Total synthesis and absolute configuration of macrocidin A, a cyclophane tetramic acid natural product

Article abstract of DOI:10.1002/anie.200906362

(Figure Presented) Stereocontrolled access to the cyclophane framework of macrocidin A has been achieved for the first time. The key steps include the iridium-catalyzed asymmetric hydrogenation without fission of the C-I bond, the macrolactam formation by intramolecular ketene trapping, and the Lacey-Dieckmann cyclization for the construction of the tetramic acid ring.

Full text of DOI:10.1002/anie.200906362

Angewandte
Chemie
DOI: 10.1002/anie.200906362
Total Synthesis
Total Synthesis and Absolute Configuration of Macrocidin A,
a Cyclophane Tetramic Acid Natural Product**
Tomohiro Yoshinari, Ken Ohmori, Marcus G. Schrems, Andreas Pfaltz,* and Keisuke Suzuki*
Macrocidin A (1) and macrocidin B (2) represent a new
family of plant pathogens produced by Phoma macrostoma, a
microorganism parasitic to Canadian thistle.[1] The intriguing
structure of 1, which includes a tetramic acid[2] group installed
in a cyclophane skeleton, was determined by extensive 2D
NMR studies and single-crystal X-ray analysis, although the
absolute configuration remains to be addressed because of a
paucity of the natural sample. The macrocidins have signifi-
cant herbicidal activity on broadleaf weeds but not on grasses,
which makes them a potential lead for new herbicide design.
Their biological activity and novel chemical structures have
made these compounds attractive targets for chemical syn-
thesis. Whilst construction of the macrocyclic skeleton has
been addressed,[3] the synthesis of the full structure remains to
be achieved. Herein, we describe the first total synthesis of
macrocidin A (1) using macrolactam formation followed by
cyclization.
Scheme 1. Retrosynthetic analysis of macrocidin A.
Scheme 1 outlines our retrosynthetic analysis based upon
the construction of the acyltetramic acid moiety using the
Lacey–Dieckmann cyclization[4] of macrolactam I, which in
turn would be accessible by the intramolecular trapping of an
acylketene species (a) that may be thermally generated from
dioxinone precursor II.[5] This key intermediate (II) could be
assembled from the stereodefined epoxy alcohol III and
tyrosine unit IV. One of the challenges in the synthesis of III
was the establishment of the C12 stereogenic center,[6] for
which we planned to employ either a substrate- or catalyst-
controlled diastereoselective hydrogenation of trisubstituted
olefin V. Finally, olefin V could be obtained from phospho-
nate VI and aldehyde VII.
[*] T. Yoshinari, Dr. K. Ohmori, Prof. Dr. K. Suzuki
Department of Chemistry
Scheme 2 shows the preparation of trisubstituted olefins
10 and 11, which began with the two-step conversion of
propargyl alcohol into allyl alcohol 5.[7] Epoxide 6, which was
prepared by a Katsuki–Sharpless asymmetric epoxidation
reaction (93% ee),[8] was silylated and subjected to rhodium-
catalyzed hydroboration,[9] followed by oxidation to give
alcohol 8. Swern oxidation of 8, followed by a Horner–
Emmons reaction with chiral phosphonate 12[10] afforded
olefin 10 (E/Z = 9:1). Recrystallization (n-hexane/ethyl ace-
tate) gave pure (E)-10, which had a stereodefined trisubsti-
tuted olefin and a menthone chiral auxiliary[11] ready for
diastereoselective hydrogenation. The substrate for the
catalyst-controlled diastereoselective hydrogenation, aceto-
Tokyo Institute of Technology,SORST-JSTAgency
2-12-1, O-okayama, Meguro-ku, Tokyo, 152-8551 (Japan)
Fax: (+81)3-5734-2788
E-mail: ksuzuki@chem.titech.ac.jp
Dr. M. G. Schrems, Prof. Dr. A. Pfaltz
Department of Chemistry, University of Basel
St.Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
[**] This work was supported by the Global COE program (Chemistry)
and a Grant-in-Aid for Scientific Research (JSPS). T.Y. thanks the
JSPS for a Research Fellowship for Young Scientists.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906362.
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the product (14) in excellent yield, although the stereoselec-
tivity was uniformly 1:1. Therefore, unfortunately, the stereo-
selective influence of the chiral auxiliary on the hydrogena-
tion reaction was negligible.
At this stage, we decided to investigate the catalyst-
controlled asymmetric hydrogenation reaction, primarily
considering iridium catalysts with chiral N,P ligands that are
known to be uniquely effective for unfunctionalized olefins
and do not require neighboring group participation.[13]
Attempts at the enantioselective hydrogenation of prochiral
substrate 15 with catalysts A–E (Scheme 4) were mostly
Scheme 2. Preparation of substrates 10 and 11. a) Allyl bromide, CuI,
NaI, K2CO3, acetone, RT, 5 h (85%). b) LiAlH4, THF, reflux, 2 h (75%).
c) (iPrO)4Ti, l-(+)-diethyl tartrate, tBuOOH, M.S. 4 ꢀ, CH2Cl2, ꢀ208C,
24 h (80%, 93% ee). d) tBuPh2SiCl, imidazole, DMF, RT, 1 h (99%).
e) Catecholborane, [Rh(PPh3)3Cl], THF, 08C, 1.5 h; H2O2, pH 7 phos-
phate buffer (72%). f) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78!08C,
1.5 h, (quant.). g) 12, LiN(iPr)2, THF, ꢀ78!08C (99%, E/Z=9:1);
recrystallization (n-hexane/EtOAc), 57%. h) 13, LiN(iPr)2, HMPA, THF,
ꢀ78!08C (96%, E/Z=9:1), SiO2 gel chromatography. M.S.=molecu-
lar sieves, TBDPS=tert-butyldiphenylsilyl, DMF=N,N-dimethylforma-
mide, DMSO=dimethyl sulfoxide, HMPA=hexamethylphosphora-
mide.
Scheme 4. The attempted asymmetric hydrogenation of 15.
nide 11, was also prepared in a similar manner, except for the
use of HMPA as a co-solvent in the olefination step to prevent
aggregation of the phosphonate anion that is derived from 13.
The E/Z ratio was again 9:1, but (E)-11 was easily isolated by
silica gel column chromatography.
In addressing the controlled construction of the C12
stereogenic center, our initial attempts used the chiral, non-
racemic substrate 10, hoping that the menthone moiety would
control the diastereomeric facial selection (Scheme 3). How-
ever, no reaction occurred with homogeneous catalysts, such
as Wilkinson[12a] or Crabtree[12b] complexes, presumably owing
to the high steric hindrance around the olefin. Conversely,
several heterogeneous catalysts were active enough to give
disappointing, with poor catalytic activities observed except
in the case of catalyst A.[13a] In the presence of 2 mol% of A
(CF3CH2OH; room temperature; 12 h), the highly enantio-
selective hydrogenation of 15 did proceed to give the desired
product 16 with excellent stereoselectivity (97:3), albeit in low
yield (18%). The problem was the low reactivity, and even at
pressures as high as 10 MPa the reaction was sluggish. When
carried out at 408C, a slightly higher yield of 16 was obtained
(40%) with recovery of 15 in 38% yield. However, no further
improvement was possible, either by extending the reaction
time or by increasing the catalyst loading, because the
epoxide moiety seemed to be damaged by the fairly high
Lewis acidity of the iridium catalyst or the Brønsted acidity of
iridium hydride intermediates.
After considerable experimentation, a solution was found
by converting the epoxide into the corresponding iodohydrin
prior to the hydrogenation (Scheme 5). Therefore, alcohol 17
was prepared by the desilylation of 11 (nBu4NF, THF, 08C,
1 h, 99%), which allowed the highly regioselective (92:8)
epoxide ring opening (NaI, B(OAc)3, AcOH, acetone),[14] to
give 1,3-diol 18 as the major product along with a small
amount of 1,2-diol 18’ in 94% combined yield (18/18’ = 92:8);
these products were easily separated by silica gel column
Scheme 3. Diastereoselective hydrogenation of 10.
882
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Indeed, we were pleased to find that the first step was
realized quite smoothly by the heating of 23 in toluene
(reflux, 2 h), giving macrolactam 24 in 90% yield, ready for
the final step of the total synthesis. However, we were
disappointed by the complete failure of the attempted Lacey–
Dieckmann condensation to convert macrolactam 24 into
macrocidin A (1) using tBuOK or various other basic reagents
(e.g. nBu4NF, NaOMe).
Single-crystal X-ray diffraction analysis of 24[21] suggested
an inherent problem in the cyclization substrate: the distance
between C10 and C19[6] was too large (4.61 ꢀ) to allow bond
formation (Figure 1). To bring the two centers closer together,
Scheme 5. Hydrogenation of 18. a) NaI, B(OAc)3, AcOH, acetone,
ꢀ20!08C, 2 h (94%). b) H2 (10 MPa), A (2 mol%), CF3CH2OH,
408C, 12 h (96%). c) K2CO3, methanol, RT, 1 h (quant.).
chromatography.[15] Pleasingly, the attempted hydrogenation
of 18 in the presence of iridium catalyst A proceeded
[16]
ꢀ
smoothly, without any reductive fission of the C I bond,
affording the desired compound 19 in excellent yield (96%)
and excellent stereoselectivity (97:3).[17] Treatment of 19 with
potassium carbonate in methanol regenerated the oxirane
ring to regioselectively afford epoxy alcohol 20 in quantitative
yield.[18]
Figure 1. Conformational analysis of macrolactam 24 and a strategy for
the construction of the tetramic acid ring.
For preparation of the macrolactam precursor, tyrosine
unit 21[19] was coupled with epoxy alcohol 20 using the
Mitsunobu reaction (TMAD and nBu3P);[20] detachment of
the benzyloxycarbonyl protecting group then gave amine 23.
The pivotal construction of the macrocidin skeleton involved
two stages: 1) macrolactam formation via intramolecular
ketene trapping, and 2) Lacey–Dieckmann cyclization for
constructing the tetramic acid (Scheme 6).
the geometry of the amide group would have to be changed
from the s-trans to the s-cis conformation. It occurred to us
that such a conformational change would be achieved if a
protecting group was introduced at the amide nitrogen atom,
thus providing a more favorable situation for the cyclization.
Along these lines, we prepared para-azidobenzyl (PAB)[22]
derivative 28, which was later employed in the eventual route,
starting from the Mitsunobu reaction (DEAD, PPh3) of epoxy
alcohol 20 and phenol 25[23] (Scheme 7). In this instance, the
Scheme 7. Synthesis of para-azidobenzyl-protected macrocidin A (29).
a) DEAD, PPh3, toluene, RT, 3 h (89%). b) nBu4NF, THF, RT, 4 h
(91%). c) Toluene, reflux, 2 h (86%). d) tBuOK, tBuOH, THF, RT,
30 min (87%). DEAD=diethyl azodicarboxylate, Teoc=2-(trimethyl-
silyl)ethoxycarbonyl. PAB=p-azidobenzyl.
Scheme 6. Attempts for the macrolactam formation and the Lacey–
Dieckmann condensation. a) TMAD, nBu3P, toluene, RT, 3 h (89%).
b) H2, Pd(OH)2/C, MeOH, RT, 4 h (98%). c) Toluene, reflux, 2 h
(90%). Cbz=benzyloxycarbonyl, TMAD=N,N,N’,N’-tetramethyl azodi-
carboxamide.
use of TMAD and nBu3P was not suitable, because the azide
moiety in phenol 25 was reduced by the latter reagent. The 2-
(trimethylsilyl)ethoxycarbonyl (Teoc) group in 26 was
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883

Communications
[5] a) G. Jꢁger, J. Wenzelburger, Justus Liebigs Ann. Chem. 1976,
1689 – 1712; b) M. Sato, N. Kanuwa, T. Kato, Chem. Pharm. Bull.
1982, 30, 1315 – 1321; c) M. Sato, H. Ogasawa, E. Yoshizumi, T.
Kato, Chem. Pharm. Bull. 1983, 31, 1902 – 1909.
removed to give compound 27, which smoothly underwent
macrolactam formation to 28 in 86% yield by heating to
reflux in toluene. To our delight, the protected substrate 28
indeed underwent Lacey–Dieckmann cyclization upon treat-
ment with tBuOK (room temperature, 0.5 h) to give the
corresponding tetramic acid 29 in 87% yield. Notably, the
C14 and C15 proton signals of 29 appeared at higher field
(C14, d = 0.49; C15, d = 0.80); this is ascribable to the
anisotropic effect of the benzene ring within a rigid cyclo-
phane skeleton.
[6] The natural product numbering.
[7] a) N. P. Villalva-Servꢂn, A. Laurent, A. G. Fallis, Can. J. Chem.
2004, 82, 227 – 239; b) J. A. Rao, M. P. Cava, J. Org. Chem. 1989,
54, 2751 – 2753.
[8] S. Ma, B. Ni, Chem. Eur. J. 2004, 10, 3286 – 3300. The
enantiomeric excess was assessed by chiral HPLC analysis of
the corresponding para-toluenesulfonate (DAICEL CHIRAL-
PAK IA, f 0.46 ꢃ 25 cm, n-hexane/iPrOH = 95:5, 0.5 mLminꢀ1
,
The final step was the particularly problematic removal of
the amide protecting group. After a number of unsuccessful
attempts using other protecting groups,[24] the para-azidoben-
zyl protecting group,[22] employed in 29, was found to be the
only group that could be successfully removed in the final step
of the synthesis. Reduction of the azide moiety in 29 gave the
corresponding amine, which, upon exposure to DDQ in the
presence of water, afforded macrocidin A (1) as a pale beige
solid that exhibited physical properties consistent with the
reported data (1H and 13C NMR, IR, mass spectra).[1]
Although the melting point was not reported in the original
paper,[1] reprecipitation (dichloromethane/methanol) gave 1
as a fine, pale beige powder with a melting point of 205–
2078C. The sign and magnitude of the optical rotation
concurred well with the reported values of natural macro-
cidin A: ½aꢁ2D7 = + 42 (c = 0.18, methanol), lit. ½aꢁ2D5 = + 45 (c =
0.35, methanol), thus establishing the absolute configuration
of the natural product as shown (Scheme 8).
308C). For a review on Katsuki–Sharpless epoxidation, see: T.
Katsuki, V. S. Martin, Org. React. 1996, 48, 1 – 299.
[9] D. Mꢁnnig, H. Nꢄth, Angew. Chem. 1985, 97, 854 – 855; Angew.
Chem. Int. Ed. Engl. 1985, 24, 878 – 879.
[10] Chiral phosphonate 12 was synthesized by
a three-step
sequence: 1) Meldrumꢅs acid, propionyl chloride, pyridine,
CH2Cl2. 2) Toluene, (ꢀ)-menthone, reflux. 3) LiN(iPr)2, ClP-
(OEt)2, THF, then H2O2, CH2Cl2. For the preparation of achiral
phosphonate 13, see: R. K. Boeckmann, Jr., T. M. Kmenecka,
S. G. Nelson, J. R. Pruitt, T. E. Barta, Tetrahedron Lett. 1991, 32,
2581 – 2584.
[11] For the preparation and reaction of menthone as a chiral
auxiliary in dioxinone chemistry, see: a) M. Sato, K. Takayama,
T. Furuya, N. Inukai, T. Kato, Chem. Pharm. Bull. 1987, 35,
3971 – 3974; b) M. Demuth, A. Palomer, H. D. Sluma, A. K. Dey,
C. Kruger, Y. H. Tsay, Angew. Chem. 1986, 98, 1093 – 1095;
Angew. Chem. Int. Ed. Engl. 1986, 25, 1117 – 1119; c) K. Ohmori,
Bull. Chem. Soc. Jpn. 2004, 77, 875 – 885.
[12] a) J. A. Osborn, F. H. Jardine, J. F. Young, G. Wilkinson, J.
Chem. Soc. 1966, 1711 – 1732; b) R. H. Crabtree, Acc. Chem.
Res. 1979, 12, 331 – 338.
[13] a) S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. 2006, 118,
5318 – 5321; Angew. Chem. Int. Ed. 2006, 45, 5194 – 5197; b) S.
Bell, B. Wꢆstenberg, S. Kaiser, F. Menges, T. Netscher, A. Pfaltz,
Science 2006, 311, 642 – 644.
[14] Y. Tomata, M. Sasaki, K. Tanino, M. Miyashita, Tetrahedron
Lett. 2003, 44, 8975 – 8977. Under the original conditions (NaI,
B(OMe)3, AcOH, acetone), the regioselectivity was 84:16; this
was improved to 92:8 by switching from B(OMe)3 to B(OAc)3.
[15] It is noted that regioisomer 18ꢀ underwent the hydrogenation
with slightly lower stereoselectivity and in lower yield. A side
product was obtained that was derived from tetrahydropyran
formation as well as the deacetonization/decarboxylation as
shown below.
Scheme 8. Total synthesis of macrocidin A. a) H2, 10% Pd/C, MeOH,
THF, RT, 2 h. b) DDQ, H2O, THF, room temperature, 0.5 h (78%, 2
steps). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
In summary, we have achieved the first total synthesis of
macrocidin A. and have established the absolute configura-
tion. Further work is ongoing to synthesize macrocidin B and
other analogues of biological relevance.
Received: November 11, 2009
Published online: December 28, 2009
Keywords: asymmetric catalysis · hydrogenation · iridium ·
.
natural products · total synthesis
ꢀ
[16] For the hydrogenation of substrates that contain C I bonding, a
[1] P. R. Graupner, A. Carr, E. Clancy, J. Gilbert, K. L. Bailey, J.-A.
Derby, B. C. Gerwick, J. Nat. Prod. 2003, 66, 1558 – 1561.
[2] a) R. Schobert, A. Schlenk, Bioorg. Med. Chem. 2008, 16, 4203 –
4221; b) B. J. L. Royles, Chem. Rev. 1995, 95, 1981 – 2001.
[3] C. V. Ramana, M. A. Mondal, V. G. Puranic, M. K. Gurjar,
Tetrahedron Lett. 2006, 47, 4061 – 4064.
report has been published on the tolerance of vinyl iodide to
hydrogenation over Crabtreeꢅs catalyst: R. W. Denton, K. A.
Parker, Org. Lett. 2009, 11, 2722 – 2723.
[17] The absolute and relative configuration of 19 was verified by X-
ray analysis at the stage of 24.
[4] R. N. Lacey, J. Chem. Soc. 1954, 850 – 854.
884
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[18] Formation of the disubstituted epoxide is known to be kineti-
cally preferable to formation of the primary epoxide: R. M.
Hanson, Org. React. 2002, 60, 1 – 156.
[19] J. B. West, C.-H. Wong, J. Org. Chem. 1986, 51, 2728 – 2735.
[20] a) O. Mistunobu, Synthesis 1981, 1 – 28; b) T. Tsunoda, J. Otsuka,
Y. Yamamiya, S. Ito, Chem. Lett. 1994, 539 – 542.
[21] CCDC 756980 (24) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[22] K. Fukase, M. Hashida, S. Kusumoto, Tetrahedron Lett. 1991, 32,
3557 – 3558.
[23] For the preparation of phenol 25; see the Supporting Informa-
tion.
[24] Other protecting groups that were tested but did not allow the
final deprotection include: benzyl, 2,4-dimethoxybenzyl, and
3,4-dimethoxybenzyl groups. This was presumably owing to the
susceptibility of the epoxide and the tetramic acid moieties
under hydrogenolytic, acidic (TFA), or oxidative (DDQ or
cerium ammonium nitrate) conditions.
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