Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production

Article abstract of DOI:10.1021/acs.joc.8b01708

The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient six-step synthesis, chiral amino acids were transformed into 3-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 a? 2.2:1, respectively) could be chromatographically separated. From five amino acids (both antipodes) was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted piperazines, each as a single absolute stereoisomer, all but one in multigram quantities. In keeping with our overall purpose of constructing more Csp³-enriched compound libraries for drug discovery, these diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis and as intermediates for the production of novel piperazine compounds.

Full text of DOI:10.1021/acs.joc.8b01708

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Article
Synthesis of Enantiomerically Pure 3-Substituted-Piperazine-2-
Acetic Acid Esters as Intermediates for Library Production
Shiva Krishna Reddy Guduru, Srinivas Chamakuri, Idris O Raji,
Kevin R MacKenzie, Conrad Santini, and Damian W Young
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01708 • Publication Date (Web): 05 Sep 2018
Downloaded from http://pubs.acs.org on September 17, 2018
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Synthesis of Enantiomerically Pure 3-Substituted-Piperazine-2-Acetic
Acid Esters as Intermediates for Library Production
#‡
#‡
#‡
#§‡
Shiva Krishna Reddy Guduru , Srinivas Chamakuri , Idris O. Raji , Kevin R. MacKenzie , Conrad
#§*
#§‡*
Santini , and Damian W. Young
#
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Center for Drug Discovery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030 USA
Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston,
§
Texas 77030 USA
‡
Department of Pharmacology and Chemical Biology, Baylor College of Medicine, One Baylor Plaza,
Houston, Texas 77030 USA
ABSTRACT: The piperazine heterocycle is broadly exploited in FDAꢀapproved drugs and
biologically active compounds, but its chemical diversity is usually limited to ring nitrogen
substitutions, leaving the four carbon atoms underutilized. Using an efficient six step synthesis,
chiral amino acids were transformed into 3ꢀsubstitutedꢀpiperazineꢀ2ꢀacetic acid esters as
diastereomeric mixtures whose cis and trans products (dr: 0.56→2.2:1 respectively) could be
chromatographically separated. From five amino acids (both antipodes), a complete matrix of 20
monoꢀprotected chiral 2,3ꢀdisubstituted piperazines was obtained, each as a single absolute
stereoisomer, all but one in multiꢀgram quantities. In keeping with our overall purpose of
constructing 3ꢀdimensional fragment libraries, these diverse and versatile piperazines can be
functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library
synthesis or intermediates for the production of novel piperazine compounds.
Introduction
Smallꢀmolecule screening underlies the earliest phase of the chemical probe and therapeutic
1
discovery process. A convincing body of data supports the premise that smallꢀmolecule
libraries built around the principle of chemical diversity will lead to a higher hit rate across wider
2ꢀ4
swaths of biological target space.
Accordingly, the effort to populate smallꢀmolecule
collections with structurally diverse molecular entities in screening collections stands as a major
intellectual and strategic goal for synthetic organic chemistry.
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Our efforts to generate smallꢀmolecule libraries optimized for biological discovery have focused
on the synthesis of scaffold families in which systematic variation of structural features on the
core scaffold generates a complete matrix of constitutional isomers (Figure 1). Within the
hierarchy of a scaffold family, systematic chemical diversity can be applied to establish a core
scaffold having different substitution patterns. Each core scaffold offers unique regiochemical
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substitution possibilities, and if the substituents are placed on sp ꢀcarbon atoms, then each
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regioisomer affords both relative and absolute stereochemical configurations. The complete set
of regio and stereoisomers can be elaborated further for library synthesis. Systematic chemical
diversity provides an effective means of sampling chemical space by exploiting different vector
substitutions that can in principle lead to greater molecular recognition potential toward a variety
of biological targets. The generation of optimal screening libraries based on these principles is a
major objective of our laboratory.
Figure 1. A general representation of a scaffold family and the concept of systematic chemical diversity.
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The piperazine heterocycle is frequently encountered within FDA approved drugs and other
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reported biologically active compounds; however, its derivatization has mostly been limited to
1,4ꢀsubstitution on the nitrogen atoms. Piperazines have features that can be exploited for
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rendering structural diversity including , two sites of nitrogen diversification and four sp carbon
atoms at which stereochemical diversity can be generated. We perceived the four piperazine
carbon atoms as opportunities to apply systematic chemical diversity principles and produce a
threeꢀbranch family of functionalized enantiomerically pure piperazines from commercially
available chiral starting materials. The three branches of the scaffold family are demarcated by
their substitution patterns as 2,3, 2,5 and 2,6 and the familial relationship is illustrated in Figure
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2.
Figure 2. Scaffold family of disubstituted piperazineꢀ2ꢀacetic acid ester regioisomers.
The synthesis of the 2,6ꢀpiperazine acetic acid ester branch has been previously reported by
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us and in this report we describe our efforts toward the preparation of the 2,3ꢀbranch of the
scaffold family.
Results and Discussion
Our targeted scaffold family represents a significant departure from how piperazines are
normally employed in that the carbon atoms are used to add functionality. Our interest in
deploying these scaffolds for parallel synthesis of screening libraries required us to develop
syntheses that could be scaled to meet our material requirements. The acetate ester side chain
was included to both enable the synthesis of the piperazine ring and to insure, after hydrolysis,
that the derived diversified compounds would have enhanced solubility in aqueous media while
minimizing the potential for aggregation even at high concentrations (mM range). In certain
cases the carboxylic acid could also serve as a site for further diversification.
Piperazines that are 2,3ꢀdisubstituted can be formally considered to be products arising from the
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bridging of the nitrogens of 1,2ꢀethylenediamines with an ethylene linker. There is precedent
for the conversion of certain 1,2ꢀethylenediamines to 2,3ꢀdisubstituted piperazines utilizing
various sources for the twoꢀcarbon bridge. The simplest example, ethylene glycol, has been
reported to participate in the direct, one step conversion of 1,2ꢀdiamines to 2,3ꢀdisubstituted
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piperazines under Pd/MgO, iridium
or ruthenium catalysis. Alternatively, 2ꢀbromoethyl
diphenylsulfonium triflates are reported to effect conversion of 1,2ꢀdiamines to 2,3ꢀdisubstituted
piperazines through a double Nꢀalkylation mechanism.
vinyl diphenylsulfonium triflates, obtained by treatment of the aforementioned 2ꢀbromoethyl
diphenylsulfonium triflates with base, followed by reaction with 1,2ꢀdiamines through a tandem
16,18,19
Related methodology employs
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azaꢀMichael addition followed by intramolecular N alkylation.
Another report describes a
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tandem azaꢀMichael reaction of 1,2ꢀdiamines to phenyl vinyl selenone followed by
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intramolecular N alkylation. Two step protocols have also been described using chloroacetyl
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chloride
or αꢀdicarbonyl compounds as the source of the two carbon bridge. The
employment of oxalate esters
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and ethyl glyoxylate to convert 1,2ꢀdiamines to 1,4ꢀ
piperazineꢀdiones is followed by reduction of the cyclic bisꢀamides to give 2,3ꢀdisubstituted
piperazines. Each of the aforementioned methodologies is characterized by an initial
stereoselective synthesis of a chiral 1,2ꢀdiamine that requires controlling the establishment of
two vicinal stereogenic centers. From the perspective of generating scaffold families, this is
disadvantageous given that individual syntheses would be required for each 1,2ꢀdiamine
stereoisomer. We were motivated by our previous efforts involving a route toward producing a
mixture of enantiomerically pure 2,6ꢀ disubstituted piperazines diastereomers in a single pot.
The strategy relied on a relatively nonꢀselective generation of diastereomeric piperazines
followed by an efficient and scalable chromatographic separation of the diasetereomeric
products. We surmised that a similar design for establishing the requisite 2,3ꢀpiperazine scaffold
branch could be achieved using starting materials from the chiral pool and the development a
synthesis for the nonꢀselective formation of a second, vicinal stereocenter to generate a mixture
of enantiomerically pure 2,3ꢀpiperazine diastereomers. Accordingly, use of the opposite
enantiomer of the starting material from the chiral pool could produce the antipodes of all the
scaffolds.
Retrosynthetic analysis of the 2,3ꢀsubstituted members of the piperazineꢀ2ꢀacetic acid ester
scaffold branch is depicted in Scheme 1. The paths labeled “inter” and “intra” refer to the
manner in which the second stereocenter is formed. The “intra” path envisions the formation of
the second stereocenter by an intramolecular azaꢀMichael reaction of N to an acrylate moiety,
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analogous to the method used to prepare the previously reported 2,6ꢀsubstituted piperazine
family branch. The acrylate is, in turn, obtained from an amino alcohol that is derived from an
amino acid. We anticipated that the intramolecular azaꢀMichael reaction would be moderately
diastereoselective in a manner observed for the 2,6 case (dr ≈ 3:1). The “inter” path envisions
the formation of the second stereocenter by an intermolecular azaꢀMichael reaction of
ethanolamine to an acrylate also derived from the same amino acid. In the “inter” path option we
anticipated that the diastereoselectivity of the azaꢀMichael reaction would be marginal at best,
which for our purposes is the better outcome since we seek to acquire large quantities of both
diastereomers that emerge at the end of the synthesis. Following an appropriate Nꢀprotection/Oꢀ
activation sequence, the amino acid derived nitrogen would be unmasked and ring closure
would occur via intramolecular S 2 displacement.
N
There is limited precedent for both pathways en route to 2,3ꢀsubstituted piperazines. For the
intra” route the unmasking a Boc protected amine under acidic conditions followed by
“
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neutralization to effect an intramolecular azaꢀMichael cyclization has been reported.
Other
examples have been demonstrated utilizing the trityl group on the incipient nucleophilic nitrogen,
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unmasked under acidic conditions
or directly employed under basic conditions . The
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removal of an Fmoc protecting group prior to an azaꢀMichael addition has been reported
as
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well as the azaꢀMichael of an amide nitrogen to an acrylate preꢀactivated with TBSOTf . There
are also examples of direct acid catalysis without preactivation when the attacking nucleophile is
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an aniline nitrogen as well as base promoted azaꢀMichael of Cbz protected nitrogen
For the “inter” route there are limited examples of ethanolamine, either directly or as a synthon,
.
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being used as an azaꢀMichael donor.
Closure of a piperazine ring from βꢀhydroxyamine
precursors has generally been carried out by either halogenation, mesylate displacement
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or with the Mitsunobu protocol
. None of these precedents had been applied toward the
production of complete stereoisomeric matrices of 2,3ꢀpiperazine products.
Scheme 1. Retrosynthetic analysis of 3ꢀsubstitutedꢀpiperazineꢀ2ꢀacetic acid ethyl esters.
For simplicity of design, systematic chemical diversity would ideally utilize a common bond
forming strategy for each of the various branches of the scaffold family. In this manner,
structurally different building blocks could be carried through the same bond forming maneuvers
to generate different scaffold family members. Thus, in keeping with the successful precedent
established during the 2,6 scaffold work, initial studies focused on the “intra” pathway. We
quickly encountered two major, ultimately insurmountable problems with the “intra” approach.
The first was the preparation of acrylate A from alcohol B, a twoꢀstep process that involved the
oxidation of B to the intermediate aldehyde (not shown) followed by exposure of the aldehyde to
(
carbethoxymethylene)triphenylphosphorane. This conversion was uniformly unsatisfactory,
consistently affording troublesome mixtures containing varying amounts of the desired acrylate
A in poor yields. Even more troublesome was the surprising failure of the intramolecular azaꢀ
Michael addition to afford the piperazine scaffold. Similar to natural product total synthesis,
systematic chemical diversity rests on goal of generating a predetermined final set of structures
and is agnostic to the route taken. Therefore, a unique synthesis pathway may need to be
employed toward the generation of complete scaffold families. Thus we adopted the “inter”
retrosynthetic strategy (Scheme 2) which offered us the advantages of scalability and access to
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equal amounts of both diastereomers. The NꢀBoc amino acids 1aꢀk were reduced to their
corresponding alcohols 2a-k by exposure to BH •THF. Subsequent oxidation using DessꢀMartin
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conditions generated the corresponding aldehydes (not shown). The crude aldehydes were
immediately treated with (carbethoxymethylene)triphenylphosphorane to afford the acrylates 3a-
k, all having trans geometry.
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The potential for racemization of the intermediate aldehydes prepared using the above
methodology was a major concern. For that reason, we undertook the synthesis of racemic 2a,
as an exemplar, using the same method as shown in Scheme 2. Both the chiral and the racemic
alcohols were converted to their respective trans acrylates 3a as described. Chiral HPLC
analysis of both materials showed no loss of enantiomeric purity in the chiral acrylate 3a.
Acrylates 3a-k were reacted with ethanolamine (4eq). As anticipated, the azaꢀMichael addition
occurred at rt with modest diastereoselectivity, affording mixtures of diastereomers 4a-k. The
relative stereochemistry of the Michael adducts was deduced by a combination of NMR
spectroscopy and Xꢀray crystallography from the derived piperazines later in the sequence as
described below (see Table 1). Treatment of 4a-k with NsCl/Na CO gave the Nꢀnosylated
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products 5a-k which were purified by chromatography.
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Scheme 2. Synthesis of 3ꢀsubstitutedꢀpiperazineꢀ2ꢀacetic acid ethyl esters.
At this point the serineꢀOꢀbenzyl ether derived intermediates 5e and 5k were set aside for
chromatographic separation of diastereomers as described below (Scheme 3). The remaining
intermediates 5a-d and 5f-j were advanced through the sequence shown in Scheme 2.
Reaction of diastereomers 5a-d and 5f-j with MsCl/TEA gave the Oꢀmesylated intermediates
6a-d and 6f-j which were carried forward in crude form. Treatment of 6a-d and 6f-j with TFA
resulted in the unmasking of the amino acid derived nitrogen. Neutralization afforded the
piperazines 7a-d and 7f-j. Piperazines 7d/7j could be separated into their individual
diastereomers 7d cis/trans and 7j cis/trans. The separation of piperazines 7a-c and 7f-h
proved to be difficult but Boc reprotection of the nitrogen at the 4ꢀposition rendered the
remaining diastereomers 8a-c cis, 9a-c trans, 8f-h cis and 9f-h trans separable by normal
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phase column chromatography. The strategic preparation and separation of diastereomeric
mixtures is key to the efficient implementation of the systematic chemical diversity strategy.
There were some notable variations in the Scheme 2 sequence. In the case of valine, which is
the only amino acid with branching at the β carbon that was successfully employed in this work,
the rate and yield of the Michael addition of ethanolamine to the acrylates 3d/3j were
significantly reduced. In all other cases, such as the phenylalanine derived acrylates 3b/3g
where there is no branching at the β carbon, the reaction went to 100% completion in 48h at rt
to afford the desired Michael adducts as the major product. In the case of valine, the reaction
required a week to approach completion (>90% by LCMS). Heating the reaction only led to
complex mixtures. Even when carried out at rt, the conjugate addition to acrylates 3d/3j gave a
mixture of products in which adducts 4d/4j were present in significant but varying amounts. After
advancing the Michael adducts 4d/4j, as described above, to their derived piperazines 7d/7j
each pair of diastereomers was separated into its individual stereoisomers 7d cis, 7d trans, 7k
cis and 7k trans as described above.
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In the case of the serineꢀOꢀbenzyl ether derived intermediates 5e/5k, diastereomers 5e syn/anti
and 5k syn/anti could be individually isolated prior to cyclization (Scheme 3). The four
intermediates were advanced through their derived mesylates 6e syn/anti and 6k syn/anti to
the piperazines 7e cis, 7e trans, 7k cis and 7k trans.
Scheme 3. Synthesis of piperazine scaffolds derived from serineꢀOꢀbenzyl ether.
Each cyclization reaction gives two products of the target molecular mass that are resolved by
silica gel chromatography. Analytical chiral HPLC shows that each product is enantiomerically
pure, proving that the amino acid derived chiral center has not racemized en route to the final
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product. NMR spectra and assignments using C and N HMBC confirm the compound idenꢀ
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tities, establishing that the two products are the expected diastereomers. We use C NMR
chemical shifts of the C and C carbons to identify the 2,3 cis and 2,3 trans products; these
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identifications are confirmed with other NMR observables. From the relative stereochemistry of
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the products and the chirality of the starting material, we infer the absolute stereochemistry of
the final piperazine products. The approach is presented for compounds 7d cis and 7d trans
(
dr = 1:1.1) as shown in Figure 3.
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2
2
2
2
3
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0
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8
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0
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8
9
0
Figure 3. NMR analysis of conformational states of compounds 7d cis and 7d trans.
In trans products, substituents at C and C are diꢀaxial to minimize allylic 1,3ꢀstrain with the
2
3
nosyl amide as well as to avoid steric clashes that would occur between adjacent diꢀequatorial
13
groups. Axial carbon substituents at C and C will induce 6ppm upfield perturbations of the C
2
3
chemical shifts of both the C and C atoms of the piperazine ring due to threeꢀbond γꢀgauche
6
5
57,58
interactions.
In cis products, which equilibrate between 2,3ꢀaxial/equatorial and 2,3ꢀ
equatorial/axial states, only one of the remote atoms (C or C ) will experience the γꢀgauche
5
6
interaction at a given time, and rapid equilibration averages the shift perturbation over C and
5
13
C . The sum of the C and C C shifts in the trans product, which experiences two γꢀgauche
6
5
6
interactions with remote ring substituents, should be about 6 ppm less than for the cis product,
59
which experiences only one. For 7d the sum of these chemical shifts in the minor product (C :
5
46.99 ppm, C : 41.56 ppm) is 7.38 ppm greater than in the major product (C : 39.33 ppm, C :
6
5
6
41.84 ppm), indicating that the major product is trans. The Xꢀray crystal structure of the major
diastereomer starting from (S)ꢀVal, obtained by crystallization from hexane/DCM, confirms that
the major product is 7d trans (Figure 4).
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Figure 4. Xꢀray structure of 7d trans
1
3
Solution NMR data that further confirms the identity of these diastereomers include C linewidth
increases at lower temperature for the cis but not the trans product, consistent with slow
equilibration between cis ring conformers and the presence of only a single ring conformer for
the trans product. For the trans product, NOEs between the C substituent methylene protons
2
and the H axial proton, and between the C substituent methine proton and the H axial proton,
6
3
5
confirm a trans diꢀaxial configuration of the 2,3ꢀsubstituents (for products with a Boc substituent
at N , the presence of Boc rotamers complicates but does not prevent this NOE analysis).
4
Conformational averaging limits our ability to infer configuration of the cis product from NOEs or
3
3
J couplings. All observed J and J for trans products are consistent with the assigned
HH
CH
stereochemistry.
Stereochemical inferences about all other pairs of diastereomers have been similarly based on
13
3
C chemical shift differences at positions C and C , variable temperature NMR, NOEs, and J
5
6
couplings. Crystal structures of both the major and minor products derived from (S)ꢀPhe further
confirm the validity of this approach. Because in our synthetic approach we make two
1
diastereomers from a single chiral starting material, we can always compare informative H
1
13
1
13
chemical shifts, H multiplet structure, C chemical shifts, and Hꢀ C threeꢀbond J couplings of
both diastereomers as described above to confirm the stereochemical identities.
As further confirmation of the above argument, Xꢀray crystallographic data for compound 9g
trans was obtained (crystallized from hexane/DCM). Piperazine 8g cis did not crystallize. The
Boc protecting group of 8g cis was removed, the free amine recovered and converted to its HCl
salt 10 which afforded crystals suitable for Xꢀray crystallography (Scheme 4). In both cases the
Xꢀray data confirmed assignments made on the basis of the above described NMR studies
(Figure 5).
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9
0
Scheme 4. Preparation of compound 10 for Xꢀray crystallography.
Xꢀray structure of 9g trans
Xꢀray structure of 10 (derived from 8g cis)
Figure 5. Structures of 9g trans and 10 determined by Xꢀray crystallography.
Key to our design of generating both diastereomers, with the exception of the branched Val and
Leu cases, virtually no diastereoselectivity of the synthetic sequence shown in Scheme 2 was
observed across the range of amino acids used. Both Val and Leu displayed variability in both
the dr of the azaꢀMichael addition of ethanolamine to their acrylates 3c/3h and 3d/5h and in the
1
appearance of intermediates 5c/5h and 5d/5j in the H NMR spectra. Their derived piperazine
scaffolds, however, were identical between enantiomers. Table 1 shows the results obtained.
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0
derived from (S) amino acids
derived from (R) amino acids
Amount
Produced
(g)(cis)
Amount
produced
*
Entry
#
dr
er (%:%)
R
PG
cis/trans
(g)(trans)
cis/trans
(
S)ꢀCH3
1
2
3
4
5
6
7
8
Boc
Boc
Boc
Boc
Boc
Boc
H
1.1:1
1.1:1
1.2:1
1.3:1
1.1:1
2.2:1
1:1.1
1:1.8
7.7
7.0
7.3
9.5
6.4
3.7
2.8
0.16
7.0
6.2
6.1
7.3
5.6
1.7
3.0
0.30
>99.8:0.2/>99.8:0.2
>99.8:0.2/>99.8:0.2
98.9:1.1/>99.8:0.2
>99.8:0.2/98.5:1.5
>99.8:0.2/97.9:2.1
>99.8:0.2/97.4:2.6
>99.8:0.2/>99.8:0.2
>99.8:0.2/>99.8:0.2
8
a cis/9a trans
R)-CH3
f cis/9f trans
S)-CH Ph
(
8
(
2
8
b cis/9b trans
R)-CH Ph
8g cis/9g trans
(S)ꢀiBu
8c cis/9c trans
(R)ꢀiBu
(
2
8h cis/9h trans
(
S)ꢀiPr
d cis/7d trans
R)ꢀiPr
j cis/7j trans
R)ꢀ
CH OCH Ph
7
(
H
7
(
§
#
9
H
H
1.5:1
1.3:1
4.5
3.1
1.1
95.4:4.6/97.9:2.1
2
2
7
e cis/7e trans
S)ꢀ
CH OCH Ph
(
§
#
10
1.4
97.8:2.2/97.9:2.1
2
2
7k cis/7k trans
*
§
Table 1. Scaffolds synthesized via Scheme 2 and 3. er = enantiomeric ratio %retention:%inversion. the
stereochemical designation of the carbon bearing the benzyloxymethyl sidechain changes from (S) to (R) upon
cyclization to the piperazine. Therefore, (S) Ser gives (R) 7e cis/trans and (R) Ser gives (S) 7k cis/trans. the
#
observed er reflected the er of the starting material serine Oꢀbenzyl ether. See SI for chiral analytical data.
Chiral analysis was carried out by HPLC. The piperazine scaffolds were synthesized in racemic
form according to the sequence in Scheme 2. For each racemate, the diastereomers were
separated by column chromatography and then subjected to chiral HPLC analysis. After optimal
conditions were found to separate the racemate into its component antipodes, the
enantiomerically enriched scaffolds were analyzed using these same conditions to determine
the enantiomeric ratio (er)..From this analysis, it was demonstrated that the stereointegrity was
well preserved in all cases.
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The ability of the piperazines to access a variety of conformations while presenting the same
regiospecific substituents is a key advantage of systematic chemical diversity. Of the four
possible conformers shown for the two diastereomers, three are populated in solution at rt
2
3
(Figure 3). The introduction of either sp or sp character independently to N and N will further
1
4
perturb the conformations of the scaffolds. This change in hybridization can thus add an
additional element of conformational diversity by placing the substituents in unique orientations
with respect to the piperazine ring. Generating all possible stereoisomers as shown in Table 1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
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0
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8
9
0
(
and the corresponding stereoisomers of the regioisomeric 2,6 and 2,5 family branches) the
alternative modes of N diversification will create a set of analogs that will immediately provide
deep insight into SAR against target proteins.
Finally, the overarching goal for producing these piperazine scaffolds was for their combinatorial
diversification and integration into smallꢀmolecule screening libraries. Rather than being limited
to the truncated chemical space that is accessible by following the traditional N ꢀN
1
4
diversification paradigm, we have expanded the reach of these piperazines by incorporating, at
the outset, the stereochemical diversity offered by one of the four saturated carbon centers. The
production of libraries can therefore proceed in a combinatorial fashion by substitution on N1
and N to produce scores of novel drugꢀlike frameworks.
4
Using scaffold 9g trans as an exemplar, Scheme 5 depicts the alternative modes of orthogonal
3
diversification that we envision for our scaffolds using the examples of methyl (which imparts sp
2
character) and acetyl (which imparts sp character) as the diversity elements. Removal of the
Boc protecting group from 9g trans affords the enantiomerically pure common intermediate 11.
Reductive methylation at N is followed by unmasking of N to give 12. Treatment of 12 with
4
1
AcCl affords the bisꢀdiversified ester 13. Subsequent hydrolysis gives the final piperazine acetic
acid 14. Reversal of the order of diversification ultimately gives the alternative regioisomerically
substituted 17.
The stereochemical diversity represented within these scaffolds in concert with the synthetic
2
3
capability to derivatize the two nitrogen atoms to introduce sp or sp character generates the
additional feature of conformational diversity; this will provide an extended ability to controllably
2
populate conformational microꢀenvironments that are not attainable in sp ꢀenriched compounds.
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Scheme 5. Alternative Nꢀdiversification sequences for scaffold 9g trans.
Conclusion
In this report, we disclose the use of systematic chemical diversity to guide the synthesis of a
20ꢀmember branch of 3ꢀsubstituted piperazineꢀ2ꢀacetic acid esters, most of them on multigram
scale, as part of a family of piperazine acetic acid esters. The resulting piperazine scaffolds are
poised for their use as starting materials for compound library production by combinatorial
synthesis. The strategy involved an intermolecular azaꢀMichael reaction on an acrylate to
furnish a chiral 1,2ꢀdiamine followed by an S 2 reaction to form the piperazine ring. It is
N
noteworthy that this pathway is distinct from our previously reported intramolecular azaꢀMichael
reaction to form the 2,6ꢀpiperazines which was found to be unproductive in this instance. This
illustrates that systematic chemical diversity may require unique synthetic strategies toward the
generation of complete scaffold families. The work described here completes a second branch
of the piperazine scaffold family. Consequently, the synthesis of the final 2,5ꢀpiperazine branch
is currently in progress and will be described in a future report.
Experimental
The abbreviation “Ns” refers exclusively to 2ꢀnitrophenylsulfonyl.
General Methods. All starting materials and reagents were purchased from commercial
sources and used without further purification. Solvents were purchased as either anhydrous
grade products in sealed containers or reagent grade and used as received. All reactions were
carried out in dry glassware under a nitrogen atmosphere using standard disposable or gastight
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syringes, disposable or stainless steel needles, cannula, and septa. Stirring was achieved with
magnetic stir bars or with an overhead mechanical stirrer. Flash column chromatography was
performed with SiO (230ꢀ400 mesh) or by using an automated chromatography instrument with
2
an appropriately sized column. Thin layer chromatography was performed on silica gel 60F254
plates (E. Merck). NonꢀUV active compounds were visualized on TLC using one of the following
1
13
stains: KMnO , ninhydrin, pꢀanisaldehyde, PMA, 2,4ꢀDNP or bromocresol green. H and
C
4
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
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0
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2
3
4
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8
9
0
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3
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9
0
NMR spectra were recorded on an instrument operating at either 600MHz or 800MHz, and
50MHz or 200MHz respectively. IR spectra were obtained neat on an FTꢀIR instrument and
1
ꢀ1
are expressed in cm . LCMS data were collected using an HPLC instrument coupled to a low
resolution mass spectrometer with single quadrupole ionization operating in either positive or
negative ion mode. The analytical method utilized a C column (2.1×50mm, 1.8ꢀm) eluting with
1
8
a linear gradient of 95%/5% water/CH CN (modified with 0.05% formic acid; T=0min
3
flow=0.35mL/min) to 95%/5% CH CN/water (T=3.5min flow= 0.5mL/min) then 95%/5%
3
CH CN/water to T=5min (0.5ml/min). Peak detection was done at 254nm and 230nm for UV
3
active compounds. For nonꢀUV active compounds total ion count was used. Highꢀresolution
mass spectrometry (HRMS) spectra were obtained on a Thermo Scientific Q Exactive hybrid
quadrupoleꢀOrbitrap mass spectrometer equipped with a HESI source and using lock masses
for correction. Samples were introduced into the HRMS via reversed phase HPLC on an
Accucore Vanquish C18+ column (2.1×100mm, 1.5ꢀm) eluting with a linear gradient of 95%/5%
water/acetonitrile (modified with 0.1% formic acid) to 10%/90% water/acetonitrile over 8 min.
Chiral HPLC analysis of piperazines was carried out on an instrument with automated 6ꢀcolumn
array (Daicel Chiralpak Iꢀseries, IA through IF, 4.6×150mm, 5ꢀm). Racemates were screened
using a heptane (A)/ethanol (B) gradient (flow=1mL/min) as follows: T=0min (%A/%B) 95/5,
T=1min 95/5, T=11min 10/90 (linear gradient), T=13min 10/90, T=13.1min 95/5, T=15min 95/5.
Racemates that gave unsatisfactory resolution of enantiomers were rescreened using the above
gradient with iPrOH instead of EtOH. Additional editing of the gradient to optimize separation
was carried out as needed. Chiral materials were analyzed using optimized conditions and their
traces were compared to the racemic traces for determination of enantiomeric ratio (er).
To determine our limit of detection (LOD) by chiral HPLC, 5ꢀL aliquots of 2mg/mL stocks (10ng
injections) of purified protected scaffolds were subjected to chiral HPLC analysis to resolve and
quantify enantiomers and determine enantiomeric ratios. Scouting solvent conditions across six
4.6mm x 150mm chiral columns (ChiralPak IAꢀIE) identified chromatographic conditions for
every compound that successfully effected baseline resolution of the enantiomers of the
racemic products. Absorbance at 254nm (nosyl or benzyl) was used to detect and quantify the
amount of scaffold. Serial dilutions of the 2mg/mL stocks established that our LOD is
approximately 0.02ng/injection, or 0.2% of the total material loaded under these conditions.
Therefore the limit of our detection of enantiomeric ratio is ≥99.8:0.2. All chiral traces of the
scaffolds are included in the Supplementary Information.
Automated preparative reverseꢀphase HPLC purification was performed using a Mass Directed
Fractionation (MDF) system with UVꢀDAD detection and a single quadrupole mass
spectrometer. The instrument used a C18 column (21.2mm i.d. × 150mm, 5 ꢀm, w/19mm ×
10mm guard column). The crude product was dissolved in methanol and purified utilizing an
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elution of water (modified with 0.05% formic acid) and methanol, with a linear gradient
increasing from 5% to 100% methanol over 15 m at a flow rate of 20 mL/min. Purification was
carried out by mass trigger only.
1
Where indicated H NMR peak assignments were made using COSY, NOESY, HSQC and
HMBC protocols. All chemical shifts are quoted on the δ scale and were referenced to residual
nonꢀdeuterated solvent as an internal standard. Signal multiplicities are described using the
following abbreviations: s = singlet, d = doublet, t = triplet, b = broad, quar = quartet, quin =
quintet, m = multiplet, v = very; abbreviations are combined, e.g. vbs = very broad singlet. The
NMRs of products isolated as unseparated mixtures of diastereomers are included for reference
only.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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0
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0
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0
1
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8
9
0
Scheme 2 (Representative Procedures)
Tertꢀbutyl (S)ꢀ(1ꢀhydroxyꢀ3ꢀphenylpropanꢀ2ꢀyl)carbamate (2b).
A 2000mL rb flask was
equipped with a stir bar, rubber septum and nitrogen inlet. The flask was charged with (Nꢀtertꢀ
butoxycarbonyl)ꢀSꢀphenylalanine (50.0 g, 188.46 mmol) followed by dry THF (100 mL). The
mixture was stirred until dissolution was complete. The solution was cooled to 0° C in an
ice/water bath. BH •THF (1M, 380 mL, 380 mmol, 2.0 eq) was added by cannula. The reaction
3
was stirred for 3h at 0° C. The septum and nitrogen inlet were removed and brine (125 mL) was
added very slowly until outgassing ceased, then more rapidly afterward. Water (200 mL) was
added followed by EtOAc (300 mL). The twoꢀphase mixture was transferred to a separatory
funnel and partitioned. The aqueous was extracted with EtOAc (300 mL) and discarded. The
combined organic was dried over MgSO , filtered and evaporated in vacuo to a colorless oil
4
(
44.05 g, 93% crude yield). The crude alcohol was used without further purification (Note: in
some cases the crude alcohol was observed to contain a white solid, possibly boron salts.
These were removed by an additional water wash.) Crude yields were 60%ꢀ98% across the
1
range of substrates. H NMR (600 MHz, CDCl ) δ 7.32 (m, 2H), 7.25 (m, 3H), 4.81 (vbd, J = 6.0
3
Hz, 1H), 3.89 (vbs, 1H), 3.68 (dd, J = 11.0, 3.8 Hz, 1H), 3.57 (dd, J = 11.1, 5.3 Hz, 1H), 2.86 (d,
13
J = 7.3 Hz, 2H), 1.43 (s, 9H). C NMR (151 MHz, CDCl ) δ 156.2, 137.8, 129.3, 128.6, 126.5,
3
7
9.7, 64.4, 53.7, 37.5, 28.4. IR: 3350, 2984, 1684, 1526, 1314, 1268. HRMS (HESIꢀTOF) m/z
+
+
calc for (M+H) (C H NO ) 252.1600, found 252.1595.
14 22
3
The following additional intermediates were prepared using the method described for 2b.
1
Tertꢀbutyl (S)ꢀ(1ꢀhydroxypropanꢀ2ꢀyl)carbamate (2a). 32 g, colorless oil, 69% crude yield. H
NMR (600 MHz, CDCl ) δ 4.74 (vbd, J = 7.3 Hz, 1H), 3.87 – 3.71 (m, 1H), 3.64 (dd, J = 11.8, 5.2
3
13
Hz, 1H), 3.55 – 3.45 (m, 1H), 2.90 (vbs, 1H), 1.45 (s, 9H), 1.15 (d, J = 6.8 Hz, 3H). C NMR
(
1
151 MHz, CDCl ) δ 156.4, 79.7, 67.3, 48.6, 28.4, 17.3. IR: 3337, 2975, 1682, 1515, 1365, 1247,
3
+
+
163. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 176.1287, found 176.1283.
8 18 3
Tertꢀbutyl (S)ꢀ(1ꢀhydroxyꢀ4ꢀmethylpentanꢀ2ꢀyl)carbamate (2c). 32 g, colorless oil, 79% crude
1
yield. H NMR (600 MHz, CDCl ) δ 4.64 (d, J = 7.9 Hz, 1H), 3.79 – 3.72 (bm, 1H), 3.67 – 3.65
3
(
m, 1H), 3.51 (dd, J = 11.0, 6.0 Hz, 1H), 1.67 (dquar, J = 13.4, 6.7 Hz, 1H), 1.46 (s, 9H), 1.34 –
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.28 (m, 2H), 0.94 (dd, J = 6.6, 2.7 Hz, 6H). C NMR (151 MHz, CDCl ) δ 156.6, 79.6, 66.5,
3
2.7, 51.0, 40.6, 34.9, 28.4, 24.8, 23.0, 22.2, 18.9, 13.8. IR: 3332, 2955, 2360, 1683, 1508,
365, 1275, 1165. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 218.1756, found
+
+
11 24 3
218.1751.
Tertꢀbutyl (S)ꢀ(1ꢀhydroxyꢀ3ꢀmethylbutanꢀ2ꢀyl)carbamate (2d). 32 g, colorless oil, 98% crude
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
yield. H NMR (600 MHz, CDCl ) δ 4.76 (vbd, J = 8.6 Hz, 1H), 3.81 (vbd, J = 6.2 Hz, 1H), 3.71 –
3.59 (m, 2H), 3.46 – 3.42 (m, 1H), 1.84 (dt, J = 13.4, 6.8 Hz, 1H), 1.45 (s, 9H), 0.96 (d, J = 6.8
3
13
Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). C NMR (151 MHz, CDCl ) δ 156.9, 79.6, 64.2, 58.1, 29.3,
8.4, 19.5, 18.5. IR: 3338, 2963, 1684, 1507, 1390, 1365, 1246, 1165. HRMS (HESIꢀTOF) m/z
calc for (M+H) (C H NO ) 204.1600, found 204.1597.
3
2
+
+
10
22
3
Tertꢀbutyl (R)ꢀ(1ꢀ(benzyloxy)ꢀ3ꢀhydroxypropanꢀ2ꢀyl)carbamate (2e). 46.5 g, colorless oil, 97%
1
crude yield. H NMR (600 MHz, CDCl ) δ 7.39 – 7.31 (m, 5H), 4.55 (AB, J = 14.6, 2.7 Hz, 2H),
.83 – 3.76 (m, 2H), 3.72 – 3.64 (m, 3H), 1.46 (s, 9H). C NMR (151 MHz, CDCl ) δ 156.1,
37.7, 128.5, 127.9, 127.7, 79.7, 73.5, 70.7, 64.0, 51.6, 28.4. IR: 3332, 2980, 2359, 1685, 1497,
1365, 1275, 1260, 1164. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 282.1705, found
3
13
3
1
3
+
+
15
24
4
282.1700.
1
Tertꢀbutyl (R)ꢀ(1ꢀhydroxypropanꢀ2ꢀyl)carbamate (2f). 43 g, colorless oil, 92% crude yield. H
NMR (600 MHz, CDCl ) δ 4.72 (t, J = 7.8 Hz, 1H), 3.78 – 3.74 (m, 1H), 3.63 (dt, J = 11.4, 3.1
Hz, 1H), 3.50 (dd, J = 11.0, 6.1 Hz, 1H), 2.90 (vbs, 1H), 1.45 (s, 9H), 1.15 (d, J = 6.8 Hz, 3H).
3
13
C NMR (151 MHz, CDCl ) δ 156.4, 79.7, 67.3, 48.6, 28.4, 17.3. IR: 3350, 2980, 2934, 1677,
522, 1445, 1249, 1071. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 176.1287, found
3
+
+
1
8 18 3
176.1282.
Tertꢀbutyl (R)ꢀ(1ꢀhydroxyꢀ3ꢀphenylpropanꢀ2ꢀyl)carbamate (2g). 36.5 g, colorless oil, 79% crude
1
13
yield. H NMR identical to 2b. C NMR (151 MHz, CDCl ) δ 156.2, 137.8, 129.3, 128.5, 126.5,
9.7, 64.4, 53.7, 37.4, 28.4. IR: 3350, 2984, 2938, 1684, 1526, 1442, 1365, 1314, 1268, 1250,
1166. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 252.1600, found 252.1595.
3
7
+
+
14
22
3
Tertꢀbutyl (R)ꢀ(1ꢀhydroxyꢀ4ꢀmethylpentanꢀ2ꢀyl)carbamate (2h). 33 g, colorless oil, 85% crude
1
13
yield. H NMR identical to 2c. C NMR (201 MHz, CDCl ) δ 156.6, 79.6, 66.8, 51.1, 40.5, 28.4,
24.8, 23.0, 22.2. IR: 3325, 2955, 2870, 1685, 1508, 1366, 1275, 1260, 1168. HRMS (HESIꢀ
TOF) m/z calc for (M+H) (C H NO ) 218.1756, found 218.1752.
3
+
+
11
24
3
Tertꢀbutyl (R)ꢀ(1ꢀhydroxyꢀ3ꢀmethylbutanꢀ2ꢀyl)carbamate (2j). 31 g, colorless oil, 60% crude
1
13
yield. H NMR identical to 2d. C NMR (151 MHz, CDCl ) δ 156.9, 79.6, 64.2, 58.1, 29.3, 28.4,
9.5, 18.5. IR: 3332, 2963, 1684, 1506, 1390, 1365, 1246, 1165. HRMS (HESIꢀTOF) m/z calc
for (M+H) (C H NO ) 204.1600, found 204.1597.
3
1
+
+
10
22
3
Tertꢀbutyl (S)ꢀ(1ꢀ(benzyloxy)ꢀ3ꢀhydroxypropanꢀ2ꢀyl)carbamate (2k). 8.2 g, colorless oil, 86%
1
13
crude yield. H NMR identical to 2e. C NMR (151 MHz, CDCl ) δ 156.1, 137.6, 128.5, 127.9,
3
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27.7, 79.7, 73.5, 70.7, 64.0, 51.6, 28.4. IR: 3338, 3005, 2979, 2359, 1685, 1497, 1365, 1275,
+
+
1260, 1164. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 282.1705, found 282.1699.
15
24
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Ethyl (S,E)-4-((tert-butoxycarbonyl)amino)-5-phenylpent-2-enoate (3b). A 2000mL 3ꢀneck
rb flask was equipped with a mechanical stirrer and a nitrogen inlet. The flask was charged with
a solution of crude tertꢀbutyl (S)ꢀ(1ꢀhydroxyꢀ3ꢀphenylpropanꢀ2ꢀyl)carbamate 2b (40.00 g, 159.1
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
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mmol) in dry DCM (720 mL). Solid NaHCO (40.10 g, 477.5 mmol, 3 eq) was added, followed by
3
DMP (101.20 g, 238.60 mmol, 1.50 eq). The reaction mixture was stirred at rt for 2h and
followed by TLC (30% EtOAc/hex). The reaction mixture was cooled to 0° C and treated with aq
Na S O solution (50% w/v, 200 mL) followed by sat aq NaHCO (100 mL) and water (200 mL).
The two phase mixture was vigorously stirred for 15m. Stirring was stopped and the phases
were allowed to separate. The lower DCM phase was drawn from the flask by siphon. The flask
was charged with DCM (600 mL). Stirring was resumed for 5m, then stopped. The lower organic
phase was drawn from the flask by siphon. The aq phase was drawn from the flask by siphon
and discarded. The combined organic phase was returned to the flask and washed with brine
2
2
3
3
(
300 mL). The organic phase was drawn from the flask by siphon, dried over MgSO , filtered
4
and evaporated to afford the crude aldehyde as an oil. The aldehyde was immediately used
without further characterization.
A 1000 mL rb flask was equipped with a magnetic stir bar and ground glass jointed nitrogen
inlet. The flask was charged with a solution of tertꢀbutyl (S)ꢀ(1ꢀoxoꢀ3ꢀphenylpropanꢀ2ꢀ
yl)carbamate derived from the above procedure in dry DCM (480 mL). Solid
(ethoxycarbonylmethylene)triphenylphosphorane (60.90 g, 175.01 mmol) was added in portions
with stirring at rt. The homogenous solution was stirred at rt for 24h. The solution was partially
evaporated in vacuo to a moderately viscous oil. Solid silica gel was added to the oil and the
mixture swirled to effect complete suspension of the silica gel. All volatiles were then removed in
vacuo and the free flowing dry silica gel placed atop a silica gel column hand packed with
hexanes. Elution of the column (5ꢀ10% EtOAc/hexanes) afforded the title compound as a
1
colorless oil (23.0 g, 45% yield from crude 2b). H NMR (600 MHz, CDCl ) δ 7.32 (t, J = 7.4 Hz,
3
2H), 7.28 – 7.26 (m, 1H), 7.19 (dd, J = 7.0, 1.8 Hz, 2H), 6.93 (dd, J = 15.7, 5.0 Hz, 1H), 5.88
(
dd, J = 15.7, 1.8 Hz, 1H), 4.64 – 4.56 (m, 2H), 4.20 (quar, J = 7.1 Hz, 2H), 2.94 – 2.90 (m, 2H),
13
1.42 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H). C NMR (151 MHz, CDCl ) δ 166.1, 154.9, 147.6, 136.4,
3
129.4, 128.6, 126.9, 121.1, 60.5, 28.3, 14.2. IR: 3351, 2979, 1716, 1688, 1520, 1161. HRMS
+
+
(
HESIꢀTOF) m/z calc for (M+H) (C H NO ) 320.1862, found 320.1856.
18 26 4
The following additional intermediates were prepared using the method described for 3b.
Ethyl (S,E)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (3a). 24 g, colorless oil, 54% yield
1
from crude 2a. H NMR (600 MHz, CDCl ) δ 6.87 (dd, J = 15.8, 4.7 Hz, 1H), 5.90 (dd, J = 15.7,
1.7 Hz, 1H), 4.61 (d, J = 8.4 Hz, 1H), 4.41 (vbs, 1H), 4.20 (dquar, J
2H), 1.45 (s, 9H), 1.29 (d, J = 7.1 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H) . C NMR (151 MHz, CDCl )
3
= 6.5 Hz, J = 0.6 Hz,
d
quar
3
1
3
δ 166.4, 154.9, 149.4, 120.1, 79.7, 60.4, 47.0, 28.4, 20.3, 14.2. IR: 3349, 2977, 1689, 1515,
+
+
1366, 1245, 1161, 1045. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 244.1549, found
12 22 4
244.1544.
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Ethyl (S,E)-4-((tert-butoxycarbonyl)amino)-6-methylhept-2-enoate (3c). 27 g, colorless oil,
1
6
5% yield from crude 2c. H NMR (600 MHz, CDCl ) δ 6.87 (dd, J = 15.6, 5.2 Hz, 1H), 5.92 (dd,
3
J = 15.6, 1.5 Hz, 1H), 4.51 (d, J = 8.8 Hz, 1H), 4.38 – 4.31 (m, 1H), 4.19 (dquar, Jquar = 7.1 Hz,
J = 1.5 Hz, 2H), 1.69 (septet, J = 6.8 Hz, 1H), 1.45 (s, 9H), 1.39 (t, J = 7.3 Hz, 2H), 1.29 (t, J =
d
13
7
.0 Hz, 3H), 0.94 (t, J = 6.7 Hz, 6H). C NMR (151 MHz, CDCl ) δ 166.4, 155.1, 148.9, 120.4,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
9.6, 60.4, 49.8, 43.9, 28.4, 24.7, 22.7, 22.2, 14.2. IR: 3349, 2958, 1688, 1517, 1366, 1275,
+
+
1261, 1161. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 286.2018, found 286.2013.
15
28
4
Ethyl (S,E)-4-((tert-butoxycarbonyl)amino)-5-methylhex-2-enoate (3d). 36 g, colorless oil,
1
5
8% yield from crude 2d. H NMR (600 MHz, CDCl ) δ 6.87 (dd, J = 15.7, 5.1 Hz, 1H), 5.93 (dd,
3
J = 15.6, 1.6 Hz, 1H), 4.60 (d, J = 8.1 Hz, 1H), 4.20 (dquar, Jquar = 7.3, J = 2.1 Hz, 3H), 1.87
d
(septet, J = 13.1, 6.6 Hz, 1H), 1.46 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H),
13
0
.92 (d, J = 6.8 Hz, 3H). C NMR (151 MHz, CDCl ) δ 166.3, 155.4, 147.3, 121.5, 79.7, 60.4,
3
5
6.7, 32.3, 28.4, 18.8, 18.0, 14.2. IR: 3341, 2966, 1698, 1514, 1366, 1301, 1158. HRMS (HESIꢀ
+
+
TOF) m/z calc for (M+H) (C H NO ) 272.1862, found 272.1856.
14 26
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Ethyl (R,E)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (3e).
35 g,
1
colorless oil, 60% yield from crude 2e. H NMR (600 MHz, CDCl ) δ 7.39 – 7.35 (m, 2H), 7.32
3
(
ddd, J = 6.1, 2.1, 1.2 Hz, 3H), 6.95 (dd, J = 15.7, 5.0 Hz, 1H), 6.00 (dd, J = 15.7, 1.8 Hz, 1H),
4.60 – 4.49 (m, 3H), 4.21 (dquar, J = 7.1 Hz, J = 1.4 Hz, 2H), 3.60 (m, 1H), 1.46 (s, 9H),
quar
d
1
3
1
1
1
.31 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl ) δ 166.1, 155.2, 146.1, 137.5, 128.5, 127.9,
3
27.7, 122.0, 79.8, 73.3, 71.3, 60.4, 51.4, 28.4, 14.2. IR: 3349, 2982, 1706, 1496, 1365, 1275,
260, 1161. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 350.1967, found 350.1964.
+
+
19
28
5
Ethyl (R,E)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (3f). 28 g, colorless oil, 46% yield
1
13
from crude 2f. H NMR identical to 3a. C NMR (151 MHz, CDCl ) δ 166.4, 154.9, 149.3, 120.2,
3
7
9.7, 60.4, 47.0, 28.4, 20.3, 14.2. IR: 3330, 2982, 1718, 1677, 1523, 1366, 1247, 1161. HRMS
+
+
(
HESIꢀTOF) m/z calc for (M+H) (C H NO ) 244.1549, found 244.1542.
12 22 4
Ethyl (R,E)-4-((tert-butoxycarbonyl)amino)-5-phenylpent-2-enoate (3g). 35 g, colorless oil,
1
13
7
3% yield from crude 2g. H NMR identical to 3b. C NMR (151 MHz, CDCl ) δ 166.1, 154.9,
3
1
47.6, 136.4, 129.4, 128.6, 126.9, 121.1, 79.9, 60.5, 52.3, 40.9, 28.3, 14.2. IR: 3351, 2979,
+
+
1716, 1688, 1520, 1366, 1288, 1161. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO )
18
26
4
320.1862, found 320.1856.
Ethyl (R,E)-4-((tert-butoxycarbonyl)amino)-6-methylhept-2-enoate (3h). 25.6 g, colorless
1
13
oil, 59% yield from crude 2h. H NMR identical to 3c. C NMR (201 MHz, CDCl ) δ 166.4,
3
155.1, 148.9, 120.4, 79.7, 60.4, 49.8, 43.9, 28.4, 24.7, 22.7, 22.2, 14.2. IR: 3340, 2958, 1689,
+
+
1
517, 1366, 1275, 1261, 1165. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 286.2018,
15 28 4
found 286.2013.
Ethyl (R,E)-4-((tert-butoxycarbonyl)amino)-5-methylhex-2-enoate (3j). 3.8 g, colorless oil,
1
13
5
6% yield from crude 2j. H NMR identical to 3d. C NMR (151 MHz, CDCl ) δ 166.3, 155.3,
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2
2
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2
2
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2
47.3, 121.5, 79.7, 60.4, 56.7, 32.3, 28.4, 18.8, 18.0, 14.2. IR: 3340, 2966, 1698, 1654, 1515,
+
+
231, 1277, 1158. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H NO ) 272.1862, found
14
26
4
72.1855.
Ethyl (S,E)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)pent-2-enoate (3k).
7.3 g,
1
13
colorless oil, 71% yield from crude 2k. H NMR identical to 3e. C NMR (151 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
166.2, 155.2, 146.1, 137.5, 128.5, 127.9, 127.7, 122.0, 79.9, 73.3, 71.3, 60.5, 51.4, 28.4, 14.3.
+
IR: 3346, 2983, 1703, 1496, 1365, 1275, 1260, 1161. HRMS (HESIꢀTOF) m/z calc for (M+H)
(C H NO ) 350.1967, found 350.1961.
+
19
28
5
Ethyl (4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)ꢀ5ꢀphenylpentanoate (4b).
A 1000 mL round bottom flask was equipped with a magnetic stir bar, septum and nitrogen inlet.
The flask was charged with a solution of ethyl (S,E)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ5ꢀ
phenylpentꢀ2ꢀenoate 3b (23.00 g, 72.00 mmol) in dry DCM (60 mL). Ethanolamine (17.20 mL,
288.00 mmol, 4.00 eq) was added by syringe. The homogenous solution was stirred at rt for
4
8h. The progress of the reaction was followed by TLC (80% EtOAc/hex). The solution was
evaporated to an oil, redissolved in EtOAc (200 mL) and washed with brine. The aqueous layer
was back extracted with EtOAc (200 mL). The combined organic phases were dried over
MgSO , filtered and evaporated to give the title compound as an oil (22 g, 80% crude yield). The
4
title compound was used without further purification.
The following additional intermediates were prepared using the method described for 4b.
Ethyl (4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)pentanoate (4a). 30 g,
colorless oil, 86% crude yield from 3a.
Ethyl (4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)ꢀ6ꢀmethylheptanoate (4c).
32 g, colorless oil, 95% crude yield from 3c.
Ethyl (4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)ꢀ5ꢀmethylhexanoate (4d). 37
g, colorless oil, 83% crude yield from 3d.
Ethyl (4R)ꢀ5ꢀ(benzyloxy)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)pentanoate
(4e). 39 g, colorless oil, 94% crude yield from 3e.
Ethyl (4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)pentanoate (4f). 27 g,
colorless oil, 77% crude yield from 3f.
Ethyl (4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)ꢀ5ꢀphenylpentanoate (4g).
38 g, colorless oil, 91% crude yield from 3g.
Ethyl (4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)ꢀ6ꢀmethylheptanoate (4h).
31.8 g, colorless oil, 102% crude yield from 3h.
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Ethyl (4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)ꢀ5ꢀmethylhexanoate (4j). 4.5
g, colorless oil, 96% crude yield from 3j.
Ethyl
(4S)ꢀ5ꢀ(benzyloxy)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)pentanoate
(
4k). 8.5 g, colorless oil, 99% crude yield from 3k.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
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3
3
3
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5
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6
7
8
9
0
Ethyl
(4S)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)-5-phenylpentanoate (5b). A 1000 mL rb flask was equipped with a
magnetic stirring bar and nitrogen inlet. The flask was charged with a solution of crude ethyl
(
5
4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((2ꢀhydroxyethyl)amino)ꢀ5ꢀphenylpentanoate 4b (22.00 g,
7.80 mmol) in dry ACN (225 mL). Solid Na CO (36.80 g, 347.00 mmol, 6.0 eq) was added,
2
3
followed by 2ꢀnitrobenzenesulfonyl chloride (NsCl, 25.60 g, 116.00 mmol, 2.0 eq). The reaction
°
was stirred at 45 C for 24h. The reaction was cooled to rt and filtered. The filtrate was
partitioned between brine (200 mL) and EtOAc (100 mL; Note: it is not necessary to remove
acetonitrile if brine is used. No emulsification is observed). The aq phase was extracted with
EtOAc (100 mL). The combined organic phases were dried over MgSO , filtered and evaporated
4
to an oil. The crude product was chromatographed over silica gel with an EtOAc/hexane
gradient (20ꢀ40% EtOAC/hexanes) to afford the inseparable title compounds as a yellow oil
1
(
22.0 g, 38.90 mmol, 67% yield from crude 4b). H NMR (600 MHz, CDCl ) δ 8.17 (dt, J = 7.2,
3
3
3
0
.0 Hz, 1H), 7.74 – 7.57 (m, 3H), 7.27 – 7.13 (m, 6H), 4.40 – 4.35 (m, 2H), 4.15 – 4.07 (m, 4H),
.92 (bm, 2H), 3.71 – 3.66 (m, 1H), 3.53 (dt, J = 15.6, 5.9 Hz, 1H), 3.21 (dd, J = 14.4, 3.7 Hz,
.66H), 2.76 (bm, 1H), 2.74 (dd, J = 16.0, 3.8 Hz, 1.5H), 2.48 (dd, J = 16.1, 3.6 Hz, 0.69H), 2.32
13
(dd, J = 14.4, 10.8 Hz, 0.72H), 1.28 – 1.22 (m, 13H). C NMR (151 MHz, CDCl ) δ 171.9,
3
171.2, 170.0, 155.8, 148.1, 137.5, 134.0, 132.5, 131.9, 131.8, 131.61, 131.58, 131.4, 129.5,
129.1, 128.55, 128.45, 128.38, 126.54, 126.46, 125.0, 124.1, 123.9, 79.8, 79.4, 62.4, 61.9, 61.3,
61.1, 60.4, 58.8, 58.6, 54.2, 53.4, 47.9, 47.6, 39.3, 39.0, 36.5, 36.3, 28.12, 28.10, 28.03, 21.0,
14.2, 14.1, 14.0. IR: 2978, 1701, 1543, 1367, 1246, 1160. HRMS (HESIꢀTOF) m/z calc for
+
+
(
M+H) (C H N O S) 566.2172, found 566.2170.
26 36 3 9
The following additional intermediates were prepared using the method described for 5b.
Ethyl
nitrophenyl)sulfonamido)pentanoate (5a). 30 g, yellow oil 71% yield from crude 4a. H NMR
600 MHz, CDCl ) δ 8.14 – 7.98 (m, 1H), 7.83 – 7.60 (m, 3H), 4.51 (vbs, 1H), 4.28 – 4.03 (m,
(4S)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
1
(
3
3H), 3.90 – 3.62 (m, 3H), 3.50 (t, J = 6.0 Hz, 1H), 2.76 – 2.72 (m, 0.62H), 2.62 – 2.48 (m,
1.34H), 1.40 (s, 3H), 1.36 (s, 6H), 1.31 (d, J = 4.6 Hz, 1H), 1.28 – 1.14 (m, 4H), 1.05 (bd, J = 5.6
13
Hz, 3H). C NMR (151 MHz, CDCl ) δ 172.1, 170.9, 170.1, 155.5, 148.0, 133.9, 131.8, 131.70,
3
1
3
31.65, 131.4, 125.0, 124.0, 79.9, 69.9, 62.1, 61.8, 61.3, 61.2, 61.1, 60.4, 59.5, 48.8, 47.9, 47.4,
6.9, 36.5, 28.30, 28.28, 28.22, 19.5, 19.2, 14.2, 14.1, 14.0. IR: 2979, 1701, 1543, 1367, 1159.
+
+
HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 490.1859, found 490.1856.
20
32
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9
Ethyl
(4S)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)-6-methylheptanoate (5c). 29 g, yellow oil, 59% yield from crude
1
4
c. H NMR (600 MHz, CDCl ) δ 8.15 – 8.04 (m, 1H), 7.74 – 7.70 (m, 3H), 7.62 – 7.56 (m, 1H),
3
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2
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3
3
3
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3
3
3
3
4
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
.27 (d, J = 10.1 Hz, 1H), 4.18 – 4.07 (m, 3H), 3.92 – 3.77 (m, 4H), 3.59 – 3.49 (m, 3H), 2.75
(
dd, J = 16.0, 8.5 Hz, 1H), 2.55 – 2.51 (m, 0.4H), 2.48 – 2.45 (m, 1.3H), 1.45 – 1.26 (m
overlapping s, 12H), 1.26 (m overlapping t, J = 7.1 Hz, 6H), 0.90 (m, 3H), 0.79 (d, J = 6.8 Hz,
13
3H), 0.76 (d, J = 6.6 Hz, 3H). C NMR (151 MHz, CDCl ) δ 172.2, 155.9, 148.0, 133.8, 131.8,
3
1
3
1
31.62, 131.61, 124.02, 123.95, 79.9, 62.3, 61.9, 61.2, 61.1, 59.2, 51.0, 47.5, 41.9, 39.4, 36.8,
5.5, 28.3, 28.3, 24.6, 23.6, 21.1, 19.3, 14.12, 14.05. IR: 2985, 1701, 1543, 1367, 1275, 1260,
160. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 532.2329, found 532.2327.
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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8
9
0
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8
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0
1
2
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
23
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Ethyl
(4S)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)-5-methylhexanoate (5d). 16 g, yellow oil, 27% yield from crude 4d.
1
H NMR (600 MHz, CDCl ) δ 8.18 (dd, J = 7.2, 1.5 Hz, 1H), 8.03 (d, J = 9.0 Hz, 0.7H), 7.76 –
3
7.67 (m, 4H), 7.63 (d, J = 6.8 Hz, 0.8H), 7.57 (d, J = 9.1 Hz, 0.8H), 5.15 (d, J = 10.9 Hz, 0.6H),
4.41 – 4.29 (m, 2H), 4.14 – 3.89 (m, 6H), 3.86 – 3.71 (m, 4H), 3.60 (dt, J = 15.7, 5.1 Hz, 1H),
3.52 – 3.39 (m, 2H), 2.70 – 2.58 (m, 2.5H), 2.49 (d, J = 6.1 Hz, 0.6H), 2.36 (dd, J = 16.8, 2.0 Hz,
13
1H), 1.88 – 1.82 (m, 1H), 1.37 – 1.19 (m, 22H), 0.96 – 0.87 (m, 8H). C NMR (151 MHz, CDCl )
3
δ 172.1, 171.2, 171.0, 156.8, 156.5, 148.2, 148.1, 134.0, 133.6, 132.8, 132.3, 132.2, 131.7,
131.5, 131.2, 124.1, 123.7, 79.9, 79.7, 62.1, 62.0, 61.3, 60.9, 60.4, 56.9, 56.8, 56.5, 47.8, 36.5,
3
1
5
6.4, 29.2, 28.27, 28.26, 26.9, 20.7, 20.2, 15.0, 14.4, 14.2, 14.0. IR: 3427, 2969, 1707, 1544,
367, 1244, 1159. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 518.2172, found
18.2170.
+
+
22
36
3
9
Ethyl
(4R)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)pentanoate (5e). 15g, yellow oil, 41% yield from crude 4e. See
Scheme 3 for separation of 5e syn/5e anti diastereomers.
Ethyl
(4R)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
1
nitrophenyl)sulfonamido)pentanoate (5f). 29 g, yellow oil, 66% yield from crude 4f. H NMR
1
13
(
600 MHz, CDCl ) H NMR identical to 5a. C NMR (151 MHz, CDCl ) δ 172.1, 171.2, 170.9,
3
3
1
1
70.1, 155.5, 148.2, 148.0, 135.0, 133.9, 132.7, 132.4, 132.0, 131.9, 131.7, 131.64, 131.60,
31.5, 125.0, 124.1, 79.9, 61.8, 61.3, 61.2, 61.1, 60.4, 59.6, 48.8, 47.9, 36.9, 28.3, 28.2, 21.0,
19.6, 19.2, 14.2, 14.1, 14.0. IR: 2979, 1701, 1543, 1367, 1159. HRMS (HESIꢀTOF) m/z calc for
+
+
(
M+H) (C H N O S) 490.1859, found 490.1858.
20 32 3 9
Ethyl
(4R)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)-5-phenylpentanoate (5g). 32 g, yellow oil, 56% yield from crude
1
1
13
4g. H NMR (600 MHz, CDCl ) H NMR identical to 5b. C NMR (151 MHz, CDCl ) δ 171.9,
3
3
170.9, 155.8, 148.1, 137.5, 137.0, 135.2, 134.0, 133.7, 132.54, 132.47, 132.38, 132.32, 131.9,
131.8, 131.62, 131.56, 131.45, 129.5, 129.09, 129.05, 128.62, 128.56, 128.45, 128.39, 126.6,
126.5, 125.0, 124.4, 124.1, 123.9, 79.8, 79.5, 62.4, 61.9, 61.3, 61.1, 60.4, 58.8, 58.6, 54.2, 53.4,
47.9, 47.6, 39.4, 39.0, 36.5, 36.4, 31.6, 28.12, 28.10, 25.3, 22.7, 21.0, 20.7, 14.2, 14.1, 14.0. IR:
+
3376, 2978, 1701, 1543, 1367, 1246, 1160. HRMS (HESIꢀTOF) m/z calc for (M+H)
+
(
C H N O S) 566.2172, found 566.2171.
26 36 3 9
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Ethyl
(4R)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)-6-methylheptanoate (5h). 22 g, yellow oil, 45% yield from crude
1
4
h. H NMR (600 MHz, CDCl ) δ 8.08 – 7.97 (m, 1H), 7.77 – 7.66 (m, 2H), 7.62 – 7.52 (m, 1H),
3
5.06 (d, J = 10.7 Hz, 1H), 4.31 – 4.19 (m, 1H), 4.06 (dquar, Jquar = 7.2 Hz, J = 2.5 Hz, 2H), 3.98
d
–
3.83 (m, 1H), 3.80 (ddd, J = 10.9, 8.7, 2.9 Hz, 1H), 3.50 (ddd, J = 16.0, 5.7, 2.8 Hz, 1H), 3.34
(
ddd, J = 16.0, 7.1, 2.8 Hz, 1H), 2.72 – 2.52 (m, 2H), 1.50 – 1.43 (m, 1H), 1.42 – 1.38 (m, 2H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
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7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
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2
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7
8
9
0
13
1.30 – 1.24 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H), 0.92 (dd, J = 12.7, 6.6 Hz, 6H). C NMR (201
MHz, CDCl ) δ 171.1, 156.3, 148.3, 133.7, 132.5, 131.6, 131.4, 123.7, 79.6, 62.3, 61.3, 59.7,
3
51.1, 48.1, 42.9, 36.3, 28.3, 28.2, 28.2, 25.0, 23.8, 21.5, 14.0. IR: 2985, 1701, 1544, 1367,
+
+
1275, 1260, 1161, 1024. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 532.2329,
23 38 3 9
found 532.2322.
Ethyl
(4R)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)-5-methylhexanoate (5j). 1.32 g, yellow oil, 18% yield from crude 4j.
1
H NMR (600 MHz, CDCl ) δ 8.18 (dd, J = 7.2, 1.5 Hz, 1H), 8.03 (d, J = 9.0 Hz, 0.7H), 7.76 –
3
7.67 (m, 4H), 7.63 (d, J = 6.8 Hz, 0.8H), 7.57 (d, J = 9.1 Hz, 0.8H), 5.15 (d, J = 10.9 Hz, 0.6H),
4.41 – 4.29 (m, 2H), 4.14 – 3.89 (m, 6H), 3.86 – 3.71 (m, 4H), 3.60 (dt, J = 15.7, 5.1 Hz, 1H),
3.52 – 3.39 (m, 2H), 2.70 – 2.58 (m, 2.5H), 2.49 (d, J = 6.1 Hz, 0.6H), 2.36 (dd, J = 16.8, 2.0 Hz,
1
H), 1.88 – 1.82 (m, 1H), 1.41 (s, 5H), 1.37 (s, 4H), 1.28 – 1.19 (m, 5H), 0.96 – 0.87 (m, 6H).
1
3
C NMR (151 MHz, CDCl ) δ 172.1, 171.2, 171.0, 156.8, 156.5, 148.2, 148.1, 134.0, 133.6,
3
132.8, 132.3, 132.2, 131.7, 131.5, 131.2, 124.1, 123.7, 79.8, 79.7, 62.1, 62.0, 61.3, 60.9, 60.4,
56.9, 56.8, 56.5, 47.8, 36.5, 36.4, 29.2, 28.27, 28.26, 26.9, 20.7, 20.2, 15.0, 14.4, 14.2, 14.0. IR:
+
3427, 2969, 1708, 1544, 1367, 1244, 1159, 1024. HRMS (HESIꢀTOF) m/z calc for (M+H)
+
(
C H N O S) 518.2172, found 518.2170.
22 36 3 9
Ethyl
(4S)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)pentanoate (5k). 4.7 g, yellow oil, 38% yield from crude 4k. See
Scheme 3 for separation of 5k syn/5k anti diastereomers.
Ethyl
(4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ2ꢀ
nitrophenyl)sulfonamido)ꢀ5ꢀphenylpentanoate (6b). A 500 mL rb flask was equipped with a
magnetic stir bar, rubber septum and nitrogen inlet. The flask was charged with a solution of
ethyl (4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((Nꢀ(2ꢀhydroxyethyl)ꢀ2ꢀnitrophenyl)sulfonamido)ꢀ5ꢀ
phenylpentanoate 5b (22.0 g, 38.89 mmol) in dry DCM (200 mL). The flask was cooled to −78°
C. TEA (6.51 mL, 46.7 mmol, 1.20 eq) was added by syringe, followed by MsCl (3.61 mL, 46.7
mmol, 1.20 eq). The reaction was stirred at −78° C for 1h. Complete conversion to the mesylate
was confirmed by TLC (20% EtOAc/hex). The cold reaction was poured into a separatory funnel
followed by saturated aq NaHCO (200 mL). The layers were separated and the organic washed
once with brine (200 mL). The organic layer was dried over MgSO , filtered and evaporated to
give the title compound as a yellow oil. The compounds were immediately used without further
purification or characterization.
3
4
The following additional intermediates were prepared using the method described for 6b. In all
cases TLC data (20% EtOAc/hex, double elution) indicated 100% conversion of alcohols 5a-d,
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5
5
5
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5
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f-j to their corresponding mesylates. The crude products, all yellow oils, were used without
further characterization and under the assumption of quantitative yield.
Ethyl
(4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ2ꢀ
nitrophenyl)sulfonamido)pentanoate (6a).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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4
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
Ethyl
(4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ6ꢀmethylꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ2ꢀ
nitrophenyl)sulfonamido)heptanoate (6c).
Ethyl
(4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ5ꢀmethylꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ2ꢀ
nitrophenyl)sulfonamido)hexanoate (6d).
Ethyl
(4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ4ꢀ
nitrophenyl)sulfonamido)pentanoate (6f).
Ethyl
(4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ4ꢀ
nitrophenyl)sulfonamido)ꢀ5ꢀphenylpentanoate (6g).
Ethyl
(4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ6ꢀmethylꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ4ꢀ
nitrophenyl)sulfonamido)heptanoate (6h).
Ethyl
(4R)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ5ꢀmethylꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ4ꢀ
nitrophenyl)sulfonamido)hexanoate (6j).
Ethyl 2ꢀ((3S)ꢀ3ꢀbenzylꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperazinꢀ2ꢀyl)acetate (7b). A 500 mL rb flask
was equipped with a magnetic stir bar and nitrogen inlet. The flask was charged with a solution
of
ethyl
(4S)ꢀ4ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ((Nꢀ(2ꢀ((methylsulfonyl)oxy)ethyl)ꢀ2ꢀ
nitrophenyl)sulfonamido)ꢀ5ꢀphenylpentanoate 6b (assuming 100% conversion of 5b to 6b) in dry
°
DCM (100 mL). The solution was cooled to 0 C and was treated with TFA (17.85 mL, 233.34
mmol, 6 eq). The solution was stirred for 16h as it slowly warmed in the cold bath. The reaction
progress was followed by TLC (30% EtOAc/hexanes) and LCMS analysis of samples withdrawn
from the reaction and partitioned between aq NaHCO and EtOAc. Toluene (20 mL) was added
3
and the solution evaporated in vacuo to an oil. Toluene (20 mL) was again added and swirled to
effect dissolution, then evaporated to an oil. The oil was dissolved in EtOAc (150 mL) and, with
stirring, treated dropwise with sat aq NaHCO (200 mL) until basic. The twoꢀphase mixture was
3
vigorously stirred at rt for 1h. The reaction was partitioned and the aq was extracted with EtOAc
(2 x 100 mL). The combined EtOAc layers were washed with brine, dried over MgSO , filtered
4
and evaporated to an oil to afford an inseparable mixture of diastereomers 7b as a yellow oil
(
16g, 75% crude yield). The crude product was taken forward into the next step without further
purification (Note: diastereomers 7d and 7j could be separated by chromatography over silica
+
+
gel (40% EtOAc/hexanes). LCMS m/z calc for (M+H) (C H N O S) 448.2, found 448.1.
21 26
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6
The following additional intermediates were prepared using the method described for 7b.
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Ethyl 2ꢀ((3S)ꢀ3ꢀmethylꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperazinꢀ2ꢀyl)acetate (7a). 22.0 g, 96% crude
+
+
yield from 5a. LCMS m/z calc for (M+H) (C H N O S) 372.1, found 372.1.
15
22
3
6
Ethyl 2ꢀ((3S)ꢀ3ꢀisobutylꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperazinꢀ2ꢀyl)acetate (7c). 20.0 g, 88% crude
+
+
yield from 5c. LCMS m/z calc for (M+H) (C H N O S) 414.2, found 414.1.
18
28
3
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ethyl 2-((2R,3S)-3-isopropyl-1-((2-nitrophenyl)sulfonyl)piperazin-2-yl)acetate (7d cis, the
more retained isomer). Isolated by chromatography (40% EtOAc/hexanes). 2.8 g, 22% yield
1
from 5d. H NMR (600 MHz, CDCl ) δ 8.12 (dd, J = 5.2, 1.4 Hz, 1H), 7.77 – 7.59 (m, 3H), 4.49
3
(
dt, J = 8.3, 3.8 Hz, 1H), 3.90 (dquar, Jquar = 7.2 Hz, J = 3.5 Hz, 2H), 3.81 (dt, J = 13.8 Hz, J =
d d t
1
.4 Hz, 1H), 3.30 (dt, J = 13.2 Hz, J = 2.9 Hz, 1H), 3.02 (bd, J = 11.8 Hz, 1H), 2.80
t d
(
overlapping dd, J = 15.3, 8.9 Hz, 2H), 2.51 (dd, J = 15.2, 4.5 Hz, 1H), 2.44 (d, J = 9.8 Hz, 1H),
1.36 (dpent, J = 9.7, 6.6 Hz, 1H), 1.18 (dt, J = 7.2 Hz, J = 0.9 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H),
t
d
1
3
0
1
1
.94 (d, J = 6.5 Hz, 3H). C NMR (151 MHz, CDCl ) δ 171.4, 147.6, 134.3, 133.2, 131.7, 131.4,
3
24.0, 65.7, 60.7, 53.5, 47.0, 41.5, 31.2, 29.3, 19.7, 18.7, 14.0. IR: 3004, 2988, 1728, 1541,
25
275, 1260, 1159. Chiral analysis on ChiralPak IE (heptane/iPrOH). [α] −4.96 (c 5.0, EtOH).
HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 400.1542, found 400.1533.
D
+
+
17
26
3
6
Ethyl 2-((2S,3S)-3-isopropyl-1-((2-nitrophenyl)sulfonyl)piperazin-2-yl)acetate (7d trans, the
1
less retained isomer). 3.0 g, 24% yield from 5d. H NMR (600 MHz, CDCl ) δ 8.11 (dt, J = 6.0
3
t
Hz, J = 1.5 Hz, 1H), 7.79 – 7.61 (m, 3H), 4.35 (dt, J = 10.3 Hz, J = 1.5 Hz, 1H), 4.10 (dquar,
d
d
t
Jquar = 7.1, J = 2.6 Hz, 2H), 3.78 (dt, J = 10.9 Hz, J = 2.0 Hz, 1H), 3.31 (dd, J = 16.2, 10.2 Hz,
d
d
t
1H), 3.24 – 3.13 (m, 1H), 3.04 (dt, J = 12.3 Hz, J = 3.6 Hz, 1H), 2.69 (ddd, J = 11.9, 3.5, 1.6
t
d
Hz, 1H), 2.42 (dd, J = 16.2, 2.9 Hz, 1H), 2.16 (dd, J = 10.5, 1.4 Hz, 1H), 2.01 (dpent, Jpent = 10.3
Hz, J = 6.6 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.5 Hz, 3H).
d
13
C NMR (151 MHz, CDCl ) δ 171.3, 147.6, 133.6, 131.8, 131.3, 124.3, 61.0, 60.6, 50.6, 41.8,
3
3
9.3, 35.4, 24.6, 19.9, 18.9, 14.2. IR: 3004, 2988, 1728, 1541, 1275, 1260, 1158. Chiral analysis
25
on ChiralPak IA (heptane/EtOH). [α]
−4.62 (c 5.0, EtOH) HRMS (HESIꢀTOF) m/z calc for
D
+
+
(
M+H) (C H N O S) 400.1542, found 400.1532.
17 26 3 6
Ethyl 2ꢀ((3R)ꢀ3ꢀmethylꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperazinꢀ2ꢀyl)acetate (7f). 20 g, 90% crude
+
+
yield from 5f. LCMS m/z calc for (M+H) (C H N O S) 372.1, found 372.1.
15
22
3
6
Ethyl 2ꢀ((3R)ꢀ3ꢀbenzylꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperazinꢀ2ꢀyl)acetate (7g). 24 g, 77% crude
+
+
yield from 5g. LCMS m/z calc for (M+H) (C H N O S) 448.2, found 448.2.
21
26
3
6
Ethyl 2ꢀ((3R)ꢀ3ꢀisobutylꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperazinꢀ2ꢀyl)acetate (7h). 20 g, 83% crude
+
+
yield from 5h. LCMS m/z calc for (M+H) (C H N O S) 414.2, found 414.1.
18
28
3
6
Ethyl 2-((2S,3R)-3-isopropyl-1-((2-nitrophenyl)sulfonyl)piperazin-2-yl)acetate (7j cis, the
more retained isomer). Isolated by chromatography (40% EtOAc/hexanes). 160 mg, 32% yield
1
13
from 5j. H NMR identical to 7d cis. C NMR (151 MHz, CDCl ) δ 171.4, 147.6, 134.3, 133.2,
3
131.7, 131.5, 124.0, 65.7, 60.7, 53.5, 47.0, 41.5, 31.2, 29.3, 19.7, 18.7, 14.0. IR: 3004, 2988,
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9
1
1
1
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
25
1
5
728, 1541, 1275, 1260, 1159. Chiral analysis on ChiralPak IE (heptane/iPrOH). [α] +4.66 (c
D
+
+
.0, EtOH) HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 400.1542, found 400.1539.
17
26
3
6
Ethyl 2-((2R,3R)-3-isopropyl-1-((2-nitrophenyl)sulfonyl)piperazin-2-yl)acetate (7j trans, the
less retained isomer). 302 mg, 60% yield from 5j. H NMR identical to 7d trans. C NMR (151
1
13
MHz, CDCl ) δ 171.3, 147.7, 133.5, 131.8, 131.4, 124.3, 61.1, 60.6, 50.6, 41.8, 39.3, 35.4, 24.6,
9.9, 18.9, 14.2. IR: 3004, 2988, 1728, 1541, 1275, 1260, 1159. Chiral analysis on ChiralPak IA
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
25
+
(
(
heptane/EtOH). [α]
C H N O S) 400.1542, found 400.1533.
+4.43 (c 5.0, EtOH) HRMS (HESIꢀTOF) m/z calc for (M+H)
D
+
17 26
3
6
Tert-butyl (2S,3R)-2-benzyl-3-(2-ethoxy-2-oxoethyl)-4-((2-nitrophenyl)sulfonyl)piperazine-
1-carboxylate (8b cis) and Tert-butyl (2S,3S)-2-benzyl-3-(2-ethoxy-2-oxoethyl)-4-((2-
nitrophenyl)sulfonyl)piperazine-1-carboxylate (9b trans). A 500mL rb flask was equipped
with a magnetic stir bar. The flask was charged with a solution of the mixture of diastereomers
ethyl 2ꢀ((3S)ꢀ3ꢀbenzylꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperazinꢀ2ꢀyl)acetate 7b (16.00g, 35.75mmol)
in THF (180 mL). Water (90 mL) was added followed by Na CO (11.35g, 107.25mmol) and
2
3
Boc O (27.30g, 125.13mmol). The reaction was followed by TLC (30% EtOAc/hexane). Stirring
2
at rt for 24h produced a clear solution with a small amount of separated water at the bottom of
the flask. The mixture was partitioned between EtOAc (200 mL) and more water (200 mL). The
layers were separated and the aq extracted again with EtOAc (200 mL). The aq was discarded
and the organic was dried over MgSO , filtered and evaporated to an oil. The crude products
were chromatographed over silica gel with an EtOAc/hexane gradient (10%ꢀ30%
EtOAc/hexane) to afford the two title compounds as yellow oils.
4
1
8b cis (the more retained isomer). 5.7 g, 29% yield from crude 7b. H NMR (600 MHz, CDCl ) δ
.94 (dd, J = 7.8, 1.3 Hz, 1H), 7.77 – 7.59 (m, 3H), 7.33 – 7.25 (m, 3H), 7.25 – 7.20 (m, 1H),
.20 – 7.10 (m, 2H), 4.25 (dt, J = 7.2, J = 3.4 Hz, 1H), 4.19 (dt, J = 9.2 Hz, J = 3.4 Hz, 1H),
.05 (two overlapping dquart, Jquar = 7.1 Hz, J = 3.5 Hz, 2H), 3.79 – 3.68 (m, 2H), 3.62 – 3.54
3
7
7
4
t
d
t
d
d
(
m, 1H), 3.52 – 3.45 (m, 1H), 3.14 (dd, J = 14.2, 9.4 Hz, 1H), 2.97 – 2.90 (m, 2H), 2.82 (dd, J =
13
16.0, 6.8 Hz, 1H), 1.26 – 1.24 (overlapping t and s, 12H). C NMR (151 MHz, CDCl ) δ 170.3,
3
1
5
1
54.1, 147.8, 137.9, 134.2, 133.6, 132.0, 130.5, 129.1, 128.5, 126.5, 124.4, 80.3, 61.1, 58.3,
8.0, 45.8, 41.6, 34.5, 33.8, 28.0, 14.1. IR: 3009, 2986, 1735, 1681, 1543, 1360, 1277, 1260,
25
160. Chiral analysis on ChiralPak ID (heptane/iPrOH). [α]
−1.30 (c 5.0, EtOH). HRMS
D
+
+
(HESIꢀTOF) m/z calc for (M+H) (C H N O S) 548.2067, found 548.2061.
26
34
3
8
1
9b trans (the less retained isomer). 6.4 g, 35% yield from crude 7b. H NMR (600 MHz, CDCl )
3
δ 8.13 – 8.08 (m, 1H), 7.76 – 7.68 (m, 3H), 7.28 – 7.15 (m, 3H), 7.11 – 7.06 (m, 2H), 4.49 (t, J =
.6 Hz, 1H), 4.38 (dd, J = 9.3, 5.5 Hz, 1H), 4.24 – 4.22 (m, 1H), 4.18 – 4.17 (m, 1H), 4.10 (quar,
J = 7.1 Hz, 2H), 3.94 – 3.90 (m, 2H), 3.37 – 3.30 (m, 1H), 3.18 (dt, J = 7.1 Hz, J = 3.5 Hz, 1H),
2.90 – 2.82 (m, 2H), 2.65 (dd, J = 13.9, 5.5 Hz, 1H), 2.44 (dd, J = 16.4, 3.0 Hz, 1H), 1.25 – 1.15
7
t
d
13
(
1
1
two singlets overlapping m, 12H). C NMR (151 MHz, CDCl ) δ 170.4, 170.2, 154.7, 154.6,
47.7, 137.6, 137.1, 133.93, 133.88, 133.20, 133.19, 132.0, 131.7, 131.5, 129.21, 129.16,
29.09, 128.5, 128.4, 128.2, 126.5, 126.4, 124.5, 124.4, 80.4, 80.2, 60.89, 60.87, 55.5, 54.1,
3
52.8, 52.2, 40.9, 39.1, 37.1, 35.6, 35.5, 35.1, 34.7, 28.2, 27.9, 14.1, 14.0. IR: 3004, 2987, 1731,
25
1
688, 1542, 1364, 1275, 1260, 1160. Chiral analysis on ChiralPak ID (heptane/EtOH). [α]D
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2
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5
6
7
8
9
+
+
−
5
1.26 (c 5.0, EtOH). HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 548.2067, found
48.2060.
26
34
3
8
The following additional piperazines were prepared using the above described procedure. In all
cases the cis isomers were the more retained and the trans isomers were the less retained by
silica gel chromatography (10%ꢀ30% EtOAc/hexanes).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cis (8a, 8c, 8f-8h) the more retained isomers
Tert-butyl (2S,3R)-3-(2-ethoxy-2-oxoethyl)-2-methyl-4-((2-nitrophenyl)sulfonyl)piperazine-
1
1
8
4
6
-carboxylate (8a cis). 8.0 g, yellow oil, 28% yield from crude 7a. H NMR (600 MHz, CDCl ) δ
.07 (ddd, J = 5.3, 2.9, 1.4 Hz, 1H), 7.73 – 7.68 (m, 3H), 4.23 (dt, J = 7.0 Hz, J = 3.6 Hz, 1H),
.05 – 4.01 (m, 3H), 3.69 – 3.42 (m, 4H), 2.82 (dd, J = 16.2, 7.2 Hz, 1H), 2.66 (ddd, J = 16.3,
.8, 0.8 Hz, 1H), 1.46 (d, J = 0.9 Hz, 9H), 1.30 (dd, J = 7.0, 1.0 Hz, 3H), 1.23 (dt, J = 6.7 Hz, J
3
t
d
t
d
13
= 1.0 Hz, 3H). C NMR (151 MHz, CDCl ) δ 170.4, 154.4, 147.9, 134.2, 133.6, 131.9, 130.6,
24.4, 80.5, 61.0, 57.9, 52.9, 45.3, 41.7, 34.4, 28.4, 14.2, 14.0. IR: 3004, 2987, 1732, 1687,
3
1
1
5
25
543, 1365, 1275, 1260, 1161. Chiral analysis on ChiralPak IF (heptane/EtOH). [α] −0.83 (c
.0, EtOH). HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 472.1754, found 472.1751.
D
+
+
20 30
3
8
Tert-butyl
(2S,3R)-3-(2-ethoxy-2-oxoethyl)-2-isobutyl-4-((2-
nitrophenyl)sulfonyl)piperazine-1-carboxylate (8c cis). 6.4 g, yellow oil, 25% yield from
1
crude 7c. H NMR (600 MHz, CDCl ) δ 8.06 – 8.04 (m, 1H), 7.72 – 7.66 (m, 3H), 4.25 (dt, J =
7.0 Hz, J = 3.5 Hz, 1H), 4.06 – 3.99 (two overlapping dquar, J
.95 (ddd, J = 10.6, 4.5, 3.4 Hz, 1H), 3.62 – 3.46 (m, 4H), 2.79 (dd, J = 16.2, 7.3 Hz, 1H), 2.68
dd, J = 16.2, 6.8 Hz, 1H), 1.90 (ddd, J = 14.1, 10.7, 4.4 Hz, 1H), 1.61 – 1.52 (m, 1H), 1.45 (s,
3
t
= 7.2 Hz, J = 3.6 Hz, 2H),
d
quar
d
3
(
9
H), 1.22 (two overlapping t, J = 7.1 Hz, 4H), 0.92 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H).
13
C NMR (151 MHz, CDCl ) δ 170.4, 154.6, 147.9, 134.2, 133.6, 131.9, 130.6, 124.4, 80.5, 61.0,
58.0, 55.8, 45.0, 36.7, 34.4, 28.3, 24.6, 23.4, 21.8, 14.1. IR: 3004, 2986, 1732, 1686, 1543,
3
25
1
365, 1275, 1260, 1161. Chiral analysis on ChiralPak IE (heptane/EtOH). [α] −1.67 (c 5.0,
D
+
+
EtOH) HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 514.2223, found 514.2217.
23
36
3
8
Tert-butyl (2R,3S)-3-(2-ethoxy-2-oxoethyl)-2-methyl-4-((2-nitrophenyl)sulfonyl)piperazine-
-carboxylate (8f cis). 7.0 g, yellow oil, 27% yield from crude 7f. H NMR (600 MHz, CDCl ). H
1
1
1
3
13
NMR identical to 8a cis. C NMR (151 MHz, CDCl ) δ 170.4, 154.4, 147.9, 134.2, 133.6,
31.9, 130.6, 124.4, 80.5, 61.0, 57.9, 52.9, 45.3, 41.7, 34.4, 28.4, 14.2, 14.0. IR: 3004, 2987,
732, 1687, 1543, 1365, 1275, 1260, 1161. Chiral analysis on ChiralPak IF (heptane/EtOH).
3
1
1
25
+
+
[α]D +0.79 (c 5.0, EtOH). HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 472.1754,
20
30
3
8
found 472.1750.
Tert-butyl (2R,3S)-2-benzyl-3-(2-ethoxy-2-oxoethyl)-4-((2-nitrophenyl)sulfonyl)piperazine-
-carboxylate (8g cis). 9.5 g, yellow oil, 28% yield from crude 7g. H NMR (600 MHz, CDCl ).
1
1
1
3
13
H NMR identical to 8b cis. C NMR (151 MHz, CDCl ) δ 170.3, 154.1, 147.8, 137.9, 134.2,
33.6, 132.0, 130.5, 129.17, 128.5, 126.5, 124.4, 80.3, 61.1, 58.3, 58.0, 45.8, 41.6, 34.5, 33.8,
8.0, 14.1. IR: 3004, 2987, 1731, 1688, 1542, 1364, 1275, 1260, 1160. Chiral analysis on
3
1
2
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
25
ChiralPak ID (heptane/iPrOH). [α]
(
+1.22 (c 5.0, EtOH). HRMS (HESIꢀTOF) m/z calc for
D
+
+
M+H) (C H N O S) 548.2067, found 548.2064.
26 34 3 8
Tert-butyl
(2R,3S)-3-(2-ethoxy-2-oxoethyl)-2-isobutyl-4-((2-
nitrophenyl)sulfonyl)piperazine-1-carboxylate (8h cis). 3.7 g, yellow oil, 33% yield from
1
1
13
crude 7h. H NMR (600 MHz, CDCl ). H NMR identical to 8c cis. C NMR (151 MHz, CDCl ) δ
70.4, 154.6, 147.8, 134.1, 133.6, 131.9, 130.6, 124.4, 80.5, 61.0, 58.0, 55.8, 45.0, 36.7, 34.4,
8.3, 24.6, 23.4, 21.8, 14.1. IR: 3005, 2988, 2360, 2341, 1731, 1686, 1544, 1365, 1275, 1260,
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
1
25
163. Chiral analysis on ChiralPak IE (heptane/EtOH). [α] +1.70 (c 5.0, EtOH). HRMS (HESIꢀ
D
+
+
TOF) m/z calc for (M+H) (C H N O S) 514.2223, found 514.2222.
23
36
3
8
Trans (9a, 9c, 9f-9h) the less retained isomers
Tert-butyl (2S,3S)-3-(2-ethoxy-2-oxoethyl)-2-methyl-4-((2-nitrophenyl)sulfonyl)piperazine-
-carboxylate (9a trans). 7.0 g, yellow oil, 25% yield from crude 7a. H NMR (600 MHz, CDCl )
1
1
3
δ 8.10 (t, J = 7.0 Hz, 1H), 7.75 – 7.69 (m, 3H), 4.24 – 4.23 (m, 1H), 4.15 – 4.04 (m, 4H), 3.86 –
.84 (m, 1H), 3.30 – 3.12 (overlapping dpent, Jpent = 12.7 Hz, J = 2.8 Hz, 2H), 2.86 – 2.76
overlapping dd, J = 10.6, 7.0 Hz, 2H total), 2.45 (dt, J = 11.0 Hz, J = 3.3 Hz, 1H), 1.47 (s, 3H),
t d
3
(
d
1
.44 (s, 6H) 1.27 (two overlapping t, J = 7.1 Hz, 3H total), 1.07 (d, J = 6.8 Hz, 2H), 1.02 (d, J =
13
6.8 Hz, 1H). C NMR (151 MHz, CDCl ) δ 170.6, 154.8, 147.6, 133.8, 133.3, 131.9, 131.2,
24.4, 124.3, 80.4, 60.9, 60.8, 54.4, 54.0, 49.6, 48.7, 40.9, 40.8, 38.4, 36.8, 35.1, 34.7, 28.3,
8.2, 15.6, 15.1, 14.1, 14.0. IR: 3004, 2987, 1731, 1688, 1542, 1364, 1275, 1260, 1161, 1125.
3
1
2
25
Chiral analysis on ChrialPak IF (heptane/EtOH). [α] −0.86 (c 5.0, EtOH). HRMS (HESIꢀTOF)
m/z calc for (M+H) (C H N O S) 472.1754, found 472.1751.
D
+
+
20
30
3
8
Tert-butyl
(2S,3S)-3-(2-ethoxy-2-oxoethyl)-2-isobutyl-4-((2-
nitrophenyl)sulfonyl)piperazine-1-carboxylate (9c trans). 5.6 g, yellow oil, 22% yield from
1
crude 7c. H NMR (600 MHz, CDCl ) δ 8.11 (dd, J = 7.3, 1.8 Hz, 1H), 7.76 – 7.69 (m, 3H), 4.21
4.07 (m, 5H), 3.91 – 3.80 (m, 1H), 3.23 – 3.02 (m, 2H), 2.85 (dd, J = 16.5, 10.8 Hz, 0.75H),
.78 (dd, J = 16.5, 9.7 Hz, 0.25H), 2.46 (dd, J = 16.6, 3.1 Hz, 1H), 1.46 (s, 7H), 1.43 (s, 2H),
3
–
2
1.37 – 1.12 (m, 7H), 0.81 (d, J = 6.4 Hz, 3H), 0.76 (d, J = 6.4 Hz, 2H), 0.72 (d, J = 6.5 Hz, 1H).
13
C NMR (151 MHz, CDCl ) δ 170.6, 154.8, 147.6, 133.8, 133.3, 132.0, 131.5, 131.3, 124.4,
0.4, 60.9, 52.7, 51.9, 51.1, 40.78, 40.75, 38.7, 38.5, 38.3, 37.0, 28.3, 28.2, 24.6, 24.4, 22.6,
2.4, 22.3, 14.2, 14.1. IR: 3004, 2986, 1732, 1686, 1543, 1365, 1275, 1260, 1161. Chiral
3
8
2
25
analysis on ChiralPak IE (heptane/EtOH). [α] −1.69 (c 5.0, EtOH). HRMS (HESIꢀTOF) m/z
calc for (M+H) (C H N O S) 514.2223, found 514.2222.
D
+
+
23
36
3
8
Tert-butyl (2R,3R)-3-(2-ethoxy-2-oxoethyl)-2-methyl-4-((2-nitrophenyl)sulfonyl)piperazine-
-carboxylate (9f trans). 6.2 g, yellow oil, 24% from crude 7f. H NMR (600 MHz, CDCl ). H
1
1
1
3
13
NMR identical to 9a trans. C NMR (151 MHz, CDCl ) δ 170.6, 154.8, 147.6, 133.8, 133.3,
131.9, 131.2, 124.4, 124.3, 80.4, 60.9, 60.8, 54.4, 54.0, 49.6, 48.7, 40.9, 40.8, 38.4, 36.8, 35.1,
4.7, 28.3, 28.2, 15.6, 15.1, 14.1, 14.0. IR: 3004, 2987, 1732, 1688, 1543, 1365, 1275, 1260,
3
3
25
1
(
161, 1122. Chiral analysis on ChiralPak IF (heptane/EtOH). [α] +0.87 (c 5.0, EtOH). HRMS
HESIꢀTOF) m/z calc for (M+H) (C H N O S) 472.1754, found 472.1753.
20 30 3 8
D
+
+
ACS Paragon Plus Environment

Page 29 of 39
The Journal of Organic Chemistry
1
2
3
4
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8
9
Tert-butyl (2R,3R)-2-benzyl-3-(2-ethoxy-2-oxoethyl)-4-((2-nitrophenyl)sulfonyl)piperazine-
1
1
-carboxylate (9g trans). 7.3 g, yellow oil, 24% yield from crude 7g. H NMR (600 MHz,
1
13
CDCl ). H NMR identical to 9b trans. C NMR (151 MHz, CDCl ) δ 170.4, 170.2, 154.65,
3
3
154.59, 147.7, 137.6, 137.1, 133.93, 133.88, 133.21, 133.19, 132.0, 131.7, 131.5, 129.2, 129.1,
1
3
1
28.4, 128.3, 126.5, 126.4, 124.5, 124.4, 80.4, 80.2, 60.89, 60.87, 55.5, 54.1, 52.8, 52.2, 40.9,
9.1, 37.1, 35.6, 35.5, 35.1, 34.7, 28.2, 27.9, 14.1, 14.0. IR: 3004, 2987, 1731, 1688, 1542,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
4
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4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
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0
1
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
25
364, 1275, 1260, 1161, 1125. Chiral analysis on ChirlPak ID (heptane/EtOH). [α] +1.23 (c
D
+
+
5.0, EtOH). HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 548.2067, found 548.2061.
26
34
3
8
Tert-butyl
(2R,3R)-3-(2-ethoxy-2-oxoethyl)-2-isobutyl-4-((2-
nitrophenyl)sulfonyl)piperazine-1-carboxylate (9h trans). 1.4 g, yellow oil, 12% from crude
1
1
13
7
h. H NMR (600 MHz, CDCl ). H NMR identical to 9c trans. C NMR (151 MHz, CDCl ) δ
3
3
170.6, 154.8, 147.6, 133.8, 133.3, 131.9, 131.3, 124.4, 80.4, 60.9, 52.7, 51.9, 51.1, 40.8, 40.8,
38.7, 38.5, 38.3, 37.0, 28.3, 28.2, 24.6, 24.4, 22.6, 22.4, 22.3, 14.2, 14.1. IR: 3005, 2988, 2360,
2
5
1
(
730, 1687, 1366, 1275, 1260, 1164. [α] +1.72 (c 5.0, EtOH). HRMS (HESIꢀTOF) m/z calc for
D
+
+
M+H) (C H N O S) 514.2223, found 514.2222.
23 36 3 8
Scheme 3
Ethyl
(3R,4R)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)pentanoate (5e syn, the less retained isomer). The title compound
was obtained from compounds 5e (Scheme 2) by column chromatography (10ꢀ40%
1
EtOAc/hexanes). 8.5g, yellow oil, 26% yield from crude 4e. H NMR (600 MHz, CDCl ) δ 8.15
3
(
d, J = 8.1 Hz, 1H), 7.62 – 7.56 (m, 3H), 7.37 (dd, J = 8.5, 0.9 Hz, 2H), 7.31 (dd, J = 6.3, 1.0 Hz,
3H), 4.95 (d, J = 9.8 Hz, 1H), 4.64 – 4.55 (m, 1H), 4.40 – 4.33 (m, 2H), 4.13 – 4.02 (m, 2H),
.85 – 3.81 (m, 2H), 3.72 (dd, J = 9.5, 2.7 Hz, 1H), 3.65 (dt, J = 15.6, 4.7 Hz, 1H), 3.49 – 3.42
m, 2H), 2.78 (dd, J = 16.3, 8.9 Hz, 1H), 2.50 (bd, J = 16.7 Hz, 1H), 1.42 (s, 9H), 1.23 (t, J = 7.1
3
(
13
Hz, 3H). C NMR (151 MHz, CDCl ) δ 171.6, 155.9, 148.0, 138.0, 133.8, 132.5, 131.7, 128.4,
3
127.6, 127.5, 123.9, 80.0, 72.9, 68.7, 61.9, 60.9, 52.3, 36.2, 28.3, 14.1. IR: 3004, 2987, 1707,
+
+
1
543, 1367, 1275, 1260, 1160. HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S)
27 38 3 10
596.2278, found 596.2269.
Ethyl
(3S,4R)-5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-((N-(2-hydroxyethyl)-2-
nitrophenyl)sulfonamido)pentanoate (5e anti, the more retained isomer). The title compound
was obtained from compounds 5e (Scheme 2) by column chromatography (10ꢀ40%
1
EtOAc/hexanes). 6.5g, yellow oil, 20% yield from crude 4e. H NMR (600 MHz, CDCl ) δ 8.02
3
(
d, J = 8.1 Hz, 1H), 7.68 (dt, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.38 (d, J =
t d
5.0 Hz, 4H), 7.35 – 7.30 (m, 1H), 5.39 (bd, J = 10.3 Hz, 1H), 4.62 (td, J = 8.3, 5.6 Hz, 1H), 4.55
(
½ AB, J = 11.7 Hz, 1H), 4.50 (½ AB, J = 11.7 Hz, 1H), 4.01 (dt, J = 7.1 Hz, J = 3.5 Hz, 3H),
t
d
3
=
1
.89 – 3.79 (m, 2H), 3.58 (t, J = 3.4 Hz, 2H), 3.46 – 3.42 (m, 2H), 2.62 (dquar, J
= 15.0 Hz, Jd
quar
13
6.7 Hz, 2H), 1.39 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H). C NMR (151 MHz, CDCl ) δ 170.8, 155.9,
3
48.2, 137.6, 133.6, 132.6, 131.6, 131.5, 128.4, 127.9, 127.8, 123.8, 80.0, 73.3, 70.4, 62.3,
61.2, 56.3, 52.3, 48.2, 36.1, 28.3, 14.0. IR: 3004, 2987, 1707, 1543, 1367, 1275, 1260, 1160.
+
+
HRMS (HESIꢀTOF) m/z calc for (M+H) (C H N O S) 596.2278, found 596.2275.
27
38
3
10
ACS Paragon Plus Environment