Diastereoselective synthesis of enantioenriched homopropargyl amino alcohols from α-dibenzylamino aldehydes and their use as chiral synthons

Article abstract of DOI:10.1016/j.tet.2006.05.060

Homochiral α-dibenzylamino aldehydes, prepared from the corresponding α-amino acids, react with propargyl bromide and zinc in DMF/THF (1:1) or DMF/Et₂O (1:1) at 20 °C to afford, in good yields and dr, homopropargylic 1,2-amino alcohols. anti Di

Full text of DOI:10.1016/j.tet.2006.05.060

Tetrahedron 62 (2006) 7783–7792
Diastereoselective synthesis of enantioenriched homopropargyl
amino alcohols from a-dibenzylamino aldehydes
and their use as chiral synthons
*
Jose M. Andres, Rafael Pedrosa, Alfonso Perez-Encabo and Marıa Ramırez
´
´
ꢀ
ꢀ
ꢀ
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Valladolid, Doctor Mergelina s/n, 47011-Valladolid, Spain
ꢀ
Received 6 April 2006; revised 22 May 2006; accepted 24 May 2006
Available online 12 June 2006
Abstract—Homochiral a-dibenzylamino aldehydes, prepared from the corresponding a-amino acids, react with propargyl bromide and
zinc in DMF/THF (1:1) or DMF/Et2O (1:1) at 20 ꢀC to afford, in good yields and dr, homopropargylic 1,2-amino alcohols. anti Diastereomers
were always formed as major products in this reaction. These compounds are versatile intermediates for a variety of synthetic targets:
g-amino-b-hydroxy-ketones, 4-amino-1,3-diols, 1,7-diamino-2,6-diols, and u-amino-d-hydroxy esters.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
results obtained on the diastereoselective propargylation of
those compounds and the transformation of the resulting
homopropargyl amino alcohols into useful synthetic inter-
mediates.
Homopropargyl alcohols are interesting intermediates in
organic synthesis that are prepared by reaction of carbonyl
compounds with propargyl or allenyl organometallics.1 In
some cases, mixtures of allenyl and homopropargyl alcohols
are obtained depending on the nature of the carbonyl com-
pound, propargyl halide, and the metal and solvent used in
the reaction.2
2. Results and discussion
The reaction of a-dibenzylamino aldehydes with propargyl
bromide and zinc dust was initially tested by taking L-alani-
nal derivative 1a as a model. The reaction did not take place
when diethyl ether was used as a solvent (entry 1 in Table 1),
but led to a mixture of diastereomeric dibenzylamino homo-
propargyl alcohols anti-2a and syn-2a in good yield and de
when the reaction was carried out in mixtures of Et2O or
THF and DMF as solvents (entries 2–6 in Table 1). The ratio
of diastereoisomers did not appreciably change with the
The diastereoselective propargylation of carbonyl com-
pounds was first described for a-alkoxy aldehydes with
zinc and propargyl bromide in DMF/THF leading to the
anti adducts as major diastereoisomers in good yield and dia-
stereomeric excess (de).3,4 Propargylation of some protected
a-amino aldehydes has also been studied. For instance,
N-Boc-leucinal reacts with propargyl bromide and zinc in
DMF/Et2O leading to the corresponding anti homopropargyl
amino alcohol with very good de,5 and diastereoselective
propargylation of a-acetamido aldehyde constitutes a key
step in the synthesis of Neu5Ac.6 There are no antecedents
on propargylation of a-dibenzylamino aldehydes although
allenylation of 2-dibenzylamino-3-phenylpropionaldehyde
leads to the anti homopropargyl amino alcohol in moderate
de,7 and some enantioselective propargylation of aldehydes
leading to homochiral propargyl alcohols are also known.8
Table 1. Stereoselective propargylation of a-dibenzylamino aldehydes 1a–f
Entry
1a
Solvent
Ta (ꢀC)
Yield (%)b
anti/sync
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Et2O
20
20
0/20
0/20
0
0
20
0/20
0/20
0/20
0/20
—
—
DMF/Et2O (1:1)
DMF/Et2O (1:1)
DMF/THF (1:1)
DMF/Et2O (1:5)
DMF/Et2O (5:1)
DMF/Et2O (1:1)
DMF/Et2O (1:1)
DMF/THF (1:1)
DMF/THF (1:1)
DMF/Et2O (1:1)
2a (63)
2a (71)
2a (81)
2a (60)
2a (54)
2b (80)
2c (70)
2d (57)
2e (61)
2f (61)
80:20
81:19
82:18
82:18
85:15
90:10
85:15
89:11
70:30
18:82
9
10
11
As a part of a project on the reactivity of a-dibenzylamino
aldehydes with different nucleophiles,9 we present now the
a
Reactions were run with 2 equiv of propargyl bromide and 3 equiv of zinc.
Numbers correspond to combined yield of pure and isolated diastereo-
isomers.
b
c
Keywords: Propargylation; Amino acids; Amino aldehydes; Asymmetric
synthesis; Zinc.
* Corresponding author. Tel.: +34 983 423211; fax: +34 983 423013;
e-mail: pedrosa@qo.uva.es
The diastereomeric ratio was determined by integration of the signals of
1H NMR spectra of the reaction mixture.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.060

7784
J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
temperature of the reaction or by the ethereal solvent or by
the ratio of Et2O and DMF, but the best yield was obtained
for the reaction in THF/DMF at 0–20 ꢀC (entry 4 in Table
1). The best diastereoselection for the reaction was observed
when a mixture of DMF/Et2O 5:1 was used as solvent
(entry 6 in Table 1). The reaction was extended to dibenzyl-
amino aldehydes 1b–f and the results are summarized in
Scheme 1 and Table 1.
stereochemical problem associated with the aldol reaction.
To this end, anti-2a–e and syn-2e,f were subjected to hydra-
tion by reaction with 10% solution of H2SO4 and a catalytic
amount of HgSO4 at room temperature.16 Ketones anti-3a–e
and syn-3e,f were isolated in moderate to good yield as single
diastereoisomers (Scheme 2 and Table 2), as shown by
the identity of their physical and spectral data with those
previously described for anti-3a and 3b.15
OH
OH
OH
O
OH
i
R
CHO
NBn2
1a-d
R
R
R
R
i
+
NBn2
NBn2
NBn2
anti-3a-c
NBn2
anti-2a-c
syn-2a-d
anti-2a-d
OH
O
OH
a: R = Me
b: R = i-Pr
c: R = CH2Ph
R
R
d: R = CH2OTBDMS
i
NBn2
NBn2
anti-2e
OH
OH
anti-3e
i
Ph
CHO
Ph
Ph
+
OH
O
OH
NBn2
syn-2e
NBn2
1e
NBn2
anti-2e
R
i
i
R
NBn2
syn-2e
NBn2
syn-3e
OH
OH
i
CHO
OH
O
N
Bn
+
OH
N
N
Bn
Bn
syn-2f
N
Bn
syn-3f
N
1f
anti-2f
Bn
syn-2f
Scheme 1. Reagents and conditions: (i) 1. Zn dust, HC^CCH2Br, DMF/
THF (1:1) or DMF/Et2O (1:1), rt. 2. NH4Cl.
Scheme 2. Reagents and conditions: (i) H2SO4, HgSO4, MeOH, rt.
Table 2. Hydration of the triple bond of compounds syn- and anti-2
The stereoselection was improved when increasing the size
of the chain in the starting amino aldehyde, raising to ca.
9:1 for L-dibenzylaminovalinal 1b and L-dibenzylaminoseri-
nal derivative 1d. On the contrary, the presence of a phenyl
group in 1e decreased the ratio of diastereoisomers to 7:3
(entry 10 in Table 1). This fact has been previously observed
for nucleophilic additions to phenylglycinal derivatives.9b–d
Entry
2
R
t (h)
Aldol
Yield (%)a
1
2
3
4
5
6
anti-2a
anti-2b
anti-2c
syn-2e
anti-2e
syn-2f
Me
iPr
PhCH2
Ph
Ph
7
5
6
3
5
5
anti-3a
anti-3b
anti-3c
syn-3e
anti-3e
syn-3f
75
65
75
51
56
51
—
Interestingly, the reaction of L-N-benzyl prolinal 1f with
propargyl bromide and zinc dust in DMF/Et2O at room
temperature leads to a mixture of anti- and syn-2f in moder-
ate yield and good de, but in this case the syn adduct was
formed as major diastereoisomer. This behavior, which can
be explained through a Cram-chelated model, had been pre-
viously observed for additions to prolinal derivatives.9c,10
a
Numbers correspond to yield of pure and isolated products.
Compounds 3b–e were transformed into 4-amino-1,3-diols
4b–e in moderate to good yields and excellent de by reduc-
tion with different complex metal hydrides (Scheme 3 and
OH OH
OH
O
OH OH
[MH]
+
R
R
R
All the diastereoisomers, except anti- and syn-2d, were pu-
rified by flash chromatography and their stereochemistry
was determined on the basis of 1H NMR spectral data9c,10,11
and confirmed for anti-2b by transformation into (3S,4R)-3-
dibenzylamino-2-methyl-4-heptanol by reduction on Pearl-
man’s catalyst and dibenzylation with benzyl bromide and
K2CO3 in acetonitrile. This amino alcohol was also obtained
by reaction of 1b with propylmagnesium bromide as previ-
ously described.12
NBn2
NBn2
NBn2
anti-anti-4b-e
anti-3b-e
anti-syn-4b-e
nOe
Me
H
OH OH
DMP
H
TsOH, 70 ºC
O
Me
Me
O
NBn2
anti-syn-4b
i-Pr
NBn2
cis-5b
g-Amino-b-hydroxy carbonyl compounds are important
parts of biologically interesting molecules,13 and their syn-
thesis has attracted much attention.14 In this way, we consider
the transformation of dibenzylamino homopropargyl alco-
hols 2 into g-amino-b-hydroxy ketones 3 as an alternative
to the aldol type reaction of a-amino aldehydes with ace-
tone.15 The versatility of our method allowed the synthesis
of either anti- or syn diastereoisomers depending on the
stereochemistry of the starting compound, avoiding the
nOe
Me
Me
OH OH
H
DMP
TsOH, 70 ºC
O
H
Me
O
i-Pr
NBn2
NBn2
trans-5b
anti-anti-4b
Scheme 3.

J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
Table 3. Stereoselective reduction of b-hydroxy ketones anti-3
7785
OH
OH
Entry 3
Hydride
Solvent
Ta Yielda syn/antib
(ꢀC) (%)
ii
NH2
NH2
8b
OH
1
2
3
4
5
6
7
anti-3b NaBH4
MeOH
ꢁ20 62
80:20
>95:5
23:77
>95:5
34:66
>95:5
37:63
OH
anti-3b Et3B/NaBH4 THF/MeOH (4:1) ꢁ78 52
anti-3b NaBH(OAc)3 CH3CN/HOAc
ꢁ40 66
anti-3c Et3B/NaBH4 THF/MeOH (4:1) ꢁ78 50
anti-3c NaBH(OAc)3 CH3CN/HOAc
ꢁ40 40
anti-3e Et3B/NaBH4 THF/MeOH (4:1) ꢁ78 68
anti-3e NaBH(OAc)3 CH3CN/HOAc
ꢁ40 88
NBn2
OH
OTBDMS
NBn2
OH
7b
i
NBn2
anti-6b
a
NBn2
Numbers correspond to combined yield of pure and isolated diastereo-
isomers.
The diastereomeric ratio was determined by integration of the signals of
NBn2
ii
epi-7b
b
1H NMR spectra of the reaction mixture.
OH
OH
NH2
NH2
Table 3). The selection of the reducing agent allowed the
preparation of either diastereoisomers of 4b–e.
epi-8b
Scheme 4. Reagents and conditions: (i) 1. n-BuLi (1.1 equiv), THF, ꢁ78 ꢀC,
1 h. 2. 1b (1.1 equiv), THF, ꢁ78 ꢀC, 1 h. 3. TBAF (1.2 equiv), THF, 0 ꢀC,
5 h. 4. NH4Cl. (ii) H2, Pd(OH)2/C, MeOH.
The reduction of anti-3b with NaBH4 in methanol yielded
a mixture of anti-syn-4b and anti-anti-4b in a ratio 4:1 but
the reduction in the presence of Et2BOMe, generated in
situ from Et3B and MeOH,17 leads to anti-syn-4b as a single
diastereoisomer. Alternatively, the reaction of anti-3b with
Evans’s reagent (NaBH(OAc)3)18 in a mixture of aceto-
nitrile/acetic acid as solvent at ꢁ40 ꢀC gave anti-anti-4b
as major diastereoisomer although in moderate de (entry 3
in Table 3). The reduction of anti-3c–e follows the same
pattern as described for anti-3b. The reduction with NaBH4/
Et2BOMe yielded anti-syn-4c–e as a single diastereoisomer,
whereas the reaction with NaBH(OAc)3 leads to anti-anti-
4c–e as major isomers in moderate de.
Finally, both anti-6b and anti-6e were transformed into the
u-amino-d-hydroxy ethyl esters anti-10b and anti-10e, re-
spectively, in two steps as summarized in Scheme 5. Depro-
tonation with n-BuLi in THF at ꢁ78 ꢀC of anti-6b and 6e,
followed by reaction with ethyl chloroformate in THF at
ꢁ40 ꢀC lead to esters anti-9b and anti-9e in good yields.
These esters cannot be purified because extensive decompo-
sition was observed when subjected to flash chromato-
graphy, but they were transformed in moderate yields into
the saturated amino hydroxyl ester derivatives anti-10b
and anti-10e by hydrogenation on Pearlman’s catalyst in
the presence of Boc2O using EtOAc as solvent.
The stereochemistry of the amino diols anti-syn-4b and anti-
anti-4b was established by transformation into 1,3-dioxane
derivatives cis-5b and trans-5b, respectively, by reaction
with 2,2-dimethoxypropane and p-toluenesulfonic acid as
catalyst (Scheme 3). The NOESY experiment of cis-5b
shows cross peak for the signal of the axial methyl group
at C-2 and the hydrogen atoms at C-4 and C-6, demonstrat-
ing the cis-relationship of the substituents at C-4 and C-6.
For trans-5b the cross peaks appeared for the signals of
the methyl groups at C-2 and C-4 and the hydrogen atom
at C-6 in the dioxane ring, pointing a trans-disposition of
the methyl at C-4 and the substituent at C-6. The stereo-
chemistry was generalized for amino diols 4c–e.
OTBDMS
CO2Et
NHBoc
anti-10b
ii
OTBDMS
OTBDMS
CO2Et
CO2Et
i
NBn2
anti-6b
NBn2
anti-9b
OTBDMS
OTBDMS
Ph
Ph
i
NBn2
anti-6e
NBn2
anti-9e
The interest in homopropargyl amino alcohols 2 as synthetic
intermediates was extended to the preparation of u-amino-
d-hydroxy acids and C2-symmetrical 1,7-diamino-2,6-diols
previously used as chiral ligands19 and in the synthesis
of pharmacological active compounds.20 Homopropargyl
amino alcohol anti-2b was transformed into anti-6b by treat-
ment with TBDMSCl and imidazole in DMF. Lithium
acetylide, prepared by deprotonation of anti-6b with
n-BuLi in THF at ꢁ78 ꢀC, was reacted with L-dibenzyl-
amino valinal 1b and after desilylation with TBAF yielded
a mixture (4:1) of diastereomeric bis-amino alcohols 7b
and epi-7b in 66% yield (Scheme 4). After separation, the
major diastereoisomer 7b was transformed into the homo-
chiral C2-symmetrical 1,7-diamino-2,6-diol derivative 8b
by hydrogenation/hydrogenolysis on Pearlman’s catalyst.
The same treatment on epi-7b leads to epi-8b also in excel-
lent yield.
ii
OTBDMS
Ph
CO2Et
NHBoc
anti-10e
Scheme 5. Reagents and conditions: (i) 1. n-BuLi (1.5 equiv), THF, ꢁ78 ꢀC,
1 h. 2. ClCO2Et (2 equiv), THF, ꢁ78 ꢀC to ꢁ40 ꢀC, 0.5 h. 3. NH4Cl. (ii) H2,
Pd(OH)2/C, Boc2O, EtOAc.
In summary, reaction of chiral a-dibenzylamino aldehydes
with propargyl bromide and zinc yielded anti amino alcohols
as major diastereoisomer. As an alternative to the aldol reac-
tion, these compounds were transformed in good yields to
g-amino-b-hydroxy ketones, by hydration of the triple bond.
In a different way, lithium derivatives of these homopro-
pargyl amino alcohols reacted with ethyl chloroformate to

7786
J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
yield enantioenriched u-amino-d-hydroxy esters or with
chiral a-dibenzylamino aldehydes leading to propargyl di-
amino diols, which were further elaborated to the corre-
sponding saturated homochiral C2 diamino diols.
(silica gel, hexane/EtOAc 30:1): 694 mg (2.16 mmol,
72%). Colorless oil. [a]2D3 ꢁ5.5 (c 1.0, CHCl3). IR (film):
1
3568, 3457, 3303, 2116, 1064, 748, 699 cmꢁ1. H NMR
(CDCl3): 1.03 (d, 1H, J¼6.7 Hz, CH3); 1.13 (d, 1H,
J¼6.9 Hz, CH3); 1.98 (m, 1H, ^CH); 2.24 (m, 1H,
CH(CH3)2); 2.30 (m, 1H, CHHCHOH); 2.43 (m, 2H, CHN
and OH); 2.62 (ddd, 1H, J¼16.6, 3.5, 2.5 Hz, CHHCHOH);
3.64 (d, 2H, J¼13.5 Hz, CHHPh); 3.96 (d, 2H, J¼13.5 Hz,
CHHPh); 7.15–7.40 (m, 10H, Har). 13C NMR (CDCl3):
20.0 (CH3); 23.4 (CH3); 25.5 (CH2–C^C); 26.3
(CH(CH3)2); 55.2 (CH2Ph); 65.4 (CHN); 68.7 (CHOH);
70.4 (^CH); 81.9 (C^CH); 127.0, 128.3, 129.0 (CHar);
139.5 (Car). C22H27NO (321.5): calcd C 82.20, H 8.47,
N 4.36; found C 82.34, H 8.30, N 4.49.
3. Experimental
3.1. General
The reactions were carried out in oven-dried glassware un-
der argon atmosphere and using anhydrous solvents. Starting
N,N-dibenzyl a-amino aldehydes 1a–e were prepared as
previously described.9a Propargyl bromide, as 80 wt % solu-
1
tion in toluene, is commercially available. The H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were registered
using TMS as an internal standard. IR spectra were recorded
as film or KBr dispersion. Optical rotations were measured
in a 1 dm cell. Microanalyses were performed by the Depar-
3.2.3. (2S,3R)-2-Dibenzylamino-1-phenylhex-5-yn-3-ol
(anti-2c). This compound was obtained as the major dia-
stereomer in the propargylation of amino aldehyde 1c
(659 mg, 2 mmol) and purified by flash chromatography
(silica gel, hexane/EtOAc 15:1): 440 mg (1.19 mmol,
60%). Colorless oil. [a]2D3 +14.3 (c 1.1, CHCl3). IR (film):
´
tamento de Quımica Inorganica.
ꢀ
1
3.2. General procedure for propargylation of a-amino
aldehydes
3450, 3297, 3300, 2117, 1072, 744, 699 cmꢁ1. H NMR
(CDCl3): 1.95 (t, 1H, J¼2.6 Hz, ^CH); 2.05 (br s, 1H,
OH); 2.24 (ddd, 1H, J¼16.7, 8.4, 2.6 Hz, CHHC^CH);
2.60 (ddd, 1H, J¼16.7, 4.2, 2.7 Hz, CHHC^CH); 3.61 (d,
2H, J¼13.8 Hz, NCHHPh); 3.02 (m, 3H, CH2CHN); 3.73
(d, 2H, J¼13.8 Hz, NCHHPh); 3.99 (m, 1H, CHOH);
7.15–7.35 (m, 15H, Har). 13C NMR (CDCl3): 25.7
(CH2C^C); 32.0 (CH2Ph); 54.6 (NCH2Ph); 62.7 (CHN);
70.5 (CHOH); 70.8 (C^CH); 81.2 (C^CH); 125.8,
126.9, 128.2, 128.3, 128.7, 129.4 (CHar); 139.5, 140.8
(Car). C26H27NO (369.5): calcd C 84.51, H 7.37, N 3.79;
found C 84.28, H 7.07, N 3.94.
The amino aldehyde (2 mmol) and propargyl bromide
(80 wt % in toluene, 0.44 mL, 4 mmol) were dissolved in a
mixed solvent (DMF/ether or DMF/THF, 1:1, 8 mL). To this
well-stirred solution was added activated zinc dust (washed
with 2% HCl, water, methanol, and dried in vacuum;
392 mg, 6 mmol) slowly at 0 ꢀC. After 5 min, the exother-
mic reaction brought itself to reflux. The whole reaction
mixture was stirred at room temperature until the reaction
was finished (TLC) and then quenched with aqueous satu-
rated solution of ammonium chloride (20 mL). The organic
layer was separated and the aqueous phase was extracted
with diethyl ether (3ꢂ20 mL). The combined organic layers
were washed with brine, and dried over anhydrous MgSO4.
The solvents were eliminated under vacuum and the residue
was purified by flash chromatography (silica gel, hexane/
ethyl acetate 15:1 to 50:1).
3.2.4. (2S,3S)-2-Dibenzylamino-1-phenylhex-5-yn-3-ol
(syn-2c). This compound was obtained as the minor dia-
stereomer in the propargylation of amino aldehyde 1c
(659 mg, 2 mmol) and purified by flash chromatography
(silica gel, hexane/EtOAc 15:1): 74 mg (0.2 mmol, 10%).
Colorless oil. [a]2D3 +23.0 (c 0.54, CHCl3). IR (film): 3300,
1
2118, 1072, 744, 701 cmꢁ1. H NMR (CDCl3): 1.81 (t,
3.2.1. (2S,3R)-2-Dibenzylaminohex-5-yn-3-ol (anti-2a).
This compound was obtained as the major diastereomer
in the propargylation of amino aldehyde 1a (760 mg,
3 mmol) and purified by flash chromatography (silica gel,
hexane/EtOAc 15:1): 586 mg (2.0 mmol, 67%). Colorless
oil. [a]2D3 +37.8 (c 1.0, CHCl3). IR (film): 3435, 3300,
1H, J¼2.6 Hz, ^CH); 2.15 (ddd, 1H, J¼17.0, 6.3, 2.6 Hz,
CHHC^CH); 2.25 (ddd, 1H, J¼17.0, 3.6, 2.6 Hz,
CHHC^CH); 2.76 (dd, 1H, J¼13.0, 6.0 Hz, PhCHH);
3.09 (m, 2H, CHN and CHHPh); 3.39 (d, 2H, J¼13.2 Hz,
NCHHPh); 3.94 (d, 2H, J¼13.2 Hz, NCHHPh); 3.69 (m,
1H, CHOH); 4.31 (br s, 1H, OH); 7.10–7.40 (m, 15H,
Har). 13C NMR (CDCl3): 24.6 (CH2C^C); 32.0 (CH2Ph);
54.1 (NCH2Ph); 62.5 (CHN); 68.9 (CHOH); 70.1
(C^CH); 80.9 (C^CH); 126.4, 127.2, 128.4, 128.6,
129.1, 129.2 (CHar); 138.7, 139.8 (Car). C26H27NO
(369.5): calcd C 84.51, H 7.37, N 3.79; found C 84.36,
H 7.22, N 3.59.
1
2117, 1028, 748, 699 cmꢁ1. H NMR (CDCl3): 1.20 (d,
3H, J¼6.6 Hz, CH3); 1.96 (t, 1H, J¼2.6 Hz, ^C–H); 2.12
(br s, 1H, OH); 2.27 (ddd, J¼16.7, 8.0, 2.6 Hz, CHHCHOH);
2.72 (dq, 1H, J¼8.2, 6.6 Hz, CHN); 2.82 (ddd, J¼16.7, 3.6,
2.7 Hz, CHHCHOH); 3.44 (d, 2H, J¼13.7 Hz, CHHPh);
3.76 (d, 2H, J¼13.7 Hz, CHHPh); 7.20–7.45 (m, 10H,
Har). 13C NMR (CDCl3): 8.3 (CH3); 25.1 (CH2C^C);
54.3 (CH2Ph); 56.7 (CHN); 70.7 (C^CH); 71.8 (CHOH);
81.5 (CH^C); 126.9, 128.2, 128.7 (CHar); 139.6 (Car).
C20H23NO (293.4): calcd C 81.87, H 7.90, N 4.77; found
C 81.64, H 7.75, N 4.65.
3.2.5. (2S,3R)-2-Dibenzylamino-1-(tert-butyldimethyl-
silyloxy)hex-5-yn-3-ol (anti-2d). This compound was ob-
tained as the major product together with the diastereomer
syn-2b in the propargylation of amino aldehyde 1d
(1.53 g, 4 mmol) and purified by flash chromatography
(silica gel, hexane/EtOAc 50:1): 970 mg (2.3 mmol, 57%
combined yield, de¼78%). Colorless oil. [a]2D3 +39.5 (c
1.1, CHCl3). IR (film): 3307, 1602, 1493, 1089, 777, 746,
3.2.2. (4R,5S)-5-Dibenzylamino-6-methylhept-1-yn-4-ol
(anti-2b). This compound was obtained as the major dia-
stereoisomer in the propargylation of amino aldehyde 1b
(844 mg, 3 mmol) and purified by flash chromatography
698 cmꢁ1
.
1H NMR (CDCl3): 1.94 (t, 1H, J¼2.6 Hz,

J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
7787
HC^); 2.29 (ddd, 1H, J¼16.7, 7.7, 2.6 Hz, CHHCHOH);
2.77 (m, 2H, CHN, CHHCHOH); 3.63 (d, 1H, J¼13.7 Hz,
CHHPh); 3.90 (d, 1H, J¼13.7 Hz, CHHPh); 4.07 (m, 3H,
CHOH, CH2OTBDMS); 7.20–7.40 (m, 10H, Har). 13C
NMR (CDCl3): 18.0 (C(CH3)3); 25.2 (CH2C^C); 25.8
(C(CH3)3); 55.1 (CH2Ph); 60.5 (CH2O); 60.8 (CHN); 70.1
(CHOH); 126.9 (C^C); 128.2, 128.4, 128.8 (CHar); 139.6
(Car).
3.2.9. (S)-1-[(S)-1-Benzyl-2-pyrrolidinyl]but-3-yn-1-ol
(syn-2f). This compound was obtained as the major dia-
stereomer in the propargylation of amino aldehyde 1f
(568 mg, 3 mmol) and purified by flash chromatography (sil-
ica gel, hexane/EtOAc 2:1): 282 mg (1.23 mmol, 41%). Col-
orless oil. [a]2D3 ꢁ24.7 (c 1.0, MeOH). IR (film): 3410, 3293,
2117, 1072, 744, 701 cmꢁ1. 1H NMR (CDCl3): 1.70 (m, 3H,
CH2 and CHHCN); 1.97 (m, 1H, CHHCHN); 2.03 (t,
1H, J¼2.6 Hz, C^CH); 2.38 (m, 1H, CHHN); 2.43 (m,
2H, CHHC^CH); 2.91 (m, 1H, CHHN); 3.05 (ddd, 1H,
J¼8.9, 5.2, 3.3 Hz, CHN); 3.48 (q, 1H, J¼6.3, 5.2 Hz,
CHOH); 3.58 (d, 1H, J¼13.3 Hz, CHHPh); 4.02 (d, 1H,
J¼13.3 Hz, CHHPh); 7.20–7.30 (m, 5H, Har). 13C NMR
(CDCl3): 24.5, 24.7 (CH2); 29.1 (CH2C^C); 54.3
(CH2Ph); 61.6 (CH2N); 66.3 (CHN); 70.1 (C^CH); 72.0
(CHOH); 81.2 (C^CH); 127.0, 128.1, 128.3, 128.4
(CHar); 139.4 (Car). C15H19NO (229.3): calcd C 78.56, H
8.35, N 6.11; found C 78.75, H 8.29, N 6.04.
3.2.6. (1R,2S)-1-Dibenzylamino-1-phenylpent-4-yn-2-ol
(anti-2e). This compound was obtained as the major dia-
stereomer in the propargylation of amino aldehyde 1e
(1.58 g, 5 mmol) and purified by flash chromatography
(silica gel, hexane/EtOAc 15:1): 759 mg (2.14 mmol, 43%).
Colorless oil. [a]2D3 ꢁ110.0 (c 0.9, CHCl3). IR (film):
1
3550, 3447, 3300, 2118, 1028, 748, 703 cmꢁ1. H NMR
(CDCl3): 1.99 (t, 1H, J¼2.6 Hz, ^CH); 2.43 (ddd, 1H, J¼
16.9, 7.9, 2.6 Hz, CHHCHOH); 3.02 (m, 1H, CHHCHOH);
3.07 (d, 2H, J¼13.7 Hz, CHHPh); 3.67 (d, 1H, J¼9.2 Hz,
CHN); 3.83 (d, 2H, J¼13.7 Hz, CHHPh); 4.45 (m, 1H,
CHOH); 7.20–7.55 (m, 15H, Har). 13C NMR (CDCl3):
24.8 (CH2); 54.6 (CH2Ph); 66.7 (CHN); 69.1 (CHOH); 70.8
(C^CH); 81.4 (C^CH); 127.1, 127.8, 128.3, 128.4, 128.8,
129.9 (CHar); 134.4, 139.1 (Car). C25H25NO (355.5): calcd
C 84.47, H 7.09, N 3.94; found C 84.23, H 6.95, N 4.10.
3.2.10. (4R,5S)-5-Dibenzylamino-4-hydroxyhexan-2-one
(anti-3a). To a solution of amino alcohol anti-2a (293 mg,
1.0 mmol) and HgSO4 (75 mg, 0.25 mmol) in MeOH
(4 mL) at 0 ꢀC was added 10% H2SO4 (1.0 mL), and the re-
sultant reaction mixture was stirred at room temperature for
2–5 h (TLC). The pH of the reaction was adjusted to 7 with
saturated NaHCO3 and the mixture extracted with Et2O
(3ꢂ10 mL). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, concentrated,
and chromatographed (silica gel, hexane/EtOAc 6:1):
232 mg of anti-3a (0.75 mmol, 75%). Colorless oil. [a]D23
+43.5 (c 1, CHCl3). Lit.15 [a]D23 +45.2 (c 1.1, CHCl3). IR
3.2.7. (1R,2R)-1-Dibenzylamino-1-phenylpent-4-yn-2-ol
(syn-2e). This compound was obtained as the minor dia-
stereomer in the propargylation of amino aldehyde 1e
(1.58 g, 5 mmol) and purified by flash chromatography
(silica gel, hexane/EtOAc 15:1): 325 mg (0.91 mmol,
18%). Colorless oil. [a]2D3 ꢁ74.9 (c 1.1, CHCl3). IR (film):
.
(film): 3452, 1704, 1061, 748, 700 cmꢁ1 1H NMR
1
3405, 3305, 1074, 753, 702 cmꢁ1. H NMR (CDCl3): 1.81
(CDCl3): 1.16 (d, 3H, J¼6.6 Hz, CH3CH); 2.08 (s, 3H,
CH3CO); 2.37 (dd, 1H, J¼18.1, 8.9 Hz, CHHCO); 2.64
(dq, 1H, J¼8.6, 6.6 Hz, CHN); 3.03 (dd, 1H, J¼18.1,
2.3 Hz, CHHCO); 3.06 (br s, 1H, OH); 3.39 (d, 2H,
J¼13.6 Hz, CHHPh); 3.72 (d, 2H, J¼13.6 Hz, CHHPh);
3.98 (m, 1H, CHOH); 7.20–7.40 (m, 10H, Har). 13C NMR
(CDCl3): 8.2 (CH3CH); 30.6 (CH3CO); 47.5 (CH2CO);
54.2 (CH2Ph); 56.4 (CHN); 69.6 (CHOH); 126.8, 128.2,
128.7 (CHar); 139.7 (Car); 210.7 (CO).
(t, 1H, J¼2.6 Hz, ^CH); 1.92 (ddd, 1H, J¼17.0, 6.5,
2.6 Hz, CHHCHOH); 2.28 (ddd, 1H, J¼17.0, 3.2, 2.6 Hz,
CHHCHOH); 3.05 (d, 2H, J¼13.2 Hz, CHHPh); 3.72 (d,
1H, J¼10.3 Hz, CHN); 3.95 (d, 2H, J¼13.2 Hz, CHHPh);
4.36 (ddd, 1H, J¼10.3, 6.5, 3.2 Hz, CHOH); 4.62 (br s,
1H, OH); 7.20–7.50 (m, 15H, Har). 13C NMR (CDCl3):
23.8 (CH2); 53.6 (CH2Ph); 66.1 (CHN); 66.5 (CHOH);
69.9 (^CH); 80.4 (C^CH); 127.3, 128.2, 128.5, 128.6,
129.0, 129.8 (CHar); 133.1, 138.3 (Car). C25H25NO
(355.5): calcd C 84.47, H 7.09, N 3.94; found C 84.27, H
6.92, N 3.99.
3.2.11. (4R,5S)-5-Dibenzylamino-4-hydroxy-6-methyl-
heptan-2-one (anti-3b). This compound was obtained
from anti-2b (450 mg, 1.4 mmol), by the method described
for anti-3a and purified by flash chromatography (silica gel,
hexane/EtOAc 8:1): 309 mg (0.91 mmol, 65%). Colorless
oil. [a]2D3 +10.6 (c 1.1, CHCl3). Lit.15 [a]2D3 +10.3 (c 1.0,
3.2.8. (R)-1-[(S)-1-Benzyl-2-pyrrolidinyl]but-3-yn-1-ol
(anti-2f). This compound was obtained as the minor dia-
stereomer in the propargylation of amino aldehyde 1f
(568 mg, 3 mmol) and purified by flash chromatography
(silica gel, hexane/EtOAc 2:1): 62 mg (0.27 mmol, 9%).
Colorless oil. [a]2D3 +20.5 (c 0.3, MeOH). IR (film): 3198,
1
CHCl3). IR (film): 3470, 1705, 1069, 749, 700 cmꢁ1. H
NMR (CDCl3): 1.08 (d, 3H, J¼6.7 Hz, CH3); 1.18 (d, 3H,
J¼6.8 Hz, CH3); 2.17 (s, 3H, CH3CO); 2.22 (m, 1H,
CH(CH3)2); 2.45 (t, 1H, J¼6.3 Hz, CHN); 2.56 (dd, 1H, J¼
17.0, 10.0 Hz, CHHCO); 2.76 (dd, 1H, J¼17.0, 2.0 Hz,
CHHCO); 3.20 (br s, 1H, OH); 3.70 (d, 2H, J¼13.6 Hz,
CHHPh); 3.76 (d, 2H, J¼13.6 Hz, CHHPh); 4.34 (m, 1H,
CHOH); 7.20–7.40 (m, 10H, Har). 13C NMR (CDCl3):
20.0 (CH3); 23.3 (CH3); 26.4 (CH(CH3)2); 30.8 (CH3CO);
48.2 (CH2CO); 55.1 (CH2Ph); 65.3 (CHN); 66.3 (CHOH);
127.0, 128.3, 129.3 (CHar); 139.6 (Car); 209.9 (CO).
1
1617, 1388, 1053, 733, 706 cmꢁ1. H NMR (CDCl3): 1.73
(m, 4H, CH2); 2.03 (t, 1H, J¼5.4 Hz, C^CH); 2.15 (s,
1H, CHHCN); 2.28 (m, 1H, CHHC^C); 2.57 (ddd, 1H, J¼
9.6, 7.0, 2.7 Hz, CHHC^C); 2.80 (td, 1H, J¼7.7, 2.7 Hz,
CHN); 2.97 (m, 1H, CHHCN); 3.32 (d, 1H, J¼13.0 Hz,
CHHPh); 3.98 (dt, 1H, J¼7.2, 2.7 Hz, CHOH); 4.06 (d,
1H, J¼13.0 Hz, CHHPh); 7.20–7.45 (m, 5H, Har). 13C
NMR (CDCl3): 22.9, 23.0 (CH2); 23.1 (CH2C^CH); 54.4
(CH2Ph); 58.1 (CH2N); 66.2 (CHN); 67.2 (CHOH); 69.8
(C^CH); 80.8 (C^CH); 127.0, 128.3, 128.7 (CHar);
139.0 (Car). C15H19NO (229.3): calcd C 78.56, H 8.35,
N 6.11; found C 78.71, H 8.42, N 6.04.
3.2.12. (4R,5S)-5-Dibenzylamino-4-hydroxy-6-phenyl-
hexan-2-one (anti-3c). This compound was obtained from
anti-2c (259 mg, 0.7 mmol) by the method described for

7788
J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
anti-3a and purified by flash chromatography (silica gel,
hexane/EtOAc 8:1): 203 mg (0.52 mmol, 75%). Colorless
oil. [a]2D3 +17.2 (c 1.1, CHCl3). IR (film): 3482, 1706,
NMR (CDCl3): 24.2 (CH2); 27.5 (CH2); 30.9 (CH3); 47.3
(CH2CO); 54.2 (CH2Ph); 61.1 (CH2N); 67.4 (CHN); 69.7
(CHOH); 126.9, 128.3, 128.5 (CHar); 139.5 (Car); 209.0
(CO). C15H21NO2 (247.3): calcd C 72.84, H 8.56, N 5.66;
found C 72.72, H 8.40, N 5.80.
1
1365, 1073, 736, 702 cmꢁ1. H NMR (CDCl3): 2.06 (s,
3H, CH3); 2.41 (dd, 1H, J¼17.8, 9.5 Hz, CHHCO); 2.77
(dd, 1H, J¼17.8, 2.3 Hz, CHHCO); 2.92 (m, 1H, CHN);
3.00 (m, 1H, CHHPh); 3.08 (dd, 1H, J¼14.0, 7.6 Hz,
CHHPh); 3.61 (d, 2H, J¼13.8 Hz, CHHPh); 3.72 (d, 2H,
J¼13.8 Hz, CHHPh); 4.27 (m, 1H, CHOH); 7.15–7.35 (m,
15H, Har). 13C NMR (CDCl3): 30.6 (CH3); 32.1 (CH2Ph);
48.0 (CH2CO); 54.5 (NCH2Ph); 62.7 (CHN); 68.1
(CHOH); 125.8, 126.8, 128.1, 128.2, 128.7, 129.4 (CHar);
139.6, 141.1 (Car); 210.2 (CO). C26H29NO2 (387.5): calcd
C 80.59, H 7.54, N 3.61; found C 80.74, H 7.74, N 3.42.
3.2.16. (2R,4R,5S)-5-Dibenzylamino-6-methylheptane-
2,4-diol (anti-syn-4b). A solution of triethylborane (1.0 M
in hexane, 0.23 mL, 0.23 mmol, 1.1 equiv) was added to
a mixture of anhydrous THF (2 mL) and MeOH (0.5 mL)
at 0 ꢀC under nitrogen. After stirring for 1 h at room temper-
ature, the mixture was cooled to ꢁ78 ꢀC followed by the
addition of b-hydroxy ketone anti-3b (71 mg, 0.21 mmol,
1 equiv) in THF (0.5 mL) and stirring was continued for
30 min. Then sodium borohydride (10 mg, 0.25 mmol,
1.2 equiv) was added, and the mixture was stirred for 3–
4 h, depending on the substrate used. The reaction mixture
was quenched with aqueous NH4Cl (3 mL) and extracted
with Et2O (3ꢂ5 mL). The combined organic extracts were
washed with brine, dried (MgSO4), and the volatiles were
evaporated. The crude product was dissolved in THF (1 mL)
and aqueous 10% NaOH solution (1 mL) and the mixturewas
stirred vigorously for 1 h. Then THF was removed and the
aqueous phase was extracted with CHCl3 (3ꢂ5 mL). The
combined organic extracts were washed with H2O and dried
with anhydrous MgSO4. The solvents were eliminated under
vacuum and the residue was purified by flash chromato-
graphy (silica gel, hexane/EtOAc 6:1): 37 mg (0.11 mmol,
52%). Colorless oil. [a]2D3 ꢁ12.1 (c 0.5, CHCl3). IR (film):
3.2.13. (4S,5R)-5-Dibenzylamino-4-hydroxy-5-phenyl-
pentan-2-one (anti-3e). This compound was obtained from
anti-2e (427 mg, 1.2 mmol) by the method described for
anti-3a and purified by flash chromatography (silica gel,
hexane/EtOAc 8:1): 250 mg (0.67 mmol, 56%). Colorless
solid, mp 112–113 ꢀC. [a]D23 ꢁ119.8 (c 1, CHCl3). IR
(KBr): 3581, 1716, 748, 701 cmꢁ1. 1H NMR (CDCl3): 2.20
(s, 3H, CH3); 2.45 (br s, 1H, OH); 2.54 (dd, 1H, J¼17.7,
9.2 Hz, CHHCO); 3.07 (d, 2H, J¼13.7 Hz, CHHPh); 3.29
(dd, 1H, J¼17.7, 2.3 Hz, CHHCO); 3.62 (d, 1H, J¼9.5 Hz,
CHN); 3.83 (d, 2H, J¼13.7 Hz, CHHPh); 4.78 (m, 1H,
CHOH); 7.20–7.50 (m, 15H, Har). 13C NMR (CDCl3): 30.9
(CH3); 47.8 (CH2CO); 54.4 (CH2Ph); 66.3 (CHN); 66.9
(CHOH); 127.0, 127.6, 128.2, 128.3, 128.8, 129.9 (CHar);
134.5, 139.3 (Car); 209.7 (CO). C25H27NO2 (373.5): calcd
C 80.40, H 7.29, N 3.75; found C 80.50, H 7.45, N 3.60.
1
3380, 1452, 1070, 749, 699 cmꢁ1. H NMR (CDCl3): 0.91
(d, 3H, J¼6.6 Hz, (CH3)2CH); 1.16 (d, 3H, J¼6.2 Hz,
(CH3CH)); 1.28 (d, 3H, J¼6.5 Hz, (CH3)2CH); 1.50 (m,
1H, CHHCHOH); 1.61 (m, 1H, CHHCHOH); 2.16 (m, 1H,
CH(CH3)2); 2.54 (dd, 1H, J¼10.3, 4.9 Hz, CHN); 3.69
(m, 1H, CHOH); 3.74 (d, 2H, J¼13.3 Hz, CHHPh); 3.93
(d, 2H, J¼13.3 Hz, CHHPh); 3.95 (m, 1H, CH3CHOH);
4.17 (br s, 1H, OH); 7.20–7.40 (m, 10H, Har). 13C NMR
(CDCl3): 20.8 (CH3); 23.2 (CH3); 23.7 (CH3); 28.4
(CH(CH3)2); 39.8 (CH2); 56.4 (CH2Ph); 66.8 (CHOH);
69.5 (CHOH); 71.7 (CHN); 127.5, 128.6, 129.2 (CHar);
139.4 (Car). C22H31NO2 (341.5): calcd C 77.38, H 9.15,
N 4.10; found C 77.21, H 9.29, N 3.98.
3.2.14. (4R,5R)-5-Dibenzylamino-4-hydroxy-5-phenyl-
pentan-2-one (syn-3e). This compound was obtained from
syn-2e (355 mg, 1.0 mmol) by the method described for
anti-3a and purified by flash chromatography (silica gel,
hexane/EtOAc 6:1): 190 mg (0.51 mmol, 51%). Colorless
solid, mp 100–101 ꢀC (from hexane). [a]2D3 ꢁ132.4 (c 1,
1
CHCl3). IR (KBr): 3388, 1710, 1076, 757, 701 cmꢁ1. H
NMR (CDCl3): 2.04 (s, 3H, CH3); 2.10 (dd, 1H, J¼16.0,
2.2 Hz, CHHCO); 2.30 (dd, 1H, J¼16.0, 9.1 Hz, CHHCO);
3.02 (d, 2H, J¼13.3 Hz, CHHPh); 3.50 (d, 1H, J¼10.4 Hz,
CHN); 3.98 (d, 2H, J¼13.3 Hz, CHHPh); 4.40 (br s, 1H,
OH); 4.74 (m, 1H, CHOH); 7.15–7.50 (m, 15H, Har). 13C
NMR (CDCl3): 30.8 (CH3); 47.9 (CH2CO); 53.4 (CH2Ph);
64.5 (CHN); 66.9 (CHOH); 127.2, 128.1, 128.5, 128.9,
129.7 (CHar); 133.1, 138.3 (Car); 207.2 (CO). C25H27NO2
(373.5): calcd C 80.40, H 7.29, N 3.75; found C 80.03, H
7.13, N 3.75.
3.2.17. (2S,4R,5S)-5-Dibenzylamino-6-methylheptane-
2,4-diol (anti-anti-4b). To a solution of NaBH(OAc)3
(407 mg, 1.92 mmol, 8 equiv) in anhydrous acetonitrile
(1 mL) was added anhydrous acetic acid (1 mL) and the mix-
ture was stirred at ambient temperature for 30 min. The mix-
ture was cooled to ꢁ40 ꢀC and a solution of hydroxy ketone
anti-3b (81 mg, 0.24 mmol, 1 equiv) in anhydrous aceto-
nitrile (0.5 mL) was added via syringe. After stirring
at ꢁ40 ꢀC for 2 h (TLC), the reaction mixture was quenched
by addition of 0.5 M aqueous sodium potassium tartrate
(3 mL). The mixture was allowed to warm to 23 ꢀC and
stirred for 30 min. The mixture was then diluted with
CH2Cl2 (5 mL) and washed with aqueous saturated NaHCO3
(5 mL). The aqueous layer was back extracted with CH2Cl2
(3ꢂ10 mL), and the combined organic layers were washed
with aqueous saturated NaHCO3, dried with anhydrous
MgSO4, and concentrated in vacuo. The crude product
was dissolved in THF (1 mL) and aqueous 10% NaOH solu-
tion (1 mL) and then the mixture was stirred vigorously for
1 h. Then THF was removed and the aqueous phase was
3.2.15. (S)-4-[(S)-1-Benzyl-2-pyrrolidinyl]-4-hydroxy-
butan-2-one (syn-3f). This compound was obtained from
syn-2f (92 mg, 0.4 mmol) by the method described for
anti-3a and purified by flash chromatography (silica gel,
hexane/EtOAc 3:2): 52 mg (0.21 mmol, 52%). Colorless
oil. [a]2D3 ꢁ53.1 (c 0.52, CHCl3). IR (film): 3438, 1711,
1
1357, 1073, 746, 701 cmꢁ1. H NMR (CDCl3): 1.69 (m,
3H, CH2 and CHHCHN); 1.93 (m, 1H, CHHCHN); 2.21
(s, 3H, CH3CO); 2.39 (m, 1H, CHHN); 2.53 (dd, 1H,
J¼16.2, 9.1 Hz, CHHCO); 2.64 (dd, 1H, J¼16.2, 3.4 Hz,
CHHCO); 2.82 (m, 1H, CHN); 2.93 (m, 1H, CHHN); 3.54
(d, 1H, J¼13.2 Hz, CHHPh); 3.88 (m, 1H, CHOH); 3.96
(d, 1H, J¼13.2 Hz, CHHPh); 7.30–7.40 (m, 5H, Har). 13C

J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
7789
extracted with CHCl3 (3ꢂ5 mL). The combined organic
extracts were washed with H2O and dried with anhydrous
MgSO4. The solvents were eliminated under vacuum and
the residue was purified by flash chromatography (silica
gel, hexane/EtOAc 6:1) to give 42 mg of anti-anti-4b
(0.12 mmol, 51%) and 12 mg of anti-syn-4b (0.036 mmol,
15%). Colorless oil. [a]2D3 +20.3 (c 0.66, CHCl3). IR
anti-syn-4b and purified by flash chromatography (silica
gel, hexane/EtOAc 4:1): 30 mg (0.08 mmol, 68%). Color-
less oil. [a]2D3 ꢁ48.1 (c 0.5, CHCl3). IR (film): 3385, 1452,
1070, 744, 700 cmꢁ1 1H NMR (CDCl3): 1.26 (d, 3H,
.
J¼6.1 Hz, CH3); 1.38 (ddd, 1H, J¼14.7, 10.1, 5.4 Hz,
CHHCHOH); 2.37 (ddd, 1H, J¼14.7, 2.3, 1.9 Hz,
CHHCHOH); 3.10 (d, 1H, J¼13.8 Hz, CHHPh); 3.58 (d,
J¼8.8 Hz, CHN); 3.84 (d, 1H, J¼13.8 Hz, CHHPh); 4.10
(m, 1H, CH3CHOH); 4.50 (m, 1H, CHOH); 7.20–7.50 (m,
15H, Har). 13C NMR (CDCl3): 24.1 (CH3); 42.0 (CH2);
54.7 (CH2Ph); 68.3 (CH3CHOH); 68.9 (CHN); 72.0
(CHOH); 127.1, 127.9, 128.4, 128.7, 128.9, 130.0 (CHar);
134.5, 139.4 (Car). C25H29NO2 (375.5): calcd C 79.96, H
7.78, N 3.73; found C 80.17, H 7.95, N 3.82.
(film): 3398, 1452, 1070, 759, 700 cmꢁ1
.
1H NMR
(CDCl3): 0.95 (d, 3H, J¼6.6 Hz, (CH3)2CH); 1.19 (d, 3H,
J¼6.3 Hz, (CH3CH)); 1.25 (d, 3H, J¼6.6 Hz, (CH3)2CH);
1.54 (ddd, 1H, J¼13.9, 7.4, 2.0 Hz, CHHCHOH); 1.67
(ddd, 1H, J¼13.9, 10.7, 3.1 Hz, CHHCHOH); 2.16 (m,
1H, CH(CH3)2); 2.58 (dd, 1H, J¼9.5, 5.3 Hz, CHN); 3.25
(br s, 1H, OH); 3.73 (d, 2H, J¼13.4 Hz, CHHPh); 3.89 (d,
2H, J¼13.4 Hz, CHHPh); 3.93 (m, 1H, CHOH); 4.03 (m,
1H, CH3CHOH); 7.15–7.40 (m, 10H, Har). 13C NMR
(CDCl3): 20.6 (CH3); 23.4 (CH3); 28.1 (CH(CH3)2); 39.8
(CH2); 56.3 (CH2Ph); 65.8 (CHOH); 66.7 (CHOH); 66.9
(CHN); 127.4, 128.5, 129.2 (CHar); 139.7 (Car).
C22H31NO2 (341.5): calcd C 77.38, H 9.15, N 4.10; found
C 77.24, H 9.28, N 4.24.
3.2.21. (1R,2S,4R)-1-Dibenzylamino-1-phenylpentane-
2,4-diol (anti-anti-4e). This compound was obtained as
the major diastereomer in the reaction of anti-3e (49 mg,
0.13 mmol) with NaBH(OAc)3 by the method described
for anti-anti-4b and purified by flash chromatography (silica
gel, hexane/Et2O 1:1): 27 mg (0.07 mmol, 55%). Colorless
oil. [a]2D3 ꢁ102.3 (c 0.44, CHCl3). IR (film): 3402, 1452,
3.2.18. (2R,4R,5S)-5-Dibenzylamino-6-phenylhexane-
2,4-diol (anti-syn-4c). This compound was obtained from
anti-3c (77 mg, 0.2 mmol), by the method described for
anti-syn-4b and purified by flash chromatography (silica
gel, hexane/EtOAc 4:1): 39 mg (0.1 mmol, 50%). Colorless
oil. [a]2D3 +16.7 (c 0.7, CHCl3). IR (film): 3378, 1602, 1452,
1121, 1072, 744, 700 cmꢁ1. 1H NMR (CDCl3): 1.20 (d, 3H,
J¼6.2 Hz, CH3); 1.48 (m, 1H, CHHCHOH); 1.76 (m, 1H,
CHHCHOH); 2.78 (dd, 1H, J¼12.9, 6.5 Hz, PhCHHCHN);
3.04 (m, 1H, CHN); 3.11 (m, 1H, PhCHHCHN); 3.45 (s
broad, 2H, OH); 3.57 (d, 1H, J¼13.6 Hz, NCHHPh); 3.81
(d, 1H, J¼13.6 Hz, NCHHPh); 3.83 (m, 1H, CHOH); 3.91
(m, 1H, CH3CHOH); 7.15–7.35 (m, 15H, Har). 13C NMR
(CDCl3): 24.0 (CH3); 31.9 (CH2CHN); 41.4 (CH2CHOH);
55.2 (NCH2Ph); 63.3 (CH3CHOH); 69.3 (CHN); 72.6
(CHOH); 126.1, 127.2, 128.4, 128.5, 128.8, 129.2 (CHar);
139.4, 140.0 (Car). C26H31NO2 (389.5): calcd C 80.17, H
8.02, N 3.60; found C 80.01, H 7.90, N 3.55.
1071, 741, 701 cmꢁ1 1H NMR (CDCl3): 1.26 (d, 3H,
.
J¼6.2 Hz, CH3); 1.81 (ddd, 1H, J¼14.6, 7.7, 2.5 Hz,
CHHCHOH); 2.16 (ddd, 1H, J¼14.6, 8.5, 3.1 Hz,
CHHCHOH); 3.10 (d, 1H, J¼13.7 Hz, CHHPh); 3.70 (d,
1H, J¼9.3 Hz, CHN); 3.9 (d, 1H, J¼13.7 Hz, CHHPh);
3.80 (m, 1H, CH3CHOH), 4.70 (dt, 1H, J¼9.1, 3.0 Hz,
CHOH); 7.20–7.50 (m, 15H, Har). 13C NMR (CDCl3):
23.6 (CH3); 40.7 (CH2); 54.5 (CH2Ph); 65.1 (CH3CHOH);
67.1 (CHN); 68.1 (CHOH); 127.8, 128.3, 128.8, 130.0
(CHar); 134.7, 139.4 (Car). C25H29NO2 (375.5): calcd C
79.96, H 7.78, N 3.73; found C 79.85, H 7.90, N 3.80.
3.2.22. (2R,4R,5S)-5-Dibenzylamino-2,4-isopropyliden-
dioxy-6-methylheptano (cis-5b). To a solution of amino
diol anti-syn-4b (34 mg, 0.1 mmol) in 2,2-dimethoxypro-
pane (2 mL), at room temperature, was added p-TsOH$H2O
(8 mg). The mixture was stirred at 70 ꢀC for 2 h, and then
quenched with aqueous saturated solution of NaHCO3
(3 mL). The aqueous phase was extracted with EtOAc
(3ꢂ10 mL) and dried over anhydrous MgSO4. The solvents
were eliminated under vacuum and the residue was purified
by flash chromatography (silica gel, hexane/EtOAc 30:1) to
yield 33 mg of cis-5b (0.087 mmol, 87%) as a colorless oil.
[a]2D3 ꢁ21.1 (c 0.5, CHCl3). IR (film): 1454, 1378, 1258,
3.2.19. (2S,4R,5S)-5-Dibenzylamino-6-phenylhexane-2,4-
diol (anti-anti-4c). This compound was obtained as the
major diastereomer in the reaction of anti-3c (85 mg,
0.22 mmol) with NaBH(OAc)3 by the method described
for anti-anti-4b and purified by flash chromatography (silica
gel, hexane/EtOAc 4:1): 23 mg (0.06 mmol, 27%). Color-
less oil. [a]2D3 +27.8 (c 0.36, CHCl3). IR (film): 3368,
1179, 746, 698 cmꢁ1 1H NMR (CDCl3): 0.99 (d, 3H,
.
J¼6.6 Hz, (CH3)2CH); 1.02 (d, 3H, J¼6.1 Hz, (CH3)2CH);
1.17 (d, 3H, J¼6.1 Hz, CH3CH); 1.35 (s, 3H, CH3); 1.48
(s, 3H, CH3); 1.67 (m, 1H, CHHCHO); 2.20 (m, 1H,
CH(CH3)2); 2.30 (dd, 1H, J¼6.5, 4.4 Hz, CHN); 3.61 (d,
2H, J¼13.7 Hz, CHHPh); 3.67 (d, 2H, J¼13.7 Hz, CHHPh);
3.99 (m, 1H, CH3CHO); 4.25 (ddd, 1H, J¼11.7, 6.2, 2.4 Hz,
CHO); 7.20–7.40 (m, 10H, Har). 13C NMR (CDCl3): 19.4,
20.0 ((CH3)2CH); 22.4 (CH3CHO); 23.1 (CH3); 25.5
(CH(CH3)2); 30.2 (CH3); 38.1 (CH2); 54.8 (CH2Ph); 65.2
(CHO); 65.6 (CH3CHO); 67.3 (CHN); 98.2 (O2C(CH3)2),
126.8, 128.1, 128.9 (CHar); 140.1 (Car). C25H35NO2
(381.5): calcd C 78.70, H 9.25, N 3.67; found C 78.49, H
9.30, N 3.51.
1
1453, 1122, 1074, 740, 700 cmꢁ1. H NMR (CDCl3): 1.16
(d, 3H, J¼6.3 Hz, CH3); 1.63 (m, 2H, CH2CHOH);
2.86 (dd, 1H, J¼12.7, 5.8 Hz, CHHCHN); 3.07 (m, 1H,
CHN); 3.12 (m, 1H, CHHCHN); 3.59 (d, 1H, J¼13.7 Hz,
NCHHPh); 3.79 (d, 1H, J¼13.7 Hz, NCHHPh); 3.93 (m,
1H, CH3CHOH); 4.05 (m, 1H, CHOH); 7.15–7.35 (m,
15H, Har). 13C NMR (CDCl3): 23.3 (CH3); 32.1 (CH2CHN);
40.9 (CH2CHOH); 55.0 (CH2Ph); 63.2 (CH3CHOH); 65.7
(CHN); 68.9 (CHOH); 126.0, 127.1, 128.3, 128.4, 128.8,
129.3 (CHar); 139.5, 140.6 (Car). C26H31NO2 (389.5): calcd
C 80.17, H 8.02, N 3.60; found C 80.34, H 7.91, N 3.71.
3.2.20. (1R,2S,4S)-1-Dibenzylamino-1-phenylpentane-
2,4-diol (anti-syn-4e). This compound was obtained from
anti-3e (45 mg, 0.12 mmol), by the method described for
3.2.23. (2S,4R,5S)-5-Dibenzylamino-2,4-isopropyliden-
dioxy-6-methylheptane (trans-5b). This compound was

7790
J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
obtained from anti-anti-4b (34 mg, 0.1 mmol), by the
method described for cis-5b and purified by flash chro-
matography (silica gel, hexane/EtOAc 15:1): 18 mg
(0.048 mmol, 48%). Colorless oil. [a]2D3 ꢁ11.7 (c 0.5,
CHCl3). IR (film): 1454, 1378, 1224, 1120, 748,
((CH3)3CSi); 25.1 (CH2); 25.5 ((CH3)3CSi); 54.5 (CH2Ph);
66.4 (CHN); 70.5 (C^CH); 71.7 (CHO); 82.1 (C^CH);
126.9, 127.1, 127.7, 128.3, 128.9, 130.3 (CHar); 135.7,
139.4 (Car). C31H39NOSi (469.7): calcd C 79.26, H 8.37,
N 2.98; found C 79.02, H 8.18, N 2.86.
701 cmꢁ1
.
1H NMR (CDCl3): 1.03 (d, 3H, J¼6.6 Hz,
(CH3)2CH); 1.04 (d, 3H, J¼6.5 Hz, (CH3)2CH); 1.21 (d,
3H, J¼6.2 Hz, CH3CH); 1.33 (s, 3H, CH3); 1.45 (s, 3H,
CH3); 1.60 (ddd, 1H, J¼12.7, 9.8, 7.0 Hz, CHHCHO);
1.74 (ddd, 1H, J¼12.7, 9.3, 5.6 Hz, CHHCHO); 2.25 (m,
1H, CH(CH3)2); 2.28 (m, 1H, CHN); 3.57 (d, 2H,
J¼13.7 Hz, CHHPh); 3.73 (d, 2H, J¼13.7 Hz, CHHPh);
3.88 (m, 1H, CH3CHO); 4.27 (ddd, 1H, J¼12.2, 9.2,
7.0 Hz, CHO); 7.20–7.40 (m, 10H, Har). 13C NMR
(CDCl3): 20.2, 21.6 ((CH3)2CH); 22.8 (CH3CHO); 24.5
(CH3); 25.0 (CH3); 25.9 (CH(CH3)2); 40.1 (CH2); 54.7
(CH2Ph); 62.8 (CHO); 64.3 (CH3CHO); 65.3 (CHN);
100.3 (O2C(CH3)2); 126.7, 128.1, 129.0 (CHar); 140.2
(Car). C25H35NO2 (381.5): calcd C 78.70, H 9.25, N 3.67;
found C 78.55, H 9.20, N 3.60.
3.2.26. (3S,4R,8R,9S)-3,9-Bis-dibenzylamino-2,10-di-
methyl-5-undecyne-4,8-diol (7b). To a solution of anti-6b
(323 mg, 0.74 mmol) in anhydrous THF (4 mL) at ꢁ78 ꢀC
was added 1.6 M n-BuLi in hexane (0.51 mL, 0.81 mmol,
1.1 equiv) under argon. After the mixture was stirred for
1 h at ꢁ78 ꢀC, a solution of amino aldehyde 1b (229 mg,
0.81 mmol, 1.1 equiv) in THF was added. The mixture was
kept at ꢁ78 ꢀC for 2 h and then allowed to warm to room
temperature overnight. Then, TBAF (281 mg, 0.89 mmol,
1.2 equiv) was added at 0 ꢀC and the mixture was stirred
at room temperature for 6 h. Saturated aqueous NH4Cl
(5 mL) was added to quench the reaction, then THF was
removed, and the aqueous phase was extracted with CHCl3
(3ꢂ10 mL). The organic extracts were combined, washed
with brine, dried (MgSO4), and concentrated under reduced
pressure. The crude product was purified by flash chro-
matography (silica gel, hexane/ethyl acetate 15:1 to 8:1):
235 mg (0.39 mmol, 53%). Colorless oil. [a]2D3 ꢁ68.0
(c 0.6, CHCl3). IR (film): 3415, 2227, 1736, 1604, 750,
3.2.24. (4R,5S)-5-Dibenzylamino-4-(tert-butyldimethyl-
silyloxy)-6-methyl-1-heptyne (anti-6b). To a solution of
anti-2b (482 mg, 1.55 mmol) and imidazole (270 mg,
4.5 mmol, 3 equiv) in DMF (3 mL) was added TBDMSCl
(340 mg, 2.25 mmol, 1.5 equiv) at 0 ꢀC and the mixture was
stirred at room temperature overnight. The reaction mixture
was quenched with aqueous saturated NH4Cl solution
(10 mL) and decanted. The aqueous phase was extracted
with ether (3ꢂ10 mL), and the combined organic phases
were washed with brine, dried (MgSO4), and the solvent
was evaporated. The product was purified by flash chroma-
tography (silica gel, hexane/EtOAc 50:1) yielding anti-6b
as a colorless solid: 425 mg (0.98 mmol, 65%). Mp 57–
58 ꢀC. [a]D23 ꢁ19.8 (c 1.2, CHCl3). IR (film): 3310, 1952,
695 cmꢁ1
.
1H NMR (CDCl3): 0.96 (d, 3H, J¼6.4 Hz,
CH3); 0.98 (d, 3H, J¼6.5 Hz, CH3); 1.08 (d, 3H,
J¼6.8 Hz, CH3); 1.30 (d, 3H, J¼7.1 Hz, CH3); 2.20 (m,
2H, CH(CH3)2 and CHHC^C); 2.32 (m, 1H, CHHC^C);
2.41 (m, 1H, CH(CH3)2); 2.53 (dd, 1H, J¼10.6, 4.6 Hz,
CHN); 2.64 (dd, 1H, J¼16.7, 3.0 Hz, CHN) 3.60 (s, 4H,
CH2Ph); 3.73 (d, 2H, J¼13.1 Hz, CHHPh); 3.93 (m, 1H,
CH2CHOH); 4.25 (m, 1H, CHOH); 4.31 (d, 2H, J¼
13.1 Hz, CHHPh); 7.15–7.35 (m, 20H, Har). 13C NMR
(CDCl3): 20.0 (CH3); 20.6 (CH3); 22.5 (CH3); 23.3 (CH3);
26.1 (CH(CH3)2); 26.4 (CH2CHOH); 29.2 (CH(CH3)2);
55.0, 55.9 (CH2Ph); 60.3 (CHOH); 65.6 (CHN); 66.5
(CHN); 68.9 (CH2CHOH); 82.1 (C^C); 83.2 (C^C);
126.9, 127.2, 128.2, 128.4, 128.9, 129.3 (CHar); 139.6
(Car). C41H50N2O2 (602.8): calcd C 81.69, H 8.36, N 4.65;
found C 81.25, H 7.96, N 4.34.
1090, 745, 700 cmꢁ1 1H NMR (CDCl3): 0.20, 0.21 (s,
.
3H, CH3Si); 0.92 (s, 9H, (CH3)3C); 0.97 (d, 3H, J¼
6.6 Hz, CH3); 1.09 (d, 3H, J¼6.8 Hz, CH3); 1.94 (t, 1H,
J¼2.8 Hz, ^CH); 2.22 (m, 1H, CH(CH3)2); 2.52 (m, 2H,
CH2C^CH); 3.50 (d, 2H, J¼14.1 Hz, CHHPh); 3.91 (d,
2H, J¼14.1 Hz, CHHPh); 4.37 (m, 1H, CHO); 7.15–7.45
(m, 10H, Har). 13C NMR (CDCl3): ꢁ4.4, ꢁ3.3 (CH3Si);
18.1 ((CH3)3CSi); 21.2, 21.8 (CH3); 25.9 ((CH3)3C); 27.0
((CH3)2CH); 28.1 (CH2C^CH); 54.7 (CH2Ph); 66.1
(CHN); 69.5 (CHOTBDMS); 71.0 (C^CH); 81.8
(C^CH); 126.6, 127.9, 129.0 (CHar); 140.4 (Car).
C28H41NOSi (435.7): calcd C 77.18, H 9.48, N 3.21; found
C 76.76, H 9.08, N 2.99.
3.2.27. (3S,4S,8R,9S)-3,9-Bis-dibenzylamino-2,10-
dimethyl-5-undecyne-4,8-diol (epi-7b). This compound was
obtained as the minor product in the reaction of the lithiated
compound derived from anti-6b (323 mg, 0.74 mmol) with
the amino aldehyde 1b and purified by flash chromatography
(silica gel, hexane/EtOAc 15:1 to 8:1): 60 mg (0.1 mmol,
13%). Colorless oil. [a]2D3 ꢁ52.0 (c 1.1, MeOH). [a]D23
ꢁ2.0 (c 1.1, CHCl3). IR (film): 3405, 2232, 1450, 745,
3.2.25. (4S,5R)-5-Dibenzylamino-4-(tert-butyldimethyl-
silyloxy)-5-phenyl-1-pentyne (anti-6e). This compound
was obtained from anti-2e (249 mg, 0.7 mmol) by the method
described for anti-6b and purified by flash chromatography
(silica gel, hexane/EtOAc 50:1): 221 mg (0.47 mmol,
67%). Colorless oil. [a]2D3 ꢁ45.0 (c 0.77, CHCl3). IR
700 cmꢁ1
.
1H NMR (CDCl3): 1.05 (d, 3H, J¼6.7 Hz,
CH3); 1.10 (d, 3H, J¼7.0 Hz, CH3); 1.13 (d, 3H,
J¼6.8 Hz, CH3); 1.15 (d, 3H, J¼6.9 Hz, CH3); 2.28 (m,
2H, CH(CH3)2); 2.40 (m, 2H, CH2C^C); 2.61 (dd, 1H,
J¼8.5, 3.8 Hz, CHN); 2.71 (d, 1H, J¼16.6 Hz, CHN);
3.58 (d, 2H, J¼13.2 Hz, CHHPh); 3.66 (d, 2H, J¼13.6 Hz,
CHHPh); 3.73 (d, 2H, J¼13.6 Hz, CHHPh); 3.84 (d, 2H,
J¼13.2 Hz, CHHPh); 4.04 (m, 1H, CH2CHOH); 4.46 (d,
1H, J¼8.5 Hz, CHOH); 7.20–7.45 (m, 20H, Har). 13C
NMR (CDCl3): 19.5 (CH3); 20.1 (CH3); 23.4 (CH3); 25.8
(CH(CH3)2); 26.2 (CH(CH3)2); 26.4 (CH2CHOH); 53.8,
55.1 (CH2Ph); 59.2 (CHOH); 65.4 (CHN); 66.8 (CHN);
68.7 (CH2CHOH); 82.1 (C^C); 83.9 (C^C); 127.0,
1
(film): 3309, 2122, 1454, 1252, 1109, 745, 699 cmꢁ1. H
NMR (CDCl3): ꢁ0.31 (s, 3H, CH3Si); 0.08 (s, 3H,
CH3Si); 0.62 (s, 9H, (CH3)3C); 1.91 (t, 1H, J¼2.6 Hz,
^CH); 2.69 (ddd, 1H, J¼16.9, 4.9, 2.6 Hz, CHHCHO);
3.01 (m, 1H, CHHCHO); 3.16 (d, 2H, J¼13.7 Hz, CHHPh);
3.79 (d, 1H, J¼9.1 Hz, CHN); 3.90 (d, 2H, J¼13.7 Hz,
CHHPh); 4.53 (m, 1H, CHOTBDMS); 7.20–7.50 (m, 15H,
Har). 13C NMR (CDCl3): ꢁ5.4, ꢁ4.0 (CH3Si); 17.8

J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
7791
127.3, 128.3, 128.4, 129.0, 129.2 (CHar); 138.8, 139.7 (Car).
C41H50N2O2 (602.8): calcd C 81.69, H 8.36, N 4.65; found C
81.32, H 8.05, N 4.40.
(C(CH3)3); 21.1, 21.8 (CH3CH); 25.9 ((CH3)3C); 26.9
((CH3)2CH); 28.1 (CH2CHO); 54.8 (CH2Ph); 61.7
(CH2CH3); 66.5 (CHN); 69.1 (CHO); 75.1 (C^CCO2Et);
86.5 (C^CCO2Et); 126.7, 128.0, 128.9 (CHar); 140.0
(Car); 153.5 (CO2Et).
3.2.28. (3S,4R,8R,9S)-3,9-Diamino-2,10-dimethylunde-
cane-4,8-diol (8b). To a solution of diol 7b (316 mg,
0.52 mmol) in MeOH (5 mL) was added Pd(OH)2/C
(95 mg) in one portion. The mixture was stirred under hydro-
gen for 1 h and the catalyst was removed by filtration and
washed with methanol. The solvent was evaporated under
reduced pressure to give 8b as a colorless solid: 128 mg
(0.52 mmol, 100%). Mp 152–153 ꢀC. [a]D23 +38.8 (c 1.0,
3.2.31. (5S,6R)-Ethyl 6-dibenzylamino-5-(tert-butyldi-
methylsilyloxy)-6-phenyl hex-2-ynoate (anti-9e). This
compound was obtained as a product in the reaction of
the lithiated compound derived from anti-6e (188 mg,
0.4 mmol) with ethyl chloroformate by the procedure
described for anti-9b. Yield: 145 mg (0.27 mmol, 67%).
Colorless oil. IR (film): 2238, 1710, 1254, 1100, 750,
1
MeOH). IR (KBr): 3348, 1598, 1473, 1062, 980 cmꢁ1. H
1
NMR (CD3OD): 0.96 (d, 6H, J¼6.8 Hz, CH3); 0.97 (d,
6H, J¼6.7 Hz, CH3); 1.35–1.65 (m, 6H, CH2CH2CH2);
1.86 (m, 2H, CH(CH3)2); 2.56 (dd, 2H, J¼6.6, 5.4 Hz,
CHN); 3.65 (m, 2H, CHOH). 13C NMR (CD3OD): 18.7
(CH3); 20.6 (CH3); 23.7 (CH2); 30.1 (CH(CH3)2); 32.0
(CH2CHOH); 63.1 (CHN); 72.4 (CHOH). C13H30N2O2
(246.4): calcd C 63.37, H 12.27, N 11.37; found C 63.30,
H 12.11, N 11.49.
700 cmꢁ1. H NMR (CDCl3): ꢁ0.42 (s, 3H, CH3Si); 0.02
(s, 3H, CH3Si); 0.55 (s, 9H, (CH3)3C); 1.28 (t, 3H,
J¼7.1 Hz, CH3CH2); 2.75 (dd, 1H, J¼17.4, 5.5 Hz,
CHHC^C); 3.08 (d, 2H, J¼13.7 Hz, CHHPh); 3.19 (dd,
1H, J¼17.4, 3.7 Hz, CHHC^C); 3.63 (d, 1H, J¼9.4 Hz,
CHN); 3.81 (d, 2H, J¼13.7 Hz, CHHPh); 4.18 (q, 2H,
J¼7.1 Hz, CH2CH3); 4.51 (m, 1H, CHO); 7.15–7.45 (m,
15H, Har). 13C NMR (CDCl3): ꢁ5.5, ꢁ4.2 (CH3Si); 14.0
(CH3CH2); 17.8 ((CH3)3CSi); 25.4 ((CH3)3C); 25.6
(CH2C^C); 54.5 (CH2Ph); 61.6 (CH2CH3); 66.8 (CHN);
3.2.29. (3S,4S,8R,9S)-3,9-Diamino-2,10-dimethylunde-
cane-4,8-diol (epi-8b). This compound was obtained by
debenzylation of epi-7b (54 mg, 0.09 mmol) as described
for 8b: 15 mg (0.063 mmol, 70%). Colorless solid. [a]D23
70.9
(CHOTBDMS);
75.0
(C^CCO2Et);
87.5
(C^CCO2Et); 127.0, 127.3, 127.9, 128.4, 128.7, 130.3
(CHar); 135.2, 139.1 (Car); 153.6 (CO2Et).
1
+15.9 (c 0.3, MeOH). H NMR (CD3OD): 1.00 (d, 6H,
J¼6.9 Hz, CH3); 1.03 (d, 3H, J¼6.9 Hz, CH3); 1.06 (d,
3H, J¼7.0 Hz, CH3); 1.30–1.85 (m, 6H, CH2CH2CH2);
1.94 (m, 1H, CH(CH3)2); 1.99 (m, 1H, CH(CH3)2); 2.76
(m, 2H, CHN); 3.73 (dd, 1H, J¼8.4, 4.4 Hz, CHOH); 3.80
(dd, 1H, J¼10.0, 4.6 Hz, CHOH). 13C NMR (CD3OD):
17.9 (CH3); 19.2 (CH3); 20.2 (CH3); 20.3 (CH3); 23.2
(CH2); 29.3 (CH(CH3)2); 29.8 (CH(CH3)2); 31.4
(CH2CHOH); 35.3 (CH2CHOH); 62.4 (CHN); 63.6
(CHN); 70.1 (CHOH); 70.6 (CHOH). C13H30N2O2
(246.4): calcd C 63.37, H 12.27, N 11.37; found C 63.56,
H 12.37, N 11.22.
3.2.32. (5R,6S)-Ethyl 5-(tert-butyldimethylsilyloxy)-6-
tert-butoxycarbonylamino-7-methyl octanoate (anti-
10b). To a solution of anti-9b (1.02 g, 2 mmol) in EtOAc
(20 mL) were added di-tert-butyl dicarbonate (655 mg,
3 mmol, 1.5 equiv) and Pd(OH)2/C (250 mg) in one portion.
The mixture was stirred under 1 hydrogen atmosphere and
the reaction was monitored by TLC. When the reaction
was completed, the catalyst was removed by filtration and
washed with EtOAc. The solvent was concentrated under
reduced pressure and the residue was purified by flash chro-
matography (silica gel, hexane/EtOAc 30:1): 276 mg
(0.64 mmol, 32%). Colorless oil. [a]2D3 ꢁ10.0 (c 1.0,
CHCl3). IR (film): 3462, 3369, 1734, 1720, 1705, 1171,
837 cmꢁ1. 1H NMR (CDCl3): 0.05 (s, 3H, CH3Si); 0.07 (s,
3H, CH3Si); 0.87 (d, 3H, J¼6.8 Hz, CH3CH); 0.89 (s, 9H,
(CH3)3CSi); 0.92 (d, 3H, J¼6.8 Hz, CH3CH); 1.25 (t, 3H,
J¼7.1 Hz, CH3CH2); 1.43 (s, 9H, (CH3)3CO); 1.63 (m,
4H, CH2CH2CH2CO2Et); 1.92 (m, 1H, CH(CH3)2); 2.29
(m, 2H, CH2CO2Et); 3.49 (m, 1H, CHN); 3.72 (m, 1H,
CHO); 4.12 (q, 2H, J¼7.1 Hz, CH2CH3); 4.53 (d, 1H,
J¼10.3 Hz, NH). 13C NMR (CDCl3): ꢁ4.8, ꢁ4.5 (CH3Si);
14.1 (CH3CH2); 17.4 (CH3CH); 17.9 ((CH3)3CSi); 20.8
(CH3CH and CH2); 25.8 ((CH3)3CSi); 27.5 ((CH3)2CH);
28.3 ((CH3)3CO); 32.9 (CH2); 34.4 (CH2); 57.5 (CHN);
60.1 (CH2CH3); 73.1 (CHO); 78.7 ((CH3)3CO); 155.8
3.2.30. (5R,6S)-Ethyl 6-dibenzylamino-5-tert-butyldi-
methylsilyloxy-7-methyloct-2-ynoate (anti-9b). To a solu-
tion of anti-6b (958 mg, 2.2 mmol) in anhydrous THF (20 mL)
at ꢁ78 ꢀC was added 1.6 M n-BuLi in hexane (2.1 mL,
3.3 mmol, 1.5 equiv) under argon. After the mixture was
stirred for 1 h at ꢁ78 ꢀC, ethyl chloroformate (0.42 mL,
4.4 mmol, 2 equiv) was added. The mixture was kept
at ꢁ40 ꢀC for 1 h and then allowed to warm to 0 ꢀC and
quenched with saturated aqueous NH4Cl solution (20 mL).
Then THF was removed and the aqueous phase was ex-
tracted with Et2O (3ꢂ20 mL). The organic extracts were
combined, washed with brine, dried (MgSO4), and concen-
trated under reduced pressure to yield an oil that was used
without further purification in the next step: 970 mg
(1.91 mmol, 87%). Colorless oil. IR (film): 2234, 1712,
t
(CO2 Bu); 173.2 (CO2Et). C22H45NO5Si (431.7): calcd C
61.21, H 10.51, N 3.24; found C 61.39, H 10.59, N 3.30.
1
1252, 1072, 748, 699 cmꢁ1. H NMR (CDCl3): 0.19 (s,
6H, CH3Si); 0.90 (s, 9H, (CH3)3C); 0.96 (d, 3H, J¼6.5 Hz,
CH3CH); 1.05 (d, 3H, J¼6.8 Hz, CH3CH); 1.31 (t, 3H,
J¼7.1 Hz, CH3CH2); 2.19 (m, 1H, CH(CH3)2); 2.42 (dd,
1H, J¼7.6, 2.9 Hz, CHN); 2.65 (d, 2H, J¼6.6 Hz,
CH2CHO); 3.50 (d, 2H, J¼13.9 Hz, CHHPh); 3.86 (d, 2H,
J¼13.9 Hz, CHHPh); 4.23 (q, 2H, J¼7.1 Hz, CH2CH3);
4.37 (m, 1H, CHO); 7.15–7.45 (m, 10H, Har). 13C NMR
(CDCl3): ꢁ4.4, ꢁ3.5 (CH3Si); 14.0 (CH3CH2); 18.1
3.2.33. (5S,6R)-Ethyl 5-(tert-butyldimethylsilyloxy)-6-
tert-butoxycarbonylamino-6-phenyl hexanoate (anti-
10e). This compound was obtained from anti-9e (135 mg,
0.25 mmol) by the method described for anti-10b and puri-
fied by flash chromatography (silica gel, hexane/EtOAc
15:1): 55 mg (0.12 mmol, 47%). Colorless oil. [a]2D3 ꢁ14.9
(c 1.0, CHCl3). IR (film): 3366, 1713, 1170, 776,
701 cmꢁ1. 1H NMR (CDCl3): 0.08 (s, 3H, CH3Si); 0.09 (s,

7792
J. M. Andreꢀs et al. / Tetrahedron 62 (2006) 7783–7792
7. Poisson, J.-F.; Normant, J. F. J. Org. Chem. 2000, 65, 6553–
6560.
3H, CH3Si); 0.92 (s, 9H, (CH3)3CSi); 1.20 (t, 3H, J¼7.2 Hz,
CH3CH2); 1.40 (s, 9H, (CH3)3CO2); 1.65 (m, 4H,
CH2CH2CHO); 2.19 (m, 2H, CH2CO2Et); 3.98 (m,
1H, CHO); 4.06 (q, 2H, J¼7.2 Hz, CH2CH3); 4.65 (m, 1H,
CHN); 5.28 (m, 1H, NH); 7.15–7.35 (m, 5H, Har).
13C NMR (CDCl3): ꢁ4.7, ꢁ4.5 (CH3Si); 14.1 (CH3);
18.1 ((CH3)3CSi); 21.1 (CH2); 25.9 ((CH3)3CSi); 28.3
((CH3)3CO2C); 32.8 (CH2CHO); 34.2 (CH2CO2); 60.2
(CH2CH3); 74.4 (CHOTBDMS); 79.3 ((CH3)3CO2); 127.3,
8. For recent examples of enantioselective propargylation: (a)
Lai, C.; Soderquist, J. A. Org. Lett. 2005, 7, 799–802; (b)
Inoue, M.; Nakada, M. Org. Lett. 2004, 6, 2977–2980; (c)
Lee, K.-C.; Lin, M.-J.; Loh, T.-P. Chem. Commun. 2004,
2456–2457; (d) Loh, T.-P.; Lin, M.-J.; Tan, K.-L. Tetrahedron
Lett. 2003, 44, 507–509; (e) Konishi, S.; Hanawa, H.;
Maruoka, K. Tetrahedron: Asymmetry 2003, 14, 1603–1605.
t
´
9. (a) Andres, J. M.; Barrio, R.; Martınez, M. A.; Pedrosa, R.;
Perez-Encabo, A. J. Org. Chem. 1996, 61, 4210–4213; (b)
ꢀ
128.0, 128.1 (CHar); 155.2 (NHCO2 Bu); 173.2 (CO2Et).
C25H43NO5Si (465.7): calcd C 64.48, H 9.31, N 3.01; found
C 64.57, H 9.14, N 3.05.
ꢀ
ꢀ
´
Andres, J. M.; Martınez, M. A.; Pedrosa, R.; Perez-Encabo,
A. Tetrahedron: Asymmetry 2001, 12, 347–353; (c) Andres,
ꢀ
ꢀ
ꢀ
J. M.; Pedrosa, R.; Perez, A.; Perez-Encabo, A. Tetrahedron
2001, 57, 8521–8530; (d) Andres, J. M.; Pedrosa, R.; Perez-
ꢀ
ꢀ
Acknowledgements
ꢀ
Encabo, A. Eur. J. Org. Chem. 2004, 1558–1666.
ꢀ
Tetrahedron 1999, 55, 14137–14144.
´
Authors thank the Spanish Ministerio de Educacion y Cien-
ꢀ
10. Andres, J. M.; de Elena, N.; Pedrosa, R.; Perez-Encabo, A.
cia (DGI, Project CTQ2005-01191/BQU) for financial
support.
11. (a) van der Zeijden, A. A. H. Tetrahedron: Asymmetry 1995, 6,
913–918; (b) Ishimaru, K.; Tsuru, K.; Yabuta, K.; Wada, M.;
Yamamoto, Y.; Akiba, K. Tetrahedron 1996, 52, 13137–13144.
12. Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141–1143.
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