Synthetic studies directed toward the proposed structure for heteroscyphic acid A

Article abstract of DOI:10.1039/b602700h

A route to the carbon skeleton of the proposed structure for heteroscyphic acid A was developed utilizing a Mn(iii)/Cu(ii) mediated oxidative free-radical cyclization and nucleophilic addition to (3-methylpentadienyl)iron(1+) cation. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602700h

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Synthetic studies directed toward the proposed structure for
heteroscyphic acid A{
Subhabrata Chaudhury, Shukun Li and William A. Donaldson*
Received (in Bloomington, IN, USA) 21st February 2006, Accepted 21st March 2006
First published as an Advance Article on the web 6th April 2006
DOI: 10.1039/b602700h
A route to the carbon skeleton of the proposed structure for
heteroscyphic acid A was developed utilizing a Mn(III)/Cu(II)
mediated oxidative free-radical cyclization and nucleophilic
addition to (3-methylpentadienyl)iron(1+) cation.
Heteroscyphic acids A and B are novel clerodane-type diterpenes
isolated from cultured cells of the liverwort Heteroscyphus planus.1
The structural assignments for the heteroscyphic acids (1a and 1b,
Scheme 1) were made on the basis of their MS and NMR spectral
+
Scheme 2 Model alkylations via (3-methylpentadienyl)Fe(CO)2PPh3
.
data. In particular, the 12Z-stereochemistry for 1b was assigned on
the basis of NOEs between Me-16 and H-12 and between H-14
and H-11. There are no reports of synthetic studies on the
heteroscyphic acids. As part of our interest in the application of
acyclic (pentadienyl)iron cations to organic synthesis,2 we
recognized that the 12Z-dienyl functionality proposed for 1a
might be available by addition of a bicyclo[4.4.0]decene anion (2)
to a (3-methylpentadienyl)Fe(CO)2L+ cation (3)3 (Scheme 1). The
(dicarbonyl)triphenylphosphine ligated cation (3a, L 5 PPh3) was
chosen, since we have recently discovered that addition of carbon
nucleophiles to the tricarbonyl ligated cation (3b, L 5 CO) affords
cyclohexenone products via attack at a C2 internal carbon.3
To explore the viability of this strategy, the anions derived from
2-carboethoxycyclohexenone and from methyl cyclohexanecar-
boxylate were reacted with cation 3a to afford the neutral diene
complexes 4 and 5 respectively (Scheme 2). Oxidative decomplexa-
tion of 4 or 5 with cerium ammonium nitrate [CAN] gave the
dienes 6 or 7.
It was envisioned that preparation of the requisite bicyclo[4.4.0]-
decane skeleton would rely on an oxidative free radical cyclization4
of a b-ketoester. To this end, Swern oxidation of 5-hexen-1-ol,
followed by Wittig olefination of the crude aldehyde gave the 2,7-
octadienoate 8 (Scheme 3). Reduction of 8, followed by treatment
of the resultant allylic alcohol with NBS/PPh3 gave the
corresponding bromide 9.5 Alkylation of the dianion generated
from methyl acetoacetate6 with 9 gave the requisite acyclic
b-ketoester 10. Treatment of 10 with Mn(III)/Cu(II), according to
the literature procedure,7 gave a separable mixture of trans-
decalone 12 along with a minor amount of the cis-isomer 11. Acid
catalyzed isomerization of the exocyclic olefin 12 smoothly gave
the endocyclic isomer 13. The large axial–axial coupling between
H9 and H10 (13.5 Hz) indicated that the C-9 ester group of 13
Scheme 1 Retrosynthetic strategy to the proposed structures for
heteroscyphic acids A and B.
Department of Chemistry, Marquette University, P. O. Box 1881,
Milwaukee, WI, 53201-1881, USA.
E-mail: william.donaldson@marquette.edu; Fax: 414 288 7066;
Tel: 414 288 7374
{ This work was supported by the National Science Foundation (CHE-
0415771) and NIH-NSF instrumentation grants (S10 RR019012 and
CHE-0521323). Mass spectrometry was provided by the Washington
University Mass Spectrometry Resource, an NIH Research Resource
(Grant No. P41RR0954).
Scheme 3 Preparation of the bicyclo[4.4.0]decane skeleton.
Chem. Commun., 2006, 2069–2070 | 2069
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appears ca. d 6.8–6.7 (dd) while the signals for the diene carbons
C14, C15, and the dienyl methyl C16 appear at ca. d 135, 114 and
20 ppm. These chemical shifts are characteristic of a 3-methyl-
1,3Z-dienyl group.11 It was surprising to note that the NMR
spectral data for the dienyl sidechains of 17 and 19 did not match
well with that reported for the heteroscyphic acids A and B. For 1a,b
the signal for H14 appears ca. d 6.35–6.4 (dd) while the signals for
the diene carbons C14, C15, and the dienyl methyl C16 appear at
ca. d 141, 111 and 12 ppm. These chemical shifts are more
consistent with those observed for a number of diterpenes
possessing a 3-methyl-1,3E-dienyl group.11b,c,12
In summary, a stereoselective route to the 3-methyl-1,3Z-
pentadienyl sidechain via nucleophilic addition to the (3-methyl-
pentadienyl)iron cation 3 was devised. This methodology was
explored for the synthesis of the proposed structure of hetero-
scyphic acid A. Re-evaluation of the NMR spectral data for the
heteroscyphic acids revealed that the side chains of these
compounds more likely possess the E-stereochemistry.
Assignment of the structure of the heteroscyphic acids awaits
their total synthesis.13
Scheme 4 Installation of the 3-methyl-1,3Z-pentadienyl side chain.
occupies an equatorial position. Conversion of the b-ketoester into
the MOM enol ether 14, followed by ‘‘double reduction’’8 afforded
the bicyclic ester 15. As anticipated,8 kinetic protonation of the
ester enolate intermediate proceeded from the equatorial position,
resulting in an axial disposition for the ester group in 15. The H9
resonance of 15 did not evidence any large couplings
(HW 5 9.6 Hz), consistent with an equatorial disposition.
Reaction of the anion generated from b-ketoester 13 with cation
3a gave a mixture of diene-iron complexes 16/169 (Scheme 4). Due
to signal overlap, it was not possible to assign the structure(s) of
the components of this mixture, however we anticipated that these
complexes were diastereomeric with respect to the diene-iron
coordination due to attack at one or the other terminal positions
of the achiral pentadienyl cation 3a. This mixture of diastereomers
was of no consequence, since decomplexation of the mixture 16/169
with CAN gave the ‘‘free’’ ligand 17 as a single product. The
relative stereochemistry of 17 at C9 was assigned on the basis of
difference NOE experiments; irradiation of the methyl singlet at
d 1.03 ppm caused enhancement of the signal corresponding to one
of the C11 protons at d 2.83 ppm. This relative stereochemistry for
alkylation of 13 corresponds to that known for the alkylation of
other bicyclo[4.4.0]decane ketoesters (i.e. alkylation on the a-face).9
It should be noted that this stereochemistry is opposite to that
required for heteroscyphic acid.
Notes and references
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1994, 37, 1263; (b) K. Nabeta, T. Ishikawa, T. Kawae and H. Okuyama,
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and H. Okuyama, J. Chem. Soc., Perkin Trans. 1, 1995, 3111.
2 (a) S. Li and W. A. Donaldson, Synthesis, 2003, 2064; (b) Y. K. Yun,
K. Godula, Y. Cao and W. A. Donaldson, J. Org. Chem., 2003, 68, 901;
(c) J. M. Lukesh and W. A. Donaldson, Chem. Commun., 2005, 110; (d)
N. J. Wallock and W. A. Donaldson, Org. Lett., 2005, 7, 2047.
3 S. Chaudhury and W. A. Donaldson, J. Am. Chem. Soc., accepted for
publication.
4 B. Snider, Chem. Rev., 1996, 96, 339.
5 L. D. Boger and R. J. Mathvink, J. Org. Chem., 1992, 57, 1429.
6 S. N. Huckin and L. Weiler, J. Am. Chem. Soc., 1974, 96, 1082.
7 Oxidative cyclization of the ethyl ester of 10 has previously been
reported: P. A. Zoretic, M. Ramchandani and M. L. Caspar, Synth.
Commun., 1991, 21, 915.
8 R. M. Coates and J. E. Shaw, J. Org. Chem., 1970, 35, 2601.
9 M. Czarny, K. K. Maheshwari, J. A. Nelson and T. A. Spencer, J. Org.
Chem., 1975, 40, 2079 and references therein.
10 (a) T. Ling, C. Chowdhury, B. Kramer, B. G. Vong, M. A. Palladino
and E. A. Theodorakis, J. Org. Chem., 2001, 66, 8843; (b) S. C. Welch,
C. P. Hagan, J. H. Kim and P. S. Chu, J. Org. Chem., 1977, 42, 2879; (c)
S. C. Welch, C. P. Hagan, D. H. White, W. P. Fleming and J. W. Trotter,
J. Am. Chem. Soc., 1977, 99, 549.
11 (a) C. Gaspar-Marques, M. F. Simoes, A. Duarte and B. Rodriguez,
J. Nat. Prod., 2003, 66, 491; (b) M. Furlan, M. N. Lopes, J. B. Fernandes
and J. R. Pirani, Phytochemistry, 1996, 41, 1159; (c) A. J. Barrero,
J. F. Sanchez, E. J. Alvarez-Manzaneda, M. Munoz and A. Haidour,
Phytochemistry, 1992, 31, 615; (d) A. F. Barrero, J. F. Sanchez,
J. Altarejos, A. Perales and R. Torres, J. Chem. Soc., Perkin Trans. 1,
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12 (a) A. Debella, O. Kunert, M. G. Schmid, G. Michl, F. Bucar, D. Abebe
and E. Saslinger, Monatsh. Chem., 2000, 131, 401; (b) E. Piers and
J. S. M. Wai, Can. J. Chem., 1994, 72, 146; (c) D. Herlem, F. Khuong-
Huu and A. S. Kende, Tetrahedron, 1994, 50, 2055; (d) J. Bastard,
D. K. Duc, M. Fetizon, M. J. Francis, P. K. Grant, R. T. Weavers,
C. Kaneko, G. V. Baddeley, J.-M. Bernassau, R. R. Burfitt,
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F. Bohlmann and H. Czerson, Phytochemistry, 1979, 18, 115.
13 For examples of structural assignments which were eventually corrected
by total synthesis see: K. C. Nicolaou and S. A. Snyder, Angew. Chem.,
Int. Ed., 2005, 44, 1012.
Reaction of the anion generated from 15 with cation 3a likewise
gave a mixture of diene complexes 18/189. Decomplexation with
CAN and purification by chromatography on AgNO3 impreg-
nated silica gel gave 19. The relative stereochemistry at C9 was
assigned on the basis of the upfield chemical shift of the C19
methyl group (d 0.84 ppm) and the observed NOESY correlation
between this signal and the methyl ester. This relative stereo-
chemistry for alkylation of 15 corresponds to that known for the
alkylation of other bicyclo[4.4.0]decane 2-carboxylates (i.e. alkyla-
tion on the b-face).10
The dienyl sidechains of 6, 7, 17, and 19 were all assigned the Z
stereochemistry on the basis of their NMR spectral data. In
particular, the signal for H14 (heteroscyphic acid numbering)
2070 | Chem. Commun., 2006, 2069–2070
This journal is ß The Royal Society of Chemistry 2006