGarvey, G. J.; Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983,
105, 1988-2006.
(12) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley-Interscience: New York, 1991; Chapter 2, p 77.
(b) Fleet, G. W. J.; Son, J. C. Tetrahedron 1988, 44, 2637-2647.
(13) Hydrogenolysis of trityl ethers has been reported: Mirrington, R.
N.; Schmalzl, K. J. J. Org. Chem. 1972, 37, 2877-2881. However, others
have described the selective cleavage of a benzylamine in the presence of
a trityl ether: Thompson, D. K.; Hubert, C. N.; Wightman, R. H.
Tetrahedron 1993, 49, 3827-3840.
(7) Weir, C. A.; Taylor, C. M. J. Org. Chem. 1999, 64, 1554-1558.
(8) Fleet, G. W. J.; Son, J. C.; Green, D. St. C.; di Bello, I. C.; Winchester,
B. Tetrahedron 1988, 44, 2649-2655.
(9) See: (a) Bouchez, V.; Stasik, I.; Beaupe`re, D.; Uzan, R. Carbohydr.
Res. 1997, 300, 139-143. (b) Han, S. Y.; Joullie´, M. M.; Fokin, V. V.;
Petasis, N. A. Tetrahedron: Asymmetry 1994, 5, 2535-2562 and references
therein.
788
Org. Lett., Vol. 1, No. 5, 1999

Scheme 3
methylsilyl ethers.14 These reaction conditions (25% v/v
In conclusion, we have executed an effective and efficient
synthesis of N-((fluorenylmethoxy)carbonyl)-3,4-bis-O-(tert-
butyldimethylsilyl)-D-2,3-cis-3,4-cis-DHP (13). The reaction
sequence is composed of nine steps and proceeds in an
overall yield of 19%. We hope that the reaction chemistry
presented herein can be applied to the synthesis of other
stereoisomers of 3,4-dihydroxyproline. This is currently
under investigation and will be reported in due course.
formic acid in acetonitrile) proved to be too harsh for
1
substrate 11; H NMR and HRMS analysis of the major
product indicated that only a single TBS group remained in
the molecule. Fortunately, by reducing the amount of formic
acid (to 7% v/v in acetonitrile), it was possible to obtain
primary alcohol 12 (57% yield), accompanied by a 40%
recovery of 11. This represents a 97% yield, based on
recovered starting material. Compound 12 was oxidized to
acid 1315 using ruthenium tetroxide (generated in situ from
NaIO4 (4.1 equiv) and RuCl3‚xH2O (0.022 mol %) in MeCN/
CCl4/H2O (1.0:1.0:1.5 ratio by volume)).
Acknowledgment. We thank the Marsden Fund (Grant
96-UOA-617), administered by the Royal Society of New
Zealand, for financial support. We thank Michael F. Walker
for running mass spectrometry experiments and for main-
tenance of the NMR facility at the University of Auckland.
(14) Bessodes, M.; Komiotis, D.; Antonakis, K. Tetrahedron Lett. 1986,
27, 579-580.
OL990763V
(15) Compound 13 was obtained as a colorless oil: Rf 0.54 (1:1 hexanes-
EtOAc); [R]20 ) +13.1° (c ) 0.70, CHCl3). Mixture of rotamers: 1H
D
NMR (400 MHz, CDCl3) δ 0.16 (s, 6H), 0.18 (s, 6H), 0.88 (s, 18H), 3.42-
3.54 (m, 1.5H), 3.62-3.70 (m, 0.5 H), 4.12-4.17 (m, 1H), 4.25 (t, J ) 6.8
Hz, 2H), 4.37-4.42 (m, 3H), 7.31 (t, J ) 7.1 Hz, 2H), 7.38 (t, J ) 7.3 Hz,
2H), 7.51-7.60 (m, 1H), 7.74 (d, J ) 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ -5.0, -4.8, 18.2, 25.6, 25.8, 46.9, 51.9 & 52.6, 62.9, 67.6 &
68.7, 72.9 & 73.2, 73.7, 119.9, 125.2, 125.6, 127.1, 127.7, 141.3, 155.2 &
155.3, 168.6. HRMS (CI+): calcd for C32H48NO6Si2 (M + H)+, 598.3020;
found, 598.3022.
Org. Lett., Vol. 1, No. 5, 1999
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