Mitsunobu approach to the synthesis of optically active α,α-disubstituted amino acids

Article abstract of DOI:10.1021/ol802325h

Chiral tertiary α-hydroxy esters of known stereochemical configuration were transformed to α-azido esters by Mitsunobu reaction with HN₃. Optimization of this reaction was shown to proceed at room temperature with high chemical yield using 1,1-(azodicarbonyl)dipiperidine (ADDP) and trimethylphosphine (PMe₃). Complete inversion of configuration was observed at the α-carbon. Several α,α- disubstituted amino acids were synthesized in high overall chemical yield and optical purity.

Full text of DOI:10.1021/ol802325h

ORGANIC
LETTERS
2009
Vol. 11, No. 4
807-810
Mitsunobu Approach to the Synthesis of
Optically Active r,r-Disubstituted
Amino Acids
Jonathan E. Green,†,‡ David M. Bender,† Stona Jackson,† Martin J. O’Donnell,*,‡
and James R. McCarthy*,†
Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285, and Department
of Chemistry and Chemical Biology, Indiana UniVersity Purdue UniVersity
Indianapolis, 402 N. Blackford St., Indianapolis, Indiana 46202
jmccarthy@lilly.com; odonnell@chem.iupui.edu
Received October 31, 2008
ABSTRACT
Chiral tertiary r-hydroxy esters of known stereochemical configuration were transformed to r-azido esters by Mitsunobu reaction with HN3.
Optimization of this reaction was shown to proceed at room temperature with high chemical yield using 1,1-(azodicarbonyl)dipiperidine (ADDP)
and trimethylphosphine (PMe3). Complete inversion of configuration was observed at the r-carbon. Several r,r-disubstituted amino acids
were synthesized in high overall chemical yield and optical purity.
Quaternary R-amino acids have been incorporated as building
blocks into synthetic peptides and in efforts to elucidate and
enhance biological activity. R,R-Disubstituted amino acids
have been shown to affect the conformation, biological
activity, and stability of peptides.1 Despite their importance
in medicinal and biological chemistry, nonproteinogenic
nonracemic amino acids remain challenging synthetic targets.
To date, relatively few examples have been reported in which
the amino group is the last to be introduced at the R-carbon.
These examples include rearrangements,3 reactions with
electrophilic4 or nucleophilic5 nitrogen sources, and reactions
involving chiral aziridines.6 We herein report the use of
hydrazoic acid7 in the Mitsunobu reaction8 to convert chiral
R-hydroxy esters into R,R-disubstituted amino acids. This
new route provides two advantages in that the azide acts
A survey of the chemical literature concerning nonracemic
R,R-disubstituted amino acids reveals a variety of synthetic
methods.2 The strategies employed can be classified accord-
ing to the order of placement of the acid and amino moieties
along with two variable functional groups on the R-carbon.2f
(3) (a) Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem.
2001, 66, 2667–2673. (b) Wu, Z.-L.; Li, Z.-Y. J. Org. Chem. 2003, 68,
2479–2482. (c) Cristau, H.-J.; Marat, X.; Vors, J.-P.; Pirat, J.-L. Tetrahedron
Lett. 2003, 44, 3179–3181.
(4) Smulik, J. A.; Vedejs, E. Org. Lett. 2003, 5, 4187–4190.
(5) For selected examples involving azide, see: (a) Shao, H.; Rueter,
J. K.; Goodman, M. J. Org. Chem. 1998, 63, 5240–5244. (b) Avenoza, A.;
Cativiela, C.; Corzana, F.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M.
Tetrahetron: Asymmetry 2001, 12, 949–957. (c) Mart´ın, R.; Islas, G.;
Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron 2001, 57, 6367–6374.
(d) Pedregal, C.; Prowse, W. Bioorg. Med. Chem. 2002, 10, 433–436. (e)
Sato, K.-i.; Sekiguchi, T.; Hozumi, T.; Yamazaki, T.; Akai, S. Tetrahedron
Lett. 2002, 43, 3087–3090. (f) Masaki, Y.; Arasaki, H.; Iwata, M. Chem.
Lett. 2003, 32, 4–5. (g) Forman, G. S.; Scaffidi, A.; Stick, R. V. Aust.
J. Chem. 2004, 57, 25–28.
† Eli Lilly & Co.
‡ Indiana University Purdue University Indianapolis.
(1) (a) Ripka, W. C.; De Lucca, G. V.; Back, A. C., II; Pottorf, R. S.;
Blaney, J. M. Tetrahedron 1993, 49, 3593–3608. (b) Hruby, V. J. Acc.
Chem. Res. 2001, 34, 389–397. (c) Sagan, S.; Karoyan, P.; Lequin, O.;
Chassaing, G.; Lavielle, S. Current Med. Chem. 2004, 11, 2799–2822.
(2) (a) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Pergamon Press: Oxford, 1989. (b) Cativiela, C.; D´ıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517–3599. (c) Cativiela, C.; D´ıaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645–732. (d) Ohfune,
Y.; Shinada, T. Eur. J. Org. Chem. 2005, 512, 7–5143. (e) Vogt, H.; Bra¨se,
S. Org. Biomol. Chem. 2007, 5, 406–430. (f) D´ıaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2007, 18, 569–623.
(6) McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365.
(7) CAUTION: Hydrazoic acid is toxic and potentially explosive. All
procedures using hydrazoic acid should be performed behind a safety shield
in a well-ventilated hood.
10.1021/ol802325h CCC: $40.75
Published on Web 01/21/2009
2009 American Chemical Society

Scheme 1
.
Synthesis of R-Methylphenylalanine from
Scheme 2
.
Limitations of the Reaction of NaN3 with Chiral
R-Mesylate Ester Using NaN3 in DMF
Tertiary R-Mesylate Esters
effectively as a masking group eliminating the need for
nitrogen protection and readily available chiral starting
materials are utilized.
In the course of studying the reactivity of tertiary leaving
groups, we discovered that mesylate (R)-1a reacted smoothly
with excess NaN3 at room temperature to give azide (S)-2a
with complete inversion of stereochemical configuration
(Scheme 1). Azide reduction and ester hydrolysis gave (S)-
R-methylphenylalanine [(S)-3a] in high overall yield. These
results were intriguing in light of the fact that SN2 displace-
ments at tertiary centers are rare.5 However, the scope of
this strategy was found to be limited. Mesylate (R)-1b
decomposed rapidly at room temperature, which required that
it be reacted immediately with NaN3 in DMF to give
moderate yields of azide (S)-2b (Scheme 2). Simultaneous
hydrogenolysis of the benzyl ester and azide reduction gave
(S)-R-methylphenylglycine [(S)-3b] in 36% ee, indicating
either significant epimerization during formation of the
mesylate or an increase in SN1 character of the azide
displacement. Mesylate (R)-1c was also found to be unstable,
having a propensity to eliminate to the corresponding R,ꢀ-
unsaturated derivatives E- and Z-4 under the reaction
conditions as well as on standing at room temperature.
The low yield and poor stereoselectivity in the synthesis
of (S)-3b via the mesylate led to a search for an alternative
more general method of accomplishing the azide displace-
ment of tertiary R-hydroxy esters. It was reasoned that the
Mitsunobu reaction could be an advantageous alternative
since the alcohol is activated in situ in the presence of the
nucleophile and the activated species is short-lived. In
addition, recent reports indicated that the Mitsunobu reaction
could take place on chiral tertiary alcohols with high
stereoselectivity.9
azodicarboxylate (DIAD), PPh3, and HN3 (Table 1, Entry
1). The azide product was observed by reverse-phase HPLC
in 29% conversion from the starting alcohol after 24 h.
Optimization of the reaction was performed, studying various
Table 1. Optimization of the Azide Mitsunobu Reaction on
R-Hydroxy Ester (()-5a
azodicarbonyl
reagent
phosphine
reagent
% conversion
after 24 h
entrya
1
2
3
4
5
6
7
8b
DIAD
ADDP
ADDP
ADDP
TMAD
TMAD
DIAD
ADDP
PPh3
PPh3
PBu3
PMe3
PBu3
PMe3
PMe3
PMe3
29
0
The Mitsunobu reaction was carried out on racemic
R-hydroxy ester (()-5a using standard reagents: diethyl
64
89
81
56
0
(8) (a) Mitsunobu, O. Synthesis 1981, 1, 28. (b) Hughes, D. L. Org.
React. 1992, 42, 335–656. (c) Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc.
1993, 115, 8451–8452. (d) Maycock, C. D.; Afonso, C. M.; Barros, T.;
Godinho, L. S. Tetrahedron 1994, 50, 9671–9678. (e) Hughes, D. L. Org.
Prep. Proced. Int. 1996, 28, 127–164. (f) Wis´niewski, K.; Kołdziejczyk,
A. S.; Falkiewicz, B. J. Peptide Science 1998, 4, 1–14. (g) Watanabe, T.;
Gridnev, I. D.; Imamoto, T. Chirality 2000, 12, 346–351. (h) Lee, S. H.;
Yoon, J.; Chung, S.-H.; Lee, Y.-S. Tetrahedron 2001, 57, 2139–2145. (i)
Goksu, S.; Secen, H.; Sutbeyaz, Y. Synthesis 2002, 2373–2378. (j) Ko,
S. Y. J. Org. Chem. 2002, 67, 2689–2691.
99
a Reaction conditions for all entries except entry 8: 1.5 equiv phosphine
reagent, 1.5 equiv HN3, 1.5 equiv azodicarbonyl reagent, toluene 0-25 °C.
b Optimal reaction conditions (entry 8): PMe3 (2 equiv), HN3 (2 equiv),
ADDP (2 equiv), THF 0-25 °C.
808
Org. Lett., Vol. 11, No. 4, 2009

Table 2. Azide Mitsunobu Reactiona on Tertiary R-Hydroxy Esters and Conversion to R,R-Disubstituted Amino Acids
a Conditions: HN3 (2 equiv), PMe3 (2 equiv), ADDP (2.2 equiv), THF, 0-25 °C, 24-30 h. See Supporting Information for full experimental details.
b Optical purities determined by chiral HPLC. c Isolated yields. d >99% elimination observed by HPLC in Mitsunobu reaction.
combinations of reagents, molar equivalents, solvent, and
temperature (Entries 2-8). Tsunoda and Itoˆ et al.10 reported
the use of 1,1-(azodicarbonyl)dipiperidine (ADDP) and
N,N,N′,N′-tetramethylazodicarboxamide (TMAD) with PBu3
as alternatives to the DIAD/PPh3 system. The combination
of ADDP with PPh3 gave no reaction (Entry 2). By switching
from PPh3 to PBu3, a moderate 64% conversion was observed
(Entry 3). Using PMe3, conversion to the azide increased to
89% (Entry 4).
8: 2.0 equiv of PMe3 and HN3, 2.2 equiv of ADDP). Under
these conditions, the reaction proceeded with 99% conversion
from alcohol to azide in 24 h.
Following optimization of the chemical yield of the azide
Mitsunobu reaction, a variety of chiral R-hydroxy esters
(5a-f) were synthesized (Table 2). Examples containing
benzylic substituents (Entries 1,2,6,7) were prepared by
Sharpless asymmetric dihydroxylation (AD)12 of the corre-
sponding R,ꢀ-unsaturated esters. The resulting diols were
It is interesting that TMAD in combination with PBu3 and
PMe3 (Entries 5 and 6, respectively) were less efficient than
ADDP/PMe3, while DIAD/PMe3 gave no reaction (Entry 7).
Since ADDP/PMe3 gave the highest conversion to product
in 24 h, the reaction was further optimized by switching to
THF as solvent and increasing reagent equivalents11 (Entry
(9) (a) Shi, Y.-J.; Hughes, D. L.; McNamara, J. M. Tetrahedron Lett.
2003, 44, 3609–3611. (b) Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc.
2004, 126, 7359–7367. (c) Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc.
1993, 115, 8451–8452.
(10) (a) Tsunoda, T.; Yamamiya, Y.; Itoˆ, S. Tetrahedron Lett. 1993,
34, 1639–1642. (b) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Itoˆ, S. Chem.
Lett. 1994, 539–542. (c) Itoˆ, S. Yakugaku Zasshi 2001, 121, 567–583.
Org. Lett., Vol. 11, No. 4, 2009
809

converted to the alcohols by catalytic ꢀ-C-O hydrogenoly-
sis in 73-93% yield (see Supporting Information for full
experimental details). The chiral alcohols were >90% ee,
and could be enriched to >99% ee by a single recrystalli-
zation of the preceding diol intermediate. The R-hydroxy
esters in entries 3 and 4 [(R)- and (S)-5b] were prepared by
benzylation of the commercially available chiral atrolactic
acid hemihydrates. The (S)-R-hydroxybutanoic acid deriva-
tive in Entry 8 [(S)-5f] was obtained by resolution of the
racemic acid, followed by benzylation.
The absolute configuration of alcohols 5a-f was deter-
mined by comparison of optical rotations with literature
values where available or inferred by known stereochemical
preferences of the Sharpless AD reaction. The alcohols
shown in Table 2 were subjected to the optimized Mitsunobu
reaction conditions to generate the corresponding azido
derivatives. Hydrogenation of the azides followed by ester
hydrolysis or, in the case of benzyl esters, simultaneous
hydrogenolysis, gave the optically active R,R-disubstituted
amino acids (3a-f). These amino acids were analyzed by
chiral HPLC using literature methods.13 The azide Mitsunobu
reactions on the chiral R-hydroxy esters listed in Table 2
gave high yields of the corresponding R-azido esters with
the exception of (()-5c (Entry 5), which resulted in >99%
elimination. With the exception of entry 5, the Mitsunobu
reactions took place with complete inversion of stereochem-
ical configuration and optical purity was completely con-
served. These results are remarkable given that each example
has considerable steric hindrance at the R-carbon. In addition,
the reactions were carried out at room temperature and were
completed in 24-30 h. These examples also demonstrate
the utility of the azide Mitsunobu reaction as part of a general
method to synthesize nonracemic R,R-disubstituted amino
acids from chiral tertiary alcohols. The preparation of new
biologically active R,R-disubstituted amino acids utilizing
this reaction is under investigation.
Acknowledgment. We are grateful to Stefan Thibodeaux,
Thomas Perun, and Jonathan Paschal of Eli Lilly and
Company for analytical support.
(11) Lai, J.-Y.; Yu, J.; Hawkins, R. D.; Falck, J. R. Tetrahedron Lett.
1995, 36, 5691–5694.
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483–2547.
(13) (a) Pe´ter, A.; To¨ro¨k, G.; Armstrong, D. W J. Chromatogr. A 1998,
793, 283–296. (b) Ekborg-Ott, K. H.; Liu, Y.; Armstrong, D. W. Chirality
1998, 10, 434–483. (c) Petritis, K.; Valleix, A.; Elfakir, C.; Dreux, M.
J. Chromatogr. A 2001, 913, 331–340.
OL802325H
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Org. Lett., Vol. 11, No. 4, 2009