Enantiopure preparation of the two enantiomers of the pseudo-C2-symmetric N,N-dibenzyl-1,2:4,5-diepoxypentan-3-amine

Full text of DOI:10.1021/jo015920u

J . Org. Chem. 2001, 66, 8661-8665
8661
Sch em e 1. Retr osyn th etic An a lysis
En a n tiop u r e P r ep a r a tion of th e Tw o
En a n tiom er s of th e P seu d o-C2-Sym m etr ic
N,N-Diben zyl-1,2:4,5-d iep oxyp en ta n -3-a m in e
J ose´ M. Concello´n,* Estela Riego,
Humberto Rodr´ıguez-Solla, and Ana M. Plut´ın†
Departamento de Quı´mica Orga´nica e Inorga´nica, Facultad
de Quı´mica, Universidad de Oviedo, J ulia´n Claverı´a 8,
33071 Oviedo, Spain
jmcg@sauron.quimica.uniovi.es
Received J uly 12, 2001
example of symmetrically substituted 3-amino-2,4-diols
has been described.5
Recently, we have reported some synthetic applications
of halomethyllithium in the preparation of enantiopure
1-aminoalkyl chloromethyl ketones6 and aminoepoxides6b
starting from R-amino esters and R-amino aldehydes,
respectively. Furthermore, we have also described some
synthetic applications of these R-amino R′-chloro
ketones.6b,7 On the basis of this methodology, we wish to
report here an enantiopure preparation of the pseudo-
C2-symmetric (2R,4R)- and (2S,4S)-N,N-dibenzyl-1,2:4,5-
diepoxypentan-3-amine, 1 and 2, respectively (Scheme
1). Retrosynthetic analysis (Scheme 1) suggested that 1
and 2 could be obtained from the same starting product
3, assuming that the formation of each oxirane ring
comes from the sequential addition of two different
nucleophiles, hydride and halomethyllithium, to the
corresponding to theoretical ester function of the starting
compound. Thus, depending on the order of addition, the
two oxirane rings of both enantiomers 1 (via A) and 2
(via B) could be obtained. Compounds 1 and 2 could be
used to obtain amino diols such as 3-amino-2,4-diols and
1,3,5-triamino-2,4-diols in enantiomerically pure form.8
In both proposed synthetic routes to the bis-epoxides 1
and 2, other highly functionalized, enantiopure com-
pounds are obtained.
In tr od u ction
The enantioselective synthesis of organic compounds
with C2 symmetry and pseudosymmetry has received
much attention due to the applications of these molecules
both as chiral ligands,1 to prepare chiral catalysts,2 and
as a core unit of pseudopeptide HIV protease inhibitors
and other bioactive compounds.3 Among the numerous
compounds with C2 symmetry that have been prepared
in recent years,4 to the best of our knowledge, only an
* To whom correspondence should be addressed. Fax: 34-98-510-
3446.
† Current address: Laboratorio de S´ıntesis Orga´nica, Facultad de
Qu´ımica, Universidad de La Habana, 10400, La Habana, Cuba.
(1) (a) Whitesell, J . K. Chem. Rev. 1989, 89, 1581. (b) Konradi, A.
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E.; Liable-Sands, L.; Rheingold, A. L.; Borovik, A. S. Tetrahedron Lett.
1998, 39, 6831 and references therein.
(2) (a) Marinetti, A.; Kruger, V.; Buzin, F. X. Tetrahedron Lett. 1997,
38, 2947. (b) Cserepi-Szucs, S.; Bakos, J . J . Chem. Soc., Chem.
Commun. 1997, 635. (c) Schenk, W. A.; Stubbe, M.; Hagel, M. J .
Organomet. Chem. 1998, 560, 257. (d) Sugimura, T.; Inoue, S.; Tai, A.
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(3) (a) Kempf, D. J .; Sham, H. L. Curr. Pharm. Des. 1996, 2, 225.
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Kohlbrenner, W. E.; Simmer, R.; Helfrich, R.; Paul, D. A.; Knigge, M.
Science 1990, 249, 527.
(4) For several classes of compounds with C2 symmetry, see (a)
Aguilar, N.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron Lett.
1999, 40, 3913. (b) Aguilar, N.; Moyano, A.; Perica`s, M. A.; Riera, A.
Tetrahedron Lett. 1999, 40, 3917. (c) Ettmayer, P.; Hu¨bner, M.; Gstach
H. Tetrahedron Lett. 1994, 35, 3901. (d) Lam, P. Y. S.; J adhav, P. K.;
Eyermann, C. J .; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J . L.;
Otto, M. J .; Rayner, M. M.; Wong, Y. N.; Chang, C. H.; Weber, P. C.;
J ackson, D. A.; Sharpe, T. R.; Erickson-Vitanen, S. Science 1994, 263,
380. (e) Rossano, L. T.; Lo, Y. S.; Anzalone, L.; Lee, Y. C.; Meloni, D.
J .; Moore, J . R.; Gale, T. M.; Arnett, J . F. Tetrahedron Lett. 1995, 36,
4967. (f) Hulten, J .; Bonham, N. M.; Nillroth, U.; Hansson, T.;
Zuccarello, G.; Bouzide, A.; Aqvist, J .; Classon, B.; Danielson, U. H.;
Karle´n, A.; Kvarnstro¨m, I.; Samuelsson, B.; Hallberg, A. J . Med. Chem.
1997, 40, 885. (g) Nugiel, D. A.; J acobs, K.; Cornelius, L.; Chang, C.
H.; J adhav, P. K.; Holler, E. R.; Klabe, R. M.; Bacheler, L. T.; Cordova,
B.; Garber, S.; Reid, C.; Logue, K. A.; Gorey-Feret, L. J .; Lam, G. M.;
Erikson-Vitanen, S.; Seitz, S. P. J . Med. Chem. 1997, 40, 1465. (h)
Lam, P. Y. S.; Ru, Y.; J adhav, P. K.; Aldrich, P. E.; DeLucca, G. V.;
Eyermann, C. J .; Chang, C. H.; Emmet, G.; Holler, E. R.; Daneker, W.
F.; Li, L.; Confalone, P. N.; McHugh, R. J .; Han, Q.; Li, R.; Markwalder,
J . A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Klabe,
R. M.; Shum, L.; Winslow, D. L.; Kornhauser, D. M.; J ackson, D. A.;
Erikson-Vitanen, S.; Hodge, C. N. J . Med. Chem. 1996, 39, 3514. (i)
Nugiel, D. A.; J ackson, K.; Worley, T.; Patel, M.; Kaltenbach, R. F.;
Meyer, D. T.; J adhav, P. K.; Delucca, G. V.; Smyser, T. E.; Klabe, R.
M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J . Med. Chem. 1996,
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J . Org. Chem. 1996, 61, 444.
Resu lts a n d Discu ssion
The synthesis of (2R,4R)-N,N-dibenzyl-1,2:4,5-diepoxy-
pentan-3-amine 1 from the methyl N,N-dibenzylated
O-protected ester 4,9 derived from serine 3, is depicted
in Scheme 2. In the first step, treatment of the protected
compound 4 with in situ10 generated chloromethyllithium
(5) Andre´s, J . M.; Pedrosa, R. Tetrahedron 1998, 54, 5607.
(6) (a) Barluenga, J .; Baragan˜a, B.; Alonso, A.; Concello´n, J . M.J .
Chem. Soc., Chem. Commun. 1994, 969. (b) Barluenga, J .; Baragan˜a,
B.; Concello´n, J . M. J . Org. Chem. 1995, 60, 6696.
(7) (a) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J . Org. Chem.
1997, 62, 5974. (b) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J .
Org. Chem. 1999, 64, 2843. (c) Barluenga, J .; Baragan˜a, B.; Concello´n,
J . M. J . Org. Chem. 1999, 64, 5048. (d) Concello´n, J . M.; Bernad, P.
L.; Riego, E.; Garc´ıa-Granda, S.; Force´n-Acebal, A. J . Org. Chem. 2001,
66, 2764.
(8) Bis-epoxides have been used in the synthesis of 1,4-diamino-2,3-
diols: (a) Feit, P. W. J . Med. Chem. 1964, 7, 14. (b) Feit, P. W. Chem.
Ber. 1963, 96, 712. (c) Mash, E. A.; Hemperly, S. B.; Nelson, K. A.;
Heidt, P. C.; Van Deusen, S. J . J . Org. Chem. 1990, 55, 2045. (d) Ghosh,
A. K.; McKee, S. P.; Thompson, W. J . Tetrahedron Lett. 1991, 32, 5729.
(e) Zuccarello, G.; Bouzide, A.; Kvanstro¨m, I.; Niklasson, G.; Svensson,
S. C. T.; Brisander, M.; Danielsson, H.; Nillroth, U.; Karle´n, A.;
Hallberg, A.; Classon, B.; Samuelsson, B. J . Org. Chem. 1998, 63, 4998.
(f) Hill, R. K.; Bradberry, T. F. Experientia, 1982, 38, 70. (g) Devine,
P. N.; Oh, T. Tetrahedron Lett. 1991, 32, 883.
(9) Laib, T.; Chastanet, J .; Zhu, J . J . Org. Chem. 1998, 63, 1709.
(10) Concello´n, J . M.; Llavona, L.; Bernad, P. L., J r. Tetrahedron
1995, 51, 5573.
10.1021/jo015920u CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/09/2001

8662 J . Org. Chem., Vol. 66, No. 25, 2001
Notes
Sch em e 2. Syn th esis of
(2R,4R)-N,N-d iben zyl-1,2:4,5-d iep oxyp en ta n -3-a m in e
1 (via A)a
Sch em e 3. Syn th esis of
(2S,4S)-N,N-d iben zyl-1,2:4,5-d iep oxyp en ta n -3-a m in e
2 (via B)a
a
Reagents: (a) [LiCH2Cl], THF, -78 °C, 90%; (b) LiAlH4, THF,
a
-100 °C, 87%; (c) MeLi, THF, -78 °Cfrt, 87%; (d) (NBu4)F, THF,
80%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, -63 °C, 98%; (f) [LiCH2I],
THF, -78 °Cfrt, 86%.
Reagents: (a) [LiCH2I], THF, -78 °Cfrt, 86%; (b) (NBu4)F,
THF, 97%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, -63 °C, 98%; (d)
[LiCH2Cl], THF, -78 °C, 85%; (e) (COCl)2, DMSO, Et3N, CH2Cl2,
-63 °C, 98%; (f) LiAlH4, THF, -100 °C, 95%; (g) NaH, CH2Cl2, rt,
96%.
at -78 °C (from chloroiodomethane and methyllithium)
gave, after hydrolysis, the corresponding chlorinated
amino ketone 5 in 90% yield. Reduction of 5 with LiAlH4
at -100 °C afforded the chlorohydrin 6 in 87% yield.
Epoxidation of 6 was achieved by lithiation of the
hydroxyl group by using methyllithium (87% yield), the
diastereoisomeric excess (de) of 7 being >95%. Depro-
tection of hydroxyl group of 7 with (NBu4)F and subse-
quent careful oxidation, under Swern conditions, led to
the corresponding amino aldehyde 9 (98% yield from 7).
The final product 1 was obtained in 86% yield and 95%
de by iodomethylation of 9 with in situ generated
iodomethyllithium at -78 °C (from diiodomethane and
methyllithium). The epoxidation of the obtained lithium
alcoholate took place spontaneously in these reaction
conditions, affording the C2-pseudosymmetrical bis-ep-
oxide 1.
F igu r e 1. Some synthetic applications of intermediate com-
pounds.
rohydrin 16, which when treated with sodium hydride
produced the expected (2S,4S)-N,N-dibenzyl-1,2:4,5-diep-
oxypentan-3-amine 2 (96% yield and 95% de).
Since all the intermediate compounds (4-9 and 11-
16) were obtained with a high degree of purity, except
for the products 8 and 12 from the deprotection step, they
could be used without further purification. This has
allowed the isolation of the bis-epoxides 1 and 2 in high
yield.
On the basis of our earlier studies which examined the
nonchelation controlled reduction of chiral R-dibenzyl-
amino R′-chloro ketones and the addition of iodomethyl-
lithium to R-aminoaldehydes,6b the absolute configuration
of amino diepoxide 1 is believed to be (2R,4R).11
Synthesis of 1 and 2 proceeded with no detectable
racemization. The enantiomeric purity of diepoxides 1
and 2 was determined by chiral HPLC (Chiralcel OD-
RH) analysis, showing in both cases an enantiomeric
excess (ee) >98%. To exclude the possibility of coelution
of both enantiomers, a mixture of 1 and 2 was prepared
and analyzed by HPLC.
It is noteworthy that all the carbon atoms of all the
intermediate compounds (3-16) in the two synthetic
routes described are functionalized. These functional
groups have very different reactivities, and consequently
they could be transformed selectively into other com-
pounds. For this reason these compounds could be used
as chiral building blocks in the synthesis of enantiopure
compounds. To illustrate this potential, amino epoxides
7 and 12 were treated with propylamine and benzyl-
amine, respectively, affording the corresponding diamino
compounds 17 (60% yield) and 18 (66% yield) (see Figure
1) with total regioselectivity (300 MHz 1H NMR), the ring
opening being at the less substituted primary carbon.
Likewise, 10 was successively treated with in situ gener-
The synthesis of (2S,4S)-N,N-dibenzyl-1,2:4,5-diepoxy-
pentan-3-amine 2 is depicted in Scheme 3. Transforma-
tion of R-amino aldehyde 1011a into the amino epoxide
11 by using in situ generated iodomethyllithium at -78
°C (from diiodomethane and methyllithium) was ac-
complished in 86% yield and with high diastereoselec-
tivity (de ) 95%). Desilylation of 11 was achieved by
using (NBu4)F, followed by Swern oxidation afforded
aldehyde 13, which was chloromethylated by treatment
with in situ generated chlomethyllithium (from chlor-
oiodomethane and methyllithium) affording the corre-
sponding chlorohydrin 14 in 85% yield (from 12). To
obtain the required configuration at the second oxirane
ring, 14 was successively oxidized, (Swern oxidation) to
the chloroketone 15 (98% yield), and reduced with LiAlH4
at -100 °C (95% yield) affording the appropriate chlo-
(11) (a) The stereochemistry of 1 is also based upon the study of
the addition of organometallics compounds to dibenzylated R-amino
aldehydes: Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1141. (b) Reetz, M. T. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1531.

Notes
J . Org. Chem., Vol. 66, No. 25, 2001 8663
) 13.4), 3.71 (1 H, dd, J ) 11.7, 2.8), 3.50 (1 H, dd, J ) 11.7,
5.7), 2.92-2.86 (1 H, m) 0.98 (9 H, s), 0.17 (3 H, s), 0.15 (3 H, s);
13C NMR (CDCl3, 75 MHz) δ 138.6 (C), 128.8, 128.3, and 127.1
(3 × CH), 67.9 (CH), 60.6 (CH), 58.9 (CH2), 54.4 (CH2), 47.3
(CH2), 25.6 (CH3), 17.8 (C), -5.7 (CH3), -5.8 (CH3); IR (neat)
3426 (br); MS, m/z 418.1 (M+ - CH3, <1), 354.1 (100), 288.0 (33),
91.0 (92). HRMS Calcd for C23H31ClNO2Si (M - CH3)+: 418.1969.
Found: 418.1971.
ated chloromethyllithium and lithium powder affording
the corresponding allylamine 19 (65% yield, based on the
aldehyde 10) in enantiomeric pure form (see Figure 1).12
In conclusion, the results reported here represent a
synthetic route for the preparation of (2R,4R)- and
(2S,4S)-N,N-dibenzyl-1,2:4,5-diepoxypentan-3-amine, 1
and 2, in enantiomerically pure form, and with good yield.
This synthetic route is simple, and the starting material
(serine) is easily available. Moreover, other enantiopure
highly functionalized compounds have been prepared,
and we have shown some synthetic applications of these
compounds.
(+)-(2R)-2-{1′(S)-(Diben zyla m in o)-2′-[(ter t-bu tyld im eth -
ylsila n yl)oxy]eth yl}oxir a n e (7). To a -78 °C stirred solution
of the amino alcohol 6 (1.16 g, 2.7 mmol) in dry THF (10 mL)
was added methyllithium (2.7 mL of 1.5 M solution in diethyl
ether, 4.05 mmol). After stirring at 25 °C for 1 h, the reaction
was quenched with a saturated aqueous solution of NH4Cl (5
mL) and extracted with diethyl ether (10 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The crude epoxide 7 was examined by 1H NMR to give
a de >95% and used without further purification. The crude
product was chromatographed on silica gel (50/1 hexane/triethy-
lamine) to provide pure epoxide 7, as a pale yellow oil, to
determinate the optical rotation: Rf ) 0.41 (hexane/ethyl acetate
10/1); [R]22D ) +13.6 (c 1.38, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 7.45-7.24 (10 H, m), 3.94 (4 H, s), 3.83-3.81 (2 H, m), 3.23 (1
H, ddd, J ) 7.0, 4.4, 3.9), 2.77 (1 H, dd, J ) 5.3, 4.4), 2.67-2.60
(2 H, m), 0.92 (9 H, s), 0.06 (3 H, s), 0.04 (3 H, s); 13C NMR
(CDCl3, 75 MHz) δ 140.1 (C), 128.9, 128.3, and 127.0 (3 × CH),
62.5 (CH2), 60.7 (CH), 55.3 (CH2), 51.5 (CH), 44.5 (CH2), 25.7
(CH3), 17.9 (C), -5.7 (CH3), -5.8 (CH3); IR (neat) 3084, 3028.
Anal. Calcd for C24H35NO2Si: C, 72.49; H, 8.87; N, 3.52. Found:
C, 72.05; H, 8.71; N, 3.48.
Exp er im en ta l Section
Gen er a l. 1H NMR spectra were recorded at 300 or 200 MHz.
13C NMR spectra were recorded at 75 or 50 MHz. Chemical shifts
are reported in ppm relative to TMS in CDCl3. Only the
molecular ions and/or base peaks in MS are given. Optical
rotations were measured in CHCl3. The enantiomeric purity was
determined by chiral HPLC analysis using a Chiralcel OD-RH
(0.46 × 15 cm, Daicel) column. Analytical TLC was conducted
in precoated silica gel 60 F-254 on aluminum sheets; compounds
were visualized with UV light or iodine. Flash chromatography
was carried out on Merck silica gel 60 (230-400 mesh).
DMSO was distilled from CaH2 and stored over activated 4
Å molecular sieves. Methyl R-amino O-protected ester 4 and
R-aminoaldehyde 10 were prepared according to literature
procedures.9,11a All reactions were conducted in oven-dried
glassware under dry nitrogen. All solvents were purified before
using. THF was distilled from sodium in a recycling still using
benzophenone ketyl as indicator; dichloromethane was distilled
from P2O5.
(-)-(3S)-3-(Diben zyla m in o)-4-[(ter t-bu tyld im eth ylsila n -
yl)oxy]-1-ch lor obu ta n -2-on e (5). To a -78 °C stirred solution
of the methyl R-amino O-protected ester 4 (1.29 g, 3.1 mmol)
and chloroidomethane (0.45 mL, 6.2 mmol) in dry THF (15 mL)
was added methyllithium (4.1 mL of 1.5 M solution in diethyl
ether, 6.2 mmol) dropwise over 5 min. After stirring the mixture
at -78 °C for 30 min, it was treated with a saturated aqueous
solution of NH4Cl (5 mL) and extracted with diethyl ether (3 ×
15 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated in vacuo, yielding the chloromethyl
ketone 5 as a yellowish solid. The crude ketone 5 was reduced
without further purification: Rf ) 0.46 (hexane/ethyl acetate
10/1); [R]22D ) -56.1 (c 0.90, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 7.37-7.29 (10 H, m), 4.27 (2 H, AB syst., J ) 16.2), 4.10 (2 H,
dd, J ) 6.3, 2.0), 3.85 (2 × 2 H, AB syst., J ) 13.7), 3.67 (1 H,
t, J ) 6.3), 0.95 (9 H, s), 0.14 (3 H, s), 0.12 (3 H, s); 13C NMR
(CDCl3, 75 MHz) δ 201.5 (C), 138.8 (C), 128.7, 128.3 and 127.2
(3 × CH), 65.2 (CH), 59.9 (CH2), 55.0 (CH2), 48.2 (CH2), 25.7
(CH3), 17.9 (C), -5.7 (CH3), -5.8 (CH3); IR (neat) 1730; MS, m/z
382.2 (M+ - CH2Cl, <1), 354.2 (49), 190.0 (31), 147.0 (40), 91.0
(100), 75.0 (55). HRMS Calcd for C24H32NO2Si (M - CH2Cl)+:
382.2202. Found: 382.2200.
(-)-(2R)-2-[1′(S)-(Dib en zyla m in o)-2′-h yd r oxyet h yl]ox-
ir a n e (8). The tert-butyldimethylsilyl ether 7 (1 mmol) in THF
(10 mL) was stirred with (Bu4N)F (3 mL of 1 M solution in THF,
3 mmol) at room temperature for 48 h. The reaction mixture
was diluted with water (10 mL) and extracted with CH2Cl2 (3 ×
10 mL). Removal of the solvent followed by purification by flash
column chromatography over silica gel (1/1 hexane/ethyl acetate)
provided pure compound 8 as a yellowish oil: Rf ) 0.20 (hexane/
ethyl acetate 3/1); [R]22 ) -23.1 (c 0.90, CHCl3); 1H NMR
D
(CDCl3, 200 MHz) δ 7.40-7.29 (10 H, m), 3.93 (2 × 2 H, AB
syst., J ) 13.1), 3.67 (1 H, dd, J ) 10.5, 10.0), 3.49 (1 H, dd, J
) 10.5, 5.7), 3.16 (1 H, ddd, J ) 6.7, 4.1, 2.6), 3.04 (1 H, s), 2.78
(1 H, dd, J ) 4.8, 4.1), 2.66 (1 H, ddd, J ) 7.4, 5.4, 2.0), 2.49 (1
H, dd, J ) 4.8, 2.6); 13C NMR (CDCl3, 50 MHz) δ 138.7 (C), 128.8,
128.2, and 127.0 (3 × CH), 60.9 (CH), 58.1 (CH2), 54.0 (CH2),
49.3 (CH), 43.5 (CH2); IR (neat) 3427 (br); MS, m/z 283.1 (M+,
5), 252.1 (18), 181.1 (8), 91.0 (100). HRMS Calcd for C18H21NO2:
283.1572. Found: 283.1573.
(2S, 3R)-2-(Diben zyla m in o)-3,4-ep oxybu ta n a l (9). A solu-
tion of dry DMSO (0.50 mL, 7.04 mmol) in dry CH2Cl2 (2.8 mL)
was added dropwise to a -63 °C solution of oxalyl chloride (0.31
mL, 3.52 mmol) in dry CH2Cl2 (2.8 mL) over 10 min. The mixture
was stirred at the same temperature for 5 min, and a solution
of the epoxyalcohol 8 (3.2 mmol) in dry CH2Cl2 (23 mL) was
added within 10 min. The reaction was stirred for an additional
20 min and then treated dropwise with triethylamine (1.4 mL,
16 mmol) in CH2Cl2 (5 mL) over 15 min. The mixture was stirred
for another 30 min. Water was then added, and the aqueous
layer was reextracted with additional CH2Cl2 (3 × 20 mL). The
organic layers were combined, washed with saturated NaCl
solution (50 mL), and dried over Na2SO4. The solvents were
removed in vacuo, yielding the R-aminoaldehyde 9 as an orange
oil, which were used without further purification. Due to
instability of the epoxyaldehyde 9, it was characterized by NMR
spectroscopy: 1H NMR (CDCl3, 200 MHz) δ 9.60 (1 H, s), 7.45-
7.24 (10 H, m), 3.92 (4 H s), 3.34 (1 H, ddd, J ) 7.4, 4.3, 2.6),
2.97 (1 H, d, J ) 7.4), 2.89 (1 H, dd, J ) 4.6, 4.3), 2.48 (1 H, dd,
J ) 4.6, 2.6); 13C NMR (CDCl3, 50 MHz) δ 201.2 (C), 138.4 (C),
128.8, 128.2 and 127.2 (3 × CH), 69.4 (CH), 55.6 (CH2), 48.3
(CH), 43.8 (CH2).
(+)-(2R,3S)-3-(Diben zyla m in o)-4-[(ter t-bu tyld im eth ylsi-
la n yl)oxy]-1-ch lor obu ta n -2-ol (6). To a -100 °C stirred
solution of the ketone 5 (1 mmol) in dry THF (5 mL) was added
LiAlH4 (0.3 mL of 1.0 M solution in THF, 0.3 mmol). The
resulting solution was stirred for 6 h at the same temperature
and added to water. The mixture was filtered through a pad of
Celite, and the filtrate was extracted with diethyl ether (3 × 10
mL). The combined organic layers were dried (Na2SO4), filtered,
and concentrated in vacuo. The crude amino alcohol 6 was used
without further purification. The crude product was chromato-
graphed on silica gel (3/1 hexane/ethyl acetate) to provide pure
amino alcohol 6, as a colorless oil, to determinate the optical
rotation: Rf ) 0.30 (hexane/ethyl acetate 10/1); [R]22 ) +36.0
D
(c 1.23, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.38-7.25 (10 H,
(-)-(2R ,4R )-N ,N -D ib e n zy l-1,2:4,5-d ie p o x y p e n t a n -3-
a m in e (1). To a -78 °C stirred solution of R-aminoaldehyde 9
(3.2 mmol) and diidomethane (0.77 mL, 9.6 mL) in dry THF (10
mL) was added methyllithium (6.4 mL of 1.5 M solution in
diethyl ether, 9.6 mmol) dropwise over 5 min. After stirring the
mixure at -78 °C for 30 min, it was allowed to warm to room
temperature. Stirring was continued for 1 h, and then the
m), 4.28 (1 H, s), 4.01-3.92 (3 H, m), 3.83 (2 × 2 H, AB syst., J
(12) The enantiomeric purity of the allylamines prepared by using
this methodology was determined by chiral HPLC (Chiralcel OD-H)
analysis: Concello´n, J . M.; Baragan˜a, B.; Riego, E. Tetrahedron Lett.
2000, 41, 4361.

8664 J . Org. Chem., Vol. 66, No. 25, 2001
Notes
reaction was hydrolyzed with a saturated aqueous solution of
NH4Cl (5 mL) and extracted with diethyl ether (3 × 10 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated in vacuo. The crude bis-epoxide 1 was examined
by 1H NMR to give a de ) 95%. The crude product was
chromatographed on silica gel, which was saturated with tri-
ethylamine (3/1 hexane/ethyl acetate) to provide pure bis-epoxide
67.5 (CH), 55.3 (CH2), 47.5 (CH2), 47.4 (CH), 46.6 (CH2); IR (neat)
1736. Anal. Calcd for C19H20ClNO2: C, 69.19; H, 6.11; N, 4.25.
Found: C, 69.05; H, 6.14; N, 4.30. HRMS Calcd for C19H20NO2-
Cl: 329.1182. Found: 329.1187.
(-)-(2S,3S,4S)-3-(Diben zyla m in o)-1-ch lor o-4,5-ep oxypen -
ta n -2-ol (16). This product was prepared following the procedure
to obtain 6, but starting from 15, and isolated as a yellowish
1 as a yellowish oil: Rf ) 0.35 (hexane/ethyl acetate 5/1); [R]22
oil: Rf ) 0.35 (hexane/ethyl acetate 3/1); [R]22 ) -2.4 (c 0.62,
D
D
1
) -2.9 (c 1.2, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.44-7.22
CHCl3); 1H NMR (CDCl3, 200 MHz) δ 7.40-7.28 (10 H, m), 4.17-
4.03 (1 H, m), 3.89 (2 × 2 H, AB syst., J ) 13.3), 3.91-3.79 (2
H, m), 3.54 (1 H, dd, J ) 11.3, 6.7), 3.13 (1 H, ddd, J ) 6.7, 3.8,
(10 H, m), 3.96 (2 × 2 H, AB syst., J ) 13.7), 3.31-3.26 (1 H,
m), 3.14-3.10 (1 H, m), 2.78 (1 H, dd, J ) 5.1, 4.3), 2.71 (1 H,
dd, J ) 4.8, 4.0), 2.53 (1 H, dd, J ) 5.1, 2.8), 2.48 (1 H, dd, J )
5.1, 2.8), 2.27 (1 H, dd, J ) 7.7, 5.4); 13C NMR (CDCl3, 75 MHz)
δ 139.5 (C), 128.5, 128.0, and 126.8 (3 × CH), 62.0 (CH), 55.3
(CH2), 51.9 (CH), 50.0 (CH), 45.2 (CH2), 43.8 (CH2); IR (neat)
3064, 3029; MS, m/z 295.1 (M+, <1), 252.1 (83), 91.0 (100).
HRMS Calcd for C19H21NO2: 295.1572. Found: 295.1577. Anal.
Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.29;
H, 7.10; N, 4.68. Chiral HPLC analysis ee >98% (Chiralcel OD-
RH, UV detector 210 nm, 0.5 mL/min, 65/35 acetonitrile/water,
tR 17.6 min).
2.8), 2.99 (1 H, dd, J ) 4.9, 3.8), 2.73 (1 H, dd, J ) 4.9, 2.8); 13
C
NMR (CDCl3, 75 MHz) δ 137.9 (C), 128.5, 128.4, and 127.3 (3 ×
CH), 70.2 (CH), 61.5 (CH), 54.6 (CH2), 47.9 (CH), 47.5 (CH2),
46.1 (CH2); IR (neat) 3356 (br). HRMS Calcd for C19H22NO2Cl:
331.1339. Found: 331.1312.
(+)-(2S ,4S )-N ,N -D ib e n zy l-1,2:4,5-d ie p o x y p e n t a n -3-
a m in e (2). To a stirred solution of the amino alcohol 16 (0.33 g,
1 mmol) in CH2Cl2 (5 mL) was added NaH (0.24 g, 10 mmol).
After stirring at room temperaure for 1 h, the reaction was
carefully quenched with water (5 mL) and extracted with CH2-
Cl2 (3 × 10 mL). The combined organic layers were dried (Na2-
SO4), filtered, and concentrated in vacuo. The crude bis-epoxide
2 was examined by 1H NMR to give a de ) 95%. The product
was chromatographed on silica gel, which was saturated with
triethylamine, (3/1 hexane/ethyl acetate) to provide pure bis-
epoxide 2 as a yellowish oil: [R]22D ) +3.2 (c 0.73, CHCl3). Chiral
HPLC analysis ee >98% (Chiralcel OD-RH, UV detector 210 nm,
0.5 mL/min, 65/35 acetonitrile/water, tR 13.2 min).
Gen er a l P r oced u r e for Rin g Op en in g of th e Am in o
Ep oxid es 7 a n d 12. To a solution of the corresponding amino
epoxide 7 or 12 (0.5 mmol) and LiClO4 (0.05 g, 0.5 mmol) in
acetonitrile (1 mL) was added the corresponding amine (0.6
mmol), and the reaction mixture was stirred at room tempera-
ture. The reaction was followed by TLC. Then, water was added
and the mixture was extracted with diethyl ether (3 × 5 mL).
Removal of the solvents followed by purification by flash column
chromatography over silica gel (1/1 hexane/ethyl acetate) pro-
vided pure compounds 17 and 18, as pale yellow oils.
(+)-(2S)-2-{1′(S)-(Diben zyla m in o)-2′-[(ter t-bu tyld im eth -
ylsila n yl)oxy]eth yl}oxir a n e (11). This product was prepared
following the procedure to obtain 1, but starting from 10 instead
of 9, and the epoxide 11 was isolated as a pale yellow oil. The
crude epoxide 11 was examined by 1H NMR to give a de ) 95%:
Rf ) 0.48 (hexane/ethyl acetate 10/1); [R]22 ) +16.6 (c 1.08,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.49-7.26 (10 H, m), 3.98-
3.85 (6 H, m), 3.21-3.17 (1 H, m), 2.80 (1 H, dd J ) 5.3, 4.3),
2.71-2.65 (1 H, m), 2.60 (1 H, dd, J ) 5.3, 2.7), 1.02 (9 H, s),
0.16 (6 H, s); 13C NMR (CDCl3, 75 MHz) δ 140.0 (C), 128.3, 127.9,
and 126.6 (3 × CH), 60.8 (CH2), 60.2 (CH), 55.0 (CH2), 50.7 (CH),
45.7 (CH2), 25.7 (CH3), 17.9 (C), -5.7 (CH3), -5.8 (CH3); IR (neat)
3062, 3028; MS, m/z 397.2 (M+, <1), 354.2 (10), 252.1 (100), 91.0
(89). HRMS Calcd for C24H35NO2Si: 397.2437. Found: 397.2442.
(-)-(2S)-2-[1′(S)-(Dib en zyla m in o)-2′-h yd r oxiet h yl]ox-
ir a n e (12). This product was prepared following the procedure
to synthesize 8, but starting from 11. The amino epoxide 12 was
isolated as a yellowish oil: Rf ) 0.23 (hexane/ethyl acetate 3/1);
[R]22 ) -43.8 (c 0.60, CHCl3); 1H NMR (CDCl3, 200 MHz) δ
(+)-(2S,3S)-3-(Diben zyla m in o)-4-[(ter t-bu tyld im eth ylsi-
D
7.36-7.26 (10 H, m), 3.89 (2 × 2 H, AB syst., J ) 13.6), 3.79-
3.69 (1 H, m), 3.63 (1 H, dd, J ) 11.0, 5.1), 3.18 (1 H, ddd, J )
5.4, 4.9, 2.6), 2.86 (1 H, dd, J ) 4.9, 4.6), 2.86-2.76 (1 H, m),
2.61 (1 H, dd, J ) 4.6, 2.6); 13C NMR (CDCl3, 50 MHz) δ 138.8
(C), 128.6, 128.4, and 127.2 (3 × CH), 59.5 (CH), 58.2 (CH2),
54.2 (CH2), 49.0 (CH), 45.1 (CH2); IR (neat) 3425 (br). Anal. Calcd
for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 75.98; H,
7.59; N, 4.81.
la n yl)oxi]-1-p r op yla m in obu ta n -2-ol (17). Rf ) 0.20 (ethyl
acetate); [R]22 ) +13.3 (c 0.75, CHCl3); 1H NMR (CDCl3, 300
D
MHz) δ 7.45-7.26 (10 H, m), 3.95-3.83 (3 H, m), 3.87 (2 × 2 H,
AB syst., J ) 13.5), 2.83-2.46 (2 H, m), 2.62-2.46 (3 H, m),
1.55-1.43 (2 H, m), 1.02 (9 H, s), 0.92 (3 H, t, J ) 7.2), 0.18 (6
H, s); 13C NMR (CDCl3, 75 MHz) δ 139.2 (C), 129.1, 128.3, and
127.0 (3 × CH), 66.7 (CH), 61.5 (CH), 59.8 (CH2), 54.5 (CH2),
53.0 (CH2), 51.5 (CH2), 25.8 (CH3), 22.6 (CH2), 18.0 (C), 11.6
(CH3), -5.6 (CH3), -5.7 (CH3); IR (neat) 3364 (br). HRMS Calcd
for C27H44Si N2O2: 456.3172. Found: 456.3153.
(2S, 3S)-2-(Diben zyla m in o)-3,4-ep oxybu ta n a l (13). This
product was prepared following the procedure to prepare 9, but
starting from 12, and isolated as an orange oil. Due to instability
of the epoxyaldehyde 13, it was characterized by NMR spec-
troscopy: 1H NMR (CDCl3, 200 MHz) δ 9.79 (1 H, s), 7.48-7.27
(10 H, m), 3.99 (2 × 2 H, AB syst., J ) 13.8), 3.32 (1 H, ddd, J
) 5.4, 3.8, 2.8), 3.17 (1 H, d, J ) 5.4), 2.88 (1 H, dd, J ) 4.9,
3.8), 2.66 (1 H, dd, J ) 4.9, 2.8); 13C NMR (CDCl3, 50 MHz) δ
200. 9 (C), 138.3 (C), 128.3, 128.2, and 127.2 (3 × CH), 67.5 (CH),
55.2 (CH2), 48.1 (CH), 44.5 (CH2).
(2R, 3S, 4S)-3-(Diben zyla m in o)-1-ch lor o-4,5-ep oxyp en -
ta n -2-ol (14). This product was prepared following the procedure
to obtain 5, but starting from 13. The crude chlorohydrin 14 was
used without further purification: 1H NMR (CDCl3, 200 MHz)
δ 7.44-7.18 (10 H, m), 4.24-4.19 (1 H, m), 3.84 (2 × 2 H, AB
syst., J ) 14.0), 3.81-3.75 (2 H, m), 3.36 (1 H, ddd, J ) 7.4, 4.4,
2.8), 2.88 (1 H, dd, J ) 5.1, 4.4), 2.68 (1 H, dd, J ) 5.1, 2.8), 2.44
(1 H, dd, J ) 7.4, 6.0); 13C NMR (CDCl3, 75 MHz) δ 138.8 (C),
128.4, 128.2, and 127.0 (3 × CH), 71.4 (CH), 61.2 (CH), 55.1
(CH2), 48.9 (CH), 48.6 (CH2), 45.5 (CH2).
(-)-(2S,3R)-2-(Diben zyla m in o)-4-ben zyla m in obu ta n -1,3-
d iol (18). Rf ) 0.14 (ethyl acetate); [R]22D ) -6.6 (c 0.44, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 7.42-7.26 (15 H, m), 4.02-3.94 (2
H, m), 3.91 (1 H, dd, J ) 11.4, 6.3), 3.72 (2 H, s), 3.71 (2 × 2 H,
AB syst., J ) 13.7), 2.88 (1 H, dd, J ) 12.2, 3.7), 2.66-2.56 (2
H, m); 13C NMR (CDCl3, 75 MHz) δ 139.4 (C), 139.2 (C), 128.7,
128.3, 128.2, 128.1, 127.1, and 126.9 (6 × CH), 69.0 (CH), 60.5
(CH), 58.9 (CH2), 54.5 (CH2), 53.4 (CH2), 52.1 (CH2); IR (neat)
3368 (br). Anal. Calcd for C25H30N2O2: C, 76.89; H, 7.74; N, 7.17.
Found: C, 76.71; H, 7.82; N, 7.15. HRMS Calcd for
C
25H30N2O2: 390.2307. Found: 390.2231.
(+)-(S)-N,N-Diben zyl-1-[(ter t-bu tyld im eth ylsila n yl)oxy]-
bu t-3-en -2-a m in e (19). To a -78 °C stirred solution of the
R-amino aldehyde 10 (0.39 g, 1.02 mmol) and chloroidomethane
(0.22 mL, 3.06 mmol) in dry THF (5 mL) was added methyl-
lithium (2.0 mL of 1.5M solution in diethyl ether, 3.06 mmol)
dropwise over 5 min. After stirring at -78 °C for 30 min, lithium
powder (0.07 g, 10.2 mmol) was added and the reaction mixture
was stirred at for 8 h -40 °C. The reaction was hydrolyzed with
ice, and after the usual workup, crude allylamine 19 was
obtained. Flash column chromatography over silica gel (20/1
hexane/ethyl acetate) provided pure allylamine 19 as a pale
(+)-(3S, 4S)-3-(Diben zyla m in o)-1-ch lor o-4,5-ep oxyp en -
ta n -2-on e (15). This product was prepared by oxidation of 14
following the procedure to prepare 9, and isolated as an orange
oil: Rf ) 0.36 (hexane/ethyl acetate 5/1); [R]22 ) +36.4 (c 0.70,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.42-7.27 (10 H, m), 4.34
(2 H, AB syst., J ) 16.4) 3.87 (2 × 2 H, AB syst., J ) 14.0), 3.37
(1 H, ddd, J ) 8.3, 3.5, 2.6), 3.03 (1 H, d, J ) 8.3), 2.96 (1 H, dd,
J ) 5.2, 3.5), 2.62 (1 H, dd, J ) 5.2, 2.6); 13C NMR (CDCl3, 75
MHz) δ 200.3 (C), 138.0 (C), 128.5, 128.4, and 127.5 (3 × CH),
yellow oil: Rf ) 0.29 (hexane/ethyl acetate 20/1); [R]22 ) +5.5
D
(c 1.00, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.50-7.26 (10 H,
m), 5.95 (1 H, ddd, J ) 17.4, 10.5, 6.5), 5.38 (1 H, d, J ) 10.5),
5.26 (1 H, d, J ) 17.4), 3.83 (2 H, dd, J ) 10.4, 6.5), 3.77 (2 × 2
H, AB syst., J ) 14.3), 3.32 (1 H, q, J ) 6.5), 0.97 (9 H, s), 0.09

Notes
J . Org. Chem., Vol. 66, No. 25, 2001 8665
(6 H, s); 13C NMR (CDCl3, 75 MHz) δ 140.4 (C), 134.7, 128.4,
127.9, and 127.9 (4 × CH), 118.2 (CH2), 64.3 (CH2), 61.9 (CH),
54.3 (CH2), 25.8 (CH3), 18.1 (C), -5.5 (CH3), -5.6 (CH3); IR (neat)
1603. Anal. Calcd for C24H35NO: C, 75.53; H, 9.24; N, 3.67.
Found: C, 75.71; H, 9.26; N, 3.65.
(Grant PB97-1278) and Principado de Asturias (PB-
EXP01-11). H.R.-S. and E.R. thank Principado de As-
turias and Ministerio de Ciencia y Tecnolog´ıa, respec-
tively, for a predoctoral fellowship.
Su p p or tin g In for m a tion Ava ila ble: Copies of 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. The authors are grateful to Dra.
Cecilia Go´mez (Universidad de Alicante) for spectro-
scopic mass determination and to Dr. J . A. Pe´rez-Andre´s
for his time. This research was supported by DGICYT
J O015920U