Asymmetric synthesis of actinoidic acid derivatives

Article abstract of DOI:10.1021/ol006110s

(equation presented) Synthesis of fully protected actinoidic acid derivative 3 and selectively protected biaryl bisamino acid 4, intermediates for vancomycin total synthesis, are reported.

Full text of DOI:10.1021/ol006110s

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2459-2462
Asymmetric Synthesis of Actinoidic
Acid Derivatives
Sabine Boisnard, Luc Neuville, Miche`le Bois-Choussy, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette, France
zhu@icsn.cnrs-gif.fr
Received May 26, 2000
ABSTRACT
Synthesis of fully protected actinoidic acid derivative 3 and selectively protected biaryl bisamino acid 4, intermediates for vancomycin total
synthesis, are reported.
Vancomycin (1) and related glycopeptide antibiotics have
attracted multidisciplinary interest for decades due to their
clinic importance.1 Indeed, together with teicoplanin, they
are the drug of last resort for the treatment of infections due
to methicillin-resistant Staphylococcus aureus and other
Gram positive organisms resistant to â-lactam antibiotics.
The complex molecular architecture and the recent emer-
gence of vancomycin-resistance phenomenon have rendered
them attractive synthetic targets.2 The intensive research
efforts have culminated in three landmark total syntheses of
vancomycin aglycon.3 In connection with our work aimed
at developing a new strategy toward the construction of AB-
COD rings,4 an efficient synthesis of suitably protected biaryl
diamino diacid units common to the 12-membered AB ring
of all glycopeptides of this family was required. Asymmetric
synthesis of such compounds was not trivial as one not only
has to construct a sterically congested biaryl moiety5 but also
has to introduce two very racemization prone aryl glycines.6
Controlling the axial chirality posed yet another synthetic
problem which has recently been addressed.7,8
Previously, we reported a synthesis of racemic actinoidic
acid derivative (2) employing Meyers’s oxazoline chemistry.9
With a view to developing a more convergent synthesis, we
decided to use a suitably protected D-phenylglycinol as a
nucleophilic partner in the intermolecular nucleophilic
(5) (a) Rama Rao, A. V.; Chakraborty, T. K.; Joshi, S. P. Tetrahedron
Lett. 1992, 33, 4045-4048. (b) Rama Rao, A. V. Reddy, K. L.; Reddy, M.
M. Tetrahedron Lett. 1994, 35, 5039-5042.
(6) Evans, D. A.; Ecrard, D. A.; Rychnovsky, S. D.; Fruh, T.; Whit-
tingham, W. G.; DeVries, K. M. Tetrahedron Lett. 1992, 33, 1189-1192.
(7) Lipshutz, B. H.; Peter Mu¨ller, P.; Leinweber, D. Tetrahedron Lett.
1999, 40, 3677-3680.
(1) (a) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. 1999, 38,
1173-1193. (b) Zhu, J. Exp. Opin. Ther. Pat. 1999, 9, 1005-1019.
(2) (a) Zhu, J. Synlett 1997, 133-144. (b) Nicolaou, K. C.; Boddy, C.
N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096-
2152.
(3) (a) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.;
Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700-2704;
2704-2708. (b) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes,
R.; Solomon, M. E.; Ramanjulu, J. M.; Boddy, C. N. C.; Takayanagi, M.
Angew. Chem., Int. Ed. 1998, 37, 2708-2714; 2714-2716; 2717-2719.
(c) Boger, D. L.; Miyazaki, S.; Kim, S. H.; Wu, J. H.; Loiseleur, O.; Castle,
S. L. J. Am. Chem. Soc. 1999, 121, 3226-3227. (d) For total synthesis of
vancomycin, see: Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Winssinger,
N.; Hughes, R.; Bando, T. Angew. Chem., Int. Ed. 1999, 38, 240-244.
(4) Neuville, L.; M. Bois-Choussy, Zhu, J. Tetrahedron Lett. 2000, 41,
1747-1751.
(8) (a) Miyano, S.; Tobita, M.; Hashimoto, H. Bull. Chem. Soc. Jpn.
1981, 54, 3522-3526. (b) Meyers, A. I.; Lutomski, K. A. J. Am. Chem.
Soc. 1982, 104, 879-881. (c) Wilson, J. M.; Cram, D. J. J. Am. Chem.
Soc. 1982, 104, 881-884. (d) Yamamoto, K.; Fukushima, H.; Nakazaki,
M. J. Chem. Soc., Chem. Commun. 1984, 1490-1491. (e) Hayashi, T.;
Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-
8156. (f) Osa, T.; Kashiwagi, Y.; Yanagisawa, Y.; Bobbitt, J. M. J. J. Chem.
Soc., Chem. Commun. 1994, 2535-2537.
(9) Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M.
Tetrahedron Lett. 1993, 34, 7401-7404.
10.1021/ol006110s CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/12/2000

substitution reaction (SNAr). We report now the realization
of such a strategy featuring a key coupling reaction between
two oxazolines (5 and 6, Figure 1). The characteristic feature
Scheme 1
a one-to-one ratio (Scheme 2).14 Apparently, chirality transfer
from the sp3 carbon center to give biaryl asymmetry was
negligible, which is in fact not unexpected. The coupling
reaction has to be carried out under strictly anhydrous and
inert conditions in order to get reproducibly high yields. The
main side reaction was the demethylation of compound 5.
This coupling reaction is one of the few examples wherein
Meyers’s reaction has been used for the construction of a
biaryl bisoxazoline compound.10,11 To fully demonstrate the
dual role of oxazoline, a selective transformation of these
functions was required. After surveying various reaction
conditions, the one developed by Feuer15 was found to fulfill
this demanding task nicely. Thus, treatment of biaryl 11 with
trifluoroacetic acid in anhydrous methanol gave amino ester
12 which was immediately N-protected using CbzOSu to
afford N-CBz derivative 13 in 77% overall yield. No acyl
migration was observed in either step. The B ring oxazoline
was perfectly stable under these conditions and was subse-
quently converted into an aldehyde following a three-step
sequence. Thus, heating the acetone solution of 13 in the
presence of methyl iodide followed by reduction of the so-
produced oxazolinium salt with L-Selectride to oxazolidine
and acidic workup (aqueous citric acid) provided 14 in
excellent overall yield.16
Figure 1.
of this synthesis is the exploitation of two distinct roles of
oxazoline, one as an activating group for SNAr reaction10
and the other as a protecting group for the chiral amino
alcohol derived from D-phenylglycine.11
The synthesis of oxazoline (6) was shown in Scheme 1.
Esterification of D-phenylglycine (7) followed by acylation
with pivaloyl chloride gave compound 8, which was trans-
formed into amino alcohol 9 in three straightforward steps.
Protection of the phenol group of 9 as its methyl ether was
best carried out after reduction of the ester function in order
to avoid any exposure of racemization-prone methyl 4-hy-
droxyphenylglycinate to the basic conditions. Thionyl chlo-
ride induced ring closure of hydroxyamide (9) afforded
oxazoline (6) in 85% yield together with a small amount of
chloroamide (10). The latter can be converted to the desired
oxazoline under basic conditions in quantitative yield (KOH,
EtOH, reflux).12
Asymmetric Strecker reaction was projected for the
introduction of the second amino acid unit. Phenylglycinol
was first attempted as a chiral auxiliary.5a,17 Although the
Formation of Grignard reagent from 6 using the entrain-
ment method13 followed by addition of oxazoline 59 gave
biaryl 11 in 87% yield as a mixture of two atropisomers in
(14) No experiment has been caried out to determine the energy barrier
for interconversion of two atropisomers. The aryl-aryl bond rotation in
compound 14 might be an easy process according to Meyers: Meyers, A.
I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446-5452.
(15) Feuer, H.; Bevinakatti, S. H.; Luo, X. G. J. Heterocycl. Chem. 1987,
24, 9-13.
(10) (a) Rueman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837-860.
(b) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297-2360;
(11) For the protection of carboxylic acid as oxazoline, see: Meyers, A.
I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978, 43, 1372-1379. (b)
Degnan, A. P.; Meyers, A. I. J. Am. Chem. Soc. 1999, 121, 2762-2769.
(12) Frump, J. A. Chem. ReV. 1971, 71, 483-505.
(16) Wilson, S. R.; Mao, D. T.; Khatri, H. N. Synth. Commun. 1980,
10, 17-23.
(13) Lai, Y. H. Synthesis 1981, 585-604.
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Org. Lett., Vol. 2, No. 16, 2000

Scheme 2
chemical yield was excellent, chiral induction was moderate
3 with over a 70% yield.21 Following the same sequence,
18 was converted to 21 with similar efficiency. Partial
epimerization (5-10%) at one of the two chiral carbon
centers occurred during this last transformation.22 However,
both 3 and 21 can be separated from their respective epimers,
epi-3 and epi-21. Analysis of NMR spectra of these
compounds indicated that atropisomerization did not take
place. Finally, comparison of the CD spectra of 19 and 20
with those of actinoidic acid derivatives reported in the
literature allowed us to determine their axial chirality to be
M and P, respectively (Scheme 3). It follows, therefore, that
at best. Chiral sulfinimines were next examined as substrates
in view of their high performance in the asymmetric synthesis
of amino acids.18 Condensation of aldehyde 14 with (S)-p-
toluenesulfinamide (15), derived from SS (-)-Andersen
reagent, in the presence of titanium tetraethoxide19 gave the
desired sulfoximine (16) which was then reacted with
diethylaluminum cyanide in the presence of 2-propanol to
provide amino nitrile with excellent diastereoselectivity.20
Indeed, only two separable diastereomers were detectable
from NMR spectra which were assigned and later comfirmed
by CD spectra to be two atropisomers. The S configuration
was attributed to the newly created chiral carbon center
according to Davis’ empirical model.18 Hydrolysis of amino
nitrile to amino ester was realized by heating a solution of
17 in anhydrous methanol saturated with gaseous HCl to give
compound 19 after protection of amino groups. Both N-Cbz
and O-pivaloyl functions were removed under these condi-
tions. Jone’s oxidation of alcohol to acid followed by
esterification gave, after purification, diastereomerically pure
Scheme 3
(17) Vergne, C.; Bouillon, J. P.; Chastanet, J. Bois-Choussy, M.; Zhu,
J. Tetrahedron: Asymmetry 1998, 9, 3095-3103.
(18) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. ReV. 1998, 27, 13-
18.
Org. Lett., Vol. 2, No. 16, 2000
2461

17 and 18 and 3 and 21 must have the configurations depicted
in Scheme 2.23
glycopeptides. The dual role of oxazoline as an activating
group for promoting biaryl formation and as a protecting
group of chiral vicinal amino alcohols was demonstrated in
this synthesis.
Differentiation of the two amino acid functionalities of
19 is possible. Thus, deprotection of N-Boc under mild acid
conditions followed by treatment with triphosgene in the
presence of triethylamine gave oxazolidinone 4 which can
be engaged in the synthesis of the AB-COD ring of
vancomycin.
Acknowledgment. Financial support from this institute
and from MRES in the form of doctoral fellowships to S.
Boisnard and L. Neuville is gratefully acknowledged. We
thank Professors Fleischhauer and Raabe of Institut fu¨r
Organische Chemie, Germany, for kindly recording the CD
spectra of compounds 19 and 20. We thank Professor P.
Potier for his interest in this work.
In conclusion, we have developed an asymmetric synthesis
of biaryl bisamino acids common to vancomycin-type
(19) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.; Fanelli, D.
L.; Zhang, H. J. Org. Chem. 1999, 64, 1403-1406. (b) Liu, G.; Cogan, D.
A.; Ellman, J. A.; J. Am. Chem. Soc. 1997, 119, 9913-9914.
(20) Davis, F. A.; Fanelli, D. L. J. Org. Chem. 1998, 63, 1981-1985.
(21) The oxoammonium salt mediated oxidation (Tempo-NaClO) gave
ring chlorinated acid in 95% yield. Modification of reaction conditions failed
to avoid this undesired chlorinination reaction, cf. ref 4.
(22) Experimental evidences suggested that epimerization occurred at
the A ring unit via possibly the amino aldehyde intermediate which has
been isolated and proved to be stereochemically unstable.
Supporting Information Available: Full experimental
details and characterization data for compounds 3, 4, and
11-21 and the CD specta of compounds 19 and 20. This
material is available free of charge via the Intenet at
http://pubs.acs.org.
(23) Jeffs, P. W.; Chan, G.; Mueller, L.; DeBrosse, C.; Webb, L.; Sitrin,
R. J. Org. Chem. 1986, 57, 4272-4278.
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