A convergent synthesis of the tricyclic core of the dictyosphaeric acids

Article abstract of DOI:10.1021/ol702887e

(Chemical Equation Presented) The first synthetic route to the tricyclic core of the dictyosphaeric acids has been established starting from readily available (S)-(-)-4-(tert-butyldimethylsilyloxy)cyclohexenone and involving 9 steps, including a ring-clos

Full text of DOI:10.1021/ol702887e

ORGANIC
LETTERS
2008
Vol. 10, No. 2
353-356
A Convergent Synthesis of the Tricyclic
Core of the Dictyosphaeric Acids
Christopher W. Barfoot,† Alan R. Burns,† Michael G. Edwards,†
Martin N. Kenworthy,† Mahmood Ahmed,‡ Stephen E. Shanahan,§ and
Richard J. K. Taylor*,†
Department of Chemistry, UniVersity of York, Heslington, York YO10 5DD,
United Kingdom, GlaxoSmithKline, New Frontiers Science Park (North),
Third AVenue, Harlow, Essex CM19 5AW, United Kingdom, and
GlaxoSmithKline, Chemical DeVelopment, Old Powder Mills, Tonbridge.
Kent TN11 9AN, United Kingdom
rjkt1@york.ac.uk
Received November 30, 2007
ABSTRACT
The first synthetic route to the tricyclic core of the dictyosphaeric acids has been established starting from readily available (S)-(−)-4-(tert-
butyldimethylsilyloxy)cyclohexenone and involving 9 steps, including a ring-closing metathesis to produce a 13-membered macrolactone, and
a doubly tethered intramolecular Michael addition.
Dictyosphaeric acids A (1) and B (2) were isolated by Ireland
and co-workers in 20041 from the fermentation of a previ-
ously undescribed Penicillium sp. F01V25, itself obtained
from the marine algae Dictyosphaeria Versluyii. The dictyo-
sphaeric acids are polyketide-derived natural products con-
taining a highly oxygenated tricyclic core comprising deca-
lactone, dihydrofuran, and cyclohexanone components (Fig-
ure 1). Dictyosphaeric acid A has 5 stereogenic centers, 4
of which are contiguous, and dictyosphaeric acid B has 6
stereogenic centers, 5 of which are contiguous, and both
contain an unusual polyene carboxylic acid side chain. The
relative stereochemistry of the dictyosphaeric acids was
determined by extensive 1D and 2D NMR studies1 but, as
yet, the absolute stereochemistry is unknown.
When subjected to biological screening, dictyosphaeric
acid A exhibited antibacterial activity toward Gram-positive
bacteria and inhibition of methicillin-resistant Staphylococcus
aureus (MRSA).1 On the other hand, dictyosphaeric acid B
did not exhibit any significant biological activity,1 which
presumably indicates the importance of the R,â-unsaturated
ketone in the antibacterial pharmacophore of dictyosphaeric
acid A.
The only other structurally related natural products are the
colletofragarones A1 (3) and A2 (4), isolated by Ueno and
co-workers in 19962 from the fungus Colletotrichum fragar-
iae and shown to act as germination inhibitors. The colleto-
fragarones have the same carbon skeleton as the dictyo-
† University of York.
‡ GlaxoSmithKline, New Frontiers Science Park.
§ GlaxoSmithKline, Chemical Development.
(1) Bugni, T. S.; Janso, J. E.; Williamson, R. T.; Feng, X.; Bernan, V.
S.; Greenstein, M.; Carter, G. T.; Maiese, W. M.; Ireland, C. M. J. Nat.
Prod. 2004, 67, 1396-1399.
(2) Inoue, M.; Takenaka, H.; Tsurushima, T.; Ueno, T. Tetrahedron Lett.
1996, 37, 5731-5734.
10.1021/ol702887e CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/21/2007

Scheme 1. Retrosynthetic Analysis
9 appeared to be accessible using the intramolecular Michael
addition (IMA)5 of â-keto ester 10, which in turn should be
available by straightforward elaboration of functionalized
cyclohexenone 11.6,7
Before commencing on the synthesis outlined in Scheme
1, model studies were carried out to validate this approach
to the tricyclic decalactone core (Scheme 2).
Figure 1. Dictyosphaeric acids, colletofragarones, and Sch 642305.
sphaeric acids, although they differ in terms of the oxygen-
ation pattern of the 10-membered ring and also lack the
carboxylic acid moiety at the terminus of the triene side
chain. The relative and absolute stereochemistry of the
colletofragarones has yet to be fully assigned.
Scheme 2. Model Studies to the Tricyclic Decalactone Core
To date, there have been no reported syntheses of the
dictyosphaeric acids (or the colletofragarones3) although there
have been several publications on the synthesis of the related
bicyclic bacterial DNA primase inhibitor, (+)-Sch 642305
(5).4
Herein, we report the first synthesis of the tricyclic core
of the dictyosphaeric acids by a convergent route that should
also allow access to the dictyosphaeric acid and colleto-
fragarone natural products, as well as novel synthetic
analogues of both natural product families, to probe further
the biological activity. The retrosynthetic analysis adopted
in this research is illustrated in Scheme 1.
Thus, redox simplification and a cross-coupling discon-
nection leads from dictyosphaeric acid 1 to precursors 6 and
7. Compound 6 should be available from γ-lactone 8, and
by also introducing unsaturation into the decalactone portion
of 8, ring-closing metathesis (RCM) can be employed to
construct the tricyclic ring system. The metathesis precursor
The readily available divinyl precursor 128 was first
subjected to IMA using sodium hydride in THF. The bicyclic
lactone 13 was obtained with the expected syn-ring junction
(3) For colletofragarone analogues see: Drew, M. G. B.; Jahans, A.;
Harwood, L. M.; Apoux, S. A. B. H. Eur. J. Org. Chem. 2002, 3589-
3594.
(4) (a) Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2005, 46, 6633-
6636. (b) Ishigimi, K.; Katsuta, R.; Watanabe, H. Tetrahedron 2006, 8,
2224-2230. (c) Snider, B.; Zhou, J. Org. Lett. 2006, 8, 1283-1286. (d)
Trauner, D.; Wilson, E. M. Org. Lett. 2007, 7, 1327-1329. (e) Fujioka,
H.; Ohba, Y.; Nakahara, K.; Takatsuji, M.; Murai, K.; Ito, M.; Kita, Y.
Org. Lett. 2007, 9, 5605-5608.
(5) Little, R. D.; Masjedizadeh, M. R. Org. React. 1995, 47, 315-552.
(6) Danishefsky, S. J.; Simoneau, B. J. J. Am. Chem. Soc. 1989, 111,
2599-2604.
(7) (a) Morgan, B. S.; Hoenner, D.; Evans, P.; Roberts, S. M. Tetrahe-
dron: Asymmetry 2004, 15, 2807-2809. (b) Bickley, J. F.; Evans, P.;
Morgan, B. S.; Roberts, S. M. Tetrahedron: Asymmetry 2006, 17, 355-
362.
(8) Divinyl compound 12 was readily prepared in racemic form following
a similar sequence to that shown in Scheme 3.
354
Org. Lett., Vol. 10, No. 2, 2008

(NOE) but the reaction was slow and gave mixtures of
products, and the yield was disappointing. Generally, in-
tramolecular reactions have advantages over the equivalent
intermolecular reactions due to gains in reaction rates. We
reasoned that, by having a double tether, the cyclization
process would be further facilitated. We therefore decided
to first prepare the 13-membered compound 15 and then look
at the “doubly tethered intramolecular Michael addition”
(DTIMA) to install the γ-lactone and the decalactone systems
at the same time.
Scheme 3. Synthesis of RCM Precursor
As can be seen (Scheme 2), RCM on the divinyl com-
pound 12 produced the required macrolactone 15 and on
treatment with NaH/THF the DTIMA proceeded cleanly and
in 1 h (rather than overnight) to give the required product
14 in an excellent 94% yield. The RCM-DTIMA sequence
shown therefore showed great promise as a rapid and efficient
entry to the tricyclic macrolide core of the dictyosphaeric
acids.
A short study to determine the optimum conditions for
the RCM reaction was then undertaken. As shown in Table
1, performing the reaction at high temperature caused
[R]22 -109.6 (c 1.45, CH2Cl2)}.6,7 Enone 17 was then
D
R-iodinated using the procedure developed by Krafft et al.10
to afford iodo-enone 18 in excellent yield.
Stille coupling of 18 with allyltributylstannane gave
allylated adduct 19 (83%), which was subsequently depro-
tected with TBAF and coupled with acid 2011 to give RCM
precursor 21 in excellent yield using T3P12 (conventional
coupling agents, such as DCC, EDC, and HATU, were less
efficient).
Table 1. RCM of 12 To Form 15
catalyst
(mol %)
additive
(mol %)
solvent,
temp (°C)
yield
(%)
entry
1
2
3
4
5
6
Grubbs II (10)
Grubbs II (10)
Grubbs II (10)
Grubbs II (10)
Grubbs II (20)
Hoveyda-Grubbs (10)
PhMe, 110 65a,b
CH2Cl2, 40 30c
With substrate 21 in hand, we proceeded to study the key
RCM step for formation of the 13-membered ring in bicycle
22 (Scheme 4). The optimum conditons involved performing
Ti(OiPr)4 (30) CH2Cl2, 40 51
Ti(OiPr)4 (30) PhMe, 55
Ti(OiPr)4 (30) PhMe, 55
69
75
CH2Cl2, 40 69
a Unwanted isomerization of product occurred, with the double bond
formed through RCM partially moving into conjugtion with the enone
system. b Analogous conditions with Grubbs I gave only 50% yield, although
without significant isomerization. c Incomplete conversion of starting mate-
rial.
Scheme 4. Synthesis of Fully Saturated Tricyclic
Intermediates
unwanted isomerization of the product (entry 1). Lowering
the temperature by changing solvent led to incomplete
conversion of the starting material and poor yield (entry 2).
However, the addition of Ti(OiPr)4 to the reaction, to break
up any chelation between the starting material and Ru-
catalyst,9 resulted in improved yields, with toluene proving
to be the best solvent for the reaction (entries 3, 4, and 5).
Ultimately though, utilizing the Hoveyda-Grubbs catalyst
(10 mol %) in refluxing dichloromethane gave the best and
most consistent results (entry 6).
We then went on to apply this RCM-DTIMA sequence to
prepare the complete carbon skeleton of the dictyosphaeric
acids in enantiomerically pure form; the preparation of the
RCM precursor 21 is shown in Scheme 3. The (S)-TBS-
protected γ-hydroxy enone 17 was readily prepared from
commercially available 1-methoxycyclohexa-1,4-diene (16)
the reaction with 10 mol % of the Hoveyda-Grubbs catalyst
in refluxing dichloromethane, as described in Table 1, giving
via literature methods {[R]21 -106.5 (c 1.43, CH2Cl2; lit.7
(10) Krafft, M. E.; Cran, J. W. Synlett 2005, 8, 1263-1266.
(11) Acid 20 was prepared in 99% yield from the DCC coupling of the
commercially available (S)-(+)-4-pentene-2-ol and malonic acid.
(12) Wissmann, H.; Kleiner, H. J. Angew. Chem., Int. Ed. 1980, 19, 133-
134.
D
(9) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-
9136.
Org. Lett., Vol. 10, No. 2, 2008
355

Scheme 5. Introduction of Triene Side Chain
the desired bicycle 22 in 69% yield, as a separable 3:2 ratio
eomers (and as compound 23 was the single diastereomer
shown, this observation indicates the ease of epimerization
adjacent to the cyclohexanone group in these compounds).
In conclusion, we have developed a highly convergent and
concise synthesis of the carbon skeleton of the dictyosphaeric
acids. The route involves nine linear steps from the readily
available (S)-(-)-4-(tert-butyldimethylsilyloxy)cyclohex-
enone and incorporates a ring-closing metathesis to produce
a 13-membered macrolactone and a doubly tethered intramo-
lecular Michael addition. We are currently optimizing and
diversifing this synthetic route to allow the total synthesis
of the natural products, and access to novel analogues, and
these studies will be reported in due course.
of E/Z isomers.13
Next, we investigated the DTIMA process on mixture 22
and were delighted to observe that with NaH/THF, cycliza-
tion proceeded in high yield (84%); hydrogenation to remove
the alkene isomers provided the fully saturated tricyclic
intermediates 23 and 24 (Scheme 4), the relative stereo-
chemistry being determined by extensive NOE studies.
To complete the synthesis of the carbon skeleton of the
dictyosphaeric acids, what remained was to introduce the
triene side chain, and this was achieved through organome-
tallic cross coupling (Scheme 5). Thus, dicarbonyl compound
2314 was deprotonated and converted into the vinyl triflate
25.15 Without isolation, triflate 25 was successfully coupled
to trienylstannane 2616 using palladium catalysis giving the
target system 27 as an inseparable mixture of two diaster-
Acknowledgment. We thank Elsevier Science (M.N.K.
and M.G.E.) for postdoctoral funding, the BBSRC (C.W.B.
and A.R.B.) for studentship funding, and GlaxoSmithKline
for CASE support. We are also grateful to Archimica for a
generous gift of T3P and to Dr. T. Dransfield (University of
York) for invaluable assistance with mass spectrometry.
(13) These alkene isomers could be separated by column chromatography
on AgNO3-doped silica gel, which allowed for full structural characterization
(see: Ruprah, P. K.; Cros, J.-P.; Pease, J. E.; Whittingham, W. G.; Williams,
J. M. J. Eur. J. Org. Chem. 2002, 3145-3152).
(14) Single diastereomer 23 was utilized initially in an attempt to avoid
mixtures of products and to simplify the data analysis. However, the reaction
can also be performed on the mixture of 23 and 24 with similar results.
(15) NMR spectroscopy indicated formation of a single triflate. Such
regioselectivity is amply precedented; see, for example: Paquette, L. A.;
Wang, T.-Z.; Sivik, M. R. J. Am. Chem. Soc. 1994, 116, 11323-11334.
(16) Prepared by Stille coupling of the known ethyl E,E-5-bromopenta-
2,4-dienoate (Wei, X.; Taylor, R. J. K. J. Org. Chem. 2000, 65, 616-620)
with (E)-1,2-di(tributylstannyl)ethene.
Supporting Information Available: Full experimental
details and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702887E
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Org. Lett., Vol. 10, No. 2, 2008