Intramolecular cyclohexadienone annulations of fischer carbene complexes: Model studies for the synthesis of phomactins

Article abstract of DOI:10.1021/ol070904q

The intramolecular cyclohexadienone annulation of chromium carbene complexes is examined as a method to provide general access to the Phomactin family of natural products. The importance of the stereochemistry of the carbene complex and the number of carbons in the tether connecting the carbene complex and the alkyne are probed. Additionally, the degree of the 1,4-asymmetric induction is examined.

Full text of DOI:10.1021/ol070904q

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2799-2802
Intramolecular Cyclohexadienone
Annulations of Fischer Carbene
Complexes: Model Studies for the
Synthesis of Phomactins
Jie Huang, Huan Wang, Chunrui Wu, and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
wulff@chemistry.msu.edu
Received April 18, 2007
ABSTRACT
The intramolecular cyclohexadienone annulation of chromium carbene complexes is examined as a method to provide general access to the
Phomactin family of natural products. The importance of the stereochemistry of the carbene complex and the number of carbons in the tether
connecting the carbene complex and the alkyne are probed. Additionally, the degree of the 1,4-asymmetric induction is examined.
Since the discovery1 of the phomactins in the early to mid
1990s, their unusual carbon skeleton combined with attractive
bioactivity as PAF antagonists has prompted much interest
among synthetic organic chemists.2-4 The structures of the
phomactins share a common bicyclo[9.3.1]pentadecane ring
system featuring a highly substituted cyclohexane bearing a
quarternary center and a 12-membered macrocycle (Figure
1).
The phomactins and members of the taxol family share a
common biosynthetic pathway (Figure 2).2,5 Cyclization of
geranylgeranyl diphosphate gives rise to the verticillenyl
carbocation 13, which can lead to verticilllene 12 by simple
proton loss or to taxadiene 11 via an intramolecular proton
transfer and subsequent intramolecular cyclization. Alterna-
tively, it has been shown that cation 13 is the precursor to
(3) For studies directed at the synthesis of phomactins, see: (a) Foote,
K. M.; Hayes, C. J.; Pattenden, G. Tetrahedron Lett. 1996, 37, 275. (b)
Chen, D.; Wang, J.; Totah, N. I. J. Org. Chem. 1999, 64, 1776. (c) Seth, P.
P.; Totah, N. I. J. Org. Chem. 1999, 64, 8750. (d) Seth, P. P.; Totah, N. I.
Org. Lett. 2000, 2, 2507. (e) Kallan, N. C.; Halcomb, R. L. Org. Lett. 2000,
2, 2687. (f) Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695. (g)
Seth, P. P.; Chen, D.; Wang, J.; Gao, X.; Totah, N. I. Org. Lett. 2000, 56,
10185. (h) Foote, K.; John, M.; Pattenden, G. Synlett 2001, 365. (i) Mi, B.;
Maleczka, R. Org. Lett. 2001, 3, 1491. (j) Chemler, S. R.; Iserloh, U.;
Danishefsky, S. J. Org. Lett. 2001, 3, 2949. (k) Houghton, T.; Choi, S.;
Rawal, V. H. Org. Lett. 2001, 3, 3615. (l) Mohr, P. J.; Halcomb, R. L.
Org. Lett. 2002, 4, 2413. (m) Cole, K.; Hsung, R. P. Org. Lett. 2003, 5,
4843. (n) Balnaves, A. S.; McGowan, G.; Shapland, P. D. P.; Thomas, E.
J. Tetrahedron Lett. 2003, 44, 2713. (o) Foote, K. M.; Hayes, C. J.; John,
M. P.; Pattenden, G. Org. Biomol. Chem. 2003, 1, 3917. (p) Cheing, J. W.
C.; Goldring, W. P. D.; Pattenden, G. Chem. Commun. 2003, 2788. (q)
Cole, K. P.; Hsung, R. P. Chem. Commun. 2005, 5784. (r) Ryu, K.; Cho,
Y.-S.; Jung, S.-I.; Cho, C.-G. Org. Lett. 2006, 8, 3343.
(1) (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463. (b) Chu,
M.; Patel, M. G.; Gullo, V. P.; Truumees, I.; Puar, M. S.; McPhail, A. T.
J. Org. Chem. 1992, 57, 5817. (c) Chu, M.; Truumees, I.; Gunnarsson, I.;
Bishop, W. R.; Kreutner, W.; Horan, A. C.; Patel, M. G.; Gullo, V. P.;
Puar, M. S. J. Antibiot. 1993, 46, 554. (d) Sugano, M.; Sato, A.; Iijima, T.;
Furuya, K.; Haruyama, H.; Yoda, K.; Hata, T. J. Org. Chem. 1994, 59,
564. (e) Sugano, M.; Sato, A.; Ijima, T.; Furuya, K.; Kuwano, H.; Hata, T.
J. Antibiot. 1995, 48, 1188. (f) Koyama, K.; Ishino, M.; Takatori, K.; Sugita,
T.; Kinoshita, K.; Takahashi, K. Tetrahedron Lett. 2004, 45, 6947.
(2) For a review of the phomactins, see: Goldring, W. P. D.; Pattenden,
G. Acc. Chem. Res. 2006, 39, 354.
(4) For the total syntheses of phomactins, see: Phomactin D: (a)
Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996, 37,
7107. Phomactin A: (b) Goldring, W. P. D.; Pattenden, G. Chem. Commun.
2002, 1736. (c) Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125,
1712. (d) Diaper, C. M.; Goldring, W. P. D.; Pattenden, G. Org. Biomol.
Chem. 2003, 1, 3949. Phomactin G: (e) Goldring, W. P. D.; Pattenden, G.
Org. Biomol. Chem. 2004, 2, 466.
10.1021/ol070904q CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

of the phomactins in much the same way that the epoxy
ketone 15 has been proposed to be the biosynthetic precursor
to all of the phomactins.2 All of the previous synthetic
approaches3 and total syntheses4 of the phomactins have
constructed the six-membered ring before the macrocycle is
closed. Closure of the macrocycle has been effected by a
number of different tactical methods including NHK
coupling,3i,4b,d,e Suzuki coupling,4c,3e Stille coupling,3k sulfone
coupling to an allyic halide,4a,3n and oxa[3+3] cycloaddition.3m,q
Our retrosynthesis for the phomactins involves the intra-
molecular cyclohexadienone annulation of the carbene
complex 17 (Scheme 1). Thermolysis of 17 would be
Scheme 1. Retrosynthetic Analysis for the Phomactins
Figure 1. Phomactin family of natural products.
phomactatriene 14 via a series of 1,2-hydrogen and 1,2-
methyl shifts.5a Phomactatriene 14 is also a natural product
and has been isolated from Phoma sp. and its stereochemistry
recently corrected.5b It has been suggested by Pattenden that
the last common intermediate in the biosynthesis of all the
phomactins is the keto epoxide 15, which results from
oxidations of phomactatriene.2
anticipated to lead to the formation of 6-membered and 12-
membered rings in the same event.
The benzannulation reaction of R,â-unsaturated carbene
complexes with alkynes is one of the most important methods
for the synthesis of phenols (Scheme 2). This reaction was
discovered in 1975 by Do¨tz and since that time6 the reaction
has been extensively studied and widely applied in organic
Scheme 2. Cyclohexadienone Annulation and Benzannulation
Figure 2. Biosynthesis of phomactins and taxol.
We envisioned that the bicyclic cyclohexadienone 16 could
also serve as a common intermediate for the synthesis of all
(5) (a) Tokiwano, T.; Endo, T.; Tsukagoshi, T.; Goto, H.; Fukushi, E.;
Oikawa, H. Org. Biomol. Chem. 2005, 3, 2713. (b) Tokiwano, T.; Fukushi,
E.; Endo, T.; Oikawa, H. Chem. Commun. 2004, 1324.
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Org. Lett., Vol. 9, No. 15, 2007

synthesis.7 We reported the cyclohexadienone annulation in
1985, which involves the reaction of carbene complexes of
the type 18 where both substituents of the â-carbon are non-
hydrogen.8 The reaction of such complexes with alkynes is
general and allows for rapid entry to cyclohexadienones
bearing a quaternary carbon.7 The intramolecular variant of
the benzannulation reaction has been known9,10 for quite
some time and has been utilized in the total synthesis of
deoxyfrenolicin,9b,c,g angelicin,9d,e sphondin,9e and arnebinol.9h
The intramolecular version of the cyclohexadienone annu-
lation is unknown and is the subject of the present work.
The retrosynthesis of the phomactins shown in Scheme 1
requires the carbene complex 17 and thus as model systems
we chose to prepare a family of carbene complexes of the
type 22 (Scheme 2) in which the alkyne is tethered to the
â-carbon of the alkenyl substituent of the carbene complex.
It was anticipated that it would be important not only to
include complexes of the type 22 with different tether lengths
in the initial screen of the intramolecular cyclohexadienone
annulation but also to include complexes with both cis and
trans double bonds in the carbene complex. It is known11
that â,â-disubstituted alkenyl carbene complexes are con-
figurationally stable under the conditions of the cyclohexa-
dienone annulation and thus it is certainly possible that cis
and trans isomers of 22 could behave differently during the
intramolecular process involving the carbene complex and
the tethered alkyne unit. The E-isomer of complex 22 was
prepared from the E-vinyl iodide precursor E-21 via the
standard Fischer method involving the addition of the
vinyllithium derived from E-21 with chromium hexacarbonyl
followed by methylation. The Z-isomer of 22 was prepared
from the corresponding Z-isomer of the vinyl iodide 21 (not
shown) and the details can be found in the Supporting
Information. More rapid entry to these carbene complexes
is possible via the aldol reaction12 of the methyl carbene
complex 23 with the ketone 24 (Scheme 2); unfortunately,
this route produces a mixture of the Z- and E-isomers of 22
which proved to be inseparable.
The intramolecular cyclohexadienone annulation of car-
bene complex 22 was examined with complexes of four
different tether lengths and the results are presented in Table
1. The yield of the desired bicyclic cyclohexadienone 25
Table 1. Intramolecular Cyclohexadienone Annulation of
Complex 22a
% yield % yield anti-26:
entry complex
n
solvent
of 25b
of 26b
syn-26c
1
2
3
E-22a
E-22a
E-22a
6
6
6
THFd
MeCNe
benzenef,g
18
22
46
1.3:1.0
1.8:1.0
1.1:1.0
4
5
6
E-22b
E-22b
E-22b
8
8
8
THF
MeCN
benzene
45
45
10
h
7
8
9
10
11
Z-22c
10 THF
15
37
43
64
36
Z+E-22ci 10 THF
14
1.0:1.0
E-22c
E-22c
E-22c
10 THF
10 MeCN
10 benzene
12
13
14
E-22d
E-22d
E-22d
13 THF
13 MeCN
13 benzene
64
51
32
a Unless otherwise specified, all reactions were carried out at 0.005 M
in 22 at 100 °C for 24 h. b Isolated yields after chromatography on silica
gel. c The anti isomer is shown and was characterized by X-ray diffraction.
d 6% yield of trimer isolated. e 4% yield of trimer isolated. f 13% yield of
trimer observed. g Yields were calculated from the weight of a mixture of
compounds and ratios determined by HPLC. h Five additional compounds
were observed in the crude reaction which were not separated and
characterized. i 71:29 ratio of E:Z isomers.
(6) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644.
(7) For reviews on the benzannulation and cyclohexadienone annulations,
see: (a) Wulff, W. D. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, R. G. A.,Wilkinson, G., Eds.; Pergemon Press: New York,
1995; Vol. 12, pp 469-547. (b) Minatti, A.; Do¨tz, K. H. Top. Organomet.
Chem. 2004, 13, 123. (c) Waters, M. L.; Wulff, W. D. Org. React. In press.
(8) Tang, P. C.; Wulff, W. D. J. Am. Chem. Soc. 1984, 106, 1132.
(9) For reactions tethered through the oxygen on the carbene carbon,
see: (a) Semmelhack, M. F.; Bozell, J. J. Tetrahedron Lett. 1982, 23, 2931.
(b) Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess, E. J.;
Zask, A. J. Am. Chem. Soc. 1982, 104, 5850. (c) Semmelhack, M. F.; Bozell,
J. J.; Keller, L.; Sato, T.; Spiess, E. J.; Wulff, W.; Zask, A. Tetrahedron
1985, 41, 5803. (d) Peterson, G. A.; Kunng, F.-A.; McCallum, J. S.; Wulff,
W. D. Tetrahedron Lett. 1987, 28, 1381. (e) Wulff, W. D.; McCallum, J.
S.; Kunng, F.-A. J. Am. Chem. Soc. 1988, 110, 7419. (f) Balzer, B. L.;
Cazanoue, M.; Finn, M. G. J. Am. Chem. Soc. 1992, 114, 8735. (g) Gross,
M. F.; Finn, M. G. J. Am. Chem. Soc. 1994, 116, 10921. (h)Watanabe, M.;
Tanaka, K.; Saikawa, Y.; Nakata, M. Tetrahedron Lett. 2007, 48, 203.
(10) For reactions tethered through the alkenyl group on the carbene
carbon, see: (a) Wang, H.; Wulff, W. D. J. Am. Chem. Soc. 1998, 120,
10573. (b) Do¨tz, K. H.; Gerhardt, A. J. Organomet. Chem. 1999, 578, 223.
(c) Wang, H.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 2000,
122, 9862. (d) Do¨tz, K. H.; Mittenzwey, S. Eur. J. Org. Chem. 2002, 39.
(e) Wang, H.; Huang, J.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem.
Soc. 2003, 125, 8980. (f) Gopalsamuthiram, V.; Wulff, W. D. J. Am. Chem.
Soc. 2004, 126, 13936.
increases with increasing tether length until n ) 10 and then
appears to level off. The phomactins have nine carbons in
the larger bridge and the results in Table 1 are encouraging
since reasonable yields of the cyclized product 25 can be
realized with both eight and ten methylene tethers. However,
none of the desired cyclized product 25 is seen with the
complex 22a with six methylene spacers. In this case,
depending on solvent, up to a 46% yield of the dimeric
cyclohexadienone 26 was observed as a 1.1:1.0 mixture of
diastereomers along with smaller amounts of the correspond-
ing trimeric product (not shown). In acetonitrile the ratio of
the dimers was formed in a 1.8:1.0 ratio and the stereo-
chemistry of the major diastereomer was confirmed by an
X-ray diffraction study. This study of intramolecular cyclo-
hexadienone annulation of complexes 22 also clearly reveals
that the stereochemistry of the double bond of the carbene
(11) Hsung, R. P.; Quinn, J. F.; Weisenberg, B. A.; Wulff, W. D.; Yap,
G. P. A.; Rheingold, A. L. Chem. Commun. 1997, 615.
(12) Wang, H.; Hsung, R. P.; Wulff, W. D. Tetrahedron Lett. 1998, 39,
1849.
Org. Lett., Vol. 9, No. 15, 2007
2801

complex is very important. The Z-isomer of complex 22
gives a 15% yield of 25, whereas, the E-isomer gives a 43%
yield (entries 7 vs 9). Interestingly, a 79:21 mixture of E:Z
isomers of 22c was prepared by the aldol reaction indicated
in Scheme 2 and the thermolysis of this mixture gave a 37%
yield of 25 (Table 1, entry 8). On the basis of the data for
the pure E- and Z-isomers (entries 7 and 9), the expected
yield would have been 35%.
Table 2. 1,4-Asymmetric Induction in Intramolecular
Cyclohexadienone Annulationa
We have previously shown that high levels of 1,4-
asymmetric induction could be achieved in the intermolecular
cyclohexadienone annulations with propargyl ethers.11 For
example, the reactions of the carbene complex 27 with the
trityl propargyl ether 28 are stereospecific (Scheme 3). It is
temp
(°C)
% yield of
entry
complex
R
35 + 36b
35:36c
1
2
3
4
5
6
7
8
9
E-34a
OTr
55
100
55
100
55
100
55
100
100
100
100
65
52
45
47
66
69
44
36
66
94
54
1.0:1.1
1.2:1.0
3.0:1.0
2.0:1.0
2.1:1.0
1.6:1.0
1.0:1.1
1.0:1.0
1.0:1.0
1.0:1.2
1.0:1.0
E-34b
E-34c
E-34d
OTIPS
OMe
Scheme 3. 1,4-Asymmetric Induction in Intermolecular
Cyclohexadienone Annulation
OMOM
E-34e
E-34f
E-34g
t-Bu
Me
Ph
10
11
a Unless otherwise specified, all reactions were carried out at 0.005 M
in 34 in THF for 16-24 h. b Isolated yields after chromatography on silica
gel. c Ratio determined by 1H NMR. Assignment of relative stereochemistry
was made on the basis of an X-ray structure of 35b.
high selectivity in the intermolecular benzannuation13 and
cyclohexadienone annulations.11 Clearly, from the data in
Table 2, the intramolecularity of the reaction leads to very
low stereoselectivities with propargyl oxygen substituents.
This is not necessarily a surprise given the geometrical
constraints that can be associated with intramolecular
processes. The best selectivity of 3:1 was observed with a
siloxy group and this is consistent with the increased electron
releasing ability of a siloxy group.13,14 This result is
significant since it provides for an asymmetric entry to the
phomactins via carbene complex 17. The introduction of the
proper configuration at the alcohol carbon in 17 would allow
for 1,4-asymmetric induction in 16 and thus to asymmetric
syntheses of the phomactins.
The success of these model systems is quite encouraging
for the development of an approach to the phomactins
involving a double cyclization of an alkyne tethered carbene
complex. Thermolysis of these complexes generates mac-
rocyclic embedded cyclohexadienones and work directed to
the synthesis of the phomactins utilizing this process will
be reported in due course.
thought that the origins of this stereoselectivity derives from
a stereoelectronic preference for the propargyl oxygen to be
anti to the chromium in the η1,η3-vinyl carbene complexed
intermediate, which can exist as the two diastereomeric forms
31 and 33 when E-27 was cylized. Of the two, intermediate
31 is expected to be the more stable for steric reasons.
Insertion of a CO ligand gives the vinyl ketene complex 32
and then an electrocyclic ring closure with upward movement
of the methyl would be expected to avoid close contacts of
the methyl group with the chromium and its CO ligands to
provide 29 as the major product. Thus cyclization of Z-27
gave the opposite selectivity favoring formation of 30.
A series of carbene complexes 34 were prepared which
had ten carbons in the tether and which had a variety of
propargyl substituents to determine the extent of 1,4-
asymmetric induction in the intramolecular cyclohexa-
dieneone annulation (Table 2). It was no surprise that carbon
substituents gave 1:1 mixtures of isomers since this had also
been found to be the case for intermolecular benzannula-
tions.13 However, oxygen substiutents were found to give
Acknowledgment. This work was supported by a grant
from the NIH (GM 33589).
Supporting Information Available: Experimental pro-
cedures, compound characterization, and X-ray data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL070904Q
(13) Hsung, R. P.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc.
1994, 116, 6449.
(14) Lorsbach, B. A.; Prock, A.; Giering, W. P. Organometallics 1995,
14, 1694.
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