Unified Synthesis of Densely Functionalized Amino Acid Building Blocks for the Preparation of Caprazamycin Nucleoside Antibiotics

Article abstract of DOI:10.1002/ejoc.201801667

Naturally occurring caprazamycin nucleoside antibiotics are promising lead structures for the development of novel antimicrobial agents. However, efficient synthetic access to the structurally complex caprazamycin scaffold is not trivial. The stereocontro

Full text of DOI:10.1002/ejoc.201801667

A Journal of
Accepted Article
Title: Unified Synthesis of Densely Functionalized Amino Acid
Building Blocks for the Preparation of Caprazamycin Nucleoside
Antibiotics
Authors: Ruth Linder and Christian Ducho
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801667
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
Unified Synthesis of Densely Functionalized Amino Acid Building
Blocks for the Preparation of Caprazamycin Nucleoside
Antibiotics
Ruth Linder,[a] and Christian Ducho*[a]
Abstract: Naturally occurring caprazamycin nucleoside antibiotics
are promising lead structures for the development of novel
antimicrobial agents. However, efficient synthetic access to the
structurally complex caprazamycin scaffold is not trivial. The
stereocontrolled construction of the seven-membered diazepanone
core moiety is particularly challenging. So far, two main strategies to
build up the diazepanone system (via reductive amination or
Mitsunobu reaction) have been established, but they require different
non-proteinogenic amino acid building blocks to be connected with
the nucleoside moiety. Previously, these amino acid structures were
obtained from different starting materials with no overlap of the
according synthetic routes. In this work, we describe an efficient
unified synthetic access to densely functionalized amino acid
building blocks for both approaches towards the diazepanone core.
This will enable the preparation of caprazamycin analogues with
high modularity and variability.
overexpress the enzyme[7] and assay its activity (and therefore
inhibition) in vitro.[8] Structure-activity relationship (SAR) studies
have been reported for many of the aforementioned sub-classes
of nucleoside antibiotics, among them the muraymycins[9] and
caprazamycins.[10] In the case of caprazamycins, this has
furnished the structurally simplified anti-tuberculotic drug
candidate CPZEN-45.[11] However, the pronounced structural
complexity of nucleoside antibiotics represents a significant
hurdle in such investigations as the total synthesis of
corresponding analogues is not trivial.
Caprazamycins are
a
highly promising sub-class of
nucleoside antibiotics with respect to their activity against M.
tuberculosis. Synthetic access to the caprazamycin scaffold (e.g.,
natural products caprazamycin A 1 and caprazamycin B 2,
Scheme 1) is very challenging though. Both for the synthesis of
the parent natural products and of caprazamycin analogues, the
target structures are usually traced back to a protected version 3
of the nucleoside-peptide core structure (often referred to as
'caprazol'). The preparation of the caprazol unit involves two
major tasks: (i) the synthesis of the uridine-derived, 5'-O-
aminoribosylated nucleosyl amino acid and (ii) the construction
of the substituted diazepanone ring. Several researchers have
developed approaches to overcome these hurdles. Ichikawa and
Matsuda have reported a synthesis of the caprazol unit in which
the diazepanone was formed by reductive amination.[12]
Takemoto has achieved the first total synthesis of caprazamycin
Introduction
Bacterial resistances against established antibiotics are on the
rise and represent a serious threat to human health.[1,2] It is
therefore crucial to develop new antibacterial agents. Ideally,
such compounds should display novel or clinically unexploited
modes of action in order to avoid cross resistance to exisiting
antimicrobial drugs.
A
1 utilizing a Mitsunobu reaction for diazepanone ring
closure.[13] Watanabe and Shibasaki have developed a total
synthesis of caprazamycin B 2 which involved a reductive
amination protocol for construction of the diazepanone.[14] Other
Nucleoside antibiotics are such
a class of potential
antibacterial drug candidates.[3] They are naturally occurring
uridine derivatives inhibiting the bacterial membrane enzyme
MraY (translocase I), which catalyzes a key step in the early
intracellular stages of cell wall (i.e., peptidoglycan) formation.[4]
Thus, such MraY inhibitors fulfill the paradigm to address a
clinically unexploited bacterial target.[5]
noteworthy contributions include Sarabia's synthesis of
a
6'-epimer of the caprazol unit via a Rh(II)-catalyzed carbene
insertion key step[15] and Miyaoka's preparation of a caprazol
5'-epimer by intramolecular nucleophilic epoxide opening.[16]
Taken together, the most promising strategies for the
construction of the substituted diazepanone ring system appear
to be intramolecular reductive amination or Mitsunobu-type
nucleophilic displacement. Thus, corresponding precursors of
key intermediate 3 would be either aldehyde 4 or primary alcohol
5 (Scheme 1). For their syntheses, non-proteinogenic amino
acid building blocks 6 and 7, respectively, are required, with the
olefin in 6 serving as a 'masking' unit for the reactive aldehyde
moiety. Overall, the aforementioned literature on caprazamycin
syntheses[12-16] strongly suggest that even subtle structural
changes significantly influence the outcome of the diazepanone-
forming reactions. For instance, when Sarabia aimed for a
6'-epimer of the caprazol core structure, ring closure of the
diazepanone by nucleophilic epoxide opening or by Mitsunobu
reaction failed.[15] On the other hand, Mitsunobu-type
Nucleoside antibiotics have been grouped into several sub-
classes, e.g., muraymycins, caprazamycins, liposidomycins,
mureidomycins, pacidamycins, sansanmycins, capuramycins,
and tunicamycins.[3] Using these natural product scaffolds for
antibacterial drug development is facilitated by recently reported
X-ray crystal structures of MraY[6] as well as efficient methods to
[a]
R. Linder, Prof. Dr. C. Ducho
Department of Pharmacy, Pharmaceutical and Medicinal Chemistry
Saarland University
Campus C2 3, 66123 Saarbrücken (Germany)
E-mail: christian.ducho@uni-saarland.de
Homepage: www.ducholab.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
Scheme 1. Selected examples 1 and 2 of naturally occurring caprazamycin nucleoside antibiotics as well as their retrosynthesis leading to non-proteinogenic
amino acid building blocks 6 and 7 (boxed) as principle target structures of this study. PG1-PG5 = protecting groups.
diazepanone formation was successfully employed in
Takemoto's total synthesis of caprazamycin A1 1.[13] It should be
noted that the substrates for the Mitsunobu transformation in
both aforementioned cases differed not only in the
stereochemistry at C-6', but also in their protecting group and
subsitution patterns. In stark contrast to Sarabia's results,
was prepared starting from a derivative of the (R)-Garner
aldehyde and therefore ultimately from D-serine.[21] Overall,
these synthetic routes towards building blocks 6 and 7 are very
diverse and show little to no overlap.
In this work, we have therefore aimed to develop a unified
synthesis of densely functionalized, non-proteinogenic amino
acids of both principle types 6 and 7. Our goals were as follows:
(i) both amino acid structures should be accessible from one
shared precursor or a small set of precursors, respectively;
(ii) the diversification towards 6 or 7 should occur at a rather late
stage; (iii) different protecting group patterns should be
accessible; (iv) the unified route should also enable the
synthesis of stereoisomers of 6 and 7, respectively. Taken
together, these considerations were envisioned to furnish a
small set of amino acid building blocks for a maximum of
strategic and structural flexibility in the future preparation of
caprazamycins and their analogues.
Miyaoka's synthesis of
a caprazol 5'-epimer successfully
proceeded via intramolecular nucleophilic epoxide opening.[16]
Again, the ring closure precursors in both cases differed in more
than just their stereochemical configurations.
This review of the available literature on caprazamycin
syntheses demonstrates that detailed SAR studies on
caprazamycins and their analogues require strategic flexibility in
the synthetic routes to diverse target structures. Hence, different
amino acid precursors of types 6 or 7 should ideally be available
from a small set of shared precursors, thus enabling a rapid
switching between different syntheses of
3 (Scheme 1).
However, browsing available syntheses of caprazamycins and
their analogues[12-16] reveals that amino acid building blocks of
types 6 or 7 were obtained via totally different routes and from
different precursors. Ichikawa and Matsuda prepared an amino
acid of type 6 or a reduced variant thereof starting from a
derivative of the (R)-configured Garner aldehyde[17] and
therefore, ultimately, from D-serine.[10c,12,18] In contrast,
Takemoto obtained a building block of type 7 from L-diethyl
tartrate.[13] Watanabe and Shibasaki chose a different route
towards an analogue of 6 as they employed a catalytic
enantioselective nitroaldol reaction.[14b] Thus, they constructed
the stereocenters in 6 not via an ex-chiral pool-type strategy, but
by stereoselective catalysis. In his comparative synthetic studies
towards 6'-epi-caprazol,[15] Sarabia used analogues of 6 and 7
Results and Discussion
In order to develop the desired unified synthetic route, we
decided to transform D-serine 8 into the (R)-configured Garner
aldehyde 9, according to established protocols (Scheme 2).[17]
Chiral aldehyde 9 appeared to be an ideal candidate for the
envisioned shared precursor en route to 6 and 7 for the following
reasons: (i) it had already been proven useful in the works of
Ichikawa and Matsuda[12] as well as Miyaoka[16] (vide supra);
(ii) switching from D-serine to L-serine as starting material would
readily enable the synthesis of enantiomeric target structures,
thus ultimately providing access to stereochemically altered
caprazamycin analogues; (iii) addition reactions to the Garner
aldehyde can differ in diastereoselectivities,[22] which might
furnish either syn- or anti-configured products, finally providing
obtained
from
L-methionine[19]
and
via
Sharpless
aminohydroxylation,[20] respectively. In the synthesis of 5'-epi-
caprazol,[16] Miyaoka required a -amino analogue of 7, which
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
,-syn or ,-anti -hydroxy--amino acids. In this context, it
should be noted that ,-anti-configured building blocks of types
6 and 7 lead to caprazamycins with native stereochemistry (see
Scheme 1), while an ,-syn-configuration would furnish
epimeric caprazamycin analogues.
overall yield (d.r. 7:1), as a result of spontaneous ring closure
after deprotonation of the alcohol with sodium hydride (Scheme
3). Using this diastereomeric mixture of 11, the cis and trans
configurations of the oxazolidinone moieties in (S)-11 and (R)-11,
1
respectively, were proven by 1D NOE H NMR studies. The two
protons attached to the oxazolidinone ring in the minor trans
isomer (R)-11 showed
a very weak NOE, whereas cis-
configured (S)-11 as the major component gave a strong NOE.
In addition, 10a (a fraction with d.r. 3:2) was acidically
deprotected to afford diol 12 in 67% yield (d.r. 9:1). Subsequent
acetal formation then furnished 1,3-dioxane 13 in 58% yield (d.r.
19:1). The six-membered ring in 13 was ideally suited to assign
relative configurations based on 1H NMR coupling constants.
Rigorous NMR analysis of 13 revealed the major diastereomer
to be (S)-configured at the stereocenter in question. Taken
together, it was therefore unambiguously proven that, as
anticipated, the major diastereomer formed in the Grignard
addition step was the anti-configured (*S) Felkin-Anh product.
Scheme 2. Synthesis of differently protected amino alcohols 10a-c as shared
set of precursors.
The addition of vinyl magnesium bromide to 9 gave allylic
alcohol 10a[10c,12,18] in 76% yield in a non-stereocontrolled
manner (Scheme 2). The further synthetic processing of 10a
required protection of the hydroxy group. Hence, 10a was
silylated to give TPDPS derivative 10b in 77% yield and TIPS-
protected congener 10c in 91% yield, respectively. We prepared
both O-protected derivatives because of the different stabilities
of the silyl ether moieties and in order to pave the way for target
structures with different protecting group patterns. Allylic
alcohols 10a-c already contained the vicinal amino alcohol motif
found in 6 and 7 and can therefore be considered to be the
envisioned small set of shared precursors for both target
structures.
Scheme 3. Synthesis of bicyclic carbamates 11 and 1,3-dioxane 13 for the
NMR-based stereochemical elucidation of 10a. CSA = camphorsulfonic acid.
The diastereoselectivity of the Grignard addition to 9 was
rather low, with 10a being isolated as a diastereomeric mixture
(d.r. 3:1, Scheme 2). In principle, this would provide the desired
flexibility to prepare all possible stereoisomers of the target
structures after separation of the diastereomeric mixtures.
However, the separation of the obtained epimeric mixture of 10a
was tedious, and consequently, it was envisioned to separate
the diastereomers at later stages of the synthetic routes.
The synthetic route was continued with silylated Grignard
addition products 10b and 10c. Acidic cleavage of the
isopropylidene acetal in TBDPS-protected 10b gave amino
alcohol 14a in 94% yield without significant change of
diastereomeric purity (d.r. 3:1, Scheme 4). This was followed by
N-nosyl protection with para-nitrobenzenesulfonyl chloride
(product 15a) in 92% yield, with slight enrichment of the major
(*S)-isomer after purification (d.r. 4:1). Remarkably, this
procedure was not fully applicable for the TIPS-protected
congener 10c. The corresponding intermediate 14b was instable
and had to be protected immediately (without purification) with
the pNs group. Consequently, a yield of only 34% over two steps
was obtained for TIPS-protected 15b. We also explored other
commonly used methods for cleavage of the acetonide unit in
10c, such as acetyl chloride or TFA, but none of them led to
improved yields.
Based on precedent,[22] it was postulated that the major
diastereomer of the epimeric mixture of 10a would be the anti-
configured (*S) Felkin-Anh product, which would correspond to
the anti-stereochemistry in target structures 6 and 7. In order to
ensure that this proposed assignment was correct, we
transformed the diastereomeric mixture of 10a into cyclic
analogues. This was expected to enable the elucidation of
relative configurations based on nuclear Overhauser
enhancement (NOE) NMR experiments or 1H NMR coupling
constants. Therefore, 10a (a diastereomerically enriched fraction
with d.r. 4:1) was converted into bicyclic carbamates 11 in 38%
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
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conditions, no protection of the primary hydroxy group was
needed. Finally, a two-step protocol of oxidation (using TEMPO
and bis-(acetoxy)-iodobenzene) with subsequent tert-butyl ester
formation using a trichloroacetimidate afforded amino acids 17a
and 17b in yields of 87% and 51%, respectively, over both steps
of this sequence.
Protected amino acids 17a and 17b were then utilized as
shared precursors for the synthesis of five different target amino
acid building blocks. First, amino deprotection of 17a (a fraction
with d.r. 3:1) was performed with thiophenol in the presence of
potassium carbonate (Scheme 5). For the resultant product,
diasteromers could be separated by column chromatography,
thus affording (S)-18 and (R)-18 in diastereomerically pure form
and in yields of 58% and 21%, respectively. These two pure
stereoisomers of 18 represented the first target structures as
they were representatives of amino acids of type 6 (see Scheme
1). Second, both silylated precursors 17a (a fraction with d.r.
3:1) and 17b (a fraction with d.r. 5:6) were subjected to
ozonolysis to cleave the olefin moieties. Resultant crude
aldehydes 19a and 19b (each as epimeric mixtures) were
directly converted in the next step. In the case of TIPS-protected
19b, reduction of the aldehyde gave the corresponding primary
alcohol. At this stage, diastereomers could be separated by
column chromatography to furnish (S)-20 and (R)-20 in
diastereomerically pure form and in yields of 32% and 30%,
respectively, over two steps. Amino deprotection under the
aforementioned conditions then gave amino acid building blocks
(S)-21 and (R)-21 in yields of 68% and 22%, respectively
(Scheme 5). These two pure stereoisomers of 21 represented
another stereoisomeric couple of target structures as they were
representatives of amino acids of type 7 (see Scheme 1).
Scheme 4. Synthesis of protected amino acids 17a,b as shared precursors of
the target structures. pNs = para-nitrobenzenesulfonyl.
The subsequent N-methylation step turned out to be
challenging. Initial attempts using the conditions reported by
Ichikawa and Matsuda (methyl iodide, sodium hydride, DMF)[10c]
were unsuccessful. We initially explored several variations of the
protecting group pattern, including N-trichloroethoxycarbonyl
(Troc) in combination with O-dimethoxytrityl (DMTr), as well as
different methylating reagents (i.e., dimethyl sulfate), but no
reaction was observed. This was not overcome when the
protecting group pattern was further changed to N-Cbz and
O-TBDMS (reactions not shown). However, the nosyl derivatives
15a and 15b were sufficiently reactive when methyl iodide was
applied in the presence of cesium carbonate, thus furnishing 16a
in 89% yield and 16b in 77% yield (Scheme 4). Under these
Remarkably, when a similar sequence was attempted with
TBDPS-protected congener 19a, the reduction step led to a
migration of the TBDPS group onto the primary alcohol, thus
affording 22 in 56% yield over two steps (d.r. 7:3, Scheme 5).
We initially tried to reprotect the secondary alcohol with different
silyl protecting groups which was unsuccessful, probably due to
Scheme 5. Synthesis of amino acid target structures 18, 21 and (R)-24 (boxed).
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
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steric hindrance. However, acetylation of the hydroxy group was
feasible and gave 23 in 85% yield (d.r. 7:3). When a fraction of
this material (with d.r. 6:1) was subjected to amino deprotection,
only one stereoisomer (R)-24 was isolated in 52% yield. With
respect to its amount, this diastereomer had to be equivalent to
the major component of the precursor mixtures, i.e., it had to be
a derivative of the anti-configured Grignard addition product.
Due to altered priorities, this relative configuration corresponded
to a formal (3R)-stereochemistry in derivative 24. Amino acid 24
We have also considered alternative options for the
'masking' of the aldehyde moiety when reductive amination
strategies are employed for diazepanone formation. In amino
acid building blocks of type 6, the aldehyde unit is masked as an
olefin and therefore needs to be formed oxidatively, e.g., by bis-
hydroxylation/periodate cleavage sequences.[12] However, such
oxidative transformations might cause severe side reactions
when applied to the densely functionalized caprazamycin
scaffold. Therefore, alternative options for formation of the
aldehyde moiety in caprazamycin syntheses are desirable. We
managed to separate the diastereomeric mixture of TIPS-
protected aldehyde 19b (which had just been used as a crude
synthetic intermediate before, see Scheme 5) by column
chromatography (not shown). Resultant isomers (S)-19b and
(R)-19b were then transformed in dimethyl acetal-forming
reactions, furnishing (S)-27 and (R)-27 in diastereomerically
pure form and in yields of 42% and 93%, respectively (Scheme
6). The moderate yield of isomer (S)-27 resulted from an
obvious side reaction that was not observed for (R)-27, i.e.,
unwanted cleavage of the tert-butyl ester and subsequent ring
closure of the acid with the aldehyde (not shown). Finally, amino
deprotection gave (S)-28 and (R)-28 in diastereomerically pure
form and in yields of 86% and 69%, respectively, as additional
target structures. When 28 is employed for the synthesis of the
diazepanone caprazamycin core, very mild acidic conditions are
anticipated to selectively cleave the dimethyl acetal moiety, thus
liberating the aldehyde for subsequent ring closure by reductive
amination. Hence, amino acid building blocks 28 can be
classified as novel functional equivalents to amino acids of type
6 (see Scheme 1).
also represented
a target structure as it was another
representative of amino acids of type 7 (see Scheme 1).
Building blocks 21 were not protected at the primary alcohol
functionality, assuming that subsequent peptide coupling
reactions for caprazamycin syntheses would proceed selectively
at the secondary amine. However, it was envisioned that the
synthetic route shown in Scheme 5 would enable the facile
introduction of an additional protecting group for the primary
alcohol. This was demonstrated by DMTr protection of the
hydroxy functionality. Starting from synthetic intermediates
(S)-20 and (R)-20, DMTr protection afforded (S)-25 and (R)-25
in diastereomerically pure form and in yields of 40% and 85%,
respectively (Scheme 6). Subsequent amino deprotection gave
two pure stereoisomers (S)-26 (48% yield) and (R)-26 (82%
yield) as additional target structures representing amino acids of
type 7 (see Scheme 1). When either diasteromer of 26 is
employed for the synthesis of the diazepanone caprazamycin
core, very mild acidic conditions are anticipated to selectively
cleave the DMTr group, thus liberating the primary alcohol for
Mitsunobu-type ring closure.
Conclusions
In summary, we have accomplished a unified synthesis of five
different densely functionalized amino acid target compounds
(see boxed structures in Schemes 5 and 6). Starting from
D-serine 8 and via the (R)-Garner aldehyde 9, amino alcohols
10a-c were synthesized as a small set of shared precursors.
These were then transformed into two amino acid precursors
17a and 17b. Further conversions of these key intermediates
afforded the following target compounds: (i) 18 and 28 as
representatives or functional analogues, respectively, of amino
acid building blocks of type 6; (ii) 21, (R)-24 and 26 as
representatives of amino acid building blocks of type 7 (also see
Scheme 1). With the exception of (R)-24, all of these amino acid
target structures were obtained both with anti-configuration of
the amino alcohol motif (equivalent to native caprazamycin
structures) and as syn-configured congeners (equivalent to
epimeric caprazamycin analogues), each in diastereomerically
pure form. Stereochemical purity was efficiently achieved by
chromatographic separations at late stages of the synthetic
routes.
Overall, the reported unified synthetic strategy fulfilled the
outlined goals (vide supra): (i) both amino acid structures of
types 6 and 7 were accessible from one shared precursor (8/9)
or a small set of precursors (10a-c/17a,b), respectively; (ii) the
Scheme 6. Synthesis of amino acid target structures 26 and 28 (boxed).
DMTr = 4,4'-dimethoxytrityl.
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
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the minor component is labeled with an asterisk. Low resolution ESI
mass spectrometry was performed on a Thermo Scientific Spectra
diversification towards 6 or 7 occured at a rather late stage, i.e.,
after the synthesis of 17a,b; (iii) similar target structures with
different protecting group patterns were prepared; (iv) the unified
route also enabled the synthesis of stereoisomers of 6 and 7,
respectively. It should be noted that, when L-serine is employed
as a general starting material, all enantiomers of the target
structures are in principle accessible as well. Therefore, the
reported route provides facile access to all stereochemical
variations of the corresponding structural motif in caprazamycins.
The different protecting group patterns of the target
compounds and the two different approaches of 'masking' the
reactive aldehyde (olefin vs. dimethyl acetal) will provide
maximum flexibility in the non-trivial construction of the
caprazamycin diazepanone core. In combination with the strong
potential for stereochemical variations, the reported set of target
amino acids (accessed via a unified route) therefore represents
System with
a Finnigan ion-trap mass spectrometer MSQ. High
resolution (HR) ESI mass spectrometry was carried out on a Bruker time-
of-flight (TOF) maXis. Optical rotations were recorded on a Krüss
Optronic Germany polarimeter with a Na source using a 5 cm cell.
Infrared spectroscopy (IR) was performed on
a Bruker Vertex 70
spectrometer equipped with an integrated ATR unit (PlatinumATRTM).
Wavenumbers () are quoted in cm-1. UV spectroscopy was carried out
on an Agilent Cary 100 spectrophotometer. Wavelengths of maximum
absorption (max) are reported in nm.
General procedure (GP) for cleavage of the pNs protecting group: A
solution of the protected amine and K2CO3 (3.0 eq) in dry DMF was
stirred at rt for 5 min. Thiophenol (1.2 eq) was added and the solution
was stirred at rt. After complete conversion, sat. NaHCO3 solution was
added and the mixture was extracted with EtOAc (3 x). The combined
organics were washed with water (2 x) and brine, dried over Na2SO4 and
the solvent was evaporated under reduced pressure. The resultant crude
product was purified by column chromatography.
a
highly useful 'toolbox' for the future synthesis of
caprazamycins and their analogues for more detailed SAR
studies. It should be noted that -hydroxy--amino acids are
ubiquitous structural motifs that are frequently found in many
peptidic natural products. Therefore, our reported 'toolbox' might
also be very versatile for the total synthesis of other peptide-
derived target structures.
(N-Boc-(4R,1'SR)-4-(1'-(tert-butyldiphenylsilyloxy)-2'-propenyl)-2,2-
dimethyl-1,3-oxazolidine (10b): To a solution of 10a[10c,12,18] (686 mg,
2.67 mmol, d.r. 3:1) in dry DMF (10 mL), imidazole (725 mg, 10.7 mmol)
followed 15 min later by TBDPS chloride (2.10 mL, 2.20 g, 8.00 mmol)
were added and the mixture was stirred at rt for 4 h. Water (30 mL) and
EtOAc (30 mL) were added. The organic layer was washed with water
(2 x 30 mL) and brine (90 mL) and dried over Na2SO4. The solvent was
evaporated under reduced pressure and the resultant crude product was
purified by column chromatography (petroleum ether-EtOAc, 15:1) to
give 10b as a brownish oil (1.01 g, 77%, d.r. 3:1). 1H NMR (500 MHz,
CDCl3):  = 1.06-1.11 (m, 9H, SiC(CH3)3, SiC(CH3)3*), 1.40-1.56 (m, 15H,
C(CH3)2, C(CH3)3, C(CH3)2*, C(CH3)3*), 3.87-4.21 (m, 3H, H-4, H-4*, H-5,
H-5*), 4.24-4.41 (m, 0.75H, H-1'), 4.61-4.71 (m, 0.25H, H-1'*), 4.66 (dd,
J = 17.4, 8.4 Hz, 0.75H, H-3'a), 4.78 (dd, J = 19.0, 8.4 Hz, 0.75H, H-3'b),
4.92-5.13 (m, 0.5H, H-3'*), 5.63-5.81 (m, 0.75H, H-2'), 8.81-5.94 (m,
0.25H, H-2'*), 7.32-7.49 (m, 6H, Ph), 7.62-7.74 (m, 4H, Ph) ppm.
Experimental Section
General Methods: Chemicals were purchased from standard suppliers
and used without further purification. Ozone was generated using a
Fischer ozone generator model 502. Reactions involving oxygen and/or
moisture sensitive reagents were carried out under an atmosphere of
nitrogen using anhydrous solvents. The glass equipment used for these
reactions was dried by heating prior to use. Anhydrous solvents were
obtained in the following manner: CH2Cl2 and DMF were purchased in
HPLC quality, dried with a solvent purification system (MBRAUN MB
SPS 800) and stored over activated molecular sieves (4 Å). Pyridine was
dried over CaH2 and distilled. MeOH was of absolute quality, degassed
and stored over activated molecular sieves (3 Å). Solvents for reactions
without inert conditions, extractions, and chromatography were of
technical quality and distilled prior to their use. All other solvents were of
p.a. quality, and distilled water was used throughout. Column
chromatography was carried out on silica gel 60 (0.040-0.063 mm, 230-
400 mesh ASTM, VWR) under flash conditions. TLC was performed on
aluminium plates precoated with silica gel 60 F254 (VWR). Visualization of
the spots was carried out using UV light (254 nm) where appropriate
and/or staining under heating (KMnO4 staining solution: 1 g KMnO4, 6 g
K2CO3 and 1.5 mL 5% NaOHaq (w/v), all dissolved in 100 mL H2O;
ninhydrin staining solution: 0.3 g ninhydrin, 3 mL AcOH, all dissolved in
100 mL 1-butanol, H2SO4 staining solution: 4 g vanillin, 25 mL conc.
H2SO4, 80 mL AcOH, all dissolved in 680 mL MeOH). Preparative TLC
was performed on a Chromatotron (Harrison Research, Model 7924T-01,
T-Squared Technology) using glass plates coated with 1 mm or 2 mm
layers of silica gel containing a fluorescent indicator (VWR 60 PF254).
500 MHz-1H NMR and 126 MHz-13C NMR spectra were recorded on
Bruker AVANCE-500 spectrometers. All 13C NMR spectra are 1H-
decoupled. All spectra were recorded at room temperature except where
indicated otherwise and were referenced internally to solvent reference
frequencies. Chemical shifts () are quoted in ppm. Coupling constants
(J) are reported in Hz to the nearest 0.1 Hz. The assignment of signals
was carried out using 1H,1H-COSY and HSQC spectra obtained on the
spectrometers mentioned above. In the case of diastereomeric mixtures,
13C NMR (126 MHz, CDCl3):
 = 19.42 (SiC(CH3)3), 23.15, 24.81
(C(CH3)2), (C(CH3)2*), 27.00, 27.10 (SiC(CH3)3, SiC(CH3)3*), 28.32, 28.39
(C(CH3)3, C(CH3)3*), 60.52 (C-5*), 61.89 (C-5), 63.42 (C-4*), 64.59 (C-4),
73.61 (C-1'*), 76.19 (C-1'), 79.69 (C(CH3)3), 79.95 (C(CH3)3*), 93.76
(C(CH3)2), 94.27 (C(CH3)2*), 116.65 (C-3'), 117.30 (C-3'*), 127.36,
127.43, 127.59, 129.45, 129.55, 133.86, 135.58, 135.81 (Ph), 136.24
(C-2'*), 138.22 (C-2'), 152.14, 152.82 (NHC=O, NHC=O*) ppm. MS
(ESI): m/z = 518.1 [M+Na]+. HRMS (ESI): calcd. for C29H41NO4Si [M+H]+
496.2878; found 496.2896. TLC (petroleum ether-EtOAc, 5:1): Rf = 0.65.
(N-Boc-(4R,1'SR)-4-(1'-(triisopropylsilyloxy)-2'-propenyl)-2,2-
dimethyl-1,3-oxazolidine (10c): To a solution of 10a (3.23 g, 12.6 mmol,
d.r. 3:2) in dry CH2Cl2 (10 mL), 2,6-lutidine (1.81 mL, 1.67 g, 16.3 mmol)
and TIPS triflate (4.40 mL, 5.00 g, 16.3 mmol) were added at 0 °C and
the mixture was stirred at 0 °C for 80 min. HCl (1 M, 75 mL) was added
and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The
combined organics were washed with brine (100 mL) and dried over
Na2SO4. The solvent was evaporated under reduced pressure and the
resultant crude product was purified by column chromatography
(petroleum ether-EtOAc, 50:11:1) to give 10c (4.70 g, 91%, d.r. 3:2) as
a colorless oil. 1H NMR (500 MHz, [D6]DMSO, 100 °C):  = 0.92-1.11 (m,
21H, 3 x CH(CH3)2), 1.38-1.52 (m, 15H, C(CH3)3, C(CH3)2), 3.74-3.80 (m,
0.4H, H-4*), 3.87-4.07 (m, 2.6H, H-4, H-5, H-5*), 4.47-4.54 (m, 0.4H,
H-1'*), 4.69-4.77 (m, 0.6H, H-1'), 5.09-5.22 (m, 2H, H-3', H-3'*), 5.77-5.89
(m, 1H, H-2', H-2'*) ppm. 13C NMR (126 MHz, [D6]DMSO, 100 °C):  =
12.40, 12.78 (C(CH3)2), 18.25, 28.55 (C(CH3)2), 28.66 (C(CH3)3), 61.27
(C-4), 62.53 (C-5), 63.01 (C-4*), 63.91 (C-5*), 72.27 (C-1'), 74.42 (C-1'*),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
79.73, 79.92 (C(CH3)3, C(CH3)3*), 94.06 (C(CH3)2), 97.16 (C(CH3)2*),
116.52 (C-3'), 116.93 (C-3'*), 137.70 (C-2'), 140.10 (C-2'*) ppm. MS
(ESI): m/z = 436.2 [M+Na]+. HRMS (ESI): calcd. for C22H43NO4Si [M+H]+
414.3034; found 414.3029. TLC (petroleum ether-EtOAc, 7:3): Rf = 0.64.
(2R,3SR)-2-Amino-3-((tert-butyldiphenylsilyl)oxy)pent-4-en-1-ol
(14a): HCl (5 M, 1.57 mL, 7.87 mmol) was added to a solution of 10b
(975 mg, 1.97 mmol, d.r. 3:1) in THF (5 mL), and the mixture was stirred
under reflux for 3 h. CH2Cl2 (10 mL) and MeOH (10 mL) were added and
the aqueous layer was brought to pH 2 by addition of 5% NaOH. After
extraction with EtOAc (3 x 20 mL), the combined organics were dried
over Na2SO4 and the solvent was evaporated under reduced pressure.
The resultant crude product was purified by column chromatography
(CH2Cl2-MeOH, 99:1) to give 14a as a brownish oil (660 mg, 94%, d.r.
3:1). 1H NMR (500 MHz, CDCl3):  = 0.94 (s, 9H, C(CH3)3, C(CH3)3*),
2.59-2.87 (m, 3H, H-2, NH2, NH2*), 3.22-3.61 (m, 3H, H-1, OH, OH*),
3.97-4.06 (m, 1H, H-3, H-3*), 4.75-4.98 (m, 2H, H-5, H-5*), 5.56-5.71 (m,
1H, H-4, H-4*), 7.19-7.33 (m, 6H, Ph, Ph*), 7.46-7.55 (m, 4H, Ph, Ph*)
ppm. 13C NMR (126 MHz, CDCl3):  = 19.35 (C(CH3)3, C(CH3)3*), 27.03
(C(CH3)3, C(CH3)3*), 57.44 (C-2*), 57.54 (C-2), 62.42 (C-1), 62.73 (C-1*),
76.31 (C-3, C-3*), 117.83 (C-5*), 118.19 (C-5), 127.47, 127.72, 129.74,
129.91, 133.36, 133.42, 135.84, 135.88 (Ph), 136.34 (C-4), 136.97 (C-4*)
ppm. MS (ESI): m/z = 356.1 [M+H]+. HRMS (ESI): calcd. for C21H29NO2Si
[M+Na]+ 378.1860; found 378.1846. TLC (CH2Cl2-MeOH, 5:1): Rf = 0.31.
(7aR)-5,5-Dimethyl-(1SR)-vinyldihydro-1H,3H,5H-oxazolo[3,4-
c]oxazol-3-one (11): To a solution of 10a[10c,12,18] (100 mg, 0.389 mmol,
d.r. 4:1) in dry DMF (5 mL), NaH (60% dispersion in mineral oil, 19.0 mg,
0.467 mmol) was added at 0 °C and the mixture was stirred at 0 °C for
10 h and at rt for 13 h. Water (10 mL) was added and the aqueous layer
was extracted with EtOAc (2 x 10 mL). The combined organics were
dried over Na2SO4. The solvent was evaporated under reduced pressure
and the resultant crude product was purified by column chromatography
(petroleum ether-EtOAc, 6:1) to give 11 as a colorless oil (27 mg, 38%,
d.r. 7:1). 1H NMR (500 MHz, C6D6):  = 1.32 (s, 0.4H, C(CH3)2*), 1.37 (s,
2.6H, C(CH3)2), 1.86 (s, 2.6H, C(CH3)2), 1.88 (s, 0.4H, C(CH3)2*), 3.13-
3.19 (m, 0.1H, H-7a*), 3.37 (d, J = 7.4, 1.8 H, H-7), 3.48-3.53 (m, 0.2H,
H-7a*, H-7b*), 3.61 (dd, J = 16.1, 8.1 Hz, 0.9H, H-7a), 4.10-4.14 (m, 0.1H,
H-1*), 4.40-4.43 (m, 0.9H, H-1), 4.96-5.01 (m, 1H, H-2'a, H-2'a*), 5.14 (dt,
J = 17.1, 1.1 Hz, 0.1H, H-2'b*), 5.20-5.32 (m, 1.8H, H-1', H-2'b), 5.53 (ddd,
J = 17.1, 10.5, 6.6 Hz, 0.1H, H-1'*) ppm. 13C NMR (126 MHz, C6D6):  =
23.43(C(CH3)2), 23.47 (C(CH3)2*), 27.41(C(CH3)2*), 27.86 (C(CH3)2),
60.97 (C-7a), 63.63 (C-7a*), 64.00 (C-7), 67.4 (C-7*), 74.17 (C-1), 78.21
(C-1*), 94.77 (C-5), 94.80 (C-5*), 118.06 (C-2'*), 118.33 (C-2'), 131.34
(C-1'), 134.86 (C-1'*), 156.26 (C=O) ppm. MS (ESI): m/z = 184.1 [M+H]+.
HRMS (ESI): calcd. for C9H13NO3 [M+H]+ 183.0968; found 183.0968.
TLC (petroleum ether-EtOAc, 3:2): Rf = 0.36.
(2R,3SR)-2-Amino-3-((triisopropylsilyloxy)-pent-4-en-1-ol (14b): HCl
(5 M, 2.70 mL, 13.5 mmol) was added to a solution of 10c (1.40 g,
3.38 mmol, d.r. 3:2) in THF (25 mL), and the mixture was stirred under
reflux for 4.5 h. The solution was cooled to rt and the solvent was
evaporated under reduced pressure. The resultant crude 14b (990 mg)
was used without further purification. With respect to the limited stability
of the crude product, it was prepared freshly and directly used in the
subsequent reaction. 1H NMR (500 MHz, C6D6):  = 1.11-1.23 (m, 21H,
CH(CH3)2, CH(CH3)2*), 2.85 (ddd, J = 9.7, 7.3, 5.1 Hz, 0.85H, H-2), 2.94
(ddd, J = 9.5, 7.1, 4.7 Hz, 0.15H, H-2*), 3.55 (dd, J = 9.7, 7.3 Hz, 0.85H,
H-1a), 3.61 (dd, J = 10.5, 7.1 Hz, 0.15H, H-1*a), 3.70-3.77 (m, 1H, H-1b,
H-1*b), 4.20-4.27 (m, 1H, H-3, H-3*), 5.04-5.21 (m, 2H, H-5, H-5*), 5.71-
5.86 (m, 1H, H-4, H-4*) ppm. 13C NMR (126 MHz, C6D6):  = 11.35
(CH(CH3)2*), 11.41 (CH(CH3)2), 16.92 (CH(CH3)2), 16.95 (CH(CH3)2*),
56.79 (C-2), 56.95 (C-2*), 61.87 (C-1*), 62.13 (C-1), 75.23 (C-3*), 75.40
(C-3), 114.99 (C-5), 115.34 (C-5*), 137.12 (C-4*), 137.84 (C-4) ppm.
N-Boc-(2R,3SR)-2-amino-pent-4-en-1,3-diol (12): A solution of 10a
(105 mg, 0.408 mmol, d.r. 3:2) in acetic acid (3 mL) and water (0.5 mL)
was stirred at rt for 1.5 d. The solvent was evaporated under reduced
pressure and the resultant crude product was purified by column
chromatography (petroleum ether-EtOAc, 2:1) to give 12 as a brownish
oil (59 mg, 67%, d.r. 9:1). 1H NMR (500 MHz, [D6]DMSO, 100 °C):  =
1.37 (s, 9H, C(CH3)3*, C(CH3)3), 3.34-3.52 (m, 3H, H-1*, H-1, OH, OH*),
3.89-3.98 (m, 0.9H, H-3), 4.11-4.19 (m, 0.1H, H-3*), 4.36-4.48 (m, 0.9H,
OH), 4.54-4.60 (m, 0.1H, OH*), 4.74-4.81 (m, 0.1H, H-2*), 4.85-4.93 (m,
0.9H, H-2), 5.00-5.08 (m, 1H, H-5a*, H-5a), 5.12-5.24 (m, 1H, H-5b*, H-5b),
5.76-5.90 (m, 1H, H-4*, H-4), 6.01 (d, J = 7.5 Hz, 0.1H, NH*), 6.27 (d,
J = 8.4 Hz, 0.9H, NH). TLC (petroleum ether-EtOAc, 1:2): Rf = 0.18.
N-((2R,3SR)-3-((tert-butyldiphenylsilyl)oxy)-1-hydroxypent-4-en-2-
yl)-4'-nitrobenzenesulfonamide (15a): To a solution of 14a (1.75 g,
4.91 mmol, d.r. 3:1) in CH2Cl2 (25 mL) at 0 °C, DIPEA (1.09 mL, 825 mg,
6.38 mmol) and after 10 min pNsCl (1.14 g, 5.16 mmol) were added. The
mixture was stirred at 0 °C for 1 h and was then quenched by the
addition of HCl (1 M, 20 mL). The organic layer was washed with HCl
(1 M, 2 x 20 mL) and brine and dried over Na2SO4. The solvent was
evaporated under reduced pressure to give 15a (2.44 g, 92%, d.r. 4:1).
1H NMR (500 MHz, C6D6):  = 1.18 (s, 8.1H, C(CH3)3), 1.20 (s, 0.9H,
C(CH3)3*), 3.36-3.45 (m, 1.9H, H-2, H-2*, H-1a), 3.56 (dd, J = 10.8,
5.2 Hz, 0.1H, H-1*a), 3.63 (dd, J = 11.2, 5.6 Hz, 0.1H, H-1*b), 3.72-3.78
(m, 0.9H, H-1b), 4.39-4.43 (m, 0.9H, H-3), 4.45-4.48 (m, 0.1H, H-3*), 4.78
(dt, J = 10.5, 1.3 Hz, 0.9H, H-5a), 4.82 (dt, J = 10.3, 1.4 Hz, 0.1H, H-5*a),
4.87 (dt, J = 17.2, 1.3 Hz, 0.9H, H-5b), 4.94 (dt, J = 17.2, 1.3 Hz, 0.1H,
H-5*b), 5.14 (d, J = 7.9 Hz, 0.9H, NH), 5.24 (d, J = 8.5 Hz, 0.1H, NH*),
5.55 (ddd, J = 17.2, 10.3, 6.9 Hz, 0.9H, H-4), 5.69 (ddd, J = 17.2, 10.3,
6.7 Hz, 0.1H, H-4*), 7.29-7.36 (m, 6H, Ph), 7.52-7.81 (m, 8H, Ph) ppm.
13C NMR (126 MHz, C6D6):  = 19.36 (C(CH3)3), 27.02 (C(CH3)3), 58.95
(C-2*), 60.04 (C-2), 60.77 (C-1*), 61.49 (C-1), 74.24 (C-3*), 75.83 (C-3),
117.42 (C-5*), 118.07 (C-5), 123.86, 127.82, 128.03, 128.18, 130.20,
130.35, 133.10, 133.11, 136.08, 136.12 (Ph), 136.25 (C-4*), 136.53 (C-4),
146.56, 149.66 (Ph) ppm. MS (ESI): m/z = 563.1 [M+Na]+. HRMS (ESI):
calcd. for C27H32N2O6SSi [M+H]+ 541.1823; found 541.1794. TLC
(petroleum ether-EtOAc, 7:3): Rf = 0.37.
N-Boc-(2R,4RS,5R)-amino-2-phenyl-4-vinyl-1,3-dioxane
(13):
A
solution of 12 (50 mg, 0.23 mmol, d.r. 9:1), camphorsulfonic acid (5.3 mg,
23 mol) and benzaldehyde dimethyl acetal (69 L, 70 mg, 0.46 mmol) in
CH2Cl2 (4 mL) was stirred at rt for 5.5 h. After NaHCO3 (40 mg) was
added to the solution, stirring was continued for 1 h. The solution was
filtered and the solvent was evaporated under reduced pressure. The
resultant crude product was purified by column chromatography
(petroleum ether-EtOAc, 5:1) to give 13 as a brownish oil (134 mg, 58%,
d.r. 19:1). 1H NMR (500 MHz, [D6]DMSO, 100 °C):  = 1.41 (s, 9H,
C(CH3)3), 3.49 (ddd, J = 10.8, 9.8, 5.2 Hz, 1H, H-5), 3.66 (dd, J = 10.8,
10.8 Hz, 1H, H-6a), 4.09 (dd, J = 10.8, 5.2 Hz, 1H, H-6e), 4.20 (dd, J = 9.8,
5.9 Hz, 1H, H-4), 5.21 (dt, J = 10.8, 1.3 Hz, 1H, H-2'a), 5.36 (dt, J = 17.4,
1.3 Hz, 1H, H-2'b), 5.53 (s, 1H, H-2), 5.90 (ddd, J = 17.4, 10.8, 5.9 Hz, 1H,
H-1'), 6.49 (d, J = 7.9 Hz, 1H, NH), 7.32-7.53 (m, 5H, Ph). 13C NMR
(126 MHz, [D6]DMSO, 100 °C):  = 28.70 (C(CH3)3), 48.65 (C-5), 69.56
(C-6), 78.79 (C(CH3)3), 80.55 (C-4), 100.59 (C-2), 117.45 (C-2'), 126.62,
128.34 (C-2'', C-3'', C-5'', C-6''), 129.01 (C-4''), 135.89 (C-1'), 138.81
(C-1''), 155.53 (C=O) ppm. MS (ESI): m/z = 328.1 [M+Na]+. HRMS (ESI):
calcd. for C17H23NO4 [M+H]+ 306.1700; found 306.1701. TLC (petroleum
ether-EtOAc, 3:1): Rf = 0.45.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
N-((2R,3SR)-3-(triisopropylsilyloxy)-1-hydroxypent-4-en-2-yl)-4'-
nitrobenzenesulfonamide (15b): 15b was prepared in the same way as
15a, using 14b (990 mg, 3.38 mmol, d.r. 3:2), CH2Cl2 (25 mL), DIPEA
(1.30 mL, 981 mg, 7.60 mmol) and pNsCl (768 mg, 3.50 mmol). Column
chromatography (CH2Cl2) gave 15b (468 mg, 34 % over 2 steps from 10c,
d.r. 3:2). 1H NMR (500 MHz, C6D6):  = 0.94-1.08 (m, 21H, CH(CH3)2,
CH(CH3)2*), 1.27-1.32 (m, 1H, OH, OH*), 3.16-3.23 (m, 0.25H, H-2*),
3.30-3.37 (m, 0.75H, H-2), 3.38-3.48 (m, 1.5H, H-1), 3.62-3.70 (m, 0.5H,
H-1*), 4.41-4.45 (m, 0.75H, H-3), 4.48-4.52 (m, 0.25H, H-3*), 4.78 (dt,
J = 10.4, 1.4 Hz, 0.75H, H-5a), 4.86 (dt, J = 10.6, 1.4 Hz, 0.25H, H-5*a),
5.01-5.06 (m, 1.75H, H-5b, H-5*b, NH), 5.23 (d, J = 7.1 Hz, 0.25H, NH*),
5.43-5.58 (m, 1H, H-4, H-4*), 7.50-7.56 (m, 4H, Ph) ppm. 13C NMR
(126 MHz, C6D6):  = 12.41 (CH(CH3)2), 12.54 (CH(CH3)2*), 17.99
(CH(CH3)2), 18.10 (CH(CH3)2*), 59.47 (C-2), 59.80 (C-2*), 60.88 (C-1),
61.36 (C-1*), 74.06 (C-3), 76.22 (C-3*), 117.12 (C-5), 117.56 (C-5*),
123.92 (C-2', C-3', C-5', C-6', C-2'*, C-3'*, C-5'*, C-6'*), 137.25 (C-4),
137.56 (C-4*), 146.41 (C-1'), 149.79 (C-4', C-4'*) ppm. MS (ESI): m/z =
481.1 [M+Na]+. HRMS (ESI): calcd. for C20H34N2O6SSi [M+H]+ 459.1980;
found 459.1976. TLC (CH2Cl2-MeOH, 95:5): Rf = 0.49.
2.2, 2.0 Hz, 0.3H, H-3'*, H-5'*), 7.59 (ddd, J = 9.1, 2.2, 2.2 Hz, 0.7H, H-3',
H-5'), 7.63-7.68 (m, 2H, H-2', H-2'*, H-6', H-6'*) ppm. 13C NMR (126 MHz,
C6D6):  = 12.50 (CH(CH3)2), 12.75 (CH(CH3)2*), 18.15 (CH(CH3)2), 18.18
(CH(CH3)2*), 30.43 (NCH3*), 30.62 (NCH3), 58.64 (C-1), 59.50 (C-1*),
63.45 (C-2), 64.28 (C-2*), 76.00 (C-3), 76.75 (C-3*), 117.31 (C-5, C-5*),
123.92 (C-2', C-2'*, C-6', C-6'*), 128.37, 128.49 (C-3', C-3'*, C-5', C-5'*),
137.80 (C-4), 139.15 (C-4*), 145.09 (C-1'), 145.61 (C-1'*), 149.57 (C-4'*),
149.64 (C-4') ppm. MS (ESI): m/z = 495.1 [M+Na]+. HRMS (ESI): calcd.
for C21H36N2O6SSi [M+H]+ 473.2136; found 473.2130. TLC (petroleum
ether-EtOAc, 3:1): Rf = 0.45.
tert–Butyl-(2S,3SR)-3-((tert-butyldiphenylsilyl)oxy)-2-((N-methyl-4-
nitrophenyl)sulfonamido)pent-4-enoate (17a):
A solution of 15a
(865 mg, 1.56 mmol, d.r. 7:1), TEMPO (73.0 mg, 0.469 mmol) and bis-
(acetoxy)-iodobenzene (1.11 g, 3.44 mmol) in MeCN (5 mL) and water
(5 mL) was stirred at rt for 5 h. It was then extracted with Et2O (20 mL).
The organic layer was washed with sat. NaHCO3 solution and the
aqueous layer was acidified with HCl (1 M) and extracted with EtOAc.
The combined organics were dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The resultant crude carboxylic acid
(1.04 g) was used in the next reaction without purification. To a solution
of the crude carboxylic acid (790 mg) in CH2Cl2 (18 mL), tert-butyl
trichloroacetimidate (3.04 g, 13.9 mmol) and boron trifluoride etherate
(51 L, 59 mg, 0.42 mmol) were added at 0 °C. The mixture was stirred
at rt for 2 h, and then a mixture of EtOAc and sat. NaHCO3 solution (1:1,
80 mL) was added. The organic layer was washed with sat. NaHCO3
solution (2 x 40 mL) and brine, dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography (petroleum ether-EtOAc, 6:1) to give
17a as a colorless oil (758 mg, 87%, d.r. 7:1). 1H NMR (500 MHz, CDCl3):
 = 0.99 (s, 9H, C(CH3)3), 1.20 (s, 0.9H, C(CH3)3*), 1.27 (s, 8.1H;
C(CH3)3), 2.78 (s, 2.7H, NCH3), 3.13 (s, 0.3H, NCH3*), 4.46 (dd, J = 8.9,
6.9 Hz, 0.9H, H-3), 4.50 (d, J = 4.9 Hz, 0.1H, H-2*), 4.60 (d, J = 6.9 Hz,
0.9H, H-2), 4.61- 4.66 (m, 1H, H-3*, H-5a), 5.68-5.73 (m, 0.1H, H-5*a),
5.85-5.88 (m, 0.9H, H-5b), 4.92-4.95 (m, 0.1H, H-5*b), 5.74-5.87 (m, 1H,
H-4, H-4*), 7.29-7.45 (m, 6H, Si-Ph), 7.56-7.72 (m, 4H, Si-Ph), 7.90-7.99
(m. 2H, H-3', H-3'*, H-5', H-5'*), 8.25-8.32 (m, 2H, H-2', H-2'*, H-6', H-6'*)
ppm. 13C NMR (126 MHz, CDCl3):  = 19.25 (SiC(CH3)3), 26.93 (C(CH3)3),
27.80 (C(CH3)3), 31.61 (NCH3), 64.48 (C-2), 75.11 (C-3), 82.54 (C(CH3)3),
118.95 (C-5), 123.99, 127.28, 127.45, 128.61, 129.63, 129.76, 132.79,
133.36, 136.59 (Ph), 136.01 (C-4), 145.26 (C-1'), 149.81 (C-4'), 166.95
(C-1) ppm. MS (ESI): m/z = 647.2 [M+Na]+. HRMS (ESI): calcd. for
C32H40N2O7SSi [M+H]+ 647.2218; found 647.2221. TLC (petroleum ether-
EtOAc, 4:1): Rf = 0.46.
N-Methyl-((2R,3SR)-3-((tert-butyldiphenylsilyl)oxy)-1-hydroxypent-4-
en-2-yl)-4'-nitrobenzenesulfonamide (16a): A solution of 15a (980 mg,
1.81 mmol, d.r. 6:1) in DMF (16 mL) was added dropwise to a solution of
Cs2CO3 (709 mg, 2.17 mmol) in DMF (2 mL) at 0 °C. After 5 min of
stirring, a solution of methyl iodide (507 L, 1.16 g, 8.14 mmol) in DMF
(2 mL) was added and the mixture was stirred at 0 °C for 30 min and at rt
for 16 h. The reaction was quenched wirth sat. NH4Cl solution. The
aqueous layer was extracted with EtOAc (3 x 50 mL). The combined
organics were washed with brine, dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography (petroleum ether-EtOAc, 5:1) to give
16a as a colorless oil (893 mg, 89%, d.r. 7:1). 1H NMR (500 MHz, C6D6):
 = 1.24 (s, 6.75H, C(CH3)3), 1.26 (s, 2.25H, C(CH3)3*), 2.60 (s, 2.25H,
NCH3), 2.82 (s, 0.75H, NCH3*), 3.40 (dd, J = 11.1, 9.4 Hz, 0.25H, H-1*a),
3.55-3.63 (m, 1H, H-1a, H-1*b), 3.79 (dd, J = 11.4, 3.7 Hz, 0.75H, H-1b),
4.03 (dt, J = 9.1, 4.9 Hz, 0.25H, H-2*), 4.24 (ddd, J = 8.5, 6.9, 4.1 Hz,
0.75H, H-2), 4.34 (dd, J = 8.5, 6.9 Hz, 0.75H, H-3), 4.46-4.50 (m, 0.25H,
H-3*), 4.65-4.75 (m, 1.5H, H-5), 4.83-4.91 (m, 0.5H, H-5*), 5.71-5.84 (m,
1H, H-4, H-4*), 7.30-7.39 (m, 6H, Ph), 7.59-7.63 (m, 2H, Ph), 7.77-7.90
(m, 6H, Ph) ppm. 13C NMR (126 MHz, C6D6):  = 19.40 (C(CH3)3,
C(CH3)3*), 27.13 (C(CH3)3, C(CH3)3*), 30.16 (NCH3), 30.64 (NCH3*),
58.92 (C-1*), 59.78 (C-1), 63.10 (C-2*), 63.97 (C-2), 75.88 (C-3*), 76.11
(C-3), 117.76 (C-5*), 117.90 (C-5), 123.56, 123.60, 127.80, 127.93,
127.99, 128.18, 128.38, 128.53, 130.05, 130.16, 130.20, 133.40, 133.49,
133.60, 136.14, 136.27, 136.30, 136.35 (Ph), 136.94 (C-4*), 137.95 (C-4),
145.24, 145.58, 149.54 (Ph) ppm. MS (ESI): m/z = 577.1 [M+Na]+.
HRMS (ESI): calcd. for C28H34N2O6SSi [M+H]+ 555.1980; found 555.2010.
TLC (petroleum ether-EtOAc, 7:3): Rf = 0.39.
tert–Butyl-(2S,3SR)-3-((triisopropylsilyloxy)-2-((N-methyl-4-
nitrophenyl)sulfonamido)pent-4-enoate (17b): 17b was prepared in
the same way as 17a, using 16b (1.11 g, 2.35 mmol, d.r. 3:2), TEMPO
(110 mg, 0.704 mmol), bis-(acetoxy)-iodobenzene (1.66 g, 5.17 mmol),
MeCN (20 mL) and H2O (20 mL). The mixture was stirred for 2 h. The
obtained crude carboxylic acid (1.40 g) was used in the next reaction
without purification. The next reaction was carried out using carboxylic
acid (790 mg, 2.24 mmol), tert-butyl trichloroacetimidate (2.80 mL, 3.43 g,
15.7 mmol), boron trifluoride etherate (83 L, 95 mg, 0.67 mmol) and
CH2Cl2 (25 mL). The mixture was stirred for 2 h. Column chromatography
(petroleum ether-EtOAc, 20:110:1) gave 17b as a brownish oil (620 mg,
51%, d.r. 3:2). 1H NMR (500 MHz, C6D6):  = 1.02-1.14 (m, 30H,
3 x CH(CH3)2, 3 x CH(CH3)2*, C(CH3)3, C(CH3)3*), 2.73 (s, 0.6H, NCH3*),
3.13 (s, 2.4H, NCH3), 4.67 (d, J = 4.2 Hz, 0.8H, H-2), 4.70-4.73 (m, 0.4H,
H-2*, H-3*), 4.91 (dd, J = 8.1, 4.2 Hz, 0.8H, H-3), 4.93-4.99 (m, 1H, H-5a,
H-5*a), 5.01-5.06 (m, 0.8H, H-5b), 5.06-5.11 (m, 0.2H, H-5*b), 5.94 (ddd,
J = 17.2, 10.2, 8.1 Hz, 0.8H, H-4), 5.98-6.05 (m, 0.2H, H-4*), 7.50-7.56
(m, 2H, H-3', H-3'*, H-5', H-5'*), 7.63-7.70 (m, 2H, H-2', H-2'*, H-6', H-6'*)
N-Methyl-((2R,3SR)-3-((triisopropylsilyloxy)-1-hydroxy-pent-4-en-2-
yl)-4'-nitrobenzolsulfonamide (16b): 16b was prepared in the same
way as 16a, using 15b (1.10 g, 2.40 mmol, d.r. 3:2), Cs2CO3 (938 mg,
2.88 mmol), methyl iodide (672 L, 1.53 g, 10.8 mmol) and DMF (40 mL).
Column chromatography (petroleum ether-EtOAc, 5:1) gave 16b (873 mg,
77%, d.r. 3:2). 1H NMR (500 MHz, C6D6):  = 0.60 (t, J = 4.7 Hz, 0.7H,
OH), 0.67 (t, J = 5.2 Hz, 0.3H, OH*), 0.99-1.13 (m, 21H, CH(CH3)2), 2.65
(s, 3H, NCH3, NCH3*), 3.25 (ddd, J = 11.4, 9.4, 4.7 Hz, 0.7H, H-1a), 3.49
(ddd, J = 11.6, 6.4, 5.2 Hz, 0.3H, H-1*a), 3.54-3.61 (m, 1H, H-1b, H-1*b),
3.94 (ddd, J = 8.7, 6.4, 4.7 Hz, 0.3H, H-2*), 4.01 (ddd, J = 9.4, 4.7,
4.2 Hz, 0.7H, H-2), 4.37 (dd, J = 8.7, 6.4 Hz, 0.3H, H-3*), 4.45-4.48 (m,
0.7H, H-3), 4.85-4.89 (m, 0.3H, H-5*a), 4.91 (ddd, J = 10.4, 1.6, 0.9 Hz,
0.7H, H-5a), 5.03 (ddd, J = 17.3, 1.3, 0.9 Hz, 0.3H, H-5*b), 5.12 (dt,
J = 17.3, 1.6 Hz, 0.7H, H-5b), 5.65 (ddd, J = 17.3, 10.4, 7.3 Hz, 0.7H,
H-4), 5.74 (ddd, J = 17.3, 10.3, 8.3 Hz, 0.3H, H-4*), 7.52 (ddd, J = 8.8,
ppm. 13C NMR (126 MHz, C6D6):
 = 12.70 (CH(CH3)2), 12.78
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
(CH(CH3)2*), 17.82 (CH(CH3)2*), 18.18 (CH(CH3)2), 27.52 (C(CH3)3*),
27.56 (C(CH3)3), 31.32 (NCH3*), 33.26 (NCH3), 64.85 (C-2*), 65.48 (C-2),
74.94 (C-3*), 76.25 (C-3), 81.87 (C(CH3)3*), 82.12 (C(CH3)3), 118.03
(C-5), 118.37 (C-5*), 123.75 (C-2', C-2'*, C-6', C-6'*), 128.48, 128.50
(C-3', C-3'*, C-5', C-5'*), 137.95 (C-4), 138.42 (C-4*), 145.05 (C-1'),
145.45 (C-1'*), 149.76 (C-4'*, C-4'), 167.22 (C-1), 167.30 (C-1*) ppm. MS
(ESI): m/z = 565.2 [M+Na]+. HRMS (ESI): calcd. for C25H42N2O7SSi
[M+Na]+ 565.2374; found 565.2383. TLC (petroleum ether-EtOAc, 3:1):
Rf = 0.59.
1605, 1532, 1349, 1138 cm-1. UV (MeOH): max = 277 nm. MS (ESI): m/z
=
567.2 [M+Na]+. HRMS (ESI): calcd. for C25H40N2O8Si [M+Na]+
567.2167; found 567.2165. TLC (petroleum ether-EtOAc, 4:1): Rf = 0.52.
20
(R)-19b: []D = +25.8 (c = 0.4, MeOH). 1H NMR (500 MHz, C6D6):  =
0.91-1.04 (m, 30H, 3 x CH(CH3)2, C(CH3)3), 2.90 (s, 3H, NCH3), 4.66 (dd,
J = 3.9, 1.0 Hz, 1H, H-3), 5.29 (d, J = 3.9 Hz, 1H, H-2), 7.45-7.48 (m, 2H,
H-3', H-5'), 7.62-7.65 (m, 2H, H-2', H-6'), 9.74 (d, J = 1.0 Hz, 1H, H-4)
ppm. 13C NMR (126 MHz, C6D6):  = 12.76 (CH(CH3)2), 17.86 (CH(CH3)2),
27.35 (C(CH3)3), 33.26 (NCH3), 63.71 (C-2), 80.22 (C-3), 83.16 (C(CH3)3),
123.86 (C-2', C-6'), 128.46 (C-3', C-5'), 144.41 (C-1'), 149.91 (C-4'),
165.72 (C-1), 200.54 (C-4) ppm. IR (ATR):  = 3423, 2929, 2866, 1597,
1392, 1350, 1137 cm-1. UV (MeOH): max = 272 nm. MS (ESI): m/z =
567.2 [M+Na]+. HRMS (ESI): calcd. for C25H40N2O8Si [M+Na]+ 567.2167;
found 567.2161. TLC (petroleum ether-EtOAc, 4:1): Rf = 0.57.
tert–Butyl-(2S,3S)-3-((tert-butyldiphenylsilyl)oxy)-2-(methyl-
amino)pent-4-enoate
butyldiphenylsilyl)oxy)-2-(methylamino)pent-4-enoate
[(S)-18]
and
tert–butyl-(2S,3R)-3-((tert-
[(R)-18]:
(S)-18 and (R)-18 were prepared according to the GP, using 17a (1.21 g,
1.94 mmol, d.r. 3:1), K2CO3 (803 mg, 5.81 mmol), thiophenol (239 L,
256 mg, 2.33 mmol) and DMF (25 mL). The mixture was stirred at rt for
4 h. Column chromatography (CH2Cl2CH2Cl2-EtOAc, 100:1) gave
tert-Butyl-(2S,3S)-3-((triisopropylsilyloxy)-4-hydroxy-2-(N-methyl-4'-
nitrophenyl)sulfonamido)butanoate [(S)-20] and tert-butyl-(2S,3R)-3-
((triisopropylsilyloxy)-4-hydroxy-2-(N-methyl-4'-
(S)-18 as a colorless oil (491 mg, 58%) and (R)-18 as a colorless oil
20
(179 mg, 21%). (S)-18: []D
=
+12.4 (c = 1.0, CH2Cl2). 1H NMR
nitrophenyl)sulfonamido)butanoate [(R)-20]:
A solution of 17b
(500 MHz, C6D6):  = 1.22 (s, 9H, SiC(CH3)3), 1.35 (s, 9H, C(CH3)3), 2.31
(s, 3H, NCH3), 3.19 (d, J = 3.4 Hz, 1H, H-2), 4.68 (dddd, J = 7.2, 3.4, 1.3,
1.2 Hz, 1H, H-3), 4.90 (ddd, J = 10.2, 1.6, 1.2 Hz, 1H, H-5a), 4.95 (ddd,
J = 17.3, 1.6, 1.3 Hz, 1H, H-5b), 6.04 (ddd, J = 17.3, 10.2, 7.2 Hz, 1H,
H-4), 7.21-7.25 (m, 6H, Ph), 7.83-7.93 (m, 4H, Ph) ppm. 13C NMR
(126 MHz, C6D6):  = 19.74 (SiC(CH3)3), 27.32 (SiC(CH3)3), 28.20
(C(CH3)3), 35.24 (NCH3), 69.81 (C-2), 77.62 (C-3), 80.54 (C(CH3)3),
116.53 (C-5), 129.95, 130.01, 134.18, 134.43, 136.48, 136.58 (Ph),
137.94 (C-4), 172.22 (C-1) ppm. IR (ATR):  = 2964, 2932, 2857, 1730,
1152, 1111, 1076, 700 cm-1. UV (CH2Cl2): max = 265 nm. MS (ESI): m/z
(127 mg, 0.234 mmol, d.r. 5:6) in MeOH (4 mL), CH2Cl2 (0.5 mL) and
pyridine (75 L) was cooled to -78 °C, and ozone was bubbled through
this solution at -78 °C for 20 min. After the addition of dimethyl sulfide
(106 L, 90.7 mg, 2.34 mmol), the reaction was stirred and allowed to
warm to rt overnight. The solvent was evaporated under reduced
pressure, and the resultant crude aldehyde 19b was dissolved in MeOH
(3 mL). Sodium borohydride (88 mg, 2.3 mmol) was added at 0 °C and
the mixture was stirred for 4.5 h. The reaction was quenched by addition
of sat. NH4Cl solution (10 mL), and the aqueous layer was extracted with
Et2O (3 x 10 mL). The combined organics were washed with water (2 x
25 mL) and brine, dried over Na2SO4 and the solvent was evaporated
under reduced pressure. The resultant crude product was purified by
column chromatography (petroleum ether-EtOAc, 20:110:1) to give
(S)-20 as a yellowish oil (41 mg, 32%) and (R)-20 as a yellowish oil
(39 mg, 30%). (S)-20: 1H NMR (500 MHz, C6D6):  = 1.02 (s, 9H,
C(CH3)3), 1.06-1.16 (m, 21H, CH(CH3)2), 2.20-2.27 (m, 1H, OH), 2.74 (s,
3H, NCH3), 3.63-3.70 (m, 1H, H-4a), 3.71-3.78 (m, 1H, H-4b), 4.22 (ddd,
J = 7.7, 4.7, 3.3 Hz, 1H, H-3), 4.79 (d, J = 7.7 Hz, 1H, H-2), 7.45-7.50 (m,
2H, H-3', H-5'), 7.64-7.68 (m, 2H, H-2', H-6') ppm. 13C NMR (126 MHz,
C6D6): δ = 13.28 (CH(CH3)2), 18.34 (CH(CH3)2), 27.62 (C(CH3)3), 31.75
(NCH3), 61.51 (C-2), 63.26 (C-4), 73.14 (C-3), 82.05 (C(CH3)3), 124.02
(C-2', C-6'), 128.83 (C-3', C-5'), 144.71 (C-1'), 150.05 (C-4'), 167.43 (C-1)
= 462.1 [M+Na]+. HRMS (ESI): calcd. for C26H37NO3Si [M+H]+ 440.2615;
20
found 440.2612. TLC (CH2Cl2-MeOH, 92:8): Rf = 0.25. (R)-18: []D
=
+40.6 (c = 1.3, CH2Cl2). 1H NMR (500 MHz, C6D6):  = 1.21 (s, 9H,
SiC(CH3)3), 1.44 (s, 9H, C(CH3)3), 2.21 (s, 3H, NCH3), 3.27 (d, J = 4.5 Hz,
1H, H-2), 4.55 (dd, J = 7.9, 4.5 Hz, 1H, H-3), 4.83-4.88 (m, 2H, H-5), 6.22
(ddd, J = 16.4, 10.1, 8.1 Hz, 1H, H-4), 7.18-7.24 (m, 6H, Ph), 7.78-7.89
(m, 4H, Ph) ppm. 13C NMR (126 MHz, C6D6):  = 19.70 (SiC(CH3)3),
27.33 (SiC(CH3)3), 28.30 (C(CH3)3), 34.81 (NCH3), 69.15 (C-2), 77.38
(C-3), 80.65 (C(CH3)3), 117.12 (C-5), 129.94, 130.01, 134.32, 134.33,
136.46, 136.51 (Ph), 137.86 (C-4), 172.42 (C-1) ppm. IR (ATR):  = 2965,
2932, 2857, 1725, 1151, 1107, 1070, 700 cm-1. UV (CH2Cl2): max
=
265 nm. MS (ESI): m/z = 462.1 [M+Na]+. HRMS (ESI): calcd. for
C26H37NO3Si [M+H]+ 440.2615; found 440.2645. TLC (CH2Cl2-MeOH,
92:8): Rf = 0.33.
ppm. MS (ESI): m/z
=
569.2 [M+Na]+. HRMS (ESI): calcd. for
C24H42N2O8Si [M+H]+ 547.2504; found 547.2503. TLC (petroleum ether-
EtOAc, 4:1): Rf = 0.53. (R)-20: 1H NMR (500 MHz, C6D6):  = 0.93-1.03
(m, 30H, CH(CH3)2, C(CH3)3), 2.97-3.04 (m, 1H, OH), 3.16 (s, 3H, NCH3),
3.70-3.77 (m, 1H, H-4a), 3.77-3.85 (m, 1H, H-4b), 4.71-4.78 (m, 2H, H-2,
tert-Butyl-(2S,3S)-3-((triisopropylsilyloxy)-2-((N-methyl-4'-
nitrophenyl)sulfonamido)-4-oxobutanoate [(S)-19b] and tert-butyl-
(2S,3R)-3-((triisopropylsilyloxy)-2-((N-methyl-4'-nitrophenyl)sulfon-
H-3), 7.36-7.41 (m, 2H, H-3', H-5'), 7.65-7.70 (m, 2H, H-2', H-6') ppm. 13
C
NMR (126 MHz, C6D6):  = 12.93 (CH(CH3)2), 18.34 (CH(CH3)2), 27.56
(C(CH3)3), 34.58 (NCH3), 61.43 (C-2), 63.01 (C-4), 75.39 (C-3), 82.43
(C(CH3)3), 124.01 (C-2', C-6'), 128.63 (C-3', C-5'), 144.25 (C-1'), 150.09
(C-4'), 167.73 (C-1) ppm. MS (ESI): m/z = 569.2 [M+Na]+. HRMS (ESI):
calcd. for C24H42N2O8Si [M+H]+ 547.2504; found 547.2501. TLC
(petroleum ether-EtOAc, 4:1): Rf = 0.46.
amido)-4-oxobutanoate [(R)-19b]:
A
solution of 17b (670 mg,
1.23 mmol, d.r. 5:6) in MeOH (8 mL), CH2Cl2 (1 mL) and pyridine
(0.4 mL) was cooled to -78 °C, and ozone was bubbled through this
solution at -78 °C for 20 min. After the addition of dimethyl sulfide (465 L,
547 mg, 12.3 mmol), the reaction was stirred and allowed to warm to rt
overnight. The solvent was evaporated under reduced pressure, and the
resultant crude product was purified by column chromatography
(petroleum ether-EtOAc, 20:1) to give (S)-19b as a colorless oil (218 mg,
tert-Butyl-(2S,3S)-3-((triisopropylsilyloxy)-4-hydroxy-2-
20
32%) and (R)-19b as a colorless oil (257 mg, 38%). (S)-19b: []D
(methylamino)butanoate [(S)-21]: (S)-21 was prepared according to the
GP, using (S)-20 (56 mg, 0.10 mmol), K2CO3 (42 mg, 0.31 mmol),
thiophenol (13 L, 14 mg, 0.12 mmol) and DMF (3 mL). The mixture was
stirred at rt for 5 h. Column chromatography (petroleum ether-EtOAc,
= -159.0 (c = 0.7, MeOH).1H NMR (500 MHz, C6D6):  = 1.00-1.07 (m,
30H, 3 x CH(CH3)2, C(CH3)3), 2.99 (s, 3H, NCH3), 4.84 (dd, J = 3.4,
1.0 Hz, 1H, H-3), 4.99 (d, J = 3.4 Hz, 1H, H-2), 7.44-7.49 (m, 2H, H-3',
H-5'), 7.63-7.68 (m, 2H, H-2', H-6'), 9.55 (d, J = 1.0 Hz, 1H, H-4) ppm.
13C NMR (126 MHz, C6D6):  = 12.74 (CH(CH3)2), 17.87 (CH(CH3)2),
27.42 (C(CH3)3), 33.53 (NCH3), 62.37 (C-2), 79.55 (C-3), 83.11 (C(CH3)3),
123.82 (C-2', C-6'), 128.51 (C-3', C-5'), 144.30 (C-1'), 149.92 (C-4'),
166.25 (C-1), 199.34 (C-4) ppm. IR (ATR):  = 3408, 2931, 2867, 1737,
20
9:15:1) gave (S)-21 as a yellowish oil (25 mg, 68%). []D = +39.1
(c = 0.5, CH2Cl2). 1H NMR (500 MHz, C6D6):  = 1.04-1.15 (m, 21H,
CH(CH3)2), 1.37 (s, 9H, C(CH3)3), 2.20 (s, 3H, NCH3), 3.31 (d, J = 5.2 Hz,
1H, H-2), 3.83 (dd, J = 10.5, 7.4 Hz, 1H, H-4a), 3.91 (dd, J = 10.5, 4.2 Hz,
1H, H-4b), 4.28 (ddd, J = 7.4, 5.2, 4.2 Hz, 1H, H-3) ppm. 13C NMR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
(126 MHz, C6D6):

=
13.05 (CH(CH3)2), 18.36 (CH(CH3)2), 28.09
(Chromatotron) to give 23 as a yellowish oil (370 mg, 85%, d.r. 7:3).
1H NMR (500 MHz, C6D6):  = 1.06 (s, 6.3H, C(CH3)3), 1.07 (s, 2.7H,
C(CH3)3*), 1.21 (s, 6.3H, C(CH3)3), 1.22 (s, 2.7H, C(CH3)3*), 1.69 (s, 2.1H,
C=OCH3), 1.70 (s, 0.9H, C=OCH3*), 2.63 (s, 2.1H, NCH3), 2.78 (s, 0.9H,
NCH3*), 3.84-3.96 (m, 2H, H-4, H-4*), 5.20 (d, J = 7.0 Hz, 0.7H, H-2),
5.31 (d, J = 7.6 Hz, 0.3H, H-2*), 5.55 (ddd, J = 7.0, 5.4, 2.2 Hz, 0.7H,
H-3), 5.76 (ddd, J = 7.6, 4.8, 2.6 Hz, 0.3H, H-3*), 7.18-7.32 (m, 6H, Si-
Ph), 7.46-7.50 (m, 1.5H, H-3', H-5'), 7.54-7.59 (m, 2H, H-2', H-6', H-3'*,
H-5'*), 7.59-7.63 (m, 0.6H, H-2'*, H-6'*), 7.76-7.89 (m, 4H, Si-Ph) ppm.
13C NMR (126 MHz, C6D6):  = 19.33 (SiC(CH3)3), 20.33 (C=OCH3),
26.82 (C(CH3)3), 27.35 (C(CH3)3), 31.22 (NCH3), 59.18 (C-2), 62.83 (C-4),
72.19 (C-3), 82.29 (C(CH3)3), 123.83, 128.58, 130.13, 130.16, 133.22,
135.82, 135.95, 144.48, 149.76 (Ph), 166.62, 168.86 (C-1, C=OCH3)
(C(CH3)3), 35.29 (NCH3), 66.07 (C-4), 69.44 (C-2), 74.27 (C-3), 81.11
(C(CH3)3), 171.82 (C-1) ppm. IR (ATR):  = 2925, 2864, 1736, 1465,
1368, 1257, 1158, 681 cm-1. MS (ESI): m/z = 362.2 [M+Na]+. HRMS
(ESI): calcd. for C18H39NO4Si [M+H]+ 362.2721; found 362.2722. TLC
(petroleum ether-EtOAc, 4:1): Rf = 0.12.
tert-Butyl-(2S,3R)-3-((triisopropylsilyloxy)-4-hydroxy-2-
(methylamino)butanoate [(R)-21]: (R)-21 was prepared according to
the GP, using (R)-20 (243 mg, 0.444 mmol), K2CO3 (184 mg, 1.33 mmol),
thiophenol (59 L, 64 mg, 0.58 mmol) and DMF (5 mL). The mixture was
stirred at rt for 5 h. Column chromatography (petroleum ether-EtOAc,
20
8:16:1) gave (R)-21 as a yellowish oil (36 mg, 22%). [α]D = +16.0
ppm. MS (ESI): m/z
C33H42N2O9SSi [M+Na]+ 693.2272; found 693.2275. TLC (CH2Cl2): Rf =
0.81.
=
693.3 [M+Na]+. HRMS (ESI): calcd. for
(c = 0.5, CH2Cl2). 1H NMR (500 MHz, C6D6):  = 1.01-1.20 (m, 21H,
CH(CH3)2), 1.37 (s, 9H, C(CH3)3), 2.10 (s, 3H, NCH3), 3.11 (d, J = 2.0 Hz,
1H, H-2), 3.79 (dd, J = 12.0, 2.2 Hz, 1H, H-4a), 3.92 (dd, J = 12.0, 4.1 Hz,
1H, H-4b), 4.21 (ddd, J = 4.1, 2.2, 2.0 Hz, 1H, H-3) ppm. 13C NMR
(126 MHz, C6D6):

=
13.04 (CH(CH3)2), 18.32 (CH(CH3)2), 27.98
tert-Butyl-(2S,3R)-3-acetoxy-4-((tert-butyldiphenylsilyl)oxy)-2-
(methylamino)butanoate [(R)-24]: (R)-24 was prepared according to
the GP, using 23 (42 mg, 0.10 mmol, d.r. 6:1), K2CO3 (22 mg, 0.19 mmol),
thiophenol (8.0 L, 8.3 mg, 75 mol) and DMF (1 mL). The mixture was
stirred at rt for 4 h. Column chromatography (petroleum ether-EtOAc,
9:17:1) gave (R)-24 as a yellowish oil (16 mg, 52%).1H NMR (500 MHz,
C6D6):  = 1.16 (s, 9H, SiC(CH3)3), 1.33 (s, 9H, C(CH3)3), 1.78 (s, 3H,
C=OCH3), 2.20 (s, 3H, NCH3), 3.44 (d, J = 7.4 Hz, 1H, H-2), 4.03-4.05 (m,
2H, H-4), 5.38 (ddd, J = 7.4, 5.1, 4.4 Hz, 1H, H-3), 7.18-7.24 (m, 6H, Si-
Ph), 7.76-7.83 (m, 4H, Si-Ph) ppm. 13C NMR (126 MHz, C6D6):  = 19.37
(SiC(CH3)3), 20.56 (C=OCH3), 26.84 (C(CH3)3), 27.85 (C(CH3)3), 34.65
(NCH3), 63.63 (C-4), 64.27 (C-2), 74.86 (C-3), 80.69 (C(CH3)3), 129.84,
133.76, 135.90 (Ph), 169.21 (C=OCH3), 171.51 (C-1) ppm. MS (ESI): m/z
= 486.2 [M+H]+. TLC (petroleum ether-EtOAc, 4:1): Rf = 0.50.
(C(CH3)3), 34.54 (NCH3), 67.77 (C-4), 68.62 (C-2), 72.75 (C-3), 80.89
(C(CH3)3), 171.07 (C-1) ppm. IR (ATR):  = 2942, 2866, 1729, 1391,
1155, 1113, 919, 680 cm-1. MS (ESI): m/z = 362.2 [M+Na]+. HRMS (ESI):
calcd. for C18H39NO4Si [M+H]+ 362.2721; found 362.2719. TLC
(petroleum ether-EtOAc, 4:1): Rf = 0.11.
tert-Butyl-(2S,3RS)-4-((tert-butyldiphenylsilyl)oxy)-3-hydroxy-2-((N-
methyl-4'-nitrophenyl)sulfonamido)butanoate (22): A solution of 17a
(1.10 g, 1.76 mmol, d.r. 3:1) in MeOH (16 mL), CH2Cl2 (2 mL) and
pyridine (0.57 mL) was cooled to -78 °C, and ozone was bubbled through
this solution at -78 °C for 20 min. After the addition of dimethyl sulfide
(785 L, 666 mg, 17.6 mmol), the reaction was stirred and allowed to
warm to rt overnight. The solvent was evaporated under reduced
pressure, and the resultant crude 19a (1.10 g) was used in the next
reaction without purification. Crude 19a (505 mg, d.r. 3:1) was dissolved
in MeOH (20 mL) and cooled to 0 °C. Sodium borohydride (304 mg,
8.06 mmol) was added to the solution and the mixture was stirred at 0 °C
for 30 min and at rt for 6.5 h. The reaction was quenched by addition of
sat. NH4Cl solution (60 mL), and the aqueous layer was extracted with
Et2O (3 x 60 mL). The combined organics were washed with H2O (2 x
100 mL) and brine, dried over Na2SO4 and the solvent was evaporated
under reduced pressure. The resultant crude product was purified by
column chromatography (petroleum ether-EtOAc, 12:16:1) to give 22
as a colorless oil (220 mg, 39%, d.r. 7:3). 1H NMR (500 MHz, C6D6):  =
1.08 (s, 6.3H, C(CH3)3), 1.10 (s, 2.7H, C(CH3)3*), 1.15 (s, 2.7H, C(CH3)3*),
1.16 (s, 6.3H, C(CH3)3), 2.20 (d, J = 5.5 Hz, 0.3H, OH*), 2.48 (d,
J = 5.9 Hz, 0.7H, OH), 2.80 (s, 2.1H, NCH3), 2.92 (s, 0.9H, NCH3*), 3.71-
3.78 (m, 1.4H, H-4), 3.83-3.87 (m, 0.6H, H-4*), 3.91-3.97 (m, 0.7H, H-3),
4.17-4.23 (m, 0.3H, H-3*), 4.87 (d, J = 6.3 Hz, 0.3H, H-2*), 4.91 (d,
J = 5.5 Hz, 0.7H, H-2), 7.20-7.29 (m, 6H, Si-Ph), 7.48-7.55 (m, 2H, H-3',
H-5'), 7.57-7.62 (m, 2H, H-2', H-6'), 7.70-7.79 (m, 4H, Si-Ph) ppm. 13C
NMR (126 MHz, C6D6):  = 19.32 (SiC(CH3)3), 26.87 (C(CH3)3), 27.47
(C(CH3)3), 31.79 (NCH3), 60.53 (C-2), 65.01 (C-4), 72.70 (C-3), 82.29
(C(CH3)3), 123.07, 123.83, 128.41, 130.15, 130.21, 133.16, 135.85,
144.83, 149.76 (Ph), 167.94 (C-1) ppm. MS (ESI): m/z = 651.2 [M+Na]+.
HRMS (ESI): calcd. for C31H40N2O8SSi [M+H]+ 651.2167; found 651.2171.
TLC (CH2Cl2): Rf = 0.66.
tert-Butyl-(2S,3S)-4-(4'',4'''-dimethoxytrityloxy)-3-
((triisopropylsilyloxy)-2-(N-methyl-4'-nitrophenyl)sulfonamido)-
butanoate [(S)-25]: A solution of (S)-20 (34 mg, 62 mol) and DMTr
chloride (30 mg, 87 mol) in dry pyridine (1 mL) was stirred at rt for 4 d.
The solvent was evaporated under reduced pressure, and the resultant
crude product was purified by column chromatography (petroleum ether-
CH2Cl2, 1:1 + 1% pyridine) to give (S)-25 as a yellowish foam (21 mg,
40%). []D20 = -9.5 (c = 0.7, CH2Cl2).1H NMR (500 MHz, C6D6):  = 0.77-
0.87 (m, 3H, CH(CH3)2), 0.89-0.99 (m, 18H, CH(CH3)2), 1.17 (s, 9H,
C(CH3)3), 3.18 (s, 3H, NCH3), 3.31 (s, 3H, OCH3), 3.32 (s, 3H, OCH3),
3.56 (dd, J = 9.4, 4.5 Hz, 1H, H-4a), 3.85 (dd, J = 9.4, 9.4 Hz, 1H, H-4b),
4.84 (ddd, J = 9.4, 4.5, 2.8 Hz, 1H, H-3), 5.56 (d, J = 2.8 Hz, 1H, H-2),
6.81-6.88 (m, 4H, H-3'', H-3''', H-5'', H-5'''), 7.03-7.08 (m, 1H, H-4''''),
7.23-7.28 (m, 2H, H-3'''', H-5''''), 7.62-7.71 (m, 8H, H-2', H-3', H-5'. H-6',
H-2'', H-2''', H-6'', H-6'''), 7.80-7.84 (m, 2H, H-2'''', H-6'''') ppm. 13C NMR
(126 MHz, C6D6):  = 12.57 (CH(CH3)2), 18.23, 18.29 (CH(CH3)2), 27.69
(C(CH3)3), 33.83 (NCH3), 54.61 (OCH3), 62.10 (C-2), 64.13 (C-4), 74.55
(C-3), 82.31 (C(CH3)3), 88.10 (CPh3), 113.51, 113.59 (C-3'', C-5'', C-3''',
C-5'''), 123.71 (C-3', C-5'), 127.03 (C-4''''), 128.19 (C-3'''', C-5''''), 128.75,
129.05 (C-2'', C-6'', C-2'''; C-2''', C-6''''; C-6''''), 130.62, 130.83 (C-2', C-6'),
136.26, 136.46 (C-1'', C-1'''), 144.78 (C-1'), 145.66 (C-1''''), 149.79 (C-4'),
159.14, 159.19 (C-4', C-4''), 168.76 (C-1) ppm. MS (ESI): m/z = 871.4
[M+Na]+.TLC (CH2Cl2): Rf = 0.69.
tert-Butyl-(2S,3RS)-3-acetoxy-4-((tert-butyldiphenylsilyl)oxy)-2-((N-
methyl-4'-nitrophenyl)sulfonamido)butanoate (23): NEt3 (180 L,
132 mg, 1.30 mmol), DMAP (15.9 mg, 0.130 mmol) and acetic anhydride
(123 L, 133 mg, 1.30 mmol) were added to a solution of 22 (410 mg,
0.652 mmol, d.r. 7:3) in Et2O (10 mL) at 0 °C. After stirring at rt for 18 h,
HCl (1 M, 40 mL) was added. The organic layer was washed with brine,
dried over Na2SO4 and the solvent was evaporated under reduced
pressure. The resultant crude product was purified by preparative TLC
tert-Butyl-(2S,3R)-4-(4'',4'''-dimethoxytrityloxy)-3-
((triisopropylsilyloxy)-2-(N-methyl-4'-nitrophenyl)sulfonamido)-
butanoate [(R)-25]: A solution of (R)-20 (67 mg, 0.12 mmol) and DMTr
chloride (58 mg, 0.17 mmol) in dry pyridine (3 mL) was stirred at rt for
4.5 d. The solvent was evaporated under reduced pressure, and the
resultant crude product was purified by column chromatography
(petroleum ether-EtOAc, 20:1 + 0.5% pyridine) to give (R)-25 as a
yellowish foam (88 mg, 85%). 1H NMR (500 MHz, C6D6):  = 0.78-0.87
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
(m, 3H, CH(CH3)2), 0.90-0.94 (m, 18H, CH(CH3)2), 1.11 (s, 9H, C(CH3)3),
3.21 (s, 3H, NCH3), 3.27 (s, 6H, OCH3), 3.45 (dd, J = 9.0, 5.0 Hz, 1H,
H-4a), 3.79 (dd, J = 9.6, 9.0 Hz, 1H, H-4b), 4.48 (ddd, J = 9.6, 5.0, 1.5 Hz,
1H, H-3), 5.62 (d, J = 1.5 Hz, 1H, H-2), 6.81-6.85 (m, 4H, H-3'', H-3''',
H-5'', H-5'''), 7.05-7.10 (m, 1H, H-4''''), 7.21-7.27 (m, 2H, H-3'''', H-5''''),
7.54-7.74 (m, 10H, H-2', H-3', H-5'. H-6', H-2'', H-2''', H-6'', H-6''', H-2'''',
H-6'''') ppm. 13C NMR (126 MHz, C6D6):  = 13.15 (CH(CH3)2), 18.33,
18.34 (CH(CH3)2), 27.91 (C(CH3)3), 33.12 (NCH3), 54.80 (OCH3), 62.47
(C-2), 65.25 (C-4), 76.43 (C-3), 81.97 (C(CH3)3), 87.56 (CPh3), 113.66
(C-3'', C-5'', C-3''', C-5'''), 124.02 (C-3', C-5'), 125.69 (C-4''''), 127.31
(C-3'''', C-5''''), 128.55, 128.76, 129.32 (C-2'', C-6'', C-2'''; C-2''', C-6'''';
C-6''''), 130.68 (C-2', C-6'), 136.24, 136.40 (C-1'', C-1'''), 145.19, 145.28
(C-1', C-1''''), 149.94 (C-4'), 159.37, 159.39 (C-4', C-4''), 167.37 (C-1).
MS (ESI): m/z = 871.4 [M+Na]+. TLC (CH2Cl2-MeOH, 99:0.1): Rf = 0.81.
(m, 18H, CH(CH3)2), 1.16-1.24 (m, 3H, CH(CH3)2), 3.09 (s, 3H, OCH3),
3.25 (s, 3H, NCH3), 3.46 (s, 3H, OCH3), 4.35 (d, J = 7.4 Hz, 1H, H-4),
4.68 (dd, J = 7.4, 2.8 Hz, 1H, H-3), 5.18 (d, J = 2.8 Hz, 1H, H-2), 7.60-
7.64 (m, 2H, H-3', H-5'), 7.69-7.73 (m, 2H, H-2', H-6') ppm. 13C NMR
(126 MHz, C6D6):  = 13.82 (CH(CH3)2), 18.99, 19.07 (CH(CH3)2), 28.09
(C(CH3)3), 34.43 (NCH3), 56.78, 57.26 (OCH3), 62.33 (C-2), 75.95 (C-3),
82.90 (C(CH3)3), 106.44 (C-4), 124.09 (C-2', C-6'), 129.47 (C-3', C-5'),
145.14 (C-1'), 150.31 (C-4'), 168.80 (C-1) ppm. IR (ATR):  = 2932, 2858,
1731, 1154, 1112, 1075, 702, 508 cm-1. UV (MeOH): max = 277 nm. MS
(ESI): m/z = 613.2 [M+Na]+. HRMS (ESI): calcd. for C26H46N2O9SSi
[M+H]+ 613.2585; found 613.2581. TLC (petroleum ether-EtOAc, 4:1):
Rf = 0.48.
tert-Butyl-(2S,3R)-4,4-dimethoxy-3-(triisopropylsilyl-oxy)-2-((N-
methyl-4'-nitrophenyl)sulfonamido)-butanoate [(R)-27]: (R)-27 was
prepared in the same way as isomer (S)-27, using (R)-19b (233 mg,
0.428 mmol), para-toluenesulfonic acid (8.1 mg, 43 mol) and trimethyl
orthoformate (5 mL). The reaction mixture was stirred at rt for 16 h.
tert-Butyl-(2S,3S)-4-(4',4''-dimethoxytrityloxy)-3-
((triisopropylsilyloxy)-2-(methylamino)butanoate [(S)-26]: (S)-26 was
prepared according to the GP, using (S)-25 (16 mg, 19 mol), K2CO3
(7.8 mg, 56 mol), thiophenol (2.3 L, 2.5 mg, 23 mol) and DMF (1 mL).
The mixture was stirred at rt for 15 h. Column chromatography
(petroleum ether-CH2Cl2, 1:2 + 0.5% pyridine) gave (S)-26 as a yellowish
Column chromatography (petroleum ether-EtOAc, 25:120:1) gave
20
(R)-27 as
a
colorless oil (235 mg, 93%). []D
= +38.2(c = 1.1,
CH2Cl2).1H NMR (500 MHz, C6D6):  = 1.12-1.16 (m, 30H, CH(CH3)2,
(CH3)3), 3.08 (s, 3H, OCH3), 3.10 (s, 3H, NCH3), 3.26 (s, 3H, OCH3), 4.36
(dd, J = 6.9, 2.7 Hz, 1H, H-3), 4.68 (d, J = 6.9 Hz, 1H, H-4), 5.24 (d,
J = 2.7 Hz, 1H, H-2), 7.58-7.62 (m, 2H, H-3', H-5'), 7.66-7.70 (m, 2H, H-2',
H-6') ppm. 13C NMR (126 MHz, C6D6):  = 13.61 (CH(CH3)2), 18.46,
18.53 (CH(CH3)2), 27.61 (C(CH3)3), 32.78 (NCH3), 52.95, 54.73 (OCH3),
61.86 (C-2), 76.64 (C-3), 81.91 (C(CH3)3), 104.78 (C-4), 123.75 (C-2',
C-6'), 128.25, 128.63 (C-3', C-5'), 144.72 (C-1'), 149.81 (C-4'), 166.95
(C-1) ppm. IR (ATR):  = 2933, 2864, 1731, 1533, 1350, 1152, 1112, 739
cm-1. UV (MeOH): max = 276 nm. MS (ESI): m/z = 613.2 [M+Na]+. HRMS
(ESI): calcd. for C26H46N2O9SSi [M+H]+ 613.2585; found 613.2578. TLC
(petroleum ether-EtOAc, 4:1): Rf = 0.45.
20
foam (6.0 mg, 48 %). []D = +7.1 (c = 0.7, CH2Cl2).1H NMR (500 MHz,
C6D6):  = 0.87-1.11 (m, 21H, CH(CH3)2), 1.45 (s, 9H, C(CH3)3), 2.54 (s,
3H, NCH3), 3.27-3.31 (m, 7H, H-4a, OCH3), 3.85-3.87 (m, 1H, H-2), 4.00
(dd, J = 8.9, 8.6 Hz, 1H, H-4b), 4.60-4.66 (m, 1H, H-3), 6.70-6.81 (m, 4H,
H-3', H-3'', H-5', H-5''), 7.02-7.09 (m, 1H, H-4'''), 7.17-7.22 (m, 2H, H-3''',
H-5'''), 7.52-7.58 (m, 4H, H-2', H-2'', H-6', H-6''), 7.69-7.74 (m, 2H, H-2''',
H-6''') ppm. MS (ESI): m/z = 686.4 [M+Na]+.
tert-Butyl-(2S,3R)-4-(4',4''-dimethoxytrityloxy)-3-
((triisopropylsilyloxy)-2-(methylamino)butanoate [(R)-26]: (R)-26 was
prepared according to the GP, using (R)-25 (88 mg, 0.10 mmol), K2CO3
(43 mg, 0.31 mmol), thiophenol (13 L, 14 mg, 0.12 mmol) and DMF
(1 mL). The mixture was stirred at rt for 15 h. Column chromatography
(petroleum ether-CH2Cl2, 1:2 + 0.5% pyridine) gave (R)-26 as a yellowish
tert-Butyl-(2S,3S)-4,4-dimethoxy-3-(triisopropylsilyl-oxy)-2-(N-
methylamino)-butanoate [(S)-28]: (S)-28 was prepared according to the
GP, using (S)-27 (98 mg, 0.17 mmol), K2CO3 (69 mg, 0.50 mmol),
thiophenol (20 L, 22 mg, 0.20 mmol) and DMF (1 mL). The mixture was
stirred at rt for 19 h. Column chromatography (CH2Cl2) gave (S)-28 as a
20
foam (56 mg, 82%). []D = +7.1 (c = 0.7, CH2Cl2).1H NMR (500 MHz,
C6D6):  = 1.02-1.15 (m, 21H, CH(CH3)2), 1.38 (s, 9H, C(CH3)3), 2.45 (s,
3H, NCH3), 3.30 (s, 6H, OCH3), 3.50 (dd, J = 9.1, 5.3 Hz, 1H, H-4), 3.70
(d, J = 2.2 Hz, 1H, H-2), 3.76 (dd, J = 9.1, 7.9 Hz, 1H, H-4), 4.56 (ddd,
J = 7.9, 5.3, 2.2 Hz, 1H, H-3), 6.75-6.80 (m, 4H, H-3', H-3'', H-5', H-5''),
7.03-7.09 (m, 1H, H-4'''), 7.17-7.22 (m, 2H, H-3''', H-5'''), 7.53-7.58 (m,
4H, H-2', H-2'', H-6', H-6''), 7.69-7.73 (m, 2H, H-2''', H-6''') ppm. 13C NMR
20
colorless oil (58 mg, 86%). []D = 9.0 (c = 0.7, CH2Cl2). 1H NMR
(500 MHz, C6D6):  = 1.15-1.29 (m, 21H, CH(CH3)2, 1.40 (s, 9H, (CH3)3),
2.39 (s, 3H, NCH3), 3.15 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 3.46 (d,
J = 1.8 Hz, 1H, H-2), 4.37 (dd, J = 7.2, 1.8 Hz, 1H, H-3), 4.63 (d,
(126 MHz, C6D6):

=
12.91 (CH(CH3)2), 18.30 (CH(CH3)2), 28.18
J = 7.2 Hz, 1H, H-4) ppm. 13C NMR (126 MHz, C6D6):
 = 13.45
(C(CH3)3), 35.68 (NCH3), 54.60 (OCH3), 65.60 (C-4), 67.44 (C-2), 75.79
(C-3), 80.43 (C(CH3)3), 87.07 (CPh3), 113.34 (C-3', C-5', C-3'', C-5''),
126.86 (C-4'''), 127.37 (C-3''', C-5'''), 128.76 (C-2''', C-6'''), 130.60, 130.66
(C-2'; C-2'', C-6'; C-6''), 136.60, 136.74 (C-1', C-1''), 145.80 (C-1'''),
159.02, 159.05 (C-4', C-4''), 171.25 (C-1) ppm. IR (ATR):  = 3397, 2931,
(CH(CH3)2), 18.58 (CH(CH3)2), 28.05 (C(CH3)3), 34.84 (NCH3), 54.62,
54.95 (OCH3), 65.33 (C-2), 75.23 (C-3), 80.50 (C(CH3)3), 106.03 (C-4),
172.40 (C-1) ppm. IR (ATR):  = 2940, 2867, 1737, 1459, 1144, 1105,
1069, 677 cm-1. MS (ESI): m/z = 406.2 [M+H]+. HRMS (ESI): calcd. for
C20H43NO5Si [M+H]+ 406.2983; found 406.2978. TLC (petroleum ether-
EtOAc, 4:1): Rf = 0.44.
2866, 2364, 1606, 1509, 1318, 1251, 1132 cm-1. UV (MeOH): max
=
233 nm. MS (ESI): m/z = 686.4 [M+Na]+. HRMS (ESI): calcd. for
C39H57NO6Si [M+H]+ 664.4028; found 664.4027. TLC (CH2Cl2-MeOH,
96:4): Rf = 0.63.
tert-Butyl-(2S,3R)-4,4-dimethoxy-3-(triisopropylsilyl-oxy)-2-(N-
methylamino)-butanoate [(R)-28]: (R)-28 was prepared according to
the GP, using (R)-27 (19 mg, 32 mol), K2CO3 (13 mg, 97 mol),
thiophenol (4.0 L, 4.2 mg, 39 mol) and DMF (1 mL). The mixture was
stirred at rt for 7 h. Column chromatography (petroleum ether-EtOAc,
tert-Butyl-(2S,3S)-4,4-dimethoxy-3-(triisopropylsilyl-oxy)-2-((N-
methyl-4'-nitrophenyl)sulfonamido)-butanoate [(S)-27]: A solution of
(S)-19b (230 mg, 0.422 mmol) and para-toluenesulfonic acid (8.0 mg,
42 mol) in trimethyl orthoformate (5 mL) was stirred at rt for 13 h. EtOAc
(50 mL) and sat. NaHCO3 solution (50 mL) were added. The aqueous
layer was extracted with EtOAc (3 x 50 mL). The combined organics
were washed with brine, dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The resultant crude product was
purified by column chromatography (petroleum ether-EtOAc, 25:120:1)
20
22:19:1) gave (R)-28 as a colorless oil (9.0 mg, 69%). []D = -15.0
(c = 0.4, CH2Cl2). 1H NMR (500 MHz, C6D6):  = 1.22-1.24 (m, 21H,
CH(CH3)2, 1.43 (s, 9H, (CH3)3), 2.47 (s, 3H, NCH3), 3.22 (s, 3H, OCH3),
3.30 (s, 3H, OCH3), 3.45 (d, J = 2.0 Hz, 1H, H-2), 4.40 (dd, J = 7.3,
2.0 Hz, 1H, H-3), 4.57 (d, J = 7.3 Hz, 1H, H-4) ppm. 13C NMR (126 MHz,
C6D6):  = 13.07 (CH(CH3)2), 18.37 (CH(CH3)2), 28.02 (C(CH3)3), 36.46
(NCH3), 55.42, 55.83 (OCH3), 67.30 (C-2), 76.80 (C-3), 80.31 (C(CH3)3),
106.78 (C-4), 170.57 (C-1) ppm. IR (ATR):  = 2941, 2798, 1734, 1464,
1391, 1148, 1108, 1069, 882, 702 cm-1. UV (MeOH): max = 237 nm. MS
20
to give (S)-27 as a colorless oil (106 mg, 42%). []D = -28.8 (c = 1.2,
MeOH).1H NMR (500 MHz, C6D6):  = 1.10 (s, 9H, C(CH3)3), 1.12-1.16
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801667
European Journal of Organic Chemistry
FULL PAPER
(ESI): m/z = 406.2 [M+H]+. HRMS (ESI): calcd. for C20H43NO5Si [M+H]+
406.2983; found 406.2981. TLC (petroleum ether-EtOAc, 4:1): Rf = 0.33.
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Keywords: natural products • antibiotics • amino acids • modular
synthesis • protecting groups
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10.1002/ejoc.201801667
European Journal of Organic Chemistry
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The total synthesis of caprazamycin
nucleoside antibiotics and their
Amino Acids
Ruth Linder, Christian Ducho*
analogues is not trivial. For instance, it
requires a densely functionalized
amino acid building block to construct
the diazepanone core motif. We now
report a unified synthesis of five
different amino acid building blocks of
this type, thus providing a highly
useful 'toolbox' for the synthesis of
caprazamycins as well as other
complex peptidic natural products.
Page No. – Page No.
Unified Synthesis of Densely
Functionalized Amino Acid Building
Blocks for the Preparation of
Caprazamycin Nucleoside Antibiotics
This article is protected by copyright. All rights reserved.