Total synthesis of erythronolide A by MgII-mediated cycloadditions of nitrile oxides

Article abstract of DOI:10.1002/anie.200500172

(Chemical Equation Presented) A cycloaddition comes of age: The focal points of a stereoselective total synthesis of erythronolide A (see structure) are two Mg^II-mediated cycloadditions of nitrile oxides. Of broader significance, the strategy not only facilitates the synthesis of specific polyketide targets (i.e. natural products) but also opens up new possibilities for the preparation of non-natural analogues.

Full text of DOI:10.1002/anie.200500172

Communications
Natural Product Synthesis
of > 95:5 as determined by 1H NMR spectroscopy
(Scheme 1). Oxidation of the secondary hydroxy group in 4
under conditions described by Ley et al. [8] and treatment with
Grignard reagent 6[9] afforded tertiary alcohol 7 in 64% yield
Total Synthesis of Erythronolide A by MgII-
Mediated Cycloadditions of Nitrile Oxides**
Dieter Muri, Nina Lohse-Fraefel,
and Erick M. Carreira*
Since its discovery in 1952,[1] eryth-
romycin A has captured the imagi-
nation of research groups all over the
world. The total syntheses of eryth-
romycin A and its related derivatives
(erythronolide A, erythromycin B,
erythronolide B,
thronolide A,
(9S)-dihydroery-
6-deoxyerythrono-
lide B, 9,12-anhydroerythronolide A)
have become benchmarks for the
study of new methodologies in poly-
ketide synthesis.[2–4] We have recently
reported a general approach for the
synthesis of polyketide building
blocks by means of Kanemasaꢀs
MgII-mediated cycloadditions of ni-
trile oxides to allylic alcohols.[5] The
nature of this approach allows the
modular preparation of the entire
spectrum of functionality and stereo-
chemical permutations found in po-
Scheme 1. Conditions: a) TPAP, NMO, CH2Cl2, RT, 1.5 h, 82%; b) 6, THF, ꢀ788C, 1 h, 64%,
(d.r.>98:2); c) TESOTf, 2,6-lutidine, CH2Cl2, 08C, 1 h, 93%; d) Raney Ni (W2), B(OH)3, H2,
MeOH/H2O, RT, 2 h, 89%; e) Zn(BH4)2, CH2Cl2, ꢀ308C, 2.5 h, 60% (d.r.>95:5); f) PhCH(OMe)2,
CSA (10 mol%), toluene, 50 mbar, RT, 1.5 h, 87%; g) DDQ, pH 7 buffer, CH2Cl2, 08C, 2 h, 85%;
h) TEMPO (15 mol%), NaOCl, KBr (10 mol%), pH 8.6 buffer, CH2Cl2, 08C, 10 min; j) H2NOH·HCl,
pyridine, EtOH, RT, 20 min, 85% (over 2 steps). CSA=camphorsulfonic acid, DDQ=2,3-dichloro-
5,6-dicyanobenzoquinone, NMO=N-methylmorpholine N-oxide, PMB=para-methoxybenzyl,
TBS=tert-butyldimethylsilyl, TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxyl, TESOTf=triethylsilyl
trifluoromethanesulfonate, TPAP=tetrapropylammonium perruthenate.
lyketide-derived structures. In this communication, we dem-
onstrate the power and generality of this cycloaddition in the
context of the total synthesis of eryth-
(98:2 d.r., 1H NMR). The tertiary hydroxy group was
protected as triethylsilyl ether (93% yield). Reductive
ꢀ
cleavage of the N O bond (Raney Ni, B(OH)3, 93%
ronolide A (1). Erythronolide A was
yield),[10] syn reduction of the ensuing hydroxy ketone (Zn-
(BH4)2, 60% yield),[11] and protection of the isolated 1,3-diol
provided 9 (87% yield) as a single diastereomer (1H NMR).
Adduct 9 was converted to oxime 10 by a short three-step
sequence of reactions in 72% overall yield.
completed in 21 linear steps from the
readily available oxime 2.[5a] Of addi-
tional importance, we demonstrate the
potential of the strategy to provide
access to nonnatural analogues (keto-
lides) of this important agent.
The synthesis commences with the
cycloaddition of oxime 2 to allylic
With oxime 10 in hand, we were ready for the second
cycloaddition of a nitrile oxide. We were pleased to observe
that this highly functionalized nitrile oxide smoothly under-
went MgII-mediated 1,3-dipolar cycloaddition with allylic
alcohol 3; the former is available in three steps from (S)-
methyl-3-hydroxyisobutyrate (Roche ester)[6] and the latter in
two steps by Noyori reduction of propargylic ketone and
semihydrogenation over the Lindlar catalyst.[7] Oxime 2 was
treated with tBuOCl (ꢀ788C), which, after addition to a
solution of iPrOH, EtMgBr, and 3, provided isoxazoline 4 in
86% yield on a 35-mmol scale and with a diastereomeric ratio
alcohol
3
under our standard reaction conditions
(Scheme 2).[6] Isoxazoline 11 was obtained in excellent yield
1
(86%) as a single diastereomer as determined by H NMR
spectroscopy. The nitrile oxide derived from 10 represents
one of the most complex substrates used in dipolar cyclo-
addition reactions and attests to the versatility of the cyclo-
addition strategy for the synthesis of polyketides.
Oxidation of the secondary hydroxy group in 11 with
TEMPO/NaOCl provided the corresponding ketone in 93%
yield, which was subjected to Wittig olefination[12] (PrPPh3Br
and tBuLi) to give a trisubstituted olefin in 78% yield and
33:1 Z/E ratio. Dihydroxylation of this olefin with
(DHQD)2PHAL/K2OsO4·2H2O (4 mol%) furnished the
1,2-diol 12 in 81% yield and 96:4 d.r.[13,14] Selective depro-
tection of the primary tert-butyldimethylsilyl ether over the
tertiary triethylsilyl ether could be accomplished with
HF·pyridine/pyridine (1:3).[15] Chemoselective two-step oxi-
[*] D. Muri, N. Lohse-Fraefel, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Hꢁnggerberg
8093 Zꢀrich (Switzerland)
Fax: (+41)1-632-1328
E-mail: carreira@org.chem.ethz.ch
[**] This research was supported by the Swiss National Science
Foundation and F. Hoffmann-LaRoche AG.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4036
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DOI: 10.1002/anie.200500172
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Angewandte
Chemie
would extend the methodology beyond an
aldol-equivalent strategy to one that could
provide unusual analogues not directly
accessible either through genetic engineer-
ing or traditional synthetic methods. A
number of erythromycin analogues inves-
tigated in the pharmaceutical industry are
heterocyclic derivatives (bridging C9–C11,
for example) prepared from the natural
product.[19] We thus became interested in
the generation of nonnatural analogues
such as 18 (Scheme 4). In a similar reaction
sequence as described above, isoxazoline 4
could easily be converted to oxime 16 and
subsequently to carboxylic acid 17. Under
modified Yamaguchi conditions, we
obtained macrolactone 18 in 60% yield.
Since the nitrile oxide and allylic alcohol
partners can be varied readily, this strategy
enables an approach to a plethora of
Scheme 2. Conditions: a) i) tBuOCl, CH2Cl2, ꢀ788C, 1.5 h, ii) iPrOH, EtMgBr, 3, CH2Cl2,
08C!RT, 86%, (d.r.>99:1); b) TEMPO (15 mol%), NaOCl, KBr (10 mol%), pH 8.6 buffer,
CH2Cl2, 08C, 1 h, 93%; c) PrPPh3Br, tBuLi, THF, ꢀ788C!RT, 15 h, 78%, (Z:E 33:1);
d) (DHQD)2PHAL (20 mol%), K3[Fe(CN)6], MeSO3NH2, K2CO3, K2OsO4·2H2O, tBuOH/
H2O, 08C, 2.5 h, 81% (d.r. 96:4); e) HF·py:py (1:3), 08C, 3 h, 80%; f) TEMPO (15 mol%),
NaOCl, KBr (10 mol%), pH 8.6 buffer, CH2Cl2, 08C, 30 min; g) NaClO2, 2-methyl-2-butene,
pH 3.8 buffer, tBuOH, 08C, 30 min, 83% (over 2 steps). py=pyridine, (DHQD)2PHAL=di-
hydroquinidine phthalazine ligand. R=TES.
dation (TEMPO/NaOCl, NaClO2, 83% yield) completed the
synthesis of erythronolide A seco acid 13.
At the outset of this project, it was far from certain
whether the cyclization could be successfully executed with
the isoxazoline carboxylic acid 13. The classic work of
Woodward on the total synthesis of erythromycin A under-
scores the sensitivity of related macrolactonizations of
carboxylic acids to the constellation of protecting groups.[16]
On the basis of modeling, we hypothesized that an isoxazoline
bridging C9–C11 would lead to a favorable conformation of
13 and facilitate macrolactonization. Indeed, following a
modified Yamaguchi protocol,[17] the desired macrolactone
was isolated in 78% yield without detection of any other
Scheme 4. Conditions: a) i) 2,4,6-Cl3C6H2COCl, NEt3, THF, 08C,
30 min; ii) DMAP, toluene, 508C, 4 h, 60%.
cyclization by-products (Scheme 3). Deprotection of the
ꢀ
triethylsilyl ether and subsequent N O bond cleavage
(Raney-Ni, AcOH) provided 15 in 93% yield, thus complet-
ing the formal total synthesis of erythronolide A. Treatment
of 15 with Pd(OAc)2 for 6 h under an atmosphere of H2
derivatives that may exhibit useful properties and allow the
development of new antibiotics against multiresistant bacte-
rial strains.
1
produced erythronolide A. Its H and 13C NMR spectra as
well as melting point and optical rotation are identical with
In summary, we have reported a stereoselective total
synthesis of erythronolide A, whose focal points are two MgII-
mediated cycloadditions of nitrile oxides, making this the
shortest synthesis of erythronolide A to date: 21 linear steps,
4% overall yield. These accomplishments establish this
methodology as a powerful tool for the synthesis of polyke-
tide natural products. The isoxazoline serves as a robust
protecting group for b-hydroxyketones that can be cleaved at
a late stage of the synthesis within a densely functionalized
structure. Moreover, the isoxazoline proved suitable for the
delicate macrolactonization of erythronolide A seco acid 13.
Of broader significance, the strategy, beyond its use as an
aldol equivalent process, opens up new possibilities for the
preparation of nonnatural analogues.
those of naturally derived erythronolide A.[18]
An important aspect of this cycloaddition strategy would
be the ability to access nonnatural polyketides. This approach
Scheme 3. Conditions: a) i)2,4,6-Cl3C6H2COCl, NEt3, THF, 08C, 30 min;
ii) DMAP, toluene, 508C, 4 h, 78%; b) HF·NEt3, NEt3, CH3CN, RT, 64 h,
>99%; c) Raney-Ni (W2), AcOH, H2, EtOH, RT, 20 min, 93%; d) Pd-
(OAc)2, MeOH, H2, RT, 6 h, 40%. DMAP=4-N,N-dimethylamino-
pyridine.
Received: January 17, 2005
Published online: May 20, 2005
Angew. Chem. Int. Ed. 2005, 44, 4036 –4038
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4037

Communications
was excellent: S. D. Burke, F. J. Schoenen, M. S. Nair, Tetrahe-
dron Lett. 1987, 28, 4143.
Keywords: asymmetric synthesis · cycloaddition ·
erythronolides · macrolactonization · nitrile oxides
.
[14] For recent reviews on Sharpless asymmetric dihydroxylations,
see: a) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem.
Rev. 1994, 94, 2483; b) R. A. Johnson, K. B. Sharpless in
Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH, New
York, 2000, pp. 357.
[15] On a similar system, selective deprotection of the tertiary
hydroxy group was observed under acidic conditions (dichloro-
acetic acid, MeOH, 08C).
[1] J. M. McGuire, R. L. Bunch, R. C. Anderson, H. E. Boaz, E. H.
Flynn, H. M. Powell, J. W. Smith, Antibiot. Chemother. 1952, 2,
281.
[2] The first total synthesis of an erythronolide analogue was
reported in 1978: E. J. Corey, E. J. Trybulski, L. S. Melvin, Jr.,
K. C. Nicolaou, J. A. Secrist, R. Lett, J. R. Sheldrake, D. J.
Brunell, M. F. Haslanger, S. Kim, S.-e. Yoo, J. Am. Chem. Soc.
1978, 100, 4618; E. J. Corey, E. J. Trybulski, L. S. Melvin, Jr.,
K. C. Nicolaou, J. A. Secrist, R. Lett, J. R. Sheldrake, D. J.
Brunell, M. F. Haslanger, S. Kim, S.-e. Yoo, J. Am. Chem. Soc.
1978, 100, 4620.
[3] For reviews on early synthetic work, see: a) I. Paterson, M. M.
Mansuri, Tetrahedron 1985, 41, 3569; b) J. Mulzer, Angew. Chem.
1991, 103; Angew. Chem. Int. Ed. Engl. 1991, 30, 1452.
[4] For recent studies on the syntheses of erythromycins and
erythronolides, see: a) R. Stꢁrmer, K. Ritter, R. W. Hoffmann,
Angew. Chem. 1993, 105, 112; Angew. Chem. Int. Ed. Engl. 1993,
32, 101; b) S. F. Martin, T. Hida, P. R. Kym, M. Loft, A. Hodgson,
J. Am. Chem. Soc. 1997, 119, 3193; c) D. A. Evans, A. S. Kim, R.
Metternich, V. J. Novack, J. Am. Chem. Soc. 1998, 120, 5921;
d) P. J. Hergenrother, A. Hodgson, A. S. Judd, W.-C. Lee, S. F.
Martin, Angew. Chem. 2003, 115, 3400; Angew. Chem. Int. Ed.
2003, 3278; e) Z.-H. Peng, K. A. Woerpel, J. Am. Chem. Soc.
2003, 125, 6018.
[5] a) J. W. Bode, N. Fraefel, D. Muri, E. M. Carreira, Angew. Chem.
2001, 113, 2128; Angew. Chem. Int. Ed. 2001, 40, 2082; b) for
comprehensive reviews on cycloadditions of nitrile oxides, see: P.
Caramella, P. Grꢁnanger in 1,3-Dipolar Cycloaddition Chemis-
try, Vol. 1 (Ed.: A. Padwa), Wiley-Interscience, New York, 1984,
pp. 292 – 392; C. J. Easton, C. M. M. Hughes, G. P. Savage, G. W.
Simpson, Adv. Heterocycl. Chem. 1994, 60, 261; c) for applica-
tions of cycloadditions of nitrile oxides in the synthesis of
heterocycles and natural products, see: “Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products” by V. Jꢂger, P. A. Colinas in The
Chemistry of Heterocyclic Compounds, Vol. 59 (Eds.: A.
Padwa, W. H. Pearson), Wiley, New York, 2002, pp. 361 – 472.
[6] Oxime 2 was prepared in three steps from (S)-methyl-3-
hydroxyisobutyrate, which is available for less than 1 E per
gram from Mitsubishi Rayon Co., Ltd. We would like to thank
Mitsubishi Rayon Co. for a generous gift of (S)-methyl-3-
hydroxyisobutyrate.
[7] a) Several preparations of chiral olefin 3 have been reported; for
our purposes it was prepared from enantiomerically pure 2-
hydroxy-3-pentyne, itself prepared by the method of R. Noyori,
J. Am. Chem. Soc. 1997, 119, 8738; b) for another procedure, see:
O. Hamed, P. M. Henry, Organometallics 1997, 16, 4903.
[8] W. P Griffith, S. V. Ley, G. P. Whitecomb, A. D. White, J. Chem.
Soc. Chem. Commun. 1987, 1625.
[9] Compound 6 was prepared from the corresponding bromide by
lithium–halogen exchange with tBuLi and subsequent trans-
metalation with MgBr2; the bromide is available in three steps
from (S)-methyl-3-hydroxyisobutyrate: P. M. Smith, E. J.
Thomas, J. Chem. Soc. Perkin Trans. 1 1998, 3541.
[10] a) D. P. Curran, J. Am. Chem. Soc. 1983, 105, 5826; b) D. P.
Curran, S. A. Scanga, C. J. Fenk, J. Org. Chem. 1984, 49, 3474.
[11] a) Y. Ito, M. Yamaguchi, Tetrahedron Lett. 1983, 24, 5385; b) T.
Nakata, Y. Tani, M. Hatozaki, T. Oishi, Chem. Pharm. Bull.
1984, 32, 1411; c) D. A. Evans, M. D. Ennis, and T. Le, N.
Mandel, G. Mandel, J. Am. Chem. Soc. 1984, 106, 1154.
[12] G. Wittig, U. Schꢃllkopf, Chem. Ber. 1954, 87, 1318.
[13] Substrate-directed dihydroxylation on a similar system proved
troublesome; no diastereoselectivity was observed but the yield
[16] Woodwardꢀs early investigation revealed a 9-(S)-hydroxy group,
protected as a cyclic acetal, ideal for a successful lactonization of
the carboxylic acid: a) R. B. Woodward, E. Logusch, K. P.
Nambiar, K. Sakan, D. E. Ward, B.-W. Au-Yeung, P. Balaram,
L. J. Browne, P. J. Card, C. H. Chen, R. B. ChÞnevert, A. Fliri, K.
Frobel, H.-J. Gais, D. G. Garratt, K. Hayakawa, W. Heggie, D. P.
Hesson, D. Hoppe, I. Hoppe, J. A. Hyatt, D. Ikeda, P. A. Jacobi,
K. S. Kim, Y. Kobuke, K. Kojima, K. Krowicki, V. J. Lee, T.
Leutert, S. Malchenko, J. Martens, R. S. Matthews, B. S. Ong,
J. B. Press, T. V. Rajan Babu, G. Rousseau, H. M. Sauter, M.
Suzuki, K. Tatsuta, L. M. Tolbert, E. A. Truesdale, I. Uchida, Y.
Ueda, T. Uyehara, A. T. Vasella, W. C. Vladechick, P. A. Wade,
R. M. Williams, H. N.-C. Wong, J. Am. Chem. Soc. 1981, 103,
3210; b) R. B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan,
D. E. Ward, B.-W. Au-Yeung, P. Balaram, L. J. Browne, P. J.
Card, C. H. Chen, R. B. ChÞnevert, A. Fliri, K. Frobel, H.-J.
Gais, D. G. Garratt, K. Hayakawa, W. Heggie, D. P. Hesson, D.
Hoppe, I. Hoppe, J. A. Hyatt, D. Ikeda, P. A. Jacobi, K. S. Kim,
Y. Kobuke, K. Kojima, K. Krowicki, V. J. Lee, T. Leutert, S.
Malchenko, J. Martens, R. S. Matthews, B. S. Ong, J. B. Press,
T. V. Rajan Babu, G. Rousseau, H. M. Sauter, M. Suzuki, K.
Tatsuta, L. M. Tolbert, E. A. Truesdale, I. Uchida, Y. Ueda, T.
Uyehara, A. T. Vasella, W. C. Vladechick, P. A. Wade, R. M.
Williams, H. N.-C. Wong, J. Am. Chem. Soc. 1981, 103, 3213;
R. B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan, D. E.
Ward, B.-W. Au-Yeung, P. Balaram, L. J. Browne, P. J. Card,
C. H. Chen, R. B. ChÞnevert, A. Fliri, K. Frobel, H.-J. Gais, D. G.
Garratt, K. Hayakawa, W. Heggie, D. P. Hesson, D. Hoppe, I.
Hoppe, J. A. Hyatt, D. Ikeda, P. A. Jacobi, K. S. Kim, Y. Kobuke,
K. Kojima, K. Krowicki, V. J. Lee, T. Leutert, S. Malchenko, J.
Martens, R. S. Matthews, B. S. Ong, J. B. Press, T. V. Rajan Babu,
G. Rousseau, H. M. Sauter, M. Suzuki, K. Tatsuta, L. M. Tolbert,
E. A. Truesdale, I. Uchida, Y. Ueda, T. Uyehara, A. T. Vasella,
W. C. Vladechick, P. A. Wade, R. M. Williams, H. N.-C. Wong, J.
Am. Chem. Soc. 1981, 103, 3215.
[17] a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi,
Bull. Chem. Soc. Jpn. 1979, 52, 1989; studies in the context of
erythronolide macrolactoniziation: Y. Sakurai, M. Hikota, K.
Horita, O. Yonemitsu, Chem. Pharm. Bull. 1992, 40, 2540.
[18] a) Formation of erythromycin A oxime, see: A. M. Costa, J.
Vilarrasa, Tetrahedron Lett. 2000, 41, 3371; b) Glycoside cleav-
age, see: R. A. LeMahieu, M. Carson, R. W. Kirstead, J.
Antibiot. 1975, 28, 704; c) Regeneration of the ketone, see:
R. A. LeMahieu, M. Carson, R. W. Kierstead, L. M. Fern, J.
Med. Chem. 1974, 17, 953.
[19] For recent modifications, see, for example: a) Y. Watanabe, T.
Adachi, T. Asaka, M. Kashimura, S. Morimoto, Heterocycles
1990, 31, 2121; b) R. L. Elliott, D. Pireh, G. Griesgraber, A. M.
Nilius, P. J. Ewing, M. H. Bui, P. M. Raney, R. K. Flamm, K. Kim,
R. F. Henry, D. T. W. Chu, J. J. Plattner, Y. S. Or, J. Med. Chem.
1998, 41, 1651; c) T. Tanikawa, T. Asaka, M. Kashimura, K.
Suzuki, H. Sugiyama, M. Sato, K. Kameo, S. Morimoto, A.
Nishida, J. Med. Chem. 2003, 46, 2706; d) M. C. Hsu, A. J. Junia,
A. R. Haight, W. Zhang, J. Org. Chem. 2004, 69, 3907.
4038
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