The diazo route to diazonamide A: Studies on the tyrosine-derived fragment

Article abstract of DOI:10.1039/b510653b

Various approaches to the tyrosine-derived fragment of the marine secondary metabolite diazonamide A are described. Initial efforts were focused on the originally proposed structure of the natural product, and a feasibility study established that a model

Full text of DOI:10.1039/b510653b

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
The diazo route to diazonamide A: studies on the tyrosine-derived
fragment†‡
Francine N. Palmer,a Franck Lach,a Cyril Poriel,a Adrian G. Pepper,a Mark C. Bagley,a
Alexandra M. Z. Slawinb and Christopher J. Moody*c
a Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
b School of Chemistry, University of St. Andrews, Fife, Scotland, UK KY16 9ST
c School of Chemistry, University of Nottingham, University Park, Nottingham, UK NG7 2RD.
E-mail: c.j.moody@nottingham.ac.uk
Received 27th July 2005, Accepted 22nd August 2005
First published as an Advance Article on the web 14th September 2005
Various approaches to the tyrosine-derived fragment of the marine secondary metabolite diazonamide A are
described. Initial efforts were focused on the originally proposed structure of the natural product, and a feasibility
study established that a model 4-aryltryptamine could be readily prepared. Protected 4-bromotryptamine underwent
Pd(0)-catalyzed coupling with the boronic acid derived from 2-bromophenyl allyl ether by Claisen rearrangement,
O-methylation and lithiation–boration. The resulting biaryl was elaborated into an a-diazo-b-ketoester,
dirhodium(II)-catalyzed reaction of which with N-Z-valinamide gave the desired tryptamine-oxazole following
cyclodehydration of the intermediate ketoamide. A potential precursor to the benzofuran ring of the original
structure of diazonamide A was prepared in eight steps from N-Z-tyrosine tert-butyl ester. Iodination, O-protection
and Stille coupling gave the cinnamyl alcohol 25, converted via the bromide into the allyl aryl ether 27. Subsequent
Claisen rearrangement and oxidative cleavage of the alkene gave the lactol 29, converted into the desired
benzofuranone 31. The revision in the structure of diazonamide A to 2 resulted in the targeting of an alternative
tyrosine-derived model benzofuranone 41 synthesized in four steps from N-Z-tyrosine methyl ester 36 by a route
involving Claisen rearrangement of cinnamyl ether 37. Poor yields in this sequence prompted an investigation into
the intramolecular Heck reaction as a route to benzofuranone 50. Coupling of 3-iodotyrosine 44 with
2-phenylbutenoic acid 48 gave ester 49 that readily underwent intramolecular Heck reaction to give benzofuranone
50, albeit with poor stereocontrol.
Introduction
The marine secondary metabolite diazonamide A, isolated from
the colonial ascidian Diazona chinensis, was assigned as structure
1 on the basis of an X-ray crystallographic study of a derivative.2
This unique and complex strained structure, together with the
reported nanomolar in vitro cytotoxicity against human tumor
cell lines,2,3 ensured that diazonamide A immediately attracted
the attention of synthetic organic chemists. Hence in the 15 years
since the structure of diazonamide A was reported in 1991,
more than 10 research groups have published approaches to
this fascinating natural product.4–31 The story acquired a new
dimension in 2001 when Harran and co-workers completed
a total synthesis of structure 1 only to discover that it was
different from the natural product.32,33 On the basis of a re-
examination of the original X-ray data, Harran proposed the
alternative structure 2 for diazonamide A (Fig. 1). Not only
did this subsequently prove to be correct, but it also better
fits a biosynthetic route in which the bicyclic core derives from
modification of a Tyr-Val-Trp-Trp tetrapeptide. Final proof that
the revised structure 2 was indeed that of diazonamide A came
in 2002 when Nicolaou and co-workers published the first total
synthesis of the natural product.34,35 Subsequently, the Nicolaou
group reported a second route to diazonamide A,36,37 whilst
Harran and co-workers completed their own total synthesis of
the correct structure.38 Despite the fact that Nicolaou’s and
Harran’s endeavours in total synthesis have now solved the
structural problem of diazonamide A, such is its attraction as
Fig. 1 The original and revised structures for the marine secondary
metabolite diazonamide A.
a target molecule that it continues to hold the attention of a
number of research groups.
Our own interest in diazonamide A started over a decade
† The diazo route to diazonamide A. Part 2.1
‡ Electronic supplementary information (ESI) available: Experimental
details. See http://dx.doi.org/10.1039/b510653b
ago when we reported an approach to a benzofuranone
related to the original structure using the DMAP-induced
C-acylation reaction, and an approach to 5-(3-indolyl)oxazoles
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 0 5 – 3 8 1 1
3 8 0 5
©

View Article Online
using dirhodium(II) catalyzed reactions of diazocarbonyl
compounds.39,40 We have also reported preliminary results on a
second approach to the tyrosine-derived benzofuran unit of the
original structure using the Claisen rearrangement,41 and further
studies on the indole fragments.42,43 The first paper in this series
described our efforts towards the indole bis-oxazole fragment
of diazonamide A,1 whilst the present paper describes the full
details of our various approaches to the tyrosine-derived frag-
ment of the natural product. Some of the work reported here has
appeared in the preliminary publications referred to above.41,43
diazonamide A 1, together with the assumption that the c-
lactol could derive simply from the corresponding lactone, leads
back to the bicycle 3. Formation of the oxazole would result
from a Robinson–Gabriel cyclodehydration of a 1,4-dicarbonyl
compound 4 that in turn could be accessed via a Yonemitsu
DDQ-oxidation of the indole-CH2-group;44,45 breaking of the
two amide bonds in the retrosynthetic sense leads to compound
5. Oxazole formation using the N-H insertion reaction of a
rhodium carbene intermediate, a reaction extensively developed
in our laboratory,46–50 and a palladium-catalyzed biaryl forma-
tion then reveals three fragments: the 4-bromotryptamine 6,
the carboxamide 7, and a-diazo-b-ketoester 8, the precursor of
the rhodium carbene intermediate (Scheme 1). Finally, it was
envisaged that the diazocarbonyl compound 8 would derive
from the corresponding aldehyde 9 (R = CHO) by either our
previously developed diethylzinc mediated reactions of ethyl
diazoacetate,51 or the Roskamp protocol,52 followed by diazo-
transfer. This reveals the 3-formylbenzofuranone 9 (R = CHO),
which in turn could be formed from the corresponding ester,
amide, vinyl or unsubstituted compounds 9 (R = CO2Rꢀ,
CONRꢀ2, vinyl or H) (Scheme 1).
Results and discussion
Retrosynthetic analysis
Although devised some years ago, our retrosynthetic analysis of
diazonamide A remains largely unaltered in its overall strategy,
notwithstanding the fact that it was designed for the original
structure 1 of the natural product. Thus, in common with
most other reported strategies, our initial simplification was
to disconnect the valine side-chain (or a-hydroxy isocaproic
acid as in the correct structure) and the two chlorine atoms.
It was established early on in the diazonamide saga that both
these chlorines could be introduced by a late stage electrophilic
chlorination reaction.6,13 This initial analysis of the “old”
This paper focuses on our approaches to benzofuranones 9
of the original diazonamide A structure and our attempts to
adapt the methodology to the corresponding oxindoles of the
correct structure. However, the paper is introduced by an early
Scheme 1 Retrosynthetic analysis of the original structure of diazonamide A 1 [Pg = protecting group].
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 0 5 – 3 8 1 1
3 8 0 6

View Article Online
feasibility study in which a very simple model for aldehyde 9
(R = CHO) was investigated to confirm that elaboration at both
the aldehyde and bromide functional groups to incorporate both
oxazole and tryptamine fragments was indeed possible to give
model structure 10, a simpler version of one of our proposed
key intermediates 5 (Scheme 1).
Synthesis of model 4-aryltryptamine 10
The synthesis of the model compound 10 started with the known
4-bromoindole-3-carboxaldehyde 1153 that was converted into
the corresponding tryptamine by conventional means involv-
ing Henry reaction with nitromethane, and reduction of the
resulting nitroalkene with lithium aluminium hydride. The 4-
bromotryptamine was not purified, but was protected on both
indole and side-chain nitrogens as the di-Boc-derivative 12 ready
for Pd-catalyzed coupling at the indole 4-position (Scheme 2).
Scheme 2
The synthesis of the coupling partner 14 for 4-bromoindole
12 started with the allyl ether 13 of 2-bromophenol. Lewis acid-
catalyzed Claisen rearrangement, methylation of the resulting
phenol,54 and lithium–halogen exchange followed by quenching
with trimethyl borate gave the boronic acid 14. Suzuki coupling
of bromide 12 and boronic acid 14 using caesium carbonate as
base gave the biaryl 15 in excellent yield. Oxidative cleavage
of the allyl side-chain to the key aldehyde 16 was achieved
in a two-step procedure by osmium tetroxide dihydroxylation
followed by periodate cleavage. Reaction of the aldehyde 16 with
ethyl diazoacetate in the presence of tin(II) chloride,52 gave the
b-ketoester 17, that underwent smooth diazo-transfer with 4-
acetamidobenzenesulfonyl azide55 to give the required a-diazo-
b-ketoester 18. The stage was now set for the key rhodium
carbene N-H insertion reaction, and this proceeded as planned,
though in modest yield, to give the 1,4-dicarbonyl ketoamide 19.
Final Robinson–Gabriel cyclodehydration using the Wipf Ph3P–
I2–Et3N protocol56 gave the model tryptamine-biaryl-oxazole
10, albeit in poor yield (Scheme 3). Although some of the
above (unoptimized) reactions only proceed in modest yield,
the feasibility study has established that given an appropriate
aromatic precursor containing a bromide and an aldehyde,
then both bromine and aldehyde groups can be elaborated into
tryptamine and oxazole units respectively as required in our
proposed route to diazonamide A.
Synthesis of benzofuranone 9 (R = H), a potential precursor to
Scheme 3 Ar = 4-AcNHC6H4.
the original structure of diazonamide A
As outlined above, a benzofuranone 9 (R = H) was identified as a
possible precursor to the tyrosine-derived benzofuran fragment
of the original structure of diazonamide A 1 on the basis that it
not only contains the required tyrosine unit (in protected form),
but also a bromine at C-7 (benzofuran numbering) that will
allow transition-metal catalyzed sp2–sp2 coupling to form the
biaryl bond to the 4-position of an appropriate indole at a
later stage in the synthesis, cf. the feasibility study described
above. Additionally, the use of Black’s C-acylation procedure
based on Steglich’s original observations,57 should allow the
introduction of an additional carbon substituent that will
become the aldehyde at the 3-position of the benzofuran—
the C-10 quaternary centre in diazonamide A—for further
elaboration to an oxazole as also described in the model
study above. This C-acylation procedure was used in a simple
benzofuranone in our early preliminary studies,39,40 and also
recently by Vedejs in his approach to a fragment of diazonamide
A.19 It was anticipated that a benzofuranone 9 (R = H) would be
accessible by lactonization of an appropriate phenol and side-
chain carboxylate, that in turn could be derived by oxidative
cleavage of an allyl group double bond. The requirement for an
ortho-allyl phenol immediately suggests a strategy involving a
Claisen rearrangement as outlined in Scheme 4.
The starting material for the synthesis of the required
benzofuranone 31 was the known N-benzyloxycarbonyl tyrosine
tert-butyl ester 22.58 ortho-Iodination of the phenol was achieved
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 0 5 – 3 8 1 1
3 8 0 7

View Article Online
Scheme 4 Ar = protected 3-tyrosinyl residue.
under neutral conditions using chloramine-T–sodium iodide.59,60
The ortho-iodophenol was not purified, but immediately O-
alkylated under conditions known to minimize racemization61
to give the benzyl ether 23 in 55% yield over the two steps
(Scheme 5). After considerable experimentation, it was found
that the palladium catalyzed coupling of the iodotyrosine
derivative 23 with allyl alcohol, under the conditions [Pd(OAc)2,
Ph3P, AgOAc, DMF] developed by Jeffery to prevent subsequent
isomerization of the double bond,62 gave the required cinnamyl
alcohol derivative 25 but in modest yield (30–35%). Therefore
we resorted to a Stille coupling of the iodide 23 with the tri-n-
butylstannyl allyl alcohol 24, prepared from propargyl alcohol
by stannylcupration methodology,63 and this gave the cinnamyl
alcohol 25 in excellent yield (91%). Conversion into the allylic
bromide 26 without any isomerization of the double bond,
was followed by reaction with 2-bromophenol using sodium
hydroxide as base under phase transfer conditions to give
the cinnamyl aryl ether 27. This substrate underwent Claisen
rearrangement on heating under reflux in DMF to give the
phenol 28 as a mixture of diastereomers. Reaction of alkene
28 with catalytic osmium tetroxide with potassium periodate as
co-oxidant resulted in oxidative cleavage of the double bond,
and cyclization of the intermediate aldehyde to the lactol 29.
Oxidation of the lactol 29 to the desired lactone 31 proved
surprisingly difficult, and a number of commonly used reagents
(PCC, PDC, Fetizon’s reagent, Swern conditions) failed to effect
this transformation. Eventually it was found that the iodinane
oxide 30,64 a reagent reported by Grieco et al. to be useful for sim-
ilar oxidations,65 converted the lactol 29 into the required lactone
31 in 83% yield (Scheme 5). Thus the required benzofuranone 31
has been prepared in eight steps from the N-protected tyrosine
ester 22. Although we did initiate some preliminary experiments
to establish a quaternary centre at the benzofuranone 3-position
(C-10 in diazonamide),66 these were curtailed when the revised
structure of diazonamide A was revealed.
Synthesis of alternative benzofuranone precursors to “both”
structures of diazonamide A
The publication of the revised and correct structure 2 for
diazonamide A in 200132,33 caused us to reconsider our strategy.
Although on the face of it, the required O to N switch in
the heterocyclic core of the natural product, i.e. replacement
of a benzofuranone precursor by the corresponding oxindole,
seemed simple enough, the strategies described above both rely
on a Claisen rearrangement of an allyl ether of 2-bromophenol.
A few unsuccessful experiments with N-allyl derivatives of 2-
bromoaniline quickly confirmed that an analogous strategy
based on the aza-Claisen rearrangement67 was unlikely to be
successful, and therefore an alternative approach was adopted.
This approach targets different tyrosine-derived benzofuranone
precursors 32 and 34 on the basis that deprotection of the phenol
in 32 or the aniline in 34 (X = NHPg) should result in cyclization
to give the benzofuranone 33 or oxindole 35 rings of the original
and revised structures of diazonamide A respectively. Likewise,
reduction of a nitro-group in 34 (X = NO2) would also result
in cyclization to the oxoindole 35 (Scheme 6). Although it was
not obvious which of the two benzofuranone structures, 32 (X =
OH) or 33, would be favoured under equilibrating conditions, we
were confident that in the “correct” nitrogen series, the desired
Scheme 5
oxindole 35 would be favoured over its benzofuranone precursor
34 (X = NH2).
Our first route to such benzofuranones did involve a Claisen
rearrangement. Thus N-benzyloxycarbonyltyrosine methyl ester
36 was converted into the cinnamyl ether 37 by reaction with
cinnamyl bromide. The Claisen rearrangement was investigated
under a variety of conditions, none of which were entirely
satisfactory, the best being prolonged heating in boiling 1,2-
dichlorobenzene (bp 178–180 ◦C). The rearrangement pro-
ceeded in 45% yield to give the 3-allyl tyrosine derivative 38
as a mixture of diastereomers; ozonolysis of the alkene followed
by reductive work-up with dimethyl sulfide gave a hemiacetal
3 8 0 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 0 5 – 3 8 1 1

View Article Online
successfully prepared by iodination of a tyrosine derivative
(Scheme 5), in this case it proved easier to start from commer-
cially available 3-iodotyrosine itself. Thus 3-iodotyrosine 41 was
N-protected as its benzyl carbamate 42, although this process
was always complicated by over-reaction at the phenolic oxygen,
and the resulting di-benzyloxycarbonyl derivative had to be
removed after the next step. Esterification was achieved using
phase-transfer catalyzed alkylation with tert-butyl bromide58 to
give the iodotyrosine derivative 43. The alkene required for the
Heck reaction was incorporated from 2-phenylbutenoic acid
47, itself prepared by an adaptation of a literature method
for the analogous heptenoic acid derivative.70 Ethyl tetrolate
44 underwent Pd-catalyzed hydrostannylation in high yield to
give ethyl 2-tri-n-butylstannnylbut-2-enoate 45, presumed at
this stage to result from trans-addition. The reaction was not
regioselective and the major (ca. 3 : 1) vinylstannane 45 was ac-
companied by its regioisomer, ethyl 3-tri-n-butylstannnylbut-2-
enoate, inseparable at this stage, but readily removed later. Stille
reaction of the vinylstannane(s) with iodobenzene gave ethyl 2-
phenylbutenoate 46 (now a 7 : 1 mixture with its regioisomer
ethyl 3-phenylbutenoate), hydrolyzed to the corresponding acid
47 (Scheme 8). The acid 47 was readily purified by crystallization
and by comparison of melting points with literature data, the
Scheme 6
directly, the lactol 40, as a complex mixture of isomers, with no
evidence for the intermediate aldehyde 39. Although lactol 39
could, in principle, be readily oxidized to the corresponding
lactone, a benzofuranone, all of the reactions described in
Scheme 7 are unsatisfactory in terms of yield, and therefore no
attempt was made to repeat the sequence with the appropriate
substituents in the aromatic ring of the cinnamyl group.
Scheme 7
In view of the poor yields in the above Claisen rearrangement-
based approach to benzofuranones, an alternative strategy based
on the intramolecular (and asymmetric) Heck reaction was
adopted.68,69 Related uses of the intramolecular reaction in the
synthesis of diazonamide A fragments have been reported by
both Wipf and Pattenden and co-workers.6,8 The substrate for
the model intramolecular Heck reaction was the iodotyrosine
derivative 48. Although the related iodotyrosine 23 had been
Scheme 8 BTEAC = benzyltriethylammonium chloride; DMA =
dimethylacetamide; Pd2(dba)3·CHCl3
=
tris(dibenzylideneacetone)-
dipalladium(0) chloroform adduct.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 0 5 – 3 8 1 1
3 8 0 9

View Article Online
(E)-geometry of the alkene was confirmed. Coupling of the
phenol 43 with the acid 47 using standard carbodiimide method-
ology gave the substrate 48 for the intramolecular Heck reaction
in good yield (Scheme 8). Our first attempt at the intramolecular
Heck used literature conditions [Pd(OAc)2, PPh3, Ag2CO3,
THF],71 but these proved unsuccessful, and we eventually settled
on the conditions employed by Wipf in his diazonamide A work,6
namely Pd2(dba)3·CHCl3 as catalyst, (S)-BINAP as the phos-
phine, in the presence of silver phosphate in dimethylacetamide
(DMA). This gave the desired product 49 in 63% yield as a 3 : 2
mixture of diastereomers (Scheme 8). Hence the intramolecular
reaction has given the desired benzofuranone, with the C-10
(diazonamide numbering) quaternary centre installed, albeit as
a mixture of stereoisomers; the stereochemistry of the major
diastereomer remains unknown. A number of attempts were
made to improve the stereochemical outcome of the Heck
reaction employing other chiral phosphines (Tol-BINAP, DIOP,
etc.) but with little improvement in either yield or selectivity.
Similar poor levels of stereoselectivity were also observed by
Wipf in his work.6
upon reduction of the nitro group (cf. Scheme 6). The 2-
arylbutenoic acid 56 was easily obtained by condensation of the
anion of methyl (2-nitro)phenylacetate72 54 with acetaldehyde
to give ester 55, followed by hydrolysis. X-Ray crystallography
confirmed the (E)-geometry of the alkene (Fig. 2). The acid
56 was coupled to iodotyrosine 43 in good yield to give the
desired substrate 57 (Scheme 10). However, compound 57 failed
to undergo intramolecular Heck reaction under a variety of
conditions, the presence of the nitro-group apparently having a
major adverse effect on this reaction.
With the 3,3-disubstituted benzofuranone 49 in hand, it re-
mained only to cleave the vinyl group oxidatively to give the alde-
hyde 50 that could be elaborated using diazocarbonyl chemistry
(cf. Scheme 3) into the required oxazole. This transformation
proved surprisingly difficult, and could not be achieved directly
using a wide range of conditions (ozone, OsO4–NaIO4, RuCl3–
NaIO4, KMnO4). Given that a related 2,3-dihydrobenzofuran
is reported to undergo clean oxidative cleavage,8 we speculated
that the lactone 49 was somehow too strained, and therefore
it was reduced to the corresponding lactol 51 using sodium
borohydride in poor yield (Scheme 9). Protection of the lactol as
its acetate 52 was followed by smooth ozonolysis of the alkene
to give aldehyde 53 in essentially quantitative yield, as a complex
mixture of isomers that could not be completely characterized.
Although it was satisfying that the desired oxidative cleavage
had finally been achieved in the lactol derivative 52, the lack of
reactivity of the corresponding lactone 49 remains a mystery.
Fig. 2 X-Ray crystal structure of (E)-2-(2-nitrophenyl)but-2-enoic acid
56.§
Scheme 10
Conclusions
This paper has described a number of routes to potentially useful
intermediates for the synthesis of the tyrosine-derived fragment
˚
˚
§ Crystal data: C10H9NO4; M = 207.18; a = 10.244(2) A; b = 13.920(3) A;
Scheme 9
◦
◦
◦
˚
c = 13.155(3) A; a = 90 ; b = 92.4243(17) ; c = 90 ; temp. = 93(2) K;
P2(1)/n; Z = 8; l = 0.115 mm−1; reflections collected = 11668; indepen-
dent reflections 3344 [R(int) = 0.0314]; Final R indices [I > 2r(I)] R1 =
0.0367, wR2 = 0.0886; R indices (all data) R1 = 0.0471, wR2 = 0.0937.
CCDC reference numbers 279634. See http://dx.doi.org/10.1039/
b510653b for crystallographic data in CIF or other electronic format.
Finally an intramolecular Heck reaction was attempted with
a substrate bearing an additional nitro-group in order to
access a 3,3-disubstituted benzofuranone 58 that should be
readily converted into the oxindole of the natural product
3 8 1 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 0 5 – 3 8 1 1

View Article Online
of the marine natural product diazonamide A. Although a
number of problems remain, in particular, unsatisfactory yields
in key steps, and lack of stereochemical control leading to
mixtures of diastereoisomers, that must be addressed before a
synthesis can be completed, the above routes have successfully
delivered appropriately functionalized benzofuranones that,
with subsequent improvement, might be incorporated into a
total synthesis of diazonamide A by linking with the successful
diazocarbonyl-based approach to the model 4-aryltryptamine.
32 J. Li, S. Jeong, L. Esser and P. G. Harran, Angew. Chem., Int. Ed.,
2001, 40, 4765.
33 J. Li, A. W. G. Burgett, L. Esser, C. Amezcua and P. G. Harran,
Angew. Chem., Int. Ed., 2001, 40, 4770.
34 K. C. Nicolaou, M. Bella, D. Y. K. Chen, X. H. Huang, T. T. Ling
and S. A. Snyder, Angew. Chem., Int. Ed., 2002, 41, 3495.
35 K. C. Nicolaou, D. Y. K. Chen, X. H. Huang, T. T. Ling, M. Bella
and S. A. Snyder, J. Am. Chem. Soc., 2004, 126, 12888.
36 K. C. Nicolaou, P. B. Rao, J. L. Hao, M. V. Reddy, G. Rassias, X. H.
Huang, D. Y. K. Chen and S. A. Snyder, Angew. Chem., Int. Ed.,
2003, 42, 1753.
37 K. C. Nicolaou, J. L. Hao, M. V. Reddy, P. B. Rao, G. Rassias,
S. A. Snyder, X. H. Huang, D. Y. K. Chen, W. E. Brenzovich, N.
Giuseppone, P. Giannakakou and A. O’Brate, J. Am. Chem. Soc.,
2004, 126, 12897.
38 A. W. G. Burgett, Q. Y. Li, Q. Wei and P. G. Harran, Angew. Chem.,
Int. Ed., 2003, 42, 4961.
Experimental
Full experimental details are given in the Electronic Supplemen-
tary Information.‡
39 C. J. Moody, K. J. Doyle, M. C. Elliott and T. J. Mowlem, Pure Appl.
Chem., 1994, 66, 2107.
Acknowledgements
40 C. J. Moody, K. J. Doyle, M. C. Elliott and T. J. Mowlem, J. Chem.
Soc., Perkin Trans. 1, 1997, 2413.
41 F. Lach and C. J. Moody, Tetrahedron Lett., 2000, 41, 6893.
42 M. C. Bagley, S. L. Hind and C. J. Moody, Tetrahedron Lett., 2000,
41, 6897.
43 M. C. Bagley, C. J. Moody and A. G. Pepper, Tetrahedron Lett., 2000,
41, 6901.
We thank the EPSRC, the Leverhulme Trust and the Association
pour la Recherche contre le Cancer (fellowship to F.L.) for
support, the EPSRC Mass Spectrometry Centre at Swansea for
mass spectra, and the EPSRC Chemical Database Service at
Daresbury.73
44 Y. Oikawa, T. Yoshioka, K. Mohri and O. Yonemitsu, Heterocycles,
1979, 12, 1457.
45 T. Yoshioka, K. Mohri, Y. Oikawa and O. Yonemitsu, J. Chem. Res.
(S), 1981, 194.
References
1 Part 1. J. R. Davies, P. D. Kane and C. J. Moody, J. Org. Chem., 2005,
70, 7305.
2 N. Lindquist, W. Fenical, G. D. Van Duyne and J. Clardy, J. Am.
Chem. Soc., 1991, 113, 2303.
3 Z. Cruz-Monserrate, H. C. Vervoort, R. L. Bai, D. J. Newman, S. B.
Howell, G. Los, J. T. Mullaney, M. D. Williams, G. R. Pettit, W.
Fenical and E. Hamel, Mol. Pharmacol., 2003, 63, 1273.
4 J. P. Konopelski, J. M. Hottenroth, H. M. Oltra, E. A. Ve´liz and
Z.-C. Yang, Synlett, 1996, 609.
46 C. J. Moody and K. J. Doyle, Prog. Heterocycl. Chem., 1997, 9, 1.
47 M. C. Bagley, R. T. Buck, S. L. Hind and C. J. Moody, J. Chem. Soc.,
Perkin Trans. 1, 1998, 591.
48 C. J. Moody and M. C. Bagley, J. Chem. Soc., Perkin Trans. 1, 1998,
601.
49 M. C. Bagley, K. E. Bashford, C. L. Hesketh and C. J. Moody, J. Am.
Chem. Soc., 2000, 122, 3301.
5 H. C. Hang, E. Drotleff, G. I. Elliott, T. A. Ritsema and J. P.
Konopelski, Synthesis, 1999, 398.
6 P. Wipf and F. Yokokawa, Tetrahedron Lett., 1998, 39, 2223.
7 P. Wipf and J. L. Methot, Org. Lett., 2001, 3, 1261.
8 A. Boto, M. Ling, G. Meek and G. Pattenden, Tetrahedron Lett.,
1998, 39, 8167.
9 S. Jeong, X. Chen and P. G. Harran, J. Org. Chem., 1998, 63, 8640.
10 X. Chen, L. Esser and P. G. Harran, Angew. Chem., Int. Ed., 2000,
39, 937.
11 J. Li, X. Chen, A. W. G. Burgett and P. G. Harran, Angew. Chem.,
Int. Ed., 2001, 40, 2682.
50 J. R. Davies, P. D. Kane and C. J. Moody, Tetrahedron, 2004, 60,
3967.
51 C. J. Moody and C. N. Morfitt, Synthesis, 1998, 1039.
52 C. R. Holmquist and E. J. Roskamp, J. Org. Chem., 1989, 54,
3258.
53 M. Somei, K. Kizu, M. Kunimoto and F. Yamada, Chem. Pharm.
Bull., 1985, 33, 3696.
54 H. Pudleiner and H. Laatsch, Synthesis, 1989, 286.
55 J. S. Baum, D. A. Shook, H. M. L. Davies and H. D. Smith, Synth.
Commun., 1987, 17, 1709.
56 P. Wipf and C. P. Miller, J. Org. Chem., 1993, 58, 3604.
57 T. H. Black, S. M. Arrivo, J. S. Schumm and J. M. Knobeloch, J. Org.
Chem., 1987, 52, 5425.
12 P. Magnus and J. D. Kreisberg, Tetrahedron Lett., 1999, 40, 451.
13 P. Magnus and E. G. McIver, Tetrahedron Lett., 2000, 41, 831.
14 F. Chan, P. Magnus and E. G. McIver, Tetrahedron Lett., 2000, 41,
835.
58 P. Chevallet, P. Garrouste, B. Malawska and J. Martinez, Tetrahedron
Lett., 1993, 34, 7409.
15 J. D. Kreisberg, P. Magnus and E. G. McIver, Tetrahedron Lett., 2001,
59 T. Kometani, D. S. Watt and T. Ji, Tetrahedron Lett., 1985, 26,
42, 627.
2043.
16 P. Magnus and C. Lescop, Tetrahedron Lett., 2001, 42, 7193.
17 J. D. Kreisberg, P. Magnus and S. Shinde, Tetrahedron Lett., 2002,
43, 7393.
18 P. Magnus, J. D. Venable, L. Shen and V. Lynch, Tetrahedron Lett.,
2005, 46, 707.
19 E. Vedejs and J. Wang, Org. Lett., 2000, 2, 1031.
20 E. Vedejs and D. A. Barda, Org. Lett., 2000, 2, 1033.
21 E. Vedejs and M. A. Zajac, Org. Lett., 2001, 3, 2451.
22 M. A. Zajac and E. Vedejs, Org. Lett., 2004, 6, 237.
23 D. E. Fuerst, B. M. Stoltz and J. L. Wood, Org. Lett., 2000, 2, 3521.
24 T. Sawada, D. E. Fuerst and J. L. Wood, Tetrahedron Lett., 2003, 44,
4919.
60 N. R. Curtis, J. J. Kulagowski, P. D. Leeson, I. M. Mawer, M. P.
Ridgill, M. Rowley, S. Grimwood and G. R. Marshall, Bioorg. Med.
Chem. Lett., 1996, 6, 1145.
61 D. L. Boger and D. Yohannes, J. Org. Chem., 1987, 52, 5283.
62 T. Jeffery, Tetrahedron Lett., 1991, 32, 2121.
63 J.-F. Betzer, F. Delaloge, B. Muller, A. Pancrazi and J. Prunet, J. Org.
Chem., 1997, 62, 7768.
64 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277.
65 P. A. Grieco, J. L. Collins, E. D. Moher, T. J. Fleck and R. S. Gross,
J. Am. Chem. Soc., 1993, 115, 6078.
66 For example, allylation at the 3-position of 31 (LHMDS, THF,
−78 ◦C, allyl iodide) created the quaternary centre (mixture of
diastereomers).
25 K. C. Nicolaou, S. A. Snyder, K. B. Simonsen and A. E. Koumbis,
Angew. Chem., Int. Ed., 2000, 39, 3473.
67 K. C. Majumdar and T. Bhattacharyya, J. Indian Chem. Soc., 2002,
26 K. C. Nicolaou, X. Huang, N. Giuseppone, P. B. Rao, M. Bella, M. V.
Reddy and S. A. Snyder, Angew. Chem., Int. Ed., 2001, 40, 4705.
27 K. C. Nicolaou, S. A. Snyder, X. H. Huang, K. B. Simonsen, A. E.
Koumbis and A. Bigot, J. Am. Chem. Soc., 2004, 126, 10162.
28 K. C. Nicolaou, S. A. Snyder, N. Giuseppone, X. H. Huang, M.
Bella, M. V. Reddy, P. B. Rao, A. E. Koumbis, P. Giannakakou and
A. O’Brate, J. Am. Chem. Soc., 2004, 126, 10174.
29 A. Radspieler and J. Liebscher, Synthesis, 2001, 745.
30 D. Schley, A. Radspieler, G. Christoph and J. Liebscher, Eur. J. Org.
Chem., 2002, 369.
79, 112.
68 S. E. Gibson and R. J. Middleton, Contemp. Org. Synth., 1996, 3,
447.
69 A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945.
70 F. Bellina, A. Carpita, M. Desantis and R. Rossi, Tetrahedron, 1994,
50, 12029.
71 M. M. Abelman, L. E. Overman and V. D. Tran, J. Am. Chem. Soc.,
1990, 112, 6959.
72 G. Prasad, P. E. Hanna, W. E. Noland and S. Venkatraman, J. Org.
Chem., 1991, 56, 7188.
31 K. S. Feldman, K. J. Eastman and G. Lessene, Org. Lett., 2002, 4,
3525.
73 D. A. Fletcher, R. F. McMeeking and D. J. Parkin, J. Chem. Inf.
Comp. Sci., 1996, 36, 746.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 8 0 5 – 3 8 1 1
3 8 1 1