Totally selective ring-opening of amino epoxides with ketones: A general entry to enantiopure (2R,3S)- and (2S,3S)-3-aminoalkano-1,2-diols

Article abstract of DOI:10.1021/ol047785o

(Chemical Equation Presented) Transformation of enantiopure diastereoisomers (2R,1′S)- and (2S,1′S)-2-(1-aminoalkyl)epoxides into the corresponding 4-(1-aminoalkyl)-1,3-dioxolanes is achieved by reaction with different ketones in the presence of BF_3<

Full text of DOI:10.1021/ol047785o

ORGANIC
LETTERS
2005
Vol. 7, No. 2
247-250
Totally Selective Ring-Opening of Amino
Epoxides with Ketones: A General
Entry to Enantiopure (2R,3S)- and
(2S,3S)-3-Aminoalkano-1,2-diols
Jose´ M. Concello´n,*,† Jose´ Ramo´n Sua´rez,† Santiago Garc´ıa-Granda,‡ and
M. Rosario D´ıaz‡
Departamento de Qu´ımica Orga´nica e Inorga´nica and Departamento de Qu´ımica
F´ısica y Anal´ıtica, Facultad de Qu´ımica, UniVersidad de OViedo, Julia´n ClaVer´ıa,
8, 33071 OViedo, Spain
jmcg@fq.unioVi.es
Received October 28, 2004
ABSTRACT
Transformation of enantiopure diastereoisomers (2R,1
dioxolanes is achieved by reaction with different ketones in the presence of BF3
′
S)- and (2S,1
′
S)-2-(1-aminoalkyl)epoxides into the corresponding 4-(1-aminoalkyl)-1,3-
Et2O. The conversion takes place in very high yields, total
‚
selectivity, and without epimerization. A mechanism to explain this transformation is proposed. The obtained 1,3-dioxolanes can be deprotected,
and (2R,3S)- and (2S,3S)-3-aminoalkano-1,2-diols were isolated.
The direct transformation of epoxides into 1,3-dioxolanes
has been previously reported using several Lewis acid
catalysts such as BF3‚OEt2,1 SnCl4,2 SnCl2,3 and TiCl44 and
other catalysts.5 However, in some of these methodologies,
poor selectivity or yields were obtained. In addition, the
synthesis of 1,3-dioxolanes derived from other acyclic
ketones different from propanone was unsuccessful,1,3 and
only one paper describing the reaction of an optically pure
epoxide with propanone without racemization has been
described.6 Given these facts, a general methodology to
transform enantiopure epoxides into 1,3-dioxolanes without
racemization and by using different acyclic ketones would
be desirable.
In addition, the enantiopure 3-aminoalkano-1,2-diols ob-
tained by deprotection of the synthesized 4-(1-aminoalkyl)-
1,3-dioxolanes are important building blocks.
(5) (a) Iranpoor, N.; Zeynizadeh, B. J. Chem. Res., Synop. 1998, 466-
467. (b) Habibi, M.; Tangestaninejad, S.; Mirkhani, V.; Yadollahi, B. Catal.
Lett. 1975, 3-4, 205-207. (c) Adams, R.; Bernard, T.; Brosius, K. J.
Organomet. Chem. 1999, 582, 358-361. (d) Iranpoor, N.; Kazemi, F. Synth.
Commun. 1998, 28, 3189-3193. (e) Busci, I.; Meleg, A.; Molna´r, A.;
Barto´k, M. J. Mol. Catal. 2001, 168, 47-52. (f) Mohammadpoor-Baltork,
I.; Khosropour, A.; Aliyan, H. Synth. Commun. 2001, 31, 3411-3416. (g)
Firouzabadi, H.; Iranpoor, N.; Shaterian, H. Bull. Chem. Soc. Jpn. 2002,
75, 2195-2205. (h) Tangestaninejad, S.; Habibi, M.; Mirkhani, V.;
Moghadam, M. J. Chem. Res., Synop. 2001, 365-367. (i) Zhu, Z.; Espenson,
J. Organometallics 1997, 16, 3658-3663.
† Departamento de Qu´ımica Orga´nica e Inorga´nica.
‡ Departamento de Qu´ımica F´ısica y Anal´ıtica.
(1) Torok, D.; Figueroa, J.; Scott, W. J. Org. Chem. 1993, 58, 7274-
7276.
(2) Bogert, M.; Roblin, R. J. Am. Chem. Soc. 1933, 55, 3741-3745.
(3) Vyan, J. R.; Meyer, J. A.; Meyer, K. D. J. Org. Chem. 2003, 68,
9144-9147.
(4) Nagata, T.; Takai, T.; Yamada, T.; Imagawa, K.; Mukaiyama, T.
Bull. Chem. Soc. Jpn. 1994, 67, 2614-2616.
(6) Colvin, E. W.; Robertson, A. D.; Wakharkar, S. J. Chem. Soc., Chem.
Commun. 1983, 312-314.
10.1021/ol047785o CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/24/2004

Previously, we have also described an efficient synthesis
of enantiopure (2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl)ep-
oxides, by total stereoselective reduction of the easily
available R-amino-R′-chloroketones7 with LiAlH4 or by
highly stereoselective addition of in situ generated iodo-
methyllithium (from diiodomethane and methyllithium) to
R-aminoaldehydes, respectively.8
Building on these results, we now report the conversion
of both enantiopure diastereoisomers (2R,1′S)- and (2S,1′S)-
2-(1-aminoalkyl)epoxides into the corresponding 4-(1-ami-
noalkyl)-1,3-dioxolanes without epimerization, by reaction
with different ketones in the presence of BF3‚OEt2. The
obtained 1,3-dioxolanes were deprotected, and enantiopure
(2R,3S)- and (2S,3S)-3-aminoalkano-1,2-diols were isolated
in high yield with total or high diastereoselectivity.
The selectivity of the reaction was determined by 1H NMR
spectroscopy (300 MHz) of the crude mixture of products,
showing the presence of a single diastereoisomer. After
analyses of NMR data we have concluded that the reaction
takes place with total regioselectivity and without epimer-
ization, in contrast to other previously described methods.
The structure of compounds 2 and, consequently, the
absolute configuration was established by single-crystal
X-ray analysis of 2d.10
To investigate the scope of this reaction, we have subjected
the other diastereoisomers, (2S,1′S)-2-(1-aminoalkyl)epoxides
3, to the same reaction conditions (ketones and BF3‚Et2O, 0
°C, 1 h). In all cases, the corresponding (4S,1′S)-4-(1-
Initial attempts involved the reaction of (2R,1′S)-2-(1-
aminoalkyl)epoxides with propanone, in the presence of BF3‚
Et2O at 0 °C, for 1 h, with propanone also being used as the
solvent. Hydrolysis of the reaction mixture gave enantiopure
(4R,1′S)-4-(1-aminoalkyl)-2,2-dimethyl-1,3-dioxacyclopen-
Scheme 2. Synthesis of 1,3-Dioxolanes 4
Scheme 1. Synthesis of 1,3-Dioxolanes 2
aminoalkyl)-1,3-dioxolanes 4 (Scheme 2 and Table 2) were
obtained in high or excellent yields (> 83%).
Table 2. Synthesis of 1,3-Dioxolanes 4
entry
4
R1
R2
de (%)a
yield(%)b
1
2
3
4
5
6
7
4a
4b
4c
4d
4d
4e
4f
Me
i-Bu
i-Bu
Bn
Bn
Bn
Me
Et
(CH2)5
Me
Me
>98
91
91
95
83
85
91
86
84
83
tanes 2 in very high yields (>89%) as the sole product
(Scheme 1, Table 1).
92
80c
92d
>98d
Et
(CH2)4
Table 1. Synthesis of 1,3-Dioxolanes 2
Bn
entry
2
R1
R2
yield(%)a
a Diastereoisomeric excess determinated by 1H NMR analysis of the crude
products. b Isolated yield after column chromatography based on the starting
amino epoxide 3. c The epoxide was prepared from LiCH2Cl (de ) 80%);
see ref 7. d Diastereoisomeric excess determinated by GC-MS analysis of
pure products.
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Me
Me
Me
i-Bu
i-Bu
Bn
Me
Et
(CH2)4
Me
(CH2)5
Me
90
86
92
89
87
92
The synthesis of dioxolanes 4 with the same diastereo-
isomeric excess (de) as the starting amino epoxides 311 was
a Isolated yield after column chromatography based on the starting amino
epoxide 1.
(9) Representative Experimental Procedure. To a stirred solution of
the corresponding amino epoxide 1 or 3 (0.2 mmol) in CH2Cl2 (1 mL, or
propanone when this ketone was used), BF3‚OEt2 (0.025 mL, 0.2 mmol)
and the corresponding ketone (0.22 mmol) were added at 0 °C. After 1 h
of stirring, an aqueous saturated solution of sodium bicarbonate (5 mL)
was added, and the mixture was stirred at room temperature for 5 min.
Then, the aqueous phase was extracted with CH2Cl2 (3 × 5 mL), and the
combined organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. Flash column chromatography on silica gel (hexane/
EtOAc 20:1) provided pure compounds 2 and 4.
(10) CCDC-252205 (2d) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via www.ccdc-
.cam.ac.uk/conts/retrieving.html (or the Cambridge Data Centre, 12 Union
Road, Cambridge CB21EZ, UK; fax (+44)1223-336.033; or deposit@
ccdc.cam.ac.uk).
Attempts to obtain 1,3-dioxolanes derived from other
ketones (cyclohexanone, cyclopentanone, pentan-3-one) were
also successful, in contrast to previous results.3 In these cases,
the reaction were carried out with 1.1 equiv of ketone,
CH2Cl2 was used as solvent at 0 °C for 1 h, and no important
differences were observed, giving the corresponding 1,3-
dioxolanes 2 in very high isolated yields.9
(7) Barluenga, J.; Baragan˜a, B.; A. Alonso, Concello´n, J. M. J. Chem.
Soc., Chem. Commun. 1994, 969-970.
(8) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1995,
60, 6696-6699.
(11) (1′S,4S)-2-(1-aminoalkyl)epoxides 3 were obtained with a dia-
stereoselection ranging from 91% to >98%; see ref 7.
248
Org. Lett., Vol. 7, No. 2, 2005

an indirect support of the total selectivity of the ring-opening
reaction. The de was determined by 1H NMR (300 MHz) of
the crude mixture of products or by GC-MS of pure
compound.
As is shown in Tables 1 and 2, transformation of amino
epoxides 1 and 3 into 1,3-dioxolanes 2 and 4 seems to be
general. Therefore, the reaction was performed with both
diastereisomers of amino epoxides derived from alanine,
leucine, and phenylalanine7 and several ketones (linear and
cyclic). Furthermore, in contrast to previous results,3 it is
noteworthy that the reaction of aminoepoxides with ketones
can be carried out without epimerization and by using ketones
other than propanone.
would react with the aziridinium intermediate 7 (mechanism
B) to afford the same final compound 2.
When the reaction was carried out with unsymmetrical
ketones, a mixture of diastereoisomers (approximately 1:1)
was obtained. Interestingly, the two obtained diastereoiso-
mers could be separated by conventional column chroma-
tography. The stereochemistry of both diastereoisomers was
unambiguosly assigned by NOESY experiments.
Scheme 4. Reaction with No Symmetrical Ketone
This transformation and the observed stereochemistry of
the products 2 and 4 may be explained by assuming the
selective complexation of the epoxide oxygen with the Lewis
acid, followed by nucleophilic C-3 opening of the epoxide
by the carbonyl oxygen of ketone through a SN2-like
mechanism (mechanism A, Scheme 3) and finally dioxolane
The 1,3-dioxolanes 2 and 4 can be easily deprotected by
acid treatment to provide enantiopure (2R,3S)- or (2S,3S)-
3-aminoalkano-1,2-diols 9 or 10 in very high yield. Hence,
the treatment of aminoepoxides 1 and 3 with ketones and
subsequent deprotection allows access to the same two
diastereoisomers, which could be obtained by a hypothetical
hydroxymethylenation of R-aminoaldehydes following both
nonchelation and chelation control mechanism.
Scheme 3. Proposed Mechanism
Scheme 5. Deprotection of 1,3-Dioxolanes
In conclusion we have described an efficient transforma-
tion of (2R,1′S)- and (2S,1′S)-2-(1-aminoalkyl)epoxides into
the corresponding 4-(1-aminoalkyl)-1,3-dioxolanes by reac-
tion with different ketones in the presence of BF3‚OEt2. The
reaction takes place with very high yield (82-95%) and
without epimerization. The obtained 1,3-dioxolanes were
deprotected and enantiopure (2R,3S)- or (2S,3S)-3-amino-
alkano-1,2-diols were isolated in very high yield with total
or very high stereoselectivity.
ring formation. Alternatively, after coordination of the
oxirane oxygen to the BF3, an intramolecular ring opening
at C-2 by the dibenzylamino group, with inversion of
configuration, would afford the aziridinium salt 7. Ketones
Acknowledgment. We thank Ministerio de Ciencia y
Tecnolog´ıa (BQU2001-3807) for financial support and J. S.
Org. Lett., Vol. 7, No. 2, 2005
249

Hartman for his revision of the English. J.M.C. thanks
Carmen Ferna´ndez-Flo´rez for her assistance.
of 2, 4, 9, and 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: General methods;
spectroscopic data of 2, 4, 9, and 10; and 13C NMR spectra
OL047785O
250
Org. Lett., Vol. 7, No. 2, 2005