Diastereoselective syntheses of 2-amino propargyl alcohols. Chiral building blocks for enantiopure amino γ-lactones and 5-hydroxy-piperidinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2006.05.131

α-Dibenzylamino aldehydes, derived from the corresponding natural α-amino acids, react with metal acetylides to yield anti-amino propargyl alcohols in good yield and diastereomeric excess. syn Amino alcohols are prepared from the anti diastereoisomers and

Full text of DOI:10.1016/j.tetlet.2006.05.131

Tetrahedron Letters 47 (2006) 5317–5320
Diastereoselective syntheses of 2-amino propargyl alcohols.
Chiral building blocks for enantiopure amino c-lactones and
5-hydroxy-piperidinone derivatives
*
´
´
´
´
Jose Marıa Andres, Rafael Pedrosa and Alfonso Perez-Encabo
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid, Spain
Received 21 April 2006; revised 17 May 2006; accepted 19 May 2006
Available online 12 June 2006
Abstract—a-Dibenzylamino aldehydes, derived from the corresponding natural a-amino acids, react with metal acetylides to yield
anti-amino propargyl alcohols in good yield and diastereomeric excess. syn Amino alcohols are prepared from the anti diastereo-
isomers and all of them are elaborated in few steps to enantiopure amino lactones and hydroxy-piperidin-2-ones.
Ó 2006 Elsevier Ltd. All rights reserved.
The asymmetric synthesis of propargyl 1,2-amino alco-
hols has attracted a great interest1 because they have
been used as building blocks for different types of enan-
tiopure organic compounds.2 Some interesting syntheses
of these substrates have been described, including diaste-
reoselective reductions,3 condensations,4 and additions
to chiral imines,5 but the most direct method consists
of the reaction of chiral a-amino aldehydes with
organometallics.1
The reaction of D-dibenzylamino phenylglycinal 1a with
ethynylmagnesium bromide in a mixture of THF and
diethyl ether at 0 °C yielded the anti-1,2-amino propargyl
alcohol (anti-2a) in 78% yield and moderate diastereo-
selectivity (dr = 4:1). In the same way, the reaction of
L-dibenzylamino aldehydes 1b–d yielded the correspond-
ing anti amino alcohols 2b–d in good yield and de
(Scheme 1 and Table 1).
The preparation of the minor diastereoisomer formed in
the reaction from L-valinal (syn-2c) was envisaged from
anti-2c by oxidation to the corresponding ketone and
hydride reduction as previously described8 for different
amino alcohols, but attempts to oxidize anti-2c failed
giving complex mixtures of reaction under all the
The major problem for that reaction refers to the con-
trol of the stereoselection and generally, mixtures of anti
and syn diastereoisomers are obtained, although the nat-
ure of either the organometallic or the substituents at
the nitrogen atom allows for the formation of one dia-
stereoisomer in moderate to good diastereomeric excess
(de).6 In this way, lithium acetylides react with di-
benzylamino aldehydes leading to anti diastereoisomers
in excellent de,1,7 but with diethylzinc yielding the syn
adduct as the major isomer.8
OH
O
i
Ph
Ph
R
H
H
NBn
anti-2a
2
NBn
1a
2
In this letter, we present a direct, highly diastereoselec-
tive synthesis of both diastereoisomers of 4-substituted
4-dibenzylamino but-1-yn-3-ols from a-dibenzylamino
aldehydes8,9 and their transformation into enantiopure
c-lactones and 5-hydroxy-piperidinone derivatives.
HO
O
i
R
NBn
2
NBn
2
anti-2b-d
c: R = i-Pr d: R = CH Ph
1b-d
Keywords: a-Amino aldehydes; Asymmetric synthesis; Diastereoselec-
tive addition; Hydroxy-piperidinones; Lactones.
b: R = Me
2
*
Scheme 1. Reagents and conditions: (i) 1. HCCMgBr, THF/Et2O,
0 °C; 2. Aqueous NH4Cl.
Corresponding author. Tel.: +34 983 423 211; fax: +34 983 423
013; e-mail: pedrosa@qo.uva.es
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.131

5318
J. M. Andre´s et al. / Tetrahedron Letters 47 (2006) 5317–5320
Table 1. Stereoselective ethynylation of a-dibenzylamino aldehydes
1a–d
treatment on anti-2c gave anti-7c in 35% overall yield
(Scheme 3).
Entry
1
2
Yield (%)a
anti:synb
Finally, anti-2a–d were quickly transformed into enan-
tiopure (5R,6S) or (5S,6R)-5-hydroxy-6-substituted pip-
eridin-2-ones 10a–d as shown in Scheme 4 and Table 2,
depending on the configuration of the starting amino
aldehyde derivatives. Protection of anti-2a–d as TBDMS
1
2
3
4
1a
1b
1c
1d
2a
2b
2c
2d
78
73
71
47
82:18
91:9
90:10
92:8
a Numbers correspond to combined yield of pure and isolated
diastereoisomers.
b The diastereomeric ratio was determined by integration of the signals
of 1H NMR spectra of the reaction mixture.
O
OTBDMS
CO Et
O
iii
2
assayed experimental conditions. This problem was cir-
cumvented by the oxidation of anti-3c under Swern’s
conditions to a-dibenzylamino ketone 4c in 64% yield.
Propargyl amino alcohol anti-3c was prepared, as a sin-
gle diastereoisomer in 54% yield, by reaction of 1c with
lithium trimethylsilylacetylide in THF at ꢀ78 °C. The
reduction of 4c with lithium aluminum hydride in
Et2O at ꢀ78 °C, followed by desilylation with TBAF
in THF at rt, gave syn-2c in 64% yield and excellent
de (Scheme 2). After purification by flash chromatogra-
phy, the stereochemistry of syn- and anti-2 was estab-
NHBoc
syn-6c
NHBoc
syn-7c
ii
OH
OTBDMS
i
NBn
2
CO Et
NBn
2
2
syn-2c
syn-5c
OH
OTBDMS
1
i
lished on the basis of their H NMR spectral data.10
NBn
2
NBn
CO Et
2
2
The interest of these 1,2-amino propargylalcohols as
chiral synthons was firstly tested for anti- and syn-2c,
by their conversion into dibenzylamino c-lactones
syn-7c and anti-7c (Scheme 3). The former has been
previously prepared, because it is an important part of
a compound (AG7088), which acts as rhinovirus prote-
ase inhibitor.11 The unprotected aminoalcohols derived
from syn- and anti-5c have also been used in the direct
stereoselective syntheses of dipeptide isosteres.12
anti-2c
anti-5c
ii
O
O
OTBDMS
CO Et
NHBoc
anti-6c
iii
2
NHBoc
anti-7c
Scheme 3. Reagents and conditions: (i) 1. TBDMSCl, imidazole,
DMF, rt. 2. n-BuLi (1.2 equiv), THF, ꢀ78 °C. 3. ClCO2Et (1.5 equiv),
THF, ꢀ78 to ꢀ40 °C. 4. Aqueous NH4Cl; (ii) H2/Pd(OH)2(C), Boc2O,
MeOH; (iii) TBAF, THF, rt.
In our case, after protection of the hydroxyl group with
TBDMSCl and imidazole, syn-2c was deprotonated with
n-BuLi in THF at ꢀ78 °C and then reacted with ethyl
chloroformate in THF at ꢀ40 °C to yield syn-5c in
78% yield. Hydrogenation of this compound over Perl-
man’s catalyst in methanol and Boc anhydride led to
syn-6c, which was transformed into the final amino
lactone derivative syn-7c by deprotection with TBAF
in THF at rt with subsequent lactonization. The same
OH
OTBDMS
i
R
R
NBn
2
NBn
CO Bn
2
2
anti-8b-d
anti-2b-d
ii
HO
i
TBDMSO
iii
HO
R
1c
NBn
TMS
2
R
N
H
O
N
H
O
anti-3c
9b-d
10b-d
ii
OH
HO
Ph
i, ii, iii
O
HO
Ph
iii
N
H
O
NBn
2
NBn
TMS
NBn
2
2
10a
anti-2a
syn-2c (dr > 20:1)
4c
Scheme 4. Reagents and conditions: (i) 1. TBDMSCl, imidazole,
DMF, rt. 2. n-BuLi (1.2 equiv), THF, ꢀ78 °C. 3. ClCO2Bn (1.5 equiv),
THF, ꢀ78 to ꢀ40 °C. 4. Aqueous NH4Cl; (ii) 1. H2/Pd(OH)2(C),
MeOH. 2. DCC, 4-PPY, CH2Cl2; (iii) TBAF, THF, rt.
Scheme 2. Reagents and conditions: (i) 1. TMSCCLi, THF/hexanes,
ꢀ78 °C. 2. Aqueous NH4Cl; (ii) Swern oxidation; (iii) 1. LiAlH4, Et2O,
ꢀ78 °C. 2. TBAF, THF, rt.

J. M. Andre´s et al. / Tetrahedron Letters 47 (2006) 5317–5320
5319
Table 2. Yields (%) for the transformations summarized in Scheme 4
References and notes
Substrate
i (%)
ii (%)
iii (%)
1. Reetz, M. T. Chem. Rev. 1999, 99, 1121.
anti-2a
anti-2b
anti-2c
anti-2d
56
57
60
58
70
79
68
72
90
76
74
81
´
´
2. (a) Alemani, C.; Bach, J.; Farras, J.; Garcıa, J. Org. Lett.
1999, 1, 1831; (b) Ohno, H.; Toda, A.; Takemoto, Y.; Fuji,
N.; Ibuka, T. J. Chem. Soc., Perkin Trans. 1 1999, 2949;
(c) Ohno, H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2001,
3, 2269.
3. Dondoni, A.; Perrone, D.; Turturici, E. J. Org. Chem.
1999, 64, 5557.
4. Gridley, J. J.; Coogan, M. P.; Knight, D. W.; Malik, K.
M. A.; Sharland, C. M.; Shingkhonrat, J.; Williams, S.
Chem. Commun. 2003, 2550.
5. Poisson, J.-F.; Normant, J. F. Org. Lett. 2001, 3, 1889.
6. (a) D’Aniello, F.; Schoenfelder, A.; Mann, A.; Taddei, M.
J. Org. Chem. 1996, 61, 9631; (b) Lee, B. W.; Lee, J. H.;
Jang, K. C.; Kang, J. E.; Kim, J. H.; Park, K.-H.; Park, K.
H. Tetrahedron Lett. 2003, 44, 5905; (c) Henegan, M.;
Procter, G. Synlett 1992, 489.
7. Clayden, J.; McCarthy, C.; Cumming, J. G. Tetrahedron:
Asymmetry 1998, 9, 1427.
´
´
8. Andres, J. M.; Barrio, R.; Martınez, M. A.; Pedrosa, R.;
´
Perez-Encabo, A. J. Org. Chem. 1996, 61, 4210.
9. Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1141.
10. (a) Van der Zeijden, A. A. H. Tetrahedron: Asymmetry
1995, 6, 913; (b) Ishimaru, K.; Tsuru, K.; Yabuta, K.;
Wada, M.; Yamamoto, Y.; Akiba, K. Tetrahedron 1996,
52, 13137.
11. Ma, D.; Xie, W.; Zou, B.; Lei, Q.; Pei, D. Tetrahedron
Lett. 2004, 45, 8103.
Figure 1. ORTEP representation of X-ray structure for compound
10c.
12. Sa¨ıah, M. K. E.; Pellicciari, R. Tetrahedron Lett. 1995, 36,
4497.
ether, followed by deprotonation with n-BuLi and reac-
tion with benzyl chloroformate, yielded anti-8a–d in
good yields. Hydrogenation over Perlman’s catalyst of
anti-8a–d gave the TBDMS derivative of the corre-
sponding saturated d-amino c-hydroxy acid, which
was cyclized,13 without isolation, to 2-piperidinones
9a–d by treatment with dicyclohexylcarbodiimide and
4-pyrrolidinopyridine in methylene chloride at rt.
Deprotection of 9a–d with TBAF in THF yielded 10a–
d that was isolated by flash chromatography and crystal-
lization.14 The stereochemistry for compound 10c was
established by X-ray diffraction analysis15 (Fig. 1), and
extended for all the piperidinones.
13. Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 619.
14. Selected data for compounds 10a–d. (5S,6R)-5-Hydroxy-
6-phenylpiperidin-2-one (10a). Colorless solid, mp 182–
23
183 °C (from EtOAc). ½aꢁD +31.6 (c 0.75, MeOH). IR
1
(KBr): 3293, 1633, 1359, 1085, 752, 703 cmꢀ1. H NMR
(CD3OD): 1.84 (m, 2H, CHHCHOH); 2.41 (m, 1H,
CHHCO); 2.57 (m, 1H, CHHCO); 3.90 (m, 1H, CHOH);
4.46 (d, 1H, J = 4.7 Hz, CHN); 4.91 (br s, 2H, OH and
NH); 7.25–7.45 (m, 5H, Har). 13C NMR (CD3OD): 25.9
(CH2CO); 28.4 (CH2CHOH); 64.6 (CHN); 70.5 (CHOH);
128.1, 129.0, 129.8 (CHar); 142.1 (Car); 174.9 (CO).
C11H13NO2 (191.2): calcd C 69.09, H 6.85, N 7.32; found
C 68.84, H 6.71, N 7.38. (5R,6S)-5-Hydroxy-6-methyl-
piperidin-2-one (10b). Colorless solid, mp 141–142 °C
23
(from EtOAc/hexane). ½aꢁD ꢀ20.0 (c 0.5, MeOH). IR
Compounds 10a–d and related piperidin-2-ones have
been used as starting materials in the asymmetric syn-
thesis of different alkaloids16 and our method comple-
ments other diastereoselective syntheses previously
described.17
(KBr): 3360, 3172, 1647, 1346, 1073, 944, 827 cmꢀ1 1H
.
NMR (CD3OD): 1.22 (d, 3H, J = 6.5 Hz, CH3); 1.80 (m,
1H, CHHCHOH); 2.00 (m, 1H, CHHCHOH); 2.30 (m,
1H, CHHCO); 2.45 (m, 1H, CHHCO); 3.31 (dq, 1H,
J = 6.5 Hz, J = 5.9 Hz, CHN); 3.56 (ddd, 1H, J =
8.8 Hz, J = 5.9 Hz, J = 3.2 Hz, CHOH); 4.89 (br s, 2H,
OH and NH). 13C NMR (CD3OD): 20.4 (CH3); 27.7
(CH2CO); 29.0 (CH2CHOH); 55.7 (CHN); 70.1 (CHOH);
174.2 (CO). C6H11NO2 (129.2): calcd C 55.80, H 8.58, N
In summary, the described methodology allows for the
preparation of diastereoisomeric enantioenriched amino
propargyl alcohols and their transformation into useful
chiral building blocks for the synthesis of complex
molecules. Different enantiopure 6-substituted 5-hydr-
oxy-piperidin-2-ones can be easily prepared from
commercially available a-amino acids.
10.84; found
C 55.66, H 8.48, N 10.90. (5R,6S)-
5-Hydroxy-6-isopropylpiperidin-2-one (10c). Colorless
23
solid, mp 84–85 °C (from EtOAc/hexane). ½aꢁD ꢀ7.7 (c
0.4, CHCl3). IR (KBr): 3370, 1634, 1260, 1084, 830,
705 cmꢀ1 1H NMR (CDCl3): 0.92 (d, 3H, J = 6.7 Hz,
.
CH3); 0.96 (d, 3H, J = 7.0 Hz, CH3); 1.90 (m, 3H,
CHHCHOH and CH(CH3)2); 2.29 (ddd, 1H,
J = 18.0 Hz, J = 8.1 Hz, J = 6.5 Hz, CHHCO); 2.48 (dt,
1H, J = 18.0 Hz, J = 6.4 Hz, CHHCO); 3.07 (m, 1H,
CHN); 3.59 (br s, 1H, OH); 3.85 (m, 1H, CHOH); 6.24
(br s, 1H, NH). 13C NMR (CDCl3): 16.7 (CH3); 19.6
(CH3); 27.3 (CH2CO); 27.8 (CH2CHOH); 29.8
Acknowledgments
´
The authors thank the Spanish Ministerio de Educacion
y Ciencia (DGI, Project CTQ2005-01191/BQU) for
financial support.

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J. M. Andre´s et al. / Tetrahedron Letters 47 (2006) 5317–5320
((CH3)2CH); 64.1 (CHN); 65.1 (CHOH); 172.6 (CO). C12H15NO2 (205.2): calcd C 70.22, H 7.37, N 6.82; found
C8H15NO2 (157.2): calcd C 61.12, H9.62, N 8.91; found
C 60.88, H 9.49, N 9.00.(5R,6S)-6-Benzyl-5-hydroxy-
piperidin-2-one (10d). Colorless solid, mp 101–102 °C
C 69.90, H 7.24, N 6.91.
15. Crystallographic data can be obtained from the Cam-
bridge Crystallographic Data Center, 12, union Road,
Cambridge CB2 1EZ, UK, E-mail: deposit@
ccdc.cam.ac.uk.
23
(from EtOAc). ½aꢁD ꢀ37.9 (c 1.2, MeOH). IR (film):
3305, 3208, 1643, 1360, 1069, 763, 724, 700 cmꢀ1 1H
.
NMR (CD3OD): 1.82 (m, 1H, CHHCHOH); 1.98 (m,
1H, CHHCHOH); 2.21 (dt, 1H, J = 18.0 Hz, J = 6.3 Hz,
CHHCO); 2.44 (m, 1H, CHHCO); 2.81 (dd, 1H, J =
13.8 Hz, J = 6.7 Hz, CHHPh); 2.90 (dd, 1H, J = 13.8 Hz,
J = 6.3 Hz, CHHPh); 3.54 (m, 1H, CHN); 3.71 (m, 1H,
CHOH); 4.90 (br s, 2H, OH and NH); 7.20–7.35 (m, 5H,
Har). 13C NMR (CD3OD): 26.7 (CH2CO); 28.3
(CH2CHOH); 41.3 (CH2Ph); 61.2 (CHN); 66.5 (CHOH);
128.0, 129.8, 130.7 (CHar); 138.6 (Car); 174.5 (CO).
16. (a) Toyooka, N.; Yoshida, Y.; Yotsui, I.; Momose, T. J.
Org. Chem. 1999, 64, 4914; (b) Toyooka, N.; Yoshida, Y.;
Momose, T. Tetrahedron Lett. 1995, 36, 3715; (c) Cook,
G. R.; Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59,
3575; (d) Cook, G. R.; Beholz, L. G.; Stille, J. R.
Tetrahedron Lett. 1994, 35, 1669.
17. (a) Lee, H. K.; Chun, J. S.; Pk, C. S. Tetrahedron Lett.
2001, 42, 3483; (b) Lee, H. K.; Chun, J. S.; Pak, C. S.
Tetrahedron 2003, 59, 6445.