amino acid/peptide mixtures11 and to upgrade the optical
purity of borane precursors.4e
In a typical preparative procedure, a slight excess of
commercially available crystalline 9-BBN dimer was dis-
solved in hot methanol and heated to reflux with free amino
acid 4. The suspension became nearly homogeneous over 1
h. Filtration of unreacted amino acid and evaporation of the
methanol, followed by trituration of the gummy residue with
1
hexanes, afforded H NMR pure 3, which was best used
without further purification.16
Scheme 1
Figure 1. Boron complexes of amino acids.
In the course of synthesizing several ornithine-based
natural products,12 we were presented with two challenges.
First, we desired to differentiate between the side chain
functional groups and the amino acid functionality. Second,
we desired to perform nonaqueous reactions despite the fact
that amino acids are only soluble in water. One of the most
difficult cases of functional group differentiation, one might
imagine, would be selecting between the two primary amino
groups of the amino acids lysine and ornithine. Selective
complexation of the R-amine of lysine has been reported in
the literature via copper and diethylboryl complexes.6
However, these complexes were generally soluble in few
organic solvents.13 In particular, the diethylboryl complex
2a of lysine (R ) CH2CH2NH2) can only be made in polar
solvents such as DMF or DMSO (60% yield) and crystallizes
with a mole of adherent solvent.6 We reasoned that in order
to infer greater organic solubility to these complexes, one
could increase the lipophilicity of the substituents attached
to the complexing agent. We settled on 9-borabicyclononane
(9-BBN) owing to its high degree of lipophilicity and its
commercial availability.14 While such complexes have previ-
ously been prepared, the advantages of this particular
substituent for boron have not been utilized to its full
extent.5,6,15
This protecting group could be removed without epimer-
ization of the amino acid under extremely mild conditions,
either by exchange with ethylenediamine (heat to reflux for
30 s in methanol, followed by trituration with diethyl ether
to remove excess ethylenediamine and the 9-BBN complex)
or dilute methanolic HCl.6 Examination of several other
functionalized amino acids revealed that the favorable soluble
properties and good yields for preparation and cleavage of
the complexes was general (Tables 1 and 2).
Table 1. Formation and Cleavage of 9-BBN Complexes
formation cleavage cleavage
entry
R
% yielda
Ab
Bc
3a
3b
(CH2)4NH2 lysine
(CH2)3NH3Cl
90
96
78
75
91
94
ornithine HCl
3c
3d
3e
3f
C6H5OH tyrosine
CH2OH serine
CH2SH cysteine
CH2CO2H aspartic acid
(CH2)3NHC (dNH)NH2
arginine
92
86
50
98
70
89
62
75
80
78
94
d
83
76
62
3g
(11) Strang, C. J.; Henson, E.; Okamoto, Y.; Paz, M. A.; Gallop, P. M.
Anal. Biochem. 1989, 178, 276.
a See Supporting Information for specific details. b Aqueous HCl cleav-
age. c Ethylenediamine cleavage. d Oiled out as a complex mixture of
borylated products that were difficult to purify.
(12) (a) 9-BBN-Protected Amino Acids and Their Use in Natural Product
Synthesis. Fields, S. C.; Graupner, P. L.; Tromiczak, E. G. Oral presentation
at the Gulf Coast Chemistry Conference, September 19, 1996, Pensacola,
FL. (b) Pyridazocidin: A NoVel Quaternary Amine Phytotoxin. Chapin, E.
L.; Cleveland, J. A.; Fields, S. C.; Gerwick, B. C.; Graupner, P. R. Poster
Presentation at the American Chemical Society for Pharacognosy, May 10,
1996. (c) 9-BBN-Protected Amino Acids and Their Use in Natural Product
Synthesis. Part I. Electrophilic Reactions. Total Synthesis of Octicidin. Dent,
W. H.; Fields, S. C.; Graupner, P. R.; Tromiczak, E. G. Poster presentation
at the CU-Roche/Syntex Symposium, May 22, 1996, Boulder, CO. (d)
9-BBN-Protected Amino Acids and Their Use in Natural Product Synthesis.
Part II. Nucleophilic Reactions. Total Synthesis of Pyridazocidin. Fields,
S. C.; Gerwick, B. C.; Graupner, P. R.; Tromiczak, E. G. Poster presentation
at the CU-Roche/Syntex Symposium, May 22, 1996, Boulder, CO.
(13) In fact, we were unable to react lysine with triethylborane in a variety
of solvents. We ultimately obtained this complex by reacting diethylborinic
acid with lysine in aqueous methanol.
In contrast to the aforementioned copper and diethylboryl
complexes with lysine, we found the analogous 9-BBN
derivative to be remarkably soluble in THF, acetone, dioxane,
DMF, methanol, and water, while it was insoluble in diethyl
ether, hexane, and the halocarbons. This prompted us to
(16) If the complexes are further purified to powders rather than using
the initially formed amorphous solids “as is”, they generally require greater
effort (e.g., sonication) to redissolve in organic solvents, but they will
redissolve. This is most likely a result of the micelle-like ordering of the
complexes, which interferes with solvation in solvents of low to medium
polarity.
(14) Aldrich: $4.11/g, available as the crystalline dimer.
(15) Gonzalez, A.; Granell, J.; Piniella, J. F.; Alvarez-Larena, A.
Tetrahedron 1998, 54, 13313.
1250
Org. Lett., Vol. 4, No. 8, 2002