Stereoselective synthesis of uridine-derived nucleosyl amino acids

Article abstract of DOI:10.1021/jo201935w

Novel hybrid structures of 5′-deoxyuridine and glycine were conceived and synthesized. Such nucleosyl amino acids (NAAs) represent simplified analogues of the core structure of muraymycin nucleoside antibiotics, making them useful synthetic building blocks for structure-activity relationship (SAR) studies. The key step of the developed synthetic route was the efficient and highly diastereose-lective asymmetric hydrogenation of didehydro amino acid precursors toward protected NAAs. It was anticipated that the synthesis of unprotected muraymycin derivatives via this route would require a suitable intermediate protecting group at the N-3 of the uracil base. After initial attempts using PMB- and BOM-N-3 protection, both of which resulted in problematic deprotection steps, an N-3 protecting group-free route was envisaged. In spite of the pronounced acidity of the uracil-3-NH, this route worked equally efficient and with identical stereoselectivities as the initial strategies involving N-3 protection. The obtained NAA building blocks were employed for the synthesis of truncated 5′-deoxymuraymycin analogues (Figure presented).

Full text of DOI:10.1021/jo201935w

Article
pubs.acs.org/joc
Stereoselective Synthesis of Uridine-Derived Nucleosyl Amino Acids
Anatol P. Spork,‡ Daniel Wiegmann,‡ Markus Granitzka,† Dietmar Stalke,† and Christian Ducho*,‡,§
‡Department of Chemistry, Institute of Organic and Biomolecular Chemistry, Georg-August-University Gottingen, Tammannstr. 2,
̈
37 077 Gottingen, Germany
̈
†Department of Chemistry, Institute of Inorganic Chemistry, Georg-August-University Gottingen, Tammannstr. 4, 37 077 Gottingen,
̈
̈
Germany
§Department of Chemistry, University of Paderborn, Warburger Strasse 100, 33 098 Paderborn, Germany
S
* Supporting Information
ABSTRACT: Novel hybrid structures of 5′-deoxyuridine and glycine
were conceived and synthesized. Such nucleosyl amino acids (NAAs)
represent simplified analogues of the core structure of muraymycin
nucleoside antibiotics, making them useful synthetic building blocks
for structure−activity relationship (SAR) studies. The key step of the
developed synthetic route was the efficient and highly diastereose-
lective asymmetric hydrogenation of didehydro amino acid precursors
toward protected NAAs. It was anticipated that the synthesis of
unprotected muraymycin derivatives via this route would require a
suitable intermediate protecting group at the N-3 of the uracil base. After initial attempts using PMB- and BOM-N-3 protection,
both of which resulted in problematic deprotection steps, an N-3 protecting group-free route was envisaged. In spite of the
pronounced acidity of the uracil-3-NH, this route worked equally efficient and with identical stereoselectivities as the initial
strategies involving N-3 protection. The obtained NAA building blocks were employed for the synthesis of truncated 5′-
deoxymuraymycin analogues.
remarkable aspect about structure 3 is the C−C linkage of the
5′-carbon atom of the uridine moiety to the α-carbon atom of a
glycine unit (C-6′). Thus, 3 might be considered a hybrid of an
amino acid with a nucleoside, making it a relevant structural
motif for several applications (vide supra). Synthetic access to
protected versions of 3 include the aldol-type reaction of a
glycine-derived enolate with a uridine-5′-aldehyde,13 Sharpless
aminohydroxylation,14 and diasteroselective epoxide formation
using sulfur ylide chemistry, followed by double-inversion
opening of the epoxide.15 However, the stereocontrolled
construction of both stereocenters at C-5′ and C-6′ of β-
hydroxy amino acid 3 is not trivial.
INTRODUCTION
■
The chemical modification of naturally occurring nucleoside
and nucleotide structures is an important field in nucleic acid
and medicinal chemistry. For instance, nucleoside analogues are
known to be potential antiviral and anticancer agents.1
Modified oligonucleotides are important tools for biomedical
research2 as well as DNA-based nanotechnology.3 Within such
areas of research, mixing structural principles of nucleic acids
and peptides is an important issue. The most striking example
of this approach might be the design of peptide nucleic acids
(PNA), nucleic acid analogues with an artificial peptidic
backbone.4 Furthermore, amide internucleotide linkages have
been introduced into oligonucleotides,5 and DNA-peptide or
-protein conjugates have gained widespread attention.6
Amino acid−nucleoside hybrid structures can also be found
in natural products. Nucleoside antibiotics are microbially
produced secondary metabolites often bearing unusual nucleo-
side moieties.7 Most of these naturally occurring nucleoside
derivatives inhibit the bacterial membrane protein translocase I
(MraY), a key enzyme in the intracellular part of peptidoglycan
formation.8 With respect to the emerging resistances of
bacterial strains toward established antibiotics,9 MraY is
discussed as a potential new drug target.10 Representative
examples of the complex structures found in nucleoside
antibiotics are given by the muraymycins11 and caprazamycins12
(e.g., muraymycin A1 1 and caprazamycin A 2, Figure 1). Both
of those Streptomyces-produced classes of natural products share
a common nucleoside core structure of type 3. The most
Several analogues of both the muraymycins13,16 and the
caprazamycins17 have already been prepared and tested for
their antibiotic potencies. Remarkably, muraymycin analogues
derived from the 5′-epimer of 3 (not displayed) were also
proven to be biologically active. Thus, truncated synthetic
muraymycin analogues 4a−e with the unnatural (5′R)-
configuration showed reasonable antibacterial activities (Figure
1). Derivatives lacking the synthetic protecting groups still
present in 4a−e were surprisingly found to be nearly inactive.
Astonishingly, the congeners of this series of analogues with
natural product-like (5′S)-configuration (not displayed) did not
feature any significant biological potency.13
Received: September 19, 2011
Published: November 7, 2011
© 2011 American Chemical Society
10083
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
Figure 1. The nucleoside antibiotics muraymycin A1 1 and caprazamycin A 2, their common uridine-derived core structure 3 and bioactive synthetic
muraymycin analogues 4a-e.
Besides these results, the aminoribosyl unit of the
muraymycins has been found not to be essential for
antibacterial activity as proven by a bioactive nonaminoribosy-
lated derivative (muraymycin A5, not displayed).11 This has led
to the design of 5′-deoxy analogues of 3, i.e., compounds of
type 5 (with (6′S)-configuration as in the natural products 1
and 2) and of type 6 (displaying unnatural (6′R)-configuration,
Figure 2). Uridine-derived nucleosyl amino acids (NAAs) 5 and
to the role of the 5′-substituent and to the stereochemistry at
the 6′-position.
We have recently described the concise stereoselective
synthesis of unprecedented uridine-derived NAAs 5 and 6 in
communication format.18 They could be used as building
blocks for the preparation of truncated muraymycin derivatives
7a and 8a, which represent analogues of the established
muraymycin-based synthetic antibiotics 4. However, it would
also be desirable to obtain partially or globally deprotected
muraymycin derivatives such as 7b and 8b (as analogues of 4e)
or 7c and 8c, respectively, for SAR studies (Figure 2). From a
synthetic point of view, the choice of the N-3 protecting group
at the uracil base might be crucial in order to achieve this goal.
In this work, we therefore present a more detailed study on the
synthesis of uridine-derived NAAs with a particular focus on
different strategies for uracil protection.
RESULTS AND DISCUSSION
■
The principle synthetic route toward NAA structures of type 5
and 6 involved the oxidation of protected uridine derivatives to
the respective 5′-aldehydes, the Wittig−Horner transformation
of the aldehydes into didehydro amino acids, and finally, the
stereoselective hydrogenation of those key intermediates to
furnish protected NAAs.18 In order to obtain the hydrogenation
precursors, protecting groups had to be installed first.
Trisilylated uridine 919 (which can easily be obtained from
uridine in quantitative yield) was N-3-alkylated (products 1015a
and 11, yields 85% and 87%) and then selectively 5′-O-
desilylated20 to yield 1215a and 13 in yields of 79% and 72%,
respectively (Scheme 1). Because of the acidity of the uracil
NH, p-methoxybenzyl (PMB, for 10 and 12) or benzylox-
ymethyl (BOM, for 11 and 13) protection of the uracil-N-3
position was anticipated to be necessary in order to allow the
subsequent Wittig−Horner reaction to proceed efficiently.
There is precedent though for Wittig reactions using basic
nonstabilized ylides and Wittig−Horner transformations
employing basic deprotonated phosphonates with N-3-
unprotected uridine derivatives.21 However, yields for such
processes were either not disclosed21a or moderate at best.21b
Figure 2. Uridine-derived nucleosyl amino acid (NAA) building blocks
5 and 6 and the corresponding muraymycin analogues 7 and 8.
6 represent truncated analogues of the nucleoside moieties
found in nucleoside antibiotics such as 1 and 2, lacking the 5′-
hydroxy group as the site for aminoribosylation. Compounds
derived from NAA structures 5 and 6 therefore represent
interesting candidates with improved chemical tractability for
structure−activity relationship (SAR) studies. They might be
valuable additions to the existing SAR results for truncated
muraymycin analogues 4 (vide supra), particularly with respect
10084
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
Scheme 1. Synthesis of Didehydro Amino Acids 17 and 18
1
Alcohols 12 and 13 were oxidized with IBX to give protected
uridine 5′-aldehydes 14 and 15 as Wittig−Horner substrates in
98% yield each (Scheme 1). Though they showed limited
stability, freshly prepared aldehydes 14 and 15 could easily be
used for the subsequent Wittig−Horner transformations with
amino acid phosphonate 1622 under basic conditions. This
reaction furnished uridine-derived didehydro amino acids (Z)-
1718 and (Z)-18 in isolated yields of 67% and 82%, respectively.
As expected,23 the Wittig−Horner reactions displayed
pronounced (Z)-stereoselectivity. In the case of 17, the
corresponding (E)-isomer (E)-17 was obtained as a byproduct
only (6% isolated yield after column chromatography),18 while
for 18, the (E)-congener (E)-18 was not found at all. We have
previously described that similar transformations can also be
carried out using the N-Boc-protected amino acid phosphonate.
However, the acidic Boc deprotection at a later stage of the
synthetic route was problematic,18 and consequently, this
approach is not described in further detail here.
It is known that homogeneous asymmetric hydrogenation
reactions occur more rapidly and with significantly better
stereoselectivities for (Z)-didehydro amino acids than for the
(E)-isomers.24 It was therefore essential to prove unambigu-
ously that the main products obtained from the Wittig−Horner
reactions were indeed (Z)-configured, though this was strongly
suggested by numerous precedent. In order to determine the
stereochemical configuration of the didehydro amino acids
using established NMR criteria,25 both the (Z)- and the (E)-
isomers of 17 as well as 18 were required. However, in contrast
to (E)-17, the BOM-protected congener (E)-18 could not be
obtained as a byproduct from the Wittig−Horner reaction and
thus had to be prepared separately. Treatment of (Z)-18 with
potassium hexamethyldisilazide (KHMDS) led to partial
isomerization of the olefinic double bond, most likely resulting
from deprotonation of the amino acid α-NH providing an
azaallyl anion. After chromatographic separation from remain-
ing (Z)-18, (E)-18 could be isolated in 23% yield (Scheme 2).
With both (E)-isomers in hand, application of the
aforementioned empirical NMR criteria for configurational
assignment of the double bond was attempted. It had been
reported by Mazurkiewicz et al. that both the β-CH as well as
the α-NH of (E)-didehydro amino acids was further downfield-
shifted than the corresponding signals of the respective (Z)-
isomers in 1H NMR spectra recorded in deuterated chloroform
Scheme 2. Synthesis of (E)-18 and Relevant H NMR NOEs
of (Z)-18
(δβ‑CH(E) > δβ‑CH(Z) and δα‑NH(E) > δα‑NH(Z), respectively).25
This was found to be true for the β-CH, but the rule was
violated for the α-NH signals of both 17 and 18. However, the
configuration of (Z)-17 had been verified by a 1H−1H NOESY
NMR (2D) experiment before.18 1H NOE NMR (1D) studies
now clearly proved the proposed configuration of (Z)-18 to be
correct. For (Z)-18, no transfer of nuclear spin polarization by a
nuclear Overhauser effect (NOE) from the β-CH to the α-NH
was found. In contrast, an NOE-derived signal proving a
polarization transfer from the nucleoside H-4′ to the amino acid
α-NH was observed (Scheme 2, also see the Supporting
Information).
With both precursor compounds (Z)-17 and (Z)-18 in hand,
asymmetric hydrogenation providing the desired NAA
structures was performed. The chiral homogeneous catalysts
(+)-1,2-bis-((2S,5S)-2,5-dimethylphospholano)benzene-
(cyclooctadiene)rhodium(I) tetrafluoroborate ((S,S)-Me-DU-
PHOS-Rh) 19 and (−)-1, 2-bis-((2R, 5R)-2, 5-
dimethylphospholano)benzene(cyclooctadiene)rhodium(I) tet-
rafluoroborate ((R,R)-Me-DUPHOS-Rh) 2026 have been
shown to be highly useful for such transformations, particularly
when N-urethane-protected didehydro amino acids were
employed.27 As briefly reported in our previous communica-
tion,18 hydrogenation of (Z)-17 in the presence of 19 gave
NAA (S)-21 in excellent diastereoselectivity (dr > 98:2 as
1
determined by H NMR), while catalyst 20 furnished NAA
(R)-21 with similar selectivity. Primary reaction products 21
could easily be deprotected by subsequent hydrogenolysis
under heterogeneous catalysis (palladium on charcoal) in a
one-pot fashion to provide NAAs (S)-22 and (R)-22 in overall
yields of 86% and 80%, respectively (Scheme 3). The
assignment of the stereochemical configuration at C-6′ was
10085
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
Scheme 3. Synthesis of Nucleosyl Amino Acids (S)-22 and (R)-22 as Well as (S)-23 and (R)-23
Table 1. Hydrogenolytic Deprotection of (S)-23 and (R)-23
a
b
c
entry
isomer
scale/mg
catalyst
solvent
time/h
amount 25 /%
yield 24 /%
d
d
d
1
2
6′S
6′S
6′S
6′S
6′S
6′R
6′R
6′R
6′R
6′R
6′R
30
20
50
40
790
30
50
30
40
30
30
10% Pd/C
Pd black
Pd black
Pd black
Pd black
Pd black
Pd black
Pd black
Pd black
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOAc
MeOH
MeOH
MeOH
20
6
∼80
∼5
∼5
3
120
2.5
8.5
12
96
18
2.5
2
4
<5
92
d
5
∼30
5−10
∼20
∼90
<5
d
d
d
6
7
8
9
96
d
e
10
11
Pearlman
∼90
∼70
d
Lindlar
96
a
b
c
1
Amount of starting material. Amount of undesired byproduct 25 detected in the crude reaction product by H NMR. Isolated yield of desired
d
e
product 24. 24 could not be isolated as 24 and 25 were chromatographically inseparable. Pearlman’s catalyst = 20% Pd(OH)2/C.
based on literature precedent clearly indicating that 19 would
always provide L-amino acids while 20 leads to the respective D-
isomers.26,27 It could be ruled out that this catalyst-provided
stereoinduction was overruled by substrate-controlled selectiv-
ity for the hydrogenation of (Z)-17 as the reaction was of
catalyst-controlled nature.18 The asymmetric hydrogenation
step worked equally well with BOM-protected congener (Z)-
18, thus giving rise to the synthesis of NAAs (S)-23 and (R)-23
in yields of 94% and 93%, respectively, and again with excellent
diastereoselectivities (dr > 98: 2 each as determined by H
NMR, Scheme 3).
The envisaged preparation of NAAs and derived muraymycin
analogues lacking a uracil-N-3 protecting group (vide supra)
would require either (i) the selective cleavage of the PMB
group from (S)-22 and (R)-22 or subsequent reaction
products, respectively, or (ii) the concomitant hydrogenolytic
removal of both the Cbz and the BOM group from (S)-23 and
(R)-23. We have previously reported that (S)-22 and (R)-22
can readily be converted into muraymycin analogues 7a and
8a.18 The most obvious strategy would be to remove the PMB
group from these compounds at a late stage to obtain 7b and
8b (also see Figure 2). To our surprise, any attempt to
efficiently cleave the PMB group from 7a or 8a under oxidative
conditions was not successful in spite of literature precedent for
its use for uracil-N-3 protection.13,28 No reaction was observed
when DDQ was employed. In contrast, treatment with CAN
led to tedious product mixtures, most likely due to the
pronounced acidic nature of aqueous solutions of CAN. When
buffered CAN solutions were used in order to overcome this
problem, no reaction was observed. As a result of the hurdles
1
10086
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
encountered for the PMB removal, it was decided to focus on
the BOM-based strategy, i.e., the selective hydrogenolytic
deprotection of NAAs (S)-23 and (R)-23.
catalysts were also tested for the deprotection of (R)-23. Using
Pearlman’s catalyst (20% palladium hydroxide on charcoal), it
was anticipated that reaction times might be reduced to such an
extent that overreduction might be avoided. In contrast, (R)-25
was furnished in ca. 90% in this reaction (entry 10). Even with
the usually mild and selective poisoned Lindlar catalyst, ca. 70%
formation of (R)-25 was observed (entry 11). It was therefore
decided not to continue any attempts to further optimize the
hydrogenolysis reaction.
Due to the practical limitations of concomitant Cbz and
BOM cleavage from (S)-23 and (R)-23 (vide supra), alternative
strategies were sought. It was obvious from the straightforward
deprotection of the Cbz group in (S)-21 and (R)-21 (see
Scheme 3) that problems were caused by the BOM group.
However, only few protecting groups for the uracil-N-3 are
established. It would therefore be an attractive option to
perform the synthesis of NAAs (S)-24 and (R)-24 without
protection of the uracil-N-3 position. It was anticipated though
that a Wittig−Horner transformation of a uridine derivative
lacking nucleobase protection should be hindered in terms of
yield and/or stereoselectivity due to the acidity of the uracil-3-
NH (vide supra). However, after selectively silylated uridine
2620 (obtained by 5′-O-deprotection of 9 in 93% yield) had
been oxidized to the corresponding 5′-aldehyde 27 with IBX in
98% yield,15,29 aldehyde 27 could be reacted with phosphonate
16 in the presence of base to furnish didehydro amino acid (Z)-
28 with a yield of 85% (Scheme 4). This surprisingly efficient
For the concomitant hydrogenolysis of the Cbz and the
BOM group from (S)-23 and (R)-23, different conditions were
investigated (Table 1). On the basis of literature precedent,14a
it was anticipated that the formaldehyde liberated upon
cleavage of the BOM group might react with the 6′-amino
group. Thus, the N-methylated product would be furnished
under the reductive conditions of hydrogenolysis reactions. In
order to overcome this limitation, an excess of n-butylamine
was added to the reaction mixture to capture the formaldehyde,
giving n-butylmethylamine as a sufficiently volatile byproduct.
Experiments for similar hydrogenolytic BOM cleavage reactions
using the according thymidine derivatives in the absence of n-
butylamine indeed proved that the 6′-N-methylated product
was formed to a major extent, thus confirming the need to add
the amine as a formaldehyde scavenger (reaction not shown).
However, when 10% palladium on charcoal was used as a
standard catalyst for the hydrogenolytic deprotection of (S)-23,
not only the desired product (S)-24 was obtained, but ca. 80%
formation of undesired byproduct (S)-25 resulting from
unwanted reduction of the uracil-C5−C6 double bond was
observed (Table 1, entry 1). As (S)-25 could not be separated
from (S)-24 by column chromatography, it was essential to
minimize the unwanted overreduction leading to byproduct
formation to a level significantly below 5%. In a first series of
experiments, palladium black was used as hydrogenation
catalyst instead of palladium on support material. Thus, the
amount of (S)-25 was limited to ca. 5% (Table 1, entry 2), but
it was difficult to drive the reaction to completion under these
conditions. The reaction time could be prolonged to several
days without increased overreduction (entry 3), but quantita-
tive conversions were still not feasible this way. The strategy to
compensate for the apparent limited reactivity of the catalyst,
which might have been the result of partial poisoning due to the
presence of excess n-butylamine, was then to add significantly
larger amounts of the catalyst. Using an excess of palladium
black, high conversion was achieved in a short reaction time,
and byproduct formation was reduced to a minimum. Hence,
the deprotected NAA (S)-24 was isolated in 92% yield (entry
4). Unfortunately, this transformation was not robust toward
upscale. When the amount of starting material was raised ca.
20-fold, byproduct (S)-25 was formed in 30% again (entry 5).
Overall, the practical applicability of the deprotection reaction
was therefore limited by two drawbacks: first, the costs of high
amounts of palladium black needed for selective hydro-
genolysis, and second, the reaction being tied to small scales
in the range of ca. 30−50 mg starting material.
Scheme 4. Synthesis of (Z)-28 and Proof of the
Stereochemical Assignment
Similar observations were made for the hydrogenolytic
deprotection of (R)-23 providing NAA (R)-24. The tendency
to display formation of byproduct (R)-25 resulting from
overreduction was even slightly more pronounced (Table 1,
entries 6 and 7 vs entries 2 and 3). An attempt to replace
methanol as solvent with ethyl acetate, speculating for milder
hydrogenation conditions in this solvent, gave a surprisingly
high amount of (R)-25 (ca. 90%, Table 1, entry 8). However,
the previously successful strategy (vide supra) could also be
applied for this diastereomer. An excess of palladium black led
to high conversion in a short reaction time and minimal
byproduct formation. The deprotected NAA (R)-24 was thus
isolated in 96% yield, but again on a small scale only (40 mg
(R)-23 as starting material, entry 9). Two other palladium
Wittig−Horner reaction did not provide any (E)-isomer at all.
Even without the (E)-isomer as a reference compound, the
assignment of the double-bond configuration of (Z)-28 was
1
supported by similar H NOE NMR experimental results as
observed for (Z)-18. Furthermore, when (Z)-28 was reacted
with benzyloxymethyl chloride in the presence of base, material
identical to (Z)-18 (as proven by rigorous NMR analysis) could
10087
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
Scheme 5. Synthesis of Nucleosyl Amino Acids (S)-24 and (R)-24
be isolated in 51% yield (Scheme 4). This alkylation of (Z)-28
Scheme 6. Synthesis of Nucleosyl Amino Acids (S)-31 and
(R)-31
proceeded without isomerization of the double bond. This was
demonstrated by treatment of (Z)-28 with all reagents used for
the transformation into (Z)-18 except of benzyloxymethyl
chloride, which led to the reisolation of (Z)-28 in nearly
quantitative yield (reaction not shown).
With key intermediate (Z)-28 obtained by the Wittig−
Horner reaction in hand, asymmetric hydrogenation was
performed (Scheme 5). Similar to the transformations carried
out with uracil-N-3 protected precursors (Z)-17 and (Z)-18
(vide supra), high diastereoselectivities (dr > 98:2 as
1
determined by H NMR) were obtained with chiral catalysts
19 and 20, furnishing nucleosyl amino acids (S)-29 and (R)-29
in excellent yields of 94% and 93%, respectively. The
subsequent hydrogenolytic Cbz cleavage was hindered by the
pronounced tendency of both diastereomers of 29 to undergo
unwanted hydrogenation of the uracil-C5−C6 double bond.
However, under transfer hydrogenation conditions using 1,4-
cyclohexadiene as hydrogen source, this undesired side reaction
was avoided, and target nucleosyl amino acids (S)-24 and (R)-
24 were isolated in nearly quantitative yields (Scheme 5).
Though the stereochemical assignment of all nucleosyl
amino acids synthesized in this study was clearly supported by
literature precedent regarding rhodium(I) catalysts 19 and
20,18,26,27 further proof by X-ray crystallography was desired.
The growth of single crystals of nucleosyl amino acid
derivatives was limited by their low crystallization tendency
though. In the course of our synthetic studies on the native
nucleoside core structure of muraymycin antibiotics, we have
already noticed that N-3-unprotected analogues of this type of
compounds appear to crystallize more easily,15b and con-
sequently, both diastereomers of 24 were suitable candidates
for single crystal growth. In order to further support crystal
formation, the 6′-amino group of (S)-24 and (R)-24 was
transformed into a p-nitrophenylurea moiety13 to provide (S)-
30 and (R)-30 in yields of 86% and 75%, respectively (Scheme
6). Unfortunately, neither diastereomer of 30 gave suitable
crystals. However, after both (S)-30 and (R)-30 had been
desilylated to (S)-31 and (R)-31 (24% and 29% yield,
respectively, reactions not optimized), single crystals of (R)-
31 suitable for X-ray diffraction could be obtained.30 Although
the absolute structure determination based on the Flack-x
parameter30g refinement was bound to fail, the consideration of
the inherent stereochemical configuration of the ribose moiety
enabled the relative assignment of the stereogenic center at the
6′-position of (R)-31 ((R) as postulated, structure displayed in
the Supporting Information). Crystal structure analysis thus
demonstrated that the proposed stereochemical assignment of
(R)-24 and therefore also diastereomer (S)-24 (as well as their
respective precursors (R)-29 and (S)-29) had indeed been
correct.
Further transformations of 29 into NAAs 22 and 23
demonstrated that this stereochemical assignment was valid
throughout regardless of the protecting group pattern of the
didehydro amino acid precursor. When both (S)-29 and (R)-29
were alkylated at the uracil-N-3 with p-methoxybenzyl chloride
under mildly basic conditions and subsequently selectively
deprotected by hydrogenolysis, (S)-22 and (R)-22 were
obtained in yields of 67% and 66%, respectively, over two
steps. Similar transformations of (S)-29 and (R)-29 using
benzyloxymethyl chloride as alkylating agent and leaving out
the Cbz cleavage step gave (S)-23 and (R)-23 in yields of 74%
and 83%, respectively (Scheme 7). The identity of the thus
obtained compounds with the material furnished from
asymmetric hydrogenation of PMB- or BOM-protected
precursors (Z)-17 and (Z)-18 (vide supra) was proven by
rigorous NMR analyses and HPLC coinjections.
Based on the efficient synthesis of N-3-unprotected nucleosyl
amino acids 24, the preparation of novel muraymycin analogues
7b,c and 8b,c was feasible (Scheme 8). In principle, two routes
can be employed to install the truncated muraymycin side
chain: (i) reductive amination with a building block already
containing the terminal amino acid moiety and the amino-
propyl linker or (ii) reductive amination with an N-3-protected
3-aminopropanal derivative, thus allowing the introduction of
different amino acid or peptide motifs by standard coupling
procedures following selective deprotection. In contrast to our
previous report,18 we have opted for the latter strategy with
respect to its convergent nature, thus potentially enabling
synthetic access to a variety of diverse muraymycin analogues
with different peptide structures. Consequently, both (S)-24
and (R)-24 were reacted with aldehyde 32 in reductive
amination transformations, leading to the isolation of key
intermediates (S)-33 and (R)-33 in 91% and 85% yield,
respectively. Selective hydrogenolytic removal of the Cbz group
under transfer hydrogenation conditions, followed by peptide
coupling with N-Cbz-leucine, furnished (S)-34 and (R)-34 in
10088
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
design of these compounds had been inspired by the core
structure of naturally occurring muraymycin nucleoside anti-
biotics. Employing a highly stereoselective asymmetric hydro-
genation of didehydro amino acid precursors, synthetic access
to protected NAA building blocks such as (S)-24 and (R)-24
was achieved with perfect stereocontrol and overall yields of
71% each in just six steps from uridine. However, the protecting
group strategy regarding the uracil-N-3 played an essential role.
Although N-3-alkylated muraymycin derivatives can display
antibacterial activity,13 it was desired to establish a synthetic
route suitable for the synthesis of N-3-unprotected NAAs as
building blocks for novel muraymycin analogues. As both PMB-
and BOM-protection of the uracil moiety gave unsatisfactory
results regarding deprotection, an approach completely
avoiding N-3 protection proved to be optimal. This highlights
that transformations of uridine derivatives requiring basic
conditions, such as the Wittig−Horner reaction used for the
synthesis of the didehydro amino acid precursors, can be
performed efficiently with good yields and stereoselectivities
without protection of the reasonably acidic uracil-3-NH. Based
on these results, it appears recommendable to try reactions of
uridine or thymidine derivatives without nucleobase protection
first, even if the NH acidity is anticipated to represent a hurdle
for the envisaged transformation.
The N-3-unprotected NAA building blocks (S)-24 and (R)-
24 were employed for the synthesis of novel 5′-deoxy analogues
of the muraymycin antibiotics. Target compounds 7b,c and
8b,c were obtained in overall yields of 50−63% over three or
four steps from (S)-24 and (R)-24, respectively. A preliminary
biological screening of some selected compounds indicated no
potent antibiotic to be among the synthesized muraymycin
analogues. This lack of activity does not necessarily indicate
poor biological potential though as it might be owed to the
polarity, e.g., of 7c and 8c, which might limit cellular uptake. In
future work, the novel 5′-deoxy muraymycin analogues will
therefore also be investigated in an MraY enzyme assay31 to
evaluate their binding potency to the biological target MraY
itself. If strong MraY binders are identified, their cellular uptake
will potentially be enhanced by the application of prodrug
methodology.
Scheme 7. Transformations of Nucleosyl Amino Acids 29
into 22 and 23
70% and 75% yield, respectively, over two steps. Cbz
deprotection by hydrogenolysis then provided novel N-3-
unprotected target structures 7b and 8b in nearly quantitative
yields. Finally, global acidic deprotection with TFA in water led
to target compounds 7c and 8c in the form of the
corresponding bis-TFA salts in yields of 80% and 83%,
respectively (Scheme 8).
The target muraymycin analogues 7c and 8c as well as
previously reported compounds 7a and 8a18 were subjected to
a preliminary screen for antibacterial activity using agarose plate
techniques and a variety of different bacterial strains. No
significant activity could be detected so far.
CONCLUSION
■
In summary, we have accomplished the concise and efficient
synthesis of uridine-derived nucleosyl amino acids (NAAs) as
formal hybrids of nucleoside and amino acid structures. The
Scheme 8. Synthesis of Target Muraymycin Analogues 7b,c and 8b,c
10089
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
at 10 °C. After the addition of EtOAc, the organic layer was washed
with half-saturated NaCl solution (1×), dried over Na2SO4, and
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography.
General Procedure C (Asymmetric Hydrogenation of
Didehydro Amino Acids). Under strictly anaerobic conditions,
the respective Me-DUPHOS-Rh catalyst was added to a solution of
the (Z)-didehydro amino acid in MeOH. The reaction mixture was
stirred under an atmosphere of H2 (1 bar) at rt for the listed time. The
solvent was evaporated under reduced pressure and the resultant crude
product was purified by column chromatography.
General Procedure D (Hydrogenolytic Deprotection Using
Transfer Conditions). To a solution of the protected compound in
MeOH, 10% Pd/C, and 1,4-cyclohexadiene were added, and the
reaction mixture was stirred at rt for 3 h. After filtration through a
syringe filter and rinsing of the filter with MeOH (3×), the filtrate was
evaporated under reduced pressure. The resultant products were
sufficiently pure (>97% as judged by 1H NMR) without further
purification.
EXPERIMENTAL SECTION
■
General Methods. Compounds 9,19 16,22 and 2620 were
prepared according to established procedures. Reactions involving
oxygen and/or moisture sensitive reagents were carried out under an
atmosphere of argon using anhydrous solvents. Anhydrous solvents
were obtained in the following manner: THF was dried over sodium/
benzophenone and distilled, MeOH was dried over activated
molecular sieves (3 Å) and degassed, MeCN was dried over P2O5
and distilled, and DMF was dried over activated molecular sieves (4 Å)
and degassed. All other solvents were of technical quality and distilled
prior to use, and deionized water was used throughout. Column
chromatography was carried out on silica gel 60 (0.040−0.063 mm,
230−400 mesh ASTM) under flash conditions. TLC was performed
on aluminum plates precoated with silica gel 60 F254. Visualization of
the spots was carried out using UV light (254 nm) and/or staining
under heating (H2SO4 staining solution: 4 g of vanillin, 25 mL of
concd H2SO4, 80 mL of AcOH, and 680 mL of MeOH; KMnO4
staining solution: 1 g of KMnO4, 6 g of K2CO3, and 1.5 mL of 1.25 M
NaOH solution, all dissolved in 100 mL of H2O; ninhydrin staining
solution: 0.3 g of ninhydrin, 3 mL of AcOH, and 100 mL of 1-
butanol). Analytical HPLC was performed on a standard system with a
diode array UV detector and equipped with a LiChroCart column (4 ×
125 mm) containing reversed-phase silica gel Purospher RP18e (5
μm). Method I: eluent A water (0.1% TFA), eluent B MeCN; 0−15
min gradient of B (3−30%), 15−20 min 100% B, 20−22 min gradient
of B (100−3%), 22−30 min 3% B; flow 1.0 mL/min. Method II:
eluent A water (0.1% TFA), eluent B MeCN; 0−18 min gradient of B
(84−95%), 18−24 min 100% B, 24−30 min 84% B; flow 1.0 mL/min.
Method III: eluent A water (0.1% TFA), eluent B MeCN; 0−15 min
gradient of B (60−100%), 15−20 min 100% B, 20−30 min 60% B;
flow 1.0 mL/min. Preparative HPLC was carried out on a standard
system with a UV/vis detector (detection at 260 nm) and equipped
with a column (10 × 250 mm) containing reversed-phase silica gel
Nucleodur 100−5 C18ec (5 μm). Eluent A water (0.1% TFA), eluent
B 80:20 MeCN−water (0.1% TFA); 0−20 min gradient of B (5−
General Procedure E (N-3 Alkylation of Uridine Derivatives
under Mild Conditions). To a solution of the uridine derivative in
CH2Cl2, tetra-n-butylammonium iodide (TBAI), the alkylating agent
(p-methoxybenzyl chloride or benzyloxymethyl chloride), and aqueous
Na2CO3 solution were added and stirred at rt for the listed time with
TLC control. The reaction mixture was diluted with CH2Cl2 or
EtOAc. The organic layer was washed with sat NaHCO3 solution
(1×), dried over Na2SO4, and evaporated under reduced pressure. The
resultant crude product was purified by column chromatography.
N-Unprotected (6′S)-Configured Muraymycin Analogue
(7b). General procedure D with N-Cbz-protected muraymycin
analogue (S)-34 (150 mg, 0.168 mmol), 1,4-cyclohexadiene (159
μL, 1.68 mmol), 10% Pd/C (25 mg, 23 μmol), and MeOH (5 mL) to
1
give 7b as a colorless solid (126 mg, 99%): H NMR (600 MHz,
CD3OD) δ 0.09 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.12 (s, 3H,
SiCH3), 0.13 (s, 3H, SiCH3), 0.91 (s, 9H, SiC(CH3)3), 0.92 (d, J = 6.7
Hz, 3H, Leu-5-Ha), 0.93 (s, 9H, SiC(CH3)3), 0.95 (d, J = 6.5 Hz, 3H,
Leu-5-Hb), 1.37 (ddd, J = 13.5, 7.9, 6.6 Hz, 1H, Leu-3-Ha), 1.49 (s,
9H, OC(CH3)3), 1.52 (ddd, J = 13.5, 7.7, 6.4 Hz, 1H, Leu-3-Hb),
1.65−1.73 (m, 3H, propylene-2-H, Leu-4-H), 1.90 (ddd, J = 13.9, 11.1,
4.6 Hz, 1H, 5′-Ha), 2.04 (ddd, J = 13.9, 9.4, 2.8 Hz, 1H, 5′-Hb), 2.53
(ddd, J = 11.6, 7.4, 6.5 Hz, 1H, propylene-1-Ha), 2.64 (ddd, J = 11.6,
7.2, 6.9 Hz, 1H, propylene-1-Hb), 3.20−3.36 (m, 4H, 6′-H, propylene-
3-H, Leu-2-H), 3.90 (dd, J = 4.7, 4.5 Hz, 1H, 3′-H), 4.06 (ddd, J =
11.1, 4.7, 2.8 Hz, 1H, 4′-H), 4.33 (dd, J = 4.5, 4.4 Hz, 1H, 2′-H), 5.75
(d, J = 8.0 Hz, 1H, 5-H), 5.78 (d, J = 4.4 Hz, 1H, 1′-H), 7.66 (d, J = 8.0
Hz, 1H, 6-H); 13C NMR (126 MHz, CD3OD) δ −4.5, −4.4, −4.4,
−4.0, 18.9, 18.9, 22.6, 23.4, 25.9, 26.4, 26.5, 28.5, 30.4, 38.1, 38.1, 45.7,
46.1, 54.7, 60.7, 75.9, 76.6, 82.6, 82.8, 91.9, 103.0, 142.8, 152.2, 166.1,
174.9, 178.1; MS (ESI+) m/z 756.5 (M + H+); HRMS (ESI+) m/z
calcd for C36H70N5O8Si2 756.4757 (M + H+), found 756.4766 (M +
H+); IR (ATR) ν 1687, 1253, 1153, 1118, 1066, 867, 836, 812, 775;
UV (MeOH) λmax (log ε) 259 (4.25); mp 68 °C; [α]20D +25.9 (c 1.0,
MeOH).
1
10%), 20−30 min 100% B, 30−35 min 5% B; flow 3.0 mL/min. H
NMR spectra were recorded at 300 or 600 MHz. 13C NMR spectra
were recorded at 75, 76, or 126 MHz and were H-decoupled. 19F
1
1
NMR spectra were recorded at 283 MHz and were H-decoupled. All
spectra were measured at room temperature except of samples in
DMSO-d6 and D2O (standard 35 °C). All NMR spectra were
referenced internally to solvent reference frequencies wherever
possible. Chemical shifts (δ) are quoted in ppm, and coupling
constants (J) are reported in Hz. Assignment of signals was carried out
1
using H,1H−COSY, HSQC, and HMBC spectra. Infrared spectros-
copy (IR) was either performed on a spectrometer equipped with an
ATR unit or on a machine lacking the ATR unit, with solids being
measured as KBr pills. Peaks are given as wavenumbers (ν) in cm−1
.
UV/vis spectroscopy: wavelengths of maximum absorption (λmax) are
reported in nm with the corresponding logarithmic molar extinction
coefficient (log (ε/dm3 mol−1 cm−1)) given in parentheses. Melting
points (mp) are not corrected. Optical rotations were recorded with a
Na source using a 10 cm cell (concentrations in g/100 mL).
Fully Deprotected (6′S)-Configured Muraymycin Analogue
(7c·2TFA). A solution of N-unprotected (6′S)-configured muraymy-
cin analogue 7b (33 mg, 44 μmol) in 80% aqueous TFA (6.6 mL) was
stirred at rt for 24 h. The reaction mixture was diluted with water (20
mL), and the solvent was evaporated under reduced pressure. The
resultant crude product was purified by preparative HPLC to give
General Procedure A (Oxidation of 5′-O-Unprotected
Uridine Derivatives). To a solution of the 5′-O-unprotected uridine
derivative in MeCN was added IBX, and the reaction mixture was
heated to 80 °C for 45 min. After cooling to 0 °C, the insoluble
material was filtered off and washed with EtOAc (3×). The filtrate was
evaporated to dryness under reduced pressure. The resultant products
1
1
7c·2TFA as a colorless solid (24 mg, 80%): H NMR (600 MHz,
were sufficiently pure (>95% as judged by H NMR) without further
D2O) δ 1.06 (d, J = 6.7 Hz, 3H, Leu-5-Ha), 1.07 (d, J = 6.8 Hz, 3H,
Leu-5-Hb), 1.75 (dqq, J = 7.1, 6.8, 6.7 Hz, 1H, Leu-4-H), 1.83 (dd, J =
7.4, 7.1 Hz, 2H, Leu-3-H), 2.06 (dddd, J = 7.6, 7.4, 7.0, 7.0 Hz, 2H,
propylene-2-H), 2.42 (ddd, J = 15.0, 10.4, 6.2 Hz, 1H, 5′-Ha), 2.59
(ddd, J = 15.0, 6.6, 2.8 Hz, 1H, 5′-Hb), 3.22 (ddd, J = 12.6, 7.4, 7.4 Hz,
1H, propylene-1-Ha), 3.26 (ddd, J = 12.6, 7.6, 7.6 Hz, 1H, propylene-
1-Hb), 3.42 (ddd, J = 14.1, 7.0, 7.0 Hz, 1H, propylene-3-Ha), 3.48
(ddd, J = 14.1, 7.0, 7.0 Hz, 1H, propylene-3-Hb), 4.07 (dd, J = 7.4, 7.4
Hz, 1H, Leu-2-H), 4.11 (dd, J = 6.6, 6.1 Hz, 1H, 6′-H), 4.21 (dd, J =
6.4, 5.9 Hz, 1H, 3′-H), 4.28 (ddd, J = 10.4, 6.4, 2.8 Hz, 1H, 4′-H), 4.55
purification. With respect to the poor stability of the uridine 5′-
aldehydes, they were prepared freshly and directly used for subsequent
Wittig−Horner transformations. For the same reason, characterization
1
of the aldehydes was limited to H NMR and MS.
General Procedure B (Wittig−Horner Reaction of Uridine 5′-
Aldehydes). To a solution of KHMDS in THF was added a solution
of the phosphonate in THF at −78 °C. After 15 min, a solution of the
protected uridine 5′-aldehyde in THF was added dropwise at −78 °C.
The reaction mixture was stirred for 17 h and slowly warmed to rt
during this period. The reaction was quenched by addition of MeOH
10090
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
(dd, J = 5.9, 3.8 Hz, 1H, 2′-H), 5.87 (d, J = 3.8 Hz, 1H, 1′-H), 6.01 (d,
J = 8.1 Hz, 1H, 5-H), 7.76 (d, J = 8.1 Hz, 1H, 6-H); 13C NMR (126
MHz, D2O) δ 23.7, 24.2, 26.6, 28.1, 35.3, 38.9, 42.5, 47.0, 54.6, 61.9,
EtOAc (150 mL) were added. The organic layer was washed with satd
NaHCO3 solution (3 × 50 mL), dried over Na2SO4, and evaporated
under reduced pressure. The resultant crude product was purified by
column chromatography (4:1 petroleum ether−Et2O) to give 10 as a
1
75.2, 75.5, 82.4, 94.5, 104.9, 119.0 (q, JCF = 291.6 Hz, F3CCOO),
145.4, 154.0, 165.5 (q, 2JCF = 35.2 Hz, F3CCOO), 168.7, 173.3, 174.1;
19F NMR (283 MHz, D2O) δ −75.4; MS (ESI+) m/z 472.3 (M − (2
TFA)+H+); HRMS (ESI+) m/z calcd for C20H34N5O8 472.2402 (M −
(2 TFA) + H+), found 472.2405 (M − (2 TFA) + H+); IR (ATR) ν
1665, 1184, 1130, 1060, 835, 798, 720, 551, 519; UV (H2O) λmax (log
ε) 260 (3.94); mp 69 °C; analytical HPLC tR 6.5 min (method I);
colorless oil (972 mg, 85%): H NMR (300 MHz, C6D6) δ −0.03 (s,
1
3H, SiCH3), −0.03 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3), 0.04 (s, 3H,
SiCH3), 0.18 (s, 3H, SiCH3), 0.24 (s, 3H, SiCH3), 0.86 (s, 9H,
SiC(CH3)3), 0.93 (s, 9H, SiC(CH3)3), 1.01 (s, 9H, SiC(CH3)3), 3.25
(s, 3H, OCH3), 3.52 (dd, J = 11.8, 1.6 Hz, 1H, 5′-Ha), 3.76 (dd, J =
11.8, 2.1 Hz, 1H, 5′-Hb), 4.08 (ddd, J = 6.0, 2.1, 1.6 Hz, 1H, 4′-H), 4.13
(dd, J = 6.0, 3.9 Hz, 1H, 3′-H), 4.22 (dd, J = 3.9, 3.2 Hz, 1H, 2′-H),
5.04 (d, J = 13.4 Hz, 1H, PMB-CH2-Ha), 5.15 (d, J = 13.4 Hz, 1H,
PMB-CH2-Hb), 5.77 (d, J = 8.1 Hz, 1H, 5-H), 6.07 (d, J = 3.2 Hz, 1H,
1′-H), 6.72 (d, J = 8.8 Hz, 2H, PMB-3-H, PMB-5-H), 7.70 (d, J = 8.8
Hz, 2H, PMB-2-H, PMB-6-H), 7.88 (d, J = 8.1 Hz, 1H, 6-H); 13C
NMR (126 MHz, C6D6) δ −5.5, −5.2, −4.7, −4.5, −4.0, −3.9, 18.4,
18.4, 18.7, 26.2, 26.2, 26.3, 43.7, 54.7, 61.8, 70.9, 76.8, 84.2, 90.3,
101.8, 114.0, 129.9, 131.5, 137.8, 151.5, 159.6, 162.1; MS (ESI+) m/z
729.4 (M + Na+); HRMS (ESI+) m/z calcd for C35H62N2NaO7Si3
729.3757 (M + Na+), found 729.3776 (M + Na+); IR (ATR) ν 1665,
1247, 1132, 1105, 1068, 831, 808, 773, 748; UV (MeCN) λmax (log ε)
223 (4.14), 263 (3.97); TLC Rf 0.38 (7:3 petroleum ether−Et2O);
[α]20 +26.5 (c 1.1, CHCl3).
preparative HPLC tR 15.3 min; [α]20 +29.2 (c 0.77, H2O).
D
N-Unprotected (6′R)-Configured Muraymycin Analogue
(8b). General Procedure D with N-Cbz-protected muraymycin
analogue (R)-34 (135 mg, 0.152 mmol), 1,4-cyclohexadiene (144
μL, 1.52 mmol), 10% Pd/C (25 mg, 23 μmol), and MeOH (4.5 mL)
1
to give 8b as a colorless solid (114 mg, 99%): H NMR (600 MHz,
CD3OD) δ 0.08 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.12 (s, 3H,
SiCH3), 0.14 (s, 3H, SiCH3), 0.90 (s, 9H, SiC(CH3)3), 0.92 (d, J = 6.6
Hz, 3H, Leu-5-Ha), 0.94 (s, 9H, SiC(CH3)3), 0.95 (d, J = 6.2 Hz, 3H,
Leu-5-Hb), 1.37 (ddd, J = 13.5, 8.0, 6.6 Hz, 1H, Leu-3-Ha), 1.47 (s,
9H, OC(CH3)3), 1.52 (ddd, J = 13.5, 7.6, 6.4 Hz, 1H, Leu-3-Hb),
1.63−1.73 (m, 3H, propylene-2-H, Leu-4-H), 1.93−2.01 (m, 2H, 5′-
H), 2.48 (ddd, J = 11.6, 7.6, 6.5 Hz, 1H, propylene-1-Ha), 2.66 (ddd, J
= 11.6, 7.3, 6.7 Hz, 1H, propylene-1-Hb), 3.20−3.31 (m, 4H, 6′-H,
propylene-3-H, Leu-2-H), 3.93 (dd, J = 4.5, 4.3 Hz, 1H, 3′-H), 4.16
(ddd, J = 9.8, 4.3, 4.1 Hz, 1H, 4′-H), 4.31 (dd, J = 4.9, 4.5 Hz, 1H, 2′-
H), 5.74 (d, J = 8.1 Hz, 1H, 5-H), 5.82 (d, J = 4.9 Hz, 1H, 1′-H), 7.65
(d, J = 8.1 Hz, 1H, 6-H); 13C NMR (126 MHz, CD3OD) δ −4.4,
−4.4, −4.4, −4.0, 18.9, 19.0, 22.6, 23.4, 25.9, 26.4, 26.5, 28.4, 30.6,
37.7, 38.2, 45.7, 46.2, 54.7, 61.1, 75.8, 76.7, 82.7, 83.0, 91.4, 103.0,
142.7, 152.3, 166.1, 175.3, 178.1; MS (ESI+) m/z 756.5 (M + H+);
HRMS (ESI+) m/z calcd for C36H70N5O8Si2 756.4757 (M + H+),
found 756.4756 (M + H+); IR (ATR) ν 1692, 1252, 1151, 1085, 1063,
866, 835, 812, 775; UV (MeOH) λmax (log ε) 260 (4.25); mp 72 °C;
[α]20 +27.1 (c 1.0, MeOH).
2 ′D, 3 ′ , 5 ′ - T r i s ( O - t e r t - b u t y l d i m e t h y l s i l y l ) - 3 - ( N -
benzyloxymethyl)uridine (11). To a suspension of NaH (60%
dispersion in mineral oil, 960 mg, 24.0 mmol) in DMF (60 mL) was
slowly added a solution of trisilylated uridine 919 (9.42 g, 16.0 mmol)
in DMF (30 mL) at 0 °C. Benzyloxymethyl chloride (2.67 mL, 3.01 g,
19.2 mmol) was added dropwise, and the reaction mixture was stirred
at 0 °C for 5 h. Et2O (600 mL) and satd NaHCO3 solution (100 mL)
were added. The organic layer was washed with water (4 × 250 mL),
satd NaHCO3 solution (1 × 250 mL), and brine (1 × 250 mL), dried
over Na2SO4, and evaporated under reduced pressure. The resultant
crude product was purified by column chromatography (19:1
petroleum ether−EtOAc) to give 11 as a colorless oil (9.84 g,
87%): 1H NMR (300 MHz, C6D6) δ −0.03 (s, 3H, SiCH3), −0.02 (s,
3H, SiCH3), 0.03 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3), 0.21 (s, 3H,
SiCH3), 0.33 (s, 3H, SiCH3), 0.87 (s, 9H, SiC(CH3)3), 0.94 (s, 9H,
SiC(CH3)3), 1.04 (s, 9H, SiC(CH3)3), 3.54 (dd, J = 11.8, 1.3 Hz, 1H,
5′-Ha), 3.79 (dd, J = 11.8, 2.2 Hz, 1H, 5′-Hb), 4.08−4.17 (m, 2H, 3′-H,
4′-H), 4.25 (dd, J = 3.6, 2.9 Hz, 1H, 2′-H), 4.67 (d, J = 13.2 Hz, 1H,
BOM-CH2-Ha), 4.72 (d, J = 13.2 Hz, 1H, BOM-CH2-Hb), 5.45 (d, J =
16.4 Hz, 1H, NCH2O-Ha), 5.48 (d, J = 16.4 Hz, 1H, NCH2O-Hb),
5.73 (d, J = 8.2 Hz, 1H, 5-H), 5.99 (d, J = 2.9 Hz, 1H, 1′-H), 7.03−
7.15 (m, 3 H, BOM-3-H, BOM-4-H, BOM-5-H), 7.36 (d, J = 6.8 Hz,
2H, BOM-2-H, BOM-6-H), 7.92 (d, J = 8.2 Hz, 1H, 6-H); 13C NMR
(76 MHz, C6D6) δ −5.7, −5.4, −4.9, −4.8, −4.0, −4.0, 18.2, 18.3, 18.5,
26.0, 26.1, 26.1, 61.4, 70.4, 70.5, 72.3, 76.7, 83.9, 90.6, 101.5, 127.5,
127.9, 128.2, 138.6, 139.0, 151.2, 162.2; MS (ESI+) m/z 729.4 (M +
Na+); HRMS (ESI+) m/z calcd for C35H62N2NaO7Si3 729.3757 (M +
Na+), found 729.3755 (M + Na+); IR (ATR) ν 1667, 1253, 1129,
1100, 1067, 832, 808, 775, 734; UV (MeCN) λmax (log ε) 264 (3.97);
FuDlly Deprotected (6′R)-Configured Muraymycin Analogue
(8c·2TFA). A solution of N-unprotected (6′R)-configured muraymy-
cin analogue 8b (36 mg, 48 μmol) in 80% aqueous TFA (7.2 mL) was
stirred at rt for 24 h. The reaction mixture was diluted with water (20
mL) and the solvent was evaporated under reduced pressure. The
resultant crude product was purified by preparative HPLC to give
1
8c·2TFA as a colorless solid (28 mg, 83%): H NMR (600 MHz,
D2O) δ 1.06 (d, J = 6.6 Hz, 3H, Leu-5-Ha), 1.08 (d, J = 6.7 Hz, 3H,
Leu-5-Hb), 1.76 (dqq, J = 7.2, 6.7, 6.6 Hz, 1H, Leu-4-H), 1.84 (dd, J =
7.4, 7.2 Hz, 2H, Leu-3-H), 2.03 (dddd, J = 8.3, 7.5, 7.0, 6.8 Hz, 2H,
propylene-2-H), 2.48 (ddd, J = 15.6, 11.1, 4.7 Hz, 1H, 5′-Ha), 2.60
(ddd, J = 15.6, 5.6, 2.8 Hz, 1H, 5′-Hb), 3.19 (ddd, J = 12.6, 8.3, 7.5 Hz,
1H, propylene-1-Ha), 3.24 (ddd, J = 12.6, 8.3, 7.5 Hz, 1H, propylene-
1-Hb), 3.39 (ddd, J = 14.0, 7.0, 7.0 Hz, 1H, propylene-3-Ha), 3.45
(ddd, J = 14.0, 6.8, 6.8 Hz, 1H, propylene-3-Hb), 4.08 (dd, J = 7.4, 7.4
Hz, 1H, Leu-2-H), 4.12 (dd, J = 5.6, 4.7 Hz, 1H, 6′-H), 4.16 (ddd, J =
11.1, 6.6, 2.8 Hz, 1H, 4′-H), 4.24 (dd, J = 6.6, 6.1 Hz, 1H, 3′-H), 4.56
(dd, J = 6.1, 3.7 Hz, 1H, 2′-H), 5.85 (d, J = 3.7 Hz, 1H, 1′-H), 6.01 (d,
J = 8.0 Hz, 1H, 5-H), 7.78 (d, J = 8.0 Hz, 1H, 6-H); 13C NMR (126
MHz, D2O) δ 23.7, 24.2, 26.5, 28.1, 34.5, 39.0, 42.5, 47.3, 54.6, 62.4,
TLC Rf 0.48 (4:1 petroleum ether−EtOAc); [α]20 +26.4 (c 0.9,
D
CHCl3).
3′,5′-Bis(O-tert-butyldimethylsilyl)-3-(N-(p-methoxybenzyl))-
uridine (12). To a solution of uridine derivative 10 (9.63 g, 13.6
mmol) in THF (100 mL) was added dropwise a 1:1 TFA−water
mixture (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for
8 h and adjusted to pH 9 by the addition of satd NaHCO3 solution
(400 mL) and solid Na2CO3, and EtOAc (600 mL) was added. The
organic layer was washed with satd NaHCO3 solution (2 × 200 mL),
and the combined aqueous solutions were extracted with EtOAc (1 ×
100 mL). The combined organics were dried over Na2SO4 and
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography (9:1 CH2Cl2−EtOAc) to give 12
1
75.0, 75.4, 82.1, 94.9, 105.0, 119.0 (q, JCF = 292.1 Hz, F3CCOO),
2
145.8, 154.1, 165.46 (q, JCF = 35.2 Hz, F3CCOO), 168.7, 173.3,
174.1; 19F NMR (283 MHz, D2O) δ −75.4; MS (ESI+) m/z 472.3 (M
− (2 TFA)+H+); HRMS (ESI+) m/z calcd for C20H34N5O8 472.2402
(M − (2 TFA)+H+), found 472.2396 (M − (2 TFA)+H+); IR (ATR)
ν 1665, 1182, 1130, 1054, 834, 798, 767, 720, 551; UV (H2O) λmax
(log ε) 261 (3.77); mp 68 °C; analytical HPLC tR 6.2 min (method I);
preparative HPLC tR 14.9 min; [α]20 +22.3 (c 0.61, H2O).
2′,3′,5′-Tris(O-tert-butylDdimethylsilyl)-3-(N-(p-
methoxybenzyl))uridine (10). To a suspension of NaH (60%
dispersion in mineral oil, 97 mg, 2.4 mmol) in DMF (3 mL) was
slowly added a solution of trisilylated uridine 919 (950 mg, 1.62 mmol)
in DMF (5 mL) at 0 °C and the mixture stirred at 0 °C for 15 min. p-
Methoxybenzyl chloride (0.44 mL, 3.2 mmol) was added dropwise,
and the reaction mixture was stirred at rt for 11 h. Water (5 mL) and
1
as a colorless solid (6.36 g, 79%): H NMR (300 MHz, CDCl3) δ
−0.02 (s, 3H, SiCH3), 0.00 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.08
(s, 3H, SiCH3), 0.81 (s, 9H, SiC(CH3)3), 0.90 (s, 9H, SiC(CH3)3),
3.40 (dd, J = 8.2, 2.7 Hz, 1H, OH), 3.70 (ddd, J = 12.3, 8.2, 2.4 Hz,
1H, 5′-Ha), 3.77 (s, 3H, OCH3), 3.91 (ddd, J = 12.3, 2.7, 2.4 Hz, 1H,
10091
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
5′-Hb), 4.06 (ddd, J = 2.4, 2.4, 2.4 Hz, 1H, 4′-H), 4.16 (dd, J = 4.7, 2.4
Hz, 1H, 3′-H), 4.57 (dd, J = 6.1, 4.7 Hz, 1H, 2′-H), 4.99 (d, J = 13.5
Hz, 1H, PMB-CH2-Ha), 5.05 (d, J = 13.5 Hz, 1H, PMB-CH2-Hb), 5.45
(d, J = 6.1 Hz, 1H, 1′-H), 5.76 (d, J = 8.1 Hz, 1H, 5-H), 6.81 (d, J = 8.7
Hz, 2H, PMB-3-H, PMB-5-H), 7.44 (d, J = 8.7 Hz, 2H, PMB-2-H,
PMB-6-H), 7.46 (d, J = 8.1 Hz, 1H, 6-H); 13C NMR (126 MHz,
CDCl3) δ −5.1, −4.8, −4.7, −4.5, 17.9, 18.0, 25.7, 25.8, 43.6, 55.2,
62.0, 72.2, 73.1, 86.7, 94.8, 102.0, 113.6, 128.8, 131.0, 141.1, 151.0,
159.1, 162.5; MS (ESI+) m/z 615.7 (M + Na+); HRMS (ESI+) m/z
calcd for C29H49N2O7Si2 593.3073 (M + H+), found 593.3073 (M +
H+); IR (KBr) ν 2931, 1666, 1514, 1461, 1250, 1097, 837, 776, 582;
UV (MeCN) λmax (log ε) 194 (4.72), 222 (4.17), 263 (4.00); mp 69
°C; TLC Rf 0.57 (1:1 CH2Cl2−EtOAc); [α]20D +32.6 (c 1.2, CHCl3).
3′,5′-Bis(O-tert-butyldimethylsilyl)-3-(N-benzyloxymethyl)-
uridine (13). To a solution of uridine derivative 11 (3.53 g, 4.99
mmol) in THF (50 mL) was added dropwise a 1:1 TFA−water
mixture (25 mL) at 0 °C. The reaction mixture was stirred at 0 °C for
7 h and then adjusted to pH 9 by the addition of satd NaHCO3
solution (400 mL) and solid Na2CO3, and EtOAc (600 mL) was
added. The organic layer was washed with satd NaHCO3 solution (1 ×
200 mL) and brine (1 × 200 mL), dried over Na2SO4, and evaporated
under reduced pressure. The resultant crude product was purified by
column chromatography (9:1 CH2Cl2−EtOAc) to give 13 as a
colorless solid (2.13 g, 72%): 1H NMR (300 MHz, DMSO-d6) δ
−0.02 (s, 3H, SiCH3), 0.03 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.10
(s, 3H, SiCH3), 0.82 (s, 9H, SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3),
3.58 (ddd, J = 12.0, 4.4, 3.0 Hz, 1H, 5′-Ha), 3.70 (ddd, J = 12.0, 4.6, 3.4
Hz, 1H, 5′-Hb), 3.92 (ddd, J = 3.4, 3.2, 3.0 Hz, 1H, 4′-H), 4.15 (dd, J =
4.3, 3.2 Hz, 1H, 3′-H), 4.27 (dd, J = 5.4, 4.3 Hz, 1H, 2′-H), 4.58 (s, 2H,
BOM-CH2), 5.24 (dd, J = 4.6, 4.4 Hz, 1H, OH), 5.33 (s, 2H,
NCH2O), 5.85 (d, J = 8.3 Hz, 1H, 5-H), 5.85 (d, J = 5.4 Hz, 1H, 1′-H),
7.22−7.36 (m, 5H, Aryl-H), 8.03 (d, J = 8.3 Hz, 1H, 6-H); 13C NMR
(126 MHz, DMSO-d6) δ −5.0, −4.9, −4.9, −4.6, 17.5, 17.7, 25.5, 25.6,
60.1, 69.8, 70.9, 71.5, 74.6, 85.3, 87.8, 101.1, 127.0, 127.2, 127.9, 137.8,
139.5, 150.7, 161.6; MS (ESI+) m/z 615.3 (M + Na+); HRMS (ESI+)
m/z calcd for C29H48N2NaO7Si2 615.2892 (M + Na+), found 615.2891
(M + Na+); IR (ATR) ν 1715, 1666, 1151, 1100, 1084, 1054, 876, 830,
771; UV (MeCN) λmax (log ε) 206 (4.22), 264 (3.98); mp 105 °C;
(KHMDS)). Purification by column chromatography (4:1 petroleum
ether−EtOAc) gave (Z)-17 as a colorless solid (1.82 g, 67%) and (E)-
1
17 as a colorless solid (159 mg, 6%). (Z)-17: H NMR (300 MHz,
CDCl3) δ −0.01 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3), 0.04 (s, 3H,
SiCH3), 0.05 (s, 3H, SiCH3), 0.83 (s, 9H, SiC(CH3)3), 0.86 (s, 9H,
SiC(CH3)3), 1.46 (s, 9H, OC(CH3)3), 3.75 (s, 3H, OCH3), 3.91 (dd, J
= 5.5, 4.1 Hz, 1H, 3′-H), 4.28 (dd, J = 4.1, 3.9 Hz, 1H, 2′-H), 4.82 (dd,
J = 7.4, 5.5 Hz, 1H, 4′-H), 4.97 (d, J = 13.5 Hz, 1H, PMB-CH2-Ha),
5.04 (d, J = 13.5 Hz, 1H, PMB-CH2-Hb), 5.11 (s, 2H, Cbz-CH2), 5.62
(d, J = 3.9 Hz, 1H, 1′-H), 5.74 (d, J = 8.1 Hz, 1H, 5-H), 6.28 (d, J = 7.4
Hz, 1H, 5′-H), 6.70 (s, 1H, NH), 6.79 (d, J = 8.8 Hz, 2H, PMB-3-H,
PMB-5-H), 7.15 (d, J = 8.1 Hz, 1H, 6-H), 7.28−7.35 (m, 5H, Cbz-
aryl-H), 7.41 (d, J = 8.8 Hz, 2H, PMB-2-H, PMB-6-H); 13C NMR
(126 MHz, CDCl3) δ −4.7, −4.5, −4.3, 18.1, 18.2, 25.8, 25.9, 27.9,
43.5, 55.3, 67.5, 74.6, 76.2, 79.6, 82.6, 92.9, 102.1, 113.6, 124.8, 128.1,
128.2, 128.4, 128.9, 130.7, 130.8, 135.7, 138.2, 150.5, 153.5, 159.0,
162.3, 162.7; MS (ESI+) m/z 860.4 (M + Na+); HRMS (ESI+) m/z
calcd for C43H63N3NaO10Si2 860.3944 (M + Na+), found 860.3952 (M
+ Na+); IR (KBr) ν 2957, 1715, 1666, 1514, 1456, 1251, 1157, 1055,
839; UV (MeCN) λmax (log ε) 225 (4.31), 257 (4.14); mp 72 °C;
TLC Rf 0.42 (7:3 petroleum ether−EtOAc); [α]20 +39.1 (c 1.1,
D
CHCl3). (E)-17: 1H NMR (300 MHz, CDCl3) δ −0.25 (s, 3H,
SiCH3), −0.05 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3), 0.10 (s, 3H,
SiCH3), 0.77 (s, 9H, SiC(CH3)3), 0.93 (s, 9H, SiC(CH3)3), 1.46 (s,
9H, OC(CH3)3), 3.75 (s, 3H, OCH3), 4.44 (dd, J = 3.2, 2.5 Hz, 1H, 3′-
H), 4.51 (dd, J = 6.9, 3.2 Hz, 1H, 2′-H), 4.98 (d, J = 13.9 Hz, 1H,
PMB-CH2-Ha), 4.99 (dd, J = 8.6, 2.5 Hz, 1H, 4′-H), 5.04 (d, J = 13.9
Hz, 1H, PMB-CH2-Hb), 5.09 (d, J = 12.2 Hz, 1H, Cbz-CH2-Ha), 5.18
(d, J = 12.2 Hz, 1H, Cbz-CH2-Hb), 5.76 (d, J = 6.9 Hz, 1H, 1′-H), 5.77
(d, J = 8.0 Hz, 1H, 5-H), 6.43 (d, J = 8.6 Hz, 1H, 5′-H), 6.68 (s, 1H,
NH), 6.78 (d, J = 8.7 Hz, 2H, PMB-3-H, PMB-5-H), 7.09 (d, J = 8.0
Hz, 1H, 6-H), 7.30−7.36 (m, 5H, Cbz-aryl-H), 7.37 (d, J = 8.7 Hz,
2H, PMB-2-H, PMB-6-H); 13C NMR (126 MHz, CDCl3) δ −5.1,
−4.2, 18.0, 18.2, 25.9, 26.0, 28.0, 43.6, 55.3, 67.5, 74.5, 75.4, 79.1, 82.8,
92.6, 102.2, 113.6, 126.0, 127.9, 128.0, 128.2, 128.5, 128.8, 130.4,
135.8, 139.6, 150.6, 154.1, 158.9, 162.5, 163.0; MS (ESI+) m/z 860.5
(M + Na+); HRMS (ESI+) m/z calcd for C43H63N3NaO10Si2 860.3944
(M + Na+), found 860.3948 (M + Na+); IR (KBr) ν 2959, 2935, 1673,
1391, 1339, 1251, 1161, 1051, 839; UV (MeCN) λmax (log ε) 224
(4.28), 257 (4.09); mp 69 °C; TLC Rf 0.35 (7:3 petroleum ether−
EtOAc); [α]20 −21.9 (c 1.1, CHCl3).
TLC Rf 0.40 (4:1 CH2Cl2-EtOAc); [α]20 −15.3 (c 1.0, CHCl3).
D
3′,5′-Bis(O-tert-butyldimethylsilyl)-3-(N-(p-methoxybenzyl))-
uridine-5′-aldehyde (14). General procedure A with uridine
derivative 12 (100 mg, 0.170 mmol), IBX (118 mg, 0.420 mmol),
3-(N-BOM)D-Protected Didehydro Nucleosyl Amino Acid
(18). Synthesis of (Z)-18 from 15. General procedure B with
aldehyde 15 (500 mg, 0.846 mmol), phosphonate 1622 (265 mg, 0.710
mmol), KHMDS (0.5 M in toluene, 1.42 mL, 0.710 mmol), and THF
(4.2 mL (15), 5.0 mL (16), 6.7 mL (KHMDS)). Purification by
column chromatography (4:1 petroleum ether−EtOAc) gave (Z)-18
as a colorless solid (483 mg, 82%) while (E)-18 could not be isolated.
1
and MeCN (3 mL) to give 14 as a colorless solid (98 mg, 98%): H
NMR (300 MHz, CDCl3) δ −0.19 (s, 3H, SiCH3), −0.06 (s, 3H,
SiCH3), 0.09 (s, 6H, SiCH3), 0.78 (s, 9H, SiC(CH3)3), 0.90 (s, 9H,
SiC(CH3)3), 3.75 (s, 3H, OCH3), 4.20−4.49 (m, 3H, 2′-H, 3′-H, 4′-
H), 4.99−5.03 (m, 2H, PMB-CH2), 5.75 (d, J = 6.0 Hz, 1H, 1′-H),
5.81 (d, J = 8.1 Hz, 1H, 5-H), 6.79 (d, J = 8.8 Hz, 2H, PMB-3-H,
PMB-5-H), 7.41 (d, J = 8.8 Hz, 2H, PMB-2-H, PMB-6-H), 7.52 (d, J =
8.1 Hz, 1H, 6-H), 9.79 (s, 1H, 5′-H); MS (ESI+) m/z 645.3 (M +
MeOH + Na+); HRMS (ESI+) m/z calcd for C30H50N2NaO8Si2
645.2998 (M + MeOH + Na+), found 645.3004 (M + MeOH + Na+).
3′,5′-Bis(O-tert-butyldimethylsilyl)-3-(N-benzyloxymethyl)-
uridine-5′-aldehyde (15). General procedure A with uridine
derivative 13 (4.11 g, 6.93 mmol), IBX (4.85 g, 17.3 mmol), and
MeCN (60 mL) to give 15 as a colorless solid (4.01 g, 98%): 1H NMR
(300 MHz, CDCl3) δ −0.03 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3), 0.10
(s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.84 (s, 9H, SiC(CH3)3), 0.91 (s,
9H, SiC(CH3)3), 4.21 (dd, J = 4.1, 3.3 Hz, 1H, 3′-H), 4.32 (dd, J = 5.6,
4.1 Hz, 1H, 2′-H), 4.52 (d, J = 3.3 Hz, 1H, 4′-H), 4.66 (s, 2H, BOM-
CH2), 5.43 (d, J = 14.0 Hz, 1H, NCH2O-Ha), 5.48 (d, J = 14.0 Hz, 1H,
NCH2O-Hb), 5.72 (d, J = 5.6 Hz, 1H, 1′-H), 5.81 (d, J = 8.1 Hz, 1H, 5-
H), 7.25−7.35 (m, 5H, Aryl-H), 7.60 (d, J = 8.1 Hz, 1H, 6-H), 9.82 (s,
1H, 5′-H); MS (ESI+) m/z 613.3 (M + Na+); HRMS (ESI+) m/z calcd
for C29H46N2NaO7Si2 613.2736 (M + Na+), found 613.2729 (M +
Na+).
1
(Z)-18: H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H, SiCH3), 0.07 (s,
3H, SiCH3), 0.08 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.87 (s, 9H,
SiC(CH3)3), 0.88 (s, 9H, SiC(CH3)3), 1.46 (s, 9H, OC(CH3)3), 3.92
(dd, J = 6.5, 3.8 Hz, 1H, 3′-H), 4.28 (dd, J = 3.8, 3.2 Hz, 1H, 2′-H),
4.67 (s, 2H, BOM-CH2), 4.86 (dd, J = 7.6, 6.5 Hz, 1H, 4′-H), 5.12 (s,
2H, Cbz-CH2), 5.42 (d, J = 12.2 Hz, 1H, NCH2O-Ha), 5.46 (d, J =
12.2 Hz, 1H, NCH2O-Hb), 5.58 (d, J = 3.2 Hz, 1H, 1′-H), 5.74 (d, J =
8.2 Hz, 1H, 5-H), 6.24 (d, J = 7.6 Hz, 1H, 5′-H), 6.74 (s, 1H, NH),
7.20 (d, J = 8.2 Hz, 1H, 6-H), 7.26−7.37 (m, 10H, BOM-aryl-H, Cbz-
aryl-H); 13C NMR (126 MHz, CDCl3) δ −4.7, −4.7, −4.3, −4.3, 18.1,
18.2, 25.9, 25.9, 27.9, 67.5, 70.2, 72.2, 74.7, 76.1, 79.2, 82.6, 93.2,
101.9, 124.4, 127.6, 128.1, 128.2, 128.2, 128.4, 131.2, 135.7, 137.8,
138.8, 150.5, 153.4, 162.4, 162.6; MS (ESI+) m/z 860.4 (M + Na+);
HRMS (ESI+) m/z calcd for C43H63N3NaO10Si2 860.3944 (M + Na+),
found 860.3950 (M + Na+); IR (ATR) ν 1663, 1254, 1221, 1151,
1054, 836, 775, 734, 696; UV (MeCN) λmax (log ε) 205 (4.46), 258
(4.12); mp 43 °C; TLC Rf 0.52 (7:3 petroleum ether−EtOAc); [α]20
+50.1 (c 1.0, CHCl3).
D
Synthesis of (Z)-18 from (Z)-28. General procedure E with
didehydro nucleosyl amino acid (Z)-28 (20 mg, 28 μmol),
benzyloxymethyl chloride (0.42 M solution in CH2Cl2, 0.10 mL, 42
μmol), TBAI (0.5 mg, 1 μmol), Na2CO3 (0.82 M solution in water,
3-(N-PMB)-Protected Didehydro Nucleosyl Amino Acid
(17). General procedure B with aldehyde 14 (1.99 g, 3.37 mmol),
phosphonate 1622 (1.21 g, 3.24 mmol), KHMDS (0.5 M in toluene,
6.48 mL, 3.24 mmol), and THF (12 mL (14), 25 mL (16), 20 mL
10092
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
0.13 mL, 0.11 mmol), CH2Cl2 (1.0 mL), and a reaction time of 18 h.
Purification by column chromatography (17:3 petroleum ether−
EtOAc) gave (Z)-28 as a colorless solid (12 mg, 51%). Analytical data
were identical to those given above.
solution in CH2Cl2, 0.25 mL, 0.11 mmol) and Na2CO3 (0.82 M
solution in water, 0.28 mL, 0.23 mmol) were added after 15 h.
Purification by double column chromatography (1) 17:3 petroleum
ether−EtOAc, (2) 9:1 CH2Cl2−Et2O) furnished the 3-alkylated
derivative as a colorless solid (35 mg). This was then deprotected
by application of general procedure D with the Cbz-protected 3-
alkylated nucleosyl amino acid (10 mg, 12 μmol), 1,4-cyclohexadiene
(11 μL, 0.12 mmol), 10% Pd/C (5 mg, 5 μmol), and MeOH (3 mL)
to give (S)-22 as a colorless solid (7.9 mg, 67% over two steps from
(S)-29). Analytical data were identical to those given above.
3-(N-PMB)-Protected Nucleosyl Amino Acid ((R)-22). Syn-
thesis of (R)-22 from (Z)-17. General procedure C with didehydro
nucleosyl amino acid (Z)-17 (1.00 g, 1.19 mmol), (R,R)-Me-
DUPHOS-Rh (24 mg, 40 μmol), and MeOH (25 mL) and a reaction
time of 14 d. In contrast to the general procedure, the reaction mixture
was not evaporated under reduced pressure, but 10% Pd/C (120 mg,
0.113 mmol) was added and stirring under an H2 atmosphere (1 bar)
was continued for 5 h. The reaction mixture was then filtered through
a pad of Celite, the Celite washed with hot MeOH (100 mL), and the
filtrate evaporated under reduced pressure. The resultant crude
product was purified by column chromatography (40:40:19:1
petroleum ether−CH21Cl2−EtOAc−NEt3) to give (R)-22 as a colorless
solid (675 mg, 80%): H NMR (300 MHz, CD3OD) δ −0.02 (s, 3H,
SiCH3), 0.06 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.13 (s, 3H,
SiCH3), 0.84 (s, 9H, SiC(CH3)3), 0.94 (s, 9H, SiC(CH3)3), 1.48 (s,
9H, OC(CH3)3), 2.07 (dd, J = 6.8, 5.7 Hz, 2H, 5′-H), 3.65 (dd, J = 5.7,
5.7 Hz, 1H, 6′-H), 3.75 (s, 3H, OCH3), 3.89 (dd, J = 4.5, 4.5 Hz, 1H,
3′-H), 4.13 (dd, J = 6.8, 4.5 Hz, 1H, 4′-H), 4.32 (dd, J = 4.5, 4.5 Hz,
1H, 2′-H), 4.97 (d, J = 13.7 Hz, 1H, PMB-CH2-Ha), 5.05 (d, J = 13.7
Hz, 1H, PMB-CH2-Hb), 5.77 (d, J = 4.5 Hz, 1H, 1′-H), 5.83 (d, J = 8.1
Hz, 1H, 5-H), 6.82 (d, J = 8.8 Hz, 2H, PMB-3-H, PMB-5-H), 7.35 (d,
J = 8.8 Hz, 2H, PMB-2-H, PMB-6-H), 7.61 (d, J = 8.1 Hz, 1H, 6-H);
13C NMR (75 MHz, CD3OD) δ −4.5, −4.5, −4.3, −4.0, 18.8, 19.0,
Synthesis of (E)-18. To a solution of didehydro nucleosyl amino
acid (Z)-18 (100 mg, 0.120 mmol) in THF (5 mL) was added
dropwise KHMDS (0.5 M in toluene, 72 μL, 36 μmol) at 0 °C, and
the reaction mixture was stirred at 0 °C for 2 h. Water (2 mL) and
EtOAc (100 mL) were added. The organic layer was washed with half-
saturated NaCl solution (1 × 150 mL), dried over Na2SO4, and
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography (4:1 petroleum ether−EtOAc) to
1
give (E)-18 as a colorless solid (23 mg, 23%): H NMR (600 MHz,
CDCl3) δ −0.08 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3), 0.05 (s, 3H,
SiCH3), 0.11 (s, 3H, SiCH3), 0.84 (s, 9H, SiC(CH3)3), 0.93 (s, 9H,
SiC(CH3)3), 1.46 (s, 9H, OC(CH3)3), 4.45−4.50 (m, 1H, 3′-H), 4.62
(d, J = 12.1 Hz, 1H, BOM-CH2-Ha), 4.65 (d, J = 12.1 Hz, 1H, BOM-
CH2-Hb), 4.68 (dd, J = 6.6, 3.5 Hz, 1H, 2′-H), 5.06 (dd, J = 8.8, 2.7
Hz, 1H, 4′-H), 5.11 (d, J = 12.2 Hz, 1H, Cbz-CH2-Ha), 5.16 (d, J =
12.2 Hz, 1H, Cbz-CH2-Hb), 5.42 (d, J = 9.9 Hz, 1H, NCH2O-Ha),
5.48 (d, 1H, J = 9.9 Hz, NCH2O-Hb), 5.66 (d, J = 6.6 Hz, 1H, 1′-H),
5.76 (d, J = 8.1 Hz, 1H, 5-H), 6.45 (d, J = 8.8 Hz, 1H, 5′-H), 6.69 (s,
1H, NH), 7.13 (d, J = 8.1 Hz, 1H, 6-H), 7.23−7.37 (m, 10H, BOM-
aryl-H, Cbz-aryl-H); 13C NMR (126 MHz, CDCl3) δ −5.0, −4.3,
−4.2, −4.2, 18.0, 18.2, 25.9, 26.0, 28.0, 67.6, 70.1, 72.0, 74.5, 75.0, 79.2,
82.8, 93.9, 101.9, 126.0, 127.5, 127.6, 128.0, 128.2, 128.2, 128.5, 135.7,
137.7, 140.9, 140.9, 150.6, 154.2, 162.6, 163.1; MS (ESI+) m/z 860.4
(M + Na+); HRMS (ESI+) m/z calcd for C43H63N3NaO10Si2 860.3944
(M + Na+), found 860.3968 (M + Na+); IR (ATR) ν 1714, 1666,
1251, 1152, 1050, 838, 775, 735, 697; UV (MeCN) λmax (log ε) 259
(4.05); mp 47 °C; TLC Rf 0.38 (7:3 petroleum ether−EtOAc); [α]20
−24.0 (c 0.7, CHCl3).
D
3-(N-PMB)-Protected Nucleosyl Amino Acid ((S)-22). Syn-
thesis of (S)-22 from (Z)-17. General procedure C with didehydro
nucleosyl amino acid (Z)-17 (1.00 g, 1.19 mmol), (S,S)-Me-
DUPHOS-Rh (12 mg, 20 μmol), and MeOH (25 mL) and a reaction
time of 3 d. In contrast to the general procedure, the reaction mixture
was not evaporated under reduced pressure, but 10% Pd/C (136 mg,
0.128 mmol) was added and stirring under an H2 atmosphere (1 bar)
was continued for 5 h. The reaction mixture was then filtered through
a pad of Celite, the Celite washed with hot MeOH (100 mL), and the
filtrate evaporated under reduced pressure. The resultant crude
product was purified by column chromatography (40:40:19:1
petroleum ether−CH21Cl2−EtOAc−NEt3) to give (S)-22 as a colorless
solid (723 mg, 86%): H NMR (300 MHz, CD3OD) δ −0.01 (s, 3H,
SiCH3), 0.06 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.12 (s, 3H,
SiCH3), 0.85 (s, 9H, SiC(CH3)3), 0.93 (s, 9H, SiC(CH3)3), 1.47 (s,
9H, OC(CH3)3), 1.86 (ddd, J = 14.1, 11.3, 5.3 Hz, 1H, 5′-Ha), 2.13
(ddd, J = 14.1, 8.0, 2.5 Hz, 1H, 5′-Hb), 3.55 (dd, J = 8.0, 5.3 Hz, 1H, 6′-
H), 3.75 (s, 3H, OCH3), 3.85 (dd, J = 5.0, 5.0 Hz, 1H, 3′-H), 4.14
(ddd, J = 11.3, 5.0, 2.5 Hz, 1H, 4′-H), 4.27 (dd, J = 5.0, 4.2 Hz, 1H, 2′-
H), 4.96 (d, J = 13.7 Hz, 1H, PMB-CH2-Ha), 5.06 (d, J = 13.7 Hz, 1H,
PMB-CH2-Hb), 5.80 (d, J = 4.2 Hz, 1H, 1′-H), 5.84 (d, J = 8.1 Hz, 1H,
5-H), 6.82 (d, J = 8.8 Hz, 2H, PMB-3-H, PMB-5-H), 7.35 (d, J = 8.8
Hz, 2H, PMB-2-H, PMB-6-H), 7.64 (d, J = 8.1 Hz, 1H, 6-H); 13C
NMR (75 MHz, CD3OD) δ −4.5, −4.5, −4.3, −4.0, 18.8, 19.0, 26.4,
26.5, 28.3, 39.1, 44.5, 53.6, 55.7, 76.0, 76.6, 82.8, 83.0, 92.7, 102.5,
114.7, 130.3, 131.4, 140.8, 152.2, 160.7, 164.7, 174.6; MS (ESI+) m/z
706.2 (M + H+); HRMS (ESI+) m/z calcd for C35H60N3O8Si2
706.3913 (M + H+), found 706.3915 (M + H+); IR (KBr) ν 2931,
1670, 1513, 1456, 1391, 1250, 1159, 839, 777; UV (MeCN) λmax (log
ε) 194 (4.72), 223 (4.16), 263 (3.99); mp 69 °C; TLC Rf 0.17
(40:40:19:1 petroleum ether−CH2Cl2−EtOAc−NEt3); analytical
26.4, 26.5, 28.3, 37.4, 44.5, 53.8, 55.7, 75.5, 76.6, 82.6, 83.1, 93.0,
102.4, 114.7, 130.3, 131.4, 141.0, 152.2, 160.7, 164.7, 174.3; MS (ESI+)
m/z 706.3 (M + H+); HRMS (ESI+) m/z calcd for C35H60N3O8Si2
706.3913 (M + H+), found 706.3909 (M + H+); IR (KBr) ν 2931,
1670, 1514, 1456, 1391, 1250, 1160, 839, 777; UV (MeCN) λmax (log
ε) 223 (4.14), 263 (3.96); mp 52 °C; TLC Rf 0.17 (40:40:19:1
petroleum ether−CH2Cl2−EtOAc−NEt3); Analytical HPLC tR 10.9
min (method III); [α]20 +30.1 (c 0.9, MeOH).
D
Synthesis of (R)-22 from (R)-29. General procedure E with
nucleosyl amino acid (R)-29 (42 mg, 58 μmol), p-methoxybenzyl
chloride (0.44 M solution in CH2Cl2, 0.25 mL, 0.11 mmol), TBAI (1
mg, 3 μmol), Na2CO3 (0.82 M solution in water, 0.28 mL, 0.23
mmol), and CH2Cl2 (2 mL) and a reaction time of 30 h. In contrast to
the general procedure, more p-methoxybenzyl chloride (0.44 M
solution in CH2Cl2, 0.25 mL, 0.11 mmol) and Na2CO3 (0.82 M
solution in water, 0.28 mL, 0.23 mmol) were added after 15 h.
Purification by double column chromatography ((1) 17:3 petroleum
ether−EtOAc, (2) 9:1 CH2Cl2−Et2O) furnished the 3-alkylated
derivative as a colorless solid (34 mg). This was then deprotected
by application of general procedure D with the Cbz-protected 3-
alkylated nucleosyl amino acid (10 mg, 12 μmol), 1,4-cyclohexadiene
(11 μL, 0.12 mmol), 10% Pd/C (5 mg, 5 μmol), and MeOH (3 mL)
to give (R)-22 as a colorless solid (8.0 mg, 66% over two steps from
(R)-29). Analytical data were identical to those given above.
3-(N-BOM)-Protected Nucleosyl Amino Acid ((S)-23). Syn-
thesis of (S)-23 from (Z)-18. General procedure C with didehydro
nucleosyl amino acid (Z)-18 (730 mg, 0.871 mmol), (S,S)-Me-
DUPHOS-Rh (8.0 mg, 10 μmol), and MeOH (20 mL) and a reaction
time of 4 d. Purification by column chromatography (4:1 petroleum
1
ether−EtOAc) gave (S)-23 as a colorless solid (690 mg, 94%): H
HPLC tR 10.6 min (Method III); [α]20 +44.6 (c 1.2, MeOH).
NMR (600 MHz, C6D6) δ −0.02 (s, 3H, SiCH3), 0.02 (s, 3H, SiCH3),
0.13 (s, 3H, SiCH3), 0.13 (s, 3H, SiCH3), 0.93 (s, 9H, SiC(CH3)3),
0.98 (s, 9H, SiC(CH3)3), 1.32 (s, 9H, OC(CH3)3), 2.09 (ddd, J = 15.1,
10.9, 4.8 Hz, 1H, 5′-Ha), 2.23 (ddd, J = 15.1, 7.4, 2.5 Hz, 1H, 5′-Hb),
3.72 (dd, J = 5.3, 4.1 Hz, 1H, 3′-H), 4.37 (dd, J = 4.1, 3.8 Hz, 1H, 2′-
H), 4.42 (ddd, J = 10.9, 5.3, 2.5 Hz, 1H, 4′-H), 4.61 (ddd, J = 7.4, 6.5,
4.8 Hz, 1H, 6′-H), 4.66 (d, J = 14.3 Hz, 1H, BOM-CH2-Ha), 4.68 (d, J
D
Synthesis of (S)-22 from (S)-29. General procedure E with
nucleosyl amino acid (S)-29 (42 mg, 58 μmol), p-methoxybenzyl
chloride (0.44 M solution in CH2Cl2, 0.25 mL, 0.11 mmol), TBAI (1
mg, 3 μmol), Na2CO3 (0.82 M solution in water, 0.28 mL, 0.23
mmol), and CH2Cl2 (2 mL) and a reaction time of 30 h. In contrast to
the general procedure, more p-methoxybenzyl chloride (0.44 M
10093
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
= 14.3 Hz, 1H, BOM-CH2-Hb), 5.00 (s, 2H, Cbz-CH2), 5.42 (d, J =
18.2 Hz, 1H, NCH2O-Ha), 5.44 (d, J = 18.2 Hz, 1H, NCH2O-Hb),
5.64 (d, J = 6.5 Hz, 1H, NH), 5.70 (d, J = 8.2 Hz, 1H, 5-H), 5.72 (d, J
= 3.8 Hz, 1H, 1′-H), 7.03−7.20 (m, 8H, BOM-3-H, BOM-4-H, BOM-
5-H, Cbz-aryl-H) 7.32 (d, J = 8.2 Hz, 1H, 6-H), 7.34 (d, J = 7.6 Hz,
2H, BOM-2-H, BOM-6-H); 13C NMR (126 MHz, C6D6) δ −4.6,
−4.5, −4.1, −3.9, 18.4, 18.4, 26.1, 26.2, 28.0, 36.9, 52.8, 67.1, 70.5,
72.3, 75.3, 76.0, 81.0, 82.3, 92.9, 102.1, 127.6, 127.7, 128.4, 128.5,
128.6, 136.9, 138.9, 139.2, 151.2, 155.8, 162.1, 170.8; MS (ESI+) m/z
862.4 (M + Na+); HRMS (ESI+) m/z calcd for C43H65N3NaO10Si2
862.4101 (M + Na+), found 862.4103 (M + Na+); IR (ATR) ν 1713,
1665, 1252, 1153, 1058, 837, 775, 734, 696; UV (MeCN) λmax (log ε)
205 (4.45), 264 (4.01); mp 38 °C; TLC Rf 0.27 (7:3 petroleum ether−
H), 3.88 (dd, J = 5.0, 4.5 Hz, 1H, 3′-H), 4.12 (ddd, J = 11.2, 5.0, 2.6
Hz, 1H, 4′-H), 4.30 (dd, J = 4.5, 4.2 Hz, 1H, 2′-H), 5.73 (d, J = 8.1 Hz,
1H, 5-H), 5.76 (d, J = 4.2 Hz, 1H, 1′-H), 7.65 (d, J = 8.1 Hz, 1H, 6-H);
13C NMR (126 MHz, CD3OD) δ −4.5, −4.4, −4.4, −4.0, 18.9, 18.9,
26.4, 26.5, 28.3, 39.5, 53.8, 76.0, 76.6, 82.6, 82.9, 92.0, 103.0, 142.6,
152.3, 166.3, 175.2; MS (ESI+) m/z 586.4 (M + H+); HRMS (ESI+)
m/z calcd for C27H52N3O7Si2 586.3338 (M + H+), found 586.3337 (M
+ H+); IR (ATR) ν 1687, 1252, 1153, 1056, 867, 835, 812, 774, 735;
UV (MeOH) λmax (log ε) 207 (3.96), 262 (4.00); mp 48 °C; TLC Rf
0.27 (19:1 CH2Cl2−MeOH); [α]20 +42.6 (c 1.1, MeOH).
D
3-Unprotected Nucleosyl Amino Acid ((R)-24). General
procedure D with Cbz-protected nucleosyl amino acid (R)-29 (150
mg, 0.208 mmol), 1,4-cyclohexadiene (197 μL, 2.08 mmol), 10% Pd/
C (20 mg, 19 μmol), and MeOH (4 mL) to give (R)-24 as a colorless
EtOAc); analytical HPLC tR 15.1 min (method II); [α]20 +51.3 (c
D
1
1.0, CHCl3).
solid (120 mg, 99%): H NMR (300 MHz, CD3OD) δ 0.10 (s, 3H,
Synthesis of (S)-23 from (S)-29. General procedure E with
nucleosyl amino acid (S)-29 (21 mg, 29 μmol), benzyloxymethyl
chloride (0.44 M solution in CH2Cl2, 0.10 mL, 44 μmol), TBAI (0.5
mg, 1 μmol), Na2CO3 (0.82 M solution in water, 0.14 mL, 0.12
mmol), and CH2Cl2 (1.0 mL) and a reaction time of 23 h. Purification
by column chromatography (17:3 petroleum ether−EtOAc) gave (S)-
23 as a colorless solid (18 mg, 74%). Analytical data were identical to
those given above.
SiCH3), 0.11 (s, 3H, SiCH3), 0.12 (s, 3H, SiCH3), 0.14 (s, 3H,
SiCH3), 0.90 (s, 9H, SiC(CH3)3), 0.95 (s, 9H, SiC(CH3)3), 1.48 (s,
9H, OC(CH3)3), 1.99−2.06 (m, 2H, 5′-H), 3.53 (dd, J = 6.0, 5.6 Hz,
1H, 6′-H), 3.90 (dd, J = 5.1, 4.4 Hz, 1H, 3′-H), 4.14 (ddd, J = 8.3, 5.3,
5.1 Hz, 1H, 4′-H), 4.30 (dd, J = 4.4, 4.2 Hz, 1H, 2′-H), 5.73 (d, J = 8.1
Hz, 1H, 5-H), 5.78 (d, J = 4.2 Hz, 1H, 1′-H), 7.64 (d, J = 8.1 Hz, 1H,
6-H); 13C NMR (126 MHz, CD3OD) δ −4.5, −4.5, −4.3, −4.0, 18.9,
18.9, 26.4, 26.5, 28.3, 38.3, 54.1, 75.8, 76.7, 82.5, 82.6, 91.9, 102.9,
142.4, 152.4, 166.4, 175.7; MS (ESI+) m/z 586.3 (M + H+); HRMS
(ESI+) m/z calcd for C27H52N3O7Si2 586.3338 (M + H+), found
586.3334 (M + H+); IR (ATR) ν 1687, 1252, 1153, 1087, 1053, 866,
835, 812, 775; UV (MeOH) λmax (log ε) 207 (3.94), 262 (3.99); mp
3-(N-BOM)-Protected Nucleosyl Amino Acid ((R)-23). Syn-
thesis of (R)-23 from (Z)-18. General procedure C with didehydro
nucleosyl amino acid (Z)-18 (730 mg, 0.871 mmol), (R,R)-Me-
DUPHOS-Rh (8.0 mg, 10 μmol), and MeOH (20 mL) and a reaction
time of 7 d. In contrast to the general procedure, more (R,R)-Me-
DUPHOS-Rh (8.0 mg, 10 μmol) was added after 5 d. Purification by
column chromatography (4:1 petroleum ether−EtOAc) gave (R)-23
54 °C; TLC Rf 0.27 (19:1 CH2Cl2−MeOH); [α]20 +25.1 (c 0.9,
D
MeOH).
3′,5′-Bis(O-tert-butyldimethylsilyl)uridine-5′-aldehyde (27).
General procedure A with uridine derivative 2620 (2.30 g, 4.87 mmol),
IBX (3.41 g, 12.2 mmol), and MeCN (46 mL) to give 27 as a colorless
1
as a colorless solid (680 mg, 93%): H NMR (600 MHz, C6D6) δ
−0.04 (s, 3H, SiCH3), −0.01 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3),
0.20 (s, 3H, SiCH3), 0.92 (s, 9H, SiC(CH3)3), 0.96 (s, 9H,
SiC(CH3)3), 1.36 (s, 9H, OC(CH3)3), 1.91 (ddd, J = 14.7, 11.6, 3.9
Hz, 1H, 5′-Ha), 2.23 (ddd, J = 14.7, 5.0, 4.0 Hz, 1H, 5′-Hb), 3.72 (dd, J
= 6.1, 4.3 Hz, 1H, 3′-H), 4.25−4.30 (m, 2H, 2′-H, 4′-H), 4.64 (d, J =
18.4 Hz, 1H, BOM-CH2-Ha), 4.66 (d, J = 18.4 Hz, 1H, BOM-CH2-
Hb), 4.73 (ddd, J = 8.5, 5.0, 3.9 Hz, 1H, 6′-H), 4.97 (d, J = 12.3 Hz,
1H, Cbz-CH2-Ha), 5.14 (d, J = 12.3 Hz, 1H, Cbz-CH2-Hb), 5.34 (d, J
= 2.0 Hz, 1H, 1′-H), 5.36 (d, J = 15.6 Hz, 1H, NCH2O-Ha), 5.38 (d, J
= 15.6 Hz, 1H, NCH2O-Hb), 5.39 (d, J = 8.2 Hz, 1H, 5-H), 5.91 (d, J
= 8.5 Hz, 1H, NH), 6.65 (d, J = 8.2 Hz, 1H, 6-H), 7.00−7.22 (m, 8H,
BOM-3-H, BOM-4-H, BOM-5-H, Cbz-aryl-H), 7.33 (d, J = 7.6 Hz,
2H, BOM-2-H, BOM-6-H); 13C NMR (126 MHz, C6D6) δ −4.7,
−4.7, −3.9, −3.9, 18.3, 18.3, 26.2, 26.2, 28.1, 34.8, 53.6, 67.0, 70.4,
72.4, 74.7, 75.7, 81.0, 82.0, 93.7, 101.9, 127.6, 127.7, 128.3, 128.4,
128.5, 128.6, 137.0, 138.9, 138.2, 150.9, 156.2, 161.9, 170.4; MS (ESI+)
1
solid (2.25 g, 98%): H NMR (300 MHz, CDCl3) δ −0.01 (s, 3H,
SiCH3), 0.03 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.10 (s, 3H,
SiCH3), 0.85 (s, 9H, SiC(CH3)3), 0.91 (s, 9H, SiC(CH3)3), 4.22 (dd, J
= 4.0, 3.3 Hz, 1H, 3′-H), 4.30 (dd, J = 5.6, 4.0 Hz, 1H, 2′-H), 4.53 (d, J
= 3.3 Hz, 1H, 4′-H), 5.72 (d, J = 5.6 Hz, 1H, 1′-H), 5.78 (d, J = 8.1 Hz,
1H, 5-H), 7.66 (d, J = 8.1 Hz, 1H, 6-H), 8.54 (s, 1H, NH), 9.80 (s, 1H,
5′-H); MS (ESI+) m/z 493.2 (M + Na+); HRMS (ESI+) m/z calcd for
C21H38N2NaO6Si2 493.2161 (M + Na+), found 493.2160 (M + Na+).
3-Unprotected Didehydro Nucleosyl Amino Acid ((Z)-28).
General procedure B with aldehyde 27 (2.93 g, 6.22 mmol),
phosphonate 1622 (1.86 g, 4.98 mmol), KHMDS (0.5 M in toluene,
9.96 mL, 4.98 mmol), and THF (30 mL (27), 25 mL (16), 25 mL
(KHMDS)). Purification by column chromatography (3:1 petroleum
ether−EtOAc) gave (Z)-28 as a colorless solid (3.03 g, 85%) while the
(E)-isomer could not be isolated: 1H NMR (600 MHz, CDCl3) δ 0.07
(s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.12 (s, 3H,
SiCH3), 0.89 (s, 9H, SiC(CH3)3), 0.90 (s, 9H, SiC(CH3)3), 1.48 (s,
9H, OC(CH3)3), 3.95 (dd, J = 6.3, 3.8 Hz, 1H, 3′-H), 4.34 (dd, J = 3.8,
3.3 Hz, 1H, 2′-H), 4.88 (dd, J = 7.7, 6.3 Hz, 1H, 4′-H), 5.14 (s, 2H,
Cbz-CH2), 5.58 (d, J = 3.3 Hz, 1H, 1′-H), 5.73 (d, J = 8.1 Hz, 1H, 5-
H), 6.26 (d, J = 7.7 Hz, 1H, 5′-H), 6.75 (s, 1H, 6′-NH), 7.27 (d, J = 8.1
Hz, 1H, 6-H), 7.30−7.39 (m, 5H, Cbz-aryl-H), 8.56 (s, 1H, 3-NH);
13C NMR (126 MHz, CDCl3) δ −4.9, −4.8, −4.5, −4.4, 18.0, 18.1,
25.8, 25.8, 27.8, 67.5, 74.7, 76.1, 79.1, 82.6, 92.8, 102.3, 124.6, 128.1,
128.3, 128.5, 131.3, 135.8, 140.4, 149.8, 162.7, 163.1; MS (ESI+) m/z
740.3 (M + Na+); HRMS (ESI+) m/z calcd for C35H55N3NaO9Si2
740.3369 (M + Na+), found 740.3379 (M + Na+); IR (ATR) ν 1686,
1254, 1222, 1152, 1051, 833, 814, 776, 735; UV (MeCN) λmax (log ε)
255 (4.20); mp 65 °C; TLC Rf 0.29 (3:2 petroleum ether−EtOAc);
m/z 862.4 (M
+
Na+); HRMS (ESI+) m/z calcd for
C43H65N3NaO10Si2 862.4101 (M + Na+), found 862.4098 (M +
Na+); IR (ATR) ν 1714, 1665, 1151, 1061, 865, 837, 775, 735, 696;
UV (MeCN) λmax (log ε) 205 (4.40), 263 (3.96); mp 41 °C; TLC Rf
0.38 (7:3 petroleum ether-EtOAc); Analytical HPLC tR 14.7 min
(method II); [α]20 +50.7 (c 1.2, CHCl3).
D
Synthesis of (R)-23 from (R)-29. General procedure E with
nucleosyl amino acid (R)-29 (21 mg, 29 μmol), benzyloxymethyl
chloride (0.44 M solution in CH2Cl2, 0.10 mL, 44 μmol), TBAI (0.5
mg, 1 μmol), Na2CO3 (0.82 M solution in water, 0.14 mL, 0.12
mmol), and CH2Cl2 (1.0 mL) and a reaction time of 23 h. Purification
by column chromatography (17:3 petroleum ether−EtOAc) gave (R)-
23 as a colorless solid (20 mg, 83%). Analytical data were identical to
those given above.
[α]20 +47.9 (c 1.0, CHCl3).
3-Unprotected Nucleosyl Amino Acid ((S)-24). General
procedure D with Cbz-protected nucleosyl amino acid (S)-29 (150
mg, 0.208 mmol), 1,4-cyclohexadiene (197 μL, 2.08 mmol), 10% Pd/
C (20 mg, 19 μmol), and MeOH (4 mL) to give (S)-24 as a colorless
D
3-Unprotected Nucleosyl Amino Acid ((S)-29). General
procedure C with didehydro nucleosyl amino acid (Z)-28 (1.26 g,
1.75 mmol), (S,S)-Me-DUPHOS-Rh (12 mg, 20 μmol), and MeOH
(30 mL) and a reaction time of 6 d. In contrast to the General
Procedure, more (S,S)-Me-DUPHOS-Rh (9.0 mg, 15 μmol) was
added after 5 d. Purification by column chromatography (7:3
petroleum ether−EtOAc) gave (S)-29 as a colorless solid (1.19 g,
94%): 1H NMR (300 MHz, C6D6) δ 0.01 (s, 3H, SiCH3), 0.05 (s, 3H,
1
solid (119 mg, 98%): H NMR (300 MHz, CD3OD) δ 0.09 (s, 3H,
SiCH3), 0.10 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.13 (s, 3H,
SiCH3), 0.90 (s, 9H, SiC(CH3)3), 0.93 (s, 9H, SiC(CH3)3), 1.47 (s,
9H, OC(CH3)3), 1.84 (ddd, J = 14.0, 11.2, 5.1 Hz, 1H, 5′-Ha), 2.11
(ddd, J = 14.0, 8.2, 2.6 Hz, 1H, 5′-Hb), 3.51 (dd, J = 8.2, 5.1 Hz, 1H, 6′-
10094
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
SiCH3), 0.16 (s, 3H, SiCH3), 0.20 (s, 3H, SiCH3), 0.95 (s, 9H,
SiC(CH3)3), 1.00 (s, 9H, SiC(CH3)3), 1.33 (s, 9H, OC(CH3)3), 2.14
(ddd, J = 14.1, 10.7, 5.2 Hz, 1H, 5′-Ha), 2.28 (ddd, J = 14.1, 7.1, 2.6
Hz, 1H, 5′-Hb), 3.76 (dd, J = 5.3, 4.6 Hz, 1H, 3′-H), 4.38−4.46 (m,
2H, 2′-H, 4′-H), 4.61 (ddd, J = 7.1, 6.3, 5.2 Hz, 1H, 6′-H), 5.02 (s, 2H,
Cbz-CH2), 5.60 (d, J = 8.0 Hz, 1H, 5-H), 5.61 (s, 1H, 1′-H), 5.76 (d, J
= 6.3 Hz, 1H, 6′-NH), 7.05−7.28 (m, 6H, 6-H, Cbz-aryl-H) 9.60 (s,
1H, 3-NH); 13C NMR (126 MHz, C6D6) δ −4.8, −4.7, −4.3, −4.1,
18.2, 18.2, 26.0, 26.1, 27.8, 36.5, 52.8, 67.0, 75.0, 75.9, 80.9, 82.2, 92.8,
102.4, 128.3, 128.4, 128.6, 137.0, 140.8, 150.6, 155.9, 163.0, 171.0; MS
(ESI+) m/z 742.3 (M + Na+); HRMS (ESI+) m/z calcd for
C35H57N3NaO9Si2 742.3526 (M + Na+), found 742.3527 (M +
Na+); IR (ATR) ν 1683, 1252, 1153, 866, 836, 775, 735, 697; UV
(MeCN) λmax (log ε) 206 (4.20), 261 (3.99); mp 70 °C; TLC Rf 0.23
purified by column chromatography (petroleum ether−EtOAc
gradient (25−30%)) to give (R)-30 as a colorless solid (62 mg,
1
75%): H NMR (300 MHz, CDCl3, 55 °C) δ 0.05 (s, 3H, SiCH3),
0.06 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.87 (s,
9H, SiC(CH3)3), 0.92 (s, 9H, SiC(CH3)3), 1.49 (s, 9H, OC(CH3)3),
2.07 (ddd, J = 14.4, 11.4 Hz, J = 3.8 Hz, 1H, 5′-Ha), 2.39 (ddd, J =
14.4, 5.5, 2.5 Hz, 1H, 5′-Hb), 3.77 (dd, J = 4.8, 4.6 Hz, 1H, 3′-H), 4.17
(ddd, J = 11.4, 4.8, 2.5 Hz, 1H, 4′-H), 4.32 (dd, J = 4.6, 4.2 Hz, 1H, 2′-
H), 4.73 (ddd, J = 8.2, 5.5, 3.8 Hz, 1H, 6′-H), 5.48 (d, J = 4.2 Hz, 1H,
1′-H), 5.66 (d, J = 8.1 Hz, 1H, 5-H), 6.49 (d, J = 8.2 Hz, 1H, 6′-NH),
7.25 (d, J = 8.1 Hz, 1H, 6-H), 7.54 (d, J = 9.2 Hz, 2H, urea-aryl-2-H,
urea-aryl-6-H), 8.03 (s, 1H, urea-aryl-NH), 8.09 (d, J = 9.2 Hz, 2H,
urea-aryl-3-H, urea-aryl-5-H), 9.70 (s, 1H, 3-NH); 13C NMR (126
MHz, CDCl3, 50 °C) δ −4.7, −4.7, −4.6, −4.2, 17.9, 18.1, 25.8, 25.9,
28.1, 34.8, 51.9, 73.7, 75.3, 81.8, 82.8, 93.1, 102.2, 117.8, 125.1, 141.6,
142.2, 142.2, 150.1, 154.3, 163.8, 170.8; MS (ESI+) m/z 772.4 (M +
Na+); HRMS (ESI+) m/z calcd for C34H55N5NaO10Si2 772.3380 (M +
Na+), found 772.3377 (M + Na+); IR (ATR) ν 1682, 1329, 1253,
1154, 1110, 865, 836, 776, 751; UV (MeCN) λmax (log ε) 261 (3.99),
332 (4.16); mp 92 °C; TLC Rf 0.06 (7:3 petroleum ether−EtOAc);
(3:2 petroleum ether−EtOAc); [α]20 +54.9 (c 1.0, CHCl3).
D
3-Unprotected Nucleosyl Amino Acid ((R)-29). General
procedure C with didehydro nucleosyl amino acid (Z)-28 (270 mg,
0.376 mmol), (R,R)-Me-DUPHOS-Rh (9.0 mg, 15 μmol), MeOH (20
mL) and a reaction time of 14 d. In contrast to the general procedure,
more (R,R)-Me-DUPHOS-Rh (6.0 mg, 9.9 μmol) was added both
after 7 and 11 d. Purification by column chromatography (7:3
petroleum ether−EtOAc) gave (R)-29 as a colorless solid (253 mg,
93%): 1H NMR (300 MHz, C6D6) δ 0.03 (s, 3H, SiCH3), 0.04 (s, 3H,
SiCH3), 0.18 (s, 3H, SiCH3), 0.24 (s, 3H, SiCH3), 0.95 (s, 9H,
SiC(CH3)3), 1.00 (s, 9H, SiC(CH3)3), 1.39 (s, 9H, OC(CH3)3), 2.04
(ddd, J = 13.8, 10.9, 4.2 Hz, 1H, 5′-Ha), 2.30 (ddd, J = 13.8, 4.6, 2.4
Hz, 1H, 5′-Hb), 3.74 (dd, J = 6.6, 3.9 Hz, 1H, 3′-H), 4.29 (ddd, J =
10.9, 6.6, 2.4 Hz, 1H, 4′-H), 4.39 (dd, J = 3.9, 2.4 Hz, 1H, 2′-H), 4.75
(ddd, J = 8.6, 4.6, 4.2 Hz, 1H, 6′-H), 5.01 (d, J = 12.3 Hz, 1H, Cbz-
CH2-Ha), 5.16 (d, J = 12.3 Hz, 1H, Cbz-CH2-Hb), 5.31 (d, J = 2.4 Hz,
1H, 1′-H), 5.39 (d, J = 8.2 Hz, 1H, 5-H), 6.03 (d, J = 8.6 Hz, 1H, 6′-
NH), 6.70 (d, J = 8.2 Hz, 1H, 6-H), 7.04−7.27 (m, 5H, Cbz-aryl-H)
10.34 (s, 1H, 3-NH); 13C NMR (126 MHz, C6D6) δ −4.8, −4.8, −4.1,
−4.1, 18.2, 18.2, 26.0, 26.0, 27.9, 34.6, 53.6, 66.9, 74.5, 75.5, 80.9, 81.9,
93.6, 102.3, 128.3, 128.5, 128.6, 137.1, 140.0, 150.6, 156.3, 163.4,
170.7; MS (ESI+) m/z 742.3 (M + Na+); HRMS (ESI+) m/z calcd for
C35H57N3NaO9Si2 742.3526 (M + Na+), found 742.3527 (M + Na+);
IR (ATR) ν 1685, 1252, 1154, 1064, 866, 836, 813, 775, 736; UV
(MeCN) λmax (log ε) 206 (4.19), 261 (3.98); mp 63 °C; TLC Rf 0.24
[α]20 +11.1 (c 1.0, CHCl3).
D
Desilylated Nucleosyl Amino Acid Urea Derivative ((S)-31).
To a solution of nucleosyl amino acid urea derivative (S)-30 (61 mg,
81 μmol) in THF (4 mL) was added TBAF trihydrate (101 mg, 0.320
mmol) at 10 °C. The reaction mixture was stirred at rt for 3 h, and
then petroleum ether (1 mL) was added. The resultant mixture was
directly applied on a silica gel column and purified twice by column
chromatography ((1) 1:4 petroleum ether−THF, (2) CH2Cl2−MeOH
gradient (5−10%)) to give (S)-31 as a colorless solid (10 mg, 24%):
1H NMR (300 MHz, CD3OD) δ 1.46 (s, 9H, OC(CH3)3), 2.16 (ddd,
J = 14.4, 9.3, 5.9 Hz, 1H, 5′-Ha), 2.34 (ddd, J = 14.4, 6.0, 3.3 Hz, 1H,
5′-Hb), 3.95 (dd, J = 6.7, 5.7 Hz, 1H, 3′-H), 4.03 (ddd, J = 9.3, 6.7, 3.3
Hz, 1H, 4′-H), 4.19 (dd, J = 5.7, 3.4 Hz, 1H, 2′-H), 4.73 (dd, J = 6.0,
5.9 Hz, 1H, 6′-H), 5.72 (d, J = 8.0 Hz, 1H, 5-H), 5.75 (d, J = 3.4 Hz,
1H, 1′-H), 7.59 (d, J = 9.3 Hz, 2H, urea-aryl-2-H, urea-aryl-6-H), 7.64
(d, J = 8.0 Hz, 1H, 6-H), 8.15 (d, J = 9.3 Hz, 2H, urea-aryl-3-H, urea-
aryl-5-H); 13C NMR (126 MHz, CD3OD) δ 28.2, 36.5, 52.8, 74.8,
74.8, 81.2, 83.3, 92.8, 102.9, 118.6, 126.0, 143.3, 147.5, 152.1, 156.3,
166.1, 172.6; MS (ESI−) m/z 520.2 (M − H−); HRMS (ESI−) m/z
calcd for C22H26N5O10 520.1685 (M − H−), found 520.1683 (M −
H−); IR (ATR) ν 1678, 1335, 1111, 1093, 1055, 851, 566, 548, 526;
UV (MeOH) λmax (log ε) 202 (4.40), 263 (4.08), 327 (4.13); mp 215
(3:2 petroleum ether−EtOAc); [α]20 +44.1 (c 1.1, CHCl3).
D
Silylated Nucleosyl Amino Acid Urea Derivative ((S)-30). To
a solution of nucleosyl amino acid (S)-24 (70 mg, 0.12 mmol) in THF
(6 mL), 4-nitrophenyl isocyanate (23 mg, 0.14 mmol) was added and
the reaction mixture was stirred at rt for 20 h. The solvent was
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography (petroleum ether−EtOAc
gradient (25−30%)) to give (S)-30 as a colorless solid (77 mg,
°C; TLC Rf 0.13 (92:8 CH2Cl2−MeOH); [α]20 +60.9 (c 0.35,
D
MeOH).
Desilylated Nucleosyl Amino Acid Urea Derivative ((R)-31).
To a solution of nucleosyl amino acid urea derivative (R)-30 (52 mg,
69 μmol) in THF (4 mL) was added TBAF trihydrate (88 mg, 0.28
mmol) at 10 °C. The reaction mixture was stirred at rt for 3.5 h, and
then petroleum ether (1 mL) was added. The resultant mixture was
directly applied on a silica gel column and purified twice by column
chromatography ((1) 1:4 petroleum ether−THF, (2) CH2Cl2−MeOH
gradient (5−10%)) to give (R)-31 as a colorless solid (10 mg, 29%):
1H NMR (300 MHz, CD3OD) δ 1.49 (s, 9H, OC(CH3)3), 2.18−2.19
(m, 2H, 5′-H), 3.92−4.03 (m, 2H, 3′-H, 4′-H), 4.22 (dd, J = 5.1, 3.8
Hz, 1H, 2′-H), 4.49 (dd, J = 6.2, 5.7 Hz, 1H, 6′-H), 5.65 (d, J = 8.0 Hz,
1H, 5-H), 5.78 (d, J = 3.8 Hz, 1H, 1′-H), 7.55−7.60 (m, 3H, 6-H, urea-
aryl-2-H, urea-aryl-6-H), 8.14 (d, J = 9.1 Hz, 2H, urea-aryl-3-H, urea-
aryl-5-H); 13C NMR (126 MHz, CD3OD) δ 28.3, 36.1, 53.0, 74.7,
74.7, 81.6, 83.3, 92.8, 103.0, 118.6, 126.0, 142.9, 143.2, 147.5, 152.2,
156.6, 166.0, 172.9; MS (ESI+) m/z 544.2 (M + Na+); HRMS (ESI+)
m/z calcd for C22H27N5NaO10 544.1650 (M + Na+), found 544.1641
(M + Na+); IR (ATR) ν 1668, 1503, 1327, 1221, 1149, 1108, 1032,
750, 551; UV (MeOH) λmax (log ε) 202 (4.41), 263 (4.01), 328
1
86%): H NMR (300 MHz, CDCl3) δ 0.05 (s, 3H, SiCH3), 0.05 (s,
3H, SiCH3), 0.06 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.86 (s, 9H,
SiC(CH3)3), 0.87 (s, 9H, SiC(CH3)3), 1.46 (s, 9H, OC(CH3)3),
2.03−2.18 (m, 1H, 5′-Ha), 2.21−2.31 (m, 1H, 5′-Hb), 3.77 (dd, J = 4.5,
4.4 Hz, 1H, 3′-H), 4.21−4.28 (m, 1H, 4′-H), 4.30 (dd, J = 4.4, 4.2 Hz,
1H, 2′-H), 4.57 (ddd, J = 6.6, 6.1, 6.0 Hz, 1H, 6′-H), 5.64 (d, J = 4.2
Hz, 1H, 1′-H), 5.83 (d, J = 8.0 Hz, 1H, 5-H), 6.49 (d, J = 6.6 Hz, 1H,
6′-NH), 7.54 (d, J = 9.2 Hz, 2H, urea-aryl-2-H, urea-aryl-6-H), 7.56 (d,
J = 8.0 Hz, 1H, 6-H), 8.03 (s, 1H, urea-aryl-NH), 8.11 (d, J = 9.2 Hz,
2H, urea-aryl-3-H, urea-aryl-5-H), 9.93 (s, 1H, 3-NH); 13C NMR (126
MHz, CDCl3) δ −4.8, −4.8, −4.7, −4.3, 17.9, 18.0, 25.7, 25.7, 27.9,
35.8, 52.0, 74.0, 75.2, 82.0, 83.0, 92.2, 102.4, 117.6, 125.2, 141.9, 141.9,
141.9, 150.5, 154.0, 163.8, 171.8; MS (ESI+) m/z 772.4 (M + Na+);
HRMS (ESI+) m/z calcd for C34H55N5NaO10Si2 772.3380 (M + Na+),
found 772.3377 (M + Na+); IR (ATR) ν 1681, 1329, 1252, 1155,
1110, 867, 835, 776, 751; UV (MeCN) λmax (log ε) 262 (3.99), 332
(4.16); mp 102 °C; TLC Rf 0.05 (7:3 petroleum ether−EtOAc);
[α]20 +53.6 (c 1.1, CHCl3).
(4.16); mp 218 °C; TLC Rf 0.11 (92:8 CH2Cl2−MeOH); [α]20
+33.2 (c 0.90, MeOH).
D
SilDylated Nucleosyl Amino Acid Urea Derivative ((R)-30). To
a solution of nucleosyl amino acid (R)-24 (66 mg, 0.11 mmol) in THF
(6 mL), 4-nitrophenyl isocyanate (21 mg, 0.13 mmol) was added and
the reaction mixture was stirred at rt for 20 h. The solvent was
evaporated under reduced pressure. The resultant crude product was
6′-N-Alkylated Nucleosyl Amino Acid ((S)-33). To a solution
of 3-unprotected nucleosyl amino acid (S)-24 (66 mg, 0.11 mmol) in
THF (3.5 mL) were added anhydrous molecular sieves (4 Å), and the
mixture was stirred at rt for 5 min. Aldehyde 32 (23 mg, 0.11 mmol)
was then added and the reaction mixture was stirred at rt for 20 h with
10095
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
MeCN (1 mL) being added after 15 h. Subsequently, Amberlyst-15TM
(4.9 mg, 23 μmol), sodium triacetoxyborohydride (47 mg, 0.22 mmol)
and THF (2 mL) were added and stirring at rt was continued for
further 18 h. The unsoluble material was then filtered off and washed
with EtOAc (3 × 10 mL). The filtrate was washed with satd Na2CO3
solution (1 × 50 mL) and the aqueous layer was extracted with EtOAc
(1 × 30 mL). The combined organics were dried over Na2SO4 and
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography (98:2 CH2Cl2−MeOH) to give
(S)-33 as a colorless solid (78 mg, 91%): 1H NMR (600 MHz,
DMSO-d6) δ 0.00 (s, 3H, SiCH3), 0.03 (s, 3H, SiCH3), 0.07 (s, 3H,
SiCH3), 0.09 (s, 3H, SiCH3), 0.83 (s, 9H, SiC(CH3)3), 0.88 (s, 9H,
SiC(CH3)3), 1.40 (s, 9H, OC(CH3)3), 1.52 (dddd, J = 7.0, 6.9, 6.7, 6.7
Hz, 2H, propylene-2-H), 1.85−1.97 (m, 3H, 5′-H, 6′-NH), 2.39 (ddd, J
= 11.5, 7.0, 7.0 Hz, 1H, propylene-1-Ha), 2.52 (ddd, J = 11.5, 6.9, 6.9
Hz, 1H, propylene-1-Hb), 3.03 (ddd, J = 6.7, 6.7, 5.6 Hz, 2H,
propylene-3-H), 3.12 (dd, J = 7.7, 6.1 Hz, 1H, 6′-H), 3.88 (ddd, J =
8.5, 4.4, 4.3 Hz, 1H, 4′-H), 3.91 (dd, J = 4.5, 4.3 Hz, 1H, 3′-H), 4.33
(dd, J = 4.9, 4.2 Hz, 1H, 2′-H), 5.00 (s, 2H, Cbz-CH2), 5.67 (d, J = 8.1
Hz, 1H, 5-H), 5.71 (d, J = 4.9 Hz, 1H, 1′-H), 7.15 (dd, J = 5.6, 5.6 Hz,
1H, Cbz-NH), 7.30−7.37 (m, 5H, Cbz-aryl-H), 7.60 (d, J = 8.1 Hz,
1H, 6-H), 11.32 (s, 1H, 3-NH); 13C NMR (126 MHz, DMSO-d6) δ
−5.0, −5.0, −4.9, −4.6, 17.5, 17.6, 25.5, 25.6, 27.6, 29.9, 36.3, 38.4,
44.6, 59.1, 65.0, 73.5, 74.5, 80.2, 80.9, 88.5, 102.0, 127.6, 127.6, 128.2,
137.2, 140.9, 150.5, 156.0, 162.9, 173.3; MS (ESI+) m/z 777.5 (M +
H+); HRMS (ESI+) m/z calcd for C38H65N4O9Si2 777.4285 (M + H+),
found 777.4298 (M + H+); IR (ATR) ν 1686, 1251, 1151, 1065, 866,
835, 812, 774, 695; UV (MeOH) λmax (log ε) 207 (4.21), 263 (3.99);
mp 57 °C; TLC Rf 0.07 (96:4 CH2Cl2−MeOH); [α]20D +26.5 (c 0.84,
MeOH).
56 μmol) was then dissolved in THF (4 mL). To a solution of N-Cbz-
L-leucine (13 mg, 50 μmol) in THF (2 mL) were added HOBt (6.8
mg, 50 μmol), EDC hydrochloride (9.6 mg, 50 μmol), and DIPEA
(8.7 μL, 50 μmol). The resultant suspension was stirred at rt for 45
min and then added to the aforementioned solution of the amine at 0
°C. The reaction mixture was stirred at 0 °C for 10 h and at rt for 6 h.
It was then diluted with EtOAc (50 mL) and washed with satd
Na2CO3 solution (1 × 50 mL). The organic layer was dried over
Na2SO4 and evaporated under reduced pressure. The resultant crude
product was purified by column chromatography (97.5:2.5 CH2Cl2−
MeOH) to give (S)-34 as a colorless solid (32 mg, 70% over two steps
from (S)-33): 1H NMR (600 MHz, DMSO-d6) δ −0.00 (s, 3H,
SiCH3), 0.03 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.09 (s, 3H,
SiCH3), 0.83 (s, 9H, SiC(CH3)3), 0.84 (d, J = 6.9 Hz, 3H, Leu-5-Ha),
0.86 (d, J = 6.6 Hz, 3H, Leu-5-Hb), 0.88 (s, 9H, SiC(CH3)3), 1.35 (s,
9H, OC(CH3)3), 1.40−1.53 (m, 4H, propylene-2-H, Leu-3-H), 1.55−
1.62 (m, 1H, Leu-4-H), 1.86−1.90 (m, 2H, 5′-H), 2.35−2.41 (m, 1H,
propylene-1-Ha), 2.48−2.53 (m, 1H, propylene-1-Hb), 3.00−3.06 (m,
1H, propylene-3-Ha), 3.08−3.14 (m, 2H, 6′-H, propylene-3-Hb),
3.87−3.91 (m, 2H, 3′-H, 4′-H), 3.95−4.00 (m, 1H, Leu-2-H), 4.33
(dd, J = 4.9, 4.6 Hz, 1H, 2′-H), 5.00 (d, J = 12.6 Hz, 1H, Cbz-CH2-Ha),
5.03 (d, J = 12.6 Hz, 1H, Cbz-CH2−Hb), 5.67 (d, J = 8.1 Hz, 1H, 5-
H), 5.70 (d, J = 4.9 Hz, 1H, 1′-H), 7.24 (d, J = 8.2 Hz, 1H, Leu-NH),
7.28−7.38 (m, 5H, Cbz-aryl-H), 7.60 (d, J = 8.1 Hz, 1H, 6-H), 7.79
(dd, J = 5.6, 5.5 Hz, 1H, propylene-NH), 11.31 (s, 1H, 3-NH); 13C
NMR (126 MHz, DMSO-d6) δ −5.0, −5.0, −4.9, −4.6, 17.5, 17.6,
21.5, 22.8, 24.1, 25.5, 25.6, 27.6, 29.6, 36.3, 36.6, 40.9, 44.6, 53.1, 59.1,
65.2, 73.5, 73.5, 80.2, 80.8, 88.5, 102.0, 127.5, 127.6, 128.2, 137.0,
140.9, 152.2, 155.8, 162.9, 171.9, 173.3; MS (ESI+) m/z 890.5 (M +
H+); HRMS (ESI+) m/z calcd for C44H76N5O10Si2 890.5125 (M +
H+), found 890.5124 (M + H+); IR (ATR) ν 1686, 1251, 1153, 1043,
867, 835, 813, 775, 696; UV (MeOH) λmax (log ε) 204 (4.34), 262
(4.01), 318 (2.62); mp 71 °C; TLC Rf 0.24 (19:1 CH2Cl2−MeOH);
6′-N-Alkylated Nucleosyl Amino Acid ((R)-33). To a solution
of 3-unprotected nucleosyl amino acid (R)-24 (74 mg, 0.13 mmol) in
THF (4 mL) were added anhydrous molecular sieves (4 Å), and the
mixture was stirred at rt for 5 min. Aldehyde 32 (27 mg, 0.13 mmol)
was then added, and the reaction mixture was stirred at rt for 20 h with
MeCN (1 mL) being added after 15 h. Subsequently, Amberlyst-15
(5.7 mg, 27 μmol), sodium triacetoxyborohydride (55 mg, 0.26
mmol), and THF (2 mL) were added and stirring at rt was continued
for further 18 h. The unsoluble material was then filtered off and
washed with EtOAc (3 × 10 mL). The filtrate was washed with satd
Na2CO3 solution (1 × 50 mL), and the aqueous layer was extracted
with EtOAc (1 × 30 mL). The combined organics were dried over
Na2SO4 and evaporated under reduced pressure. The resultant crude
product was purified by column chromatography (98:2 CH2Cl2−
analytical HPLC tR 9.9 min (method III); [α]20 +14.8 (c 1.1,
D
MeOH).
N-Cbz-Protected Muraymycin Analogue ((R)-34). General
procedure D with 6′-N-alkylated nucleosyl amino acid (R)-33 (63
mg, 81 μmol), 1,4-cyclohexadiene (77 μL, 0.81 mmol), 10% Pd/C (10
mg, 9.4 μmol) and MeOH (4 mL) to give the N-deprotected
derivative as a colorless solid (51 mg). Some of this material (41 mg,
64 μmol) was then dissolved in THF (4 mL). To a solution of N-Cbz-
L-leucine (15 mg, 58 μmol) in THF (2.3 mL), HOBt (7.8 mg, 58
μmol), EDC hydrochloride (11 mg, 58 μmol) and DIPEA (10 μL, 58
μmol) were added. The resultant suspension was stirred at rt for 45
min and then added to the aforementioned solution of the amine at 0
°C. The reaction mixture was stirred at 0 °C for 10 h and at rt for 6 h.
It was then diluted with EtOAc (50 mL) and washed with satd
Na2CO3 solution (1 × 50 mL). The organic layer was dried over
Na2SO4 and evaporated under reduced pressure. The resultant crude
product was purified by column chromatography (97.5:2.5 CH2Cl2−
MeOH) to give (R)-34 as a colorless solid (39 mg, 75% over two steps
from (R)-33): 1H NMR (600 MHz, DMSO-d6) δ −0.02 (s, 3H,
SiCH3), 0.03 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.09 (s, 3H,
SiCH3), 0.83 (s, 9H, SiC(CH3)3), 0.84 (d, J = 6.9 Hz, 3H, Leu-5-Ha),
0.86 (d, J = 6.7 Hz, 3H, Leu-5-Hb), 0.88 (s, 9H, SiC(CH3)3), 1.37−
1.52 (m, 4H, propylene-2-H, Leu-3-H), 1.41 (s, 9H, OC(CH3)3),
1.55−1.62 (m, 1H, Leu-4-H), 1.77 (ddd, J = 14.0, 8.6, 4.0 Hz, 1H, 5′-
Ha), 1.88 (ddd, J = 14.0, 9.4, 4.6 Hz, 1H, 5′-Hb), 2.30−2.35 (m, 1H,
propylene-1-Ha), 2.51−2.55 (m, 1H, propylene-1-Hb), 2.99−3.13 (m,
3H, 6′-H, propylene-3-H), 3.95−4.05 (m, 3H, Leu-2-H, 3′-H, 4′-H),
4.34 (dd, J = 5.8, 4.4 Hz, 1H, 2′-H), 5.00 (d, J = 12.7 Hz, 1H, Cbz-
CH2-Ha), 5.03 (d, J = 12.7 Hz, 1H, Cbz-CH2-Hb), 5.66 (d, J = 8.1 Hz,
1H, 5-H), 5.76 (d, J = 5.8 Hz, 1H, 1′-H), 7.23 (d, J = 8.3 Hz, 1H, Leu-
NH), 7.28−7.37 (m, 5H, Cbz-aryl-H), 7.59 (d, J = 8.1 Hz, 1H, 6-H),
7.78 (dd, J = 5.6, 5.6 Hz, 1H, propylene-NH), 11.31 (s, 1H, 3-NH);
13C NMR (126 MHz, DMSO-d6) δ −5.1, −4.9, −4.8, −4.7, 17.4, 17.6,
21.5, 22.8, 24.1, 25.5, 25.6, 27.6, 29.8, 36.4, 36.6, 41.0, 44.7, 53.1, 59.0,
65.2, 73.4, 74.9, 80.2, 81.7, 88.0, 102.0, 127.5, 127.6, 128.2, 137.0,
140.8, 150.6, 155.7, 162.8, 171.9, 173.7; MS (ESI+) m/z 890.5 (M +
H+); HRMS (ESI+) m/z calcd for C44H76N5O10Si2 890.5125 (M +
1
MeOH) to give (R)-33 as a colorless solid (83 mg, 85%): H NMR
(600 MHz, DMSO-d6) δ −0.02 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3),
0.07 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.83 (s, 9H, SiC(CH3)3),
0.89 (s, 9H, SiC(CH3)3), 1.41 (s, 9H, OC(CH3)3), 1.47−1.54 (m, 2H,
propylene-2-H), 1.78 (ddd, J = 13.8, 8.5, 4.2 Hz, 1H, 5′-Ha), 1.83 (s,
1H, 6′-NH), 1.88 (ddd, J = 13.8, 8.7, 4.6 Hz, 1H, 5′-Hb), 2.34 (ddd, J =
11.3, 7.1, 7.0 Hz, 1H, propylene-1-Ha), 2.54 (ddd, J = 11.3, 7.1, 6.8 Hz,
1H, propylene-1-Hb), 3.02 (ddd, J = 6.6, 6.5, 5.7 Hz, 2H, propylene-3-
H), 3.08 (dd, J = 8.7, 4.2 Hz, 1H, 6′-H), 3.99−4.04 (m, 2H, 3′-H, 4′-
H), 4.34 (dd, J = 5.8, 4.4 Hz, 1H, 2′-H), 5.00 (s, 2H, Cbz-CH2), 5.66
(d, J = 8.1 Hz, 1H, 5-H), 5.76 (d, J = 5.8 Hz, 1H, 1′-H), 7.14 (dd, J =
5.7, 5.7 Hz, 1H, Cbz-NH), 7.28−7.38 (m, 5H, Cbz-aryl-H), 7.59 (d, J
= 8.1 Hz, 1H, 6-H), 11.32 (s, 1H, 3-NH); 13C NMR (126 MHz,
DMSO-d6) δ −5.1, −4.9, −4.8, −4.7, 17.4, 17.6, 25.5, 25.6, 27.6, 30.0,
36.3, 38.4, 44.5, 59.0, 65.0, 73.4, 74.9, 80.2, 81.7, 88.0, 102.0, 127.6,
127.6, 128.2, 137.2, 140.8, 150.6, 156.0, 162.8, 173.7; MS (ESI+) m/z
777.5 (M + H+); HRMS (ESI+) m/z calcd for C38H65N4O9Si2
777.4285 (M + H+), found 777.4291 (M + H+); IR (ATR) ν 1687,
1251, 1149, 1086, 1063, 866, 835, 812, 774; UV (MeOH) λmax (log ε)
256 (4.28), 305 (3.98); mp 59 °C; TLC Rf 0.09 (96:4 CH2Cl2−
MeOH); [α]20 +15.6 (c 0.67, MeOH).
N-Cbz-ProtDected Muraymycin Analogue ((S)-34). General
procedure D with 6′-N-alkylated nucleosyl amino acid (S)-33 (60
mg, 77 μmol), 1,4-cyclohexadiene (73 μL, 0.77 mmol), 10% Pd/C (10
mg, 9.4 μmol), and MeOH (4 mL) to give the N-deprotected
derivative as a colorless solid (48 mg). Some of this material (36 mg,
10096
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
H+), found 890.5122 (M + H+); IR (ATR) ν 1686, 1551, 1151, 1049,
866, 836, 812, 775, 696; UV (MeOH) λmax (log ε) 204 (4.32), 263
(4.01); mp 69 °C; TLC Rf 0.27 (19:1 CH2Cl2−MeOH); Analytical
S. Curr. Drug Targets 2004, 5, 191−195. (d) Bonate, P. L.; Arthaud, L.;
Cantrell, W. R.; Stephenson, K.; Secrist, J. A.; Weitman, S. Nat. Rev.
Drug Discovery 2006, 5, 855−863.
HPLC tR 10.5 min (method III); [α]20 +15.9 (c 1.0, MeOH).
(2) (a) Wagner, R. W. Nature 1994, 372, 333−335. (b) Xodo, L. E.;
Cogoi, S.; Rapozzi, V. Curr. Pharm. Des. 2004, 10, 805−819. (c) Arenz,
C. Angew. Chem. 2006, 118, 5170−5172; Angew. Chem., Int. Ed. 2006,
D
Optimization of the Hydrogenolytic Deprotection of (S)-23
and (R)-23. Hydrogenolysis reactions described in Table 1 were
carried out as follows. To a solution of (S)-23 or (R)-23 in the listed
solvent (0.125 mL/mg starting material) was added the listed catalyst.
The reaction mixture was stirred under an atmosphere of H2 (1 bar,
balloon) at rt for the listed time. After filtration through a syringe filter
and rinsing of the filter with MeOH (3×), the solvent of the filtrate
was removed under reduced pressure. The resultant products were
45, 5048−5050. (d) De Mesmaeker, A.; Haner, R.; Martin, P.; Moser,
̈
H. E. Acc. Chem. Res. 1995, 28, 366−374. (e) Cobb, A. J. A. Org.
Biomol. Chem. 2007, 5, 3260−3275.
(3) (a) Rothemund, P. W. K. Nature 2006, 440, 297−302.
(b) Feldkamp, U.; Niemeyer, C. M. Angew. Chem. 2006, 118,
1888−1910; Angew. Chem., Int. Ed. 2006, 45, 1856−1876.
(c) Gramlich, P. M. E.; Wirges, C. T.; Manetto, A.; Carell, T.
Angew. Chem. 2008, 120, 8478−8487; Angew. Chem., Int. Ed. 2008, 47,
8350−8358.
1
analyzed by H NMR spectroscopy.
X-ray Structure Determination of (R)-31. A single crystal was
selected from the Schlenk flask under argon atmosphere and covered
with perfluorinated polyether oil on a microscope slide, which was
cooled with a nitrogen gas flow using the X-TEMP 2.30a,b An
appropriate crystal was selected using a polarize microscope, mounted
on the tip of a MiTeGen MicroMount, fixed to a goniometer head and
shock-cooled by the crystal cooling device. The data of (R)-31 were
collected on a Bruker SMART APEXII Quazar diffractometer with D8
goniometer (100 K, Mo Kα radiation, λ = 71.073 pm; mirror
optics).30c The data were integrated with SAINT,30d and an empirical
absorption correction (SADABS) was applied.30e The structure was
solved by direct methods (SHELXS) and refined on F2 using the full-
matrix least-squares methods of SHELXL.30f All non-hydrogen atoms
were refined with anisotropic displacement parameters. The hydrogen
atoms at the nitrogen and oxygen atoms are refined freely using
distance restraints, all carbon bonded hydrogen atoms bonded to sp2
(sp3) carbon atoms were assigned ideal positions and refined using a
riding model with Uiso constrained to 1.2 (1.5) times the Ueq value of
the parent carbon atom. The crystallographic data (excluding structure
factors) have been deposited with the Cambridge Crystallographic
Centre and are available under no. 840892. Copies of the data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(4) (a) Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Science
1991, 254, 1497−1500. (b) Zhilina, Z. V.; Ziemba, A. J.; Ebbinghaus,
S. W. Curr. Top. Med. Chem. 2005, 5, 1119−1131. (c) Karkare, S.;
Bhatnagar, D. Appl. Microbiol. Biotechnol. 2006, 71, 575−586.
(5) (a) Lebreton, J.; De Mesmaeker, A.; Waldner, A.; Fritsch, V.;
Wolf, R. M.; Freier, S. M. Tetrahedron Lett. 1993, 34, 6383−6386.
(b) De Mesmaeker, A.; Waldner, A.; Lebreton, J.; Hoffmann, P.;
Fritsch, V.; Wolf, R. M.; Freier, S. M. Synlett 1993, 733−736. (c) De
Mesmaeker, A.; Waldner, A.; Lebreton, J.; Hoffmann, P.; Fritsch, V.;
Wolf, R. M.; Freier, S. M. Angew. Chem. 1994, 106, 237−240; Angew.
Chem., Int. Ed. 1994, 33, 226−229. (d) Lebreton, J.; Waldner, A.;
Fritsch, V.; Wolf, R. M.; De Mesmaeker, A. Tetrahedron Lett. 1994, 35,
5225−5228. (e) Rozners, E.; Katkevica, D.; Bizdena, E.; Stromberg, R.
J. Am. Chem. Soc. 2003, 125, 12125−12136. (f) Selvam, C.; Thomas,
S.; Abbott, J.; Kennedy, S. D.; Rozners, E. Angew. Chem. 2011, 123,
2116−2118; Angew. Chem., Int. Ed. 2011, 50, 2068−2070.
(6) (a) Dai, N.; Guo, J.; Teo, Y. N.; Kool, E. T. Angew. Chem. 2011,
123, 5211−5215; Angew. Chem., Int. Ed. 2011, 50, 5105−5109.
(b) Niemeyer, C. M. Angew. Chem. 2010, 122, 1220−1238; Angew.
Chem., Int. Ed. 2010, 49, 1200−1216.
(7) (a) Kimura, K.-I.; Bugg, T. D. H. Nat. Prod. Rep. 2003, 20, 252−
273. (b) Winn, M.; Goss, R. J. M.; Kimura, K.-I.; Bugg, T. D. H. Nat.
Prod. Rep. 2010, 27, 279−304.
(8) (a) Struve, W. G.; Neuhaus, F. C. Biochem. Biophys. Res. Commun.
1965, 18, 6−12. (b) Struve, W. G.; Sinha, R. K.; Neuhaus, F. C.;
Prime, M. S. Biochemistry 1966, 5, 82−93. (c) Heydanek, M. G.;
Struve, W. G.; Neuhaus, F. C. Biochemistry 1969, 8, 1214−1221.
(d) Ikeda, M.; Wachi, M.; Jung, H. K.; Ishino, F.; Matsuhashi, M. J.
Bacteriol. 1991, 173, 1021−1025. (e) Boyle, D. S.; Donachie, W. D. J.
Bacteriol. 1998, 180, 6429−6432.
(9) (a) Taubes, G. Science 2008, 321, 356−361. (b) Cooper, M. A.;
Shlaes, D. Nature 2011, 472, 32.
(10) (a) Dini, C. Curr. Top. Med. Chem. 2005, 5, 1221−1236.
(b) Bugg, T. D. H.; Lloyd, A. J.; Roper, D. I. Infect. Disorders Drug
Targets 2006, 6, 85−106.
(11) McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.;
Lotvin, J.; Petersen, P. J.; Siegel, M. M.; Singh, G.; Williamson, R. T. J.
Am. Chem. Soc. 2002, 124, 10260−10261.
(12) Igarashi, M.; Nakagawa, N.; Doi, S.; Hattori, N.; Naganawa, H.;
Hamada, M. J. Antibiot. 2003, 56, 580−583.
(13) Yamashita, A.; Norton, E.; Petersen, P. J.; Rasmussen, B. A.;
Singh, G.; Yang, Y.; Mansour, T. S.; Ho, D. M. Bioorg. Med. Chem. Lett.
2003, 13, 3345−3350.
(14) (a) Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem. 2005,
117, 1888−1890; Angew. Chem., Int. Ed. 2005, 44, 1854−1856.
(b) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2007, 72,
9936−9946. (c) Tanino, T.; Ichikawa, S.; Shiro, M.; Matsuda, A. J. Org.
Chem. 2010, 75, 1366−1377.
(15) (a) Spork, A. P.; Koppermann, S.; Ducho, C. Synlett 2009,
2503−2507. (b) Spork, A. P.; Koppermann, S.; Dittrich, B.; Herbst-
Irmer, R.; Ducho, C. Tetrahedron: Asymmetry 2010, 21, 763−766.
(16) (a) Lin, Y.-I.; Li, Z.; Francisco, G. D.; McDonald, L. A.; Davis,
R. A.; Singh, G.; Yang, Y.; Mansour, T. S. Bioorg. Med. Chem. Lett.
2002, 12, 2341−2344. (b) Tanino, T.; Ichikawa, S.; Al-Dabbagh, B.;
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 19F NMR spectra of all new compounds (including
1
details of the H NOE NMR experiments) and data on the X-
ray crystal structure of (R)-31 including a full-page size thermal
ellipsoid and packing plot. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: christian.ducho@uni-paderborn.de.
■
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (DFG, SFB
803 “Functionality controlled by organization in and between
membranes”) and the Fonds der Chemischen Industrie (FCI,
Sachkostenzuschuss) for financial support. We are also grateful
for support from the Danish National Research Foundation
(DNRF) funded Center of Materials Crystallography (CMC)
(D.S., M.G.). Technical support by Friederike Lizzy is gratefully
acknowledged.
DEDICATION
■
Dedicated to Professor Joachim Thiem on the occasion of his
70th birthday.
REFERENCES
■
(1) (a) De Clercq, E. J. Med. Chem. 2010, 53, 1438−1450. (b) De
Clercq, E. Biochem. Pharmacol. 2011, 82, 99−109. (c) Miura, S.; Izuta,
10097
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098

The Journal of Organic Chemistry
Article
Bouhss, A.; Oyama, H.; Matsuda, A. ACS Med. Chem. Lett. 2010, 1,
258−262.
(17) (a) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2008, 73,
569−577. (b) Hirano, S.; Ichikawa, S.; Matsuda, A. Bioorg. Med. Chem.
2008, 16, 428−436. (c) Hirano, S.; Ichikawa, S.; Matsuda, A. Bioorg.
Med. Chem. 2008, 16, 5123−5133. (d) Ii, K.; Ichikawa, S.; Al-Dabbagh,
B.; Bouhss, A.; Matsuda, A. J. Med. Chem. 2010, 53, 3793−3813.
(18) Spork, A. P.; Ducho, C. Org. Biomol. Chem. 2010, 8, 2323−2326.
(19) Hisamatsu, Y.; Hasada, K.; Amano, F.; Tsubota, Y.; Wasada-
Tsutsui, Y.; Shirai, N.; Ikeda, S.; Odashima, K. Chem.Eur. J. 2006,
12, 7733−7741.
(20) Zhu, X.-F.; Williams, H. J.; Scott, A. I. J. Chem. Soc., Perkin Trans.
1 2000, 2305−2306.
(21) (a) Smith, D. B.; Martin, J. A.; Klumpp, K.; Baker, S. J.;
Blomgren, P. A.; Devos, R.; Granycome, C.; Hang, J.; Hobbs, C. J.;
Jiang, W.-R.; Laxton, C.; Le Pogam, S.; Leveque, V.; Ma, H.; Maile, G.;
Merrett, J. H.; Pichota, A.; Sarma, K.; Smith, M.; Swallow, S.; Symons,
J.; Vesey, D.; Najera, I.; Cammack, N. Bioorg. Med. Chem. Lett. 2007,
17, 2570−2576. (b) Nencka, R.; Sinnaeve, D.; Karalic, I.; Martins, J.
C.; Van Calenbergh, S. Org. Biomol. Chem. 2010, 8, 5234−5246.
(22) (a) Schmidt, U.; Lieberknecht, A.; Schanbacher, U.; Beuttler, T.;
Wild, J. Angew. Chem. 1982, 94, 797−798; Angew. Chem., Int. Ed. 1982,
21, 776−777. (b) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis
1984, 53−60. (c) Schmidt, U.; Wild, J. Liebigs Ann. Chem. 1985,
1882−1894. (d) Hamzavi, R.; Dolle, F.; Tavitian, B.; Dahl, O.;
Nielsen, P. E. Bioconjugate Chem. 2003, 14, 941−954.
(23) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487−490.
(24) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.;
Wienkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946−5952.
(25) Mazurkiewicz, R.; Kuznik, A.; Grymel, M.; Kuznik, N. Magn.
́
́
Reson. Chem. 2005, 43, 36−40.
(26) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518−8519.
(27) (a) Masquelin, T.; Broger, E.; Muller, K.; Schmid, R.; Obrecht,
̈
D. Helv. Chim. Acta 1994, 77, 1395−1411. (b) Ducho, C.; Hamed, R.
B.; Batchelar, E. T.; Sorensen, J. L.; Odell, B.; Schofield, C. J. Org.
Biomol. Chem. 2009, 7, 2770−2779.
(28) Gentle, C. A.; Harrison, S. A.; Inukai, M.; Bugg, T. D. H. J.
Chem. Soc., Perkin Trans 1 1999, 1287−1294.
(29) (a) Sarabia, F.; Martín-Ortiz, L. Tetrahedron 2005, 61, 11850−
11865. (b) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001−3003.
(30) (a) Kottke, T.; Stalke, D. J. Appl. Crystallogr. 1993, 26, 615−619.
(b) Stalke, D. Chem. Soc. Rev. 1998, 27, 171−178. (c) Schulz, T.;
Meindl, K.; Leusser, D.; Stern, D.; Graf, J.; Michaelsen, C.; Ruf, M.;
Sheldrick, G. M.; Stalke, D. J. Appl. Crystallogr. 2009, 42, 885−891.
(d) SAINT v7.68A in Bruker APEX v2011.9, Bruker AXS Inst. Inc.,
Madison, 2008. (e) Sheldrick, G. M. SADABS 2008/2, Gottingen,
̈
2008. (f) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112−122.
(g) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876−881.
(31) (a) Bouhss, A.; Crouvoisier, M.; Blanot, D.; Mengin-Lecreulx,
D. J. Biol. Chem. 2004, 279, 29974−29980. (b) Stachyra, T.; Dini, C.;
Ferrari, P.; Bouhss, A.; van Heijernoort, J.; Mengin-Lecreulx, D.;
Blanot, D.; Biton, J.; Le Beller, D. Antimicrob. Agents Chemother. 2004,
48, 897−902.
10098
dx.doi.org/10.1021/jo201935w | J. Org. Chem. 2011, 76, 10083−10098