Synthetic studies toward macrocidins: an RCM approach for the construction of the central cyclic core

Article abstract of DOI:10.1016/j.tetlet.2006.03.192

The central macrocyclic core of the macrocidins was constructed using RCM as the key reaction. A preliminary investigation dealing with the key reactions, that is, the Dieckmann cyclization and the RCM, revealed that RCM of the β-ketoamide is better than

Full text of DOI:10.1016/j.tetlet.2006.03.192

Tetrahedron Letters 47 (2006) 4061–4064
Synthetic studies toward macrocidins: an RCM approach
for the construction of the central cyclic core
C. V. Ramana,* Mohabul A. Mondal, Vedavati G. Puranik and Mukund K. Gurjar
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 22 February 2006; revised 23 March 2006; accepted 29 March 2006
Abstract—The central macrocyclic core of the macrocidins was constructed using RCM as the key reaction. A preliminary inves-
tigation dealing with the key reactions, that is, the Dieckmann cyclization and the RCM, revealed that RCM of the b-ketoamide is
better than RCM of the corresponding acyltetramic acid.
Ó 2006 Elsevier Ltd. All rights reserved.
Macrocidins A (1) and B (2), the first representatives of
a new family of cyclic tetramic acids, were recently
isolated from the liquid cultures of Phoma macrostoma
obtained from diseased Canada thistle growing in
several geographically diverse regions.1,2 The novel
macrocyclic skeleton and the relative configuration of
1 were determined by extensive 2D NMR and by a
single crystal X-ray structure. Biological testing of
purified samples against different types of herbs revealed
that these compounds have significant herbicidal activity
on broadleaf weeds, but apparently not on grass weeds.
The observed bleaching and stunting, primarily in the
new growth of susceptible weeds, led to the conclusion
that the macrocidins were phloem mobile. The combina-
tion of interesting herbicidal activity and novel chemical
structures makes the macrocidins attractive targets for
synthesis. Herein, we describe the synthetic studies
toward des-methylmacrocidin A (3) (Fig. 1).
The retrosynthetic analysis is represented by two strate-
gies, viz route-A and route-B, which differ the in order in
which the critical structural elements—the tetramic acid
O
O
O
O
O
H
O
HN
HN
HN
HN
HN
OH
OH
OH
Me
OH
Me
O
O
route A
O
O
O
HO
H
O
H
H
O
O
O
O
O
O
O
H
4
H
H
5a
Macrocidin A (1)
Macrocidin B (2) des-Methylmacrocidin A (3)
route B
O
O
O
H
NH2
HN
HN
HN
O
O
OMe
O
O
CO2Me
CO2Me
O
+
O
O
O
O
O
O
O
8
9
7
6
5b
Figure 1. Macrocidins A and B and the retrosynthetic route for des-methylmacrocidin A (3).
Keywords: Macrocidins; Acyltetramic acid; Lacey–Dieckmann cyclization; Ring closing metathesis.
*
Corresponding author. Tel.: +91 20 25902577; fax: +91 20 25893614; e-mail: vr.chepuri@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.192

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C. V. Ramana et al. / Tetrahedron Letters 47 (2006) 4061–4064
or the 18-membered macrocycle are formed. One issue
in the case of route-A would be the effect of the tauto-
meric structures 5a and 5b.3 The tautomeric structure
represented by 5b could prevent the RCM reaction from
taking place. The surrogate of the epoxide present
at C16–C17 of 3 would be the E-double bond.
Condensation of a tyrosine derivative and a substituted
[1,3]dioxin-4-one was envisaged to produce the key
material 7. Among the various synthetic methods4 that
could be utilized to construct acyltetramic acid units,
the Lacey–Dieckmann cyclization5 appeared to be the
most appropriate in this context.
Grubbs’ catalyst. However, the Lacey–Dieckmann cycli-
zation of the corresponding N-PMB derivative 11
(Scheme 2) in the presence of KOtBu was successful in
giving rise to the tetramic acid derivative 12.
The critical RCM reaction of 12 with 1st and 2nd gener-
ation Grubbs’ catalysts was unsatisfactory and only
traces of macrocyclic derivative 13 were isolated. This
suggested that the tautomeric structure 5b was favored.
The RCM reaction of ketoamide 11 with the 1st gener-
ation Grubbs’ catalyst was satisfactory and produced
the 18-membered cyclic lactam derivative 14 in 63%
yield. A Lacey–Dieckmann cyclization of 14 using
KOtBu in t-butanol gave the core structure 13. The
spectral and analytical data of 13 were in accordance
with the assigned structure.9 The large coupling (J =
Methyl O-allyl-L-tyrosinate (8)6 and [1,3]dioxin-4-one 97
were heated under reflux in toluene in a Dean–Stark
apparatus with continual removal of water to give
b-ketoamide 7 (Scheme 1). Efforts to transform 7 into
the corresponding tetramic acid derivative 5 were
unsuccessful. The same observation was noted with the
macrocycle 68 derived by the RCM reaction of 7 with
1
15.6 Hz) in the H NMR spectrum of 13 (which exists
as an equilibrating 1:3 keto-enol mixture) indicated the
required E-configuration of the cyclic olefin. A single
O
O
O
NH2
OH
HN
HN
CO2Me
O
O
KO
tBu
CO2Me
toluene
O
+
O
reflux, 7 h
72%
t-BuOH, rt
O
O
8
9
7
O
5
H
N
O
MeO2C
O
HN
OH
O
Grubbs' 1st gen
(10 mol%)
KOtBu
O
7
t-BuOH, rt
CH2Cl2, reflux, 12 h
63%
O
O
6
4
Scheme 1.
O
O
O
PMB
PMB
O
PMB
PMB
N
OH
N
NH
CO2Me
N
Grubbs' 2nd gen
(20 mol%)
OH
KOtBu
CO2Me
PPTS, toluene
O
O
9
+
reflux, 7 h
72%
CH2Cl2, reflux, 12 h
17%
t-BuOH, rt, 0.5 h
91%
O
O
O
O
13
Grubbs' 1st gen (10 mol%)
CH2Cl2, reflux, 36 h
63%
12
10
11
PMB
N
MeO2C
PMB
PMB
N
O
O
O
N
OH
OH
OH
KOtBu
O
O
t-BuOH, rt, 0.5 h
Table 1
O
56%
O
O
O
15
14
13
Scheme 2.

C. V. Ramana et al. / Tetrahedron Letters 47 (2006) 4061–4064
4063
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Afantitis, A.; Athanasellis, G.; Markopoulos, J.; Igglessi-
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2003, 4593–4600.
4. (a) Kohl, H.; Bhat, S. V.; Patell, J. R. Tetrahedron Lett.
1974, 12, 983–986; (b) Boekcman, R. K., Jr.; Weidner, C.
H.; Perni, R. B.; Napier, J. J. J. Am. Chem. Soc. 1989, 111,
8036–8037; (c) Paquette, L. A.; Macdonald, D.; Anderson,
L. G.; Wright, J. J. Am. Chem. Soc. 1989, 111, 8037–8039;
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Sumaria, S. J. Chem. Soc., Perkin Trans. 1 1990, 1959–
1968; (e) Poncet, J.; Jouin, P.; Castro, B.; Nicolas, L.;
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J. Chem. Soc., Perkin Trans. 1 1994, 1, 2513–2515; (h)
Petroliagi, M.; Igglessi-Markopoulou, O. J. Chem. Soc.,
Perkin Trans. 1 1997, 23, 3543–3548; (i) Andrews, M. D.;
Brewster, A. G.; Crapnell, K. M.; Ibbett, A. J.; Jones, T.;
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Perkin Trans. 1 1998, 223–235; (j) Matthews, J.; Rivero, R.
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poulou, O.; Markopoulos, J.; Skylaris, C.-K. Eur. J. Org.
Chem. 2003, 4593–4600; (n) Paintner, F. F.; Metz, M.;
Bauschke, G. Synlett 2003, 627–630; (o) Schobert, R.;
Jagusch, C. Tetrahedron 2005, 61, 2301–2307.
Figure 2. ORTEP structure of 13.
Table 1. Attempted conditions for the epoxidation of 13
Entry
Reagents and conditions
Result
1
2
3
4
5
6
7
MCPBA, CH2Cl2, ꢁ78 °C
MCPBA, CH2Cl2, rt
No reaction
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
OxoneÒ, acetone, EtOAc, rt
H2O2, NaHCO3, THF–water
H2O2, NaHCO3, CHCl3–water
H2O2, NaHCO3, PhCN–methanol
Diisopropyl tartarate, Ti(OiPr)4,
t
THF, ꢁ78 °C, BuOOH
8
PhCO2Ag, I2, Ph, reflux
No reaction
crystal X-ray structural analysis of 13 confirmed the
structure (Fig. 2).10
However, the final endeavor to install the epoxide on the
C16–C17 olefin, a reaction which looked to be straight
forward, turned out to be difficult. Many reagents
(Table 1) were utilized but the substrate 13 was unstable
to the reaction conditions and gave intractable mixtures
of compounds from which no pure product could be
isolated in an appreciable yield. This study showed that
the epoxide function would have to be installed by an
another synthetic protocol because, under reaction
conditions needed to epoxidize the olefin, the acyl-
tetramic acid group rapidly decomposed,11 at least in
our hands.
5. Lacey, R. N. J. Chem. Soc. 1954, 850–854.
6. Green, R.; Taylor, P. J. M.; Bull, S. D.; James, T. J.;
Mohan, M. F.; Merritt, A. T. Teterahedron: Asymmetry
2003, 14, 2619–2623.
7. Winkler, J. D.; Hey, J. P.; Hannon, F. J. Heterocycles
1987, 25, 55–60.
25
8. Spectral data of compound 6: ½aꢀD 15:3 (c 1.1, CHCl3). IR
(CHCl3): t 3340, 3019, 2931, 1727, 1973, 1611, 1511, 1217,
1
767 cmꢁ1. H NMR (500 MHz, CDCl3) d: 1.22–1.46 (m,
4H), 2.03 (d, J = 12.0 Hz, 1H), 2.04 (d, J = 12 Hz, 1H)
2.22 (ddd, J = 5.2, 9.3, 17.3 Hz, 1H), 2.40 (ddd, J = 5.9,
9.5, 17.3 Hz, 1H), 2.71 (dd, J = 10.0, 14.2 Hz, 1H), 3.18
(m, 2H), 3.35 (d, J = 14.5 Hz, 1H), 3.80 (s, 3H), 4.57 (dd,
J = 5.8, 14.2 Hz, 1H), 4.62 (dd, J = 5.5, 14.2 Hz, 1H), 4.67
(m, 1H), 5.45 (dt, J = 5.3, 15.6 Hz, 1H), 5.59 (dt, J = 6.9,
15.6 Hz, 1H), 6.75 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz,
2H). 13C NMR (125 MHz, CDCl3) d: 21.7 (t), 27.5 (t), 31.0
(t), 36.9 (t), 43.6 (t), 49.6 (t), 52.4 (q), 53.3 (d), 67.4 (t),
115.9 (d), 127 (d), 127.5 (s), 129.9 (d), 134.4 (d), 156.5 (s),
164.2 (s), 171.8 (s), 206.4 (s) ppm. ESI-MS: m/z 360.15
(51%, [M+H]+), 382.12 (100%, [M+Na]+). Anal. Calcd
for C20H25NO5: C, 66.83; H, 7.01; N, 3.90. Found: C,
66.66; H, 7.13; N, 3.72.
To conclude, our synthetic strategy to build the macro-
cyclic structure and the acyltetramic acid of macrocidins
was successful, although the macrocyclic intermediate
13 was found to be unstable to epoxidation conditions.
Acknowledgement
25
Financial support by CSIR (New Delhi) in the form of a
research fellowship to M.A.M. is gratefully acknowledged.
9. Spectral data of compound 13: ½aꢀD ꢁ 36:2 (c 1.2, CHCl3).
IR (CHCl3): t 3400, 3019, 2932, 1708, 1613, 1511, 1461,
1433, 1246, 1215, 1034, 757 cmꢁ1 1H NMR (500 MHz,
.
CDCl3) d: 1.04–1.13 (m, 2H), 1.15–1.23 (m, 1H), 1.26–1.34
(m, 1H), 1.89–1.94 (m, 2H), 2.02–2.07 (m, 1H), 2.97 (dd,
J = 4.1, 14.4 Hz, 1H), 3.04 (dd, J = 2.7, 14.4 Hz, 1H), 3.20
(dt, J = 6.7, 11.6 Hz, 1H), 3.79 (s, 3H), 4.14 (d,
J = 14.8 Hz, 1H), 4.55–4.60 (m, 3H), 5.27–5.42 (m, 1H),
5.34 (d, J = 14.8 Hz, 1H), 5.52 (dt, J = 7.4, 15.6 Hz, 1H),
6.68 (br s, 2H), 6.76–6.78 (m, 1H), 6.87 (br d, J = 8.0 Hz,
2H), 6.95 (br s, 1H), 7.21 (br d, J = 8.0 Hz, 2H). 13C NMR
(125 MHz, CDCl3) d: 27.5 (t), 28.6 (t), 32.1 (t), 32.2 (t), 32.4
(t), 42.6 (t), 55.2 (q), 64.1 (d), 66.8 (t), 101.5 (s), 114.3 (d),
References and notes
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C. V. Ramana et al. / Tetrahedron Letters 47 (2006) 4061–4064
114.4 (d), 125.5 (d), 125.6 (s), 127.4 (s), 129.6 (d), 129.7 (d),
Centre as deposition No. CCDC 298644. Copies of the
data can be obtained, free of charge, on application to the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
11. For reactions of tetronic acids with MCPBA, see: Scho-
bert, R.; Siegfried, S.; Weinga¨rtner, J.; Nieuwenhuyzen,
M. J. Chem. Soc., Perkin Trans. 1 2001, 2009–2011.
136.7 (d), 155.9 (s), 159.5 (s), 173.4 (s), 187.1 (s), 193.4 (s)
ppm. ESI-MS: m/z = 448.18 (69%, [M+H]+), 470.18
(100%, [M+Na]+). Anal. Calcd for C27H29NO5: C, 72.46;
H, 6.53; N, 3.13. Found: C, 72.28; H, 6.45; N, 2.98.
10. The crystallographic data of compound 13 have been
deposited with the Cambridge Crystallographic Data