Asymmetric catalytic synthesis of enantiopure N-protected 1,2-amino alcohols

Article abstract of DOI:10.1021/ol048322l

(Chemical Equation Presented) The asymmetric aminolytic kinetic resolution (AKR) of racemic terminal epoxides using carbamates as the nucleophile catalyzed by (salen)Co^III complex provides a practical and straightforward method for the synthesis of both aliphatic and aromatic N-Boc- or N-Cbz-protected 1,2-amino alcohols in almost enantiomerically pure form (ee ≥ 99%). The AKR uses an easily accessible catalyst and inexpensive starting materials, and the reactions are conveniently carried out at room temperature under an air atmosphere.

Full text of DOI:10.1021/ol048322l

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3973-3975
Asymmetric Catalytic Synthesis of
Enantiopure N-Protected 1,2-Amino
Alcohols
Giuseppe Bartoli,* Marcella Bosco, Armando Carlone, Manuela Locatelli,
Paolo Melchiorre,* and Letizia Sambri
Department of Organic Chemistry “A. Mangini”,
UniVersity of Bologna V.le Risorgimento 4, 40136 Bologna, Italy
giuseppe.bartoli@unibo.it; pm@ms.fci.unibo.it
Received August 23, 2004
ABSTRACT
The asymmetric aminolytic kinetic resolution (AKR) of racemic terminal epoxides using carbamates as the nucleophile catalyzed by (salen)CoIII
complex provides a practical and straightforward method for the synthesis of both aliphatic and aromatic N-Boc- or N-Cbz-protected 1,2-
amino alcohols in almost enantiomerically pure form (ee
g 99%). The AKR uses an easily accessible catalyst and inexpensive starting materials,
and the reactions are conveniently carried out at room temperature under an air atmosphere.
The biological importance of vicinal amino alcohols con-
tinues to stimulate the development of new effective methods
for the synthesis of these compounds in enantiomerically pure
form.1 Among the catalytic asymmetric methods available,2-4
the ring opening of racemic terminal epoxides catalyzed by
chiral (salen)Cr-Cl complex 1 with TMSN3 followed by
reduction of the azido moiety constitutes an ingenious route
to 1-amino-2-ols.3
An intriguing alternative approach lies in the development
of an enantioselective kinetic resolution based on the use of
carbamates as the nitrogen source. Such a strategy would
constitute a highly practical and useful tool for the direct
preparation of optically active 1,2-amino alcohols bearing
easily removable N-protecting groups. This aim represents
an ambitious challenge from a synthetical standpoint as,
surprisingly, no effective methods to open epoxides with
carbamates have been devised to date.5
We report here the first asymmetric aminolytic kinetic
resolution (AKR) of racemic terminal epoxides using car-
bamates as the nucleophile catalyzed by chiral (salen)CoIII
complexes to afford N-Cbz- or N-Boc-protected 1-amino-
2-ols in almost enantiomerically pure form (ee g 99%,
Scheme 1). The presented AKR shows extraordinary enan-
(1) (a) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (b) Ager, D. J.;
Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835. (c) Kolb, H. C.;
Sharpless, K. B. In Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; p 243.
(2) While chiral 2-amino-1-ols are readily accessible by reduction of
R-amino acids, asymmetric routes to 1,2-amino alcohols with a stereogenic
hydroxy-substituted carbon center are relatively uncommon. For some
leading references, see: (a) Li, G.; Chang, H.-T.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 451. (b) Sasai, H.; Suzuki, T.; Arai, S.;
Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418. (c) Effenberger,
T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1515. (d) Ohkuma, T.; Ishii, D.;
Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510. (e) Adderley,
N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´, D. I. Angew. Chem., Int. Ed.
2003, 42, 4241.
(3) (a) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc.
1996, 118, 7420. Review: (b) Jacobsen, E. N. Acc. Chem. Res. 2000, 33,
421.
(4) For carbamate-based aminohydroxylation of olefins, see: Li, G.;
Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
2813.
(5) During the manuscript preparation, an interesting opening of enan-
tiopure terminal epoxides with N-Boc-2-nitrobenzenesulfonamide was
reported: Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2004, 43,
3952.
10.1021/ol048322l CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/01/2004

Table 1. Kinetic Resolution of Racemic 4 with Carbamatesa
Scheme 1. Carbamate-Based Asymmetric AKR of Racemic
Terminal Epoxides
tioselectivity even at room temperature (s ) selectivity factor
exceeding 3000 for some substrates), using a low loading
(2-5 mol %) of a readily available catalyst, a minimum
amount of solvent under an air atmosphere, and inexpensive,
easily handled starting materials. Noteworthy, and at variance
with analogous kinetic resolution procedures,3 complete
regioselectivity for the terminal position is achieved not only
with aliphatic epoxides but also with aromatic derivatives.
Given the high selectivities obtained in the recently
reported asymmetric aminolysis of trans-aromatic epoxides
with anilines catalyzed by (salen)Cr-Cl complex 1,6 we
sought to extend the use of this catalyst to the carbamate-
based AKR of terminal epoxides. However, reaction of (()-
glycidyl phenyl ether 4 (2.2 equiv) with tert-butyl carbamate
3a (1 equiv) in the presence of complex 1 (0.016 equiv, 1.5
mol % relative to racemic epoxide) in CH2Cl2 led to no
conversion (entry 1, Table 1). Thus, we turned our attention
to the Jacobsen’s (salen)CoIII-OAc complex 2a that had been
demonstrated to be a highly effective and enantioselective
catalyst for the hydrolytic kinetic resolution of racemic
terminal epoxides.7 Use of the acetate complex 2a, prepared
by aerobic oxidation of the catalytically inactive (salen)CoII
complex 2 in the presence of acetic acid, afforded the N-Boc-
protected amino alcohol 5a in moderate yield but in very
high optical purity (96% ee, entry 3). In situ generation of
2a under AKR conditions by suspension of 2 in the solvent
and addition of HOAc under an aerobic atmosphere resulted
in a more reactive system (entry 4).
The identity of the counterion8 for the (salen)CoIII catalyst
and the reaction solvent proved to be crucial in terms of both
reactivity and selectivity: performing the reaction in tert-
butyl methyl ether (TBME) in the presence of complex 2
(1.5 mol %) and p-nitrobenzoic acid (3 mol %) as the
oxidizing additive resulted in 85% conversion of 3a after
20 h and formation of 5a in enantiomerically pure form (entry
7). The optimized procedure (2 mol % of 2, 4 mol % of
additive, entry 8) afforded enantiopure product 5a in 99%
isolated yield based on carbamate after 24 h at room
temperature.9
conv
(%)b
eec
entry
3
cat.
additive
solvent
(%)
sd
1
2
a
a
a
a
a
a
a
a
b
c
d
1
2
2a
2
2
2
2
2
2
2
2
none
none
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
0
3
45
65
80
65
85
96
96
4
AcOH
5
p-nitrobenzoic acid CH2Cl2
p-nitrobenzoic acid THF
p-nitrobenzoic acid TBME
>99
98
6
7
>99
8e
9g
10e
11h
p-nitrobenzoic acid TBME >95 (99)f
p-nitrobenzoic acid TBME
95 (93)f
p-nitrobenzoic acid TBME >95 (97)f
p-nitrobenzoic acid TBME
75 (67)f
98.9 450
99.5 865
99.0 470
99.5 610
a Experimental conditions (1 mmol scale): open-air reactions run in
undistilled solvent (5 M) for 20 h using a 2.2:1 ratio of 4 to 3 and 1.5 mol
% of catalyst relative to racemic epoxide. b Determined by 1H NMR of the
crude mixture and based on consumption of 3. c The ee values were
determined by HPLC on Chiralpak AD-H column. d Selectivity factor; see
ref 10 for details. e 2 mol % of 2, 4 mol % of additive, and 24 h reaction
time. f Number in parentheses indicates yield of isolated product based on
3. g 4 mol % of 2, 8 mol % of additive, and 24 h reaction time. h 4 mol %
of 2, 8 mol % of additive, and 50 h reaction time.
methyl carbamate 3d (entries 9-11). In particular, the
reaction of 3b and 3d proceeds with very high selectivity (s
) selectivity factor ) 865 and 610, respectively)10 although
a slight decrease in reactivity is observed. The extension of
the AKR strategy to various carbamates represents an
important feature from a synthetical standpoint, providing
orthogonal sets of easily removable N-protecting groups.
The asymmetric AKR catalyzed by (salen)CoIII complex
displays extraordinary scope, as a wide range of structurally
and electronically varied terminal epoxides 6 can be opened
with tert-butyl carbamate 3a providing enantiopure N-Boc-
protected 1,2-amino alcohols 7a-i in high yield and complete
regioselectivity for the terminal position; the results are
reported in Table 2.
The AKR of 4 is also effective with different nucleophiles
such as benzyl carbamate 3b, urethane 3c and 9-fluorenyl-
Both linear (entries 1-3) and relatively hindered (entry
4) aliphatic epoxides undergo AKR with extraordinary
selectivity. The presence of coordinating functional groups
does not appear to affect the efficiency of the system, as
(6) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Massaccesi, M.;
Melchiorre, P.; Sambri, L. Org. Lett. 2004, 6, 2173.
(7) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307.
(8) See footnote 24 in ref 7b. See also ref 15.
(10) The selectivity factors s were calculated using the equation s )
ln[1 - c(1 + ee)]/ln[1 - c(1 - ee)], where ee is the enantiomeric excess
of the amino alcohol product and c is the conversion (set to equal the isolated
yield). Given the high selectivity of AKR (s > 400), the absolute magnitudes
of s factors are certainly lacking precision; see the Supporting Information
for details.
(9) Small amounts of 1,2-diol and p-nitrobenzoate addition product were
also generated, presumably as a result of adventitious water and counterion
addition. For the latter path, see: Jacobsen, E. N.; Kakiuchi, F.; Konsler,
R. G.; Larrow, J. F.; Tokunaga, M. Tetrahedron Lett. 1997, 38, 773. The
use of molecular sieves to inhibit diol production had no significant effects.
3974
Org. Lett., Vol. 6, No. 22, 2004

Noteworthy, the AKR of styrene oxide 6g proceeds with
complete regioselectivity for the terminal position, affording
the enantiopure N-Boc-protected aminol in good yield (entry
7). The use of benzyl carbamate 3b results in a lower
reactivity (entry 8), although the high regio- and enantio-
control of the process is preserved. Various substituted
styrene oxide derivatives display similar behavior, generating
only one isomer in enantiomerically pure form (entries 9 and
10). These results add significant importance to the AKR
strategy since aromatic epoxides represent a challenging class
of substrates for kinetic resolutions as conflicting steric and
electronic factors generally affect the regioselectivity in the
ring opening of terminal epoxides.12 Moreover, 1-aryl-2-
amino ethanol isomers, precursors of pharmaceutically sig-
nificant compounds,13 are difficult to achieve by carbamate-
based asymmetric aminohydroxylation of olefins.14
Table 2. AKR of Terminal Epoxides with tert-Butyl
Carbamate 3aa
time yieldc eed
entry xb
R
(h)
(%)
(%)
se
725
630
1700
1
2
3
4
5
6f
7
8g
9
2
2
2
4
4
4
4
5
5
5
CH3, 6a
24
24
24
24
24
24
36
48
48
48
99
99
99
84
95
87
90
52
76
62
99.3
99.2
99.7
99.9 >3000
99.5 900
99.9 >3000
99.9 >3000
99.5
99.8
99.8
(CH2)3CH3, 6b
(CH2)4CHdCH2, 6c
c-C6H11, 6d
CH2O(1-naphthyl), 6e
CH2Cl, 6f
C6H5, 6g
C6H5, 6g
p-BrC6H4, 6h
o-NO2C6H4, 6i
The exceptionally high levels of selectivity observed
in the AKR are consistent with other highly selective
(salen)CoIII-catalyzed kinetic resolutions of terminal epoxides
in which a peculiar, bimolecular, nearly perfect chiral
recognition mechanism is operating.15 A thorough investiga-
tion to elucidate the mechanism of catalysis is underway and
will be reported in due course.
In summary, the presented (salen)CoIII-catalyzed amino-
lytic kinetic resolution of racemic terminal epoxides with
carbamates provides a general and straightforward method
for the synthesis of enantiopure (ee g 99%) N-protected 1,2-
amino alcohols.16 Importantly, the AKR uses easily re-
movable N-protecting groups, an easily accessible catalyst
and inexpensive, easily handled starting materials. The
reactions are conveniently carried out at room tempera-
ture, under an air atmosphere and with a small amount of
catalyst and solvent. All these positive practical features17
render the AKR a potentially useful method for large-scale
applications.
540
1690
1460
10
a Experimental conditions (1 mmol scale): open-air reactions run in
undistilled TBME (5 M) using a 2.2:1 ratio of 6/3a. b Catalyst loading
relative to racemic epoxide. c Yield of isolated product based on 3a. d The
ee values of 7 or of the corresponding O-benzyl derivatives were determined
by HPLC on Chiralpak AD-H or AS-H columns; see the Supporting
Information for details. e Selectivity factor; see ref 10 for details. f Performed
at 0 °C using benzyl carbamate 3b. g Performed using carbamate 3b to afford
N-Cbz-protected amino alcohol 7gb.
both 1-naphthyl glycidyl ether and epichlorohydrin afford
the corresponding 1-amino-2-ols 7e and 7f in good yield and
in enantiomerically pure form (entries 5 and 6).
The viability of the AKR strategy is illustrated by the
practical synthesis of enantiopure (S)-propanolol 8 (Scheme
2, eq 1), a widely used anti-hypertensive drug (â-blocker).11
Scheme 2. Practical Utility of the AKR Strategy
Acknowledgment. This work was carried out in the
framework of the National Project “Stereoselezione in Sintesi
Organica. Metodologie e Applicazioni” supported by MIUR,
Rome, and FIRB National Project “Progettazione, preparazi-
one e valutazione farmacologica di nuove molecole organiche
quali potenziali farmaci innovativi”.
Supporting Information Available: Experimental pro-
cedures, full characterization, and copies of both HPLC
analyses and proton spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL048322L
Moreover, given the versatility of the N-protected aminol
products, a wide range of synthetically useful transformations
can be envisaged. For example, the highly enantioenriched
N-Boc protected aziridine 9 can be easily synthesized in good
yield (78% based on 3a) starting from racemic epoxide 4
using a practical one-pot procedure (Scheme 2, eq 2).
(12) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 6086.
See also ref 3a.
(13) For a recent example, see: Nesterenko, V.; Putt, K. S.; Hergenrother,
P. J. J. Am. Chem. Soc. 2003, 125, 14672.
(14) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207.
See also ref 13.
(15) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 1360. See also ref 12.
(16) Also the unreacted epoxides can be recovered in high ee (>90%).
(17) For practical considerations on kinetic resolution strategy, see: Keith,
J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth., Catal. 2001, 343, 5.
(11) Klunder J. M.; Ko, S. Y.; Sharpless, K. B. J. Org. Chem. 1986, 51,
3710.
Org. Lett., Vol. 6, No. 22, 2004
3975