Enantio- and diastereoselective synthesis of (R,R)-β-methoxytyrosine

Article abstract of DOI:10.1021/ol071350u

The nonproteinogenic amino acid (2R,3R)-β-methoxytyrosine, a constituent of several cyclic depsipeptide natural products, was synthesized in protected form (8) from a readily available cinnamate ester in four steps and 62% overall yield with a greater tha

Full text of DOI:10.1021/ol071350u

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3511-3513
Enantio- and Diastereoselective
Synthesis of (R,R)-â-Methoxytyrosine
David C. Cranfill and Mark A. Lipton*
Department of Chemistry and Cancer Center, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
lipton@purdue.edu
Received June 7, 2007
ABSTRACT
The nonproteinogenic amino acid (2R,3R)-â-methoxytyrosine, a constituent of several cyclic depsipeptide natural products, was synthesized
in protected form (8) from a readily available cinnamate ester in four steps and 62% overall yield with a greater than 28:1 er and 19:1 dr. This
method provides a highly efficient, enantio- and diastereoselective synthesis of an important amino acid.
The nonproteinogenic amino acid (2R,3R)-â-methoxytyrosine
(1, Figure 1) is found in the cyclic depsipeptide natural
products callipeltin A1 (2) and papuamides A (3) and B2 (4).
All of these related natural products were shown to possess
potent anti-HIV activity and broad spectrum cytotoxicity.1,2
The interesting biological activities and complex struc-
tures of 2-4 have attracted the attention of the synthetic
community, thus requiring an efficient synthesis of 1.
Because the configuration of 1 could not be determined
during the initial structural studies of 2-4, initial synthetic
efforts by our group3 and others4 usually focused on the
production of multiple isomers of â-methoxytyrosine ranging
from moderate to high stereoselectivity. More recently, work
done by our group3 and others4b,5 has conclusively proved
that the configuration of â-methoxytyrosine in 2-4 is
(2R,3R). In light of this information, it was our objective to
develop an efficient, enantio- and diastereoselective synthesis
of 1.
Evans has previously shown that cinnamate esters undergo
asymmetric aziridination with chiral bis(oxazoline)-copper
complexes, which can be followed by diastereoselective ring
opening to form phenylalanine derivatives.6 It was envisaged
that this strategy could be used to synthesize 1 in highly
stereocontrolled fashion.
The synthsesis began (Scheme 1) by aziridination of
p-coumarate TBS ether7 with Cu(OTf)2 and (-)-2,2′-
isopropylidenebis[(4S)-4-phenyl-2-oxazoline] as the catalyst/
ligand system, PhINNs8 (N-(p-nitrophenylsulfonyl)imino-
phenyliodinane) as the nitrene source, and dichloromethane
as the solvent. The reaction is judged to be complete and
filtered to remove the copper as soon as all of the PhINNs
dissolves; allowing the reaction to run longer results in the
formation of side products. The aziridine is then dissolved
(1) Zampella, A.; D’Auria, V.; Paloma, L.; Casapullo, A.; Minale, L.;
Debitus, C.; Henin, Y. J. Am. Chem. Soc. 1996, 118, 6202.
(2) Ford, P.; Gustafson, K.; McKee, T.; Shigematsu, N.; Maurizi, L.;
Pannel, L.; Williams, D.; Silva, E.; Lassota, P.; Allen, T.; Soest, R.;
Andersen, R.; Boyd, M. J. Am. Chem. Soc. 1999, 121, 5899.
(3) Oku, N.; Krishnamoorthy, R.; Benson, A.; Ferguson, R.; Lipton, M.;
Phillips, L.; Gustafson, K. J. Org. Chem. 2005, 70, 6842.
(5) Makino, K.; Nagata, E.; Hamada, Y. Tetrahedron Lett. 2005, 46,
6827.
(4) (a) Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. J. Org. Chem.
2002, 67, 9210. (b) Zampella, A.; D’Orsi, R.; Sepe, V.; Casapullo, A.; Monti,
M.; D’Auria, M. Org. Lett. 2005, 7, 3585. (c) Hansen, D.; Wan, X.; Carroll,
P.; Joullie, M. J. Org. Chem. 2005, 70, 3120. (d) Makino, K.; Hiroki, Y.;
Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784.
(6) Evans, D.; Faul, M.; Bilodeau, M.; Anderson, B.; Barnes, D. J. Am.
Chem. Soc. 1993, 115, 5328.
(7) Oyama, K.; Kondo, T. Org. Lett. 2003, 5, 209.
(8) Fukuyama, T.; Jow, C.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
10.1021/ol071350u CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/03/2007

Figure 1. (2R,3R)-â-Methoxytyrosine (1), callipeltin A (2), and papuamides A (3) and B (4).
in methanol to form 6 in 89% yield with a greater than 19:1
Initially, the aziridine was opened by using catalytic TFA
dr and 28:1 er.9
in MeOH, but the diastereoselectivity of ring opening was
moderate (2:1). This was interpreted as meaning that the
benzylic carbon-nitrogen bond was so weakened by the
electron-rich nature of the phenol that ring opening was
occurring by both SN1 and SN2 mechanisms. In an attempt
to eliminate the SN1 character of the reaction, the aziridine
was subjected to ring opening in methanol that contained
no acid catalyst. Under those circumstances, clean anti
substitution was observed, leading to no loss of diastereo-
selectivity.
Scheme 1
It was also observed that if the copper is not removed by
filtration prior to the addition of MeOH, the dr decreases to
9:1. The probable explanation is that the unremoved copper
acts as a Lewis acid, thereby catalyzing a nondiastereo-
selective, SN1-type ring opening of the aziridine. Our
previous results with protic acids (vide supra) lend support
to that hypothesis.
PhINNs is used as the limiting reagent in the aziridination
reaction with excess alkene present to help ensure consump-
tion of reagent. If the alkene is used as the limiting reagent
the yield decreases to 40% and greater amounts of side
products form. The more commonly used PhINTs (N-(p-
toluenesulfonyl)iminophenyliodinane) was also used as the
nitrene source in the aziridination reaction, but the tosyl
group proved difficult to remove from the sensitive product
later in the synthesis. When acetonitrile was used as the
solvent for the aziridination reaction, the er decreased to 2:1.
It is probable that acetonitrile competes with the bis-
(oxazoline) as a ligand for the copper, leading to aziridination
catalysis by achiral copper complexes when acetonitrile is
used as the solvent.
To complete the synthesis, compound 6 (Scheme 2) was
treated with 4-methoxythiophenol10 and K2CO3 to deprotect
Scheme 2
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Org. Lett., Vol. 9, No. 18, 2007

the nosyl group, affording the free amine 7 in 90% yield,
and was reprotected with an Fmoc to yield 8 in 78% yield.
To confirm the configurational assignment of 8 as (2R,3R),
7 was treated with TBAF (Scheme 3) to deprotect the TBS
published spectra of the (2S,3S) and not the (2S,3R) dia-
stereomer. The specific rotation of the (2S,3S) diastereomer
was reported as +42.0 (c 0.80, MeOH)4b and the value for
10 was found to be -77.0 (c 0.41, MeOH), confirming the
absolute configuration of 10 as (2R,3R).
In summary, we have reported an enantio- and diastereo-
selective synthesis of a protected form of (2R,3R)-â-
methoxytyrosine. We believe that this method will prove
amenable to the large-scale synthesis of the protected form
of (2R,3R)-â-methoxytyrosine for our studies and others’.
A protected version of the amino acid (8) suitable for use in
solid-phase synthesis was synthesized in four steps and 62%
overall yield with a greater than 19:1 dr and 28:1 er.
Scheme 3
Acknowledgment. We thank the National Institutes of
Health (AI-50888) for support of this work. D.C.C. thanks
the Purdue Research Foundation for a graduate fellowship.
group, yielding 10 in 68% yield. The (2S,3R) and (2S,3S)
diastereomers of 10 have been previously reported in the
literature,4b and the NMR spectra of 10 agree with the
Supporting Information Available: Full experimental
details and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(9) Enantiomeric ratio was determined by using Mosher’s method and
examining the 19F NMR spectrum of 9.
(10) Narayan, R.; VanNieuwenhze, M. Org. Lett. 2005, 7, 2655.
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