Mechanistic evidence supporting the biosynthesis of photodeoxytridachione

Article abstract of DOI:10.1016/j.tetlet.2003.08.021

This letter describes a two-step photochemical rearrangement of a conjugated pentaene. The results provide evidence that the marine product photodeoxytridachione is formed in two sequential photochemical reactions.

Full text of DOI:10.1016/j.tetlet.2003.08.021

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7471–7473
Mechanistic evidence supporting the biosynthesis of
photodeoxytridachione
Se´bastien Bru¨ckner,a Jack E. Baldwin,a,* John Moses,a Robert M. Adlingtona and
Andrew R. Cowleyb
aDyson Perrins Laboratory, Oxford University, South Parks Road, Oxford OX1 3QY, UK
bChemical Crystallography, Oxford University, South Parks Road, Oxford OX1 3QR, UK
Received 27 May 2003; revised 30 July 2003; accepted 8 August 2003
Abstract—This letter describes a two-step photochemical rearrangement of a conjugated pentaene. The results provide evidence
that the marine product photodeoxytridachione is formed in two sequential photochemical reactions.
© 2003 Elsevier Ltd. All rights reserved.
Biosynthetically, it is believed that photodeoxytrida-
chione 1 arises from the assembly of seven propionate
units (Scheme 1), the same building blocks used in the
biosynthesis of spectinabilin and the SNF family of
compounds.1–3
synthesised and photolysed. The photochemical rear-
rangement, which took place, allowed the formation of
photodeoxytridachione’s core 6 in 60% yield. Since no
intermediate was isolated, we previously could only
suggest a mechanism for this transformation (Scheme
3).
Furthermore, it has been demonstrated that
photodeoxytridachione 1 can be generated from the
metabolite 9,10-deoxytridachione 2 both in vitro and in
vivo photochemically (Scheme 2).1 However, there has
been some uncertainty regarding the mechanism of
formation of 2. Faulkner1b suggested the non-isolated
molecule 3 might be a possible precursor of both 9,10-
deoxytridachione 2 and photodeoxytridachione 1, via a
photochemical 6p conrotatory and consecutive s2a+
p2a electrocyclisation,4 respectively (Scheme 2).
Our proposed mechanism involved initial selective E–Z
isomerisation to give 5, the presence of which has been
confirmed by NMR during irradiation. This would be
followed by a p4s+p2a electrocyclisation to give bicy-
clo[3.1.0]hexene 6. However, our findings did not seem
to be in agreement with Faulkner’s proposals and
observations.1b
Therefore, we investigated a more appropriate pentaene
model system analogous to 3. With this in mind, the
This prompted us to investigate further the biomimetic
synthesis of photodeoxytridachione 1.
Recently, a synthetic model study of this compound has
been reported by our laboratory;2 tetraene 4 has been
Scheme 1.
* Corresponding author. Tel.: +44-(0)-1865-275-671; fax: +44-(0)-
1865-275-632; e-mail: jack.baldwin@chem.ox.ac.uk
Scheme 2.
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doi:10.1016/j.tetlet.2003.08.021

7472
S. Bru¨ckner et al. / Tetrahedron Letters 44 (2003) 7471–7473
Moreover, while the bicyclo[3.1.0] hexene 16 (deter-
mined by two-dimensional NMR and NOE) has been
obtained in 40% yield, compound 15 was also isolated
in 17% yield after 2 days irradiation of 13 (Scheme 6).
This structure was corroborated by X-ray analysis of
the derivatised ester 175 (Scheme 6, Fig. 1). Further-
more, ester 15 was shown to be an intermediate in the
formation of 16. An NMR study clearly showed a
direct and complete conversion of 15 (UVDCM: 15:
umax=264 nm, m=18400) into 16 upon irradiation of 15
under direct sunlight. No evidence for 14 by retro-elec-
trocyclisation was observed. The stereochemistry of 15
results from a double isomerisation followed by an
electrocyclisation. Indeed, together with the C8ꢀC9
alkene the C10ꢀC11 double bond must undergo a photo-
chemically induced E–Z isomerisation to generate 14.
This intermediate can undergo a symmetry-allowed
photochemically induced 6p conrotatory electrocyclisa-
tion4 to give cyclohexadiene 15. This is followed by a
photochemical allowed s2a+p2a electrocyclisation4,6
which completely converts the cyclodiene 15 into 16,
raising the yield of 16 to 57%.
Scheme 3.
Scheme 4. Reagents and conditions: (a) Ref. 3; (b) toluene,
reflux; (c) Dibal-H, Et2O, 0°C; (d) MnO2, CHCl3, rt; (e)
benzene, reflux.
Scheme 6.
Scheme 5.
(E,E,E,E,E)-pentaene ester 13 has been synthesised
using the strategy previously reported.3 Thus aldehyde
8 was coupled to the stabilised ylide 9 to give the fourth
propionate unit (Scheme 4). After reduction of the ester
10 to the alcohol stage, an oxidation gave the aldehyde
11. Finally a Wittig reaction with the functionalised
ylide 12 afforded the expected all (E)-pentaene 13 in
good overall yield.
As was found with tetraene 4,2 ester 13 is transformed,
under photochemical conditions (UVDCM: 13: umax
=
373 nm, m=35200, 2 days irradiation with a 600 W
tungsten bulb), to give the photodeoxytridachione core
16 (Scheme 5).
Figure 1. X-Ray structure of cyclohexadiene 17.5

S. Bru¨ckner et al. / Tetrahedron Letters 44 (2003) 7471–7473
7473
In conclusion, we have demonstrated the connection
between the linear all E-pentaene 13, intermediate 15
and the bicyclic[3.1.0] compound 16. The established
mechanism supports a conversion of metabolite 3 into
9,10-deoxytridachione 2, which then undergoes a direct
photochemically induced s2a+p2a electrocyclisation to
afford photodeoxytridachione 1. This is fully in accor-
dance with the proposed biological pathway.1 Full
detail of these and other results of polyenic compounds
will be reported in due course.
Faulkner, D. J. Tetrahedron 1981, 37 (Suppl. 1), 233; (c)
Miller, A. K.; Trauner, D. Angew. Chem., Int. Ed. Engl.
2003, 42, 549.
2. Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R.
M.; Claridge, T. D. W.; Odell, B. Org. Lett. 2003, 5,
661.
3. Moses, J. E.; Baldwin, J. E.; Marquez, R.; Adlington, R.
M.; Cowley, A. R. Org. Lett. 2002, 4, 3731.
4. Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed.
Engl. 1969, 8, 781.
5. The atomic coordinates for 17 are available upon
request from the Cambridge Crystallographic Data Cen-
tre, University Chemical Laboratory, Lensfield Road,
Cambridge CB2 1EW (Deposition number CCDC
209300). The crystallographic numbering system differs
from that used in the text; therefore any request should
be accompanied by the full literature citation of this
paper.
Acknowledgements
We thank Drs T. D. W. Claridge and B. Odell for
NMR assistance, Dr A. R. Cowley for the X-ray struc-
ture of compound 17, and Roche for funding (S.B.).
6. Although such photocyclisations have been well studied,
we cannot discard the possibility that the reaction mech-
anism involves a highly stereoselective diradical process.
References
1. (a) Salem, L. Science 1976, 191, 822; (b) Ireland, C.;