Diastereoselective allylstannane additions to (S)-5,6-dihydro-2H-5- phenyloxazin-2-one. A concise synthesis of (S)-β-methylisoleucine

Article abstract of DOI:10.1021/ol1001126

Chemical Equation Presented The addition of allyl stannanes to (S)-4,5-dihydro-5-phenyl-2H-oxazinone (3) was achieved under Bronsted acid catalysis to give 2-allylmorpholinones with high diastereoselectivity (up to dr 14.2:1). The product of dimethylallyltributylstannane addition to 3 was converted to L-β-methylisoleucine, an α-amino acid residue found In the complex, biologically active marine-derived peptides polytheonamides A and B, and polydiscamides A-C.

Full text of DOI:10.1021/ol1001126

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1256-1259
Diastereoselective Allylstannane
Additions to
(S)-5,6-Dihydro-2H-5-phenyloxazin-2-one.
A Concise Synthesis of
(S)-ꢀ-Methylisoleucine
Julie A. Pigza§,‡ and Tadeusz F. Molinski*,§,†
Department of Chemistry and Biochemistry, and Skaggs School of Pharmacy and
Pharmaceutical Sciences, UniVersity of California San Diego, 9500 Gilman DriVe
MC0358, La Jolla, California 92093
tmolinski@ucsd.edu
Received January 15, 2010
ABSTRACT
The addition of allyl stannanes to (S)-4,5-dihydro-5-phenyl-2H-oxazinone (3) was achieved under Brønsted acid catalysis to give
2-allylmorpholinones with high diastereoselectivity (up to dr 14.2:1). The product of dimethylallyltributylstannane addition to 3 was converted
to L-ꢀ-methylisoleucine, an r-amino acid residue found in the complex, biologically active marine-derived peptides polytheonamides A and B,
and polydiscamides A-C.
Marine peptides often contain highly modified amino acids,
including chlorinated amino acids,1 ꢀ-amino acids,2 and
highly substituted ꢀ,ꢀ-dimethyl-R-amino acids.3 L-tert-Leu-
cine (1a) and L-tert-amylglycine (ꢀ-methylisoleucine, 1b)
occur in the 48-mers polytheonamides A and B (two highly
cytotoxic ꢀ-helix, membrane-pore forming peptides from the
marine sponge, Theonella swinhoei).4 The peptides polydis-
camide A from Discodermia5a (2, Figure 1) and the
polydiscamides B-C from the sponge Ircinia,5b which
are the first nonendogenous inhibitors of sensory neuron-
specific G-protein coupled receptors (SNSRs), also contain
1a and 1b.6 The amino acid γ-hydroxy-tert-leucine (L-
pantonine, 1c) was proposed as an intermediate in the
biosynthesis of pantoic acid.7 With an eye to the synthesis
of highly biologically active, cyclic peptides, we sought
to fulfill a need for a general synthesis of highly
ꢀ-branched R-amino acids.
§ Department of Chemistry and Biochemistry.
† Skaggs School of Pharmacy and Pharmaceutical Sciences.
‡ Present address: Queensborough Community College 222-05 56th
Avenue, Bayside, NY 11364.
(1) Jime´nez, J. I.; Vansach, T.; Yoshida, W. Y.; Sakamoto, B.; Po¨rzgen,
P.; Horgen, F. D. J. Nat. Prod. 2009, 72, 1573.
(5) (a) Gulavita, N. K.; Gunasekera, S. P.; Pomponi, S. A.; Robinson,
E. V. J. Org. Chem. 1992, 57, 1767. (b) Feng, Y.; Carroll, A. R.; Pass,
D. M.; Archbold, J. K.; Avery, V. M.; Quinn, R. J. J. Nat. Prod. 2008, 71,
8.
(2) (a) Zabriskie, T. M.; Klocke, J. A.; Ireland, C. M.; Marcus, A. H.;
Molinski, T. F.; Faulkner, D. J.; Xu, C.; Clardy, J. J. Am. Chem. Soc. 1986,
108, 3123. (b) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett.
1986, 27, 2797.
(6) Curiously, the first identification of naturally occurring 1b was from
an extraterrestrial source: the Murchison meteorite, a carbonaceous chon-
drite. Cronin, J. R.; Pizzarello, S. Geochim. Cosmochim. Acta 1986, 50,
2419.
(3) Coleman, J. E.; Desilva, E. D.; Kong, F. M.; Andersen, R. J.; Allen,
T. M. Tetrahedron 1995, 51, 10653.
(4) Hamada, T.; Matsunaga, S.; Yano, G.; Fusetani, N. J. Am. Chem.
Soc. 2005, 127, 110.
(7) Ackermann, W. W.; Kirby, H. J. Biol. Chem. 1948, 175, 483.
10.1021/ol1001126  2010 American Chemical Society
Published on Web 02/17/2010

transformation: formal preparation of amino acids by oxida-
tive insertion of NH2 to the R-carbon of a carboxylic acid
of either configuration by choice of an appropriate chiral
auxiliary,13 R- or S-phenylglycinol, obtained readily from
the corresponding commercially available phenylglycines.
The highly electrophilic 3-unsubstituted oxazinone 314 is
particularly attractive as a chiral glycine equivalent that can
add a variety of carbon-centered nucleophiles at the CdN
bond to give morpholinone amino acid precursors; however,
the diastereoselectivity and yield of these additions can be
variable. For example, addition of MeMgBr or t-BuMgBr
to 3 in the presence of BF3·Et2O gave one detectable
diastereomer in poor yield (34% and 33%, respectively).15
We now describe the synthesis of 3-allylmorpholinones by
highly diastereoselective allyl stannane additions to 3
promoted by Brønsted acid to give 4, and subsequent
conversion to ꢀ-methylisoleucine (1b).
Figure 1. Structures of L-tert-leucine (1a), L-ꢀ-methylisoleucine
(tert-amylglycine, 1b), pantonine (1c), and polydiscamide A (2), a
marine-derived peptide containing ꢀ,ꢀ-dimethyl-substituted R-amino
acids.
Oxazoline (ii, R ) H, Figure 2) was prepared in two steps
from S-phenylglycinol16,17 in 80% yield.10,18 The original
procedure for SeO2-promoted rearrangement of the oxazoline
to (S)-oxazinone 310 required refluxing 1,4-dioxane for 2 h.
Instead, short exposure of the substrate (∼1 mmol scale) to
SeO2 in a microwave reactor (10 min, 300 W, 110 °C),
adapted from Snider’s procedure for SeO2-promoted allylic
oxidations,19 improved the yield of 3 (74%) and reduced
byproducts.
Racemic syntheses of tert-alkyl-R-amino acids have been
reported.8 Asymmetric preparation of L-1a and L-1b was
achieved by tandem-enzyme coupled reductive amination of
the corresponding R-ketoacids.9 However, this biotechnology
is not amenable to preparation of the D-antipode due to the
enantiospecificity of the enzymes. In this report, we dem-
onstrate a concise asymmetric synthesis of L-1b that exploits
an efficient allylstannane addition to highly electrophilic 2H-
oxazinone, 3, a chiral glycine equivalent, and is amenable
to preparation of D-1 or other highly branched amino acids.
SeO2-promoted oxidative rearrangement of 2-substituted
oxazolines ii (Figure 2) to 5,6-dihydro-2H-1,4-oxazin-2-ones
As reported earlier,20 BF3·Et2O-promoted additions of
allyltrimethylsilane, methallyltrimethylsilane, and dimethyl-
allyltrimethylsilane to (S)-3 (entries 1-3, Table 1) gave only
modest diastereoselectivity and/or low yields of 4. The
diastereoselectivity of BF3·Et2O-promoted allyltrimethylsilane
addition to 3 was 8:1 to give 4a (entry 1, 73% yield), but
with the more hindered nucleophiles, dimethylallyltrimeth-
ylsilane and methallyltrimethylsilane, the diastereoselectivity
diminished to 5:1 (entry 2, 25% yield) and 2:1 (entry 3, 60%),
respectively.21 Addition of allyltributylstannane in the pres-
(12) (a) Pigza, J. A.; Quach, T.; Molinski, T. F. J. Org. Chem. 2009,
74, 5510. (b) Liu, C.; Masuno, M. N.; MacMillan, J. B.; Molinski, T. F.
Angew. Chem., Int. Ed. 2004, 43, 5951.
(13) (a) Harwood, L. M.; Macro, J.; Watkin, D.; Williams, C. E.; Wong,
L. F. Tetrahedron: Asymmetry 1992, 3, 1127. (b) Ager, D.; Cooper, N.;
Cox, G. G.; Garro-Helion, F.; Harwood, L. M. Tetrahedron: Asymmetry
1996, 7, 2563.
(14) The 5,6-diphenylmorpholinone 3a has been used both as a
nucleophilic glycine equivalent and precursor for in situ prepartion of the
electrophilic 3b. (a) Williams, R. M. Aldrichim. Acta 1992, 25, 11. (b)
Williams, R. M.; Hendrix, J. A. Chem. ReV. 1992, 92, 889, and references
cited therein. (c) Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. J. Am.
Chem. Soc. 1988, 110, 1547. 3b and 3c have been converted to arylglycines
by Mannich reaction with arenes. (d) Tohma, S.; Rikimaru, K.; Endo, A.;
Shimamoto, K.; Kan, T.; Fukuyama, T. Synthesis 2004, 909. (e) Chen, Y.-
J.; Lei, F.; Liu, L.; Wang, D. Tetrahedron 2003, 59, 7609. 3b,c were made
in 5-6 steps from phenylglycine, and 3a from benzoin.
Figure 2. Oxazoline-oxazinone oxidative rearrangement.
(e.g., 3, hereafter, referred to as ‘oxazinones’),10 followed
by hydrogenation-hydrogenolysis,11 allows convenient access
to a wide variety of R-amino acids, iii.12 Thus, the conversion
of carboxylic acid i to iii constitutes a highly useful
(15) Harwood, L. M.; Tyler, S. N. G.; Anslow, A. S.; MacGilp, I. D.;
Drew, M. G. B. Tetrahedron: Asymmetry 1997, 8, 4007.
(16) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schraum, M. J. Org.
Chem. 1993, 58, 3568
.
(8) (a) Barker, J.; Cook, S. L.; Lasterra-Sanches, E.; Thomas, S. E.
J. Chem. Soc., Chem. Commun. 1992, 830. (b) Bretschneider, T.; Miltz,
W.; Munster, P.; Steglich, W. Tetrahedron 1988, 44, 5403.
(9) Krix, G.; Bommarius, A. S.; Drauz, K.; Kottenhahn, M.; Schwarm,
M.; Kula, M.-R. J. Biotechnol. 1997, 53, 29.
(17) Hsiao, Y.; Hegedus, L. S. J. Org. Chem. 1997, 62, 3586.
(18) Gorunova, O. N.; Keuseman, K. J.; Goebel, B. M.; Kataeva, N. A.;
Churakov, A. V.; Kuz’mina, L. G.; Dunina, V. V.; Smoliakova, I. P. J.
Organomet. Chem. 2004, 689, 2382
.
(19) Zou, Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B.
Org. Lett. 2007, 9, 1825.
(10) (a) Shafer, C. M.; Molinski, T. F. J. Org. Chem. 1996, 61, 2044.
(b) Shafer, C. M.; Morse, D. I.; Molinski, T. F. Tetrahedron 1996, 52,
14475.
(20) Shafer, C. M.; Pigza, J. A.; Molinski, T. F. Lett. Org. Chem. 2009,
6, 224.
(11) Cox, G. G.; Harwood, L. M. Tetrahedron: Asymmetry 1994, 5,
1669.
(21) Diastereomers of 4 were assigned by NOE measurements10,12 and
conversion of 4b to (S)-1b.
Org. Lett., Vol. 12, No. 6, 2010
1257

Table 1. Acid-Promoted Allylsilane and Allylstannane Additions to Oxazinone (S)-3
a Isolated yield after SiO2 column chromatography (yields in parentheses are based on recovered starting material). b dr, from 1H NMR integration.
c Diastereomers not separated. d Unoptimized. e In addition to an unidentified byproduct (see refs 20 and 22). f Major diastereomer separated by crystallization.
g Reference ) this work.
ence of either BF3·Et2O or TFA also gave 4a with low
diastereoselectivities (dr 3.2:1 and 5:1, respectively, entries
5 and 6),22 as did use of methallyltributylstannane23 to give
4c (37%, dr 1.4:1, entry 11). Gratifyingly, addition of
dimethylallyltributylstannane to 3 in the presence of TFA
(-78 °C, CH2Cl2, 1 h, entry 9) gave a dramatic increase in
both the yield and diastereoselectivity for 4b (dr 14.8:1, 80%
yield). The major diastereomer (3S,5S)-4b was purified from
the diastereomeric mixture by selective recrystallization from
Et2O/pentane (dr >20:1 Scheme 1).24 A similar outcome was
observed when the addition was carried out in acetonitrile
at -30 °C (dr 12.5:1, 62% yield, entry 10), but diastereo-
selectivity eroded when the reaction was conducted with TFA
in CH2Cl2 at higher temperatures (-20 °C, dr 6.2:1, 68%
yield, entry 8) or when using BF3·Et2O instead of TFA (-78
°C, dr 7.1:1, 64%, entry 7).
The surprising difference in the outcome of additions of
the two dimethylallyltrialkylsilane (entry 2) and stannanes
(entries 9 and 10) to oxazinone 3 deserves some comment.
The role of the Brønsted or Lewis acid is activation of the
imine to an iminium ion (Figure 3). For electronic reasons,
Scheme 1. Conversion of Morpholinone (3S,5S)-4b to
L-ꢀ-Methylisoleucine 1b
Figure 3.
Possible transition states for the reaction of 3·H+ with
dimethylallylsilane or dimethylallylstannane.
both dimethylallyltrialkylsilane and the corresponding stan-
nane add at their more substituted sp2 olefinic carbon.
Consequently, the higher diastereoselectivity in the formation
of (3S,5S)-4b from the stannane in the presence of TFA may
be due to relaxed steric congestion with the ion pair
1258
Org. Lett., Vol. 12, No. 6, 2010

3·H+ TFA- compared to the corresponding bulkier 3·BF3
complex. Under these conditions, tighter association of the
vinyl bond to the CdN bond is allowed, serving to amplify
differences in energies between top and bottom facial
additions (Figure 3, parts a and b, respectively) in the
respective transition states and favoring approach of the
nucleophilic allyl equivalent from the side opposite the Ph
group.
(3S,5S)-4b (Scheme 1, H2, Pd-C, 96%) to give 5 models a
potential route to the preparation of specifically labeled [2H]-
and [3H]-(S)-1b. Oxidative or reductive modifications of the
terminal vinyl group or olefin metathesis should provide
access to other highly modified natural and non-natural amino
acids, including the γ-methysulfinyl-tert-leucine residue
found in polytheonamide A.4
In summary, the versatility of chiral glycine synthon 3
for R-amino acid synthesis has been extended to highly
diastereoselective additions of dimethylallylstannane and a
concise conversion of the product (3S,5S)-4b to the highly
branched amino acid (-)-ꢀ-methylisoleucine (L-1b). The
configurations of amino acids derived through allylstannane
additions to 3 complement those from hydrogenation of
oxazinones11,12 (Figure 2, 3 R ) alkyl). Consequently,
antipodal amino acids can be obtained in high yield from
oxazinones derived from a common phenylglycinol chiral
auxiliary.
The synthesis of (-)-ꢀ-methylisoleucine (1b) was ac-
complished by conversion of the dimethylallylated mor-
pholinone (3S,5S)-4b as follows (Scheme 1). Hydrogenation
of (3S,5S)-4b under acidic conditions (6 atm, Pd(OH)2,
MeOH, 1 M HCl) followed by exhaustive acid hydrolysis
(refluxing HCl) provided the optically pure amino acid salt
(L-1b·HCl, Scheme 1), which was converted to the free amino
acid by ion-exchange chromatography (elution with 2 M
NH4OH) to neutral L-1b (96% yield, two steps). The optical
rotation of L-1b ([R]22D +12.7 (c 0.48, 1 M HCl), lit.9 +9.9
6,25
1
(c 1 M, 1 M HCl)) and H and 13C NMR data
matched
the literature values. Thus, L-1b was obtained in three steps
from the chiral glycine equivalent (S)-3 in an overall yield
of 58%.
Additions of dimethylallyl anion equivalent to 3 should
find wider applicability in the synthesis of other ꢀ,ꢀ-
dimethyl-substituted amino acids. The versatile vinyl “handle”
in intermediate (3S,5S)-4b may find uses for the preparation
of amino acid derivatives related to 1b. For example,
selective hydrogenation of the terminal vinyl group of
Acknowledgment. We thank Y. Su (UCSD) and R. New
(UC Riverside) for HRMS measurements. The 500 MHz
NMR spectrometers were purchased with a grant from the
NSF (CRIF, CHE0741968). This work was supported by the
NIH (AI-039987).
Note Added after ASAP Publication. Figure 2 contained
errors in the version published ASAP February 17, 2010;
the corrected version posted on the web February 19, 2010.
Supporting Information Available: Experimental pro-
(22) Side-product formation led to diminished yields of the desired
4a.
1
cedures, full spectroscopic data, and H, 13C NMR spectra
(23) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Chem. Lett. 1986, 1857.
(24) Removal of Sn-containing byproducts was conveniently effected
by chromatography over SiO2 impregnated with KF: Harrowven, D. C.;
Guy, I. L. Chem. Commun. 2004, 1968.
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(25) Barker, J.; Cook, S. L. Inorg. Chim. Acta 1994, 220, 137
.
OL1001126
Org. Lett., Vol. 12, No. 6, 2010
1259