A total synthesis of hydroxylysine in protected form and investigations of the reductive opening of p-methoxybenzylidene acetals

Article abstract of DOI:10.1021/jo049136w

A synthesis of (2S,5R)-5-hydoxylysine, based on (R)-malic acid and Williams glycine template as chiral precursors, has been developed. This afforded hydroxylysine, suitably protected for direct use in peptide synthesis, in 32% yield over the 13-step sequence. Regioselective reductive opening of a p-methoxybenzylidene acetal and alkylation of the Williams glycine template were key steps in the synthetic sequence. Surprisingly, the regioselectivity in opening of the p-methoxybenzylidene acetal was reversed as compared to what was expected. It was found that this was due to chelation of the trialkylsilyl choride, used as an electrophile in the reductive opening, to an adjacent azide functionality. It was also discovered that an equivalent amount of trialkylsilyl hydride was formed in the reaction, a finding that led to additional mechanistic insight into reductive openings of p-methoxybenzylidene acetals with sodium cyanoborohydride as reducing agent.

Full text of DOI:10.1021/jo049136w

A Total Synthesis of Hydroxylysine in Protected Form and
Investigations of the Reductive Opening of p-Methoxybenzylidene
Acetals
Tomas Gustafsson,† Magnus Schou,† Fredrik Almqvist,† and Jan Kihlberg*,†,#
Organic Chemistry, Department of Chemistry, Umea˚ University, SE-901 87 Umea˚, Sweden, and
AstraZeneca R&D Mo¨lndal, SE-431 83 Mo¨lndal, Sweden
jan.kihlberg@chem.umu.se
Received May 23, 2004
A synthesis of (2S,5R)-5-hydoxylysine, based on (R)-malic acid and Williams glycine template as
chiral precursors, has been developed. This afforded hydroxylysine, suitably protected for direct
use in peptide synthesis, in 32% yield over the 13-step sequence. Regioselective reductive opening
of a p-methoxybenzylidene acetal and alkylation of the Williams glycine template were key steps
in the synthetic sequence. Surprisingly, the regioselectivity in opening of the p-methoxybenzylidene
acetal was reversed as compared to what was expected. It was found that this was due to chelation
of the trialkylsilyl choride, used as an electrophile in the reductive opening, to an adjacent azide
functionality. It was also discovered that an equivalent amount of trialkylsilyl hydride was formed
in the reaction, a finding that led to additional mechanistic insight into reductive openings of
p-methoxybenzylidene acetals with sodium cyanoborohydride as reducing agent.
Introduction
tions of a carbonyl group at C-5 in the side chain, and
thus required separation of the resulting diasteromers
to provide optically pure material.9,10 A procedure that
combined the Scho¨llkopf method to generate the R-ste-
reogenic center and a Sharpless asymmetric aminohy-
droxylation to create the 2-aminoethanol moiety of
hydroxylysine turned out to be less suitable for prepara-
tion of the naturally occurring (2S,5R)-isomer than for
synthesis of the (2S,5S)-isomer.11 However, an attractive
approach based on chiral glycine template methodology
and use of (R)-hydroxynitrile lyase for the introduction
of chirality at the R-position and in the side chain,
respectively, has been described.12 Two recent reports
describe the synthesis of both (2S,5R)- and (2S,5S)-5-
hydroxylysine through a route based on stereoselective
hydroxylation of 6-substituted piperidin-2-ones.13,14
In view of our previous studies on the synthesis of
glycosylated derivatives of hydroxylysine,15,16 including
a C-glycosidic analogue,17 we were interested in the
development of a synthetic route to (2S,5R)-5-hydroxy-
Collagen is the most abundant protein found in mam-
mals. This fibrous protein has structural functions and
is found in slightly different forms in almost all organs.
Lysine residues in collagen can undergo posttranslational
hydroxylation to give (2S,5R)-5-hydroxylysine, which was
first discovered in protein hydrolysates.1,2 In addition, the
hydroxylysine residues may be glycosylated, either with
a â-D-galactopyranosyl- or an R-D-glucopyranosyl-(1f2)-
â-D-galactopyranosyl moiety.3 The structure of the natu-
rally occurring (2S,5R)-5-hydroxylysine was determined
in 1950,4,5 and the first synthesis of racemic 5-hydroxy-
lysine was reported at the same time.6 Since then a
number of syntheses leading to stereoisomeric mixtures
of hydroxylysine have been published, and it has been
shown that the four stereoisomers can be separated by
fractional crystallization after derivatization.7,8
During recent years some approaches for stereoselec-
tive syntheses of (2S,5R)-5-hydroxylysine and its stereo-
isomers have been reported. Two routes starting from
S-glutamic acid were based on nonstereoselective reduc-
(9) Adamczyk, M.; Johnson, D. D.; Reddy, R. E. Tetrahedron 1999,
55, 63-88.
(10) Allevi, P.; Anastasia, M. Tetrahedron: Asymmetry 2000, 11,
3151-3160.
(11) Lo¨hr, B.; Orlich, S.; Kunz, H. Synlett 1999, 1139-1141.
(12) van den Nieuwendijk, A. M. C. H.; Kriek, N. M. A. J.; Brussee,
J.; van Boom, J. H.; van der Gen, A. Eur. J. Org. Chem. 2000, 3683-
3691.
(13) Marin, J.; Didierjean, C.; Aubry, A.; Briand, J.-P.; Guichard,
G. J. Org. Chem. 2002, 67, 8440-8449.
(14) Marin, J.; Violette, A.; Briand, J.-P.; Guichard, G. Eur. J. Org.
Chem. 2004, 3027-3039.
(15) Broddefalk, J.; Ba¨cklund, J.; Almqvist, F.; Johansson, M.;
Holmdahl, R.; Kihlberg, J. J. Am. Chem. Soc. 1998, 120, 7676-7683.
(16) Broddefalk, J.; Forsgren, M.; Sethson, I.; Kihlberg, J. J. Org.
Chem. 1999, 64, 8948-8953.
(17) Wellner, E.; Gustafsson, T.; Ba¨cklund, J.; Holmdahl, R.; Kihl-
berg, J. ChemBioChem 2000, 1, 272-280.
† Umea˚ University.
# AstraZeneca R&D Mo¨lndal.
(1) Van Slyke, D. D.; Hiller, A. Proc. Natl. Acad. Sci. U.S.A. 1921,
7, 185-186.
(2) Van Slyke, D. D.; Hiller, A.; Dillon, R. T.; MacFadyen, D. Proc.
Soc. Exp. Biol. Med. 1938, 38, 548-549.
(3) Spiro, R. G. J. Biol. Chem. 1967, 242, 4813-4823.
(4) Sheehan, J. C.; Bolhofer, W. A. J. Am. Chem. Soc. 1950, 72,
2469-2472.
(5) Bergstro¨m, S.; Lindstedt, S. Arch. Biochem. Biophys. 1950, 26,
323-324.
(6) Sheehan, J. C.; Bolhofer, W. A. J. Am. Chem. Soc. 1950, 72,
2472-2474.
(7) Fones, W. S. J. Am. Chem. Soc. 1953, 75, 4865-4866.
(8) Fones, W. S. Biochem. Prepr. 1961, 8, 62-69.
10.1021/jo049136w CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/12/2004
8694
J. Org. Chem. 2004, 69, 8694-8701

Total Synthesis of Hydroxylysine
Our aim was then to open the p-methoxybenzylidene
acetal of 6 under reductive conditions to generate a
primary alcohol while leaving the secondary alcohol
protected as a p-methoxybenzyl ether. Several examples
of regioselective reductions of p-methoxybenzylidene
acetals in compounds closely related to 6 have been
reported.20-23 In these cases, use of DIBAL, which
complexes with the sterically least hindered oxygen atom
in the 1,3-dioxane moiety, resulted in unmasking of the
primary hydroxyl group in high yields. Most unexpect-
edly, this selectivity was reversed when 6 was treated
with DIBAL in dichloromethane, and secondary alcohol
7a was obtained as the major product in 60% yield (Table
1, entry 1). Exchange of dichloromethane for diethyl ether
or THF as solvent did not allow reduction with DIBAL.
Several attempts toward reduction of 6 with borane and
a Lewis acid under carefully controlled conditions re-
sulted in either no reaction or reduction of the azide
functionality. However, when Bu2BOTf was used as
Lewis acid 7a was formed, but in a modest 37% yield
(Table 1, entry 2).
FIGURE 1. Retrosynthetic analysis of (2S,5R)-5-hydroxy-
lysine (1).
SCHEME 1a
In carbohydrate chemistry, sodium cyanoborohydride
together with an electrophile is employed on a routine
basis for regioselective reduction of both 4,6-O-ben-
zylidene and 4,6-O-p-methoxybenzylidene acetals at-
tached to hexopyranosides (Figure 2).24-26 With a proton
(TFA) as an electrophile, thermodynamic protonation at
O-4 favors opening of p-methoxybenzylidene acetals to
give the corresponding 6-O-p-methoxybenzyl ethers.26 If
a larger electrophile such as trimethylsilyl chloride is
chosen, selectivity is reversed to favor formation of the
4-O-p-methoxybenzyl ether. In this case attack of the
trimethylsilyl chloride occurs at O-6 and is assumed to
be kinetically and/or sterically controlled. Reduction of
6 with sodium cyanoborohydride and trimethylsilyl chlo-
ride proceeded regioselectively, but again secondary
alcohol 7a was formed instead of the expected primary
alcohol (Table 1, entry 3). Thus, the azidomethylene chain
of 6 does not seem to impose sufficient steric hindrance
to direct the electrophilic trimethylsilyl group to the
primary oxygen atom. Alternatively, the azidomethylene
group may be involved in directing the electrophile to the
secondary oxygen atom of 6. Use of larger silyl chlorides
did not influence the regioselectivity, but the reductions
proceeded to give mixtures of 7a and the silylated
derivatives 7b-d (Table 1, entries 4-8). In all these
reductions 2 equiv of sodium cyanoborohydride and the
silyl chloride were used with acetonitrile as solvent at
room temperature. Use of tert-butyldimethylsilyl chloride
gave almost exclusive silylation of the secondary hydroxyl
group and in acetonitrile 7b was obtained in 89% yield
(entry 5). By switching to DMF as solvent, the same
selectivity was achieved and silylation was complete but
the isolated yield of 7b was lower. When even larger silyl
chlorides, such as TIPSCl and TBDPSCl, were used, the
reduction still proceeded, but silylation of the alcohol
occurred to a lower extent (entries 7 and 8). In view of
these results it was perhaps not surprising that use of
a Reagents and conditions: (a) BH3‚SMe2, B(OMe)3, THF, rt;
(b) p-methoxybenzaldehyde, pyridinium toluene-4-sulfonate, CH2Cl2,
reflux (89% from 2); (c) TsCl, Et3N, DMAP, CH2Cl2, rt (98%); (d)
NaN3, DMF, 55 °C (88%); (e) NaCNBH3, TBDMSCl, CH3CN, rt
(89%).
lysine (1, Figure 1). Synthesis of hydroxylysine requires
control of two stereogenic centers, the R-position and the
hydroxylated C-5 in the side chain. In the synthetic route
presented here the stereogenic integrity at C-5 was
ascertained by preparing the side chain of hydroxylysine
from (R)-malic acid (2), while chirality at the R-position
was ensured by alkylation of a chiral glycine template
(Figure 1).
Results and Discussion
Synthesis of a Hydroxylysine Side Chain Equiva-
lent. The synthetic route to (2S,5R)-5-hydroxylysine (1)
began by reduction of (R)-malic acid (2) with borane in
the presence of trimethylborate (Scheme 1). This fur-
nished triol 318 without epimerization of the stereogenic
center.19 Although the reduction appeared to proceed in
quantitative yield, purification of 3 by column chroma-
tography reduced the reaction time and improved the
yield in the next step. Selective acetalization20 of the 1,3-
diol in 3 was achieved by treatment with p-methoxyben-
zaldehyde and pyridinium p-toluenesulfonate in dichlo-
romethane to give 421 in 89% yield from 2. Then tosylation
of the hydroxyl group in 4, followed by substitution of
the tosylate with sodium azide in DMF, afforded 6 (86%
from 4).
(18) Hanessian, S.; Ugolini, A.; Dube´, D.; Glamyan, A. Can. J. Chem.
1984, 62, 2146-2147.
(22) Panek, J. S.; Liu, P. J. Am. Chem. Soc. 2000, 122, 11090-11097.
(23) Blakemore, P. R.; Kim, S.-K.; Schulze, V. K.; White, J. D.;
Yokochi, A. F. T. J. Chem. Soc., Perkin Trans. 1 2001, 1831-1845.
(24) Garegg, P. J.; Hultberg, H. Carbohydr. Res. 1981, 93, c10-c11.
(25) Garegg, P. J. Pure Appl. Chem. 1984, 56, 845-858.
(26) Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1984, 2371-2374.
(19) Triol 3 had [R]D +26 (c 1.0, MeOH) [lit. +26 (c 1.0, MeOH,
Sigma-Aldrich)].
(20) Toshima, H.; Maru, K.; Saito, M.; Ichihara, A. Tetrahedron
1999, 55, 5793-5808.
(21) Breuilles, P.; Oddon, G.; Uguen, D. Tetrahedron Lett. 1997, 38,
6607-6610.
J. Org. Chem, Vol. 69, No. 25, 2004 8695

Gustafsson et al.
TABLE 1. Influence of Reducing Agent and Lewis Acid on the outcome of the Reductive Opening of the Benzylidene
Acetal in 6
reducing
agent (2 equiv)
Lewis acid
(2 equiv)
solvent,
temp
7a,
R ) H
7b-d,
R ) SiR′3
entry
1
2
DIBAL
DIBAL
Bu2BOTf
TMSCl
TESCl
CH2Cl2, -78 °C
CH2Cl2, -78 °C
MeCN, rt
60%a
37%
93%
62%
8%
BH3‚THF
NaCNBH3
NaCNBH3
NaCNBH3
NaCNBH3
NaCNBH3
NaCNBH3
NaCNBH3
NaCNBH3
3
4
MeCN, rt
7c, R ) TES, 15%
5
TBDMSCl
TBDMSCl
TBDPSCl
TIPSCl
TFA
MeCN, rt
7b, R ) TBDMS, 89%
7b, R ) TBDMS, 72%
7d, R ) TBDPS, 30%
6
DMF, rt
-
7
MeCN, rt
60%
81%
85%
-
8
MeCN, rt
9
MeCN, rt
10
-
MeCN, rt
a In addition, some formation of a product corresponding to 7a, from which the PMB group had been cleaved off, was observed.
SCHEME 2a
FIGURE 2. A schematic example of how the choice of
electrophile determines the regioselectivity in reductive open-
ing of 4,6-O-p-methoxybenzylidene acetals attached to carbo-
hydrates.
a Reagents and conditions: (a) DDQ, CH3CN/H2O, rt; (b) MsCl,
TFA as Lewis acid resulted in the same regioselectivity
triethylamine, DMAP, CH2Cl2, 0 °C; (c) NaI, acetone, reflux (76%
(entry 9). When the reduction was attempted in the
over three steps); (d) 16b, NaHMDS, 15-crown-5, THF, -78 to -20
absence of Lewis acid compound 6 remained unreacted
(entry 10), confirming that electrophilic activation of the
acetal is required for the reaction to proceed.
°C (94%); (e) (i) PPh3, THF/H2O, microwave, (ii) Boc2O, triethyl-
amine, THF (85%); (f) (i) H2 (65 psi), Pd/C, THF/H2O, rt, (ii)
FmocOSu, Na2CO3, acetone/H2O (77%).
The unexpected regioselectivity obtained in the reduc-
tive opening of the benzylidene acetal of 6 prompted a
slight modification of the original synthetic route. Thus,
the synthesis of hydroxylysine was continued by depro-
tection of the p-methoxybenzyl ether of 7b with DDQ
(Scheme 2). Unfortunately, the p-methoxybenzaldehyde
formed in this step turned out to be difficult to remove
by column chromatography. Therefore the mixture of
alcohol 8 and p-methoxybenzaldehyde was subjected to
mesylation followed by substitution with sodium iodide
before purification to give 10 (76% overall yield from 7b).
Alkyl iodide 10, obtained in eight steps from (R)-malic
acid, thus constitutes a building block corresponding to
the side chain of hydroxylysine.
Preparation of Hydroxylysine by Enantioselec-
tive Alkylation. Several glycine equivalents are avail-
able for preparation of chiral amino acids, and we decided
to evaluate templates 14-16 (Figure 3) in alkylations
with iodide 10. Myers and co-workers have described that
glycine coupled to pseudoephedrine (i.e. 14) can be
alkylated with alkyl halides.27 In our hands no reaction
FIGURE 3. Chiral glycine templates investigated in alkyla-
tions with iodide 10.
occurred between 14 and 10, and the starting materials
could usually be recovered. In a few of the attempts a
deiodinated product, formed by transmetalation of 10
followed by protonation, could be isolated. Attention was
then directed to the attractive method of catalytic enan-
tioselective alkylation developed in the groups of Corey28-30
(27) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem.
Soc. 1997, 119, 656-673.
(28) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414-12415.
8696 J. Org. Chem., Vol. 69, No. 25, 2004

Total Synthesis of Hydroxylysine
and Lygo.31-33 These research groups have reported
several successful stereoselective alkylations of ben-
zophenone-protected tert-butyl glycine 15 using a cin-
chonidinium-derived catalyst. Usually alkylations were
performed with highly activated electrophiles, such as
benzyl and allyl halides, but examples of nonactivated
alkyl halides used in model studies also exist.28,29 Dis-
appointingly, alkylation according to this method failed
for iodide 10, and unreacted 10 was recovered from the
reaction mixture.
group was then directly protected with a tert-butoxycar-
bonyl group before compound 12 was purified by flash
column chromatography (85% yield from azide 11).
Removal of the 2,3-diphenylmorpholinone auxiliary and
the Cbz protective group from 12 was accomplished by
hydrogenolysis at 65 psi. Finally, the hydroxylysine
R-amino group was reprotected by treatment with Fmoc-
succinimide, which gave orthogonally protected hydroxy-
lysine 13 in 77% yield from 12. Compound 13, obtained
in this manner, was compared to a sample of 13 prepared
from hydroxylysine obtained from the chiral pool,15 and
was confirmed to be identical with respect to retention
time on reversed-phase HPLC, optical rotation, as well
as 1H and 13C NMR spectral data. Since both enantiomers
of malic acid, as well as Williams template, are com-
mercially available it is anticipated that the present
synthetic strategy should allow all four stereoisomeres
of hydroxylysine to be synthesized in a stereoselective
manner.
Regioselectivity in Reductive Opening of p-Meth-
oxybenzylidene Acetals. As discussed above reductive
opening of the benzylidene acetal in 6 with sodium
cyanoborohydride, using tert-butyldimethylsilyl chloride
as electrophile, surprisingly gave a mixture of 7a and 7b
in which the p-methoxybenzyl group was located on the
primary oxygen atom (Table 1 and Scheme 3). To
investigate if the unexpected regioselectivity in the
reduction of 6 was due to the presence of the azido group
two oxygen analogues, 1838 and 21,39 and the nonfunc-
tionalized analogue 25,21 were synthesized. Replacement
of the azido group in this manner was done so as to vary
both the steric hindrance and the field/inductive effect40
(0.48, 0.29, and 0.42 for N3, MeO, and AcO, respectively)
of the substituent located in position four of the 1,3-
dioxane ring. Methyl ether 18 and acetate 21 were both
obtained from 4 in over 80% yields under standard
conditions (Scheme 3). Analogue 25 was prepared from
1,3-butanediol 24 by acetalization under the same condi-
tions as for conversion of triol 3 into 4. When 18 was
treated with sodium cyanoborohydride and tert-butyldi-
methylsilyl chloride the regioselectivity in the opening
of the p-methoxybenzylidene acetal was reversed as
compared to reduction of the acetal in azide 6.41 Conse-
quently 19 (PMB on the primary oxygen atom) and 20
(PMB on the secondary oxygen atom) were obtained in a
ratio of ∼1:3.42 Reduction of acetate 21 under identical
conditions led to an even more pronounced selectivity for
location of the PMB group on the secondary oxygen atom.
Thus compounds 22 and 23 were formed in a ratio of
15:85. In contrast reduction of analogue 25 led to a near
1:1 mixture of the two possible isomers 26 and 27.
Surprisingly, secondary alcohols 22 and 26 resisted
silylation while the related secondary alcohols 7 and 19
were predominantly silylated during the reductive open-
ing.
Finally, the route developed by Williams relying on 2,3-
diphenylmorpholinones 16 as R-amino acid templates
was attempted.34,35 This approach has previously been
used in another synthesis of (2S,5R)-5-hydroxylysine by
Brussee and co-workers.12 Both enantiomers of morpholi-
nones 16 are commercially available with the nitrogen
atom protected with either a tert-butoxycarbonyl (Boc)
or a benzyloxycarbonyl (Cbz) group (cf. 16a and 16b,
respectively). The Boc-protected template has been re-
ported to give better yields in alkylating reactions,36 and
this was also observed by Brussee and co-workers in their
synthesis of hydroxylysine.12 However, in the synthesis
of amino acids that subsequently will be protected by an
NR-Fmoc group, the Cbz-protected template has the
advantage that hydrogenolysis liberates both the R-amino
and the R-carboxyl group. Gratifyingly, alkylation of Cbz-
protected template 16b with iodide 10, using sodium
hexamethyldisilazane as base in the presence of 15-
crown-5, proceeded well and only a single diastereomer
could be detected by HPLC and NMR spectroscopy
(Scheme 2).37 On a larger scale, better yields of 11 were
obtained (94% for 1-3 mmol scales, as compared to 60-
70% for 0.1 mmol scales) in accordance with previous
experience of enolate-alkylations in our laboratory. In
Brussee’s synthesis of hydroxylysine, the steric bulk
exerted by the protective group of the hydroxyl (TBDMS)
and amino (Boc and p-methoxybenzyl) groups of the side
chain equivalent used as alkylating agent led to low
yields, which prompted a change in the synthetic route.12
Such a problem was not observed in our case, in all
ꢀ
probability due to the side chain N -group being protected
in the form of a small azido group.
To complete the synthesis of hydroxylysine, protected
for use in Fmoc peptide synthesis, the azido group of 11
was reduced with triphenylphosphine, either by stirring
overnight at room temperature or by heating in a
microwave oven at 130 °C for 5 min. The resulting amino
(29) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347-5350.
(30) Corey, E. J.; Bo, Y. X.; Busch-Peterson, J. J. Am. Chem. Soc.
1998, 120, 13000-13001.
(31) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595-
8598.
(32) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999,
40, 1385-1388.
(33) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron 2001, 57,
6447-6453.
The regioselectivities obtained in the reductive opening
of acetals 6, 18, 21, and 25 may be rationalized as follows.
(34) Bender, D. M.; Williams, R. M. J. Org. Chem. 1997, 62, 6690-
6691.
(35) Williams, R. M.; Im, M. N. J. Am. Chem. Soc. 1991, 113, 9276-
9286.
(38) Sulikowski, G. A.; Lee, W.-M.; Jin, B.; Wu, B. Org. Lett. 2000,
2, 1439-1442.
(39) Herrado´n, B. J. Org. Chem. 1994, 59, 2891-2893.
(40) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-
195.
(41) Two equivalents of sodium cyanoborohydride and tert-butyldi-
methyl silyl chloride was used with acetonitrile as solvent at room
temperature.
(36) Baldwin, J. E.; Lee, V.; Schofield, C. J. Synlett 1992, 249-251.
(37) Compound 11 was epimerized at the stereogenic center corre-
sponding to CR in hydroxylysine by treatment with NaHMDS (1 equiv)
in THF. Analysis of the diasteromeric mixture by reversed-phase HPLC
displayed two peaks having identical mass spectra. Only one of the
two diastereomers was detected by HPLC when 11 was prepared by
alkylation of 16b with 10.
J. Org. Chem, Vol. 69, No. 25, 2004 8697

Gustafsson et al.
SCHEME 3a
a Reagents and conditions: (a) (i) TsCl, triethylamine, DMAP, CH2Cl2, rt, (ii) NaN3, DMF, 55 °C (86%); (b) NaCNBH3, TBDMSCl,
CH3CN, rt; (c) MeI, NaH, THF, rt (83%); (d) AcCl, triethylamine, CH2Cl2, rt (85%); (e) p-methoxybenzaldehyde, pyridinium toluene-4-
sulfonate, CH2Cl2, reflux (68%).
For 25, the slight steric hindrance from the methyl group
should direct the chelating silyl chloride to the less
hindered, primary oxygen atom resulting in regioselective
location of the PMB group on the secondary oxygen atom
(i.e. formation of 27). However, the field/inductive effect
from the methyl group increases the Lewis basicity of
the secondary oxygen atom somewhat, thereby directing
the silyl chloride to the secondary and the PMB group to
the primary oxygen atom. As a consequence of these
opposing effects 26 and 27 are formed in almost equal
amounts. By analogy with reductive opening of p-meth-
oxybenzylidene acetals attached to O-4 and O-6 of
carbohydrates (cf. Figure 2), the field/inductive and steric
effects from the methoxymethylene and acetoxymethyl-
ene groups in 18 and 21 both contribute to directing the
chelating silyl chloride to the primary oxygen atom. In
agreement with this prediction, formation of products 20
and 23, in which the PMB group is located on the
secondary oxygen atom dominate over the regioisomeric,
primary PMB ethers 19 and 22. As expected, the regio-
selectivity is enhanced by the increased electron-with-
drawing effect of the acetate in 21 as compared to that
of the methoxy group of 18. Just as for 18 and 21, steric
and inductive effects from the azidomethylene group in
6 would be expected to direct the silyl chloride to the
primary oxygen atom, thus resulting in formation of
secondary PMB ethers 17 as the main products. However,
if chelation of the silyl chloride occurred between the
azide and the adjacent secondary oxygen atom in 6 this
would provide a possible explanation for the unexpected
regioselectivity that led to primary PMB ether 7. In an
initial attempt to investigate this hypothesis azide 6 and
the methoxy analogue 18 were treated with 0.5-2 equiv
of TDBSMCl in acetonitrile-d3. However, no alterations
1
in any of the H and 13C NMR chemical shifts of 6 and
18 could be detected, and chelation could thus not be
confirmed. Instead, 15N-enriched azide 6 was prepared
from tosylate 4 and mono-15N-labeled sodium azide. The
15N NMR spectrum of 15N-6 consisted of two singlets with
equal intensity set 36.7 ppm apart. The downfield signal
was assumed to originate from the nitrogen atom at-
tached to the methylene carbon and the other one from
the distal nitrogen atom. In this case, addition of 1 equiv
of TDBMSCl to a sample of 15N-6 in acetonitrile-d3 caused
another, sharp resonance to appear slightly upfield of the
signal from the nitrogen bound to the methylene carbon
atom, indicating chelation of the silyl chloride to the azido
group.
Mechanistic Studies. If <2 equiv of tert-butyldi-
methylsilyl chloride were used for the reductive opening
of the benzylidene acetal of 6 the reaction still proceeded
completely to 7, but at a slower rate and with a lower
extent of silylation. When 1 equiv of the silyl chloride
was employed no silylation to give 7b was obtained and
secondary alcohol 7a was formed as the only product.
With 1.5 equiv, partial silylation gave a 1:1 mixture of
nonsilylated and silylated products 7a and 7b. Identical
results were obtained for the oxygen analogues 18 and
21. It thus appears that 1 equiv of the silyl chloride is
(42) Products were identified, and yields estimated, in the following
way. After reductive opening of compound 18 the nonsilylated and
silylated products were separated by flash column chromatography.
This gave a mixture of 19a and 20a and another mixture consisting
of 19b and 20b, and allowed the combined yields of 19a + 20a and
19b + 20b to be determined. The mixture of 19a and 20a was then
acetylated, after which the structures were confirmed and the ratio
between the two products was determined by using 1H NMR spectro-
scopy. In a similar way treatment of the mixture of 19b and 20b with
TBAF, followed by acetylation, allowed identification and an estimation
of the yields to be performed. For the secondary hydroxyl group in
19a/b acetylation led to a downfield 1H NMR shift of ∼1.15 ppm for
the proximal hydrogen atom. As expected acetylation of the primary
hydroxyl group in 20a/b caused a smaller shift (∼0.35 ppm) of the
adjacent hydrogen atoms. The identity and the yields for compounds
22a/b, 23a/b, 26a/b, and 27a/b obtained after reductive opening of 21
and 25 were determined in the same manner.
8698 J. Org. Chem., Vol. 69, No. 25, 2004

Total Synthesis of Hydroxylysine
SCHEME 4
glycine equivalent, with a side chain building block
prepared in eight steps from (R)-malic acid, constitutes
a key step in the synthetic route. In the present case only
alkylation of William’s 2,3-diphenylmorpholinone R-ami-
no acid template was successful. In contrast, glycine
coupled to pseudoephedrine, or benzophenone-protected
tert-butyl glycine in the presence of a cinchonidinium-
derived catalyst, could not be successfully alkylated. The
regioselective reductive opening of a p-methoxyben-
zylidene acetal with sodium cyanoborohydride in the
presence of a trialkylsilyl chloride constitutes another key
step in the synthesis. Unexpectedly, it was discovered
that a neighboring azido group reversed the regioselec-
tivity of this opening, compared with what could be
predicted from previous reports in the literature. This
was found to be due to complexation between the silyl
chloride and the azido group. It was also discovered that
1 equiv of silyl chloride was reduced to a silane during
the reductive opening, whereas additional amounts led
to silylation of one of the hydroxyl groups originally
protected in the acetal. In addition to providing an
increased mechanistic understanding of the reductive
openings of p-methoxybenzylidene acetals our studies
also revealed a new route for orthogonal protection of the
two hydroxyl groups of 1,3-diols with p-methoxybenzyl
and tert-butyldimethylsilyl groups, respectively.
consumed during the reductive acetal opening. The
consumption of the silyl chloride may be explained by a
mechanism that begins by electrophilic activation of the
acetal of 6 which, in turn, enables reductive opening to
form the PMB-protected intermediate 28 (Scheme 4). The
alkoxide in 28 can then react with one of the two Lewis
acids, i.e., the silyl chloride or the cyanoborane. Of these
two the borane should be the stronger Lewis acid, and it
reacts rapidly to form borate 29. This in turn is a more
powerful reducing agent than sodium cyanoborohydride
and reduces the silyl chloride to a silane with simulta-
neous formation of 30. Silanes require strong Lewis acids,
such as borontrifluoride etherate, to reduce acetals, and
it is therefore inert under these conditions. One equiva-
lent of silyl chloride is thus consumed in the reduction
whereas additional amounts react with boron ester 30
so that the stronger Si-O bond of silyl ether 31 is formed.
In support of this mechanism, tert-butyldimethylsilane
or triethylsilane was detected by GC when TBDMSCl or
TESCl, respectively, was used as electrophile in the
reductive opening of the acetal in 6. In the GC analysis
tBuMe2SiH or Et3SiH was added as internal reference
to confirm the identity of the silanes. In addition, the
silane hydrogen atom could easily be observed at 3.63
(tBuMe2SiH) or 3.62 (Et3SiH) ppm, using one-dimen-
sional 1H NMR spectroscopy and COSY experiments (H-
Si-C-H couplings were used to confirm the assignment
of Si-H). Moreover, integration of the NMR spectra from
the crude products obtained in the reductive openings
showed that the silanes were formed in approximately
equivalent amounts as compared to products 7.
Experimental Section
General experimental details are provided in the Supporting
Information.
[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]metha-
nol (4). A solution of (R)-malic acid (2, 10.0 g, 74.6 mmol) in
THF (50 mL) was transferred to a solution of BH3‚SMe2 (2 M
in THF, 120 mL, 240 mmol) and B(OMe)3 (27 g, 260 mmol) in
THF (50 mL) cooled to 0 °C. After the mixture was stirred at
room temperature for 16 h MeOH (75 mL) was added and the
solution was concentrated. The crude product was purified by
flash column chromatography (CH2Cl2:MeOH 9:1-5:1) and the
solvents were evaporated. The residue was suspended in
CH2Cl2 (270 mL) and 4-methoxybenzaldehyde (15.2 g, 112
mmol) and pyridinium toluene-4-sulfonate (187 mg, 0.746
mmol) were added. The resulting mixture was heated at reflux
overnight in a Soxhlet apparatus containing 4 Å molecular
sieves. NaHCO3 (250 mg) was added and the solvent was
evaporated. Flash column chromatography (heptane:ethyl
acetate 2:1-1:1) gave alcohol 421 (14.9 g, 89%) as a colorless
oil.
[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]methyl
4-Methylbenzenesulfonate (5). Triethylamine (13.5 mL, 97
mmol), 4-(N,N-dimethylamino)pyridine (790 mg, 6.47 mmol),
and toluene-4-sulfonyl chloride (13.6 g, 71.1 mmol) were added
to a solution of alcohol 4 (14.5 g, 64.7 mmol) in CH2Cl2 (110
mL). The solution was stirred for 15 min, precipitated triethyl-
ammonium chloride was filtered off ,and the solvent was
evaporated. Flash column chromatography (heptane:ethyl
acetate 4:1-1:1) gave tosylate 5 (23.8 g, 98%) as a slightly
yellow solid. [R]D +2.3 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.78
(d, J ) 8.3 Hz, 2H, Ph), 7.32 (d, J ) 8.6 Hz, 2H, Ph), 7.29 (d,
J ) 8.3 Hz, 2H, Ph), 6.86 (d, J ) 8.6 Hz, 2H, Ph), 5.41 (s, 1H,
PhCHO2), 4.26 (ddd, J ) 11.6, 5.3, 1.3 Hz, 1H, CH2OTs), 4.14-
4.01 (m, 3H, CH2OTs, 2 OCH2CH2), 3.93 (dt, J ) 11.6, 2.5 Hz,
1H, CHCH2OTs), 3.80 (s, 3H, OCH3), 2.43 (s, 3H, PhCH3), 1.93
(dq, J ) 12.0, 5.1 Hz, 1H, CCH2C), 1.51-1.49 (m, 1H, CCH2C);
13C NMR (CDCl3) δ 159.9 (Ph), 144.8 (Ph), 132.6 (Ph), 130.4
(Ph), 129.7 (Ph), 127.9 (Ph), 127.3 (Ph), 113.4 (Ph), 100.8
(PhCHO2), 73.9 (CHCH2OTs), 71.5 (OCH2CH2), 66.1 (OCH3),
55.2 (TsOCH2), 27.0 (CH3Ph), 21.5 (OCH2CH2); HR-MS (FAB)
calcd for C19H22O6S 379.1215 [M]+, found 379.1214.
It should be pointed out that, in addition to an
increased understanding of how reductive opening of
p-methoxybenzylidene acetals proceed, the above studies
have led to a new method for orthogonal protection of
1,3-diols. Thus, regioselective reductive opening of a
p-methoxybenzylidene acetal attached to a 1,3-diol re-
sults in protection of the two hydroxyl groups with
p-methoxybenzyl and tert-butyldimethylsilyl groups, re-
spectively, provided that 2 equiv of TBDMSCl are used.
However, as illustrated by the examples shown in
Scheme 3, the regioselective location of the two protective
groups is determined by the adjacent functionalities.
Conclusions
A synthesis of (2S,5R)-5-hydroxylysine, protected for
use in peptide synthesis, has been accomplished in 13
steps with an overall yield of 32%. Alkylation of a chiral
J. Org. Chem, Vol. 69, No. 25, 2004 8699

Gustafsson et al.
(2R,4S)-4-(2-Azidoethyl)-2-(4-methoxyphenyl)-1,3-diox-
ane (6). NaN3 (20.2 g, 312 mmol) was added to a solution of
tosylate 5 (23.6 g, 62.4 mmol) in DMF (170 mL) and the
mixture was heated at 55 °C for 24 h, then poured onto H2O
and EtOAc. The organic phase was washed five times with
H2O, dried over Na2SO4, filtered, and concentrated. Flash
column chromatography (heptane:ethyl acetate 3:1) gave azide
6 (13.7 g, 88%) as a colorless oil. [R]D -11.1 (c 1.0, CHCl3); 1H
NMR (CDCl3) δ 7.43 (d, J ) 8.6 Hz, 2H, Ph), 6.89 (d, J ) 8.6
Hz, 2H, Ph), 5.52 (s, 1H, PhCHO2), 4.30 (ddd, J ) 11.3, 5.1,
1.2 Hz, 1H, OCH2CH2), 4.12-4.05 (m, 1H, CHCH2N3), 3.98 (dt,
J ) 12.0, 1.2 Hz, 1H, OCH2CH2), 3.80 (s, 3H, OCH3), 3.43 (dd,
J ) 13.0, 6.8 Hz, 1H, N3CH2), 3.29 (dd, J ) 13.0, 3.9 Hz, 1H,
N3CH2), 1.93 (dq, J ) 12.0, 5.1 Hz, 1H, CCH2C), 1.51-1.49
(m, 1H, CH2CH2O); 13C NMR (CDCl3) δ 159.9 (Ph), 130.6 (Ph),
127.2 (Ph), 113.5 (Ph), 100.9 (PhCHO2), 75.9 (CHCH2N3), 66.4
(OCH2CH2), 55.2 (OCH3), 54.7 (N3CH2), 28.1 (CCH2C); HR-
MS (FAB) calcd for C12H16N3O3 250.1192 [M + H]+, found
250.1197.
Benzyl (3S,5S,6R)-3-[(3R)-4-Azido-3-(tert-butyldimeth-
ylsilyloxy)butyl]-2-oxo-5,6-diphenylmorpholine-4-car-
boxylate (11). Iodide 10 (917 mg, 2.58 mmol) was added to a
solution of 15-crown-5 (1.13 g, 5.16 mmol), William’s template
16b, and NaHMDS (498 mg, 2.58 mmol) in THF (60 mL) cooled
to -78 °C. After 30 min at -78 °C the solution was allowed to
attain -20 °C during 4 h, poured onto H2O, and extracted
three times with EtOAc. The combined organic phases were
dried over Na2SO4, filtered, and concentrated. Flash column
chromatography (heptane:ethyl acetate 4:1) gave 11 (1.50 g,
94%) as a white amorphous solid. [R]D -25.7 (c 1.0, CHCl3);
1H NMR (DMSO-d6, run at 368 K to avoid duplication of the
spectrum due to the presence of morpholine conformers) δ
7.30-7.01 (m, 13H, Ph), 6.57 (d, J ) 7.3 Hz, 2H, Ph), 6.18 (d,
J ) 2.3 Hz, 1H, COOCHPh), 5.29 (d, J ) 2.3 Hz, 1H, NCHPh),
5.05-4.92 (m, 2H, PhCH2OCO), 4.79 (d, J ) 7.3 Hz, OCOCHN),
3.97-3.89 (m, 1H, N3CH2CH), 3.42-3.34 (m, 1H, N3CH2),
3.28-3.20 (m, 1H, N3CH2), 2.23-2.12 (m, 2H, OCOCHCH2),
1.79-1.70 (m, 2H, N3CH2CHCH2), 0.90 and 0.87 (2s, 9H,
C(CH3)3), 0.12 and -0.02 (2s, 6H, Si(CH3)2);43 HR-MS (FAB)
calcd for C34H43N4O5Si 615.3003 [M + H]+, found 615.3007.
[(1R)-1-Azidomethyl-3-(4-methoxybenzyloxy)propyl]-
oxy-tert-butyldimethylsilane (7b). TBDMSCl (16.2 g, 108
mmol) and NaCNBH3 (6.8 g, 108 mmol) were added to a
solution of azide 6 (13.4 g, 53.8 mmol) in CH3CN (300 mL).
After being stirred for 30 min, the reaction was quenched by
the addition of NaHCO3 (aq, sat.). The mixture was extracted
three times with CH2Cl2, and the combined organic phases
were washed with NaHCO3 (aq, sat.) and H2O, dried over
Na2SO4, filtered, and concentrated. Flash column chromatog-
raphy (heptane:ethyl acetate 3:1) gave 7b (17.5 g, 89%) as a
colorless oil. [R]D +1.1 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.24
(d, J ) 8.6 Hz, 2H, Ph), 6.88 (d, J ) 8.6 Hz, 2H, Ph), 4.45 (s,
2H, PhCHO2), 4.01-3.94 (m, 1H, N3CH2CH), 3.80 (s, 3H,
OCH3), 3.69 (ddd, J ) 9.4, 5.9, 4.5 Hz, 1H, PMBOCH2), 3.62
(ddd, J ) 9.4, 7.9, 4.2 Hz, 1H, PMBOCH2), 3.32-3.22 (m, 1H,
N3CH2), 3.20 (d, J ) 3.3 Hz, 1H, N3CH2), 1.86-1.69 (m, 2H,
PMBOCH2-
Benzyl (3S,5S,6R)-3-[(3R)-4-(tert-Butoxycarbonylamino)-
3-(tert-butyldimethylsilyloxy)butyl]-2-oxo-5,6-diphenyl-
morpholine-4-carboxylate (12). PPh3 (599 mg, 2.28 mmol)
was added to a solution of azide 11 (936 mg, 1.52 mmol) in
moist THF (14 mL). This solution was heated in a microwave
oven for 5 min at 130 °C in three portions (4.7 mL each).
Alternatively, the solution could be stirred at room tempera-
ture for 16 h. Boc2O (498 mg, 2.28 mmol) and triethylamine
(185 mg, 1.83 mmol) were added, and the resulting solution
was stirred for 20 min after which 5 drops of H2O2 (30% aq)
was added and allowed to react for 5 min. Evaporation of the
solvents and purification of the residue by flash column
chromatography (heptane:ethyl acetate 9:1-4:1) gave 12 (891
mg, 85%) as a white amorphous solid. [R]D -23.8 (c 1.0, CHCl3);
1H NMR (DMSO-d6, run at 368 K to avoid duplication of the
spectrum due to the presence of morpholine conformers) δ
7.20-6.91 (m, 13H, Ph), 6.56 (d, J ) 7.7 Hz, 2H, Ph), 6.31 (br
s, 1H, BocHN), 6.19 (d, J ) 3.3 Hz, 1H, COOCHPh), 5.29 (d,
J ) 3.3 Hz, 1H, NCHPh), 5.01-4.92 (m, 2H, PhCH2OCO), 4.79
(d, J ) 7.5 Hz, OCOCHN), 3.84-3.76 (m, 1H, N3CH2CH),
3.06-2.98 (m, 2H, N3CH2), 2.24-2.15 (m, 2H, OCOCHCH2),
1.71-1.55 (m, 2H, N3CH2CHCH2), 1.36 (s, 9H, OC(CH3)3), 0.88
and 0.86 (2s, 9H, SiC(CH3)3), 0.08 and 0.06 (2s, 6H, Si(CH3)2);43
HR-MS (FAB):calcd for C39H53N2O7Si 689.3622 [M + H]+,
found 689.3625.
CH2), 0.93 (s, 9H, tBu), 0.13 (s, 6H, SiCH3); 13C NMR (CDCl3)
δ 159.2 (Ph), 130.0 (Ph), 128.1 (Ph), 113.5 (Ph), 72.6 (CH2Ph),
69.2 (N3CH2CH), 65.9 (PMBOCH2), 56.9 (N3CH2), 56.2 (OCH3),
35.0 (PMBOCH2CH2), 25.7 (C(CH3)3), 17.6 (C(CH3)3), -4.6
(SiCH3), -4.9 (SiCH3); HR-MS (FAB) calcd for C18H32N3O3Si
366.2213 [M + H]+, found 366.2215.
[(1R)-1-Azidomethyl-3-iodopropyl]oxy-tert-butyldi-
methylsilane (10). DDQ (1.13 g, 4.96 mmol) was added to a
solution of 7b (1.51 g, 4.13 mmol) in CH2Cl2:H2O 8:1 (v:v, 30
mL). After the solution was stirred for 20 min, the solids were
filtered off through a pad of Celite that was washed with
CH2Cl2. The solution was concentrated and the residue was
purified by flash column chromatography (heptane:ethyl
acetate 3:1) to afford a mixture of alcohol 8 and p-methoxy-
benzaldehyde. Triethylamine (627 mg, 6.20 mmol), DMAP (50
mg, 0.413 mmol), and methanesulfonyl chloride (710 mg, 6.20
mmol) were added to this mixture dissolved in CH2Cl2 (6 mL)
at 0 °C. After being stirred for 10 min the mixture was poured
onto HCl (0.1% aq) and CH2Cl2 at 0 °C. The organic phase
was washed with NaCl (aq, sat.), dried over Na2SO4, filtered,
and concentrated. The residue (crude 9) was dissolved in
acetone (10 mL), NaI (1.24 g, 8.26 mmol) was added, and the
resulting slurry was heated to reflux for 1 h. The reaction was
quenched by the addition of NaCl (aq, sat.) and the organic
phase was extracted twice with CH2Cl2. The combined organic
phases were dried over Na2SO4, filtered, and concentrated.
Flash column chromatography (heptane:ethyl acetate 15:1)
gave iodide 10 (1.11 g, 76%) as a colorless oil of low viscosity.
[R]D +13.5 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 3.91 (dq, J )
6.7, 4.8 Hz, 1H, CHOTBDMS), 3.34 (dd, J ) 12.6, 4.8 Hz, 1H,
N3CH2), 3.24-3.17 (m, 2H, ICH2), 3.16 (dd, J ) 12.6, 4.8 Hz,
1H, N3CH2), 2.09-2.01 (m, 2H, ICH2CH2), 0.91 (s, 9H, C(CH3)3),
0.14 (s, 6H, Si(CH3)2); 13C NMR (CDCl3) δ 71.4 (CHOTBDMS),
56.1 (N3CH2), 38.6 (ICH2), 25.8 (C(CH3)3), 18.0 (C(CH3)3), 1.8
(ICH2CH2), -4.6 (SiCH3), -4.8 (SiCH3); HR-MS (FAB) calcd
for C10H23IN3O3Si 356.0655 [M + H]+, found 356.0658.
ꢀ
(5R)-NR-(Fluoren-9-ylmethoxycarbonyl)-N -(tert-bu-
toxycarbonyl)-5-O-(tert-butyldimethylsilyl)-5-hydroxy-L-ly-
sine (13). Pd/C (10%, 580 mg) was added to a solution of 12
(580 mg, 0.842 mmol) in THF:H2O (1:1, 18 mL) containing 1
drop of AcOH. The mixture was hydrogenated overnight at
65 psi, filtered through Celite, and concentrated. The solid
residue was dissolved in acetone (10 mL), and N-(9H-fluorene-
2-ylmethoxycarbonyloxy)succinimide (298 mg, 0.884 mmol)
and Na2CO3 (10% aq, 8 mL) were added. After being stirred
overnight the homogeneous solution was poured onto HCl (0.1
M aq) and extracted three times with EtOAc. The organic
phases were then dried over Na2SO4, filtered, and concen-
trated. Purification by flash column chromatography (heptane:
ethyl acetate 9:1-3:1) gave amino acid 13 (386 mg, 77%).
Optical rotation and 1H and 13C NMR data were identical with
values previously reported.15 HR-MS (FAB) calcd for C32H47N2O7-
Si 599.3153 [M + H]+, found 599.3145.
(2R,4R)-4-Methoxymethyl-2-(4-methoxyphenyl)-1,3-di-
oxane (18). NaH (75 mg, 3.1 mmol) and MeI (117 µL, 1.9
mmol) were added to a solution of alcohol 4 (350 mg, 1.6 mmol)
in THF (5 mL) and the mixture was stirred at room temper-
ature for 5 min, then poured onto NH4Cl (aq) and EtOAc. The
organic phase was washed NaCl (aq, sat.) and dried over Na2-
(43) The TBDMS group underwent slow cleavage at room temper-
ature, which prevented recording of 13C NMR data.
8700 J. Org. Chem., Vol. 69, No. 25, 2004

Total Synthesis of Hydroxylysine
SO4, filtered, and concentrated to afford methyl ether 18 (308
Acknowledgment. This work was founded by grants
from the Swedish Research Council and the Go¨ran
Gustafsson Foundation for Research in Natural Sciences
and Medicine. We are grateful to Prof. Stephen Han-
essian for inspiring discussions.
1
mg, 83%) as a slightly yellow oil. H and 13C NMR data were
identical with values previously reported.38
[(2R,4R)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]methyl
Acetate (21). Acetyl chloride (137 µL, 1.9 mmol) and triethyl-
amine (337 µL, 2.4 mmol) were added to a solution of alcohol
4 (362 mg, 1.6 mmol). After 15 min at room temperature, the
solution was poured onto HCl (0.1 M, aq) and CH2Cl2. The
organic phase was washed with NaCl (aq, sat.), dried over
Na2SO4, filtered, and concentrated. To remove p-methoxyben-
zaldehyde formed through hydrolysis the residue was dissolved
in CH2Cl2 and treated with TsNHNH2 on polystyrene. After
filtration and concentration, acetate 21 (366 mg, 85%) was
obtained as a colorless oil. 1H and 13C NMR data were identical
with values previously reported.39
Supporting Information Available: General methods
and materials; 1H NMR and 13C NMR spectra for compounds
5, 6, 7b, 10, 11, and 12; 15N NMR spectra for 15N-labeled 6, in
the presence and absence of TBDMSCl; HPLC chromatograms
illustrating the diastereomeric purity of compounds 11 and
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO049136W
J. Org. Chem, Vol. 69, No. 25, 2004 8701