A general method for the synthesis of bastaranes and isobastaranes: First total synthesis of bastadins 5, 10, 12, 16, 20, and 21

Article abstract of DOI:10.1002/chem.200400904

A general strategy for the synthesis of twenty naturally occurring bastadins (all but bastadin 3) is presented. A key retrosynthetic disconnection of the two amide bonds, common in all target molecules, bisects the macrocyclic core into two diaryl ether f

Full text of DOI:10.1002/chem.200400904

A General Method for the Synthesis of Bastaranes and Isobastaranes:
First Total Synthesis of Bastadins 5, 10, 12, 16, 20, and 21
Elias A. Couladouros,*[a, b] Emmanuel N. Pitsinos,[b] Vassilios I. Moutsos,[b] and
Georgios Sarakinos[b]
Abstract: A general strategy for the
synthesis of twenty naturally occurring
bastadins (all but bastadin 3) is pre-
sented. A key retrosynthetic disconnec-
tion of the two amide bonds,common
in all target molecules,bisects the mac-
rocyclic core into two diaryl ether frag-
ments,an a,w-diamine (western part)
and an a,w-dicarboxylic acid (eastern
part). Efficient preparation of the syn-
thetically challenging o-mono or dibro-
mo-substituted diaryl ether linkages
was achieved employing the diaryl io-
donium salt method. Regarding the
western part,variations of the aliphatic
chain were more efficiently secured by
the preparation of two different a,w-
aminonitrile moieties. Cobalt boride
mediated reduction of the nitrile func-
tionality established the required di-
amines and,at the same time,provided
the necessary variation of the aromat-
ic-ring bromination pattern. Regarding
the eastern part,two different dicar-
boxyl precursors had to be prepared in
order to accommodate bromination-
pattern variations. Coupling and subse-
quent macrolactamization of different
combinations of these key intermedi-
ates may lead at will to any member of
this family of marine natural products.
Four bastaranes (bastadins 5,10,12
and 16) and two isobastaranes (basta-
dins 20 and 21) were synthesized as a
demonstration of the flexibility and ef-
ficiency of the approach presented.
Keywords: diaryl ethers · hyperva-
lent compounds · natural products ·
oximino amides · total synthesis
Introduction
rived through oxidative phenolic coupling of tyramine–tyro-
sine units in an apparently combinatorial fashion.[1h,2] The
pluralism of their macrocyclic framework substitution pat-
tern parallels a diverse and important biological profile,in-
cluding anticancer[1d,f,k] and antimicrobial activity,[1b,k,3] inhi-
bition of inosine-5’-phosphate dehydrogenase,[1h] inhibition
of lipoxygenases,[4] and specific interaction with intracellular
calcium channels.[1i,l,5]
Due to the this last property,they are considered useful
chemical probes for related biological studies,[6] albeit only
bastadins 5,10 and 19 are commercially available in pure
form. Although chemical synthesis could in principle allevi-
ate this problem,the preparation of such diaryl ethers (i.e.
Bastadins are an ever-growing family of marine natural
products isolated from sponges of the order Verongida.[1]
Apart from open-chain bastadins 1 and 2 and biphenylyl
bastadin 3,they are macrocyclic bis-diaryl ethers and,de-
pending on the relative orientation of their diaryl ether seg-
ments,are further classified either as bastaranes or isobas-
taranes (Figure 1). They feature unique a-oximino amides,
both of E configuration,and an unprecedented mixture of
mono- and di-o-brominated diarylethers,biosynthetically de-
[a] Prof. E. A. Couladouros
o-heteroatom-substituted) remains
a challenge,despite
Chemistry Laboratories
recent methodological advances.[7] Thus,even the copper( ii)-
promoted coupling of boronic acids with phenols,which has
been haled as a general solution for the construction of
diaryl ethers due to its versatility and mild conditions em-
ployed,[7b] is not applicable in the case of bastadins. To ad-
dress this problem,ingenious biomimetic approaches,em-
ploying either a thallium trinitrate[8] or a chemoenzymatic-
mediated phenolic oxidative dimerization,[9] have been suc-
cessfully attempted. Nonetheless,the prerequisite of di- o-
brominated precursors restricts their applicability to the
Agricultural University of Athens
Iera Odos 75,GR 118 55 Athens (Greece)
Fax : (+30)210-677-7849
E-mail: ecoula@chem.demokritos.gr
[b] Prof. E. A. Couladouros,Dr. E. N. Pitsinos,Dr. V. I. Moutsos,
Dr. G. Sarakinos
Natural Product Synthesis and Bioorganic Chemistry Laboratory
Institute of Physical Chemistry,NCSR “Demokritos”
P.O. Box 60228,GR 153 10 Ag. Paraskevi,Athens (Greece)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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DOI: 10.1002/chem.200400904
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FULL PAPER
preparation of open chain bastadins and the per-o-brominat-
ed bastadin 6. Furthermore,alternative methodologies have
only been successful,thus far,in the preparation of non-nat-
ural bastarane intermediates and derivatives.[10]
As part of a project aiming to develop a general and flexi-
ble synthetic strategy towards bastadins,we have recently
demonstrated the efficiency of a rarely employed method,[11]
the coupling of phenols with an aryl iodonium salt (1a,
Scheme 1),to yield either mono- or di- o-brominated diaryl
ethers and its utility for the construction of bastarane deriv-
atives.[12] In this manuscript we present in detail the evolu-
tion of our strategy and demonstrate its generality by the
first total syntheses of group B and C bastaranes (basta-
dins 5,10,12,and 16),as well as isobastaranes (bastadins 20
and 21) from common,advanced synthetic intermediates.
Abstract in Greek:
Figure 1. Naturally occurring bastadins (except bastadin 3).
Scheme 1. Application of the diaryl iodonium salt method for the prepa-
ration of bastadin precursors.
Results and Discussion
Retrosynthetic analysis: A key disconnection at the two
amide bonds reduces all macrocyclic bastadins into two suit-
ably substituted precursors,namely a,w-diamine 2 and a,w-
dicarboxylic acid 3 (Scheme 2). In order to ensure a topo-
logically controlled coupling and subsequent macrolactami-
zation between these entities,their terminal functionalities
should be selectively differentiated. Therefore,diaryl ether
4,possessing one primary carboxyl and one ester group at
each end,respectively,was envisioned as the appropriate
key intermediate for the eastern part of both bastaranes and
isobastaranes. However,to guarantee that all variations at
the Y3-position will be accessible,two versions ( 4a and 4b)
of this advanced intermediate should be prepared.
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E. A. Couladouros et al.
Scheme 2. General retrosynthetic analysis for bastaranes and isobastaranes.
On the other hand,diaryl ether 5a,terminated at each
end with a nitrile group and a protected amine,respectively,
could serve as the common building block for the western
part of all target molecules. Thus,regiospecific o-bromina-
tion[13] was anticipated to secure variations at the Y2-posi-
tion,while variations at the Y 1-position could be conven-
iently achieved at this advanced stage concomitant with ni-
trile group reduction by cobalt boride.[12,14] In addition,re-
With regard to the exact nature of the iodonium saltꢁs
phenol group protection,although,in preliminary studies,
the more widely used methoxy derivative (1a,Scheme 1) al-
lowed us entry to the bastaranic framework,efficient final
deprotection was problematic. Consequently,the benzyloxy
derivative (1b,Scheme 2) was opted for the total synthesis
of bastadins as a compromise between saltꢁs accessibility
and ease of deprotection. It should be noted that even
though this derivative has been employed in synthesis be-
fore,[11d] no detailed protocol for its preparation from p-ben-
zyloxybenzaldehyde (12) was available and considerable ex-
perimentation was required to establish a reproducible
one.[16]
Finally,the synthetic potential of esters 4a,b for the prep-
aration of open chain bastadins 1 and 2 is evident. Thus,the
flexibility of the iodonium salt method allows for the con-
ception of a convergent and common retrosynthetic scheme
encompassing all naturally occurring bastadins except for
bastadin 3.
À
garding the W Z region (Groups A,B or C in Figure 1),
model studies have shown that the benzylic hydroxyl group
could lead either to the respective aliphatic or olefinic deriv-
ative,providing thus a possible common entry to all varia-
tions of this part of the molecule.[12b,15] Nevertheless,use of
the more easily accessible deoxy analogue 5b (vide infra)
for the preparation of isobastaranes and group C bastaranes
might be preferable,since the efficiency of a parallel
straightforward approach would counterbalance the benefit
of a divergent common route.
Both the a-oximino ester (in the case of 4a,b) and the ni-
trile groups (in the case of 5a,b) can be retrosynthetically
reduced to a formyl one,revealing benzaldehydes 6a,b and
7a,b respectively,as key synthetic intermediates. These can
be easily obtained by the coupling of an aryl iodonium salt
with the appropriate phenols (8a,b or 9a,b respectively).
Further application of the o-specific phenolic bromination
and olefin dihydroxylation (racemic,for 8a,b,or asymmetric
variant,for 9a,b) transformations reveals the protected p-
bromo- and p-vinyl-phenols (10 and 11) as the required
starting materials.
Synthesis of eastern part precursors: The required mono- or
di-o-brominated phenols 8a,b were easily obtained from 4-
bromophenol (10) in six steps and 78% overall yield.[12a]
Treatment of either phenol with iodonium salt 1b in the
presence of potassium carbonate in DMF furnished in excel-
lent yield the corresponding diaryl ethers 6a or 6b
(Scheme 3). Transformation of the formyl group to the de-
sired a-oximino ester (16a or 16b) was accomplished by a
four-step sequence amenable to large-scale work. Thus,
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Synthesis of Bastaranes and Isobastaranes
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Scheme 3. Preparation of eastern part precursors. Y3 =H (a series); Y3 =Br (b series). Reagents and conditions: a) K2CO3,imidazole, 1b,DMF,80 8C,
96% (6a),98% ( 6b); b) piperidine,dimethyl malonate,Ac 2O,THF,80 8C,99% ( 13a),97% ( 13b); c) NaBH4,MeOH:CH 3CN (1:1),0 8C to RT,86%
(14a),83% ( 14b); d) NaOMe,BuONO,MeOH,0 8C,88 % ( 15a),87% ( 15b); e) K2CO3,imidazole,BnBr,DMF,RT,91% (
16a),88% ( 16b); f) NBS,
CH3CN,90 8C,52 % ( 17a),56% ( 17b); g) 1n HCl(aq.),THF,RT,99%; h) TBSCl,imidazole,DMF,0 8C to RT, 88% (19a),89% ( 19b); i) KBr,TEMPO,
0.3m NaOCl(aq),NaHCO , H2O/CH2Cl2, 08C; BnONH2·HCl,pyridine,EtOH,RT,96% ( 20a),93% ( 20b); j) 1.0m TBAF,THF,RT,24% ( 21a) and 69%
3
(22a) or 11% (21b) and 88% (22b); k) KBr,TEMPO,0.3 m NaOCl(aq),NaHCO 3, H2O/CH3CN,0 8C,96% ( 23a),98% ( 23b),97% ( 25a),98% ( 25b);
l) pentamethylbenzene,TFA,0 8C,94% ( 24a),96% ( 24b); m) NBS,CH CN,0 8C,100%; n) Boc O,DMAP,THF,0 8C to RT,81%; o) 1 n NaOH,THF/
3
2
MeOH/H2O,0 8C,85%.
Knoevenagel condensation with dimethyl malonate followed
by sodium borohydride mediated olefin reduction[17] and
termediates 20a or 20b,respectively. Although,inspection
of their 13C NMR spectra revealed that introduction of the
second oxime was less stereoselective than that of the first
one,separation of the Z/E isomers was not possible until
subsequent TBAF-mediated (TBAF=tetrabutyl ammonium
fluoride) silyl ether protective group cleavage. Disappoint-
ingly,the desired ( E,E)-bis-oxime 21a was obtained in 24%
yield whilst the E,Z-isomer 22a was formed in 69% from
20a. Similarly,the ( E,E)-bis-oxime 21b was obtained in
11% yield whilst the E,Z-isomer 22b was formed in 88%
from 20b. Since oximes are know to isomerize thermally,
photochemically,or upon treatment with acid,we decided
to overlook this issue at this point hoping that,if necessary,
it will be possible to rectify oxime configuration at a latter
stage of the synthesis.[19,21] Thus, 22a or 22b was oxidized to
the corresponding carboxylic acid 23a or 23b.
Having served its purpose,it was now time to remove the
phenol benzyl ether protective group in order to pave the
way for the crucial o-specific bromination. The presence of
two O-benzyl-protected oximes in the same molecule made
this task far from trivial. Thus,hydrogenolysis or treatment
with boron tribromide in thioanisole resulted in cleavage of
all benzyl ethers. Gratifyingly,it was found that selective de-
protection could be achieved in excellent yield with tri-
fluoroacetic acid (TFA) in the presence of pentamethylben-
zene. More important,under the reaction conditions com-
subsequent treatment with butylisonitrite/sodium methoxide
[18]
furnished oximes 15a or 15b,respectively.
To complete
the sequence,the resulting oximes were converted to the
corresponding O-benzyl derivatives. Gratifyingly,inspection
of the 13C NMR spectra revealed that both oxime 16a and
16b had the required E configuration.[19]
At this stage,regiospecific o-bromination of the benzyl-
oxy-substituted aromatic ring of 16a or 16b was attempted
by using N-bromosuccinimide (NBS) in acetonitrile.[20] The
reaction required reflux temperature to proceed and was ac-
companied by loss of the acetonide protective group. More
important,however,was the finding that bromination,al-
though regiospecific,had occurred meta- rather than ortho-
to the benzyloxy substituent to yield 17a or 17b,respective-
ly. Phenol deprotection and subsequent bromination prom-
ised a possible solution to this unexpected obstacle.[13] How-
ever,since this protection was necessary for subsequent syn-
thetic steps,investigation of this possibility was postponed.
Towards installing the remaining a-oximino acid function-
ality,the acetonide protective group of 16a or 16b was hy-
drolyzed to the corresponding free diol (18a or 18b),of
which the primary hydroxy group was selectively protected
and the secondary one was subsequently oxidized to yield,
upon treatment with O-benzylhydroxylamine,bis-oxime in-
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E. A. Couladouros et al.
plete isomerization of the oxime configuration occurred.
Thus,inspection of the 13C NMR spectra of 24a and 24b in-
dicated that both products had now the desired E,E geome-
try and were identical in all respects with the phenols ob-
tained in the same fashion from alcohols 21a or 21b. Regio-
specific nuclear o-bromination with NBS in acetonitrile was
now uneventful and proceeded in excellent yield at 08C to
afford the eastern part precursors of bastaranes,acids 4a
and 4b.
To be employed in the preparation of isobastaranes the
acid and ester moieties of these building blocks had to be in-
terchanged. To this end,acid 4a was converted to the corre-
sponding tert-butyl ester 26a by treatment with (Boc)2O/
DMAP (Boc=butoxycarbonyl,DMAP =4-dimethylamino
pyridine) in THF[22] with concomitant phenol protection.
Subsequent selective saponification[23] afforded acid 27a, a
building block for the eastern part of isobastaranes basta-
din 20 and 21.
these aldehydes,conversion of the resulting alcohols ( 28a or
28b) to the corresponding iodides and subsequent displace-
ment by cyanide anion provided nitriles 29a or 29b. Then,
the now redundant benzyl ether protection was hydrogeno-
lyzed to yield phenols 5a or 5b,respectively. Sodium boro-
hydride reduction in the presence of CoCl2 completed the
preparation of western-part building blocks securing at the
same time diversity at the Y1-position. Thus,dibromoamine
30a was obtained as a 1:1 mixture with its monobromo
counterpart 31a. This mixture,or the corresponding mixture
of amines 30b/31b,was easily separated after coupling with
the desired eastern part precursors (vide infra).
Apparently,coupling of these building blocks (compounds
4, 27 and 30, 31) in a combinatorial fashion,should furnish
after a few steps,all naturally occurring bastaranes and iso-
bastaranes together with some unnatural (or not yet isolat-
ed) analogues. A few examples are given below.
Total synthesis of group B bastaranes: Coupling of the mix-
ture of amine pair 30a/31a with acid 4a provided after chro-
matographic separation “tetramers” 32 and 33 (Scheme 5).
At this stage,the o-position of phenols 32 and 33 was very
efficiently and specifically brominated. Products 34 and 35
were then subjected to saponification,TFA-mediated cleav-
age of the Boc group,and macrolactamization. Subsequent
TBAF-mediated cleavage of the tert-butyl dimethyl silyl
(TBS) group afforded protected bastadins 10 (compound
36) and 12 (compound 37) respectively,in high yields. After
various attempts,the most reliable and reproducible depro-
tection protocol was found to be treatment with BBr3 in the
presence of thioanisole as cation scavenger,[25] resulting in
the fully deprotected final products,identical in all respects
Synthesis of western part precursors: Preparation of phenol
9a,required for the construction of western part precursors
of group B bastadins,was achieved in eight steps and 58%
overall yield starting from p-benzyloxybenzaldehyde
(12).[12b] It should be noted that the stereogenic center em-
bedded in this building block and ultimately defining the
chirality of the whole synthetic sequence was established by
asymmetric dihydroxylation using the Sharpless protocol.[24]
The enantioselectivity of this transformation was determined
spectroscopically (1H NMR spectroscopy; Mosher ester de-
rivative) to be ꢀ97% ee.[12b]
On the other hand,phenol 9b,required for the prepara-
tion of isobastaranes and group C bastaranes,was prepared
very efficiently by bromination and subsequent protection
of tyramine.[9]
Coupling of phenol 9a or phenol 9b with iodonium salt
1b furnished in good yield the corresponding diaryl ethers
7a or 7b (Scheme 4). Sodium borohydride reduction of
Scheme 5. Synthesis of naturally occurring group B bastaranes. Reagents
Scheme 4. Preparation of western part precursors. X=H (a series); X=
OTBS (b series). Reagents and conditions: a) K2CO3,pyridine, 1b,90 8C,
82% (7a),85% ( 7b); b) NaBH4,MeOH:THF (1:1),0 8C to RT,96%
and conditions: a) EDC,HOBt, iPr2EtN,DMF/CH 2Cl2, 08C to RT,68%
(32:33=1:1); b) NBS,CH 3CN,0 8C,75%
( 34),78% ( 35); c) LiOH,
MeOH/THF/H2O,RT; TFA/CH 2Cl2,RT; PyBOP, iPr2EtN,DMF/CH 2Cl2,
08C to RT; TBAF,THF,RT,52% ( 36),61% ( 37); d) BBr3,thioanisole,
08C to RT,48% (for bastadin 10),51% (for bastadin 12); e) BnBr,
(28a),98% ( 28b); c) PPh3,imidazole,I 2,THF,RT; KCN,DMF,40
8C,
86% (29a),84% ( 29b); d) H2,10% Pd/C,dioxane,RT,95% ( 5a),98%
(5b); e) CoCl2·6H2O,NaBH 4,MeOH,0 8C,80% (estimated yield for 1:1
mixture).
K2CO3,DMF,83%; f) TEMPO,NaOCl,KBr,NaHCO
3,CH 3CN,0 8C;
NaBH4,MeOH,0 8C,78%.
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Synthesis of Bastaranes and Isobastaranes
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(TLC,NMR) with the corresponding natural material.
Moreover,in order to ensure that the sensitive benzylic chir-
ality had not been compromised during the final,rather
harsh deprotection step,synthetic bastadin 10 was converted
to its tetrabenzyl derivative 38. Oxidation of the benzylic al-
cohol moiety and subsequent restoration by sodium borohy-
dride mediated reduction furnished the corresponding race-
mate 39. HPLC chromatography of 38, 39,and the corre-
sponding mixture on a chiral column (CHIRALPAKꢂ AD-
À1
H,hexane:2-propanol =60:40,0.5 mLmin
)
revealed
beyond any doubt the homochirality of the synthetically pre-
pared bastadin.[26a]
Thus,a combination of three out of the seven key inter-
mediates prepared gave,after seven chemical operations in
a parallel fashion,bastadins 10 and 12 in 6% and 8% over-
all yields (based on acid 4a),respectively.
Scheme 7. Synthesis of naturally occurring isobastaranes. Reagents and
conditions: a) EDC,HOBt, iPr2EtN,DMF/CH 2Cl2, 08C to RT,76%
(45:46=1:1); b) TFA/CH2Cl2,pentamethylbenzene,RT; PyBOP, iPr2EtN,
DMF/CH2Cl2, 08C to RT,55%; c) BBr 3,thioanisole,0 8C to RT,55%
(for bastadin 21),46% (for bastadin 20); d) NBS,CH 3CN,0 8C,72%.
Total synthesis of group Cbastaranes : Similarly,coupling of
amine pair 30b/31b with acid 4b provided after chromato-
graphic separation “tetramers” 40 and 41 (Scheme 6). Re-
protective groups and subsequent macrolactamization fur-
nished the protected isobastarane 47. Immediate deprotec-
tion,utilizing the above described protocol,afforded basta-
din 21 within five chemical operations and in 11% total
yield. On the other hand,regiospecific bromination of 47
followed by deprotection afforded bastadin 20 within six
chemical operations and in 5% total yield.[26b]
Conclusion
We have shown the applicability of our strategy towards the
total synthesis of bastadins. Practically,bastaranes of
groups B and C as well as isobastaranes and open chain bas-
tadins may be synthesized in a short,efficient,and highly
convergent way,by using advanced common intermediates.
Elaboration of the above encouraging results into a univer-
sal practical common route,including group A derivatives,
remains to be investigated.
Scheme 6. Synthesis of naturally occurring group C bastaranes. Reagents
and conditions: a) EDC,HOBt, iPr2EtN,DMF/CH 2Cl2, 08C to RT,58%
(40:41=1:1); b) NBS,CH 3CN,0 8C,75% ( 42); c) LiOH,MeOH/THF/
H2O,RT; TFA/CH 2Cl2,RT; PyBOP, iPr2EtN,DMF/CH 2Cl2, 08C to RT,
58% (43),66% ( 44); d) BBr3,thioanisole,0 8C to RT,43% (for basta-
din 5),41% (for bastadin 16).
Experimental Section
General: All reactions were carried out under a dry argon atmosphere
with anhydrous,freshly distilled solvents under anhydrous conditions
unless otherwise noted. All reactions were magnetically stirred with
Teflon stir bars,and temperatures were measured externally. Reactions
requiring anhydrous conditions were carried out in oven-dried (1208C,
24 h) or flame-dried (vacuum < 0.5 Torr) glassware. Yields refer to chro-
matographically and spectroscopically (1H NMR spectroscopy) homoge-
neous materials. All reagents were obtained from Aldrich and used with-
out further purification. All reactions were monitored by thin-layer chro-
matography (TLC) carried out on 0.25 mm Merck silica gel plates (60F-
254). Merck silica gel (60,particle size 0.040–0.063 mm) was used for
flash column chromatography. Infrared spectra (IR) were recorded,as
neat films on potassium bromide plates,on Nicolet Magna FT-IR 550.
Mass spectra were recorded on an IonSpec Ultima FTMS (MALDI) or
an Agilent (ESI-TOF) instrument. Optical rotations were recorded with
a Perkin–Elmer 241 polarimeter. Nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker AM-250 or a Bruker Avance DRX-
500 instrument as noted individually. Chemical shifts are measured in
giospecific bromination of 40 led to intermediate 42. Depro-
tection of the carboxylic acid and amine moieties of 41 or
42 and subsequent macrolactamization furnished the diben-
zyl derivative 43 of bastadin 5 or the corresponding deriva-
tive 44 of bastadin 16. Finally,protective-group removal was
accomplished as above by treatment with BBr3 in the pres-
ence of thioanisole to yield free bastadin 5 or 16,respective-
ly in 5% overall yield (based on acid 4b).[26b]
Total synthesis of isobastaranes: Coupling the same amine
pair 30b/31b with acid 27a provided,after chromatographic
separation,“tetramers” 45 and 46 (Scheme 7). The latter
was treated with TFA to remove the Boc and tert-butyl ester
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E. A. Couladouros et al.
parts per million (d) relative to the deuterated solvent used in the experi-
ment. Multiplicities are designated as singlet (s),doublet (d),triplet (t),
or multiplet (m). Broad or obscured peaks are indicated as “br” or “obs”
respectively.
3H; ArH),7.08 (dd, J=8.5,2.0 Hz,1H; Ar H),7.00 (d, J=8.5 Hz,1H;
ArH),6.57 (d, J=2.0 Hz,1H; Ar H),5.31 (s,2H; OC H2Ph),4.39–4.29
(m,1H; ArCH 2CHCH2),4.10 (dd, J=8.2,6.0 Hz,1H; ArCH 2CHCHH),
3.78 (s,3H; COOC H3),3.65 (s,3H; COOC H3),3.72–3.59 (obs m,1H;
ArCH2CHCHH),2.92 (dd, J=14.1,7.0 Hz,1H; ArC HHCHCH2),2.80
(dd, J=14.1,5.5 Hz,1H; ArCH HCHCH2),1.46 (s,3H; C H3CCH3),
1.38 ppm (s,3H; CH 3CCH3); 13C NMR (62.5 MHz,CDCl 3): d=166.9,
164.5,149.9,147.3,146.2,141.7,138.1,136.2,133.6,128.5,127.9,127.1,
General procedure for the preparation of 6a or 6b: Imidazole (13 mmol)
and potassium carbonate (42 mmol) were added to a solution of phenol
8a or 8b (21 mmol) in DMF (140 mL). The mixture was stirred at ambi-
ent temperature for 1 h and,after addition of iodonium salt
1b
125.8,125.5,123.1,117.9,114.6,114.4,109.4,75.7,70.8,68.6,52.4,38.7,
(31 mmol),was heated at 80 8C for 6 h. The mixture was then poured into
water (250 mL) and extracted with EtOAc (3”50 mL). The combined or-
ganic phases were washed with brine (50 mL),dried over Na 2SO4,and
concentrated under reduced pressure. The residue thus obtained was pu-
rified by flash column chromatography (20% EtOAc in hexanes).
Data for 6a: Yield 96% as colorless oil; 1H NMR (250 MHz,CDCl 3):
d=9.71 (s,1H; C HO),7.51 (dd, J=8.6,2.2 Hz,1H; Ar H),7.40 (d, J=
2.2 Hz,1H; Ar H),7.32 (d, J=1.9 Hz,1H; Ar H),7.25–7.15 (m,5H;
ArH),7.02 (d, J=8.6 Hz,1H; Ar H),6.99 (dd, J=8.6,1.9 Hz,1H; Ar H),
6.69 (d, J=8.6 Hz,1H; Ar H),5.13 (s,2H; OC H2Ph),4.23–4.15 (m,1H;
ArCH2CHCH2),3.90 (dd, J=8.2,6.0 Hz,1H; ArCH 2CHCHH),3.52 (dd,
J=8.2,7.1 Hz,1H; ArCH 2CHCHH),2.83 (dd, J=13.8,6.3 Hz,1H;
26.8,25.5 ppm; IR (KBr): n˜ =3092,3069,3037,2990,2953,2879,1731,
1629,1604,1576,1550,1515,1457,1439 cm
À1; HR-MALDI-FTMS: m/z
[M+Na]+ calcd for C31H30Br2O8: 711.0199; found: 711.0191.
General procedure for the preparation of 14a or 14b: A stirred solution
of 13a or 13b (26 mmol) in a mixture of methanol (100 mL) and acetoni-
trile (100 mL) was treated at 08C with sodium borohydride (28 mmol).
The mixture was allowed to gradually warm up to ambient temperature
over 4 h and during this period two more portions of sodium borohydride
(10 mmol) were added in order to achieve complete consumption of the
starting material. The reaction mixture was then poured into a saturated
aqueous solution of ammonium chloride (200 mL) and extracted with
EtOAc (3”50 mL). The combined organic phases were washed with
ArCHH),2.66 (dd,
J=13.8,6.3 Hz,1H; ArCH
H),1.33 (s,3H;
CH3CCH3),1.26 ppm (s,3H; CH 3CCH3); 13C NMR (62.5 MHz,CDCl 3):
d=190.2,154.8,152.2,146.3,135.7,134.7,134.4,130.4,129.4,128.6,128.2,
128.1,126.9,119.3,118.9,114.1,113.8,109.3,76.2,70.8,68.8,38.9,27.0,
25.7 ppm; IR (KBr): n˜ =3094,3072,3035,2990,2940,2876,2835,2737,
2
brine (50 mL),dried over Na SO4,and concentrated under reduced pres-
sure. The residue thus obtained was purified by flash column chromatog-
raphy (30% EtOAc in hexanes).
Data for 14a: Yield 86% as colorless oil; 1H NMR (250 MHz,CDCl 3):
d=7.47 (d, J=1.9 Hz,1H; Ar H),7.34–7.18 (m,5H; Ar H),7.02 (dd, J=
8.6,1.9 Hz,1H; Ar H),6.93 (s,1H; Ar H),6.92 (s,1H; Ar H),6.83 (s,1H;
ArH),6.64 (d, J=8.6 Hz,1H; Ar H),5.06 (s,2H; OC H2Ph),4.30–4.19
(m,1H; ArCH 2CHCH2),3.97 (dd, J=8.2,6.0 Hz,1H; ArCH 2CHCHH),
1696,1602,1583,1509,1491,1459,1439 cm
À1; HR-MALDI-FTMS: m/z
[M+Na]+ calcd for C26H25BrO5: 519.0777; found: 519.0792.
Data for 6b: Yield 98% as colorless oil; 1H NMR (250 MHz,CDCl 3):
d=9.71 (s,1H; C HO),7.52–7.43 (m,5H; Ar H),7.40–7.26 (m,3H;
ArH),7.09 (d, J=8.3 Hz,1H; Ar H),6.96 (d, J=1.7 Hz,1H; Ar H),5.31
(s,2H; OC H2Ph),4.37–4.27 (m,1H; ArCH 2CHCH2),4.05 (dd, J=8.0,
3.68 (s,6H; COOC H3),3.64–3.55 (m,2H; ArCH
2CHCHH,
CH2CH(COOMe)2),3.12 (d, J=7.8 Hz,2H; C H2CH(COOMe)2),2.92
(dd, J=14.1,6.3 Hz,1H; ArC HHCHCH2),2.72 (dd, J=14.1,6.3 Hz,1H;
ArCHHCHCH2),1.42 (s,3H; C H3CCH3),1.35 ppm (s,3H; CH 3CCH3);
13C NMR (62.5 MHz,CDCl 3): d=168.8,153.1,148.7,145.1,136.6,133.9,
133.3,131.2,128.9,128.1,127.5,126.8,125.2,121.3,117.2,115.6,112.5,
6.0 Hz,1H; ArCH 2CHCHH),3.61 (dd,
J=8.0,7.1 Hz,1H;
ArCH2CHCHH),2.87 (dd, J=14.2,6.9 Hz,1H; ArC HH),2.77 (dd, J=
14.2,5.4 Hz,1H; ArCH H),1.42 (s,3H; C H3CCH3),1.36 ppm (s,3H;
CH3CCH3); 13C NMR (62.5 MHz,CDCl 3): d=190.1,152.9,147.1,146.5,
138.1,135.8,133.6,129.8,128.4,127.9,127.3,127.0,117.7,113.7,112.7,
109.0,76.2,70.8,68.6,53.4,52.3,38.7,33.7,26.8,25.5 ppm; IR (KBr):
3071,3042,2989,2952,2874,1756,1740,1610,1583,1514,1489,1455,
n˜ =
109.2,75.4,70.7,68.4,38.5,26.7,25.4 ppm; IR (KBr):
2991,2934,2879,2854,2738,1692,1600,1551,1514,1454 cm
n˜ =3062,3037,
1437 cmÀ1; HR-MALDI-FTMS: m/z [M+Na]+ calcd for C31H33BrO8:
À1; HR-
MALDI-FTMS: m/z [M+Na]+ calcd for C26H24Br2O5: 596.9883; found:
635.1251; found: 635.1257.
Data for 14b: Yield 83% as colorless oil; 1H NMR (250 MHz,CDCl 3):
d=7.55–7.45 (m,4H; Ar H),7.42–7.27 (m,3H; Ar H),6.94 (d, J=7.7 Hz,
1H; ArH),6.79 (brd, J=8.2 Hz,1H; Ar H),6.29 (brs,1H; Ar H),5.24 (s,
2H; OCH2Ph),4.40–4.30 (m,1H; ArCH 2CHCH2),4.08 (dd, J=7.5,
6.3 Hz,1H; ArCH 2CHCHH),3.65 (s,6H; COOC H3),3.70–3.52 (m,2H;
596.9895.
General procedure for the preparation of 13a or 13b: A solution of alde-
hyde 6a or 6b (20 mmol),piperidine (40 mmol),dimethyl malonate
(22 mmol),and acetic anhydride (22 mmol) in THF (130 mL) was stirred
at 808C for 24 h. The mixture was allowed to cool to ambient tempera-
ture and was then poured into a saturated aqueous solution of ammonium
chloride (200 mL) and extracted with EtOAc (3”50 mL). The combined
organic phases were washed with brine (50 mL),dried over Na 2SO4,and
concentrated under reduced pressure. The residue thus obtained was pu-
rified by flash column chromatography (20% EtOAc in hexanes) to yield
product 13a or 13b and some unreacted starting aldehyde 6a or 6b.
ArCH2CHCHH,CH 2CH(COOMe)2),3.06 (d,
J=7.8 Hz,2H;
CH2CH(COOMe)2),2.92 (dd, J=14.1,6.8 Hz,1H; ArC HHCHCH2),
2.81 (dd, J=14.1,5.4 Hz,1H; ArCH HCHCH2),1.46 (s,3H; C H3CCH3),
1.40 ppm (s,3H; CH 3CCH3); 13C NMR (62.5 MHz,CDCl 3): d=168.7,
147.6,146.3,146.1,137.5,136.9,133.4,130.6,128.2,127.5,127.1,122.7,
117.8,115.7,114.5,109.2,75.5,71.2,68.4,53.4,52.2,38.4,33.8,26.7,
Data for 13a: Yield 99% (70% conversion) as light yellow oil; 1H NMR
(250 MHz,CDCl 3): d=7.57 (s,1H; ArC H=C),7.47 (d, J=1.9 Hz,1H;
ArH),7.32–7.18 (m,5H; Ar H),7.14 (dd, J=8.6,2.2 Hz,1H; Ar H),7.06
(dd, J=8.6,1.9 Hz,1H; Ar H),6.96 (d, J=8.6 Hz,1H; Ar H),6.96 (d, J=
2.2 Hz,1H; Ar H),6.74 (d, J=8.6 Hz,1H; Ar H),5.11 (s,2H; OC H2Ph),
25.4 ppm; IR (KBr): n˜ =3093,3067,3037,2987,2952,2936,2870,1758,
1737,1612,1593,1551,1516,1460,1434 cm
À1; HR-MALDI-FTMS: m/z
[M+Na]+ calcd for C31H32Br2O8: 713.0356; found: 713.0365.
General procedure for the preparation of 15a or 15b: Sodium methoxide
(47 mmol) and BuONO (26 mmol) were added to a stirred solution of
14a or 14b (24 mmol) in methanol (300 mL) at 08C. The mixture was al-
lowed to stand at 08C for 24 h and then additional BuONO (13 mmol)
was added. After being kept at 08C for another 24 h,the reaction mix-
ture was poured into a saturated aqueous solution of ammonium chloride
(300 mL) and extracted with EtOAc (3”100 mL). The combined organic
phases were washed with brine (50 mL),dried over Na 2SO4,and concen-
trated under reduced pressure. The residue thus obtained was purified by
4.30–4.20 (m,1H; ArCH 2CHCH2),3.97 (dd,
J=8.2,6.0 Hz,1H;
ArCH2CHCHH),3.76 (s,3H; COOC H3),3.67 (s,3H; COOC H3),3.58
(dd, J=8.2,7.1 Hz,1H; ArCH 2CHCHH),2.88 (dd, J=13.8,6.3 Hz,1H;
ArCHHCHCH2),2.72 (dd, J=13.8,6.3 Hz,1H; ArCH HCHCH2),1.40 (s,
3H; CH3CCH3),1.32 ppm (s,3H; CH 3CCH3); 13C NMR (62.5 MHz,
CDCl3): d=166.9,164.4,152.3,151.6,145.7,141.5,135.9,134.4,134.1,
129.2,128.3,127.8,127.2,126.8,125.8,123.5,120.2,118.7,114.5,113.5,
flash column chromatography (30% EtOAc in hexanes).
109.1,76.1,70.5,68.6,52.4,38.8,26.8,25.5 ppm; IR (KBr):
n˜ =3092,3066,
1
3034,2986,2951,2877,2824,1760,1739,1629,1602,1576,1512,1489,
Data for 15a: Yield 88% as colorless foam; H NMR (250 MHz,CDCl ):
3
À1
1455,1435 cm
;
HR-MALDI-FTMS: m/z [M+Na]+ calcd for
d=10.70–10.00 (brs,1H; N OH),7.38 (d, J=1.9 Hz,1H; Ar H),7.24–7.07
(m,5H; Ar H),7.00–6.87 (m,3H; Ar H),6.82 (d, J=8.2 Hz,1H; Ar H),
6.58 (d, J=8.6 Hz,1H; Ar H),4.94 (s,2H; OC H2Ph),4.32–4.21 (m,1H;
ArCH2CHCH2),3.87 (dd, J=8.2,6.0 Hz,1H; ArCH 2CHCHH),3.79 (s,
C31H31BrO8: 633.1094; found: 633.1094.
1
Data for 13b: Yield 97% (88% conversion) as light yellow oil; H NMR
(250 MHz,CDCl 3): d=7.58–7.46 (m,5H; ArC H=C,Ar H),7.43–7.29 (m,
412
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11,406 – 421

Synthesis of Bastaranes and Isobastaranes
FULL PAPER
2H; ArCH2C=NOH),3.69 (s,3H; COOC H3),3.53 (dd, J=8.2,6.7 Hz,
1H; ArCH2CHCHH),2.80 (dd, J=13.8,6.3 Hz,1H; ArC HHCHCH2),
2.64 (dd, J=13.8,6.3 Hz,1H; ArC HHCHCH2),1.35 (s,3H; C H3CCH3),
1.27 ppm (s,3H; CH 3CCH3); 13C NMR (62.5 MHz,CDCl 3): d=163.7,
153.2,150.5,148.5,144.9,136.7,133.9,133.0,129.3,129.0,128.2,127.5,
reduced pressure. The residue thus obtained was purified by flash column
chromatography (30% EtOAc in hexanes + 3% methanol).
1
Data for 17a: Yield 52% as yellow oil; H NMR (250 MHz,CDCl 3): d=
7.47 (d, J=1.9 Hz,1H; Ar H),7.34–7.15 (m,11H; Ar H),6.98 (dd, J=8.4,
1.9 Hz,1H; Ar H),6.70 (s,1H; Ar H),6.59 (d, J=8.4 Hz,1H; Ar H),5.25
(s, 2H; OCH2Ph),5.03 (s,2H; OC H2Ph),3.96 (s,2H; ArC H2CNOBn),
3.96–3.63 (m,2H; ArCH 2CHCH2,ArCH 2CHCHH),3.81 (s,3H;
COOCH3),3.50–3.43 (m,1H; ArCH 2CHCHH),2.75–2.66 ppm (m,4H;
ArCH2CHCH2,CHO H,CH 2OH); HR-MALDI-FTMS: m/z [M+Na]+
calcd for C33H31Br2NO7: 734.0359; found: 734.0367.
126.8,125.6,122.0,117.2,115.4,112.5,109.2,76.2,70.8,68.4,52.5,38.6,
29.5,26.7,25.4 ppm; HR-MALDI-FTMS:
C29H30BrNO7: 606.1098; found: 606.1095,.
m/z [M+Na]+ calcd for
1
Data for 15b: Yield 87% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=10.60–9.45 (brs,1H; N OH),7.56–7.45 (m,4H; Ar H),7.43–7.25 (m,
3H; ArH),6.89 (brs,2H; Ar H),6.46 (s,1H; Ar H),5.23 (s,2H;
OCH2Ph),4.46–4.36 (m,1H; ArCH 2CHCH2),4.07 (dd, J=8.2,6.4 Hz,
1
Data for 17b: Yield 56% as yellow oil; H NMR (250 MHz,CDCl 3): d=
7.52–7.18 (m,13H; Ar H),6.14 (s,1H; Ar H),5.20 (s,2H; OC H2Ph),5.18
(s,2H; OC H2Ph),3.88 (brs,3H; ArC H2CNOBn,ArCH 2CHCH2),3.75
(s,3H; COOC H3),3.63 (dd, J=11.0,3.3 Hz,1H; ArCH 2CHCHH),3.46
(dd, J=11.0,7.0 Hz,1H; ArCH 2CHCHH),3.25 (brs,1H; O H),2.97
(brs,1H; O H),2.77–2.61 ppm (m,2H; ArC H2CHCH2); HR-MALDI-
FTMS: m/z [M+Na]+ calcd for C33H30Br3NO7: 811.9464; found:
811.9493,.
1H; ArCH2CHCHH),3.77 (s,2H; ArC
COOCH3),3.65 (dd, J=8.2,6.5 Hz,1H; ArCH 2CHCHH),2.89 (dd, J=
14.2,5.0 Hz,1H; ArC HHCHCH2),2.80 (dd, J=14.2,6.3 Hz,1H;
H2C=NOH),3.75 (s,3H;
ArCHHCHCH2),1.46 (s,3H; C H3CCH3),1.38 ppm (s,3H; CH 3CCH3);
13C NMR (62.5 MHz,CDCl 3): d=163.6,150.7,148.0,146.2,137.1,136.8,
133.8,130.8,129.0,128.6,128.3,127.6,127.2,123.1,118.0,115.5,115.3,
109.5,75.4,71.3,67.8,52.4,38.2,29.6,26.4,25.0 ppm; HR-MALDI-
FTMS: m/z [M+Na]+ calcd for C29H29Br2NO7: 684.0203; found:
684.0229.
General procedure for the preparation of 18a or 18b: An aqueous so-
lution of HCl (1n,100 mL) was added to a solution of 16a or 16b
(24 mmol) in THF (100 mL),and the mixture was stirred at ambient tem-
perature overnight. Approximately half of the solvent was evaporated
under reduced pressure and the remaining mixture was extracted with
EtOAc (3”30 mL). The combined organic phases were washed with
General procedure for the preparation of 16a or 16b: Oxime 15a or 15b
(25 mmol) was dissolved in DMF (70 mL),the solution was cooled at
08C and then potassium carbonate (38 mmol) and imidazole (10 mmol)
were added. The mixture was stirred for 30 min and then benzyl bromide
(27 mmol) was added. The reaction mixture was allowed to gradually
warm up to ambient temperature and after 12 h it was poured into water
(150 mL) and extracted with EtOAc (3”30 mL). The combined organic
phases were washed with brine (30 mL),dried over Na 2SO4,and concen-
trated under reduced pressure. The residue thus obtained was purified by
flash column chromatography (15% EtOAc in hexanes).
Data for 16a: Yield 91% as light yellow oil; 1H NMR (250 MHz,
CDCl3): d=7.43 (d, J=1.9 Hz,1H; Ar H),7.33–7.14 (m,10H; Ar H),
6.98–6.90 (m,3H; Ar H),6.85 (d, J=8.2,Hz,1H; Ar H),6.55 (d, J=
8.2 Hz,1H; Ar H),5.25 (s,2H; OC H2Ph),5.00 (s,2H; OC H2Ph),4.31–
brine (30 mL),dried over Na SO4,and concentrated under reduced pres-
2
sure. The residue thus obtained was purified by flash column chromatog-
raphy (30% EtOAc in hexanes + 3% methanol).
Data for 18a: Yield 99% as light yellow foam; 1H NMR (250 MHz,
CDCl3): d=7.48 (d, J=2.0 Hz,1H; Ar H),7.34–7.20 (m,10H; Ar H),
7.00–6.94 (m,3H; Ar H),6.89 (d, J=8.3 Hz,1H; Ar H),6.62 (d, J=
8.3 Hz,1H; Ar H),5.29 (s,2H; OC H2Ph),5.05 (s,2H; OC H2Ph),3.92–
3.84 (m,1H; ArCH 2CHCH2),3.86 (s,2H; ArC H2CNOBn),3.83 (s,3H;
COOCH3),3.65 (dd, J=11.1,3.3 Hz,1H; ArCH 2CHCHH),3.47 (dd, J=
11.1,6.9 Hz,1H; ArCH 2CHCHH),2.77–2.63 (m,2H; ArC H2CHCH2),
2.20 ppm (brs,2H; 2”O H); 13C NMR (62.5 MHz,CDCl 3): d=163.8,
153.4,150.6,148.7,144.8,136.8,136.1,134.0,133.3,129.4,129.1,128.5,
4.20 (m,1H; ArCH 2CHCH2),3.91 (dd,
J=8.2,6.0 Hz,1H;
128.3,127.7,126.9,125.8,122.2,117.1,115.6,112.6,77.8,72.8,71.0,65.8,
ArCH2CHCHH),3.82 (s,2H; ArC H2CNOBn),3.79 (s,3H; COOC H3),
3.56 (dd, J=8.2,7.1 Hz,1H; ArCH 2CHCHH),2.87 (dd, J=13.8,6.3 Hz,
1H; ArCHHCHCH2),2.67 (dd, J=13.8,6.3 Hz,1H; ArCH HCHCH2),
52.8,38.5,30.5 ppm; IR (KBr): n˜ =3416,3092,3068,3040,2950,2980,
1729,1607,1573,1497,1487,1455,1440 cm
À1; HR-ESI: m/z [M+Na]+
calcd for C33H32BrNO7: 656.1260; found: 656.1254.
1.38 (s,3H;
C
H3CCH3),1.31 ppm (s,3H; CH
3CCH3); 13C NMR
Data for 18b: Yield 99% as light yellow foam; 1H NMR (250 MHz,
CDCl3): d=7.61–7.43 (m,4H; Ar H),7.39–7.22 (m,7H; Ar H),6.88 (d,
J=8.3 Hz,1H; Ar H),6.79 (dd, J=8.3,1.8 Hz,1H; Ar H),6.66 (s,1H;
ArH),6.35 (d, J=1.8 Hz,1H; Ar H),5.22 (s,4H; 2”OC H2Ph),3.93–3.80
(m,1H; ArCH 2CHCH2),3.75 (s,5H; ArC H2CNOBn,COOC H3),3.63
(dd, J=11.0,3.2 Hz,1H; ArCH 2CHCHH),3.46 (dd, J=11.0,6.9 Hz,1H;
(62.5 MHz,CDCl 3): d=163.7,153.4,150.6,148.7,144.6,136.7,136.1,
133.8,133.0,129.3,128.9,128.4,128.2,127.6,126.9,125.8,122.4,116.8,
115.4,112.3,109.1,77.8,76.3,70.8,68.7,52.7,38.7,30.5,26.9,25.6 ppm;
IR (KBr): n˜ =3093,3066,3035,2989,2952,2935,2877,1726,1607,1582,
1509,1488,1453,1430 cm À1; HR-MALDI-FTMS: m/z [M+Na]+ calcd for
C36H36BrNO7: 696.1567; found: 696.1557.
Data for 16b: Yield 88% as light yellow oil; 1H NMR (250 MHz,
CDCl3): d=7.53–7.19 (m,12H; Ar H),6.88 (d, J=8.3 Hz,1H; Ar H),6.80
(dd, J=8.3,1.6 Hz,1H; Ar H),6.43 (d, J=1.6 Hz,1H; Ar H),5.24 (s,
ArCH2CHCHH),2.78 (brs,2H; 2”O
H),2.75–2.60 ppm (m,2H;
ArCH2CHCH2); 13C NMR (62.5 MHz,CDCl 3): d=164.2,163.8,150.7,
149.5,147.8,146.3,138.0,137.1,136.2,133.6,128.7,128.4,128.2,128.1,
127.9,127.7,127.3,123.2,118.1,116.1,115.9,115.0,77.5,72.4,71.5,65.7,
52.7,38.3,30.5 ppm; HR-ESI:
714.0525; found: 714.0521.
m/z [M+H]+ calcd for C33H31Br2NO7:
2H; OCH2Ph),5.23 (s,2H; OC
ArCH2CHCH2),4.03 (dd, J=8.0,6.0 Hz,1H; ArCH 2CHCHH),3.78 (s,
5H; ArCH2CNOBn,COOC H3),3.61 (dd, J=8.0,7.3 Hz,1H;
H2Ph),4.34–4.24 (m,1H;
General procedure for the preparation of 19a or 19b: A stirred solution
of diol 18a or 18b (25 mmol) and imidazole (40 mmol) in DMF (100 mL)
was cooled at 08C and then TBSCl (30 mmol) was added in small por-
tions. The mixture was stirred at this temperature for 3 h and was then al-
lowed to gradually warm up to ambient temperature. After 8 h the reac-
tion mixture was poured into a saturated aqueous solution of ammonium
chloride (100 mL) and extracted with EtOAc (3”30 mL). The combined
organic phases were washed with water (50 mL) and brine (50 mL),dried
over Na2SO4,and concentrated under reduced pressure. The residue thus
obtained was purified by flash column chromatography (20% EtOAc in
hexanes).
Data for 19a: Yield 88% as colorless oil; 1H NMR (250 MHz,CDCl 3):
d=7.46 (d, J=2.0 Hz,1H; Ar H),7.33–7.16 (m,10H; Ar H),6.97 (dd, J=
8.4,2.0 Hz,1H; Ar H),6.92 (s,2H; Ar H),6.86 (d, J=8.2 Hz,1H; Ar H),
6.59 (d, J=8.4 Hz,1H; Ar H),5.26 (s,2H; OC H2Ph),5.02 (s,2H;
OCH2Ph),3.86–3.73 (m,1H; ArCH 2CHCH2),3.83 (s,2H; ArC H2-
ArCH2CHCHH),2.88 (dd, J=14.1,6.8 Hz,1H; ArC HHCHCH2),2.74
(dd, J=14.1,5.6 Hz,1H; ArCH HCHCH2),1.44 (s,3H; C H3CCH3),
1.36 ppm (s,3H; CH 3CCH3); 13C NMR (62.5 MHz,CDCl 3): d=163.6,
150.7,147.9,146.3,146.1,137.3,137.1,136.3,133.4,128.8,128.3,128.0,
127.9,127.7,127.2,123.1,118.0,115.7,115.3,109.4,77.5,75.7,71.4,68.5,
52.6,38.6,30.6,26.8,25.5 ppm; HR-MALDI-FTMS:
for C36H35Br2NO7: 774.0672; found: 774.0655.
m/z [M+Na]+ calcd
General procedure for the preparation of 17a or 17b: A stirred solution
of 16a or 16b (2.5 mmol) and NBS (3 mmol) in acetonitrile (30 mL) was
heated at reflux for 4 h. The reaction mixture was allowed to cool to am-
bient temperature and was then poured into a saturated aqueous solution
of sodium bicarbonate (30 mL) containing 5% w/v potassium iodide. The
mixture was extracted with EtOAc (3”30 mL),and the combined organ-
ic phases were washed with saturated aqueous solution of Na2SO3
(30 mL) and brine (30 mL),dried over Na 2SO4,and concentrated under
Chem. Eur. J. 2005, 11,406 – 421
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
413

E. A. Couladouros et al.
CNOBn),3.80 (s,3H; COOC
H3),3.57 (dd,
J=9.9,3.8 Hz,1H;
128.7,128.7,128.6,128.5,128.4,128.4,128.3,128.3,128.3,128.2,127.7,
123.5,123.5,118.4,116.3,115.8,78.0,78.0,75.6,71.9,63.7,58.7,53.1,35.6,
ArCH2CHCHH),3.43 (dd, J=9.9,6.4 Hz,1H; ArCH 2CHCHH),2.68 (d,
J=6.5 Hz,2H; ArC H2CHCH2),2.33 (d, J=4.5 Hz,1H; O H),0.89 (s,
9H; tBuSi),0.05 (s,3H; C H3Si),0.04 ppm (s,3H; C H3Si); 13C NMR
(62.5 MHz,CDCl 3): d=164.3,163.8,153.2,150.7,148.7,144.9,136.8,
136.2,134.0,133.9,129.4,129.1,128.5,128.3,128.2,127.7,127.0,125.7,
122.3,117.0,115.6,112.5,77.9,72.5,71.0,66.0,52.8,38.3,30.6,25.8,3.7,
3.7 ppm; IR (KBr): n˜ =3558,3089,3068,3032,2954,2929,2883,2857,
31.1,31.0,26.3,18.6,4.3,4.1 ppm; IR (KBr):
2930,2884,2854,1731,1607,1548,1500,1456 cm
n˜ =3092,3064,3031,2953,
À1
;
HR-ESI: m/z
[M+H]+ calcd for C46H50Br2N2O7Si: 929.1827; found: 929.1834.
General procedure for the preparation of alcohols 21a, 21b, 22a, and
22b: A solution of silyl ether 20a or 20b (7.0 mmol) in THF (30 mL) was
treated for 30 min at ambient temperature with 1.0m solution of TBAF
in THF (7 mL). The reaction mixture was then poured into a saturated
aqueous solution of ammonium chloride (50 mL) and extracted with
EtOAc (3”30 mL). The combined organic phases were washed with
water (20 mL) and brine (20 mL),dried over Na 2SO4,and concentrated
under reduced pressure. The residue thus obtained was purified by flash
column chromatography (30% EtOAc in hexanes) to yield,in order of
1730,1609,1572,1498,1485,1456,1441 cm
calcd for C39H46BrNO7Si: 748.2300; found: 748.2297.
À1; HR-ESI: m/z [M+H]+
Data for 19b: Yield 89% as colorless oil; 1H NMR (250 MHz,CDCl 3):
d=7.48–7.38 (m,4H; Ar H),7.35–7.16 (m,8H; Ar H),6.82 (d, J=8.3 Hz,
1H; ArH),6.74 (dd, J=8.3,1.7 Hz,1H; Ar H),6.38 (d, J=1.7 Hz,1H;
ArH),5.17 (s,2H; OC H2Ph),5.16 (s,2H; OC H2Ph),3.85–3.71 (m,1H;
ArCH2CHCH2),3.71 (s,2H; ArC H2CNOBn),3.69 (s,3H; COOC H3),
3.56 (dd, J=9.9,4.0 Hz,1H; ArCH 2CHCHH),3.43 (dd, J=9.9,6.3 Hz,
1H; ArCH2CHCHH),2.71–2.57 (m,2H; ArC H2CHCH2),2.42 (brd, J=
2.3 Hz,1H; O H),0.89 (s,9H; tBuSi),0.05 ppm (s,6H; C H3Si); 13C NMR
(62.5 MHz,CDCl 3): d=163.5,150.6,147.6,146.3,146.2,138.2,137.1,
136.3,133.5,128.8,128.3,128.1,127.9,127.8,127.6,127.2,123.0,117.9,
115.7,115.2,77.4,72.0,71.4,66.0,52.5,38.1,30.5,25.7,18.1,3.4,3.4 ppm;
HR-ESI-TOF: m/z [M+H]+ calcd for C39H45Br2NO7Si: 826.1405; found:
826.1410.
elution, 22a and 21a or 22b and 21b,respectively.
1
Data for 21a: Yield 24% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.50 (d, J=2.0 Hz,1H; Ar H),7.43–7.18 (m,15H; Ar H),7.04–6.95
(m,3H; Ar H),6.91 (d, J=8.1 Hz,1H; Ar H),6.59 (d, J=8.3 Hz,1H;
ArH),5.31 (s,2H; OC H2Ph),5.17 (s,2H; OC H2Ph),5.04 (s,2H;
OCH2Ph),4.10 (brs,2H; C H2OH),3.89 (s,2H; ArC H2CNOBn),3.82 (s,
3H; COOCH3),3.66 (s,2H; ArC H2CNOBn),2.53 ppm (brs,1H; O H);
13C NMR (62.5 MHz,CDCl 3): d=163.7,159.8,156.8,153.5,150.5,148.7,
144.6,137.3,136.6,136.1,133.7,131.1,129.3,129.2,128.7,128.3,128.2,
127.9,127.8,127.6,126.8,125.8,122.3,116.9,116.0,115.5,112.4,128.4,
General procedure for the preparation of 20a or 20b: Alcohol 19a or
19b (7.2 mmol) was dissolved in dichloromethane (80 mL). A solution of
KBr in water (4.3 mL,0.5 m; 2.2 mmol) and a solution of TEMPO in di-
chloromethane (8 mL,9m m; 72 mmol) were added to this mixture. An
aqueous solution of NaOCl (37 mL,0.3 m; 11 mmol) containing NaHCO3
(1.1 g,13 mmol) was added in small portions (over 1 h) to this vigorously
stirred mixture at 08C. The reaction was allowed to proceed for an addi-
tional hour and was then quenched by the addition of 2-propanol (1 mL).
EtOAc (150 mL) was added to the mixture and it was washed successive-
ly with water (50 mL) and brine (50 mL). The combined organic phases
were dried over Na2SO4 and concentrated under reduced pressure. The
residue thus obtained was dissolved in ethanol (25 mL) and treated at
ambient temperature with O-benzyl hydroxylamine hydrochloride (1.2 g,
7.4 mmol) and pyridine (0.6 mL,7.4 mmol). The mixture was poured into
aqueous HCl (0.01n,30 mL) and extracted with EtOAc (3”30 mL). The
combined organic phases were washed with water (2”30 mL) and brine
(30 mL),dried over Na 2SO4,and concentrated under reduced pressure.
The residue thus obtained was purified by flash column chromatography
(20% EtOAc in hexanes).
128.1,77.7,76.1,70.9,62.4,52.6,31.2,30.5 ppm; IR (KBr):
3069,3035,2955,2926,2871,1728,1609,1490,1460 cm
n˜ =3505,3094,
À1
.
1
Data for 21b: Yield 11% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.53–7.44 (m,4H; Ar H),7.43–7.23 (m,13H; Ar H),6.90 (d, J=
8.3 Hz,1H; Ar H),6.83 (dd, J=8.3,1.9 Hz,1H; Ar H),6.42 (d, J=1.9 Hz,
1H; ArH),5.25 (s,2H; OC H2Ph),5.24 (s,2H; OC H2Ph),5.17 (s,2H;
OCH2Ph),4.15 (s,2H; C H2OH),3.78 (s,2H; ArC H2CNOBn),3.75 (s,
3H; COOCH3),3.66 (s,2H; ArC H2CNOBn),2.45 ppm (brs,1H; O H);
13C NMR (62.5 MHz,CDCl 3): d=163.6,156.1,150.7,148.0,146.3,146.2,
137.1,136.3,135.6,133.3,128.8,128.4,128.3,128.2,128.0,128.0,127.9,
127.9,127.7,127.2,123.2,118.1,115.8,115.2,77.5,76.3,71.4,62.6,52.6,
31.1,30.5 ppm; IR (KBr): n˜ =3500,3096,3069,3035,2955,2931,2876,
À1
1733,1609,1555,1505,1456,1439 cm
.
1
Data for 22a: Yield 69% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.47 (d, J=2.0 Hz,1H; Ar H),7.37–7.17 (m,15H; Ar H),7.00–6.92
(m,3H; Ar H),6.88 (d, J=8.3 Hz,1H; Ar H),6.58 (d, J=8.3 Hz,1H;
ArH),5.27 (s,2H; OC H2Ph),5.12 (s,2H; OC H2Ph),5.02 (s,2H;
OCH2Ph),4.29 (brs,2H; C H2OH),3.84 (s,2H; ArC H2CNOBn),3.80 (s,
3H; COOCH3),3.53 ppm (s,2H; ArC H2CNOBn); 13C NMR (62.5 MHz,
CDCl3): d=163.81,59.8,153.6,150.6,148.7,144.8,137.5,136.8,136.1,
133.6,132.1,129.4,128.7,128.4,128.2,128.0,127.9,127.7,126.9,125.8,
122.3,117.1,115.6,112.6,109.5,128.4,128.3,77.8,76.1,71.0,58.5,52.7,
Data for 20a: Yield 96% (ca. 3:1 mixture of isomers) as light yellow oil;
1H NMR (250 MHz,CDCl 3): d=7.50 (d, J=2.0 Hz,1H; Ar H),7.48 (d,
J=2.0 Hz,3H; Ar H),7.38–7.16 (m,60H; Ar H),7.00–6.91 (m,12H;
ArH),6.86 (d, J=8.2 Hz,3H; Ar H),6.56 (d, J=8.4 Hz,3H; Ar H),6.54
(2 d, J=8.4 Hz,1H; Ar H),5.26 (s,8H; OC H2Ph),6.56 (s,2H;
OCH2Ph),6.54 (s,6H; OC H2Ph),5.03 (2 s,6H; OC H2Ph),5.02 (s,2H;
OCH2Ph),4.42 (s,6H; C H2OTBS),4.06(s,2H; C H2OTBS),3.83 (s,6H;
ArCH2CNOBn),3.80 (s,9H; COOC H3),3.70 (s,2H; ArC H2CNOBn),
3.54 (2 s,6H; ArC H2CNOBn),0.87 (s,9H; tBuSi),0.85 (s,27H; tBuSi),
0.00 (s,6H; C H3Si), À0.05 ppm (s,18H; C H3Si); 13C NMR (62.5 MHz,
CDCl3): d=163.8,160.8,158.0,153.2,150.7,148.8,145.0,137.9,136.8,
136.8,136.1,134.0,133.8,133.1,129.4,129.1,128.7,128.5,128.3,128.3,
36.5,30.5 ppm; IR (KBr): n˜ =3535,3091,3072,3032,2957,2928,2878,
À1
1726,1616,1492,1460 cm
;
HR-ESI: m/z [M+H]+ calcd for
C40H37BrN2O7: 737.1857; found: 737.1854.
1
Data for 22b: Yield 88% as colorless foam; H NMR (500 MHz,CDCl ):
3
d=7.51–7.46 (m,4H; Ar H),7.40–7.25 (m,13H; Ar H),6.88 (d, J=
8.3 Hz,1H; Ar H),6.80 (dd, J=8.3,1.9 Hz,1H; Ar H),6.33 (d, J=1.9 Hz,
1H; ArH),5.23 (s,4H; 2”OC H2Ph),5.14 (s,2H; OC H2Ph),4.43 (s,2H;
CH2OH),3.76 (s,2H; ArC H2CNOBn),3.74 (s,3H; COOC H3),3.59 ppm
(s,2H; ArC H2CNOBn); 13C NMR (125 MHz,CDCl 3): d=163.7,159.5,
150.6,147.9,146.3,146.3,137.4,137.1,136.8,136.2,133.1,128.7,128.4,
128.3,128.1,127.9,127.7,127.6,127.0,126.9,125.7,125.6,122.3,122.2,
116.9,116.9,115.6,115.6,112.3,77.9,75.9,75.8,71.0,71.0,62.9,57.9,52.8,
35.1,30.6,30.3,25.8,18.2,4.0,3.7 ppm; HR-ESI:
C46H51BrN2O7Si: 851.2722; found: 851.2721.
m/z [M+H]+ calcd for
128.1,128.0,127.9,127.7,128.4,127.3,123.2,118.2,115.9,115.0,77.5,
76.1,71.5,58.3,52.7,36.0,30.5 ppm; IR (KBr):
n˜ =3521,3095,3071,3036,
2957,2927,2876,1731,1612,1553,1506,1457,1439 cm
À1; HR-ESI-TOF:
Data for 20b: Yield 93% (ca. 8:1 mixture of isomers) as light yellow oil;
1H NMR (250 MHz,CDCl 3): d=7.54–7.44 (m,36H; Ar H),7.43–7.21 (m,
117H; ArH),6.87 (brd, J=8.3 Hz,9H; Ar H),6.79 (brdd, J=8.3,2.0 Hz,
9H; ArH),6.41 (brd, J=2.0 Hz,9H; Ar H),5.24 (brs,36H; OC H2Ph),
5.13 (s,2H; OC H2Ph),5.12 (s,16H; OC H2Ph),4.51 (s,16H; C H2OTBS),
4.15 (s,2H; C H2OTBS),3.76 (s,27H; COOC H3),3.75 (s,16H; ArC H2-
CNOBn),3.72 (s,2H; ArC H2CNOBn),3.58 (s,18H; ArC H2CNOBn),
0.92 (s,9H; tBuSi),0.90 (s,72H; tBuSi),0.07 (s,6H; C H3Si),0.02 ppm (s,
m/z [M+H]+ calcd for C40H36Br2N2O7: 815.0962; found: 815.0961.
General procedure for the preparation of acids 23a, 23b, 25a, and 25b:
One of the above alcohols (4.6 mmol) was dissolved in acetonitrile
(140 mL) and a solution of KBr in water (2.8 mL,0.5 m; 1.4 mmol) and a
solution of TEMPO in acetonitrile (2.9 mL,16m m; 46 mmol) were added.
To this stirred mixture was added in small portions (over 1 h) and at 08C
an aqueous solution of NaOCl (39 mL,0.3 m; 11.5 mmol) containing
NaHCO3 (1.2 g,13 mmol). The reaction was allowed to proceed for two
additional hours and was then quenched by addition of 2-propanol
48H; CH3Si); 13C NMR (62.5 MHz,CDCl ): d=164.1,160.5,157.4,151.2,
3
148.2,146.9,146.7,138.3,137.8,137.7,136.8,134.0,133.7,129.3,128.9,
414
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11,406 – 421

Synthesis of Bastaranes and Isobastaranes
FULL PAPER
(2 mL). EtOAc (150 mL) was added to the mixture and it was washed
successively with water (50 mL) and brine (50 mL). The combined organ-
ic phases were dried over Na2SO4 and concentrated under reduced pres-
sure. The residue thus obtained was purified by flash column chromatog-
raphy (30% EtOAc in hexanes + 2% AcOH) to yield the corresponding
115.9,114.4,78.6,77.6,52.7,30.7,29.5 ppm; HR-ESI-TOF:
calcd for C33H28Br2N2O8: 739.0285; found: 739.0283.
m/z [M+H]+
General procedure for the preparation of 4a or 4b: A stirred solution of
the phenol (1.1 mmol) in acetonitrile (30 mL) was treated at 08C with N-
bromosuccinimide (195 mg,1.1 mmol). After 1 h the reaction was
quenched by addition of an aqueous solution of potassium iodide (2 mL,
10% w/v) followed by addition of Na2SO3·7H2O in small portions until
complete disappearance of the red color of the mixture. Water (30 mL)
was added and the mixture was extracted with EtOAc (3”20 mL). The
combined organic extracts were washed with brine (10 mL),dried over
Na2SO4,and concentrated under reduced pressure. The residue was fur-
ther purified by flash column chromatography (30% EtOAc in hexanes
+ 3% AcOH).
carboxylic acid.
1
Data for 23a: Yield 96% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.49 (d, J=1.9 Hz,1H; Ar H),7.41–7.18 (m,15H; Ar H),7.05–6.88
(m,4H; Ar H),6.59 (d, J=8.3 Hz,1H; Ar H),5.28 (s,4H; 2”OC H2Ph),
5.04 (s,2H; OC H2Ph),3.86 (s,2H; ArC H2CNOBn),3.82 (s,3H;
COOCH3),3.72 ppm (s,2H; ArC H2CNOBn); 13C NMR (62.5 MHz,
CDCl3): d=163.8,153.8,150.6,149.7,148.7,144.8,136.7,136.1,133.9,
130.6,129.3,129.2,128.8,128.7,128.6,128.4,128.3,127.6,127.0,125.9,
Data for 4a: Yield 100% as light yellow foam; 1H NMR (250 MHz,
CDCl3): d=7.41 (brs,1H; Ar H),7.33–7.05 (m,11H; Ar H),6.94 (brd,
J=8.4 Hz,1H; Ar H),6.57 (brd, J=1.4 Hz,1H; Ar H),6.39 (brd, J=
8.4 Hz,1H; Ar H),5.21 (s,2H; OC H2Ph),5.03 (brs,2H; OC H2Ph),3.69
122.2,117.0,115.6,112.5,78.5,77.9,71.0,52.8,36.3,30.5 ppm; IR (KBr):
n˜ =3267,3094,3069,3040,2951,2881,1733,1609,1495,1455 cm
À1; HR-
ESI-TOF: m/z [M+H]+ calcd for C40H35BrN2O8: 751.1649; found:
751.1644.
1
(brs,5H; ArC H2CNOBn,COOC H3),3.65 ppm (brs,2H; ArC
CNOBn); 13C NMR (62.5 MHz,CDCl 3): d=163.6,151.4,150.0,143.6,
143.5,135.9,134.2,133.9,129.4,128.7,128.5,128.3,128.0,128.3,118.9,
118.6,113.4,110.2,78.0,76.5,52.8,30.2,29.4 ppm; HR-ESI-TOF:
[M+Na]+ calcd for C33H28Br2N2O8: 763.0090; found: 763.0076.
H2-
Data for 23b: Yield 98% as colorless foam; H NMR (500 MHz,CDCl ):
3
d=7.56–7.45 (m,4H; Ar H),7.43–7.27 (m,13H; Ar H),6.94–6.90 (m,
1H; ArH),6.86–6.83 (m,1H; Ar H),6.38–6.34 (m,1H; Ar H),5.28 (s,
2H; OCH2Ph),5.27 (s,2H; OC H2Ph),5.26 (s,2H; OC H2Ph),3.80 (brs,
2H; ArCH2CNOBn),3.78 (s,3H; COOC H3),3.72 ppm (s,2H; ArC H2-
CNOBn); 13C NMR (125 MHz,CDCl 3): d=163.7,161.4,150.6,149.3,
148.3,146.3,146.2,137.1,136.2,135.8,135.6,134.9,133.4,128.7,128.6,
m/z
Data for 4b: Yield 100% as light yellow foam; 1H NMR (500 MHz,
CDCl3): d=7.38 (brs,2H; Ar H),7.30–7.08 (m,10H; Ar H),6.97 (brs,
1H; ArH),6.16 (brs,1H; Ar H),5.11 (brs,2H; OC H2Ph),5.03 (brs,2H;
OCH2Ph),3.70 (brs,2H; ArC H2CNOBn),3.58 (brs,3H; COOC H3),
3.55 ppm (brs,2H; ArC H2CNOBn); 13C NMR (125 MHz,CDCl 3): d=
166.6,163.4,150.0,146.8,143.7,141.7,137.1,136.0,135.6,133.8,128.9,
128.6,128.5,128.2,128.1,128.0,127.1,117.6,113.7,109.5,77.8,77.0,52.7,
31.0,30.2 ppm; HR-ESI-TOF: m/z [M+H]+ calcd for C33H27Br3N2O8:
816.9390; found: 816.9388.
128.4,128.1,128.0,127.7,127.3,123.2,118.2,115.8,114.8,77.9,77.5,71.4,
52.8,36.2,30.5 ppm; HR-ESI-TOF:
m/z [M+H]+ calcd for
C40H34Br2N2O8: 829.0755; found: 829.0749.
1
Data for 25a: Yield 97% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.54 (brs,1H; Ar H),7.43–6.88 (m,19H; Ar H),6.50 (brd, J=6.9 Hz,
1H; ArH),5.32 (brs,2H; OC H2Ph),5.26 (brs,2H; OC H2Ph),5.01 (brs,
2H; OCH2Ph),3.86 (AB
, J=16.9 Hz, Dn=18.2 Hz,2H; ArC H2-
q
CNOBn),3.81 ppm (brs,5H; ArC H2CNOBn,COOC H3); 13C NMR
(62.5 MHz,CDCl 3): d=163.6,150.5,148.6,144.7,153.1,136.6,136.1,
135.7,133.9,129.2,128.4,128.3,128.3,128.2,128.1,128.1,127.5,126.8,
Preparation of 26a: DMAP (24 mg,0.2 mmol) and Boc 2O (320 mg,
1.5 mmol) were added to a solution of acid 4a (300 mg,0.41 mmol) in
THF (5 mL) cooled to 08C. The mixture was stirred at this temperature
for 12 h and then poured into water (10 mL) and extracted with EtOAc
(2”5 mL). The combined organic phases were washed with brine
(10 mL),dried over Na 2SO4,and concentrated under reduced pressure.
The residue thus obtained was purified by flash column chromatography
(10% EtOAc in hexanes) to yield diester 26a (298 mg,81%) as colorless
oil. 1H NMR (250 MHz,CDCl 3): d=7.46 (d, J=2.1 Hz,1H; Ar H),7.36–
7.18 (m,11H; Ar H),7.02 (dd, J=8.4,2.1 Hz,1H; Ar H),6.69 (d, J=
8.4 Hz,1H; Ar H),6.68 (d, J=1.9 Hz,1H; Ar H),5.26 (s,2H; OC H2Ph),
5.22 (s,2H; OC H2Ph),3.78 (s,2H; ArC H2C=N),3.77 (s,5H; ArC H2C=
N,COOC H3),1.47 (s,9H; OC(C H3)3),1.46 ppm (s,9H; OC(C H3)3);
13C NMR (62.5 MHz,CDCl 3): d=164.3,163.4,162.0,151.6,151.1,150.1,
149.5,149.3,138.5,136.3,135.5,134.3,133.5,129.4,128.6,128.5,128.4,
125.5,122.2,116.8,115.5,112.2,77.7,70.8,52.6,30.4,29.6 ppm; IR (KBr):
À1
n˜ =3347,3069,2920,2852,1714,1674,1615,1515,1495,1460 cm
.
1
Data for 25b: Yield 98% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.55–7.17 (m,17H; Ar H),6.89 (brd, J=7.9 Hz,1H; Ar H),6.81 (brd,
J=7.7 Hz,1H; Ar H),6.42 (brs,1H; Ar H),5.23 (s,2H; OC H2Ph),5.21
(s, 4H; 2”OCH2Ph),3.74 ppm (brs,7H; 2”ArC H2CNOBn,COOC H3);
13C NMR (125 MHz,CDCl 3): d=163.2,150.3,147.5,146.0,145.9,136.8,
135.9,133.3,128.5,128.3,128.0,127.9,127.7,127.6,127.3,126.9,122.7,
117.6,115.5,115.0,77.2,71.1,52.3,30.2,29.3 ppm.
General procedure for the preparation of 24a or 24b: TFA (8 mL) was
added to a mixture of benzyl ether (0.9 mmol) and pentamethyl benzene
(2.7 g,18 mmol) at 0 8C. The mixture was stirred at this temperature for
30 min and was then allowed to warm up to ambient temperature. After
2 h the mixture was evaporated under reduced pressure and the residue
was purified by flash column chromatography (30% EtOAc in hexanes
+ 3% AcOH) to yield the corresponding free phenol.
128.3,128.2,119.5,119.2,117.8,113.9,84.2,82.8,78.1,77.8,52.9,30.7,
30.4,27.9,27.5 ppm; HR-ESI-TOF:
C42H44Br2N2O10: 893.1290; found: 893.1279.
m/z [MÀH]À calcd for
Preparation of acid 27a:
A solution of the above diester (97 mg,
0.1 mmol) in a mixture of THF (5 mL) and MeOH (3 mL) was treated at
08C with a solution of NaOH in H2O (1n,0.3 mL). The progress of the
reaction was monitored by TLC and upon completion it was quenched
by addition of acetic acid (0.5 mL). The mixture was poured into water
(10 mL) and extracted with EtOAc (4”10 mL). The combined organic
phases were washed with brine (10 mL),dried over Na 2SO4,and concen-
trated under reduced pressure. Further purification by flash column chro-
matography (30% EtOAc in hexanes + 3% acetic acid) afforded acid
27a (75 mg,85%) as colorless oil. 1H NMR (500 MHz,CDCl 3): d=7.58
(d, J=1.9 Hz,1H; Ar H),7.46–7.37 (m,8H; Ar H),7.34–7.30 (m,3H;
ArH),7.15 (dd, J=8.4,1.9 Hz,1H; Ar H),6.82 (d, J=8.4 Hz,1H; Ar H),
6.81 (s,1H; Ar H),5.38 (s,2H; OC H2Ph),5.31 (s,2H; OC H2Ph),3.90 (s,
2H; ArCH2C=N),3.86 (s,2H; ArC H2C=N),1.58 ppm (s,18H; 2”
OC(CH3)3); 13C NMR (125 MHz,CDCl 3): d=163.5,162.0,151.5,151.1,
150.0,149.4,148.9,138.6,136.2,135.4,134.9,134.2,133.5,129.4,128.6,
1
Data for 24a: Yield 94% as white amorphous solid; H NMR (250 MHz,
CDCl3): d=7.53 (d, J=1.9 Hz,1H; Ar H),7.42–7.20 (m,10H; Ar H),7.10
(dd, J=8.4,1.9 Hz,1H; Ar H),6.92 (brs,1H; Ar H),6.73 (brs,1H;
ArH),6.72 (d, J=8.2 Hz,1H; Ar H),5.32 (brs,2H; OC H2Ph),5.24 (brs,
2H; OCH2Ph),3.86 (brs,2H; ArC H2CNOBn),3.80 (s,2H; ArC H2-
CNOBn),3.78 ppm (s,3H; COOC H3); 13C NMR (62.5 MHz,CDCl ): d=
3
163.7,163.1,152.1,150.7,145.7,142.7,136.1,135.5,134.4,132.1,129.6,
128.7,128.4,128.3,128.2,128.1,125.7,128.2,119.2,118.7,116.3,113.6,
78.5,77.8,52.7,30.6,29.4 ppm; HR-ESI-TOF:
C33H29BrN2O8: 661.1180; found: 661.1177.
m/z [M+H]+ calcd for
1
Data for 24b: Yield 96% as white amorphous solid; H NMR (500 MHz,
CDCl3): d=7.48 (brs,2H; Ar H),7.43–7.21 (m,10H; Ar H),6.92 (d, J=
8.2 Hz,1H; Ar H),6.83 (brd, J=8.2 Hz,1H; Ar H),6.33 (brs,1H; Ar H),
5.31 (brs,2H; OC H2Ph),5.22 (brs,2H; OC H2Ph),3.86 (brs,2H; ArC H2-
CNOBn),3.74 ppm (brs,5H; ArC H2CNOBn,COOC H3); 13C NMR
(125 MHz,CDCl 3): d=163.7,150.9,147.7,144.1,143.2,136.3,135.4,
135.3,133.7,128.9,128.5,128.5,128.3,128.2,128.0,127.6,124.2,118.2,
128.5,128.5,128.3,128.2,128.1,119.6,119.1,117.8,113.9,84.2,82.9,78.4,
77.8,30.4,29.8,27.9,27.5 ppm; HR-ESI-TOF:
C41H42Br2N2O10: 903.1098; found: 903.1122.
m/z [M+Na]+ calcd for
Chem. Eur. J. 2005, 11,406 – 421
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
415

E. A. Couladouros et al.
General procedure for the preparation of 7a or 7b: Potassium carbonate
(48 mmol) was added to a solution of phenol 9a or 9b (8.0 mmol) in pyri-
dine (30 mL). The mixture was stirred at ambient temperature for 1 h
and,after addition of iodonium salt 1b (10 mmol),was heated at 90 8C
for 4 h. The mixture was then poured into water (100 mL) and extracted
with EtOAc (3”30 mL). The combined organic phases were washed in
sequence with saturated aqueous CuSO4 solution (4”30 mL) and brine
(30 mL),dried over Na 2SO4,and concentrated under reduced pressure.
The residue thus obtained was purified by flash column chromatography
(15% EtOAc in hexanes).
Data for 7a: Yield 82% as colorless foam; [a]2D0 =+7.0 (c=1.0 in
CH2Cl2); 1H NMR (250 MHz,CDCl 3): d=9.70 (s,1H; C HO),7.59 (brs,
2H; ArH),7.47 (dd, J=8.2,1.9 Hz,1H; Ar H),7.40–7.25 (m,5H; Ar H),
7.08 (d, J=8.2 Hz,1H; Ar H),6.92 (d, J=1.9 Hz,1H; Ar H),5.32 (s,2H;
General procedure for the preparation of 29a or 29b: PPh3 (210 mg,
0.8 mmol),imidazole (82 mg,1.2 mmol) and iodine (203 mg,0.8 mmol)
were added to a stirred solution of alcohol 28a or 28b (0.41 mmol) in
THF (10 mL) at ambient temperature. After 30 min the solvent was re-
moved under reduced pressure and DMF (2 mL) and KCN (52 mg,
0.8 mmol) were added. The mixture was stirred at 408C for 30 min and
then was poured into saturated aqueous NH4Cl solution (10 mL) and ex-
tracted with EtOAc (3”10 mL). The combined organic phases were
washed in sequence with water (20 mL) and brine (20 mL),dried over
Na2SO4,and concentrated under reduced pressure. The residue thus ob-
tained was purified by flash column chromatography (20% EtOAc in
hexanes).
Data for 29a: Yield 86% as amorphous white solid; [a]2D0 =+8.7 (c=1.3
in CH2Cl2); 1H NMR (250 MHz,CDCl ): d=7.53 (s,2H; Ar H),7.42–7.17
3
(m,5H; Ar H),6.89 (d, J=8.2 Hz,1H; Ar H),6.82 (dd, J=8.2,1.9 Hz,
1H; ArH),6.21 (d, J=1.9 Hz,1H; Ar H),5.16 (s,2H; C H2Ph),4.81 (t,
J=5.6 Hz,1H; N HBoc),4.70 (dd, J=7.1,3.7 Hz,1H; ArC HOTBS),3.40
CH2Ph),4.92–4.74 (m,2H; ArC
HOTBS,N HBoc),3.39 (m,1H;
CHHNHBoc),3.07 (m,1H; CH HNHBoc),1.43 (s,9H; tBuOCO),0.90
(s,9H; tBuSi),0.07 (s,3H; C H3Si), À0.03 ppm (s,3H; C H3Si); 13C NMR
(62.5 MHz,CDCl 3): d=190.3,155.7,153.0,147.8,146.6,142.8,135.9,
130.5,129.9,128.6,128.1,127.2,127.1,118.0,113.9,113.1,79.5,72.1,70.9,
(s,2H; ArC H2CN),3.30 (m,1H;
C
HHNHBoc),3.00 (m,1H;
CHHNHBoc),1.38 (s,9H; tBuOCO),0.85 (s,9H; tBuSi),0.02 (s,3H;
CH3Si), À0.10 ppm (s,3H; C H3Si); 13C NMR (62.5 MHz,CDCl 3): d=
155.8,148.0,147.4,146.6,142.6,136.7,130.5,128.5,127.9,127.3,122.7,
122.2,118.1,117.6,116.1,113.8,79.6,72.3,71.4,48.9,28.4,25.7,22.9,18.1,
3.3,3.0 ppm; IR (KBr): n˜ =3446,3078,3069,3037,2959,2929,2858,2253,
48.9,28.3,25.7,18.1,3.2,3.0 ppm; IR (KBr):
n˜ =3454,3364,3067,3034,
À1
2957,2932,2857,2734,1716,1696,1602,1580,1510,1454,1434 cm
;
HR-MALDI-FTMS: m/z [M+Na]+ calcd for C33H41Br2NO6Si: 756.0962;
found: 756.0966.
À1; HR-MALDI-FTMS: m/z [M+Na]+
Data for 7b: Yield 85% as colorless oil; 1H NMR (250 MHz,CDCl 3):
d=9.74 (s,1H; C HO),7.51–7.32 (m,8H; Ar H),7.10 (d, J=8.3 Hz,1H;
ArH),6.95 (d, J=1.9 Hz,1H; Ar H),5.36 (s,2H; C H2Ph),4.66 (brm,
1H; NHBoc),3.43–3.55 (m,2H; C H2NHBoc),2.80 (t, J=7.0 Hz,2H;
ArCH2CH2),1.46 ppm (s,9H; tBuOCO); 13C NMR (62.5 MHz,CDCl 3):
d=190.1,155.6,152.8,146.9,146.4,139.4,136.7,135.7,133.1,129.8,129.7,
128.3,127.8,127.1,126.9,117.7,116.8,113.7,112.7,78.9,70.7,41.0,34.8,
28.1 ppm; IR (KBr): n˜ =3436,3355,3070,3035,2980,2934,2859,2736,
1713,1599,1516,1457,1432 cm
calcd for C34H42Br2N2O5Si: 767.1122; found: 767.1152.
1
Data for 29b: Yield 84% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.46–7.23 (m,7H; Ar H),6.95 (d, J=8.3 Hz,1H; Ar H),6.88 (dd, J=
8.3,1.6 Hz,1H; Ar H),6.28 (d, J=1.6 Hz,1H; Ar H),5.22 (s,2H;
CH2Ph),4.67 (brs,1H; N HBoc),3.51 (s,2H; ArC H2CN),3.37–3.29 (m,
2H; CH2NHBoc),2.75 (t, J=6.9 Hz,2H; ArC H2CH2),1.42 ppm (s,9H;
tBuOCO); 13C NMR (62.5 MHz,CDCl 3): d=155.7,147.3,146.6,139.2,
136.7,133.2,128.4,128.2,127.8,127.3,122.7,122.1,118.0,116.0,113.8,
1694,1601,1579,1511,1458,1436 cm
À1; HR-ESI: m/z [M+Na]+ calcd for
79.5,71.3,41.3,35.1,28.3,22.8 ppm; IR (KBr):
n˜ =3430,3365,3065,3040,
C27H27Br2NO5: 626.0154; found: 626.0155.
À1
2976,2931,2869,2252,1706,1614,1596,1552,1516,1454,1431 cm
;
General procedure for the preparation of 28a or 28b: Sodium borohy-
dride (1.6 mmol) was added in small portions to a stirred solution of al-
dehyde 7a or 7b (1.0 mmol) in a mixture of MeOH (5 mL) and THF
(5 mL) at 08C. After 30 min the reaction mixture was allowed to reach
ambient temperature and saturated aqueous NH4Cl solution (10 mL) was
carefully added. The mixture was extracted with EtOAc (3”20 mL). The
combined organic phases were washed in sequence with water (30 mL)
and brine (30 mL),dried over Na 2SO4,and concentrated under reduced
pressure. The residue thus obtained was purified by flash column chro-
matography (30% EtOAc in hexanes).
Data for 28a: Yield 96% as amorphous white solid; [a]2D0 =+10.5 (c=0.9
in CH2Cl2); 1H NMR (250 MHz,CDCl 3): d=7.58 (brs,2H; Ar H),7.53–
7.27 (m,5H; Ar H),6.98 (d, J=8.6 Hz,1H; Ar H),6.92 (dd, J=8.6,
1.9 Hz,1H; Ar H),6.41 (d, J=1.9 Hz,1H; Ar H),5.28 (s,2H; CH2Ph),
4.90–4.74 (m,2H; ArC HOTBS,N HBoc),4.49 (s,2H; ArC H2OH),3.40
HR-ESI: m/z [M+H]+ calcd for C28H28Br2N2O4: 615.0494; found:
615.0490.
General procedure for the preparation of 5a or 5b: Pd/C (10%,120 mg)
was added to a degassed solution of benzyl ether 29a or 29b (0.32 mmol)
in dioxane (20 mL); the mixture was stirred under an atmosphere of hy-
drogen for 12 h at ambient temperature. Upon reaction completion,the
mixture was filtered through a Celite bed to remove catalyst and the fil-
trate was concentrated under reduced pressure to yield the corresponding
free phenol.
Data for 5a: Yield 95% as colorless foam; [a]D20 =+8.5 (c=1.0 in
1
CH2Cl2); H NMR (250 MHz,CDCl ): d=7.61 (s,2H; Ar H),7.05 (d, J=
3
8.2 Hz,1H; Ar H),6.96 (dd, J=8.2,1.9 Hz,1H; Ar H),6.28 (d, J=1.9 Hz,
1H; ArH),5.94 (brs,1H; ArO H),4.90–4.74 (m,2H; ArC HOTBS,
NHBoc),3.55 (s,2H; ArC H2CN),3.40 (m,1H; C HHNHBoc),3.10 (m,
1H; CHHNHBoc),1.45 (s,9H; tBuOCO),0.93 (s,9H; tBuSi),0.09 (s,
3H; CH3Si), À0.02 ppm (s,3H; C H3Si); 13C NMR (62.5 MHz,CDCl 3):
d=157.8,147.7,145.4,143.7,143.4,130.7,123.3,121.7,118.1,116.6,113.2,
(m,1H;
C
HHNHBoc),3.08 (m,1H; CH
HNHBoc),1.45 (s,9H;
tBuOCO),0.92 (s,9H; tBuSi),0.08 (s,3H; C H3Si), À0.03 ppm (s,3H;
CH3Si); 13C NMR (62.5 MHz,CDCl 3): d=155.8,148.4,147.2,146.6,
142.4,137.2,134.3,130.5,128.5,127.8,127.3,121.4,118.3,115.9,113.0,
79.6,72.3,71.5,64.8,49.0,28.4,25.8,18.2,3.3,3.1 ppm; IR (KBr):
3443,3065,3033,2957,2932,2858,1702,1616,1595,1553,1512,1459,
1426 cmÀ1; HR-MALDI-FTMS: m/z [M+Na]+ calcd for C33H43Br2NO6Si:
79.7,72.3,49.0,29.7,28.4,25.8,23.0,18.2,3.4,3.1 ppm; IR (KBr):
n˜ =
3368,2957,2932,2856,2256,1705,1604,1518,1455 cm
À1; HR-MALDI-
n˜ =
FTMS: m/z [M+Na]+ calcd for C27H36Br2N2O5Si: 677.0652; found:
677.0658.
Data for 5b: Yield 98% as colorless foam; 1H NMR (250 MHz,CDCl 3):
d=7.46 (s,2H; Ar H),7.04 (d, J=8.2 Hz,1H; Ar H),6.95 (dd, J=8.2,
1.9 Hz,1H; Ar H),6.30 (d, J=1.9 Hz,1H; Ar H),5.93 (brs,1H; ArO H),
4.67 (brs,1H; N HBoc),3.56 (s,2H; ArC H2CN),3.43–3.35 (m,2H;
CH2NHBoc),2.81 (t, J=7.0 Hz,2H; ArC H2CH2),1.45 ppm (s,9H;
tBuOCO); 13C NMR (62.5 MHz,CDCl 3): d=147.0,145.3,139.9,133.4,
758.1118; found: 758.1104.
1
Data for 28b: Yield 98% as colorless foam; H NMR (250 MHz,CDCl ):
3
d=7.48 (brs,1H; Ar H),7.46 (brs,1H; Ar H),7.35–7.25 (m,5H; Ar H),
6.93 (d, J=8.3 Hz,1H; Ar H),6.86 (dd, J=8.3,1.6 Hz,1H; Ar H),6.45
(d, J=1.6 Hz,1H; Ar H),5.20 (s,2H; CH2Ph),5.01 (brt, J=4.1 Hz,1H;
NHBoc),4.36 (s,2H; ArC H2OH),3.26–3.18 (brm,2H; C H2NHBoc),
3.15 (brs,1H; O H),2.65 (t, J=6.6 Hz,2H; ArC H2CH2),1.42 ppm (s,
9H; tBuOCO); 13C NMR (62.5 MHz,CDCl 3): d=155.7,147.3,146.5,
146.2,138.8,136.8,134.3,132.9,128.1,128.0,127.5,127.1,120.9,117.9,
128.3,123.2,121.6,118.1,116.5,113.1,41.4,35.3,28.3,23.0; IR (KBr):
3361,2979,2932,2856,2255,1695,1606,1516,1456,1441 cm
n˜ =
À1; HR-
MALDI-FTMS: m/z [M+Na]+ calcd for C21H22Br2N2O4: 546.9838;
found: 546.9848.
115.4,112.6,79.0,71.1,63.8,41.0,34.7,28.1 ppm; IR (KBr):
n˜ =3422,
3550,3066,3037,2978,2933,2868,1692,1616,1598,1549,1512,1455,
General procedure for the reduction of nitriles 5a,b: A vigorously stirred
solution of nitrile 5a or 5b (0.21 mmol) in MeOH (6 mL) was cooled in
1426 cmÀ1; HR-MALDI-FTMS: m/z [M+Na]+ calcd for C27H29Br2NO5:
628.0305; found: 628.0202.
an ice bath and CoCl2·6H2O (catalytic amount,5 mg) was added. NaBH
4
416
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11,406 – 421

Synthesis of Bastaranes and Isobastaranes
FULL PAPER
(20 mg,0.53 mmol) was carefully added in small portions to this light
pink mixture in such a rate as to maintain the black precipitate of boride
that appeared following each addition. Upon completion of the reaction,
a saturated aqueous solution of NH4Cl (15 mL) was added,and the mix-
ture was stirred for an additional 15 min. The mixture was extracted with
EtOAc (4”10 mL) and the combined organic phases were washed with
2H; ArCH2C=N),3.76 (s,3H; COOC H3),3.69 (s,2H; ArC H2C=N),
3.47–3.43 (m,2H; C H2NHCO),3.39–3.31 (m,2H; C H2NHCO),2.76
(brt, J=6.6 Hz,2H; ArC H2CH2),2.69 (t, J=7.0 Hz,2H; ArC H2CH2),
1.45 ppm (s,9H; OC(C H3)3); 13C NMR (125 MHz,CDCl 3): d=163.5,
161.9,155.8,151.5,150.9,150.2,147.1,145.6,143.7,143.5,141.7,136.8,
136.1,134.0,133.9,133.3,131.0,129.1,128.8,128.6,128.4,128.3,128.2,
127.2,125.0,119.6,118.0,117.8,116.4,114.0,109.4,77.9,77.8,52.8,41.7,
brine (10 mL),dried over Na SO4,and concentrated under reduced pres-
2
40.7,35.3,34.9,30.4,28.9,28.4 ppm; HR-ESI-TOF:
for C54H52Br4N4O11: 1271.0258; found: 1271.0211.
m/z [M+Na]+ calcd
sure. The mixture of amines 30a/31a or 30b/31b thus obtained as light
brown oil was used without further purification for coupling with the ap-
propriate acid.
1
Data for 41: Yield 29% as colorless oil; H NMR (500 MHz,CDCl ): d=
3
7.50 (s,2H; Ar H),7.43 (s,1H; Ar H),7.40–7.25 (m,11H; Ar H),7.08 (s,
1H; ArH),6.98 (d, J=8.1 Hz,1H; Ar H),6.78 (d, J=8.1 Hz,1H; Ar H),
6.68 (t, J=5.6 Hz,1H; N HCO),6.31 (s,1H; Ar H),6.22 (s,1H; Ar H),
5.83 (brs,1H; ArO H),5.22 (s,2H; OC H2Ph),5.18 (s,2H; OC H2Ph),
General procedure for the coupling of acids 4a or 4b or 27a with amine
mixtures 30a/31a or 30b/31b: N,N-diisopropylethylamine (25 mL,
0.14 mmol),1-hydroxybenzotriazole (20 mg,0.15 mmol) and 1-[3-(dime-
thylamino)propyl]-3-ethylcarbodiimide hydrochloride (30 mg,0.16 mmol)
were added to a stirred solution of acid (0.13 mmol) and the crude mix-
ture of amines (0.2 mmol) in a mixture of dichloromethane (10 mL) and
DMF (0.5 mL) at 08C. The mixture was stirred overnight and allowed to
gradually warm up to ambient temperature. Water (10 mL) was added
and the mixture was extracted with EtOAc (3”10 mL). The combined
organic extracts were washed with brine (2”5 mL),dried over Na 2SO4,
and concentrated under reduced pressure; the residue was purified by
flash column chromatography (20% EtOAc in hexanes).
Data for 32: Yield 34% as colorless oil; [a]2D0 =+2.5 (c=0.95 in CH2Cl2);
1H NMR (500 MHz,CDCl 3): d=7.62 (s,1H; Ar H),7.54 (s,1H; Ar H),
7.39–7.24 (m,9H; Ar H),7.21 (d, J=7.5 Hz,1H; Ar H),7.16 (s,1H;
ArH),7.12 (d, J=8.4 Hz,1H; Ar H),6.94 (d, J=8.2,1H; Ar H),6.86 (d,
J=8.4 Hz,1H; Ar H),6.82 (d, J=8.2 Hz,1H; Ar H),6.70 (d, J=8.4 Hz,
1H; ArH),6.69–6.64 (m,2H; Ar H, NHCO),5.96 (brs,1H; ArO H),5.61
(brs,1H; ArO H),5.24 (s,2H; OC H2Ph),5.18 (s,2H; OC H2Ph),4.83
4.74 (brs,1H;
N
HBoc),3.85 (s,2H; ArC
H2C=N),3.76 (s,3H;
COOCH3),3.69 (s,2H; ArC H2C=N),3.43–3.34 (m,4H; 2”C H2NHCO),
2.84–2.73 (m,2H; ArC H2CH2),2.65 (t, J=6.8 Hz,2H; ArC H2CH2),
1.45 ppm (s,9H; OC(C H3)3); 13C NMR (125 MHz,CDCl 3): d=163.5,
161.9,155.8,150.8,150.2,147.3,147.1,144.1,143.7,143.6,141.7,139.7,
136.8,136.1,133.9,133.6,133.3,130.5,128.7,128.5,128.3,128.3,128.2,
127.1,123.7,118.2,117.8,116.1,113.9,113.7,109.4,77.8,77.7,52.8,41.4,
40.7,35.2,34.8,30.4,28.9,28.4 ppm; HR-ESI-TOF:
for C54H51Br5N4O11: 1348.9363; found: 1348.9386.
m/z [M+Na]+ calcd
Data for 46: Yield 38% as colorless foam; 1H NMR (500 MHz,CDCl 3):
d=7.48 (d, J=1.8 Hz,1H; Ar H),7.44 (s,1H; Ar H),7.38–7.23 (m,8H;
ArH),7.19–7.18 (m,2H; Ar H),7.04–7.03 (m,2H; Ar H),6.95 (d, J=
8.2 Hz,1H; Ar H),6.84–6.79 (m,3H; Ar H),6.73–6.67 (m,3H; N HCO,
ArH),6.62 (d, J=1.8 Hz,1H; Ar H),6.06 (brs,1H; ArO H),5.29 (s,2H;
OCH2Ph),5.08 (s,2H; OC H2Ph),4.70 (brs,1H; N HBoc),3.80 (brs,4H;
2”ArCH2C=N),3.46–3.30 (m,4H; 2”C H2NHCO),2.78–2.64 (m,4H;
(brm,1H;
ArCH2C=N),3.80 (s,3H; COOC H3),3.75 (s,2H; ArC H2C=N),3.47–
3.35 (m,3H; HHNHBoc,CH 2CH2NHCO),3.07–3.00 (m,1H;
N
HBoc),4.76 (brm,1H; ArC
HOTBS),3.86 (s,2H;
2”ArCH2CH2),1.49 (s,9H; OC(C
H3)3),1.49 (s,9H; OC(C
H3)3),
1.44 ppm (s,9H; OC(C H3)3); 13C NMR (125 MHz,CDCl 3): d=161.9,
161.8,155.7,151.7,151.1,151.0,150.0,148.9,145.7,143.3,138.4,136.2,
135.9,134.1,133.8,133.2,130.9,130.0,129.2,129.0,128.4,128.2,128.0,
125.0,119.7,119.2,119.1,118.3,117.8,117.6,116.4,113.8,113.5,84.1,
82.7,77.7,77.3,41.5,40.6,35.1,34.7,30.3,29.1,28.3,27.9,27.4 ppm; HR-
ESI-TOF: m/z [M+Na]+ calcd for C62H67Br3N4O13: 1335.2147; found:
1335.2083.
C
CHHNHBoc),2.69 (t, J=6.9 Hz,2H; C H2CH2NHCO),1.44 (s,9H;
OC(CH3)3),0.91 (s,9H; SiC(C H3)3),0.07 (s,3H; C H3Si), À0.05 ppm (s,
3H; CH3Si); 13C NMR (125 MHz,CDCl 3): d=163.5,162.0,155.7,152.5,
151.6,151.4,150.0,145.8,143.6,143.4,143.0,139.5,136.3,135.9,134.4,
133.4,131.2,130.9,129.6,128.6,128.5,128.5,128.3,128.3,128.2,128.1,
126.1,125.2,118.9,118.5,118.3,116.5,113.5,113.4,109.8,79.4,77.9,77.4,
72.6,52.7,48.9,40.5,34.7,30.2,28.8,28.3,25.7,
(KBr): n˜ =3650,3100,3036,2960,2861,1729,1679,1617,1518,1060,
1006 cmÀ1 HR-ESI-TOF: m/z [M+Na]+ calcd for C60H67Br3N4O12Si:
À4.7, À5.0 ppm; IR
General procedure for the regiospecific o-brominations: A stirred so-
lution of the phenol (15 mmol) in acetonitrile (2 mL) was treated at 08C
with N-bromosuccinimide (2.7 mg,15 mmol). After 2 h the reaction was
quenched by addition of an aqueous solution of potassium iodide
(0.5 mL,10% w/v). To the resulting mixture was added in small portions
Na2SO3·7H2O until complete disappearance of its red color. Water
(10 mL) was added and the mixture was extracted with EtOAc (3”
10 mL). The combined organic extracts were washed with brine (10 mL),
dried over Na2SO4,and concentrated under reduced pressure. The resi-
due was further purified by flash column chromatography.
;
1323.1967; found: 1323.1956.
Data for 33: Yield 34% as colorless oil; [a]2D0 =+3.7 (c=0.51 in CH2Cl2);
1H NMR (500 MHz,CDCl ): d=7.61 (brs,2H; Ar H),7.55 (s,1H; Ar H),
3
7.41–7.26 (m,9H; Ar H),7.18 (s,1H; Ar H),7.13 (d, J=8.4 Hz,1H;
ArH),6.96 (d, J=8.1 Hz,1H; Ar H),6.76 (d, J=8.1,1H; Ar H),6.72 (d,
J=8.4 Hz,1H; Ar H),6.69 (s,1H; Ar H),6.66 (brt, J=6.0 Hz,1H;
NHCO),6.22 (s,1H; Ar H),5.97 (brs,1H; ArO H),5.74 (brs,1H;
ArOH),5.26 (s,2H; OC H2Ph),5.18 (s,2H; OC H2Ph),4.91 (brm,1H;
NHBoc),4.81 (brm,1H; ArC HOTBS),3.87 (s,2H; ArC H2C=N),3.81
Data for 34: Yield 75% as colorless oil; [a]2D0 =+4.2 (c=4.6 in CH2Cl2);
1H NMR (500 MHz,CDCl ): d=7.64 (brs,1H; Ar H),7.56 (d, J=1.6 Hz,
3
(s,3H; COOC H3),3.76 (s,2H; ArC
H2C=N),3.45–3.39 (m,3H;
1H; ArH),7.40–7.23 (m,11H; Ar H),7.18 (d, J=1.4 Hz,1H; Ar H),
7.14–7.11 (m,2H; Ar H),6.86 (d, J=8.4 Hz,1H; Ar H),6.73 (t, J=
5.1 Hz,1H; CH 2NHCO),6.72 (d, J=8.2 Hz,1H; Ar H),6.69 (d, J=
1.5 Hz,1H; Ar H),6.60 (s,1H; Ar H),6.22 (brs,2H; 2”ArO H),5.25 (s,
2H; OCH2Ph),5.21 (s,2H; OC H2Ph),4.89 (brm,1H; N HBoc),4.79
CHHNHBoc,CH CH2NHCO),3.14–3.05 (m,1H; CH HNHBoc),2.64 (t,
2
J=6.9 Hz,2H; C H2CH2NHCO),1.46 (s,9H; OC(C H3)3),0.94 (s,9H;
SiC(CH3)3),0.11 (s,3H; C H3Si),0.00 ppm (s,3H; C H3Si); 13C NMR
(125 MHz,CDCl 3): d=163.5,162.0,155.7,151.5,151.3,150.0,147.9,
144.0,143.6,143.4,143.3,142.8,136.3,135.9,134.4,133.5,130.4,129.6,
128.6,128.5,128.4,128.2,128.1,123.6,119.0,118.5,118.1,116.0,113.6,
(brm,1H; ArC HOTBS),3.87 (s,2H; ArC
H2C=N),3.79 (s,3H;
COOCH3),3.76 (s,2H; ArC H2C=N),3.45–3.37 (m,3H; C HHNHBoc,
CH2CH2NHCO),3.09–2.99 (m,1H; CH HNHBoc),2.66 (t, J=6.9 Hz,
2H; CH2CH2NHCO),1.45 (s,9H; OC(C H3)3),0.93 (s,9H; SiC(C H3)3),
0.09 (s,3H; C H3Si), À0.03 ppm (s,3H; C H3Si); 13C NMR (125 MHz,
CDCl3): d=163.5,162.1,155.7,152.0,151.5,151.3,150.0,143.9,143.6,
143.3,143.2,140.1,136.3,135.9,134.4,133.5,131.7,131.3,129.6,128.7,
128.6,128.5,128.3,128.2,128.1,128.0,126.2,119.0,118.5,117.8,113.7,
113.6,110.0,109.7,79.4,77.9,77.5,72.6,52.7,49.0,40.3,34.6,30.2,28.8,
28.3,25.7, À4.7, À5.0 ppm; HR-ESI-TOF m/z [M+Na]+ calcd for
C60H66Br4N4O12Si: 1401.1072; found: 1401.1075.
109.8,77.9,77.4,72.1,52.7,48.8,40.5,34.7,30.2,28.8,28.3,25.7,
À4.7,
À4.9 ppm; IR (KBr): n˜ =3650,3100,3066,3032,2955,2932,2860,1717,
À1
1674,1604,1525,1452,1366,1129,1106 cm
; HR-ESI-TOF: m/z
[M+Na]+ calcd for C60H66Br4N4O12Si: 1401.1072; found: 1401.1077.
1
Data for 40: Yield 28% as colorless oil; H NMR (500 MHz,CDCl ): d=
3
7.50 (s,2H; Ar H),7.46 (s,1H; Ar H),7.43–7.23 (m,10H; Ar H),7.08 (s,
1H; ArH),7.06 (d, J=8.2 Hz,1H; Ar H),6.98 (d, J=8.2 Hz,1H; Ar H),
6.86 (d, J=8.2 Hz,1H; Ar H),6.82 (dd, J=8.2,1.5 Hz,1H; Ar H),6.69 (t,
J=5.9 Hz,1H; N HCO),6.61 (d, J=1.3 Hz,1H; Ar H),6.31 (d, J=
1.3 Hz,1H; Ar H),6.09 (brs,1H; ArO H),5.70 (brs,1H; ArO H),5.22 (s,
2H; OCH2Ph),5.18 (s,2H; OC H2Ph),4.61 (brs,1H; N HBoc),3.85 (s,
Data for 35: Yield 78% as colorless oil; [a]2D0 =+2.9 (c=7.3 in CH2Cl2);
1H NMR (500 MHz,CDCl ): d=7.60 (brs,2H; Ar H),7.55 (s,1H; Ar H),
3
Chem. Eur. J. 2005, 11,406 – 421
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
417

E. A. Couladouros et al.
7.39–7.25 (m,9H; Ar H),7.17 (s,1H; Ar H),7.13 (d, J=8.4 Hz,1H;
ArH),7.05 (s,1H; Ar H),6.72 (d, J=8.4,1H; Ar H),6.72 (d, J=8.4 Hz,
1H; ArH),6.98 (brm,2H; Ar H,CH 2NHCO),6.17 (s,1H; Ar H),6.09
(brs,1H; ArO H),5.98 (brs,1H; ArO H),5.25 (s,2H; OC H2Ph),5.19 (s,
2H; OCH2Ph),4.91 (brm,1H; N HBoc),4.81 (brm,1H; ArC HOTBS),
3.86 (s,2H; ArC H2C=N),3.80 (s,3H; COOC H3),3.75 (s,2H; ArC H2C=
N),3.47–3.34 (m,3H; C HHNHBoc,CH 2CH2NHCO),3.13–3.05 (m,1H;
CHHNHBoc),2.62 (t, J=6.9 Hz,2H; C H2CH2NHCO),1.45 (s,9H;
OC(CH3)3),0.93 (s,9H; SiC(C H3)3),0.10 (s,3H; C H3Si), À0.01 ppm (s,
3H; CH3Si); 13C NMR (125 MHz,CDCl 3): d=163.6,162.1,155.8,151.5,
151.3,150.1,147.5,143.9,143.6,143.3,141.6,136.3,135.9,134.5,133.6,
extracts were washed sequentially with water (2”20 mL) and brine
(20 mL),dried over Na SO4,and concentrated under reduced pressure.
2
In the case of group B bastaranes,removal of the Boc protection was ac-
companied by partial loss of the TBS protective group. As a conse-
quence,the residue obtained after macrolactamization contained a mix-
ture of free and TBS-protected products that,for convenience,was not
separated at this stage. The crude mixture was treated with 1.0m solution
of TBAF in THF to afford after standard aqueous workup and flash
column chromatography (40% EtOAc in hexanes) the desired product.
Data for 36: Yield 52% (from 34) as colorless oil; [a]2D0 =+6.8 (c=0.44
in CH2Cl2); 1H NMR (500 MHz,CDCl 3): d=7.65 (d, J=1.8 Hz,1H;
ArH),7.56 (d, J=1.9 Hz,1H; Ar H),7.43–7.26 (m,9H; Ar H),7.24 (d,
J=1.8 Hz,1H; Ar H),7.17–7.13 (m,3H; Ar H),7.01 (d, J=1.6 Hz,1H;
ArH),6.98 (d, J=8.4 Hz,1H; Ar H),6.96 (brt, J=6.3 Hz,1H; N HCO),
6.75 (d, J=1.7 Hz,1H; Ar H),6.69 (d, J=8.4 Hz,1H; Ar H),6.60 (brt,
J=5.8 Hz,1H; N HCO),6.47 (d, J=1.6 Hz,1H; Ar H),5.20 (s,2H;
OCH2Ph),5.03 (AB q, J=11.6 Hz, Dn=15.8 Hz,2H; OC H2Ph),4.84 (dd,
J=6.5,3.7 Hz,1H; C HOH),3.79 (s,2H; ArC H2C=N),3.77 (AB q, J=
13 Hz, Dn=27 Hz,2H; ArC H2C=N),3.73–3.68 (m,1H; C HHNHCO),
3.42–3.26 (m,3H; C H2NHCO,CH HNHCO),2.62–2.52 ppm (m,2H;
ArCH2CH2); 13C NMR (125 MHz,CDCl 3): d=163.3,162.2,151.7,151.5,
151.4,151.4,144.7,143.5,143.4,142.7,139.9,136.3,136.0,134.6,133.4,
131.4,130.6,129.7,128.8,128.6,128.5,128.4,128.3,128.3,128.2,126.8,
119.1,118.5,117.9,113.7,113.0,109.7,109.5,79.6,78.0,77.6,72.2,52.8,
48.9,40.3,34.7,30.3,28.9,28.4,25.7,
À4.7, À4.9 ppm; HR-ESI-TOF: m/z
[M+Na]+ calcd for C60H65Br5N4O12Si: 1479.0177; found: 1479.0233.
1
Data for 42: Yield 75% as colorless oil; H NMR (500 MHz,CDCl ): d=
3
7.51 (s,2H; Ar H),7.46 (s,1H; Ar H),7.43–7.25 (m,10H; Ar H),7.11 (s,
1H; ArH),7.08 (s,2H; Ar H),6.87 (d, J=8.3 Hz,1H; Ar H),6.71 (t, J=
5.9 Hz,1H; N HCO),6.55 (s,1H; Ar H),6.31 (s,1H; Ar H),6.04 (brs,
1H; ArOH),5.22 (s,2H; OC H2Ph),5.21 (s,2H; OC H2Ph),4.62 (brs,
1H; NHBoc),3.85 (s,2H; ArC H2C=N),3.76 (s,3H; COOC H3),3.69 (s,
2H; ArCH2C=N),3.45–3.32 (m,4H; 2”C H2NHCO),2.77 (brt, J=
7.7 Hz,2H; ArC H2CH2),2.68 (t, J=7.0 Hz,2H; ArC H2CH2),1.44 ppm
(s,9H; OC(C H3)3); 13C NMR (125 MHz,CDCl 3): d=163.5,162.0,155.8,
151.2,150.8,150.2,147.1,144.3,143.7,143.1,141.7,136.7,136.1,136.1,
Table 1. NMR data for bastadin 5 (500 MHz,[D ]acetone).
134.1,133.9,133.4,131.7,130.9,129.2,128.8,128.6,128.4,128.3,128.2,
6
127.8,127.2,120.0,117.9,117.2,114.0,109.9,109.4,77.9,52.8,41.7,40.5,
35.3,34.7,30.4,28.9,28.4 ppm; HR-ESI-TOF:
C54H51Br5N4O11: 1348.9363; found: 1348.9346.
Data for 48: Yield 72% colorless oil; 1H NMR (500 MHz,CDCl 3): d=
7.51 (brs,1H; Ar H),7.43 (brs,1H; Ar H),7.38–7.28 (m,9H; Ar H),
7.22–7.20 (m,2H; Ar H),7.06–7.02 (m,3H; Ar H),6.86 (d, J=8.4 Hz,
1H; ArH),6.70 (brt, J=6 Hz,1H; N HCO),6.69 (d, J=8.3 Hz,1H;
ArH),6.65 (brt, J=6 Hz,1H; N HCO),6.57 (brs,1H; ArH),6.49 (brs,
1H; ArH),6.01 (brs,1H; ArO H),5.89 (brs,1H; ArO H),5.18 (s,2H;
OCH2Ph),5.14 (s,2H; OC H2Ph),3.85 (s,2H; ArC H2C=N),3.67 (s,2H;
Position
13C
d
1H
d
HMBC
m/z [M+Na]+ calcd for
1
2
3
4
5
6
7
8
28.4
152.5
163.3
3.67 (s,2H)
H-36,H-38
N2OH,H-1
H-1
7.73 (brt,1H)
3.52–3.41 (m,2H)
2.84–2.74 (obs m,2H)
41.3
34.8
H-6
H-5,H-8,H-12
H-5,H-6,H-11
H-6,H-12
H-8,H-11
H-8,H-11,H-12
138.0
134.5
114.5
152.3
121.2
130.6
144.6
144.4
110.4
128.7
132.5
117.7
35.0
7.54 (d, J=1.9 Hz,1H)
ArCH2C=N),3.60–3.56 (m,2H;
C
H2NHCO),3.38–3.34 (m,2H;
9
CH2NHCO),2.78–2.76 (m,2H; ArC H2CH2),2.64–2.60 ppm (m,2H;
ArCH2CH2); 13C NMR (125 MHz,CDCl 3): d=162.3,152.0,151.5,151.2,
151.1,144.5,143.6,143.0,142.7,137.0,136.4,134.6,134.1,133.5,131.6,
130.3,129.5,129.4,129.2,128.7,128.6,128.3,128.0,127.5,121.0,119.2,
118.8,118.0,116.4,114.7,113.7,109.5,109.4,77.4,40.6,40.3,34.9,34.7,
28.9,28.9 ppm; HR-ESI-TOF: m/z [M+H]+ calcd for C48H40Br4N4O8:
1116.9652; found: 1116.9623.
10
11
12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
33
34
35
36
37
38
N2OH
N24OH
15-OH
34-OH
7.00 (d, J=8.3 Hz,1H)
7.22 (dd, J=8.3,1.9 Hz,1H)
H-6,H-8
H-19
H-17
H-17,15-OH
H-19,H-20
H-20,H-21
H-17,H-20
H-17,H-19,H-21
H-20
7.14 (d, J=1.8 Hz,1H)
General procedure for the preparation of a,w-amino acids: In the case of
bastaranes,a solution of the protected a,w-amino acid (30 mmol) in a
mixture of THF (3 mL) and methanol (3 mL) was treated at 08C with an
aqueous solution of LiOH (3n,0.2 mL) for 5 h. The residue obtained
after standard aqueous workup of the reaction was dissolved in dichloro-
methane (3 mL) and treated at 08C with TFA (1.5 mL). Evaporation of
the reaction mixture under reduced pressure provided the free a,w-
amino acid that was used in the next step without further purification.
6.64 (d, J=1.8 Hz,1H)
2.84–2.74 (obs m,2H)
3.52–3.41 (m,2H)
7.32 (brt,1H)
40.4
164.5
151.9
29.7
H-25
H-25,N 24OH
H-27,H-31
H-25
3.85 (s,2H)
7.63 (s,1H)
138.8
134.5
118.2
147.6
118.2
134.5
145.6
142.9
109.8
128.0
129.8
114.3
In the case of isobastaranes,a solution of the protected a,w-amino acid
(56 mmol) and pentamethylbenzene (125 mg,0.8 mmol) in dichlorome-
thane (3 mL) was treated at 08C with TFA (3 mL). The reaction mixture
was allowed to gradually warm up to ambient temperature and,after 2 h,
the solvent and excess TFA was removed under reduced pressure to pro-
vide the corresponding free a,w-amino acid that was used in the next
step without further purification.
H-25,H-31
H-27
H-27,H-31
H-31
H-25,H-27
H-38
H-36,H-38
H-36,34-OH
H-1,H-38
H-1,H-38
H-1,H-36
7.63 (s,1H)
General procedure for the macrolactamizations: N,N-diisopropylethyl-
amine (60 mL,0.34 mmol),and benzotriazol-1-yloxytripyrrolidinophos-
phonium hexafluorophosphate (138 mg,0.41 mmol) were added to a stir-
red solution of the a,w-amino acid (56 mmol) in a mixture of dichlorome-
thane (100 mL) and DMF (10 mL) at 08C. The temperature of the reac-
tion was maintained at 08C for 1 h and then the mixture was allowed to
gradually warm up to ambient temperature. After 24 h the reaction mix-
ture was poured into saturated aqueous solution of ammonium chloride
(100 mL) and extracted with EtOAc (5”30 mL). The combined organic
7.18 (d, J=1.8 Hz,1H)
6.41 (d, J=1.8 Hz,1H)
10.47 (s,1H)
11.32 (s,1H)
8.74 (s,1H)
8.70 (s,1H)
418
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11,406 – 421

Synthesis of Bastaranes and Isobastaranes
FULL PAPER
Table 2. NMR data for bastadin 20 (500 MHz,[D ]DMSO).
ESI-TOF m/z [M+H]+ calcd for
C48H39Br5N4O9: 1210.8706; found:
1210.8738.
6
Position
13C
1H
COSY
H-36
HMBC
d
d
In the case of group C bastaranes and
isobastaranes,flash column chromato-
graphic purification (30% EtOAc in
hexanes) of the residue obtained after
macrolactamization afforded the de-
sired product.
1
27.7
3.45 (s,2H)
H-36,H-38
N2OH,H-1
H-1,H-5
2
3
151.2
162.8
4
5
6
7.86 (t, J=6 Hz,1H)
3.19–3.15 (m,2H)
2.5 (obs m)
H-5
H-4,H-6
H-5
40.0
33.5
H-6
H-5,H-12,H-8
H-5,H-6
H-6,H-12
H-8,10-OH
H-12
H-12
H-6,H-8
H-16,H-18,H-19
H-16,H-19
H-18,H-20
H-20
Data for 43: Yield 58% as colorless
oil; 1H NMR (500 MHz,CDCl 3): d=
7.53 (s,2H; Ar H),7.48 (s,1H; Ar H),
7.42–7.27 (m,9H; Ar H),7.17 (s,1H;
ArH),7.13 (dd, J=8.0,1.1 Hz,1H;
ArH),7.09–7.07 (m,1H; Ar H),7.02
(s, 1H; ArH),7.00 (d, J=8.2 Hz,1H;
ArH),6.71 (t, J=6.3 Hz,1H; N HCO),
6.59 (s,1H; Ar H),6.54 (t, J=6.0 Hz,
1H; NHCO),6.34 (s,1H; Ar H),5.98
(brs,1H; ArO H),5.94 (brs,1H;
ArOH),5.18 (s,2H; OC H2Ph),4.80 (s,
2H; OCH2Ph),3.79 (s,2H; ArC H2C=
N),3.72 (s,2H; ArC H2C=N),3.51–
3.47 (m,2H; C H2NHCO),3.33–3.29
7
8
9
131.7
127.2
110.4
144.8
143.3
117.1
150.8
113.2
133.4
137.3
129.5
120.4
33.8
7.09 (d, J=2 Hz,1H)
H-12
10
11
12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
33
34
35
36
37
38
N2OH
N24OH
10-OH
34-OH
6.35 (d, J=2 Hz,1H)
7.51 (d, J=2 Hz,1H)
H-8
H-18
7.10 (dd, J=8,2 Hz,1H)
6.83 (d, J=8.4 Hz,1H)
2.71–2.68 (m,2H)
3.40–3.36 (m,2H)
8.08 (t, J=6 Hz,1H)
H-16H, -19
H-18
H-21
H-20H, -22
H-21
H-16,H-20
H-16
H-20
39.8
(m,2H;
C
H2NHCO),2.75 (t,
J=
163.3
151.7
28.4
H-21,H-25
N24OH,H-25
H-27,H-31
H-30
H-25
H-27,H-30
H-27,H-30,H-31
6.7 Hz,2H; ArC H2CH2),2.54 ppm (t,
J=7.4 Hz,2H; ArC H2CH2); 13C NMR
(125 MHz,CDCl 3): d=162.1,162.0,
152.0,151.0,150.7,147.0,143.9,142.7,
141.5,137.4,136.7,136.3,136.1,134.3,
133.9,133.6,131.4,129.6,128.8,128.6,
128.6,128.4,128.3,128.2,127.9,127.4,
121.2,117.9,115.8,115.1,113.3,113.1,
109.1,77.7,77.1,40.4,40.0,35.0,34.5,
3.70 (s,2H)
H-27
137.1
134.3
113.2
150.8
120.4
129.5
144.8
143.3
110.4
127.2
128.9
116.9
7.44 (d, J=2 Hz,1H)
H-25H, -31
6.80 (d, J=8.3 Hz,1H)
7.08 (dd, J=8,2 Hz,1H)
H-31
H-27H, -30
H-25,H-27
H-38
H-36,H-38
H-36,34-OH
H-1,H-38
H-1
29.3,28.9 ppm; HR-ESI-TOF:
m/z
[MÀH]À calcd for C48H39Br5N4O8:
7.01 (d, J=2 Hz,1H)
H-1,H-38
H-36
1192.8612; found: 1192.8566,.
Data for 44: Yield 66% as colorless
oil; 1H NMR (500 MHz,CDCl 3): d=
7.55 (s,2H; Ar H),7.47 (s,2H; Ar H),
7.42–7.24 (m,8H; Ar H),7.18 (d, J=
1.6 Hz,1H; Ar H),7.13–7.11 (m,2H;
ArH),6.98 (d, J=8.2 Hz,1H; Ar H),
6.81 (t, J=6.4 Hz,1H; N HCO),6.75
(dd, J=8.2,1.7 Hz,1H; Ar H),6.50 (t,
J=5.9 Hz,1H; N HCO),6.39 (d, J=
6.29 (d, J=2 Hz,1H)
11.70 (s,1H)
11.82 (s,1H)
9.84 (brs,1H)
9.78 (brs,1H)
H-1,H-36
1.7 Hz,1H; Ar H),6.31 (d, J=1.7 Hz,1H; Ar H),5.98 (brs,1H; ArO H),
5.72 (brs,1H; ArO H),5.18 (s,2H; OC H2Ph),4.88 (s,2H; OC H2Ph),
3.80 (s,2H; ArC H2C=N),3.74 (s,2H; ArC H2C=N),3.53–3.49 (m,2H;
CH2NHCO),3.36–3.32 (m,2H; C H2NHCO),2.79 (t, J=7.0 Hz,2H;
131.3,131.2,129.8,129.1,128.7,128.6,128.4,128.3,128.2,127.4,126.5,
121.2,118.7,118.6,115.7,115.2,113.5,109.7,109.6,77.5,77.5,72.4,47.0,
40.1,34.6,29.1,28.7 ppm; IR (KBr):
2873,2855,1671,1611,1527,1502,1455 cm
n˜ =3406,3092,3065,3034,2926,
À1
; HR-ESI-TOF: m/z
ArCH2CH2),2.60 ppm (t,
J=7.5 Hz,2H; ArC H2CH2); 13C NMR
[M+Na]+ calcd for C48H40Br4N4O9: 1154.9421; found: 1154.9447.
(125 MHz,CDCl 3): d=162.3,162.0,151.9,150.8,147.4,147.0,144.0,
143.5,141.5,139.5,136.8,136.2,134.0,133.6,130.1,128.8,128.6,128.4,
128.3,128.3,128.2,127.9,123.7,118.3,117.8,115.9,113.1,113.0,109.0,
77.7,77.4,40.5,39.7,34.8,34.4,29.4,28.8 ppm; HR-ESI-TOF:
Data for 37: Yield 61% (from 35) as colorless oil; [a]2D0 =+1.5 (c=1.8 in
CH2Cl2); 1H NMR (500 MHz,CDCl 3): d=7.64 (brs,2H; Ar H),7.58 (d,
J=1.9 Hz,1H; Ar H),7.43–7.37 (m,4H; Ar H),7.35–7.31 (m,3H; Ar H),
7.28 (s,1H; Ar H),7.25 (d, J=1.9 Hz,1H; Ar H),7.21–7.17 (m,3H;
ArH),7.08 (brt, J=6.0 Hz,1H; N HCO),7.01 (d, J=1.6 Hz,1H; Ar H),
6.72 (d, J=8.4 Hz,1H; Ar H),6.68 (d, J=1.7 Hz,1H; Ar H),6.60 (brt,
J=6.0 Hz,1H; N HCO),6.22 (d, J=1.6 Hz,1H; Ar H),5.21 (s,2H;
OCH2Ph),5.05 (AB q, J=12 Hz, Dn=21 Hz,2H; OC H2Ph),4.89 (dd, J=
m/z
[M+H]+ calcd for C48H39Br5N4O8: 1194.8757; found: 1194.8757.
1
Data for 47: Yield 55% (from 46) as colorless glass; H NMR (500 MHz,
CDCl3): d=7.48 (d, J=2.0 Hz,1H; Ar H),7.41 (d, J=1.9 Hz,1H; Ar H),
7.38–7.24 (m,9H; Ar H),7.20–7.16 (m,2H; Ar H),7.02–6.96 (m,2H;
ArH),6.92 (d, J=8.2 Hz,1H; Ar H),6.82 (d, J=8.3 Hz,1H; Ar H),6.77
(dd, J=8.2,1.8 Hz,1H; Ar H),6.69 (brt, J=6 Hz,1H; N HCO),6.67–
6.61 (m,2H; N HCO,ArH),6.57 (d, J=1.8 Hz,1H; Ar H),6.54 (d, J=
1.8 Hz,1H; Ar H),5.15 (s,2H; OC H2Ph),5.13 (brs,1H; ArO H),5.11 (s,
2H; OCH2Ph),5.10 (brs,1H; ArO H),3.83 (s,2H; ArC H2C=N),3.66 (s,
2H; ArCH2C=N),3.57–3.54 (m,2H; C H2NHCO),3.37–3.33 (m,2H;
CH2NHCO),2.76–2.71 (m,2H; ArC H2CH2),2.64–2.60 ppm (m,2H;
ArCH2CH2); 13C NMR (125 MHz,CDCl 3): d=162.3,162.2,152.0,151.7,
151.6,151.3,145.4,143.7,143.6,143.0,136.4,134.7,134.0,133.5,130.9,
7.1,3.1 Hz,1H;
C
HOH),3.80 (AB
, J=13 Hz, Dn=30 Hz,2H;
q
ArCH2C=N),3.80–3.75 (m,3H; ArC H2C=N,CH HNHCO),3.42–3.22 (m,
3H; CHHNHCO,C H2NHCO),2.67–2.53 ppm (m,2H; C H2CH2NHCO);
13C NMR (125 MHz,CDCl 3): d=163.9,162.2,151.4,151.3,147.6,144.0,
143.8,143.1,142.2,141.5,136.3,135.9,134.6,133.7,130.8,130.6,130.0,
128.9,128.9,128.7,128.6,128.4,128.3,128.2,126.8,119.0,118.2,117.9,
112.2,109.4,77.7,77.5,72.4,47.3,39.5,34.3,29.2,28.6 ppm; IR (KBr):
n˜ =3408,3071,3036,2931,2880,1671,1613,1526,1502,1456 cm
À1; HR-
Chem. Eur. J. 2005, 11,406 – 421
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
419

E. A. Couladouros et al.
130.2,129.5,129.3,129.2,128.8,128.6,128.3,128.1,128.0,124.7,120.4,
119.1,118.5,118.2,117.4,116.2,114.5,113.7,109.5,77.4,77.3,40.9,40.3,
34.9,34.7,29.0,28.9 ppm; HR-ESI-TOF:
Table 3. NMR data for bastadin 21 (500 MHz,[D ]DMSO).
6
Position
13C
1H
HMBC
m/z [M+Na]+ calcd for
d
d
C48H41Br3N4O8: 1061.0367; found: 1061.0375.
1
27.9
3.48 (s,2H)
H-36,H-38
General procedure for the deprotection of bastadins: A stirred solution
of the dibenzyl ether derivative of bastadin (5 mmol) in thioanisole
(2 mL) was cooled in an ice bath and a solution of BBr3 in dichlorome-
thane (1m,400 mL) was added. The ice bath was removed and the reac-
tion was allowed to proceed at ambient temperature for 1 h. Aqueous
HCl (0.5m,10 mL) was carefully added at 0 8C and,after stirring at ambi-
ent temperature for 45 min,the mixture was extracted with EtOAc (4”
10 mL). The combined organic phases were washed sequentially with
water (2”10 mL) and brine (10 mL),dried over Na 2SO4,and then con-
centrated under reduced pressure. Residual thioanisole was removed
under vacuum,and the oil thus obtained was purified by thin-layer chro-
matography (3% MeOH in dichloromethane) to afford free bastadin.
Bastadin 10: Yield 48% as amorphous white solid; [a]2D0 =À4.4 (c=0.16
in MeOH); 1H NMR (500 MHz,[D 6]DMSO): d=11.13 (s,1H; NO H),
10.88 (s,1H; NO H),8.74 (brs,2H; 2”ArO H),7.69 (d, J=1.8 Hz,1H;
ArH),7.59 (d, J=1.8 Hz,1H; Ar H),7.54 (brt, J=5.9 Hz,1H; N HCO),
7.38 (brdd, J=6.4,5.7 Hz,1H; N HCO),7.31 (dd, J=8.4,1.8 Hz,1H;
ArH),7.27 (d, J=1.7 Hz,1H; Ar H),7.22 (dd, J=8.4,1.9 Hz,1H; Ar H),
7.15 (d, J=1.7 Hz,1H; Ar H),6.99 (d, J=8.4 Hz,1H; Ar H),6.82 (d, J=
8.4 Hz,1H; Ar H),6.69 (d, J=1.8 Hz,1H; Ar H),6.63 (d, J=1.8 Hz,1H;
ArH),4.91 (brs,1H; CHO H),4.84 (brm,1H; C HOH),3.81 (AB q, J=
13.4 Hz, Dn=28.8 Hz,2H; ArC H2C=N),3.74 (s,2H; ArC H2C=N),3.55–
3.50 (m,1H; CH HNHCO),3.49–3.41 (m,2H; C H2NHCO),3.37–3.32
2
2
3
151.6
162.8
H-1,N OH
H-1,H-4,H-5
4
5
6
7.87 (t, J=6 Hz,1H)
3.22–3.18 (m,2H)
2.5 (obs m)
39.9
33.9
H-6
H-5,H-8
7
8
9
131.0
119.8
142.2
147.3
116.4
125.0
152.5
111.2
132.7
135.3
129.3
117.6
33.1
H-5,H-6,H-11
H-6,H-12
H-8,H-11,10-OH
H-8,H-12,10-OH
10-OH
6.52 (d, J=2 Hz,1H)
10
11
12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
33
34
35
36
37
38
N2OH
N24OH
10-OH
34-OH
6.83 (d, J=8 Hz,1H)
6.78 (dd, J=8,2 Hz,1H)
H-6,H-8
H-16,H-18,H-19
H-16,H-19
H-18,H-20
H-19,H-20,H-21
H-16,H-20
7.48 (d, J=2 Hz,1H)
7.01 (dd, J=8,2 Hz,1H)
6.58 (d, J=8 Hz,1H)
2.70–2.68 (m,2H)
3.41–3.37 (m,2H)
8.02 (t, J=6 Hz,1H)
H-16,
H-20
39.1
163.6
152.5
28.8
H-21,H-22,H-25
H-25,N 24OH
H-27,H-31
H-25,H-28
H-25,H-31
3.67 (s,2H)
(m,1H;
C
HHNHCO),2.71 ppm (t,
J=7.0 Hz,2H; ArC H2CH2);
134.4
129.4
120.0
150.8
112.9
132.9
144.7
143.0
110.4
126.7
128.4
116.9
13C NMR (125 MHz,[D 6]acetone): d=165.1,165.0,154.2,153.7,153.6,
153.1,146.7,145.7,145.5,142.7,136.8,135.9,133.9,132.7,131.6,131.3,
130.2,130.1,130.0,128.9,121.8,121.8,119.7,119.4,115.5,115.4,111.7,
7.05 (dd, J=8,2 Hz,1H)
6.81 (d, J=8 Hz,1H)
H-27,H-28,H-31
H-28,H-31
H-27
H-38,34-OH
H-36,H-38
H-36,34-OH
H-1,H-38
H-1
111.5,73.0,49.0,41.7,36.2,29.4 ppm; HR-MALDI-FTMS:
calcd for C34H28Br4N4O9: 974.8482; found: 974.8487.
m/z [M+Na]+
7.43 (d, J=2 Hz,1H)
7.04 (d, J=2 Hz,1H)
Bastadin 12: Yield 51% as amorphous white solid; [a]2D0 =À14 (c=0.17
in MeOH); 1H NMR (500 MHz,[D 6]acetone): d=11.15 (s,1H; NO H),
10.88 (s,1H; NO H),8.74 (brs,1H; ArO H),8.71 (brs,1H; ArO H),7.72
(brs,2H; Ar H),7.59 (d, J=2.1 Hz,1H; Ar H),7.54 (dd, J=6.1,4.4 Hz,
1H; CH2NHCO),7.50 (brt, J=5.8 Hz,1H; CH 2NHCO),7.28 (dd, J=
4.4,2.1 Hz,1H; Ar H),7.27 (dd, J=4.0,1.9 Hz,1H; Ar H),7.07 (d, J=
1.9 Hz,1H; Ar H),6.85 (d, J=8.4 Hz,1H; Ar H),6.66 (d, J=1.9 Hz,1H;
ArH),6.37 (d, J=1.9 Hz,1H; Ar H),5.11 (brd, J=4.4 Hz,1H; CHO H),
4.91–4.88 (m,1H; C HOH),3.88 (AB q, J=13.3 Hz, Dn=19.3 Hz,2H;
ArCH2C=N),3.75 (s,2H; ArC H2C=N),3.57–3.52 (m,1H; C HHNHCO),
3.44–3.30 (m,3H; C HHNHCO,C H2NHCO),2.70 ppm (t, J=2.7 Hz,
2H; ArCH2CH2); 13C NMR (125 MHz,[D 6]acetone): d=165.3,165.1,
153.7,153.6,153.2,149.1,147.0,146.7,145.9,145.5,144.0,136.9,136.0,
6.34 (d, J=2 Hz,1H)
11.69 (s,1H)
11.79 (s,1H)
9.34 (brs,1H)
9.83 (brs,1H)
H-1,H-36
Bastadin 21: Yield 55% as amorphous white solid; for NMR data see
Table 3; HR-MALDI-FTMS: m/z [M+Na]+ calcd for C34H29Br3N4O8:
133.1,132.7,131.8,131.4,130.2,128.5,122.0,119.5,115.6,114.2,111.6,
111.5,72.7,49.0,41.2,35.8,29.3 ppm; HR-MALDI-FTMS:
calcd for C34H27Br5N4O9: 1052.7587; found: 1052.7615.
m/z [M+Na]+
880.9428; found: 880.9422.
1
Data for 38: Yield 83% as colorless oil; H NMR (500 MHz,CDCl ): d=
3
Bastadin 5: Yield 43% as amorphous white solid; for NMR data see
Table 1; HR-ESI-TOF: m/z [MÀH]À calcd for C34H27Br5N4O8: 1012.7673;
found: 1012.7654.
Bastadin 16: Yield 41% as amorphous white solid; 1H NMR (500 MHz,
[D6]acetone): d=11.33 (s,1H; N 24OH),10.42 (s,1H; N 2OH),8.71 (s,
1H; ArOH),8.00 (s,1H; ArO H),7.70 (t, J=5.8 Hz,1H; 4-N HCO),7.62
7.69 (d, J=2.0 Hz,1H; Ar H),7.59 (d, J=1.8 Hz,1H; Ar H),7.56 (d, J=
6.7 Hz,2H; Ar H),7.49 (d, J=6.7 Hz,2H; Ar H),7.43–7.25 (m,16H;
ArH),7.21–7.19 (m,2H; Ar H),7.14 (dd, J=8.4,2.0 Hz,1H; Ar H),7.11
(d, J=1.9 Hz,1H; Ar H),6.98 (brt, J=6.4 Hz,1H; N HCO),6.93 (d, J=
8.3 Hz,1H; Ar H),6.83 (d, J=1.9 Hz,1H; Ar H),6.64 (brt, J=6.1 Hz,
1H; NHCO),6.59 (d, J=8.4 Hz,1H; Ar H),6.55 (d, J=1.8 Hz,1H;
ArH),5.21 (s,2H; OC H2Ph),5.19 (brs,2H; OC H2Ph),5.10 (brs,2H;
OCH2Ph),5.09 (brs,2H; OC H2Ph),4.83 (dd, J=6.7,3.4 Hz,1H;
CHOH),3.84 (AB q, J=13 Hz, Dn=22 Hz,2H; ArC H2C=N),3.81 (s,
2H; ArCH2C=N),3.74–3.69 (m,1H; C HHNHCO),3.41–3.22 (m,3H;
CH2NHCO,CH HNHCO),2.75 (brs,1H; CHO H),2.65–2.58 ppm (m,
2H; ArCH2CH2).
(s,2H; H-27,H-31),7.57 (s,2H; H-8,H-12),7.41 (t,
NHCO),7.18 (d, J=1.7 Hz,1H; H-36),6.90 (d, J=8.1 Hz,1H; H-16),
6.76 (dd, J=8.1,1.8 Hz,1H; H-17),6.38 (d, J=1.7 Hz,1H; H-38),6.33
(d, J=1.8 Hz,1H; H-19),3.92 (s,2H; H-25),3.68 (s,2H; H-1),3.51–3.47
J=5.9 Hz,1H; 22-
(m,2H; H-21),3.41–3.37 (m,2H; H-5),2.88 (t,
J=7.1 Hz,H-6),
2.73 ppm (t, J=7.1 Hz,H-20); 13C NMR (125 MHz,[D 6]acetone): d=
165.7,164.7,153.7,153.2,149.0,148.7,147.0,146.6,146.2,144.0,142.0,
140.1,135.6,135.5,131.9,131.2,129.2,125.3,119.6,119.4,118.3,115.4,
114.7,111.0,42.0,41.6,36.1,35.7,29.3 ppm; HR-ESI-TOF:
calcd for C34H27Br5N4O8: 1036.7638; found: 1036.7643.
m/z[M+Na]+
Bastadin 20: Yield 46% as amorphous white solid; for NMR data see
Table 2; HR-ESI-TOF: m/z [M+Na]+ calcd for C34H28Br4N4O8:
958.8533; found: 958.8519.
420
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11,406 – 421

Synthesis of Bastaranes and Isobastaranes
FULL PAPER
[10] a) K. L. Bailey,T. F. Molinski, J. Org. Chem. 1999, 64,2500–2504;
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c) K. L. Bailey,T. F. Molinski, Tetrahedron Lett. 2002, 43,9657–
9661; d) D. Leone-Stumpf,T. Lindel, Eur. J. Org. Chem. 2003,1853–
1858.
[11] a) F. M. Beringer,A. Brierley,M. Drexler,E. M. Gindlerand,C. C.
Lumpkin, J. Am. Chem. Soc. 1953, 75,2708–2712; b) R. W. Dos-
kotch,E. H. Fairchild,C. D. Hufford, Tetrahedron 1974, 30,3237–
3239; c) R. W. Doskotch,A. B. Ray,W. Kubelka,E. H. Fairchild,
C. D. Hufford,J. L. Beal, Tetrahedron 1974, 30,3229–3236; d) M. J.
Acknowledgement
This work was supported in part by a Greek–Polish joint research and
technology program and by the program “Advanced Functional Materi-
als” (1422/B1/3.3.1/362/15.04.2002) co-funded by the General Secretariat
for Research and Technology of the Greek Ministry of Development and
the European Community. The authors would like to thank Prof. G. R.
Pettit of the Cancer Research Institute,Arizona State University for a
generous donation of authentic bastadin 10 and 12.
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1
The structure of synthetic product was verified by H NMR,HSQC,
and HMBC spectra that are available as Supporting Information.
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Received: September 3,2004
Published online: November 24,2004
Chem. Eur. J. 2005, 11,406 – 421
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