Synthesis of enantiopure α'-amino α,β-epoxy ketones from α'-amino bromomethyl ketones

Article abstract of DOI:10.1021/jo982435z

Preparation of enantiomerically pure α'-amino α,β-epoxy ketones 2 in an efficient synthesis starting from α'-amino bromomethyl ketones 5 and the obtention of amino diepoxido 10a as synthetic application of 2 are described. We also report the generalization of the synthesis of 1-aminoalkyl halomethyl ketones to their bromo derivatives.

Full text of DOI:10.1021/jo982435z

5048
J . Org. Chem. 1999, 64, 5048-5052
Syn th esis of En a n tiop u r e r′-Am in o r,â-Ep oxy Keton es fr om
r′-Am in o Br om om eth yl Keton es
J ose´ Barluenga,* Beatriz Baragan˜a, and J ose´ M. Concello´n*
Instituto Universitario de Quı´mica Organometa´lica “Enrique Moles”, Universidad de Oviedo,
J ulia´n Claverı´a s/ n, 33071 Oviedo, Spain
Alejandro Pin˜era-Nicola´s, M. Rosario D´ıaz, and Santiago Garc´ıa-Granda
Departamento de Quı´mica Fı´sica y Analı´tica, Facultad de Qu´ımica, J ulia´n Claverı´a 8,
Universidad de Oviedo, 33071-Oviedo, Spain
Received December 14, 1998
Preparation of enantiomerically pure R′-amino R,â-epoxy ketones 2 in an efficient synthesis starting
from R′-amino bromomethyl ketones 5 and the obtention of amino diepoxido 10a as synthetic
application of 2 are described. We also report the generalization of the synthesis of 1-aminoalkyl
halomethyl ketones to their bromo derivatives.
In tr od u ction
and treatment with organometallic compounds affords
3-azetidinols.7 Both reactions proceed with high dia-
stereoselectivity. These results prompted us to investi-
gate the unreported behavior of amino chloro ketones as
enolates in aldol condensation reactions, which would
afford chiral R,â-epoxy ketones.
In addition, R,â-epoxy ketones are known as versatile
synthetic intermediates because of their multiple func-
tionality. Stereoselective synthesis of R′-amino R,â-epoxy
ketones would furnish a new entry into various amino
polyoxygenated compounds. Moreover, tripeptide R,â-
epoxy ketones were found to be proteasome inhibitors and
the previously reported method for their synthesis needs
a multistep manipulation starting from the vinyl ke-
tones.8
While optically active R-amino aldehydes have been
widely used as chiral building blocks in organic synthe-
sis,1 the chemistry of amino ketones has not been
extensively developed. A possible reason for this can be
that these ketones are usually synthesized through
multistep transformations of R-amino acids or with
moderate yields. By contrast, R-amino aldehydes are
readily available.1 So, N-acyl amino acids have been
converted into the corresponding ketones by reaction with
organolithium reagents with moderate yields;2 with other
N-protected amino acids it is necessary to prepare
carboxyl-activated derivatives in a multistep process to
afford the corresponding ketones.3 To synthesize R′-amino
R-halo ketones, a more specialized method is required.
Thus, the procedure most commonly used for the syn-
thesis of R′-amino R-halo ketones is the treatment of the
R-amino acid derived mixed anhydride with diazomethane
and further acidolysis with HX.4 Chlorinated ketones are
interesting because they serve as irreversible enzyme
inhibitors5 and as precursors to the hydroxyethylamine
isosteres subunits present in many inhibitors of renin and
HIV-protease.4g-i
In this paper we report the preparation of enantio-
merically pure R′-amino R,â-epoxy ketones 2 in an
efficient synthesis starting from R′-amino bromomethyl
ketones 5 and the further transformation of compound
(4) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. In Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: from Cyclo-
propanes to Ylides; J ohn Wiley: New York, 1998; pp 1-50. (b) Powers,
J . C.; Wilcox, P. E. J . Am. Chem. Soc. 1970, 92, 1782. (c) Barrish, J .
C.; Gordon, E.; Alam, M.; Lin, P.-F.; Bisacchi, G. S.; Chen, P.; Cheng,
P. T. W.; Fritz, A. W.; Greytok, J . A.; Hermsmeier. M. A.; Humphreys,
W. G.; Lis, K. A.; Marella, M. A.; Merchant, Z.; Mitt, M.; Morrison, R.
A.; Obermeier, M. T.; Pluscec, J .; Skoog, M.; Slusarchyk, W. A.; Spergel,
S. H.; Stevenson, J . M.; Sun, C.-q.; Sundeen, J . E.; Taunk, P.; Tino, J .
A.; Warrack, B. M.; Colonno, R. J .; Zahler, R. J . Med. Chem. 1994, 37,
1758. (d) Getman, D. P.; DeCrescenzo, G. A.; Heintz, R. M.; Talley, J .
J .; Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr, J . J .; Mueller, R.
A.; Vazquez, M. L.; Shieh, H.-S.; Stallings, W. C.; Stegeman, R. A. J .
Med. Chem. 1993, 36, 288. (e) Beier, C.; Schaumann, E.; Adiwidjaja,
G. Synlett, 1998, 41. (f) Heisoo, A.; Raidaru, G.; Linask, K.; J a¨rv, J .;
Zatterstro¨m, M.; Langel, U¨ . Tetrahedron: Asymmetry 1995, 6, 2245.
(g) Rotella, D. R. Tetrahedron Lett. 1995, 36, 5453. (h) Albeck, A.;
Persky, R. Tetrahedron 1994, 50, 6333. (i) Parkes, K. E. B.; Bushnell,
D. J .; Crackett, P. H.; Dunsdon, S. J .; Freeman, A. C.; Gunn, M. P.;
Hopkins R. A.; Lambert, R. W.; Martin, J . A.; Merrett, J . H.; Redshaw,
S.; Spurden, W. C.; Thomas, G. J . J . Org. Chem. 1994, 59, 3656.
(5) Tsuda, Y.; Okada, Y.; Nagamatsu, Y.; Okamoto, U. Chem. Pharm.
Bull. 1987, 35, 3576.
Recently, we have reported an alternative method to
obtain, without racemization, chiral R′-amino R-chloro
ketones6 by the direct reaction of easily available R-amino
esters with in situ generated chloromethyllithium. This
synthetic procedure leads to chloro ketones without the
use of diazomethane. We have also described some
synthetic applications of R′-amino chloromethyl ketones.
Thus, their reduction gives threo aminoalkyl epoxides6b
(1) For reviews of the synthesis and use of R-amino aldehydes, see:
(a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. (b)
J urczak, J .; Golebioski, A. Chem. Rev. 1989, 89, 149.
(2) (a) Klix, R. C.; Chamberlin, S. A.; Bhata, A. V.; Davis, D. A.;
Hayes, T. K.; Rojas, F. G.; Koops, R. W. Tetrahedron Lett. 1995, 36,
1791. (b) Roemmele, R. C.; Rapoport, H. J . Org. Chem. 1989, 54, 1866.
(c) Knudsen, C. G.; Rapoport, H. J . Org. Chem. 1983, 48, 2260.
(3) (a) Sardina, F. J .; Paleo, M. R.Tetrahedron Lett. 1996, 37, 3403.
(b) Hamby, J . M.; Hodges, J . C. Heterocycles 1993, 35, 843. (c) Reetz,
M. T.; Drewwes, M. W.; Lennick, K.; Schmitz, A.; Holdgru¨n, X.
Tetrahedron: Asymmetry 1991, 1, 375. (d) Dufour, M. N.; J ouin, P.;
Poncet, J .; Pantaloni, A.; Castro, B. J . Chem. Soc., Perkin Trans. 1
1986, 1895.
(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) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J . Org. Chem. 1997,
62, 5974.
(8) Spaltenstein, A.; Leben, J . L.; Huang, J . J .; Reinhardt, K. R.;
Viveros, H.; Sigafoos, J .; Crouch, R. Tetrahedron Lett. 1996, 37, 1343.
10.1021/jo982435z CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/17/1999

Synthesis of Enantiopure R′-Amino R,â-Epoxy Ketones
J . Org. Chem., Vol. 64, No. 14, 1999 5049
Sch em e 1
Sch em e 3
Sch em e 2
Ta ble 1. Syn th esis of Br om om eth yl Keton es 5
Ta ble 2. Syn th esis of r′-Am in o r,â-Ep oxi Keton es 2
product
R
yield (%)a
product
R1
R2
R3
yield (%)a
deb
5a
5b
5c
Me
i-Bu
Bn
86
83
85
2a c
2b
Me
i-Bu
Bn
Bn
Me
Ph
Ph
Ph
-(CH2)4
-(CH2)5
H
H
H
-
-
85
80
87
70
68
90
90
2c
>95d
>95
>95
a
Isolated yield based on the starting R-amino ester 3.
2d c
2e
2 into an amino diepoxide 10a as a synthetic application.
Our approach to the synthesis of enantiopure R′-amino
R,â-epoxy ketones is based on the Darzens reaction which
is one of the more reliable methods for the construction
of R,â-epoxy ketones.9 We also describe the generalization
of the synthesis of R′-amino halomethyl ketones to their
bromo derivatives.
a
b
Isolated yield based on the starting ketone 5. Diastereoiso-
meric excess determined by 300 MHz 1H NMR analysis of the
crude products 2. c Lithium enolate was used. ee > 99% HPLC
d
(Chiracel OD-H; UV detector; 0.8 mL/min; 215 nm; 200:1 hexane/
2-propanol; tR) 13.8 min).
intermediate 4, which is stable under the reaction
conditions due to the presence of the electronegative
bromine and nitrogen substituents.11
Resu lts a n d Discu ssion
Bromo enolates 6 were generated at -100 °C in dry
THF using KHMDS; enolate 6a was isolated as the
trimethylsilyl enol ether derivative 7a by treatment with
chlorotrimethylsilane. The Z relative configuration of 7a
was established by NOE experiments; irradiation of the
vinylic proton produced a 11.5% positive NOE in the C-N
methine hydrogen, and no positive NOE was observed
in the methyl groups of TMS, confirming the cis relation-
ship of the bromine and trimethylsilyloxy substituents12
(see Scheme 3)
The reaction of potassium enolates 6 with aromatic
aldehydes or cyclic ketones at -100 °C gave, after
hydrolysis, the corresponding R,â-epoxy ketones 2 in high
yields and with high diastereoselectivity (see Scheme 3
and Table 2). Using lithium enolates (from lithium
hexamethyldisilazide), the corresponding R,â-epoxy ke-
tones 2 were isolated in similar yields after warming the
reaction to -78 °C (to see footnote in Table 2). The
structures of the epoxy ketones obtained in the reactions
of either potassium or lithium enolates were found to be
the same. Generation of lithium enolates using LDA gave
reduced yields and lower diastereoselectivities of 2, while
sodium enolates (from sodium hexamethyldisilazide)
resulted in poor yields and lower diastereoselectivities
of 2.
Our initial idea was to examine the suitability of R′-
amino chloromethyl ketones as substrates in a Darzens-
type reaction with aldehydes and ketones. At first, we
attempted the condensation of the R-chloro ketone de-
rived from leucine 1b and benzaldehyde. Successive
treatment of ketone 1b with potassium hexamethyl-
disilazide (KHMDS) and benzaldehyde in THF at low
temperature (-100 °C) led to the corresponding R,â-epoxy
ketone 2b in 75% yield with moderate diastereoisomeric
excess (de ) 50%) (Scheme 1).
As bromo enolates show enhanced selectivity relative
to the corresponding chloro derivatives,10 we thought that
the diastereoselectivity could be improved by starting
from amino bromo ketones 5. For this reason, the
preparation of previously unreported chiral R′-amino
bromomethyl ketones 5 was carried out. Hence, treat-
ment of ethyl N,N-dibenzylated R-amino carboxylates 3
with in situ generated bromomethyllithium at -78 °C
gave, after hydrolysis, the corresponding bromomethyl
ketones 5 in high yields (see Scheme 2 and Table 1).
Bromomethyllithium was generated by reaction of di-
bromomethane with methyllithium. The isolation of the
pure ketones 5 required only removal of the solvents
(purity > 95%, 300 MHz 1H NMR spectroscopy). The
synthesis of the bromomethyl ketones 5 proceeds via
(11) A related intermediate was isolated by silylation to furnish the
corresponding monosilylketal derivative: Barluenga, J .; Pedregal, B.;
Concello´n, J . M. Tetrahedron Lett. 1993, 31, 4563.
(12) Other Z geometry assignments of a related enolate by NOE
experiments: Goh, J . B.; Lagu, B. R.; Wurster, J .; Liotta, D. C.
Tetrahedron Lett. 1994, 35, 6029.
(9) (a) Rosen, T. In Comprenhensive Organic Synthesis; Trost B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 409-439.
(b) Mukaiyama, T.; Haga, T.; Iwasawa, N. Chem. Lett. 1982, 1601.
(10) Abdel-Magid, A.; Pridgen, L. N.; Eggleston, D. S.; Lantos, I. J .
Am. Chem. Soc. 1986, 108, 4595.

5050 J . Org. Chem., Vol. 64, No. 14, 1999
Barluenga et al.
Sch em e 4
Sch em e 5
the enolate obtained by Liotta is the presence of a
bromine atom instead of a methyl group. Taking into
consideration that litium and potassium bromo enolates
6 give the same diastereoselection and according to the
results reported by Liotta, we propose open transition
state 9b (Scheme 4) to explain the stereochemistry of the
epoxy ketones 2. In this model, the aldehyde approaches
from the less hindered face of the enolate, explaining the
absolute configuration of a carbon atom bonded to
bromine. The presence of bromine in the enolate would
explain the different absolute configuration of the C-OH
in our adduct compared with the C-OH of Liotta. Thus,
the enolate approaches from the si face of the aldehyde
involving an open transition state model in which the
oxygen of the aldehyde and the bromine of the enolate
are oriented to minimize the dipole moment.16 The two
remaining possibilities, 9c or 9d , are rejected for steric
reasons (9c) or for electrostactic reasons (9d ). The transi-
tion state 9b affords the anti alcoholate 8, which after
epoxidation yields the observed (1R,2S,4S) R,â-epoxy
ketones 2.
To extend the synthetic utility of R,â-epoxy ketones 2,
2a was treated with iodomethyllithium to obtain com-
pound 10a in high yield (75%) and with high diastereo-
selectivity (de ) 95%). The reaction was carried out
without isolating the R,â-epoxy ketone 2a . It is interest-
ing to note that three new stereogenic centers have been
created with high diastereoisomeric excess in a one-pot
reaction starting from the R-bromo ketone 5a . Iodo-
methyllithium was generated by reaction of diiodomethane
and methyllithium. The absolute configuration of 10a
(see Scheme 5) was established by single-crystal X-ray
analysis. As depicted in Scheme 5, the absolute config-
uration of the newly created asymmetric centers was
2S,3S,4S,5R.
The reaction was carried out using aromatic aldehydes
and cyclic ketones. With ketones, higher reaction tem-
peratures and longer reaction times were needed to afford
the Darzens condensation products, because ketones are
less reactive and more sterically hindered.
The diastereoisomeric excesses of R,â-epoxy ketones 2
1
(>95%) were determined by 300 MHz H NMR analysis
of reaction crudes showing the presence of one diastereo-
isomer exclusively. The degree of stereoselectivity was
not affected by the size of the substituents in the bromo
enolate or in the carbonyl compound employed in this
study (see Table 2).
The racemization of N-protected carbonyl compounds
derived from phenylalanine has been carefully docu-
mented.13 Under the described reaction conditions, con-
densation of ketone 5c derived from phenylalanine with
benzaldehyde took place with no detectable racemization.
The enantiomeric purity of product 2c was determinated
by chiral HPLC (Chiracel OD-H) analysis, showing an
enantiomeric excess (ee) >98%. A racemic mixture of 2c
was prepared, from the corresponding racemic R-amino
acid, to exclude the possibility of coelution of both
enantiomers by HPLC.
The relative trans configuration in the oxirane ring
(Scheme 3) of R,â-epoxy ketones 2 was assigned on the
basis of the value of 1H NMR coupling constants between
the oxirane protons (J trans) 1.7 Hz; average literature
values14 for J trans < 3.1 Hz). The absolute configuration
of 2c (see Scheme 3) was established by single-crystal
X-ray analysis. As depicted in Scheme 3, the absolute
configuration of the newly created asymmetric centers
was 1R,2S,4S. The configuration of the other the epoxy
ketones 2 was assigned by analogy.
This stereochemistry is different from that previously
reported for Liotta et al. for the aldol reactions of the
sodium or lithium enolates of R-(N,N-dibenzylamino)alkyl
ethyl ketones with aldehydes, in which E-enolates pro-
vide adducts with syn stereochemistry of the newly
generated stereocenters.15 On the basis of the sodium
tendency to form ionic associations with oxygen, rather
than two point chelates, Liotta et al. have proposed an
open transition state to explain the stereochemistry
observed, in which the two oxygen atoms are oriented in
opposite directions for electrostactic reasons (9a in
Scheme 4). The only difference between enolate 6 and
In conclusion, we have demonstrated the synthetic
utility of the reaction of chiral R′-amino bromomethyl
ketones with carbonyl compounds affording enantiomeri-
cally pure R′-amino R,â-epoxy ketones with high yield and
diastereoselectivity. This method is simple, the starting
ketones 5 are readily available, and two new stereogenic
centers are created. R,â-Epoxy ketone 2a was trans-
formed into the diepoxide 10a with high yield and
diastereoselectivity.
Exp er im en ta l Section
Gen er a l. Analytical TLC was conducted in precoated silica
gel 60 F-254 on aluminum sheets; compounds were visualized
with UV light or iodine. 1H NMR spectra were recorded at 300
or 200 MHz. 13C NMR spectra were recorded at 75 or 50 MHz.
(13) Rittle, K. E.; Homnick, C. F.; Ponciello, G. S.; Evans, B. E. J .
Org. Chem. 1982, 47, 3016.
(14) Pretsch, E.; Clerc, T.; Seibl, J .; Simon, W. In Tabellen zur
Strukturaufkla¨rung Organisher Verbindungen mit Spektroskopischen
Methoden; Springer-Verlag: Berlin, 1976.
(15) (a) Lagu, B. R.; Crane, H. M.; Liotta, D. C. J . Org. Chem. 1993,
58, 4191. (b) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35, 4485.
(c) Goh, J . B.; Lagu, B. R.; Wurster, J .; Liotta, D. C. Tetrahedron Lett.
1994, 35, 6029.
(16) The transition structures corresponding to the addition of
bromoenolate 6 (derived from N,N-dimethylalanine) to the si and re
faces of the benzaldehyde were located using a model of the actual
compounds and located using the AM1 Hamiltonian as implemented
in the program GAUSSIAN 94, Revision D. 2: M. J . Frisch et al.,
Gaussian, Inc., Pittsbourgh, PA, 1995. According with these results,
the si transition structure 9b leading to the only experimentally found
anti alcoholate 8 is 1.3 kcal mol-1 more stable than the alternative re
transition structure, leading to the syn isomer.

Synthesis of Enantiopure R′-Amino R,â-Epoxy Ketones
J . Org. Chem., Vol. 64, No. 14, 1999 5051
Chemical shifts are reported in ppm relative to TMS in CDCl3.
Only the molecular ions and/or base peaks in MS are given.
The enantiomeric purity was determined by chiral HPLC
analysis using a Chiracel OD-H (0.46 × 25 cm, Diacel) column.
Dibromomethane, methyllithium, KHMDS, LiHMDS, benz-
aldehyde, cyclohexanone, and cyclopentanone were purchased
from Aldrich and were used without further purification. All
the reactions were conducted in oven-dried glassware under
dry nitrogen. All solvents were purified before use. THF was
distilled from sodium benzophenone ketyl; methanol was
distilled from magnesium turnings.
Gen er a l P r oced u r e for t h e Syn t h esis of r′-Am in o
Br om om eth yl Keton es 5. To a -78 °C stirred solution of
the corresponding protected R-amino ester 3 (10 mmol) and
dibromomethane (1.25 mL; 18 mmol) in dry THF (40 mL) was
added methyllithium (12 mL of 1.5 M solution in diethyl ether;
18 mmol) dropwise over 5 min. After stirring at -78 °C for 30
min, the mixture was treated with a saturated aqueous
solution of NH4Cl (5 mL) and extracted with diethyl ether. The
combined organic layers were dried (Na2SO4), filtered, and
concentrated in vacuo. The crude ketones 5 were used without
further purification.
128.3, 128.6, 128.7, 129.0, 135.6, 138.4, 204.7; IR (KBr) 1724,
3030, 3063 cm-1; MS (EI) m/z 280 (M+ - C7H7, 5); 106 (75), 91
(100); HMRS calcd for C18H18NO2 (M+ - C7H7) 280.1337, found
280.1339. Anal. Calcd for C25H25NO2: C, 80.83; H, 6.78; N,
3.77. Found: C, 80.70; H, 6.70; N, 3.69.
(1R,2S,4S)-4-Diben zylam in o-1,2-epoxy-6-m eth yl-1-ph en -
ylh ep ta n -3-on e (2b) (80% yield): Rf 0.60 (10:1 hexane-ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J ) 6.0 Hz,
3H), 0.99 (d, J ) 6.0 Hz, 3H), 1.42-1.50 (m, 1 H), 1.55-1.60
(m, 1 H), 1.89-1.98 (m, 1 H), 3.45 (d, J ) 13.3 Hz, 2H), 3.58
(dd, J ) 2.8, 9.7 Hz, 1H), 3.65 (d, J ) 13.3 Hz, 2H), 3.76 (d, J
) 1.7 Hz, 1H), 3.98 (d, J ) 1.7 Hz, 1H), 7.18-7.54 (m, 15 H);
13C NMR (75 MHz, CDCl3) δ 22.0, 23.5, 25.5, 30.2, 54.2, 59.3,
62.0, 63.2, 126.0, 127.2, 128.2, 128.5, 128.8, 129.9, 135.6, 138.7,
203.2; IR (KBr) 1724, 3030, 3063 cm-1; MS (EI) m/z 412 (M+
- 1), 356 (M+ - C7H7, 5), 226 (100). Anal. Calcd for C28H31
-
NO2: C, 81.32; H, 7.55; N, 3.38. Found: C, 81.10; H, 7.60; N,
3.39.
(1R,2S,4S)-4-Dib en zyla m in o-1,2-ep oxy-1,5-d ip h en yl-
p en ta n -3-on e (2c) (87% yield): mp 106-109 °C; Rf 0.58 (10:1
hexane-ethyl acetate); [R]25 ) -97.1° (c 0.68, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 3.01 (dd, J ) 3.5, 13.4 Hz, 1H), 3.28
(dd, J ) 9.2, 13.4 Hz, 1H), 3.55-3.62 (m, 3H), 3.74-3.87 (m,
4H), 7.17-7.49 (m, 20 H); 13C NMR (75 MHz, CDCl3) δ 28.6,
54.3, 59.1, 62.1, 66.8, 126.0, 126.1, 127.3, 128.3, 128.4, 128.5,
128.8, 129.0, 120.5, 135.4, 138.4, 138.8, 202.5; IR (KBr) 1724,
3030, cm-1; MS (EI) m/z 356 (M+ - C7H7, 5), 300 (70), 91 (100);
HMRS calcd for C24H22NO2 (M+ - C7H7) 356.1650, found
356.1650. Chiral HPLC analysis ee > 99% (Chiracel OD-H,
UV detector 206 nm, 0.8 mL/min, 50:1 hexane/ethanol, tR 12.3
min).
(S)-3-(Diben zyla m in o)-1-br om obu ta n -2-on e (5a ) (86%
yield): Rf 0.46 (10:1 hexane-ethyl acetate); [R]25 ) -98.1°
D
(c 0.96, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.27 (d, J ) 6.7
Hz, 3 H), 3.48 (d, J ) 6.7 Hz, 2 H), 3.66-3.78 (m, 3 H), 4.19
(d, J ) 13.2 Hz, 1 H), 4.27 (d, J ) 13.2 Hz, 1 H), 7.28-7.40
(m, 10 H); 13C NMR (75 MHz, CDCl3) δ 6.6, 33.8, 54.6, 60.4,
127.4, 128.5, 128.7, 138.4, 202.8; IR (KBr) 1734 cm-1; MS (EI)
m/z 347 (M+ + 2, <1), 345 (M+, <1), 224 (M+ - C2H2BrO, 98),
91 (100). Anal. Calcd for C18H20BrNO: C, 62.44; H, 5.82; N,
4.04. Found: C, 62.35; H, 5.78; N, 4.01.
(2S,2′S)-2-(Diben zyla m in o)-1-(1-oxa sp ir o[2,4]h ep ta n -2-
yl)p r op a n -1-on e (2d ) (70% yield): Rf 0.42 (10:1 hexane-ethyl
acetate); [R]25D ) -120.8° (c 0.39, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.44-2.22 (m, 8 H), 3.00 (dd, J ) 3.5, 13.5 Hz, 1 H),
3.25 (dd, J ) 9.1, 13.5 Hz, 1 H), 3.30-3.68 (m, 3 H), 3.80-
3.87 (m, 3 H), 7.18-7.41 (m, 15 H); 13C NMR (75 MHz, CDCl3)
δ 24.8, 24.9, 28.7, 28.9, 33.9, 54.6, 62.7, 67.1, 72.5, 126.0, 127.4,
128.3, 128.4, 128.6, 129.6, 138.6, 139.0, 204.7; IR (KBr) 1721,
3027 cm-1. Anal. Calcd for C29H31NO2: C, 81.85; H, 7.34; N,
3.29. Found: C, 81.60; H, 7.40; N, 3.33.
(2S,2′S)-2-(Diben zyla m in o)-1-(1-oxa sp ir o[2,5]octa n -2-
yl)p r op a n -1-on e (2e) (68% yield): Rf 0.37 (10:1 hexane-ethyl
acetate); [R]25D ) -114.9° (c 0.47, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.23-2.03 (m and d, J ) 6.7 Hz, 13 H), 3.48 (d, J )
14.0 Hz, 2 H), 3.63-3.76 (m, 4 H), 7.28-7.49 (m, 10 H); 13C
NMR (75 MHz, CDCl3) δ 6.1, 24.2, 24.4, 25.3, 27.2, 35.2, 54.5,
61.8, 64.9, 66.7, 127.3, 128.3, 128.4, 138.6, 206.3; IR (KBr)
1721, 3027 cm-1; MS (EI) m/z 363 (M+, 7), 348 (M+ - CH3,
64), 224 (100); HMRS calcd for C24H29NO2 363.2200, found
363.2198.
(S)-3-(Diben zyla m in o)-1-br om o-5-m eth ylh exa n -2-on e
(5b) (83% yield): Rf 0.24 (10:1 hexane-ethyl acetate); [R]25
D
) -106.0° (c 1.17, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.84
(d, J ) 6.0 Hz, 3 H), 0.92 (d, J ) 6.0 Hz, 3 H), 1.41-1.55 (m,
2 H), 1.77-1.91 (m, 1 H), 3.41-3.61 (m, 3 H), 3.73 (d, J )
13.6 Hz, 2 H), 4.07 (s, 2 H), 7.27-7.37 (m, 10 H); 13C NMR (75
MHz, CDCl3) δ 21.9, 23.2, 25.2, 30.8, 33.5, 54.2, 61.7, 127.1,
128.2, 128.7, 138.6, 200.7; IR (KBr) 1721 cm-1; MS (EI), m/z
389 (M+ + 2, 1), 387 (M+, 1), 266 (M+ - C2H2BrO, 90), 91 (100).
(S)-3-(Dib en zyla m in o)-1-b r om o-4-p h en ylb u t a n -2-on e
(5c) (83% yield): Rf 0.36 (10:1 hexane-ethyl acetate); [R]25
)
D
-105.4° (c 1.19, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.08
(dd, J ) 3.9, 13.5 Hz, 1 H), 3.32 (dd, J ) 9.6, 13.5 Hz, 1 H),
3.66 (d, J ) 13.5 Hz, 2 H), 3.84-3.97 (m, 4 H), 4.25 (d, J )
13.5 Hz, 1 H), 7.25-7.46 (m, 15 H); 13C NMR δ 28.5, 34.2, 54.4,
66.2, 126.0, 127.3, 128.3, 128.7, 128.9, 129.3, 138.3, 138.4,
199.8; IR (KBr) 1732 cm-1; MS (EI), m/z 332 (M+ + 2 - C7H7,
10), 330 (M+ - C7H7, 10), 300 (100), 91(98). Anal. Calcd for
C
24H24BrNO: C, 68.25; H, 5.72; N, 3.31. Found: C, 68.18; H,
5.75; N, 3.27.
Syn th esis of (S)-(Z)-N,N-Diben zyl-3-tr im eth ylsilyloxy-
4-br om obu t-3-en -2-a m in e (7a ). To a -100 °C stirred solution
of the coresponding R-bromo ketone 4 (2 mmol) in dry THF
(40 mL) was added potasium hexamethyldisilazide (2.6 mL of
a 1 M solution in toluene, 2.6 mmol). After the mixture was
stirred for 1 h, trimethylchlorosilane (2.4 mmol) was added
and the reaction mixture was stirred for another 30 min at
this temperature. The solvents were removed at a reduced
inert gas pressure, obtaining pure compound 7a in 87% yield:
1H NMR (300 MHz, CDCl3) δ 0.33 (s, 9 H), 1.31 (d, J ) 7.0
Hz, 3 H), 3.38 (q, J ) 7.0 Hz, 1 H), 3.65 (d, J ) 14.2 Hz, 2 H),
3.81 (d, J ) 14.2 Hz, 2 H), 5.48 (s, 1 H), 7.28-7.46 (m, 10 H);
13C NMR (75 MHz, CDCl3) δ 1.0, 14.5, 53.8, 57.0, 86.4, 126.7,
128.1, 128.2, 140.1, 154.5. Anal. Calcd for C21H28BrNOSi: C,
60.28; H, 6.74; N, 3.35. Found: C, 60.01; H, 6.70; N, 3.39.
Syn th esis of (2S,3S,4S,5R) N,N-Diben zyl-4,5-ep oxy-3,3-
(ep oxym eth a n e)-5-p h en ylp en ta n -2-a m in e 10a . To a -100
°C stirred solution of 5a (0.51 g, 1.5 mmol) in dry THF (30
mL) was added potasium hexamethyldisilazide (1.95 mL of a
0.5 M solution in toluene, 1.95 mmol). After the mixture was
stirred for 1 h, benzaldehyde (0.15 mL, 1.5 mmol) was added
and the reaction mixture was stirred for another 30 min at
this temperature. Diiodomethane (0.22 mL, 3 mmol) was
added, and then methyllithium (2 mL of a 1.5 M solution in
Gen er a l P r oced u r e for th e Syn th esis of r′-Am in o r,â-
Ep oxy Keton es 2. To a -100 °C stirred solution of the
coresponding R-bromo ketone 4 (2 mmol) in dry THF (40 mL)
was added potassium hexamethyldisilazide (2.6 mL of a 1 M
solution in toluene, 2.6 mmol). After the mixture was stirred
for 1 h, the aldehyde or ketone (2 mmol) was added and the
reaction mixture was stirred for another 30 min at this
temperature. When the cabonyl compound was a ketone, the
reaction was allowed to warm to room temperature overnight.
The mixture was quenched with a satured aqueous solution
of NH4Cl (5 mL) and extracted with diethyl ether. The
combined organic layers were dried (Na2SO4), filtered, and
concentrated in vacuo. The amino epoxy ketones 2 were
examined by 1H NMR to give the diastereomeric excess
reported in Table 2. Flash column chromatography over silica
gel (20:1 hexane-ethyl acetate) provided pure compounds 2.
(1R,2S,4S)-4-Diben zylam in o-1,2-epoxy-1-ph en ylpen tan -
3-on e (2a ) (85% yield): Rf 0.52 (10:1 hexane-ethyl acetate);
[R]25 ) -61.8° (c 0.50, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
1.27 (d, J ) 6.7 Hz, 3H), 3.41 (d, J ) 13.5 Hz, 2H), 3.64 (d, J
) 13.5 Hz, 2H), 3.69 (q, J ) 6.7 Hz, 1H), 3.91 (d, J ) 1.7 Hz,
1H), 3.97 (d, J ) 1.7 Hz, 1H), 7.16-7.48 (m, 15 H); 13C NMR
(75 MHz, CDCl3) δ 5.7, 54.4, 59.4, 61.4, 61.6, 126.1, 127.3,

5052 J . Org. Chem., Vol. 64, No. 14, 1999
Barluenga et al.
diethyl ether, 3 mmol) was added dropwise at -78 °C. After
stirring at -78 °C for 30 min, the mixture was hydrolyzed with
a saturated aqueous solution of NH4Cl (5 mL) and extracted
with diethyl ether. The combined organic layers were dried
(Na2SO4), filtered, and concentrated in vacuo. The diepoxide
10a was examined by 1H NMR to give the diastereomeric
excess reported in Table 2. Flash column chromatography over
silica gel provided pure compound 10a in 75% yield: mp 97-
Ack n ow led gm en t. The authors are grateful to Dr.
P. Bernad (Servicio de Espectrometr´ıa de Masas, Uni-
versidad de Oviedo) for spectroscopic mass determina-
tion, to Dr. F. J . Gonza´lez for theorical calculations of
the transition structures, and to Dr. A. Dominey for his
time. This research was supported by DGICYT (Granst
PB92-1005 and PB93-0330). B. Baragan˜a thanks II Plan
Regional de Investigacio´n del Principado de Asturias for
a predoctoral fellowship.
99 °C; Rf 0.37 (10:1 hexane-ethyl acetate); [R]25 ) -24.9° (c
D
1
0.65, CHCl3); H NMR (300 MHz, CDCl3) δ 1.02 (d, J ) 6.9
Hz, 3 H), 2.51 (d, J ) 5.2 Hz, 1 H), 2.74 (d, J ) 5.2 Hz, 1 H),
3.30-3.39 (m, 4 H), 3.86 (d, J ) 1.7 Hz, 1 H), 3.91 (d, J ) 13.7
Hz, 2 H), 7.13-7.50 (m, 15 H); 13C NMR (75 MHz, CDCl3) δ
5.0, 45.9, 52.8, 54.2, 56.7, 59.1, 61.4, 126.6, 126.8, 128.1, 128.3,
128.4, 128.6, 136.8, 139.5; IR (KBr) 3007, 3028 cm-1; MS (EI)
m/z 385 (M+, <1), 224 (M+ - C10H9O2, 100); HMRS calcd for
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagrams
of 2c and 10a , X-ray crystallographic data, atomic coordinates,
bond lengths and angles, and torsional angles for structures
2c and 10a , and copies of the 13C NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
26H27NO2 385.2042, found 385.2038. Anal. Calcd for C26H27-
NO2: C, 81.01; H, 7.06; N, 3.63. Found: C, 80.90; H, 7.10; N,
3.66.
J O982435Z