Stereocontrolled access to orthogonally protected anti,anti-4- aminopiperidine-3,5-diols through chemoselective reduction of enantiopure β-lactam cyanohydrins

Article abstract of DOI:10.1021/jo701452a

(Chemical Equation Presented) The cyanosilylation of enantiopure 4-oxoazetidine-2-carbaldehydes with tert-butyldimethylsilyl cyanide was promoted by either molecular sieves or catalytic amount of sodium carbonate to give O-silylated β-lactam cyanohydrins

Full text of DOI:10.1021/jo701452a

Stereocontrolled Access to Orthogonally Protected
anti,anti-4-Aminopiperidine-3,5-diols through Chemoselective
Reduction of Enantiopure â-Lactam Cyanohydrins
Benito Alcaide,*,† Pedro Almendros,‡ Gema Cabrero,† and M. Pilar Ruiz†
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad Complutense de Madrid,
28040 Madrid, Spain, and Instituto de Qu´ımica Orga´nica General, CSIC, Juan de la CierVa 3,
28006 Madrid, Spain
alcaideb@quim.ucm.es; iqoa392@iqog.csic.es
ReceiVed July 4, 2007
The cyanosilylation of enantiopure 4-oxoazetidine-2-carbaldehydes with tert-butyldimethylsilyl cyanide
was promoted by either molecular sieves or catalytic amount of sodium carbonate to give O-silylated
â-lactam cyanohydrins with good yield and diastereoselectivity. In contrast, Lewis acids did not effectively
promote the cyanosilylation under different experimental conditions, and instead hydrocyanation took
place affording the corresponding free cyanohydrins in variable yield and selectivity. Starting from â-lactam
cyanohydrin hybrids, two concise, complementary stereocontrolled routes to optically pure orthogonally
protected anti,anti-4-amino-3,5-piperidine diols were achieved. Key features of the first approach include
chemoselective reductive opening of the â-lactam ring with LiBH4 to a 3-amino-5-hydroxy pentanenitrile
followed by reductive cyclization of a conveniently functionalized cyanomesylate derivative with NaBH4/
NiCl2. The second approach involves LiAlH4 reduction of protected anti,anti-4-amino-3,5-dihydroxypi-
peridin-2-ones, which were easily obtained by chemoselective reduction of the cyano group in the â-lactam
cyanohydrin hybrids with NaBH4/NiCl2 and subsequent intramolecular rearrangement of the resulting
amino â-lactams. Both routes make use of an oxidative N-dearylation with diacetoxyiodobenzene of a
4-methoxyphenylamino group as a common synthetic step. Specifically, the utility of this novel reaction
sequence has been demonstrated by the synthesis of fully orthogonally protected sialidase inhibitors.
Introduction
dases and glycoprotein-processing enzymes.3 These inhibitors
have shown a great therapeutic potential as drugs for the
treatment of a variety of carbohydrate-mediated diseases such
as diabetes, cancer, and viral infections including HIV.4 More
The piperidine ring is a ubiquitous structural feature of many
natural products and pharmacologically active compounds.
Therefore, a continuous interest exists in the development of
new methodologies for asymmetric synthesis of this six-
membered azaheterocycle.1 In recent years, polyhydroxylated
piperidines, also called azasugars or iminosugars,2 and their
synthetic analogues have attracted a great deal of attention due
to their ability to mimic sugars and selectively inhibit glycosi-
(2) For selected reviews, see: (a) Afarinkia, K.; Bahar, A. Tetrahe-
dron: Asymmetry 2005, 16, 1239. (b) Asano, N. Curr. Top. Med. Chem.
2003, 3, 471. (c) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003,
3, 541. (d) Nash, R. J.; Watson, A. A.; Asano, N. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Elsevier: Oxford, UK,
1996; Vol. 11, p 345. (e) Elbein, A. D.; Molyneux, R. J. In ComprehensiVe
Natural Products; Barton, D., Nakanishi, K., Eds.; Elsevier: New York,
1999; Vol. 3, p 129.
(3) (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. ReV. 2000, 100,
4683. (b) Bols, M. Acc. Chem. Res. 1998, 31, 1. (c) Iminosugars as
Glycosidase Inhibitors. Nojirimicin and Beyond; Stu¨tz, A. E., Ed.; Wiley-
VCH: Weinheim, Germany, 1999.
† Universidad Complutense.
‡ CSIC.
(1) For reviews on the synthesis of piperidines, see: (a) Buffat, M. G.
P. Tetrahedron 2004, 60, 1701. (b) Felpin, F.-X.; Lebreton, J. Eur. J. Org.
Chem. 2003, 3693-3712. (c) Weintraub, Ph. M.; Sabol, J. S.; Kane, J. M.;
Borcherding, D. R. Tetrahedron 2003, 59, 2953. (d) Laschat, S.; Dickner,
T. Synthesis 2000, 1781. (e) Bailey, P. D.; Millwood, P. A.; Smith, P. D.
Chem. Commun. 1998, 633-640.
(4) (a) Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely, P. Curr.
Pharm. Des. 2003, 9, 1177. (b) Greimel, P.; Spreitz, J.; Stutz, A. E.;
Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3, 513. (c) Nishimura, Y.
Curr. Top. Med. Chem. 2003, 3, 575.
10.1021/jo701452a CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/15/2007
7980
J. Org. Chem. 2007, 72, 7980-7991

Access to anti,anti-4-Aminopiperidine-3,5-diols
SCHEME 1
specifically, N-functionalized trans,trans-4-acetamido-3,5-pip-
eridine diols have been described as a new structural class of
sialidase inhibitor which combines transition state analogy with
the ability to include aglycon mimicry.5 In addition, protected
piperidine-3,5-diols6 have been used as asymmetric catalysts
in organometallic additions to aldehydes,7 and cis-4-amino-3-
methoxypiperidine has been reported as a substructure of
cisapride, a potent gastric prokinetic agent with reduced
Dopamine D2 receptor antagonistic activity.8
Besides the key role that â-lactams have played in the fight
against pathogenic bacteria, the use of 2-azetidinones as chiral
building blocks in organic synthesis is now well-established.9
Due to ring strain, 2-azetidinones are susceptible to ring-
cleavage reactions with a broad range of reagents with high or
often complete regio- and stereoselectivity.10 Selective bond
cleavage of the 2-azetidinone ring coupled with further interest-
ing synthetic transformations renders these fascinating molecules
powerful synthetic building blocks in the stereocontrolled
synthesis of a wide variety of nitrogen-containing compounds.11
On the other hand, cyanohydrins are versatile synthetic inter-
mediates for the synthesis of a variety of interesting compounds.
Both the hydroxy and nitrile groups of the cyanohydrins can
be further transformed into a variety of useful functional units.12
Thus, the nitrile group can be hydrolyzed to create different
types of R-hydroxy carbonyl compounds or reduced to form
1,2-amino alcohol derivatives.13 In light of the synthetic utility
of both classes of compounds, the stereoselective preparation
of optically pure â-lactam cyanohydrin hybrids arises as an
important endeavor since they are potential versatile precursors
to functionalized azaheterocycles. We have used carbonyl
â-lactams as chiral templates14 and have recently shown their
transformation to a variety of potentially bioactive products.15
We now report two short, complementary â-lactam cyanohydrin-
based routes to orthogonally protected enantiopure anti,anti-4-
amino-3,5-piperidine diols, by a strategy that allows stereocon-
trolled construction of all three contiguous stereocenters. Our
retrosynthetic strategies are outlined in Scheme 1. Specifically,
the utility of this novel reaction sequence has been demonstrated
by the synthesis of fully orthogonally protected sialidase
inhibitors.
Results and Discussion
In light of the synthetic utility of cyanohydrins, their
enantioselective preparation has been extensively investigated
and comprehensively reviewed.16 Among different reported
examples, only a few papers refer to chiral protected R-ami-
noaldehydes.17 Our interest in the use of 4-oxoazetidine-2-
carbaldehydes as substrates for addition reactions14a prompted
us to evaluate their cyanosilylation reaction with tert-butyldim-
ethylsilyl cyanide (TBSCN). We choose TBSCN as the cyanide
source instead of the simpler trimethylsilyl cyanide in order to
obtain more robust O-TBS derivatives compatible with reaction
conditions used in the synthetic routes, thus avoiding problems
associated with the sensitive trimethylsilyloxy moiety. In this
context, we began this work by investigating the effect of various
Lewis acids on the cyanosilylation with TBSCN of 4-oxoaze-
(5) Parr, I. B.; Horenstein, B. A. J. Org. Chem. 1997, 62, 7489.
(6) (a) Olofsson, B.; Boga´r, K.; Fransson, A.-B. L.; Ba¨ckvall, J.-E. J.
Org. Chem. 2006, 71, 8256. (b) Ouchi, H.; Mihara, Y.; Takahata H. J.
Org. Chem. 2005, 70, 5207 and references cited therein.
(7) Roudeau, R.; Pardo, D. G.; Cossy, J. Tetrahedron 2006, 62, 2388.
(8) Cossy, J.; Molina, J. L.; Desmurs, J.-R. Tetrahedron Lett. 2001, 42,
5713 and references cited therein.
(9) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. ReV. 2007, http://
dx.doi.org/10.1021/cr0307300.
(10) For a review on the selective bond cleavage of the â-lactam nucleus,
see: Alcaide, B.; Almendros, P. Synlett 2002, 381.
(11) For reviews, see: (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.;
Oiarbide, M. Curr. Med. Chem. 2004, 11, 1837. (b) Deshmukh, A. R. A.
S.; Bhawal, B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.;
Jayanthi, A. Curr. Med. Chem. 2004, 11, 1889. (c) Alcaide, B.; Almendros,
P. Curr. Med. Chem. 2004, 11, 1921. (d) Palomo, C.; Aizpurua, J. M.;
Ganboa, I.; Oiarbide, M. Synlett 2001, 1813. (e) Palomo, C.; Aizpurua, J.
M.; Ganboa, I.; Oiarbide, M. Amino Acids, 1999, 16, 321. (f) Ojima, I.;
Delaloge, F. Chem. Soc. ReV. 1997, 26, 377. (g) Palomo, C.; Aizpurua, J.
M.; Ganboa, I. In EnantioselectiVe Synthesis of â-Amino Acids; Juaristi,
E., Ed.; Wiley-VCH: New York, 1997; p 279. (h) Ojima, I. AdV. Asym.
Synth. 1995, 1, 95. (i) Ojima, I. The Organic Chemistry of â-Lactams; Georg,
G. I., Ed.; VCH Publishers: New York, 1993; p 197. (j) Manhas, M. S.;
Wagle, D. R.; Chiang, J.; Bose, A. K. Heterocycles 1988, 27, 1755.
(12) See, for example: (a) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649.
(b) Effenberger, F.; Kremser, A.; Stelzer, U. Tetrahedron: Asymmetry 1996,
7, 607. (c) Effenberger, F.; Stelzer, U. Tetrahedron: Asymmetry 1995, 6,
283.
(15) (a) Alcaide, B.; Almendros, P.; Mart´ınez del Campo, T. Angew.
Chem., Int. Ed. 2006, 45, 4501. (b) Alcaide, B.; Almendros, P.; Redondo,
M. C. Chem. Commun. 2006, 2616. (c) Alcaide, B.; Almendros, P.; Luna,
A.; Torres, M. R. J. Org. Chem. 2006, 71, 4818. (d) Alcaide, B.; Almendros,
P.; Aragoncillo, C.; Redondo, M. C.; Torres, M. R. Chem.sEur. J. 2006,
12, 1539. (e) Alcaide, B.; Almendros, P.; Redondo, M. C.; Ruiz, M. P. J.
Org. Chem. 2005, 70, 8890. (f) Alcaide, B.; Almendros, P.; Cabrero, G.;
Ruiz, M. P. Org. Lett. 2005, 7, 3981.
(16) For reviews, see: (a) Synthesis and application of nonracemic
cyanohydrins and (R)-amino nitriles. Tetrahedron Symposium-in-Print;
North, M., Ed. 2004, 60, 10383-10568. (b) Brunel, J.-M.; Holmes, I. P.
Angew. Chem., Int. Ed. 2004, 43, 2752. (c) North, M. Tetrahedron:
Asymmetry 2003, 14, 147. (d) North, M. Synlett 1993, 807.
(13) See, for example: (a) Schwindt, M. A.; Belmont, D. T.; Carlson,
M.; Franklin, Ll. C.; Hendrickson, V. S.; Karrick, G. L.; Poe, R. W.;
Sobieray, D. M.; van De Vusse, J. J. Org. Chem. 1996, 61, 9564. (b) Brown,
R. F. C.; Donohue, A. C.; Jackson, W. R.; McCarthy, T. D. Tetrahedron
1994, 50, 13739. (c) Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990,
55, 181. (d) Ziegler, T.; Ho¨rsch, B.; Effenberger, F. Synthesis 1990, 575-
578.
(14) For the applications of 4-oxoazetidine-2-carbaldehydes as efficient
chiral synthons, see: (a) Alcaide, B.; Almendros, P. Chem. Soc. ReV. 2001,
30, 226. For a review on the chemistry of azetidine-2,3-diones, see: (b)
Alcaide, B.; Almendros, P. Org. Prep. Proced. Int. 2001, 33, 315.
(17) (a) Andre´s, J. M.; Mart´ınez, M. A.; Pedrosa, R.; Pe´rez-Encabo, A.
Tetrahedron: Asymmetry 2001, 12, 347. (b) Myers, A. G.; Kung, D. W.;
Zhong, B.; Movassaghi, M.; Kwon, S. J. Am. Chem. Soc. 1999, 121, 8401.
(c) Shibata, N.; Itoh, E.; Terashima, S. Chem. Pharm Bull. 1998, 46, 733.
(d) Terashima, S. Synlett 1992, 691. (e) Herranz, R.; Vinuesa, S.; Pe´rez,
C.; Garc´ıa-Lo´pez, M. T. J. Chem. Soc., Perkin Trans. 1 1991, 2749. (f)
Herranz, R.; Castro-Pichel, J.; Vinuesa, S.; Garc´ıa-Lo´pez, M. T. J. Org.
Chem. 1990, 55, 2232. (g) Herranz, R.; Castro-Pichel, J.; Garc´ıa-Lo´pez, T.
Synthesis 1989, 703-706. (h) Reetz, M. T.; Drewes, M. W.; Harms, K.;
Reif, W. Tetrahedron Lett. 1988, 29, 3295. (i) Rich, D. H.; Moon, B. J.;
Boparai, A. S. J. Org. Chem. 1980, 45, 2288.
J. Org. Chem, Vol. 72, No. 21, 2007 7981

Alcaide et al.
TABLE 1. Lewis Acid Mediated TBSCN Addition to â-Lactam Aldehydes 1a,ba
Lewis acid
(mol %)
T
(°C)
t
yieldc
(%)
entry
R1
solvent
CH2Cl2
(h)
product
syn/antib
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
InCl3 (100)
InCl3 (30)
InCl3 (10)
InCl3 (10)
InCl3 (10)
InCl3 (50)
InCl3 (100)
InCl3 (100)
InCl3 (100)
SnCl4 (100)
ZnCl2 (100)
BiCl3 (20)
none
∆
rt
rt
rt
∆
∆
∆
rt
∆
∆
∆
rt
rt
rt
∆
24
45
6
97
41
6
d
2a
2a
2a
2a
2a
2a
2a
2a
2a/3a
3a
2a/3a
2a/3a
2b
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
CH3CN/H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3CN
65:35
60:40
90:10
90:10
90:10
90:10
81:19
74:26
65:35
47:53
70:30
g
15
84
12
40
35
54
73
32
50e
68
45f
15h
61
15
6
30
22
5
21
20
48
7
InCl3 (10)
InCl3 (100)
57:43
90:10
Ph
30
2b
a All reactions were performed using an aldehyde/TBSCN ratio of 1/1.2 mmol. b The ratio was determined by integration of well-resolved signals in the
1H NMR spectra of the crude reaction mixtures before purification. c Combined yield of pure, isolated products (syn/anti-2) after silica gel chromatography
with correct analytical and spectral data. d A complex mixture of uncharacterized products was obtained. e In addition, a further 5% yield of a mixture of
O-silylated cyanohydrins 3a was obtained. f In addition, a further 8% yield of a mixture of O-silylated cyanohydrins 3a was obtained. g Undetermined
mixture of syn/anti-isomers both for 2a and 3a. h In addition, a further 18% yield of a mixture of O-silylated cyanohydrins 3a was obtained.
tidine-2-carbaldehyde 1a,18 which was selected as a model
substrate. First, we investigated reaction of 1a with TiCl4, BF3‚
Et2O, and ZnBr2, which are well-documented promoters for
cyanosilylation of chiral aldehydes.17,19 The reaction failed to
give the corresponding cyanation products under different
experimental conditions and a complex mixture of uncharac-
terized products being obtained in all cases. Similar results were
observed for the InCl3 (100 mol %)-induced reaction in
dichloromethane as solvent, both at room temperature and at
reflux (Table 1, entry 1).20 However, when a catalytic amount
of InCl3 (10 mol %) was used, quantitative conversion to the
cyanohydrin 2a was obtained after 4 h in dichloromethane at
room temperature, as a 60/40 mixture of syn/anti isomers (Table
1, entry 3). Fortunately, both diastereomers of compound 2a
could be easily separated and obtained in reasonable yield by
flash chromatography on silica gel, the major isomer syn-2a
being the less polar compound. We also found that on increasing
the amount of InCl3 (30 mol %) both the efficiency and the
reaction rate decreased (Table 1, entry 2). In order to improve
the selectivity of the process, the effect of altering the reaction
solvent was then explored (tetrahydrofuran, acetonitrile, and
DMSO). A significant solvent effect on the diastereoselectivity
was observed, the more polar solvents increased the selectivity
although the reaction proceeded more slowly and with dimin-
ished efficiency in acetonitrile (Table 1, entries 4 and 5). When
the reaction was run in acetonitrile, the effect of the amount of
InCl3 and temperature on the conversion rate as well as on the
selectivity was studied. It was found that the efficiency of the
process did improve upon increasing the amount of catalyst
while retaining the selectivity of the reaction when cyanohydrin
formation was performed in refluxing acetonitrile (Table 1,
entries 5-7). A similar experiment in DMSO at room temper-
ature gave slightly improved yield but worse selectivity (Table
1, entry 8), and a poor result in terms of both selectivity and
efficiency of the reaction was achieved when a 4/1 mixture of
acetonitrile/water was used (Table 1, entry 9). On the basis of
these results, we chose to use equimolecular amounts of different
Lewis acid in acetonitrile as solvent. A mixture (90/10) of
cyanohydrin 2a, major compound, and O-silylated cyanohydrin
3a was obtained for the SnCl4 (1 equiv)-promoted reaction after
5 h, in both cases as mixtures of syn/anti isomers (Table 1,
entry 10). Interestingly, the ZnCl2 (1 equiv)-promoted reaction
gave in good yield cyanohydrin 2a with poor anti-selectivity
(Table 1, entry 11). The reaction with BiCl3 (1 equiv) results
in a complete recovery of the starting aldehyde, while use of
less BiCl3 (20 mol %) in acetonitrile at room temperature
afforded an 84/16 mixture of cyanohydrin 2a and its O-silyl
derivative 3a, respectively, in both cases as a 70/30 mixture of
(18) Starting substrates, enantiopure cis-4-oxoazetidine-2-carbaldehydes
1a-e, were prepared from the [2 + 2] cycloaddition reactions of (R)-2,3-
O-isopropylideneglyceraldehyde imines with alkoxyacetyl chlorides in the
presence of Et3N, followed by sequential acidic acetonide hydrolysis, and
oxidative cleavage. See, for example: Wagle, D. R.; Garai, C.; Chiang, J.;
Monteleone, M. G.; Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas,
M. S.; Bose, A. K. J. Org. Chem. 1988, 53, 4227.
(19) For the silylcyanation of related R-alkoxy aldehydes using TMSCN
in the presence of Lewis acid, see: (a) Ward, D. E.; Hrapchak, M. J.; Sales,
M. Org. Lett. 2000, 2, 57. (b) Yang, Y.; Wang, D. Synlett 1997, 1379. (c)
Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A.; Garc´ıa, J. I.
Tetrahedron 1996, 52, 9563. (d) Ipaktschi, J.; Heydari, A.; Kalinowski,
H.-O. Chem. Ber. 1994, 127, 905. (e) Nakai, T.; Gu, J. H.; Okamoto, M.;
Terada, M.; Mikami, K. Chem. Lett. 1992, 1169. (f) Reetz, M. T.; Fox, D.
N. A. Tetrahedron Lett. 1993, 34, 1119. (g) Effenberger, F.; Hopf, M.;
Ziegler, T.; Hudelmayer, J. Chem. Ber. 1991, 124, 1651. (h) Nishimura,
S.; Hayashi, N. Chem. Lett. 1991, 1815. (i) Dostert, P.; Melloni, P.; Torre,
A. D.; Varasi, M.; Merlini, L.; Bonsignori, A.; Ricciardi, S. Eur. J. Med.
Chem. 1990, 25, 757. (j) Reetz, M. T.; Kesseler, K.; Jung, A. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 989.
(20) For the use of indium(III) chloride as a Lewis acid catalyst in the
synthesis of R-aminonitriles by a one-pot three-component Strecker reaction,
see: Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529.
7982 J. Org. Chem., Vol. 72, No. 21, 2007

Access to anti,anti-4-Aminopiperidine-3,5-diols
TABLE 2. Silylcyanation of â-Lactam Aldehydes 1 with TBSCNa
promoter
(mol %)
t
yieldc
(%)
entry
aldehyde
R1
R2
(h)
product
syn/antib
1
2
3
4
5
6
7
8
9
(+)-1a
(+)-1a
(+)-1a
(+)-1a
(+)-1b
(+)-1b
(+)-1c
(+)-1d
(+)-1d
(+)-1e
Me
Me
Me
Me
Ph
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Bn
MS 4 Åd
3.0
1.0
0.4
3a
3a
3a
82:18
82:18
82:18
f
87:13
88:12
82:18
60:40
62:38
67:33
87
94
75
75g
60
81
89
64
81
54
Na2CO3 (25)
Bu4NCN (10)
Et3N (50)
2a/3ae
3b
MS 4 Åd
3.5
0.75
1.5
2.0
0.75
1.5
Ph
Na2CO3 (25)
Na2CO3 (25)
MS 4 Åd
Na2CO3 (25)
Na2CO3 (25)
3b
3c
3d
3d
Bn
Me
Me
Me
Bn
allyl
10
3e
a All reactions were performed using an aldehyde/TBSCN ratio of 1/1.2 mmol. b The ratio was determined by integration of well-resolved signals in the
1H NMR spectra of the crude reaction mixtures before purification. c Combined yield of pure, isolated products syn/anti-3 after silica gel chromatography
with correct analytical and spectral data. d A ratio of 4 Å molecular sieves/aldehyde ) 500 mg/mmol was used. e A 15/85 mixture of compounds 2a/3a was
obtained as determined by 1H NMR analysis of the crude reaction mixture before purification. f Compound 2a was obtained as a 43:57 mixture of syn/
anti-isomers as determined by 1H NMR analysis of the crude reaction mixture before purification. Compound 3a was obtained as a 87:13 mixture of
syn/anti-isomers as determined by 1H NMR analysis of the crude reaction mixture before purification. g In addition, a further 13% yield of a 43:57 mixture
of cyanohydrins 2a was obtained.
syn/anti isomers (Table 1, entry 12).21 Use of HfCl4 (1 equiv
or 20 mol %) to promote the cyanosilylation of compound 1a
was unsuccessful, the starting aldehyde being recovered almost
unchanged, after prolonged reaction times in acetonitrile both
at room temperature and at reflux. Finally, a blank test using
TBSCN in acetonitrile at room temperature without a Lewis
acid promoter gave a 23/34/43 mixture of compounds 1a/2a/
3a, respectively, from which the syn/anti ratio of isomers could
not be determined (Table 1, entry 13). From the above study,
we could conclude that Lewis acids are unable to effectively
promote the cyanosilylation under different experimental condi-
tions, and instead hydrocyanation takes place affording the
corresponding free cyanohydrin in variable yield and selectivity.
In terms of yield, the best result was obtained using InCl3 (10
mol %) in dichloromethane at room temperature (Method A,
see Supporting Information), while use of InCl3 (100 mol %)
in acetonitrile at reflux was necessary for better diastereose-
lectivity (Method B, see Supporting Information). On the other
hand, no significant steric effect on the diastereoselectivity was
observed under the above optimized conditions for aldehyde
1b having a sterically more demanding phenoxy group at C3
than aldehyde 1a. However, the efficiency and the reaction rate
decreased for 1b (Table 1, entries 14 and 15).
good yield and reasonable diastereoselectivity (Table 2, entry
1) (Method A, see Experimental Section). In this way, formation
of cyanohydrin 2a was suppressed. Switching solvents (CH2-
Cl2, THF, toluene, DMSO) had no beneficial effects. In terms
of achieving good yields with reasonable selectivity of reaction,
room temperature seemed to be the temperature of choice for
running the experiments.
Then, we turned our attention to the use of bases such as
Bu4NCN,23 Et3N,24 and Na2CO3.25 As shown in Table 2, the
best results were obtained using Na2CO3 (25 mol %) in
acetonitrile at room temperature (entry 2) (Method B, see
Experimental Section), affording compound 3a in excellent yield
as a 4.5/1 mixture of syn/anti-isomers. Next, we decided to
extend the process to other â-lactam aldehydes 1b-e, bearing
different substituents both at C3 and at N1 (Table 2, entries
5-10). The steric properties of both the C3 and N1 substituents
on the 2-azetidinone ring appear to influence the stereoselectivity
of the addition, with sterically less demanding groups decreasing
the diastereoisomeric ratio. In fact, when a phenoxy group was
used instead of a methoxy group, the stereoselectivity increased
(Table 2, entries 5 and 6). Also, placing a less bulky group at
N1, such as benzyl or allyl, decreased both the efficiency and
the selectivity of the addition (Table 2, entries 8-10). Fortu-
nately, both diastereomers of compound 3 could be easily
separated by flash chromatography on silica gel in all cases.
Chemical correlation between cyanosilyl derivatives syn-3a and
anti-3a and their corresponding cyanohydrins syn-2a and anti-
2a was achieved by hydrolysis of the formers with 20% aqueous
HCl in acetonitrile in moderate yield.
Next, we focused our efforts on the cyanosilylation of
aldehyde 1a using an equimolar amount of Lewis acid in
combination with an excess of 4 Å molecular sieves (MS), but
this proved to be equally unfeasible. On the other hand, when
the cyanosilylation was carried out in the presence of 4 Å MS22
in acetonitrile at room temperature, and in the absence of a
Lewis acid, the cyanosilyl derivative 3a was obtained in very
The syn/anti stereochemistry for new compounds 2 and 3
1
was assigned by comparison of its H NMR data with that
(21) Bismuth(III) chloride has been reported as a versatile catalyst for
cyanation of aldehydes with trimethylsilyl cyanide as well as for the
synthesis of R-aminonitriles by a one-pot three-component Strecker reaction.
See, for example: (a) De, S. K.; Giggs, R. A. Tetrahedron Lett. 2004, 45,
7407. (b) Wada, M.; Takahashi, T.; Domae, T.; Fukuma, T.; Miyoshi, N.;
Smith, K. Tetrahedron: Asymmetry 1997, 8, 3939.
(22) For the use of molecular sieves (4 Å) in the cyanobenzoylation and
hydrocyanation of aldehydes, see: Watahiki, T.; Ohba, S.; Oriyama, T.
Org. Lett. 2003, 5, 2679.
(23) For the use of TBACN as catalyst for the cyanosilylation of carbonyl
compounds with trialkylsilyl cyanides, see: Amurrio, I.; Co´rdoba, R.; Csa´ky¨,
A. G.; Plumet, J. Tetrahedron 2004, 60, 10521.
(24) See, for example: (a) Denmark, S. E.; Chung, W.-J. J. Org. Chem.
2006, 71, 4002. (b) Paraskar, A. S.; Sudalai, A. Tetrahedron Lett. 2006,
47, 5759.
(25) He, B.; Li, Y.; Feng, X.; Zhang, G. Synlett 2004, 1776.
J. Org. Chem, Vol. 72, No. 21, 2007 7983

Alcaide et al.
reported in the literature for related products.26 In this way, the
vicinal coupling constant between H4 and H4′ is higher for syn-
isomers (J4.4 ) 5.3 Hz for 2a and J4.4 ) 7.8-6.3 Hz for
compounds 3) than for anti-isomers (J4.4 ) 2.7 Hz for 2a and
J4.4 ) 5.9-2.4 Hz for compounds 3). Moreover, assignment of
configuration of cyanohydrins syn-2a and anti-2a27 has been
recently reported by Riguera et al. by comparison of the
SCHEME 2
1
corresponding H and 13C NMR spectra of their (R)- and (S)-
2-methoxy-2-phenylacetates.28 The stereochemistry for the rest
of the â-lactams was initially assigned on the basis of the above
data and was finally confirmed by chemical correlation with
their corresponding piperidines (see below). The observed syn-
diastereoselectivity for both compounds 2 and 3 might be
tentatively explained by invoking the Felkin-Anh model,
analogously to the related addition processes described in our
laboratories.14a
Polyfunctional â-lactam cyanohydrin derivatives may be
considered versatile intermediates in organic synthesis because
of their inherent dual reactivity. With O-silylated â-lactam
cyanohydrins 3 in hand, we next explored different reducing
agents in order to find the best conditions for their chemose-
lective reduction. Since these compounds 3 may yield many
different products, a number of different metal hydrides were
screened using â-lactam cyanohydrin syn-3a as a model
substrate.
29
First, we used LiAlH4 that led to the disappearance of
starting material, and no recognizable products were isolated
after treatment with aqueous base. These results clearly point
out the delicate balance of reactivity between the reducing agent
and reactive functional groups in the molecule. On the other
to find rapid, complete chemoselective reduction of the cyano
group affording amino â-lactam 4a in quantitative yield (Scheme
2).
30
hand, NaBH4 was revealed to be ineffective for promoting
any reduction on â-lactam cyanohydrin syn-3a; the â-amino
ester arising from the basic opening of the â-lactam ring was
the only formed product after prolonged reaction time. It is well-
known that the reducing behavior of sodium borohydride is
dramatically improved with the addition of transition metal
salts.31 Among these, Ni(II) and Co(II) salts have drawn wide
attention in the modification of NaBH4 reactivity and have found
application in the reduction of nitriles.32 Therefore, we inves-
tigated the reduction of compound syn-3a with NiCl2‚6H2O (1
equiv) and an excess of NaBH4 in methanol. We were pleased
Having developed an efficient method to selectively reduce
the nitrile function on compounds syn-3a, we needed to explore
other reagents that could chemoselectively react with the
â-lactam ring. Lithium borohydride has been reported as a
selective reducing agent for esters and amides, but its use has
never been reported for â-lactams.33 To our surprise, reduction
of the model compound syn-3a with LiBH4 in diethyl ether as
solvent at room temperature smoothly gave the corresponding
â-amino-δ-hydroxy nitrile 6a in excellent yield and with total
chemoselectivity (Scheme 2). Further reduction of compound
6a with nickel boride under the conditions used before resulted
in the formation of diamino alcohol 7a in 47% yield. Finally,
to complete the reduction processes, we subjected the Boc-
protected derivative 5a to treatment with LiBH4/Et2O at room
temperature, affording the corresponding â-amino-δ-hydroxy
carbamate 7b in excellent yield (Scheme 2). Amino alcohols
such as 7a and 7b may serve as chelating agents as well as
versatile chiral building blocks for both organic synthesis and
the preparation of macrocycles.34
(26) See, among others: (a) Andre´s, J. M.; de Elena, N.; Pedrosa, R.;
Pe´rez-Encabo, A. Tetrahedron 1999, 55, 14137. (b) Ishimaru, K.; Tsuru,
K.; Yabuta, K.; Wada, M.; Yamamoto, Y.; Akiba, K. Tetrahedron 1996,
52, 13137. (c) van der Zeijden, A. A. H. Tetrahedron: Asymmetry 1995,
6, 913. (d) Fujita, M.; Hiyama, T. J. Am. Chem. Soc. 1984, 106, 4629.
(27) Samples of cyanohydrins syn-2a and anti-2a were supplied from
our laboratory in connection with a general study on the assignment of
absolute configuration of cyanohydrins by NMR.
(28) Louzao, I.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. Commun.
2006, 1422
(29) Van Brabandt W.; Dejaegher, Y.; Van Landeghem, R.; De Kimpe,
N. Org. Lett. 2006, 8, 1101 and references cited therein.
(30) Del Buttero, P.; Molteni, G.; Roncoroni, M. Tetrahedron Lett. 2006,
47, 2209.
(31) See, for example: (a) Periasamy, M.; Thirumalaikumur, M. J.
Organomet. Chem. 2000, 609, 137. (b) Carlier, P. R.; Lo, K. M.; Williams,
I. D. J. Org. Chem. 1995, 60, 7511. (c) Ito, K.; Itsuno, S.; Sakurai, Y.
Synthesis 1988, 995. (d) Ganem, B.; Osby, J. O. Chem. ReV. 1986, 86,
763. (e) Wade, R. C. J. Mol. Catal. 1983, 18, 273. (f) Niino, Y.; Nishiki,
M.; Mitsuo, N.; Miyataka, H.; Satoh, T. Tetrahedron Lett. 1982, 23, 193.
(g) Chung, S.-K. J. Org. Chem. 1979, 44, 1014. (h) Nystrom, R. F. J. Am.
Chem. Soc. 1955, 77, 2544.
(32) (a) Caddick, S.; Judd, D. B.; Lewis, A. K. de K.; Reich, M. T.;
Williams, M. R. V. Tetrahedron, 2003, 59, 5417. (b) Khurana, J. M.;
Kukreja, G. Synth. Commun. 2002, 32, 1265. (c) Caddick, S.; Haynes, A.
K. de K.; Judd, D. B.; Williams, M. R. V. Tetrahedron Lett. 2000, 41,
3513.
DIBAL-H has been reported to react both with a cyano and
â-lactam ring to give aldehydes35 and â-amino alcohols or
azetidines,36 respectively. In our hands, the cyano group was
(33) See, for example: (a) Soai, K.; Ookawa, A. J. Org. Chem. 1986,
51, 4000. (b) Piers, E.; Chong, J. M. J. Org. Chem. 1982, 47, 1605.
(34) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (b) Ager, D. J.;
Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835. (c) Kolb, H. C.;
Sharpless, K. B. In Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 1998; p 243.
(35) Proudfoot, J. R.; Li, X.; Djerassi, C. J. Org. Chem. 1985, 50, 2026.
(36) (a) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K.; Yamashita,
M.; Abe, R. J. Org. Chem. 1991, 56, 5263. (b) Yamashita, M.; Ojima, I. J.
Am. Chem. Soc. 1983, 105, 6339.
7984 J. Org. Chem., Vol. 72, No. 21, 2007

Access to anti,anti-4-Aminopiperidine-3,5-diols
TABLE 3. Reduction of â-Lactam Cyanohydrins 3 with NaBH4/NiCl2‚6H2O: Synthesis of Amino â-Lactams 4 and â-Lactam Carbamates 5a
t
yieldb
(%)
substrate
R1
R2
R3
R4
(min)
product
R2
R5
anti-(+)-3a
syn-(+)-3c
Me
Bn
PMP
PMP
H
OTBS
OTBS
H
20
20
anti-(+)-4a
syn-(+)-4bd
syn-(+)-4c
syn-(-)-4d
syn-(+)-4ef
anti-(+)-5a
syn-(-)-5b
syn-(+)-5cf
PMP
PMP
PMP
Bn
Pr
PMP
Bn
H
H
H
H
100c
56e
14
syn-(-)-3d
syn-(-)-3e
anti-(+)-3a
syn-(-)-3d
syn-(-)-3e
Me
Me
Me
Me
Me
Bn
OTBS
OTBS
H
OTBS
OTBS
H
H
OTBS
H
H
25
20
30
25
20
91c
65
allyl
PMP
Bn
H
Boc
Boc
Boc
71
86
51
allyl
Pr
a In all cases, complete transformation to the reduced products was observed by 1H NMR spectroscopy. b Yield of pure, isolated product with correct
analytical and spectral data. c Yield of crude isolated product with no further purification necessary after workup. d A 4:1 ratio of products syn-4b/syn-4c
was obtained as determined by integration of well-resolved signals in the 1H NMR spectra of the crude reaction mixtures before purification. e The reduction
product syn-(+)-4b was obtained (56%) along with the O-debenzylated product syn-(+)-4c (R1 ) H) (14%) after purification by column chromatography.
f The N-propyl-â-lactam was isolated as a result of the reduction of both the nitrile group and the double bond.
TABLE 4. Reduction of â-Lactam Cyanohydrins 3 with LiBH4/
Et2O: Synthesis of 3-Amino-5-hydroxypentanenitriles 6
SCHEME 3
t
yielda
(%)
substrate
R1
R2
R3
R4
(min) product
syn-(+)-3c Bn PMP OTBS
H
H
OTBS
50
60
90
(+)-6b
(+)-6c
(+)-6d
74
54
40
syn-(-)-3d Me Bn
anti-(+)-3e Me allyl
OTBS
H
a Yield of pure, isolated product with correct analytical and spectral data.
unaffected when compound syn-3a was treated with DIBAL-H
in THF, giving γ-formyl nitrile 8 and â-amino-δ-hydroxy nitrile
6a in variable yield depending on the reaction conditions. Thus,
aldehyde 837 was the main product at -78 °C for 6 min, while
compound 6a was the sole component when reaction was
conducted at room temperature for longer reaction times. Finally,
monochloroalane (AlH2Cl) was examined.36 We found that
AlH2Cl prepared in situ from LiAlH4 and AlCl3 in diethyl ether
gave cyano azetidine 9 in reasonable yield, without being
accompanied by other reduction products (Scheme 2).
Having established chemoselective reduction methods for the
model compound syn-3a, we further probed the generality of
these two processes. Thus, using the NaBH4/NiCl2/methanol
system, cyanohydrins anti-3a and syn-3d were efficiently
reduced to their corresponding amino derivatives anti-4a and
syn-4d, respectively (Table 3). Remarkably, changing the group
on nitrogen from aryl to benzyl had little consequence on the
isolated yield of the amino â-lactam product (Table 3). However,
partial debenzylation of the 3-benzyloxy group was observed
in compound syn-3c, with a 4:1 mixture of products, major syn-
4b and minor O-debenzylated syn-4c, being obtained in this
case. Formation of O-debenzylated syn-4c could not be elimi-
nated completely despite attempting the reaction at shorter times.
Starting from N-allyl cyanohydrin syn-3e, the N-propyl-â-lactam
syn-4e was isolated in good yield, as a result of the reduction
of both the nitrile group and the CdC double bond. Isolation
of primary amines 4 under the above experimental conditions
is worthy of mention as they could be obtained free of secondary
amines and without trapping as protected NH amides by the in
situ addition of any acylation agent.32b,c Nevertheless, the use
of di-tert-butyl dicarbonate as trapping agent allowed easy
preparation of the corresponding tert-butyl carbamates 5a-c,
which obviously offer greater synthetic versatility for further
transformations due to their facile deprotection (Table 3).
(37) Preparation of aldehydes by reduction of â-lactams is unusual. The
formation of intermediate amino aldehydes on route to renieramycin H,
ecteinascidin (ET-743), and related natural products has just been described.
See, for instance: (a) Vincent, G.; Williams, R. M. Angew. Chem., Int. Ed.
2007, 46, 1517. (b) Jin, W.; Metobo, S.; Williams, R. M. Org. Lett. 2003,
5, 2095. (c) Herberich, B.; Kinugawa, M.; Va´zquez, A.; Williams, R. M.
Tetrahedron Lett. 2001, 42, 543.
Table 4 summarizes the results of the reduction with LiBH4/
Et2O of cyanohydrins syn-3c, syn-3d, and anti-3e, although in
these cases, lower yields were achieved for compounds contain-
ing an aliphatic group on the amide nitrogen.
J. Org. Chem, Vol. 72, No. 21, 2007 7985

Alcaide et al.
SCHEME 4
SCHEME 5
Having demonstrated the facile functional group manipula-
tions of â-lactam cyanohydrins 3 through their chemoselective
reduction, we turned our attention to the asymmetric synthesis
of fully orthogonally protected anti,anti-4-amino-3,5-piperidine
diols (Scheme 3). Our first task was to develop a direct access
to the piperidine ring from diamino alcohol 7a under Mitsunobu
conditions.38 However, all attempts to transform 7a in its
corresponding 4-aminopiperidine failed using different experi-
mental conditions. Then, we decided to use 3-amino-5-hydroxy
nitriles 6a and 6b as starting materials. In order to avoid
problems associated with the presence of a free amino group,
the p-anisylamino group in compounds 6 was converted into a
tert-butyl carbamate by oxidation with (diacetoxyiodo)benzene
(DIB) in MeOH/AcOH followed by reaction with di-tert-butyl
dicarbonate of the resulting primary amino group.39 In this
manner, compounds 10a and 10b were prepared in reasonable
yield. Interestingly, no protection of the primary hydroxyl group
was necessary during oxidation with DIB.40 Then, alcohols 10
were transformed to mesylates 11 by exposure to methane-
sulfonyl chloride and triethylamine in the presence of DMAP.
Treatment of mesylates 11 with NaBH4/NiCl2/methanol at room
temperature smoothly led to N-unsubstituted piperidines 12 in
good yields (Scheme 3).
asymmetric synthesis of compounds 14 has been reported, which
starts from 1,2-isopropylidene-R-D-xylofuranose.5
Next, we decided to apply the above methodology to the
synthesis of fully orthogonally protected sialidase inhibitor
analogues starting from compounds 6a and 6b. anti,anti-4-
Acetamidopiperidines such as 13 and 14 are of interest in studies
concerning sialidase (or neuraminidase) transition state analogue
inhibitors.5,41 To the best of our knowledge, only one multistep
In order to introduce the 4-acetamido group in a straightfor-
ward manner, oxidation of 6a and 6b with DIB/MeOH/AcOH
was followed by treatment with acetic anhydride giving
compounds 15a and 15b in good yields, along with compounds
16a and 16b as byproducts, respectively. Further treatment of
compounds 15a and 15b with methanesulfonyl chloride/triethy-
lamine/DMAP in dichloromethane at room temperature gave
nitriles 17a and 17b. Reductive cyclization with NaBH4/NiCl2/
methanol followed by subsequent treatment with methyl bro-
moacetate/potassium carbonate/lithium iodide in acetonitrile at
60 °C afforded N-methoxycarbonylmethyl piperidines 18a and
18b, respectively, in moderate overall yields (Scheme 4).
Formation of compounds 16 is unprecedented and could be
rationalized as shown in Scheme 5. After oxidative removal of
the p-anisyl group in 6a and 6b, the primary amino group should
react with formaldehyde, probably as its methoxyhemiketal, to
give the 1,3-oxazine derivatives 16a and 16b via nucleophilic
cyclization of the intermediate N-(3-hydroxy)methanimine.
(38) For a related cyclization to piperidines, see: (a) Balasubramanian,
Th.; Hassner, A. Tetrahedron: Asymmetry 1998, 9, 2201. For a review,
see: (b) Mitsunobu, O. Synthesis 1981, 1.
(39) For use of DIB on the oxidative removal of the o-anisyl group,
see: (a) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2004, 126, 3734. (b) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.;
Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 984.
(40) To our surprise, all attemps to oxidize the mesylate derivative of
alcohols 6a and 6b were unsuccessful.
(41) See, for example: (a) Glanzer, B. I.; Gyorgydeak, Z.; Bernet, B.;
Vasella, A. HelV. Chim. Acta 1991, 74, 343. (b) Walliman, K.; Vasella, A.
HelV. Chim. Acta 1990, 73, 1359. (c) Czollner, L.; Kuszmann, J.; Vasella,
A. HelV. Chim. Acta 1990, 73, 1338. (d) Bernet, B.; Murty, A. R. C. B.;
Vasella, A. HelV. Chim. Acta 1990, 73, 940.
7986 J. Org. Chem., Vol. 72, No. 21, 2007

Access to anti,anti-4-Aminopiperidine-3,5-diols
TABLE 5. Selected Coupling Constants for Piperidines 12, 18, 21, and 22a
compound
R1
R2
R3
2J2a,2e
3J2a,3a
3J2e,3
3J3,4
3J4,5
3J5,6a
3J5,6e
2J6a,6e
12a
12b
18ac
18b
21a
21b
22a
22be
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Boc
Boc
Ac
H
12.4
12.2
10.7
10.8
12.0
11.8
10.4
10.7
10.0
10.2
10.1
10.2
9.7
8.5
10.0
10.0
5.0
4.8
5.0
4.7
4.6
4.7
4.8
4.7
8.9
9.8
9.6
b
9.3
8.8
9.5
9.5
8.9
9.8
9.7
b
11.5
10.0
10.2
10.2
9.5
9.7
9.9
10.2
---b
4.2
4.7
2.1
2.7
4.2
5.0
4.7
11.5
12.1
10.5
10.2
12.1
12.0
10.5
10.6
H
Ed
Ed
H
Ac
PMP
PMP
PMP
PMP
b
H
8.6
9.5
9.7
Ed
Ed
a All spectra were recorded at 300 MHz (except for compound 12b, 500 MHz), at 25 °C, and using CDCl3 as solvent. b Measurement of this coupling
4
3
constant was unsuccessful on the spectra. c Additionally, a long-range coupling J2e,6e ) 1.8 Hz and J4,NH ) 9.1 Hz were observed. d E ) CH2CO2Me.
4
e Additionally, a long-range coupling J2e,6e ) 1.9 Hz was observed.
SCHEME 6
Gratifyingly, when compounds 20a and 20b were treated with
LAH in diethyl ether at room temperature for 30 min, the
piperidines 21a and 21b were obtained in good yields (Scheme
6). Fully protected sialidase inhibitor analogues 18a and 18b
were prepared from 2-piperidones 20a and 20b via the four-
step sequence as shown (Scheme 6). Removal of the PMP group
in the final step of the synthesis avoided the formation of
byproducts as oxazines 16, although the yield remained rather
similar in both cases. Thus, starting from common synthetic
intermediates, â-lactam cyanohydrins syn-3a and syn-3c, the
overall yield for piperidines 18a and 18b was similar for both
routes.
The structure and stereochemistry of piperidines 12, 18, and
20-22 were assigned by NMR studies. The cis-stereochemistry
of the four-membered ring was set during the cyclization step
to form the 2-azetidinone ring, and it was transferred unaltered
during the further synthetic steps. The cyclic structures (by
DEPT, HETCOR, and COSY) and the stereochemistry (by
vicinal proton couplings) of piperidines 12, 18, and 20-22 were
established by NMR one- and two-dimensional techniques. The
values collected in Table 5 for vicinal coupling constants show
an unequivocally fixed antiperiplanar orientation both for H3-
3
H4 protons (8.8 Hz < J3,4 < 9.8 Hz) as well as for H4-H5
3
protons (8.6 Hz < J4,5 < 9.8 Hz), in agreement with the
anti,anti configuration proposed for the 3,4,5-trisubstituted
piperidines.44 Taking into account that O-silylated cyanohydrins
3 could be obtained and cyclized to piperidines, the stereo-
chemistry at the carbinolic stereogenic center for compounds 3
(and hence 2) as well as for synthetic intermediates 4-11, 15-
17, and 19 was confirmed by comparison with well-established
configuration of different prepared 3,4,5-trisubstituted pip-
eridines.
To improve the overall yield of our synthesis, we explored
another route starting from â-lactam cyanohydrins syn-3a and
syn-3c. Reaction of these compounds with sodium methoxide
in methanol at room temperature resulted in the chemoselective
opening of the â-lactam ring with formation of the correspond-
ing â-amino esters 19a and 19b in very good yields. Reduction
of the cyano group in compounds 19a and 19b with NaBH4/
NiCl2/methanol afforded the corresponding 2-piperidones 20a
and 20b in good yields.42 Initial reduction of compound 20a
with LAH in THF43 both at room temperature and at reflux
resulted in partial O-desilylation, and the piperidine 21a was
isolated as the major compound in moderate yield in all cases.
(42) 2-Piperidones 20a and 20b were also prepared from amino â-lactams
4a and 4b by treatment with sodium methoxide in methanol at reflux, in
57 and 74% yields, respectively. However, partial epimerization was
observed for compound 20b, a 53:47 mixture of epimers at C3 being
obtained.
(43) Peyronel, J.-F.; Samuel, O.; Fiaud, J.-C. J. Org. Chem. 1987, 52,
5320.
(44) Alvarez-Ibarra, C.; Cuervo, R.; Ferna´ndez-Monreal, M. C.; Ruiz,
M. P. J. Org. Chem. 1992, 57, 4270 and references cited therein.
J. Org. Chem, Vol. 72, No. 21, 2007 7987

Alcaide et al.
119.7, 130.3, 156.8, 164.4; IR (CHCl3, cm-1) ν 1759; MS (ES)
m/z 376 (M+•, 21), 319 (M - 57, 43), 291 (41), 264 (15), 259 (9),
247 (9), 178 (58), 149 (100). Anal. Calcd for C19H28N2O4Si: C,
60.61; H, 7.50; N, 7.44. Found: C, 60.71; H, 7.51; N, 7.26. Isomer
anti-(+)-3a: white solid; mp 97-98 °C (hexanes/ethyl acetate);
[R]D ) +79.9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.110
(s, 3H), 0.204 (s, 3H), 0.923 (s, 9H), 3.681 (s, 3H), 3.798 (s, 3H),
4.389 (dd, 1H, J ) 5.2, 2.7 Hz), 4.693 (d, 1H, J ) 5.2 Hz), 4.888
(d, 1H, J ) 2.7 Hz), 6.866 (AA′XX′, 2H), 7.503 (AA′XX′, 2H);
13C NMR (75 MHz, CDCl3) δ -5.6, -5.2, 17.9, 25.4, 55.4, 59.5,
60.4, 61.4, 81.8, 114.2, 117.1, 119.5, 130.0, 156.8, 164.0; IR
(CHCl3, cm-1) ν 2054, 1755; MS (ES) m/z 376 (M+•, 17), 319 (M
- 57, 48), 291 (11), 264 (17), 259 (5), 247 (4), 178 (56), 149 (100).
Anal. Calcd for C19H28N2O4Si: C, 60.61; H, 7.50; N, 7.44. Found:
C, 60.59; H, 7.57; N, 7.34.
Conclusions
In summary, two novel, complementary routes to orthogonally
protected enantiopure anti,anti-4-amino-3,5-piperidine diols
were developed in reasonable overall yields starting from
optically pure â-lactam cyanohydrin hybrids, utilizing chemose-
lective reduction protocols of both â-lactam or nitrile moieties
as well as oxidative N-dearylation with diacetoxyiodobenzene
of a 4-methoxyphenylamino group as key common synthetic
steps. In addition, the present strategy allows stereocontrolled
construction of all three contiguous stereocenters early in the
sequence. A concise asymmetric synthesis of fully orthogonally
protected sialidase inhibitors illustrates the utility of the new
synthetic protocols.
General Procedure for Preparation of Amino â-Lactams 4.
Sodium borohydride (3.5 mmol) was slowly added to a solution of
the appropriate O-silylated cyanohydrin 3 (0.5 mmol) and nickel-
(II) chloride hexahydrate (0.5 mmol) in methanol (4.2 mL) at 0 °C
under argon. The reaction mixture was allowed to warm to room
temperature and was stirred until disappearance of starting material
(TLC). Methanol was evaporated under vacuum, and the resulting
crude was diluted with ethyl acetate (100 mL). Then, an aqueous
saturated solution of NaHCO3 was added (50 mL). The resulting
mixture was filtered through a pad of Celite, and the solution was
extracted with ethyl acetate (4 × 50 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure to afford
the corresponding amino â-lactam 4.
(+)-(3R,4R)-4-((1R)-2-Amino-1-{[tert-butyl(dimethyl)silyl]-
oxy}ethyl)-3-methoxy-1-(4-methoxyphenyl)azetidin-2-one, syn-
(+)-4a. From 100 mg (0.27 mmol) of cyanohydrin syn-(+)-3a (20
min), 101 mg of analytically pure amine syn-(+)-4a (100%) was
obtained as colorless oil: [R]D ) +89.5 (c 0.6, CHCl3); 1H NMR
(200 MHz, CDCl3) δ -0.341 (s, 3H), 0.018 (s, 3H), 0.780 (s, 9H)
1.737 (br s, 2H), 2.920 (m, 2H), 3.632 (s, 3H), 3.784 (s, 3H), 4.123
(m, 1H), 4.547 (d, 1H, J ) 5.6 Hz), 4.547 (m, 1H), 6.827 (AA′XX′,
2H), 7.438 (AA′XX′, 2H); 13C NMR (50 MHz, CDCl3) δ -5.0,
-4.9, 18.0, 25.8, 45.0, 55.5, 58.1, 59.4, 72.7, 82.1, 113.8, 119.6,
131.6, 156.2, 165.8; IR (CHCl3, cm-1) ν 3385, 1744; MS (ES) m/z
380 (M+•, 41), 323 (M+• - 57, 16), 292 (100), 149 (10). Anal.
Calcd for C19H32N2O4Si: C, 59.97; H, 8.48; N, 7.36. Found: C,
60.22; H, 8.73; N, 7.16.
General Procedure for Preparation of â-Lactam Carbamates
5. Sodium borohydride (3.5 mmol) was slowly added over a solution
of the appropriate O-silylated cyanohydrin 3 (0.5 mmol), nickel-
(II) chloride hexahydrate (0.5 mmol), and di-tert-butyl dicarbonate
(1.0 mmol) in methanol (4.2 mL) at 0 °C under argon. The reaction
mixture was allowed to warm to room temperature and was stirred
until disappearance of starting material (TLC). Methanol was
evaporated under vacuum, and the resulting crude was diluted with
ethyl acetate (100 mL). Then, a saturated aqueous solution of
NaHCO3 was added (50 mL). The resulting mixture was filtered
through a pad of Celite, and the filtrate was extracted with ethyl
acetate (4 × 50 mL). The organic layer was dried (MgSO4) and
concentrated under reduced pressure. Flash chromatography on
silica gel of the residue, eluting with hexanes/ethyl acetate mixtures
gave â-lactam carbamates 5.
(+)-tert-Butyl (2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[(2R,3R)-
3-methoxy-1-(4-methoxyphenyl)-4-oxoazetidin-2-yl]ethylcar-
bamate, syn-(+)-5a. From 137 mg (0.36 mmol) of cyanohydrin
syn-(+)-3a (20 min), carbamate syn-(+)-5a (160 mg, 92%) was
obtained as a pure colorless oil after purification by flash chroma-
tography (hexanes/ethyl acetate 3:1): [R]D ) +27.3 (c 0.8, CHCl3);
1H NMR (200 MHz, CDCl3) δ -0.348 (s, 3H), 0.006 (s, 3H), 0.774
(s, 9H), 1.474 (s, 9H), 3.178 (dt, 1H, J ) 14.2, 4.3 Hz), 3.565
(ddd, 1H, J ) 14.0, 8.3, 2.8 Hz), 3.672 (s, 3H), 3.786 (s, 3H),
4.167 (m, 1H), 4.286 (dd, 1H, J ) 8.6, 5.1 Hz), 4.554 (d, 1H, J )
5.4 Hz), 4.868 (br s, 1H), 6.833 (AA′XX′, 2H), 7.415 (AA′XX′,
2H); 13C NMR (50 MHz, CDCl3) δ -5.1, -5.0, 17.9, 25.8, 28.4,
Experimental Section
General. The same experimental techniques were used as
previously reported.15
General Procedure for the Reaction between Aldehydes 1
and TBSCN. Preparation of the O-[tert-Butyl(dimethyl)silyl]-
â-lactam Cyanohydrin Derivatives 3. Method A. A solution of
TBSCN (0.60 mmol) in anhydrous acetonitrile (1.7 mL) was added
dropwise via syringe to a stirred suspension of the appropriate
4-oxoazetidine-2-carbaldehyde 1 (0.50 mmol) and molecular sieves
(4 Å, 250 mg) in the same solvent (1.7 mL), at room temperature
and under argon atmosphere. The mixture was stirred until
disappearance of starting material (TLC). Then, a saturated aqueous
NaCl solution (5 mL) was added, and the resulting mixture was
extracted with DCM (5 × 10 mL). The organic layer was dried
(MgSO4), filtered, and concentrated under reduced pressure. After
flash chromatography on silica gel of the residue, eluting with
hexanes/ethyl acetate mixtures, the two separated syn/anti isomers
of derivatives 3 were obtained. Method B. A solution of TBSCN
(3.41 mmol) in anhydrous acetonitrile (9.3 mL) was added dropwise
via syringe to a stirred suspension of the appropriate 4-oxoazetidine-
2-carbaldehyde 1 (2.84 mmol) and Na2CO3 (0.71 mmol) in the same
solvent (9.3 mL), at room temperature and under argon atmosphere.
The mixture was stirred until disappearance of starting material
(TLC). Then, a saturated aqueous NaCl solution (30 mL) was added,
and the resulting mixture was extracted with DCM (5 × 60 mL).
The organic layer was dried (MgSO4), filtered, and concentrated
under reduced pressure. After flash chromatography on silica gel
of the residue, eluting with hexanes/ethyl acetate mixtures, the two
separated syn/anti isomers of derivatives 3 were obtained.45
(+)-(2S)-{[tert-Butyl(dimethyl)silyl]oxy}[(2R,3R)-3-methoxy-
1-(4-methoxyphenyl)-4-oxoazetidin-2-yl]acetonitrile, syn-(+)-3a,
and (+)-(2R)-{[tert-Butyl(dimethyl)silyl]oxy}[(2R,3R)-3-meth-
oxy-1-(4-methoxyphenyl)-4-oxoazetidin-2-yl]acetonitrile, anti-
(+)-3a. Method A. From 150 mg (0.64 mmol) of 4-oxoazetidine-
2-carbaldehyde (+)-1a and after chromatography of the residue
eluting with hexanes/ethyl acetate (5:1), both analytically pure less
polar isomer syn-(+)-3a (169 mg, 70%) and the more polar one
anti-(+)-3a (40 mg, 17%) were obtained. Method B. From 400
mg (1.70 mmol) of 4-oxoazetidine-2-carbaldehyde (+)-1a and after
chromatography of the residue eluting with hexanes/ethyl acetate
(5:1), both analytically pure less polar isomer syn-(+)-3a (495 mg,
77%) and the more polar one anti-(+)-3a (108 mg, 17%) were
obtained (94% overall yield). Isomer syn-(+)-3a: white solid; mp
76-77 °C (hexanes/ethyl acetate); [R]D ) +70.4 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3) δ -0.138 (s, 3H), 0.121 (s, 3H), 0.804
(s, 9H), 3.672 (s, 3H), 3.785 (s, 3H), 4.588 (dd, 1H, J ) 5.1, 7.7
Hz), 4.682 (d, 1H, J ) 5.1 Hz), 4.713 (d, 1H, J) 7.7 Hz), 6.841
(AA′XX′, 2H), 7.433 (AA′XX′, 2H); 13C NMR (75 MHz, CDCl3)
δ -5.6, -5.5, 17.9, 25.3, 55.5, 59.7, 60.4, 62.9, 82.5, 114.0, 118.0,
(45) Full spectroscopic and analytical data for compounds not included
in this Experimental Section are described in the Supporting Information.
7988 J. Org. Chem., Vol. 72, No. 21, 2007

Access to anti,anti-4-Aminopiperidine-3,5-diols
44.0, 55.5, 58.5, 59.7, 71.1, 79.5, 82.4, 113.9, 119.6, 131.6, 156.1,
156.3, 165.8; IR (CHCl3, cm-1) ν 3462, 1747, 1709; MS (ES) m/z
480 (M+•, 5), 407 (M - 73, 4), 367 (42), 323 (11), 307 (51), 234
(41), 201 (100), 149 (77), 73 (84), 57 (80). Anal. Calcd for
C24H40N2O6Si: C, 59.97; H, 8.39; N, 5.83. Found: C, 60.13; H,
8.62; N, 5.74.
General Procedure for the Preparation of 3-Amino-5-hy-
droxypentanenitriles 6. Lithium borohydride (2.25 mmol) was
added in portions to a solution of the appropriate O-silylated
cyanohydrin 3 (0.75 mmol) in anhydrous diethyl ether (18.6 mL)
at 0 °C under argon. The reaction mixture was allowed to warm to
room temperature and stirred until disappearance of starting material
(TLC). Then, a saturated aqueous solution of NaHCO3 (20 mL)
was added, and the resulting mixture was extracted with ethyl
acetate (5 × 55 mL). The organic layer was dried (MgSO4), and
the solvent was removed under reduced pressure. Flash chroma-
tography on silica gel of the residue, eluting with hexanes/ethyl
acetate mixtures, gave compounds 6.
(+)-(2S,3R,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-5-hydroxy-
4-methoxy-3-[(4-methoxyphenyl)amino]pentanenitrile, (+)-6a.
From 280 mg (0.74 mmol) of cyanohydrin syn-(+)-3a, compound
(+)-6a (232 mg, 82%) was obtained as a pure colorless oil after
purification by flash chromatography (hexanes/ethyl acetate 3:1):
[R]D ) +13.3 (c 0.9, CHCl3); 1H NMR (200 MHz, CDCl3) δ 0.119
(s, 3H), 0.203 (s, 3H), 0.914 (s, 9H), 3.575 (s, 3H), 3.756 (s, 3H),
3.842-3.702 (m, 4H), 4.623 (d, 1H, J ) 5.6 Hz), 6.644 (AA′BB′,
2H), 6.791 (AA′BB′, 2H); 13C NMR (50 MHz, CDCl3) δ -5.4,
-5.2, 18.0, 25.5, 55.7, 58.3, 59.0, 62.0, 62.0, 77.6, 115.2, 115.3,
118.5, 139.5, 153.2; IR (CHCl3, cm-1) ν 3393; MS (ES) m/z 380
(M+•, 6), 305 (M+• - 75, 2), 210 (M+• - 170, 100), 178 (24), 160
(53). Anal. Calcd for C19H32N2O4Si: C, 59.97; H, 8.48; N, 7.36.
Found: C, 59.79; H, 8.62; N, 7.02.
General Procedure for Preparation of Carbamates 10 and
Amides 15. To a solution of diacetoxy iodobenzene (DIB) (1.70
mmol) in a mixture of methanol (4.7 mL) and acetic acid (0.10
mL) was slowly added a solution of the corresponding 3-amino-
5-hydroxypentanenitrile 6 (0.42 mmol) in methanol (1.2 mL) over
20 min. Upon complete addition, the reaction was stirred at rt for
30 min. Then, a 10% aq HCl solution (4.8 mL, wt %) was added.
The mixture was stirred for 30 min, at which time a 10% aq
Na2S2O3 solution (4.8 mL, wt %) was added, and stirring was
allowed to continue for an additional 30 min. After that, sodium
carbonate was added until the solution was made basic (for
carbamates 10) or neutral (for amides 15), and a solution of di-
tert-butyl dicarbonate or acetic anhydride (1.70 mmol) in DCM (2
mL) was added as required. The mixture was stirred overnight at
rt. Afterward, methanol was removed under reduced pressure, and
the resulting mixture was extracted with DCM (4 × 40 mL). The
organic layer was dried (MgSO4) and concentrated under reduced
pressure. Flash chromatography on silica gel of the residue eluting
with hexanes/ethyl acetate mixtures afforded analytically pure
carbamate 10 or amide 15.
(-)-N-{(1R,2R)-2-(Benzyloxy)-1-[(S)-{[tert-butyl(dimethyl)-
silyl]oxy}(cyano)methyl]-3-hydroxypropyl}acetamide, (-)-15b.
From 196 mg (0.43 mmol) of (+)-6b and, after flash chromatog-
raphy (hexanes/ethyl acetate 1:1), two fractions were obtained. From
the more polar one, compound (-)-15b (93 mg, 55%) was obtained
as a pure pale brown oil: [R]D ) -27.3 (c 0.4, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 0.184 (s, 3H), 0.240 (s, 3H), 0.937 (s, 9H),
2.024 (s, 3H), 3.492 (m, 1H), 3.681 (m, 1H), 4.071 (ddd, 1H, J )
7.3, 5.5, 1.6 Hz), 4.314 (ddd, 1H, J ) 8.5, 6.6, 1.8 Hz), 4.628 (d,
1H, J ) 11.0 Hz), 4.686 (d, 1H, J ) 6.3 Hz), 4.782 (d, 1H, J )
10.8 Hz), 6.116 (d, 1H, J ) 8.8 Hz), 7.426-7.309 (m, 5H); 13C
NMR (50 MHz, CDCl3) δ -5.4, -5.3, 18.0, 23.1, 25.5, 52.2, 61.2,
61.4, 73.9, 75.0, 118.5, 128.3, 128.6, 128.6, 137.3, 171.2; IR
(CHCl3, cm-1) ν 3427, 1661; MS (ES) m/z 335 (M+• - 57, 29),
222 (M+• - 170, 16), 91 (100). Anal. Calcd for C20H32N2O4Si: C,
61.19; H, 8.22; N, 7.14. Found: C, 61.34; H, 8.02; N, 6.99. From
the less polar fraction, (+)-(2S)-[(4R,5R)-5-(benzyloxy)-1,3-ox-
azinan-4-yl]{[tert-butyl(dimethyl)silyl]oxy}acetonitrile, (+)-16b
(24 mg, 15%) was isolated as a pure pale brown oil: [R]D ) +5.4
(c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.154 (s, 3H), 0.211
(s, 3H), 0.924 (s, 9H), 3.133 (dd, 1H, J ) 7.4, 2.1 Hz), 3.598 (br
s, 1H), 3.598 (d, 1H, J ) 11.7 Hz), 4.241 (d, 1H, J ) 11.7 Hz),
4.265 (d, 1H, J ) 10.4 Hz), 4.561 (d, 1H, J ) 7.4 Hz), 4.626 (d,
1H, J ) 11.4 Hz), 4.662 (d, 1H, J ) 10.2 Hz), 4.720 (1H, d, J )
11.5 Hz), 7.445-7.307 (m, 5H); 13C NMR (75 MHz, CDCl3) δ
-5.2, -5.2, 18.1, 25.5, 60.6, 63.0, 67.4, 70.0, 71.5, 79.3, 118.3,
127.9, 128.2, 128.4, 137.5; IR (CHCl3, cm-1) ν 3310; MS (ES)
m/z 361 (M+• - 1, 1), 305(M+• - 57, 20), 192 (M+• - 170, 69),
91 (100). Anal. Calcd for C19H30N2O3Si: C, 62.95; H, 8.34; N,
7.73. Found: C, 63.03; H, 8.37; N, 7.54.
General Procedure for Preparation of Mesylates 11 and 17.
Triethylamine (1.12 mmol), DMAP (cat.), and methanesulfonyl
chloride (0.56 mmol) were sequentially added dropwise via syringe
to a solution of the corresponding alcohol, 10 or 15 (0.28 mmol),
in anhydrous DCM (4.4 mL) at rt under argon atmosphere. The
resulting mixture was stirred until disappearance of starting material
(TLC). The crude mixture was diluted with DCM (60 mL) and
washed successively with an aq saturated solution of NH4Cl (1 ×
15 mL) and brine (1 × 15 mL). The organic layer was dried
(MgSO4), filtered, and concentrated under reduced pressure. Chro-
matography of the residue eluting with hexanes/ethyl acetate
mixtures gave analytically pure mesylates 11 or 17, respectively.
(-)-(2R,3R,4S)-3-[(tert-Butoxycarbonyl)amino]-4-{[tert-butyl-
(dimethyl)silyl]oxy}-4-cyano-2-methoxybutyl Methanesulfonate,
(-)-11a. From 75 mg (0.20 mmol) of (-)-10a, compound (-)-
11a (76 mg, 84%) was obtained as a pure pale brown oil after
purification by flash chromatography (hexanes/ethyl acetate 4:1):
[R]D ) -3.7 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.188
(s, 3H), 0.242 (s, 3H), 0.934 (s, 9H), 1.449 (s, 9H), 3.047 (s, 3H),
3.569 (s, 3H), 3.910 (1H, dd, J ) 8.3, 6.1 Hz), 4.018 (t, 1H, J )
6.0 Hz), 4.146 (dd, 1H, J ) 10.4, 6.2 Hz), 4.277 (dd, 1H, J )
10.4, 5.9 Hz), 4.618 (d, 1H, J ) 5.9 Hz), 5.133 (d, 1H, J ) 9.5
Hz); 13C NMR (75 MHz, CDCl3) δ -5.4, -5.3, 17.9, 25.4, 28.2,
37.5, 53.2, 59.7, 61.6, 67.2, 74.5, 80.71, 118.2, 155.2; IR (CHCl3,
cm-1) ν 1712; MS (ES) m/z 379 (M+• - 73, 32), 339 (M+• - 57
- 56, 100), 295 (M+• - 57 - 56 - 44, 14), 282 (M+• - 170, 22),
243 (M+• - 153 - 56, 50), 226 (M+• - 170 - 56, 22), 182 (M+•
- 170 - 56 - 44, 81), 153 (42), 86 (M+• - 170 - 56 - 44 - 96,
62), 75 (19), 73 (29), 57 (57). Anal. Calcd for C18H36N2O7SSi: C,
47.76; H, 8.02; N, 6.19. Found: C, 47.87; H, 8.19; N, 5.99.
General Procedure for Preparation of Piperidines 12. Starting
from methane sulfonates 11, piperidines 12 were obtained adopting
the same protocol indicated above for the synthesis of amino
â-lactams 4.
(-)-tert-Butyl (1R,2R)-1-[(S)-{[tert-Butyl(dimethyl)silyl]oxy}-
(cyano)methyl]-3-hydroxy-2-methoxypropylcarbamate, (-)-10a.
From 134 mg (0.35 mmol) of (+)-6a, compound (-)-10a (77 mg,
58%) was obtained after purification by flash chromatography
(hexanes/ethyl acetate 3:1) as a pure pale yellow oil: [R]D ) -6.8
(c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.185 (s, 3H), 0.242
(s, 3H), 0.935 (s, 9H), 1.452 (s, 9H), 2.402 (t, 1H, J ) 6.3 Hz),
3.525 (s, 3H), 3.530 (m, 1H), 3.751 (m, 2H), 3.982 (dd, 1H, J )
8.2, 6.7 Hz), 4.624 (d, 1H, J ) 6.3 Hz), 5.053 (d, 1H, J ) 9.3 Hz);
13C NMR (50 MHz, CDCl3) δ -5.4, -5.3, 18.0, 25.5, 28.2, 53.5,
59.2, 60.9, 62.0, 77.4, 80.6, 118.4, 156.2; IR (CHCl3, cm-1) ν 3447,
1703; MS (ES) m/z 347 (M+• - 27, 8), 301 (M+• - 73, 30), 261
(M+• - 57 - 56, 100), 217 (M+• - 57 - 56 - 44, 42), 204 (M+•
- 170, 37), 148 (M+• - 170 - 56, 77), 104 (M+• - 170 - 56 -
44, 81), 75 (42), 73 (37), 57 (86). Anal. Calcd for C17H34N2O5Si:
C, 54.51; H, 9.15; N, 7.48. Found: C, 54.61; H, 9.33; N, 7.35.
(-)-tert-Butyl (3R,4R,5S)-3-{[tert-Butyl(dimethyl)silyl]oxy}-
5-methoxypiperidin-4-yl-carbamate, (-)-12a. From 60 mg (0.13
mmol) of mesylate (-)-11a, and after purification by flash
chromatography on silica gel, eluting first with ethyl acetate and
finally with methanol, compound (-)-12a (28 mg, 59%) was
J. Org. Chem, Vol. 72, No. 21, 2007 7989

Alcaide et al.
obtained as a pure white solid: mp 130-132 °C (methanol/ethyl
acetate); [R]D ) -8.5 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 0.052 (s, 3H), 0.070 (s, 3H), 0.872 (s, 9H), 1.447 (9H, s), 2.408
(1H, t, J ) 11.5 Hz), 2.450 (t, 1H, J ) 11.2 Hz), 3.085 (dd, 1H, J
) 12.4, 5.0 Hz), 3.178 (t, 1H, J ) 8.9 Hz), 3.289 (m, 2H), 3.412
(s, 3H), 3.612 (m, 1H), 4.538 (br d, 1H, J ) 7.8 Hz); 13C NMR
(50 MHz, CDCl3) δ -4.8, -4.6, 17.9, 25.7, 28.4, 49.0, 52.7, 57.9,
61.2, 70.8, 79.1, 155.6; IR (CHCl3, cm-1) ν 1695; MS (ES) m/z
287 (M+• - 73, 7), 247 (M+• - 57 - 56, 100), 201 (36), 186 (28)
116 (7), 101 (6), 73 (15), 57 (18). Anal. Calcd for C17H36N2O4Si:
C, 56.63; H, 10.06; N, 7.77. Found: C, 56.79; H, 9.91; N, 7.59.
General Procedure for Preparation of Methyl Esters 19. A
solution of the appropriate O-silylated cyanohydrin 3 (0.31 mmol)
in methanol (7.5 mL) was added to sodium methoxide (0.31 mmol)
at rt under argon atmosphere. The mixture was stirred at the same
temperature for 75 min. Brine (15 mL) was added to the crude,
and methanol was evaporated under reduced pressure. The resulting
mixture was extracted with ethyl acetate (5 × 30 mL). The organic
layer was dried (MgSO4) and concentrated under reduced pressure
to afford compound 19, which could be used in the next step without
ulterior purification.
°C under argon atmosphere. The reaction mixture was allowed to
warm at room temperature and stirred at rt for 30 min. The crude
was cooled at 0 °C, and a saturated aqueous solution of NaHCO3
was added (5 mL). The resulting mixture was extracted with ethyl
acetate (5 × 17 mL). The organic layer was dried (MgSO4), and
the solvent was removed under reduced pressure. The residue was
diluted with anhydrous acetonitrile (2.2 mL), and then methyl
bromoacetate (0.39 mmol), potassium carbonate (0.78 mmol), and
a catalytic amount of lithium iodide were sequentially added at rt
under argon atmosphere. The reaction mixture was stirred at rt for
3 h. Then, water was added (1.4 mL), and the resulting mixture
was extracted with DCM (5 × 7 mL). The organic layer was dried
(MgSO4), filtered, and the solvent removed under reduced pressure.
Flash chromatography on silica gel of the residue eluting with
hexanes/ethyl acetate mixtures gave analytically pure compounds
22.
(+)-Methyl {(3S,4R,5R)-3-(Benzyloxy)-5-{[tert-butyl(dimeth-
yl)silyl]oxy}-4-[(4-methoxyphenyl)amino]piperidin-1-yl}-
acetate, (+)-22b. From 118 mg (0.26 mmol) of the piperidine-2-
one (+)-20b and, after flash chromatography (hexanes/ethyl acetate
3:1), pure piperidine (+)-22b (67 mg, 50%) was obtained as a pale
1
(+)-Methyl (2R,3R,4S)-2-(Benzyloxy)-4-{[tert-butyl(dimethyl)-
silyl]oxy}-4-cyano-3-[(4-methoxyphenyl)amino]butanoate, (+)-
19b. From 142 mg (0.31 mmol) of the O-silylated cyanohydrin
syn-(+)-3c, pure compound (+)-19b (148 mg, 98%) was obtained
brown oil: [R]D ) +25.5 (c 0.5, CHCl3); H NMR (300 MHz,
CDCl3) δ -0.070 (s, 3H), 0.032 (s, 3H), 0.803 (s, 9H), 2.291 (t,
1H, J ) 10.4 Hz), 2.291 (t, 1H, J ) 10.4 Hz), 2.969 (ddd, 1H, J
) 10.7, 4.8, 1.8 Hz), 3.068 (t, 1H, J ) 9.4 Hz), 3.177 (ddd, 1H, J
) 10.6, 4.7, 1.7 Hz), 3.313 (br s, 2H), 3.417 (td, 1H, J ) 9.9, 4.7
Hz), 3.598 (td, 1H, J ) 9.5, 4.6 Hz), 3.744 (s, 6H), 4.549 (AB,
2H, J ) 11.8 Hz), 6.716 (br s, 4H), 7.332-7.178 (m, 5H); 13C
NMR (50 MHz, CDCl3) δ -4.8, -4.6, 17.9, 25.7, 51.7, 55.8, 56.4,
58.5, 59.6, 65.1, 72.2, 72.4, 78.2, 114.4, 115.0, 127.6, 127.9, 128.3,
138.3, 143.7, 151.9, 170.6; IR (CHCl3, cm-1) ν 1746; MS (ES)
m/z 514 (M+·, 80), 499 (M+• - 15, 2), 457 (M+• - 57, 10), 455
(M+• - 59, 10), 279 (M+• - 235, 100), 255 (M+• - 259, 100),
222 (M+• - 235 - 57, 10), 164 (M+• - 259 - 91, 68), 91 (52),
73 (22). Anal. Calcd for C28H42N2O5Si: C, 65.34; H, 8.22; N, 5.44.
Found: C, 65.24; H, 8.38; N, 5.60.
1
as a pale brown oil: [R]D ) +2.2 (c 1.0, CHCl3); H NMR (200
MHz, CDCl3) δ 0.095 (s, 3H), 0.179 (s, 3H), 0.883 (s, 9H), 3.618
(s, 3H), 3.740 (s, 3H), 4.044 (dd, 1H, J ) 6.3, 2.2 Hz), 4.538 (d,
1H, J ) 2.2 Hz), 4.606 (d, 1H, J ) 11.0 Hz), 4.661 (d, 1H, J )
6.4 Hz), 4.853 (d, 1H, J ) 10.7 Hz), 6.609 (AA′BB′, 2H), 6.750
(AA′BB′, 2H), 7.505-7.336 (m, 5H); 13C NMR (50 MHz, CDCl3)
δ -5.4, -5.3, 18.0, 25.5, 52.2, 55.7, 59.9, 62.3, 73.6, 74.9, 114.8,
115.5, 118.3, 128.2, 128.4, 128.9, 136.5, 139.7, 153.0, 170.9; IR
(CHCl3, cm-1) ν 3369, 1751; MS (ES) m/z 484 (M+•, 3), 314 (M+•
- 170, 60), 91 (100). Anal. Calcd for C26H36N2O5Si: C, 64.43; H,
7.49; N, 5.78. Found: C, 64.15; H, 7.57; N, 5.69.
General Procedure for Preparation of Piperidin-2-ones 20.
Method A. A solution of the appropriate amino â-lactam 4 (0.68
mmol) in methanol (16.2 mL) was added to sodium methoxide (0.82
mmol) at rt under argon atmosphere. The mixture was stirred at
reflux for 8 h. Brine (30 mL) was added to the crude, and methanol
was evaporated under reduced pressure. The resulting mixture was
extracted with ethyl acetate (5 × 60 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure. Flash
chromatography of the residue on silica gel using hexanes/ethyl
acetate mixtures afforded the corresponding compound 20. Method
B. Starting from the appropriate methyl ester 19, piperidine-2-ones
20 were obtained adopting the same protocol indicated above for
the synthesis of amino â-lactams 4.
General Procedure for Synthesis of Piperidines 18. Method
A. Sodium borohydride (1.54 mmol) was added in portions to a
solution of the appropriate mesylate 17 (0.22 mmol) and nickel(II)
chloride hexahydrate (0.22 mmol) in methanol (1.7 mL) at 0 °C
under argon. The reaction mixture was allowed to warm to room
temperature, stirred at rt for 45 min, and then methanol was
evaporated under vacuum. The residue was diluted with ethyl
acetate (50 mL), and an aq saturated solution of NaHCO3 was added
(25 mL). The resulting mixture was filtered, and the solution was
extracted with ethyl acetate (4 × 25 mL). The organic layer was
dried (MgSO4), filtered, and the solvent removed under reduced
pressure. The residue was diluted with anhydrous acetonitrile (2.4
mL), and methyl bromoacetate (0.33 mmol), potassium carbonate
(0.66 mmol), and a catalytic amount of lithium iodide were
sequentially added at rt under argon atmosphere. The reaction
mixture was stirred at 60 °C for 2 h, and it was allowed to cool to
rt. Water was then added (1.5 mL), and the resulting crude was
extracted with DCM (5 × 10 mL). The organic layer was dried
(MgSO4), filtered, and the solvent removed under reduced pressure.
The residue was purified by flash chromatography on silica gel to
afford the corresponding analytically pure piperidine 18. Method
B. Starting from the appropriate piperidine 22, piperidines 18 were
obtained adopting the same protocol indicated above for amides
15.
(+)-(3R,4R,5R)-3-(Benzyloxy)-5-{[tert-butyl(dimethyl)silyl]-
oxy}-4-[(4-methoxyphenyl)amino]piperidin-2-one,(+)-20b.Method
B. From 65 mg (0.13 mmol) of the methyl ester (+)-19b and after
flash chromatography (hexanes/ethyl acetate 1:1), pure compound
(+)-20b (34 mg, 56%) was obtained as a pale brown oil: [R]D
)
1
+5.0 (c 0.2, CHCl3); H NMR (300 MHz, CDCl3) δ -0.020 (s,
3H), 0.053 (s, 3H), 0.845 (s, 9H), 3.225-3.363 (m, 2H), 3.542 (t,
1H, J ) 7.6 Hz), 3.740 (d, 1H, J ) 7.6 Hz), 3.760 (s, 3H), 3.750-
3.840 (m, 1H), 4.705 (d, 1H, J ) 11.7 Hz), 4.938 (d, 1H, J ) 11.7
Hz), 5.984 (br s, 1H), 6.628 (AA′BB′, 2H), 6.744 (AA′BB′, 2H),
7.342 (br s, 5H); 13C NMR (50 MHz, CDCl3) δ -4.8, -4.7, 17.9,
25.7, 45.7, 55.7, 62.1, 71.0, 73.0, 77.6, 114.6, 115.4, 128.0, 128.4,
128.6, 137.6, 141.7, 152.6, 171.5; IR (CHCl3, cm-1) ν 3402, 1684;
MS (ES) m/z 456 (M+•, 22), 399 (M+• - 57, 6), 365 (M+• - 91,
33), 308 (6), 292 (100), 91 (48). Anal. Calcd for C25H36N2O4Si:
C, 65.75; H, 7.95; N, 6.13. Found: C, 65.89; H, 7.67; N, 5.98.
General Procedure for Synthesis of Piperidines 22. A solution
of the appropriate piperidine-2-one 20 (0.26 mmol) in anhydrous
diethyl ether (1.25 mL) was slowly added via syringe to a
suspension of LAH (0.78 mmol) in anhydrous diethyl ether at 0
(+)-Methyl ((3S,4R,5R)-4-(Acetylamino)-3-(benzyloxy)-5-
{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)acetate, (+)-18b.
Method A. From 88 mg (0.19 mmol) of mesylate (-)-17b and,
after flash chromatography (hexanes/ethyl acetate 1:1), pure pip-
eridine (+)-18b (34 mg, 40%) was obtained. Method B. From 52
mg (0.10 mmol) of piperidine (+)-22b and, after flash chroma-
tography (hexanes/ethyl acetate 1:1), pure piperidine (+)-18b (25
mg, 55%) was obtained as a pale brown oil: [R]D ) +6.9 (c 0.5,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 0.013 (s, 3H), 0.024 (s,
7990 J. Org. Chem., Vol. 72, No. 21, 2007

Access to anti,anti-4-Aminopiperidine-3,5-diols
3H), 0.846 (s, 9H), 1.937 (s, 3H), 2.267 (t, 1H, J ) 10.2 Hz), 2.267
(t, 1H, J ) 10.2 Hz), 2.931 (dd, 1H, J ) 10.8, 4.7 Hz), 3.162 (br
dd, 1H, J ) 8.4, 2.1 Hz), 3.297 (br s, 2H), 3.597 (m, 2H), 3.732
(s, 3H), 3.732 (m, 1H), 4.438 (d, 1H, J ) 12.1 Hz), 4.652 (d, 1H,
J ) 12.1 Hz), 5.020 (br d, 1H, J ) 7.5 Hz), 7.344-7.282 (m, 5H);
13C NMR (50 MHz, CDCl3) δ -4.8, -4.5, 17.8, 23.8, 25.6, 51.6,
56.1, 58.4, 59.4, 69.6, 71.6, 75.1, 127.7, 127.9, 128.3, 138.4, 169.9,
Acknowledgment. We would like to thank the DGI-MEC
(Project CTQ2006-10292) and CAM-UCM (Grant GR69/06)
for financial support. G.C. thanks the MEC for a predoctoral
grant.
Supporting Information Available: Compound characterization
data and experimental procedures for compounds 2a,b, 3b-e, anti-
(+)-4a, 4b-e, anti-(+)-5a, 5b,c, 6b-d, (+)-7a, (-)-7b, (+)-8, (+)-
9, (-)-10b, (-)-11b, (-)-12b, (-)-15a, (-)-16a, 17, (-)-18a, (+)-
19a, (-)-20a, 21, and (-)-22a. This material is available free of
charge via the Internet at http://pubs.acs.org.
170.6; IR (CHCl3, cm-1) ν 1743, 1660; MS (ES) m/z 435 (M+•
-
15, 7), 393 (M+• - 57, 86), 391 (M+• - 59, 52), 359 (M+• - 91,
14), 285 (M+• - 57 - 108, 20), 283 (M+• - 59 - 108, 17),
258 (15), 209 (76), 116 (35), 91(100). Anal. Calcd for C23H36
N2O5Si: C, 61.30; H, 8.50; N, 6.22. Found: C, 61.49; H, 8.33; N,
5.98.
JO701452A
J. Org. Chem, Vol. 72, No. 21, 2007 7991