Rapid access with diversity to enantiopure flexible PNA monomers following asymmetric orthogonal strategies

Article abstract of DOI:10.1016/j.tetasy.2014.06.002

Different synthetic procedures are described in the rapid elaboration of flexible PNA monomers based on the 6-amino-8-base-octanoate and 5-amino-7-base-heptanoate scaffolds. Asymmetric Aza-Michael monoaddition is successfully applied to starting materials derived from sebacic/azelaic long-chain diacids and 6-membered oxacyclohexane commercial derivatives. Chain length, orthogonality of the ester functionalities, and Z/E isomerism of these prime substrates yielded high-valuable multifunctional intermediates through this asymmetric conjugate addition. Key features are the diversity toward PNA monomer synthesis, orthogonal chemoselective transformations, and Mitsunobu nucleobase substitution as an exceptional approach to introduce nucleobases in the final step.

Full text of DOI:10.1016/j.tetasy.2014.06.002

Tetrahedron: Asymmetry 25 (2014) 1046–1060
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Rapid access with diversity to enantiopure flexible PNA monomers
following asymmetric orthogonal strategies
⇑
Carlos T. Nieto, Mateo M. Salgado, Sara H. Domínguez, David Díez, Narciso M. Garrido
Organic Chemistry Department, University of Salamanca, Pza de la Merced, 1-5, CP 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 May 2014
Accepted 27 May 2014
Different synthetic procedures are described in the rapid elaboration of flexible PNA monomers based on
the 6-amino-8-base-octanoate and 5-amino-7-base-heptanoate scaffolds. Asymmetric Aza-Michael
monoaddition is successfully applied to starting materials derived from sebacic/azelaic long-chain dia-
cids and 6-membered oxacyclohexane commercial derivatives. Chain length, orthogonality of the ester
functionalities, and Z/E isomerism of these prime substrates yielded high-valuable multifunctional inter-
mediates through this asymmetric conjugate addition. Key features are the diversity toward PNA mono-
mer synthesis, orthogonal chemoselective transformations, and Mitsunobu nucleobase substitution as an
exceptional approach to introduce nucleobases in the final step.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Ku-wahara’s12 5-amino-7-thymine-3-oxaheptanoate unit, both
synthetized using chiral pool approaches.
Peptide nucleic acids PNA are a class of xeno-nucleic acids
(non-natural nucleic acid homologues)1 with potential applica-
tions in gene-targeted therapeutics,2 biosensing,3 biomaterials,4
and supramolecular constructs.5 Ribose-phosphate backbone
replacement by a poly-amide chain increases the binding affinity
of natural DNA to PNA, as has been extensively tested experi-
mentally and theoretically. The enzymatic resistance to endoge-
nous nucleases is also improved, allowing a larger residence time
and activity. Additionally, the peptide nature is easily exploited
through solid-phase protocols in oligomer elaborations.6 These
high-valuable properties have been extensively studied since
the pioneering work of Nielsen.7 The original 2-aminoethyl-gly-
cine nucleic acid8 has been the starting model for the design
and synthesis of new PNA-monomers with improved or tuned
properties in the search of antigene and antisense molecules.9
In this sense, backbone modifications allow the preorganization
profile of the final peptide-nucleotides to be controlled.10 Flexi-
ble peptide nucleic acids are a subdivision of xeno-nucleic acids
with a low conformational restriction, with attractive profiles in
preorganization management, through homopolymers or PNA-
composite elaboration. Relevant examples of flexible derivatives
are Leumann’s11 5-amino-7-thymine-heptanoate monomer and
Herein we report the synthesis of orthogonally protected 5/6-
amino-7/8-base-hepta/octanoate PNA monomers through different
short asymmetric approaches, starting from different long-chain
Michael acceptors. As has been demonstrated,13 chirality of the
monomeric units imposes a defined complementary hybridization
scheme toward DNA/RNA: parallel or antiparallel. The methodolo-
gies applied allow flexible chiral PNA units with attractive potenti-
ality in biomedicine,14 food analysis, and authentication15 or
bioimaging to be obtained.16
2. Results and discussion
Scheme 1 shows a general vision of the synthetic plan. Fully
protected PNA monomers are elaborated using d-valerolactone,
3,4-dihydro-2H-pyran, and sebacic/azelaic acids as prime materi-
als. From sebacic and azelaic acids we obtained the derivatives
(E,E)-1a, (E,Z)-1c, and (E,E)-1d,17 scalable to gram quantities, fol-
lowing the methodology described by Scheffer.18 The straightfor-
ward protocol afforded the (E,E) Michael double acceptors in
excellent yields as major products, while the (E,Z) acceptors were
obtained in minor amounts. Chromatography of the reaction
crudes allows the isolation of the single olefin isomers. Separately,
one-pot transformation of d-valerolactone19 and 3,4-dihydro-2H-
pyran20 to the Michael acceptor (E)-1b was also accomplished
through Horner–Wadsworth–Emmons homologation. These
affordable materials are high-valuable building blocks due to the
⇑
Corresponding author. Tel.: +34 92 329 4474; fax: +34 92 329 4574.
E-mail address: nmg@usal.es (N.M. Garrido).
http://dx.doi.org/10.1016/j.tetasy.2014.06.002
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
1047
CO2R
1d
elaboration of 2-amino-9-thymine-nonanoate monomer and
(R)-homopipecolic acid.22b This acid was later transformed to the
dimethyl ester 3 with TMSCH2N2, as has been demonstrated in
the literature as requisite to overcome ozonolysis problems.25
Ozonolytic cleavage was carried out after prior hydrogen chloride
gas, in order to avoid N-oxide formation.26 Hydrogen peroxide oxi-
dative conditions lead to a 1:1 mixture of 4a–b in moderate yields.
Aldehyde 4a is essentially the same intermediate as 13a, which
may be protected as dioxolane in the following decandiendioate
route. Mild oxidation of aldehyde 4a to acid 4b was achieved with
NaClO2 in a phosphate buffered solution, improving the productiv-
ity of the route to this acid.
CO2R
sebacid
acid
(E,E)-
1c
(E,Z)-
CO2R
R = 3-pentyl
CO2R
Flexible PNA
10→8
10→7
NHBoc
O
NHBoc
tBuO2C
Base
CO2Me
-1b
Base
O
4
3
5→7
O
Bn
4
(E)
Ph
N
Parallel to this sequence, heptanoate route was developed
(Scheme 2), starting with the Aza-Michael diastereoselective addi-
CO2Me
HO2C
OH
3
5→7
tion of lithium (R)-N-benzyl-N-(a-methylbenzyl)amide to adduct
9→7
8, in a 77% yield. Jones oxidation allowed the satisfactory prepara-
tion of intermediate 4b, converging both routes. These last two
steps demonstrate an alternative synthetic procedure to interme-
diate 4b, in higher yield and productivity. From 4b, the amino
and carboxylic functionalities were protected through tert-butyl
protecting groups in two steps. tert-Butyl esterification of acid 4b
with Boc2O and DMAP catalyst afforded diester 5 in a 82% yield,
while the amine group was released and reprotected under hydro-
gen in the presence of Boc2O, to give the protected carbamate 6 in a
83% yield. Although both functionalities are tert-butyl like, nowa-
days there are several reported procedures which justify the
orthogonality of both functional groups.27 Finally, the methyl ester
was transformed into a more suitable functional group for nucleo-
base insertion such as alcohol 7a and mesylate 7b. Chemoselective
reduction of ester 6 to alcohol 7a was carried out with lithium
borohydride in excellent yields, without degradation of the tert-
butyl ester moiety. Activation of the hydroxyl group was achieved
through mesylation to 7b in 96% yield.
O
O
CO2Me
azelaic
acid
1a
(E,E)-
CO2H
Scheme 1. General synthetic plan.
multiple synthetic transformations that may undergo17,21 and have
been successfully used in our group in the elaboration of other
homochiral PNA monomers,22 morphan-like b-amino acids,23 and
homopipecolic acid.22b
Stereoselective C–N bond generation, chain contraction, and
orthogonal functional group interconversions complete the path
to the schematized PNA monomers. The synthetic routes are orga-
nized into two divisions: the mixed nonadiendioate/heptanoate
group and the decadiendioate group. These major divisions differ
in the synthetic methodologies applied as well as the chain length
of the substrate, which were adjusted from 10?8/7 in the first one
and from 9/5?7 in the latter.
As nucleobases are poor nucleophiles in general, certain special-
conditions are required to increase nucleobase coupling. Addition-
ally, the 1-mesylate-3-Boc-amine propanoate fragment is known
to overcome cyclization to cyclic carbamate in basic conditions.28
Hence, a detailed reaction study was undertaken using protected
substrates 9a–b; which keeps the problematic region of the origi-
nal system. Table 1 summarizes the different reaction assays.
Nonadiendioate route starting point is the Michael orthogonal
acceptor 1a (Scheme 2). Aza-Michael asymmetric addition of lith-
ium (R)-N-benzyl-N-(a-methylbenzyl)amide afforded monoadduct
2 in good yields, with total control of the new stereocenter gener-
ated.24 This polyfunctional compound has been investigated in the
Nonadiendioate/Heptanoate Division
Bn
Bn
Bn
Ph
N
Ph
N
Ph
N
CO2Me
CO2H
(E,E)-1a
CO2Me
CO2R1
c)
e)
a)
CO2Me
CO2Me
OH
(4a, 29%)
(4b, 31%)
(4b, 91%)
84%
COR1
1
8
1
4a
4b
, R =H
13a
2
, R =H
f) 88%
b) 93%
3, R1= Me
, R =OH
1
(48%, 3 steps)
g) 82%
1
5
, R = OtBu
azelaic acid
NHBoc
d) 77%
h) 83%
NHBoc
O
O
(64%)
(68%)
NHBoc
CO2Me
nucleobase
insertion
CO2Me
i)
Base
OR1
O
OH
(E)-1b
90%
CO2tBu
CO2tBu
CO2tBu
7a, R1=H
6
j) 96%
1
7b
, R = Ms
Scheme 2. Reagents and conditions: (a) (R)-N-benzyl-N-
H2O2, rt; (d) (R)-N-benzyl-N-
-methylbenzylamine, n-BuLi, THF, À78 °C; (e) CrO3, H2SO4, acetone, rt; (f) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, rt; (g) Boc2O, DMAP,
tBuOH, 30 °C; (h) H2-Pd(OH)2/C, Boc2O, AcOEt, 50 psi; (i) LiBH4, THF, rt; (j) MsCl, Py, DMAP, DCM, rt.
a-methylbenzylamine, n-BuLi, THF, À78 °C; (b) TMSCH2N2, toluene/MeOH 1:1, rt; (c) HCl (g), O3 (g), À78 °C, then
a

1048
C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
Table 1
allowed the substitution compound to be obtained as the single
product in a 68% yield. No cyclic carbamate 10c was detected this
time.
Screening of different nucleobase coupling conditions to model system 9a–b
NHBoc
NHBoc
conditions
These analyses’ results were translated to the original system
(Table 2). When Taddei conditions are applied to mesylate 7b, a
1:1 regioisomeric mixture of substitution products is obtained,
with traces of cyclic carbamate 11c. When N3-Bz-thymine is used,
the single regioisomer 11d was obtained also accompanied with a
small amount of carbamate 11c. This protected form of thymine31
has been extensively used in PNA chemistry, as a consequence of a
better solubility, as well as avoiding the nucleophilic competition
between N1/N3.
OR1
, R1 = H
9b, R1 = Ms
Base
O
9a
10a, Base = T
a) 75%
10c,
10b, Base = 6ClP
HN
O
Entry
9
Conditions
Tempa
Baseb
10c
Yieldd
1
2
3
4
5
6
7
8
9b
9b
9b
9b
9b
9b
9b
9a
TBAI, K2CO3, DMF
TBAI, K2CO3, DMF
TBAI, K2CO3, DMF
TBAI, DBU, DMF
TBAI, DBU, DMF
TBAI, K2CO3, DMF
TBAI, K2CO3, DMF
PBu3, DIAD, THF
70
70
150
70
150
rt
70
—
T
T
T
T
6ClP
6ClP
6ClP
10c
10a
10a
10a
10a
10a
10a
10b
29
27
12
33
6
25
20
68
Finally, Mitsunobu conditions were separately applied to
alcohol 7a with N3-Bz-thymine, 6-chloropurine, and 2-amino-6-
chloropurine, successfully giving the PNA fully-protected mono-
mers 11a, 11b, and 11d in good yields. These purine monomers
11a, 11b are not only immediate predecessors of adenine and
guanine, but also of modified purine analogs such as hypoxan-
thine, 2-aminopurine, 2,6-diaminopurine, or thioguanine, which
are readily accessible. Thereby, Mitsunobu coupling conditions
are superior to Taddei basic media ones. Additionally, 11d was
transformed into Leumann’s enantiomer 11f in two steps:
chemoselective cleavage of the benzoyl group of the pyrimidine
ring followed by one-pot transesterification from 11e. Comparison
rt
Reagents and conditions: (a) MsCl, Py, DMAP, DCM, rt.
a
Celsius.
b
T = Thymine; 6ClP = 6-Chloropurine.
Main product (except entry 8).
Yield of 10a–b.
c
d
Entries 1–7 describe basic media reaction conditions in DMF, first
used by Taddei.29
of the specific rotation value of 11f, [
a
]
20 = À11.2 (c 0.24, MeOH),
D
with Leumann’s enantiomer,11
[a
]
D
20 = +12.1 (c 0.01, MeOH),
In general, the reaction affords low yields of the substitution
product at 70/150 °C, mixed with cyclic carbamate 10c
(1,3-oxazinan-2-one). This secondary compound is suspected to
be generated either by base (DBU or K2CO3) or nucleobase
mediation.
Repeating the reaction under the same conditions but in
absence of nucleobase afforded a 1:1 mixture of substrate and
cyclic carbamate, demonstrating that the cyclization process does
not require the presence of a nucleobase. In order to maximize
the conversion, Mitsunobu methodology was also applied due
to the successful results in other nucleobase chemistry.30
Employing PBu3 combined with DIAD and the nucleobase in THF
shows good agreement. The stereochemical integrity achieved
in the first Michael stereoselective addition (>95% d.e.) is
maintained.
Scheme 3 shows the complete reaction paths of the decadi-
endioate division. Initial diastereoselective conjugate addition
of lithium (R)-N-benzyl-N-(
afforded adducts 12a–b in moderate to good yields, but with
clear difference: the Z-olefin in 1c is isomerized from
(Z)- /b to (E)-b/ , while the E-olefin remains unaltered. This
reaction behavior is common when using lithium amides with
(Z)- /b unsaturated esters, which undergoes deconjugation
a-methylbenzyl)amide to 1c–d
a
a
c
a
instead of Michael addition, as it has been previously reported
by our group.21 This attractive strategy is readily exploited in
the next stage: ozonolytic cleavage afforded aldehydes 13a–b
in good yields, which are one methylene homologues, affording
a simple procedure to obtain two sets of compounds differing in
the chain length. After that, aldehydes 13a–b were protected
through dioxolane formation with ethyleneglycol in acid media,
with 76% and 82% yields, respectively. One-pot protecting group
interconversion was carried out for compounds 14a–b through
Table 2
Screening of nucleobase insertion conditions to system 7a–b
NHBoc
BocHN
N
11a
entry 4
7a, R1=H
7b,
N
1
OR1
N
R =Ms
3
3
Cl
CO2tBu
CO2tBu
N
entry 5
NH2
palladium-catalyzed benzylic removal under
a
hydrogen
entries 1-3
NHBoc
NHBoc
N
atmosphere, in the presence of Boc2O, affording carbamates
15a–b in excellent yields.
11b
N
N
N
3
3
Finally, chemoselective reduction of the ester to alcohol was
achieved with DIBAL-H, obtaining hydroxyl compounds 16a–b in
excellent yields. At this point of the route, each homologue is
subjected to divergent transformations. Functional group inter-
conversion over 16b through Appel procedure afforded bromide
17 in a 79% yield. Final thymine substitution following Taddei’s
protocol allowed the double protected thymine PNA monomer
18 to be obtained in moderate yields. Despite its non-acidic
character, this protected monomer is an interesting prototype
to imine-derived nucleic derivatives, where the imine function-
ality not only serves as monomer linker, but may be broadly
modified. Separately, acetylation of alcohol 16a to acetate 19
was carried out, followed by ozonolytic cleavage. After the
oxidative transformation, 2-hydroxy ethyl ester 20 was obtained
CO2R2
Cl
CO2tBu
N
O
N
O
O
R1
11d, R1=Bz, R2=tBu
11c
tBuO2C
O
HN
a) 97%
b) 54%
1
2
11e,
11f
R =H, R =tBu
1
2
, R =H, R =Et
3
Entry
7
Conditions
Tempa
Baseb
11
Yield
1
2
3
4
5
7b
7b
7a
7a
7a
TBAI, K2CO3, DMF
TBAI, DBU, DMF
PBu3, DIAD, THF
PBu3, DIAD, THF
PBu3, DIAD, THF
70
70
rt
T
TBz
TBz
11ec
11c
11c
11a
11b
35c
23
75
61
53
rt
rt
6-ClP
2A6ClP
Reagents and conditions: (a) LiOHÁH2O, MeOH/THF/H2O 3:1:1, rt; (b) HCl (g), EtOH,
then Boc2O, rt.
a
Celsius.
in
a 86% yield. Substitution of the acetate functionality by
b
T = thymine; TBz = N3-Bz-thymine; 6ClP = 6-Chloropurine; 2A6ClP = 2-Amino-
nucleobases will afford a PNA monomer in a similar way to
compound 7b.
6-chloropurine.
c
1:1 mixture of thymine regioisomers with traces of cyclic carbamate 11c.

C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
1049
Decadiendioate Division (R = 3-Pentyl)
sebacic acid
CO2R
Bn
Bn
Ph
N
Ph
N
CO2R
CO2R
a)
a)
(E,Z)-1c
(E,E)-1d
CO2R
CO2R
CO2R
42%
70%
12b
1c
(E,Z)- , (3%)
12a
(E,E)-1d, (65%)
NHBoc
NHBoc
Bn
Bn
N
Ph
CO2R
Ph
N
R1
O
CO2R
O
O
CO2R
b)
d)
e)
(98%)
c)
12a, 12b
CHO
(13a, 92%)
(13b, 98%)
O
(14a, 82%)
(14b, 89%)
(15a, 98%)
(15b, 93%)
n
O
n
O
n
15a, n=1
15b, n=2
1
16b
, R = OH
13a, n=1
13b, n=2
14a, n=1
14b, n=2
f) 79%
1
17
, R = Br
OAc
OH
BocHN
BocHN
OAc
BocHN
g) 38%
e)
90%
i)
NHBoc
h)
56%
7b
OH
86%
O
N
O
O
O
O
O
O
O
O
N
H
O
18
20
19
16a
Scheme 3. Reagents and conditions: (a) N-benzyl-N-
80 °C; (d) H2-Pd(OH)2/C, Boc2O, AcOEt, 50 psi; (e) DIBAL-H, THF, À78 °C; (f) CBr4, PPh3, DCM, rt; (g) thymine, TBAI, K2CO3, DMF, 70 °C; (h) Ac2O, Py, rt; (i) O3 (g), DCM, À78 °C.
a-methylbenzylamine, nBuLi, THF, À78 °C; (b) HCl (g), O3 (g), À78 °C, then Me2S, rt; (c) ethylene glycol, pTsOH, benzene,
gas. Reaction monitoring was followed by TLC, type Merck 60 F254,
which visualization was achieved with UV light and ninhydrin as
appropriate stain. Flash chromatography was carried out on Kiesel-
gel 40 (Merck, 0.040–0.063) silica. Yields and characterization data
belong to chromatography purified compounds. Retention factor
was measured from the purified compounds (Rf). Deuterated sol-
vents were purchased from Carlo Erba. Optical rotations were mea-
3. Conclusion
This article demonstrates the utility of the described starting
materials in applied synthesis. Aza-Michael asymmetric monoad-
dition to orthogonally functionalized
a,b-unsaturated esters led
to attractive polyfunctional intermediates with broad synthetic
applications. Long chain diesters (decadiendioate) or orthogonally
protected medium-size esters (nonadiendioate) undergo exclu-
sively mono-addition of lithium amides. Z/E isomerism of olefin
conjugated esters plays a relevant role: after lithium amide mono-
addition, Z olefins are rearranged to E-nonconjugated esters, while
the E homologues were found unaltered. Following the combina-
tion of this asymmetric induction with orthogonal transformations
allows the development of high-value synthetic methodologies in
the preparation of flexible enantiopure peptide nucleic acids.
Imine-based protected nucleic acid 18 was obtained in a 7% of
overall yield, while its homologue 20 yielded 22%, both following
similar transformations. Leumann’s fully protected thymine-
enantiomer 11d has been obtained in an overall 31% and 24 yield
from 1b and 1a, respectively, while it was obtained in a 4% by Leu-
mann. Purine based monomers 11a–b were also obtained in a 25%
and 22% yield, respectively, giving immediate predecessors of ade-
nine, guanine, modified, hypoxanthine, 2-aminopurine, 2,6-diam-
inopurine or thioguanine analogs. These purine PNAs are fully
protected monomers (carboxylic acid, amine and nucleobase).
Mitsunobu-type nucleobase substitution procedures allow a signif-
icant increase in conversion yields compared to original Taddei’s
technique.
sured on a Perkin Elmer 241 polarimeter in 1 dm cells ([a]
20).
D
Infrared spectra were recorded on a Shimadzu IRAffinity-1 (IR).
NMR experiments were recorded on a Varian 200 VX (1H NMR/
200 MHz, 13C NMR/50 MHz) and on a Bruker DRX 400 (1H NMR/
400 MHz). 2D HMBC and HMQC or representative compounds
were also recorded to assign protons and carbons on new struc-
tures. Chemical shifts are reported in ppm (parts per million) rela-
tive to referenced values. High-resolution mass spectrometry
(HRMS) analyses were performed on an Applied Biosystems QSTAR
XL (ESI, electrospray ionization) and in a VG-TS 250 (EI, electronic
impact), at 70 eV (m/z).
4.2. (2E,7E)-9-Methoxy-9-oxonona-2,7-dienoic acid (E,E)-1a22b
In a two-necked round bottom flask provided with a condenser,
20 g of azelaic acid (CAS: 123-99-9, 188.2 g/mol, 106 mmol) was
placed together with 27 mL of SOCl2 (thionyl chloride, CAS:
7719-09-7, 118.9 g/mol, 372 mmol). The second neck was sealed
and the suspension was magnetically stirred and heated at reflux
(75 °C) for 90 min. The solids were gradually dissolved. After
90 min, the reaction was cooled to room temperature and a drop-
ping funnel filled with Br2 (bromine, CAS: 7726-95-6, 159.8 g/mol)
was place in the second neck. Next, 19 mL of Br2 (372 mmol) was
added dropwise. The dark red mixture was irradiated with two
200 W incandescent light bulbs and stirring was continued for
12 h. The lamps were switched off and the mixture was cooled in
an ice bath. Next, 86 ml of MeOH was carefully added dropwise,
which generated vapors. The orange mixture was allowed to stir
for an additional 90 min. Finally, an excess of satd NaHCO3 was
added and stirred for 30 min. The reaction mixture was extracted
4. Experimental
4.1. General
All chemical reagents were purchased from Sigma-Aldrich or
Acros. High-purity reaction solvents were purified accordingly to
literature procedures. All reactions were carried out in borosilicate
PyrexÒ type glassware and under inert conditions, using Ar as inert

1050
C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
with AcOEt 3 times. The organic extract was washed successively
with water (3 times), a saturated solution of NaHCO3 (3 times), a
saturated solution of Na2S2O3 (3 times), and brine (1 time). The
resulting organic solution was dried over anhydrous Na2SO4, fil-
tered, and evaporated under reduced pressure, producing 38.77 g
of dimethyl 2,8-dibromononanedioate (98%). 3 g of this compound
(374.0 g/mol; 8.02 mmol) was dissolved in 60 mL of MeOH/THF/
H2O 3:3:1 in a round bottom flask. 420 mg of LiOHÁH2O (lithium
hydroxide monohydrate, CAS: 1310-66-3, 41.9 g/mol, 10 mmol)
was added and the resulting solution was stirred at room temper-
ature for 5 h. The pH of the solution was checked (basic) and AcOEt
was added. The mixture was partitioned between water and AcOEt
and the aqueous solution was extracted again with AcOEt. The
aqueous solution was acidified with HCl 1 M and extracted three
times with DCM. This organic solution was washed with brine,
dried with anhydrous Na2SO4, filtered, and the solvent was
evaporated to dryness. Flash chromatography (Hexanes/AcOEt
8:2) afforded 1.7 g of 2,8-dibromo-9-methoxy-9-oxononanoic acid
(59%). 1.7 g of this acid (360.0 g/mol; 4.72 mmol) was dissolved in
30 mL of DMF and the resulting solution was heated at reflux
(150 °C) for 12 h. An excess of water was added and the reaction
mixture was allowed to cool to room temperature. An excess of
AcOEt was then added to the reaction mixture. The organic extract
was washed successively with water (5 times), a satd solution of
Na2S2O3, (3 times) and brine (1 time). The dark organic
solution was dried with anhydrous Na2SO4, filtered, and
evaporated under reduced pressure. Flash chromatography
(Hexanes/AcOEt 85:15) afforded 785 mg of (2E,7E)-9-methoxy-9-
oxonona-2,7-dienoic acid (E,E)-1a (84%). Overall yield 58%, 3 steps.
AcOEt, 1:1); IR (neat):
m
max = 3367 (O–H), 2937 (C–H), 1718
(C@O), 1436, 1201 (C–O) cmÀ1
;
1H NMR (200 MHz, CDCl3):
d = 6.95 (dt, J = 15.5 and 6.8 Hz, 1H, H-3), 5.81 (d, J = 15.7 Hz, 1H,
H-2), 3.70 (s, 1H, CO2CH3), 3.63 (t, J = 5.7 Hz, 2H, H-7), 2.22 (q,
J = 6.7 Hz, 2H, H-4), 1.87 (br s, 1H, OH), 1.60–1.52 (4H, H-5 and
H-6) ppm; 13C NMR (50 MHz, CDCl3): d = 167.3 (s, C-1), 149.5 (d,
C-3), 121.2 (d, C-2), 62.4 (t, C-7), 51.6 (s, CO2CH3), 32.2 (t, C-6),
32.0 (t, C-4), 24.4 (t, C-5) ppm; HRMS (ESI): m/z (M+Na) calcd for
C8H14O3Na, 181.0835; found, 181.0840,
D
= À2.76 ppm.
4.4. Methyl (E)-7-hydroxyhept-2-enoate (E)-1b
In a round bottom flask, 3.84 g of 3,4-dihydro-2H-pyran was
suspended in water. Next, 0.4 mL of HCl 1 M was added and the
reaction was stirred at room temperature for 3 h, after which
7.62 g of K2CO3 (potassium carbonate, CAS: 584-08-7, 138.2 g/
mol, 0.055 mmol), 11.6 g of methyl diethylphosphonoacetate
(CAS: 1067-74-9, 210.1 g/mol, 0.055 mmol) and 16 mL of DMSO
were added. The reaction mixture was sealed, the inner atmo-
sphere was replaced by inert gas and stirred at 50 °C overnight.
The reaction mixture was extracted with AcOEt (3 times) and the
organic solution was dried with anhydrous Na2SO4 and filtered
through a paper filter. Solvent removal under reduced pressure
and flash chromatography afforded 4.868 g of ester 1b (Hexanes/
AcOEt 98:2, 68% yield).
4.5. Di(pentan-3-yl) (2E,8Z)-deca-2,8-dienedioate (E,Z)-1c and
di(pentan-3-yl) (2E,8E)-deca-2,8-dienedioate (E,E)-1d
Rf = 0.39 (Hexanes/AcOEt, 1:1) cmÀ1
;
1H NMR (200 MHz, CDCl3):
In a two-necked round bottom flask provided with a condenser,
3 g of sebacic acid (CAS: 111-20-6, 202.2 g/mol, 14.8 mmol) was
placed together with 4.7 mL of SOCl2 (thionyl chloride, CAS:
7719-09-7, 118.9 g/mol, 61 mmol). The second neck was sealed
and the suspension was magnetically stirred and heated at reflux
(75 °C) for 90 min. The solids were gradually dissolved. After
90 min, the reaction was cooled to room temperature and a drop-
ping funnel filled with Br2 (bromine, CAS: 7726-95-6, 159.8 g/mol)
was placed in the second neck. 2.4 mL of Br2 (46.5 mmol) were
added dropwise. The dark red mixture was irradiated with two
200 W incandescent light bulbs and stirring was continued for
12 h. The lamps were switched off and the mixture was cooled in
an ice bath. Next, 19 ml of 3-pentanol was carefully added drop-
wise, generating vapors. The orange mixture was allowed to stir
for an additional 90 min. Finally, an excess of satd NaHCO3 was
added and stirred for 30 min. The reaction mixture was extracted
with AcOEt 3 times. The organic extract was washed successively
with water (3 times), a saturated solution of NaHCO3 (3 times), a
saturated solution of Na2S2O3 (3 times), and brine (1 time). The
resulting organic solution was dried over anhydrous Na2SO4, fil-
tered, and evaporated under reduced pressure, producing 9.0 g of
di-3-pentyl 2,9-dibromonodecadioate (99%). Next 5.02 g of this
product (500.3 g/mol; 10.0 mmol) was dissolved in 20 mL of DMF
and the resulting solution was heated under reflux (150 °C) for
12 h. An excess of water was added and the reaction mixture
was allowed to cool to room temperature. An excess of AcOEt
was then added to the reaction mixture. The organic extract
was washed successively with water (5 times), a satd solution of
Na2S2O3 (3 times) and brine (1 time). The dark organic solution
was dried with anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. Flash chromatography (Hexanes/AcOEt 97:3)
afforded 198.4 mg of di(pentan-3-yl) (2E,8Z)-deca-2,8-dienedioate
(E,Z)-1c (3.2%) and 2.20 g of di(pentan-3-yl) (2E,8E)-deca-2,8-
dienedioate (E,E)-1d (65%).
d = 7.03 (dt, J = 15.6 6.9 Hz, 1H, H3), 6.93 (dt, J = 15.6 7.0 Hz, 1H,
H-7), 5.83 (d, J = 15.7, 2H, H-2 and H-8), 3.72 (s, 3H, CO2CH3),
2.25 (4H, H-4 and H-6), 1.654 (quintet, J = 7.3 Hz, 2H, H-5) ppm;
13C NMR (50 MHz, CDCl3): d = 171.3 (s, C-1), 167.2 (s, C-9), 150.9
(d, C-7), 148.7 (d, C-3), 121.6 (d, C-8), 121.4 (d, C-2), 51.6 (q,
COCH3), 31.5 (d, C-6), 31.5 (d, C-4), 26.2 (d, C-5) ppm; HRMS
(ESI): m/z (M+Na) calcd for
221.0786, = 0.76 ppm.
C10H14O4Na, 221.0784; found,
D
4.3. Methyl (E)-7-hydroxyhept-2-enoate (E)-1b
In a round bottom flask, 3.0 g of d-valerolactone (100.0 g/mol;
30 mmol) was dissolved in 10 mL of dry THF. The flask was sealed,
purged with Ar, and cooled to À78 °C in a CO2–acetone bath. Next
24 mL of DIBAL-H (diisobutylaluminum hydride, CAS: 1191-15-7,
142.2 g/mol, 36 mmol, 1.5 M toluene solution) were added and
the reaction was magnetically stirred for 90 min. In a pear-shaped
flask, 7.56 g of methyl diethylphosphonoacetate (CAS: 1067-74-9,
210.1 g/mol, 0.036 mmol) was dissolved in 24 mL of dry THF. This
flask was sealed, purged with Ar and cooled at À78 °C. Next,
22.5 mL of nBuLi (n-butyllithium, CAS: 109-72-8, 64.1 g/mol,
45 mmol) was added, turning the solution yellowish. The solution
was stirred 15 min at À78 °C, then warmed to 0 °C in an ice bath
for 30 min and finally to À78 °C for 15 min. The yellowish solution
was added dropwise over the reaction mixture. Once the addition
was finished, the resulting mixture was magnetically stirred for 4 h
at À78 °C. Then, the flask was allowed to warm to room tempera-
ture and stirred for 20 h more. Finally, the reaction was quenched
with a saturated solution of sodium-potassium tartrate. 60 min
later, the reaction mixture was extracted with AcOEt (3 times).
The organic layers were combined and washed with satd NaHCO3
(3 times) and brine (1 time). The AcOEt washed solution was dried
with anhydrous Na2SO4, filtered, and the solvent was removed
under reduced pressure. Flash chromatography afforded 1.509 g
of ester 1b (Hexanes/AcOEt 98:2, 64% yield). Rf = 0.46 (Hexanes/
(E,Z)-1c: Rf = 0.64 (Hexanes/ether, 7:3; Â2); IR (neat):
m
max = 2971 (C–H), 1715 (C@O), 1416, 1267 (C–O), 982 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d = 6.94 (dt, J = 15.6 and 7.0 Hz, 1H, H-3),

C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
1051
6.18 (dt, J = 11.8 and 7.5 Hz, 1H, H-8), 5.81 (d, J = 15.6, 1H, H-2),
4.7. Dimethyl (R,E)-7-(benzyl((R)-1-phenylethyl)amino)non-2-
enedioate 322b
5.78 (d, J = 11.8 Hz, 1H, H-9), 4.79 (m, 2H, CH(CH2CH3)2), 2.68–
2.65 (m, 2H, H-4), 2.24–2.16 (m, 2H, H-7), 1.60–1.50 (4H, H-5
and H-6), 1.58 (q, J = 7.5 Hz, 8H, CH(CH2CH3)2), 0.88 (t, J = 7.5 Hz,
12H, CH(CH2CH3)2) ppm; 13C NMR (50 MHz, CDCl3): d = 166.4 (s,
C-1), 166.2 (s, C-10), 149.0 (d, C-3), 148.3 (d, C-8), 121.8 (t, C-2),
120.5 (t, C-9), 76.4 (d, CH(CH2CH3)), 76.3 (d, CH(CH2CH3)), 31.8
(t, C-4), 28.5 (2Ât, C-5 and C-6), 27.6 (t, C-7), 26.4 (4Ât,
CH(CH2CH3)2), 9.5 (4Âq, CH(CH2CH3)2) ppm; HRMS (EI): m/z (%):
251 (20), 198 (22), 181 (100), 182 (22), 135 25) 107 (30).
In
a
round bottom flask, 529 mg of acid
2
(410 g/mol;
1.29 mmol) was dissolved in 20 mL of toluene/MeOH 1:1. The flask
was sealed and purged with Ar and cooled to 0 °C in an ice bath.
Next, 0.97 mL of TMSCHN2 ((trimethylsilyl)diazomethane solution,
CAS: 18107-18-1, 114.2 g/mol, 1.9 mmol, 2.0 M solution) was
added through syringe and the light yellow reaction solution was
magnetically stirred for 5 min at 0 °C, after which it was allowed
to warm to room temperature over 30 min. The solvent was
removed under reduced pressure, affording 508 mg of product 3,
(E,E)-1d: Rf = 0.57 (Hexanes/ether, 7:3; Â2); IR (neat):
m
max = 2880 (C–H), 1727 (C@O), 1462, 1267 (C–O), 1034 cmÀ1 1H
;
NMR (200 MHz, CDCl3): d = 6.93 (dt, J = 15.6 and 6.6 Hz, 2H, H-3
and H-8), 5.82 (d, J = 15.6 Hz, 1H, H-2 and H-9), 4.81 (q,
J = 7.4 Hz, 2H, CH(CH2CH3)2), 2.21 (m, 4H, H-4 and H-7), 1.55 (q,
J = 7.4 Hz, 8H, CH(CH2CH3)2), 1.50 (m, 4H, H-5 and H-6), 0.88 (t,
J = 7.4 Hz, 12H, CH(CH2CH3)2) ppm; 13C NMR (50 MHz, CDCl3):
d = 166.0 (s, C-1 and C-10), 147.7 (d, C-3 and C-8), 122.0 (t, C-2
and C-9), 76.1 (2Âd, CH(CH2CH3)), 31.6 (t, C-4 and C-7), 27.5
(2Ât, C-5 and C-6), 26.4 (4Ât, CH(CH2CH3)2), 9.3 (4Âq, CH(CH2-
CH3)2). HRMS (ESI): m/z (M+H) calcd for C20H35O4, 339.4880;
93% yield. Rf = 0.85 (Hexanes/AcOEt, 1:1) cmÀ1 1H NMR
;
(200 MHz, CDCl3): d = 7.41–6.93 (10H, CarH), 6.97 (dt, J = 15.6
6.8 Hz, 1H, H-3), 5.83 (dt, J = 15.6 1.4 Hz, 1H, H-2), 3.89–3.81 (2H,
CHCH3 and NCHAH), 3.76–3.72 (4H, CHCO2CH3 and NCHHB), 3.56
(s, 3H, CH2CO2CH3), 3.33 (m, 1H, H-7), 2.17–2.00 (6H, H-4, H-6
and H-8), 1.53 (2H, H-5), 1.34 (d, J = 7.1 Hz, 3H, CHCH3) ppm; 13C
NMR (50 MHz, CDCl3): d = 173.3 (s, C-1), 167.4 (s, C-9), 149.7 (d,
C-3), 143.1 (s, Cipso), 141.7 (s, Cipso), 128.5 (d, Car), 128.4 (d, Car),
128.1 (d, Car), 127.3 (d, Car), 126.9 (d, Car), 121.0 (d, C-2), 58.1 (d,
CHCH3), 53.8 (d, C-7), 51.7 (q, CO2CH3), 51.6 (q, CO2CH3), 50.2 (t,
CH2Car), 36.4 (t, C-8), 33.2 (t, C-4), 32.3 (t, C-6), 25.6 (t, C-5), 20.2
(q, CHCH3) ppm; HRMS (ESI): m/z (M+H) calcd for C26H34NO4,
found, 339.4877,
D = 0.88 ppm.
4.6. (R,E)-7-(Benzyl((R)-1-phenylethyl)amino)-9-methoxy-9-
oxonon-2-enoic acid 222b
424.2487; found, 424.2475,
D
= 2.83 ppm. (M+Na) calcd for
= 4.48 ppm.
C26H33NO4Na, 446.2307; found, 446.2287,
D
At first, 468 mg of 1a (198.1 g/mol; 2.3 mmol) was dissolved in
10 mL of dry THF in a round bottom flask. The flask was sealed,
purged with Ar, and cooled to À78 °C in a CO2–acetone bath. In a
4.8. Methyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-7-oxo-
heptanoate (4a) and (R)-5-(benzyl((R)-1-phenylethyl)amino)-
7-methoxy-7-oxoheptanoic acid 4b
second pear-shaped flask, 1.89 g of (R)-(+)-N-benzyl-N-a-methyl-
benzylamine (CAS: 38235-77-7, viscous light yellow oil, 211.3 g/
mol, 8.9 mmol) was dissolved in 10 mL of dry THF. This one was
also sealed, purged with Ar, and cooled to À78 °C. Once cooled,
5.3 mL of nBuLi (n-buthyllithium, CAS: 109-72-8, 64.1 g/mol,
8.51 mmol, 1.6 M solution) was added dropwise, turning the solu-
tion from colorless to a dark pink. The solution was stirred for
15 min at À78 °C, warmed to 0 °C in an ice bath along 30 min,
and finally to À78 °C again for 15 min. The pink solution was added
dropwise over the substrate solution and the resulting mixture
turned orange. Once the addition was finished, the resulting mix-
ture was magnetically stirred for 3 h before quenching with an
excess of satd NH4Cl. The solution turned from orange to yellow
with precipitate. After 60 min, the yellow reaction mixture was
extracted with AcOEt (3 times). The organic layers were combined
and washed with water (3 times) and brine (1 time). The AcOEt
washed solution was dried over anhydrous Na2SO4, filtered, and
the solvent was removed under reduced pressure affording a crude
yellowish oil. This crude was redissolved in DCM, washed 3 times
with a 10% citric acid (3 times), and dried again with anhydrous
Na2SO4. Final filtration and solvent removal led to a viscous yel-
lowish oil. Flash chromatography afforded 814 mg of product 3
(Hexanes/AcOEt 9:1, 84% yield). Rf = 0.61 (Hexanes/AcOEt, 1:1);
At first, 287 mg of diester 3 (424.4 g/mol; 0.68 mmol) was dis-
solved in 5 mL of dry DCM in a round bottom flask. Next, HCl gas
(hydrogen chloride, CAS: 7647-01-0, 36.5 g/mol) was bubbled
through a pipette for 10 min, while the reaction solution was
cooled at À78 °C in a CO2–acetone bath. Next, ozone (O3, gas, gen-
erated in situ) was bubbled for 15 min until the solution turned
light blue. Finally, 1.5 mL of H2O2 (hydrogen peroxide, CAS:
7722-84-1, 34.0 g/mol, 13.6 mmol, 30% solution) was added and
the reaction was allowed to warm to room temperature. Next,
5 mL of 1 M NaOH was added, which caused the reaction mixture
to turn white. After 15 min of stirring, the reaction was extracted
with DCM (3 times). The organic solution was washed once with
brine. Drying the solution over anhydrous Na2SO4, filtration and
solvent removal under reduced pressure, afforded the acid. Flash
chromatography afforded 72 mg of aldehyde 4a (Hexanes/AcOEt
9:1, 29% yield), and 80 mg of acid 4b (Hexanes/AcOEt 7:3, 31%
yield).
Compound 4a:22b Rf = 0.83 (Hexanes/AcOEt, 1:1); [
(c 0.4, CHCl3); IR (neat): max = 2933 (C–H), 1734 (C@O, ester),
1701 (C@O, acid), 1201 (C–O), 1155 cmÀ1 1H NMR (200 MHz,
a]
20 = +12.5
D
m
;
[
a]
D
20 = +4.6 (c 1.6, CHCl3); IR (film):
m
max = 2926 (C–H), 1732
CDCl3): d = 9.71 (t, J = 1.6 Hz, 1H, H-7), 7.43–7.21 (10H, CarH),
3.84–3.70 (2H, CHCH3 and NCHAH), 3.55–3.50 (4H, NCHHB and
CO2CH3), 3.33 (m, 1H, H-5), 2.33 (td, J = 7.1 1.6 Hz, 2H, H-6),
2.08–1.92 (m, 2H, H-2), 1.67–1.47 (4H, H-3 and H-4), 1.36 (d,
J = 6.9 Hz, 3H, CHCH3) ppm; 13C NMR (50 MHz, CDCl3): d = 202.8
(s, C-7), 173.4 (s, C-1), 143.2 (s, Cipso), 141.7 (s, Cipso), 128.5 (d,
Car), 128.4 (d, Car), 128.3 (d, Car), 128.1 (d, Car), 127.3 (d, Car),
127.0 (d, Car), 58.2 (d, CHCH3), 53.7 (d, C-5), 51.7 (q, CO2CH3),
50.2 (t, NCH2), 43.8 (t, C-6), 36.2 (t, C-2), 33.1 (t, C-4), 20.2
(q, CHCH3), 19.6 (t, C-3) ppm; HRMS (ESI): m/z (M+Na) calcd for
(C@O), 1688 (C@O, 1452 (C–N), 1299, 1145 (C–O) cmÀ1 1H NMR
;
(200 MHz, CDCl3): d = 7.46–7.26 (10H, CarH), 7.05 (dt, J = 15.5
7.1 Hz, 1H, H3), 5.83 (d, J = 15.7 Hz, 1H, H2), 3.84 (q, J = 7.0 Hz,
1H, CH(CH3)), 3.80 (AB, JAB = 15.0 Hz, 1H, NCHAH), 3.57–3.50 (4H,
CO2CH3 and NCHHB), 3.35–3.25 (1H, m, H-7), 2.20–2.01 (6H, H-4,
H-6 and H-8), 1.63–1.48 (2H, H-5), 1.35 (d, J = 7.0 Hz, 3H, CHCH3)
ppm; 13C NMR (50 MHz, CDCl3): d = 173.3 (s, C-1), 172.0 (s, C-9),
152.2 (d, C-3), 143.2 (s, Cipso), 141.6 (s, Cipso), 128.5 (d, Car), 128.4
(d, Car), 128.1 (d, Car), 127.3 (d, Car), 126.9 (d, Car), 121.0 (d, C-2),
58.3 (d, CHCH3), 53.8 (d, C-7), 51.7 (s, CO2CH3), 50.2 (t, CH2Car),
36.4 (t, C-8), 33.2 (t, C-4), 32.3 (t, C-6), 25.4 (t, C-5), 20.2 (q, CHCH3)
ppm; HRMS (ESI): m/z (M+H) calcd for C25H31NO4, 410.2331;
C23H29NO3Na, 390.2045; found, 390.2039,
Compound 4b: Rf = 0.54 (Hexanes/AcOEt, 1:1); [
3.36, CHCl3); IR (neat): max = 2933 (C–H), 1734 (C@O, ester),
1701 (C@O, acid), 1201 (C–O), 1155 cmÀ1 1H NMR (400 MHz,
D
= 1.54 ppm.
a]
20 = +2.1 (c
D
m
;
found, 410.2325,
D
= À0.98 ppm.

1052
C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
CDCl3): d = 7.44–7.22 (10H, CarH), 3.84 (q, J = 6.9 Hz, 1H, CHCH3),
3.78 (AB, JAB = 14.6 Hz, 1H, NCHAH), 3.57–3.53 (4H, NCHHB and
CO2CH3), 3.33 (m, 1H, H-5), 2.29 (m, 2H, H-6), 2.08–1.92 (2H, H-
2), 1.74–1.53 (4H, H-3 and H-4), 1.36 (d, J = 6.9 Hz, 3H, CHCH3)
ppm; 13C NMR (50 MHz, CDCl3): d = 179.3 (s, C-7), 173.1 (s, C-1),
142.8 (s, Cipso), 141.3 (s, Cipso), 128.2 (d, Car), 128.2 (d, Car), 128.1
(d, Car), 127.8 (d, Car), 126.9 (d, Car), 126.7 (d, Car), 57.7 (d, CHCH3),
53.5 (d, C-5), 51.4 (q, CO2CH3), 49.9 (t, NCH2), 36.3 (t, C-6), 33.8 (t,
C-2), 32.8 (t, C-4), 22.1 (t, C-3), 19.6 (q, CHCH3) ppm; HRMS (ESI):
5 mL pressure flask. The flask was connected to an H2 gas line
and the pressure was adjusted to 3.4 atm. The flask was mechani-
cally stirred for 2 days. The flask was pressurized to atmospheric
conditions and the mixture was filtered through a pad of CeliteÒ,
and washed with AcOEt and DCM. The solvents were removed
under reduced pressure, affording 297 mg of carbamate 6 after
flash chromatography (Hexanes/AcOEt 95:5, 83% yield). Rf = 0.90
(Hexanes/AcOEt, 1:1); [a]
20 = +15.3 (c 1.8, CHCl3); IR (neat):
D
m
max = 3367 (N–H), 2978 (C–H), 1734 (C@O), 1367, 1165 (C–O)
m/z (M+H) calcd for
= À3.90 ppm.
C
23H30NO4, 384.2175; found, 384.2190,
cmÀ1
;
1H NMR (400 MHz, CDCl3): d = 4.91 (d, J = 7.9 Hz, 1H, NH),
D
3.89 (1H, H-3), 3.67 (s, 3H, CO2CH3), 2.51 (d, J = 5.1 Hz, 2H, H-2),
2.22 (td, J = 7.1 and 2.7 Hz, 2H, H-6), 1.70–1.49 (4H, H-4 and H-
5), 1.43 (9H, s, C(CH3)3) ppm; 13C NMR (50 MHz, CDCl3):
d = 172.9 (s, C-7), 172.2 (s, C-1), 155.5 (s, NCOO), 80.4 (s, CO2-
C(CH3)3), 79.5 (s, NCO2C(CH3)3), 51.8 (q, CO2CH3), 47.5 (d, C-3),
39.3 (t, C-2), 35.2 (t, C-6), 34.1 (t, C-4), 28.5 (q, CO2C(CH3)3), 28.3
(q, NCO2C(CH3)3), 21.8 (t, C-5) ppm; HRMS (ESI): m/z (M+Na) calcd
4.9. (R)-5-(Benzyl((R)-1-phenylethyl)amino)-7-methoxy-7-oxo-
heptanoic acid 4b
At first, 72 mg of aldehyde 4a (367.2 g/mol; 0.19 mmol) and
0.5 mL of 2-methyl-2-butene (CAS: 513-35-9, 70.1 g/mol,
5.9 mmol) were dissolved in 5 mL of tBuOH. The flask was sealed
and purged with Ar. An aqueous solution consisting of 26 mg of
NaClO2 (sodium chlorite, CAS: 7758-19-2, 90.4 g/mol, 0.29 mmol)
and 30 mg of NaH2PO4ÁH2O (sodium phosphate monobasic mono-
hydrate, CAS: 10049-21-5, 137.9 g/mol, 0.22 mmol) in 5 mL of H2O
was added, and the resulting solution was stirred for one hour. The
solvent was removed under reduced pressure. Next, H2O was
added and the solution was acidulated until pH = 2. The aqueous
solution was extracted with AcOEt (3 times). The organic solution
was washed with H2O 2 times. Drying the solution over anhydrous
Na2SO4, filtration and forward solvent removal under reduced
pressure, afforded 66 mg of acid 4b, 88% yield.
for C17H31NO6Na, 368.2043; found, 368.2025,
D
= À5.0 ppm.
4.12. tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7-hydro-
xyheptanoate 7a
A 2 M solution of LiBH4 was prepared in the next manner:
217.8 mg of LiBH4 (lithium borohydride, CAS: 16949-15-8, 21.8 g/
mol) was dissolved in 5 mL of dry THF in a 5 mL volumetric flask.
The solution was shaken and sonicated for 5 min, until the solids
were dissolved. Next 167 mg of ester 6 was dissolved in 2 mL of
dry THF, sealed, and the atmosphere was replaced by inert gas.
Next, 2 mL of 2 M lithium borohydride solution was added through
a syringe, and the reaction mixture was stirred for 6 h after which
1 mL of a saturated solution of NH4Cl was added, and stirring was
continued until gas generation ceased. The reaction mixture was
extracted with AcOEt 3 times. The organic layer was washed with
brine (1 time) and dried over anhydrous Na2SO4. Filtration and sol-
vent removal under reduced pressure, afforded 138 mg of alcohol
4.10. 7-(tert-Butyl) 1-methyl (R)-3-(benzyl((R)-1-phenylethyl)-
amino)heptanedioate 5
At first, 2.128 g of acid 4b (383.7 g/mol; 5.55 mmol) was dis-
solved in 20 mL of tBuOH in a round bottom flask, together with
2.6 g of Boc2O (di-tert-butyl dicarbonate, CAS: 24424-99-5,
218.3 g/mol, 11.7 mmol). Next 204 mg of DMAP (4-(dimethyl-
amino)pyridine, CAS: 1122-58-3, 122.2 g/mol, 1.7 mmol) was
added and the reaction mixture was stirred at 30 °C for 2 d, with
a CaCl2 tube as desiccant seal. Solvent removal afforded the tert-
butyl ester and flash chromatography afforded 1.99 g of ester 5
(Hexanes/AcOEt 95:5, 82% yield). Rf 0.83 (Hexanes/AcOEt, 1:1);
7a, 90% yield. Rf = 0.64 (Hexanes/AcOEt, 4:1); [
CHCl3); IR (neat): max = 3367 (O-H), 2931 (C–H), 1707 (C@O),
1365, 1168 (C–O) cmÀ1 1H NMR (400 MHz, CDCl3): d = 4.42 (d,
a]
20 = +9.8 (c 0.7,
D
m
;
J = 9.1 Hz, 1H, NH), 3.81–3.69 (1H, H-5), 3.68–3.58 (2H, H-7), 2.23
(td, J = 7.5 and 4.8 Hz, 2H, H-2), 1.87–1.47 (6H, H-3, H-4 and H-
6), 1.44 (9H, s, C(CH3)3) ppm; 13C NMR (50 MHz, CDCl3):
d = 173.0 (s, C-1), 157.4 (s, NCOO), 80.5 (s, CO2C(CH3)3), 80.1 (s,
NCO2C(CH3)3), 58.9 (t, C-7), 47.3 (d, C-5), 39.3 (t, C-6), 35.3 (t, C-
2), 35.1 (t, C-4), 28.6 (q, CO2C(CH3)3), 28.3 (q, NCO2C(CH3)3), 21.7
(t, C-3) ppm; HRMS (ESI): m/z (M+Na) calcd for C16H31NO5Na,
[a
]
D
20 = +9.8 (c 0.6, CHCl3); IR (neat):
m
max = 2974 (C–H), 1730
(C@O), 1450, 1367, 1151 (C–O) cmÀ1
;
1H NMR (400 MHz, CDCl3):
d = 7.44–7.24 (10H, CarH), 3.86 (q, J = 7.0 Hz, 1H, CHCH3), 3.80
(AB, JAB = 14.7 Hz, 1H, NCHAH), 3.57 (AB, JAB = 14.7 Hz, 1H, NCHHB),
3.55 (s, 3H, CO2CH3), 3.36–3.30 (m, 1H, H-3), 2.17 (td, J = 7.0 Hz and
1.9, 2H, H-2), 2.05 (t, J = 7.9 Hz, 2H, H-6), 1.69–1.51 (4H, H-4 and
H-5), 1.46 (s, 9H, CO2C(CH3)3), 1.37 (d, J = 7.0 Hz, 3H, CHCH3)
ppm; 13C NMR (50 MHz, CDCl3): d = 173.3 (s, C-7), 173.2 (s, C-1),
143.1 (s, Cipso), 141.6 (s, Cipso), 128.5 (d, Car), 128.3 (d, Car), 127.1
(d, Car), 126.9 (d, Car), 80.1 (s, C(CH3)3), 57.8 (d, CHCH3), 53.8 (d,
C-3), 51.6 (q, CO2CH3), 50.1 (t, NCH2), 36.7 (t, C-2), 35.7 (t, C-6),
33.0 (t, C-4), 28.3 (q, C(CH3)3), 22.9 (q, CHCH3), 19.6 (t, C-5) ppm;
HRMS (ESI): m/z (M+H) calcd for C27H38NO4, 440.2801; found,
340.2094; found, 340.2102,
D = 2.22 ppm.
4.13. tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7- ((methyl-
sulfonyl)oxy)heptanoate 7b
At first, 74 lL of pyridine and 2.82 mg of DMAP (4-(dimethyl-
amino)pyridine, CAS: 1122-58-3, 122.2 g/mol, 0.023 mmol)
were added to a round bottom flask with 89 mg of alcohol 7a
(395.0 g/mol; 0.23 mmol) in 5 mL of dry DCM. The flask was sealed
and the inner atmosphere was replaced with Ar. Next, 44 lL of
440.2805,
D
= À0.93 ppm.
MsCl (methanesulfonyl chloride, CAS: 124-63-0, 114.6 g/mol,
0.68 mmol) was added through syringe and the reaction mixture
was magnetically stirred at room temperature for 12 h. An excess
of satd K2CO3 was added dropwise with vigorous bubbling, and
stirring was continued for an extra hour. The reaction mixture
was extracted with AcOEt (3 times) and the organic layers were
combined and washed with water (3 times) and brine (1 time).
Drying the solution with anhydrous Na2SO4, filtration, and solvent
removal under reduced pressure, afforded 102 mg of mesylate 7b,
4.11. 7-(tert-Butyl) 1-methyl (R)-3-((tert-butoxycarbonyl)-
amino)heptanedioate 6
At first, 356 mg of protected substrate
5 (439.0 g/mol,
0.812 mmol) and 568 mg of Boc2O (di-tert-butyl dicarbonate,
CAS: 24424-99-5, 218.3 g/mol, 2.6 mmol) were dissolved in 3 mL
of dry AcOEt. Next, 120 mg of Pd(OH)2 on carbon (palladium
hydroxide on carbon 20% wet, Perlman’s catalyst, CAS: 12135-22-
7, 140.4 g/mol) were added, and the mixture was placed in a
96% yield. Rf = 0.69 (Hexanes/AcOEt, 1:1); [
a]
20 = À1.0 (c 2.2,
D

C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
1053
CHCl3); IR (neat):
m
max = 3375 (N–H), 2976 (C–H), 1701 (C@O),
1H NMR (200 MHz, CDCl3): d = 4.39 (d,
anhydrous Na2SO4, filtration through a paper filter and solvent
removal under reduced pressure afforded a crude oil. Flash chro-
matography afforded 942 mg of product 4b (Hexanes/AcOEt 8:2,
91% yield).
1174 (S@O), 974 cmÀ1
;
J = 8.0 Hz, 1H, NH), 4.27 (t, J = 6.4 Hz, 2H, H-7), 3.71 (1H, H-5),
3.03 (s, 3H, OSO2CH3), 2.23 (td, J = 6.9 and 1.8 Hz, 2H, H-2), 2.03–
1.51 (6H, H-3, H-4 and H-6), 1.43 (s, 18H, C(CH3)3) ppm; 13C
NMR (50 MHz, CDCl3): d = 172.8 (s, C-1), 155.8 (s, NCOO), 80.5 (s,
CO2C(CH3)3), 79.4 (s, NCO2C(CH3)3), 67.4 (t, C-7), 47.5 (d, C-5),
37.4 (q, OSO2CH3), 35.2 (t, C-6), 35.1 (t, C-2), 35.0 (t, C-4), 28.5
(q, CO2C(CH3)3), 28.3 (q, NCO2C(CH3)3), 21.5 (t, C-3) ppm; HRMS
(ESI): m/z (M+Na) calcd for C17H33NO7NaS, 418.1869; found,
4.16. tert-Butyl (3-hydroxypropyl)carbamate 9a
In a round bottom flask, 1.00 g of 3-amino-1-propanol (CAS:
156-87-6, 75.1 g/mol, 13.3 mmol) was dissolved together with
3.17 g of Boc2O (di-tert-butyl dicarbonate, CAS: 24424-99-5,
218.3 g/mol, 13.3 mmol) in 20 mL of dry DCM. The mixture was
stirred overnight at room temperature. The reaction mixture was
extracted with AcOEt, and the organic layer was washed with
water (2 times), 1 M HCl (2 times), and brine (1 time). Drying the
solution over anhydrous Na2SO4, filtration and forward solvent
removal under reduced pressure, afforded 2.12 g of protected
amine 9a, 91% yield. 1H NMR (200 MHz; CHCl3): d = 4.96 (br s,
1H, NH), 3.62 (t, J = 5.6 Hz, 2H, H-3), 3.23 (q, J = 6.2 Hz, 2H, H-1),
3.06 (br s, 1H, OH), 1.63 (quintet, J = 6.2 Hz, 2H, H-2), 1.40 (s, 9H,
C(CH3)3) ppm; 13C NMR (50 MHz; CHCl3): d = 157.3 (s, NCOO),
79.7 (s, C(CH3)3), 59.4 (t, C-3), 37.1 (t, C-1), 32.9 (t, C-2), 28.5 (q,
C(CH3)3) ppm; HRMS (ESI): m/z (M+H) calcd for C8H18NO3,
418.1865,
D
= À1.18 ppm.
4.14. Methyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-7-hydro-
xyheptanoate 8
At first, 1.48 g of 1b (158.0 g/mol; 9.37 mmol) was dissolved in
60 mL of dry THF in a round bottom flask. The flask was sealed,
purged with Ar, and cooled to À78 °C in am CO2–acetone bath. In
a second pear-shaped flask, 7.18 g of (R)-(+)-N-benzyl-N-a-methyl-
benzylamine (CAS: 38235-77-7, 211.3 g/mol, 34 mmol) was dis-
solved in 60 mL of dry THF. This one was also sealed, purged with
Ar and cooled to À78 °C. Once cooled, 16 mL of nBuLi (n-buthyllithi-
um, CAS: 109-72-8, 64.1 g/mol, 32 mmol, 1.6 M solution) was
added dropwise, turning the solution from colorless to a dark pink.
The solution was stirred for 15 min at À78 °C, warmed to 0 °C in an
ice bath for 30 min and finally to À78 °C again for min. The pink
solution was added dropwise over the substrate solution and the
resulting mixture turned orange. Once the addition was finished,
the resulting mixture was magnetically stirred for 3 h before
quenching with an excess of satd NH4Cl. The solution turned from
orange to yellow with precipitate. After 60 min, the yellow reaction
mixture was extracted with AcOEt (3 times). The organic layers
were combined and washed with water (3 times) and brine (1
time). The AcOEt washed solution was dried over anhydrous Na2-
SO4, filtered, and the solvent was removed under reduced pressure
affording a crude yellowish oil. This crude was redissolved in DCM,
washed 3 times with a 10% citric acid (3 times) ,and dried again
with anhydrous Na2SO4. Final filtration and solvent removal lead
to a viscous yellowish oil. Flash chromatography afforded 2.66 g
of product 2 (Hexanes/AcOEt 9:1, 77% yield). Rf = 0.55 (Hexanes/
176.1281; found, 176.1288,
D
= À1.0 ppm.
4.17. 3-((tert-Butoxycarbonyl)amino)propyl methanesulfonate
9b
At first, 186 mg of pyridine and 7 mg of DMAP (4-(dimethyl-
amino)pyridine, CAS: 1122-58-3, 122.2 g/mol, 0.059 mmol) were
added to
a round bottom flask with 100 mg of alcohol 9a
(175.0 g/mol; 0.57 mmol) in 5 mL of dry DCM. The flask was sealed
and the inner atmosphere was replaced with Ar. Next 170 mg of
MsCl (methanesulfonyl chloride, CAS: 124-63-0, 114.6 g/mol,
1.8 mmol) were added through syringe and the reaction mixture
was magnetically stirred at room temperature for 12 h. An excess
of satd K2CO3 was added dropwise, with a vigorous bubbling,
and stirring was continued for an hour. The reaction mixture was
extracted with AcOEt (3 times) and the organic layers were com-
bined and washed with water (3 times) and brine (1 time). Drying
the solution over anhydrous Na2SO4, filtration and solvent removal
under reduced pressure, afforded 110 mg of mesylate 9b, 75%
yield. 1H NMR (200 MHz; CHCl3): d = 4.78 (br s, 1H, NH), 4.28 (t,
J = 6.0 Hz, 2H, H-1), 3.23 (2H, H-3), 3.02 (s, 3H, SO2CH3), 1.92 (quin-
tet, J = 6.2 Hz, 2H, H-2), 1.42 (s, 9H, C(CH3)3) ppm; 13C NMR
(50 MHz; CHCl3): d = 156.2 (s, NCOO), 79.6 (s, C(CH3)3), 67.7 (t,
C-1), 37.5 (q, SO2CH3), 36.9 (t, C-3), 29.8 (t, C-2), 28.5 (q, C(CH3)3)
ppm; HRMS (ESI): m/z (M+H) calcd for C9H19NSO5, 254.1062;
AcOEt, 1:1); [
a
]
D
20 = +8.1 (c 0.7, CHCl3); IR (neat):
m
max = 3431 (O-
H), 2933 (C–H), 1730 (C@O), 1450, 1155 (C–O) cmÀ1
;
1H NMR
(400 MHz, CDCl3): d = 7.43–7.22 (10H, CarH), 3.85 (q, J = 6.9 Hz,
1H, CHCH3), 3.79 (AB, JAB = 14.9 Hz, 1H, NCHAH), 3.62 (t, J = 6.3 Hz,
3H, H-7), 3.59–3.55 (1H, NCHHB), 3.55 (s, 3H, CO2CH3), 3.31 (m,
1H, H-3), 2.09 (ABX, JABX = 14.7 4.6 Hz, 1H, H-2A), 2.03 (ABX,
JABX = 14.6 and 8.3 Hz, 1H, H-2B), 1.64–1.37 (6H, H-4, H-5 and H-
6), 1.35 (d, J = 7.0 Hz, 3H, CHCH3) ppm; 13C NMR (50 MHz, CDCl3):
d = 173.5 (s, CO2CH3), 143.3 (s, Cipso), 141.8 (s, Cipso), 128.5 (d, Car),
128.4 (d, Car), 128.3 (d, Car), 128.1 (d, Car), 127.1 (d, Car), 126.9 (d,
Car), 63.1 (t, C-7), 58.1 (d, CHCH3), 54.0 (d, C-3), 51.6 (q, CO2CH3),
50.1 (t, NCH2), 36.6 (t, C-2), 33.4 (t, C-6), 32.8 (t, C-4), 23.3 (t,
C-5), 19.8 (q, CHCH3) ppm; HRMS (ESI): m/z (M+H) calcd for
found, 254.1073,
D
= À4.33 ppm.
4.18. 1,3-Oxazinan-2-one 10c, Table 1-entry 1.3
In a round bottom flask, 90 mg of K2CO3 (potassium carbonate,
CAS: 584-08-7, 138.2 g/mol, 0.652 mmol) was suspended in 5 mL
of dry DMF. This mixture was stirred for 1 h at 70 °C. Separately,
80 mg of mesylate 9b (253.0 g/mol; 0.32 mmol) and 39 mg of
TBAI (tetrabutylammonium iodide, CAS: 311-28-4, 396.4 g/mol,
0.097 mmol), were dissolved in 3 mL of dry DMF in round bottom
flask. This mixture was added to the initial mixture, and the reac-
tion was stirred for 12 h at 70 °C. An excess of water was added to
the reaction mixture, which was later extracted with AcOEt (3
times). The organic extract was washed with water (5 times), dried
over anhydrous Na2SO4, filtered, and the solvent was removed
under reduced pressure. Flash chromatography afforded 9 mg of
cyclic carbamate 10c32 (Hexanes/AcOEt 95:5, 29% yield) and
12 mg of starting material 9b (Hexanes/AcOEt 9:1).
C23H32NO3, 370.2376; found, 370.2374,
D
= À0.73 ppm.
4.15. (R)-5-(Benzyl((R)-1-phenylethyl)amino)-7-methoxy-7-
oxoheptanoic acid 4b
In a round bottom flask, 1.0 g of 8 (369.3 g/mol; 2.7 mmol) was
dissolved in 10 mL of acetone. Jones reagent was then added until a
red persisted. The reaction mixture was stirred for 30 min after
which 10 mL of 2-propanol were added, turning the solution from
dark red to dark green. The reaction mixture was extracted with
AcOEt (3 times) and the organic layers were combined and washed
with water (6 times). Drying the ethyl acetate solution over

1054
C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
4.19. tert-Butyl (3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)propyl)carbamate 10a, Table 1-entry 2
ded 3.5 mg of cyclic carbamate 10c (Hexanes/AcOEt 95:5, 19%
yield) and 17 mg of product 10a (Hexanes/AcOEt 9:1, 33%).
In a round bottom flask, 86 mg of thymine (CAS: 65-71-4,
126.1 g/mol, 0.68 mmol) and 63 mg of K2CO3 (potassium carbon-
ate, CAS: 584-08-7, 138.2 g/mol, 0.456 mmol) were suspended in
5 mL of dry DMF. This mixture was stirred for 1 h at 70 °C. Sepa-
rately, 56 mg of mesylate 9b (253.0 g/mol; 0.22 mmol) and
27 mg of TBAI (tetrabutylammonium iodide, CAS: 311-28-4,
396.4 g/mol, 0.067 mmol), were dissolved in 3 mL of dry DMF in
a round bottom flask. This mixture was added to the initial mix-
ture, and the reaction was stirred for 12 h at 70 °C. Excess water
was added to the reaction mixture, which was later extracted with
AcOEt (3 times). The organic extract was washed with water (5
times). The organic extract was washed with water (5 times), dried
over anhydrous Na2SO4, filtered, and the solvent was removed
under reduced pressure. Flash chromatography afforded 4 mg of
cyclic carbamate 10c (Hexanes/AcOEt 95:5, 18% yield) and 17 mg
of product 10a (Hexanes/AcOEt 9:1, 27%). Rf = 0.44 (Hexanes/
4.22. tert-Butyl (3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)propyl)carbamate 10a, Table 1-entry 5
In a round bottom flask, 99 mg of thymine (CAS: 65-71-4,
126.1 g/mol, 0.79 mmol) and 28 mg of DBU (1,8-diazabicy-
clo[5.4.0]undec-7-ene, CAS: 6674-22-2, 152.2 g/mol, 0.183 mmol)
were suspended in 5 mL of dry DMF. This mixture was stirred for
1 h at 70 °C. Separately, 27 mg of mesylate 9b (253.0 g/mol;
0.11 mmol) and 12 mg of TBAI (tetrabutylammonium iodide,
CAS: 311-28-4, 396.4 g/mol, 0.03 mmol), were dissolved in 3 mL
of dry DMF in a round bottom flask. This mixture was added to
the initial mixture, and the reaction was stirred for 12 h at 70 °C.
Excess water was added to the reaction mixture, which was later
extracted with AcOEt (3 times). The organic extract was washed
with water (5 times). The organic extract was washed with water
(5 times), dried over anhydrous Na2SO4, filtered, and the solvent
was removed under reduced pressure. Flash chromatography affor-
ded 2 mg of product 10a (Hexanes/AcOEt 9:1, 6%).
AcOEt, 1:1) cmÀ1 1H NMR (200 MHz; CHCl3): d = 9.15 (1H, br s,
;
CONHCO), 7.04 (br s, 1H, NCH), 5.04 (br s, 1H, NH), 3.77 (t,
J = 6.6 Hz, 2H, H-3), 3.23 (q, J = 6.1 Hz, 2H, H-1), 1.92 (s, 3H,
CCH3), 1.84 (quintet, J = 6.4 Hz, 2H, H-2), 1.43 (s, 9H, C(CH3)3)
ppm; 13C NMR (50 MHz; CHCl3): d = 164.5 (s, HNCOC), 156.3 (s,
NCOO), 151.4 (s, NCON), 140.6 (d, CH), 111.2 (s, CCH3), 79.7 (s,
C(CH3)3), 45.9 (t, C-3), 37.2 (t, C-1), 29.7 (t, C-2), 28.6 (q,
C(CH3)3), 12.5 (q, CCH3) ppm; HRMS (ESI): m/z (M+Na) calcd for
4.23. tert-Butyl (3-(6-chloro-9H-purin-9-yl)propyl)carbamate
10b, Table 1-entry 6
In a round bottom flask, 45 mg of 6-chloropurine (CAS: 87-42-3,
154.5 g/mol, 0.292 mmol) and 40 mg of K2CO3 (potassium carbon-
ate, CAS: 584-08-7, 138.2 g/mol, 0.292 mmol) were suspended in
5 mL of dry DMF. This mixture was stirred for 1 h at 70 °C. Sepa-
rately, 60 mg of mesylate 9b (253.0 g/mol; 0.24 mmol) and
29 mg of TBAI (tetrabutylammonium iodide, CAS: 311-28-4,
396.4 g/mol, 0.072 mmol), were dissolved in 3 mL of dry DMF in
a round bottom flask. This mixture was added to the initial mix-
ture, and the reaction was stirred for 12 h at 70 °C. Excess water
was added to the reaction mixture, which was later extracted with
AcOEt (3 times). The organic extract was washed with water (5
times). The organic extract was washed with water (5 times), dried
over anhydrous Na2SO4, filtered, and the solvent was removed
under reduced pressure. Flash chromatography afforded 2 mg of
cyclic carbamate 10c (Hexanes/AcOEt 95:5, 9% yield) and 18 mg
of product 10b (Hexanes/AcOEt 7:3, 25%). Rf = 0.09 (Hexanes/
C13H21N3O4Na, 306.1424; found, 306.1429, D = 1.5 ppm.
4.20. tert-Butyl (3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)propyl)carbamate 10a, Table 1-entry 3
In a round bottom flask, 99 mg of thymine (CAS: 65-71-4,
126.1 g/mol, 0.79 mmol) and 72 mg of K2CO3 (potassium carbon-
ate, CAS: 584-08-7, 138.2 g/mol, 0.524 mmol) were suspended in
5 mL of dry DMF. This mixture was stirred for 1 h at 70 °C. Sepa-
rately, 65 mg of mesylate 9b (253.0 g/mol; 0.25 mmol) and
31 mg of TBAI (tetrabutylammonium iodide, CAS: 311-28-4,
396.4 g/mol, 0.079 mmol), were dissolved in 3 mL of dry DMF in
round bottom flask. This mixture was added to the initial mixture,
and the reaction was stirred for 12 h at 70 °C. Excess water was
added to the reaction mixture, which was extracted with AcOEt
(3 times). The organic extract was washed with water (5 times).
The organic extract was washed with water (5 times), dried over
anhydrous Na2SO4, filtered, and the solvent was removed under
reduced pressure. Flash chromatography afforded 2 mg of cyclic
carbamate 10c (Hexanes/AcOEt 95:5, 7% yield) and 9 mg of product
10a (Hexanes/AcOEt 9:1, 12%).
AcOEt, 1:1); IR (neat):
m
max = 3329 (N–H), 2976 (C–H), 1695
(C@O), 1654, 1595, 1170 (C–O) cmÀ1
;
1H NMR (200 MHz; CHCl3):
d = 8.77 (s, 1H, CH2NCHN), 8.26 (1H, br s, NCHNCCl), 5.00 (br s,
1H, NH), 4.37 (t, J = 6.7 Hz, 2H, H-3), 3.13 (q, J = 6.0 Hz, 2H, H-1),
2.10 (quintet, J = 6.4 Hz, 2H, H-2), 1.45 (s, 9H, C(CH3)3) ppm; 13C
NMR (50 MHz; CHCl3): d = 156.3 (NCOO), 152.1 (CCl), 152.0
(NCHNCCl), 151.3 (CH2NCN), 145.8 (CH2NCHN), 131.8 (NCCCl),
79.9 (C(CH3)3), 42.0 (C-3), 37.4 (C-1), 30.7 (C-2), 28.5 (C(CH3)3)
ppm; HRMS (ESI): m/z (M+Na) calcd for C13H18N5O2ClNa,
4.21. tert-Butyl (3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)propyl)carbamate 10a, Table 1-entry 4
334.1041; found, 334.1046,
D = 1.4 ppm.
In a round bottom flask, 71 mg of thymine (CAS: 65-71-4,
126.1 g/mol, 0.56 mmol) and 52 mg of DBU (1,8-diazabicy-
clo[5.4.0]undec-7-ene, CAS: 6674-22-2, 152.2 g/mol, 0.341 mmol)
were suspended in 5 mL of dry DMF. This mixture was stirred for
1 h at 70 °C. Separately, 46 mg of mesylate 9b (253.0 g/mol;
0.18 mmol) and 22 mg of TBAI (tetrabutylammonium iodide,
CAS: 311-28-4, 396.4 g/mol, 0.056 mmol), were dissolved in 3 mL
of dry DMF in round bottom flask. This mixture was added to the
initial mixture, and the reaction was stirred for 12 h at 70 °C.
Excess water was added to the reaction mixture, which was later
extracted with AcOEt (3 times). The organic extract was washed
with water (5 times). The organic extract was washed with water
(5 times), dried over anhydrous Na2SO4, filtered, and the solvent
was removed under reduced pressure. Flash chromatography affor-
4.24. tert-Butyl (3-(6-chloro-9H-purin-9-yl)propyl)carbamate
10b, Table 1-entry 7
In a round bottom flask, 86 mg of 6-chloropurine (CAS: 87-42-3,
154.5 g/mol, 0.558 mmol) and 51 mg of K2CO3 (potassium carbon-
ate, CAS: 584-08-7, 138.2 g/mol, 0.372 mmol) were suspended in
5 mL of dry DMF. This mixture was stirred for 1 h at 70 °C. Sepa-
rately, 46 mg of mesylate 9b (253.0 g/mol; 0.18 mmol) and
22 mg of TBAI (tetrabutylammonium iodide, CAS: 311-28-4,
396.4 g/mol, 0.055 mmol), were dissolved in 3 mL of dry DMF in
a round bottom flask. This mixture was added to the initial mix-
ture, and the reaction was stirred for 12 h at 70 °C. Excess water
was added to the reaction mixture, which was later extracted with
AcOEt (3 times). The organic extract was washed with water (5

C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
1055
times). The organic extract was washed with water (5 times), dried
over anhydrous Na2SO4, filtered, and the solvent was removed
under reduced pressure. Flash chromatography afforded 2 mg of
cyclic carbamate 10c (Hexanes/AcOEt 95:5, 11% yield) and 11 mg
of product 10b (Hexanes/AcOEt 7:3, 20%).
3 mL of dry DMF in a round bottom flask. This mixture was added
to the initial mixture, and the reaction was stirred for 12 h at 70 °C.
Excess water was added to the reaction mixture, which was later
extracted with AcOEt (3 times). The organic extract was washed
with water (5 times). The organic extract was washed with water
(5 times), dried over anhydrous Na2SO4, filtered, and the solvent
was removed under reduced pressure. Flash chromatography affor-
ded 20 mg of product 11d (Hexanes/AcOEt 75:25, 23%). Rf = 0.55
4.25. tert-Butyl (3-(6-chloro-9H-purin-9-yl)propyl)carbamate
10b, Table 1-entry 8
(Hexanes/AcOEt, 1:1); [
a]
20 = À16.8 (c 1.0, MeOH); IR (neat):
D
In a round bottom flask, 100 mg of alcohol 9a (175.0 g/mol;
0.57 mmol), 143 mg of PBu3 (tributylphosphine, CAS: 998-40-3,
202.3 g/mol, 0.71 mmol), 143 mg of DIAD (diisopropyl azodicar-
boxylate, CAS: 2446-83-5, 202.2 g/mol) and 109 mg of 6-chloropu-
rine (CAS: 87-42-3, 154.5 g/mol, 0.71 mmol) were dissolved in
4 mL of dry THF. After sealing the flask and replacing the inner
atmosphere with Ar, the reaction mixture was magnetically stirred
at room temperature 48 h. Excess water was added to the reaction
mixture and then extracted with AcOEt (3 times). The organic lay-
ers were combined and washed with water (3 times) and brine (1
time). Drying the solution over anhydrous Na2SO4, filtration, and
solvent removal under reduced pressure, afforded a crude oil. Flash
chromatography afforded 101 mg of product 10b (Hexanes/AcOEt
7:3, 68% yield).
m
max = 3354 (N–H), 2976 (C–H), 1701 (C@O), 1647, 1251 (C–O)
cmÀ1
;
1H NMR (400 MHz, CDCl3): d = 7.91 (dd, J = 8.5 and 1.2 Hz,
2H, o-CarH), 7.63 (tt, J = 7.4 and 1.6 Hz, 1H, p-CarH), 7.63 (t,
J = 7.4 Hz, 1H, m-CarH), 7.23 (br s, 1H, NCH), 4.43 (d, J = 9.1 Hz,
1H, NH), 3.93 (1H, H-7A), 3.61 (2H, H-5 and H-7B), 2.21 (q,
J = 6.3 Hz, 2H, H2), 1.95 (s, 3H, CCH3), 1.91 (1H, H-4A), 1.74–1.37
(5H, H-3, H-4B and H-6), 1.44 (s, 18H, C(CH3)3) ppm; 13C NMR
(50 MHz, CDCl3): d = 172.8 (s, C-1), 169.3 (NCOCar), 163.4 (s,
NCO), 156.0 (s, NCOO), 150.0 (s, NCON), 141.0 (d, NCH), 135.1 (d,
p-Car), 131.9 (s, Cipso), 130.6 (d, o-Car), 129.3 (d, m-Car), 110.8 (s,
CCH3), 80.5 (s, CO2C(CH3)3), 79.8 (s, NCO2C(CH3)3), 48.4 (d, C-5),
46.8 (t, C-7), 35.2 (t, C-2), 35.1 (t, C-4), 34.9 (t, C-6), 28.5 (q,
CO2C(CH3)3), 28.3 (q, NCO2C(CH3)3), 21.5 (t, C-3), 12.6 (q,
CCH3) ppm; HRMS (ESI): m/z (M+Na) calcd for C28H39N3O7Na,
552.2680; found, 552.2695,
D = 2.67 ppm.
4.26. Mixture of 11e regioisomers N1/N3-11e, Table 2-entry 1
4.28. tert-Butyl (R)-7-(3-benzoyl-5-methyl-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl)-5-((tert-butoxycarbonyl)amino)-
heptanoate 11d, Table 2-entry 3
In a round bottom flask, 98 mg of thymine (CAS: 65-71-4,
126.1 g/mol, 0.77 mmol) and 72 mg of K2CO3 (potassium carbon-
ate, CAS: 584-08-7, 138.2 g/mol, 0.518 mmol) were suspended in
5 mL of dry DMF. This mixture was stirred for 1 h at 70 °C. Sepa-
rately, 102 mg of mesylate 7b (395.0 g/mol; 0.26 mmol) and
31 mg of TBAI (tetrabutylammonium iodide, CAS: 311-28-4,
396.4 g/mol, 0.078 mmol), were dissolved in 3 mL of dry DMF in
a round bottom flask. This mixture was added to the initial mix-
ture, and the reaction was stirred for 12 h at 70 °C. Excess water
was added to the reaction mixture, which was later extracted with
AcOEt (3 times). The organic extract was washed with water (5
times). The organic extract was washed with water (5 times), dried
over anhydrous Na2SO4, filtered, and the solvent was removed
under reduced pressure. Flash chromatography afforded 23 mg of
cyclic carbamate 11c (Hexanes/AcOEt 9:1, 37%) and 38 mg of a
1:1 PNA regioisomers mixture N1/N3-11d (Hexanes/AcOEt 7:3,
35%).
In a round bottom flask, 46 mg of alcohol 7a (395.0 g/mol;
0.118 mmol), 52 mg of PBu3 (tributylphosphine, CAS: 998-40-3,
202.3 g/mol, 0.261 mmol), 52 mg of DIAD (diisopropyl azodicar-
boxylate, CAS: 2446-83-5, 202.2 g/mol, 0.261 mmol), and 60 mg
of N3-benzoyl-thymine31 (230.2 g/mol, 0.261 mmol)2 were dis-
solved in 4 mL of dry THF. After sealing the flask and replacing
the inner atmosphere with Ar, the reaction mixture was magneti-
cally stirred at room temperature 48 h. Excess water was added to
the reaction mixture and then extracted with AcOEt (3 times). The
organic layers were combined and washed with water (3 times)
and brine (1 time). Drying the solution over anhydrous Na2SO4, fil-
tration, and solvent removal under reduced pressure, afforded a
crude oil. Flash chromatography afforded 47 mg of product 11d
(Hexanes/AcOEt 75:25, 75% yield).
Compound 11c: Rf = 0.90 (Hexanes/AcOEt, 1:1); IR (neat):
m
max = 3253 (N–H), 2927 (C–H), 1718 (C@O), 1363, 1153 (C–O)
cmÀ1 1H NMR (400 MHz, CDCl3): d = 5.43 (s, 1H, NH), 4.33 (dt,
;
4.29. tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7-(6-chloro-
9H-purin-9-yl)heptanoate 11a, Table 2-entry 4
J = 11.2 4.3 Hz, 1H, CHAHO), 4.33 (td, J = 11.2 and 2.7 Hz, 1H, CHHB-
O), 3.47 (quintet, J = 5.6 Hz, 1H, CHN), 2.25 (td, J = 6.8 2.8 Hz, 2H, H-
2), 2.02 (1H, CHAHCH2O), 1.75–1.49 (5H, H-3, H-4 and CHHBCH2O),
1.44 (s, 9H, C(CH3)3) ppm; 13C NMR (50 MHz, CDCl3): d = 172.6 (C-
1), 154.2 (NCOO), 80.9 (C(CH3)3), 65.8 (CH2O), 50.9 (CHN), 36.1 (C-
2), 35.2 (C-4), 28.4 (C(CH3)3), 27.5 (t, CH2CH2O), 20.9 (C-3) ppm;
HRMS (ESI): m/z (M+Na) calcd for C12H21NO4Na, 266.1362; found,
In a round bottom flask, 39 mg of alcohol 7a (395.0 g/mol;
0.099 mmol), 44 mg of PBu3 (tributylphosphine, CAS: 998-40-3,
202.3 g/mol, 0.22 mmol), 44 mg of DIAD (diisopropyl azodicarbox-
ylate, CAS: 2446-83-5, 202.2 g/mol, 0.22 mmol), and 34 mg of
6-chloropurine (CAS: 87-42-3, 154.5 g/mol, 0.22 mmol) were dis-
solved in 4 mL of dry THF. After sealing the flask and replacing
the inner atmosphere with Ar, the reaction mixture was magneti-
cally stirred at room temperature for 48 h. Excess water was added
to the reaction mixture and then extracted with AcOEt (3 times).
The organic layers were combined and washed with water
(3 times) and brine (1 time). Drying the solution over anhydrous
Na2SO4, filtration and forward solvent removal under reduced
pressure, afforded a crude oil. Flash chromatography afforded
26 mg of product 11a (Hexanes/AcOEt 75:25, 61% yield). Rf = 0.47
266.1356,
D
= À2.55 ppm.
4.27. tert-Butyl (R)-7-(3-benzoyl-5-methyl-2,4-dioxo-3,4-di-
hydropyrimidin-1(2H)-yl)-5-((tert-butoxycarbonyl)amino)-
heptanoate 11d, Table 2-entry 2
In a round bottom flask, 113 mg of N3-benzoyl-thymine31
(230.2 g/mol, 0.492 mmol)2 and 45 mg of DBU (1,8-diazabicy-
clo[5.4.0]undec-7-ene, CAS: 6674-22-2, 152.2 g/mol, 0.328 mmol)
were suspended in 5 mL of dry DMF. This mixture was stirred 1 h
at 70 °C. Separately, 64 mg of mesylate 7b (395.0 g/mol;
0.164 mmol) and 19 mg of TBAI (tetrabutylammonium iodide,
CAS: 311-28-4, 396.37 g/mol, 0.049 mmol), were dissolved in
(Hexanes/AcOEt, 1:1); [
a
]
20 = À10.5 (c 1.4, MeOH); IR (neat):
D
m
max = 3329 (N–H), 2978 (C–H), 1701 (C@O, ester), 1593, 1251
(C–O) cmÀ1
;
1H NMR (400 MHz, CDCl3): d = 8.75 (s, 1H, NCHNCCl),
8.73 (s, rotamer, 1H, NCHNCCl), 8.33 (s, 1H, CH2NCHN), 8.30 (s, rot-

1056
C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
amer, 1H, CH2NCHN), 4.49 (d, J = 8.0 Hz, 1H, NH), 4.40 (ABXY,
JABXY = 14.1 7.2 and 5.2 Hz, 1H, H-7A), 4.33 (quintet, J = 7.2 Hz, 1H,
H-7B), 3.61 (1H, H-5), 2.18 (m, 2H, H2), 1.91–1.84 (2H, H-6),
166–1.40 (2H, H-3 and H-4), 1.44 (s, 9H, CO2C(CH3)3), 1.40 (s, 9H,
NCO2C(CH3)3) ppm; 13C NMR (50 MHz, CDCl3): d = 172.7 (s, C-1),
156.1 (s, NCOO), 152.1 (d, ClCNCH), 152.0 (s, CCl), 151.2 (s, ClCCC),
146.2 (d, CNCHNC), 131.9 (s, ClCC), 80.5 (s, CO2C(CH3)3), 80.0 (s,
NCO2C(CH3)3), 48.3 (d, C-5), 42.0 (t, C-7), 36.1 (t, C-6), 35.1 (t, C-
2), 35.0 (t, C-4), 28.5 (q, CO2C(CH3)3), 28.3 (q, NCO2C(CH3)3), 21.4
(t, C-3) ppm; HRMS (ESI): m/z (M+Na) calcd for C21H32N5O4NaCl,
141.3 (d, NCH), 110.7 (s, CCH3), 80.5 (s, CO2C(CH3)3), 79.8 (s,
NCO2C(CH3)3), 48.3 (d, C-5), 46.4 (t, C-7), 35.3 (t, C-2), 35.1 (t, C-
4), 34.9 (t, C-6), 28.5 (q, CO2C(CH3)3), 28.3 (q, NCO2C(CH3)3),
21.4 (t, C-3), 12.5 (q, CCH3) ppm; HRMS (ESI): m/z (M+Na) calcd
for C21H35N3O6Na, 448.2418; found, 448.2420,
D = 0.42 ppm.
4.32. Ethyl (R)-5-((tert-butoxycarbonyl)amino)-7-(5-methyl-
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)heptanoate 11f
At first, 4.8 mg of 11e (425.2 g/mol, 0.073 mmol) were dissolved
in 3 mL of dry EtOH. Next, HCl gas (hydrogen chloride, CAS: 7647-
01-0, 36.4 g/mol) was bubbled for 5 min. The solvent was removed
under reduced pressure and the crude was dissolved in 2 mL of dry
DCM. Next, 8 mg of Boc2O (di-tert-butyl dicarbonate, CAS: 24424-
99-5, 218.2 g/mol, 0.038 mmol) and 9 mg of DMAP (4-(dimethyl-
amino)pyridine, CAS: 1122-58-3, 122.1 g/mol, 0.073 mmol). The
solution was magnetically stirred at room temperature for 12 h.
Next, 10 mL of DCM were added and the mixture was washed with
water (2 times), 1 M HCl (2 times) and brine (1 time). The solution
was dried over anhydrous Na2SO4, filtered, and the solvent
removed under reduced pressure. Flash chromatography afforded
2.4 mg of product 11f (Hexanes/AcOEt 7:3, 54% yield). Rf = 0.45
476.2035; found, 476.2040,
D = 1.04 ppm.
4.30. tert-Butyl (R)-7-(2-amino-6-chloro-9H-purin-9-yl)-5-
((tert-butoxycarbonyl)amino)heptanoate 11b, Table 2-entry 5
In a round bottom flask, 35 mg of alcohol 7a (395.0 g/mol;
0.103 mmol), 63 mg of PBu3 (tributylphosphine, CAS: 998-40-3,
202.3 g/mol, 0.311 mmol), 63 mg of DIAD (diisopropyl azodicar-
boxylate, CAS: 2446-83-5, 202.21 g/mol, 0.311 mmol), and 53 mg
of 2-amino-6-chloropurine (CAS: 10310-21-1, 169.5 g/mol,
0.311 mmol) were dissolved in 4 mL of dry THF. After sealing the
flask and replacing the inner atmosphere with Ar, the reaction mix-
ture was magnetically stirred at room temperature for 48 h. Water
excess was added to the reaction mixture and later was extracted
with AcOEt (3 times). The organic layers were combined and
washed with water (3 times) and brine (1 time). Drying the solution
over anhydrous Na2SO4, filtration, and forward solvent removal
under reduced pressure, afforded a crude oil. Flash chromatography
afforded 22 mg of product 11b (Hexanes/AcOEt 75:25, 53% yield).
(Hexanes/AcOEt, 1:1); [
a]
20 = À11.2 (c 0.24, MeOH); 1H NMR
D
(400 MHz, CDCl3): d = 8.03 (s, 1H, CONHCO), 7.12 (s, 1H, NCH),
4.41 (d, J = 7.4 Hz, 1H, NHCO), 4.12 (q, J = 7.1 Hz, 2H, OCH2CH3),
3.82 (m, 1H, H-7A), 3.60 (m, 2H, H-5 and H-7B), 2.30 (2H, H-2),
1.92 (s, 3H, CCH3), 1.69–1.45 (6H, H-3, H-4 and H-6), 1.45 (s, 9H,
C(CH3)3), 1.25 (t, J = 7.1 Hz, 3H, OCH2CH3) ppm; 13C NMR
(50 MHz, CDCl3): d = 173.1 (s, C-1), 163.5 (s, NCO), 156.0 (s, NCOO),
150.2 (s, NCON), 140.9 (d, NCH), 110.2 (s, CCH3), 79.2 (s,
CO2C(CH3)3), 60.6 (t, OCH2CH3), 48.8 (d, C-5), 46.7 (t, C-7), 33.9
(t, C-2), 35.1 (t, C-4), 33.8 (t, C-6), 28.5 (q, C(CH3)3), 21.4 (t, C-3),
14.3 (q, OCH2CH3), 12.4 (q, CCH3) ppm; HRMS (ESI): m/z (M+H)
Rf = 0.35 (Hexanes/AcOEt, 1:1); [
(neat):
(C@O, carbamate), 1251 (C–O) cmÀ1
a
]
20 = À15.7 (c 1.2, MeOH); IR
D
m
max = 3329 (N–H), 2976 (C–H), 1701 (C@O, ester), 1610
;
1H NMR (200 MHz, CDCl3):
d = 7.88 (s, 1H, NCHN), 5.23 (br s, 2H, NH2), 4.56 (d, J = 8 Hz, 1H,
NH), 4.13 (2H, H-7), 3.62 (br s, 1H, H-5), 2.21 (t, J = 7.0 Hz, 2H, H-
2), 2.03–1.46 (6H, H-3, H-4 and H-6), 1.44 (s, 9H, CO2C(CH3)3),
1.42 (s, 9H, NCO2C(CH3)3) ppm; 13C NMR (50 MHz, CDCl3):
d = 172.9 (s, C-1), 159.2 (s, CNH2), 155.9 (s, NCOO), 153.9 (s, CCl),
151.4 (s, ClCCC), 143.0 (d, NCH), 125.6 (s, ClCC), 80.5 (s,
CO2C(CH3)3), 79.8 (s, NCO2C(CH3)3), 48.5 (d, C-5), 41.3 (t, C-7),
35.7 (t, C-2), 35.1 (t, C-4), 35.0 (t, C-6), 28.5 (q, CO2C(CH3)3), 28.3
(q, NCO2C(CH3)3), 21.4 (t, C-3) ppm; HRMS (ESI): m/z (M+Na) calcd
calcd for C19H32N3O6, 398.2285; found, 398.2287,
D = 0.34 ppm.
4.33. Di(pentan-3-yl) (R,E)-8-(benzyl((R)-1-phenylethyl)amino)-
dec-3-enedioate 12a
At first, 76 mg of 1c (338.2 g/mol; 0.22 mmol) were dissolved in
1 mL of dry THF in a round bottom flask. The flask was sealed,
purged with Ar, and cooled to À78 °C in a CO2–acetone bath. In a
for C21H33N6O4NaCl, 491.2144; found, 491.2150,
D
= 1.21 ppm.
second pear-shaped flask, 145 mg of (R)-(+)-N-benzyl-a-methyl-
benzylamine (CAS: 38235-77-7, 211.3 g/mol, 0.69 mmol) were dis-
solved in 3 mL of dry THF. This one was also sealed, purged with Ar
and cooled to À78 °C. Once cooled, 0.41 mL of nBuLi (n-buthyllithi-
um, CAS: 109-72-8, 64.1 g/mol, 0.66 mmol, 1.6 M solution) were
added dropwise, turning the solution from colorless to a dark pink.
The solution was stirred for 15 min at À78 °C, warmed to 0 °C in an
ice bath for 30 min and finally to À78 °C for 15 min. The pink solu-
tion was added dropwise over the substrate solution and the
resulting mixture turned orange. Once the addition was finished,
the resulting mixture was magnetically stirred for 3 h before
quenching with an excess of satd NH4Cl. The solution turned from
orange to yellow with precipitate. After 60 min, the yellow reaction
mixture was extracted with AcOEt (3 times). The organic layers
were combined and washed with water (3 times) and brine (1
time). The AcOEt washed solution was dried with anhydrous Na2-
SO4, filtered, and the solvent was removed under reduced pressure
affording a crude yellowish oil. This crude was redissolved in DCM,
washed 3 times with a 10% citric acid (3 times) and dried over
anhydrous Na2SO4. Final filtration and solvent removal gave a vis-
cous yellowish oil. Flash chromatography afforded 85 mg of prod-
uct 12a (Hexanes/AcOEt 95:5, 70% yield). Rf = 0.66 (Hexanes/AcOEt,
4.31. tert-Butyl (R)-5-((tert-butoxycarbonyl)amino)-7-(5-meth-
yl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)heptanoate 11e
At first, 9 mg of 11d (529.2 g/mol; 0.058 mmol) was dissolved in
2 mL of MeOH/THF/H2O 3:3:1 in a round bottom flask. 5 mg of
LiOHÁH2O (lithium hydroxide monohydrate, CAS: 1310-66-3,
41.9 g/mol, 0.13 mmol) was added and the resulting solution was
stirred at room temperature for 5 h. The pH of the solution was
checked (basic) and AcOEt was added. The mixture was partitioned
between water and AcOEt and the aqueous solution was extracted
again with AcOEt. The aqueous solution was acidified with HCl 1 M
and extracted three times with DCM. This organic solution was
washed with brine, dried over anhydrous Na2SO4, filtered, and
the solvent was evaporated to dryness. Flash chromatography
afforded 7 mg of product 11e (Hexanes/AcOEt 7:3, 97% yield).
Rf = 0.40 (Hexanes/AcOEt, 1:1); [
(neat):
(C–O) cmÀ1
a
]
20 = À15.4 (c 0.7, MeOH); IR
D
m
max = 3327 (N–H), 2976 (C–H), 1701 (C@O), 1670, 1166
;
1H NMR (400 MHz, CDCl3): d = 8.49 (s, 1H, CONHCO),
7.12 (s, 1H, NCH), 4.47 (d, J = 9.2 Hz, 1H, NHCO), 3.88 (quintet,
J = 6.6 Hz, 1H, H-7A), 3.59 (m, 2H, H-5 and H-7B), 2.23 (td, J = 7.1
and 4.3 Hz, 2H, H-2), 1.91 (s, 3H, CCH3), 1.72–1.41 (6H, H-3, H-4
and H-6), 1.44 (s, 18H, C(CH3)3) ppm; 13C NMR (50 MHz, CDCl3):
d = 172.9 (s, C-1), 164.2 (s, NCO), 156.0 (s, NCOO), 150.9 (s, NCON),
9:1); [
1732 (C@O), 1688 (C@O), 1458 (C–N), 1260, 1157 (C–O) cmÀ1
1H NMR (400 MHz, CDCl3): d = 7.4–7.2 (10H, CarH), 5.54 (m, 2H,
a] mmax = 2971 (C–H),
20 = +6.9 (c 0.93, CHCl3); IR (film):
D
;

C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
1057
H-7 and H-8), 4.77 (q, J = 5.4 Hz, 1H, CH(CH2CH3)), 4.68 (q,
J = 5.4 Hz, 1H, CH(CH2CH3)), 3.82 (q, J = 7.0 Hz, 1H, CH(CH3)), 3.81
(d, J = 13.9 Hz, 1H, NCHAH), 3.49 (d, J = 13.9 Hz, 1H, NCHHB), 3.36
(m, 1H, H-3), 3.01 (d, J = 5.1 Hz, 2H, H-9), 1.98 (m, 1H, H-2 and
H-6), 1.57 (m, 8H, CH(CH2CH3)2), 1.50 (4H, H-4 and H-5), 1.34 (d,
J = 7.0 Hz, 3H, CHCH3), 0.89 (t, J = 7.5 Hz, 6H, CH(CH2CH3)2), 0.84
(t, J = 7.5 Hz, 6H, CH(CH2CH3)2) ppm; 13C NMR (50 MHz, CDCl3):
d = 172.6 (2Âs, C-1 and C-10), 142.9 (s, Cipso), 141.8 (s, Cipso),
128.2–126.6 (10Âd, Car), 134.4 (d, C-8), 122.0 (d, C-7), 77.0 (d,
CH(CH2CH3)), 76.6 (d, CH(CH2CH3)), 58.3 (d, CHCH3), 53.7 (d,
C-3), 50.1 (t, CH2Car), 38.5 (t, C-9), 36.7 (t, C-2), 33.2 (t, C-6),
32.4 (t, C-4), 26.6 (t, C-5), 26.5 (2Ât, CH(CH2CH3)2), 26.3 (2Ât,
CH(CH2CH3)2), 20.5 (q, CHCH3), 9.5 (4Âq, CH(CH2CH3)2) ppm;
HRMS (EI): m/z (M+) calcd for C35H51NO4, 549.3818; found,
(10Âd, Car), 76.4 (d, CH(CH2CH3)2), 58.5 (d, CHCH3), 53.5 (d, C-3),
50.2 (t, CH2Car), 43.6 (t, C-6), 36.3 (t, C-2), 33.0 (t, C-4), 26.3 (2Ât,
CH(CH2CH3)2), 20.7 (q, CHCH3), 19.5 (t, C-5), 9.5 (2Âq, CH(CH2-
CH3)2) ppm; HRMS (ESI): m/z (M+H) calcd for C27H38NO3,
424.2852; found, 424.2845,
D = 1.65 ppm.
4.36. 3-Pentyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-8-oxo-
octanoate 13b
At first, 97 mg of diester 12b (549.3 g/mol; 0.18 mmol) was dis-
solved in 6 mL of dry DCM in a round bottom flask. Next, HCl gas
(hydrogen chloride, CAS: 7647-01-0, gas, 36.5 g/mol) was bubbled
through a pipette for 10 min, while the reaction solution was
cooled at À78 °C in a CO2–acetone bath. Next, ozone (O3, gas, gen-
erated in situ) was bubbled for 15 min until the solution was light
blue. Finally, 0.2 mL of Me2S (dimethyl sulfide, CAS: 75-18-3,
62.1 g/mol, 2.7 mmol) was added and the reaction was allowed
to warm to room temperature. Next 10 mL of 1 M KOH was added,
turning the reaction mixture white. After 30 min of stirring, the
reaction was extracted with DCM (3 times). The organic solution
was washed with brine 1 time. The solution was dried over anhy-
drous Na2SO4, filtered, and the solvent was removed under reduced
pressure. Flash chromatography afforded 75 mg of product 13b
(Hexanes/AcOEt 95:5, 98% yield). Rf = 0.67 (Hexanes/AcOEt, 8:2);
549.3829,
D
= À2.00 ppm.
4.34. Di(pentan-3-yl) (R,E)-8-(benzyl((R)-1-phenylethyl)amino)-
dec-2-enedioate 12b
See literature for complete procedure.21 Rf = 0.57 (Hexanes/
AcOEt, 9:1); [
a
]
D
20 = +6.2 (c 2.62, CHCl3); IR (film):
m
max = 3000
;
(C–H), 1714 (C@O), 1640 (C@O), 1500 (C–N), 1460 cmÀ1
1H NMR
(400 MHz, CDCl3): d = 7.4–7.2 (10H, CarH), 6.95 (dt, J = 15.6
6.9 Hz, 1H, H-8), 5.81 (d, J = 15.6 Hz, 1H, H-9), 4.82 (q, J = 6.8 Hz,
1H, CH(CH2CH3)), 4.67 (q, J = 6.8 Hz, 1H, CH(CH2CH3)), 3.81 (q,
J = 7.0 Hz, 1H, CH(CH3)), 3.81 (d, J = 15.0 Hz, 1H, NCHAH), 3.50 (d,
J = 15.0 Hz, 1H, NCHHB), 3.33 (m, 1H, H-3), 2.17 (q, J = 6.9 Hz, 2H,
H-7), 2.04 (dd, J = 14.6 and 6.0 Hz, 1H, H-2B), 1.96 (dd, J = 14.6
and 3.0 Hz, 1H, H-2A), 1.60 (m, 4H, H-4, H-5 and H-6), 1.50 (m,
8H, CH(CH2CH3)2), 1.33 (d, J = 7.0 Hz, 3H, CHCH3), 0.89 (t,
J = 7.4 Hz, 6H, CH(CH2CH3)2), 0.85 (t, J = 7.4 Hz, 3H, CH(CH2CH3)),
0.81 (t, J = 7.4 Hz, 3H, CH(CH2CH3)) ppm; 13C NMR (50 MHz,
CDCl3): d = 172.6 (s, C-1), 166.6 (s, C-10), 148.8 (d, C-8), 143.2 (s,
[a
]
D
20 = +6.8 (c 1.28, CHCl3); IR (neat):
m
max = 2971 (C–H), 1724
;
(C@O), 1456 (C–N), 1277 (C–O), 1202 cmÀ1 1H NMR (400 MHz,
CDCl3): d = 9.73 (t, J = 1.8 Hz, 1H, H-8), 7.4–7.2 (10H, CarH), 5.67
(m, 1H, CH(CH2CH3)), 3.8 (m, 1H, CH(CH3)), 3.82 (d, J = 7.5 Hz,
1H, NCHAH), 3.50 (d, J = 7.5 Hz, 1H, NCHHB), 3.35 (m, 1H, H3),
2.38 (m, 2H, H7), 2.0 (m, 2H, H2), 1.75–1.35 (10H, H-4, H-5, H-6
and CH(CH2CH3)2), 1.33 (d, J = 7.0 Hz, 3H, CHCH3), 0.84 (t,
J = 7.4 Hz, 3H, CH(CH2CH3)), 0.81 (t, J = 7.4 Hz, 3H, CH(CH2CH3))
ppm; 13C NMR (50 MHz, CDCl3): d = 202.3 (d, C-8), 172.6 (s, C-1),
142.8 (s, Cipso), 141.7 (s, Cipso), 128.3–126.6 (10Âd, Car), 76.6 (d,
CH(CH2CH3)2), 58.3 (d, CHCH3), 53.5 (d, C-3), 50.0 (t, C-7), 50.0 (t,
CH2Car), 36.4 (t, C-2), 33.3 (t, C-4), 26.4 (2Ât, CH(CH2CH3)2), 21.9
(t, C-5), 20.6 (q, CHCH3), 20.5 (t, C-6), 9.5 (2Âq, CH(CH2CH3)2)
ppm; HRMS (ESI): m/z (M+H) calcd for C28H40NO3, 438.3008;
C
ipso), 141.9 (s, Cipso), 128.2–126.6 (10Âd, Car), 121.7 (d, C-9), 76.4
(2Âd, CH(CH2CH3)2), 58.6 (d, CHCH3), 53.9 (d, C-3), 50.2 (t, CH2Car),
36.6 (t, C-2), 33.6 (t, C-7), 33.4 (t, C-4), 32.1 (t, C-6), 27.8 (t, C-5),
26.5 (2Ât, CH(CH2CH3)2), 26.3 (2Ât, CH(CH2CH3)2), 20.7 (q, CHCH3),
9.5 (4Âq, CH(CH2CH3)2) ppm; HRMS (EI): m/z (M+) calcd for
C35H51NO4, 549.3818; found, 549.3837,
D
= À3.46 ppm.
found, 438.2993, D = 3.42 ppm.
4.35. 3-Pentyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-7-oxo-
4.37. 3-Pentyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-6-(1,3-
heptanoate 13a
dioxolan-2-yl)hexanoate 14a
At first, 83 mg of diester 12a (549.3 g/mol; 0.15 mmol) was dis-
solved in 5 mL of dry DCM in a round bottom flask. Next, HCl gas
(hydrogen chloride, CAS: 7647-01-0, 36.5 g/mol) was bubbled
through a pipette for 10 min, while the reaction solution was
cooled at À78 °C in a CO2–acetone bath. Next, ozone (O3, gas, gen-
erated in situ) was bubbled for 15 min until the solution was light
blue. Finally, 0.2 mL of Me2S (dimethyl sulfide, CAS: 75-18-3,
62.1 g/mol, 2.7 mmol) was added and the reaction was allowed
to warm to room temperature. Next, 5 mL of 1 M KOH was added,
turning the reaction mixture white. After 30 min of stirring, the
reaction was extracted with DCM (3 times). The organic solution
was washed with brine 1 time. Drying the solution over anhydrous
Na2SO4, filtration and forward solvent removal under reduced
pressure, afforded 58 mg of aldehyde 13a, 92% yield. Rf = 0.53
At first, 420 mg of ester 13a (423.3 g/mol; 0.99 mmol) was dis-
solved in 10 mL of dry benzene in a round bottom flask. Next,
40 mg of pTsOHÁH2O (p-toluenesulfonic acid monohydrate, CAS:
6192-52-5, 190.2 g/mol, 0.21 mmol) followed by 3 mL of ethylene
glycol (CAS: 107-21-1, 62.1 g/mol, 53 mmol) were added, and the
reaction solution was heated at reflux overnight. The solution was
cooled and 5 mL of water was added. After 30 min of stirring, the
reaction was extracted with ether (3 times). The organic solution
was washed with 5% NaHCO3 solution (1 time) and brine (1 time).
Drying the solution over anhydrous Na2SO4, filtration, and solvent
removal under reduced pressure, afforded a reaction crude. Flash
chromatography afforded 344 mg of product 14a (Hexanes/AcOEt
95:5, 82% yield). Rf = 0.55 (Hexanes/AcOEt, 8:2); [
0.7, CHCl3); IR (neat): max = 2969 (C–H), 1724 (C@O), 1493 (C–N),
1140 (C–O), 1028 cmÀ1 1H NMR (400 MHz, CDCl3): d = 7.4–7.2
a]
20 = +11.9 (c
D
m
(Hexanes/AcOEt, 8:2); IR (neat):
m
max = 2969 (C–H), 1726 (C@O),
;
;
1454 (C–N), 1260 (C–O), 1155 cmÀ1
1H NMR (200 MHz, CDCl3):
(10H, CarH), 4.85 (t, J = 4.7 Hz, 1H, H-7), 4.68 (q, J = 5.5 Hz, 1H,
CH(CH2CH3)), 3.96 (m, 2H, OCH2CH2O), 3.84 (m, 2H, OCH2CH2O),
3.82 (q, J = 7.0 Hz, 1H, CH(CH3)), 3.81 (d, J = 14.9 Hz, 1H, NCHAH),
3.50 (d, J = 14.9 Hz, 1H, NCHHB), 3.39 (m, 1H, H-3), 1.98 (m, 2H, H-
2), 1.8–1.4 (m, 6H, H-4, H-5 and H-6), 1.50 (q, J = 7.5 Hz, 2H, CH(CH2-
CH3)), 1.51 (q, J = 7.5 Hz, 2H, CH(CH2CH3)), 1.35 (d, J = 7.0 Hz, 3H,
CHCH3), 0.85 (t, J = 7.5 Hz, 3H, CH(CH2CH3)), 0.83 (t, J = 7.5 Hz, 3H,
CH(CH2CH3)) ppm; 13C NMR (50 MHz, CDCl3): d = 172.5 (s, C-1),
d = 9.7 (s, 1H, H-7), 7.4–7.2 (10H, CarH), 4.70 (q, J = 6.0 Hz, 1H,
CH(CH2CH3)), 3.82 (d, J = 14.5 Hz, 1H, NCHAH), 3.8 (q, J = 7.0 Hz,
1H, CH(CH3)), 3.55 (d, J = 14.5 Hz, 1H, NCHHB), 3.4 (1H, m, H-3),
2.32 (t, J = 4.7 Hz, 2H, H6), 2.0 (m, 2H, H-2), 1.7–1.5 (m, 4H,
CH(CH2CH3)2), 1.34 (d, J = 7.0 Hz, 3H, CHCH3), 0.84 (t, J = 7.4 Hz,
6H, CH(CH2CH3)2) ppm; 13C NMR (50 MHz, CDCl3): d = 202.3 (s,
C-7), 172.5 (s, C-1), 143.0 (s, Cipso), 141.6 (s, Cipso), 128.2-126.6

1058
C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
142.9 (s, Cipso), 141.8 (s, Cipso), 128.9–126.5 (10Âd, Car), 104.7 (d, C-
7), 76.3 (d, CH(CH2CH3)2), 64.9 (2Ât, OCH2CH2O), 58.3 (d, CHCH3),
53.9 (d, C-3), 50.2 (t, CH2Car), 36.8 (t, C-2), 33.8 (t, C-6), 33.6 (t, C-
4), 26.3 (2Ât, CH(CH2CH3)2), 21.5 (t, C-5), 20.4 (q, CHCH3), 9.5
(2Âq, CH(CH2CH3)2) ppm; HRMS (EI): m/z (M+) calcd for
CH3)2), 64.7 (2Ât, OCH2CH2O), 47.8 (d, C-3), 39.4 (t, C-2), 34.5 (t,
C-6), 33.5 (t, C-4), 28.3 (q, C(CH3)3), 26.3 (2Ât, CH(CH2CH3)2),
20.5 (t, C-5), 9.4 (2Âq, CH(CH2CH3)2) ppm; HRMS (ESI): m/z
(M+H) calcd for
= À4.54 ppm.
C19H36NO6, 374.2543; found, 374.2560,
D
C29H41NO4, 467.3035; found, 467.3038,
D
= À0.64 ppm.
4.40. 3-Pentyl (R)-3-((tert-butoxycarbonyl)amino)-7-(1,3-
4.38. 3-Pentyl (R)-3-(benzyl((R)-1-phenylethyl)amino)-7-(1,3-
dioxolan-2-yl)heptanoate 15b
dioxolan-2-yl)heptanoate 14b
At first, 338 mg of protected substrate 14b (481.3 g/mol,
0.70 mmol) and 567 mg of Boc2O (di-tert-butyl dicarbonate, CAS:
24424-99-5, 218.3 g/mol, 2.60 mmol) were dissolved in 3 mL of
dry AcOEt. 135 mg of Pd(OH)2 on carbon (palladium hydroxide
on carbon 20% wet, Perlman’s catalyst, CAS: 12135-22-7, 140.4 g/
mol) were added, and the mixture was placed in a 5 mL pressure
flask. The flask was connected to a H2 gas line and the pressure
was adjusted to 3.4 atm. The flask was mechanically stirred for
2 days. The flask was pressurized to atmospheric conditions and
the mixture was filtered through a pad of CeliteÒ, and washed with
AcOEt and DCM. The excess Boc2O was removed through Kugel
Rohr distillation, affording 250 mg of carbamate 15b, 93% yield.
At first, 200 mg of ester 13b (437.3 g/mol; 0.46 mmol) was dis-
solved in 12 mL of dry benzene in a round bottom flask. Next
15 mg of pTsOHÁH2O (p-toluenesulfonic acid monohydrate, CAS:
6192-52-5, 190.2 g/mol, 0.07 mmol) followed by 1.2 mL of ethyl-
ene glycol (CAS: 107-21-1, 62.1 g/mol, 21.2 mmol) were added,
and the reaction solution was heated at reflux overnight. The solu-
tion was cooled and 5 mL of water was added. After 30 min of stir-
ring, the reaction was extracted with ether (3 times). The organic
solution was washed with 5% NaHCO3 solution (1 time) and brine
(1 time). Drying the solution over anhydrous Na2SO4, filtration, and
forward solvent removal under reduced pressure, afforded a crude.
Flash chromatography afforded 196 mg of product 14b (Hexanes/
Rf = 0.73 (CHCl3/MeOH, 9:1); [a]
20 = +10.4 (c 1.1, CHCl3); IR (neat):
D
20
AcOEt 95:5, 89% yield). Rf = 0.24 (Hexanes/AcOEt, 9:1); [
+9.0 (c 1.30, CHCl3); IR (neat):
1493 (C–N), 1028, 964 cmÀ1 1H NMR (400 MHz, CDCl3): d = 7.4–
a
]
=
m
max = 2938 (C–H), 1717 (C@O), 1366 (C–N), 1246 (C–O),
D
mmax = 2971 (C–H), 1724 (C@O),
1036 cmÀ1
;
1H NMR (400 MHz, CDCl3): d = 4.95 (d, J = 9.2 Hz, 1H,
;
NH), 4.83 (t, J = 4.8 Hz, 1H, H-7), 4.76 (q, J = 6.6, 1H, CH(CH2CH3)2),
3.94 (m, 2H, OCH2CH2O), 3.88 (m, 1H, H-3), 3.84 (m, 2H, OCH2CH2-
O), 2.51 (m, 2H, H-2), 1.63 (m, 8H, H-4, H-5, H-6 and H-7), 1.53 (m,
4H, CH(CH2CH3)2), 1.42 (s, 9H, CH(CH3)3), 0.87 (t, J = 7.5 Hz, 3H,
CH(CH2CH3)2) ppm; 13C NMR (50 MHz, CDCl3): d = 171.4 (s, C-1).
155.3 (s, NCO), 104.6 (d, C-8), 79.1 (s, C(CH3)3), 77.0 (d, CH(CH2-
CH3)2), 64.8 (2Ât, OCH2CH2O), 48.0 (d, C-3), 39.6 (t, C-2), 34.7 (t,
C-7), 33.8 (t, C-4), 28.4 (q, C(CH3)3), 26.4 (2Ât, CH(CH2CH3)2),
26.0 (t, C-5), 23.8 (t, C-6), 9.5 (2Âq, CH(CH2CH3)2) ppm; HRMS
(ESI): m/z (M+) calcd for C20H37NO6, 387.2621; found, 387.2627,
7.2 (10H, CarH), 4.83 (t, J = 4.7, 1H, H-8), 4.67 (q, J = 6.7, 1H, CH(CH2-
CH3)), 3.96 (m, 2H, OCH2CH2O), 3.84 (m, 2H, OCH2CH2O), 3.82 (q,
J = 7.0 Hz, 1H, CH(CH3)), 3.81 (d, J = 15.0 Hz, 1H, NCHAH), 3.48 (d,
J = 15.0 Hz, 1H, NCHHB), 3.36 (1H, m, H-3), 1.96 (m, 2H, H-2),
1.65 (m, 2H, H-7), 1.60–1.30 (m, 6H, H-4, H-5 and H-6), 1.55–
1.40 (m, 4H, CH(CH2CH3)2), 1.32 (d, J = 7.0 Hz, 3H, CHCH3), 0.84
(t, J = 7.4 Hz, 3H, CH(CH2CH3)), 0.81 (t, J = 7.4 Hz, 3H, CH(CH2CH3))
ppm; 13C NMR (50 MHz, CDCl3): d = 172.6 (s, C-1), 143.0 (s, Cipso),
141.8 (s, Cipso), 128.1–126.5 (10Âd, Car), 104.7 (d, C-8), 76.4 (d,
CH(CH2CH3)2), 64.8 (2Ât, OCH2CH2O), 58.3 (d, CHCH3), 53.9 (d, C-
3), 50.1 (t, CH2Car), 33.9 (t, C-2), 33.6 (t, C-7), 26.9 (t, C-4), 26.3
(t, C-5), 26.3 (2Ât, CH(CH2CH3)2), 24.0 (t, C-6), 20.4 (q, CHCH3),
9.5 (2Âq, CH(CH2CH3)2) ppm; HRMS (ESI): m/z (M+H) calcd for
D
= À1.54 ppm.
4.41. tert-Butyl (R)-(6-(1,3-dioxolan-2-yl)-1-hydroxyhexan-3-
yl)carbamate 16a
C30H43NO4, 482.3270; found, 482.3258, D = 2.49 ppm.
In a round bottom flask, 30 mg of ester 15a (373.3 g/mol,
0.08 mmol) was added and dissolved in 1 mL of dry DCM. The flask
was sealed, purged with Ar, and cooled to À78 °C in a CO2–acetone
bath. Once cooled, 0.34 mL of DIBAL-H (diisobutylaluminum
hydride, CAS: 1191-15-7, 142.2 g/mol, 2.07 mmol, 1.5 M toluene
solution) was added dropwise via syringe. Stirring was continued
until TLC monitoring showed the consumption of starting material.
Excess water was added and the reaction mixture was allowed to
warm to room temperature. The reaction solution was poured into
an Erlenmeyer flask with 5 mL of AcOEt where 1 g of Na2SO4 and
1 g of NaHCO3 were suspended. This mixture was stirred vigor-
ously for 1 h. Finally, the solids were filtered through a pad of Cel-
iteÒ and the solvent were removed under reduced pressure. Flash
chromatography afforded 22 mg of product 16a (Hexanes/AcOEt
4.39. 3-Pentyl (R)-3-((tert-butoxycarbonyl)amino)-6-(1,3-
dioxolan-2-yl)hexanoate 15a
At first, 270 mg of protected substrate
5 (467.3 g/mol,
0.57 mmol) and 460 mg of Boc2O (di-tert-butyl dicarbonate, CAS:
24424-99-5, 218.3 g/mol, 2.11 mmol) were dissolved in 2 mL of
dry AcOEt. 100 mg of Pd(OH)2 on carbon (palladium hydroxide
on carbon 20% wet, Perlman’s catalyst, CAS: 12135-22-7, 140.4 g/
mol) were added, and the mixture was placed in a 5 mL pressure
flask. The flask was connected to an H2 gas line and the pressure
was adjusted to 3.4 atm. The flask was mechanically stirred for
2 days. The flask was pressurized to atmospheric conditions and
the mixture was filtered through a pad of CeliteÒ, and washed with
AcOEt and DCM. The excess Boc2O was removed through Kugelrohr
distillation, affording 206 mg of carbamate 15a, 98% yield. Rf = 0.52
7:3, 90% yield). Rf = 0.29 (Hexanes/AcOEt, 1:1); [
1.3, CHCl3); IR (neat):
(C@O), 1456 (C–N), 1171 (C–O) cmÀ1 1H NMR (400 MHz, CDCl3):
;
a]
20 = À2.1 (c
D
m
max = 3600 (O–H), 2949 (C–H), 1688
(Hexanes/AcOEt, 1:1); [
a]
20 = +11.2 (c 1.2, CHCl3); IR (neat):
D
m
max = 2972 (C–H), 1715 (C@O), 1460 (C–NC–N), 1248 (C–O)
d = 4.85 (t, J = 4.6 Hz, 1H, H-7), 4.38 (m, 1H, NH), 3.95 (m, 2H, OCH2-
CH2O), 3.83 (m, 2H, OCH2CH2O), 3.90 (m, 1H, H-3), 3.62 (m, 2H, H-
1), 1.8–1.5 (m, 8H, H-2, H-4, H-5 and H-6), 1.44 (s, 9H, CH(CH3)3)
ppm; 13C NMR (50 MHz, CDCl3): d = 156.9 (s, NCO), 104.4 (d, C-
7), 79.7 (s, C(CH3)3), 64.6 (2Ât, OCH2CH2O), 58.9 (t, C-1), 47.5 (d,
C-3), 39.0 (t, C-2), 35.5 (t, C-6), 33.6 (t, C-4), 28.3 (q, C(CH3)3),
20.6 (t, C-5) ppm; HRMS (ESI): m/z (M+H) calcd for C14H28NO5,
cmÀ1
;
1H NMR (400 MHz, CDCl3): d = 4.94 (m, 1H, NH), 4.84 (t,
J = 4.6 Hz, 1H, H-7), 4.76 (q, J = 6.7 Hz, 1H, CH(CH2CH3)2), 3.94 (m,
2H, OCH2CH2O), 3.90 (m, 1H, H-3), 3.83 (m, 2H, OCH2CH2O), 2.50
(m, 2H, H-2), 1.66 (m, 2H, H-6), 1.58-1.52 (m, 8H, H-4, H-5 and
CH(CH2CH3)2), 1.43 (s, 9H, CH(CH3)3), 0.88 (t, J = 7.5 Hz, 3H,
CH(CH2CH3)2) ppm; 13C NMR (50 MHz, CDCl3): d = 171.3 (s, C-1).
155.2 (s, NCO), 104.3 (d, C-7), 78.9 (s, C(CH3)3), 76.9 (d, CH(CH2-
290.1967; found, 290.1965,
D = 0.69 ppm.

C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
1059
4.42. tert-Butyl (R)-(7-(1,3-dioxolan-2-yl)-1-hydroxyheptan-3-
yl)carbamate 16b
0.02 mmol), were dissolved in 2 mL of dry DMF in a round bottom
flask. This mixture was added to the initial mixture, and the reac-
tion was stirred for 6 h at 70 °C. Excess water was added to the
reaction mixture, which was later extracted with AcOEt (3 times).
The organic extract was washed with water (5 times). The organic
extract was washed with water (5 times), dried over anhydrous
Na2SO4, filtered, and the solvent was removed under reduced pres-
In a round bottom flask, 400 mg of ester 15b (387.3 g/mol,
1.0 mmol) was placed and dissolved in 10 mL of dry DCM. The flask
was sealed, purged with Ar, and cooled to À78 °C in a CO2–acetone
bath. Once cooled, 2.2 mL of DIBAL-H (diisobutylaluminum
hydride, CAS: 1191-15-7, 142.2 g/mol, 13.6 mmol, 1.5 M toluene
solution) was added dropwise via syringe. Stirring was continued
until TLC monitoring showed consumption of the starting material.
Excess water was added and the reaction mixture was allowed to
warm to room temperature. The reaction solution was poured into
an Erlenmeyer flask with 20 mL of AcOEt where 5 g of Na2SO4 and
5 g of NaHCO3 were suspended. This mixture was stirred vigor-
ously for 1 h. Finally, the solids were filtered through a pad of Cel-
iteÒ and the solvent was removed under reduced pressure. Flash
chromatography afforded 304 mg of product 16b (Hexanes/AcOEt
sure. Flash chromatography afforded 10.8 mg of product 18 (Hex-
20
anes/AcOEt 4:6, 38%). Rf = 0.36 (Hexanes/AcOEt, 1:4); [
À17.5 (c 1.0, CHCl3); IR (neat):
1684 (C@O), 1422 (C–N), 1169 (C–O) cmÀ1
a]
=
D
m
max = 3352 (N–H), 2947 (C–H),
;
1H NMR (400 MHz,
CDCl3): d = 8.67 (s, 1H, CONHCO), 7.13 (br s, 1H, NCH), 4.82 (t,
J = 4.7 Hz, 1H, H-8), 4.43 (d, J = 8.7 Hz, 1H, HNCOO), 3.98 (m, 2H,
OCH2CH2O), 3.90 (m, 1H, H-3), 3.84 (m, 2H, OCH2CH2O), 3.57 (m,
2H, H-1), 1.91 (s, 3H, CCH3), 1.6–1.4 (m, 8H, H-2, H-4, H-5 and
H-6), 1.43 (s, 9H, CH(CH3)3) ppm; 13C NMR (50 MHz, CDCl3):
d = 163.9 (s, NCO), 155.9 (s, NCOO), 150.7 (s, NCON), 141.0 (d,
NCH), 110.5 (s, CCH3), 104.4 (s, C-8), 79.5 (s, C(CH3)3), 64.8 (2Ât,
OCH2CH2O), 48.5 (d, C-3), 46.2 (t, C-1), 35.8 (t, C-7), 34.8 (t, C-2),
33.6 (t, C-4), 28.4 (q, C(CH3)3), 25.7 (t, C-5), 23.8 (t, C-6), 12.2 (q,
CCH3) ppm; HRMS (ESI): m/z (M+) calcd for C20H33N3O6,
8:2, 98% yield). Rf = 0.27 (CHCl3/MeOH, 95:5); [
0.91, CHCl3); IR (neat):
(C@O), 1526 (C–N), 1250 (C–O) cmÀ1
a
]
20 = À1.8 (c
D
m
max = 3500 (O-H), 2950 (C–H), 1688
;
1H NMR (400 MHz, CDCl3):
d = 4.82 (t, J = 4.7 Hz, 1H, H-8), 4.38 (d, J = 8.7 Hz, 1H, NH), 3.94
(m, 2H, OCH2CH2O), 3.83 (m, 2H, OCH2CH2O), 3.75 (m, 1H, H-3),
3.61 (m, 2H, H-1), 1.85 (m, 2H, H-2), 1.65 (m, 2H, H-7), 1.43 (s,
9H, CH(CH3)3), 1.5–1.4 (m, 6H, H-4, H-5 and H-6) ppm; 13C NMR
(50 MHz, CDCl3): d = 157.1 (s, NCO), 104.5 (d, C-8), 79.8 (s,
C(CH3)3), 64.8 (2Ât, OCH2CH2O), 58.9 (t, C-1), 47.4 (d, C-3), 39.1
(t, C-2), 35.8 (t, C-7), 33.7 (t, C-4), 28.4 (q, C(CH3)3), 26.0 (t, C-5),
23.8 (t, C-6) ppm; HRMS (ESI): m/z (M+H) calcd for C15H30NO5,
411.2369; found, 411.2364,
D = 1.21 ppm.
4.45. (R)-3-((tert-Butoxycarbonyl)amino)-6-(1,3-dioxolan-2-yl)-
hexyl acetate 19
In a round bottom flask, 23 mg of alcohol 16a (289.2 g/mol,
0.08 mmol) was placed and dissolved in 1 mL of recently distilled
pyridine. The flask was sealed and purged with Ar and cooled to
0 °C. Once cooled, 0.5 mL of Ac2O (acetic anhydride, CAS: 108-24-
7, 102.1 g/mol) was added dropwise via syringe. Stirring was
continued for 6 h. Crushed iced was then added, and the reaction
mixture was extracted with AcOEt (3 times). The organic extract
was washed with 20% CuSO4 (3 times), brine (1 time), dried with
anhydrous Na2SO4, filtered, and the solvent was removed under
reduced pressure. Flash chromatography afforded 15 mg of prod-
uct 19 (Hexanes/AcOEt 95:5, 56%). Rf = 0.39 (Hexanes/AcOEt,
304.2124; found, 304.2135,
D
= À3.61 ppm.
4.43. tert-Butyl (R)-(7-(1,3-dioxolan-2-yl)-1-bromoheptan-3-yl)-
carbamate 17
In a round bottom flask, 230 mg of alcohol 16b (303.2 g/mol;
0.76 mmol), 239 mg of PBu3 (triphenylphosphine, CAS: 603-35-0,
262.3 g/mol, 0.91 mmol), and 360 mg of CBr4 (tetrabromomethane,
CAS: 558-13-4, 331.6 g/mol, 0.91 mmol) were dissolved in 4 mL of
dry DCM. After sealing the flask and replacing the inner atmo-
sphere with Ar, the reaction mixture was magnetically stirred at
room temperature for 30 min. The solvent was removed under
reduced pressure and the residue was dissolved in ether. Cooling
the solution in an ice bath promoted the precipitation of the phos-
phine oxide. Filtration and solvent removal under reduced pressure
afforded a crude oil. Flash chromatography afforded 249 mg of
product 17 (Hexanes/AcOEt 9:1, 79% yield). Rf = 0.48 (Hexanes/
1:1); [
a]
20 = À4.0 (c 0.59 CHCl3); IR (neat):
m
max = 3362 (N–H),
D
2955 (C–H), 1740 (C@O), 1458 (C–N), 1244 (C–O) cmÀ1
;
1H NMR
(400 MHz, CDCl3): d = 4.84 (t, J = 4.7 Hz, 1H, H-7), 4.27 (1H, NH),
4.12 (t, J = 7.0 Hz, 2H, H-1), 3.96 (m, 2H, OCH2CH2O), 3.84 (m, 2H,
OCH2CH2O), 3.67 (m, 1H, H-3), 2.04 (s, 3H, CH3COO), 1.8–1.5 (m,
6H, H-2, H-4, H-5 and H-6), 1.43 (s, 9H, CH(CH3)3) ppm; 13C NMR
(50 MHz, CDCl3): d = 171.0 (s, CH3COO), 155.5 (s, NCO), 104.3 (d,
C-7), 79.1 (s, C(CH3)3), 64.8 (2Ât, OCH2CH2O), 61.6 (t, C-1), 48.0
(d, C-3), 35.2 (t, C-4), 34.0 (t, C-2), 33.6 (t, C-6), 28.3 (q, C(CH3)3),
20.9 (t, C-5), 20.2 (q, CH3COO) ppm; HRMS (ESI): m/z (M+) calcd
AcOEt, 1:1); [
a
]
D
20 = À8.7 (c 1.9, CHCl3); IR (neat):
m
max = 2947
(C–HC–H), 1697 (C@O), 1522 (C–N), 1246 (C–O), 1040 cmÀ1
;
1H
NMR (400 MHz, CDCl3): d = 4.83 (t, J = 4.7 Hz, 1H, H-8), 4.32 (m,
1H, NH), 3.94 (m, 2H, OCH2CH2O), 3.82 (m, 2H, OCH2CH2O), 3.65
(m, 1H, H-3), 3.40 (t, J = 7.5 Hz, 2H, H-1), 2.00 (m, 2H, H-2), 1.65
(m, 2H, H-7), 1.42 (s, 9H, CH(CH3)3), 1.4–1.3 (6H, m, H-4, H-5
and H-6) ppm; 13C NMR (50 MHz, CDCl3): d = 155.6 (s, NCO),
104.5 (d, C-8), 79.3 (s, C(CH3)3), 64.8 (2Ât, OCH2CH2O), 50.0 (t, C-
3), 39.2 (d, C-2), 35.2 (t, C-7), 33.6 (t, C-4), 29.7 (t, C-1), 28.3 (q,
C(CH3)3), 25.7 (t, C-5), 23.8 (t, C-6) ppm; HRMS (ESI): m/z (M+H)
for C16H29NO6, 331.1994; found, 331.2002,
D
= À2.41 ppm.
4.46. 2-Hydroxyethyl (R)-7-acetoxy-5-((tert-butoxycarbonyl)-
amino)heptanoate 20
At first, 10 mg of compound 19 (331.4 g/mol; 0.03 mmol) was
dissolved in 3 mL of dry DCM in a round bottom flask. Ozone (O3,
gas, generated in situ) was bubbled for 15 min until the solution
was light blue. Finally, an Ar flow was bubbled for 5 min. Solvent
removal under reduced pressure, afforded 9 mg of ester 20, 86%
calcd for C15H29BrNO4, 366.1280; found, 366.1297,
D
= À4.64 ppm.
4.44. tert-Butyl (R)-(7-(1,3-dioxolan-2-yl)-1-(5-methyl-2,4-di-
oxo-3,4-dihydropyrimidin-1(2H)-yl)heptan-3-yl)carbamate 18
yield. Rf = 0.25 (Hexanes/AcOEt, 1:1); [
IR (neat):
(C–N), 1246 (C–O) cmÀ1
a
]
20 = À4.0 (c 0.7, CHCl3);
D
m
max = 3500 (O-H), 2930 (C–H), 1738 (C@O), 1460
;
1H NMR (400 MHz, CDCl3): d = 4.42 (1H,
In a round bottom flask, 32 mg of thymine (CAS: 65-71-4,
126.1 g/mol, 0.03 mmol) and 15.2 mg of K2CO3 (potassium carbon-
ate, CAS: 584-08-7, 138.2 g/mol, 0.11 mmol) were suspended in
2 mL of dry DMF. This mixture was stirred 1 h at 70 °C. Separately,
27 mg of bromide 17 (366.3 g/mol; 0.07 mmol) and 6.0 mg of
TBAI (tetrabutylammonium iodide, CAS: 311-28-4, 396.4 g/mol,
NH), 4.21 (t, J = 4.0 Hz, 2H, OCH2CH2OH), 4.12 (t, J = 6.3 Hz, 2H,
H-7), 3.82 (t, J = 4.5 Hz, 2H, OCH2CH2OH), 3.67 (m, 1H, H-5), 2.38
(m, 2H, H-2), 2.05 (s, 3H, CH3COO), 1.82 (2H, m, H-6), 1.8–1.6 (m,
4H, H-3 and H-4), 1.43 (s, 9H, CH(CH3)3) ppm; 13C NMR (50 MHz,
CDCl3): d = 173.5 (s, C-7), 171.0 (s, CH3COO), 155.5 (s, NCO), 79.3
(s, C(CH3)3), 66.0 (t, OCH2CH2OH), 61.4 (t, OCH2CH2OH), 61.1 (t,

1060
C. T. Nieto et al. / Tetrahedron: Asymmetry 25 (2014) 1046–1060
2109; (c) Kiviniemi, A.; Murtola, M.; Ingman, P.; Virta, P. J. Org. Chem. 2013, 78,
5153–5159; (d) Mishra, R.; Su, W.; Pohmann, R.; Pfeuffer, J.; Sauer, M. G.;
Ugurbil, K.; Engelmann, J. Bioconjugate Chem. 2009, 20, 1860–1868; (e) Sethi,
D.; Chen, C.-P.; Jing, R.-Y.; Thakur, M. L.; Wickstrom, E. Bioconjugate Chem.
2012, 23, 158–163.
C-7), 47.7 (d, C-5), 34.5 (t, C-2), 33.9 (t, C-4), 33.6 (t, C-6), 28.3 (q,
C(CH3)3), 21.1 (t, C-3), 20.9 (q, CH3COO) ppm; HRMS (ESI): m/z
(M+H) calcd for
C16H30NO7, 348.2022; found, 348.2031, D =
À2.58 ppm.
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Acknowledgments
The authors are grateful for financial support from MINECO,
Spain (CTQ2009-11172/BQU) and Universidad de Salamanca, the
European Social Fund (ESF) and Junta de Castilla
(SA162A12-1, B1039/SA25/10, BIO/SA74/13) and excellence GR-
178. The authors also thank Dr. A. M. Lithgow for work on the
NMR spectra and Dr. César Raposo for the Mass spectra. C.T.N.
thanks Junta de Castilla y León for a FPI predoctoral fellowship.
y León,
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