Development of a chemoenzymatic strategy for the synthesis of optically active and orthogonally protected polyamines

Article abstract of DOI:10.1016/j.tet.2009.08.001

The chemical preparation and stereoselective enzymatic desymmetrization of a series of prochiral 2-substituted-1,3-propanediamines have been carried out using Pseudomonas cepacia lipase as biocatalyst. Syntheses of novel optically active orthogonally protected di- or triamines have been achieved for the first time with different grade of enantiodiscrimination depending on the C-2 substitution of the propane-1,3-diamine fragment. Final monoselective deprotection reactions of (S)-3-allyl-2-tert-butyl-1-(9-fluorenylmethyl)propane-1,2,3-triyltriscarbamate have allowed us to obtain a panel of novel enantiomerically enriched disubstituted triamines, compounds of difficult access by conventional synthetic methods.

Full text of DOI:10.1016/j.tet.2009.08.001

Tetrahedron 65 (2009) 8393–8401
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of a chemoenzymatic strategy for the synthesis of optically
active and orthogonally protected polyamines
a
a
,
b
b
*
´
´
Eduardo Busto , Vicente Gotor-Fernandez , Jose Montejo-Bernardo , Santiago Garcıa-Granda ,
,
Vicente Gotor a
*
a
´
´
´
´
Departamento de Quımica Organica e Inorganica, Instituto Universitario de Biotecnologıa de Asturias, Universidad de Oviedo, E-33071 Oviedo, Spain
b Departamento de Qu´ımica F´ısica y Anal´ıtica, Universidad de Oviedo E-33071 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2009
Received in revised form 31 July 2009
Accepted 1 August 2009
Available online 6 August 2009
The chemical preparation and stereoselective enzymatic desymmetrization of a series of prochiral
2-substituted-1,3-propanediamines have been carried out using Pseudomonas cepacia lipase as bio-
catalyst. Syntheses of novel optically active orthogonally protected di- or triamines have been achieved
for the first time with different grade of enantiodiscrimination depending on the C-2 substitution of the
propane-1,3-diamine fragment. Final monoselective deprotection reactions of (S)-3-allyl-2-tert-butyl-1-
(9-fluorenylmethyl)propane-1,2,3-triyltriscarbamate have allowed us to obtain
a panel of novel
enantiomerically enriched disubstituted triamines, compounds of difficult access by conventional syn-
thetic methods.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
present in a determined molecule. For example, many carbamates
have been used as protecting groups, preventing the corresponding
Nowadays, preparation of optically pure products is a highly
demanding task, which provides practical solutions for many ne-
cessities in the industrial sector.1 In particular, enantiomerically
pure amines are a class of organic compounds with attractive
synthetic possibilities, having important applications as chiral li-
gands and building blocks for the preparation of agrochemicals,
drugs and fine chemicals in an stereoselective manner.2 A few
chemical strategies have been satisfactorily developed for the
production of this group of nitrogenated compounds3 such as re-
ductive amination of ketones,4 catalytic hydrogenation of imines5
or enamines,6 hydrosilylation of imines or oximes,7 alkylation of
imines8 or amino hydroxylation processes,9 but also in recent years
enzymatic environmentally friendly approaches have offered ade-
quate methodologies for the access to optically active amines
starting from racemic amines, ketones or imines by using lipases,10
transaminases11 or amino oxidases.12
amines from air-sensitive oxidations and allowing easy work-up
procedures of the protected compounds.15
In the challenging search for the synthesis of optically active
diamines,16 we have recently developed
a chemoenzymatic
strategy for the production of optically active aminocarbamates
based on the enzymatic desymmetrization of 2-substituted-1,3-
propanediamines in 1,4-dioxane,17 being found Pseudomonas
cepacia lipase (PCL)18 as an ideal stereoselective biocatalyst for the
alkoxycarbonylation of these prochiral compounds. Here we wish
to report the advances achieved in the asymmetric preparation of
novel optically active diamines and orthogonally protected
triamines.
2. Results and discussion
We focused our initial studies in the synthesis of new optically
active organic compounds comparing the reactivity of a set of di-
amines in the enantioselective desymmetrization reaction cata-
lyzed by P. cepacia lipase. These substrates differ in the C-2
substitution present in the 1,3-diamine fragment, and we have paid
attention to the influence of the heteroatom present in the C-2
position and its corresponding substitution (Scheme 1).
1,2-Diamino and 1,3-diamino compounds play an important
role in medicinal chemistry,13 and can act as precursors in the
synthesis of polyamines, macrocycles and bifunctional chelating
agents.14 Use of different protecting groups is a common strategy
for the preparation of polyfunctional organic compounds such as
peptides or carbohydrates, specially when similar motifs are
Previous results have demonstrated the versatility of PCL in the
stereoselective alkoxycarbonylation of diamines, showing an ex-
cellent enantiopreference towards the pro-R orientation of pro-
chiral 2-substituted-propane-1,3-diamines, specially when phenyl
* Corresponding authors. Tel./fax: þ34 98 5103448.
E-mail address: vgs@fq.uniovi.es (V. Gotor).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.001

8394
E. Busto et al. / Tetrahedron 65 (2009) 8393–8401
Imidazole
DMAP
BuSiMe2Cl
Benzyl chloroformate
Na2CO3
t
t
OH
OH
OSi BuMe2
OSi BuMe2
t
H2, Pd-C 10%
MeOH, rt
H2O, 0 ºC to rt
5 h (87%)
CH2Cl2, rt
5h (85%)
H2N
NH2
NH2
CbzHN
NHCbz
H2N
NH2
CbzHN
NHCbz
24 h (77%)
1
3
2
4a
Mesyl chloride
Pyridine
R
R
R
R
NaN3
tert-Butyl dicarbonate
H2, Pd-C 10%
DMF, 55 ºC
24 h
MeOH, rt
14 h (92%)
CH2Cl2, 0 ºC to rt
24 h (83-85%)
MeOH, rt
24 h (82-90% for
two steps)
N3 N3
H2N
NH2
HO
OH
HO
OH
MsO
OMs
7a, R= OMe
9a, R= OMe
4b, R= OMe
6
8a, R= OMe
7b, R= NHBoc
9b, R= NHBoc
8b, R= NHBoc
4c, R= NHBoc
LiAlH4, Et2O, 0 ºC to rt, 24 h (66%)
OMe
MeO
OMe
O
O
5
Scheme 1. Chemical synthesis of diamines 4a–c.
rings were considered in the C-2 position. For that reason we de-
cided to study the enzymatic desymmetrization of diamines with
heteroatoms in the C-2 position such as oxygen or nitrogen, which
are protected as the corresponding silyl ether (OSitBuMe2), or
present as a methoxy group (OMe) or a N-tert-butoxycarbonyl
substitution (NHBoc). Then we started the synthesis of the aimed
diamines and our first choice was 2-(tert-butyldimethylsilyloxy)-
propane-1,3-diamine (4a) that can be easily accessible in good
overall yield from 2-hydroxy-1,3-diaminopropane (1) by selective
N-protection with benzyl chloroformate,19 next O-protection using
tert-butyldimethylsilyl chloride (tBuMe2SiCl) and final removal of
the benzyloxycarbonyl (Cbz) group in hydrogenolysis conditions
catalyzed by Pd–C (Scheme 1).
It has to be pointed out that the selective O-protection was di-
rectly attempted from 1 but the resulting diamine 4a could not be
isolated in high purity from the reaction mixture. Therefore we
decided to carry out the synthesis through the three mentioned
steps. This issue is critical because diamines present usually serious
drawbacks at the purification step by flash chromatography or
extraction protocols, so we must afford the desired diamino com-
pound after a clean reaction before running out the enzymatic
processes. A hydrogenation process is an ideal manner as the di-
amine can be nicely purified by a simple filtration using CeliteÒ,
allowing an easy and rapid handling of the diamine.
Next the preparations of prochiral 4b–c were undertaken,
compounds that differ from diamine 4a in the substitution present
in the oxygen atom (OMe instead of OtBuSiMe2) or in the hetero-
atom directly bounded to the C-2 position of the 1,3-propanedi-
amine fragment (NHBoc). In this manner for the chemical synthesis
of 4b we selected 2-methoxydimethylmalonate (5) as starting
material, which was reduced using lithium aluminium hydride
(LiAlH4) leading in to the diol 7a in 66% yield and improving the 54%
isolated yield previously reported by Krushinski Jr. and co-
workers.20 Next diprotection with mesyl chloride in the presence of
triethylamine (Et3N), nucleophilic substitution of both meth-
anesulphonyl groups by sodium azide (NaN3) in DMF at 55 ꢀC and
final hydrogenation using Pd–C 10% allowed the recovery of di-
amine 4b in good overall yield. For 4c we followed a similar pro-
tocol to the one described by Benoist and co-workers,21 using
serinol (6) as initial compound for the synthesis. Thus, serinol was
N-Boc-monoprotected forming 7b that was subjected to an iden-
tical reaction sequence than 7a: Protection with mesyl chloride,
nucleophilic substitution and catalytic hydrogenation, affording
diamine 4c in good overall yield.
At this point, the enzymatic desymmetrizations of prochiral
diamines 4a–c were performed using diallyl carbonate, PCL and 1,4-
dioxane at 30 ꢀC, best alkoxycarbonylating agent, biocatalyst and
solvent found for the enantioselective preparation of related 2-
substituted-propane-1,3-diamine structures by enzymatic pro-
cesses (Scheme 2).17 The resulting optically active monocarbamates
11a–c were conveniently derivatized yielding the amidocarba-
mates 12a–c, which were injected in the HPLC for the measurement
of the enantiomeric excesses.
Previously, the racemic compounds 12a–c were prepared in
a two-steps sequence based on the chemical monoacylation of the
prochiral diamines obtaining racemic monoamides 13a–c,22 which
were subsequently transformed into (ꢁ)-12a–c by reaction with
allyl chloroformate in dry dichloromethane.
Lipase-catalyzed desymmetrization reactions gave very differ-
ent results depending on the C-2 substitution present in the 1,3-
propanediamine fragment and the results are summarized in
Table 1.
For all tested substitutions monocarbamates were isolated in
moderate to good yields after a flash chromatography purification
step (40–68%), however PCL displayed absolutely different enantio-
discrimination values, observing the best result when the nitrogen
atom was directly connected to the C-2 atom of the 1,3-propanedi-
amine core (entry 3, 91% ee), meanwhile both substrates with oxygen
substitutions reached the corresponding monocarbamates in 8% and
40% ee for 11a and 11b, respectively.
Previously we found that higher ee were achieved when a sp2
carbon atom was adjacent to the stereogenic centre, observing
a loss of selectivity if an extra methylene group was located be-
tween the aromatic ring and the chiral carbon.17b Thus, the 2-N-
tert-butoxycarbonyl substitution (nitrogen atom adopting a planar
trigonal conformation) led to (þ)-11c in very high enantiomeric
excess in contrast to the low or moderate enantiopreferences ob-
served with the 2-oxygenated derivatives where the oxygen atom
adopt a tetrahedrical diposition in an sp3 hybridization.
The absolute configuration of (þ)-11c was assigned by an X-ray
diffraction analysis of the corresponding Mosher amide (R,R)-15
prepared by reaction of the mentioned compound with (S)-(þ)-
methoxy- -trifluoromethylphenyl acetic acid chloride (14) and
later purification by a crystrallization process (Scheme 2). As can be
a-
a

E. Busto et al. / Tetrahedron 65 (2009) 8393–8401
8395
Benzoyl chloride
R
R
or benzoic anhydride
Et3N
R
O
PCL
*
*
+
O
NH NH2
O
NH HN
1,4-dioxane, 70 h
30 ºC, 250 rpm
(40-68%)
CH2Cl2, 4 h
rt (60-92%).
O
O
H2N
NH2
10
O
O
O
(_)-12a, R= OSi BuMe2
t
t
t
4a, R= OSi BuMe2
4b, R= OMe
4c, R= NHBoc
(_)-11a, R= OSi BuMe2
(_)-12b, R= OMe
(_)-11b, R= OMe
(_)-12c, R= NHBoc
(+)-11c, R= NHBoc
R
R
Allyl chloroformate
R
Benzoic anhydride
Pyridine
H2N HN
O
NH HN
CH2Cl2, 4 h
rt (20-31%).
CH2Cl2, 4 h
rt (75-84%);
H2N
NH2
O
O
O
t
t
t
( )-12a, R= OSi BuMe2
( )-12b, R= OMe
( )-12c, R= NHBoc
( )-13a, R= OSi BuMe2
( )-13b, R= OMe
( )-13c, R= NHBoc
4a, R= OSi BuMe2
4b, R= OMe
4c, R= NHBoc
O
O
HN
O
HN
O
O
DMAP
+
F3C
Cl
OMe
CH2Cl2
rt (80%)
F3C OMe
O
NH HN
O
NH NH2
O
O
O
(S)-14
(R,R)-15
(R)-11c
Scheme 2. Enzymatic enantioselective desymmetrization of diamines 4a–c, chemical synthesis of racemic amidocarbamates 12a–c, and preparation of Mosher derivative (R,R)-15
from optically active (R)-11c.
Table 1
As far as we know, this is the first synthetic example of an op-
tically active triamine orthogonally protected with different rests in
its three amino groups. Some other researchers have prepared
optically active triamines although there are non-examples of three
different protecting groups at the same time.25 With this ortho-
gonally protected triamine in hand, we explored the possibility of
monoselectively release each of the three carbamate functional-
ities. Deprotection in mild reaction conditions is mandatory for the
survival of sensitive functionalities.
Enzymatic desymmetrization of diamines 4a–c using PCL, diallyl carbonate and 1,4-
dioxane at 30 ꢀC
Entry
R
ee (%)a
Isolated Yield (%)b
1
2
3
OSitBuMe2 (4a)
OMe (4b)
8
40
91
62
40
68
NHBoc (4c)
a
Determined by HPLC after convenient derivatization.
Isolated yield by flash chromatography.
b
For instance, by simply treating (S)-16 with phosphoric acid
(H3PO4) in THF after 2 h at room temperature, the tert-butoxy-
carbonyl group was released and (S)-17 isolated in 85% yield.26
Alternatively the allyloxycarbonyl group (Aloc) was cleavaged by
reaction with 1,3-dimethylbarbituric acid in the presence of palla-
dium (II) acetate and triphenylphosphine (PPh3) at 35 ꢀC obtaining
(S)-18 in 80% yield.27 Finally smooth deprotection of the 9-fluo-
renylmethyloxycarbonyl (Fmoc) group of triamine (S)-16 was ach-
ieved by using a 20% solution of piperidine in DMF isolating the
already described (R)-11c in 85% yield.
This synthetic approach allowed us to recover enantiomerically
enriched diprotected triamines (N-Fmoc, N-Boc, N-Fmoc, N-Aloc or
N-Aloc, N-Boc derivatives), which evidence the versatility and po-
tential of this chemoenzymatic route as nitrogen atoms can be
functionalized at wish by means of a protection–deprotection
strategy.
Figure 1. X-ray structure obtained for (R,R)-15 obtained from optically active (R)-11c
by reaction with (S)-(þ)-14.
seen in Figure 1, both stereogenic centres from the acid residue
and the 2-position of the diamine fragment present a (R)-
configuration.23
3. Conclusions
Establishing conditions for cleavage of protecting groups are
critical for the production of important polyfunctionalized scaf-
folds, key components for many areas in organic chemistry.
Orthogonally protected triamines have been less investigated than
diamines although they present potential applications in medicinal,
supramolecular and combinatorial chemistry.24 Therefore, we de-
cided to prepare the orthogonally protected triamine (S)-16 by
protecting the free amino group of (R)-11c using 9-fluorenylmethyl
chloroformate in the presence of sodium bicarbonate (NaHCO3) at
room temperature (Scheme 3).
In summary, a chemoenzymatic approach has been described
for the synthesis of optically active carbamates. A great influence in
the lipase-mediated desymmetrization has been observed
depending on the substitution present in the C-2 position of the
1,3-propanediamine fragment. Therefore, we have accomplished
the synthesis of a fully orthogonally protected triamine, which later
has been monoselectively deprotected under mild reaction condi-
tions obtaining three optically active amino compounds. This
strategy leads for the first time to optically active compounds,
which are very difficult to obtain by conventional stereoselective

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E. Busto et al. / Tetrahedron 65 (2009) 8393–8401
NH2
H3PO4
THF
2 h, rt (85%)
O
NH HN
O
O
O
(S)-17
O
O
O
1,3-Dimethylbarbituric
acid, Pd(OAc)2, PPh3
9-Fluorenylmethyl
HN
O
O
O
HN
HN
O
chloroformate, NaHCO3
CH2Cl2, 35 ºC
4 h (80%)
H2O, 1,4-dioxane
rt, 6 h (83%)
O
NH NH2
O
NH HN
O
H2N HN
O
O
O
O
(R)-11c
(S)-16
(S)-18
O
HN
O
Piperidine, DMF
15 min, rt (85%).
O
O
NH NH2
(R)-11c
Scheme 3. Chemical synthesis of triamine (S)-16 and monoselective deprotection reactions.
synthetic methods and suitable for performing additional modifi-
cations in the triamine core.
flash chromatography (50% EtOAc/hexane) affording 2 as a white
solid (3.46 g, 87%). Rf (50% EtOAc/hexane): 0.23; mp: 125–127 ꢀC; IR
(KBr): nmax/cmꢂ1 3359, 1701, 1545, 1324, 1256 and 1175; dH
(300.13 MHz, CDCl3, Me4Si): 3.25–3.38 (m, 4H), 3.62 (br s, 1H),
3.76–3.81 (m, 1H), 5.09 (s, 4H), 5.53–5.55 (br s, 2H), 7.29–7.38 (m,
10H); dC (75.5 MHz, CDCl3, Me4Si): 43.6 (2CH2), 66.9 (2CH2), 70.3
(CH), 128.0 (4CH), 128.1 (2CH), 128.5 (4CH), 136.1 (2C), 157.5 (2C);
MS (ESIþ, m/z): 359 [(MþH)þ, 100%]; HRMS (ESIþ) calcd for
C19H22NaN2O5 (MþNa)þ: 381.1433; found: 381.1421.
4. Experimental section
4.1. General
P. cepacia lipase immobilized over ceramics (PCL or also PSL-C
I, 1638 U/g) was used for the desymmetrization procedures. All
other reagents were purchased from different commercial sour-
ces and used without further purification. Solvents were distilled
over an adequate desiccant under nitrogen. Flash chromatogra-
phies were performed using silica gel 60 (230–240 mesh).
Melting points were taken on samples in open capillary tubes
and are uncorrected. IR spectra were recorded on using NaCl
plates or KBr pellets. 1H, 13C NMR, DEPT were obtained using
4.3. Benzyl 2-(tert-butyldimethylsilyloxy)propane-1,3-
diyldicarbamate (3)
Over a solution of 2 (1.00 g, 2.77 mmol) in CH2Cl2 (25 mL) at 0 ꢀC
was added imidazol (566 mg, 8.33 mmol), DMAP (67 mg,
0.27 mmol) and tert-butyldimethylsilyl chloride (666 mg,
5.55 mmol). The solution was stirred for 5 h at room temperature,
after this time the solvent was removed by distillation at reduced
pressure obtaining a crude that was purified by flash chromato-
graphy (10–30% EtOAc/hexane) affording 3 as a white solid (1.11 g,
a
Bru¨ ker NAV-300 spectrometer (1H, 300.13 MHz and 13C,
75.5 MHz) or a Bru¨ ker NAV-400 spectrometer (1H, 400.13 MHz
and 13C, 100.6 MHz). The chemical shifts are given in delta (
d
)
values and the coupling constants (J) in Hertz (Hz). ESIþ, EIþ,
APCIþ or APCIꢂ experiments using a liquid chromatograph mass
detector were performed to record mass spectra (MS). High
resolution mass spectra (HRMS) experiments were measured by
ESIþ. Measurement of the optical rotation was done in a Perkin–
Elmer 241 polarimeter. High performance liquid chromatography
(HPLC) analyses were carried out in a liquid chromatograph UV
detector at 210 nm using a CHIRALCEL OD or a CHIRALPAK AS
column (25 cmꢃ4.6 mm I.D.), conditions and retention times are
given in the Supplementary data.
85%). Rf (20% EtOAc/hexane): 0.21; mp: 87–89 ꢀC; IR (KBr): nmax
/
cmꢂ1 3367, 1697, 1532, 1291 and 1192; dH (300.13 MHz, CDCl3,
Me4Si): 0.11 (s, 6H), 0.91 (s, 9H), 2.97–3.07 (m, 2H), 3.41–3.52 (m,
2H), 3.87–3.92 (m,1H), 5.12 (AB system, JAB¼12.4 Hz, 4H), 5.31 (br s,
2H), 7.31–7.39 (m, 10H); dC (75.5 MHz, CDCl3, Me4Si): ꢂ5.2 (2CH3),
17.7 (C), 25.4 (3CH3), 43.0 (2CH2), 66.5 (2CH2), 69.2 (CH), 127.7
(4CH), 127.8 (2CH), 128.2 (4CH), 136.1 (2C), 156.6 (2C); MS (ESIþ,
m/z): 473 [(MþH)þ, 100%].
4.4. 2-(tert-Butyldimethylsilyloxy)propane-1,3-diamine (4a)
4.2. Benzyl 2-hydroxypropane-1,3-diyldicarbamate (2)
To a suspension containing dicarbamate 3 (800 mg, 1.69 mmol)
and Pd–C 10% (120 mg) in a 100 mL round-bottom flask a H2 bal-
loon was connected and deoxygenated MeOH (8.0 mL) was care-
fully added. The resulting suspension was stirred at room
temperature during 24 h and after this time the reaction was
stopped filtering the mixture through CeliteÒ. The solvent was
evaporated under reduced pressure affording 4a as a colourless oil
(266 mg, 77%). Rf (2% NH3/MeOH): 0.21; dH (300.13 MHz, CD3OD,
Over a solution of 2-hydroxy-1,3-diaminopropane (1, 1.00 g,
11.1 mmol) and Na2CO3 (2.82 g, 26.64 mmol) in H2O (19 mL) at 0 ꢀC
was added benzyl chloroformate (3.25 mL, 26.64 mmol). The so-
lution was stirred for 5 h at room temperature, after this time it was
extracted with CH2Cl2 (3ꢃ20 mL), the organic phases were com-
bined, dried over Na2SO4 and the solvent was removed by distil-
lation at reduced pressure obtaining a crude that was purified by

E. Busto et al. / Tetrahedron 65 (2009) 8393–8401
8397
Me4Si): 0.31 (s, 6H), 1.12 (s, 9H), 2.81–2.95 (m, 4H), 3.83–4.95 (m
(75.5 MHz, CDCl3, Me4Si): 28.2 (3CH3), 37.5 (2CH3), 48.4 (CH), 66.8
(2CH2), 80.9 (C), 154.8 (C); MS (ESIþ, m/z): 348 [(MþH)þ, 40%], 248
[(MꢂNHBoc)þ, 100%].
1H); dC (75.5 MHz, CD3OD, Me4Si):
d
ꢂ3.1 (2CH3), 20.2 (CH), 28.7
(3CH3), 46.9 (2CH2), 76.4 (CH).
4.5. 2-Methoxypropane-1,3-diol (7a)
solution of 2-methoxydimethylmalonate (5, 387
4.9. 2-Methoxypropane-1,3-diazide (9a)
A
mL,
To a solution under nitrogen atmosphere of compound 8a
(392 mg, 1.50 mmol) in dry DMF (7.5 mL) was added sodium
azide (1.26 g, 19.32 mmol), and the resulting suspension was
stirred at 55 ꢀC during 24 h. After this time the reaction was
quenched with H2O (50 mL) and the residue was extracted with
Et2O (3ꢃ50 mL). The organic phases were combined and dried
over Na2SO4, the solvent evaporated under reduced pressure
affording a crude that was purified by flash chromatography (5%
EtOAc/hexane). The azide fractions were carefully evaporated
under reduced pressure avoiding complete dryness and the hy-
drogenation step was performed at this stage without further
manipulation of this unstable compound. Rf (5% EtOAc/hexane):
2.8 mmol) in dry Et2O (11 mL) was cooled to 0 ꢀC and LiAlH4
(425 mg, 11.2 mmol) was carefully added during 15 min. The
resulting solution was stirred for 24 h at room temperature and
then the reaction was stopped adding H2O (1.5 mL) at 0 ꢀC. Salts
were filtered off through Celite, and the filtrate was washed with
Et2O (6ꢃ10 mL). Organic phases were combined, dried over Na2SO4
and the solvent evaporated under reduced pressure obtaining
a reaction crude that was purified by flash chromatography (20%
MeOH/EtOAc), affording 7a as a colourless oil (196 mg, 66%). Rf (20%
MeOH/EtOAc): 0.33; IR (NaCl): nmax/cmꢂ1 3383, 2940, 1124 and
1069; dH (300.13 MHz, CDCl3, Me4Si): 2.06–2.10 (t, 3JHH¼5.9 Hz, 2H),
3
3
3.36–3.43 (q, JHH¼6.3 Hz, 1H), 3.50 (s, 3H), 3.68–3.86 (m, 4H); dC
0.16; dH (300.13 MHz, CDCl3, Me4Si): 3.37 (d, JHH¼6.7 Hz, 4H),
(75.5 MHz, CDCl3, Me4Si): 57.3 (2CH2), 61.2 (CH3), 81.2 (CH); MS
3.48–3.53 (m, 4H); dC (75.5 MHz, CDCl3, Me4Si): d 50.8 (2CH2),
(ESIþ, m/z): 107 [(MþH)þ, 100%].
58.4 (CH3), 78.8 (CH).
4.6. tert-Butyl 1,3-dihydroxypropan-2-yl carbamate (7b)19
4.10. tert-Butyl 1,3-diazidopropan-2-yl carbamate (9b)
To a solution of serinol (6, 1.00 g, 11.0 mmol) in MeOH (50 mL)
was added tert-butyl dicarbonate (2.63 g, 12.1 mmol) and this so-
lution was stirred for 14 h at room temperature. After this time the
solvent was removed by distillation at reduced pressure obtaining
a crude that was purified by flash chromatography, affording 7b as
a white solid (1.92 g, 92%). Rf (5% MeOH/CH2Cl2): 0.29; mp: 84–
85 ꢀC; IR (NaCl): nmax/cmꢂ1 3410, 1686, 1531, 1250 and 1168; dH
(300.13 MHz, CDCl3, Me4Si): 1.42 (s, 9H), 3.30 (br s, 2H), 3.41–3.74
To a solution of compound 8b (750 mg, 2.25 mmol) in dry DMF
(11.0 mL) sodium azide (871 mg, 13.56 mmol) was added under
nitrogen atmosphere, and the resulting suspension was stirred at
55 ꢀC during 24 h. After this time the reaction was quenched with
H2O (25 mL) and the residue was extracted with Et2O (3ꢃ25 mL).
The organic phases were combined and dried over Na2SO4, the
solvent evaporated under reduced pressure, affording a crude that
was purified by flash chromatography (5% EtOAc/hexane). The
azide fractions were carefully evaporated under reduced pressure
avoiding complete dryness, and the hydrogenation step was per-
formed at this stage without further manipulation of this unstable
compound. Rf (5% EtOAc/hexane): 0.23; dH (300.13 MHz, CDCl3,
Me4Si): 1.48 (s, 9H), 3.41–3.53 (m, 4H), 3.78–3.89 (m,1H), 4.81 (br s,
1H); dC (75.5 MHz, CDCl3, Me4Si): 27.9 (3CH3), 49.1 (CH), 51.3
(2CH2), 79.9 (C), 154.6 (C).
(m, 5H), 5.31 (br s, 1H); dC (75.5 MHz, CDCl3, Me4Si):
d 28.4 (3CH3),
53.2 (CH), 63.0 (2CH2), 79.9 (C), 156.5 (C); MS (ESIþ, m/z): 192
[(MþH)þ, 100%].
4.7. 2-Methoxypropane-1,3-diyl dimethyl bissulfate (8a)
To a solution of diol 7a (250 mg, 2.35 mmol) in dry CH2Cl2
(15 mL) was added pyridine (733
m
L, 9.35 mmol), and the mixture
was cooled at 0 ꢀC. Then mesyl chloride (716
mL, 9.35 mmol) was
4.11. 2-Methoxypropane-1,3-diamine (4b)
added and the resulting solution was stirred at room temperature
for 24 h after complete disappearance of the starting material. The
solvent was evaporated by distillation at reduced pressure,
obtaining a reaction crude that was purified by flash chromato-
graphy (50% EtOAc/hexane), yielding 8a as a colourless oil (523 mg,
85%). Rf (50% EtOAc/hexane): 0.17; IR (NaCl): nmax/cmꢂ1 3431, 1630,
1335 and 1166; dH (300.13 MHz, CDCl3, Me4Si): 2.99 (s, 6H), 3.39 (s,
3H), 3.61–3.69 (m, 1H), 4.16–4.30 (m, 4H); dC (75.5 MHz, CDCl3,
Me4Si): 36.9 (2CH3), 57.7 (CH3), 66.9 (2CH2), 75.9 (CH); MS (ESIþ,
m/z): 263 [(MþH)þ, 100%].
To a suspension containing azide 9a (1.65 mmol) and Pd–C 10%
(130 mg) in a 100 mL round-bottom flask, was connected a H2
balloon and deoxygenated MeOH was carefully added (6.5 mL). The
resulting suspension was stirred at room temperature during 24 h
and after this time the reaction was stopped filtering the mixture
through CeliteÒ. The solvent was evaporated under reduced pres-
sure affording 4b as a colourless oil (257 mg, 82% for two steps). Rf
(5% NH3/MeOH): 0.21; dH (300.13 MHz, CD3OD, Me4Si): 2.80–2.97
(m, 4H), 3.32–3.41 (m, 1H), 3.64 (s, 3H); dC (75.5 MHz, CD3OD,
Me4Si): 44.2 (2CH2), 59.0 (CH3), 85.2 (CH).
4.8. 2-(tert-Butoxycarbonylamino)propane-1,3-diyl
dimethanesulfonate (8b)
4.12. tert-Butyl 1,3-diaminopropan-2-ylcarbamate (4c)
To a solution of diol 7b (1.64 g, 8.60 mmol) in dry CH2Cl2 (50 mL)
pyridine (4.3 mL, 34.23 mmol) was added and the mixture was
cooled at 0 ꢀC. Then mesyl chloride (4.4 mL, 34.23 mmol) was
added and the resulting solution was stirred at room temperature
for 24 h after complete disappearance of the starting material. The
solvent was evaporated by distillation at reduced pressure,
obtaining a reaction crude that was purified by flash chromato-
graphy (2% MeOH/CH2Cl2), yielding 8b as a white solid (2.45 g,
To a suspension containing azide 9b (1.51 mmol) and Pd–C
10% (115 mg) in a 100 mL round-bottom flask a H2 balloon was
connected and deoxygenated MeOH (6.0 mL) was also carefully
added. The resulting suspension was stirred at room temperature
during 24 h and after this time the reaction was stopped filtering
the mixture through CeliteÒ. The solvent was evaporated under
reduced pressure affording 4c as a colourless oil (232 mg, 90% for
two steps). Rf (5% NH3/MeOH): 0.22; dH (400.13 MHz, CD3OD,
Me4Si): 1.61 (s, 9H), 2.72–2.87 (m, 4H), 3.62–3.68 (m, 1H); dC
(100.6 MHz, CD3OD, Me4Si): 30.0 (3CH3), 45.5 (2CH2), 57.8 (CH),
81.3 (C), 159.7 (C).
83%). Rf (5% MeOH/CH2Cl2): 0.29; mp: 99–100 ꢀC; IR (KBr): nmax
/
cmꢂ1 1694, 1526, 1534 and 1175; dH (300.13 MHz, CDCl3, Me4Si):
1.47 (s, 9H), 3.09 (s, 6H), 4.22–4.39 (m, 5H), 5.02 (br s, 1H); dC

8398
E. Busto et al. / Tetrahedron 65 (2009) 8393–8401
4.13. (L)-Allyl (3-amino-2-(tert-butyldimethylsilyloxy)-
propyl)carbamate [(L)-11a]
4.16. (L)-Allyl [3-(benzoylamino)-2-(tert-
butyldimethylsilyloxy)propyl]carbamate [(L)-12a]
To a suspension of diamine 4a (146 mg, 0.71 mmol) and PCL
To a solution of compound (ꢂ)-11a (60 mg, 0.20 mmol) in dry
(213 mg) in dry 1,4-dioxane (7.1 mL), diallyl carbonate (100
m
L,
CH2Cl2 (2.0 mL) under nitrogen atmosphere NEt3 (54 mL,
0.71 mmol) was added 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 70 h, the enzyme was filtered off and washed
with MeOH (3ꢃ10 mL). The solvent was evaporated under re-
duced pressure and the resulting crude was purified by flash
chromatography (60% MeOH/EtOAc), affording monoamine
(ꢂ)-11a as a colourless oil (126 mg, 62% isolated yield, 8% ee). Rf
(60% MeOH/EtOAc): 0.24; IR (NaCl): nmax/cmꢂ1 3435, 1715,
1545, 1399 and 1253; dH (300.13 MHz, CDCl3, Me4Si): 0.07 (s,
6H), 0.89 (s, 9H), 1.55 (br s, 2H), 2.64–2.78 (m, 2H), 3.18–3.35
0.40 mmol) and benzoyl chloride (28 mL, 0.24 mmol) were suc-
cessively added. The mixture was stirred for 4 h at room tem-
perature and after this time the solvent was evaporated under
reduced pressure, obtaining a reaction crude that was purified by
flash chromatography (30% EtOAc/hexane) affording amidocarba-
mate (ꢂ)-12a as a white solid (65 mg, 83%). Rf (30% EtOAc/hex-
ane): 0.23; mp: 121–123 ꢀC; IR (NaCl): nmax/cmꢂ1 3435, 1734,
1545, 1324 and 1211; dH (300.13 MHz, CDCl3, Me4Si): 0.14 (s, 6H),
0.93 (s, 9H), 2.97–3.10 (m, 2H), 3.52–3.59 (m, 1H), 3.88–3.97 (m,
2H), 4.58–4.61 (m, 2H), 5.21–5.42 (m, 3H), 5.87–6.00 (m, 1H), 7.05
3
(br s, 1H), 7.40–7.51 (m, 3H), 7.83 (d, JHH¼7.2 Hz, 2H); dC
3
(m, 2H), 3.71–3.75 (m, 1H), 4.55 (d, JHH¼5.0 Hz, 2H), 5.21–5.32
(75.5 MHz, CDCl3, Me4Si): ꢂ4.4 (2CH3), 18.4 (C), 26.2 (2CH3), 42.1
(m, 3H), 5.86–5.98 (m, 1H); dC (75.5 MHz, CDCl3, Me4Si): ꢂ4.7
(CH2), 44.0 (CH2), 66.2 (CH2), 69.0 (CH), 118.2 (CH2), 127.4 (2CH),
(2CH3), 18.0 (C), 25.8 (3CH3), 44.1 (CH2), 45.2 (CH2), 65.3 (CH2),
129.0 (2CH), 132.0 (CH), 133.1 (CH), 134.5 (C), 157.6 (C), 168.0 (C);
20
72.2 (CH2), 117.6 (CH2), 132.9 (CH), 156.5 (C); MS (ESIþ, m/z):
MS (ESIþ, m/z): 392 [(MþH)þ, 100%]; [
a]
¼ꢂ1.3 (c 1.0, CH2Cl2) for
D
288 [(MþH)þ, 100%]; [
a
]
¼ꢂ1.5 (c 1.0, CHCl3) for 8% ee.
8% ee.
20
D
4.14. (L)-Allyl (3-amino-2-methoxypropyl)-
carbamate [(L)-11b]
4.17. (L)-Allyl [3-(benzoylamino)-2-methoxypropyl]-
carbamate [(L)-12b]
To a suspension of diamine 4b (52 mg, 0.50 mmol) and PCL
(150 mg) in dry 1,4-dioxane (5.0 mL) was added diallyl carbonate
(70 mL, 0.50 mmol) under nitrogen atmosphere, and the mixture
To a solution of compound (R)-(ꢂ)-11b (22 mg, 0.12 mmol) in
dry CH2Cl2 (1.0 mL) under nitrogen atmosphere were successively
added NEt3 (13 mL, 0.14 mmol) and benzoyl chloride (16 mL,
was shaken at 30 ꢀC and 250 rpm, following the progress of the
reaction by TLC analysis. The reaction was stopped after 70 h,
the enzyme was filtered off and washed with MeOH (3ꢃ5 mL). The
solvent was evaporated under reduced pressure and the resulting
crude was purified by flash chromatography (70% MeOH/EtOAc),
affording monoamine (ꢂ)-11b (38 mg, 40% isolated yield, 40% ee).
Rf (70% MeOH/EtOAc): 0.15; IR (NaCl): nmax/cmꢂ1 3325, 2943, 1075,
1616, 1525, 1234 and 1021; dH (300.13 MHz, CDCl3, Me4Si): 1.51 (br
0.14 mmol). The mixture was stirred for 4 h at room temperature
and after this time the solvent was evaporated under reduced
pressure obtaining a reaction crude that was purified by flash
chromatography (60% EtOAc/hexane) affording monoamide
(ꢂ)-12b as a colourless oil (30 mg, 84%). Rf (60% EtOAc/hex-
ane): 0.21; IR (NaCl): nmax/cmꢂ1 3320, 1701, 1635, 1522 and
1236; dH (300.13 MHz, CDCl3, Me4Si): 3.17–3.31 (m, 2H), 3.45 (s,
3H), 3.47–3.53 (m, 2H), 3.90–3.99 (m,1H), 4.62 (d, 3JHH¼5.3 Hz, 2H),
5.23–5.37 (m, 2H), 5.45 (br s, 1H), 5.88–5.99 (m, 1H), 7.05 (br s, 1H),
3
s, 2H), 2.73–2.87 (m, 2H), 3.23–3.50 (m, 6H), 4.53 (d, JHH¼5.3 Hz,
2H), 5.15–5.33 (m, 3H), 5.87–5.99 (m, 1H); dC (75.5 MHz, CDCl3,
3
7.44–7.53 (m, 3H), 7.85 (d, JHH¼5.3 Hz, 2H); dC (75.5 MHz, CDCl3,
Me4Si): 41.3 (CH2), 42.4 (CH2), 57.2 (CH3), 65.5 (CH2), 80.5 (CH),
Me4Si): 36.7 (CH2), 40.3 (CH2), 57.2 (CH3), 65.7 (CH2), 77.7 (CH),
117.7 (CH2), 126.9 (2CH), 128.5 (2CH), 131.5 (CH), 133.1 (CH), 134.0
117.6 (CH2), 132.8 (CH), 156.5 (CH); MS (ESIþ, m/z): 189 [(MþH)þ,
20
100%]; MS (ESIþ, m/z): 263 [(MþH)þ, 100%]; [
a
]
¼ꢂ1.5 (c 1.0,
D
(C), 157.1 (C), 167.7 (C); MS (ESIþ, m/z): 293 [(MþH)þ, 100%];
CHCl3) for 40% ee.
20
[a
]
¼ꢂ1.9 (c 1.0, CHCl3) for 40% ee.
D
4.15. (R)-(D)-Allyl tert-butyl (3-aminopropane-1,2-
diyl)biscarbamate [(R)-(D)-11c]
4.18. (R)-(L)-Allyl [3-(benzoylamino)-2-(tert-
butoxycarbonylamino)propyl]carbamate [(R)-(L)-12c]
To a suspension of diamine 4c (307 mg, 1.71 mmol) and PCL
(513 mg) in dry 1,4-dioxane (17.1 mL), diallyl carbonate (245
m
L,
To a solution of compound (R)-(þ)-11c (40 mg, 0.15 mmol) in
1.71 mmol) was added 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 70 h, the enzyme was filtered off and washed
with MeOH (3ꢃ25 mL). The solvent was evaporated under re-
duced pressure and the resulting crude was purified by flash
chromatography (60% MeOH/EtOAc), affording monoamine (R)-
(þ)-11c as a colourless oil (317 mg, 68% isolated yield, 91% ee).
Rf (60% MeOH/EtOAc): 0.24; IR (NaCl): nmax/cmꢂ1 3335, 2978,
1699, 1531, 1456, 1367, 1253 and 1170; dH (300.13 MHz, CDCl3,
Me4Si): 1.41 (s, 9H), 2.10 (br s, 2H), 2.69–2.78 (m, 2H), 3.20–
3.44 (m, 2H), 3.54–3.60 (m, 1H), 4.55 (d, 3JHH¼5.0 Hz, 2H), 5.16–
5.29 (m, 3H), 5.48 (m, 1H), 5.83–5.93 (m, 1H); dC (75.5 MHz,
CDCl3, Me4Si): 28.2 (3CH3), 42.6 (2CH2), 52.5 (CH), 65.5 (CH2),
79.3 (C), 117.5 (CH2), 132.7 (CH), 156.1 (C), 156.9 (C); MS (APCIþ,
dry CH2Cl2 (2.0 mL) under nitrogen atmosphere NEt3 (26 mL,
0.18 mmol) and benzoic anhydride (42 mg, 0.18 mmol) were
successively added. The mixture was stirred for 4 h at room
temperature and after this time the solvent was evaporated
under reduced pressure, obtaining a reaction crude that was
purified by flash chromatography (50% EtOAc/hexane) affording
amidocarbamate (R)-(ꢂ)-12c as a colourless oil (52 mg, 92%). Rf
(50% EtOAc/hexane): 0.21; IR (NaCl): nmax/cmꢂ1 3341, 1682, 1539
and 1266; dH (300.13 MHz, CDCl3, Me4Si): 1.49 (s, 9H), 3.28–3.51
3
(m, 3H), 3.71–3.84 (m, 2H), 4.60 (d, JHH¼5.0 Hz, 2H), 5.18–5.38
(m, 2H), 5.69–5.75 (br s, 2H), 5.90–6.00 (m, 1H), 7.40–7.61 (m,
3
3H), 7.65 (br s, 1H), 7.85 (d, JHH¼7.1 Hz, 2H); dC (75.5 MHz,
CDCl3, Me4Si): 28.3 (3CH3), 41.0 (CH2), 41.5 (CH2), 52.3 (CH), 65.9
(CH2), 79.8 (C), 117.8 (CH2), 128.5 (2CH), 128.8 (2CH), 131.6 (C),
132.5 (CH), 133.7 (CH), 156.3 (C), 157.7 (C), 168.4 (C); MS (ESIþ,
m/z): 274 [(MþH)þ, 100%]; HRMS (ESIþ) calcd for C12H23NaN3O4
m/z): 378 [(MþH)þ, 100%]; HRMS (ESIþ) calcd for C19H27NaN3O5
20
20
(MþNa)þ: 296.1581; found: 296.1574; [
a
]
¼þ5.0 (c 1.0, EtOH)
(MþNa)þ: 400.1843; found: 400.1854. [
a
]
¼ꢂ2.7 (c 1.0, CH2Cl2)
D
D
for 91% ee.
for 91% ee.

E. Busto et al. / Tetrahedron 65 (2009) 8393–8401
8399
4.19. ( )-N-(3-Amino-2-tert-butyldimethylsilyloxy)-
propylbenzamide (13a)
flash chromatography (100% MeOH) affording amino amide 13c as
a colourless oil (62 mg, 30%). Rf (100%MeOH): 0.21; IR (NaCl): nmax
/
cmꢂ1 3423, 1732, 1644, 1565, 1432, 1389, 1255 and 1146; dH
(300.13 MHz, CDCl3, Me4Si): 1.47 (s, 9H), 1.56 (br s, 2H), 2.83–2.93
(m, 2H), 3.48–3.65 (m, 2H), 3.71–3.85 (m, 1H), 5.55 (br s, 1H), 7.39–
7.54 (m, 4H), 7.82 (d, 3JHH¼7.3 Hz, 2H); dC (75.5 MHz, CDCl3, Me4Si):
28.8 (3CH3), 43.7 (CH2), 44.0 (CH2), 52.2 (CH), 80.2 (C), 127.4 (2CH),
128.9 (2CH), 131.5 (CH), 134.0 (C), 157.4 (C), 168.4 (C); MS (APCIþ,
m/z): 294 [(MþH)þ, 100%].
To a solution of compound 4a (108 mg, 0.53 mmol) in dry CH2Cl2
(2.0 mL) under nitrogen atmosphere was added Bz2O (120 mg,
0.53 mmol) in portions, and the mixture was stirred for 4 h at room
temperature. After this time the solvent was evaporated under
reduced pressure obtaining a reaction crude that was purified by
flash chromatography (20% MeOH/EtOAc) affording racemic amino
amide 13a as a colourless oil (47 mg, 29%). Rf (20% MeOH/EtOAc):
0.18; IR (NaCl): nmax/cmꢂ1 3211, 1710, 1644, 1445, 1320 and 1253; dH
(300.13 MHz, CDCl3, Me4Si): 0.08 (s, 6H), 0.91 (s, 9H), 1.68 (br s, 2H),
2.81 (m, 2H), 3.42–3.72 (m, 2H), 3.83–3.91 (m, 1H), 7.18 (br s, 1H),
4.24. ( )-Allyl [3-(benzoylamino)-2-(tert-
butoxycarbonylamino)propyl]carbamate (12c)
3
7.37–7.57 (m, 3H), 7.76 (d, JHH¼7.2 Hz, 2H); dC (75.5 MHz, CDCl3,
To
0.18 mmol) in dry CH2Cl2 (2.0 mL) under nitrogen atmosphere were
successively added pyridine (15 L, 0.20 mmol) and allyl chloro-
formate (21 L, 0.20 mmol). The mixture was stirred for 4 h at room
a solution of the racemic amino amide 13c (53 mg,
Me4Si): ꢂ4.3 (2CH3), 18.4 (C), 26.2 (3CH3), 44.0 (CH2), 46.0 (CH2),
71.8 (CH), 127.8 (2CH), 129.0 (2CH), 131.8 (CH), 134.9 (C), 168.0 (C);
MS (APCIþ, m/z): 309 [(MþH)þ, 100%].
m
m
temperature and after this time the solvent was evaporated under
reduced pressure obtaining a reaction crude that was purified by
flash chromatography (100% EtOAc) affording amidocarbamate 12c
as a colourless oil (57 mg, 84%).
4.20. ( )-Allyl [3-(benzoylamino)-2-(tert-butyldimethyl-
silyloxy)propyl]carbamate (12a)
Then to a solution of the racemic amino amide 13a (45 mg,
0.14 mmol) in dry CH2Cl2 (2.0 mL) under nitrogen atmosphere were
4.25. (R,R)-Allyl [3-(30,30,30-trifluoromethyl-20-methoxy-20-
phenylpropanoylamino)-2-(tert-butoxycarbonyl-
amino)propyl]carbamate [(R,R)-15]
successively added pyridine (13
mL, 0.17 mmol) and allyl chloro-
formate (18 L, 0.17 mmol). The mixture was stirred for 4 h at room
m
temperature and after this time the solvent was evaporated under
reduced pressure obtaining a reaction crude that was purified by
flash chromatography (30% EtOAc/hexane) affording racemic ami-
docarbamate 12a as a white solid (45 mg, 82%).
To a solution of (R)-(þ)-11c (30 mg, 0.11 mmol) in dry CH2Cl2
(1 mL) was added DMAP (27 mg, 0.22 mmol) and (S)-(þ)-
a-
methoxy-a-trifluoromethylphenyl acetic acid chloride (24 mL,
0.13 mmol). The solution was stirred at room temperature for 4 h
and after this time the solvent was removed by distillation at re-
duced pressure obtaining a reaction crude that was purified by
flash chromatography (80% EtOAc/hexane) affording amidocarba-
mate (R,R)-15 as a white solid (43 mg, 80%, 91% ee). This solid was
recrystallized in a CH2Cl2/hexane mixture obtaining colourless
crystals of diastereomerically pure (R,R)-15, which were suitable for
X-ray monocrystal analysis. dH (300.13 MHz, CDCl3, Me4Si): 1.43 (s,
9H), 3.13–3.18 (m, 1H), 3.32–3.55 (m, 5H), 3.61–3.70 (m, 2H), 4.43–
4.56 (m, 2H), 5.20–5.32 (m, 2H), 5.51 (br s, 1H), 5.58 (br s, 1H), 5.87–
5.93 (m, 1H), 7.41–7.45 (m, 3H), 7.50–7.53 (m, 2H), 7.63 (br s, 1H).
4.21. ( )-N-(3-Amino-2-methoxypropyl)benzamide (13b)
To a solution of compound 4b (48 mg, 0.46 mmol) in dry CH2Cl2
(4.5 mL) under nitrogen atmosphere was added benzoic anhydride
(339 mg, 1.50 mmol), and the mixture was stirred for 4 h at room
temperature and after this time the solvent was evaporated under
reduced pressure obtaining a reaction crude that was purified by
flash chromatography (100% EtOAc to 100% MeOH) affording
monoamide 13b as a colourless oil (29 mg, 31%). Rf (1% NH3/MeOH):
0.18; IR (NaCl): nmax/cmꢂ1 3423, 1780, 1545, 1432 and 1234; dH
(300.13 MHz, CDCl3, Me4Si): 2.00 (br s, 2H), 2.71–2.95 (m, 2H), 3.45
(s, 3H), 3.49–3.91 (m, 2H), 7.20 (br s, 1H), 7.39–7.56 (m, 3H), 7.86 (d,
3JHH¼7.7 Hz, 2H); dC (75.5 MHz, CDCl3, Me4Si): 40.3 (CH2), 40.6
(CH2), 57.4 (CH3), 78.5 (CH), 127.0 (2CH), 128.5 (2CH), 131.2 (CH),
134.5 (C), 167.6 (C); MS (ESIþ, m/z): 209 [(MþH)þ, 100%].
4.26. (S)-3-Allyl-2-tert-butyl-1-(9-fluorenylmethyl)propane-
1,2,3-triyltriscarbamate [(S)-(L)-16]
Over a solution of (R)-(þ)-11c (300 mg, 1.10 mmol) and NaHCO3
(277 mg, 3.30 mmol) in H2O (17 mL) at 0 ꢀC was added dropwise
a solution of 9-fluorenylmethyl chloroformate (1.32 mmol, 341 mg)
in 1,4-dioxane (17 mL). This solution was stirred at room temper-
ature for 6 h, after this time it was extracted with EtOAc (3ꢃ20 mL),
the organic phases were combined, dried over Na2SO4 obtaining
a reaction crude that was purified by flash chromatography (50%
EtOAc/hexane) affording (S)-(ꢂ)-16 as a white solid (453 mg, 83%).
Rf (50% EtOAc/hexane): 0.23; mp: 148–150; IR (KBr): nmax/cmꢂ1
3338, 1699, 1527, 1251 and 1164; dH (300.13 MHz, CDCl3, Me4Si):
1.49 (s, 9H), 3.11–3.42 (m, 3H), 3.61–3.68 (m, 1H), 4.19–4.23 (m, 1H),
4.41 (d, 3JHH¼5.0 Hz, 2H), 4.51–4.54 (m, 2H), 5.17–5.31 (m, 2H), 5.45
(br s, 1H), 5.61–5.73 (br s, 2H), 5.83–5.99 (m, 1H), 7.22–7.41 (m, 4H),
4.22. ( )-Allyl [3-(benzoylylamino)-2-methoxypropyl]-
carbamate (12b)
To a solution of the monoamide 13b (29 mg, 0.14 mmol) in dry
CH2Cl2 (1 mL) under nitrogen atmosphere were successively added
pyridine (12 mL, 0.15 mmol) and allyl chloroformate (16 mL,
0.15 mmol). The mixture was stirred for 4 h at room temperature
and after this time the solvent was evaporated under reduced
pressure obtaining a reaction crude that was purified by flash
chromatography (60% EtOAc/hexane) affording amidocarbamate
12b as a colourless oil (33 mg, 75%).
3
3
4.23. ( )-tert-Butyl 1-amino-3-benzamidopropan-2-
ylcarbamate (13c)
7.60 (d, JHH¼7.2 Hz, 2H), 7.78 (d, JHH¼7.3 Hz, 2H); dC (75.5 MHz,
CDCl3, Me4Si): 28.8 (3CH3), 42.0 (CH2), 42.1 (CH2), 47.6 (CH), 52.5
(CH), 66.3 (CH2), 67.4 (CH2), 80.2 (C), 118.2 (CH2), 120.4 (2CH), 125.4
(2CH), 127.5 (2CH), 127.8 (2CH), 133.1 (CH), 141.7 (2C), 144.2 (2C),
156.4 (C), 157.8 (C), 157.9 (C); MS (APCIꢂ, m/z): 533 [(Mþ37Cl)ꢂ, 33%]
To a solution of compound 4c (142 mg, 0.75 mmol) in dry CH2Cl2
(2.0 mL) under nitrogen atmosphere was added Bz2O (170 mg,
0.75 mmol) in portions, and the mixture was stirred for 4 h at room
temperature. After this time the solvent was evaporated under
reduced pressure obtaining a reaction crude that was purified by
531 [(Mþ35Cl)ꢂ, 100%]; HRMS (ESIþ) calcd for C27H33N3NaO6
20
(MþNa)þ: 518.2267; found: 518.2286. [
a
]
¼ꢂ2.3 (c 1.0, CH2Cl2) for
D
91% ee.

8400
E. Busto et al. / Tetrahedron 65 (2009) 8393–8401
4.27. (S)-Allyl 9-fluorenylmethyl (2-aminopropane-1,3-
diyl)biscarbamate [(S)-(D)-17]
HRMS (ESIþ) calcd for C12H23NaN3O4 (MþNa)þ: 296.1581; found:
20
296.1574. [
a]
¼þ4.7 (c 1.0, EtOH) for 91% ee.
D
Over a solution of (S)-(þ)-16 (50 mg, 0.10 mmol) in THF
Acknowledgements
(100 mL) was added H3PO4 (300 mL), the mixture was stirred for
2 h at room temperature, then the reaction was quenched adding
a saturated solution of NaHCO3 (10 mL). The aqueous phase was
extracted with EtOAc (3ꢃ10 mL), the organic were combined and
dried over Na2SO4, the solvent was removed by distillation at
reduced pressure obtaining a reaction crude that was purified by
flash chromatography (20% MeOH/EtOAc) affording (S)-(þ)-17 as
a colourless oil (34 mg, 85%). Rf (20% MeOH/EtOAc): 0.24; IR
(NaCl): nmax/cmꢂ1 3355, 1687, 1539, 1435, 1342 and 1286; dH
(400.13 MHz, CD3OD, Me4Si): 3.13–3.16 (m, 1H), 3.25–3.38 (m,
Financial support of this work by Spanish Ministerio de Ciencia e
Innovacio´n (MICINN), Project MEC-CTQ 2007-61126, MAT2006-
01997 and ‘Factorı´a de Cristalizacio´n’ Consolider Ingenio 2010, is
gratefully acknowledged. V.G.-F. thanks MEC for a personal grant
(Ramo´n y Cajal Program).
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.08.001.
3
4H), 4.39–4.45 (m, 1H), 4.58–4.61 (m, 2H), 4.73 (d, JHH¼5.0 Hz,
2H), 5.35–5.51 (m, 2H), 6.07–6.16 (m, 1H), 7.48–7.59 (m, 4H), 7.83
3
3
(d, JHH¼7.3 Hz, 2H), 7.98 (d, JHH¼7.2 Hz, 1H); dC (75.5 MHz,
CDCl3, Me4Si): 45.9 (2CH2), 50.0 (CH), 53.9 (CH), 67.9 (CH2), 69.0
(CH2), 118.9 (CH2), 122.2 (2CH), 127.4 (2CH), 129.4 (2CH), 130.0
(2CH), 135.9 (CH), 143.9 (2C), 146.5 (2C), 160.3 (2C); MS (APCIþ,
References and notes
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(MþH)þ: 396.1918; found: 396.1924. [
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To a solution of Pd(OAc)2 (2.5 mg, 0.01 mmol), PPh3 (8 mg,
0.03 mmol) and 1,3-dimethylbarbituric acid (42 mg, 0.27 mmol) in
dry CH2Cl2 (1.2 mL) (S)-(ꢂ)-16 (50 mg, 0.10 mmol) was added un-
der nitrogen atmosphere. The mixture was stirred for 4 h at 35 ꢀC
and after this time the solvent was evaporated under reduced
pressure obtaining a reaction crude, which was redisolved in
CH2Cl2 (10 mL) and washed with NaHCO3 (1ꢃ10 mL). The organic
phase was dried over Na2SO4, and the solvent was removed under
reduced pressure obtaining a crude that was purified by flash
chromatography (50% MeOH/EtOAc), affording amino carbamate
(S)-(ꢂ)-18 as a colourless oil (33 mg, 80%). Rf (50% MeOH/EtOAc):
0.22; IR (NaCl): nmax/cmꢂ1 3243,1695,1555,1445,1221 and 1155; dH
(400.13 MHz, CDCl3, Me4Si): 1.49 (s, 9H), 1.92 (br s, 2H), 2.70–2.82
(m, 2H), 3.21–3.39 (m, 2H), 3.58–3.65 (m, 1H), 4.15–4.23 (m, 1H),
4.39–4.46 (m, 2H), 5.23 (br s, 1H), 5.52 (br s, 1H), 7.28–7.42 (m, 4H),
3
3
7.61 (d, JHH¼7.3 Hz, 2H), 7.81 (d, JHH¼7.5 Hz, 2H); dC (100.6 MHz,
CDCl3, Me4Si): 28.3 (3CH3), 42.6 (CH2), 42.8 (CH2), 47.2 (CH), 52.2
(CH), 66.7 (CH2), 79.6 (C), 119.6 (2CH), 125.0 (2CH), 127.0 (2CH),
127.6 (2CH), 141.0 (2C), 144.0 (2C), 156.1 (C), 157.0 (C); MS (APCIþ,
m/z): 412 [(MþH)þ, 100%]; HRMS (ESIþ) calcd for C23H29NaN3O4
20
(MþNa)þ: 434.2050; found: 434.2067. [
a
]
¼ꢂ3.7 (c 1.0, CH2Cl2) for
D
91% ee.
4.29. (R)-Allyl tert-butyl (3-aminopropane-1,2-
diyl)biscarbamate [(R)-(D)-11c]
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(S)-(ꢂ)-16 (50 mg, 0.1 mmol) was dissolved in a 20% solution of
piperidine in DMF (500 mL), the solution was stirred for 15 min,
after complete disappearance of the starting material the solvent
was removed by distillation at reduced pressure obtaining a crude
that was purified by flash chromatography (60% MeOH/EtOAc),
affording (R)-(þ)-11c as a colourless oil (23 mg, 85%). Rf (60%
MeOH/EtOAc): 0.24; IR (NaCl): nmax/cmꢂ1 3335, 2978, 1699, 1531,
1456, 1367, 1253 and 1170; dH (300.13 MHz, CDCl3, Me4Si): 1.41 (s,
9H), 2.10 (br s, 2H), 2.69–2.78 (m, 2H), 3.20–3.34 (m, 2H), 3.54–3.60
(m, 1H), 4.51 (d, 3JHH¼5.0 Hz, 2H), 5.16–5.29 (m, 3H), 5.48 (m, 1H),
5.83–5.93 (m, 1H); dC (75.5 MHz, CDCl3, Me4Si): 28.2 (3CH3), 42.6
(CH2), 42.6 (CH2), 52.5 (CH), 65.5 (CH2), 79.3 (C), 117.5 (CH2), 132.7
(CH), 156.1 (C), 156.9 (C) MS (APCIþ, m/z): 274 [(MþH)þ, 100%];
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8401
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Centre as supplementary publication numbers. CCDC 734247. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.
cam.ac.Uk).
´
3607; (d) de Parrodi, C. A.; Juaristi, E. Synlett 2006, 2699–2715; (e) Gonzalez-
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´
´
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23. Data collection was made using the program CrysAlis CCD. Cristal structure was
solved by direct methods using the program SHELXS-86. Anisotropic least-
squares refinement was carried out with SHELXL-97. Absolute configuration
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