Synthesis of highly functionalized amino acids: An expedient access to L- and D-β-hydroxyenduracididine derivatives

Article abstract of DOI:10.1002/ejoc.200900971

The nonproteinogenic amino acids (3S,4S)-L- and (3S,4S)-Dβ- hydroxyenduracididine (βhEnd), each containing a cyclic guanidine group and three contiguous stereocenters, have been synthesized for the first time, starting from commercially available diaceton

Full text of DOI:10.1002/ejoc.200900971

FULL PAPER
DOI: 10.1002/ejoc.200900971
Synthesis of Highly Functionalized Amino Acids: An Expedient Access to
L
- and -β-Hydroxyenduracididine Derivatives
D
Clemens J. Schwörer[a] and Markus Oberthür*[a]
Keywords: Amino acids / Antibiotics / Chiral pool / Total synthesis / Nucleophilic substitution
The nonproteinogenic amino acids (3S,4S)-
L
- and (3S,4S)-
D
-
and C-4 afford products that are diastereomerically pure and
easy to purify, thereby allowing the gram-scale preparation
of βhEnd derivatives that are suitably protected for peptide
coupling reactions.
β-hydroxyenduracididine (βhEnd), each containing a cyclic
guanidine group and three contiguous stereocenters, have
been synthesized for the first time, starting from commer-
cially available diacetone
tions for the introduction of the two nitrogen groups at C-2
D
-glucose. The key inversion reac-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Nonribosomally synthesized peptides often contain un-
usual amino acids that are functionalized by hydroxylation,
amination, methylation, halogenation, etc.[1] In many cases,
these structural modifications exert a distinct influence on
the biological activities of these compounds.[2] Detailed
structure–activity relationship studies or investigations into
mechanisms of action often rely on the de novo chemical
synthesis of the parent natural products as well as their ana-
logues. Straightforward and reliable access to such amino
acids and, more importantly, suitably protected derivatives
is therefore a basic prerequisite for such endeavors.
The availabilities of such amino acids from natural
sources, however, are often limited. Although the biosynth-
eses of a number of nonproteinogenic amino acids have
been elucidated,[3] enzymatic methods usually do not pro-
vide sufficient amounts for total synthesis efforts. Accord-
ingly, the chemical synthesis of nonproteinogenic amino ac-
ids remains an important task.[4] As part of our ongoing
research program directed towards the synthesis of bioac-
tive cyclic peptides, we became interested in efficient routes
to protected derivatives of two highly functionalized amino
acids: the β-hydroxyenduracididines (βhEnds, Figure 1).
Both amino acids are constituents of the mannopeptimy-
cins (e.g., mannopeptimycin ε, Figure 1), a group of glyco-
peptides produced by Streptomyces hygroscopicus NRRL
30439 with promising antibiotic activity against resistant
bacterial strains.[5]
Figure 1. Structures of mannopeptimycin ε and the two β-hydroxy-
enduracididine diastereomers and structural comparisons with en-
duracididine and arginine.
The cyclic hexapeptide portion of the mannopeptimycins
contains two different βhEnd diastereomers: (3S,4S)--
βhEnd (-βhEnd) and (3S,4S)--βhEnd (-βhEnd). These
linear α-amino acids, which differ only in the stereochemis-
try at C-2, are each hydroxylated at C-3 and possess an
unusual, five-membered cyclic guanidine at C-4 and C-5.
[a] Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße, 35032 Marburg, Germany
Fax: +49-6421-2822021
E-mail: oberthuer@chemie.uni-marburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900971.
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They can thus be regarded as conformationally restricted duction of the various functional groups (generation of the
and hydroxylated analogues of - and -arginine, respec- cyclic guanidine at C-4/C-5, adjustment of the oxidation
tively.
state at C-1, introduction of the nitrogen functionalities at
Biosynthetically, -βhEnd is derived from -enduracidid- C-2, C-4, and C-5). In a number of exploratory studies we
ine by C-3 hydroxylation through the action of the enzyme have observed that the close proximity of functional groups
MppO,[6] whereas -βhEnd is presumably generated from present in this system can lead to a variety of unexpected
-βhEnd by an epimerization domain of the NRPS as- side reactions in normally straightforward transformations.
sembly line at the stage of the tethered linear hexapeptide.[7] From these results we have devised a synthesis for both dia-
Recently, it was shown that the simultaneous replace- stereomers of βhEnd, a retrosynthetic overview of which is
ment of both βhEnds with - and -arginine renders the given in Scheme 1. The synthesis is based on a chiral pool
resulting mannopeptimycin derivative antibiotically inac- approach, in which the configuration of the three stereocen-
tive.[8] In addition, the hydroxylation of βhEnd was also ters is traced back to diacetone -glucose as a cheap and
reported to be beneficial for optimal activity,[5b] thereby readily available starting material.
highlighting the importance of these structural elements.
According to this plan, the protected βhEnd derivatives
Currently, the two isomers can only be obtained as a mix- 1 and 2 would be obtained from the same azido alcohol 5,
ture after hydrolysis of the mannopeptimycins,[5a] which which, in the forward direction, was envisaged initially to
makes a chemical synthesis desirable. Accordingly, here we deliver azide 3 by means of an inversion reaction at C-2.
describe an efficient and reliable route to protected deriva- This would then be followed by introduction of the cyclic
tives of both diastereomers of βhEnd (1 and 2, see C-4/C-5 guanidino group and oxidation at C-1 to yield the
Scheme 1) on a synthetically useful scale by a chiral pool -βhEnd derivative 1. It was also envisioned that alcohol
approach.
5 would supply the corresponding C-2 epimeric -βhEnd
precursor 6 by inversion of the C-2 hydroxy group. The
azido alcohol 6 would then be subjected to the same reac-
tion sequence as described above, thereby providing the -
βhEnd derivative 2 via the azide 4. The common precursor
5 was traced back to the differentially protected -xylitol 7,
which would allow the introduction of the C-4 azido group
with inversion. Finally, the -xylitol 7 would be derived
from commercially available diacetone -glucose by stan-
dard procedures.
The synthesis of the common precursor for both βhEnd
diastereomers, the azido alcohol 5, started with the known
3-O-benzyl-1,2-O-isopropylidene--xylose (8, Scheme 2),[9]
which is easily obtainable on a multigram scale from diace-
tone -glucose in three steps and in 84% yield (1. NaH,
BnBr; 2. AcOH/H2O; 3. NaIO4, then NaBH4). Protection
of the primary 5-OH group as a p-methoxyphenyl (PMP)
ether[10] was achieved under Mitsunobu conditions
(PMPOH, DIAD, PPh3)[11] and afforded the xylose deriva-
tive 9 in 90% yield. After acidic cleavage of the isopropylid-
ene group, the subsequent reduction of the crude lactol
either with NaBH4 or with LiAlH4 proceeded slowly, with
some starting material remaining even after prolonged reac-
tion times. The best results were obtained with LiAlH4 in
THF for 14 h, which afforded a xylitol/lactol mixture (ca.
6:1) that was difficult to separate, so the mixture was there-
fore treated directly after workup with 2,2-dimethoxypro-
pane and pTsOH. At this stage, the desired xylitol 1,2-ace-
tonide 7, which was obtained as the major product (70%,
three steps), could be easily separated from xylofuranose 9
(15%) by flash chromatography.
Scheme 1. Retrosynthetic scheme for the preparation of β-hydroxy-
enduracididine derivatives 1 and 2.
For the introduction of the nitrogen functionality at C-
4, the O-4 mesylate derived from the alcohol 7 was inverted
Results and Discussion
The synthesis of the βhEnd derivatives 1 and 2 not only with NaN3 in DMF to give the azide 10 (90%). Acid-cata-
requires the implementation of three contiguous stereocen- lyzed removal of the isopropylidene acetal and selective
ters of the -ribo- (-βhEnd, 1) and the -arabino configura- protection of the primary hydroxy group with TBSCl then
tion (-βhEnd, 2), but also needs to establish the correct afforded the azido alcohol 5 (96%, two steps), which was
order of the individual reaction steps required for the intro- obtained in multigram quantities.
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Synthesis of Highly Functionalized Amino Acids
Scheme 3. Introduction of nitrogen at C-2 to establish the required
configuration of the -series.
Scheme 2. Synthesis of the azido alcohol 5.
According to our synthetic plan for the corresponding -
βhEnd derivative 2, it was necessary to invert the C-2 hy-
droxy group of the azide 5. To achieve this goal, we first
converted the alcohol into the corresponding mesylate
(Scheme 4). Subsequent inversion with cesium acetate and
saponification of the obtained ester led to a product mix-
ture that contained the expected C-2 alcohol 6, but also two
additional products resulting from cleavage (diol 16) and
1,2-migration of the TBS group (2-O-TBS ether 15) in an
unsatisfying combined yield of 37%.
Inversion of Sterically Hindered Secondary Alcohols
The inversion of secondary alcohols can be a challenging
task because alternative reaction pathways (elimination, in-
tramolecular attack of nucleophilic groups within the mole-
cule, etc.) can become prominent if backside attack of exter-
nal nucleophiles is hindered. Whereas the displacement of
the O-4 mesylate derived from alcohol 7 with sodium azide
had proceeded smoothly (see above), for the inversion of
the C-2 hydroxy group we had to explore various methods
and nitrogen nucleophiles. Our initial efforts in the -series
concentrated on the direct inversion of the hydroxy group
in the azido alcohol 5 under Mitsunobu conditions (DIAD,
PPh3, THF, room temp.), with phthalimide as the acidic
component (Scheme 3). In these attempts, however, the iso-
lated yields of the corresponding phthalimido derivative 11,
obtained after deprotection of the primary TBS group to
facilitate chromatographic purification, never exceeded
50%.
To overcome these problems, we next converted the C-4
azide into the Boc-protected amine (H2, Pd/C, Boc2O,
MeOH; 96%).[12] With alcohol 12 now to hand, it was pos-
sible to introduce the C-2 nitrogen by means of an azide
nucleophile. Mesylation of O-2 and subsequent inversion
with NaN3, for example, proceeded smoothly, but gave rise
to a mixture of two products due to partial removal of the
primary TBS group under the reaction conditions. The
crude mixture was therefore treated with aqueous HCl in
THF to remove the TBS group completely, which afforded
the azido alcohol 13 in 69% yield over three steps.
Scheme 4. Inversion of the C-2 hydroxy group.
We therefore opted to cleave the silyl group of the inter-
Even better yields were obtained when alcohol 12 was mediate mesylate prior to treatment with CsOAc. This
subjected to Mitsunobu reaction conditions with hydrazoic strategy not only improved the yield of the inversion, but
acid in toluene. Under these conditions, the primary TBS now also led to a single product that was easily purifiable
group was completely stable, and the inverted C-2 azide 14, on a short silica gel column and was identified as the O-1
which contains the required configuration of the -βhEnd acetate 17, resulting from a 2,1-migration of the ester (70%
system, was obtained in an excellent yield (89%).
from 5). Because of potential problems associated with
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O,N-migration in the later steps of the synthesis, we next afford the primary alcohol 3 (77%, three steps, Scheme 6),
removed the acetyl group (K2CO3, MeOH) prior to forma- which served as the precursor for the introduction of the
tion of the Boc-protected C-4 amine 18 (H2, Pd/C, Boc2O, cyclic guanidine.
MeOH; 90% for both steps). Reprotection of the primary
hydroxy group as the TBS ether (TBSCl, DMAP, 96%) gave
the secondary alcohol 19.
With alcohol 19 to hand, we tested the same transforma-
tions as had been used for the epimeric alcohol 12 for the
introduction of nitrogen at C-2 (Scheme 5). Interestingly,
for this stereoisomer, the azide displacement reaction of the
intermediate mesylate led to the inverted azido alcohol 20
(obtained after cleavage of the primary TBS ether) only as
the minor product (13%), because in this case the intramo-
lecular displacement of the mesylate by the carbonyl oxygen
of the adjacent C-4 carbamate became predominant, thus
leading to the cyclic carbamate 21 in 75% yield.[13] This
difference in behavior emphasizes the often hard to predict
influence of the relative configuration on the reaction out-
come in a highly functionalized system such as the present
one.
Scheme 6. Completion of the syntheses of βhEnd derivatives 1 and
2.
Towards this end, the Boc-protected amine at C-4 was
first liberated (satd. HCl/Et2O) and converted to afford the
linear guanidine 23 by treatment with S-methyl N,NЈ-
bis(benzyloxycarbonyl)isothiourea (88%, two steps).[15] Cy-
clization of the guanidine by means of an intramolecular
Mitsunobu reaction, followed by removal of the TBDPS
group (Bu4NF, THF; 70%, two steps), then smoothly pro-
Scheme 5. Introduction of the C-2 azido group to establish the re-
quired configuration of the -series.
duced the cyclic guanidine 25 (Scheme 6). Finally, direct
oxidation of the primary alcohol, by use of a combination
of TEMPO, NaOCl2, and bleach,[16] afforded carboxylic
Successful inversion at C-2, however, was again ac-
acid 1 (89%). In an analogous manner, the TBS ether 22
was then converted into the -βhEnd derivative 2 in 40%
yield by the six-step sequence described for the preparation
of the corresponding -configured 1.
In summary, the -βhEnd derivative 1 has been synthe-
sized in 21 steps (13 straightforward chromatographic puri-
fications), starting from diacetone glucose, in 15.6% overall
yield, whereas the -βhEnd carboxylic acid 2 was obtained
in 24 steps and in an overall yield of 10.3%. Our synthetic
approach utilizes easily scalable transformations and pro-
vides both βhEnd isomers in gram quantities.
complished under Mitsunobu conditions (DIAD, PPh3,
HN3, 0 °C, 92%), which afforded the azide 22 in excellent
yields with no formation of the cyclic carbamate, thus high-
lighting the efficiency of the Mitsunobu reaction with hy-
drazoic acid for the inversion of a sterically hindered sec-
ondary hydroxy group.
Introduction of the Cyclic Guanidine and Oxidation at C-1
After the successful elaboration of the -ribo-configured
14 and the -arabino-configured 22, we focused on the in-
stallment of the cyclic C-4/C-5 guanidine system and oxi-
dation at C-1 in both series. For the remaining transforma-
tions, the primary TBS group proved to be too labile and
was therefore exchanged for the TBDPS group in a two-
Conclusions
In conclusion, we have developed a reliable and straight-
step sequence (i. aq. HCl, THF; ii. TBDPSCl, DMAP).[14] forward route to β-hydroxyenduracididine building blocks
On starting from the TBS ether 14 in the -series, the corre- in synthetically useful amounts. The presented route is the
sponding TBDPS derivative was obtained nearly quantita- result of an extensive optimization with regard to the reac-
tively. Next, the PMP group was cleaved with CAN[10] to tion sequence and features consistently high-yielding trans-
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Synthesis of Highly Functionalized Amino Acids
409.1622; found 409.1628. C22H26O6 (386.44): calcd. C 68.38, H
6.78; found C 67.89, H 7.13.
formations, such as the introduction of azido groups at ste-
rically hindered secondary carbon atoms by use of the Mit-
sunobu reaction. Both carboxylic acids 1 and 2 are suitably
3-O-Benzyl-1,2-O-isopropylidene-5-O-(4-methoxyphenyl)-D-xylitol
protected for peptide coupling reactions and open access (7): Xylofuranose 9 (9.63 g, 24.9 mmol) was dissolved in 1,4-diox-
ane (160 mL) and HCl (1 , 98.0 mL) and the mixture was heated
at 80 °C for 2 h. After cooling, the mixture was neutralized with
satd. aq. NaHCO3 and then extracted with EtOAc, (3ϫ). The com-
bined organic layers were washed with brine, dried (MgSO4), and
filtered. After the solvent had been removed under reduced pres-
sure, the obtained lactol (Rf = 0.25, petroleum ether/EtOAc, 1:1)
was dissolved in dry THF (125 mL), and LiAlH4 (1.89 g,
49.8 mmol) was added at 0 °C. After stirring for 14 h at room tem-
perature, the solution was acidified by careful addition of HCl (2 )
and subsequently stirred for 1 h at room temperature. The suspen-
to the corresponding amines by esterification (e.g., AllBr,
KHCO3, DMF, room temperature) and reduction of the
azide (H2S, NEt3, CH2Cl2; see Supporting Information). In
addition, the carbobenzyloxy and benzyl groups can be eas-
ily removed by hydrogenolysis (H2, Pd-C, MeOH and Pd-C,
HCOONH4, MeOH, reflux, respectively). The use of these
building blocks in the total synthesis of the mannopeptimy-
cins is currently being explored and will be reported in due
course. In addition, the two diastereomers can serve as sur-
rogates for - or -arginine, featuring conformationally re- sion was filtered off through a pad of Celite, and the precipitate
was thoroughly washed with EtOAc. The filtrate was extracted with
EtOAc (3ϫ), and the combined organic layers were washed with
brine, dried (MgSO4), and filtered. The solvent was removed under
reduced pressure and the residual xylitol/lactol mixture was dis-
solved in CH2Cl2 (150 mL). After addition of 2,2-dimethoxypro-
pane (12.5 mL, 99.6 mmol) and a catalytic amount of pTsOH, the
solution was stirred at room temperature for 2 h and was then neu-
tralized with NEt3 and concentrated in vacuo. Flash chromatog-
raphy of the residue (petroleum ether/EtOAc, 4:1Ǟ2:1Ǟ1:1) gave
the xylitol 7 (6.64 g, 69%) as a colorless oil; in addition, xylofur-
anose 8 (1.44 g, 15%) was recovered. Rf = 0.25 (petroleum ether/
stricted guanidino groups, and could be used to study the
influence of arginine side-chains on the interactions of bio-
logically active peptides with their targets.
Experimental Section
General Methods: TLC chromatography was performed with silica
gel (60 F254. Detection was carried out by fluorescence quenching
under UV light (λ = 254 nm) or by staining with 20% H2SO4 or
ninhydrin solution followed by heating to ca. 300 °C. Flash
chromatography was performed on silica gel 60 (0.040–0.063 mm,
Merck KGaA). NMR spectra were recorded with Bruker AV 300,
Bruker DRX 500, and Bruker DRX 600 spectrometers. Mass spec-
tra were recorded with a Finnigan MAT 95 spectrometer. Specific
rotations were measured with a Perkin–Elmer 241 polarimeter. Ele-
mental analysis was performed with a Heraeus CHN-Rapid instru-
ment.
1
EtOAc, 4:1). [α]2D0 = –34.7 (c = 1.0, CHCl3). H NMR (500 MHz,
CDCl3): δ = 1.40 (s, 3 H, isopropyl-CH3), 1.47 (s, 3 H, isopropyl-
3
CH3), 2.63 (br. s, 1 H, 4-OH), 3.69 (dd, 3J = 6.6, J = 1.8 Hz, 1 H,
3-H), 3.78 (s, 3 H, PMP-OCH3), 3.80–3.88 (m, 2 H, 1-Ha, 5-Ha),
3
3.90–3.96 (m, 2 H, 4-H, 5-Hb), 4.01 (dd, 2J = 8.3, J1,2 = 6.6 Hz, 1
3
H, 1-Hb), 4.45 (q, J1.2/2,3 = 6.8 Hz, 1 H, 2-H), 4.67 (d, 2J =
2
11.6 Hz, 1 H, Ph-CHaHb), 4.87 (d, J = 11.6 Hz, 1 H, Ph-CHaHb),
6.77–6.85 (m, 4 H, PMP-HAr), 7.27–7.35 (m, 5 H, Bn-HAr) ppm.
13C NMR (125 MHz, CDCl3): δ = 25.7 (isopropyl-CH3), 26.7 (iso-
propyl-CH3), 55.9 (PMP-OCH3), 66.2 (C-1), 69.4 (C-5), 70.3 (C-
4), 74.4 (Ph-CH2), 77.3 (C-2), 78.3 (C-3), 109.6 (isopropyl-Cq),
114.8 (PMP-CAr), 115.6 (PMP-CAr), 128.1 (Bn-CAr), 128.5 (Bn-
CAr), 128.6 (Bn-CAr), 138.1 (Bn-CAr), 152.7 (PMP-CAr), 154.3
(PMP-CAr) ppm. HRMS (ESI): calcd. for [C22H28O6Na]+:
411.1778; found 411.1781.
3-O-Benzyl-1,2-O-isopropylidene-5-O-(4-methoxyphenyl)-α-D-xylo-
furanose (9): DIAD (7.9 mL, 39.3 mmol) was added dropwise at
0 °C under Ar to a solution of xylofuranose 8 (8.47 g, 30.2 mmol),
PPh3 (10.3 g, 39.3 mmol), and p-methoxyphenol (11.2 g,
90.6 mmol) in dry THF (250 mL). After the mixture had been
heated at 80 °C for 1 h, the solvent was removed and the residue
was dissolved in CH2Cl2. The organic layer was washed with aq.
NaOH (10%, 2ϫ) and brine (1ϫ). The aqueous layers were reex-
tracted with CH2Cl2, and the combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was dissolved in diethyl ether (20 mL), and petroleum ether
(100 mL) was then added to precipitate the phosphane oxide
formed during the reaction. After standing overnight at room tem-
perature, the resulting suspension was filtered, and the filtrate was
concentrated under reduced pressure. Flash chromatography (pe-
troleum ether/EtOAc, 4:1) afforded the PMP ether 9 (10.25 g, 88%)
4-Azido-3-O-benzyl-4-deoxy-1,2-O-isopropylidene-5-O-(4-methoxy-
phenyl)-L-arabinitol (10): Xylitol 7 (9.58 g, 24.7 mmol) was dis-
solved in dry CH2Cl2 (230 mL) under Ar, and NEt3 (5.86 mL,
41.9 mmol) and MsCl (2.70 mL, 34.5 mmol) were added at 0 °C.
After stirring at room temperature for 2 h, the reaction mixture
was diluted with CH2Cl2, washed with satd. aq. NaHCO3 and
brine, dried (MgSO4), filtered, and concentrated to afford the crude
mesylate (Rf = 0.25, petroleum ether/EtOAc, 4:1) as an oil. The
residue was dissolved in dry DMF (170 mL), and NaN3 (9.74 g,
as a colorless oil. Rf = 0.50 (petroleum ether/EtOAc, 4:1). [α]2D1
=
1
–36.9 (c = 1.0, CHCl3). H NMR (600 MHz, CDCl3): δ = 1.34 (s, 148.0 mmol) was added. After stirring for 17 h at 100 °C, the sol-
3 H, isopropyl-CH3), 1.51 (s, 3 H, isopropyl-CH3), 3.77 (s, 3 H,
vent was removed in vacuo and the residue was coevaporated with
toluene (2ϫ). The residue was partitioned between CH2Cl2 and
3
3
PMP-OCH3), 4.07 (d, J3,4 = 3.2 Hz, 1 H, 3-H), 4.18 (d, J4,5
=
2
6.1 Hz, 2 H, 5-H2), 4.51 (d, J = 12.0 Hz, 1 H, Ph-CHaHb), 4.55 water, and the aqueous layer was extracted with CH2Cl2 (2ϫ). The
3
3
3
(dt, J4,5 = 6.1, J3,4 = 3.2 Hz, 1 H, 4-H), 4.65 (d, J1,2 = 3.8 Hz, 1
combined organic layers were dried (MgSO4) and filtered, and the
solvent was removed in vacuo. Purification of the residue by flash
chromatography (petroleum ether/EtOAc, 4:1) gave the azide 10
(9.14 g, 90%) as a colorless oil. Rf = 0.85 (petroleum ether/EtOAc,
3
H, 2-H), 4.68 (d, 2J = 12.0 Hz, 1 H, Ph-CHaHb), 5.98 (d, J1,2
=
3.8 Hz, 1 H, 1-H), 6.81–6.87 (m, 4 H, PMP-HAr), 7.24–7.32 (m,
5 H, Bn-HAr) ppm. 13C NMR (150 MHz, CDCl3): δ = 26.4, 27.0
(isopropyl-CH3), 55.8 (PMP-OCH3), 65.8 (C-5), 72.2 (Ph-CH2),
78.8 (C-4), 81.5 (C-3), 82.6 (C-2), 105.3 (C-1), 112.0 (isopropyl-Cq),
2:1). [α]1D9 = +8.0 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3):
1
δ = 1.41 (s, 3 H, isopropyl-CH3), 1.47 (s, 3 H, isopropyl-CH3), 3.67
3
3
114.8 (PMP-CAr), 115.7 (PMP-CAr), 127.9 (Bn-CAr), 128.0 (Bn- (dd, J = 6.6, J = 5.3 Hz, 1 H, 3-H), 3.79 (s, 3 H, PMP-OCH3),
CAr), 128.6 (Bn-CAr), 137.5 (Bn-CAr), 152.9 (PMP-CAr), 154.1 3.76–3.85 (m, 2 H, 4-H, 1-Ha), 4.09 (dd, J = 8.2, J = 6.6 Hz, 1 H,
(PMP-CAr) ppm. HRMS (ESI): calcd. for [C22H26O6Na]+: 1-Hb), 4.14 (dd, J = 10.1, J4,5 = 6.3 Hz, 1 H, 5-Ha), 4.30 (dd, J
2
3
2
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= 10.1, J4,5 = 3.2 Hz, 1 H, 5-Hb), 4.33–4.38 (m, 1 H, 2-H), 4.66 (25 mL), and HCl (8 , 1.9 mL) was added. After stirring for 2 h
3
2
2
(d, J = 11.3 Hz, 1 H, Ph-CHaHb), 4.78 (d, J = 11.3 Hz, 1 H, Ph-
at room temperature, the reaction mixture was diluted with EtOAc
CHaHb), 6.83–6.88 (m, 4 H, PMP-HAr), 7.28–7.36 (m, 5 H, Bn- (150 mL), washed with satd. aq. NaHCO3 (2ϫ), and dried
HAr) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.8 (isopropyl-
CH3), 26.5 (isopropyl-CH3), 55.9 (PMP-OCH3), 61.8 (C-4), 66.1
(C-1), 68.2 (C-5), 74.9 (Ph-CH2), 77.1 (C-2), 78.4 (C-3), 109.6 (iso-
(MgSO4), and the solvent was removed under reduced pressure.
Flash chromatography (petroleum ether/EtOAc, 2:1Ǟ1:1) afforded
the ribitol 11 (1.04 g, 49%) as a colorless oil. Rf = 0.25 (petroleum
propyl-Cq), 114.9 (PMP-CAr), 115.7 (PMP-CAr), 128.1 (Bn-CAr), ether/EtOAc, 2:1). [α]2D2 = –10.1 (c = 1.0, CHCl3). 1H NMR
128.3 (Bn-CAr), 128.6 (Bn-CAr), 137.8 (Bn-CAr), 152.4 (PMP-CAr), (500 MHz, CDCl3): δ = 2.79 (br. s, 1 H, 1-OH), 3.74 (s, 3 H, PMP-
154.5 (PMP-CAr) ppm. HRMS (ESI): calcd. for [C22H27N3O5-
OCH3), 3.83–3.87 (m, 1 H, 4-H), 4.07–4.19 (m, 3 H, 1-H2, 5-Ha),
3
3
Na]+: 436.1843; found 436.1839. C22H27N3O5 (413.47): calcd. C 4.21 (dd, J = 10.0, J = 4.0 Hz, 1 H, 5-Hb), 4.51 (dd, J = 9.1, J =
2
63.91, H 6.58, N 10.16; found C 63.67, H 6.73, N 9.94.
4.4 Hz, 1 H, 3-H), 4.55–4.59 (m, 1 H, 2-H), 4.79 (d, J = 10.7 Hz,
1 H, Ph-CHaHb), 4.83 (d, 2J = 10.7 Hz, 1 H, Ph-CHaHb), 6.73–
6.79 (m, 4 H, PMP-HAr), 7.27–7.37 (m, 5 H, Bn-HAr), 7.70–7.75
(m, 2 H, Pht-HAr), 7.80–7.84 (m, 2 H, Pht-HAr) ppm. 13C NMR
(125 MHz, CDCl3): δ = 54.1 (C-2), 55.8 (OCH3), 61.8 (C-1), 62.3
(C-4), 68.0 (C-5), 75.3 (Ph-CH2), 76.4 (C-3), 114.8 (PMP-CAr),
115.8 (PMP-CAr), 123.8 (Pht-CAr), 128.3 (Bn-CAr), 128.5 (Bn-CAr),
128.7 (Bn-CAr), 131.7 (Pht-CAr), 134.5 (Pht-Cq,Ar), 137.4 (Bn-CAr),
152.2 (PMP-CAr), 154.4 (PMP-CAr), 168.9 (Pht-C=O) ppm.
HRMS (ESI): calcd. for [C27H26N4O6Na]+: 525.1745; found
525.1746.
4-Azido-3-O-benzyl-1-O-(tert-butyldimethylsilyl)-4-deoxy-5-O-(4-
methoxyphenyl)-L-arabinitol (5): Arabinitol 10 (9.14 g, 22.1 mmol)
was dissolved in 1,4-dioxane (150 mL) and HCl (1 , 75 mL), and
the mixture was stirred at room temperature for 14 h. The reaction
mixture was neutralized with satd. aq. NaHCO3 and extracted with
EtOAc (3ϫ). The combined organic layers were dried (MgSO4) and
filtered, and the solvent was removed under reduced pressure to
afford the crude diol (Rf = 0.15, petroleum ether/EtOAc, 2:1) as an
oil. The residue was redissolved in dry CH2Cl2 (220 mL), and NEt3
(6.20 mL, 44.2 mmol), TBSCl (4.3 g, 28.7 mmol), and a catalytic
amount of DMAP were added at 0 °C. After stirring for 14 h at
room temperature, the reaction was quenched by addition of
MeOH (10 mL) and stirred for another 15 min at room tempera-
ture. The reaction mixture was diluted with CH2Cl2 and washed
with satd. aq. NaHCO3. The aqueous layer was reextracted with
CH2Cl2, the combined organic layers were dried (MgSO4) and fil-
tered, and the solvent was removed under reduced pressure. Flash
chromatography (petroleum ether/EtOAc, 4:1Ǟ2:1) afforded the
primary TBS ether 5 (10.3 g, 96%) as a colorless oil. Rf = 0.70
3-O-Benzyl-1-O-(tert-butyldimethylsilyl)-4-[(tert-butyloxycarbonyl)-
amino]-4-deoxy-5-O-(4-methoxyphenyl)-L-arabinitol (12): Boc2O
(3.43 g, 15.7 mmol) and Pd/C (1.18 g, 10%) were added to a solu-
tion of arabinitol 5 (5.89 g, 12.1 mmol) in MeOH (60 mL). After
stirring for 16 h under H2 (1 bar) at room temperature, the reaction
mixture was filtered through a pad of Celite. The solvent was re-
moved under reduced pressure and the residue was subjected to
flash chromatography (petroleum ether/EtOAc, 6:1Ǟ4:1) to yield
the N-Boc derivative 12 (6.53 g, 96%) as a colorless oil. Rf = 0.55
(petroleum ether/EtOAc, 4:1). [α]2D0 = +23.1 (c = 1.0, CHCl3). H
(petroleum ether/EtOAc, 4:1). [α]2D1 = +12.6 (c = 1.0, CHCl3). H
1
1
NMR (500 MHz, CDCl3): δ = 0.09 (s, 3 H, TBS-CH3), 0.10 (s, 3
NMR (500 MHz, CDCl3): δ = 0.08 (s, 3 H, TBS-CH3), 0.09 (s, 3
H, TBS-CH3), 0.93 (s, 9 H, TBS-tBu-CH3), 2.37 (br. s, 1 H, 2-OH), H, TBS-CH3), 0.93 (s, 9 H, TBS-tBu-CH3), 1.47 (s, 3 H, Boc-tBu-
2
3
2
3
3.55 (dd, J = 10.0, J1,2 = 7.1 Hz, 1 H, 1-Ha), 3.74 (dd, J = 10.0,
CH3), 3.37 (bd, JOH,2 = 5.1 Hz, 1 H, 2-OH), 3.63–3.69 (m, 1 H,
3J1,2 = 6.0 Hz, 1 H, 1-Hb), 3.79 (s, 3 H, PMP-OCH3), 3.85–3.91
1-Ha), 3.75–3.79 (m, 1 H, 1-Hb), 3.79 (s, 3 H, OCH3), 3.81–3.87
(m, 2 H, 2-H, 3-H), 3.99 (dd, J = 9.2, J = 4.8 Hz, 1 H, 5-Ha), 4.19–
3
3
(m, 2 H, 2-H, 3-H), 3.97 (dt, J4,5 = 6.5, J4,5 = 2.7 Hz, 1 H, 4-H),
2
3
2
2
4.12 (dd, J = 9.9, J4,5 = 6.5 Hz, 1 H, 5-Ha), 4.30 (dd, J = 9.9,
3J4,5 = 2.7 Hz, 1 H, 5-Hb), 4.66 (m, 2 H, Ph-CH2), 6.83–6.89 (m, 4
H, PMP-HAr), 7.28-7.38 (m, 5 H, Bn-HAr) ppm. 13C NMR
(125 MHz, CDCl3): δ = –5.3 (TBS-CH3), –5.2 (TBS-CH3), 18.4
4.29 (m, 2 H, 4-H, 5-Hb), 4.56 (d, J = 11.2 Hz, 1 H, Ph-CHaHb),
4.63 (d, J = 11.2 Hz, 1 H, Ph-CHaHb), 5.43 (d, JNH,4 = 9.0 Hz,
2
3
1 H, 4-NH), 6.82–6.88 (m, 4 H, PMP-HAr), 7.22–7.31 (m, 5 H, Bn-
H
Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.3 (TBS-CH3), –5.2
(TBS-tBu-Cq), 26.0 (TBS-tBu-CH3), 55.6 (PMP-OCH3), 61.2 (C- (TBS-CH3), 18.2 (TBS-tBu-Cq), 25.9 (TBS-tBu-CH3), 28.4 (Boc-
4), 63.8 (C-1), 68.6 (C-5), 71.4 (C-2), 75.0 (Bn-CH2), 76.7 (C-3), tBu-CH3), 50.0 (C-4), 55.8 (PMP-OCH3), 63.5 (C-1), 67.4 (C-5),
114.9 (PMP-CAr), 115.7 (PMP-CAr), 128.3 (Bn-CAr), 128.4 (Bn- 71.0 (C-2), 73.9 (Ph-CH2), 76.0 (C-3), 80.1 (Boc-tBu-Cq), 114.8
CAr), 128.7 (Bn-CAr), 137.6 (Bn-CAr), 152.5 (PMP-CAr), 154.4 (PMP-CAr), 115.4 (PMP-CAr), 127.8 (Bn-CAr), 128.2 (Bn-CAr),
(PMP-CAr) ppm. HRMS (ESI): calcd. for [C35H37N3O5SiNa]+:
510.2395; found 510.2395.
128.4 (Bn-CAr), 138.0 (Bn-CAr), 152.4 (PMP-CAr), 154.2 (PMP-
CAr), 156.4 (Boc-C=O) ppm. HRMS (ESI): calcd. for [C30H47N1-
O7SiNa]+: 584.3014; found 584.3022.
4-Azido-3-O-benzyl-2,4-deoxy-2-(1,3-dioxoisoindolinyl)-5-O-(4-meth-
oxyphenyl)-L-ribitol (11): DIAD (2.55 mL, 12.7 mmol) and phthal-
2-Azido-3-O-benzyl-4-[(tert-butyloxycarbonyl)amino]-2,4-deoxy-5-
imide (2.18 g, 14.8 mmol) were added at 0 °C to a solution of PPh3
(3.32 g, 12.7 mmol) in dry THF (65 mL). A solution of alcohol 5
(2.06 g, 4.23 mmol) in dry THF (24 mL) was then added and the
mixture was stirred at room temperature for 14 h. The solvent was
removed under reduced pressure, the residue was dissolved in
CH2Cl2, washed with NaOH (1 ), and dried (MgSO4), and the
solvent was removed in vacuo. The residue was dissolved in diethyl
ether (20 mL), and petroleum ether (100 mL) was then added to
precipitate the phosphane oxide formed during the reaction. After
standing overnight at room temperature, the resulting suspension
was filtered, and the filtrate was concentrated under reduced pres-
sure. Flash chromatography (petroleum ether/EtOAc, 8:1Ǟ4:1) af-
forded the phthalimide derivative (Rf = 0.70, petroleum ether/
EtOAc, 4:1), that still contained some unidentified impurities ac-
cording to the 1H NMR spectrum. It was dissolved in THF
O-(4-methoxyphenyl)-L-ribitol (13): NEt3 (1.47 mL, 10.5 mmol) and
MsCl (0.63 mL, 8.02 mmol) were added at 0 °C to a solution of
alcohol 12 (3.46 g, 6.17 mmol) in dry CH2Cl2 (60 mL). After stir-
ring for 2 h at room temperature, the reaction mixture was diluted
with CH2Cl2, washed with satd. aq. NaHCO3 and brine, and dried
(MgSO4), and the solvent was removed under reduced pressure.
The crude mesylate (Rf = 0.55, petroleum ether/EtOAc, 4:1) was
dissolved in dry DMF (55 mL), and NaN3 (2.44 g, 37.0 mmol) was
added. After the mixture had been heated at 100 °C for 17 h, the
solvent was removed under reduced pressure. The residue was dis-
solved in EtOAc, and water, the layers were separated, and the
aqueous layer was extracted with EtOAc (2ϫ). The combined or-
ganic layers were dried (MgSO4) and the solvent was removed un-
der reduced pressure. The residue was dissolved in THF (55 mL),
and aq. HCl (8 , 2.17 mL) was added. After stirring for 2 h at
6134
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6129–6139

Synthesis of Highly Functionalized Amino Acids
room temperature, the reaction mixture was neutralized with satd.
aq. NaHCO3 and extracted with EtOAc (3ϫ). The combined or-
ganic layers were dried (MgSO4) and the solvent was removed un-
der reduced pressure. Flash chromatography (petroleum ether/
combined organic layers were dried (MgSO4) and the solvent was
removed under reduced pressure. The residue was dissolved in pe-
troleum ether/EtOAc, (4:1) and filtered through a pad of silica, and
the solvent was removed in vacuo. The crude acetate (Rf = 0.65,
EtOAc, 2:1Ǟ1:1) afforded the ribitol 13 (2.00 g, 69%) as a colorless petroleum ether/EtOAc, 4:1) was dissolved in MeOH (50 mL), and
amorphous solid. Rf = 0.20 (petroleum ether/EtOAc, 4:1). [α]2D6
+1.4 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 1.46 (s,
=
NaOMe (5.4  solution in MeOH, 0.22 mL, 1.20 mmol) was
added. After stirring for 1 h at room temperature, the reaction mix-
ture was neutralized by addition of Lewatit S acidic ion-exchange
1
3 H, Boc-tBu-CH3), 2.85 (br. s, 1 H, 1-OH), 3.75–3.81 (m, 1 H, 2-
3
H), 3.79 (s, 3 H, PMP-OCH3), 3.90 (dd, J = 8.2, 3J = 2.9 Hz, 1 resin and filtered, and the solvent was removed under reduced pres-
H, 3-H), 3.93–4.08 (m, 3 H, 1-H2, 5-Ha), 4.08–4.15 (m, 1 H, 4-H),
sure. Flash chromatography (petroleum ether/EtOAc,
6:1Ǟ4:1Ǟ1:1) afforded the 1-O-TBS ether 6 (0.75 g, 13%), the 2-
2
4.18–4.23 (m, 1 H, 5-Hb), 4.50 (d, J = 11.0 Hz, 1 H, Ph-CHaHb),
2
3
4.78 (d, J = 11.0 Hz, 1 H, Ph-CHaHb), 5.15 (d, JNH,4 = 8.1 Hz, O-TBS ether 15 (0.55 g, 10%), and the diol 16 (0.60 g, 14%) as col-
1 H, 4-NH), 6.81–6.88 (m, 4 H, PMP-HAr), 7.20–7.39 (m, 5 H, Bn- orless oils.
H
Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 28.3 (Boc-tBu-CH3),
Compound 6: Rf = 0.65 (petroleum ether/EtOAc, 6:1). [α]2D6 = +17.6
(c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 0.09 (s, 3 H,
50.9 (C-4), 55.8 (PMP-OCH3), 61.8 (C-1), 64.1 (C-2), 67.1 (C-5),
74.7 (Ph-CH2), 79.4 (C-3), 80.5 (Boc-tBu-Cq), 114.8 (PMP-CAr),
115.4 (PMP-CAr), 128.1 (Bn-CAr), 128.2 (Bn-CAr), 128.5 (Bn-CAr),
137.4 (Bn-CAr), 152.3 (PMP-CAr), 154.3 (PMP-CAr), 155.8 (Boc-
C=O) ppm. HRMS (ESI): calcd. for [C24H42N4O6Na]+: 495.2214;
found 495.2219.
1
TBS-CH3), 0.10 (s, 3 H, TBS-CH3), 0.93 (s, 9 H, TBS-tBu-CH3),
3
2.57 (d, JOH,2 = 5.0 Hz, 1 H, 2-OH), 3.64–3.71 (m, 2 H, 1-Ha, 3-
H), 3.77–3.83 (m, 2 H, 1-Hb, 2-H), 3.78 (s, 3 H, PMP-OCH3), 4.17–
2
3
4.26 (m, 2 H, 5-Ha, 4-H), 4.30 (dd, J = 9.3, J4,5 = 2.6 Hz, 1 H,
5-Hb), 4.60 (d, 2J = 11.3 Hz, 1 H, Ph-CHaHb), 4.79 (d, 2J =
11.3 Hz, 1 H, Ph-CHaHb), 6.82–6.92 (m, 4 H, PMP-HAr), 7.30–
7.39 (m, 5 H, Bn-HAr) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.4
(TBS-CH3), 18.3 (TBS-tBu-Cq), 25.9 (TBS-tBu-CH3), 55.7 (PMP-
OCH3), 62.0 (C-4), 63.7 (C-1), 68.4 (C-5), 71.0 (C-2), 74.1 (Ph-
CH2), 79.1 (C-3), 114.7 (PMP-CAr), 115.7 (PMP-CAr), 128.0 (Bn-
2-Azido-3-O-benzyl-1-O-(tert-butyldimethylsilyl)-4-[(tert-butyloxy-
carbonyl)amino]-2,4-deoxy-5-O-(4-methoxyphenyl)-L-ribitol (14):
PPh3 (4.84 g, 18.5 mmol) and DIAD (3.73 mL, 18.5 mmol) were
added at 0 °C to a solution of the arabinitol 12 (5.76 g, 10.3 mmol)
in dry toluene (150 mL). A solution of HN3 in toluene[17] (2 ,
9.20 mL) was then added. The mixture was stirred for 30 min at
0 °C and then for another 16 h at room temperature. The reaction
mixture was diluted with EtOAc, and washed with satd. aq.
NaHCO3. The aqueous layer was reextracted with EtOAc (2ϫ), the
combined organic layers were dried (MgSO4) and filtered, and the
solvent was removed in vacuo. The residue was purified by flash
chromatography (petroleum ether/EtOAc, 8:1Ǟ6:1) to yield the ri-
bitol 14 (5.26 g, 88%) as a colorless oil. Rf = 0.65 (petroleum ether/
CAr), 128.1 (Bn-CAr), 128.5 (Bn-CAr), 137.7 (Bn-CAr), 152.5 (PMP-
CAr), 154.2 (PMP-CAr) ppm. HRMS (ESI): calcd. for [C35H37N3O-
5SiNa]+: 510.2395; found 510.2398.
Compound 15: Rf = 0.40 (petroleum ether/EtOAc, 6:1). 1H NMR
(300 MHz, CDCl3): δ = 0.13 (s, 3 H, TBS-CH3), 0.14 (s, 3 H, TBS-
CH3), 0.94 (s, 9 H, TBS-tBu-CH3), 1.97 (br. s, 1 H, 1-OH), 3.68–
3.83 (m, 3 H, 1-H2, 3-H), 3.78 (s, 3 H, PMP-OCH3), 3.93–3.99 (m,
2
3
1 H, 2-H), 4.00–4.15 (m, 2 H, 4-H, 5-Ha), 4.24 (dd, J = 9.4, J4,5
1
EtOAc, 8:1). [α]1D5 = +8.1 (c = 1.0, CHCl3). H NMR (300 MHz,
= 2.5 Hz, 1 H, 5-Hb), 4.69 (d, J = 11.0 Hz, 1 H, Ph-CHaHb), 4.76
2
CDCl3): δ = 0.07 (s, 6 H, TBS-CH3), 0.89 (s, 9 H, TBS-tBu-CH3),
1.43 (s, 9 H, Boc-tBu-CH3), 3.73–4.15 (m, 10 H, 5-H2, 4-H, 3-H,
(d, J = 11.0 Hz, 1 H, Ph-CHaHb), 6.80–6.89 (m, 4 H, PMP-HAr),
2
7.27–7.38 (m, 5 H, Bn-HAr) ppm. 13C NMR (75 MHz, CDCl3): δ
= –4.6 (TBS-CH3), –4.5 (TBS-CH3), 18.1 (TBS-tBu-Cq), 25.8
(TBS-tBu-CH3), 55.7 (PMP-OCH3), 61.7 (C-4), 63.7 (C-1), 68.7 (C-
5), 72.7 (C-2), 74.5 (Ph-CH2), 80.1 (C-3), 114.7 (PMP-CAr), 115.7
(PMP-CAr), 128.0 (Bn-CAr), 128.1 (Bn-CAr), 128.5 (Bn-CAr), 137.6
(Bn-CAr), 152.5 (PMP-CAr), 154.3 (PMP-CAr) ppm. HRMS (ESI):
calcd. for [C35H37N3O5SiNa]+: 510.2395; found 510.2392.
2-H, 1-H2, PMP-OCH3), 4.46 (d, J = 11.0 Hz, 1 H, Ph-CHaHb),
2
4.71 (d, J = 11.0 Hz, 1 H, Ph-CHaHb), 5.01 (d, JNH,4 = 9.2 Hz,
2
3
1 H, 4-NH), 6.78–6.82 (m, 4 H, PMP-HAr), 7.16–7.27 (m, 5 H, Bn-
H
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = –5.5 (2ϫTBS-CH3),
18.2 (TBS-tBu-Cq), 25.8 (TBS-tBu-CH3), 28.3 (Boc-tBu-CH3), 50.8
(C-4), 55.8 (PMP-OCH3), 62.9 (C-1), 64.5 (C-2), 67.3 (C-5), 74.5
(Ph-CH2), 78.1 (C-3), 79.9 (Boc-tBu-Cq), 114.8 (PMP-CAr), 115.4
(PMP-CAr), 127.9 (Bn-CAr), 128.2 (Bn-CAr), 128.4 (Bn-CAr), 137.6
(Bn-CAr), 152.5 (PMP-CAr), 154.2 (PMP-CAr), 155.2 (Boc-
C=O) ppm. HRMS (ESI): calcd. for [C30H46N4O6SiNa]+:
609.3079; found 609.3085. C30H46N4O6Si (586.79): calcd. C 61.40,
H 7.90, N 9.55; found C 61.27, H 7.98, N 9.32.
Compound 16: Rf = 0.15 (petroleum ether/EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): δ = 2.21 (br. s, 1 H, 1-OH), 2.87 (br. s, 1 H, 2-
OH), 3.63–3.83 (m, 4 H, 1-H2, 3-H), 3.77 (s, 3 H, PMP-OCH3),
3.83–3.93 (m, 1 H, 2-H), 4.07–4.20 (m, 2 H, 5-Ha, 4-H), 4.20–4.31
2
2
(m, 1 H, 5-Hb), 4.63 (d, J = 11.1 Hz, 1 H, Ph-CHaHb), 4.73 (d, J
= 11.1 Hz, 1 H, Ph-CHaHb), 6.77–6.94 (m, 4 H, PMP-HAr), 7.27–
7.42 (m, 5 H, Bn-HAr) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.7
(PMP-OCH3), 61.7 (C-4), 63.4 (C-1), 68.5 (C-5), 71.4 (C-2), 74.1
(Ph-CH2), 79.0 (C-3), 114.7 (PMP-CAr), 115.7 (PMP-CAr), 128.2
(Bn-CAr), 128.6 (Bn-CAr), 137.3 (Bn-CAr), 152.3 (PMP-CAr), 154.4
(PMP-CAr) ppm. HRMS (ESI): calcd. for [C19H23N3O5Na]+:
396.1530; found 396.1532.
4-Azido-3-O-benzyl-1-O-(tert-butyldimethylsilyl)-4-deoxy-5-O-(4-
methoxyphenyl)-
methylsilyl)-4-deoxy-5-O-(4-methoxyphenyl)-
Azido-3-O-benzyl-4-deoxy-5-O-(4-methoxyphenyl)-
L
-ribitol (6), 4-Azido-3-O-benzyl-2-O-(tert-butyldi-
-ribitol (15), and 4-
-ribitol (16):
L
L
NEt3 (2.70 mL, 19.5 mmol) and MsCl (1.25 mL, 16.1 mmol) were
added at 0 °C to a solution of the arabinitol 5 (5.58 g, 11.4 mmol)
in dry CH2Cl2 (110 mL). After stirring for 2 h at room temperature,
the reaction mixture was diluted with CH2Cl2, washed with satd.
aq. NaHCO3 and brine, and dried (MgSO4), and the solvent was
removed under reduced pressure. The crude mesylate (Rf = 0.45,
petroleum ether/EtOAc, 4:1) was dissolved in dry toluene (110 mL),
and 18-crown-6 (1.51 g, 5.7 mmol) and CsOAc (12.0 g, 57.2 mmol)
were added. After having been heated at reflux for 48 h, the reac-
tion mixture was diluted with EtOAc and water. The layers were
separated and the aqueous layer was extracted with EtOAc. The
1-O-Acetyl-4-azido-3-O-benzyl-4-deoxy-5-O-(4-methoxyphenyl)-L-
ribitol (17): NEt3 (3.64 mL, 26 mmol) and MsCl (1.85 mL,
23.7 mmol) were added to a solution of the arabinitol 5 (8.11 g,
13.2 mmol) in dry CH2Cl2 (100 mL). After stirring for 2 h at room
temperature, the solution was diluted with CH2Cl2 and washed
with satd. aq. NaHCO3 (2ϫ), and the aqueous layer was reex-
tracted with CH2Cl2. The combined organic layers were washed
with brine, dried (MgSO4), and filtered, and the solvent was re-
Eur. J. Org. Chem. 2009, 6129–6139
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6135

C. J. Schwörer, M. Oberthür
FULL PAPER
moved under reduced pressure. The crude mesylate (Rf = 0.45, pe-
troleum ether/EtOAc, 4:1) was dissolved in THF (150 mL), and
HCl (6 , 10.0 mL) was added. After stirring for 3 h at room tem-
perature, the reaction mixture was neutralized with satd. aq.
NaHCO3 and then extracted with EtOAc (3ϫ). The combined or-
ganic layers were washed with brine, dried (MgSO4), and filtered,
and the solvent was removed in vacuo. The crude primary alcohol
(Rf = 0.20, petroleum ether/EtOAc, 4:1) was dissolved in dry tolu-
ene (130 mL), and 18-crown-6 (1.71 g, 6.47 mmol) and cesium ace-
tate (13.6 g, 70.6 mmol) were added. After heating for 24 h to re-
flux, the cooled reaction mixture was diluted with EtOAc and
water. The aqueous layer was extracted with EtOAc (2ϫ), the com-
bined organic layers were dried (MgSO4) and filtered, and the sol-
vent was removed under reduced pressure. Flash chromatography
(petroleum ether/EtOAc, 4:1) afforded the ribitol 17 (3.84 g, 70%)
temperature, the reaction mixture was quenched by addition of
MeOH (20 mL) and then stirred for another 15 min. The solution
was diluted with CH2Cl2 and washed with satd. aq. NaHCO3. The
aqueous layer was extracted with CH2Cl2 (2ϫ), the combined or-
ganic layers were dried (MgSO4) and filtered, and the solvent was
removed under reduced pressure. The residue was subjected to flash
chromatography (petroleum ether/EtOAc, 6:1Ǟ4:1) to yield the
TBS ether 19 (4.15 g, 96%) as a colorless oil. Rf = 0.65 (petroleum
ether/EtOAc, 4:1). [α]2D4 = +11.4 (c = 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 0.09 (s, 3 H, TBS-CH3), 0.10 (s, 3 H, TBS-
CH3), 0.93 (s, 9 H, TBS-tBu-CH3), 1.46 (s, 9 H, Boc-tBu-CH3),
2
3
2.86 (br. s, 1 H, 2-OH), 3.72 (dd, J = 9.9, J1,2 = 6.6 Hz, 1 H, 1-
2
3
Ha), 3.78 (s, 3 H, PMP-OCH3), 3.82 (dd, J = 9.9, J1,2 = 4.6 Hz,
1 H, 1-Hb), 3.84–3.89 (m, 2 H, 2-H, 3-H), 4.82 (dd, J = 9.2, J4,5
= 4.7 Hz, 1 H, 5-Ha), 4.11–4.17 (m, 1 H, 5-Hb), 4.21–4.28 (m, 1 H,
4-H), 4.58 (d, 2J = 11.3 Hz, 1 H, Ph-CHaHb), 4.68 (d, 2J = 11.3 Hz,
2
3
as a colorless oil. Rf = 0.15 (petroleum ether/EtOAc, 4:1). [α]1D7
=
1
3
+37.2 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 2.08 (s,
1 H, Ph-CHaHb), 5.14 (d, J4,NH = 8.9 Hz, 1 H, 4-NH), 6.83–6.85
3 H, OAc-CH3), 2.66 (s, 1 H, 2-OH), 3.70 (m,1 H, 3-H), 3.77 (s, 3 (m, 4 H, PMP-HAr), 7.23–7.32 (m, 5 H, Bn-HAr) ppm. 13C NMR
H, PMP-OCH3), 4.05 (m, 1 H, 2-H), 4.11–4.28 (m, 4 H, 4-H, 1-
(125 MHz, CDCl3): δ = –5.4 (TBS-CH3), 18.2 (TBS-tBu-Cq), 25.9
2
Ha, 5-H2), 4.36 (dd, J = 11.8, J = 2.9 Hz, 1 H, 1-Hb), 4.62 (d, J (TBS-tBu-CH3), 29.3 (Boc-CH3), 50.4 (C-4), 55.7 (PMP-OCH3),
= 11.2 Hz, 1 H, Ph-CHaHb), 4.74 (d, 2J = 11.2 Hz, 1 H, Ph-
CHaHb), 6.85 (m, 4 H, PMP-HAr), 7.33 (m, 5 H, Bn-HAr) ppm. 13
NMR (75 MHz, CDCl3): δ = 20.4 (OAc-CH3), 55.3 (PMP-OCH3),
63.6 (C-1), 67.7 (C-5), 72.2 (C-2), 73.6 (Ph-CH2), 78.0 (C-3), 79.6
(Boc-tBu-Cq), 114.6 (PMP-CAr), 115.4 (PMP-CAr), 127.7 (Bn-CAr),
128.1 (Bn-CAr), 128.3 (Bn-CAr), 138.0 (Bn-CAr), 152.6 (PMP-CAr),
C
61.0 (C-4), 65.5 (C-1), 68.1 (C-5), 69.7 (C-2), 73.6 (Bn-CH2), 78.3 154.0 (PMP-CAr), 155.6 (Boc-C=O) ppm. HRMS (ESI): calcd. for
(C-3), 114.4 (PMP-CAr), 115.3 (PMP-CAr), 127.8 (Bn-CAr), 127.9
(Bn-CAr), 128.2 (Bn-CAr), 136.8 (Bn-CAr), 151.9 (PMP-CAr), 154.0
(PMP-CAr), 171.1 (OAc-C=O) ppm. HRMS (ESI): calcd. for
[C21H25N3O6Na]+: 438.1636; found 438.1642. C21H25N3O6
(415.44): calcd. C 60.71, H 6.07, N 10.11; found C 60.19, H 6.35,
N 9.76.
[C30H47N1O7SiNa]+: 584.3014; found 584.3022.
2-Azido-3-O-benzyl-4-[(tert-butyloxycarbonyl)amino]-2,4-deoxy-5-
O-(4-methoxyphenyl)-L-arabiniol (20) and Cyclic Carbamate 21: The
alcohol 19 (0.88 g, 1.57 mmol) was converted into the correspond-
ing mesylate and treated with sodium azide as in the procedure
described for the synthesis of 13. Flash chromatography (petroleum
ether/EtOAc, 4:1ǞCH2Cl2/MeOH, 10:1) afforded the arabinitol 20
(0.11 g, 13%) as a colorless oil and the cyclic carbamate 21 (0.44 g,
75%) as a colorless solid.
3-O-Benzyl-4-[(tert-butyloxycarbonyl)amino]-4-deoxy-5-O-(4-meth-
oxyphenyl)-L-ribitol (18): K2CO3 (0.62 g, 4.44 mmol) was added to
a solution of the ribitol 17 (3.72 g, 8.94 mmol) in MeOH/CH2Cl2
(1:1, 90 mL). After stirring for 4 h at room temperature, the reac-
tion mixture was diluted with CH2Cl2 and water, and the aqueous
layer was extracted with CH2Cl2 (2ϫ). The combined organic lay-
ers were dried (MgSO4) and filtered, and the solvent was removed
under reduced pressure. The crude diol (Rf = 0.20, petroleum ether/
EtOAc, 2:1) was dissolved in MeOH (50 mL), Boc2O (2.54 g,
11.6 mmol) and Pd/C (10%, 0.30 g) were added, and the mixture
was stirred under H2 (1 bar) for 16 h at room temperature. The
reaction mixture was then filtered through a pad of Celite and the
filtrate was concentrated under reduced pressure. After flash
chromatography (petroleum ether/EtOAc, 2:1Ǟ1:1), the N-Boc de-
rivative 18 (3.60 g, 90%) was obtained as a colorless oil. Rf = 0.30
(petroleum ether/EtOAc, 2:1). [α]1D9 = +6.4 (c = 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.44 (s, 9 H, Boc-tBu-CH3), 2.67
(m, 2 H, 1-OH, 2-OH), 3.78 (s, 3 H, PMP-OCH3), 3.84–3.90 (m, 4
H, 2-H, 3-H, 5-H2), 3.98–4.07 (m, 1 H, 1-Ha), 4.09–4.21 (m, 2 H,
Compound 20: Rf = 0.20 (petroleum ether/EtOAc, 2:1). [α]2D2
=
1
+22.8 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 1.46 (s,
9 H, Boc-tBu-CH3), 2.22 (br. s, 1 H, 1-OH), 3.64–3.70 (m, 1 H, 2-
H), 3.73–3.80 (m, 1 H, 1-Ha), 3.78 (s, 3 H, PMP-OCH3), 3.83 (dd,
3J = 7.2, 3J = 3.2 Hz, 1 H, 3-H), 3.87 (dd, 2J = 11.1, 3J1,2 = 6.8 Hz,
3
1 H, 1-Hb), 4.01 (dd, 2J = 9.4, J4,5 = 4.3 Hz, 1 H, 5-Ha), 4.17 (dd,
3
2J = 9.4, J4,5 = 3.4 Hz, 1 H, 5-Hb), 4.31 (br. s, 1 H, 4-H), 4.46–
4.64 (m, 2 H, Ph-CH2), 5.13 (d, 3J4,NH = 8.9 Hz, 1 H, 4-NH), 6.82–
6.89 (m, 4 H, PMP-HAr), 7.23–7.36 (m, 5 H, Bn-HAr) ppm. 13C
NMR (125 MHz, CDCl3): δ = 28.3 (Boc-tBu-CH3), 50.4 (C-4), 55.7
(PMP-OCH3), 62.5 (C-1), 63.6 (C-2), 67.1 (C-5), 74.2 (Ph-CH2),
77.0 (C-3), 80.0 (Boc-tBu-Cq), 114.8 (PMP-CAr), 115.3 (PMP-CAr),
128.1 (Bn-CAr), 128.3 (Bn-CAr), 128.5 (Bn-CAr), 137.3 (Bn-CAr),
152.2 (PMP-CAr), 154.2 (PMP-CAr), 155.4 (Boc-C=O) ppm.
HRMS (ESI): calcd. for [C24H32N4O6Na]+: 495.2214; found
495.2223.
2
2
4-H, 1-Hb), 4.56 (d, J = 11.1 Hz, 1 H, Ph-CHaHb), 4.68 (d, J =
Compound 21: Rf = 0.60 (CH2Cl2/MeOH, 10:1). [α]2D2 = –22.8 (c =
3
11.1 Hz, 1 H, Ph-CHaHb), 5.11 (d, J = 8.3 Hz, 1 H, 4-NH), 6.80–
1
1.0, CHCl3). H NMR (500 MHz, CDCl3): δ = 2.85 (br. s, 1 H, 1-
6.87 (m, 4 H, PMP-HAr), 7.20–7.34 (m, 5 H, Bn-HAr) ppm. 13C
NMR (75 MHz, CDCl3): δ = 28.3 (Boc-tBu-CH3), 50.8 (C-4), 55.8
(OCH3), 63.4 (C-5), 67.6 (C-1), 72.0 (C-2), 74.5 (Bn-CH2), 80.1 (C-
3), 80.2 (Boc-tBu-Cq), 114.8 (PMP-CAr), 115.4 (PMP-CAr), 128.1
(Bn-CAr), 128.2 (Bn-CAr), 128.6 (Bn-CAr), 137.7 (Bn-CAr), 152.3
(PMP-CAr), 154.3 (PMP-CAr), 155.8 (Boc-C=O) ppm. HRMS
(ESI): calcd. for [C24H33N1O7]+: 470.2149; found 470.2160.
OH), 3.69–3.78 (m, 1 H, 1-Ha), 3.76 (s, 3 H, PMP-OCH3), 3.81
2
3
(dd, J = 9.5, J4,5 = 7.2 Hz, 1 H, 5-Ha), 3.85–3.92 (m, 2 H, 2-H,
5-Hb), 3.94–4.02 (m, 2 H, 1-Hb, 4-H), 4.39–4.44 (m, 1 H, 3-H), 4.50
(d, J = 12.1 Hz, 1 H, Ph-CHaHb), 4.67 (d, J = 12.1 Hz, 1 H, Ph-
2
2
CHaHb), 6.50 (d, J4,NH = 2.6 Hz, 1 H, 4-NH), 6.77–6.86 (m, 4 H,
3
PMP-HAr), 7.28–7.38 (m, 5 H, Bn-HAr) ppm. 13C NMR (125 MHz,
CDCl3): δ = 52.5 (C-4), 55.7 (PMP-OCH3), 61.3 (C-1), 68.3 (C-2),
3-O-Benzyl-1-O-(tert-butyldimethylsilyl)-4-[(tert-butyloxycarbonyl)- 69.0 (C-5), 71.5 (Ph-CH2), 76.7 (C-3), 114.8 (PMP-CAr), 115.5
amino]-4-deoxy-5-O-(4-methoxyphenyl)-
L
-ribitol (19): TBSCl
(PMP-CAr), 128.2 (Bn-CAr), 128.3 (Bn-CAr), 128.6 (Bn-CAr), 136.8
(Bn-CAr), 151.9 (PMP-CAr), 153.8 (PMP-CAr), 155.4 [NH-(C=O)-
O] ppm. HRMS (ESI): calcd. for [C20H23N1O6Na]+: 396.1418;
found 396.1425.
(1.74 g, 11.5 mmol), NEt3 (2.16 mL, 15.4 mmol), and a catalytic
amount of DMAP were added to a solution of the diol 18 (3.44 g,
7.69 mmol) in dry CH2Cl2 (50 mL). After stirring for 16 h at room
6136
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6129–6139

Synthesis of Highly Functionalized Amino Acids
2-Azido-3-O-benzyl-1-O-(tert-butyldimethylsilyl)-4-[(tert-butyloxy-
carbonyl)amino]-2,4-deoxy-5-O-(4-methoxyphenyl)-L-arabinitol
HRMS (ESI): calcd. for [C33H45N4O5Si]+: 605.3154; found
605.3153.
(22): The ribitol 19 (4.32 g, 7.69 mmol) was converted into the az-
ide 22 by the procedure described for the synthesis of the azide 14.
Flash chromatography (petroleum ether/EtOAc, 8:1Ǟ6:1) afforded
the arabinitol 22 (4.15 g, 92%) as a colorless oil. Rf = 0.45 (petro-
2-Azido-3-O-benzyl-1-O-(tert-butyldiphenylsilyl)-4-[(tert-butyloxy-
carbonyl)amino]-2,4-deoxy-L-arabinitol (4): The arabinitol 22
(4.02 g, 6.86 mmol) was converted into the alcohol 4 by the pro-
cedure described for the synthesis of the alcohol 3. Flash
chromatography (petroleum ether/EtOAc, 4:1Ǟ3:1Ǟ2:1) afforded
the arabinitol 4 (2.98 g, 72%) as a colorless oil. Rf = 0.15 (petro-
1
leum ether/EtOAc, 8:1). [α]1D9 = +22.7 (c = 1.0, CHCl3). H NMR
(300 MHz, CDCl3): δ = 0.06 (s, 3 H, TBS-CH3), 0.08 (s, 3 H, TBS-
CH3), 0.91 (s, 9 H, TBS-tBu-CH3), 1.45 (s, 9 H, Boc-tBu-CH3),
19
1
leum ether/EtOAc, 4:1). [α] = –21.0 (c = 1.0, CHCl3). H NMR
3.62–3.78 (m, 2 H, 3-H, 5-Ha), 3.72–3.86 (m, 5 H, PMP-OCH3, 2-
D
(300 MHz, CDCl3): δ = 1.08 (s, 9 H, TBDPS-tBu-CH3), 1.44 (s, 9
H, Boc-tBu-CH3), 3.53–3.92 (m, 7 H, 1-H2, 2-H, 3-H, 4-H, 5-H2),
4.55 (d, 2J = 11.4 Hz, 1 H, Ph-CHaHb), 4.60 (d, 2J = 11.4 Hz, 1 H,
3
H, 5-Hb), 3.95–4.03 (m, 1 H, 1-Ha), 4.18 (dd, 2J = 9.4, J1,2
=
3.0 Hz, 1 H, 1-Hb), 4.25–4.37 (m, 1 H, 4-H), 4.51 (d, 2J = 11.2 Hz,
1 H, Ph-CHaHb), 4.57 (d, J = 11.2 Hz, 1 H, Ph-CHaHb), 5.16 (d,
2
3
Ph-CHaHb), 5.24 (d, JNH,4 = 7.0 Hz, 1 H, 4-NH), 7.18–7.31 (m, 5
3JNH,4 = 9.7 Hz, 1 H, 4-NH), 6.77–6.89 (m, 4 H, PMP-HAr), 7.15–
7.33 (m, 5 H, Bn-HAr) ppm. 13C NMR (75 MHz, CDCl3): δ = –5.5
(TBS-CH3), –5.4 (TBS-CH3), 14.2 (TBS-tBu-Cq), 18.2 (TBS-tBu-
Cq), 25.8 (TBS-tBu-CH3), 28.3 (Boc-tBu-CH3), 50.4 (C-4), 55.8
(OCH3), 63.5 (C-5/C-2), 63.7 (C-5/C-2), 67.5 (C-1), 74.1 (Bn-CH2),
76.3 (Boc-tBu-Cq), 79.8 (C-3), 114.8 (PMP-CAr), 115.3 (PMP-CAr),
127.9 (Bn-CAr), 128.2 (Bn-CAr), 128.4 (Bn-CAr), 137.5 (Bn-CAr),
152.3 (PMP-CAr), 154.2 (PMP-CAr), 155.3 (Boc-C=O) ppm.
HRMS (ESI): calcd. for [C30H46N4O6SiNa]+: 609.3079; found
609.3088. C30H46N4O6Si (586.79): calcd. C 61.40, H 7.90, N 9.55;
found C 61.35, H 7.76, N 9.72.
H, TBDPS-HAr), 7.33–7.50 (m, 6 H, Bn-HAr, TBDPS-HAr), 7.60–
7.71 (m, 4 H, TBDPS-HAr) ppm. 13C NMR (75 MHz, CDCl3): δ
= 19.1 (TBDPS-tBu-Cq), 26.8 (TBDPS-tBu-CH3), 28.3 (Boc-tBu-
CH3), 52.6 (C-4), 62.5 (C-2), 63.9 (C-1/C-5), 64.2 (C-1/C-5), 74.3
(Bn-CH2), 77.1 (C-3), 79.9 (Boc-tBu-Cq), 127.9 (Bn-CAr), 128.1 (2
signals, TBDPS-CAr, Bn-CAr), 128.4 (Bn-CAr), 129.9 (2 signals,
TBDPS-CAr), 132.7 (TBDPS-CAr), 132.9 (TBDPS-CAr), 135.6 (2
signals, TBDPS-CAr), 137.3 (Bn-CAr), 156.0 (Boc-C=O) ppm.
HRMS (ESI): calcd. for [C33H45N4O5Si]+: 605.3154; found
605.3153.
2-Azido-3-O-benzyl-4-[N,NЈ-bis(benzyloxycarbonyl)guanidino]-1-O-
(tert-butyldiphenylsilyl)-2,4-deoxy-L-ribitol (23): Satd. HCl/Et2O
2-Azido-3-O-benzyl-1-O-(tert-butyldiphenylsilyl)-4-[(tert-butyloxy-
carbonyl)amino]-2,4-deoxy-L-ribitol (3): The ribitol 14 (5.00 g,
(80 mL) was added at 0 °C to a solution of the ribitol 3 (2.56 g,
4.23 mmol) in ethyl ether (10 mL). After the mixture had been
stirred for 1 h at 0 °C, the solvent was removed under reduced pres-
sure. The crude amine was dissolved in THF (35 mL), and NEt3
(1.78 mL, 12.7 mmol), 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thi-
opseudourea (1.97 g, 5.50 mmol), and HgCl2 (2.30 g, 8.46 mmol)
were added. After stirring for 3 h at room temperature, the reaction
mixture was filtered through a pad of Celite. The filtrate was di-
luted with EtOAc, and washed with satd. aq. NH4Cl (2ϫ). The
aqueous layer was reextracted with EtOAc, the combined organic
layers were dried (MgSO4) and filtered, and the solvent was re-
moved in vacuo. Flash chromatography of the residue (petroleum
ether/EtOAc, 4:1Ǟ2:1) furnished the guanidine 23 (3.03 g, 88%) as
a colorless oil. Rf = 0.30 (petroleum ether/EtOAc, 4:1). [α]1D4 = –22.5
8.52 mmol) was dissolved in THF (85 mL) and HCl (6 , 5.00 mL).
After stirring for 3 h at room temperature, the reaction mixture was
neutralized with satd. aq. NaHCO3 and then extracted with EtOAc
(3ϫ). The combined organic layers were dried (MgSO4) and the
solvent was removed under reduced pressure. The crude alcohol (Rf
= 0.20, petroleum ether/EtOAc, 4:1) was dissolved in dry CH2Cl2
(80 mL), and NEt3 (2.98 mL, 21.3 mmol), TBDPSCl (3.35 mL,
12.8 mmol), and a catalytic amount of DMAP were added at 0 °C.
After stirring for 16 h at room temperature, the reaction was
quenched by addition of MeOH (10 mL) and stirred for another
15 min. The reaction mixture was diluted with CH2Cl2, washed
with satd. aq. NaHCO3, dried (MgSO4), filtered, and concentrated
in vacuo. Flash chromatography (petroleum ether/EtOAc, 6:1) af-
forded the TBDPS ether (5.81 g, 95%, Rf = 0.50, petroleum ether/
EtOAc, 6:1) as a colorless oil. The O1-TBDPS ether (5.81 g,
8.17 mmol) was dissolved in acetonitrile/water (4:1, 60 mL) and
CAN (13.2 g, 19.5 mmol) was added at 0 °C. After stirring for
15 min at 0 °C, the reaction mixture was poured into EtOAc
(300 mL). The organic layer was extracted with satd. aq. NaHCO3
(2ϫ) and the aqueous layer was reextracted with EtOAc. The com-
bined organic layers were dried (MgSO4) and filtered, and the sol-
vent was removed under reduced pressure. After flash chromatog-
raphy (petroleum ether/EtOAc, 4:1Ǟ3:1Ǟ2:1), the alcohol 3
(3.84 g, 73%) was obtained as a yellow oil. Rf = 0.25 (petroleum
ether/EtOAc, 4:1). [α]1D4 = –48.1 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.10 (s, 9 H, TBDPS-tBu-CH3), 1.44 (s, 9
H, Boc-tBu-CH3), 2.40 (br. s, 1 H, 5-OH), 3.58–4.05 (m, 7 H, 1-
H2, 2-H, 3-H, 4-H, 5-H2), 4.42–4.45 (m, 2 H, Ph-CH2), 5.15 (d,
3JNH,4 = 8.1 Hz, 1 H, 4-NH), 7.08–7.20 (m, 2 H, TBDPS-HAr),
1
(c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.00 (s, 9 H,
TBDPS-tBu-CH3), 3.54–3.67 (m, 2 H, 5-H2), 3.72–3.88 (m, 3 H, 1-
Ha, 2-H, 3-H), 3.93 (dd, J = 10.8, J = 3.2 Hz, 1 H, 1-Hb), 4.22–
2
4.33 (m, 1 H, 4-H), 4.33 (d, J = 10.9 Hz, 1 H, Ph-CHaHb), 4.43
2
(d, J = 10.9 Hz, 1 H, Ph-CHaHb), 4.96–5.03 (m, 2 H, Cbz-CH2),
5.05–5.15 (m, 2 H, Cbz-CH2), 6.98–7.06 (m, 2 H, TBDPS-HAr),
7.07–7.40 (m, 19 H, Bn-HAr, TBDPS-HAr, Cbz-HAr), 7.55–7.65 (m,
3
4 H, TBDPS-HAr), 8.88 (d, JNH,4 = 7.7 Hz, 1 H, 4-NH), 11.59 (s,
1 H, guanidine-NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1
(TBDPS-tBu-Cq), 26.8 (TBDPS-tBu-CH3), 53.0 (C-4), 61.9 (C-1),
64.0 (C-2), 64.2 (C-5), 67.2 (Cbz-CH2), 68.3 (Cbz-CH2), 74.5 (Ph-
CH2), 78.5 (C-3), 127.9–128.9 (9 signals, TBDPS-CAr, Bn-CAr, Cbz-
CAr), 129.9 (Bn-CAr), 132.8 (TBDPS-CAr, Cbz-CAr), 134.6 (Cbz-
CAr), 134.7 (TBDPS-CAr), 135.7 (TBDPS-CAr), 136.8 (Bn-CAr
,
Cbz-CAr), 153.6 (Cbz-C=O), 155.9 (Cbz-C=O), 163.4 (guanidine-
C) ppm. HRMS (ESI): calcd. for [C45H51N6O7Si]+: 815.3583;
found 815.3598.
7.23–7.33 (m, 3 H, TBDPS-HAr), 7.34–7.51 (m, 6 H, Bn-HAr
,
TBDPS-HAr), 7.66–7.76 (m, 4 H, TBDPS-HAr) ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.1 (TBDPS-tBu-Cq), 26.8 (TBDPS-tBu- 2-Azido-3-O-benzyl-4-[N,NЈ-bis(benzyloxycarbonyl)guanidino]-1-O-
CH3), 28.4 (Boc-tBu-CH3), 52.1 (C-4), 62.1 (C-1), 64.3 (C-2), 64.4
(C-5), 74.6 (Ph-CH2), 79.4 (C-3), 79.8 (Boc-tBu-Cq), 127.8
(tert-butyldiphenylsilyl)-2,4-deoxy-
tol 4 (2.44 g, 4.03 mmol) was converted into the guanidine 24 by
L-arabinitol (24): The arabini-
(TBDPS-CAr), 128.1 (TBDPS-CAr), 128.2 (Bn-CAr), 128.6 (Bn- the procedure described for the synthesis of compound 23. Flash
CAr), 129.9 (Bn-CAr), 132.8 (TBDPS-CAr), 135.6 (TBDPS-CAr),
135.7 (TBDPS-CAr), 137.1 (Bn-CAr), 155.6 (Boc-C=O) ppm.
chromatography (petroleum ether/EtOAc, 4:1Ǟ2:1) afforded 24
(2.86 g, 87%) as a colorless oil. Rf = 0.25 (petroleum ether/EtOAc,
Eur. J. Org. Chem. 2009, 6129–6139
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6137

C. J. Schwörer, M. Oberthür
FULL PAPER
4:1). [α]1D9 = –2.7 (c = 1.0, MeOH). H NMR (300 MHz, CDCl3):
1
(1): NaH2PO4 buffer (0.67 , 3.0 mL) and Na2HPO4 buffer (0.67 ,
3.0 mL) were added to a solution of the alcohol 25 (980 mg,
δ = 1.05 (s, 9 H, TBDPS-tBu-CH3), 3.39–3.48 (m, 1 H, 2-H), 3.65
(dd, 2J = 11.6, 3J4,5 = 3.3 Hz, 1 H, 5-Ha), 3.75–3.94 (m, 4 H, 1-H2, 1.75 mmol) in acetonitrile (10 mL). TEMPO (14 mg, 0.09 mmol),
3-H, 5-Hb), 4.28–4.38 (m, 1 H, 4-H), 4.52 (d, 2J = 11.5 Hz, 1 H,
NaClO2 (317 mg, 3.50 mmol), and aq. NaOCl solution (ca. 10%,
0.20 mL) were then added. After the mixture had been stirred for
1 h at 40 °C, additional amounts of TEMPO (14 mg, 0.09 mmol),
NaClO2 (317 mg, 3.50 mmol), and aq. NaOCl (ca. 10%, 0.20 mL)
were added, and the reaction mixture was stirred for another 1 h
at 40 °C. This procedure was repeated until no more starting mate-
rial could be detected by TLC (petroleum ether/EtOAc, 1:2). The
solution was then diluted with CH2Cl2 and washed with aq.
NaHSO3 (10 %, 2ϫ) and brine. The organic layer was dried
2
Ph-CHaHb), 4.65 (d, J = 11.5 Hz, 1 H, Ph-CHaHb), 5.04–5.14 (m,
2 H, Cbz-CH2), 5.21 (s, 2 H, Cbz-CH2), 7.19–7.14 (m, 5 H,
TBDPS-HAr), 7.27–7.45 (m, 16 H, TBDPS-HAr, Cbz-HAr, Bn-HAr),
3
7.59–7.67 (m, 5 H, TBDPS-HAr), 9.13 (d, J4,NH = 7.4 Hz, 1 H, 4-
NH), 11.65 (s, 1 H, guanidine-NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.0 (TBDPS-tBu-Cq), 26.7 (TBDPS-tBu-CH3), 53.8
(C-4), 62.5 (C-5), 63.3 (C-2), 63.6 (C-1), 67.1 (Cbz-CH2), 68.3 (Cbz-
CH2), 73.6 (Bn-CH2), 76.1 (C-3), 127.8–128.1 (5 signals, Cbz-CAr
,
Bn-CAr), 128.4 (Bn-CAr), 128.7 (Bn-CAr), 128.8 (TBDPS-CAr), (MgSO4) and filtered, and the solvent was removed under reduced
129.9 (2 signals, TBDPS-CAr), 132.8 (TBDPS-CAr, Cbz-CAr), 134.6 pressure. The residue was purified by flash chromatography
(Cbz-CAr), 135.6 (TBDPS-CAr/Bn-CAr), 136.7 (Bn-CAr, Cbz-CAr),
153.4 (Cbz-C=O), 156.2 (Cbz-C=O), 163.2 (guanidine-Cq) ppm.
(CH2Cl2/MeOH, 9:1Ǟ4:1) to give the protected -β-hydroxyendur-
acididine 1 (892 mg, 89%) as a colorless amorphous solid. Rf =
HRMS (ESI): calcd. for [C45H51N6O7Si]+: 815.3583; found 0.35 (CH2Cl2/MeOH, 9:1). [α]2D1 = –41.4 (c = 1.0, CHCl3). 1H NMR
815.3584.
(500 MHz, [D6]DMSO): δ = 3.83–3.94 (m, 1 H, 5-Ha), 3.97–4.04
2
(m, 1 H, 5-Hb), 4.04–4.16 (m, 3 H, 2-H, 3-H, 4-H), 4.48 (d, J =
4-Amino-2-azido-3-O-benzyl-5-[(benzyloxycarbonyl)amino]-4,5-
N,NЈ-[(benzyloxycarbonyl)carbimino]-2,4,5-deoxy-L-ribitol (25): A
11.7 Hz, 1 H, Ph-CHaHb), 4.72 (d, 2J = 11.7 Hz, 1 H, Ph-CHaHb),
5.04 (s, 2 H, Cbz-CH2), 5.19 (s, 2 H, Cbz-CH2), 7.17–7.49 (m, 15
H, Bn-HAr, Cbz-HAr), 8.81 (s, 1 H, 4-NH) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 45.1 (C-5), 52.9 (C-4), 64.2 (C-2), 66.2
(Cbz-CH2), 67.0 (Cbz-CH2), 71.9 (Ph-CH2), 79.8 (C-3), 127.3–
128.3 (9 signals, Bn-CAr, Cbz-CAr), 136.0 (Cbz-CAr), 137.2 (Cbz-
CAr), 138.2 (Bn-CAr), 150.4 (Cbz-C=O), 158.2 (Cbz-C=O), 162.9
(guanidine-C), 169.9 (C-1) ppm. HRMS (ESI): calcd. for
[C29H29N6O7]+: 573.2092; found 573.2097.
solution of the ribitol 23 (2.13 g, 2.61 mmol) in dry THF (25 mL)
was added dropwise to a solution of PPh3 (1.71 g, 6.53 mmol) and
DIAD (1.31 mL, 6.53 mmol) in dry THF (25 mL). After the mix-
ture had been stirred for 3 h at 40 °C, the solvent was removed
under reduced pressure and the residue was subjected to flash
chromatography (petroleum ether/EtOAc, 4:1Ǟ2:1) to give the cy-
clic guanidine, which coeluted with the DIAD-derived hydrazine
(Rf = 0.55, petroleum ether/EtOAc, 2:1). The mixture was dissolved
in THF (25 mL), and TBAF (1  in THF, 5.22 mL, 5.22 mmol)
was added. After the mixture had been stirred for 2.5 h at room
temperature, the solvent was removed in vacuo. Flash chromatog-
raphy (petroleum ether/EtOAc, 1:1Ǟ1:2) of the residue afforded
the ribitol 25 (1.02 g, 70%) as a colorless oil. Rf = 0.55 (petroleum
ether/EtOAc, 1:2). [α]2D2 = –24.2 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 3.62 (dd, J = 6.6, J = 3.6 Hz, 1 H, 1-Ha),
3.67–3.97 (m, 5 H, 1-Hb, 2-H, 3-H, 4-H, 5-H2), 4.22–4.37 (m, 1 H,
1-OH), 4.52 (d, 2J = 11.5 Hz, 1 H, Ph-CHaHb), 4.72 (d, 2J =
11.5 Hz, 1 H, Ph-CHaHb), 5.05–5.26 (m, 4 H, 2ϫCbz-CH2), 7.11–
7.49 (m, 15 H, Bn-HAr, Cbz-HAr) ppm. 13C NMR (75 MHz,
CDCl3): δ = 47.3 (C-5), 60.4 (C-4), 61.4 (C-1), 62.9 (C-2), 67.8
(Cbz-CH2), 68.4 (Cbz-CH2), 73.2 (Ph-CH2), 81.7 (C-3), 128.2–
128.7 (6 signals, Bn-CAr, Cbz-CAr), 134.9 (Cbz-CAr), 135.5 (Cbz-
CAr), 137.2 (Bn-CAr) ppm. HRMS (ESI): calcd. for [C29H31N6-
O6]+: 559.2300; found 559.2307.
4-Amino-2-azido-3-O-benzyl-5-[(benzyloxycarbonyl)amino]-4,5-
N,NЈ-[(benzyloxycarbonyl)carbimino]-2,4,5-deoxy-L-arabinonic Acid
(2): The arabinitol 26 (1.98 g, 2.43 mmol) was oxidized by the pro-
cedure described for the synthesis of the acid 1. Flash chromatog-
raphy (CH2Cl2/MeOH, 9:1Ǟ4:1) afforded the protected -β-
hydroxyenduracididine derivative 2 (886 mg, 90%) as a colorless
amorphous solid. Rf = 0.15 (CH2Cl2/MeOH, 10:1). [α]2D0 = –42.7 (c
= 1.0, CHCl3). 1H NMR (300 MHz, [D6]DMSO): δ = 3.54–3.62
(m, 1 H, 2-H), 3.87–4.09 (m, 3 H, 4-H, 5-H2), 4.31–4.40 (m, 1 H,
3-H), 4.52 (d, 2J = 11.4 Hz, 1 H, Ph-CHaHb), 4.73 (d, 2J = 11.4 Hz,
1 H, Ph-CHaHb), 5.05 (s, 2 H, Cbz-CH2), 5.19 (s, 2 H, Cbz-CH2),
7.17–7.25 (m, 5 H, Cbz-HAr/Bn-HAr), 7.26–7.39 (m, 8 H, Cbz-HAr
/
Bn-HAr), 7.40–7.48 (m, 2 H, Cbz-HAr/Bn-HAr), 9.07 (br. s, 1 H, 4-
NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 45.1 (C-5), 54.5
(C-4), 64.0 (C-2), 66.1 (Cbz-CH2), 67.0 (Cbz-CH2), 73.4 (Bn-CH2),
80.2 (C-3), 127.3–128.3 (8 signals, Cbz-CAr/Bn-CAr), 135.9 (Cbz-
CAr/Bn-CAr), 137.2 (Cbz-CAr/Bn-CAr), 138.4 (Cbz-CAr/Bn-CAr),
4-Amino-2-azido-3-O-benzyl-5-[(benzyloxycarbonyl)amino]-4,5-
N,NЈ-[(benzyloxycarbonyl)carbimino]-2,4,5-deoxy-L-arabinitol (26):
150.5 (Cbz-C=O), 163.5 (guanidine-C), 171.0 (C-1) ppm. HRMS
(ESI): calcd. for [C29H27N6O7]–: 571.1947; found 571.1928.
The guanidine 24 (1.98 g, 2.43 mmol) was cyclized and deprotected
to afford 26 by the procedure described for the synthesis of com-
pound 25. Flash chromatography (petroleum ether/EtOAc,
1:1Ǟ1:2) afforded the arabinitol 26 (0.96 g, 71%) as a colorless oil.
Rf = 0.30 (petroleum ether/EtOAc, 1:2). [α]1D8 = –24.5 (c = 1.0,
Supporting Information (see also the footnote on the first page of
this article): Detailed procedures for the synthesis of 3-O-benzyl-
1,2-O-isopropylidene--xylose (8), and the esterification and re-
1
duction of the azido function of compound 2, H and 13C NMR
spectra for all compounds.
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 3.47–3.56 (m, 1 H, 2-
H), 3.61–4.01 (m, 5 H, 1-H2, 3-H, 5-H2), 4.07–4.19 (m, 1 H, 4-H),
4.61 (d, 2J = 11.0 Hz, 1 H, Ph-CHaHb), 4.81–4.94 (m, 1 H, Ph-
CHaHb), 5.11–5.27 (m, 4 H, Cbz-CH2), 7.21–7.45 (m, 15 H, Cbz-
HAr, Bn-HAr), 9.71 (br. s, 1 H, 4-NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 47.4 (C-5), 62.2 (C-1), 64.3 (C-4), 67.8 (C-2), 68.4
(Cbz-CH2), 75.2, (Bn-CH2), 82.3 (C-3), 128.1–128.7 (Cbz-CAr, Bn-
CAr) ppm. HRMS (ESI): calcd. for [C29H31N6O6]+: 559.2300;
found 559.2299.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (Ob 332/1-1 and Ob 332/1-2).
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6129–6139

Synthesis of Highly Functionalized Amino Acids
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Received: August 25, 2009
Published Online: October 27, 2009
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Eur. J. Org. Chem. 2009, 6129–6139
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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