Preparation and synthetic applications of enantiopure (2S,3S)- or (2R,3S)-2-halomethyl-1,2-epoxyalkan-3-amines

Article abstract of DOI:10.1021/jo9823590

Enantiomerically pure (2S,3S)-3 and its diastereoisomer (2R,3S)-2- halomethy-1-1,2-epoxyalkan-3-amine 4 have been obtained from 1-aminoalkyl halomethyl ketones 1 and (iodomethyl)lithium or (chloromethyl)lithium, respectively. Some synthetic applications of compounds 3 are described: chiral unsaturated 1,3-aminoalcohols 8 or 2-(halomethylidene)-3- (dibenzylamino)-alkan-1-ol 11 is obtained from 3 by halogeno-lithium or by hydrogen-lithium exchange, respectively. Transformation of 8c into its methyl ester derivative 9c is also reported.

Full text of DOI:10.1021/jo9823590

J . Org. Chem. 1999, 64, 2843-2846
2843
P r ep a r a tion a n d Syn th etic Ap p lica tion s of En a n tiop u r e (2S,3S)- or
(2R,3S)-2-Ha lom eth yl-1,2-ep oxya lk a n -3-a m in 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
Received December 1, 1998
Enantiomerically pure (2S,3S)-3 and its diastereoisomer (2R,3S)-2-halomethyl-1,2-epoxyalkan-3-
amine 4 have been obtained from 1-aminoalkyl halomethyl ketones 1 and (iodomethyl)lithium or
(chloromethyl)lithium, respectively. Some synthetic applications of compounds 3 are described:
chiral unsaturated 1,3-aminoalcohols 8 or 2-(halomethylidene)-3-(dibenzylamino)-alkan-1-ol 11 is
obtained from 3 by halogeno-lithium or by hydrogen-lithium exchange, respectively. Transforma-
tion of 8c into its methyl ester derivative 9c is also reported.
In tr od u ction
Recently, we have reported the direct preparation of
chiral 1-aminoalkyl chloromethyl ketones by reaction of
N,N-dibenzylated R-amino esters with in situ generated
(chloromethyl)lithium.8 We have also investigated the
reduction of these dibenzylamino chloromethyl ketones
and their reaction with organometallic compounds, ob-
taining enantiopure threo amino alkyl epoxides8 and
3-azetidinols,9 respectively. The high diastereoselectivity
of these reactions prompted us to study new applications
of chiral 1-aminoalkyl chloromethyl ketones in the syn-
thesis of enantiomerically pure building blocks. In this
paper, we report the preparation of enantiomerically pure
(2S,3S)-3 and its diastereoisomer (2R,3S)-2-halomethyl-
1,2-epoxyalkan-3-amine 4 in an efficient synthesis start-
ing from 1-aminoalkyl halomethyl ketones 1 and halo-
methyllithium. We also describe some synthetic applica-
tions of compounds 3: chiral unsaturated 1,3-aminoal-
cohols 8 are obtained by halogen-lithium exchange,
while hydrogen-lithium exchange leads to 2-(halometh-
ylidene)-3-(dibenzylamino)-alkan-1-ol 11.
Optically active epoxides with adjacent functional
groups are interesting intermediates for the synthesis of
natural/biologically active compounds.1 In particular,
chiral 1-chloro-2,3-epoxypropane (epichlorohydrin) is a
useful building block in organic synthesis.2 However, to
the best of our knowledge, there is no direct methodology3
for the synthesis of chiral substituted epihalohydrins.
These chiral compounds, such as 2-(1-aminoalkyl)epi-
halohydrins 3 and 4, are attractive starting materials for
further chemical transformations, yielding products of
predetermined stereo- and regiochemistry. For example,
the oxirane ring can be opened by a variety of nucleo-
philes,4 the halogen atom can be metalated5 or displaced
by nucleophiles,6 and the acidic protons of 3 are suscep-
tible to abstraction by bases.7
(1) For general reviews of the reactivity of 2,3-epoxy alcohols, see:
(a) Rossiter, B. E. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1985; Vol. 5, Chapter 7. (b) Hanson, R.
M. Chem. Rev. 1991, 91, 437. For other recent synthetic applications
of 2,3-epoxy alcohols, see: (c) Bonini, C.; Federici, C.; Rossi, L.; Righi,
G. J . Org. Chem. 1995, 60, 4803. For the reactivity of R,â-epoxy
ketones, see: (d) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51,
2596. For synthetic applications of vinyloxiranes, see: (e) Molander,
G. A.; La Belle, B. E.; Hahn, G. J . Org. Chem. 1986, 51, 5259. For the
reactivity of R,â-epoxy silanes, see: (f) Gorzynski, J . Synthesis 1984,
629. For synthetic applications of R-amino epoxides, see: (g) Pegorier,
L.; Petit, Y.; Larcheveˆque, M. J . Chem. Soc., Chem. Commun. 1994,
633. (h) Albeck, A.; Persky, R. Tetrahedron 1994, 50, 6333. (i) Hua, D.
Y.; Miao, S. W.; Chen, J . S.; Iguchi, S. J . Org. Chem. 1991, 56, 4. (j)
Luly, J . R.; Dellaraia, J . F.; Plattner, J . J . Soderquist, J . L. Yi, N. J .
Org. Chem. 1987, 52, 1487. (k) Evans, E. V., Rittle, E. K.; Homnicik,
C. F.; Springer, J . P.; Hirshfield, J .; Veber, D. F. J . Org. Chem. 1985,
50, 4615. (l) Luly, J . R.; Plattner, J . J .; Stein, H.; Yi, N.; Cohen, J .;
Tricario, K.; Dellaria, J . F. Pharmacologist 1985, 27, 260.
(2) (a) Takano, S.; Yanese, M.; Sekiguchi, Y.; Ogasawara, K.
Tetrahedron Lett. 1987, 28, 1783. (b) Chong, J . M. Tetrahedron Lett.
1992, 33, 33. (c) Yadav, J . S.; Deshpande, P. K.; Sharma, G. V. M.
Tetrahedron, 1990, 46, 7033. (c) Polson, G.; Dittmer, D. C. J . Org.
Chem. 1988, 53, 791. (d) Abrate, F.; Bravo, P.; Frigerio, M.; Viani, F.;
Zanda, M. Tetrahedron: Asymmetry 1996, 7, 581.
(3) A multistep synthesis of chiral substituted epihalohydrins has
been described via Sharpless epoxidation, treatment with tosyl chlo-
ride, and further displacement by chloride or bromide: Discordia, R.
P.; Dittmer, D. C. J . Org. Chem. 1990, 55, 1414.
Resu lts a n d Discu ssion
Treatment of 1-aminoalkyl chloro- or bromomethyl
ketones 110 with in situ generated (iodomethyl)lithium
at -78 °C gave the corresponding alcoholate 2. When the
reaction mixture was allowed to warm to room temper-
ature, 2-(1-aminoalkyl)epichloro- or epibromohydrins 3
were obtained, respectively (see Scheme 1). The epoxi-
dation of 2 proceeds with total regioselectivity, based
upon the better leaving group potential of iodine over
both bromine and chloride.11
On the basis of our earlier studies which examined the
nonchelation controlled addition of organometallic com-
(6) J ohnson, F.; Panella, J . P.; Carlson, A. A. J . Org. Chem. 1962,
27, 2241.
(7) Yadav, J . S.; Deshpande, P. P. K.; Sharma, G. V. M. Tetrahedron
1990, 46, 7033.
(8) (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.
(9) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. J . Org. Chem. 1997,
62, 5974.
(10) Barluenga, J .; Baragan˜a, B.; Concello´n, J . M. Unpublished
results.
(4) (a) For general applications of epoxides in organic synthesis,
see: Behrens, C. H.; Sharpless, K. B. Aldrichimica Acta 1993, 16, 67.
For other recent applications of epoxides, see: (b) Gala, D.; Dibene-
detto, D. J . Tetrahedron Lett. 1994, 35, 8299. (c) Chini, M.; Crotti, P.;
Favero, L.; Macchia, F.; Pineschi, M. Tetrahedron Lett. 1994, 35, 433.
(d) Auge´, J .; Leroy, F. Tetrahedron Lett. 1996, 37, 7715.
(11) In the case of bromomethyl ketones, the reaction was slowly
allowed to warm to room temperature overnight to avoid the formation
of a mixture of regioisomers due to the small difference between
bromine and iodide as leaving groups.
(5) Barluenga, J .; Concello´n, J . M.; Llavona, L.; Bernad, P. L.
Tetrahedron 1995, 51, 5573.
10.1021/jo9823590 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/27/1999

2844 J . Org. Chem., Vol. 64, No. 8, 1999
Barluenga et al.
Sch em e 1
Sch em e 3
Ta ble 1. Syn th esis of Ep ih a loh yd r in s 3
product
R
X
yield (%)a
deb
Sch em e 2
3a
3b
3c
3d
3e
Me
i-Bu
Bn
Me
Bn
Cl
Cl
Cl
Br
Br
77
68
72
75
70
>95
<95
>95c
>95
>95
a
b
Isolated yield based on the starting ketone 1. Diastereoiso-
meric excess determined by 300 MHz 1H NMR analysis of the
crude products 3. c ee > 99% HPLC (Chiracel OD-H; UV detector;
0.8 mL/min; 215 nm; 200:1 hexane/2-propanol; tR ) 13.8 min).
Sch em e 4
pounds9 and hydride8 to ketone 1, the stereochemistry
of 3 is believed to be anti. Further precedent for anti
addition to ketone 1 is also based upon the work of Reetz
and co-workers who studied the addition of organome-
tallic compounds to dibenzylated amino aldehydes12 and
the reduction of dibenzylated R-aminoalkanones.13 In
these examples the addition of the nucleophile takes
place in a nonchelation controlled fashion based on steric
constraints imparted by the bulky N,N-dibenzyl protect-
ing group, which prevents competitive chelation control.
Therefore, the energetically more favored transition state
has the larger substituent, dibenzylamine, and also the
electronegative atom (usually O or Cl, but in this instance
N) anti to the attack of the nucleophiles.14 The diaster-
eomeric excess (de) of compounds 3 (>95%) was deter-
mined by 300 MHz 1H NMR analysis of the crude
product.
Ta ble 2. Syn th esis of Allylic Alcoh ols 8 a n d 11
product
starting ketone
R
yield (%)a
8a
8b
8c
8a
8b
8c
11a
11b
1b
1b
1b
1a
1a
1a
1b
1a
Me
i-Bu
Bn
Me
i-Bu
Bn
82
76
70
85
78
75
81
78
Me
Me
Iodomethylation of 1 proceeds with no detectable
racemization. The enantiomeric purity of compound 3c15
was determined by chiral HPLC analysis (Chiracel OD-
H) showing an enantiomeric excess (ee) > 99%. To
exclude the possibility of coelution of both enantiomers,
a racemic mixture of 3c was prepared and analyzed by
HPLC.
A retrosynthetic analysis (Scheme 2) suggested that
the epichlorohydrin 4 could be obtained from bromo-
methyl ketone 1a and (chloromethyl)lithium, assuming
that the formation of 3 or 4 comes from the sequential
addition of two different nucleophiles to the ester function
of 5. Thus both diastereoisomers (2S,3S) (path A) and
(2R,3S) (path B) could be prepared. In fact, treatment of
bromomethyl ketone 1a with (chloromethyl)lithium gave
the corresponding alcoholate 6a (see Scheme 3). When
the reaction mixture was slowly allowed to warm to room
temperature, the epichlorohydrin 4a was isolated in 75%
yield with total diastereoselectivity (de > 98%).
a
Isolated yield based on the starting ketone 1.
To prove the usefulness of enantiopure compounds 3
in organic synthesis, these compounds were transformed
into chiral 2-methylene-3-(dibenzylamino)alkan-1-ols 8
and 2-(halomethylidene)-3-(dibenzylamino)alkan-1-ols 11.
Thus, the metalation of epichlorohydrins 3a -c or epi-
bromohydrins 3d -e (see Table 1) with lithium powder
or tert-butyllithium, respectively, led to enantiopure allyl
aminoalcohols 8 (Scheme 4). The halogen-lithium ex-
change gave â-functionalized organolithium compound 7,
which undergoes a spontaneous â-elimination yielding
compounds 8. Chiral allyl aminoalcohols 8 were prepared
in a one-pot synthesis starting from ketones 1 without
isolating the epihalohydrins 3. Successive treatment of
1 with iodomethyllithium at -78 °C, lithium powder at
-40 °C or tert-butyllithium at -78 °C, and slow warming
to room temperature gave rise to allyl aminoalcohols 8.
Yields and diastereoisomeric excesses are summarized
in Table 2.
(12) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141.
(13) Reetz, M. T.; Lennick, K.; Schmitz, A.; Schmitz, A.; Holdgru¨n,
X. Tetrahedron: Asymmetry 1990, 1, 375.
(14) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
(15) The high tendency of Boc-protected aminoaldehyde derived from
phenylalanine to racemize has been documented: Rittle, K. E.;
Homnick, C. F.; Ponciello, G. S.; Evans, B. E. J . Org. Chem. 1982, 47,
3016.
These unsaturated aminoalcohols 8 are precursors of
R,â-unsaturated aminoesters; therefore, J ones oxidation
of 8c and esterification affords 9c in 70% yield (Scheme
4).
Finally, 2-(halomethylidene)-3-(dibenzylamino)alkan-
1-ols 11 were prepared in a one-pot synthesis starting

Synthesis of 2-Halomethyl-1,2-epoxyalkan-3-amines
J . Org. Chem., Vol. 64, No. 8, 1999 2845
(2S,3S)-N,N-Diben zyl-3-Ch lor om eth yl-3,4-ep oxybu ta n -
2-a m in e (3a ) (77% yield): Rf 0.24 (hexane/ethyl acetate 20:
Sch em e 5
1); [R]20 ) +22.7 (c 0.52, CHCl3); 1H NMR (300 MHz, CDCl3)
D
δ 1.00 (d, J ) 6.9 Hz, 3 H), 2.66-2.70 (m, 2 H), 3.36-3.40 (m,
3 H), 3.47 (q, J ) 6.9 Hz, 1 H), 4.04 (d, J ) 13.8 Hz, 2 H), 4.43
(d, J ) 11.2 Hz, 1 H), 7.29-7.46 (m, 10 H); 13C NMR (75 MHz,
CDCl3) δ 4.6, 45.7, 47.2, 50.2, 54.2, 60.8, 126.8, 128.1, 128.7,
139.3; IR (NaCl) 3028 cm-1; MS, m/e 317 (M+ + 2, 2), 316 (M+
+ 1, 1), 315 (M+, 6), 224 (M+ - C7H7, 100); HRMS calcd for
from halomethyl ketones 1 (see Scheme 5). Successive
treatment of compounds 1 with (iodomethyl)lithium to
obtain the epihalohydrins 3, lithium diisopropylamide
(LDA) at -78 °C, and slow warming to room temperature
affords vinyl halides 11. As depicted in Scheme 5, the
proposed mechanism involves the initial formation of the
â-functionalized organolithium compound 10 by hydro-
gen-lithium exchange and a further spontaneous â-
elimination to afford the vinyl halide 11. This reaction
took place with total diastereoselectivity; NMR analysis
(300 MHz) of the reaction crude showed the presence of
only one diastereoisomer. The stereochemistry of com-
pounds 11 was determined by NOESY experiments.
Irradiation of the vinyl hydrogen produced positive NOE
in the CHN, methyl hydrogens and benzyl hydrogens,
indicating a cis relative configuration between the halo-
gen and hydroxy group.
In conclusion, the results reported represent a general
method for the preparation of two enantiopure diastere-
oisomers of substituted epihalohydrins with high yield
and diastereoselectivity (de > 98%) from readily available
starting materials. Moreover, we have demonstrated
some synthetic applications of these substituted epi-
halohydrins obtaining 2-methylene-3-(dibenzylamino)-
alkan-1-ols 8 and 2-(halomethylidene)-3-(dibenzylamino)-
alkan-1-ols 11.
C
19H22ClNO 315.1390, found 315.1385. Anal. Calcd for C19H22-
ClNO: C, 73.25; H, 7.02; N, 4.43. Found: C, 73.07; H, 7.08;
N, 4.46.
(2S ,3S )-N ,N -Dib e n zyl-2-ch lor om e t h yl-1,2-e p oxy-5-
m eth ylh exa n -3-a m in e (3b) (68% yield): Rf 0.54 (hexane/
ethyl acetate 10:1); [R]20D ) -0.5 (c 0.77, CHCl3); 1H NMR (300
MHz, CDCl3) δ 1.04-1.14 (m, 6 H), 1.26-1.79 (m, 3 H), 2.71
(dd, J ) 1.1, 4.1 Hz, 1 H), 2.80 (d, J ) 4.1 Hz, 1 H), 3.28-3.52
(m, 4 H), 4.16 (d, J ) 13.6 Hz, 2 H), 4.42 (dd, J ) 1.1, 10.9 Hz,
1 H), 7.37-7.54 (m, 10 H); 13C NMR δ (75 MHz, CDCl3) 22.2,
23.4, 26.3, 30.4, 45.6, 48.8, 53.4, 54.7, 60.4, 126.8, 128.1, 128.9,
139.9; IR (NaCl) 3028 cm-1; MS, m/e 359 (M+ + 2, 1), 358 (M+
+ 1, < 1), 357 (M+, 3), 266 (M+ - C7H7, 100); HRMS calcd for
C
22H28ClNO 357.1859, found 357.1855.
(2S,3S)-N,N-Diben zyl-3-ch lor om eth yl-3,4-epoxy-1-ph en -
ylbu ta n -2-a m in e (3c) (72% yield): Rf 0.50 (hexane/ethyl
acetate 10:1); [R]20D ) -6.8 (c 0.94, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 2.58-2.75 (m, 3 H), 3.21 (dd, J ) 3.4, 15.5 Hz, 1 H),
3.36 (d, J ) 11.0 Hz, 1 H), 3.51 (d, J ) 13.5 Hz, 2 H), 3.82 (dd,
J ) 3.4, 9.6 Hz, 1 H), 4.19 (d, J ) 13.5 Hz, 2 H), 4.40 (d, J )
11.0 Hz, 1 H), 7.18-7.44 (m, 15 H); 13C NMR (75 MHz, CDCl3)
δ 27.1, 46.4, 48.7, 54.7, 55.4, 60.6, 126.0, 127.0, 128.27, 128.32,
128.6, 128.9, 139.4, 140.0; IR (NaCl) 3028 cm-1; MS, m/e 300
(M+ - C7H7, M+ - C3H4ClO, 20), 299 (M+ - C3H5ClO, 20), 91
(100); chiral HPLC analysis ee > 99% (Chiracel OD-H, UV
detector 215 nm, 0.8 mL/min, 200:1 hexane/2-propanol, tR 13.8
min).
(2S,3S)-N,N-Diben zyl-3-br om om eth yl-3,4-ep oxybu ta n -
2-a m in e (3d ) (75% yield): Rf 0.51 (10:1); [R]20 ) +20.8 (c
D
075, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.96 (d, J ) 6.9
Hz, 3 H), 2.59 (d, J ) 4.3 Hz, 1 H), 2.70 (dd, J ) 1.5, 4.3 Hz,
1 H), 3.07 (d, J ) 9.9 Hz, 1 H), 3.34 (d, J ) 13.5 Hz, 2 H), 3.53
(q, J ) 6.9 Hz, 1 H), 4.00 (d, J ) 13.5 Hz, 2 H), 4.36 (d, J )
9.9 Hz, 1 H), 7.26-7.42 (m, 10 H); 13C NMR (75 MHz, CDCl3)
δ 4.6, 45.7, 47.2, 50.2, 54.2, 60.8, 126.8, 128.1, 128.7, 139.3;
IR (KBr) 3028 cm-1; MS, m/e 361 (M+ + 2, 10), 359 (M+, 10),
255 (M+ - C3H4BrO, 100); HRMS calcd for C19H22BrNO
359.0885, found 359.0887. Anal. Calcd for C19H22BrNO: C,
63.34; H, 6.15; N, 3.89. Found: C, 63.19; H, 6.08; N, 3.85.
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 (254 nm) or iodine. 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. MS and HRMS were measured at 70 eV.
Only the most significant IR absorptions and 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.
(2S,3S)-N,N-Diben zyl-3-br om om eth yl-3,4-epoxy-1-ph en -
ylbu ta n -2-a m in e (3e) (70% yield): Rf 0.51 (hexane/ethyl
acetate 10:1); [R]20 ) -19.1 (c 0.68, CHCl3); 1H NMR (200
D
All reagents were purchased from Aldrich or Acros and were
used without further purification. Halogenated ketones 1 were
prepared according to literature procedures.8 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 immediately prior to use.
MHz, CDCl3) δ 2.47 (d, J ) 4 Hz, 1 H), 2.56-2.68 (m, 2 H),
3.04 (d, J ) 9.8 Hz, 1 H), 3.16 (dd, J ) 3.2, 15.7 Hz, 1 H), 3.44
(d, J ) 13.4 Hz, 2 H), 3.81-3.90 (m, 1 H), 4.13 (d, J ) 13.4
Hz, 2 H), 4.29 (dd, J ) 1.8, 9.8 Hz, 1 H), 7.17-7.38 (m, 15 H);
13C NMR (50 MHz, CDCl3) δ 27.0, 35.1, 50.1, 54.8, 54.8, 60.8,
126.1, 127.0, 128.3, 128.5, 128.6, 128.8, 139.5, 140.0; IR (KBr)
3028 cm-1; MS, m/e 300 (M+ - C7H7, M+ - C3H4BrO, 20), 299
(M+ - C3H5ClO, 20), 91 (100). Anal. Calcd for C25H26BrNO:
C, 68.81; H, 6.00; N, 3.21. Found: C, 68.73; H, 5.97; N, 3.25.
Gen er a l P r oced u r e for th e P r ep a r a tion of (2S,3S)-2-
Halom eth yl-1,2-epoxyalkan -3-am in es 3. To a -78 °C stirred
solution of the corresponding ketone 1 (5 mmol) and di-
iodomethane (0.8 mL; 10 mmol) in dry THF (20 mL) was added
methyllithium (7 mL of 1.5 M solution in diethyl ether; 10.5
mmol) dropwise over 5 min. After stirring at -78 °C for 30
min, the mixture was allowed to warm to room temperature
and stirring was continued for 1 h at room temperature. In
the case of bromomethyl ketones, the reaction mixture was
slowly allowed to warm to room temperature overnight. The
solution was quenched with saturated aqueous NH4Cl (5 mL)
and extracted with diethyl ether. The combined organic layers
were dried (Na2SO4), and the solvents were removed in vacuo.
Syn th esis of (2S,3R)-N,N-Diben zyl-3-ch lor om eth yl-3,4-
ep oxybu ta n -2-a m in e (4a ). The procedure described for the
preparation of 3d was employed, but instead of diiodomethane,
chloroiodomethane was used. 4a : 75% yield; Rf 0.42 (hexane/
1
ethyl acetate 10:1); [R]20 ) +16.7 (c 0.90, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 0.98 (d, J ) 6.9 Hz, 3 H), 2.78 (d, J ) 4.3
Hz, 1 H), 2.99 (d, J ) 4.3 Hz, 1 H), 3.46 (d, J ) 13.3 Hz, 2 H),
3.51 (q, J ) 6.9 Hz, 1 H), 3.59 (d, J ) 11.6 Hz, 1 H), 3.82 (d,
J ) 13.3 Hz, 2 H), 4.09 (d, J ) 11.6 Hz, 1 H), 7.23-7.44 (m,
10 H); 13C NMR (75 MHz, CDCl3) δ 4.8, 46.9, 49.2, 50.4, 54.5,
59.3, 127.0, 128.3, 128.7, 139.1; IR (NaCl) 3028 cm-1; MS, m/e
1
The crude substituted epihalohydrins 3 were examined by H
NMR to give the diastereoisomeric excess reported in Table
1. Flash column chromatography on silica gel (20:1 hexane/
ethyl acetate) provided pure 2-(1-aminoalkyl)epihalohydrins
3.
317 (M+ + 2, 14), 316 (M+ + 1, 10), 315 (M+, 42), 224 (M+
-
C7H7, 100); HRMS calcd for C19H22ClNO 315.1390, found
315.1372.

2846 J . Org. Chem., Vol. 64, No. 8, 1999
Barluenga et al.
Gen er a l P r oced u r e for th e Syn th esis of Allylic Am i-
n oa lcoh ols 8. Meth od A. To a -78 °C stirred solution of the
corresponding ketone 1b (5 mmol) and diiodomethane (0.8 mL;
10 mmol) in dry THF (20 mL) was added methyllithium (7
mL of 1.5 M solution in diethyl ether; 10.5 mmol) dropwise
over 5 min. After stirring at -78 °C for 30 min, the mixture
was allowed to warm to room temperature and stirring was
continued for 1 h at room temperature. Then, lithium powder
(0.35 g, 50 mmol) was added at -40 °C and the reaction
mixture was stirred and slowly allowed to warm to room
temperature overnight. The solution was quenched with ice
and extracted with diethyl ether. The combined organic layers
were dried (Na2SO4), and the solvents were removed in vacuo,
yielding crude aminoalcohols 8, which were purified by flash
column chromatography (8:1 hexane/ethyl acetate).
Meth od B. To a -78 °C stirred solution of the corresponding
ketone 1a (5 mmol) and diiodomethane (0.8 mL; 10 mmol) in
dry THF (20 mL) was added methyllithium (7 mL of 1.5 M
solution in diethyl ether; 10.5 mmol) dropwise over 5 min.
After stirring at -78 °C for 30 min, the reaction mixture was
slowly allowed to warm to room temperature overnight. Then,
t-BuLi (6 mL of 1.7 M solution in pentane; 10.2 mmol) was
added at -78 °C, and after stirring at this temperature for 1
h, the reaction mixture was allowed to warm to room temper-
ature. The solution was quenched with H2O (5 mL) and
extracted with diethyl ether. The combined organic layers were
dried (Na2SO4), and the solvents were removed in vacuo,
yielding crude aminoalcohols 8, which were purified by column
flash chromatography (8:1 hexane/ethyl acetate).
with diethyl ether. The combined organic layers were dried
(Na2SO4), and the solvents were removed in vacuo, yielding
the coreesponding crude amino acid.
Diazomethane (10 mL of a solution in ethyl ether, 3 mmol)
was added to a stirred solution of crude amino acid in diethyl
ether (10 mL) at 25 °C, and the mixture was stirred for 15
min. Then the reaction mixture was quenched with acetic acid,
washed with H2O, and extracted with diethyl ether. The
combined organic layers were dried (Na2SO4), and the solvents
were removed in vacuo. Crude amino ester 9c, was purified
by flash column chromatography (15:1 hexane/ethyl acetate)
to provide pure amino ester 9c in 70% yield: Rf 0.57 (hexane/
1
ethyl acetate 10:1); [R]20 ) +17.5 (c 0.62, CHCl3); H NMR
D
(200 MHz, CDCl3) δ 2.95 (dd, J ) 8.6, 14.2 Hz, 1 H), 3.27 (dd,
J ) 6.4, 14.2 Hz, 1 H), 3.58-3.76 (m, 7 H), 4.17-4.22 (m, 1
H), 5.62 (s, 1 H), 6.29 (s, 1 H), 7.10-7.31 (m, 15 H); 13C NMR
(50 MHz, CDCl3) δ 34.0, 51.7, 54.6, 59.0, 125.8, 125.82, 126.6,
127.9, 128.0, 128.6, 129.0, 139.3, 139.4, 139.6, 168.4; IR (KBr)
1720, 1630 cm-1
.
Gen er a l P r oced u r e for th e Syn th esis of Ha logen a ted
Vin ylic Am in o Alcoh ols 11. To a -78 °C stirred solution of
the corresponding ketone 1 (5 mmol) and diiodomethane (0.8
mL; 10 mmol) in dry THF (20 mL) was added methyllithium
(7 mL of 1.5 M solution in diethyl ether; 10.5 mmol) dropwise
over 5 min. After stirring at -78 °C for 30 min, the mixture
was allowed to warm to room temperature and stirring was
continued for 1 h at room temperature. Then, lithium diiso-
propylamide [prepared from MeLi (4 mL of 1.5 M solution in
diethyl ether, 6 mmol) and diisopropylamine (0.84 mL, 6 mmol)
in THF (10 mL)] was added at -78 °C, and the reaction
mixture was stirred and slowly allowed to warm to room
temperature overnight. The solution was quenched with a
saturated aqueous solution of NH4Cl (5 mL) and extracted with
diethyl ether. The combined organic layers were dried (Na2-
SO4), and the solvents were removed in vacuo, yielding crude
halogenated amino alcohols 11, which were purified by flash
column chromatography (15:1 hexane/ethyl acetate).
(S)-3-Diben zylam in e-2-m eth ylyden ebu tan -1-ol (8a) (82%
yield): Rf 0.34 (hexane/ethyl acetate 5:1); [R]20D ) +33.1 (c 0.94,
1
CHCl3); H NMR (300 MHz, CDCl3) δ 1.20 (d, J ) 6.7 Hz, 3
H), 3.30 (d, J ) 13.1 Hz, 2 H), 3.50 (q, J ) 6.7 Hz, 1 H), 3.84
(d, J ) 13.1 Hz, 2 H), 4.09 (d, J ) 12.8 Hz, 1 H), 5.01 (d, J )
12.8 Hz, 1 H), 5.18 (s, 2 H), 7.21-7.33 (m, 10 H); 13C NMR (75
MHz, CDCl3) δ 7.9, 53.2, 54.9, 67.4, 112.4, 127.1, 128.4, 128.9,
138.8, 148.9; IR (NaCl) 3393, 1651 cm-1; MS, m/e 281 (M+, 5),
224 (M+ - C3H5O, 30), 91 (100); HRMS calcd for C19H23NO
281.1780, found 281.1780. Anal. Calcd for C19H23NO: C, 81.10;
H, 8.24; N, 4.98. Found: C, 80.91; H, 8.18; N, 4.94.
(S)-(Z)-3-Diben zyla m in e-2-ch lor om eth ylid en ebu ta n -1-
ol (11a ) (81% yield): Rf 0.30 (hexane/ethyl acetate 10:1); [R]20
D
1
) -1.9 (c 0.79, CHCl3); H NMR (300 MHz, CDCl3) δ 1.28 (d,
(S)-3-Diben zyla m in e-5-m eth yl-2-m eth ylyd en eh exa n -1-
J ) 7.0 Hz, 3 H), 3.38 (d, J ) 13.1 Hz, 2 H), 3.74 (q, J ) 7.0
Hz, 1 H), 3.85 (d, J ) 13.1 Hz, 2 H), 4.30 (d, J ) 14.2 Hz, 1 H),
4.55 (d, J ) 14.2 Hz, 1 H), 4.67 (s, 1 H), 6.01 (s, 1 H), 7.27-
7.41 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 8.0, 53.2, 55.1,
61.6, 115.5, 127.4, 128.5, 128.9, 138.0, 142.1; IR (NaCl) 3410,
1630 cm-1. Anal. Calcd for C19H22ClNO: C, 73.25; H, 7.02; N,
4.43. Found: C, 73.07; H, 7.09; N, 4.46.
ol (8b) (76% yield): Rf 0.46 (hexane/ethyl acetate 5:1); [R]20
D
) +22.1 (c 0.53, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.80 (d,
J ) 6.2 Hz, 3 H), 0.96 (d, J ) 6.2 Hz, 3 H), 1.48-1.72 (m, 3
H), 3.35 (d, J ) 13.3 Hz, 2 H), 3.75 (t, J ) 6.6 Hz, 1H), 3.85 (d,
J ) 13.3 Hz, 2 H), 4.07 (d, J ) 12.5 Hz, 1 H), 4.14 (d, J ) 12.5
Hz, 1 H), 5.01 (s,1 H), 5.32 (s, 1 H), 7.23-7.36 (m, 10 H); 13C
NMR (75 MHz, CDCl3) δ 21.8, 24.1, 25.3, 31.7, 53.1, 58.3, 68.2,
113.2, 127.1, 128.0, 129.1, 139.0, 145.9; IR (NaCl) 3399, 1560
cm-1; MS, m/e 323 (M+, 10), 266 (M+ - C3H5O), 100. Anal.
Calcd for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C,
81.51; H, 9.08; N, 4.31.
(S)-(Z)- 3-Diben zyla m in e-2-br om om eth ylid en ebu ta n -
1-ol (11b) (78% yield): Rf 0.31 (hexane/ethyl acetate 10:1);
[R]20 ) -6.7 (c 0.30, CHCl3); 1H NMR (200 MHz, CDCl3) δ
D
1.29 (d, J ) 6.7 Hz, 3 H), 3.38 (d, J ) 13.2 Hz, 2 H), 3.72 (q,
J ) 6.7 Hz, 1 H), 3.83 (d, J ) 13.2 Hz, 2 H), 4.23 (d, J ) 14.1
Hz, 1 H), 4.48 (d, J ) 14.1 Hz, 1 H), 4.67 (s, 1 H), 6.14 (s, 1 H),
7.27-7.41 (m, 10 H); 13C NMR (50 MHz, CDCl3) δ 8.2, 53.4,
56.1, 64.2, 104.4, 127.5, 128.6, 129.0, 138.0, 145.0; IR (NaCl)
3418, 1620 cm-1. Anal. Calcd for C19H22BrNO: C, 63.34; H,
6.15; N, 3.89. Found: C, 63.22; H, 6.10; N, 3.92.
(S)-3-Diben zyla m in e-2-m et h ylid en e4-p h en ylbu t a n -1-
ol (8c) (70% yield): Rf 0.55 (hexane/ethyl acetate 3:1); [R]20
D
) +36.1 (c 0.76, CHCl3); 1H NMR (300 MHz, CDCl3) δ 3.49
(dd, J ) 10.1, 14.3 Hz, 1 H), 3.34 (dd, J ) 3.7, 14.3 Hz, 1 H),
3.56 (d, J ) 13.3 Hz, 2 H), 3.78 (dd, J ) 3.7, 10.1 Hz, 1 H),
4.03 (d, J ) 13.3 Hz, 2 H), 4.12 (s, 2 H), 5.22 (s, 1 H), 5.38 (s,
1 H), 7.16-7.43 (m, 15 H); 13C NMR (75 MHz, CDCl3) δ 28.9,
53.4, 61.1, 67.4, 114.0, 125.8; 127.1, 128.2, 128.3, 128.8, 129.0,
138.9, 139.6, 145.7; IR (KBr) 3387, 1603 cm-1; MS, m/e 358
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 and to Dr. A. Dominey for his time. This research
was supported by DGICYT (Grant PB92-1005). B.
Baragan˜a thanks II Plan Regional de Investigacio´n del
Principado de Asturias for a predoctoral fellowship.
(M+ + 2, < 1), 357 (M+, < 1), 356 (M+ - 1, < 1), 266 (M+
-
C7H7, 100). Anal. Calcd for C25H27NO: C, 83.99; H, 7.61; N,
3.92. Found: C, 83.81; H, 7.66; N, 3.88.
Syn th esis of Meth yl (S)-3-Diben zyla m in e-4-p h en yl-2-
m eth ylen bu ta n oa te (9c). To a 0 °C stirred solution of 8c
(0.54 g, 1.5 mmol) in acetone (10 mL) was added the J ones
reagent (3.9 mL of 2.6 M solution of CrO3 in H2SO4; 1.5 mmol);
the resulting solution was stirred for 0.5 h, at the same
temperature. The reaction mixture was treated with ethanol
(5 mL), filtered through a pad of Celite, treated with a
saturated aqueous solution of NH4Cl (5 mL), and extracted
Su p p or tin g In for m a tion Ava ila ble: Su p p or tin g In -
for m a tion Ava ila ble: Copies of the 13C NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9823590