Chemoenzymatic asymmetric synthesis of optically active pentane-1,5-diamine fragments by means of lipase-catalyzed desymmetrization transformations

Article abstract of DOI:10.1021/jo2007972

A novel family of prochiral pentane-1,5-diamines has been efficiently synthesized, possessing stabilities significantly higher than those of corresponding propane-1,3-diamine analogues. Diamines have been later desymmetrized using Pseudomonas cepacia lipase as an efficient biocatalyst for the mono- but also stereoselective protection of one of their amino groups. Reaction parameters such as type and loading of enzyme, temperature, solvent, and acyl donor have been exhaustively analyzed, searching for optimal conditions for the production of interesting optically active nitrogenated compounds. Thus, acylation and alkoxycarbonylation processes have been compared in terms of conversion and enantiomeric excess values. The best results were found in the reaction of prochiral diamines with ethyl methoxyacetate as acyl donor and 1,4-dioxane as solvent, yielding (S)-monoamides in 33 - 59% isolated yield and 54 - 99% ee, depending on the aromatic pattern substitution.

Full text of DOI:10.1021/jo2007972

ARTICLE
pubs.acs.org/joc
Chemoenzymatic Asymmetric Synthesis of Optically Active
Pentane-1,5-diamine Fragments by Means of Lipase-Catalyzed
Desymmetrization Transformations†
Nicolꢀas Ríos-Lombardía, Eduardo Busto, Vicente Gotor-Fernꢀandez,* and Vicente Gotor*
Departamento de Química Orgꢀanica e Inorgꢀanica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo,
33071 Oviedo (Asturias), Spain
S Supporting Information
b
ABSTRACT: A novel family of prochiral pentane-1,5-diamines
has been efficiently synthesized, possessing stabilities significantly
higher than those of corresponding propane-1,3-diamine analo-
gues. Diamines have been later desymmetrized using Pseudomo-
nas cepacia lipase as an efficient biocatalyst for the mono- but also
stereoselective protection of one of their amino groups. Reaction
parameters such as type and loading of enzyme, temperature,
solvent, and acyl donor have been exhaustively analyzed, search-
ing for optimal conditions for the production of interesting optically active nitrogenated compounds. Thus, acylation and
alkoxycarbonylation processes have been compared in terms of conversion and enantiomeric excess values. The best results were
found in the reaction of prochiral diamines with ethyl methoxyacetate as acyl donor and 1,4-dioxane as solvent, yielding (S)-
monoamides in 33ꢀ59% isolated yield and 54ꢀ99% ee, depending on the aromatic pattern substitution.
’ INTRODUCTION
sources. In this sense, desymmetrization of prochiral or meso-
compounds using biocatalysts is a challenging strategy28,29 and in
particular for lipases when diamines are involved in the process.30
Recently, we demonstrated the versatility of hydrolytic enzymes
for the stereoselective alkoxycarbonylation of 2-substituted-
propane-1,3-diamines31ꢀ35 but also the acylation and hydrolysis
of 3-arylpentane-1,5-diol fragments.36 On the basis of our research
experience in the synthesis of prochiral 1,3-diamine derivatives, we
have now turned our attention toward the preparation and next
lipase-catalyzed desymmetrization of a novel family of prochiral
3-arylpentane-1,5-diamines, searching for optimal synthetic meth-
ods for the production of optically active monocarbamates and
monoamides.
Polyamines are central motifs in chemistry but also play an
essential role in living systems.1 In fact, they possess very diverse
biological applications such as metabolic or plant growth regulators,
DNA stabilizing agents, ion channels modulators, or cell membrane
transport systems.2,3 In addition, polyamines are adequate building
blocks for the production of more complex and useful structures, e.g.
polymers, semiconductors or cyclic receptors,4,5 possessing remark-
able importance when their chiral versions are considered.6 From
this vast group of nitrogenated compounds, cadaverine is one of its
most important integrants because of different implications.
Also known as pentane-1,5-diamine, cadaverine is chemically
produced from petrol-based raw material or alternatively through a
greener decarboxylation of lysine by the action of a lysine decarboxy-
lase.7 Pentane-1,5-diamine possesses an unpleasant odor, and it is
produced by protein hydrolysis during putrefaction of animal
tissues, being very toxic when found in high concentrations. In
addition to its utility as building blocks of natural products8 or
interesting biologically active compounds such as cyclic amines,9
antitumor,10,11 or antitubercular agents,12 its role as enzyme in-
hibitor has been widely explored.13,14 The possibility to produce
chiral complexes highlights the importance of the pentane-1,5-
diamine fragment because of their use as chiral shift agents,15 ligands
in organocatalysis,16ꢀ18 chemical catalysts,19ꢀ22 macrocycles for
chiral recognition,23ꢀ25 or with binding affinity capacities.26
’ RESULTS AND DISCUSSION
First of all, we focused on the development of an efficient and
straightforward preparation for prochiral 3-phenylpentane-1,5-di-
amine (4a), an ideal model substrate for the optimization of the
synthetic enzymatic study. Starting from 3-phenylpentane-1,5-diol,
which is easily accessible from commercially available 3-phenyl-1,5-
pentanedioic acid,36 the chemical diactivation was carried out with
mesyl chloride (MsCl) in the presence of pyridine (Scheme 1).
Substitution reaction with sodium azide in DMF led to the diazide
3a in very high yield, which was finally hydrogenated in the presence
of PdꢀC. Unfortunately, some uncontrolled experiments occurred,
depending on the rate of methanol and hydrogen addition. In fact, in
In recent years, large efforts have been made to develop mono-
selective protection of polyfunctional compounds.27 Enzymatic
methods are very practical for the development of stereoselective
processes, taking advantage of the chiral composition of enzymatic
Received: April 18, 2011
Published: May 31, 2011
r
2011 American Chemical Society
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Scheme 1. Chemical Synthesis of Diamine 4a
techniques play a fundamental role in enzyme catalysis,37ꢀ39 obser-
ving that when using PSL IM-immobilized enzyme in diatomaceous
earth (entry 3) or PSL SD, a crude enzyme preparation containing
dextrin as diluent (entry 4), the activity, but mainly the stereoselec-
tivity, dramatically diminished until the recovery of the racemic
product for PSL SD. However, in all cases only starting material or the
final monoallyl carbamate was identified in the reaction medium,
proving this enzymatic approach as an excellent possibility for the
selective protection of chemically equivalent amino groups.
An extra chemical reaction was required for the determination
of the enantiomeric excess, as the amino carbamate 6 was not a
good candidate for chiral HPLC analysis. For that reason,
chemical protection of the remaining free amino group was
performed using acetyl chloride in dry dichloromethane, obtain-
ing optically active amido carbamate (S)-7 in quantitative yields
from (S)-6 (Scheme 2). Complementary to this approach,
racemic 7 was prepared by slow and carefully addition of acetic
anhydride over diamine 4a, which led to the formation of the amino
amide (()-8 that was subsequently protected with allyl chlorofor-
mate, finally yielding the racemic amido carbamate 7 in only 9% yield
because of the appearance of homodisubstituted final products or the
starting material. Although the recovered amount of racemic amido
carbamate 8 was low, that was enough for our purposes in the
development of adequate chiral HPLC methods for the determina-
tion of the optical purity of final products.
The results from our study highlight the successful develop-
ment of a synthetic strategy for the selective protection of
diamines. Note also that some elegant chemical processes for the
monoselective protection of diamines have recently appeared in the
literature.40,41 Once PSL-C I was chosen as the best biocatalyst for the
desymmetrization of 4a, we studied this process in depth, searching
for an improvement in the selectivity and activity of our catalyst. In
this sense, a screening of solvents was performed, including polar and
nonpolar solvents that allowed good solubility of the starting diamine.
In addition to 1,4-dioxane, other solvents such as tert-butyl methyl
ether, diethyl ether, tetrahydrofuran, toluene, acetonitrile, and tert-
butyl alcohol were used with a 100 mM substrate concentration. Data
are summarized in Table 2; note again that only starting material or
monocarbamate was identified in the reaction medium after 72 h of
reaction, the highest conversion being attained with ether solvents
such as TBME or Et2O.
Although similar or lower stereoselectivities were observed
(60ꢀ86% ee) compared with the biotransformation in 1,4-
dioxane (88% ee), very much higher isolated yields were attained
in the reactions with nonpolar ether solvents such as TBME or Et2O
(entries 2 and 3). This is a surprising result because lower solubilities
are achieved for 4a with the latter solvents, although the improved
performance of immobilized lipases in nonpolar solvents compared
to higher polar solvents is known.42
Next we took into account other parameters that have
influence on the enzymatic performance such as loading of
biocatalyst and temperature, again using 1,4-dioxane because of
the higher enantiomeric excesses achieved and the possibility to
carry out the biotransformations at higher temperatures without
solvent volatility problems. In all cases, the reaction tempera-
ture correlates with isolated yields of the optically active mono-
carbamates (Table 3). An increase in the temperature led to
higher amounts of the final products (32ꢀ45% conversion,
entries 1ꢀ3) although the stereopreference shown by PSL
decreases at higher temperatures (80ꢀ88% ee). To reach higher
conversions in shorter reaction times, the amount of PSL was
doubled, achieving a similar level of selectivities and an optimum
Table 1. Enzymatic Desymmetrization of Diamine 4a Using
Lipases (ratio 1:1 in weight of substrate with respect to the
enzyme) and Diallyl Carbonate (1 equiv) in 1,4-Dioxane (0.1 M)
during 72 h at 30 °C and 250 Revolutions per Minute (rpm)
entry
enzyme
yield (%)a
(S)-6, ee (%)b
1
2
3
4
CAL-B
PSL-C I
PSL IM
PSL SD
78 (100)
32 (34)
14 (17)
17 (18)
0
88
30
0
a Isolated yield after flash chromatography. Conversion values in brack-
ets measured by 1H NMR of the reaction crude. b Enantiomeric excess
of (S)-6 determined by HPLC after appropriate derivatization.
one occurrence, the interaction between 3-phenylpentane-1,5-di-
azide, palladium, and hydrogen led to an explosion of the 50-mL
round-bottom flask. At that point, we decided to replace this simple
method for the synthesis of propane-1,3-diamines by a safer reaction
using triphenylphosphine in MeOH, leading to the diamine 4a in
good yield. Although for safety reasons the latter method is recom-
mended, a chromatographic separation was needed for the purifica-
tion of the resulting diamine. In contrast with the extraordinary
instability shown by propane-1,3-diamines, 3-phenylpentane-1,5-
diamine showed excellent stability to moisture over long storage
times, allowing subsequent chemical or enzymatic modification.
Because of the excellent levels of stereoselectivity shown by
Pseudomonas cepacia lipase (PSL-C I), also currently known as
Burkholderia cepacia lipase, in the mono- and stereoselective
alkoxycarbonylation of 2-arylpropane-1,3-diamines,31ꢀ35 we
decided to use this lipase-catalyzed system for the desymmetriza-
tion of 4a. Thus, not only PSL but also other commercially
available lipases were screened toward 4a, e.g., Candida antarctica
lipase B (CAL-B), Candida antarctica lipase A (CAL-A), Candida
rugosa lipase (CRL), porcine pancreatic lipase (PPL), lipase from
Rhizomucor miehei (RM), or AK lipase from Pseudomonas fluorescens
(AK). Reactions were first conducted using diallyl carbonate as
carbamoylating agent, 1,4-dioxane as solvent, and at 30 °C, reaction
conditions identical to those previously used in the desymmetrization
of 2-substituted-propane-1,3-diamines (Table 1). Unfortunately, but
according to previous experiences with propanediamines,31 only
CAL-B (entry 1) showed an excellent level of activity, leading to
the racemic monocarbamate 6 in 78% isolated yield and full exten-
sion. Only PSL-C I from Amano acted with a high stereopreference
in the formation of the allyl monocarbamate (S)-6 although with a
low grade of conversion (34%, entry 2). Note that immobilization
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Scheme 2. Enzymatic Desymmetrization of Diamine 4a Using Diallyl Carbonate Followed by Derivatization to the Amido
Carbamate 7, Which Has Been Also Prepared in Racemic Form for the Measurement of Enantiomeric Excesses
Table 2. Enzymatic Desymmetrization of 4a with PSL-C I
(ratio 1:1 in weight of substrate respect to the enzyme) and
Diallyl Carbonate (1 equiv) in Organic Solvent (0.1 M)
during 72 h at 30 °C and 250 rpm
The acylation reaction is an alternative to the carbomoylation
process for the selective modification of polyfunctional com-
pounds. Activated esters such as vinyl acetate are used in the
reaction with secondary alcohols, and nonactivated esters (e.g.,
ethyl acetate or ethyl methoxyacetate) are usually employed in the
reaction with amino groups to avoid the chemical reaction that
often occurs between amines and activated esters. Thus, PSL was
also applied to the acylation of prochiral diamine 4a using ethyl
acetate (EtOAc, 10a), finding results similar to that of alkoxy-
carbonylation reaction with diallyl carbonate (Scheme 3, entries 1 and
2 of Table 4). For the determination of the enantiomeric excess,
the resulting (S)-monoamide 8 was subjected to carbamoylation
with allyl chloroformate (9), a process that occurs at room
temperature in 92% yield after 2 h. When ethyl methoxy-
acetate (10b) was used instead of ethyl acetate, an almost total
conversion was achieved in the formation of (S)-monoamide
11a, reaching a similar enantiomeric excess value (entry 3).
Significantly, the optically active amido amine was identified as a
unique product in the reaction, being isolated in 58% yield after
chromatographic purification and demonstrating the usefulness
of the stereoselective monoprotection with practical applica-
tions, as the diprotected product was not observed in the crude
reaction product. This is not a surprising result, as ester 10b has
been successfully applied as an ideal acyl donor in lipase-
catalyzed kinetic and dynamic kinetic resolution of primary
amines.43ꢀ45 To simplify the enzymatic system, reactions with-
out an inert atmosphere were attempted, interestingly leading to
results identical to those under nitrogen atmosphere.
entry
solvent
yield (%)a
(S)-6, ee (%)b
1
2
3
4
5
6
7
1,4-dioxane
TBME
Et2O
32 (34)
60 (66)
49 (79)
37 (48)
23 (33)
14 (16)
31 (38)
88
86
86
86
82
60
81
THF
Toluene
MeCN
tBuOH
a Isolated yields after flash chromatography. Conversion values in
brackets measured by 1H NMR of the reaction crude. b Enantio-
meric excess of (S)-6 determined by HPLC after appropriate
derivatization.
Table 3. Enzymatic Desymmetrization of 4a Using PSL-C I
and Diallyl Carbonate (1 equiv) in 1,4-Dioxane (0.1 M)
during 72 h at 250 rpm
entry
PSL-C I:4aa
T (°C)
yield (%)b
(S)-6, ee (%)c
1
2
3
4
5
6
1:1
1:1
1:1
2:1
2:1
2:1
30
45
60
30
45
60
32 (34)
35 (41)
45 (54)
29 (39)
63 (75)
41 (50)
88
83
80
88
87
84
With all these results in hand we decided to move forward
toward the development of a general route for the synthesis and
lipase-catalyzed desymmetrization of prochiral pentane-1,5-di-
amines. Probing the efficiency of the previously proposed
synthetic pathway for diamine 4a, diols 1bꢀf obtained from
their corresponding commercially available dicarboxylic acids36
were subjected to a dimesylation, azide substitution, and reduc-
tion sequence leading to the corresponding diamines 4bꢀf
with high overall yields, ranging from a global 61% for the
o-methoxyphenyl derivative 4f to 75% for the p-methylphenyl
4c or the p-methoxyphenyl 4d (Scheme 4).
a Ratio of weight of enzyme (PSL-C I) with respect to the substrate
(diamine 4a). b Isolated yield after flash chromatography. Conversion
values in brackets measured by 1H NMR of the reaction crude.
c Enantiomeric excess of (S)-6 determined by HPLC after appropriate
derivatization.
temperature of 45 °C for the recovery of (S)-6 in 63% isolated
yield and 87% ee (entry 5). Finally we scaled-up the reaction,
searching for an improvement in the isolation of the final
product, and as expected, using 1.35 mmol instead of 0.17 mmol
(entry 1 of Table 3) resulted in an increase in isolated yield from
32 to 48% and maintained the same enantiomeric excess (88%).
For the para-substituted compounds including the fluoro (b),
methyl (c), and methoxy (d) groups, in all cases good to high
selectivities were achieved (82ꢀ90%, entries 2ꢀ4 of Table 5) for
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Scheme 3. Enzymatic Desymmetrization of Prochiral Diamine 4a Using Ethyl Esters 10a,b, Followed by Chemical Synthesis of
Optically Active (R)-Amido Carbamates 7 and 12a for ee Measurement
Table 4. Enzymatic Desymmetrization of 4a Using PSL-C I
(ratio 1:1 of weight of substrate with respect to the enzyme)
and an Ester or Carbonate (1 equiv) in 1,4-Dioxane (0.1 M) at
30 °C during 72 h at 250 rpm
Table 5. Enzymatic Desymmetrization of 4aꢀf Using PSL-C
I (ratio 1:1 in weight of substrate with respect to the enzyme)
and Ethyl Methoxyacetate (10b, 1 equiv) in 1,4-Dioxane (0.1
M) at 30 °C during 72 h at 250 rpm
entry
donor
yield (%)a
(S)-6, -8, -11a, ee (%)b
entry
diamine
yield (%)a
(S)-11aꢀf, ee (%)b
1
2
3
5
32 (34)
27 (52)
58 (100)
88
90
91
1
2
3
4
5
6
4a (H)
58
58
59
51
50
33
91
82
90
86
>99
54
10a
10b
4b (p-F)
4c (p-Me)
4d (p-OMe)
4e (m-OMe)
4f (o-OMe)
a Isolated yield after flash chromatography for (S)-6, (S)-8, and (S)-11a.
1
Conversion values in brackets measured by H NMR of the reaction
crude. b Enantiomeric excess of (S)-6, (S)-8, and (S)-11a determined
by HPLC after appropriate derivatization.
a Isolated yield of (S)-11aꢀf after flash chromatography. b Enantio-
meric excesses of (S)-11aꢀf determined by HPLC after adequate
derivatization.
the production of (S)-monoamides 11bꢀd in moderate yields
(51ꢀ59%). At this point, we were interested in analyzing the
influence of the substituent position inside the aromatic ring,
considering prochiral diamines possessing the methoxy substitution
in the phenyl ring located at the 3-position of the 1,5-diamine
fragment. Excellent results were attained in terms of activity and
stereoselectivity for the production of enantiopure (S)-monoamide
11e (entry 5) while a lower reactivity and the lowest chiral induction
was reached for 4f (entry 6) in the PSL-catalyzed desymmetrization
acylation with ethyl methoxyacetate (10b).
enzymatic desymmetrization of diamine 4a. Note that the (R)-allyl
carbamate is obtained from the lipase-catalyzed enantioselective
desymmetrization of 2-phenylpropane-1,3-diamine31,32 while the
(S)-allyl carbamate or (S)-amides are synthesized from 3-phenyl-
pentane-1,5-diamine. Comparing the optical rotation values and the
peak elution orders for all the 1,5-monoamido carbamates, the same
(S)-stereopreference was assigned for the PSL action toward the
panel of prochiral diamines studied in this manuscript (see also
Supporting Information for more data).
Lastly, the determination of the absolute configuration for (S)-
11a obtained by chemoenzymatic methods was demonstrated,
designing a synthetic route from known monoacetate (S)-14,
which is easily prepared in enantiopure form through the lipase-
desymmetrization of 3-phenyl-pentane-1,5-diol (1a) with vinyl
acetate (13) and AK lipase (Scheme 5). In this manner,
transformation of the (S)-14 free hydroxyl group led to com-
pound (R)-15 with changed absolute stereochemistry because of
CIP priority rules. A substitution reaction with sodium azide in
hot DMF and a hydrogenation reaction with simultaneous ester
hydrolysis led to the amino alcohol (S)-17. Then N-selective
protection with 1 equiv of methoxyacetyl chloride (18) added
portionwise in the absence of triethylamine led to the amido alcohol
(S)-19, which was next O-activated using mesyl chloride in the
presence of pyridine. Reaction with NaN3 and hydrogenation of the
corresponding product mediated by PdꢀC in MeOH allowed the
formation of the amido amine (R)-11a, which was reacted with allyl
chloroformate (9) in order to finally obtain the enantiopure amido
carbamate (S)-12a. In this case, the hydrogenation was preferred
rather than the reduction of the azide with PPh3, looking for an easy
purification of the resulting polar compound and the avoidance of
high temperatures because of possible undesired racemization in the
process. Optical rotation and retention times after HPLC analysis
were compared with the ones obtained by lipase-catalyzed desym-
metrization of prochiral diamine, undoubtedly confirming the (S)-
absolute stereochemistry of the final product (S)-11a from the
’ CONCLUSIONS
In summary, starting from commercially available dicarboxylic
acids, a short and straightforward method for the production of
optically active monoamides or amido carbamates derived from
the pentane-1,5-diamine has been developed for the first time.
Good overall yields have been achieved for the production of
prochiral 3-arylpentane-1,5-diamines, finding Pseudomonas cepacia
lipase as an optimum biocatalyst for their mono- and stereo-
selective protection under mild reaction conditions, espe-
cially when higher amounts of reactants are used in the bio-
transformation. Different enzymatic reaction parameters have
been exhaustively analyzed, identifying the type of immobilized
enzyme and the class of synthetic processes as fundamental issues
for the development of elegant monoacylation enzymatic pro-
cesses. The wide scope of the process has been demonstrated by
the good to excellent results obtained in the desymmetrization of
prochiral diamines. Playing an important role in the pattern
substitution in the aromatic rings for the isolation of optically
active amides in high enantiomeric excess, PSL gives predomi-
nantly meta-substitution. Most significant results have been
summarized in Figure 1. Finally, the determinations of the
absolute configurations of monoamino carbamates have been
demonstrated by chemical synthetic processes.
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Scheme 4. Chemical Synthesis of Diamines 4bꢀf Followed by Lipase-Catalyzed Desymmetrization Processes
Scheme 5. Chemoenzymatic Synthesis of Amido Amine (R)-11a and Amido Carbamate (S)-12a from 3-Phenylpentane-1,5-diol (1a)
room temperature for 14 h after complete disappearance of the starting
material. The solvent was evaporated by distillation at reduced pressure,
obtaining a crude reaction product that was purified by flash chroma-
tography (30ꢀ50% EtOAc/hexane) to yield the corresponding dime-
sylate 2a,b,dꢀf as a colorless oil and 2c as a white solid (84ꢀ91%). 2a
(90% yield): Rf (50% EtOAc/hexane): 0.16; IR (NaCl): ν 3030, 2941,
1353, 1174, 973, 919, 734, 704 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz):
δ 1.90ꢀ2.03 (m, 2H), 2.04ꢀ2.19 (m, 2H), 2.86 (s, 6H), 2.87ꢀ2.99 (m,
1H), 3.86ꢀ3.97 (m, 2H), 4.00ꢀ4.12 (m, 2H), 7.10ꢀ7.18 (m, 2H),
7.19ꢀ7.25 (m, 1H), 7.26ꢀ7.35 (m, 2H); 13C NMR (CDCl3, 75.5
MHz): δ 35.3 (2C), 36.8 (2C), 37.8, 67.7 (2C), 127.0, 127.3 (2C), 128.7
(2C), 141.0; MS (ESIþ, m/z): 359 [(M þ Na)þ, 100%]; HRMS (ESIþ,
m/z) calcd for (C13H20NaO6S2)þ [(M þ Na)þ]: 359.0594; found:
359.0597. 2b (89% yield): Rf (50% EtOAc/hexane): 0.29; IR (NaCl): ν
Figure 1. Summary of the best synthetic reactions for the enzymatic
3031, 2942, 1604, 1510, 1352, 1224, 1174, 974, 917, 837 cmꢀ1; 1H NMR
desymmetrization of diamines 4aꢀf after final purification by flash
(CDCl3, 300.13 MHz): δ 1.86ꢀ2.05 (m, 2H), 2.07ꢀ2.23 (m, 2H), 2.91
chromatography.
(s, 6H), 2.95ꢀ3.05 (m, 1H), 3.88ꢀ3.99 (m, 2H), 4.05ꢀ4.15 (m, 2H),
3
7.02 (t, JHH = 8.7 Hz, 2H), 7.10ꢀ7.21 (m, 2H); 13C NMR (CDCl3,
’ EXPERIMENTAL SECTION
75.5 MHz): δ 35.6 (2C), 37.1 (2C), 37.2, 67.4 (2C), 115.7 (d, 2JCF = 21
Hz, 2C), 129.0 (d, 3JCF = 7 Hz, 2C), 136.9, 161.7 (d, 1JCF = 246 Hz); MS
General Procedure for the Synthesis of Dimesylates 2aꢀf.
(ESIþ, m/z): 377 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C13H19FNaO6S2)þ [(M þ Na)þ]: 377.0499; found: 377.0508. 2c
(91% yield): Rf (50% EtOAc/hexane): 0.27; Melting point: 54ꢀ56 °C;
IR (KBr): ν 3026, 2940, 1351, 1173, 973, 921, 819, 736 cmꢀ1; 1H NMR
To a solution of the corresponding diol 1aꢀf (9.39 mmol) in dry
CH2Cl2 (94 mL) was added pyridine (4.54 mL, 56.33 mmol), and the
mixture was cooled at 0 °C. Then methanesulfonyl chloride (MsCl,
4.08 mL, 56.33 mmol) was added and the resulting solution stirred at
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(CDCl3, 300.13 MHz): δ 1.88ꢀ2.02 (m, 2H), 2.04ꢀ2.18 (m, 2H), 2.29
(s, 3H), 2.87 (s, 6H), 2.82ꢀ2.94 (m, 1H), 3.88ꢀ3.95 (m, 2H),
3.80 (s, 3H), 6.70ꢀ6.83 (m, 3H), 7.25 (t, 3JHH = 8.0 Hz, 1H); 13C NMR
(CDCl3, 75.5 MHz): δ 35.4 (2C), 40.1, 49.1 (2C), 54.9, 111.7, 113.3,
119.6, 129.7, 143.7, 159.8. 3f (89% yield): Rf (5% EtOAc/hexane): 0.45;
1H NMR (CDCl3, 300.13 MHz): δ 1.84ꢀ2.07 (m, 4H), 3.03ꢀ3.23 (m,
4H), 3.24ꢀ3.38 (m, 1H), 3.84 (s, 3H), 6.90 (d, 3JHH = 8.2 Hz, 1H), 6.96
(t, 3JHH = 7.6 Hz, 1H), 7.13 (dd, 3JHH = 7.4 Hz, 4JHH = 1.6 Hz, 1H), 7.24
3
4.03ꢀ4.10 (m, 2H), AB system (δA = 7.03 δB = 7.11, JHH = 7.9 Hz);
13C NMR (CDCl3, 75.5 MHz): δ 20.7, 35.4 (2C), 36.8 (2C), 37.4, 67.8
(2C), 127.2 (2C), 129.4 (2C), 136.6, 137.8; MS (ESIþ, m/z): 373 [(M þ
Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C14H22NaO6S2)þ [(M þ
Na)þ]: 373.0750; found: 373.0764. 2d (90% yield): Rf (50% EtOAc/
hexane): 0.29; IR (NaCl): ν 2941, 1514, 1353, 1250, 1174, 973, 914, 832,
3
(t, JHH = 8.0 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz): δ 33.7, 34.2
(2C), 49.5 (2C), 55.1, 110.6, 120.7, 127.6, 127.9, 129.9, 157.5.
1
733 cmꢀ1; H NMR (CDCl3, 300.13 MHz): δ 1.84ꢀ2.01 (m, 2H),
General Procedure for the Synthesis of Diamines 4aꢀf. To
a solution of the corresponding diazide 3aꢀf (4.91 mmol) in MeOH
(49 mL) was added PPh3 (1.44 g, 14.7 mmol), and the resulting
suspension was stirred until the triphenylphosphine was completely
dissolved. After this time, H2O (264 μL, 14.7 mmol) was added to the
reaction vessel and the resulting solution stirred at 70 °C for 14 h until
complete disappearance of the diazide by TLC analysis. Then the
solvent was evaporated by distillation at reduced pressure, obtaining a
crude reaction product that was purified by flash chromatography (100%
MeOH to 10% NH3/MeOH), affording the corresponding diamine
4aꢀf as a yellowish oil (80ꢀ92%). 4a (80% yield): Rf (10% NH3/
MeOH): 0.14; IR (NaCl): ν 3352, 3290, 2934, 2821, 1581, 1493, 1454,
2.03ꢀ2.18 (m, 2H), 2.79ꢀ2.87 (m, 1H), 2.88 (s, 6H), 3.75 (s, 3H),
3.86ꢀ3.98 (m, 2H), 4.01ꢀ4.13 (m, 2H), AB system (δA = 6.83 δB = 7.06,
3JHH = 8.7 Hz); 13C NMR (CDCl3, 75.5 MHz): δ 35.5 (2C), 36.9 (2C),
37.0, 55.0, 67.7 (2C), 114.2 (2C), 128.3 (2C), 132.8, 158.5; MS (ESIþ, m/
z): 389 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C14H22-
NaO7S2)þ [(M þ Na)þ]: 389.0699; found: 389.0707. 2e (85% yield): Rf
(50% EtOAc/hexane): 0.27; IR (NaCl): ν 3027, 2941, 1600, 1488, 1352,
1
1258, 1173, 1040, 973, 918, 794, 733 cmꢀ1; H NMR (CDCl3, 300.13
MHz): δ 1.89ꢀ2.04 (m, 2H), 2.05ꢀ2.20 (m, 2H), 2.90 (s, 6H), 2.82ꢀ2.97
(m, 1H), 3.77 (s, 3H), 3.88ꢀ4.01 (m, 2H), 4.04ꢀ4.15 (m, 2H), 6.67ꢀ6.80
(m, 3H), 7.23(t,3JHH = 8.3 Hz, 1H); 13CNMR(CDCl3, 75.5 MHz): δ35.3
(2C), 36.9 (2C), 37.9, 55.0, 67.7 (2C), 112.0, 113.4, 119.6, 129.4, 142.7,
159.8; MS (ESIþ, m/z): 389 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z)
calcd for (C14H22NaO7S2)þ [(M þ Na)þ]: 389.0699; found: 389.0704. 2f
(84%yield):Rf (50%EtOAc/hexane):0.30;IR(NaCl):ν2943, 1493, 1353,
1
1389, 1316, 1132, 1034, 762, 704 cmꢀ1; H NMR (CD3OD, 300.13
MHz): δ 1.72ꢀ1.97 (m, 4H), 2.40ꢀ2.62 (m, 4H), 2.65ꢀ2.78 (m, 1H),
7.14ꢀ7.25 (m, 3H), 7.26ꢀ7.35 (m, 2H); 13C NMR (CD3OD, 75.5
MHz): δ 40.1 (2C), 40.7 (2C), 42.8, 128.1, 129.1 (2C), 130.2 (2C),
145.9; MS (ESIþ, m/z): 179 [(M þ H)þ, 100%]; HRMS (ESIþ, m/z)
calcd for (C11H19N2)þ [(M þ H)þ]: 179.1543; found: 179.1548. 4b
(91% yield): Rf (10% NH3/MeOH): 0.14; IR (NaCl): ν 3357, 3286,
1
1244, 1174, 969, 916, 733 cmꢀ1; H NMR (CDCl3, 300.13 MHz): δ
2.01ꢀ2.23 (m, 4H), 2.86 (s, 6H), 3.24ꢀ3.37 (m, 1H), 3.79 (s, 3H),
3.92ꢀ4.12 (m, 4H), 6.83ꢀ6.95 (m, 2H), 7.10 (d, 3JHH = 6.2 Hz, 1H), 7.20
(t, 3JHH = 7.4 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz): δ 32.7, 33.9 (2C),
36.8 (2C), 55.1, 68.3 (2C), 110.8, 120.8, 128.1, 128.5, 128.7, 157.4; MS
(ESIþ, m/z): 389 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C14H22NaO7S2)þ [(M þ Na)þ]: 389.0699; found: 389.0706.
1
2925, 2863, 1579, 1512, 1315, 837 cmꢀ1; H NMR (CD3OD, 300.13
MHz): δ 1.68ꢀ1.96 (m, 4H), 2.40ꢀ2.64 (m, 4H), 2.69ꢀ2.85 (m, 1H),
7.06 (t, 3JHH = 8.8 Hz, 2H), 7.21ꢀ7.31 (m, 2H); 13C NMR (CD3OD,
75.5 MHz): δ 40.5 (2C), 40.7 (2C), 41.7, 116.1 (d, 2JCF = 21 Hz, 2C),
130.1 (d, 3JCF = 7 Hz, 2C), 141.8, 162.9 (d, 1JCF = 243 Hz); MS (ESIþ,
m/z): 197 [(M þ H)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C11H18FN2)þ [(M þ H)þ]: 197.1449; found: 197.1452. 4c (92%
yield): Rf (10% NH3/MeOH): 0.13; IR (NaCl): ν 3354, 3289, 2925,
General Procedure for the Synthesis of Diazides 3aꢀf. To a
solution of the corresponding dimesylate 2aꢀf (5.30 mmol) in dry DMF
(21 mL) was added sodium azide (2.10 g, 31.79 mmol) under nitrogen
atmosphere, and the resulting suspension was stirred at 55 °C during
14 h. After this time, the reaction was quenched with H2O (25 mL) and
the residue extracted with Et2O (3 ꢁ 25 mL). The organic phases were
combined and dried over Na2SO4, and the solvent was evaporated under
reduced pressure, affording a crude product that was purified by flash
chromatography (5% EtOAc/hexane), which yielded the corresponding
diazide 3aꢀf as a colorless oil (89ꢀ94%), that were next reduced
without longer storage times inclusively at low temperatures. 3a (93%
yield): Rf (5% EtOAc/hexane): 0.42; 1H NMR (CDCl3, 300.13 MHz):
δ 1.78ꢀ2.04 (m, 4H), 2.76ꢀ2.90 (m, 1H), 2.99ꢀ3.12 (m, 2H),
3.13ꢀ3.25 (m, 2H), 7.13ꢀ7.20 (m, 2H), 7.21ꢀ7.29 (m, 1H),
7.25ꢀ7.40 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 35.3 (2C),
40.1, 49.2 (2C), 126.9, 127.5 (2C), 128.8 (2C), 142.1. 3b (89% yield): Rf
(5% EtOAc/hexane): 0.27; 1H NMR (CDCl3, 300.13 MHz): δ
1.73ꢀ2.01 (m, 4H), 2.77ꢀ2.90 (m, 1H), 2.96ꢀ3.10 (m, 2H),
3.12ꢀ3.24 (m, 2H), 7.02 (t, 3JHH = 8.5 Hz, 2H), 7.09ꢀ7.19 (m, 2H);
13C NMR (CDCl3, 75.5 MHz): δ 35.6 (2C), 39.3, 49.1 (2C), 115.6 (d,
2JCF = 21 Hz, 2C), 128.8 (d, 3JCF = 8 Hz, 2C), 137.7, 161.6 (d, 1JCF = 245
Hz). 3c (89% yield): Rf (5% EtOAc/hexane): 0.45; 1H NMR (CDCl3,
300.13 MHz): δ 1.76ꢀ2.02 (m, 4H), 2.35 (s, 3H), 2.72ꢀ2.85 (m, 1H),
2.98ꢀ3.11 (m, 2H), 3.12ꢀ3.25 (m, 2H), AB system (δA = 7.06 δB =
7.15, 3JHH = 7.9 Hz); 13C NMR (CDCl3, 75.5 MHz): δ 20.9, 35.5 (2C),
39.6, 49.2 (2C), 127.3 (2C), 129.4 (2C), 136.4, 138.8. 3d (94% yield): Rf
(5% EtOAc/hexane): 0.27; 1H NMR (CDCl3, 300.13 MHz): δ
1.70ꢀ2.02 (m, 4H), 2.69ꢀ2.85 (m, 1H), 2.97ꢀ3.10 (m, 2H),
3.11ꢀ3.27 (m, 2H), 3.79 (s, 3H), AB system (δA = 6.86 δB = 7.06,
3JHH = 8.5 Hz); 13C NMR (CDCl3, 75.5 MHz): δ 35.5 (2C), 39.1, 49.1
(2C), 54.9, 114.0 (2C), 128.2 (2C), 133.8, 158.3. 3e (94% yield): Rf (5%
EtOAc/hexane): 0.26; 1H NMR (CDCl3, 300.13 MHz): δ 1.77ꢀ2.00
(m, 4H), 2.73ꢀ2.86 (m, 1H), 2.99ꢀ3.11 (m, 2H), 3.12ꢀ3.23 (m, 2H),
1
2862, 1580, 1513, 1469, 1317, 816 cmꢀ1; H NMR (CD3OD, 300.13
MHz): δ 1.66ꢀ1.91 (m, 4H), 2.29 (s, 3H), 2.37ꢀ2.54 (m, 4H),
2.56ꢀ2.73 (m, 1H), 7.10 (brs, 4H); 13C NMR (CD3OD, 75.5 MHz):
δ 21.4, 40.9 (2C), 41.0 (2C), 42.4, 128.8 (2C), 130.5 (2C), 137.3, 142.9;
MS (ESIþ, m/z): 193 [(M þ H)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C12H21N2)þ [(M þ H)þ]: 193.1699; found: 193.1706. 4d (88%
yield): Rf (10% NH3/MeOH): 0.10; IR (NaCl): ν 3362, 3281, 2926,
2863, 1610, 1511, 1301, 1247, 1179, 1035, 830 cmꢀ1 1H NMR
;
(CD3OD, 300.13 MHz): δ 1.63ꢀ1.96 (m, 4H), 2.39ꢀ2.60 (m, 4H),
2.62ꢀ2.79 (m, 1H), 3.80 (s, 3H), AB system (δA = 6.90 δB = 7.17,
3JHH = 8.3 Hz); 13C NMR (CD3OD, 75.5 MHz): δ 40.8 (4C), 41.9,
56.0, 115.3 (2C), 129.8 (2C), 137.9, 160.0; MS (ESIþ, m/z): 209 [(M þ
H)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C12H21N2O)þ [(M þ
H)þ]: 209.1648; found: 209.1648. 4e (88% yield): Rf (10% NH3/
MeOH): 0.15; IR (NaCl): ν 3361, 3282, 2927, 2862, 1597, 1589, 1488,
1259, 1159, 1044, 785, 703 cmꢀ1; 1H NMR (CD3OD, 300.13 MHz): δ
1.68ꢀ1.88 (m, 4H), 2.38ꢀ2.58 (m, 4H), 2.60ꢀ2.74 (m, 1H), 3.77 (s,
3
3H), 6.72ꢀ6.83 (m, 3H), 7.21 (t, JHH = 8.2 Hz, 1H); 13C NMR
(CD3OD, 75.5 MHz): δ 40.9 (4C), 42.9, 55.9, 112.9, 114.7, 121.2,
130.9, 147.8, 161.7; MS (ESIþ, m/z): 209 [(M þ H)þ, 100%]; HRMS
(ESIþ, m/z) calcd for (C12H21N2O)þ [(M þ H)þ]: 209.1648; found:
209.1650. 4f (82% yield): Rf (10% NH3/MeOH): 0.20; IR (NaCl): ν
3364, 3285, 2933, 2859, 1594, 1491, 1463, 1239, 1027, 756 cmꢀ1; 1H
NMR (CD3OD, 300.13 MHz): δ 1.71ꢀ1.95 (m, 4H), 2.38ꢀ2.54 (m,
4H), 3.15ꢀ3.33 (m, 1H), 3.82 (s, 3H), 6.89ꢀ6.71 (m, 2H), 7.12ꢀ7.28
(m, 2H); 13C NMR (CD3OD, 75.5 MHz): δ 34.1, 40.2 (2C), 40.9 (2C),
56.3, 112.1, 122.4, 128.6, 128.8, 133.6, 159.2; MS (ESIþ, m/z): 209
[(M þ H)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C12H21N2O)þ
[(M þ H)þ]: 209.1648; found: 209.1647.
5714
dx.doi.org/10.1021/jo2007972 |J. Org. Chem. 2011, 76, 5709–5718

The Journal of Organic Chemistry
ARTICLE
Enzymatic Desymmetrization of Diamine 4a Using Diallyl
Carbonate. To a suspension of diamine 4a (100 mg, 0.56 mmol) and
Pseudomonas cepacia lipase type I (PSL-C I, 100 mg) in dry 1,4-dioxane
(5.6 mL) was added diallyl carbonate (5, 81 μL, 0.56 mmol) under
nitrogen atmosphere, and the mixture was shaken at 30 °C and 250 rpm,
following the progress of the reaction by TLC analysis. The reaction was
stopped after 72 h, and the enzyme was filtered off and washed with
MeOH (3 ꢁ 5 mL). The solvent was evaporated under reduced pressure
and the resulting crude purified by flash chromatography (60% MeOH/
EtOAc), affording 63 mg of the amino carbamate (S)-(þ)-6 as a
colorless oil (32% isolated yield, 88% ee; see Tables 1ꢀ4). Rf (60%
MeOH/EtOAc): 0.11; IR (NaCl): ν 3327, 3027, 2933, 2875, 1703,
1538, 1453, 1257, 1145, 1029, 994, 928, 759 cmꢀ1; 1H NMR (CDCl3,
300.13 MHz): δ 1.61ꢀ1.95 (m, 4H), 2.39ꢀ2.77 (m, 5H), 2.88ꢀ3.08
(m, 2H), 4.49 (d, 3JHH = 5.0 Hz, 2H), 4.94 (brs, 1H), 5.16 (d, 3Jcis = 10.5
Hz, 1H), 5.23 (d, 3Jtrans = 17.1 Hz, 1H), 5.77ꢀ5.95 (m, 1H), 7.08ꢀ7.21
(m, 3H), 7.22ꢀ7.31 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 36.6
(2C), 39.1, 39.6, 40.9, 65.2, 117.3, 126.4, 127.3 (2C), 128.5 (2C), 132.9,
143.8, 156.1; MS (ESIþ, m/z): 263 [(M þ H)þ, 100%]; HRMS (ESIþ,
m/z) calcd for (C15H23N2O2)þ [(M þ H)þ]: 263.1754; found:
solvent evaporated under reduced pressure, and the resulting crude
product purified by flash chromatography (60% MeOH/EtOAc to 100%
MeOH), affording 41 mg of the amide (S)-(þ)-8 as a colorless oil (27%
isolated yield, 90% ee; see Table 4). Rf (80% MeOH/EtOAc): 0.16; IR
(NaCl): ν 3285, 3082, 2932, 2871, 1647, 1560, 1450, 1371, 1298, 1135,
1035, 762, 735 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz): δ 1.64ꢀ2.01 (m,
9H), 2.48ꢀ2.62 (m, 2H), 2.62ꢀ2.77 (m, 1H), 2.95ꢀ3.11 (m, 1H),
3.11ꢀ3.27 (m, 1H), 5.47 (brs, 1H), 7.08ꢀ7.23 (m, 3H), 7.24ꢀ7.36 (m,
2H); 13C NMR (CDCl3, 75.5 MHz): δ 23.1, 36.4, 38.1, 39.8, 40.0, 41.4,
126.5, 127.4 (2C), 128.6 (2C), 144.2, 169.9; MS (ESIþ, m/z): 221 [(M þ
H)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C13H21N2O)þ [(M þ H)þ]:
221.1648; found: 221.1649; [R]D20 = þ8.9 (c 0.7, EtOH) for 90% ee.
Enantiomeric Excess Measurement of Compound 8 Ob-
tained by Lipase-Catalyzed Desymmetrization of Diamine
4a Using Ethyl Acetate. To a solution of compound (S)-(þ)-8
(11 mg, 0.05 mmol) in dry CH2Cl2 (0.5 mL) were successively added
Et3N (9 μL, 0.07 mmol) and allyl chloroformate (9, 8 μL, 0.07 mmol)
under nitrogen atmosphere. The mixture was stirred for 2 h at room
temperature, and after this time, the solvent was evaporated under
reduced pressure, obtaining a crude reaction product that was purified by
flash chromatography (60% EtOAc/hexane to 100% EtOAc) to afford
14 mg of the amido carbamate (R)-(ꢀ)-7 as a colorless oil (92%).
20
263.1748; [R]D þ14.3 (c 0.7, EtOH) for 88% ee.
Enantiomeric Excess Measurement for Compound 6 Ob-
tained by Lipase-Catalyzed Desymmetrization of Diamine
4a Using Diallyl Carbonate. To a solution of compound (S)-(þ)-
6a (20 mg, 0.08 mmol) in dry CH2Cl2 (0.8 mL) were successively added
Et3N (12 μL, 0.09 mmol) and acetyl chloride (6 μL, 0.09 mmol) under
nitrogen atmosphere. The mixture was stirred for 2 h at room tempera-
ture, and after this time the solvent was evaporated under reduced
pressure, obtaining a crude reaction product that was purified by flash
chromatography (60% EtOAc/hexane to 100% EtOAc) to afford 23 mg
of the amido carbamate (S)-(þ)-7 as a colorless oil (99%). Rf (100%
EtOAc): 0.21; IR (NaCl): ν 3056, 2932, 1710, 1655, 1541, 1453, 1369,
1266, 1140, 1038, 993, 738 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz): δ
1.66ꢀ1.82 (m, 2H), 1.84ꢀ2.02 (m, 5H), 2.54ꢀ2.70 (m, 1H),
2.92ꢀ3.22 (m, 4H), 4.47 (d, 3JHH = 5.1 Hz, 2H), 4.78 (brs, 1H), 5.19
(d, 3Jcis = 10.5 Hz, 1H), 5.27 (d, 3Jtrans = 17.1 Hz, 1H), 5.80ꢀ5.97 (m,
20
[R]D ꢀ0.9 (c 1.0, EtOH) for 90% ee.
Enzymatic Desymmetrization of Diamines 4aꢀf Using
Ethyl Methoxyacetate. To a suspension of the corresponding
diamine 4aꢀf (0.56 mmol) in dry 1,4-dioxane (5.6 mL) Pseudomonas
cepacia were successively added lipase type I (PSL-C I, 100 mg) and
ethyl methoxyacetate (10b, 66 μL, 0.56 mmol), and the mixture was
shaken at 30 °C and 250 rpm following the progress of the reaction by
TLC analysis. The progress of the reaction was followed by TLC analysis
during 72 h. Then the enzyme was filtered off and washed with MeOH
(3 ꢁ 5 mL). The solvent was evaporated under reduced pressure and the
resulting crude product purified by flash chromatography (60% MeOH/
EtOAc to 100% MeOH), affording the corresponding amide (S)-(þ)-
11aꢀf as a colorless oil (33ꢀ59% isolated yield, 54ꢀ99% ee; see
Tables 4 and 5). (S)-(þ)-11a (58% yield, 91% ee): Rf (80% MeOH/
EtOAc): 0.14; IR (NaCl): ν 3413, 2935, 1665, 1539, 1494, 1453, 1267,
2H), 7.10ꢀ7.17 (m, 2H), 7.18ꢀ7.24 (m, 1H), 7.25ꢀ7.35 (m, 2H); 13
C
1
1199, 1117, 735, 703 cmꢀ1; H NMR (CDCl3, 300.13 MHz): δ 1.40
NMR (CDCl3, 75.5 MHz): δ 22.9, 35.7, 36.8, 38.0, 39.0, 41.0, 65.4,
117.5, 126.7, 127.4 (2C), 128.8 (2C), 132.8, 143.7, 156.4, 170.4; MS
(ESIþ, m/z): 327 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C17H24N2NaO3)þ [(M þ Na)þ]: 327.1679; found: 327.1682.
(brs, 2H), 1.67ꢀ1.99 (m, 4H), 2.54 (t, 3JHH = 7.1 Hz, 2H), 2.62ꢀ2.75
(m, 1H), 3.03ꢀ3.28 (m, 2H), 3.53 (s, 3H), 3.81 (s, 2H), 6.39 (brs, 1H),
7.09ꢀ7.23 (m, 3H), 7.24ꢀ7.37 (m, 2H); 13C NMR (CDCl3, 75.5
MHz): δ 36.4, 37.2, 40.0, 40.6, 41.4, 59.0, 71.9, 126.4, 127.4 (2C), 128.6
(2C), 143.9, 169.2; MS (ESIþ, m/z): 251 [(M þ H)þ, 100%]; HRMS
(ESIþ, m/z) calcd for (C14H23N2O2)þ [(M þ H)þ]: 251.1754; found:
20
[R]D þ1.2 (c 1.0, EtOH) for 88% ee.
Synthesis of the Racemic Amido Carbamate 7. To a solution
of diamine 4a (89 mg, 0.50 mmol) in dry THF (1.0 mL) was added
Ac2O (47 μL, 0.50 mmol) in portions under nitrogen atmosphere, and
the mixture was stirred for 4 h at room temperature. After this time, the
solvent was evaporated under reduced pressure obtaining a crude
reaction product that was passed through a plug of SiO2 (100% MeOH
to 1% NH3/MeOH). The solvent was removed by distillation under
reduced pressure, isolating a colorless oil containing the amido amine
(()-8, which was immediately dissolved in dry CH2Cl2 (1 mL)
successively adding pyridine (5 μL, 0.07 mmol) and allyl chloroformate
(9, 6 μL, 0.07 mmol). The mixture was stirred for 4 h at room
temperature, and after this time, the solvent was evaporated under
reduced pressure, obtaining a crude reaction product that was purified by
flash chromatography (100% EtOAc) to afford 13 mg of the amido
carbamate (()-7 as a colorless oil (9% for both steps).
20
251.1760; [R]D þ5.8 (c 1.0, EtOH) for 91% ee. (S)-(þ)-11b (58%
yield, 82% ee): Rf (80% MeOH/EtOAc): 0.18; IR (NaCl): ν 3414, 3300,
1
3050, 2935, 1664, 1603, 1539, 1509, 1222, 1118, 837, 735 cmꢀ1; H
NMR (CDCl3, 300.13 MHz): δ 1.58ꢀ1.93 (m, 4H), 2.49 (brs, 2H),
2.56ꢀ2.73 (m, 1H), 2.94ꢀ3.25 (m, 4H), 3.31 (s, 3H), 3.75 (s, 2H), 6.48
(brs, 1H), 6.93 (t, 3JHH = 8.5 Hz, 2H), 7.01ꢀ7.14 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz): δ 36.4, 36.9, 38.3, 39.4, 40.4, 58.8, 71.6, 115.3 (d,
2JCF = 21 Hz, 2C), 128.6 (d, 3JCF = 7 Hz, 2C), 139.4, 161.3 (d, 1JCF = 244
Hz), 169.3; MS (ESIþ, m/z): 269 [(M þ H)þ, 100%]; HRMS (ESIþ,
m/z) calcd for (C14H22FN2O2)þ [(M þ H)þ]: 269.1660; found:
20
269.1668; [R]D þ3.3 (c 1.0, EtOH) for 82% ee. (S)-(þ)-11c (59%
yield, 90% ee): Rf (80% MeOH/EtOAc): 0.19; IR (NaCl): ν 3300, 2929,
1
1664, 1538, 1451, 1198, 1117, 818 cmꢀ1; H NMR (CDCl3, 300.13
MHz): δ 1.59ꢀ1.94 (m, 4H), 2.16 (brs, 2H), 2.28 (s, 3H), 2.32ꢀ2.44
(m, 1H), 2.46ꢀ2.70 (m, 2H), 2.96ꢀ3.24 (m, 2H), 3.31 (s, 3H), 3.76 (s,
2H), 6.41 (brs, 1H), AB system (δA = 7.00 δB = 7.06, 3JHH = 7.7 Hz);
13C NMR (CDCl3, 75.5 MHz): δ 20.8, 36.4, 37.1, 39.7, 39.9, 40.8, 58.9,
71.7, 127.1 (2C), 129.2 (2C), 135.7, 140.7, 169.2; MS (ESIþ, m/z): 265
[(M þ H)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C15H25N2O2)þ
Enzymatic Desymmetrization of Diamine 4a Using Ethyl
Acetate. To a suspension of diamine 4a (100 mg, 0.56 mmol) in dry
1,4-dioxane (5.6 mL) were successively added Pseudomonas cepacia
lipase type I (PSL-C I, 100 mg) and ethyl acetate (10a, 55 μL,
0.56 mmol), and the mixture was shaken at 30 °C and 250 rpm. The
progress of the reaction was followed by TLC analysis during 72 h. Then
the enzyme was filtered off and washed with MeOH (3 ꢁ 5 mL), the
[(M þ H)þ]: 265.1911; found: 265.1914; [R]D þ4.1 (c 1.0, EtOH)
20
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ARTICLE
for 90% ee. (S)-(þ)-11d (51% yield, 86% ee): Rf (80% MeOH/EtOAc):
0.16; IR (NaCl): ν 3411, 2935, 1661, 1611, 1539, 1513, 1248, 1179,
4H), 2.30 (s, 3H), 2.43ꢀ2.64 (m, 1H), 2.92ꢀ3.25 (m, 4H), 3.34 (s, 3H),
3.80 (s, 2H), 4.52 (s, 2H), 4.70 (brs, 1H), 5.17 (d, 3Jcis = 10.5 Hz, 1H), 5.26
(d, 3Jtrans = 17.1 Hz, 1H), 5.79ꢀ5.99 (m, 1H), 6.37 (brs, 1H), AB system
(δA = 7.02 δB = 7.10, 3JHH = 7.7 Hz); 13C NMR (CDCl3, 75.5 MHz): δ
20.8, 36.3, 36.6, 37.0, 39.1, 40.8, 58.9, 65.3, 71.8, 117.3, 127.1 (2C), 129.3
(2C), 132.9, 136.1, 140.2, 156.1, 169.3; MS (ESIþ, m/z): 371 [(M þ Na)þ,
100%]; HRMS (ESIþ, m/z) calcd for (C19H28N2NaO4)þ [(M þ Na)þ]:
1
1117, 735 cmꢀ1; H NMR (CDCl3, 300.13 MHz): δ 1.52ꢀ1.96 (m,
4H), 2.41ꢀ2.67 (m, 3H), 2.91ꢀ3.21 (m, 2H), 3.31 (s, 3H), 3.73 (s, 3H),
3.75 (s, 2H), 5.01 (brs, 2H), 6.58 (brs, 1H), AB system (δA = 6.77 δB =
7.03, 3JHH = 8.3 Hz); 13C NMR (CDCl3, 75.5 MHz): δ 36.3, 37.0 (2C),
38.8, 40.1, 55.0, 58.9, 71.6, 113.9 (2C), 128.2 (2C), 135.2, 158.0, 169.3; MS
(ESIþ, m/z): 281 [(M þ H)þ, 100%]; HRMS (ESIþ, m/z) calcd for
20
371.1941; found: 371.1943; [R]D ꢀ2.0 (c 1.0, EtOH) for 90% ee.
20
(C15H25N2O3)þ [(M þ H)þ]: 281.1860; found: 281.1861; [R]D þ8.9
(R)-(ꢀ)-12d (97% yield, 86% ee): Rf (100% EtOAc): 0.38; IR (NaCl):
ν 3411, 3328, 2963, 1714, 1667, 1536, 1512, 1454, 1248, 1178, 1117, 1035,
(c 1.0, EtOH) for 86% ee. (S)-(þ)-11e (50% yield, >99% ee): Rf (80%
MeOH/EtOAc): 0.14; IR (NaCl): ν 3409, 3306, 2936, 1663, 1597, 1541,
1487, 1261, 1117, 735, 703 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz): δ 1.39
(brs, 2H), 1.63ꢀ1.96 (m, 4H), 2.42ꢀ2.70 (m, 3H), 3.01ꢀ3.26 (m, 2H),
3.34 (s, 3H), 3.77 (s, 3H), 3.78 (s, 2H), 6.38 (brs, 1H), 6.66ꢀ6.77 (m, 3H),
7.19 (t, 3JHH = 7.9 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz): δ 36.3, 37.2,
39.9, 40.5, 41.5, 55.0, 58.9, 71.8, 111.3, 113.3, 119.8, 129.5, 145.7, 159.8,
169.2; MS (ESIþ, m/z): 281 [(M þ H)þ, 100%]; HRMS (ESIþ, m/z)
calcd for (C15H25N2O3)þ [(M þ H)þ]: 281.1860; found: 281.1863;
1
736 cmꢀ1; H NMR (CDCl3, 300.13 MHz): δ 1.63ꢀ1.79 (m, 2H),
1.80ꢀ1.96 (m, 2H), 2.50ꢀ2.66 (m, 1H), 2.87ꢀ3.05 (m, 2H), 3.06ꢀ3.21
(m, 2H), 3.35 (s, 3H), 3.77 (s, 3H), 3.80 (s, 2H), 4.51 (d, 3JHH = 5.5 Hz,
2H), 4.72 (brs, 1H), 5.18 (d, 3Jcis = 10.5 Hz, 1H), 5.26 (d, 3Jtrans = 17.1 Hz,
1H), 5.82ꢀ5.97 (m, 1H), 6.39 (brs, 1H), AB system (δA = 6.83 δB = 7.05,
3JHH =8.7Hz);13CNMR(CDCl3, 75.5 MHz): δ36.4, 36.7, 37.1, 39.1, 40.3,
55.1, 58.9, 65.3, 71.8, 114.0 (2C), 117.4, 128.2 (2C), 132.9, 135.2, 156.1,
158.2, 169.3; MS (ESIþ, m/z): 387 [(M þ Na)þ, 100%]; HRMS (ESIþ,
m/z) calcd for (C19H28N2NaO5)þ [(M þ Na)þ]: 387.1890; found:
20
[R]D þ5.6 (c 1.0, EtOH) for >99% ee. (S)-(þ)-11f (33% yield, 54%
20
ee): Rf (80% MeOH/EtOAc): 0.15; IR (NaCl): ν 3410, 3307, 2939, 1660,
1593, 1540, 1490, 1263, 1117, 735, 703 cmꢀ1; 1H NMR (CDCl3, 300.13
MHz): δ 1.45 (brs, 2H), 1.59ꢀ1.90 (m, 4H), 2.38ꢀ2.53 (m, 2H),
2.76ꢀ2.90 (m, 1H), 3.15ꢀ3.32 (m, 2H), 3.34 (s, 3H), 3.77 (s, 5H), 6.69
387.1890; [R]D ꢀ4.1 (c 1.0, EtOH) for 86% ee. (R)-(ꢀ)-12e (97%
yield, >99% ee): Rf (100% EtOAc): 0.40; IR (NaCl): ν 3327, 2936, 1713,
1665, 1537, 1258, 1117 cmꢀ1 1H NMR (CDCl3, 300.13 MHz): δ
;
1.61ꢀ1.83 (m, 2H), 1.84ꢀ1.98 (m, 2H), 2.53ꢀ2.66 (m, 1H), 2.95ꢀ3.08
(m, 2H), 3.10ꢀ3.23 (m, 2H), 3.36 (s, 3H), 3.79 (s, 3H), 3.81 (s, 2H), 4.52
(d, 3JHH = 5.5 Hz, 2H), 4.68 (brs, 1H), 5.19 (d, 3Jcis = 10.5 Hz, 1H), 5.25 (d,
3Jtrans = 17.1 Hz, 1H), 5.82ꢀ5.96 (m, 1H), 6.39 (brs, 1H), 6.67ꢀ6.78 (m,
3H), 7.22 (t, 3JHH = 7.7 Hz, 1H); 13C NMR (CDCl3, 75.5 MHz): δ 36.2,
36.5, 37.0, 39.1, 41.3, 55.1, 59.0, 65.3, 71.8, 111.6, 113.3, 117.4, 119.7, 129.8,
132.9, 145.1, 156.1, 159.9, 169.4; MS (ESIþ, m/z): 387 [(M þ Na)þ,
100%]; HRMS (ESIþ, m/z) calcd for (C19H28N2NaO5)þ [(M þ Na)þ]:
3
3
(brs, 1H), 6.81 (d, JHH = 8.2 Hz, 1H), 6.89 (t, JHH = 7.3 Hz, 1H),
7.06ꢀ7.17(m, 2H);13CNMR(CDCl3, 75.5 MHz): δ31.7, 35.9, 36.6, 39.6,
39.9, 55.2, 58.8, 71.8, 110.3, 120.9, 126.9, 127.1, 131.6, 157.1, 168.9; MS
(ESIþ, m/z): 281 [(M þ H)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C15H25N2O3)þ [(M þ H)þ]: 281.1860; found: 281.1858; [R]D þ9.2
20
(c 1.0, EtOH) for 54% ee.
General Procedure for the Measurement of the Enantio-
meric Excess of Compounds 11aꢀf Obtained by Lipase-
Catalyzed Desymmetrization of Diamines 4aꢀf. To a solution
of the corresponding monoamide (S)-(þ)-11aꢀf (0.08 mmol) in dry
CH2Cl2 (0.8 mL) were successively added Et3N (12 μL, 0.09 mmol) and
allyl chloroformate (9, 10 μL, 0.09 mmol) under nitrogen atmosphere. The
mixture was stirred for 2 h at room temperature, and after this time, the
solvent was evaporated under reduced pressure, obtaining a crude reaction
product that was purified by flash chromatography (60% EtOAc/hexane-
100% EtOAc) to afford the corresponding amido carbamate (R)-12aꢀf as a
colorless oil (94ꢀ97%). (R)-(ꢀ)-12a (94% yield, 91% ee): Rf (100%
EtOAc): 0.19; IR (NaCl): ν3321, 2935, 1712, 1663, 1538, 1453, 1256, 1117,
736, 703 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz): δ 1.66ꢀ2.01 (m, 4H),
2.55ꢀ2.71 (m, 1H), 2.92ꢀ3.07 (m, 2H), 3.35 (s, 3H), 3.81 (s, 2H), 4.52 (s,
2H), 4.69 (brs, 1H), 5.19 (d, 3Jcis = 10.4 Hz, 1H), 5.27 (d, 3Jtrans = 17.1 Hz,
1H), 5.80ꢀ5.97 (m, 1H), 6.39 (brs, 1H), 7.08ꢀ7.24 (m, 3H), 7.25ꢀ7.39
(m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 36.2, 36.6, 37.0, 39.1, 41.3, 59.0,
65.3, 71.8, 117.4, 126.7, 127.4 (2C), 128.8 (2C), 132.9, 143.4, 156.1, 169.4;
MS (ESIþ, m/z): 357 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for
20
387.1890; found: 387.1894; [R]D ꢀ3.0 (c 1.0, EtOH) for >99% ee.
(R)-(þ)-12f (97% yield, 54% ee): Rf (100% EtOAc): 0.43; IR (NaCl):
1
ν 3328, 2938, 1711, 1667, 1539, 1256, 1117 cmꢀ1; H NMR (CDCl3,
300.13 MHz): δ 1.64ꢀ1.94 (m, 4H), 2.78ꢀ2.96 (m, 2H), 3.03ꢀ3.17 (m,
1H), 3.18ꢀ3.36 (m, 2H), 3.39 (s, 3H), 3.83 (s, 5H), 4.51 (d, 3JHH = 5.5 Hz,
2H), 4.85 (brs, 1H), 5.18 (d, 3Jcis = 10.5 Hz, 1H), 5.25 (d, 3Jtrans = 17.1 Hz,
1H), 5.82ꢀ5.96 (m, 1H), 6.64 (brs, 1H), 6.86 (d, 3JHH = 8.2 Hz, 1H), 6.94
(td, 3JHH = 7.4 Hz, 4JHH = 1.0 Hz, 1H), 7.09ꢀ7.23 (m, 2H); 13C NMR
(CDCl3, 75.5 MHz): δ 32.0, 35.7, 35.8, 36.7, 39.1, 55.3, 59.0, 65.2,
71.9, 110.6, 117.3, 121.3, 127.1, 127.4, 131.0, 133.0, 156.1, 157.2, 169.2;
MS (ESIþ, m/z): 387 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd
for (C19H28N2NaO5)þ [(M þ Na)þ]: 387.1890; found: 387.1891;
20
[R]D þ14.0 (c 1.0, EtOH) for 54% ee.
General Procedure for the Synthesis of the Racemic
Amido Carbamates 12aꢀf. To a solution of the corresponding
diamine 4aꢀf (0.50 mmol) in H2O (50 μL) was added diallyl carbonate
(5, 72 μL, 0.50 mmol), and the mixture was stirred for 14 h at room
temperature. After this time, the solvent was evaporated under reduced
pressure, obtaining a crude reaction product that was passed through a
plug of SiO2 (80% MeOH/EtOAc). The solvent was removed by
distillation under reduced pressure, isolating a colorless oil that con-
tained the corresponding racemic allyl monocarbamate 6aꢀf, which was
immediately dissolved in dry CH2Cl2 (1 mL), successively adding Et3N
(6 μL, 0.05 mmol) and methoxyacetyl chloride (18, 5 μL, 0.05 mmol)
under nitrogen atmosphere. The mixture was stirred for 4 h at room
temperature, and after this time, the solvent was evaporated under
reduced pressure, obtaining a crude reaction product that was purified by
flash chromatography (100% EtOAc) to afford the corresponding amido
carbamate (()-12aꢀf as a colorless oil (7ꢀ10% for both steps).
Synthesis of (R)-5-[(Methysulfonyl)oxy]-3-phenylpentyl
Acetate (15). To a solution of (S)-5-hydroxy-3-phenylpentyl acetate
(14, 600 mg, 2.70 mmol) in dry CH2Cl2 (27 mL) was added pyridine
(292 μL, 4.05 mmol), and the mixture was cooled at 0 °C. Then
methanesulfonyl chloride (MsCl, 325 μL, 4.05 mmol) was added and
20
(C18H26N2NaO4)þ [(M þ Na)þ]: 357.1785; found: 357.1788; [R]D
ꢀ2.7 (c 1.0, EtOH) for 91% ee. (R)-(ꢀ)-12b (95% yield, 82% ee): Rf
(100% EtOAc): 0.36; IR (NaCl): ν 3413, 3330, 2935, 1709, 1667, 1537,
1509, 1254, 1224, 1118, 734 cmꢀ1; H NMR (CDCl3, 300.13 MHz): δ
1
1.64ꢀ1.82 (m, 2H), 1.83ꢀ2.01 (m, 2H), 2.51ꢀ2.68 (m, 1H), 2.91ꢀ3.06
(m, 2H), 3.07ꢀ3.24 (m, 2H), 3.36 (s, 3H), 3.81 (s, 2H), 4.52 (d, 3JHH = 5.4
Hz, 2H), 4.73 (brs, 1H), 5.18 (d, 3Jcis = 10.5 Hz, 1H), 5.26 (d, 3Jtrans = 17.1
Hz, 1H), 5.80ꢀ5.96 (m, 1H), 6.40 (brs, 1H), 6.99 (t, 3JHH = 8.7 Hz, 2H),
7.06ꢀ7.16(m, 2H);13CNMR(CDCl3, 75.5 MHz): δ36.4, 36.6, 37.0, 39.0,
40.5, 59.0, 65.4, 71.8, 115.5 (d, 2JCF = 21 Hz, 2C), 117.5, 128.6 (d, 3JCF
=
7 Hz, 2C), 132.9, 139.1, 156.1, 161.5 (d, 1JCF = 244 Hz), 169.5; MS (ESIþ,
m/z): 375 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C18H25FN2NaO4)þ [(M þ Na)þ]: 375.1691; found: 375.1695; [R]D
20
ꢀ5.1 (c1.0, EtOH) for 82% ee. (R)-(ꢀ)-12c (96% yield, 90% ee): Rf (100%
EtOAc): 0.47; IR (NaCl): ν3330, 2934, 1697, 1673, 1537, 1452, 1250, 1200,
1117, 922, 733 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz): δ 1.63ꢀ2.01 (m,
5716
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The Journal of Organic Chemistry
ARTICLE
the resulting solution stirred at room temperature for 14 h after com-
plete disappearance of the starting material. The solvent was evaporated
by distillation at reduced pressure, obtaining a crude reaction product
that was purified by flash chromatography (30ꢀ50% EtOAc/hexane) to
yield 786 mg of (R)-(ꢀ)-15 as a colorless oil (97%). Rf (50% EtOAc/
hexane): 0.47; IR (NaCl): ν 3028, 2941, 1736, 1356, 1245, 1174, 1038,
971, 960, 735, 704 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz): δ 1.84ꢀ2.08
(m, 6H), 2.09ꢀ2.22 (m, 1H), 2.81ꢀ2.94 (m, 4H), 3.78ꢀ3.88 (m, 1H),
3.89ꢀ4.02 (m, 2H), 4.05ꢀ4.14 (m, 1H), 7.11ꢀ7.18 (m, 2H),
7.19ꢀ7.26 (m, 1H), 7.27ꢀ7.35 (m, 2H); 13C NMR (CDCl3, 75.5
MHz): δ 20.8, 35.1, 35.6, 37.0, 38.7, 62.2, 67.9, 126.9, 127.4 (2C), 128.8
(2C), 141.9, 170.8; MS (ESIþ, m/z): 323 [(M þ Na)þ, 100%]; HRMS
(ESIþ, m/z) calcd for (C14H20NaO5S)þ [(M þ Na)þ]: 323.0924;
NMR (CDCl3, 75.5 MHz): δ 36.8, 37.1, 39.2, 39.8, 58.8, 60.0, 71,6,
126.2, 127.3 (2C), 128.4 (2C), 143.8, 169.4; MS (ESIþ, m/z): 274
[(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C14H21-
NNaO3)þ [(M þ Na)þ]: 274.1414; found: 274.1412; [R]D þ1.2
20
(c 0.5, EtOH) for >99% ee.
Synthesis of (S)-[(5-Methoxyacetyl)amino]-3-phenylpen-
tyl Methanesulfonate (20). To a solution of (S)-19 (57 mg,
0.23 mmol) in dry CH2Cl2 (2.3 mL) was added pyridine (25 μL, 0.34
mmol) and the mixture was cooled at 0 °C. Then methanesulfonyl chloride
(27 μL, 0.34 mmol) was added and the resulting solution was stirred at
room temperature for 14 h after complete disappearance of the starting
material. The solvent was evaporated by distillation at reduced pressure,
obtaining a crude reaction product that was purified by flash chroma-
tography (100% EtOAc) to yield 57 mg of (S)-(þ)-20 as a colorless oil
(76%). Rf (100% EtOAc): 0.35; IR (NaCl): ν 3407, 2936, 1670, 1535,
1352, 1173, 1116, 968, 735, 704 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz):
δ 1.73ꢀ2.05 (m, 3H), 2.06ꢀ2.23 (m, 1H), 2.70ꢀ2.84 (m, 1H), 2.87 (s,
3H), 3.01ꢀ3.26 (m, 2H), 3.34 (s, 3H), 3.78 (s, 2H), 3.87ꢀ3.99 (m, 1H),
4.02ꢀ4.14 (m, 1H), 6.43 (brs, 1H), 7.10ꢀ7.25 (m, 3H1), 7.26ꢀ7.38
(m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 35.6, 35.9, 36.8, 36.9, 39.7,
58.9, 67.8, 71.7, 126.9, 127.3 (2C), 128.7 (2C), 142.1, 169.2; MS (ESIþ,
m/z): 352 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for
(C15H23NNaO5S)þ [(M þ Na)þ]: 352.1189; found: 352.1193;
20
found: 323.0924. [R]D ꢀ3.6 (c 1.0, EtOH) for >99% ee.
Synthesis of (S)-5-Azido-3-phenylpentyl Acetate (16). To a
solution of compound (R)-(ꢀ)-15 (766 mg, 2.55 mmol) in dry DMF
(10 mL) was added sodium azide (252 mg, 3.83 mmol) under nitrogen
atmosphere, and the resulting suspension stirred at 55 °C during 14 h.
After this time, the reaction was quenched with H2O (25 mL) and the
residue extracted with Et2O (3 ꢁ 25 mL). The organic phases were
combined and dried over Na2SO4, and the solvent was evaporated under
reduced pressure, affording a crude reaction product that was purified by
flash chromatography (10% EtOAc/hexane) to yield 585 mg of
(S)-(ꢀ)-16 as a colorless oil (93%). Rf (10% EtOAc/hexane): 0.34;
20
[R]D þ8.8 (c 0.5, EtOH) for >99% ee.
IR (NaCl): ν 2938, 2098, 1738, 1454, 1368, 1243, 1042, 762, 703 cmꢀ1
;
Synthesis of N-[(S)-5-Azido-3-phenylpentyl]-2-methoxy-
acetamide (21). To a solution of compound (S)-(þ)-20 (45 mg,
0.14 mmol) in dry DMF (1.5 mL) was added sodium azide (14 mg,
0.21 mmol) under nitrogen atmosphere, and the resulting suspension
was stirred at 55 °C during 14 h. After this time, the reaction was
quenched with H2O (25 mL) and the residue extracted with Et2O (3 ꢁ
25 mL). The organic phases were combined and dried over Na2SO4, and
the solvent was evaporated under reduced pressure, affording a crude
reaction product that was purified by flash chromatography (30%
EtOAc/hexane) to yield 36 mg of (S)-(þ)-21 as a colorless oil
(95%). Rf (30% EtOAc/hexane): 0.10; IR (NaCl): ν 3413, 3325,
1H NMR (CDCl3, 300.13 MHz): δ 1.74ꢀ2.07 (m, 7H), 2.74ꢀ2.87 (m,
1H), 2.97ꢀ3.09 (m, 1H), 3.10ꢀ3.21 (m, 1H), 3.80ꢀ3.91 (m, 1H),
3.92ꢀ4.02 (m, 1H), 7.11ꢀ7.18 (m, 2H), 7.18ꢀ7.26 (m, 1H),
7.26ꢀ7.35 (m, 2H); 13C NMR (CDCl3, 75.5 MHz): δ 20.7, 35.1,
35.5, 39.6, 49.1, 62.3, 126.7, 127.4 (2C), 128.6 (2C), 142.2, 170.8; MS
(ESIþ, m/z): 270 [(M þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for
20
(C13H17N3NaO2)þ [(M þ Na)þ]: 270.1213; found: 270.1215. [R]D
ꢀ5.8 (c 1.0, EtOH) for >99% ee.
Synthesis of (S)-5-Amino-3-phenylpentan-1-ol (17). To a
solution of azide (S)-(ꢀ)-16 (565 mg, 2.29 mmol) in MeOH (23 mL)
was added PPh3 (336 mg, 3.43 mmol), and the resulting suspension was
stirred until the triphenylphosphine was completely dissolved. After this
time, H2O (61 μL, 3.43 mmol) was added to the reaction vessel and the
resulting solution stirred at 50 °C for 14 h, until complete disappearance
of the starting material by TLC analysis. Then the solvent was
evaporated by distillation at reduced pressure, obtaining a crude reaction
product that was purified by flash chromatography (100% MeOH to 10%
NH3/MeOH) to yield 362 mg of (S)-(þ)-17 as a colorless oil (88%). Rf
(2% NH3/MeOH): 0.27; IR (NaCl): ν 3357, 3290, 2930, 2869, 1597,
1490, 1451, 1051, 761, 735, 703 cmꢀ1; 1H NMR (CDCl3, 300.13 MHz): δ
1.58ꢀ1.90 (m, 4H), 2.48 (t, 3JHH = 7.2 Hz, 2H), 2.63 (brs, 3H), 2.70ꢀ2.83
(m, 1H), 3.29ꢀ3.48 (m, 2H), 7.05ꢀ7.18 (m, 3H), 7.19ꢀ7.30 (m, 2H);
13C NMR (CDCl3, 75.5 MHz): δ39.5 (4C), 59.6, 126.0, 127.3 (2C), 128.2
(2C), 144.6; MS (ESIþ, m/z): 180 [(M þ H)þ, 100%]; HRMS (ESIþ,
m/z) calcd for (C11H18NO)þ [(M þ H)þ]: 180.1383; found: 180.1381.
2934, 2098, 1669, 1535, 1451, 1262, 1116, 702 cmꢀ1 1H NMR
;
(CDCl3, 300.13 MHz): δ 1.58ꢀ2.06 (m, 4H), 2.61ꢀ2.78 (m, 1H),
2.88ꢀ3.25 (m, 4H), 3.34 (s, 3H), 3.79 (s, 2H), 6.40 (brs, 1H),
7.09ꢀ7.17 (m, 2H), 7.18ꢀ7.25 (m, 1H), 7.26ꢀ7.36 (m, 2H); 13C
NMR (CDCl3, 75.5 MHz): δ 35.6, 36.1, 37.0, 40.8, 49.1, 58.9, 71.7,
126.7, 127.3 (2C), 128.7 (2C), 142.6, 169.2; MS (ESIþ, m/z): 299 [(M
þ Na)þ, 100%]; HRMS (ESIþ, m/z) calcd for (C14H20N4NaO2)þ [(M
þ Na)þ]: 299.1478; found: 299.1476; [R]D þ14.0 (c 0.5, EtOH) for
20
>99% ee.
Synthesis of N-[(R)-5-Amino-3-phenylpentyl]2-methoxy-
acetamide (11a). To a free-air suspension containing the azide
(S)-(þ)-21 (30 mg, 0.11 mmol) and PdꢀC 10% (8 mg) was connected
a H2 balloon at the same time that deoxygentated MeOH (432 μL) was
carefully added to a 25 mL round-bottom flask. The resulting suspension
was stirred at room temperature during 24 h, and after this time, the
reaction was stopped, filtering the mixture through diatomaceous earth.
The solvent was evaporated under reduced pressure, affording 27 mg of
20
[R]D þ6.5 (c 1.0, EtOH) for >99% ee.
Synthesis of N-[(S)-5-Hydroxy-3-phenylpentyl]-2-meth-
oxyacetamide (19). To a solution of compound (S)-(þ)-17
(100 mg, 0.56 mmol) in dry CH2Cl2 (6.0 mL) was added methoxyacetyl
chloride (18, 50 μL, 0.55 mmol) in small portions at 10 min intervals
under nitrogen atmosphere. The mixture was stirred for 4 h at room
temperature and then the solvent evaporated under reduced pressure
obtaining a crude reaction product that was purified by flash chroma-
tography on silica gel (100% EtOAc), affording 92 mg of the amino
amide (S)-(þ)-19 as a yellowish oil (66%). Rf (100% EtOAc): 0.27;
IR (NaCl): ν 3404, 3336, 2933, 1660, 1541, 1451, 1117, 703 cmꢀ1; 1H
NMR (CDCl3, 300.13 MHz): δ 1.67ꢀ1.99 (m, 4H), 2.56ꢀ2.87
(m, 2H), 3.00ꢀ3.24 (m, 2H), 3.31 (s, 3H), 3.33ꢀ3.54 (m, 2H), 3.75
(s, 2H), 6.48 (br s, 1H), 7.09ꢀ7.20 (m, 3H), 7.21ꢀ7.32 (m, 2H); 13C
20
(R)-(ꢀ)-11a as a colorless oil (99%). [R]D ꢀ6.0 (c 1.0, EtOH) for
>99% ee.
Synthesis of Allyl {(S)-5-[(Methoxyacetyl)amino]-3-phe-
nylpentyl}carbamate (12a). To a solution of compound (R)-(ꢀ)-
11a (13 mg, 0.05 mmol) in dry CH2Cl2 (0.5 mL) were successively added
Et3N (9 μL, 0.07 mmol) and allyl chloroformate (8 μL, 0.07 mmol)
under nitrogen atmosphere. The mixture was stirred for 2 h at room
temperature, and after this time, the solvent was evaporated under
reduced pressure, obtaining a crude reaction product that was purified by
flash chromatography (60% EtOAc/hexane to 100% EtOAc) to afford
17 mg of the amido carbamate (S)-(þ)-12a as a colorless oil (98%).
20
[R]D þ3.1 (c 1.0, EtOH) for >99% ee.
5717
dx.doi.org/10.1021/jo2007972 |J. Org. Chem. 2011, 76, 5709–5718

The Journal of Organic Chemistry
ARTICLE
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’ AUTHOR INFORMATION
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Corresponding Authors
*E-mail: vicgotfer@uniovi.es (V.G.-F.); vgs@uniovi.es (V.G.).
Phone: þ34 985 103448. Fax: þ34 985 103448.
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This work was supported by the Spanish Ministerio de
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the Spanish Ministerio de Ciencia e Innovacioꢀn (MICINN) for
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†Dedicated to Francisco Palacios on the occasion of his 60th birthday.
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