Toward a general strategy for the synthesis of 3,4-dihydroxyprolines from pentose sugars

Article abstract of DOI:10.1021/jo025538x

A general strategy is proposed, wherein a pentose sugar γ-lactone can be converted, via a series of nine reactions, to a 3,4-dihydroxyproline, suitably protected for use in peptide synthesis. Thus, D-ribonolactone (6) has been converted to N-fluorenylmethoxycarbonyl-3,4-di-O-tert-butyldimethylsilyloxy-D-2,3-cis-3, 4-cis-proline (7) in 18.9% overall yield. Likewise, L-arabinonolactone (11) has been converted to N-fluorenylmethoxycarbonyl-3,4-di-O-tert-butyldimethylsilyloxy-L-2,3-cis-3, 4-trans-proline (36) in 13.7% overall yield and L-lyxonolactone (12) to N-fluorenylmethoxycarbonyl- 3,4-di-O-tert-butyldimethylsilyloxy-L-2,3-trans-3,4-cis-proline (37) in 11.2% overall yield. These building blocks have also been fully deprotected to give the free amino acids. We believe that this series of reactions ought to be applicable to the synthesis of any of the eight stereoisomers of 3,4-dihydroxyproline, by judicious selection of the pentose starting material.

Full text of DOI:10.1021/jo025538x

4466
J . Org. Chem. 2002, 67, 4466-4474
Tow a r d a Gen er a l Str a tegy for th e Syn th esis of
3,4-Dih yd r oxyp r olin es fr om P en tose Su ga r s
Carol M. Taylor,*,† William D. Barker,† Claudette A. Weir,‡ and J ae H. Park‡
Institute of Fundamental Sciences, Massey University, Private Bag 11-222,
Palmerston North, New Zealand, and Department of Chemistry, University of Auckland,
Private Bag 92019, Auckland, New Zealand
C.M.Taylor@massey.ac.nz
Received J anuary 19, 2002
A general strategy is proposed, wherein a pentose sugar γ-lactone can be converted, via a series of
nine reactions, to a 3,4-dihydroxyproline, suitably protected for use in peptide synthesis. Thus,
D-ribonolactone (6) has been converted to N-fluorenylmethoxycarbonyl-3,4-di-O-tert-butyldimeth-
ylsilyloxy-D-2,3-cis-3,4-cis-proline (7) in 18.9% overall yield. Likewise, L-arabinonolactone (11) has
been converted to N-fluorenylmethoxycarbonyl-3,4-di-O-tert-butyldimethylsilyloxy-L-2,3-cis-3,4-
trans-proline (36) in 13.7% overall yield and L-lyxonolactone (12) to N-fluorenylmethoxycarbonyl-
3,4-di-O-tert-butyldimethylsilyloxy-L-2,3-trans-3,4-cis-proline (37) in 11.2% overall yield. These
building blocks have also been fully deprotected to give the free amino acids. We believe that this
series of reactions ought to be applicable to the synthesis of any of the eight stereoisomers of 3,4-
dihydroxyproline, by judicious selection of the pentose starting material.
In tr od u ction
3,4-Dihydroxyproline (DHP) contains three stereogenic
centers: C2, C3, and C4. There are eight possible
stereoisomers. Three members of the L-series have been
isolated from natural sources (Figure 1).1 The L-2,3-cis-
3,4-trans isomer (1) was isolated from the cell wall
hydrolysates of the diatom Navicula pelliculosa 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 and identified in the virotoxin
cyclic heptapeptides.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, an adhesive
protein produced by the marine mussel Mytilus edulis.4
There is a plethora of DHP syntheses in the literature.5
Indeed, our first synthesis involved an adaptation of
Fleet’s chemistry6 to convert D-gulonolactone (4) to
F igu r e 1. Naturally occurring 3,4-dihydroxyprolines.
Sch em e 1
* To whom correspondence should be addressed. Fax: 64-6-350-
5682.
† Massey University.
‡ University of Auckland.
(1) (a) Mauger, A. B. J . Nat. Prod. 1996, 59, 1205-1211. (b) Taylor,
S. W.; Waite, J . H. In Prolyl Hydroxylase, Protein Disulfide Isomerase,
and Other Structurally Related Proteins; Guzman, N. A., Ed.; Marcel
Dekker: New York, 1998; pp 97-107.
(2) (a) Nakajima, T.; Volcani, B. E. Science 1969, 164, 1400-1401.
(b) Karle, I. L.; Daly, J . W.; Witkop, B. Science 1969, 164, 1401-1402.
(c) Karle, I. L. Acta Crystallogr. 1970, B26, 765-770.
(3) (a) Buku, A.; Faulstich, H.; Wieland, T.; Dabrowski, J . Proc. Natl.
Acad. Sci. U.S.A. 1980, 77, 2370-2371. (b) Faulstich, H.; Buku, A.;
Bodenmueller, H.; Wieland, T. Biochemistry 1980, 19, 3334-3343.
(4) Taylor, S. W.; Waite, J . H.; Ross, M. M.; Shabanowitz, J .; Hunt,
D. F. J . Am. Chem. Soc. 1994, 116, 10803-10804.
(5) For some recent examples with extensive references to previous
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.; J iang, J .; J oullie´, M. M.
Tetrahedron: Asymmetry 1998, 9, 47-53. (d) Fujii, M.; Miura, T.;
Kajimoto, T.; Ida, Y. Synlett 2000, 1046-1048. (e) Lee, B. W.; J eong,
I.-Y.; Yang, M. S.; Choi, S. U.; Park, K. H. Synthesis 2000, 1305-1309.
(6) (a) Fleet, G. W. J .; Son, J . C. Tetrahedron 1988, 44, 2637-2647.
(b) Fleet, G. W. J .; Son, J . C.; Green, D. St. C.; Cenci di Bello, I.;
Winchester, B. Tetrahedron 1988, 44, 2649-2655.
compound 5 (Scheme 1),7 a building block that has proven
useful in peptide synthesis.8 However, our ultimate goal
was to investigate the role of DHPs in nature. To properly
investigate SARs, we sought an alternative synthetic
strategy with the potential to afford all eight stereoiso-
mers.
Most existing syntheses were limited, by their reaction
chemistry, to the synthesis of only a subset of the eight
stereoisomers. For example, syn-dihydroxylation of a 3,4-
dehydroproline5c,9 can lead only to DHPs with 3,4-cis
relative stereochemistry. Conversely, the opening of an
epoxide has been a useful tool in the synthesis of DHPs
(7) Weir, C. A.; Taylor, C. M. J . Org. Chem. 1999, 64, 1554-1558.
(8) Taylor, C. M.; Weir, C. A. J . Org. Chem. 2000, 65, 1414-1421.
(9) Hudson, C. B.; Robertson, A. V.; Simpson, W. R. J . Aust. J . Chem.
1968, 21, 769-782.
10.1021/jo025538x CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/17/2002

Synthesis of 3,4-Dihydroxyprolines from Pentose Sugars
J . Org. Chem., Vol. 67, No. 13, 2002 4467
Sch em e 2
Sch em e 3
with 3,4-trans relative stereochemistry.10,11 We had found
Fleet’s chemistry to be effective and efficient, but valu-
able reaction steps were expended excising a carbon
atom, and a stereogenic center was destroyed in the
process. Moreover, the use of the acetonide protecting
group is only useful with DHPs that have a 3,4-cis
relative stereochemistry.
While producing the whole gamut of stereoisomers has
not been the objective of previous DHP syntheses, this
philosophy has been of interest in a closely related group
of compounds. Polyhydroxylated pyrrolidines5a,12 and
piperidines13 have been recognized as potent glycosidase
inhibitors for many years; D-lactams have also been
investigated recently.14 In some syntheses of these mol-
ecules, there has been a deliberate attempt to produce a
large number of stereoisomers. A good example is the
work of Huang et al., who prepared four stereoisomers
of 2-hydroxymethyl-3,4-dihydroxypyrroline from L-serine
in six steps (Scheme 2).5a The other four stereoisomers
should be accessible from D-serine. Their approach could
be described as “stereodivergent” in that there are two
steps in their sequence where stereochemical diversity
is introduced. Thus, a mixture of diastereoisomers is
produced in some reaction steps, which provides rapid
access to variable amounts of each stereoisomer.
Our approach is complementary: while we would
potentially like to be able to access any stereoisomer, we
would like to be able to produce a single compound in an
efficient and predictable manner. Thus, our second-
generation synthesis utilizes the pentose sugars as the
source of chirality. The three stereogenic centers of the
monosaccharide are transmitted, via a predictable series
of reactions, to the three stereogenic centers of the amino
acid. In a preliminary communication, we described the
conversion of D-ribono-γ-lactone (6) to compound 7 (Scheme
1).15 We proposed that this synthesis ought to be gener-
ally applicable to the synthesis of 3,4-dihydroxyprolines.
We now report the conversion of two additional pentose
sugars to 3,4-dihydroxyprolines, to demonstrate the
generality of this approach.
Ta ble 1. Retr osyn th etic An a lysis of
3,4-Dih yd r oxyp r olin es
DHP isomer
pentose precursor
L-2,3-cis-3,4-cis
2S,3S,4R
2S,3S,4S
2S,3R,4S
2S,3R,4R
2R,3R,4S
2R,3R,4R
2R,3S,4R
2R,3S,4S
L-ribose
L-arabinose
L-lyxose
L-xylose
D-ribose
D-arabinose
D-lyxose
D-xylose
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
D-2,3-cis-3,4-trans
D-2,3-trans-3,4-cis
D-2,3-trans-3,4-trans
In principle, it should be possible to prepare any isomer
of DHP, by selection of the appropriate pentose precursor
(Table 1). While we appreciated at the outset that each
sugar and its derivatives would behave differently, we
felt that the transformations ought to be achievable using
a common series of reaction conditions. We began our
investigations with D-ribonolactone because it is readily
available (vide supra). We also sought to prepare two
natural products. Compound 1 was an attractive target
because the starting sugar (L-arabinose) is inexpensive,
and the final product has been isolated from nature and
well-characterized.2 Compound 3 was also pursued be-
cause we have prepared this via another route and firmly
established the relative and absolute stereochemistry.7
P h a se I: Develop m en t of a Su it a b ly P r ot ect ed
La cton e. Our synthetic strategy required that we be able
to selectively deprotect the C5-OH at a late stage in the
synthesis. We thought it would be trivial to selectively
introduce a protecting group at the primary alcohol. For
some time, we focused on silyl protecting groups. Despite
good precedents in ribonucleotide chemistry,16 we invari-
ably obtained mixtures of two monosilylated compounds
and one bis-silylated derivative. The only suitable pro-
tecting group we were ever able to introduce regioselec-
tively at C5 was the trityl ether, so we have used this
throughout our syntheses. We reasoned that a tert-butyl-
dimethylsilyl ether would be a good protecting group at
C2 and C3; they are reported to be more stable to acid
than a trityl ether17 and ought to survive the hydro-
genolysis conditions required later in the synthesis.18
Resu lts a n d Discu ssion
Our retrosynthetic analysis is outlined in Scheme 3.
In the final stages of our synthesis, we need to selectively
deprotect the primary alcohol and oxidize it to the
carboxylic acid (phase III). The pyrrolidine ring system
will be generated using Fleet’s double displacement
chemistry (phase II). The substrate for this can be
envisioned to arise from a pentose γ-lactone (phase I).
(10) Kahl, J .-U.; Wieland, T. Liebigs Ann. Chem. 1981, 1445-1450.
(11) Herdeis, C.; Aschenbrenner, A.; Kirfel, A.; Schwabenla¨nder, F.
Tetrahedron: Asymmetry 1997, 8, 2421-2432.
(12) (a) Lombardo, M.; Fabbroni, S.; Trombini, C. J . Org. Chem.
2001, 66, 1264-1268. (b) Hulme, A. N.; Montgomery, C. H.; Henderson,
D. K. J . Chem. Soc., Perkin Trans. 1 2000, 1837-1841.
(16) (a) Ogilvie, K. K.; Thompson, E. A.; Quilliam, M. A.; Westmore,
J . B. Tetrahedron Lett. 1974, 33, 2865-2868. (b) Ogilvie, K. K.;
Hakimelahi, G. H. Carbohydr. Res. 1983, 115, 234-239.
(17) Bessodes. M.; Komiotis, D.; Antonakis, K. Tetrahedron Lett.
1986, 27, 579-580.
(18) Earlier studies had shown that TIPS ethers were not stable to
hydrogenolysis: Weir, C. A. Ph.D. Thesis, University of Auckland,
2000. See also: Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc.
1972, 94, 6190-6191.
(13) (a) Poupon, E.; Luong, B.-X.; Chiaroni, A.; Kunesch, N.; Husson,
H.-P. J . Org. Chem. 2000, 65, 7208-7210. (b) Pandey, G.; Kapur, M.
Tetrahedron Lett. 2000, 41, 8821-8824.
(14) Nishimura, Y.; Adachi, H.; Satoh, T.; Shitara, E.; Nakamura,
H.; Kojima, F.; Takeuchi, T. J . Org. Chem. 2000, 65, 4871-4882.
(15) Weir, C. A.; Taylor, C. M. Org. Lett. 1999, 1, 787-789.

4468 J . Org. Chem., Vol. 67, No. 13, 2002
Taylor et al.
γ-lactone in an efficient manner.26,27 The oxidation is
performed with bromine in a buffered solution; no heavy
metal salts are utilized. The lactone, without any puri-
fication, is treated directly with Ac2O/pyridine. Applica-
tion of the oxidation procedure to 9 and 10 and subjection
of the crude lactone to the tritylation reagents, led to
much improved yields of 13 and 14 over two steps
(Scheme 4).
Sch em e 4
The remainder of the reaction chemistry is detailed in
Scheme 5. In an attempt to illustrate the “generality” of
our sequence we have used a single set of structures that
do not specify stereochemistry. Below each structure are
the compounds, their absolute stereochemistry, and the
yields for each case. The top row refers to the compounds
derived from D-ribonolactone, the middle row the L-
arabinose series, and the bottom row the L-lyxose series.
II. Con ver sion of th e La cton e to a P yr r olid in e.
Silylation of the diols to give 15-17 was straightforward.
Treatment of D-ribose derivative 15 with LiBH4 gave a
good yield of the diol 18 (Scheme 5). L-Lyxose derivative
17 gave a 73% yield of the desired diol 20; another
product was evident by TLC but was not investigated
further due to the acceptable yield of 20. Unfortunately,
under these reaction conditions, L-arabinose derivative
16 gave a mixture of two products that were difficult to
separate. It transpired that the two products were diols
19 and 39 (Scheme 6); the latter resulting from silyl
migration during and/or after the reduction process. The
mixture of diols was converted to mesylates 22 and 40,
which were readily separated by flash chromatography,
although they could not be distinguished easily by 1H
NMR. The major mesylate did not give a cyclic product
on treatment with benzylamine, suggesting that it was
40, since the requisite cyclization would be the disfavored
4-exo-tet process.
Silyl migration could be minimized by switching to
sodium borohydride in methanol and incorporating a
stoichiometric amount of cerium(III) chloride.28,29 While
these reaction conditions worked well for the conversion
of 16 to 19, they did not give good results in the
attempted reduction of 15 and 17. This is the one step
in our sequence where optimization of reaction conditions
led to different reagents for different stereoisomers.
Nevertheless, the principle of the transformation (reduc-
tive opening of the lactone) remains intact.
Diols 18-20 were converted to the corresponding bis-
mesylates under standard conditions. A solution of the
diol in pyridine was added dropwise to a premixed
suspension of methanesulfonyl chloride and DMAP in
pyridine. A side reaction sometimes encountered was the
intramolecular reaction of a monomesylate to give a
tetrahydrofuran (Scheme 7). In the case of the L-arabi-
nose series, a significant amount of compound 42 was
isolated, purified, and characterized. The proton and
carbon NMR spectra were reminiscent of lactone 16,
suggesting a conformationally restricted ring system,
rather than an open chain. The 13C NMR spectrum of 16
contained a signal at δ 176.1 ppm, reflecting the lactone
A prerequisite of our synthetic strategy is access to the
pentose γ-lactones. D-Ribonolactone is commercially avail-
able at reasonable cost and has been previously converted
to its 5-O-trityl derivative 8 (Scheme 4).19 It was neces-
sary for us to prepare the other γ-lactones and there is
good precedent for this in the literature. Unfortunately,
we experienced inordinate problems in isolating useful
quantities of γ-lactones, and we feel compelled to share
these trials and tribulations.
The oxidation of aldoses by aqueous bromine is well
documented.20 Specifically, Kiliani isolated L-arabinonic
acid as its calcium salt,21 and Ruff prepared D-arabinonic
acid.22 D-Lyxonic acid was isolated as its lead salt and
converted to the lactone by Wohl and List.23 Following
the more modern procedure of Morgenlie,24 we performed
the oxidation in aqueous bromine in the dark; addition
of Ag2CO3 at the conclusion of the reaction led to the
precipitation of AgBr. Filtration and concentration of the
filtrate ought to afford the γ-lactone. Unfortunately, using
this protocol, we were unable to obtain useful quantities
of the lactones in a reproducible manner. In 1997,
Bouchez and co-workers reported a different procedure
in which barium carbonate was incorporated in the
reaction mixture.25 In our hands, the oxidation of 9 and
10 in this manner was capricious, but 11 and 12,
respectively, were obtained in useful quantities. The
limitation of the method seems to be the efficiency with
which the lactone can be leached from the barium salts
with hot acetone.
It has recently been brought to our attention that
D-xylose can be converted to 2,3,5-tri-O-acetyl-D-xylono-
(19) 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.
(20) Collins, P. M.; Ferrier, R. J . Monosaccharides: Their Chemistry
and Their Roles in Natural Products; Wiley: Chichester, 1995; pp 128-
134.
(21) Kiliani, H. Ber. 1886, 19, 3029-3036.
(26) Barker, S. F.; Angus, D.; Taillefumier, C.; Probert, M. R.;
Watkin, D. J .; Watterson, M. P.; Claridge, T. D. W.; Hungerford, N.
L.; Fleet, G. W. J . Tetrahedron Lett. 2001, 42, 4247-4250.
(27) Sun, R. C.; Okabe, M. Org. Synth. 1995, 72, 48-56.
(28) Martin, A.; Watterson, M. P.; Brown, A. R.; Imtiaz, F.; Win-
chester, B. G.; Watkin, D. J .; Fleet, G. W. J . Tetrahedron: Asymmetry
1999, 10, 355-366.
(22) (a) Ruff, O. Ber. 1899, 32, 550-560. (b) Ruff, O. Ber. 1901, 34,
1362-1372.
(23) Wohl, A.; List, E. Ber. 1897, 30, 3101-3108.
(24) (a) Morgenlie, S. Acta Chem. Scand. 1973, 27, 2607-2613. (b)
Han, S. Y.; J oullie´, M. M.; Fokin, V. V.; Petasis, N. A. Tetrahedron:
Asymmetry 1994, 5, 2535-2562.
(25) Bouchez, V.; Stasik, I.; Beaupe`re, D.; Uzan, R. Carbohydr. Res.
1997, 300, 139-142.
(29) The cleavage of trityl ethers using Ce(III) chloride and NaI has
been reported: Yadav, J . S.; Reddy, B. V. S. Synlett 2000, 1275-1276.

Synthesis of 3,4-Dihydroxyprolines from Pentose Sugars
Sch em e 5
J . Org. Chem., Vol. 67, No. 13, 2002 4469
Sch em e 6
Sch em e 7
functionality. There was no such signal in the 13C NMR
spectrum of 42; instead, there was a signal at δ 74.5 ppm,
which was inverted in the 135° DEPT spectrum. We took
this as evidence for the tetrahydrofuran structure.
Heating the bis-mesylates 21-23 in neat benzylamine
led to the formation of pyrrolidines 24-26, respectively,
in good yield. The benzyl group was removed by hydro-
genolysis at atmospheric pressure with Pd/C catalyst, and
the resulting secondary amine was readily protected by
reaction with fluorenylmethyl chloroformate (Fmoc-Cl)
to give the Fmoc-derivatives 27-29. Attempts to protect
the amine in situ by incorporating Fmoc-OSucc in the
hydrogenolysis reaction, as described by Dzubeck and
Schneider,30 were unsuccessful.
III. Ela bor a tion to Ca r boxylic Acid . Selective cleav-
age of the trityl ether from 27 was not straightforward.
Following literature precedent,31 we attempted to simul-
(30) Dzubeck, V.; Schneider, J . P. Tetrahedron Lett. 2000, 41, 9953-
9956.

4470 J . Org. Chem., Vol. 67, No. 13, 2002
Taylor et al.
cooled to 0 °C, and bromine (1.1 equiv) was added in four equal
portions, at 20 min intervals. The resulting orange solution
was stirred at 0 °C for 1 h and then at rt for 18 h. The reaction
mixture was quenched by the addition of formic acid (0.5 mL/
mmol) and the solution concentrated. The residue was dis-
persed in glacial acetic acid (5 mL/mmol), the solution con-
centrated, and the residue dried in vacuo overnight.
taneously cleave the benzylic ether bond during the
hydrogenolysis step (vide infra). However, the trityl ether
remained intact, even at elevated pressures (3 atm H2).
Under acidic conditions, one of the TBDMS groups turned
out to be quite labile.15 However, a carefully controlled
concentration of formic acid in acetonitrile led to reason-
able yields of primary alcohols 30-32. While 30 was
oxidized to 7 using ruthenium tetroxide, the yield was
mediocre.15 It turned out to be more efficient to perform
the oxidation in two steps: a Swern oxidation followed
by sodium chlorite oxidation gave acids 7, 36, and 37 in
good overall yields. We believe that these compounds will
be useful building blocks in peptide synthesis.
Cor r ela tion w ith th e Na tu r a l P r od u cts. While we
had produced useful building blocks for peptide synthesis,
it remained for us to establish the relative and absolute
stereochemistry of our DHPs. We were unsuccessful in
our attempts to secure crystallographic data for any of
our pyrrolidine derivatives. Proof of the relative and
absolute stereochemistries therefore relied on the conver-
sion of 35 and 36 to the corresponding natural products
1 and 3. Removal of the protecting groups was ac-
complished in two steps and the free DHPs were purified
by ion-exchange chromatography. The proton NMR data
for compounds 1 and 3 agreed well with that reported
for the natural products and all three DHPs gave 1H and
13C NMR data, which was in good agreement with
previous data where available.
The residue was dissolved in pyridine (3 mL/mmol) and
triphenylmethyl chloride (1.2 equiv) and DMAP (0.2 equiv)
added. The solution was stirred under an atmosphere of
nitrogen at 70 °C for 16 h. The cooled mixture was concen-
trated, diluted with dichloromethane (30 mL/mmol), and
washed with 10% aq HCl (2 × 25 mL/mmol) and satd aq
NaHCO3 (25 mL/mmol). The organic layer was dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
column chromatography, eluting with 1:1 hexanes-EtOAc.
5-O-Tr ip h en ylm eth yl-L-a r a bin on o-γ-la cton e (13): on a
scale of 3.33 mmol (59%); TLC Rf 0.36 (5:1 hexanes-EtOAc);
[R]20 ) -20.2 (c 1.18, CHCl3) (lit.32 [R]20 ) +17 (c 1.18,
D
D
1
CHCl3)); H NMR (CDCl3, 400 MHz) δ 3.17 (dd, J ) 11.1, 4.8
Hz, 1H), 3.36 (dd, J ) 11.1, 2.7 Hz, 1H), 3.84 (br. s, 1H), 4.11-
4.16 (m, 1H), 4.17 (dd, J ) 16.6, 8.3 Hz, 1H), 4.38 (d, J ) 8.3
Hz, 1H), 4.73 (br. s, 1H), 7.10-7.36 (m 15H); 13C NMR (CDCl3,
100 MHz) δ 62.3, 74.5, 75.0, 80.3, 87.4, 127.7, 128.4, 129.0,
143.7, 175.3; HRMS (EI) calcd for M+ C24H22O5 390.1467, obsd
390.1467.
5-O-Tr ip h en ylm eth yl-L-lyxon o-γ-la cton e (14): on a scale
of 3.33 mmol (51%); TLC Rf 0.22 (1:1 hexanes-EtOAc); [R]20
D
) +8.4 (c 0.35, MeOH); 1H NMR (CDCl3, 200 MHz) δ 3.41 (dd,
J ) 10.6, 4.6 Hz, 1H), 3.59 (dd J ) 10.6, 6.6 Hz, 1H), 4.30 (dd,
J ) 4.5, 2.9 Hz, 1H), 4.35-4.39 (m, 1H), 4.41 (d, J ) 4.6 Hz,
1H), 7.10-7.49 (m, 15H); 13C NMR (CDCl3, 50 MHz) δ 61.5,
69.5, 70.8, 79.4, 87.2, 127.2, 127.9, 128.5, 143.3, 175.9; HRMS
(EI) calcd for M+ C24H22O5 390.1467, obsd 390.1454.
Con clu sion
5-O-Tr ip h en ylm eth yl-D-r ibon o-γ-la cton e (8). Prepared
according to Ireland et al. from D-ribonolactone:19 TLC Rf 0.22
(1:1 hexanes-EtOAc); [R]20D ) +52.2 (c 1.02, CH2Cl2); 1H NMR
(CDCl3, 200 MHz) δ 3.99 (dd, J ) 11.0, 2.6 Hz, 2H), 4.25 (d, J
) 5.5 Hz, 1H), 4.51 (app. t, J ) 2.6 Hz, 1H), 4.87 (d, J ) 5.5
Hz, 1H), 7.20-7.69 (m, 15H); 13C NMR (acetone-d6, 50 MHz)
δ 64.1, 69.8, 70.9, 84.3, 88.2, 127.8, 128.2, 128.4, 128.5, 128.9,
129.4, 129.6, 144.4, 145.3, 176.3; HRMS (EI) calcd for M+
We have now synthesized two naturally occurring
L-DHPs (1 and 3), in addition to D-2,3-cis-3,4-cis-DHP
(38). We have synthesized DHPs with a 2,3-cis relation-
ship (1 and 38) and a 2,3-trans relationship (3). We have
also synthesized DHPs with a 3,4-cis relationship (3 and
38) and a 3,4-trans relationship (1). We believe that these
three examples demonstrate the potential generality of
this series of reactions. Moreover, building blocks 7, 36,
and 37 will be useful compounds in the synthesis of
peptides, which will enable us to continue our studies
into the role of hydroxylated prolines in nature.
C
24H22O5 390.1467, obsd 390.1459.
Gen er a l P r oced u r e for P r otection of C3-OH a n d C4-
OH a s ter t-Bu t yld im et h ylsilyl E t h er s. A solution of the
5-O-trityl-protected lactone (1.0 equiv) in DMF (1 mL/mmol)
was added dropwise to a solution of tert-butyldimethylsilyl
chloride (3.4 equiv) and imidazole (5.4 equiv) in DMF (1 mL/
mmol), and the resulting solution was stirred under N2 at rt
for 48 h. The reaction mixture was diluted with chloroform
(50 mL/mmol) and washed with water (2 × 50 mL/mmol). The
organic layer was dried (MgSO4), filtered, and concentrated.
The residue was purified by flash column chromatography,
eluting with 5:1 hexanes-EtOAc.
Exp er im en ta l Section
Gen er a l Meth od s. Reactions were carried out under an
atm of nitrogen. THF was freshly distilled from sodium/
benzophenone. Toluene was freshly distilled from sodium.
Acetonitrile and dichloromethane were freshly distilled from
calcium hydride. Pyridine, benzylamine, and triethylamine
were each dried and distilled from calcium hydride and stored
over KOH pellets. Cyclohexene was dried and distilled from
calcium hydride and stored over 4 Å molecular sieves. tert-
Butyl alcohol was dried over MgSO4, distilled from calcium
hydride, and stored over 4 Å molecular sieves. Methanesulfo-
nyl chloride was dried and distilled from phosphorus pentoxide
under vacuum and stored over 4 Å molecular sieves. Methanol
was dried and distilled from magnesium turnings and stored
over 4 Å molecular sieves. DMF was dried and distilled from
BaO and stored over 4 Å molecular sieves. All other reagents
were from commercial suppliers and were used without further
purification. Tesser’s base was prepared by mixing together
1,4-dioxane, methanol, and 4 N NaOH in a 30:9:1 ratio by
volume.
2,3-Bis-O-ter t-bu tyld im eth ylsilyl-5-O-tr ip h en ylm eth yl-
D-r ibon o-γ-la cton e (15): on a scale of 2.09 mmol (97%); TLC
Rf 0.46 (5:1 hexanes-EtOAc); [R]20 ) +22.7 (c 1.15, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ 0.01 (s, 3H), 0.09 (s, 3H), 0.19
(s, 3H), 0.26 (s, 3H), 0.87 (s, 9H), 1.00 (s, 9H), 3.28 (dd, J )
11.0, 3.0 Hz, 1H), 3.69 (dd, J ) 11.0, 3.0 Hz, 1H), 4.02 (d, J )
5.4 Hz, 1H), 4.35 (app. t, J ) 3.0 Hz, 1H), 4.76 (d, J ) 5.4 Hz,
1H), 7.25-7.67 (m, 15H); 13C NMR (CDCl3, 50 MHz) δ -5.3,
-4.9, -4.8, -4.7, 17.9, 18.3, 25.5, 25.8, 62.2, 70.2, 71.9, 84.5,
87.5, 127.3, 127.9, 128.4, 142.9, 174.9; HRMS (FAB) calcd for
MH+ C36H51O5Si2 619.3275, obsd 619.3261. Anal. Calcd for
C
36H50O5Si2: C, 69.86; H, 8.14. Found: C, 69.94; H, 8.24.
(32) (a) Tatsuta, K.; Takahashi, M.; Tanaka, N. J . Antibiot. 2000,
Gen er a l P r oced u r e for F or m a tion of γ-La cton e a n d
P r otection of C5-OH a s Its Tr ip h en ylm eth yl Eth er . The
aldopentose (1 equiv) was dissolved in Milli-Q water (3 mL/
mmol), and K2CO3 (1.15 equiv) was added. The solution was
53, 88-91. (b) Concerned by the vast discrepancy in these values, we
measured the rotation of both D-arabinono-γ-lactone and L-arabinono-
γ-lactone prepared in our laboratory from D-arabinose and L-arabinose,
respectively. For D-arabinono-γ-lactone: [R]20 ) +43.4 (c 1.38, H2O);
D
for L-arabinono-γ-lactone: [R]20 ) -40.2 (c 0.99, H2O), lit.24a [R]20
)
D
D
-33 (c 1.0, H2O), lit.24b [R]20 ) -74 (c 0.54, H2O). When we protect
D
(31) Mirrington, R. N.; Schmalzl, K. J . J . Org. Chem. 1972, 37,
2877-2881.
the 5-OH of this L-arabinono-γ-lactone as its trityl ether we most
definitely observe a negative rotation.

Synthesis of 3,4-Dihydroxyprolines from Pentose Sugars
J . Org. Chem., Vol. 67, No. 13, 2002 4471
2,3-Bis-O-ter t-bu tyld im eth ylsilyl-5-O-tr ip h en ylm eth yl-
L-a r a bin o-γ-la cton e (16): on a scale of 1.07 mmol (88%); TLC
Rf 0.45 (5:1 hexanes-EtOAc); [R]20 ) -7.1 (c 1.02, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ -0.38 (s, 3H), -0.15 (s, 3H), 0.01
(s, 3H), 0.02 (s, 3H), 0.58 (s, 9H), 0.80 (s, 9H), 3.02 (dd, J )
9.7, 6.9 Hz, 1H), 3.22 (dd, J ) 9.7, 2.4 Hz, 1H), 3.57-3.70 (m,
3H), 3.71-3.77 (m, 1H), 3.87 (dt, J ) 6.9, 2.4 Hz, 1H), 7.06-
7.18 (m, 9H), 7.34-7.40 (m, 6H); 13C NMR (CDCl3, 100 MHz)
δ -4.6, -4.4, -4.3, -4.0, 18.1, 18.4, 26.0, 26.2, 63.1, 66.2, 72.6,
73.4, 75.8, 87.0, 127.3, 128.2, 129.3, 144.5; HRMS (FAB) calcd
for [M + Na]+ C36H54O5Si2Na 645.3408, obsd 645.3422.
Gen er a l P r oced u r e for F or m a tion of Bis-Meth a n e-
su lfon a tes. A solution of the diol (1.0 equiv) in dry pyridine
(2.0 mL/mmol) was added dropwise to a cooled (0 °C), premixed
suspension of methanesulfonyl chloride (4.0 equiv) and DMAP
(0.2 equiv) in dry pyridine (1.0 mL/mmol). The resulting orange
solution was stirred under N2 at rt for 14 h. The reaction
mixture was diluted with chloroform (60 mL/mmol) and
washed with 10% aq HCl (2 × 25 mL/mmol), satd aq NaHCO3
(25 mL/mmol), and water (25 mL/mmol). The organic layer was
dried (MgSO4), filtered, and concentrated. The residue was
purified by flash column chromatography, eluting with 5:1
hexanes-EtOAc.
Rf 0.63 (5:1 hexanes-EtOAc); [R]20 ) -9.0 (c 1.03, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ -0.29 (s, 3H), -0.01 (s, 3H), 0.13
(s, 3H), 0.20 (s, 3H), 0.73 (s, 9H), 0.91 (s, 9H), 3.16 (dd, J )
10.7, 5.4 Hz, 1H), 3.40 (dd, J ) 10.7, 2.2 Hz, 1H), 4.20 (q, J )
6.9 Hz, 1H), 4.21-4.26 (m, 1H), 4.32 (d, J ) 6.9 Hz, 1H), 7.16-
7.29 (m, 9H), 7.41-7.47 (m, 6H); 13C NMR (CDCl3, 100 MHz)
δ -2.0, -1.9, -1.4, -1.3, 20.6, 21.0, 28.5, 28.6, 65.4, 78.3, 79.1,
84.0, 89.7, 128.7, 130.1, 131.0, 146.2, 176.1; HRMS (EI) calcd
for [M - C6H5]+ C30H45O5Si2 541.2806, obsd 541.2809. Anal.
Calcd for C36H50O5Si2: C, 69.86; H, 8.14. Found: C, 70.03; H,
8.07.
2,3-Bis-O-ter t-bu tyld im eth ylsilyl-5-O-tr ip h en ylm eth yl-
L-lyxon o-γ-la cton e (17): on a scale of 0.19 mmol (84%); TLC
Rf 0.39 (5:1 hexanes-EtOAc); [R]20 ) +24.2 (c 0.75, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ -0.17 (s, 3H), 0.00 (s, 3H), 0.15
(s, 3H), 0.19 (s, 3H), 0.65 (s, 9H), 0.92 (s, 9H), 3.17 (dd, J )
10.8, 2.8 Hz, 1H), 3.60 (dd, J ) 10.8, 7.9 Hz, 1H), 4.26 (dd, J
) 4.0, 2.8 Hz, 1H), 4.32 (d, J ) 4.0 Hz, 1H), 4.48 (dt, J ) 7.9,
2.8 Hz, 1H), 7.20-7.35 (m, 9H), 7.42-7.54 (m, 6H); 13C NMR
(CDCl3, 100 MHz) δ -4.8, -4.5, -4.1, -3.8, 18.5, 19.0, 26.0,
26.4, 64.0, 72.7, 73.3, 80.3, 87.5, 127.5, 128.3, 129.1, 144.0,
174.6; HRMS (DCI) calcd for MH+ C36H51O5Si2 619.3275, obsd
619.3265. Anal. Calcd for C36H50O5Si2: C, 69.86; H, 8.14.
Found: C, 69.74; H, 8.20.
2,3-Bis-O-ter t-b u t yld im et h ylsilyl-1,4-b is-O-m et h a n e-
su lfon yl-5-O-tr ip h en ylm eth yl-D-r ibitol (21): on a scale of
1.91 mmol (84%); TLC Rf 0.35 (3:1 hexanes-EtOAc); [R]20
)
D
+9.0 (c 0.65, CHCl3); 1H NMR (CDCl3, 200 MHz) δ 0.04 (s,
3H), 0.09 (s, 3H), 0.16 (s, 3H), 0. 17 (s, 3H), 0.82 (s, 9H), 1.00
(s, 9H), 3.11 (s, 3H), 3.19 (s, 3H), 3.43 (dd, J ) 11.1, 8.6 Hz,
1H), 3.57 (dd, J ) 11.1, 2.7 Hz, 1H), 3.88-3.93 (m, 1H), 4.04
(dd, J ) 5.2, 3.6 Hz, 1H), 4.19 (dd, J ) 10.3, 5.8 Hz, 1H), 4.41
(dd, J ) 10.3, 3.6 Hz, 1H), 5.25 (dt, J ) 8.6, 2.7 Hz, 1H), 7.31-
7.53 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ -4.9, -4.8, -4.5,
17.9, 25.8, 37.4, 38.8, 62.5, 70.2, 72.2, 74.9, 82.5, 87.6, 127.3,
127.9, 128.6, 143.1; HRMS (FAB) calcd for MH+ C38H59O9S2-
Si2 779.3139, obsd 779.3150.
Gen er a l P r oced u r e for R ed u ct ive R in g Op en in g of
La cton e. A solution of lithium borohydride (2 mol/L in THF,
4.0 equiv) was added dropwise over 30 min to a stirred solution
of the 5-O-triphenylmethyl-2,3-di-O-tert-butyldimethylsilyl-γ-
lactone (1.0 equiv) in dry THF (2.5 mL/mmol). The resulting
colorless solution was stirred under N2 at rt for 18 h. The
excess borohydride was quenched by the addition of satd aq
NH4Cl solution (2 mL/mmol). The reaction mixture was
partitioned between brine (50 mL/mmol) and ethyl acetate (75
mL/mmol) and the organic layer separated, dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
column chromatography, eluting with 5:1 hexanes-EtOAc.
2,3-Bis-O-ter t-bu tyld im eth ylsilyl-5-O-tr ip h en ylm eth yl-
D-r ibitol (18): on a scale of 2.06 mmol (93%); TLC Rf 0.42 (3:1
2,3-Bis-O-ter t-b u t yld im et h ylsilyl-1,4-b is-O-m et h a n e-
su lfon yl-5-O-tr ip h en ylm eth yl-L-a r a bin itol (22): on a scale
of 0.69 mmol (74%); TLC Rf 0.30 (5:1 hexanes-EtOAc); [R]20
D
1
) -22.3 (c 0.75, CHCl3); H NMR (CDCl3, 400 MHz) δ -0.03
(s, 3H), -0.01 (s, 3H), -0.01 (s, 3H), 0.05 (s, 3H), 0.76 (s, 9H),
0.81 (s, 9H), 2.84 (s, 3H), 3.02 (s, 3H), 3.26 (dd, J ) 11.7, 2.0
Hz, 1H), 3.49 (dd, J ) 11.7, 8.9 Hz, 1H), 3.82-3.87 (m, 3H),
4.23 (d, J ) 8.6 Hz, 1H), 5.03 (d, J ) 8.6 Hz, 1H), 7.18-7.32
(m, 9H), 7.40-7.46 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ
-4.7, -4.5, -4.4, -4.3, 18.3, 18.4, 26.0, 26.1, 37.4, 39.4, 63.4,
71.1, 73.9, 74.7, 84.0, 88.1, 127.6, 128.3, 129.0, 143.7; HRMS
(CI) calcd for [M - C6H5]+ C32H53O9S2Si2 701.2670, obsd
701.2694.
hexanes-EtOAc); [R]20 ) +5.2 (c 1.55, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ 0.15 (s, 3H), 0.29 (s, 3H), 0.32 (s, 3H),
0.33 (s, 3H), 1.10 (s, 9H), 1.20 (s, 9H), 2.74 (br. s, 1H), 3.11
(br. s, 1H), 3.44 (t, J ) 9.0 Hz, 1H), 3.61 (dd, J ) 9.5, 3.3 Hz,
1H), 3.84-3.93 (br. m, 2H), 4.00-4.07 (m, 2H), 4.23-4.27 (m,
1H), 7.47-7.61 (m, 9H), 7.69-7.79 (m, 6H); 13C NMR (CDCl3,
50 MHz) δ -4.9, -4.6, -4.5, -4.3, 17.9, 18.1, 25.8, 25.9, 63.2,
65.1, 71.9, 73.9, 76.1, 86.8, 127.0, 127.8, 128.6, 143.7; HRMS
(DCI) calcd for [M - C4H9]+ C32H45O5Si2 565.2805, obsd
565.2809.
2,3-Bis-O-ter t-b u t yld im et h ylsilyl-1,4-b is-O-m et h a n e-
su lfon yl-5-O-tr ip h en ylm eth yl-L-lyxitol (23): on a scale of
0.59 mmol (99%); TLC Rf 0.33 (3:1 hexanes-EtOAc); [R]20
)
D
2,3-Bis-O-ter t-bu tyld im eth ylsilyl-5-O-tr ip h en ylm eth yl-
L-lyxitol (20): on a scale of 0.04 mmol (73%); TLC Rf 0.43 (3:1
-25.6 (c 0.45, CHCl3); 1H NMR (CDCl3, 400 MHz) δ -0.05 (s,
3H), -0.04 (s, 3H), -0.01 (s, 3H), 0.05 (s, 3H), 0.75 (s, 18H),
2.84 (s, 3H), 3.00 (s, 3H), 3.39 (dd, J ) 10.9, 7.7 Hz, 1H), 3.49
(dd, J ) 10.9, 2.6 Hz, 1H), 3.51 (s, 1H), 3.88-3.98 (m, 2H),
4.15 (d, J ) 8.4 Hz, 1H), 4.70-4.78 (m, 1H), 7.14-7.30 (m,
9H), 7.32-7.45 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ -4.8,
-4.5, -4.1, -4.0, 18.4, 18.5, 26.1, 26.2, 37.6, 39.0, 63.0, 70.7,
73.6, 75.0, 83.2, 88.0, 127.8, 128.5, 129.0, 143.8; HRMS (FAB)
calcd for [M + Na]+ C38H58O9S2Si2Na 801.2959, obsd 801.2975.
Gen er a l P r oced u r e for N-Ben zylp yr r olid in e F or m a -
tion . The bis-mesylate (1.0 equiv) was dissolved in benzyl-
amine (1 mL/mmol) and the solution heated at 85 °C under
N2 for 60 h. The excess benzylamine was removed under
reduced pressure and the residue partitioned between chlo-
roform (200 mL/mmol) and brine (100 mL/mmol). The organic
layer was washed with water (100 mL/mmol), dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
column chromatography, eluting with 15:1 hexanes-EtOAc.
(2S,3R,4S)-1-Ben zyl-3,4-bis(ter t-bu tyldim eth ylsilyloxy)-
2-tr ip h en ylm eth oxym eth ylp yr r olid in e (24): on a scale of
hexanes-EtOAc); [R]20 ) -4.1 (c 0.55, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ -0.34 (s, 3H), -0.04 (s, 3H), -0.01 (s,
3H), 0.04 (s, 3H), 0.59 (s, 9H), 0.81 (s, 9H), 2.76 (t, J ) 9.0 Hz,
1H), 2.77 (br. s, 1H), 3.17 (dd, J ) 9.0, 5.9 Hz, 1H), 3.34 (dd,
J ) 11.2, 3.2 Hz, 1H), 3.55-3.68 (m, 3H), 3.80 (t, J ) 7.0 Hz,
1H), 3.94 (d, J ) 3.2 Hz, 1H), 7.07-7.21 (m, 9H), 7.27-7.35
(m, 6H); 13C NMR (CDCl3, 100 MHz) δ -4.9, -4.3, -4.2, -3.6,
18.4, 18.5, 26.2, 26.3, 62.4, 65.0, 70.7, 73.6, 76.1, 87.1, 127.4,
128.3, 129.1, 144.1; HRMS (FAB) calcd for [M + Na]+ C36H54O5-
Si2Na 645.3408, obsd 645.3383.
2,3-Bis-O-ter t-bu tyld im eth ylsilyl-5-O-tr ip h en ylm eth yl-
L-a r a bin itol (19). A mixture of lactone (502 mg, 0.81 mmol,
1.0 equiv) and anhydrous cerium(III) chloride (801 mg, 3.25
mmol, 4.0 equiv) in dry methanol (10 mL) was stirred under
N2 at -10 °C for 10 min. Sodium borohydride (123 mg, 3.25
mmol, 4.0 equiv) was added and the mixture stirred at -10
°C for 30 min. Excess NaBH4 was quenched by the addition of
NH4Cl (500 mg) and the mixture concentrated. The residue
was extracted with EtOAc (3 × 20 mL), and the combined
extracts were washed with brine (50 mL), dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
column chromatography, eluting with 5:1 hexanes-EtOAc to
give the titled compound as a colorless oil (492 mg, 98%): TLC
0.36 mmol (76%); TLC Rf 0.40 (10:1 hexanes-EtOAc); [R]20
D
) +24.9 (c 0.90, CHCl3); 1H NMR (CDCl3, 200 MHz) δ 0.02 (s,
3H), 0.06 (s, 3H), 0.08 (s, 3H), 0.11 (s, 3H), 0.86 (s, 9H), 0.89
(s, 9H), 2.67 (dd, J ) 10.3, 4.7 Hz, 1H), 2.98 (dd, J ) 10.3, 3.7
Hz, 1H), 3.30-3.41 (m, 2H), 3.66-3.76 (m, 1H), 3.92 (d, J )

4472 J . Org. Chem., Vol. 67, No. 13, 2002
Taylor et al.
13.7 Hz, 1H), 4.06-4.11 (m, 1H), 4.20-4.28 (m, 1H), 4.54 (d,
J ) 13.7 Hz, 1H) 7.33-7.67 (m, 20H); 13C NMR (CDCl3, 50
MHz) δ 1.9, 2.0, 2.2, 2.3, 18.1, 25.8, 25.9, 57.1, 60.9, 65.3, 66.3,
73.2, 74.3, 86.7, 126.6, 127.6, 128.1, 128.9, 140.1, 144.6; HRMS
(FAB) calcd for MH+ C43H60NO3Si2 694.4111, obsd 694.4092.
(2R,3S,4S)-1-Ben zyl-3,4-bis(ter t-bu tyldim eth ylsilyloxy)-
2-tr ip h en ylm eth oxym eth ylp yr r olid in e (25): on a scale of
11.0, 8.0, 3.0 Hz, 0.5H), 3.90-3.95 (m, 0.5H), 4.00 (t, J ) 6.3
Hz, 0.5H), 4.07-4.16 (m, 1H), 4.15 (t, J ) 6.3 Hz, 0.5H), 4.26-
4.44 (m, 2.5H), 4.71-4.84 (m, 1H), 7.13-7.49 (m, 20H), 7.64
(t, J ) 7.3 Hz, 1H), 7.71 (t, J ) 7.3 Hz, 1H), 7.79 (d, J ) 7.3,
1H); 13C NMR (CDCl3, 100 MHz) (mixture of rotamers) δ -4.9,
-4.6, -4.5, -4.4, 17.9, 18.0, 25.9, 47.0 and 47.3, 51.1 and 51.4,
58.8, 59.9, 66.7 and 67.1, 74.8 and 75.4, 77.4 and 77.1, 87.4,
119.7 and 119.8, 119.9, 124.7 and 124.8, 125.0 and 125.1, 126.9
and 127.0, 127.4 and 127.6, 127.7 and 128.8, 141.2 and 141.3,
143.8 and 143.9, 144.1 and 144.2, 154.3 and 154.4; HRMS
(FAB) calcd for MH+ C51H64NO5Si2 826.4323, obsd 826.4274.
Anal. Calcd for C51H63NO5Si2: C, 74.14; H, 7.69; N, 1.70.
Found: C, 73.58; H, 7.93; N, 1.70.
0.26 mmol (79%); TLC Rf 0.45 (10:1 hexanes-EtOAc); [R]20
D
1
) -21.4 (c 1.02, CHCl3); H NMR (CDCl3, 400 MHz) δ -0.14
(s, 3H), 0.01 (s, 3H), 0.02 (s, 3H), 0.05 (s, 3H), 0.75 (s, 9H),
0.90 (s, 9H), 2.34 (dd, J ) 10.4, 3.7 Hz, 1H), 3.14 (dd, J )
10.6, 4.9 Hz, 1H), 3.17-3.22 (m, 1H), 3.28 (dd, J ) 9.7, 3.7
Hz, 1H), 3.39 (dd, J ) 9.7, 7.2 Hz, 1H), 3.67 (d, J ) 13.6 Hz,
1H), 4.00 (app. q, J ) 3.7 Hz, 1H), 4.06 (dd, J ) 5.7, 3.7 Hz,
1H), 4.30 (d, J ) 13.6 Hz, 1H), 7.19-7.37 (m, 14H), 7.47-7.53
(m, 6H); 13C NMR (CDCl3, 100 MHz) δ -4.6, -4.2, -4.1, -4.1,
18.3, 26.2, 26.3, 59.0, 61.4, 65.7, 66.3, 78.2, 79.7, 87.6, 126.9,
127.2, 128.1, 128.5, 129.0, 129.3, 140.9, 144.5; HRMS (DEI)
calcd for M+ C43H59NO3Si2 693.4034, obsd 693.4024.
(2R,3R,4S)-3,4-Bis(ter t-b u t yld im et h ylsilyloxy)-1-flu o-
r en ylm eth oxyca r bon yl-2-tr ip h en ylm eth oxym eth ylp yr -
r olid in e (29): on a scale of 0.34 mmol (90%); TLC Rf 0.33 (5:1
hexanes-EtOAc); [R]20 ) -14.3 (c 0.28, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) (mixture of rotamers) δ -0.03 (s, 1.5H),
-0.02 (s, 6H), -0.01 (s, 1.5H), 0.00 (s, 3H), 0.79 (s, 13.5H),
0.83 (s, 4.5H), 3.01 (dd, J ) 9.7, 6.0 Hz, 0.5H), 3.06 (dd, J )
9.7, 2.5 Hz, 0.5H), 3.15-3.37 (m, 2H), 3.43-3.52 (m, 1H), 3.58-
3.64 (m, 0.5H), 3.78-3.84 (m, 0.5H), 3.92-3.97 (m, 1H), 4.00-
4.11 (m, 1H), 4.14-4.27 (m, 2H), 4.30-4.41 (m, 1H), 7.06-
7.44 (m, 20H), 7.52 (t, J ) 6.3 Hz, 1H), 7.61 (t, J ) 7.2 Hz,
1H), 7.65 (d, J ) 7.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
(mixture of rotamers) δ -4.3, -4.1, -3.9, 18.6, 18.7, 26.4, 26.5,
47.7 and 47.8, 50.5 and 50.8, 62.4 and 62.7, 65.6 and 66.1, 67.5,
71.3 and 71.7, 75.1 and 75.7, 87.4, 120.2, 120.4, 120.5, 125.3,
125.4, 125.6, 126.3, 127.5, 127.6, 128.3, 129.1, 141.8, 143.9,
144.3, 144.5, 144.7, 155.6; HRMS (FAB) calcd for [M + Na]+
(2R,3R,4S)-1-Ben zyl-3,4-bis(ter t-bu tyldim eth ylsilyloxy)-
2-tr ip h en ylm eth oxym eth ylp yr r olid in e (26): on a scale of
0.02 mmol (67%); TLC Rf 0.56 (5:1 hexanes-EtOAc); [R]20
)
D
1
-5.3 (c 0.30, CHCl3); H NMR (CDCl3, 400 MHz) δ -0.03 (s,
3H), -0.01 (s, 6H), 0.03 (s, 3H), 0.86 (s, 9H), 0.87 (s, 9H), 2.59
(t, J ) 8.4 Hz, 1H), 2.87-2.98 (m, 4H), 3.67 (d, J ) 13.1 Hz,
1H), 3.84 (d, J ) 3.8 Hz, 1H), 3.92-3.99 (m, 2H), 7.17-7.34
(m, 14H), 7.40-7.46 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ
-4.3, -4.2, -4.1, -3.8, 18.6, 18.7, 26.4, 26.5, 57.4, 61.9, 65.8,
71.0, 72.8, 75.8, 87.0, 127.3, 128.0, 128.2, 128.7, 129.2, 129.3,
140.1, 144.6; HRMS (DEI) calcd for M+ C43H59NO3Si2 693.4034,
obsd 693.4033.
C
C
51H63NO5Si2Na 848.4143, obsd 848.4117. Anal. Calcd for
51H63NO5Si2: C, 74.14; H, 7.69; N, 1.70. Found: C, 74.43; H,
Gen er a l P r oced u r e for Deben zyla tion a n d F m oc P r o-
tection . N-Benzyl-protected pyrrolidine (1.0 equiv) was dis-
solved in absolute ethanol (15 mL/mmol), and 10% palladium
on carbon was added (300 mg/mmol). The reaction vessel was
evacuated, and the reaction mixture was stirred under an
atmosphere of H2 at rt for 8 h. The catalyst was removed by
filtration through a pad of Celite and washed thoroughly with
ethanol (15 mL/mmol). The filtrate and washings were con-
centrated, and the crude amine residue was dissolved in
toluene (5 mL/mmol). The amine solution was added dropwise
to a solution of fluorenylmethyl chloroformate (1.1 equiv) in
toluene (10 mL/mmol). Triethylamine (1.1 equiv) was added
and the solution stirred at rt under N2 for 16 h. The solid was
removed by filtration and rinsed thoroughly with toluene (6
mL/mmol). The filtrate and washings were concentrated and
purified by flash column chromatography, eluting with 10:1
hexanes-EtOAc.
7.65; N, 1.55.
Gen er a l Meth od for Clea va ge of Tr ityl Eth er . The
pyrrolidine derivative (1.0 equiv) was dissolved in dry aceto-
nitrile (20 mL/mmol), formic acid (100 equiv) was added, and
the progress of the reaction was monitored by TLC. When the
reaction had proceeded to a satisfactory point, the solution was
diluted with EtOAc (100 mL/mmol) and washed with water
(100 mL/mmol), satd aq NaHCO3 (2 × 100 mL/mmol), and
brine (100 mL/mmol). The organic layer was dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
column chromatography, eluting with 5:1 hexanes-EtOAc.
(2S,3R,4S)-3,4-Bis(ter t-bu tyld im eth ylsilyloxy)-1-flu or e-
n ylm eth oxyca r bon yl-2-h yd r oxym eth ylp yr r olid in e (30):
on a scale of 0.12 mmol, with a reaction time of 10 min (70%
plus 25% recovered starting material): TLC Rf 0.28 (3:1
hexanes-EtOAc); [R]20 ) +12.6 (c 1.00, CHCl3); 1H NMR
D
(2S,3R,4S)-3,4-Bis(ter t-bu tyld im eth ylsilyloxy)-1-flu or e-
n ylm eth oxyca r bon yl-2-tr ip h en ylm eth oxym eth ylp yr r o-
lid in e (27): on a scale of 0.35 mmol (75%); TLC Rf 0.35 (5:1
(CDCl3, 200 MHz) (mixture of rotamers) δ 0.09 (s, 6H), 0.11
(s, 6H), 0.89 (s, 3H), 0.93 (s, 15H) 3.33-3.41 (m, 1H), 3.46-
3.57 (m, 2H), 3.79-3.85 (m, 0.5H), 3.89-3.99 (m, 1.5H), 4.06-
4.15 (m, 2H), 4.18-4.29 (m, 2H), 4.41 (dd, J ) 13.5, 6.7 Hz,
1H), 4.48-4.52 (m, 1H), 7.29-7.43 (m, 4H), 7.49-7.56 (m, 2H),
7.74-7.78 (m, 2H); 13C NMR (CDCl3, 50 MHz) (mixture of
rotamers) δ -4.9, -4.8, 18.1, 18.2, 25.6, 25.8, 47.2 and 47.3,
52.4 and 53.1, 58.7 and 61.5, 60.1 and 62.0, 67.1 and 67.4, 70.9
and 71.9, 73.2 and 73.3, 119.9, 124.9 and 125.1, 127.0 and
127.2, 127.6 and 127.7, 141.3 and 141.4, 143.8 and 143.9, 155.0
and 156.1; HRMS (CI) calcd for MH+ C32H50NO5Si2 584.3228,
obsd 584.3229.
hexanes-EtOAc); [R]20 ) +18.0 (c 1.10, CHCl3); 1H NMR
D
(CDCl3, 200 MHz) (mixture of rotamers) δ 0.01 (s, 3H), 0.05
(s, 3H), 0.08 (s, 3H), 0.13 (s, 3H), 0.80 (s, 6H), 0.84 (s, 6H),
0.86 (s, 6H), 3.20-3.47 (m, 2H), 3.69-3.95 (m, 2H), 4.12-4.23
(m, 2H), 4.47-4.78 (m, 4H), 7.22-7.37 (m, 12H), 7.41-7.59
(m, 8H), 7.73-7.91 (m, 3H); 13C NMR (CDCl3, 100 MHz)
(mixture of rotamers) δ -5.1, -4.9, 17.8, 18.0, 25.6, 25.8, 47.2
and 47.4, 53.2 and 53.7, 59.3 and 59.6, 63.3 and 63.8, 67.2 and
67.6, 70.9 and 72.1, 72.9 and 73.5, 86.5, 119.9, 125.2 and 125.7,
126.5 and 126.7, 127.0, 127.3, 128.8, 141.3, 143.7 and 144.0,
144.3 and 144.5, 155.2 and 156.1; HRMS (FAB) calcd for MH+
(2R,3S,4S)-3,4-Bis(ter t-bu tyld im eth ylsilyloxy)-1-flu or e-
n ylm eth oxyca r bon yl-2-h yd r oxym eth ylp yr r olid in e (31):
on a scale of 0.12 mmol, with a reaction time of 4 h (71%);
C
51H64NO5Si2 826.4323, obsd 826.4324. Anal. Calcd for C51H63-
NO5Si2: C, 74.14; H, 7.69; N, 1.70. Found: C, 74.14; H, 7.96;
N, 1.78.
TLC Rf 0.23 (7:2 hexanes-EtOAc); [R]20 ) -8.9 (c 1.01,
D
1
CHCl3); H NMR (CDCl3, 200 MHz) (mixture of rotamers) δ
(2R,3S,4S)-3,4-Bis(ter t-bu tyld im eth ylsilyloxy)-1-flu or e-
n ylm eth oxyca r bon yl-2-tr ip h en ylm eth oxym eth ylp yr r o-
lid in e (28): on a scale of 0.21 mmol (65%); TLC Rf 0.27 (5:1
0.07 (s, 3H), 0.08 (s, 3H), 0.10 (s, 6H), 0.88 (s, 9H), 0.89 (s,
9H), 3.35 (dd, J ) 11.2, 1.5 Hz, 1H), 3.61 (dd, J ) 11.2, 4.1
Hz, 1H), 3.67-3.89 (m, 2H), 3.90-4.13 (m, 3H), 4.26 (t, J )
6.7 Hz, 1H), 4.41 (s, 1H), 4.43-4.57 (m, 2H), 7.27-7.47 (m,
4H), 7.59 (dd, J ) 7.1, 3.4 Hz, 2H), 7.76 (d, J ) 7.1, Hz, 2H);
13C NMR (CDCl3, 50 MHz) (mixture of rotamers) δ -5.1, -4.8,
-4.6, -4.5, 17.9, 25.6, 25.7, 47.2, 53.1, 63.3, 63.4, 67.5, 74.8,
77.0 and 78.3, 120.0, 124.9 and 125.0, 127.0, 127.7, 141.3,
143.9, 157.0; HRMS (CI) calcd for MH+ C32H50NO5Si2 584.3228,
obsd 584.3218.
hexanes-EtOAc); [R]20 ) +18.0 (c 1.10, CHCl3); 1H NMR
D
(CDCl3, 200 MHz) (mixture of rotamers) δ -0.01 (s, 3H), 0.10
(s, 1.5H), 0.11 (s, 1.5H), 0.13 (s, 1.5H), 0.15 (s, 1.5H), 0.17 (s,
1.5H), 0.18 (s, 1.5H), 0.83 (s, 4.5H), 0.85 (s, 4.5H), 0.93 (s,
4.5H), 0.98 (s, 4.5H), 3.11 (dd, J ) 9.6, 3.6 Hz, 0.5H), 3.15-
3.27 (m, 1.5H), 3.39 (d, J ) 10.4 Hz, 0.5H),3.46 (dd, J ) 9.6,
3.6 Hz, 0.5H), 3.61 (br. d, J ) 8.0 Hz, 0.5H), 3.83 (ddd, J )

Synthesis of 3,4-Dihydroxyprolines from Pentose Sugars
J . Org. Chem., Vol. 67, No. 13, 2002 4473
(2R,3R,4S)-3,4-Bis(ter t-b u t yld im et h ylsilyloxy)-1-flu o-
r en ylm eth oxycar bon yl-2-h ydr oxym eth ylpyr r olidin e (32):
on a scale of 0.25 mmol, with a reaction time of 1 h (67%);
4.27 (m, 1.5H), 4.25 (t, J ) 6.7 Hz, 0.5H), 4.43-4.58 (m, 2H),
7.30-7.39 (m, 2H), 7.42 (q, J ) 7.8 Hz, 2H), 7.53 (t, J ) 7.8
Hz, 1H), 7.62 (dd, J ) 7.3, 3.8 Hz, 1H), 7.78 (app t, J ) 8.5
Hz, 2H), 9.26 (d, J ) 1.8 Hz, 0.5H), 9.59 (d, J ) 1.8 Hz, 0.5H);
13C NMR (CDCl3, 100 MHz) (mixture of rotamers) δ -4.1, -4.0,
-3.8, -3.7, -3.6, -3.5, 19.1, 26.8, 48.0 and 48.1, 51.3 and 51.4,
68.4 and 68.5, 72.0 and 72.1, 72.3 and 72.9, 74.8 and 75.6,
120.9, 121.0, 125.6, 125.7, 125.9, 126.0, 127.9, 128.0, 128.7,
128.9, 142.3, 144.6, 144.7, 155.6 and 156.4; HRMS (FAB) calcd
for MH+ C32H48NO5Si2 582.3071, obsd 582.3052.
TLC Rf 0.24 (7:2 hexanes-EtOAc); [R]20 ) +7.7 (c 0.13,
D
1
CHCl3); H NMR (CDCl3, 400 MHz) (mixture of rotamers) δ
0.06 (s, 3H), 0.09 (s, 3H), 0.11 (s, 3H), 0.12 (s, 3H), 0.88 (s,
4.5H), 0.92 (s, 13.5H), 3.22-3.30 (m, 0.5H), 3.37-3.45 (m, 2H),
3.58-3.66 (m, 1H), 3.80-3.85 (m, 1H), 3.87 (q, J ) 4.0 Hz,
1H), 4.00-4.06 (m, 0.5H), 4.08-4.15 (m, 1H), 4.27 (t, J ) 6.8
Hz, 1H), 4.39-4.50 (m, 1.5H), 4.51-4.67 (m, 0.5H), 7.33 (dt, J
) 7.5, 1.0 Hz, 2H), 7.42 (t, J ) 7.5 Hz, 2H), 7.56 (d, J ) 7.5
Hz, 0.5H), 7.60 (d, J ) 7.5 Hz, 1.5H), 7.78 (d, J ) 7.5 Hz, 2H);
13C NMR (CDCl3, 100 MHz) (mixture of rotamers) δ -5.0 and
-4.9, -4.5, -4.5, -4.3 and -4.2, 18.2, 25.9, 47.3, 51.0 and 51.4,
61.2, 65.8 and 66.0, 66.6, 70.8 and 71.1, 74.4, 119.9 and 120.1,
125.0 and 125.1, 127.1 and 127.2, 127.9 and 128.0, 141.4 and
141.5, 143.8 and 144.0, 155.6 and 156.9; HRMS (FAB) calcd
for MH+ C32H50NO5Si2 584.3228, obsd 584.3256.
Gen er a l Meth od for Oxid a tion to Ca r boxylic Acid . A
solution of the aldehyde (1.0 equiv) in a mixture of tert-butanol
(40 mL/mmol) and cyclohexene (4 mL/mmol) was added over
10 min to a solution of sodium chlorite (10.0 equiv) and
potassium dihydrogen phosphate (10.0 equiv) dissolved in
Milli-Q water (20 mL/mmol). The resulting solution was stirred
at rt under N2 for 4 h. The reaction mixture was diluted with
EtOAc (1 L/mmol) and washed with brine (1 L/mmol), dried
(MgSO4), filtered, and concentrated. The residue was purified
by flash column chromatography, eluting with 100% EtOAc.
D-2,3-cis-3,4-cis-N-F lu or en ylm et h oxyca r b on yl-3,4-d i-
h yd r oxy-3,4-d i-O-ter t-bu tyld im eth ylsilylp r olin e (7): on a
scale of 0.17 mmol (82%); TLC Rf 0.54 (1:1 hexanes-EtOAc);
Gen er a l P r oced u r e for Oxid a tion to Ald eh yd e. Dimeth-
yl sulfoxide (4.0 equiv) was added dropwise to a solution of
oxalyl chloride (2.0 equiv) in CH2Cl2 (20 mL/mmol) at -78 °C.
The solution was stirred under N2 at -78 °C for 20 min. A
solution of the primary alcohol (1.0 equiv) in CH2Cl2 (20 mL/
mmol) was added dropwise and the solution stirred under N2
at -78 °C for a further 30 min. The reaction mixture was
diluted with CH2Cl2 (500 mL/mmol) and washed with 1 M HCl
solution until just acidic. The organic layer was washed with
satd aq NaHCO3 (300 mL/mmol) then brine (300 mL/mmol),
dried (MgSO4), filtered, and concentrated. The residue was
purified by flash column chromatography, eluting with 7:2
hexanes-EtOAc.
[R]20 ) +13.1 (c 0.70, CHCl3); 1H NMR (CDCl3, 400 MHz)
D
(mixture of rotamers) 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, 0.5H), 4.21-4.17 (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 (CDCl3, 100 MHz) (mixture of
rotamers) δ -5.0, -4.8, 18.2, 25.6, 25.8, 46.9, 51.9 and 52.6,
62.9, 67.6 and 68.7, 72.9 and 73.2, 73.7, 119.9, 125.2 and 125.6,
127.1, 127.7, 141.3, 155.2 and 155.3, 168.6; HRMS (CI) calcd
for MH+ C32H48NO6Si2 598.3020, obsd 598.3022.
(2R,3R,4S)-3,4-Bis(ter t-b u t yld im et h ylsilyloxy)-1-flu o-
r en ylm eth oxyca r bon yl-2-for m ylp yr r olid in e (33): on
a
scale of 0.29 mmol (92%); TLC Rf 0.56 (7:2 hexanes-EtOAc);
L-2,3-cis-3,4-tr a n s-N-F lu or en ylm et h oxyca r b on yl-3,4-
d ih yd r oxy-3,4-d i-O-ter t-b u t yld im et h ylsilylp r olin e (36):
[R]20 ) -0.7 (c 2.97, CHCl3); 1H NMR (CDCl3, 400 MHz)
D
(mixture of rotamers) δ 0.09-0.16 (m, 12H), 0.90-0.94 (m,
18H), 3.51 (app. t, J ) 3.2 Hz, 1H), 3.97 (dd, J ) 7.8, 3.2 Hz,
0.5H), 4.07 (dd, J ) 7.8, 3.2 Hz, 0.5H), 4.13-4.22 (m, 1.5H),
4.26-4.42 (m, 2.5H), 4.49 (dd, J ) 10.5, 6.5 Hz, 0.5H), 4.54
(dd, J ) 10.5, 6.5 Hz, 0.5H), 7.32 (t, J ) 7.5 Hz, 2H), 7.38-
7.44 (m, 2H), 7.52 (d, J ) 7.5 Hz, 0.5H), 7.55 (d, J ) 7.5 Hz,
0.5H), 7.60 (t, J ) 7.5 Hz, 1H), 7.68 (t, J ) 7.5 Hz, 2H), 9.47
(d, J ) 3.2 Hz, 0.5H), 9.53 (d, J ) 2.9 Hz, 0.5H); 13C NMR
(CDCl3, 100 MHz) (mixture of rotamers) δ -4.5, -4.3, -4.2,
18.5, 18.7, 26.1, 26.2, 47.5 and 47.6, 52.4 and 52.9, 66.2, 67.9
and 68.2, 72.1 and 72.8, 76.3 and 77.1, 120.4, 125.3 and 125.5,
127.4, 128.1, 141.6 and 141.7, 143.9, 144.2 and 144.3, 155.4
and 155.7, 199.7 and 199.9; HRMS (FAB) calcd for MH+
on a scale of 0.05 mmol (93%); TLC Rf 0.14 (3:1 hexanes-
1
EtOAc); [R]20 ) -31.5 (c 0.98, CHCl3); H NMR (CDCl3, 400
D
MHz) (mixture of rotamers) δ 0.07 (s, 3H), 0.09 (s, 6H), 0.10
(s, 3H), 0.86 (s, 13.5H), 0.86 (s, 4.5H), 3.40 (d, J ) 10.6 Hz,
0.5H), 3.46 (d, J ) 10.6 Hz, 0.5H), 3.72-3.81 (m, 1H), 4.05-
4.19 (m, 1.5H), 4.22-4.32 (m, 1.5H), 4.33-4.47 (m, 2.5H), 4.55
(d, J ) 5.8 Hz, 0.5H), 7.26-7.33 (m, 2H), 7.34-7.43 (m, 2H),
7.49-7.64 (m, 2H), 7.70 (d, J ) 7.5 Hz, 2H); 13C NMR (CDCl3,
100 MHz) (mixture of rotamers) δ -5.1, -4.8, 17.8, 25.6, 25.7,
47.1 and 47.2, 52.2, 62.9 and 63.1, 67.6 and 67.8, 74.6 and 75.2,
77.4 and 78.3, 119.9, 124.9, 125.0 and 125.1, 127.0 and 127.7,
141.3, 144.0, 155.3, 173.4 and 173.9; HRMS (FAB) calcd for
MH+ C32H48NO6Si2 598.3020, obsd 598.3017.
C
32H48NO5Si2 582.3026, obsd 582.3060.
(2S,3S,4S)-3,4-Bis(ter t-bu tyld im eth ylsilyloxy)-1-flu or e-
L-2,3-tr a n s-3,4-cis-N-F lu or en ylm et h oxyca r b on yl-3,4-
d ih yd r oxy-3,4-d i-O-ter t-b u t yld im et h ylsilylp r olin e (37):
n ylm eth oxyca r bon yl-2-for m ylp yr r olid in e (34): on a scale
on a scale of 0.082 mmol (83%); TLC Rf 0.36 (10:1 CH2Cl2-
of 0.04 mmol (96%): TLC Rf 0.33 (7:2 hexanes-EtOAc); [R]20
MeOH); [R]20 ) -2.1 (c 0.49, CHCl3); H NMR (CDCl3, 400
1
D
D
) -38.7 (c 0.96, CHCl3); 1H NMR (CDCl3, 400 MHz) (mixture
of rotamers) δ 0.03-0.08 (m, 12H), 0.84 (s, 4.5H), 0.86 (s, 4.5H),
0.86 (s, 4.5H), 0.87 (s, 4.5H), 3.48 (d, J ) 11.1 Hz, 0.5H), 3.61
(d, J ) 11.1 Hz, 0.5H), 3.78 (dd, J ) 11.1, 3.6 Hz, 1H), 3.97
(br. s, 0.5H), 4.02 (br. s, 0.5H), 4.05-4.09 (m, 0.5H), 4.18 (t, J
) 6.2 Hz, 0.5H), 4.22-4.32 (m, 2H), 4.38-4.53 (m, 2H), 7.25-
7.33 (m, 2H), 7.34-7.43 (m, 2H), 7.48 (d, J ) 7.5 Hz, 0.5H),
7.51 (d, J ) 7.5 Hz, 0.5H), 7.60 (t, J ) 8.6 Hz, 1H), 7.76 (t, J
) 7.5 Hz, 1H), 9.28 (d, J ) 2.9 Hz, 0.5H), 9.50 (d, J ) 2.9 Hz,
0.5H); 13C NMR (CDCl3, 100 MHz) (mixture of rotamers) δ
-5.3, -4.8, -4.7, 17.8, 25.5, 25.6, 47.1 and 47.2, 53.2 and 53.7,
67.5 and 67.8, 75.0 and 75.9, 79.1 and 80.4, 120.0, 124.7 and
124.8, 124.9 and 125.0, 127.0 and 127.7, 141.3, 143.8, 155.1
MHz) (mixture of rotamers) δ 0.07 (s, 1.5H), 0.09 (s, 6H), 0.11
(s, 4.5H), 0.88 (s, 9H), 0.91 (s, 9H), 3.34-3.47 (m, 1H), 3.60
(dd, J ) 9.6, 6.4 Hz, 0.5H), 3.66 (dd, J ) 10.2, 6.4 Hz, 0.5H),
4.12-4.24 (m, 2.5H), 4.23 (d, J ) 2.0 Hz, 1H), 4.29 (t, J ) 7.0
Hz, 0.5H), 4.36 (dd, J ) 3.5, 2.0 Hz, 0.5H), 4.40 (t, J ) 7.0 Hz,
0.5H), 4.44 (d, J ) 2.2 Hz, 0.5H), 4.46 (d, J ) 2.9 Hz, 0.5H),
7.27-7.45 (m, 4H), 7.51-7.62 (m, 2H), 7.72 (d, J ) 7.4 Hz,
1H), 7.78 (d, J ) 7.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
(mixture of rotamers) δ -4.8, -4.7, -4.4, -4.3, -4.2, -4.1,
18.5, 26.1, 26.2, 47.5, 50.3 and 50.5, 66.1 and 66.4, 68.1 and
68.3, 71.4 and 71.9, 75.9, 120.3 and 120.4, 125.4 and 125.5,
127.4 and 127.5, 128.0 and 128.2, 141.6 and 141.7, 144.1 and
144.4, 155.0 and 156.2, 174.9 and 175.9; HRMS (FAB) calcd
for MH+ C32H48NO6Si2 598.3020, obsd 598.3049.
Gen er a l P r oced u r e* for th e Rem ova l of P r otectin g
Gr ou p s To Affor d Dih yd r oxyp r olin es. Trifluoroacetic acid
(1 mL) was added to a solution of the protected dihydroxypro-
line (20-50 µmol) in dichloromethane (1 mL) and the solution
stirred under an atmosphere of nitrogen at rt overnight. The
reaction mixture was concentrated, dissolved in Tesser’s base
(2 mL), and stirred at rt for 1 h. The reaction mixture was
diluted with water (20 mL) and washed with ethyl acetate
(2 × 10 mL). The aqueous phase was concentrated and the
and 156.0, 201.1 and 201.2; HRMS (DEI) calcd for M+ C32H47
NO5Si2 581.2993, obsd 581.2978.
-
(2S,3R,4S)-3,4-Bis(ter t-bu tyld im eth ylsilyloxy)-1-flu or e-
n ylm eth oxyca r bon yl-2-for m ylp yr r olid in e (35): on a scale
of 0.10 mmol (83%); TLC Rf 0.30 (7:2 hexanes-EtOAc); [R]20
D
) +11.8 (c 0.09, CHCl3); 1H NMR (CDCl3, 400 MHz) (mixture
of rotamers) δ 0.08-0.17 (m, 12H), 0.90 (s, 4.5H), 0.92 (s, 4.5H),
0.94 (s, 9H), 3.41 (dd, J ) 9.9, 6.8 Hz, 0.5H), 3.47 (dd, J ) 9.9,
6.6 Hz, 0.5H), 3.60 (q, J ) 5.6 Hz, 1H), 3.93 (dd, J ) 3.5, 2.1
Hz, 0.5H), 3.96-4.05 (m, 1H), 4.14 (t, J ) 7.1 Hz, 0.5H), 4.20-

4474 J . Org. Chem., Vol. 67, No. 13, 2002
Taylor et al.
residue purified by ion-exchange chromatography (Dowex H+)
eluting with 0.5 M NH4OH.
tetrabutylammonium fluoride in THF (163 µL, 163 µmol, 3.0
equiv) was added to a solution of compound 36 (32.3 mg, 54.2
µmol) in THF (2 mL) and the solution stirred under an atm of
N2 at rt for 4 h. The reaction mixture was concentrated and
then dissolved in Tesser’s base (2 mL) and stirred at rt for 1
h. The reaction mixture was diluted with water (20 mL) and
washed with EtOAc (2 × 10 mL). The aqueous phase was
concentrated and the residue purified by ion-exchange chro-
matography (Dowex H+) eluting with 0.5 M NH4OH to afford
the titled compound as a white solid (4.7 mg, 59%): TLC Rf
0.30 (6:4:1 CHCl3-CH3OH-H2O); [R]20D ) -37.5 (c 0.24, H2O)
(lit.2a [R]20 ) -61.2 (c 0.5%, H2O), lit.10b [R]24 ) -56 (c 0.62,
D-2,3-cis-3,4-cis-Dih yd r oxyp r olin e (38). [This isomer has
been synthesized previously.33 The enantiomer has been
synthesized several times.5b,34-37 For a racemic synthesis see
ref 9.] On a scale of 52.0 µmol to give 38 as a colorless solid
(4.4 mg, 58%): TLC Rf 0.37 (6:4:1 CHCl3-CH3OH-H2O); [R]20
D
) +26.7 (c 0.18, H2O) (lit.33 [R]20 ) +55.9 (c 0.6, H2O) [for
D
the enantiomer: lit.34 [R]20 ) -56.8 (c 0.16, H2O)]); 1H NMR
D
(D2O, 400 MHz) δ 3.10 (dd, J ) 11.4, 8.7 Hz, 1H), 3.41 (dd, J
) 11.4, 7.6 Hz, 1H), 4.01 (d, J ) 3.9 Hz, 1H), 4.23-4.37 (m,
2H); 13C NMR (D2O, 68 MHz) δ 47.1, 64.9, 70.7, 71.0, 170.8;
HRMS (FAB+) calcd for MH+ C5H10NO4 148.0609, obsd
148.0618.
D
D
H2O); lit.43 [R]27 ) -63.2 (c 0.5, H2O), lit.44 [R]22 ) -63.0 (c
D
D
0.8, H2O) [enantiomer: lit.45 [R]20 ) +46.2 (c 1.0, H2O), lit.46
D
L-2,3-tr a n s-3,4-cis-Dih yd r oxyp r olin e (3). [This isomer
has been synthesized several times.5b,6a,7,33,38,39 The enantiomer
has also been synthesized.38,40 For racemic syntheses see ref
9 and 41.] On a scale of 22.0 µmol to give 3 as a colorless solid
[R]20D ) +63.4 (c 0.35, H2O)]); 1H NMR (D2O, 400 MHz) δ 3.14
(d, J ) 12.8 Hz, 1H), 3.53 (dd, J ) 12.8, 3.8 Hz, 1H), 4.18 (d,
J ) 3.8 Hz, 1H), 4.26 (br d, J ) 7.7 Hz, 1H), 4.30 (br d, J )
7.7 Hz, 1H); 13C NMR (D2O, 68 MHz) δ 51.3, 65.6, 75.4, 75.9,
171.5. HRMS (FAB+) calcd for MH+ C5H10NO4 148.0609, obsd
148.0612.
(3.0 mg, 93%): TLC Rf 0.34 (6:4:1 CHCl3-CH3OH-H2O); [R]20
D
) +1.9 (c 0.27, H2O) (lit.6a [R]20 ) +7.5 (c 0.16, H2O), lit.7
D
[R]20 ) +5.9 (c 0.35, H2O), lit.33 [R20]D ) +7.2 (c 0.5, H2O),
D
lit.38 [R]20D ) +7.5 (c 0.5, H2O), [enantiomer: lit.38 [R]20D ) -7.4
Ack n ow led gm en t. We thank the Marsden Fund
(Grant Nos. 96-UOA-617 and 00-MAU-018), adminis-
tered by the Royal Society of New Zealand, and the
Health Research Council of New Zealand (Grant No. 00/
232/BRC/PJ /U OF A, reference no. 00/232) for financial
support. We thank The Wellcome Trust for a large
equipment grant. For work conducted at the University
of Auckland: we thank Michael F. Walker for running
mass spectrometry experiments and for maintenance of
the NMR facility. For work conducted at Massey Uni-
versity, we thank the mass spectrometry facility at Hort
Research and Dr. P. J . B. Edwards for maintenance of
the NMR facility.
(c 0.5, H2O), lit.40 [R]20 ) -6.8 (c 0.43, H2O)]); 1H NMR (D2O,
D
400 MHz) δ 3.16 (dd, J ) 12.4, 4.4 Hz, 1H), 3.40 (dd, J ) 12.4,
4.9 Hz, 1H), 3.83 (d, J ) 4.8 Hz, 1H), 4.14-4.25 (m, 2H); 13C
NMR (D2O, 100 MHz) δ 48.7, 64.7, 70.3, 74.5, 172.6; HRMS
(FAB) calcd for MH+ C5H10NO4 148.0609, obsd 148.0634.
*The removal of the TBDMS groups from 36 was sluggish
under acidic conditions and it was adventitious to use
TBAF in this case: L-2,3-cis-3,4-tr a n s-Dih yd r oxyp r olin e
(1). [This isomer has been synthesized previously.10b,42-44 The
enantiomer has also been synthesized.45,46] A 1 M solution of
(33) Ikota, N. Heterocycles 1993, 36, 2035-2050.
(34) Austin, G. N.; Baird, P. D.; Fleet, G. W. J .; Peach, J . M.; Smith,
P. W.; Watkin, D. J . Tetrahedron 1987, 43, 3095-3108.
(35) Fujii, M.; Miura, T.; Kajimoto, T.; Ida, Y. Synlett 2000, 1046-
1048.
(36) (a) Moss, W. O.; Bradbury, R. H.; Hales, N. J .; Gallagher, T. J .
Chem. Soc., Chem. Commun. 1990, 51-53. (b) Moss, W. O.; Bradbury,
R. H.; Hales, N. J .; Gallagher, T. J . Chem. Soc., Perkin Trans. 1 1992,
1901-1906.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
all compounds reported. This material is available free of
charge via the Internet at http://pubs.acs.org.
(37) Defoin, A.; Sifferlen, T.; Streith, J . Synlett 1997, 1294-1296.
(38) Zanardi, F.; Battistini, L.; Nespi, M.; Rassu, G.; Spanu, P.;
Cornia, M.; Casiraghi, G. Tetrahedron: Asymmetry 1996, 7, 1167-1180.
(39) Baldwin, J . E.; Field, R. A.; Lawrence, C. C.; Lee, V.; Robinson,
J . K.; Schofield, C. J . Tetrahedron Lett. 1994, 35, 4649-4652.
(40) (a) Dho, J . C.; Fleet, G. W. J .; Peach, J . M.; Prout, K.; Smith,
P. W. Tetrahedron Lett. 1986, 27, 3203-3204. (b) Baird, P. D.; Dho, J .
C.; Fleet, G. W. J .; Peach, J . M.; Prout, K.; Smith, P. W. J . Chem. Soc.,
Perkin Trans. 1 1987, 1785-1791.
J O025538X
(43) Arakawa, Y.; Yoshifuji, S. Chem. Pharm. Bull. 1991, 39, 2219-
2224.
(44) (a) Ohfune, Y.; Kurokawa, N. Tetrahedron Lett. 1985, 26, 5307-
5308. (b) Novales-Li, P.; Watanabe, K.; Hiroshi, T.; Ohfune, Y.;
Kurokawa, N.; Kurono, M. Eur. J . Pharmacol. 1987, 143, 415-423.
(45) Lee, B. W.; J eong, I.-Y.; Yang, M. S.; Choi, S. U.; Park, K. H.
Synthesis 2000, 1305-1309.
(46) Bashyal, B. P.; Chow, H. F.; Fellows, L. E.; Fleet, G. W. J .
Tetrahedron 1987, 43, 415-422.
(41) Behr, J .-B.; Defoin, A.; Mahmood, N.; Streith, J . Helv. Chim.
Acta 1995, 78, 1166-1177.
(42) Deming, T. J .; Fournier, M. J .; Mason, T. L.; Tirrell, D. A. Pure
Appl. Chem. 1997, A34, 2143-2150.