A practical method for the synthesis of highly enantioenriched trans -1,2-amino alcohols

Article abstract of DOI:10.1021/ol401013s

A highly enantioselective addition of phenyl carbamate to meso-epoxides has been developed to efficiently generate protected trans-1,2-amino alcohols. This transformation is promoted by an oligomeric (salen)Co-OTf catalyst and has been used to prepare two useful 2-aminocycloalkanol hydrochlorides in enantiopure form on a multigram scale from commercially available starting materials.

Full text of DOI:10.1021/ol401013s

ORGANIC
LETTERS
2013
Vol. 15, No. 12
2895–2897
A Practical Method for the Synthesis of Highly
Enantioenriched trans-1,2-Amino Alcohols
James A. Birrell and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
jacobsen@chemistry.harvard.edu
Received April 11, 2013
ABSTRACT
A highly enantioselective addition of phenyl carbamate to meso-epoxides has been developed to efficiently generate protected trans-1,2-amino
alcohols. This transformation is promoted by an oligomeric (salen)CoÀOTf catalyst and has been used to prepare two useful 2-aminocycloalkanol
hydrochlorides in enantiopure form on a multigram scale from commercially available starting materials.
Enantioenriched trans-1,2-amino alcohols are useful
building blocks for the preparation of complex molecules
and chiral catalysts, as well as ligands and auxiliaries for
asymmetric synthesis.1 Catalytic asymmetric approaches
to synthesize this class of compounds have been developed,
but their applicaton on a preparative scale has been
limited.2 A chief concern in known methods is the use of
hydrazoic acid as an ammonia equivalent,2a,b since this
reagent is potentially dangerous and requires special safety
measures. Bartoli has demonstrated that carbamates
can be employed successfully in (salen)Co(III)-catalyzed
kinetic resolutions of terminal epoxides.3 However, there
are no known examples of enantioselective carbamate
additions to meso epoxides, which are intrinsically much
less reactive than terminal epoxides in (salen)Co(III)-
catalyzed reactions.
Bimetallic mechanisms have been established for
(salen)metal-catalyzed nucleophilic ring opening of both
terminal and meso-epoxides,4 and polymer-supported,
dendrimeric, and oligomeric (salen)Co(III) complexes have
been developed to facilitate cooperativity between metal
centers.5 These multimeric complexes have been shown to
(4) (a) Hansen, K. B.;Leighton, J. L.;Jacobsen, E. N.J. Am. Chem. Soc.
1996, 118, 10924–10925. (b) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond,
D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360–1362.
(5) (a) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
4147–4154. (b) Breinbauer, R.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2000, 39, 3604–3607. (c) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc.
2001, 123, 2687–2688. (d) Ready, J. M.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2002, 41, 1374–1377. (e) White, D. E.; Jacobsen, E. N. Tetra-
hedron: Asymmetry 2003, 14, 3633–3638. (f) White, D. E. Ph.D. Thesis,
Harvard University, Cambridge, MA, 2005. (g) Zheng, X.; Jones, C. W.;
Weck, M. J. Am. Chem. Soc. 2007, 129, 1105–1112. (h) Madhavan, N.;
Jones, C. W.; Weck, M. Acc. Chem. Res. 2008, 41, 1153–1165. (i) Thomas,
R. M.; Widger, P. C. B.; Ahmed, S. M.; Jeske, R. C.; Hirahata, W.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2010, 132, 16520–
16525. (j) Haak, R. M.; Wezenberg, S. J.; Kleij, A. W. Chem. Commun.
2010, 46, 2713–2723.
(1) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835–
876. (b) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev.
2000, 100, 2159–2231. (c) Bergmeier, S. C. Tetrahedron 2000, 56, 2561–
2576. (d) Anaya de Parrodi, C.; Juaristi, E. Synlett 2006, 2699–2715.
(2) (a) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768–2769. (b)
Martınez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am.
´
Chem. Soc. 1995, 117, 5897–5898. (c) Schneider, C.; Sreekanth, A. R.;
ꢀ
Mai, E. Angew. Chem., Int. Ed. 2004, 43, 5691–5694. (d) Carree, F.; Gil,
R.; Collin, J. Org. Lett. 2005, 7, 1023–1026. (e) Arai, K.; Salter, M. M.;
Yamashita, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46, 955–957.
(3) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Org. Lett. 2004, 6, 3973–3975. (b) Bartoli, G.; Bosco, M.; Carlone,
A.; Locatelli, M.; Melchiorre, P.; Sambri, L. Org. Lett. 2005, 7, 1983–1985.
r
10.1021/ol401013s
2013 American Chemical Society
Published on Web 06/06/2013

display striking improvements in both rate and selectivity
in relation to their monomeric analogs.6 Herein we report
the use of an oligomeric (salen)CoÀOTf complex5e,f,7 to
catalyze the highly enantioselective addition of phenyl
carbamate to meso-epoxides (Scheme 1). This reaction
enables an efficient, operationally simple, and scaleable
approach to protected trans-1,2-amino alcohols in high
enantiomeric excess from commercially available starting
materials.
Table 1. Catalyst and Reaction Optimization
In preliminary studies, we found that oligomeric
(salen)CoÀOTf complexes provide marked improvements
in reactivity in the kinetic resolution of 1,2-epoxyhexane
with tert-butyl carbamate.5f For example, only 0.2 mol %
of the oligomeric complex 3was needed to effectively catalyze
this reaction, whereas under similar conditions 4.4 mol % of a
related monomeric (salen)Co(III) was required.3a
Scheme 1. Oligomeric (salen)Co(III)-Catalyzed Carbamate
Addition to meso-Epoxides
catalyst
(mol %)
temp
yieldb
(%)
eec
entrya
(°C)
(%)
1
2
3
4
2 (5)
2 (5)
3 (1)
3 (1)
23
50
23
50
3
n.d.
21
33
21
91
97
95
a Reactions run on a 0.5 mmol scale. b Yield determined by 1H NMR
analysis relative to p-xylene as an internal standard. c Enantiomeric
excess determined by GC analysis using commercial chiral columns.
The addition of carbamates to cyclohexene oxide was
selected as a model reaction, and it was found that phenyl
carbamate was particularly effective as a nucleophlic
reacting partner.8,9 Clean addition to cyclohexene oxide
with subsequent intramolecular cyclization was observed
to afford trans-4,5-disubstituted oxazolidinone product 1
(Table 1).10 The cyclization appears to be relatively rapid,
as the initial addition intermediate is not detectable. While
both monomeric and oligomeric (salen)CoÀOTf com-
plexes were found to catalyze this transformation, both
the rate and enantioselectivity were far superior with the
oligomeric catalyst 3 (entry 3). The best balance of rate and
enantioselectivity was achieved in reactions carried out at
50 °C, with oxazolidinone 1 obtained in 91% yield and
95% ee after 24 h (entry 4).
The addition of phenyl carbamate to a variety of meso-
epoxides was evaluated under the optimized reaction con-
ditions (Table 2). Epoxides with unsaturation in the ring
were viable substrates, but underwent reaction with slower
rates than cyclohexene oxide (entries 2À3). Carbamate
addition to five-membered ring epoxide derivatives pro-
ceeded with very high enantioselectivity (entries 4À5). The
products from these reactions did not undergo intramolecu-
lar cyclization, presumably due to the unfavorable strain in
trans-fused 5À5 ring systems.11 Instead, the monomeric
addition product was generated together with carbamate-
bridged oligomers (Scheme 2). However, this mixture could
be subjected to hydrolysis by treatment with base to liberate
the trans-1,2-amino alcohol in high overall yield (see below).
The practical applicability of the carbamate addition
protocol is illustrated in the preparation of trans-2-amino-
cyclohexanol hydrochloride (6) and trans-2-aminocyclo-
pentanol hydrochloride (7) on a multigram scale using
0.5 and 1 mol % of catalyst, respectively (Scheme 3).12,13
(6) For an example in the context of enantioselective intramolecular
openings of oxetanes, see: Loy, R. N.; Jacobsen, E. N. J. Am. Chem. Soc.
2009, 131, 2786–2787.
(7) For applications of this catalyst in total synthesis, see: (a) Chae, J.;
Buchwald, S. L. J. Org. Chem. 2004, 69, 3336–3339. (b) Snider, B. B.;
Zhou, J. Org. Lett. 2006, 8, 1283–1286. (c) Adachi, M.; Zhang, Y.;
Leimkuhler, C.; Sun, B.; LaTour, J. V.; Kahne, D. E. J. Am. Chem.
Soc. 2006, 128, 14012–14013. (d) McGowan, M. A.; Stevenson, C. P.;
Schiffler, M. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 6147–
6150. (e) Rajapaksa, N. S.; McGowan, M. A.; Rienzo, M.; Jacobsen,
E. N. Org. Lett. 2013, 15, 706–709.
(8) Aryl carbamates are uniquely effective nucleophiles in this trans-
formation; tert-butyl carbamate, methyl carbamate, benzyl carbamate,
S-phenyl thiocarbamate, acetamide, trifluoroacetamide, or trichloroa-
cetamide all proved unreactive.
(9) A correlation between reactionrateand the electronics ofa seriesof
substituted aryl carbamates was observed, with electron-deficient carba-
mates proceeding most rapidly. For a comparison of the reaction rates of
electronically substituted carbamates, see the Supporting Information.
(10) For a (salen)Al-catalyzed method for the synthesis of cis-4,5-
disubstituted oxazolidinones from epoxides and isocyanates, see: Bar-
onsky, T.; Beattie, C.; Harrington, R. W.; Irfan, R.; North, M.; Osende,
J. G.; Young, C. ACS Catal. 2013, 3, 790–797.
(11) (a) Chang, S.;McNally, D.;Shary-Tehrany, S.;Hickey, M. J.;Boyd,
R. H. J. Am. Chem. Soc. 1970, 92, 3109–3118. (b) Allinger, N. L.; Tribble,
M. T.; Miller, M. A.; Wertz, D. H. J. Am. Chem. Soc. 1971, 93, 1637–1648.
(12) Compounds 6 and 7 were also prepared on a 10 mmol scale
without a recrystallization step, providing the following results: 6 (1.4 g,
91% yield, 94% ee); 7 (1.2 g, 86% yield, 98% ee). The difference in yields
between the 10 and 100 mmol-scale reactions is a result of the recrys-
tallization procedure.
(13) For classical resolution approaches to these compounds, see: (a)
Schiffers, I.; Rantanen, T.; Schmidt, F.; Bergmans, W.; Zani, L.; Bolm,
C. J. Org. Chem. 2006, 71, 2320–2331. (b) Schiffers, I.; Bolm, C. Org.
Synth. 2008, 85, 106–117. For an alternative method, see: (c) Overman,
L. E.; Sugai, S. J. Org. Chem. 1985, 50, 4154–4155.
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Org. Lett., Vol. 15, No. 12, 2013

Table 2. Substrate Scope
Scheme 2. (salen)Co(III)-Catalyzed Carbamate Addition to
Cyclopentene Oxide
Scheme 3. Preparative-Scale Reactions
Crucial to this development was the use of an oligomeric
(salen)CoÀOTf complex as the catalyst and aryl carba-
mate nucleophiles. This method is amenable to large-scale
synthesis due to the low catalyst loadings and high con-
centration used, its operational simplicity, and the use of
inexpensive, commercially availalable starting materials.
a Reactions run on a 1.0 mmol scale. b Isolated yield of purified
product. c Enantiomeric excess determined by GC or HPLC analysis on
commercial chiral columns.
Acknowledgment. Thisworkwas supportedbythe NIH
(GM-43214).
Following the catalytic reaction, the reaction mixture was
subjected to basic deprotection conditions and the prod-
ucts were recrystallized as the hydrochloride salts in
>99% ee. These amino alcohols are versatile building
blocks for organic synthesis and can readily be trans-
formed into a variety of valuable chiral products.13a,14
In summary, we have developed an efficient protocol for
the catalytic enantioselective synthesis of protected trans-
1,2-amino alcohols in high yield and enantiomeric excess.
Supporting Information Available. Complete experi-
mental procedures and characterization data, 1H and 13
C
NMR spectra, GC and HPLC traces of racemic and
enantioenriched protected trans-1,2-amino alcohol and
2-aminocycloalkanol hydrochloride products, and data
comparing the reaction rates of electronically substituted
carbamates. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) Schaus, S. E.; Larrow, J. F.; Jacobsen, E. N. J. Org. Chem. 1997,
62, 4197–4199.
The authors declare no competing financial interest.
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