Diastereoselective ethynylation of chiral α-(dibenzylamino) aldehydes: Synthesis of meso- and homochiral C2-symmetrical 1,6-diamino-2,5-diols

Article abstract of DOI:10.1002/ejoc.200600214

Homochiral α-(dibenzylamino) aldehydes, prepared from the corresponding α-amino acids, react with ethynylmagnesium bromide in THF/Et₂O at 0°C to afford, in good yields and dr, propargylic 1,2-amino alcohols; anti diastereomers were always forme

Full text of DOI:10.1002/ejoc.200600214

FULL PAPER
DOI: 10.1002/ejoc.200600214
Diastereoselective Ethynylation of Chiral α-(Dibenzylamino) Aldehydes:
Synthesis of meso- and Homochiral C2-Symmetrical 1,6-Diamino-2,5-diols
José M. Andrés,[a] Rafael Pedrosa,*[a] and Alfonso Pérez-Encabo[a]
Keywords: Amino acids / Amino aldehydes / Asymmetric synthesis / Ethynylation
Homochiral α-(dibenzylamino) aldehydes, prepared from the
corresponding α-amino acids, react with ethynylmagnesium
bromide in THF/Et2O at 0 °C to afford, in good yields and
dr, propargylic 1,2-amino alcohols; anti diastereomers were
always formed as the major products in this reaction. These
compounds are versatile intermediates in the synthesis of
meso- and enantiopure 1,6-diamino-2,5-diols with C2 sym-
metry.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
adducts can be obtained depending on the nature of the
protecting groups at the nitrogen atom.[8] N-Boc-protected
amino aldehydes give the syn diastereoisomer on reaction
with lithium acetylides[2] and also the syn diastereoisomer
was obtained from the reaction of ethynylmagnesium bro-
mide with 9-fluorenylamino aldehydes.[9] In contrast, ben-
zyl(tosyl)amino aldehydes yielded the anti diastereoisomer
with high diastereoselectivity[10] and the alkynylation of di-
benzylamino aldehydes with lithium acetylides also gave the
anti adducts exclusively.[11,12]
Recently, we reported on the diastereoselective alkylation
of α-(dibenzylamino) aldehydes with diethylzinc leading to
syn-1,2-amino alcohols[13] as a complementary route to the
preparation of anti adducts obtained by reaction with lith-
ium, magnesium or copper derivatives.[14] In addition, di-
benzylamino aldehydes react with diethylaluminium cya-
nide,[15] Reformatsky reagents,[16] or CF3TMS[17] to yield
the anti diastereoisomer as the major product.
Introduction
Propargyl 1,2-amino alcohols (I) are very important
starting compounds in organic synthesis (Figure 1). They
can be transformed into 4-amino-3-hydroxy acids (II) by
hydroboration/oxidation or into protected 3-amino-2-hy-
droxy acids (III) by ruthenium-catalyzed oxidation of the
acetylenic bond.[1] Chiral 3-substituted 2-ethynylaziridines
(IV) have also been prepared by Mitsunobu[2] reaction or
intramolecular amination[3] of bromoallenes obtained from
I. Methods for the asymmetric synthesis of these intermedi-
ates, such as diastereoselective reduction of acetylenic
ketones,[1,4] diastereoselective condensation of propargyl al-
dehydes with tin enolates,[5] addition of alkoxyallenylzinc
compounds to imines[6] and some others,[7] have been de-
scribed, but the most direct synthesis involves the addition
of metal acetylides to protected chiral α-amino aldehydes.
In this paper we summarize our results on the reaction
of α-(dibenzylamino) aldehydes 1a–e and ketone 1f with
ethynylmagnesium bromide leading to propargyl 1,2-amino
alcohols and their transformations into meso- and enantio-
pure amino alcohol derivatives with C2 symmetry. The
asymmetric synthesis of these compounds has attracted
much interest because they have been used as chiral li-
gands[18] and are an important part of pseudopeptides
which act as HIV protease inhibitors.[19] In addition, al-
though the synthesis of 1,4-diamino-2,3-diols with C2 sym-
metry has been thoroughly developed[20] the asymmetric
preparation of 1,5-diamino-2,4-diols[21] and 1,6-diamino-
2,5-diols[22] has attracted less attention.
Figure 1. Different transformations for amino propargyl alcohols.
Nevertheless, the control of facial selectivity in these ad-
dition reactions is not easy and mixtures of syn and anti
[a] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid,
Results and Discussion
Doctor Mergelina s/n, 47011 Valladolid, Spain
Fax: +34-983-423013
The reaction of α-(dibenzylamino) aldehydes 1a–e with
ethynylmagnesium bromide in a mixture of THF/Et2O at
E-mail: pedrosa@qo.uva.es
3442
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3442–3450

Diastereoselective Ethynylation of Chiral α-(Dibenzylamino) Aldehydes
FULL PAPER
0 °C yielded the propargyl 1,2-amino alcohols 2a–e in good
chemical yields. The anti adducts were formed as the major
diastereoisomer in high diastereomeric excess (de) and the
diastereoselectivity was not affected by the size of the sub-
stituent when R was an alkyl group (Scheme 1 and Table 1,
Entries 1–3). In contrast, the facial discrimination was
lower in the reaction of -phenylglycinal (ent-1e, R = Ph)
or in the presence of additional heteroatoms in the chain of
the amino aldehyde, 1d (-serinal) (Table 1, Entries 4 and
5). α-(Dibenzylamino) ketone 1f also reacted with ethynyl-
magnesium bromide to give the tertiary propargyl carbinol
anti-2f in excellent de (Table 1, Entry 6). This behavior is
similar to that described for reactions with other magne-
sium or lithium derivatives.[23]
Scheme 2. Reagents and conditions: (i) 1. nBuLi (2.1 equiv.),
THF, –78 °C, 1 h; 2. TMSCl, THF, –78 °C; 3. NH4Cl; (ii)
(COCl)2, DMSO, Et3N, CH2Cl2, –78 °C; (iii) LiAlH4, Et2O,
–78 °C; (iv) TBAF, THF, room temp.
The transformation of these propargyl 1,2-amino
alcohols into 1,6-diamino-2,5-diols was envisaged by their
reaction with α-(dibenzylamino) aldehydes, taking as a
model anti-2b and its TBDMS derivative anti-5b and - or
-valinal as the aldehyde. If the stereochemical behavior of
these reactions is in agreement with the Felkin–Anh model,
a meso-diamino diol would be obtained as the major dia-
stereoisomer in the reaction with -dibenzylvalinal (ent-1b)
and the C2-symmetrical homochiral 1,6-diamino-2,5-diol
derivative from -dibenzylvalinal (1b). In fact, the dianion
prepared by treatment of anti-2b with nBuLi (2 equiv.) re-
acted with ent-1b in THF at –78 °C to yield a mixture of
6b and its C-7 epimer (epi-6b) but in low yield and with
moderate diastereoselectivity (Scheme 3 and Table 2, En-
try 1). The same behavior was observed in the reaction of
anti-2b with -dibenzylvalinal (1b), leading to a mixture of
7b and epi-7b in low yield and with moderate diastereoselec-
tivity (Table 2, Entry 4).
Scheme 1. Reagents and conditions: (i) 1. HCϵCMgBr, THF/Et2O,
0 °C; 2. NH4Cl.
Table 1. Stereoselective ethynylation of α-(dibenzylamino) alde-
hydes 1a–e and α-(dibenzylamino) ketone 1f.
Entry
1[a]
R
RЈ
2
Yield [%][b] anti/syn[c]
1
2
3
4
5
6
1a
1b
1c
1d
ent-1e
1f
Me
iPr
H
H
H
H
H
2a
2b
2c
2d
ent-2e
2f
78
73
71
47
70
66
91:9
90:10
92:8
82:18
82:18
95:5
PhCH2
CH2OTBDMS
Ph
PhCH2
Me
[a] Reactions were carried out with 1.2 equiv. of ethynylmagnesium
bromide. [b] Numbers correspond to the combined yield of pure,
isolated diastereoisomers. [c] The diastereomeric ratio was deter-
mined by integration of the signals of the 1H NMR spectrum of
the reaction mixture.
Pure diastereoisomers were obtained from the reaction
mixtures by flash chromatography except for the -serinal
derivatives syn- and anti-2d. In this case, the mixture of dia-
stereoisomers was desilylated by reaction with TBAF in
THF at room temperature, but the resulting 2-amino-1,3-
diols were also inseparable by flash chromatography.
Amino alcohol syn-2b was synthesized from anti-2b as
summarized in Scheme 2. Amino alcohol anti-2b was con-
verted into anti-3b by deprotonation with nBuLi (2 equiv.)
in THF at –78 °C and treatment with TMSCl (1 equiv.).
Scheme 3. Reagents and conditions: (i) TBDMSCl, imidazole,
DMAP, CH2Cl2, room temp.; (ii) 1. nBuLi, THF, –78 °C, 1 h; 2.
ent-1b, THF, –78 °C; 3. TBAF, room temp.; 4. NH4Cl; (iii) 1.
nBuLi, THF, –78 °C, 1 h; 2. 1b, THF, –78 °C; 3. TBAF, room
temp.; 4. NH4Cl.
Much better results were obtained when the lithium de-
Swern oxidation of anti-3b led to propargyl ketone 4b, rivative of the silylated compound anti-5b was used as the
which was reduced with lithium aluminium hydride to syn- nucleophile. Deprotonation of anti-5b with nBuLi followed
3b as a single diastereoisomer. Deprotection of this com- by reaction with ent-1b yielded a mixture of 6b and epi-6b
pound by reaction with TBAF in THF at room temperature in 70% yield and with a good diastereomeric ratio after
yielded syn-2b in good yield.
desilylation of the condensation product with TBAF in
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
Table 2. Reaction of propargyl derivatives anti-2b and anti-5b with amino aldehydes ent-1b and 1b.
FULL PAPER
Entry
Acetylenic derivative
nBuLi [equiv.]
Amino aldehyde
Product
Yield [%][a]
dr[b]
1
2
anti-2b
anti-5b
anti-5b
anti-2b
anti-5b
2.1
1.1
1.1
2.1
1.1
ent-1b
ent-1b
ent-1b
1b
6b
6b
6b
7b
7b
40
70
63
38
67
65:35
84:16
88:12
72:28
86:14
3[c]
4
5
1b
[a] Numbers correspond to the combined yield of pure and isolated diastereoisomers. [b] The diastereomeric ratio was determined by
1
integration of the signals of the H NMR spectrum of the reaction mixture. [c] The reaction was carried out at –95 °C and with HMPA
(2 equiv.) as additive.
THF (Table 2, Entry 2). The diastereomeric ratio was im-
proved to 88:12 when the reaction was carried out at –95 °C
in the presence of HMPA, but the yield was slightly lower
(63%) (Table 2, Entry 3).
After isolation of the diastereoisomers by flash
chromatography, the structure of the major isomer (6b) was
determined to be a meso form (3S,4R,7S,8R) on the basis
of its H NMR spectral[24] and optical rotation data ([α]2D3
1
= 0). This fact led us to assign the stereochemistry for epi-
6b as (3S,4R,7R,8R).
The lithium salt of anti-5b also reacted with 1b to yield,
after desilylation, a mixture of 7b and epi-7b in 67% yield
and good diastereoselectivity (Table 2, Entry 5). This mix-
ture was inseparable by flash chromatography.
All these compounds were transformed into the corre-
sponding saturated diamino diols 8b and 10b, as summa-
rized in Scheme 4. Reduction and debenzylation of 6b by
stirring with Pearlman’s catalyst under hydrogen led to the
meso form of 8b, as determined by H NMR and optical
rotation measurements, and the same treatment of epi-6b
1
Scheme 4. Reagents and conditions: (i) H2, Pd(OH)2/C, THF/
MeOH; (ii) BnBr, K2CO3, CH3CN, reflux.
yielded epi-8b also in excellent yield. The mixture of dia-
stereoisomers 7b and epi-7b was subjected to hydrogenation
as described above and benzylated with excess benzyl bro-
mide and potassium carbonate in refluxing acetonitrile to
give a mixture of saturated bis(dibenzylamino) diols 9b and
epi-9b. Now the epimers were easily separated by flash
chromatography and the stereochemistry of 9b was assigned
as the C2-symmetrical homochiral (3S,4R,7R,8S)-3,8-
bis(dibenzylamino)-2,9-dimethyldecane-4,7-diol on the ba-
1
sis of its H NMR spectral characteristics. Compound 9b
was debenzylated to 10b by hydrogenolysis as described
above.
Two different transformations of 6b were studied
Scheme 5. Reagents and conditions: (i) LiAlH4, THF, reflux; (ii)
(COCl)2, DMSO, Et3N, CH2Cl2, –78 °C; (iii) NaBH4, THF/
MeOH, –20 to 0 °C.
(Scheme 5). Treatment of this compound with lithium alu-
minium hydride[25] in refluxing THF led to the meso form
of (E)-1,6-diaminohex-3-ene-2,5-diol derivative (E)-11b in
good yield as a single diastereoisomer. On the other hand,
Swern oxidation of 6b gave, in moderate yield, the propar-
gyl diketone 12b, which was transformed into the meso be used as the starting material for the synthesis of a dif-
form of the saturated 1,6-diamino-2,5-dione derivative 13b ferent meso form of 8b that differs in the relative stereo-
by reduction with sodium borohydride in THF/methanol chemistry of the vicinal dibenzylamino and hydroxy groups.
at –20 °C. The same diketone 13b was also obtained from In this case the relative stereochemistry of the vicinal sub-
8b after complete benzylation with benzyl bromide and po- stituents would be syn whereas in compound 8b the relative
tassium carbonate in acetonitrile and Swern oxidation of stereochemistry was anti.
the tetrabenzylated amino alcohol.
Compound 13b was allowed to react with different metal
Taking into account the stereochemistry of the reduction hydrides and the results are summarized in Scheme 6 and
of chiral α-(dibenzylamino) ketones, compound 13b could Table 3.
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Diastereoselective Ethynylation of Chiral α-(Dibenzylamino) Aldehydes
FULL PAPER
zylamino) aldehydes 1a–e and α-amino ketone 1f were prepared
as described previously.[13,26] Ethynylmagnesium bromide, as 0.5 
solution in THF, is commercially available. The 1H (300 MHz) and
13C NMR (75 MHz) spectra were recorded using TMS as the in-
ternal standard. IR spectra were recorded as a film or KBr disper-
sion. Optical rotations were measured with a digital polarimeter in
a 1-dm cell. Microanalyses were performed by the Departamento
de Química Inorgánica.
General Procedure for the Ethynylation of α-Amino Aldehydes: A
0.5  solution of HCϵCMgBr (7.2 mL) in THF (3.6 mmol,
1.2 equiv.) was added dropwise to a solution of amino aldehyde
(3 mmol, 1.0 equiv.) in anhydrous diethyl ether (15 mL) at 0 °C (ice
bath) under argon. The mixture was stirred at 0 °C until the reac-
tion was finished (TLC) and then quenched with an aqueous satu-
rated solution of ammonium chloride (30 mL). The THF was then
removed and the aqueous phase was extracted with diethyl ether
(3×15 mL). The combined organic layers were washed with brine
and dried with anhydrous MgSO4. The solvents were eliminated
under vacuum and the residue was purified by flash chromatog-
raphy (silica gel; hexane/ethyl acetate, 15:1–50:1).
Scheme 6. Reduction of 13b by metal hydrides (see Table 3).
Table 3. Reaction of diketone 13b with differents hydrides.
Entry Hydride
Solvent
Temp. [°C]
14b
15b
16b
[%][a] [%][a] [%][a]
1
2
3
NaBH4 MeOH/THF
20
0 Ǟ 65
0 Ǟ 20
40
21
–
–
45
46
–
11
19
LiAlH4
LiBH4
THF
THF/EtOH
[a] Isolated yield.
(3R,4S)-4-(Dibenzylamino)pent-1-yn-3-ol (anti-2a): This compound
was obtained as the major diastereomer from the reaction of amino
aldehyde 1a (760 mg, 3 mmol) with ethynylmagnesium bromide
and was purified by flash chromatography (silica gel; hexane/
EtOAc, 15:1) and recrystallization from n-hexanes; 594 mg
(2.13 mmol, 71%); colorless solid, m.p. 53–54 °C. [α]2D3 = +31.7 (c
Treatment of 13b with excess of sodium borohydride in
THF/methanol at room temperature for 72 h led to an epi-
meric mixture of diamino hydroxy ketone 14b and unre-
acted diketone. Lithium aluminium hydride reduced com-
pound 13b to yield the semireduced product 14b and a mix-
ture of diastereoisomeric diamino diols 15b and 16b in a
ratio of 4:1; further addition of lithium aluminium hydride
did not modify the reaction mixture (Table 3, Entry 2). Fi-
nally, 13b was totally reduced to a mixture of 15b and 16b
(dr Ϸ 7:3) when treated with lithium borohydride in THF/
ethanol at 20 °C. The stereochemistry of 16b was estab-
lished by comparison with the tetrabenzylated diamino diol
prepared by the reaction of 8b with excess benzyl bromide
and potassium carbonate in acetonitrile, while the stereo-
= 0.6, CHCl ). IR (film): ν = 3410, 3295, 2110, 1030, 750, 700 cm–1.
˜
3
1H NMR (CDCl3): δ = 1.27 (d, J = 6.9 Hz, 3 H, CH3), 2.48 (d, J
= 1.3 Hz, 1 H, HCϵ), 3.08 (m, 1 H, CHN), 3.42 (d, J = 13.3 Hz,
2 H, CHHPh), 4.19 (m, 1 H, CHOH), 4.21 (d, J = 13.3 Hz, 2 H,
CHHPh), 7.25–7.50 (m, 10 H, Har) ppm. 13C NMR (CDCl3): δ =
9.2 (CH3), 54.5 (CH2Ph), 55.4 (CHN), 62.6 (CHOH), 74.2
(CϵCH), 83.8 (CϵCH), 127.2, 128.4, 129.0 (CHar), 139.0 (Car)
ppm. C19H21NO (279.4): calcd. C 81.68, H 7.58, N 5.01; found C
81.45, H 7.43, N 4.89.
1
(3S,4S)-4-(Dibenzylamino)-5-methylhex-1-yn-3-ol (syn-2b): This
compound was obtained as the minor diastereomer from the reac-
tion of amino aldehyde 1b (844 mg, 3 mmol) with ethynylmagne-
sium bromide and was purified by flash chromatography (silica gel;
chemistry of 15b was assigned on the basis of H NMR
spectroscopic data[24] and the value of the optical rotation
([α]2D3 = 0).
hexane/EtOAc, 30:1); 65 mg (0.21 mmol, 7%); colorless oil. [α]2D3
=
+31.2 (c = 0.95, CHCl ). IR (film): ν = 3405, 3303, 1050, 750,
˜
3
Conclusion
700 cm–1. H NMR (CDCl3): δ = 1.12 (d, J = 7.0 Hz, 3 H, CH3),
1
1.15 (d, J = 7.1 Hz, 3 H, CH3), 2.28 [m, 1 H, CH(CH3)2], 2.43 (d,
J = 2.1 Hz, 1 H, HCϵ), 2.64 (dd, J = 8.5, 4.0 Hz, 1 H, CHN), 3.57
(d, J = 13.2 Hz, 2 H, CHHPh), 3.81 (d, J = 13.2 Hz, 2 H, CHHPh),
4.00 (br. s, 1 H, OH), 4.46 (dd, J = 8.5, 2.1 Hz, 1 H, CHOH), 7.20–
7.40 (m, 10 H, Har) ppm. 13C NMR (CDCl3): δ = 19.4, 23.4 (CH3),
25.8 [CH(CH3)2], 53.8 (CH2Ph), 58.9 (CHN), 66.6 (CHOH), 74.3
(CϵCH), 83.9 (CϵCH), 127.3, 128.5, 129.2 (CHar), 138.7 (Car)
ppm. C21H25NO (307.4): calcd. C 82.04, H 8.20, N 4.56; found C
81.92, H 8.32, N 4.61.
In summary, the reaction of chiral α-(dibenzylamino) al-
dehydes with ethynylmagnesium bromide yielded anti-
amino alcohols as the major diastereoisomer; syn-amino
alcohols can also be prepared from the anti isomers. Lith-
ium derivatives of these propargyl amino alcohols reacted
with chiral α-(dibenzylamino) aldehydes to give meso- or
C2-homochiral propargyl diamino diols which were further
elaborated to the corresponding saturated diamino diols.
The addition reactions of both the magnesium derivative
and the acetylide derived from the propargyl amino alcohol
occurred in good yields and diastereomeric excesses, and
enantio-enriched compounds were easily obtained by flash
chromatography.
(3R,4S)-4-(Dibenzylamino)-5-methylhex-1-yn-3-ol (anti-2b): This
compound was obtained as the major diastereomer from the reac-
tion of amino aldehyde 1b (844 mg, 3 mmol) with ethynylmagne-
sium bromide and was purified by flash chromatography (silica gel;
hexane/EtOAc, 30:1); 606 mg (1.97 mmol, 66%); colorless oil.
[α]2D3 = –56.8 (c = 1.1, CHCl ). IR (film): ν = 3400, 3300, 2590,
˜
3
755, 700 cm–1. 1H NMR (CDCl3): δ = 0.95 (d, J = 6.4 Hz, 3 H,
CH3), 1.30 (d, J = 6.4 Hz, 3 H, CH3), 2.37 (d, J = 2.1 Hz, 1 H,
HCϵ), 2.44 [m, 1 H, CH(CH3)2], 2.54 (dd, J = 10.6, 5.0 Hz, 1 H,
CHN), 3.70 (d, J = 13.0 Hz, 2 H, CHHPh), 4.25 (m, 1 H, CHOH),
4.29 (d, J = 13.0 Hz, 2 H, CHHPh), 7.15–7.40 (m, 10 H, Har) ppm.
Experimental Section
General: The reactions were carried out in oven-dried glassware
under argon and with anhydrous solvents. Starting α-(diben-
Eur. J. Org. Chem. 2006, 3442–3450
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J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
FULL PAPER
13C NMR (CDCl3): δ = 20.4, 22.4 (CH3), 28.9 [CH(CH3)2], 55.6
(CH2Ph), 59.8 (CHN), 65.9 (CHOH), 73.4 (CϵCH), 83.8 (CϵCH),
127.2, 128.4, 129.4 (CHar), 139.2 (Car) ppm. C21H25NO (307.4):
calcd. C 82.04, H 8.20, N 4.56; found C 82.18, H 8.02, N 4.70.
13.3 Hz, 2 H, CHHPh), 3.86 (d, J = 10.6 Hz, 1 H, CHN), 3.89 (d,
J = 13.3 Hz, 2 H, CHHPh), 4.36 (br. s, 1 H, OH), 4.93 (dd, J =
10.6, 2.1 Hz, 1 H, CHOH), 7.25–7.50 (m, 15 H, Har) ppm. 13C
NMR (CDCl3): δ = 53.5 (CH2Ph), 59.7 (CHN), 67.2 (CHOH), 73.6
(CϵCH), 82.2 (CϵCH), 127.5, 128.3, 128.7, 129.0, 129.6 (CHar),
133.0, 138.0 (Car) ppm. C24H23NO (341.5): calcd. C 84.42, H 6.79,
N 4.10; found C 84.22, H 6.62, N 4.14.
(3S,4S)-4-(Dibenzylamino)-5-phenylpent-1-yn-3-ol (syn-2c): This
compound was obtained as the minor diastereomer from the reac-
tion of amino aldehyde 1c (988 mg, 3 mmol) with ethynylmagne-
sium bromide and was purified by flash chromatography (silica gel;
hexane/EtOAc, 20:1); 60 mg (0.17 mmol, 6%); colorless solid, mp.
134–135 °C (from hexane/EtOAC). [α]2D3 = +88.7 (c = 0.3, CHCl3).
(1R,2S)-1-(Dibenzylamino)-1-phenylbut-3-yn-2-ol (ent-anti-2e): This
compound was obtained as the minor diastereomer from the reac-
tion of amino aldehyde ent-1e (1.58 g, 5 mmol) with ethynylmagne-
IR (KBr): ν = 3436, 3273, 2118, 1019, 755, 736, 692 cm–1. 1H NMR sium bromide and was purified by flash chromatography (silica gel;
˜
(CDCl3): δ = 2.39 (d, J = 2.1 Hz, 1 H, HCϵ), 3.01 (dd, J = 14.3,
hexane/EtOAc, 12:1); 980 mg (2.87 mmol, 57%); colorless oil.
9.2 Hz, 1 H, CHHPh), 3.11 (dd, J = 14.3, 3.8 Hz, 1 H, CHHPh), [α]2D3 = –94.5 (c = 1.0, CHCl ). IR (film): ν = 3425, 3292, 1494,
˜
3
3.19 (m, 1 H, CHN), 3.39 (d, J = 13.2 Hz, 2 H, CHHN), 3.77 (d, 1454, 1028, 748, 699 cm–1. 1H NMR (CDCl3): δ = 2.66 (d, J =
J = 13.2 Hz, 2 H, CHHN), 4.05 (br. s, 1 H, OH), 4.29 (dd, J = 9.2, 2.2 Hz, 1 H, HCϵ), 2.70 (br. s, 1 H, OH), 3.22 (d, J = 13.6 Hz, 2
2.1 Hz, 1 H, CHOH), 7.05–7.40 (m, 15 H, Har) ppm. 13C NMR H, CHHPh), 3.98 (d, J = 7.4 Hz, 1 H, CHN), 4.11 (d, J = 13.6 Hz,
(CDCl3): δ = 33.0 (CH2Ph), 53.7 (CH2N), 61.9 (CHN), 64.7 2 H, CHHPh), 4.84 (dd, J = 7.4, 2.2 Hz, 1 H, CHOH), 7.25–7.55
(CHOH), 74.1 (CϵCH), 83.2 (CϵCH), 126.4, 127.4, 128.5, 128.6, (m, 15 H, Har) ppm. 13C NMR (CDCl3): δ = 54.9 (CH2Ph), 62.4
129.0, 129.5 (CHar), 138.4, 139.9 (Car) ppm. C25H25NO (355.5):
calcd. C 84.47, H 7.09, N 3.94; found C 84.32, H 6.94, N 3.74.
(CHN), 66.0 (CHOH), 74.9 (CϵCH), 84.0 (CϵCH), 127.1, 128.0,
128.2, 128.3, 129.0, 129.7 (CHar), 134.3, 139.2 (Car) ppm.
C24H23NO (341.5): calcd. C 84.42, H 6.79, N 4.10; found C 84.18,
H 6.65, N 4.26.
(3R,4S)-4-(Dibenzylamino)-5-phenylpent-1-yn-3-ol (anti-2c): This
compound was obtained as the major diastereomer from the reac-
tion of amino aldehyde 1c (988 mg, 3 mmol) with ethynylmagne-
sium bromide and was purified by flash chromatography (silica gel;
hexane/EtOAc, 20:1); 696 mg (1.96 mmol, 65%); colorless solid,
(3S,4S)-4-(Dibenzylamino)-3-methyl-5-phenylpent-1-yn-3-ol
(syn-
2f): This compound was obtained as the minor diastereomer from
the reaction of amino ketone 1f (1.38 g, 4 mmol) with ethynylmag-
nesium bromide and was purified by flash chromatography (silica
m.p. 131–132 °C (from hexane/EtOAc). [α]2D3 = +63.4 (c = 1.0,
1
CHCl ). IR (KBr): ν = 3272, 2107, 1494, 1024, 747, 700 cm–1. H gel; hexane/EtOAc, 20:1); 49 mg (0.13 mmol, 3%); colorless oil.
˜
3
NMR (CDCl3): δ = 2.60 (d, J = 2.0 Hz, 1 H, HCϵ), 3.03 (dd, J = [α]2D3 = +54.1 (c = 1.0, CHCl ). IR (film): ν = 3298, 1495, 1454,
˜
3
1
12.2, 9.7 Hz, 1 H, CHHPh), 3.16 (m, 1 H, CHN), 3.24 (dd, J =
12.2, 4.1 Hz, 1 H, CHHPh), 3.53 (d, J = 13.2 Hz, 2 H, CHHN),
4.07 (m, 1 H, CHOH), 4.19 (br. s, 1 H, OH), 4.36 (d, J = 13.2 Hz,
1074, 745, 699 cm–1. H NMR (CDCl3, 333 K): δ = 1.54 (s, 3 H,
CH3), 2.54 (s, 1 H, HCϵ), 2.63 (br. s, 1 H, OH), 3.25 (m, 3 H,
CHHPh and CHN), 3.49 (d, J = 13.4 Hz, 2 H, CHHN), 4.12 (d, J
2 H, CHHN), 7.20–7.50 (m, 15 H, Har) ppm. 13C NMR (CDCl3): = 13.4 Hz, 2 H, CHHN), 7.15–7.45 (m, 15 H, Har) ppm. 13C NMR
δ = 31.4 (CH2Ph), 54.9 (CH2N), 60.0 (CHN), 62.1 (CHOH), 75.1 (CDCl3): δ = 27.8 (CH3), 32.3 (CH2Ph), 55.6 (CH2N), 67.1 (CHN),
(CϵCH), 83.8 (CϵCH), 126.4, 127.4, 128.5, 128.6, 129.1, 129.2
(CHar), 138.3, 138.8 (Car) ppm. C25H25NO (355.5): calcd. C 84.47,
H 7.09, N 3.94; found C 84.22, H 6.80, N 4.09.
70.6 (COH), 73.1 (CϵCH), 87.6 (CϵCH), 126.3, 127.1, 128.3,
128.7, 129.0, 129.5 (CHar), 139.3, 140.9 (Car) ppm. C26H27NO
(369.5): calcd. C 84.51, H 7.37, N 3.79; found C 84.31, H 7.20, N
3.68.
(2S,3R)- and (2S,3S)-1-(tert-Butyldimethylsilyloxy)-2-(dibenzyl-
amino)pent-4-yn-3-ol (anti/syn-2d): This compound was obtained
as an inseparable mixture of diastereomers from the reaction of
(3R,4S)-4-(Dibenzylamino)-3-methyl-5-phenylpent-1-yn-3-ol (anti-
2f): This compound was obtained as the major diastereomer from
amino aldehyde 1d (844 mg, 2.2 mmol) with ethynylmagnesium the reaction of amino ketone 1f (1.38 g, 4 mmol) with ethynylmag-
bromide and was purified by flash chromatography (silica gel; hex-
ane/EtOAc, 30:1); 420 mg (1.03 mmol, 47%); colorless oil. IR
nesium bromide and was purified by flash chromatography (silica
gel; hexane/EtOAc, 20:1); 931 mg (2.52 mmol, 63%); colorless so-
lid, m.p. 104–105 °C (from hexane). [α]2D3 = +26.2 (c = 1.0, CHCl3).
(film): ν = 3421, 3305, 2110, 1100, 838, 749, 699 cm–1. 1H NMR
˜
(CDCl3): δ = 0.16, 0.17 (s, 3 H, CH3Si), 0.98 [s, 9 H, (CH3)3CSi],
IR (film): ν = 3295, 2104, 1495, 1115, 740, 700 cm–1. 1H NMR
˜
2.40 (d, J = 2.1 Hz, 1 H, CϵCHsyn), 2.46 (d, J = 2.4 Hz, 1 H,
(CDCl3, 333 K): δ = 1.21 (s, 3 H, CH3), 2.54 (s, 1 H, HCϵ), 3.05
CϵCHanti), 2.97 (m, 1 H, CHNsyn), 3.16 (m, 1 H, CHNanti), 3.71 (m, 2 H, CH2Ph), 3.35 (dd, J = 14.3, 7.0 Hz, 1 H, CHN), 3.40 (d,
(d, J = 13.1 Hz, 2 H, CHHPh), 3.89 (dd, J = 10.4, 6.4 Hz, 1 H, J = 12.6 Hz, 2 H, CHHN), 4.32 (br. s, 2 H, CHHN), 5.44 (br. s, 1
CHHOTBDMS), 4.04 (br. s, 1 H, OH), 4.17 (dd, J = 10.4, 6.8 Hz,
1 H, CHHOTBDMS), 4.21 (d, J = 13.1 Hz, 2 H, CHHPh), 4.41 (m,
H, OH), 7.20–7.50 (m, 15 H, Har) ppm. 13C NMR (CDCl3, 333 K):
δ = 29.5 (CH3), 32.6 (CH2Ph), 55.1 (CH2N), 67.3 (COH), 67.7
1 H, CHOH), 7.25–7.40 (m, 10 H, Har) ppm. 13C NMR (CDCl3): δ (CHN), 73.0 (CϵCH), 87.7 (CϵCH), 126.5, 127.4, 128.5, 128.7,
= –5.5 (CH3Si), 18.1 [(CH3)3CSi], 25.9 [(CH3)3Si], 54.5 (CH2Phsyn), 129.3, 129.5 (CHar), 138.8, 140.3 (Car) ppm. C26H27NO (369.5):
55.2 (CH2Phanti), 59.8 (CHN), 60.9 (CHOH and CH2OTBDMS),
74.1 (CϵCH), 83.8 (CϵCH), 127.2, 128.4, 129.0 (CHar), 138.9
(Carsyn), 139.3 (Caranti) ppm.
calcd. C 84.51, H 7.37, N 3.79; found C 84.25, H 7.23, N 3.60.
(3R,4S)-4-(Dibenzylamino)-5-methyl-1-(trimethylsilyl)hex-1-yn-3-ol
(anti-3b): nBuLi in hexanes (1.6 , 2 mL, 3.2 mmol, 2.1 equiv.) was
added to a solution of anti-2b (460 mg, 1.5 mmol) in anhydrous
THF (6 mL) at –78 °C under argon. After stirring the mixture at
–78 °C for 45 min, TMSCl (0.22 mL, 1.65 mmol, 1.1 equiv.) was
added. The mixture was warmed to 0 °C and maintained at this
temperature for 2 h and then quenched with saturated aqueous
NH4Cl solution (20 mL). The THF was removed and the aqueous
phase was extracted with Et2O (3×20 mL). The organic extracts
(1R,2R)-1-(Dibenzylamino)-1-phenylbut-3-yn-2-ol (ent-syn-2e): This
compound was obtained as the minor diastereomer from the reac-
tion of amino aldehyde ent-1e (1.58 g, 5 mmol) with ethynylmagne-
sium bromide and was purified by flash chromatography (silica gel;
hexane/EtOAc, 12:1); 215 mg (0.63 mmol, 13%); colorless solid,
m.p. 117–118 °C (from hexane). [α]2D3 = –162.7 (c = 1.0, CHCl3).
IR (KBr): ν = 3392, 3286, 2119, 1454, 1055, 747, 698 cm–1. 1H
˜
NMR (CDCl3): δ = 2.13 (d, J = 2.1 Hz, 1 H, HCϵ), 3.08 (d, J = were combined, washed with brine, dried (MgSO4) and concen-
3446
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3442–3450

Diastereoselective Ethynylation of Chiral α-(Dibenzylamino) Aldehydes
FULL PAPER
trated under reduced pressure. The crude product was purified by
flash chromatography (silica gel; hexane/ethyl acetate, 30:1);
0.15 mmol, 0.1 equiv.) were added to a solution of anti-2b (461 mg,
1.5 mmol) in CH2Cl2 (10 mL) at 0 °C and the mixture was stirred
at room temperature for 48 h. The reaction was quenched with
aqueous saturated NH4Cl solution (10 mL) and decanted. The
250 mg (0.66 mmol, 44%); colorless solid, m.p. 72–73 °C. [α]2D3
=
–118.0 (c = 0.5, CHCl ). IR (film): ν = 3330, 2165, 1030, 760,
˜
3
700 cm–1. H NMR (CDCl3): δ = 0.01 [s, 9 H, Si(CH3)3], 0.90 (d, aqueous phase was extracted with CH2Cl2 (2×10 mL), the com-
1
J = 6.4 Hz, 3 H, CH3), 1.23 (d, J = 6.4 Hz, 3 H, CH3), 2.36 [m, 1
bined organic phases were washed with water, dried (MgSO4) and
H, CH(CH3)2], 2.45 (dd, J = 10.6, 4.9 Hz, 1 H, CHN), 3.63 (d, J the solvent was evaporated. The product was purified by flash
= 13.0 Hz, 2 H, CHHPh), 4.03 (d, J = 8.6 Hz, 1 H, OH), 4.12 (m,
chromatography (silica gel; hexane/EtOAc, 30:1) to yield anti-5b as
1 H, CHOH), 4.25 (d, J = 13.0 Hz, 2 H, CHHPh), 7.15–7.30 (m, a colorless oil; 538 mg (1.28 mmol, 85%). [α]2D3 = –76.7 (c = 1.1,
10 H, Har) ppm. 13C NMR (CDCl3): δ = –0.3 [Si(CH3)3], 20.6,
CHCl ). IR (film): ν = 3305, 1255, 1083, 745, 700 cm–1. H NMR
1
˜
3
22.6 (CH3), 29.1 [CH(CH3)2], 55.8 (CH2Ph), 60.6 (CHN), 66.6 (CDCl3): δ = 0.25 and 0.27 [2s, 6 H, Si(CH3)2], 0.97 [s, 9 H, C(CH3)3],
(CHOH), 90.0 (CϵCSi), 106.0 (CϵCSi), 127.3, 128.4, 129.5 1.00 (d, J = 6.7 Hz, 6 H, CH3CH), 2.19 [m, 1 H, CH(CH3)2], 2.49
(CHar), 139.5 (Car) ppm. C24H33NOSi (379.6): calcd. C 75.93, H
8.76, N 3.69; found C 75.79, H 8.89, N 3.83.
(d, J = 2.3 Hz, 1 H, ϵCH), 2.55 (dd, J = 10.1, 2.5 Hz, 1 H, CHN),
3.56 (d, J = 13.9 Hz, 2 H, CHHPh), 4.02 (d, J = 13.9 Hz, 2 H,
CHHPh), 4.90 (m, 1 H, CHO), 7.20–7.40 (m, 10 H, Har) ppm. 13
C
(S)-4-(Dibenzylamino)-5-methyl-1-(trimethylsilyl)hex-1-yn-3-one
(4b): DMSO (0.1 mL, 1.4 mmol) was added dropwise to a stirred
solution of oxalyl chloride (60 µL, 0.7 mmol) in dichloromethane
(2 mL) cooled to –78 °C under argon. After 15 min, a solution of
anti-3b (190 mg, 0.5 mmol) in dichloromethane (2 mL) was added
and the mixture was stirred at –78 °C for 30 min and triethylamine
(0.2 mL, 1.43 mmol) was added. Then the reaction mixture was
allowed to warm to room temperature whilst being stirred for
45 min and the mixture quenched with water (2 mL). The aqueous
phase was extracted with CH2Cl2 (2×5 mL) and the combined or-
ganic layers were washed with saturated aqueous NaHCO3 and
water. The organic phase was dried (MgSO4) and concentrated to
yield an oil that was purified by flash chromatography (silica gel;
hexane/EtOAc, 30:1); 122 mg (0.32 mmol, 64 %); colorless oil.
NMR (CDCl3): δ = –4.9, –4.0 (CH3Si), 18.1 [C(CH3)3], 20.8, 21.4
(CH3CH), 25.9 [C(CH3)3], 27.2 [CH(CH3)2], 55.0 (CH2Ph), 60.7
(CHN), 68.2 (CHO), 74.7 (CϵCH), 85.9 (CϵCH), 126.7, 128.0,
129.1 (CHar), 140.3 (Car) ppm. C27H39NOSi (421.7): calcd. C
76.90, H 9.32, N 3.32; found C 76.79, H 9.44, N 3.38.
(3S,4R,7S,8R)-3,8-Bis(dibenzylamino)-2,9-dimethyldec-5-yne-4,7-
diol (6b): nBuLi (1.6  in hexanes, 0.7 mL, 1.1 mmol, 1.1 equiv.)
was added to a solution of anti-5b (422 mg, 1 mmol) in anhydrous
THF (5 mL) at –78 °C under argon. After stirring the mixture at
–78 °C for 1 h, a solution of amino aldehyde ent-1b (282 mg,
1 mmol, 1 equiv.) was added. The mixture was kept at –78 °C for
2 h and then warmed to room temperature overnight. Then TBAF
(315 mg, 1.0 mmol, 1 equiv.) was added at 0 °C and the mixture
was stirred at room temperature for 4 h. Saturated aqueous NH4Cl
(10 mL) was added to quench the reaction, the THF was removed
and the aqueous phase extracted with CHCl3 (3×10 mL). The or-
ganic extracts were combined, washed with brine, dried (MgSO4)
and concentrated under reduced pressure. The crude product was
purified by flash chromatography (silica gel; CHCl3/Et2O, 80:1) to
yield anti-6b (347 mg, 0.59 mmol, 59%) as the major product; col-
orless solid, m.p. 207–208 °C. [α]2D3 = 0 (c = 0.8, CHCl3). IR (KBr):
[α]2D3 = –196.3 (c = 1.2, CHCl ). IR (film): ν = 2145, 1660, 1250,
˜
3
750, 700 cm–1. 1H NMR (CDCl3): δ = 0.30 [s, 9 H, Si(CH3)3], 0.84
(d, J = 6.5 Hz, 3 H, CH3), 1.05 (d, J = 6.6 Hz, 3 H, CH3), 2.28 [m,
1 H, CH(CH3)2], 3.06 (d, J = 10.7 Hz, 1 H, CHN), 3.58 (d, J =
14.0 Hz, 2 H, CHHPh), 4.03 (d, J = 14.0 Hz, 2 H, CHHPh), 7.20–
7.50 (m, 10 H, Har) ppm. 13C NMR (CDCl3): δ = –0.9 [Si(CH3)3],
19.6, 19.8 [CH(CH3)2], 26.4 [CH(CH3)2], 54.0 (CH2Ph), 72.9
(CHN), 100.1 (CϵCSi), 104.2 (CϵCSi), 126.9, 128.1, 128.8
(CHar), 139.1 (Car), 189.7 (C=O) ppm. C24H31NOSi (377.6): calcd.
C 76.34, H 8.28, N 3.71; found C 76.55, H 8.45, N 3.80.
ν = 3360, 1070, 755, 700 cm–1. 1H NMR (CDCl ): δ = 0.77 (d, J =
˜
3
6.5 Hz, 6 H, CH3), 1.14 (d, J = 6.5 Hz, 6 H, CH3), 2.29 [m, 2 H,
CH(CH3)2], 2.46 (dd, J = 10.7, 4.5 Hz, 2 H, CHN), 3.65 (d, J =
13.1 Hz, 4 H, CHHPh), 4.25 (m, 6 H, CHOH and CHHPh), 7.15–
7.40 (m, 20 H, Har) ppm. 13C NMR (CDCl3): δ = 20.4, 22.3 (CH3),
29.2 [CH(CH3)2], 55.7 (CH2Ph), 60.1 (CHN), 66.2 (CHOH), 85.1
(Cϵ), 127.2, 128.4, 129.4 (CHar), 139.3 (Car) ppm. C40H48N2O2
(588.8): calcd. C 81.59, H 8.22, N 4.76; found C 81.36, H 8.16, N
4.95.
(3S,4S)-4-(Dibenzylamino)-5-methyl-1-(trimethylsilyl)hex-1-yn-3-ol
(syn-3b): A solution of compound 4b (100 mg, 0.26 mmol) in anhy-
drous Et2O (1 mL) was added to a suspension of LiAlH4 (15 mg,
0.40 mmol, 1.5 equiv.) in anhydrous THF (2 mL) at –78 °C and the
suspension was stirred at this temperature for 15 min. Then the
mixture was treated at –78 °C with H2O (15 µL), a 15% NaOH
solution (15 µL) and H2O (45 µL), and then warmed to room tem-
perature. The solids were removed by filtration, the solvent was
evaporated and the residue purified by flash chromatography (silica
gel; hexane/EtOAc, 30:1); 79 mg (0.21 mmol, 65%), colorless oil.
(3S,4R,7R,8R)-3,8-Bis(dibenzylamino)-2,9-dimethyldec-5-yne-4,7-
diol (epi-6b): This compound was obtained as the minor product
in the reaction of the lithiated compound derived from anti-5b
(422 mg, 1 mmol) with the amino aldehyde ent-1b and purified by
flash chromatography (silica gel; CHCl3/Et2O, 80:1); 64 mg
[α]2D3 = +36.1 (c = 1.0, CHCl ). IR (film): ν = 3413, 2170, 1250,
˜
3
1059, 844, 749, 699 cm–1 1H NMR (CDCl3): δ = 0.16 [s, 9 H,
.
(0.11 mmol, 11%); colorless oil. [α]2D3 = –64.6 (c = 0.9, CHCl3). IR
Si(CH3)3], 1.13 (d, J = 6.8 Hz, 3 H, CH3), 1.15 (d, J = 6.8 Hz, 3
H, CH3), 2.28 [m, 1 H, CH(CH3)2], 2.62 (dd, J = 8.4, 3.9 Hz, 1 H,
CHN), 3.58 (d, J = 13.3 Hz, 2 H, CHHPh), 3.78 (br. s, 1 H, OH),
3.83 (d, J = 13.3 Hz, 2 H, CHHPh), 4.49 (d, J = 8.4 Hz, 1 H,
CHOH), 7.20–7.40 (m, 10 H, Har) ppm. 13C NMR (CDCl3): δ =
–0.3 [Si(CH3)3], 19.2, 23.5 (CH3), 25.6 [CH(CH3)2], 53.8 (CH2Ph),
59.4 (CHN), 66.9 (CHOH), 91.0 (CϵCSi), 105.7 (CϵCSi), 127.2,
128.4, 129.1 (CHar), 138.8 (Car) ppm. C24H33NOSi (379.6): calcd.
C 75.93, H 8.76, N 3.69; found C 75.73, H 8.92, N 3.85.
1
(film): ν = 3380, 1093, 750, 700 cm–1. H NMR (CDCl ): δ = 0.94
˜
3
(d, J = 6.4 Hz, 3 H, CH3), 1.03 (d, J = 6.9 Hz, 3 H, CH3), 1.08 (d,
J = 6.9 Hz, 3 H, CH3), 1.28 (d, J = 6.4 Hz, 3 H, CH3), 2.19 [m, 1
H, CH(CH3)2], 2.38 [m, 1 H, CH(CH3)2], 2.54 (m, 2 H, CHN), 3.61
(d, J = 13.2 Hz, 2 H, CHHPh), 3.67 (m, 4 H, CHHPh), 4.22 (d, J
= 13.2 Hz, 2 H, CHHPh), 4.28 (m, 1 H, CHOH), 4.55 (d, J =
6.8 Hz, 1 H, CHOH), 7.10–7.40 (m, 20 H, Har) ppm. 13C NMR
(CDCl3): δ = 19.9, 20.6, 22.5 (CH3), 26.9, 29.2 [CH(CH3)2], 54.0,
55.5 (CH2Ph), 59.7, 60.1 (CHN), 66.3, 66.9 (CHOH), 85.2, 86.2
(3R,4S)-3-(tert-Butyldimethylsilyloxy)-4-(dibenzylamino)-5-methyl- (Cϵ), 127.1, 127.3, 128.3, 128.4, 129.0, 129.5 (CHar), 138.8, 139.3
1-hexyne (anti-5b): TBDMSCl (340 mg, 2.25 mmol, 1.5 equiv.),
(Car) ppm. C40H48N2O2 (588.8): calcd. C 81.59, H 8.22, N 4.76;
imidazole (225 mg, 3.75 mmol, 2.5 equiv.) and DMAP (20 mg,
found C 81.44, H 8.08, N 4.90.
Eur. J. Org. Chem. 2006, 3442–3450
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3447

J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
FULL PAPER
(3R,4R,7R,8S)-3,8-Bis(dibenzylamino)-2,9-dimethyldec-5-yne-4,7-
diol (7b): This compound was obtained as the major product in the
reaction of the lithiated compound derived from anti-5b (717 mg,
1.7 mmol) with the amino aldehyde 1b by the procedure described
for the preparation of 6b and was purified by flash chromatography
(silica gel; hexane/EtOAc, 8:1); 670 mg (1.14 mmol, 67%); colorless
oil. [α]2D3 = –103.0 (c = 0.9, CHCl3) (for an 86:14 mixture of dia-
C40H52N2O2 (592.8): calcd. C 81.04, H 8.84, N 4.73; found C 81.12,
H 8.73, N 4.86.
(3S,4R,7R,8S)-3,8-Diamino-2,9-dimethyldecane-4,7-diol (10b): This
compound was obtained by hydrogenation of 9b (318 mg,
0.54 mmol) as described for the preparation of 8b and was purified
by flash chromatography (silica gel; CH2Cl2/MeOH/NH4OH,
6:4:0.2); 113 mg (0.49 mmol, 90 %); colorless solid, m.p. 111–
stereomers). IR (KBr): ν = 3402, 1453, 1044, 749, 698 cm–1. 1H
˜
112 °C. [α]2D3 = +46.0 (c = 0.4, MeOH). IR (KBr): ν = 3348, 1597,
˜
NMR (CDCl3): δ = 0.76 (d, J = 6.5 Hz, 6 H, CH3), 1.15 (d, J =
6.5 Hz, 6 H, CH3), 2.22 [m, 2 H, CH(CH3)2], 2.48 (dd, J = 10.7,
4.3 Hz, 2 H, CHN), 3.63 (d, J = 13.0 Hz, 4 H, CHHPh), 4.18 (d,
J = 13.0 Hz, 4 H, CHHPh), 4.29 (m, 4 H, CHOH and OH), 7.15–
7.40 (m, 20 H, Har) ppm. 13C NMR (CDCl3): δ = 20.5, 22.4 (CH3),
29.3 [CH(CH3)2], 55.4 (CH2Ph), 60.1 (CHN), 66.1 (CHOH), 85.2
(CϵC), 127.2, 128.4, 129.3 (CHar), 139.1 (Car) ppm.
1474, 1060, 942 cm–1. 1H NMR (CD3OD): δ = 0.98 (d, J = 6.7 Hz,
12 H, CH3), 1.60 (m, 4 H, CH2), 1.88 [m, 2 H, CH(CH3)2], 2.59
(dd, J = 6.8, 5.4 Hz, 2 H, CHN), 3.69 (m, 2 H, CHOH) ppm. 13C
NMR (CD3OD): δ = 18.8, 20.5 (CH3), 28.1 (CH2), 30.1 [CH(CH3)
2], 63.0 (CHN), 71.8 (CHOH) ppm. C12H28N2O2 (232.4): calcd. C
62.03, H 12.15, N 12.06; found C 61.78, H 11.96, N 12.23.
(3S,4R,7S,8R)-3,8-Bis(dibenzylamino)-2,9-dimethyldec-5-ene-4,7-
diol [(E)-11b]: Compound 6b (118 mg, 0.2 mmol, 1.0 equiv.) was
added to a suspension of LiAlH4 (30 mg, 0.8 mmol, 4 equiv.) in
anhydrous THF (4 mL) at 0 °C. The ice bath was removed and the
suspension was stirred at reflux for 1 h. Then the mixture was
treated at 0 °C with H2O (30 µL), a 15% NaOH solution (30 µL)
and H2O (90 µL) and stirred for 2 h. The white solids were removed
by filtration, the filtrate was concentrated and the residue purified
by flash chromatography (silica gel; CHCl3/Et2O, 60:1); 77 mg
(0.13 mmol, 65%); colorless solid, m.p. 195–196 °C. [α]2D3 = 0 (c =
(3S,4R,7S,8R)-3,8-Diamino-2,9-dimethyldecane-4,7-diol (8b):
Pd(OH)2/C (22 mg) was added in one portion to a solution of 6b
(88 mg, 0.15 mmol) in MeOH (3 mL). The mixture was stirred un-
der hydrogen for 1 h and the catalyst was removed by filtration and
washed with methanol. The solvent was evaporated under reduced
pressure and the residue was purified by flash chromatography (sil-
ica gel; CH2Cl2/MeOH/NH4OH, 6:4:0.2) to give 8b as a colorless
solid; 33 mg (0.14 mmol, 95%); m.p. 151–152 °C. [α]2D3 = 0 (c = 1,
MeOH). IR (KBr): ν = 3350, 1590, 1045 cm–1. 1H NMR (CD OD):
˜
3
δ = 0.97 (d, J = 6.8 Hz, 6 H, CH3), 0.99 (d, J = 6.7 Hz, 6 H,
CH3), 1.32 (m, 2 H, CHHCHOH), 1.85 [m, 4 H, CHHCHOH and
CH(CH3)2], 2.60 (dd, J = 7.0, 5.2 Hz, 2 H, CHN), 3.67 (m, 2 H,
CHOH) ppm. 13C NMR (CD3OD): δ = 18.9, 20.5 [CH(CH3)2],
28.9 (CH2), 30.1 [CH(CH3)2], 63.2 (CHN), 72.8 (CHOH) ppm.
C12H28N2O2 (232.4): calcd. C 62.03, H 12.15, N 12.06; found C
61.78, H 11.97, N 11.95.
1, CHCl ). IR (KBr): ν = 3350, 1453, 1090, 1070, 753, 700 cm–1.
˜
3
1H NMR (CDCl3): δ = 0.88 (d, J = 6.4 Hz, 6 H, CH3), 1.20 (d, J
= 6.5 Hz, 6 H, CH3), 2.17 [m, 2 H, CH(CH3)2], 2.52 (dd, J = 10.7,
4.9 Hz, 2 H, CHN), 3.55 (d, J = 8.4 Hz, 2 H, OH), 3.63 (d, J =
13.3 Hz, 4 H, CHHPh), 3.87 (d, J = 13.3 Hz, 4 H, CHHPh), 3.94
(m, 2 H, CHOH), 6.10 (s, 2 H, CH=CH), 7.10–7.40 (m, 20 H, Har)
ppm. 13C NMR (CDCl3): δ = 20.8, 23.1 (CH3), 28.7 [CH(CH3)2],
56.0 (CH2Ph), 67.3 (CHN), 68.5 (CHOH), 127.2, 128.3, 129.1
(CHar), 129.5 (CH=), 139.8 (Car) ppm. C40H50N2O2 (590.8): calcd.
C 81.31, H 8.53, N 4.74; found C 81.07, H 8.37, N 4.56.
(3S,4R,7R,8R)-3,8-Diamino-2,9-dimethyldecane-4,7-diol (epi-8b):
This compound was obtained by hydrogenation of epi-6b (59 mg,
0.1 mmol) with Pd(OH)2/C in MeOH by the procedure described
for the preparation of 8b and was purified by flash chromatography
(silica gel; CH2Cl2/MeOH/NH4OH, 6:4:0.2); 18 mg (0.08 mmol,
80%); colorless oil. [α]2D3 = +35.0 (c = 0.5, MeOH). 1H NMR
(CDCl3): δ = 0.94 (d, J = 7.0 Hz, 3 H, CH3), 0.95 (d, J = 7.0 Hz,
3 H, CH3), 0.96 (d, J = 7.1 Hz, 3 H, CH3), 1.00 (d, J = 6.9 Hz, 3
H, CH3), 1.65 (m, 4 H, CH2), 1.85 [m, 2 H, CH(CH3)2], 2.42 (m,
1 H, CHN), 2.50 (m, 1 H, CHN), 3.60 (m, 2 H, CHOH), 4.90 (br.
s, 6 H, OH and NH2) ppm. 13C NMR (CDCl3): δ = 17.6, 18.3,
20.6, 20.8 (CH3), 28.5 (CH2), 30.3, 30.9 [CH(CH3)2], 31.7 (CH2),
62.2, 62.8 (CHN), 72.6, 72.8 (CHOH) ppm. C12H28N2O2 (232.4):
calcd. C 62.03, H 12.15, N 12.06; found C 62.25, H 12.34, N 12.01.
(3S,8R)-3,8-Bis(dibenzylamino)-2,9-dimethyldec-5-yne-4,7-dione
(12b): DMSO (0.12 mL, 1.7 mmol) was added dropwise to a stirred
solution of oxalyl chloride (71 µL, 0.8 mmol) in CH2Cl2 (2 mL)
cooled to –78 °C under argon. After 15 min, a solution of 6b
(177 mg, 0.3 mmol) in CH2Cl2 (2 mL) was added, the mixture was
stirred at –78 °C for 45 min and then triethylamine (0.24 mL,
1.7 mmol) was added. Then the mixture was allowed to reach room
temperature whilst being stirred for 45 min and quenched with
water (2 mL). The aqueous phase was extracted with CH2Cl2
(2×5 mL) and the combined organic layers were washed with satu-
rated aqueous NaHCO3 and water. The organic phase was dried
(MgSO4) and concentrated to yield an oil that was purified by flash
chromatography (silica gel; hexane/EtOAc, 8:1); 131 mg
(0.22 mmol, 75%); colorless oil. [α]2D3 = 0 (c = 1, CHCl3). IR (film):
(3S,4R,7R,8S)-3,8-Bis(dibenzylamino)-2,9-dimethyldecane-4,7-diol
(9b): This compound was obtained from an 86:14 mixture of 7b/
epi-7b (588 mg, 1 mmol) by catalytic hydrogenation with Pd(OH)2/
C (150 mg) in MeOH (10 mL) followed by treatment with BnBr
(0.25 mL, 2.1 mmol, 2.1 equiv.) and K2CO3 (276 mg, 2 mmol,
2 equiv.) in acetonitrile (6 mL) at reflux. After flash chromatog-
raphy (silica gel; hexane/EtOAc, 8:1), compound 9b was obtained
ν = 1665, 1100, 735, 700 cm–1. 1H NMR (CDCl ): δ = 0.83 (d, J =
˜
3
6.5 Hz, 6 H, CH3), 1.08 (d, J = 6.5 Hz, 6 H, CH3), 2.29 [m, 2 H,
CH(CH3)2], 3.13 (d, J = 10.8 Hz, 2 H, CHN), 3.55 (d, J = 14.0 Hz,
4 H, CHHPh), 4.02 (d, J = 14.0 Hz, 4 H, CHHPh), 7.15–7.45 (m,
20 H, Har) ppm. 13C NMR (CDCl3): δ = 19.8, 20.0 (CH3), 26.6
[CH(CH3)2], 54.2 (CH2Ph), 73.1 (CHN), 88.0 (Cϵ), 127.2, 128.4,
128.8 (CHar), 138.6 (Car), 189.0 (C=O) ppm. C40H44N2O2 (584.8):
calcd. C 82.15, H 7.58, N 4.79; found C 82.01, H 7.54, N 4.84.
as a colorless oil; 450 mg (0.76 mmol, 76%). [α]2D3 = –21.9 (c = 1.2,
1
CHCl ). IR (KBr): ν = 3400, 1453, 1071, 749, 699 cm–1. H NMR
˜
3
(CDCl3): δ = 0.90 (d, J = 6.5 Hz, 6 H, CH3), 1.19 (d, J = 6.5 Hz,
6 H, CH3 ), 1 . 5 4 (m, 2 H , C HHCHOH), 1. 72 (m, 2 H,
CHHCHOH), 2.17 [m, 2 H, CH(CH3)2], 2.46 (dd, J = 9.4, 4.4 Hz, (3S,8R)-3,8-Bis(dibenzylamino)-2,9-dimethyldecane-4,7-dione (13b):
2 H, CHN), 3.48 (br. s, 2 H, OH), 3.60 (m, 2 H, CHOH), 3.74 (d, This compound was obtained by reduction of 12b (88 mg,
J = 13.5 Hz, 4 H, CHHPh), 3.82 (d, J = 13.5 Hz, 4 H, CHHPh), 0.15 mmol) with NaBH4 (51 mg, 1.35 mmol, 9 equiv.) in MeOH/
7.15–7.35 (m, 20 H, Har) ppm. 13C NMR (CDCl3): δ = 20.9, 23.1
THF (2 mL, 9:2) at –20 °C and purified by flash chromatography
(CH3), 27.9 [CH(CH3)2], 31.5 (CH2), 56.1 (CH2Ph), 67.2 (CHN), (silica gel; hexane/EtOAc, 20:1); 35 mg (0.06 mmol, 40%); colorless
70.2 (CHOH), 127.1, 128.4, 129.1 (CHar), 139.9 (Car) ppm.
solid, m.p. 136–137 °C. [α]2D3 = 0 (c = 1, CHCl ). IR (KBr): ν =
˜
3
3448
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3442–3450

Diastereoselective Ethynylation of Chiral α-(Dibenzylamino) Aldehydes
FULL PAPER
3435, 1700, 750, 700 cm–1. 1H NMR (CDCl3): δ = 0.86 (d, J =
6.5 Hz, 6 H, CH3), 1.17 (d, J = 6.6 Hz, 6 H, CH3), 2.26 [m, 2 H,
13C NMR (CDCl3): δ = 20.8, 23.3 (CH3), 28.1 [CH(CH3)2], 30.6
(CH2), 56.2 (CH2Ph), 66.9 (CHN), 70.4 (CHOH), 127.1, 128.3,
CH(CH3)2], 2.56 (m, 2 H, CHHCO), 2.72 (m, 2 H, CHHCO), 3.16 129.1 (CHar), 139.8 (Car) ppm. C40H52N2O2 (592.8): calcd. C
(d, J = 10.6 Hz, 2 H, CHN), 3.57 (d, J = 14.2 Hz, 4 H, CHHPh), 81.04, H 8.84, N 4.73; found C 81.08, H 8.68, N 4.85.
4.06 (d, J = 14.2 Hz, 4 H, CHHPh), 7.20–7.50 (m, 20 H, Har) ppm.
13C NMR (CDCl3): δ = 20.1, 20.3 (CH3), 27.2 [CH(CH3)2], 39.7
(CH2CO), 54.4 (CH2Ph), 70.7 (CHN), 126.9, 128.3, 128.7 (CHar),
Acknowledgments
139.7 (Car), 210.7 (C=O) ppm. C40H48N2O2 (588.8): calcd. C
81.59, H 8.22, N 4.76; found C 81.29, H 7.96, N 4.51.
(DGI, Project CTQ2005-01191/BQU) for financial support.
The authors thank the Spanish Ministerio de Educación y Ciencia
(3S,8R)-3,8-Bis(dibenzylamino)-7-hydroxy-2,9-dimethyldecan-4-one
(14b): This compound was obtained as the sole isolated product
in the reduction of 13b (30 mg, 0.05 mmol) with NaBH4 (15 mg,
0.4 mmol, 8 equiv.) in THF/MeOH (1:1, 1.5 mL) at room tempera-
ture and was purified by flash chromatography (silica gel; hexane/
EtOAc, 10:1); 12 mg (0.02 mmol, 40%); colorless oil. [α]2D3 = 0 (c =
[1] C. Alemany, J. Bach, J. Farràs, J. García, Org. Lett. 1999, 1,
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1, CHCl ). IR (film): ν = 3435, 1700, 750, 700 cm–1. 1H NMR
˜
3
[4] A. Dondoni, D. Perrone, E. Turturici, J. Org. Chem. 1999, 64,
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[10] M. Heneghan, G. Procter, Synlett 1992, 489–490.
(CDCl3): δ = 0.70 (d, J = 6.5 Hz, 3 H, CH3), 1.07 (d, J = 6.7 Hz,
3 H, CH3), 1.10 (d, J = 7.3 Hz, 3 H, CH3), 1.18 (d, J = 7.0 Hz, 3
H, CH3), 1.61 (m, 1 H, CHHCHOH), 1.95 (m, 1 H, CHHCHOH),
2.17 [m, 1 H, CH(CH3)2], 2.32 [m, 3 H, CHN, CHHCO and
CH(CH3)2], 2.63 (dt, J = 18.5, 7.5 Hz, 1 H, CHHCO), 2.99 (d, J
= 10.6 Hz, 1 H, CHNCO), 3.46 (d, J = 14.2 Hz, 2 H, CHHPh),
3.47 (d, J = 13.0 Hz, 2 H, CHHPh), 3.76 (m, 1 H, CHOH), 3.95
(d, J = 13.0 Hz, 2 H, CHHPh), 3.99 (d, J = 14.2 Hz, 2 H, CHHPh),
4.58 (br. s, 1 H, OH), 7.20–7.40 (m, 20 H, Har) ppm. 13C NMR
(CDCl3): δ = 19.2, 20.1, 20.2, 24.1 (CH3), 24.8, 27.1 [CH(CH3)2],
28.4 (CH2CHOH), 42.8 (CH2CO), 53.9, 54.5 (CH2Ph), 66.1 (CHN
and CHOH), 71.0 (CHNCO), 126.9, 127.3, 128.3, 128.5, 128.7,
129.2 (CHar), 138.9, 139.8 (Car), 213.1 (C=O) ppm. C40H50N2O2 [11] For a review, see: M. T. Reetz, Chem. Rev. 1999, 99, 1121–1162.
[12] J. Clayden, C. McCarthy, J. G. Cumming, Tetrahedron: Asym-
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2004, 1558–1566.
(590.8): calcd. C 81.31, H 8.53, N 4.74; found C 81.51, H 8.69, N
4.60.
(3S,4S,7R,8R)-3,8-Bis(dibenzylamino)-2,9-dimethyldecane-4,7-diol
(15b): This compound was obtained as the major product in the
reduction of 13b (30 mg, 0.05 mmol) with LiBH4 (9 mg, 0.4 mmol,
8 equiv.) in THF/EtOH (1:1, 1.5 mL) at room temperature and was
purified by flash chromatography (silica gel; hexane/EtOAc, 8:1);
14 mg (0.023 mmol, 46%); colorless solid, m.p. 170–171 °C (from
hexane/EtOAc). [α]2D3 = 0 (c = 1, CHCl ). IR (KBr): ν = 3370, 1450,
˜
3
1065, 755, 700 cm–1. H NMR (CDCl3): δ = 1.01 (d, J = 7.3 Hz, 6
1
H, CH3 ), 1.02 (d, J = 7.1 Hz, 6 H, CH3 ), 1.13 (m, 2 H,
CHHCHOH), 1.78 (m, 2 H, CHHCHOH), 2.21 [m, 2 H, CH-
(CH3)2], 2.32 (dd, J = 9.3, 1.9 Hz, 2 H, CHN), 3.43 (d, J = 13.0 Hz,
4 H, CHHPh), 3.70 (m, 2 H, CHOH), 3.90 (d, J = 13.0 Hz, 4 H,
CHHPh), 4.55 (br. s, 2 H, OH), 7.15–7.40 (m, 20 H, Har) ppm.
13C NMR (CDCl3): δ = 19.2, 24.0 (CH3), 24.6 [CH(CH3)2], 31.5
(CH2), 53.9 (CH2Ph), 65.7 (CHN), 67.3 (CHOH), 127.1, 128.4,
129.2 (CHar), 139.0 (Car) ppm. C40H52N2O2 (592.8): calcd. C
81.04, H 8.84, N 4.73; found C 80.86, H 8.61, N 4.54.
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R. J. McHugh, Q. Han, R. Li, J. A. Markwalder, S. P. Seitz,
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(3S,4R,7S,8R)-3,8-Bis(dibenzylamino)-2,9-dimethyldecane-4,7-diol
(16b): A mixture of 8b (41 mg, 0.18 mmol), benzyl bromide (95 µL,
0.8 mmol, 4.4 equiv.) and K2CO3 (100 mg, 0.72 mmol, 4 equiv.) in
CH3CN (2 mL) was stirred at reflux until the reaction was finished
(TLC). The solid was separated by filtration, the filtrate was con-
centrated under reduced pressure and the residue purified by flash
chromatography (silica gel; CH2Cl2); 75 mg (0.13 mmol, 70%); col-
orless solid, m.p. 168–169 °C. [α]2D3 = 0 (c = 1, CHCl3). IR (KBr):
ν = 3385, 1070, 753, 700 cm–1. 1H NMR (CDCl ): δ = 0.91 (d, J =
˜
3
6.5 Hz, 6 H, CH3), 1.22 (d, J = 6.5 Hz, 6 H, CH3), 1.30 (m, 2 H,
CHHCHOH), 1.82 (m, 2 H, CHHCHOH), 2.21 [m, 2 H, CH-
(CH3)2], 2.49 (dd, J = 9.4, 5.1 Hz, 2 H, CHN), 3.31 (br. s, 2 H,
OH), 3.49 (m, 2 H, CHOH), 3.70 (d, J = 13.4 Hz, 4 H, CHHPh),
3.83 (d, J = 13.4 Hz, 4 H, CHHPh), 7.20–7.40 (m, 20 H, Har) ppm.
Eur. J. Org. Chem. 2006, 3442–3450
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3449

J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
FULL PAPER
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Received: March 9, 2006
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Published Online: May 30, 2006
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Eur. J. Org. Chem. 2006, 3442–3450