The synthesis of alisamycin, nisamycin, LL-C10037α and novel epoxyquinol and epoxyquinone analogues of manumycin A

Article abstract of DOI:10.1055/s-1998-2064

Versatile synthetic routes are described for the preparation of a range of epoxyquinol and epoxyquinone analogues of the antitumour antibiotic manumycin A lacking the lower side chain, and these procedures have also been applied to prepare the bioactive natural product LL-C10037α. The extension of this methodology to provide a general synthetic route to the manumycin family of antibiotics is discussed and exemplified by the first total synthesis of alisamycin and ent-alisamycin. This route includes the novel, stereoselective organometallic addition of the Corey-Wollenberg reagent (E- 2-tributylstannylethenyllithium) to the manumycin nucleus and palladium catalysed Stille coupling technology for the introduction of the polyunsaturated 2-amino-3-hydroxycyclopentenone derived amide. Similar methodology has also been employed to complete the first total synthesis of the antibiotic nisamycin.

Full text of DOI:10.1055/s-1998-2064

FEATURE ARTICLE
775
a
The Synthesis of Alisamycin, Nisamycin, LL-C10037 and Novel Epoxyquinol and
Epoxyquinone Analogues of Manumycin A
Richard J. K. Taylor,a* Lilian Alcaraza‡ Isabelle Kapfer-Eyer,a Gregor Macdonald,a§ Xudong Wei,a Norman Lewisb
a Department of Chemistry, University of York, Heslington, York YO1 5DD, UK
E-mail: rjkt1@york.ac.uk
b SmithKline Beecham Pharmaceuticals, Leigh, Tonbridge, Kent TN11 9AN, UK
Received 28 November 1997; revised 12 January 1998
Dedicated to Professor Sandy McKillop to mark his retirement from the University of East Anglia, Norwich and the many achievements, both
in research and teaching, during his career there.
Abstract: Versatile synthetic routes are described for the prepara-
tion of a range of epoxyquinol and epoxyquinone analogues of the
antitumour antibiotic manumycin A lacking the lower side chain,
and these procedures have also been applied to prepare the bioac-
tive natural product LL-C10037a. The extension of this method-
ology to provide a general synthetic route to the manumycin
family of antibiotics is discussed and exemplified by the first total
synthesis of alisamycin and ent-alisamycin. This route includes
the novel, stereoselective organometallic addition of the Corey–
Wollenberg reagent (E-2-tributylstannylethenyllithium) to the
manumycin nucleus and palladium catalysed Stille coupling tech-
nology for the introduction of the polyunsaturated 2-amino-3-
hydroxycyclopentenone derived amide. Similar methodology has
also been employed to complete the first total synthesis of the
antibiotic nisamycin.
The manumycin natural products possess a range of bio-
activities in addition to their anti-bacterial properties.
These include antifungal activity and inhibitory activity
against polymorphonuclear leukocyte elastase and inter-
leukin-1b converting enzyme. Of greatest interest, how-
ever, is the discovery that the manumycins A–C act as
selective inhibitors of ras farnesyltransferase and as such
have potential in cancer chemotherapy.17 It is noteworthy
that the oxidative degradation products of the manumy-
cins, epoxyquinones 24–26 (Figure 3), retain their anti-tu-
mour activity indicating that the lower side chain is not
too important in this regard. The dihydroxy manumycin
analogues 19–23 were also shown to retain cytotoxicity
but were ineffective antibiotics, indicating the importance
of the epoxide group for antibacterial activity.16
Key words: LL-C10037a, alisamycin, nisamycin, manumycin
analogues, Stille coupling
The manumycin family of antibiotics has grown steadily
since the isolation of manumycin A (1) from Streptomyces
Parvalus in 1963.1,2 Other members (Figure 1) include
manumycin B (2),3 manumycin C (3),3 manumycin E (4),4
manumycin F (5),4 manumycin G (6),4 asukamycin (7),5
alisamycin (8),6–8 ent-alisamycin (9),9 El-1625-2 (10),9
El-1511-3 (11)9 and El-1511-5 (12).9 All of these com-
pounds have the same E,E,E-trienyl lower side chains ter-
minating in a 2-amino-3-hydroxycyclopentenone derived
amide. U-56407 (13)10 is reported to possess a Z,Z,E-tri-
enyl lower side chain (although this stereochemical as-
signment must be treated with caution5b) whereas
colabomycin (14)11 is a higher vinylogue, nisamycin
(15)12 lacks the terminal amide linkage, and U-62162
(16)13 has a saturated lower side chain. The upper side
chains of the family members are more distinctive but all
of these compounds are based on the epoxyaminocyclo-
hexenone nucleus which is also found in the anti-tumour
antibiotic LL-C10037a (17),14 and the broad spectrum an-
tibiotic MM-14201 (18).15 Most remarkably, all diastere-
oisomers of the central nucleus are represented in the
manumycin family. Thus, manumycin A (1), together
with 2 and 10 have the anti-(4R, 5R, 6S) configuration
whereas manumycin C (3) and 6, 7, 9 and 11–14 all have
the isomeric syn-hydroxy epoxide (4S, 5R, 6S) configura-
tion found in LL-C10037a (17). Manumycin F (5) is in
the enantiomeric anti-series (4R, 5S, 6R); alisamycin (8)
and nisamycin (15) are in the enantiomeric syn (4R, 5S,
6R) series along with MM 14201 (18). The related diols,
TherehavebeenanumberofstudiesbyFloss,Gould,Zeeck
andothers3b,5b,18 toelucidatethebiosyntheticpathwaylead-
ing to the manumycin family and related compounds. It has
been established that the polyene side chains are of
polyketide origin and that the C5N unit which terminates the
lowersidechainisderivedfrom5-aminolevulinicacid.The
biosynthesisofthemC7Nnucleus, however, provedsurpris-
ing in that it is not shikimate derived but rather originates
from 3-amino-4-hydroxybenzoic acid18a which in turn is
constructed from succinate and glycerol.3b
Despite their promising biological properties and interest-
ing biogenesis, synthetic approaches to the manumycins
have not been reported (although Wipf et al. have pre-
pared analogues lacking the lower side chain19). In de-
signing a synthetic route to the manumycin antibiotics we
adopted an approach which would also allow us to prepare
a range of quinol 29 and quinone 30 analogues lacking the
lowersidechainforfurtherstructure-activitystudies.Thus,
as shown in Scheme 1, the protected amido quinone ep-
oxide 28 was identified as a key intermediate for the syn-
thesis of both novel manumycin analogues and the natural
products themselves. We envisaged preparing 28 by acyla-
tion of 27 with the acid chloride corresponding to the upper
side chain, the simplified target molecules then being ob-
tained by straightforward functional group modification. It
shouldbenotedthatthealternativesequenceinvolvingacy-
lation before epoxidation, is not viable in these systems due
to facile N-deacylation during epoxidation.19,22
manumycin D (19),3,16 TMC-1 A (20),16 TMC-1 B (21),16 Amides 28 were also seen as the cornerstone of the syn-
TMC-1 C (22),16 and TMC-1 D (23)16 (Figure 2) have thetic route to the manumycin family, as is shown in ret-
also been isolated.
rosynthetic form in Scheme 2.

776
Feature Article
SYNTHESIS
Biographical Sketches
Richard Taylor gained his B. Sc. and Ph. D. from the University of Sheffield, carrying
out his postgraduate research into steroid synthesis under the supervision of Dr. D.
Neville Jones. He then carried out postdoctoral research with Dr. Ian Harrison at Syntex,
PaloAlto and Professor Franz Sondheimer at University College, London. After academ-
ic jobs with the Open University (1975–79) and the University of East Anglia, Norwich
(1979–1993) he moved to a Chair of Organic Chemistry at the University of York in
1993. Professor Taylor’s research interests centre on the development of new organome-
tallic and organosulfur based synthetic methodology and its application to the synthesis
of compounds of biological importance. Natural product classes studied include steroids,
prostaglandins, prostacyclins, thromboxanes, leukotrienes, insect pheromones, and a
range of marine, fungal and plant metabolites.
Lilian Alcaraz was born in 1969 in France and received his Ph. D. degree in 1995 from
the University of Strasbourg. His research was carried out on a novel synthetic approach
to the total synthesis of Taxol as well as the development of new methodology using
ylides under the direction of Dr. C. Mioskowski. In December 1995, Lilian joined the
University of York as an ARC (France) Fellow and in 1996 was awarded a Marie-Curie
(EC) postdoctoral fellowship. He is currently working as a research chemist for Astra
Charnwood.
Isabelle Kapfer-Eyer was born in 1966 in France and received her Ph. D. degree in 1993
from the Université Louis Pasteur, Strasbourg. Her research was carried out in bio-organ-
ic chemistry under the direction of Professor M. Goeldner. In 1993, Isabelle joined the
University of York as an EC TMR Fellow. In 1995 she took a teaching position
(A. T. E. R.) in organic chemistry at the University of Strasbourg and is currently preparing
for the agregation diploma in physical sciences.
Gregor Macdonald was born in Scotland in 1971 and received his B. Sc. from the Uni-
versity of Edinburgh in 1992. After two years with the Wellcome Foundation he joined
the University of York to carry out his Ph. D. He was awarded the Kathryn Mary Stott
Prize and a Pfizer Prize for his postgraduate research. He is currently working as a re-
search chemist at SmithKline Beecham Pharmaceuticals.
Xudong Wei was born in 1965 in China and was awarded his Ph. D. degree in 1991 from
Nanjing University. His research was carried out on new oxidative methodology and the
addition reactions of iminoxy radicals under the supervision of Professor Hongwen Hu.
Dr. Wei was appointed to a lectureship at Nanjing University in 1991 researching into
heterocyclic chemistry. From 1994–1995 he carried out postdoctoral research with Pro-
fessor Bernd Speiser at the University of Tübingen and in 1995–1996 was awarded a
Royal Fellowship to study in York. Since then he has been supported by the University
of York Innovation and Research Priming fund and the EPSRC.
Norman Lewis gained his B. Sc. and Ph. D. from the University of Bristol, under the
supervision of Professor J. MacMillan. After carrying out postdoctoral research at the
University of British Columbia (Professor J. Kutney) and the E. T. H., Zurich (Professor
A. Eshenmoser), he joined Smith, Kline and French in 1982. He is now Associate Direc-
tor in the the Synthetic Chemistry Department (part of Chemical Development) at Smith-
Kline Beecham Pharmaceuticals, Tonbridge.

May 1998
SYNTHESIS
777
Figure 1

778
Feature Article
SYNTHESIS
Figure 2
Figure 3
Thus, we planned to use organometallic elaboration of 28
with vinyllithium reagent 3120 to give the vinylstannane
32. This organometallic addition was obviously the cru-
cial (and most speculative) step in the sequence and is dis-
cussed in more detail later. The use of the Stille coupling
between vinylstannane 32 and bromodienamide 3321 was
central to the end-game of this succinct synthetic ap-
proach (see later).
Scheme 1
bromoxone24 (and to that employed by Wipf and Kim19 in
their synthesis of LL-C10037a). The BOC derivative
of 2,5-dimethoxyaniline (34) was oxidised using
19,23–25
PhI(OAc)2
to give monoacetal 35 in 78% yield
Results and Discussion
(Scheme 3). Several epoxidation methods were investi-
gated for the conversion of 35 into monoepoxide 36. On a
small scale (0.4 mmol) sodium perborate26 gave the best
results (36% + 45% recovery of starting material) but the
efficiency diminished as the reaction was scaled up. On a
larger scale the preferred procedure involved the use of
(a) Preparation and Elaboration of Amine 2722
The preparation of the key epoxycyclohexenylamine 27
was achieved using methodology based on that employed
in our synthesis of the diepoxycyclohexanone antibiotic
aranorosin23 and the marine antitumour natural product

May 1998
SYNTHESIS
779
of manumycin analogues and therefore other acylating
conditions were explored (Scheme 4). It was eventually
found that acylation to give amides 28 could be carried out
using a number of acid chlorides 3728a providing lithium
tert-butoxide in THF was employed as the base.28b Reduc-
tion of ketones 28 was achieved with sodium borohydride
and then acetal hydrolysis carried out using tosic acid and
pyridinium p-toluenesulfonate (PPTS)19 to give separable
mixtures of the syn- and anti-hydroxy epoxides 29. Com-
pound syn-29a is the anti-tumour agent LL-C10037a 17
and its NMR characteristics were entirely consistent with
published data.14,19 This new route22 to (±)-LL-C10037a
is only 7 steps long and, although unoptimised, proceeds
in ca. 10% overall yield. It also reduces the number of pro-
tection-deprotection steps compared to the published pro-
cedure (9 steps, ca. 7% overall yield).19 Amides 29b and
29c are analogues of alisamycin (8) and asukamycin (7),
respectively, lacking the lower side chains.
Scheme 2
Scheme 3
H2O2/K2CO3 in aqueous THF (methoxy conjugate addi-
tion adducts were observed when methanol was employed
as solvent).
Scheme 4
In order to obtain the key amine intermediate 27 from 36
selective removal of the BOC group in the presence of the
methyl acetal was required. This was efficiently achieved
using boron trifluoride–diethyl ether complex and activat-
ed molecular sieves in dichloromethane at room tempera-
ture. This novel and mild procedure, which was developed
for this transformation, has also proved to be more widely
applicable.27 To our delight, amine 27 proved to be a sta-
ble, crystalline solid (mp 156–157°C) which could be
We also extended this chemistry to produce the manumy-
cin quinone analogues 30 lacking the C-4 polyene chain
(Scheme 4). Thus PDC oxidation of alcohols 29 produced
the known epoxyquinones 30a14b,29 and 30c5a in fair to ex-
cellent yields.
(b) Alternative Routes to Epoxyquinones 30
stored at –20°C for several weeks without noticeable de- The route to epoxyquinones 30 shown in Scheme 4 is rath-
composition. It is a vinylogous amide and therefore, not er long and other routes were investigated as shown in
surprisingly, proved to be rather unreactive to standard Schemes 5 and 6.30,31 Thus, we first attempted to prepare
acylation conditions. Acetylation was achieved in good amine 39 which, on acylation, would lead directly to a
yield (79%; 84% based on recovered starting material) range of quinones. The direct hydrolysis of 36 to give 38
with excess acetic anhydride and DMAP in THF but the or 39 was not successful but an efficient indirect route to
transformation did not give reproducible yields, and did prepare 38 was developed (Scheme 5). Once again, the
not proceed at all when acetyl chloride was employed. use of boron trifluoride–diethyl ether27 gave efficient re-
The requirement for an excess of an acid anhydride moval of the BOC group, amine 39 being obtained as a
seemed to limit the value of this route for the preparation crystalline material (mp 133–134°C dec.) which proved to

780
Feature Article
SYNTHESIS
be stable when stored at –20°C. Unfortunately, amine 39
was very unreactive towards acylation using a range of
conditions (including tert-BuOLi, THF). It was eventual-
ly found that acylation could be accomplished using acid
chlorides in the presence of bis(trimethylsilyl)trifluorom-
ethylacetamide (BSTFA) as a chloride scavenger.32 Even
with these optimum conditions, however, the acylation
yields were satisfactory only with saturated acid chlo-
rides. With benzoyl chloride, the yield was reduced and
no acylation at all was observed with polyunsaturated sys-
tems such as 37c.
Scheme 6
tones 28 by organometallic addition to C-4. This approach
appeared to be fraught with potential problems, particular-
ly concerning the regio and stereoselectivity of the addi-
tion reaction. The likely low reactivity of the C-4 carbonyl
group, which is a vinylogous imide, and which would pre-
sumably be further deactivated by deprotonation of the
amide substituent, was a particular concern. In view of
this, we first carried out the model studies as shown in
Scheme 7. To our delight, reaction of amides 28b and 28c
with phenyllithium in THF, gave good yields of adducts
41 as single diastereoisomers with no other byproducts
observed. The syn-stereochemistry of compounds 41 was
assigned on steric grounds and by analogy with the reduc-
tion reactions shown in Scheme 5 where the syn-isomer
predominates.34a In view of the importance of this stere-
ochemical assignment, however, we felt that more con-
crete evidence was required. Unfortunately, high field
NMR spectroscopy did not provide an unambiguous an-
swer and we therefore sought a crystalline adduct. Suit-
Scheme 5
The routes to epoxyquinones shown in Scheme 5 is still
lengthy and is limited to more reactive acid chlorides. We
therefore developed the third route shown in Scheme 6. In
this procedure 2,5-dimethoxyaniline (34) is acylated in
the first step and then hypervalent iodine oxidation fol-
lowed by acetal removal gives the amidoquinones 40.
Monoepoxidation of dienones 40 was attempted using hy-
drogen peroxide and tert-butyl hydroperoxide with a
range of bases (Na2CO3, NaOH, triton B, triethylamine,
pyridine etc.) but it was eventually discovered that the
best procedure utilised tert-butyl hydroperoxide with
DBU as base.33 Epoxides 30 were found to be very sensi-
tive towards basic conditions and thus, for optimum
yields, it was important to minimise the reaction time.
This was not a problem given the susceptibility of 40 to-
wards epoxidation: reaction times of 30 seconds gave
yields of 67–81%. For these high yields of epoxides 30 it
was essential to remove the DBU and excess peroxide im-
mediately after the completion of the reaction. This was
achieved by washing the reaction mixture with saturated
aqueous iron(II) sulfate in place of the metasulfite
procedure33 normally employed.
(c) Organometallic Addition Reactions
As shown in Scheme 2, the proposed synthetic route to the
manumycin natural products involved elaboration of ke-
Scheme 7

May 1998
SYNTHESIS
781
able crystals were obtained from adduct 42 produced by covered that these impurities could be avoided by use of
phenyllithium addition to the N-BOC analogue 36, and X- the Negishi catalyst36 with adduct 47 being obtained in an
ray crystallography34b confirmed the syn-hydroxy ep- excellent 83% yield. The E,E,E-stereochemistry of ad-
oxide relationship [which is present in alisamycin (8) and ducts 45 and 47 were established by high field NMR stud-
other members of the manumycin family].
ies.
(d) Construction of the Manumycin Lower Side Chain
(e) Initial Approach to Alisamycin
As mentioned earlier (Scheme 2) we planned to elaborate We were now in a position to attempt the first synthesis of
the lower manumycin side chain via a palladium-cataly- a member of the manumycin family of antibiotics. Alisa-
sed Stille coupling procedure.21,35,36 Model studies, mycin (8) was chosen to illustrate the methodology.
shown in Scheme 8, were carried out to establish the via- Alisamycin6–9 is a potent antibiotic (MIC 1.6 mg/mL
bility of this approach with cyclohexane carbinol vinyl- against staphylococcus aureus) which also possesses
stannane 4337 and bromodienes 4421,38 as substrates. A weak antifungal and cytotoxic activity.6 Its structure was
range of palladium catalysts were investigated, initially established by Chatterjee et al.7 using a combination of
with ester 44a, and although adduct 45a was isolated it mass spectrometry, IR, UV and NMR spectroscopy, and
was discovered that dimerisation of the vinylstannane oc- the absolute configuration was revealed as 4R, 5S, 6R us-
curred to a significant extent to produce 46 unless the re- ing the exciton chirality method together with CD studies
action solvent was rigorously degassed.39
of degradation products.8 The enantiomer 9 also occurs
naturally.9 The first synthetic approach to racemic alisa-
mycin is shown in Scheme 9.41
Using 5% PdCl2(MeCN)2 under these conditions, 44a
gave trienyl ester 45a in 82% yield. Acid 44b also under-
went efficient coupling, although the first formed product
(tentatively assumed to be the stannyl ester40) had to be
treated with fluoride and then hydrolysed to provide ad-
duct 45b. In this case, the optimum procedure utilised the
palladium(0) catalyst generated from PdCl2(PPh3)2 and
DIBAL-H using Negishi’s procedure.36 We then attempt-
ed the direct introduction of the fully functionalised lower
side chain unit 33 (previously described by us21), and
found that coupling again proceeded in good yield using
PdCl2(MeCN)2 providing that the solvent was efficiently
deoxygenated. Unfortunately, using these conditions, ad-
duct 47 was contaminated by minor impurities. We dis-
Scheme 9
Thus, treatment of protected quinone 28b with E-2-tribu-
tylstannylethenyllithium (31), generated from the corre-
sponding bis-stannane,20 introduced an embryonic C-4
side chain giving 48 in 55% yield (79% based on recov-
ered starting material). Stille coupling of vinylstannyl re-
agent 48 with bromodienamide 3321 proceeded efficiently
using PdCl2(PPh3)2/DIBAL-H in DMF/THF at room tem-
Scheme 8

782
Feature Article
SYNTHESIS
perature to give 49 in 72% yield. All that was required to duced alisamycin 8 in 64% yield, the structure being con-
complete the synthesis of alisamycin was to deprotect the firmed by comparison of IR, MS, 1H and 13C NMR data
acetal functionality of 49. Unfortunately, using a number with authentic spectra.44 The NMR data for the epoxycy-
of procedures,31,42,43 either little reaction occurred or, un- clohexenone nucleus was particularly informative [found
der more forcing conditions, decomposition was ob- dH: H-3, 7.41 (d, J = 2.5 Hz), H-5, 3.72 (dd, J = 3.5,
served. Similar problems were encountered when 2.5 Hz), H-6, 3.67 (d, J = 3.5 Hz); dC: C-3, 126.0, C-5,
attempting to deprotect the phenyl analogue 41b (Scheme 57.4, C-6, 53.0; authentic7 dH: H-3, 7.40 (d, J = 2.6 Hz),
10): the only product that could be isolated was ketone 50 H-5, 3.70 (dd, J = 3.6, 2.6 Hz), H-6, 3.65 (d, J = 3.6 Hz);
resulting from enamide hydrolysis (with lithium perchlo- dC: C-3, 126.3, C-5, 57.4, C-6, 52.9]. It should be noted
rate in MeCN43 50 was formed in almost quantitative that although this produces racemic 8, this is in fact a mix-
yield).
ture of two natural products, alisamycin and ent-alisamy-
cin. The novel regioisomer 53 of alisamycin was also
prepared by homologation of 51 in 75% yield.
This methodology was also employed to prepare nisamy-
cin (15), and its methyl ester 54, as shown in Scheme 12.
Thus, vinylstannane 52, used to prepare alisamycin, was
coupled with bromodiene 44a to produce the methyl ester
of nisamycin 54 in 82% yield. All attempts to convert es-
ter 54 into acid 15 were unsuccessful, however. Acid 15
was therefore prepared, albeit in moderate yield, by the di-
rect coupling reaction between vinylstannane 52 and bro-
modiene 44b. This reaction again produces the stannyl
ester derivative 54 (R = SnBu3) which is converted into
the acid by treatment with KF followed by neutralisation
with phosphate buffer.40 Adduct 15 is (±)-nisamycin, the
only member of the manumycin family to lack the termi-
nal C5N unit. This is the first synthesis of nisamycin, an
antibiotic which also possesses antifungal and cytotoxic
properties, and which has proved useful for the prepara-
tion of manumycin analogues containing novel amide
linkages.12 Synthetic nisamycin 15 was fully character-
ised and gave NMR data fully consistent with those pub-
lished [dH: 7.41 (d, 1 H, J = 2.5 Hz, H-3), 3.72 (dd, 1 H, J
= 4.0, 2.5 Hz, H-5), 3.66 (d, 1 H, J = 4.0 Hz, H-6); dC:
126.3 (C-3), 57.4 (C-5), 52.9 (C-6). Lit.12a values, dH: 7.41
Scheme 10
(f) Successful Synthesis of Alisamycin and Nisamycin via
Organometallic Additions to Ouinone 30b
We therefore turned to a more direct (and even more spec-
ulative) synthetic approach (Scheme 11). In this proce-
dure, organometallic addition was carried out using the
unprotected epoxyquinone 30b. Treatment with E-2-
tributylstannylethenyllithium (31) gave two major prod-
ucts 51 and 52 (46%, 1:1.3), resulting from attack at each
of the ring carbonyl groups. The stereochemical assign-
ments were again made on the basis of steric consider-
ations and, in the case of 52, this was confirmed by
conversion into alisamycin and nisamycin.
Adducts 51 and 52 were separated by chromatography
and individually coupled to bromodienamide 33 using
PdCl2(PPh3)2/DIBAL-H as before. The use of 52 pro-
Scheme 11

May 1998
SYNTHESIS
783
60 (70–200) using the eluant specified. Preparative TLC was carried
out using pre-prepared plates (Merck silica gel 60 F-254, 5715). PE is
petroleum ether (bp 40–60°C). Where necessary Et2O and THF were
distilled from Na/benzophenone ketyl, and CH2Cl2 from CaH, imme-
diately before use. H2O is distilled water. Except where specified, all
reagentswerepurchasedfromcommercialsourcesandwereusedwith-
out further purification. All synthetic compounds are racemic.
3-tert-Butoxycarbonylamino-4,4-dimethoxycyclohexa-2,5-dien-1-
one (35):
To a stirred solution of N-tert-butylcarbonyl-2,5-dimethoxyaniline46
(10.0 g, 0.041 mol) in anhyd MeOH (100 mL) at 0°C under N2 was
added PhI(OAc)2 (15.9 g, 0.049 mol) portionwise over 1 h. The mix-
ture was stirred at 0°C for 6 h before being diluted with CH2Cl2
(200 mL)/H2O (100 mL) and then neutralised using aq NaHCO3.
The organic layers were separated and washed with H2O (60 mL)
and brine (60 mL), dried (MgSO4) and the solvent evaporated under
reduced pressure to give a brown oil. Column chromatography
(Et2O/PE, 3:7 and then 1:1) gave 35 as an off-white solid, yield:
8.35 g (78%); Rf 0.30 (Et2O/PE, 1:1); mp 130–l31°C.
IR (CCl4): n = 3415, 2986, 1743, 1672, 1502, 1232, 1153 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.01 (d, 1 H, J = 1.9 Hz, H-2), 6.85
(br s, 1 H, NH), 6.53 (d, 1 H, J = 10.2 Hz, H-5), 6.41 (dd, 1 H, J í
10.2, 1.9 Hz, H-6), 3.27 (s, 6 H, 2 ´ OMe), 1.51 (s, 9 H, tBu).
13C NMR (67.5 MHz, CDCl3): d = 185.3, 151.3, 148.2, 138.0, 133.1,
111.0, 94.1, 82.1, 51.3, 27.9.
Scheme 12
MS (CI): m/z (%) = 270 (MH+, 100).
HRMS (CI): Calc for C13H20NO5: 270.1342. Found: 270.1338.
Anal: Calc C, 57.98; H, 7.11; N, 5.20. Found: C, 58.21; H, 7.13; N,
5.07.
(d, 1 H, J = 2.1 Hz), 3.70 (dd, 1 H, J = 4.0, 2.1 Hz), 3.63
(d, 1 H, J = 4.0 Hz); dC: 126.9, 57.3, 52.8].
3-tert-Butoxycarbonylamino-4,4-dimethoxy-5,6-epoxycyclohex-
2-en-1-one (36):
(g) Summary and Future Work
To a stirred solution of dienone 35 (2.7 g, 10.03 mmol) and H2O2
(29% soln., 34 mL, 301.2 mmol) in THF (50 mL) was added aq
K2CO3 (0.8 M, 12.5 mL, 10.0 mmol) dropwise at 0°C. After stirring
at r.t. for 6 d, the mixture was diluted with EtOAc (50 mL) and brine
(10 mL) added. The aqueous layer was then extracted with EtOAc
(6 ´ 50 mL). The combined organic layers were dried (MgSO4) and
the solvent evaporated under reduced pressure to give a brown oil.
Column chromatography (CH2Cl2/EtOAc, 95:5) gave the title com-
pound 36 as a white solid; yield: 1.4 g (49%); Rf 0.40 (CH2Cl2/
EtOAc, 95:5); mp 144–145°C.
We have devised new chemistry for the preparation of a
range of manumycin analogues of increasing complexity
and utilised these procedures to prepare the natural prod-
ucts LL-C10037a, alisamycin and nisamycin, the last two
for the first time. The novel organometallic methodology
for Southern side-chain introduction and elaboration is
applicable to all of the manumycin family. We are cur-
rently optimising the synthetic route to the nucleus in
enantiomerically pure form and will then apply this meth-
odology to other members of this group of natural prod-
ucts.45
IR (CCl4): n = 3416, 2980, 1747, 1679, 1630, 1500, 1153 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.05 (br s, 1 H, NH), 6.77 (d, 1 H,
J = 2.2 Hz, H-2), 3.82 (d, 1 H, J = 4.1 Hz, H-5), 3.65 (s, 3 H, OMe),
3.51 (dd, 1 H, J = 4.1, 2.2 Hz, H-6), 3.31 (s, 3 H, OMe), 1.50 (s, 9 H,
tBu).
13C NMR (67.5 MHz, CDCl3): d = 192.3, 151.1, 146.6, 106.1, 95.5,
82.5, 52.1, 51.5, 51.4, 50.6, 28.1.
The EPSRC and SmithKline Beecham are acknowledged for a
CASE studentship (G. M.), and ARC (France), the EC and the
EPSRC for fellowships (L. A., I. K. and X. W.). We also thank Drs. T.
A. Dransfield and G. K. Barlow for their expert assistance with MS
and NMR studies, respectively, and Dr. H. Kogler for copies of spec-
tra of authentic alisamycin.
MS (CI): m/z (%) = 286 (MH+, 100).
HRMS (CI): Calc for C13H20NO6: 286.1291. Found: 286.1290.
Anal: Calc C, 54.73; H, 6.71; N, 4.91. Found: C, 54.87; H, 6.78; N,
4.81.
Unreacted starting material 35 (350 mg, 13%) was also recovered
NMR spectra were recorded on Jeol GX-270 or Bruker AMX 500 from this reaction.
instruments. TMS or CDCl3/CHCl3 was used as the internal stan-
dard. Carbon spectra were verified using DEPT experiments. Mps
3-Amino-4,4-dimethoxy-5,6-epoxycyclohex-2-en-1-one (27):
were recorded on an Electrothermal IA9100 digital melting point
apparatus and are uncorrected. IR spectra were recorded on an ATI
Mattson Genesis FTIR spectrometer. Low resolution electron impact
(EI) mass spectra were recorded on a Kratos MS 25 spectrometer.
Chemical ionisation (CI), fast atom bombardment (FAB) and HRMS
were recorded on a Micromass Autospec spectrometer. Elemental
analyses were carried out at the University of East Anglia, Norwich.
Chromatography is medium pressure flash column chromatography
and was performed using ICN silica gel (32–63) or Matrex silica gel
To a stirred solution of BOC compound 36 (291 mg, 1.02 mmol) and
powdered activated 4 Å molecular sieves (625 mg) in anhyd CH2Cl2
(15 mL) was added BF3·Et2O (0.19 mL, 1.53 mmol) in CH2Cl2
(5 mL) dropwise at 0°C over 30 min. The reaction was left to stir at
r.t. for 20 h. On completion, the solvent was evaporated under redu-
ced pressure to give a brown oil. Column chromatography (EtOAc/
MeOH, 95:5) gave 27 as a white solid; yield: 136 mg (72%); Rf 0.30
(EtOAc); mp 156–157°C.
IR (CDCl3): n = 3401, 2944, 2854, 1621, 1255 cm–1.

784
Feature Article
SYNTHESIS
1H NMR [270 MHz, (CD3)2CO] : d = 6.42 (br s, 2 H, NH2), 5.00 (d,
1 H, J = 2.0 Hz, H-2), 3.84 (d, 1 H, J = 4.0 Hz, H-5), 3.56 (s, 3 H,
OMe), 3.35 (s, 3 H, OMe), 3.24 (dd, 1 H, J = 4.0, 2.0 Hz, H-6).
13C NMR (67.5 MHz, CDCl3): d = 190.6, 156.9, 96.3, 95.7, 52.8,
51.3, 51.7, 50.2.
MS (CI): m/z (%) = 374 (MH+, 53), 342 (100).
HRMS (CI): Calc for C21H28NO5: 374.1968. Found: 374.1964.
Preparation of SecondaryAlcohols (29); General Procedure:
To a stirred solution of amide 28 in MeOH was added NaBH4 (1
equiv.) at 0°C under N2. After stirring for ca. 1 h at 0°C, the reaction
was warmed to r.t. at which point H2O was added followed by suf-
ficient sat. NH4Cl to give a neutral solution. The MeOH was evapo-
rated under reduced pressure and the residue extracted with EtOAc.
The organic layer was dried (Na2SO4) and the solvent evaporated
under reduced pressure to give a quantative yield of product as a
mixture of the two diastereomers. The crude material was dissolved
in acetone/H2O (8:1) and p-toluenesulphonic acid (0.15 equiv.) and
pyridinium p-toluenesulphonate (0.9 equiv.) added at 0°C under N2.
The mixture was stirred at r.t. until the reaction was complete (3.5–
7 d). Volatiles were then removed under reduced pressure and H2O
added. Extraction with EtOAc, drying of the combined organic lay-
ers (Na2SO4) and removal of the solvent under reduced pressure
gave the crude product. Column chromatography or preparative TLC
(EtOAc/PE) gave the syn and anti-diastereomers as white solids.
MS (CI): m/z (%) = 186 (MH+, 100).
HRMS (CI): Calc for C8H12NO4: 186.0766. Found: 186.0769.
Preparation of Amides (28); General Procedure:
A solution of lithium tert-butoxide (1.0 M solution in THF, 1.1
equiv.) was added dropwise over 15 min to a stirred solution of
amine 27 (1 equiv.) in anhyd THF at 0°C under N2.After stirring at
0°C for 30 min, a solution of the acid chloride 3728a (1.2 equiv.) in
THF was added dropwise over 1 h. The reaction was allowed to
warm and then stirred at r.t. until acylation was complete. The THF
was evaporated under reduced pressure and EtOAc and H2O were
added. The two layers were separated and the aqueous layer
extracted with EtOAc. The combined organic layers were washed
with brine, dried (MgSO4) and the solvent evaporated under reduced
pressure to give a dark oily residue. Column chromatography
(EtOAc/PE, 1:1) gave the desired compound, usually as an off-white
solid which could be recrystallised from CH2Cl2/PE.
2-(Acetamido)-5,6-epoxy-4-hydroxy-cyclohex-2-en-1-one (29a):
Anti-isomer [(±)-5-epi-LL-C10037a] as colourless needles; yield:
12%; Rf 0.25 (EtOAc/DCM, 1:1); mp 148–149°C (from CH2Cl2/
Et2O) (lit.19 mp 154°C dec.).
3-Acetamido-4,4-dimethoxy-5,6-epoxycyclohex-2-en-1-one (28a):
White solid; yield: 65%; Rf 0.45 (EtOAc); mp 107–108°C.
IR (CCl4): n = 3415, 2956, 2927, 2854, 1722, 1680, 1498, 1223,
1120, 1064 cm–1.
IR (CHCl3): n = 3687, 3595, 3392, 3039, 1682, 1516, 1375,
1026 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.70 (br s, 1H, NH), 7.61 (dd, 1H,
J = 5.3, 2.4 Hz, H-3), 4.90 (dddd, 1H, J = 7.0, 5.3, 1.3, 1.2 Hz, H-4),
3.85 (ddd, 1H, J = 3.5, 2.4, 1.3 Hz, H-5), 3.62 (dd, 1H, J = 3.5,
1.2 Hz, H-6), 2.51 (d, 1H, J = 7.0 Hz, OH), 2.14 (3H, Me).
13C NMR (67.5 MHz, CDCl3): d = 188.7, 169.6, 130.3, 122.9, 63.1,
57.3, 52.2, 24.7.
1H NMR (270 MHz, CDCl3): d = 7.66 (br s, 1 H, NH), 7.15 (d, 1 H,
J = 2.0 Hz, H-2), 3.82 (d, 1 H, J = 4.3 Hz, H-5), 3.66 (s, 3 H, OMe),
3.53 (dd, 1 H, J = 4.3, 2.0 Hz, H-6), 3.30 (s, 3 H, OMe), 2.19 (s, 3 H,
Me).
13C NMR (67.5 MHz, CD3COCD3): d = 193.7, 170.9, 147.7, 108.3,
96.3, 52.6, 52.3, 51.4, 50.4, 24.9.
MS (CI): m/z (%) = 201 (MNH4+, 47), 184 (MH+, 100).
HRMS (CI): Calc for C8H10NO4: 184.0610. Found: 184.0614.
MS (CI): m/z (%) = 245 (MNH4 , 35), 228 (MH+, 100).
+
HRMS (CI): Calc for C10H14NO5: 228.0872. Found: 228.0873.
Syn-isomer [(±)-LL-C10037a 17] as a colourless powder; yield:
37%; Rf 0.20 (EtOAc/CH2Cl2, 1:1); mp 168–170°C dec. (from ace-
tone/Et2O) (lit.19 mp 167°C dec.).
3-(5-Cyclohexylpenta-2E,4E-dienamido)-4,4-dimethoxy-5,6-epoxy-
cyclohex-2-en-1-one (28b):
White solid; yield: 73%; Rf 0.37 (EtOAc/PE, 1:1); mp 135–136°C.
IR (CH2Cl2): n = 3406, 3051, 2983, 2854, 1701, 1674, 1633, 1548,
1500, 1340, 1261, 1120 cm–1.
IR (CHCl3): n = 3687, 3597, 3394, 3033, 1684, 1516, 1373,
1032 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.56 (br s, 1H, NH), 7.44 (dd, 1H,
J = 3.0, 2.2 Hz, H-3), 4.85 (ddd, 1H, J = 10.5, 3.2, 3.0 Hz, H-4), 3.88
(ddd, 1H, J = 3.9, 3.2, 2.2 Hz, H-5), 3.60 (d, 1H, J = 3.9 Hz, H-6),
2.25 (d, 1H, J = 10.5 Hz, OH), 2.14 (3H, Me).
1H NMR (270 MHz, CDCl3): d = 7.71 (s, 1 H, NH), 7.28 (dd, 1 H, J
= 14.8, 9.7 Hz, H-3¢), 7.22 (d, 1 H, J = 1.9 Hz, H-2), 6.19–6.06 (m, 2
H, H-4¢ and H-5¢), 5.88 (d, 1 H, J = 14.8 Hz, H-2¢), 3.82 (d, 1 H, J =
4.1 Hz, H-5), 3.64 (s, 3 H, OMe), 3.51 (dd, 1 H, J = 4.1, 1.9 Hz, H-
6), 3.28 (s, 3 H, OMe), 2.09 (m, 1 H, cy-H), 1.70–1.03 (m, 10 H, cy).
13C NMR (67.5 MHz, CDCl3): d = 192.7, 164.9, 151.6, 145.2, 125.3,
120.7, 145.6, 108.6, 95.4, 52.0, 51.4, 51.2, 50.6, 41.1, 32.1, 25.9,
25.4.
13C NMR (67.5 MHz, CDCl3): d = 188.4, 169.2, 128.4, 124.5, 64.5,
54.1, 52.6, 24.6.
MS (CI): m/z (%) = 201 (MNH4+, 100), 184 (MH+, 34).
HRMS (CI): Calc for C8H10NO4: 184.0610. Found: 184.0611.
MS (CI): m/z (%) = 348 (MH+, 96), 316 (100).
HRMS: Calc for C19H26NO5: 348.1811. Found: 348.1812.
2-(5-Cyclohexylpenta-2E,4E-dienamido)-5,6-epoxy-4-hydroxy-
cyclohex-2-en-1-one (29b):
Anti isomer as a white solid; yield: 19%; Rf 0.36 (EtOAc/PE, 1:2);
mp 184–185°C.
3-(7-Cyclohexylhepta-2E,4E,6E-trienamido)-4,4-dimethoxy-5,6-ep-
oxycyclohex-2-en-1-one (28c):
IR (CH2Cl2): n = 3944, 3691, 3062, 2989, 1676, 1632, 1550, 1514,
White solid; yield: 67%; Rf 0.35 (EtOAc/PE, 1:1); mp 151–153°C.
IR (CH2Cl2): n = 3392, 3051, 2987, 1694, 1668, 1606, 1550, 1498,
1265, 1157, 1120 cm–1.
1422, 1265, 1155, 1024 cm–1.
1H NMR (500 MHz, CD3COCD3): d = 8.32 (s, 1 H, NH), 7.66 (dd, 1
H, J = 4.4, 2.3 Hz, H-3), 7.20 (dd, 1 H, J = 14.9, 10.6 Hz, H-3,), 6.33
(d, 1 H, J = 14.9 Hz, H-2¢), 6.21 (dd, 1 H, J = 10.6, 15.3 Hz, H-4¢),
6.13 (dd, 1 H, J = 15.3, 6.8 Hz, H-5¢), 4.80 (m, 1 H, H-4), 3.83 (ddd,
1 H, J = 3.7, 2.3, 0.9 Hz, H-5), 3.58 (dd, 1 H, J = 3.7, 0.9 Hz, H-6),
2.83 (br s, 1 H, OH), 2.10–2.04 (m, 1 H, cy-H) and 1.76–1.12 (m, 10
H, cy).
1H NMR (270 MHz, CDCl3): d = 7.81 (s, 1 H, NH), 7.36 (dd, 1 H, J
= 14.9, 11.6 Hz, H-3¢), 7.27 (d, 1 H, J = 2.0 Hz, H-2), 6.60 (dd, 1 H,
J = 14.9, 10.6 Hz, H-5¢), 6.24 (dd, 1 H, J = 11.6, 14.9 Hz, H-4¢), 6.13
(dd, 1 H, J = 10.6, 15.2 Hz, H-6¢), 5.97 (d, 1 H, J = 14.9 Hz, H-2¢),
5.95 (dd, 1 H, J = 15.2, 6.8 Hz, H-7¢), 3.86 (d, 1 H, J = 4.0 Hz, H-5),
3.67 (s, 3 H, OMe), 3.54 (dd, 1 H, J = 4.0, 2.0 Hz, H-6), 3.32 (s, 3 H,
OMe), 2.10–2.05 (m, 1 H, cy-H), 1.77–1.06 (m, 10 H, cy).
13C NMR (67.5 MHz, CDCl3): d = 192.9, 165.0, 147.1, 144.7, 143.0,
127.3, 127.3, 121.3, 145.8, 108.6, 95.4, 52.1, 51.5, 51.3, 50,61, 41.1,
32.4, 26.0, 25.8.
13C NMR (67.5 MHz, CD3COCD3): d = 190.4, 166.1, 150.0, 143.7,
127.2, 125.1, 131.8, 123.8, 63.7, 58.7, 53.6, 42.1, 33.3, 26.9, 26.7.
MS (CI): m/z (%) = 304 (MH+, 100).
HRMS (CI): Calc for C17H22NO4: 304.1549. Found: 304.1553.

May 1998
SYNTHESIS
785
1H NMR (270 MHz, CDCl3): d = 7.88 (br s, 1 H, NH), 7.52 (d, 1 H,
J = 2.3 Hz, H-3), 3.92 (d, 1 H, J = 3.6 Hz, H-6), 3.84 (dd, 1 H, J =
3.6, 2.3 Hz, H-5), 2.23 (s, 3 H, Me).
Syn isomer as a white solid; yield: 67%; mp 177–178°C; Rf 0.22
(EtOAc/PE, 1:2).
IR (CH2Cl2): n = 3328, 2924, 1652, 1548, 1371, 1252, 1108, 1066,
1005 cm–1.
13C NMR (67.5 MHz, CDCl3): d = 191.1, 188.0, 169.3, 138.5, 115.4,
53.8, 52.4, 24.9.
1H NMR (500 MHz, CD3COCD3): d = 8.23 (s, 1 H, NH), 7.49 (dd, 1
H, J = 2.8, 2.7 Hz, H-3), 7.19 (dd, 1 H, J = 14.9, 10.7 Hz, H-3¢), 6.31
(d, 1 H, J = 14.9 Hz, H-2¢), 6.20 (dd, 1 H, J = 15.3, 10.7 Hz, H-4¢),
6.12 (dd, 1 H, J = 15.3, 6.8 Hz, H-5¢), 4.93 (ddd, 1 H, J = 7.6, 2.9, 2.8
Hz, H-4), 3.85 (ddd, 1 H, J = 4.1, 2.9, 2.7 Hz, H-5), 3.51 (d, 1 H, J =
4.1 Hz, H-6), 2.81 (m, 1 H, OH), 2.14–2.06 (m, 1 H, cy-H), 1.76–
1.11 (m, 10 H, cy).
MS (CI): m/z (%) = 199 (MNH4+, 18), 182 (MH+, 80).
HRMS (CI): Calc for C8H8NO4: 182.0453. Found: 182.0456.
The 1H NMR data was entirely consistent with published14b values.
See also preparation by two other procedures described later.
2-(7-Cyclohexylhept-2E,4E,6E-trienamido)-5,6-epoxy-1,4-benzoqui-
none (30c):
As a dark yellow oil from 29c (anti); yield: 48%; Rf 0.72 (EtOAc/PE,
1:1).
13C NMR (67.5 MHz, CD3COCD3): d = 190.4, 165.8, 149.9, 143.4,
127.6, 127.2, 129.8, 123.8, 65.3, 55.1, 53.3, 42.1, 33.3, 26.9, 26.7.
MS (Cl): m/z (%) = 304 (MH+, 100).
HRMS (CI): Calc for C17H22NO4: 304.1549. Found: 304.1553.
Anal: Calc C, 67.31; H, 6.98; N, 4.62. Found: 66.90; H, 6.84; N, 4.59.
IR (CHCl3): n = 3373, 3028, 2929, 2854, 1693, 1678, 1606, 1504,
1317, 1261, 1174, 1117, 1088, 1012, 723 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.85 (br s, 1 H, NH), 7.63 (d, 1 H, J
= 2.4 Hz, H-3), 7.39 (dd, 1 H, J = 14.9, 11.4 Hz, H-3¢), 6.63 (dd, 1 H, J
= 15.0, 10.3 Hz, H-5¢), 6.31–6.09 (m, 2 H, H-4¢ and H-6¢), 5.95 (d, 1 H,
J = 14.9, H-2¢), 6.01–5.94 (m, 1 H, H-7¢), 3.93 (d, 1 H, J = 3.6 Hz, H-
6), 3.85 (dd, 1 H, J = 2.4, 3.6 Hz, H-5), 1.80–1.05 (m, 11 H, cy-H and cy).
13C NMR (67.5 MHz, CDCl3): d = 191.0, 188.2, 164.9, 147.6, 145.6,
143.7, 130.9, 128.8, 127.2, 120.4, 115.2, 53.9, 52.5, 41.1, 32.4, 26.0.
MS (EI): m/z (%) =327 (M+, 13).
2-(7-Cyclohexylhepta-2E,4E,6E-trienamido)-5,6-epoxy-4-hydroxy-
cyclohex-2-en-1-one (29c):
Anti isomer as a white solid; yield: 16%; Rf 0.39 (EtOAc/PE, 1:2);
mp 180–182°C.
IR (CH2Cl2): n = 3944, 3693, 3062, 2985, 1673, 1606, 1423, 1273,
1155, 987 cm–1.
1H NMR (500 MHz, CD3COCD3): d = 8.33 (s, 1 H, NH), 7.67 (dd, 1
H, J = 3.9, 2.4 Hz, H-3), 7.26 (dd, 1 H, J = 14.9, 11.3 Hz, H-3¢), 6.63
(dd, 1 H, J = 14.9, 10.7 Hz, H-5¢), 6.38 (d, 1 H, J = 14.9 Hz, H-2¢), 6.32
(dd, 1 H, J = 14.9, 11.3 Hz, H-4¢), 6.18 (dd, 1 H, J = 15.3, 10.7 Hz, H-
6¢), 5.92 (dd, J = 15.3, 7.1 Hz, H-7¢), 4.80 (m, 1 H, H-4), 3.83 (br dd, 1
H, J = 3.7, 2.4 Hz, H-5), 3.58 (d, 1 H, J = 3.7 Hz, H-6), 2.80–2.77 (m, 1
H, OH), 2.11–2.06 (m, 1 H, cy-H) and 1.75–1.11 (m, 10 H, cy).
13C NMR (125 MHz, CD3COCD3): d = 190.1, 165.2, 145.9, 142.8,
141.8, 129.3, 128.6, 124.4, 129.1, 124.1, 63.5, 58.4, 53.2, 41.8, 33.2,
26.7, 26.5.
HRMS (EI): Calc for C19H21NO4: 327.1471. Found: 327.1480.
The NMR data were consistent with published5a values. See also
preparation described later.
2-tert-Butoxycarbonylamino-5,6-epoxy-1,4-benzoquinone (38):
Following the general procedure for the preparation of secondary
alcohols and then the general procedure for the oxidation of secon-
dary alcohols, oxo acetal 36 gave dione 38 which was purified by
chromatography (EtOAc/CH2Cl2, 1:9) to give 38 as a light yellow
oil; yield: 55% from 36; Rf 0.72 (EtOAc/PE, 1:1).
MS (CI): m/z (%) = 330 (MH+, 100).
HRMS (CI): Calc for C19H24NO4: 330.1705. Found: 330.1697.
IR (CCl4): n = 3390, 2983, 2935, 1747, 1703, 1680, 1612, 1502,
1317, 1236, 1215, 1151, 997 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.26 (br s, 1 H, NH), 7.16 (d, 1 H,
J = 2.3 Hz, H-3), 3.89 (d, 1 H, J = 3.6 Hz, H-6), 3.81 (dd, 1 H, J =
3.6, 2.3 Hz, H-5), 1.50 (s, 9H, tBu).
Syn isomer as a white solid; yield: 64%; mp 175–176°C; Rf 0.22
(EtOAc/PE, 1:2).
IR (CH2Cl2): n = 3944, 3693, 3052, 2987, 1674, 1608, 1516, 1423,
1263, 1157, 987 cm–1.
13C NMR (67.5 MHz, CDCl3): d = 190.6, 187.7, 150.9, 139.8, 113.1,
83.1, 53.8, 52.5, 28.0.
1 H NMR (500 MHz, CD3COCD3): d = 8.23 (s, 1 H, NH), 7.49 (dd, 1
H, J = 2.9, 2.7 Hz, H-3), 7.25 (dd, 1 H, J = 14.9, 11.4 Hz, H-3¢), 6.63
(dd, 1 H, J = 14.9, 10.7 Hz, H-5¢), 6.35 (d, 1 H, J =14.9 Hz, H-2¢),
6.32 (dd, 1 H, J = 14.9, 11.4 Hz, H-4¢), 6.18 (dd, 1 H, J = 15.3, 10.7
Hz, H-6¢), 5.91 (dd, 1 H, J = 15.3, 7.0 Hz, H-7¢), 4.92 (ddd, 1 H, J =
7.5, 3.0, 2.9 Hz, H-4), 3.85 (ddd, 1 H, J = 4.1, 3.0, 2.7 Hz, H-5), 3.50
(d, 1 H, J = 4.1 Hz, H-6), 2.79 (m, 1 H, OH), 2.07 (m, 1 H, cy-H),
1.75–1.11 (m, 10 H, cy).
MS (Cl): m/z (%) = 257 (MNH4+, 100), 240 (MH+, 57).
HRMS (CI): Calc for C11H14NO5: 240.0872. Found: 240.0872.
2-Amino-5,6-epoxy-1,4-benzoquinone (39):
Urethane 38 (221 mg, 0.92 mmol) was dissolved in anhyd CH2Cl2
(10 mL) under N2 at 0°C and powdered, activated 4Å molecular sie-
ves (800 mg) were added followed by dropwise addition of a solu-
tion of BF3·Et2O (0.17 mL, 1.1 mmol), the temperature was allowed
to rise slowly to r.t. and the mixture was stirred at r.t. for 20 h. Direct
purification by chromatography (EtOAc/PE, 1:1 to pure EtOAc)
afforded a yellow powder; yield: 126 mg (98%); Rf 0.30 (EtOAc/PE,
1:1) mp 133–134°C (dec.).
13C NMR (67.5 MHz, CD3 COCD3): d = 190.2, 165.7, 145.9, 142.8,
141.7, 129.26, 128.7, 127.4, 129.6, 124.3, 65.2, 54.9, 53.2, 41.9,
33.3, 26.8, 26.6.
MS (CI): m/z (%) = 330 (MH+, 100).
HRMS (CI): Calc for C19H24NO4: 330.1705. Found: 330.1697.
IR (DCM): n = 3685, 3504, 3392, 1710, 1655, 1620, 1404, 1344,
1010, 839 cm–1.
Oxidation of Secondary Alcohols 29; General Procedure:
To a stirred solution of alcohol 29 (1 equiv.) in CH2Cl2 under N2 at
0°C was added PDC (1.5–2.0 equiv.) in one portion. After stirring at
r.t. overnight (athough the reactions were often finished earlier), the
inorganics were removed by filtration and the solvent evaporated
under reduced pressure. The resulting brown oil was purified by
column chromatography (EtOAc/PE).
1 H NMR (270 MHz, CDCl3): d = 5.56 (d, 1 H, J = 2.3 Hz, H-3), 4.89
(br s, 2 H, NH2), 3.75 (d, 1 H, J = 3.6 Hz, H-6), 3.65 (dd, 1 H, J =
3.6, 2.3 Hz, H-5).
13C NMR (67.5 MHz, CDCl3): d = 189.6, 189.5, 147.1, 103.3, 54.3,
52.6.
MS (CI): m/z (%) = 157 (MNH4+, 48), 140 (MH+, 100).
HRMS (Cl): Calc for C6H9N2O3: 157.0613. Found: 157.0619.
2-Acetamido-5,6-epoxy-1,4-benzoquinone (30a):
As a pale yellow solid from 29a (syn); yield: 87%; Rf 0.60 (EtOAc/
DCM, 1:1); mp (from EtOAc/PE) 169–170°C (dec.).
IR (CCl4): n = 3386, 1728, 1699, 1685, 1610, 1502, 1315, 1213,
758 cm–1.
Preparation of Amides 30 by Acylation of 39; General Proce-
dure:
Amine 39 (1 equiv.) was dissolved in anhyd CH2Cl2 and stirred
under N2 at 0°C and BSTFA (5 equiv.) was added. Then, a solution

786
Feature Article
SYNTHESIS
of the acid chloride (1.5 equiv.) in CH2Cl2 was added over 10 min.
The resulting mixture was stirred at r.t. for up to 4 d until reaction
was complete. Volatile material was removed under reduced pressure
and the residue was purified by chromatography.
2-(5-Cyclohexylpenta-2E,4E-dienamido)-1,4-benzoquinone (40b):
As an orange solid; yield: 70%; Rf 0.33 (EtOAc/PE, 1:3); mp 164–
l65°C.
IR (CHCl3): n = 3369, 2929, 2854, 1666, 1631, 1595, 1500, 1342,
1321, 1178, 1115, 1001, 893 cm–1.
1H NMR (270 MHz, CDCl3): d = 8.03 (s, 1 H, NH), 7.67 (d, 1 H, J =
2.3 Hz, H-3), 7.34 (dd, 1 H, J = 14.8, 10.2 Hz, H-3¢), 6.81–6.72 (m, 2
H, H-4¢ and H-5¢), 6.24–6.16 (m, 2 H, H-5 and H-6), 5.95 (d, 1 H, J =
14.8 Hz, H-2¢), 2.20–2.02 (m, 1 H, cy-H), 1.78–1.12 (m, 10 H, cy).
13C NMR (67.5 MHz, CDCl3): d = 187.9, 182.8, 164.9, 152.1, 145.7,
125.4, 120.3, 138.5, 138.3, 133.1, 114.5, 41.2, 32.1, 25.9, 25.8.
MS (EI): m/z (%) = 285 (M+, 21), 202 (27), 163 (78).
2-Acetamido-5,6-epoxy-1,4-benzoquinone (30a):
Yield: 65% (+ 25% recovered 39): data as before.
2-Lauramido-5,6-epoxy-1,4-benzoquinone (30d):
As yellow needles; yield: 99%; Rf 0.40 (EtOAc/PE, 1:4); mp 108°C
(from CH2Cl2/PE).
IR (CCl4): n = 3384, 2927, 2856, 1699, 1682, 1610, 1500, 1315,
1213, 1174 cm–1.
HRMS (EI): Calc. for C17H19NO3: 285.1365. Found: 285.1373.
The NMR data were consistent with published12c values.
1H NMR (270 MHz, CDCl3): d = 7.83 (br s, 1 H, NH), 7.55 (d, 1 H,
J = 2.4 Hz, H-3), 3.92 (d, 1 H, J = 3.6 Hz, H-6), 3.84 (dd, 1 H, J =
3.6, 2.4 Hz, H-5), 2.44–2.32 (m, 2 H), 1.65–1.59 (m, 2 H), 1.26–1.18
(m, 16 H), 0.91–0.82 (m, 3 H).
2-(E-Cinnamido)-1,4-benzoquinone (40f):
As a dark solid; yield: 65%, Rf 0.30 (PE/EtOAc, 2:1); mp 204–
205.5 °C (dec.).
13C NMR (67.5 MHz, CDCl3): d = 191.1, 188.2, 172.5, 138.5, 115.3,
53.8, 52.4, 37.9, 33.7, 31.9, 29.5, 29.4, 29.3, 29.2, 29.0, 24.9, 22.7,14.1.
MS (EI): m/z (%) = 321 (M+, 4), 43 (100).
IR (nujol): n = 3326, 1693, 1663, 1645, 1625, 1597, 1500, 1345,
1140, 883, 721 cm–1.
1H NMR (270 MHz, CDCl3): d = 8.19 (br s, 1 H, NH), 7.77 (d, 1 H,
J = 15.5 Hz, H-3¢), 7.73 (d, 1 H, J = 2.2 Hz, H-3), 7.57 (m, 2 H,
ArH), 7.45–7.40 (m, 3 H, ArH), 6.84–6.74 (m, 2 H, H-5,6), 6.59 (d, l
H, J = 15.5 Hz, H-2¢).
HRMS (EI): Calc for C18H27NO4: 321.1940. Found: 321.1939.
2-Benzamido-5,6-epoxy-1,4-benzoquinone (30e):
As yellow crystals; yield: 65%; Rf 0.25 (EtOAc/PE, 1:4); mp 111–
112°C (from CH2Cl2/PE);
13C NMR (67.5 MHz, CDCl3): d = 187.8, 182.7, 164.5, 144.9, 138.5,
138.3, 133.9, 133.1, 130.8, 129.0, 128.3, 119.2, 114.9.
MS (EI): m/z (%) = 253 (M+, 8), 131 (100).
IR (CCl4): n = 3390, 1694, 1682, 1601, 1510, 1490, 1350, 1311,
1238, 1215, 1172, 1063, 901, 881, 785, 704 cm–1.
1H NMR (270 MHz, CDCl3): d = 8.66 (br s, 1 H, NH), 7.86–7.83 (m,
2 H, ArH), 7.69 (d, 1 H, J = 2.3 Hz, H-3), 7.65–7.49 (m, 3 H, ArH),
3.98 (d, 1 H, J = 3.6 Hz, H-6), 3.87 (dd, 1 H, J = 3.6, 2.3 Hz, H-5).
13C NMR (67.5 MHz, CDCl3): d = 191.0, 188.2, 165.8, 138.8,
133.2, 132.8, 129.1, 127.3, 115.5, 53.8, 52.5.
HRMS (EI): Calc. for C15H11NO3: 253.0739. Found: 253.0745.
(b) Epoxidation of Quinones 40:
To a solution of quinone 40 (0.2 mmol) in EtOAc (40 mL) in a
100 mL separating funnel was added tert-butyl hydroperoxide in
nonane (5–6 M, 5 equiv.) containining DBU (1.0 equiv.). The mix-
ture was shaken for 30 sec, washed with sat. aq iron(II) sulphate
(3 ´ 30 mL), then brine (2 ´ 30 mL), and then dried (Na2SO4). After
evaporation of the solvent, the residue was purified by column chro-
matography (EtOAc/PE, 1:4) to give epoxyquinones 30:
MS (EI): m/z (%) = 243 (M+, 1), 105 (100).
HRMS (EI): Calc for C13H9NO4: 243.0532. Found: 243.0538.
Preparation of Amides 30 by Epoxidation of Quinones 40; Gen-
eral Procedure:
(a) Preparation of Quinones 40:
To a solution of 2,5-dimethoxyaniline (34) (1 equiv.), pyridine (1.1
equiv.) and a catalytic amount (ca. 5 mg/mmol amine) of DMAP in
CH2Cl2 was added the corresponding acid chloride 37 (1.1 equiv.) in
CH2Cl2 at 0°C under N2. The resulting solution was then stirred at
r.t. for 12 h. The mixture was then poured into H2O, and extracted
with EtOAc. The organic layers were combined and washed with
2 M HCl and sat. aq NaHCO3, and dried (Na2SO4). After the removal
of the solvent, the dark residue was purified by column chromatogra-
phy to give the corresponding amide which was used directly in the
next step.
A solution of the amide (1 equiv.) in anhyd MeOH was stirred at 0°C
under N2 and treated portionwise with iodobenzene diacetate (1.5
equiv.). The reaction was then stirred at 0°C for 4 h. If starting mate-
rial was still remaining (TLC), the reaction was warmed to r.t. for 1
h. On completion, the mixture was diluted with CH2Cl2 and H2O and
then neutralized with aq NaHCO3. The reaction was extracted with
CH2Cl2 and the organic layers combined, washed with H2O and
brine, and then treated with Amberlyst-15 (ca. 3.5 g/mmol) and
several drops of H2O. ln the case of 40a the hydrolysis was carried
out at r.t. for about 12 h, and in the case of 40b,f the reaction was run
at 35–40°C for about 4 h and monitored by TLC. The Amberlyst-15
was then filtered off, the solvent evaporated and the residue was was-
hed with a small amount of Et2O to give the quinones 40 as dark yel-
low solids after filtration. The filtrates were concentrated and
subjected to column chromatography to give additional product.
2-Acetamido-5,6-epoxy-1,4-benzoquinone (30a):
Yield: 67%: data as before.
2-(5-Cyclohexylpenta-2E,4E-dienamido)-5, 6-epoxy-1,4-benzoqui-
none (30b):
As an off-white solid; yield: 8 l%; Rf 0.55 (PE/EtOAc, 1:1); mp 159–
160°C.
IR (CCl4): n = 3381, 2929, 2854, 1695, 1680, 1633, 1605, 1502,
1350, 1313, 1213, 1172, 1115, 999 cm –1
.
1H NMR (270 MHz, CDCl3): d = 7.90 (br s, 1 H, NH), 7.61 (d, 1 H,
J = 2.3 Hz, H-3), 7.36–7.17 (m, 1 H, vinyl), 6.23–6.09 (m, 2 H,
vinyl), 5.93 (d, 1 H, J = 15.8 Hz, H-2¢), 3.93 (d, 1 H, J = 3.6 Hz, H-
6), 3.83 (dd, 1 H, J = 2.3, 3.6 Hz, H-5), 2.17–2.00 (m, 1 H, cy-H),
1.77–1.68 (m, 5 H, cy), 1.32–1.10 (m, 5 H, cy).
13C NMR (67.5 MHz, CDCl3): d = 191.0, 188.1, 165.0, 152.4, 146.1,
139.0, 125.3, 120.0, 115.2, 53.8, 52.5, 41.2, 32.1, 25.9, 25.7.
MS (EI): m/z (%)= 301 (M+, 10), 163 (100).
HRMS (EI): Calc. for C17H19NO4: 301.1314. Found: 301.1323.
2-(E-Cinnamido)-5,6-epoxy-1,4-benzoquinone (30f):
Yield: 68% as a white solid; Rf 0.27 (PE/EtOAc, 2:1); mp 183–
185°C (dec.).
IR (nujol): n = 3349, 1672, 1627, 1610, 1505, 1173, 1140, 868,
665 cm–1.
1H NMR (270 MHz, CDCl3): d = 8.00 (br s, 1 H, NH), 7.76 (d, 1 H,
J = 15.5 Hz, H-3¢), 7.67 (d, 1 H, J = 2.4 Hz, H-3), 7.59–7.52 (m, 2 H,
ArH), 7.44–7.38 (m, 3 H, ArH), 6.54 (d, 1 H, J = 15.5 Hz, H-2¢), 3.95
(d, 1 H, J = 3.6 Hz, H-6), 3.86 (dd, 1 H, J = 2.4, 3.6 Hz, H-5).
2-Acetamido-/,4-benzoquinone (40a):
As a dark solid; yield: 66%; mp 145–147°C (Lit:47 146–148°C with
data in accord with the literature.47

May 1998
SYNTHESIS
787
13C NMR (67.5 MHz, CDCl3): d = 191.0, 188.2, 164.5, 145.3, 138.9,
133.75, 130.9, 129.0, 128.3, 118.8, 115.6, 53.9, 52.5.
r.t., then the solvent was removed under reduced pressure and the
crude product directly purified by column chromatography (PE/
EtOAc, 3:2) to give ester 45a as a colourless oil; yield: 21.3 mg
(82%); Rf 0.50 (PE/EtOAc, 1:1).
MS (CI): m/z (%) = 287 (MNH4+, 35), 270 (MH+, 100).
HRMS (CI): Calc. for C15H12NO4: 270.0766. Found: 270.0770.
IR (neat): n = 3376, 2930, 2857, 1699, 1615, 1420, 1260, 1134, 1004
cm–1.
3-(7-Cyclohexylhepta-2E,4E,6E-trienamido)-4,4-dimethoxy-5,6-
epoxy-1-phenylcyclohex-2-en-1-ol (41c); Typical Procedure:
To a stirred solution of PhLi (1.8 M in THF, 0.26 mL, 0.47 mmol) in
THF (4 mL) at –40°C under N2 was added ketone 28c (25 mg,
0.067 mmol) in THF (4 mL) dropwise over 3 h. After stirring at –40°C
for 30 min, the reaction was warmed to r.t., quenched with sat.
NH4Cl (50 mL) and extracted with EtOAc (5 ´ 40 mL). The combi-
ned organic layers were washed with H2O (40 mL) and brine (40
mL), dried (Na2SO4) and the solvent evaporated under reduced pres-
sure to give a yellow oil. Purification by column chromatography
(EtOAc/PE, 1:1) gave 41c as a colourless oil; yield: 26 mg (86%); Rf
0.40 (EtOAc/PE, 1:1).
1H NMR (500 MHz, CDCl3): d = 7.32 (dd, 1 H, J = 15.3, 11.3 Hz,
H-3), 6.56 (dd, 1 H, J = 10.8, 15.0 Hz, H-5), 6.39 (dd, 1 H, J = 10.8,
15.0 Hz, H-6), 6.32 (dd, 1 H, J = 11.3, 15.0 Hz, H-4), 6.03 (d, 1 H, J
= 15.3 Hz, H-2), 5.88 (d, 1 H, J = 15.0 Hz, H-7), 3.75 (s, 3 H, OMe),
1.75–1.25 (m, 10 H, cy).
13C NMR (125 MHz, CDCl3): d = 167.5, 146.0, 144.6, 140.6, 129.6,
126.7, 120.3, 71.7, 51.5, 37.8, 25.4, 21.9.
MS (EI): m/z (%) = 236 (M+, 65), 55 (100).
HRMS (EI): Calc for C14H20O3: 236.1413. Found: 236.1410.
7-(1¢-Hydroxycyclohexyl)hepta-2E,4E,6E-trienoic Acid (45b):
A solution of DIBAL-H (1.0 M in THF, 0.02 mL, 0.020 mmol) was
added to a solution of PdCl2(PPh3)2 (7.2 mg, 0.01 mmol) in THF
(0.5 mL) at r.t. under N2. After stirring for 10 min, a solution of stan-
nane 4337 (85 mg, 0.21 mmol) in anhyd, degassed DMF (0.5 mL)
followed by a solution of bromodiene 44b21,38 (33.8 mg, 0.19 mmol)
in anhyd, degassed DMF (0.5 mL) were added to the solution of the
pre-reduced catalyst at r.t. The reaction was stirred overnight at r.t.,
then treated with acetone (0.2 mL) and 1 M aq KF (0.2 mL). After
stirring for 1 h, the mixture was filtered, washed with a 0.1 M solu-
tion of KH2PO4 (3 mL), extracted with EtOAc (3 ´ 3 mL) and the
combined organic layers were dried (MgSO4) and the solvent was
removed. The crude product was purified by column chromatogra-
phy (PE/EtOAc, 1:1) to give the ester 45b as a white solid; yield:
30.4 mg (72%); Rf 0.17 (PE/EtOAc, 1:1); mp 96–98 C°.
IR (CHCl3): n = 3691, 3606, 3408, 3032, 2931, 2856, 1699, 1682,
1603, 1512, 1450, 1371, 1246, 1122, 1063, 780 cm–1.
1H NMR (270 MHz, CD3COCD3): d = 8.11 (s, 1 H, NH), 7.67–7.64
(m, 2 H, ArH), 7.37–7.23 (m, 3 H, ArH), 7.17 (dd, 1 H, J = 14.9, 11.3
Hz, H-3¢), 6.79 (1 H, d, J = 2.3 Hz, H-2), 6.58 (dd, 1 H, J = 15.2, 10.8
Hz, H-6¢), 6.26 (d, 1 H, J = 14.9 Hz, H-2¢), 6.26 (dd, 1 H, J = 15.2,
11.3 Hz, H-4¢), 6.15 (dd, 1 H, J = 15.2, 10.8 Hz, H-5¢), 5.88 (dd, 1 H,
J = 15.2, 7.3 Hz, H-7¢), 3.68 (d, 1 H, J = 4.3 Hz, H-5), 3.49 (s, 3 H,
OMe), 3.32 (dd, 1 H, J = 4.3, 2.3 Hz, H-6), 3.34 (s, 3 H, OMe), 2.08
(s, 1 H, OH), 1.80–l.07 (m, 11 H, cy).
13C NMR (125 MHz, CD3COCD3): d = 165.0, 145.6, 142.0, 141.3,
129.4, 129.0, 128.7, 128.2, 127.2, 125.1, 96.3, 73.0, 53.2, 51.0, 50.6,
50.0, 41.9, 33.4, 26.7, 26.6.
MS (EI): m/z (%) = 451 (M+, 14).
IR (film): n = 3406, 2933, 2856, 1685, 1615, 1419, 1268, 1134, 1006
HRMS (EI): Calc for C27H33NO5: 451.2359. Found: 451.2359.
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.39 (dd, 1 H, J = 15.0, 11.5 Hz,
H-3), 6.60 (dd, 1 H, J = 15.0, 10.5 Hz, H-5), 6.40 (dd, 1 H, J = 15.0, 10.5
Hz, H-6), 6.35 (dd, 1 H, J = 15.0, 11.5 Hz, H-4), 6.06 (d, 1 H, J = 15.0
Hz, H-2), 5.88 (d, J = 15.0 Hz, 1 H, H-7), 1.80–l.25 (m, 10 H, cy).
13C NMR (125 MHz, CDCl3): d = 171.7, 146.6 (2C), 141.5, 129.3,
126.5, 119.6, 71.7, 37.6, 25.3, 21.8.
3-(5-Cyclohexylpenta-2E,4E-dienamido)-4,4-dimethoxy-5,6-epoxy-
1-phenylcyclohex-2-en-1-ol (41b):
In a similar manner, ketone 28b was converted into 41b, which was
fully characterised, in 60% yield.
3-[(tert-Butoxycarbonyl)amido]-4,4-dimethoxy-5,6-epoxy-1-phe-
nylcyclohex-2-en-1-ol (42):
MS (CI): m/z (%) = 240 (MNH4+, 10), 205 (100).
HRMS (CI): Calc for C13H22NO3: 240.1600. Found: 240.1593.
To a stirred solution of PhLi (1.8 M in THF, 0.29 mL, 0.53 mmol) in
THF (3 mL) at –40°C under N2 was added ketone 36 (50 mg,
0.18 mmol) in THF (2 mL), dropwise over 3 h. After stirring at –40°C N-(2
²-Hydroxy-5²-oxocyclopent-1²-en-1²-yl)-7-(1¢-hydroxy-
for 1 h, the reaction was warmed slowly to r.t., quenched with sat. cyclohexyl)hepta-2E,4E,6E-trienamide (47):
NH4Cl (30 mL) and extracted with EtOAc (3 ´ 50 mL). The combi- Bromodiene 3321 (25 mg, 0.09 mmol) and stannane 4337 (46 mg,
ned organic layers were washed with H2O (40 mL) and brine 0.11 mmol) were coupled using the same procedure described later
(40 mL), dried (MgSO4) and the solvent evaporated under reduced for alisamycin. Purification by column chromatography (CH2Cl2/
pressure to give a pale yellow oil. Purification by column chromato- MeOH, 19:1) gave 47 as a yellow solid; yield: 24.3 mg (83%); Rf
graphy (EtOAc/PE, 1:3) gave 42 as a pale yellow solid; yield: 59 mg 0.13 (CH2Cl2/MeOH, 19:1); mp 132–133°C.
(93%); Rf 0.49 (Et2O/PE, 1:1); mp 217–219°C.
IR (CDCl3): n = 3689, 3600, 3373, 3155, 2985, 2935, 1817, 1793,
IR (CHCl3): n = 3577, 3425, 2981, 1725, 1504, 1450, 1369, 1346, 1628, 1603, 1531, 1469, 1379, 1217, 1165, 1095 cm–1.
1242, 1159, 1124, 1063, 1041, 991, 947 cm–1.
1H NMR (500 MHz, CDCl3): d = 13.64 (s, 1 H, enol-OH), 7.54 (s, 1
1H NMR (270 MHz, CDCl3): d = 7.19–6.81 (m, 5 H, ArH), 6.18 (s, 1 H, NH), 7.34 (dd, 1 H, J = 14.9, 11.4 Hz, H-3¢), 6.61 (dd, 1 H, J =
H, NH), 5.89 (br s, 1 H, H-2), 3.28 (d, 1 H, J = 4.3 Hz, H-5), 3.16 (s, 14.5, 10.7 Hz, H-5¢), 6.40 (dd, 1 H, J = 15.2, 10.7 Hz, H-6¢), 6.32 (dd,
3 H, OMe), 3.08 (dd, 1 H, J = 4.3, 2.4 Hz, H-6), 2.95 (s, 3 H, OMe), 1 H, J = 14.5, 11.4 Hz, H-4¢), 6.06 (d, 1 H, J = 15.2 Hz, H-7¢), 5.99
2.16 (s, 1 H, OH), 1.03 (s, 9 H, t-Bu).
(d, 1 H, J = 14.9 Hz, H-2¢), 2.80–2.50 (m, 4 H, H-4² and H-5²), 1.69–
13C NMR (67.5 MHz, CDCl3): d = 152.4, 141.7, 128.7, 128.4, 127.9, 1.22 (m, 10 H, cy).
127.7, 125.9, 113.8, 95.0, 72.9, 57.5, 50.9, 53.2, 49.9, 28.2.
MS (CI): m/z (%) = 381 (MNH4+, 7), 363 (15), 346 (100).
HRMS (CI): Calc for C19H29N2O6: 381.20262. Found: 381.2026.
13C NMR (67.5 MHz, CDCl3): d = 197.3, 173.8, 167.1, 146.8, 144.4,
141.7, 129.1, 126.6, 119.8, 115.0, 71.7, 32.1, 25.6, 25.3, 21.9.
MS (EI): m/z (%) = 317 (M+, 24), 299 (21), 188 (100).
HRMS (EI): Calc for C /zH23NO4: 317.1627. Found: 317.1629.
Methyl 7-(1¢-Hydroxycyclohexyl)hepta-2E,4E,6E-trienoate (45a):
A solution of stannane 4337 (50 mg, 0.12 mmol) in anhyd, degassed
DMF (0.4 mL) followed by a solution of bromodiene 44a21,38 (21
mg, 0.11 mmol) in anhyd, degassed DMF (0.4 mL) were added to a
solution of PdCl2(MeCN)2 (1.3 mg, 0.005 mmol) in anhyd, degassed
DMF (0.2 mL) at r.t. under N2. The reaction was stirred overnight at
2-(5¢-Cyclohexylpenta-2¢E,4¢E-dienamido)-4-(2²-E-tributylstan-
nylethenyl)-4-hydroxy-5,6-epoxycyclohex-2-en-1-one (52) and
Regioisomer (51):
BuLi (2.5 M in hexanes, 0.24 mL, 0.60 mmol) was added dropwise
over 15 min to a stirred solution of E-1,2-bis(tributylstannyl)ethene20

788
Feature Article
SYNTHESIS
(483 mg, 0.80 mmol) in THF (6 mL) under N2. The reaction was stir-
red at –78°C for 30 min and then at 0°C for 90 min. The stirred solu-
tion of 31 was then re-cooled to –78°C and epoxyquinone 30b
(60 mg, 0.20 mmol) in THF (2 mL) was added dropwise, under N2
over 30 min. After stirring at –78°C for 1 h, the reaction was quen-
ched at this temperature with sat. NH4Cl (10 mL) and extracted with
EtOAc (3 ´ 40 mL). The combined organic layers were washed with
brine (25 mL), dried (MgSO4) and the solvent evaporated under
reduced pressure to give a yellow oil. Purification by column chro-
matography (EtOAc/PE, 3:7) gave 52 as a colourless oil; yield:
31 mg (26%); Rf 0.62 (EtOAc/PE, 3:7).
2.5, 3.5 Hz, H-5), 3.67 (d, 1 H, J = 3.5 Hz, H-6), 2.65 (br s, 1 H, OH),
2.64–2.52 (m, 4 H, H-4² and H-5²), 2.15–2.05 (m, 1 H, cy-H), 1.80–
l.05 (m, 10 H, cy).
13C NMR (125 MHz, CDCl3): d = 197.1, 188.4, 173.5, 165.2, 165.0,
150.7, 144.1, 143.5, 139.5, 136.0, 131.6 (2 C), 128.1, 125.9, 125.4,
121.4, 121.0, 114.8, 71.2, 57.4, 53.0, 41.1, 32.2, 32.1, 26.0, 25.8,
25.6.
MS (FAB): m/z (%) = 543 (MNa+, 37), 521 (MH+, 100).
HRMS (FAB): Calc for C29H33N2O7: 521.2288. Found: 521.2294.
The NMR data were consistent with published7,44 values.
IR (film): n = 3345, 2954, 2925, 2852, 1667, 1632, 1612, 1522, 1464,
Following the same procedure on the same scale, vinylstannane (51)
gave the regioisomer (53) as a pale yellow solid; yield: 6.3 mg
(75%); Rf 0.39 (CH2Cl2/MeOH, 9:1); mp = 233–236°C (dec.).
IR (CHCl3): n = 3257, 2924, 2850, 1653, 1616, 1605, 1497, 1375,
1209, 1009 cm–1.
1450, 1365, 1246, 997 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.56 (br s, 1 H, NH), 7.40 (d, 1 H,
J = 2.6 Hz, H-3), 7.23 (dd, 1 H, J = 10.0, 15.0 Hz, H-3¢), 6.49 (d, 1 H,
J = 19.3 Hz, H-7), 6.14–6.11 (m, 2 H, H-4¢ and H-5¢), 5.98 (d, 1 H, J
= 19.3 Hz, H-8), 5.85 (d, 1 H, J = 15.0 Hz, H-2¢), 3.67–3.63 (m, 2 H,
H-5 and H-6), 2.15–2.05 (m, 1 H, cy-H), 1.77–0.93 (m, 37 H, cy +
3 ´ Bu).
1H NMR (500 MHz, CDCl3) d = 13.50 (s, 1 H, enol-OH), 7.53 (br s,
1 H, NH), 7.42 (br s, 1 H, NH), 7.33 (dd, 1 H, J = 15.0, 11.5 Hz, H-
11), 7.24 (dd, 1 H, J = 15.0, 10.0 Hz, H-3¢), 7.12 (d, 1 H, J = 2.0 Hz,
H-2), 6.64 (dd, 1 H, J = 14.5, 11.0 Hz, H-8), 6.57 (dd, 1 H, J = 14.5,
11.0 Hz, H-9), 6.46 (dd, 1 H, J = 14.5, 11.5 Hz, H-10), 6.20–6.12 (m,
2 H, H-4¢ and H-5¢), 6.08 (d, 1 H, J = 15.0 Hz, H-l2), 5.83 (d, 1 H, J
= 14.5 Hz, H-7), 5.81 (d, 1 H, J = 15.0 Hz, H-2¢), 3.66 (d, 1 H, J = 4.5
Hz, H-5), 3.59 (dd, 1 H, J = 4.5, 2.0 Hz, H-6), 3.27 (br s, 1 H, OH),
2.65–2.45 (m, 4 H, H-4² and H-5²), 2.18–2.04 (m, 1 H, cy-H), 1.85–
1.05 (m, 10 H, cy).
13C NMR (125 MHz, CDCl3): d = 189.1, 164.9, 150.4, 145.5, 143.8,
133.5, 128.0, 127.4, 125.5, 121.2, 73.0, 57.7, 52.9, 41.1, 32.2, 29.0,
27.8, 26.0, 25.8, 13.6, 9.6.
MS (CI): m/z (%) = 620 [MH+ (for 120Sn), 7].
HRMS (CI): Calc for C31H50NO4116Sn: 616.2757. Found: 616.2767.
The regioisomeric adduct 51 was also obtained as a colourless oil;
yield: 24 mg (20%); Rf 0.38 (EtOAc/PE, 1:4).
13C NMR (125 MHz, CDCl3): d = 197.4, 192.6, 174.1, 165.4, 165.2,
152.0, 150.1, 145.5, 143.1, 138.5, 134.2, 132.7, 132.6, 125.4, 122.2,
120.5, 114.9, 106.9, 72.6, 56.9, 54.3, 41.2, 32.2, 26.0, 25.8, 25.6.
MS (FAB+): m/z (%) = 543 (MNa+, 23), 521 (MH+, 32).
IR (NaCl): n = 3334, 2954, 2926, 2852, 1666, 1633, 1610, 1504,
1373, 1340, 1211, 998 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.37 (br s, 1 H, NH), 7.34–7.24 (m,
1 H, H-3¢), 7.12 (d, 1 H, J = 2.0 Hz, H-2), 6.67 (d, 1 H, J = 19.5 Hz,
H-7), 6.20–6.08 (m, 2 H, H-4¢ and H-5¢), 5.86 (d, 1 H, J = 19.5 Hz,
H-8), 5.80 (d, 1 H, J = 14.5 Hz, H-2¢), 3.61–3.55 (m, 2 H, H-5 and H-
6), 2.92 (br s, 1 H, OH), 2.17–2.05 (m, 1 H, cy-H, 1.80–1.05 (m, 28
H, cy + 9 ´ CH2), 1.00–0.80 (m, 9 H, 3 ´ Me).
HRMS (FAB+): Calc for C29H33N2O7: 521.2288. Found: 521.2299.
Nisamycin Methyl Ester (54):
A solution of DIBAL-H (1.0 M in THF, 0.03 mL, 0.030 mmol) was
added to a solution of PdCl2(PPh3)2 (10.0 mg, 0.014 mmol) in THF
(2.0 mL) at r.t. under N2 and stirred for 10 min. To a portion (0.1 mL)
of the pre-reduced catalyst at r.t. under N2 was added a solution of
stannane 52 (12 mg, 0.019 mmol) in anhyd, degassed DMF (0.2 mL)
followed by a solution of bromodiene 44a (4.5 mg, 0.023 mmol) in
anhyd, degassed DMF (0.2 mL). The reaction was stirred overnight
at r.t., diluted with EtOAc (5 mL), washed with H2O (3 ´ 3 mL) and
the organic layer dried (MgSO4) and the solvent removed. The crude
product was purified using preparative TLC (PE/EtOAc, 3:2) to give
the ester 54 as a pale yellow oil; yield: 6.8 mg (82%); Rf 0.46 (PE/
EtOAc, 3:2).
13C NMR (125 MHz, CDCl3): d = 193.0, 165.4, 151.6, 150.5, 145.2,
143.1, 135.0, 125.4, 120.6, 107.0, 74.2, 57.1, 54.4, 41.2, 32.2, 29.0,
27.1, 26.0, 25.8, 13.7, 9.7.
MS (Cl): m/z (%) = 620 [MH+(for 120Sn), 0].
HRMS (CI): Calc for C31H50NO4116Sn: 616.2757. Found:
616.2750.
(±)-Alisamycin (8) and Regioisomer (53):
A solution of DIBAL-H (1.0 M in THF, 0.051 mL, 0.051 mmol) was
added to a solution of PdCl2(PPh3)2 (18 mg, 0.026 mmol) in THF
(4 mL) at r.t. under N2. After stirring at r.t. for 5 min, 0.1 mL of this
solution was removed and used immediately in the following cou-
pling reaction. Solutions of vinylstannane 52 (10 mg, 0.016 mmol) in
anhyd, degassed DMF (0.2 mL) and bromodiene 3321 (4.9 mg,
0.018 mmol) in anhyd, degassed DMF (0.2 mL) were added in rapid
succession to a vigorously stirred solution of the pre-generated cata-
lyst (ca. 0.65´10–3 mmol) in THF (0.1 mL) at r.t. under N2. After
stirring at r.t. for 12 h, the mixture was poured into H2O (10 mL) and
extracted with EtOAc (3´15 mL). The combined organic layers
were dried (Na2SO4) and the solvent evaporated under reduced pres-
sure to give a yellow residue. Preparative TLC (CH2Cl2/EtOAc, 4:6)
gave 8 as a yellow waxy solid; yield: 5.4 mg (64%); Rf 0.22 (CH2Cl2/
MeOH, 95:5); mp 186–188°C [lit.7 > 250°C for (–)-8].
IR (film): n = 3363, 2924, 2852, 1697, 1670, 1618, 1520, 1361,
1259, 1134, 1003 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.56 (br s, 1 H, NH), 7.41 (d, 1 H,
J = 2.5 Hz, H-3), 7.30 (dd, 1 H, J = 15.0, 11.0 Hz, H-11), 7.24 (dd, l
H, J = 15.0, 10.5 Hz, H-3¢), 6.62–6.50 (m, 2 H, H-8 and H-9), 6.41
(dd, 1 H, J = 15.0, 11.0 Hz, H- 10), 6.20–6.10 (m, 2 H, H-4¢ and H-
5¢), 5.94 (d, 1 H, J = 15.0 Hz, H-2¢), 5.85 (d, 1 H, J = 15.0 Hz, H-7),
5.84 (d, 1 H, J = 15.0 Hz, H-12), 3.76 (s, 3 H, OMe), 3.71 (dd, 1 H, J
= 4.0, 2.5 Hz, H-5), 3.66 (d, 1 H, J = 4.0 Hz, H-6), 2.80 (br s, 1 H,
OH), 2.18–2.08 (m, 1 H, H-6¢), 1.80–1.05 (m, 10 H, cy).
13C NMR (125 MHz, CDCl3): d = 188.6, 167.3, 165.1, 150.8, 144.1,
143.8, 138.5, 135.5, 132.2, 131.7, 128.0, 126.3, 125.4, 121.9, 120.9,
71.1, 57.4, 52.9, 51.6, 41.1, 32.2, 26.0, 25.8.
MS (FAB+): m/z (%) = 462 (MNa+, 28), 176 (100).
IR (CHCl3): n = 3311, 2960, 2925, 2852, 1666, 1599, 1514, 1369,
HRMS (FAB+): Calc for C25H29NNaO6: 462.1893. Found:
462.1900.
1259, 1095, 1012 cm–1.
1H NMR (500 MHz, CDCl3): d = 13.48 (br s, 1 H, enol-OH), 7.56
(br s, 1 H, NH), 7.45 (br s, 1 H, NH), 7.41 (d, 1 H, J = 2.5 Hz, H-3),
7.33 (dd, 1 H, J = 11.3, 14.8 Hz, H-11), 7.21 (dd, 1 H, J = 14.8, 10.5
Hz, H-3¢), 6.58 (dd, 1 H, J = 14.8, 11.3 Hz, H-8), 6.58 (dd, 1 H, J =
11.3, 14.5 Hz, H-9), 6.42 (dd, 1 H, J = 14.8, 11.3 Hz, H-10), 6.12 (m,
2 H, H-4¢ and H-5¢), 6.04 (d, 1 H, J = 14.8 Hz, 12-H), 5.86 (d, 1 H,
J = 14.5 Hz, H-6), 5.84 (d, 1 H, J = 15.0 Hz, H-2¢), 3.72 (dd, 1 H, J =
(±)-Nisamycin (15):
A solution of DlBAL-H (1.0 M in THF, 0.028 mL, 0.028 mmol) was
added to a solution of PdCl2(PPh3)2 (10 mg, 0.014 mmol) in THF
(1 mL) at r.t. under N2 and the solution stirred for 10 min. To this
solution of the pre-reduced catalyst at r.t. was added a solution of

May 1998
SYNTHESIS
789
stannane 52 (10 mg, 0.016 mmol) in anhyd, degassed DMF (0.2 mL) (11) Grote, R.; Zeeck, A.; Drautz, H.; Zähner, H. J. Antibiot. 1988,
followed by a solution of bromodiene 44b (3.5 mg, 0.019 mmol) in
anhyd, degassed DMF (0.2 mL). The reaction was stirred for 24 h at
41, 1178; Grote, R.; Zeeck, A.; Beale, J. M. J. Antibiot. 1988,
41, 1186.
r.t., and then treated with acetone (0.2 mL) and aq KF (1 M, 0.2 mL). (12) (a) Hayashi, K-I.; Nakagawa, M.; Fujita, T.; Tanimori, S.; Na-
After stirring for a further 1 h, the mixture was filtered, washed with
KH2PO4 (0.1 M, 1 mL), extracted with EtOAc (3 ´ 3 mL), the com-
bined organic layers were dried (MgSO4) and the solvent removed.
The crude product was purified by preparative TLC (CH2Cl2/MeOH,
95:5) to give the acid 15 as a pale yeiiow solid; yield: 4.0 mg (58%);
Rf 0.27 (CH2Cl2/MeOH, 9:1); mp 107–l09°C.
kayama, M. J. Antibiot. 1993, 46, 1904.
(b) Hayashi, K-I., Nakagawa, M.; Nakayama, M. J. Antibiot.
1994, 47, 1104.
(c) Hayashi, K-I.; Nakagawa, M.; Fujita, T.; Tanimori, S.; Na-
kayama, M. J. Antibiot. 1994, 47, 1110.
(13) Slechta, L.; Cialdella, J. I.; Mizsak, S. A.; Hoeksema, H. J. An-
tibiot. 1982, 35, 556.
IR (CHCl3): n = 3360, 2954, 2926, 2852, 1680, 1614, 1520, 1367,
1261, 1128, 1005 cm–1.
(14) (a) Lee, M. D.; Fantini, A. A.; Morton, G. O.; James, J. C.; Bor-
ders, D. B.; Testa, R. T. J. Antibiot. 1984, 37, 1149.
(b) For a correction to the original structural assignment see
Shen, B.; Whittle, Y. G.; Gould, S. J.; Keszler, D. A. J. Org.
Chem. 1990, 55, 4422 and references therein.
1H NMR (500 MHz, CDCl3): d = 7.57 (br s, 1 H, NH), 7.41 (d, 1 H,
J = 2.5 Hz, H-3), 7.36 (dd, 1 H, J = 15.0, 11.5 Hz, H-11), 7.24 (dd, 1
H, J = 15.0, 9.5 Hz, H-3¢), 6.65–6.55 (m, 2 H, H-8 and H-9), 6.45
(dd, 1 H, J = 14.5, 11.5 Hz, H-10), 6.20–6.09 (m, 2 H, H-4¢ and H-
5¢), 5.94 (d, 1 H, J = 15.0 Hz, H-2¢), 5.87 (d, 1 H, J = 14.5 Hz, H-7),
5.85 (d, 1 H, J = 15.0 Hz, H- 12), 3.72 (dd, 1 H, J = 4.0, 2.5 Hz, H-5),
3.66 (d, 1 H, J = 4.0 Hz, H-6), 2.97 (br s, 1 H, OH), 2.17–2.08 (m, 1
H, H-6¢), 1.90–1.05 (m, 10 H, cy).
(15) Box, S. J. ; Gilpin, M. L.; Gwynn, M.; Hanscomb, G.; Spear, S.
R.; Brown, A. G. J. Antibiot. 1983, 36, 1631.
For the clarification of absolute stereochemistry see Gould, S.
J.; Shen, B.; Whittle, Y. G. J. Am. Chem. Soc. 1989, 111, 7932.
(16) Kohno, J.; Nishio, M.; Kawano, K.; Nakanishi, N.; Suzuki, S.-
I.; Uchida, T.; Komatsubara, S. J. Antibiot. 1996, 49, 1212.
(17) Hara, M.; Han, M. Proc. Natl. Acad. Sci., USA 1995, 92, 3333.
Hara, M.; Akasaka, K.; Akinaga, S.; Okabe, M.; Nakano, H.;
Gomez, R.; Wood, D.; Uh, M.; Tamanoi, F. Proc. Natl. Acad.
Sci., USA 1993, 90, 2281.
13C NMR (125 MHz, CDCl3): d = 188.5, 170.6, 165.2, 150.9, 145.8,
144.2, 139.4, 136.1, 131.9, 131.5, 128.0, 126.3, 125.4, 121.1, 120.8,
71.2, 57.4, 52.9, 41.1, 32.2, 26.0, 25.8.
MS (FAB+): m/z (%) = 426 (MH+, 14), 93 (100).
HRMS (FAB+): Calc for C24H28NO6 : 426.1917. Found: 426.1920.
The NMR data were consistent with published12a values.
Omura, S.; Takeshima, H. Drugs of the Future 1994, 19, 751.
(18) (a) Gould, S. J.; Kirchmeier, M. J.; LaFever, R. E. J. Am. Chem.
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(b) Hu, Y.; Melville, C. R.; Gould, S. J.; Floss, H. G. J. Am.
Chem. Soc. 1997, 119, 4301 and references therein.
(19) Wipf, P.; Kim, Y. J. Org. Chem. 1994, 59, 3518; Wipf, P.; Kim,
Y.; Jahn, H. Synthesis 1995, 1549.
‡ Present address: Medicinal Chemistry Department, Astra Charn-
wood, Bakewell Road, Loughborough LE11 5RH Leics, UK.
§ Present address: SmithKline Beecham Pharmaceuticals, Leigh,
Tonbridge, Kent TN11 9AN, UK.
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see also: Johnson, C. R.; Miller, M. W. J. Org. Chem. 1995, 60,
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(28) (a) Several of the acid chlorides are commercially available; po-
lyunsaturated acid chlorides 37b,c were prepared from the cor-
responding acids (oxalyl chloride, cat. DMF). The acids used to
prepare 37b,c were obtained using our glutaconaldehyde me-
thodology (Lewis, N.; McKen, P. W.; Taylor, R. J. K. Synlett
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methodology.
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790
Feature Article
SYNTHESIS
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cant increase in yield.
(30) Preliminary studies indicated that the direct deprotection of ace-
tals 28 might be possible using Montmorillonite K10 (see ref.
31).
(41) Preliminary communication: Alcaraz, L.; Macdonald, G. J.;
Kapfer, I.; Lewis, N. J.; Taylor, R. J. K. Tetrahedron Lett. 1996,
37, 6619.
(31) Gautier, E. C. L.; Graham, A. E.; McKillop, A.; Standen, S. P.;
Taylor, R. J. K. Tetrahedron Lett. 1997, 38, 1881.
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M.; Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M.
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(42) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
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Kocienski, P. Protecting Groups, Thieme: New York, 1994.
For more recent procedures see Johnstone, C.; Kerr, W. J.;
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(33) Yadav, V. K.; Kapoor, K. K. Tetrahedron 1995, 51, 8573.
(34) (a) For a related organometallic addition giving a syn-hydroxy
epoxide see: Carnduff, J.; Hafiz, M.; Hendrie, R.; Monaghan, F.
Tetrahedron Lett. 1984, 25, 6033.
(b) Cronin, L.; Walton, P. H. Unpublished results.
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(43) Lipshutz, B. H.; Harvey, D. F. Synth. Commun. 1982, 12, 267.
(44) Reference 7 and Dr. H. Kogler, personal communication.
(45) After the completion of this manuscript, synthetic studies in our
laboratory indicated that the published stereochemistry of ma-
numycin A1,2 may be in error (Alcaraz, L.; Ragot, J.; Taylor, R.
J. K. Unpublished results). Our studies show that manumycin A
probably possesses the syn-hydroxy epoxide (4S, 5R, 6S) struc-
ture [as shown for manumycin C (3)]; this finding suggests that
the assignment of the anti-hydroxy epoxide configuration to
other members of the manumycin family may also require ste-
reochemical revision.
see also: Amaria, A.; Mitchell, T. N. J. Organomet. Chem.
1980, 199, 49.
(38) Soullez, D.; Plé, G.; Duhamel, L. J. Chem. Soc., Perkin Trans.
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see also Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J.
Org. Chem. 1993, 58, 5434.
(40) The stannyl ester (44, R = SnBu3) was also employed in the cou-
pling reaction (see Thibonnet, J.; Abarbi, M.; Parrain, J.-L.;
Watanabe, T.; Takeuchi, T.; Otsuka, M.; Umezawa, K. Chem.
Commun. 1994, 437.
(47) Buttrus, N. H.; Cornforth, Sir J.; Hitchcock, P. B.; Kumar, A.;
Stuart, A. S. J. Chem. Soc., Perkin Trans. 1 1987, 851.