Iterative oxazole assembly via α-chloroglycinates: Total synthesis of (-)-muscoride A

Article abstract of DOI:10.1002/anie.200390363

An efificient iterative synthesis of oxazoles involves the cyclization of 2-alkynyl glycinates (see scheme) formed from the reaction of 1-alkynyl aluminum reagents with α-chloroglycinates. This approach was used in the total synthesis of the bisoxazole na

Full text of DOI:10.1002/anie.200390363

Angewandte
Chemie
R2
Synthesis of Oxazoles
R2
Iterative Oxazole Assembly via
a-Chloroglycinates: Total Synthesis of
(ꢀ)-Muscoride A**
O
O
R3
1
R1
N
H
R3
R1
N
5
6
Pierre-Yves Coqueron, Charles Didier, and
Marco A. Ciufolini*
a
b
R1 = simple alkyl / aryl; R2 = R3 = H (reference [2])
R1 = subst. alkyl / aryl; R2 = alkyl, aryl; R3 = COOR
Mt
R2
O
X
Ongoing work directed toward the synthesis of oxazole-
containing natural products revealed the desirability for a
mild method for iterative oxazole construction based on the
approach shown in Scheme 1.[1] Ageneric primary amide 1
(possibly derived from an a-amino acid) would be advanced
to oxazole-4-carboxamide 2, which upon subjection to the
same reaction sequence leads to bisoxazole 3. Apolyoxazole
4 bearing diverse substituents R would materialize after n
such iterations.
5b
6b
R1
N
H
COOR
9
7
8
X = OH
X = Cl
Scheme 2. Cyclization of N-acyl propargylamines in oxazole formation.
mediate 5b be built de novo from amides 1. Herein, we
provide details of how these principles were translated into
practice and we demonstrate an application of the new
chemistry to the synthesis of the bisoxazole natural product
(ꢀ)-muscoride A( 26, see Scheme 5).
R2
O
O
O
[ ? ]
repeat
R1
NH2
R2
N
R1
NH2
1
Alkynyl glycine derivatives can be prepared by the
method of Williams and co-workers,[3] which involves the
reaction of 1-stannylalkynes (e.g. 9, Mt = Bu3Sn) with a-
chloroglycinates 8, readily obtained, in turn, by treatment of
a-hydroxyglycinates 7 with SOCl2.[4] This approach was
readily reproduced, but we found it more practical to use
alkynyl dimethylaluminum reagents generated in situ (e.g. 9,
2
R
O
O
O
O
R3
O
R'
O
N
R1
N
R1
N
N
n
3
4
H2N
H2N
Mt = AlMe2)[5] for the crucial C C-bond-forming step, espe-
ꢀ
cially during large-scale operations.[6,7]
Scheme 1. Iterative approach to oxazole construction.
Addition of a primary amide to a glyoxylate ester and
dissolution of the resulting a-hydroxyglycinates 7 in SOCl2
resulted in conversion into essentially pure (by NMR
spectroscopic analysis) 8,[8] which reacted rapidly with dime-
thylaluminum acetylides to form the corresponding alkynyl
glycinates 5b. These intermediates were isolated and charac-
terized in several instances, but we found that prolonged
reaction times (> 2 h) induce a considerable degree of in situ
cyclization to form oxazoles 6b. However, complete cycliza-
tion may require an inconveniently long contact time, which
may also result in side reactions. Fortunately, gentle basic
treatment (aqueous NaHCO3) of 5b was found to induce
rapid conversion into 6b. Complete oxazole formation is thus
best achieved during a mild basic workup of the reaction
mixture.[9]
The documented cyclization of simple N-acyl propargyl-
amines (e.g. 5a!6a, Scheme 2)[2] offered an attractive
solution to the issue of oxazole assembly, provided that the
transformation could be effected with alkynylglycine-type
substrates 5b, in which R1 may contain potentially labile
stereocenters. Furthermore, this logic requires that inter-
[*] Prof. Dr. M. A. Ciufolini,P.-Y. Coqueron,C. Didier
Laboratoire de Synth›se et MØthodologie Organiques
CNRS UMR 5078,UniversitØ Claude Bernard Lyon 1
and
École SupØrieure de Chimie,Physique,Electronique de Lyon
43 Bd. du 11 Novembre 1918
69622 Villeurbanne cedex (France)
Fax: (+33)4-72-43-29-63
E-mail: ciufi@cpe.fr
Table 1 lists representative oxazoles 10 synthesized by the
new procedure. Yields are uniformly good to excellent.
Heterocycles 10 often need to be converted into the
corresponding free acids as a prelude to subsequent oper-
ations. In this case, it is expedient to employ the stronger base
LiOH in the workup/cyclization step, whereupon the desired
acids are obtained directly (Table 1, 10b). Treatment of
silylated products of the type 10g (or of their alkynyl glycine
forerunners) with LiOH results in loss of the TMS group as
well.[10]
[**] We thank Aventis CropScience and the CNRS (BDI Fellowship to
P.-Y.C.),the MENRT,the CNRS,and the RØgion Rhône-Alpes for
support of our research. We are grateful to Ms. Laurence Rousset,
Mr. Aymeric Morla,and Dr. Denis Bouchu for the mass spectro-
metric data. M.A.C. is the recipient of a Merck&Co Academic
Development Award.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1:
Bn
Cl
O
O
O
COOEt
N
H
COOEt
a – c
d
N
10b
N
n-C7H15
14
N
n-C7H15
Ph
R1
R2
R3
Yield [%]
15
O
Ph
a
b
c
d
e
f
Ph
Ph
Ph
Ph
nBu
H[a]
nBu
Et
nBu
nBu
nBu
n-C6H13
n-C6H13
Ph
n-C6H13
Ph
91
81
90
89
77
84
84
Cl
Bn
O
COOEt
d
O
N
H
COOEt
e, b – c
N
N
11
Me
N
cyclo-C6H11
cyclo-C6H11
[c]
Ph
TMS[c]
O
g
H
MeO
O
NPht
H
51[b]
16
17
MeO
h
allyl
CH2OMe
NPht
Scheme 4. Reagents and conditions: a) SOCl2,reflux,20 min,then gas-
eous NH3,room temperature,71%; b) CHOCOOEt,THF,reflux,12 h;
c) SOCl2,room temperature,90% (steps b,c for 14),68% (steps b,c
[a] The butyl ester of 8 was used as in this experiment,as in entry a;
however,the reaction was worked up with aqueous LiOH (see text),
resulting in saponification of the ester. [b] The corresponding vinyl-
oxazole resulting from elimination of MeOH was also formed in 21%
yield (see text). [c] PhtN=phthalimido,TMS =trimethylsilyl.
ꢁ
for 16); d) PhC CAlMe2,Et 2O/THF,0 8C!RT,2 h,79% ( 15),65%
(17); e) EtOOCCl,Et 3N,0 8C,then gaseous NH 3,room temperature,
44%.
Products 8 derived from a-amino acids behaved normally
in the oxazole-forming sequence (e.g. Table 1, with l-valine-
derived 8h). Best results were obtained when the a-amino
group of the initial amino acid was blocked as an imide or a
the conversion of 10h into (R)-(þ)-a-methylbenzylamide 12,
NMR spectra of which revealed the presence of only one
diastereomer, indicating no erosion of stereochemical integ-
rity during oxazole formation. Finally, the cyclization of
alkynyl glycines derived from propargyl ethers proceeded
with partial elimination of a molecule of alcohol to give
vinyloxazoles: In the case of 5h, by-product 13 (21% yield)
accompanied oxazole 10h.[12]
The iterative mode of oxazole construction is exemplified
herein with substrates 10b and 11 (Scheme 4). Overall yields
were comparable to those of monooxazoles described in
Table 1.
As an application of the new findings, we describe a total
synthesis of (ꢀ)-muscoride A( 26),[13] a secondary metabolite
of the freshwater cyanobacterium Nostoc muscorum, as
outlined in Scheme 5. This bisoxazole natural product dis-
plays only modest antibiotic activity, but it has served as a
useful platform to test methods of oxazole construction.[14]
Our synthesis commenced with the reaction of l-N-Troc-
prolinamide (18)[15] with ethyl glyoxylate. Chlorination of the
resulting 19 furnished 20, which upon sequential exposure to
the dimethylaluminum derivative of TMS acetylene and
aqueous LiOH workup, afforded oxazole carboxylic acid 21
through cyclization, ester hydrolysis, and desilylation.[16] The
corresponding amide 22[17] was subjected to the same
sequence. The resulting acid 23 was esterified (prenyl alcohol,
BOP), and the Troc group was cleaved with Cd/Pb couple.[18]
N-Acylation of the emerging 25 with the pentafluorophenyl
ester of l-N-(3,3-dimethyl-1-propenyl)valine, as described by
Wipf and Venkatraman, led to the formation of (ꢀ)-muscor-
ide A, [a]2D5 = ꢀ80.2 (c = 0.5, MeOH; ref. [13]: ꢀ89, c = 0.7,
MeOH) in 23% yield, consistent with previous work.[14a] The
overall yield of 26 from 18 was thus 3.5% over ten steps.
In conclusion, the new oxazole-forming reaction appears
to be generally applicable to the preparation of heterocycles
ꢀ
tertiary amide, that is, when no N H bonds remained in the
intermediates leading to 10. Notably, a phthalimide segment
(e.g. 8h) is resistant to the action of the acetylenic organo-
metallic compound. On the other hand, selective ester
saponification in oxazoles that bear an N-phthalimido group
was problematic as a result of competing semihydrolysis of
the protecting group and consequent formation of highly
polar materials. This difficulty may be circumvented by use of
allyl glyoxylate in the synthetic scheme. The emerging allyl
esters of the type 10h are then selectively cleaved under
catalysis by Pd0 to form 11 (Scheme 3).[11] This is apparent in
Ph
H
O
COOH
N
H
a
b
N
N
10h
O
O
H
MeO
NPht
H
MeO
11
NPht
12
COO
N
O
H
NPht
13
Scheme 3. Reagents and conditions: a) dimedone,[Pd(PPh 3)4],THF,
room temperature,91%; b) ( R)-(þ)-a-methylbenzylamine,EDCI,
DMAP,CH 2Cl2,room temperature,63%. EDCI =3-(3-dimethylamino-
propyl)-1-ethylcarbodiimide,DMAP =4-dimethylaminopyridine.
1412
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Angew. Chem. Int. Ed. 2003, 42, No. 12

Angewandte
Chemie
Lett. 1999, 40, 7951; k) C. M. Shafer, T. F. Molinski, Heterocycles
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H
H
N
2000, 53, 1167; l) M. Lautens, A. Roy, Org. Lett. 2000, 2, 555;
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J. V. Pivnichny, L. M. Warmke, M. Zakson-Aiken, K. A. Owens,
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Meinke, S. L. Colletti, Org. Lett. 2001, 3, 3715; z) A. Couture, P.
Grandclaudon, C. Hoarau, J. Cornet, J. P. Hꢀnichart, R. Houssin,
J. Org. Chem. 2002, 67, 3601; aa) K. J. Hodgetts, M. T. Kershaw,
Org. Lett. 2002, 4, 2904; ab) K.-I. Itoh, S. Takahashi, T. Ueki, T.
Sugiyama, T. T. Takahashi, C. A. Horiuchi, Tetrahedron Lett.
2002, 43, 7035; ac) J. D. Kreisberg, P. Magnus, S. Shinde,
Tetrahedron Lett. 2002, 43, 7393, and references therein; see
also reference [12].
a
c
NH2
COOEt
N
N
O
O
X
Troc
Troc
18
19 X = OH
20 X = Cl
b
Me
H
H
O
N
N
N
CO-Z
N
CO-Z
N
O
Troc
a – c
O
W
Me
21 Z = OH
Me
23 W = Troc, Z = OH
d
e
f
22 Z = NH2
24 W = Troc, Z = prenyl
25 W = H, Z = prenyl
Me
H
O
O
N
g
N
O
N
O
O
H
Me
NH
26
Scheme 5. Reagents and conditions: a) CHOCOOEt (1.2 equiv),THF,
reflux,12 h,95% ( 19),75% ( 23); b) SOCl2 (neat),10 min,room tem-
perature,quant. (crude); c) Me 2AlC CSiMe3 (1 equiv),Et O/THF,
08C!RT,2 h,then workup with aqueous LiOH (2 equiv),aqueous
THF,72% ( 20,crude),60% ( 24,crude); d) EtOOCCl (2 equiv),Et 3N
(2 equiv),CH 2Cl2, 08C,then gaseous NH ,room temperature,85%;
e) prenyl alcohol (2 equiv),BOP (1.5 equiv),Et 3N (3 equiv),CH 2Cl2,
room temperature,12 h,65%; f) Cd/Pb couple,THF,aqueous
NH4OAc buffer,room temperature,80%; g) 25 (1.5 equiv relative to
the activated valine derivative),DMAP (1 equiv),CHCl 3,reflux,24 h,
23%. Troc=trichloroethoxycarbonyl; BOP=(benzotriazol-1-yloxy)tris-
(dimethylamino)phosphonium hexafluorophosphate.[14a]
ꢁ
[2] a) B. M. Nilsson, U. Hacksell, J. Heterocycl. Chem. 1989, 26, 269;
b) F. Eloy, A. Deryckere, Chim. Ther. 1973, 437; c) Y. Yura,
Chem. Pharm. Bull. Jpn. 1962, 10, 1087; d) P. Wipf, L. T.
Rahman, S. R. Rector, J. Org. Chem. 1998, 63, 7132; e) A.
Arcadi, S. Cacchi, L. Cascia, G. Fabrizi, F. Marinelli, Org. Lett.
2001, 3, 2501.
[3] R. M. Williams, D. J. Aldous, S. C. Aldous, J. Org. Chem. 1990,
55, 4657.
[4] a) U. Zoller, D. Ben-Ishai, Tetrahedron 1975, 31, 863; b) D. Ben-
Ishai, I. Sataty, Z. Bernstein, Tetrahedron 1976, 32, 1571; c) Z.
Bernstein, D. Ben-Ishai, Tetrahedron 1977, 33, 881; an alter-
2
3
native route to
reference [8].
8 is described in reference [3]; see also
of type 10. The technique lends itself to an iterative mode of
polyoxazole construction and appears to be fully compatible
with multistep synthetic operations.
[5] The use of alkynyl aluminum reagents was inspired by: A. R.
Katritzky, D. C. Oniciu, N. M. Yoon, J. Org. Chem. 1999, 64, 488.
[6] Application of the method of Williams and co-workers[3] was
complicated by the poor solubility of several intermediates of
the type 8 in CCl4 or other nonpolar solvents, which are required
for best results.
[7] Other acetylenic organometallic compounds produced poor
results. Thus, we failed to induce conversion of 8 into 5b with Li
or Na acetylides (complex mixtures). Base-promoted formation
of the imine corresponding to 8 (see conversion of compound 5
into 3 in: J. Vidal, J.-C. Hannachi, G. Hourdin, J.-C. Mulatier, A.
Collet, Tetrahedron Lett. 1998, 39, 8845) prior to exposure to an
alkynyl organometallic compound did not solve the problem.
Trimethylsilylacetylenes proved to be unreactive toward 8 under
a variety of conditions. The facile reaction of vinylboronic acids
with iminium-type electrophiles (see N. A. Petasis, I. A. Zavia-
lov, J. Am. Chem. Soc. 1997, 119, 7703) prompted us to explore
alkynyl boronic acids as acetylide donors. Results were unsat-
isfactory.
Received: October 10, 2002 [Z50331]
Keywords: alkynes · aluminum · natural products · oxazoles ·
.
polyoxazoles
[1] For general methods of oxazole synthesis, see: a) A. R.
Katritzky, A. F. Pozharskii in Handbookof Heterocyclic Chemis-
try, 2nd ed., Pergamon, Oxford, 2000, p. 569; b) F. W.
Hartner, Jr. in Comprehensive Heterocyclic Chemistry II,
Vol. 3 (Eds.: A. R. Katritzky, C. W. Rees), Elsevier, New York,
1996, p. 261; for more recent methods, see: c) S. Swaminathan,
A. K. Singh, W. S. Li, J. J. Venit, K. J. Natalie, Jr., J. H. Simpson,
R. E. Weaver, L. J. Silverberg, Tetrahedron Lett. 1998, 39, 4769;
d) M. C. Begley, R. T. Buck, S. L. Hind, C. J. Moody, J. Chem.
Soc. Perkin Trans. 1 1998, 591; e) M. Falorni, G. Dettori, G.
Giacomelli, Tetrahedron: Asymmetry 1998, 9, 1419; f) R. S.
Varma, D. Kumar, J. Heterocycl. Chem. 1998, 35, 1533; g) W. W.
Pei, S. H. Li, X. P. Nie, Y. W. Li, J. Pei, B. Z. Chen, J. Wu, X. L.
Ye, Synthesis 1998, 1298; h) C. M. Shafer, T. F. Molinski, J. Org.
Chem. 1999, 64, 4995; i) B. A. Kulkarni, A. Ganesan, Tetrahe-
dron Lett. 1999, 40, 5633; j) L. M. Martin, B. H. Hu, Tetrahedron
[8] The following modification of the procedure of Ben-Ishai and
co-workers[4] was used: a-hydroxyglycinate 7 was dissolved in
SOCl2 (30 equiv) and stirred at room temperature for 10 min.
The mixture was diluted with an equal volume of CH2Cl2 and
concentrated to afford the crude a-chloroglycinate 8.
[9] Representative procedure for the preparation of oxazoles:
commercial nBuLi (1.2 mmol) was added dropwise to a solution
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of 1-octyne (1.2 mmol) in THF (0.9 mL) at ꢀ788C under Ar.
After stirring for 5 min, the mixture was transferred through a
cannula into a cold (08C) solution of commercial dimethylalu-
minum chloride (solution in hexane, 1.2 mmol) in diethyl ether
(0.9 mL). The mixture was stirred at 08C for 1 h and was then
transferred dropwise through a cannula into a cold (08C)
solution of chloroglycinate 8a (1.2 mmol) in THF (2 mL). The
cold bath was removed and the mixture was stirred for 2 h. The
mixture was then was carefully concentrated in vacuo to about
1/3 of the original volume. Dilution with chloroform (5 mL),
filtration through a plug of silica gel (elution with neat EtOAc),
concentration, treatment with solid NaHCO3 (2.4 mmol) in
THF/H2O (1:1, 5 mL) for 2 h, extraction with diethyl ether, and
concentration provided the crude oxazole. Purification by silica-
gel column chromatography with cyclohexane/EtOAc (6:1) gave
pure 10a (1.1 mmol).
[10] Desilylation without ester hydrolysis may be induced in essen-
tially quantitative yield by treatment of, for example, 10g, with
tetrabutylammonium fluoride (TBAF) (2 equiv) in CH2Cl2 (1 h,
room temperature).
[11] For reviews of allyl-type blocking groups, see: a) H. Kunz,
Angew. Chem. 1987, 99, 297; Angew. Chem. Int. Ed. Engl. 1987,
26, 294; b) T. W. Greene, P. G. M. Wuts, Protective Groups in
Organic Synthesis, Wiley Interscience, New York, NY, 1999,
p. 409, and references therein.
[12] Asimilar reaction has been described in P. Wipf, L. T. Rahman,
S. R. Rector, J. Org. Chem. 1998, 63, 7132.
[13] A. Nagatsu, H. Kajitani, J. Sakakibara, Tetrahedron Lett. 1995,
36, 4097.
[14] For previous syntheses, see: a) P. Wipf, S. Venkatraman, J. Org.
Chem. 1996, 61, 6517; b) J. C. Muir, G. Pattenden, R. Thomas,
Synthesis 1998, 613.
[15] Prepared from N-Troc-l-proline (96 mmol) (see S. A. Boys, W. J.
Thompson, J. Org. Chem. 1987, 52, 1790) by reaction with SOCl2
(10 equiv) in CH2Cl2 (200 mL) at reflux (20 min), concentration
to dryness, dissolution into more CH2Cl2 (200 mL), and treat-
ment with gaseous ammonia (room temperature, 90 min).
Partitioning with water (100 mL), washing with brine, and
concentration gave an orange residue, which was triturated
with diethyl ether to furnish 18 as a white solid, [a]2D5 = ꢀ72 (c =
2.85, CHCl3).
[16] Scrutiny of the NMR spectra of the crude (R)-(þ)-a-methyl-
benzylamide derivative of 21 revealed the presence of only one
diastereomer (1:1 mixture of Troc rotamers) signifying that
stereochemical integrity had once again been preserved.
[17] The structure of 22 was confirmed by single-crystal X-ray
crystallographic analysis.
[18] Q. Dong, C. A. Anderson, M. A. Ciufolini, Tetrahedron Lett.
1995, 36, 5681.
1414
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