A Pauson-Khand approach to the hamigerans

Article abstract of DOI:10.1021/ol7018604

(Chemical Equation Presented) An intramolecular Pauson-Khand reaction has been used in the construction of the tricyclic core common to the hamigeran terpenes. For effective cyclization, it was necessary to tether the olefin-containing moiety to the aroma

Full text of DOI:10.1021/ol7018604

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4697-4700
A Pauson−Khand Approach to the
Hamigerans
Christian E. Madu and Carl J. Lovely*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Arlington,
Arlington, Texas 76019
loVely@uta.edu
Received August 1, 2007
ABSTRACT
An intramolecular Pauson−Khand reaction has been used in the construction of the tricyclic core common to the hamigeran terpenes. For
effective cyclization, it was necessary to tether the olefin-containing moiety to the aromatic framework to reduce its conformation mobility;
this was accomplished using a silylene protecting group. Efficient construction of the aryl enyne from a salicylic acid derivative was accomplished
via ortho lithiation and Sonogashira cross-coupling chemistry.
The hamigerans (Figure 1) are a small class of brominated
Fromont found off the Chicken and Egg Islands, near New
Zealand.1 These terpenes possess several unique structural
features including the benzannulation of an indenyl (1-4)
or an azulene fragment (5 and 6). In addition to these novel
structural features, these natural products exhibited antiviral
activity against several viruses, including polio.1 As a result
of both the structural and biological features, these natural
products have attracted attention from several groups and
have resulted in the completion of a number of total syntheses
of 1-4 and several reports of construction of the core
skeleton.2,3 To date, no syntheses of the higher homologues
5 and 6 have appeared in the literature. Our own interest in
(1) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R.
J. Nat. Prod. 2000, 63, 79.
(2) (a) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem., Int. Ed. 2001,
40, 3675. (b) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem., Int. Ed.
2001, 40, 3679. (c) Clive, D. L. J.; Wang, J. Angew. Chem., Int. Ed. 2003,
42, 3406. (d) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2003, 44, 7049.
(e) Clive, D. L. J.; Wang, J. Tetrahedron Lett. 2003, 44, 7731. (f) Nicolaou,
K. C.; Gray, D. L. F.; Tae, J. J. Am. Chem. Soc. 2004, 126, 613. (g) Trost,
B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M. J. Am. Chem.
Soc. 2004, 126, 4480. (h) Clive, D. L. J.; Wang, J. J. Org. Chem. 2004, 69,
2773. (i) Sperry, J. B.; Wright, D. L. Tetrahedron Lett. 2005, 46, 411. (j)
Trost, B. M.; Pissot-Soldermann, C.; Chen, I. Chem.sEur. J. 2005, 11,
951.
Figure 1. Hamigeran family of natural products.
terpenes which were isolated by Cambie and co-workers from
a marine sponge, Hamigerans tarangaensis, Bergquist and
(3) For a review of this area, see: Clive, D. L. J.; Wang, J. Org. Prep.
Proced. Int. 2005, 37, 1.
10.1021/ol7018604 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/16/2007

developing approaches to these natural products grew out
of experience with the Pauson-Khand (PK) reaction of aryl
enynes,4,5 which suggested that use of this particular discon-
nection might provide a concise approach into the core
framework found in these molecules. In this report, we
describe our investigation of the feasibility of this approach.
Our retrosynthetic analysis of this family of natural
products is depicted in Figure 2. Initial adjustment of the
highly substituted cyclopentenones of the type that we wished
to prepare. As far as we are aware, only two reports exist
describing PK cyclizations of substrates related to 8;5b,8
however, substrates which contained either a terminal TMS
moiety on the acetylene or an internal methyl substituent on
the olefin either gave low yields or failed to cyclize.5b
Subsequent studies from our group have demonstrated that
this reluctance can be overcome by the incorporation of steric
buttressing elements (bulky ortho substituents), which in
effect reduce the entropic penalty associated with cyclization
and thus enhance both rates and yields of cyclization.5a,c,d,9
Therefore, as we proceeded through our studies, this issue
was at the forefront of our minds.
Our synthetic efforts began with the preparation of the
iodobenzaldehyde derivative 16 (Scheme 2), which we
Scheme 1
Figure 2. Retrosynthetic analysis of the hamigerans.
oxidation state in the cyclopentyl moiety leads to the enone
7, which we planned on constructing using an intramolecular
PK reaction. The precursor would then be the corresponding
enyne 8, which in turn would be constructed by the addition
of an organometallic reagent to install the allyl moiety and
a Sonogashira reaction to install the alkyne,6 leaving the
iodobenzaldehyde derivative 9 as a precursor. This, in turn,
would disconnect back to the salicylic acid derivative via a
directed ortho metalation (DOM) sequence.7 Of particular
note here is that there is an element of divergency in this
approach, in which simply choosing the appropriate orga-
nometallic reagent would allow access to either subfamily
(1-4 or 5-6) from a common intermediate. Further, the use
of a nonracemic methallyl organometallic reagent would
permit an asymmetric synthesis.
planned on constructing via directed ortho metalation, in
analogy with Nicolaou’s approach to these natural products.
Scheme 2
All of the proposed chemistry had solid precedents in the
literature, with the exception of the PK reaction leading to
(4) (a) Schore, N. E. Chem. ReV. 1988, 88, 1081. (b) Schore, N. E. Org.
React. 1991, 40, 1. (c) Schore, N. E. Transition Metal Alkyne Complexes:
Pauson-Khand Reaction. In ComprehensiVe Organometallic Chemistry-
II; Hegedus, L. S., Ed.; Pergamon: Oxford, 1995; Vol. 12, p 703. (d) Geis,
O.; Schmalz, H.-G. Angew. Chem., Int. Ed. 1998, 37, 911. (e) Ingate, S.
T.; Marco-Contelles, J. Org. Prep. Proced. Int. 1998, 30, 123. (f) Chung,
Y. K. Coord. Chem. ReV. 1999, 188, 297. (g) Brummond, K. M.; Kent, J.
L. Tetrahedron 2000, 56, 3263. (h) Gibson, S. E.; Stevanazzi, A. Angew.
Chem., Int. Ed. 2003, 42, 1800. (i) Blanco-Urgoiti, J.; Anorbe, L.; Perez-
Serrano, L.; Dominguez, G.; Perez-Castells, J. Chem. Soc. ReV. 2004, 33,
32. (j) Gibson, S. E.; Mainolfi, N. Angew. Chem., Int. Ed. 2005, 44, 3022.
(k) Struebing, D.; Beller, M. Top. Organomet. Chem. 2006, 18, 165.
(5) (a) Lovely, C. J.; Seshadri, H.; Wayland, B. R.; Cordes, A. W. Org.
Lett. 2001, 3, 2607. (b) Lovely, C. J.; Seshadri, H. Synth. Commun. 2001,
31, 2479. (c) Madu, C. E.; Seshadri, H.; Lovely, C. J. Tetrahedron 2007,
63, 5019. (d) Madu, C. E.; Lovely, C. J. Synlett 2007, 2011.
Accordingly the tert-butyl amide 1110 was prepared by
standard acylation chemistry from the salicylic acid and then
(6) Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107, 874.
(7) Snieckus, V. Chem. ReV. 1990, 90, 879.
(8) Blanco-Urgoiti, J.; Casarrubios, L.; Dominguez, G.; Perez-Castells,
J. Tetrahedron Lett. 2001, 42, 3315.
(9) For a review of this general area, see: Sammes, P. G.; Weller, D. J.
Synthesis 1995, 1205.
4698
Org. Lett., Vol. 9, No. 23, 2007

treated with n-BuLi and the resulting aryl lithium trapped
with iodine affording 12 (Scheme 1). We planned on
hydrolyzing the amide and then adjusting the oxidation state
of the resulting acid. Unfortunately, we were unable to
hydrolyze the amide under a variety of standard conditions.11
During these experiments, we became aware of an investiga-
tion of the hydrolysis of related benzamide derivatives by
the Keck group.12 In this report, a series of benzamides were
converted to the corresponding imidates by treatment with
Meerwein’s salt and hydrolyzed with aqueous NaHCO3 to
give the methyl ester. Among several observations, they
noted that the presence of a substituted o-phenolic hydroxyl
in systems related to 12 resulted in the complete shutdown
of hydrolysis, but if the substituent were removed the
hydrolysis proceeded uneventfully. Accordingly, we at-
tempted this manoeuvre by first cleaving the methyl ether
with excess BBr3 (Scheme 1) and then treating the resulting
amide 13 with Meerwein’s salt and then aqueous base. In
this way, we were able to obtain the methyl ester 14 in 89%
yield for the three-step sequence. The phenolic OH was
remethylated, providing 15, and then the oxidation state of
the ester was adjusted via reduction and oxidation to provide
the key aldehyde 16 (Scheme 2).
Scheme 3
than use 11, however, the corresponding TBS derivative was
used in the DOM chemistry,14 providing the iodide in 87%
yield.15 Sonogashira cross-coupling with the 2-methyl-2-
butynol and hydrolysis of the amide using the two-step
procedure via the imidate provided 23, which also underwent
concomitant desilylation. Oxidation state adjustment through
reduction with DIBAL-H to the benzyl alcohol and oxidation
with MnO2 gave the key aldehyde 24. Reaction with
methallylmagnesium chloride smoothly provided the diol 25,
Once efficient access to the iodobenzaldehyde derivative
16 was obtained, the introduction of the two unsaturated
fragments required for the PK cyclization was investigated
(Scheme 2). After some experimentation, it was found that
the methylbutyne moiety could be incorporated via a
Sonogashira reaction, provided that the butynol derivative
17 was employed, rather than the parent alkyne.13 Presum-
ably, the low boiling point of the parent alkyne contributes
to this result. Subsequently, a simple Grignard reaction with
methallylmagnesium chloride completed the sequence to give
the PK precursor 19. Unfortunately, when this substrate was
converted into the corresponding Co2(CO)6 complex, it failed
to undergo PK cyclization under a variety of thermal or
oxidative conditions.
Scheme 4
As indicated above, this outcome was not necessarily
unexpected, as we had previously found that highly congested
systems of this type were not readily accessible without the
presence of bulky ortho substituents to facilitate the cycliza-
tion. Presumably in this case, the O-methyl group adopts a
conformation to avoid steric interactions with the alkene-
bearing substituent, resulting in a nonproductive decomplex-
ation rather than desired cyclization. Therefore, we decided
to investigate whether linking the phenolic moiety and the
homoallylic alcohol might lead to improved efficiencies in
the PK reaction.
Our initial attempt to access such cyclization substrates
involved the deprotection of the methyl ether 19 with BBr3;
unfortunately, this proved unsuccessful, and so an alternative
approach was sought, and this is outlined in Scheme 3. Rather
which on treatment with (t-Bu)2Si(OTf)2 provided the
silylene derivative 26 in excellent yield.16 Gratifyingly, this
(10) Kwon, B. S.; Tae, J. Heterocycles 2004, 62, 137.
(11) For example, attempts to hydrolyze the amide with concentrated
sulfuric acid led to loss of the tert-butyl moiety and the formation of the
primary amide.
(12) Keck, G. E.; McLaws, M. D.; Wager, T. T. Tetrahedron 2000, 56,
9875.
(14) Keck’s work indicated that the TBS moiety would be removed under
the conditions used for the amide hydrolysis, and thus this sequence was
more efficient.
(15) Baba, Y.; Ogoshi, Y.; Hirai, G.; Yanagisawa, T.; Nagamatsu, K.;
Mayumi, S.; Hashimoto, Y.; Sodeoka, M. Bioorg. Med. Chem. Lett. 2004,
14, 2963.
(13) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2002, 67, 86.
Org. Lett., Vol. 9, No. 23, 2007
4699

enyne on conversion to the Co2(CO)6 complex, followed by
thermal activation at 70 °C in PhMe, led to conversion to
the desired tetracyclic adduct 27 in 70% yield as a single
diastereomer.17 While we have been unable to unequivocally
assign the stereochemistry of the cycloadduct, it is of no real
consequence as the hydroxyl center will become sp2-
hybridized in subsequent intermediates. However, on the
basis of the usual stereochemical biases of the intramolecular
PK reaction leading to the placement of the peripheral
substituents exo, we propose the indicated stereochemistry
(Scheme 4).18
Pauson-Khand reaction of an aryl enyne. Critical to the
success of this cyclization is the presence of a bulky silylene
protecting group which tethers the two reacting fragments,
thereby facilitating the reaction by reducing the entropic
penalty and provides steric acceleration through buttressing
effects. Current efforts are directed toward the completion
of the total synthesis of hamigeran B from 27 and the
preparation of nonracemic precursors.
Acknowledgment. This work was supported by the
Robert A. Welch Foundation (Y-1362). The NSF (CHE-
9601771, CHE-0234811) is thanked for partial funding of
the purchases of the NMR spectrometers used in this work.
In summary, we have developed an efficient 10-step
sequence from 4-methylsalicylic acid to the complete carbon
framework of several members of the hamigeran family of
natural products. The key step involves an intramolecular
Supporting Information Available: Detailed experi-
1
mental procedures and copies of H and 13C NMR spectra
(16) Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871.
(17) Gillard, J. W.; Fortin, R.; Grimm, E. L.; Maillard, M.; Tjepkema,
M.; Bernstein, M. A.; Glaser, R. Tetrahedron Lett. 1991, 32, 1145.
(18) (a) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851.
(b) Magnus, P.; Principe, L. M.; Slater, M. J. J. Org. Chem. 1987, 52, 1483.
See also refs 5d and 8.
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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